Human anti-il-23 antibodies, compositions, methods and uses

(56) References cited:

WO-A1-2005/108425 US-A1- 2004 223 969

ΕΡ 2 548 577 Β1

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ΕΡ 2 548 577 Β1

Description

FIELD OF THE INVENTION [0001] The present invention relates to antibodies, including specified portions or variants, specific fór at least one IL23 protein or fragment thereof, as well as anti-idiotype antibodies, and nucleic acids encoding anti-1L-23p 19 antibodies, complementary nucleic acids, vectors, hőst cells, and methods of making and using thereof, including therapeutic formulations, administration and devices.

BACKGROUND OF THE INVENTION [0002] Interleukin (IL)-12 is a secreted heterodimeric cytokine comprised of 2 disulfide-linked glycosylated protein subunits, designated p35 and p40 fór their approximate molecular weights. IL-12 is produced primarily by antigenpresenting cells and drives cell-mediated immunity by binding to a two-chain receptor complex that is expressed on the surface of T cells or natural killer (NK) cells. The IL-12 receptor beta-1 (IL-12Rpi) chain binds to the p40 subunit of IL12, providing the primary interaction between IL-12 and its receptor. However, it is IL-12p35 ligation ofthe second receptor chain, IL-12RP2, that confers intracellularsignaling (e.g. STAT4 phosphorylation) and activation ofthe receptorbearing cell (Presky et al, 1996). IL-12 signaling concurrent with antigén presentation is thought to invoke T cell differentiation towards the T helper 1 (Th1) phenotype, characterized by interferon gamma (IFNy) production (Trinchieri, 2003). Th1 cells are believed to promote immunity to somé intracellular pathogens, generate complement-fixing antibody isotypes, and contribute to tumor immunosurveillance. Thus, IL-12 is thought to be a significant component to hőst defense immuné mechanisms.

[0003] It was discovered that the p40 protein subunit of IL-12 can alsó associate with a separate protein subunit, designated p19, to form a növel cytokine, IL-23 (Oppman et al, 2000). IL-23 alsó signals through a two-chain receptor complex. Since the p40 subunit is shared between IL-12 and IL-23, it follows that the IL-12Rpi chain is alsó shared between IL-12 and IL-23. However, it is the IL-23p19 ligation of the second component of the IL-23 receptor complex, IL-23R, that confers IL-23 specific intracellularsignaling (e.g., STAT3 phosphorylation) and subsequent IL-17 production by T cells (Parham et al, 2002; Aggarwal et al. 2003). Recent studies have demonstrated that the biological functions of IL-23 are distinct from those of IL-12, despite the structural similarity between the two cytokines (Langrish et al, 2005). [0004] Abnormal regulation of IL-12 and Th1 cell populations has been associated with many immune-mediated diseases since neutralization of IL-12 by antibodies is effective in treating animal models of psoriasis, multiple sclerosis (MS), rheumatoid arthritis, inflammatory bowel disease, insulin-dependent(type 1)diabetes mellitus, and uveitis(Leonard et al, 1995; Hong et al, 1999; Maifait et al, 1998; Davidson et al, 1998). However, since these studies targeted the shared p40 subunit, both IL-12 and IL-23 were neutralized in vivő. Therefore, itwas unclearwhether IL-12 or IL-23 was mediating disease, or if both cytokines needed to be inhibited to achieve disease suppression. Recent studies have confirmed through IL-23p19 deficient mice or specific antibody neutralization of IL-23 that IL-23 inhibition can provide equivalent benefit as anti-l L-12p40 strategies (Cua etal, 2003, Murphy etal, 2003, Bensőn et al 2004). Therefore, there is increasing evidence fór the specific role of IL-23 in immune-mediated disease. Neutralization of IL-23 without inhibition of IL-12 pathways could then provide effective therapy of immune-mediated disease with limited impact on important hőst defense immuné mechanism. This would represent a significant improvement over current therapeutic options. US 2004/223969 and WO 2005/108425 disclose anti-p19 antibodies.

SUMMARY OF THE INVENTION [0005] The invention provides an isolated IL-23p19 antibody, which is an antibody that binds to the p19 subunit of IL23, comprising:

(i) (a) at least one light chain variable region, said light chain variable region comprising:

a complementarity determining region light chain 1 (CDRL1) amino acid sequence of SEQ ID NO:46; a CDRL2 amino acid sequence of SEQ ID NO:52; and a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS:58-61; and (b) at least one heavy chain variable region, said heavy chain variable region comprising:

a complementarity determining region heavy chain 1 (CDRH1) amino acid sequence of SEQ ID NO:1;

EP 2 548 577 Β1 a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS:7 and 8; and a CDRH3 amino acid sequence of SEQ ID NO:40;

(ü) (a) at least one light chain variable region, said light chain variable region comprising:

a CDRL1 amino acid sequence of SEQ ID NO:47; a CDRL2 amino acid sequence of SEQ ID NO:53; and a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS:62-67; and (b) at least one heavy chain variable region, said heavy chain variable region comprising:

a CDRH1 amino acid sequence of SEQ ID NO:2;

a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS:9-15; and a CDRH3 amino acid sequence of SEQ ID NO:41;

(iü) (a) at least one light chain variable region, said light chain variable region comprising:

a CDRL1 amino acid sequence of SEQ ID NO:49; a CDRL2 amino acid sequence of SEQ ID NO:55; and a CDRL3 amino acid sequence of SEQ ID NO:70; and (b) at least one heavy chain variable region, said heavy chain variable region comprising:

a CDRH1 amino acid sequence of SEQ ID NO:4; a CDRH2 amino acid sequence of SEQ ID NO:18; and a CDRH3 amino acid sequence of SEQ ID NO:43;

(iv) (a) at least one light chain variable region, said light chain variable region comprising:

a CDRL1 amino acid sequence of SEQ ID NO:50; a CDRL2 amino acid sequence of SEQ ID NO:56; and a CDRL3 amino acid sequence selected from the group consisting of SEQ ID NOS:58-68 and 71-73; and (b) at least one heavy chain variable region, said heavy chain variable region comprising:

a CDRH1 amino acid sequence selected from the group consisting of SEQ ID NO:5; a CDRH2 amino acid sequence selected from the group consisting of SEQ ID NOS:19 and 21-27; and a CDRH3 amino acid sequence of SEQ ID NO: 44;

(v) (a) a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS:82-85; and (b) a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS:80 and 81;

(vi) (a) a light chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS:93-98; and (b) a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS:86-92;

ΕΡ 2 548 577 Β1 (vii) (a) a light chain variable region amino acid sequence of SEQ ID NO: 102; and (b) a heavy chain variable region amino acid sequence of SEQ ID NQ:101;

(viii) (a) a light chain variable region amino acid sequence selected from the group consisting ofSEQ ID NOS: 113-116; and (b) a heavy chain variable region amino acid sequence selected from the group consisting of SEQ ID NOS: 103-112;

(ix) (a) a light chain variable region amino acid sequence having at least 95% identify to any of the amino acid sequences selected from the group consisting of SEQ ID NOS:82-85; and (b) a heavy chain variable region amino acid sequence having at least 95% identify to any ofthe amino acid sequences selected from the group consisting of SEQ ID NOS:80 and 81;

(x) (a) a light chain variable region amino acid sequence having at least 95% identify to any of the amino acid sequences selected from the group consisting of SEQ ID NOS:93-98; and (b) a heavy chain variable region amino acid sequence having at least 95% identify to any ofthe amino acid sequences selected from the group consisting of SEQ ID NOS:86-92;

(xi) (a) a light chain variable region amino acid sequence having at least 95% identity to the amino acid sequence ofSEQ ID NO:102; and (b) a heavy chain variable region amino acid sequence having at least 95% identity ofthe amino acid sequence ofSEQ ID NO:101;

(xii) (a) a light chain variable region amino acid sequence having at least 95% identity to any of the amino acid sequences selected from the group consisting ofSEQ ID NOS:113-116; and (b) a heavy chain variable region amino acid sequence having at least 95% identity to any ofthe amino acid sequences selected from the group consisting of SEQ ID NQS:103-112;

(xiii) (a) a light chain variable region amino acid sequence encoded by the nucleotide sequence selected from the group consisting ofSEQ ID NOS:136-138; and (b) a heavy chain variable region amino acid sequence encoded by the nucleotide sequence selected from the group consisting ofSEQ ID NOS:133-135;

(xiv) (a) a light chain variable region sequence encoded by a nucleotide sequence having at least 95% identity to any ofthe nucleotide sequences selected from the group consisting ofSEQ ID NOS:136-138; and (b) a heavy chain variable region sequence encoded by a nucleotide sequence having at least 95% identity to any ofthe nucleotide sequences selected from the group consisting ofSEQ ID NOS:133-135; or (xv) (a) a light chain variable region sequence encoded by a nucleotide sequence having at least 95% identity to any ofthe nucleotide sequences selected from the group consisting ofSEQ ID NOS:142-144; and

ΕΡ 2 548 577 Β1 (b) a heavy chain variable region sequence encoded by a nucleotide sequence having at least 95% identity to any ofthe nucleotide sequences selected from the group consisting of SEQ ID NOS: 139-141.

[0006] The invention alsó provides an isolated nucleic acid molecule encoding at least one isolated IL-23p19 antibody according to the invention.

[0007] The invention alsó provides an isolated nucleic acid vector comprising the isolated nucleic acid molecule ofthe invention.

[0008] The invention alsó provides a prokaryoticoreukaryotic hőst cell comprising: (a) the isolated nucleic acid molecule according to the invention; or (b) (i) a nucleic acid vector encoding a Iight chain variable region, said Iight chain variable region comprising: a CDRL1 amino acid sequence of SEQ ID NO:50; a CDRL2 amino acid sequence of SEQ ID NO:56; and a CDRL3 amino acid sequence of SEQ ID NO:73; and (ii) a nucleic acid vector encoding a heavy chain variable region, said heavy chain variable region comprising: a CDRH1 amino acid sequence of SEQ ID NO:5; a CDRH2 amino acid sequence of SEQ ID NO:20; and a CDRH3 amino acid sequence of SEQ ID NO:44.

[0009] The invention alsó provides an in vitro method fór producing at least one IL-23p19, comprising translating the nucleic acid molecule according to the invention under conditions such that the IL-23p19 antibody is expressed in detectable or recoverable amounts.

[0010] The invention alsó provides a composition comprising at least one isolated IL-23p19 antibody according to the invention and at least one pharmaceutically acceptable carrier or diluent.

[0011] The invention alsó provides the antibody ofthe invention fór use in an in vivő method fór diagnosing or treating an IL-23 related condition in a cell, tissue, organ or animal. The invention alsó provides a medical device, comprising an IL-23p19 antibody according to the invention.The invention alsó provides an article of manufacture fór humán pharmaceutical or diagnostic use, comprising packaging matéria! and a Container comprising a solution or a lyophilized form of an IL-23p19 antibody according to the invention.

[0012] The invention alsó provides a method fór producing an isolated IL-23p19 antibody according to the invention, comprising providing a hőst cell or non-human transgenic animal or transgenic plánt or plánt cell capable of expressing in recoverable amounts said antibody.

DESCRIPTION OF THE FIGURES [0013]

Figure 1A shows that humán IL-23p19 antibodies bind specifically to hrlL-23 and nőt hrlL-12 or hrp40 monomer. An anti-IL-12/IL-23 p40 antibody is shown to bind IL-23, IL-12 and the p40 monomer.

Figure 1B shows that humán IL-23p 19 antibodies bind to humán IL-23, bút nőt to murine IL-23 or its subunits.

Figure 2 shows the IL-23 binding to two ofthe plate-immobilized IL-23p19 antibodies ofthe invention.

Figure 3A shows that antibodies MOR04083 and MOR04190 block normál IL-23/IL-23R binding.

Figure 3B shows that antibodies MOR04083 and MOR04190 do nőt block normál IL-23/IL-12R01 binding.

Figure 3C shows that antibodies MOR04083, MOR04190, and MOR04217 do nőt inhibit IL-12 binding to IL-12R01Fc binding.

Figure 4 shows that the IL-23p19 antibodies MOR04083 and MOR04190 ofthe invention inhibit hrlL-23 mediated STAT 3 phosphorylation.

Figure 5A shows that the IL-23p19 antibodies MOR04083 and MOR04190 ofthe invention inhibit recombinant hrlL23 mediated IL-17 production.

Figure 5B shows that the IL-23p19 antibodies MOR04083 and MOR04190 ofthe invention inhibit native hrlL-23 mediated IL-17 production.

Figure 5C shows that the IL-23p 19 antibodies MOR04083 and MOR04190 of the invention inhibit native cynomologous monkey IL-23 mediated IL-17 production.

Figure 6 shows that the IL-23p19 antibodies MQR04083 and MQR04190 ofthe invention do nőt inhibit hrlL-12

EP 2 548 577 Β1 mediated IFNy production.

Figures 7A-C show that the IL-23p19 antibodies MOR04083, MOR04190, and MOR04217 ofthe invention crosscompete with each other fór binding to hulL-23.

Figure 8 shows that the IL-23p19 antibodies MOR05028, 05038, 05040, 05042, 05045, 05049, and 05053 ofthe invention inhibit recombinant hrlL-23 mediated IL-17 production.

Figure 9 shows that the IL-23p19 antibodies MOR05028, 05038, 05040, 05042, 05045, 05049, and 05053 ofthe invention block normál IL-23/IL-23R binding.

Figure 10 shows that the IL-23p 19 antibodies 5040^Q/EV and 3759^EQ/QS of the invention bind specifically to hrlL-23 and nőt hrlL-12 or hrp40 monomer, comparable to the anti-IL-23p19 murine monoclonal antibody, mAb23A. The anti-IL-12/IL-23p40 antibody mAb12A is shown to bind IL-23, IL-12 and the p40 monomer.

Figure 11A shows that the I L-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention block normál IL-23/IL-23R binding.

Figure 11B shows that the IL-23p19 antibodies 5040^Q/EVand 3759^EQ/QS ofthe invention do nőt block normál IL23/IL-12Rpi binding.

Figure 11C shows that the I L-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention do nőt inhibit IL-12 binding to IL-12RP1-Fc binding.

Figure 12 shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention do nőt inhibit IL-12 induced INFy production from NK92MI cells.

Figure 13 shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention inhibit recombinant hrlL-23 mediated IL-17 production.

Figure 14 shows that the IL-23p19 antibodies 5040^Q/EVand 3759^EQ/QS ofthe invention inhibit native hrlL-23 mediated IL-17 production.

Figure 15 shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention inhibit native cynomologous monkey IL-23 mediated IL-17 production.

Figure 16A shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS of the invention and mAb23A compete with the binding to of IL-23 to immobilized mAb23A.

Figure 16B shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS ofthe invention and, to a lesser extent, mAb23A compete with the binding to of IL-23 to immobilized 5040^Q/EV mAb.

Figure 16C shows that the IL-23p19 antibodies 5040^Q/EV and 3759^EQ/QS of the invention and mAb23A compete with the binding to of IL-23 to immobilized 3759^EQ/QS mAb.

DESCRIPTION OF THE INVENTION [0014] The present invention provides isolated, recombinant and/or synthetic anti-IL-23p19 antibodies, including, without limitation, mammalian (e.g., humán antibodies) and IL-23p19 anti-idiotype antibodies thereto, as well as compositions and encoding nucleic acid molecules comprising at least one polynucleotide encoding at least one anti-IL-23p19 antibody or anti-idiotype antibody. The present invention further includes, bút is nőt limited to, methods of making and using such nucleic acids and antibodies, including diagnostic and therapeutic compositions, methods and devices.

[0015] As used herein, an anti-IL-23p19 antibody, IL-23p19 antibody, anti-IL-23p19 antibody portion, oranti-IL23p19 antibody fragment and/or anti-IL-23p19 antibody variant and the like include any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as bút nőt limited to, at least one complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework region, or any portion thereof, or at least one portion of an IL-23 receptor or binding protein, which can be incorporated intő an antibody of the present

ΕΡ 2 548 577 Β1 invention. Such antibody optionally further affects a specific ligand, such as bút nőt limited to, where such antibody modulates, decreases, increases, antagonizes, agonizes, mitigates, alleviates, blocks, inhibits, abrogates and/or interferes with at least one IL-23 activity or binding, or with IL-23 receptor activity or binding, in vitro, in situ and/or in vivő. As a non-limiting example, a suitable anti-IL-23p19 antibody, specified portion or variant ofthe present invention can bind at least one IL-23 molecule, or specified portions, variants or domains thereof. A suitable anti-lL-23p19 antibody, specified portion, or variant can alsó optionally affect at least one of IL-23p19 activity or function, such as bút nőt limited to, RNA, DNAor protein synthesis, IL-23 release, IL-23 receptor signaling, membráné IL-23 cleavage, IL-23 activity, IL23 production and/or synthesis.

[0016] The term antibody is further intended to encompass antibodies, digestion fragments, specified portions and variants thereof, including, without limitation, antibody mimetics or comprising portions of antibodies that mimic the structure and/or function of an antibody or specified fragment or portion thereof, including, without limitation, singie chain antibodies, singie domain antibodies, and fragments thereof. Functional fragments include antigen-binding fragments that bind to a humán IL-23p19. Fór example, antibody fragments capable of binding to IL-23p19 or portions thereof, including, bút nőt limited to, Fab (e.g., by papain digestion), Fab’ (e.g., by pepsin digestion and partial reduction) and F(ab’)₂ (e.g., by pepsin digestion), facb (e.g., by plasmin digestion), pFc’ (e.g., by pepsin or plasmin digestion), Fd (e.g., by pepsin digestion, partial reduction and reaggregation), Fv or scFv (e.g., by molecular biology techniques) fragments, are encompassed bythe invention (see, e.g., Colligan, Immunology, supra).

[0017] Such fragments can be produced by enzymatic cleavage, synthetic or recombinant techniques, as known in the art and/or as described herein. Antibodies can alsó be produced in a variety of truncated forms using antibody genes in which one or more stop codons have been introduced upstream of the natural stop site. Fór example, a combination gene encoding a F(ab’)₂ heavy chain portion can be designed to include DNA sequences encoding the CH₁ domain and/or hinge region of the heavy chain. The various portions of antibodies can be joined together chemically by conventional techniques, or can be prepared as a contiguous protein using genetic engineering techniques.

[0018] The term humán antibody, as used herein, is intended to include antibodies having variable and constant regions derived from or closely matching humán germline immunoglobulin sequences. The humán antibodies of the invention may include amino acid residues nőt encoded by humán germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivő). Thus, as used herein, the term humán antibody refers to an antibody in which substantially every part ofthe protein (e.g., CDR, framework, C_L, C_H domains (e.g., C_H1, C_H2, C_H3), hinge, (V_L, V_H)) is substantially similar to a humán germline antibody. Humán antibodies have been classified intő groupings based on their amino acid sequence similarities, see e.g. http:// people.cryst.bbk.ac.uk/~ubcg07s/. Thus, using a sequence similarity search, an antibody with similar linear sequence can be chosen as a template to create humanized antibodies.

[0019] Humanization (alsó called Reshaping or CDR-grafting) is now a well-established technique tor reducing the immunogenicity of monoclonal antibodies (mAbs) from xenogeneic sources (commonly rodent) and tor improving the effectorfunctions (ADCC, complement activation, Clq binding). The engineered mAb is engineered using the techniques of molecular biology, however simple CDR-grafting of the rodent complementarity-determining regions (CDRs) intő humán frameworks often results in loss of binding affinity and/or specificity ofthe original mAb. In order to humanize an antibody, the design ofthe humanized antibody includes variations such as conservative amino acid substitutions in residues of the CDRs, and back substitution of residues from the rodent mAb intő the humán framework regions (backmutations). The positions can be discerned or identified by sequence comparison tor structural analysis or by analysis of a homology model of the variable regions’ 3D structure. The process of affinity maturation has most recently used phage libraries to vary the amino acids at chosen positions. Similarly, many approaches have been used to choose the most appropriate humán frameworks in which tograftthe rodent CDRs. As the datasetsof known parameters tor antibody structures increases, so does the sophistication and refinement of these techniques. Consensus or germline sequences from a singie antibody or fragments of the framework sequences within each light or heavy chain variable region from several different humán mAbs can be used. Another approach to humanization is to modify only surface residues ofthe rodent sequence with the mostcommon residues found in humán mAbs and has been termed resurfacingorveneering. Known humán lg sequences are disclosed, e.g., www.ncbi.nlm.nih.gov/entrez/query.fcgi; www.ncbi.nih.gov/igblast; www.atcc.org/phage/hdb.html; www.kabatdatabase.com/top.html; www.antibodyresource.com/onlinecomp.html; www.appliedbiosystems.com; www.biodesign.com; antibody.bath.ac.uk; www. unizh.ch; www. cryst.bbk.ac.uk/~ubcg07s; Kábát et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983). Often, the humán or humanized antibody is substantially non-immunogenic in humans.

[0020] Similarly, antibodiesdesignated primate(monkey, baboon, chimpanzee, etc.), rodent(mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, and family specific antibodies. Further, chimeric antibodies can include any combination ofthe above. Such changes or variations optionally and preferably retain or reduce the immunogenicity in humans or other species relatíve to non-modified antibodies. Thus, a humán antibody is distinct from a chimeric or humanized antibody.

[0021] It is pointed out that a humán antibody can be produced by a non-human animal or prokaryotic or eukaryotic

ΕΡ 2 548 577 Β1 cell that is capable of expressing functionally rearranged humán immunoglobulin (e.g., heavy chain and/or light chain) genes. Further, when a humán antibody is a single chain or single domain antibody, it can comprise a linker peptide that is nőt found in native humán antibodies. Fór example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region ofthe heavy chain and the variable region of the light chain. Such linker peptides are considered to be of humán origin.

[0022] Bispecific, heterospecific, heteroconjugate or similar antibodies can alsó be used that are monoclonal, preferably, humán or humanized, antibodies that have binding specificities fór at least two different antigens. In the present case, one of the binding specificities is fór at least one IL-23p19 protein subunit, the other one is fór any other antigén. Methods fór making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Natúré 305:537 (1983)). Because ofthe random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. The purification ofthe correct molecule is usually done by affinity chromatography steps. Similar procedures are disclosed, e.g., in WO 93/08829, US Patent Nos, 6210668, 6193967, 6132992, 6106833, 6060285, 6037453, 6010902, 5989530, 5959084, 5959083, 5932448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91/00360, WO 92/00373, EP 03089, Traunecker et al., EMBO J. 10:3655 (1991), Suresh et al., Methods in Enzymology 121:210 (1986).

[0023] Anti-IL-23p19 antibodies useful in the methods and compositions ofthe present invention can optionally be characterized by high affinity binding to IL-23p19 and, optionally and preferably, as having low toxicity. In particular, an antibody, specified fragment or variant of the invention, where the individual components, such as the variable region, constant region and framework, individually and/or collectively, optionally and preferably possess low immunogenicity, is useful in the present invention. The antibodies that can be used in the invention are optionally characterized by their ability to treat patients fór extended periods with measurable alleviation of symptoms and low and/or acceptable toxicity. Low or acceptable immunogenicity and/or high affinity, as well as other suitable properties, can contribute to the therapeutic results achieved. Low immunogenicity is defined herein as the incidence of titrable levels of antibodies to the anti-IL-23p19 antibody in patients treated with anti-IL-23p19 antibody as occurring in less than 25% of patients treated, preferably, in less than 10% of patients treated with the recommended dose fór the recommended course of therapy during the treatment period.

[0024] The isolated nucleic acids of the present invention can be used fór production of at least one anti-lL-23p19 antibody or specified variant thereof, which can be used to measure or effect in an cell, tissue, organ or animal (including mammals and humans), to diagnose, monitor, modulate, treat, alleviate, help prevent the incidence of, or reduce the symptoms of, at least one IL-23 related condition, selected from, bút nőt limited to, at least one of an immuné disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, or other known or specified IL-23 related condition.

[0025] Such a method can comprise administering an effective amount of a composition or a pharmaceutical composition comprising at least one anti-IL-23p19 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation, prevention, or reduotion in symptoms, effects or mechanisms. The effective amount can comprise an amount of about 0.001 to 500 mg/kg per single (e.g., bolus), multiple or continuous administration, or to achieve a serum concentration of 0.01-5000 μg/ml serum concentration per single, multiple, or continuous administration, or any effective rangé or value therein, as done and determined using known methods, as described herein or known in the relevant árts.

Antibodies of the Present Invention - Production and Generation [0026] At least one anti-IL-23p19 antibody ofthe present invention can be optionally produced by a cell line, a mixed cell line, an immortalized cell or clonal population of immortalized cells, as well known in the art. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, etal., Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001). [0027] Antibodies that are specific fór humán IL-23p19 proteinsor fragments thereof can be obtained from recombinant humán antibody libraries using an appropriate antigén, such as an isolated IL-23p19 protein and/or a portion thereof (including synthetic molecules, such as synthetic peptides). Other specific or generál antibodies, including, without limitation, mammalian antibodies, can be similarly raised. Preparation of antigens, and isolation of antibodies from humán libraries can be performed using any suitable technique.

[0028] In one approach, a recombinant antibody is obtained by phage display using antibody libraries (Hoogenboom HR. OverView of antibody phage-display technology and its applications. Methods in Molecular Biology. 178:1-37, 2002). In a preferred approach, a recombinant humán Fab is isolated from the HuCal Gold™ Library developed by MorphoSys,

ΕΡ 2 548 577 Β1

AG (Kretzschmar, 2002) and subsequently improved in its activity by CDR cassette diversification (Knappik et al., 2000; Krebs etal., 2001).

[0029] Recombinant humán antibodies recovered from phage display libraries may be engineered to replace certain residues with specific amino acids corresponding to consensus or specific humán antibody sequences. These sequences are identified by comparisons to databases of known humán germline or rearranged antibodies.

[0030] Known humán lg sequences are disclosed, e.g., www.ncbi.nlm.nih.gov/entrez/query.fcgi; www. ncbi.nih.gov/igblast; www.atcc.org/phage/hdb.html; www. mrc-cpe.cam.ac.uk/ALIGNMENTS.php; www.kabatdatabase.com/top.html; ftp. ncbi.nih.gov/repository/kabat; www.imgt.cines.fr.8104/; www. biochem.unizh.ch/antibody/index.html; www. sciquest.com; www.abcam.com; www.antibodyresource.com/onlinecomp.html; www. public.iastate.edu/~pedro/research_tools.html; www.whfreeman.com/immunology/CH05/kuby05.htm; www. hhmi.org/grants/lectures/1996/vlab; www.path.cam.ac.uk/~mrc7/mikeimages.html; mcb.harvard.edu/BioLinks/lmmunology.html; www.immunologylink.com; pathbox. wusti.edu/~hcenter/index.html; www.appliedbiosystems.com; www. nal.usda.gov/awic/pubs/antibody; www.m.ehime-u.ac.jp/~yasuhito/Elisa.html; www.biodesign.com; www. cancerresearchuk.org; www.biotech.ufl.edu; www.isac-net.org; baserv. uci.kun.nl/~jraats/linksl.html; www.recab.uni-hd.de/immuno.bme.nwu.edu; www. mrc-cpe.cam.ac.uk; www.ibt.unam.mx/vir/V_mice.html; http://www. bioinf.org.uk/abs; antibody.bath.ac.uk; www. unizh.ch; www.cryst.bbk.ac.uk/~ubcg07s; www. nimr.mrc.ac.uk/CC/ccaewg/ccaewg.html; www. path.carn.ac.uk/~mrc7/hurmanisation/TAHHP.html; www.ibt.unam.mx/vir/structure/stat_aim.html; www. biosci.missouri.edu/smithgp/index.html; www.jerini.de; Kábát et al., Sequences of Proteins of Immunological Interest, U.S. Dept. Health (1983).

[0031] Such replaced amino acids can be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any other suitable characteristic, as known in the art. In generál, the CDR residues are directly and most substantially involved in infiuencing antigén binding.

[0032] Optionally, humán antibodies can be engineered with retention of high affinity forthe antigén and otherfavorable biological properties. To achieve this goal, the humán antibodies can be optionally prepared by a process of analysis of the parental sequences and various conceptual engineered products using three-dimensional models ofthe parental, engineered, and humán sequences. Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis ofthe likely role ofthe residues in thefunctioning ofthe candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigén. In this way, residues can be selected and combined from the parent and reference humán sequences so that the desired antibody characteristic, such as affinity fór the target antigen(s), is achieved. Alternatively, or in addition to, the above procedures, engineering can be accomplished empirically by CDR cassette diversification and selectíon fór the desired activity, such as described fór the MorphoSys HuCAL system (Knappik et al., 2000; Krebs et al., 2001).

[0033] In addition, the IL-23p19 antibody ofthe present invention may comprise a humán germline light chain framework. In particular embodiments, the light chain germline sequence is selected from humán VK sequences including, bút nőt limited to, A1, A10, A11, A14, A17, A18, A19, A2, A20, A23, A26, A27, A3, A30, A5, A7, B2, B3, L1, L10, L11, L12, L14, L15, L16, L18, L19, L2, L20, L22, L23, L24, L25, L4/18a, L5, L6, L8, L9, O1, O11, 012, 014, 018, 02, 04, and 08. In certain embodiments, this light chain humán germline framework is selected from V1-11, V1-13, V1-16, V1-17, V1-18, V1-19, V1-2, V1-20, V1-22, V1-3, V1-4, V1-5, V1-7, V1-9, V2-1, V2-11, V2-13, V2-14, V2-15, V2-17, V2-19, V2-6, V2-7, V2-8, V3-2, V3-3, V3-4, V4-1, V4-2, V4-3, V4-4, V4-6, V5-1, V5-2, V5-4, and V5-6. See PCT WO 2005/005604 fór a description of the different germline sequences.

[0034] In other embodiments, the IL-23 antibody ofthe present invention may comprise a humán germline heavy chain framework. In particular embodiments, this heavy chain humán germline framework is selected from VH1-18, VH1-2, VH1-24,VH1-3,VH1-45,VH1-46,VH1-58,VH1-69,VH1-8,VH2-26,VH2-5,VH2-70,VH3-11,VH 3-13, VH 3-15, VH3-16, VH3-20, VH3-21, VH3-23, VH3-30, VH3-33, VH3-35, VH3-38, VH3-43, VH3-48, VH3-49, VH3-53, VH3-64, VH3-66, VH3-7, VH3-72, VH3-73, VH3-74, VH3-9, VH4-28, VH4-31, VH4-34, VH4-39, VH4-4, VH4-59, VH4-61, VH5-51, VH6-1, and VH7-81. See PCT WO 2005/005604 fór a description of the different germline sequences.

[0035] In particular embodiments, the light chain variable region and/or heavy chain variable region comprises a framework region or at least a portion of a framework region (e.g., containing 2 or 3 subregions, such as FR2 and FR3). In certain embodiments, at least FRL1, FRL2, FRL3, or FRL4 is fully humán. In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is fully humán. In somé embodiments, at least FRL1, FRL2, FRL3, or FRL4 is a germline sequence (e.g., humán germline) or comprises humán consensus sequences fór the particular framework (readily available at the sources of known humán lg sequences described above). In other embodiments, at least FRH1, FRH2, FRH3, or FRH4 is a germline sequence (e.g., humán germline) or comprises humán consensus sequences forthe particular framework. In preferred embodiments, the framework region is a humán framework region.

[0036] Engineering of antibodies ofthe present invention can be performed using any known method, such as bút nőt limited to those described in, Winter (Jones et al., Natúré 321:522 (1986); Riechmann et al., Natúré 332:323 (1988);

ΕΡ 2 548 577 Β1

Verhoeyen et al., Science 239:1534 (1988)), Sims et al., J. Immunoi. 151: 2296 (1993); Chothia and Lesk, J. Mól. Bioi. 196:901 (1987), Carter et al., Proc. Natl. Acad. Sci. U.S.A. 89:4285 (1992); Presta et al., J. Immunoi. 151:2623(1993), US patent Nos: 5723323, 5976862, 5824514, 5817483, 5814476, 5763192, 5723323, 5,766886, 5714352, 6204023, 6180370, 5693762, 5530101, 5585089, 5225539; 4816567, PCT/: US98/16280, US96/18978, US91/09630, US91/05939, US94/01234, GB89/01334, GB91/01134, GB92/01755; WO90/14443, WO90/14424, W090/14430, EP 229246.

[0037] In certain embodiments, the antibody comprises an altered (e.g., mutated) Fc region. For example, in somé embodiments, the Fc region has been altered to reduce or enhance the effector functions of the antibody. In somé embodiments, the Fc region is an isotype selected from IgM, IgA, IgG, IgE, or other isotype.

[0038] Alternatively or additionally, it may be useful to combine amino acid modifications with one or more further amino acid modifications that altér C1q binding and/or the complement dependent cytotoxicity (CDC) function ofthe Fc region of an IL-23p 19 binding molecule. The binding polypeptide of particular interest may be one that binds to C1 q and displays complement dependent cytotoxicity. Polypeptides with pre-existing C1q binding activity, optionallyfurther having the ability to mediate CDC may be modified such that one or both of these activities are enhanced. Amino acid modifications that altér C1q and/or modify its complement dependent cytotoxicity function are described, for example, in WO/0042072.

[0039] As disclosed above, one can design an Fc region ofthe I L-23p19 antibody ofthe present invention with altered effector function, e.g., by modifying C1q binding and/or FcyR binding and thereby changing CDC activity and/or ADCC activity. Effectorfunctions are responsiblefor activating ordiminishing a biological activity (e.g., in a subject). Examples of effector functions include, bút are nőt limited to: C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor; BCR), etc. Such effector functions may require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays (e.g., Fc binding assays, ADCC assays, CDC assays, etc.).

[0040] For example, one can generate a variant Fc region of the IL-23p 19 antibody with improved C1 q binding and improved FcyRIII binding (e.g., having both improved ADCC activity and improved CDC activity). Alternatively, if it is desired that effector function be reduced or ablated, a variant Fc region can be engineered with reduced CDC activity and/or reduced ADCC activity. In other embodiments, only one of these activities may be increased, and, optionally, alsó the other activity reduced (e.g., to generate an Fc region variant with improved ADCC activity, bút reduced CDC activity and vice versa).

[0041] Fc mutations can alsó be introduced and engineered to altér their interaction with the neonatal Fc receptor (FcRn) and improve their pharmacokinetic properties. A collection of humán Fc variants with improved binding to the FcRn have been described (Shields et al., (2001). High resolution mapping ofthe binding site on humán lgG1 for FcyRI, FcyRII, FcyRIII, and FcRn and design of IgG 1 variants with improved binding to the FcyR, (J. Bioi. Chem. 276:6591-6604). [0042] Another type of amino acid substitution serves to altér the glycosylation pattern ofthe Fc region ofthe IL-23p19 antibody. Glycosylation of an Fc region is typically either N-linked or O-linked. N-linked refers to the attachment ofthe carbohydrate rnoiety to the side chain of an asparagine residue. O-linked glycosylation refers to the attachment of one ofthe sugars N-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may alsó be used. The recognition sequences for enzymatic attachment ofthe carbohydrate rnoiety to the asparagine side chain peptide sequences are asparagine-X-serine and asparagineX-threonine, where X is any amino acid except proline. Thus, the presence of either of these peptide sequences in a polypeptide creates a potential glycosylation site.

[0043] The glycosylation pattern may be altered, for example, by deleting one or more glycosylation site(s) found in the polypeptide, and/or adding one or more glycosylation site(s) that are nőt present in the polypeptide. Addition of glycosylation sites to the Fc region of an IL-23p19 antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). An exemplary glycosylation variant has an amino acid substitution of residue Asn 297 ofthe heavy chain. The alteration may alsó be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original polypeptide (for O-linked glycosylation sites). Additionally, a change of Asn 297 to Alá can remove one of the glycosylation sites.

[0044] In certain embodiments, the IL-23p19 antibody ofthe present invention is expressed in cells that express béta (1,4)-N-acetylglucosaminyltransferase Ili (GnT Ili), such that GnT Ili adds GIcNAc to the IL-23p19 antibody. Methods for producing antibodies in such a fashion are provided in WO/9954342, WO/03011878, patent publication 20030003097A1, and Umana etal., Natúré Biotechnology, 17:176-180, Feb. 1999.

[0045] Screening antibodies for specifie binding to similar proteins or fragments can be conveniently achieved using peptide display libraries. This method involves the screening of large collections of peptides for individual members having the desired function or structure. Antibody screening of peptide display libraries is well known in the art. The displayed peptide sequences can be from 3 to 5000 or more amino acids in length, frequently from 5-100 amino acids

EP 2 548 577 Β1 long, and often from about 8 to 25 amino acids long. In addition to direct Chemical synthetic methods fór generating peptide libraries, several recombinant DNA methods have been described. One type involves the display of a peptide sequence on the surface of a bacteriophage or cell. Each bacteriophage or cell contains the nucleotide sequence encoding the particular displayed peptide sequence. Such methods are described in PCT Patent Publication Nos. 91/17271,91/18980, 91/19818, and 93/08278.

[0046] Other systems fór generating libraries of peptides have aspects of both in vitro Chemical synthesis and recombinant methods. See, PCT Patent Publication Nos. 92/05258, 92/14843, and 96/19256. See alsó, U.S. Patent Nos. 5,658,754; and 5,643,768. Peptide display libraries, vector, and screening kits are commercially available from such suppliers as Invitrogen (Carlsbad, CA), and Cambridge Antibody Technologies (Cambridgeshire, UK). See, e.g., U.S. Pat. Nos. 4704692, 4939666, 4946778, 5260203, 5455030, 5518889, 5534621,5656730, 5763733, 5767260, 5856456, assigned to Enzon; 5223409, 5403484, 5571698, 5837500, assigned to Dyax, 5427908, 5580717, assigned to Affymax; 5885793, assigned to Cambridge Antibody Technologies; 5750373, assigned to Genentech, 5618920, 5595898, 5576195, 5698435, 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra. [0047] Antibodies of the present invention can alsó be prepared using at least one anti-1L-23p 19 antibody encoding nucleic acid to provide transgenic animals or mammals, such as goats, cows, horses, sheep, rabbits and the like, that produce such antibodies in their milk. Such animals can be provided using known methods. See, e.g., bút nőt limited to, US Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5,994,616; 5,565,362; 5,304,489, and the like.

[0048] Antibodies of the present invention can additionally be prepared using at least one anti-lL-23p19 antibody encoding nucleic acid to provide transgenic plants and cultured plánt cells (e.g., bút nőt limited to, tobacco and maize) that produce such antibodies, specified portions or variants in the plánt parts or in cells cultured therefrom. As a nonlimiting example, transgenic tobacco leaves expressing recombinant proteins have been successfully used to provide large amounts of recombinant proteins, e.g., using an inducible promoter. See, e.g., Cramer et al., Curr. Top. Microbol. Immunoi. 240:95-118 (1999) and references cited therein. Alsó, transgenic maize have been used to express mammalian proteins at commercial production levels, with biological activities equivalent to those produced in other recombinant systems or purified from natural sources. See, e.g., Hood et al., Adv. Exp. Med. Bioi. 464:127-147 (1999) and references cited therein. Antibodies have alsó been produced in large amounts from transgenic plánt seeds including antibody fragments, such as single chain antibodies (scFv’s), including tobacco seeds and potato tubers. See, e.g., Conrad et al., Plánt Mól. Bioi. 38:101-109 (1998) and references cited therein. Thus, antibodies ofthe present invention can alsó be produced using transgenic plants, according to known methods. See alsó, e.g., Fischer et al., Biotechnoi. Appl. Biochem. 30:99-108 (Oct., 1999), Ma et al., Trends Biotechnoi. 13:522-7 (1995); Ma et al., Plánt Physiol. 109:341-6 (1995); Whitelam et al., Biochem. Soc. Trans. 22:940-944 (1994); and references cited therein.

[0049] The antibodies of the invention can bind humán IL-23p19 with a wide rangé of affinities (K_D). In a preferred embodiment, at leastonem Ab ofthe present invention can optionally bind humán IL-23p19 with high affinity. Fór example, a humán or other mAb can bind humán IL-23p19 with a K_D equal to or less than about 10^-7 M, such as bút nőt limited to, 0.1-9.9 (or any rangé or value therein) X 10^-7, 10⁸, 10⁹, ΙΟ¹⁰, 10¹¹, ΙΟ¹², ΙΟ¹³, 10¹⁴, 10¹⁵ or any rangé or value therein, as determined by surface plasmon resonance or the Kinexa method, as practiced by those of skill in the art. In one embodiment, the antibodies ofthe invention bind humán IL-23p19 with a K_D between about 4 and about 4400pM. [0050] The affinity oravidity of an antibody fór an antigén can be determined experimentally using any suitable method. (See, fór example, Berzofsky, et al., Antibody-Antigen Interactions, In Fundamental Immunology, Paul, W. E., Ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, W. H. Freeman and Company: New York, NY (1992); and methods described herein). The measured affinity of a particular antibody-antigen interaction can vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of affinity and other antigen-binding parameters (e.g., K_D, K_on, K_off) are preferably made with standard ized solutionsof antibody and antigén, and a standardized buffer, such as the buffer described herein.

[0051] Competitive assays can be performed with the antibody of the present invention in order to determine what proteins, antibodies, and other antagonists compete fór binding to IL-23p19 with the antibody of the present invention and/or share the epitope region. These assays as readily known to those of ordinary skill in the art evaluate competition between antagonists or ligands fór a limited number of binding sites on a protein, e.g., p19. The protein and/or antibody is immobilized or insolubilized before or after the competition and the sample bound to the p19 subunit is separated from the unbound sample, fór example, by decanting (where the protein/antibody was preinsolubilized) or by centrifuging (where the protein/antibody was precipitated after the competitive reaction). Alsó, the competitive binding may be determined by whether function is altered by the binding or lack of binding of the antibody to the protein, e.g., whether the antibody molecule inhibits or potentiates the enzymatic activity of, fór example, a label. ELISA and other functional assays may be used, as well known in the art.

[0052] Certain embodiments of the anti-lL-23p19 antibodies of the invention have the sequences shown in the Sequence Tables below. Fór example, an anti-IL-23p19 antibody ofthe invention has one ofthe light chain CDR1 sequences of SEC ID NOS:46-51; one of the light chain CDR2 sequences of SEC ID NOS:52-57; one of the light chain CDR3 sequences of SEC ID NOS:58-79; one of the heavy chain CDR1 sequences SEC ID NOS:1-6; one of the heavy chain

EP 2 548 577 Β1

CDR2 sequences SEQ ID NOS:7-39 and 146; and/or one ofthe heavy chain CDR3 sequences SEQ ID NQS:40-45.

Nucleic Acid Molecules [0053] Using the information provided herein, fór example, the nucleotide sequences encoding at least 70-100% of the contiguous amino acids of at least one ofthe light chain variable regions ofthe antibodies ofthe invention (e.g., SEQ ID NOS: 136-138 and 142-144) and at least one of the heavy chain variable regions of the antibodies of the invention (e.g., SEQ ID NOS: 133-135 and 139-141), specified fragments, variants orconsensus sequences thereof, óra deposited vector comprising at least one of these sequences, a nucleic acid molecule of the present invention encoding at least one anti-IL-23p19 antibody can be obtained using methods described herein or as known in the art.

[0054] Nucleic acid molecules of the present invention can be in the form of RNA, such as mRNA, hnRNA, tRNA or any other form, or in the form of DNA, including, bút nőt limited to, cDNA and genomic DNA obtained by cloning or produced synthetically, orany combinations thereof. The DNA can betriple-stranded, double-stranded orsingle-stranded, or any combination thereof. Any portion of at least one strand ofthe DNA or RNA can be the coding strand, alsó known as the sense strand, or it can be the non-coding strand, alsó referred to as the anti-sense strand.

[0055] Isolated nucleic acid molecules ofthe present invention can include nucleic acid molecules comprising an open reading frame (ORF), optionally, with one or more introns, e.g., bút nőt limited to, at least one specified portion of at least one CDR, such as CDR1, CDR2 and/or CDR3 of at least light chain (SEQ ID NOS: 46-51,52-57, or 58-79) or at least one heavy chain (SEQ ID NOS: 1-6, 7-39, or 40-45); nucleic acid molecules comprising the coding sequence fór an anti-IL-23p19 antibody or variable region (e.g., light chain variable regions of SEQ ID NOS: 82-85, 93-98, 100, 102, 113-116, and 128-132 and heavy chain variable regions of SEQ ID NOS: 80, 81,86-92, 99, 101,103-112, 117-127, and 147); and nucleic acid molecules which comprise a nucleotide sequence substantially different from those described above bút which, due to the degeneracy ofthe genetic code, still encode at least one anti-IL-23p19 antibody as described herein and/or as known in the art. Of course, the genetic code is well known in the art. Thus, it would be routine fór one skilled in the art to generate such degenerate nucleic acid variants that code fór specific anti-1L-23p 19 antibodies of the present invention. See, e.g., Ausubel, et al., supra, and such nucleic acid variants are included in the present invention. [0056] As indicated herein, nucleic acid molecules ofthe present invention which comprise a nucleic acid encoding an anti-IL-23p19 antibody can include, bút are nőt limited to, those encoding the amino acid sequence ofan antibody fragment, by itself; the coding sequence fór the entire antibody óra portion thereof; the coding sequence fór an antibody, fragment or portion, as well as additional sequences, such as the coding sequence of at least one signal leaderor fusion peptide, with or without the aforementioned additional coding sequences, such as at least one intron, together with additional, non-coding sequences, including bút nőt limited to, non-coding 5’ and 3’ sequences, such as the transcribed, non-translated sequences that play a role in transcription, mRNA Processing, including splicing and polyadenylation signals (fór example, ribosome binding and stability of mRNA); an additional coding sequence that codes fór additional amino acids, such as those that provide additional functionalities. Thus, the sequence encoding an antibody can be fused to a marker sequence, such as a sequence encoding a peptide that facilitates purification ofthe fused antibody comprising an antibody fragment or portion.

Polynucleotides Selectively Hybridizing to a Polynucleotide as Described Herein [0057] The present invention provides isolated nucleic acids that hybridize under selective hybridization conditions to a polynucleotide disclosed herein. Thus, the polynucleotides of this embodiment can be used fór isolating, detecting, and/or quantifying nucleic acids comprising such polynucleotides. Fór example, polynucleotides ofthe present invention can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In somé embodiments, the polynucleotides are genomic or cDNA sequences isolated, or otherwise complementary to, a cDNA from a humán or mammalian nucleic acid library.

[0058] Preferably, the cDNA library comprises at least 80% full-length sequences, preferably, at least 85% or 90% full-length sequences, and, more preferably, at least 95% full-length sequences. The cDNA libraries can be normalized to increase the representation of rare sequences. Low or moderate stringency hybridization conditions are typically, bút nőt exclusively, employed with sequences having a reduced sequence identity relatíve to complementary sequences. Moderate and high stringency conditions can optionally be employed fór sequences of greater identity. Low stringency conditions allow selective hybridization of sequences having about 70% sequence identity and can be employed to identify orthologous or paralogous sequences.

[0059] Optionally, polynucleotides of this invention will encode at least a portion ofan antibody encoded by the polynucleotides described herein. The polynucleotides of this invention embrace nucleic acid sequences that can be employed fór selective hybridization to a polynucleotide encoding an antibody ofthe present invention. See, e.g., Ausubel, supra; Colligan, supra.

EP 2 548 577 Β1

Construction of Nucleic Acids [0060] The isolated nucleic acids ofthe present invention can be made using (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, and/or (d) combinations thereof, as well-known in the art.

[0061] The nucleic acids can conveniently comprise sequences in addition to a polynucleotide ofthe present invention. Fór example, a multi-cloning site comprising one or more endonuclease restriction sites can be inserted intő the nucleic acid to aid in isolation ofthe polynucleotide. Alsó, translatable sequences can be inserted to aid in the isolation ofthe translated polynucleotide ofthe present invention. Fór example, a hexa-histidine marker sequence provides a convenient means to purify the proteíns ofthe present invention. The nucleic acid ofthe present invention, excluding the coding sequence, is optionally a vector, adapter, or linker fór cloning and/or expression of a polynucleotide of the present invention.

[0062] Additional sequences can be added to such cloning and/or expression sequences to optimize their function in cloning and/or expression, to aid in isolation of the polynucleotide, or to improve the introduction of the polynucleotide intő a cell. Use of cloning vectors, expression vectors, adapters, and linkers is well known in the art. (See, e.g., Ausubel, supra; or Sambrook, supra)

Recombinant Methods fór Constructing Nucleic Acids [0063] The isolated nucleic acid compositions of this invention, such as RNA, cDNA, genom ic DNA, orany combination thereof, can be obtained from biological sources using any number of cloning methodologies known to those of skill in the art. In somé embodiments, oligonucleotide probes that selectively hybridize, under stringent conditions, to the polynucleotides of the present invention are used to identify the desired sequence in a cDNA or genomic DNA library. The isolation of RNA, and construction of cDNA and genomic libraries, are well known to those of ordinary skill in the art. (See, e.g., Ausubel, supra; or Sambrook, supra)

Nucleic Acid Screening and Isolation Methods [0064] A cDNA or genomic library can be screened using a probe based upon the sequence of a polynucleotide of the present invention, such as those disclosed herein. Probes can be used to hybridize with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. Those of skill in the art will appreciate that various degrees of stringency of hybridization can be employed in the assay; and either the hybridization or the wash médium can be stringent. As the conditions fór hybridization become more stringent, there must be a greater degree of complementarity between the probe and the target fór duplex formation to occur. The degree of stringency can be controlled by one or more of temperature, ionic strength, pH and the presenee of a pariiaily denaturing solvent, such as formamide. Fór example, the stringency of hybridization is conveniently varied by changing the polarity of the reactant solution through, fór example, manipulation ofthe concentration of form amidé within the rangé of 0% to 50%. The degree of complementarity (sequence identity) required fór detectable binding will vary in accordance with the stringency of the hybridization médium and/or wash médium. The degree of complementarity will optimally be 100%, or 70-100%, or any rangé or value therein. However, it should be understood that minor sequence variations in the probes and primers can be compensated fór by reducing the stringency ofthe hybridization and/or wash médium.

[0065] Methods of amplification of RNA or DNA are well known in the art and can be used according to the present invention without undue experimentation, based on the teaching and guidance presented herein.

[0066] Known methods of DNA or RNA amplification include, bút are nőt limited to, polymerase chain reaction (PCR) and related amplification processes (see, e.g., U.S. Patent Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188, to Mullis, et al.; 4,795,699 and 4,921,794 to Tábor, et al; 5,142,033 to Innis; 5,122,464 to Wilson, et al.; 5,091,310 to Innis; 5,066,584 to Gyllensten, et al; 4,889,818 to Gelfand, et al; 4,994,370 to Silver, et al; 4,766,067 to Biswas; 4,656,134 to Ringold) and RNA mediated amplification that uses anti-sense RNA to the target sequence as a template fór doublestranded DNA synthesis (U.S. Patent No. 5,130,238 to Malek, et al, with the tradename NASBA). (See, e.g., Ausubel, supra; or Sambrook, supra.) [0067] Fór instance, polymerase chain reaction (PCR) technology can be used to amplify the sequences of polynucleotides of the present invention and related genes direotiy from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods can alsó be useful, fór example, to clone nucleic acid sequences that code fór proteíns to be expressed, to make nucleic acids to use as probes fordetecting the presenee ofthe desired mRNA in samples, fór nucleic acid sequencing, or fór other purposes. Examples of techniques sufficient to direct persons of skill through in vitro amplification methods are found in Berger, supra, Sambrook, supra, and Ausubel, supra, as well as Mullis, et al., U.S. Patent No. 4,683,202 (1987); and Innis, et al., PCR Protocols A Guide to Methods and Applications, Eds., Academic Press Inc., San Diego, CA (1990). Commercially available kits fór genomic PCR amplification are known in the art. See, e.g., Advantage-GC Genomic PCR Kit (Clontech). Additionally, e.g., the T4 gene 32 protein (Boehringer Mannheim)

ΕΡ 2 548 577 Β1 can be used to improve yield of long PCR products.

Synthetic Methods fór Constructing Nucleic Acids [0068] The isolated nucleic acids ofthe present invention can alsó be prepared by direct Chemical synthesis by known methods (see, e.g., Ausubel, et al., supra). Chemical synthesis generally produces a single-stranded oligonucleotide, which can be converted intő double-stranded DNA by hybridization with a complementary sequence, or by polymerization with a DNA polymerase using the single strand as a template. One of skill in the art will recognize that while Chemical synthesis of DNA can be limited to sequences of about 100 or more bases, longer sequences can be obtained by the ligation of shorter sequences.

Recombinant Expression Cassettes [0069] The present invention further provides recombinant expression cassettes comprising a nucleic acid of the present invention. A nucleic acid sequence of the present invention, fór example, a cDNA or a genomic sequence encoding an antibody ofthe present invention, can be used to construct a recombinant expression cassette that can be introduced intő at least one desired hőst cell. A recombinant expression cassette will typically comprise a polynucleotide ofthe present invention operably linked to transcriptional initiation regulatory sequences that will direct the transcription ofthe polynucleotide in the intended hőst cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be employed to direct expression ofthe nucleic acids ofthe present invention.

[0070] In somé embodiments, isolated nucleic acids that serve as promoter, enhancer, or other elements can be introduced in the appropriate position (upstream, downstream or in the intron) of a non-heterologous form of a polynucleotide of the present invention so as to up or down regulate expression of a polynucleotide of the present invention. Fór example, endogenous promoters can be altered in vivő or in vitro by mutation, deletion and/or substitution.

Vectors and Hőst Cells [0071] The present invention alsó relates to vectors that include isolated nucleic acid molecules ofthe present invention, hőst cells that are genetically engineered with the recombinant vectors, and the production of at least one anti-lL-23p19 antibody by recombinant techniques, as is well known in the art. See, e.g., Sambrook, et al., supra; Ausubel, etal., supra. [0072] The polynucleotides can optionally be joined to a vector containing a selectable marker fór propagation in a hőst. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a vírus, it can be packaged in vitro using an appropriate packaging cell line and then transduced intő hőst cells.

[0073] The DNA insert should be operatively linked to an appropriate promoter. The expression constructs will further contain sites fór transcription initiation, termination and, in the transcribed region, a ribosome binding site fór translation. The coding portion ofthe mature transcripts expressed by the constructs will preferably include a translation initiating at the beginning and a termination codon (e.g., UAA, UGAor UAG) appropriately positioned at the end ofthe mRNAto be translated, with UAA and UAG preferred fór mammalian or eukaryotic cell expression.

[0074] Expression vectors will preferably bút optionally include at least one selectable marker. Such markers include, e.g., bút are nőt limited to, methotrexate (MTX), dihydrofolate reductase (DHFR, US Pat.Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017, ampicillin, neomycin (G418), mycophenolic acid, orglutamine synthetase (GS, US Pat.Nos. 5,122,464; 5,770,359; 5,827,739) resistance fór eukaryotic cell culture, and tetracycline or ampicillin resistance genes fór culturing in E. coli and other bacteria or prokaryotics. Appropriate culture mediums and conditions fór the above-described hőst cells are known in the art. Suitable vectors will be readily apparent to the skilled artisan. Introduction of a vector construct intő a hőst cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other known methods. Such methods are described in the art, such as Sambrook, supra, Chapters 1-4 and 16-18; Ausubel, supra, Chapters 1,9,13,15,16.

[0075] At least one antibody ofthe present invention can be expressed in a modified form, such as a fusion protein, and can include nőt only secretion signals, bút alsó additional heterologous functional regions. Fór instance, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of an antibody to improve stability and persistence in the hőst cell, during purification, or during subsequent handling and storage. Alsó, peptide moieties can be added to an antibody of the present invention to facilitate purification. Such regions can be removed prior to final preparation of an antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Chapters 17.29-17.42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18.

[0076] Those ofordinary skill in the art are knowledgeable in the numerous expression systems available fór expression

ΕΡ 2 548 577 Β1 ofa nucleic acid encoding a protein ofthe present invention. Alternatively, nucleic acids ofthe present invention can be expressed in a hőst cell by turning on (by manipulation) in a hőst cell that contains endogenous DNA encoding an antibody ofthe present invention. Such methods are well known in the art, e.g., as described in US patent Nos. 5,580,734, 5,641,670, 5,733,746, and 5,733,761.

[0077] lllustrative of cell cultures useful fór the production ofthe antibodies, specified portions or variants thereof, are mammalian cells. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensionsorbioreactorscan alsó be used. A number of suitable hőst cell lines capable of expressing intactglycosylated proteins have been developed in the art, and include the COS-1 (e.g., ATCC CRL 1650), COS-7 (e.g., ATCC CRL1651), HEK293, BHK21 (e.g., ATCC CRL-10), CHO (e.g., ATCC CRL 1610) and BSC-1 (e.g., ATCC CRL-26) cell lines, Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8.653, SP2/0-Ag14, 293 cells, HeLa cells and the like, which are readily available from, fór example, American Type Culture Collection, Manassas, Va (www.atcc.org). Preferred hőst cells include cells oflymphoid origin, such as myelomaand lymphoma cells. Particularly preferred hőst cells are P3X63Ag8.653 cells (ATCC Accession NumberCRL-1580) and SP2/0-Ag14cells (ATCC Accession NumberCRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8.653 óra SP2/0-Ag14 cell.

[0078] Expression vectors fór these cells can include one or more ofthe following expression controi sequences, such as, bút nőt limited to, an origin of replication; a promoter (e.g., laté or early SV40 promoters, the CMV promoter (US Pat.Nos. 5,168,062; 5,385,839), an HSV tk promoter, a pgk(phosphoglycerate kinase) promoter, an EF-1 alpha promoter (US Pat.No. 5,266,491), at least one humán immunoglobulin promoter; an enhancer, and/or Processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites (e.g., an SV40 large T Ag poly A addition site), and transcriptional terminator sequences. See, e.g., Ausubel et al., supra; Sambrook, et al., supra. Other cells useful fór production of nucleic acids or proteins ofthe present invention are known and/or available, fór instance, from the American Type Culture Collection Catalogue of Cell Lines and Hybridomas (www.atcc.org) or other known or commercial sources.

[0079] When eukaryotic hőst cells are employed, polyadenlyation or transcription terminator sequences are typically incorporated intő the vector. An example of a terminator sequence is the polyadenlyation sequence from the bovine growth hormoné gene. Sequences fór accurate splicing ofthe transcript can alsó be included. An example of a splicing sequence is the VP1 intron from SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)). Additionally, gene sequences to controi replication in the hőst cell can be incorporated intő the vector, as known in the art.

Purification of an Antibody [0080] An anti-IL-23p19 antibody can be recovered and purified from recombinant cell cultures by well-known methods including, bút nőt limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. High performance liquid chromatography (HPLC) can alsó be employed fór purification. See, e.g., Colligan, Current Protocols in Immunology, orCurrent Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001), e.g., Chapters 1,4, 6, 8, 9, 10.

[0081] Antibodies ofthe present invention include naturally purified products, products of Chemical synthetic procedures, and products produced by recombinant techniques from a eukaryotic hőst, including, fór example, yeast, higher plánt, insect and mammalian cells. Depending upon the hőst employed in a recombinant production procedure, the antibody of the present invention can be glycosylated or can be non-glycosylated, with glycosylated preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 10, 12, 13, 16, 18 and 20, Colligan, Protein Science, supra, Chapters 12-14.

Anti-IL-23p19 Antibodies [0082] An anti-lL-23p19 antibody described herein includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule, such as bút nőt limited to, at least one ligand binding portion (LBP), such as bút nőt limited to, a complementarity determining region (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a framework region (e.g., FR1, FR2, FR3, FR4 or fragment thereof, further optionally comprising at least one substitution, insertion ordeletion), a heavy chain or light chain constant region, (e.g., comprising at least one CH1, hingel, hinge2, hinge3, hinge4, CH2, or CH3 or fragment thereof, further optionally comprising at least one substitution, insertion or deletion), or any portion thereof, that can be incorporated intő an antibody ofthe present invention. An antibody ofthe invention can include or be derived from any mammal, such as bút nőt limited to, a humán, a mouse, a rabbit, a rat, a rodent, a primate, or any combination thereof, and the like. [0083] The isolated antibodies disclosed herein comprise the antibody amino acid sequences disclosed herein encoded by any suitable polynucleotide, or any isolated or prepared antibody. Preferably, the humán antibody or antigen-binding fragment binds humán IL-23p19 and, thereby, partially or substantially neutralizes at least one biological activity ofthe

ΕΡ 2 548 577 Β1 protein. An antibody, or specified portion or variant thereof, that partially or preferably substantially neutralizes at least one biological activity of at least one IL-23 protein or fragment can bind the protein or fragment and thereby inhibit activities mediated through the binding of IL-23 to the IL-23 receptor or through other IL-23-dependent or mediated mechanisms. As used herein, the term neutralizing antibody refers to an antibody that can inhibit an IL-23-dependent activity by about 20-120%, preferably by at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 100% or more depending on the assay. The capacity of an anti-IL-23p19 antibody to inhibit an IL-23dependent activity is preferably assessed by at least one suitable IL-23 protein or receptor assay, as described herein and/or as known in the art. A humán antibody of the invention can be of any eláss (IgG, IgA, IgM, IgE, IgD, etc.) or isotype and can comprise a kappa or lambda light chain. In one embodiment, the humán antibody comprises an IgG heavy chain or defined fragment, fór example, at least one of isotypes, IgG 1, lgG2, lgG3 or lgG4 (e.g., γ1 ,□ γ2, γ3, or γ4). Antibodies of this type can be prepared by employing a transgenic mouse or other trangenic non-human mammal comprising at least one humán light chain (e.g., IgG, IgA, and IgM) transgenes as described herein and/or as known in the art. In another embodiment, theanti-human IL-23p19 antibody comprises an IgG 1 heavy chain and an IgG 1 light chain. [0084] At least one antibody disclosed herein at least one specified epitope specific to at least one IL-23p19 protein, subunit, fragment, portion or any combination thereof. The at least one epitope can comprise at least one antibody binding region that comprises at least one portion of the protein, which epitope is preferably comprised of at least one extracellular, soluble, hydrophillic, external or cytoplasmic portion ofthe protein. The at least one specified epitope can comprise any combination of at least one amino acid sequence of at least 1-3 amino acids to the entire specified portion of contiguous amino acids of amino acid residues 93-105 of SEQ ID NO:145 (that contains the initial 19 amino acid signal sequence fór the p19 protein subunit) (or amino acid residues 74-86 of the p19 sequence without inclusion of the signal sequence), fór example, amino acid residues 93, 93-94, 93-95, 93-96, 97-99, 100-102 of SEQ ID NO:145, etc. that include any portions or combinations of these sequences.

[0085] Generally, the antibody or antigen-binding fragment disclosed herein will comprise an antigen-binding region that comprises at least one complementarity determining region (CDR1, CDR2 and CDR3) or variant of at least one heavy chain variable region and at least one complementarity determining region (CDR1, CDR2 and CDR3) or variant ofat least one light chain variable region. Optionally, the CDR sequences may be derived from humán germline sequences or closely match the germline sequences. Fór example, the CDRs from a synthetic library derived from the original mouse CDRs can be used. As a non-limiting example, the antibody or antigen-binding portion or variant can comprise at least one ofthe heavy chain CDR3, e.g., selected from SEQ ID NOS: 1-6, 7-39 and 146, or 40-45, and/or a light chain CDR3, e.g., selected from SEQ ID NOS: SEQ ID NOS: 46-51,52-57, or 58-79. In a partícuíar embodiment, the antibody or antigen-binding fragment can have an antigen-binding region that comprises at least a portion ofat least one heavy chain CDR (i.e., CDR1, CDR2 and/or CDR3) (e.g., those disclosed herein). In another partícuíar embodiment, the antibody or antigen-binding portion or variant can have an antigen-binding region that comprises at least a portion of at least one light chain CDR (i.e., CDR1, CDR2 and/or CDR3) (e.g., those disclosed herein).

[0086] In a preferred embodiment, the three heavy chain CDRs and the three light chain CDRs of the antibody or antigen-binding fragment can be prepared by chemically joining together the various portions (e.g., CDRs, framework) ofthe antibody using conventional techniques, by preparing and expressing a (i.e., one or more) nucleic acid molecule that encodes the antibody using conventional techniques of recombinant DNA technology or by using any other suitable method.

[0087] The anti-1L-23p 19 antibody can comprise at least one of a heavy or light chain variable region having a defined amino acid sequence. Fór example, in a preferred embodiment, the anti-lL-23p19 antibody comprises at least one of at least one heavy chain variable region optionally selected from SEQ ID NOS: 80, 81,86-92, 99, 101, 103-112, 117-127, and 147 and/or at least one light chain variable region optionally selected from SEQ ID NOS: 82-85, 93-98, 100, 102, 113-116, and 128-132. Antibodies that bind to humán IL-23p19 and that comprise a defined heavy or light chain variable region can be prepared using suitable methods. The antibody, specified portion or variant can be expressed using the encoding nucleic acid or portion thereof in a suitable hőst cell.

Amino Acid Codes [0088] The amino acids that make up anti-l L-23p19 antibodies ofthe present invention are often abbreviated. The amino acid designations can be indicated by designating the amino acid by its single letter code, its three letter code, name, or three nucleotide codon(s) as is well understood in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994). An anti-IL-23p19 antibody ofthe present invention can include one or more amino acid substitutions, deletions or additions, either from natural mutations or humán manipulation, as specified herein. Amino acids in an anti-IL-23p19 antibody ofthe present invention that are essential fór function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (e.g., Ausubel, supra, Chapters8,15; Cunningham and Wells, Science 244:1081-1085(1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested fór biological

ΕΡ 2 548 577 Β1 activity, such as, bút nőt limited to, at least one IL-23 neutralizing activity. Sites that are critical fór antibody binding can alsó be identified by structural analysis, such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mól. Bioi. 224:899-904 (1992) and de Vos, et al., Science 255:306-312 (1992)).

[0089] Anti-1L-23p 19 antibodies disclosed herein can include, bút are nőt limited to, at least one portion, sequence or combination selected from 5 to all of the contiguous amino acids of the variable region sequences of SEQ ID NOS: 82-85, 93-98, 100, 102, 113-116, and 128-132 and SEQ ID NOS: 80, 81,86-92, 99, 101, 103-112, 117-127, and 147. [0090] Non-limiting variants that can enhance or maintain at least one ofthe listed activities include, bút are nőt limited to, any of the above polypeptides, further comprising at least one mutation corresponding to at least one substitution in the residues varied among the disclosed variant amino acid sequences.

[0091] An anti-IL-23p19 antibody can further optionally comprise a polypeptide with an amino acid sequence that varies from the sequences disclosed herein (e.g., one or more conservative substitutions from the sequences provided herein). Alsó, more specifically, disclosed herein are variants ofthe amino acid sequence of a Iight chain variable region of SEQ ID NOS: 82-85, 93-98, 100, 102, 113-116, and 128-132 or the amino acid sequence of a heavy chain variable region of SEQ ID NOS: 80, 81,86-92, 99, 101, 103-112, 117-127, and 147.

[0092] As those of skill will appreciate, the present invention includes at least one biologically active antibody of the present invention. Biologically active antibodies have a specific activity at least 20%, 30%, or 40%, and, preferahiy, at least 50%, 60%, or 70%, and, most preferahiy, at least 80%, 90%, or 95%-1000% or more of that of the native (nonsynthetic), endogenous or related and known antibody. Methods of assaying and quantifying measures of enzymatic activity and substrate specificity are well known to those of skill in the art.

[0093] In another aspect, the invention relates to humán antibodies and antigen-binding fragments, as described herein, which are modified by the covalent attachment of an organic moiety. Such modification can produce an antibody or antigen-binding fragment with improved pharmacokinetic properties (e.g., increased in vivő serum half-life). The organic moiety can be a linear or branched hydrophilic polymeric group, fatty acid group, or fatty acid ester group. In particuiar embodiments, the hydrophilic polymeric group can have a molecular weight of about 800 to about 120,000 Daltons and can be a polyalkane glycol (e.g., polyethylene glycol (PEG), polypropylene glycol (PPG)), carbohydrate poíymer, amino acid poíymer or polyvinyl pyrolidone, and the fatty acid or fatty acid ester group can comprise from about eight to about forty earbon atorns.

[0094] The modified antibodies and antigen-binding fragments of the invention can comprise one or more organic moieties that are covalently bonded, directly or indirectly, to the antibody. Each organic moiety that is bonded to an antibody or antigen-binding fragment of the invention can independently be a hydrophilic polymeric group, a fatty acid group or a fatty acid ester group. As used herein, the term fatty acid encompasses mono-carboxylic acids and dicarboxylic acids. A hydrophilic polymeric group, as the term is used herein, refers to an organic poíymer that is more soluble in water than in octane. Fór example, polylysine is more soluble in water than in octane. Thus, an antibody modified by the covalent attachment of polylysine is encompassed by the invention. Hydrophilic polymers suitable fór modifying antibodies ofthe invention can be linear or branched and include, fór example, polyalkane glyeols (e.g., PEG, monomethoxy-polyethylene glycol (mPEG), PPG and the like), carbohydrates (e.g., dextran, cellulose, oligosaccharides, polysaccharides and the like), polymers of hydrophilic amino acids (e.g., polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g., polyethylene oxide, polypropylene oxide and the like) and polyvinyl pyrolidone. Preferahiy, the hydrophilic poíymer that modifies the antibody ofthe invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecular entity. Fór example, PEG₅₀₀₀ and PEG₂oooO’ wherein the subseript is the average molecular weight ofthe poíymer in Daltons, can be used. The hydrophilic polymeric group can be substituted with one to about six alkyl, fatty acid or fatty acid ester groups. Hydrophilic polymers that are substituted with a fatty acid or fatty acid ester group can be prepared by employing suitable methods. Fór example, a poíymer comprising an amine group can be coupled to a carboxylate ofthe fatty acid or fatty acid ester, and an activated carboxylate (e.g., activated with N, N-carbonyl diimidazole) on a fatty acid or fatty acid ester can be coupled to a hydroxyl group on a poíymer.

[0095] Fatty acids and fatty acid esters suitable fór modifying antibodies of the invention can be saturated or can contain one or more units of unsaturation. Fatty acids that are suitable fór modifying antibodies ofthe invention include, fór example, n-dodecanoate (C₁₂, laurate), n-tetradecanoate (C₁₄, myristate), n-octadecanoate (C₁₈, stearate), n-eicosanoate (C₂₀, arachidate), n-docosanoate (C₂₂, behenate), n-triacontanoate (C₃₀), n-tetracontanoate (C₄₀), c/s-A9octadecanoate (C₁₈, oleate), all c/s-A5,8,11,14-eicosatetraenoate (C₂₀, arachidonate), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid, and the like. Suitable fatty acid esters include mono-esters of dicarboxylic acids that comprise a linear or branched lower alkyl group. The lower alkyl group can comprise from one to about twelve, preferahiy, one to about six, earbon atorns.

[0096] The modified humán antibodies and antigen-binding fragments can be prepared using suitable methods, such as by reaction with one or more modifying agents. A modifying agent as the term is used herein, refers to a suitable organic group (e.g., hydrophilic poíymer, a fatty acid, a fatty acid ester) that comprises an activating group. An activating group is a Chemical moiety or functional group that can, under appropriate conditions, react with a second Chemical group thereby forming a covalent bond between the modifying agent and the second Chemical group. Fór example,

ΕΡ 2 548 577 Β1 amine-reactive activating groups include electrophilic groups, such as tosylate, mesylate, haló (chloro, bromo, fluoro, iodo), N-hydroxysuccinimidyl esters (NHS), and the like. Activating groups that can react with thiols include, forexample, maleimide, iodoacetyl, acrylolyl, pyridyl disulfides, 5-thiol-2-nitrobenzoic acid thiol (TNB-thiol), and the like. An aldehyde functional group can be coupled to amine- or hydrazide-containing molecules, and an azide group can react with a trivalent phosphorous group to form phosphoramidate or phosphorimide linkages. Suitable methods to introduce activating groups intő molecules are known in the art (see fór example, Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA(1996)). An activating group can be bonded directly to the organic group (e.g., hydrophilic poíymer, fatty acid, fatty acid ester), or through a linker moiety, fór example, a divalent group wherein one or more carbon atoms can be replaced by a heteroatom, such as oxygen, nitrogén orsulfur. Suitable linker moieties include, forexample, tetraethylene glycol,-(CH₂)₃-, -NH-(CH₂)₆-NH-, -(CH₂)₂-NH- and -CH₂-O-CH₂-CH₂-O-CH₂-CH₂-O-CH-NH-. Modifying agents that comprise a linker moiety can be produced, fór example, by reacting a mono-Boc-alkyldiamine (e.g., mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with a fatty acid in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to form an amidé bond between the free amine and the fatty acid carboxylate. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to expose a primary amine that can be coupled to another carboxylate, as described, orcán be reacted with maleicanhydride and the resulting product cyclized to produce an activated maleimido derivative ofthe fatty acid. (See, fór example, Thompson, et al., WO 92/16221) [0097] The modified antibodies of the invention can be produced by reacting a humán antibody or antigen-binding fragment with a modifying agent. Fór example, the organic moieties can be bonded to the antibody in a non-site specific manner by employing an amine-reactive modifying agent, fór example, an NHS ester ofPEG. Modified humán antibodies or antigen-binding fragments can alsó be prepared by reducing disulfide bonds (e.g., intra-chain disulfide bonds) of an antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment can then be reacted with a thiol-reactive modifying agent to produce the modified antibody ofthe invention. Modified humán antibodies and antigenbinding fragments comprising an organic moiety that is bonded to specific sites of an antibody ofthe present invention can be prepared using suitable methods, such as reverse proteolysis (Fisch et al., Biocohjugate Chem., 3:147-153 (1992); Werlen etal., Bioconjugate Chem., 5:411-417(1994); Kumaran etal., Protein Sci. 6(10):2233-2241 (1997); ltoh et al., Bioorg. Chem., 24(1): 59-68 (1996); Capellas et al., Biotechnoi. Bioeng., 56(4):456-463 (1997)), and the methods described in Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996).

Anti-ldiotype Antibodies to Anti-IL-23p19 Antibody Compositions [0098] In addition to monoclonal anti-IL-23p19 antibodies an anti-idiotypic (anti-ld) antibody specific fór such antibodies ofthe invention is alsó disclosed. An anti-ld antibody is an antibody which recognizes unique determinants generally associated with the antigen-binding region of another antibody. The anti-ld can be prepared by immunizing an animal of the same species and genetic type (e.g., mouse strain) as the source of the Id antibody with the antibody or a CDR containing region thereof. The immunized animal will recognize and respond to the idiotypic determinants ofthe immunizing antibody and produce an anti-ld antibody. The anti-ld antibody may alsó be used as an immunogen to induce an immuné response in yet another animal, producing a so-called anti-anti-ld antibody.

[0099] Alsó disclosed is at least one anti-lL-23p19 antibody composition comprising at least one, at least two, at least three, at least four, at least five, at least six or more anti-IL-23p19 antibodies thereof, as described herein and/or as known in the art that are provided in a non-naturally occurring composition, mixture orform. Such compositions comprise non-naturally occurring compositions comprising at least one or two full length, C- and/or N-terminally deleted variants, domains, fragments, or specified variants, ofthe anti-IL-23p19 antibody amino acid sequence selected from the group consisting of 70-100% of the contiguous amino acids of SEQ ID NOS:1-132, 146, and 147, or specified fragments, domains or variants thereof. Preferred anti-IL-23p19 antibody compositions include at least one or two full length, fragments, domains or variants of at least one CDR or LBP containing portions of the anti-lL-23p19 antibody sequence described herein, forexample, 70-100% of SEQ ID NOS: 1-132,146, and 147, or specified fragments, domains or variants thereof. Further preferred compositions comprise, forexample, 40-99% of at least one of 70-100% of SEQ ID NOS: 1-132, 146, and 147, orspecified fragments, domains orvariants thereof. Such composition percentages are by weight, volume, concentration, molarity, or molality as liquid or dry Solutions, mixtures, suspension, emulsions, particles, powder, or colloids, as known in the art or as described herein.

Antibody Compositions Comprising Further Therapeutically Active Ingredients [0100] The antibody compositions ofthe invention can optionally further comprise an effective amount of at least one compound or protein selected from at least one of an anti-infective drug, a cardiovascular (CV) system drug, a Central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (Gl) tract drug, a hormonal drug, a drug fór fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immu18

ΕΡ 2 548 577 Β1 nomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like. Such drugs are well known in the art, including formulations, indications, dosing and administration fór each presented herein (see, e.g., Nursing 2001 Handbook of Drugs, 21st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ; Pharmcotherapy Handbook, Wells et al., ed., Appleton & Lángé, Stamford, CT).

[0101] The anti-infective drug can be at least one selected from amebicides or at least one of antiprotozoals, anthelmintics, antifungals, antimalarials, antituberculotics or at least one antileprotics, aminoglycosides, penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones, antivirals, macrolide anti-infectives, and miscellaneous antiinfectives. The CV drug can be at least one selected from inotropics, antiarrhythmics, antianginals, antihypertensives, antilipemics, and miscellaneous cardiovascular drugs. The CNS drug can be at least one selected from nonnarcotic analgesics or at least one selected from antipyretics, nonsteroidal anti-inflammatory drugs, narcotic or at least one opiod analgesics, sedative-hypnotics, anticonvulsants, antidepressants, antianxiety drugs, antipsychotics, Central nervous system stimulants, antiparkinsonians, and miscellaneous Central nervous system drugs. The ANS drug can be at least one selected from cholinergics (parasympathomimetics), anticholinergics, adrenergics (sympathomimetics), adrenergic blockers (sympatholytics), skeletal muscle relaxants, and neuromuscular blockers. The respiratory tract drug can be at least one selected from antihistamines, bronchodilators, expectorants or at least one antitussive, and miscellaneous respiratory drugs. The Gl tract drug can be at least one selected from antacids or at least one adsorbent or at least one antiflatulent, digestive enzyme or at least one gallstone solubilizer, antidiarrheals, laxatives, antiemetics, and antiulcer drugs. The hormonal drug can be at least one selected from corticosteroids, androgens or at least one anabolic steroid, estrogen or at least one progestin, gonadotropin, antidiabetic drug or at least one glucagon, thyroid hormoné, thyroid hormoné antagonist, pituitary hormoné, and parathyroid-like drug. The drug fór fluid and electrolyte balance can be at least one selected from diuretics, electrolytes or at least one replacement solution, acidifier or at least one alkalinizer. The hematologic drug can be at least one selected from hematinics, anticoagulants, blood derivatives, and thrombolytic enzymes. The antineoplastics can be at least one selected from alkylating drugs, antimetabolites, antibiotic antineoplastics, antineoplastics that altér hormoné balance, and miscellaneous antineoplastics. The immunomodulation drug can be at least one selected from immunosuppressants, vaccines or at least one toxoid, antitoxin or at least one antivenin, immuné serum, and biological response modifier. The ophthalmic, otic, and nasal drugs can be at least one selected from ophthalmic anti-infectives, ophthalmic antiinflammatories, miotics, mydriatics, ophthalmic vasoconstrictors, miscellaneous ophthalmics, otics, and nasal drugs. The topical drug can be at least one selected from local anti-infectives, scabicides or at least one pediculicide or topical corticosteroid. The nutritional drug can be at least one selected from vitamins, minerals, or calorics. See, e.g., contents of Nursing 2001 Drug Handbook, supra.

[0102] The at least one amebicide or antiprotozoal can be at least one selected from atovaquone, chloroquine hydrochloride, chloroquine phosphate, metronidazole, metronidazole hydrochloride, and pentamidine isethionate. The at least one anthelmintic can be at least one selected from mebendazole, pyrantel pamoate, and thiabendazole. The at least oneantifungal can be at least one selected from amphotericin B, amphotericin B cholesteryl sulfate complex, amphotericin B lipid complex, amphotericin B liposomal, fluconazole, flucytosine, griseofulvin microsize, griseofulvin ultramicrosize, itraconazole, ketoconazole, nystatin, and terbinafine hydrochloride. The at least one antimalarial can be at least one selected from chloroquine hydrochloride, chloroquine phosphate, doxycycline, hydroxychloroquine sulfate, mefloquine hydrochloride, primaquine phosphate, pyrimethamine, and pyrimethamine with sulfadoxine. The at least one antituberculotic or antileprotic can be at least one selected from clofazimine, cycloserine, dapsone, ethambutol hydrochloride, isoniazid, pyrazinamide, rifabutin, rifampin, rifapentine, and streptomycin sulfate. The at least one aminoglycoside can be at least one selected from amikacin sulfate, gentamicin sulfate, neomycin sulfate, streptomycin sulfate, and tobramycin sulfate. The at least one penicillin can be at least one selected from amoxcillin/clavulanate potassium, amoxicillin trihydrate, ampicillin, ampicillin sodium, ampicillin trihydrate, ampicillin sodium/sulbactam sodium, cloxacillin sodium, dicloxacillin sodium, mezlocillin sodium, nafcillin sodium, oxacillin sodium, penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V potassium, piperacillin sodium, piperacillin sodium/tazobactam sodium, ticarcillin disodium, and ticarcillin disodium/clavulanate potassium. The at least one cephalosporin can be at least one selected from cefaclor, cefadroxil, cefazolin sodium, cefdinir, cefepime hydrochloride, cefixime, cefmetazole sodium, cefonicid sodium, cefoperazone sodium, cefotaximesodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoximesodium, ceftriaxonesodium, cefuroxime axetil, cefuroximesodium, cephalexin hydrochloride, cephalexin monohydrate, cephradine, and loracarbef. The at least one tetracycline can be at least one selected from demeclocycline hydrochloride, doxycycline calcium, doxycycline hyclate, doxycycline hydrochloride, doxycycline monohydrate, minocycline hydrochloride, and tetracycline hydrochloride. The at least one sulfonamide can be at least one selected from co-trimoxazole, sulfadiazine, sulfamethoxazole, sulfisoxazole, and sulfisoxazole acetyl. The at least one fluoroquinolone can be at least one selected from alatrofloxacin mesylate, ciprofloxacin, enoxacin, levofloxacin, lomefloxacin hydrochloride, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, and trovafloxacin mesylate. The at least one fluoroquinolone can be at least one selected from alatrofloxacin mesylate, ciprofloxacin, enoxacin, levofloxacin, lomefloxacin hydrochloride, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, and trovafloxacin mesylate.

ΕΡ 2 548 577 Β1

The at least one antiviral can be at least one selected from abacavir sulfate, acyclovir sodium, amantadine hydrochloride, amprenavir, cidofovir, delavirdine mesylate, didanosine, efavirenz, famciclovir, fomivirsen sodium, foscarnet sodium, ganciclovir, indinavir sulfate, lamivudine, lamivudine/zidovudine, nelfinavir mesylate, nevirapine, oseltamivir phosphate, ribavirin, rimantadine hydrochloride, ritonavir, saquinavir, saquinavir mesylate, stavudine, valacyclovir hydrochloride, zalcitabine, zanamivir, and zidovudine. The at least one macro line anti-infective can be at least one selected from azithromycin, clarithromycin, dirithromycin, erythromycin base, erythromycin estolate, erythromycin ethylsuccinate, erythromycin lactobionate, and erythromycin stearate. The at least one miscellaneous anti-infective can be at least one selected from aztreonam, bacitracin, chloramphenicol sodium sucinate, clindamycin hydrochloride, clindamycin palmitate hydrochloride, clindamycin phosphate, imipenem and cilastatin sodium, meropenem, nitrofurantoin macrocrystals, nitrofurantoin microcrystals, quinupristin/dalfopristin, spectinomycin hydrochloride, trimethoprim, and vancomycin hydrochloride. (See, e.g., pp. 24-214 of Nursing 2001 Drug Handbook.) [0103] The at least one inotropic can be at least one selected from amrinone lactate, digoxin, and milrinone lactate. The at least one antiarrhythmiccan be at least one selected from adenosine, amiodarone hydrochloride, atropiné sulfate, bretylium tosylate, diltiazem hydrochloride, disopyramide, disopyramide phosphate, esmolol hydrochloride, flecainide acetate, ibutilidefumarate, lidocaine hydrochloride, mexiletine hydrochloride, moricizine hydrochloride, phenytoin, phenytoin sodium, procainamide hydrochloride, propafenone hydrochloride, propranolol hydrochloride, quinidine bisulfate, quinidine gluconate, quinidine polygalacturonate, quinidine sulfate, sotalol, tocainide hydrochloride, and verapamil hydrochloride. The at least one antianginal can be at least one selected from amlodipidine besylate, amyl nitrite, bepridil hydrochloride, diltiazem hydrochloride, isosorbide dinitrate, isosorbide mononitrate, nadolol, nicardipine hydrochloride, nifedipine, nitroglycerin, propranolol hydrochloride, verapamil, and verapamil hydrochloride. The at least one antihypertensive can be at least one selected from acebutolol hydrochloride, amlodipine besylate, atenolol, benazepril hydrochloride, betaxolol hydrochloride, bisoprolol fumarate, candesartan cilexetil, captopril, carteolol hydrochloride, carvedilol, clonidine, clonidine hydrochloride, diazoxide, diltiazem hydrochloride, doxazosin mesylate, enalaprilat, enalapril maleate, eprosartan mesylate, felodipine, fenoldopam mesylate, fosinopril sodium, guanabenz acetate, guanadrel sulfate, guanfacine hydrochloride, hydralazine hydrochloride, irbesartan, isradipine, labetalol hydrchloride, lisinopril, losartan potassium, methyldopa, methyldopate hydrochloride, metoprolol succinate, metoprolol tartrate, minoxidil, moexipril hydrochloride, nadolol, nicardipine hydrochloride, nifedipine, nisoldipine, nitroprusside sodium, penbutolol sulfate, perindopril erbumine, phentolamine mesylate, pindolol, prazosin hydrochloride, propranolol hydrochloride, quinapril hydrochloride, ramipril, telmisartan, terazosin hydrochloride, timolol maleate, trandolapril, valsartan, and verapamil hydrochloride. The at least one antilipemic can be at least one selected from atorvastatin calcium, cerivastatin sodium, cholestyramine, colestipol hydrochloride, fenofibrate (micronized), fluvastatin sodium, gemfibrozil, lovastatin, niacin, pravastatin sodium, and simvastatin. The at least one miscellaneous CV drug can be at least one selected from abciximab, alprostadil, arbutamine hydrochloride, cilostazol, clopidogrel bisulfate, dipyridamole, eptifibatide, midodrine hydrochloride, pentoxifylline, ticlopidine hydrochloride, and tirofiban hydrochloride. (See, e.g., pp. 215-336 of Nursing 2001 Drug Handbook.) [0104] The at least one nonnarcotic analgesic or antipyretic can be at least one selected from acetaminophen, aspirin, choline magnesium trisalicylate, diflunisal, and magnesium salicylate. The at least one nonsteroidal anti-inflammatory drug can be at least one selected from celecoxib, diclofenac potassium, diclofenac sodium, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, indomethacin sodium trihydrate, ketoprofen, ketorolac tromethamine, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, and sulindac. The at least one narcotic or opiod analgesic can be at least one selected from alfentanil hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, codeine phosphate, codeine sulfate, fentanyl citrate, fentanyl transdermal system, fentanyl transmucosal, hydromorphone hydrochloride, meperidine hydrochloride, methadone hydrochloride, morphine hydrochloride, morphine sulfate, morphine tartrate, nalbuphine hydrochloride, oxycodone hydrochloride, oxycodone pectinate, oxymorphone hydrochloride, pentazocine hydrochloride, pentazocine hydrochloride and naloxone hydrochloride, pentazocine lactate, propoxyphene hydrochloride, propoxyphene napsylate, remifentanil hydrochloride, sufentanil citrate, and tramadol hydrochloride. The at least one sedative-hypnotic can be at least one selected from chloral hydrate, estazolam, flurazepam hydrochloride, pentobarbital, pentobarbital sodium, phenobarbital sodium, secobarbital sodium, temazepam, triazolam, zaleplon, and zolpidem tartrate. The at least one anticonvulsant can be at least one selected from acetazolamide sodium, carbamazepine, clonazepam, clorazepate dipotassium, diazeparn, divalproex sodium, ethosuximde, fosphenytoin sodium, gabapentin, lamotrigine, magnesium sulfate, phenobarbital, phenobarbital sodium, phenytoin, phenytoin sodium, phenytoin sodium (extended), primidone, tiagabine hydrochloride, topiramate, valproate sodium, and valproic acid. The at least one antidepressant can be at least one selected from amitriptyline hydrochloride, amitriptyline pamoate, amoxapine, bupropion hydrochloride, citalopram hydrobromide, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine hydrochloride, imipramine hydrochloride, imipramine pamoate, mirtazapine, nefazodone hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phenelzine sulfate, sertraline hydrochloride, tranylcypromine sulfate, trimipramine maleate, and venlafaxine hydrochloride. The at least one antianxiety drug can be at least one selected from alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazeparn, doxepin hydrochloride, hydroxyzine embonate, hydroxyzine hydrochloride, hydroxyzine

ΕΡ 2 548 577 Β1 pamoate, lorazepam, mephrobamate, midazolam hydrochloride, and oxazepam. The at least one antipsychotic drug can be at least one selected from chlorpromazine hydrochloride, clozapine, fluphenazine decanoate, fluephenazine enanthate, fluphenazine hydrochloride, haloperidol, haloperidol decanoate, haloperidol lactate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, olanzapine, perphenazine, pimozide, prochlorperazine, quetiapine fumarate, risperidone, thioridazine hydrochloride, thiothixene, thiothixene hydrochloride, and trifluoperazine hydrochloride. The at leastone Central nervous system stimulant can be at leastone selected from amphetamine sulfate, caffeine, dextroamphetamine sulfate, doxapram hydrochloride, methamphetamine hydrochloride, methylphenidate hydrochloride, modafinil, pemoline, and phentermine hydrochloride. The at least one antiparkinsonian can be at least one selected from amantadine hydrochloride, benztropine mesylate, biperiden hydrochloride, biperiden lactate, bromocriptine mesylate, carbidopa-levodopa, entacapone, levodopa, pergolide mesylate, pramipexole dihydrochloride, ropinirole hydrochloride, selegiline hydrochloride, tolcapone, and trihexyphenidyl hydrochloride. The at least one miscellaneous Central nervous system drug can be at least one selected from bupropion hydrochloride, donepezil hydrochloride, droperidol, fluvoxamine maleate, lithium carbonate, lithium citrate, naratriptan hydrochloride, nicotine polacrilex, nicotine transdermal system, propofol, rizatriptan benzoate, sibutramine hydrochloride monohydrate, sumatriptan succinate, tacrine hydrochloride, and zolmitriptan. (See, e.g., pp. 337-530 of Nursing 2001 Drug HandbookJ [0105] The at least one cholinergic (e.g., parasymathomimetic) can be at least one selected from bethanechol chloride, edrophonium chloride, neostigmine bromide, neostigmine methylsulfate, physostigmine salicylate, and pyridostigmine bromide. The at least one anticholinergic can be at least one selected from atropiné sulfate, dicyclomine hydrochloride, glycopyrrolate, hyoscyamine, hyoscyamine sulfate, propantheline bromide, scopolamine, scopolamine butylbromide, and scopolamine hydrobromide. The at least one adrenergic (sympathomimetics) can be at least one selected from dobutamine hydrochloride, dopamine hydrochloride, metaraminol bitartrate, norepinephrine bitartrate, phenylephrine hydrochloride, pseudoephedrine hydrochloride, and pseudoephedrine sulfate. The at leastone adrenergic blocker (sympatholytic) can be at least one selected from dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, and propranolol hydrochloride. The at least one skeletal muscle relaxant can be at least one selected from baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine hydrochloride, dantrolene sodium, methocarbamol, and tizanidine hydrochloride. The at least one neuromuscular blocker can be at least one selected from atracurium besylate, cisatracurium besylate, doxacurium chloride, mivacurium chloride, pancuronium bromide, pipecuronium bromide, rapacuronium bromide, rocuronium bromide, succinylcholine chloride, tubocurarine chloride, and vecuronium bromide. (See, e.g., pp. 531-84 of Nursing 2001 Drug HandbookJ [0106] The at least one antihistamine can be at least one selected from brompheniramine maleate, cetirizine hydrochloride, chlorpheniramine maleate, clemastine fumarate, cyproheptadine hydrochloride, diphenhydramine hydrochloride, fexofenadine hydrochloride, loratadine, promethazine hydrochloride, promethazine theoclate, and triprolidine hydrochloride. The at leastone bronchodilator can be at least one selected from albuterol, albuterol sulfate, aminophylline, atropiné sulfate, ephedrine sulfate, epinephrine, epinephrine bitartrate, epinephrine hydrochloride, ipratropium bromide, isoproterenol, isoproterenol hydrochloride, isoproterenol sulfate, levalbuterol hydrochloride, metaproterenol sulfate, oxtriphylline, pirbuterol acetate, salmeterol xinafoate, terbutaline sulfate, and theophylline. The at least one expectorant or antitussive can be at least one selected from benzonatate, codeine phosphate, codeine sulfate, dextramethorphan hydrobromide, diphenhydramine hydrochloride, guaifenesin, and hydromorphone hydrochloride. The at leastone miscellaneous respiratory drug can be at least one selected from acetylcysteine, beclomethasone dipropionate, beractant, budesonide, calfactant, cromolyn sodium, dornase alfa, epoprostenol sodium, flunisolide, fluticasone propionate, montelukast sodium, nedocromil sodium, palivizumab, triamcinolone acetonide, zafirlukast, and zileuton. (See, e.g., pp. 585-642 of Nursing 2001 Drug HandbookJ [0107] The at least one antacid, adsorbent, or antiflatulent can be at least one selected from aiuminum carbonate, aiuminum hydroxide, calcium carbonate, magaldrate, magnesium hydroxide, magnesium oxide, simethicone, and sodium bicarbonate. The at least one digestive enzyme or gallstone solubilizer can be at least one selected from pancreatin, pancrelipase, and ursodiol. The at least one antidiarrheal can be at least one selected from attapulgite, bismuth subsalicylate, calcium polycarbophil, diphenoxylate hydrochloride and atropiné sulfate, loperamide, octreotide acetate, ópium tincture, and ópium tincure (camphorated). The at least one laxative can be at least one selected from bisocodyl, calcium polycarbophil, cascarasagrada, cascara sagrada aromaticfluidextract, cascara sagradafluidextract, castoroil, docusate calcium, docusate sodium, glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesium sulfate, methylcellulose, mineral oil, polyethylene glyeol or eleetrolyte solution, psyllium, senna, and sodium phosphates. The at least one antiemetic can be at leastone selected from chlorpromazine hydrochloride, dimenhydrinate, dolasetron mesylate, dronabinol, granisetron hydrochloride, meclizine hydrochloride, metocloproamide hydrochloride, ondansetron hydrochloride, perphenazine, prochlorperazine, prochlorperazine edisylate, prochlorperazine maleate, promethazine hydrochloride, scopolamine, thiethylperazine maleate, and trimethobenzamide hydrochloride. The at leastone antiulcerdrug can be at least one selected from cimetidine, cimetidine hydrochloride, famotidine, lansoprazole, misoprostol, nizatidine, omeprazole, rabeprozolesodium, rantidine bismuth citrate, ranitidine hydrochloride, and sucralfate. (See, e.g., pp. 643-95 of Nursing 2001 Drug HandbookJ

EP 2 548 577 Β1 [0108] The at least one corticosteroid can be at least one selected from betamethasone, betamethasone acetate or betamethasone sodium phosphate, betamethasone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, fludrocortisone acetate, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, prednisone, triamcinolone, triamcinolone acetonide, and triamcinolone diacetate. The at least one androgen or anabolic steroid can be at least one selected from danazol, fluoxymesterone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, testosterone, testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone transdermal system. The at least one estrogen or progestin can be at least one selected from esterified estrogens, estradiol, estradiol cypionate, estradiol/norethindrone acetate transdermal system, estradiol valerate, estrogens (conjugated), estropipate, ethinyl estradiol, ethinyl estradiol and desogestrel, ethinyl estradiol and ethynodiol diacetate, ethinyl estradiol and desogestrel, ethinyl estradiol and ethynodiol diacetate, ethinyl estradiol and levonorgestrel, ethinyl estradiol and norethindrone, ethinyl estradiol and norethindrone acetate, ethinyl estradiol and norgestimate, ethinyl estradiol and norgestrel, ethinyl estradiol and norethindrone and acetate andferrousfumarate, levonorgestrel, medroxyprogesterone acetate, mestranol and norethindron, norethindrone, norethindrone acetate, norgestrel, and progesterone. The at least one gonadroptropin can be at least one selected from ganirelix acetate, gonadoreline acetate, histrelin acetate, and menotropins. The at least one antidiabetic or glucaon can be at least one selected from acarbose, chlorpropamide, glimepiride, glipizide, glucagon, glyburide, insulins, metformin hydrochloride, miglitol, pioglitazone hydrochloride, repaglinide, rosiglitazone maleate, and troglitazone. The at least one thyroid hormoné can be at least one selected from levothyroxine sodium, liothyronine sodium, liotrix, and thyroid. The at least one thyroid hormoné antagonist can be at least one selected from methimazole, potassium iodide, potassium iodide (saturated solution), propylthiouracil, radioactive iodine (sodium iodide ¹³¹1), and strong iodine solution. The at least one pituitary hormoné can be at least one selected from corticotropin, cosyntropin, desmophressin acetate, leuprolide acetate, repository corticotropin, somatrem, somatropin, and vasopressin. The at least one parathyroid-like drug can be at least one selected from calcifediol, calcitonin (humán), calcitonin (salmon), calcitriol, dihydrotachysterol, and etidronate disodium. (See, e.g., pp. 696-796 of Nursing 2001

Drug Handbook.) [0109] The at least one diuretic can be at least one selected from acetazolamide, acetazolamide sodium, amiloride hydrochloride, bumetanide, chlorthalidone, ethacrynate sodium, ethacrynic acid, furosemide, hydrochlorothiazide, indapamide, mannitol, metolazone, spironolactone, torsemide, triamterene, and urea. The at least one electrolyte or replacement solution can be at least one selected from calcium acetate, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, calcium lactate, calcium phosphate (dibasic), calcium phosphate (tribasic), dextran (high-molecular-weight), dextran (low-molecular-weight), hetastarch, magnesium chloride, magnesium sulfate, potassium acetate, potassium bicarbonate, potassium chloride, potassium gluconate, Ringer’s injection, Ringer’s injection (lactated), and sodium chloride. The at least one acidifier or alkalinizer can be at least one selected from sodium bicarbonate, sodium lactate, and tromethamine. (See, e.g., pp. 797-833 of Nursing 2001 Drug Handbook.J [0110] The at least one hematinic can be at least one selected from ferrous fumarate, ferrous gluconate, ferrous sulfate, ferrous sulfate (dried), írón dextran, írón sorbitol, polysaccharide-iron complex, and sodium ferric gluconate complex. The at least one anticoagulant can be at least one selected from ardeparin sodium, dalteparin sodium, danaparoid sodium, enoxaparin sodium, heparin calcium, heparin sodium, and warfarin sodium. The at least one blood derivative can be at least one selected from albumin 5%, albumin 25%, antihemophilic factor, anti-inhibitor coagulant complex, antithrombin Ili (humán), factor IX (humán), factor IX complex, and plasma protein fractions. The at least one thrombolytic enzyme can be at least one selected from alteplase, anistreplase, reteplase (recombinant), streptokinase, and urokinase. (See, e.g., pp. 834-66 of Nursing 2001 Drug Handbook.J [0111] The at least one alkylating drug can be at least one selected from busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, lomustine, mechlorethamine hydrochloride, melphalan, melphalan hydrochloride, streptozocin, temozolomide, and thiotepa. The at least one antimetabolite can be at least one selected from capecitabine, cladribine, cytarabine, floxuridine, fludarabine phosphate, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, methotrexate sodium, and thioguanine. The at least one antibiotic antineoplastic can be at least one selected from bleomycin sulfate, dactinomycin, daunorubicin citrate liposomal, daunorubicin hydrochloride, doxorubicin hydrochloride, doxorubicin hydrochloride liposomal, epirubicin hydrochloride, idarubicin hydrochloride, mitomycin, pentostatin, plicamycin, and valrubicin. The at least one antineoplastic that alters hormoné balance can be at least one selected from anastrozole, bicalutamide, estramustine phosphate sodium, exemestane, flutamide, goserelin acetate, letrozole, leuprolide acetate, megestrol acetate, nilutamide, tamoxifen citrate, testolactone, and toremifene citrate. The at least one miscellaneous antineoplastic can be at least one selected from asparaginase, bacillus Calmette-Guerin (BCG) (live intravesical), dacarbazine, docetaxel, etoposide, etoposide phosphate, gemcitabine hydrochloride, irinotecan

ΕΡ 2 548 577 Β1 hydrochloride, mitotane, mitoxantrone hydrochloride, paclitaxel, pegaspargase, porfimer sodium, procarbazine hydrochloride, rituximab, teniposide, topotecan hydrochloride, trastuzumab, tretinoin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. (See, e.g., pp. 867-963 of Nursing 2001 Drug Handbook.) [0112] The at leastone immunosuppressant can be at leastone selected from azathioprine, basiliximab, cyclosporine, daclizumab, lymphocyte immuné globulin, muromonab-CD3, mycophenolate mofetil, mycophenolate mofetil hydrochloride, sirolimus, and tacrolimus. The at least one vaccine ortoxoid can be at leastone selected from BCG vaccine, cholera vaccine, diphtheria and tetanus toxoids (adsorbed), diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed, diphtheria and tetanus toxoids and whole-cell pertussis vaccine, Haemophilius b conjugate vaccines, hepatitis A vaccine (inactivated), hepatisis B vaccine (recombinant), influenza vírus vaccine 1999-2000 trivalent types A & B (purified surface antigén), influenza vírus vaccine 1999-2000 trivalent types A & B (subvirion or purified subvirion), influenza vírus vaccine 1999-2000 trivalent types A & B (whole virion), Japanese encephalitis vírus vaccine (inactivated), Lyme disease vaccine (recombinant OspA), measles and mumps and rubellá vírus vaccine (live), measles and mumps and rubellá vírus vaccine (live attenuated), measles vírus vaccine (live attenuated), meningococcal polysaccharide vaccine, mumps vírus vaccine (live), plague vaccine, pneumococcal vaccine (polyvalent), poliovirus vaccine (inactivated), poliovirus vaccine (live, órai, trivalent), rabies vaccine (adsorbed), rabies vaccine (humán diploid cell), rubellá and mumps vírus vaccine (live), rubellá vírus vaccine (live, attenuated), tetanus toxoid (adsorbed), tetanus toxoid (fluid), typhoid vaccine (órai), typhoid vaccine (parenteral), typhoid Vi polysaccharide vaccine, varicella vírus vaccine, and yellow fever vaccine. The at leastone antitoxin orantivenin can be at leastone selected from black widow spider antivenin, Crotalidae antivenom (polyvalent), diphtheria antitoxin (equine), amd Micrurus fulvius antivenin. The at least one immuné serum can be at least one selected from cytomegalovirus immuné globulin (intraveneous), hepatitis B immuné globulin (humán), immuné globulin intramuscular, immuné globulin intravenous, rabies immuné globulin (humán), respiratory syncytial vírus immuné globulin intravenous (humán), Rho(D) immuné globulin (humán), Rho(D) immuné globulin intravenous (humán), tetanus immuné globulin (humán), and varicella-zoster immuné globulin. The at least one biological response modifier can be at least one selected from aldesleukin, epoetin alfa, filgrastim, glatiramer acetate fór injection, interferon alfacon-1, interferon alfa-2a (recombinant), interferon alfa-2b (recombinant), interferon beta-1a, interferon beta-1b (recombinant), interferon gamma-1b, levamisole hydrochloride, oprelvekin, and sargramostim. (See, e.g., pp. 964-1040 of Nursing 2001 Drug Handbook.) [0113] The at least one ophthalmic anti-infective can be selected form bacitracin, chloramphenicol, ciprofloxacin hydrochloride, erythromycin, gentamicin sulfate, ofloxacin 0.3%, polymyxin B sulfate, sulfacetamide sodium 10%, sulfacetamide sodium 15%, sulfacetamide sodium 30%, tobramycin, and vidarabine. The at leastone ophthalmic anti-inflammatory can be at leastone selected from dexamethasone, dexamethasone sodium phosphate, diclofénac sodium 0.1 %, fluorometholone, flurbiprofen sodium, kétorolac tromethamine, prednisolone acetate (suspension) and prednisolone sodium phosphate (solution). The at leastone miotic can be at leastone selected from acetylocholine chloride, carbachol (intraocular), carbachol (topical), echothiophate iodide, pilocarpine, pilocarpine hydrochloride, and pilocarpine nitráté. The at least one mydriatic can be at least one selected from atropiné sulfate, cyclopentolate hydrochloride, epinephrine hydrochloride, epinephryl borate, homatropine hydrobromide, phenylephrine hydrochloride, scopolamine hydrobromide, and tropicamide. The at least one ophthalmic vasoconstrictor can be at leastone selected from naphazoline hydrochloride, oxymetazoline hydrochloride, and tetrahydrozoline hydrochloride. The at least one miscellaneous ophthalmic can be at leastone selected from apraclonidine hydrochloride, betaxolol hydrochloride, brimonidine tartrate, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, emedastinedifumarate.fluorescein sodium, ketotifenfumarate, latanoprost, levobunolol hydrochloride, metipranolol hydrochloride, sodium chloride (hypertonic), and timolol maleate. The at least one otic can be at least one selected from boric acid, carbamide peroxide, chloramphenicol, and triethanolamine polypeptide oleate-condensate. The at leastone nasal drug can be at least one selected from beclomethasone dipropionate, budesonide, ephedrine sulfate, epinephrine hydrochloride, flunisolide, fluticasone propionate, naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tetrahydrozoline hydrochloride, triamcinolone acetonide, and xylometazoline hydrochloride. (See, e.g., pp. 1041-97 of Nursing 2001 Drug Handbook.) [0114] The at least one local anti-infective can be at least one selected from acyclovir, amphotericin B, azelaic acid cream, bacitracin, butoconazole nitráté, clindamycin phosphate, clotrimazole, econazole nitráté, erythromycin, gentamicin sulfate, ketoconazole, mafenide acetate, metronidazole (topical), miconazole nitráté, mupirocin, naftifine hydrochloride, neomycin sulfate, nitrofurazone, nystatin, silversulfadiazine, terbinafine hydrochloride, terconazole, tetracycline hydrochloride, tioconazole, and tolnaftate. The at least one scabicide or pediculicide can be at least one selected from crotamiton, lindane, permethrin, and pyrethrins. The at least one topical corticosteroid can be at least one selected from betamethasone dipropionate, betamethasone valerate, clobetasol propionate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcionide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocorisone valerate, mometasone furoate, and triamcinolone acetonide. (See, e.g., pp. 1098-1136 of Nursing 2001 Drug Handbook.) [0115] The at least one vitamin or mineral can be at least one selected from vitamin A, vitamin B complex, cyanocobalamin, folic acid, hydroxocobalamin, leucovorin calcium, niacin, niacinamide, pyridoxine hydrochloride, riboflavin,

ΕΡ 2 548 577 Β1 thiamine hydrochloride, vitamin C, vitamin D, cholecalciferol, ergocalciferol, vitamin D analogue, doxercalciferol, paricalcitol, vitamin E, vitamin K analogue, phytonadione, sodium fluoride, sodium fluoride (topical), trace elements, chromium, copper, iodine, manganese, selenium, and zinc. The at least one caloric can be at least one selected from amino acid infusions (crystalline), amino acid infusions in dextrose, amino acid infusions with electrolytes, amino acid infusions with electrolytes in dextrose, amino acid infusions fór hepatic failure, amino acid infusions fór high metabolic stress, amino acid infusions fór renal failure, dextrose, fát emulsions, and medium-chain triglycerides. (See, e.g., pp. 1137-63 of Nursing 2001 Drug Handbook.) [0116] Anti-IL-23p19 antibody compositions disclosed herein can further comprise at least one of any suitable and effective amount of a composition or pharmaceutical composition comprising at least one anti-lI,-23p19 antibody contacted or administered to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy, optionally further comprising at least one selected from at least one TNF antagonist (e.g., bút nőt limited to a TNF Chemical or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1 orTBP-ll), nerelimonmab, infliximab, etanercept, CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anethetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, acarbapenem, cephalosporin, aflurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormoné, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormoné, a hormoné replacement drug, an estrogen receptor modulátor, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a béta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analóg, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Non-limiting examples of such cytokines include, bút are nőt limted to, any of IL-1 to IL-28 (e.g., IL-1, IL-2, etc.). Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lángé, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000).

[0117] Such anti-cancer or anti-infectives can alsó include toxin molecules that are associated, bound, co-formulated or co-administered with at least one antibody ofthe present invention. The toxin can optionally act to selectively kill the pathologic cell or tissue. The pathologic cell can be a cancer or other cell. Such toxins can be, bút are nőt limited to, purified or recombinant toxin or toxin fragment comprising at least one functional cytotoxic domain of toxin, e.g., selected from at least one of ricin, diphtheria toxin, a venom toxin, óra bacterial toxin. The term toxin alsó includes both endotoxins and exotoxins produced by any naturally occurring, mutant or recombinant bacteria or viruses which may cause any pathological condition in humans and other mammals, including toxin shock, which can result in death. Such toxins may include, bút are nőt limited to, enterotoxigenic E. coli heat-labile enterotoxin (LT), heat-stable enterotoxin (ST), Shigella cytotoxin, Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1), Staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), Streptococcal enterotoxins and the like. Such bacteria include, bút are nőt limited to, strains of a species of enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (e.g., strains of serotype 0157:H7), Staphylococcus species (e.g., Staphylococcus aureus, Staphylococcus pyogenes), Shigella species (e.g., Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei), Salmonella species (e.g., Salmonella typhi, Salmonella cholera-suis, Salmonella ehteritidis), Clostridium species (e.g., Clostrídium perfringens, Clostrídium dificile, Clostrídium botulinum), Camphlobacterspec\es(e.g., Camphlobacterjejuni, Camphlobacterfetus), Heliobacterspec\es, (e.g., Heliobacterpylori), Aeromonas species (e.g., Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (e.g., Vibrios cholerae, Vibrios parahemolyticus), Klebsiella species, Pseudomonas aeruginosa, and Streptococci. See, e.g., Stein, ed., INTERNÁL MEDICINE, 3rd ed., pp 1-13, Little, Brown and Co., Boston, (1990); Evans et al., eds., Bacterial Infections of Humans: Epidemiology and Controi, 2d. Ed., pp 239-254, Plenum Medical Book Co., New York (1991); Mandell et al, Principles and Practice of Infectious Diseases, 3d. Ed., Churchill Livingstone, New York (1990); Berkow et al, eds., The Merck Manual, 16th edition, Merck and Co., Rahway, N.J., 1992; Wood et al, FEMS Microbiology Immunology, 76:121 -134 (1991); Marrack et al, Science, 248:705-711 (1990). [0118] Anti-IL-23p19 antibody compounds, compositions orcombinations ofthe present invention can further comprise at leastone of any suitable auxiliary, such as, bút nőt limited to, diluent, binder, stabilizer, buffers, salts, lipophilicsolvents, preservative, adjuvant or the like. Pharmaceutically acceptable auxiliaries are preferred. Non-limiting examples of, and methods of preparing such sterilé Solutions are well known in the art, such as, bút limited to, Gennaro, Ed., Remington’s Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (Easton, PA) 1990. Pharmaceutically acceptable carriers

EP 2 548 577 Β1 can be routinely selected that are suitable fór the mode of administration, solubility and/or stability of the anti-lL-23p19 antibody, fragment or variant composition as well known in the art or as described herein.

[0119] Pharmaceutical excipients and additives useful in the present composition include, bút are nőt limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars, such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugár polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin, such as humán serum albumin (HSA), recombinant humán albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody components, which can alsó function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. One preferred amino acid is glycine.

[0120] Carbohydrate excipients suitable fór use in the invention include, fór example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starehes, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), myoinositol and the like. Preferred carbohydrate excipients fór use in the present invention are mannitol, trehalose, and raffinose.

[0121] Anti-IL-23p19 antibody compositions can alsó include a bufferora pH-adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts, such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Preferred buffers fór use in the present compositions are organic acid salts, such as citrate.

[0122] Additionally, anti-IL-23p19 antibody compositions ofthe invention can include polymeric excipients/additives, such as polyvinylpyrrolidones, ficolls (a polymeric sugár), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-pcyclodextrin), polyethylene glyeols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates, such as TWEEN 20 and TWEEN 80), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0123] These and additional known pharmaceutical excipients and/or additives suitable fór use in the anti-lL-23p19 antibody, portion or variant compositions according to the invention are known in the art, e.g., as listed in Remington: The Science & Practice of Pharmacy, 19th ed., Williams & Williams, (1995), and in the Physician’s Desk Reference, 52nd ed., Medical Economics, Montvale, NJ (1998). Preferrred carrier or excipient materials are carbohydrates (e.g., saccharides and alditols) and buffers (e.g., citrate) or polymeric agents. An exemplary carrier molecule is the mucopolysaccharide, hyaluronic acid, which may be useful fór intraarticular delivery.

Formulations [0124] As noted above, the invention provides fór stable formulations, which preferably comprise a phosphate buffer with saline or a chosen salt, as well as preserved Solutions and formulations containing a preservative as well as multiuse preserved formulations suitable fór pharmaceutical orveterinary use, comprising at least one anti-IL-23p19 antibody ofthe invention in a pharmaceutically acceptable formulation. Preserved formulations contain at least one known preservative or optionally selected from the group consisting ofat least one phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g., hexahydrate), alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, polymers, or mixtures thereof in an aqueous diluent. Any suitable concentration or mixture can be used as known in the art, such as about 0.0015%, or any rangé, value, orfraction therein. Non-limiting examples include, no preservative, about 0.1-2% m-cresol (e.g., 0.2, 0.3. 0.4, 0.5, 0.9, 1.0%), about 0.1-3% benzyl alcohol (e.g., 0.5, 0.9,1.1,1.5,1.9,2.0, 2.5%), about 0.001-0.5% thimerosal (e.g., 0.005, 0.01), about 0.001-2.0% phenol (e.g., 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% alkylparaben(s) (e.g., 0.00075, 0.0009, 0.001,0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1,0.2, 0.3, 0.5, 0.75, 0.9, 1.0%), and the like.

[0125] As noted above, the invention provides an artiele of manufacture, comprising packaging matéria! and at least one vial comprising a solution of at least one anti-lL-23p19 antibody of the invention with the preseribed buffers and/or preservatives, optionally in an aqueous diluent, wherein said packaging matéria! comprises a label that indicates that such solution can be held over a period of 1,2, 3, 4, 5, 6, 9, 12,18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or greater. The invention further comprises an artiele of manufacture, comprising packaging matériái, a first vial comprising lyophilized at least one anti-l L-23p19 antibody ofthe invention, and a second vial comprising an aqueous diluent of preseribed buffer or preservative, wherein said packaging matéria! comprises a label that instructs a patient to reconstitute the at least one anti-1L-23p 19 antibody in the aqueous diluent to form a solution that can be held over a period of twenty-four hours or greater.

[0126] The at least one anti-lL-23p19 antibody used in accordance with the present invention can be produced by

EP 2 548 577 Β1 recombinant means, including from mammalian cell or transgenic preparations, or can be purified from other biological sources, as described herein or as known in the art.

[0127] The rangé of at least one anti-l L-23p19 antibody in the product ofthe present invention includes amounts yielding upon reconstitution, if in a wet/dry system, concentrations from about 1.0 μg/ml to about 1000 mg/ml, although lower and higher concentrations are operable and are dependent on the intended delivery vehicle, e.g., solution formulations will differfrom transdermal patch, pulmonary, transmucosal, orosmotic or micro pump methods.

[0128] Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative. Preferred preservatives include those selected from the group consisting ofphenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof. The concentration of preservative used in the formulation is a concentration sufficient to yield an anti-microbial effect. Such concentrations are dependent on the preservative selected and are readily determined by the skilled artisan.

[0129] Other excipients, e.g., isotonicity agents, buffers, antioxidants, and preservative enhancers, can be optionally and preferably added to the diluent. An isotonicity agent, such as glycerin, is commonly used at known concentrations. A physiologically tolerated buffer is preferably added to provide improved pH controi. The formulations can cover a wide rangé of pHs, such as from about pH 4 to about pH 10, and preferred ranges from about pH 5 to about pH 9, and a most preferred rangé of about 6.0 to about 8.0. Preferably, the formulations ofthe present invention have a pH between about 6.8 and about 7.8. Preferred buffers include phosphate buffers, most preferably, sodium phosphate, particularly, phosphate buffered saline (PBS).

[0130] Other additives, such as a pharmaceutically acceptable solubilizers like Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) or nonionic surfactants, such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluronic® polyls, other block co-polymers, and chelators, such as EDTA and EGTA, can optionally be added to the formulations or compositions to reduce aggregation. These additives are particularly useful if a pump or plastic Container is used to administer the formulation. The presence of pharmaceutically acceptable surfactant mitigates the propensity fór the protein to aggregate.

[0131] The formulations ofthe present invention can be prepared by a process which comprises mixing at least one anti-IL-23p19 antibody ofthe invention and a preservative selected from the group consisting of phenol, m-cresol, pcresol, o-cresol, chlorocresol, benzyl alcohol, alkylparaben, (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof in an aqueous diluent. Mixing the at least one anti-IL-23p19 antibody and preservative in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, fór example, a measured amount of at least one anti-IL-23p19 antibody in buffered solution is combined with the desired preservative in a buffered solution in quantities sufficient to provide the protein and preservative at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. Fór example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized fór the concentration and means of administration used.

[0132] The claimed formulations can be provided to patients as clear Solutions or as dual vials comprising a vial of lyophilized at least one anti-IL-23p19 antibody that is reconstituted with a second vial containing water, a preservative and/or excipients, preferably, a phosphate buffer and/or saline and a chosen salt, in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice fór a single or multiple cycles of patient treatment and thus can provide a more convenient treatment régimén than currently available.

[0133] The present claimed articles of manufacture are useful fór administration over a period ranging from immediate to twenty-four hours or greater. Accordingly, the presently claimed articles of manufacture offer significant advantages to the patient. Formulations ofthe invention can optionally be safely stored at temperatures of from about 2°C to about 40°C and retain the biological activity ofthe protein fór extended periods of time, thus allowing a package label indicating that the solution can be held and/or used over a period of 6, 12, 18, 24, 36, 48, 72, or 96 hours or greater. If preserved diluent is used, such label can include use up to 1-12 months, one-half, one and a half, and/or two years.

[0134] Thesolutionsofat least one anti-IL-23p19 antibody ofthe invention can be prepared by a process that comprises mixing at least one antibody in an aqueous diluent. Mixing is carried out using conventional dissolution and mixing procedures. To prepare a suitable diluent, fór example, a measured amount of at least one antibody in water or buffer is combined in quantities sufficient to provide the protein and, optionally, a preservative or buffer at the desired concentrations. Variations of this process would be recognized by one of ordinary skill in the art. Fór example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized fór the concentration and means of administration used.

[0135] The claimed products can be provided to patients as clear Solutions or as dual vials comprising a vial of lyophilized at least one anti-IL-23p19 antibody that is reconstituted with a second vial containing the aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice fór a single

ΕΡ 2 548 577 Β1 or multiple cycles of patient treatment and thus provides a more convenient treatment régimén than currently available. [0136] The claimed products can be provided indirectly to patients by providing to pharmacies, clinics, or other such institutions and facilities, clear Solutions or dual vials comprising a vial of lyophilized at least one anti-lL-23p19 antibody that is reconstituted with a second vial containing the aqueous diluent. The clear solution in this case can be up to one liter or even larger in size, providing a large reservoir from which smaller portions of the at least one antibody solution can be retrieved one or multiple times fór transfer intő smaller vials and provided by the pharmacy or clinic to their customers and/or patients.

[0137] Recognized devices comprising single vial systems include pen-injector devices fór delivery ofa solution, such as BD Pens, BD Autojector®, Humaject®' NovoPen®, B-D®Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, e.g., as made or developed by Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com), Disetronic(Burgdorf, Switzerland, www.disetronic.com; Bioject, Portland, Oregon (www.bioject.com); National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical.com), Medi-Ject Corp (Minneapolis, MN, www.mediject.com), and similary suitable devices. Recognized devices comprising a dual vial system include those pen-injector systems fór reconstituting a lyophilized drug in a cartridge fór delivery of the reconstituted solution, such as the HumatroPen®. Examples of other devices suitable include pre-filled syringes, auto-injectors, needle free injectors and needle free IV infusion sets.

[0138] The products presently claimed include packaging matériái. The packaging matéria! provides, in addition to the information required by the regulatory agencies, the conditions under which the product can be used. The packaging matéria! ofthe present invention provides instructions to the patient to reconstitute the at least one anti-IL-23p19 antibody in the aqueous diluent to form a solution and to use the solution over a period of 2-24 hours or greater fór the two vial, wet/dry, product. Fór the single vial, solution product, the label indicates that such solution can be used over a period of 2-24 hours or greater. The presently claimed products are useful fór humán pharmaceutical product use.

[0139] The formulations of the present invention can be prepared by a proeess that comprises mixing at least one anti-IL-23p19 antibody ofthe invention and a selected buffer, preferably, a phosphate buffer containing saline óra chosen salt. Mixing the at least one anti-lL-23p19 antibody and buffer in an aqueous diluent is carried out using conventional dissolution and mixing procedures. To prepare a suitable formulation, fór example, a measured amount of at least one antibody in water or buffer is combined with the desired buffering agent in water in quantities sufficient to provide the protein and buffer at the desired concentrations. Variations of this proeess would be recognized by one of ordinary skill in the art. Fór example, the order the components are added, whether additional additives are used, the temperature and pH at which the formulation is prepared, are all factors that can be optimized fór the concentration and means of administration used.

[0140] The claimed stable or preserved formulations can be provided to patients as clear Solutions or as dual vials comprising a vial of lyophilized at least one anti-lL-23p19 antibody that is reconstituted with a second vial containing a preservative or buffer and excipients in an aqueous diluent. Either a single solution vial or dual vial requiring reconstitution can be reused multiple times and can suffice fór a single or multiple cycles of patient treatment and thus provides a more convenient treatment régimén than currently available.

[0141] Other formulations or methods of stabilizing the anti-IL-23p19 antibody may result in other than a clear solution of lyophilized powder comprising the antibody. Among non-clear Solutions are formulations comprising particulate suspensions, said particulates being a composition containing the anti-l l,-23p19 antibody in a structure of variable dimension and known variously as a microsphere, microparticle, nanopartiele, nanosphere, or liposome. Such relatively homogenous, essentially spherical, particulate formulations containing an active agent can be formed by contacting an aqueous phase containing the active agent and a polymer and a nonaqueous phase followed by evaporation of the nonaqueous phase to cause the coalescence of particles from the aqueous phase as taught in U .S. 4,589,330. Porous microparticles can be prepared using a first phase containing active agent and a polymer dispersed in a continuous solvent and removing said solvent from the suspension by freeze-drying or dilution-extraction-precipitation as taught in U.S. 4,818,542. Preferred polymers fór such preparations are natural or synthetic copolymers or polymers selected from the group consisting of gleatin agar, starch, arabinogalactan, albumin, collagen, polyglycolic acid, polylactic aced, glycolide-L(-) lactide poly(episilon-caprolactone, poly(epsilon-caprolactone-CO-lactic acid), poly(epsilon-caprolactone-CO-glycolic acid), poly^-hydroxy butyric acid), polyethylene oxide, polyethylene, poly(alkyl-2-cyanoacrylate), poly(hydroxyethyl methacrylate), polyamides, poly(amino acids), poly(2-hydroxyethyl DL-aspartamide), poly(ester urea), poly(L-phenylalanine/ethylene glycol/1,6-diisocyanatohexane) and poly(methyl methacrylate). Particularly preferred polymers are polyesters, such as polyglycolic acid, polylactic aced, glycolide-L(-) lactide poly(episilon-caprolactone, poly(epsilon-caprolactoneCO-lactic acid), and poly(epsilon-caprolactone-CO-glycolic acid. Solvents useful fór dissolving the polymer and/or the active include: water, hexafluoroisopropanol, methylenechloride, tetrahydrofuran, hexane, benzene, or hexafluoroacetone sesquihydrate. The proeess of dispersing the active containing phase with a second phase may include pressure forcing said first phase through an orifice in a nozzle to affect droplet formation.

[0142] Dry powder formulations may result from processes other than lyophilization, such as by spray drying or solvent

ΕΡ 2 548 577 Β1 extraction by evaporation or by precipitation of a crystalline composition followed by one or more steps to remove aqueous or nonaqueous solvent. Preparation of a spray-dried antibody preparation is taught in U.S. 6,019,968. The antibodybased dry powder compositions may be produced by spray drying Solutions or slurries of the antibody and, optionally, excipients, in a solvent under conditions to provide a respirable dry powder. Solvents may include polar compounds, such as water and ethanol, which may be readily dried. Antibody stability may be enhanced by performing the spray drying procedures in the absence of oxygen, such as under a nitrogén blanket or by using nitrogén as the drying gas. Another relatively dry formulation is a dispersion of a plurality of perforated microstructures dispersed in a suspension médium that typically comprises a hydrofluoroalkane propellant as taught in WO 9916419. The stabilized dispersions may be administered to the lung of a patient using a metered dose inhaler. Equipment useful in the commercial manufacture of spray dried medicaments are manufactured by Buchi Ltd. or Niro Corp.

[0143] At least one anti-lL-23p19 antibody in either the stable or preserved formulations or Solutions described herein, can be administered to a patient in accordance with the present invention via a variety of delivery methods including SC or IM injection; transdermal, pulmonary, transmucosal, implant, osmotic pump, cartridge, micro pump, or other means appreciated by the skilled artisan, as well-known in the art.

Therapeutic Applications [0144] A method tor modulating ortreating at least one IL-23 related disease, in a cell, tissue, organ, animal, or patient, as known in the art oras described herein, using at leastone IL-23p19 antibody ofthe present invention, e.g., administering or contacting the cell, tissue, organ, animal, or patient with a therapeutic effective amount of I L-23p 19 antibody is disclosed herein. A method tor modulating or treating at least one IL-23 related disease, in a cell, tissue, organ, animal, or patient including, bút nőt limited to, at leastone of obesity, an immuné related disease, a cardiovasculardisease, an infectious disease, a malignant disease or a neurologic disease is disclosed herein.

[0145] A method tor modulating or treating at least one IL-23 related immuné related disease, in a cell, tissue, organ, animal, or patient including, bút nőt limited to, at least one of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, osteolysis, aseptic loosening of orthopedic implants, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis/uveitis/optic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener’s granulomatosis, sarcoidosis, orchitis/vasectomy reversal procedures, allergic/atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, trauma/hemorrhage, burns, ionizing radiation exposure, acute pancreatitis, aduit respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn’s pathology, sickle cell anémia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anémia, hemolytic disesease, thrombocytopenia, graft rejection of any organ or tissue, kidney translplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, boné marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, boné graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynaud’s disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type Ili hypersensitivity reactions, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison’s disease, diabetes mellitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson’sdisease, hemachromatosis, alpha-1-antitrypsindeficiency, diabeticretinopathy, hashimoto’s thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), famíliái hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, okt3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including bút nőt limited to, asthenia, anémia, cachexia, and the like), chronic salicylate intoxication, and the like is disclosed herein. See, e.g., the Merck Manual, 12th-17th Editions, Merck & Company, Rahway, NJ (1972,1977,1982,1987,1992,1999), Pharmacotherapy Handbook, Wells et al., eds., Second Edition, Appleton and Lángé, Stamford, Conn. (1998, 2000).

[0146] A method tor modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal, or patient, including, bút nőt limited to, at leastone of cardiacstun syndrome, myocardial infarction, congestive heart failure,

ΕΡ 2 548 577 Β1 stroke, ischemic stroke, hemorrhage, acute coronary syndrome, arteriosclerosis, atherosclerosis, restenosis, diabetic ateriosclerotic disease, hypertension, artéria! hypertension, renovascular hypertension, syncope, shock, syphilis ofthe cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specifie arrythmias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation ofthe aorta, occlusion ofthe abdominal aorta and its branches, peripheral vascular disorders, occlusive artéria! disorders, peripheral atherlosclerotic disease, thromboangitis obliterans, functional peripheral artéria! disorders, Raynaud’s phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like is disclosed herein. Such a method can optionally eomprise administering an effective amount of a composition or pharmaceutical composition comprising at leastone anti-l L-23p19 antibody to a cell, tissue, organ, animal or patient in need ofsuch modulation, treatment ortherapy. [0147] A method for modulating ortreating at least one IL-23 related infectious disease in a cell, tissue, organ, animal or patient, including, bút nőt limited to, at least one of: acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HÍV infection/H IV neuropathy, meningitis, hepatitis (e.g., A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, e. coli 0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, mycobacterium tuberculosis, mycobacterium avium intracellulare, pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitis/epidydimitis, legionella, lyme disease, influenza a, epstein-barr vírus, viral-associated hemaphagocytic syndrome, viral encephalitis/aseptic meningitis, and the like is disclosed herein.

[0148] A method for modulating ortreating at least one IL-23 related malignant disease in a cell, tissue, organ, animal or patient, including, bút nőt limited to, at least one of: leukémia, acute leukémia, acute lymphoblastic leukémia (ALL), acute lymphocytic leukémia, B-cell, T-cell or FAB ALL, acute myeloid leukémia (AML), acute myelogenous leukémia, chromic myelocytic leukémia (CML), chronic lymphocytic leukémia (CLL), hairy cell leukémia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin’s disease, a malignamt lymphoma, non-hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, Kaposi’s sarcoma, colorectal carcinoma, pancreatic carcinoma, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplasticsyndrome/hypercalcemia of malignancy, solid tumors, bladder cancer, breast cancer, colorectal cancer, endometiral cancer, head cancer, neck cancer, hereditary nonpolyposis cancer, Hodgkin’s lymphoma, liver cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, testicular cancer, adenocarcinomas, sarcomas, malignant melanoma, hemangioma, metastatic disease, cancer related boné resorption, cancer related boné pain, and the like is disclosed herein.

[0149] A method for modulating ortreating at least one IL-23 related neurologic disease in a cell, tissue, organ, animal or patient, including, bút nőt limited to, at least one of: neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders, such as lesions ofthe corticospinal system; disorders ofthe basal ganglia; hyperkinetic movement disorders, such as Huntington’s Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson’s disease; Progressive supranucleo Palsy; structural lesions ofthe cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich’s ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum’s disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi-system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders ofthe motor unit, such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer’s disease; Down’s Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; WernickeKorsakoffsyndrome; chronicalcoholism; Creutzfeldt-Jakobdisease; Subacutesclerosing panencephalitis, HallerrordenSpatz disease; Dementia pugilistica; neurotraumatic injury (e.g., spinal cord injury, brain injury, concussion, repetitive concussion); pain; inflammatory pain; autism; depression; stroke; cognitive disorders; epilepsy; and the like. Such a method can optionally eomprise administering an effective amount of a composition or pharmaceutical composition comprising at least one TNF antibody or specified portion or variant to a cell, tissue, organ, animal or patient in need of such modulation, treatment ortherapy is disclosed herein. See, e.g., the Merck Manual, 16th Edition, Merck & Company, Rahway, NJ (1992).

[0150] A method for modulating or treating at least one IL-23 related wound, trauma or tissue injury or related chronic condition, in a cell, tissue, organ, animal or patient, including, bút nőt limited to, at least one of: bodily injury or a trauma associated with órai surgery including periodontal surgery, tooth extraction(s), endodontic treatment, insertion of tooth

ΕΡ 2 548 577 Β1 implants, application and use of tooth prosthesis; or wherein the wound is selected from the group consisting of aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, infarctions and subcutaneous wounds; or wherein the wound is selected from the group consisting of ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds; or wherein the wound is an aphthous wound, a traumatic wound or a herpes associated wound is disclosed herein.

[0151] Wounds and/or ulcers are normally found protruding from the skin or on a mucosal surface or as a result of an infarction in an organ (stroke). A wound may be a result of a soft tissue defect or a lesion or of an underlying condition. In the present context, the term skin relates to the outermost surface ofthe body of an animal, including a humán, and embraces intact or almost intact skin as well as an injured skin surface. The term mucosa relates to undamaged or damaged mucosa of an animal, such as a humán, and may be the órai, buccal, aurai, nasal, lung, eye, gastrointestinal, vaginái, or rectal mucosa.

[0152] In the present context the term wound denotes a bodily injury with disruption of the normál integrity of tissue structures. The term is alsó intended to encompass the terms soré, lesion, necrosis, and ulcer. Normally, the term soré is a popular term fór almost any lesion of the skin or mucous membranes and the term ulcer is a local defect, or excavation, ofthe surface of an organ or tissue, which is produced by the sloughing ofnecrotic tissue. Lesion generally relates to any tissue defect. Necrosis is related to dead tissue resulting from infection, injury, inflammation or infarctions. [0153] The term wound used in the present context denotes any wound (see below fór a classification of wounds) and at any particular stage in the healing proeess, including the stage before any healing has initiated or even before a specific wound like a surgical incision is made (prophylactic treatment). Examples of wounds which can be prevented and/or treated are, e.g., aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds (i.e., wounds in which there is no disruption of the skin bút there is injury to underlying structures), open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, etc. Examples of sores are bed sores, canker sores, chrome sores, cold sores, pressure sores, etc. Examples of ulcers are, e.g., a peptic ulcer, duódénál ulcer, gastric ulcer, gouty ulcer, diabetic ulcer, hypertensive ischemic ulcer, stasis ulcer, ulcus cruris (venous ulcer), sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, and veneral ulcer, e.g., caused by gonorrhoea (including urethritis, endocervicitis and proctitis). Conditions related to wounds or sores which may be successfully treated are burns, anthrax, tetanus, gas gangrene, scarlatina, erysipelas, syeosis barbae, folliculitis, impetigo contagiosa, or impetigo bullosa, etc. There is often a certain overlap between the use ofthe terms wound and ulcer and wound and soré and, furthermore, the terms are often used at random. Therefore, as mentioned above, in the present context the term wound encompasses the terms ulcer, lesion, soré and infarction, and the terms are indiseriminately used unless otherwise indicated.

[0154] The kinds of wounds to be treated according include alsó (i) generál wounds, such as, e.g., surgical, traumatic, infectious, ischemic, thermal, Chemical and bullous wounds; (ii) wounds specific fór the órai cavity, such as, e.g., postextraction wounds, endodontic wounds especiaily in connection with treatment of cysts and abseesses, ulcers and lesions of bacterial, viral or autó immunological origin, mechanical, Chemical, thermal, infectious and lichenoid wounds; herpes ulcers, stomatitis aphthosa, acute necrotising ulcerative gingivitis and burning mouth syndrome are specific examples; and (iii) wounds on the skin, such as, e.g., neoplasm, burns (e.g. Chemical, thermal), lesions (bacterial, viral, autoimmunological), bites and surgical incisions. Another way of classifying wounds is as (i) small tissue loss due to surgical incisions, minor abrasions and minor bites, or as (ii) significant tissue loss. The latter group includes ischemic ulcers, pressure sores, fistulae, lacerations, severe bites, thermal burns and donor site wounds (in soft and hard tissues) and infarctions.

[0155] Other wounds that are of importance are wounds like ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds. Ischemic ulcers and pressure sores are wounds which normally only heal very slowly and especiaily in such cases, an improved and more rapid healing proeess is of course of great importance fór the patient. Furthermore, the costs involved in the treatment of patients suffering from such wounds are markedly reduced when the healing is improved and takes piacé more rapidly.

[0156] Donor site wounds are wounds which, e.g., occur in connection with removal of hard tissue from one part of the body to another part ofthe body, e.g., in connection with transplantation. The wounds resulting from such operations are very painful and an improved healing is therefore most valuable. The term skin is used in a very broad sense embracing the epidermal layer of the skin and - in those cases where the skin surface is more or less injured - alsó the dermal layer of the skin. Apart from the stratum corneum, the epidermal layer of the skin is the outer (epithelial) layer and the deeper connective tissue layer of the skin is called the dermis.

[0157] Alsó disclosed is a method fór modulating or treating psoriasis, psoriatic arthritis, Crohn’s disease, multiple selerosis, and optic neuritis, among the other diseases listed above as IL-23 related, in a cell, tissue, organ, animal, or patient including, bút nőt limited to, at least one of immuné related disease, cardiovascular disease, infectious, malignant and/or neurologic disease. Such a method can optionally comprise administering an effective amount of at least one composition or pharmaceutical composition comprising at least one anti-l L-23p19 antibody to a cell, tissue, organ, animal

ΕΡ 2 548 577 Β1 or patient in need of such modulation, treatment or therapy.

[0158] Any method disclosed herein can comprise administering an effective amount ofa composition or pharmaceutical composition comprising at least one anti-IL-23p19 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such a method can optionally further comprise co-administration or combination therapy fór treating such diseases or disorders, wherein the administering of said at least one anti-1L-23p 19 antibody, specified portion or variant thereof, further comprises administering, before concurrently, and/or after, at least one selected from at least one TNF antagonist (e.g., bút nőt limited to, a TNF Chemical or protein antagonist, TNF monoclonal or polyclonal antibody or fragment, a soluble TNF receptor (e.g., p55, p70 or p85) or fragment, fusion polypeptides thereof, or a small molecule TNF antagonist, e.g., TNF binding protein I or II (TBP-1 orTBP-ll), nerelimonmab, infliximab, etanercept (Enbrel™), adalimulab (Humira™), CDP-571, CDP-870, afelimomab, lenercept, and the like), an antirheumatic(e.g., methotrexate, auranofin, aurothioglucose, azathioprine, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormoné, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), afilgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormoné, a hormoné replacement drug, an estrogen receptor modulátor, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a béta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analóg, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Suitable dosages are well known in the art. See, e.g., Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lángé, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000); Nursing 2001 Handbook of Drugs, 21st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, Prentice-Hall, Inc, Upper Saddle River, NJ.

[0159] TNF antagonists suitable fór compositions, combination therapy, co-administration, devices and/or methods of the present invention (further comprising at least one antibody, specified portion and variant thereof, of the present invention), include, bút are nőt limited to, anti-TNF antibodies (e.g., at least one TNF antagonist as defined above), antigen-binding fragments thereof, and receptor molecules which bind specifically to TNF; compounds which prevent and/or inhibit TNF synthesis, TNF release or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g, pentoxifylline and rolipram), A2b adenosine receptor agonists and A2b adenosine receptor enhancers; compounds which prevent and/or inhibit TNF receptor signalling, such as mitogen activated protein (MAP) kinase inhibitors; compounds which block and/or inhibit membráné TNF cleavage, such as metalloproteinase inhibitors; compounds which block and/or inhibit TNF activity, such as angiotensin converting enzyme (ACE) inhibitors (e.g., captopril); and compounds which block and/or inhibit TNF production and/or synthesis, such as MAP kinase inhibitors.

[0160] As used herein, a tumor necrosis factor antibody, TNF antibody, TNFa antibody, or fragment and the like decreases, blocks, inhibits, abrogates or interferes with TNFa activity in vitro, in situ and/or, preferably, in vivő. Fór example, a suitable TNF humán antibody can bind TNFa and includes anti-TNF antibodies, antigen-binding fragments thereof, and specified mutants or domains thereof that bind specifically to TNFa. A suitable TNF antibody or fragment can alsó decrease block, abrogate, interfere, prevent and/or inhibit TNF RNA, DNA or protein synthesis, TNF release, TNF receptor signaling, membráné TNF cleavage, TNF activity, TNF production and/or synthesis.

[0161] An example of a TNF antibody or antagonist is the chimeric antibody cA2. Additional examples of monoclonal anti-TNF antibodies that can be are described in the art (see, e.g., U.S. Patent No. 5,231,024; Möller, A. et al., Cytokine 2(3):162-169(1990); U.S. Application No. 07/943,852(filed September 11,1992); Rathjen etal., International Publication No. WO 91/02078 (published February 21,1991); Rubin et al., EPO Patent Publication No. 0 218 868 (published April 22, 1987); Yone et al., EPO Patent Publication No. 0 288 088 (October26, 1988); Liang, et al., Biochem. Biophys. Rés. Comm. 137:847-854 (1986); Meager, etal., Hybridoma 6:305-311 (1987); Fendly et al., Hybridoma 6:359-369 (1987); Bringman, et al., Hybridoma 6:489-507 (1987); and Hirai, et al., J. Immunoi. Meth. 96:57-62 (1987).

TNF Receptor Molecules [0162] Preferred TNF receptor molecules useful in the present invention are those that bind TNFa with high affinity (see, e.g., Feldmann et al., International Publication No. WO 92/07076 (published April 30, 1992); Schall et al., Cell 61:361-370 (1990); and Loetscher et al., Cell 61:351-359 (1990)) and optionally possess low immunogenicity. In particular, the 55 kDa (p55 TNF-R) and the 75 kDa (p75 TNF-R) TNF cell surface receptors are useful in the present invention. Truncated forms of these receptors, comprising the extracellular domains (ECD) of the receptors or functionai portions

ΕΡ 2 548 577 Β1 thereof (see, e.g., Corcoran et al., Eur. J. Biochem. 223:831-840 (1994)), are alsó useful. Truncated forms ofthe TNF receptors, comprising the ECD, have been detected in urine and serum as 30 kDa and 40 kDa TNFa inhibitory binding proteins (Engelmann, H. et al., J. Bioi. Chem. 265:1531-1536 (1990)). TNF receptor multimeric molecules and TNF immunoreceptor fusion molecules, and derivatives and fragments or portions thereof, are additional examples of TNF receptor molecules which are useful in the methods and compositions ofthe present invention.

[0163] TNF receptor multimeric molecules comprise all óra functional portion ofthe ECD of two or more TNF receptors linked via one or more polypeptide linkers or other nonpeptide linkers, such as polyethylene glycol (PEG). An example of such a TNF immunoreceptorfusion molecule is TNF receptor/IgG fusion protein. TNF immunoreceptorfusion molecules and methods fór their production have been described in the art (Lesslauer et al., Eur. J. Immunoi. 21:2883-2886 (1991); Ashkenazi et al., Proc. Natl. Acad. Sci. USA 88:10535-10539 (1991); Peppel et al., J. Exp. Med. 174:1483-1489 (1991); Kolls etal., Proc. Natl. Acad. Sci. USA 91:215-219 (1994); Butieret al., Cytokine 6(6):616-623 (1994); Baker etal., Eur. J. Immunoi. 24:2040-2048(1994); Beutler et al., U.S. Patent No. 5,447,851; and U.S. Application No. 08/442,133 (filed May 16, 1995), each of which references are entirely incorporated herein by reference). Methods fór producing immunoreceptor fusion molecules can alsó be found in Capon et al., U.S. Patent No. 5,116,964; Capon et al., U.S. Patent No. 5,225,538; and Capon etal., Natúré 337:525-531 (1989).

[0164] Cytokines include any known cytokine. See, e.g., CopewithCytokines.com. Cytokine antagonists include, bút are nőt limited to, any antibody, fragment or mimetic, any soluble receptor, fragment or mimetic, any small molecule antagonist, or any combination thereof.

Therapeutic Treatments [0165] Any method ofthe disclosed herein can comprise a method fór treating an IL-23 mediated disorder, comprising administering an effective amount ofa composition or pharmaceutical composition comprising at least one anti-l L-23p19 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy. Such a method can optionally further comprise co-administration or combination therapy fór treating such diseases or disorders, wherein the administering of said at least one anti-IL-23p19 antibody, specified portion or variant thereof, further comprises administering before, concurrently, and/or after, at least one selected from an anti-infective drug, a cardiovascular (CV) system drug, a Central nervous system (CNS) drug, an autonomic nervous system (ANS) drug, a respiratory tract drug, a gastrointestinal (Gl) tract drug, a hormonal drug, a drug tor fluid or electrolyte balance, a hematologic drug, an antineoplastic, an immunomodulation drug, an ophthalmic, otic or nasal drug, a topical drug, a nutritional drug or the like, at least one TNF antagonist (e.g., bút nőt limited to a TNF antibody or fragment, a soluble TNF receptor or fragment, fusion proteins thereof, óra small molecule TNF antagonist), an antirheumatic (e.g., methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, gold sodium thiomalate, hydroxychloroquine sulfate, leflunomide, sulfasalzine), a muscle relaxant, a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial (e.g., aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, cephalosporin, a flurorquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an antipsoriatic, a corticosteriod, an anabolic steroid, a diabetes related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium related hormoné, an antidiarrheal, an antitussive, an antiemetic, an antiulcer, a laxative, an anticoagulant, an erythropoietin (e.g., epoetin alpha), a filgrastim (e.g., G-CSF, Neupogen), a sargramostim (GM-CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (e.g., basiliximab, cyclosporine, daclizumab), a growth hormoné, a hormoné replacementdrug, an estrogen receptor modulátor, a mydriatic, a cycloplegic, an alkylating agent, an antimetabolite, a mitotic inhibitor, a radiopharmaceutical, an antidepressant, antimanic agent, an antipsychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a béta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analóg, dornase alpha (Pulmozyme), a cytokine or a cytokine antagonist. Such drugs are well known in the art, including formulations, indications, dosing and administration fór each presented herein (see., e.g., Nursing 2001 Handbook of Drugs, 21st edition, Springhouse Corp., Springhouse, PA, 2001; Health Professional’s Drug Guide 2001, ed., Shannon, Wilson, Stang, PrenticeHall, Inc, Upper Saddle River, NJ; Pharmcotherapy Handbook, Wells et al., ed., Appleton & Lángé, Stamford, CT). [0166] Typically, treatment of pathologic conditions is effected by administering an effective amount or dosage of at least one anti-IL-23p19 antibody composition that totál, on average, a rangé from at least about 0.01 to 500 milligrams of at least one anti-IL-23p19 antibody per kilogram of patient per dose, and, preferably, from at least about 0.1 to 100 milligrams antibody/kilogram of patient per single or multiple administration, depending upon the specific activity of the active agent contained in the composition. Alternatively, the effective serum concentration can comprise 0.1-5000 gg/ml serum concentration per single or multiple adminstration. Suitable dosages are known to medical practitioners and will, of course, depend upon the partícuíar disease state, specific activity of the composition being administered, and the partícuíar patient undergoing treatment. In somé instances, to achieve the desired therapeutic amount, itcan be necessary to provide fór repeated administration, i.e., repeated individual administrations ofa partícuíar monitored or metered dose, where the individual administrations are repeated until the desired daily dose or effect is achieved.

ΕΡ 2 548 577 Β1 [0167] Preferred doses can optionally include about 0.1-99 and/or 100-500 mg/kg/administration, or any rangé, value or fraction thereof, or to achieve a serum concentration of about 0.1-5000 μg/ml serum concentration per single or multiple administration, or any rangé, value or fraction thereof. A preferred dosage rangé fór the anti-lL-23p19 antibody of the present invention is from about 1 mg/kg, up to about 3, about 6 or about 12 mg/kg of body weight of the patient. [0168] Alternatively, the dosage administered can vary depending upon known factors, such as the pharmacodynamic characteristics ofthe particuiar agent, and its mode and route of administration; age, health, and weight ofthe recipient; natúré and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily 0.1 to 50, and, preferahiy, 0.1 to 10 milligrams per kilogram per administration or in sustained release form is effective to obtain desired results.

[0169] As a non-limiting example, treatment of humans or animals can be provided as a one-time or periodic dosage of at least one antibody ofthe present invention about 0.1 to 100 mg/kg or any rangé, value or fraction thereof per day, on at least one of day 1-40, or, alternatively or additionally, at least one of week 1-52, or, alternatively or additionally, at least one of 1-20 years, or any combination thereof, using single, infusion or repeated doses.

[0170] Dosage forms (composition) suitable fór internál administration generally contain from about 0.001 milligram to about 500 milligrams of active ingredient per unit or Container. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-99.999% by weight based on the totál weight of the composition.

[0171] Fór parenteral administration, the antibody can be formulated as a solution, suspension, emulsion, partiele, powder, or lyophilized powder in association, or separately provided, with a pharmaceutically acceptable parenteral vehicle. Examples ofsuch vehicles are water, saline, Ringer’s solution, dextrose solution, and about 1-10% humán serum albumin. Liposomes and nonaqueous vehicles, such as fixed oils, can alsó be used. The vehicle or lyophilized powder can contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and Chemical stability (e.g., buffers and preservatives). The formulation is sterilized by known or suitable techniques.

[0172] Suitable pharmaceutical carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, A. Osol, a standard reference text in this field.

Alternative Administration [0173] Many known and developed modes can be used fór administering pharmaceutically effective amounts of at least one anti-IL-23pl9 antibody according to the present invention. While pulmonary administration is used in the following description, other modes of administration can be used with suitable results. IL-23p19 antibodies ofthe present invention can be delivered in a carrier, as a solution, emulsion, colloid, or suspension, or as a dry powder, using any of a variety of devices and methods suitable fór administration by inhalation or other modes described here within or known in the art.

Parenteral Formulations and Administration [0174] Formulations fór parenteral administration can contain as common excipients sterilé water or saline, polyalkylene glyeols, such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Aqueous or oily suspensions fór injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. Agents fór injection can be a non-toxic, non-orally administrable diluting agent, such as aqueous solution, a sterilé injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer’s solution, isotonic saline, etc. are allowed; as an ordinary solvent or suspending solvent, sterilé involatile oil can be used. Fór these purposes, any kind of involatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono- or di- or tri-glycerides. Parental administration is known in the art and includes, bút is nőt limited to, conventional means of injections, a gas pressured needle-less injection device as described in U.S. Pat. No. 5,851,198, and a laser perforator device as described in U.S. Pat. No. 5,839,446.

Alternative Delivery [0175] The disclosure further relates to the administration of at least one anti-IL-23p19 antibody by parenteral, subcutaneous, intramuscular, intravenous, intrarticular, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracelial, intracerebellar, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intramyocardial, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravesical, intralesional, bolus, vaginái, rectal, buccal, sublingual, intranasal, or transdermal means. At least one anti-IL-23p19 antibody composition can be prepared fór use fór parenteral (subeutaneous, intramuscular or intravenous) or any other administration particuiarly in the form

EP 2 548 577 Β1 of liquid Solutions or suspensions; fór use in vagina! or rectal administration particularly in semisolid forms, such as, bút nőt limited to, creams and suppositories; fór buccal, orsublingual administration, such as, bút nőt limited to, in the form oftablets or capsules; or intranasally, such as, bút nőt limited to, the form of powders, nasal drops or aerosols or certain agents; or transdermally, such as nőt limited to a gél, ointment, lotion, suspension or patch delivery system with Chemical enhancers such as dimethyl sulfoxide to either modify the skin structure or to increase the drug concentration in the transdermal patch (Junginger, et al. In Drug Permeation Enhancement; Hsieh, D. S., Eds., pp. 59-90 (Marcel Dekker, Inc. New York 1994), orwith oxidizing agents that enable the application of formulations containing proteins and peptides onto the skin (WO 98/53847), or applications of electric fields to create transient transport pathways, such as electroporation, orto increase the mobilityof charged drugs through the skin, such as iontophoresis, or application of ultrasound, such as sonophoresis (U.S. Pat. Nos. 4,309,989 and 4,767,402)

Pulmonary/Nasal Administration [0176] Fór pulmonary administration, preferably, at least one anti-IL-23p19 antibody composition is delivered in a partiele size effective fór reaching the lower airways of the lung or sinuses. At least one anti-1L-23p 19 antibody can be delivered by any of a variety of inhalation or nasal devices known in the art fór administration of a therapeutic agent by inhalation. These devices capable of depositing aerosolized formulations in the sinus cavity or alveoli of a patient include metered dose inhalers, nebulizers, dry powder generators, sprayers, and the like. Other devices suitable fór directing the pulmonary or nasal administration of antibodies are alsó known in the art. All such devices can use formulations suitable fór the administration fór the dispensing of antibody in an aerosol. Such aerosols can be comprised of either Solutions (both aqueous and non aqueous) or solid particles.

[0177] Metered dose inhalers like the Ventolin® metered dose inhaler, typically use a propellent gas and require actuation during inspiration (See, e.g., WO 94/16970, WO 98/35888). Dry powder inhalers like Turbuhaler™ (Astra), Rotahaler® (Glaxo), Diskus® (Glaxo), Spiros™ inhaler (Dura), devices marketed by Inhale Therapeutics, and the Spinhaler® powder inhaler (Fisons), use breath-actuation of a mixed powder (US 4668218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale, WO 94/06498 Fisons). Nebulizers like AERx™ Aradigm, the Ultravent® nebulizer (Mallinckrodt), and the Acorn II® nebulizer (Marquest Medical Products) (US 5404871 Aradigm, WO 97/22376), produce aerosols from Solutions, while metered dose inhalers, dry powder inhalers, etc. generate small partiele aerosols. These specific examples of commercially available inhalation devices are intended to be a representative of specific devices.

[0178] Preferably, a composition comprising at least one anti-IL-23p19 antibody is delivered by a dry powder inhaler or a sprayer. There are several desirable features of an inhalation device fór administering at least one antibody of the present invention. Fór example, delivery by the inhalation device is advanfageousiy reliable, reproducible, and accurate. The inhalation device can optionally deliver small dry particles, e.g., less than about 10 pim, preferably about 1-5 pim, forgood respirability.

Administration of IL-23p19 Antibody Compositions as a Spray [0179] A spray including IL-23p19 antibody composition can be produced by forcing a suspension or solution of at least one anti-IL-23p19 antibody through a nozzle under pressure. The nozzle size and configuration, the applied pressure, and the liquid feed rate can be chosen to achieve the desired output and partiele size. An eleetrospray can be produced, fór example, by an electric field in connection with a capillary or nozzle feed. Advanfageousiy, particles of at least one anti-IL-23p19 antibody composition delivered by a sprayer have a partiele size less than about 10 μηι, preferably, in the rangé of about 1 μπι to about 5 μη, and, most preferably, about 2 μπι to about 3 μη.

[0180] Formulations of at least one anti-IL-23p19 antibody composition suitable fór use with a sprayer typically include antibody composition in an aqueous solution at a concentration of about 0.1 mg to about 100 mg of at least one anti-lL23p19 antibody composition per ml of solution or mg/gm, or any rangé, value, or fraction therein. The formulation can include agents, such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can alsó include an excipient or agent fór stabilization of the antibody composition, such as a buffer, a reducing agent, a búik protein, or a carbohydrate. Búik proteins useful in formulating antibody compositions include albumin, protamine, or the like. Typical carbohydrates useful in formulating antibody compositions include sucrose, mannitol, lactose, trehalose, glucose, or the like. The antibody composition formulation can alsó include a surfactant, which can reduce or prevent surface-induced aggregation of the antibody composition caused by atomization of the solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol fatty acid esters. Amounts will generally rangé between 0.001 and 14% by weight ofthe formulation. Especially preferred surfactants are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20, orthe like. Additional agents known in the art fór formulation of a protein, such as IL-23p19 antibodies, or specified portions or variants, can alsó be included in the formulation.

ΕΡ 2 548 577 Β1

Administration of IL-23p19 Antibody Compositions by a Nebulizer [0181] Antibody compositions can be administered by a nebulizer, such as jet nebulizer or an ultrasonic nebulizer. Typically, in a jet nebulizer, a compressed air source is used to create a high-velocity air jet through an orifice. As the gas expands beyond the nozzle, a low-pressure region is created, which draws a solution of antibody composition through a capillary tűbe connected to a liquid reservoir. The liquid stream from the capillary tűbe is sheared intő unstable filaments and droplets as it exits the tűbe, creating the aerosol. A rangé of configurations, flow rates, and baffle types can be employed to achieve the desired performance characteristicsfrom a given jet nebulizer. In an ultrasonic nebulizer, high-frequency electrical energy is used to create vibrational, mechanical energy, typically employing a piezoelectric transducer. This energy is transmitted to the formulation of antibody composition either directly or through a coupiing fluid, creating an aerosol including the antibody composition. Advantageously, particles of antibody composition delivered by a nebulizer have a partiele size less than about 10 μπι, preferably, in the rangé of about 1 μπι to about 5 pim, and, most preferably, about 2 μπι to about 3 μπι.

[0182] Formulations of at least one anti-IL-23p19 antibody suitable fór use with a nebulizer, either jet or ultrasonic, typically include a concentration of about 0.1 mg to about 100 mg of at least one anti-IL-23p19 antibody protein per ml of solution. The formulation can include agents, such as an excipient, a buffer, an isotonicity agent, a preservative, a surfactant, and, preferably, zinc. The formulation can alsó include an excipient or agent fór stabilization of the at least one anti-IL-23p19 antibody composition, such as a buffer, a reducing agent, a búik protein, or a carbohydrate. Búik proteins useful in formulating at least one anti-lL-23p19 antibody compositions include albumin, protamine, or the like. Typical carbohydrates useful in formulating at least one anti-IL-23p19 antibody include sucrose, mannitol, lactose, trehalose, glucose, or the like. The at least one anti-1L-23p 19 antibody formulation can alsó include a surfactant, which can reduce or prevent surface-induced aggregation of the at least one anti-1L-23p 19 antibody caused by atomization of the solution in forming an aerosol. Various conventional surfactants can be employed, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbital fatty acid esters. Amounts will generally rangé between about 0.001 and 4% by weight of the formulation. Especially preferred surfactants fór purposes of this invention are polyoxyethylene sorbitan mono-oleate, polysorbate 80, polysorbate 20, or the like. Additional agents known in the art fór formulation of a protein, such as antibody protein, can alsó be included in the formulation.

Administration of IL-23p19 Antibody Compositions by a Metered Dose Inhaler [0183] In a metered dose inhaler (MDI), a propellant, at least one anti-IL-23p19 antibody, and any excipients or other additives are contained in a canisteras a mixture including a liquefied compressed gas. Actuation ofthe metering valve releases the mixture as an aerosol, preferably containing particles in the size rangé of less than about 10 μπι, preferably, about 1 μπι to about 5 μm, and, most preferably, about 2 μπι to about 3 μπι. The desired aerosol partiele size can be obtained by employing a formulation of antibody composition produced by various methods known to those of skill in the art, including jet-milling, spray drying, critical point condensation, orthe like. Preferred metered dose inhalers include those manufactured by 3M or Glaxo and employing a hydrofluorocarbon propellant. Formulations of at least one antiIL-23p 19 antibody fór use with a metered-dose inhaler device will generally include a finely divided powder containing at least one anti-IL-23p19 antibody as a suspension in a nonaqueous médium, fór example, suspended in a propellant with the aid of a surfactant. The propellant can be any conventional matéria! employed fór this purpose, such as chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol and 1,1,1,2-tetrafluoroethane, HFA-134a (hydrofluroalkane-134a), HFA-227 (hydrofluroalkane-227), or the like. Preferably, the propellant is a hydrofluorocarbon. The surfactant can be chosen to stabilize the at least one anti-1L-23p 19 antibody as a suspension in the propellant, to protect the active agent against Chemical degradation, and the like. Suitable surfactants include sorbitan trioleate, soya lecithin, oleic acid, or the like. In somé cases, solution aerosols are preferred using solvents, such as ethanol. Additional agents known in the art fór formulation of a protein can alsó be included in the formulation. One of ordinary skill in the art will recognize that the methods ofthe current invention can be achieved by pulmonary administration of at least one anti-IL-23p19 antibody composition via devices nőt described herein.

Órai Formulations and Administration [0184] Formulations fór órai administration rely on the co-administration of adjuvants (e.g., resorcinols and nonionic surfactants, such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Formulations fór delivery of hydrophilic agents including proteins and antibodies and a combination of at least two surfactants intended fór órai, buccal, mucosal, nasal, pulmonary, vagina! transmembrane, or rectal administration are taught in U.S. 6,309,663. The active constituent

EP 2 548 577 Β1 compound ofthe solid-type dosageform fór órai administration can be mixed with at leastone additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, syntheticorsemisynthetic polymer, and glyceride. These dosage forms can alsó contain other type(s) of additives, e.g., inactive diluting agent, lubricant, such as magnesium stearate, paraben, preserving agent, such as sorbic acid, ascorbicacid, .alpha.-tocopherol, antioxidantsuch as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc.

[0185] Tablets and pilis can be further processed intő enteric-coated preparations. The liquid preparations fór órai administration include emulsion, syrup, elixir, suspension and solution preparations allowable fór medical use. These preparations can contain inactive diluting agents ordinarily used in said field, e.g., water. Liposomes have alsó been described as drug delivery systems fór insulin and heparin (U.S. Pat. No. 4,239,754). More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals (U.S. Pat. No. 4,925,673). Furthermore, carrier compounds described in U.S. Pat. No. 5,879,681 and U.S. Pat. No. 5,5,871,753 and used to deliver biologically active agents orally are known in the art.

Mucosal Formulations and Administration [0186] Aformulation fór orally administering a bioactive agent encapsulated in one or more biocompatible polymer or copolymer excipients, preferably, a biodegradable polymer or copolymer, affording microcapsules which due to the proper size of the resultant microcapsules results in the agent reaching and being taken up by the folliculi lymphatic aggregati, otherwise known as the Peyer’s patch, or GÁLT of the animal without loss of effectiveness due to the agent having passed through the gastrointestinal tract. Similar folliculi lymphatic aggregati can be found in the bronchei tubes (BALT) and the large intestine. The above-described tissues are referred to in generál as mucosally associated lymphoreticular tissues (MALT). Fór absorption through mucosal surfaces, compositions and methods of administering at leastone anti-IL-23p19 antibody include an emulsion comprising a plurality of submicron particles, a mucoadhesive macromolecule, a bioactive peptide, and an aqueous continuous phase, which promotes absorption through mucosal surfaces by achieving mucoadhesion of the emulsion particles (U.S. Pat. No. 5,514,670). Mucous surfaces suitable fór application ofthe emulsions ofthe present invention can include corneal, conjunctival, buccal, sublingual, nasal, vaginái, pulmonary, stomachic, intestinal, and rectal routes of administration. Formulations fór vagina! or rectal administration, e.g., suppositories, can contain as excipients, fór example, polyalkyleneglycols, vaseline, cocoa butter, and the like. Formulations fór intranasal administration can be solid and contain as excipients, fór example, lactose or can be aqueous or oily Solutions of nasal drops. Fór buccal administration, excipients include sugars, calcium stearate, magnesium stearate, pregelinatined stareh, and the like (U.S. Pat. No. 5,849,695).

Transdermal Formulations and Administration [0187] Fór transdermal administration, the at least one anti-IL-23p19 antibody is encapsulated in a delivery device, such as a liposome or polymeric nanoparticles, microparticle, microcapsule, or microspheres (referred to collectively as microparticles unless otherwise stated). A number of suitable devices are known, including microparticles made of synthetic polymers, such as polyhydroxy acids, such as polylactic acid, polyglycolic acid and copolymers thereof, polyorthoesters, polyanhydrides, and polyphosphazenes, and natural polymers, such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and combinations thereof (U.S. Pat. No. 5,814,599).

Prolonged Administration and Formulations [0188] It can be desirable to deliver the compounds ofthe present invention to the subject over prolonged periods of time, fór example, fór periods of one week to one year from a single administration. Various slow release, depót or implant dosage forms can be utilized. Fór example, a dosage form can contain a pharmaceutically acceptable non-toxic sait of the compounds that has a low degree of solubility in body fluids, fór example, (a) an acid addition sait with a polybasic acid, such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene mono- ordi-sulfonic acids, polygalacturonic acid, and the like; (b) a sait with a polyvalent metál cation, such as zinc, calcium, bismuth, bárium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation formed from e.g., Ν,Ν’-dibenzyl-ethylenediamine or ethylenediamine; or (c) combinations of (a) and (b), e.g., a zinc tannate sait. Additionally, the compounds of the present invention or, preferably, a relatively insoluble sait, such as those just described, can be formulated in a gél, fór example, an aluminum monostearate gél with, e.g., sesame oil, suitable fór injection. Particularly preferred salts are zinc salts, zinc tannate salts, pamoate salts, and the like. Another type of slow release depót formulation fór injection would contain the compound or sait dispersed fór encapsulation in a slow degrading, non-toxic, non-antigenic polymer, such as a polylactic acid/polyglycolic acid polymer fór example as described in U.S. Pat. No. 3,773,919. The compounds or, preferably, relatively insoluble salts,

ΕΡ 2 548 577 Β1 such as those described above, can alsó be formulated in cholesterol mátrix silastic pellets, particularly fór use in animals. Additional slow release, depót or implant formulations, e.g., gas or liquid liposomes, are known in the literature (U.S. Pat. No. 5,770,222 and Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson ed., Marcel Dekker, Inc., N.Y., 1978).

[0189] Having generally described the invention, the same will be more readily understood by reference to the following examples, which are provided by way of illustration and are nőt intended as limiting.

Examples

Example 1 - Isolation of humán anti-human IL-23 specific antibodies by phage display [0190] General methods have been described fór selection of antigen-specific antibodies from the HuCAL™ libaries prepared at MorphoSys (Knappik et al., 2000; Krebs et al., 2001; Rauchenberger et al, 2003). Vh region specific subpools ofthe HuCAL Gold™ Fab library (Kretzschmar & von Ruden, 2002) was used fór the selection of antibodies against recombinant humán IL-23 (hrlL-23). Several different selection strategies were used and include:

1. Selection against recombinant h IL-23 protein that was immobilized directly on plastic, with or without preadsorption ofthe library on recombinant humán IL-12 protein (hrlL-12) alsó adsorbed directly on plastic. The recombinant hlL23 and hlL-12 proteins were produced at Centocor.

2. Selection with recombinant humán IL-23 protein in solution, followed by recovery ofthe bound phage by capture ofthe hlL-23 protein on an immobilized hrlL-12p40 mAb. Selections were carried with or without preadsorption of the library on recombinant hrlL-12 protein captured with the same mAb.

3. Selection with chemically biotinylated hrlL-23 protein in solution, followed by capture of the bound phage with SA-coated magnetic beads. Selections were carried out with or without hrlL-12 protein in molar excess as a competitor.

[0191] Recovered phagemid DNAwas converted enmasse intő a Fab expression vector and individual clones following transformation were sereened fór binding to hrlL-23 and nőt to hrlL-12. Sequencing ofthe positive clones identified 76 unique Fabs.

Example 2 - Characterization of Fabs [0192] Positive Fabs were produced and purified as previously described (Knappik et al., 2000; Krebs et al., 2001; Rauchenberger et al, 2003) and confirmed fór binding specificity to hrlL-23 bút nőt to hrlL-12 or to the p40 subunit of hrlL-12 (hrp40) in assays similar to those described in Example 3 below. Confirmed Fabs were tested fór (1) inhibition of hrlL-23 binding to humán IL-23 receptor (hlL-23R) or to humán IL-12 receptor β1 (hIL-12Rp 1), (2) lack of inhibition of hrlL-12 binding to IL-12RILpi, (3) inhibition of hrlL-23 binding to TALL-104 cells naturally expressing IL-23R and IL12Rpi, and (4) binding affinity to hrlL-23, hrlL-12 and hrp40 subunit. The binding specificity and affinity are summarized in Table 1 and the inhibition of hrlL-23 binding to hlL-23R is listed in Table 2. Fab12A in Table 1 is a reference standard that is derived from an IL-12p40 specific mAb. IL-23R-Fc in Table 2 is a reference standard corresponding to the extracellular domain of humán IL-23R fused to a humán Fc.

[0193] In generál, the receptor inhibition assays were similar to those described below in Example 4 fór the mAb derivatives of these Fabs. One additional assay was to measure the inhibition of rhlL-23 binding to TALL 104 cells. These cells express both the humán IL-23 and IL-12 R béta 1 receptors. 10 ofthe 13 candidate Fabs had the desired activity profile of no reactivity with humán IL-12 or p40 proteins in any assay and at least partial inhibition of hrlL-23 binding to the IL-23 receptor. The CDR sequences of six of the Fabs (4083, 4190, 4205, 4217, 4649, and 4658) are shown in Table 4 (bőid font). The full V-region sequences fór these Fabs are shown in Table 8.

Production of Fabs in a humán IgG 1 formát [0194] Candidate Fabs were cloned intő humán IgG 1 / kappa or lambda mAb formát vectors and produced by transient transfection in HEK293 cells fór further analysis as mAbs. Overall, eleven ofthe 13 active Fabs show a desired profile as mAbs. They are specific fór IL-23 and at least partially inhibited humán IL-23 binding to the humán IL-23R-Fc fusion protein (Table 3). The assays and results are cited in the Examples that follow.

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Example 3 - Subunit Specificity of hll_-23p19 mAbs derived from antibody phage display.

[0195] Purified mouse anti-hIL-23 mAbs were evaluated in cytokine capture ELISA to determine their antigén subunit specificity. Briefly, IL-23 mAbs were coated onto plates and incubated with 100 ng/ml) hrlL-23, hrlL-12, and hrp40, respectively. Following incubation with biotinylated anti-p40 mAb, the binding was detected using HRP - conjugated streptavidin. An anti-p40 mAb and an anti-IL-12 mAb (20C2, Catalog No. 555065, BD Pharmingen, San Diego, CA) with known specificity were used as Controls.

Figures 1 Aand 1B demonstrate the binding specificity fór two of these mAbs, MOR04083 (same as4083) and MOR04190 (same as 4190). Figure 1A shows that the mAbs bind specifically hrlL-23 and nőt hrlL-12 or hrp40 monomer. Because the IL-23p19 subunit must covalently associate with p40 to be secreted from mammalian cells, IL-23 mAbs that do nőt recognize p40 monomer must bind either the IL-23p19 subunit alone or a joint epitope of the p19-p40 heterodimer. Therefore, these IL-23 mAbs are referred to as IL-23p19 mAbs. In comparison, all 3 proteins (hrlL-23, hrlL-12 and hrp40) bind to mAb 12A, a neutralizing anti-human p40 specific antibody. Figure 1B shows that the same mAbs do nőt bind to murine IL-23 or to murine p40. In a reverse formát, the immobilized mAbs have similar binding curves to hrlL-23 in solution (Figure 2), consistent with their comparable binding affinity as Fabs (Table 1). The binding specificity of these and the other candidate mAbs is summarized in Table 3.

Example 4 - Inhibition of IL-23 Receptor Binding by IL-23p19 mAbs [0196] To demonstrate that the IL-23p19 mAbs are neutralizing antibodies against the p19 subunit, the mAbs were tested fortheir inhibition of IL-23 and IL-23R binding. In this experiment, a humán IL-23R-Fcfusion protein was immobilized on a plate. Thisfusion protein consists ofthe extracellulardomain of humán IL-23 receptor fused to a humán Fcsegment. Biotinylated hrlL-23 was added to the plate either alone or after preincubation with individual IL-23p19 mAbs. Soluble IL-23R (IL-23R-Fc) was used as a positive control. IL-23 binding was detected with HRP-conjugated streptavidin. As shown in Figure 3A, the mAbs MOR04083 and MOR04190 prevent IL-23/IL-23R binding with a potency about 3-fold weaker than soluble IL-23R-Fc. There was no inhibition by B21M, a mAb with unrelated specificity. In contrast, when IL-12Rp 1 was immobilized on a plate, these mAbs did nőt inhibit IL-23/IL-12Rpi binding (Figure 3B)). IL-23 binding was inhibited by the p40 neutralizing mAb CNTO 1275 (same as mAb 12A), as expected. Similarly, these mAbs do nőt block IL-12/IL-12Rp 1 binding (Figure 3C). CNTO 1275 again served as a positive control. The selective inhibition of IL-23/IL23R binding and the lackof interference with IL-12 or IL-23 binding to IL-12Rpi further demonstrates that these IL-23p19 mAbs do nőt bind the p40 subunit and thus are neutralizing anti-human IL-23p19 antibodies. The receptor inhibition studies with these mAbs are summarized in Table 3.

Example 5 - Neutralization of IL-23 Biological Function by IL-23p19 mAbs [0197] IL-23 is known to induce intracellular STAT3 phosphorylation and IL-17 production by T cells. Therefore, the

IL-23p 19 mAbs were tested fór their ability to inhibit these biological functions of humán IL-23.

[0198] In one experiment, natural killer (NKL) cells were stimulated with hrlL-23 either alone or after preincubation with the MOR04083 and MOR0190 mAbs at 20 ug/ml and 10 ug/ml, respectively. MAb 12A (1 |jLg/ml) was the positive control and C8.3 (10 ug/ml), a non-neutralizing anti-human p40 mAb, was the negative control. Treated cells were stained with fluorochrome-conjugated anti-phospho-STAT3 antibodies and analyzed by intracellular flow cytometry (Figure 4). These mAbs completely inhibit STAT3 phosphorylation, albeit with lower potency than the neutralizing anti-p40 mAb 12A. The lower potency ofthe IL-23p19 mAbs likely reflects their relatively weak affinity.

[0199] In another experiment, freshly isolated murine splenocytes were treated with hrlL-23 preincubated with titrated IL-23p19 mAbs or control mAbs. hrlL-23 with no antibody preincubation was used as the positive control. After 3 days in culture, cell supernatants were collected and assayed by ELISA using an IL-17 ELISA duó set (R&D Systems). As shown in Figure 5A, IL-23p19 mAbs MOR04083 and MOR04190 inhibited hrlL-23 mediated IL-17 production. These mAbs alsó inhibited IL-17 production induced by native IL-23 produced by humán (Figure 5B) and cynomologous monkey (Figure 5C) PBMCs.

[0200] In comparison, IL-23p19 mAbs were tested fór their ability to inhibit hrlL-12 induced IFNy production. Briefly, NK92MI cells were treated with IL-12 preincubated with titrated IL-23p19 mAbs or control mAbs (Figure 6). IL-12 with no antibody preincubation was used as the negative control and CNTO 1275 as the positive control. ELISA analysis performed 24 hours post-stimulation showed no effect of IL-23p19 mAbs MOR04083 and 4190 on IL-12 induced IFNy production demonstrating that the antibodies do nőt bind and neutralize the p40 subunit shared by IL-12 and IL-23. The results of these assays are summarized in Table 3.

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Example 6- Epitope identification of IL-23p19 mAbs [0201] Competition binding analysis was performed to determine if the neutralizing IL-23p19 mAbs bind to similaror different IL-23p19 epitopes. The results fór mAbs, MOR04083, MOR04190 and MOR04217, are shown in Figure 7. IL23 mAbs were individually coated on ELISA plates. Competing mAbs were added, followed by the addition of biotinylated hrlL-23. Fór positive control, the same mAb fór coating was used as the competing mAb (self-competition). IL-23 binding was detected using streptavidin. All three mAbs show cross-competition to varying extents, indicating binding to spatially related sites.

Example 7 - Affinity maturation of candidate neutralizing Fabs [0202] Fabs MOR04083, 04190, 04649 and 04658 were selected fór independent affinity maturation based on the above characterization in both Fab and mAb formats. Utilizing the cassette feature ofthe HuCal™ system (Knappik et al., 2000), two variant phage libraries were constructed fór each Fab, one fór CDR3 of the light chain variable region (VL) and the other fór CDR2 of the heavy chain variable region (VH). These libraries were selected against biotinylated hrlL-23 in solution under varying stringencies ofwash and antigén concentration. 35 unique Fabs were recovered, each showing improved binding activity relatíve to the starting parental Fab. Subsequently, three additional Fabs (5267, 5268, and 5269; all VL-CDR3 variants of 4083) were selected in a second round of screening. The CDR sequences of the parental Fabs, the matured derivatives from the VL-CDR3 or VH-CDR2 libraries, and variants of those sequences are shown in Tables 4A and B. The complete V-region sequences are shown in Table 8.

Example 8 - Production and characterization of affinity matured Fabs [0203] The 38 selected Fabs were produced, purified and characterized essentially as described in Examples 2-4 above. Ten ofthe Fabs gave pooryields and/or showed heterogeneous patterns in size exclusion chromatography and were excluded from further analysis. The remaining 28 Fabs were analyzedforspecificity of binding, affinity, and inhibition of receptor binding. All of the Fabs were specific fór IL-23p19 and had 10-500 fold higher affinities fór hrlL-23 than the eorresponding parental Fab (Tables 5 and 6). All showed improved IC50 vaiues fór inhibition of hrlL-23 binding to the IL-23R Fc fusion protein and, like the parental Fabs, did nőt inhibit either IL-23 or IL-12 binding to IL-12Rb1 receptor Fc fusion protein (Tables 5 and 6). As expected from these results, nőne ofthe Fabs inhibited hrlL-23 binding to TALL-104 cells as measured by flow cyotometry, consistent with the similar lack of inhibition by the parental Fabs.

Example 9 - Production and characterization ofthe affinity matured Abs in a mAb formát [0204] 34 ofthe 35 selected Fabs were cloned intő humán lgG1 / kappa or lambda mAb formát vectors and produced as mAbs by transient transfection in HEK293 cells fór further analysis. All the antibodies were evaluated fór inhibition of IL-17 production as described in Example 5, above (Table 7). In most cases, each of the matured derivatives was more potent than its eorresponding parent, with improvements in IC50 up to 200 fold. The biochemical properties ofthe 34 mAbs were evaluated by SDS-PAGE and size exclusion chromatography fór indications of aggregation, chain heterogeneity, and incomplete disulfide bond formation between the heavy and light chains and in the hinge region. [0205] From the combined activity and biochemical analysis, 7 mAbs were selected fór more detailed analysis, at least one from each original parental antibody. Antibodies MOR05058 and 05059, derived from the VL CDR3 diversity libraries of MOR04649, were excluded from this set (see Examples 10 and 11). All selected candidates inhibited IL-17 production induced by native IL-23 from humán (Figure 8) and cynomologous monkey PBMCs (notshown). As expected, all inhibited hrlL-23 binding to hrlL-23R Fc fusion protein with a potency greater than that ofthe control mAb IL-23A (Figure 9). With the possibie exception of MOR05053, these selected mAbs did nőt inhibit native IL-12 bioactivity (notshown), consistent with the lack of binding of those available as Fabs to hrlL-12 protein.

Example 10 - Production and characterization of cross-chain combination mAbs [0206] The parent Fabs MOR04190, 04649, and 4658 gave rise to improved Fabs from both the VH CDR2 and VL CDR3 diversity libraries. The Fabs derived from MOR04649 were of particular interest due to their relafively potent activity from both types of libraries. However, the parental MOR04649 Fab contains a predicted, bút potentially unfavorable, N-linked glycosylation site in VH CDR2 that is nőt present in any of the 6 improved Fabs derived from the VH CDR2 library. To eliminate this glycosylation site and test fór potential improved activity, the heavy chains of MOR05042 and 05045 were expressed with the light chains of MOR05058 and 5059 in HEK293 cells (Table 4C - mAbs 42-58, 42-59, 45-58, and 45-59). Nőne ofthe combinations were more potent antagonists (IL-17 production and inhibition IL23 binding to IL-23R) than the respective donor chain mAbs and each showed a greater tendency towards aggregation

EP 2 548 577 Β1 by size exclusion chromatography (nőt shown).

Example 11 - Substitution mutagenesis of selected matured mAbs and their characterization [0207] Amino acid substitutions were introduced intő selected mAbs to eliminate the predicted N-linked glycosylation site and/or conform the amino termini of variable regions with their closest predicted humán germline V-region sequence. The predicted N-linked glycosylation site in the Vh of 5058 and 5059 (NYS in CDR2, same as in the parent Vh of MOR04649) was eliminated by substitution of arginine (4649r) or aspartic acid (4649d) fór asparagine at position 59 (direct numbering). The CDR sequences of these VH regions are shown in Table 4A and the full V-region sequences are gíven in Table 8. These variants were produced by transient expression in HEK 293 cells and purified by Protein A affinity chromatography. These mAbs showed improved potency relatíve to the parental antibodies in their inhibition of IL-17 production. The arginine substitution in MOR05059 had the best profile based on activity and biochemical characterization and was named mAb 3759 Table 4C).

[0208] MAbs5040 and 3759 were selected asthe top leads based on a theiractivities and biochemical characterization. Amino acid substitutions were introduced fór conformity with humán germline antibody sequence and a single amino acid substitution was made in the = 5040 VL region to revert a framework mutation back to germline, substituting a valine fór threonine at position 86.

[0209] The amino acid sequences changed from the original mAb formát were as follows:

Antibody VH VL

5040 E(3) to Q D(1) to E, T(86) to V

3759 Q(1)E(3)toEQ D(1)l(2)toQS [0210] The E3 to Q change in VH of both antibodies is reversion of an E substitution introduced upon cloning of the Fab intő the mAb formát vector. Q was present at this position in the original Fabs and can be used as a variant to the E substitution in various mAbs.

[0211] These variants are designated 5040^Q/EV and 3759^EQ/QS. The component V-regions of 5040^Q/EV are 5040 VH and 4190^ev VL (Table 4C). The component V-regions of 3759^EQ/QS are 4649r^E VH and 5059^QS VL (Table 4C). The sequences of the CDRs and full V-regions of the component chains of both antibodies are shown in Tables 4 and 8, respectively. Similar substitutions can be identified fór any ofthe candidates by comparison to their predicted humán germline sequences.

[0212] The mAbs 5040^Q/EV and 3759^EQ/QS were produced by transient expression in HEK 293 cells and purified by Protein A affinity chromatography. These mAbs retain complete specificity fór humán IL-23 relatíve to IL-12 and p40, as shown in Figure 10. These mAbs inhibit the binding of recombinant humán IL-23 to IL-23R-Fc and are more potent than the reference, mAb23A (Figure 11 A). As expected from their specificity profile, they do nőt inhibit IL-23 (Figure 11B) or IL-12 (Figure 11C) binding to IL-12Rpi. Consistent with this pattern of receptor inhibition, these mAbs do nőt inhibit IL12 induced IFNy production from NK92M1 cells (Figure 12), bút do inhibit both recombinant (Figure 13) and native (Figure 14) IL-23 induced production of IL-17 from murine splenocytes. These mAbs alsó show very strong inhibition of IL-17 induction by native IL-23 from cynomologous monkey (Figure 15), demonstrating a high degree of cross-reactivity with IL-23 from cynomologous monkey. These mAbs alsó inhibited STAT3 phosphorylation induced in humán NK cells by recombinant humán IL-23 (nőt shown).

[0213] The mAbs 5040^Q/EV and 3759^EQ/QS recognize closely positioned epitopes on IL-23 as demonstrated by their inhibition of mAB23A binding (Figure 16A) and their reciprocal competition with each other (Figures 16B and 16C). The epitope of mAb23A has been mapped on humán p19 in the region around I93-G105:

l₉₃HQGLIFYEKLLG₁₀₅

The competition results show that epitopes fór mAbs 5040^Q/EV and 3759^EQ/QS lie in the same region.

Example 12 - Coding sequence variants of mAbs 5040^Q/EV and 3759^EQ/QS and their characterization.

[0214] The coding sequence of the variable regions of the antibodies were engineered intő three different coding sequence variants to evaluate the impact on expression of these proteíns. The first variant used the codons as obtained from the original library, with a few nucleotide substitutions to remove consensus mRNA splice sites. The second variant, germline codon exchange (GCE), was designed by aligning the variable region amino acid sequences to germline genes, identifying the closest matching germline gene and replacing the codons in the original coding sequence with the synonomous codons that are used in the germline gene. At positíons where the amino acid residue did nőt have a match

ΕΡ 2 548 577 Β1 to germline genes, the codon that is used at the highest frequency in highly expressed humán proteins was substituted fór the original codon. The third codon variant was designed by replacing the starting antibody codons with the codon that is used at the highest frequency in highly expressed humán proteins. Each codon variant did express as measured by transient transfection in HEK 293 cells and CHO cells. This result shows that stable cell line tranfectants can be established in these, and likely other hőst cells and the highest expressing variant can be used fór development of a production cell line. The mAbs are evaluated as described in Example 11, in addition to otherfunctional and biochemical and biophysical properties analyses. Table 9 shows the variable heavy and Iight chain nucleotide sequences fór the 5040^q/ev and 3759^EQ/QS mAb variants.

[0215] Fór the purposes of this invention, 70-100% amino acid or nucleotide sequence identity (i.e., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any rangé or value therein) is determined using a suitable computer algorithm, as known in the art.

Table 10

SEQ ID NO:145 (humán IL-23pl9 subunit)

<td> Met</td><td> Leu</td><td> Gly</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Val</td><td> Met</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Pro</td><td> Trp</td><td> Thr</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td colspan="2"> 10</td><td></td><td></td><td></td><td colspan="2"> 15</td><td></td>

<td> Alá</td><td> Gin</td><td> Gly</td><td> Arg</td><td> Alá</td><td> Val</td><td> Pro</td><td> Gly</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Trp</td><td> Thr</td><td> Gin</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Cys</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Ser</td><td> Gin</td><td> Lys</td><td> Leu</td><td> Cys</td><td> Thr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Ser</td><td> Alá</td><td> His</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Pro</td><td> Leu</td><td> Val</td><td> Gly</td><td> His</td><td> Met</td><td> Asp</td><td> Leu</td><td> Arg</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Asp</td><td> Glu</td><td> Glu</td><td> Thr</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Thr</td><td> Asn</td><td> Asp</td><td> Val</td><td> Pro</td><td> His</td><td> Ile</td><td> Gin</td><td> Cys</td><td> Gly</td><td> Asp</td><td> Gly</td><td> Cys</td><td> Asp</td><td> Pro</td><td> Gin</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gly</td><td> Leu</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Gin</td><td> Phe</td><td> Cys</td><td> Leu</td><td> Gin</td><td> Arg</td><td> Ile</td><td> His</td><td> Gin</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Ile</td><td> Phe</td><td> Tyr</td><td> Glu</td><td> Lys</td><td> Leu</td><td> Leu</td><td> Gly</td><td> Ser</td><td> Asp</td><td> Ile</td><td> Phe</td><td> Thr</td><td> Gly</td><td> Glu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Pro</td><td> Ser</td><td> Leu</td><td> Leu</td><td> Pro</td><td> Asp</td><td> Ser</td><td> Pro</td><td> Val</td><td> Alá</td><td> Gin</td><td> Leu</td><td> His</td><td> Alá</td><td> Ser</td><td> Leu</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Leu</td><td> Gly</td><td> Leu</td><td> Ser</td><td> Gin</td><td> Leu</td><td> Leu</td><td> Gin</td><td> Pro</td><td> Glu</td><td> Gly</td><td> His</td><td> His</td><td> Trp</td><td> Glu</td><td> Thr</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gin</td><td> Ile</td><td> Pro</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Gin</td><td> Pro</td><td> Trp</td><td> Gin</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Leu</td><td> Arg</td><td> Phe</td><td> Lys</td><td> Ile</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Leu</td><td> Gin</td><td> Alá</td><td> Phe</td><td> Val</td><td> Alá</td><td> Val</td><td> Alá</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td> Alá</td><td> Arg</td><td> Val</td><td> Phe</td><td> Alá</td><td> His</td><td> Gly</td><td> Alá</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Pro</td><td></td><td></td><td></td>

180 185

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Table 1: Binding Specificity of Candidate Fabs

<img file="HUE034269T2_D0001.tif" />

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Table 2: IC50 of Candidate Fabs in hrIL-23 / hIL-23R Assay

<img file="HUE034269T2_D0002.tif" />

EP 2 548 577 Β1

Table 3: Characterization of the Parental Antibodies in a mAb Formát.

<td> mAb</td><td> IL-23 binding</td><td colspan="3"> Biochemical receptor binding assays</td><td> pSTAT3 Assay</td><td> IL-12 bioassay in NK92MI</td><td colspan="3"> IL-23 induced IL-17 production assay</td>

<td> MÓR#</td><td> hrll_-23 subunit specificity</td><td> IL-12/IL12Rb1</td><td> IL-23/IL12Rb1</td><td> IL-23/IL-23R</td><td> Results at noted concentration</td><td> IFNg in NK92MI cells</td><td> hrlL-17 neutralization</td><td> Native humán IL-23 neutralization</td><td> Native cyno IL23 neutralization</td>

<td> 4083 (k)</td><td> p19</td><td> -</td><td> -</td><td> 4-</td><td> 4-/- at10 + at20</td><td> -</td><td> 4-</td><td> +</td><td> +</td>

<td> 4190 (k)</td><td> p19</td><td> -</td><td> -</td><td> 4·</td><td> + at10</td><td> -</td><td> 4-</td><td> 4-</td><td> 4-</td>

<td> 4649 (A)</td><td> p19</td><td> -</td><td> -</td><td> 4-</td><td> +Z- at 1 + at10</td><td> -</td><td> 4-</td><td> +</td><td> 4-</td>

<td> 4658 (A)</td><td> p19</td><td> -</td><td> -</td><td> +/-</td><td> -/+at10</td><td> -</td><td> -/+</td><td> +</td><td> 4·</td>

<td> 4205</td><td> p19</td><td> -</td><td> -</td><td> -/+</td><td> + at 10</td><td> NZd</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4217</td><td> p19</td><td> -</td><td> -</td><td> -/+</td><td> -at10</td><td> N/d</td><td> /+</td><td> N/d</td><td> N/d</td>

<td> 4185</td><td> p19</td><td> -</td><td> -</td><td> -/+</td><td> -ai7</td><td> N/d</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4235</td><td> p19</td><td> -</td><td> -</td><td> -/+</td><td> -at10</td><td> N/d</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4090</td><td> p19</td><td> -</td><td> -</td><td> -</td><td> N/d</td><td> N/d</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4647</td><td> p19</td><td></td><td> -</td><td> +/-</td><td> -at10</td><td> -</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4491</td><td> p19</td><td> -</td><td> -</td><td> +/-</td><td> -at10</td><td> -</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4651</td><td> p19</td><td> -</td><td> -</td><td> +/-</td><td> -at10</td><td> -</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4085</td><td> p19*</td><td> -</td><td> -</td><td> -</td><td> -at3</td><td> -</td><td> -</td><td> N/d</td><td> N/d</td>

<td> 4086</td><td> p19*</td><td> -</td><td> -</td><td> -</td><td> - at 5</td><td> N/d</td><td> 4-***</td><td> N/d</td><td> N/d</td>

<td> 4655</td><td> p19*</td><td> -</td><td> -</td><td> -</td><td> -at1O</td><td> -</td><td> q.***</td><td> N/d</td><td> N/d</td>

<td> 4193</td><td> IL-12/IL-23p40</td><td> -</td><td> -</td><td> -/+</td><td> -at6</td><td> 4-</td><td> 4-</td><td> N/d</td><td> N/d</td>

<td> 4201</td><td> IL-12/IL-23p40</td><td> -</td><td> +, no titration</td><td> -/+</td><td> N/d</td><td> 4-</td><td> 4-</td><td> N/d</td><td> N/d</td>

<td> 4704</td><td> IL-12/IL-23p40</td><td> -/+**</td><td> -/+</td><td> -/+</td><td> + at10</td><td> 4-</td><td> 4-</td><td> N/d</td><td> N/d</td>

<td> Symbol</td><td> Description</td>

<td> -</td><td> No inhibition</td>

<td> -/+</td><td> Slight Inhibiiton</td>

<td> +/-</td><td> Weak, incomplete inhibition</td>

<td> +</td><td> Inhibition</td>

<td> ♦</td><td> Did nőt bind to linked rhlL-23 with no His-tag (from R&amp;D Systems)</td>

<td> **</td><td> Better inhibits R&amp;D IL-12, than CNTO IL-12</td>

<td> ’»*</td><td> Caused cell death at high concentration</td>

<td> N/d</td><td> Nőt done</td>

ΕΡ 2 548 577 Β1

Table 4Α: He V-region CDR sequences of candidate antibodies

<td> Clone #</td><td> VH</td><td> H-CDR1 (SEQID NO:)</td><td> H-CDR2 (SEQ ED NO:)</td><td> H-CDR3 (SEQ ID NO:)</td><td> Comments</td>

<td> 4083</td><td> 1A</td><td> NYAIS (1)</td><td> GlIPMF GYANYAQKFQG (7)</td><td> DIYAGMDV (40)</td><td> Primary hit</td>

<td> 5028</td><td></td><td></td><td> Gl XFB'^THY&amp;QKSgG (8)</td><td></td><td> Affinity maturation</td>

<td> 4190</td><td> 1A</td><td> SNYIS (2)</td><td> GIIPIFGHANYAQKFQG (9)</td><td> SKKGMYGGWTYPLMM FDL (41)</td><td> Primary hit</td>

<td> 5033</td><td></td><td></td><td> fi 1FPI-3NAÍYAGKH’QG (10)</td><td></td><td> Affinity maturation</td>

<td> 5034</td><td></td><td></td><td> IXdfnfggOyaqkfqg (11)</td><td></td><td> Affinity maturation</td>

<td> 5036</td><td></td><td></td><td> |XDSWGGAYYAQKFQG (12)</td><td></td><td> Affinity maturation</td>

<td> 5037</td><td></td><td></td><td> |1dpmfggayya.qkfqg (13)</td><td></td><td> Affinity maturation</td>

<td> 5038</td><td></td><td></td><td> -INAHLÖGXfeAQKFQG (14)</td><td></td><td> Affinity maturation</td>

<td> 5040</td><td></td><td></td><td> fS PGTGINáYYAQKFQG (15)</td><td></td><td> Affinity maturation</td>

<td> 4190x</td><td></td><td></td><td> Ζ^Ζ^Ζ^Ζ,ΖθΖ^θΥΑ QKFQG!! (16)</td><td></td><td> Predicted</td>

<td> 4205</td><td> 5</td><td> NYWIS (3)</td><td> WIRPGDSDTRYSPSFEG (17)</td><td> HYYGMDY (42)</td><td> Primary hit</td>

<td> 4217</td><td> 3</td><td> 1.1.1.1.1 sywit (4)</td><td> VSYISSSGSSTYYADSVK G (18)</td><td> GTFWSFGNYFAN (43)</td><td> Primary hit</td>

<td> 4649</td><td> 5</td><td> NYWIG (5)</td><td> IIDPSNSYTNYSPSFQG (19)</td><td> WYYKPFDV (44)</td><td> Primary hit</td>

<td> 4649r</td><td></td><td></td><td> IIDPSNSYTRYSPSFQG (20)</td><td></td><td> Δ glycosylation site</td>

<td> 46491³</td><td></td><td></td><td> IIDPSNSYTRYSPSPQG</td><td></td><td> Plus El substitutions</td>

<td> 4649d</td><td></td><td></td><td> IIDPSNSYTDY5PSFQG (21)</td><td></td><td> Δ glycosylation site</td>

<td> 5041</td><td></td><td></td><td> 1 iSPi^SVWySPSFQG (22)</td><td></td><td> Affinity maturation</td>

<td> 5042</td><td></td><td></td><td> lISPiGSSWYSPSFQG (23)</td><td></td><td> Affinity maturation</td>

<td> 5043</td><td></td><td></td><td> FláFD&amp;$HTWY$P$FQG (24)</td><td></td><td> Affinity maturation</td>

<td> 5044</td><td></td><td></td><td> £IŐPÍG$Ttwy$F$FbG</td><td></td><td> Affinity</td>

ΕΡ 2 548 577 Β1

<td></td><td></td><td></td><td> (25)</td><td></td><td> maturation</td>

<td> 5045</td><td></td><td></td><td> I I SPfG S A WYS P SFQG (26)</td><td></td><td> Affinity maturation</td>

<td> 5046</td><td></td><td></td><td> 11DPVS SWTKYS P SF'QG (27)</td><td></td><td> Affinity maturation</td>

<td> 4649x</td><td></td><td></td><td> IIX₁PX₂X₃SX₄TX₅ YSPSF QG** (28)</td><td></td><td> predicted</td>

<td> 4658</td><td> 3</td><td> SFGMS (6)</td><td> NISSSGSS— TYYADSVKG (29)</td><td> YWGTPYLMQFDN (45)</td><td> Primary hit</td>

<td> 5039</td><td></td><td></td><td> xtlBHKYXNYATYYAASVK G (30)</td><td></td><td> Affinity maturation</td>

<td> 5047</td><td></td><td></td><td> NIEHKYLGYATSYAASVK G (146)</td><td></td><td> Affinity maturation</td>

<td> 5048</td><td></td><td></td><td> |»^|G¥Tr£YA&amp;GVK B(31)</td><td></td><td> Affinity maturation</td>

<td> 5049</td><td></td><td></td><td> GIASKyLGYTTSYAaSVK β:(32)</td><td></td><td> Affinity maturation</td>

<td> 5050</td><td></td><td></td><td> S IKSKYTGYTTYYAAPVK 11(33)</td><td></td><td> Affinity maturation</td>

<td> 5051</td><td></td><td></td><td> íiWkyS.syttlyaasvk 'ti (34)</td><td></td><td> Affinity maturation</td>

<td> 5052</td><td></td><td></td><td> SIOKYAS YTT^YA&amp;SVK 1|(35)</td><td></td><td> Affinity maturation</td>

<td> 5053</td><td></td><td></td><td> NI.BGKYTSYTTYYAAS-VK G (36)</td><td></td><td> Affinity maturation</td>

<td> 5054</td><td></td><td></td><td> GIgÍ3K¥A$YATLYAASVK Íl(37).........</td><td></td><td> Affinity maturation</td>

<td> 5055</td><td></td><td></td><td> $1EH?XXG¥ATVYAA$VK ftl(38)</td><td></td><td> Affinity maturation</td>

<td> 5056</td><td></td><td></td><td> S IÉHKYL-SY’AT YYA&amp;GVR G &lt;39)</td><td></td><td> Affinity maturation</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

All antibodies expressed as Fabs have Q at residue 3 in Vh, whereas when expressed as mAbs, most had E at residue 3.

** X_x is D or S; X₂ is S, V, D, or T; X₃ is N, S, or G; X₄ is Y,

W, Τ, Η, V, S, or A;

X_s is N, D, R_r K_r or W !! Z_x is G, I, or L; Z₂ is I or S; Z₃ is I, P, N, or D; Z₄ is P, G, or A; Z₅ is I, Μ, P,

Τ, Η, N, or V; Z₆ is F, I, G, or L; Z₇ G or I; Z₈ is Η, Y, N, or G; Z_g is A or T; Z₁₀ is N, W, or Y ++ a_x is S or A; a₂ is T or G; a₃ is P or L; a₄ is S or N; a₅ is S, M, or L; a₅ is I or V ## b_x is T, F, D, or S; b₂ is S, I, A, T, R, or L; b₃ is N, T, L, S, or G; b₄ is Τ, Y, S_r or I; b₅ is P or L; b₆ is F or P

ΕΡ 2 548 577 Β1

Table 4Β: LcV-region CDR sequences of candidate antibodies

<td> Clone #</td><td> VL</td><td> L-CDR1 (SEQIDNO:)</td><td> L-CDR2 (SEQ ID NO:)</td><td> L-CDR3 (SEQ ID NO:)</td><td> Comments</td>

<td> 4083</td><td> k3</td><td> RASQSVLGNYLA (46)</td><td> GASSRAT (52)</td><td> HQYGSISTT (58)</td><td> Primary hit</td>

<td> 5267</td><td></td><td></td><td></td><td> QQYSHLLIT (59)</td><td> Affinity maturation</td>

<td> 5268</td><td></td><td></td><td></td><td> QQYSHISLT (60)</td><td> Affinity maturation</td>

<td> 5269</td><td></td><td></td><td></td><td> QQFAHILLT (61)</td><td> Affinity maturation</td>

<td> 4190</td><td> K3</td><td> RASQSVSSNYLA (47)</td><td> YASRRAT (53)</td><td> QQTSNTPFT (62)</td><td> Primary hit</td>

<td> 4190^EV</td><td></td><td></td><td></td><td> QQTSNTPFT</td><td> Plus E1 &amp; V86 substitutions</td>

<td> 5029</td><td></td><td></td><td></td><td> QQFITYLPT (63)</td><td> Affinity maturation</td>

<td> 5030</td><td></td><td></td><td></td><td> QQDALSPFT (64)</td><td> Affinity maturation</td>

<td> 5031</td><td></td><td></td><td></td><td> QQDRGTPFT (65)</td><td> Affinity maturation</td>

<td> 5032</td><td></td><td></td><td></td><td> QQSLNIPFT (66)</td><td> Affinity maturation</td>

<td> 5057</td><td></td><td></td><td></td><td> QQDTSSPFT (67)</td><td> Affinity maturation</td>

<td> 4190x</td><td></td><td></td><td></td><td> QQb₁b₂b₃b₄b₅b₆FT## (68)</td><td> Predicted</td>

<td> 4205</td><td> λ1</td><td> SGSSSNIGSYYV N (48)</td><td> GNTHRPS (54)</td><td> QTYASLGPGEV (69)</td><td> Primary Hit</td>

<td> 4217</td><td> κ1</td><td> RASQSIFYNLA (49)</td><td> GASNRAT (55)</td><td> QQYSSEPVT (70)</td><td> Primary Hit</td>

<td> 4649</td><td> λ1</td><td> TGSSSNIGSGYD VH (50)</td><td> GNSKRPS (56)</td><td> SSWT-PSSW (71)</td><td> Primary hit</td>

<td> 5058</td><td></td><td></td><td></td><td> SSWTDTPNMIV (72)</td><td> Affinity maturation</td>

<td> 5059</td><td></td><td></td><td></td><td> ASWTDGLSLVV (73)</td><td> Affinity maturation</td>

<td> 5059^qs</td><td></td><td></td><td></td><td> ASWTDGLSLVV</td><td> Plus Q1, S2 substitutions</td>

<td> 4649x</td><td></td><td></td><td></td><td> 3-| SWTD I I (74)</td><td> Predicted</td>

<td> 4658</td><td> λ2</td><td> TGTSSDVGGYNSVS (51)</td><td> SVSSRPS (57)</td><td> SSYDTNKPLW (75)</td><td> Primary hit</td>

<td> 5060</td><td></td><td></td><td></td><td> GSYDVYGRFYV (76)</td><td> Affinity maturation</td>

<td> 5061</td><td></td><td></td><td></td><td> SSYYFYLQRIV (77)</td><td> Affinity maturation</td>

<td> 5062</td><td></td><td></td><td></td><td> QTYYFSYSGPV (78)</td><td> Affinity maturation</td>

<td> 5063</td><td></td><td></td><td></td><td> GSWDPIFSYEV (79)</td><td> Affinity maturation</td>

ΕΡ 2 548 577 Β1

Table 4C: Antibodies produced, purified and evaluated

<td> Ab Name</td><td> VH</td><td> VL</td><td> Fab*^#</td><td> MAb*</td><td> Comments</td>

<td> 4083</td><td> 4083</td><td> 4083</td><td> X</td><td> X</td><td></td>

<td> 5028</td><td> 5028</td><td> 4083</td><td> X</td><td> X</td><td></td>

<td> 5267**</td><td> 4083</td><td> 5267</td><td> X</td><td> (in progress)</td><td></td>

<td> 5268**</td><td> 4083</td><td> 5268</td><td> X</td><td> (in progress)</td><td></td>

<td> 5269**</td><td> 4083</td><td> 5269</td><td> X</td><td> (in progress)</td><td></td>

<td> 4190</td><td> 4190</td><td> 4190</td><td> X</td><td> X</td><td></td>

<td> 5033</td><td> 5033</td><td> 4190</td><td></td><td> X</td><td></td>

<td> 5034</td><td> 5034</td><td> 4190</td><td> X</td><td> X</td><td></td>

<td> 5036</td><td> 5036</td><td> 4190</td><td> X</td><td> X</td><td></td>

<td> 5037</td><td> 5037</td><td> 4190</td><td></td><td> X</td><td></td>

<td> 5038</td><td> 5038</td><td> 4190</td><td> X</td><td> X</td><td></td>

<td> 5040</td><td> 5040</td><td> 4190</td><td></td><td> X</td><td></td>

<td> 5040^q/ev</td><td> 5040</td><td> 4190^EV</td><td></td><td> X</td><td> Vh-Q3 back substitution in mAb</td>

<td> 5029**</td><td> 4190</td><td> 5029</td><td></td><td> X</td><td></td>

<td> 5030**</td><td> 4190</td><td> 5030</td><td></td><td> X</td><td></td>

<td> 5031**</td><td> 4190</td><td> 5031</td><td></td><td> X</td><td></td>

<td> 5032**</td><td> 4190</td><td> 5032</td><td></td><td> X</td><td></td>

<td> 5057**</td><td> 4190</td><td> 5057</td><td></td><td> X</td><td></td>

<td> 4205</td><td> 4205</td><td> 4205</td><td> X</td><td> X</td><td></td>

<td> 4217</td><td> 4217</td><td> 4217</td><td> X</td><td> X</td><td></td>

<td> 4649</td><td> 4649</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 5041</td><td> 5041</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 5042</td><td> 5042</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 42-58</td><td> 5042</td><td> 5058</td><td></td><td> X</td><td> Pair 5058 VL with VH lacking CDR2 glycosylation site</td>

<td> 42-59</td><td> 5042</td><td> 5059</td><td></td><td> X</td><td> Pair 5059 VL with VH lacking CDR2 glycosylation site</td>

<td> 5043</td><td> 5043</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 5044</td><td> 5044</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 5045</td><td> 5045</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 45-58</td><td> 5045</td><td> 5058</td><td></td><td> X</td><td> Pair 5058 VL with VH lacking CDR2 glycosylation site</td>

<td> 45-59</td><td> 5045</td><td> 5059</td><td></td><td> X</td><td> Pair 5059 VL with VH lacking CDR2 glycosylation site</td>

<td> 5046</td><td> 5046</td><td> 4649</td><td> X</td><td> X</td><td></td>

<td> 5058</td><td> 4649</td><td> 5058</td><td> X</td><td> X</td><td></td>

<td> 5059</td><td> 4649</td><td> 5058</td><td> X</td><td> X</td><td></td>

ΕΡ 2 548 577 Β1

<td> 3758</td><td> 4649r</td><td> 5058</td><td></td><td> X</td><td></td>

<td> 3759</td><td> 4649r</td><td> 5059</td><td></td><td> X</td><td></td>

<td> 3759^EQ/QS</td><td> 4649r^E</td><td> 5059^QS</td><td></td><td> X</td><td> Vh-Q3 substitution in mAb</td>

<td> 3658</td><td> 4649d</td><td> 5058</td><td></td><td> X</td><td></td>

<td> 3659</td><td> 4649d</td><td> 5059</td><td></td><td> X</td><td></td>

<td> 4658</td><td> 4658</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5039</td><td> 5039</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> |||gg</td><td> 1</td><td> 1</td><td></td><td> |</td><td></td>

<td> 5048</td><td> 5048</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5049</td><td> 5049</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5050</td><td> 5050</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5051</td><td> 5051</td><td> 4658</td><td></td><td> X</td><td></td>

<td> 5052</td><td> 5052</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5053</td><td> 5053</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5054</td><td> 5054</td><td> 4658</td><td></td><td> X</td><td></td>

<td> 5055</td><td> 5055</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5056</td><td> 5056</td><td> 4658</td><td> X</td><td> X</td><td></td>

<td> 5060</td><td> 4658</td><td> 5060</td><td> X</td><td> X</td><td></td>

<td> 5061</td><td> 4658</td><td> 5061</td><td> X</td><td> X</td><td></td>

<td> 5062</td><td> 4658</td><td> 5062</td><td> X</td><td> X</td><td></td>

<td> 5063</td><td> 4658</td><td> 5063</td><td> X</td><td> X</td><td></td>

* Except as indicated in the “comments” box, position 3 in the heavy chain was Q in the Fabs and E in the mAbs.

** The affinity matured kappa light chains of 4083 and 4190 contain a T to V substitution relatíve to the parents in FW3 (FAVYYC). V is a germline residue at this position.

Several Fabs listed as “affinity matured” showed somé aggregation during purification and thus were nőt evaluated. They were previously evaluated as hits as crude samples.

Table 5: Characterization of Affinity-Matured Fabs: specificity, receptor neutralization, and affinity.

<td> MORO# 4083</td><td> Library</td><td> K_D[pM]SET (n: 1) 1600</td><td> IL-23/IL-23R IC so [nM](n: 1 -4) 7.1 ± 8.3</td><td> IL -23/ IL-12R ^b1 O.K</td><td> IL -12 (R&amp;D)/ IL -12R b., O.K.</td><td> Specificity ELISA O.K.</td><td> FACS (TALL -104)</td>

<td> 5028</td><td> H-CDR2</td><td> 133</td><td> 0.43 ± 0.58</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5267</td><td></td><td> 2000</td><td> 0.14</td><td> O.K.</td><td> O.K.</td><td> n.d.</td><td> n.d.</td>

<td> 5268</td><td> L-CDR3</td><td> 660</td><td> 0.15</td><td> O.K.</td><td> O.K.</td><td> n.d.</td><td> n.d.</td>

<td> 5269</td><td></td><td> 960</td><td> 0.2</td><td> O.K.</td><td> O.K.</td><td> n.d.</td><td> n.d.</td>

<td> 4190</td><td> -</td><td> 4400</td><td> 1.3 ± 1.5</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

ΕΡ 2 548 577 Β1 (continued)

<td> MORO# 4083</td><td> Library</td><td> K_D[pM]SET (n: 1) 1600</td><td> IL-23/IL-23R IC go [nM](n: 1 -4) 7.1 ± 8.3</td><td> IL -23/ IL-12R ^b1 O.K</td><td> IL-12 (R&amp;D)/IL -12R b., O.K.</td><td> Specificity ELISA O.K.</td><td> FACS (TALL -104)</td>

<td> 5034</td><td></td><td> 126</td><td> 0.4 ± 0.15</td><td> O.K.</td><td> O.K.</td><td> O.K</td><td> -</td>

<td> 5036</td><td> H-CDR2</td><td> 32</td><td> 0.32 ± 0.02</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5038</td><td> -</td><td> 38</td><td> 0.17 ± 0.05</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 4649</td><td></td><td> 1100</td><td> 1.2</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5041</td><td></td><td> 41</td><td> 0.07 ± 0.04</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5042</td><td></td><td> 4</td><td> 0.06 ± 0.03</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5043</td><td rowspan="2"> H-CDR2</td><td> 18</td><td> 0.05 ± 0.03</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5044</td><td> 43</td><td> 0.05 ± 0.04</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5045</td><td></td><td> 9</td><td> 0.05 ± 0.02</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5046</td><td></td><td> 23</td><td> 0.08 ± 0.01</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5058</td><td rowspan="2"> L-CDR3</td><td> 33</td><td> 0.11 ± 0.08</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

<td> 5059</td><td> 93</td><td> 0.69 ± 0.72</td><td> O.K.</td><td> O.K.</td><td> O.K.</td><td> -</td>

ΕΡ 2 548 577 Β1

Table 7: Characterization of Affinity-Matured Antibodies in mAb Formát: Inhibition of IL-17 production.

Inhibition of hrIL-23 binding to immobilized IL-23R-Fc tusion protein. IC50 values írom titration curves.

The mAbs (see Table 4C) are listed in order of decreasing potency. The matured antibodies are grouped according to their respective parents: pink (5028 is írom 4083); (5040, 5038, 5029, 5030, 5057, 5036, 5032, 5034, 5033, and 5037 are with 4190); (5042, 5045, 5058, 5041, 5059, 5044, 5043, 5046, and 4083 are with 4649); (5054, 5053, 5049, 5048, 5052, 5047, 5050, 5051, 5055, 5056, 5039, 5063, 5062, and 5061 are with 4658). MAb 23A is a reference murine anti-human IL-23 mAb

<td> mAb</td><td> IC50, ug/ml</td>

<td> ....../''“ííÖaÖÉ ;</td><td> 0.00127</td>

<td></td><td> 0.001396</td>

<td> 5040</td><td> 0.002641</td>

<td> 595«</td><td> 0.002847</td>

<td> 7.....</td><td> 0.003007</td>

<td> 5054</td><td> 0.003227</td>

<td> 5053</td><td> 0.00493</td>

<td> 5659</td><td> 0.01062</td>

<td> : ““ ‘ “®Q44 ‘ '</td><td> 0.01414</td>

<td> i - «943 ' '</td><td> 0.01439</td>

<td> 5049</td><td> 0.01616</td>

<td> 5043</td><td> 0.01624</td>

<td> 5052</td><td> 0.0178</td>

<td> 5047</td><td> 0.02342</td>

<td> 5050</td><td> 0.02766</td>

<td> 5038</td><td> 0.02815</td>

<td> 364«</td><td> 0.04281</td>

<td> 5029</td><td> 0.04907</td>

<td> mAb23A</td><td> 0.05415</td>

<td> 5030</td><td> 0.06458</td>

<td> 5051</td><td> 0.0663</td>

<td> 5055</td><td> 0.09155</td>

<td> 5053</td><td> 0.09198</td>

<td> .......W¹</td><td> 0.1039</td>

<td> 5Ö57</td><td> 0.1103</td>

<td> 5039</td><td> 0.1606</td>

<td> 5035</td><td> 0.1702</td>

<td> 5032</td><td> 0.1716</td>

<td> 5034</td><td> 0.1854</td>

<td> 5053</td><td> 0.1981</td>

<td> 50&amp;2</td><td> 0.1989</td>

<td> 5031</td><td> 0.2149</td>

<td> 4190</td><td> 0.218</td>

<td> «β»»</td><td></td>

<td> 5033</td><td> 0.2834</td>

<td> 5051</td><td> 0.3087</td>

<td> 5037</td><td> 0.3364</td>

<td></td><td></td>

<td></td><td></td>

ΕΡ 2 548 577 Β1

Table 8. Sequences of initial IL-23pl9 mAbs and their matured and engineered derivatives.

MOR04083 Family (SEQ ID NOS: 80 &amp; 81)

117

4083 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGI,EWMGGIIPMFGYANYAQKFQGRVTITAPESTSTA

YMELSSFRSEDTAVY YGARD1YAGMDVWGQGTLVTVSS

5028 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGGIIP vFGf thYAQKFQGRVT ITADESTSTA

YMELSSLRSEOTAVYYCARPIYAGMOVWGQGTLVTVSS (SEQ ID NOS: 82-85)

108

4083 Vk (1)

DIVLTQSPATIiSIiSPGERATLSCRASQSVIjGNYLAWYQQKPGQAPRLIiIYGASSRATGVPARFSGSGSGTPFTIiTISSL·

EPEDFAVYYCHQYGSISTTFGQGTKVEIK

5268 Vk (1)

OIVLTQSPATLSLSPGERATLSCRASQSVLGNYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSL

EPEPFAVYYCqQYshlSLTFGQGTKVEIK

5267 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVLGNYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSL

EPEDFAVYYCqQYshlilTFGQGTKVEIK

5269 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVLGNYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSL

EPEDFAVYYCqQfahlllTFGQGTKVEIK

MOR04190 Family (SEQ ID NOS: 86-92)

127

4190 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYmWVRQAPGQGLEWMGGIIPIFGHANYAQKFQGRVTITADESTSTA

ΥΜΕΕ53Ι.Κ3ΕΡΤΑνΥΥ0ΑΕ3ΚΚ6ΜΥ66ΜΤΥΡΕΜΜΡΡΕΜ606ΤΕνΤν33

5033 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGilIPpiGnAwYAQKFQGRVTITADESTSTA

YMELSSLRSEDTAVYYCARSKKGMYGGWTYPLMMFDLWGQGTLVTVSS

5040 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGispgtginAyYAQKFQGRVTITADESTSTA

YMELSSLRSEOTAVYYCARSKKGMYGGWTYPLMMFDLWGQGTLVTVSS

5038 Vh (1) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGInahlGgtwYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARSKKGMYGGWTYPLMMFDIiWGQGTLVTVSS

5034 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGlIdPnFGgAyYAQKFQGRVTITADESTSTA

YMELSSLRSEDTAVYYCARSKKGMYGGWTYPLMMFDLWGQGTLVTVSS

5036 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGlIdPvFGgAyYAQKFQGRVTITADESTSTA

YMELSSLRSEDTAVYYCARSKKGMYGGWTYPLMMFDLWGQGTLVTVSS

5037 Vh (1)

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSNYISWVRQAPGQGLEWMGlIdPmFGgAyYAQKFQGRVTITADESTSTA

YMELSSLRSEDTAVYYCARSKKGMYGGWTYPLMMFDLWGQGTLVTVSS

EP 2 548 577 Β1 (SEQ ID NOS: 93-98)

108

4190 Vk (1)

ΡΐνΐΤ03ΡΑΤΙ,3ί5ΡεΕΚΑΤΤ3εΚΑ505ν35ΝΥΙΑΜΥ00ΚΡ60ΑΡΚ1₁Ι₁ΙΥΥΑ5ΚΚΑΤΕνΡΑΚΓ565636ΤΡΓΤίΤΙ53Π EPEDFATYYCQQTSNTPFTFGQGTKVEIK 4190^EVVk (1)

EIVLTQSPATLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLI.IYYASRRATGVPARFSGSGSGTDFTLTISSL

EPEPFAvYYCQQTSNTPFTFGQGTKVEIK

5029 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYYASRRATGVPARFSGSGSGTDFTLTISSL EPEDFAvYYCQQfitylpTFGQGTKVEIK

5030 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYYASRRATGVPARFSGSGSGTDFTLTISSL

EPEDFAvYYCQQdalsPFTFGQGTKVEIK

5031 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLIjIYYASRRATGVPARFSGSGSGTDFTLTISSL

EPEDFAvYYCQQdrgTPFTFGQGTKVEIK

5032 Vk (1)

DIVLTQSPATLSLSPGERATLSCRASQSVSSNYLAWYQQKPGQAPRLLIYYASRRATGVPARFSGSGSGTDFTLTISSL

EPEDFAvYYCQQslNiPFTFGQGTKVEIK

ΕΡ 2 548 577 Β1

MOR04205 (SEQ ID NO: 99)

116

4205 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFINYWmWVRQAPGKGLEWMGWIRPGOSOTRYSPSFEGQVTISADKSISTA

YLQWSSLKASPTAMYYCARHYYGMDYWGQGTLVTVSS (SEQ ID NO: 100)

110

4205 VI (1)

DIVLTQPPSVSGAPGQRVTISCSGSSSNmgYYVNWYQQLPGTAPKLLIYGNTHRPSGVPORFSGSKSGTSASLAITGL·

ΟεΕΡΕΑΡΥΥΟΏΤΥΑδΙΟΡΰΕνΡΟΰΰΤΚΕΤνΕ

MOR04217 (SEQ ID NO: 101)

121

4217 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMWVRQAPGKGLEWVSWjSSGSSTYYADSVKGRFTISRDNSKNTIi

YLQMN'SLRAEDTAVYYCAPGTFMSFGNYFAIJWGQGYLVTVSS (SEQ ID NO: 102)

107

4217 Vk (1)

DÍVLTQSPATLSLSPGERATLSCRASQSJTYOTiAWYQQKPGQAPRLLIYGASNRATGVPARFSGSGSGTDFTLTISSLE

PEPFATYYCQQYSSEPVTFGQGTKVEIK

MOR04649 Family (SEQ ID NOS: 103-112)

117

4649 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFStfYWmOTRQMPGKGLEWMG]UÖ3E^3NSYTNYSPSFQGQVTISADKSISTA

YLQWSSLKASDTMlYYCARWYYKPFpyWGQGTLVTVSS

4649d Vh (1)

QVQLVQSCABVKKPCESLKISCKGSGYSFSNYWICWVRQMPCKCLEWMCIIPPSNSYTdYSPSFQCQVTISADKSISTA

YLQWSSLKASDTAMYYCARWYYKPFPVWGQGTLVTVSS

4649r Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIDPSNSYTrYSPSFQGQVTISADKSISTA

YLQWSSLKASPTAMYYCARWYYKPFDVWGQGTLVTVSS

4649r^E Vh (1) eVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIPPSNSYTrYSPSFQGQVTIS/WKSISTAYLQWSSLKASDTAMYYCARWYYKPFPVWGQGTLVTVSS

5046 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIDPvsSwTkYSPSFQGQVTISAPKSISTA

YLQWSSLKASPTAMYYCARWYYKPFPVWGQGTLVTVSS

5044 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIsPSgStTwYSPSFQGQVTISAPKSISTA

YLQWSSLKASDTAMYYCARWYYKPFDVWGQGTLVTVSS

5043 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGf IsPdgShTwYSPSFQGQVTISAPKSISTA

YLQWSSLKASDTAMYYCARWYYKPFPVWGQGTLVTVSS

5041 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIISPtgSvTwYSPSFQGQVTISAPKSISTA

YLQWSSLKASDTAMYYCARWYYKPFPVWGQGTLVTVSS

ΕΡ 2 548 577 Β1

5042 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIsPtgSsTwYSPSFQGQVTISAPKSISTA YLQWSSLKASBTAMYYCARWYYKPFDVWGQGTLVTVSS 5045 Vh (1)

QVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIsPtgSaTwYSPSFQGQVTISADKSISTA

YLQWSSLKA.SDTAMYYCARWYYKPFDVWGQGTLVTVSS * Consensus N-linked glycosylation site in 4649 Vh (SEQ ID NOS: 113-116)

111

4649 VL (1)

PIVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKLLIYGNSKRPSGVPPRFSGSKSGTSASLAITG LQSEDEADYYCSSWT—PSSWFGGGTKLTVL

5058 VL (1)

DIVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKLLIYGNSKRPSGVPDRFSGSKSGTSASLAITG

LQSEDEADYYCSSWTdtPnmiVFGGGTKLTVL

5059 VL (1)

RIVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKLLIYGNSKRPSGVPDRFSGSKSGTSASLAITG LQSEDEAPYYCaSWTdglSlWFGGGTKLTVL 5059^esVL (1) qsVLTQPPSVSGAPGQRVTISCTGSSSNIGSGYDVHWYQQLPGTAPKLLIYGNSKRPSGVPDRFSGSKSGTSASLAITG

LQSEPEAPYYCaSWTdglSlWFGGGTKLTVL

EP 2 548 577 Β1

MOR04658 Family (SEQ ID NOS: 117-127)

123

4658 Vh (1) QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGÍGSWRQAPGKGLEWVSNISSS^

GS^TEQÍÍWSyigGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5048 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSNIehkfmGytTYYAagVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5050 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFT FSSFGMSWVRQAPGKGLEWVS S IehkytGy tTYYAapVKGRFT ISRDNSKN TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5053 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSNIehkytsytTYYAaSVKGRFTISRDNSKN TLYLQMNSL'RAEDTAVY YCARYWGTP YLMQFDNWGQGTLVTVSS 5039 -Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSNIehkylnyaTYYAaSVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5055 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSNIehkylGyaTvYAaSVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5056 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSsIehkylsyaTYYAagVKGRFTISRDNSKN 1LYLQMNST3RAEDTR.VYYCRRYWGTPYLM.QFONWGQGTÍVTVSS 5052 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSsIehkylaytTfYAaSVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5049 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSglehkylsytThYAaSVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5051 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSqlehkylsytTlYAaSVKGRFTISRDNSKN

TLYLQMNSLRAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS

5054 -Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSglehkylsyaT'lYAaSVKGRFTISRDNSKN

ΤΕΥΕ0ΜΝ3ΕΡΑΕϋΤΑνΥΥΰΑΡΥΜΘΤΡΥΕΜ0ΕΒΝΜΘ06ΤΕνΤν33 (SEQ ID NO: 147)

5047 Vh (1)

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSNIehkylGyaTsYAaSVKGRFTISRDNSKNTLYLQMNSL

RAEDTAVYYCARYWGTPYLMQFDNWGQGTLVTVSS (SEQ ID NOS: 128-132)

111

4658 VL (1)

DIAI.TQPASVSGSPGQSITISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYSVSSRPSGVSNRFSGSKSGNTASI_ITISG LQAE DEADYYCSSYDTNKPLyyFGGGTKLTVL

5061 VL (1)

DIALTQPASVSGSPGQSITISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYSVSSRPSGVSNRFSGSKSGNTASLTISG LQAE DEADY YCS S Yyf ylqriVFGGGTKLTVL

5062 VL (1)

DIALTQPASVSGSPGQSITISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYSVSSRPSGVSNRFSGSKSGNTASLTISG LQAEDEADYYCqtYyf sysgpVFGGGTKLTVL 5060 VL (1)

DIALTQPASVSGSPGQSITISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYSVSSRPSGVSNRFSGSKSGNTASLTISG LQAEDEADYYCgSYDvygrfyVFGGGTKLTVL

5063 VL (1)

DIALTQPASVSGSPGQSITISCTGTSSDVGGYNSVSWYQQHPGKAPKLMIYSVSSRPSGVSNRFSGSKSGNTASLTISG LQAEDEADYYCgSwDpifsyeVFGGGTKLTVL

EP 2 548 577 Β1

Table 9 - Nucleotide Sequences

IL-23 pl9 5040^q/ev

VH-GCE (SEQ ID NO:133): (VH amino acid sequence is 5040Vh)

Q V Q L VQS GAE VKKP G S S 1 CAGGTGCAGC TGGTGCAGTC TGGGGCTGAG GTGAAGAAGC CTGGGTCCTC

GTCCACGTCG ACCACGTCAG ACCCCGACTC CACTTCTTCG GACCCAGGAG

CDR1 •VKV SCKA SGG TFS S N Y I · 51 GGTGAAGGTC TCCTGCAAGG CTTCTGGAGG CACCTTCAGC AGCAACTACA

CCACTTCCAG AGGACGTTCC GAAGACCTCC GTGGAAGTCG TCGTTGATGT

- SWV RQA PGQG LEW MGI 101 TCAGCTGGGT GCGACAGGCC CCTGGACAAG GGCTTGAGTG GATGGGGATC

AGTCGACCCA CGCTGTCCGG GGACCTGTTC CCGAACTCAC CTACCCCTAG

CDR2

SPGT GIN AYY A Q K F Q G R · 151 AGCCCTGGCA CCGGTATCAA CGCATACTAC GCACAGAAGT TCCAGGGCAG

TCGGGACCGT GGCCATAGTT GCGTATGATG CGTGTCTTCA AGGTCCCGTC •VTI TADE STS ΤΑΥ Μ E L S · 201 AGTCACGATT ACCGCGGACG AATCCACGAG CACAGCCTAC ATGGAGCTGA

TCAGTGCTAA TGGCGCCTGC TTAGGTGCTC GTGTCGGATG TACCTCGACT

CDR3 • SLR SÉD TAVY YCA RSK 251 GCAGCCTGAG ATCTGAGGAC ACGGCCGTGT ATTACTGTGC GAGAAGCAAG

CGTCGGACTC TAGACTCCTG TGCCGGCACA TAATGACACG CTCTTCGTTC

CDR3

KGMY GGW TYP LMMF DLW301 AAGGGCATGT ACGGCGGCTG GACCTACCCC CTGATGATGT TCGACCTGTG

TTCCCGTACA TGCCGCCGAC CTGGATGGGG GACTACTACA AGCTGGACAC •GQG TLVT VSS 351 GGGCCAGGGC ACCCTGGTGA CCGTGAGCAG C

CCCGGTCCCG TGGGACCACT GGCACTCGTC G

ΕΡ 2 548 577 Β1

IL-23 ρ19 5040^Q/EV

VH-HCO (SEQ ID NO:134): (VH amino acid sequence is 5040Vh)

QVQL VQS GAE VKKP G S S ·

CAGGTGCAGC TGGTGCAGAG CGGCGCCGAG GTGAAGAAGC CCGGCAGCAG

GTCCACGTCG ACCACGTCTC GCCGCGGCTC CACTTCTTCG GGCCGTCGTC

CDR1 •VKV SCKA SGG TFS S N Y I · 51 CGTGAAGGTG AGCTGCAAGG CCAGCGGCGG CACCTTCAGC AGCAACTACA

GCACTTCCAC TCGACGTTCC GGTCGCCGCC GTGGAAGTCG TCGTTGATGT • S W V RQA PGQG LEW M G I 101 TCAGCTGGGT GCGCCAGGCC CCCGGCCAGG GCCTGGAGTG GATGGGCATC

AGTCGACCCA CGCGGTCCGG GGGCCGGTCC CGGACCTCAC CTACCCGTAG

CDR2

SPGT GIN AYY AQKF Q G R 151 AGCCCCGGCA CCGGCATCAA CGCCTACTAC GCCCAGAAGT TCCAGGGCCG

TCGGGGCCGT GGCCGTAGTT GCGGATGATG CGGGTCTTCA AGGTCCCGGC •VTI TADE STS ΤΑΥ Μ E L S 201 CGTGACCATC ACCGCCGACG AGAGCACCAG CACCGCCTAC ATGGAGCTGA

GCACTGGTAG TGGCGGCTGC TCTCGTGGTC GTGGCGGATG TACCTCGACT • SLR SÉD TAVY YCA RSK 251 GCAGCCTGCG CAGCGAGGAC ACCGCCGTGT ACTACTGCGC CCGCAGCAAG

CGTCGGACGC GTCGCTCCTG TGGCGGCACA TGATGACGCG GGCGTCGTTC

CDR3

KGMY GGW TYP LMMF D L W · 301 AAGGGCATGT ACGGCGGCTG GACCTACCCC CTGATGATGT TCGACCTGTG

TTCCCGTACA TGCCGCCGAC CTGGATGGGG GACTACTACA AGCTGGACAC •GQG TLVT VSS 351 GGGCCAGGGC ACCCTGGTGA CCGTGAGCAG C

CCCGGTCCCG TGGGACCACT GGCACTCGTC G

ΕΡ 2 548 577 Β1

IL-23 ρ19 5040^Q/EV

VH-MOR (SEQ ID ΝΟ:135): (VH amino acid sequence is 5040vh)

QVQL VQS GAE VKKP GSS·

CAGGTGCAAT TGGTTCAGTC TGGCGCGGAA GTGAAAAAAC CGGGCAGCAG

GTCCACGTTA ACCAAGTCAG ACCGCGCCTT CACTTTTTTG GCCCGTCGTC

CDR1

-VKV SCKA SGG TFS S N Y I · Sl CGTGAAAGTG AGCTGCAAAG CCTCCGGAGG CACTTTTTCT TCTAATTATA

GCACTTTCAC TCGACGTTTC GGAGGCCTCC GTGAAAAAGA AGATTAATAT • SWV RQA PGQG LEW MGI 101 TTTCTTGGGT GCGCCAAGCC CCTGGGCAGG GTCTCGAGTG GATGGGCATT

AAAGAACCCA CGCGGTTCGG GGACCCGTCC CAGAGCTCAC CTACCCGTAA

CDR2

SPGT GIN AYY AQKF Q G R · 151 TCTCCTGGTA CTGGTATTAA TGCTTATTAT GCTCAGAAGT TTCAGGGTCG

AGAGGACCAT GACCATAATT ACGAATAATA CGAGTCTTCA AAGTCCCAGC

-VTI TADE STS TAY MELS201 GGTGACCATT ACCGCGGATG AAAGCACCAG CACCGCGTAT ATGGAACTGA

CCACTGGTAA TGGCGCCTAC TTTCGTGGTC GTGGCGCATA TACCTTGACT

SLR SÉD TAVY YCA RSK 251 GCAGCCTGCG TAGCGAAGAT ACGGCCGTGT ATTATTGCGC GCGTTCTAAG

CGTCGGACGC ATCGCTTCTA TGCCGGCACA TAATAACGCG CGCAAGATTC

CDR3

K G Μ Y GGW TYP LMMF DLW301 AAGGGTATGT ATGGTGGTTG GACTTATCCT CTTATGATGT TTGATCTTTG

TTCCCATACA TACCACCAAC CTGAATAGGA GAATACTACA AACTAGAAAC

-GQG TLVT VSS 351 GGGCCAAGGC ACCCTGGTGA CGGTTAGCTC A

CCCGGTTCCG TGGGACCACT GCCAATCGAG T

ΕΡ 2 548 577 Β1

IL-23 ρ19 5040^q/ev

VK-HCO (SEQ ID NO: 136): (VK amino acid sequence is 4190^EV)

EIVL T Q Ξ P A T LSLS P G E 1 GAGATCGTGC TGACCCAGAG CCCCGCCACC CTGAGCCTGA GCCCCGGCGA

CTCTAGCACG ACTGGGTCTC GGGGCGGTGG GACTCGGACT CGGGGCCGCT

CDR1 • R A T LSCR ASQ SVS S N Y L 51 GCGCGCCACC CTGAGCTGCC GCGCCAGCCA GAGCGTGAGC AGCAACTACC

CGCGCGGTGG GACTCGACGG CGCGGTCGGT CTCGCACTCG TCGTTGATGG •AWY Q Q K P G Q A PRL LIY 101 TGGCCTGGTA CCAGCAGAAG CCCGGCCAGG CCCCCCGCCT GCTGATCTAC

ACCGGACCAT GGTCGTCTTC GGGCCGGTCC GGGGGGCGGA CGACTAGATG

CDR2

YASR RAT GVP ARFS G S G · 151 TACGCCAGCC GCCGCGCCAC CGGCGTGCCC GCCCGCTTCA GCGGCAGCGG

ATGCGGTCGG CGGCGCGGTG GCCGCACGGG CGGGCGAAGT CGCCGTCGCC

-SGT DFTL TIS SLE PEDF201 CAGCGGCACC GACTTCACCC TGACCATCAG CAGCCTGGAG CCCGAGGACT

GTCGCCGTGG CTGAAGTGGG ACTGGTAGTC GTCGGACCTC GGGCTCCTGA

CDR3

AVY YCQ QTSN TPF TFG 251 TCGCCGTGTA CTACTGCCAG CAGACCAGCA ACACCCCCTT CACCTTCGGC

AGCGGCACAT GATGACGGTC GTCTGGTCGT TGTGGGGGAA GTGGAAGCCG

QGTK VEI K 301 CAGGGCACCA AGGTGGAGAT CAAG

GTCCCGTGGT TCCACCTCTA GTTC

ΕΡ 2 548 577 Β1

IL-23 ρ19 5040^Q/EV

VK-HCO (SEQ ID ΝΟ:137): (VK amino acid sequence is 4190^EV)

EIVL TQS Ρ A T LSLS P G E 1 GAAATTGTGT TGACACAGTC TCCAGCCACC CTGTCTTTGT CTCCAGGGGA

CTTTAACACA ACTGTGTCAG AGGTCGGTGG GACAGAAACA GAGGTCCCCT

CDR1 •RAT LSCR ASQ SVS SNYL51 AAGAGCCACC CTCTCCTGCA GGGCCAGTCA GAGTGTTAGC AGCAACTACT

TTCTCGGTGG GAGAGGACGT CCCGGTCAGT CTCACAATCG TCGTTGATGA • AWY QQK PGQA PRL L I Y 101 TAGCCTGGTA CCAACAGAAA CCTGGCCAGG CTCCCAGGCT CCTCATCTAT

ATCGGACCAT GGTTGTCTTT GGACCGGTCC GAGGGTCCGA GGAGTAGATA

CDR2

YASR RAT GVP ARFS GSG15.1 TACGCATCCC GCAGGGCCAC TGGCGTGCCA GCCAGGTTCA GTGGCAGTGG

ATGCGTAGGG CGTCCCGGTG ACCGCACGGT CGGTCCAAGT CACCGTCACC •SGT DFTL TIS SLE PEDF201 GTCTGGGACA GACTTCACTC TCACCATCAG CAGCCTAGAG CCTGAAGATT

CAGACCCTGT CTGAAGTGAG AGTGGTAGTC GTCGGATCTC GGACTTCTAA

CDR3

- AVY YCQ QTSN TPF TFG 251 TTGCAGTTTA TTACTGTCAG CAGACTTCTA ATACTCCTTT TACCTTTGGC

AACGTCAAAT AATGACAGTC GTCTGAAGAT TATGAGGAAA ATGGAAACCG

QGTK VEI K 301 CAGGGTACGA AAGTTGAAAT TAAA

GTCCCATGCT TTCAACTTTA ATTT

EP 2 548 577 Β1

IL-23 pl9 5040^q/ev

VK-HCO (SEQ ID NO: 138) : (VK amino acid sequence is 4190^EV)

EIVL TQS P A T LSLS PGEI GAGATCGTGC TGACCCAGAG CCCGGCGACC CTGAGCCTGT CTCCGGGCGA

CTCTAGCACG ACTGGGTCTC GGGCCGCTGG GACTCGGACA GAGGCCCGCT

CDR1 •RAT LSCR ASQ SVS SNYL· 51 ACGTGCGACC CTGAGCTGCA GAGCGAGCCA GTCTGTTTCT TCTAATTATC

TGCACGCTGG GACTCGACGT CTCGCTCGGT CAGACAAAGA AGATTAATAG • AWY QQK PGQA PRL LIY 101 TGGCTTGGTA CCAGCAGAAA CCAGGTCAAG CACCGCGTCT ATTAATTTAT

ACCGAACCAT GGTCGTCTTT GGTCCAGTTC GTGGCGCAGA TAATTAAATA

CDR2

YASR RAT GVP ARFS G Ξ G 151 TATGCTTCTC GTCGTGCAAC TGGGGTCCCG GCGCGTTTTA GCGGCTCTGG

ATACGAAGAG CAGCACGTTG ACCCCAGGGC CGCGCAAAAT CGCCGAGACC •SGT DFTL TIS SLE PEDF· 201 ATCCGGCACG GATTTTACCC TGACCATTAG CAGCCTGGAA CCTGAAGACT

TAGGCCGTGC CTAAAATGGG ACTGGTAATC GTCGGACCTT GGACTTCTGA

CDR3 • AVY YCQ QTSN TPF TFG 251 TTGCGGTGTA TTATTGCCAG CAGACTTCTA ATACTCCTTT TACCTTTGGC

AACGCCACAT AATAACGGTC GTCTGAAGAT TATGAGGAAA ATGGAAACCG

QGTK VEI K 301 CAGGGTACGA AAGTTGAAAT TAAA

GTCCCATGCT TTCAACTTTA ATTT

ΕΡ 2 548 577 Β1

IL-23 ρ19 3759^eq/qs

VH-GCE (SEQ ID NO:139) : (VH amino acid sequence ís 4 649r^B)

EVQL VQS GAE VKKP G E S ·

GAGGTGCAGC TGGTGCAGTC TGGAGCAGAG GTGAAAAAGC CCGGGGAGTC

CTCCACGTCG ACCACGTCAG ACCTCGTCTC CACTTTTTCG GGCCCCTCAG

CDR1

-LKI SC KG SGY SFS N Y W I 51 TCTGAAGATC TCCTGTAAGG GTTCTGGATA CAGCTTTAGC AACTACTGGA

AGACTTCTAG AGGACATTCC CAAGACCTAT GTCGAAATCG TTGATGACCT

- GWV RQM PGKG LEW MGI lül TCGGCTGGGT GCGCCAGATG CCCGGGAAAG GCCTGGAGTG GATGGGGATC

AGCCGACCCA CGCGGTCTAC GGGCCCTTTC CGGACCTCAC CTACCCCTAG

CDR2

IDPS NSY TRY SPSP Q G Q · ISI ATCGACCCTA GCAACTCTTA CACCAGATAC AGCCCGTCCT TCCAAGGCCA

TAGCTGGGAT CGTTGAGAAT GTGGTCTATG TCGGGCAGGA AGGTTCCGGT • V T I SADK SIS TAY L Q W S · 201 GGTCACCATC TCAGCCGACA AGTCCATCAG CACCGCCTAC CTGCAGTGGA

CCAGTGGTAG AGTCGGCTGT TCAGGTAGTC GTGGCGGATG GACGTCACCT • S L K ÁSD TAMY YCA R W Y 251 GCAGCCTGAA GGCCTCGGAC ACCGCCATGT ATTACTGTGC GAGATGGTAC

CGTCGGACTT CCGGAGCCTG TGGCGGTACA TAATGACACG CTCTACCATG

CDR3

YKPF DVW GQG TLVT VSS301 TACAAGCCCT TCGACGTGTG GGGCCAGGGC ACCCTGGTGA CCGTGAGCAG

AGGTTCGGGA AGCTGCACAC CCCGGTCCCG TGGGACCACT GGCACTCGTC

- S

351 C G

ΕΡ 2 548 577 Β1

IL-23 ρ19 3 759^EQA!S

VH-HCO (SEQ ID NO:140): (VH amino acid sequence is 4649r^E)

EVQL VQS GAE V Κ Κ P G E S ·

I GAGGTGCAGC TGGTGCAGAG CGGCGCCGAG GTGAAGAAGC CCGGCGAGAG

CTCCACGTCG ACCACGTCTC GCCGCGGCTC CACTTCTTCG GGCCGCTCTC

CDR1 • L Κ I SCKG SGY SFS NYWI· 51 CCTGAAGATC AGCTGCAAGG GCAGCGGCTA CAGCTTCAGC AACTACTGGA

GGACTTCTAG TCGACGTTCC CGTCGCCGAT GTCGAAGTCG TTGATGACCT • GWV RQM PGKG LEW MGI 101 TCGGCTGGGT GCGCCAGATG CCCGGCAAGG GCCTGGAGTG GATGGGCATC

AGCCGACCCA CGCGGTCTAC GGGCCGTTCC CGGACCTCAC CTACCCGTAG

CDR2

IDPS NSY TRY SPSF Q G Q · 151 ATCGACCCCA GCAACAGCTA CACCCGCTAC AGCCCCAGCT TCCAGGGCCA

TAGCTGGGGT CGTTGTCGAT GTGGGCGATG TCGGGGTCGA AGGTCCCGGT

- V T I SADK SIS TAY LQWS· 2GI GGTGACCATC AGCGCCGACA AGAGCATCAG CACCGCCTAC CTGCAGTGGA

CCACTGGTAG TCGCGGCTGT TCTCGTAGTC GTGGCGGATG GACGTCACCT • SLK ÁSD TAMY YCA RWY 251 GCAGCCTGAA GGCCAGCGAC ACCGCCATGT ACTACTGCGC CCGCTGGTAC

CGTCGGACTT CCGGTCGCTG TGGCGGTACA TGATGACGCG GGCGACCATG

CDR3

YKPF DVW GQG TLVT V S S 301 TACAAGCCCT TCGACGTGTG GGGCCAGGGC ACCCTGGTGA CCGTGAGCAG

ATGTTCGGGA AGCTGCACAC CCCGGTCCCG TGGGACCACT GGCACTCGTC • S

351 C G

EP 2 548 577 Β1

IL-23 pl9 3759^EÍ/t!S

VH-MÓR (SEQ ID NO.-141): (VH amino acid sequence is 4649r^E)

EVQL VQS GAE VKKP G E S ·

GAGGTGCAAT IGGTTCAGAG CGGCGCGGAA GTGAAAAAAC CGGGCGAAAG

CICCACGTTA ACCAAGTCTC GCCGCGCCTT CACTTTTTTG GCCCGCTTTC

CDR1 •LKI SCKG SGY SFS N Y W I · 1 CCTGAAAATT AGCTGCAAAG GTTCCGGATA TTCCTTTTCT AATTATTGGA

GGACTTTTAA ICGACGTTTC CAAGGCCTAT AAGGAAAAGA TTAATAACCT • GWV RQM PGKG LEW M G I 1.01 TTGGTTGGGT GCGCCAGATG CCTGGGAAGG GTCTCGAGTG GATGGGCATT

AACCAACCCA CGCGGTCTAC GGACCCTTCC CAGAGCTCAC CTACCCGTAA CDR2

IDPS NSY TRY SPSF Q G Q 151 ATCGATCCGT CTAATAGCTA IACCCGCTAT TCTCCGAGCT TTCAGGGCCA

TAGCTAGGCA GATTATCGAT ATGGGCGATA AGAGGCTCGA AAGTCCCGGT •VII SADK SIS TAY L Q W S 201 GGIGACCAIT AGCGCGGATA AAAGCATTAG CACCGCGTAT CTTCAATGGA

CCACTGGTAA TCGCGCCTAT TTTCGTAATC GTGGCGCATA GAAGTTACCT • SLK ÁSD TAMY YCA RWY 251 GCAGCCTGAA AGCGAGCGAT ACGGCCATGT ATTATTGCGC GCGTTGGTAT

CGTCGGACTT TCGCTCGCTA TGCCGGTACA TAATAACGCG CGCAACCATA

CDR3

YKPF DVW GQG TLVT VSS· 301 TATAAGCCTT TTGATGTTTG GGGCCAAGGC ACCCTGGTGA CGGTTAGCTC

ATATTCGGAA AACTACAAAC CCCGGTTCCG TGGGACCACT GCCAATCGAG • S

351 A

T

ΕΡ 2 548 577 Β1

IL-23 ρ19 3 759^eq'°^s

VL-GCE (SEQ ID NO:142): (VL amino acid sequence is 5059°^s)

QSVL Γ Q P PSV S G A P G Q R ·

CAGTCTGTGC TGACGCAGCC GCCCTCAGTG TCTGGGGCCC CAGGGCAGAG

GTCAGACACG ACTGCGTCGG CGGGAGTCAC AGACCCCGGG GTCCCGTCTC

CDR1 •VTI SCTG SSS NIG S G Y D 51 GGTCACCATC TCCTGCACTG GGAGCAGCTC CAACATCGGG AGCGGTTAIG

CCAGTGGTAG AGGACGTGAC CCTCGTCGAG GTTGTAGCCC TCGCCAATAC • VHW YQQ L P G T APK L L I lül ATGTACACTG GTACCAGCAG CTTCCAGGAA CAGCCCCCAA ACTCCTCATC

TACATGTGAC CATGGTCGTC GAAGGTCCTT GTCGGGGGTT TGAGGAGTAG

CDR2

YGNS KRP SGV PDRF SGS151 TATGGTAACA GCAAGCGGCC CTCAGGGGTC CCTGACCGAT TCTCTGGCTC ataccattgt CGTTCGCCGG GAGTCCCCAG ggactggcta agagaccgag •KSG TSAS LAI TGL QSED·

201 CAAGTCTGGC ACCTCAGCCT CCCTGGCCAT CACTGGGCTC CAGAGCGAGG

GTTCAGACCG TGGAGTCGGA GGGACCGGTA GTGACCCGAG GTCTCGCTCC

CDR3 • E AD Y Y C ASWT DGL SLV 251 ATGAGGCTGA TTATTACTGC GCCAGCTGGA CCGACGGCCT GAGCCTGGTG

TACTCCGACT AATAATGAC.G CGGTCGACCT GGCTGCCGGA CTCGGACCAC

VFGG GTK LTV LG 01 GTGTTCGGCG GCGGCACCAA GCTGACCGTG CTGGGC

CACAAGCCGC CGCCGTGGTT CGACTGGCAC GACCCG

ΕΡ 2 548 577 Β1

IL-23 ρ19 3 759^eq/qs

VL-HCO (SEQ ID NO: 143) : (VL amino acid sequence is 5059°^s)

QSVL Γ Q P PSV SGAP G Q R ·

I '’..A^;‘:.:-'.'_:.CGTGC TGACCCAGCC CCCCAGCGTG AGCGGCGCCC CCGGCCAGCG

GTCTCGCACG ACTGGGTCGG GGGGTCGCAC TCGCCGCGGG GGCCGGTCGC

CDR1

- V T I SCTG SSS NIG SGYD· 51 CGTGACCATC AGCTGCACCG GCAGCAGCAG CAACATCGGC AGCGGCTACG

GCACTGGTAG TCGACGTGGC CGTCGTCGTC GTTGTAGCCG TCGCCGATGC • VHW YQQ L P G Γ APK LLI

3.Ül ACGTGCACTG GTACCAGCAG CTGCCCGGCA CCGCCCCCAA GCTGCTGATC TGCACGTGAC CATGGTCGTC GACGGGCCGT GGCGGGGGTT CGACGACTAG

CDR2

YGNS KRP S G V PDRF SGS ISI TACGGCAACA GCAAGCGCCC CAGCGGCGTG CCCGACCGCT TCAGCGGCAG

ATGCCGTTGT CGTTCGCGGG GTCGCCGCAC GGGCTGGCGA AGTCGCCGTC •KSG TSAS LAI TGL QSED 201 CAAGAGCGGC ACCAGCGCCA GCCTGGCCAT CACCGGCCTC CAGAGCGAGG

GTTCTCGCCG TGGTCGCGGT CGGACCGGTA GTGGCCGGAG GTCTCGCTCC

CDR3 • E AD YYC ASWT DGL SLV 251 ACGAGGCCGA CTACTACTGT GCCAGCTGGA CCGACGGCCT GAGCCTGGTG

TGCTCCGGCT GATGATGACA CGGTCGACCT GGCTGCCGGA CTCGGACCAC

VFGG GTK LTV LG 30,1 GTGTTCGGCG GCGGCACCAA GCTGACCGTG CTGGGC

CACAAGCCGC CGCCGTGGTT CGACTGGCAC GACCCG

ΕΡ 2 548 577 Β1

IL-23 ρ19 3 759^bq/qs

VL-MOR (SEQ ID ΝΟ:144): (VL amino acid sequence is 5059%

QSVL T Q P P S V SGAP GQR1 CAGAGCGTGC TGACCCAGCC GCCTTCAGTG AGTGGCGCAC CAGGTCAGCG

GTCTCGCACG ACTGGGTCGG CGGAAGTCAC TCACCGCGTG GTCCAGTCGC

CDR1

-VTI SCTG SSS NIG S G Y D 51 TGTGACCATC TCGTGTACGG GCAGCAGCAG CAACATTGGT TCTGGTTATG

ACACTGGTAG AGCACATGCC CGTCGTCGTC GTTGTAACCA AGACCAATAC

- VHW YQQ L P G T APK LLI 3.03. ATGTGCATTG GTACCAGCAG TTGCCCGGGA CGGCGCCGAA ACTTCTGATT

TACACGTAAC CATGGTCGTC AACGGGCCCT GCCGCGGCTT TGAAGACTAA

CDR2

YGNS KRP SGV PDRF SGS51 TATGGTAATT CTAAGCGTCC CTCAGGCGTG CCGGATCGTT TTAGCGGATC

ATACCATTAA GATTCGCAGG GAGTCCGCAC GGCCTAGCAA AATCGCCTAG

KSG TSAS L A I TGL QSED

201 CAAAAGCGGC ACCAGCGCGA GCCTTGCGAT TACGGGCCTG CAAAGCGAAG

GTTTTCGCCG TGGTCGCGCT CGGAACGCTA ATGCCCGGAC GTTTCGCTTC

CDR3

<td> • E A D</td><td> Y Y C</td><td> A S W 1</td><td> ? D G L</td><td> S L V</td>

<td> 251 ACGAAGCGGA</td><td> TTATTATTGC</td><td> GCTTCTTGGA</td><td> CTGATGGTCT</td><td> TTCTCTTGTT</td>

<td> TGCTTCGCCT</td><td> AATAATAACG</td><td> CGAAGAACCT</td><td> GACTACCAGA</td><td> AAGAGAACAA</td>

<td colspan="2"> V F G G G T K</td><td> LTV</td><td> L G</td><td></td>

<td> 20; GTGTTTGGCG</td><td> GCGGCACGAA</td><td> GTTAACCGTT</td><td> CTTGGC</td><td></td>

<td> CACAAACCGC</td><td> CGCCGTGCTT</td><td> CAATTGGCAA</td><td> GAACCG</td><td></td>

EP 2 548 577 B1

Table 10

SEQ ID NO:145 (humán IL-23pl9 subunit)

Met Leu Gly Ser Arg Alá 1 5

Alá Gin Gly Arg Alá Val

Cys Gin Gin Leu Ser Gin 35

Pro Leu Val Gly His Met 50

Thr Asn Asp Val Pro His 65 70

Gly Leu Arg Asp Asn Ser

Leu Ile Phe Tyr Glu Lys 100

Pro Ser Leu Leu Pro Asp 115

Leu Gly Leu Ser Gin Leu 130

Gin Gin Ile Pro Ser Leu 145 150

Leu Arg Phe Lys Ile Leu

165

Alá Arg Val Phe Alá His 180

SEQUENCE LISTING [0216] <110> JANSSEN BIOTECH, INC.

<120> HUMÁN ANTI-IL-23 ANTIBODIES, <130> P060067EP <140>

<141 > 2006-12-28 <150> EP 06846836.2 <151> 2006-12-28 <150> PCT/US2006/062674 <151> 2006-12-28

<td rowspan="2"> Val</td><td rowspan="2"> Met</td><td colspan="2"> Leu Leu Leu Leu Leu Pro Trp</td>

<td> 10</td><td> 15</td>

<td> Pro</td><td> Gly</td><td> Gly Ser Ser</td><td> Pro Alá Trp Thr</td>

<td></td><td></td><td> 25</td><td> 30</td>

<td> Lys</td><td> Leu</td><td> Cys Thr Leu</td><td> Alá Trp Ser Alá</td>

<td></td><td> 40</td><td></td><td> 45</td>

<td> Asp</td><td> Leu</td><td> Arg Glu Glu</td><td> Gly Asp Glu Glu</td>

<td> 55</td><td></td><td></td><td> 60</td>

<td> Ile</td><td> Gin</td><td> Cys Gly Asp</td><td> Gly Cys Asp Pro</td>

<td></td><td></td><td> 75</td><td></td>

<td> Gin</td><td> Phe</td><td> Cys Leu Gin</td><td> Arg Ile His Gin</td>

<td></td><td></td><td> 90</td><td> 95</td>

<td> Leu</td><td> Leu</td><td> Gly Ser Asp</td><td> Ile Phe Thr Gly</td>

<td></td><td></td><td> 105</td><td> 110</td>

<td> Ser</td><td> Pro</td><td> Val Alá Gin</td><td> Leu His Alá Ser</td>

<td></td><td> 120</td><td></td><td> 125</td>

<td> Leu</td><td> Gin</td><td> Pro Glu Gly</td><td> His His Trp Glu</td>

<td> 135</td><td></td><td></td><td> 140</td>

<td> Ser</td><td> Pro</td><td> Ser Gin Pro</td><td> Trp Gin Arg Leu</td>

<td></td><td></td><td> 155</td><td></td>

<td> Arg</td><td> Ser</td><td> Leu Gin Alá</td><td> Phe Val Alá Val</td>

<td></td><td></td><td> 170</td><td> 175</td>

<td> Gly</td><td> Alá</td><td> Alá Thr Leu</td><td> Ser Pro</td>

185

COMPOSITIONS, METHODS AND USES

ΕΡ 2 548 577 Β1 <150> 60/754,889 <151> 2005-12-29 <160> 147 < 170> FastSEQ fór Windows Version 4.0 <210> 1 <211>5 <212> PRT <213> Homo sapiens <400> 1

Asn Tyr Alá Ile Ser 1 5 <210> 2 <211>5 <212> PRT <213> Homo sapiens <400> 2

Ser Asn Tyr Ile Ser 1 5 <210> 3 <211>5 <212> PRT <213> Homo sapiens <400> 3

Asn Tyr Trp Ile Ser 1 5 <210> 4 <211>5 <212> PRT <213> Homo sapiens <400> 4

Ser Tyr Trp Ile Thr 1 5 <210> 5 <211>5 <212> PRT <213> Homo sapiens <400> 5

Asn Tyr Trp Ile Gly 1 5 <210> 6

ΕΡ 2 548 577 Β1 <211>5 <212> PRT <213> Homo sapiens <400>6

Ser Phe Gly Met Ser 1 5 <210>7 <211> 17 <212> PRT <213> Homo sapiens <400>7

Gly Ile Ile Pro Met Phe Gly Tyr Alá Asn Tyr Alá Gin Lys 15 10

Gly <210> 8 <211> 17 <212> PRT <213> Homo sapiens <400> 8

Phe Gin 15

Gly Ile Ile Pro Val Phe Gly Phe Thr His Tyr Alá Gin Lys 15 10

Gly <210> 9 <211> 17 <212> PRT <213> Homo sapiens <400> 9

Phe Gin 15

Gly Ile Ile Pro Ile Phe Gly His Alá Asn Tyr Alá Gin Lys 15 10

Gly <210> 10 <211> 17 <212> PRT <213> Homo sapiens <400> 10

Ile Ile Ile Pro Pro Ile Gly Asn Alá Trp Tyr Alá Gin Lys

Phe Gin 15

Phe Gin

10

Gly

EP 2 548 577 Β1 <210> 11 <211> 17 <212> PRT <213> Homo sapiens <400> 11

Leu Ile Asp Pro Asn Phe Gly Gly Alá Tyr Tyr Alá Gin Lys Phe Gin 15 10 15

Gly <210> 12 <211> 17 <212> PRT <213> Homo sapiens <400> 12

Leu Ile Asp Pro Val Phe Gly Gly Alá Tyr Tyr Alá Gin Lys Phe Gin 15 10 15

Gly <210> 13 <211> 17 <212> PRT <213> Homo sapiens <400> 13

Leu Ile Asp Pro Met Phe Gly Gly Alá Tyr Tyr Alá Gin Lys Phe Gin 15 10 15

Gly <210> 14 <211> 16 <212> PRT <213> Homo sapiens <400> 14

Ile Asn Alá His Leu Gly Gly Thr Trp Tyr Alá Gin Lys Phe Gin Gly 15 10 15 <210> 15 <211> 17 <212> PRT <213> Homo sapiens <400> 15

Ile Ser Pro Gly Thr Gly Ile Asn Alá Tyr Tyr Alá Gin Lys Phe Gin 15 10 15

Gly

EP 2 548 577 Β1 <210> 16 <211> 17 <212> PRT <213> Artificial Sequence <220>

<223> Synthesized humán sequence <220>

<221 > unsure <222> (1) <223> Where Xaa can be G, I, or L <220>

<221 > unsure <222> (2) <223> Where Xaa can be I or S <220>

<221 > unsure <222> (3) <223> Where Xaa can be I, P, N, or D <220>

<221 > unsure <222> (4) <223> Where Xaa can be P, G, or A <220>

<221 > unsure <222> (5) <223> Where Xaa can be I, Μ, P, <223> T, Η, N, orV <220>

<221 > unsure <222> (6) <223> Where Xaa can be F, I, G, or L <220>

<221 > unsure <222> (7) <223> Where Xaa can G or I <220>

<221 > unsure <222> (8) <223> Where Xaa can be Η, Y, N, or G <220>

<221 > unsure <222> (9) <223> Where Xaa can be A or T <220>

<221 > unsure <222> (10) <223> Where Xaa can be N, W, or Y

ΕΡ 2 548 577 Β1 <400> 16

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Alá Gin Lys Phe Gin 15 10 15

Gly <210> 17 <211> 17 <212> PRT <213> Homo sapiens <400> 17

Trp Ile Arg Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Glu 15 10 15

Gly <210> 18 <211> 19 <212> PRT <213> Homo sapiens <400> 18

Val Ser Tyr Ile Ser Ser Ser Gly Ser Ser Thr Tyr Tyr Alá Asp Ser 15 10 15

Val Lys Gly <210> 19 <211> 17 <212> PRT <213> Homo sapiens <400> 19

Ile Ile Asp Pro Ser Asn Ser Tyr Thr Asn Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 20 <211> 17 <212> PRT <213> Homo sapiens <400> 20

Ile Ile Asp Pro Ser Asn Ser Tyr Thr Arg Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 21 <211> 17 <212> PRT

ΕΡ 2 548 577 Β1 <213> Homo sapiens <400> 21

Ile Ile Asp Pro Ser Asn Ser Tyr Thr Asp Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 22 <211> 17 <212> PRT <213> Homo sapiens <400> 22

Ile Ile Ser Pro Thr Gly Ser Val Thr Trp Tyr Ser Pro Ser Phe Gin

10 15

Gly <210> 23 <211> 17 <212> PRT <213> Homo sapiens <400> 23

Ile Ile Ser Pro Thr Gly Ser Ser Thr Trp Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 24 <211> 17 <212> PRT <213> Homo sapiens <400> 24

Phe Ile Ser Pro Asp Gly Ser His Thr Trp Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 25 <211> 17 <212> PRT <213> Homo sapiens <400> 25

Ile Ile Ser Pro Ser Gly Ser Thr Thr Trp Tyr Ser Pro Ser Phe Gin 15 10 15

Gly

EP 2 548 577 Β1 <210> 26 <211> 17 <212> PRT <213> Homo sapiens <400> 26

Ile Ile Ser Pro Thr Gly Ser Alá Thr Trp Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 27 <211> 17 <212> PRT <213> Homo sapiens <400> 27

Ile Ile Asp Pro Val Ser Ser Trp Thr Lys Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 28 <211> 17 <212> PRT <213> Artificial Sequence <220>

<223> Synthesized humán sequence <220>

<221 > unsure <222> (3) <223> Where Xaa can be D or S <220>

<221 > unsure <222> (5) <223> Where Xaa can be S, V, D, or T <220>

<221 > unsure <222> (6) <223> Where Xaa can be N, S, or G <220>

<221 > unsure <222> (8) <223> Where Xaa can be Y, W, T, Η, V, S, or A <220>

<221 > unsure <222> (10) <223> Where Xaa can be N, D, R, K, or W <400> 28

ΕΡ 2 548 577 Β1

Ile Ile Xaa Pro Xaa Xaa Ser Xaa Thr Xaa Tyr Ser Pro Ser Phe Gin 15 10 15

Gly <210> 29 <211> 17 <212> PRT <213> Homo sapiens <400> 29

Asn Ile Ser Ser Ser Gly Ser Ser Thr Tyr Tyr Alá Asp Ser Val Lys 15 10 15

Gly <210> 30 <211> 19 <212> PRT <213> Homo sapiens <400> 30

Asn Ile Glu His Lys Tyr Leu Asn Tyr Alá Thr Tyr Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 31 <211> 19 <212> PRT <213> Homo sapiens <400> 31

Asn Ile Glu His Lys Phe Met Gly Tyr Thr Thr Tyr Tyr Alá Alá Gly 15 10 15

Val Lys Gly <210> 32 <211> 19 <212> PRT <213> Homo sapiens <400> 32

Gly Ile Glu His Lys Tyr Leu Ser Tyr Thr Thr His Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 33 <211> 19 <212> PRT <213> Homo sapiens

ΕΡ 2 548 577 Β1 <400> 33

Ser Ile Glu His Lys Tyr Thr Gly Tyr Thr Thr Tyr Tyr Alá Alá Pro 15 10 15

Val Lys Gly <210> 34 <211> 19 <212> PRT <213> Homo sapiens <400> 34

Gin Ile Glu His Lys Tyr Leu Ser Tyr Thr Thr Leu Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 35 <211> 19 <212> PRT <213> Homo sapiens <400> 35

Ser Ile Glu His Lys Tyr Leu Ser Tyr Thr Thr Phe Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 36 <211> 19 <212> PRT <213> Homo sapiens <400> 36

Asn Ile Glu Gly Lys Tyr Thr Ser Tyr Thr Thr Tyr Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 37 <211> 19 <212> PRT <213> Homo sapiens <400> 37

Gly Ile Glu His Lys Tyr Leu Ser Tyr Alá Thr Leu Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 38 <211> 19 <212> PRT

ΕΡ 2 548 577 Β1 <213> Homo sapiens <400> 38

Asn Ile Glu His Lys Tyr Leu Gly Tyr Alá Thr Val Tyr Alá Alá Ser 15 10 15

Val Lys Gly <210> 39 <211> 19 <212> PRT <213> Homo sapiens <400> 39

Ser Ile Glu His Lys Tyr Leu Ser Tyr Alá Thr Tyr Tyr Alá Alá Gly 15 10 15 ₂₀ Val Lys Gly <210> 40 <211>8 <212> PRT <213> Homo sapiens <400> 40

Asp Ile Tyr Alá Gly Met Asp Val

15 <210> 41 <211> 18 <212> PRT <213> Homo sapiens <400> 41 ₄₀ Ser Lys Lys Gly Met Tyr Gly Gly Trp Thr Tyr Pro Leu Met Met Phe

10 15

Asp Leu <210> 42 <211>7 <212> PRT <213> Homo sapiens <400> 42

His Tyr Tyr Gly Met Asp Tyr 1 5 <210> 43 <211 >12 <212> PRT <213> Homo sapiens

EP 2 548 577 Β1 <400> 43

Gly Thr Phe Trp Ser Phe Gly Asn Tyr Phe Alá Asn 15 10 <210> 44 <211>8 <212> PRT <213> Homo sapiens <400> 44

Trp Tyr Tyr Lys Pro Phe Asp Val 1 5 <210> 45 <211> 12 <212> PRT <213> Homo sapiens <400> 45

Tyr Trp Gly Thr Pro Tyr Leu Met Gin Phe Asp Asn 15 10 <210> 46 <211> 12 <212> PRT <213> Homo sapiens <400> 46

Arg Alá Ser Gin Ser Val Leu Gly Asn Tyr Leu Alá 15 10 <210> 47 <211> 12 <212> PRT <213> Homo sapiens <400> 47

Arg Alá Ser Gin Ser Val Ser Ser Asn Tyr Leu Alá 15 10 <210> 48 <211> 13 <212> PRT <213> Homo sapiens <400> 48

Ser Gly Ser Ser Ser Asn Ile Gly Ser Tyr Tyr Val Asn 15 10 <210> 49 <211> 11 <212> PRT

ΕΡ 2 548 577 Β1 <213> Homo sapiens <400> 49

Arg Alá Ser Gin Ser Ile Phe Tyr Asn Leu Alá 15 10 <210> 50 <211> 14 <212> PRT <213> Homo sapiens <400> 50

Thr Gly Ser Ser Ser Asn Ile Gly Ser Gly Tyr Asp Val His 15 10 <210> 51 <211> 14 <212> PRT <213> Homo sapiens <400> 51

Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr Asn Ser Val Ser 15 10 <210> 52 <211>7 <212> PRT <213> Homo sapiens <400> 52

Gly Alá Ser Ser Arg Alá Thr 1 5 <210> 53 <211>7 <212> PRT <213> Homo sapiens <400> 53

Tyr Alá Ser Arg Arg Alá Thr 1 5 <210> 54 <211>7 <212> PRT <213> Homo sapiens <400> 54

Gly Asn Thr His Arg Pro Ser 1 5 <210> 55

ΕΡ 2 548 577 Β1 <211>7 <212> PRT <213> Homo sapiens <400> 55

Gly Alá Ser Asn Arg Alá Thr 1 5 <210> 56 <211>7 <212> PRT <213> Homo sapiens <400> 56

Gly Asn Ser Lys Arg Pro Ser 1 5 <210> 57 <211>7 <212> PRT <213> Homo sapiens <400> 57

Ser Val Ser Ser Arg Pro Ser 1 5 <210> 58 <211>9 <212> PRT <213> Homo sapiens <400> 58

His Gin Tyr Gly Ser Ile Ser Thr Thr 1 5 <210> 59 <211>9 <212> PRT <213> Homo sapiens <400> 59

Gin Gin Tyr Ser His Leu Leu Ile Thr 1 5 <210> 60 <211>9 <212> PRT <213> Homo sapiens <400> 60

Gin Gin Tyr Ser His Ile Ser Leu Thr 1 5

EP 2 548 577 Β1 <210> 61 <211>9 <212> PRT <213> Homo sapiens <400> 61

Gin Gin Phe Alá His Ile Leu Leu Thr 1 5 <210> 62 <211>9 <212> PRT <213> Homo sapiens <400> 62

Gin Gin Thr Ser Asn Thr Pro Phe Thr 1 5 <210> 63 <211>9 <212> PRT <213> Homo sapiens <400> 63

Gin Gin Phe Ile Thr Tyr Leu Pro Thr 1 5 <210> 64 <211>9 <212> PRT <213> Homo sapiens <400> 64

Gin Gin Asp Alá Leu Ser Pro Phe Thr 1 5 <210> 65 <211>9 <212> PRT <213> Homo sapiens <400> 65

Gin Gin Asp Arg Gly Thr Pro Phe Thr 1 5 <210> 66 <211>9 <212> PRT <213> Homo sapiens <400> 66

ΕΡ 2 548 577 Β1

Gin Gin Ser Leu Asn Ile Pro Phe Thr 1 5 <210> 67 <211>9 <212> PRT <213> Homo sapiens <400> 67

Gin Gin Asp Thr Ser Ser Pro Phe Thr 1 5 <210> 68 <211> 10 <212> PRT <213> Artificial Sequence <220>

<223> Synthesized humán sequence <220>

<221 > unsure <222> (3) <223> Where Xaa can be T, F, D, or S <220>

<221 > unsure <222> (4) <223> Where Xaa can be S, I, A, T, R, or L <220>

<221 > unsure <222> (5) <223> Where Xaa can be N, T, L, S, or G <220>

<221 > unsure <222> (6) <223> Where Xaa can be T, Y, S, or I <220>

<221 > unsure <222> (7) <223> Where Xaa can be P or L <220>

<221 > unsure <222> (8) <223> Where Xaa can be F or P <400> 68

Gin Gin Xaa Xaa Xaa Xaa Xaa Xaa Phe Thr 15 10 <210> 69 <211> 11

EP 2 548 577 B1 <212> PRT <213> Homo sapiens <400> 69

Gin Thr Tyr Alá Ser Leu Gly Pro Gly Glu Val 15 10 <210> 70 <211>9 <212> PRT <213> Homo sapiens <400> 70

Gin Gin Tyr Ser Ser Glu Pro Val Thr 1 5 <210> 71 <211>9 <212> PRT <213> Homo sapiens <400> 71

Ser Ser Trp Thr Pro Ser Ser Val Val 1 5 <210> 72 <211> 11 <212> PRT <213> Homo sapiens <400> 72

Ser Ser Trp Thr Asp Thr Pro Asn Met Ile Val 15 10 <210> 73 <211> 11 <212> PRT <213> Homo sapiens <400> 73

Alá Ser Trp Thr Asp Gly Leu Ser Leu Val Val 15 10 <210> 74 <211> 11 <212> PRT <213> Artificial Sequence <220>

<223> Synthesized humán sequence <220>

<221 > unsure

EP 2 548 577 B1 <222> (1) <223> Where Xaa can be S or A <220>

<221 > unsure <222> (6) <223> Where Xaa can be T or G <220>

<221 > unsure <222> (7) <223> Where Xaa can be P or L <220>

<221 > unsure <222> (8) <223> Where Xaa can be S or N <220>

<221 > unsure <222> (9) <223> Where Xaa can be S, M, or L <220>

<221 > unsure <222> (10) <223> Where Xaa can be I or V <400> 74

Xaa Ser Trp Thr Asp Xaa Xaa Xaa Xaa Xaa Val 15 10 <210> 75 <211> 11 <212> PRT <213> Homo sapiens <400> 75

Ser Ser Tyr Asp Thr Asn Lys Pro Leu Val Val 15 10 <210> 76 <211> 11 <212> PRT <213> Homo sapiens <400> 76

Gly Ser Tyr Asp Val Tyr Gly Arg Phe Tyr Val 15 10 <210> 77 <211> 11 <212> PRT <213> Homo sapiens

EP 2 548 577 Β1 <400> 77

Ser Ser Tyr Tyr Phe Tyr Leu Gin Arg Ile Val 15 10 <210> 78 <211> 11 <212> PRT <213> Homo sapiens <400> 78

Gin Thr Tyr Tyr Phe Ser Tyr Ser Gly Pro Val 15 10 <210> 79 <211> 11 <212> PRT <213> Homo sapiens <400> 79

Gly Ser Trp Asp Pro Ile Phe Ser Tyr Glu Val 15 10 <210> 80 <211> 117 <212> PRT <213> Homo sapiens <400> 80

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Alá</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Gly</td><td> Ile</td><td> Ile</td><td> Pro</td><td> Met</td><td> Phe</td><td> Gly</td><td> Tyr</td><td> Alá</td><td> Asn</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Asp</td><td> Ile</td><td> Tyr</td><td> Alá</td><td> Gly</td><td> Met</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 81 <211> 117 <212> PRT <213> Homo sapiens <400> 81

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Alá</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Gly</td><td> Ile</td><td> Ile</td><td> Pro</td><td> Val</td><td> Phe</td><td> Gly</td><td> Phe</td><td> Thr</td><td> His</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Asp</td><td> Ile</td><td> Tyr</td><td> Alá</td><td> Gly</td><td> Met</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 82 <211> 108 <212> PRT <213> Homo sapiens <400> 82

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Leu</td><td> Gly</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Gly</td><td> Alá</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> His</td><td> Gin</td><td> Tyr</td><td> Gly</td><td> Ser</td><td> Ile</td><td> Ser</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Thr</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 83 <211> 108 <212> PRT <213> Homo sapiens <400> 83

ΕΡ 2 548 577 Β1

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Leu</td><td> Gly</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Gly</td><td> Alá</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Tyr</td><td> Ser</td><td> His</td><td> Ile</td><td> Ser</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 84 <211> 108 <212> PRT <213> Homo sapiens <400> 84

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Leu</td><td> Gly</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Gly</td><td> Alá</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Tyr</td><td> Ser</td><td> His</td><td> Leu</td><td> Ile</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Ile</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 85 <211> 108 <212> PRT <213> Homo sapiens <400> 85

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Leu</td><td> Gly</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Gly</td><td> Alá</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Phe</td><td> Alá</td><td> His</td><td> Ile</td><td> Leu</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

ΕΡ 2 548 577 Β1 <210> 86 <211> 127 <212> PRT <213> Homo sapiens <400> 86

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Gly</td><td> Ile</td><td> Ile</td><td> Pro</td><td> Ile</td><td> Phe</td><td> Gly</td><td> His</td><td> Alá</td><td> Asn</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 87 <211> 127 <212> PRT <213> Homo sapiens <400> 87

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Ile</td><td> Pro</td><td> Pro</td><td> Ile</td><td> Gly</td><td> Asn</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 88 <211> 127 <212> PRT <213> Homo sapiens <400> 88

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Gly</td><td> Ile</td><td> Asn</td><td> Alá</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 89 <211> 126 <212> PRT <213> Homo sapiens <400> 89

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Asn</td><td> Alá</td><td> His</td><td> Leu</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td><td> Gin</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td><td> Met</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Alá</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 90 <211> 127 <212> PRT <213> Homo sapiens <400> 90

EP 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Leu</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Asn</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Alá</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 91 <211> 127 <212> PRT <213> Homo sapiens <400> 91

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Leu</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Alá</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 92 <211> 127 <212> PRT <213> Homo sapiens <400> 92

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Ser</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Val</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Leu</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Met</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Alá</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Gin</td><td> Lys</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Thr</td><td> Alá</td><td> Asp</td><td> Glu</td><td> Ser</td><td> Thr</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Met</td><td> Glu</td><td> Leu</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Ser</td><td> Lys</td><td> Lys</td><td> Gly</td><td> Met</td><td> Tyr</td><td> Gly</td><td> Gly</td><td> Trp</td><td> Thr</td><td> Tyr</td><td> Pro</td><td> Leu</td><td> Met</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Met</td><td> Phe</td><td> Asp</td><td> Leu</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<210> 93 <211> 108 <212> PRT <213> Homo sapiens <400> 93

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Thr</td><td> Ser</td><td> Asn</td><td> Thr</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 94 <211> 108 <212> PRT <213> Homo sapiens <400> 94

ΕΡ 2 548 577 Β1

<td> Glu</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Thr</td><td> Ser</td><td> Asn</td><td> Thr</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 95 <211> 108 <212> PRT <213> Homo sapiens <400> 95

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Phe</td><td> Ile</td><td> Thr</td><td> Tyr</td><td> Leu</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Pro</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 96 <211> 108 <212> PRT <213> Homo sapiens <400> 96

EP 2 548 577 Β1

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Asp</td><td> Alá</td><td> Leu</td><td> Ser</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

100 105 <210> 97 <211> 108 <212> PRT <213> Homo sapiens <400> 97

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Asp</td><td> Arg</td><td> Gly</td><td> Thr</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 98 <211> 108 <212> PRT <213> Homo sapiens <400> 98

ΕΡ 2 548 577 Β1

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Arg</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Pro</td><td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Ser</td><td> Leu</td><td> Asn</td><td> Ile</td><td> Pro</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 99 <211> 116 <212> PRT <213> Homo sapiens <400> 99

<td colspan="7"> Gin Val Gin Leu Val Gin Ser</td><td rowspan="2"> Gly</td><td colspan="7"> Alá Glu Val Lys Lys Pro Gly</td><td rowspan="2"> Glu</td>

<td> 1</td><td colspan="6"> 5</td><td colspan="4"> 10</td><td colspan="3"> 15</td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Thr</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Trp</td><td> Ile</td><td> Arg</td><td> Pro</td><td> Gly</td><td> Asp</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Arg</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Glu</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> His</td><td> Tyr</td><td> Tyr</td><td> Gly</td><td> Met</td><td> Asp</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

115 <210> 100 <211> 110 <212> PRT <213> Homo sapiens <400> 100

ΕΡ 2 548 577 Β1

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Pro</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Asn</td><td> Ile</td><td> Gly</td><td> Ser</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Val</td><td> Asn</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ile</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Thr</td><td> His</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Phe</td><td> Ser</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Alá</td><td> Ile</td><td> Thr</td><td> Gly</td><td> Leu</td><td> Gin</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Ser</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Thr</td><td> Tyr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Pro</td><td> Gly</td><td> Glu</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 101 <211> 121 <212> PRT <213> Homo sapiens <400> 101

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Thr</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Tyr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Asp</td><td> Ser</td><td> Val</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td><td> Leu</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Gly</td><td> Thr</td><td> Phe</td><td> Trp</td><td> Ser</td><td> Phe</td><td> Gly</td><td> Asn</td><td> Tyr</td><td> Phe</td><td> Alá</td><td> Asn</td><td> Trp</td><td> Gly</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 102 <211> 107 <212> PRT <213> Homo sapiens <400> 102

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Glu</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Arg</td><td> Alá</td><td> Ser</td><td> Gin</td><td> Ser</td><td> Ile</td><td> Phe</td><td> Tyr</td><td> Asn</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Leu</td><td> Alá</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Arg</td><td> Leu</td><td> Leu</td><td> Ile</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Tyr</td><td> Gly</td><td> Alá</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Alá</td><td> Thr</td><td> Gly</td><td> Val</td><td> Pro</td><td> Alá</td><td> Arg</td><td> Phe</td><td> Ser</td><td> Gly</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Asp</td><td> Phe</td><td> Thr</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Glu</td><td> Pro</td>

ΕΡ 2 548 577 Β1

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td> 80</td>

<td> Glu</td><td> Asp</td><td> Phe</td><td> Alá</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Gin</td><td> Tyr Ser Ser Glu Pro</td><td> Val</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td> 95</td><td></td>

<td> Thr</td><td> Phe</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Val</td><td> Glu</td><td> Ile</td><td> Lys</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td>

<210> 103 <211> 117 <212> PRT <213> Homo sapiens <400> 103

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Asn</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 104 <211> 117 <212> PRT <213> Homo sapiens <400> 104

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Asp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 105 <211> 117 <212> PRT <213> Homo sapiens <400> 105

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td rowspan="2"> Trp</td><td colspan="7"> Ile Gly Trp Val Arg Gin Met</td><td colspan="3" rowspan="2"> Pro Gly Lys</td><td rowspan="2"> Gly</td><td rowspan="2"> Leu 45</td><td rowspan="2"> Glu</td><td rowspan="2"> Trp</td><td rowspan="2"> Met</td>

<td colspan="3"> 35</td><td colspan="4"> 40</td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Arg</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 106 <211> 117 <212> PRT <213> Homo sapiens <400> 106

<td> Glu</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Ser</td><td> Asn</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Arg</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 107 <211> 117 <212> PRT <213> Homo sapiens <400> 107

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Asp</td><td> Pro</td><td> Val</td><td> Ser</td><td> Ser</td><td> Trp</td><td> Thr</td><td> Lys</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 108 <211> 117 <212> PRT <213> Homo sapiens <400> 108

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Thr</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 109 <211> 117 <212> PRT <213> Homo sapiens <400> 109

100

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Phe</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Asp</td><td> Gly</td><td> Ser</td><td> His</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 110 <211> 117 <212> PRT <213> Homo sapiens <400> 110

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Val</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

Val Thr Val Ser Ser 115 <210> 111 <211> 117 <212> PRT <213> Homo sapiens <400> 111

101

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 112 <211> 117 <212> PRT <213> Homo sapiens <400> 112

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Gin</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Glu</td><td> Val</td><td> Lys</td><td> Lys</td><td> Pro</td><td> Gly</td><td> Glu</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Lys</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Lys</td><td> Gly</td><td> Ser</td><td> Gly</td><td> Tyr</td><td> Ser</td><td> Phe</td><td> Ser</td><td> Asn</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Trp</td><td> Ile</td><td> Gly</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Met</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Met</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Gly</td><td> Ile</td><td> Ile</td><td> Ser</td><td> Pro</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Alá</td><td> Thr</td><td> Trp</td><td> Tyr</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Gin</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Alá</td><td> Asp</td><td> Lys</td><td> Ser</td><td> Ile</td><td> Ser</td><td> Thr</td><td> Alá</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Trp</td><td> Ser</td><td> Ser</td><td> Leu</td><td> Lys</td><td> Alá</td><td> Ser</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Met</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Trp</td><td> Tyr</td><td> Tyr</td><td> Lys</td><td> Pro</td><td> Phe</td><td> Asp</td><td> Val</td><td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 113 <211> 109 <212> PRT <213> Homo sapiens <400> 113

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Pro</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Asn</td><td> Ile</td><td> Gly</td><td> Ser</td><td> Gly</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Asp</td><td> Val</td><td> His</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Leu</td><td> Ile</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Phe</td>

102

ΕΡ 2 548 577 Β1

55 60

<td> Ser 65</td><td> Gly</td><td colspan="2"> Ser Lys</td><td> Ser</td><td> Gly 70</td><td> Thr</td><td colspan="2"> Ser Alá</td><td> Ser</td><td> Leu 75</td><td> Alá</td><td> Ile</td><td colspan="2"> Thr Gly</td><td> Leu 80</td>

<td> Gin</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Ser</td><td> Ser</td><td> Trp</td><td> Thr</td><td> Pro</td><td> Ser</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Ser</td><td> Val</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 114 <211> 111 <212> PRT <213> Homo sapiens <400> 114

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td colspan="4"> Thr Gin Pro Pro</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Pro</td><td colspan="2"> Gly Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Asn</td><td> Ile</td><td> Gly</td><td> Ser</td><td> Gly</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Asp</td><td> Val</td><td> His</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Leu</td><td> Ile</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Alá</td><td> Ile</td><td> Thr</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Ser</td><td> Ser</td><td> Trp</td><td> Thr</td><td> Asp</td><td> Thr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Pro</td><td> Asn</td><td> Met</td><td> Ile</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 115 <211> 111 <212> PRT <213> Homo sapiens <400> 115

<td> Asp</td><td> Ile</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Pro</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Asn</td><td> Ile</td><td> Gly</td><td> Ser</td><td> Gly</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Tyr</td><td> Asp</td><td> Val</td><td> His</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Pro</td><td> Gly</td><td> Thr</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Leu</td><td> Ile</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Alá</td><td> Ile</td><td> Thr</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Alá</td><td> Ser</td><td> Trp</td><td> Thr</td><td> Asp</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Ser</td><td> Leu</td><td> Val</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 116 <211> 111 <212> PRT <213> Homo sapiens

103

EP 2 548 577 Β1 <400> 116

<td> Gin</td><td> Ser</td><td> Val</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Pro</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Arg</td><td> Val</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Asn</td><td> Ile</td><td> Gly</td><td> Ser</td><td> Gly</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td colspan="3"> Tyr Asp Val</td><td rowspan="2"> His</td><td rowspan="2"> Trp</td><td colspan="2" rowspan="2"> Tyr Gin</td><td colspan="8"> Gin Leu Pro Gly Thr Alá Pro Lys</td><td rowspan="2"> Leu</td>

<td colspan="2"></td><td> 35</td><td> 40</td><td colspan="7"> 45</td>

<td> Leu</td><td> Ile</td><td> Tyr</td><td> Gly</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Pro</td><td> Asp</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Alá</td><td> Ile</td><td> Thr</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Ser</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Alá</td><td> Ser</td><td> Trp</td><td> Thr</td><td> Asp</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Ser</td><td> Leu</td><td> Val</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 117 20 <211> 121 <212> PRT <213> Homo sapiens <400> 117

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Ser</td><td> Ser</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Asp</td><td> Ser</td><td> Val</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td><td> Leu</td><td> Tyr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td><td> Tyr</td><td> Cys</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td><td> Trp</td><td> Gly</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 118 <211> 123 <212> PRT <213> Homo sapiens <400> 118

104

EP 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Phe</td><td> Met</td><td> Gly</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 119 <211> 123 <212> PRT <213> Homo sapiens <400> 119

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Thr</td><td> Gly</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Pro</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 120 <211> 123 <212> PRT <213> Homo sapiens <400> 120

105

EP 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Thr</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 121 <211> 123 <212> PRT <213> Homo sapiens <400> 121

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Asn</td><td> Tyr</td><td> Alá</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

115 120 <210> 122 <211> 123 <212> PRT <213> Homo sapiens <400> 122

106

ΕΡ 2 548 577 Β1

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Gly</td><td> Tyr</td><td> Alá</td><td> Thr</td><td> Val</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 123 <211> 123 <212> PRT <213> Homo sapiens <400> 123

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Ser</td><td> Tyr</td><td> Alá</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Gly</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 124 <211> 123 <212> PRT <213> Homo sapiens <400> 124

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Ser</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> Phe</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

107

ΕΡ 2 548 577 Β1

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 125 <211> 123 <212> PRT <213> Homo sapiens <400> 125

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> His</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 126 <211> 123 <212> PRT <213> Homo sapiens <400> 126

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Gin</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Ser</td><td> Tyr</td><td> Thr</td><td> Thr</td><td> Leu</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 127 <211> 123

108

ΕΡ 2 548 577 Β1 <212> PRT <213> Homo sapiens <400> 127

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Ser</td><td> Tyr</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 128 <211> 111 <212> PRT <213> Homo sapiens <400> 128

<td> Asp</td><td> Ile</td><td> Alá</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Alá</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Ile</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Ser</td><td> Asp</td><td> Val</td><td> Gly</td><td> Gly</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Asn</td><td> Ser</td><td> Val</td><td> Ser</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> His</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Met</td><td> Ile</td><td> Tyr</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Ser</td><td> Ser</td><td> Tyr</td><td> Asp</td><td> Thr</td><td> Asn</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Lys</td><td> Pro</td><td> Leu</td><td> Val</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 129 <211> 111 <212> PRT <213> Homo sapiens <400> 129

109

EP 2 548 577 Β1

<td> Asp</td><td> Ile</td><td> Alá</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Alá</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Ile</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Ser</td><td> Asp</td><td> Val</td><td> Gly</td><td> Gly</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Asn</td><td> Ser</td><td> Val</td><td> Ser</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> His</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Met</td><td> Ile</td><td> Tyr</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Ser</td><td> Ser</td><td> Tyr</td><td> Tyr</td><td> Phe</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Gin</td><td> Arg</td><td> Ile</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 130 <211> 111 <212> PRT <213> Homo sapiens <400> 130

<td> Asp</td><td> Ile</td><td> Alá</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Alá</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Ile</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Ser</td><td> Asp</td><td> Val</td><td> Gly</td><td> Gly</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Asn</td><td> Ser</td><td> Val</td><td> Ser</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> His</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Met</td><td> Ile</td><td> Tyr</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gin</td><td> Thr</td><td> Tyr</td><td> Tyr</td><td> Phe</td><td> Ser</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Ser</td><td> Gly</td><td> Pro</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 131 <211> 111 <212> PRT <213> Homo sapiens <400> 131

<td> Asp</td><td> Ile</td><td> Alá</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Alá</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Ile</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Ser</td><td> Asp</td><td> Val</td><td> Gly</td><td> Gly</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Asn</td><td> Ser</td><td> Val</td><td> Ser</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> His</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Met</td><td> Ile</td><td> Tyr</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gly</td><td> Ser</td><td> Tyr</td><td> Asp</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Gly</td><td> Arg</td><td> Phe</td><td> Tyr</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

110

ΕΡ 2 548 577 Β1 <210> 132 <211> 111 <212> PRT <213> Homo sapiens <400> 132

<td> Asp</td><td> Ile</td><td> Alá</td><td> Leu</td><td> Thr</td><td> Gin</td><td> Pro</td><td> Alá</td><td> Ser</td><td> Val</td><td> Ser</td><td> Gly</td><td> Ser</td><td> Pro</td><td> Gly</td><td> Gin</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Ile</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Cys</td><td> Thr</td><td> Gly</td><td> Thr</td><td> Ser</td><td> Ser</td><td> Asp</td><td> Val</td><td> Gly</td><td> Gly</td><td> Tyr</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Asn</td><td> Ser</td><td> Val</td><td> Ser</td><td> Trp</td><td> Tyr</td><td> Gin</td><td> Gin</td><td> His</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Alá</td><td> Pro</td><td> Lys</td><td> Leu</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Met</td><td> Ile</td><td> Tyr</td><td> Ser</td><td> Val</td><td> Ser</td><td> Ser</td><td> Arg</td><td> Pro</td><td> Ser</td><td> Gly</td><td> Val</td><td> Ser</td><td> Asn</td><td> Arg</td><td> Phe</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Gly</td><td> Ser</td><td> Lys</td><td> Ser</td><td> Gly</td><td> Asn</td><td> Thr</td><td> Alá</td><td> Ser</td><td> Leu</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Gly</td><td> Leu</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gin</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Glu</td><td> Alá</td><td> Asp</td><td> Tyr</td><td> Tyr</td><td> Cys</td><td> Gly</td><td> Ser</td><td> Trp</td><td> Asp</td><td> Pro</td><td> Ile</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Phe</td><td> Ser</td><td> Tyr</td><td> Glu</td><td> Val</td><td> Phe</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Thr</td><td> Lys</td><td> Leu</td><td> Thr</td><td> Val</td><td> Leu</td><td></td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<210> 133 <211> 381 <212> DNA <213> Homo sapiens <400> 133 caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60 tcctgcaagg cttctggagg caccttcagc agcaactaca tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatggggatc agccctggca ccggtatcaa cgcatactac 180 gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240 atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagaagcaag 300 aagggcatgt acggcggctg gacctacccc ctgatgatgt tcgacctgtg gggccagggc 360 accctggtga ccgtgagcag c 381 <210> 134 <211> 381 <212> DNA <213> Homo sapiens <400> 134 caggtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcagcag cgtgaaggtg 60 agctgcaagg ccagcggcgg caccttcagc agcaactaca tcagctgggt gcgccaggcc 120 cccggccagg gcctggagtg gatgggcatc agccccggca ccggcatcaa cgcctactac 180 gcccagaagt tccagggccg cgtgaccatc accgccgacg agagcaccag caccgcctac 240 atggagctga gcagcctgcg cagcgaggac accgccgtgt actactgcgc ccgcagcaag 300 aagggcatgt acggcggctg gacctacccc ctgatgatgt tcgacctgtg gggccagggc 360 accctggtga ccgtgagcag c 381 <210> 135 <211> 381 <212> DNA <213> Homo sapiens <400> 135

111

ΕΡ 2 548 577 Β1 caggtgcaat agctgcaaag cctgggcagg gctcagaagt atggaactga aagggtatgt accctggtga tggttcagtc cctccggagg gtctcgagtg ttcagggtcg gcagcctgcg atggtggttg cggttagctc tggcgcggaa cactttttct gatgggcatt ggtgaccatt tagcgaagat gacttatcct a

gtgaaaaaac tctaattata tctcctggta accgcggatg acggccgtgt cttatgatgt cgggcagcag tttcttgggt ctggtattaa aaagcaccag attattgcgc ttgatctttg cgtgaaagtg gcgccaagcc tgcttattat caccgcgtat gcgttctaag gggccaaggc <210> 136 <211> 324 <212> DNA <213> Homo sapiens <400> 136 gagatcgtgc ctgagctgcc cccggccagg gcccgcttca cccgaggact cagggcacca tgacccagag gcgccagcca ccccccgcct gcggcagcgg tcgccgtgta aggtggagat ccccgccacc gagcgtgagc gctgatctac cagcggcacc ctactgccag caag ctgagcctga agcaactacc tacgccagcc gacttcaccc cagaccagca gccccggcga tggcctggta gccgcgccac tgaccatcag acaccccctt gcgcgccacc ccagcagaag cggcgtgccc cagcctggag caccttcggc <210> 137 <211> 324 <212> DNA <213> Homo sapiens <400> 137 gaaattgtgt ctctcctgca cctggccagg gccaggttca cctgaagatt cagggtacga tgacacagtc gggccagtca ctcccaggct gtggcagtgg ttgcagttta aagttgaaat tccagccacc gagtgttagc cctcatctat gtctgggaca ttactgtcag taaa ctgtctttgt agcaactact tacgcatccc gacttcactc cagacttcta ctccagggga tagcctggta gcagggccac tcaccatcag atactccttt aagagccacc ccaacagaaa tggcgtgcca cagcctagag tacctttggc <210> 138 <211> 324 <212> DNA <213> Homo sapiens <400> 138 gagatcgtgc ctgagctgca ccaggtcaag gcgcgtttta cctgaagact cagggtacga tgacccagag gagcgagcca caccgcgtct gcggctctgg ttgcggtgta aagttgaaat cccggcgacc gtctgtttct attaatttat atccggcacg ttattgccag taaa ctgagcctgt tctaattatc tatgcttctc gattttaccc cagacttcta ctccgggcga tggcttggta gtcgtgcaac tgaccattag atactccttt acgtgcgacc ccagcagaaa tggggtcccg cagcctggaa tacctttggc <210> 139 <211> 351 <212> DNA <213> Homo sapiens <400> 139

112

ΕΡ 2 548 577 Β1 gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc tcctgtaagg gttctggata cagctttagc aactactgga tcggctgggt gcgccagatg cccgggaaag gcctggagtg gatggggatc atcgacccta gcaactctta caccagatac agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag caccgcctac ctgcagtgga gcagcctgaa ggcctcggac accgccatgt attactgtgc gagatggtac tacaagccct tcgacgtgtg gggccagggc accctggtga ccgtgagcag c <210> 140 <211> 351 <212> DNA <213> Homo sapiens <400> 140 gaggtgcagc tggtgcagag cggcgccgag gtgaagaagc ccggcgagag cctgaagatc agctgcaagg gcagcggcta cagcttcagc aactactgga tcggctgggt gcgccagatg cccggcaagg gcctggagtg gatgggcatc atcgacccca gcaacagcta cacccgctac agccccagct tccagggcca ggtgaccatc agcgccgaca agagcatcag caccgcctac ctgcagtgga gcagcctgaa ggccagcgac accgccatgt actactgcgc ccgctggtac tacaagccct tcgacgtgtg gggccagggc accctggtga ccgtgagcag c <210> 141 <211> 351 <212> DNA <213> Homo sapiens <400> 141 gaggtgcaat tggttcagag cggcgcggaa gtgaaaaaac cgggcgaaag cctgaaaatt agctgcaaag gttccggata ttccttttct aattattgga ttggttgggt gcgccagatg cctgggaagg gtctcgagtg gatgggcatt atcgatccgt ctaatagcta tacccgctat tctccgagct ttcagggcca ggtgaccatt agcgcggata aaagcattag caccgcgtat cttcaatgga gcagcctgaa agcgagcgat acggccatgt attattgcgc gcgttggtat tataagcctt ttgatgtttg gggccaaggc accctggtga cggttagctc a <210> 142 <211> 336 <212> DNA <213> Homo sapiens <400> 142 cagtctgtgc tgacgcagcc gccctcagtg tctggggccc cagggcagag ggtcaccatc tcctgcactg ggagcagctc caacatcggg agcggttatg atgtacactg gtaccagcag cttccaggaa cagcccccaa actcctcatc tatggtaaca gcaagcggcc ctcaggggtc cctgaccgat tctctggctc caagtctggc acctcagcct ccctggccat cactgggctc cagagcgagg atgaggctga ttattactgc gccagctgga ccgacggcct gagcctggtg gtgttcggcg gcggcaccaa gctgaccgtg ctgggc <210> 143 <211> 336 <212> DNA <213> Homo sapiens <400> 143

113

ΕΡ 2 548 577 Β1 cagagcgtgc tgacccagcc ccccagcgtg agcggcgccc ccggccagcg cgtgaccatc 60 agctgcaccg gcagcagcag caacatcggc agcggctacg acgtgcactg gtaccagcag 120 ctgcccggca ccgcccccaa gctgctgatc tacggcaaca gcaagcgccc cagcggcgtg 180 cccgaccgct tcagcggcag caagagcggc accagcgcca gcctggccat caccggcctc 240 cagagcgagg acgaggccga ctactactgt gccagctgga ccgacggcct gagcctggtg 300 gtgttcggcg gcggcaccaa gctgaccgtg ctgggc 336 <210> 144 <211> 336 <212> DNA <213> Homo sapiens <400> 144 cagagcgtgc tgacccagcc gccttcagtg agtggcgcac caggtcagcg tgtgaccatc 60 tcgtgtacgg gcagcagcag caacattggt tctggttatg atgtgcattg gtaccagcag 120 ttgcccggga cggcgccgaa acttctgatt tatggtaatt ctaagcgtcc ctcaggcgtg 180 ccggatcgtt ttagcggatc caaaagcggc accagcgcga gccttgcgat tacgggcctg 240 caaagcgaag acgaagcgga ttattattgc gcttcttgga ctgatggtct ttctcttgtt 300 gtgtttggcg gcggcacgaa gttaaccgtt cttggc 336 <210> 145 <211> 189 <212> PRT <213> Homo sapiens <400> 145

<td> Met</td><td> Leu</td><td> Gly</td><td> Ser</td><td> Arg</td><td> Alá</td><td> Val</td><td> Met</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Leu</td><td> Pro</td><td> Trp</td><td> Thr</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Alá</td><td> Gin</td><td> Gly</td><td> Arg</td><td> Alá</td><td> Val</td><td> Pro</td><td> Gly</td><td> Gly</td><td> Ser</td><td> Ser</td><td> Pro</td><td> Alá</td><td> Trp</td><td> Thr</td><td> Gin</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Cys</td><td> Gin</td><td> Gin</td><td> Leu</td><td> Ser</td><td> Gin</td><td> Lys</td><td> Leu</td><td> Cys</td><td> Thr</td><td> Leu</td><td> Alá</td><td> Trp</td><td> Ser</td><td> Alá</td><td> His</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Pro</td><td> Leu</td><td> Val</td><td> Gly</td><td> His</td><td> Met</td><td> Asp</td><td> Leu</td><td> Arg</td><td> Glu</td><td> Glu</td><td> Gly</td><td> Asp</td><td> Glu</td><td> Glu</td><td> Thr</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Thr</td><td> Asn</td><td> Asp</td><td> Val</td><td> Pro</td><td> His</td><td> Ile</td><td> Gin</td><td> Cys</td><td> Gly</td><td> Asp</td><td> Gly</td><td> Cys</td><td> Asp</td><td> Pro</td><td> Gin</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Gly</td><td> Leu</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Gin</td><td> Phe</td><td> Cys</td><td> Leu</td><td> Gin</td><td> Arg</td><td> Ile</td><td> His</td><td> Gin</td><td> Gly</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Leu</td><td> Ile</td><td> Phe</td><td> Tyr</td><td> Glu</td><td> Lys</td><td> Leu</td><td> Leu</td><td> Gly</td><td> Ser</td><td> Asp</td><td> Ile</td><td> Phe</td><td> Thr</td><td> Gly</td><td> Glu</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Pro</td><td> Ser</td><td> Leu</td><td> Leu</td><td> Pro</td><td> Asp</td><td> Ser</td><td> Pro</td><td> Val</td><td> Alá</td><td> Gin</td><td> Leu</td><td> His</td><td> Alá</td><td> Ser</td><td> Leu</td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td> 125</td><td></td><td></td><td></td>

<td> Leu</td><td> Gly</td><td> Leu</td><td> Ser</td><td> Gin</td><td> Leu</td><td> Leu</td><td> Gin</td><td> Pro</td><td> Glu</td><td> Gly</td><td> His</td><td> His</td><td> Trp</td><td> Glu</td><td> Thr</td>

<td></td><td> 130</td><td></td><td></td><td></td><td></td><td> 135</td><td></td><td></td><td></td><td></td><td> 140</td><td></td><td></td><td></td><td></td>

<td> Gin</td><td> Gin</td><td> Ile</td><td> Pro</td><td> Ser</td><td> Leu</td><td> Ser</td><td> Pro</td><td> Ser</td><td> Gin</td><td> Pro</td><td> Trp</td><td> Gin</td><td> Arg</td><td> Leu</td><td> Leu</td>

<td> 145</td><td></td><td></td><td></td><td></td><td> 150</td><td></td><td></td><td></td><td></td><td> 155</td><td></td><td></td><td></td><td></td><td> 160</td>

<td> Leu</td><td> Arg</td><td> Phe</td><td> Lys</td><td> Ile</td><td> Leu</td><td> Arg</td><td> Ser</td><td> Leu</td><td> Gin</td><td> Alá</td><td> Phe</td><td> Val</td><td> Alá</td><td> Val</td><td> Alá</td>

<td></td><td></td><td></td><td></td><td> 165</td><td></td><td></td><td></td><td></td><td> 170</td><td></td><td></td><td></td><td></td><td> 175</td><td></td>

<td> Alá</td><td> Arg</td><td> Val</td><td> Phe</td><td> Alá</td><td> His</td><td> Gly</td><td> Alá</td><td> Alá</td><td> Thr</td><td> Leu</td><td> Ser</td><td> Pro</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> 180</td><td></td><td></td><td></td><td></td><td> 185</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 146 <211> 19 <212> PRT <213> Homo sapiens

114

ΕΡ 2 548 577 Β1 <400> 146

Asn Ile Glu His Lys 1 5

Val Lys Gly

Tyr Leu Gly Tyr Alá Thr Ser Tyr Alá Alá Ser <210> 147 <211> 123 <212> PRT <213> Homo sapiens <400> 147

<td> Gin</td><td> Val</td><td> Gin</td><td> Leu</td><td> Val</td><td> Glu</td><td> Ser</td><td> Gly</td><td> Gly</td><td> Gly</td><td> Leu</td><td> Val</td><td> Gin</td><td> Pro</td><td> Gly</td><td> Gly</td>

<td> 1</td><td></td><td></td><td></td><td> 5</td><td></td><td></td><td></td><td></td><td> 10</td><td></td><td></td><td></td><td></td><td> 15</td><td></td>

<td> Ser</td><td> Leu</td><td> Arg</td><td> Leu</td><td> Ser</td><td> Cys</td><td> Alá</td><td> Alá</td><td> Ser</td><td> Gly</td><td> Phe</td><td> Thr</td><td> Phe</td><td> Ser</td><td> Ser</td><td> Phe</td>

<td></td><td></td><td></td><td> 20</td><td></td><td></td><td></td><td></td><td> 25</td><td></td><td></td><td></td><td></td><td> 30</td><td></td><td></td>

<td> Gly</td><td> Met</td><td> Ser</td><td> Trp</td><td> Val</td><td> Arg</td><td> Gin</td><td> Alá</td><td> Pro</td><td> Gly</td><td> Lys</td><td> Gly</td><td> Leu</td><td> Glu</td><td> Trp</td><td> Val</td>

<td></td><td></td><td> 35</td><td></td><td></td><td></td><td></td><td> 40</td><td></td><td></td><td></td><td></td><td> 45</td><td></td><td></td><td></td>

<td> Ser</td><td> Asn</td><td> Ile</td><td> Glu</td><td> His</td><td> Lys</td><td> Tyr</td><td> Leu</td><td> Gly</td><td> Tyr</td><td> Alá</td><td> Thr</td><td> Ser</td><td> Tyr</td><td> Alá</td><td> Alá</td>

<td></td><td> 50</td><td></td><td></td><td></td><td></td><td> 55</td><td></td><td></td><td></td><td></td><td> 60</td><td></td><td></td><td></td><td></td>

<td> Ser</td><td> Val</td><td> Lys</td><td> Gly</td><td> Arg</td><td> Phe</td><td> Thr</td><td> Ile</td><td> Ser</td><td> Arg</td><td> Asp</td><td> Asn</td><td> Ser</td><td> Lys</td><td> Asn</td><td> Thr</td>

<td> 65</td><td></td><td></td><td></td><td></td><td> 70</td><td></td><td></td><td></td><td></td><td> 75</td><td></td><td></td><td></td><td></td><td> 80</td>

<td> Leu</td><td> Tyr</td><td> Leu</td><td> Gin</td><td> Met</td><td> Asn</td><td> Ser</td><td> Leu</td><td> Arg</td><td> Alá</td><td> Glu</td><td> Asp</td><td> Thr</td><td> Alá</td><td> Val</td><td> Tyr</td>

<td></td><td></td><td></td><td></td><td> 85</td><td></td><td></td><td></td><td></td><td> 90</td><td></td><td></td><td></td><td></td><td> 95</td><td></td>

<td> Tyr</td><td> Cys</td><td> Alá</td><td> Arg</td><td> Tyr</td><td> Trp</td><td> Gly</td><td> Thr</td><td> Pro</td><td> Tyr</td><td> Leu</td><td> Met</td><td> Gin</td><td> Phe</td><td> Asp</td><td> Asn</td>

<td></td><td></td><td></td><td> 100</td><td></td><td></td><td></td><td></td><td> 105</td><td></td><td></td><td></td><td></td><td> 110</td><td></td><td></td>

<td> Trp</td><td> Gly</td><td> Gin</td><td> Gly</td><td> Thr</td><td> Leu</td><td> Val</td><td> Thr</td><td> Val</td><td> Ser</td><td> Ser</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> 115</td><td></td><td></td><td></td><td></td><td> 120</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>