PL2374818T3

High affinity antibodies to human IL-6 receptor

Abstract

This record has no abstract on file.

Term

0.7 yearsto projected expiry

Projected expiry 1 June 2027, counted from filing; an application has no term until it is granted.

14 claims: 7 independent, 7 dependent

1
Zastrzeżenia patentowe 1. Przeciwciało lub jego fragment wiążący antygen, które swoiście wiąże ludzki receptor interleukiny 6 (hIL6R) z KD wynoszącą 500 pM lub mniej, mierzoną techniką powierzchniowego rezonansu plazmonowego, gdzie:(i) CDR łańcucha ciężkiego obejmują SEKW NR ID: 5, 7 i 9 jako odpowiednio CDR1, CDR2 i CDR3 łańcucha ciężkiego, i (ii) CDR łańcucha lekkiego obejmują SEKW NR ID:13, 15 i 17 jako odpowiednio CDR1, CDR2 i CDR3 łańcucha lekkiego.
2
Przeciwciało lub fragment wiążący antygen według zastrzeżenia 1, obejmujące pary HCVR/LCVR z SEKW NR ID:3/11.
3
Przeciwciało lub fragment wiążący antygen według zastrzeżenia 1 albo 2, które swoiście wiążą hIL-6R z KD wynoszącą 300 pM lub mniej, mierzoną techniką powierzchniowego rezonansu plazmonowego.
4
Przeciwciało lub fragment wiążący antygen według zastrzeżenia 1, 2 albo 3, które swoiście wiążą hIL-6R z powinowactwem przynajmniej półtora razy wyższym w stosunku to wiązania małpiego IL-6R.
5
Przeciwciało lub fragment wiążący antygen według któregokolwiek z poprzednich zastrzeżeń, gdzie fragment wiążący antygen jest wybrany spośród Fab, F(ab')2 i scFv.
6
Izolowana cząsteczka kwasu nukleinowego kodująca przeciwciało lub fragment wiążący antygen według któregokolwiek z poprzednich zastrzeżeń.
7
Wektor ekspresyjny zawierający cząsteczkę kwasu nukleinowego określoną w zastrzeżeniu 6.
8
Izolowana komórka gospodarza zawierająca wektor ekspresyjny określony w zastrzeżeniu 7.
9
Komórka gospodarza według zastrzeżenia 8, gdzie komórką gospodarza jest komórka prokariotyczna lub eukariotyczna wybrana spośród komórek E. coli lub CHO.
10
Sposób wytwarzania przeciwciała anty-IL-6R lub jego fragmentu wiążącego antygen, obejmujący hodowlę komórek gospodarza określonych wzastrzeniu 8 albo 9 w warunkach pozwalających na produkcję przeciwciała lub jego fragmentu i odzyskiwanie przeciwciała lub fragmentu tak wytworzonego.
11
Zastosowanie przeciwciała lub fragmentu przeciwciała wiążącego antygen jak określonego w którymkolwiek z zastrzeżeń 1 do 5 do wytwarzania środkaleczniczeg przeznaczonego do atenuacji lub inhibicji choroby lub zaburzenia modulowanego przez IL-6 u ludzi, przy czym chorobą lub zaburzeniem modulowanym przez IL-6 jest zapalenie stawów, chroniczne reumatoidalne zapalenie lub toczeń rumieniowaty układowy.
12
Przeciwciało lub fragment wiążący antygen jak określone wktórymkolwiek z zastrzeżeń 1 do 5 do zastsowania w atenuacji lub inhibicji choroby lub zaburzenia modulowanego przez IL-6 u ludzi, gdzie chorobą lub zaburzeniem modulowanym przez IL-6 jest zapalenie stawów, choroba zapalna jelit lub toczeń rumieniowaty układowy. PZ/1778AGR EP 2 374 818 B1
13
Kompozycja farmaceutyczna obejmująca przeciwciało lub fragment przeciwciała wiążący antygen jak określono w którymkolwiek z zastrzeżeń 1 do 5 i farmaceutycznie dopuszczalny nośnik lub zaróbkę.
14
Zastosowanie według zastrzeżenia 11 lub przeciwciało lub fragment według zastrzeżenia 12, w którym zapalenie stawów jest chronicznym reumatoidalnym zapaleniem stawów albo chorobą zapalna jelit jest choroba Crohna lub wrzodziejące zapalenie jelita grubego. PZ/1778AGR EP 2 374 818 B1 Odnośniki cytowane w opisie Poniższa lista odnośników cytowanych przez zgłaszającego ma na celu wyłącznie pomoc dla czytającego i nie stanowi części dokumentu patentu europejskiego. Pomimo, że dołożono największej staranności przy jej tworzeniu, nie można wykluczyć błędów lub przeoczeń i EUP nie ponosi żadnej odpowiedzialności w tym względzie. Dokumenty patentowe cytowane w opisie • US 5670373 A [0002] • US 5795965 A [0002] • US 5817790 A [0002] [0041] • US 6410691 B [0002] • EP 409607 B1 [0002] • US 5888510 A [0002] • US 6723319 A [0002] • US 5545807 A [0025] • US 6787637 B [0025] • US 6596541 B [0025] [0037] • US 20040101920 A [0033] • WO 60810664 A [0052] • WO 60843232 A [0052] Literatura nie patentowa, cytowana w opisie • REDDY et al. J. Immunol., 2000, vol. 164, 1925-1933 [0003] • SHIELD et al. JBC, 2002, vol. 277, 26733 [0007] • WARD et al. Nature, 1989, vol. 241, 544-546 [0017] • BIRD et al. Science, 1988, vol. 242, 423-426 [0017] • HUSTON et al. Proc. Natl. Acad. Sci. USA, 1988, vol. 85, 5879-5883 [0017] • HOLLIGER et al. Proc. Natl. Acad Sci. USA, 1983, vol. 90, 6444-6448 [0017] • PEARSON. Methods Mol. Biol., 1994, vol. 24, 307-331 [0023] • GONNET et al. Science, 1992, vol. 256, 1443-45 [0023] • ALTSCHUL et al. J. Mol. Biol., 1990, vol. 215, 403-410 [0024] • ALTSCHUL et al. Nucleic Acids Res., 1997, vol. 25, 3389-402 [0024] • GREEN et al. Nature Genetics, 1994, vol. 7, 13-21 [0025] • ANGAL et al. Molecular Immunology, 1993, vol. 30, 105 [0027] • Antibodies:A Laboratory Manual. Cold Spring Harbor Laboratory, 1988 [0032] • REINEKE. Methods Mol Biol, 2004, vol. 248, 443-63 [0032] • TOMER. Protein Science, 2000, vol. 9, 487-496 [0032] • POWELL et al. J Pharm Sci Technol., 1998, vol. 52, 238-311 [0035] • MALIK;LILLEHOJ. Antibody techniques. Academic Press, 1994 [0037] • O'HAGAN. Vaccine Adjuvant. Human Press, 2000 [0037] • WANG et al. J Immunol Methods, 2000, vol. 244, 217-225 [0038]

Independent claims14

1,197 paragraphs in 138 sections, as filed

[0001] Interleukin-6 (IL-6) is a pleiotropic cytokine produced by immune cells and others that plays a key role in regulating the immune response, acute phase reaction and hematopoiesis. It binds to soluble and membrane IL-6R (α chain) to form a binary complex, which complex can interact with the cell membrane-linked gp130 protein (β chain), and induces the formation of a signaling complex containing two of IL-6, IL -6R, and gp130.

[0002] Antibodies binding to hIL-6R are described in US 5,670,373. 5,795,965. 5817.790. 6,410,691, and EP 409 607B1. Therapeutic methods are described in US 5,888,510 and 6,723,319.

BRIEF DESCRIPTION OF THE INVENTION [0003] In a first aspect, the present invention discloses human antibodies, preferably recombinant human antibodies, that specifically bind human interleukin-6 receptor (hIL-6R).

These antibodies are characterized by binding to hIL-6R with high affinity and slow dissociation kinetics, and the ability to neutralize IL-6 activity. Antibodies may be full-length (e.g., IgG1 or IgG4 antibody) or may only contain an antigen-binding fragment (e.g., Fab, F (ab ') 2 or scFv fragment), and may be modified to change their functionality, e.g. eliminating residual effector functions (Reddy et al. (2000) J. Immunol. 164: 1925-1933). In a preferred aspect, the present invention discloses an antibody or antigen-binding fragment thereof that binds the human IL6 receptor (SEQ ID NO: 1) to a KD of about 500 pM or less as measured by surface plasmon resonance. In a more specific aspect, the antigen binding antibody or fragment has a KD value of less than 300 pM, or less than 200 pM, or even less than 100 pM. In various aspects, the antibody or antigen-binding fragment thereof blocks IL-6 activity with an IC50 of 250 pM or less, as measured by a luciferase bioassay. In more specific aspects, the antibody or antigen binding fragment thereof has an IC 50 of 150 pM or less.

[0004] In further aspects, the antibody or antigen-binding fragment of the present invention binds hIL-6R with an affinity at least twice as high as it binds monkey IL-6R. In more preferred aspects, the antibody or antigen-binding fragment binds the hIL-6R protein (SEQ ID NO: 1) with an affinity about 3 times higher than its binding to monkey IL6R (extracellular domain of Macaca fascicularis shown in SEQ ID NO: 251) .

[0005] Thus, the present invention provides an antibody or antigen-binding fragment thereof that specifically binds the human interleukin-6 receptor (hIL-6R) to a KD of 500 pM or less as measured by surface plasmon resonance technique, wherein:

(i) the heavy chain CDRs comprise SEQ ID NOs: 5, 7 and 9 as heavy chain CDR1, CDR2 and CDR3, respectively; and (ii) the light chain CDRs comprise SEQ ID NOs: 13, 15 and 17 as light chain CDR1, CDR2 and CDR3, respectively.

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EP 2 374 818 B1

In specific embodiments, the antibody or antigen binding fragment thereof comprises an HCVR / LCVR pair SEQ ID NO: 3/11 [0006] In a second aspect, the present invention provides isolated nucleic acid molecules encoding the antibody or antigen binding antibody fragment of the present invention. In one embodiment, the nucleic acid molecule of the present invention encodes the antibody or HCVR-containing fragment thereof described above. In specific embodiments, the nucleic acid molecule encoding HCVR is SEQ ID NO: 2. In a related aspect, the present invention provides an isolated nucleic acid molecule encoding LCVR as described above. In specific embodiments, the nucleic acid molecule encoding LCVR is SEQ ID NO: 10.

[0007] The present invention discloses anti-hIL-6R antibodies or antigen binding fragments thereof having a modified glycosylation system. In some applications, modifications to remove unwanted glycosylation sites, or antibodies that lack a fucose moiety in the oligosaccharide chain, may be preferred, for example to increase antibody dependent cellular cytotoxicity (ADCC) (see Shield et al. (2002) JBC 277: 26733). In other applications, galactosylation modifications may be made to alter complement-dependent cytotoxicity (CDC).

[0008] In further aspects, the present invention provides recombinant expression vectors carrying the nucleic acid molecules of the present invention, and host cells into which these vectors have been introduced, as well as methods of producing antibodies or antigen-binding fragments of the present invention obtained by culturing host cells according to of the present invention. The host cell may be a prokaryotic or eukaryotic cell, preferably the host cell is an E. coli cell or a mammalian cell such as a CHO cell.

In a further aspect, the present invention includes a pharmaceutical composition comprising a human antibody or antigen-binding antibody fragment that specifically binds hIL-6R and a pharmaceutically acceptable carrier.

[0010] In further aspects, the present invention provides an antibody or antigen-binding fragment of the antibody as defined above for use in attenuating or inhibiting an IL-6-modulated disease or disorder in humans, wherein the disease or disorder modulated by IL-6 is arthritis, inflammatory bowel disease or systemic lupus erythematosus. Thus, the disorder is selected from arthritis, including chronic rheumatoid arthritis, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, or systemic lupus erythematosus.

[0011] In further aspects, the present invention provides the use of an antibody or antigen-binding antibody fragment as defined above in the manufacture of a medicament for attenuating or inhibiting an IL-6-modulated disease or disorder in humans, wherein the IL-6-modulated disease or disorder is arthritis. inflammatory bowel disease or systemic lupus erythematosus.

[0012] Other objectives and benefits will be revealed when analyzing the following detailed description.

DETAILED DESCRIPTION [0013] Before the present methods are described, it should be clarified that the present invention is not limited to specific methods, and the methods and conditions as such may vary. It should also be

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It will be appreciated that the terminology used in this specification is used only to determine specific embodiments and is not intended to limit the scope of the invention, because the scope of the present invention will be limited only by the appended claims.

[0014] Unless otherwise specified, all technical and scientific terminology will have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used, preferred methods and materials are described as examples.

[0015] The term "human IL6R" (hIL-6R), as used herein, refers to a human cytokine receptor that specifically binds interleukin-6 (IL-6). The extracellular domain of hIL-6R is indicated in SEQ ID NO: 1.

[0016] The term "antibody", as used herein, refers to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains joined together by disulfide bridges. Each heavy chain has a heavy chain variable region (herein abbreviated as HCVR or VH) and a heavy chain constant region. The heavy chain constant region contains three domains: CH1, CH2 and CH3. Each light chain has a light chain variable region (hereinafter abbreviated as LCVR or VL) and a light chain constant region. The light chain constant region consists of one domain (CL1). The VH and VL areas can be further subdivided into hypervariable areas, called complementarity determining areas (CDRs), separated by more conserved areas, referred to as structural areas (FRs). Each VH and VL area consists of three CDRs and four FRs, arranged from N-terminus to C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0017] The term "antigen binding fragment" of an antibody (or, more simply, "antibody portion" or "antibody fragment"), as used herein, refers to one or more antibody fragments that maintain the ability of specific antigen binding (e.g. hIL6R). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen binding antibody fragment" include (i) Fab fragment, a monomial fragment consisting of the VL, VH, CL1 and CH1 domains; (ii) F (ab ') 2 fragment, a binomial fragment containing two Fab fragments joined disulfide bridge in the hinge region; (iii) Fd fragment consisting of the VH and CH1 domains; (iv) Fv fragment consisting of the VL and VH domains of one arm of the antibody, (v) dAb fragment (Ward et al. (1989) Nature 241: 544-546) consisting of the VH domain; and (vi) isolated complementarity determining region (CDR). In addition, despite the fact that both domains of the Fv fragment, VL and VH are encoded by separate genes, they can be connected using recombinant methods, through a synthetic linker that allows them to be obtained as a single, continuous chain in which the VL and VH regions pair to produce monomial molecules (known as single chain Fv (scFv); see e.g. Bird et al. (1988) Science 242: 423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883). Such single chain antibodies are also encompassed by the term "antigen binding area" of the antibody. Other forms of single chain antibodies, such as dual specificity antibodies, are also included (dibodies) (see, e.g., Holliger et al. (1983) Proc. Natl. Acad Sci. USA 90: 6444-6448).

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[0018] The term "neutralizing" or "blocking" antibody as used herein refers to an antibody whose binding to hIL6R results in inhibition of biological activity of hIL-6. Inhibition of biological activity of hIL-6 can be assessed by measuring one or more indicators of prior art biological activity of hIL-6, such as hIL-6 induced cell activation and hIL-6 binding to hIL-6R (see examples below).

[0019] A "CDR" or complementarity determining area is a hyper variable area divided by more conserved areas, called "structured areas" (FRs). In various embodiments of the anti-hIL-6R antibody or fragment of the present invention, FRs may be identical to human germline sequences, or may be modified naturally or artificially. A CDR group may be defined as a consensus amino acid sequence.

[0020] The term "surface plasmon resonance" (surface plasmon resonance measurement), as used herein, refers to an optical phenomenon that allows the analysis of interactions in real time by detecting changes in protein concentrations within a biosensory matrix, for example using a system BIAcore ™ (Pharmacia Biosensor AB).

[0021] The term "epitope" is an antigenic determinant that interacts with a specific antigen binding site in the variable region of the antibody molecule known as paratope. A single antigen may have more than one epitope. Epitopes can be conformational or linear. The conformational epitope is produced by spatially arranged amino acids from various segments of the linear polypeptide chain. The linear epitope is produced by successive amino acid residues in the polypeptide chain. In some cases, the epitope may contain sugar, phosphate, or sulfonyl groups on the antigen.

[0022] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, means one which, when optimally matched to the insertion and deletion of another nucleic acid (or its complementary strand), exhibits nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of nucleotide bases, as measured by any known sequence identity algorithm, such as FASTA, BLAST or Gap as discussed below.

[0023] With respect to polypeptides, the term "substantial similarity" or "substantially similar" means two peptide sequences which, when optimally matched as using GAP or BESTFIT programs using default gap weights, share at least 95% of the identical sequence, and even more preferably at least 98% or 99% of the identical sequence. Preferably, residues at positions that are not identical differ by substitutions of conserved amino acids. A "substitution of conserved amino acids" is one in which the substituted amino acid residue is another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). Generally, conservative amino acid substitution will not significantly affect the functional properties of the protein. In cases where two or more amino acid sequences differ from others by a conservative substitution, the percent sequence identity or degree of similarity may be adjusted upwards to take into account the conservative nature of the substitution. Methods for making this correction are well known to those skilled in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331. Examples

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Amino acid groups with side residues with similar chemical properties include 1) aliphatic side groups: glycine, alanine, valine, leucine and isoleucine; 2) aliphatic-hydroxyl side groups: serine and threonine; 3) containing an amide side group: asparagine and glutamine; 4) aromatic side groups: phenylalanine, tyrosine, and tryptophan; 5) basic side groups: lysine, arginine, and histidine; 6) acidic side groups: aspartate and glutamate, and 7) sulfuric side groups: cysteine and methionine. Preferred substitutions for conserved amino acids are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamate. Alternatively, a conservative change is any change that has a positive value in the logarithmic-probabilistic matrix PAM250 disclosed in Gonnet et al. (1992) Science 256: 1443 45. A "moderately conservative" substitution is one that has a non-negative value in the PAM250 logarithmic-probabilistic matrix.

[0024] The sequence similarity of polypeptides, which is also called sequence identity, is usually determined by means of sequence analysis software. Protein analysis software matches similar sequences using measures of similarity attributed to various substitutions, deletions, or other changes, including conservative amino acid changes. For example, the GCG software includes programs such as Gap and Bestfit, which can be used with default parameters to determine sequence homology between related polypeptides, such as homologous polypeptides from different species of organisms, or between wild protein and its mutants. See. e.g. GCG Version 6.1. Polypeptide sequences can also be compared using FASTA using default or recommended parameters, and the program in GCG Version 6.1., FASTA (e.g. FASTA2 or FASTA3) provides matches and percent sequence identity of the best-fit regions between the query and search sequences (Pearson (2000) supra). Another preferred algorithm for comparing the sequences of the present invention is the BLAST database containing a large number of sequences from various organisms, in particular blastp or tblastn, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and Altschul et al. (1997) Nucleic Acids Res. 25: 3389 402.

Production of human antibodies [0025] Methods for generating human antibodies include, for example, VelocImmuneTM (Regeneron Pharmaceuticals), XenoMouse technologyTM (Green et al. (1994) Nature Genetics 7: 13-21; Abgenix), "minilocus" approach, and phage display (see for example US 5,545,807, US 6,787,637). VelocImmune technologyTM (US 6, 596.541) includes a method of generating highly specific human antibodies against a matched antigen. This technology is based on the generation of a transgenic mouse having a genome comprising human heavy and light chain variable regions operably linked to an endogenous mouse constant region such that such a mouse produces an antibody containing a human variable domain and a mouse constant region in response to antigenic stimulation. DNA encoding antibody heavy and light chain variable regions are isolated and operably linked to DNA encoding human heavy and light chain constant regions. DNA is then expressed in a cell that can express a full human antibody. In a specific embodiment, the cell is a CHO cell.

[0026] Antibodies may be therapeutically more beneficial in blocking ligand-receptor interactions

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Or receptor-component inhibition than by killing cells by complement binding (complement dependent cytotoxicity, CDC) and by participating in antibody dependent cell modulated cytotoxicity (ADCC). The constant region of an antibody is important in its ability to bind a complement and affect cell-dependent cytotoxicity. Thus, the antibody isotype can be selected depending on whether participation in cytotoxicity modulation is desired.

[0027] Human immunoglobulins can exist in two forms that are associated with hinge heterogeneity. In one form, the immunoglobulin molecule contains a stable construct of four chains weighing about 150-160 kDa, in which the dimers are joined together via a disulfide bridge between heavy chains. In a second form, the dimers are not connected by a disulfide bridge between the chains, and the molecule about 75-80 kDa is formed from covalently linked light and heavy chains (half-antibody). These forms are very difficult to separate, even after affinity purification. The frequency of the second form with different full IgG isotypes depends, but is not limited, on structural differences associated with the hinge region of the antibody isotype. Indeed, a single amino acid substitution in the human IgG4 hinge region can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30: 105) to levels typically observed using human IgG1 hinges. The present invention includes antibodies having one or more hinge mutations, or CH2 or CH3 regions, which may be desirable, for example, to increase the yield of the desired form of antibody.

[0028] Antibodies of the present invention are preferably produced using VelocImmune technology TM. A transgenic mouse in which the endogenous immunoglobulin heavy and light chain variable regions are replaced with corresponding human variable regions is challenged with a preferred antigen and lymphatic cells (such as B cells) are recovered from the mouse expressing the antibodies. Lymphatic cells can be fused with myeloma line cells to produce immortal hybridoma lines, and such hybridoma lines are screened and selected to identify those that produce antibodies specific for the desired antigen. DNA encoding heavy chain and light chain variable regions can be isolated and linked to the desired isotype heavy chain and light chain constant region. Such antibody proteins can be produced in a cell such as a CHO cell. Alternatively, DNA encoding antigen-specific chimeric antibodies or light and heavy chain variable domains can be isolated directly from antigen-specific lymphocytes.

[0029] In one aspect, the transgenic mouse contains up to 18 functional human variable heavy chain genes and 12 functional human variable kappa light chain genes. In another aspect, the transgenic mouse contains up to 39 human variable heavy chain genes and 30 human variable kappa light chain genes. In yet another aspect, the transgenic mouse contains up to 80 human variable heavy chain genes and 40 human variable kappa light chain genes.

[0030] Generally, the antibodies of the present disclosure have high affinity, typically having KD from about 10-9 up to about 10-12 M when the measurement is made with solid phase immobilization

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Or in solution phase.

[0031] Initially, high affinity chimeric antibodies are isolated as having a human variable region and a murine constant region. As described below, the antibodies are characterized and selected based on advantageous features, including binding affinity for hIL-6R, the ability to block hIL-6, and / or selectivity for human proteins. Mouse constant regions are replaced with the desired human constant regions to generate the full human antibody of the present invention, e.g. wild or modified IgG4 or IgG1 (e.g. SEQ ID NO: 242, 243, 244). While selected constant regions can be changed according to specific applications, high antigen binding affinity and specificity are features dependent on the variable region.

Epitope Mapping and Related Technologies [0032] To screen for specific epitope binding, for example, a routine cross-blocking antibody test is performed such as described in Antibodies: A Laboratory Manual 1988 Cold Spring Harbor Laboratory, Harlow and Lane, eds. Other methods include scanning of alanine mutants, peptide blots (binding) (Reineke (2004) Methods Mol Biol 248: 44363), or peptide cleavage analysis as described below. In addition, methods such as epitope excision or extraction, and chemical modification of antigens may be used (Tomer (2000) Protein Science: 9: 487-496).

[0033] Modification-Assisted Profiling (MAP), also known as Antigen Structure-based Antibody Profiling (ASAP), is a way to categorize large numbers of monoclonal antibodies (mAbs) directed against this antigen alone according to the similarity of the binding profile of each antibody to chemically modified antigen surfaces (US Patent Application No. 2004/0101920). Each category may reflect a unique epitope, or strongly different from or partially overlapping an epitope from a different category. This technology allows the rapid filtering of genetically identical antibodies so that this classification can focus on genetically different antibodies. When MAP is used for hybridoma screening, this technique can help identify rare hybridoma clones with the desired characteristics. MAP can be used to sort hIL-6R antibodies of the present invention into groups of antibodies binding different epitopes.

[0034] Agents useful in modifying the structure of immobilized (immobilized) antigens are enzymes, such as, for example, proteolytic enzymes and chemicals. Antigenic proteins can be immobilized on the surfaces of biosensor plates or polystyrene grains. The latter can be used with tests, for example the Luminex multiplex detection testTM (Luminex Corp., TX). Because LuminexTM can use multiplex analysis with about 100 types of different grains, it provides almost unlimited antigenic surfaces with different modifications, resulting in improved resolution of epitope profiling compared to the biosensory test.

Therapeutic Formulations and Administration [0035] Administration of the therapeutic agents of the present invention will be used with

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Suitable carriers, excipients, and other agents that are added to the formulation to provide improved transfer, delivery, tolerance and the like. Many suitable formulations can be found in the list of formulations of well-known pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th edition, Mack Publishing Company, Easton, Pa., 1975), especially Chapter 87 by Blaug and Seymour. These formulations include, for example, powders, pastes, ointments, gels, waxes, oily lipids, lipids (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbohydrate emulsions (polyethylene glycols of different molecular weights), semi-solid gels, and semi-solid mixtures containing carbocarbons. Each of the above mixtures may be suitable for the particular treatment and therapy of the present invention, provided that the formulation does not deactivate the active substance of that formulation and the formulation is physiologically compatible and tolerable for a given route of administration. See also Powell et al. PDA (1998) J Pharm Sci Technol. 52: 238-311 and references cited therein for further information on excipients and carriers known to pharmaceutical chemists.

EXAMPLES [0036] The following examples are provided to provide ordinary experts in the field of comprehensive disclosure and description of how to make and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. Every effort has been made to ensure the precision of numbers (e.g. quantities, temperatures, etc.) but some experimental errors and deviations should be included. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is given in degrees Celsius, and pressure is atmospheric or close.

Example 1. Production of human IL-6 receptor binding antibodies.

[0037] Immunization of rodents can be carried out by any prior art method (see for example Harlow and Lane (1988) supra; Malik and Lillehoj, Antibody techniques: Academic Press, 1994, CA). In a preferred embodiment, the hIL-6R antigen is administered directly to mice that contain DNA loci encoding both the human Ig heavy chain variable region and the Kappa light chain variable region (Velocimmune ™, Regeneron Pharmaceuticals, Inc.; US 6,596,541), with an adjuvant to stimulate the response immune. Adjuvants include Freund's full and incomplete adjuvant, MPL + TDM (Sigma) adjuvant system, or RIBI (muramyl dipeptides) (see O'Hagan, Vaccine Adjuvant, by Human Press, 2000, NJ). Such an adjuvant may prevent rapid dispersion of the polypeptide by sequestering the antigen in local concentration, and may contain factors that can stimulate the host's immune response. In one embodiment, hIL-6R is administered indirectly as a plasmid DNA that contains the hIL-6R gene and expresses hIL-6R using host protein expression mechanisms to produce antigenic polypeptide in vivo. In both approaches, the immunization schedule requires several administrations at intervals of several weeks. The antibody immune response is monitored by standard antigen specificity assay. When the animals reach their maximum immune response, antibody-expressing B cells are collected and combined with murine myeloma cells in

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In order to preserve their survival, forming hybridoma cells. To select functionally desired monoclonal antibodies, medium from hybridoma cell culture or transfected cells were screened for specificity, antigen binding affinity, and potency in blocking hIL to hIL-6R binding (as described below).

Example 2. Anti-hIL6R antibodies produced by direct isolation of splenocytes [0038] DNA encoding the VH and VL domains can be isolated directly from single antigen-positive B cells. Briefly, immunized hIL-6Ra transgenic mice were killed and splenocytes were removed. Erythrocytes were removed by lysis and the collected splenocytes were pelletized. The re-suspended splenocytes were pre-incubated in a human IgG, FITC-anti-mFc, and biotinIL6Ra cocktail for 1 hour. Stained cells were washed twice with PBS and then stained in a human and rat IgG cocktail, APC-anti-mlgM, and SA-PE for an hour. Stained cells were washed once with PBS and analyzed by flow cytometry with a MoFlo apparatus (Cytomation). Each IgG-positive, IgM-negative, and antigen-positive B cell was sorted and plated individually into a well in a 96-well plate. RT-PCR of antibody genes from these B cells was performed according to the method described by Wang et al. (2000) (J Immunol Methods 244: 217-225). Briefly, cDNA from each of the B cells was synthesized by RT-PCR. Each resulting RT product was then divided and transferred to the appropriate well in two 96-well plates. One of the sets of RT products was pre-amplified by PCR using a degenerate 5 'primer specific for the human leader sequence of the IgG heavy chain variable region and a 3' primer specific for the mouse heavy chain constant region to form an amplicon. The amplicon was then again amplified by PCR using a 5 'degenerate primer specific for the structural region 1 of the human IgG heavy chain variable region sequence and a nested 3' primer specific for the murine heavy chain constant region. A second set of RT products obtained was pre-amplified by PCR using a 5 'degenerate primer specific for the kappa human light chain variable region leader and a 3' primer specific for the kappa mouse light chain constant to generate the amplicon. The amplicon was re-amplified by PCR using a 5 'degenerate primer specific for the structural region 1 of the human kappa light chain variable region and nested 3' primer specific for the murine kappa light chain constant region. The heavy chain and light chain PCR products were cloned into Sap I linearized antibody vectors containing the IgG1 heavy chain constant region and the kappa light chain constant region, respectively. The heavy chain plasmid has lox2272 and lox511 sites flanking the heavy chain expression cassette. In addition, immediately after lox2272 in the heavy chain plasmid is a hygromycin resistance gene that does not have a promoter or an initiating ATG. The hygromycin resistance gene is also transcribed linked to the following eGFP gene via an IRES sequence. The light chain plasmid has IoxP and lox2272 sites flanking the light chain expression cassette. In addition, the light chain plasmid has the SV40 promoter just before ATG at the lox2272 site, so that after integration into the appropriate host cell, the SV40 promoter proximal to the lox2272 sequence and the initiating ATG codon in the light chain plasmid are introduced adjacent to the resistance gene

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Hygromycin in the heavy chain plasmid in the correct reading frame to enable transcription and translation of hygromycin and eGFP resistance genes . Purified recombinant plasmids having the heavy chain variable region sequence and plasmids having the light chain variable region sequence from the same B cell were combined and transfected into a modified CHO host cell line together with a Cre recombinase expressing plasmid. The modified CHO host cell line contains, in the 5 'to 3' direction, the IoxP site, eCFP, the lox2272 site, DsRed, and the lox511 site in the transcriptionally active region. Consequently, CHO host cells can be isolated by flow cytometry as blue or red positive or green negative cells. When the recombinant plasmids expressing the heavy chain and light chain genes are transfected together with the Cre recombinase expressing plasmid, site-specific recombination modulated by Cre recombinase results in the integration of antibody plasmids at the chromosomal locus containing the lox sites and the replacement of the eCFP and DsRed genes. The recombinants can then be isolated as blue or red negative, or green positive cells by flow cytometry. Thus, CHO cells transfected with recombinant plasmids having the heavy chain variable region sequence and plasmids having the light chain variable region sequence from the same B cell were sorted by flow cytometry, and the correct recombinants showing a blue and red negative phenotype and green positive were isolated and stable cell lines were derived CHO expressing antibodies to isolated clones.

Example 3. Determination of antigen binding affinity [0039] The KD value of antigen binding to the selected antibody described above was determined by surface kinetics in a real-time surface plasmon resonance biosensor test (BIAcore)TM). More specifically, the affinity of antibodies for human IL-6R was measured using a BIAcore® 2000 or BIAcore® 3000 apparatus. The antibody was captured on anti-mouse IgG medium and exposed to various concentrations of recombinant hIL-6R proteins in both monomeric and dimeric form. Kinetic analysis was performed using BIAevaluation ™ software to obtain binding and dissociation constants.

[0040] The binding affinity of the hlL-6R binding antibody was also measured for hybridoma culture media as well as purified proteins by means of a platelet competitive immunoassay. Antibody proteins were purified using G protein affinity chromatography from hybridoma cell medium that was depleted of bovine IgG (Invitrogen). For a competitive ELISA, in brief, constant amounts of antibody at different levels were premixed with serial dilutions of the antigen protein, hIL-6R-hFc, from 0 to 10 μg / ml, and incubated for two hours at room temperature until reaching pseudo-equilibrium binding between the antibody and antigen. These solutions were then transferred to 96-well pre-coated hIL-6RhFc plates to allow free antibodies in the mixture to bind to the hIL-6R-hFc coating plate. Plates were typically coated with a solution of 1 to 2 μg / ml hIL-6R-hFc protein in PBS overnight at

4 ° C with subsequent blocking of non-specific bonds by BSA. After washing away excess antibody from the solution, plate-bound antibodies were detected by HRP-conjugated

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Polyclonal goat anti-mouse IgG or IgA and was detected using colorimetric or chemiluminescent substrates. The dependence of the signals on the concentration of antigen in the solution was tested by means of a 4-parameter fit using the Prism ™ program (Graph Pad) and expressed as IC50. A competitive immunoassay was also carried out using an Kinexa ™ instrument (Sapidyne Inc.) for a solution at equilibrium.

[0041] The results are shown in Table 1 (control: humanized anti-human IL-6R monoclonal antibody (US Patent Nos. 5,817,790 SEQ ID NO: 69 and 71). Antibody (HCVR and LCVR amino acid sequences): VQ8A9-6 (3, 11 ); VQ8F11-21 (19, 27); VV7G4-1 (35, 43); VV7G4-10 (51, 59) VV6C10-1 (67, 75); VV6C10-3 (83, 91); VV6C10-4 ( 99, 107); VV6F12-11 (115, 123); VV9A6-11 (131, 139); VV6A9-5 (147, 155), VV3D8-4 (163, 171); VV1G4-7 (179, 187); 248982-13-1-E5 (195, 203); 248982-13-2-A9 (211, 219). Monomer and dimer KD determined by BIAcore ™; KD in solution with Kinexa ™; IC50 by ELISA (na = not tested).

Table 1. Antigen binding affinity

<td>Antibody</td><td>Kd of monomer (NM)</td><td>Dimer Kd (nM)</td><td>Kd solution monomer (nM)</td><td>IC50 ELISA Dimeru (nM)</td>

<td>Control</td><td> 1.790</td><td>nd</td><td> 1.960</td><td>nd</td>

Example 4. Neutralization of hIL-6 activity [0042] The hIL-6 blocking activity of anti-hIL-6R antibodies of the present invention was checked by means of hIL-6 blocking immunoassays, in vitro biological assays of hIL-6 dependent cell growth and surface plasmon resonance (BIAcoreTM). An immunoassay was used to screen for the ability of antibodies to block binding of hIL-6 to hIL-6R, and an in vitro bioassay was used to determine the potency of the antibody's ability to neutralize the transduction of hIL-6R-modulated signals.

[0043] In an immunoassay, the recombinant hIL-6 protein in PBS was coated on a 96 well plate overnight at 4 ° C. This plate was used to capture free hIL-6R-hFc from antibody sample solutions, and the amount of hIL-6RhFc captured was quantified by curve

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EP 2 374 818 B1. Sample solutions consisted of a constant amount of recombinant hIL6R-hFc protein (100 pM) and various amounts of antibody, either in crude hybridoma culture medium or in the form of purified protein, in the range of 0 to about 50 nM in serial dilutions. Antibody-antigen mixtures were incubated at room temperature for 2 hours to achieve antibody-antigen binding balance. Equilibrated sample solutions were then applied to hIL-6 coated plates to measure free hIL-6R-hFc. After 1 hour binding, the plate was washed and bound hIL-6R-hFc was detected with HRP-conjugated goat anti-hFc polyclonal antibody (Jackson Immuno Research), and developed with TMB substrate (BD Pharmigen). IC50 values were determined as the amount of antibody required to reduce by 50% the amount of detectable IL-6R-hFc linked to the platelet hIL-6 ligand. The results are shown in the first column of Table 2.

[0044] In addition, the ability of the test antibody to block the binding of hIL-6 to hIL-6R was determined by surface plasmon resonance. Purified hIL-6R-hFc antigen molecules were captured by means of polyclonal goat anti-human IgG antibodies immobilized on the CM-5 surface via an amine bond at a density of 250 RU. The hIL-6 solution (0.25ml, 50 nM) was injected onto the surface of the receptors and the level of hIL-6 binding (first injection of IL-6) was recorded. Bound hIL-6 was then removed with 3M MgCl2 pulse followed by conditioning buffer. Anti-hIL6R antibody in hybridoma culture medium was injected onto the surface of the bound receptors followed by a second injection of hIL-6. Percent reduction in hL6 binding as a result of formation of the antibody and receptor complex was used as an indicator for the separation of hIL-6 blockers from non-blocking antibodies (second column, Table 2).

Table 2. Neutralization of hlL-6 binding

<td>Antibody</td><td>hIL6R / hIL6 Inhibition of binding IC50 (nM)</td><td>hIL6 / hIL6R Inhibition of binding (%)</td><td>XG-1 cells inhibition IC50 proliferation (NM)</td><td>HepG2 / Stat3 Activity IC50 luciferase (NM)</td>

<td>Control</td><td> 2.20</td><td> 91</td><td> 1.50</td><td> 0.854</td>

[0045]

The ability of hIL-6R binding antibody to block IL-6 activity in vitro was measured in the line

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HIL-6 dependent myeloma XG-1. XG-1 cells maintained in hlL-6 containing medium were washed twice with hlL-6 containing medium and incubated for 24 hours in hIL-6 free medium to exhaust remaining hIL-6. The starved cells were then again centrifuged and resuspended at 4 x 105 cells per ml and plated 20,000 cells per well in a 96 well tissue culture plate. Purified antibody proteins were serially diluted and added to seeded cells at concentrations from 0 to 50 nM. Then, recombinant hIL-6 protein was added to the wells to a final concentration of 8 pM. Cells were allowed to grow for 72 hours at 37 ° C in a 5% CO2 water-jacketed incubator. At the end of the culture period, viable cells were measured using the CCK-8 kit (Dojindo, Japan). The IC 50 was determined as described above, and determined in the third column of Table 2.

[0046] The ability of the antibody to block IL-6 activity through hIL-6R binding was also measured in vitro in the hIL-6 sensitive hepatoma line, HepG2. HepG2 cells were transfected with a reporter plasmid containing the STAT3 transcription regulatory element (Signal Transducer and activator Transcription 3) linked to the luciferase gene. Transfected cells were trypsinized,5 centrifuged and resuspended in the medium to a concentration of about 2.5 x 105 cells per ml and seeded at 20,000 cells per well in a 96 well tissue culture plate. Purified antibody proteins were serially diluted and added to seeded cells at concentrations ranging from 0 to 100 nM. Recombinant hIL-6 protein was then added to the wells to a final concentration of 50 pM. Response was measured after incubating the cells for 6 hours at 37 ° C in a 5% CO2 water-jacketed incubator. Luciferase activity was measured using the Steady-Glo ™ luciferase assay kit (Promega). IC50s were determined as above, and are shown in the fourth column of Table 2.

Example 5. Diversity of bound epitopes [0047] A competitive antibody binding immunoassay was performed using a humanized anti-human IL-6R antibody as control. Briefly, the 96-well enzyme plate was coated at 20ng per well with recombinant hIL-6R protein overnight at 4 ° C. After blocking non-specific BSA binding, the hIL-6R binding sites on the half plate were saturated by binding the control antibody by adding 500 ng control per well, and only binding buffer was added to the other half. After three hours of binding at room temperature, purified antibodies were added to a final concentration of 50 ng / ml with or without control antibody in the well. After one hour of further binding, the free antibody was washed away, and the plate-bound antibody was detected with HRP-conjugated goat anti-mouse IgG or IgA polyclonal antibody, and the plate was developed with chromogenic HRP substrates and absorbance measured at 450 nm. The percent reduction in anti-hIL6R antibody binding by the presence of controls is shown in Table 3 below. A similar experiment was performed using surface plasmon resonance (Table 3). Both methods gave consistent results. Antibodies VQ8F11, VV3D8, VV6A9, VV6C10-1 bound epitopes overlapping the control antibody; while the VQ8A9, VV1G4, VVW6F12, VV7G4, VV9A6, and VV6C10-3 antibodies appeared to bind separate epitopes since the antigen binding was not blocked by the control antibody. Partial competence may result from spatial hindrance with the first bound antibody, although epitopes as such may not overlap

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Table 3. Competitive antigen binding to a control antibody

<td>Antibody</td><td>BIAcore ™ (% reduction)</td><td>Immunoassay (% reduction)</td>

Example 6. Cross-species binding [0048] Four antibodies were checked for cross-reaction with the monkey recombinant IL-6R protein using BIAcore ™ technology. Briefly, a biosensor plate with immobilized goat polyclonal anti-mouse Fc antibody was used to present monoclonal hIL-6R antibodies with 75 RU density. Recombinant human or monkey monomeric IL-6R protein (Macaca fascicularis, extracellular domain; SEQ ID NO: 251), at a concentration of 1.25 to 40 nM, was injected onto the surface of the antibodies. Receptor binding to the antibody and dissociation of the bound complex were monitored in real time. Both the joining constant (ka) and dissociation constant (kd) were obtained, and the KD was calculated (Table 4).

Table 4. Comparison of binding affinity for human and monkey IL-6R protein

<td>Antibody</td><td>Antigen</td><td>ka (M '1S '1)</td><td>kd (S-1)</td><td>Kd (nM)</td>

<td rowspan="2">Control</td><td>Human IL6R</td><td>1.74 + 05</td><td>1.67-04</td><td> 0.963</td>

<td>IL6R monkey</td><td>1.44 + 05</td><td>1.68-04</td><td> 1.170</td>

<td rowspan="2">VQ8F11-21</td><td>Human IL6R</td><td>8.51 + 05</td><td>4.38-05</td><td> 0.051</td>

<td>IL6R monkey</td><td>3.39 + 05</td><td>4.86-05</td><td> 0.143</td>

<td rowspan="2">VV1G4-7</td><td>Human IL6R</td><td>2.57 + 05</td><td>6.18-05</td><td> 0.240</td>

<td>IL6R monkey</td><td>no binding</td><td> -</td><td> -</td>

<td rowspan="2">VV6A9-5</td><td>Human IL6R</td><td>5.18 + 05</td><td>8.41-05</td><td> 0.162</td>

<td>IL6R monkey</td><td>5.00 + 05</td><td>7.70-05</td><td> 0.154</td>

<td rowspan="2">VQ8A9-6</td><td>Human IL6R</td><td>7.32 + 05</td><td>2.76-04</td><td> 0.377</td>

<td>IL6R monkey</td><td>7.31 E + 05</td><td>4.16-04</td><td> 0.569</td>

[0049] Among the four antibodies tested, VQ8F11, VV6A9, and VQ8A9 strongly reacted with the monkey receptor with KD values that were about 1.5 to about 3 times higher than binding to the human receptor, respectively. VV1G4, which was not blocked by the control antibody (Table 3), showed no binding to the monkey receptor, despite strong binding to the human receptor, with a KD of 241 pM.

Example 7. Effect of solid region on binding affinity [0050] The binding affinity for monomeric hIL-6R of four murine IgG, human IgG1 or human IgG4 (wild and modified) antibodies was determined by the BIAcore ™ assay as described above, except that the surface of goat polyclonal anti-human Fc antibodies was

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EP 2 374 818 B1 used to bind hlgG antibodies. The monomeric hIL-6R protein was injected at concentrations of 12.5, 6.25, 3.12, and 1.56 nM. The ability of the binding antibody to neutralize hIL-6-dependent HepG2 / STAT3 signal transduction was also measured by luciferase assay (IC50). The IC50 for different IgG isotypes was similar, suggesting that the isotype had no effect on the affinity of the antibody for antigen.

Table 5. Comparison of IgG isotypes

<td>Antibody</td><td>IgG</td><td>ka (M '1S '1)</td><td>kd (S-1)</td><td>Kd (nM)</td><td>IC50 (nM)</td>

<td>VQ8F11-21</td><td>hIgGI</td><td>6.22 + 05</td><td>4.54-05</td><td> 0.073</td><td> 0.150</td>

<td></td><td>modhIgG4</td><td>8.81 E + 05</td><td> 4.705-05</td><td> 0.053</td><td> 0.249</td>

<td>VQ8A9-6</td><td>hIgGI</td><td>1.09 + 06</td><td>2.60-04</td><td> 0.238</td><td> 0.130</td>

<td></td><td>MIGGIANO</td><td>9.95 E + 05</td><td>2.21 E-04</td><td> 0.222</td><td> 0.097</td>

<td>VV6A8-5</td><td>hIgGI</td><td>7.12 + 05</td><td>8.87-05</td><td> 0.125</td><td> 0.204</td>

<td>VQ1G4-21</td><td>hIgGI</td><td>3.34 + 05</td><td>7.92-05</td><td> 0.237</td><td> 0.767</td>

ASPECTS OF THIS DISCLOSURE [0051] The following are aspects of the disclosure:

(1) The antibody or antigen-binding fragment thereof that specifically binds human interleukin-6 receptor (hIL6R) to a KD of about 500 pM or less, and 300pM or less, measured by surface plasmon resonance.

(2) The antibody or antigen binding fragment of (1) that binds hIL-6R with an affinity at least twice that of monkey IL-6R.

(3) The antibody or antigen binding fragment of (1) or (2), comprising the domain of the heavy chain complementarity determining region 3 (CDR3) and the light chain CDR3 domain, wherein the heavy chain CDR3 domain comprises the amino acid sequence according to formula X1 - X2- X3 - X4 X5 - X6 - X7

X8X9 - X10 - X11X1X13 - X14 - X15

X16 - X17- X18- X19 (SEQ ID NO: 247), where X1 = Ala, X2 = Lys, X3 = Gly, X4 = Arg, X5 = Asp, X6 = Cheese or Ala, X7 = Phe, X8 = Asp; X9 = How much, X10 = Pro or none, X11 = Phe or none, X12 = Val or none, X13 = Tyr or none, X14 = Tyr or none, X15 = Tyr or none, X16 = Gly or none, X17 = Met or none, X18 = Asp or none, and X19 = Val or none; and

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The light chain CDR3 domain contains the amino acid sequence according to formula X1 - X2 - X3 - X4 - X5 X6 - X7 - X5 - X9 (SEQ ID NO: 250) where X1 = Gln, X2 = Gln or His, X3 = Ala, X4 = Asn or Tyr, X5 = Cheese, X = Phe, X7 = Pro, X8 = Pro and X9 = Thr.

(4) The antibody or antigen binding fragment according to (3), further comprising a heavy chain CDR1 domain comprising the amino acid sequence according to formula X1 - X2 - X3 - X4X5 - X6 - X7 - X8 (SEQ ID NO: 245) where X1 = Gly or Arg, X2 = Phe, X3 = Thr, X4 = Phe, X5 = Asp, X6 = Asp, X7 = Tyr, and X8 = Ala;

a heavy chain CDR2 domain comprising the amino acid sequence according to formula X1 - X2 - X3 - X4 X5 - X6 - X7 - X8 (SEQ ID NO: 246) where X1 = Ile or Val, X2 = Cheese, X3 = Trp, X4 = Asn, X5 = Cheese, X6 = Gly, X7 = Cheese, and X8 = How much;

a light chain CDR1 domain comprising the amino acid sequence according to formula X1 - X2 - X3 - X4 - X5

- X6 - X7 - X8 (SEQ ID NO: 248), where X1 = Gln, X2 = Gly, X3 = How much, X4 = Cheese, X5 = Cheese, and X6 = Trp; and 123 a light chain CDR2 domain comprising the amino acid sequence according to formula X1 - X2 - X3 (SEQ ID NO: 249), where X1 = Gly or Ala, X2 = Ala, and X3 = Cheese

(5) The antibody or antigen binding fragment of (1) or (2), comprising:

a heavy chain CDR3 domain selected from the group consisting of SEQ ID NO: 25, 153, 9, 185, 41, 57, 73, 89, 105, 121, 137, 169, 201 and 217; and a light chain CDR3 domain selected from the group consisting of SEQ ID NOs: 33, 161, 17, 193, 49, 65, 81, 97, 113, 129, 145, 177, 209 and 225.

(6) The antibody or antigen binding fragment according to (5), further comprising: a heavy chain CDR1 domain selected from the group consisting of SEQ ID NO: 21, 149, 5, 181, 37, 53, 69, 85, 101, 117, 133, 165, 197, and 213;

a heavy chain CDR2 domain selected from the group consisting of SEQ ID NO: 23, 151, 7, 183, 39,

55, 71, 87, 103, 119, 135, 167, 199 and 215;

a light chain CDR1 domain selected from the group consisting of SEQ ID NO: 29, 157, 13, 189, 45,

61, 77, 93, 109, 125, 141, 173, 205 and 221; and a light chain CDR2 domain selected from the group consisting of SEQ ID NO: 31, 159, 15, 191, 47, 63, 79, 95, 111, 127, 143, 175, 207 and 223.

(7) The antibody or antigen binding fragment according to (5) or (6), wherein the heavy chain CDR and light chain CDR include

SEQ ID NO: 21, 23, 25 and SEQ ID NO: 29, 31, 33;

SEQ ID NO: 149, 151, 153 and SEQ ID NO: 157, 159, 161;

SEQ ID NO: 5, 7, 9 and SEQ ID NO: 13, 15, 17; and

SEQ ID NO: 181, 183, 185 and SEQ ID NO: 189, 191, 193, respectively.

(8) The antibody or antigen binding fragment of (1) or (2) comprising a heavy chain variable region (HCVR) selected from the group consisting of SEQ ID NO: 19, 147, 3, 179,

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227, 231, 35, 51, 67, 83, 99, 115, 131, 239, 241, 163, 235, 195 and 211; and a light chain variable region (LCVR) selected from the group consisting of SEQ ID NOs: 27, 155, 11, 187,

229, 233, 43, 59, 75, 91, 107, 123, 139, 171, 237, 203 and 219.

(9) The antibody or antigen binding fragment of (8) comprising HCVR / LCVR pairs selected from the group consisting of SEQ ID NO: 19/27; 147/155; 3/11; 179/187; 227/229; 231/233; 35/43; 51/59; 67/75; 83/91; 99/107; 115/123; 131/139; 239/155; 241/155; 163/171; 235/237; 195/203 and 211/219.

(10) An isolated nucleic acid molecule encoding an antibody or antigen-binding antibody fragment according to any one of (1) to (9).

(11) Vector comprising the nucleotide sequence of (10).

(12) A host-vector system for producing (producing) an antibody or antigen-binding antibody fragment that specifically binds to the human IL-6 receptor, comprising the vector according to (11), in a suitable host cell.

(13) The host-vector system according to (12), wherein the host cell is a prokaryotic or eukaryotic cell selected from E. coli or CHO cells.

(14) A method of producing an anti-IL-6R antibody or antigen-binding fragment thereof, comprising culturing host-vector cells specified in (12) or (13) under conditions permitting the production of the antibody or fragment thereof and recovery of the antibody or fragment thus produced.

(15) Use of the antibody or antigen-binding antibody fragment according to any one of (1) to (9) for the manufacture of a medicament for attenuation (alleviation) or inhibition (inhibition) of an IL-6-modulated disease or disorder in humans.

(16) The antibody or antigen binding antibody fragment according to any one of (1) to (9) for use in attenuation (alleviation) or inhibition (inhibition) of a disease or disorder modulated by IL-6 in humans.

(17) A pharmaceutical composition comprising the antibody or antigen-binding antibody fragment according to any one of (1) to (9) and a pharmaceutically acceptable carrier or excipient.

(18) A method for attenuating or inhibiting an IL-6-modulated disease or disorder in humans, the method comprising administering an effective amount of an antibody or antigen-binding antibody fragment according to any one of (1) to (9) in a human patient.

(19) The method of (18), wherein the disease or disorder modulated by IL-6 is arthritis such as chronic rheumatoid arthritis; inflammatory bowel disease such as Crohn's disease or ulcerative colitis; or systemic lupus erythematosus.

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List of sequences <110> Regeneron Pharmaceuticals, Inc.

<120> Antibodies with high affinity for the human IL-6 receptor <130> 6010A-WO <140> will be indicated <141> 2007-06-01 <150> 60 / 810.664 <151> 2006-06-02 <150> 60 /843.232 <151> 2006-09-08 <160> 251 <170> FastSEQ for windows Version 4.0 <210> 1 <211> 358 <212> PRT <213> Homo sapiens <400> 1 <220>

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<td>Underworld</td><td>val</td><td>ala</td><td>val</td><td>Gly</td><td>Cys</td><td>ala</td><td>Leu</td><td>Leu</td><td>ala</td><td>ala</td><td>Leu</td><td>Leu</td><td>ala</td><td>ala</td><td>Pro</td>

<td>Gly</td><td>val</td><td>Leu</td><td>twenty Thr</td><td>Cheese</td><td>Leu</td><td>Pro</td><td>Gly</td><td>25 Asp</td><td>Cheese</td><td>val</td><td>Thr</td><td>Leu</td><td>thirty Thr</td><td>Cys</td><td>Pro</td>

<td>Pro</td><td>50 ala</td><td>ala</td><td>Gly</td><td>Cheese</td><td>His</td><td>55 Pro</td><td>Cheese</td><td>Arg</td><td>Trp</td><td>ala</td><td>60 Gly</td><td>Underworld</td><td>Gly</td><td>Arg</td><td>Arg</td>

<td>65 Leu</td><td>Leu</td><td>Leu</td><td>Arg</td><td>cheese</td><td>70 vai</td><td>Gin</td><td>Leu</td><td>His</td><td>Asp</td><td>75 Cheese</td><td>Gly</td><td>own</td><td>Tyr</td><td>Cheese</td><td>80 cys</td>

<td>Pro</td><td>Pro</td><td>Glu</td><td>100 Glu</td><td>Pro</td><td>Gin</td><td>Leu</td><td>Cheese</td><td>105 Cys</td><td>phe</td><td>Arg</td><td>lys</td><td>Cheese</td><td>110 Pro</td><td>Leu</td><td>Cheese</td>

<td>own</td><td>val</td><td>115 val</td><td>Cys</td><td>GILJ</td><td>Trp</td><td>Gly</td><td>120 Pro</td><td>Arg</td><td>Cheese</td><td>Thr</td><td>Pro</td><td>125 Cheese</td><td>Leu</td><td>Thr</td><td>Thr</td>

<td>lys</td><td>130 ala</td><td>val</td><td>Leu</td><td>Leu</td><td>val</td><td>135 Arg</td><td>lys</td><td>phe</td><td>Gin</td><td>own</td><td>140 Cheese</td><td>Pro</td><td>ala</td><td>Glu</td><td>Asp</td>

<td>145 phe</td><td>Gin</td><td>Glu</td><td>Pro</td><td>Cys</td><td>150 Gin</td><td>Tyr</td><td>Cheese</td><td>Gin</td><td>Glu</td><td>155 Cheese</td><td>Gin</td><td>lys</td><td>phe</td><td>Cheese</td><td>160 Cys</td>

<td>Gin</td><td>Leu</td><td>ala</td><td>val</td><td>165 Pro</td><td>Glu</td><td>Gly</td><td>Asp</td><td>Cheese</td><td>17 0 Cheese</td><td>phe</td><td>Tyr</td><td>How much</td><td>val</td><td>175 Cheese</td><td>Underworld</td>

<td>Cys</td><td>val</td><td>ala</td><td>180 Cheese</td><td>Cheese</td><td>val</td><td>Gly</td><td>Cheese</td><td>185 lys</td><td>phe</td><td>Cheese</td><td>lys</td><td>Thr</td><td>190 Gin</td><td>Thr</td><td>phe</td>

<td>Thr</td><td>210 ala</td><td>val</td><td>ala</td><td>Arg</td><td>own</td><td>215 Pro</td><td>Arg</td><td>Trp</td><td>Leu</td><td>Cheese</td><td>220 val</td><td>Thr</td><td>Trp</td><td>Gin</td><td>Asp</td>

<td>225 Pro</td><td>His</td><td>Cheese</td><td>Trp</td><td>own</td><td>230 Cheese</td><td>Cheese</td><td>phe</td><td>Tyr</td><td>Arg</td><td>235 Leu</td><td>Arg</td><td>phe</td><td>Glu</td><td>Leu</td><td>240 Arg</td>

<td>Tyr</td><td>Arg</td><td>ala</td><td>Glu</td><td>245 Arg</td><td>Cheese</td><td>lys</td><td>Thr</td><td>phe</td><td>250 Thr</td><td>Thr</td><td>Trp</td><td>Underworld</td><td>val</td><td>255 lys</td><td>Asp</td>

<td>Leu</td><td>Gin</td><td>His</td><td>260 His</td><td>Cys</td><td>val</td><td>How much</td><td>His</td><td>265 Asp</td><td>ala</td><td>Trp</td><td>Cheese</td><td>Gly</td><td>270 Leu</td><td>Arg</td><td>His</td>

<td>val</td><td>val</td><td>275 Gin</td><td>Leu</td><td>Arg</td><td>ala</td><td>Gin</td><td>280 Glu</td><td>Glu</td><td>phe</td><td>Gly</td><td>Gin</td><td>285 Gly</td><td>Glu</td><td>Trp</td><td>Cheese</td>

<td>Glu</td><td>290 Trp</td><td>Cheese</td><td>Pro</td><td>Glu</td><td>ala</td><td>295 Underworld</td><td>Gly</td><td>Thr</td><td>Pro</td><td>Trp</td><td>300 Thr</td><td>Glu</td><td>Cheese</td><td>Arg</td><td>Cheese</td>

<td>305 Pro</td><td>Pro</td><td>ala</td><td>Glu</td><td>own</td><td>310 Glu</td><td>val</td><td>Cheese</td><td>Thr</td><td>pro</td><td>315 Underworld</td><td>Gin</td><td>ala</td><td>Leu</td><td>Thr</td><td>320 Thr</td>

<td>own</td><td>lys</td><td>Asp</td><td>Asp</td><td>325 Asp</td><td>own</td><td>How much</td><td>Leu</td><td>phe</td><td>330 Arg</td><td>Asp</td><td>Cheese</td><td>ala</td><td>own</td><td>335 ala</td><td>Thr</td>

<td>Cheese</td><td>Leu</td><td>Pro 355</td><td>340 val</td><td>Gin</td><td>Asp</td><td></td><td></td><td> 345</td><td></td><td></td><td></td><td></td><td> 350</td><td></td><td></td>

<210> 2 <211> 379 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 2 gaagtgcagc tggtggagtc tgggggaaac ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt catctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaagatgga 300 ggcagcagct ggttaccgtt cgtctactac tacggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcgtcag 379

PZ / 1778AGR

EP 2 374 818 B1 <210> 3 <211> 126 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 3

<td>Glu</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>own</td><td>Leu</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>How much</td><td>phe</td><td>ASP</td><td>Asp</td><td>Tyr</td>

<td>ala</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</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>Cheese</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Trp</td><td>own</td><td>Cheese</td><td>Gly</td><td>Cheese</td><td>How much</td><td>Gly</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala</td><td>lys</td><td>own</td><td>Cheese</td><td>Leu</td><td>Tyr</td>

<td>Leu</td><td>Gln.</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>lys</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Cheese</td><td>Cheese</td><td>Trp</td><td>Leu</td><td>Pro</td><td>phe</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Gly</td>

<td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td>

<210> 4 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 4 ggattcatct ttgatgatta tgcc 24 <210> 5 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 5

Gly Phe ile Phe Asp Asp Tyr Ala 1 5 <210> 6 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> artificial

PZ / 1778AGR

EP 2 374 818 B1 <400> 6 attagttgga atagtggtag cata 24 <210> 7 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 7

How much Ser Trp Asn cheese Gly Ser Ile l 5 <210> 8 <211> 57 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 8 gcaaaagatg gaggcagcag ctggttaccg ttcgtctact actacggtat ggacgtc 57 <210> 9 <211> 19 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 9

Ala Lys Asp gly Gly Cheese Ser Trp Leu Pro Phe Val Tyr Tyr Tyr Gly

10 15

Met Asp Val <210> 10 <211> 325 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 10 gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctcccgggga aagagccacc 60 ctctcctgca gggccagtca gagtattagc agcaactttg cctggtacca gcagaaacct 120 ggccaggctc ccaggctcct catctatggt gcacccacca gggccactgg tatcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctgcagtct 240 gaagattttg cagtttatta ctgtcagcag tatagtagct ggcctccgta cacttttggc 300 caggggacca agctggagat caaac 325 <210> 11

PZ / 1778AGR

EP 2 374 818 B1 <211> 108 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 11

<td>Glu</td><td>How much</td><td>val</td><td>mec</td><td>Thr</td><td>Gin</td><td>cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>GILJ</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>own</td>

<td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>Thr</td><td>Arg</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ala</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Cheese</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Tyr</td><td>Cheese</td><td>Cheese</td><td>Trp</td><td>Pro</td><td>Pro</td>

<210> 12 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 12 cagagtatta gcagcaac 18 <210> 13 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 13

Gin Ser Ile Ser Cheese Asn 1 5 <210> 14 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 14 ggtgcatcc 9 <210> 15 <211> 3 <212> PRT <213> Artificial sequence

PZ / 1778AGR

EP 2 374 818 B1

<223> Artificial <400> 15

Gly Ala Ser 1 <210> 16 <211> 30 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 16 cagcagtata gtagctggcc tccgtacact 30 <210> 17 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 17

Gin Gin Tyr Ser Ser Trp Pro Pro Tyr Thr 15 10 <210> 18 <211> 349 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 18 gaagtgcagc tggtggagtc tgggggaggc ttggttcagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctagatt cacctttgat gattatgcca cgcaccgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag aataggttat 180 gcggactctg tgaagggecg attcaccatc tccagagaca acgccgagaa ctccctcttt 240 ctgcaaatga acggtctgag agcagaggac acggccttgt attactgtgc aaaaggccga 300 gattcttttg atatctgggg ccaagggaca atggtcaccg tctcttcag 349 < 210> 19 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 19

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu 1</td><td>val</td><td>Gin</td><td>Leu</td><td>val 5</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly 10</td><td>Leu</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly 15</td><td>Arg</td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu twenty</td><td>Cheese</td><td>Cya</td><td>ala</td><td>ala</td><td>Cheese 25</td><td>Arg</td><td>phe</td><td>Thr</td><td>phe</td><td>Asp thirty</td><td>Asp</td><td>Tyr</td>

<td>ala</td><td>Underworld</td><td>His 35</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala 40</td><td>Pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu 45</td><td>Glu</td><td>Trp</td><td>val</td>

<td>Cheese</td><td>Gly 50</td><td>how much</td><td>Cheese</td><td>Trp</td><td>own</td><td>Cheese 55</td><td>Gly</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr 60</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>lys 65</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much 70</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala 75</td><td>Glu</td><td>own</td><td>Cheese</td><td>Leu</td><td>phe 80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Gly 85</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp $ 0</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr 95</td><td>Cys</td>

<td>ala</td><td>lys</td><td>Gly</td><td>Arg 100</td><td>Asp</td><td>Cheese</td><td>phe</td><td>Asp</td><td>How much 105</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr 110</td><td>Underworld</td><td>val</td>

Thr Val Ser Ser 115 <210> 20 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 20 agatttacct ttgatgatta tgcc 24 <210> 21 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 21

Arg Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 22 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 22 attagttgga atagtggtag aata 24 <210> 23 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> artificial

PZ / 1778AGR

<400> 23

Ile Ser Trp Asn ser Gly Arg Ile 1 5 <210> 24 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 24 gcaaaaggcc gagattcttt tgatatc 27 <210> 25 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 25

Ala Lys Gly Arg Asp Ser Phe Asp Ile 1 5 <210> 26 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 26 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatggt gcatccagtt tggaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caagttatta ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300 gggaccaagc tggagatcaa ac 322 <210> 27 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 27

PZ / 1778AGR

EP 2 374 818 B1

<td>ASp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Gly</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Trp</td>

<td>Tyr</td><td>Gly</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Cheese</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>ala</td><td>own</td><td>Cheese</td><td>phe</td><td>Pro</td><td>Tyr</td>

<210> 28 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 28 cagggtatta gcagctgg 18 <210> 29 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 29

Gln Gly ile Ser Ser Trp 1 5 <210> 30 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 30 ggtgcatcc 9 <210> 31 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 31

PZ / 1778AGR

EP 2 374 818 B1

Gly Ala Ser 1 <210> 32 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 32 caacaggcta acagtttccc gtacact 27 <210> 33 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 33

Gln Gln Ala Asn Ser Phe Pro Tyr Thr 1 5 <210> 34 <211> 370 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 34 caggttcagc tggtgcagtc tggagctgag ctgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacttttacc cattatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatgatga cacaaactat 180 gcacagaagt tccaggggag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgttt attactgtgc gagagaagcg 300 cagctcgtcc tctactacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctcag 370 <210> 35 <211> 123 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 35

PZ / 1778AGR

EP 2 374 818 B1

<td>Gln 1</td><td>val</td><td>Gln</td><td>Leu</td><td>val 5</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu 10</td><td>Leu</td><td>lys</td><td>lys</td><td>pro</td><td>Gly 15</td><td>ala</td>

<td>Cheese</td><td>val</td><td>lys</td><td>val twenty</td><td>Cheese</td><td>cys</td><td>lys</td><td>ala</td><td>Cheese 25</td><td>Gly</td><td>Tyr</td><td>Thr</td><td>phe</td><td>Thr thirty</td><td>His</td><td>Tyr</td>

<td>Gly</td><td>How much</td><td>Cheese 35</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala 40</td><td>Pro</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Leu 45</td><td>GILJ</td><td>Trp</td><td>Underworld</td>

<td>Gly</td><td>Trp 50</td><td>How much</td><td>Cheese</td><td>ala</td><td>Tyr</td><td>own 55</td><td>Asp</td><td>ASp</td><td>Thr</td><td>own</td><td>Tyr 60</td><td>ala</td><td>Gln</td><td>lys</td><td>phe</td>

<td>Gln 65</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Underworld 70</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Thr</td><td>Cheese 75</td><td>Thr</td><td>Cheese</td><td>Thr</td><td>ala</td><td>Tyr 80</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Arg</td><td>Cheese 85</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Asp</td><td>Asp 90</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr 95</td><td>Cys</td>

Ala Arg Glu Ala Gln beu Val Leu Tyr Tyr Tyr Tyr Gly Met Asp Val 100 105 110

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 36 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 36 ggttacactt ttacccatta tggt 24 <210> 37 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 37

Gly Tyr Thr Phe Thr His Tyr Gly 1 5 <210> 38 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 38 atcagcgctt acaatgatga caca 24 <210> 39 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> artificial

PZ / 1778AGR

<400> 39

Ile Ser Ala Tyr Asn Asp Asp Thr 1 5 <210> 40 <211> 48 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 40 gcgagagaag cgcagctcgt cctctactac tactacggta tggacgtc 48 <210> 41 <211> 16 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 41

Ala Arg Glu Ala Gln Leu Val Leu Tyr Tyr Tyr Tyr Gly Met Asp Val 15 10 15 <210> 42 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 42 _ gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcttcttag cctggaacca acagaaacct 120 ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cagtttatta ctgccagcag cgtaacaatt ggccgtacat ttttggccag 300 gggaccaagc tggagatcag ac 322 <210 > 43 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 43

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>How much</td><td>val</td><td>Lau</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Cheese</td><td>phe</td>

<td>Tyr</td><td>Asp</td><td>ala</td><td>Cheese</td><td>own</td><td>Arg</td><td>ala</td><td>Thr</td><td>Gly</td><td>How much</td><td>Pro</td><td>ala</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<210> 44 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 44 cagagtgtta gcagcttc 18 <210> 45 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 45

Gin Ser Val Ser Ser phe 1 5 <210> 46 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 46

Gatgcatcc 9 <210> 47 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> artificial

PZ / 1778AGR

<400> 47

Asp Ala Ser 1 <210> 48 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 48 cagcagcgta acaattggcc gtacatt 27 <210> 49 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 49

Gin Gin Arg Asn Asn Trp Pro Tyr Ile 1 S <210> 50 <211> 370 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 50 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc agttatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcgctt acaatgatga cacaaactat 180 gcacagaagt tccaggggag agtcaccatg accacagaca catccacgag cacagcctac 240 atggagctga ggagcctgag atctgacgac acggccgttt attactgtgc gagagaagcg 300 cagctcgtcc tctactacta ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtctcctcag 370 <210> 51 <211> 123 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 51

PZ / 1778AGR

EP 2 374 818 B1

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>Cheese</td><td>val</td><td>lys</td><td>val</td><td>Cheese</td><td>Cys</td><td>lys</td><td>ala</td><td>Cheese</td><td>Gly</td><td>Tyr</td><td>Thr</td><td>phe</td><td>Thr</td><td>Cheese</td><td>Tyr</td>

<td>Gly</td><td>How much</td><td>Cheese</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Pro</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td>Gly</td><td>Trp</td><td>How much</td><td>Cheese</td><td>ala</td><td>Tyr</td><td>own</td><td>Asp</td><td>Asp</td><td>Thr</td><td>own</td><td>Tyr</td><td>ala</td><td>Gin</td><td>lys</td><td>phe</td>

<td>Gin</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Underworld</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>Thr</td><td>Cheese</td><td>Thr</td><td>ala</td><td>Tyr</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Asp</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>Arg</td><td>Glu</td><td>ala</td><td>Gin</td><td>Leu</td><td>val</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td>

<td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td>

<210> 52 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 52 ggttacacct ttaccagtta tggt 24 <210> 53 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 53

Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <210> 54 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 54 atcagcgctt acaatgatga caca 24 <210> 55 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 55

PZ / 1778AGR

EP 2 374 818 B1

How much Ser Ala Tyr Asn Asp Asp Thr 1 5 <210> 56 <211> 48 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 56 gcgagagaag cgcagctcgt cctctactac tactacggta tggacgtc 48 <210> 57 <211> 16 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 57

Ala Arg Glu Ala Gln Leu Val Leu Tyr Tyr Tyr Tyr Gly Met Asp Val 15 10 15 <210> 58 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 58 _ gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agcttcttag cctggaacca acagaaacct 120 ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cagtttatta ctgccagcag cgtagcaatt ggccgtacat ttttggccag 300 gggaccaagc tggagatcaa ac 322 <210 > 59 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 59

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>How much</td><td>val</td><td>Leu</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Cheese</td><td>phe</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>Arg</td><td>Cheese</td><td>own</td><td>Trp</td><td>Pro</td><td>Tyr</td>

<210> 60 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 60 cagagtgtta gcagcttc 18 <210> 61 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 61

Gln Ser Val Ser 1 <210> 62 <211> 9 <212> DNA <213> Artificial sequence

Phe 5 cheese <220>

<223> Artificial <400> 62 gatgcatcc 9 <210> 63 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 63

PZ / 1778AGR

EP 2 374 818 B1

Asp Ala Ser 1 <210> 64 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 64 cagcagcgta gcaattggcc gtacatt 27 <210> 65 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 65

Gln Gln Arg Ser Asn Trp Pro Tyr Ile 1 5 <210> 66 <211> 349 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 66 gaagtgcagc tggtggagtc tgggggaggc Ctggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgccc tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggc gttagttgga atggtggtag aataggctat 180 gcggactctg tgaaaggccg attoacoatc tccagagaca acgccaagaa ctccctcttt 240 ctgcaaatga acagtctgag agttgaggac acggccttgt attattgtgc aaaaggccgg 300 gacgcttttg atatctgggg ccaagggaca ttggtcaccg tctcttcag 349 < 210> 67 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 67

Glu Val Gln Leu Val Glu Cheese Gly Gly Gly Leu Val Gln Pro Gly Arg 15 10 15

Cheese Leu Arg Leu Cheese Cys Ala Ala Cheese Gly Phe Thr phe Asp Asp Tyr

PZ / 1778AGR

EP 2 374 818 B1

<td>Cheese</td><td>Gly 50</td><td>val</td><td>Cheese</td><td>Trp</td><td>own</td><td colspan="2">Gly Gly 55</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr 60</td><td>ala</td><td>Asp</td><td>cheese</td><td>val</td>

<td>lys 65</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>How much 70</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala 75</td><td>lys</td><td>own</td><td>Cheese</td><td>Leu</td><td>phe 80</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese 85</td><td>Leu</td><td>Arg</td><td>val</td><td>Glu</td><td>Asp 90</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr 95</td><td>Cys</td>

Thr Val Ser Ser 115 <210> 68 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 68 ggattcacct ttgatgatta tgcc 24 <210> 69 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 69

Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 70 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 70 gttagttgga atggtggtag aata 24 <210> 71 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 71

PZ / 1778AGR

EP 2 374 818 B1

Val Ser Trp Asn Gly Gly Arg Ile 1 5 <210> 72 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 72 gcaaaaggcc gggatgcttt tgatatc 27 <210> 73 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 73

Ala Lys Gly Arg Asp Ala Phe Asp Ile 1 5 <210> 74 <211> 325 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 74 gaaattgtgt ctctcctgca ggccaggctc aggttcagtg gaagattttg cctgggacca tgacacagtc gggccagtca ccaggctcct gcagtgggtc cattttatta aagtggatgt tccagccacc ctgtctttgt ctccagggga aagagccacc 60 gagtgttagc agttacttag cctggtacca acagaaacct 120 catctatgat gcatccaaca gggccactgg catcccagcc 180 tgggacagac ttcactctca ccatcagcag cctagagcct 240 ctgtcagcag cgtaacaacc ggcctccatt cactttcggc 300 cagac 325 <210> 75 <211> 108 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 75

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>How much</td><td>val</td><td>Leu</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<210> 76 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 76 cagagtgtta gcagttac 18 <210> 77 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 77

Gin Ser Val Ser Ser Tyr 1 5 <210> 78 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 78 gatgcatcc 9 <210> 79 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 79

Asp Ala Ser

PZ / 1778AGR

EP 2 374 818 B1 <210> 80 <211> 30 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 80 cagcagcgta acaaccggcc tccattcact 30 <210> 81 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 81

Gln Gln Arg Asn Asn Arg Pro Pro Phe Thr 15 10 <210> 82 <211> 370 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 82 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgtaagg cttctggttt caacttcttt cattatggta tcacctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagcactt acaatggtga cacaatctat 180 gcacagaagg tccagggcag agtcaccatg accacagaca cagccacgag cacggcctat 240 atggaactga ggagcctgag atctgacgac acggccgtgt attactgtgc gagatcggaa 300 cagcaggtgg actactactt ctacggtatg gacgtctggg gccaagggac cacggtcacc 360 gtttcctcag 370 <210> 83 <211> 123 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 83

PZ / 1778AGR

EP 2 374 818 B1

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>Cheese</td><td>val</td><td>lys</td><td>val</td><td>Cheese</td><td>Cys</td><td>lys</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>own</td><td>phe</td><td>phe</td><td>His</td><td>Tyr</td>

<td>Gly</td><td>How much</td><td>Thr</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Pro</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td>Gly</td><td>Trp</td><td>How much</td><td>Cheese</td><td>Thr</td><td>Tyr</td><td>own</td><td>Gly</td><td>Asp</td><td>Thr</td><td>How much</td><td>Tyr</td><td>ala</td><td>Gln</td><td>lys</td><td>val</td>

<td>Gln</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Underworld</td><td>Thr</td><td>Thr</td><td>Asp</td><td>Thr</td><td>ala</td><td>Thr</td><td>Cheese</td><td>Thr</td><td>ala</td><td>Tyr</td>

<td>ala</td><td>Arg</td><td>Cheese</td><td>Glu</td><td>Gln</td><td>Gln</td><td>val</td><td>Asp</td><td>Tyr</td><td>Tyr</td><td>phe</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td>

<td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td>

<210> 84 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 84 ggtttcaact tctttcatta tggt 24 <210> 85 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 85

Gly Phe Asn Phe Phe His Tyr Gly 1 5 <210> 86 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 86 atcagcactt acaatggtga caca 24 <210> 87 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 87

PZ / 1778AGR

EP 2 374 818 B1

How much Ser Thr Tyr Asn Gly Asp Thr 1 5 <210> 88 <211> 48 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 88 gcgagatcgg aacagcaggt ggactactac ttctacggta tggacgtc 48 <210> 89 <211> 16 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 89

Ala Arg Ser Glu Gin Gin Val Asp Tyr Tyr Phe Tyr Gly Met Asp Val 1 S 10 15 <210> 90 <211> 325 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 90 gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agttacttag cctggtacca acagaaacct 120 ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cattttatta ctgtcagcag cgtaacaacc ggcctccatt cactttcggc 300 cctgggacca aagtggatgt cagac 325 <210> 91 <211> 108 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 91

PZ / 1778AGR

EP 2 374 818 B1

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>how much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Glu</td><td>Pro</td>

<210> 92 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 92 cagagtgtta gcagttac 18 <210> 93 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 93

Gln Ser Val Ser Ser Tyr 1 5 <210> 94 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 94 gatgcatcc 9 <210> 95 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 95

Asp Ala Ser

PZ / 1778AGR

EP 2 374 818 B1 <210> 96 <211> 30 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 96 cagcagcgta acaaccggcc tccattcact 30 <210> 97 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 97

Gin Gin Arg Asn Asn Arg Pro Pro Phe Thr 15 10 <210> 98 <211> 370 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 98 caggttcagc tcctgtaagg cctggacaag gcacagaagg atggaactga cagcaggtgg gtttcctcag <210> 99 <211> 123 <212> PRT tggtgcagtc cttctggttt ggcttgagtg tccagggcag ggagcctgag actactactt tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 caacttcttt cattatggta tcacctgggt gcgacaggcc 120 gatgggatgg atcagcactt acaatggtga cacaatctat 180 agtcaccatg accacagaca cagccacgag cacggcctat 240 atctgacgac acggccgtgt attactgtgc gagatcggaa 300 ctacggtatg gacgtctggg gccaagggac cacggtcacc 360

370 <213> Artificial sequence <220>

<223> Artificial <400> 99

PZ / 1778AGR

EP 2 374 818 B1

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>ASP</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>Arg</td><td>Cheese</td><td>Glu</td><td>Gln</td><td>Gln</td><td>val</td><td>Asp</td><td>Tyr</td><td>Tyr</td><td>phe</td><td>Tyr</td><td>oiy</td><td>Underworld</td><td>Asp</td><td>val</td>

<td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td>

<210> 100 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 100 ggtttcaact tctttcatta tggt 24 <210> 101 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 101

Gly Phe Asn Phe Phe His Tyr Gly 1 5 <210> 102 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 102 atcagcactt acaatggtga caca 24 <210> 103 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 103

PZ / 1778AGR

EP 2 374 818 B1

How much Ser Thr Tyr Asn Gly Asp Thr 1 5 <210> 104 <211> 48 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 104 gcgagatcgg aacagcaggt ggactactac ttctacggta tggacgtc 48 <210> 105 <211> 16 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 105

Ala Arg Ser Glu Gin Gin Val Asp Tyr Tyr Phe Tyr Gly Met Asp Val 15 10 15 <210> 106 <211> 325 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 106 gaaattgtgt cgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgca gggccagtca gagtgttagc agttacttag cctggtacca acagaaacct 120 ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cattttatta ctgtcagcag cgtaacaacc ggcctccatt cactttcggc 300 cctgggacca aagtggatgt cagac 325 <210> 107 <211> 108 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 107

<td>GILJ</td><td>How much</td><td>val</td><td>Leu</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

PZ / 1778AGR

EP 2 374 818 B1

<td rowspan="2">Tyr</td><td rowspan="2">Asp 50</td><td colspan="2" rowspan="2">Ala Ser</td><td rowspan="2">own</td><td colspan="9">Arg Ala Thr Gly Ile Pro Ala Arg Phe</td><td rowspan="2">Cheese</td><td rowspan="2">Gly</td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Asp</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>how much</td><td>cheese</td><td>cheese</td><td>Leu</td><td>Glu</td><td>Pro</td>

<210> 108 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 108 cagagtgtta gcagttac 18 <210> 109 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 109

Gin Ser Val Ser Ser Tyr 1 5 <210> 110 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 110 gatgcatcc 9 <210> 111 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 111

Asp Ala Ser <210> 112 <211> 30 <212> DNA

PZ / 1778AGR

<213> Artificial sequence <220>

<223> Artificial <400> 112 cagcagcgta acaaccggcc tccattcact 30 <210> 113 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 113

Gin Gin Arg Asn Asn Arg Pro Pro Phe Thr 15 10 <210> 114 <211> 361 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 114 caggtgcagc tggtgcagtc tggggctgag gtgaaagagc ctggggcctc agtgaagatc 60 tcctgcaagg cttctggata caccttcacc tcttatgata tcatctgggt gcgacaggcc 120 actggacaag ggcttgagtg gatgggatgg atgaacccaa acagtggtga cagaggctat 180 acacagaacc tccagggcag agtcaccttg accagggaca cctccataag tacagtctac 240 atggaactga gcagcctgag atctgaggac acggccgtat attattgtgc gcgagactac 300 agtaaccact actacggttt ggacgtctgg ggccaaggga ccacggtcac tgtctcctca 360 g 361 <210> 115 <211> 120 <212> PRT <213> Sequence artificial <220>

<223> Artificial <400> 115

PZ / 1778AGR

EP 2 374 818 B1

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>Glu</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>Cheese</td><td>val</td><td>lys</td><td>How much</td><td>Cheese</td><td>Cys</td><td>lys</td><td>ala</td><td>Cheese</td><td>Gly</td><td>Tyr</td><td>Thr</td><td>phe</td><td>Thr</td><td>Cheese</td><td>Tyr</td>

<td>Asp</td><td>How much</td><td>How much</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</td><td>Thr</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td>Gly</td><td>Trp</td><td>Underworld</td><td>own</td><td>Pro</td><td>own</td><td>Cheese</td><td>Gly</td><td>Asp</td><td>Arg</td><td>Gly</td><td>Tyr</td><td>Thr</td><td>Gin</td><td>own</td><td>Leu</td>

<td>Gin</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Leu</td><td>Thr</td><td>Arg</td><td>Asp</td><td>Thr</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Thr</td><td>val</td><td>Tyr</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cya</td>

<td>ala</td><td>Arg</td><td>ASp</td><td>Tyr</td><td>Cheese</td><td>own</td><td>His</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Leu</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gin</td>

<td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 116 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 116 ggatacacct tcacctctta tgat 24 <210> 117 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 117

Gly Tyr Thr Phe Thr Ser Tyr Asp 1 5 <210> 118 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 118 atgaacccaa acagtggtga caga 24 <210> 119 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 119

PZ / 1778AGR

EP 2 374 818 B1

Met Asn Pro Asn Ser Gly Asp Arg 1 5 <210> 120 <211> 39 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 120 gcgcgagact acagtaacca ctactacggt ttggacgtc 39 <210> 121 <211> 13 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 121

Ala Arg Asp Tyr Ser Asn His Tyr Tyr Gly Leu Asp Val 15 10 <210> 122 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 122 gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60 atcacttgct gggccagtca ggacattagc aattatttag cctggtatca gcaaaaacca 120 gggaaagccc ctaagctcct gatctttgtt gcatccactt tgcagagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240 gaagattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300 gggaccaagg tggagatcag ac 322 <210> 123 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 123

PZ / 1778AGR

EP 2 374 818 B1

<td>Asp</td><td>How much</td><td>Gin</td><td>Leu</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>phe</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Trp</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Asp</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td>phe</td><td>val</td><td>ala</td><td>Cheese</td><td>Thr</td><td>Leu</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Cheese</td><td>Gly</td><td>Cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Pro</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>phe</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Leu</td>

<210> 124 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 124 caggacatta gcaattat 18 <210> 125 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 125

Gin Asp Ile Ser Asn Tyr 1 5 <210> 126 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 126 gttgcatcc 9 <210> 127 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 127

Val Ala Ser

PZ / 1778AGR

<210> 128 <211> 30 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 128 caacagttta atagttaccc gctcactttc 30 <210> 129 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 129

Gin Gin Phe Asn Ser- Tyr Pro Leu Thr 1 5 <210> 130 <211> 370 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 130 caggttcagc tcctgcaagg cctggacaag gcacagaagt atggagctga cagctcgtcc gtctcctcag tggtgcagtc cttctggtta ggcttgagtg tccaggggag ggagcctgag tctactacta tggagctgag cacccttacc gatgggatgg agtcaccatg atctgacgac ctacggtatg gtgaagaagc agttatggta atcagcgctt accacagaca acggccgttt gacgtctggg ctggggcctc tcagctgggt acaatgatga catccacgag attactgtgc gccaagggac agtgaaggtc gcgacaggcc cacaaactat cacagcctac gagagaagcg cacggtcacc

120

180

240

300

360

370 <210> 131 <211> 123 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 131

PZ / 1778AGR

EP 2 374 818 B1

<td>Gin</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>ala</td><td>Arg</td><td>Glu</td><td>ala</td><td>Gin</td><td>Leu</td><td>val</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Underworld</td><td>Asp</td><td>val</td>

<td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td>

<210> 132 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 132 ggttacacct ttaccagtta tggt 24 <210> 133 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 133

Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <210> 134 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 134 atcagcgctt acaatgatga caca 24 <210> 135 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> artificial

PZ / 1778AGR

<400> 135

Ile Ser Ala Tyr Asn Asp Asp Th.r 1 5 <210> 136 <211> 48 <212> DNA <213> Artificial sequence <220>

<220>

<223> Artificial <400> 136 gcgagagaag cgcagctcgt cctctactac tactacggta tggacgtc 48 <210> 137 <211> 16 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 137

Ala Arg Glu Ala Gln Leu Val Leu Tyr Tyr Tyr Tyr Gly Met Asp Val 1 5 10 15 <210> 138 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 138 gaaattgtgt ctctcctgca ggccaggctc aggttcagtg gaagattttg gggaccaagc tgacacagtc gggccagtca ccaggctcct gcagtgggtc cagtttatta tggagatcaa tccagccacc ctgtctttgt ctccagggga aagagccacc 60 gagtgttagc agcttcttag cctggaacca acagaaacct 120 catctatgat gcatccaaca gggccactgg catcccagcc 180 tgggacagac ttcactctca ccatcagcag cctagagcct 240 ctgccagcag cgtagcaatt ggccgtacat ttttggccag 300 AC 322 <210> 139 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 139

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Cheese</td><td>own</td><td>Trp</td><td>Pro</td><td>Tyr</td>

100 105 <210> 140 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 140 cagagtgtta gcagcttc 18 <210> 141 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 141

Gin ser Val Ser Ser Phe 1 5 <210> 142 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 142 gatgcatcc 9 <210> 143 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 143

PZ / 1778AGR

EP 2 374 818 B1

Asp Ala Ser <210> 144 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 144 cagcagcgta gcaattggcc gtacatt 27 <210> 145 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 145

Gln Gln Arg Ser Asn Trp Pro Tyr Ile 1 5 '<210> 146 <211> 349 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 146 gaagtgcagc tcctgtgcag ccagggaagg gcggactctg ctgcaaatga gatgcttttg tggtggagtc cctctggatt gcctggagtg tgaaaggccg acagtctgag atatctgggg t GGG GGA GGC cacctttgat ggtctcaggt attcaccatc agttgaggac ccaagggaca ttggtacagc gattatgccc gttagttgga tccagagaca acggccttgt ttggtcaccg ctggcaggtc tgcactgggt atggtggtag acgccaagaa attattgtgc tctcttcag

<td>cctgagactc</td><td> 60</td>

<td>ccggcaagct</td><td> 120</td>

<td>aataggctat</td><td> 180</td>

<td>ctccctcttt</td><td> 240</td>

<td>aaaaggccgg</td><td> 300</td>

<210> 147 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 147

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>val</td><td colspan="3">Gln Leu Val</td><td>Glu</td><td colspan="10">Cheese Gly Gly Gly Leu Val Gln Pro Gly Arg</td>

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Asp</td><td>Asp</td><td>Tyr</td>

<td>Cheese</td><td>Gly</td><td>val</td><td>Cheese</td><td>Trp</td><td>own</td><td>Gly</td><td rowspan="2">Gly</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>val</td><td>ol</td><td>Asp</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

SE 90 9S

Ala Lys Gly Arg Asp Ala Phe Asp Ile Trp Oly Gln Gly Thr Leu Val

100 105 110

Thr Val Cheese cheese

115 <210> 148 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 148 ggattcacct ttgatgatta tgcc 24 <210> 149 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 149. Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 150 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 150 gttagttgga atggtggtag aata 24 <210> 151 <211> 8 <212> PRT <213> Artificial sequence <220>

PZ / 1778AGR

<223> Artificial <400> 151

Val Ser Trp Asn Gly Gly Arg Ile 1 5 <210> 152 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 152 gcaaaaggcc gggatgcttt tgatatc 27 <210> 153 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 153

Ala Lys Gly Arg Asp Ala Phe Asp Ile 1 5 <210> 154 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 154 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacat gcttacagtt tcccgtacac ttttggccag 300 gggaccaagc tggagatcaa ac 322 <210> 155 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 155

PZ / 1778AGR

EP 2 374 818 B1

<td>Asp</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>val</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>His</td><td>ala</td><td>Tyr</td><td>Cheese</td><td>phe</td><td>Pro</td><td>Tyr</td>

<210> 156 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 156 cagggtatta gcagctgg 18 <210> 157 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 157

Gln Gly Ile Cheese Ser Trp 1 5 <210> 158 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 158 gctgcatcc 9 <210> 159 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 159

Ala Ala Cheese

PZ / 1778AGR

EP 2 374 818 B1 <210> 160 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 160 caacatgctt acagtttccc gtacact 27 <210> 161 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 161

Gin His Ala Tyr ser Phe Pro Tyr Thr 1 5 <210> 162 <211> 349 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 162 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc tcctgtgcag cctctggatt cacctttgat gattatgcct ccagggaagg gcctggagtg ggtctcaggt attagttgga gcggactctg tgaagggccg attcaccatt tccagagaca ctgcaaatga acagtctgag agctgaggac acggccttgt gatgcttttg atatctgggg ccaagggaca ttggtcaccg ctggcaggtc tgcactgggt acagtggtag acgccaagaa attattgtgc tctcttcag cctgagactc 60 ccggcaagct 120 aataggctat ctccctcttt 180 240 300 aaaaggccgg

349 <210> 163 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 163

PZ / 1778AGR

EP 2 374 818 B1

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu twenty</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese 25</td><td>Gly</td><td>phe</td><td>Thr</td><td>phe</td><td>Asp thirty</td><td>Asp</td><td>Tyr</td>

<td>Cheese</td><td>Gly 50</td><td>How much</td><td>Cheese</td><td>Trp</td><td>own</td><td>Cheese 55</td><td>Gly</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr 60</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese 85</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp 90</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr 95</td><td>Cys</td>

<td>ala Thr</td><td>lys val</td><td>Gly Cheese 115</td><td>Arg 100 Cheese</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much 105</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr 110</td><td>Leu</td><td>val</td>

<210> 164 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 164 ggattcacct ttgatgatta tgcc 24 <210> 165 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 165

Gly Phe Thr Phe Asp Asp Tyr Ala <210> 166 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 166 attagttgga acagtggtag aata 24 <210> 167 <211> 8 <212> PRT <213> Artificial sequence

PZ / 1778AGR

EP 2 374 818 B1

<223> Artificial <400> 167

How much Ser Trp Asn Ser Gly * Arg xie 1 5 <210> 168 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 168 gcaaaaggcc gggatgcttt tgatatc 27 <210> 169 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 169

Ala Lys Gly Arg Asp Ala Phe Asp Ile 1 · 5.

<210> 170 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 170 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300 gggaccaagc tggagatcaa ac 322 <210> 171 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 171

PZ / 1778AGR

EP 2 374 818 B1

<td>Asp</td><td>How much</td><td>Gin</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>cheese</td><td>Pro</td><td>cheese</td><td>Cheese</td><td>val</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>ASp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Gly</td><td>how much</td><td>Cheese</td><td>Cheese</td><td>Trp</td>

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>ala</td><td>own</td><td>Cheese</td><td>phe</td><td>Pro</td><td>Tyr</td>

<210> 172 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 172 cagggtatta gcagctgg 18 <210> 173 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 173

Gin Gly Ile Cheese Ser Trp 1 5 <210> 174 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 174 gctgcatcc 9 <210> 175 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <210> 175

Ala Ala Cheese

PZ / 1778AGR

EP 2 374 818 B1 <210> 176 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 176 caacaggcta acagtttccc gtacact 27 <210> 177 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 177

Gln Gln Ala Asn Ser Phe Pro Tyr Thr 1 5 <210> 178 <211> 361 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 178 caggtgcagc tggtgcagtc tggggctgag gtgaaagagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggata caccttcace tcttatgata tcatctgggt gcgacaggcc 120 actggącaag ggcttgagtg gatgggatgg atgaacccaa acagtggtaa cacaggctat 180 acacagaacc tccagggcag agtcaccttg accaggaaca cctccataac tacagtctac 240 atggaactga gcagcctgag ctctgaggac acggccgttt attactgtgc gcgagactac 300 agtagccact actacggttt ggacgtctgg ggccaaggga ccacggtcac cgtctcctca 360 a 361 <210> 179 <211> 120 <212> PRT <213> Sequence artificial <220>

<223> Artificial <400> 179

Gln val Gln L & u val Gln Cheese Gly Ala Glu Val Lys Glu Pro Gly Al * l 5 10 15

PZ / 1778AGR

EP 2 374 818 B1

<td rowspan="2">Cheese</td><td rowspan="2">val</td><td rowspan="2">lys</td><td rowspan="2">val twenty</td><td rowspan="2">Cheese</td><td rowspan="2">Cys</td><td rowspan="2">lys</td><td colspan="7">Ala Ser Gly Tyr Thr Phe Thr</td><td rowspan="2">Cheese</td><td rowspan="2">Tyr</td>

<td>Asp</td><td>How much</td><td>how much</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Thr</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td>Gly</td><td>Trp</td><td>Underworld</td><td>own</td><td>Pro</td><td>own</td><td>Cheese</td><td>Gly</td><td>own</td><td>Thr</td><td>Gly</td><td>Tyr</td><td>Thr</td><td>Gln</td><td>own</td><td>Leu</td>

<td>Gln</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Leu</td><td>Thr</td><td>Arg</td><td>own</td><td>Thr</td><td>Cheese</td><td>How much</td><td>Thr</td><td>Thr</td><td>val</td><td>Tyr</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Tyr</td><td>Cheese</td><td>Cheese</td><td>His</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Leu</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gln</td>

<td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 180 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 180 ggatacacct tcacctctta tgat 24 <210> 181 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> artificial <400> 181

Gly Tyr Thr Phe Thr Ser Tyr Asp 1 5 <210> 182 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 182 atgaacccaa acagtggtaa caca 24 <210> 183 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 183

PZ / 1778AGR

EP 2 374 818 B1

Met Asn Pro Asn Ser Gly Asn Thr 1 5 <210> 184 <211> 39 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 184 gcgcgagact acagtagcca ctactacggt ttggacgtc 39 <210> 185 <211> 13 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 185

Ala Arg Asp Tyr Sar Ser His Tyr Tyr Gly Leu Asp Val 10 10 <210> 186 <211> 322 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 186 gacatccagt tgacecagtc tccatccttc ctgtctacat ctataggaga cagagtcacc 60 atcacttgct gggccagtca ggacattagc aattatttag cctggtatca gcaaaaacca 120 gggaaagccc ctaagctcct gatctttgtt gcatccactt tgcagagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagtag cctgcagcct 240 gaggattttg caacttatta ctgtcaacag tttaatagtt acccgctcac tttcggcgga 300 gggaccaagg tggaaatcaa ac 322 <210> 187 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 187

PZ / 1778AGR

EP 2 374 818 B1

<td>ASP</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Trp</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Asp</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>phe</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Leu</td>

<210> 188 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 188 caggacatta gcaattat 18 <210> 189 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 189

Gin Asp He Ser Asn Tyr 1 5 <210> 190 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 190 gttgcatcc 9 <210> 191 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 191

Val Ala Ser

PZ / 1778AGR

<210> 192 <211> 30 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 192 caacagttta atagttaccc gctcactttc 30 <210> 193 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 193

Gin Gin Phe Asn Ser Tyr Pro Leu Thr Phe 15 10 <210> 194 <211> 378 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 194 caggtccagc tggtgcagtc tgggggagac ttggtacagc ccggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaaact 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggggc cataggctat 180 gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtac aaaagaagaa 300 gtgggagcta cggtggatta tttctacttc tacggtatgg acgtctgggg ccaagggacc 360 acggtcaccg tctcctca 378 <210> 195 <211> 126 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 195

PZ / 1778AGR

EP 2 374 818 B1

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Asp</td><td>Leu</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>ala</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>Thr</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>Cheese</td><td>Gly</td><td>how much</td><td>Cheese</td><td>Trp</td><td>own</td><td>Cheese</td><td>Gly</td><td>ala</td><td>How much</td><td>Gly</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td>

<210> 196 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 196 ggattcacct ttgatgatta tgcc 24 <210> 197 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 197

Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 198 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 198 attagttgga atagtggggc cata 24 <210> 199 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 199

PZ / 1778AGR

EP 2 374 818 B1

Ile Ser Trp Asn Ser Gly Ala Ile 1 5 <210> 200 <211> 57 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 200 acaaaagaag aagtgggagc tacggtggat tatttctact tctacggtat ggacgtc 57 <210> 201 <211> 19 <212> PRT <213> Artificial sequence <220>

<223> artificial <400> 201

Thr Lys Glu Glu Val Gly Ala Thr Val Asp Tyr Phe Tyr Phe Tyr Gly 15 10 15

Met Asp Val <210> 202 <211> 318 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 202 gaaattgtga tgactcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60 ctctcctgct gggccagtca gagtgttagc aactacttag cctggtacca acagaaacct 120 ggccaggctc ccagactcct catctatgat gcatccaaca gggccactgg catcccagcc 180 aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240 gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctacgtt cggccaaggg 300 accaaggtgg aaatcaaa 318 <210> 203 <211> 106 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 203

PZ / 1778AGR

EP 2 374 818 B1

<td>GILJ</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin.</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>Glu</td><td>Arg</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>Cys</td><td>Trp</td><td>ala</td><td>Cheese</td><td>Gin</td><td>Cheese</td><td>val</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Arg</td><td>Cheese</td><td>own</td><td>Trp</td><td>Pro</td><td>Thr</td>

<210> 204 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 204 cagagtgtta gcaactac 18 <210> 205 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 205

Gin Ser Val Ser Asn Tyr 1 5 <210> 206 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 206 gatgcatcc 9 <210> 207 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 207

Asp Ala Ser

PZ / 1778AGR

EP 2 374 818 B1 <210> 208 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 208 cagcagcgta gcaactggcc tacg 24 <210> 209 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 209

Gin Gin Arg Ser Asn Trp Pro Thr 1 S <210> 210 <211> 348 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 210 caagtgcagc tggtgcagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt attagttgga atagtggtag ggtaggctat 180 gcggactctg tgaagggecg attcaccatc tccagagaca acgccaagaa ctccctgtat 240 ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtac aaaaggccgg 300 gatgcttttg atatctgggg ccaggggaca atggtcaccg tetettea 348 < 210> 211 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 211

PZ / 1778AGR

EP 2 374 818 B1

<td>Gin 1</td><td>val</td><td>Gin</td><td>Leu</td><td>val 5</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly 10</td><td>Leu</td><td>val</td><td>Gin</td><td>Pro</td><td>Gly 15</td><td>Arg</td>

<td>Cheese</td><td>Gly 50</td><td>How much</td><td>Cheese</td><td>Trp</td><td>own</td><td>Cheese 55</td><td>Gly</td><td>Arg</td><td>val</td><td>Gly</td><td>Tyr 60</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Thr Thr</td><td>lys val</td><td>Gly Cheese 115</td><td>Arg 100 Cheese</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much 105</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr 110</td><td>Underworld</td><td>val</td>

<210> 212 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 212 ggattcacct ttgatgatta tgcc 24 <210> 213 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 213

Gly Phe Thr Phe Asp Asp Tyr Ala 1 5 <210> 214 <211> 24 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 214 attagttgga atagtggtag ggta 24 <210> 215 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 215

PZ / 1778AGR

EP 2 374 818 B1

How much Ser Trp Asn Ser Gly Arg Val 1 5 <210> 216 <211> 27 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 216 acaaaaggcc gggatgcttt tgatatc 27 <210> 217 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 217

Thr Lys Gly Arg Asp Ala Phe Asp Ile 1 5 <210> 218 <211> 321 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 218 gatattgtga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc etaagetcet gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtacac ttttggccag 300 gggaccaagc tggagatcaa a 321 <210> 219 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 219

Asp Ile Val Met Thr Gln Cheese Pro Cheese Cheese Val Cheese Ala Cheese Val Gly 1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp

PZ / 1778AGR

EP 2 374 818 B1

<td>Tyr</td><td>ala</td><td>ala</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>ala</td><td>own</td><td>cheese</td><td>phe</td><td>Pro</td><td>Tyr</td>

<210> 220 <211> 18 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 220 cagggtatta gcagctgg 18 <210> 221 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 221

Gin Gly Ile Ser Cheese Trp 1 5 <210> 222 <211> 9 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 222 gctgcatcc 9 <210> 223 <211> 3 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 223

Ala Ala Ser <210> 224 <211> 27

PZ / 1778AGR

<212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 224 caacaggcta acagtttccc gtacact 27 <210> 225 <211> 9 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 225 <210> 226

Gln Gln Ala Asn Ser Phe Pro Tyr Thr 1 5 <210> 226 <211> 378 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 226 gaagtgcagc tggtggaatc tggaggagga ctggtgcagc ctggaagatc tctgagactg 60 tcttgtgctg cttctggatt tatctttgat gattatgcta tgcattgggt gagacaggct 120 cctggaaagg gactggaatg ggtgtctgga atctcttgga attctggatc tatcggatat 180 gctgattctg tgaagggaag atttacaatc tctagagata atgctaagaa ttctctgtat 240 ctgcagatga attctctgag agctgaagat acagctctgt attattgtgc taaggatgga 300 ggatcttctt ggctgccttt tgtgtattat tatggaatgg atgtgtgggg acagggaaca 360 acagtgacag tgtcttct 378 <210> 227 <211> 126 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 227

PZ / 1778AGR

EP 2 374 818 B1

<td>ol</td><td>val</td><td>Gin</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</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>Arg</td>

<td>ala</td><td>Underworld</td><td>His</td><td>Trp</td><td>val</td><td>Arg</td><td>Gin</td><td>ala</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>Leu</td><td>Gin</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>lys</td><td>Asp</td><td>Gly</td><td>Gly</td><td>Cheese</td><td>Cheese</td><td>Trp</td><td>Leu</td><td>Pro</td><td>phe</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Tyr</td><td>Gly</td>

<td>Underworld</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gin</td><td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td>

<210> 228 <211> 324 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 228 gaaatcgtga tgacacagtc tcctgctaca ctgtctgtgt ctcctggaga aagagctaca 60 ctgtcttgta gagcttctca gtctatctct tctaatctgg cttggtatea gcagaagcct 120 ggacaggctc ctagactgct gatetatgga gcttctacaa gagctacagg aatccctgct 180 agattttctg gatctggatc tggaacagaa tttacactga caatctcttc tctgcagtct 240 gaagattttg ctgtgtatta ttgtcagcag tattettett ggcctcctta tacatttgga 300 cagggaacaa agctggaaat caag 324 <210> 229 <211> 108 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 229

<td>Glu</td><td>How much</td><td>val</td><td>Underworld</td><td>Thr</td><td>Gin</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Thr</td><td>Leu</td><td>Cheese</td><td>val</td><td>Cheese</td><td>Pro</td><td>Gly</td>

<td>Cheese</td><td>Gly</td><td>cheese</td><td>Gly</td><td>Thr</td><td>Glu</td><td>phe</td><td>Thr</td><td>Leu</td><td>Thr</td><td>How much</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Gin</td><td>Cheese</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gin</td><td>Gin</td><td>Tyr</td><td>cheese</td><td>Cheese</td><td>Trp</td><td>pro</td><td>Pro</td>

<210> 230 <211> 348 <212> DNA <213> Artificial sequence <220>

PZ / 1778AGR

EP 2 374 818 B1 <223> Artificial <400> 230 gaggtccagc tggtcgagtc aggaggaggc ctcgtccaac cagggcgcag cctccgactc 60 tcctgtgccg ccagtaggtt tacuttcgat gactatgcca tgcactgggt ccggcaggcc 120 cctggtaagg gcttggagtg ggtgtccggt atctcctgga actccggacg tatcggtcac 180 gccgacagcg tgaagggaag gttcactatc tctcgtgaca acgccaagaa ctccttgtat 240 ctgcaaatga acagcctccg ggccgaagac accgccttgt attactgtgc caagggtagg 300 gatagtttcg atatctgggg tcaaggcacc atggtgactg tgtcttca 348 <210> 231 <211> 116 <212> PRT <213> Sequence artificial <220>

<223> Artificial <400> 231

<td>Cheese</td><td>Leu</td><td>Arg</td><td>Leu twenty</td><td>Cheese</td><td>Cys</td><td>ala</td><td>ala</td><td>Cheese 25</td><td>Arg</td><td>phe</td><td>Thr</td><td>phe</td><td>Asp thirty</td><td>ASp</td><td>Tyr</td>

<td>lys</td><td>Gly</td><td>Arg</td><td>phe</td><td>Thr</td><td>how much</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>own</td><td>ala</td><td>Glu</td><td>own</td><td>Cheese</td><td>Leu</td><td>phe</td>

70 75 80

Leu Gin Met Asn Gly Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

90 95

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

<210> 232 <211> 321 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 232 gacatacaga tgacccaaag cccaagcagc gttagcgctt ccgtaggcga cagggtgaca 60 attacatgca gagcctctca gggaatttct tcatggctgg catggtatca gcagaagccc 120 ggaaaagctc ccaagctgct gatatatggt gcctcctctc tccaaagcgg agccccatca 180 cgcttctccg ggagtggctc tggtacagat tttactttga caatctctag ccttcagcct 240 gaagactttg ctacatacta ctgtcagcag gccaacagtt ttccttacac cttcggtcag 300 ggaactaaac tggaaattaa g 321 <210> 233 <211> 107 <212> PRT <213> Artificial sequence <400> 233 <220>

<223> artificial

PZ / 1778AGR

EP 2 374 818 B1

<td>ASP</td><td>How much</td><td>Gln</td><td>Underworld</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>val</td><td>cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>ala</td><td>own</td><td>Cheese</td><td>phe</td><td>Pro</td><td>Tyr</td>

<210> 234 <211> 360 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 234 caggtgcagc tggtgcagtc tggagctgaa gtgaagaagc ctggagcttc tgtgaaggtg tcttgtaagg cttctggata tacatttaca tcttatgata tcatctgggt gagacaggct acaggacagg gactggaatg gatgggatgg acgaatccta attctggaaa tacaggatat gctcagaagt ttcagggaag agtgacaatg acaagaaata catctatctc tacagtgtat atggaactgt cttctctgag atctgaagat acagctgtgt attattgtgc tagagattat tcttctcatt attatggact ggatgtgtgg ggacagggaa caacagtgac agtgtcttct <210> 235 <211 > 120 <212> PRT <213> Artificial sequence

120

180

240

300

360 <220>

<223> Artificial <400> 235

<td>Gln</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>ala</td><td>Glu</td><td>val</td><td>lys</td><td>lys</td><td>Pro</td><td>Gly</td><td>ala</td>

<td>Asp</td><td>How much</td><td>How much</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala</td><td>Thr</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Leu</td><td>Glu</td><td>Trp</td><td>Underworld</td>

<td>Gln</td><td>Gly</td><td>Arg</td><td>val</td><td>Thr</td><td>Underworld</td><td>Thr</td><td>Arg</td><td>own</td><td>Thr</td><td>Cheese</td><td>How much</td><td>Cheese</td><td>Thr</td><td>val</td><td>Tyr</td>

<td>Underworld</td><td>Glu</td><td>Leu</td><td>Cheese</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>Cheese</td><td>Glu</td><td>ASP</td><td>Thr</td><td>ala</td><td>val</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>Arg</td><td>Asp</td><td>Tyr</td><td>Cheese</td><td>Cheese</td><td>His</td><td>Tyr</td><td>Tyr</td><td>Gly</td><td>Leu</td><td>Asp</td><td>val</td><td>Trp</td><td>Gly</td><td>Gln</td>

<td>Gly</td><td>Thr</td><td>Thr</td><td>val</td><td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 236 <211> 321 <212> DNA <213> Artificial sequence <220>

PZ / 1778AGR

EP 2 374 818 B1 <223> Artificial <400> 236 gatatccagc tgacacagtc tccttctttt ctgtctgctt ctgtgggaga tagagtgaca 60 atcacatgta gagcttctca ggatatctct aattatctgg cttggtatca gcagaagcct 120 ggaaaggctc ctaagctgct gatctatgtg gcttctacac tgcagtctgg agtgccttct 180 agattttctg gatctggatc tggaacagaa tttacactga caatctcttc tctgcagcct 240 gaagattttg ctacatatta ttgtcagcag tttaattctt atcctctgac atttggagga 300 ggaacaaagg tggaaatcaa g 321 <210> 237 <211> 107 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 237

<td>Asp</td><td>How much</td><td>Gln</td><td>Leu</td><td>Thr</td><td>Gln</td><td>Cheese</td><td>Pro</td><td>Cheese</td><td>phe</td><td>Leu</td><td>Cheese</td><td>ala</td><td>Cheese</td><td>val</td><td>Gly</td>

<td>Asp</td><td>Arg</td><td>val</td><td>Thr</td><td>How much</td><td>Thr</td><td>Cys</td><td>Arg</td><td>ala</td><td>Cheese</td><td>Gln</td><td>Asp</td><td>How much</td><td>Cheese</td><td>own</td><td>Tyr</td>

<td>Tyr</td><td>val</td><td>ala</td><td>Cheese</td><td>Thr</td><td>Leu</td><td>Gln</td><td>Cheese</td><td>Gly</td><td>val</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>phe</td><td>Cheese</td><td>Gly</td>

<td>Glu</td><td>Asp</td><td>phe</td><td>ala</td><td>Thr</td><td>Tyr</td><td>Tyr</td><td>Cys</td><td>Gln</td><td>Gln</td><td>phe</td><td>own</td><td>Cheese</td><td>Tyr</td><td>Pro</td><td>Leu</td>

<210> 238 <211> 349 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 238 gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttgat gattatgccc tgcactgggt ccggcaagct 120 ccagggaagg gcctggagtg ggtctcaggt gttagttgga atggtggtag aataggctat 180 gcggactctg tgaaaggccg attcaccatc tccagagaca acgccaagaa ctccctcttt 240 ctgcaaatga acagtctgag agttgaggac acggccttgt attattgtgc aaaaggccgg 300 gatgcttttg atatctgggg ccaagggaca ttggtcaccg tctcttcag 349 < 210> 239 <211> 116 <212> PRT <213> Artificial sequence <400> 239 <220>

<223> artificial

PZ / 1778AGR

EP 2 374 818 B1

<td>Glu</td><td>val</td><td>Gln</td><td>Leu</td><td>val</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly</td><td>Leu</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly</td><td>Arg</td>

<td>Cheese</td><td>Gly</td><td>val</td><td>Cheese</td><td>Trp</td><td>own</td><td>Gly</td><td>Gly</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese</td><td>Leu</td><td>Arg</td><td>val</td><td>Glu</td><td>Asp</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr</td><td>Cys</td>

<td>ala</td><td>lys</td><td>Gly</td><td>Arg</td><td>Asp</td><td>ala</td><td>phe</td><td>ASP</td><td>How much</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr</td><td>Underworld</td><td>val</td>

<td>Thr</td><td>val</td><td>Cheese</td><td>Cheese</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> 240 <211> 348 <212> DNA <213> Artificial sequence <220>

<223> Artificial <400> 240 gaagtgcagc tggtggaatc tggaggagga ctggtgcagc ctggaagatc tctgagactg 60 tcttgtgctg cttctggatt tacatttgat gattatgcta tgcattgggt gagacaggct 120 cctggaaagg gactggaatg ggtgtctgga gtgtcttgga atggaggaag aatcggatat 180 gctgattctg tgaagggaag atttacaatc tctagagata atgctaagaa ttctctgtat 240 ctgcagatga attctctgag agctgaagat acagctctgt attattgtgc taagggaaga 300 gatgcttttg atatctgggg acagggaaca atggtgacag tgtcttct 348 < 210> 241 <211> 116 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 241

<td>Glu 1</td><td>val</td><td>Gln</td><td>Leu</td><td>val 5</td><td>Glu</td><td>Cheese</td><td>Gly</td><td>Gly</td><td>Gly 10</td><td>Leu</td><td>val</td><td>Gln</td><td>Pro</td><td>Gly 15</td><td>Arg</td>

<td>ala</td><td>Underworld</td><td>His 35</td><td>Trp</td><td>val</td><td>Arg</td><td>Gln</td><td>ala 40</td><td>pro</td><td>Gly</td><td>lys</td><td>Gly</td><td>Leu 45</td><td>Glu</td><td>Trp</td><td>val</td>

<td>Cheese</td><td>Gly 50</td><td>val</td><td>cheese</td><td>Trp</td><td>own</td><td>Gly 55</td><td>Gly</td><td>Arg</td><td>How much</td><td>Gly</td><td>Tyr 60</td><td>ala</td><td>Asp</td><td>Cheese</td><td>val</td>

<td>Leu</td><td>Gln</td><td>Underworld</td><td>own</td><td>Cheese 85</td><td>Leu</td><td>Arg</td><td>ala</td><td>Glu</td><td>Asp 90</td><td>Thr</td><td>ala</td><td>Leu</td><td>Tyr</td><td>Tyr 95</td><td>Cys</td>

<td>ala Thr</td><td>lys val</td><td>Gly Cheese 115</td><td>Arg 100 Cheese</td><td>Asp</td><td>ala</td><td>phe</td><td>Asp</td><td>How much 105</td><td>Trp</td><td>Gly</td><td>Gln</td><td>Gly</td><td>Thr 110</td><td>Underworld</td><td>val</td>

<210> 242 <211> 330 <212> PRT <213> Artificial sequence <220>

PZ / 1778AGR

<223> Artificial <400> 242

<td>ala 1</td><td>Cheese</td><td>Thr</td><td>lys</td><td>Gly 5</td><td>Pro</td><td>Cheese</td><td>val</td><td>phe</td><td>Pro 10</td><td>Leu</td><td>ala</td><td>Pro</td><td>Cheese</td><td>Cheese 15</td><td>lys</td>

<td>Cheese</td><td>Thr</td><td>Cheese</td><td>Gly twenty</td><td>Gly</td><td>Thr</td><td>ala</td><td>ala</td><td>Leu 25</td><td>Gly</td><td>Cys</td><td>Leu</td><td>val</td><td colspan="2">Lys. Asp 30</td><td>Tyr</td>

<td>phe</td><td>Pro</td><td>Glu 35</td><td>Pro</td><td>val</td><td>Thr</td><td>val</td><td>Cheese 40</td><td>Trp</td><td>own</td><td>Cheese</td><td>Gly</td><td>ala 45</td><td>Leu</td><td>Thr</td><td>Cheese</td>

<td>Gly</td><td>val 50</td><td>His</td><td>Thr</td><td>phe</td><td>Pro</td><td>ala 55</td><td>val</td><td>Leu</td><td>Gin</td><td>Cheese</td><td>Cheese 60</td><td>Gly</td><td>Leu</td><td>Tyr</td><td>Cheese</td>

<td>Leu 65</td><td>Cheese</td><td>Cheese</td><td>val</td><td>val</td><td>Thr 70</td><td>val</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Cheese 75</td><td>Leu</td><td>Gly</td><td>Thr</td><td>Gin</td><td>Thr 80</td>

<td>Tyr</td><td>How much</td><td>Cys</td><td>own</td><td>val 85</td><td>own</td><td>His</td><td>lys</td><td>Pro</td><td>Cheese 90</td><td>own</td><td>Thr</td><td>lys</td><td>val</td><td>Asp 95</td><td>lys</td>

<td>lys</td><td>val</td><td>Glu</td><td>Pro 100</td><td>lys</td><td>cheese</td><td>Cys</td><td>Asp</td><td>LYB 105</td><td>Thr</td><td>His</td><td>Thr</td><td>Cys</td><td>Pro 110</td><td>Pro</td><td>Cya</td>

<td>Pro</td><td>ala</td><td>Pro 115</td><td>Glu</td><td colspan="2">Leu Leu</td><td colspan="3">Gly Gly Pro 120</td><td>Cheese</td><td>val</td><td colspan="3">Phe Leu Phe 125</td><td>Pro</td><td>Pro</td>

<td>lys</td><td>Pro</td><td>lys</td><td>Asp</td><td>Thr</td><td>Leu</td><td>Underworld</td><td>How much</td><td>Cheese</td><td>Arg</td><td>Thr</td><td>Pro</td><td>Glu</td><td>val</td><td>Thr</td><td>Cys</td>

<td>val</td><td>val</td><td>val</td><td>Asp</td><td>val</td><td>Cheese</td><td>His</td><td>Glu</td><td>Asp</td><td>Pro</td><td>Glu</td><td>val</td><td>lys</td><td>phe</td><td>own</td><td>Trp</td>

<td>Glu</td><td>Gin</td><td>Tyr</td><td>own</td><td>Cheese</td><td>Thr</td><td>Tyr</td><td>Arg</td><td>val</td><td>val</td><td>Cheese</td><td>val</td><td>Leu</td><td>Thr</td><td>val</td><td>Leu</td>

<td>His</td><td>Gin</td><td>Asp</td><td>Trp</td><td>Leu</td><td>own</td><td>Gly</td><td>lys</td><td>Glu</td><td>Tyr</td><td>lys</td><td>Cys</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td>

<td>lys</td><td>ala</td><td>Leu</td><td>pro</td><td>ala</td><td>Pro</td><td>How much</td><td>Glu</td><td>lys</td><td>Thr</td><td>How much</td><td>Cheese</td><td>lys</td><td>ala</td><td>lys</td><td>Gly</td>

<td>Gin</td><td>Pro</td><td>Arg</td><td>Glu</td><td>Pro</td><td>Gin</td><td>val</td><td>Tyr</td><td>Thr</td><td>Leu</td><td>Pro</td><td>Pro</td><td>Cheese</td><td>Arg</td><td>Asp</td><td>Glu</td>

<td>Leu</td><td>Thr</td><td>lys</td><td>own</td><td>Gin</td><td>val</td><td>Cheese</td><td>Leu</td><td>Thr</td><td>Cys</td><td>Leu</td><td>val</td><td>lys</td><td>Gly</td><td>phe</td><td>Tyr</td>

<td>Pro</td><td>Cheese</td><td>Asp</td><td>How much</td><td>ala</td><td>val</td><td>Glu</td><td>Trp</td><td>Glu</td><td>Cheese</td><td>own</td><td>Gly</td><td>Gin</td><td>Pro</td><td>Glu</td><td>own</td>

<td>own</td><td>Tyr</td><td>lys</td><td>Thr</td><td>Thr</td><td>Pro</td><td>Pro</td><td>val</td><td>Leu</td><td>Asp</td><td>Cheese</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>phe</td><td>phe</td>

<td>Leu</td><td>Tyr</td><td>Cheese</td><td>lys</td><td>Leu</td><td>Thr</td><td>val</td><td>Asp</td><td>lys</td><td>Cheese</td><td>Arg</td><td>Trp</td><td>Gin</td><td>Gin</td><td>Gly</td><td>own</td>

<td>val</td><td>phe</td><td>Cheese</td><td>Cys</td><td>Cheese</td><td>val</td><td>Underworld</td><td>His</td><td>Glu</td><td>ala</td><td>Leu</td><td>His</td><td>own</td><td>His</td><td>Tyr</td><td>Thr</td>

<td>Gin</td><td>lys</td><td>Cheese</td><td>Leu</td><td>cheese</td><td>Leu</td><td>cheese</td><td>pro</td><td>Gly</td><td>lys</td><td></td><td></td><td></td><td></td><td></td><td></td>

<210> 243 <211> 327 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 243

PZ / 1778AGR

EP 2 374 818 B1

<td>Cheese</td><td>Thr</td><td>Cheese</td><td>Glu twenty</td><td>Cheese</td><td>Thr</td><td>ala</td><td>ala</td><td>Leu 25</td><td>Gly</td><td>Cys</td><td>Leu</td><td>val</td><td>lys thirty</td><td>Asp</td><td>Tyr</td>

<td>Tyr</td><td>Thr</td><td>Cys</td><td>own</td><td>val 85</td><td>Asp</td><td>His</td><td>lys</td><td>Pro</td><td>Cheese 90</td><td>own</td><td>Thr</td><td>lys</td><td>val</td><td>ASP 95</td><td>lys</td>

<td>Arg</td><td>val</td><td>Glu</td><td>Cheese 100</td><td>lys</td><td>Tyr</td><td>Gly</td><td>Pro</td><td>Pro 105</td><td>Cys</td><td>Pro</td><td>Cheese</td><td>Cys</td><td>Pro 110</td><td>ala</td><td>Pro</td>

<td>Glu</td><td>phe</td><td>Leu 115</td><td>Gly</td><td>Gly</td><td>Pro</td><td>Cheese</td><td>val 120</td><td>phe</td><td>Leu</td><td>phe</td><td>Pro</td><td>Pro 125</td><td>lys</td><td>Pro</td><td>lys</td>

<td>Asp</td><td>Thr 130</td><td>Leu</td><td>Underworld</td><td>How much</td><td>Cheese</td><td>Arg 135</td><td>Thr</td><td>Pro</td><td>Glu</td><td>val</td><td>Thr 140</td><td>Cys</td><td>val</td><td>val</td><td>val</td>

<td>Asp 145</td><td>val</td><td>Cheese</td><td>Gin</td><td>Glu</td><td>Asp 150</td><td>Pro</td><td>Glu</td><td>val</td><td>Gin</td><td>phe 155</td><td>own</td><td>Trp</td><td>Tyr</td><td>val</td><td>Asp 160</td>

<td>own</td><td>Cheese</td><td>Thr</td><td>Tyr 180</td><td>Arg</td><td>val</td><td>val</td><td>Cheese</td><td>val 185</td><td>Leu</td><td>Thr</td><td>val</td><td>Leu</td><td>His 190</td><td>Gin</td><td>Asp</td>

<td>Trp</td><td>Leu</td><td>own</td><td>Gly</td><td>lys</td><td>Glu</td><td>Tyr</td><td>lys</td><td>Cys</td><td>lys</td><td>val</td><td>Cheese</td><td>own</td><td>lys</td><td>Gly</td><td>Leu</td>

<td>Pro</td><td>Cheese</td><td>195 Cheese</td><td>How much</td><td>Glu</td><td>lys</td><td>Thr</td><td>200 How much</td><td>Cheese</td><td>lys</td><td>ala</td><td>lys</td><td>205 Gly</td><td>Gin</td><td>Pro</td><td>Arg</td>

<td>Glu</td><td>210 Pro</td><td>Gin</td><td>val</td><td>Tyr</td><td>Thr</td><td>215 Leu</td><td>Pro</td><td>Pro</td><td>Cheese</td><td>Gin</td><td>220 Glu</td><td>Glu</td><td>Underworld</td><td>Thr</td><td>lys</td>

<td>225 own</td><td>Gin</td><td>val</td><td>Cheese</td><td>Leu</td><td>230 Thr</td><td>Cys</td><td>Leu</td><td>val</td><td>lys</td><td>235 Gly</td><td>phe</td><td>Tyr</td><td>Pro</td><td>Cheese</td><td>240 ASP</td>

<td>How much</td><td>ala</td><td>val</td><td>Glu</td><td>245 Trp</td><td>Glu</td><td>Cheese</td><td>own</td><td>Gly</td><td>250 Gin</td><td>Pro</td><td>Glu</td><td>own</td><td>own</td><td>255 Tyr</td><td>lys</td>

<td>Thr</td><td>Thr</td><td>Pro</td><td>260 Pro</td><td>val</td><td>Leu</td><td>Asp</td><td>Cheese</td><td>265 Asp</td><td>Gly</td><td>Cheese</td><td>phe</td><td>phe</td><td>270 Leu</td><td>Tyr</td><td>Cheese</td>

<td>Arg</td><td>Leu</td><td>275 Thr</td><td>val</td><td>Asp</td><td>lys</td><td>Cheese</td><td>280 Arg</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Gly</td><td>285 own</td><td>val</td><td>phe</td><td>Cheese</td>

<td>Cys</td><td>290 Cheese</td><td>val</td><td>Underworld</td><td>His</td><td>Glu</td><td>295 ala</td><td>Leu</td><td>His</td><td>own</td><td>His</td><td>300 Tyr</td><td>Thr</td><td>Gin</td><td>lys</td><td>Cheese</td>

<td>305 Leu</td><td>Cheese</td><td>Leu</td><td>Cheese</td><td>Leu</td><td>310 Gly</td><td>lys</td><td></td><td></td><td></td><td> 315</td><td></td><td></td><td></td><td></td><td> 320</td>

325 <210> 244 <211> 327 <212> PRT <213> Artificial sequence <220>

<223> Artificial <400> 244

PZ / 1778AGR

EP 2 374 818 B1

<td>Leu .65</td><td>Cheese</td><td>Cheese</td><td>val</td><td>val</td><td>Thr 70</td><td>val</td><td>Pro</td><td>Cheese</td><td>Cheese</td><td>Cheese 75</td><td>Leu</td><td>Gly</td><td>Thr</td><td>lys</td><td>Thr 80</td>

<td>Tyr</td><td>Thr</td><td>Cys</td><td>own</td><td>val 85</td><td>ASp</td><td>His</td><td>lys</td><td>Pro</td><td>Cheese 90</td><td>own</td><td>Thr</td><td>lys</td><td>val</td><td>Asp 95</td><td>lys</td>

<td>Arg</td><td>val</td><td>Glu</td><td>Cheese 100</td><td>lys</td><td>Tyr</td><td>Gly</td><td>Pro</td><td>Pro 105</td><td>Cys</td><td>Pro</td><td>Pro</td><td>Cys</td><td>Pro 110</td><td>ala</td><td>Pro</td>

<td>Own.</td><td>Cheese</td><td>Thr</td><td>Tyr 180</td><td>Arg</td><td>val</td><td>val</td><td>Cheese</td><td>val 185</td><td>Leu</td><td>Thr</td><td>val</td><td>Leu</td><td>His 190</td><td>Gin</td><td>Asp</td>

<td>Trp</td><td>Leu</td><td>own 195</td><td>Gly</td><td>lys</td><td>Glu</td><td>Tyr</td><td>lys 200</td><td>Cys</td><td>lys</td><td>val</td><td>Cheese</td><td>own 205</td><td>lys</td><td>Gly</td><td>Leu</td>

<td>Pro</td><td>Cheese 210</td><td>Cheese</td><td>How much</td><td>Glu</td><td>lys</td><td>Thr 215</td><td>How much</td><td>Cheese</td><td>lys</td><td>ala</td><td>lys 220</td><td>Gly</td><td>Gin</td><td>Pro</td><td>Arg</td>

<td>Glu 225</td><td>Pro</td><td>Gin</td><td>val</td><td>Tyr</td><td>Thr 230</td><td>Leu</td><td>Pro</td><td>Pro</td><td>Cheese</td><td>Gin 235</td><td>Glu</td><td>Glu</td><td>Underworld</td><td>Thr</td><td>lys 240</td>

<td>own</td><td>Gin</td><td>val</td><td>Cheese</td><td>Leu 245</td><td>Thr</td><td>Cys</td><td>Leu</td><td>val</td><td>lys 250</td><td>Gly</td><td>phe</td><td>Tyr</td><td>Pro</td><td>Cheese 255</td><td>Asp</td>

<td>How much</td><td>ala</td><td>val</td><td>Glu 260</td><td>Trp</td><td>Glu</td><td>Cheese</td><td>own</td><td>Gly 265</td><td>Gin</td><td>Pro</td><td>Glu</td><td>own</td><td>own 270</td><td>Tyr</td><td>lys</td>

<td>Thr</td><td>Thr</td><td>Pro 275</td><td>Pro</td><td>val</td><td>Leu</td><td>Asp</td><td>Cheese 280</td><td>Asp</td><td>Gly</td><td>Cheese</td><td>phe</td><td>phe 285</td><td>Leu</td><td>Tyr</td><td>Cheese</td>

<td>Arg</td><td>Leu 290</td><td>Thr</td><td>val</td><td>Asp</td><td>lys</td><td>Cheese 295</td><td>Arg</td><td>Trp</td><td>Gin</td><td>Glu</td><td>Gly 300</td><td>own</td><td>val</td><td>phe</td><td>Cheese</td>

<td>Cya 305 Leu</td><td>Cheese Cheese</td><td>val Leu</td><td>Underworld: Cheese</td><td>His Leu</td><td>Glu 310 Gly</td><td>ala Ly9</td><td>Leu</td><td>His</td><td>own</td><td>His 315</td><td>Tyr</td><td>Thr</td><td>Gin</td><td>lys</td><td>Cheese 320</td>

325 <210> 245 <211> 6 <212> PRT <213> Artificial sequence <220>

<223> Artificial <220>

<221> VARIANT <222> (1) ... (6) <223> Xaa = Any amino acid <400> 245

Xaa Xaa Xaa Xaa Xaa Xaa 1 5 <210> 246 <211> 3 <212> PRT <213> Artificial sequence

PZ / 1778AGR

EP 2 374 818 B1

<223> Artificial <220>

<221> VARIANT <222> (1) ... (3) <223> Xaa = Any amino acid

400> 246

Xaa Xaa Xaa 1 <210> 247 <211> 10 <212> PRT <213> Artificial sequence <220>

<223> Artificial <220>

<221> VARIANT <222> (1) ... (10) <223> Xaa = Any amino acid <400> 247

Xaa Xaa xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa 15 10 <210> 248 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <220>

<221> VARIANT <222> (1) ... (8) <223> Xaa = Any amino acid <400> 248 <210> 249 <211> 8 <212> PRT <213> Artificial sequence <220>

<223> Artificial <220>

<221> VARIANT <222> (1) ... (8) <223> Xaa = Any amino acid <400> 249 xaa xaa xaa xaa xaa xaa xaa xaa

PZ / 1778AGR

EP 2 374 818 B1 <210> 250 <211> 19 <212> PRT <213> Artificial sequence <220>

<223> Artificial <220>

<221> VARIANT <222> (1) ... (19) <223> Xaa = Any amino acid <400> 250 xaa Xaa xaa Xaa Xaa xaa Xaa xaa xaa Xaa Xaa Xaa Xaa xaa Xaa Xaa 15 10 15 xaa xaa Xaa < 210> 251 <211> 311 <212> PRT <213> Macaca Fascicularis <400> 251

<td>Cheese</td><td>Leu</td><td>Pro</td><td>Gly twenty</td><td>Asp</td><td>Cheese</td><td>val</td><td>Thr</td><td>Leu 25</td><td>Thr</td><td>cys</td><td>Pro Gly</td><td>Gly thirty</td><td>Glu</td><td>Pro</td>

PZ / 1778AGR

EP 2 374 818 B1

<td>Cheese</td><td>His 50</td><td>Leu</td><td>Cheese</td><td>Arg</td><td>Trp</td><td>ala 55</td><td>Gly</td><td>val</td><td>Gly</td><td>Arg</td><td>Arg 60</td><td>Leu</td><td>Leu</td><td>Leu</td><td>Arg</td>

<td>Cheese 65</td><td>val</td><td>Gin</td><td>Leu</td><td>His</td><td>Asp 70</td><td>Cheese</td><td>Gly</td><td>own</td><td>Tyr</td><td>Cheese 75</td><td>Cys</td><td>Tyr</td><td>Arg</td><td>ala</td><td>Gly 80</td>

<td>Pro</td><td>Gin</td><td>Leu</td><td>Cheese 100</td><td>Cys</td><td>phe</td><td>Arg</td><td>lys</td><td>Cheese 105</td><td>Pro</td><td>Leu</td><td>Cheese</td><td>own</td><td>vai 110</td><td>ala</td><td>Cys</td>

<td>Glu</td><td>Trp</td><td>Gly 115</td><td>Pro</td><td>Arg</td><td>Cheese</td><td>Thr</td><td>Pro 120</td><td>Cheese</td><td>Pro</td><td>Thr</td><td>Thr</td><td>lys 125</td><td>ala</td><td>val</td><td>Leu</td>

<td>Leu</td><td>val 130</td><td>Arg</td><td>lys</td><td>phe</td><td>Gin</td><td>own 135</td><td>Cheese</td><td>Pro</td><td>ala</td><td>Glu</td><td>Asp 140</td><td>phe</td><td>Gin</td><td>Glu</td><td>Pro</td>

<td>Cys 145</td><td>Gin</td><td>Tyr</td><td>Cheese</td><td>Gin</td><td>Glu 150</td><td>Cheese</td><td>Gin</td><td>lys</td><td>phe</td><td>Cheese 155</td><td>Cys</td><td>Gin</td><td>Leu</td><td>ala</td><td>val 160</td>

<td>Pro</td><td>Glu</td><td>Gly</td><td>Asp</td><td>Cheese 165</td><td>Cheese</td><td>phe</td><td>Tyr</td><td>How much</td><td>val 170</td><td>Cheese</td><td>Underworld</td><td>Cys</td><td>val</td><td>ala 175</td><td>Cheese</td>

<td>Cheese</td><td>val</td><td>Gly</td><td>Cheese 180</td><td>lys</td><td>Leu</td><td>Cheese</td><td>lys</td><td>Thr 185</td><td>Gin</td><td>Thr</td><td>phe</td><td>Gin</td><td>Gly 190</td><td>Cys</td><td>Gly</td>

<td>Arg</td><td>own 210</td><td>Pro</td><td>Arg</td><td>Trp</td><td>Leu</td><td>Cheese 21S</td><td>val</td><td>Thr</td><td>Trp</td><td>Gin</td><td>Asp 220</td><td>Pro</td><td>His</td><td>Cheese</td><td>Trp</td>

<td>own 225</td><td>Cheese</td><td>Cheese</td><td>phe</td><td>Tyr</td><td>Arg 230</td><td>Leu</td><td>Arg</td><td>phe</td><td>Glu</td><td>Leu 235</td><td>Arg</td><td>Tyr</td><td>Arg</td><td>ala</td><td>Glu 240</td>

<td>Arg</td><td>Cheese</td><td>lys</td><td>Thr</td><td>phe 245</td><td>Thr</td><td>Thr</td><td>Trp</td><td>Underworld</td><td>val 250</td><td>lys</td><td>Asp</td><td>Leu</td><td>Gin</td><td>His 255</td><td> His</td>

<td>Cys</td><td>val</td><td>How much</td><td>His 260</td><td>Asp</td><td>ala</td><td>Trp</td><td>Cheese</td><td>Gly 265</td><td>Leu</td><td>Arg</td><td>His</td><td>val</td><td>val 270</td><td>Gin</td><td>Leu</td>

<td>Arg</td><td>ala</td><td>Gin 275</td><td>Glu</td><td>Glu</td><td>phe</td><td>Gly</td><td>Gin 260</td><td>gly</td><td>Glu</td><td>Trp</td><td>Cheese</td><td>Glu 285</td><td>Trp</td><td>Cheese</td><td>Pro</td>

<td>Glu own 305</td><td>ala 290 Glu</td><td>Underworld val</td><td>Gly Cheese</td><td>Thr Thr</td><td>Pro Pro 310</td><td>Trp 295 Thr</td><td>Thr</td><td>Glu</td><td>Cheese</td><td>Arg</td><td>Cheese 300</td><td>Pro</td><td>Pro</td><td>ala</td><td>Glu</td>

PZ / 1778AGR

EP 2 374 818 B1

Contents138

97 members in 39 offices

This recordMember, by publication datePriority claim29 more offices are in the list below

Priority claims3

Priority claims
Document	Office	Kind	Date
81066406	United States of America	P	2006-06-02
84323206	United States of America	P	2006-09-08
07777380	European Patent Office (EPO)	A	2007-06-01

Members97

Family members, oldest first
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US2007280945A1	United States of America	A1	2007-12-06
AU2007254831A1	Australia	A1	2007-12-13
CA2652976A1	Canada	A1	2007-12-13
WO2007143168A2	World Intellectual Property Organization (WIPO)	A2	2007-12-13
WO2007143168A3	World Intellectual Property Organization (WIPO)	A3	2008-04-24
MX2008014804A	Mexico	A	2009-01-27
ECSP088993A	Ecuador	A	2009-01-30
NO20085309L	Norway	L	2009-03-02
KR20090024690A	Republic of Korea	A	2009-03-09
CR10462A	Costa Rica	A	2009-03-20
EP2041177A2	European Patent Office (EPO)	A2	2009-04-01
MA30535B1	Morocco	B1	2009-06-01
CN101454345A	China	A	2009-06-10
GT200800272A	Guatemala	A	2009-08-21
US7582298B2	United States of America	B2	2009-09-01
SV2008003113A	El Salvador	A	2009-10-27
JP2009539349A	Japan	A	2009-11-19
ZA200809771B	South Africa	B	2009-11-25
TNSN08502A1	Tunisia	A1	2010-04-14
RU2008152443A	Russian Federation	A	2010-07-20
NZ573557A	New Zealand	A	2010-08-27
US2010316627A1	United States of America	A1	2010-12-16
US2010316636A1	United States of America	A1	2010-12-16
HN2008001792A	Honduras	A	2011-03-30
IL195393D0	Israel	D0	2011-08-01
ME00519B	Montenegro	B	2011-10-10
EP2374818A1	European Patent Office (EPO)	A1	2011-10-12
US8043617B2	United States of America	B2	2011-10-25
RU2433138C2	Russian Federation	C2	2011-11-10
EP2041177B1	European Patent Office (EPO)	B1	2011-12-14
AT537190T	Austria	T	2011-12-15
ATE537190T1	Austria	T1	2011-12-15
US8080248B2	United States of America	B2	2011-12-20
US2012003697A1	United States of America	A1	2012-01-05
BRPI0712224A2	Brazil	A2	2012-01-17
US2012045440A1	United States of America	A1	2012-02-23
DK2041177T3	Denmark	T3	2012-02-27
PT2041177E	Portugal	E	2012-03-05
UA97645C2	Ukraine	C2	2012-03-12
AU2007254831B2	Australia	B2	2012-03-22
ES2377579T3	Spain	T3	2012-03-29
SI2041177T1	Slovenia	T1	2012-03-30
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US8183014B2	United States of America	B2	2012-05-22
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US8192741B2	United States of America	B2	2012-06-05
CN102585002A	China	A	2012-07-18
CN101454345B	China	B	2012-08-08
RS52176B	Serbia	B	2012-08-31
PL2041177T3	Poland	T3	2012-09-28
US2012258098A1	United States of America	A1	2012-10-11
MY147468A	Malaysia	A	2012-12-14
EP2374818B1	European Patent Office (EPO)	B1	2012-12-19
DK2374818T3	Denmark	T3	2013-01-21
PT2374818E	Portugal	E	2013-02-13
ES2398076T3	Spain	T3	2013-03-13
SI2374818T1	Slovenia	T1	2013-03-29
HRP20130228T1	Croatia	T1	2013-04-30
PL2374818T3This record	Poland	T3	2013-05-31
US2013157313A1	United States of America	A1	2013-06-20
RS52643B	Serbia	B	2013-06-28
IL195393A	Israel	A	2013-07-31
JP5307708B2	Japan	B2	2013-10-02
US8568721B2	United States of America	B2	2013-10-29
JP2013226143A	Japan	A	2013-11-07
US2014255390A1	United States of America	A1	2014-09-11
US2014255995A1	United States of America	A1	2014-09-11
KR101464502B1	Republic of Korea	B1	2014-12-01
CA2652976C	Canada	C	2015-08-11
JP5805703B2	Japan	B2	2015-11-04
CY1112456T1	Cyprus	T1	2015-12-09
JP2016026171A	Japan	A	2016-02-12
US9308256B2	United States of America	B2	2016-04-12
CY1113708T1	Cyprus	T1	2016-06-22
US2016229916A1	United States of America	A1	2016-08-11
MY159787A	Malaysia	A	2017-01-31
JP6140777B2	Japan	B2	2017-05-31
NO340778B1	Norway	B1	2017-06-19
NO2017060I1	Norway	I1	2017-11-14
LUC00050I1	Luxembourg	I1	2017-11-22
LTPA2017038I1	Lithuania	I1	2017-12-11
HUS1700050I1	Hungary	I1	2017-12-28
LUC00050I2	Luxembourg	I2	2018-01-23
NL300911I2	Netherlands (Kingdom of the)	I2	2018-02-01
US9884916B2	United States of America	B2	2018-02-06
CY2017039I1	Cyprus	I1	2018-04-04
CY2017039I2	Cyprus	I2	2018-04-04
LTC2041177I2	Lithuania	I2	2018-09-10
FR17C1057I1	France	I1	2019-01-11
US2019256606A1	United States of America	A1	2019-08-22
US10584173B2	United States of America	B2	2020-03-10
BRPI0712224B1	Brazil	B1	2020-11-17
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BRPI0712224B8	Brazil	B8	2021-05-25
US11370843B2	United States of America	B2	2022-06-28
US2023094591A1	United States of America	A1	2023-03-30
US2025206829A1	United States of America	A1	2025-06-26