Human anti-b7rp1 neutralizing antibodies

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HUMAN ANTI-B7RPI NEUTRALIZING ANTIBODIES AMGEN, INC. and MEDAREX, INC.C: 64246 WO 2007/011941 PCT/US2006/027862

Human anti-B7RPl Neutralizing Antibodies

This application claims priority to U.S. provisional patent application, SerialNo. 60/700,265, filed July 18, 2005, the disclosure of which is explicitly incorporatedby reference herein.

FIELD OF THE INVENTION

The invention relates to human monoclonal antibodies that bind B7 relatedprotein-1 (B7RP1). Compositions and methods for treating diseases and disordersrelated to immunosuppression and immune activation are also described.

BACKGROUND OF THE INVENTION T-cells initiate the immune response, mediate antigen-specific effectorfunctions, and regulate the activity of other leukocytes by secreting cytokines. For thegeneration of a proper T-lymphocyte (T-cell) immune'response, two signals must beprovided to the T-cell by antigen presenting cells (APC). Antigen must be presentedto the T-cell receptor (TCR) via a major histocompatibility complex (MHC), in anevent that determines specificity. T-cells can only recognize antigen presented on anAPC. In addition to the antigen receptor, proper T-cell activation also requires theinteraction of other cell-surface molecules on both the T-cell and the APC. Thesemolecules, referred to as co-stimulatory molecules, consist of a receptor on theresponding cell and a ligand present on the inducer cell. This antigen independent,co-stimulatory signal must be delivered by engagement of members of the B7 familyon the APC with their receptors on T-cells. A productive immune response leads toproliferation, differentiation, clonal expansion, and effector function. In the absenceof the second, co-stimulatory signal, T-cells undergo a state of long-lasting antigen-specific unresponsiveness, termed anergy. Phase Π clinical experiments havedemonstrated that blocking one co-stimulation pathway is efficacious in the treatmentof psoriasis (Abrams et al., 2000, J Exp Med. 192:681-94: Abrams et al., 1999, J.Clin. Invest. 103:1243-52) and rheumatoid arthritis (Kremer et al, 2003, New 1 WO 2007/011941 PCT/US2006/027862

England Journal of Medicine 349:1907-15). indicating that this general strategy is a good target for immunomodulatory therapy. A particular co-stimulatory B7 molecule, B7 related protein-1 (B7RP1), is atype 1 transmembrane protein with a signal sequence and extracellular domain at the 5 amino-terminus, an extracellular domain comprising two Ig loops, a transmembranedomain, and a carboxy terminal intracellular domain (PCT Application PublicationNo. WO 00/46240). B7RP1 preferentially binds to ICOS (which stands for “induciblecostimulator”; Yoshinga et ai, 2000, Int. Immun. 12:1439-1447) expressed on thecell surface of T-cells. ICOS plays an important role in the production of both type 1 10 and type 2 cytokines by activated T-cells (Coyle et ai, 2000, Immunity 13:95-105). B7RP1 is the sole ligand expressed constitutively on APCs (Yoshinaga et ai,1999, Nature. 402:827-32), while ICOS is expressed only on activated T-cells(McAdam et al, 2000, Journal of Immunology 165:5035-40). B7RP1-dependentsignaling is required for the activation of the effector (i.e. fully activated) T-cell, as 15 well as its maturation from its naive precursor (Dong et ai, 2003, Journal ofAutoimmunity. 21:255-60; Coyle et ai, 2000, Immunity. 11:95-105). Consequently,the B7RP1/ICOS interaction is required for proper T-cell-dependent recall immuneresponses (Dong et ai, 2003, Journal of Autoimmunity. 21:255-60).

Current attempts to interfere with the co-stimulatory T-cell pathway have 20 focused primarily on co-stimulatory polypeptides that block T-cell activation only,but have not focused on activation and maturation. Consequently, these therapiesprovide general inhibition of T-cell function. In contrast, blocking the B7RP1/ICOSinteraction provides a more specific inhibition of T-cell function by affecting onlymature effector T-cells. Thus, blocking the B7RP1/ICOS interaction in a clinical 25 setting is highly desirable because it would provide a more limited side-effect profilethan co-stimulation therapies that block naive T-cell activation only.

SUMMARY OF THE INVENTION

The invention provides monoclonal antibodies that bind to B7 related protein- 30 1 (B7RP1). In one embodiment, the monoclonal antibodies are human monoclonal antibodies that neutralize biological activities of B7RP1 and are particularly useful forinhibiting partially or completely the immune co-stimulatory activity of B7RP1. Also 2 PCT/US2006/027862 WO 2007/011941 provided by the invention are cells, particularly hybridoma cells that produce the monoclonal antibodies of the invention. In particular aspects, the antibodies of the invention bind specifically to the H or D region of B7RP1 as described herein.

The invention further provides fusion proteins comprising the sequence of anantibody Fc region and one or more sequences identified as SEQ ID NO: 1 throughSEQ ID NO. 40. Such molecules can be prepared using methods as described, forexample, in International Patent Application, Publication No. WO 00/24782, which ishereby incorporated by reference. Such molecules can be expressed, for example, inmammalian cells (e.g. Chinese Hamster Ovary cells) or bacterial cells (e.g. E. colicells).

In certain aspects, the invention provides antibodies comprising a heavy chainand a tight chain, wherein the heavy chain comprises an heavy chain constant regionselected from IgGl, IgG2, IgG3, IgG4, IgM, IgA and IgE heavy chain constantregions or any allelic variation thereof (as discussed in Kabat et al., 1991, SEQUENCESof Proteins of Immunological Interest, Fifth Edition, U.S. Department of Healthand Human Services, NIH Publication No. 91-3242), incorporated herein byreference, and the variable region of the heavy chain comprises an amino acidsequence as set forth in any of SEQ ID NO: 7 through SEQ ID NO. 14, or an antigen-binding or an itnmunologically functional immunoglobulin fragment thereof. Anantibody of the invention comprises either an amino acid sequence of the IgG2 heavychain constant region as set forth in SEQ ID NO: 41 or an antigen-binding or animmunologically functional immunoglobulin fragment thereof, or an amino acidsequence of the IgGl heavy chain constant region as set forth in SEQ ID NO: 42 or anantigen-binding or an immunologically functional immunoglobulin fragment thereof.In certain embodiments, the antibodies are monoclonal antibodies, human antibodies,or preferably human monoclonal antibodies.

In certain aspects, the invention provides antibodies comprising a heavy chainand a light chain, wherein the light chain comprises a constant region having anamino acid sequence as set forth in SEQ ED NO: 43 or an antigen-binding or animmunologically functional immunoglobulin fragment thereof, and the light chainvariable region comprises an amino acid sequence as set forth in any of SEQ ID NO: 1 through SEQ ID NO. 6, or an antigen-binding or an immunologically functionalimmunoglobulin fragment thereof. In certain embodiments, the antibodies are 3 PCT/US2006/027862 WO 2007/011941 monoclonal antibodies, human antibodies, or preferably human monoclonalantibodies.

In certain aspects, antibodies of the invention comprise a heavy chain and alight chain, wherein the variable region of the heavy chain comprises an amino acidsequence as set forth in SEQ ID NO: 7 or SEQ ID NO: 8, or an antigen-binding or animmunologically functional immunoglobulin fragment thereof. In other aspects, thelight chain variable region comprises an amino acid sequence as set forth in SEQ IDNO: 1, or an antigen-binding or an immunologically functional immunoglobulinfragment thereof.

In other aspects, antibodies of the invention comprise a heavy chain and a lightchain, wherein the variable region of the heavy chain comprises an amino acidsequence as set forth in SEQ ID NO: 9, or an antigen-binding or an immunologicallyfunctional immunoglobulin fragment thereof. In other aspects, the light chainvariable region comprises an amino acid sequence as set forth in SEQ ID NO: 2, or anantigen-binding or an immunologically functional immunoglobulin fragment thereof.

In additional aspects, the heavy chain comprises at least one complementaritydetermining region (CDR) having an amino acid sequence as set forth in any of SEQID NO: 27 through SEQ ID NO. 40, or an antigen-binding or an immunologicallyfunctional immunoglobulin fragment thereof. In still further aspects, the light chaincomprises at least one CDR having an amino acid sequence as set forth in any of SEQID NO: 15 through SEQ ED NO. 26, or an antigen-binding or an immunologicallyfunctional immunoglobulin fragment thereof.

The invention also provides antibodies that bind specifically to B7RP1,wherein the heavy chain comprises a variable region comprising an amino acidsequence as set forth in SEQ ID NO: 7 or SEQ ID NO: 8, or an antigen-binding or animmunologically functional immunoglobulin fragment thereof, and the light chaincomprises a variable region comprising an amino acid sequence as set forth in SEQID NO: 1, or an antigen-binding or an immunologically functional immunoglobulinfragment thereof.

In addition, the invention provides antibodies that bind specifically to B7RP1,wherein the heavy chain comprises a variable region comprising an amino acidsequence as set forth in SEQ ID NO: 9, or an antigen-binding or an immunologically 4 WO 2007/011941 PCT/US2006/027862 functional immunoglobulin fragment thereof, and the light chain comprises a variableregion comprising an amino acid sequence as set forth in SEQ ID NO: 2, or anantigen-binding or an immunologically functional immunoglobulin fragment thereof.

In certain aspects, the invention also provides antibodies, comprising a heavychain and a light chain, wherein the heavy chain comprises a heavy chain variableregion, and wherein the heavy chain variable region comprises a sequence that has atleast about 75%, at least about 80%, at least about 85%, at least about 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% identity to the aminoacid sequence as set forth in any of SEQ ID NO: 7 through SEQ ID NO. 14, andwherein the light chain comprises a light chain variable region, and wherein the lightchain variable region comprises a sequence that has at least about 80%, at least about85%, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at leastabout 99% identity to the amino acid sequence as set forth in any of SEQ ID NO: 1through SEQ ID NO. 6, wherein the antibody binds specifically to B7RP1.

The invention also provides antibodies that bind specifically to B7RP1,wherein the heavy chain comprises an amino acid sequence as set forth in SEQ IDNO: 44 or SEQ ID NO: 46, or an antigen-binding or an immunologically functionalimmunoglobulin fragment thereof, and the light chain comprises an amino acidsequence as set forth in SEQ ID NO: 45, or an antigen-binding or an immunologicallyfunctional immunoglobulin fragment thereof.

The invention also provides antibodies that bind specifically to B7RP1,wherein the heavy chain comprises an amino acid sequence as set forth in SEQ IDNO: 47, or an antigen-binding or an immunologically functional immunoglobulinfragment thereof; and the light chain comprises an amino acid sequence as set forth inSEQ ID NO: 48, or an antigen-binding or’ an immunologically functionalimmunoglobulin fragment thereof

In certain aspects, the invention provides antibodies, comprising a heavy chainand a light chain, wherein the heavy chain comprises a heavy chain variable region,and wherein the heavy chain variable region comprises at least one CDR having asequence that has at least about 75%, at least about 80%, at least about 85%, at leastabout 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99%identity to the amino acid sequence as set forth in any of SEQ ID NO; 27 through 5 WO 2007/011941 PCT/US2006/027862 SEQ ID NO. 40, and wherein the light chain comprises a light chain variable region,and wherein the light chain variable region comprises at least one CDR having anamino acid sequence that has as least about 80%, at least about 85%, at least about90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least about 99% identity tothe amino acid sequence as set forth in SEQ ID NO: 15 through SEQ ID NO. 26,wherein the antibody binds specifically to B7RP1.

The invention also provides single chain antibodies, single chain Fvantibodies, F(ab) antibodies, F(ab)’ antibodies and (Fab’)2 antibodies.

In particular aspects, the invention provides a light chain comprising an aminoacid sequence as set forth in SEQ ID NO: 15 through SEQ ID NO. 26, or an antigen-binding or an immunologically functional immunoglobulin fragment thereof.

In addition, the invention provides a heavy chain comprising an amino acidsequence as set forth in any of SEQ ID NO: 27 through SEQ ID NO. 40, or anantigen-binding or an immunologically functional immunoglobulin fragment thereof.

The invention also relates to isolated human antibodies that specifically bindB7RP1, wherein the antibody comprises: (a) human heavy chain framework regions, ahuman heavy chain CDR1 region, a human heavy chain CDR2 region, and a humanheavy chain CDR3 region; and (b) human light chain framework regions, a humanlight chain CDR1 region, a human light chain CDR2 region, and a human light chainCDR3 region. In certain aspects, the human heavy chain CDR1 region can be theheavy chain CDR1 region as shown in any of SEQ ID NO: 27, 30, or 35 and thehuman light chain CDR1 region can be the light chain CDR1 region shown in any ofSEQ ID NO: 15, 18, or 24. In other aspects, the human heavy chain CDR2 region canbe the heavy chain CDR2 region as shown in any of SEQ ID NO: 28, 31, 33, 36, or39, and the human light chain CDR2 region can be the light chain CDR2 as shown inany of SEQ ID NO: 16,19, or 21. In still other aspects, the human heavy chain CDR3region is the heavy chain CDR3 region as shown in any of SEQ ID NO: 29, 32, 34,37, 38 or 40, and the human light chain CDR3 region is the light chain CDR3 regionas shown in any of SEQ ID NO: 17, 20,22,23, 25, or 26.

The antibodies of the invention are characterized by the ability to bindspecifically to B7RP1. Furthermore, antibodies of the invention have the capacity toantagonize at least one in vitro and/or in vivo activity associated with B7RP1 6 WO 2007/011941 PCT/US2006/027862 polypeptides. The invention provides isolated anti-human B7RP1 human antibodieswith high affinity binding to B7RP1 polypeptides, wherein the antibodies bind to ahuman B7RP1 polypeptide and dissociates from the human B7RP1 polypeptide with adissociation constant (Ko) of about ΙΟ"6 Μ, ΙΟ'7 Μ, 10'8 M, 10‘9 M, 10“10 Μ, 10"11 M,10"12 M, or less, as determined using KinExA, or which inhibit B7RP1 inducedsurvival in an in vitro neutralization assay with an EC50 of about I O’6 Μ, 10*7 Μ, 10'8Μ, 10'9M, 10-’°M, 10‘nM, 1042 M, or less.

The invention also provides isolated human antibodies or an antigen-bindingor immunologically functional immunoglobulin fragments thereof that bindspecifically to B7RP1, wherein the antibodies or fragments comprise a heavy chainvariable region comprising a heavy chain CDR1, CDR2, and CDR3, wherein:

a) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 27, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 28, and the heavy chain CDR 3 has an amino acid sequence asset forth in SEQ ID NO: 29;

b) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 30, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 31, and the heavy chain CDR 3 has an amino acid sequence asset forth in SEQ ID NO: 32;

c) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 27, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 33, and the heavy chain CDR 3 has an amino acid sequence asset forth in SEQ ID NO: 34;

d) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 35, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 36, and the heavy chain CDR 3 has an amino acid sequence asset forth in SEQ ID NO: 37;

e) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 27, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 33, and the heavy chain CDR 3 has an amino acid sequence asset forth in SEQ ID NO: 38; or 7 WO 2007/011941 PCT/US2006/027862

1) the heavy chain CDR1 has an amino acid sequence as set forth in SEQ ID NO: 35, the heavy chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 39, and the heavy chain CDR 3 has an amino acid sequence as set forth in SEQ ID NO: 40.

The invention also provides an isolated human antibody or an antigen-bindingor an immunologically functional immunoglobulin fragment thereof that bindsspecifically to B7RP1, wherein the antibody or fragment comprises a light chainvariable region comprising a light chain CDR1, CDR2, and CDR3, wherein:

a) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 15, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 16, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ID NO: 17;

b) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 18, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 19, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ID NO: 20;

c) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 15, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 21, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ID NO: 22;

d) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 18, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 19, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ID NO: 23;

e) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 24, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 16, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ED NO: 25; or

f) the light chain CDR1 has an amino acid sequence as set forth in SEQ ID

NO: 24, the light chain CDR2 has an amino acid sequence as set forth in SEQ ID NO: 16, and the light chain CDR 3 has an amino acid sequence as set forthin SEQ ID NO: 26. 8 WO 2007/011941 PCT/US2006/027862

The invention also provides antibodies that compete with binding of theantibodies described herein to B7RP1. In certain aspects, a competitive antibody ofthe invention competes with binding of an antibody that comprises any of SEQ IDNO: 1-40 to human B7RPL

Also part of the invention are polynucleotide sequences that encode anti-human B7RP1 human antibodies, vectors comprising the polynucleotide sequencesencoding anti-human B7RP1 human antibodies, host cells transformed with vectorsincorporating polynucleotides that encode anti-human B7RP1 human antibodies,formulations comprising anti-human B7RP1 human antibodies and methods ofmaking and using same.

The invention also provides methods for detecting B7RP1 in a biologicalsample, comprising the step of contacting the sample with an antibody of theinvention or antigen-binding fragment thereof. An anti-B7RPl antibody of theinvention may be employed in any known assay method, such as competitive bindingassays, direct and indirect sandwich assays, immunoprecipitation assays and enzyme-linked immunosorbent assays (ELISA) (See, Sola, 1987, Monoclonal Antibodies: AManual of Techniques, pp. 147-158, CRC Press, Inc.) for the detection andquantitation of B7RP1. The antibodies can bind B7RP1 with an affinity that isappropriate for the assay method being employed.

In addition, the invention provides methods for treating a disease associatedwith increased production of B7RP1, increased sensitivity to B7RP1, and/or diseasesrelated to control of T-cell responses, comprising the step of administering apharmaceutically effective amount of a pharmaceutical composition comprising atleast one antibody of the invention or an antigen-binding or an immunologicallyfunctional immunoglobulin fragment thereof to an individual in need thereof.

Embodiments of the invention will become evident from the followingdetailed description and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure IA depicts the 16H antibody variable region sequence (SEQ ID NO: 7)and the corresponding 16H variable region germline (16Hg) sequence (SEQ ID NO:8). 9 WO 2007/011941 PCT/US2006/027862

Figure IB depicts results of co-stimulation assays using anti-CD3 andhB7RPl-Fc fusion protein demonstrating that 16Hg retains its biological activitiescompared with 16H.

Figure 2 shows the results of Biacore® binding assays with 16H, 16Hg, and5 5D antibodies.

Figure 3 shows the results of KinExA binding assay with 5D antibody.

Figure 4 shows the results of KinExA binding assay with 2H antibody.

Figure 5 shows the results of KinExA binding assay with 2H germline (2Hg)antibody.

10 Figure 6 depicts the results of binding-competition assays showing that 16H antibody competes away binding of ICOS-Fc on B7RP-1, analyzed by flowcytometry.

Figure 7 depicts a summary of a B7RP-1 single nucleotide polymorphism(SNP) analysis. 15 Figure 8 depicts a summaiy of the analysis of a set of anti-human B7RP-1 monoclonal antibodies in ELISA competition assays. Values shown are IC50S forinhibition of binding of an ICOS-Fc fusion protein.

Figure 9A shows fluorescent staining of B7RP1 extracellular domain (ECD)with labeled 16H, 5D, and ICOS antibodies. 20 Figure 9B shows similar binding efficacy of 16H and 5D antibodies to a B7RP1 SNP variant.

Figure 9C depicts the results of co-stimulation assays with 16H or 5Dantibodies and SNP variants.

Figure 10A shows plate co-stimulation assay results with 1Β7ν2 monoclonal 25 antibodies compared with a number of different anti-murine B7RP-1 monoclonalantibodies.

Figures 10B, 10C, and 10D show the results of antigen challenge experiments,analyzed for antigen-specific serum IgM (Figure 10B), IgG2a (Figure 10C), and IgGl(Figure 10D), 10 WO 2007/011941 PCT/US2006/027862

Figure 11 depicts ELISA results demonstrating that serum IL-5 levels are repressed by 1B7v2 antibodies.

Figure 12A shows that 16H antibodies can bind to cynomolgus monkeyB7RP1 (right panel) and human B7KP1 (left panel).

Figure 12B shows that 16H, 16Hg, and 5D antibodies can inhibit cynomolgusmonkey B7RPl/ICOS-dependent T cell activation.

Figure 13A depicts individual cynomolgus monkey and group mean titervalues at day 53 and day 57 after secondary challenge with tetanus toxoid on day 42in animals treated with 16H antibodies.

Figure 13B depicts individual cynomolgus monkey and group mean titervalues at day 53 and day 57 after secondary challenge with tetanus toxoid on day 42in animals treated with 5D antibodies.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The section headings used herein are for organizational purposes only and arenot to be construed as limiting the subject matter described. All references cited inthis application are expressly incorporated by reference herein for any purpose.

Definitions

Conventional techniques may be used for recombinant DNA, oligonucleotidesynthesis, and tissue culture and transformation (e.g., electroporation, lipofection).Enzymatic reactions and purification techniques may be performed according tomanufacturer's specifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures may be generally performedaccording to methods well known in the art and as described in various general andmore specific references that are cited and discussed throughout the presentspecification. See e.g., Sambrook et ai, 2001, Molecular Cloning: ALABORATORY manual, 3d ed., Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y., which is incorporated herein by reference for any purpose. Unlessspecific definitions are provided, the nomenclature utilized in connection with, andthe laboratory procedures and techniques of, analytical chemistry, synthetic organic 11 PCT/US2006/027862 WO 2007/011941 chemistry, and medicinal and pharmaceutical chemistry described herein are thosewell known and commonly used in the art. Similarly, conventional techniques maybe used for chemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients.

As utilized in accordance with the present disclosure, the following terms,unless otherwise indicated, shall be understood to have the following meanings. Thephrases “biological property”, “biological characteristic”, and the term “activity” inreference to an antibody of the present invention are used interchangeably herein andinclude, but are not limited to, epitope affinity and specificity (e.g., anti-humanB7RP1 human antibody binding to human B7RP1), ability to antagonize the activityof the targeted polypeptide (e.g., B7RP1 activity), the in vivo stability of the antibody,and the immunogenic properties of the antibody. Other identifiable biologicalproperties or characteristics of an antibody recognized in the art include, for example,cross-reactivity, (/. e., with non-human homologs of B7RP1, or with other proteins ortissues, generally), and ability to preserve high expression levels of protein inmammalian cells. The aforementioned properties or characteristics can be observedor measured using art-recognized techniques including, but not limited to ELISA,competitive ELISA, surface plasmon resonance analysis, in vitro and in vivoneutralization assays (e.g., Example 2), and immunohistochemistry with tissuesections from different sources including human, primate, or any other appropriatesource. Particular activities and biological properties of anti-human B7RP1 humanantibodies are described in further detail in the Examples below.

The term "isolated polynucleotide" as used herein shall mean a polynucleotideof genomic DNA, cDNA, RNA, or synthetic origin or some combination thereof,which by virtue of its origin the isolated polynucleotide (1) is not associated with allor a portion of a polynucleotide with which the isolated polynucleotide is found innature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) doesnot occur in nature as part of a larger sequence.

The term "polynucleotide" as referred to herein means single-stranded ordouble-stranded nucleic acid polymers of at least 10 nucleotides in length. In certainembodiments, the nucleotides comprising the polynucleotide can be ribonucleotidesor deoxyribonucleotides or a modified form of either type of nucleotide. Saidmodifications include base modifications such as bromuridine, ribose modifications 12 WO 2007/011941 PCT/US2006/027862 such as arabinoside and 2,,3’-dideoxyribose and internucleotide linkage modificationssuch as phosphorothioate, phosphorodithioate, phosphoroselenoate,phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate andphosphoroamidate. The term "polynucleotide" specifically includes single and doublestranded forms of DNA or RNA.

The term "oligonucleotide" referred to herein includes naturally occurring, andmodified nucleotides linked together by naturally occurring, and/or non-naturallyoccurring oligonucleotide linkages. Oligonucleotides are a polynucleotide subsetcomprising members that are generally single-stranded and have a length of 200nucleotides or fewer. In certain embodiments, oligonucleotides are 10 to 60nucleotides in length. In certain embodiments, oligonucleotides are 12,13,14,15,16,17,18,19, or 20 to 40 nucleotides in length. Oligonucleotides may be single strandedor double stranded, e.g. for use in the construction of a genetic mutant.Oligonucleotides of the invention may be sense or antisense oligonucleotides withreference to a protein-coding sequence.

The term "naturally occurring nucleotides" includes deoxyribonucleotides andribonucleotides. The term "modified nucleotides" includes nucleotides with modifiedor substituted sugar groups and the like. The term "oligonucleotide linkages" includesoligonucleotide linkages such as phosphorothioate, phosphorodithioate,phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate,phosphoroamidate, and fee like. See, e.g., LaPlanche et al., 1986, Nitcl Acids Res.,14:9081; Stec et al., 1984, J. Am. Chem, Soc., 106:6077: Stein et al, 1988, NttclAcids Res., 16:3209; Zon et al, 1991, Anti-Cancer Drug Design, 6:539; Zon et al,1991, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, pp. 87-108 (F.Eckstein, Ed.), Oxford University Press, Oxford England; Stec et al, U.S. Pat. No.5,151,510; Uhlmann and Peyman, 1990, Chemical Reviews, 20:543, the disclosures ofwhich are hereby incorporated by reference for any purpose. An oligonucleotide caninclude a detectable label to enable detection of the oligonucleotide or hybridizationthereof.

The term “isolated protein” referred to herein means that a subject protein (1)is free of at least some other proteins with which it would be found in nature, (2) isessentially free of other proteins from the same source, e.g., from the same species,(3) is expressed by a cell from a different species, (4) has been separated from at least 13 PCT/US2006/027862 WO 2007/011941 about 50 percent of polynucleotides, lipids, carbohydrates, or other materials withwhich it is associated in nature, (5) is not associated (by covalent or noncovalentinteraction) with portions of a protein with which the “isolated protein” is associatedin nature, (6) is operably associated (by covalent or noncovalent interaction) with apolypeptide with which it is not associated in nature, or (7) does not occur in nature.Such an isolated protein can be encoded by genomic DNA, cDNA, mRNA or otherRNA, of synthetic origin, or any combination thereof. In one embodiment, theisolated protein is substantially free from proteins or polypeptides or othercontaminants that are found in its natural environment that would interfere with itsuse (therapeutic, diagnostic, prophylactic, research or otherwise).

An “isolated” antibody is one that has been identified and separated and/orrecovered from a component of its natural environment. Contaminant components ofits natural environment are materials that would interfere with diagnostic ortherapeutic uses for the antibody, and may include enzymes, hormones, and otherproteinaceous or non-proteinaceous substances. In certain embodiments, the antibodyis purified (1) to greater than 95% or greater than 99% by weight of antibody asdetennined by the Lowry method, (2) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of a spinning cupsequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducingconditions using Coomassie blue or silver stain. Isolated antibody includes theantibody in situ within recombinant cells since at least one component of theantibody’s natural environment will not be present.

The terms "polypeptide" or “protein” means molecules having the sequence ofnative proteins, that is, proteins produced by naturally-occurring and specifically non-recombinant cells, or genetically-engineered or recombinant cells, and comprisemolecules having the amino acid sequence of the native protein, or molecules havingdeletions from, additions to, and/or substitutions of one or more amino acids of thenative sequence. The terms “polypeptide” and “protein” specifically encompass anti-B7RP1 antibodies, or sequences that have deletions from, additions to, and/orsubstitutions of one or more amino acid of an anti- B7RP1 antibody.

The term "polypeptide fragment" refers to a polypeptide that has an amino-terminal deletion, a carboxyl-terminal deletion, and/or an internal deletion. In certainembodiments, fragments are at least 5 to about 500 amino acids long. It will be 14 WO 2007/011941 PCT/US2006/027862 appreciated that in certain embodiments, fragments are at least 5, 6, 8,10, 14, 20, 50,70, 100, 110, 150, 200, 250, 300, 350, 400, or 450 amino acids long. Particularlyuseful polypeptide fragments include functional domains, including binding domainsparticularly antigen-binding domains, especially wherein the antigen is an epitope ofhuman B7RP1. In the case of an anti-B7RPl antibody, useful fragments include butare not limited to a CDR region, a variable domain of a heavy or light chain, a portionof an antibody chain or just its variable region including two CDRs, and the like.

The term “specific binding agent” refers to a naturally occurring or non-naturally occurring molecule that specifically binds to a target. Examples of specificbinding agents include, but are not limited to, proteins, peptides, nucleic acids,carbohydrates, and lipids. In certain embodiments, a specific binding agent is anantibody.

The term “specific binding agent to B7RP1” refers to a specific binding agentthat specifically binds any portion of B7RP1. In certain embodiments, a specificbinding agent to B7RPI is an antibody that binds specifically to B7RP1.

By way of example, an antibody “binds specifically” to a target if theantibody, when labeled, can be competed away from its target by the correspondingnon-labeled antibody.

The term “immunologically functional immunoglobulin fragment” as usedherein refers to a polypeptide fragment that contains at least the CDRs of theimmunoglobulin heavy and light chains. An immunologically functionalimmunoglobulin fragment of the invention is capable of binding to an antigen. Incertain embodiments, the antigen is a ligand that specifically binds to a receptor. Inthese embodiments, binding of an immunologically functional immunoglobulinfragment of the invention prevents binding of the ligand to its receptor, interruptingthe biological response resulting from ligand binding to the receptor. In oneembodiment, an immunologically functional immunoglobulin fragment of theinvention binds specifically to B7EP1. Preferably, the fragment binds specifically tohuman B7RP1.

The term “naturally-occurring” or “native” as used herein and applied to anobject refers to the fact that the object can be found in nature. For example, apolypeptide or polynucleotide sequence that is present in an organism (including 15 WO 2007/011941 PCT/US2006/027862 viruses) that can be isolated from a source in nature and that has not beenintentionally modified by man is naturally-occurring. The term “non-naturallyoccurring” or “non-native” as used herein refers to a material that is not found innature or that has been structurally modified or synthesized by man. For example, 5 “non-naturally occurring” can refer to a variant, such as a polynucleotide variant thatcan be produced using art-known mutagenesis techniques, or a polypeptide variantproduced by such a polynucleotide variant. Such variants include, for example, thoseproduced by nucleotide substitutions, deletions or additions that may involve one ormore nucleotides. Polynucleotide variants can be altered in coding or non-coding 10 regions or both. Alterations in the coding regions may produce conservative or non-conservative amino acid substitutions, deletions, or additions. Especially certainamong these are silent substitutions, additions, deletions, and conservativesubstitutions, which do not alter the properties and activities of a B7RP1 antibody ofthe invention. One of skill in the art can readily determine how to generate such a 15 variant using methods well known in the art.

The term "operably linked" means that the components to which the term isapplied are in a relationship that allows them to carry out their inherent functionsunder suitable conditions. For example, a control sequence "operably linked" to aprotein coding sequence is ligated thereto so that expression of the protein coding 20 sequence is achieved under conditions compatible with the transcriptional activity ofthe control sequences.

The term "control sequence" as used herein refers to polynucleotide sequencesthat can effect expression, processing or intracellular localization of coding sequencesto which they are operably linked. The nature of such control sequences may depend 25 upon the host organism. In particular embodiments, control sequences forprokaryotes may include a promoter, ribosomal binding site, and transcriptiontermination sequence. In other particular embodiments, control sequences foreukaryotes may include promoters comprising one or a plurality of recognition sitesfor transcription factors, transcription enhancer sequences, transcription termination 30 sequences and polyadenylation sequences. In certain embodiments, "controlsequences” can include leader sequences and/or fusion partner sequences.

The term "vector" includes a nucleic acid molecule capable of canying into acell another nucleic acid to which it has been linked. One type of vector is a 16

I WO 2007/011941 PCT/US2006/027862 "plasmid", which refers to a circular double stranded DNA loop into which additionalDNA segments may be ligated. Another type of vector is a viral vector, whereinadditional DNA segments may be ligated into the viral genome. Certain vectors arecapable of autonomous replication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomal mammalianvectors). Other vectors (e.g., non-episomal mammalian vectors) can be integratedinto the genome of a host cell upon introduction into the host cell and thereby arereplicated along with the host genome. Moreover, certain vectors are capable ofdirecting the expression of genes to which they are operatively linked. Such vectorsare referred to herein as "recombinant expression vectors" (or simply, "expressionvectors"). In general, expression vectors useful in the practice of recombinant DNAtechniques are often in the form of plasmids. In the present specification, "plasmid"and "vector" may be used interchangeably as the plasmid is the most commonly usedform of vector. However, the invention is intended to include such other forms ofexpression vectors, such as viral vectors (e.g., replication defective retroviruses,adenoviruses and adeno-associated viruses), which serve equivalent functions.

The phrase "recombinant host cell" (or simply "host cell") includes a cell intowhich a recombinant expression vector has been introduced. It will be understood bythose of skill in the art that such terms are intended to refer not only to the particularsubject cell but to the progeny of such a cell. Because certain modifications mayoccur in succeeding generations due to either mutation or environmental influences,such progeny may not, in fact, be identical to the parent cell, but are still includedwithin the scope of the term "host cell" as used herein. A wide variety of hostexpression systems can be used to express the antibodies of the present inventionincluding bacterial, yeast, baculoviral and mammalian expression systems (as well asphage display expression systems). An example of a suitable bacterial expressionvector is pUC19, To express an antibody recombinantly, a host cell is transfectedwith one or more recombinant expression vectors carrying DNA fragments encodingthe immunoglobulin light and heavy chains of the antibody such that the light andheavy chains are expressed in the host cell and can be secreted into the medium inwhich the host cells are cultured, from which medium the antibodies can berecovered. Standard recombinant DNA methodologies are used to obtain antibodyheavy and light chain genes, incorporate these genes into recombinant expression 17 PCT/US2006/027862 WO 2007/011941 vectors and introduce the vectors into host cells, such as those described in Sambrook et a!., 2001, MOLECULAR CLONING, A LABORATORY manual, Cold Spring Harbor

Laboratories, Ausubel, F.M. et al. (eds.), Current Protocols in Molecular

Biology, Greene Publishing Associates, (1989) and in U.S. Patent No. 4,816,397 to

Boss et al.

The term “transduction” is used to refer to the transfer of genes from onebacterium to another, usually by a phage. “Transduction” also refers to theacquisition and transfer of eukaryotic cellular sequences by retroviruses.

The term “transfection” is used to refer to the uptake of foreign or exogenousDNA by a cell, and a cell has been “transfected” when the exogenous DNA has beenintroduced inside the cell membrane, A number of transfection techniques are wellknown in the art and are disclosed herein. See, e.g., Graham et al., 1973, Virology 52:456; Sambrook et al., 2001, molecular cloning, a laboratory MANUAL, ColdSpring Harbor Laboratories; Davis et al., 1986, BASIC METHODS IN MOLECULARBIOLOGY, Elsevier; and Chu et al., 1981, Gene 13: 197. Such techniques can be usedto introduce one or more exogenous DNA moieties into suitable host cells.

The term “transformation” as used herein refers to a change in a cell’s geneticcharacteristics, and a cell has been transformed when it has been modified to contain anew DNA. For example, a cell is transformed where it is genetically modified fromits native state. Following transfection or transduction, the transforming DNA mayrecombine with DNA from the cell by physically integrating into a chromosome ofthe cell, or may be maintained transiently as an episomal element without beingreplicated, or may replicate independently as a plasmid. A cell is considered to havebeen stably transformed when the DNA is replicated with the division of the cell.

The term “antigen” refers to a molecule or a portion of a molecule capable ofbeing bound by a selective binding agent, such as an antibody, and additionallycapable of being used in an animal to produce antibodies capable of binding to anepitope of that antigen. An antigen may have one or more epitopes.

In certain embodiments, antibody variants include glycosylation variantswherein the number and/or type of glycosylation site has been altered compared to theamino acid sequences of the parent polypeptide. In certain embodiments, proteinvariants comprise a greater or a lesser number of N-linked glycosylation sites than the 18 PCT/US2006/027862 WO 2007/011941 native protein. An N-linked glycosylation site is characterized by the sequence: Asn-Xaa-Ser or Asn-Xaa-Thr, wherein the amino acid residue designated as Xaa may beany amino acid residue except proline. The substitution of amino acid residues tocreate this sequence provides a potential new site for the addition of an N-linkedcarbohydrate chain. Alternatively, substitutions that eliminate this sequence willremove an existing N-linked carbohydrate chain. Also provided is a rearrangement ofN-linked carbohydrate chains wherein one or more N-linked glycosylation sites(typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional antibody variants include cysteine variantswherein one or more cysteine residues are deleted from or substituted for anotheramino acid (e.g., serine) compared to the parent amino acid sequence. Cysteinevariants may be useful when antibodies must be refolded into a biologically activeconformation such as after the isolation of insoluble inclusion bodies. Cysteinevariants generally have fewer cysteine residues than the native protein, and typicallyhave an even number to minimize interactions resulting from unpaired cysteines.

In additional embodiments, antibody variants can include antibodiescomprising a modified Fc fragment or a modified heavy chain constant region. An Fcfragment, which stands for “fragment that crystallizes,” or a heavy chain constantregion can be modified by mutation to confer on an antibody altered bindingcharacteristics. See, for example, Burton and Woof, 1992, Advances in Immunology51: 1-84; Ravetch and Bolland, 2001, Annu. Rev. Immunol. 12: 275-90; Shields et al.,2001, Journal of Biol. Chem 276: 6591-6604; Telleman and Junghans, 2000,Immunology 100: 245-251; Medesan et al., 1998, Eur. J. Immunol. 28: 2092-2100; allof which are incorporated herein by reference). Such mutations can includesubstitutions, additions, deletions, or any combination thereof, and are typicallyproduced by site-directed mutagenesis using one or more mutagenicoligonucleotide(s) according to methods described herein, as well as according tomethods known in the art (see, for example, Sambrook et al., MOLECULAR CLONING: ALABORATORY MANUAL, 3rd Ed., 2001, Cold Spring Harbor, N.Y.and Berger andKimmel, methods in enzymology, Volume 152, Guide to Molecular CloningTechniques, 1987, Academic Press, Inc., San Diego, CA., which are incorporatedherein by reference). 19 WO 2007/011941 PCT/US2006/027862

According to certain embodiments, amino acid substitutions may (1) reducesusceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter bindingaffinity, and/or (4) confer or modify other physicochemical or functional properties onsuch polypeptides. According to certain embodiments, single or multiple amino acid 5 substitutions (in certain embodiments, conservative amino acid substitutions) may bemade in the naturally occurring sequence (in certain embodiments, in the portion ofthe polypeptide outside the domain(s) forming intermolecular contacts). In certainembodiments, a conservative amino acid substitution typically does not substantiallychange the structural characteristics of the parent sequence (e.g., a replacement amino 10 acid should disrupt or tend to disrupt secondary structure that characterizes a parentsequence, such as a helix). Examples of art-recognized polypeptide secondaiy andtertiary structures are described in PROTEINS, STRUCTURES AND MOLECULARPRINCIPLES, (Creighton, Ed.), 1984, W. H. Freeman and Company, New York;introduction το protein structure (C. Branden and J. Tooze, eds.), 1991, 15 Garland Publishing, New York, N.Y.; and Thornton et al., 1991, Nature 354:105.each of which are incorporated herein by reference.

"Antibody" or "antibody peptide(s)" refer to an intact antibody, or a bindingfragment thereof that competes with the intact antibody for specific binding. Incertain embodiments, binding fragments are produced by recombinant DNA 20 techniques. In additional embodiments, binding fragments are produced by enzymaticor chemical cleavage of intact antibodies. Binding fragments include, but are notlimited to, F(ab), F(ab’), F(ab% Fv, and single-chain antibodies.

The invention provides antibodies that comprise a heavy chain and a lightchain, wherein the heavy and light chains together form an antigen binding structure 25 capable of specifically binding B7RP1. A full-length heavy chain includes a variableregion domain, Vh, and three constant region domains, ChI, Ch2, and Ch3. The Vhdomain is at the amino-terminus of the polypeptide, and the Ch3 domain is at thecarboxyl-terminus. The term “heavy chain”, as used herein, encompasses a full-length heavy chain and fragments thereof. A full-length light chain includes a 30 variable region domain, Vl, and a constant region domain, Cl. Like the heavy chain,the variable region domain of the light chain is at the amino-terminus of thepolypeptide. The term “light chain”, as used herein, encompasses a full-length lightchain and fragments thereof. A F(ab) fragment is comprised of one light chain and 20 PCT/US2006/027862 WO 2007/011941 the ChI and variable regions of one heavy chain, The heavy chain of a F(ab)molecule cannot form a disulfide bond with another heavy chain molecule. A F(ab’)fragment contains one light chain and one heavy chain that contains more of theconstant region, between the CrI and CH2 domains, such that an interchain disulfidebond can be formed between two heavy chains to form a F(ab’)2 molecule. The Fvregion comprises the variable regions from both the heavy and light chains, but lacksthe constant regions. Single-chain antibodies are Fv molecules in which the heavyand light chain variable regions have been connected by a flexible linker to form asingle polypeptide chain, which forms an antigen-binding region. Single chainantibodies are discussed in detail in International Patent Application Publication No.WO 88/01649 and U.S. Patent Nos. 4,946,778 and 5,260,203. A bivalent antibody other than a "multispecific" or "multifunctional" antibody,in certain embodiments, is understood to comprise binding sites having identicalantigenic specificity.

In assessing antibody binding and specificity according to the invention, anantibody substantially inhibits adhesion of a ligand to a receptor when an excess ofantibody reduces the quantity of ligand bound to receptor by at least about 20%, 40%,60%, 80%, 85%, or more (as measured, inter alia, using an in vitro competitivebinding assay).

By “neutralizing antibody” is meant an antibody molecule that is able to blockor substantially reduce an effector function of a target antigen to which it binds.Accordingly, a “neutralizing” anti-B7RPl antibody is capable of blocking orsubstantially reducing an effector function, such as receptor binding and/or elicitationof a cellular response, of B7RP1. “Substantially reduce” is intended to mean at leastabout 60%, at least about 70%, at least about 75%, at least about 80%, at least about85%, or at least about 90% reduction of an effector function of the target antigen (e.g.,human B7RP1).

The term "epitope" includes any site on an antigen that is capable of specific ·binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitopedeterminants include chemically active surface groupings of molecules such as aminoacids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certainembodiments, may have specific three-dimensional structural characteristics, and/or 21 WO 2007/011941 PCT/US2006/027862 specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody. In certain embodiments, an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In certain embodiments, an antibody is said to 5 specifically bind an antigen when the equilibrium dissociation constant is about 10"6M, 1(T7Μ, IO'8 M, 10'9M, 10"loM, ΙΟ'11 Μ, 10'12 M, or less than about 10*12M.

An antibody binds “essentially the same epitope” as a reference antibody,when the two antibodies recognize identical or sterically overlapping epitopes. Themost widely used and rapid methods for determining whether two antibodies bind to 10 identical or sterically overlapping epitopes are competition assays, which can beconfigured in all number of different formats, using either labeled antigen or labeledantibody. Usually, the antigen is immobilized on a substrate, and the ability ofunlabeled antibodies to block the binding of labeled antibodies is measured usingradioactive isotopes or enzyme labels. 15 The term "agent" is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biologicalmaterials.

As used herein, the terms "label" or "labeled" refers to incorporation of adetectable marker, e.g., by incorporation of a radiolabeled amino acid or attachment to 20 a polypeptide of biotin moieties that can be detected by labeled avidin (e.g.,streptavidin comprising a detectable marker such as a fluorescent marker, achemiluminescent marker or an enzymatic activity that can be detected by optical orcolorimetric methods). In certain embodiments, the label can also be therapeutic.Various methods of labeling polypeptides and glycoproteins are known in the art and 25 may be used advantageously in the methods disclosed herein. Examples of labels forpolypeptides include, but are not limited to radioisotopes or radionuclides such as 3H,14C, 15N, 35S, 9QY, 99mTc, I1!In, 12SI, and l31I, fluorescent labels (e.g., fluoresceinisothiocyanate or FITC, rhodamine, or lanthanide phosphors), enzymatic labels (e.g.,horseradish peroxidase, β-galactosidase, . luciferase, alkaline phosphatase), 30 chemiluminescent labels, hapten labels such as biotinyl groups, and predeterminedpolypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pairsequences, binding sites for secondary antibodies, metal binding domains, or epitope 22 PCT/US2006/027862 WO 2007/011941 tags). In certain embodiments, labels are attached by spacer arms (such as (CH2)n,where n < about 20) of various lengths to reduce potential steric hindrance.

The term “biological sample”, as used herein, includes, but is not limited to,any quantity of a substance from a living thing or formerly living thing. Such livingthings include, but are not limited to, humans, mice, monkeys, rats, rabbits, and otheranimals. Such substances include, but are not limited to, blood, serum, urine, cells,organs, tissues, bone, bone marrow, lymph nodes, and skin.

The term "pharmaceutical agent or drug" as used herein refers to a chemicalcompound or composition capable of inducing a desired therapeutic effect whenproperly administered to a patient. The expression “pharmaceutically effectiveamount” in reference to a pharmaceutical composition comprising one or a pluralityof the antibodies of the invention is understood to mean, according to the invention,an amount of the said pharmaceutical composition that is capable of abolishing, in apatient, the decrease in the sensitivity threshold to external stimuli with a return ofthis sensitivity threshold to a level comparable to that observed in healthy subjects. A “disorder” is any condition that would benefit from treatment according tothe present invention. “Disorder” and “condition” are used interchangeably hereinand include chronic and acute immune system disorders or immune system diseasesassociated with inappropriate immune response, including those pathologicalconditions which predispose the mammal to the disorder in question. A number ofconditions and disorders that would benefit from the treatment according to thepresent invention are described, for example, in International Patent Application No.PCT/US00/01871 (Publication No. WO 00/46240), the disclosure of which isincorporated by reference in its entirety.

The terms “immune system disease” and “immune system condition”encompass any medical condition or disorder associated with increased levels ofB7RP1, increased sensitivity to B7RP1, or T-cell mediated diseases, including, butnot limited to, autoimmune disease, graft survival, bone marrow and organtransplantation, allosensitization due to blood transfusions, toxic shock syndrome, T-cell dependent B-cell mediated diseases, chronic inflammatory diseases associatedwith chronic immune cell dysfunction, lymphoproliferative disorders (such asmultiple myeloma, Waldenstom’s macroglobulinemia, and crioglobulinemias), and 23 PCT/US2006/027862 WO 2007/011941 cancer. Non-limiting examples of autoimmune diseases include systemic lupuseiythematosis, rheumatoid arthritis, immune thrombocytopenic purpura (ΓΓΡ),multiple sclerosis, diabetes, and psoriasis. Non-limiting examples of chronicinflammatory diseases include inflammatory bowel disease (such as Crohn’s diseaseand ulcerative colitis), Grave’s disease, Hashimoto’s thyroiditis, and diabetesmellitus.

The terms “immune system disease” and “immune system condition” alsoencompass any clinical condition that would be ameliorated by the inhibition ofantibody production, such as hypersensitivity reactions. Hypersensitivity reactionscan be caused, for example, by hay fever, allergies, asthma, atopy, and acute edema.Non-limiting examples of diseases that cause antibody-mediated hypersensitivityreactions include systemic lupus erythematosis, arthritis (such as rheumatoid arthritis,reactive arthritis, psoriatic arthritis), nephropathies (such as glomerulo-nephritis,membranous, mesangiocapillary, focal segmental, focal necrotizing, crescentic, andproliferative nephropathies such as tubulopathies), skin disorders (such as pemphigusand pemphigoid, erythema nodosum), endocrinopathies (such as thyroiditis, Grave’sdisease, Hashimoto’s disease, insulin dependent diabetes mellitus), variouspneumopathies (such as extrinsic alveolitis), various vasculopathies, coeliac disease,diseases with aberrant production of IgA, many anemias and thrombocytopenias,Guillain-Barre Syndrome, and myasthenia gravis.

As used herein, the terms “effective amount” and "therapeutically effectiveamount” when used with reference to a vehicle- or a pharmaceutical compositioncomprising one or more anti-human B7RP1 human antibodies refers to an amount ordosage sufficient to produce a desired result (i.e., where for therapy with the vehicle-or anti-human B7RP1 human antibodies of the present invention the desired result isthe desired modulation of T-cell responses, for example) or to support an observabledecrease in the level of one or more biological activities of B7RP1. Morespecifically, a therapeutically effective amount is an amount of the anti-human B7RP1human antibody(ies) sufficient to inhibit, for some period of time, one or more of theclinically defined pathological processes associated with the condition at issue, e.g.immune disorders and diseases, in a subject treated in vivo with the agent. In thepresent invention, an “effective amount” of an anti-B7RPl antibody may modulate T-cell responses in a patient. In the methods of the present invention, the term “control” 24 WO 2007/011941 PCT/US2006/027862 and grammatical variants thereof, are used to refer to the prevention, partial orcomplete inhibition, reduction, delay or slowing down of an unwanted event, e.g.immune response. The effective amount may vary depending on the specific vehicle-or anti-human B7RP1 human antibody(ies) selected, and is also dependent on avariety of factors and conditions related to the subject to be treated and the severity ofthe disorder. For example, if the vehicle- or anti-human B7RP1 human antibody(ies)is to be administered in vivo, factors such as the age, weight and health of the patientas well as dose response curves and toxicity data obtained in preclinical animal workwould be among those considered. If the agent is to be contacted with the cells invitro, one would also design a variety of pre-clinical in vitro studies to assess suchparameters as uptake, half-life, dose, toxicity, etc. The determination of an effectiveamount or a therapeutically effective amount for a given agent is well within theability of those skilled in the art.

As used herein, the terms “B7 related protein-1” and “B7RP1” are defined asall mammalian species of native sequence B7RP1, which is described in InternationalPatent Application Publication No. WO 00/46240, which is incorporated herein byreference.

As used herein, "substantially pure" or “substantially purified” means acompound or species that is the predominant species present (i.e., on a molar basis itis more abundant than any other individual species in the composition). In certainembodiments, a substantially purified fraction is a composition wherein the speciescomprises at least about 50 percent (on a molar basis) of all macromolecular speciespresent. In certain embodiments, a substantially pure composition will comprise morethan about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in thecomposition. In certain embodiments, the species is purified to essential homogeneity(contaminant species cannot be detected in the composition by conventional detectionmethods) wherein the composition consists essentially of a single macromolecularspecies.

The term “patient” includes human and animal subjects. “Treatment” or “treat” refers to both therapeutic treatment and prophylactic orpreventative measures. Those in need of treatment include those already with the 25 WO 2007/011941 PCT/US2006/027862 disorder as well as those prone to have the disorder or those in which the disorder is tobe prevented.

Unless otherwise required by context, singular terms shall include pluralitiesand plural terms shall include the singular.

According to certain embodiments of the invention, antibodies directed toB7RP1 may be used to treat immune system disorders and immune system diseases,including but not limited to, those mentioned above.

In one aspect of the invention are provided fully human monoclonal antibodiesraised against and having biological and immunological specificity for binding tohuman B7RP1. In another aspect the invention provides nucleic acids comprisingnucleotide sequences encoding amino acid sequences for heavy and light chainimmunoglobulin molecules, particularly sequences corresponding to the variableregions thereof. Particular embodiments of this aspect of the invention are sequencescorresponding to complementarity determining regions (CDRs), specifically fromCDR1 through CDR3, of the heavy and light chains provided by the invention. In yetanother aspect the invention provides hybridoma cells and cell lines that express theimmunoglobulin molecules and antibodies, such as monoclonal antibodies of theinvention. The invention also provides biologically and immunologically purifiedpreparations of antibodies, such as monoclonal antibodies raised against and havingbiological and immunological specificity for binding to human B7RP1.

The ability to clone and reconstruct megabase-sized human loci in yeastartificial chromosomes (YACs) and to introduce them into the mouse germlineprovides an advantageous approach to elucidating the functional components of verylarge or crudely mapped loci as wetl as generating useful models of human disease.Furthermore, the utilization of such technology for substitution of mouse loci withtheir human equivalents provides unique insights into the expression and regulation ofhuman gene products during development, their communication with other systems,and their involvement in disease induction and progression.

An important practical application of such a strategy is the "humanization” ofthe mouse humoral immune system. Introduction of human immunoglobulin (Ig) lociinto mice in which the endogenous Ig genes have been inactivated offers theopportunity to study mechanisms underlying programmed expression and assembly of 26 PCT/US2006/027862 WO 2007/011941 antibodies as well as their role in B-cell development. Furthermore, such a strategyprovides a source for production of fully human monoclonal antibodies (MAbs).

The term “human antibody” includes antibodies having variable and constantregions substantially corresponding to human germline immunoglobulin sequences.In certain embodiments, human antibodies are produced in non-human mammals,including, but not limited to, rodents, such as mice and rats, and lagomorphs, such asrabbits. In certain embodiments, human antibodies are produced in hybridoma cells.In certain embodiments, human antibodies are produced recombinantly.

The term “recombinant” in reference to an antibody includes antibodies thatare prepared, expressed, created or isolated by recombinant means. Representativeexamples include antibodies expressed using a recombinant expression vectortransfected into a host cell, antibodies isolated from a recombinant, combinatorialhuman antibody library, antibodies isolated from an animal (e.g., a mouse) that istransgenic for human immunoglobulin genes (see e.g., Taylor, et al., 1992, Nucl.Acids Res. 22:6287-6295); or antibodies prepared, expressed, created or isolated byany means that involves splicing of human immunoglobulin gene sequences to otherDNA sequences. Such recombinant human antibodies have variable and constantregions derived from human germiine immunoglobulin sequences.

Human antibodies have at least three advantages over non-human andchimeric antibodies for use in human therapy: 1) because the effector portion of the antibody is human, it may interact betterwith the other parts of the human immune system (e.g., destroy the target cells moreefficiently by complement-dependent cytotoxicity (CDC) or antibody-dependentcellular cytotoxicity (ADCC)); 2) the human immune system should not recognize the human antibody asforeign, and, therefore the antibody response against such an injected antibody shouldbe less than against a totally foreign non-human antibody or a partially foreignchimeric antibody; 3) injected non-human antibodies have been reported to have a half-life in thehuman circulation much shorter than the half-life of human antibodies. Injectedhuman antibodies will have a half-life essentially identical to naturally occurringhuman antibodies, allowing smaller and less frequent doses to be given. 27

I WO 2007/011941 PCT/US2006/027862

Thus, fully human antibodies are expected to minimize the immunogenic andallergic responses intrinsic to mouse or mouse-derivatized MAbs, and to therebyincrease the efficacy and safety of the administered antibodies. Fully humanantibodies of the invention, therefore, can be used in the treatment of diseases anddisorders associated with inappropriate immune response, the treatment thereofrequiring repeated antibody administration. Thus, one particular advantage of theanti-B7RPl antibodies of the invention is that the antibodies are fully human and canbe administered to patients in a non-acute manner while minimizing adverse reactionscommonly associated with human anti-mouse antibodies or other previouslydescribed non-fully human antibodies from non-human species.

One skilled in the art can engineer mouse strains deficient in mouse antibodyproduction with large fragments of the human Ig loci so that such mice producehuman antibodies in the absence of mouse antibodies. Large human Ig fragmentsmay preserve the large variable gene diversity as well as the proper regulation ofantibody production and expression. By exploiting the mouse cellular machinery forantibody diversification and selection and the lack of immunological tolerance tohuman proteins, the reproduced human antibody repertoire in these mouse strainsyields high affinity antibodies against any antigen of interest, including humanantigens. Using the hybridoma technology, antigen-specific human MAbs with thedesired specificity may be produced and selected.

Transgenic animals (e.g., mice) can also be used to produce human antibodiesin the absence of endogenous immunoglobulin production. For example, transfer ofthe human germ-line immunoglobulin gene array in such germ-line mutant mice willresult in the production of human antibodies upon antigen challenge (see, e.g.,Jakobovits et al., 1993, Proc. Natl. Acad. Sci. USA 20:2551-2555; Jakobovits et al.,1993, Nature 362:255-258: Bruggemann et al,, 1993, Year in Immun. 7:33, 1994,Nature 148:1547-1553) and, 1996, Nature Biotechnology .14:826; Gross et al., 2000,Nature 404:995-999; and U.S. Patents Nos. 5,877,397, 5,874,299, 5,814,318,

<img img-format="tif" img-content="drawing" file="IL188642AD00021.tif" id="idf0001" />

(each of which is incorporated herein by reference in its entirety for all purposes)).Human antibodies can also be produced in phage display libraries (Hoogenboom and techniques of Cole et al. and Boemer et al. are also available for the preparation of 28 WO 2007/011941 PCT/US2006/027862 human monoclonal antibodies (Cole et at, 1985, MONOCLONAL ANTIBODIES ANDCANCER THERAPY Alan R. Liss, p. 77; and Boerner et al., 1991, J. Immunol. 142:86-95).

Recombinant human antibodies may also be subjected to in vitro mutagenesis(or, when an animal transgenic for human Ig sequences is used, in vivo somaticmutagenesis) and, thus, the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from those related to humangermline Vh and VL sequences, may not naturally exist within the human antibodygermline repertoire in vivo.

In certain embodiments, the skilled artisan can use constant regions fromspecies other than human along with the human variable region(s) in such mice toproduce chimeric antibodies. A bispecific or bifunctional antibody typically is an artificial hybrid antibodyhaving two different heavy chain/light chain pairs and two different binding sites.Bispecific antibodies may be produced by a variety of methods including, but notlimited to, fusion of hybridomas or linking of F(ab') fragments. See, e.g., Songsivilai&amp;amp; Lachmann, 1990, Ciin. Exp Immunol. Ί9;. 315-321; Kostelny et ai, 1992, J.Immunol. 148:1547-1553.

The invention provides antibodies that bind to human B7RP1. Theseantibodies can be produced by immunization with full-length B7RP1 or fragmentsthereof. The antibodies of the invention can be polyclonal or monoclonal, and/or maybe recombinant antibodies. In preferred embodiments, antibodies of the invention arehuman antibodies prepared, for example, by immunization of transgenic animalscapable of producing human antibodies (see, for example, International PatentApplication, Publication W0 93/12227).

The complementarity determining regions (CDRs) of the light chain and heavychain variable regions of anti- B7RP1 antibodies of the invention can be grafted toframework regions (FRs) from the same, or another, species. In certain embodiments,the CDRs of the light chain and heavy chain variable regions of anti-B7RPl antibodymay be grafted to consensus human FRs, To create consensus human FRs, FRs fromseveral human heavy chain or light chain amino acid sequences are aligned to identifya consensus amino acid sequence. The FRs of the anti-B7RPl antibody heavy chain 29 WO 2007/011941 PCT/US2006/027862 or light chain can be replaced with the FRs from a different heavy chain or lightchain. Rare amino acids in the FRs of the heavy and light chains of anti-B7RPlantibody typically are not replaced, while the rest of the FR amino acids can bereplaced. Rare amino acids are specific amino acids that are in positions in whichthey are not usually found in FRs. The grafted variable regions from anti-B7RPlantibodies of the invention can be used with a constant region that is different fromthe constant region of anti-B7RPl antibody. Alternatively, the grafted variableregions are part of a single chain Fv antibody. CDR grafting is described, e.g., in U.S.Patent Nos. 6,180,370, 5,693,762, 5,693,761, 5,585,089, and 5,530,101, which arehereby incorporated by reference for any purpose.

Antibodies of the invention can be prepared using transgenic mice that have asubstantial portion of the human antibody producing locus inserted in antibody-producing cells of the mice, and that are further engineered to be deficient inproducing endogenous, murine, antibodies. Such mice are capable of producinghuman immunoglobulin molecules and antibodies and do not produce or producesubstantially reduced amounts of murine immunoglobulin molecules and antibodies.Technologies utilized for achieving this result are disclosed in the patents,applications, and references disclosed in the specification herein. In certainembodiments, the skilled worker may employ methods as disclosed in InternationalPatent Application Publication No. WO 98/24893, which is hereby incorporated byreference for any purpose. See also Mendez et al., 1997, Nature Genetics 15:146-156, which is hereby incorporated by reference for any purpose.

The monoclonal antibodies (mAbs) of the invention can be produced by avariety of techniques, including conventional monoclonal antibody methodology, e.g.,the standard somatic cell hybridization technique of Kohler and Milstein (1975,Nature 256:495). Other techniques for producing monoclonal antibodies may beemployed, e.g., viral or oncogenic transformation of B-lymphocytes.

An exemplary animal system for preparing hybridomas is the mouse.Hybridoma production in the mouse is known in the art and immunization protocolsand techniques for isolation of immunized splenocytes for fusion are also known inthe art. Fusion partners (e.g., murine myeloma cells) and fusion procedures are alsoknown. 30 WO 2007/011941 PCT/US2006/027862

In a certain embodiment, human monoclonal antibodies directed againstB7RP1 can be generated using transgenic mice carrying parts of the human immunesystem rather than the mouse system. These transgenic mice, referred to herein as“HuMab” mice, contain a human immunoglobulin gene minilocus that encodesunreatranged human heavy (μ and γ) and κ light chain immunoglobulin sequences,together with targeted mutations that inactivate the endogenous μ and κ chain loci(Lonberg et al., 1994, Nature 368:856-859). Accordingly, the mice exhibit reducedexpression of mouse IgM or κ and in response to immunization, the introduced humanheavy chain and light chain transgenes undergo class switching and somatic mutationto generate high affinity human IgG κ monoclonal antibodies (Lonberg et al., supra.;Lonberg and Huszar, 1995, Intern, Rev. Immunol. £3:65-93; Harding and Lonberg,1995, Ann.N.Y. Acad.Sci. 764:536-546). The preparation of HuMab mice is describedin detail in Taylor et al., 1992, Nucleic Acids Res. 20:6287-6295; Chen et al., 1993,International Immunology 5:647-656; Tuaillon et al., 1994, J. Immunol. 152:2912-2920; Lonberg et ai, 1994, Nature 368:856-859: Lonberg, 1994, Handbook of Exp.Pharmacology 113:49-101; Taylor et ai, 1994, International Immunology 6:579-591;Lonberg &amp;amp; Huszar, 1995, Intern. Rev. Immunol. £3:65-93; Harding &amp;amp; Lonberg, 1995,Ann. N.Y. Acad. Sci 764:536-546: Fishwild et ai, 1996, Nature Biotechnology14:845-851, the contents of all of which are hereby incorporated by reference in theirentirety. See further U.S. Patent Nos. 5,545,806; 5,569,825; 5,625,126; 5,633,425;5,789,650; 5,877,397; 5,661,016; 5,814,318; 5,874,299; and 5,770,429; all to Lonbergand Kay, as well as U.S. Patent No. 5,545,807 to Surani et ai; International PatentApplication Publication Nos. WO 93/1227, published June 24, 1993; WO 92/22646,published December 23, 1992; and WO 92/03918, published March 19, 1992, thedisclosures of all of which are hereby incorporated by reference in their entirety.Alternatively, transgenic mice strains described in the Examples below can be used togenerate human anti-B7RPl antibodies,

The present invention provides human monoclonal antibodies that are specificfor and neutralize bioactive human B7RP1 polypeptides. Also provided are antibodyheavy and light chain amino acid sequences which are highly specific for andneutralize B7RP1 polypeptides when they are bound to them. This high specificityenables the anti-human B7RP1 human antibodies, and human monoclonal antibodieswith like specificity, to be effective immunotherapy for B7RP1 associated diseases. 31 WO 2007/011941 PCT/US2006/027862

In one aspect, the invention provides isolated human antibodies that bind thesame or essentially the same epitope as the 16H antibody provided herein.

In one aspect, the invention provides isolated human antibodies comprising atleast one of the amino acid sequences shown in SEQ ID NOS: 1-40 or 44-58 thatbinds a B7RP1 polypeptide epitope with high affinity and has the capacity toantagonize B7RP1 polypeptide activity. These antibodies may bind the same oressentially the same epitope as the anti-B7RPl antibodies shown in the Examplesherein.

In certain embodiments, the isolated antibodies bind to B7RP1 polypeptidewith a dissociation constant (Kd) of about ΙΟ'6 Μ, ΙΟ"7 Μ, 10'8 M, 10‘9 Μ, 10'10 M, 10'11 M or less and inhibits B7RP1 induced survival in an in vitro neutralization assaywith an EC50 of about 10-6 Μ, 10~7 Μ, 10'8 Μ, 10'9 M or less. Examples of anti-human B7RP1 human antibodies that meet the aforementioned binding andneutralization criteria are provided herein.

In certain embodiments, anti-human B7RP1 human antibodies of the inventionare referred to herein as 16H, 16Hg (germline), 5D, 2H, 2Hg (germline), 15H, 41H,and 43H. Antibody 16H comprises Vl and Vh polypeptide sequences as shown inSEQ ID NO: 7 and SEQ ID NO: 1, respectively. Antibody 16Hg comprises a variablelight chain (Vl) and variable heavy chain (Vh) polypeptide sequences as shown inSEQ ID NO: 1 and SEQ ID NO: 8, respectively. Antibody 5D comprises Vl and Vhpolypeptide sequences as shown in SEQ ID NO: 2 and SEQ ID NO: 9, respectively.Antibody 2H comprises Vl and Vh polypeptide sequences as shown in SEQ ID NO: 3and SEQ ID NO: 10, respectively. Antibody 2Hg comprises Vl and Vh polypeptidesequences as shown in SEQ ID NO: 3 and SEQ ID NO: 11, respectively. Antibody15H comprises Vl and Vh polypeptide sequences as shown in SEQ ID NO: 4 andSEQ ID NO: 12, respectively. Antibody 41H comprises Vl and Vh polypeptidesequences as shown in SEQ ID NO: 5 and SEQ ID NO: 13, respectively. Antibody43H comprises Vl and Vh polypeptide sequences as shown in SEQ ID NO: 6 andSEQ ID NO: 14, respectively. The properties of the anti-human B7RP1 human antibodies of the present invention are specifically disclosed in the Examples.Particularly notable is the high affinity for B7RP1 polypeptide and high capacity toantagonize B7RP1 polypeptide activity demonstrated herein. 32

......_J WO 2007/011941 PCT/US2OO6/027862

The dissociation constant (Kd) of an anti-human B7RP1 human antibody canbe determined by surface plasmon resonance as generally described in the Examplesbelow. Generally, surface plasmon resonance analysis measures real-time bindinginteractions between ligand (recombinant B7RP1 polypeptide immobilized on abiosensor matrix) and analyte (antibodies in solution) by surface plasmon resonance(SPR) using the BIAcore® system (Pharmacia Biosensor, Piscataway, NJ). Surfaceplasmon analysis can also be performed by immobilizing the analyte (antibodies on abiosensor matrix) and presenting the ligand (recombinant V in solution). Thedissociation constant (Kd) of an anti-human B7RP1 human antibody can also bedetermined by using KinExA methodology. In certain embodiments of the invention,the antibodies bind to B7RP1 with a Kd of approximately ΙΟ'3 Μ, 10'6M, ΙΟ'7 Μ, 10'8Μ, 10'9M, ΙΟ'10 Μ, 1O‘H M, or 10‘12 M. The term “Kd”, as used herein, is intended torefer to the dissociation constant of a particular antibody-antigen interaction. Forpurposes of the present invention Kd was determined as shown in the Examplesbelow.

In certain embodiments, the antibodies of the invention are of the IgGi, IgG2,IgG3, or IgG4 isotype. The antibodies may be of the IgG2 or IgGi isotype. In otherembodiments, the antibodies of the invention may be of the IgM, IgA, IgE, or IgDisotype. In certain embodiments of the invention, the antibodies comprise a humankappa light chain and a human IgGi, IgG2, IgG3, or IgG4 heavy chain. Expressionof antibodies of the invention comprising an IgGi or an IgG2 heavy chain constantregion is described in the Examples below. In particular embodiments, the variableregions of the antibodies are ligated to a constant region other than the constant regionfor the IgGi, IgG2, IgG3, or IgG4 isotype. In certain embodiments, the antibodies ofthe invention have been cloned for expression in mammalian cells.

In certain embodiments, conservative modifications to the heavy chains andlight chains of anti-B7RPl antibodies (and corresponding modifications to theencoding nucleotides) will produce anti-B7RPl antibodies having functional andchemical characteristics similar to those of the anti-B7RPl antibodies disclosedherein. In contrast, substantial modifications in the functional and/or chemicalcharacteristics of anti-B7RPl antibodies may be accomplished by selectingsubstitutions in the amino acid sequence of the heavy and light chains that differsignificantly in their effect on maintaining (a) the structure of the molecular backbone 33 WO 2007/011941 PCT/US2006/027862 in the area of the substitution, for example, as a sheet or helical conformation, (b) thecharge or hydrophobicity of the molecule at the target site, or (c) the bulk of the sidechain. . For example, a "conservative amino acid substitution" may involve asubstitution of a native amino acid residue with a nonnative residue such that there islittle or no effect on the polarity or charge of the amino acid residue at that position.Furthermore, any native residue in the polypeptide may also be substituted withalanine, as has been previously described for "alanine scanning mutagenesis."

Amino acid substitutions (whether conservative or non-conservative) can bedetermined by those skilled in the art at the time such substitutions are desired. Incertain embodiments, amino acid substitutions can be used to identify those aminoacid residues of an anti-B7RPl antibody that are involved in binding specificityand/or affinity of the antibody for B7RP1 (e.g. residues that are involved in binding ofthe antibody to a particular epitope), such as amino acid residues in CDR1, CDR2,and/or CDR3 regions of the light or heavy chains as described herein. Such aminoacid substitutions may increase or decrease the affinity of the anti-B7RPl antibodiesdescribed herein.

Minor changes in an amino acid sequence such as deletion, addition orsubstitution of one, a few or even several amino acids may lead to an allelic form ofthe original protein which has substantially identical properties. Therefore, inaddition to the antibodies specifically described herein, other "substantiallyhomologous" antibodies can be readily designed and manufactured utilizing variousrecombinant DNA techniques well known to those skilled in the art. In general,modifications of the genes may be readily accomplished by a variety of well-knowntechniques, such as site-directed mutagenesis. Therefore, the present inventioncontemplates “variant” or “mutant” anti-B7RPl human antibodies havingsubstantially similar characteristics to the anti-B7RPl human antibodies disclosedherein (See, for example, WO 00/56772, all of which is hereby incorporated herein byreference). Thus, by the term "variant” or “mutant” in reference to an anti-B7RPlhuman antibody is meant any binding molecule (molecule X) (i) in which thehypervariable regions CDR1, CDR2, and CDR3 of the heavy chain or thehypervariable regions CDR1, CDR2, and CDR3 of the light chain taken as a wholeare at least about 80% homologous, at least about 90% homologous, or at least about 34 WO 2007/011941 PCT/US2006/027862 95% homologous to the hypervariable regions as shown in SEQ ID NO: 15 throughSEQ ID NO. 26 or SEQ ID NO: 27 through SEQ ID NO: 40, respectively, and (ii)wherein the variant or mutant is capable of inhibiting the activity of human B7RP1 tothe same extent as a reference anti-B7RPl human antibody having framework regionsidentical to those of molecule X. Such antibodies may bind to human B7RP1 or tomouse B7RP1 or both. The mouse B7RP1 sequence is described in WO 00/46240,which is incorporated by reference.

Ordinarily, an anti-B7RPl human antibody variant will have light and/orheavy chain CDRs, when taken as a whole, that are at least about 80% amino acidsequence identity, at least about 85% sequence identity, at least about 90% sequenceidentity, at least about 91% sequence identity, at least about 92% sequence identity, atleast about 93% sequence identity, at least about 94% sequence identity, at least about95% sequence identity, at least about 96% sequence identity, at least about 97%sequence identity, at least about 98% sequence identity, or at least about 99% aminoacid sequence identity to the amino acid sequence as shown in SEQ ID NOS: 15through SEQ ID NO. 26 and/or SEQ ID NOS: 27 through SEQ ID NO. 40,respectively. Such antibodies may bind to human B7RP1 or to mouse B7RP1 or toboth.

An anti-B7RPl human antibody variant will have a light chain variable region,when taken as a whole, that has at least about 80% amino acid sequence identity, atleast about 81% sequence identity, at least about 82% sequence identity, at least about83% sequence identity, at least about 84% sequence identity, at least about 85%sequence identity, at least about 86% sequence identity, at least about 87% sequenceidentity, at least about 88% sequence identity, at least about 89% sequence identity, atleast about 90% sequence identity, at least about 91% sequence identity, at least about92% sequence identity, at least about 93% sequence identity, at least about 94%sequence identity, at least about 95% sequence identity, at least about 96% sequenceidentity, at least about 97% sequence identity, at least about 98% sequence identity, atleast about 99% amino acid sequence identity to the amino acid sequence as shown inSEQ ID NOS: 1 through SEQ ID NO. 6, and/or a heavy chain variable region, whentaken as a whole, that has at least about 70% amino acid sequence identity, at leastabout 75% sequence identity, at least about 80% sequence identity, at least about 81%sequence identity, at least about 82% sequence identity, at least about 83% sequence 35 PCT/US2006/027862 WO 2007/011941 identity, at least about 84% sequence identity, at least about 85% sequence Identity, atleast about 86% sequence identity, at least about 87% sequence identity, at least about88% sequence identity, at least about 89% sequence identity, at least about 90%sequence identity, at least about 91% sequence identity, at least about 92% sequenceidentity, at least about 93% sequence identity, at least about 94% sequence identity, atleast about 95% sequence identity, at least about 96% sequence identity, at least about97% sequence identity, at least about 98% sequence identity, or at least about 99%amino acid sequence identity to the amino acid sequence as shown in SEQ ID NOS: 7through SEQ ID NO. 14. Such antibodies may bind to human B7RP1 and/or mouseB7RP1.

As will be appreciated by those of skill in the art, many of the potential CDR-contact residues are amenable to substitution by other amino acids and still allow theantibody to retain substantial affinity for the antigen. Likewise, many of theframework residues not in contact with the CDRs in the heavy and light chains canaccommodate substitutions of amino acids from the corresponding positions fromother human antibodies, by human consensus amino acids, or from other mouseantibodies, without significant loss of the affinity or non-immunogenicity of thehuman antibody. Selection of various alternative amino acids may be used to produceversions of the disclosed anti-B7RPl antibodies and fragments thereof that havevarying combinations of affinity, specificity, non-immunogenicity, ease ofmanufacture, and other desirable properties. A “variant” in reference to a polynucleotide is intended to refer to a nucleicacid molecule having at least about 75% nucleic acid sequence identity with apolynucleotide sequence of the present invention. Ordinarily, a polynucleotidevariant will have at least about 75% nucleic acid sequence identity, at least about 80%nucleic acid sequence identity, at least about 81% nucleic acid sequence identity, atleast about 82% nucleic acid sequence identity, at least about 83% nucleic acidsequence identity, at least about 84% nucleic acid sequence identity, at least about85% nucleic acid sequence identity, at least about 86% nucleic acid sequence identity,at least about 87% nucleic acid sequence identity, at least about 88% nucleic acidsequence identity, at least about 89% nucleic acid sequence identity, at least about90% nucleic acid sequence identity, at least about 91% nucleic acid sequence identity,at least about 92% nucleic acid sequence identity, at least about 93% nucleic acid 36 WO 2007/011941 PCT/US2006/027862 sequence identity, at least about 94% nucleic acid sequence identity, at least about 95% nucleic acid sequence identity, at least about 96% nucleic acid sequence identity, at least about 97% nucleic acid sequence identity, at least about 98% nucleic acid sequence identity, or at least about 99% nucleic acid sequence identity with a novel nucleic acid sequence disclosed herein.

In alternative embodiments, antibodies of the invention can be expressed incell lines other than hybridoma cell lines. In these embodiments, sequences encodingparticular antibodies can be used for transformation of a suitable mammalian hostcell. According to these embodiments, transformation can be achieved using anyknown method for introducing polynucleotides into a host cell, including, for examplepackaging the polynucleotide in a virus (or into a viral vector) and transducing a hostcell with the virus (or vector) or by transfection procedures known in the art, asexemplified by U.S. Pat. Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (all ofwhich are hereby incorporated herein by reference for any purpose). Generally, thetransformation procedure used may depend upon the host to be transformed. Methodsfor introducing heterologous polynucleotides into mammalian cells are well known inthe art and include, but are not limited to, dextran-mediated transfection, calciumphosphate precipitation, polybrene mediated transfection, protoplast fusion,electroporation, encapsulation of the polynucleotide(s) in liposomes, and directmicroinjection of the DNA into nuclei. A nucleic acid molecule encoding the amino acid sequence of a heavy chainconstant region, a heavy chain variable region, a light chain constant region, or a lightchain variable region of an anti-B7RPl antibody of the invention is inserted into anappropriate expression vector using standard ligation techniques. In one embodiment,the anti-B7RPI antibody heavy chain or light chain constant region is appended to theC-terminus of the appropriate variable region and is ligated into an expression vector.The vector is typically selected to be functional in the particular host cell employedthe vector is compatible with the host cell machinery such that amplification ofthe gene and/or expression of the gene can occur). For a review of expression vectors, see methods in. enzymology 185 (Goeddel. ed.), 1990, Academic Press.

Typically, expression vectors used in any of the host cells will containsequences for plasmid maintenance and for cloning and expression of exogenousnucleotide sequences. Such sequences, collectively referred to as “flanking 37 WO 2007/011941 PCT/US2006/027862 sequences” in certain embodiments will typically include one or more of thefollowing nucleotide sequences: a promoter, one or more enhancer sequences, anorigin of replication, a transcriptional termination sequence, a complete intronsequence containing a donor and acceptor splice site, a sequence encoding a leadersequence for polypeptide secretion, a ribosome binding site, a polyadenylationsequence, a polylinker region for inserting the nucleic acid encoding the polypeptideto be expressed, and a selectable marker element. Each of these sequences isdiscussed below.

Optionally, the vector may contain a “tag”-encoding sequence, i.e., anoligonucleotide molecule located at the 5* or 3’ end of the anti-B7RPl antibodypolypeptide coding sequence; the oligonucleotide sequence encodes polyHis (such ashexaHis), or another “tag” such as FLAG, HA (hemaglutinin influenza virus), or mycfor which commercially available antibodies exist. This tag is typically fused to thepolypeptide upon expression of the polypeptide, and can serve as a means for affinitypurification or detection of the anti-B7RPl antibody from the host cell. Affinitypurification can be accomplished, for example, by column chromatography usingantibodies against the tag as an affinity matrix. Optionally, the tag can subsequentlybe removed from the purified anti-B7RPl antibody polypeptide by various meanssuch as using certain peptidases for cleavage.

Flanking sequences may be homologous (i.e., from the same species and/orstrain as the host ceil), heterologous (i.e., from a species other than the host cellspecies or strain), hybrid (/.e., a combination of flanking sequences from more thanone source), synthetic or native. As such, the source of a flanking sequence may beany prokaryotic or eukaryotic organism, any vertebrate or invertebrate organism, orany plant, provided that the flanking sequence is functional in, and can be activatedby, the host cell machinery.

Flanking sequences useful in the vectors of this invention may be obtained byany of several methods well known in the art. Typically, flanking sequences usefulherein will have been previously identified by mapping and/or by restrictionendonuclease digestion and can thus be isolated from the proper tissue source usingthe appropriate restriction endonucleases. In some cases, the full nucleotide sequenceof a flanking sequence may be known. Here, the flanking sequence may besynthesized using the methods described herein for nucleic acid synthesis or cloning. 38 WO 2007/011941 PCT/US2006/027862

Whether all or only a portion of the flanking sequence is known, it may beobtained using polymerase chain reaction (PCR) and/or by screening a genomiclibrary with a suitable probe such as an oligonucleotide and/or flanking sequencefragment from the same or another species. Where the flanking sequence is notknown, a fragment of DNA containing a flanking sequence may be isolated from alarger piece of DNA that may contain, for example, a coding sequence or evenanother gene or genes. Isolation may be accomplished by restriction endonucleasedigestion to produce the proper DNA fragment followed by isolation using agarosegel purification, Qiagen® column chromatography (Chatsworth, CA), or othermethods known to the skilled artisan. The selection of suitable enzymes toaccomplish this purpose will be readily apparent to one of ordinary skill in the art.

An origin of replication is typically a part of those prokaryotic expressionvectors purchased commercially, and the origin aids in the amplification of the vectorin a host cell. If the vector of choice does not contain an origin of replication site, onemay be chemically synthesized based on a known sequence, and ligated into thevector. For example, the origin of replication from the plasmid pBR322 (NewEngland Biolabs, Beverly, MA) is suitable for most gram-negative bacteria, andvarious viral origins (e.g., SV40, polyoma, adenovirus, vesicular stomatitus virus(VSV), or papillomaviruses such as HPV or BPV) are useful for cloning vectors inmammalian cells. Generally, the origin of replication component is not needed formammalian expression vectors (for example, the SV40 origin is often used onlybecause it also contains the virus early promoter). A transcription termination sequence is typically located 3’ to the end of apolypeptide coding region and serves to terminate transcription. Usually, atranscription termination sequence in prokaryotic cells is a G-C rich fragmentfollowed by a poly-T sequence. While the sequence is easily cloned from a library oreven purchased commercially as part of a vector, it can also be readily synthesizedusing methods for nucleic acid synthesis such as those described herein, A selectable marker gene encodes a protein necessary for the survival andgrowth of a host cell grown in a selective culture medium. Typical selection markergenes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g.,ampicillin, tetracycline, or kanamycin for prokaryotic host cells; (b) complementauxotrophic deficiencies of the cell; or (c) supply critical nutrients not available from 39 PCT/US2006/027862 WO 2007/011941 complex or defined media. Exemplary selectable markers are the kanamycinresistance gene, the ampicillin resistance gene, and the tetracycline resistance gene.Advantageously, a neomycin resistance gene may also be used for selection in bothprokaryotic and eukaryotic host cells.

Other selectable genes may be used to amplify the gene that will be expressed.Amplification is the process wherein genes that are required for production of aprotein critical for growth or cell survival are reiterated in tandem within thechromosomes of successive generations of recombinant cells. Examples of suitableselectable markers for mammalian cells include dihydrofolate reductase (DHFR) andpromoterless thymidine kinase genes. Mammalian cell transformants are placedunder selection pressure wherein only the transformants are uniquely adapted tosurvive by virtue of the selectable gene present in the vector. Selection pressure isimposed by culturing the transformed cells under conditions in which theconcentration of selection agent in the medium is successively increased, therebyleading to the amplification of both the selectable gene and the DNA that encodesanother gene, such as an antibody that binds to B7RP1 polypeptide. As a result,increased quantities of a polypeptide such as an anti-B7RPl antibody are synthesizedfrom the amplified DNA. A ribosome-binding site is usually necessary for translation initiation ofmRNA and is characterized by a Shine-Dalgamo sequence (prokaryotes) or a Kozaksequence (eukaryotes). The element is typically located 3’ to the promoter and 5’ tothe coding sequence of the polypeptide to be expressed.

In some cases, such as where glycosylation is desired in a eukaryotic host cellexpression system, one may manipulate the various pre- or prosequences to improveglycosylation or yield. For example, one may alter the peptidase cleavage site of aparticular signal peptide, or add pro-sequences, which also may affect glycosylation.The final protein product may have, in the -1 position (relative to the first amino acidof the mature protein) one or more additional amino acids incident to expression,which may not have been totally removed. For example, the final protein productmay have one or two amino acid residues found in the peptidase cleavage site,attached to the amino-terminus. Alternatively, use of some enzyme cleavage sitesmay result in a slightly truncated form of the desired polypeptide, if the enzyme cutsat such an area within the mature polypeptide. 40 PCT/US2006/027862 WO 2007/011941

Expression and cloning vectors of the invention will typically contain apromoter that is recognized by the host organism and operably linked to the moleculeencoding the anti-B7RPl antibody. Promoters are untranscribed sequences locatedupstream (/.e., 5’) to the start codon of a structural gene (generally within about 100 to1000 bp) that control transcription of the structural gene. Promoters areconventionally grouped into one of two classes: inducible promoters and constitutivepromoters. Inducible promoters initiate increased levels of transcription from DNAunder their control in response to some change in culture conditions, such as thepresence or absence of a nutrient or a change in temperature. Constitutive promoters,on the other hand, uniformly transcribe genes to which they are operably linked, thatis, with little or no control over gene expression. A large number of promoters,recognized by a variety of potential host cells, are well known, A suitable promoter isoperably linked to the DNA encoding heavy chain or light chain comprising an anti-B7RP1 antibody of the invention by removing the promoter from the source DNA byrestriction enzyme digestion and inserting the desired promoter sequence into thevector.

Suitable promoters for use with yeast hosts are also well known in the art.Yeast enhancers are advantageously used with yeast promoters. Suitable promotersfor use with mammalian host ceils are well known and include, but are not limited to,those obtained from the genomes of viruses such as polyoma virus, fowlpox virus,adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus,cytomegalovirus, retroviruses, hepatitis-B virus and Simian Virus 40 (SV40). Othersuitable mammalian promoters include heterologous mammalian promoters, forexample, heat-shock promoters and the actin promoter.

Additional promoters which may be of interest include, but are not limited to:SV40 early promoter (Bemoist and Chambon, 1981, Nature 290:304-10); CMVpromoter (Thomsen et al., 1984, Proc. Natl. Acad. Sci. USA 81:659-663); thepromoter contained in the 3’ long terminal repeat of Rous sarcoma virus (Yamamoto,et al., 1980, Cell 22:187-97); herpes thymidine kinase promoter (Wagner et al., 1981,Proc. Natl. Acad. Sci. U.S.A, 2&amp;amp;: 1444-45); promoter and regulatory sequences fromthe metallothionine gene (Brinster et al., 1982, Nature 296:39-42); and prokaryoticpromoters such as the beta-lactamase promoter (Villa-Kamaroff et al., 1978, Proc.Natl. Acad. Set U.S.A., 75:3727-31); or the tac promoter (DeBoer et al., 1983, Proc. 41 PCT/US2006/027862 WO 2007/011941

Natl. Acad Sci. U.S.A., 80:21-25). Also of interest are the following animaltranscriptional control regions, which exhibit tissue specificity and have been utilizedin transgenic animals: the elastase I gene control region that is active in pancreaticacinar cells (Swift et al., 1984, Cell £8:639-46; Ornitz et al., 1986, Cold SpringHarbor Symp. Quant Biol. 50:399-409 (1986); MacDonald, 1987, Hepatology 7:425-515); the insulin gene control region that is active in pancreatic beta cells (Hanahan,1985, Nature 315:115-22); the immunoglobulin gene control region that is active inlymphoid cells (Grosschedl et al, 1984, Cell 38:647-58; Adames et al, 1985, Nature318:533-38: Alexander et al, 1987, Mol Cell Biol, 2:1436-44); the mouse mammarytumor virus control region that is active in testicular, breast, lymphoid and mast cells(Leder et al, 1986, Cell 45:485-95); the albumin gene control region that is active inliver (Pinkert et al, 1987, Genes and Devel 1:268-76); the alpha-feto-protein genecontrol region that is active in liver (Krumlauf et al, 1985, Mol. Cell Biol, 5:1639-48; Hammer et al, 1987, Science 235:53-58); the alpha 1-antitrypsin gene controlregion that is active in liver (Kelsey et al, 1987, Genes and Devel 1:161-71); thebeta-globin gene control region that is active in myeloid cells (Mogram et al, 1985,Nature 315:338-40: Kollias et al, 1986, Cell 46:89-94); the myelin basic protein genecontrol region that is active in oligodendrocyte cells in the brain (Readhead et al,1987, Cell 48:703-12); the myosin light chain-2 gene control region that is active inskeletal muscle (Sani, 1985, Nature £14:283-86); and the gonadotropic releasinghormone gene control region that is active in the hypothalamus (Mason et al, 1986,Science 234:1372-78).

An enhancer sequence may be inserted into the vector to increase transcriptionof DNA encoding light chain or heavy chain comprising an anti-B7RPl antibody ofthe invention by higher eukaryotes. Enhancers are c/s-acting elements of DNA,usually about 10-300 bp in length, that act on the promoter to increase transcription.Enhancers are relatively orientation and position independent, having been found atpositions both 5* and 3’ to the transcription unit.. Several enhancer sequencesavailable from mammalian genes are known (eg, globin, elastase, albumin, alpha-feto-protein and insulin). Typically, however, an enhancer from a virus is used. TheSV40 enhancer, the cytomegalovirus early promoter enhancer, the polyoma enhancer,and adenovirus enhancers known in the art are exemplary enhancing elements for theactivation of eukaryotic promoters. While an enhancer may be positioned in the 42 PCT/US2006/027862 WO 2007/011941 vector either 5’ or 3’ to a coding sequence, it is typically located at a site 5’ from thepromoter.

Expression vectors of the invention may be constructed from a starting vectorsuch as a commercially available vector. Such vectors may or may not contain all ofthe desired flanking sequences. Where one or more of the flanking sequencesdescribed herein are not already present in the vector, they may be individuallyobtained and ligated into the vector. Methods used for obtaining each of the flankingsequences are well known to one skilled in the art.

After the vector has been constructed and a nucleic acid molecule encodinglight chain, a heavy chain, or a light chain and a heavy chain comprising an anti-B7RP1 antibody has been inserted into the proper site of the vector, the completedvector may be inserted into a suitable host cell for amplification and/or polypeptideexpression. The transformation of an expression vector for an anti-B7RPl antibodyinto a selected host cell may be accomplished by well known methods includingtransfection, infection, calcium phosphate co-precipitation, electroporation,microinjection, lipofection, DEAE-dextran mediated transfection, or other knowntechniques. The method selected will in part be a function of the type of host cell tobe used. These methods and other suitable methods are well known to the skilledartisan, and are set forth, for example, in Sambrook et al, supra. A host cell, when cultured under appropriate conditions, synthesizes an anti-B7RP1 antibody that can subsequently be collected from the culture medium (if thehost cell secretes it into the medium) or directly from the host cell producing it (if it isnot secreted). The selection of an appropriate host cell will depend upon variousfactors, such as desired expression levels, polypeptide modifications that are desirableor necessary for activity (such as glycosylation or phosphorylation) and ease offolding into a biologically active molecule

Mammalian cell lines available as hosts for expression are well known in theart and include, but are not limited to, immortalized cell lines available from theAmerican Type Culture Collection (ATCC), including but not limited to Chinesehamster ovary (CHO) cells, HeLa cells, baby hamster kidney (BHK) cells, monkeykidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), and anumber of other cell lines. In certain embodiments, cell lines may be selected through 43 WO 2007/011941 PCT/US2006/027862 determining wmcn cen tines nave high expression levels and constitutively produce antibodies with B7RP1 binding properties. In another embodiment, a cell line from the B cell lineage that does not make its own antibody but has a capacity to make and secrete a heterologous antibody can be selected.

Antibodies of the invention are useful for detecting B7RP1 in biologicalsamples and identification of cells or tissues that produce B7RP1 protein. Antibodiesof the invention that specifically bind to B7RP1 may be useful in treatment of B7RP1mediated diseases. Said antibodies can be used in binding assays to detect B7RP1and to inhibit B7RP1 from forming a complex with B7RP1 receptors. Said antibodiesthat bind to B7RP1 and block interaction with other binding compounds may havetherapeutic use in modulating B7RP1 mediated diseases. In certain embodiments,antibodies to B7RP1 may block B7RP1 binding to its receptor, which may result indisruption of the B7RP1 induced signal transduction cascade.

The present invention also relates to the use of one or more of the antibodiesof the present invention in the manufacture of a medicament for the treatment of adisorder or condition caused by increased expression of B7RP1 or increasedsensitivity to B7RP1 in a patient such as any one of disorders or conditions disclosedherein.

In certain embodiments, the invention provides pharmaceutical compositionscomprising a therapeutically effective amount of one or a plurality of the antibodies ofthe invention together with a pharmaceutically acceptable diluent, carrier, solubilizer,emulsifier, preservative and/or adjuvant. Acceptable formulation materials arenontoxic to recipients at the dosages and concentrations employed. In preferredembodiments, pharmaceutical compositions comprising a therapeutically effectiveamount of anti-B7RPl antibodies are provided.

In certain embodiments, acceptable formulation materials are nontoxic torecipients at the dosages and concentrations employed.

In certain embodiments, the pharmaceutical composition may containformulation materials for modifying, maintaining or preserving, for example, the pH,osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate ofdissolution or release, adsorption or penetration of the composition. In suchembodiments, suitable formulation materials include, but are not limited to, amino 44 WO 2007/011941 PCT/US2006/027862 acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobials;antioxidants (such as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite);buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates or other organicacids); bulking agents (such as mannitol or glycine); chelating agents (such asethylenediamine tetraacetic acid (EDTA)); complexing agents (such as caffeine,polyvinylpyrrolidone, beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin); fillers;monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannoseor dextrins); proteins (such as serum albumin, gelatin or immunoglobulins); coloring,flavoring and diluting agents; emulsifying agents; hydrophilic polymers (such aspolyvinylpyrrolidone); low molecular weight polypeptides; salt-forming counterions(such as sodium); preservatives (such as benzalkonium chloride, benzoic acid,salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben,chlorhexidine, sorbic acid or hydrogen peroxide); solvents (such as glycerin,propylene glycol or polyethylene glycol); sugar alcohols (such as mannitol orsorbitol); suspending agents; surfactants or wetting agents (such as pluronics, PEG,sorbitan esters, polysorbates such as polysorbate 20, polysorbate 80, triton,tromethamine, lecithin, cholesterol, tyloxapal); stability enhancing agents (such assucrose or sorbitol); tonicity enhancing agents (such as alkali metal halides, forexample, sodium or potassium chloride, mannitol sorbitol); delivery vehicles;diluents; excipients and/or pharmaceutical adjuvants. See remington’sPHARMACEUTICAL SCIENCES, 18th Edition, (A.R. Gennaro, ed.), 1990, MackPublishing Company.

In certain embodiments, the optimal pharmaceutical composition will bedetermined by one skilled in the art depending upon, for example, the intended routeof administration, delivery format and desired dosage. See, for example,REMINGTON'S pharmaceutical SCIENCES, supra. In certain embodiments, suchcompositions may influence the physical state, stability, rate of in vivo release andrate, of in vivo clearance of the antibodies of the invention.

In certain embodiments, the primary vehicle or carrier in a pharmaceuticalcomposition may be either aqueous or non-aqueous in nature. For example, a suitablevehicle or carrier may be water for injection, physiological saline solution or artificialcerebrospinal fluid, possibly supplemented with other materials common incompositions for parenteral administration. Neutral buffered saline or saline mixed 45 WO 2007/011941 PCT/US2006/027862 wnn serum atoumin are lurcher exemplary vehicles. In certain embodiments,pharmaceutical compositions of the present invention comprise Tris buffer of aboutpH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, and may further include sorbitol,sucrose, Tween-20 and/or a suitable substitute therefor. In certain embodiments ofthe invention, anti-B7RPl antibody compositions may be prepared for storage bymixing the selected composition having the desired degree of purity with optionalformulation agents (remington's pharmaceutical sciences, supra) in the form of alyophilized cake or an aqueous solution. Further, in certain embodiments, the anti-B7RP1 antibody product may be formulated as a lyophilizate using appropriateexcipients such as sucrose.

The pharmaceutical compositions of the invention can be selected forparenteral delivery. Alternatively, the compositions may be selected for inhalation orfor deliveiy through the digestive tract, such as orally. Preparation of suchpharmaceutically acceptable compositions is within the skill of the art.

The formulation components are present in concentrations that are acceptableto the site of administration. In certain embodiments, buffers are used to maintain thecomposition at physiological pH or at a slightly lower pH, typically within a pH rangeof from about 5 to about 8.

When parenteral administration is contemplated, the therapeutic compositionsfor use in this invention may be provided in the form of a pyrogen-free, parenterallyacceptable aqueous solution comprising the desired anti-B7RPl antibody in apharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteralinjection is sterile distilled water in which the anti-B7RPl antibody is formulated as asterile, isotonic solution, properly preserved. In certain embodiments, the preparationcan involve the formulation of the desired molecule with an agent, such as injectablemicrospheres, bio-erodible particles, polymeric compounds (such as polylactic acid orpolyglycolic acid), beads or liposomes, that may provide controlled or sustainedrelease of the product which can be delivered via depot injection. In certainembodiments, hyaluronic acid may also be used, having the effect of promotingsustained duration in the circulation. In certain embodiments, implantable drugdelivery devices may be used to introduce the desired antibody molecule. 46 WO 2007/011941 PCT/US2006/027862 rnarmaceuticai compositions of the invention can be formulated forinhalation. In these embodiments, anti-B7RPl antibodies are advantageouslyformulated as a dry, inhalable powder. In certain embodiments, anti-B7RPl antibodyinhalation solutions may also be formulated with a propellant for aerosol delivery. Incertain embodiments, solutions may be nebulized. Pulmonary administration andformulation methods therefore are further described in International PatentApplication No. PCT/US94/001875, which is incorporated by reference and describespulmonary delivery of chemically modified proteins.

It is also contemplated that formulations can be administered orally. Anti-B7RP1 antibodies that are administered in this fashion can be formulated with orwithout carriers customarily used in the compounding of solid dosage forms such astablets and capsules. In certain embodiments, a capsule may be designed to releasethe active portion of the formulation at the point in the gastrointestinal tract whenbioavailability is maximized and pre-systemic degradation is minimized. Additionalagents can be included to facilitate absorption of the anti-B7RPl antibody. Diluents,flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents,tablet disintegrating agents, and binders may also be employed. A pharmaceutical composition of the invention is provided to comprise aneffective quantity of one or a plurality of anti-B7RPl antibodies in a mixture withnon-toxic excipients that are suitable for the manufacture of tablets. By dissolving thetablets in sterile water, or another appropriate vehicle, solutions may be prepared inunit-dose form. Suitable excipients include, but are not limited to, inert diluents, suchas calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate;or binding agents, such as starch, gelatin, or acacia; or lubricating agents such asmagnesium stearate, stearic acid, or talc.

Additional pharmaceutical compositions will be evident to those skilled in theart, including formulations involving anti-B7RPl antibodies in sustained- orcontrolled-delivery formulations. Techniques for formulating a variety of othersustained- or controlled-delivery means, such as liposome carriers, bio-erodiblemicroparticles or porous beads and depot injections, are also known to those skilled inthe art. See, for example, International Patent Application No. PCT/US93/00829,which is incorporated by reference and describes controlled release of porouspolymeric microparticles for delivery of pharmaceutical compositions. Sustained- 47 PCT/US2006/027862 WO 2007/011941 release preparations may include semipermeable polymer matrices in the form ofshaped articles, e.g. films, or microcapsules. Sustained release matrices may includepolyesters, hydrogels, polylactides (as disclosed in U.S. Patent No. 3,773,919 andEuropean Patent Application Publication No. EP 058481, each of which isincorporated by reference), copolymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., 1983, Biopolymers 22:547-556), poly (2-hydroxyethyl-methacrylate) (Langer et al., 1981, J. Biomed. Mater. Res. 15:167-277 and Langer,1982, Chem. Tech. 12:98-105), ethylene vinyl acetate (Langer et al., supra} or poly-D(-)-3-hydroxybutyric acid (European Patent Application Publication No. EP133,988). Sustained release compositions may also include liposomes that can beprepared by any of several methods known in the art. See e.g., Eppstein et al., 1985,Proc. Natl. Acad. Sci. USA 82:3688-3692; European Patent Application PublicationNos. EP 036,676; EP 088,046 and EP 143,949, incorporated by reference.

Pharmaceutical compositions used for in vivo administration are typicallyprovided as sterile preparations. Sterilization can be accomplished by filtrationthrough sterile filtration membranes. When the composition is lyophilized,sterilization using this method may be conducted either prior to or followinglyophilization and reconstitution. Compositions for parenteral administration can bestored in lyophilized form or in a solution. Parenteral compositions generally areplaced into a container having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by a hypodermic injection needle.

Once the pharmaceutical composition has been formulated, it may be stored insterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated orlyophilized powder. Such formulations may be stored either in a ready-to-use form orin a form (e.g., lyophilized) that is reconstituted prior to administration.

The invention also provides kits for producing a single-dose administrationunit. The kits of the invention may each contain both a first container having a driedprotein and a second container having an aqueous formulation. In certainembodiments of this invention, kits containing single and multi-chambered pre-filledsyringes (e.g., liquid syringes and lyosyringes) are provided.

The effective amount of an anti-B7RPl antibody-containing pharmaceuticalcomposition to be employed therapeutically will depend, for example, upon the 48 WO 2007/011941 PCT/US2006/027862 xnerapeuuc context ana oojeccives. One skilled in the art will appreciate that theappropriate dosage levels for treatment will vary depending, in part, upon themolecule delivered, the indication for which the anti-B7RPl antibody is being used,the route of administration, and the size (body weight, body surface or organ size)and/or condition (the age and general health) of the patient. In certain embodiments,the clinician may titer the dosage and modify the route of administration to obtain theoptimal therapeutic effect. A typical dosage may range from about 0.1 μg/kg to up toabout 30 mg/kg or more, depending on the factors mentioned above. In certainembodiments, the dosage may range from 0,1 pg/kg up to about 30 mg/kg; from 1pg/kg up to about 30 mg/kg; or from 5 pg/kg up to about 30 mg/kg.

Dosing frequency will depend upon the pharmacokinetic parameters of theparticular anti-B7RPl antibody in the formulation used. Typically, a clinicianadministers the composition until a dosage is reached that achieves the desired effect.The composition may therefore be administered as a single dose, or as two or moredoses (which may or may not contain the same amount of the desired molecule) overtime, or as a continuous infusion via an implantation device or catheter. Furtherrefinement of the appropriate dosage is routinely made by those of ordinary skill inthe art and is within the ambit of tasks routinely performed by them. Appropriatedosages may be ascertained through use of appropriate dose-response data. In certainembodiments, the antibodies of the invention can be administered to patientsthroughout an extended time period. Chronic administration of an antibody of theinvention minimizes the adverse immune or allergic response commonly associatedwith antibodies that are raised against a human antigen in a non-human animal, forexample, a non-fully human antibody produced in a non-human species.

The route of administration of the pharmaceutical composition is in accordwith known methods, e.g. orally, through injection by intravenous, intraperitoneal,intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular,intraarterial, intraportal, or intralesional routes; by sustained release systems or byimplantation devices. In certain embodiments, the compositions may be administeredby bolus injection or continuously by infusion, or by implantation device.

The composition also may be administered locally via implantation of amembrane, sponge or another appropriate material onto which the desired molecule 49 WO 2007/011941 PCT/US2006/027862 ims uccn ausuroeu or encapsulated. In certain embodiments, where an implantationdevice is used, the device may be implanted into any suitable tissue or organ, anddelivery of the desired molecule may be via diffusion, timed-release bolus, orcontinuous administration.

It also may be desirable to use anti-B7RPl antibody pharmaceuticalcompositions according to the invention ex vivo. In such instances, cells, tissues ororgans that have been removed from the patient are exposed to anti-B7RPl antibodypharmaceutical compositions after which the cells, tissues and/or organs. aresubsequently implanted back into the patient.

In particular, anti-B7RPl antibodies can be delivered by implanting certaincells that have been genetically engineered, using methods such as those describedherein, to express and secrete the polypeptide. In certain embodiments, such cellsmay be animal or human cells, and may be autologous, heterologous, or xenogeneic.In certain embodiments, the cells may be immortalized. In other embodiments, inorder to decrease the chance of an immunological response, the cells may beencapsulated to avoid infiltration of surrounding tissues. In further embodiments, theencapsulation materials are typically biocompatible, semi-permeable polymericenclosures or membranes that allow the release of the protein product(s) but preventthe destruction of the cells by the patient’s immune system or by other detrimentalfactors from the surrounding tissues.

EXAMPLES

The following examples, including the experiments conducted and resultsachieved are provided for illustrative purposes only and are not to be construed aslimiting the invention.

Example 1

Production of Human Monoclonal Antibodies Against B7 related protein-1 (B7RP1)

Antigen 50 PCT/US2O06/O27862 WO 2007/011941

Purified recombinant human B7RP-1 (hB7RP-l) prepared as described inInternational Patent Application Publication No. WO 00/46240, which is incorporatedherein by reference, or CHO cells transfected to express hB7RP-l were used as theantigen. Mature human B7RP-1 has the amino acid sequence of residues X to 302 inthe sequence shown in WO 00/46240 as SEQ ID NO: 17, wherein X can be 19, 20,21,22,24 or 28.

Transgenic HuMab Mice

Fully human monoclonal antibodies to B7RP-1 were prepared using HCo7 andHCol2 strains of HuMab transgenic mice, both of which express human antibodygenes. In both of these mouse strains, the endogenous mouse kappa light chain genehas been homozygously disrupted as described in Chen et al. (1993) EMBO J.12:811-820 and the endogenous mouse heavy chain gene has been homozygouslydisrupted as described in Example 1 of PCT Publication WO 01/09187. Each of thesemouse strains carries a human kappa light chain transgene, KCo5, as described inFishwild et al. (1996) Nature Biotechnology 14:845-851. The HCo7 strain carries theHCo7 human heavy chain transgene as described in U.S. Patent Nos. 5,545,806;5,625,825; and 5,545,807, The HCol2 strain carries the HCol2 human heavy chaintransgene as described in Example 2 of PCT Publication WO 01/09187.

HuMab Immunizations:

To generate fully human monoclonal antibodies to B7RP-1, HuMab mice ofthe HCo7 or HCol2 strain were immunized with purified recombinant B7RP-1 orCHO cells transfected to express B7RP-1. General immunization schemes forHuMab mice are described in Lonberg et al (1994) Nature 368(6474): 856-859;Fishwild et al. (1996) Nature Biotechnology 14: 845-851 and PCT Publication WO98/24884. The mice were 6-16 weeks of age upon the first infusion of antigen, Apurified recombinant preparation of B7RP-1 antigen (50 pg) or a preparation oftransfected CHO cells (3.5 x 106 ~ 1 x 107 cells) was used to immunize the HuMabmice intraperitonealy.

Transgenic mice were immunized twice with purified antigen in completeFreund’s adjuvant intraperitonealy, followed by 2-4 weeks of IP immunizations (up toa total of 8 immunizations) with the purified antigen in incomplete Freund’s adjuvant. 51 PCT/US2006/027862 WO 2007/011941

Immunization with CHO cells transfected to express B7RP-1 was the same exceptthat complete Freund’s adjuvant and incomplete Freund’s adjuvant were not usedwith the cells. The immune response was monitored by retroorbital bleeds. Theplasma was screened by ELISA (as described below), and mice with sufficient titersof anti-B7RP-l human immunogolobulin were used for fusions. Mice were boostedintravenously with antigen 3 and 2 days before sacrifice and removal of the spleen.Typically, 10-20 fusions for each antigen were performed. Several dozen mice wereimmunized for each antigen. A total of 28 mice of the HCo7 and HCol2 mice strainswere immunized with B7RP-1.

Selection of HuMab Mice Producing Anti-B7RP-1 Antibodies:

To select HuMab mice producing antibodies that bound B7RP-1, sera fromimmunized mice was tested by ELISA as described by Fishwild et ai (1996). Briefly,microtiter plates were coated with purified recombinant B7RP-1 at 1-2 pg /ml in PBS,50 μΐ/wells incubated 4 °C overnight then blocked with 200 μΐ/well of 5% chickenserum in PBS/Tween (0.05%). Dilutions of plasma from B7RP-1-immunized micewere added to each well and incubated for 1-2 hours at ambient temperature. Theplates were washed with PBS/Tween and then incubated with a goat-anti-human IgGFc polyclonal antibody conjugated with horseradish peroxidase (HRP) for 1 hour atroom temperature. After washing, the plates were developed with ABTS substrate(Sigma, A-1888, 0.22 mg/ml) and analyzed by spectrophotometer at OD 415-495.Mice that developed the highest titers of anti-B7RP-l antibodies were used forfusions. Fusions were performed as described below and hybridoma supernatantswere tested for anti-B7RP-l activity by ELISA.

Generation of Hybridomas Producing Human Monoclonal Antibodies to B7RP-1:

The mouse splenocytes, isolated from the HuMab mice, were fused with PEGto a mouse myeloma cell line based upon standard protocols. The resultinghybridomas were then screened for the production of antigen-specific antibodies.Single cell suspensions of splenic lymphocytes from immunized mice were fused toone-fourth the number of SP2/0 nonsecreting mouse myeloma cells (ATCC, CRL1581) with 50% PEG (Sigma). Cells were plated at approximately 1x10 5/well in flat 52 PCT/US2006/027862 WO 2007/011941 bottom microtiter plate, followed by about two week incubation in selective mediumcontaining 10% fetal bovine serum, 10% P388D1 (ATCC, CRL TIB-63) conditionedmedium, 3-5% origen (IGEN) in DMEM (Mediatech, CRL 10013, with high glucose,L-glutamine and sodium pyruvate) plus 5 mM HEPES, 0.055 mM 2-mercaptoethanol,50 mg/ml gentamycin and lx HAT (Sigma, CRL P-7185). After 1-2 weeks, cellswere cultured in medium in which the HAT was replaced with HT. Individual wellswere then screened by ELISA (described above) for human anti-B7RP-l monoclonalIgG antibodies. Once extensive hybridoma growth ocourred, medium was monitoredusually after 10-14 days. The antibody secreting hybridomas were replated, screenedagain and, if still positive for human IgG, anti-B7RP-l monoclonal antibodies weresubcloned at least twice by limiting dilution. The stable subclones were then culturedin vitro to generate small amounts of antibody in tissue culture medium for furthercharacterization.

Example 2

Cloning the anti-B7RPl Antibody Heavy and Light Chains

The hybridoma expressing the B7RP1 binding monoclonal antibody 16H wasused as a source to isolate total RNA using TRIzol® reagent (Invitrogen). A 5'RACE (rapid amplification of cDNA ends) oligonucleotide (5*- CGA CUG GAGCAC GAG GAC ACU GAC AUG GAC UGA AGG AGU AGA AA-3’; SEQ ID NO:69) was ligated to the RNA using the GeneRacer™ Kit (Invitrogen) components andprotocol. First strand cDNA was synthesized using a random primer with anextension adapter (5&gt;-_ GGC CGG ATA GGC CTC CAN NNN NNT-3’) (SEQ IDNO: 59) and a 5’ RACE (rapid amplification of cDNA ends) preparative assay wasperformed using the GeneRacer™ Kit (Invitrogen) according to instructions from themanufacturer. For preparing complete light chain encoding cDNA, the forwardprimer was the GeneRacer™ nested primer, and the reverse primer was (5’- GGGGTC AGG CTG GAA CTG AGG-3*) (SEQ ID NO: 60). For preparing cDNAencoding the variable region of the heavy chain, the forward primer was theGeneRacer™ nested primer and the reverse primer was (5’- TGA GGA CGC TGACCA CAC G-3’) (SEQ ID NO: 61). RACE products were cloned into pCR4-TOPO 53 PCT/US2006/027862 WO 2007/011941 (Invitrogen) and the sequences determined. Consensus sequences were used to designprimers for full-length antibody chain PCR amplification.

For preparing cDNA encoding anti-B7RPl 16H kappa light chain, the 5’ PCRprimer encoded the amino terminus of the signal sequence, an Xbal restrictionenzyme site, and an optimized Kozak sequence (5*-CAG CAG AAG CTT CTA GACCAC CAT GGA CAT GAG GGT CCT CGC TCA GCT CCT GGG-3’) (SEQ ID NO:62). The 3’ primer encoded the carboxyl terminus and termination codon, as well as aM restriction site (5’-CTT GTC GAC TCA ACA CTC TCC CCT GTT GAA GCTC-3’) (SEQ ID NO: 63). The resulting PCR product fragment was purified, digestedwith Xbal and Sail, and then gel isolated and ligated into the mammalian expressionvector pDSRa20 (see International Application, Publication No. WO 90/14363,which is herein incorporated by reference for any purpose. pDSRa20 was producedby changing nucleotide 2563 in pDSRal9 from a “Guanosine” to an “Adenosine” bysite directed mutagenesis.).

For preparing cDNA encoding anti- B7RP1 16H heavy chain the 5’ PCRprimer encoded the amino terminus of the signal sequence, an Xbal restrictionenzyme site, and an optimized Kozak sequence (5’-ACA ACA AAG CTT CTA GACCAC CAT GGA GTT GGG GCT GAA CTG G-3’) (SEQ ID NO: 64). The 3’ primerencoded the carboxyl end of the variable region, including a naturally occurring sensestrand BsmBl site (5’- GTG GAG GCA CTA GAG ACG GTG ACC AGG ATT CC -3’; SEQ ID NO: 65). The resulting product was purified, digested with Xbal andBsmBl, gel isolated and ligated into the pDSRa20 vector containing the human IgGlconstant region and also into the pDSRa20 vector containing the human IgG2constant region. All of the hybridoma derived anti-B7RPl heavy chain variableregions, regardless of the native constant region associated, were cloned as describedabove into both the pDSRa20 vectors containing the human IgGl and the humanIgG2 constant regions.

Example 3

Expression-o£Anti-B7RPl Antibodies in Chinese Hamster Ovary (CHOI Cells

Stable expression of the 16H anti-B7RPl mAb was achieved by co-transfection of 16H-heavy chain/pDSRa!9 IgG2 B7RPl-kappa/pDSRal9 plasmids 54 WO 2007/011941 PCT/US2006/027862 into dihydrofolate reductase deficient (DHFR“) serum-free adapted Chinese hamsterovary (CHO) cells using a calcium phosphate method (the full length 16H heavychain sequence is shown in SEQ ID NO: 44; the 16H kappa chain sequence is shownin SEQ ID NO: 45). Transfected cells were selected in medium containing dialyzedserum but not containing hypoxanthine-thymidine to ensure the growth of cellsexpressing the DHFR enzyme. Transfected clones were screened using assays suchas ELISA in order to detect the expression of 16H anti-B7RPl mAb in theconditioned medium. The highest expressing clones were subjected to increasingconcentrations of methotrexate (MTX) for DHFR amplification. MTX amplifiedclones were screened using assays such as ELISA in order to detect higher expressionof 16H anti-B7RPl mAb in the conditioned medium. The highest expressing cloneswere subjected to subcloning to obtain a homogeneous population and creation of cellbanks.

Other recombinant anti-B7RPl antibodies of the invention can be generated inChinese hamster ovary cells deficient in DHFR using the same protocol as describedabove for the anti-B7RPl monoclonal antibody. The DNA sequences encoding thecomplete heavy chain or light chain of each anti-B7RPl antibody of the invention arecloned into expression vectors. CHOd-cells are co-transfected with an expressionvector capable of expressing a complete heavy chain and an expression vectorexpressing the complete light chain of the appropriate anti-B7RBl antibody. Forexample, to generate a 5D anti-B7RPl antibody, cells are co-transfected with a vectorcapable of expressing a complete heavy chain comprising the amino acid sequence asset forth in SEQ ID NO: 47 and a vector capable of expressing a complete light chaincomprising the amino acid sequence set forth in SEQ ID NO: 48. Table 2 summarizesexemplary complete light chains and exemplary complete heavy chains for anti-B7RP1 antibodies having human IgG heavy chain constant regions. One of skill inthe art will recognize that the IgGl or IgG2 could be substituted for each other (/.e.where IgGl is listed in the table, IgG2 could be present, and vice versa).Alternatively, any other immunoglobulin (e.g,, IgM, IgA, IgE or IgH) could be usedto generate antibodies of the invention.

Table 2 55 WO 2007/011941 PCT/US2006/027862

Antibody Heavy Chflln Variable Region+ Heavy Chain Constant Region Complete Heavy Chain 16H(IgG2) SEQ ID NO: 7 + SEQ ID NO: 41 SEQ ID NO: 44 16H(IgGl) SEQ ID NO: 7 + SEQ ID NO: 42 SEQ ID NO: 70 16Hg(IgG2) SEQ ID NO: 8 + SEQ ID NO: 41 SEQ ID NO: 46 WHgflgOl) SEQ ID NO: 8 + SEQ ID NO: 42 SEQ ID NO; 71 SDagOl) SEQ ID NO: 9 + SEQ ID NO: 42 SEQ ID NO: 47’ 5D(IgG2) SEQ ID NO: 9 + SEQ ID NO; 41 SEQ ID NO: 72 2H(IgG2) SEQ ID NO: 10 + SEQ ID NO: 41 SEQ ID NO: 49 2H(IgGl) SEQ ID NO: 10 + SEQ ID NO: 42 SEQ ID NO: 73 2Hg(IgG2) SEQ ID NO: 11 + SEQ ID NO: 41 SEQ ID NO: 51 2Hg(IgGl) SEQ ID NO: 11 + SEQ ID NO: 42’ SEQ ID NO: 74 43H(IgG2) SEQ ID NO: 14 + SEQ ID NO: 41 SEQ ID NO: 52 43H(IgGl) SEQ ID NO: 14 + SEQ ID NO: 42 SEQ ID NO: 75 41H(IgG2) SEQ ID NO: 13 + SEQ ID NO: 41 SEQ ID NO: 54 41H(IgOl) SEQ ID NO: 13 + SEQ ID NO: 42 SEQ ID NO: 76 15H(IgG2) SEQ ID NO: 12 + SEQ ID NO: 41 SEQ ID NO: 56 15H(IgGl) SEQ ID NO: 12 + SEQ ID NO: 42 SEQ ID NO: 57 Antibody Light Chain Variable Region+ Light Chain Constant Region Complete Light Chain 16H SEQ ID NO: 1 + SEQ ID NO: 43 SEQ.IDNO:45 5D SEQ ID NO: 2 + SEQ ID NO: 43 SEQ ID NO: 48 2H SEQ ID NO: 3 + SEQ ID NO: 43 SEQ ID NO: 50 43H SEQ ID NO: 6 + SEQ ID NO: 43 SEQ ID NO :53 41H SEQ ID NO: 5 + SEQ ID NO: 43 SEQ ID NO: 55 15H SEQ ID NO: 4 + SEQ ID NO: 43 SEQ ID NO: 58

Example 4

Production of anti-B7RPl Antibody

Anti-B7RP1 antibody is produced by expression in a clonal line of CHO cells. 5 For each production run, cells from a single vial are thawed into serum-free cellculture media. The cells are grown initially in a T-flask followed by spinner flasksand then grown in stainless steel reactors of Increasing scale up to a 2000L bioreactor.Production is carried out in a 2000L bioreactor using a fed batch culture, in which anutrient feed containing concentrated media components is added to maintain cell 10 growth and culture viability. Production lasts for approximately two weeks duringwhich time anti-B7RPl antibody is constitutively produced by the cells and secretedinto the cell culture medium.

The production reactor is controlled at a predetermined pH, temperature, anddissolved oxygen level: pH is controlled by carbon dioxide gas and sodium carbonate 15 addition; dissolved oxygen is controlled by air, nitrogen, and oxygen gas flows. 56 WO 2007/011941 PCT/US2006/027862

At the end of production, the cell broth is fed into a disk stack centrifuge andthe culture supernatant is separated from the cells. The concentrate is further clarifiedthrough a depth filter followed by a 0.2 pm filter. The clarified conditioned media isthen concentrated by tangential flow ultrafiltration. The conditioned media isconcentrated 15- to 30- fold. The resulting concentrated conditioned medium is theneither processed through purification or frozen for purification at a later date.

Example 5

Germlining the 16H mAb

Sequence alignment of the 16H antibody with human germline sequencesshowed that the framework sequence in the variable region of the 16H antibody wasmost identical to the Vh 3-07 and JH4 germiine sequences, with only three amino aciddifferences (Figure 1A). The framework sequence for the VK region of the 16Hantibody was found to be identical to the VK1-L15 germiine sequence. It istheoretically possible that somatic hypermutations are recognized as foreign by theimmune response of a patient; in which case the patient would generate an anti-idiotype response that could neutralize the therapeutic. To reduce this possibility, thethree amino acid changes in the VH framework region were converted back to the Vh3-07 and JH4 germiine sequences (Figure 1A). Since the germiine Vh and Jh genesegments are present in every human genome, the germiine version of 16H is notlikely to be recognized as foreign by the immune response of a dosed patient. Plateco-stimulation bioassays were conducted to determine if the germlined antibodiescould induce T-cell proliferation with an IC50 similar to the IC50 of the non-germlinedantibodies. The co-stimulation assays were conducted as described below using anti-CD3 and hB7RP-l-Fc fusion protein confirmed that this germlined antibody, referredto as 16Hgermline or 16Hg, retains its biological activities (Figure IB).

Example 6

Affinity Measurement of Monoclonal Antibodies by Biacore® and KinExA

Three antibodies (5D and 16H, prepared as described in Example 1, and 16Hgermiine, prepared as described in Example 5) were purified and submitted to binding 57 WO 2007/011941 PCT/US2006/027862 affinity analysis. B7RP1-Fc was immobilized at a high density on a CM5 sensor chipusing standard amine coupling chemistry. A fixed concentration of mAb was thenincubated with varying concentrations of B7RP-1 or B7RP1-Fc for at least eight hoursat room temperature to allow them to reach equilibrium. The samples were theninjected over the B7RP1-Fc surface, and the binding signal observed represented freeantibody remaining in solution at equilibrium. By using two different antibodyconcentration (0.2nM and InM), the Kp of the interaction between a particular mAband ligand was calculated from nonlinear regression analysis of the competitioncurves using a dual-curve one-site homogeneous binding model (Adamczyk et ai,1999, Bioconjugate Chem. 10:1032-37; Adamczyk et ai, 2000, Methods 20:319-28).As shown in Figure 2 and Table 3, the 16H, 16Hg, and 5D mAbs all bound bothsoluble B7RP-1 and B7RP-1-Fc proteins at high affinities. In addition, the resultsindicated that the 16H (non-germline) and the 16Hg (germline) reacted similarly,demonstrating that germlining did not significantly affect binding between antibodyand ligand.

Table 3

Summary of Kp Values B7RP-1 B7RP1-Fc 5D 37 pM 1.6 pM 16H 1.9 nM 27 pM 16H (germline) 2.7 nM 17 pM

Binding of 5D, 2H, and 2H germline antibodies was also tested using KinExA(kinetic exclusion assay) technology. In this assay, hB7RP-l was coupled to agarosebeads. The beads were used to create a bead column. Samples containing antibody ata fixed concentration, which were allowed to come to equilibrium with varyingconcentrations of hB7RP-l, were then passed over the bead column. Antibody notcomplexed with ligand bound to the coated beads. A fluorescent tagged anti-human Fc secondary antibody was used to detectbound test antibody. The signal obtained was proportional to free antibody in solutionat a given ligand concentration. Using two different antibody concentrations, the Kpof the interaction was calculated from nonlinear regression analysis of the competitioncurves using a dual-curve one-site homogeneous binding model (Adamczyk et ai, 58 PCT/US2006/027862 WO 2007/011941 1999, Bioconjugate Chem. 10:1032-37; Adamczyk et al, 2000, Methods 20:319-28).Figures 3, 4, and 5 show the dual-curve fits for antibodies 5D, 2H and 2H(germline).Using this technique, an approximately 10-fold difference was seen in the KdS forantibodies 5D and 2H.

The results of the Biacore® and KinExA assays demonstrated that antibody 5Dhas a higher affinity for hB7RP-l than do either 2H or 16H. Also, the germlineversion of antibody 2H does not show a significant difference from the non-germlineconstruct.

Example 7

Functional Characteristics of anti-B7RPl Antibodies

The functional characteristics of B7RP-1 antibodies of the invention wereevaluated using binding-competition assays, in vitro co-stimulation assays and in vitrotetanus toxoid assays.

Binding-competition studies

Binding-competition studies were conducted with the 16H mAbs todemonstrate that they can compete for ICOS binding for B7RP-1. CHO cellstransfected with a gene encoding the full-length human B7RP-1 were first incubatedwith decreasing amounts of unlabeled 16H mAb and subsequently stained with afluorescently-labeled ICOS-Fc fusion protein. The cells were then analyzed usingflow cytometry. As shown in Figure 6, ICOS-Fc stained the B7RP-1-transfectedCHO cells; 0.4pg/ml of 16H mAb did not affect ICOS-Fc binding. However, 6 and25 pg/ml of 16H efficiently competed away ICOS-Fc binding, indicating that the 16HmAb indeed competed for ICOS binding on B7RP-1.

Co-stimulation Assays

Cell culture plates (Falcon, Cat No.353077, U bottom) were coated with 1pg/ml anti-human CD3 antibodies (PharMingen Cat No.555336) and lOug/ml anti-human IgG (Fc specific, Sigma Cat No.I3391). The anti-CD3 antibodies and anti- 59 WO 2007/011941 PCT/US2006/027862 human immunoglobulin in phosphate buffered saline (PBS) were added to each well(ΙΟΟμΙ/well). The coated plates were incubated at 4°C overnight or at roomtemperature for 2 hours. The plates were then washed with PBS twice. Afterwashing, 1pg/ml human B7-2Fc (R&amp;amp;D System, Cat No.l41-B2) or 5pg/mlhB7RPlFc, each diluted in PBS, were added to each well (100pl per well). The plateswere then incubated at room temperature for 3 hours and washed twice with PBSthereafter. Purified human T cells were added (lxl05 per well) in 200μ1 volume ofmedia (RPMI 1640 supplemented with 10% fetal calf serum (FCS), penicillin-streptomycin-L-glutamine (PSG), β-mercpatoethanol (2-ME), N-Acetyl aspartate(NAA) and Napyruvate) and incubated at 37°C, 5% CO2 for 48 hours. 3Ή thymidine(ICN CatNo.2404205) was added at lpCi/well and the cells were incubated overnightat 37°C, 5% CO2. The cells were then harvested and counted.

Cell culture plates (Falcon, Cat No.353077, U bottom) were coated with 0.1pg/ml anti-human CD3 as above. hB7RPl transfected CHO cells (5000RADirradiated) were added at 2xl04per well followed by purified human T cells at lxl05per well in 200μ1 volume. Plates were incubated at 37°C, 5% CO2 for 48 hours asabove. 3Ή thymidine was added at lpCi/well. Cells were incubated overnight,harvested, and counted as above.

Tetanus Toxoid Assays PBMC were purified from human blood using a Ficoll-Paque (AmershamBiosciences) gradient as follows. Blood was diluted 1:2 with PBS, diluted blood waslayered on top of the Ficoll (1/3 room temp Ficoll + 2/3 diluted blood), centrifuged at2500 rpm for 30 minutes at room temperature, the top layer (plasma &amp;amp; platelets) wasaspirated off, and the mononuclear cell layer was transferred to a fresh 50 ml tube.The isolated PBMC were washed with PBS (3x the volume of the mononuclear celllayer) and centrifuged for 10 minutes at 1300 rpm at room temperature and washed asabove. The PBMC were resuspended in media (RPMI 1640 + 10% heat-inactivatedFBS + IX PSG + IX NEAA + 55 μΜ 2-ME) and the cells were counted, PMBC were added to wells of a 96-well round bottom plate at 100 μΐPBMC/well (3xl0s/ml). Tetanus toxoid (20 pg/ml; University of Massachusetts) wasadded for a final concentration of 5 pg/ml. The cells were incubated for 3 days at 60 PCT/US2006/027862 WO 2007/011941 37°C; 100 μΐ supernatant were collected and incubated for an addition 6 to 8 hours inthe presence of 1 pCi/well 3H-thymidine (MP Biomedicals). The cells were thenharvested and counted.

Table 4 summarizes the functional characteristics of certain antibodies of the5 invention as determined using the assays described above.

Table 4

Plate Biacore Fc Biacore mono CHO Tetanus Toxoid 2H 43 89 1445 15 15H 36 141 16H 53 27 1900 276 27 16Hg 32 17 2700 523 41H 52 115 43H 46 35 5D 55 1.6 37 1456 15 ICOS-Fc 200-1000 1000 10,672 a-CD86 40

*ECso/KD values in pM 10 Example 8

Epitope Mapping

Experiments were conducted to identify the region on B7R1M to which the16H/16Hg and 5D monoclonal antibodies bind. To do this, a novel Fluorescence-Activated Cell Sorter (FACS) binding assay was developed. The human extracellular 15 domain (ECD) of B7RP1 (SEQ ID NO: 66) as well as truncated forms of B7RP-1containing either the Igl (IgV-like; SEQ ID NO: 67) or the Ig2 (IgC-like; SEQ IDNO: 68) were expressed as N-terminal, in-frame fusions with chicken avidin. SEQ ID NO: 66 (ECD):

DTQEKEVRAMVGSDVELSCACPEGSRFDLNDVYVYWQTSESKTVVTYHIPQNSSLENVDSRYRNRALMS

20 PAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSLGFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSINGYPRPNVYWINKTDNSLLDQALQNDTVFLNMRGLYDVVSVLRIARTFSVNIGCCIENVLLQQNLTVGSQTGNDIGERDKXTENP SEQ ID NO: 67 (IgV-like): 61 WO 2007/011941 PCT/US2006/027862

DTQEKEVRAMVGSDVELSCACPEGSRFDX.NDVYVYWQTSESKTWTYHIPQNSSLENVDSRYRNRALMS

PAGMLRGDFSLRLFNVTPQDEQKFHCLVLSQSLGFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTF

T SEQ ID NO: 68 (IgC-like):

5 XiGFQEVLSVEVTLHVAANFSVPVVSAPHSPSQDELTFTCTSINGYPRPNVYWINKTDNSLLDQALQNDTVFLNMRGLYDVVSVLRIARTPSVNIGCCXENVLLQQNLTVGSQTGNDIGERDKITENP

Expression vectors containing genes encoding these fusion proteins wereindividually transiently transfected into 293T cells and the conditioned media fromthese cell lines were used as the source of fusion protein. The avidin-tag was used to 10 capture the B7RP1 fusion proteins from solution using a biotin-coated bead. Fusionproteins were incubated with either fluorescently-labeled 16H or 5D mAbs or afluorescently-labeled ICOS-Fc fusion protein, and incubated with biotin-coated beads.

The beads were recovered and analyzed using flow cytometry on a Becton-DickinsonBioscience FACScan (BD, Franklin Lakes, NJ). As shown in Figure 9A, fluorescent 15 staining of the beads was detected with the 16H, 5D, and the ICOS reagents when the full ECD of B7RP-1 was attached, indicating that all three of these reagents couldbind to the ECD of B7RP-1. Similarly, all three reagents bound to the avidin fusionprotein containing only the Igl domain, indicating that both ICOS and the blockinganti-B7RP-l mAbs could bind to this region. In contrast, neither ICOS nor the anti- 20 B7RP-I mAbs could bind to the fusion protein containing only the membrane-proximal Ig2 domain. Thus, the ICOS, 16H, and 5D binding regions on B7RP-1 werelocated in the Igl domain.

The antibodies generated as described above in Example 1 and tested forbinding using the avidin fusion binding assay, could be divided into two epitope 25 classes, H and D, as shown in Table 5. Of the 100 antibodies initially selected basedon their ability to bind B7RP1, 15 failed to bind in the avidin fusion binding assay,most likely because of degradation.

Table 5

Classification of mAbs by epitope Class # H epitope 75 D epitope 10 New epitope, ICOS blocker 0 62 WO 2007/011941 PCT/US2006/027862

New epitope, not an ICOS blocker 0 No detectable binding 15

Example 9 SNP identification and functional analysis

One major single nucleotide polymorphism (SNP) variant was identified inB7RP-1 that is present in the population with an allele frequency of 28.4% (Figure 7).The variant was identified within the mature protein coding sequence. A search of theNational Center for Biotechnology Information (NCBI) databank revealed a secondpotential SNP variant; the second variant was identified in a 1.5 individual (threechromosome) analysis. The first SNP variant (VI281) was located in the first IgV-like domain, whereas the NCBI SNP variant (L221F) was located in the second IgC-like domain.

As discussed above, both the 16H and 5D monoclonal antibodies bind to thefirst IgV-like domain, this it is unlikely that the latter L221F variant affects either 16Hor 5D mAb binding or function. Nonetheless, to determine if either of these SNPvariants affects 16H or 5D binding and/or function, two different experiments wereconducted. In the first set of experiments, avidin fusion proteins were constructedwith the two SNP variants and tested for binding to 16H or 5D antibodies in the flowcytometric assay as described above. These representative mAbs from the H and Depitope classes bound to the SNP variants with similar efficacy as the wild-typeB7RP-1 (Figure 9B). These data suggested that antibodies from both the H and Depitope classes bind to the B7RP-1 SNP variants.

In the second approach, Fc fusion proteins were constructed using the B7RP-1SNP variant sequences and compared for the ability of these proteins to stimulate Tcells in the plate co-stimulation assay (Figure 9C). Both the 16H and 5D antibodiesinhibited co-stimulation mediated by the SNP variant Fc fusion proteins with similarEC50S as the wild-type fusion protein. Taken together these data indicated that thetwo potential B7RP-1 SNP variants were recognized by the antibodies of theinvention. Thus, the antibodies of the invention can bind to target in patientscontaining these SNP variants. 63 WO 2007/011941 PCT/US2006/027862

Example 10

In vivo Animal Efficacy Models

The ability of B7RP-1 antibodies to inhibit immune response was analyzedusing a murinized rat anti-murine B7RP-1 monoclonal antibody (1B7v2) andchallenging BALB/c mice with keyhole-limpet hemocyanin (KLH).

Generation of the murinized rat anti-murine B7RP-1 monoclonal antibody JB7v2 A Chinese-Hamster-Ovary cell line that overexpressed a full-length murineB7RP-1 was injected into rats as a primary immunization, and subsequently with amurine B7RP-1-Fc fusion protein to boost the immune response. Spleens wereharvested 3 or 4 days post-intravenous boost and the splenic B cells fused with theY3-Agl.2.3 rat myeloma line (ATCC CRL-1631). Cells were then selected in mediasupplemented with hypoxanthine-aminopterin-thymidine (HAT) for 2 weeks andsubsequently single-cell subcloned by limiting dilution. These procedures aredescribed in "Practical Immunology, 2nd ed." Leslie Hudson and Frank C. Hay;Blackwell Scientific Publications 1980.

Genes encoding the 1B7 immunoglobulin were cloned from the 1B7 cell lineusing standard procedures (Sambrook et al., 2001, MOLECULAR CLONING: ALABORATORY manual, 3d ed., Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y). The isotype switch of the human anti-huB7RPl MAbs wasaccomplished by cloning the variable region fragments containing Xbal and BsmBlrestriction site cohesive ends into the pDSRa vector with the human IgGl or huIgG2constant region which also had Xbal and toiBI ends. For the 1B7 rat anti-muB7RPlthe chimera was formed by a three step overlapping PCR process. The rat variableregion was PCR amplified with a 3' primer that contained part, -25-35 nucleotides, ofthe murine constant region. The murine constant region was amplified with a 5'primer that contained part, -25-35 nucleotides, of the rat variable region. The twofragments were then used as template and the 5' rat variable region (Xbal containing)and the murine 3' constant region (Sail containing) primers were used to generate acomplete light chain or heavy chain. The light chain and heavy chain PCR productswere then digested with AM and SaR and cloned into pDSRa!9. A total of 25pg of 64 WO 2007/011941 PCT/US2006/027862 linearized DNA (12.5 qg pDC323B LC + 12.5 μg pDC324 HC) were transfected intoCS-9 cells using electroporation and selected on DHFR-supplemented medium.

To test the efficacy of the 1B7v2 mAb, plate co-stimulation assays wereconducted with this mAb. The results were compared with other anti-murine B7RP-1mAbs (Figure 10A). As discussed above, 1B7 is the original hybridoma-producedmAb; two different preparations (labeled 1.33 and 7.4) were tested. 5E1 and 11G10were other anti-mB7RP-l monoclonals generated in the fusions described above.Finally, HK5.3 was a commercially-available anti-mB7RP-l (ebiosciences # 16-5985-85).

The 1Β7ν2 mAb blocked T cell activation in this assay equal to or better thanany of the other mAbs, and thus was selected as the surrogate therapeutic for furtherstudies.

Antigen Challenge in Mice

Keyhole Limpet Hemocyanin (KLH) was purchased from PierceBiotechnology (Rockford, Illinois). Dosing solution #1 (KLH 5mg/kg in lmg/mouseALUM) was prepared with equal parts of 2x ALUM (500mg of ALUM plus 50mlPBS (phosphate buffered saline)) and 2x KLH (2.0ml dH20 (RNAse-Free) mixedwith 20mg of lyophilized KLH, brought to 20ml with lx PBS). Dosing solution #2(KLH lmg/kg in lmg/mouse ALUM) was prepared with 1 part 2x KLH mixed with 4parts lx phosphate buffered saline.

Female BALB/c mice were primed either with 1 mg/kg of KLH/alum and re-immunized on day 21 with 5mg/kg KLH only, introduced by intraperitoneal injection.Mice were treated by intraperitoneal injection with !B7v,2, the isotype controlantibody (anti-AGP3 PB) or the vehicle (PBS) alone, starting on day 1 (one day priorto priming with KLH/alum) in a final volume of 200μ1 every 5 days.

The mice were bled every 7 days retro-orbital ly (approximately 200μ1) toobtain approximately 50-1 ΟΟμΙ of serum for analysis of antigen-specific serum IgM(Figure 10B), IgG2a (Figure 10C), and IgGl (Figure 10D). Both the isotype-controland vehicle-treated mice showed significant primaiy and secondary immuneresponses. The IgM response was not affected by treatmenk whereas, blockade of 65 WO 2007/011941 PCT/US2006/027862 B7RP-1-IC0S with 1Β7ν2 decreased both primary and secondary IgG2a and IgGi responses in a statistically-significant manner. IL-5 is a cytokine released by T cells in response to antigen stimulation thatinduces B cell differentiation and function. As the B7RP-1/ICOS interaction isbelieved to be critical for T-cell-dependent B cell function, measuring serum IL-5levels was used to determine if interdiction of the B7RP-1/ICOS axis was indeedaffecting T cell function. As expected, blockade of B7RP-1 also inhibited antigen-induced serum IL-5 levels. Sera were harvested from the mice from the antigenchallenge experiment outlined above 24 hours after the antigen challenge on day 21,and serum IL-5 levels were determined by ELISA. As shown in Figure 11, elevatedIL-5 levels were detected in the test mice as early as 9 hours after challenge; levelsbegan to decline by 48 hours and returned to baseline by 72 hours. Treatment of themice with 1Β7ν2 mAb lead to a statistically significant repression of IL-5 levels at the24-hour time point.

Example 11

Binding to cvnomolgus monkey B7RP-1

To determine if the anti-hB7RP-l mAbs also bind to cynomolgus monkeyB7RP-1, flow cytometric staining experiments were conducted with the 16H mAb andB cells purified from cynomolgus monkeys and humans. As shown in Figure 12A,addition of fluorescently-labeled 16H to cyno B cells lead to staining, indicating that16H was indeed binding to cyno B7RP-1 (right panel). As expected, 16H also.stainedhuman B cells (left panel). In addition, 16H, 16Hg, and 5D were tested in plate co-stimulation assays using cyno T cells, cyno B7RP-1-Fc, and anti-CD3 mAb. Asshown in Figure 12B, ail three mAbs inhibited cyno B7RP-1-dependent cyno T cellactivation, indicating that these mAbs functionally block the cyno ICOS-B7RP-1interaction.

Example 12 T-Cell Dependent Antigen Responses in the Cynomolgus Monkey FollowingAdministration of the Anti-B7RP-1 Antibodies 66 PCT/US2006/027862 WO 2007/011941 A cynomolgus monkey study was conducted with two anti-B7RP-lmonoclonal antibodies, 16H and 5D, to assess the ability of these antibodies to inhibita T-cell dependent B cell antigen response as determined by serum levels of antigen-specific antibody. Briefly, the anti-keyhole limpet hemocyanin (KLH) and anti-tetanus toxoid antibody responses were examined following antigen challenge in thepresence of B7RP-1 antibodies in the cynomolgus monkey.

Test Article 1 was 16H and Test Article 2 was 5D. The Control Article wasthe vehicle for B7RP-1 antibody (0.01 sodium acetate, pH 5.0, 5% sorbitol, 0.004%Tween 20). Keyhole Limpet Hemocyanin (KLH) was purchased from PierceBiotechnology (Rockford, Illinois),

The KLH was prepared by reconstitution with sterile water to yield a 10mg/mL stock solution. The stock solution was diluted with sterile water to yield a 1mg/mL dosing solution. Tetanus Toxoid used for these experiments was Super-Tet®Tetanus Toxoid w/Havlogen®, purchased from Intervet™ Inc. (Milsboro, Delaware).The dose level for these experiments was 75 IU (0.5 mL of 150 IU/mL).

Table 6 shows the treatment group distribution of 28 cynomolgus monkeys.

Table 6

Group No. Number ofMales/Females Test Article Route Dose Level (mg/kg) Dose Volume (mL/kg) Dose SolutionCone. (mg/mL) 1 2/2 Control IV 0 1 0 2 2/2 B7RP-1 5D IV 0.1 1 0.1 3 2/2 B7RP-1 5D IV 1.0 1 1.0 4 2/2 B7RP-1 5D IV 8.0 1 10.0 5 2/2 B7RP-1 16H IV 0.1 1 0.1 6 2/2 B7RP-1 16H IV 1.0 1 1.0 7 2/2 B7RP-1 16H fV 8.0 1 10.0

Test article doses were administered via intravenous injection to all animals onDays 1, 8,15, 22, 29, 36, 43, and 50. Animals scheduled for necropsy in Groups 1-4(1/sex/group) received an additional dose on Day 57. Evaluation of immune responsewas conducted on all animals via immunization with KLH and tetanus toxoid antigensfollowed by blood sampling for antigen-specific immunoglobulins (IgM and IgG).

Titer values were present following primary administration of both the KLHand tetanus antigens. For KLH, primary titer values ranged from 0 to 900 for bothIgM and IgG. As the primary KLH challenge was administered prior to test article 67 PCT/US2006/027862 WO 2007/011941 administration, no effect of the B7RP-1 antibodies was evaluated. For tetanus toxoid,primary titer values ranged from 0 to 50 for IgM and from 0 to 4050 for IgG, Therewere no differences in the primary response to tetanus toxoid between the B7RP-1antibody groups and the control group.

As expected, titer values for IgG were increased following secondaryadministration of both the KLH and tetanus antigens, when compared to the primarytiter values. For KLH, secondary titer values ranged from 0 to 300 for IgM and from0 to 8100 for IgG. However, there was no evidence of inhibition of the KLHsecondary response attributed to administration of the B7RP-1 antibodies.

For tetanus toxoid, secondary titer values were below 50 for IgM and rangedfrom 1350 to 36450 for IgG. Results for individual animal and group mean values arepresented in the Figure 13 A (16H antibody) and Figure 13B (5D antibody) for Days53 and 57 following the secondary challenge with tetanus toxoid on Day 42.

On Day 53, the number of animals reaching peak response was 3/4, 1/4, and1/4 at the 0.1,1, and 8 mg/kg dose levels of 16H, respectively, and 1/4,1/4, and 1/4 atthe 0.1, 1, and 8 mg/kg dose levels of 5D respectively, compared to 2/4 controlanimals. Thus, in general, the number of animals reaching a high titer on Day 53 wasreduced in the B7RP-1 antibody-treated groups. On Day 57, titer values weremaintained in the control animals, while titer values for several of the B7RP-1antibody-treated animals declined from the Day 53 values. The number of animalswith high titers on Day 57 was 0/4, 0/4, and 1/4 at the 0.1,1, and 8 mg/kg dose levelsof 16H, respectively, and 0/4,0/4, and 0/4 at the 0.1,1, and 8 mg/kg dose levels of 5Drespectively, compared to 2/4 control animals.

These results demonstrated that the two B7RP-1 antibodies 16H and 5Dinhibited a T-cell dependent B cell antigen response in cynomolgus monkeys, asdetermined by serum levels of tetanus toxoid-specific antibody. In addition, thepresence of the B7RP-1 antibodies was important for blockage of the B7RP-1-ICOSinteraction during the primary response in order to detect an effect following thesecondary challenge.

These results and the results from Example 10 demonstrated that both thesurrogate therapeutic and the therapeutic candidates blocked T and B cell- dependentimmune responses in murine and monkey model systems, which indicated that 68 PCT/US2006/027862 WO 2007/011941 blocking this co-stimulatory axis may be efficacious in the treatment of B-cell-mediated diseases such as Systemic Lupus Erythematosus (SLE), asthma, andRheumatoid Arthritis (RA).

It should be understood that the foregoing disclosure emphasizes certain5 specific embodiments of the invention and that alt modifications or alternativesequivalent thereto are within the spirit and scope of the invention as set forth in the appended claims. 69 70 188642/2

SEQUENCE LISTING &lt;110&gt; Siu, JerryShen, DavidYoshinaga* SteveHuang, Haichun &lt;120&gt; Human anti-B7RPl Neutralizing Antibodies&lt;130&gt; 04-833 &lt;160&gt; 76 &lt;170&gt; Patentln version 3.3 &lt;210&gt; 1 &lt;211&gt; 107

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 1

Asp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Ala Ser val Gly 1 5 10 15 Asp Arg val Thr He Thr Cys Arg Ala Ser Gl n Gly lie Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Al a Pro Lys Ser Leu He 35 40 45 Tyr Ala Ala Ser Ser Leu Gin Ser Gly val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gl n Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Ser Tyr Pro Arg 85 90 95 Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 &lt;210&gt; 2 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 2 Glu lie val Leu Thr Gin Ser Pro Al a Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala ser Gl n Ser val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Gly Gin Al a Pro Arg Leu Leu lie 35 40 45 Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 71 188642/2 50 55 60 Ser Gly Ser Gly Thr ASp Phe Thr Leu Thr lie Ser Ser Leu Glu pro 65 70 75 80 Glu Asp Phe Ala val Tyr Tyr Cys Gin Gin Arg Asn Asn Trp Pro Trp 85 90 95 Thr Phe Gly Gl n Gly Thr Lys Val Glu ile Lys 100 105 &lt;210&gt; 3 &lt;211&gt; 107 &lt;212&gt; prt &lt;213&gt; Homo sapiens &lt;400&gt; 3 Asp Ile Gin Met Thr Gl n Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gin Gly Ile Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Al a Pro Lys Ser Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu Gin Ser Gly val Pro Ser Arg phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr ASp Phe Thr Leu Thr lie Ser ser Leu Gin pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Arg 85 90 95 Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys 100 105 &lt;210&gt; 4 &lt;211&gt; 108 &lt;212&gt; prt &lt;213&gt; Homo sapiens &lt;400&gt; 4 Glu Ile Val Leu Thr Gin Ser Pro Ala Thr Leu Ser Leu Ser Pro Gl y 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser val Ser Ser Tyr 20 25 30 Leu Ala Trp Tyr Gin Gl n Lys Pro Gly Gin Al a Pro Arg Leu Leu Ile 35 40 45 72 188642/2

Tyr Asp Ala Ser Asn Arg Ala Thr Gly lie Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala val Tyr Tyr Cys Gin Gin Arg Ser Asn Trp Pro Ala 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys val Glu lie Lys 100 105 &lt;2l0&gt; 5 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo sapi ens &lt;400&gt; 5 Asp lie Gin Met Thr Gl n Ser Pro Ser Ser Leu ser Ala Ser Val Gly 1 5 10 15 Asp Arg val Thr lie20 Thr Cys Arg Ala 25 Ser Gin Gly lie Ser 30 Ser Trp Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala pro Lys Ser Leu lie 35 40 45 Tyr Ala Al a Ser ser Leu Gl n Ser Gly Val Pro ser Arg Phe Ser Gl y 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gl n Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Thr Tyr Pro Arg 85 90 95 Thr Phe Gly Gl n Gl y Thr Lys Val Glu lie Lys 100 105 &lt;210&gt; 6 &lt;211&gt; 107 &lt;212&gt; PRT &lt;213&gt; Homo &lt;400&gt; 6 Asp lie Gin

Met Thr 5 Gin Ser Pro Ser Ser 10 Leu Ser Ala Ser val 15 Gly Thr lie Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30 Tyr Gin Gl n Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45 73 188642/2

Phe Ala Ala Ser Ser Leu Gin Ser Gly Val pro Ser Arg Phe Ser Gly SO 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gin Gly Thr Lys Leu Glu lie Lys 100 105 &lt;210&gt; 7 &lt;211&gt; 121 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 7 Glu Val Gin Leu val Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr Xie Lys Gin Asp Gly Asn Glu Lys Tyr Tyr Val ASp Ser val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly lie Leu Trp Phe Gly ASp Leu Pro Thr Phe Trp Gly 100 105 110 Gin Gly lie Leu val Thr val Ser Ser 115 120 &lt;210&gt; 8 &lt;211&gt; 121 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 8 Glu val Gin Leu val Glu Ser Gly Gly Gly Leu Val Gl n Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 74 188642/2

Trp Met Ser Trp Val35 Arg Gin Ala Pro40 Gly Lys Gly Leu Glu Trp val45 Al a Tyr lie Lys Gin Asp Gly Asn Glu Lys Tyr Tyr val Asp Ser val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Gl u Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Al a Arg Glu Gly lie Leu Trp Phe Gly Asp Leu Pro Thr phe Trp Gly 100 105 110 Gin Gly Thr Leu val Thr val Ser Ser 115 120 &lt;210&gt; 1 9 &lt;211&gt; 121 &lt;212&gt; PRT &lt;213&gt; I Homo sapiens &lt;400&gt; 9 Gin Val Gl n Leu val Glu Ser Gly Gly Gly val Val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu 20 Ser Cys Ala Al a Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr Gly Met Hi s Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ala val lie Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg Phe Thr lie Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gl n Met Asn Ser Leu Arg Ala Glu Asp Thr Al a val Phe Tyr cys 85 90 95 Ala Arg Asp Leu Asn lie Met val Trp Gly lie Phe ASp Tyr Trp Gly 100 105 110 Gin Gly Thr Leu val Thr Val Ser Ser 115 120 &lt;210&gt; 10 &lt;211&gt; 121

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 10 75 188642/2

Glu Val1 Gin Leu Val 5 Glu Ser Gly Gly Gly Leu Val10 Gin pro Gly Gly15 Ser Leu Arg Leu Ser Cys val Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Al a Tyr lie Lys Gl n Asp Gly Ser Glu Lys Tyr Tyr val ASp Ser val 50 55 60 Lys Gl y Arg phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg ASp Gly lie Leu Trp Phe Gly ASp lie Pro Thr Tyr Trp Gly 100 105 110 Gin Gly lie Leu val Thr val Ser Ser 115 120 &lt;210&gt; 11 &lt;211&gt; 121 &lt;212&gt; PRT &lt;213&gt; I Homo sapi ens &lt;400&gt; : 11 Gl u Val Gin Leu val Glu Ser Gly Gly Gly Leu Val Gl n pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gl n Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ala Tyr lie Lys Gin Asp Gly Ser Glu Lys Tyr Tyr val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala val Tyr Tyr Cys 85 90 95 Ala Arg ASp Gly Xie Leu Trp Phe Gly Asp lie pro Thr Tyr Trp Gly 100 105 110

Gin Gly Thr Leu val Thr val Ser Ser115 120 76 188642/2 &lt;210&gt; 12 &lt;211&gt; 120

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 12

Glu Val1 Gin Leu val 5 Gin Ser Gly Gly Gly Leu10 val His Pro Gl y Gl y15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Hi s Trp Val Arg Gin Al a pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ser Ala He Gly Thr Gly Gly Gly Thr Tyr Tyr Ala ASp Ser val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Al a Glu ASp Met Al a Met Tyr Tyr Cys Ala 85 90 95 Lys Ser Gly Val Pro Leu Leu Trp phe Gly Glu Phe Tyr Trp Gly Gin 100 105 110 Gly Thr Leu val Thr val Ser Ser 115 120 &lt;210&gt; 13 &lt;211&gt; 121 &lt;212&gt; PRT &lt;213&gt; i Homo sapiens &lt;400&gt; ' 13 Glu val Gl n Leu val Glu Ser Gly Gly Gly Leu Val Gl n Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gl n Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr50 lie, Lys Gin Asp Gly 55 Ser Glu Lys Tyr Tyr 60 Val Asp Ser Val Lys Gly Arg Phe Thr He Ser Arg Asp Asn Al a Lys Asn Ser Leu Tyr 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys85 90 95 77 188642/2

Ala Arg Asp Gly lie Leu Trp Phe Gly Asp Leu Pro Thr Tyr Trp Gly 100 105 110 Gin Gly Thr. Leu val Thr Val Ser Ser 115 120 &lt;210&gt; 14 &lt;211&gt; 118 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 14 Glu Val Gin Leu val Gin Ser Gly Gly Gly Leu val His Pro Gly Gly 1 5 10 15 ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr phe Ser Ser Tyr 20 25 30 Ala Met His Trp val Arg Gin Ala Pro Gly Lys Gly Leu Gl U Trp val 35 40 45 Ser Ala lie Gly Al a Gly Gly Gly Thr Tyr Tyr Al a ASp Ser Val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Al a Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys Al a 85 90 95 Arg val val Val val val Gly Phe Phe Asp Tyr Trp Gly Gl n Gly Thr 100 105 110

Leu Val Thr val Ser Ser115 &lt;210&gt; 15 &lt;211&gt; 11

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 15

Arg Ala Ser Gin Gly lie Ser Asn Trp Leu Ala1 5 10 &lt;210&gt; 16 &lt;211&gt; 7

&lt;212&gt; PRT &lt;213&gt; Homo sapiens&lt;400&gt; 16

Ala Ala Ser Ser Leu Gin Ser1 5 78 188642/2 &lt;210&gt; 17 &lt;211&gt; 9

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 17

Gin Gin Tyr Asp Ser Tyr Pro Arg Thr &lt;210&gt; 18 &lt;211&gt; 11

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 18

Arg Ala Ser Gin Ser Val Ser Ser Tyr Leu Ala1 5 10 &lt;210&gt; 19 &lt;211&gt; 7

&lt;212&gt; PRT &lt;213&gt; Homo sapiens&lt;400&gt; 19

Asp Ala Ser Asn Arg Ala Thr1 5 &lt;210&gt; 20 &lt;211&gt; 9

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 20

Gin Gin Arg Asn Asn Trp Pro Trp Thr1 5 &lt;210&gt; 21 &lt;211&gt; 7

&lt;212&gt; PRT &lt;213&gt; Homo sapiens&lt;400&gt; 21

Thr Ala Ser Ser Leu Gin Ser1 5 &lt;210&gt; 22 &lt;211&gt; 9

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 22

Gin Gin Tyr Asn Ser Tyr Pro Arg Thr &lt;210&gt; 23

&lt;211&gt; 10&lt;212&gt; PRT 79 188642/2

&lt;213&gt; &lt;400&gt; Gin Gli1 Homo 23 n Arg sapiens Ser Asn Trp5 Pro Ala &lt;210&gt; 24 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 24 Arg Ala Ser Gin Gly lie Ser Ser 1 5 &lt;210&gt; 25 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Homo sapi ens &lt;400&gt; 25 Gin Gin Tyr Asn Thr Tyr Pro Arg 1 5 &lt;210&gt; 26 &lt;211&gt; 9 &lt;212&gt; PRT &lt;213&gt; Homo sapi ens &lt;400&gt; 26 Gin Gin Tyr Asn Ser Tyr pro Tyr 1 5 &lt;210&gt; 27 &lt;211&gt; 5 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 27 Ser Tyr Trp Met Ser 1 5 &lt;21O&gt; 28 &lt;211&gt; 17 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 28 Tyr lie i Lys Gin Asp Gly Asn Glu 1 5 Gly &lt;210&gt; 29 &lt;211&gt; 12 &lt;212&gt; PRT

Leu Thr10

Trp Leu Ala10

Thr

Lys Tyr Tyr val Asp Ser val Lys10 15 80 188642/1 &lt;213&gt; Homo sapiens &lt;400&gt; 29

Glu Gly lie Leu Trp Phe Gly Asp Leu Pro Thr Phe1 5 10 &lt;210&gt; 30 &lt;211&gt; 5

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 30

Ser Tyr Gly Met His1 5 &lt;210&gt; 31 &lt;211&gt; 17

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 31

Val lie Trp Tyr Asp Gly ser Lys Lys Tyr Tyr Ala Asp Ser val Glu15 10 15

Gly &lt;210&gt; 32 &lt;211&gt; 12

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 32

Asp Leu Asn lie Met Val Trp Gly lie Phe Asp Tyr15 10 &lt;210&gt; 33 &lt;211&gt; 17

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 33

Tyr lie Lys Gin Asp Gly Ser Glu Lys Tyr Tyr val Asp Ser val Lys15 10 15

Gly &lt;210&gt; 34 &lt;211&gt; 12

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 34

Asp Gly lie Leu Trp Phe Gly Asp lie Pro Thr Tyr1 5 10 81 188642/1 &lt;210&gt; 35 &lt;211&gt; 5 &lt;212&gt; PRT&lt;213&gt; Homo&lt;400&gt; 35

Ser Tyr Ala1 &lt;210&gt; 36 &lt;211&gt; 16&lt;212&gt; PRT&lt;213&gt; Homo&lt;400&gt; 36

Ala lie Gly1 &lt;210&gt; 37 &lt;211&gt; 11&lt;212&gt; PRT&lt;213&gt; Homo&lt;400&gt; 37

Gly Val Pro1 &lt;210&gt; 38 &lt;211&gt; 12 &lt;212&gt; PRT &lt;213&gt; Homo &lt;400&gt; 38 Asp Gl1 y Xie &lt;210&gt; 39 &lt;211&gt; 16 &lt;212&gt; PRT &lt;213&gt; Homo &lt;400&gt; 39 Ala lie Gly 1 &lt;210&gt; 40 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Homo &lt;400&gt; 40 sapiens

Met His5 sapi ens

Thr Gly Gly5 sapi ens

Leu Leu Trp5 sapiens

Leu Trp Phe5 sapiens

Ala Gly Gly5 sapiens

Gly Thr

Tyr Tyr10

Ala Asp Ser Val Lys Gly15

Phe Gly

Gly Asp

Gly Thr val val val val1 &lt;210&gt; 41 &lt;211&gt; 326

&lt;212&gt; PRT

Glu Phe10

Leu Pro10

Tyr Tyr10 val Gly Phe Phe Asp Tyr5 10

Tyr

Thr Tyr

Ala Asp Ser val Lys Gly15 82 188642/1 &lt;213&gt; I lomo sap’ iens &lt;400&gt; 41 Ala Ser Thr Lys Gly Pro Ser val Phe Pro Leu Ala Pro Cys Ser Arg 1 5 10 15 Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu val Lys ASp Tyr 20 25 30 Phe Pro Glu pro val Thr val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly val His Thr Phe Pro Ala val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val val Thr val Pro Ser Ser Asn Phe Gly Thr Gin Thr 65 70 75 80 Tyr Thr Cys Asn val ASp Hi s Lys Pro Ser Asn Thr Lys val Asp Lys 85 90 95 Thr val Glu Arg Lys Cys Cys val Glu Cys Pro Pro Cys Pro Ala Pro 100 105 110 Pro val Ala Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp 115 120 125 Thr Leu Met lie Ser Arg Thr pro Glu val Thr Cys Val val val Asp 130 135 140 val Ser Hi s Glu ASp Pro Glu Val Gin Phe Asn Trp Tyr Val Asp Gly 145 150 155 160 val Glu val Hi s Asn Ala Lys Thr Lys Pro Arg Glu Glu Gl n Phe Asn 165 170 175 Ser Thr Phe Arg val val Ser val Leu Thr Val val His Gin ASp Trp 180 185 190 Leu Asn Gly Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Gly Leu Pro 195 200 205 Ala Pro ile Gl u Lys Thr Ile Ser Lys Thr Lys Gly Gl n Pro Arg Glu 210 215 220 Pro Gin val Tyr Thr Leu pro Pro Ser Arg Glu Glu Met Thr Lys Asn 225 230 235 240 Gin Val Ser Leu Thr cys Leu val Lys Gly Phe Tyr Pro Ser Asp Ile 245 250 255 Ala val Glu Trp Gl u ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr 260 265 270 83 188642/1

Thr Pro pro Met Leu ASp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 275 280 285 Leu Thr val Asp Lys Ser Arg Trp Gin Gl n Gly Asn val Phe Ser Cys 290 295 300 Ser Val Met Hi s Glu Ala Leu His Asn Hi s Tyr Thr Gin Lys Ser Leu 305 310 315 320 Ser Leu Ser Pro Gly Lys 325 &lt;210&gt; 42 &lt;211&gt; 330

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 42

Ala 1 Ser Thr Lys Gly Pro Ser val 5 Phe Pro Leu Ala Pro Ser Ser Lys 10 15 Ser Thr Ser Gly 20 Gly Thr Ala Ala Leu 25 Gly Cys Leu val Lys 30 ASp Tyr Phe Pro Gl u Pro Val Thr val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly val Hi s Thr Phe Pro Al a val Leu Gin Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser val val Thr val Pro Ser Ser Ser Leu Gly Thr Gin Thr 65 70 75 80 Tyr lie Cys Asn val Asn Hi s Lys Pro Ser Asn Thr Lys val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr Hi s Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu phe Pro Pro 115 120 125 Lys Pro Lys ASp Thr Leu Met lie Ser Arg Thr Pro Glu val Thr Cys 130 135 140 val Val val ASp val Ser Hi s Glu ASp pro Glu val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu val Hi s Asn Ala Lys Thr Lys pro Arg Glu 165 170 175

Glu Gin Tyr Asn Ser Thr Tyr Arg Val val Ser val Leu Thr Val Leu 84 188642/1 180 185 190 Hi s Gin ASp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys val Ser Asn 195 200 205 Lys Ala Leu pro Ala Pro lie Glu Lys Thr He Ser Lys Ala Lys Gly 210 215 220 Gl n Pro Arg Glu Pro Gin val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gin val ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Il e Al a Val Glu Trp Glu Ser Asn Gly Gin Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser ASp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr val ASp Lys Ser Arg Trp Gl n Gin Gly Asn 290 295 300 val Phe Ser Cys Ser Val Met Hi s Glu Ala Leu His Asn HIS Tyr Thr 305 310 315 320 Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 &lt;2l0&gt; - 43 &lt;211&gt; : 107 &lt;212&gt; I PRT &lt;21; J&gt; I rHomo sap‘ iens &lt;400&gt; 43 Arg Thr val Ala Ala pro Ser Val Phe lie Phe pro Pro Ser Asp Glu 1 5 10 15 Gin Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gin Trp Lys val Asp Asn Ala Leu Gin 35 40 45 Ser Gly Asn Ser Gin Glu Ser val Thr Glu Gl n Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Al a Cys Gl u Val Thr Hi s Gin Gly Leu Ser Ser 85 90 95 85 188642/1

Pro val Thr Lys Ser Phe Asn Arg Gly Glu Cys100 105 &lt;210&gt; 44 &lt;211&gt; 447 &lt;212&gt; PRT&lt;213&gt; Homo sapiens&lt;400&gt; 44

Glu val1 Gin Leu val 5 Glu Ser Gly Gly Gly Leu10 val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Al a Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ala Tyr lie Lys Gin Asp Gly Asn Glu Lys Tyr Tyr Val ASp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Ala val Tyr Tyr Cys 85 90 95 Al a Arg Glu Gly lie Leu Trp Phe Gly Asp Leu Pro Thr Phe Trp Gly 100 105 110 Gl n Gly lie Leu val Thr val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Al a Leu Thr Ser Gly val His Thr Phe Pro Ala 165 170 175 val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val ASp His 195 200 205 Lys Pro Ser Asn Thr Lys val Asp Lys Thr val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 240 86 188642/1

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255 Pro Glu val Thr Cys val Val val ASp val Ser Hi s Glu ASp pro Glu 260 265 270 val Gin Phe Asn Trp Tyr val ASp Gly val Glu val Hi s Asn Al a Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gl n Phe Asn Ser Thr Phe Arg val val Ser 290 295 300 Val Leu Thr val Val Hi s Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Al a Pro Tie Glu Lys Thr Tie 325 330 335 Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Gl U Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser ASP lie Ala val Glu Trp Glu Ser Asn 370 375 380 Gly Gin pro Glu Asn Asn Tyr cys Thr Thr pro Pro Met Leu Asp Ser 385 390 395 400 ASp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val ASp Lys Ser Arg 405 410 415 Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met His Glu Ala Leu 420 425 430 Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; , 45 &lt;2ii&gt; ; 214 &lt;212&gt; PRT &lt;213&gt; 1 Homo sapi ens &lt;400&gt; - 45 Asp lie Gin Met Thr Gin Ser pro Ser Ser Leu Ser Ala Ser val Gly 1 5 10 15 ASp Arg val Thr lie Thr Cys Arg Ala Ser Gin Gly He Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45 87 188642/1

Tyr Ala Ala50 Ser Ser Leu Gin Ser Gly55 val Pro Ser Arg60 Phe Ser Gly Ser Gly Ser Gl y Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asp Ser Tyr Pro Arg 85 90 95 Thr Phe Gly Gl n Gly Thr Lys Val Glu lie Lys Arg Thr val Ala Ala 100 105 110 Pro Ser Val Phe lie Phe pro Pro Ser ASp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys val Gin Trp Lys Val Asp Asn Ala Leu Gl n Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser Val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Gl u Lys His Lys val Tyr 180 185 190 Ala cys Gl u Val Thr Hi S Gl n Gly Leu Ser Ser Pro val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys210 &lt;210&gt; 46 &lt;211&gt; 447

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 46

Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu val Gin pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Al a Tyr lie Lys Gin ASp Gly Asn Glu Lys Tyr Tyr Val Asp Ser val 50 55 60

Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 88 188642/1 65 70 75 80

Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala90 val Tyr Tyr 95 Cys 85 Ala Arg Glu Gly lie Leu Trp Phe Gly ASP Leu Pro Thr Phe Trp Gly 100 105 110 Gin Gly Thr Leu val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 val phe pro Leu Ala pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Al a 130 135 140 Ala Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr val 145 150 155 160 Ser Trp Asn Ser Gly Al a Leu Thr Ser Gly val His Thr Phe Pro Ala 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val Val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val ASp His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 val Glu Cys Pro Pro Cys Pro Ala Pro pro val Ala Gly pro Ser val 225 230 235 240 Phe Leu Phe pro Pro Lys Pro Lys Asp Thr Leu Met lie ser Arg Thr 245 250 255 Pro Gl u Val Thr Cys val val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Gin Phe Asn Trp Tyr val Asp Gly val Glu val Hi s Asn Al a Lys 275 280 285 Thr Lys Pro Arg Glu Gl u Gin Phe Asn Ser Thr Phe Arg Val val Ser 290 295 300 val Leu Thr val val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys val Ser Asn Lys Gly Leu Pro Al a Pro Il e Glu Lys Thr lie 325 330 335 Ser Lys Thr Lys Gly Gin Pro Arg Glu pro Gin val Tyr Thr Leu Pro 340 345 350 89 188642/1

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin Val Ser Leu Thr365 Cys Leu 355 360 val Lys Gly Phe Tyr Pro Ser Asp lie Ala val Glu Trp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 ASp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val Asp Lys Ser Arg 405 410 415 Trp Gin Gl n Gly Asn Val Phe Ser Cys Ser Val Met Hi s Glu Ala Leu - 420 425 430 Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 47 &lt;211&gt; 451 &lt;212&gt; PRT &lt;213&gt; I Homo sapi ens &lt;400&gt; 47 Gin val Gin Leu Val Glu Ser Gly Gly Gly val val Gin Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met Hi s Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val lie Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Glu Gly Arg phe Thr lie ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Al a Glu Asp Thr Ala val Phe Tyr cys 85 90 95 Ala Arg Asp Leu Asn lie Met Val Trp Gly lie Phe Asp Tyr Trp Gly 100 105 110 Gin Gly Thr Leu val Thr val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Al a Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr val 145 150 155 160 90 188642/1

Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly val170 Hi s Thr Phe Pro 175 Ala 165 val Leu Gl n Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gl n Thr Tyr lie Cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys val Asp Lys Lys val Gl u Pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys pro pro Cys Pro Al a Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser val Phe Leu Phe pro Pro Lys Pro Lys ASp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr Cys Val val Val Asp Val Ser Hi s 260 265 270 Glu Asp Pro Glu val Lys Phe Asn Trp Tyr Val Asp Gly val Glu val 275 280 285 His Asn Al a Lys Thr Lys Pro Arg Glu Gl u Gin Tyr Asn Ser Thr Tyr 290 295 300 val Val Ser Val Leu Thr val Leu Hi s Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Ala Leu Pro Ala Pro lie 325 330 335 Glu Lys Thr He Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin val Ser 355 360 365 Leu Thr Cys Leu val Lys Gly Phe Tyr Pro Ser Asp lie Al a Val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 91‘ 188642/1 HIS Glu Ala Leu435 His Asn His Tyr 440 Thr Gin Lys Ser Leu Ser445 Leu Ser Pro Gly Lys 450 &lt;210&gt; - 48 &lt;211&gt; ; 214 &lt;212&gt; l PRT &lt;213&gt; 1 -io mo sapiens &lt;400&gt; ‘ 48 Gl u lie Val Leu Thr Gl n Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Al a Thr Leu Ser Cys Arg Ala Ser Gin Ser val Ser Ser Tyr 20 25 30 Leu Al a Trp Tyr Gl n Gin Lys Pro Gly Gin Ala Pro Arg Leu Leu lie 35 40 45 Tyr ASp Ala Ser Asn Arg Ala Thr Gly lie Pro Al a Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Glu Pro 65 70 75 80 Glu ASp Phe Ala val Tyr Tyr Cys Gin Gin Arg Asn Asn Trp Pro Trp 85 90 95 Thr Phe Gly Gin Gly Thr Lys val Glu lie Lys Arg Thr val Al a Ala 100 105 110 Pro Ser Val Phe lie Phe Pro Pro Ser Asp Gl u Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Al a 130 135 140 Lys Val Gin Trp Lys val Asp Asn Ala Leu Gl n Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser Val Thr Gl u Gin ASp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys Hi s Lys Val Tyr 180 185 190 Ala Cys Glu val Thr Hi s Gin Gly Leu Ser Ser Pro val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu cys210 92 188642/1 &lt;210&gt; 49 &lt;211&gt; 433

&lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 49

Arg 1 Thr Val Ala Ala 5 Pro Ser val Phe lie Phe Pro Pro Ser Asp Glu 10 15 Gin Leu Lys Ser Gly Thr Ala Ser Val val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Al a Lys val Gin Trp Lys val Asp Asn Ala Leu Gin 35 40 45 Ser Gly Asn Ser Gin Glu Ser val Thr Glu Gin Asp Ser Lys Asp Ser 50 55 60 Thr Tyr ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys Hi s Lys val Tyr Ala cys Glu Val Thr Hi s Gin Gly Leu Ser Ser 85 90 95 Pro val Thr Lys Ser Phe Asn Arg Gly Glu Cys Ala Ser Thr Lys Gly 100 105 110 Pro Ser val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 115 120 125 Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro val 130 135 140 Thr val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val HIS Thr Phe 145 150 155 160 Pro Ala Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val 165 170 175 Thr val Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val 180 185 190 Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr val Glu Arg Lys 195 200 205 Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 210 215 220 Ser val Phe Leu Phe Pro pro Lys Pro Lys Asp Thr Leu Met lie Ser 225 230 235 240

Arg Thr Pro Glu val Thr Cys Val val val Asp val Ser His Glu Asp 93 188642/1 245 250 255

Pro Glu val Gin 260 Phe Asn Trp Tyr val265 Asp Gly val Glu val270 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg val 275 280 285 val Ser val Leu Thr Val val Hi s Gin Asp Trp Leu Asn Gly Lys Glu 290 295 300 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Al a pro lie Glu Lys 305 310 315 320 Thr He Ser Lys Thr 325 Lys Gly Gin Pro Arg 330 Glu Pro Gl n val Tyr 335 Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gin val Ser Leu Thr 340 345 350 Cys Leu val Lys Gly Phe Tyr Pro Ser Asp Il e Al a Val Glu Trp Glu 355 360 365 Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr pro Pro Met Leu 370 375 380 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 385 390 395 400 Ser Arg Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met Hi s Glu 405 410 415 Ala Leu Hi s Asn His Tyr Thr Gl n Lys Ser Leu Ser Leu Ser Pro Gly 420 425 430 Lys &lt;210&gt; 50 &lt;211&gt; 214 &lt;212&gt; PRT &lt;213&gt; Homo sapi ens &lt;400&gt; 50 ASp He Gl n Met Thr Gin Ser pro Ser Ser Leu Ser Ala Ser val Gly 1 5 10 15 ASp Arg val Thr He Thr Cys Arg Ala Ser Gin Gly He Ser Asn Trp 20 25 30 Leu Ala Trp Tyr Gl n Gl n Lys Pro Glu Lys Ala Pro Lys Ser Leu He 35 40 45 94 188642/1

Tyr Thr Ala Ser Ser Leu Gin Ser Gly val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin Pro 65 70 75 80 Gl u Asp Phe Al a Thr Tyr Tyr Cys Gin Gin Tyr Asn Ser Tyr Pro Arg 85 90 95 Thr Phe Gly Gin Gl y Thr Lys val Glu lie Lys Arg Thr val Ala Ala 100 105 110 Pro Ser val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys val Gin Trp Lys val ASp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser val Thr Glu Gin ASP Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu val Thr HIS Gl n Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 &lt;210&gt; 51 &lt;211&gt; ‘ 447 &lt;212&gt; i PRT &lt;213&gt; l Homo sap· i ens &lt;400&gt; ! 51 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu val Gl n Pro Gly Gly 1 ί 5 10 15 Ser Leu Arg Leu Ser Cys Ala Al a Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Al a Tyr lie Lys Gin Asp Gly Ser Glu Lys Tyr Tyr val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 95 188642/1

Leu Gin Met Asn Ser 85 Leu Arg Ala Ala Arg ASp Gly 100 Ile Leu Trp Phe Gin Gly Thr 115 Leu val Thr val Ser 120 val Phe 130 pro Leu Al a Pro Cys 135 Ser Ala 145 Leu Gly Cys Leu val 150 Lys Asp Ser Trp Asn Ser Gly 165 Ala Leu Thr val Leu Gin Ser 180 Ser Gly Leu Tyr Pro Ser Ser 195 Asn Phe Gly Thr Gin 200 Lys Pro 210 Ser Asn Thr Lys val 215 Asp Val 225 Glu Cys Pro Pro Cys 230 Pro Ala Phe Leu Phe Pro Pro 245 Lys Pro Lys Pro Glu val Thr 260 Cys Val val val val Gin Phe 275 Asn Trp Tyr val Asp 280 Thr Lys 290 Pro Arg Glu Glu Gin 295 Phe Val 305 Leu Thr val val Hi s310 Gin Asp Cys Lys Val Ser Asn 325 Lys Gly Leu Ser Lys Thr Lys 340 Gly Gl n Pro Arg

Glu Asp Thr Ala val Tyr Tyr Cys 90 95 Gly 105 ASp Ile Pro Thr Tyr 110 Trp Gly Ser Ala Ser Thr Lys 125 Gly pro Ser Arg Ser Thr Ser 140 Glu Ser Thr Ala Tyr Phe Pro 155 Glu Pro val Thr Val 160 Ser Gly 170 Val Hl s Thr Phe Pro 175 Ala Ser 185 Leu Ser Ser val val 190 Thr val Thr Tyr Thr Cys Asn 205 val Asp His Lys Thr val Glu 220 Arg Lys Cys Cys Pro Pro val 235 Al a Gly Pro Ser val 240 Asp Thr 250 Leu Met Ile Ser Arg 255 Thr Asp 265 Val Ser Hl S Glu Asp 270 Pro Glu Gly Val Glu Val His 285 Asn Al a Lys Asn Ser Thr Phe 300 Arg Val val Ser Trp Leu Asn 315 Gly Lys Glu Tyr Lys 320 Pro Ala 330 Pro lie Glu Lys Thr 335 Ile Glu Pro Gin val Tyr Thr Leu Pro 345 350 96 188642/1

Pro Ser Arg Glu Glu Met Thr Lys Asn Gin val360 Ser Leu365 Thr Cys Leu 355 val Lys Gly Phe Tyr Pro Ser Asp lie Ala val Glu Trp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met Hi s Gl u Ala Leu 420 425 430 His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser pro Gly Lys 435 440 445 &lt;210&gt; 52 &lt;211&gt; ‘ 444 &lt;212&gt; 1 PRT &lt;213&gt; 1 Homo sapi ens &lt;400&gt; 52 Glu Val Gin Leu val Gin Ser Gly Gly Gly Leu val Hl s Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Gly Ser Gly phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Hi s Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala lie Gly Ala Gly Gly Gly Thr Tyr Tyr Ala Asp Ser val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Ala Glu Asp Met Ala val Tyr Tyr Cys Ala 85 90 95 Arg val Val val Val100 val Gly Phe Phe 105 ASp Tyr Trp Gly Gin 110 Gly Thr Leu val Thr Val Ser Ser Ala ser Thr Lys Gly Pro Ser val Phe Pro 115 120 125 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 130 135 140 Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr val ser Trp Asn 145 150 155 160 97 188642/1

Ser Gly Ala Leu Thr165 Ser Gly Val His Thr Phe170 Pro Al a val Leu 175 Gl n Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val val Thr val pro Ser Ser 180 185 190 ASH Phe Gly Thr Gl n Thr Tyr Thr Cys Asn val Asp Hi s Lys pro Ser 195 200 205 Asn Thr Lys val Asp Lys Thr Val Glu Arg Lys cys Cys Val Glu Cys 210 215 220 Pro Pro Cys Pro Ala Pro Pro val Ala Gly pro Ser val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys ASp Thr Leu Met lie Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys val val val Asp Val Ser His Glu Asp pro Glu Val Gin Phe 260 265 270 Asn Trp Tyr Val Asp Gly val Gl u Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val val Ser Val Leu Thr 290 295 300 val Val Hi s Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ala Pro He Glu Lys Thr lie Ser Lys Thr 325 330 335 Lys Gly Gin Pro Arg Glu Pro Gin Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350 Glu Glu Met Thr Lys Asn Gin val Ser Leu Thr Cys Leu val Lys Gly 355 360 365

Phe Tyr Pro370 Ser Asp lie Ala val375 Glu Trp Glu Ser 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu ASP Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Lys Leu Thr val ASp Lys Ser Arg Trp Gl n Gin 405 410 415

Gly Asn val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn his420 425 430 98 188642/1

Tyr Thr Gin Lys Ser Leu Ser Leu440 Ser Pro Gly Lys 435 &lt;210&gt; ! 53 &lt;2ii&gt; ; 214 &lt;212&gt; 1 PRT &lt;213&gt; I Homo sapi ens &lt;400&gt; ! 53 ASp lie Gin Met Thr Gin Ser Pro Ser Ser Leu Ser Al a Ser val Gly 1 5 10 15 ASp Arg val Thr Ile Thr Cys Arg Al a Ser Gin Gly Ile Ser Ser Trp 20 25 30 Leu Al a Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45 Phe Ala Ala Ser Ser Leu Gl n Ser Gly val Pro Ser Arg phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gin Pro 65 70 75 80 Gl u Asp Phe Al a Thr Tyr Tyr Cys Gin Gl n Tyr Asn Ser Tyr Pro Tyr 85 90 95 Thr Phe Gly Gl n Gly Thr Lys Leu Glu lie Lys Arg Thr val Al a Ala 100 105 110 Pro Ser val Phe Ile Phe Pro Pro Ser ASp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys val Gin Trp Lys val ASp Asn Al a Leu Gl n Ser Gly Asn Ser Gin 145 150 155 160 Gl u Ser val Thr Glu Gin Asp Ser Lys ASp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala ASp Tyr Glu Lys Hi s Lys val Tyr 180 185 190 Ala Cys Glu Val Thr Hi s Gl n Gly Leu Ser Ser Pro val Thr Lys Ser 195 200 205

Phe Asn Arg Gly Glu Cys210 &lt;210&gt; 54 &lt;211&gt; 447 99 188642/1 &lt;212&gt; I PRT &lt;213&gt; 1 -iomo sapn iens &lt;400&gt; 54 Glu Val Gin Leu val Glu Ser Gly Gly Gly Leu val Gin pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Al a Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Gl u Trp val 35 40 45 Ala Tyr Xie Lys Gin Asp Gly Ser Gl u Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Al a Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gl n Met Asn Ser Leu Arg Ala Glu ASp Thr Al a val Tyr Tyr Cys 85 90 95 Al a Arg Asp Gl y lie Leu Trp Phe Gly Asp Leu Pro Thr Tyr Trp Gly 100 105 110 Gin Gly Thr Leu Val Thr val Ser Ser Al a Ser Thr Lys Gly Pro Ser 115 120 125 val Phe Pro Leu Ala Pro cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 130 135 140 Ala Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly val His Thr Phe Pro Ala 165 170 175 val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr Val 180 185 190 Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val Asp Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val ASp Lys Thr val Glu Arg Lys Cys Cys 210 215 220 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 225 230 235 1 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie Ser Arg Thr 245 250 255

Pro Glu val Thr Cys Val val val Asp val Ser His Glu Asp Pro Glu 100 188642/1 260 265 270 val Gin Phe Asn Trp Tyr275 val Asp Gly val280 Glu val His Asn285 Ala Lys Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg val val Ser 290 295 300 Val Leu Thr val Val Hi s Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys val ser Asn Lys Gly Leu Pro Ala Pro lie Glu Lys Thr lie 325 330 335 Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Gl u Glu Met Thr Lys Asn Gin Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser ASp lie Al a val Glu Trp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val Asp Lys Ser Arg 405 410 415 Trp Gin Gin Gly Asn val Phe Ser cys Ser val Met His Glu Al a Leu 420 425 430 Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser pro Gly Lys 435 440 445 &lt;210&gt; 55 &lt;211&gt; 214 &lt;212&gt; PRT &lt;213&gt; I Homo sapi ens &lt;400&gt; 55 ASp lie Gin Met Thr Gin Ser pro Ser Ser Leu Ser Ala Ser val Gly 1 5 10 15 Asp Arg val Thr lie Thr Cys Arg Ala Ser Gl n Gly lie Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gin Gin Lys pro Glu Lys Ala Pro Lys Ser Leu He 35 40 45 Tyr Al a Al a Ser Ser Leu Gin Ser Gly val Pro Ser Arg Phe Ser Gly 50 55 60 101 188642/1

Ser Gly65 Ser Gly Thr Asp Phe Thr Leu Thr lie Ser Ser Leu Gin pro 80 70 75 Glu ASp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn Thr Tyr pro Arg 85 90 95 Thr Phe Gly Gin Gly Thr Lys Val Glu lie Lys Arg Thr val Ala Al a 100 105 110 Pro Ser val Phe lie Phe Pro Pro Ser Asp Glu Gin Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gin Trp Lys val Asp Asn Ala Leu Gin Ser Gly Asn Ser Gin 145 150 155 160 Glu Ser val Thr Glu Gin Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys val Tyr 180 185 190 Ala Cys Glu val Thr His Gin Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 &lt;210&gt; 56 &lt;211&gt; 446 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 56 Glu Val Gin Leu val Gin Ser Gly Gly Gly Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Ala Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Hl S Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ser Ala lie Gly Thr Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gin Met Asn ser Leu Arg Ala Glu Asp Met Ala Met Tyr Tyr Cys Ala 85 90 95 102 188642/1

Lys Ser Gly Val Pro Leu Leu Trp Phe Gly Glu Phe105 Tyr Trp 110 Gly Gin 100 Gly Thr Leu val Thr val Ser Ser Ala Ser Thr Lys Gly pro Ser val 115 120 125 phe Pro Leu Al a Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Al a 130 135 140 Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Hi s Thr Phe Pro Ala val 165 170 175 Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val Pro 180 185 190 Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val Asp Hi s Lys 195 200 205 pro Ser Asn Thr Lys val Asp Lys Thr val Glu Arg Lys Cys Cys Val 210 215 220 Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Al a Gly Pro Ser val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys ASp Thr Leu Met lie Ser Arg Thr Pro 245 250 255 Glu val Thr Cys Val val Val Asp Val Ser Hi s Glu Asp Pro Glu val 260 265 270 Gin Phe Asn Trp Tyr val Asp Gly val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Gl u Gin Phe Asn Ser Thr Phe Arg val val Ser val 290 295 300 Leu Thr val val Hi s Gl n ASp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gly Leu Pro Al a Pro lie Glu Lys Thr lie Ser 325 330 335 Lys Thr Lys Gly Gl n Pro Arg Glu Pro Gin val Tyr Thr Leu pro Pro 340 345 350 Ser Arg Glu Gl u Met Thr Lys Asn Gl n Val Ser Leu Thr Cys Leu val 355 360 365 103 188642/1

Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu Trp 380 Glu Ser Asn Gly 370 375 Gin pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val Asp Lys Ser Arg Trp 405 410 415 Gin Gl n Gly Asn Val Phe Ser Cys Ser val Met Hi s Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 57 &lt;211&gt; &lt; 450 &lt;212&gt; I PRT &lt;213&gt; 1 Homo sapi ens &lt;400&gt; 57 Glu val Gl n Leu Val Gin Ser Gly Gly Gly Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Al a Met Hi s Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ser Ala lie Gly Thr Gly Gly Gly Thr Tyr Tyr Ala ASp Ser val Lys 50 55 60 Gly Arg Phe Thr lie Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80 Gin Met Asn Ser Leu Arg Ala Glu Asp Met Ala Met Tyr Tyr Cys Ala 85 90 95 Lys Ser Gly val Pro Leu Leu Trp Phe Gly Glu Phe Tyr Trp Gly Gin 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Al a Ser Thr Lys Gly Pro Ser val 115 120 125 Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Al a 130 135 140 Leu Gly Cys Leu val Lys ASp Tyr Phe Pro Glu Pro val Thr val Ser 145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly val His Thr Phe Pro Ala val165 170 175 104 188642/1

Leu Gin ser Ser Gly180 . Leu Tyr Ser Leu Ser Ser val185 Val Thr 190 Val Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn val Asn HIS Lys 195 200 205 Pro Ser Asn Thr Lys val Asp Lys Lys val Glu pro Lys Ser Cys Asp 210 215 220 Lys Thr Hi s Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met lie 245 250 255 Ser Arg Thr Pro Glu val Thr Cys val Val val ASP Val Ser Hi s Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu val His 275 280 285 Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg 290 295 300 val val Ser val Leu Thr val Leu Hi s Gin Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie Glu 325 330 335 Lys Thr Il e Ser Lys Ala Lys Gly Gl n Pro Arg Glu Pro Gin val Tyr 340 345 350 Thr Leu Pro Pro ser Arg Asp Glu Leu Thr Lys Asn Gin val ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp He Ala val Glu Trp 370 375 380 Glu Ser Asn Gly Gl n Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val ASp 405 410 415 Lys Ser Arg Trp Gl n Gin Gly Asn val Phe Ser Cys Ser val Met Hi s 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro 435 440 445 105 188642/1

Gly Lys450 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; I &lt;400&gt; Glu lie1 58 215 PRT Homo sapiens 58 Gin Ser Pro val Leu Thr 5 Glu Arg Al a Thr 20 Leu Ser Cys Arg Leu Ala Trp 35 Tyr Gin Gin Lys Pro 40 Tyr ASp 50 Al a Ser Asn Arg Al a55 Thr Ser 65 Gly Ser Gly Thr Asp 70 Phe Thr Gl u Asp Phe Al a Val 85 Tyr Tyr Cys Leu Thr Phe Gly 100 Gly Gly Thr Lys Ala Pro Ser 115 Val Phe lie Phe Pro 120 Gly Thr 130 Al a Ser val val cys 135 Leu Ala 145 Lys Val Gin Trp Lys 150 Val ASp Gin Glu Ser val Thr 165 Glu Gin Asp Ser Ser Thr Leu 180 Thr Leu Ser Lys Tyr Al a Cys 195' Glu val Thr His Gin 200 Ser Phe 210 Asn Arg Gly Glu Cys 215

Al a Thr 10 Leu Ser Leu ser Pro 15 Gly Ala 25 Ser Gin ser val Ser 30 Ser Tyr Gly Gin Al a Pro Arg 45 Leu Leu lie Gly lie Pro Ala 60 Arg Phe Ser Gly Leu Thr lie 75 Ser Ser Leu Glu Pro 80 Gin Gin 90 Arg Ser Asn Trp pro 95 Ala val 105 Glu lie Lys Arg Thr 110 Val Ala Pro Ser Asp Glu Gin 125 Leu Lys Ser Leu Asn Asn Phe 140 Tyr Pro Arg Glu Asn Al a Leu 155 Gin Ser Gly Asn Ser 160 Ser Lys 170 Asp Ser Thr Tyr Ser 175 Leu Ala 185 Asp Tyr Glu Lys His 190 Lys val Gly Leu Ser Ser Pro 205 val Thr Lys &lt;210&gt; 59 &lt;211&gt; 24

&lt;212&gt; DNA 106 188642/1 &lt;213&gt; Homo sapiens &lt;220&gt; &lt;221&gt; misc_feature &lt;222&gt; ¢18)..¢23) &lt;223&gt; n is a, c, g, or t &lt;400&gt; 59 ggccggatag gcctccannn nnnt 24 &lt;210&gt; 60 &lt;211&gt; 21

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 60 ggggtcaggc tggaactgag g 21 &lt;210&gt; 61 &lt;211&gt; 19

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 61 tgaggacgct gaccacacg 19 &lt;210&gt; 62 &lt;211&gt; 54

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 62 cagcagaagc ttctagacca ccatggacat gagggtcctc gctcagctcc tggg 54 &lt;210&gt; 63 &lt;211&gt; 34

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 63 cttgtcgact caacactctc ccctgttgaa gctc 34 &lt;210&gt; 64 &lt;211&gt; 43

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 64 acaacaaagc ttctagacca ccatggagtt ggggctgaac tgg 43 &lt;210&gt; 65 &lt;211&gt; 32

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 65 gtggaggcac tagagacggt gaccaggatt cc 32 &lt;210&gt; 66 &lt;211&gt; 228

&lt;212&gt; PRT &lt;213&gt; Homo sapiens 107 188642/1 &lt;400&gt; 66

Asp 1 Leu Thr Gin Glu Al a20 Lys Glu val Arg Ala Gly Ser25 Met val Gly Ser Asp val 15 Asp Glu val Ser Cys 5 Cys Pro Glu 10 Arg Phe Asp Leu Asn 30 Tyr val Tyr Trp Gin Thr Ser Glu Ser Lys Thr val val Thr Tyr Hi s 35 40 45 lie Pro Gin Asn Ser Ser Leu Glu Asn val Asp Ser Arg Tyr Arg Asn 50 55 60 Arg Ala Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe Ser Leu 65 70 75 80 Arg Leu Phe Asn val Thr Pro Gin ASp Glu Gin Lys Phe Hl s Cys Leu 85 90 95 val Leu Ser Gin Ser Leu Gly Phe Gin Glu val Leu Ser val Gl u val 100 105 110 Thr Leu Hl s val Al a Ala Asn Phe Ser Val Pro Val Val Ser Ala Pro 115 120 125 His Ser Pro Ser Gin ASp Glu Leu Thr Phe Thr Cys Thr Ser lie Asn 130 135 140 Gly Tyr Pro Arg Pro Asn val Tyr Trp lie Asn Lys Thr Asp Asn Ser 145 150 155 160 Leu Leu Asp Gin Ala Leu Gin Asn Asp Thr Val Phe Leu Asn Met Arg 165 170 175 Gly Leu Tyr ASp Val val Ser Val Leu Arg Ile Ala Arg Thr Pro Ser 180 185 190 val Asn lie Gly Cys Cys Ile Glu Asn Val Leu Leu Gin Gin Asn Leu 195 200 205 Thr val Gly Ser Gin Thr Gly Asn Asp Ile Gly Glu Arg ASp Lys Ile 210 215 220

Thr Glu225 i Asn Pro &lt;210&gt; 67 &lt;211&gt; 139 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 67 108 188642/1

Asp Thr1 Gin Glu Lys Glu val 5 Arg Ala Met val10 Gly Ser ASp val 15 Glu Leu Ser Cys Al a Cys Pro Gl u Gly Ser Arg Phe Asp Leu Asn ASp val 20 25 30 Tyr Val Tyr Trp Gin Thr Ser Glu Ser Lys Thr Val val Thr Tyr HI S 35 40 45 lie Pro 50 Gin Asn Ser Ser Leu 55 Glu Asn val Asp Ser 60 Arg Tyr Arg Asn Arg Ala Leu Met Ser Pro Ala Gly Met Leu Arg Gly Asp Phe Ser Leu 65 70 75 80 Arg Leu Phe Asn val Thr Pro Gin ASp Glu Gin Lys Phe His Cys Leu 85 90 95 val Leu Ser Gl n Ser Leu Gly Phe Gl n Glu val Leu Ser val Glu val 100 105 110 Thr Leu His Val Ala Al a Asn Phe Ser Val Pro val Val Ser Ala Pro 115 120 125 His Ser Pro Ser Gin Asp Glu Leu Thr Phe Thr 130 135 &lt;210&gt; 68 &lt;211&gt; 127 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 68 Leu Gly Phe Gin Glu val Leu Ser val Glu Val Thr Leu Hi s val Ala 1 5 10 15 Al a Asn phe Ser Val Pro val val Ser Ala Pro Hi s Ser Pro Ser Gin 20 25 30 Asp Glu Leu Thr Phe Thr Cys Thr Ser lie Asn Gly Tyr Pro Arg Pro 35 40 45 Asn Val Tyr Trp lie Asn Lys Thr Asp Asn Ser Leu Leu Asp Gin Ala 50 55 60 Leu Gin Asn Asp Thr val Phe Leu Asn Met Arg Gly Leu Tyr Asp val 65 70 75 80 val Ser val Leu Arg lie Al a Arg Thr Pro Ser val Asn Il e Gly Cys 85 90 95 Cys He Glu Asn val Leu Leu Gin Gl n Asn Leu Thr val Gly ser Gin 100 105 110 109 188642/1

Thr Gly Asn Asp lie Gly Glu Arg Asp Lys lie Thr Glu Asn Pro115 120 125 &lt;210&gt; 69 &lt;211&gt; 39

&lt;212&gt; DNA &lt;213&gt; Homo sapiens &lt;400&gt; 69 cgacggagca cgaggacacg acaggacgaa ggagagaaa 39 &lt;210&gt; 70

&lt;211&gt; 451&lt;212&gt; PRT &lt;213&gt; I Homo sap“ i ens &lt;400&gt; 70 Gl u val Gin Leu val Gl u Ser Gly Gly Gly Leu val Gin pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser cys Ala Gly Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr lie Lys Gin Asp Gly Asn Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr He Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Al a val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly He Leu Trp Phe Gly Asp Leu Pro Thr Phe Trp Gly 100 105 110 Gin Gly Xie Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu val Lys Asp Tyr phe Pro Glu Pro Val Thr val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly val HIS Thr Phe pro Ala 165 170 175 val Leu Gin Ser ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val180 185 190 110 188642/1

Pro Ser Ser Ser195 Leu Gly Thr Gin Thr200 Tyr He Cys Asn 205 val Asn HIS Lys Pro Ser Asn Thr Lys val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys Pro Pro Cys Pro Al a Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro pro Lys Pro Lys ASp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu val Thr Cys val val val Asp val Ser His 260 265 270 Glu Asp Pro Glu val Lys Phe Asn Trp Tyr val ASp Gly val Glu val 275 280 285 Hi s Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr 290 295 300 Arg val val Ser val Leu Thr val Leu Hl S Gin ASp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Gl u Leu Thr Lys Asn Gin val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp lie Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 val Leu Asp Ser ASp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val 405 410 415 Asp Lys Ser Arq Trp Gl n Gin Gly Asn val Phe Ser Cys Ser val Met 420 425 430 His Glu Ala Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys450 &lt;210&gt; 71 &lt;211&gt; 451

Ill 188642/1 &lt;212&gt; PRT&lt;213&gt; Homo sapiens&lt;400&gt; 71 ‘

Glu 1 Val Gin Leu val 5 Glu Ser Gly Gly Gly Leu Val10 Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gl n Al a Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Ala Tyr lie Lys Gin Asp Gly Asn Gl u Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg Asp Asn Al a Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Gl u Asp Thr Al a val Tyr Tyr Cys 85 90 95 Al a Arg Glu Gly lie Leu Trp Phe Gly ASp Leu pro Thr Phe Trp Gly 100 105 110 Gl n Gly Thr Leu Val Thr val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Gl u Pro val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Al a Leu Thr Ser Gly Val Hi s Thr Phe pro Ala 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys val Asp Lys Lys val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys Pro Pro Cys Pro Ala pro Glu Leu Leu Gly 225 230 235 240 Gly pro Ser val Phe Leu Phe Pro pro. Lys Pro Lys ASp Thr Leu Met 245 250 255

He Ser Arg Thr Pro Glu Val Thr cys Val Val Val Asp val Ser His 112 188642/1 260 265 270 Glu Asp Pro Glu val Lys Phe Asn Trp Tyr val ASp Gly val Gl u val 275 280 285 Hi s Asn Ala Lys Thr Lys Pro Arg Glu Glu Gl n Tyr Asn Ser Thr Tyr 290 295 300 Arg val Val Ser val Leu Thr val Leu His Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gl n Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin val Ser 355 360 365 Leu Thr Cys Leu val Lys Gly Phe Tyr Pro Ser Asp Ile Al a val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arq Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met 420 425 430 Hi s Glu Ala Leu Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 &lt;210&gt; 72 &lt;211&gt; ‘ 447 &lt;212&gt; 1 PRT &lt;213&gt; I Homo sap" iens &lt;400&gt; ' 72 Gin val Gin Leu val Glu Ser Gly Gly Gly val val Gin pro Gly Arg 1 5 10 15 Ser Leu Arg Leu 20 Ser Cys Ala Ala Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr Gly Met His Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 113 188642/1

Ala Val lie Trp Tyr Asp Gly55 Ser Lys Lys Tyr Tyr60 Ala Asp Ser Val 50 Glu Gly Arg Phe Thr He ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Phe Tyr Cys 85 90 95 Ala Arg Asp Leu Asn He Met val Trp Gly He Phe Asp Tyr Trp Gly 100 105 110 Gin Gly Thr 1 Leu val Thr val Ser Ser Ala Ser Thr Lys Gly Pro ser 115 120 125 Val Phe Pro Leu Ala pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Al a 130 135 140 Al a Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro val Thr val 145 150 155 160 Ser Trp Asn Ser Gly Al a Leu Thr Ser Gly Val His Thr Phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val 180 185 190: Pro Ser Ser Asn Phe Gly Thr Gin Thr Tyr Thr Cys Asn val Asp Hi s 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys 210 215 220 val Glu Cys Pro Pro Cys Pro Ala Pro Pro val Al a Gly Pro Ser val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr 245 250 255 Pro Glu val Thr Cys val val val Asp val Ser Hi s Gl u Asp Pro Glu •260 265 270 Val Gin Phe Asn Trp Tyr val Asp Gly Val Glu val Hi s Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gin Phe Asn Ser Thr Phe Arg Val Val Ser 290 • 295 300 val Leu Thr val val His Gin Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys valrSer Asn Lys Gly Leu pro Ala Pro lie Glu Lys Thr He 114 188642/1 325 330 335

Ser Lys Thr Lys Gly Gin Pro Arg Glu Pro Gin val Tyr Thr Leu pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gin val Ser Leu Thr Cys Leu 355 360 365 val Lys Gly Phe Tyr Pro Ser Asp lie Al a val Glu Trp Glu Ser Asn 370 375 380 Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr pro Pro Met Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met Hi s Glu Ala Leu 420 425 430 Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 73 &lt;211&gt; - 451 &lt;212&gt; : PRT &lt;213&gt; I Homo sapi iens &lt;400&gt; 73 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1 5 10 15 ser Leu . Arg Leu Ser Cys val Gly ser Gly Phe Thr Phe ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp val 35 40 45 Al a Tyr Il e Lys Gin Asp Gly Ser Glu Lys Tyr Tyr val Asp Ser val 50 55 60 Lys Gly Arg Phe Thr lie Ser Arg ASp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gl n Met Asn Ser Leu Arg Ala Glu Asp Thr Al a val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly lie Leu Trp Phe Gly ASp lie pro Thr Tyr Trp Gly 100 105 110 Gin Gly lie Leu val Thr val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 115 188642/1

Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser 140 Gly Gly Thr Ala 130 135 Al a Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro val Thr val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly val His Thr Phe Pro Ala 165 170 175 val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser val val Thr val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr He Cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys val Asp Lys Lys val Glu pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu val Thr Cys val Val val Asp Val Ser His 260 265 270 Gl u Asp Pro Glu val Lys Phe Asn Trp Tyr val Asp Gly val Glu val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr 290 295 300 Arg val Val Ser Val Leu Thr val Leu His Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Al a Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin val Ser 355 360 365 Leu Thr Cys Leu val Lys Gly Phe Tyr Pro Ser ASp lie Ala val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val 116 188642/1 405 410 415 ASp Lys Ser Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 Hi s Glu Ala Leu Hi s Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 &lt;210&gt; 74 ‘ &lt;211&gt; 451 &lt;212&gt; PRT&lt;213&gt; Homo sapiens&lt;400&gt; 74

Glu val 1 Gin Leu val 5 Glu Ser Gly Gly Gly 10 Leu Val Gin Pro Gly 15 Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Al a Tyr He Lys Gin Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser val 50 55 60 Lys Gly Arg Phe Thr ll e ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly lie Leu Trp Phe Gly ASp He Pro Thr Tyr Trp Gly 100 105 110 Gin Gly Thr Leu Val Thr val Ser Ser Ala Ser Thr Lys Gl y Pro Ser 115, 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 * 140 Ala Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val Hi s Thr Phe Pro Ala 165 170 175

Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val val Thr val180 185 190 117 188642/1

Pro Ser Ser. Ser195 Leu Gly Thr Gin Thr200 Tyr He Cys Asn 205 Val Asn Hi s Lys Pro Ser Asn Thr Lys val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys Pro Pro Cys Pro Al a Pro Glu Leu Leu Gly 225 230 235 240 Gly pro Ser val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu Val Thr Cys val val val ASp val Ser His 260 265 270 Glu Asp Pro Glu val Lys Phe Asn Trp Tyr val Asp Gly val Glu val 275 280 285 HIS Asn Ala Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr 290 295 300 Arg val val Ser val Leu Thr val Leu Hi s Gin Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Ala Leu Pro Al a Pro lie 325 330 335 Glu Lys Thr lie Ser Lys Al a Lys Gly Gin Pro Arg Glu Pro Gin val 340 345 350 Tyr Thr Leu Pro pro Ser Arg Asp Glu Leu Thr Lys Asn Gin val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Il e Ala val Glu 370 375 380 Trp Glu Ser Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gin Gin Gly Asn val Phe Ser Cys Ser val Met 420 425 430 His Glu Ala Leu Hi s Asn Hi s Tyr Thr Gin Lys Ser Leu Ser Leu Ser 435 440 445

Pro Gly Lys450 &lt;210&gt; 75 &lt;211&gt; 448 118 188642/1 &lt;212&gt;&lt;213&gt; 1 PRT Homo sapi ens &lt;400&gt; ' 75 Glu 1 val Gin Leu val 5 Gl n Ser Gly Ser Leu Arg Leu 20 Ser Cys Ala Gly Ala Met His 35 Trp val Arg Gin Ala 40 Ser Ala 50 lie Gly Al a Gly Gly 55 Gly Gly 65 Arg phe Thr lie Ser 70 Arg Asp Gin Met Asn Ser Leu 85 Arg Al a Gl U Arg val Val val 100 val Val Gly Phe Leu val Thr val Ser Ser Ala Ser 115 120 Leu Ala 130 Pro Ser Ser Lys Ser 135 Thr Cys 145 Leu val Lys Asp Tyr 150 Phe Pro Ser Gly Al a Leu Thr 165 Ser Gly val Ser Ser Gly Leu 180 Tyr Ser Leu Ser Ser Leu Gly 195 Thr Gin Thr Tyr lie 200 Asn Thr 210 Lys Val Asp Lys Lys 215 Val Hi s225 Thr Cys, Pro Pro Cys 230 Pro Ala Val Phe Leu Phe Pro Pro Lys Pro 245

Gly Gly 10 Leu val Hi s Pro Gly 15 Gly Ser 25 Gly Phe Thr Phe Ser 30 Ser Tyr pro Gly Lys Gly Leu 45 Glu Trp val Thr Tyr Tyr Al a60 ASp Ser val Lys Asn Al a Lys 75 Asn ser Leu Tyr Leu 80 Asp Met 90 Al a val Tyr Tyr Cys 95 Ala Phe 105 ASp Tyr Trp Gly Gin 110 Gly Thr Thr Lys Gly Pro Ser 125 val Phe Pro Ser Gly Gly Thr 140 Ala Ala Leu Gly Glu Pro val 155 Thr val Ser Trp Asn 160 His Thr 170 Phe Pro Ala val Leu 175 Gin Ser 185 val val Thr Val Pro 190 Ser Ser Cys Asn Val Asn His 205 Lys Pro Ser Glu pro Lys Ser 220 Cys Asp Lys Thr Pro Glu Leu 235 Leu Gly Gly Pro Ser 240 Lys ASp 250 Thr Leu Met lie Ser 255 Arg 119 188642/1

Thr Pro Glu val260 Thr Cys Val val val 265 Asp Val Ser His Glu 270 ASp Pro Glu Val Lys Phe Asn Trp Tyr Val ASp Gly Val Glu Val His Asn Al a 275 280 285 Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr Arg val val 290 295 300 Ser Val Leu Thr val Leu Hi s Gin Asp Trp Leu Asn Gly Lys Glu Tyr 305 310 315 320 Lys Cys Lys val Ser Asn Lys Ala Leu Pro Al a Pro lie Gl U Lys Thr 325 330 335 lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin val Tyr Thr Leu 340 345 350 Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gin val Ser Leu Thr Cys 355 360 365 Leu val Lys Gly Phe Tyr Pro Ser Asp lie Al a val Glu Trp Glu Ser 370 375 380 Asn Gly Gin Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro val Leu Asp 385 390 395 400 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr val Asp Lys Ser 405 410 415 Arg Trp Gin Gin Gly Asn Val Phe Ser Cys Ser val Met Hi s Glu Ala 420 425 430 Leu His Asn His Tyr Thr Gin Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 &lt;210&gt; 76 &lt;211&gt; 451 &lt;212&gt; PRT &lt;213&gt; I Homo sapiens &lt;400&gt; 76 Glu Val Gin Leu Val Glu Ser Gly Gly Gly Leu val Gin Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp val Arg Gin Ala Pro Gl y Lys Gly Leu Glu Trp Val 35 40 45 Ala Tyr lie Lys Gin Asp Gly Ser Glu Lys Tyr Tyr val Asp Ser Val 50 55 60 120 188642/1

Lys 65 Gly Arg Phe Thr lie Ser Arg70 ASp Asn Ala 75 Lys Asn Ser Leu Tyr 80 Leu Gin Met Asn Ser Leu Arg Ala Glu Asp Thr Al a Val Tyr Tyr Cys 85 90 95 Ala Arg ASp Gly lie Leu Trp Phe Gly ASp Leu Pro Thr Tyr Trp Gly 100 105 110 Gin Gly Thr Leu val Thr val Ser Ser Ala Ser Thr Lys Gly pro Ser 115 120 125 Val Phe Pro Leu Al a Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu val Lys Asp Tyr Phe Pro Glu Pro val Thr val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly val His Thr phe Pro Al a 165 170 175 Val Leu Gin Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gin Thr Tyr lie Cys Asn Val Asn Hi s 195 200 205 Lys Pro Ser Asn Thr Lys val ASp Lys Lys val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr Hi s Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 lie Ser Arg Thr Pro Glu val Thr Cys Val val val ASp val Ser Hi s 260 265 270 Glu Asp Pro Glu val Lys Phe Asn Trp Tyr val Asp Gly val Gl u val 275 280 285 His Asn Al a Lys Thr Lys Pro Arg Glu Glu Gin Tyr Asn Ser Thr Tyr 290 295 300 Arg Val val Ser val Leu Thr Val Leu His Gin ASp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys val Ser Asn Lys Al a Leu Pro Ala Pro Ile 325 330 335

Glu Lys Thr lie Ser Lys Ala Lys Gly Gin Pro Arg Glu Pro Gin val 121 188642/1 340

Tyr Thr Leu 355 pro Pro Ser Arg Asp 360 Leu Thr 370 Cys Leu val Lys Gly 375 Phe Trp 385 Glu Ser Asn Gly Gl n390 Pro Glu val Leu Asp Ser Asp 405 Gly Ser Phe Asp Lys Ser Arg 420 Trp Gin Gin Gly Hi s Gl u Ala 435 Leu His Asn His Tyr 440 345 350

Glu Leu Thr Lys Asn 365 Gin val Ser Tyr Pro Ser Asp 380 lie Ala Val Glu Asn Asn Tyr 395 Lys Thr Thr Pro Pro 400 Phe Leu 410 Tyr ser Lys Leu Thr 415 val Asn 425 val Phe Ser Cys Ser 430 val Met Thr Gin Lys Ser Leu Ser Leu Ser 445

Pro Gly Lys450 1 , crnxan ;w:n ατα inia^n pnow ρηιζη ιγπ πτ naoa,Ρ’ηη ηχΏ- pacana mavia n^maa πρ’ΐοζ .zrtwan ™·Ώ3 mp’nn ρπίι7 oxnm ......Geoda u*r □ιηππ Pi?

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