Anti-alpha2 integrin antibodies and their uses

Abstract

The invention relates to anti-α2 integrin antibodies and their uses. Humanized antibodies are disclosed that bind to the I domain of α2 integrin and inhibit the interaction of α2β1 integrin with collagen. Also disclosed are therapeutic uses of anti-α2 integrin antibodies in treating α2β1-mediated disorders, including anti-α2 integrin antibodies that bind to α2 integrin without activating platelets.

What is claimed is: 
     
         1 . A humanized anti-α2 integrin antibody comprising a heavy chain variable region comprising the amino acid sequence of (a) HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO:2), (b) HCDR1 (GFSLTNYGIH, SEQ ID NO:1), HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO:2) and HCDR3 (ANDGVYYAMDY, SEQ ID NO:3), or (c) SEQ ID NO:40. 
     
     
         2 . The humanized anti-α2 integrin antibody of  claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:185. 
     
     
         3 . The humanized anti-α2 integrin antibody of  claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:185 in which (a) position 71 is Lys, (b) position 73 is Asn, (c) position 78 is Val, or (d) any combination of (a)-(c). 
     
     
         4 . The humanized anti-α2 integrin antibody of  claim 1 , wherein the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:70-79 and SEQ ID NOs:109-111. 
     
     
         5 . The humanized anti-α2 integrin antibody of  claim 1 , further comprising a FW4 region comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO:13). 
     
     
         6 . The humanized anti-α2 integrin antibody of  claim 5  comprising the amino acid sequence of HCDR1 (SEQ ID NO:1), HCDR2 (SEQ ID NO:2) and HCDR3 (SEQ ID NO:3). 
     
     
         7 . The humanized anti-α2 integrin antibody according to any one of  claims 1 - 6 , further comprising a light chain. 
     
     
         8 . A humanized anti-α2 integrin antibody comprising a light chain variable region comprising the amino acid sequence of (a) an LCDR1 selected from SANSSVNYIH (SEQ ID NO:4) or SAQSSWNYIH (SEQ ID NO:112), (b) LCDR2 (DTSKLAS; SEQ ID NO:5) and (c) LCDR3 (QQWTTNPLT, SEQ ID NO:6). 
     
     
         9 . The humanized anti-α2 integrin antibody of  claim 8 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:186. 
     
     
         10 . The humanized anti-α2 integrin antibody of  claim 8 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:186 in which (a) position 2 is Phe, (b) position 45 is Lys, (c) position 48 is Tyr, or (d) any combination of (a)-(c). 
     
     
         11 . The humanized anti-2 integrin antibody of  claim 8 , wherein the light chain variable region comprises an amino acid sequence selected from SEQ ID NO:41, SEQ ID NOs:80-92 and SEQ ID NO:108. 
     
     
         12 . The humanized anti-α2 integrin antibody of  claim 8  further comprising a FW4 region comprising the amino acids sequence FGQGTKVEIK of SEQ ID NO:38. 
     
     
         13 . The humanized anti-α2 integrin of  claim 12  comprising the amino acid sequence of LCDR1 (SEQ ID NO:4), LCDR2 (SEQ ID NO:5) and LCDR3 (SEQ ID NO:6) 
     
     
         14 . The humanized anti-α2 integrin antibody according to any one of  claims 8 - 13 , further comprising a heavy chain. 
     
     
         15 . A humanized anti-α2 integrin antibody comprising:
 (i) a heavy chain variable region comprising the amino acid sequence of (a) HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO:2), (b) HCDR1 (GFSLTNYGIH, SEQ ID NO:1), HCDR2 (VIWARGFTNYNSALMS, SEQ ID NO:2) and HCDR3 (ANDGVYYAMDY, SEQ ID NO:3), or (c) SEQ ID NO:40; and 
 (ii) a light chain variable region comprising the amino acid sequence of (a) an LCDR1 selected from SANSSVNYIH (SEQ ID NO:4) or SAQSSWNYIH (SEQ ID NO:4) or SAQSSWNYIH SEQ ID NO:112), (b) LCDR2 (DTSKLAS; SEQ ID NO:5) and (c) LCDR3 (QQWTTNPLT, SEQ ID NO:6). 
 
     
     
         16 . The humanized anti-α2 integrin antibody of  claim 15 , wherein (a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:185, (b) the light chain variable region comprises the amino acid sequence of SEQ ID NO:186, or (c) both (a) and (b). 
     
     
         17 . The humanized anti-α2 integrin antibody of  claim 15 , wherein (i) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:185 in which (a) position 71 is Lys, (b) position 73 is Asn, (c) position 78 is Val, or (d) any combination of (a)-(c); (ii) the light chain variable region comprises the amino acid sequence of SEQ ID NO:186 in which (a) position 2 is Phe, (b) position 45 is Lys, (c) position 48 is Tyr, or (d) any combination of (a)-(c); or (iii) both (i) and (ii). 
     
     
         18 . The humanized anti-α2 integrin antibody of  claim 15 , wherein (a) the heavy chain variable region comprises an amino acid sequence selected from SEQ ID NOs:70-79 and SEQ ID NOs:109-111; (b) the light chain variable region comprises an amino acid sequence selected from SEQ ID NO:41, SEQ ID NOs:80-92 and SEQ ID NO:108: or (c) both (a) and (b). 
     
     
         19 . The humanized anti-α2 integrin antibody of  claim 1 , wherein the antibody recognizes the I domain of human α2 integrin. 
     
     
         20 . The humanized anti-α2 integrin antibody of  claim 8 , wherein the antibody recognizes the I domain of human α2 integrin. 
     
     
         21 . The humanized anti-α2 integrin antibody of  claim 15 , wherein the antibody recognizes the I domain of human α2 integrin. 
     
     
         22 . The humanized anti-α2 integrin antibody of  claim 1 , wherein the antibody binds α2β1 integrin. 
     
     
         23 . The humanized anti-α2 integrin antibody of  claim 8 , wherein the antibody binds α2β1 integrin. 
     
     
         24 . The humanized anti-α2 integrin antibody of  claim 15 , wherein the antibody binds α2β1 integrin. 
     
     
         25 . The humanized anti-α2 integrin antibody of  claim 1 , wherein the antibody binds an epitope of α2 integrin, the epitope comprising:
 (a) a Lys residue corresponding to position 192 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 40 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (b) an Asn residue corresponding to position 225 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 73 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO: 11; 
 (c) a Gln residue corresponding to position 241 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 89 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO: 11; 
 (d) a Tyr residue corresponding to position 245 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 93 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (e) an Arg residue corresponding to position 317 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 165 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (f) an Asn residue corresponding to position 318 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 166 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; or 
 (g) any combination of (a) to (f). 
 
     
     
         26 . The humanized anti-α2 integrin antibody of  claim 8 , wherein the antibody binds an epitope of α2 integrin, the epitope comprising:
 (a) a Lys residue corresponding to position 192 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 40 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (b) an Asn residue corresponding to position 225 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 73 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (c) a Gln residue corresponding to position 241 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 89 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (d) a Tyr residue corresponding to position 245 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 93 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (e) an Arg residue corresponding to position 317 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 165 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (f) an Asn residue corresponding to position 318 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 166 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; or 
 (g) any combination of (a) to (f). 
 
     
     
         27 . The humanized anti-α2 integrin antibody of  claim 15 , wherein the antibody binds an epitope of α2 integrin, the epitope comprising:
 (a) a Lys residue corresponding to position 192 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 40 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (b) an Asn residue corresponding to position 225 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 73 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (c) a Gln residue corresponding to position 241 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 89 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (d) a Tyr residue corresponding to position 245 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 93 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (e) an Arg residue corresponding to position 317 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 165 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (f) an Asn residue corresponding to position 318 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 166 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; or 
 (g) any combination of (a) to (f). 
 
     
     
         28 . A humanized anti-α2 integrin antibody, wherein the antibody binds an epitope of α2 integrin, the epitope comprising:
 (a) a Lys residue corresponding to position 192 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 40 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (b) an Asn residue corresponding to position 225 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 73 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (c) a Gln residue corresponding to position 241 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 89 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (d) a Tyr residue corresponding to position 245 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 93 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (e) an Arg residue corresponding to position 317 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 165 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; 
 (f) an Asn residue corresponding to position 318 of the α2 integrin amino acid sequence set forth in SEQ ID NO:8 or position 166 of the α2 integrin I domain amino acid sequence set forth in SEQ ID NO:11; or 
 (g) any combination of (a) to (f). 
 
     
     
         29 . The humanized anti-α2 integrin antibody of  claim 1 , which is a full length antibody. 
     
     
         30 . The humanized anti-α2 integrin antibody of  claim 8 , which is a full length antibody. 
     
     
         31 . The humanized anti-α2 integrin antibody of  claim 15 , which is a full length antibody. 
     
     
         32 . The humanized anti-α2 integrin antibody of  claim 28 , which is a full length antibody. 
     
     
         33 . The humanized anti-α2 integrin antibody of  claim 1 , which is an antibody fragment. 
     
     
         34 . The humanized anti-α2 integrin antibody of  claim 8 , which is an antibody fragment. 
     
     
         35 . The humanized anti-α2 integrin antibody of  claim 15 , which is an antibody fragment. 
     
     
         36 . The humanized anti-α2 integrin antibody of  claim 28 , which is an antibody fragment. 
     
     
         37 . The humanized anti-α2 integrin antibody of  claim 1 , bound to a detectable label. 
     
     
         38 . The humanized anti-α2 integrin antibody of  claim 8 , bound to a detectable label. 
     
     
         39 . The humanized anti-α2 integrin antibody of  claim 15 , bound to a detectable label. 
     
     
         40 . The humanized anti-α2 integrin antibody of  claim 28 , bound to a detectable label. 
     
     
         41 . The humanized anti-α2 integrin antibody of  claim 1 , immobilized on solid phase. 
     
     
         42 . The humanized anti-α2 integrin antibody of  claim 8 , immobilized on solid phase. 
     
     
         43 . The humanized anti-α2 integrin antibody of  claim 15 , immobilized on solid phase. 
     
     
         44 . The humanized anti-α2 integrin antibody of  claim 28 , immobilized on solid phase. 
     
     
         45 . The humanized anti-α2 integrin antibody of  claim 1  wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand. 
     
     
         46 . The humanized anti-α2 integrin antibody of  claim 8  wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand. 
     
     
         47 . The humanized anti-α2 integrin antibody of  claim 15  wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand. 
     
     
         48 . The humanized anti-α2 integrin antibody of  claim 28  wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand. 
     
     
         49 . The humanized anti-α2 integrin antibody of  claim 45 , wherein the α2β1 integrin ligand is selected from collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein. 
     
     
         50 . The humanized anti-α2 integrin antibody of  claim 46 , wherein the α2β1 integrin ligand is selected from collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein. 
     
     
         51 . The humanized anti-α2 integrin antibody of  claim 47 , wherein the α2β1 integrin ligand is selected from collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein. 
     
     
         52 . The humanized anti-α2 integrin antibody of  claim 48 , wherein the α2β1 integrin ligand is selected from collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein. 
     
     
         53 . A method for determining whether a sample contains α2 integrin, α2β1 integrin, or both, comprising contacting the sample with the humanized anti-α2 integrin antibody of  claim 1  and determining whether the antibody binds to the sample, said binding being an indication that the sample contains α2 integrin, α2β1 integrin, or both. 
     
     
         54 . A method for determining whether a sample contains α2 integrin, α2β1 integrin, or both, comprising contacting the sample with the humanized anti-α2 integrin antibody of  claim 8  and determining whether the antibody binds to the sample, said binding being an indication that the sample contains α2 integrin, α2β1 integrin, or both. 
     
     
         55 . A method for determining whether a sample contains α2 integrin, α2β1 integrin, or both, comprising contacting the sample with the humanized anti-α2 integrin antibody of  claim 15  and determining whether the antibody binds to the sample, said binding being an indication that the sample contains α2 integrin, α2β1 integrin, or both. 
     
     
         56 . A method for determining whether a sample contains α2 integrin, α2β1 integrin, or both, comprising contacting the sample with the humanized anti-α2 integrin antibody of  claim 28  and determining whether the antibody binds to the sample, said binding being an indication that the sample contains α2 integrin, α2β1 integrin, or both. 
     
     
         57 . A kit comprising the humanized anti-α2 integrin antibody of  claim 1  and instructions for its use to detect α2 or α2β1 integrin protein. 
     
     
         58 . A kit comprising the humanized anti-α2 integrin antibody of  claim 8  and instructions for its use to detect α2 or α2β1 integrin protein. 
     
     
         59 . A kit comprising the humanized anti-α2 integrin antibody of  claim 15  and instructions for its use to detect α2 or α2β1 integrin protein. 
     
     
         60 . A kit comprising the humanized anti-α2 integrin antibody of  claim 28  and instructions for its use to detect α2 or α2β1 integrin protein. 
     
     
         61 . An isolated nucleic acid encoding a humanized anti-α2β1 integrin antibody of  claim 1 . 
     
     
         62 . An isolated nucleic acid encoding a humanized anti-α2β1 integrin antibody of  claim 8 . 
     
     
         63 . A vector comprising the nucleic acid of  claim 61 . 
     
     
         64 . A vector comprising the nucleic acid of  claim 62 . 
     
     
         65 . A host cell comprising:
 (a) the nucleic acid according to  claim 61 ;   (b) the nucleic acid according to  claim 62 ;   (c) the vector according to  claim 63 ;   (d) the vector according to  claim 64 ; or   (e) any combination of (a) to (d).   
     
     
         66 . A process of producing a humanized anti-α2 integrin antibody comprising culturing the host cell of  claim 65  under conditions permitting expression of the antibody. 
     
     
         67 . The process of  claim 66  further comprising recovering the humanized anti-α2 integrin antibody from the host cell. 
     
     
         68 . The process of  claim 67  wherein the humanized anti-α2β1 integrin antibody is recovered from the host cell culture medium. 
     
     
         69 . A screening method comprising:
 (a) detecting binding of α2 or α2β1 integrin to an antibody comprising the VL region of SEQ ID NO:19 and the VH region of SEQ ID NO:21 in the presence versus the absence of a test antibody; and   (b) selecting the test antibody if its presence correlates with decreased binding of the α2 or α2β1 integrin to the antibody comprising the VL region of SEQ ID NO:19 and the VH region of SEQ ID NO:21.   
     
     
         70 . The method of  claim 69 , wherein the α2 or α2β1 integrin Is immobilized on a solid support. 
     
     
         71 . A screening method comprising:
 (a) detecting binding of α2β1 integrin to collagen in the presence of a test antibody, wherein test antibody refers to an antibody that binds to an α2 I domain;   (b) detecting binding of the test antibody to the α2 I domain in the presence of Mg ++  ions;   (c) detecting binding of the test antibody to the α2 I domain in the presence of Ca ++  ions;   (d) detecting binding of the test antibody to the α2 I domain in the presence of cation-free media; and   (e) selecting the test antibody if inhibits the binding of α2β1 integrin to collagen and binds to the α2 I domain in the presence of Mg ++  ions and Ca ++  ions and cation-free media.   
     
     
         72 . A composition comprising the humanized anti-α2 integrin antibody of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         73 . A composition comprising the humanized anti-α2 integrin antibody of  claim 8  and a pharmaceutically acceptable carrier. 
     
     
         74 . A composition comprising the humanized anti-α2 integrin antibody of  claim 15  and a pharmaceutically acceptable carrier. 
     
     
         75 . A composition comprising the humanized anti-α2 integrin antibody of  claim 28  and a pharmaceutically acceptable carrier. 
     
     
         76 . A method of treating an α2β1 integrin-associated disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of the anti-α2 integrin antibody according to any one of  claims 1 - 52  or the composition according to any one of  claims 72 - 75 . 
     
     
         77 . A method for inhibiting leukocyte binding to collagen comprising administering to a subject an amount of an anti-α2β1 integrin antibody of  claim 28  effective to inhibit the binding of the leukocytes to collagen. 
     
     
         78 . The method of  claim 76 , wherein the α2β1 integrin-associated disorder is selected from inflammatory disease, autoimmune disease and a disease characterized by abnormal or increase angiogenesis. 
     
     
         79 . The method of  claim 76 , wherein the α2β1 integrin-associated disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, reactions to transplant, optical neuritis, spinal cord trauma, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, scleroderma, juvenile onset diabetes, diabetic retinopathy, age related macular degeneration, cardiovascular disease, psoriasis, cancer as well as infections that induce an inflammatory response. 
     
     
         80 . The method of  claim 76 , wherein the α2β1 integrin-associated disorder is selected from multiple sclerosis, rheumatoid arthritis, optical neuritis and spinal cord trauma. 
     
     
         81 . The method of  claim 76 , wherein the method is not associated with (a) platelet activation, (b) platelet aggregation, (c) a decrease in circulating platelet count, (d) bleeding complications, or (e) any combination of (a) to (d). 
     
     
         82 . The method of  claim 76 , wherein the anti-α2 integrin antibody comprises a heavy chain comprising SEQ ID NO:174 or SEQ ID NO:176 and a light chain comprising SEQ ID NO:178. 
     
     
         83 . The method of  claim 76 , wherein the anti-α2 integrin antibody competively inhibits the binding of an antibody comprising the VL region of SEQ ID NO:19 and the VH region of SEQ ID NO:21 to human α2β1 integrin or the I domain thereof. 
     
     
         84 . The method of  claim 80 , wherein the multiple sclerosis is characterized by relapse. 
     
     
         85 . The method of  claim 80 , wherein the method is associated with an alleviation of a flare or neuroligical sequelae associated with multiple sclerosis. 
     
     
         86 . The method of  claim 76 , wherein the anti-α2 integrin antibody inhibits the binding of α2β1 integrin to collagen and is not a ligand mimetic. 
     
     
         87 . A method of targeting a molecule, composition or a complex to a site characterized by the presence of an α2β1 integrin ligand, the method comprising attaching or binding the molecule, composition or a complex to the humanized anti-α2 integrin antibody of  claim 1 . 
     
     
         88 . A method of targeting a molecule, composition or a complex to a site characterized by the presence of an α2β1 integrin ligand, the method comprising attaching or binding the molecule, composition or a complex to the humanized anti-α2 integrin antibody of  claim 8 . 
     
     
         89 . A method of targeting a molecule, composition or a complex to a site characterized by the presence of an α2β1 integrin ligand, the method comprising attaching or binding the molecule, composition or a complex to the humanized anti-α2 integrin antibody of  claim 15 . 
     
     
         90 . A method of targeting a molecule, composition or a complex to a site characterized by the presence of an α2β1 integrin ligand, the method comprising attaching or binding the molecule, composition or a complex to the humanized anti-α2 integrin antibody of  claim 28 . 
     
     
         91 . Use of the humanized anti-α2 integrin antibody according to any one of  claims 1 - 52  as a medicament. 
     
     
         92 . Use of the humanized anti-α2 integrin antibody according to any one of  claims 1 - 52  or the composition of  claim 44  for the treatment of an α2β1 integrin-associated disorder. 
     
     
         93 . Use of the humanized anti-α2 integrin antibody according to any one of  claims 1 - 52  for the preparation of a medicament for the treatment of an α2β1 integrin-associated disorder. 
     
     
         94 . The use according to any one of  claims 91 - 93 , wherein the α2β1 integrin-associated disorder is selected from inflammatory disease, autoimmune disease and a disease characterized by inappropriate angiogenesis. 
     
     
         95 . The use according to any one of  claims 91 - 93 , wherein the α2β1 integrin-associated disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, reactions to transplant, optical neuritis, spinal cord trauma, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, scleroderma, juvenile onset diabetes, diabetic retinopathy, age related macular degeneration, cardiovascular disease, psoriasis, cancer as well as infections that induce an inflammatory response. 
     
     
         96 . The use according to any one of  claims 91 - 93 , wherein the α2β1 integrin-associated disorder is selected from multiple sclerosis, rheumatoid arthritis, optical neuritis and spinal cord trauma. 
     
     
         97 . A composition for the treatment of an α2β1 integrin-associated disorder, the composition comprising the humanized anti-α2 integrin antibody according to any one of  claims 1 - 52  and a pharmaceutically acceptable carrier or diluent. 
     
     
         98 . The composition of  claim 97 , wherein the α2β1 integrin-associated disorder is selected from inflammatory disease, autoimmune disease and a disease characterized by inappropriate angiogenesis. 
     
     
         99 . The composition of  claim 97 , wherein the α2β1 integrin-associated disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, reactions to transplant, optical neuritis, spinal cord trauma, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, scleroderma, juvenile onset diabetes, diabetic retinopathy, age related macular degeneration, cardiovascular disease, psoriasis, cancer as well as infections that induce an inflammatory response. 
     
     
         100 . The composition of  claim 97 , wherein the α2β1 integrin-associated disorder is selected from multiple sclerosis, rheumatoid arthritis, optical neuritis and spinal cord trauma. 
     
     
         101 . A package comprising the humanized anti-α2 integrin antibody according to any one of  claims 1 - 52  or the composition according to any one of  claims 72 - 75  together with instructions for the treatment of an α2β1 integrin-associated disorder. 
     
     
         102 . The package of  claim 101 , wherein the α2β1 integrin-associated disorder is selected from inflammatory disease, autoimmune disease and a disease characterized by inappropriate angiogenesis. 
     
     
         103 . The package of  claim 101 , wherein the α2β1 integrin-associated disorder is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, reactions to transplant, optical neuritis, spinal cord trauma, rheumatoid arthritis, systemic lupus erythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud's syndrome, experimental autoimmune encephalomyelitis, Sjorgen's syndrome, scleroderma, juvenile onset diabetes, diabetic retinopathy, age related macular degeneration, cardiovascular disease, psoriasis, cancer as well as infections that induce an inflammatory response. 
     
     
         104 . The package of  claim 101 , wherein the α2β1 integrin-associated disorder is selected from multiple sclerosis, rheumatoid arthritis, optical neuritis and spinal cord trauma. 
     
     
         105 . An α2 integrin epitope that binds an anti-α2 integrin antibody, wherein the epitope does not comprise the ligand-binding site of α2 integrin. 
     
     
         106 . The epitope of  claim 105 , wherein binding to the epitope is not associated with (a) platelet activation, (b) platelet aggregation, (c) a decrease in circulating platelet count, (d) bleeding complications, (e) α2 integrin activation, or (f) any combination of (a) to (e).