Anti-alpha2 integrin antibodies and their uses
View Patent ↗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.
1. A humanized anti-α2 integrin antibody comprising:
(i) a heavy chain variable region comprising: a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence GFSLTNYGIH (SEQ ID NO: 1), a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence VIWARGFTNYNSALMS (SEQ ID NO: 2), and a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence ANDGVYYAMDY (SEQ ID NO: 3); and
(ii) a light chain variable region comprising: a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence SAQSSVNYIH (SEQ ID NO:112), a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence DTSKLAS (SEQ ID NO: 5), and a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence QQWTTNPLT (SEQ ID NO: 6).
2. The humanized anti-α2 integrin antibody of claim 1 , further comprising a variable heavy chain comprising a FW4 region having the amino acid sequence WGQGTLVTVSS (SEQ ID NO:13).
3. The humanized anti-α2 integrin antibody of claim 1 further comprising a variable light chain FW4 region having the amino acids sequence FGQGTKVEIK of SEQ ID NO:38.
4. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 109.
5. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 91.
6. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 109 and a light chain variable region having the amino acid sequence of SEQ ID NO: 91.
7. The humanized anti-α2 integrin antibody of claim 1 , wherein the light chain complementarity determining region 1 (LCDR1) has the amino acid sequence SAQSSVNYIH (SEQ ID NO: 112).
8. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody comprises a constant region.
9. The humanized anti-α2 integrin antibody of claim 8 , wherein the constant region is γ1.
10. The humanized anti-α2 integrin antibody of claim 8 , wherein the constant region is γ4.
11. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody recognizes the I domain of human α2 integrin.
12. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody binds α2⊕1 integrin.
13. The humanized anti-α2 integrin antibody of claim 1 , which is a full length antibody.
14. The humanized anti-α2 integrin antibody of claim 1 , bound to a detectable label.
15. The humanized anti-α2 integrin antibody of claim 1 , immobilized on solid phase.
16. The humanized anti-α2 integrin antibody of claim 1 , wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand.
17. The humanized anti-α2 integrin antibody of claim 16 , wherein the α2β1 integrin ligand is selected from the group consisting of collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein.
18. A kit comprising the humanized anti-α2 integrin antibody of claim 1 and instructions for its use to detect α2 or α2β1 integrin protein.
19. A pharmaceutical composition comprising a humanized anti-α2 integrin antibody comprising:
(i) a heavy chain variable region comprising: a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence GFSLTNYGIH (SEQ ID NO:1), a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence VIWARGFTNYNSALMS (SEQ ID NO: 2), and a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence ANDGVYYAMDY (SEQ ID NO: 3); and
(ii) a light chain variable region comprising: a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence SAQSSVNYIH (SEQ ID NO: 112), a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence DTSKLAS (SEQ ID NO: 5), and a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence QQWTTNPLT (SEQ ID NO: 6), and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 , wherein the antibody further comprises a FW4 region comprising the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 13).
21. The pharmaceutical composition of claim 19 , wherein the antibody further comprises a FW4 region comprising the amino acids sequence FGQGTKVEIK (SEQ ID NO: 38).
22. The pharmaceutical composition of claim 19 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 109.
23. The pharmaceutical composition of claim 19 , wherein the antibody comprises a light chain variable region having the amino acid sequence of SEQ ID NO: 91.
24. The pharmaceutical composition of claim 19 , wherein the antibody comprises a heavy chain variable region having the amino acid sequence of SEQ 11) NO: 109 and a light chain variable region having the amino acid sequence of SEQ ID NO: 91.
25. The pharmaceutical composition of claim 19 , wherein the light chain complementarity determining region 1 (LCDR1) has the amino acid sequence SAQSSVNYIH (SEQ ID NO: 112).
26. The pharmaceutical composition of claim 19 , wherein the antibody comprises a constant region.
27. The pharmaceutical composition of claim 26 , wherein the constant region is γ1.
28. The pharmaceutical composition of claim 26 , wherein the constant region is γ4.
29. The pharmaceutical composition of claim 19 , wherein the antibody recognizes the I domain of human α2 integrin.
30. The pharmaceutical composition of claim 19 , wherein the antibody binds α2β1 integrin.
31. The pharmaceutical composition of claim 19 , wherein the antibody is a full length antibody.
32. The pharmaceutical composition of claim 19 , wherein the antibody is bound to a detectable label.
33. The pharmaceutical composition of claim 19 , wherein the antibody is immobilized on solid phase.
34. The pharmaceutical composition of claim 19 , wherein the antibody inhibits binding of α2 or α2β1 integrin to an α2β1 integrin ligand.
35. The pharmaceutical composition of claim 34 , wherein the α2β1 integrin ligand is selected from the group consisting of collagen, laminin, Echovirus-1, decorin, E-cadherin, matrix metalloproteinase I (MMP-I), endorepellin, collectin and C1q complement protein.
36. A kit comprising the pharmaceutical composition of claim 19 and instructions for its use to detect α2 or α2β1 integrin protein.