Antibody polypeptides that antagonize CD40L
Antibody polypeptides that specifically bind human CD40L are provided. The antibody polypeptides do not activate platelets. The antibody polypeptides are useful in the treatment of diseases involving CD40L activation, such as graft-related diseases and autoimmune diseases. The antibody polypeptides may be domain antibodies (dAbs) comprising a single V H or V K domain. The half-life of the antibody polypeptides may be increased by modifying the antibody polypeptides to be dual specific reagents that can also bind human serum albumin (HSA) or another antigen.
1. An isolated antibody polypeptide comprising a first variable domain that specifically binds human CD40L comprising the amino acid sequence of SEQ ID NO:1, wherein the amino acid sequence of the first variable domain is at least 95% identical to the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
2. The antibody polypeptide of claim 1 , wherein the antibody polypeptide is a domain antibody (dAb).
3. The antibody polypeptide of claim 1 , wherein the amino acid sequence of the first, variable domain is at least 96% identical to the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
4. The antibody polypeptide of claim 1 , wherein the amino acid sequence of the first variable domain is at least 97% identical to the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
5. The antibody polypeptide of claim 1 , wherein the amino acid sequence of the first variable domain is at least 98% identical to the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
6. The antibody polypeptide of claim 1 , wherein the amino acid sequence of the first variable domain is at least 99% identical to the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
7. The antibody polypeptide of claim 1 , wherein first variable domain comprises the amino acid sequence of: BMS2h-572-11 (SEQ ID NO: 226), BMS2h-572-12 (SEQ ID NO: 227), BMS2h-572-14 (SW ID NO: 229), BMS2h-572-6 (SEQ ID NO: 243), BMS2h-572-601 (SEQ ID NO: 244), BMS2h-572-602 (SEQ ID NO: 245), BMS2h-572-603 (SEQ ID NO: 246), BMS2h-572-603 (SEQ ID NO: 247), BMS2h-572-606 (SEQ ID NO: 249), BMS2h-572-607 (SEQ ID NO: 250), BMS2h-572-608 (SEQ ID NO: 251), BMS2h-572-609 (SEQ ID NO: 252), BMS2h-572-610 (SEQ ID NO: 253), BMS2h-572-611 (SEQ ID NO: 254), BMS2h-572-612 (SEQ ID NO: 255), BMS2h-572-61.3 (SEQ ID NO: 256), BMS2h-572-614 (SEQ ID NO: 257), BMS2h-572-615 (SEQ ID NO: 258), BMS2h-572-616 (SEQ ID NO: 259 BMS2h-572-617 (SEQ ID NO: 260), BMS2h-572-618 (SEQ ID NO: 261), BMS2h-572-619 (SEQ ID NO: 262), BMS2h-572-620 (SEQ H) NO: 263), BMS2h-572-622 (SEQ ID NO: 265), BMS2h-572-623 (SEQ ID NO: 266), BMS2h-572-624 (SEQ ID NO: 267), BMS2h-572-625 (SEQ ID NO: 268), BMS2h-572-626 (SEQ ID NO: 269), BMS2h-572-627 (SEQ ID NO: 270), BMS2h-572-630 (SEQ ID NO: 271), BMS2h-572-631 (SEQ ID NO: 272), BMS2h-572-632 (SEQ ID NO: 273), BMS2h-572-634 (SEQ ID NO: 275), BMS2h-572-635 (SEQ ID NO: 276), or BMS2h-572-9 (SEQ ID NO: 279).
8. The antibody polypeptide of claim 1 , wherein:
a) the CDR1 of the first variable domain has the same amino acid sequence as amino acids 31 to 35 of BMS2h-572-633 (SEQ ID NO: 274);
b) the CDR2 of the first variable domain has the same amino acid sequence as amino acids 51 to 66 of BMS2h-572-633 (SEQ ID NO: 274); and
c) the CDR3 of the first variable domain has the same amino acid sequence as amino acids 101 to 107 of BMS2h-572-633 (SEQ ID NO: 274).
9. The antibody polypeptide claim 1 , wherein the first variable domain consists of the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).
10. The antibody polypeptide of claim 9 , wherein the antibody polypeptide is a domain antibody (dAb).
11. The antibody polypeptide of chum 1 , wherein the antibody polypeptide is a fusion polypeptide comprising the first variable domain consisting of the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274) and an Fc domain.
12. The antibody polypeptide of claim 11 , wherein the Fc domain comprises an IgG4 Fc domain.
13. The antibody polypeptide of claim 11 , wherein the Fr domain comprises an IgG1 Fc domain.
14. The antibody polypeptide of claim 11 , consisting of the amino acid sequence of SEQ ID NO: 355.
15. The antibody polypeptide of claim 1 , wherein the antibody polypeptide further comprises a second variable domain that specifically binds a second antigen, wherein the second antigen is an antigen other than human CD40L.
16. The antibody polypeptide of claim 15 , wherein the second antigen is a cluster of differentiation (CD) molecule or a Major Histocompatibility Complex (MHC) Class II molecule.
17. The antibody polypeptide of claim 15 , wherein the second antigen is serum albumin (SA).
18. A pharmaceutical composition comprising a therapeutically-effective amount of the antibody polypeptide of claim 1 and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18 , further comprising an immunosuppressive/immunomodulatory and/or anti-inflammatory agent.
20. The pharmaceutical composition of claim 18 , wherein the antibody polypeptide is the antibody polypeptide of claim 9 .
21. The pharmaceutical composition of claim 18 , wherein the antibody polypeptide is the antibody of claim 14 .
22. A method of antagonizing CD40L activity in a patient with an immune disease in need of such treatment, comprising administering to the patient a therapeutically effective amount of the antibody polypeptide of claim 1 to antagonize CD40L activity in the patient.
23. The method of claim 22 , wherein the antibody polypeptide is the antibody polypeptide of claim 9 .
24. A method of claim 22 , wherein the antibody polypeptide is the antibody polypeptide of claim 14 .
25. The method of claim 22 , wherein the antibody polypeptide is administered in combination with an immunosuppressive/immunomodulatory and/or inflammatory agent.
26. The method of claim 22 , wherein the immune disease is an autoimmune disease or a graft-related disease.
27. The method of claim 26 , wherein the immune disease is a graft-related disease.
28. The method of claim 27 , wherein the graft-related disease comprises solid organ, tissue and/or cell transplant rejection.
29. The method of claim 27 , wherein the graft-related disease is graft versus host disease (GVHD).
30. The method of claim 27 , wherein the graft-related disease is an acute transplant rejection.
31. The method of claim 27 , wherein the graft-related disease is a chronic transplant rejection.
32. The method of claim 27 , wherein the antibody polypeptide is co-administered with a CTLA4 mutant molecule.
33. The method of claim 32 , wherein the CTLA4 mutant molecule is L104EA29Y-Ig (belatacept).
34. The method of claim 22 , wherein the immune disease is selected from the group consisting of Addison's disease, allergies, ankylosing; spondylitis, asthma, atherosclerosis, autoimmune diseases of the ear, autoimmune diseases of the eye, autoimmune hepatitis, autoimmune parotitis, colitis, coronary heart disease, Crohn's disease, diabetes, including Type 1 and/or Type 2 diabetes, epidiymitis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, hemolytic anemia, idiopathic thrombocytopenic purpura, inflammatory bowel disease, immune response to recombinant drug products, systemic lupus erythematosus, male infertility, multiple sclerosis, myasthenia gravis, pemphigus, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, transplant rejection, vasculitis, AIDS, atopic allergy, bronchial asthma, eczema, leprosy, schizophrenia, inherited depression, chronic fatigue syndrome, Alzheimer's disease, Parkinson's disease, myocardial infarction, stroke, autism, epilepsy, Arthus's phenomenon, anaphylaxis, alcohol addiction, and drug addiction.
35. The method of claim 22 , wherein the immune disease is idiopathic thrombocytopenic purpura.