NZ773527B2 - Antibodies, uses & methods - Google Patents

Abstract

The present invention relates to compositions of anti-human OX40L antibodies, wherein said compositions of said antibodies with comprise another therapeutic agent. The compositions are useful in treating hOX40L-mediated diseases or conditions, including autoimmune or systemic inflammatory diseases or conditions and transplant rejections.

Claims (31)

CLAIMS :

1. A combination comprising an antibody or an antigen binding fragment thereof that specifically binds to hOX40L, wherein the antibody or antigen binding fragment comprises a VH domain and a VL domain, wherein: 5 the VH domain comprises: (i) the HCDR1 sequence of SEQ ID NO:42 comprising less than 4 amino acid substitutions, wherein the less than 4 amino acid substitutions in the HCDR1 sequence are selected from the group consisting of N or S at position 1, A or I at position 3, and N or T at position 5 of SEQ ID NO:42; 10 (ii) the HCDR2 sequence of SEQ ID NO:44 comprising less than 5 amino acid substitutions, wherein the less than 5 amino acid substitutions in the HCDR2 sequence are selected from the group consisting of T or G at position 1, A to G at position 8, R or Y at position 10, and V or M at position 15 of SEQ ID NO:44; and (iii) the HCDR3 sequence of SEQ ID NO:46 comprising less than 5 amino acid substitutions, 15 wherein the less than 5 amino acid substitutions in the HCDR3 sequence are selected from the group consisting of I or P at position 4, M or I at position 5, A or T at position 6, T or L at position 7, and P or G at position 11 of SEQ ID NO:46, and wherein the HCDR3 sequence comprises VRGXYYY, wherein X is P or G; and and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: 20 (i) the LCDR1 sequence of SEQ ID No:56 comprising less than 2 amino acid substitutions, wherein the less than 2 amino acid substitutions in the LCDR1 sequence is S or D at amino acid position 8 of SEQ ID NO:56; (ii) the LCDR2 sequence of SEQ ID NO:58; and (iii) the LCDR3 sequence of SEQ ID NO:54 comprising less than 5 amino acid substitutions, 25 wherein the less than 5 amino acid substitutions in the LCDR3 sequence are selected from the group consisting of H or Y at position 4, V or T at position 6, S or P at position 7, and F or R at position 8 of SEQ ID NO:54; and a further therapeutic agent independently selected from the group consisting of rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti- 30 CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4- Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti- thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules and 35 Vorinostat.

2. The combination according to claim 1, wherein the antibody or antigen binding fragment thereof comprises a VH domain which comprises: (i) the HCDR1 sequence of SEQ ID NO: 42 comprising less than 3 amino acid substitutions, wherein the less than 3 amino acid substitutions in the HCDR1 sequence are selected from 5 the group consisting of N or S at position 1, and A or I at position 3; and (ii) the HCDR2 sequence of SEQ ID NO: 44 comprising less than 3 amino acid substitutions, wherein the less than 3 amino acid substitutions in the HCDR2 sequence are selected from the group consisting of T or G at position 1, and A to G at position 8 of SEQ ID NO:44. 10 3. The combination according to claim 1 or 2, wherein the HCDR3 sequence comprises

3. VRGXYYYGMDV, wherein X is P or G.

4. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a VH domain which comprises: 15 the HCDR1 sequence of SEQ ID NO:36 or 42; the HCDR2 sequence of SEQ ID NO:38 or 44; and the HCDR3 sequence of SEQ ID NO:40 or 46 comprising less than 5 amino acid substitutions, wherein the HCDR3 sequence comprises VRGXYYY, wherein X is P or G; and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: 20 the LCDR1 sequence of SEQ ID No:50 or 56; the LCDR2 sequence of SEQ ID NO:52 or 58; and the LCDR3 sequence of SEQ ID NO:54.

5. The combination according to any one of the preceding claims, wherein the antibody or antigen 25 binding fragment comprises a V domain which comprises: the HCDR1 sequence of SEQ ID NO:4 or 10; the HCDR2 sequence of SEQ ID NO:6 or 12; and the HCDR3 sequence of SEQ ID NO:8 or 14, wherein the HCDR3 sequence comprises

6. VRGXYYY, wherein X is P or G; 30 and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: the LCDR1 sequence of SEQ ID No:18 or 24; the LCDR2 sequence of SEQ ID NO:20 or 26; and the LCDR3 sequence of SEQ ID NO:22. 35 6. The antibody or antigen binding fragment thereof according to any one of claims 1-3 and 5, wherein the antibody or antigen binding fragment comprises a VH domain which comprises: the HCDR1 sequence of SEQ ID NO:4; the HCDR2 sequence of SEQ ID NO:6; and the HCDR3 sequence of SEQ ID NO:8; and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: the LCDR1 sequence of SEQ ID No:18; the LCDR2 sequence of SEQ ID NO:20; and 5 the LCDR3 sequence of SEQ ID NO:22.

7. The antibody or antigen binding fragment thereof according to any one of claims 1-3 and 5, wherein the antibody or antigen binding fragment comprises a VH domain which comprises: the HCDR1 sequence of SEQ ID NO:10; 10 the HCDR2 sequence of SEQ ID NO:12; and the HCDR3 sequence of SEQ ID NO:14; and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: the LCDR1 sequence of SEQ ID No:24; the LCDR2 sequence of SEQ ID NO:26; and 15 the LCDR3 sequence of SEQ ID NO:22.

8. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a VH domain that is at least 85% identical to SEQ ID NO: 34, and a 20 VL domain that is at least 85% identical SEQ ID NO: 48.

9. The combination according to any one of claims 1-4 and 8, wherein the antibody or antigen binding fragment comprises a V domain which comprises: the HCDR1 sequence of SEQ ID NO:36; 25 the HCDR2 sequence of SEQ ID NO:38; and the HCDR3 sequence of SEQ ID NO:40; and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: the LCDR1 sequence of SEQ ID No:50; the LCDR2 sequence of SEQ ID NO:52; and 30 the LCDR3 sequence of SEQ ID NO:54.

10. The combination according to any one of claims 1-4 and 8, wherein the antibody or antigen binding fragment comprises a VH domain which comprises: the HCDR1 sequence of SEQ ID NO:42; the HCDR2 sequence of SEQ ID NO:44; and 35 the HCDR3 sequence of SEQ ID NO:46; and wherein the antibody or antigen binding fragment comprises a V domain which comprises: the LCDR1 sequence of SEQ ID No:56; the LCDR2 sequence of SEQ ID NO:58; and the LCDR3 sequence of SEQ ID NO:60. 5

11. The combination according to any one of claims 1-4 and 9-10, wherein the antibody or antigen binding fragment comprises a heavy chain and a light chain wherein: a. the heavy chain comprises a VH domain having at least 95% identity to the amino acid sequence of SEQ ID No:34; and b. the light chain comprises a VL domain having at least 95% identity to the amino acid 10 sequence of SEQ ID No:48

12. The combination according to any one of claims 1-4 and 9-11, wherein the antibody or antigen binding fragment comprises: a VH domain comprising an amino acid sequence of SEQ ID NO: 34 and a VL domain comprising an amino acid sequence of SEQ ID NO: 48.

13. The combination according to any one of the preceding claims, wherein the antibody or antigen 15 binding fragment comprises a human gamma 4 constant region.

14. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a heavy chain constant region which is IgG4 PE.

15. The combination according to claim 14, wherein the heavy chain constant region comprises the sequence of SEQ ID No:128. 20

16. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a kappa light chain.

17. The combination according to claim 16, wherein the kappa light chain comprises a constant region selected from the group consisting of the kappa light chain constant region amino acid sequences of SEQ ID Nos: 136, 138, 140, 142 and 144. 25

18. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises first and second copies of said VH domain and/or comprises first and second copies of said VL domain.

19. The combination according to any one of the preceding claims, wherein the antibody or antigen binding fragment is a fully human antibody or antigen binding fragment. 30

20. The combination according to any one of claim 1-4 and 9-19, wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain amino acid sequence consists of the sequence of SEQ ID No:62, and/or the light chain amino acid sequence consists of the sequence of SEQ ID No:64.

21. The combination according to any one of the preceding claims, formulated for parenteral administration selected from intravenous or sub-cutaneous administration. 5

22. Use of the combination of any one of the preceding claims in the manufacture of a medicament for treating and/or preventing a hOX40L-mediated disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection.

23. Use of an antibody or antigen binding fragment thereof as defined in any one of claims 1 to 20 10 in the manufacture of a medicament for treating and/or preventing of a hOX40L mediated disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant rejection in a subject, wherein the subject is to be or has been administered a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of 15 rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin 20 antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules and Vorinostat.

24. Use according to claim 22 or 23, wherein the hOX40L-mediated disease or condition is selected from inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, allogeneic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus 25 erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, multiple sclerosis, or atherosclerosis.

25. Use of the combination of any one of claims 1 to 20 in the manufacture of a medicament for treating and/or preventing alopecia areata, celiac disease, systemic sclerosis, dermatitis or asthma. 30

26. Use of an antibody or antigen binding fragment thereof as defined in any one of claims 1 to 20 in the manufacture of a medicament for treating and/or preventing alopecia areata, celiac disease, systemic sclerosis, dermatitis or asthma in a subject, wherein the subject is to be or has been administered a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of 35 rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin 5 antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules and Vorinostat).

27. A kit comprising an antibody or an antigen binding fragment thereof as defined in any one of claims 1-20, and a further therapeutic agent independently selected from the group consisting of 10 rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin 15 antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules and Vorinostat).

28. The kit according to claim 27, wherein the kit comprises an IV or injection device that comprises the antibody or antigen binding fragment thereof.

29. Use according to any one of claims 22 or 23, wherein the medicament comprising the antibody or 20 the antigen binding fragment thereof and the further therapeutic agent are in separate compositions and/or are to be administered sequentially.

30. Use according to any one of claims 22 to 26 or 29, wherein the medicament is to be administered parenterally.

31. Use according to claim 30, wherein the parenteral administration is intravenous or sub-cutaneous 25 administration.