NZ732132B2 - Antibodies, uses & methods - Google Patents

Abstract

The present invention relates to combinations of anti-human OX40L antibodies and a further therapeutic agent, and new medical uses and methods for the treatment and/or prevention of an autoimmune or systemic inflammatory disease or condition, or transplant rejection.

Claims (25)

1. A combination comprising an antibody or an antigen binding fragment thereof, that specifically binds to hOX40L, wherein the antibody or n binding fragment comprises a VH domain which comprises: the HCDR1 sequence of SEQ ID NO:36 or 42; 5 the HCDR2 sequence of SEQ ID NO:38 or 44; and the HCDR3 sequence of SEQ ID NO:40 or 46; and wherein the antibody or antigen binding fragment comprises a VL domain which comprises: the LCDR1 sequence of SEQ ID No:50 or 56; the LCDR2 sequence of SEQ ID NO:52 or 58; and 10 the LCDR3 sequence of SEQ ID NO:54 or 60, and a further eutic agent ndently selected from the group ting of rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti- CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, Fc molecules, CCR5 receptor antagonists, anti -CD40L antibodies, anti-VLA4 antibodies, 15 anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 dies, anti-a4b7 integrin antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti-TNFa / TNFa-Fc molecules and stat.

2. The combination according to Claim 1 wherein the antibody or antigen binding fragment thereof 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 ce of SEQ ID No:34; and 5 b. the light chain comprises a VL domain having at least 95% identity to the amino 2 acid ce of SEQ ID No:48

3. The combination according to Claim 1 or 2, wherein the antibody or antigen binding fragment comprises: a VH domain comprising an amino acid sequence of SEQ ID NO: 34 and/or a VL domain comprising an amino acid sequence of SEQ ID NO: 48.

4. A combination comprising an antibody or an antigen binding fragment thereof, that ically 30 binds to hOX40L, wherein the antibody or antigen binding fragment comprises a VH 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; 35 and wherein the antibody or antigen binding fragment comprises a VL domain which ses: the LCDR1 ce 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 or 28, and a further therapeutic agent independently selected from the group consisting of rapamycin 5 (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti- CD28 antibodies, anti-IL12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 dies, Fc molecules, CCR5 receptor antagonists, D40L antibodies, anti-VLA4 dies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, D45 antibodies, cyclophosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 10 integrin antibodies, anti-IL6 antibodies, anti-IL2R dies, anti-CD25 dies, anti-TNFa / TNFa-Fc molecules and Vorinostat

5. The combination according to claim 4, wherein the antibody or antigen binding fragment comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 2 and/or comprises a VL domain comprising an amino acid sequence of SE Q ID NO:16. 15

6. A ation according to any one of the preceding claims, wherein the antibody or antigen binding fragment comprises a human gamma 4 constant region.

7. A 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.

8. A ation according to claim 7, wherein the heavy chain constant region comprises the 20 sequence of SEQ ID No:128.

9. A combination according to any one of the preceding claims, n the antibody or antigen binding fragment comprises a kappa light chain.

10. A combination according to claim 9, wherein the kappa light chain comprises a constant region selected from the group consisting of the kappa lig ht chain constant region amino acid 25 sequences of SEQ ID Nos: 136, 138, 140, 142 and 144.

11. A combination according to any one of the preceding claims, n 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.

12. A combination according to any one of the prece ding , wherein the antibody or antigen 30 binding fragment is a fully human antibody or antigen binding fragment.

13. A combination according to any one of claims 1 to 3, or the combination according to any one of claims 6 to 12 when dependent on any one of claims 1 to 3, wherein the antibody comprises a heavy chain and a light chain, the heavy chain amino acid sequence consisting of the sequence of SEQ ID No:62, and the light chain amino acid sequence consisting of the sequence of SEQ ID No:64. 5

14. A combination according to any one of claims 1 to 13, formulated for parenteral administration selected from intravenous or sub-cutaneous administration.

15. Use of a combination as defined in any of claims 1 to 13, in the cture of a medicament for treating and/or preventing a hOX40L-mediated e or condition selected from an autoimmune disease or condition, a systemic inflammatory e or condition, or transplant 10 rejection.

16. Use of an antibody or antigen binding fragment thereof as defined in any one of claims 1 to 13, in the manufacture of a medicament for treating and/or ting of a hOX40L ed disease or condition selected from an autoimmune disease or condition, a systemic inflammatory disease or condition, or transplant re n in a subject, wherein the subject is 15 to be administered a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of rapamycin (sirolimus), tacrolimus, porin, corticosteroids, rexate, mycophenolate mofetil, D28 dies, L12/IL-23 antibodies, anti-CD20 antibodies, anti-CD30 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 20 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, cyclophosphamide, hymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin dies, L6 antibodies, L2R antibodies, anti-CD25 antibodies, anti- TNFa/TNFa-Fc molecules and Vorinostat

17. Use according to claim 15 or 16, wherein the hOX40L-mediated disease or condition is selected from inflammatory bowel disease (IBD), Crohn’s e, rheumatoid arthritis, allogeneic transplant rejection, graft-versus-host disease (GvHD), ulcerative colitis, systemic lupus erythematosus (SLE), diabetes, uveitis, ankylosing spondylitis, contact hypersensitivity, le sclerosis, or atherosclerosis. 30

18. Use of a combination as defined in any of claims 1 to 13 in the manufacture of a medicament for ng and/or preventing dermatitis, asthma, alopecia, celiac disease or systemic sclerosis.

19. Use of an antibody or antigen binding fragment thereof as defined in any one of claims 1 to 13, in the manufacture of a medicament for treating and/or preventing dermatitis, asthma, alopecia, celiac e or systemic sclerosis in a subject, wherein the subject is to be administered a further therapeutic agent, wherein the further therapeutic agent is independently selected from the group consisting of rapamycin (sirolimus), imus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, anti-CD28 antibodies, anti-IL12/IL-23 anti bodies, anti-CD20 antibodies, anti-CD30 5 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 antibodies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, hosphamide, anti-thymocyte globulins, anti-complement C5 antibodies, anti-a4b7 integrin antibodies, anti-IL6 antibodies, anti-IL2R antibodies, anti-CD25 antibodies, anti- NFa-Fc les and Vorinostat. 10

20. A kit comprising an antibody or an antigen binding fragment thereof as defined in any one of claims 1-13, and a further eutic agent independently selected from the group consisting of rapamycin (sirolimus), tacrolimus, ciclosporin, corticosteroids, methotrexate, mycophenolate mofetil, D28 antibodies, anti-IL12/IL-23 anti bodies, anti-CD20 antibodies, anti-CD30 15 antibodies, CTLA4-Fc molecules, CCR5 receptor antagonists, anti-CD40L antibodies, anti-VLA4 antibodies, anti-LFA1 dies, fludarabine, anti-CD52 antibodies, anti-CD45 antibodies, hosphamide, 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 stat. 20

21. The kit according to claim 20, n the kit comprises a label or instructions for use to treat and/or prevent said disease or condition in a human.

22. The kit according to claim 20 or 21, wherein the kit ses an IV or ion device that comprises the antibody or antigen binding fragment thereof.

23. Use according to any one of claims 15 or 18, wh erein the medicament comprising the antibody 25 or the antigen binding nt thereof and the further therapeutic agent are in separate compositions and/or are to be administered sequentially.

24. Use according to any one of claims 15 to 19 or 23, wherein the medicament is to be administered parenterally. 30

25. Use according to claim 24, wherein the parenteral administration is intravenous or subcutaneous administration. mi ragga mm. Mn. 59 59 59 8302 6:80 B 2: n- $6er 9:85 w- .aqxoécm $38338 2.- muccuES 3 En 38m. NT O OOOOOO N OOOCOQ'N H ?ugpugq J01d8391 JO % SUBST¥TUTE SHEET (RULE 26)