Granted Patent B2

US 9,512,229 · App. 15/142,538 · Granted Dec 6, 2016

Inventors: Philip Bland-Ward (Cambridge, GB); Miha Kosmac (Cambridge, GB); Steve Holmes (Cambridge, GB); Ian Kirby (Cambridge, GB); Jamie Campbell (Cambridge, GB)

Assignee: Kymab Limited

C07K16/2875A61K31/436A61K39/3955A61K45/06G01N33/4833A61K2039/505A61K2039/507C07K2317/21C07K2317/22C07K2317/24C07K2317/31C07K2317/33C07K2317/54C07K2317/55C07K2317/565C07K2317/622C07K2317/624C07K2317/76

Abstract

Claims (123)

1. A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising:

administering to the subject

a) a therapeutically effective, or prophylactically effective, amount of anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L; and

b) a therapeutically effective, or prophylactically effective, amount of a second agent selected from the group consisting of:

rapamycin; tacrolimus; cyclosporine; a corticosteroid;

methylprednisolone; and anti-IL2R antibodies wherein the administering of anti-OX40L antibody of fragment thereof that antagonizes specific binding of OX40 to OX40L and the second agent results in a synergistic effect.

2. The method of claim 1 , wherein the second agent is rapamycin.

3. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant.

4. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time after a transplant.

5. The method of claim 1 , wherein the second agent is administered at least one time after a transplant.

6. The method of claim 1 , wherein the second agent is administered at least one time before a transplant.

7. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant and at least one time after the transplant.

8. The method of claim 1 , wherein the second agent is administered at least one time before a transplant and at least one time after the transplant.

9. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before transplant and the second agent is administered at least one time after transplant.

10. The method of claim 1 , wherein the second agent is administered at least one time before transplant and the anti-OX40L antibody or fragment thereof is administered at least one time after transplant.

11. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof and the second agent are administered at least one time before transplant.

12. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof and the second agent are administered at least one time after transplant.

13. The method of claim 1 , wherein the administration of the anti-OX40L antibody or fragment thereof and the second agent are continued at least until peripheral blood chimerism has been achieved in the human subject.

14. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant followed by once a week, bi-weekly or once a month administration of the same after the transplant; and

the second agent is administered at least one time after the transplant.

15. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant followed by once a week, bi-weekly or once a month administration of the same after the transplant; and

the second agent is administered daily after the transplant.

16. The method of claim 1 , wherein the antibody or antibody fragment is humanized or human antibody or antibody fragment.

17. The method of claim 1 , wherein the antibody or antibody fragment is selected from the group consisting of:

multispecific antibodies, bi-specific antibodies, single-chain Fv antibodies (scFv), camelized antibodies, Fab fragments, F(ab′) fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments thereof.

18. The method of claim 1 , wherein the antibody or antibody fragment competes for binding of OX40L with an antibody comprising the VH sequence of SEQ ID NO: 34 and the VL sequence of SEQ ID NO: 48.

19. The method of claim 1 , wherein the antibody or antibody fragment thereof comprises a HCDR3 of from 16 to 27 amino acids and derived from the recombination of a human VH gene segment, a human D gene segment and a human JH gene segment, wherein the human JH gene segment is IGHJ6 or IGHJ6*02.

20. The method of claim 1 , wherein the antibody or antibody fragment thereof comprises a CDR selected from:

a. the HCDR3 of antibody comprising variable region Seq ID No:40 or Seq ID No:46;

b. the HCDR3 of antibody comprising variable region Seq ID No:8 or SEQ ID No:14;

c. the HCDR3 of antibody comprising variable region Seq ID No:72 or Seq ID No:78;

d. the HCDR3 of antibody comprising variable region Seq ID No:100 or Seq ID No:106;

e. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 215, 217, 219, 221, 223, 225, 227, 229 or 230; and

f. an HCDR3 of any of the antibodies having the variable region amino acid sequence of Seq ID Nos: 232 or 234.

21. The method of claim 1 , wherein the antibody or antibody fragment thereof comprises:

a. the CDRs of Seq ID No:40 or Seq ID No:46 for CDRH3, SEQ ID No:38 or SEQ ID No:44 for CDRH2, SEQ ID No:36 or SEQ ID No:42 for CDRH1, SEQ ID No:50 or SEQ ID No:56 for CDRL1, SEQ ID No:52 or SEQ ID No:58 for CDRL2 and SEQ ID No:54 or SEQ ID No:60 for CDRL3;

b. the CDRs of Seq ID No:8 or SEQ ID No:14 for CDRH3, SEQ ID No:6 or SEQ ID No:12 for CDRH2, SEQ ID No:4 or SEQ ID No:10 for CDRH1, SEQ ID No:18 or SEQ ID No:24 for CDRL1, SEQ ID No:20 or SEQ ID No:26 for CDRL2 and SEQ ID No:22 or SEQ ID No:28 for CDRL3;

c. the CDRs of Seq ID No:72 or Seq ID No:78 for CDRH3, SEQ ID No:70 or SEQ ID No:76 for CDRH2, SEQ ID No:68 or SEQ ID No:74 for CDRH1, SEQ ID No:82 or SEQ ID No:88 for CDRL1, SEQ ID No:84 or SEQ ID No:90 for CDRL2 and SEQ ID No:86 or SEQ ID No:92 for CDRL3;

d. the CDRs of Seq ID No:100 or Seq ID No:106 for CDRH3, SEQ ID No:98 or SEQ ID No:104 for CDRH2, SEQ ID No:96 or SEQ ID No:102 for CDRH1, SEQ ID No:110 or SEQ ID No:116 for CDRL1, SEQ ID No:112 or SEQ ID No:118 for CDRL2 and SEQ ID No:114 or SEQ ID No:120 for CDRL3;

e. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences

SEQ ID NO: 215 and SEQ ID NO: 214;

SEQ ID NO: 217 and SEQ ID NO: 216;

SEQ ID NO: 219 and SEQ ID NO: 218;

SEQ ID NO: 221 and SEQ ID NO: 220;

SEQ ID NO: 223 and SEQ ID NO: 222;

SEQ ID NO: 225 and SEQ ID NO: 224;

SEQ ID NO: 225 and SEQ ID NO: 226;

SEQ ID NO: 227 and SEQ ID NO: 214;

SEQ ID NO: 229 and SEQ ID NO: 228; or

SEQ ID NO: 230 and SEQ ID NO: 214;

f. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences

SEQ ID NO: 232 and SEQ ID NO: 231; or

SEQ ID NO: 234 and SEQ ID NO: 233;

g. the VH and/or VL domains of Seq ID No:34 for VH and/or Seq ID No:48 for VL;

h. the VH and/or VL domains of Seq ID No:2 for VH and/or Seq ID No:16 for VL;

i. the VH and/or VL domains of Seq ID No:66 for VH and/or Seq ID No:80 for VL;

j. the VH and/or VL domains of Seq ID No:94 for VH and/or Seq ID No:108 for VL;

k. the VH domain and the VL domain of amino acid sequences

SEQ ID NO: 215 and SEQ ID NO: 214;

SEQ ID NO: 217 and SEQ ID NO: 216;

SEQ ID NO: 219 and SEQ ID NO: 218;

SEQ ID NO: 221 and SEQ ID NO: 220;

SEQ ID NO: 223 and SEQ ID NO: 222;

SEQ ID NO: 225 and SEQ ID NO: 224;

SEQ ID NO: 225 and SEQ ID NO: 226;

SEQ ID NO: 227 and SEQ ID NO: 214;

SEQ ID NO: 229 and SEQ ID NO: 228; or

SEQ ID NO: 230 and SEQ ID NO: 214;

or

l. the VH domain and the VL domain of amino acid sequences

SEQ ID NO: 232 and SEQ ID NO: 231; or

SEQ ID NO: 234 and SEQ ID NO: 233.

22. The method of claim 1 , wherein the antibody comprises the VH sequence of SEQ ID No:215 and the VL sequence of SEQ ID No:214.

23. The method of claim 1 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant and at least one time after the transplant and the second agent is administered at least one time before a transplant and at least one time after the transplant.

24. A method of treating or preventing graft versus host disease (GvHD) in a human subject in need thereof, comprising:

administering to the subject a therapeutically or prophylactically effective amount of a synergistic combination of:

a) an anti-OX40L antibody or fragment thereof that antagonizes specific binding of OX40 to OX40L; and

b) a second agent selected from the group consisting of:

rapamycin; tacrolimus; cyclosporine; a corticosteroid;

methylprednisolone; and anti-IL2R antibodies.

25. The method of claim 24 , wherein the anti-OX40L antibody or fragment thereof is administered at least one time before a transplant and at least one time after the transplant and the second agent is administered at least one time before a transplant and at least one time after the transplant.

26. The method of claim 24 , wherein the second agent is rapamycin.

27. The method of claim 24 , wherein the antibody or antibody fragment is humanized or human antibody or antibody fragment.

28. The method of claim 24 , wherein the antibody or antibody fragment thereof comprises:

a. the CDRs of Seq ID No:40 or Seq ID No:46 for CDRH3, SEQ ID No:38 or SEQ ID No:44 for CDRH2, SEQ ID No:36 or SEQ ID No:42 for CDRH1, SEQ ID No:50 or SEQ ID No:56 for CDRL1, SEQ ID No:52 or SEQ ID No:58 for CDRL2 and SEQ ID No:54 or SEQ ID No:60 for CDRL3;

b. the CDRs of Seq ID No:8 or SEQ ID No:14 for CDRH3, SEQ ID No:6 or SEQ ID No:12 for CDRH2, SEQ ID No:4 or SEQ ID No:10 for CDRH1, SEQ ID No:18 or SEQ ID No:24 for CDRL1, SEQ ID No:20 or SEQ ID No:26 for CDRL2 and SEQ ID No:22 or SEQ ID No:28 for CDRL3;

c. the CDRs of Seq ID No:72 or Seq ID No:78 for CDRH3, SEQ ID No:70 or SEQ ID No:76 for CDRH2, SEQ ID No:68 or SEQ ID No:74 for CDRH1, SEQ ID No:82 or SEQ ID No:88 for CDRL1, SEQ ID No:84 or SEQ ID No:90 for CDRL2 and SEQ ID No:86 or SEQ ID No:92 for CDRL3;

d. the CDRs of Seq ID No:100 or Seq ID No:106 for CDRH3, SEQ ID No:98 or SEQ ID No:104 for CDRH2, SEQ ID No:96 or SEQ ID No:102 for CDRH1, SEQ ID No:110 or SEQ ID No:116 for CDRL1, SEQ ID No:112 or SEQ ID No:118 for CDRL2 and SEQ ID No:114 or SEQ ID No:120 for CDRL3;

e. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences

SEQ ID NO: 215 and SEQ ID NO: 214;

SEQ ID NO: 217 and SEQ ID NO: 216;

SEQ ID NO: 219 and SEQ ID NO: 218;

SEQ ID NO: 221 and SEQ ID NO: 220;

SEQ ID NO: 223 and SEQ ID NO: 222;

SEQ ID NO: 225 and SEQ ID NO: 224;

SEQ ID NO: 225 and SEQ ID NO: 226;

SEQ ID NO: 227 and SEQ ID NO: 214;

SEQ ID NO: 229 and SEQ ID NO: 228; or

SEQ ID NO: 230 and SEQ ID NO: 214;

f. the heavy chain CDRs and the light chain CDRs of variable region amino acid sequences

SEQ ID NO: 232 and SEQ ID NO: 231; or

SEQ ID NO: 234 and SEQ ID NO: 233;

g. the VH and/or VL domains of Seq ID No:34 for VH and/or Seq ID No:48 for VL;

h. the VH and/or VL domains of Seq ID No:2 for VH and/or Seq ID No:16 for VL;

i. the VH and/or VL domains of Seq ID No:66 for VH and/or Seq ID No:80 for VL;

j. the VH and/or VL domains of Seq ID No:94 for VH and/or Seq ID No:108 for VL;

k. the VH domain and the VL domain of amino acid sequences

SEQ ID NO: 215 and SEQ ID NO: 214;

SEQ ID NO: 217 and SEQ ID NO: 216;

SEQ ID NO: 219 and SEQ ID NO: 218;

SEQ ID NO: 221 and SEQ ID NO: 220;

SEQ ID NO: 223 and SEQ ID NO: 222;

SEQ ID NO: 225 and SEQ ID NO: 224;

SEQ ID NO: 225 and SEQ ID NO: 226;

SEQ ID NO: 227 and SEQ ID NO: 214;

SEQ ID NO: 229 and SEQ ID NO: 228; or

SEQ ID NO: 230 and SEQ ID NO: 214;

or

l. the VH domain and the VL domain of amino acid sequences

SEQ ID NO: 232 and SEQ ID NO: 231; or

SEQ ID NO: 234 and SEQ ID NO: 233.

29. The method according to claim 1 , wherein the synergistic effect is measured in a Rhesus macaque model of haploidentical hematopoietic stem cell transplantation.

30. The method according to 29 , wherein the survival is increased by at least 14 days as compared to either the antibody or the second agent as a monotherapy.

Assignments (2)

Continuity (9)