COMBINATION METHODS OF THERAPY OF HIV INFECTIONS AND THEIR USE

Claims

1. A method for treating human immunodeficiency virus (HIV) infection in a human being in need thereof, comprising administering a therapeutically effective amount of: (a) a first agent that includes at least one agent selected from the group consisting of fostemsavir and temsavir or a pharmaceutically acceptable salt thereof, and (b) a second agent that includes at least one broadly neutralizing antibody or antigen-binding fragment thereof.

2. The method according to claim 1, wherein the first agent is fostemsavir or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1, wherein the first agent is temsavir or a pharmaceutically acceptable salt thereof.

4. The method according to any one of claims 1-3, wherein the second agent binds to at least one HIV envelope glycoprotein selected from the group consisting of: HIV gp160, HIV gp120 and HIV gp41.

5. The method according to any one of claims 1-4, wherein the second agent binds to HIV gp120.

6. The method according to any of paragraphs. 1-5, wherein the second agent is at least one agent selected from the group consisting of: 2G12, 2F5, 3BC176, 3BNC60, 3BNC1-17, 4E10, 8ANC131, 8ANC195, 10E8, 10-1074, 12A12, 35022, b12, B2530, CH01-04, CH103, CH31, HJ16, M66.6, N6, N6LS, N6-DE, N6-LAGA, NIH45-46, PG9, PG16, PGDM1400, PGT121, PGT128, PGT135, PGT141-PGT145, PGT151, PGV04, VRC01, VRC01-LS, VRC07, VRC07-523, VRC07-LS and Z13.

7. The method according to any one of claims 1-6, wherein the second agent is an isolated monoclonal antibody or antigen-binding fragment thereof, comprising: a heavy chain complementarity determining region (CDRH) having an amino acid sequence CDRH1 that comprises a sequence that is at least 95%, 98%, 99%, or 100% identical to SEQ ID NO: 1, an amino acid sequence CDRH2 that comprises a sequence that is 95%, 98%, 99%, or 100% identical to SEQ ID NO: 2, and an amino acid sequence CDRH3 that comprises a sequence that is at least 95%, 98%, 99%, or 100% identical to SEQ ID NO: 3, and a light chain complementarity determining region (CDRL) having an amino acid sequence CDRL1 that comprises a sequence that is at least 95%, 98%, 99%, or 100% identical to SEQ ID NO: 4, an amino acid sequence CDRL2 that comprises a sequence that is at least 95%, 98%, 99%, or 100% identical to SEQ ID NO: 5, and an amino acid sequence CDRH3 that comprises a sequence that is at least 95%, 98%, 99%, or 100% identical to SEQ ID NO:

6.

8. The method according to any one of claims 1-7, wherein the second agent is an isolated monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain variable region (V H ), having at least 95%, 98%, 99% or 100% sequence identity with SEQ ID NO:

7.

9. The method according to any one of claims 1-8, wherein the second agent is an isolated monoclonal antibody or antigen-binding fragment thereof comprising a light chain variable region (V L ), having at least 95%, 98%, 99% or 100% sequence identity to SEQ ID NO:

8.

10. The method according to any one of claims 7-9, wherein the isolated monoclonal antibody further comprises a recombinant constant domain containing the mutations M428L and N434S.

11. The method according to any one of claims 7-10, wherein the isolated monoclonal antibody further comprises a recombinant constant domain containing the mutations S239D and I332E.

12. The method according to any one of claims 7-11, wherein the isolated monoclonal antibody further comprises a recombinant constant domain containing the mutations L235A and G237A.

13. The method according to any one of claims 1-12, wherein the second agent is an isolated monoclonal antibody (N6) or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (CDRH) having the amino acid sequence CDRH1 of SEQ ID NO: 1, the amino acid sequence CDRH2 of SEQ ID NO: 2, and the amino acid sequence CDRH3 of SEQ ID NO: 3; and a light chain complementarity determining region (CDRL) having the amino acid sequence CDRL1 SEQ ID NO: 4, the amino acid sequence CDRL2 SEQ ID NO: 5, and the amino acid sequence CDRH3 SEQ ID NO:

6.

14. The method according to any one of claims 1-12, wherein the second agent is an isolated monoclonal antibody (N6LS) or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (CDRH) having the amino acid sequence CDRH1 of SEQ ID NO: 1, the amino acid sequence CDRH2 of SEQ ID NO: 2, and the amino acid sequence CDRH3 of SEQ ID NO: 3; a light chain complementarity determining region (CDRL) having the amino acid sequence CDRL1 of SEQ ID NO: 4, the amino acid sequence CDRL2 of SEQ ID NO: 5, and the amino acid sequence CDRH3 of SEQ ID NO: 6; and recombinant constant domain containing the M428L and N434S mutations.

15. The method according to any one of claims 1-12, wherein the second agent is an isolated monoclonal antibody (N6-DE) or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (CDRH) having the amino acid sequence CDRH1 of SEQ ID NO: 1, the amino acid sequence CDRH2 of SEQ ID NO: 2, and the amino acid sequence CDRH3 of SEQ ID NO: 3; a light chain complementarity determining region (CDRL) having the amino acid sequence CDRL1 of SEQ ID NO: 4, the amino acid sequence CDRL2 of SEQ ID NO: 5, and the amino acid sequence CDRH3 of SEQ ID NO: 6; and recombinant constant domain containing the S239D and I332E mutations.

16. The method according to any one of claims 1-12, wherein the second agent is an isolated monoclonal antibody (N6-LAGA) or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (CDRH) having the amino acid sequence CDRH1 SEQ ID NO: 1, the amino acid sequence CDRH2 SEQ ID NO: 2, the amino acid sequence CDRH3 SEQ ID NO: 3; a light chain complementarity determining region (CDRL) having the amino acid sequence CDRL1 of SEQ ID NO: 4, the amino acid sequence CDRL2 of SEQ ID NO: 5, and the amino acid sequence CDRH3 of SEQ ID NO: 6; and recombinant constant domain containing mutations L235A and G237A.

17. The method according to any one of claims 7-16, wherein the antigen-binding fragment is an Fv, Fab, F(ab')2, scFv or scFV2 ​​fragment.

18. The method according to any one of claims 1-17, further comprising administering a therapeutically effective amount of a third agent comprising at least one integrase inhibitor or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the third agent comprises at least one agent selected from the group consisting of: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir.

20. The method according to any one of claims 18, 19, wherein the third agent is raltegravir or cabotegravir.

21. The method according to any one of claims 18-20, wherein the third agent is cabotegravir.

22. The method according to any one of claims 1-21, wherein the first agent is temsavir, and the second agent is N6LS, and the third agent is cabotegravir.

23. The method according to any one of claims 1-22, wherein the first agent is temsavir, and the second agent is N6-DE, and the third agent is cabotegravir.

24. The method according to any one of claims 1-23, wherein each of the first agent, the second agent and the third agent is in the form of a pharmaceutical composition.

25. The method according to any one of paragraphs 1-24, wherein the first agent is administered before the second agent is administered.

26. The method of any one of claims 1-25, wherein the method comprises administering to a human about 1 mg / kg to 100 mg / kg body weight of the first agent orally once a day, twice a day, or three times a day.

27. The method according to any one of claims 1-25, wherein the method comprises administering to a human about 1 mg / kg to 100 mg / kg body weight of the first agent parenterally once a day, twice a day, or three times a day.

28. The method according to any one of claims 1-27, wherein the human being has been diagnosed with human immunodeficiency virus 1 (HIV-1) infection.

29. The method according to any one of paragraphs 1-28, wherein the person has previously been treated with one or more different HIV treatments.

30. A combination for the treatment of HIV, comprising a first pharmaceutical composition containing a first agent, which contains at least one agent selected from the group consisting of: fostemsavir and temsavir or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a second agent that comprises at least one broad-spectrum neutralizing antibody or antigen-binding fragment thereof.

31. The combination of claim 30, further comprising a third pharmaceutical composition comprising a third agent comprising at least one integrase inhibitor or a pharmaceutically acceptable salt thereof.

32. Use of a combination for the treatment of HIV, wherein the combination includes a first pharmaceutical composition comprising a first agent that includes at least one agent selected from the group consisting of fostemsavir and temsavir or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a second agent that includes at least one broad-spectrum neutralizing antibody or antigen-binding fragment thereof.

33. The use according to claim 32, wherein the first pharmaceutical composition is administered to a human prior to the administration of the second pharmaceutical composition.

34. Use according to any one of claims 32, 33, wherein the human is administered approximately 1 mg / kg to 100 mg / kg of body weight of the first pharmaceutical composition orally once a day, twice a day, or three times a day.

35. The use according to any one of paragraphs 32-34, wherein the human is administered approximately 1 mg / kg to 100 mg / kg of body weight of the first pharmaceutical composition parenterally once a day, twice a day, or three times a day.

36. The use according to any one of paragraphs 32-35, further comprising administering a third pharmaceutical composition comprising a third agent comprising at least one integrase inhibitor or a pharmaceutically acceptable salt thereof.

37. A kit for treating HIV, comprising a first pharmaceutical composition comprising a first agent that includes at least one agent selected from the group consisting of fostemsavir and temsavir or a pharmaceutically acceptable salt thereof, a second pharmaceutical composition comprising a second agent that includes at least one broadly neutralizing antibody or an antigen-binding fragment thereof, and optionally a third pharmaceutical composition comprising at least one integrase inhibitor or a pharmaceutically acceptable salt thereof.