Fusion protein for selectively depleting antigen-specific antibodies

Abstract

The present invention provides a fusion protein configured to enable the selective clearance of antigen-specific antibodies. [Solution] A fusion protein called "Seldeg" is provided, which includes a target component that specifically binds to cell surface receptors or other cell surface molecules at a pH near neutral, and an antigen component that is directly or indirectly fused with the target component. The antigen component is configured to specifically bind to a target antigen-specific antibody. The disclosure also includes a method of depleting a patient's target antigen-specific antibody by administering Seldeg having an antigen component configured to specifically bind to the target antigen-specific antibody to the patient.

Claims

1. Target components having proteins or protein fragments configured to specifically bind to cell surface receptors or cell surface molecules; and Antigen component having one molecule of an antigen, antigen fragment, or antigen analog configured to specifically bind to a target antigen-specific antibody or its variant. Seldeg, which includes, where the target component is directly or indirectly fused with the antigen component.

2. The Seldev according to claim 1, wherein the target component binds to a cell surface receptor or cell surface molecule with a dissociation constant of less than 10 μM at a pH near neutral.

3. Seldeg according to claim 2, wherein the pH near neutral is higher than 6.8 and less than 7.

5.

4. Seldev according to claim 1, comprising at least one first target component and a second target component, wherein the protein or protein fragment of the first target component is configured to bind to a different cell surface receptor or a different cell surface molecule than the protein or protein fragment of the second target component.

5. Seldig according to claim 1, wherein the target protein component comprises a heterodimer of two immunoglobulin Fc fragments, where one immunoglobulin Fc fragment of the heterodimer is fused to the antigen component and the other immunoglobulin Fc fragment is not fused.

6. Seldeg according to claim 5, wherein the immunoglobulin Fc fragment has substantially reduced binding to the Fc gamma receptor or has no detectable binding.

7. Seldev according to claim 5, wherein the immunoglobulin Fc fragment is derived from a class or isotype of immunoglobulin that does not bind to the Fc gamma receptor or complement.

8. Seldeg according to claim 5, configured to bind the immunoglobulin Fc fragment to the Fc gamma receptor and complement.

9. Seldig according to claim 5, wherein at least one of the immunoglobulin Fc fragments is modified to have a higher binding affinity for FcRn than the unmodified Fc fragment at a pH near neutral.

10. The aforementioned antigenic component is a hinge-CH of immunoglobulin Fc fragment. ２ -CH ３ Seldev according to claim 5, wherein the domain is fused to a single immunoglobulin Fc fragment at its N-terminus or C-terminus.

11. Seldev according to claim 5, wherein the immunoglobulin Fc fragment is modified to have no binding affinity to the Fc gamma receptor and / or complement (C1q) or to have a lower binding affinity to the Fc gamma receptor and / or complement (C1q) than the unmodified immunoglobulin Fc fragment.

12. The Seldev according to claim 1, wherein the target component comprises one or more antibody variable regions or fragments thereof configured to specifically bind to cell surface receptors or cell surface molecules.

13. The Seldev according to claim 12, wherein the antibody variable region or fragment thereof comprises at least one nanobody.

14. The Seldev according to claim 13, wherein the nanobody is a nanobody polymer in which one nanobody is fused to an antigen component, and all other nanobody in the nanobody polymer are not fused.

15. The Seldev according to claim 1, wherein the target component is configured to dissociate from the cell surface receptor or cell surface molecule following entry into the endosome of the complex comprising Seldev and a cell surface receptor or cell surface molecule.

16. Seldev according to claim 1, wherein the antigen component is fused to the N-terminal or C-terminal position on the target component.

17. Seldeg according to claim 1, wherein the antigen component is fused to a non-terminal position on the target component.

18. Seldev according to claim 1, wherein the antigen component fuses with the target component via a chemical reaction, via a linker, or during the formation of a combined antigen component-target component fusion protein.

19. The Seldev according to claim 1, wherein the target component includes a mutant albumin variant configured to specifically bind to one or more albumin molecules, albumin fragments, or FcRn.

20. The Seldev according to claim 1, wherein the target component comprises one or more antibody-variable domains or nanobodies configured to bind to a transferrin receptor.

21. The Seldev according to claim 1, wherein the target component comprises one or more protein molecules or protein domains configured to bind to a transferrin receptor.

22. The Seldev according to claim 1, wherein the target component comprises one or more protein molecules or protein domains configured to bind to phosphatidylserine.

23. The Seldev according to claim 1, wherein the target protein component comprises one or more antibody-variable domains or nanobodies configured to bind to phosphatidylserine.

24. Seldev according to claim 22, wherein one or more protein molecules or protein domains are configured to bind to phosphatidylserine via a calcium-dependent mechanism.

25. Seldeg according to claim 22, wherein the target component comprises the C2A domain of synaptotagmin 1.

26. Seldig according to claim 1, comprising at least one first antigen component and a second antigen component, wherein one molecule of the antigen, antigen fragment, or antigen analog of the first antigen component is different from one molecule of the antigen molecule, antigen fragment, or antigen analog of the second antigen component.

27. It comprises at least one first antigen component and a second antigen component, wherein the first antigen component Seldig according to claim 1, wherein one molecule of the antigen, antigen fragment, or antigen analog is the same as one molecule of the antigen molecule, antigen fragment, or antigen analog of the second antigen component.

28. A method for depleting target antigen-specific antibodies from a patient, Administer Seldev to the patient in an amount sufficient to clear at least 50% of the target antigen-specific antibodies from the patient's circulation or target tissues. This includes, and here Seldeg Target components having proteins or protein fragments configured to specifically bind to cell surface receptors or surface molecules; and Antigen component having one molecule of an antigen, antigen fragment, or antigen analog configured to specifically bind to a target antigen-specific antibody or its variant. A method comprising, wherein the target protein component is directly or indirectly fused with the antigen component.

29. The method according to claim 28, comprising administering Seldev in an amount sufficient to clear at least 50% of the target antigen-specific antibodies from the circulation or target tissue in the patient within 5 hours of administration.

30. The method according to claim 28, wherein the protein or protein fragment is configured to bind to a cell surface receptor or other cell surface molecule with a dissociation constant of less than 10 μM at a pH near neutral.

31. The method according to claim 28, wherein a sufficient amount of Seldig is at least equimolar to the amount of target antigen-specific antibody to be depleted.

32. The method according to claim 28, comprising administering Seldev in an amount sufficient to clear at least 90% of the target antigen-specific antibodies from the circulation or target tissue in the patient within two hours of administration.

33. The method according to claim 28, comprising administering Seldev in an amount sufficient to clear at least 50% of the target antigen-specific antibodies from the circulation or target tissue in the patient within one hour of administration.

34. The method according to claim 28, further comprising readjusting Seldev whenever it is expected that 50% of the patients have regenerated a threshold amount of target antigen-specific antibodies in circulation or in target tissue.

35. The method according to claim 28, wherein Seldig clears less than 10% of the non-target antibody in the circulation or in the tissue targeted by the target antigen-specific antibody.

36. The method according to claim 28, wherein Seldig clears an amount of untargeted antibodies in the patient's circulation or target tissue that does not cause clinically adverse effects in the patient.

37. The method according to claim 28, wherein Seldig clears less than 1% of the non-target antibody in the circulation or in the tissue targeted by the target antigen-specific antibody.

38. The method according to claim 28, wherein Seldev causes the degradation of the target antigen-specific antibody by cells expressing cell surface receptors or cell surface molecules.

39. Seldeg is administered to patients suffering from autoimmune diseases, and the target antigen-specific antibody is auto The method according to claim 28, which specifically binds to an antigen.

40. The method according to claim 28, wherein Seldev is administered to a patient who has received an organ transplant, and the target antigen-specific antibody specifically binds to the antigen on the transplanted organ.

41. The method according to claim 28, wherein Seldev is administered to increase contrast during tumor imaging, and the target antigen-specific antibody specifically binds to the tumor antigen.

42. The method according to claim 28, wherein Seldev is administered to a patient who has received a biological agent, and the target antigen-specific antibody is the biological agent.

43. The method according to claim 28, wherein if the patient has antibodies specific to the therapeutic agent, Seldev is administered to the patient before delivery of the therapeutic agent, and Seldev is configured to target antibodies specific to the therapeutic agent.

44. The method according to claim 28, wherein Seldev is administered to provide a PET image contrast agent.

45. The Seldev according to claim 1, wherein the target antigen-specific antibody is an anti-MOG antibody.

46. The Seldev according to claim 1, wherein the target antigen-specific antibody is an anti-HER2 antibody.

47. Seldev according to claim 1, comprising a protein having at least one amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32 or SEQ ID NO: 34 or its homologue.

48. Seldev according to claim 1, comprising a heterodimer of a protein having the amino acid sequences of i) SEQ ID NO: 2 plus SEQ ID NO: 6, ii) SEQ ID NO: 4 plus SEQ ID NO: 6, iii) SEQ ID NO: 8 plus SEQ ID NO: 10, iv) SEQ ID NO: 12 plus SEQ ID NO: 14, v) SEQ ID NO: 16 plus SEQ ID NO: 18 plus SEQ ID NO: 20, vi) SEQ ID NO: 20 plus SEQ ID NO: 22 plus SEQ ID NO: 24, vii) SEQ ID NO: 26 plus SEQ ID NO: 28, viiii) SEQ ID NO: 30 plus SEQ ID NO: 6, ix) SEQ ID NO: 32 plus SEQ ID NO: 6, or x) SEQ ID NO: 34 plus SEQ ID NO: 6, or homologous thereof.

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