Interferon receptor antagonists and uses thereof

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An interferon receptor antagonist with an anchoring and targeting mechanism addresses the need for selective interferon inhibition, offering a targeted therapeutic solution for interferon-related diseases with reduced off-target effects.

HK40134681APending Publication Date: 2026-07-10REGENERON PHARMACEUTICALS INC

Patent Information

Authority / Receiving Office: HK · HK
Patent Type: Applications
Current Assignee / Owner: REGENERON PHARMACEUTICALS INC
Filing Date: 2026-04-16
Publication Date: 2026-07-10

AI Technical Summary

Technical Problem

Current therapies for interferon-related diseases lack effective interferon receptor antagonists that can selectively target and inhibit interferon signaling without causing off-target effects.

Method used

Development of an interferon receptor antagonist comprising an anchoring portion, an interferon masking portion, and a targeting portion to recognize and anchor to cells expressing type 1 interferon receptors, thereby inhibiting interferon signaling.

Benefits of technology

The interferon receptor antagonist effectively inhibits interferon signaling while minimizing off-target effects, providing a targeted therapeutic approach for interferon-related diseases.

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Abstract

The present disclosure provides interferon (IFN) receptor antagonists. The IFN receptor antagonists disclosed herein comprise an anchoring moiety, an IFN masking moiety, an IFN moiety, and a separating moiety, such as a targeting moiety that recognizes an antigen associated with a cell expressing a type 1 interferon receptor and anchors the IFN receptor antagonist to such cell. The disclosure further provides pharmaceutical compositions comprising the IFN receptor antagonists, and methods of using the IFN receptor antagonists in inhibition of IFN signaling, including methods of treatment. Also disclosed are nucleic acids encoding the IFN receptor antagonists, recombinant cells expressing the IFN receptor antagonists, and methods of producing the IFN receptor antagonists.

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Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480045245.8 (22) Application Date 2024.05.10 (30) Priority Data 63 / 501,840 2023.05.12 US 63 / 597,502 2023.11.09 US (85) PCT International Application Entering National Phase Date 2025.12.31 (86) PCT International Application Application Data PCT / US2024 / 028996 2024.05.10 (87) PCT International Application Publication Data WO2024 / 238415 EN 2024.11.21 (71) Applicant Regeneron Pharmaceuticals, Inc. Address: New York, USA (72) Inventors: V. Gag, N. Block, E. Ullman, E.M. Vic, Wu Jiaxi, T. Zhang, E. Smith, A. Herman, C.L. Lin (74) Patent Agency: Beijing Liu Shen Law Firm, 11105 Patent Attorney: Qin Jian (51) Int.Cl. C07K 16 / 28 (2006.01) A61K 38 / 17 (2006.01) A61K 38 / 21 (2006.01) C07K 14 / 56 (2006.01) C07K 14 / 715 (2006.01) (54) Invention Title: Interferon Receptor Antagonist and Its Use (57) Abstract: This disclosure provides an interferon (IFN) receptor antagonist. The IFN receptor antagonist disclosed herein comprises an anchoring portion, an IFN masking portion, an IFN portion, and a septum portion, such as a targeting portion that recognizes an antigen associated with cells expressing type 1 interferon receptors and anchors the IFN receptor antagonist to such cells. This disclosure further provides pharmaceutical compositions comprising the IFN receptor antagonist, and methods of using the IFN receptor antagonist in the inhibition of IFN signaling, including therapeutic methods. Nucleic acids encoding the IFN receptor antagonist, recombinant cells expressing the IFN receptor antagonist, and methods of producing the IFN receptor antagonist are also disclosed. Claims 4 pages, Description 102 pages, Sequence Listing (electronic publication), Figures 73 pages, CN 121752592 A 2026.03.27 CN 1 21 75 25 92 A

Claims

1. A type I interferon (IFN) receptor antagonist, comprising: (a) Anchoring portion of cells that express type I interferon receptors; (b) Type I interferon α receptor 1 (IFNAR1) portion; (c) Type I interferon (IFN) portion; (d) Connect the anchoring portion to the IFNAR1 portion or the partition portion of the IFN portion; as well as (e) Optionally, a connector is used to connect the IFNAR1 portion and the IFN portion.

2. The IFN receptor antagonist of claim 1, wherein the anchoring portion is capable of binding to extracellular matrix (ECM) antigens, tumor reactive lymphocyte antigens, cell surface molecules of tumor or viral lymphocytes, T cell antigens (TCA), checkpoint inhibitors, tumor-associated antigens (TAA), dendritic cell (DC) or other antigen-presenting cell (APC) antigens, or natural killer (NK) cell antigens.

3. The IFN receptor antagonist of claim 1, wherein the anchoring portion is a targeting portion.

4. The IFN receptor antagonist of claim 3, wherein the targeting portion is scFv or Fab.

5. The IFN receptor antagonist of claim 3, wherein the targeting portion is capable of binding to a checkpoint inhibitor, optionally wherein the checkpoint inhibitor is CTLA-4, PD1, PDL1, PDL2, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, or CHK2.

6. The IFN receptor antagonist of claim 5, wherein the checkpoint inhibitor is PDL1.

7. The IFN receptor antagonist of claim 6, wherein the targeting portion is an antigen-binding fragment of an anti-PDL1 antibody.

8. The IFN receptor antagonist according to any one of claims 1 to 7, wherein the septum is an Fc domain.

9. The IFN receptor antagonist according to any one of claims 1 to 8, wherein the linker is a non-cleavable linker (NCL).

10. The IFN receptor antagonist of claim 9, wherein the NCL is the NCL described in Table E.

11. The IFN receptor antagonist according to any one of claims 1 to 10, further comprising an additional connector connecting the septum portion to the IFNAR1 portion.

12. The IFN receptor antagonist according to any one of claims 1 to 10, further comprising an additional connector connecting the septum portion to the IFN portion.

13. The IFN receptor antagonist according to any one of claims 1 to 12, further comprising an additional anchoring portion.

14. The IFN receptor antagonist of claim 13, wherein the additional anchoring portion is an additional targeting portion.

15. The IFN receptor antagonist of claim 14, wherein the additional targeting moiety is scFv or Fab.

16. The IFN receptor antagonist of claim 15, wherein the additional targeting portion specifically binds to the same target as the anchoring portion.

17. The IFN receptor antagonist according to any one of claims 14 to 16, wherein the additional targeting portion is capable of binding to a checkpoint inhibitor, said checkpoint inhibitor optionally being CTLA-4, PD1, PDL1, PDL2, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, or CHK2.

18. The IFN receptor antagonist of claim 17, wherein the checkpoint inhibitor is PDL1.

19. The IFN receptor antagonist of claim 18, wherein the additional targeting portion is an antigen-binding fragment of an anti-PD1 antibody.

20. The IFN receptor antagonist according to any one of claims 13 to 19, further comprising an additional septum operatively connected to the additional anchoring portion.

21. The IFN receptor antagonist according to any one of claims 1 to 20, wherein the IFN portion is masked by the IFNAR1 portion.

22. The IFN receptor antagonist according to any one of claims 1 to 21, wherein the IFN receptor antagonist comprises a first polypeptide chain and a second polypeptide chain.

23. The IFN receptor antagonist of claim 22, wherein the first polypeptide chain comprises: (a) the anchoring portion or its components; (b) the dividing portion; and (c) The IFNAR1 portion.

24. The IFN receptor antagonist of claim 23, wherein the second polypeptide chain comprises: (a) additional anchoring portions or components thereof; and (b) Additional separators.

25. The IFN receptor antagonist of claim 23 or 24, wherein the first polypeptide chain further comprises the IFN moiety.

26. The IFN receptor antagonist of claim 24, wherein the second polypeptide chain further comprises the IFN moiety.

27. The IFN receptor antagonist of claim 26, wherein the second polypeptide chain comprises, in an N-terminal to C-terminal orientation: (a) Additional anchoring portions or components thereof; (b) Additional dividing sections; and (c) The IFN portion.

28. The IFN receptor antagonist according to any one of claims 22 to 27, wherein the second polypeptide chain further comprises an additional IFNAR1 moiety and an additional IFN moiety.

29. The IFN receptor antagonist according to any one of claims 1 to 28, wherein the IFN portion comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, or 100% sequence identity with: (a) full-length mature human IFNα1, IFNα2b, IFNβ, IFNω, IFNε, or IFNκ, or (b) mature human IFNα1, IFNα2b, IFNβ, IFNω, IFNε, or IFNκ having a truncation of up to 15 amino acids at its N-terminus and / or its C-terminus.

30. The IFN receptor antagonist of claim 29, wherein the IFN portion comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, or 100% sequence identity with: (a) full-length mature human IFNα2b, or (b) mature human IFNα2b having a truncation of up to 15 amino acids at its N-terminus and / or its C-terminus.

31. The IFN receptor antagonist of claim 30, wherein the IFN moiety is: (a) a full-length mature human IFNα2b, or (b) a mature human IFNα2b having a truncation of up to 15 amino acids at its N-terminus and / or its C-terminus.

32. The IFN receptor antagonist according to any one of claims 1 to 31, wherein the IFNAR1 moiety comprises or is composed of an amino acid sequence having at least 90%, at least 95%, at least 98%, or 100% sequence identity with, or consisting of, the following: (i) the SD2 and SD3 domains of human IFNAR1, (ii) the SD1, SD2 and SD3 domains of human IFNAR1, or (iii) the SD1, SD2, SD3 and SD4 domains of human IFNAR1.

33. The IFN receptor antagonist of claim 28, wherein the additional IFN portion comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, or 100% sequence identity with: (a) full-length mature human IFNα1, IFNα2b, IFNβ, IFNω, IFNε, or IFNκ, or (b) mature human IFNα1, IFNα2b, IFNβ, IFNω, IFNε, or IFNκ, having a truncation of up to 15 amino acids at its N-terminus and / or its C-terminus.

34. The IFN receptor antagonist of claim 33, wherein the additional IFN portion comprises an amino acid sequence having at least about 90%, at least about 95%, at least about 98%, or 100% sequence identity with: (a) full-length mature human IFNα2b, or (b) mature human IFNα2b having a truncation of up to 15 amino acids at its N-terminus and / or its C-terminus.

35. The IFN receptor antagonist of claim 28, wherein the additional IFNAR1 moiety comprises or consists of an amino acid sequence having at least 90%, at least 95%, or at least 98% sequence identity with, or is composed of, the following amino acid sequences: (i) the SD2 and SD3 domains of human IFNAR1, (ii) the SD1, SD2 and SD3 domains of human IFNAR1, or (iii) the SD1, SD2, SD3 and SD4 domains of human IFNAR1.

36. The IFN receptor antagonist of claim 28, wherein the additional IFNAR1 portion is: (i) the SD2 and SD3 domains of human IFNAR1, (ii) the SD1, SD2, and SD3 domains of human IFNAR1, or (iii) the SD1, SD2, SD3, and SD4 domains of human IFNAR1.

37. The IFN receptor antagonist according to any one of claims 1 to 36, wherein the IFN receptor antagonist does not contain the IFNAR2 portion.

38. The IFN receptor antagonist of claim 37, wherein the IFNAR2 moiety comprises or is composed of an amino acid sequence having at least 90%, at least 95%, or at least 98% sequence identity with, or consisting of, the following: (i) the D1 domain of human IFNAR2, or (ii) the D1 and D2 domains of human IFNAR2.

39. An IFN receptor antagonist, optionally an IFN receptor antagonist according to any one of claims 1 to 38, comprising a polypeptide chain having the following configurations: (a) the configuration of the two halves shown in FIG. 1B, (b) the configuration of the two halves shown in FIG. 1C, (c) the configuration of the two halves shown in FIG. 1D, (d) the configuration of the two halves shown in FIG. 1E, and (e) the configuration of the two halves shown in FIG. 1F.

40. One or more nucleic acids encoding an IFN receptor antagonist according to any one of claims 1 to 39.

41. A host cell engineered to express an IFN receptor antagonist according to any one of claims 1 to 39 or a nucleic acid according to claim 40.

42. A method for producing an IFN receptor antagonist according to any one of claims 1 to 39, the method comprising culturing a host cell according to claim 41 and recovering the IFN receptor antagonist expressed by the host cell.

43. A pharmaceutical composition comprising an IFN receptor antagonist according to any one of claims 1 to 39 and an excipient, optionally further comprising an oncolytic virus.

44. A method for inhibiting IFN signaling in cells expressing (a) an IFN receptor and (b) a molecule specifically binding to an anchoring moiety, the method comprising contacting the cells with an IFN receptor antagonist according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 43.

45. The method of claim 44, wherein the cell is: (a) an immune cell, optionally a B cell, or (b) a cancer cell.

46. The method according to claim 44 or 45, wherein the method is an in vitro method.

47. A method of treating a subject suffering from cancer, the method comprising administering to the subject in need an IFN receptor antagonist according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 43.

48. The method of claim 47, further comprising: The oncolytic virus was administered to the subject.

49. A method of treating a subject suffering from an immune disorder or condition, the method comprising administering to the subject an IFN receptor antagonist according to any one of claims 1 to 39 or a pharmaceutical composition according to claim 43, optionally wherein the immune disorder or condition is systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), or Sjögren's syndrome (SS).