IP Library › Granted Patent US 12,325,752
Granted Patent B2
US 12,325,752 · App. 17/554,276 · Granted Jun 10, 2025

Immunoglobulin proteins that bind to NPR1 agonists

Inventors: Michael E. Dunn (Montvale, NJ); Lori C. Morton (Chappaqua, NY); Neil Stahl (Carmel, NY); Tammy T. Huang (Cross River, NY); Ishita Chatterjee (Nanuet, NY); Vishal Kamat (Northbridge, MA); Ashique Rafique (Yonkers, NY)
Assignee: REGENERON PHARMACEUTICALS, INC.
C07K16/2869A61P9/12A61K2039/505C07K2317/565C07K2317/76C07K2317/92
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Quick Facts
Patent No.
US 12,325,752
App. No.
17/554,276
Granted
Jun 10, 2025
Kind
B2
Abstract

The present disclosure provides novel immunoglobulin proteins that bind to a human natriuretic peptide receptor 1 (NPR1) agonist, preferably an anti-NPR1 antibody. In certain embodiments, the proteins of the disclosure comprise at least one immunoglobulin variable domain that binds to an anti-NPR1 antibody. In certain embodiments, the proteins of the disclosure are useful in blocking and/or reversing the effect of an administered anti-NPR1 antibody. In certain embodiments, the antigen-binding proteins are useful for effective management of blood pressure and hemodynamics in humans.

Claims (44)

1. An agent that reverses a reduction in blood pressure associated with the administration of a natriuretic peptide receptor 1 (NPR1) agonist, wherein the agent binds to the NPR1 agonist, wherein the agent is an immunoglobulin protein, wherein the immunoglobulin protein comprises three heavy chain complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3 contained within a heavy chain variable region (HCVR) and three light chain CDRs LCDR1, LCDR2 and LCDR3 contained within a light chain variable region (LCVR), wherein the immunoglobulin protein comprises the HCVR comprising the amino acid sequence of SEQ ID NO: 2 and the LCVR comprising the amino acid sequence of SEQ ID NO: 10 or the HCVR comprising the amino acid sequence of SEQ ID NO: 22 and the LCVR comprising the amino acid sequence of SEQ ID NO: 30.

2. The agent of claim 1 , wherein the NPR1 agonist is an antibody or antigen-binding fragment thereof that binds specifically to NPR1, wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs HCDR1, HCDR2, and HCDR3 contained within a HCVR comprising SEQ ID NO: 48; and three light chain CDRs LCDR1, LCDR2 and LCDR3 contained within a LCVR comprising SEQ ID NO: 52.

3. The agent of claim 2 , wherein the antibody or antigen-binding fragment thereof comprises three heavy chain CDRs HCDR1, HCDR2, and HCDR3 comprising SEQ ID NOs: 49, 50, and 51, respectively; and three light chain CDRs LCDR1, LCDR2 and LCDR3 comprising SEQ ID NOs: 53, 54, and 55, respectively.

4. The agent of claim 3 , wherein the antibody or antigen-binding fragment thereof comprises a HCVR of SEQ ID NO: 48 and a LCVR of SEQ ID NO: 52.

5. The agent of claim 2 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody.

6. The agent of claim 5 , wherein the antibody is an IgG1 antibody.

7. The agent of claim 5 , wherein the antibody is an IgG4 antibody.

8. The agent of claim 5 , wherein the antibody comprises a heavy chain comprising SEQ ID NO: 56 and a light chain comprising SEQ ID NO: 57.

9. The agent of claim 1 , wherein the NPR1 agonist is R5381.

10. The agent of claim 1 , wherein the immunoglobulin protein comprises three heavy chain CDRs HCDR1, HCDR2, and HCDR3 and three light chain CDRs LCDR1, LCDR2 and LCDR3 comprising amino acid sequences selected from SEQ ID NOs: 4, 6, 8, 12, 14 and 16; or SEQ ID NOs: 24, 26, 28, 32, 34, and 36.

11. The agent of claim 10 , wherein the HCVR comprises an amino acid sequence having at least 90%, 95%, 98%, or 99% sequence identity to the sequence of SEQ ID NOs: 2 or the sequence of SEQ ID NO: 22.

12. The agent of claim 10 , wherein the LCVR comprises an amino acid sequence having at least 90%, 95%, 98%, or 99% sequence identity to the sequence of SEQ ID NOs: 10 or the sequence of SEQ ID NO: 30.

13. The agent of claim 10 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 2 and the LCVR comprises the amino acid sequence of SEQ ID NO: 10.

14. The agent of claim 10 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 22 and the LCVR comprises the amino acid sequence of SEQ ID NO: 30.

15. The agent of claim 1 , wherein HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprise amino acid sequences selected from the group consisting of (i) SEQ ID NOs: 4, 6, 8, 12, 14 and 16; and (ii) SEQ ID NOs: 24, 26, 28, 32, 34, and 36.

16. The agent of claim 15 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 2 and the LCVR comprises the amino acid sequence of SEQ ID NO: 10.

17. The agent of claim 15 , wherein the HCVR comprises the amino acid sequence of SEQ ID NO: 22 and the LCVR comprises the amino acid sequence of SEQ ID NO: 30.

18. The agent of claim 1 wherein the immunoglobulin protein is comprised within a Fab fragment.

19. The agent of claim 18 , further comprising a multimerizing component.

20. The agent of claim 19 , wherein the multimerizing component comprises at least one Fc fragment.

21. The agent of claim 20 , wherein the at least one Fc fragment is of isotype IgG1, IgG4, or a variant thereof.

22. The agent of claim 21 , wherein the at least one Fc fragment is of IgG4 isotype.

23. The agent of claim 21 , wherein the at least one Fc fragment is of IgG1 isotype.

24. The agent of claim 20 , comprising a first Fc fragment and a second Fc fragment, wherein the first Fc fragment or the second Fc fragment, but not both Fc fragments, comprises a modification in the CH3 domain that reduces binding of the immunoglobulin protein to Protein A as compared to an immunoglobulin protein lacking the modification.

25. The agent of claim 24 , wherein the modification comprises a H315R substitution and a Y316F substitution according to EU numbering in a Fc fragment.

26. The agent of claim 20 , wherein the multimerizing component comprises a first Fc fragment comprising the amino acid sequence of SEQ ID NO: 46 and a second Fc fragment comprising the amino acid sequence of SEQ ID NO: 58.

27. The agent of claim 1 , wherein the immunoglobulin protein is a monovalent monoclonal antibody.

28. The agent of claim 27 , wherein the monovalent monoclonal antibody comprises a heavy chain comprising a amino acid sequence of SEQ ID NO: 42 or the amino acid sequence of SEQ ID NO: 44; and a light chain comprising the amino acid sequence of SEQ ID NO: 20 or the amino acid sequence of SEQ ID NO: 40.

29. The agent of claim 28 , wherein the heavy chain comprises a modification in a CH3 domain that reduces binding of the immunoglobulin protein to Protein A.

30. The agent of claim 29 , wherein the modification comprises a H315R substitution and a Y316F substitution according to EU numbering in the constant region of IgG1 or IgG4 isotype.

31. The agent of claim 28 , wherein the immunoglobulin protein further comprises a Fc fragment.

32. The agent of claim 31 , wherein the Fc fragment is of IgG1 or IgG4 isotype.

33. The agent of claim 31 , wherein the Fc fragment comprises the amino acid sequence of SEQ ID NO: 46.

34. The agent of claim 1 , wherein the agent is REGN9035 or REGN9037.

35. An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a HCVR of an immunoglobulin protein as in claim 33 .

36. An isolated polynucleotide molecule comprising a polynucleotide sequence that encodes a LCVR of an immunoglobulin protein as in claim 33 .

37. A vector comprising the polynucleotide molecule of claim 35 or the polynucleotide molecule of claim 36 .

38. A host cell expressing the vector of claim 37 .

39. A host cell expressing the polynucleotide molecule of claim 35 or the polynucleotide molecule of claim 36 .

40. The host cell of claim 39 , wherein the host cell is a CHO cell.

41. A pharmaceutical composition comprising the agent of claim 1 and a pharmaceutically acceptable carrier or diluent.

42. A method of reversing the hemodynamic effects of a NPR1 agonist, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of the agent of claim 1 to a subject in need thereof.

43. The method of claim 42 , wherein the composition is administered subcutaneously, intravenously, intradermally, intraperitoneally, or intramuscularly to the subject.

44. The method of claim 42 , wherein the subject has a disease or disorder selected from the group consisting of hypertension, heart failure, and chronic kidney disease.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 24, 2023
From: DUNN, MICHAEL E.; MORTON, LORI C.; STAHL, NEIL; HUANG, TAMMY T.; CHATTERJEE, ISHITA; KAMAT, VISHAL; RAFIQUE, ASHIQUE
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 065328/0609 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 17, 2021
From: DUNN, MICHAEL; MORTON, LORI; STAHL, NEIL; HUANG, TAMMY; CHATTERJEE, ISHITA; KAMAT, VISHAL; RAFIQUE, ASHIQUE
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 058417/0787 →
Continuity (2)
Provisional Application 63127959 · Dec 18, 2020
Related Publication 20220195058A1 · Jun 23, 2022
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