IP Library › Granted Patent US 11,518,807
Granted Patent B2
US 11,518,807 · App. 16/720,623 · Granted Dec 6, 2022

Heavy chain constant regions with reduced binding to Fc gamma receptors

Inventors: Samuel Davis (New York, NY); Eric Smith (New York, NY); Tong Zhang (Fort Lee, NJ); Supriya Patel (Mamaroneck, NY)
Assignee: Regeneron Pharmaceuticals, Inc.
C07K16/2809C07K16/2803C07K16/2887C07K2317/24C07K2317/31C07K2317/526C07K2317/53C07K2317/71C07K2317/732C07K2317/90
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Quick Facts
Patent No.
US 11,518,807
App. No.
16/720,623
Granted
Dec 6, 2022
Kind
B2
Abstract

The invention provides antibody heavy chain constant regions with a hinge region modified to reduce binding to Fcγ receptors. The modification occurs within positions 233-236 by replacement of natural residues by glycine(s) and/or deletion(s). Such modifications can reduce binding of an antibody bearing such a constant region to Fcγ receptors to background levels. The constant regions can be incorporated into any format of antibody or Fc fusion protein. Such antibodies or fusion proteins can be used in methods of treatment, particularly those in which the mechanisms of action of the antibody or Fc fusion protein is not primarily or at all dependent on effector functions, as is the case when an antibody inhibits a receptor-ligand interaction or agonizes a receptor.

Claims (40)

1. A monoclonal antibody comprising a heavy chain constant region that is human IgG4 isotype, wherein amino acid positions 233-236 of a hinge domain are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with amino acid positions numbered by EU numbering.

2. The antibody of claim 1 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 5.

3. The antibody of claim 1 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 6.

4. The antibody of claim 1 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 7.

5. The antibody of claim 1 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 8.

6. The antibody of claim 1 , wherein the antibody is a monospecific antibody.

7. The antibody of claim 2 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 5, and a second heavy chain constant region comprising SEQ ID NO: 9.

8. The antibody of claim 3 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 6, and a second heavy chain constant region comprising SEQ ID NO: 10.

9. The antibody of claim 4 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 7, and a second heavy chain constant region comprising SEQ ID NO: 11.

10. The antibody of claim 5 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 8, and a second heavy chain constant region comprising SEQ ID NO: 12.

11. A monoclonal antibody comprising a heavy chain constant region that is human IgG1 isotype, wherein amino acid positions 233-236 of a hinge domain are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with amino acid positions numbered by EU numbering.

12. The antibody of claim 11 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 16.

13. The antibody of claim 11 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 17.

14. The antibody of claim 11 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 18.

15. The antibody of claim 11 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 19.

16. The antibody of claim 11 , wherein the antibody is a monospecific antibody.

17. The antibody of claim 12 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 16, and a second heavy chain constant region comprising SEQ ID NO: 20.

18. The antibody of claim 13 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 17, and a second heavy chain constant region comprising SEQ ID NO: 21.

19. The antibody of claim 14 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 18, and a second heavy chain constant region comprising SEQ ID NO: 22.

20. The antibody of claim 15 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 19, and a second heavy chain constant region comprising SEQ ID NO: 23.

21. A monoclonal antibody comprising a heavy chain constant region that is human IgG2 isotype, wherein amino acid positions 233-236 of a hinge domain are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with amino acid positions numbered by EU numbering.

22. The antibody of claim 21 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 24.

23. The antibody of claim 21 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 25.

24. The antibody of claim 21 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 26.

25. The antibody of claim 21 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 27.

26. The antibody of claim 21 , wherein the antibody is a monospecific antibody.

27. The antibody of claim 22 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 24, and a second heavy chain constant region comprising SEQ ID NO: 28.

28. The antibody of claim 23 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 25, and a second heavy chain constant region comprising SEQ ID NO: 29.

29. The antibody of claim 24 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 26, and a second heavy chain constant region comprising SEQ ID NO: 30.

30. The antibody of claim 25 , wherein the antibody is a bispecific antibody comprising a first heavy chain constant region comprising SEQ ID NO: 27, and a second heavy chain constant region comprising SEQ ID NO: 31.

31. An antibody drug conjugate (ADC) comprising an antibody conjugated to a cytotoxic or cytostatic agent, wherein the antibody comprises an immunoglobulin heavy chain constant region, wherein amino acid positions 233-236 of a hinge domain are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with amino acid positions numbered by EU numbering.

32. The ADC of claim 31 , wherein cytotoxic or cytostatic agent is an antitubulin agent, an auristatin, a DNA minor groove binder, a DNA replication inhibitor, an alkylating agent, a platinum complex, cis-platin, mono(platinum), bis(platinum), a tri-nuclear platinum complex, carboplatin, an anthracycline, an antibiotic, an antifolate, an antimetabolite, a chemotherapy sensitizer, a duocarmycin, a camptothecin, an etoposide, a fluorinated pyrimidine, an ionophore, a lexitropsin, a nitrosourea, a platinol, a purine antimetabolite, a puromycin, a radiation sensitizer, a steroid, a taxane, a topoisomerase inhibitor, or a vinca alkaloid.

33. A fusion protein comprising an immunoglobulin heavy chain constant region, wherein amino acid positions 233-236 of a hinge domain are G, G, G and unoccupied; G, G, unoccupied, and unoccupied; G, unoccupied, unoccupied, and unoccupied; or all unoccupied, with amino acid positions numbered by EU numbering.

34. The fusion protein of claim 33 , comprising an extracellular domain of a receptor, or a ligand that binds an extracellular domain of a receptor.

35. The antibody of claim 1 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, and wherein the antibody binds to FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA at background levels in a surface plasmon resonance assay at 25° C.

36. The antibody of claim 11 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19, and wherein the antibody binds to FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA at background levels in a surface plasmon resonance assay at 25° C.

37. The antibody of claim 21 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27, and wherein the antibody binds to FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA at background levels in a surface plasmon resonance assay at 25° C.

38. The antibody of claim 35 , wherein the antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) activity at background levels.

39. The antibody of claim 36 , wherein the antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) activity at background levels.

40. The antibody of claim 37 , wherein the antibody exhibits antibody-dependent cellular cytotoxicity (ADCC) activity at background levels.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2020
From: DAVIS, SAMUEL; SMITH, ERIC; ZHANG, TONG; PATEL, SUPRIYA
To: REGENERON PHARMACEUTICALS, INC.
Reel/Frame 052562/0307 →
Continuity (3)
Continuation 15562881
Provisional Application 62140350 · Mar 30, 2015
Related Publication 20200109203A1 · Apr 9, 2020
Cited By (3)
US 12,509,514 US 12,509,516 US 12,577,304