IP Library › Granted Patent US 11,639,375
Granted Patent B2
US 11,639,375 · App. 16/493,750 · Granted May 2, 2023

CD80 variant immunomodulatory proteins and uses thereof

Inventors: Ryan Swanson (Seattle, WA); Michael Kornacker (Seattle, WA); Mark F. Maurer (Seattle, WA); Joseph L. Kuijper (Kenmore, WA)
Assignee: Alpine Immune Sciences, Inc.
C07K14/70532A61K38/1774A61P35/00G01N33/57492A61K38/00A61K2039/585C07K2319/30
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Quick Facts
Patent No.
US 11,639,375
App. No.
16/493,750
Granted
May 2, 2023
Kind
B2
Abstract

Provided herein are variant CD80 polypeptides, immunomodulatory proteins comprising variant CD80 polypeptides, and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.

Claims (35)

1. A purified variant CD80 fusion protein homodimer comprising two copies of a CD80-Fc immunomodulatory protein of the formula CD80-linker-Fc, wherein:

CD80 is a variant CD80 polypeptide comprising an IgV domain wherein the variant CD80 polypeptide comprises the amino acid substitution M47L at position 47 in an unmodified CD80 polypeptide set forth in SEQ ID NO:2 or the portion of SEQ ID NO:2 comprising an IgV domain; and

the variant CD80 polypeptide exhibits increased binding affinity to the ectodomain of human PD-L1 compared to the binding affinity of the unmodified CD80 for the ectodomain of human PD-L1.

2. The purified variant CD80 fusion protein of claim 1 , wherein the variant CD80 polypeptide further comprises:

the amino acid substitution A26E;

the amino acid substitution E35D;

the amino acid substitution D46E;

the amino acid substitution D46V; or

the amino acid substitution A71G.

3. The purified variant CD80 fusion protein of claim 1 , wherein the variant CD80 polypeptide comprises the amino acid substitutions D46E/M47L, M47L/V68A, E35D/M47L, A26E/E35D/M47L/L85Q, A26E/Q33R/E35D/M47L/L85Q/K86E, A26E/Q33R/E35D/M47L/L85Q, E35D/M47L/L85Q, A26E/Q33L/E35D/M47L/L85Q, A26E/Q33L/E35D/M47L, H18Y/A26E/Q33L/E35D/M47L/L85Q, H18Y/E35D/M47L, A26E/E35D/M43T/M47L/L85Q/R94Q, S15P/Q33L/E35D/M47L/L85Q, Y31 S/E35D/M47L/T79L/E88G, H18L/V22A/E35D/M47L/N48T/L85Q, Q27H/E35D/M47L/L85Q/R94Q/E95K, A26E/E35D/M43I/M47L/L85Q/K86E/R94W, Q33L/E35D/M47L/A71G/F92S, Q33L/E35D/M47L/V68M/L85Q/E88D, E35D/M47L/A71G/L97Q, A26E/E35D/M47L/A71G, H18Y/A26E/E35D/M47L/L85Q/D90G, E35D/M47L/A71G/L85Q, V22D/E35D/M47L/L85Q, E35D/T41S/M43I/M47L/A71G, H18Y/A26E/E35D/M47L/V68M/A71G/D90G, Q27H/E35D/D46V/M47L/A71G, E35D/D46V/M47L/V68M/L85Q/E88D, E35D/M47L/A71G/L85M/F92Y, V22D/E35D/M47L/L70M/L97Q, E35D/M43I/M47L/L85M, H18Y/E35D/M47L/A71G/A91S, M43I/M47L/A71G, E35D/M47L/A71G/L85M, V22A/E35D/M47L/A71G, E35D/M47L/A71G, A26E/Q27R/E35D/M47L/N48Y/L85Q, E35D/D46E/M47L/V68M/L85Q/F92L, E35D/M47L/V68M/A71G/L85Q/D90G, E35D/M47L/L70M, E35D/M47L/V68M, E35D/D46V/M47L/V68M/E88D, E35D/D46V/M47L/V68M/D90G, E35D/D46V/M47L/V68M/K89N, E35D/D46V/M47L/V68M/L85Q, E35D/D46V/M47L/V68M, E35D/D46V/M47L/V70M, E35D/D46V/M47L/V70M/L85Q, E24D/E35D/M47L/V68M/E95V/L97Q, E35D/D46E/M47L/V68M/A71G/Y87C/K93R, E35D/D46E/M47L/V68M/T79M/L85M, E35D/D46E/M47L/V68M/T79M/L85M/L97Q, E35D/M431/M47L/V68M, E35D/M47L/V68M/E95V/L97Q, E35D/M47L/Y53F/V68M/A71G/K93R/E95V, H18Y/E35D/M38I/M47L/V68M/L85M, H18Y/E35D/M47L/V68M/A71G/L85M, H18Y/E35D/M47L/V68M/E95V/L97Q, H18Y/E35D/M47L/Y53F/V68M/A71G, H18Y/E35D/M47L/Y53F/V68M/A71G/K93R/E95V, Q33R/E35D/M38I /M47L/V68M, R29C/E35D/M47L/V68M/A71G/L85M, T13R/E35D/M47L/V68M, T13R/Q33L/E35D/M47L/V68M/L85M, T13R/Q33R/E35D/M38I/M47L/V68M, T13R/Q33R/E35D/M38I/M47L/V68M/E95V/L97Q, T13R/Q33R/E35D/M38I/M47L/V68M/L85M, T13R/Q33R/E35D/M38I/M47L/V68M/L85M/R94Q, T13R/Q33R/E35D/M47L/V68M, T13R/Q33R/E35D/M47L/V68M/L85M, V22D/E24D/E35D/M47L/V68M, V22D/E24D/E35D/M47L/V68M/L85M/D90G, D46V/M47L, M47L/V68M, M47L/L85Q, E35D/D46V/M47L, D46V/M47L/V68M, D46V/M47L/L85Q, M47L/V68M/L85Q, E35D/D46V/M47L/L85Q, E35D/M47L/V68M/L85Q, D46V/M47L/V68M/L85Q, A26E/E35D/M47L/V68M/A71G/D90G, H18Y/E35D/M47L/V68M/A71G/D90G, H18Y/A26E/M47L/V68M/A71G/D90G, H18Y/A26E/E35D/M47L/A71G/D90G, H18Y/A26E/E35D/M47L/V68M/D90G, H18Y/A26E/E35D/M47L/V68M/A71G, E35D/M47L/V68M/A71G/D90G, H18Y/M47L/V68M/A71G/D90G, H18Y/A26E/E35D/M47L/D90G, H18Y/A26E/E35D/M47L/V68M, A26E/M47L/V68M/A71G/D90G, A26E/E35D/M47L/A71G/D90G, A26E/E35D/M47L/V68M/D90G, A26E/E35D/M47L/V68M/A71G, H18Y/E35D/M47L/A71G/D90G, H18Y/E35D/M47L/V68M/D90G, H18Y/E35D/M47L/V68M/A71G, H18Y/A26E/M47L/A71G/D90G, H18Y/A26E/M47L/V68M/D90G, H18Y/A26E/M47L/V68M/A71G, H18Y/A26E/E35D/M47L/A71G, M47L/V68M/A71G/D90G, H18Y/A26E/E35D/M47L, E35D/M47L/A71G/D90G, E35D/M47L/V68M/D90G, E35D/M47L/V68M/A71G, A26E/M47L/A71G/D90G, A26E/M47L/V68M/D90G, A26E/M47L/V68M/A71G, A26E/E35D/M47L/D90G, A26E/E35D/M47L/V68M, H18Y/M47L/A71G/D90G, H18Y/M47L/V68M/D90G, H18Y/M47L/V68M/A71G, H18Y/E35D/M47L/D90G, H18Y/E35D/M47L/A71G, H18Y/E35D/M47L/V68M, H18Y/A26E/M47L/D90G, H18Y/A26E/M47L/A71G, H18Y/A26E/M47L/V68M, H18C/A26P/E35D/M47L/V68M/A71G, H18T/A26N/E35D/M47L/V68M/A71G, H18V/A26K/E35D/M47L/V68M/A71G, H18V/A26P/E35D/M47L/V68M/A71G, H18V/A26 S/E35D/M47L/V68M/A71G/D90G, H18V/A26R/E35D/M47L/V68M/A71G/D90G, H18A/A26P/E35D/M47L/V68M/A71G/D90G, H18A/A26N/E35D/M47L/V68M/A71G/D90G, or H18F/A26H/E35D/M47L/V68M/A71G/D90G, with reference to the numbering of positions set forth in SEQ ID NO: 2.

4. The purified variant CD80 fusion protein of claim 1 , wherein the unmodified CD80 comprises the sequence of amino acids set forth in SEQ ID NO:2.

5. The purified variant CD80 fusion protein of claim 1 , wherein the unmodified CD80 comprises a portion of SEQ ID NO:2 comprising the IgV domain.

6. The purified CD80 fusion protein of claim 3 , wherein the IgV domain is the only CD80 portion of the variant CD80 polypeptide.

7. The purified variant CD80 fusion protein of claim 1 , wherein the immunomodulatory protein exhibits PD-L1-dependent CD28 costimulation.

8. A pharmaceutical composition, comprising the variant CD80 polypeptide of claim 1 .

9. The purified variant CD80 fusion protein of claim 1 , wherein the IgV domain comprises amino acids 35-135 of SEQ ID NO:1.

10. The purified variant CD80 fusion protein of claim 1 , wherein the IgV domain is set forth as amino acids 35-141 of SEQ ID NO:1.

11. The purified variant CD80 fusion protein of claim 1 , wherein the variant CD80 polypeptide comprises up to 5 amino acid substitutions.

12. The purified variant CD80 fusion protein of claim 1 , wherein the Fc domain is a variant IgG1 Fc domain with reduced effector function.

13. The purified variant CD80 fusion protein of claim 12 , wherein the variant Fc domain comprises the amino acid substitutions L234A/L235E/G237A.

14. The purified variant CD80 fusion protein of claim 1 , wherein the Fc domain is an Fc domain of IgG2.

15. The purified variant CD80 fusion protein of claim 1 , wherein the Fc domain is an Fc domain of IgG4 or is a variant IgG4 Fc domain.

16. The purified variant CD80 fusion protein of claim 15 , wherein the Fc domain is a variant IgG4Fc domain containing the S228P mutation.

17. The purified variant CD80 fusion protein of claim 1 , wherein the variant CD80 polypeptide comprises a sequence of amino acids that exhibits at least 93% sequence identity to amino acids 35-141 of SEQ ID NO:1.

18. A pharmaceutical composition comprising the purified variant CD80 fusion protein of claim 1 and a pharmaceutically acceptable excipient.

19. The purified variant CD80 fusion protein of claim 1 , wherein the IgV domain or specific binding fragment thereof is the only CD80 portion of the variant CD80 polypeptide.

20. The purified variant CD80 fusion protein of claim 3 , wherein the unmodified CD80 comprises the sequence of amino acids set forth in SEQ ID NO:2.

21. The purified variant CD80 fusion protein of claim 3 , wherein the unmodified CD80 comprises a portion of SEQ ID NO:2 comprising the IgV domain.

22. The purified variant CD80 fusion protein of claim 3 , wherein the immunomodulatory protein exhibits PD-L1-dependent CD28 costimulation.

23. A pharmaceutical composition, comprising the variant CD80 polypeptide of claim 3 .

24. The purified variant CD80 fusion protein of claim 3 , wherein the IgV domain comprises amino acids 35-135 of SEQ ID NO:1.

25. The purified variant CD80 fusion protein of claim 3 , wherein the IgV domain is set forth as amino acids 35-141 of SEQ ID NO:1.

26. The purified variant CD80 fusion protein of claim 3 , wherein the Fc domain is a variant IgG1 Fc domain with reduced effector function.

27. The purified variant CD80 fusion protein of claim 3 , wherein the Fc domain is an Fc domain of IgG4 or is a variant IgG4 Fc domain.

28. The purified variant CD80 fusion protein of claim 27 , wherein the Fc domain is a variant IgG4 Fc domain containing an S228P mutation.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 29, 2020
From: SWANSON, RYAN; KORNACKER, MICHAEL; KUIJPER, JOSEPH L.; MAURER, MARK F.; ARDOUREL, DAN; DEMONTE, DANIEL WILLIAM
To: ALPINE IMMUNE SCIENCES, INC.
Reel/Frame 051662/0321 →
Continuity (9)
Provisional Application 62582266 · Nov 6, 2017
Provisional Application 62574165 · Oct 18, 2017
Provisional Application 62537939 · Jul 27, 2017
Provisional Application 62475204 · Mar 22, 2017
Provisional Application 62472573 · Mar 17, 2017
Provisional Application 62472569 · Mar 16, 2017
Provisional Application 62472572 · Mar 16, 2017
Provisional Application 62472558 · Mar 16, 2017
Related Publication 20210130436A1 · May 6, 2021
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