IP Library › Granted Patent US 12,612,446
Granted Patent B2
US 12,612,446 · App. 18/161,799 · Granted Apr 28, 2026

CTLA-4 variant immunomodulatory proteins and uses thereof

Inventors: Lawrence Evans (Seattle, WA); Joseph L Kuijper (Seattle, WA); Ryan Swanson (Seattle, WA)
Assignee: Alpine Immune Sciences, Inc.
C07K14/70521A61K47/65A61P19/02C07K14/7051C12N5/0637C12N15/00C07K2319/02C07K2319/03C07K2319/30
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Quick Facts
Patent No.
US 12,612,446
App. No.
18/161,799
Granted
Apr 28, 2026
Kind
B2
Abstract

Provided herein are variant CTLA-4 polypeptides and immunomodulatory proteins and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of disease applications, including for treatment of autoimmune or inflammatory conditions. Compositions and methods for making and using such proteins are provided.

Claims (23)

1 . A variant CTLA-4 polypeptide, comprising one or more amino acid substitutions with reference to the extracellular domain of an unmodified CTLA-4 polypeptide or a specific binding fragment thereof comprising an IgV domain, wherein the one or more amino acid substitutions are selected from among M87T, L12F, R16H, I18T, A26T, S27P, E33V, T37S, M56T, M56V, L63H, L91R, and N110K, corresponding to positions set forth in SEQ ID NO:2, and wherein the variant CTLA-4 polypeptide specifically binds to the ectodomain of human CD80.

2 . The variant CTLA-4 polypeptide of claim 1 , wherein the unmodified CTLA-4 polypeptide comprises (i) the sequence of amino acids set forth in SEQ ID NO:2, (ii) a sequence of amino acids that has at least 95% sequence identity to SEQ ID NO:2; or (iii) a portion thereof comprising an IgV domain or specific binding fragment of the IgV domain.

3 . The variant CTLA-4 polypeptide of claim 1 , wherein the unmodified CTLA-4 comprises the sequence of amino acids set forth in SEQ ID NO:2.

4 . The variant CTLA-4 polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 2 or the specific binding fragment thereof comprising the IgV domain.

5 . The variant CTLA-4 polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide specifically binds to the ectodomain of CD80 and/or CD86 with increased affinity compared to the binding of the unmodified CTLA-4 polypeptide for the same ectodomain(s).

6 . The variant CTLA-4 polypeptide of claim 5 , wherein the increase in binding affinity for the one or more ectodomain is, independently, more than 1.2-fold, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold 40-fold, 50-fold, 100-fold or more.

7 . A variant CTLA-4 polypeptide comprising one or more amino acid substitutions with reference to the extracellular domain of an unmodified CTLA-4 polypeptide or a specific binding fragment thereof comprising an IgV domain, wherein the variant CTLA-4 polypeptide comprises the sequence of amino acids set forth in any of SEQ ID NOS: 158, 161, 163, 173, 179, 195, 210, 275, 623, 628, 629, 630, 631, 632, 633 or a specific binding fragment thereof.

8 . The variant CTLA-4 polypeptide of claim 7 , wherein the variant CTLA-4 polypeptide comprises the sequence of amino acids of the extracellular domain set forth in any of SEQ ID NOS: 6, 9, 11, 24, 30, 49, 64, 140, 590, 595, 596, 597, 598, 599, 600, or a specific binding fragment thereof.

9 . An immunomodulatory protein comprising the variant CTLA-4 polypeptide of claim 1 and a multimerization domain.

10 . The immunomodulatory protein of claim 9 , wherein the multimerization domain is an Fc domain or a variant thereof with reduced effector function.

11 . The immunomodulatory protein of claim 9 , wherein the Fc domain or variant thereof comprises the sequence of amino acids set forth in any of SEQ ID NOs: 438-442 or a sequence of amino acids that exhibits at least 85% sequence identity to any of SEQ ID NOs: 438-442.

12 . The immunomodulatory protein of claim 9 , wherein the Fc domain comprises one or more amino acid modifications selected from among E233P, L234A, L234V, L235A, L235E, G236del, G237A, S267K, N297G, V302C and K447del, each by EU numbering.

13 . The immunomodulatory protein of claim 9 , wherein the Fc domain comprises the amino acid modifications L234A/L235E/G237A.

14 . The immunomodulatory protein of claim 9 , wherein the variant CTLA-4 polypeptide blocks CD80 and/or CD86 binding to CD28 on T cells.

15 . The immunomodulatory protein of claim 9 , wherein the immunomodulatory protein further comprises a targeting moiety that binds to a cell surface antigen.

16 . The immunomodulatory protein of claim 15 , wherein the cell surface antigen is an antigen on the surface of an immune cell.

17 . The immunomodulatory protein of claim 16 , wherein the immune cell is a lymphocyte.

18 . The immunomodulatory protein of claim 17 , wherein the lymphocyte is a B cell, and NK cell or a T cell.

19 . The immunomodulatory protein of claim 16 , wherein the targeting moiety inhibits activation or proliferation of the immune cell.

20 . The immunomodulatory protein of claim 9 that is a homodimer.

21 . A conjugate, comprising a variant CTLA-4 of claim 1 linked to a moiety selected from a peptide, nucleic acid, small molecule, nanoparticle, an antibody, or an antigen-binding fragment.

22 . A pharmaceutical composition, comprising the variant CTLA-4 polypeptide of claim 1 , an immunomodulatory protein comprising a variant CTLA-4 polypeptide of claim 1 , or a conjugate comprising a variant CTLA-4 polypeptide of claim 1 , and a pharmaceutically acceptable excipient.

23 . The variant CTLA-4 polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises a sequence of amino acids that exhibits at least 90% sequence identity to SEQ ID NO:2 or the specific binding fragment thereof comprising the IgV domain.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023
From: EVANS, LAWRENCE; KUIJPER, JOSEPH L.; SWANSON, RYAN
To: ALPINE IMMUNE SCIENCES, INC.
Reel/Frame 062551/0892 →
Continuity (5)
Division 16755072
Provisional Application 62733615 · Sep 19, 2018
Provisional Application 62613379 · Jan 3, 2018
Provisional Application 62570619 · Oct 10, 2017
Related Publication 20230250152A1 · Aug 10, 2023
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