Granted Patent
B2
US 12,358,969 · App. 18/355,539 · Granted Jul 15, 2025
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.
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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 (42)
1. An immunomodulatory Fc fusion polypeptide comprising,
(i) a variant CTLA-4 polypeptide comprising the modifications L63P and Y105L, wherein the variant CTLA-4 polypeptide amino acids are numbered with reference to SEQ ID NO:2;
(ii) a first peptide linker;
(iii) an Fc region;
(iv) a second peptide linker;
(v) a portion of a second immunoglobulin superfamily (IgSF) protein, wherein the portion comprises the IgV domain of a PD-L1 protein.
2. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises one or more amino acid modifications at positions 29, 53, 56, 58, 82, 87, and 98.
3. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises one or more amino acid modifications selected from the group consisting of G29W, T53S, M56K, N58S, Q82R, M87V, and L98Q.
4. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the amino acid modifications G29W/N58S/L63P/Q82R/L98Q/Y105L.
5. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the amino acid modifications T53S/L63P/Y105L.
6. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the amino acid modifications M56K/N58S/L63P/M87V/L98Q/Y105L.
7. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO:93.
8. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO:579.
9. The polypeptide of claim 1 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO:586.
10. The polypeptide of claim 1 , wherein the portion of the PD-L1 protein does not comprise the IgC2 domain.
11. The polypeptide of claim 10 , wherein the portion of the PD-L1 is at least 85% identical to amino acids 24-130 of SEQ ID NO: 445.
12. The polypeptide of claim 1 , wherein each of the first peptide linker and the second peptide linker is GGGGS (4GS; SEQ ID NO: 535), GSGGGGS (SEQ ID NO: 534), GGGGSGGGGS (2×GGGGS; SEQ ID NO: 537), GGGGSGGGGSGGGGS (3×GGGGS; SEQ ID NO: 536), a repeat of four 4GS linkers, a repeat of five 4GS linkers, or combinations thereof.
13. The polypeptide of claim 12 , wherein the first peptide linker comprises the sequence of SEQ ID NO:534.
14. The polypeptide of claim 12 , wherein the second peptide linker comprises the sequence of SEQ ID NO: 536.
15. The polypeptide of claim 1 , wherein the Fc region is at least 85% identical to SEQ ID NO:533.
16. The polypeptide of claim 15 , wherein the Fc region comprises one or more modifications selected from the group consisting of C220S, L234A, L235E, G237A, E356D, M358L and K447del by EU numbering.
17. The polypeptide of claim 1 , wherein the Fc region is at least 85% identical to any of SEQ ID NOS:438-442 or 526-528.
18. The polypeptide of claim 17 , wherein the Fc region is selected from the group consisting of SEQ ID NOS:438-442, 526, 527, and 528.
19. The polypeptide of claim 1 , wherein the Fc region comprises the sequence of SEQ ID NO:438.
20. The polypeptide of claim 1 , wherein the Fc region is located N-terminal to the PD-L1 IgV domain.
21. The polypeptide of claim 1 , wherein the Fc region is located N-terminal to both the variant CTLA-4 polypeptide and the PD-L1 IgV domain.
22. The polypeptide of claim 21 , wherein the N-terminal to C-terminal orientation is: Fc region, first peptide linker, variant CTLA-4 polypeptide, second peptide linker, and PD-L1 IgV domain.
23. The polypeptide of claim 22 , wherein the first peptide linker and the second peptide linker are each a repeat of three GGGGS (4GS, SEQ ID NO: 535) linkers.
24. The polypeptide of claim 22 , wherein the variant CTLA-4 polypeptide comprises the amino acid modifications G29W/N58S/L63P/Q82R/L98Q/Y105L, T53S/L63P/Y105L, or M56K/N58S/L63P/M87V/L98Q/Y105L.
25. The polypeptide of claim 22 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO:93, SEQ ID NO:579, or SEQ ID NO:586.
26. The polypeptide of claim 20 , wherein the N-terminal to C-terminal orientation is: variant CTLA-4 polypeptide, first peptide linker, Fc region, second peptide linker, and PD-L1 IgV domain.
27. The polypeptide of claim 26 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO: 93, the first peptide linker comprises the sequence of SEQ ID NO: 534, the second peptide linker comprises the sequence of SEQ ID NO:536, and the Fc region comprises the sequence of SEQ ID NO:438.
28. The polypeptide of claim 26 , wherein the first peptide linker is GSGGGGS (SEQ ID NO: 534) and the second peptide linker is a repeat of three GGGGS (4GS, SEQ IDNO: 535) linkers.
29. The polypeptide of claim 26 , wherein the variant CTLA-4 polypeptide comprises the amino acid modifications G29W/N58S/L63P/Q82R/L98Q/Y105L, T53S/L63P/Y105L, or M56K/N58S/L63P/M87V/L98Q/Y105L.
30. The polypeptide of claim 26 , wherein the variant CTLA-4 polypeptide comprises the sequence of SEQ ID NO:93, SEQ ID NO:579, or SEQ ID NO:586.
31. A pharmaceutical composition comprising a polypeptide of claim 1 , and a pharmaceutically acceptable carrier, excipient, or diluent.
32. A method of reducing an immune response in a subject comprising administering the pharmaceutical composition of claim 1 to the subject.
33. The method of claim 32 , wherein the subject has an inflammatory or autoimmune disease or disorder.
34. The method of claim 33 , wherein the inflammatory or autoimmune disease or disorder is selected from the group consisting of: Hughes Syndrome, CIDP, Guillain-Barre syndrome, and Whitaker's syndrome.
35. The method of claim 33 , wherein the inflammatory or autoimmune disease or disorder is selected from the group consisting of: Addison's Disease, allergies, alopecia areata, Alzheimer's Disease, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, ankylosing spondylitis, antiphospholipid syndrome, asthma, atherosclerosis, rheumatoid arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, azoospermia, Behcet's Disease, Berger's Disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, celiac Sprue/coeliac disease, chronic fatigue immune dysfunction syndrome (CFIDS), chronic idiopathic polyneuritis, chronic inflammatory demyelinating, polyradicalneuropathy, chronic relapsing polyneuropathy, Churg-Strauss Syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CAD), COPD (chronic obstructive pulmonary disease), CREST syndrome, Crohn's disease, dermatitis, herpetiformus, dermatomyositis, diabetes, discoid lupus, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evan's Syndrome, exopthalmos, fibromyalgia, Goodpasture's Syndrome, Graves' Disease, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, immunoproliferative disease or disorder, inflammatory bowel disease (IBD), interstitial lung disease, juvenile arthritis, juvenile idiopathic arthritis (JIA), Kawasaki's Disease, Lambert-Eaton Myasthenic Syndrome, lichen planus, lupus nephritis, lymphocytic hypophysitis, Meniere's Disease, Miller Fish Syndrome/acute disseminated encephalomyeloradiculopathy, mixed connective tissue disease, multiple sclerosis (MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, ocular inflammation, pemphigus foliaceus, pemphigus vulgaris, pernicious anaemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis/autoimmune cholangiopathy, psoriasis, psoriatic arthritis, Raynaud's Phenomenon, Reiter's Syndrome/reactive arthritis, restenosis, rheumatic fever, rheumatic disease, sarcoidosis, Schmidt's syndrome, scleroderma, Sjorgen's Syndrome, stiff-man syndrome, systemic lupus erythematosus (SLE), systemic scleroderma, Takayasu arteritis, temporal arteritis/giant cell arteritis, thyroiditis, Type 1 diabetes, ulcerative colitis, uveitis, vasculitis, vitiligo, interstitial bowel disease and Wegener's Granulomatosis.
36. A method of treating a disease comprising administering a composition comprising the polypeptide of claim 1 to a subject in need thereof.
37. A nucleic acid encoding the polypeptide of claim 1 .
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 4, 2023
From: EVANS, LAWRENCE; KUIJPER, JOSEPH L.; SWANSON, RYAN
To: ALPINE IMMUNE SCIENCES, INC.
Reel/Frame 064493/0534 →
Continuity (5)
Continuation
16755072
Provisional Application
62733615
· Sep 19, 2018
Provisional Application
62613379
· Jan 3, 2018
Provisional Application
62570619
· Oct 10, 2017
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