SIRP-gamma polypeptide compositions and treatment of cancer
Inventors
Ring, Aaron Michael • Maute, Roy Louis • KRUSE, Andrew Curtis • Manglik, Aashish • Lin, Kenneth S.
Assignees
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Publication Number
US-11407801-B2
Publication Date
2022-08-09
Expiration Date
Abstract
Provided herein are SIRP-gamma, SIRP-beta or SIRP-beta2 decoy polypeptides for immunotherapy and/or treatment of cancer, anemia, transplant, asthma, allergy, auto-immune disease, and viral infection.
Core Innovation
The invention relates to engineered SIRP-gamma decoy polypeptides that bind CD47 and are used to treat a CD47-expressing cancer of a subject in need thereof. The SIRP-gamma polypeptide is defined by a specific SEQ ID NO: 2 backbone containing variable amino-acid positions X1 to X18, where each position is constrained to selected amino-acid options, and the resulting polypeptide binds CD47.
The decoy polypeptides block CD47 ligands to enable phagocytosis/ADCC of CD47+ cells, including tumor cells and cells that are virally or bacterially infected or damaged. The disclosure also includes affinity-increasing amino-acid modifications to SIRP-gamma, including variants such as SIRP-gamma variant GV3, and analogous SIRP-beta and SIRP-beta2 decoy polypeptides.
Therapeutic compositions may include optional Fc fusion, multimeric forms, detectable labels, and pharmaceutically acceptable carriers, together with methods of treatment using therapeutically effective amounts. Broad treatment uses are stated for cancer and additional diseases, including anemia, transplant rejection, asthma/allergy, autoimmune disease, and viral/bacterial infection, and combinations with other therapies such as chemotherapeutics, monoclonal antibodies, and radiotherapy are described.
Claims Coverage
The independent claim provides a method of treating a CD47-expressing cancer by administering a therapeutically effective SIRP-gamma polypeptide that binds CD47, with the SIRP-gamma polypeptide defined by a specific SEQ ID NO: 2 backbone and constrained variable positions X1 to X18. Overall, the inventive coverage centers on CD47-binding SIRP-gamma decoy polypeptides for cancer treatment, with optional architectural and regimen refinements.
Treating a CD47-expressing cancer with a CD47-binding SIRP-gamma polypeptide defined by variable positions
Administering a therapeutically effective amount of a polypeptide comprising a SIRP-gamma polypeptide consisting of the sequence EEELQX1IQPEKLLLVTVGKTATLHCTX2TSX3X4PX5GPX6X7WFRGX8GPGRX9LIYNX10X11X12GX13FPRVTTVSDX14X15KRNNMDFSIRISSITPADVGTYYCX16KFRKGX17PEX18VEFKSGPGTEMALGAKPS (SEQ ID NO: 2), wherein X1 is M, I, L or F; X2 is F, I, or L; X3 is L, I, V, H, N or D; X4 is F, I, L or V; X5 is V, I, L, P, T or A; X6 is V or I; X7 is L or Q; X8 is V or A; X9 is E or V; X10 is Q, P, L, V, A or E; X11 is K or R; X12 is E, D, K, N, Q or H; X13 is H, P or R; X14 is L, I, V, P, T, A, R, S or G; X15 is T, I, N, F, S, Y, V, A or D; X16 is V or I; X17 is S, R, N, K, T, I or M; and X18 is N, K, D, E, H or Q, and wherein the SIRP-gamma polypeptide binds CD47.
The claim set covers therapeutic treatment of a CD47-expressing cancer through administration of a CD47-binding SIRP-gamma decoy polypeptide defined by SEQ ID NO: 2 with selectable residues at X1 to X18.
Stated Advantages
Blocks CD47 ligands to enable phagocytosis/ADCC of CD47+ cells.
Enables improved binding and functional performance of engineered SIRP-gamma variants, including long dissociation half-lives and low picomolar dissociation constants reported in supporting data.
Provides improved in vivo receptor occupancy/persistence reported in supporting data.
Documented Applications
Treating a CD47-expressing cancer in a subject in need thereof.
Early clinical trial plans using decoy polypeptide plus anti-CD20 in B-cell lymphoma and a phase I dose-escalation study in advanced solid tumors.
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