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US 2020/0263154 A1Published application
Sirp-alpha variant constructs and uses thereof
AssigneeALX Oncology Inc.
InventorsLaura DEMING, Corey GOODMAN, Jaume PONS, Bang Janet SIM, Marija VRLJIC
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Abstract
The invention relates to compositions and methods of constructs comprising a SIRP-α polypeptide, including SIRP-α variants. The constructs may be engineered in a variety of ways to respond to environmental factors, such as pH, hypoxia, and/or the presence of tumor-associated enzymes or tumor-associated antigens. The constructs of the invention may be used to treat various diseases, such as cancer, preferably solid tumor or hematological cancer.
Claims28
1:
- A construct comprising a SIRP-α polypeptide or a fragment thereof, wherein said SIRP-α polypeptide or said fragment thereof preferentially binds CD47 on diseased cells or at a diseased site as compared to CD47 from non-diseased cells or at a non-diseased site.
(canceled)
3:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof is attached to a blocking peptide.
4:
- The construct of claim 3, wherein said blocking peptide binds with higher affinity to a wild-type SIRP-α than to a SIRP-α polypeptide or a fragment thereof.
5:
- The construct of claim 3, wherein said SIRP-α polypeptide or a fragment thereof binds with higher affinity to a wild-type CD47 than to said blocking peptide.
6:
- The construct of claim 3, wherein said blocking peptide is a CD47-based blocking peptide.
7:
- The construct of claim 6, wherein said CD47-based blocking peptide
- (a) has at least 80% amino acid sequence identity to the sequence of the wild-type, IgSF domain of CD47 (SEQ ID NO:
- 35) or a fragment thereof, or
- (b) comprises an amino acid sequence set forth in any one of SEQ ID NOs:
- 36-46.
2 more elements
(canceled)
9:
- The construct of claim 3, wherein said SIRP-α polypeptide or a fragment thereof is attached to said blocking peptide by a cleavable linker and optionally one or more spacers.
10:
- The construct of claim 9, wherein said cleavable linker is cleaved
- (a) under acidic pH and/or hypoxic condition, or
- (b) by a tumor-associated enzyme.
(canceled)
12:
- The construct of claim 10, wherein said tumor-associated enzyme is a protease selected from the group consisting of:
- matriptase (MTSP1), urinary-type plasminogen activator (uPA), legumain, PSA (also called KLK3, kallikrein-related peptidase-3), matrix metalloproteinase-2 (MMP-2), MMP9, human neutrophil elastase (HNE), and proteinase 3 (Pr3).
(canceled)
14:
- The construct of claim 9, wherein said cleavable linker has the sequence of L/S/G/R/S/D/N/H (SEQ ID NO:
- 47);
- /Kr/RKQ/gAS/RK/A (SEQ ID NO:
- 76);
- ---/--/-/N/-/-/- (SEQ ID NO:
- 78);
- SI/SQ/-/YQR/S/S/-/ (SEQ ID NO:
- 81);
- S/S/K/L/Q (SEQ ID NO:
- 82);
- -/P/-/-/LI/-/-/- (SEQ ID NO:
- 83);
- G/P/L/G/I/A/G/Q (SEQ ID NO:
- 85);
- P/V/G/L/I/G (SEQ ID NO:
- 86);
- H/P/V/G/L/L/A/R (SEQ ID NO:
- 87);
- -/-/-/VIAT/-/-/-/- (SEQ ID NO:
- 88);
- -/Y/Y/VTA/-/-/-/- (SEQ ID NO:
- 89);
- PRFKIIGG (SEQ ID NO:
- 90);
- PRFRIIGG (SEQ ID NO:
- 91);
- SSRHRRALD (SEQ ID NO:
- 92);
- RKSSIIIRMRDVVL (SEQ ID NO:
- 93);
- SSSFDKGKYKKGDDA (SEQ ID NO:
- 94);
- SSSFDKGKYKRGDDA (SEQ ID NO:
- 95);
- IEGR (SEQ ID NO:
- 95A);
- IDGR (SEQ ID NO:
- 96);
- GGSIDGR (SEQ ID NO:
- 97);
- PLGLWA (SEQ ID NO:
- 98);
- or DVAQFVLT (SEQ ID NO:
- 99).
41 more elements
15:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof is attached to an antibody-binding peptide, wherein the antibody-binding peptide binds to a constant region of an antibody, a fragment antigen-binding (Fab) region of an antibody, or to a variable region of an antibody.
(canceled)
17:
- The construct of claim 15, wherein said antibody-binding peptide binds the Fab region of the antibody and has at least 75% amino acid sequence identity to the sequence of a disease localization peptide (OLP) (SEQ ID NO:
- 64, 65 or 66).
18:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof is attached to an Fc domain monomer, an Fc domain, a human serum albumin (HSA), an albumin binding peptide or a polymer, wherein said polymer comprises a polyethylene glycol (PEG) chain or a polysialic acid chain.
19:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof is attached to an antibody or a fragment thereof.
20:
- The construct of claim 19, wherein said antibody
- (a) binds to one or more of the following:
- 4-1BB, 5T4, ALK1, ANG-2, B7-H3, B7-H4, c-Met, CA6, CCR4, CD123, CD19, CD20, CD22, CD27, EpCAM, CD30, CD32b, CD33, CD37, CD38, CD40, CD52, CD70, CD74, CD79b, CD98, CEA, CEACAM5, CLDN18.2, CLDN6, CS1, CTLA-4, CXCR4, DLL-4, EGFR, EGP-1, ENPP3, EphA3, ETBR, FGFR2, fibronectin, FR alpha, frizzled receptor, GCC, GD2, glypican-3, GPNMB, HER2, HER3, HLA-DR, ICAM-1, IGF-1R, IL-3R, LIV-1, mesothelin, MUC16, MUC1, NaPi2b, Nectin-4, Notch 2, Notch 1, OX-40, PD-1, PD-L1, PD-L2, PDGFR-α, PS, PSMA, SLTRK6, STEAP1, TEM1, VEGFR, CD25, DKK-1, and/or CSF-1R, or
- (b) is cetuximab, necitumumab, pembrolizumab, nivolumab, pidilizumab, MEDI0680, atezolizumab, avelumab, durvalumab, MEDI6383, MEDI6469, RG7888, ipilimumab, tremelimumab, urelumab, PF-05082566, enoblituzumab, vantictumab, varlilumab, mogamulizumab, SAR650984, daratumumab, trastuzumab, trastuzumab emtansine, pertuzumab, elotuzumab, rituximab, ofatumumab, obinutuzumab, RG7155, FPA008, anti-HER2 antibody, anti-CD20 antibody, anti-CD 19 antibody, anti-CS1 antibody, anti-CD38 antibody, panitumumab, or brentuximab vedotin.
1 more element
(canceled)
22:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof
- (a) has at least 80% sequence identity to any of SEQ ID NOs:
- 3-12 and 24-34, or
- (b) is one or a fragment of SEQ ID NO:
- 13-23.
2 more elements
(canceled)
24:
- The construct of claim 1, wherein said SIRP-α polypeptide or a fragment thereof comprises at least one amino acid substitution with a histidine residue.
25:
- The construct of claim 24, wherein said at least one amino acid substitution occurs at one or more of the following amino acid positions:
- 29, 30, 31, 32, 33, 34, 35, 52, 53, 54, 66, 67, 68, 69, 74, 93, 96, 97, 98, 100, 4, 6, 27, 36, 39, 47, 48, 49, 50, 57, 60, 72, 74, 76, 92, 94, 103, relative to a sequence of any one of SEQ ID NOs:
- 3-12.
26-28. (canceled)
29:
- A pharmaceutical composition comprising a therapeutically effective amount of the construct of claim 1.
30:
- A method of increasing phagocytosis of a target cell in a subject, comprising administering to said subject a construct according to claim 1.
Dependencies are inferred from the claim text.