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US 2017/0247476 A1Published application
Protease-activatable bispecific proteins
AssigneeAmgen Inc.
InventorsWei Yan, Martin J. Pentony, Mark L. Michaels, Patrick Baeuerle
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Abstract
Described herein are protease-activatable proteins (PABPs), which, when activated, can mediate cytolysis of target cells by effector cells. Also provided are nucleic acids encoding such PABPs and methods of making and using PABPs.
Claims39
A protein comprising
- (a) one or more polypeptide chain(s) that bind to a target cell,
- (b) one or more polypeptide chain(s) that bind to an effector cell,
- (c) a third polypeptide, and
- (d) a linker comprising a protease cleavage site that links the third polypeptide of (c) to the remainder of the protein,
- wherein the protein binds to either a target cell more effectively or to an effector cell more effectively when the protease cleavage site is essentially completely cleaved as compared to binding observed when the protease cleavage site is uncleaved.
2 more elements
A protein comprising
- (a) one or more polypeptide chain(s) that bind to a target cell,
- (b) one or more polypeptide chain(s) that bind to an effector cell,
- (c) a third polypeptide that inhibits the cytolytic activity of the protein in a cell cytolysis assay, and
- (d) a linker comprising a protease cleavage site that links the third polypeptide of (c) to the remainder of the protein,
- wherein the Ec50 of the protein in a cell cytolysis assay when the protease cleavage site is essentially completely cleaved is not more than a fifth of the Ec50 of the protein in the same assay when the protease cleavage site has not been cleaved.
2 more elements
A protein comprising one of the following pairs of polypeptide chains:
- (a) (i) a first polypeptide chain comprising an amino acid sequence having the following formula:
- VH1-CH1-L1-VH2-CH1, wherein VH1 and VH2 are immunoglobulin heavy chain variable regions, CH1 is a first heavy chain constant region, and L1 is a linker comprising a protease cleavable site, and
- (ii) a second polypeptide chain comprising an amino acid sequence having the following formula:
- VL1-CL-L2-VL2-CL, wherein VL1 and VL2 are immunoglobulin light chain variable regions, CL is a light chain constant region, and L2 is a linker that does not contain a protease cleavage site, or
- (b) (i) a first polypeptide chain comprising an amino acid sequence having the following formula:
- VH1-CH1-L1-VL2-CL, wherein VH1 is an immunoglobulin heavy chain variable region, VL2 is an immunoglobulin light chain variable region, CH1 is a first heavy chain constant region, CL is a light chain constant region, and L1 is a linker comprising a protease cleavage site, and
- (ii) a second polypeptide chain comprising an amino acid sequence having the following formula:
- VL1-CL-L2-VH2-CH1, wherein VL1 is an immunoglobulin light chain variable regions, VH2 is an immunoglobulin heavy chain variable region, L2 is a linker that does not contain a protease cleavage site, and CH1 is a first heavy chain constant region, or
- (c) (i) a first polypeptide chain comprising an amino acid sequence having the following formula:
- VL1-CL-L1-VL2-CL, wherein VL1 and V2 are immunoglobulin light chain variable regions, CL is a light chain constant region, and L1 is a linker comprising a protease cleavage site, and
- (ii) a second polypeptide chain comprising an amino acid sequence having the following formula:
- VH1-CH1-L2-VH2-CH1, wherein VH1 and VH2 are heavy chain variable regions, L2 is a linker that does not contain a protease cleavage site, and CH1 is a first heavy chain constant region, or
- (d) (i) a first polypeptide chain comprising an amino acid sequence having the following formula:
- VL1-CL-L1-VH2-CH1, wherein VH2 is an immunoglobulin heavy chain variable region, VL1 is an immunoglobulin light chain variable region, CH1 is a first heavy chain constant region, CL is a light chain constant region, and L1 is a protease-cleavable linker, and
- (ii) a second polypeptide chain comprising an amino acid sequence having the following formula:
- VH1-CH1-L2-VL2-CL, wherein VL2 is an immunoglobulin light chain variable regions, VH1 is an immunoglobulin heavy chain variable region, L2 is a linker that does not contain a protease cleavage site, CH1 is a first heavy chain constant region, and CL is a light chain constant region,
- wherein VL1 and VH1 bind to a target cell when part of an IgG or scFv antibody and VL2 and VH2 bind to an effector cell when part of an IgG or scFv antibody.
14 more elements
Dependencies are inferred from the claim text.