Anti-SIRPα antibody
Inventors
Matozaki, Takashi • SUE, MAYUMI • Nakamura, Kensuke • Yoshimura, Chigusa
Assignees
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Publication Number
US-12486329-B2
Publication Date
2025-12-02
Expiration Date
Abstract
An anti-SIRPα antibody that can be used as a tumor agent and an anti-tumor agent comprising the antibody as an active ingredient. An antibody that binds specifically to human SIRPα to inhibit binding of human SIRPα to CD47.
Core Innovation
The invention relates to an antibody that specifically binds human SIRPα and inhibits binding of human SIRPα to CD47. The antibody is defined by particular light-chain and heavy-chain CDR sequences, including light chain CDRL1, CDRL2, and CDRL3 and heavy chain CDRH1, CDRH2, and CDRH3.
To reduce effector-function related safety risk while preserving binding, the antibody is engineered with a human IgG4 constant region and mutations that reduce ADCC and/or ADCP activity. The disclosed IgG4pf/IgG4proFALA format includes FALA and PRO substitutions, and the antibody is also described with specified substitutions at positions 228, 234, and 235 according to EU/Kabat numbering.
The disclosure further includes chimeric antibodies, humanized antibodies via CDR grafting, and antigen-binding fragments such as Fab, F(ab′)2, Fab′, and scFv. Humanized heavy-chain and light-chain sequences are constructed and characterized for binding to human and monkey SIRPα variants, and functional evaluation is described for inhibition of SIRPα–CD47 binding and ADCP activity against CD47-positive Raji/Ramos cells.
Claims Coverage
The claim coverage centers on one independent antibody claim defined by specific human SIRPα-binding CDR sequences that inhibit human SIRPα binding to CD47. Additional inventive features include engineered human IgG4 constant-region constraints intended to reduce ADCC and/or ADCP, defined antigen-binding fragment formats, sequence-identity-constrained variable-region variants, and pharmaceutical compositions combining the antibody with immune checkpoint inhibitors.
Human SIRPα-binding antibody defined by six CDR sequences
An antibody binds specifically to human SIRPα to inhibit binding of human SIRPα to CD47, where the light chain CDRL1, CDRL2, and CDRL3 consist of SEQ ID NOs 7, 8, and 9, and the heavy chain CDRH1, CDRH2, and CDRH3 consist of SEQ ID NOs 10, 11, and 12.
Human IgG4 constant region with ADCC/ADCP-reducing mutation constraint
An antibody includes a human IgG4 heavy-chain constant region and a mutation that reduces ADCC and/or ADCP activity.
Specified IgG4 constant-region substitutions at positions 228, 234, and 235
An antibody has a human IgG4 heavy-chain constant region with specified amino-acid substitutions at positions 228, 234, and 235 according to EU/Kabat numbering.
Variable-region sequence identity constraints tied to human SIRPα binding
An antibody comprises a light chain variable region selected from residues 21–127 of SEQ ID NO: 27 or a variant with at least 95% identity that binds human SIRPα, and a heavy chain variable region selected from residues 20–138 of SEQ ID NO: 29 or a variant with at least 95% identity that binds human SIRPα, with a human IgG4 heavy chain constant region and a mutation that reduces ADCC and/or ADCP activity.
Antigen-binding fragment selected from Fab, F(ab′)2, Fab′, or scFv
The antibody antigen-binding fragment is selected from Fab, F(ab′)2, Fab′, or scFv.
Pharmaceutical composition including an immune checkpoint inhibitor targeting PD-L1/PD-1 or CTLA4
A pharmaceutical composition includes an immune checkpoint inhibitor that inhibits PD-L1 binding to PD-1, or alternatively is a CTLA4 inhibitor.
The inventive coverage centers on an antibody defined by specific human SIRPα CDR sequences that inhibits SIRPα binding to CD47, with dependent features specifying human IgG4 engineering to reduce ADCC and/or ADCP, allowable antigen-binding fragment formats, variable-region identity constraints, and pharmaceutical compositions combined with immune checkpoint inhibitors.
Stated Advantages
Inhibits binding of human SIRPα to CD47, thereby addressing the “don’t-eat-me” signal and enhancing phagocytosis.
Attenuates ADCC and/or ADCP activity by engineering the antibody with a human IgG4 constant region and ADCC/ADCP-reducing Fc mutations.
Preserves binding while reducing effector-function related safety risk.
Provides ADCP activity against CD47-positive Raji/Ramos cells, with reported enhancement in combination with rituximab.
Supports pharmaceutical compositions that combine with immune checkpoint inhibitors that inhibit PD-L1→PD-1 binding or are CTLA4 inhibitors.
Documented Applications
Use as an antigen-binding agent to inhibit SIRPα–CD47 binding in the context of phagocytosis by phagocytes such as macrophages and dendritic cells.
In vitro characterization and functional evaluation of inhibition of SIRPα–CD47 binding and ADCP activity against CD47-positive Raji/Ramos cells using cell-based readouts.
Comparison of anti-SIRPα antibodies in binding inhibition and ADCP/self-ADCP observations, including reported evaluations with rituximab combination.
General in vivo evaluation framework using a human SIRPA/C47 knock-in mice model is mentioned in the provided content.
Combination-therapy use with immune checkpoint inhibitors, including PD-1/PD-L1 inhibitors or CTLA4 inhibitors, to support anti-tumor efficacy.
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