Disrupting FC receptor engagement on macrophages enhances efficacy of anti-SIRPalpha antibody therapy
Inventors
Liu, Jie • Ring, Aaron Michael • Volkmer, Jens-Peter • Weissman, Irving L.
Assignees
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Publication Number
US-11718675-B2
Publication Date
2023-08-08
Expiration Date
Abstract
Anti-SIRPα antibodies, including multi-specific anti-SIRPα antibodies, are provided, as are related compositions and methods. The antibodies of the disclosure bind to SIRPα and can block the interaction of CD47 on one cell with SIRPα on a phagocytic cell. The subject anti-SIRPα antibodies find use in various therapeutic methods. Embodiments of the disclosure include isolated antibodies and derivatives and fragments thereof, pharmaceutical formulations comprising one or more of the anti-SIRPα antibodies; and cell lines that produce the antibodies. Also provided are amino acid sequences of exemplary anti-SIRPα antibodies.
Core Innovation
The disclosure describes anti-SIRPα antibodies that block CD47–SIRPα signaling to enhance macrophage-mediated phagocytosis. It addresses variability and restores therapeutic activity by engineering the antibody Fc region to reduce productive FcγR engagement while preserving FcRn interaction. In this way, the antibodies maintain binding and functional performance for phagocytosis-enhancing therapy.
The invention provides an isolated, therapeutic antibody comprising variable regions that specifically bind human SIRPα, with defined light- and heavy-chain amino acid sequences set forth by SEQ ID NOs. The human Fc region includes an amino acid substitution in the CH2 region at specified EU index positions (234/235/237) or at EU index position asparagine 297 (N297), where the substitution reduces binding to a human Fcγ receptor relative to a wild-type Fc region. These Fc-reducing substitutions are used to improve therapeutic activity despite FcγR engagement reduction.
The disclosure further describes antibody and composition formats including isolated antibodies, Fc-modified antibodies, Fc-lacking F(ab')2, and bispecific/multispecific constructs. It includes humanized KWAR23 sequence information using SEQUENCE ID NOs, and it discusses reduced inter-individual variability in phagocytosis using dead-Fc variants. The described constructs are also presented as synergizing with cell-targeting antibodies in in vitro contexts.
Claims Coverage
The identified independent claim covers a defined isolated therapeutic anti-SIRPα antibody with specific variable-region sequence requirements and specific human Fc-region substitutions that reduce binding to a human Fcγ receptor relative to wild-type Fc. The claim includes inventive features in both antigen-binding specificity (human SIRPα binding) and Fc engineering (reduced FcγR binding via EU index-position substitutions).
Defined anti-SIRPα variable regions
A variable region that specifically binds to human SIRPα, comprising a light chain having all three of amino acid sequences set forth in SEQ ID NOs: 6-8, and a heavy chain having all three amino acid sequences set forth in SEQ ID NOs: 3-5.
Fc substitutions reducing human Fcγ receptor binding
A human Fc region comprising an amino acid substitution in the CH2 region at EU index positions 234, 235, or 237; or at EU index position asparagine 297 (N297), where the amino acid substitution reduces binding to a human Fcγ receptor, relative to a wild-type Fc region.
Overall claim coverage is directed to an isolated therapeutic antibody that binds human SIRPα through specified light- and heavy-chain sequence elements (SEQ ID NOs for the light-chain and heavy-chain components) and that reduces Fcγ receptor binding through specified EU index-position substitutions in the human Fc region versus wild-type.
Stated Advantages
Enhances macrophage-mediated phagocytosis by blocking CD47–SIRPα signaling.
Reduces productive FcγR engagement while preserving FcRn interaction, restoring and improving therapeutic activity.
Reduces inter-individual variability in phagocytosis using dead-Fc variants.
Provides synergy with cell-targeting antibodies in vitro.
Documented Applications
Increasing phagocytosis of a targeted cell in a human subject by administering an effective dose of the claim-1 antibody composition.
Synergy in vitro with cell-targeting antibodies such as rituximab (anti-CD20) and cetuximab (anti-EGFR).
Phagocytosis-associated contexts including NHL phagocytosis with rituximab and colorectal cancer phagocytosis with cetuximab/anti-EGFR, as described in the disclosure.
Therapeutic use for CD47-associated diseases as described in the disclosure.
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