Heterodimeric antibodies that bind CD3 and GPC3
Inventors
Nisthal, Alex • Hassanzadeh-Kiabi, Nargess • BYKOVA, Katrina • Bernett, Matthew J. • Varma, Rajat
Assignees
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Publication Number
US-12655230-B2
Publication Date
2026-06-16
Expiration Date
Abstract
Provided herein are novel GPC3 binding domains, and antibodies that include such GPC3 binding domains (e.g., anti-GPC3×anti-CD3). Also provided herein are methods of using such antibodies for the treatment of GPC3-associated cancers.
Core Innovation
The document describes heterodimeric bispecific antibodies comprising an anti-CD3 binding component and an anti-GPC3 binding component for treating GPC3-associated cancers. A GPC3 antigen-binding domain is defined by a variable heavy domain and a variable light domain, and the domain comprises six CDRs from enumerated VH/VL pairs.
The disclosure specifies an explicit heterodimeric antibody architecture in which an anti-CD3 scFv is fused to one Fc monomer, while a GPC3 Fc monomer format is provided as a GPC3 VH2-CH1-hinge-CH2-CH3 monomer on the second position. The Fc heterodimerization is engineered using skew variants, and pI-lowering CH3/Fc variants, pI variants, and charged scFv linkers are described in modular antibody formats for adjusting antibody behavior while maintaining bispecific functionality.
The invention also addresses FcγR engagement through selected FcγR variants, including FcγR activation/inhibition tuning and FcγR ablation variants (FcKO/KO). The document enumerates multiple construction formats, including 1+1 Fab-scFv-Fc and 2+1 Fab2-scFv-Fc formats, and describes monomer valency and separation considerations, framework/linker/variant flexibility, and specific GPC3 ABD and CD3 ABD variable domain pairings, including named CDR/VH/VL combinations.
Claims Coverage
The provided material shows one independent claim, centered on a GPC3 antigen-binding domain defined by selected variable light and variable heavy domains from enumerated SEQ ID NO pairs.
GPC3 antigen binding domain defined by enumerated variable light and variable heavy sequences
A composition comprising a GPC3 antigen binding domain comprising a variable light domain and a variable heavy domain selected from the listed combinations of specific SEQ ID NO amino acid sequences.
The independent claim is limited to a GPC3 antigen-binding domain formed from specified variable light and variable heavy sequence pairings, with no additional independent claims provided.
Stated Advantages
Mitigation of cytokine release syndrome via altered CD3 affinity and monovalent CD3 engagement.
Documented Applications
Treating GPC3-associated cancers.
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