Bispecific binding agents binding to CLDN18.2 and CD3
Inventors
Bernett, Matthew • Nisthal, Alex • Moore, Gregory
Assignees
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Publication Number
US-12378313-B2
Publication Date
2025-08-05
Expiration Date
Abstract
The present invention provides binding agents comprising at least two binding domains, wherein a first binding domain has specificity for CLDN18.2 and a second binding domain has specificity for CD3, and methods of using these binding agents or nucleic acids encoding therefor for treating cancer.
Core Innovation
The document describes engineered bispecific binding agents that bind CLDN18.2 and CD3 using defined antibody variable-region pairs. The constructs include a first and a second VH/VL pair that bind CLDN18.2 and a third VH/VL pair that binds CD3, with variable-region composition specified using VH and VL domains and corresponding CDR amino-acid sequences.
The described formats include Fab-scFv and Fab2-scFv binding agent architectures, as well as trimer and tetramer multichain architectures. The variable-region pairing is engineered by selecting CLDN18.2-specific VH/VL regions for the CLDN18.2 binding sites and a CD3-specific VH/VL region for the CD3 binding site, yielding bispecific agents with multiple CLDN18.2 binding interactions and a CD3 engagement module.
The document further describes domain organization and inter-domain connectivity, including use of a scFv linker and inter-domain peptide linkers with defined disulfide-link connectivity between chain regions. Optional modifications are described, including Fc modifications, skew modifications, pI modifications, and ablation modifications, aimed at promoting chain interaction while maintaining CLDN18.2/CD3 binding. Humanization effects are also discussed as preserving binding and immune effector function.
The document describes bispecific binding agents for cancer immunotherapy that bind CLDN18.2 on tumor cells and CD3 on T cells. The bispecific binding agents are configured to form a cytotoxic T-cell-target complex, i.e., redirected T cell cytotoxicity (RTCC), and include related concepts for nucleic acids, vectors, host cells, and pharmaceutical compositions.
Claims Coverage
The provided independent claims cover bispecific binding agents that bind CLDN18.2 and CD3 using defined VH/VL pairs with specified CDR amino-acid sequences, with claim coverage also including a multichain polypeptide architecture with heavy-chain and light-chain constant regions and additional structural constraints.
Bispecific binding agent with CLDN18.2 VH/VL pairs and CD3 VH/VL pair
A bispecific binding agent that binds CLDN18.2 and CD3 comprising first, second, and third VH/VL pairs, wherein the first and second VH/VL pairs bind CLDN18.2 and the third VH/VL pair binds CD3, with specified CDR amino-acid sequences for the VH and VL regions.
Multichain CLDN18.2/CD3 bispecific with defined heavy-chain and light-chain constant regions
A bispecific binding agent comprising a first polypeptide chain with VH1, CH1, CH2, and CH3; a second polypeptide chain with VL1 and CL; a third polypeptide chain with VL2 and CL; and a fourth polypeptide chain with VH2 and CH1, a VH3 and a VL3 (or a VL3 and a VH3), and CH2 and CH3, wherein VH1 and VL1 bind to CLDN18.2, VH2 and VL2 bind to CLDN18.2, and VH3 and VL3 bind to CD3.
The independent claims require bispecific binding agents that bind CLDN18.2 and CD3 through specifically defined VH/VL pairs with explicit CDR amino-acid sequences. The multichain claim further constrains the architecture to specified heavy-chain and light-chain constant regions and maps the VH/VL components to CLDN18.2 versus CD3 binding.
Stated Advantages
Redirected T cell cytotoxicity (RTCC) with cytotoxic T-cell-target complex formation.
Reduced off-target binding to CLDN18.1 and CLDN9.
Improved potency associated with multivalency formats.
Preservation of binding after humanization.
Immune effector activity associated with RTCC and T-cell activation markers, including CD69, CD25, and CD107a.
Documented Applications
Treating cancers in a subject where the cancer cells express CLDN18.2, including gastric, esophageal, and GEJ cancers and metastases, including peritoneal and lymph node metastasis.
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