Proteins binding NKG2D, CD16 and a tumor-associated antigen
Inventors
Chang, Gregory P. • Cheung, Ann F. • DU, Jinyan • Fallon, Daniel • Grinberg, Asya • Haney, William • LUNDE, Bradley M. • O'Neil, Steven • Prinz, Bianka • Wei, Ronnie
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12378318-B2
Publication Date
2025-08-05
Expiration Date
Abstract
Multi-specific binding proteins that bind NKG2D receptor, CD 16, and a tumor-associated antigen selected from c-MET, KIT, F3, IGF1R, Lewis Y, MUC13, MUC4, MCAM, LRRC32, sialyl-Tn, gpA33, GD3, GM2, EPHA3, TNFRSF10A, TNFSF11, CD74, and PMEL are described, as well as pharmaceutical compositions and therapeutic methods useful for the treatment of cancer.
Core Innovation
The invention provides a trispecific binding protein comprising an Fc region that binds CD16 and antigen-binding sites that bind NKG2D and cMET. The protein comprises three polypeptides, including an NKG2D-binding Fab fragment and a cMET-binding scFv, with the Fc region formed across the polypeptides. This molecular architecture engages immune-cell receptors and a tumor-associated antigen to promote natural-killer-cell-mediated tumor-cell killing.
The protein demonstrates NKG2D binding, competition with natural ligands, primary natural killer cell activation, enhanced CD107a degranulation, and IFN-γ production. Cross-linking NKG2D and CD16 produces greater natural killer cell activation than individual receptor stimulation, and cMET-targeting proteins induce lysis of HT29 and HCT-116 cells exceeding monoclonal-antibody controls. Furthermore, bivalent tumor-antigen engagement strengthens binding and cytotoxicity, including against cells with low antigen expression.
Claims Coverage
The claims comprise two independent claims directed to trispecific binding proteins that bind CD16, NKG2D, and cMET across three polypeptides, encompassing two inventive features.
Three-polypeptide trispecific binding protein
A protein comprising an Fc region that binds CD16, an NKG2D-binding Fab fragment, and a cMET-binding scFv arranged across three polypeptides, with specified complementarity-determining regions and variable domain configurations.
Specified binding domains and IgG1 Fc structure
An IgG1 embodiment of the three-polypeptide protein specifying variable-domain sequences, a linker and disulfide-bridge arrangement in the cMET-binding scFv, and chain-specific modifications within the Fc region.
The independent claims cover trispecific proteins targeting CD16, NKG2D, and cMET, establishing the baseline three-polypeptide architecture and further structural specifications for the scFv and IgG1 Fc region.
Stated Advantages
The NKG2D-binding domains show high apparent melting temperatures.
Cross-linking NKG2D and CD16 produces greater natural killer cell activation than stimulation of either receptor individually.
cMET-targeting TriNKETs drive natural killer cell lysis with subnanomolar potency and produce greater specific lysis than corresponding monoclonal-antibody controls.
Bivalent tumor-antigen engagement strengthens binding and cytotoxicity, including against cells with low antigen expression.
The proteins promote natural-killer-cell-mediated tumor-cell killing, enhanced CD107a degranulation, and IFN-γ production.
Documented Applications
Cancer treatment using trispecific binding proteins that engage immune-cell targets and tumor-associated antigens such as cMET.
Binding and natural-killer-mediated lysis of HT29 and HCT-116 tumor cells using cMET-targeting TriNKET constructs.
Pharmaceutical formulations of the trispecific binding proteins.
Interested in licensing this patent?