Multi-specific binding proteins binding BCMA, NKG2D and CD16 and methods of use
Inventors
Chang, Gregory P. • Cheung, Ann F. • Haney, William • LUNDE, Bradley M. • Prinz, Bianka
Assignees
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Publication Number
US-12760105-B2
Publication Date
2026-10-13
Expiration Date
Abstract
Multi-specific binding proteins that bind BCMA, the NKG2D receptor, and CD 16 are described, as well as pharmaceutical compositions and therapeutic methods useful for the treatment of cancer.
Core Innovation
The claimed multi-specific binding protein comprises a first antigen-binding site that binds and activates human NKG2D and a second antigen-binding site that binds BCMA. It further comprises two human IgG1 Fc domains with different amino acid mutations that promote heterodimerization and together are sufficient to bind CD16. This structure brings natural killer cells into proximity with BCMA-positive tumor cells.
The first antigen-binding site includes heavy- and light-chain variable domains on the same polypeptide, and both antigen-binding sites are linked to the N-termini of their respective Fc domains comprising hinge and CH2 domains. The disclosure reports NKG2D binding and activation, blockade of natural NKG2D ligands, natural killer cell activation readouts, and BCMA-directed lysis of myeloma cells by TriNKET-BCMA constructs.
Claims Coverage
The provided relevant claims identify one independent claim, claim 1, covering a multi-specific binding protein with three inventive features: NKG2D binding and activation, BCMA binding, and engineered heterodimerizing human IgG1 Fc domains that bind CD16.
NKG2D-binding and activating site
Claim 1 covers a first antigen-binding site that binds and activates human NKG2D, wherein the heavy- and light-chain variable domains are present on the same polypeptide.
BCMA-binding site
Claim 1 covers a second antigen-binding site that binds BCMA.
Heterodimerizing human IgG1 Fc domains that bind CD16
Claim 1 covers first and second human IgG1 Fc domains comprising different amino acid mutations that promote heterodimerization and together are sufficient to bind CD16, wherein each Fc domain comprises an N-terminus, hinge, and CH2 domains, and the respective antigen-binding sites link to the N-termini of the Fc domains.
The independent claim covers the combination of NKG2D binding and activation, BCMA binding, and engineered heterodimerizing human IgG1 Fc domains that bind CD16. Dependent claims further define binding-site sequences and Fc features, and include tumor-cell-death and cancer-treatment embodiments.
Stated Advantages
The reported studies describe natural killer cell activation and enhanced myeloma-cell lysis.
Combined NKG2D and CD16 stimulation is reported to produce increased natural killer cell degranulation and IFN-γ.
Documented Applications
Enhancing directly or indirectly the death of a BCMA-expressing tumor cell by exposing the cell and a natural killer cell to the multi-specific binding protein.
Treatment of BCMA-expressing cancers, including multiple myeloma, acute myelomonocytic leukemia, T cell lymphoma, acute monocytic leukemia, and follicular lymphoma.
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