Multi-specific binding proteins that bind BCMA, NKG2D and CD16, and methods of use
Inventors
Bigelow, Mitchell • Chang, Gregory P. • Cheung, Ann F. • Grinberg, Asya • Haney, William • Wagtmann, Nicolai • LUNDE, Bradley M. • Prinz, Bianka • Wei, Ronnie • Fallon, Daniel • O'Neil, Steven
Assignees
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Publication Number
US-12384851-B2
Publication Date
2025-08-12
Expiration Date
Abstract
Multi-specific binding proteins that bind to and kill human cancer cells are described, as well as pharmaceutical compositions and therapeutic methods useful for the treatment of cancer. The cancer can be B-cell maturation antigen (BCMA)-expressing cancer. The multi-specific binding proteins provided herein exhibit high potency and maximum lysis of target cells compared to anti-BCMA monoclonal antibodies.
Core Innovation
The document describes an NKG2D/BCMA/CD16 multi-specific protein comprising an NKG2D-binding single-chain variable fragment, two BCMA-binding antigen-binding sites, and a CD16-binding antibody Fc domain or portion thereof. These proteins recruit and activate natural killer cells and cytotoxic T cells against BCMA-expressing cancers. Disclosed embodiments include F4-TriNKET® and F3-TriNKET® architectures, as well as a multi-specific protein comprising four polypeptides.
Reported results demonstrate greater and more potent natural killer cell lysis of BCMA-positive myeloma cells with F4-TriNKET® than with an anti-BCMA monoclonal antibody or monovalent TriNKET, showing subnanomolar activity. The protein increases surface BCMA, stimulates natural killer cell activation, and enhances tumor-cell lysis by activated CD8+ T cells. The background section and the specific problem being solved are not included in the provided patent content.
Claims Coverage
The provided claims identify four independent claims covering four inventive features: claims 1, 25, 26, and 29, which encompass three multi-specific protein formats and a four-polypeptide protein.
NKG2D-, BCMA-, and CD16-binding protein
Claim 1 covers a protein with an NKG2D-binding scFv, two BCMA-binding antigen-binding sites, and a CD16-binding antibody Fc domain or portion thereof, where the binding sites are defined by specified CDR sequences and the CD16-binding portion has a specified sequence identity relationship to human IgG1 Fc residues.
Alternative NKG2D-binding site in the multi-specific protein
Claim 25 covers the NKG2D-, BCMA-, and CD16-binding architecture using a different specified set of CDR sequences for the NKG2D-binding scFv, with the BCMA-binding sites and Fc portion defined by specified sequence features.
Framework-substituted multi-specific protein
Claim 26 covers a protein with an NKG2D-binding scFv containing specified framework substitutions in its heavy- and light-chain variable regions, two BCMA-binding antigen-binding sites, and a CD16-binding antibody Fc domain or portion thereof.
Protein comprising four defined polypeptides
Claim 29 covers a protein comprising a first polypeptide, a second polypeptide, and third and fourth polypeptides, each defined by amino acid sequences specified in the claim.
The independent claims cover alternative binding-site configurations and framework substitutions for an NKG2D/BCMA/CD16 multi-specific protein, as well as a four-polypeptide protein embodiment.
Stated Advantages
F4-TriNKET® produces greater potency and maximum target-cell lysis of BCMA-positive myeloma cells than an anti-BCMA monoclonal antibody or monovalent TriNKET.
F4-TriNKET® increases surface BCMA and natural killer cell activation.
F4-TriNKET® enhances tumor-cell lysis by activated CD8+ T cells.
The document reports subnanomolar activity against myeloma cells.
Documented Applications
Cancer treatment, including BCMA-expressing cancers, multiple myeloma, leukemias, and B-cell lymphomas.
Combination cancer therapy with chemotherapy, checkpoint inhibitors, targeted agents, cytokines, or surgery.
Pharmaceutical compositions in liquid or lyophilized formulations for intravenous administration.
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