Antibody variable domains targeting the NKG2D receptor
Inventors
Chang, Gregory P. • Cheung, Ann F. • Grinberg, Asya • Haney, William • LUNDE, Bradley M. • Prinz, Bianka
Assignees
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Publication Number
US-11939384-B1
Publication Date
2024-03-26
Expiration Date
Abstract
Antibody heavy chain variable domains that can be paired with antibody light chain variable domains to form an antigen-binding site targeting the NKG2D receptor on natural killer cells are described. Proteins comprising an NKG2D antigen-binding site, pharmaceutical compositions and therapeutic methods thereof, including for the treatment of cancer, are also described.
Core Innovation
The disclosure provides a cancer immunotherapy method that treats a cancer in a patient in need thereof by administering an effective amount of a protein having an antigen-binding site that binds NKG2D and an additional antigen-binding site that binds a tumor-associated antigen expressed by the cancer. The NKG2D-binding antigen-binding site is defined by antibody heavy chain variable domain complementarity-determining region amino acid sequences and antibody light chain variable domain complementarity-determining region amino acid sequences using specified SEQ ID NOs.
The protein includes an antibody heavy chain variable domain of the NKG2D-binding antigen-binding site on a first polypeptide that further comprises a first antibody constant region, and an antibody heavy chain variable domain of the additional antigen-binding site on a second polypeptide that further comprises a second antibody constant region. The first antibody constant region and the second antibody constant region form a complex that binds CD16, linking NKG2D engagement with CD16 binding through a coupled constant-region complex.
The disclosure further describes NKG2D-targeting antibody variable domains and their pairing into NKG2D antigen-binding sites, including variants and sequence-identity ranges for the variable domains. Multispecific formats are described as including TriNKETs and multispecific proteins that combine NKG2D targeting with tumor antigen-binding and CD16 binding, with reported binding/activation and cytotoxicity against tumor cells expressing tumor-associated antigens.
Claims Coverage
The partial content provides one independent claim (clm-00001). It requires a cancer immunotherapy method based on administering a specific two-antigen-binding-site protein, with the NKG2D-binding site defined by particular antibody variable-domain CDR sequences and with constant regions configured to form a CD16-binding complex. Dependent claims are described as refining the NKG2D variable domains by fixed CDR sequences or identity thresholds and refining the antibody constant regions by domain composition and Fc choice/substitutions.
Protein with dual antigen-binding sites for NKG2D and a tumor-associated antigen
Administering to the patient an effective amount of a protein comprising an antigen-binding site that binds NKG2D and an additional antigen-binding site that binds a tumor-associated antigen expressed by the cancer.
NKG2D-binding heavy- and light-chain variable domains defined by specific CDR sequences
The antigen-binding site that binds NKG2D comprises an antibody heavy chain variable domain with CDR1, CDR2, and CDR3 amino acid sequences of specified SEQ ID NOs, and an antibody light chain variable domain with CDR1, CDR2, and CDR3 amino acid sequences of specified SEQ ID NOs.
Two-polypeptide architecture with constant-region complex that binds CD16
The antibody heavy chain variable domain of the antigen-binding site that binds NKG2D is present on a first polypeptide comprising a first antibody constant region, and the antibody heavy chain variable domain of the additional antigen-binding site is present on a second polypeptide comprising a second antibody constant region, wherein the first and second antibody constant regions form a complex that binds CD16.
Overall claim coverage centers on a cancer immunotherapy protein administered to a patient, with an NKG2D-binding site defined by specified heavy-chain and light-chain variable-domain CDR sequences, combined with an additional tumor-associated antigen-binding site, and arranged as a two-polypeptide constant-region complex that binds CD16.
Stated Advantages
Cross-species NKG2D binding (human and cynomolgus).
High affinity binding to NKG2D (KD reported on the order of ~10−62 nM).
Epitope binning indicates binding to a unique NKG2D epitope.
TriNKETs reported to induce NK-cell activation markers (CD107a and IFN-γ) and enhanced cytotoxicity against tumor cells expressing CD33 or HER2.
Documented Applications
Cancer immunotherapy for treating a cancer in a patient by administering an effective amount of a protein comprising NKG2D-binding and tumor-associated-antigen-binding sites configured with CD16-binding constant regions.
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