Antibody variable domains targeting the NKG2D receptor
Inventors
Chang, Gregory P. • Cheung, Ann F. • Grinberg, Asya • Haney, William • LUNDE, Bradley M. • Prinz, Bianka
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12264200-B2
Publication Date
2025-04-01
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 disclosed invention relates to an antigen-binding site that binds NKG2D. The antigen-binding site comprises an antibody heavy chain variable domain with a complementarity-determining region 1 (CDR1) amino acid sequence of SEQ ID NO: 48, a CDR2 amino acid sequence of SEQ ID NO: 30, and a CDR3 amino acid sequence of SEQ ID NO: 71, together with an antibody light chain variable domain with a CDR1 amino acid sequence of SEQ ID NO: 32, a CDR2 amino acid sequence of SEQ ID NO: 33, and a CDR3 amino acid sequence of SEQ ID NO: 34. The NKG2D-targeting antibody variable domains are described as Kabat-determined CDRs and as antigen-binding sites that bind and agonize NKG2D.
The disclosure states that the antibody binding competes with natural ligand binding and exhibits high-affinity binding to NKG2D, with binding affinities reported in the range of approximately 10−62 nM. Binding characterization includes measured binding affinities using surface plasmon resonance (SPR) and epitope binning indicating unique epitopes for certain clones.
The disclosed material further describes optional combinations of the NKG2D-binding variable domains with Fc/constant-region domains and multi-specific formats. The disclosure includes combination into tumor antigen-binding plus CD16-binding Fc-containing proteins such as TriNKETs, and describes TriNKETs activating NK cells and mediating cytotoxicity.
Claims Coverage
The claim coverage centers on one independent claim directed to a specific NKG2D-binding antigen-binding site defined by particular heavy- and light-chain variable domain CDR amino-acid sequences. Dependent claims add sequence-identity constraints, an additional antigen-binding site, Fc/constant-region formats that bind CD16, and specific constant-region substitutions using Kabat EU numbering.
NKG2D-binding antigen-binding site defined by CDR sequences
An antigen-binding site that binds NKG2D, comprising an antibody heavy chain variable domain comprising CDR1 of SEQ ID NO: 48, CDR2 of SEQ ID NO: 30, and CDR3 of SEQ ID NO: 71; and an antibody light chain variable domain comprising CDR1 of SEQ ID NO: 32, CDR2 of SEQ ID NO: 33, and CDR3 of SEQ ID NO: 34.
NKG2D-binding variable domains with sequence-identity constraints
The antibody heavy and light chain variable domains have amino acid sequences at least 95% identical to SEQ ID NO: 7 and SEQ ID NO: 8, respectively, within the antigen-binding site.
Additional antigen-binding site in a protein
A protein that includes the antigen-binding site and an additional antigen-binding site.
CD16-binding complex formed by antibody constant regions
A protein in which first and second antibody constant regions form a complex that binds CD16.
Kabat EU constant-region point substitutions
A protein in which the first antibody constant region includes a Y349C substitution and the second antibody constant region includes an S354C substitution, using Kabat EU numbering.
Overall, the claim coverage centers on a specific NKG2D-binding antigen-binding site defined by particular heavy- and light-chain CDR sequences, and is narrowed and expanded through dependent claim features including sequence-identity constraints, inclusion of an additional antigen-binding site, CD16-binding constant-region complex formation, and specified constant-region substitutions referenced to Kabat EU numbering.
Stated Advantages
Binds and agonizes NKG2D.
Competes with natural ligand binding.
Exhibits high-affinity binding to NKG2D (reported KDs approximately in the 10−62 nM range).
Activates NK cells and mediates cytotoxicity in connection with TriNKETs.
Documented Applications
Cancer treatment and enhancing tumor cell death are described in connection with NKG2D-targeting antibodies and multi-specific formats such as TriNKETs.
Functional evaluation of NK-cell activation and cytotoxicity using assays described in the partial content, including IFN-gamma and CD107a endpoints.
Interested in licensing this patent?