Targeted heterodimeric Fc fusion proteins containing NKG2D antigen binding domains
Inventors
Bernett, Matthew J. • Desjarlais, John R. • Varma, Rajat • Moore, Gregory • Diaz, Juan • Nisthal, Alex • Liu, Ke • Rashid, Rumana • Chang, Eric
Assignees
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Publication Number
US-12448423-B2
Publication Date
2025-10-21
Expiration Date
Abstract
The present invention is directed to a novel targeted heterodimeric Fc fusion proteins comprising an IL-15/IL-15Rα Fc fusion protein and an NKG2D antigen binding domain Fc fusion proteins.
Core Innovation
The invention provides a targeted molecule that comprises an NKG2D antigen binding domain (ABD) with a variable heavy chain (VH) domain and a variable light chain (VL) domain. The VH domain has at least 95% amino acid sequence identity with SEQ ID NO: 1040, and the VL domain has at least 95% amino acid sequence identity with SEQ ID NO: 1041. The disclosed ABD is used in formats such as scFv, including scFv linkers and orientation variants, and Fab fragments.
The disclosed constructs are described in the context of targeted heterodimeric Fc fusion proteins, including IL-15/IL-15Rα Fc fusion monomer and an NKG2D ABD Fc fusion monomer, with IL-15 and IL-15Rα(sushi) variants. The disclosure further includes multiple Fc heterodimerization, pI/skew, and Fc ablation variant sets, as well as additional Fc-domain mutation sets and ABD formats that support claim-relevant construction elements.
The invention is described as steering IL-15 signaling toward CD8/NK responses by targeting NKG2D and modifying cytokine/receptor/effector functions, including the use of variant sets and Fc-related modifications. The document also describes cancer-treatment use and provides supporting implementations including nucleic acids, expression vectors, host cells, and protein production.
Claims Coverage
The claim coverage centers on one independent claim and its dependent refinements, with a total of six inventive features. The main coverage concerns an NKG2D ABD defined by VH and VL sequence identity requirements, followed by narrowing to higher identity thresholds, specified scFv or Fab formats, and a pharmaceutical composition including a pharmaceutically acceptable carrier.
Targeted molecule with nkg2d abd vh and vl sequence identity
A targeted molecule comprising an NKG2D antigen binding domain (ABD), said ABD comprising a variable heavy chain domain (VH domain) and a variable light chain domain (VL domain), wherein said VH domain has at least 95% amino acid sequence identity with SEQ ID NO: 1040 and said VL domain has at least 95% amino acid sequence identity with SEQ ID NO: 1041.
Targeted molecule with tightened nkg2d abd sequence identity
A targeted molecule wherein the VH domain has at least 97% amino acid sequence identity with SEQ ID NO: 1040 and the VL domain has at least 97% amino acid sequence identity with SEQ ID NO: 1041.
Nkg2d abd as scfv with covalent linker
The targeted molecule is specified such that the ABD is a single chain variable fragment (scFv) that includes a scFv linker covalently connecting the VH and VL domains.
Scfv linker orientation from n- to c-terminus
The targeted molecule is configured so that the ABD from the N- to C-terminus is oriented in the order VH-scFv linker-VL.
Nkg2d abd as fab fragment
The targeted molecule is specified to be an ABD Fab fragment.
Pharmaceutical composition including the targeted molecule
A pharmaceutical composition includes the targeted molecule along with a pharmaceutically acceptable carrier.
Overall, the claim set centers on an NKG2D-targeted ABD defined by VH and VL sequence identity to SEQ ID NO: 1040 and SEQ ID NO: 1041, with dependent claims narrowing to higher identity thresholds and specific ABD formats, including scFv with a covalent linker and defined N-to-C orientation, or an ABD Fab fragment. Additional coverage includes a pharmaceutical composition formulated with a pharmaceutically acceptable carrier.
Stated Advantages
Documented Applications
No documented applications found
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