Nkg2d-nkp46 cell adapter molecule and use thereof

{
  "publication_number": "US2026103524A1",
  "country": "US",
  "kind": "A1",
  "title": "Nkg2d-nkp46 cell adapter molecule and use thereof",
  "abstract": "An NK cell adapter molecule targeting an NKG2D ligand and an NKp46 and the use thereof are provided. The cell adapter molecule at least comprises: a first binding domain comprising an NKG2D extracellular domain that can specifically bind to the NKG2D ligand; and a second binding domain comprising an NKp46 antigen-binding fragment. The cell adapter molecule can promote the killing effect of natural killer cells on target cells with high levels of expression of NKG2D ligand, and can thus be used as a therapeutic agent for diseases related to NKG2D ligand expression.",
  "claims": [
    "1. A cell engager molecule comprising: (a) a first binding domain that specifically binds to a NKG2D ligand; and (b) a second binding domain that specifically binds to NKp46. 2. The cell engager molecule according to claim 1, wherein the first binding domain is derived from an extracellular domain of NKG2D. 3. The cell engager molecule according to claim 1, wherein the amino acid sequence of the first binding domain is as shown in SEQ ID NO: 1; or is an amino acid sequence that has at least 95% sequence homology or sequence identity to the amino acid sequence as shown in SEQ ID NO: 1 and is capable of binding to a NKG2D ligand. 4. The cell engager molecule according to claim 1, wherein the second binding domain comprises an antigen-binding fragment specifically against NKp46. 5. The cell engager molecule according to claim 4, wherein the antigen-binding fragment against NKp46 comprises: an Fab fragment, a single-chain antibody (scFv), a single-domain antibody, and a combination thereof. 6. The cell engager molecule according to claim 5, wherein the Fab fragment and/or single-chain antibody against NKp46 comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following heavy chain complementarity-determining regions (HCDRs): 1) HCDR1 with the amino acid sequence as shown in SEQ ID NO: 3; 2) HCDR2 with the amino acid sequence as shown in SEQ ID NO: 4; 3) HCDR3 with the amino acid sequence as shown in SEQ ID NO: 5; and the light chain variable region comprises the following light chain complementarity determining regions (CDRs): 1) LCDR1 with the amino acid sequence as shown in SEQ ID NO: 6; 2) LCDR2 with the amino acid sequence YTS; 3) LCDR3 with the amino acid sequence as shown in SEQ ID NO: 7. 7. The cell engager molecule according to claim 5, wherein the anti-NKp46 single-domain antibody comprise the following heavy chain complementarity-determining regions: 1) HCDR1 with the amino acid sequence as shown in SEQ ID NO: 3; 2) HCDR2 with the amino acid sequence as shown in SEQ ID NO: 4; 3) HCDR3 with the amino acid sequence as shown in SEQ ID NO: 5. 8. The cell engager molecule according to claim 1, wherein the second binding domain further comprises: an antigen-binding fragment derived from an anti-CD16 antibody and/or a polypeptide of an IL15 protein. 9. A recombinant protein comprising the cell engager molecule according to claim 1. 10. A polynucleotide which encodes the cell engager molecule according to claim 1. 11. A vector comprising the polynucleotide according to claim 10. 12. A engineered host cell, wherein the host cell comprises the vector according to claim 11. 13. An antibody conjugate which comprises: (a) an antibody moiety, which is the cell engager molecule according to claim 1; and (b) a coupling moiety coupled to the antibody moiety, which is selected from the group consisting of a detectable label, a drug, and a combination thereof. 14. A pharmaceutical composition which comprises: (a) an active ingredient selected from the group consisting of: the cell engager molecule according to claim 1, a recombinant protein comprising the cell engager molecule, and a combination thereof; and (b) one or more pharmaceutically acceptable carriers, diluents, fillers, binders, excipients, or a combination thereof. 15 - 20. (canceled) 21. The cell engager molecule according to claim 1, wherein the amino acid sequence of the first binding domain is as shown in SEQ ID NO: 1; or is an amino acid sequence that has at least 95% sequence homology or sequence identity to the amino acid sequence as shown in SEQ ID NO: 1 and is capable of binding to a NKG2D ligand; and the second binding domain comprises an Fab fragment, a single-chain antibody (scFv) or a single-domain antibody that specifically targets NKp46; wherein the Fab fragment and/or single-chain antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the following heavy chain complementarity-determining regions (HCDRs): 1) HCDR1 with the amino acid sequence as shown in SEQ ID NO: 3; 2) HCDR2 with the amino acid sequence as shown in SEQ ID NO: 4; 3) HCDR3 with the amino acid sequence as shown in SEQ ID NO: 5; and the light chain variable region comprises the following light chain complementarity determining regions (CDRs): 1) LCDR1 with the amino acid sequence as shown in SEQ ID NO: 6; 2) LCDR2 with the amino acid sequence YTS; 3) LCDR3 with the amino acid sequence as shown in SEQ ID NO: 7; and the NKp46 single-domain antibody comprise the following heavy chain complementarity-determining regions: 1) HCDR1 with the amino acid sequence as shown in SEQ ID NO: 3; 2) HCDR2 with the amino acid sequence as shown in SEQ ID NO: 4; 3) HCDR3 with the amino acid sequence as shown in SEQ ID NO: 5. 22. A method for treating a disease associated with upregulated NKG2D ligand expression, wherein the method comprising administering the cell engager molecule according to the claim 1 to a subject in need thereof. 23. The method according to claim 22, wherein the NKG2D ligand is selected from the group consisting of: MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, and a combination thereof. 24. The method according to claim 22, wherein the disease includes tumors, autoimmune diseases, transplant rejection, inflammation, aging, and diseases associated with senescent cell accumulation. 25. The method according to claim 24, wherein the tumor is selected from the group consisting of: acute myeloid leukemia (AML), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), lung cancer, ovarian cancer, colorectal cancer, liver cancer, gallbladder cancer, biliary tract cancer, gastric cancer, pancreatic cancer, kidney cancer, prostate cancer, breast cancer, bladder cancer, nasopharyngeal cancer, non-small cell lung cancer, glioblastoma, neuroblastoma, melanoma, and a combination thereof. 26. The method according to claim 24, wherein the disease associated with senescent cell accumulation expressing NKG2D ligands is selected from the group consisting of: muscular atrophy, fatty liver, heart failure, atherosclerosis, diabetes, myocardial hypertrophy, osteoporosis, tissue/organ fibrosis, Alzheimer's disease, Parkinson's syndrome, arthritis, chronic obstructive pulmonary disease, and other degenerative diseases caused by cellular senescence, and a combination thereof."
  ],
  "description_excerpt": "The present invention relates to the field of biomedicine, and particularly relates to a cell engager molecule consisting of an NKG2D extracellular domain capable of specifically binding to a NKG2D ligand, a linker segment, and an NKp46 antigen-binding fragment, and the application thereof.\n\nNKG2D is expressed on the surface of NK cells, CD8 T cells, activated macrophages, and tumor-infiltrating γδ T cells, typically existing as a self-formed homodimer. It directly activates NK cells through the adaptor proteins DAP10 or DAP12 to exert cytotoxic effects or acts as a co-stimulatory signal to promote T cell activation. Its ligands mainly include MICA, MICB, and ULBP1-6, which are generally not expressed or are expressed at low levels in normal cells. However, when cells are under stress conditions such as abnormal transformation, viral infection, or DNA damage, the expression of NKG2D ligands can be significantly upregulated, serving as markers of abnormal cells for recognition by the immune system. The NKG2D-NKG2D ligand signaling chain is a crucial mechanism for the immune surveillance function of the body's immune system. Immunotherapy strategies targeting this pathway are expected to have better safety and efficacy and have gradually become a frontier area in current immunotherapy approaches To date, more than 10 CAR-T and CAR-NK therapies designed based on the NKG2D-NKG2DL mechanism have entered clinical studies, with no severe treatment-related adverse events reported. Cell engager molecules constructed based on the NKG2D extracellular domain have also gained increasing attention in the field of anti-tumor therapy.",
  "cpc": [
    "C07K 16/2851",
    "A61K 47/6879",
    "A61P 35/00",
    "C07K 14/5443",
    "C07K 16/2803",
    "C07K 16/283",
    "C07K 2317/31",
    "C07K 2317/55",
    "C07K 2317/565",
    "C07K 2317/569",
    "C07K 2317/622",
    "C07K 2319/00"
  ],
  "ipc": [
    "A61K 47/68",
    "A61P 35/00",
    "C07K 14/54",
    "C07K 16/28"
  ],
  "assignees": [
    "West China Hospital of Sichuan University"
  ],
  "inventors": [
    "Xudong Zhao",
    "Dong Yang"
  ],
  "filing_date": "2023-09-18",
  "publication_date": "2026-04-16",
  "priority_date": "2022-09-16",
  "application_number": "US-202319112408-A",
  "family_id": "86021788",
  "cited_by_count": 0
}