Humanized anti-nuclear antibodies for targeting necrosis in cancer therapy

{
  "publication_number": "US12258421B2",
  "country": "US",
  "kind": "B2",
  "title": "Humanized anti-nuclear antibodies for targeting necrosis in cancer therapy",
  "abstract": "Humanized monoclonal anti-nuclear antibodies with enhanced binding affinity and tumor uptake are presented. Particularly preferred antibodies are site-directed mutants of H-CDR3 with up to about 8-fold improvement in affinity as compared to the non-humanized non-mutated form. In further preferred aspects, such humanized antibodies are employed in tumor necrosis targeted delivery of immune modulators, immune effectors, and other therapeutic or diagnostic agents.",
  "claims": [
    "1. A hybrid molecule comprising a binding portion of an antibody coupled to an immune stimulatory agent, wherein the binding portion comprises a heavy chain (VH) with three complementarity determining regions (H-CDRs) and a light chain (VL) with three CDRs (L-CDRs), wherein H-CDR1 comprises SEQ ID NO: 1, H-CDR2 comprises SEQ ID NO:2, H-CDR3 comprises a sequence selected from the group consisting of SEQ ID NOs:27-34, L-CDR1 comprises SEQ ID NO:4, L-CDR2 comprises SEQ ID NO:5, and L-CDR3 comprises SEQ ID NO:6.",
    "2. The hybrid molecule of claim 1, wherein H-CDR3 comprises SEQ ID NO:29.",
    "3. The hybrid molecule of claim 1, wherein the VH sequence has at least 90% sequence identity to SEQ ID NO:7.",
    "4. The hybrid molecule of claim 1, wherein the VL sequence has at least 90% sequence identity to SEQ ID NO:8.",
    "5. The hybrid molecule of claim 1, wherein the VH sequence has at least 96% sequence identity to SEQ ID NO:7.",
    "6. The hybrid molecule of claim 1, wherein the VL sequence has at least 96% sequence identity to SEQ ID NO:8.",
    "7. The hybrid molecule of claim 1, wherein the binding portion comprises an Fab fragment, an F(ab′)2 fragment, an Fab2 fragment, or an scFv.",
    "8. The hybrid molecule of claim 1, wherein the immune stimulatory agent comprises a cytokine, wherein the cytokine is selected from a list comprising IL-2, IL-12, IL15, IL-15 superagonists, and TLR agonists.",
    "9. The hybrid molecule of claim 1, wherein the immune stimulatory agent is an IL-15 superagonist.",
    "10. The hybrid molecule of claim 1, wherein the immune stimulatory agent is IL-12.",
    "11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the hybrid molecule of claim 1.",
    "12. A method of targeting a necrotic cell, the method comprising contacting the necrotic cell with the hybrid molecule of claim 1.",
    "13. The method of claim 12, wherein the hybrid molecule contacts the necrotic cell in vivo.",
    "14. The method of claim 12, wherein the hybrid molecule contacts the necrotic cell ex vivo.",
    "15. A method of delivering an immune stimulatory agent to a tumor microenvironment containing necrotic tumor cells, the method comprising contacting the necrotic tumor cells in the microenvironment with the hybrid molecule of claim 1 under conditions that allow the binding domain to bind to a nuclear target in the necrotic cell.",
    "16. The method of claim 15, wherein the tumor is a solid tumor.",
    "17. The method of claim 15, further comprising a step of administering a vasculature permeability enhancing agent."
  ],
  "description_excerpt": "The presently claimed invention was made by one or more parties to a joint research agreement that has been in effect since 18 Apr. 2016. The parties to the agreement are (1) NantCell, Inc. (a Delaware corporation) and (2) Cancer Therapeutics Laboratories, Inc. (a California corporation).\n\nThe field of the invention is antibodies, and especially humanized antibodies that target necrosis in a tumor.\n\nThe background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.\n\nAll publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.\n\nPreviously monoclonal antibodies directed against universal, intracellular antigens that become accessible after cell death have been employed in immunotherapy of solid tumors (see e.g., Cancer Research, 48:5842-5848, 1988; Hybridoma, 12(6):689-698, 1993; or Cancer Biotherapy & Radiopharmaceuticals, 13(4):255-68, 1998).",
  "cpc": [
    "C07K 16/44",
    "A61K 2039/505",
    "A61K 2039/54",
    "A61K 39/00",
    "A61K 47/6801",
    "A61K 51/10",
    "A61K 51/1093",
    "A61K 9/0019",
    "A61P 35/00",
    "C07K 16/005",
    "C07K 2317/24",
    "C07K 2317/565",
    "C07K 2317/567",
    "C07K 2317/622",
    "C07K 2317/92",
    "C12N 15/1058"
  ],
  "ipc": [
    "A61K 47/68",
    "A61K 51/10",
    "C07K 16/00",
    "C07K 16/44",
    "C12N 15/10",
    "A61K 39/00",
    "A61K 39/395",
    "A61P 31/18",
    "C12N 5/077"
  ],
  "assignees": [
    "Cancer Therapeutics Laboratories Inc"
  ],
  "inventors": [
    "Alan Epstein",
    "Peisheng Hu"
  ],
  "filing_date": "2022-06-14",
  "publication_date": "2025-03-25",
  "grant_date": "2025-03-25",
  "priority_date": "2017-03-20",
  "application_number": "US-202217839953-A",
  "family_id": "63584724",
  "cited_by_count": 1,
  "citations": [
    "WO2004074437A2",
    "US20130115674A1",
    "WO2015106290A1",
    "US20160235859A1",
    "WO2017011411A1",
    "US20180200366A1"
  ]
}