{
  "abstract": "Background OX40 (TNFR4) is an immunostimulatory receptor expressed in activated T-cells. The OX40-OX40L (ligand of OX40) interaction plays a crucial role in the enhancement of T-cell proliferation, survival and cytokine production. OX40-mAbs were widely tested for immunotherapy in solid tumors (agonist), and autoimmune diseases (antagonist), with well-known pharmacology profiles. We/others observed significant high-level OX40-expression in many types of lymphoma samples from patients, as well as patient- (PDX) or cell line (CDX) derived xenografts where T-cell is absent. The lymphoma subtypes include nearly all adult T-cell lymphoma/leukemia (ATL), angioimmunoblastic T-cell lymphoma (AITL), NK/T-cell lymphoma, histiocytic lymphoma, and selected DLBCLs, etc., all being unmet medical needs. We recently discovered an OX40-mAb with high binding to an epitope outside OX40L interaction areas (non-blocker) that can efficiently internalize into OX40+ lymphoma cells. We hypothesized that the ADC of this mAb, named HX111, could potentially be a candidate treatment for these lymphomas.Methods The naked mAb was conjugated to VC-MMAE to form a novel ADC, HX111, with an average DAR value of 4. Internalization and in vitro cytotoxicities of HX111 was tested in a number of OX40+ lymphoma cell lines. It was also tested several lymphoma-CDX and -PDXs for their anti-lymphoma pharmacology.Results VC-MMAE was chosen as the linker-payload of HX111 for its proven efficient killing of lymphoma cells, as shown by Adcetris. HX111 or its naked mAb were found to efficiently internalize into many OX40+ lymphoma cell lines ( e.g. HuT-102, Hut78 and Jurkat) and induced strong cytotoxicity in vitro, superior to many other OX40-mAbs tested. HX111 is also featured with strong bystander effects in a HuT-102 (OX40+) and Raji (OX40-) coculture assay. Standard pharmacology evaluation demonstrated its strong and dose-dependent anti-lymphoma activities in several OX40+ lymphoma xenografts including four lymphoma-CDXs, (HuT-102 (ATL), HuT-78 (ATL), GRANTA-519 (mantle cell lymphoma), and ARH-77 (plasma cell lymphoma)), and four DLBCL-PDXs (LY6698, LY3654, LY2219, and LY3161), as well as an AITL-PDX (LY9596). The degree of efficacies was not necessarily always correlated to the levels of OX40-expressions. In addition, we also observed enhanced anti-lymphoma effects when HX111 combined with an immune checkpoint inhibitor, HX009,1 2 a BsAb of PD-1 x SIRPα in the LY6698 B-lymphoma PDX.Conclusions The lymphoma-associated OX40-expression can be explored for the treatment of OX40+ T-cell or B-cell lymphomas, both being unmet medical needs, and HX111 could potentially be such a candidate treatment, warranting further clinical investigation.References Ke H, et al. Preclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody. Sci Rep. 2024;14(1):28201.Ke H, et al. HX009, a novel BsAb dual targeting PD1 x CD47, demonstrates potent anti-lymphoma activity in preclinical models. Sci Rep. 2023;13(1):5419.Ethics Approval All animal studies were conducted at SPF facility in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the IACUC Committee.",
  "authors": [
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Tao Yang"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China",
        "Hanx Biopharmaceuticals, Inc., Wuhan, HuBei Province, China"
      ],
      "name": "Hang Ke"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Inc., Wuhan, HuBei Province, China"
      ],
      "name": "Feiyu Peng"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Jialin Li"
    },
    {
      "affiliations": [
        "Crown Bioscience Inc., San Diego, CA, USA"
      ],
      "name": "Cen Chen"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Lei Zhang"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Faming Zhang"
    },
    {
      "affiliations": [
        "Hanx Bioharmaceuticals Inc., Oceanside, CA, USA"
      ],
      "name": "Henry Li"
    }
  ],
  "title": "1183 HX111, a FIC OX40-mAb-VC-MMAE ADC for the treatment of lymphoma",
  "uid": "0169e409-eebb-5791-9bc5-3ba003146fbd"
}