{
  "abstract": "Background Sarcomas are a diverse group of malignant mesenchymal tumors of varying histopathology and treatment responsiveness (mainly radiation/chemotherapies), including many with poor prognosis and being unmet medical needs. Tumor necrosis factor receptor superfamily member 4 (TNFR4), or OX40, is an immunostimulatory receptor usually 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. 1 OX40 monoclonal antibodies (mAbs) have widely been tested for immunotherapy for solid tumors (agonist), as well as for autoimmune diseases (antagonist), with well-known pharmacology profiles.1 2 We recently described an OX40-mAb with high binding affinity to an OX40-epitope outside the OX40-OX40L interaction areas (so a non-blocker). In the present study, we discovered the significant expression of OX40 in some solid tumor cells, particularly from certain sarcoma patients and patient-derived xenograft (PDXs, absence of T-cells), in addition to the previously known in many types of lymphomas. This prompted us to hypothesize that a novel OX40-ADC, named HX111, could potentially be a candidate treatment for these OX40-positive sarcomas.Methods Sarcoma-patient and PDX samples were evaluated for OX40-expression detected by either RNAseq or IHC. The naked OX40-mAb was conjugated to VC-MMAE to form a novel ADC, HX111, with an average DAR-value of 4. HX111 was also tested in a number of OX40+ sarcoma or other solid tumor PDX models for its anti-sarcoma pharmacology.Results We found that many samples of sarcoma patients and PDXs of different histopathology, including, but not limited to, osteosarcoma, Ewing’s sarcoma, liposarcoma, myxofibrosarcoma, synovia sarcoma, spindle cell sarcoma, etc., expressing OX40 on tumor cells, as clearly demonstrated by IHC as well as single-cell sequencing data analysis. HX111 also demonstrated strong anti-sarcoma activities in a couple of sarcoma-PDX in vivo models (e.g. SA12961 and SA4225). We have also noticed many other solid tumor PDXs including breast cancer, cervical cancers, and head&neck squamous carcinoma (HNSCs), etc., also express OX40 on the tumor cells. Some of them, with various expression levels of OX40, are also responsive to HX111 (e.g. HN9285, HN2400, CV10941 and BR1458).Conclusions The sarcoma-associated OX40-expression can be explored for the treatment of OX40+ sarcoma and other solid tumors, where HX111 could potentially be a candidate treatment, warranting further clinical investigation.References Gutierrez M, et al, OX40 Agonist BMS-986178 alone or in combination with nivolumab and/or ipilimumab in patients with advanced solid tumors. Clin Cancer Res. 2021;27(2):460–472.Guttman-Yassky E, et al, An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. Lancet. 2023;401(10372).Ethics Approval All patient samples were collected and tested with institutional ethic committee approvals, along with informed consents. 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": [
        "Renmin Hospital, Beijing, China"
      ],
      "name": "Lu Xie"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Tao Yang"
    },
    {
      "affiliations": [
        "Renmin Hospital, Beijing, China"
      ],
      "name": "Yuhang Wang"
    },
    {
      "affiliations": [
        "Crown Bioscience, Inc., Suzhou, Jiangsu Province, China"
      ],
      "name": "Zihan Xu"
    },
    {
      "affiliations": [
        "Renmin Hospital, Beijing, China"
      ],
      "name": "Jie Xu"
    },
    {
      "affiliations": [
        "Renmin Hospital, Beijing, China"
      ],
      "name": "Tingting Ren"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Hang Ke"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Inc, Wuhan, HuBei Province, China"
      ],
      "name": "Feiyu Peng"
    },
    {
      "affiliations": [
        "Crown Bioscience, Inc., Suzhou, Jiangsu Province, China"
      ],
      "name": "Sheng Guo"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Lei Zhang"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Ltd., Wuhan, HuBei Province, China"
      ],
      "name": "Faming Zhang"
    },
    {
      "affiliations": [
        "Hanx Biopharmaceuticals, Inc., Oceanside, CA, USA"
      ],
      "name": "Henry Li"
    },
    {
      "affiliations": [
        "Renmin Hospital, Beijing, China"
      ],
      "name": "Xiaodong Tang"
    }
  ],
  "title": "1184 Exploration of sarcoma-associated OX40-expression using HX111, a novel FIC OX40-MaB-VC-MMAE-ADC, to treat OX40+ sarcoma",
  "uid": "d3b48159-4ecc-5854-87de-93e2c8b7a651"
}