{
  "abstract": "Background Type I interferons (IFNs), including IFN-α and IFN-β, can induce tumor cell apoptosis and activate anti-tumor immunity via type I IFN signaling. Although they have shown clinical utility in certain cancers, type I IFNs face limitations due to poor stability, short half-life, and systemic toxicity.Moreover, the tumor microenvironment (TME) is characterized by hypoxia and acidic pH, which suppress anti-tumor immunity and reduce the functional activity of protein-based therapeutics, including cytokines and antibodies.To overcome these challenges, we developed a glycoengineered IFN-β mutein with improved biophysical properties and retained functional activity under acidic pH conditions. To enable tumor-selective delivery and expand the therapeutic window, this mutein was fused to a TROP2-targeting monoclonal antibody to create ABN202 (αTROP2), an antibody-cytokine fusion protein (ACFP).Methods To characterize the IFN-β mutein under acidic TME conditions, we compared its IFNAR1/2 binding affinity and downstream signaling activity to other type I IFNs at acidic pH. The binding affinity at acidic pH was calculated using molecular dynamics simulation. The in vitro anti-cancer activity of ABN202 (αTROP2) was evaluated under conditions mimicking the tumor microenvironment. In vivo efficacy and preclinical toxicity profiles were assessed using xenograft and human IFNAR1/2 knock-in (hIFNAR KI) mouse models.Results The IFN-β mutein exhibited enhanced IFNAR1/2 binding and type I IFN signaling under acidic conditions compared to other type I IFNs. ABN202 (αTROP2) induced potent direct tumor cell killing and enhanced immune cell-mediated cytotoxicity in vitro. In xenograft and hIFNAR KI mouse models, ABN202 showed robust anti-tumor efficacy with favorable toxicity profiles.Conclusions ABN202 (αTROP2) demonstrates potent anti-tumor efficacy in acidic tumor microenvironments, with an improved preclinical toxicity profile compared to other type I IFNs. This balance between efficacy and safety expands the therapeutic window, supporting its potential as a best-in-class type I IFN-based therapeutic.",
  "authors": [
    {
      "affiliations": [
        "ABION Inc., Seoul, Republic of Korea"
      ],
      "name": "Heegeon Park"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Jin Woong Song"
    },
    {
      "affiliations": [
        "ABION Inc., Seoul, Republic of Korea"
      ],
      "name": "Hyun Kyung Lee"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Myeung Ryun Seo"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Soojin Ryu"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Rae Eon Kim"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Yeri Yoo"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Sung Youl Hong"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Juyong Lee"
    },
    {
      "affiliations": [
        "Duksung Women’s University, Seoul, Republic of Korea"
      ],
      "name": "Kyoung Song"
    },
    {
      "affiliations": [
        "Arontier Co., Seoul, Republic of Korea"
      ],
      "name": "Junsu Ko"
    },
    {
      "affiliations": [
        "ABION Inc., Seoul, Republic of Korea"
      ],
      "name": "Sae Hyung Lee"
    },
    {
      "affiliations": [
        "ABION Inc., Seoul, Republic of Korea"
      ],
      "name": "Jun Young Choi"
    },
    {
      "affiliations": [
        "Seoul National University, Seoul, Republic of Korea"
      ],
      "name": "Young Kee Shin"
    }
  ],
  "title": "865 ABN202 (αTROP2): A TROP2-targeting IFN-β mutein fusion protein with retained activity in acidic tumor microenvironments and reduced toxicity for an improved therapeutic window",
  "uid": "8207696c-8152-5f85-b24c-2919a19ea3d4"
}