{
  "abstract": "Background Antibody-drug conjugates (ADCs) have emerged as a valuable class of targeted cancer therapies by selectively delivering cytotoxic payloads to tumor cells. However, their efficacy can be limited in tumors with low antigen expression, tumor cell heterogeneity, or acquired resistance.Methods To address these challenges, we are developing dual-payload ADCs, including immunostimulatory ADCs (iADCs), which simultaneously deliver both a cytotoxin and an immune stimulator directly to the tumor cells. This dual-action approach aims to enhance therapeutic potency by debulking tumors via the cytotoxic payload while engaging the immune system with the immune stimulator payload and has the potential to overcome emerging resistance mechanisms towards the single payload ADC.Results The preclinical pharmacology data demonstrate that iADCs offer superior in vitro and in vivo efficacy compared to conventional, single-payload ADCs, with favorable pharmacokinetics and molecular stability. Specifically, an exatecan/STING agonist dual-payload anti-HER2 iADC elicited significantly improved antitumor activity than either single payload ADCs alone, accompanied by strong immune cell activation in the tumor microenvironment. Notably, complete responders exhibited durable immune memory, effectively rejecting MC38-HER2 tumors in rechallenge experiments. Furthermore, iADCs were well tolerated in non-human primates at 25 mg/kg administered every three weeks for two doses (Q3W ×2), indicative of a favorable safety profile and supporting advancement towards clinical development.Conclusions These findings highlight the potential of iADCs as a novel treatment option that integrates targeted cytotoxicity with immune engagement, offering a promising approach to address resistance and improve long-term outcomes in cancer treatment.",
  "authors": [
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Gang Yin"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Robert Yuan"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Brian Vuillemenot"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Wadie Mahauad"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Wenjia Gu"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Stephanie Armstrong"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Miao Wen"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Jeff Hanson"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Cuong Tran"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Garrett Gross"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Werner Rubas"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Xiaofan Li"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Helena Kiefei"
    },
    {
      "affiliations": [
        "Sutro Biopharma Inc. South San Francisco, CA, USA"
      ],
      "name": "Hans-Peter Gerber"
    }
  ],
  "title": "956 Next-generation immunostimulatory antibody-drug conjugates (iADCs) combine tumor cell killing with immune activation to induce durable antitumor immunity",
  "uid": "77f95344-f86b-5a95-9079-fce0183a7b7e"
}