{
  "abstract": "Background 4-1BB (CD137) is a clinically validated immune checkpoint target with the ability to elicit potent anti-tumor immunity. Traditional antibody-based 4-1BB agonists have faced safety and efficacy challenges due to systemic and Fcγ receptor mediated toxicity. Here we describe a novel MULTi-specific, multi-Affinity antiBODY platform, the Multabody™, that exploits multi-valency to deliver an innovative 4-1BB agonist with broad therapeutic potential.Methods To understand the impact of epitope on 4-1BB agonism, we generated a panel of 4-1BB Multabodies to comprehensively evaluate potency of these molecules in comparison to the historical 4-1BB agonist, urelumab. As the Multabody does not rely upon Fc receptors for crosslinking, we engineered our Multabody constructs with mutations to abolish binding. Fcγ receptor binding was measured using biolayer interferometry (BLI). To determine the ability to agonize 4-1BB, Multabodies were tested in vitro using a Jurkat NF-κB reporter system. Efficacy and safety were examined in the hu4-1BB/hu4-1BBL knock in mice. In vivo efficacy was assessed in a syngeneic MC38 tumor model where a 4-1BB Multabody was compared with urelumab. For safety assessment, we performed histopathologic analysis of liver tissues in mice dosed with Multabodies or urelumab.Results We identified 4-1BB Multabodies that demonstrated a range of Fc-independent agonistic profiles, including those mimicking the natural ligand, 4-1BBL. A 4-1BB Multabody lead candidate, RBT101, was further evaluated in vivo using the syngeneic MC38 murine tumor model where it demonstrated robust durable complete tumor regression. Of note, the 4-1BB Multabody induced long-lived immunological memory, as mice that had previously cleared tumors following treatment with the Multabody were protected from a secondary challenge of MC38. Unlike urelumab which demonstrated splenomegaly and liver inflammation, RBT101 showed no signs of spleen or liver toxicity.Conclusions Through rational design, the Multabody™ platform offers an innovative approach to address the inherent limitations of conventional antibody-based approaches. By using multivalent clustering to multimerize receptors in an Fc-independent manner, Multabodies enable precise and tunable agonism that more closely mimic natural ligand biology. Our findings demonstrate that Multabodies represent an innovative approach to receptor agonism—combining precision, tunability, and safety—and support their continued development as promising therapeutics in oncology and beyond.",
  "authors": [
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Michael Molloy"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Peter Bayliss"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Xinwen He"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Amy Berkley"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Yu-Fan Tsao"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Abi Rao"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Debbie Jin"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Sean Phippen"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Shrayasee Saha"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Arif Jetha"
    },
    {
      "affiliations": [
        "Radiant Biotherapeutics, Toronto, ON, Canada"
      ],
      "name": "Joanne Hulme"
    }
  ],
  "title": "847 The multabody: a next-generation approach for cancer immunotherapy and 4–1BB agonist therapy",
  "uid": "abfe381b-95b8-5ea5-b05a-5e8e5dffe93e"
}