{
  "abstract": "Background Effective T-cell-mediated anti-tumor activity requires signaling through both the TCR and co-stimulatory receptors. While CD3 bispecific antibodies have shown success in hematologic malignancies, efficacy in solid tumors has been limited, partly due to T-cell exhaustion within the immunosuppressive tumor microenvironment (TME). CD28 co-stimulation is essential for sustained T-cell function and prevention of exhaustion, but non-targeted systemic CD28 activation is toxic in humans. RNDO-564 is a novel, first-in-class CD28 x Nectin-4 bispecific antibody designed to deliver tumor localized co-stimulation within Nectin-4-expressing tumors ( figure 1). Nectin-4 is overexpressed in multiple epithelial cancers, including metastatic urothelial carcinoma (mUC). By utilizing tumor-targeted CD28 agonism, RNDO-564 aims to boost anti-tumor T-cell responses while avoiding systemic toxicity.Methods We evaluated RNDO-564, an IgG-like bispecific antibody composed of a potency-optimized CD28 binding domain and a high-affinity Nectin-4 binding domain, using in vitro assays with primary human T cells and Nectin-4-positive tumor cells. We conducted mechanistic studies with chronically stimulated T cells to assess the ability of RNDO-564 to restore activity of dysfunctional T cells and with co-culture models to evaluate the potential for bystander killing of Nectin-4-negative tumor cells. We tested in vivo efficacy in a syngeneic mouse model and safety, pharmacokinetics, and immunophenotyping in cynomolgus monkeys.Results RNDO-564 induced potent, Nectin-4-dependent co-stimulation, enhancing cytotoxicity and cytokine release in T cells in the presence of TCR stimulation. CD28 agonism rescued dysfunctional T cells, restoring effector function, activation and proliferation. We observed bystander killing of Nectin-4-negative tumor cells, supporting the potential for treating tumors with heterogenous Nectin-4 expression. RNDO-564 induced in vivo dose-dependent tumor growth inhibition as a monotherapy and in combination with PD-1 blockade. Cynomolgus studies confirmed a favorable safety profile with no systemic T-cell activation.Conclusions RNDO-564 elicits robust Nectin-4-dependent in vitro and in vivo anti-tumor efficacy with a clean safety profile in non-human primates. Mechanistic data highlights its potential to restore T-cell function and overcome tumor antigen heterogeneity. A Phase 1, first-in-human, dose-escalation study in mUC and other Nectin-4-expressing tumors is ongoing.Ethics Approval Cynomolgus study was approved and designated an IACUC number D16-00594 (A4112-01).Abstract 889 Figure 1Costimulatory bispecific, RNDO-564, for immune primed tumors",
  "authors": [
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Manpreet Kaur"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Katja Rüger"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Soumili Chattopadhyay"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Elaine C Chen"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Ruth Chu"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Starlynn C Clarke"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Laura Davison"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Lynnae Jackson"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Jacqueline Morgan"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Udaya S Rangaswamy"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Imani Smith"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Thomas J Manley"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Katherine E Harris"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Shelley Force Aldred"
    },
    {
      "affiliations": [
        "Rondo Therapeutics, Hayward, CA, USA"
      ],
      "name": "Nathan D Trinklein"
    }
  ],
  "title": "889 Comprehensive characterization of RNDO-564, a first-in-class CD28 x Nectin-4 bispecific antibody for the treatment of solid tumors",
  "uid": "c2eab39d-3918-5844-b224-4325140d6424"
}