{
  "abstract": "Background The IL-18/IL-18BP axis represents a promising immunotherapeutic target in oncology. IL-18, a potent cytokine in the tumor microenvironment (TME), enhances anti-tumor immunity by activating antigen-experienced tumor-infiltrating lymphocytes, expanding T cell repertoire diversity, and activating NK cells and monocytes, thereby amplifying immune cell-mediated tumor killing. However, IL-18 binding protein (IL-18BP), a high-affinity soluble decoy receptor, sequesters IL-18 and limits its anti-tumor activity. IL-18BP is overexpressed in various tumors, with expression levels negatively correlating with patient survival and positively correlating with checkpoint inhibitor resistance. Previous clinical failures of recombinant IL-18 therapy are attributed to IL-18BP neutralization, highlighting the therapeutic potential of IL-18BP blockade. Given high IL-18BP expression levels and regulation, current IL-18BP blockers face potential saturation challenges that reduce effectiveness. To address this, we developed pH-sensitive IL-18BP binders that function through IL-18 release and enhanced IL-18BP degradation, resulting in longer-lasting antibody activity.Methods We developed a high-affinity antibody targeting IL-18BP. In vitro studies evaluated its ability to block IL-18BP-mediated IL-18 sequestration and restore IL-18 bioactivity. In vivo tumor xenograft models assessed anti-tumor efficacy, tumor penetration, immune cell activation, and cytokine production. Comparative studies with existing anti-IL-18BP approaches evaluated best-in-class potential.Results Our antibody exhibited pH-sensitive binding to IL-18BP and effectively blocked IL-18 sequestration at neutral pH, resulting in enhanced free IL-18 availability. In preclinical tumor models, treatment significantly improved and activated IL-18-mediated T cell and NK cell responses. The antibody activated both innate and adaptive anti-tumor immunity while avoiding systemic immune activation. It demonstrated best-in-class in vivo efficacy and synergy with checkpoint inhibitors.Conclusions Our anti-IL-18BP antibody represents a promising best-in-class therapeutic candidate with superior preclinical efficacy. By targeting the IL-18/IL-18BP axis, it restores IL-18-mediated anti-tumor immunity through local TME activation while maintaining improved tolerability compared to systemic IL-18 or IL-18 mutein administration. The combination of improved tumor penetration and pH-sensitive binding demonstrates superior efficacy, further validating the anti-IL-18BP therapeutic class following recent entries into first-in-human studies.Ethics Approval All experimental plans and subsequent revisions or procedures, including animal use and animal management, have been reviewed and approved by the Southern Model IACUC Animal use and management were in accordance with AAALAC regulations.",
  "authors": [
    {
      "affiliations": [
        "Wrench Bio, Watertown, MA, USA"
      ],
      "name": "Raphael Rozenfeld"
    },
    {
      "affiliations": [
        "Wrench Bio, Watertown, MA, USA",
        "Mechanica Partners, Watertown, MA, USA"
      ],
      "name": "Goran Rakocevic"
    },
    {
      "affiliations": [
        "Wrench Bio, Watertown, MA, USA"
      ],
      "name": "Natalia Ulyanova"
    },
    {
      "affiliations": [
        "Wrench Bio, Watertown, MA, USA",
        "Mechanica Partners, Watertown, MA, USA"
      ],
      "name": "Deniz Kural"
    }
  ],
  "title": "868 Best-in-class anti-IL-18BP antibody for enhanced anti-tumor immunity",
  "uid": "f4de51f0-1e9d-5cca-bfdc-bfa42c42da44"
}