{
  "abstract": "Background CD40 is a cell surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily. CD40 is broadly expressed on many immune cells, mostly by antigen-presenting cells (APCs). On APCs, it plays a central role in stimulating immune synapses during T cells priming, when through its interaction with its ligand CD40 ligand (CD40L) it licenses APCs to activate tumor antigen-specific T cells. This is accomplished through the upregulation of major histocompatibility complex molecules, increased expression of the costimulatory molecules CD86/CD80, and upregulation of TNF superfamily ligands on the APC surface, as well as by secretion of cytokines such as IL-12, which altogether fuel CD8 + T cells activation. The CD40/CD40L axis thus plays a central role in APCs proliferation, as well as antigen presentation, notably in a cancer setting.Methods Generation of peptide-tailored protease-cleavable masks and in vitro characterization in human, mouse, and cynomolgus monkey primary immuno-assays of conditionally active CP-870,893 variants.Results CP-870,893 is a clinically validated anti-CD40 agonist antibody bearing a unique FcγR-independent, soluble agonism mode of action. We previously highlighted at SITC 2024 the crystal structure of CP-870,893 Fab in complex with CD40 receptor, as well as the structure-based generation of CP-870,893 variants achieving a potency equivalent to the cognate CD40L in primary cells immuno-assays. With the intention of addressing the short half-life due to target-mediated drug disposition and the dose-limiting toxicities observed in clinical trials with monospecific anti-CD40 agonist antibodies, we now report for the first time the generation and the in vitro characterization in human, mouse, and cynomolgus monkey immuno-assays of conditionally active CP-870,893 variants featuring a peptide mask covering the paratope and a protease-cleavable linker, where full-fledged agonistic activity is unleashed only after proteases-mediated cleavage of the mask.Conclusions These in vitro cross-species findings suggest a promising path for developing safer anti-CD40 agonist-based therapeutics.",
  "authors": [
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Margot Cucchetti"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "John J Skinner"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, MA, USA"
      ],
      "name": "Yu Qiu"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Florence Efremenko"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Lucrece Aimade"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Johara Lahssini"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Sandra Viale"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Melissa Prat"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Georges Kalouche"
    },
    {
      "affiliations": [
        "Sanofi, Frankfurt, Hesse, Germany"
      ],
      "name": "Christian Beil"
    },
    {
      "affiliations": [
        "Sanofi, Frankfurt, Hesse, Germany"
      ],
      "name": "Kaj Grandien"
    },
    {
      "affiliations": [
        "Sanofi, Frankfurt, Hesse, Germany"
      ],
      "name": "Bodo Brunner"
    },
    {
      "affiliations": [
        "Sanofi, Orlando, FL, USA"
      ],
      "name": "Chelsea Fnu"
    },
    {
      "affiliations": [
        "Sanofi, Orlando, FL, USA"
      ],
      "name": "Pankaj Agrawal"
    },
    {
      "affiliations": [
        "Sanofi, Orlando, FL, USA"
      ],
      "name": "Ernesto Luna"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "Jianfeng Shi"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "Guizhong Liu"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "Songmao Zheng"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "Jiangchun Xu"
    },
    {
      "affiliations": [
        "Sanofi, Cambridge, MA, USA"
      ],
      "name": "Anna Park"
    },
    {
      "affiliations": [
        "Adagene, San Diego, CA, USA"
      ],
      "name": "Peter Luo"
    },
    {
      "affiliations": [
        "Sanofi, Vitry-sur-Seine, France"
      ],
      "name": "Ingrid Sassoon"
    }
  ],
  "title": "922 Generation and characterization of conditionally active anti-CD40 agonist agents",
  "uid": "9191a97e-8677-5fcf-9849-28777ddb1d9b"
}