{
  "abstract": "Background mRNA-4106 is a lipid nanoparticle (LNP)-formulated multivalent cancer antigen therapy that encodes seven modified, full-length shared antigens, which are broadly and aberrantly expressed across a range of solid tumors, including melanoma and non-small cell lung cancer. The shared antigen targets in mRNA-4106 were selected through comprehensive, integrated analyses of RNA sequencing, immunopeptidomics, and immunohistochemistry to identify immunogenic antigens with higher expression in tumors versus normal tissues. Leveraging Moderna’s antigen design platform, mRNA-4106 was engineered to elicit potent T cell responses independent of patient-specific HLA class I and II alleles, supporting its use as a broadly applicable, off-the-shelf therapy. By encoding full-length antigens encompassing many potential epitopes, mRNA-4106 is designed to provide broad tumor antigen coverage to maximize the likelihood of immune recognition and cytotoxic response. By enabling multivalent antigen targeting across multiple tumor types and HLA profiles, mRNA-4106 exemplifies an off-the-shelf strategy that balances immunologic breadth with clinical scalability.Methods Endogenous and modified shared antigen proteoforms were designed in silico using Moderna’s proprietary antigen design pipeline. Candidate sequences were assessed for expression, antigen processing, and HLA presentation, followed by evaluation of antigen-specific T cell activation in both in vitro and in vivo systems. Primary human T cells and TCR-engineered Jurkat reporter cells were used to confirm robust, drug product-specific responses. HLA-A*02:01 transgenic mice were immunized with mRNA-4106 antigens to evaluate in vivo antigen processing and presentation. Tumor control efficacy was assessed in a surrogate mouse model by comparing Moderna’s optimized antigen sequences to endogenous wild-type counterparts.Results and Conclusions Comprehensive bioinformatics analysis and experimental validation confirmed that mRNA-4106 antigens are broadly expressed across tumors versus normal tissues and that the optimized antigen formats are immunogenic. In vitro studies demonstrated efficient expression and HLA presentation of encoded antigens, leading to strong activation of human T cells. In vivo, mRNA-4106 antigens induced potent antigen-specific T cell responses in HLA-transgenic mice. Moderna’s optimized antigen sequences enhanced tumor control and survival in a surrogate cancer model compared to wild-type sequences. Collectively, these findings establish preclinical proof-of-concept for mRNA-4106, supporting its potential as a broadly applicable, off-the-shelf mRNA cancer antigen therapy.Ethics Approval All animal experiments described in this study report were approved and conducted in accordance with the regulations of the Institutional Animal Care and Use Committee (IACUC Protocol 23-06-007)",
  "authors": [
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "LV Xiangmin"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Nikhil Khatwani"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Glendon Wu"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Emma Goddery"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Brandon Coder"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Andressa Laino"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Nick Esch"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Divya Raghunathan"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Moomal Tasneem"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Lauren Gerbereux"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Jing Sun"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Seung Hun Han"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Sheila Yee"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Naveen Ramesh"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Siranush Sarkizova"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Heta Desai"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Christopher Thomas"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Garrett Macedonia"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Daniel Rudmann"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Sima Zacharek"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Russell Karp"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Xinlan Li"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Joshua Frederick"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Wei Zheng"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Filippos Porichis"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Kristine McKinney"
    },
    {
      "affiliations": [
        "Moderna Inc. Cambridge, MA, USA"
      ],
      "name": "Raquel Deering"
    }
  ],
  "title": "933 Preclinical proof-of-concept of an off-the-shelf mRNA cancer antigen therapy targeting pan-tumor antigens for the treatment of multiple solid tumors",
  "uid": "7b46fff7-9b89-552d-86a0-1571a81ef434"
}