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<p>T-cell engager (TCE)-based immunotherapy is clinically validated in hematological cancers. However, application in solid tumors faces hurdles including T cell penetration, the immunosuppressive tumor microenvironment, and toxicity. We develop an mRNA-encoded TCE (MTS105) targeting Glypican-3, the hepatocellular carcinoma antigen, delivered via lipid nanoparticles directly to liver tissue. In mice, rats, and cynomolgus monkeys, MTS105 exhibits higher liver exposure versus plasma. Liver-orthotopic tumor-bearing mice achieve complete, dose-dependent regression, with fast intratumoral T cell activation owing to sustained higher liver and tumor functional TCE exposure versus conventional antibody-based TCE. In vivo, MTS105 induces intratumoral CD8 cell precursor and terminally differentiated memory subsets with high activation scores. In cynomolgus monkeys, MTS105 displays favorable, linear plasma pharmacokinetics including mRNA, ionizable lipid, and translated TCE following single and repeated-four-weekly dosing (up to 45 μg/kg). No severe adverse effects or gross pathology were observed. Our results thus support the advancement of MTS105 into clinical trials, with a first-in-human study currently underway.</p>

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Organ-specific delivery of an mRNA-encoded bispecific T cell engager targeting glypican-3 in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Yan Huang,
  • Shaoli Liu,
  • Xiaoju Zhang,
  • Bingxu Zhang,
  • Feng Shi,
  • Jia Zhang,
  • Shuaibo Shao,
  • Hongya Han,
  • Xiaoyun Ma,
  • Jing Xie,
  • Jianqi Zhang,
  • Hongxiaoying Yu,
  • Yongchao Zhao,
  • Jiazheng Jin,
  • Dong Xu,
  • Liang Liu,
  • Jianing Wang,
  • Yu Tan,
  • Kelu Xu,
  • Lushuai Jin,
  • Quanjun Du,
  • Yifeng Geng,
  • Andong Liu,
  • Wei Xu

摘要

T-cell engager (TCE)-based immunotherapy is clinically validated in hematological cancers. However, application in solid tumors faces hurdles including T cell penetration, the immunosuppressive tumor microenvironment, and toxicity. We develop an mRNA-encoded TCE (MTS105) targeting Glypican-3, the hepatocellular carcinoma antigen, delivered via lipid nanoparticles directly to liver tissue. In mice, rats, and cynomolgus monkeys, MTS105 exhibits higher liver exposure versus plasma. Liver-orthotopic tumor-bearing mice achieve complete, dose-dependent regression, with fast intratumoral T cell activation owing to sustained higher liver and tumor functional TCE exposure versus conventional antibody-based TCE. In vivo, MTS105 induces intratumoral CD8 cell precursor and terminally differentiated memory subsets with high activation scores. In cynomolgus monkeys, MTS105 displays favorable, linear plasma pharmacokinetics including mRNA, ionizable lipid, and translated TCE following single and repeated-four-weekly dosing (up to 45 μg/kg). No severe adverse effects or gross pathology were observed. Our results thus support the advancement of MTS105 into clinical trials, with a first-in-human study currently underway.