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

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. T-cell engager (TCE)-based immunotherapy requires further development in solid tumors due to limited T cell penetration, immunosuppressive tumor microenvironment and toxicity. The authors here develop a glypican-3 targeting mRNA TCE (MTS105) which manifests superior T cell activation and tumor regression hepatocellular carcinoma mice model comparing to conventional TCE, and safety with cynomolgus monkey studies.