An mRNA-encoded T cell engager delivered to the liver produced strong preclinical antitumor activity against models.
Evidence
This was a preclinical platform study in liver-orthotopic tumor-bearing mice plus exposure and safety testing in mice, rats, and cynomolgus monkeys, including repeated four-weekly monkey dosing up to 45 μg/kg.
Caveat
The efficacy evidence is from animal models, and the abstract reports that human testing is only beginning.
Simplified
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 , the 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.
Key numbers
100%
Complete Tumor Regression
Achieved in liver-orthotopic tumor-bearing mice following treatment.
45 μg/kg
45 μg/kg
Maximum dose administered during repeated dosing regimen in nonhuman primates.
Full Text
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mRNA Technology