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We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)–formulated RNA (RNA-LNP) encoding a T cell–engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell–specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-μg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530). Editor's summary: Bispecific T cell–engaging antibodies (BsAbs) have been approved to treat hematological malignancies; however, current forms are limited because of manufacturing and short serum half-lives. To improve these BsAbs, Stadler et al. have created BNT142, a lipid nanoparticle (LNP)–formulated RNA encoding a BsAb against CD3 and the oncofetal antigen claudin 6 (CLDN6). The authors then showed inhibition of tumor growth in treated preclinical mouse models and favorable pharmacokinetic profiles and no adverse effects in cynomolgus monkeys. This has led to initiation of a phase 1/2 first-in-human clinical trial, which will be used to assess safety and efficacy in patients with advanced solid tumors (NCT05262530). —Dorothy Hallberg [ABSTRACT FROM AUTHOR]