Stadler et al. showed that BNT142, a lipid nanoparticle RNA formulation encoding a bispecific Ab that binds CD3 monovalently and (tumor-expressed) oncofetal antigen claudin 6 bivalently was translated, self-assembled, and secreted as active Ab RiboMab02.1 in cell cultures, mice, and cynomolgus monkeys. BNT142 mediated claudin 6+cell-dependent activation of T cell functions in vitro, and in mice, induced target cell-dependent T cell tumor infiltration, claudin 6+ cell depletion, and regression of claudin 6+ human tumor s.c. xenografts. BNT142 i.v. injection of mice and cynomolgus monkeys led to high, persistent RiboMab02.1 serum levels, and was well tolerated.
Contributed by Paula Hochman
ABSTRACT: 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-_g 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).
Author Info: (1) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (2) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (3) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany.
Author Info: (1) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (2) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (3) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (4) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (5) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (6) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (7) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (8) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (9) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (10) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (11) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (12) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (13) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (14) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (15) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (16) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (17) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (18) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. (19) BioNTech US Inc., 40 Erie Street, Suite 110, Cambridge, MA 02139, USA. (20) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. HI-TRON (Helmholtz Institute for Translational Oncology) Mainz by DKFZ, Obere Zahlbacherstr. 63, 55131 Mainz, Germany. (21) BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany. HI-TRON (Helmholtz Institute for Translational Oncology) Mainz by DKFZ, Obere Zahlbacherstr. 63, 55131 Mainz, Germany. TRON gGmbH-Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstra§e 12, 55131 Mainz, Germany. Institute for Immunology, University Medical Center (UMC) of the Johannes Gutenberg University, Obere Zahlbacherstr. 63, 55131 Mainz, Germany.
