First-in-human phase I/II trial evaluating BNT142, a first-in-class mRNA encoded, bispecific antibody targeting Claudin 6 (CLDN6) and CD3, in patients (pts) with CLDN6-positive advanced solid tumors.
Timothy A. Yap, Alberto Hernando‐Calvo, Emiliano Calvo, Víctor Moreno, Raúl Márquez, Kyriakos P. Papadopoulos, Javier Garciá Corbacho, Tatiana Hernandez Guerrero, Alexander I. Spira, David S.P. Tan, Christian H. Ottensmeier, Secil Koseoglu, Philip K Chang, Eddie Zhang, Jorge L. Martinez, Christina Trück, Rita Mágenheim, Ilhan Celik, Özlem Türeci, Uğur Şahin
Abstract
2501 Background: CLDN6 is an oncofetal cell surface protein silenced in normal adult tissues but aberrantly activated in testicular, ovarian, non-small cell lung (NSCLC) and other cancers. The investigational therapeutic BNT142 is a novel lipid nanoparticle (LNP)-encapsulated mRNA encoding the anti-CLDN6/CD3 bispecific antibody RiboMab02.1. After intravenous administration, BNT142 RNA-LNPs are taken up by liver cells and are translated into RiboMab02.1. The first results of the dose escalation part of the BNT142-01 trial testing 7 dose levels (DL) are presented here. Methods: BNT142-01 (NCT05262530) is a Phase I/II, open-label, multi-center trial to evaluate weekly BNT142 treatment with premedication (antipyretics, antihistamines, fluids) at the investigators’ discretion in pts with CLDN6+ (≥10% of cells with at least weak membrane positivity) advanced solid tumors. Primary objectives include safety, tolerability and identifying the recommended Phase 2 dose (RP2D), secondary and exploratory objectives include pharmacokinetics, pharmacodynamics and preliminary efficacy (RECIST 1.1). Results: As of 02 Dec 2024, 65 pts (median age 57 years [range 18 – 79]; 75% female; 60% ECOG 1; 44 ovarian, 10 testicular, 5 NSCLC, 6 rare cancers) received ≥1 dose (median 7, range 1 – 38) of BNT142. Of 65 pts, 46 (71%) had ≥4 prior lines of systemic therapy. Mostly mild to moderate treatment-related adverse events (TRAEs) occurred in 41 (63%) pts, including 15 (23%) pts with ≥G3 TRAEs. Most common (≥10%) TRAEs were cytokine release syndrome (CRS) in 14 (22%) pts (1 pt [2%] ≥G3), aspartate or alanine aminotransferase (AST, ALT) increased in 12 (19%) pts (8 pts [12%] ≥G3), and pyrexia, chills or fatigue in 8 (12%) pts (0/0/2 pts [0%/0%/3%] ≥G3, respectively). TRAEs leading to dose reduction, treatment interruption or discontinuation occurred in 1 (2%), 12 (19%) or 2 pts (3%), respectively (mostly G3; most common related terms AST or ALT increased and infusion related reaction). Two (3%) pts had a dose limiting toxicity (G4 ALT increased [DL5], leading to dose reduction, and G5 CRS [DL6]). BNT142 led to transient, dose-dependent increases in inflammatory cytokines. Translated RiboMab02.1 was detected in serum in a dose-dependent manner, peaking 24 – 72 h post-dose. Across all DLs, the disease control rate (DCR) was 58% with a tendency of higher efficacy in the higher DLs. In ovarian cancer, there were 7 RECIST 1.1 partial responses (PRs) and the DCR was 75%. Conclusions: BNT142 demonstrated a manageable safety profile and promising anti-tumor activity at the higher DLs, with 7 RECIST 1.1 PRs in CLDN6+ ovarian cancer, a tumor usually refractory to immunotherapy. We provide the first clinical proof-of-concept for an mRNA encoded bispecific antibody. Dose optimization is ongoing. Clinical trial information: NCT05262530 .