A phase I/II dose escalation trial with expansion cohorts to evaluate safety and preliminary efficacy of BNT142 in patients with prospectively confirmed claudin 6-positive solid tumors.
Authors: Yap Timothy A. , Papadopoulos Kyriakos P. , Garralda Elena , Spira Alexander I. , Calvo Emiliano , Saavedra Omar , Ramon-Patino Jorge L , Stadler Christiane , Koseoglu Secil , Chang Philip K , Ellinghaus Ursula , Lindemann Claudia , Ewen Eva-Maria , Zyto Elzbieta , Zamorski Alexandra , Martinez Jorge Luis , De Mattos-Arruda Leticia , Celik Ilhan , Türeci Özlem , Sahin Ugur 
Published: June 2023

TPS2669 Background: Claudin 6 (CLDN6), an oncofetal antigen that is expressed on the cell surface of several solid cancers, including testicular (95% of cases) and ovarian cancers (55% of cases), is a suitable target for cancer immunotherapy (Reinhard et al. Science. 2020; Haanen et al. AACR 2022). BNT142 comprises lipid nanoparticle-encapsulated RNAs that encode for a T-cell-engaging bispecific antibody against CLDN6 and the T cell receptor–associated molecule CD3. The resulting tribody is produced from two RNA molecules coding for CLDN6-recognizing single-chain variable fragments connected by a CD3-binding fragment antigen-binding region. After intravenous administration, BNT142 is directed to the liver where both RNAs are translated, assembled, and secreted as antibodies into the circulation. While classical recombinant protein antibody formats are affected by issues with stability and a lengthy manufacturing process, novel RNA-encoded antibodies can be developed quickly and will potentially provide more favorable exposure profiles. A previous preclinical study examining the therapeutic effect of RNA-encoded bispecific CLDN6xCD3 antibodies showed tumor regression in xenograft animal models with CLDN6+ tumors (Stadler et al. Nat Med. 2017). Methods: This is a first-in-human, Phase I/II, open-label, multicenter, dose escalation trial with expansion cohorts to evaluate the safety, efficacy, PK and PD of BNT142 in patients with CLDN6+ advanced solid tumors (NCT05262530). Patients with advanced/metastatic CLDN6+ testicular, ovarian, endometrial, and non-squamous non-small-cell lung cancer (NSCLC) are eligible for inclusion and are prospectively selected for trial entry using a CLDN6 immunohistochemistry assay in a central laboratory. Patients must have exhausted standard therapies available likely to confer a clinical benefit or not be a candidate for such available therapies. The trial design consists of a dose escalation and dose expansion part. In the dose escalation part, the treatment dose will be escalated in up to 8 dose levels (DLs) until the maximum administered and tolerated dose has been reached. Once a DL has been declared safe, the DL cohort may be backfilled to determine safety, PK/PD, and anti-tumor activity. Patients with rare or not otherwise specified CLDN6+ tumors not included in the eligible tumor types can be included in the dose escalation part. The recommended Phase II dose (RP2D) will be determined by data collected at all DLs. In the dose expansion part, CLDN6+ patients with testicular cancer, ovarian cancer, and non-squamous NSCLC who have received at least 1 systemic therapy will be treated at the RP2D. The trial was initiated in March 2022 and recruitment is ongoing at global locations in Europe and the USA. Additional sites will be opened in Europe, USA, and Asia in 2023. Clinical trial information: NCT05262530 .