Abstract P201: Zenocutuzumab is an effective HER2/HER3 Biclonics® antibody in cancers with NRG1 fusions
Authors: Gerlach Jan , Odintsov Igor , Schackmann Ron , Ladanyi Marc , van Bueren Jeroen Lammerts , Somwar Romel , Geuijen Cecile 
Published: December 2021

Abstract
Neuregulin 1 (NRG1) fusion proteins are oncogenic drivers in multiple cancer types, including non-small cell lung cancer, pancreas adenocarcinoma, and other solid tumors. NRG1 fusion proteins bind to HER3 and signal through HER2/HER3 heterodimers, leading to oncogenic transformation. Zenocutuzumab is an HER2/HER3 humanized IgG1 bispecific antibody that specifically and potently blocks NRG1 fusion-driven signaling of the heterodimeric complex. Zenocutuzumab binds via its anti-HER2 monovalent Fab arm to domain I of HER2. Docking of zenocutuzumab in this position increases the effective affinity of the anti-HER3 Fab arm, which binds to domain 3, a critical epitope that blocks binding of the HER3 ligand NRG1. Consequently, zenocutuzumab displaces NRG1 binding to HER3, even at high ligand concentrations, keeping HER3 in an inactive state and blocking HER2/HER3 heterodimerization and NRG1-mediated signaling. The clinical efficacy and safety of zenocutuzumab were recently demonstrated in patients with NRG1 fusion-driven cancers who were enrolled in the ongoing global multicenter eNRGy study and a global early access program NCT02912949 (J Clin Oncol 39;15_suppl; abstract 3003). Treatment with zenocutuzumab led to rapid and major radiologic tumor regression and biomarker responses in heavily pretreated patients with multiple NRG1 fusion-positive cancers with several different N-terminal fusion partners. Zenocutuzumab has been enhanced for antibody-dependent cell-mediated cytotoxicity (ADCC) to recruit and bolster immune effector cells to aid in tumor elimination. Here we explored the different Fc-mediated immune effector functions of zenocutuzumab. In several cancer cell lines, zenocutuzumab induced Fc-mediated dose-dependent ADCC and antibody-dependent cellular phagocytosis. Insertion of ATP1B1-NRG1 and SLC3A2-NRG1 into immortalized pancreatic ductal epithelial cells (H6c7) led to activation of the HER3 oncogenic signaling pathways including AKT. The H6c7-SLC3A2-NRG1 cells formed tumors when implanted in the subcutaneous flank of immune compromised mice (after about 10 weeks). Furthermore, a dependency of the transformed cell on this oncogene for growth and survival was also observed. Zenocutuzumab effectively inhibited proliferation of these NRG1 fusion-expressing, transformed cells. In addition, proteomic analysis showed that zenocutuzumab inhibited the HER3 and AKT-related downstream signaling pathways. In conclusion, these data provide strong mechanistic evidence supporting the clinical efficacy of zenocutuzumab in patients with NRG1 fusion-driven cancers.
Citation Format: Jan Gerlach, Igor Odintsov, Ron Schackmann, Marc Ladanyi, Jeroen Lammerts van Bueren, Romel Somwar, Cecile Geuijen. Zenocutuzumab is an effective HER2/HER3 Biclonics® antibody in cancers with NRG1 fusions [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P201.