Abstract 738: MBRC-101: a novel antibody-drug conjugate (ADC) targeting the tyrosine kinase receptor EphA5
Cancer Research(2024)
Abstract
Abstract Introduction: The receptor tyrosine kinase EphA5 has the classical receptor kinase topology with an extracellular-binding domain, a single-pass transmembrane domain, and a cytoplasmic kinase domain. Previously, EphA5 has been shown to contribute to DNA-damage repair and radiation therapy resistance in lung cancer. We investigated EphA5 expression in lung cancer as well as breast, pancreatic, gastric, and colorectal cancer and assessed its potential as a therapeutic target using a novel ADC, MBRC-101. Methods: MBRC-101 is composed of a humanized anti-EphA5 IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable valine-citrulline linker using site-specific ThioBridge™ technology. The specificity profile of the anti-EphA5 antibody was characterized using a membrane proteome array. Receptor-mediated antibody internalization was determined by real-time live-cell analysis, and cell killing assays were performed using analysis of cell confluence and luminescent-based viability. Expression of EphA5 in archival human tissue sections was evaluated by immunohistochemistry (IHC) using a commercial antibody. Efficacy studies used patient-derived xenograft (PDX) models of lung adenocarcinoma, squamous cell carcinoma of both lung and head and neck, and breast cancer. Results: IHC demonstrated selective EphA5 membrane expression in 78% (18/23) of triple negative and 88% (23/26) of hormone receptor-positive breast cancer tumors tested. EphA5 membrane expression was also detected in 85% (29/34), 73% (16/22), 70% (7/10), 70% (15/22), and 50% (6/12) of lung squamous cell carcinoma, lung adenocarcinoma, gastric, colorectal, and pancreatic patient tumors tested, respectively. EphA5 expression was not detected in adjacent, non-malignant tissue in any of the tumors examined. The anti-EphA5 antibody bound exclusively to EphA5 and did not cross-react with other members of the Eph receptor/ephrin ligand family. Binding of the anti-EphA5 antibody on the cell surface triggered rapid internalization and processing through the endosomal-lysosomal system. MBRC-101 was cytotoxic to EphA5-expressing cells and its activity was concentration-dependent and commensurate to levels of EphA5 on the cell surface. In PDX models, once weekly administrations of intravenous MBRC-101 showed dose-dependent, robust, and reproducible anti-tumor activity. Partial tumor responses were observed at doses of 2.5 mg/Kg and complete tumor responses starting at 5 mg/Kg. Toxicologic findings in Sprague-Dawley rats and cynomolgus monkeys were attributed to the MMAE payload and not target-related. Based on an HNSTD of 10 mg/kg in monkeys, the starting human dose was 0.5 mg/kg with ~15-fold safety margin. Conclusions: EphA5 is a new and promising molecular target for the development of ADC-based therapies against many human cancers. A Phase 1/1b study of MBRC-101 is currently recruiting (NCT06014658). Citation Format: Fernanda I. Staquicini, Fenny H. Tang, Vanessa de Oliveira, Daniela I. Staquicini, Yongjian Wu, Kirstin F. Barnhart, J Kellogg Parsons, Wadih Arap, Isan Chen, Renata Pasqualini. MBRC-101: a novel antibody-drug conjugate (ADC) targeting the tyrosine kinase receptor EphA5 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 738.
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