Abstract 5195: NBL-015, a next-generation fully human anti-claudin 18.2 antibody with enhanced ADCC and CDC for treating gastric and pancreatic cancers

Claudin 18.2 is a member of the claudin family and belongs to the class of tight junction proteins. Its expression on normal tissue is restricted to gastric cell lineage and on short-lived differentiated epithelial cells, while it is expressed in multiple cancer types, including pancreatic, stomach, esophageal, lung and ovarian cancers. The differential expression pattern of claudin18.2 between tumor and normal tissues makes it a promising drug target to treat those cancers, especially pancreatic and gastroesophageal tumors, which are among the malignancies with the highest unmet medical need. Zolbetuximab is a mouse-human chimeric antibody developed by Astellas Pharma. It exhibits encouraging clinical efficacy and good safety data in gastric patients with mid-high claudin18.2 expressing in their tumor tissues. However, claudin18.2 expression in the majority of tumors is moderate and heterogeneous. Expanding the therapeutic window and allowing the anti-cladudin18.2 drug to benefit patients with moderate to low claudin18.2 expression require the antibody to have a higher binding affinity and strong killing activity. NBL-015 is a fully human antibody generated from Tranni transgenic mouse and is predicted to bear with low development and immunogenicity risks. NBL-015 demonstrates high selectivity against claudin18.2, and it doesn9t bind to the close splicing variant claudin18.1. It exhibits strong binding to multiple pancreatic and gastric tumor cell lines expressing moderate to low level of CLDN18.2 endogenously. Moreover, NBL-015 is Fc engineered to enhance both ADCC and CDC activities. It shows robust tumor-killing activity comparing with antibodies with wild type Fc and to the benchmark antibody in the ex vivo models. NBL-015 also demonstrates superior anti-tumor efficacy in multiple gastric and pancreatic tumor CDX models expressing moderate to low claudin18.2, and in PBMC humanized NOG mice bearing gastric and pancreatic CDX tumors. In conclusion, our data confirm the successful discovery and optimization of a next-generation anti-claudin18.2 mAb, NBL-015, using NovaRock9s proprietary antibody discovery and development platforms. NBL-015 exhibits potent anti-tumor activity in vitro and in vivo. It is currently in process development and IND enabling studies. It is targeted to enter clinical studies in early 2021. Citation Format: Ming Lei, Anna Przybyla, Ahmed Hassan, Qingtai Su, Gabriela Hrebikova, Samantha Wallner, Danielle Lavery, Kevin Chen, Raymond Yu, Joshua Dewe, Samruddhi Patil, Haichun Huang, Yi Pei, Zhong Liu, Han Li. NBL-015, a next-generation fully human anti-claudin 18.2 antibody with enhanced ADCC and CDC for treating gastric and pancreatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5195.