Abstract 2857: DR30303, a SMART-VHHBody powered anti-CLDN18.2 VHH-Fc with enhanced ADCC activity for the treatment of gastric and pancreatic cancers

Abstract

Abstract Claudin 18.2 (CLDN18.2) is aberrantly overexpressed in gastric cancer, pancreatic adenocarcinomas, and a fraction of non-small cell lung cancer. Its tumor specificity allows CLDN18.2 to be an attractive target for developing biotherapeutics for the treatment of gastric and pancreatic cancers. DR30303 is a humanized ant-CLDN18.2 heavy chain antibody Fc fusion protein (VHH-Fc) generated via Doer Biologics’ proprietary SMART-VHHBody platform. DR30303 exhibits strong and highly selective binding to CLDN18.2, but not its close splicing variant CLDN18.1. In addition, it exhibits enhanced ADCC activity as a result of Fc engineering and low immunogenicity risk validated via in-silico T-cell epitope predictor. Its smaller size (78 kDa vs 150 kDa for conventional full-length IgG) allows DR30303 to penetrate solid tumors faster and deeper, resulting in a strong competitive advantage and differentiation compared with other anti-CLDN18.2 antibodies in the market. Single-agent therapeutic potency of DR30303 was demonstrated in various gastric and pancreatic cell-derived xenograft (CDX) mouse models with a minimum effective dose of 0.3 mg/kg dose of DR30303 led to TGI≥90%, which is significantly more potent (p<0.05) than the benchmark reference Zolbetuximab analog in same molar ratio. Moreover, DR30303 showed strong synergistic anti-tumor activities with paclitaxel, gemcitabine, and EOF (epirubicin, oxaliplatin, and fluorouracil) in patient-derived xenograft (PDX) mouse models (gastric cancer) and CDX model (pancreatic cancer). DR30303 also demonstrated favorable pharmacokinetic properties (t1/2~ 120 hours) and tolerable toxicities (MTD≥ 748.5 mg) in both SD rats and cynomolgus monkeys. Doer Biologics submitted IND to the NMPA in November 2021 and plans to initiate the Phase 1 clinical trial in H1 2022 upon IND approval. Citation Format: Yongliang Fang, Gaofeng Yao, Weixiang Zhong, Wenwen Duan, Zhenxing Zhou, Xiaofang Wen, Yonglu Chen, Jingjin Fang, Yongwei Wang, Weiqin Jiang, Junfang Xu, Yanshan Huang. DR30303, a SMART-VHHBody powered anti-CLDN18.2 VHH-Fc with enhanced ADCC activity for the treatment of gastric and pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2857.