Abstract 2869: ADG138, a novel HER2×CD3 POWERbody™ integrating bispecific TCE with precision masking to control cytokine release syndrome and on-target off-tumor toxicity for single agent and combination therapies in HER2-expressing solid tumors
Authors: Liu Guizhong , Li Yan , Dai Zhengxi , Qu Jiagui , Shi Jianfeng , Zhao Qi , Qu Linhai , Nguyen Aaron N. , Zheng Songmao , Xu Jiangchun , Du Felix , Luo Peter 
Published: June 2022

Abstract
Bispecific T-cell engagers (TCEs) have shown therapeutic promise in treating hematologic cancers. However, their utility in treating solid tumors has yet to be effectively demonstrated due to on-target off-tumor toxicity and systemic cytokine release syndrome (CRS). To explore the full potential of TCEs as a powerful modality of immunotherapy for solid tumors, we developed ADG138, a novel HER2×CD3 POWERbody™ TCE by applying our SAFEbody® precision masking technology to double mask the binding interfaces in both ADG138 arms using covalently linked designer peptides in order to limit on-target off-tumor toxicities in normal tissues and to avert systemic CRS. In the tumor microenvironment (TME), the double masked ADG138 prodrug can be activated for concomitant in situ binding to the targeted cancer cells by the HER2 arm and to T cells by the CD3 arm to selectively enhance T cell responses against tumor cells specifically. Nonclinical studies demonstrated that when activated, ADG138 was highly potent in inducing T cell mediated cytotoxicity of both high and low HER2-expressing tumor cells in vitro, whereas in its double masked prodrug form ADG138 exhibited high masking efficiency with greatly reduced HER2 binding, T cell activation, and T cell mediated cytotoxicity. In in vivo human PBMC-engrafted tumor xenograft models, ADG138 induced robust tumor regression of both high and low HER2-expressing tumors in mice. Furthermore, combination of ADG138 with our species cross-reactive immuno-oncology therapeutics mediated strong synergistic antitumor activities in HER2 positive syngeneic solid tumor models in human CD3e knock-in mice. The double masked ADG138 prodrug also exhibited excellent safety profiles and normal pharmacokinetics in exploratory toxicology studies in cynomolgus monkeys, achieving over a 300-fold higher tolerated dose in striking contrast with its parental TCE that lacks masking. These nonclinical studies demonstrated that ADG138, a novel double masked HER2×CD3 POWERbody TCE, exhibited an impressively high therapeutic index relative to its parental non-masked TCE in HER2 high and low expressing solid tumors. This provides strong support for advancing the ADG138 prodrug into clinical development for treating HER2-expressing solid tumors as a single agent and in combination with other immune stimulatory agents.
Citation Format: Guizhong Liu, Yan Li, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Linhai Qu, Aaron N. Nguyen, Songmao Zheng, Jiangchun Xu, Felix Du, Peter Luo. ADG138, a novel HER2×CD3 POWERbody™ integrating bispecific TCE with precision masking to control cytokine release syndrome and on-target off-tumor toxicity for single agent and combination therapies in HER2-expressing solid tumors [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 2869.