Abstract 2868: ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy

Abstract

Abstract Targeting CD137 by agonistic antibodies faces various challenges in the clinic. Utomilumab appears safe but has modest efficacy, while urelumab is more efficacious but causes severe dose-dependent liver toxicity. To unlock the full potential of CD137 immunotherapy, we engineered a ADG206 POWERbody࣪ by combining our SAFEbody® technology’s precision masking of the antigen binding sites with the Fc engineering in order to achieve improved safety and efficacy profiles. In normal tissues, the CD137 antigen binding interfaces of ADG206 are masked using a covalently linked designer peptide to limit on-target off-tumor toxicities, whereas in the tumor microenvironment (TME), the masked antibody can be activated to selectively bind CD137, promoting costimulatory signaling in situ. The activity of ADG206 is further heightened by incorporating Fc mutations with increased FcγR-mediated crosslinking, resulting in enhanced T cell responses and antitumor activity. In vitro nonclinical studies demonstrate that activated ADG206 binds to CD137, with agonistic activity strictly dependent on FcγR-mediated crosslinking, in contrast to FcγR-independent stimulation of CD137 by urelumab. When activated, ADG206 exhibits up to ~4-fold stronger anti-CD137 agonistic activity than urelumab for T cell activation in the presence of a primary stimulatory signal, while masked ADG206 has much lower activity. In vivo nonclinical studies demonstrate that ADG206 has robust single agent antitumor activities in multiple syngeneic murine tumor models and synergistic efficacy when combined with other immunomodulatory agents. Moreover, ADG206 is well-tolerated in rats and cynomolgus monkeys in nonclinical toxicology studies, with normal pharmacokinetic behaviors and minimal activation in circulation. These results demonstrate that ADG206 POWERbody acquires a tailor-made product profile toward a best-in-class anti-CD137 immunotherapeutic agent that combines conditional activation in the TME with strong agonistic activity through heightened FcγR-mediated crosslinking. Further clinical development of ADG206 POWERbody may hold promises for achieving the long-awaited desirable tolerability and efficacy outcome of an anti-CD137 immunotherapy in either single agent or combination regimens. Citation Format: Guizhong Liu, Zhengxi Dai, Jiagui Qu, Jianfeng Shi, Qi Zhao, Linhai Qu, Yan Li, Songmao Zheng, Jiangchun Xu, Felix Du, Peter Luo. ADG206, an anti-CD137 agonistic POWERbody࣪ with tailor-made efficacy and safety profiles by strong crosslinking and tumor selective activation for single and combinational cancer immunotherapy [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 2868.