Abstract LB509: ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking

Abstract

Abstract CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a co-stimulatory molecule of immunocytes. Agonistic antibodies against CD137 have shown promising therapeutic activity in mouse tumor models. However, molecules in the clinical development have shown limitations due to either dose-dependent severe liver toxicity (e.g. Urelumab), or modest antitumor activity (e.g. Utomilumab). We developed ZG033, a fully human IgG4 agonist of CD137 that engages with a exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. The biophysical properties and anti-tumor activities were determined using in vitro assays and in vivo mice xenograft models, respectively. ZG033 is a safe and potent antibody targeting a ligand competitive epitope, that conserved in human, cynomolgus monkey, and is associated with a differentiated pharmacology and toxicology profile. The complex structure of ZG033/CD137 was determined by X-ray crystallography. The binding affinity to human 4-1BB of ZG033 determined by Surface plasmon resonance (SPR) was moderate (KD=10 nM). ZG033 increased the production of IFN-γ by human CD8+T,CD4+T, NK cells in a Fcγ receptor-dependent manner, displaying an intermediate activation level between that of Urelumab and Utomilumab. In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation. In syngeneic mouse tumor models, ZG033 showed robust single agent anti-tumor activity starting from 0.3 mg/kg and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged as compared to Utomilumab. Furthermore, ZG033 combined with an anti-PD-L1 antibody (Atezolizumab) significantly inhibited the growth of colorectal tumor in a human PBMC-engrafted humanized mouse model. Data from toxicology test in humanized CD137 transgenic mice showed that ZG033 was well-tolerated with normal ALT and AST levels. Even high dose of ZG033 (MTD≥180mg/kg) was achieved in cynomolgus monkeys with no abnormality in hematological indexes, important organs. These data demonstrate that ZG033 is a novel CD137 agonist that displays an favorable safety profile and has a potential in either mono- or combinational immunotherapies. Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Xiaoli Zheng, Liansheng Cheng. ZG033, a novel CD137 agonist, induces superior anti-tumor activity without hepatotoxicity rely on Fc-mediated crosslinking [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 LB509.