Abstract 6368: Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced tumors

Abstract

Abstract ZG005 is a humanized anti-PD-1/TIGIT bispecific antibody that effectively blocks the binding between PD-1 and TIGIT, on immune cells, with their specific ligands PD-L1 and PVR, on tumors. As a dual blockade of PD-1/TIGIT immune checkpoints, ZG005 exhibits sustained occupancy to both targets and inhibits their pathways specifically and simultaneously, leading to synergistic effects and boosting the ability of the immune system in killing tumor cells. With high binding affinities, ZG005 elicits the activation of T cells and NK cells resulting in increased release of cytokines and the depletion of Tregs, independent of ADCC activities. ZG005 utilizes the IgG4 isotype to avoid the potential negative impact of effector function and target-crosslinking that has been reported for anti-TIGIT therapeutics using IgG1 isotype. In vivo animal studies indicate that ZG005 has potent and dose-dependent anti-tumor efficacies in syngeneic models using CT26 and MC38 colon tumors in humanized PD-1/TIGIT dKIs mice. In these models, the whole blood and TIL analyses confirmed increases in CD8+ and NK cells but reduction of Treg cell levels after ZG005 treatments. The combination of ZG005 with chemotherapeutic-reagents, cisplatin and donafenib, enhanced their anti-tumor efficacies. Toxicity and safety pharmacology studies with weekly repeat doses for four weeks in cynomolgus monkeys, indicate that ZG005 is well tolerated. Over the dose range 20-180 mg/kg, there were no obvious toxic or adverse effects, and the HNSTD and NOAEL values were 180 mg/kg and 60 mg/kg, respectively. PK/TK analyses indicate a prolonged ZG005 receptor occupancy over 80%, consistent with in vitro binding results that are attribute to the S228P mutation in the IgG4 hinge region to prevent Fab exchange and enhance stability. The IND application of ZG005 has been approved by both FDA and NMPA, and the molecule is currently in phase I clinical trials for advanced solid tumors at escalated dosing of 0.3~20 mg/kg, Q3W, via i.v. administration. Citation Format: Bing Zhu, Tongcheng Dai, Ruifeng Liu, Alfonso Suarez, Tyler Liban, Bin Zhang, Margaret Karow, Jackie Sheng, Zelin Sheng, Binhua Lv. Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6368.