Abstract 4561: Preclinical characterization of GLS-010 (AB122): A fully humanized clinical-stage anti-PD-1 antibody

Abstract

Abstract INTRODUCTION: Exhausted T cells express high levels of several immune checkpoint proteins, including the programmed death-1 (PD-1) receptor. Preclinical and clinical data support the role of the PD-1/PD-L1 axis in promoting tumor evasion by curtailing immune responses. We present here the preclinical characterization of GLS-010 (AB122), a novel fully human anti-PD-1 monoclonal antibody currently in Phase 1. METHODS: The affinity of GLS-010 (AB122) for human and cynomolgus monkey PD-1, its specificity for PD-1, and its ability to block the PD-1 interaction with PD-L1 and PD-L2 were measured by ELISA, flow cytometry and TCR-activated reporter gene assays. Functional assessment of GLS-010 (AB122) on immune responses (IFN-g, IL-2, and proliferation) was performed using mixed lymphocyte reaction (MLR) and re-stimulation with cytomegalovirus (CMV) pp665 peptide. The anti-tumor efficacy of GLS-010 (AB122) was evaluated using a mouse MC-38 tumor model grown in mice transgenic for human PD-1. For PK analysis, GLS-010 (AB122) was given in a single i.v. bolus to male and female cynomolgus monkeys at doses of 2, 6 and 18 mg/kg. RESULTS: GLS-010 (AB122) is a fully human IgG4 monoclonal antibody that binds to human PD-1 (EC50 ~ 210 pM, ELISA; 770 pM, flow cytometry), cyno PD-1 (EC50 ~ 150 pM, ELISA), but not rat or mouse PD-1. Lack of GLS-010 (AB122) binding to other related members of the CD28 family, such as ICOS, CD28 and CTLA-4, confirms the specificity of the interaction. Functional studies showed that binding of GLS-010 (AB122) to cell-expressed hPD-1 inhibits the interaction with both hPD-L1 and hPD-L2 with an IC50 of 580 pM and 670 pM, respectively (by flow cytometry) and 2.2 nM and 5.8 nM, respectively (in reporter gene assay). Using allogeneic monocyte-derived dendritic cells, we showed a dose-dependent enhancement of IFN-g production and proliferation by CD4+ T cells, saturating at concentrations below 100 pM. Similar results were obtained in an antigen-specific T cell recall response assay using CMV-infected donors. GLS-010 (AB122) was very effective at blocking MC-38 tumor growth in hPD-1 transgenic mice. PK profiles following a single i.v. dose of GLS-010 (AB122) administered to male and female cynomolgus monkeys were dose-proportional and the rate of clearance was dose-independent. CONCLUSIONS: GLS-010 (AB122) is a novel and selective antagonistic anti-hPD-1 antibody that potently blocks the interaction of human PD-1 with both PD-L1 and PD-L2. This blockade translates into potent enhancement of T cell activation in a variety of cell culture studies, which combined with its in vivo profile (in mice and monkeys) supports its ongoing clinical development in oncology. Citation Format: Joanne B. Tan, Chris Chen, Kai Chen, Guochun Li, Jing Li, Jieying Liu, Hema Singh, Guoyong Wang, Baotian Yang, Kristin Zhang, Xiaoning Zhao, Yong Zheng. Preclinical characterization of GLS-010 (AB122): A fully humanized clinical-stage anti-PD-1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4561.