Cancer immunity is regulated by co-stimulatory mechanisms that when triggered may mount effective anticancer responses. Robust antitumor responses, including complete cures, have been achieved by modulating patients' immune systems. Antibodies targeting the immune checkpoint receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand-1 (PD-L1) have demonstrated impressive activity in select patients; however, most cancers remain non-responsive to this class of agents. Inducible T cell co-stimulator (ICOS) is a T cell restricted co-stimulatory receptor belonging to the CD28/CTLA immunoglobulin super family whose expression is highly induced on CD4+ and CD8+ T cells upon T cell receptor (TCR) activation. Here we describe the development of a humanized monoclonal antibody (H2L5 IgG4PE) with specific, high-affinity binding to human ICOS capable of delivering agonistic activity and stimulating effector CD4+ and cytotoxic CD8+ T cell activation, expansion, and function. We show that the antibody isotype and FcγR-mediated crosslinking are critical features required for optimal activity of the H2L5 antibody. In mouse tumor models antibody-induced ICOS agonism elicited potent T cell activation and antitumor responses alone and synergistically in combination with other agents, including an anti-PD1 antibody. The first-in-class ICOS agonist antibody described here offers a promising next-generation immunotherapy agent to enhance the magnitude and duration of antitumor responses in patients whose tumors are already sensitive to current immunotherapy approaches as well as potentially expanding the population of patients and range of tumor types that respond to immunotherapy. A phase I clinical trial has been initiated to test H2L5 IgG4PE (GSK3359609) alone and in combination with anti-PD1 and other anticancer agents in patients with solid tumors (www.clinicaltrials.gov; NCT02723955).
Citation Format: Patrick A. Mayes, Sapna Yadavilli, Yao-Bin Liu, Meixia Bi, Tianqian Zhang, Kelhia Sendeyo, Jane Willoughby, Laura Seestaller-Wehr, Ashleigh Hahn, Sabyasachi Bhattacharya, M. Phillip DeYoung, Christina Blackwell, Hong Shi, David Killian, Michael Adam, Shu-Yun Zhang, Junping Jing, Chris Hopson, Gilles Marodon, Mark S. Cragg, Axel Hoos. Targeting inducible T cell co-stimulator (ICOS) promotes effector T cell function and antitumor response [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA22.
- ©2016 American Association for Cancer Research.