Inducible T cell Co-Stimulator (ICOS) is a co-stimulatory receptor, induced on activated T cells (TC) upon TC receptor engagement. Emerging clinical and preclinical data for checkpoint inhibitors demonstrate increased ICOS expression on effector TC, which has been linked to improved clinical outcomes. We have therefore developed an ICOS antibody optimized for agonist activity.
Syngeneic mouse tumor models and human ex-vivo PBMC and tumor infiltrating lymphocyte culture assays were utilized to evaluate the activity of a murine (7E.17G9) or human (H2L5) specific ICOS agonist antibody alone and in combination with PD-1 blockade. A selection of flow cytometry, IHC, multiplex IF, nanostring, and in silico analysis was performed to characterize and develop H2L5 for subsequent clinical evaluation.
ICOS induction either with 7E.17G9 or H2L5 agonist antibody induced significant activation and clonal expansion of both CD4+ and CD8+ effector TC. These TC had increased effector function (higher IFN-γ and Granzyme B) and increased homing to tumors resulting in antitumor responses when administered alone and in combination with PD-1 blockade. The level of expression of ICOS on effector and regulatory TC was found to overlap, suggesting that Fc-mediated depletion associated with IgG1 may result in depletion of effector TC. Preclinical data using different Fc isotypes supported the selection of the stabilized IgG4PE isotype for optimal agonism in the absence of NK-mediated depletion of effector TC. Drug concentrations associated with ICOS receptor occupancy, increases in TC activation and tumor reduction, support selected doses and biomarker strategy in the clinic. Select solid tumors types were identified for clinical studies based on expression of ICOS, ICOS-L, PD-L1 and PD-1.
IgG4PE provides the optimal isotype for delivering ICOS agonism whilst reducing the risk of depletion of ICOS positive effector TC. The comprehensive preclinical data package generated, supports clinical testing of the H2L5 IgG4PE ICOS agonist antibody (GSK3359609), currently being investigated alone and in combination with pembrolizumab, in a first in human clinical study (INDUCE-1).
Clinical trial identification
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S. Brett, S. Yadavilli, L. Seestaller-Wehr, S. Bhattacharya, H. Jackson, M. Bi, T. Zhang, Y.K. Katlinskaya, H. Shi, J. Jing, A. Hahn, S. Speller, D. David Figueroa, J. Yu, A. Hoos: Employee and stockholder: Glaxosmithkline Pharmaceuticals. D. Olive: Cofounder and shareholder: Imcheck Therapeutics. M. Cragg: Consultant: Bioinvent; Educational and advisory roles: Baxalta; Research funding: Roche, Bioinvent, Gilead, GSK. P. Mayes: Stockholder and employee: Incyte. All other authors have declared no conflicts of interest.