Immunomodulatory effects of OX40 agonists in a defined antigen challenge in cynomolgus macaques.

Abstract

3086 Background: Immunomodulatory antibodies targeting specific T cell costimulatory pathways have shown great potential as cancer therapeutics. OX40 agonists can enhance T cell proliferation and survival and cause tumor regressions in mouse models. While initial evaluations of pharmacodynamic activity of these compounds in non-human primate models have relied on non-specific T cell proliferation readouts (Ki67), additional sensitive biomarkers of pharmacodynamic activity would add value in evaluating optimal dosing and timing of candidate therapeutics. Methods: In this study, we compared the in vivo activity in cynomolgus macaques of intravenously infused OX40 agonist MEDI6469 (9B12, a murine IgG1 antibody) and MEDI6383, a human OX40 ligand fusion protein consisting of a dimer of OX40L trimers held together by Fcγ domains that also agonizes the OX40 receptor. Antigen-specific responses were evaluated to respiratory syncytial virus soluble F (sF) protein, which was administered intramuscularly on the same day as OX40 agonist treatment. Ki67 proliferation was additionally measured in whole blood. Results: Enhancement of F-specific T cell responses, serum anti-F IgG responses and functional antibodies was observed in animals that received the OX40 agonists. In addition, OX40 agonism resulted in a temporal enhancement of cellular proliferation (Ki67 staining) in CD4 and CD8 T cell memory subsets, as well as in NK cells and B cells. The strongest antigen-specific and Ki67 responses were observed in response to MEDI6383, with the exception of responses observed for NK cell proliferation which were similar between MEDI6469 and MEDI6383. Conclusions: Our study indicates that antigen-specific cellular and humoral responses may be useful biomarkers of OX40 agonist activity. Additionally, our study confirms that Ki67 readouts are informative in cynomolgus macaques, which was also demonstrated in separate studies using rhesus macaques.