Characterization of MK-4166, a clinical agonistic antibody that targets human GITR and inhibits the generation and suppressive effects of T regulatory cells

GITR is a T cell co-stimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here we report the potential utility of MK-4166, a humanized GITR monoclonal antibody selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TILs). We also investigated the role of GITR agonism in human anti-tumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a Phase I clinical study. Expression of human GITR was comparable to that of mouse GITR in tumor-infiltrating Tregs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of Tregs in vitro. In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating Tregs, suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the Treg-mediated suppressive tumor microenvironment.

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