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. 2017 Aug 15;77(16):4378-4388.
doi: 10.1158/0008-5472.CAN-16-1439. Epub 2017 Jun 13.

Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells

Selvakumar Sukumar  1 , Douglas C Wilson  2 , Ying Yu  2 , Jerelyn Wong  2 , Saraswathi Naravula  2 , Grigori Ermakov  2 , Romina Riener  2 , Bhagyashree Bhagwat  2 , Antoaneta S Necheva  3 , Jeff Grein  2 , Tatyana Churakova  2 , Ruban Mangadu  2 , Peter Georgiev  3 , Denise Manfra  3 , Elaine M Pinheiro  3 , Venkataraman Sriram  2 , Wendy J Bailey  4 , Danuta Herzyk  4 , Terrill K McClanahan  2 , Aarron Willingham  2 , Amy M Beebe  2 , Svetlana Sadekova  2
Affiliations

Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells

Selvakumar Sukumar et al. Cancer Res. .

Abstract

GITR is a T-cell costimulatory 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 mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor 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 with 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 Tregsin 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. Cancer Res; 77(16); 4378-88. ©2017 AACR.

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