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

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

  • Cancer Res. 2017 Aug 15;77(16):4378-4388. doi: 10.1158/0008-5472.CAN-16-1439.
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

Affiliations

  • 1 Merck Research Laboratories, Palo Alto, California. selvasukumar@yahoo.com.
  • 2 Merck Research Laboratories, Palo Alto, California.
  • 3 Merck Research Laboratories, Boston, Massachusetts.
  • 4 Merck Research Laboratories, West Point, Pennsylvania.
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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