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
  • 1. Merck Research Laboratories, Palo Alto, California. [email protected].
  • 2. Merck Research Laboratories, Palo Alto, California.
  • 3. Merck Research Laboratories, Boston, Massachusetts.
  • 4. Merck Research Laboratories, West Point, Pennsylvania.
PMID: 28611044 DOI: 10.1158/0008-5472.CAN-16-1439
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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