Characterization of the anti-PD-1 antibody REGN2810 and Its antitumor activity in Human PD-1 knock-in mice

Elena Burova, Aynur Hermann, Janelle Waite, T. Potocky, Venus Lai, Seongwon Hong, Matt Liu, Omaira Allbritton, Amy Woodruff, Qi Wu, Amanda D'Orvilliers, Elena Garnova, Ashique Rafique, William Poueymirou, Joel Martin, Tammy Huang, Dimitris Skokos, Joel Kantrowitz, Jon Popke, Markus MohrsDouglas MacDonald, Ella Ioffe, William Olson, Israel Lowy, Andrew Murphy, Gavin Thurston

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1and PD-L2 expressedonantigen-presenting cellsand cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4 (S228P) high-affinity anti-PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cellbased assays,REGN2810reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knockin mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD- 1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy.

Original languageEnglish
Pages (from-to)861-870
Number of pages10
JournalMolecular Cancer Therapeutics
Volume16
Issue number5
DOIs
StatePublished - 1 May 2017
Externally publishedYes

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