title: Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in HumanPD-1Knock-In Mice.
abstract: The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and 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 preclinicalin vivostudies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1-dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test thein vivoactivity of REGN2810, which does not cross-react with murine PD-1, knock-in 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.Mol Cancer Ther; 16(5); 861-70. ©2017 AACR.
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Burova
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Aynur
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Janelle
authors.initials: J
authors.lastname: Waite
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Terra
authors.initials: T
authors.lastname: Potocky
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Venus
authors.initials: V
authors.lastname: Lai
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Seongwon
authors.initials: S
authors.lastname: Hong
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Matt
authors.initials: M
authors.lastname: Liu
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Omaira
authors.initials: O
authors.lastname: Allbritton
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Amy
authors.initials: A
authors.lastname: Woodruff
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Amanda
authors.initials: A
authors.lastname: D'Orvilliers
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Elena
authors.initials: E
authors.lastname: Garnova
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Ashique
authors.initials: A
authors.lastname: Rafique
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: William
authors.initials: W
authors.lastname: Poueymirou
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Joel
authors.initials: J
authors.lastname: Martin
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Tammy
authors.initials: T
authors.lastname: Huang
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Skokos
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Joel
authors.initials: J
authors.lastname: Kantrowitz
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jon
authors.initials: J
authors.lastname: Popke
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Markus
authors.initials: M
authors.lastname: Mohrs
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Douglas
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Ella
authors.initials: E
authors.lastname: Ioffe
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: William
authors.initials: W
authors.lastname: Olson
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York. gavin.thurston@regeneron.com.
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D055879:Gene Knock-In Techniques; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor