Characterization of the Anti–PD-1 Antibody REGN2810 and Its Antitumor Activity in HumanPD-1Knock-In Mice
| العنوان: | Characterization of the Anti–PD-1 Antibody REGN2810 and Its Antitumor Activity in HumanPD-1Knock-In Mice |
|---|---|
| المؤلفون: | Amanda Dorvilliers, Venus Lai, Jon Popke, Joel H. Martin, Ashique Rafique, William C. Olson, Omaira Allbritton, William Poueymirou, Matt Liu, Amy Woodruff, Andrew J. Murphy, Terra Potocky, Janelle C. Waite, Gavin Thurston, Markus Mohrs, Ella Ioffe, Tammy T. Huang, Joel Kantrowitz, Israel Lowy, Seongwon Hong, Qi Wu, Douglas MacDonald, Dimitris Skokos, Aynur Hermann, Elena Burova, Elena Garnova |
| المصدر: | Molecular Cancer Therapeutics. 16:861-870 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, biology, medicine.medical_treatment, Immunotherapy, Pharmacology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, Oncology, Cancer immunotherapy, In vivo, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, medicine, Cytotoxic T cell, Antibody |
| الوصف: | 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 preclinical in vivo studies 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 the in vivo activity 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. |
| تدمد: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-16-0665 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::8aa8e74dc8c8263abc16819a959686aa https://doi.org/10.1158/1535-7163.mct-16-0665 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........8aa8e74dc8c8263abc16819a959686aa |
| قاعدة البيانات: | OpenAIRE |
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