Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Cheng, Xiaoxiao; Veverka, Václav; Radhakrishnan, Anand; Waters, Lorna C.; Muskett, Frederick W.; Morgan, Sara H.; Huo, Jiandong; Yu, Chao; Evans, Edward J.; Leslie, Alasdair; Griffiths, Meryn; Stubberfield, Colin R.; Griffin, Robert; Henry, Alistair J.; Jansson, Andreas; Ladbury, John E.; Ikemizu, Shinji; Carr, Mark D.; Davis, Simon J.

doi:10.1074/jbc.m112.448126

Cited by 260 publications

(307 citation statements)

References 64 publications

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“…S2A). Previous studies identified several human PD-1 residues as critical for PD-L1 and PD-L2 binding (31)(32)(33)(34), and these residues are contained within the two sequences (Supplementary Fig. S2B).…”

Section: Binding Analysis Of Nivolumab and Inhibition Of Ligand Bindingmentioning

confidence: 99%

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Wang

Thudium

Han

et al. 2014

Cancer Immunology Research

510

390

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The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846-56. Ó2014 AACR.

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Section: Binding Analysis Of Nivolumab and Inhibition Of Ligand Bindingmentioning

confidence: 99%

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Wang

Thudium

Han

et al. 2014

Cancer Immunology Research

510

390

View full text Add to dashboard Cite

show abstract

“…The molecule is well defined by electron density, safe for a region between C′D strands. However, previous reports done by Lázár [4,5,6] .…”

Section: Structure Of the Pdl-1mentioning

confidence: 38%

Programmed death ligand -1: a review

Hemashree¹

2017

Int J Recent Sci Res

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“…Of note, mouse PD-L1/B7-H1 interacts with human PD-1 (47) and human activated T cells express human PD-1. Moreover, if mice are also inoculated with human tumor cells, the malignant cells are induced to express PD-L1/B7-H1 colocalizing for the most extent with T-cell infiltrates (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2−/−IL2Rγnull Immunodeficient Mice

et al. 2015

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A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cellsurface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4 þ T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137(urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patientderived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNg and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. Cancer Res; 75(17); 3466-78. Ó2015 AACR.

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Structure and Interactions of the Human Programmed Cell Death 1 Receptor

Cited by 260 publications

References 64 publications

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Programmed death ligand -1: a review

Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2−/−IL2Rγnull Immunodeficient Mice

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