The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

Lin, David Yin-wei; Tanaka, Yoshimasa; Iwasaki, Masashi; Gittis, Apostolos G.; Su, Hua-Poo; Mikami, Bunzo; Okazaki, Taku; Honjo, Tasuku; Minato, Nagahiro; Garboczi, David N.

doi:10.1073/pnas.0712278105

Cited by 388 publications

(381 citation statements)

References 33 publications

(38 reference statements)

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“…To design the initial, "first-generation" library, we studied the crystal structure of the complex between murine PD-1 (mPD-1) and human PD-L1 (hPD-L1) (19) and identified 22 corresponding residues in human PD-1 (hPD-1) at the contact interface with PD-L1 for randomization (Fig. 1A and SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

Maute

Gordon

Mayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

312

314

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Signaling through the immune checkpoint programmed cell death protein-1 (PD-1) enables tumor progression by dampening antitumor immune responses. Therapeutic blockade of the signaling axis between PD-1 and its ligand programmed cell death ligand-1 (PD-L1) with monoclonal antibodies has shown remarkable clinical success in the treatment of cancer. However, antibodies have inherent limitations that can curtail their efficacy in this setting, including poor tissue/tumor penetrance and detrimental Fc-effector functions that deplete immune cells. To determine if PD-1:PD-L1-directed immunotherapy could be improved with smaller, nonantibody therapeutics, we used directed evolution by yeast-surface display to engineer the PD-1 ectodomain as a high-affinity (110 pM) competitive antagonist of PD-L1. In contrast to anti-PD-L1 monoclonal antibodies, high-affinity PD-1 demonstrated superior tumor penetration without inducing depletion of peripheral effector T cells. Consistent with these advantages, in syngeneic CT26 tumor models, high-affinity PD-1 was effective in treating both small (50 mm 3 ) and large tumors (150 mm 3 ), whereas the activity of anti-PD-L1 antibodies was completely abrogated against large tumors. Furthermore, we found that high-affinity PD-1 could be radiolabeled and applied as a PET imaging tracer to efficiently distinguish between PD-L1-positive and PD-L1-negative tumors in living mice, providing an alternative to invasive biopsy and histological analysis. These results thus highlight the favorable pharmacology of small, nonantibody therapeutics for enhanced cancer immunotherapy and immune diagnostics.protein engineering | cancer immunotherapy | PET imaging | PD-1 | PD-L1

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Section: Resultsmentioning

confidence: 99%

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

Maute

Gordon

Mayer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

312

314

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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

540

405

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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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“…In contrast, the IgV and IgC domains of PD-L1 are in a straight line when complexed with PD-1 but diverge 38°from straight without PD-1 (5). This flexibility between the two domains suggests PD-L1 may accommodate to the orientation of receptor during binding (5). An unanswered question is how binding of ligand transduces a signal.…”

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confidence: 96%

“…B7-1 is a rigid rod with a very similar structure alone or bound to CTLA4 (11,12). In contrast, the IgV and IgC domains of PD-L1 are in a straight line when complexed with PD-1 but diverge 38°from straight without PD-1 (5). This flexibility between the two domains suggests PD-L1 may accommodate to the orientation of receptor during binding (5).…”

mentioning

confidence: 99%

Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek

Freeman

2008

Proc. Natl. Acad. Sci. U.S.A.

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The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors

Abstract: coreceptor ͉ costimulation ͉ inhibitory receptor

Cited by 388 publications

References 33 publications

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging

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

Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek

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