Structural basis for blocking PD-1-mediated immune suppression by therapeutic antibody pembrolizumab

Na, Zhenkun; Yeo, Siok Ping; Bharath, S.R.; Bowler, Matthew W.; Balıkçı, Esra; Wang, Cheng‐I; Song, Haiwei

doi:10.1038/cr.2016.77

Cited by 122 publications

(148 citation statements)

References 11 publications

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“…However, hPD-1 lacks a well ordered C’’ strand like that found in the IgV fold of mPD-1, which is instead replaced with a flexible loop connecting the C’ and D strands. The flexibility of the C’D loop is supported by the NMR structure and complex structure of pembrolizumab/hPD-1 (discussed below) (Cheng et al, 2013; Na et al, 2016). Additionally, the interaction details of the interface are also quite different between the orthologs (Lin et al, 2008; Zak et al, 2015).…”

Section: Structural Basis Of the Pd-1/pd-l1/l2 Receptor-ligands Intermentioning

confidence: 96%

“…Crystal structures of the anti-PD-1 pembrolizumab Fab fragment complexed with hPD-1 and the anti-PD-L1 avelumab single chain Fv fragment (scFv) complexed with hPD-L1 have been determined by Na et al (2016) and our group, revealing the molecular basis of therapeutic antibody-based immune checkpoint therapy for tumors (Liu et al, 2016; Na et al, 2016). The interaction of pembrolizumab with hPD-1 is mainly located on two regions: the flexible C’D loop and the C, C’ strands.…”

Section: Structural Basis Of Therapeutic Antibody Interventionmentioning

confidence: 99%

“…The binding affinities ( K d ) of pembrolizumab to hPD-1 and avelumab to hPD-L1 are 27.0 pmol/L and 42.1 pmol/L, respectively (Na et al, 2016). On the other hand, the binding affinity between hPD-1 and hPD-L1 is 0.77–8.2 μmol/L (Collins et al, 2002; Butte et al, 2007; Cheng et al, 2013), which is much weaker than that of the antibodies.…”

Section: Structural Basis Of Therapeutic Antibody Interventionmentioning

confidence: 99%

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Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

et al. 2016

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Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

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Section: Structural Basis Of the Pd-1/pd-l1/l2 Receptor-ligands Intermentioning

confidence: 96%

Section: Structural Basis Of Therapeutic Antibody Interventionmentioning

confidence: 99%

Section: Structural Basis Of Therapeutic Antibody Interventionmentioning

confidence: 99%

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Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

et al. 2016

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“…[26] Der Komplex des antigenbindenden Fragments (Fab) mit hPD-1 (PDB ID:5 JXE) [27] ergab ein stçchiometrisches Verhältnis von 1:1. [26] Der Komplex des antigenbindenden Fragments (Fab) mit hPD-1 (PDB ID:5 JXE) [27] ergab ein stçchiometrisches Verhältnis von 1:1.…”

Section: Cokristallstrukturen Mit Monoklonalen Antikçrpernunclassified

Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

Konstantinidou¹,

Zarganes‐Tzitzikas²,

Magiera‐Mularz³

et al. 2018

Angewandte Chemie

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Die PD‐1/PD‐L1‐Wechselwirkung hat sich als ein wichtiger Angriffspunkt für die Krebs‐Immuntherapie erwiesen. Aktuelle Medikationen unter Einbeziehung monoklonaler Antikörper zeigen eindrucksvolle klinische Wirkungen beim Einsatz gegen verschiedene Tumortypen. Von der Cokristallstruktur von humanem PD‐1 mit PD‐L1 erwartet man – zusammen mit den aktuellen Kristallstrukturen mit monoklonalen Antikörpern, niedermolekularen Substanzen und Makrocyclen – einen wertvollen Ausgangspunkt für den Entwurf neuer Inhibitoren.

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“…This opened full automation to any sample presented in any mount and has provided a new tool to structural biologists, allowing the process of collecting hundreds of data sets or screening hundreds of crystals to be 'outsourced', freeing their time and often collecting better data . At the time of writing, the beamline has processed more than 39,000 samples representing a wide range of projects, from those that require extensive screening to find the best diffracting crystal (Na et al, 2017;Sorigué et al, 2017;Naschberger et al 2017) to small molecule fragment screening (Cheeseman et al, 2017;Hiruma et al, 2017) and experimental phasing at high and low resolutions (Kharde et al, 2015;Muir et al, 2016). The beamline is able to deal with a wide range of samples by combining parameters provided by the user with information gathered during processing.…”

Section: Introductionmentioning

confidence: 99%

Recent improvements to the automatic characterization and data collection algorithms on MASSIF-1

Svensson

Gilski

Nurizzo

et al. 2017

Preprint

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SynopsisSignificant improvements in the sample location, characterisation and data collection algorithms on the autonomous ESRF beamline MASSIF-1 are described. The workflows now include dynamic beam diameter adjustment and multi-position and multi-crystal data collections.. CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/236596 doi: bioRxiv preprint first posted online 2 Abstract Macromolecular crystallography (MX) is now a mature and widely used technique essential in the understanding of biology and medicine. Increases in computing power combined with robotics have enabled not only large numbers of samples to be screened and characterised but also for better decisions to be taken on data collection itself. This led to the development of MASSIF-1 at the ESRF, the world's first beamline to run fully automatically while making intelligent decisions taking user requirements into account. Since opening in late 2014 the beamline has now processed over 39,000 samples. Improvements have been made to the speed of the sample handling robotics and error management within the software routines.The workflows initially put in place, while highly innovative at the time, have been expanded to include increased complexity and additional intelligence using the information gathered during characterisation, this includes adapting the beam diameter dynamically to match the diffraction volume within the crystal. Complex multi-position and multi-crystal data collections are now also integrated into the selection of experiments available. This has led to increased data quality and throughput allowing even the most challenging samples to be treated automatically.Key words: X-ray centring; synchrotron instrumentation; macromolecular crystallography; automation; helical data collection; multiple crystal data collection . CC-BY-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/236596 doi: bioRxiv preprint first posted online 3 IntroductionAutomation is transforming the way scientific data are collected, allowing large amounts of high quality data to be gathered in a consistent manner (Quintana & Plätzer, 2015;Foster, 2005). Advances in robotics and software have been key in these developments and have had a particular impact on structural biology, allowing multiple constructs to be screened and purified (Camper & Viola, 2009;Hart & Waldo, 2013;Vijayachandran et al., 2011); huge numbers of crystallisation experiments to be performed (Elsliger et al., 2010;Ferrer et al., 2013;Heinemann et al., 2003;Joachimiak, 2009;Calero et al., 2014), samples to be mounted at synchrotrons (Cipriani et al., 2006; Cohen et al., 2002;Jacquamet et al., 2009;Papp et al., 2017;Snell et al., 2004), data to be analysed and processed (Bourenkov & Popov, 2010;Holton & Alber, 2004;Incardona et al., ...

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Structural basis for blocking PD-1-mediated immune suppression by therapeutic antibody pembrolizumab

Cited by 122 publications

References 11 publications

Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Crystal clear: visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

Recent improvements to the automatic characterization and data collection algorithms on MASSIF-1

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