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  current news   Press   selected story    
     
  8 July 2016  
 
Structural basis for blocking PD-1 mediated immune response by therapeutic antibody pembrolizumab
 
 




Authors
Zhenkun Na1, Siok Ping Yeo2 Sakshibeedu R. Bharath1, Matthew W. Bowler4,5, Esra Balıkçı1, Cheng-I Wang2* and Haiwei Song1,3*

1   Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
2   Singapore Immunology Network, 8a Biomedical Grove, Singapore 138648, Singapore
3   Department of Biochemistry, National University of Singapore, 14 Science Drive, Singapore 117543.
4   European Molecular Biology Laboratory, Grenoble Outstation, 71 avenue des Martyrs, CS 90181
    F-38042 Grenoble, France
5   Unit of Virus Host-Cell Interactions, Univ. Grenoble Alpes-EMBL-CNRS, 71 avenue des Martyrs, CS     90181 F-38042 Grenoble, France

* Correspondence:
haiwei@imcb.a-star.edu.sg;

Wang_ChengI@immuno.a-star.edu.sg

Published online ahead of print in Cell Research on 21 June 2016.

Abstract
Programmed cell death 1 (PD-1) is a crucial inhibitory receptor that suppresses immune responses upon interaction with its ligands PD-L1 and PD-L2. Immunological checkpoint blockade by monoclonal antibodies (mAbs) pembrolizumab and nivolumab against PD-1 has proven to be effective in suppressing PD-1 signaling and widely used to treat melanoma, non-small cell lung cancer and other types of cancers.  Here we report the crystal structure of the pembrolizumab Fab in complex with the ecto-domain of PD-1 at a resolution of 2.9 Å. Pembrolizumab Fab uses its complementary determining regions (CDRs) and framework region (FR) to interact with the previously unobserved C'D loop of PD-1 through extensive hydrophobic and hydrophilic interactions. The conformational epitope consists of several discontinuous segments of PD-1, which overlaps with the region that interacts with PD-L1 or PD-L2, suggesting a mechanism by which pembrolizumab prevents the binding of PD-L1 or PD-L2 to PD-1. These results have implications for the design and improvement of mAb drugs targeting PD-1.



Figure Legend :
Superposition of the hPD-1/pembrolizumab Fab complex with hPD-1/hPD-L1. hPD-1 is shown in light blue, and the light and heavy chains of Fab are in wheat and pale green, respectively. hPD-L1 is shown in magenta. For simplicity, only hPD-1 in hPD-1/pembrolizumab Fab is shown


For more information on Haiwei SONG's lab, please click here.