Seeing is believing: anti-PD-1/PD-L1 monoclonal antibodies in action for checkpoint blockade tumor immunotherapy.

Catherine W-H Zhang,Shuguang Tan,George F Gao

doi:10.1038/sigtrans.2016.29

Abstract

Structural immunology, focusing on structures of host immune related molecules, enables the immunologists to see what the molecules look like, and more importantly, how they work together. Antibody-based PD-1/PD-L1 blockade therapy has achieved brilliant successes in clinical applications. The recent breakthrough of the complex structures of checkpoint blockade antibodies with their counterparts, pembrolizumab with PD-1 and avelumab with PD-L1, have made it clear how these monoclonal antibodies compete the binding of PD-1/PD-L1 and function to blockade the receptor-ligand interaction. Herein, we summarize the structural findings of these two reports and look into the future for how this information would facilitate the development of more efficient PD-1/PD-L1 targeting antibodies, small molecule drugs, and other protein or non-protein inhibitors.

Highlights

Structural immunology, focusing on structures of host immune related molecules, enables the immunologists to see what the molecules look like, and more importantly, how they work together
Immune checkpoint blockade therapy has taken center stage from the corner especially since tumor immunotherapy was selected as Breakthrough of the Year by Science in 2013.6 T-cell activation involves multiple paired molecular interactions including T-cell receptor (TCR)/peptide major histocompatibility complex interactions, CD4/pMHC co-receptor interactions and co-stimulatory ligand-receptor interactions under the current two-signal system theory (Figure 1a left).[7,8,9,10,11,12]
Monoclonal antibodies (MAbs) abrogate the binding of Programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1).30–32 As a PD-L1 targeting antibody, avelumab is a human IgG1 antibody cotumor microenvironments, which further limits their functional potential.[36]

Summary

Introduction

Structural immunology, focusing on structures of host immune related molecules, enables the immunologists to see what the molecules look like, and more importantly, how they work together. Immune checkpoint blockade therapy has taken center stage from the corner especially since tumor immunotherapy was selected as Breakthrough of the Year by Science in 2013.6 T-cell activation involves multiple paired molecular interactions including T-cell receptor (TCR)/peptide major histocompatibility complex (pMHC) interactions, CD4 (or CD8)/pMHC co-receptor interactions and co-stimulatory ligand-receptor interactions under the current two-signal system theory (Figure 1a left).[7,8,9,10,11,12] Besides, activated

Results

Conclusion