Advances in the structural characterization of complexes of therapeutic antibodies with PD-1 or PD-L1

Abstract

Antibody-based immune checkpoint blockade (ICB)-based therapeutics have become effective clinical applications for cancers. Applications of monoclonal antibodies (mAbs) to de-activate the PD-1-PD-L1 pathway could effectively reverse the phenotype of depleted activated thymocytes (T cells) to recover their anti-tumoral activities. High-resolution structures of the complexes of the therapeutic monoclonal antibodies with PD-1 or PD-L1 have revealed the key inter-molecular interactions and provided valuable insights into the fundamental mechanisms by which these antibodies inhibit PD-L1-PD-1 binding. Each anti-PD-1 mAb exhibits a unique blockade mechanism, such as interference with large PD-1-PD-L1 contacting interfaces, steric hindrance by overlapping a small area of this site, or binding to an N-glycosylated site. In contrast, all therapeutic anti-PD-L1 mAbs bind to a similar area of PD-L1. Here, we summarized advances in the structural characterization of the complexes of commercial mAbs that target PD-1 or PD-L1. In particular, we focus on the unique characteristics of those mAb structures, epitopes, and blockade mechanisms. It is well known that the use of antibodies as anti-tumor drugs has increased recently and both PD-1 and PD-L1 have attracted substantial attention as target for antibodies derived from new technologies. By focusing on structural characterization, this review aims to aid the development of novel antibodies targeting PD-1 or PD-L1 in the future.