Engineering strategies and binding mechanisms of therapeutic anti–PD-1 antibodies approved by regulatory agencies globally

Anti-PD-1 therapeutic antibodies have represented a paradigm-shift in cancer treatment. The success of the first two anti-PD-1 antibodies approved by the FDA in 2014, pembrolizumab and nivolumab, has spurred an explosion in the discovery, engineering and development of anti-PD-1 antibody-based drugs. Currently, 16 monospecific and two bispecific anti-PD-1 therapeutic antibodies have been approved by regulatory agencies in the United States, Europe, China, and Japan. In this review, we compiled and discussed the available data on these 18 therapeutic anti-PD-1-based drugs. We first summarized the PD-1 signaling pathway and tumor immune escape mechanisms. Second, we discussed the structure of PD-1 and its molecular interaction with PD-L1/L2. Third, we reviewed the antibody engineering strategies used to optimize the variable (V) and Fc regions of the 18 approved antibodies. Fourth, we compared the affinity for PD-1 and PD-1:PD-L1 blockade activity, as well as reviewed the mechanism of binding of the published structures of PD-1 in complex with the antibodies. In doing so, we highlighted commonalities and differences of the interplay between affinity, blocking of the PD-1:PD-L1 interaction and regions recognized on PD-1 that contributed to the functional performance of the anti–PD-1 antibodies approved by regulatory agencies globally to treat cancer.