A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab

Abstract

T-cell checkpoint inhibition has a profound impact on cancer care and the programmed cell death protein 1 (PD-1)-targeted antibodies nivolumab and pembrolizumab have been two of the lead molecules of this therapeutic revolution. Their clinical comparability is a highly relevant topic of discussion, but to a significant degree is a consequence of their molecular properties. Here we provide a molecular, preclinical, and early clinical comparison of the two antibodies, based on the available data and recent literature. We acknowledge the limitations of such comparisons, but suggest that based on the available data, differences in clinical trial outcomes between nivolumab and pembrolizumab are more likely drug-independent than drug-dependent.

Keywords: Nivolumab; PD-1; Pembrolizumab; T-cell checkpoint.

Fig. 1

Structural comparison of nivolumab and pembrolizumab in complex with the extracellular domain of PD-1. (A) Ribbon diagram of the extracellular domain of PD-1. The molecular surface of PD-1 is represented in faint transparent blue, and the PD-L1 binding area in yellow. The (B) PD-1-nivolumab complex (PDB ID: 5WT9) and (C) PD-1-pembrolizumab complex (PDB ID: 5GGS) are shown as ribbon diagrams. Nivolumab and pembrolizumab are shown in red and blue, respectively. PD-1 in both complexes is drawn in light blue with transparent surfaces. (D) Surface representation of PD-1 from the PD-1-nivolumab complex. The PD-L1 and nivolumab binding areas on PD-1 are shown in yellow and red, respectively. The overlapping residues for binding both with PD-L1 and nivolumab are shown in orange. (E) Surface representation of PD-1 from the PD-1-pembrolizumab complex. The PD-L1 and pembrolizumab binding areas on PD-1 are shown in yellow and blue, respectively. The overlapping residues for binding both with PD-L1 and pembrolizumab are shown in cyan. (A), (D), and (E) are drawn with the same orientations. Amino acid single letter codes and primary sequence numbers are provided in (D) and (E). The differences in appearance in (A), (D), and (E) are a consequence of the fact that both antibodies stabilize different parts of the flexible PD-1 loop structures. Lack of stabilization of a flexible loop would impair the structural resolution by x-ray crystallography.