Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry

Abstract

Much of the recent excitement in the cancer immunotherapy approach has been generated by the recognition that immune checkpoint proteins, like the receptor PD-1, can be blocked by antibody-based drugs with profound effects. Promising clinical data have already been released pointing to the efficiency of the drug pembrolizumab to block the PD-1 pathway, triggering the T-lymphocytes to destroy the cancer cells. Thus, a deep understanding of this drug/receptor complex is essential for the improvement of new drugs targeting the protein PD-1. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT), we investigate in silico the binding energy features of the receptor PD-1 in complex with its drug inhibitor. Our computational results give a better understanding of the binding mechanisms, being also an efficient alternative towards the development of antibody-based drugs, pointing to new treatments for cancer therapy.

Investigation of protein-protein interactions and hot spot region between PD-1 and PD-L1 by fragment molecular orbital method

“…The FMO results were in agreement with the previously reported 14 PPI of Horita et al . 27 and 10 PPI of the traditional quantum chemistry results 28 . 14 PPI: E61: LC Y57, N66: HC R102, Q75: HC T30, T76: HC Y101, D77: HC S54, D77: HC N55, K78: HC Y33, K78: HC Y101, D85: HC R99, R86: LC D97, Q88: HC N59, E61: LC Y34, S62: LC Y57, and Q88: HC Y35, and 10 PPI: V64: HC F103, N66: HC F103, Y68: HC R102, K78: HC R102, K78: HC F103, D85: HC R102, Q88: LC Y33, P89: LC Y35, I126: HC R102, and I134: HC R102.…”

Study of the interactions of a novel monoclonal antibody, mAb059c, with the hPD-1 receptor

“…The desired blockade effect could be achieved by designing more direct interactions to compete the binding of PD-L1 on the front β-sheet of PD-1, as depicted in the analysis of pembrolizumab, or by increasing the blocking effect of the “hotspot” FG loop through enhancing the binding affinity via the introduction of more hydrogen bonds in different regions such as the C’D loop. In silico tools such as quantum mechanics are good approaches to delineate the profile of residue-residue interactions of PD-1/PD-L1 from the binding energy point of view, thus facilitating the design of better therapeutic antibodies targeting ideal conformational epitopes 31,32 .…”

Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment

“…The monoclonal antibodies (mAbs) against programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) are immune checkpoint inhibitors blocking inhibitory T-cell activities. [1] Anti-PD-1/PD-L1 mAbs have emerged as a therapeutic option for melanoma and other tumor types including non-small-cell lung cancer and renal cell carcinoma refractory to conventional chemotherapy. [2] Despite the therapeutic benefits of these immune checkpoint inhibitors, their use can induce immune-related adverse events (irAEs) including hypophysitis, colitis, hepatitis, pneumonitis, and rash.…”

“…Currently, mAbs targeting PD-1, including nivolumab and pembrolizumab, are approved in many countries around the world. [1] Among them, pembrolizumab is a humanized mAb (IgG4 subclass) with potential immune checkpoint inhibitory and antineoplastic activities. [1] Despite its favorable antineoplastic activities, pneumonitis, the most serious irAE, is known to develop in 5% of cases after anti-PD-1/PD-L1 mAb treatment.…”

“…[1] Among them, pembrolizumab is a humanized mAb (IgG4 subclass) with potential immune checkpoint inhibitory and antineoplastic activities. [1] Despite its favorable antineoplastic activities, pneumonitis, the most serious irAE, is known to develop in 5% of cases after anti-PD-1/PD-L1 mAb treatment. [8] Herein, we present 3 cases of pembrolizumab-induced pneumonitis with different clinical courses ranging from mild pneumonitis to rapidly progressing respiratory failure.…”