Ultra-stable Biomembrane Force Probe for Accurately Determining Slow Dissociation Kinetics of PD-1 Blockade Antibodies on Single Living Cells.

Abstract

Immune checkpoint blockade with monoclonal antibodies (mAbs) that target programmed cell death protein-1 (PD-1) has remarkably revolutionized cancer therapy. Their binding kinetics measured by surface plasmon resonance does not always correlate well with their immunotherapeutic efficacies, mainly due to the lack of two-dimensional cell plasma membrane and the capability of force sensing and manipulation. In this regard, based on a more suitable and ultra-sensitive biomechanical nanotool, biomembrane force probe (BFP), we developed a Double-edge Smart Feedback control system as an ultra-stable platform to characterize ultra-long bond lifetimes of receptor-ligand binding on living cells. We further benchmarked the dissociation kinetics for three clinically approved PD-1 blockade mAbs (Nivolumab, Pembrolizumab, and Camrelizumab), intriguingly correlating well with the objective response rates in the hepatocellular carcinoma second-line treatment. This ultra-stable BFP potentially provides a compelling kinetic platform to direct the screening, optimization, and clinical selection of therapeutic antibodies in the future.