Combining molecular simulation and AI for antibody design against cancer immunotherapy targets

Abstract

Rational design of antibody therapeutics represents an important frontier in drug discovery, and designing novel and diverse antibody candidates for immune checkpoint inhibition remains a topic of particular interest in cancer immunotherapy development. I cover efforts to establish and target novel epitopes with antibody therapeutics for immuno-oncology applications, using the immune cell exhaustion-associated receptor TIM-3 as a case study. I discuss the use of molecular dynamics simulations to identify TIM-3 conformational changes in functional contexts, the fitting of those conformational ensembles to X-ray reflectivity data, and the design of antibodies targeting unique functional TIM-3 epitopes with AI-enhanced free energy simulation approaches.