Biophysical Considerations for Rational Antibody and ADC Design

TL;DR

This paper advocates for using computational biophysics to improve antibody and ADC design by linking molecular interactions to therapeutic outcomes, aiming to enhance efficacy and safety.

Contribution

It introduces a framework integrating molecular dynamics and free energy calculations into antibody and ADC development to reduce empirical testing.

Findings

Molecular simulations reveal how conjugation affects antibody conformations.

Structural coupling impacts antigen binding and internalization.

Physics-based models can de-risk ADC development pipelines.

Abstract

Antibody-based therapeutics-including antibody-drug conjugates (ADCs), bispecific antibodies, and novel formats-are reshaping oncology, yet key determinants of efficacy, safety, and manufacturability frequently emerge after conjugation and formulation. We argue that computational biophysics provides an underexploited framework to address this gap by connecting molecular interactions to biological outcomes. We highlight how molecular dynamics, coarse-grained simulations, and free energy calculations reveal how conjugation site, linker chemistry, and drug-antibody ratio reshape conformational landscapes. We emphasize structural coupling between antibody, linker, and payload, with implications for antigen binding, internalization, and developability. We propose that integrating physics-based modeling into development pipelines-alongside experimental validation-can reduce empirical iteration and de-risk translation. As force fields, and hybrid physics-machine-learning methods improve, this field is poised to become a central driver of next-generation ADC design.