Antibody–drug conjugates (ADCs) combine the high specificity of antibodies with cytotoxic payloads. However, current strategies for the synthesis of ADCs either yield unstable or heterogeneous products or involve complex processes. Here, we report a computational approach leveraging molecular docking and molecular dynamics simulations for the design of self-assembling ADCs via the non-covalent binding of the antibody to a payload designed to act as an affinity ligand for specific conserved amino acid residues in the antibody. The method does not require modifications to the antibody structure, and yields homogenous ADCs that form in less than 8 minutes. For two ADCs consisting of hydrophilic and hydrophobic payloads conjugated to two different antibodies, we show that they retain the structure and binding properties of the antibody and its biological specificity, are stable in plasma, and improve antitumour efficacy in mice with non-small-cell lung tumour xenografts. The relative simplicity of the approach may facilitate the production of ADCs for the targeted delivery of cytotoxic payloads.
