Antibody–drug conjugates (ADCs) combine the high specificity of antibodies with cytotoxic payloads. However, the present strategies for the synthesis of ADCs either yield unstable or heterogeneous products or involve complex processes. Here, we report a computational approach that leverages molecular docking and molecular dynamics simulations to design ADCs that self-assemble through the non-covalent binding of the antibody to a payload that we designed to act as an affinity ligand for specific conserved amino acid residues in the antibody. This method does not require modifications to the antibody structure and yields homogenous ADCs that form in less than 8 min. We show that two conjugates, which consist of hydrophilic and hydrophobic payloads conjugated to two different antibodies, retain the structure and binding properties of the antibody and its biological specificity, are stable in plasma and improve anti-tumour 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.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available from the corresponding authors on reasonable request.
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We thank staff at the Advanced Instrumentation Research Facility at Jawaharlal Nehru University, Delhi and DBT grant (no. BT/PR3130/INF/22/139/2011) for use of their confocal microscopy facility.
N.G., A.Sarkar, A.Sengupta and M.R. are employees of Akamara Therapeutics and own equity. S.S. is a cofounder and board member of Akamara Therapeutics and owns equity in Akamara Therapeutics. N.G., S.S. and M.R. are listed as inventors on a patent on this technology (US Patent App. 15/124,058; WO2015148126A1).
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Gupta, N., Ansari, A., Dhoke, G.V. et al. Computationally designed antibody–drug conjugates self-assembled via affinity ligands. Nat Biomed Eng 3, 917–929 (2019). https://doi.org/10.1038/s41551-019-0470-8