Computationally designed antibody–drug conjugates self-assembled via affinity ligands


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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Fig. 1: Engineering a MAGNET ADC.
Fig. 2: Physicochemical characterization of a MAGNET ADC.
Fig. 3: MAGNET ADCs bind to the target and are stable in human plasma.
Fig. 4: The efficacy of MAGNET ADCs in vitro.
Fig. 5: MAGNET ADCs improve anti-tumour outcomes in vivo.

Data availability

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.

Change history

  • 03 January 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


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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.

Author information

N.G. conceived the idea, led the overall study, prepared and characterized the conjugates. G.B. and N.G. designed the linkers. A.A. synthesized and characterized the linkers and P.K.D. performed initial optimizations under supervision of G.B., A.Sarkar and S.K.M. G.V.D. performed all of the in silico research under the supervision of S.R. M.C. performed the ITC experiments under the supervision of V.R. and M.M. R.G. purified the linkers by HPLC. J.S., S.K. and S.C. performed all of the biological studies under supervision of A.Sengupta. M.S. analysed the PK data. M.R. and S.S. supervised all of the studies. N.G., M.R. and S.S. wrote the manuscript with input from all of the authors.

Correspondence to Nimish Gupta or Shiladitya Sengupta.

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Competing interests

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).

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