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

Nat Biomed Eng. 2019 Nov;3(11):917-929. doi: 10.1038/s41551-019-0470-8. Epub 2019 Nov 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / chemistry*
  • Antibody Specificity
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Chemical Phenomena
  • Cytotoxins / chemistry*
  • Disease Models, Animal
  • Drug Design*
  • Drug Stability
  • Hydrophobic and Hydrophilic Interactions
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacology*
  • Ligands
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Neoplasms / drug therapy
  • Protein Engineering
  • Substrate Specificity
  • Trastuzumab
  • Xenograft Model Antitumor Assays


  • Antibodies
  • Antineoplastic Agents
  • Cytotoxins
  • Immunoconjugates
  • Ligands
  • Trastuzumab