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Computationally designed antibody-drug conjugates self-assembled via affinity ligands
- Source :
- Nature biomedical engineering. 3(11)
- Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Models, Molecular
Immunoconjugates
Chemical Phenomena
Biomedical Engineering
Medicine (miscellaneous)
Mice, Nude
Bioengineering
Antineoplastic Agents
Conjugated system
Molecular Dynamics Simulation
Ligands
Protein Engineering
Molecular Docking Simulation
Antibodies
Substrate Specificity
03 medical and health sciences
Mice
0302 clinical medicine
Biological specificity
Drug Stability
Antibody Specificity
Neoplasms
Animals
Binding site
Binding Sites
biology
Molecular Structure
Chemistry
Ligand
Cytotoxins
Protein engineering
Trastuzumab
Combinatorial chemistry
Xenograft Model Antitumor Assays
Computer Science Applications
body regions
Disease Models, Animal
030104 developmental biology
Drug Design
biology.protein
Antibody
Hydrophobic and Hydrophilic Interactions
030217 neurology & neurosurgery
Biotechnology
Conjugate
Subjects
Details
- ISSN :
- 2157846X
- Volume :
- 3
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature biomedical engineering
- Accession number :
- edsair.doi.dedup.....d722eee61eee1c1c4119242ff966aec0