Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases
Open Access
- 5 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (23), eaba6752
- https://doi.org/10.1126/sciadv.aba6752
Abstract
Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.Funding Information
- V Foundation for Cancer Research (V2016-021)
- Pharmaceutical Research and Manufacturers of America Foundation (Research Starter Grant in Translational Medicine and Therapeutics)
- Stop Cancer (Research Career Development Award)
- University of Southern California (Start-Up Fund for New Faculty; Sharon L. Cockrell Cancer Research Fund)
This publication has 48 references indexed in Scilit:
- Synthesis of site-specific antibody-drug conjugates using unnatural amino acidsProceedings of the National Academy of Sciences of the United States of America, 2012
- Overview of theCCP4 suite and current developmentsActa crystallographica. Section D, Structural biology, 2011
- Structural Basis for Enzymatic Evolution from a Dedicated ADP-ribosyl Cyclase to a Multifunctional NAD HydrolaseOnline Journal of Public Health Informatics, 2009
- Mechanism-Based Small Molecule Probes for Labeling CD38 on Live CellsJournal of the American Chemical Society, 2009
- Covalent and Noncovalent Intermediates of an NAD Utilizing Enzyme, Human CD38Cell Chemical Biology, 2008
- Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7Nature Protocols, 2008
- Phasercrystallographic softwareJournal of Applied Crystallography, 2007
- Scaling and assessment of data qualityActa crystallographica. Section D, Structural biology, 2005
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004
- Structure of the extracellular region of HER2 alone and in complex with the Herceptin FabNature, 2003