Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases

Science Advances
Zhefu DaiYong Zhang

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.

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Citations

Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring
Dec 29, 2020·Bioorganic & Medicinal Chemistry·Jisoo ParkTae Hyeon Yoo
Feb 17, 2021·Chemical Communications : Chem Comm·Joongoo LeeMichael C Jewett
Feb 25, 2021·Chemical Science·Xiaojing ShiYong Zhang
Jul 2, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Zhefu DaiYong Zhang

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Methods Mentioned

BETA
xenograft
enzyme-linked immunosorbent assay
ELISA
fluorescence imaging
fluorescence
electrophoresis
X-ray
ELISAs
transfection
PCRs

Software Mentioned

NetMHCIIpan
ray Detector Software ( XDS )
MATLAB
Leica Application Suite X ( LAS X )
BiopharmaLynx
Phaser
Refmac5
ArpWarp
Ligand Builder
Coot

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