Issue 34, 2020
From the journal:

Chemical Science

A poly-ADP-ribose polymer-based antibody-drug conjugate†

Xiaojing Shi,‡a   Xiao-Nan Zhang, ORCID logo ‡a   Jingwen Chen,‡a   Qinqin Cheng,a   Hua Pei,b   Stan G. Louieb  and  Yong Zhang ORCID logo *acde  

* Corresponding authors

a Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA

b Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA

c Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA

d Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA

e Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA
E-mail: yongz@usc.edu

Abstract

Protein poly-ADP-ribosylation (PARylation) plays vital roles in many aspects of physiology and pathophysiology. This posttranslational modification is catalyzed by poly-ADP-ribose polymerases (PARPs) through additions of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to protein residues, forming linear or branched poly-ADP-ribose (PAR) polymers. In this study, we explored a new concept of utilizing functionalized PAR polymers for targeted drug delivery. This was achieved by rapid and efficient generation of auto-PARylated PARP1 with 3′-azido ADP-riboses and subsequent conjugations of anti-human epidermal growth factor receptor 2 (HER2) antibodies and monomethyl auristatin F (MMAF) payloads. This designed PARylated PARP1-antibody-MMAF conjugate could potently kill HER2-expressing cancer cells in high specificity. This proof-of-principle work demonstrates the feasibility of production of PAR polymer-based antibody-drug conjugate and its application in targeted delivery. The PAR polymer-based conjugates may lead to new types of therapeutics with potentially improved physicochemical and pharmacological properties.

Graphical abstract: A poly-ADP-ribose polymer-based antibody-drug conjugate

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Article information

DOI
https://doi.org/10.1039/D0SC01795G
Article type
Edge Article
Submitted
28 Mar 2020
Accepted
13 Aug 2020
First published
17 Aug 2020
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2020,11, 9303-9308

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A poly-ADP-ribose polymer-based antibody-drug conjugate

X. Shi, X. Zhang, J. Chen, Q. Cheng, H. Pei, S. G. Louie and Y. Zhang, Chem. Sci., 2020, 11, 9303 DOI: 10.1039/D0SC01795G

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