Site-specific antibody-drug conjugates with variable drug-to-antibody-ratios for AML therapy

Zhefu Dai; Xiao-Nan Zhang; Qinqin Cheng; Fan Fei; Tianling Hou; Jiawei Li; Alireza Abdolvahabi; Junji Watanabe; Hua Pei; Goar Smbatyan; Jianming Xie; Heinz-Josef Lenz; Stan G Louie; Yong Zhang

doi:10.1016/j.jconrel.2021.06.041

Site-specific antibody-drug conjugates with variable drug-to-antibody-ratios for AML therapy

J Control Release. 2021 Aug 10:336:433-442. doi: 10.1016/j.jconrel.2021.06.041. Epub 2021 Jun 29.

Authors

Zhefu Dai¹, Xiao-Nan Zhang¹, Qinqin Cheng¹, Fan Fei¹, Tianling Hou¹, Jiawei Li¹, Alireza Abdolvahabi², Junji Watanabe³, Hua Pei⁴, Goar Smbatyan⁵, Jianming Xie¹, Heinz-Josef Lenz⁵, Stan G Louie⁴, Yong Zhang⁶

Affiliations

¹ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
² Mass Spectrometry Core Facility, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
³ Translational Research Laboratory, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
⁴ Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
⁶ Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA; Research Center for Liver Diseases, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: yongz@usc.edu.

Abstract

Random conjugations of chemotherapeutics to monoclonal antibodies result in heterogeneous antibody-drug conjugates (ADCs) with suboptimal pharmacological properties. We recently developed a new technology for facile generation of homogeneous ADCs by harnessing human CD38 catalytic domain and its dinucleotide-derived covalent inhibitor, termed ADP-ribosyl cyclase-enabled ADCs (ARC-ADCs). Herein we advance this technology by designing and synthesizing ARC-ADCs with customizable drug-to-antibody ratios (DARs). Through varying numbers and locations of CD38 fused to an antibody targeting human C-type lectin-like molecule-1 (hCLL-1), ARC-ADCs featuring DARs of 2 and 4 were rapidly generated via a single step with cytotoxic monomethyl auristatin F (MMAF) as payloads. In contrast to anti-hCLL-1 ARC-ADC carrying 2 drug molecules, anti-hCLL-1 ARC-ADC with a DAR of 4 shows highly potent activity in killing hCLL-1-positive acute myeloid leukemia (AML) cells both in vitro and in vivo. This work provides novel ADC candidates for combating AML and supports ARC-ADC as a general and versatile approach for producing site-specific ADCs with defined DARs.

Keywords: Acute myeloid leukemia; Antibody-drug conjugate; Protein engineering; Targeted therapy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antibodies, Monoclonal
Antineoplastic Agents*
Humans
Immunoconjugates*
Leukemia, Myeloid, Acute* / drug therapy
Pharmaceutical Preparations*

Substances

Antibodies, Monoclonal
Antineoplastic Agents
Immunoconjugates
Pharmaceutical Preparations

Grants and funding

R35 GM137901/GM/NIGMS NIH HHS/United States