Site-Specific Antibody-Drug Conjugates with Variable Drug-to-Antibody-Ratios for Acute Myeloid Leukemia Therapy

• Published in: Journal of controlled release 2021-06, Vol.336, p.433-442
• Main Authors: Dai, Zhefu, Zhang, Xiao-Nan, Cheng, Qinqin, Fei, Fan, Hou, Tianling, Li, Jiawei, Abdolvahabi, Alireza, Watanabe, Junji, Pei, Hua, Smbatyan, Goar, Xie, Jianming, Lenz, Heinz-Josef, Louie, Stan G., Zhang, Yong
• Format: Article
• Language: English
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2021.06.041

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 A DP- ri bosyl c yclase-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.