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

• DOI: 10.1016/j.jconrel.2021.06.041
• Publication Date: 2021-06-29T04:09:20Z
• Authors: 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
• Keywords: Myeloid; 0301 basic medicine; Immunoconjugates; 572; Oncology and Carcinogenesis; Biomedical Engineering; Antineoplastic Agents; Acute; Antibodies; Targeted therapy; 03 medical and health sciences; Rare Diseases; Monoclonal; Humans; Pharmacology & Pharmacy; Antibody-drug conjugate; Cancer; Leukemia; Acute myeloid leukemia; Biomedical and Clinical Sciences; Antibodies, Monoclonal; Hematology; Pharmacology and Pharmaceutical Sciences; Chemical Engineering; 3. Good health; Leukemia, Myeloid, Acute; Pharmacology and pharmaceutical sciences; Pharmaceutical Preparations; 5.1 Pharmaceuticals; Immunization; Protein engineering; Development of treatments and therapeutic interventions; Biomedical engineering; Biotechnology

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.