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Open Access Publications from the University of California

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

  • Author(s): 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
  • et al.

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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.

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This item is under embargo until July 14, 2022.