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

Autor: Jiawei Li, Fan Fei, Qinqin Cheng, Jianming Xie, Stan G. Louie, Hua Pei, Junji Watanabe, Yong Zhang, Alireza Abdolvahabi, Zhefu Dai, Tianling Hou, Xiao-Nan Zhang, Goar Smbatyan, Heinz-Josef Lenz
Rok vydání: 2021
Předmět:
Myeloid
Antibody-drug conjugate
Immunoconjugates
medicine.drug_class
medicine.medical_treatment
Biomedical Engineering
Pharmaceutical Science
Antineoplastic Agents
02 engineering and technology
Acute
Monoclonal antibody
Antibodies
Targeted therapy
03 medical and health sciences
Rare Diseases
In vivo
Monoclonal
medicine
Humans
Pharmacology & Pharmacy
Cancer
030304 developmental biology
0303 health sciences
Leukemia
Acute myeloid leukemia
Chemistry
Myeloid leukemia
Hematology
Pharmacology and Pharmaceutical Sciences
Protein engineering
Chemical Engineering
021001 nanoscience & nanotechnology
In vitro
body regions
Monomethyl auristatin F
Pharmaceutical Preparations
5.1 Pharmaceuticals
Cancer research
Development of treatments and therapeutic interventions
0210 nano-technology
Biotechnology
medicine.drug
Zdroj: Journal of Controlled Release. 336:433-442
ISSN: 0168-3659
DOI: 10.1016/j.jconrel.2021.06.041
Popis: 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.
Databáze: OpenAIRE
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