Design, synthesis and evaluation of anti-CD123 antibody drug conjugates. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Li, Bin; Zhao, Weiyu; Zhang, Xinfu; Wang, Junfeng; Luo, Xiao; Baker, Sharyn D.; Jordan, Craig T.; Dong, Yizhou
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 22(2016)
• Page Start: 5855
• Page End: 5860
• Publication Date: 2016-11-15
• Subjects: CD123 -- Camptothecin -- Acute myeloid leukemia (AML) -- Leukemia stem cells (LSCs) -- Antibody drug conjugates (ADCs); AML acute myeloid leukemia -- LSCs leukemia stem cells -- ADCs antibody drug conjugates -- CPT Camptothecin -- GSH Glutathione; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.09.043
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Leukemia stem cells (LSCs) account for the development of drug resistance and increased recurrence rate in acute myeloid leukemia (AML) patients. Targeted drug delivery to leukemia stem cells remains a major challenge in AML chemotherapy. Overexpressed interleukin-3 receptor alpha chain, CD123, on the surface of leukemia stem cells was reported to be a potential target in AML treatment. Here, we designed and developed an antibody drug conjugate (CD123-CPT) by integrating anti-CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker. The linker is biodegradable in the presence of Glutathione (GSH, an endogenous component in cells), which leads to release of CPT. Anti-CD123 antibody conjugates showed significant higher cellular uptake in CD123-overexpressed tumor cells. More importantly, CD123-CPT demonstrated potent inhibitory effects on CD123-overexpressed tumor cells. Consequently, these results provide a promising targeted chemotherapeutical strategy for AML treatment.