Design, synthesis and evaluation of anti-CD123 antibody drug conjugates

作者：Li Bin; Zhao Weiyu; Zhang Xinfu; Wang Junfeng; Luo Xiao; Baker Sharyn D; Jordan Craig T; Dong Yizhou^*

来源：Bioorganic & Medicinal Chemistry, 2016, 24(22): 5855-5860.

DOI：10.1016/j.bmc.2016.09.043

• CD123
• Camptothecin
• Acute myeloid leukemia (AML)
• Leukemia stem cells (LSCs)
• Antibody drug conjugates (ADCs)

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.

• 出版日期2016-11-15