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

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.

Development of a new anti‐CD123 monoclonal antibody to target the human CD123 antigen as an acute myeloid leukemia cancer stem cell biomarker

“…They found the increased cytotoxic activity on a CD123 expressing cell line . As an interesting approach for AML therapy, Li et al designed and developed an antibody–drug conjugate (CD123‐CPT) by integrating anti‐CD123 antibody with a chemotherapeutic agent, Camptothecin (CPT), via a disulfide linker, showing suitable internalization and potent inhibitory effects on CD123‐overexpressed tumor cells .…”

Design, synthesis and evaluation of anti-CD38 antibody drug conjugate based on Daratumumab and maytansinoid

“…Dara-DM4 was synthesized according to the reported method. 18,19 Firstly, DM4 and SPDP were dissolved in DMSO to obtain 5 mM stock solution, respectively. Then, 40 μL of Daratumumab (20 mg/mL), 5.6 μL SPDP stock solution (5mM), 280 μL PBS (pH 7.40) and 80 μL NaFICO 3 (1 M) were mixed and incubated at room temperature for 1 h. After purification through a Zeba column, the intermediate was mixed with 5.6 μL DM4 and incubated at 4 °C for 18 h. The resulted mixture was purified through the Zeba column to yield Dara-DM4 (400 μL, 2 mg/mL).…”

“…Cytotoxicity of Dara-DM4 was examined in MM1S cells and macrophages by MTT assays as reported previously. 18 Macrophages were cultured as described in the literature. 21 Cell viability of Dara-DM4 was normalized by untreated cells.…”

Role of the β Common (βc) Family of Cytokines in Health and Disease

“…The anti-IL3Ra MAb, KHK2823 (Akiyama et al 2015), is currently in phase I clinical trials in patients with AML or MDS (ClinicalTrials.gov identifier: NCT02181699) as is the bispecific antibody MGD006 (Al-Hussaini et al 2016) that targets IL3Ra and CD3 (ClinicalTrials.gov identifier: NCT02152956). The development of an anti-CD123 antibody -drug conjugate that directs a chemotherapy agent, camptothecin, to the target cell (Li et al 2016a) represents an alternative use for anti-IL3Ra MAbs. In related approaches, engineered T cells expressing CARs have been developed to target IL3Ra expressed on AML blast cells and leukemic stem cells (Testa et al 2002).…”