Exogenous CD38 upregulation enables high-efficacy dually cascade targeted molecular therapy of leukemia

Acute myeloid leukemia (AML) patients face poor prognosis with high mortality rate, mainly due to the lack of suitable antigens and shortage of effective targeted therapeutics. Here, we utilize exogenous all-trans retinoic acid (ATRA) to upregulate CD38 level on AML cells and therefore boost the AML-targeting of daratumumab-directed polymersomal volasertib molecular targeted drugs (DPVol), for potent and safe AML depletion via cascade targeting. DPVol with a small size of similar to 30 nm had tailored daratumumab density, efficient and robust Vol loading, as well as reduction-triggered intracellular Vol release. ATRA stimulation substantially increased CD38 level on AML cell lines and primary cells isolated from AML patients as much as 20-fold, and accordingly enhanced the cellular uptake and anti-AML activity of DPVol, displaying a low IC50 of 16.3 nM in MV-4-11 cells. Intriguingly, ATRA + DPVol combination treatment dramatically reduced the leukemia burden in orthotopic CD38low MV-4-11 and Molm-13-Luc AML bearing mice without causing toxicity, resulting in 4.3-5.8-fold prolonged survival with 20-40 % of mice cured, superior to DPVol and ATRA + PVol. The exogenous stimulation mediated CD38 upregulation in combination with DPVol may provide a safe and cascade targeting strategy for potent treatment of leukemia.(c) 2023 Elsevier Ltd. All rights reserved.