A novel polyethylene glycol (PEG)‐drug conjugate of Venetoclax, a Bcl‐2 inhibitor, for treatment of acute myeloid leukemia (AML)

BACKGROUND: Venetoclax (VTX) is an anticancer drug. It is a selective Bcl‐2 inhibitor that is clinically used for the treatment of patients with lymphomas and leukemias. Treatment with VTX, however, is accompanied by severe adverse events such as tumor lysis syndrome and neutropenia, because VTX readily binds to serum proteins, which results in poor pharmacokinetics and poor tumor tissue concentration. To avoid such adverse events, VTX is administered using a daily or weekly ramp‐up schedule that is cumbersome in clinical situations. AIMS: To overcome these shortcomings, we prepared a novel polyethylene glycol (PEG)‐drug conjugate of VTX (PEG‐VTX) and evaluated its cytotoxic effects on acute myeloid leukemia (AML) both in vitro and in vivo. METHODS AND RESULTS: VTX and 4‐armed PEG derivatives were covalently attached through an amide bond linker. In a series of in vitro studies, PEG‐VTX selectively induced potent growth inhibition of MV4‐11 human AML cells via the inducement of Bcl‐2‐mediated apoptosis. PEG‐VTX had the effect of free VTX, presumably due to the protease‐mediated release of VTX from the conjugates. In in vivo studies with AML tumor‐xenograft mice models, intravenous PEG‐VTX promoted sufficient tumor growth suppression. Compared with a regimen of oral free VTX, the intravenous regimen in those studies used a VTX dosage that was 15–30 times smaller for an OCI‐AML‐2 xenograft model and a dosing regimen that was less frequent for an MV4‐11 xenograft model. The most important development, however, was the absence of weight loss related to severe side effects throughout the treatments. An increase in water solubility and the resultant hydrodynamic size of VTX via PEGylation improved the pharmacokinetics of VTX by avoiding protein interactions and lessening the extravasation from blood. The result was an increase in tumor accumulation and a decrease in the nonspecific distribution of VTX. CONCLUSION: The results of this study suggest that PEG‐VTX could be an alternative therapeutic option for the safe and effective treatment of patients with AML.