Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia

Ernest Moles, Christopher B. Howard, Pie Huda, Mawar Karsa, Hannah McCalmont, Kathleen Kimpton, Alastair Duly, Yongjuan Chen, Yizhou Huang, Melinda L. Tursky, David Ma, Sonia Bustamante, Russell Pickford, Patrick Connerty, Sofia Omari, Christopher J. Jolly, Swapna Joshi, Sylvie Shen, John E. Pimanda, Alla DolnikovLaurence C. Cheung, Rishi S. Kotecha, Murray D. Norris, Michelle Haber, Charles E. de Bock, Klaartje Somers, Richard B. Lock, Kristofer J. Thurecht, Maria Kavallaris

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells. Here, we report on the generation of bispecific antibodies (BsAbs) with dual binding to a leukemic cell receptor, such as CD19, CD20, CD22, or CD38, and methoxy polyethylene glycol (PEG) for the targeted delivery of PEGylated liposomal drugs to leukemia cells. This liposome targeting system follows a "mix-and-match" principle where BsAbs were selected on the specific receptors expressed on leukemia cells. BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward leukemia cell lines and patient-derived samples that are immunophenotypically heterogeneous and representative of high-risk subtypes of childhood leukemia. BsAb-assisted improvements in leukemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were minimally detrimental in vitro and in vivo toward expansion and functionality of normal peripheral blood mononuclear cells and hematopoietic progenitors. Targeted delivery of Caelyx using BsAbs further enhanced leukemia suppression while reducing drug accumulation in the heart and kidneys and extended overall survival in patient-derived xenograft models of high-risk childhood leukemia. Our methodology using BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukemia.

Original languageEnglish
Article numberabm1262
JournalScience Translational Medicine
Volume15
Issue number696
DOIs
Publication statusPublished - 17 May 2023

Fingerprint

Dive into the research topics of 'Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia'. Together they form a unique fingerprint.

Cite this