◆この研究は、子供の進行性血液がんや他のがんの治療に革新的な選択肢を提供する可能性があります。さらに、このアプローチは他の治療薬にも応用でき、子供たちにより安全な治療法を提供する可能性があります。今後は臨床への応用を目指し、UNSW Australian Centre for NanoMedicineとの協力で研究を進めていく予定です。
二重特異性抗体によるPEG化リポソームドキソルビシンの送達は、高リスク小児白血病モデルにおける治療を改善する 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 Dolnikov,Laurence C. Cheung,Rishi S. Kotecha,Murray D. Norris,Michelle Haber,Charles E. de Bock,Klaartje Somers,Richard B. Lock,Kristofer J. Thurecht,Maria Kavallaris
Science Translational Medicine Published:17 May 2023
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.
Targeting leukemia treatment
Caelyx, a PEGylated liposomal formulation of doxorubicin, has shown promise as a therapy for cancer. However, efficacy has been limited because of issues of tolerability and specificity of delivery to tumor cells. To address this, Moles et al. generated bispecific antibodies (BsAbs) that bound to PEG on the Caelyx product and to the leukemic cell markers CD19, CD20, CD22, or CD38. Targeted delivery of Caelyx with the BsAbs improved activity of Caelyx against leukemia cells with minimal evidence of toxicity toward normal immune cells. Beyond the direct implications for treating childhood leukemia, the results of this study suggest that BsAb-mediated targeting may overcome similar delivery barriers for other drugs. —CM