High-risk childhood B and T cell acute lymphoblastic leukaemia (high-risk B- and T-ALL) has a poor prognosis due to treatment failure and toxic side effects of therapy. Similarly, children diagnosed with B-ALL and acute myeloid leukaemia (AML) both harbouring MLL gene rearrangements have >50% relapse rates and poor overall survival. For these aggressive subtypes of leukaemia, there are only limited treatment options with most intensive chemotherapy regimens having reached the limit of tolerability. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited due to a lack of selectivity of the liposomal formulations for the cancer cells.
Here, we focus on the development of a dynamic and flexible “mix-and-match” approach for the targeting of liposomal drugs to high-risk childhood leukaemia. This approach allows for the rapid adjustment of therapy based on the specific cell surface receptors expressed on leukaemia cells. Specifically, PEGylated liposomal drugs are non-covalently complexed with an interchangeable panel of bispecific antibodies (BsAbs) that simultaneously bind to methoxy polyethylene glycol (PEG) on the nanoparticle surface and CD19, CD20, CD22 or CD38 receptors on leukaemia cells.
BsAbs improved the targeting and cytotoxic activity of a clinically approved and low-toxic PEGylated liposomal formulation of doxorubicin (Caelyx) toward a panel of >13 leukaemia cell lines and patient-derived leukaemia cells that are immunophenotypically heterogeneous and representative of the major high-risk subtypes of childhood leukaemia, including relapsed-refractory B-ALL and T-ALL, Philadelphia-like ALL, Philadelphia positive B-ALL, and MLL-gene rearranged B-ALL and AML. BsAb-assisted improvements in leukaemia cell targeting and cytotoxic potency of Caelyx correlated with receptor expression and were not detrimental toward healthy peripheral blood mononuclear cells or lineage differentiation of haematopoietic progenitors. In addition, this study, now published at Science Translational Medicine [1], provides proof-of-concept for multiplexing BsAbs as a potential treatment strategy to prevent immune escape and future relapses. Targeted delivery of Caelyx using BsAbs further enhanced leukaemia suppression and extended overall survival by up to three-fold in clinically-relevant patient-derived xenograft models of high-risk childhood leukaemia developed at our institute. Our methodology employing BsAbs therefore represents an attractive targeting platform to potentiate the therapeutic efficacy and safety of liposomal drugs for improved treatment of high-risk leukaemia.