A CD19L–sTRAIL Fusion Targets B-cell Precursor Acute Lymphoblastic Leukemia

Although chemotherapy is often effective in treating B-cell precursor acute lymphoblastic leukemia (BPL), a subset of patients experience tumor relapse, underscoring the need to develop additional therapeutic strategies for these patients. The soluble extracellular domain of TNF-related apoptosis-inducing ligand (sTRAIL) selectively induces apoptosis in tumor cells; however, its clinical utility is limited by a short plasma half-life and rapid release from its receptors (TRAILR). In an attempt to increase the potency of sTRAIL, Uckun and colleagues generated a fusion protein consisting of sTRAIL fused to a natural ligand (CD19L) of the CD19 receptor, which is expressed by leukemic cells from patients with high-risk BPL but not normal cells. Recombinant human CD19L–sTRAIL selectively bound to primary human CD19⁺ BPL cells and patient-derived leukemic xenograft clones in vitro and induced apoptosis more potently than sTRAIL, even at very low concentrations, via activation of CD19- and TRAILR-dependent signaling. Treatment with CD19L–sTRAIL, but not CD19L or sTRAIL alone, suppressed leukemia development in patient-derived xenograft models, suggesting that this fusion protein targets leukemia-initiating cells. Furthermore, administration of low-dose CD19L–sTRAIL exhibited potent antileukemic activity in xenograft models of relapsed human BPL, resulting in prolonged event-free survival compared with untreated leukemia-bearing mice. Importantly, CD19L–sTRAIL was well tolerated in vivo and showed a superior pharmacokinetic profile compared with that of sTRAIL, including a higher plasma concentration and a longer plasma half-life. These results support the idea that fusion to CD19L enhances the potency of sTRAIL to induce apoptosis by promoting its stable anchoring to the membrane of leukemic cells and simultaneously activating the CD19 and TRAILR pathways. In addition, these preclinical studies suggest that recombinant human CD19L–sTRAIL may be clinically effective in patients with chemotherapy-resistant relapsed BPL.

Uckun FM, Myers DE, Qazi S, Ozer Z, Rose R, D'Cruz OJ, et al. Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia. J Clin Invest 2015 Jan 26 [Epub ahead of print].

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