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Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia
Fatih M. Uckun, … , Osmond J. D’Cruz, Hong Ma
Fatih M. Uckun, … , Osmond J. D’Cruz, Hong Ma
Published January 26, 2015
Citation Information: J Clin Invest. 2015;125(3):1006-1018. https://doi.org/10.1172/JCI76610.
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Research Article Oncology Article has an altmetric score of 77

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia

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Abstract

Patients with B cell precursor acute lymphoblastic leukemia (BPL) respond well to chemotherapy at initial diagnosis; however, therapeutic options are limited for individuals with BPL who relapse. Almost all BPL cells express CD19, and we recently cloned the gene encoding a natural ligand of the human CD19 receptor (CD19L). We hypothesized that fusion of CD19L to the soluble extracellular domain of proapoptotic TNF-related apoptosis-inducing ligand (sTRAIL) would markedly enhance the potency of sTRAIL and specifically induce BPL cell apoptosis due to membrane anchoring of sTRAIL and simultaneous activation of the CD19 and TRAIL receptor (TRAIL-R) apoptosis signaling pathways. Here, we demonstrate that recombinant human CD19L-sTRAIL was substantially more potent than sTRAIL and induced apoptosis in primary leukemia cells taken directly from BPL patients. CD19L-sTRAIL effectively targeted and eliminated in vivo clonogenic BPL xenograft cells, even at femtomolar-picomolar concentrations. In mice, CD19L-sTRAIL exhibited a more favorable pharmacokinetic (PK) profile than sTRAIL and was nontoxic at doses ranging from 32 fmol/kg to 3.2 pmol/kg. CD19L-sTRAIL showed potent in vivo antileukemic activity in NOD/SCID mouse xenograft models of relapsed and chemotherapy-resistant BPL at nontoxic fmol/kg dose levels. Together, these results suggest that recombinant human CD19L-sTRAIL has clinical potential as a biotherapeutic agent against BPL.

Authors

Fatih M. Uckun, Dorothea E. Myers, Sanjive Qazi, Zahide Ozer, Rebecca Rose, Osmond J. D’Cruz, Hong Ma

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Figure 5

In vivo PKs of CD19L-sTRAIL.

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In vivo PKs of CD19L-sTRAIL.
C57BL/6 mice were injected with an i.v. bol...
C57BL/6 mice were injected with an i.v. bolus dose of 2.0 pmol/kg CD19L-sTRAIL or 6.1 pmol/kg sTRAIL in a 100 μl volume. Mice (CD19L-sTRAIL: 2/time point at 1 and 4 hours; 3/time point at 0.5, 2, and 24 hours; sTRAIL: 2/time point at 1, 2, 4 hours; 3/time point at 0.5 and 24 hours) were sacrificed at the indicated time points, and blood samples were collected immediately after CO2 euthanasia. The plasma concentrations of sTRAIL and CD19L-sTRAIL were measured in duplicate by a solid-phase sandwich ELISA using the Human TRAIL/TNFSF10 Quantikine ELISA Kit. (A) The Y-intercept of plasma concentration/time profile determined the Cmax. The PK parameters AUC (AUC0–100h), area under the moment curve (AUMC0–100h), MRT, and plasma half-life were calculated as detailed in Supplemental Methods. (B) Depicted are bar graphs showing the mean ± SEM values and P values for planned linear contrasts (ANOVA model with time and treatment factors, including an interaction term, time × treatment) for the plasma concentrations of CD19L-sTRAIL versus sTRAIL at 2, 4, and 24 hours after their i.v. administration.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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