Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia
Autor: | Zahide Ozer, Hong Ma, Fatih M. Uckun, Rebecca Rose, Dorothea E. Myers, Osmond J. D'Cruz, Sanjive Qazi |
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Rok vydání: | 2015 |
Předmět: |
Recombinant Fusion Proteins
Mice Nude Antineoplastic Agents Mice SCID Biology Pharmacology CD19 law.invention law In vivo Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Tumor Cells Cultured Biotherapeutic agent medicine Animals Humans Clonogenic assay B cell General Medicine medicine.disease Xenograft Model Antitumor Assays Mice Inbred C57BL Receptors TNF-Related Apoptosis-Inducing Ligand Leukemia medicine.anatomical_structure Apoptosis Recombinant DNA biology.protein Research Article |
Zdroj: | Journal of Clinical Investigation. 125:1006-1018 |
ISSN: | 0021-9738 |
Popis: | 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. |
Databáze: | OpenAIRE |
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