Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia.
Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia.
复制标题
重组人 CD19L-sTRAIL 有效靶向 B 细胞前体急性淋巴细胞白血病。
DOI：
10.1172/jci76610
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Ma,Hong
中科院分区：
文献类型：
--
作者：
Uckun,FatihM;Myers,DorotheaE;Qazi,Sanjive;Ozer,Zahide;Rose,Rebecca;D'Cruz,OsmondJ;Ma,Hong
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.
