Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy.
Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy.
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DOI：
10.1016/j.leukres.2009.02.006
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发表时间：
2009-09
影响因子：
2.7
通讯作者：
Taras EP
中科院分区：
文献类型：
--
作者：
Vallera DA;Chen H;Sicheneder AR;Panoskaltsis-Mortari A;Taras EP
一种称为DT2219ARL的双特异性配体导向毒素(DT2219ARL)由识别CD19和CD22的两个SFV配体和催化DT390组成，在体内具有优异的抗白血病活性。遗传改变包括反向定位VH-VL结构域和增加聚集减少/稳定连接子。在体内，这些改进导致了在生物发光异种移植成像模型中测量到的前所未有的长期无瘤幸存者，在该模型中，可以实时跟踪人类Raji Burkitt淋巴瘤的进展，也可以在Daudi模型中进行跟踪。研究表明，DT2219ARL是有效的(IC50s 0.06-0.2 nM范围)和选择性阻断。影像研究表明，这种B细胞恶性模型具有高度侵袭性，并可能导致终末前后肢瘫痪，因为DT2219ARL阻止了脊髓区域的转移。DT2219ARL代表了一类新的双功能生物，可以通过基因突变来不断改良。
A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two sFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt’s lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06–0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced preterminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.
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影响因子：
--
作者：
COLLIER, RJ
通讯作者：
COLLIER, RJ
影响因子：
11.5
作者：
Stish, Brad J.;Chen, Hua;Vallera, Daniel A.
通讯作者：
Vallera, Daniel A.
影响因子：
2.8
作者：
Olejniczak, SH;Stewart, CC;Czuczman, MS
通讯作者：
Czuczman, MS
影响因子：
4.3
作者：
PRESS, OW;VITETTA, ES;MARTIN, PJ
通讯作者：
MARTIN, PJ
影响因子：
3.9
作者：
Stish, Brad J.;Oh, Seunguk;Vallera, Daniel A.
通讯作者：
Vallera, Daniel A.