A novel immunotoxin reveals a new role for CD321 in endothelial cells.
A novel immunotoxin reveals a new role for CD321 in endothelial cells.
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DOI：
10.1371/journal.pone.0181502
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Hattori N
中科院分区：
文献类型：
--
作者：
Fukuhara T;Kim J;Hokaiwado S;Nawa M;Okamoto H;Kogiso T;Watabe T;Hattori N
目前有几种直接针对肿瘤的抗体治疗方法，抗体-药物偶联物代表了下一代治疗方法的新部分。在这里，我们使用一种独特的筛选探针DT3C来鉴定识别表面分子和功能表位的功能抗体，并提供毒素递送能力。因此，我们产生了90G4抗体，该抗体在内皮细胞中诱导dt3c依赖性细胞毒性。分子分析显示，90G4识别CD321，这是一种定位于紧密连接的蛋白质。尽管CD321在炎症和淋巴细胞跨内皮迁移中起关键作用，但其在内皮细胞中的作用机制尚不清楚。90G4免疫毒素靶向CD321诱导细胞死亡。此外，90G4免疫毒素主要在迁移内皮细胞中引起细胞毒性，而不是在形成薄片的内皮细胞中引起细胞毒性，这表明CD321在肿瘤血管生成中起关键作用。我们还发现，缺氧触发CD321重新分布到细胞基底侧的点状定位，导致紧密连接的功能损伤和运动性增加。因此，我们的研究结果提出了一种有趣的可能性，即内皮细胞CD321在紧密连接中表现出细胞定位，以及在几种情况下的多功能动力学，从而阐明了广泛表达的CD321作为抗肿瘤治疗的潜在靶点的重要性。
There are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes, and which provided toxin delivery capability. Accordingly, we generated the 90G4 antibody, which induced DT3C-dependent cytotoxicity in endothelial cells. Molecular analysis revealed that 90G4 recognized CD321, a protein localized at tight junctions. Although CD321 plays a pivotal role in inflammation and lymphocyte trans-endothelial migration, little is known about its mechanism of action in endothelial cells. Targeting of CD321 by the 90G4 immunotoxin induced cell death. Moreover, 90G4 immunotoxin caused cytotoxicity primarily in migratory endothelial cells, but not in those forming sheets, suggesting a critical role for CD321 in tumor angiogenesis. We also found that hypoxia triggered redistribution of CD321 to a punctate localization on the basal side of cells, resulting in functional impairment of tight junctions and increased motility. Thus, our findings raise the intriguing possibility that endothelial CD321 presented cellular localization in tight junction as well as multifunctional dynamics in several conditions, leading to illuminate the importance of widely-expressed CD321 as a potential target for antitumor therapy.
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DOI：
10.1111/j.1349-7006.1991.tb01803.x
发表时间：
1991-12
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Yanai N;Satoh T;Kyo S;Abe K;Suzuki M;Obinata M
通讯作者：
Obinata M
影响因子：
82.9
作者：
Zeisberg, Elisabeth M.;Tarnavski, Oleg;Kalluri, Raghu
通讯作者：
Kalluri, Raghu
DOI：
10.1084/jem.190.9.1351
发表时间：
1999-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Del Maschio A;De Luigi A;Martin-Padura I;Brockhaus M;Bartfai T;Fruscella P;Adorini L;Martino G;Furlan R;De Simoni MG;Dejana E
通讯作者：
Dejana E
影响因子：
2.7
作者：
Mihira, Hajime;Suzuki, Hiroshi I.;Watabe, Tetsuro
通讯作者：
Watabe, Tetsuro
影响因子：
7.4
作者：
Azari, Bani M.;Marmur, Jonathan D.;Babinska, Anna
通讯作者：
Babinska, Anna