Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo.
Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo.
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DOI：
10.1182/bloodadvances.2021006485
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发表时间：
2023-04-11
期刊：
影响因子：
7.5
通讯作者：
Norris, Erin H.
中科院分区：
文献类型：
--
作者：
Chen, Zu-Lin;Singh, Pradeep K.;Horn, Katharina;Calvano, Marissa R.;Kaneki, Shigeru;McCrae, Keith R.;Strickland, Sidney;Norris, Erin H.
3E8抗hk抗体在体内和体外抑制接触系统的血栓形成和炎症途径。3E8在体内和体外都能阻断PK和FXI与HK的结合。血浆接触系统失调与多种病理状况有关，如遗传性血管性水肿、阿尔茨海默病和败血症。我们之前的研究表明，3E8抗高分子量激肽原（anti-HK）抗体在离体人血浆中阻断HK的裂解和缓激肽的产生。在这里，我们发现3E8不仅可以阻止HK的切割，还可以通过阻断小鼠血浆中与HK结合的因子XI （FXI）和预钾likrein （PK）的激活。3E8还能抑制体内接触系统诱导的缓激肽的产生。有趣的是，FXII的激活也被抑制，可能是因为3E8能够阻断klikrein （PKa）对FXII的正反馈激活。在人血浆中，3E8还阻断了PK和FXI与HK的结合，并在体外抑制了血浆接触系统激活的血栓形成（FXI激活）和炎症途径（PK激活和HK裂解）。此外，3E8阻断PKa与HK的结合，并剂量依赖性地抑制PKa对HK的切割。我们的研究结果揭示了一种抑制体内接触系统激活的新策略，这可能为治疗涉及接触系统失调的人类疾病提供一种有效的方法。
3E8 anti-HK antibody inhibits thrombotic and inflammatory pathways of the contact system ex vivo and in vivo. 3E8 blocks the binding of PK and FXI to HK both ex vivo and in vivo. A dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer disease, and sepsis. We previously showed that the 3E8 anti–high molecular weight kininogen (anti-HK) antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here, we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) and prekallikrein (PK) activation by blocking their binding to HK in mouse plasma in vivo. 3E8 also inhibited contact system–induced bradykinin generation in vivo. Interestingly, FXII activation was also inhibited, likely because of the ability of 3E8 to block the positive feedback activation of FXII by kallikrein (PKa). In human plasma, 3E8 also blocked PK and FXI binding to HK and inhibited both thrombotic (FXI activation) and inflammatory pathways (PK activation and HK cleavage) of the plasma contact system activation ex vivo. Moreover, 3E8 blocked PKa binding to HK and dose-dependently inhibited PKa cleavage of HK. Our results reveal a novel strategy to inhibit contact system activation in vivo, which may provide an effective method to treat human diseases involving contact system dysregulation.
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影响因子：
4.2
作者：
Ashby, Emma L.;Love, Seth;Kehoe, Patrick G.
通讯作者：
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影响因子：
15.9
作者：
Flick, Matthew J.;LaJeunesse, Christine M.;Degen, Jay L.
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影响因子：
20.3
作者：
Chen, Zu-Lin;Revenko, Alexey S.;Strickland, Sidney
通讯作者：
Strickland, Sidney
DOI：
10.1073/pnas.1914831116
发表时间：
2019-11-12
影响因子：
11.1
作者：
Chen, Zu-Lin;Singh, Pradeep;Norris, Erin H.
通讯作者：
Norris, Erin H.
DOI：
10.1083/jcb.201212032
发表时间：
2013-07-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen ZL;Yao Y;Norris EH;Kruyer A;Jno-Charles O;Akhmerov A;Strickland S
通讯作者：
Strickland S