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公开(公告)号：EP3512552A1
公开(公告)日：2019-07-24
申请号：EP17851497.2
申请日：2017-09-14
申请人： Immunomedics, Inc.
IPC分类号： A61K39/395 , C07C259/10 , C07C311/21
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3.发明公开ANTI-HISTONE THERAPY FOR VASCULAR NECROSIS IN SEVERE GLOMERULONEPHRITIS 审中-公开抗生素抗生素抗生素耐药性BEKRERER GLOMERULONEPHRITIS
公开(公告)号：EP3160504A1
公开(公告)日：2017-05-03
申请号：EP15812106.1
申请日：2015-06-23
申请人： Immunomedics, Inc.
IPC分类号： A61K39/395 , A61K39/00 , A61K36/48 , A61K39/38
摘要： Severe glomerulonephritis involves cell necrosis as well as NETosis, programmed neutrophil death leading to expulsion of nuclear chromatin and neutrophil extracellular traps (NETs). Histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells. This was prevented by histone-neutralizing agents anti-histone IgG, activated protein C and heparin. Histone toxicity on glomeruli was TLR2/4-dependent. Anti-GBM glomerulonephritis involved NET formation and vascular necrosis. Pre-emptive anti-histone IgG administration significantly reduced all aspects of glomerulonephritis, including vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment and activation of glomerular leukocytes and glomerular crescent formation. Subjects with established glomerulonephritis treated with anti-histone IgG, recombinant activated protein C, or heparin all abrogated severe glomerulonephritis suggesting that histone-mediated glomerular pathology is a subsequent, not initial event in necrotizing glomerulonephritis. Neutralizing extracellular histones is therapeutic in severe experimental glomerulonephritis.
摘要翻译： 严重的肾小球肾炎涉及细胞坏死以及NETosis，程序性嗜中性粒细胞死亡导致核染色质和嗜中性粒细胞胞外捕获（NETs）的驱逐。 由嗜中性粒细胞释放的组蛋白会引起肾小球内皮细胞，足细胞和顶叶细胞。 这是通过组蛋白中和剂抗组蛋白IgG，活化蛋白C和肝素预防的。 组蛋白对肾小球的毒性为TLR2 / 4依赖性。 抗GBM肾小球肾炎涉及NET形成和血管坏死。 预先的抗组蛋白IgG给药显着降低肾小球肾炎的所有方面，包括血管坏死，足细胞丢失，蛋白尿，细胞因子诱导，肾小球白细胞的募集和活化以及肾小球新月形成。 用抗组蛋白IgG，重组活化蛋白C或肝素治疗的已建立的肾小球肾炎受试者都消除了严重的肾小球肾炎，表明组蛋白介导的肾小球病理学是坏死性肾小球肾炎的后续而非初始事件。 中和细胞外组蛋白在严重的实验性肾小球肾炎中是治疗性的。
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