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公开(公告)号：US10351621B2
公开(公告)日：2019-07-16
申请号：US15704344
申请日：2017-09-14
申请人： Immunomedics, Inc.
IPC分类号： A61K39/395 , A61K38/00 , A61K38/16 , C07K16/18 , A61K38/19 , C07K16/24 , A61K38/21 , C07K16/28 , A61K31/727 , A61K38/48 , A61K38/36 , A61K38/20 , A61K45/06 , A61P13/12 , A61K39/00
摘要： Acute kidney injury (AKI) is often associated with damage to remote organs, such as lungs or heart. AKI induces kidney tubular necrosis as well as NETosis, programmed neutrophil death leading to neutrophil extracellular traps (NETs). Histones released during NETosis induces further formation of NETs, which is damaging to renal tissues and remote organs. Circulating trap-forming neutrophils directly injured the lung, while other dead tissue releases contributed to injury in other organs. Suppressing renal necroinflammation using inhibitors of NET formation, tubular cell necrosis or extracellular histones prevented kidney as well as remote organ injuries. Dual inhibition of neutrophil trap formation together with tubular cell necrosis had an additive protective effect. Preferably, damage to remote organs induced by AKI may be treated and/or prevented using anti-histone agents such as anti-histone IgG, recombinant activated protein C, or heparin, alone or in combination with other therapeutic agents, such as PAD inhibitors.
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公开(公告)号：US20180057574A1
公开(公告)日：2018-03-01
申请号：US15704344
申请日：2017-09-14
申请人： Immunomedics, Inc.
IPC分类号： C07K16/18 , A61K38/19 , A61K38/20 , A61K38/21 , A61K31/727 , A61K38/48 , A61K39/395 , A61K45/06 , C07K16/28 , C07K16/24 , A61K38/36 , A61K39/00
CPC分类号： C07K16/18 , A61K31/727 , A61K38/19 , A61K38/191 , A61K38/193 , A61K38/20 , A61K38/21 , A61K38/366 , A61K38/4866 , A61K39/3955 , A61K45/06 , A61K2039/505 , A61K2300/00 , A61P13/12 , C07K16/241 , C07K16/2896 , C07K2317/21 , C07K2317/24 , C07K2317/31 , C07K2317/54 , C07K2317/55 , C07K2317/569 , C07K2317/622 , C07K2317/76 , C07K2319/00
摘要： Acute kidney injury (AKI) is often associated with damage to remote organs, such as lungs or heart. AKI induces kidney tubular necrosis as well as NETosis, programmed neutrophil death leading to neutrophil extracellular traps (NETs). Histones released during NETosis induces further formation of NETs, which is damaging to renal tissues and remote organs. Circulating trap-forming neutrophils directly injured the lung, while other dead tissue releases contributed to injury in other organs. Suppressing renal necroinflammation using inhibitors of NET formation, tubular cell necrosis or extracellular histones prevented kidney as well as remote organ injuries. Dual inhibition of neutrophil trap formation together with tubular cell necrosis had an additive protective effect. Preferably, damage to remote organs induced by AKI may be treated and/or prevented using anti-histone agents such as anti-histone IgG, recombinant activated protein C, or heparin, alone or in combination with other therapeutic agents, such as PAD inhibitors.
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公开(公告)号：US20170114126A1
公开(公告)日：2017-04-27
申请号：US15402585
申请日：2017-01-10
申请人： Immunomedics, Inc.
IPC分类号： C07K16/18 , C07K16/28 , A61K45/06 , C07K16/24 , A61K31/727 , A61K39/395
CPC分类号： C07K16/18 , A61K31/727 , A61K38/19 , A61K38/191 , A61K38/193 , A61K38/20 , A61K38/21 , A61K38/366 , A61K38/4866 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/241 , C07K16/2896 , C07K2317/21 , C07K2317/24 , C07K2317/31 , C07K2317/54 , C07K2317/55 , C07K2317/569 , C07K2317/622 , C07K2317/76 , C07K2319/00 , A61K2300/00
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.
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4.发明授权公开(公告)号：US09580495B2
公开(公告)日：2017-02-28
申请号：US14746997
申请日：2015-06-23
申请人： Immunomedics, Inc.
IPC分类号： A61K39/395 , A61K38/00 , A61K38/16 , C07K16/18 , A61K38/19 , A61K38/20 , A61K38/21 , A61K38/36 , A61K38/48 , A61K45/06 , A61K31/727 , A61K39/00
CPC分类号： C07K16/18 , A61K31/727 , A61K38/19 , A61K38/191 , A61K38/193 , A61K38/20 , A61K38/21 , A61K38/366 , A61K38/4866 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/241 , C07K16/2896 , C07K2317/21 , C07K2317/24 , C07K2317/31 , C07K2317/54 , C07K2317/55 , C07K2317/569 , C07K2317/622 , C07K2317/76 , C07K2319/00 , A61K2300/00
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，编程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出来的组蛋白可以杀死肾小球内皮细胞，足细胞和顶叶细胞。 这是由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，足细胞损失，蛋白尿，细胞因子诱导，肾小球白血球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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5.发明申请公开(公告)号：US20150368362A1
公开(公告)日：2015-12-24
申请号：US14746997
申请日：2015-06-23
申请人： Immunomedics, Inc.
CPC分类号： C07K16/18 , A61K31/727 , A61K38/19 , A61K38/191 , A61K38/193 , A61K38/20 , A61K38/21 , A61K38/366 , A61K38/4866 , A61K39/3955 , A61K45/06 , A61K2039/505 , C07K16/241 , C07K16/2896 , C07K2317/21 , C07K2317/24 , C07K2317/31 , C07K2317/54 , C07K2317/55 , C07K2317/569 , C07K2317/622 , C07K2317/76 , C07K2319/00 , A61K2300/00
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出来的组蛋白可以杀死肾小球内皮细胞，足细胞和顶叶细胞。 这是由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，足细胞损失，蛋白尿，细胞因子诱导，肾小球白血球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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