JP2014525476A - Serpinf2結合分子および使用方法 - Google Patents
Serpinf2結合分子および使用方法 Download PDFInfo
- Publication number
- JP2014525476A JP2014525476A JP2014529840A JP2014529840A JP2014525476A JP 2014525476 A JP2014525476 A JP 2014525476A JP 2014529840 A JP2014529840 A JP 2014529840A JP 2014529840 A JP2014529840 A JP 2014529840A JP 2014525476 A JP2014525476 A JP 2014525476A
- Authority
- JP
- Japan
- Prior art keywords
- tpa
- patient
- serpinf2
- serpin
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/38—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against protease inhibitors of peptide structure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
【選択図】 なし
Description
本出願は、2011年9月6日に出願された米国仮出願第61/531,278号の優先権を主張し、その全体は、参照により本明細書に組み込まれる。
本発明は、部分的に、National Institute of Health認可番号第HL092750号および同第NS073147号のもとに、政府支援によりなされた。したがって、米国政府は、本発明に一定の権利を有する。
MCA血栓塞栓症モデル47、48。正常C57BL/6J成体マウス(29〜35g)を、The Jackson Laboratory(Bar Harbor,ME)から入手した。マウスを、制御された温度および湿度で定期的な12時間の明/暗サイクルのマイクロ隔離ケージに収容し、餌および水に自由にアクセスさせた。実験は、Guide for the Care and Use of Laboratory Animals(DHHS Publication No.(NIH)85−23 Revised 1985)に記載されるガイドラインを守り、the Medical College of Georgia’s and the University of Tennessee’s Institutional Animal Care and Use Committeeによって承認されたプロトコル下で行った。マウスに、手術中、TOPO Dual Mode Ventilator(Kent Scientfic,Torrington,CT)を使用して、記載のように、1.5〜2%のイソフルランおよびO2を用いて人工呼吸を行った49。体温を、加温パッドを用いて37℃で維持した。脳血流を、光ファイバープローブを有するレーザードップラー監視器によって監視した(ADInstruments PowerLab 2/26、血流メータML191、OxyFlo Probe MSF100XP)。左総頸動脈を、頸部切開後に単離し、外頸動脈、甲状腺、および後頭動脈を、結紮した。微小血管クリップを、総頸動脈および内頚動脈に一時的に設置した。小動脈切開を、凝血を含有するPE8カテーテルの逆行性挿入のために外頸動脈に行った。凝血を、125I−フィブリノゲン(約100,000cpm/20ul、PerkinElmer NEX430110UC)と混合した正常マウスからのプールした新鮮凍結物から作製し、エバンスブルー染料で染色した。凝血を含有するPE8管を、γ線シンチレーション計測器で計測し、左外頸動脈に挿入し、ICAからMCAの起点まで挿入し、100ul体積の生理食塩水中、0.45mL/分の速度で、血栓塞栓形成を行った。Geiger−Muller計測器を使用して、適切な塞栓形成を確認した。
統計的分析を上述のように実行し、群間の相違は、P<0.05の場合に有意であると見なした。データは、平均±標準誤差として報告する。
血栓塞栓は、典型的に、脳半球血流を約80%低減させた(図1A)。血栓塞栓は、MCAの近位に容易に検出され(図1B)、罹患した皮質の白化が見られた(示されない)。プラセボ(対照)で処置した血栓塞栓群のマウスには、広範囲の神経細胞死が見られたが、血栓塞栓を受容しなかった偽処置群のマウスには神経細胞死は見られなかった。脳卒中後の内在性TPA活性の亢進についての以前の報告と一致して、対照には血栓塞栓の有意な線維素溶解が見られた(20.6±2.5%)53、54。
1. Dohmen C,Galldiks N,Bosche B,Kracht L,Graf R.The severity of ischemia determines and predicts malignant brain edema in patients with large middle cerebral artery infarction.Cerebrovasc Dis 2012;33:1−7.
2. Westermaier TM,Stetter CM,Raslan FM,Vince GHMP,Ernestus RIMP.Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats.Exp Transl Stroke Med 2012;4:8.
3. Martinet V,Guigui B,Glacet−Bernard A,et al.Macular edema in central retinal vein occlusion:correlation between optical coherence tomography,angiography and visual acuity.Int Ophthalmol 2012.
4. Abdel−Aty H,Cocker M,Meek C,Tyberg JV,Friedrich MG.Edema as a very early marker for acute myocardial ischemia:a cardiovascular magnetic resonance study.J Am Coll Cardiol 2009;53:1194−201.
5. Garcia−Dorado D,Andres−Villarreal M,Ruiz−Meana M,Inserte J,Barba I.Myocardial edema:a translational view.J Mol Cell Cardiol 2012;52:931−9.
6. Chen KH,Chao D,Liu CF,Chen CF,Wang D.Ischemia and reperfusion of the lung tissues induced increase of lung permeability and lung edema is attenuated by dimethylthiourea(PP69).Transplant Proc 2010;42:748−50.
7. Greca FH,Goncalves NM,Souza Filho ZA,Noronha L,Silva RF,Rubin MR.The protective effect of methylene blue in lungs,small bowel and kidney after intestinal ischemia and reperfusion.Acta Cir Bras 2008;23:149−56.
8. Lee HT,Park SW,Kim M,D’Agati VD.Acute kidney injury after hepatic ischemia and reperfusion injury in mice.Lab Invest 2009;89:196−208.
9. Fujimoto K,Hosotani R,Wada M,et al.Ischemia−reperfusion injury on the pancreas in rats:identification of acinar cell apoptosis.J Surg Res 1997;71:127−36.
10. Sage E,Mercier O,Van den Eyden F,et al.Endothelial cell apoptosis in chronically obstructed and reperfused pulmonary artery.Respir Res 2008;9:19.
11. Bekkers SC,Yazdani SK,Virmani R,Waltenberger J.Microvascular obstruction:underlying pathophysiology and clinical diagnosis.J Am Coll Cardiol 2010;55:1649−60.
12. Strong K,Mathers C,Bonita R.Preventing stroke:saving lives around the world.Lancet neurology 2007;6:182−7.
13. Albers GW,Amarenco P,Easton JD,Sacco RL,Teal P.Antithrombotic and thrombolytic therapy for ischemic stroke:American College of Chest Physicians Evidence−Based Clinical Practice Guidelines(8th Edition).Chest 2008;133:630S−69S.
14. Fieschi C,Argentino C,Lenzi GL,Sacchetti ML,Toni D,Bozzao L.Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours.Journal of the neurological sciences 1989;91:311−21.
15. Viitanen M,Winblad B,Asplund K.Autopsy−verified causes of death after stroke.Acta Med Scand 1987;222:401−8.
16. Bamford J,Dennis M,Sandercock P,Burn J,Warlow C.The frequency,causes and timing of death within 30 days of a first stroke:the Oxfordshire Community Stroke Project.J Neurol Neurosurg Psychiatry 1990;53:824−9.
17. Braga P,Ibarra A,Rega I,et al.Prediction of early mortality after acute stroke.J Stroke Cerebrovasc Dis 2002;11:15−22.
18. Silver FL,Norris JW,Lewis AJ,Hachinski VC.Early mortality following stroke:a prospective review.Stroke 1984;15:492−6.
19. Koennecke HC,Belz W,Berfelde D,et al.Factors influencing in−hospital mortality and morbidity in patients treated on a stroke unit.Neurology 2011;77:965−72.
20. Johnston KC,Wagner DP,Wang XQ,et al.Validation of an acute ischemic stroke model:does diffusion−weighted imaging lesion volume offer a clinically significant improvement in prediction of outcome?Stroke 2007;38:1820−5.
21. Saver JL,Johnston KC,Homer D,et al.Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials.The RANTTAS Investigators.Stroke 1999;30:293−8.
22. Marler JR,Goldstein LB.Medicine.Stroke−−tPA and the clinic.Science 2003;301:1677.
23. Alexandrov AV,Demchuk AM,Felberg RA,et al.High rate of complete recanalization and dramatic clinical recovery during tPA infusion when continuously monitored with 2−MHz transcranial doppler monitoring.Stroke 2000;31:610−4.
24. Kwiatkowski TG,Libman RB,Frankel M,et al.Effects of tissue plasminogen activator for acute ischemic stroke at one year.National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group.N Engl J Med 1999;340:1781−7.
25. Levy DE,Brott TG,Haley EC,Jr.,et al.Factors related to intracranial hematoma formation in patients receiving tissue−type plasminogen activator for acute ischemic stroke.Stroke 1994;25:291−7.
26. Lees KR,Bluhmki E,von Kummer R,et al.Time to treatment with intravenous alteplase and outcome in stroke:an updated pooled analysis of ECASS,ATLANTIS,NINDS,and EPITHET trials.Lancet 2010;375:1695−703.
27. Vivien D,Buisson A.Serine protease inhibitors:novel therapeutic targets for stroke?J Cereb Blood Flow Metab 2000;20:755−64.
28. Stehling F,Weber R,Ozcelik A,et al.Acute changes of coagulation and fibrinolysis parameters after experimental thromboembolic stroke and thrombolytic therapy.Neuroscience letters 2008;441:39−43.
29. Dietzmann K,von Bossanyi P,Krause D,Wittig H,Mawrin C,Kirches E.Expression of the plasminogen activator system and the inhibitors PAI−1 and PAI−2 in posttraumatic lesions of the CNS and brain injuries following dramatic circulatory arrests:an immunohistochemical study.Pathology,research and practice 2000;196:15−21.
30. Nagai N,Suzuki Y,Van Hoef B,Lijnen HR,Collen D.Effects of plasminogen activator inhibitor−1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice.J Thromb Haemost 2005;3:1379−84.
31. Wang YF,Tsirka SE,Strickland S,Stieg PE,Soriano SG,Lipton SA.Tissue plasminogen activator(tPA)increases neuronal damage after focal cerebral ischemia in wild−type and tPA−deficient mice.Nat Med 1998;4:228−31.
32. Nagai N,De Mol M,Lijnen HR,Carmeliet P,Collen D.Role of plasminogen system components in focal cerebral ischemic infarction:a gene targeting and gene transfer study in mice.Circulation 1999;99:2440−4.
33. Sheehan JJ,Tsirka SE.Fibrin−modifying serine proteases thrombin,tPA,and plasmin in ischemic stroke:a review.Glia 2005;50:340−50.
34. Tsirka SE,Gualandris A,Amaral DG,Strickland S.Excitotoxin−induced neuronal degeneration and seizure are mediated by tissue plasminogen activator.Nature 1995;377:340−4.
35. Tsirka SE,Bugge TH,Degen JL,Strickland S.Neuronal death in the central nervous system demonstrates a non−fibrin substrate for plasmin.Proceedings of the National Academy of Sciences of the United States of America 1997;94:9779−81.
36. Tsirka SE,Rogove AD,Bugge TH,Degen JL,Strickland S.An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus.J Neurosci 1997;17:543−52.
37. Yepes M,Sandkvist M,Coleman TA,et al.Regulation of seizure spreading by neuroserpin and tissue−type plasminogen activator is plasminogen−independent.J Clin Invest 2002;109:1571−8.
38. Suri MF,Yamagishi K,Aleksic N,Hannan PJ,Folsom AR.Novel hemostatic factor levels and risk of ischemic stroke:the Atherosclerosis Risk in Communities(ARIC)Study.Cerebrovasc Dis 2010;29:497−502.
39. Marti−Fabregas J,Borrell M,Cocho D,et al.Hemostatic markers of recanalization in patients with ischemic stroke treated with rt−PA.Neurology 2005;65:366−70.
40. Roelofs JJ,Rouschop KM,Leemans JC,et al.Tissue−type plasminogen activator modulates inflammatory responses and renal function in ischemia reperfusion injury.J Am Soc Nephrol 2006;17:131−40.
41. Zhao Y,Sharma AK,LaPar DJ,et al.Depletion of tissue plasminogen activator attenuates lung ischemia−reperfusion injury via inhibition of neutrophil extravasation.Am J Physiol Lung Cell Mol Physiol 2011;300:L718−29.
42. Hong TT,Huang J,Lucchesi BR.Effect of thrombolysis on myocardial injury:recombinant tissue plasminogen activator vs.alfimeprase.Am J Physiol Heart Circ Physiol 2006;290:H959−67.
43. Kumada M,Niwa M,Wang X,et al.Endogenous tissue type plasminogen activator facilitates NMDA−induced retinal damage.Toxicol Appl Pharmacol 2004;200:48−53.
44. Del Zoppo GJ.Focal cerebral ischemia and hemostasis:a PAI−1 conundrum.J Thromb Haemost 2005;3:1376−8.
45. Aoki T,Sumii T,Mori T,Wang X,Lo EH.Blood−brain barrier disruption and matrix metalloproteinase−9 expression during reperfusion injury:mechanical versus embolic focal ischemia in spontaneously hypertensive rats.Stroke 2002;33:2711−7.
46. Asahi M,Huang Z,Thomas S,et al.Protective effects of statins involving both eNOS and tPA in focal cerebral ischemia.J Cereb Blood Flow Metab 2005;25:722−9.
47. Zhang Z,Chopp M,Zhang RL,Goussev A.A mouse model of embolic focal cerebral ischemia.J Cereb Blood Flow Metab 1997;17:1081−8.
48. Zhang ZG,Zhang L,Ding G,et al.A model of mini−embolic stroke offers measurements of the neurovascular unit response in the living mouse.Stroke 2005;36:2701−4.
49. Houng AK,McNamee RA,Kerner A,et al.Atrial natriuretic peptide increases inflammation,infarct size,and mortality after experimental coronary occlusion.American journal of physiology 2009;296:H655−61.
50. Swanson RA,Morton MT,Tsao−Wu G,Savalos RA,Davidson C,Sharp FR.A semiautomated method for measuring brain infarct volume.J Cereb Blood Flow Metab 1990;10:290−3.
51. Robinson BR,Houng AK,Reed GL.Catalytic life of activated factor XIII in thrombi.Implications for fibrinolytic resistance and thrombus aging.Circulation 2000;102:1151−7.
52. Sazonova IY,McNamee RA,Houng AK,King SM,Hedstrom L,Reed GL.Reprogrammed streptokinases develop fibrin−targeting and dissolve blood clots with more potency than tissue plasminogen activator.J Thromb Haemost 2009;7:1321−8.
53. Zunker P,Schick A,Padro T,Kienast J,Phillips A,Ringelstein EB.Tissue plasminogen activator and plasminogen activator inhibitor in patients with acute ischemic stroke:relation to stroke etiology.Neurological research 1999;21:727−32.
54. Wang X,Lee SR,Arai K,et al.Lipoprotein receptor−mediated induction of matrix metalloproteinase by tissue plasminogen activator.Nat Med 2003;9:1313−7.
55. Hunter AJ,Hatcher J,Virley D,et al.Functional assessments in mice and rats after focal stroke.Neuropharmacology 2000;39:806−16.
56. Heinsius T,Bogousslavsky J,Van Melle G.Large infarcts in the middle cerebral artery territory.Etiology and outcome patterns.Neurology 1998;50:341−50.
57. Yepes M,Sandkvist M,Moore EG,Bugge TH,Strickland DK,Lawrence DA.Tissue−type plasminogen activator induces opening of the blood−brain barrier via the LDL receptor−related protein.J Clin Invest 2003;112:1533−40.
58. Asahi M,Wang X,Mori T,et al.Effects of matrix metalloproteinase−9 gene knock−out on the proteolysis of blood−brain barrier and white matter components after cerebral ischemia.J Neurosci 2001;21:7724−32.
59. Montaner J,Molina CA,Monasterio J,et al.Matrix metalloproteinase−9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke.Circulation 2003;107:598−603.
60. Wang X,Tsuji K,Lee SR,et al.Mechanisms of hemorrhagic transformation after tissue plasminogen activator reperfusion therapy for ischemic stroke.Stroke 2004;35:2726−30.
61. Kaur J,Zhao Z,Klein GM,Lo EH,Buchan AM.The neurotoxicity of tissue plasminogen activator?J Cereb Blood Flow Metab 2004;24:945−63.
62. Tabrizi P,Wang L,Seeds N,et al.Tissue plasminogen activator(tPA)deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model:studies in tPA−deficient mice and wild−type mice on a matched genetic background.Arteriosclerosis,thrombosis,and vascular biology 1999;19:2801−6.
Claims (28)
- 必要とされる患者において、出血または浮腫による障害または死亡を防止する方法であって、前記患者に、SerpinF2活性または濃度を低減させる有効量のSerpinF2結合分子を投与し、それによって、前記患者における出血または浮腫による障害または死亡を防止することを含む、方法。
- 前記出血または浮腫は、神経、心臓、肝臓、膵臓、呼吸器、または腎臓の出血または浮腫である、請求項1に記載の方法。
- 前記結合分子は、抗体、ペプチド、DNAアプタマー、または小分子から選択される、SerpinF2阻害剤である、請求項1に記載の方法。
- 前記SerpinF2阻害剤は、抗体である、請求項3に記載の方法。
- 前記SerpinF2阻害剤は、28〜91ナノモル/kgの用量範囲で投与される、請求項4に記載の方法。
- 必要とされる患者において、組織プラスミノーゲン活性化因子(TPA)毒性による障害または死亡を防止する方法であって、前記患者に、SerpinF2活性または濃度を低減させる有効量のSerpinF2結合分子を投与し、それによって、TPA毒性による障害または死亡を防止することを含む、方法。
- 前記TPA毒性は、出血、器官浮腫、またはアポトーシスを引き起こす、請求項6に記載の方法。
- 前記患者がTPAに誘発される損傷の危険性にあることを判定する先行ステップをさらに含む、請求項6に記載の方法。
- 前記TPA毒性は、虚血または外傷に起因する、請求項6に記載の方法。
- 前記TPA毒性は、神経、心臓、肝臓、膵臓、呼吸器、または腎臓の損傷を引き起こす、請求項6に記載の方法。
- 前記TPAは、48時間以内に事前に前記患者に投与されている、請求項6に記載の方法。
- プラスミノーゲン活性化因子またはセリンプロテアーゼ酵素は、48時間以内に事前に前記患者に投与されている、請求項6に記載の方法。
- 前記結合分子は、抗体、ペプチド、DNAアプタマー、または小分子から選択される、SerpinF2阻害剤である、請求項6に記載の方法。
- 前記SerpinF2阻害剤は、抗体である、請求項13に記載の方法。
- 前記SerpinF2阻害剤は、28〜91ナノモル/kgの用量範囲で投与される、請求項14に記載の方法。
- アポトーシスの予防を、それを必要とする患者において行う方法であって、前記患者に、SerpinF2活性または濃度を低下させる有効量のSerpinF2結合分子を投与し、それによって、前記患者におけるアポトーシスを予防することを含む、方法。
- 前記アポトーシスは、神経、心臓、肝臓、膵臓、肺、または腎臓の細胞に生じる、請求項16に記載の方法。
- 前記結合分子は、抗体、ペプチド、DNAアプタマー、または小分子から選択される、SerpinF2阻害剤である、請求項16に記載の方法。
- 前記SerpinF2阻害剤は、抗体である、請求項18に記載の方法。
- 前記SerpinF2阻害剤は、28〜91ナノモル/kgの用量範囲で投与される、請求項19に記載の方法。
- 必要とされる患者において、長期虚血を防止する方法であって、前記患者に、前記患者においてSerpinF2濃度または活性を低減させる有効量のSerpinF2結合分子を投与し、そうして前記長期虚血を防止することを含む、方法。
- 前記長期虚血は、少なくとも40分間現れている、請求項21に記載の方法。
- 前記長期虚血は、神経、心臓、肝臓、膵臓、肺、または腎臓の組織に生じる、請求項21に記載の方法。
- 前記患者が神経損傷を示す神経症状を有することを判定する先行ステップをさらに含む、請求項21に記載の方法。
- 前記神経症状は、Rankin 1またはNIH Stroke Scale 4よりも重度かまたはそれと同等として分類される、請求項24に記載の方法。
- 前記結合分子は、抗体、ペプチド、DNAアプタマー、または小分子から選択される、SerpinF2阻害剤である、請求項21に記載の方法。
- 前記SerpinF2阻害剤は、抗体である、請求項26に記載の方法。
- 前記SerpinF2阻害剤は、28〜91ナノモル/kgの用量範囲で投与される、請求項27に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161531278P | 2011-09-06 | 2011-09-06 | |
US61/531,278 | 2011-09-06 | ||
PCT/US2012/053900 WO2013036596A2 (en) | 2011-09-06 | 2012-09-06 | Serpinf2-binding molecules and methods of use |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2014525476A true JP2014525476A (ja) | 2014-09-29 |
JP2014525476A5 JP2014525476A5 (ja) | 2015-08-13 |
JP6184410B2 JP6184410B2 (ja) | 2017-08-23 |
Family
ID=47832762
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014529840A Active JP6184410B2 (ja) | 2011-09-06 | 2012-09-06 | Serpinf2結合分子および使用方法 |
Country Status (6)
Country | Link |
---|---|
US (2) | US11236176B2 (ja) |
EP (1) | EP2753359B1 (ja) |
JP (1) | JP6184410B2 (ja) |
AU (1) | AU2012304635B2 (ja) |
CA (1) | CA2846667A1 (ja) |
WO (1) | WO2013036596A2 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11078297B2 (en) * | 2014-12-22 | 2021-08-03 | Translational Sciences, Inc. | Prophylaxis of thrombosis |
WO2021022109A1 (en) * | 2019-08-01 | 2021-02-04 | Alnylam Pharmaceuticals, Inc. | SERPIN FAMILY F MEMBER 2 (SERPINF2) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002525340A (ja) * | 1998-09-29 | 2002-08-13 | リューベン・リサーチ・アンド・デベロップメント・ベー・ゼット・ウェー | 虚血性卒中の処置用の組成物を調製するための、α2抗プラスミンをインビボで減少する化合物の使用 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
JPS6147500A (ja) | 1984-08-15 | 1986-03-07 | Res Dev Corp Of Japan | キメラモノクロ−ナル抗体及びその製造法 |
EP0173494A3 (en) | 1984-08-27 | 1987-11-25 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric receptors by dna splicing and expression |
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
AU606320B2 (en) | 1985-11-01 | 1991-02-07 | International Genetic Engineering, Inc. | Modular assembly of antibody genes, antibodies prepared thereby and use |
US5260203A (en) | 1986-09-02 | 1993-11-09 | Enzon, Inc. | Single polypeptide chain binding molecules |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
EP0272609B1 (en) | 1986-12-19 | 1992-03-11 | Teijin Limited | Amino acid sequence of human alpha2-plasmin inhibitor and cdna and genomic dna encoding said amino acid sequence |
US5091513A (en) | 1987-05-21 | 1992-02-25 | Creative Biomolecules, Inc. | Biosynthetic antibody binding sites |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
ES2136092T3 (es) | 1991-09-23 | 1999-11-16 | Medical Res Council | Procedimientos para la produccion de anticuerpos humanizados. |
US6114506A (en) | 1996-09-20 | 2000-09-05 | General Hospital Corporation | Composition and method for enhancing fibrinolysis |
WO1999061072A2 (en) | 1998-05-29 | 1999-12-02 | President And Fellows Of Harvard College | Methods of inhibiting clot formation |
US6411506B1 (en) | 2000-07-20 | 2002-06-25 | Rlx Technologies, Inc. | High density web server chassis system and method |
WO2002072769A2 (en) * | 2001-03-08 | 2002-09-19 | Immunex Corporation | Human serpin polypeptides |
AU2003301843A1 (en) | 2002-05-17 | 2004-06-07 | Human Genome Sciences, Inc. | 157 human secreted proteins |
US7309774B2 (en) | 2003-02-07 | 2007-12-18 | The Board Of Regents Of The University Of Oklahoma | Antiplasmin cleaving enzyme |
WO2006005583A2 (en) | 2004-07-12 | 2006-01-19 | Geneprot Inc. | Secreted polypeptide species involved in multiple sclerosis |
WO2006133403A2 (en) * | 2005-06-07 | 2006-12-14 | The Regents Of The University Of Colorado | Inhibitors of serine protease activity and their use in methods and compositions for treatment of graft rejection and promotion of graft survival |
AU2008245618B2 (en) * | 2007-04-25 | 2014-02-20 | Translational Sciences Inc. | Method of increasing plasmin activity through antiplasmin conversion |
WO2010071787A1 (en) * | 2008-12-17 | 2010-06-24 | Arizona Board Regents, A Body Corporate Acting For And On Behalf Of Arizona State University | Pancreatic cancer markers and uses thereof |
WO2011083145A1 (en) * | 2010-01-08 | 2011-07-14 | Cavadis B.V. | Determination of exosomel biomarkers for predicting cardiovascular events |
-
2012
- 2012-09-06 CA CA2846667A patent/CA2846667A1/en active Pending
- 2012-09-06 AU AU2012304635A patent/AU2012304635B2/en active Active
- 2012-09-06 JP JP2014529840A patent/JP6184410B2/ja active Active
- 2012-09-06 EP EP12830126.4A patent/EP2753359B1/en active Active
- 2012-09-06 WO PCT/US2012/053900 patent/WO2013036596A2/en active Application Filing
-
2014
- 2014-03-06 US US14/198,804 patent/US11236176B2/en active Active
-
2022
- 2022-02-01 US US17/590,744 patent/US20220298261A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002525340A (ja) * | 1998-09-29 | 2002-08-13 | リューベン・リサーチ・アンド・デベロップメント・ベー・ゼット・ウェー | 虚血性卒中の処置用の組成物を調製するための、α2抗プラスミンをインビボで減少する化合物の使用 |
Also Published As
Publication number | Publication date |
---|---|
US20220298261A1 (en) | 2022-09-22 |
CA2846667A1 (en) | 2013-03-14 |
EP2753359A4 (en) | 2015-04-22 |
JP6184410B2 (ja) | 2017-08-23 |
AU2012304635B2 (en) | 2017-08-31 |
WO2013036596A2 (en) | 2013-03-14 |
AU2012304635A1 (en) | 2014-03-13 |
EP2753359A2 (en) | 2014-07-16 |
US11236176B2 (en) | 2022-02-01 |
EP2753359B1 (en) | 2018-02-28 |
US20140220034A1 (en) | 2014-08-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Ito | PAMPs and DAMPs as triggers for DIC | |
Fanne et al. | Blood–brain barrier permeability and tPA-mediated neurotoxicity | |
Montaner et al. | Matrix metalloproteinases and ADAMs in stroke | |
Laszik et al. | Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway | |
TWI684459B (zh) | 一種治療動脈粥樣硬化及其併發症的方法 | |
US20220298261A1 (en) | Serpinf2-Binding Molecules and Method of Use Thereof | |
CA2916399C (en) | Combination therapy using a factor xii inhibitor and a c1-inhibitor | |
Obi et al. | Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia | |
EP3391901B1 (en) | Plasminogen for use in treating liver tissue damage | |
CN108210895A (zh) | 预防动脉粥样硬化及其并发症的药物及其用途 | |
TW201822797A (zh) | 一種預防和治療腎纖維化的方法 | |
CN108210892A (zh) | 预防和治疗肝纤维化的药物及其用途 | |
CN103566362B (zh) | 重组adamts13在制备脑出血药物中的用途 | |
CN106890320A (zh) | 一种用于预防或治疗急性及慢性血栓的方法 | |
JP2009501188A (ja) | 抗血小板療法で治療される患者における脳内出血(ICH)後の出血増大及び/又は浮腫形成を予防又は軽減するための第VIIa因子又は第VIIa因子等価物の使用 | |
US20240059761A1 (en) | Use of fibrin-targeting immunotherapy to reduce Coronavirus pathogenesis | |
US20190231856A1 (en) | Compositions and methods for treating intracerebral hemorrhage | |
CN108210894A (zh) | 预防和治疗病理性肾组织损伤的药物及其用途 | |
CN106890325A (zh) | 一种预防或治疗糖尿病性神经损伤及其相关病症的方法 | |
CN106890318A (zh) | 一种预防和治疗糖尿病性心脏病的新方法 | |
JP5924611B2 (ja) | 造血細胞移植に伴う生着症候群の予防及び/又は治療のための医薬 | |
WO2012110843A1 (en) | Methods and pharmaceutical compositions for promoting fibrinolysis and thrombolysis | |
Miller | THE PLASMINOGEN RECEPTOR S100A10: STRUCTURE AND FUNCTION STUDIES | |
JP2023016990A (ja) | 凝固異常を伴う敗血症の治療及び/又は改善のための医薬 | |
JP2017537942A (ja) | 血栓症の予防法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20140527 |
|
A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20140527 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150624 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20150624 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20160427 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160722 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20161006 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20161006 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20161111 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170303 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20170310 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170531 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20170627 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20170725 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6184410 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |