CN1140414A - 抗tnf抗体作为治疗伴有白细胞介素-6血清水平升高的疾病的药物的应用 - Google Patents
抗tnf抗体作为治疗伴有白细胞介素-6血清水平升高的疾病的药物的应用 Download PDFInfo
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Abstract
本发明涉及TNF拮抗剂在制备治疗特征为白细胞介素-6血清水平升高的疾病的药物中的应用。
Description
本发明涉及抗TNF抗体在治疗伴有白细胞介素-6血清水平升高的疾病中的应用。
已知“肿瘤坏死因子”(TNF)这一术语包括两种细胞素性因子(TNF-α和TNF-β)，它们大多由激活的淋巴细胞和单核细胞产生。
例如，EP260610描述了据说能用于伴有血中TNF水平升高使TNF灭活的疾病的抗TNF抗体。这类疾病例如有败血病休克、移植排斥、过敏、自身免疫疾病、肺休克、凝固碍障或炎性骨骼疾病。
特点是白细胞介素-6血清水平升高的疾病的实例是移值、自身免疫疾病以及特别是某些败血病的结果。
医学教科书中把败血病定义为一个总的临床术语，在败血病情形中，病原菌从病灶开始进入血流，诱发很多主观和客观病理表现。进一步发现，随着病原菌种类、机体反应性、主病灶的不同以所涉及的器官的改变，临床图片可以有很大变化(Sturm等.“Grundbegriffe derInneren Medizin”，13th edition，page570，Gustav FischerVerlag，Stuttgart，1984)。
已经指出，在复杂的败血病病理生理过程中涉及一些细胞因子。根据动物试验数据，特别是TNF是引起败血病休克的重要因素(Beutler等，Science 229，(1985)869-871)。
这最终导致了用抗TNF抗体治疗败血病患者的临床研究。
不过，在近期发表的、有关用鼠单克隆抗TNF抗体治疗严重败血病的多中心II期研究中发现，就存活率而言，总人数(80名患者)并不得益于用这种抗体治疗。就存活几率而言，只有那些循环TNF浓度升高的患者似乎能得益于高剂量抗TNF抗体的施用(C.J.Fisher等.，CriticalCare Medicine，Vol.21，No.3，pages318-327)。而且，该项研究中提到TNF与II-6的血浆水平的关系。
细胞因子白细胞介素-6(II-6)在败血病中所起的作用尚不清楚并且是相互矛盾的。已知发现，一些败血病患者II-6血清水平升高(Hack等，Blood 74(1989)，1704-1710)。
Waage描述了细胞因子II-6和II-8浓度之间与休克严重程度的关系，尽管就死亡率而言II-6和II-8两者单独使用或与TNF合用对休克综合症的发展都没有作用(Waage in“Tumor Necrosis Factors”，ed.B.Beutler，Raven Press，New York，1992，pages 275-283)。
由于II-6以负反馈控制的形式抑制LPS-诱导的TNF产生，所以一些科学家认为II-6在败血病休克中起有益作用(Libert等.in“TumorNecrosis Factor：Molecular and Cellular Biology and ClinicalRelevance”，ed.W.Fiers，Karger，Basel，1993，pages 126-131)。
现在，我们出乎意料地发现，可以把TNF拮抗剂特别成功地用作治疗特点为白细胞介素-6血清水平升高的疾病的药物。
当待治疗患者治疗前的II-6水平为500pg/ml或更高时，根据本发明用TNF拮抗剂治疗败血病特别成功(例如以死亡率的显著降低为衡量标准)。II-6血清水平高于1000pg/ml的患者尤其得益于按照本发明的治疗。
II-6血清水平升高是指与健康受试者生理血清水平相比至少高10倍。
已经发现，一些败血病患者的II-6血清浓度达到健康受试者水平的20,000倍。
“正常”II-6血清水平通常低于检测极限。检测极限随所用检测系统的不同而稍有变化。但是其最大值为20pg/ml。
可以用诸如RIA或ELISA之类的常规检测方法检测II-6血清浓度。非常合适的检测系统的一个实例是Medgenix提供的II-6-EASIA。
也可以用活性测定法测定II-6浓度，例如在这种测定法中测定C反应蛋白。
合适的TNF拮抗剂有抗TNF抗体、TNF受体及其可溶性片断、TNF结合蛋白或者那些仍能结合TNF受体但无TNF活性的TNF衍生物。这些类型的TNF拮抗剂的特征是，它们捕获已形成的TNF并且使TNF不能到达TNF受体，或者它们与TNF争夺受体。
不过，阻止TNF的形成或释放的TNF拮抗剂也适于本发明的应用。例如，这类物质抑制TNF基因表达或TNF从前体形式的释放。
例如，也描述了黄嘌呤、糖皮质激素、前列腺素E2、酞胺哌啶酮、白细胞介素-4、白细胞介素-10、粒细胞刺激因子(G-CSF)、环孢菌素和α-抗胰蛋白酶的这类TNF-拮抗活性。因此，这类化合物也适合用作TNF拮抗剂。
对本发明的应用而言，抗TNF抗体是特别优选的。
适于本发明应用的抗TNF抗体是已知的(EP260610，EP351789，EP218868)。多克隆抗体和单克隆抗体都可使用。另外，象Fab或F(ab′)2片断或者单链Fv片断这样的TNF结合抗体片断也是合适的。
此外，人化或人抗TNF抗体或者它们的TNF结合片断也是非常合适的，因为这些分子不会在人类患者中引起抗鼠抗原性。也可能把各种抗TNF抗体的混合物或者抗TNF抗体与TNF受体片断的混合物用作活性物质。
本发明包括：除无菌、惰性、药学上适宜的载体外还含有抗TNF抗体的药物组合物；以及这些组合物的生产方法。
用生物技术生产活性物质的常规方式配制抗TNF抗体，通常以液体制剂或冻干制剂的形式(例如，参见Hagers Handbuch derpharmazeutischen Praxis，Vol.2，5th edition，1991，p.720，ISBN 3-540-52459-2)。上面提到的组合物是用常规方法以常规方式生产的，例如把活性物质或多种活性物质与载体或多种载体混合。
一般说来，以每24小时约0.1-约1000mg/kg体重、优选0.1-10mg/kg体重的总量施用适于本发明应用的活性物质或多种活性物质被证明是有利的，合适的话，以几个单独剂量的形式或连续输注的形式施用，并且合适的话，经几天的治疗期达到期望的结果。可以以简单的静脉内输注单剂量或者24小时连续长期输注日剂量的形式进行给药。单剂量最好含有数量为约0.1-约10mg/kg体重的活性物质或多种活性物质。特别是根据待治疗患者的年龄和身材大小、主要疾病的性质和严重程度、组合物类型和给药方式、给药的期间和间隔的不同，必要时剂量可以与所述剂量不同。下面的实施例进一步说明本发明。
实施例
用鼠抗TNF抗体片断(F(ab′)2)治疗败血病患者
在多中心临床研究中，用不同剂量的抗TNF抗体片断或者用安慰剂治疗总共122名严重败血病患者。
所用四种治疗方法的区别仅在于抗TNF抗体片断的单剂量水平不同。就是0.1mg/kg体重、0.3mg/kg体重或1.0mg/kg体重。第四组的患者接受一种“假疗法”(安慰剂)，用于比较。把患者随机分入使用抗TNF抗体片断的四种疗法中的一种。除了对败血病患者的标准疗法外，所述疗法是在诊断后以简单输注的方式进行的，共9次(9x)，间隔为8小时(即3天时间)(＝按照包含于本项研究中的标准)。共有122名患者参与此项研究，34人分到0.1mg/kg剂量组、30人分到0.3mg/kg剂量组、29人分到1.0mg/kg剂量组、29人分到安慰剂组。
治疗开始之前可以对122名患者中的119人进行II-6血清浓度测定。其中36名患者II-6血清水平高于1000pg/ml，83名患者低于1000pg/ml。
图1A表示不同的治疗组中II-6＞1000pg/ml的群体的死亡率(安慰剂，0.1，0.3和1.0mg抗体/kg体重)。
图1B表示不同的治疗组中II-6＜1000pg/ml的群体的死亡率(安慰剂，0.1、0.3和1.0mg抗体/kg体重)。
用抗TNF抗体片断治疗II-6＞1000pg/ml的患者，死亡率依赖于剂量而降低，从80.0％(＝安慰剂组)降低到36.4％(1.0mg/kg抗体)(图1A)。
用抗TNF抗体片断治疗II-6＜1000pg/ml的患者，死亡率没有降低。相反，稍有提高(安慰剂组为30.4％，而1.0mg/kg抗体组为38.9％)(图1B)。
这项临床研究的结果清楚地证明，只有当待治疗败血病患者II-6血清水平＞1000pg/ml时，用抗TNF抗体治疗严重败血病才是成功的；治疗II-6血清水平＜1000pg/ml的患者是不成功的，有时甚至是不利的。
Claims (3)
1.TNF拮抗剂作为生产治疗特征是白细胞介素-6血清水平升高的疾病的药物的应用。
2.如权利要求1所要求的应用，其中的疾病是败血病。
3.如权利要求1或2所要求的应用，其中TNF拮抗剂是单克隆抗TNF抗体。
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| DEP4403669.8 | 1994-02-07 | ||
| DE4403669 | 1994-02-07 | ||
| DEP4409513.9 | 1994-03-19 | ||
| DE4409513A DE4409513C1 (de) | 1994-02-07 | 1994-03-19 | Verwendung von anti-TNF-Antikörpern als Arzneimittel zur Behandlung von Erkrankungen mit einem erhöhten Interleukin-6 Serumspiegel |
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| CN1140414A true CN1140414A (zh) | 1997-01-15 |
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| CN95191517A Pending CN1140414A (zh) | 1994-02-07 | 1995-01-27 | 抗tnf抗体作为治疗伴有白细胞介素-6血清水平升高的疾病的药物的应用 |
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| Country | Link |
|---|---|
| US (2) | US6235281B1 (zh) |
| EP (1) | EP0804236B1 (zh) |
| JP (1) | JPH09509411A (zh) |
| CN (1) | CN1140414A (zh) |
| AT (1) | ATE235917T1 (zh) |
| AU (1) | AU1520195A (zh) |
| BR (1) | BR9506741A (zh) |
| CA (1) | CA2182723A1 (zh) |
| CZ (1) | CZ290843B6 (zh) |
| DK (1) | DK0804236T3 (zh) |
| ES (1) | ES2197912T3 (zh) |
| FI (1) | FI963101A0 (zh) |
| HR (1) | HRP950052B1 (zh) |
| HU (1) | HU220995B1 (zh) |
| IL (1) | IL112427A (zh) |
| NO (1) | NO963280L (zh) |
| NZ (1) | NZ278607A (zh) |
| PT (1) | PT804236E (zh) |
| TW (1) | TW403656B (zh) |
| WO (1) | WO1995020978A1 (zh) |
Families Citing this family (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6090382A (en) | 1996-02-09 | 2000-07-18 | Basf Aktiengesellschaft | Human antibodies that bind human TNFα |
| DE19746868A1 (de) * | 1997-10-23 | 1999-04-29 | Knoll Ag | Verwendung von TNF-Antagonisten als Arzneimittel zur Behandlung von septischen Erkrankungen |
| US20030220258A1 (en) | 2001-12-21 | 2003-11-27 | Robbert Benner | Treatment of ischemic events |
| US20050227925A1 (en) * | 2004-04-08 | 2005-10-13 | Robbert Benner | Compositions capable of reducing elevated blood urea concentration |
| US6844315B2 (en) | 1998-05-20 | 2005-01-18 | Erasmus Universiteit Rotterdam | Immunoregulator |
| US6921751B1 (en) * | 1998-05-20 | 2005-07-26 | Erasmus Universiteit Rotterdam | Immunoregulator |
| US20040202645A1 (en) * | 2003-04-08 | 2004-10-14 | Khan Nisar Ahmed | Administration of gene-regulatory peptides |
| US8680059B2 (en) * | 1998-05-20 | 2014-03-25 | Biotempt B.V. | Oligopeptide acetate and formulations thereof |
| EP1300418A1 (en) * | 2001-10-04 | 2003-04-09 | Erasmus Universiteit Rotterdam | Gene regulation by oligopeptides |
| US7358330B2 (en) * | 2001-03-29 | 2008-04-15 | Biotempt B.V. | Immunoregulatory compositions |
| CA2876779A1 (en) * | 2000-05-12 | 2001-11-22 | Genzyme Corporation | Modulators of tnf-.alpha. signaling |
| RU2181297C2 (ru) | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Способ лечения патологического синдрома и лекарственное средство |
| BR0206160A (pt) * | 2001-05-25 | 2004-10-26 | Abbott Gmbh & Co Kg | Uso de anticorpos anti-tnf como medicamentos no tratamento de distúrbios sépticos de pacientes anêmicos |
| CA2817619A1 (en) | 2001-06-08 | 2002-12-08 | Abbott Laboratories (Bermuda) Ltd. | Methods of administering anti-tnf.alpha. antibodies |
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| US20030220261A1 (en) * | 2001-12-21 | 2003-11-27 | Khan Nisar Ahmed | Treatment of iatrogenic disease |
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| US7786084B2 (en) * | 2001-12-21 | 2010-08-31 | Biotempt B.V. | Treatment of burns |
| US20030220257A1 (en) * | 2001-12-21 | 2003-11-27 | Robbert Benner | Treatment of trauma |
| US20030220260A1 (en) * | 2001-12-21 | 2003-11-27 | Khan Nisar Ahmed | Peptide compositions |
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| US20080318871A1 (en) * | 2001-12-21 | 2008-12-25 | Khan Nisar A | Treatment of neurological disorders |
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| US20070041905A1 (en) * | 2005-08-19 | 2007-02-22 | Hoffman Rebecca S | Method of treating depression using a TNF-alpha antibody |
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| US20080118496A1 (en) * | 2006-04-10 | 2008-05-22 | Medich John R | Uses and compositions for treatment of juvenile rheumatoid arthritis |
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| US20090238825A1 (en) * | 2007-05-21 | 2009-09-24 | Kovacevich Brian R | Novel rabbit antibody humanization methods and humanized rabbit antibodies |
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| US8252286B2 (en) * | 2007-05-21 | 2012-08-28 | Alderbio Holdings Llc | Antagonists of IL-6 to prevent or treat thrombosis |
| EP2171451A4 (en) | 2007-06-11 | 2011-12-07 | Abbott Biotech Ltd | METHOD FOR TREATING JUVENILIAN IDIOPATHIC ARTHRITIS |
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| JP5934652B2 (ja) | 2009-11-24 | 2016-06-15 | アルダーバイオ ホールディングス エルエルシー | Ｉｌ−６に対する抗体およびその使用 |
| FR2962651A1 (fr) | 2010-07-15 | 2012-01-20 | Oleg Iliich Epshtein | Composition pharmaceutique d'association et son utilisation dans des procedes pour traiter les maladies ou affections fonctionnelles du tractus gastro-intestinal |
| FR2962656A1 (fr) | 2010-07-15 | 2012-01-20 | Oleg Iliich Epshtein | Procede pour augmenter l'effet d'une forme activee-potentialisee d'un anticorps |
| EP2643016A2 (en) | 2010-11-23 | 2013-10-02 | Alder Biopharmaceuticals, Inc. | Anti-il-6 antibodies for the treatment of anemia |
| US9062106B2 (en) | 2011-04-27 | 2015-06-23 | Abbvie Inc. | Methods for controlling the galactosylation profile of recombinantly-expressed proteins |
| WO2013158279A1 (en) | 2012-04-20 | 2013-10-24 | Abbvie Inc. | Protein purification methods to reduce acidic species |
| US9067990B2 (en) | 2013-03-14 | 2015-06-30 | Abbvie, Inc. | Protein purification using displacement chromatography |
| US9181572B2 (en) | 2012-04-20 | 2015-11-10 | Abbvie, Inc. | Methods to modulate lysine variant distribution |
| US9512214B2 (en) | 2012-09-02 | 2016-12-06 | Abbvie, Inc. | Methods to control protein heterogeneity |
| CN104955480A (zh) | 2013-01-25 | 2015-09-30 | 西蒙有限公司 | 用于选择性减少循环的生物活性可溶性tnf的组合物以及用于治疗tnf介导的疾病的方法 |
| CA2905010A1 (en) | 2013-03-12 | 2014-09-18 | Abbvie Inc. | Human antibodies that bind human tnf-alpha and methods of preparing the same |
| US9499614B2 (en) | 2013-03-14 | 2016-11-22 | Abbvie Inc. | Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides |
| US9017687B1 (en) | 2013-10-18 | 2015-04-28 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same using displacement chromatography |
| WO2015051293A2 (en) | 2013-10-04 | 2015-04-09 | Abbvie, Inc. | Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins |
| US9181337B2 (en) | 2013-10-18 | 2015-11-10 | Abbvie, Inc. | Modulated lysine variant species compositions and methods for producing and using the same |
| US9085618B2 (en) | 2013-10-18 | 2015-07-21 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same |
| US20150139988A1 (en) | 2013-11-15 | 2015-05-21 | Abbvie, Inc. | Glycoengineered binding protein compositions |
| WO2016160976A2 (en) | 2015-03-30 | 2016-10-06 | Abbvie Inc. | Monovalent tnf binding proteins |
| EP3078675A1 (en) | 2015-04-10 | 2016-10-12 | Ares Trading S.A. | Induction dosing regimen for the treatment of tnf alpha mediated disorders |
| JOP20190162A1 (ar) | 2016-12-30 | 2019-06-27 | Biocad Joint Stock Co | تركيبة صيدلانية مائية من جسم مضاد لـ tnf? أحادي النسيلة معاود الارتباط الجيني |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3631229A1 (de) * | 1986-09-13 | 1988-03-24 | Basf Ag | Monoklonale antikoerper gegen humanen tumornekrosefaktor (tnf) und deren verwendung |
| US5183657A (en) * | 1988-03-11 | 1993-02-02 | Celltech Limited | Antibodies for use in antilymphocyte antibody therapy |
| WO1990000902A1 (en) * | 1988-07-18 | 1990-02-08 | Chiron Corporation | Monoclonal antibodies reactive with cachectin |
| AU630497B2 (en) * | 1989-09-05 | 1992-10-29 | Immunex Corporation | Tumor necrosis factor-alpha and -beta receptors |
| DE07012625T1 (de) * | 1991-03-18 | 2010-01-21 | New York University | Monoklonale und chimäre Antikörper gegen humanen Tumornekrosefaktor |
| IL99120A0 (en) * | 1991-08-07 | 1992-07-15 | Yeda Res & Dev | Multimers of the soluble forms of tnf receptors,their preparation and pharmaceutical compositions containing them |
| EP0605522B1 (en) * | 1991-09-23 | 1999-06-23 | Medical Research Council | Methods for the production of humanized antibodies |
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1994
- 1994-03-19 NZ NZ278607A patent/NZ278607A/en unknown
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1995
- 1995-01-24 IL IL11242795A patent/IL112427A/en not_active IP Right Cessation
- 1995-01-27 US US08/687,328 patent/US6235281B1/en not_active Expired - Fee Related
- 1995-01-27 JP JP7520363A patent/JPH09509411A/ja not_active Abandoned
- 1995-01-27 WO PCT/EP1995/000291 patent/WO1995020978A1/de active IP Right Grant
- 1995-01-27 CN CN95191517A patent/CN1140414A/zh active Pending
- 1995-01-27 BR BR9506741A patent/BR9506741A/pt not_active Application Discontinuation
- 1995-01-27 EP EP95906353A patent/EP0804236B1/de not_active Revoked
- 1995-01-27 DK DK95906353T patent/DK0804236T3/da active
- 1995-01-27 AU AU15201/95A patent/AU1520195A/en not_active Abandoned
- 1995-01-27 CZ CZ19962322A patent/CZ290843B6/cs not_active IP Right Cessation
- 1995-01-27 HU HU9602169A patent/HU220995B1/hu not_active IP Right Cessation
- 1995-01-27 TW TW084100744A patent/TW403656B/zh not_active IP Right Cessation
- 1995-01-27 CA CA002182723A patent/CA2182723A1/en not_active Abandoned
- 1995-01-27 ES ES95906353T patent/ES2197912T3/es not_active Expired - Lifetime
- 1995-01-27 PT PT95906353T patent/PT804236E/pt unknown
- 1995-01-27 AT AT95906353T patent/ATE235917T1/de not_active IP Right Cessation
- 1995-02-06 HR HRP4409513.9A patent/HRP950052B1/xx not_active IP Right Cessation
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1996
- 1996-08-06 FI FI963101A patent/FI963101A0/fi not_active IP Right Cessation
- 1996-08-06 NO NO963280A patent/NO963280L/no not_active Application Discontinuation
-
2001
- 2001-02-14 US US09/782,290 patent/US20010010819A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995020978A1 (de) | 1995-08-10 |
| FI963101A (fi) | 1996-08-06 |
| NO963280L (no) | 1996-10-04 |
| ATE235917T1 (de) | 2003-04-15 |
| ES2197912T3 (es) | 2004-01-16 |
| CZ232296A3 (en) | 1997-03-12 |
| NO963280D0 (no) | 1996-08-06 |
| PT804236E (pt) | 2003-08-29 |
| HRP950052A2 (en) | 1997-10-31 |
| IL112427A (en) | 1998-12-06 |
| BR9506741A (pt) | 1997-10-21 |
| AU1520195A (en) | 1995-08-21 |
| EP0804236B1 (de) | 2003-04-02 |
| FI963101A0 (fi) | 1996-08-06 |
| CZ290843B6 (cs) | 2002-10-16 |
| HU220995B1 (hu) | 2002-07-29 |
| US6235281B1 (en) | 2001-05-22 |
| JPH09509411A (ja) | 1997-09-22 |
| TW403656B (en) | 2000-09-01 |
| DK0804236T3 (da) | 2003-07-21 |
| CA2182723A1 (en) | 1995-08-10 |
| HU9602169D0 (en) | 1996-10-28 |
| NZ278607A (en) | 1999-05-28 |
| HUT76875A (en) | 1997-12-29 |
| EP0804236A1 (de) | 1997-11-05 |
| HRP950052B1 (en) | 2000-04-30 |
| US20010010819A1 (en) | 2001-08-02 |
| IL112427A0 (en) | 1995-03-30 |
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