CN1893975A - 包含长正五聚蛋白ptx3抑制剂的药物 - Google Patents

包含长正五聚蛋白ptx3抑制剂的药物 Download PDF

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CN1893975A
CN1893975A CNA2004800371947A CN200480037194A CN1893975A CN 1893975 A CN1893975 A CN 1893975A CN A2004800371947 A CNA2004800371947 A CN A2004800371947A CN 200480037194 A CN200480037194 A CN 200480037194A CN 1893975 A CN1893975 A CN 1893975A
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arthritis
ptx3
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disease
cartilage
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B·伯塔兹
P·卡尔米纳蒂
C·戈兰达
A·曼托瓦尼
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Defiante Farmaceutica SA
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Abstract

描述了长正五聚蛋白PTX3抑制剂在制备预防和治疗自身免疫性疾病及骨和软骨退行性疾病的药物中的应用。

Description

包含长正五聚蛋白PTX3抑制剂的药物
本文描述的发明涉及长正五聚蛋白PTX3抑制剂在制备治疗自身免疫性疾病及骨和软骨退行性疾病的药物中的应用。
                   发明背景
PTX3是一种能够使其自身在被二硫桥结合的同十聚体结构(homodecameric structure)中自发有机化的糖蛋白，它在不同类型细胞中表达(Bottazzi等人，J.Biol.Chem.，1997；272：32817-32823)，尤其在与炎性细胞因子白介素1β(IL-1β)和肿瘤坏死因子α(TNF-α)接触后的单核吞噬细胞和内皮细胞中表达。
PTX3由两个结构域组成：与任何已知分子无关的N-末端和与短正五聚蛋白如C-反应蛋白(CRP)类似的C-末端。已经发现人PTX3(hPTX3)和动物PTX3之间的高度相似性。
有关正五聚蛋白的综述参见H.Gewurz等人，Current Opinion inImmunology，1995，7：54-64。
重组PTX3和原代细胞(例如成纤维细胞、内皮细胞和先天免疫细胞)表达的PTX3主要在被二硫桥稳定的十聚体结构中有机化。单个PTX3单体具有约45kDa的分子量，它可以通过还原二硫桥，随后使参与单体间相互作用的还原半胱氨酸烷基化，或者通过相同物质的定点诱变作用，从十聚体蛋白中获得(Bottazzi等人，J.Biol.Chem.，1997；272：32817-32823)。
最近对罹患类风湿性关节炎患者的研究已经显示，滑膜液中的PTX3的表达水平显著提高了。这种提高的PTX3的表达与表征该疾病的炎性过程有关(Lucchetti等人，Clin.Exp.Immunol.2000；119：196-202)。
WO 03/086380描述了PTX3基因表达抑制剂在治疗包括类风湿性关节炎的自身免疫性疾病中的应用。
WO 03/086380与本发明的区别在于，相对于本发明所述的化合物和抑制方法，它采用的是完全不同的化合物和完全不同的抑制方法。
事实上，在本专利申请中，所述的PTX3拮抗剂能够直接抑制蛋白(PTX3)的生物活性。
本领域技术人员清楚这样一个事实，即用小分子调节基因表达(以选择性方式)，例如不变更参与炎症的其它基因的表达，如WO03/086380中所列的，可能是困难的。此外，在基因水平上抑制在重要生物学功能中发挥基本作用的蛋白的表达可能会引起不利的反应，例如对感染和生殖不育的易感性增加。
因此在医药领域，对于能够起到PTX3拮抗剂作用的用于治疗本发明疾病的其它抑制剂还存在迫切需求。
                        发明概述
现已发现PTX3抑制剂或拮抗剂可以用于预防和治疗自身免疫性疾病及骨和软骨的退行性疾病。
本发明PTX3抑制剂的非限制性实例是单克隆或多克隆抗-PXT3抗体，而本发明PTX3拮抗剂的非限制性实例是单体PTX3或其肽或拟肽(peptidomimetic)衍生物。
因此本发明目的是能够阻止长正五聚蛋白PTX3的生物学活性的长正五聚蛋白PTX3抑制剂或拮抗剂作为用于制备治疗选自以下的自身免疫性疾病的药物的药剂，所述疾病选自：系统性红斑狼疮(SLE)、多发性硬化(MS)、关节炎、糖尿病、甲状腺炎、溶血性贫血、萎缩性睾丸炎、古德帕斯彻病、自身免疫性视网膜病、自身免疫性血小板减少症、重症肌无力、原发性胆汁性肝硬变、慢性活动性肝炎、溃疡性结肠炎、皮炎、慢性肾小球肾炎、斯耶格伦综合征、莱特尔综合征、肌炎、全身性硬化症或多关节炎；和选自以下的骨和软骨退行性疾病：骨关节炎；骨关节病；关节退行性疾病；胶原缺乏；以软骨内骨化为特征的软骨或骨疾病：原发性关节炎，包括例如，类风湿性关节炎、幼年型关节炎、未分化的慢性关节炎和多关节炎；自身免疫源性继发性关节炎，包括例如，系统性红斑狼疮关节炎、牛皮癣关节炎、克罗恩病关节炎；代谢障碍源性关节炎，包括例如，尿酸单钠关节病、焦磷酸盐关节病、草酸钙关节病；感染性关节炎、归咎于骨质疏松症的关节炎、无菌性骨坏死、良性和恶性骨肿瘤。
                        发明详述
“长正五聚蛋白PTX3抑制剂”是指任何单克隆或多克隆抗体，不论它是天然的(人或动物)、重组的或合成来源的，它能够用于结合PTX3和阻止其生物学活性。
制备本发明单克隆抗体的一个实例由Godine，J.W.，1986描述在“Monoclonal Antibodies：Principle and Practice.学术出版社，圣地亚哥”中，而制备本发明多克隆抗体的一个实例由Harlow E.和Lane D.描述在“Antibodies：A Laboratory Manual.Cold SpringHarbor Laboratory，1988；Cold Spring Harbor，NY”中。
“单体正五聚蛋白”是指任何单体正五聚蛋白，不论它是天然的(人或动物)、重组的或合成来源的。
“单体正五聚蛋白衍生物”是指具有至少一个突变并且保留了选择性抑制PTX3活性功能的所述单体正五聚蛋白的功能性类似物，或能够刺激PTX3的线性或结构域并且保留了选择性抑制PTX3活性功能的肽或拟肽类似物。
单体正五聚蛋白的优选类型是人单体正五聚蛋白，其序列描述在WO99/32516中。
与PTX3异常激活有关的自身免疫性疾病包括：系统性红斑狼疮(SLE)、多发性硬化(MS)、关节炎、糖尿病、甲状腺炎、溶血性贫血、萎缩性睾丸炎、古德帕斯彻病、自身免疫性视网膜病、自身免疫性血小板减少症、重症肌无力、原发性胆汁性肝硬变、慢性活动性肝炎、溃疡性结肠炎、皮炎、慢性肾小球肾炎、斯耶格伦综合征、莱特尔综合征、肌炎、全身性硬化症和多关节炎。
与PTX3异常激活有关的骨和软骨退行性疾病包括：骨关节炎；骨关节病；关节退行性疾病；胶原缺乏；以软骨内骨化为特征的软骨或骨疾病：原发性关节炎，包括例如，类风湿性关节炎、幼年型关节炎、未分化的慢性关节炎和多关节炎；自身免疫源性继发性关节炎，包括例如，系统性红斑狼疮关节炎、牛皮癣关节炎、克罗恩病关节炎；代谢障碍源性关节炎，包括例如，尿酸单钠关节病、焦磷酸盐关节病、草酸钙关节病；感染性关节炎、归咎于骨质疏松症的关节炎、无菌性骨坏死、良性和恶性骨肿瘤。
以下实施例进一步阐明本发明。
                     实施例1
PTX3-缺陷小鼠用于胶原引起的关节炎(CIA)的鼠类模型(Campbell等人，Eur.J.Immunol，2000；30：1568-75)。实验目的是评价PTX3-/-小鼠对关节炎表型诱导的易感性。
在尾近端区域通过多点皮内注射，用总体积为100μl的、添加了250μg热灭活的结核分枝杆菌的弗氏完全佐剂中的100μg小鸡II型胶原(SIGMA)处理129 sv x C57 BL/6PTX3-/-小鼠。
21天后进行相同的处理。
在给药阶段结束后，用计算存在的发炎关节及其大小的任意评分系统评价关节炎的发生率和严重性。得到的结果列在表1中。
表1中报告的PTX3+/+小鼠的较大发病率提供的证据表明，PTX3-/-小鼠对发生胶原引起的关节炎的易感性较小。这个结果被PTX3+/+小鼠比PTX3-/-小鼠关节炎更严重的临床评分所证实。
得到的结果表明，PTX3缺乏或它的抑制能用于预防和治疗骨和软骨的炎症和/或退行性疾病。
                表1
PTX3+/+和PTX3-/-小鼠的胶原引起的关节炎
  动物   发病率*   临床评分°
  PTX3+/+   3/5   10
  PTX3-/-   3/7   3.6
*实验结束时的发病率(初次免疫接种后60天)
°实验结束时患关节炎动物的平均临床评分
图例：在第二次免疫接种后，一周两次评价四肢关节炎的临床迹象的出现。用1到4分给所涉及的各肢体评分；因此每只动物能够获得最多16分的评分。
就关于工业应用方面来说，单体正五聚蛋白PTX3或其肽或拟肽衍生物或抗-正五聚蛋白PTX3抗体将是药物组合物的形式，其中，活性成分被药学可接受的赋形剂和/或稀释剂，例如无菌水、羧甲基纤维素或本领域专家已知的其它赋形剂所溶解和/或所赋形。
单体正五聚蛋白可用的药物组合物的实例与WO 99/32516中描述的用于长正五聚蛋白PTX3的那些相同。
本发明化合物可以通过肠内或胃肠外途径给药，特别优选的药物形式是缓释植入剂或关节内注射形式。
根据主治医师的判断，日剂量将取决于患者的体重、年龄和全身状况。
应当注意的是，包括缓释形式的所述药物组合物的制备可以使用药剂师和制药工艺学专家熟知的常规技术和手段来进行。

Claims (8)

1.长正五聚蛋白PTX3抑制剂或拮抗剂在制备预防和治疗骨和软骨退行性疾病的药物中的应用。
2.根据权利要求1的应用，其中，长正五聚蛋白PTX3抑制剂是指能够结合PTX3的任何单克隆或多克隆抗体。
3.根据权利要求2的应用，其中，抗体是天然的(人或动物)、重组的或合成来源的。
4.根据权利要求1的应用，其中，拮抗剂是单体PTX3，或保留了选择性抑制PTX3活性功能的它的一种肽或拟肽衍生物。
5.根据权利要求4的应用，其中，拮抗剂是天然的(人或动物)、重组的或合成来源的。
6.根据权利要求4的应用，其中，单体正五聚蛋白是人源的。
7.根据权利要求1的应用，其中，自身免疫性疾病选自：系统性红斑狼疮(SLE)、多发性硬化(MS)、关节炎、糖尿病、甲状腺炎、溶血性贫血、萎缩性睾丸炎、古德帕斯彻病、自身免疫性视网膜病、自身免疫性血小板减少症、重症肌无力、原发性胆汁性肝硬变、慢性活动性肝炎、溃疡性结肠炎、皮炎、慢性肾小球肾炎、斯耶格伦综合征、莱特尔综合征、肌炎、全身性硬化症和多关节炎。
8.根据权利要求1的应用，其中，所述骨或软骨退行性疾病选自：骨关节炎；骨关节病；关节退行性疾病；胶原缺乏；以软骨内骨化为特征的软骨或骨疾病：原发性关节炎，包括例如，类风湿性关节炎、幼年型关节炎、未分化的慢性关节炎和多关节炎；自身免疫源性继发性关节炎，包括例如，系统性红斑狼疮关节炎、牛皮癣关节炎、克罗恩病关节炎；代谢障碍源性关节炎，包括例如，尿酸单钠关节病、焦磷酸盐关节病、草酸钙关节病；感染性关节炎、归咎于骨质疏松症的关节炎、无菌性骨坏死、良性和恶性骨肿瘤。
CNA2004800371947A 2003-12-23 2004-12-21 包含长正五聚蛋白ptx3抑制剂的药物 Pending CN1893975A (zh)

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CN107080845A (zh) * 2007-12-11 2017-08-22 科达治疗公司 受损伤口愈合的组合物和治疗
WO2019057024A1 (zh) * 2017-09-19 2019-03-28 王育民 含单克隆抗体或其抗原结合片段的医药组成物及其用途

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ITRM20020109A1 (it) * 2002-02-28 2003-08-28 Sigma Tau Ind Farmaceuti Derivati funzionali della pentraxina lunga ptx3 per preparare un vaccino autologo per la cura dei tumori.
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ES2389452T3 (es) 2006-05-02 2012-10-26 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Uso de timosina 1, sola o en combinación con PTX3 o ganciclovir, para el tratamiento de infección por citomegalovirus
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CN107080845A (zh) * 2007-12-11 2017-08-22 科达治疗公司 受损伤口愈合的组合物和治疗
CN106950366A (zh) * 2017-02-15 2017-07-14 中国医学科学院北京协和医院 一种acpa阴性的ra诊断标志物及其应用
WO2019057024A1 (zh) * 2017-09-19 2019-03-28 王育民 含单克隆抗体或其抗原结合片段的医药组成物及其用途
WO2019056991A1 (zh) * 2017-09-19 2019-03-28 臻崴生物科技有限公司 单克隆抗体或其抗原结合片段及其用途

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