CN102946904A - 关节炎治疗 - Google Patents
关节炎治疗 Download PDFInfo
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- CN102946904A CN102946904A CN2011800284830A CN201180028483A CN102946904A CN 102946904 A CN102946904 A CN 102946904A CN 2011800284830 A CN2011800284830 A CN 2011800284830A CN 201180028483 A CN201180028483 A CN 201180028483A CN 102946904 A CN102946904 A CN 102946904A
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Abstract
给予一种特异性靶向IL-1α的单克隆抗体(mAb)对于治疗关节炎的关节症状和关节外症状是有用的。
Description
相关申请的交叉引用
本申请要求2010年6月18日提交的美国临时专利申请序列号61/356,176的优先权,通过引用以其全文结合在此。
技术领域
本发明总体上涉及免疫学、炎症、关节炎、及医学领域。更具体地说,本发明涉及一种特异性结合白细胞介素-1α(IL-1α)的抗体(Ab)用来治疗关节炎的一种或多种症状的用途。
背景技术
关节炎,在美国是残疾的最常见原因,为不同病症的集合,如骨关节炎、类风湿性关节炎、痛风、银屑病关节炎、脓毒性关节炎、反应性关节炎。所有类型的关节炎以关节炎症为特征,引起该患病部位的疼痛、肿胀、发红、僵硬、以及热。由于罹患受试者因疼痛和僵硬而活动能力较低,关节炎能够间接导致肥胖症、高胆固醇、和/或心脏病。关节炎还能够引起关节外疾病,如虹膜炎、葡萄膜炎、口腔溃疡、胃肠道炎症、泌尿生殖道炎症、以及皮肤损害。
对于大部分类型的关节炎,不存在治愈,并且治疗在很大程度是针对症状的,例如给予止痛药和抗炎药。非甾体抗炎药(NSAID)能够用于减轻炎症和疼痛。虽然通常是有效的,NSAID可能引起副作用,如腹痛、出血、溃疡、以及肝和肾的损伤。皮质类固醇类在减轻炎症以及关节损伤上是有效的,但能够引起许多相关的副作用,包括瘀伤、体重增长、白内障、骨质变薄、糖尿病、以及高血压。其他通常用于治疗关节炎的药物是甲氨蝶呤、环孢菌素、环磷酰胺、来氟米特、羟基氯喹、柳氮磺胺吡啶、以及米诺环素。这些药物也能够引起副作用,如肝损伤和免疫抑制。肿瘤坏死因子(TNF)抑制剂,如依那西普(恩利(Enbrel))、英夫利昔单抗(类克(Remicade))、以及阿达木单抗(修美乐(Humira))对关节炎的治疗也有用。TNF抑制剂的副作用包括注射部位反应、心力衰竭、淋巴瘤以及感染风险增加。
概述
本发明基于的发现是,对患有关节炎的人类受试者给予一种特异性靶向IL-1α的抗体(Ab)减少了受试者的CD14+IL-1α+外周血单核细胞,并且明显改善关节以及关节外部位的炎症,除了给药部位疼痛以外完全没有观察到副作用。
因此,本发明以通过对受试者给予一种药物组合物来治疗与人类受试者中的关节炎相关的炎症病理的一种方法为特征,该药物组合物包含一种药学上可接受的载体和有效减轻受试者中的至少一种炎症病理症状的一定量的抗IL-1α抗体。该症状可以是关节炎症,如腕关节或肩关节炎症、或眼睛炎症如葡萄膜炎。抗IL-1α抗体可以是单克隆抗体,如IgG1。该抗IL-1α抗体可以是设计为MABp1的单克隆抗体或包括一个或多个MABp1的互补决定区(CDR)的单克隆抗体。
可以通过皮下、静脉内、肌内、眼内注射、或直接注射到发炎的关节中而将该药物组合物给予该受试者。该抗体还可以局部施用于眼睛。在该方法中,该抗IL-1α抗体有效减轻受试者中的至少一种炎症病理症状的量可以是足以使受试者的外周血抗IL-1α抗体浓度提高到至少4μg/mL、和/或足以使受试者的CD14+IL-1α+外周血单核细胞的数目降低至少5%。
该方法还可以包括在给予该药物组合物之后测量受试者外周血中的CD14+IL-1α+单核细胞数目的步骤,例如,其中该测量受试者外周血中的CD14+IL-1α+单核细胞数目的步骤是在给予该药物组合物之后的至少两个不同的时间点进行的。
在另一方面,本发明以通过向受试者给予一种药物组合物来诱导受试者中的单核细胞空泡形成(monocyte vacuolization)的一种方法为特征,该药物组合物包含一种药学上可接受的载体和有效诱导单核细胞中的空泡形成的一定量的抗IL-1α抗体。
除非另有定义,在此所使用的所有技术术语均与本发明所属领域的普通技术人员通常理解的具有相同的含义。通常被理解的生物学术语的定义能够在Rieger等人的《遗传学词汇表:经典遗传学以及分子遗传学》,第五版,施普林格出版社:纽约,1991(Glossary of Genetics:Classicaland Molecular,5th edition,Springer-Verlag:New York,1991);和Lewin的《基因V》,牛津大学出版社:纽约,1994(Lewin,Genes V,OxfordUniversity Press:New York,1994)中找到。通常被理解的医学术语的定义能够在《STEDMAN’S医学词典》,第27版,Lippincott、Williams及Wilkins著,2000(Stedman’s Medical Dictionary,27th Edition,Lippincott,Williams&Wilkins,2000)中找到。
如在此所使用的,一种“抗体”(“antibody”或“Ab”)是一种免疫球蛋白(Ig)、相同的或异源的免疫球蛋白的一种溶液、或免疫球蛋白的一种混合物。一种“抗体”还可以涉及免疫球蛋白的片段和免疫球蛋白的工程化形式,如Fab、Fab’和F(ab’)2片段;以及scFv’s、异源耦联抗体、以及采用免疫球蛋白衍生的CDR赋予抗原特异性的类似的人工分子。一种“单克隆抗体”(“monoclonal antibody”或“mAb”)是由一个克隆B细胞系表达的一种抗体或仅含有能够与一种特定抗原的特定表位发生免疫反应的一个抗原结合部位种类的抗体分子群。一种“多克隆抗体”(“polyclonal antibody”或“polyclonal Ab”)为异源抗体的一种混合物。典型地,一种多克隆抗体包含结合特定抗原的大量不同的抗体分子,其中这些不同的抗体的至少一些与该抗原的不同表位发生免疫反应。如在此所使用的,一种多克隆抗体可以是两种或多种单克隆抗体的混合物。
一种抗体的“抗原结合部分”包含在一种抗原的Fab部分的可变区之内,并且是对抗体赋予抗原特异性的该抗体的部分(即,典型地由该抗体的重链和轻链的CDR形成的三维口袋(three-dimensional pocket))。“Fab部分”或“Fab区”为木瓜蛋白酶消化的免疫球蛋白的蛋白水解片段,该片段含有该免疫球蛋白的抗原结合部分。“非Fab部分”是不在该Fab部分之内的抗体部分,例如“Fc部分”或“Fc区”。抗体的“恒定区”是在可变区之外的抗体部分。通常包含在恒定区之内的是抗体的“效应子部分”(“effector portion”),该效应子部分是结合负责促进免疫应答的其他免疫系统组分的抗体部分。因此,例如在一种抗体上结合补体成分或Fc受体(未经由抗原结合部分)的部位为该抗体的效应子部分。
当提及一种蛋白质分子如一种抗体时,“纯化的”表示从天然伴随这些分子的成分中分离。典型地,当一种抗体或蛋白质按重量计至少大约10%(例如,9%、10%、20%、30%、40%、50%、60%、70%、80%、90%、95%、98%、99%、99.9%和100%)从其天然结合的非抗体蛋白质或其他天然存在的有机分子释放时,它是纯化的。能够通过任何适当的方法,例如柱层析、聚丙烯酰胺凝胶电泳或HPLC分析来测量纯度。一种化学合成的蛋白质或在一种细胞类型中产生的其他重组蛋白是“纯化的”(在其中该蛋白质天然存在的细胞类型除外)。
对于“结合”(“bind”或“binds”)或“与……反应”表示至少一个分子识别并粘附于样品中的一种特定的第二分子,但基本上不识别或粘附样品中的其他分子。通常,与另一种分子“特异性结合”的抗体具有针对该另一种分子的大于约105、106、107、108、109、1010、1011或1012L/mol的Kd。
一种“治疗有效量”是能够在治疗的动物或人体内产生医学上希望的效果(例如,一种疾病或一种疾病的症状的改善或预防)的量。
虽然与在此描述的那些相似或等效的方法和材料可以用于本发明的实践或测试,以下描述了适合的方法和材料。另外,以下所讨论的具体实施方案仅仅是说明性的而不旨在限制。
附图简要说明
图1是显示了在对患有反应性关节炎的人类受试者给予MABp1之后的药代动力学的曲线图和表格。
图2是显示了对患有反应性关节炎的人类受试者给予MABp1之后的流式细胞血液分析的一系列曲线图和直方图。
图3是显示了对患有反应性关节炎的人类受试者给予MABp1之后的流式细胞血液分析的一系列曲线图。
详细说明
本发明包括用于治疗与受试者中的关节炎相关的症状或病理过程的组合物和方法。以下描述的优选实施方案说明了这些组合物和方法的适应性变化。虽然如此,根据这些实施方案的说明,基于以下提供的说明可以完成和/或实践本发明的其他方面。
一般方法
在此描述了涉及常规免疫学和分子生物学技术的方法。免疫学方法(例如用于抗原抗体复合物的检测和定位的测定法、免疫沉淀法、免疫印迹,等等)通常在本领域是已知的并且在方法学论文如《当代免疫学实验手册》,Coligan等人编辑,约翰威利父子出版公司,纽约(CurrentProtocols in Immunology,Coligan et al.,ed.,John Wiley&Sons,New York)中描述。分子生物学技术详细描述于专题论文中,如《分子克隆:实验室手册》,第二版,1-3卷,Sambrook等人编辑,冷泉港实验室出版社,纽约,2001(Molecular Cloning:A Laboratory Manual,2nd ed.,vol.1-3,Sambrook et al.,ed.,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,N.Y.,2001)和《当代分子生物学实验手册》,Ausubel等人编辑,格林出版和威利-交叉科学,纽约(Current Protocols in Molecular Biology,Ausubel et al.,ed.,Greene Publishing and Wiley-Interscience,New York)。抗体方法描述于《治疗性抗体手册》,Dubel,S.编辑,威利-VCH出版社,2007(Handbook of Therapeutic Abs,Dubel,S.,ed.,Wiley-VCH,2007)中。医学治疗的一般方法描述于McPhee和Papadakis的《当代医学诊断与治疗2010》,第49版,麦格劳-希尔医学,2010(McPhee and Papadakis,CurrentMedical Diagnosis and Treatment 2010,49th Edition,McGraw-Hill Medical,2010)以及Fauci等人的《哈里森内科学原理》,第17版,麦格劳-希尔专业出版,2008(Fauci et al.,Harrison’s Principles of Internal Medicine,17thEdition,McGraw-Hill Professional,2008)中。
关节炎症状的治疗
在此所述的这些组合物和方法对于通过对受试者给予一种药物组合物来治疗哺乳动物受试者中的与关节炎相关的炎症病理是有用的,该药物组合物包含有效减轻受试者中的至少一种炎症病理症状的一定量的抗IL-1α抗体。该哺乳动物受试者可以是罹患关节炎的任何受试者,包括人类、狗、猫、马、牛、绵羊类、山羊和猪。人类受试者可以是男性、女性、成人、儿童、老年人(65岁或更老)、以及患有其他疾病的人。与关节炎相关的特定症状或病理过程可以是炎症、疼痛、僵硬、或关节(例如在腕、指/趾【掌关节或跖关节】、肘、肩、髋、膝、踝、脚、颈、或背中)或关节外组织(例如虹膜炎、葡萄膜炎、口腔溃疡、胃肠道炎症、泌尿生殖道炎症、或皮肤损伤害)的退化。
抗体以及其他靶向IL-1α的药剂
特异性结合IL-1α并减轻受试者的关节炎引起的症状或病理过程的任何适合类型的抗体可能用于本发明中。例如,所使用的抗IL-1α抗体可能是单克隆抗体、多克隆抗体、单克隆抗体的混合物、或一种抗体片段或工程化抗体样分子(如一种scFv)。该抗体的Ka优选为至少1x109M-1或更大(例如大于9x1010M-1、8x1010M-1、7x1010M-1、6x1010M-1、5x1010M-1、4x1010M-1、3x1010M-1、2x1010M-1、或1x1010M-1)。在一个优选的实施方案中,本发明利用了一种全人源单克隆抗体,该全人源单克隆抗体包括(i)展示出与人IL-1α的很高结合亲和力的一个抗原结合可变区以及(ii)在通过C1q结合而激活补体系统和结合若干不同的Fc受体两方面均有效的一个恒定区。该人抗体优选是一种IgG1,虽然该人抗体也可以是不同的同种型,如IgM、IgA、或IgE,或亚类如IgG2、IgG3、或IgG4。特别有用的单克隆抗体的一个实例是MABp1,一种在2009年6月1日提交的美国专利申请序列号12/455,458中描述的IL-1α特异性IgG1单克隆抗体。其他有用的单克隆抗体为包括MABp1的至少一种但优选为所有的CDR的单克隆抗体。
由于表达人IL-1α特异性免疫球蛋白的B淋巴细胞天然存在于人类中,用于增加单克隆抗体的一种目前优选的方法是,首先从受试者中分离这种B淋巴细胞,然后使其永生化,使得它能够在培养中连续复制。可以用一种或多种人IL-1α抗原来免疫缺乏大量天然存在的表达人IL-1α特异性的免疫球蛋白的B淋巴细胞的受试者,以便增加这种B淋巴细胞的数目。人单克隆抗体是通过永生化一种分泌人抗体的细胞(例如一种人浆细胞)制备的。参见,例如美国专利号4,634,664。
在一个示例性的方法中,从一位或多位(例如5位、10位、25位、50位、100位、1000位或更多位)人类受试者中筛选了在其血液中存在这种IL-1α特异性抗体的受试者。于是那些表达所希望的抗体的受试者能够被用作B淋巴细胞供体。在一个可能的方法中,从具有表达人IL-1α特异性抗体的B淋巴细胞的人类供体获得外周血。然后从该血液样品中分离了这种B淋巴细胞,例如通过细胞分选(例如荧光激活细胞分选“FACS”、或磁珠细胞分选)筛选表达人IL-1α特异性免疫球蛋白的B淋巴细胞。然后,根据已知的技术通过病毒转化(例如使用EBV)或通过与另一种永生化细胞(如人骨髓瘤细胞)融合使这些细胞永生化。然后,能够通过有限稀释法(例如选择并继代培养在微量滴定板的孔中的人IL-1α特异性免疫球蛋白阳性的细胞,并重复该过程直到能够分离得到所希望的克隆细胞系)分离在这个表达人IL-1α特异性免疫球蛋白的群体中的B淋巴细胞。参见,例如Goding的《单克隆抗体:原理和实践》,59-103页,学术出版社,1986(Goding,Monoclonal Abs:Principles and Practice,pp.59-103,Academic Press,1986)。那些表达与人IL-1α具有至少纳摩尔或纳摩尔的结合亲和力的免疫球蛋白的克隆细胞系是优选的。可以通过常规的免疫球蛋白纯化程序如盐截留(salt cuts)、尺寸排阻、离子交换分离、以及亲和色谱从培养基或体液(例如腹水)中纯化由这些克隆细胞系分泌的单克隆抗体。
虽然永生化的B淋巴细胞可以用于体外培养以直接产生单克隆抗体,在某些情况下可能令人希望的是使用异源表达系统来产生单克隆抗体。参见,例如美国专利申请号11/754,899中描述的方法。例如,可以将编码人IL-1α特异性单克隆抗体的基因克隆并引入一种表达载体(例如一种基于质粒的表达载体),用于进行在异源宿主细胞(例如CHO细胞、COS细胞、骨髓瘤细胞、以及大肠杆菌细胞)中的表达。由于免疫球蛋白包含重(H)链和轻(L)链(在一种H2L2构型中),可以将编码每个链的基因分别分离并在不同载体中表达。
虽然由于受试者会产生一种抗抗体应答的可能性较大而通常是次优选的,但嵌合单克隆抗体(例如“人源化”单克隆抗体)可以用于本发明种,该嵌合单克隆抗体是具有源于不同动物种类的不同部分(例如与一种人免疫球蛋白的恒定区融合的一种鼠免疫球蛋白的可变区)的抗原结合分子。可以通过本领域中已知的方法制备这种嵌合抗体。参见,例如Morrison等人,《美国科学院院报》(Proc.Nat'l.Acad.Sci.USA),81:6851,1984;Neuberger等人,《自然》(Nature),312:604,1984;Takeda等人,《自然》(Nature),314:452,1984。同样,可以通过本领域已知的方法将抗体人源化。例如,可以通过各种供应商或如美国专利号5,693,762、5,530,101、或5,585,089中所述,将具有所希望的结合特异性的单克隆抗体人源化。
在此所述的这些单克隆抗体是亲和成熟的,以增强或另外地通过已知的方法如VH和VL结构域改组(Marks等人,Bio/Technology10:779-783,1992)、高变区(HVRs)和/或框架残基的随机诱变(Barbas等人,《美国科学院院报》(Proc.Nat'l.Acad.Sci.USA)91:3809-3813,1994;Schier等人,《基因》(Gene)169:147-155,1995;Yelton等人,《免疫学期刊》(J.Immunol.)155:1994-2004,1995;Jackson等人,《免疫学期刊》(J.Immunol.)154(7):3310-9,1995;and Hawkins等人,《分子生物学期刊》(J.Mol.Biol.)226:889-896,1992)改变他们的结合特异性。一种抗体的氨基酸序列变体可以通过将适当的变化引入编码该抗体的核苷酸序列中而制备。另外,可以改变编码单克隆抗体的核酸序列的修饰(例如不改变该单克隆抗体的氨基酸序列)用于增强该单克隆抗体在某些表达系统中的产生(例如针对一种给定的表达系统的内含子去除(intronelimination)和/或密码子优化)。可以通过与另一种蛋白质(例如另一种单克隆抗体)或非蛋白质分子偶联来修饰在此所述的单克隆抗体。例如,可以将一种单克隆抗体与一种水溶性聚合物(如聚乙二醇)或碳纳米管偶联(参见,例如Kam等人,《美国科学院院报》(Proc.Natl.Acad.Sci.USA)102:11600-11605,2005)。参见,美国专利申请号11/754,899。
优选地,为了确保以最小的副作用对受试者给予高效价的人IL-1α特异性单克隆抗体,本发明的单克隆抗体组合物是按重量计至少0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、20%、25%、30%、35%、40%、45%、50%、60%、70%、80%、90%、95%、96%、97%、98%、99%、99.9%(或更高)纯的(不包括任何赋形剂)。本发明的单克隆抗体组合物可以仅仅包含单一类型的单克隆抗体(即,由单个克隆B淋巴细胞系产生的一种单克隆抗体)或可以包含两种或更多种(例如,2、3、4、5、6、7、8、9、10或更多种)不同类型的单克隆抗体的混合物。
为了修饰或增强它们的功能,人IL-1α单克隆抗体可以与另一种分子(如细胞毒素)结合。一种人IL-1α特异性单克隆抗体可以与一种或多种细胞毒素结合以便更有效地杀死表达IL-1α的细胞。用于本发明的细胞毒素可以是任何能够与人IL-1α特异性单克隆抗体结合的细胞毒性药剂(例如在接触一种细胞之后可以杀死该细胞的分子)。细胞毒素的实例包括但不限于:放射性核素(例如35S、14C、32P、125I、131I、90Y、89Zr、201Tl、186Re、188Re、57Cu、213Bi、和211At)、结合放射性核素类、以及化疗剂。另外的细胞毒素的实例包括但不限于:抗代谢药(例如5-氟尿嘧啶(5-FU)、甲氨蝶呤(MTX)、氟达拉滨,等等)、抗微管药(例如长春新碱、长春碱、秋水仙碱、紫杉烷(如紫杉醇和多西他赛),等等)、烷化剂(例如环磷酰胺、美法仑、双氯乙基亚硝基脲(BCNU)等)、铂类药(例如顺铂(也称为cDDP)、卡铂、奥沙利铂、JM-216、CI-973,等等)、蒽环类(例如,多柔比星、柔红霉素,等等)、抗生素类药物(例如,丝裂霉素C)、拓扑异构酶抑制剂(例如依托泊苷、替尼泊苷、和喜树碱)、或其他细胞毒性药物如蓖麻毒素、白喉毒素(DT)、假单胞菌外毒素(PE)A、PE40、相思豆毒素、肥皂草素、美洲商陆病毒蛋白、溴化乙锭、糖皮质激素、炭疽毒素、以及其他。参见,例如美国专利号5,932,188。
虽然上述IL-1α特异性抗体优选用于本发明,在一些情况下,也可以使用其他特异性靶向IL-1α的药剂,只要它们的给药导致关节炎的一种或多种症状的改善即可。这些其他试剂可以包括特异性结合IL-1α的有机小分子类、适体类、肽类、和蛋白质类。
药物组合物和方法
可以通过药学上可接受的载体(例如无菌生理盐水)对动物或人给予该抗IL-1α抗体组合物,药学上可接受的载体是基于给药模式和途径以及标准的制药实践而选择的。药学上可接受的载体以及药物制剂的清单可以在作为本领域内的标准文本的雷明顿药物科学(Remington’sPharmaceutical Sciences)以及在USP/NF中找到。可以向这些组合物中添加其他物质,并且可以采取其他步骤来稳定和/或保存这些组合物、和/或促进它们的向受试者的给药。
例如,这些抗体组合物可以是冻干的(参见Draber等人,《免疫学方法期刊》(J.Immunol.Methods.)181:37,1995和PCT/US90/01383);可以溶于包含钠离子和氯离子的溶液中;溶于包含一种或多种稳定剂(如白蛋白、葡萄糖、麦芽糖、蔗糖、山梨醇、聚乙二醇、和甘氨酸)的溶液中;过滤(例如,使用0.45μm和/或0.2μm的过滤器);与β-丙内酯接触;和/或溶于包含一种杀微生物剂(例如一种去污剂、一种有机溶液、以及一种去污剂与有机溶剂的混合物)的溶液中。
可以通过适合的技术对动物或人给予这些抗体组合物。典型地,这种给药将是肠胃外的(例如静脉内、皮下、肌内、或者腹膜内注射)。还可以通过例如注射或局部施用直接对目标部位(例如发炎的关节、或葡萄膜或结膜)给予这些组合物。其他递送方法是本领域已知的,例如脂质体递送或从一个浸渍有该组合物的装置扩散。可以通过单次快速注射、多次注射或连续输注(例如静脉输液或通过腹膜透析)给予该组合物。
一个治疗有效量是能够在治疗的动物或人体内产生医学上所希望的结果的量。抗IL-1α抗体组合物的一个有效量是一个在关节炎患者中显示临床疗效的量,临床疗效的量度是在疼痛和功能以及预防结构损伤方面的改善。正如在医疗领域熟知的,用于任何动物或人类的剂量取决于许多因素,包括受试者的尺寸、体表面积、年龄、有待给予的特定组合物、性别、给予的时间和途径、全身健康状况、以及同时给予的其他药物。一个优选的剂量为一个足以使受试者的外周血抗IL-1α抗体的浓度升高到至少4(例如,至少4、5、6、7、8、9、10、20、30、40、50、100、200、300、400、500、1000、2500、或5000)微克/mL的剂量。预期的是,抗体的一个适当剂量可以是在大约0.2到20(例如0.5、1、2、3、4、5、6、7、8、9、10、15、20、30、50、或100)mg/kg体重的范围内的皮下给药、以及大约0.001到50(例如,0.001、0.01、1、5、10、15、25、或50)mg每只眼睛的局部给药。可以反复给予该剂量,例如每小时一次、每天一次、每周一次、或每月一次。
实例
实例1-XilonixTM
XilonixTM是一种稳定的等渗缓冲液(pH6.4)中的15mg/mL的MABp1的一种无菌的注射用液体制剂。每10mL的I型硼硅玻璃血清瓶含有5mL该制剂,并用一种20mm的Daikyo Flurotec的丁基橡胶塞和翻盖铝密封件(flip-off aluminum seal)将其密封。该产品储存在5±3°C,允许室温下偏移。该药品的确切组成如下所示:
实例2-用一种IL-1α特异性单克隆抗体治疗反应性关节炎
对一位48岁的患有反应性关节炎的男性患者给予总共220mg的MABp1,MABp1为2009年6月1日提交的美国专利申请序列号12/455,458中描述的一种IL-1α特异性单克隆抗体。该患者具有长的反应性关节炎病史,始于16岁,当时在因为他左膝的严重炎症住院治疗期间,被诊断为莱特尔综合征。这种炎症消退了,可是该患者经历了在若干关节中的周期性复发,一直到他二十几岁。直到35岁未发生进一步的发作,该患者患有持续8周的严重单侧葡萄膜炎发作。用眼科皮质类固醇和口服NSAIDS不能良好地控制葡萄膜炎,导致了某种疤痕。该患者随后经历了至少三次另外的不同强度的葡萄膜炎发作,其中一次发作需要角膜下注射皮质类固醇。
恰好在他48岁生日之前,该患者发生了在他的左肩和腕部的严重疼痛。明显的肿胀和发红伴随活动能力的几乎完全丧失累及腕部。由于强烈的肩痛,该患者不能将他的左臂外展大于约20°。在当天,对该患者给予皮质类固醇,肩峰下注射到左肩中。该患者报告,这种病症继续恶化,据说肩和腕的疼痛变得持续,打扰了工作,并且妨碍了睡眠。另外,接着发生了左眼的疼痛和刺激,表明葡萄膜炎的发作的开始。据说这是第一次关节炎症与葡萄膜炎一起出现。该患者当时正在服用眼科皮质类固醇、口服和局部眼科NSAIDS,但几乎无明显益处。
在第0天(在皮质类固醇肩峰下注射42天之后),对该患者给予MABp1皮下注射四次,递送总共110mg的MABp1(以相同剂量)。除了注射时的疼痛以外,未报告任何副作用。在注射之前即刻通过静脉穿刺进行抽血,置于两个5mL肝素钠管中。用酶联免疫吸附测定(ELISA)进行血浆分析以检测存在的内源性抗IL-1α抗体,结果表明没有已存在的抗体。
在第一天,该患者报告,他在那天早上无搏动痛而醒来,搏动痛曾经变成“醒来时的第一感觉”。在后续的几天中,有明显的活动能力的改善。注射部位没有硬结或发红。进行了抽血和流式细胞分析(FACS)以评估白细胞亚群和单核细胞中IL-1α的表达。进行血浆分析以确定MABp1的水平,并且开始收集MABp1的药代动力学(pK)数据。PBMC的FACS分析表明,大多数(72.6%)CD14+单核细胞表达了IL-1α。观察到MABp1血浆浓度为3.2μg/mL。
在第6日,进行另一次血液样品采集并且使用FACS分析MABp1.经由MABp1染色的CD14+单核细胞的频率已经下降至47.3%。MABp1的血浆水平已经增加到7μg/mL。虽然未被证实,MABp1浓度的增加被认为反映了MABp1的皮下给药的贮存效果。虽然已经存在改善,但该患者仍然呈现有相当的压痛和伴随运动的疼痛,并且自从前一个周末,该患者参加了一次派对并饮酒后葡萄膜炎出现闪辉。对该患者给予了另一个110mg的MABp1的皮下给药。
在第14天,采集血液样品并使用FACS进行分析,并且进行血浆的pK分析。经由MABp1染色的CD14+单核细胞的频率进一步下降到21.7%。然而,MABp1的血浆水平也下降至5.8μg/mL。这是不曾预料的,因为MABp1的血浆水平曾经在第一次注射之后的一周中增加。
在第一次注射MABp1之后大约一个月,再次评估该患者。注意到在活动能力上有显著的改善,并且腕部无疼痛。肩痛仅仅在外展至90°时出现。FACS分析表明没有可检测的经由MABp1染色的CD14+单核细胞。MABp1的血浆水平已经下降到1.6μg/mL,提示MABp1的半衰期为大约两周。
在接下来的几周的疗程中,该患者显示在活动能力上的逐渐的但是持续的改善。葡萄膜炎完全消退。即使该患者在第一次注射MABp1之后停用了所有药物治疗,仍然注意到这种改善。在第一次注射MABp1之后大约三个月,经由MABp1染色的CD14+单核细胞的频率恢复到治疗前水平。MABp1的血浆水平下降到0.07μg/mL。然而,该患者在肩活动能力的改善上继续表现良好。
实例3-对血浆样品进行内源性抗人IL-1α自身抗体的筛选以及MABp1的药代动力学。
开发了一种使用直接ELISA的用于筛选血浆样品的抗人IL-1α的内源性自身抗体的方法。该方法也被用来确定在给予MABp1之后的药代动力学(pK),除了制备了更高稀释度的血浆样品以外。
直接ELISA包括在一种聚苯乙烯微孔板上包被重组人IL-1α。结合的人IL-1A捕获来自测试样品的内源性抗人IL-1α抗体。然后用一种HRP结合的Fc特异性的鼠抗人IgG来检测该被捕获的内源性抗人IL-1α抗体,然后用TMB底物处理。在与HRP酶反应时,该TMB底物产生深蓝色的可溶性产物。通过加入使该蓝色产物转变成黄色的终止液来终止该酶促反应。用酶标仪在450nm下进行比色测量。
提供了每个样品的大约5mL的血浆样品。在等分之前将血浆置于2-8°C,并在-80°C储存。以1:500、1:1000、和1:2000倍稀释血浆样品,以便用作样品。使用缓冲液中的阳性对照,该阳性对照含有20μg/mL的MABp1抗体原液,按照1:5000和1:10000倍稀释于微孔板上。缓冲液被用作阴性对照以及一种预设阴性对照血浆,按照1:1000、1:1200、以及1:1500稀释。采用了一种附加的阳性血浆对照,该附加的阳性血浆对照为加入了20g/mLMABp1抗体的血浆,并对于微孔板上的样品稀释为1:5000和1:10000。
如果阳性对照值在±2的标准偏差之内,则认为该ELISA数据是可接受的。然而,如果该QC阳性对照值在±2的标准偏差之外,则认为该ELISA数据是不可接受的,且将重复该实验。使用Kaleidagraph,将标准溶液的对数平均吸光度(logarithmic mean absorbance)作为对数浓度的函数连同吸光度误差条一起标绘。该标准曲线应当表现出线性行为。从如
实例2中所述的患者身上采集的样品的药代动力学分析的结果显示在图1中。
实例4-血统亚群的流式细胞(FACS)检查
描述了全血染色和从全血中富集的外周血单核细胞(PBMC)的染色这两者的FACS程序。对所有样品进行全血和PBMC两者的染色。这种FACS分析允许血统亚群(blood lineage subset):B和T淋巴细胞、NK细胞、单核细胞、中性粒细胞、以及IL-1α+细胞的相对百分比确定。从如在实例2中所述的患者采集的样品的FACS分析的结果显示在图2和3中。血涂片的显微照片显示,当在给药后32天分析时,给予MABp1引起了外周血单核细胞中的广泛空泡形成。
实例5-用一种IL-1α特异性单克隆抗体治疗葡萄膜炎
在实例2中所述的葡萄膜炎的消退后大约两个月,该患者经历了另一次葡萄膜炎发作(主要为虹膜炎)。该患者开始用皮质类固醇和非甾体抗炎药(NSAIDS)滴剂。也使用了口服NSAIDS。葡萄膜炎对治疗无反应并发展。然而,没有关节累及的任何迹象,继续显示肩在活动能力上的改善。对该患者的受累眼睛局部给予MABp1。以每分钟一滴的速率对受累眼睛给予持续10分钟总共10滴(0.25mL中大约0.375mg)的MABp1(15mg/mL溶液)。在给药期间该患者没有任何疼痛主诉。然而,几小时之后,该患者报告了不适和烧灼感。该患者口服了NSAID并入睡。第二天早晨,该患者报告了明显的改善、疼痛减轻、以及比给药前更轻微的炎症。在MABp1滴剂的第一次给药之后24小时,以同样的方式对该患者给予10滴MABp1。再一次,注意到不适和烧灼感。该患者服用口服NSAID,并再一次卧床休息。葡萄膜炎本身完全消退了。未进行进一步的药物治疗。在接下来的四个月中未观察到葡萄膜炎的复发。
其它实施方案
应当理解的是,虽然结合其详细说明描述了本发明,前述的说明旨在说明而不是限制本发明的范围,本发明的范围是由所附权利要求书的范围来限定的。其他方面、优点、以及修改落在以下的权利要求书的范围之内。
Claims (10)
1.一种抗IL-1α抗体用来治疗与人类受试者中的关节炎相关的至少一种炎症病理症状的用途。
2.根据权利要求1所述的用途,其中该至少一种症状是关节炎症。
3.根据权利要求1所述的用途,其中该至少一种症状是眼睛的炎症。
4.根据权利要求3所述的用途,其中该炎症是葡萄膜炎。
5.根据权利要求1所述的用途,其中该抗IL-1α抗体是一种单克隆抗体。
6.根据权利要求5所述的用途,其中该单克隆抗体是IgG1。
7.根据权利要求5所述的用途,其中该单克隆抗体包含MABp1的互补决定区。
8.根据权利要求5所述的用途,其中该单克隆抗体是MABp1。
9.根据权利要求1所述的用途,其中该抗IL-1α抗体被配制成一种适合于注射给药的药物组合物。
10.根据权利要求1所述的用途,其中该抗IL-1α抗体被配制成一种适合于对眼睛局部给药的药物组合物。
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CN107596365A (zh) | 2018-01-19 |
US11390672B2 (en) | 2022-07-19 |
JP2013532154A (ja) | 2013-08-15 |
AU2011268229B2 (en) | 2015-04-16 |
EP2582391A4 (en) | 2013-11-06 |
EP2582391B1 (en) | 2018-10-03 |
HK1249427A1 (zh) | 2018-11-02 |
KR20180086297A (ko) | 2018-07-30 |
IL223290A (en) | 2017-06-29 |
IL249507A0 (en) | 2017-02-28 |
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JP6324720B2 (ja) | 2018-05-16 |
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US12116405B2 (en) | 2024-10-15 |
DK2582391T3 (en) | 2019-01-21 |
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