CN111601597B - 自身免疫性病症的治疗中的免疫蛋白酶体抑制剂和免疫抑制剂 - Google Patents
自身免疫性病症的治疗中的免疫蛋白酶体抑制剂和免疫抑制剂 Download PDFInfo
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- CN111601597B CN111601597B CN201880068868.1A CN201880068868A CN111601597B CN 111601597 B CN111601597 B CN 111601597B CN 201880068868 A CN201880068868 A CN 201880068868A CN 111601597 B CN111601597 B CN 111601597B
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Abstract
本文提供了治疗自身免疫性疾病的方法,其包括向患有所述自身免疫性疾病的受试者施用免疫蛋白酶体抑制剂和免疫抑制剂。
Description
背景技术
在真核生物中,蛋白质降解主要通过泛素-蛋白酶体途径介导,其中靶向破坏的蛋白质与76个氨基酸的多肽泛素连接。一旦被靶向,然后泛素化蛋白质就作为26S蛋白酶体的底物,所述蛋白酶体是多催化蛋白酶,通过其三种主要蛋白水解活性的作用将蛋白质切割成短肽。虽然在细胞内蛋白质转换中具有一般功能,但蛋白酶体介导的降解也在许多过程中起关键作用,如主要组织相容性复合物(MHC)I类抗原呈递、细胞凋亡、细胞生长调节、NF-κB活化、抗原加工和促炎信号的转导。
20S蛋白酶体是700kDa圆柱形形状多催化蛋白酶复合物,包含组织成四个环的28个亚基。在酵母和其它真核生物中,7个不同的α亚基形成外环并且7个不同的β亚基构成内环。α亚基充当19S(PA700)和11S(PA28)调节复合物的结合位点,以及由两个β亚基环形成的内部蛋白水解室的物理屏障。因此,在体内,蛋白酶体被认为以26S颗粒(“26S蛋白酶体”)存在。体内实验已经显示对蛋白酶体的20S形式的抑制可以容易地与对26S蛋白酶体的抑制相关。在颗粒形成期间切割活性位点β亚基的氨基端前序列使充当催化亲核试剂的氨基端苏氨酸残基暴露。负责蛋白酶体中的催化活性的亚基因此具有氨基端亲核残基,并且这些亚基属于N端亲核体(Ntn)水解酶家族(其中亲核N端残基为例如Cys、Ser、Thr和其它亲核部分)。此家族包含例如青霉素G酰基转移酶(PGA)、青霉素V酰基转移酶(PVA)、谷氨酰胺PRPP酰胺转移酶(GAT)和细菌糖基天冬酰胺酶。通过使用不同的肽底物,已经针对真核生物20S蛋白酶体限定了三种主要蛋白水解活性:胰凝乳蛋白酶样活性(CT-L),所述CT-L在大的疏水残基之后切割;胰蛋白酶样活性(T-L),所述T-L在碱性残基之后切割;以及肽基谷氨酰基肽水解活性(PGPH)或半胱天冬酶样(C-L),所述PGPH或C-L在酸性残基之后切割。在哺乳动物中,大多数细胞和组织表达“组成性蛋白酶体”,其中3个活性位点为分别对CT-L、C-L和T-L活性进行编码的β5、β1和β2。高阶脊椎动物还具有三个干扰素-γ诱导型β亚基(LMP7、LMP2和MECL1),所述三个干扰素-γ诱导型β亚基分别取代其组成性蛋白酶体对应物β5、β1和β2,从而改变蛋白酶体的催化活性。主要蛋白酶体蛋白水解活性似乎由不同的催化位点贡献,因为抑制剂、β亚基中的点突变和γ干扰素诱导β亚基的交换在各种程度上改变了这些活性。
发明内容
本文提供了治疗患有自身免疫性疾病的受试者的方法,其包括以足以治疗所述自身免疫性疾病的量向所述受试者施用(a)免疫蛋白酶体抑制剂和(b)免疫抑制剂。在各种情况下,所述受试者是人。在一些情况下,所述自身免疫性疾病是狼疮性肾炎或全身性红斑狼疮(SLE)。在一些情况下,所述自身免疫性疾病是全身性血管炎或特发性炎性肌病。
在各种情况下,所述免疫蛋白酶体抑制剂和所述免疫抑制剂同时施用,并且在一些情况下,可以共同配制。在一些情况下,所述免疫蛋白酶体抑制剂和所述免疫抑制剂顺序地施用(例如,所述免疫蛋白酶体抑制剂在所述免疫抑制剂之前或之后施用)。
在各种情况下,施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂的疗效强于单独施用所述免疫蛋白酶体抑制剂或所述免疫抑制剂的疗效。在各种情况下,所述疗效通过蛋白尿或尿蛋白/肌酐比率相比于以下降低来展现:(a)未施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂的受试者或(b)在施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之前的同一受试者。在各种情况下,所述受试者展现出所述尿蛋白/肌酐比率相比于所述免疫蛋白酶体抑制剂和所述免疫抑制剂之前的受试者的所述尿蛋白/肌酐比率降低至少50%。在各种情况下,所述受试者在施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之后展现出0.5或更低的尿蛋白/肌酐比率。
在一些情况下,所述免疫蛋白酶体抑制剂具有式(I)的结构:其中K为CH(OH)或O;E为N或CH;R1为CH3、CH2OH、CH(OH)CH3或CH2CN;R2为/> 并且R3为/>或其药学上可接受的盐。在一些情况下,所述免疫蛋白酶体抑制剂具有/>的结构或其药学上可接受的盐。在各种情况下,所述免疫蛋白酶体抑制剂以每天1-300mg的量施用。在各种情况下,所述免疫蛋白酶体抑制剂以每天40-120mg的量施用。在各种情况下,所述免疫蛋白酶体抑制剂口服、皮下、局部或静脉内施用,优选地皮下施用。在各种情况下,所述免疫蛋白酶体抑制剂以每7天到15天一次施用,优选地每7天一次。
在各种情况下,所述免疫抑制剂包括皮质类固醇、抗缩瞳剂、细胞因子拮抗剂、B细胞耗竭剂、非甾体类抗炎剂或抗疟疾剂。在一些情况下,所述免疫抑制剂包括以下中的一种或多种:阿司匹林(aspirin)、***(prednisone)、甲基强的松龙(methylprednisolone)、柳氮磺胺吡啶(sulfasalazine)、来氟米特(leflunomide)、羟氯喹(hydroxychloroquine)、贝利木单抗(belimumab)、霉酚酸酯、霉酚酸、硫唑嘌呤、利妥昔单抗(rituximab)、奥瑞利珠单抗(ocrelizumab)、依那西普(entanercept)、阿达木单抗(adalimumab)、托珠单抗(tocilizumab)、托法替尼(tofacitinib)、巴拉西替尼(baracitinib)、环孢霉素(cyclosporine)、环磷酰胺和他克莫司(tacrolimus)。在一些情况下,所述免疫抑制剂口服、皮下、局部或静脉内施用。
在一些情况下,所述免疫抑制剂包括霉酚酸酯、霉酚酸或其药学上可接受的盐。在此类情况下,所述霉酚酸酯或其药学上可接受的盐可以按霉酚酸酯的重量计以每天0.5-3g的量施用,或者所述霉酚酸或其药学上可接受的盐按霉酚酸的重量计以每天700mg到1500mg的量施用。在此类情况下,霉酚酸酯、霉酚酸或其药学上可接受的盐可以以每天一次或每天两次施用。
在一些情况下,所述免疫抑制剂为羟氯喹、硫唑嘌呤或环磷酰胺或其药学上可接受的盐。在一些情况下,所述羟氯喹或其药学上可接受的盐按羟氯喹的重量计以每天150到325mg的量施用。在一些情况下,所述硫唑嘌呤或其药学上可接受的盐按硫唑嘌呤的重量计以每天1到4mg/kg的量施用。在一些情况下,所述环磷酰胺或其药学上可接受的盐按环磷酰胺的重量计以每两周到每四周500到1000mg/m2的量施用。
附图说明
图1示出了小鼠的总蛋白尿评分,所述小鼠在25-35周内给予媒剂(圆圈)、每周一次皮下给予5mg/kg KZR-616(正方形)、每天一次口服给予30mg/kg霉酚酸酯(MMF)(上三角形)或每周一次皮下给予5mg/kg KZR-616和每天一次口服给予30mg/kg MMF(下三角形)。右上图示出了这些疗法对严重蛋白尿的预防,并且左下示出了在给予这些疗法的24到36周小鼠的存活率。
具体实施方式
本文提供了治疗患有自身免疫性疾病的受试者的方法,所述方法包括以足以治疗所述自身免疫性疾病的量施用免疫蛋白酶体抑制剂和免疫抑制剂的组合疗法。免疫蛋白酶体抑制剂和/或免疫抑制剂可以作为其药学上可接受的盐存在。术语“药学上可接受的盐”是指本文提供的化合物的相对无毒的无机或有机酸加成盐。这些盐可以在本文提供的化合物的最终分离和纯化期间原位制备,或者通过使游离碱形式的化合物与合适的有机酸或无机酸单独反应并分离因此形成的盐来制备。代表性的盐包含氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、醋酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月硅酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐(napthylate)、甲磺酸盐、葡庚糖酸盐、乳糖醛酸盐、十二烷基磺酸盐和氨基酸盐等。(参见,例如,Berge等人,(1977)“药用盐(Pharmaceutical Salts)”,《药物科学期刊(J.Pharm.Sci)》66:1-19.)
免疫蛋白酶体抑制剂和免疫抑制剂可以同时或单独施用。在同时施用的一些情况下,两种药剂是共同配制的。在单独施用的情况下,免疫抑制剂在免疫蛋白酶体抑制剂之前施用。在单独施用的其它情况下,免疫抑制剂在免疫蛋白酶体抑制剂之后施用。
本文所公开的方法可以引起蛋白尿或尿蛋白/肌酐比率相比于以下降低:(a)未施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂的受试者或(b)在施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之前的同一受试者。蛋白尿或尿蛋白/肌酐比率的测量可以通过本领域已知的任何方式进行。在一些情况下,受试者展现出尿蛋白/肌酐比率相比于施用免疫蛋白酶体抑制剂和免疫抑制剂之前的受试者的尿蛋白/肌酐比率降低至少50%。在一些情况下,受试者展现出尿蛋白/肌酐比率相比于施用免疫蛋白酶体抑制剂和免疫抑制剂之前的受试者的尿蛋白/肌酐比率降低至少55%、至少60%、至少65%、至少70%、至少75%、至少80%或至少85%。在一些情况下,所述受试者在施用免疫蛋白酶体抑制剂和免疫抑制剂之后展现出0.5或更低的尿蛋白/肌酐比率。在一些情况下,比率为0.4或更低、0.35或更低、0.3或更低、0.3或更低、0.25或更低、0.2或更低、0.15或更低或者0.1或更低。
自身免疫性疾病
本文提供的方法可用于治疗自身免疫性疾病。如本文所使用的“自身免疫性疾病”是从个体的自身组织产生并且针对个体的自身组织的疾病或病症。自身免疫性疾病的实例包含但不限于炎性反应,如包含牛皮癣和皮炎(例如,特应性皮炎)的炎性皮肤疾病;全身性硬皮病和硬化症;与炎性肠疾病(如克罗恩病和溃疡性结肠炎)相关的反应;呼吸窘迫综合征(包含成人呼吸窘迫综合征(ARDS));皮炎;脑膜炎;脑炎;葡萄膜炎;结肠炎;肾小球肾炎;如湿疹和哮喘等过敏性病状以及涉及T细胞浸润和慢性炎性反应的其它病状;动脉粥样硬化;白细胞粘附不足;类风湿性关节炎;全身性红斑狼疮(SLE);糖尿病(例如,I型糖尿病或胰岛素依赖型糖尿病);多发性硬化症;雷诺氏(Raynaud's)综合症;自身免疫性甲状腺炎;过敏性脑脊髓炎;舍格伦氏(Sjogren's)综合症;青少年发病型糖尿病;以及由通常在结核病、结节病、多发性肌炎、肉芽肿病和血管炎中发现的细胞因子和T淋巴细胞介导的与急性和迟发型超敏反应相关的免疫反应;恶性贫血(阿迪森氏病);涉及白细胞渗出的疾病;中枢神经***(CNS)炎性病症;多器官损伤综合征;溶血性贫血(包含但不限于冷球蛋白血症或库姆氏阳性贫血);重症肌无力;抗原-抗体复合物介导的疾病;抗肾小球基底膜疾病;抗磷脂综合征;过敏性神经炎;格雷夫氏(Graves')病;兰伯特-伊顿肌无力综合征;天疱疮性大疱;天疱疮;自身免疫性多内分泌腺病;瑞特氏病(Reiter's disease);僵人综合征;贝赛特氏疾病;巨细胞动脉炎;免疫复合物性肾炎;IgA肾病;IgM多发性神经病;免疫性血小板减少性紫癜(ITP)或自身免疫性血小板减少症。在特定情况下,自身免疫性疾病是全身性红斑狼疮或狼疮性肾炎。在一些情况下,自身免疫性疾病是全身性血管炎或特发性炎性肌病。
全身性红斑狼疮(SLE)是一种复杂的多器官自身免疫性疾病,其特征在于发展了除红细胞、血小板、血清蛋白和磷脂之外的尤其针对细胞核的成分的、具体地针对DNA、RNA和组蛋白的广泛的各种自身抗体。
SLE感染年轻成人,在女性中比在男性中发生地更频繁(9:1比率)。据估计美国约有250,000位患有SLE的患者(Feldman, 2013;Helmick等人, 2008)。
临床表现的范围从相对轻度的皮疹和关节炎到肾小球肾炎、抗体介导的溶血性贫血和血小板减少、血管炎、心脏疾病和包含癫痫、精神异常和脑血管意外的中枢神经***病症(Wallace,2015)(Tsokos,2011)。SLE的准确诊断可能是困难的,因为患者之间的临床表现差别很大,并且SLE的个体体征和症状可能具有多种病因。美国风湿病学院(AmericanCollege of Rheumatology,ACR)已经制定了分类标准(Hochberg,1997;Tsokos,2011)。
SLE被认为是免疫***的多种成分的功能障碍的结果,所述功能障碍包含凋亡细胞成分的缺陷性清除、T细胞耐受诱导的中断以及如抗双链DNA(抗dsDNA)等抵抗核抗原(ANA)的抗体的产生(Kaul等人,2016)。这些具有抗原的用于产生抗原抗体(Ag-Ab)复合物的ANA复合物沉积在各种组织中并且引发通过补体激活的炎性反应(例如,关节炎和肾小球肾炎)或II型超敏反应,在所述II型超敏反应中,抗体直接靶向宿主细胞并使引起吞噬作用(例如,溶血性贫血或免疫性血小板减少症)的免疫效应器机制活化。这些炎性反应导致过度补体活化、炎性细胞因子的分泌以及巨噬细胞和嗜中性粒细胞的活化。
无法治愈SLE。治疗的目标是使用各种抗炎和免疫抑制剂来控制炎症,所述抗炎和免疫抑制剂包含糖皮质激素、阿司匹林、其它非甾体类抗炎剂(NSAID)和抗疟疾药(Hahn,2011)。在批准用于SLE的3种治疗中,NSAID于1948年获得批准;羟氯喹和皮质类固醇于1955年获得批准;并且贝利木单抗作为一种靶向B细胞活化因子(BAFF)的单克隆抗体于2011年获得批准(Lamore、Parmar、Patel和Hilas,2012)。
狼疮性肾炎(LN)是SLE的最严重的并发症之一。特征在于存在蛋白尿>1克/天和活性尿沉渣(血尿、脓尿、管型)的LN在SLE的初次诊断的10年内发展了约50%的患者(Bertsias等人, 2012);(《EMA指南草案(EMA Draft Guideline)》,2015年2月)。LN与相当高的发病率相关联,所述相当高的发病率包含需要透析或肾脏移植的终末期肾脏疾病风险增加以及死亡风险增加。LN的患病率在美国为约74,000(Feldman等人, 2013;Fernandez等人, 2007;Seligman、Lum、Olson、Li和Criswell, 2002)。
当Ag-Ab复合物(主要为DNA-抗DNA)沉积在肾小球系膜和肾小球基底膜中并使血清补体活化时,LN产生。所产生的炎性反应导致肾小球上皮损伤以及功能丧失。其通常伴随有系膜肾小球膜增殖和随后的肾小球硬化。组织病理学上,LN可以采取许多形式,从正常的肾小球架构与通过免疫荧光鉴定的Ag-Ab复合物到增殖性肾小球肾炎或与终末期肾脏疾病相关的肾小球的广泛硬化。肾小球肾炎的增殖形式和膜状形式最常与通常达到肾病水平的蛋白尿相关。LN根据2003年国际肾脏病学会/肾脏病理学会(International Society ofNephrology/Renal Pathology Society,ISN/RPS)分类进行分类(Weening等人,2004)。
约50%的患者对这些治疗方案反应为蛋白尿的改善,但仅大约25%在治疗1年后达到通常被定义为蛋白尿正常化和血清肌酐稳定或改善的完全肾反应(CRR)((Rovin等人,2012;Wofsy、Hillson和Diamond,2012)。CRR的获得导致在终末期_肾脏疾病的风险方面的显著降低(Chen、Korbet、Katz、Schwartz和Lewis,2008)。因此,约75%患有LN的患者对诱导疗法反应欠佳。这些患者可以随后接受用各种替代性免疫抑制剂或实验药剂,包含利妥昔单抗、环孢菌素、他克莫司或其它药剂,与长期皮质类固醇组合的治疗(Dall'Era,2017)。这些患者除了用免疫抑制剂继续治疗引起的并发症外,还仍有发展终末期肾脏疾病的风险。
免疫蛋白酶体抑制剂
蛋白酶体已被认为是用于慢性炎性病状和自身免疫性病症中的药物开发的靶标(Elliott、Zollner和Boehncke,2003)。硼替佐米阻断细胞因子从免疫效应细胞释放,并且在包含风湿性关节炎(RA)(Palombella等人,1998)和SLE(Neubert等人,2008)的自身免疫性病症的几种动物模型中已经展示出抗炎活性。最近,硼替佐米显示出在标准免疫抑制疗法失败的患有难治性SLE和LN的患者中具有临床活性(Alexander等人,2015;de Groot等人,2015;Zhang等人,2017)。然而,与双重靶向蛋白酶体抑制相关的如贫血和血小板减少症等全身毒性限制慢性施用(Bross等人,2004)。进一步地,硼替佐米与可能由神经元中丝氨酸蛋白酶HtrA2的脱靶抑制引起的周围神经病变的剂量限制性副作用相关(Arastu-Kapur等人,2011)。周围神经病变不是由肽酮环氧化物蛋白酶体抑制剂卡非佐米诱导的(Arastu-Kapur等人,2011;Dimopoulos等人,2016)。
选择性免疫蛋白酶体抑制剂ONX 0914的发现证明,双重靶向蛋白酶体抑制剂的免疫调节作用和抗炎作用是由于对免疫效应细胞和发炎组织中的免疫蛋白酶体活性的抑制(Ichikawa等人,2012;Muchamuel等人,2009)。ONX 0914是卡非佐米的三肽酮环氧化物类似物并且在体外并在向小鼠施用后选择性地抑制免疫蛋白酶体。ONX 0914暴露抑制了免疫效应细胞中的细胞因子产生、减少了炎性T细胞亚群(如Th1和Th17)的数量和活性、增加了调节性T细胞(Treg)的数量并且阻断了自身抗体形成(Ichikawa等人,2012;Kalim、Basler、Kirk和Groettrup,2012);(Muchamuel等人,2009)。在RA的小鼠模型中,发现ONX 0914在最大耐受剂量(MTD)的十分之一剂量时预防关节特异性炎症、减少细胞因子产生并且改善关节损伤(Muchamuel等人,2009)。在多种感染模型中,用ONX 0914治疗小鼠未减少脾淋巴细胞的数量或损害病毒清除(Muchamuel等人,2009;Mundt、Engelhardt、Kirk、Groettrup和Basler,2016)。另外,ONX 0914显示出在多发性硬化症和SLE的小鼠模型中具有治疗活性,在所述小鼠模型中其表现出与硼替佐米相比相当的活性但更好的耐受性(Basler等人,2014;Ichikawa等人,2012)。
所公开的方法中设想的免疫蛋白酶体抑制剂包含如WO 07/149512(例如,ONX0914)、WO 96/13266(例如,硼替佐米)和WO 14/152134中所描述的那些免疫蛋白酶体抑制剂,其公开内容各自通过引用整体并入。设想的一些特异性免疫蛋白酶体抑制剂包含具有式(I)的结构的那些免疫蛋白酶体抑制剂:
其中
K为CH(OH)或O;
E为N或CH;
R1为CH3、CH2OH、CH(OH)CH3或CH2CN;
R2为并且
R3为
或其药学上可接受的盐。在更具体的实施例中,式(I)的化合物可以具有式(I')的立体化学:
在各种情况下,免疫蛋白酶体抑制剂可以是具有如下所示的结构的化合物:
/>
或其药学上可接受的盐。
具体设想了具有结构的免疫蛋白酶体抑制剂或其药学上可接受的盐。此化合物也可替代地被通称为KZR-616。
KZR-616诱导在体内对人类细胞中的免疫蛋白酶体进行有效且选择性的抑制,并且当施用于大鼠和猴子时诱导在血液和组织中进行有效且选择性的抑制。KZR-616不会抑制包含110种受体/配体的生化测定以及酶测定的广泛的多样化小组中的任何非蛋白酶体靶标。
在体外,KZR-616表现出对免疫蛋白酶体的LMP7亚基的有效且选择性的抑制(相对于β5),并且可以在治疗相关浓度下靶向免疫蛋白酶体的多个亚基。KZR-616对免疫蛋白酶体亚基的抑制通过不可逆机制发生,与卡非佐米和ONX0914相似(Bennett和Kirk,2008;Huber,2012)。在体外,KZR-616阻断跨多种免疫细胞类型的细胞因子产生、降低炎性T辅助细胞亚群的活性、增加调节性T细胞的数量并阻且断浆细胞形成和自身抗体产生。
KZR-616可以以每周一次(例如,每七天)到半月一次(例如,每15天一次)施用,例如,每7天一次、每8天一次、每9天一次、每10天一次、每11天一次、每12天一次、每13天一次、每14天一次或每15天一次。KZR-616的剂量可以为1-300毫克/天。如果剂量频率少于每天一次(例如,每7天一次),则给予受试者的总剂量将乘以该剂量,例如,给予7-2100mg,每7天一次。在一些情况下,KZR-616的剂量为40-120mg/天(也可以以少于每日给药频率给予)。因此,KZR-616的每日剂量并不表示每天给予的量,但可以与要以较少频率的剂量施用于受试者的其它每日剂量组合。
免疫蛋白酶体抑制剂可以口服、皮下、局部或静脉内施用。在一些具体情况下,免疫蛋白酶体抑制剂皮下施用。
免疫抑制剂
本文公开的组合疗法方法包含使用免疫抑制剂。如本文所使用的,“免疫抑制剂”是指用作抑制或掩盖本文所治疗的受试者的免疫***的物质。因此,设想了抑制细胞因子产生、下调或抑制自身抗原表达或掩盖MHC抗原的物质。此类药剂的实例包含皮质甾类、抗缩瞳剂、细胞因子拮抗剂、B细胞耗竭剂、非甾体类抗炎剂和抗疟疾剂。
所设想的免疫抑制剂包含5-氨基-6-芳基-5-取代的嘧啶(参见美国专利第4,665,077号);非甾体类抗炎药(NSAID);更昔洛韦(ganciclovir)、他克莫司、如皮质醇或醛固酮等糖皮质激素、如环氧酶抑制剂、5-脂氧合酶抑制剂或白三烯受体拮抗剂等抗炎剂;嘌呤拮抗剂,如硫唑嘌呤或霉酚酸酯(MMF);烷化剂,如环磷酰胺;溴隐亭;达那唑;氨苯砜;戊二醛(如美国专利第4,120,649号所描述的掩盖MHC抗原);用于MHC抗原和MHC片段的抗独特型抗体;环孢菌素A;类固醇,如皮质类固醇或糖皮质激素或糖皮质激素类似物,例如***、甲基强的松龙和***;二氢叶酸还原酶抑制剂,如甲氨蝶呤(口服或皮下);羟基氯喹;柳氮磺吡啶;来氟米特;细胞因子或细胞因子受体拮抗剂,所述细胞因子或细胞因子受体拮抗剂包含抗干扰素-α、-β或-γ抗体、抗肿瘤坏死因子-α抗体(英夫利昔单抗(infliximab)或阿达木单抗)、抗TNF-α免疫曙红(依那西普(etanercept)),抗肿瘤坏死因子-β抗体、抗白介素2抗体和抗IL-2受体抗体;抗LFA-1抗体,所述抗LFA-1抗体包含抗CD11a和抗CD18抗体;抗L3T4抗体;异源抗淋巴细胞球蛋白;pan-T抗体,优选地抗CD3或抗CD4/CD4a抗体:含有LFA-3结合结构域的可溶性肽(1990年7月26日公布的WO 90/08187);链激酶;TGF-β;链道酶;来自宿主的RNA或DNA;FK506:RS-61443;脱氧精胰岛素;雷帕霉素;T细胞受体(Cohen等人,美国专利第5,114,721号);T细胞受体片段(Offner等人,《科学(Science)》,251:430-432(1991);WO 90/11294;Ianeway,《自然(Nature)》,341:482(1989);和WO 91/01133);以及T细胞受体抗体(EP 340,109),如T10B9。
在一些情况下,所述免疫抑制剂是以下中的一种或多种:阿司匹林、***、甲基强的松龙、柳氮磺胺吡啶、来氟米特、羟氯喹、贝利木单抗、霉酚酸酯、霉酚酸、硫唑嘌呤、利妥昔单抗、奥瑞利珠单抗、依那西普、阿达木单抗、托珠单抗、托法替尼、巴拉西替尼、环孢霉素、环磷酰胺和他克莫司。
在一些情况下,所述免疫抑制剂包括霉酚酸酯、霉酚酸或其药学上可接受的盐。霉酚酸酯、霉酚酸或其药学上可接受的盐按霉酚酸酯或霉酚酸的重量计可以以每天500mg到3g或700mg到1500mg的量施用。在一些情况下,所述免疫抑制剂以每天一次或两次施用。
在一些情况下,所述免疫抑制剂包括羟氯喹、硫唑嘌呤或环磷酰胺或其药学上可接受的盐。所述羟氯喹或其药学上可接受的盐按羟氯喹的重量计可以以每天150到325mg的量施用。所述硫唑嘌呤或其药学上可接受的盐按硫唑嘌呤的重量计可以以每天1到4mg/kg的量施用。所述环磷酰胺或其药学上可接受的盐按环磷酰胺的重量计可以以每两周到每四周500到1000mg/m2的量施用。
所述免疫抑制剂可以口服、皮下、局部或静脉内施用。
实例
从杰克逊实验室(Jackson Laboratories)购买NZB/W F1小鼠。将所有小鼠圈养在Kezar生命科学(Kezar Life Sciences)的动物设施中。由Kezar动物资源委员会(KezarCommittee on Animal Resources)对所有实验方案进行审查和批准。患有已确立的肾炎的NZB/WF1小鼠(24周龄,具有持续性蛋白尿≥1+蛋白尿)用媒剂单独、2.5mg/kg KZR-616SCQW、30mg/kg QDx7 PO MMF或2.5mg/kg KZR-616SC QW KZR-616和30mg/kg QDx7 PO MMF的组合治疗。用尿液试纸(拜耳(Bayer)的Uristix)每周一次监测蛋白尿,并观察存活率。
为了调查与标准护理治疗MMF组合的免疫蛋白酶体抑制,对NZB/w小鼠施用单独媒剂、2.5mg/kg KZR-616 SC QW、30mg/kg QDx7 PO MMF或KZR-616与MMF的组合。与未经治疗的小鼠相比,2.5mg/kg KZR-616或30mg/kg MMF治疗显著降低了蛋白尿水平并提高了存活率。与单独的媒剂或KZR-616和MMF治疗相比,KZR-616与MMF的组合显示出显著更强的疾病抑制(如通过蛋白尿测量的)和延长的存活期。
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Claims (21)
1.(a)免疫蛋白酶体抑制剂和(b)免疫抑制剂在制备用于治疗患有狼疮性肾炎或全身性红斑狼疮的受试者的药物中的用途,其中所述免疫蛋白酶体抑制剂具有的结构或其药学上可接受的盐,以及其中所述免疫抑制剂选自霉酚酸酯和霉酚酸、或它们药学上可接受的盐。
2.根据权利要求1所述的用途,其中所述免疫蛋白酶体抑制剂以每天1-300mg的量施用。
3.根据权利要求2所述的用途,其中所述免疫蛋白酶体抑制剂以每天40-120mg的量施用。
4.根据权利要求1到3中任一项所述的用途,其中所述免疫蛋白酶体抑制剂口服、皮下、局部或静脉内施用。
5.根据权利要求4所述的用途,其中所述免疫蛋白酶体抑制剂皮下施用。
6.根据权利要求1到3和5中任一项所述的用途,其中所述免疫蛋白酶体抑制剂以每7天到每15天一次施用。
7.根据权利要求6所述的用途,其中所述免疫蛋白酶体抑制剂以每7天一次施用。
8.根据权利要求1所述的用途,其中所述霉酚酸酯或其药学上可接受的盐按霉酚酸酯的重量计以每天0.5-3g的量施用。
9.根据权利要求1所述的用途,其中所述霉酚酸或其药学上可接受的盐按霉酚酸的重量计以每天700mg到1500mg的量施用。
10.根据权利要求8到9中任一项所述的用途,其中所述免疫抑制剂以每天一次或每天两次施用。
11.根据权利要求1到3、5、和7到9中任一项所述的用途,其中所述免疫抑制剂口服、皮下、局部或静脉内施用。
12.根据权利要求1到3、5、和7到9中任一项所述的用途,其中所述免疫蛋白酶体抑制剂和所述免疫抑制剂同时施用。
13.根据权利要求12所述的用途,其中所述免疫蛋白酶体抑制剂和所述免疫抑制剂是共同配制的。
14.根据权利要求1到3、5、和7到9中任一项所述的用途,其中所述免疫蛋白酶体抑制剂和所述免疫抑制剂顺序地施用。
15.根据权利要求14所述的用途,其中所述免疫蛋白酶体抑制剂在所述免疫抑制剂之前施用。
16.根据权利要求14所述的用途,其中所述免疫蛋白酶体抑制剂在所述免疫抑制剂之后施用。
17.根据权利要求1到3、5、和7到9中任一项所述的用途,其中所述受试者是人。
18.根据权利要求1到3、5、和7到9中任一项所述的用途,其中施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂的疗效强于单独施用所述免疫蛋白酶体抑制剂或所述免疫抑制剂的疗效。
19.根据权利要求18所述的用途,其中所述疗效通过蛋白尿或尿蛋白/肌酐比率相比于以下降低来展现:(a)未施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂的受试者或(b)在施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之前的同一受试者。
20.根据权利要求19所述的用途,其中所述受试者展现出所述尿蛋白/肌酐比率相比于施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之前的所述受试者的所述尿蛋白/肌酐比率降低至少50%。
21.根据权利要求19所述的用途,其中所述受试者在施用所述免疫蛋白酶体抑制剂和所述免疫抑制剂之后展现出0.5或更低的尿蛋白/肌酐比率。
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US20210128667A1 (en) | 2021-05-06 |
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