CN115137815A - 通过使用抗c5抗体可伐利单抗来治疗或预防c5相关疾病的剂量和施用方案 - Google Patents
通过使用抗c5抗体可伐利单抗来治疗或预防c5相关疾病的剂量和施用方案 Download PDFInfo
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Abstract
本发明涉及抗C5抗体、特别是抗C5抗体可伐利单抗的剂量和施用方案,所述抗C5抗体用于在治疗或预防受试者的C5相关疾病的方法中使用,所述疾病包括阵发性睡眠性血红蛋白尿症(PNH)。本发明的剂量和治疗方案包括向所述受试者以负荷剂量施用抗C5抗体、优选抗C5抗体可伐利单抗,随后施用一个或多个维持剂量的所述抗C5抗体,其中将所施用的初始负荷剂量静脉内地给予给所述受试者,并且将所剩余的负荷剂量和所述维持剂量以低于静脉内所施用的负荷剂量的剂量皮下施用。
Description
本申请是申请号为202080054192.8的中国专利申请(申请日:2020年7月30日,发明名称:通过使用抗C5抗体可伐利单抗来治疗或预防C5相关疾病的剂量和施用方案)的分案申请。
本发明涉及抗C5抗体、特别是抗C5抗体可伐利单抗(Crovalimab)的剂量和施用方案,所述抗C5抗体用于在治疗或预防受试者的C5相关疾病的方法中使用,所述疾病包括阵发性睡眠性血红蛋白尿症(PNH)。本发明的剂量和治疗方案包括向所述受试者以负荷剂量施用抗C5抗体、优选抗C5抗体可伐利单抗,随后施用一个或多个维持剂量的所述抗C5抗体,其中将所施用的初始负荷剂量静脉内地给予给所述受试者,并且将所剩余的负荷剂量和所述维持剂量以低于静脉内所施用的负荷剂量的剂量皮下施用。
背景技术
补体系统在免疫复合物的清除以及对感染原、外来抗原、被病毒感染的细胞和肿瘤细胞的免疫应答中起核心作用。有约25-30种补体蛋白,发现它们是一堆复杂的血浆蛋白和膜辅因子。补体组分通过在一系列复杂的酶促切割和膜结合事件中相互作用来实现其免疫防御功能。由此产生的补体级联导致产生具有调理、免疫调节和裂解功能的产物。
补体系统可以通过以下三种不同的途径而激活:经典途径,凝集素途径和旁路途径。这些途径共享许多组分,并且虽然它们在其初始步骤方面不同,但它们汇聚在并共享负责激活和破坏靶细胞的相同末端补体组分(C5至C9)。
经典途径通常通过形成抗原-抗体复合物而激活。独立地,凝集素途径激活的第一步是结合特定凝集素,如甘露聚糖结合凝集素(MBL)、H-纤胶凝蛋白、M-纤胶凝蛋白、L-纤胶凝蛋白和C型凝集素CL-11。相比之下,旁路途径自发地经历低水平的转换激活,这可以在外来或其他异常表面(细菌、酵母、被病毒感染的细胞或受损组织)上容易地放大。这些途径汇聚在通过活性蛋白酶切割补体组分C3以产生C3a和C3b的点处。
C3a是一种过敏毒素。C3b与细菌和其他细胞以及某些病毒和免疫复合物结合,并且标记它们以从循环中去除(称为调理素的角色)。C3b还与其他组分形成复合物以形成C5转化酶,其将C5切割成C5a和C5b。
C5是一种以大约80μg/ml(0.4μM)在正常血清中发现的190kDa的蛋白质。C5是糖基化的,其质量的约1.5%-3.0%被认为是碳水化合物。成熟的C5是与75kDa的β链二硫键连接的115kDa的α链的异二聚体。C5被合成为1676个氨基酸的单链前体蛋白(pro-C5前体)(参见例如,US-B1 6,355,245和US-B1 7,432,356)。pro-C5前体被切割以产生β链作为氨基末端片段和α链作为羧基末端片段。α链和β链多肽片段经由二硫键彼此连接,并且构成成熟的C5蛋白。
补体系统的末端途径从C5的捕获和切割开始。在补体途径的激活期间,成熟的C5被切割成C5a和C5b片段。C5a被C5转化酶从C5的α链切割下来,作为包含α链的前74个氨基酸的氨基末端片段。成熟C5的剩余部分是片段C5b,其含有α链的与β链二硫键键合的其余部分。质量为11kDa的C5a的大约20%被认为是碳水化合物。
C5a是另一种过敏毒素。C5b与C6、C7、C8和C9组合,以在靶细胞表面形成膜攻击复合物(MAC,C5b-9,末端补体复合物(TCC))。当将足够数量的MAC插入靶细胞膜中时,形成MAC孔以介导靶细胞的快速渗透裂解。
如上文所提及的,C3a和C5a是过敏毒素。它们可以触发肥大细胞脱粒,这释放组胺和其他炎症介质,导致平滑肌收缩、血管通透性增加、白细胞激活和其他炎症现象(包括导致细胞过多的细胞增殖)。C5a还起趋化肽的作用,其用于将粒细胞(如嗜中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞和单核细胞)吸引到补体激活位点。
C5a的活性受血浆酶羧肽酶N的调节,所述血浆酶从C5a中去除羧基末端精氨酸,形成C5a-des-Arg衍生物。C5a-des-Arg仅表现出未经修饰的C5a的过敏活性和多形核趋化活性的1%。
虽然正确起作用的补体系统提供针对感染微生物的稳健防御,但补体的不当调节或激活与多种障碍的发病机制有关,所述障碍包括例如阵发性睡眠性血红蛋白尿症(PNH);类风湿性关节炎(RA);狼疮肾炎;缺血再灌注损伤;非典型溶血性尿毒综合征(aHUS);致密物沉积病(DDD);黄斑变性(例如,年龄相关性黄斑变性(AMD));溶血,肝酶升高和低血小板(HELLP)综合征;血栓性血小板减少性紫癜(TTP);自发性妊娠丢失;寡免疫性血管炎;大疱性表皮松解症;反复性妊娠丢失;多发性硬化症(MS);创伤性脑损伤;以及由心肌梗死、心肺转流术和血液透析引起的损伤(参见例如,Holers等人,Immunol.Rev.(2008),第223卷,第300-316页)。因此,抑制补体级联的过度或不受控制的激活可以为患有此类障碍的患者提供临床益处。
阵发性睡眠性血红蛋白尿症(PNH)是一种罕见的血液障碍,其中红细胞(红血球)受到损害,因此被破坏地比正常的红细胞更快。PNH由在PIG-A(磷脂酰肌醇聚糖A类)基因中具有体细胞突变的造血干细胞的克隆扩增引起,所述基因位于X染色体上。PIG-A中的突变导致糖基磷脂酰肌醇(GPI)合成的早期阻断,糖基磷脂酰肌醇是许多蛋白质锚定到细胞表面所需的分子。因此,PNH血细胞缺乏GPI锚定蛋白,其包括补体调节蛋白CD55和CD59。在正常情况下,这些补体调节蛋白阻断在细胞表面形成MAC,从而防止红血球裂解。不存在GPI锚定蛋白导致PNH中的补体介导的溶血。
PNH的特征在于溶血性贫血(红细胞数量减少)、血红蛋白尿(在尿液中存在血红蛋白,睡后特别明显)和血红蛋白血症(在血液中存在血红蛋白)。已知患有PNH的受试者具有阵发性,其在此被定义为暗色尿液的发生率。溶血性贫血是由于补体组分对红细胞的血管内破坏。其他已知的症状包括言语障碍、疲劳、勃起功能障碍、血栓形成和反复性腹痛。
依库珠单抗(Eculizumab)是一种针对补体蛋白C5的人源化单克隆抗体,并且是被批准用于治疗阵发性睡眠性血红蛋白尿症(PNH)和非典型溶血性尿毒综合征(aHUS)的第一种疗法(参见例如,Dmytrijuk等人,The Oncologist(2008),13(9),第993-1000页)。依库珠单抗抑制C5转化酶将C5切割成C5a和C5b,这防止产生末端补体复合物C5b-9。C5a和C5b-9两者均导致末端补体介导的事件,其是PNH和aHUS所特有的(参见例如,WO-A22005/074607、WO-A1 2007/106585、WO-A2 2008/069889和WO-A2 2010/054403)。对于PNH的治疗,抗C5抗体依库珠单抗或雷夫利珠单抗(Ravulizumab)代表常见的疗法。然而,高达3.5%的亚裔个体在C5中携带影响Arg885的多态性,Arg885对应于依库珠单抗和雷夫利珠单抗结合位点(Nishimura等人,N Engl J Med,第370卷,第632-639页(2014);DOI:10.1056/NEJMoa1311084)。具有这些多态性的PNH患者用依库珠单抗或雷夫利珠单抗对血管内溶血的控制较差,因此构成了具有高度未满足的医疗需求的群体。
几篇报告已经描述了抗C5抗体。例如,WO 95/29697描述了这样的抗C5抗体,其与C5的α链结合但不与C5a结合,并且阻断C5的激活。WO-A2 2002/30985描述了这样的抗C5单克隆抗体,其抑制C5a形成。另一方面,WO-A1 2004/007553描述了这样的抗C5抗体,其识别C5的α链上的C5转化酶的蛋白水解位点,并且抑制C5向C5a和C5b的转化。WO-A12010/015608描述了这样的抗C5抗体,其亲和常数为至少1x107 M-1。进一步地,WO-A12017/123636和WO-A1 2017/132259描述了抗C5抗体。此外,WO-A 2016/098356公开了这样的抗C5抗体的产生,其特征在于与在酸性pH下相比,在中性pH下以更高的亲和力与C5的β链内的表位结合。在WO-A1 2016/098356中公开的抗C5抗体之一是指抗C5抗体可伐利单抗(关于细节,参见下文的实施例1)。可伐利单抗是一种这样的抗C5抗体,其与C5的β亚基上的不同表位结合,所述表位与依库珠单抗/雷夫利珠单抗结合表位不同。体外研究已经证明,抗C5抗体可伐利单抗相等地结合野生型和Arg885突变型C5并抑制其活性(Fukuzawa等人,Sci Rep,7(1):1080.doi:10.1038/s41598-017-01087-7(2017))。相比之下,WO-A1 2017/104779在图21中报告,抗C5抗体依库珠单抗并不抑制Arg855突变型C5。进一步地,WO-A1 2018/143266涉及用于在治疗或预防C5相关疾病中使用的药物组合物。进一步地,WO-A1 2018/143266公开了如在COMPOSER研究(BP39144)中使用的抗C5抗体可伐利单抗的剂量和施用方案。COMPOSER研究是指一项用于评估抗C5抗体可伐利单抗在健康受试者和患有PNH的受试者中的安全性和功效、药代动力学(PK)和药效学(PD)的I/II期全球多中心开放标签研究。COMPOSER研究含有三个部分:在健康参与者中的第1部分,在患有阵发性睡眠性血红蛋白尿症(PNH)的患者中的第2部分和第3部分。另外,所述研究的第3部分中所包括的患者是已经用抗C5抗体依库珠单抗治疗至少3个月的患者。COMPOSER研究的第1部分的参与者被设计为包括三组健康患者:根据原始方案设计,第一组是一组以75mg/个体的剂量静脉内(IV)施用一次抗C5抗体可伐利单抗的患者;第二组患者是一组以150mg/个体的剂量静脉内(IV)施用一次抗C5抗体可伐利单抗的参与者;并且第三组是一组以170mg/个体的剂量皮下(SC)施用一次抗C5抗体可伐利单抗的受试者。因为COMPOSER研究的第1部分本质上是适应性的(基于持续评估安全性、耐受性、药代动力学(PK)和药效学(pD)数据),所以第1部分给予的实际剂量为:第一组患者75mg IV,第二组患者125mg IV,并且在COMPOSER研究的第1部分中招募的第三组患者100mg SC。
COMPOSER研究的第2部分被设计为包括一组静脉内施用三次抗C5抗体可伐利单抗的受试者:根据原始方案设计,将抗C5抗体可伐利单抗最初以300mg/个体的剂量施用(IV),然后在初始施用后一周以500mg/个体的剂量施用(IV),最后在第二次施用后两周以1000mg/个体的剂量施用(IV)。从最后静脉内施用后两周开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下施用一次。基于来自第1部分和PK模拟的新出现的临床数据,COMPOSER研究的第2部分中的患者的起始剂量已经从300mg变为375mg IV。因此,在COMPOSER研究的第2部分中给予的实际剂量如下:将抗C5抗体可伐利单抗最初以375mg/个体的剂量静脉内(IV)施用,随后在初始施用后一周以500mg/个体的剂量施用(IV),最后在第二次施用后两周以1000mg/个体的剂量施用(IV)。从最后静脉内施用后两周开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下(SC)施用一次。
所述研究的第3部分包括在招募到试验中之前用抗C5抗体依库珠单抗治疗三个月的患者,并且所述患者必须接受依库珠单抗的定期输注。所述研究的第3部分被设计为包括三组受试者。将抗C5抗体可伐利单抗最初以1000mg/个体的剂量静脉内地施用给所有组的受试者一次。从初始静脉内施用后一周(初始IV施用后第8天)开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下地施用给第一组的受试者一次,以340mg/个体的剂量每两周皮下地施用给第二组的受试者一次,并且以680mg/个体的剂量每四周皮下地施用给第三组的受试者一次。在COMPOSER第3部分中,在从抗C5抗体依库珠单抗转换到可伐利单抗的所有PNH患者中均检测到可伐利单抗、人C5与抗体依库珠单抗之间的药物-靶标-药物复合物(DTDC)。DTDC触发可伐利单抗清除的瞬时增加,这可能会增加暂时丧失对末端补体途径的完全抑制的风险(参见等人,Blood(2020),第135卷,第912-920页;doi:10.1182/blood.2019003399和Sostelly等人,Blood(2019),第134卷,第3745页)。
此外,WO-A1 2018/143266描述了可以在已经用依库珠单抗治疗的受试者中形成可伐利单抗、人C5与抗体依库珠单抗之间的免疫复合物(药物-靶标-药物复合物)。当受试者、特别是需要维持完全C5抑制的受试者(如PNH或aHUS患者)从抗C5抗体依库珠单抗转换到可伐利单抗时,两种抗C5抗体均存在于血液循环中并形成药物-靶标-药物复合物(DTDC),因为它们与人C5的不同表位结合。这些DTDC由依库珠单抗-C5-可伐利单抗-C5分子链的重复构建而来,并且当两个DTDC组装以形成更大的DTDC时,可以生长。用可伐利单抗治疗COMPOSER研究的第3部分中所包括的患者的目标是确保对末端补体途径的快速且持续的完全抑制。然而,在COMPOSER第3部分中,在从依库珠单抗进行转换的所有患者中均检测到由可伐利单抗、人C5和依库珠单抗组成的药物-靶标-药物复合物(DTDC)。DTDC、特别是大的DTDC被清除地得更慢,并且更有可能引起毒性。因为此类DTDC的形成可能导致潜在的风险,如循环损害、由于复合物的尺寸导致的血管炎风险、III型超敏反应或补体系统的异常激活,所以应当避免形成此类DTDC(还参见等人,Blood(2020),第135卷,第912-920页;doi:10.1182/blood.2019003399)。
进一步地,基于其作用机制,抗C5抗体可伐利单抗抑制缺乏补体调节蛋白的红细胞(红血球)的补体介导的裂解。如果在治疗间隔期间暂时没有阻断末端补体途径,则这些红细胞(红血球)将被裂解,并且这可能导致爆发性溶血,它是PNH患者的严重临床并发症。生物应力(感染、手术、妊娠)导致补体途径的生理性激活,其中C5上调(Schutte等人,IntArch Allergy Appl Immunol.(1975),第48(5)卷,第706-720页)。因此,在患有PNH的患者中,重要的是不仅在整个给药间隔内维持末端补体活性的完全阻断,而且还维持可伐利单抗自由结合位点的储备,以最小化爆发性溶血的发生。
因此,需要鉴定这样的给药和施用方案,其(1)最小化在患有C5相关疾病的患者、特别是从抗C5抗体依库珠单抗转换到可伐利单抗的患者中形成DTDC,(2)最大化可伐利单抗自由结合位点的水平,和(3)尽管存在个体间变异性,但仍确保患者保持高于末端补体抑制所需的抗C5抗体靶阈值浓度。
发明内容
本发明通过提供如在权利要求中所定义的实施方案解决了这一需求。
本发明涉及一种用于在治疗或预防受试者的C5相关疾病的方法中使用的抗C5抗体,其中所述方法包括以下连续步骤:
(a)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体,随后向所述受试者皮下地施用至少一个340mg负荷剂量的所述抗C5抗体;以及
(b)向所述受试者皮下地施用至少一个680mg维持剂量的所述抗C5抗体。
在本发明的上下文中,待治疗的受试者优选地是体重在40kg与100kg之间的患者。在本发明的上下文中,待治疗的受试者是患有需要补体活性抑制的C5相关疾病(例如PNH和aHUS)的受试者。此外,本发明涉及所述抗C5抗体用于治疗或预防C5相关疾病、特别是PNH的用途。在本发明的上下文中,本发明涉及治疗或预防患者的C5相关疾病、优选PNH,所述患者已经用一种可用于治疗或预防所述C5相关疾病、优选PNH的药物产品进行治疗,并且其中在最后剂量的所述药理产品后,将静脉内所施用的负荷剂量的所述抗C5抗体施用给所述受试者。因此,将本文所述的所述抗C5抗体、特别是抗C5抗体可伐利单抗的剂量和施用方案给予给已经用一种可用于治疗或预防所述C5相关疾病、优选PNH的药物产品进行治疗的患者。如下文更详细地解释的,在要求保护的剂量和治疗方案开始前已经给予给所述受试者的可用于治疗所述C5相关疾病的所述药物产品是指抗C5抗体依库珠单抗或雷夫利珠单抗,优选地是指抗C5抗体依库珠单抗。
如所附实施例中所示,如在权利要求中所定义的剂量和治疗方案确保了对末端补体活性的持续且一致的阻断(大约超过95%的受试者维持高于100μg/ml的靶阈值);参见图4和图7。进一步地,末端补体抑制在初始剂量后立即实现,并且总体上在整个给药间隔内得到维持;参见图8。进一步地,本发明的剂量和治疗方案还在未经治疗的和经依库珠单抗预治疗的两种患者中在给药间隔的大部分时间内确保了足够的自由结合位点储备;参见图2。可伐利单抗和依库珠单抗与不同的C5表位结合,因此预期将形成DTDC。如果在从依库珠单抗到抗C5抗体可伐利单抗的转换期期间,使患者同时暴露于可伐利单抗和依库珠单抗,则预期将产生DTDC(参见图5)。DTDC的形成可能有助于增加可伐利单抗清除,并且可能导致潜在的风险,如III型超敏反应,如上文所解释的。在从依库珠单抗转换到可伐利单抗的患者中,如在权利要求中所定义的剂量和治疗方案减少DTDC的形成;参见图3和图12。因此,本文所述的剂量和治疗方案概述了抗C5抗体、优选抗C5抗体可伐利单抗用于治疗或预防C5相关疾病、优选PNH的新型且改善的剂量方案。要求保护的剂量和治疗方案的安全性和治疗功效进一步报告于图9至图11中。
因此,本发明涉及一种抗C5抗体、优选抗C5抗体可伐利单抗,其用于在治疗或预防受试者、优选体重在40kg与100kg之间的受试者的C5相关疾病的方法中使用,其中所述方法包括以下连续步骤:
(a)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体,随后向所述受试者皮下地施用至少一个340mg负荷剂量的所述抗C5抗体;以及
(b)向所述受试者皮下地施用至少一个680mg维持剂量的所述抗C5抗体。
“负荷剂量”是指在治疗开始时(即在治疗方案开始时)向患有C5相关疾病、优选PNH的受试者施用的抗C5抗体剂量。在药代动力学(PK)中,“负荷剂量”是可以在治疗过程开始时向患者给予,然后降到较低剂量的初始较高药物剂量。在本发明的上下文中,首先将所述负荷剂量通过静脉内施用给予给待治疗的受试者,随后通过皮下施用给予。在本发明的上下文中,在1000mg的剂量下给予加载剂量一次。因此,在本发明的上下文中,在皮下给药的一种加载剂量或更多的加载剂量的药物组合物中,静脉内给予用于静脉内施用的组合物的装载剂量的用于静脉内给药。
在本发明的上下文中,在静脉内施用1000mg负荷剂量的所述抗C5抗体之后,将一个负荷剂量或多个负荷剂量的所述抗C5抗体皮下地施用给所述患者。在静脉内施用所述抗C5抗体开始后1天至3周(21天),将皮下所施用的一个或多个负荷剂量以340mg的所述抗C5抗体的剂量皮下地施用给所述受试者至少一次。因此,在本发明的上下文中,在静脉内施用所述抗C5抗体开始后1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天,将340mg负荷剂量的所述抗C5抗体皮下地施用给所述受试者至少一次。优选地,在静脉内施用所述抗C5抗体开始后1天,将340mg负荷剂量的所述抗C5抗体施用给所述受试者。更优选地,在静脉内施用开始后1天,将一个340mg负荷剂量的所述抗C5抗体皮下施用。在本发明的上下文中,在静脉内施用所述抗C5抗体开始后1周(7天)、2周(14天)或3周(21天),将至少一个另外的340mg负荷剂量的所述抗C5抗体皮下地施用给所述受试者。最优选地,在静脉内施用所述抗C5抗体开始后1周(7天)、2周(14天)和3周(21天),将另外的340mg负荷剂量的所述抗C5抗体皮下施用。因此,在本发明的上下文内,将1、2、3、4和/或5个负荷剂量给予给所述受试者,其中将一个负荷剂量、优选初始负荷剂量以1000mg的剂量静脉内地施用给所述受试者,并且其中将1、2、3或4个负荷剂量以340mg的剂量皮下地给予给所述患者。在本发明的上下文中,皮下施用4个负荷剂量(各自的剂量为340mg)的所述抗C5抗体是优选的,其中在静脉内施用所述抗C5抗体开始后1天将所述另外的负荷剂量皮下施用一次,随后在静脉内施用所述抗C5抗体开始后1周、2周和3周每周皮下施用一次负荷剂量。因此,可以将总量为2360mg的抗C5抗体以负荷剂量施用给所述患者。总量是指在治疗22天后施用的抗C5抗体的总剂量,即在治疗的第22天结束时达到的剂量,其通过将第1天(最初静脉内施用的负荷剂量1000mg)、第2天(在静脉内施用抗C5抗体开始后1天向患者给予的第一个皮下所施用的负荷剂量340mg)、第8天(在静脉内施用开始后1周给予的第二个皮下所施用的负荷剂量340mg)、第15天(在静脉内施用开始后2周给予的第三个皮下所施用的负荷剂量340mg)和第22天(在静脉内施用开始后3周给予的第四个皮下所施用的负荷剂量340mg)的负荷剂量相加计算而来。例如,经由对应于静脉内施用1000mg(第1天),随后皮下施用340mg(第2天)、340mg(第8天)、340mg(第15天)和340mg(第22天)的一个或多个负荷剂量而给予的所述抗C5抗体的总量为2360mg。
根据本发明,所述一个或多个初始剂量之后是以足够接近以维持所述抗C5抗体的浓度等于或高于有效靶水平的间隔的相等或较少量的后续剂量的抗C5抗体。因此,在本发明的上下文中,在所述一个或多个负荷剂量后,将一个或多个维持剂量施用给所述患者。“维持剂量”是指向患有C5相关疾病的受试者给予以维持抗C5抗体的浓度高于抗C5抗体浓度的某个有效阈值的抗C5抗体剂量。在本发明的上下文中,所述抗C5抗体的靶水平为大约100μg/ml或更高。在本发明内,可以在待治疗的受试者的生物样品中确定抗C5浓度的靶水平。用于确定生物样品中的抗C5浓度的手段和方法在技术人员的常识范围内,并且可以例如通过免疫测定来确定。优选地,在本发明的上下文中,所述免疫测定是ELISA。同样地,溶血活性可以用作要求保护的剂量和治疗方案对患有C5相关疾病的患者的有效治疗的参数。在本发明的上下文中,完全末端补体抑制(完全抑制补体系统的末端途径)可以通过小于10U/mL的溶血活性来定义。在溶血活性的背景下,可以在待治疗的患者的生物样品中确定。优选的是,溶血活性小于10U/mL,即10、9、8、7、6、5、4、3、2、1或0U/mL。用于确定待通过根据本发明的剂量和施用方案治疗的患者的生物样品中的溶血活性的手段和方法是技术人员已知的。示例性地,可以通过免疫测定来确定溶血活性。优选地,在本发明的上下文中,所述免疫测定是离体脂质体免疫测定(LIA)。在本发明的上下文中,所述生物样品是血液样品。优选地,所述血液样品是红色血液样品(红血球)。优选地,所述一个或多个维持剂量以680mg的所述抗C5抗体的一个或多个剂量皮下地施用给所述患者。因此,在本发明的上下文中,给予受试者至少一种维持或更多的维持剂量,其中维护剂量是在680mg的剂量下皮下给药的(是)。在本发明的上下文中,在静脉施用抗C5抗体的施用后,将至少一种680mg抗C5抗体的维护剂量皮下给予受试者4周(28天)。优选地,在静脉内施用所述抗C5抗体开始后4周,将680mg维持剂量皮下地施用给所述受试者一次。因此,在本发明的上下文内,在静脉内施用所述抗C5抗体开始后4周(28天),即在治疗方案的第29天,将至少一个680mg的维持剂量皮下地施用给所述患者。因此,在本发明的上下文中,在静脉内施用所述抗C5抗体开始后4周(28天),将680mg的维持剂量皮下施用,优选地施用一次。在本发明的上下文中,可以将总量为3040mg的抗C5抗体以根据本发明的负荷剂量和维持剂量施用给所述患者。总量是指在治疗29天后施用的抗C5抗体的总剂量,即在治疗的第29天结束时达到的剂量,其通过将第1天(最初静脉内施用的负荷剂量1000mg)、第2天(在静脉内施用抗C5抗体开始后1天向患者给予的第一个皮下所施用的负荷剂量340mg)、第8天(在静脉内施用开始后1周给予的第二个皮下所施用的负荷剂量340mg)、第15天(在静脉内施用开始后2周给予的第三个皮下所施用的负荷剂量340mg)、第22天(在静脉内施用开始后3周给予的第四个皮下所施用的负荷剂量340mg)的负荷剂量和皮下所施用的维持剂量680mg(第29天)相加计算而来。例如,经由对应于静脉内施用1000mg(第1天),随后皮下施用340mg(第2天)、340mg(第8天)、340mg(第15天)、340mg(第22天)和680mg(第29天)的负荷剂量和维持剂量而给予的所述抗C5抗体的总量为3040mg。
可以将680mg维持剂量的皮下施用以4周的时间间隔重复几次(Q4W)。在本发明的上下文中优选的是,将680mg的维持剂量重复至少1、2、3、4、5、6、7、8、9、10、11、12、24、36、48个月。在本发明的上下文中优选的是以4周的时间间隔重复680mg的维持剂量并且持续患者的一生。
特别地,本发明涉及一种用于在治疗或预防受试者、优选体重在40kg与100kg之间的受试者的C5相关疾病的方法中使用的抗C5抗体,其中所述方法包括以下连续步骤:
(i)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体;
(ii)在静脉内施用所述抗C5抗体开始后1天,向所述受试者皮下地施用340mg负荷剂量的所述抗C5抗体;
(iii)在静脉内施用所述抗C5抗体开始后1周(7天)、2周(14天)和3周(21天),向所述受试者每周皮下地施用一次340mg负荷剂量的所述抗C5抗体;
(iv)在静脉内施用所述抗C5抗体开始后4周(28天),向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体;以及
(v)将步骤(iv)以4周(28天)的时间间隔重复几次。
术语“静脉内施用”/“静脉内地施用”在本发明的上下文中是指将抗C5抗体施用到受试者的静脉中,使得待治疗的患者的身体在大约15分钟或更短时间、优选5分钟或更短时间内接受抗C5抗体。对于静脉内施用,所述抗C5抗体必须被配制成使得它能够经由合适的装置(如(但不限于)注射器)来施用。在本发明的上下文中,用于静脉内施用的制剂包含50至350mg的所述抗C5抗体、1至100mM的缓冲剂(如组氨酸/天冬氨酸,其pH为5.5±1.0)、1至100mM的氨基酸(如精氨酸)和0.01%至0.1%的非离子表面活性剂(如泊洛沙姆)。在本发明的上下文中优选的,将用于静脉内施用的制剂提供在含有以下组分的2mL玻璃小瓶中:170mg/ml可伐利单抗、30mM组氨酸/天冬氨酸(pH 5.8)、100mM精氨酸盐酸盐和0.05%Poloxamer 188TM。然后将所述制剂在耐受的时间段(如5分钟、15分钟、30分钟、90分钟或更短时间)内施用给所述患者。此外,将用于静脉内施用的制剂以在1ml至15ml之间、优选约6ml的注射体积给予给待治疗的患者。
术语“皮下施用”/“皮下地施用”在本发明的上下文中是指通过从药物容器中相对缓慢、持续地递送而将抗C5抗体引入动物或人类患者的皮肤下,优选地引入皮肤与下面的组织之间的口袋内。所述口袋可以通过捏起或拉起皮肤并远离下面的组织而产生。对于皮下施用,所述抗C5抗体必须被配制成使得它可以经由合适的装置(如(但不限于)注射器、预填充注射器、注射装置、输液泵、注射笔、无针装置)或经由皮下贴剂递送系统来施用。在本发明的上下文中,用于皮下施用的制剂包含50至350mg的所述抗C5抗体、1至100mM的缓冲剂(如组氨酸/天冬氨酸,其pH为5.5±1.0)、1至100mM的氨基酸(如精氨酸)和0.01%至0.1%的非离子表面活性剂(如泊洛沙姆)。在本发明的上下文中优选的,将用于静脉内施用的制剂提供在含有以下组分的2.25预填充注射器中:170mg/ml可伐利单抗、30mM组氨酸/天冬氨酸(pH 5.8)、100mM精氨酸盐酸盐和0.05%Poloxamer 188TM。在本发明的上下文中,将用于皮下施用的制剂提供在具有针安全装置的预填充注射器中。用于皮下施用的注射装置包含约1至15ml或更多、优选2.25ml的用于皮下施用的制剂,其包含所述抗C5抗体。在正常情况下,待皮下施用的注射体积为1至15ml,优选2ml(340mg可伐利单抗)或4ml(680mg可伐利单抗)。在本发明的上下文中,皮下施用是指通过从药物容器中相对缓慢、持续地递送一段时间(包括但不限于30分钟或更短时间、90分钟或更短时间)而将抗C5抗体引入待治疗的患者的皮肤下。任选地,所述施用可以通过将植入的药物递送泵植入待治疗患者的皮肤下来进行,其中所述泵递送预定量的所述抗C5抗体持续预定的时间段,如30分钟、90分钟或跨越治疗方案长度的时间段。
在本发明的上下文中,上述剂量和治疗方案可用于治疗或预防受试者的C5相关疾病,所述受试者已经用至少一种用于在治疗或预防所述疾病中使用的药理产品治疗一次或多次。例如,本发明的治疗方案可用于治疗患有C5相关疾病的患者,所述患者已经接受了用至少一种用于在治疗或预防所述疾病的方法中使用的药理产品进行的在先治疗,但是预期将更好地响应根据本发明的治疗方案。在此类情况下,可以将药物从所述药理产品转换到根据本发明的用于在治疗或预防C5相关疾病中使用的抗C5抗体。优选地,在最后剂量的所述药物产品后,将静脉内所施用的负荷剂量的所述抗C5抗体给予给待治疗的受试者。所述抗C5抗体的静脉内所施用的负荷剂量优选地具有1000mg的剂量。
在本发明的上下文中,所述药理产品包含与根据本发明静脉内或皮下给予的抗C5抗体不同的活性物质。在本发明的上下文中,药理产品的所述活性物质是靶向C5 mRNA的siRNA,或者是与根据本发明皮下地或静脉内地施用给待治疗的受试者的抗C5抗体不同的抗C5抗体。在本发明的上下文中,所述药理产品可以包含作为与给予给所述患者的抗C5抗体不同的抗体的抗C5抗体。已经在所述在先治疗中使用的药物产品中所包含的抗体可以是雷夫利珠单抗或依库珠单抗或其变体。优选地,已经在所述在先治疗中使用的药理产品中所包含的抗体是依库珠单抗或其变体。示例性地,抗C5抗体依库珠单抗的序列变体示于SEQID NO:11和12中。
在本发明的上下文中,抗体变体可以是包含Fc区变体的抗C5抗体,其中已经将一个或多个氨基酸修饰引入抗体的天然序列Fc区中。所述Fc区变体可以包含在一个或多个氨基酸位置处含有氨基酸修饰(例如,取代)的人Fc区序列(例如,人IgG1、IgG2、IgG3或IgG4Fc区)。在本发明的上下文中,抗体变体具有一些但不是所有的效应子功能,这使其成为以下应用的理想候选物,在所述应用中抗体体内半衰期是重要的,但某些效应子功能(如补体和ADCC)是不必要或有害的。可以进行体外和/或体内细胞毒性测定,以证实CDC和/或ADCC活性的降低/耗尽。例如,可以进行Fc受体(FcR)结合测定,以确保所述抗体缺乏FcγR结合(因此可能缺乏ADCC活性),但是保留FcRn结合能力。用于介导ADCC的主要细胞NK细胞只表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。造血细胞上的FcR表达总结于Ravetch和Kinet,Annu.Rev.Immunol.9:457-492(1991)的第464页的表3中。用于评估目的分子的ADCC活性的体外测定的非限制性例子描述于US-B15,500,362(参见例如,Hellstrom等人,Proc.Nat'l Acad.Sci.USA(1983),第83卷,第7059-7063页)和Hellstrom等人,Proc.Nat'l Acad.Sci.USA(1985),第82卷,第1499-1502页;US-B1 5,821,337(参见Bruggemann等人,J.Exp.Med.(1987),第166卷,第1351-1361页)中。可替代地,可以采用非放射性测定方法(参见例如,用于流式细胞术的ACTITM非放射性细胞毒性测定(CellTechnology,Inc.,加利福尼亚州山景城);和CytoTox 96(注册商标)非放射性细胞毒性测定(Promega,威斯康星州麦迪逊))。用于此类测定的有用效应细胞包括外周血单个核细胞(PBMC)和自然杀伤(NK)细胞。可替代地或另外地,可以在体内(例如,在动物模型如Clynes等人,Proc.Nat'l Acad.Sci.USA(1998),第95卷,第652-656页中公开的动物模型中)评估目的分子的ADCC活性。还可以进行C1q结合测定,以证实所述抗体不能结合C1q,因此缺乏CDC活性。参见例如,WO-A2 2006/029879和WO-A1 2005/100402中的C1q和C3c结合ELISA。为了评估补体激活,可以进行CDC测定(参见例如,Gazzano-Santoro等人,J.Immunol.Methods(1996),第202卷,第163页;Cragg等人,Blood(2003),第101卷,第1045-1052页;和Cragg等人,Blood(2004),第103卷,第2738-2743页)。还可以使用本领域已知的方法进行FcRn结合和体内清除率/半衰期确定(参见例如,Petkova等人,Int'l.Immunol.(2006),第18(12)卷,第1759-1769页)。
具有降低的效应子功能的抗体包括具有Fc区残基238、265、269、270、297、327和329中的一个或多个的取代的那些抗体(US-B1 6,737,056)。此类Fc突变体包括在氨基酸位置265、269、270、297和327中的两个或更多个处具有取代的Fc突变体,包括具有残基265和297的至丙氨酸的取代的所谓“DANA”Fc突变体(US-B1 7,332,581)。
描述了具有改善的或减弱的与FcR的结合的某些抗体变体。(参见例如,US-B1 6,737,056;WO-A2 2004/056312;和Shields等人,J.Biol.Chem.(2001),第9(2)卷,第6591-6604页)。
在某些实施方案中,抗体变体包含具有一个或多个改善ADCC的氨基酸取代的Fc区,所述取代例如在Fc区的位置298、333和/或334处的取代(残基的EU编号)。
在一些实施方案中,在Fc区中进行改变,所述改变导致改变(即,改善或减弱)的C1q结合和/或补体依赖性细胞毒性(CDC),例如如US-B1 6,194,551、WO 1999/51642和Idusogie等人,J.Immunol.(2000),第164卷,第4178-4184页中所述。
具有增加的半衰期和改善的与新生儿Fc受体(FcRn)(其负责将母体IgG转移给胎儿)的结合(Guyer等人,J.Immunol.(1976),第117卷,第587页和Kim等人,J.Immunol.(1994),第24卷,第249页)的抗体描述于US 2005/0014934中。那些抗体包含其中具有一个或多个取代的Fc区,所述取代改善Fc区与FcRn的结合。此类Fc变体包括在以下Fc区残基中的一个或多个处具有取代的那些Fc变体:238、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434,例如Fc区残基434的取代(US-B17,371,826)。关于Fc区变体的其他例子,还参见Duncan,Nature(1988),第322卷,第738-740页;US-B1 5,648,260;US-B15,624,821;和WO 1994/29351。
在本发明的上下文中,在将最后剂量的所述药理产品施用给待治疗的患者的同一天,或者在将最后剂量的所述药理产品施用给待治疗的患者后1天、2天、3天、4天、5天、6天、7天(1周)、8天、9天、10天、11天、12天、13天、14天(2周)、15天、16天、17天、18天、19天、20天、21天(3周)或更多天,施用本发明中的用于静脉内注射的组合物的初始剂量。优选地,在本发明的上下文中,在最后剂量的所述药理产品的第3天,或者在最后剂量的所述药理产品后3天、4天、5天、6天、7天(1周)、8天、9天、10天、11天、12天、13天、14天(2周)、15天、16天、17天、18天、19天、20天、21天(3周)或更多天,施用静脉内所施用的负荷剂量的所述抗C5抗体。优选地,在最后剂量的所述药理产品后7天(1周)或更多天,将静脉内所施用的负荷剂量的所述抗C5抗体给予给所述患者。在本发明的上下文中还优选的是,在最后剂量的所述药理产品后14天(2周)或更多天,静脉内施用所述负荷剂量。在本发明的上下文中最优选的是,在最后剂量的所述药理产品后21天(3周),静脉内施用所述抗C5抗体。
在本发明的上下文中,“周”是指7天的一段时间。
在本发明的上下文中,“月”是指4周的一段时间。
在本发明的上下文中,“治疗”包括“诱导治疗”和至少一个“维持治疗”的顺序相继。典型地,根据本发明的治疗包括“诱导治疗”和至少一个“维持治疗”。典型地,根据本发明的治疗可以是1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11个月、1年(12个月)、2年(24个月)、3年(36个月)或4年(48个月)。在本发明的上下文中优选的是持续患者一生的治疗。
“诱导治疗”包括以下的顺序相继:(i)向受试者静脉内地施用负荷剂量、优选1000mg剂量的抗C5抗体,和(ii)向受试者皮下地施用至少一个负荷剂量、优选340mg剂量的抗C5抗体。如上文所解释的,在本发明的上下文内优选的是,在将静脉内所施用的负荷剂量给予给所述受试者后1天、1周(7天)、2周(14天)和3周(21天),给予340mg负荷剂量的所述抗C5抗体。优选地,待静脉内施用的负荷剂量具有1000mg的剂量。皮下地给予给待治疗的受试者的负荷剂量具有1360mg的剂量。因此,在本发明的上下文中,在诱导治疗期间,将2360mg的负荷剂量静脉内地或皮下地施用给待治疗的受试者。“维持治疗”包括(i)维持期的顺序相继,其中将一个或多个维持剂量皮下地给予给受试者。在本发明的上下文中,优选的是,在静脉内施用所述负荷剂量的所述抗C5抗体开始后4周(1个月),将680mg维持剂量的所述抗C5抗体给予给所述受试者,优选地给予一次。如上文所解释的,可以将680mg维持剂量的皮下施用以4周的时间间隔重复几次(Q4W)。在本发明的上下文中优选的是以4周的时间间隔重复680mg的维持剂量并且持续患者的一生。
在本发明的上下文中,所述C5相关疾病是涉及C5的过度或不受控制的激活的补体介导的疾病或病症。在某些实施方案中,所述C5相关疾病是选自以下的至少一种疾病:阵发性睡眠性血红蛋白尿症(PNH);类风湿性关节炎(RA);狼疮肾炎;缺血再灌注损伤;非典型溶血性尿毒综合征(aHUS);致密物沉积病(DDD);黄斑变性;溶血,肝酶升高,低血小板(HELLP)综合征;血栓性血小板减少性紫癜(TTP);自发性妊娠丢失;寡免疫性血管炎;大疱性表皮松解症;反复性妊娠丢失;多发性硬化症(MS);创伤性脑损伤;由心肌梗死、心肺转流术或血液透析引起的损伤;难治性全身型重症肌无力(gMG);和视神经脊髓炎(NMO)。优选地,在本发明的上下文中,所述C5相关疾病是选自以下的至少一种疾病:PNH、aHUS、gMG和NMO。最优选地,所述C5相关疾病是PNH。进一步地,在本发明的上下文中,可以测试患有C5相关疾病PNH的受试者是否存在C5的Arg885突变。因此,本文公开的剂量方案还可以用于治疗和/或预防患有PNH的受试者,其特征在于所述受试者具有C5的Arg855突变。在上下文中,Arg885突变是指C5的遗传变异,其中维持885处的Arg被His取代。在此背景下,术语“C5”是指具有如SEQID NO:13所示的氨基酸序列的蛋白质。
在本发明的上下文中,所述抗C5抗体优选地是可伐利单抗。抗C5抗体可伐利单抗(CAS编号:1917321-26-6)的序列细节公开于提出的国际非专利药名(International Non-proprietary Names for Pharmaceutical Substances,INN)的列表编号119中,如WHODrug Information(2018),第32卷,第2期的第302和303页所公布的。抗C5抗体可伐利单抗的序列也示于SEQ ID NO:3(重链)和SEQ ID NO:4(轻链)中。在本发明中使用的抗C5抗体可伐利单抗的产生描述于WO 2016/098356(关于细节,参见实施例1)中。进一步地,在本发明的上下文中,通过用于静脉内施用或用于皮下施用的制剂将抗C5抗体可伐利单抗施用给所述患者。在本发明的上下文中优选的是,将本文提供的剂量作为一个或多个固定剂量来静脉内或皮下施用。
用于静脉内施用的制剂包含50至350mg的抗C5抗体可伐利单抗、1至100mM的缓冲剂(如组氨酸/天冬氨酸,其pH为5.5±1.0)、1至100mM的氨基酸(如精氨酸)和0.01%至0.1%的非离子表面活性剂(如泊洛沙姆)。在本发明的上下文中优选的,将用于静脉内施用的制剂提供在含有以下组分的2mL玻璃小瓶中:170mg/ml可伐利单抗、30mM组氨酸/天冬氨酸(pH 5.8)、100mM精氨酸盐酸盐和0.05%Poloxamer 188TM。
用于皮下施用的制剂包含50至350mg的抗C5抗体可伐利单抗、1至100mM的缓冲剂(如组氨酸/天冬氨酸,其pH为5.5±1.0)、1至100mM的氨基酸(如精氨酸)和0.01%至0.1%的非离子表面活性剂(如泊洛沙姆)。在本发明的上下文中优选的,将用于静脉内施用的制剂提供在含有以下组分的2.25预填充注射器中:170mg/ml可伐利单抗、30mM组氨酸/天冬氨酸(pH 5.8)、100mM精氨酸盐酸盐和0.05%Poloxamer 188TM。
抗C5抗体仿古灭绝由公司Alexion Pharmaceuticals,Inc。在商品名下销售。抗C5抗体生态蛋白的序列显示在SEQ ID NO:1(重链)和SEQ ID NO:2(轻链)。进一步地,抗C5抗体依库珠单抗的序列变体示于SEQ ID NO:11和12中。
抗C5抗体ravulizumab的序列由公司Alexion Pharmaceuticals,Inc。在商品名下销售。抗C5抗体ravulizumab(CAS编号:1803171-55-2)的序列公开在名单编号中117拟议的制药物质(Inn)的国际非专有名称(INN)在第319和320页发表于WHO药物信息(2017年),Vol。31,2。抗C5抗体雷夫利珠单抗的序列也示于SEQ ID NO:5(重链)和SEQ IDNO:6(轻链)中。
在本发明的上下文中描述的患者是患有C5相关疾病的患者。在本发明的上下文中优选的患者是体重在40kg与100kg之间的患者。在本发明的上下文中,所述C5相关疾病是涉及C5的过度或不受控制的激活的补体介导的疾病或病症。在某些实施方案中,所述C5相关疾病是选自以下的至少一种疾病:阵发性睡眠性血红蛋白尿症(PNH);类风湿性关节炎(RA);狼疮肾炎;缺血再灌注损伤;非典型溶血性尿毒综合征(aHUS);致密物沉积病(DDD);黄斑变性;溶血,肝酶升高,低血小板(HELLP)综合征;血栓性血小板减少性紫癜(TTP);自发性妊娠丢失;寡免疫性血管炎;大疱性表皮松解症;反复性妊娠丢失;多发性硬化症(MS);创伤性脑损伤;由心肌梗死、心肺转流术或血液透析引起的损伤;难治性全身型重症肌无力(gMG);和视神经脊髓炎(NMO)。优选地,在本发明的上下文中,所述C5相关疾病是选自以下的至少一种疾病:PNH、aHUS、gMG和NMO。最优选地,所述C5相关疾病是PNH。
此外,本发明涉及一种治疗或预防受试者的C5相关疾病的方法,其中所述方法包括以下连续步骤:
(a)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体,随后向所述受试者皮下地施用至少一个340mg负荷剂量的所述抗C5抗体;以及
(b)向所述受试者皮下地施用至少一个680mg维持剂量的所述抗C5抗体。
在本发明的上下文中优选的是,通过以下施用步骤进行治疗或预防受试者的C5相关疾病的所述方法:
(i)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体;
(ii)在静脉内施用所述抗C5抗体开始后1天,向所述受试者皮下地施用340mg负荷剂量的所述抗C5抗体;
(iii)在静脉内施用所述抗C5抗体开始后1周、2周和3周,向所述受试者每周皮下地施用一次340mg负荷剂量的所述抗C5抗体;
(iv)在静脉内施用所述抗C5抗体开始后4周,向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体;以及
(v)将步骤(iv)以4周的时间间隔重复几次。
如上文所解释的,在本发明的上下文中优选的是,在所述剂量和施用方案的上下文中使用的抗C5抗体是可伐利单抗。进一步地,上文给出的定义同样适用于上述治疗或预防C5相关疾病的方法。在本发明的上下文中还优选的是,待治疗的受试者的体重在40kg与100kg之间。
附图说明
图1:在健康受试者和患有C5相关疾病阵发性睡眠性血红蛋白尿症(PNH)的受试者中抗C5抗体可伐利单抗与如通过脂质体免疫测定(LIA)测量的溶血活性之间的关系
暴露-反应关系的评估证明,需要大约100μg/mL的可伐利单抗来实现完整末端补体抑制。完全末端补体抑制(完全抑制补体系统的末端途径)被定义为溶血活性﹤10U/mL。垂直点划线标出了100μg/ml可伐利单抗的药效学(PD)阈值。
图2:抗C5抗体可伐利单抗的可用自由结合位点
灰色线对应于基于从COMPOSER(BP39144)数据估计的参数的15名个体的模拟。将COMPOSER研究的数据用于模拟。y轴示出了抗C5抗体可伐利单抗(RO7112689;SKY59)的浓度。x轴示出了以天计的时间。深灰色线对应于这15名患者的中值。S0:COMPOSER第3部分的方案S5:COMPOSER研究的第4部分和III期中提出的方案。
图3:药物-靶标-药物复合物(DTDC)的时间谱
灰色线对应于基于从COMPOSER(BP39144)数据估计的参数的15名个体的模拟。将COMPOSER研究的数据用于模拟。深灰色线对应于这15名患者的中值。S0:COMPOSER第3部分的方案;S5:COMPOSER研究的第4部分和III期中提出的方案;RO7112689:可伐利单抗(SKY59)。
图4:在未经治疗的患者(上图)和将治疗从依库珠单抗转换到可伐利单抗的PNH患者(下图)中可伐利单抗的模拟浓度-时间谱
灰色区间对应于90%预测区间,并且灰色线对应于预测中值。黑色虚线对应于抗C5抗体可伐利单抗的100μg/mL靶浓度水平。
图5:描述可伐利单抗、人C5与抗体依库珠单抗之间的药物-靶标-药物复合物(DTDC)如何清除、再循环和从较小的DTDC顺序构建的模型
当患者从抗C5抗体依库珠单抗转换到可伐利单抗时,两种抗C5抗体均存在于血液循环中并形成DTDC,因为它们与人C5的不同表位结合。这些DTDC由依库珠单抗-C5-可伐利单抗-C5分子链的重复构建而来,并且当两个DTDC组装以形成更大的DTDC时,随时间生长。所述模型(图5)报告了DTDC如何被抗C5抗体可伐利单抗的FcRn受体清除和再循环。(1)如果在从1种药物到另一种药物的转换期期间,使患者同时暴露于可伐利单抗和依库珠单抗,则产生DTDC,因为所述抗体识别C5的不同表位。DTDC经由吞噬作用被带到内体中。(2)以pH依赖性方式与人C5结合的可伐利单抗抗体在内体中在酸性条件(pH6.0)下从可溶性人C5(其已经与抗C5抗体可伐利单抗结合)中解离出来,而抗C5抗体依库珠单抗在内体中在酸性条件下仍然与可溶性人C5结合。(3)抗C5抗体(抗C5抗体可伐利单抗和C5-依库珠单抗复合物)通过与细胞膜上表达的FcRn结合而被细胞吸收。C5-依库珠单抗复合物被易位到溶酶体中进行降解或者以仍与抗体结合的C5蛋白再循环。相比之下,抗C5抗体可伐利单抗具有改善的功能性/功效,因为它在酸性条件下在内体中从FcRn中解离出来而被释放回不含C5蛋白的血浆中。(4),(5)所释放的抗C5抗体可伐利单抗可用于与人C5再次结合并进一步积聚较小的DTDC。这具有使抗C5抗体可伐利单抗“再循环”的作用。DTDC、特别是C5-依库珠单抗复合物随后再次被内体降解,而抗C5抗体可伐利单抗再次被再循环以积聚较小的DTDC。
图6:COMPOSER的第4部分包括患有PNH的患者
COMPOSER第4部分评价了优化的可伐利单抗方案在患有PNH的患者中的安全性、药代动力学(PK)和药效学(PD)效应,所述患者未经抗C5疗法、优选可伐利单抗疗法治疗,或者从依库珠单抗进行了转换,其中在20周后进行首次评估。在所招募的15名患者中,8名(53%)先前没有接受过用C5抑制剂进行的治疗,并且7名(47%)从依库珠单抗转换到可伐利单抗。
图7:在COMPOSER研究的第4部分中招募的患者中的可伐利单抗暴露
所有患者均维持高于大约100μg/mL的C谷值的可伐利单抗水平,这与末端补体活性抑制相关。线表示平均值,并且阴影区域示出了95%置信区间。
图8:示出了在COMPOSER研究的第4部分中招募的患者中的中值补体活性的脂质体免疫测定(LIA)时间过程
末端补体抑制在初始剂量后立即实现,并且总体上在整个研究期内得到维持。线表示中值,并且须示出了95%置信区间。LIA测定的定量下限为10U/mL。LIA,脂质体免疫测定。
图9:在COMPOSER研究的第4部分中招募的患者中的总的和游离的C5水平的测量
(A)在未经治疗的患者中观察到有限的总C5积累,并且在转换的患者中观察到下降。(B)在初始剂量后,游离C5水平快速下降,并且在整个随访期内保持较低。
图10:在COMPOSER研究的第4部分中招募的患者中的归一化的乳酸脱氢酶(LDH)水平的测量
在未经治疗的患者中,到第15天,中值乳酸脱氢酶(LDH)水平下降到≤1.5x正常值上限(ULN),并且在整个观察期内保持低于该水平。在从依库珠单抗转换到可伐利单抗的患者中,中值基线LDH≤1.5x ULN,并且在整个观察期内保持如此。LDH,乳酸脱氢酶;ULN,正常值上限。
图11:可伐利单抗治疗相关不良事件(AE)的总结
可伐利单抗的耐受性良好,并且没有观察到严重的治疗相关不良事件(AE)。
图12:在COMPOSER研究的第3部分和第4部分可伐利单抗方案中随时间观察到的DTDC谱
实线是在尺寸排阻色谱(SEC)级分1至4(左图)和级分5至6(右图)中洗脱出来的可伐利单抗的中值百分比的总和。COMPOSER研究的第3部分的剂量方案以浅灰色显示,并且第4部分的剂量方案以深灰色显示。
图13:用可伐利单抗治疗的携带C5 Arg885His突变的PNH患者的归一化的LDH水平
可伐利单抗在具有Arg885多态性的PNH患者中实现了持续的末端补体抑制。所有患者均实现了完全末端补体抑制,如通过脂质体免疫测定(LIA)所测量的。LIA水平在进入研究时的范围从32-42U/mL,并且到第2天下降到<10U/mL且在此后得到维持。LIA测定的定量下限为10U/mL。LIA,脂质体免疫测定。
实施例
实施例1:抗C5抗体
抗C5抗体可伐利单抗的序列示于SEQ ID NO:3(重链)和SEQ ID NO:4(轻链)中。进一步地,在本发明中使用的抗C5抗体可伐利单抗的产生描述于WO 2016/098356中。简而言之,将编码305LO15的重链可变结构域(VH)(SEQ ID NO:7)的基因与编码经修饰的人IgG1重链恒定结构域(CH)变体SG115(SEQ ID NO:8)的基因组合。将编码305LO15的轻链可变结构域(VL)(SEQ ID NO:9)的基因与编码人轻链恒定结构域(CL)(SK1,SEQ ID NO:10)的基因组合。在用重链和轻链表达载体的组合共转染的HEK293细胞中表达抗体,并且将其纯化为蛋白质。
实施例2:在COMPOSER研究(BP39144;ClinicalTrials.gov标识符:NCT03157635)中使用的剂量和施用方案。
为了确定合适的剂量和施用方案,开始了I/II期COMPOSER研究(BP39144)。所述研究最初由三部分组成:在健康参与者中的第1部分,在患有阵发性睡眠性血红蛋白尿症(PNH)的患者中的第2部分和第3部分。另外,所述研究的第3部分中所包括的患者是已经用抗C5抗体依库珠单抗治疗至少3个月的患者。
所述研究的第1部分被设计为包括三组健康患者。第一组是一组以75mg/个体的剂量静脉内(IV)施用一次抗C5抗体可伐利单抗的患者。第二组患者是一组以150mg/个体的剂量静脉内(IV)施用一次抗C5抗体可伐利单抗的参与者。第三组是一组以170mg/个体的剂量皮下(SC)施用一次抗C5抗体可伐利单抗的受试者。因为COMPOSER研究的第1部分本质上是适应性的(基于持续评估安全性、耐受性、药代动力学(PK)和药效学(pD)数据),所以第1部分给予的实际剂量为:第一组患者75mg IV,第二组患者125mg IV,并且在COMPOSER研究的第1部分中招募的第三组患者100mg SC。
所述研究的第2部分被设计为包括一组静脉内施用三次抗C5抗体可伐利单抗的受试者:根据原始方案设计,将抗C5抗体可伐利单抗最初以300mg/个体的剂量施用(IV),然后在初始施用后一周以500mg/个体的剂量施用(IV),最后在第二次施用后两周以1000mg/个体的剂量施用(IV)。从最后静脉内施用后两周开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下(SC)施用一次。基于来自第1部分和PK模拟的新出现的临床数据,COMPOSER研究的第2部分中的患者的起始剂量已经从300mg变为375mg IV。因此,在COMPOSER研究的第2部分中给予的实际剂量如下:将抗C5抗体可伐利单抗最初以375mg/个体的剂量静脉内(IV)施用,随后在初始施用后一周以500mg/个体的剂量施用(IV),最后在第二次施用后两周以1000mg/个体的剂量施用(IV)。从最后静脉内施用后两周开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下(SC)施用一次。
所述研究的第3部分包括在招募到试验中之前用抗C5抗体依库珠单抗治疗至少三个月的患者,并且所述患者必须接受依库珠单抗的定期输注。所述研究的第3部分被设计为包括三组受试者。将抗C5抗体可伐利单抗最初以1000mg/个体的剂量静脉内地施用给所有组的受试者一次。从初始静脉内施用后一周(IV施用后第8天)开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下地(SC)施用给第一组的受试者一次,以340mg/个体的剂量每两周皮下地施用给第二组的受试者一次,并且以680mg/个体的剂量每四周皮下地施用给第三组的受试者一次。
在COMPOSER研究的第1部分中招募了15名健康患者。第1部分是随机的,所以初始的15名患者中只有9名得到了可伐利单抗。在COMPOSER研究的第3部分中招募了19名患者,但是三名患者已经停止。COMPOSER研究(第1部分、第2部分和第3部分)所包括的患者的细节可以总结如下:
在生成COMPOSER研究的第1部分至第3部分所包括的患者的上述细节后,COMPOSER研究第3部分的另一种患者已经从所述研究中停止。
实施例3:通过用抗C5抗体可伐利单抗治疗来实现完全且持续的末端补体抑制的剂量方案的确定
可伐利单抗在C5相关疾病(如优选阵发性睡眠性血红蛋白尿症(PNH))中的治疗目标是确保对末端补体途径的快速且持续的完全抑制。在从依库珠单抗转换到可伐利单抗的患者中,洗脱期在临床上是不恰当的。因此,通过设计,当开始可伐利单抗给药时,存在残余浓度的依库珠单抗。使用组合尺寸排阻色谱(SEC)与酶联免疫吸附测定(ELISA)的多重测定在COMPOSER第3部分中在从依库珠单抗进行转换的所有患者中均检测到由可伐利单抗、人C5和依库珠单抗组成的药物-靶标-药物复合物(DTDC)。SEC是一种基于蛋白质的斯托克斯半径和几何形状的差异的分离技术:当分子通过填充在柱中以形成填充床的凝胶过滤介质时,SEC根据尺寸的差异分离它们。与离子交换色谱或亲和色谱不同,分子不与色谱介质结合,所以缓冲介质组成不会直接影响分辨率(峰之间的分离程度)。所述介质是具有化学和物理稳定性和惰性(缺乏反应性和吸附性能)的球形颗粒的多孔基质。以分级模式使用SEC,以基于其尺寸的差异分离样品中的多种组分。对于具有不同蛋白质的复杂样品组合物(如血清),SEC与分析物(可伐利单抗)特异性ELISA的组合提供了所需的特异性和灵敏度,以检测每个分离的级分中的可伐利单抗浓度。为了能够用ELISA检测可伐利单抗浓度,将SEC分离物分级成八个级分。对于每名个体,使用此方法描述随时间的DTDC谱。为了确定预期在整个给药间隔内实现完全且持续的末端补体抑制的给药方案,开发了两种互补的模型引导的药物研发(MIDD)方法,以推荐待在临床试验中使用的剂量(III期剂量):
·用于推荐在患者中在整个给药间隔内维持可伐利单抗浓度高于100μg/ml的靶阈值浓度的皮下(SC)剂量和方案的经验群体药代动力学模型。
·用于推荐最小化在从依库珠单抗转换到可伐利单抗的患者中形成大的DTDC并且最大化所有患者中的自由可伐利单抗结合位点水平的剂量和方案的同时描述总的和游离的C5的动力学、可伐利单抗和依库珠单抗的药代动力学以及DTDC的动力学的生化模型。
3.1群体药代动力学模型
使用描述皮下(SC)施用的具有一级消除和一级吸收的双室开放模型最好地描述了抗C5抗体可伐利单抗的浓度-时间谱(参见Betts A.等人,mAbs(2018),第10卷,第5期,第751-764页)。在COMPOSER第3部分中在将治疗从依库珠单抗进行转换的患者中的药代动力学(PK)谱示出了没有在健康志愿者和未经治疗的PNH患者中观察到的瞬时更快的消除。为了描述将治疗从依库珠单抗转换到抗C5抗体可伐利单抗的患者的药代动力学(PK),将可伐利单抗的消除建模为用于未经治疗的患者的一级消除和更快的清除(其随时间呈指数下降)的组合。体重(中位数:72.3(40.6-131.5)[kg])作为间隙和体积的调节测试,并且发现使用各种缩放并入到0.75的变速下并为间隙和1来显着影响这些参数。该卷参数“间隙”是衡量身体消除药物的能力。清除率被表示为每单位时间的体积。参数“体积”代表分布体积,其是身体中可用于容纳抗C5抗体可伐利单抗的表观空间的量度。还发现年龄是吸收率的协变量,并且将其作为分类协变量引入所述模型中。年龄大于或等于50岁的患者似乎具有比年轻患者更低的吸收率。估计皮下(SC)施用后的生物利用度为大约100%。
所述模型能够精确估计PK参数,并且具有良好的预测性能,这使得其可用于模拟目的。
3.2药物-靶标-药物复合物(DTDC)生化模型
开发了一种生化数学模型,以在通过较小复合物的可逆结合形成增加尺寸的复合物的假设下研究DTDC形成和消除的动力学(参见图5)。此模型考虑了由Ab1-Ag-Ab2单元重复构成的所有复合物(抗体1(Ab1)、抗体2(Ab2)和抗原(Ag)分别表示可伐利单抗、依库珠单抗和C5),从最小的复合物(Ab1-Ag-Ab2)开始一直到含有4个Ab1、4个Ab2和8个Ag的最大的复合物(例如,复合物Ab1-Ag-Ab2-Ag-Ab1-Ag-Ab2-Ag-Ab1-Ag-Ab2-Ag-Ab1-Ag-Ab2-Ag),如在体外SEC测定中观察到的。使用配体结合模型描述了通过2个较小的复合物的结合形成复合物的每种可能的生化反应。在每种结合反应中也考虑了复合物的清除和游离可伐利单抗从DTDC的再循环(由于SMART-Ig 在溶酶体的酸性条件下将C5从可伐利单抗中释放出来)。Fukuzawa等人,Sci Rep.(2017),第7(1)卷:1080;doi:10.1038/s41598-017-01087-7描述了SMART-Ig 系统的细节。使用在CO MPOSER研究中收集的数据使用非线性混合效应方法估计了模型参数。使用总可伐利单抗、总C5和8个SEC级分(其中根据其分子量检测DTDC)来开发所述模型。对于模拟目的,模型适合性的评价是令人满意的。使用在转换时的依库珠单抗浓度以及从I/II期COM POSER研究中获得的总可伐利单抗、总C5浓度的时间谱和DTDC尺寸分布的基于色谱的测量对所述模型进行了校准(参见等人,Blood(2020),第135卷,第912-920页;doi:10.1182/blood.2019003399)。
3.3 III期剂量确定
平行使用两种模型(群体药代动力学模型和DTDC生化模型)允许鉴定这样的固定剂量和给药方案,其(1)最小化在从依库珠单抗转换到可伐利单抗的患者中形成较大的DTDC,(2)最大化可伐利单抗自由结合位点的水平,和(3)尽管存在固有的个体间变异性,但仍确保患者保持高于末端补体抑制所需的靶阈值浓度(靶C谷高于大约100μg/mL可伐利单抗)。
基于其作用机制,可伐利单抗抑制缺乏补体调节蛋白的红血球的补体介导的裂解。如果在治疗间隔期间暂时没有阻断末端补体途径,则这些红血球将被裂解,并且这可能导致爆发性溶血,它是PNH患者的严重临床并发症。生物应力(感染、手术、妊娠)导致补体途径的生理性激活,其中C5上调(Schutte等人,Int Arch Allergy Appl Immunol(1975),第48(5)卷,第706-720页)。因此,在患有PNH的患者中,重要的是不仅在整个给药间隔内维持末端补体活性的完全阻断,而且还维持可伐利单抗自由结合位点的储备,以最小化爆发性溶血的发生。
整合来自COMPOSER研究的第1部分、第2部分和第3部分的可用药代动力学(PK)和药效学(PD)数据,以使得能够表征在IV和SC施用后可伐利单抗的PK/PD关系,并且以鉴定确定完全抑制末端补体系统的活性所需的暴露水平。通过将来自第1部分中的9名健康志愿者、第2部分中的10名患有PNH的患者和第3部分中的16名患有PNH的患者的PK和PD数据合并,显示可伐利单抗可诱导血清溶血活性的浓度依赖性抑制,如通过离体脂质体免疫测定(LIA)所测量的。暴露-反应关系的评估证明,需要大约100μg/mL的可伐利单抗来实现完全末端补体抑制,定义为溶血活性<10U/mL(参见图1)。
在人口PK模型中,体重被测试为Crapimab间隙和分布体积的协变量,并且发现当给定的剂量时统一时,在使用同种异体缩放的情况下,统计学地影响这些参数,对于给定的剂量,较大的患者倾向于具有更低的曝光率与较小患者相比,暴露于暴露。为了考虑对体重效应的补偿,提出了一种基于体重的分层给药方法,以确保在所有患者中在整个给药间隔内均实现了所有患者均接受了相当的可伐利单抗暴露。
确定了以下两种剂量方案:
·对于体重>40kg至<100kg的患者
负荷剂量:在第1天静脉内施用可伐利单抗1000mg(IV),随后在第2天、第8天、第15天和第22天皮下施用可伐利单抗340mg(SC)
维持剂量:在第29天可伐利单抗680mg SC,随后此后每4周一次(Q4W)皮下施用可伐利单抗680mg SC
·对于体重>/=100kg的患者
负荷剂量:在第1天可伐利单抗1500mg IV,随后在第2天、第8天、第15天和第22天可伐利单抗340mg SC
维持剂量:在第29天可伐利单抗1020mg SC,随后此后每4周一次(Q4W)皮下施用可伐利单抗1020SC
实施例4:DTDC模型模拟结果
由此模型进行的模拟旨在鉴定剂量和给药方案,最小化在从依库珠单抗转换到可伐利单抗的患者中形成较大的DTDC,以及在从依库珠单抗进行转换的患者或未经治疗的PNH患者中提供足够的自由可伐利单抗结合位点储备。后一标准提供了给药方案所提供以保护免于爆发性溶血的溶血控制的余量的客观评价。仅使用来自COMPOSER第3部分中的从依库珠单抗转换到可伐利单抗的患者的参数估计值进行了模拟。在经依库珠单抗预治疗的患者中提供足够的自由可伐利单抗表位储备的给药方案也适用于治疗未经治疗的患者。如图2和图3所示,预期上文提及的给药方案将最大化自由表位的可用性,同时最小化最大DTDC的形成。
实施例5:群体药代动力学模型模拟结果
由群体PK模型进行模拟,以推荐剂量和给药方案,以确保在未经治疗的和经依库珠单抗预治疗的两种PNH患者中,在整个给药间隔内在大多数患者中快速建立稳态浓度并且维持谷浓度高于100μg/mL。
模拟了20,000名未经治疗的PNH患者和20,000将治疗从依库珠单抗转换到可伐利单抗的PNH患者的可伐利单抗浓度-时间谱,所述患者的中值体重为75.6kg(标准差±20.3kg;其中第5和第95百分位数分别为42.2kg和109.0kg)。模拟考虑了年龄效应,其中50%的模拟群体超过50岁,并且其中50%的模拟群体超过50岁。体重分布的选择是基于在COMPOSER研究中观察到的分布。
基于模拟结果(图4),预测上文提及的剂量和治疗方案将导致在整个给药间隔内在大约95%的个体中快速建立稳态浓度和大于100μg/mL的持续的C谷值,而无论体重如何。预测此给药方案将在未经治疗的患者和从依库珠单抗进行转换的患者两者中维持浓度高于100μg/mL,但是在后者中观察到可伐利单抗清除的瞬间增加并且随之而来的是达到稳态浓度的时间较长。
预期上文提出的剂量和给药方案将在未经治疗的和经依库珠单抗预治疗的两种患者中确保对末端补体活性的完全且一致的阻断(其中大约95%的患者维持高于靶阈值),并且在给药间隔的大部分时间内还确保足够的自由结合位点储备。在从依库珠单抗进行转换的患者中,还预期将减少较大DTDC的形成。在COMPOSER研究的第4部分中,在从依库珠单抗转换到可伐利单抗的七名患者中肯定了上述剂量。第4部分评价了上述优化的可伐利单抗方案在15名患有PNH的患者中的安全性、药代动力学(PK)和药效学(PD)效应(数据截止日期2020年1月29日),所述患者未经抗C5疗法治疗(8名患者(53%))或先前已经用抗C5抗体依库珠单抗进行治疗(7名患者(47%))。在COMPOSER研究的第4部分中招募的患者的基线特征示于图6中。最适用于减少DTDC、特别是大的DTDC的持续存在的剂量由以下组成:负荷剂量系列(在第1天静脉内施用可伐利单抗1000mg(IV),随后在第2天、第8天、第15天和第22天皮下施用可伐利单抗340mg(SC)),随后是维持给药(在第29天可伐利单抗680mg SC,随后此后每4周一次(Q4W)皮下施用可伐利单抗680mg SC)。COMPOSER第4部分的数据证实在要求保护的优化的给药方案的情况下,DTDC尺寸分布转变为较小的复合物。
上述可伐利单抗剂量和方案(在第1天静脉内施用可伐利单抗1000mg(IV),随后在第2天、第8天、第15天和第22天皮下施用可伐利单抗340mg(SC)),随后是维持给药(在第29天可伐利单抗680mg SC,随后此后每4周一次(Q4W)皮下施用可伐利单抗680mg SC)的进一步结果报告于图7至图11中。
如图7所示,在此优化的剂量方案的情况下,在整个20周(140天)的随访期内,可伐利单抗暴露可持续地维持高于大约100μg/mL的C谷值(与补体抑制相关的水平)。
进一步地,末端补体抑制在初始剂量后立即实现,并且在整个研究期内得到维持(参见图8)。
进一步地,在未经抗C5疗法治疗的PNH患者(8名患者;图9(A))中观察到有限的总C5积累,并且在转换的患者(先前已经用抗C5抗体依库珠单抗进行治疗的PNH患者(7名患者;图9(B))中观察到C5水平的下降。
进一步地,图10报告,血管内溶血得到了控制,并且大多数患者的血红蛋白稳定并避免了输血:总共10名(67%)患者(包括8名未经治疗的患者中的5名和7名转换的患者中的5名)在第20周实现了血红蛋白稳定(在没有输血的情况下避免血红蛋白相对于基线下降≥2g/dL)。从基线到第20周,11名(73%)患者(包括8名未经治疗的患者中的5名和7名转换的患者中的6名)保持没有输血。超过7.2有风险的总患者年,没有患者经历如Kulasekararaj等人,Blood(2019),第33卷,第540-549页中所定义的爆发性溶血(BTH)事件。
进一步地,揭示了抗C5抗体可伐利单抗的上述剂量和治疗方案的耐受性良好,并且没有观察到严重的治疗相关不良事件(AE)(参见图11)。
因此,本文所述的建模方法证明,要求保护的剂量方案对于治疗或预防未经治疗的、特别是经依库珠单抗预治疗的两种受试者的C5相关疾病(如PNH)是优越的。
实施例6:COMPOSER研究的第3部分与第4部分之间的DTDC尺寸分布的比较结果
在COMPOSER第3部分中,在从抗C5抗体依库珠单抗转换到可伐利单抗的所有PNH患者中均检测到可伐利单抗、人C5与抗体依库珠单抗之间的药物-靶标-药物复合物(DTDC)。本实施例的目的是描述COMPOSER研究的第3部分与第4部分的剂量方案之间的DTDC尺寸分布的比较结果。在COMPOSER研究的第3部分中,将抗C5抗体可伐利单抗最初以1000mg/个体的剂量静脉内地施用给受试者一次。从初始静脉内施用后一周(IV施用后第8天)开始,将抗C5抗体可伐利单抗以170mg/个体的剂量每周皮下(SC)施用一次,以340mg/个体的剂量每两周皮下施用一次,或者以680mg/个体的剂量每四周皮下施用一次。在COMPOSER研究的第4部分中,根据上述剂量和治疗方案施用可伐利单抗:优化的剂量和方案是负荷系列(在第1天1000mg IV,并且在第2天、第8天、第15天和第22天340mg SC),随后在第29天(第5周)开始每4周一次维持给药680mg SC。所述负荷剂量系列增加了在治疗的第一个月内接受的可伐利单抗的总剂量,以减少较大DTDC的形成,符合复合物形成的格子理论。在转换治疗的第4部分患者中研究了此优化的给药策略,并且与在第3部分招募且从依库珠单抗转换到可伐利单抗的19名患有的PNH患者进行了比较。使用尺寸排阻色谱(SEC)联用ELISA测量了DTDC尺寸分布。SEC根据其尺寸将DTDC分离成级分:在级分1-4中发现较大的DTDC,并且在级分5-6中发现较小的复合物,如单个基序和非DTDC。在来自第3部分的所有患者中均观察到DTDC(图12;在级分1-4中发现较大的DTDC,并且在级分5-6中发现较小的复合物,如单个基序和非DTDC)。第3部分的两名患者经历了与III型超敏反应相容的临床表现,其归因于DTDC。接受优化的给药策略的第4部分患者中的DTDC尺寸分布与第3部分患者相比不同地演变,与模型预测一致。在来自第4部分的转换的患者(n=7;数据截止日期2020年1月29日)中,级分1-4中的DTDC的总和在第8天开始下降,并且继续下降,与第3部分形成对照。在第22天,相对于第3部分中的患者,在第4部分的患者中最大DTDC的平均百分比减少了56%。另外,第4部分患者的血清可伐利单抗浓度保持高于100μg/mL,其是与补体抑制相关的水平。尽管在从依库珠单抗进行转换的所有第4部分患者中均观察到DTDC,但没有发生提示III型超敏反应的不良事件。总之,优化的可伐利单抗方案导致大DTDC的浓度低于接受第3部分方案的患者。
实施例7:具有C5多态性的PNH患者对可伐利单抗的反应结果
阵发性睡眠性血红蛋白尿症(PNH)的特征在于造血细胞上的内源补体调节剂CD59和CD55的缺失。外周血元素易于被补体破坏,导致血管内溶血和血栓形成。标准疗法是用依库珠单抗(一种抗C5单克隆抗体(mAb))进行末端补体抑制。然而,高达3.5%的亚裔个体在C5中携带影响Arg885的多态性,Arg885对应于依库珠单抗和雷夫利珠单抗结合位点(参见Nishimura等人,N Engl J Med,第370卷,第632-639页(2014);DOI:10.1056/NEJMoa1311084)。具有这些多态性的PNH患者用依库珠单抗对血管内溶血的控制较差,因此构成了具有高度未满足的医疗需求的群体。可伐利单抗是一种结合C5的β亚基上的不同表位的新型抗C5 mAb。体外研究已经证明,可伐利单抗相等地结合野生型和Arg885突变型C5并抑制其活性(Fukuzawa等人,Sci Rep,7(1):1080.doi:10.1038/s41598-017-01087-7(2017))。
目的:本实施例的目标是描述具有C5多态性的PNH患者对可伐利单抗的反应。
方法:将上述可伐利单抗剂量和方案(在第1天静脉内施用可伐利单抗1000mg(IV),随后在第2天、第8天、第15天和第22天皮下施用可伐利单抗340mg(SC)),随后是维持给药(在第29天可伐利单抗680mg SC,随后此后每4周一次(Q4W)皮下施用可伐利单抗680mgSC)施用给具有C5多态性(C5(SEQ ID NO:13)的Arg885突变)的PNH患者。在每次访视时确定可伐利单抗、乳酸脱氢酶(LDH)、游离的和总的C5的血浆浓度以及补体活性。随访患者的输血、爆发性溶血(BTH)事件的发生以及安全性。
结果:在COMPOSER研究(ClinicalTrials.gov标识符:NCT03157635)的第2部分(n=10)、第3部分(n=19)和第4部分(n=15)的44名患者中,四名具有预测Arg885His取代的c.2654G->A核苷酸多态性。在2019年9月的数据截止日期,随访的范围从12.4-98.3周。所有四名患者均为男性,在招募前44-734周被诊断为患有PNH,粒细胞克隆尺寸的范围从89%-95%。在招募时,一名患者从正在进行的依库珠单抗疗法进行转换,而三名先前已经停止了依库珠单抗。所有患者在招募时的LDH均>3倍正常值上限(ULN),其快速下降并且在整个随访期内维持小于1.5x ULN(图13)。一名患者在招募后需要输血(经6个月输12个单位的红细胞(RBC));此患者在招募前12个月内具有再生障碍性贫血的潜在诊断并且需要198个单位的RBC。四名患者均没有经历爆发性溶血(BTH)事件。所有四名患者均实现了完全末端补体抑制,如通过脂质体免疫测定(LIA)所测量的。LIA水平在进入研究时的范围从32-42U/mL,并且到第2天下降到<10U/mL(定量下水平)且在此后得到维持。类似地,在第6周(第43天)后,游离C5水平维持<0.5μg/mL。这些患者的安全谱与剩余的参与者类似。报告了三例严重不良事件(SAE),其均与研究治疗无关。一名患者具有两例SAE,即胆管结石和胆石病。第二名患者具有上呼吸道感染伴随住院的SAE,其在20个月后发生并在治疗时消退。
结论:可伐利单抗在具有Arg885多态性的PNH患者中实现了完全且持续的末端补体抑制。因此,可伐利单抗是用于治疗和/或预防患有PNH的患者的有前途的抗C5抗体,其中所述患者的特征在于具有C5 Arg885His突变。
综上所述,本申请包括但不限于以下各项:
1.一种用于在治疗或预防受试者的C5相关疾病的方法中使用的抗C5抗体,其中所述方法包括以下连续步骤:
(a)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体,随后向所述受试者皮下地施用至少一个340mg负荷剂量的所述抗C5抗体;以及
(b)向所述受试者皮下地施用至少一个680mg维持剂量的所述抗C5抗体。
2.根据项1所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1天至3周,将皮下所施用的340mg负荷剂量的所述抗体施用给所述受试者至少一次。
3.根据项2所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1天,将皮下所施用的340mg负荷剂量的所述抗体施用给所述受试者一次。
4.根据项2或项3所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1周或2周,将至少一个另外的340mg负荷剂量的所述抗C5抗体皮下地施用给所述受试者。
5.根据项2至4中任一项所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1周和2周,将另外的340mg负荷剂量的所述抗C5抗体每周皮下地施用给所述受试者一次。
6.根据项1至4中任一项所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后4周,将至少一个680mg维持剂量的所述抗C5抗体皮下地施用给所述受试者。
7.根据项6所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后4周,将所述680mg维持剂量的所述抗C5抗体皮下地施用给所述受试者一次。
8.根据项6或项7所述的用于所述用途的抗C5抗体,其中将向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体以至少4周的时间间隔重复几次。
9.根据项1至8中任一项所述的用于所述用途的抗C5抗体,其中通过以下施用步骤进行所述方法:
(i)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体;
(ii)在静脉内施用所述抗C5抗体开始后1天,向所述受试者皮下地施用340mg负荷剂量的所述抗C5抗体;
(iii)在静脉内施用所述抗C5抗体开始后1周、2周和3周,向所述受试者每周皮下地施用一次340mg负荷剂量的所述抗C5抗体;
(iv)在静脉内施用所述抗C5抗体开始后4周,向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体;以及
(v)将步骤(iv)以4周的时间间隔重复几次。
10.根据项1至9中任一项所述的用于所述用途的抗C5抗体,其中所述受试者接受了用至少一种可用于治疗或预防所述C5相关疾病的药理产品进行的在先治疗,其中在最后剂量的所述药理产品后,将静脉内所施用的1000mg负荷剂量的所述抗C5抗体施用给所述受试者。
11.根据项10所述的用于所述用途的抗C5抗体,其中在施用最后剂量的所述药理产品后第三天或者在施用最后剂量的所述药理产品后3天后,将静脉内所施用的1000mg负荷剂量的所述抗C5抗体施用给所述受试者。
12.根据项10或项11所述的用于所述用途的抗C5抗体,其中所述药理产品包含靶向C5mRNA的siRNA,或者与用于皮下或静脉内注射的所述组合物中所包含的抗C5抗体不同的抗C5抗体。
13.根据项10至12中任一项所述的用于所述用途的抗C5抗体,其中所述药理产品包含依库珠单抗、雷夫利珠单抗或其变体。
14.根据项1至13中任一项所述的用于所述用途的抗C5抗体,其中所述受试者的体重在40kg与100kg之间。
15.根据项1至14中任一项所述的用于所述用途的抗C5抗体,其中在所述受试者的生物样品中确定的抗C5抗体浓度为100μg/ml或更高。
16.根据项1至14中任一项所述的用于所述用途的抗C5抗体,其中在所述受试者的生物样品中确定的溶血活性小于10U/mL。
17.根据项15或项16所述的用于所述用途的抗C5抗体,其中所述生物样品是血液样品,优选红色血液样品。
18.根据项1至17中任一项所述的用于所述用途的抗C5抗体,其中所述抗C5抗体是可伐利单抗。
19.根据项1至18中任一项所述的用于所述用途的抗C5抗体,其中所述C5相关疾病选自阵发性睡眠性血红蛋白尿症(PNH);类风湿性关节炎(RA);狼疮肾炎;缺血再灌注损伤;非典型溶血性尿毒综合征(aHUS);致密物沉积病(DDD);黄斑变性;溶血,肝酶升高,低血小板(HELLP)综合征;血栓性血小板减少性紫癜(TTP);自发性妊娠丢失;寡免疫性血管炎;大疱性表皮松解症;反复性妊娠丢失;多发性硬化症(MS);创伤性脑损伤;由心肌梗死、心肺转流术或血液透析引起的损伤;难治性全身型重症肌无力(gMG);和视神经脊髓炎(NMO)。
序列表
<110> 豪夫迈·罗氏有限公司
<120> 通过使用抗C5抗体可伐利单抗来治疗或预防C5相关疾病的剂量
和施用方案
<130> AC2428 PCT S3
<150> EP 20 17 9590.3
<151> 2020-06-11
<150> EP 20 17 4781.3
<151> 2020-05-14
<150> EP 19 18 9436.9
<151> 2019-07-31
<160> 13
<170> BiSSAP 1.3.6
<210> 1
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 依库珠单抗重链
<400> 1
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Asn Tyr
20 25 30
Trp Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Ser Thr Glu Tyr Thr Glu Asn Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Phe Phe Gly Ser Ser Pro Asn Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys
210 215 220
Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
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Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 2
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 依库珠单抗轻链
<400> 2
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
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Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Leu Asn Thr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 3
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 可伐利单抗重链
<400> 3
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val His Ser Ser
20 25 30
Tyr Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Ala Ile Phe Thr Gly Ser Gly Ala Glu Tyr Lys Ala Glu Trp
50 55 60
Ala Lys Gly Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Ser Asp Ala Gly Tyr Asp Tyr Pro Thr His Ala Met His Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Arg Arg Gly Pro Lys Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
325 330 335
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Leu His Glu Ala Leu His Ala His Tyr Thr Arg Lys Glu Leu Ser
435 440 445
Leu Ser Pro
450
<210> 4
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> 可伐利单抗轻链
<400> 4
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Glu Thr Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Lys Val Gly Ser Ser
85 90 95
Tyr Gly Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr
100 105 110
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu
115 120 125
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro
130 135 140
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly
145 150 155 160
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His
180 185 190
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val
195 200 205
Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 5
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 雷夫利珠单抗重链
<400> 5
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly His Ile Phe Ser Asn Tyr
20 25 30
Trp Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly His Thr Glu Tyr Thr Glu Asn Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Phe Phe Gly Ser Ser Pro Asn Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys
210 215 220
Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
260 265 270
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala
420 425 430
Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 6
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 雷夫利珠单抗轻链
<400> 6
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Leu Asn Thr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 7
<211> 123
<212> PRT
<213> 人工序列
<220>
<223> 人工合成的序列
<400> 7
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val His Ser Ser
20 25 30
Tyr Tyr Met Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Ala Ile Phe Thr Gly Ser Gly Ala Glu Tyr Lys Ala Glu Trp
50 55 60
Ala Lys Gly Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Ser Asp Ala Gly Tyr Asp Tyr Pro Thr His Ala Met His Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 8
<211> 328
<212> PRT
<213> 人工序列
<220>
<223> 人工合成的序列
<400> 8
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Arg Arg Gly Pro Lys Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ala His Tyr Thr
305 310 315 320
Arg Lys Glu Leu Ser Leu Ser Pro
325
<210> 9
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> 人工合成的序列
<400> 9
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Ser
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Glu Thr Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Thr Lys Val Gly Ser Ser
85 90 95
Tyr Gly Asn Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> 人工合成的序列
<400> 10
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 11
<211> 650
<212> PRT
<213> 人工序列
<220>
<223> 免疫球蛋白,抗(人补体C5 α链);重链;
CAS登记号:219685-50-4
<400> 11
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Asn Tyr
20 25 30
Trp Ile Gln Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Leu Pro Gly Ser Gly Ser Thr Glu Tyr Thr Glu Asn Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Phe Phe Gly Ser Ser Pro Asn Trp Tyr Phe Asp Val Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Gly Glu Arg Pro
210 215 220
Ala Gln Gly Gly Arg Val Ser Ala Gly Ser Gln Ala Gln Pro Ser Cys
225 230 235 240
Leu Asp Ala Pro Arg Leu Cys Ser Pro Ser Pro Gly Gln Gln Gly Arg
245 250 255
Pro His Leu Ser Pro His Pro Glu Ala Ser Ala Arg Pro Thr His Ala
260 265 270
Gln Gly Glu Gly Leu Leu Ala Phe Ser Thr Arg Leu Gln Ala Gly Thr
275 280 285
Gly Trp Val Pro Leu Pro Gln Ala Leu His Thr Gln Gly Gln Val Leu
290 295 300
Gly Ser Asp Leu Pro Lys Ala Ile Ser Gly Arg Thr Leu Pro Pro Asp
305 310 315 320
Leu Ser Arg Pro Gln Gly Gln Thr Val His Ser Leu Ser Ser Asp Thr
325 330 335
Phe Leu Ser Ser Gln Ile Arg Val Thr Pro Asn Leu Leu Ser Ala Glu
340 345 350
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Gly Lys Pro Ala Gln
355 360 365
Ala Ser Pro Ser Ser Ser Arg Arg Asp Arg Cys Pro Arg Val Ala Cys
370 375 380
Ile Gln Gly Gln Pro Gln Leu Gly Ala Asp Thr Ser Thr Ser Ile Ser
385 390 395 400
Ser Ser Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro
405 410 415
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
420 425 430
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp
435 440 445
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
450 455 460
Glu Gln Phe Asn Ser Thr Asp Arg Val Val Ser Val Leu Thr Val Leu
465 470 475 480
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Thr
485 490 495
Lys Ala Ser Arg Pro Pro Ser Arg Lys Pro Ser Pro Lys Pro Lys Val
500 505 510
Gly Pro Thr Gly Cys Glu Gly His Met Asp Arg Gly Gln Leu Gly Pro
515 520 525
Pro Ser Ala Leu Gly Val Thr Ala Val Pro Thr Ser Val Pro Thr Gly
530 535 540
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu
545 550 555 560
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Leu Tyr
565 570 575
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
580 585 590
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
595 600 605
Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn
610 615 620
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
625 630 635 640
Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
645 650
<210> 12
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 免疫球蛋白,抗(人补体C5 α链);轻链;
CAS登记号:219685-50-4
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gly Ala Ser Glu Asn Ile Tyr Gly Ala
20 25 30
Leu Asn Trp Tyr Gln Arg Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Asn Val Leu Asn Thr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 13
<211> 1676
<212> PRT
<213> 智人(Homo sapiens)
<400> 13
Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr
1 5 10 15
Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg
20 25 30
Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu
35 40 45
Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe
50 55 60
Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln
65 70 75 80
Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln
85 90 95
Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser
100 105 110
Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile
115 120 125
His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg
130 135 140
Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val
145 150 155 160
Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu
165 170 175
Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser
180 185 190
Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp
195 200 205
Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu
210 215 220
Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr
225 230 235 240
Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr
245 250 255
Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg
260 265 270
Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln
275 280 285
Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu
290 295 300
Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn
305 310 315 320
Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe
325 330 335
Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr
340 345 350
Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro
355 360 365
Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly
370 375 380
Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu
385 390 395 400
Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly
405 410 415
Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu
420 425 430
Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala
435 440 445
Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr
450 455 460
Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu
465 470 475 480
His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile
485 490 495
Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe
500 505 510
Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile
515 520 525
Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr
530 535 540
Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp
545 550 555 560
Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser
565 570 575
Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met
580 585 590
Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala
595 600 605
Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe
610 615 620
Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu
625 630 635 640
Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn
645 650 655
Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile
660 665 670
Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala
675 680 685
Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys
690 695 700
Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu
705 710 715 720
Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser
725 730 735
Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu
740 745 750
His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr
755 760 765
Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys
770 775 780
Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln
785 790 795 800
Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys
805 810 815
Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser
820 825 830
Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr
835 840 845
Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly
850 855 860
Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser
865 870 875 880
Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val
885 890 895
Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe
900 905 910
Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg
915 920 925
Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu
930 935 940
Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro
945 950 955 960
Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile
965 970 975
Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu
980 985 990
Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala
995 1000 1005
Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His Tyr
1010 1015 1020
Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro Leu Ile
1025 1030 1035 1040
Glu Lys Gln Lys Leu Lys Lys Lys Leu Lys Glu Gly Met Leu Ser Ile
1045 1050 1055
Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val Trp Lys Gly Gly
1060 1065 1070
Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu Arg Val Leu Gly Gln
1075 1080 1085
Val Asn Lys Tyr Val Glu Gln Asn Gln Asn Ser Ile Cys Asn Ser Leu
1090 1095 1100
Leu Trp Leu Val Glu Asn Tyr Gln Leu Asp Asn Gly Ser Phe Lys Glu
1105 1110 1115 1120
Asn Ser Gln Tyr Gln Pro Ile Lys Leu Gln Gly Thr Leu Pro Val Glu
1125 1130 1135
Ala Arg Glu Asn Ser Leu Tyr Leu Thr Ala Phe Thr Val Ile Gly Ile
1140 1145 1150
Arg Lys Ala Phe Asp Ile Cys Pro Leu Val Lys Ile Asp Thr Ala Leu
1155 1160 1165
Ile Lys Ala Asp Asn Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser
1170 1175 1180
Thr Phe Thr Leu Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys
1185 1190 1195 1200
Thr His Pro Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala
1205 1210 1215
Leu Val Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu
1220 1225 1230
Gln His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val
1235 1240 1245
Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp Ile
1250 1255 1260
Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln Arg Tyr
1265 1270 1275 1280
Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala Ile Glu Gly
1285 1290 1295
Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg Leu Ser Met Asp
1300 1305 1310
Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu His Asn Tyr Lys Met
1315 1320 1325
Thr Asp Lys Asn Phe Leu Gly Arg Pro Val Glu Val Leu Leu Asn Asp
1330 1335 1340
Asp Leu Ile Val Ser Thr Gly Phe Gly Ser Gly Leu Ala Thr Val His
1345 1350 1355 1360
Val Thr Thr Val Val His Lys Thr Ser Thr Ser Glu Glu Val Cys Ser
1365 1370 1375
Phe Tyr Leu Lys Ile Asp Thr Gln Asp Ile Glu Ala Ser His Tyr Arg
1380 1385 1390
Gly Tyr Gly Asn Ser Asp Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr
1395 1400 1405
Lys Pro Ser Arg Glu Glu Ser Ser Ser Gly Ser Ser His Ala Val Met
1410 1415 1420
Asp Ile Ser Leu Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys
1425 1430 1435 1440
Ala Leu Val Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys
1445 1450 1455
Asp Gly His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe
1460 1465 1470
Leu Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu
1475 1480 1485
Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys Gln
1490 1495 1500
Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys Val Cys
1505 1510 1515 1520
Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly Gln Met Gln
1525 1530 1535
Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg Lys Gln Thr Ala
1540 1545 1550
Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val Ser Ile Thr Ser Ile
1555 1560 1565
Thr Val Glu Asn Val Phe Val Lys Tyr Lys Ala Thr Leu Leu Asp Ile
1570 1575 1580
Tyr Lys Thr Gly Glu Ala Val Ala Glu Lys Asp Ser Glu Ile Thr Phe
1585 1590 1595 1600
Ile Lys Lys Val Thr Cys Thr Asn Ala Glu Leu Val Lys Gly Arg Gln
1605 1610 1615
Tyr Leu Ile Met Gly Lys Glu Ala Leu Gln Ile Lys Tyr Asn Phe Ser
1620 1625 1630
Phe Arg Tyr Ile Tyr Pro Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp
1635 1640 1645
Pro Arg Asp Thr Thr Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu
1650 1655 1660
Asp Glu Phe Ala Glu Asp Ile Phe Leu Asn Gly Cys
1665 1670 1675
Claims (10)
1.一种用于在治疗或预防受试者的C5相关疾病的方法中使用的抗C5抗体,其中所述方法包括以下连续步骤:
(a)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体,随后向所述受试者皮下地施用至少一个340mg负荷剂量的所述抗C5抗体;以及
(b)向所述受试者皮下地施用至少一个680mg维持剂量的所述抗C5抗体。
2.根据权利要求1所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1天至3周,将皮下所施用的340mg负荷剂量的所述抗体施用给所述受试者至少一次。
3.根据权利要求2所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1天,将皮下所施用的340mg负荷剂量的所述抗体施用给所述受试者一次。
4.根据权利要求2或权利要求3所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1周或2周,将至少一个另外的340mg负荷剂量的所述抗C5抗体皮下地施用给所述受试者。
5.根据权利要求2至4中任一项所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后1周和2周,将另外的340mg负荷剂量的所述抗C5抗体每周皮下地施用给所述受试者一次。
6.根据权利要求1至4中任一项所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后4周,将至少一个680mg维持剂量的所述抗C5抗体皮下地施用给所述受试者。
7.根据权利要求6所述的用于所述用途的抗C5抗体,其中在静脉内施用所述抗C5抗体开始后4周,将所述680mg维持剂量的所述抗C5抗体皮下地施用给所述受试者一次。
8.根据权利要求6或权利要求7所述的用于所述用途的抗C5抗体,其中将向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体以至少4周的时间间隔重复几次。
9.根据权利要求1至8中任一项所述的用于所述用途的抗C5抗体,其中通过以下施用步骤进行所述方法:
(i)向所述受试者静脉内地施用一次1000mg负荷剂量的所述抗C5抗体;
(ii)在静脉内施用所述抗C5抗体开始后1天,向所述受试者皮下地施用340mg负荷剂量的所述抗C5抗体;
(iii)在静脉内施用所述抗C5抗体开始后1周、2周和3周,向所述受试者每周皮下地施用一次340mg负荷剂量的所述抗C5抗体;
(iv)在静脉内施用所述抗C5抗体开始后4周,向所述受试者皮下地施用680mg维持剂量的所述抗C5抗体;以及
(v)将步骤(iv)以4周的时间间隔重复几次。
10.根据权利要求1至9中任一项所述的用于所述用途的抗C5抗体,其中所述受试者接受了用至少一种可用于治疗或预防所述C5相关疾病的药理产品进行的在先治疗,其中在最后剂量的所述药理产品后,将静脉内所施用的1000mg负荷剂量的所述抗C5抗体施用给所述受试者。
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
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EP19189436 | 2019-07-31 | ||
EP19189436.9 | 2019-07-31 | ||
EP20174781.3 | 2020-05-14 | ||
EP20174781 | 2020-05-14 | ||
EP20179590 | 2020-06-11 | ||
EP20179590.3 | 2020-06-11 | ||
CN202080054192.8A CN114466660A (zh) | 2019-07-31 | 2020-07-30 | 通过使用抗c5抗体可伐利单抗来治疗或预防c5相关疾病的剂量和施用方案 |
PCT/EP2020/071551 WO2021019033A1 (en) | 2019-07-31 | 2020-07-30 | Dosage and administration regimen for the treatment or prevention of c5-related diseases by the use of the anti-c5 antibody crovalimab |
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CN202080054192.8A Division CN114466660A (zh) | 2019-07-31 | 2020-07-30 | 通过使用抗c5抗体可伐利单抗来治疗或预防c5相关疾病的剂量和施用方案 |
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CN202080054192.8A Pending CN114466660A (zh) | 2019-07-31 | 2020-07-30 | 通过使用抗c5抗体可伐利单抗来治疗或预防c5相关疾病的剂量和施用方案 |
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US (1) | US20220275071A1 (zh) |
EP (1) | EP4003408A1 (zh) |
JP (2) | JP7437260B2 (zh) |
KR (2) | KR102618269B1 (zh) |
CN (2) | CN115137815A (zh) |
AU (1) | AU2020319677A1 (zh) |
CA (1) | CA3144921A1 (zh) |
CR (1) | CR20220040A (zh) |
IL (1) | IL288636A (zh) |
MX (1) | MX2022001153A (zh) |
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TW202404632A (zh) * | 2022-04-04 | 2024-02-01 | 瑞士商赫孚孟拉羅股份公司 | 用於藉由使用抗c5抗體克羅伐單抗治療或預防格林-巴利症候群之劑量及投予方案 |
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CN114466660A (zh) | 2022-05-10 |
CA3144921A1 (en) | 2021-02-04 |
KR20240001329A (ko) | 2024-01-03 |
MX2022001153A (es) | 2022-02-22 |
KR20210016332A (ko) | 2021-02-15 |
EP4003408A1 (en) | 2022-06-01 |
JP2022104920A (ja) | 2022-07-12 |
WO2021019033A1 (en) | 2021-02-04 |
KR102618269B1 (ko) | 2023-12-27 |
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