CN116782931A - 抗cd40抗体用于治疗炎症性病况的用途 - Google Patents
抗cd40抗体用于治疗炎症性病况的用途 Download PDFInfo
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Abstract
本发明涉及抗CD40抗体及使用其治疗和/或预防自身免疫性疾病或炎症性疾病的治疗方法。
Description
序列表
本申请包含以ASCII格式电子提交的序列表,且该序列表以其整体通过引用并入本文。所述ASCII副本创建于2021年9月14日,命名为09-0706-WO-1-2021-09-17-Sequence-Listing.txt,大小为106,888字节。
发明领域
本发明一般涉及人源化抗CD40抗体用于治疗和/或预防各种自身免疫性疾病或炎症性疾病,更具体地,本申请公开了用于治疗以表达CD40的细胞为特征的各种疾病或病症的用途。
发明背景
CD40为48kDa I型整合膜糖蛋白和肿瘤坏死因子(TNF)受体超家族的成员。CD40表达在多种细胞类型上,包括正常和肿瘤性B细胞、并指树突细胞、癌瘤、上皮细胞(例如角质细胞)、成纤维细胞(例如滑膜细胞)和血小板。其也存在于单核球、巨噬细胞、一些内皮细胞和滤泡性树突状细胞上。CD40在B细胞个体发生早期表达,在CD10和CD19出现之后,但在CD21、CD23、CD24表达和表面免疫球蛋白M(sIgM)出现之前出现在B细胞前体细胞上。在扁桃体和骨髓衍生的浆细胞上也检测到CD40。
CD40的配体为CD40L(也称为CD154、gp39和TRAP)TNF超家族成员。CD40L为主要表达于经活化的CD4+T细胞和一小亚组的CD8+T细胞上的跨膜蛋白。
CD40与CD40L的相互作用诱导体液和细胞介导的免疫反应。CD40调控此配体-受体对以活化B细胞和其他抗原呈现细胞(APC),包括树突状细胞(DC)。已广泛研究CD40在B细胞上的功能。B细胞上CD40的活化诱导增殖,分化为抗体分泌细胞且在次级淋巴样器官的生发中心同种型转换。体外研究展示CD40活化对细胞因子产生(IL-6、IL-10、TNF-α、LT-α)的直接作用、黏附分子和共刺激受体(ICAM、CD23、CD80和CD86)的表达和B淋巴细胞的MHC I类、MHC II类和TAP转运体的增加的表达。对于大部分这些过程,CD40与细胞因子或其他受体配体相互作用协同作用。
单核细胞和DC上的CD40信号传导引起存活提高以及细胞因子的分泌(IL-1、IL-6、IL-8、IL-10、IL-12、TNF-α和MIP-1α)。这些APC上的CD40连接也引起共刺激分子,诸如(ICAM-1、LFA-3、CD80和CD86)的上调。CD40受体的活化为允许DC完全成熟成驱动T细胞活化的高效APC的关键信号中之一。
在小鼠模型中的近期研究展示,树突状细胞上的CD40信号传导也在TH17细胞产生中起重要作用,其被视为诸如关节炎和多发性硬化症的疾病中自身免疫性疾病的中间物。
CD40和CD40L基因敲除小鼠的可用性以及激动性和拮抗性抗小鼠抗体提供研究CD40-CD40L相互作用于若干疾病模型中的作用的可能性。已证明,施用阻断抗CD40L在NOD小鼠中的自身免疫性疾病的若干模型中是有益的,包括自发性疾病,如SNF1小鼠中的狼疮性肾炎或NOD小鼠中的糖尿病,或以实验方式诱导的形式的疾病,如胶原蛋白诱导的关节炎(CIA)或实验性自身免疫性疾病脑脊髓炎(EAE)。通过抗CD40L mAb抑制小鼠中的CIA,该抗CD40L mAb阻断关节炎症的发展、血清抗体对胶原蛋白的滴度、炎症性细胞向滑膜组织中的浸润以及软骨和骨骼的侵蚀。狼疮性肾炎和EAE两者均表明抗CD40L也可缓解持续的疾病,证实CD40-CD40L在疾病的效应阶段中的作用。
CD40-CD40L相互作用在EAE发展中的作用也在CD40L不足的小鼠中进行研究,CD40L不足的小鼠携带对髓磷脂碱性蛋白具有特异性的转基因T细胞受体。这些小鼠在用抗原预致敏之后未能产生EAE,且CD4+T细胞保持静止且不产生INF-γ。
此外,针对CD40的抑制性抗体在诸如EAE的炎症性疾病模型中展示有益作用。Lamann和同事证明,拮抗性小鼠抗人CD40 mAb mu5D12和此mAb的嵌合形式有效地防止远系繁殖的狨猴中慢性脱髓鞘EAE的临床表现。后续研究展示用嵌合抗人CD40抗体治疗性处理减少MRI可检测的炎症且延迟狨猴EAE模型中预先存在之大脑病变的扩大。
在关节炎的小鼠模型中测试具有激动性活性的抗CD40抗体,结果有一些冲突。如免疫刺激剂所预期,激动性抗小鼠CD40 mAb FGK45展示在CIA的DBA/1小鼠模型中加重疾病。然而,在另一慢性CIA模型FGK45和另一激动性抗小鼠CD40 mAb中,3/23都展现积极治疗作用。此组假定此治疗性处理方案中的激动性抗体通过在IFN-γ水平降低和IL-4和IL-10水平增加下诱导针对Th2反应的免疫偏差而具有有益作用。
还记录通过阻断CD40/CD154相互作用预防移植排斥反应。在恒河猴中的肾同种移植研究中使用ch5D12(嵌合抗CD40拮抗剂)表明CD40的拮抗作用对于疾病修饰和延长平均存活时间足以超过100天。当ch5D12与抗CD86抗体组合且仅在同种移植研究开始时给出,随后用环孢菌素长期治疗时,实现大于4年的平均存活时间,这表明此组合可潜在地诱导耐受性。
因此,临床前研究提供关于CD40-CD40L二分体在驱动高效T细胞依赖性免疫反应中的关键作用的证据。因此,CD40信号传导的阻断识别为抑制诸如RA、狼疮性肾炎、多发性硬化症或牛皮癣的疾病中的病原性自身免疫性疾病反应的适合且需要的治疗策略。然而,迄今为止,因为发现展示先前在研发中的抗CD40抗体具有显著副作用,所以尚未批准用于此类病症的治疗性干预的CD40抗体。
例如,可供狼疮性肾炎使用的所有治疗可能与较大毒性(例如不孕症、感染、恶性病)相关。此外,完全反应率保持较低且在应答者内存在较高复发率,证明长期维持治疗是合理的。最近在狼疮性肾炎(例如利妥昔单抗(rituximab)、阿柏西普(abatacept))中进行III期试验未能满足其主要终点。综合而言,对狼疮性肾炎中的新疗法存在高度未满足的需求。此需求可通过本文和US20110243932中所描述的人源化抗CD40抗体解决,此类抗体特异性结合CD40且展示抗原结合特异性、亲和力和药物动力学和药力学特性,使得其在基于CD40的病症(诸如狼疮性肾炎)的治疗性干预中使用。
发明内容
在一个实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该个体施用包含抗CD40(抗分化簇40)抗体的组合物,
其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ ID NO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ ID NO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ IDNO:25组成的组的轻链CDR3序列;或
其中该抗CD40抗体包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ IDNO:58、SEQ ID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ IDNO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ IDNO:70、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ IDNO:41、SEQ ID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:50、SEQ IDNO:51、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQ ID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ IDNO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36;
其中该组合物包含80mg、120mg、180mg或240mg该抗CD40抗体;
其中包含80mg抗CD40抗体的组合物的单剂量施用产生约888至约1550的Cmax(ngmL-1)、约126至约365的AUC0-tz(μg·h mL-1)或约330至约464的AUC0-inf(μg·h mL-1);或
其中包含120mg抗CD40抗体的组合物的单剂量施用产生约5160至约7210的Cmax(ng mL-1)、约1110至约2010的AUC0-tz(μg·h mL-1)或约1120至约2020的AUC0-inf(μg·hmL-1);或
其中包含180mg抗CD40抗体的组合物的单剂量施用产生约8650至约16300的Cmax(ng mL-1)、约2900至约6380的AUC0-tz(μg·h mL-1)或约2020至约2910的AUC0-inf(μg·hmL-1);或
其中包含240mg抗CD40抗体的组合物的单剂量施用产生约15700至约21300的Cmax(ng mL-1)、约5680至约7750的AUC0-tz(μg·h mL-1)或约5610至约7780的AUC0-inf(μg·hmL-1);或
其中包含240mg抗CD40抗体的组合物的多剂量施用(q1w或每周一次)在第一剂量之后产生约23的Cmax,1(μg mL-1)或在第一剂量之后产生约2600的AUCτ,1(μg·h mL-1);或
其中包含240mg抗CD40抗体的组合物的多剂量施用(q1w或每周一次)在第四剂量的后产生约74之Cmax,4(μg mL-1),或在第四剂量之后产生约49之Cmin,4(μg mL-1),或在第四剂量的后产生约10900的AUCτ,4(μg·h mL-1)。
根据以上实施方案的方法,其中自身免疫性疾病或炎症性疾病选自由以下组成的组:狼疮性肾炎、类风湿性关节炎、多发性硬化症、增生性狼疮性肾丝球肾炎、炎症性肠病(IBD)、牛皮癣、特发性血小板减少性紫癜(ITP)、克罗恩氏病(Crohn's Disease)和系统性红斑狼疮(SLE)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、原发性黏液性水肿、甲状腺中毒症/格雷氏病(Graves disease)、恶性贫血、自身免疫性萎缩性胃炎、自身免疫性心脏炎、爱迪生氏病(Addison's disease)、过早更年期、1型糖尿病、古德帕斯彻综合征(Goodpasture's syndrome)、重症肌无力、自身免疫性溶血性贫血、特发性白血球减少症、原发性胆汁性肝硬化、活动性慢性肝炎(HB Ag阴性)、隐原性肝硬化、干燥综合征(Sjogren'ssyndrome)、皮肌炎、硬皮病、混合结缔组织病、盘状红斑狼疮和系统性脉管炎。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:10的重链CDR1序列、SEQID NO:13的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中该抗体包含SEQ ID NO:19的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:9的重链CDR1序列、SEQ IDNO:14的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中该抗体包含SEQ ID NO:20的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:11的重链CDR1序列、SEQID NO:15的重链CDR2序列和SEQ ID NO:17的重链CDR3序列;且其中该抗体包含SEQ ID NO:21的轻链CDR1序列、SEQ ID NO:23的轻链CDR2序列和SEQ ID NO:25的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含重链可变域和轻链可变区,该重链可变域和轻链可变区分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ IDNO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQID NO:35和SEQ ID NO:31;SEQ ID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;SEQ ID NO:40和SEQ ID NO:36。
根据以上实施方案的方法,其中该抗体包含:包含SEQ ID NO:44的重链可变域和包含SEQ ID NO:43的轻链可变域;或包含SEQ ID NO:53的重链可变域和包含SEQ ID NO:52的轻链可变域;或包含SEQ ID NO:58的重链可变域和包含SEQ ID NO:56的轻链可变域。
根据以上实施方案的方法,其中该抗体包含:包含SEQ ID NO:30的重链序列和包含SEQ ID NO:26的轻链序列;或包含SEQ ID NO:35的重链序列和包含SEQ ID NO:31的轻链序列;或包含SEQ ID NO:40的重链序列和包含SEQ ID NO:36的轻链序列。
根据以上实施方案的方法,其中该自身免疫性疾病或炎症性疾病选自由狼疮性肾炎、移植物对抗宿主疾病、自身免疫性疾病或炎症性疾病和CD40相关病症组成的组。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该个体施用包含抗CD40(抗分化簇40)抗体的组合物,
其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ ID NO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ ID NO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ IDNO:25组成的组的轻链CDR3序列;或
其中该抗CD40包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ ID NO:58、SEQ ID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ IDNO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ IDNO:70、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ IDNO:41、SEQ ID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:50、SEQ IDNO:51、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQ ID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ IDNO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36;
其中该组合物包含120mg或180mg的抗CD40抗体,且其中与安慰剂相比,施用引起该个体中的总SLEDAI-SELENA评分和其分项评分得到改善。
在与方面或实施方案中的任一者相关的实施方案中,与安慰剂相比,施用引起该个体中的总SLEDAI或非肾SLEDAI评分得到改善。在一些实施方案中,在第26周或第52周改善为≥5%。在一些实施方案中,在第26周或第52周,改善为≥10%。
在另一实施方案中,本发明涉及一种测定抗CD40抗体在治疗或预防个体中的自身免疫性疾病或炎症性疾病的治疗功效的方法,该方法包含向该个体施用包含抗CD40抗体的组合物,测量该个体中的经活化的B细胞子集的水平,其中经活化的B细胞子集的水平降低(当比较治疗之前和之后的水平时)指示具有功效。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种减少患有自身免疫性疾病或炎症性疾病的个体中的经活化的B细胞子集的水平的方法,该方法包含向该个体施用包含抗CD40抗体的组合物,其中经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该个体施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物,其中该个体展现(或已经确定展现)经活化的B细胞子集的存在。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含(a)确定该个体展现经活化的B细胞子集的存在(例如通过测试获自个体的生物样品),(b)向该个体施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施例中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该个体施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物,其中已确定该个体展现经活化的B细胞子集的存在。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施例中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
应理解,本文所公开的方法、施用方案和/或给药方案中的任一者,特别是治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法也同样适用于所公开的抗CD40(抗分化簇40)抗体中的任一者在此类方法、施用方案和/或给药方案中的用途:也即如本文所公开的抗CD40抗体,其用于治疗、预防、减少和/或改善所公开的疾病和/或病况。换言之,本发明也提供如本文所公开的抗CD40抗体的用途,其用于制造用于治疗、预防、减少和/或改善所公开的疾病和/或病况中的任一者的药物。
附图说明
附图包括在内以提供对本发明的进一步理解且并入和构成本说明书的一部分,其说明本发明技术的方面且与本说明书一起用以解释本发明的原理。
图1展示在向实施例2的研究1中的中国和日本受试者单剂量施用之后的平均(±SD)BI 655064血浆浓度-时间曲线。s.c.,皮下;SD,标准偏差。上图:带SD的线性刻度。下图:半对数标度。
图2展示在向实施例2的研究2中的中国受试者多剂量施用之后的平均(±SD)BI655064血浆浓度-时间曲线。SD,标准偏差。上图:带SD的线性刻度。下图:半对数标度。
图3展示在向研究1中的中国和日本受试者进行单剂量施用之后和在向实施例2的研究2中的中国受试者进行多剂量施用之后,CD40受体占有率的平均(±SD)抑制。SD,标准偏差。注意:对于研究2,观察到未染色原始资料值下降。CD40受体占有率的抑制的计算基于来自染色对比未染色样品的荧光值比率。因此,在某些情况中,未染色样品的染色强度的较小偏差可对所计算的抑制百分比结果产生较大影响。
图4展示在向实施例2的研究1中的中国和日本受试者单剂量施用之后BI 655064血浆浓度与CD40受体占有率的抑制之间的关系。虚线指示90%抑制。
图5展示实施例3中描述的研究设计。缩写如下:MMF,霉酚酸酯;SLEDAI,系统性红斑狼疮疾病活性指数;PRR,部分肾反应;SoC,标准照护。
图6展示基于来自24小时收集的UP的BI 655064的功效。图A展示在第26周实现CRR的患者的比例。图B展示在第26周时实现CRR或PRR的患者的比例。图C展示在第52周时实现CRR的患者的经调整的比例。图D展示在第52周时实现CRR或PRR的患者的比例。CRR完全肾反应;PRR,部分肾反应;UP,尿蛋白。
图7展示基于来自点尿样液的UP/UC的BI 655064的功效。A.在第52周实现CRR的患者比例。B.在第46周和第52周时实现cCRR的经调整的比例。*事后分析展示在第46周和第52周时实现CRR的患者的模型化比例;在多比较程序和模型化(MCPMod)分析中,选择两个显著模型(p<0.2),sigEmax和指数。CRR,完全肾反应;cCRR,经证实的完全肾反应;PRR,部分肾反应;UP/UC,尿蛋白/尿肌酐比率。
图8展示其他终点的评估。A.实现CRR的时间。B.基于随时间推移相对于基线的点尿样液的UP/UC的中值变化。C.在第26周和第52周总SLEDAI相对于基线的平均变化。D.在第26周和第52周非肾SLEDAI相对于基线的平均变化。SLEDAI,系统性红斑狼疮疾病活性指数。
图9展示CD95+记忆B细胞子集相对于基线的变化。A.在第12周。B.在第26周。*p<0.05BI 240mg相比于安慰剂;**p<0.05BI 240mg和180mg相比于安慰剂。
发明详述
CD40介导的信号传导现识别为涉及多种目标病症。尽管可获得多种临床前资料,展示在这些病症中的干预将为治疗上有益的,但仍需要可用于治疗自身免疫性疾病疾病(诸如狼疮性肾炎)的拮抗性抗CD40抗体。
术语“CD40”和“CD40表面抗原”是指正常和肿瘤性B细胞表面上表达的大约48kD糖蛋白,其充当涉及细胞增殖和分化的信号的受体(Ledbetter等人,1987,J.Immunol.138:788-785)。已自制备自伯基特淋巴瘤细胞株Raji的文库分离编码CD40的cDNA分子(Stamenkovic等人,1989,EMBO J.8:1403)。
如本文所用,内源性表达CD40的细胞是以CD40的表面表达为特征的任何细胞,包括(但不限于)正常和肿瘤性B细胞、并指树突细胞、基底上皮细胞、癌细胞、巨噬细胞、内皮细胞、滤泡性树突状细胞、扁桃体细胞和骨髓衍生的浆细胞。在一些实施方案中,CD40分子是人CD40分子。
本发明的抗体特异性结合于人重组和天然CD40。一种人源化单克隆抗体,其中所述抗体特异性结合于拮抗活性IC50小于1nM的人CD40且在B细胞增殖中不具有高达100μg/ml的激动作用,且其中所述抗体的特征进一步在于该抗体在非人类灵长类动物中的体内半衰期为至少10天。
抗体或免疫球蛋白的通用结构是本领域技术人员所熟知的,这些分子是通常约150,000道尔顿的由两个相同轻(L)链和两个相同重(H)链构成的异源四聚糖蛋白。每一轻链通过一个二硫键共价连接至重链以形成异源二聚体,且异源三聚体分子经由异源二聚体的两个相同重链之间的共价二硫键形成。虽然所述轻链和重链通过一个二硫键连接于一起,但两个重链之间的二硫键数目随免疫球蛋白同种型而变化。每一重链和轻链还具有有规律地间隔的链内二硫桥键。每一重链在氨基端具有可变域(VH),之后为三个或四个恒定域(CH1、CH2、CH3和CH4)以及CH1与CH2之间的铰链区。每一轻链具有两个域:氨基端可变域(VL)和羧基端恒定域(CL)。VL域非共价缔合VH域,然而CL域通常经由二硫键共价连接至CH1域。认为特定氨基酸残基在轻链可变域与重链可变域之间形成界面(Chothia等人,1985,J.Mol.Biol.186:651-663)。
也即,不同抗体之间极不同的可变域内的某些域为“高可变的”。这些高可变域含有直接参与各特定抗体与其特异性抗原决定簇的结合和特异性的残基。轻链与重链可变域中的高可变性集中于三个称为互补决定区(CDR)或高可变环(HVL)的区段中。CDR通过序列比较定义,Kabat等人,1991,Sequences of Proteins of Immunological Interest,第5版,公共卫生处(Public Health Service),美国国家卫生研究院(National Institutesof Health),Bethesda,Md.,然而HVL在结构上根据可变域的三维结构定义,如Chothia和Lesk,1987,J.Mol.Biol.196:901-917所描述。在这两种方法产生CDR的略不同标识的情况下,结构性定义是优选的。如Kabat所定义的,在轻链可变域中,CDR-L1位于约残基24-34处,CDR-L2位于约残基50-56处,且CDR-L3位于约残基89-97处;在重链可变域中,CDR-H1位于约残基31-35处,CDR-H2位于约残基50-65处,且CDR-H3位于约残基95-102处。因此,重链和轻链的CDR1、CDR2、CDR3定义对既定抗体具有特异性的特有和功能特性。
重链和轻链中的每一者中的三个CDR通过框架区(FR)分隔开,其含有趋向于较不可变的序列。自重链可变域和轻链可变域的氨基端至羧基端,FR和CDR按以下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。FR的主要β片层使各链内的CDR彼此紧密靠近以及紧密靠近来自另一链的CDR。所得构形有助于抗原结合位点(参见Kabat等人,1991,NIH公开案第91-3242号,第I卷,第647-669页),但并非所有CDR残基必需直接参与抗原结合。
FR残基和Ig恒定域不直接参与抗原结合,但有助于抗原结合和/或介导抗体效应功能。认为一些FR残基以至少三种方式对抗原结合产生显著作用:非共价直接结合于表位、与一或多个CDR残基相互作用和影响重链与轻链之间的界面。恒定域不直接参与抗原结合,但介导各种Ig效应功能,诸如抗体参与抗体依赖性细胞毒性(ADCC)、补体依赖性细胞毒性(CDC)和抗体依赖性细胞吞噬(ADCP)。
脊椎动物免疫球蛋白的轻链基于恒定域的氨基酸序列而归属于两个明确不同的类别(κ)和(λ)中的一者。通过比较,根据恒定域的序列将哺乳动物免疫球蛋白的重链分配至五个主要类别中的一者:IgA、IgD、IgE、IgG和IgM。IgG和IgA进一步划分成子类(同种型),例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。对应于不同类别的免疫球蛋白的重链恒定域分别称为α、δ、ε、γ和μ。这些类别的天然免疫球蛋白的亚基结构和三维构型是本领域熟知的。
术语“抗体”、“抗CD40抗体”、“人源化抗CD40抗体”和“变体人源化抗CD40抗体”在本文中以最广义使用且具体地涵盖单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体(例如,双特异性抗体)和抗体片段,诸如抗体的展现所需生物活性(例如CD40结合)的可变域和其他部分。
术语“单克隆抗体”(mAb)是指大体上同质的抗体群体中的抗体;也即,该群体中的单个抗体相同,但其中可能存在少量天然产生的突变。单克隆抗体针对单一抗原决定簇“表位”具有高度特异性。因此,修饰语“单克隆”指示针对相同表位的大体上同质的抗体群,且不应视为需要通过任何特定方法来产生该抗体。应理解单克隆抗体可通过本领域中已知的任何技术或方法制得;包括例如杂交瘤方法(Kohler等人,1975,Nature 256:495)、或本领域中已知的重组DNA方法(参见例如美国专利好4,816,567)、或使用Clackson等人,1991,Nature 352:624-628和Marks等人,1991,J.Mol.Biol.222:581-597中所描述的技术使用噬菌体抗体文库分离以重组方式产生的单克隆的方法。
人源化抗CD40抗体可选自免疫球蛋白的任何类别,包括IgM、IgG、IgD、IgA和IgE,和任何同种型,包括IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。例如,恒定域可为补体固定恒定域,其中需要人源化抗体展现细胞毒活性且同种型通常为IgG1。在不需要此类细胞毒活性的情况下,恒定域可具有另一同种型,例如IgG2。替代性人源化抗CD40抗体可包含来自超过一个免疫球蛋白类别或同种型的序列,且选择特定恒定域以使所需效应子功能达到最佳在本领域技术人员的能力范围之内。在特定实施方案中,本发明提供作为IgG1抗体,且更具体地是敲除效应子功能的IgG1抗体的抗体。
人源化抗CD40抗体的FR和CDR或HVL无需与亲本序列精确对应。例如,导入CDR或HVL或共有或种系FR序列中的一或多个残基可通过取代、插入或缺失改变(例如突变诱发),使得所得氨基酸残基不再与任一亲本序列中对应位置中的原始残基一致,但抗体仍然保留与CD40结合的功能。此类改变通常并非大范围的且将为保守性改变。通常,至少75%的人源化抗体残基将与亲本共有或种系FR和导入CDR序列的残基对应,更通常至少90%,且最通常大于95%、或大于98%或大于99%。
影响重链可变区与轻链可变区之间的界面(“VL-VH界面”)的免疫球蛋白残基为影响两个链相对于彼此的接近度或定位的残基。可参与链间相互作用的某些残基包括VL残基34、36、38、44、46、87、89、91、96和98和VH残基35、37、39、45、47、91、93、95、100和103(利用Kabat等人,Sequences of Proteins of Immunological Interest(美国国家卫生研究院,Bethesda,Md.,1987)中所述的编号系统)。美国专利号6,407,213也讨论了诸如VL残基43和85和VH残基43和60的残基也可参与此相互作用。虽然这些残基仅针对于人类IgG指示,但其在物种间均适用。选择合理预期参与链间相互作用的重要抗体残基,用于取代至共有序列中。
术语“共有序列”和“共同抗体”是指在任何特定类别、同种型或亚基结构的所有免疫球蛋白中的各位置,例如人免疫球蛋白可变域包含最通常出现的氨基酸残基的氨基酸序列。共有序列可基于特定物种或许多物种的免疫球蛋白。应理解,“共有”序列、结构或抗体涵盖如某些实施方案中所描述的共有人类序列,且是指在任何特定类别、同种型或亚基结构的所有人类免疫球蛋白中的各位置包含最通常出现的氨基酸残基的氨基酸序列。因此,共有序列含有在各位置具有存在于一或多个已知免疫球蛋白中的氨基酸的氨基酸序列,但其不可精确重复任何单一免疫球蛋白的全部氨基酸序列。可变区共有序列不是从任何天然产生的抗体或免疫球蛋白获得的。Kabat等人,1991,Sequences of ProteinsofImmunological Interest,第5版.公共卫生处,National Institutes of Health,Bethesda,Md,和其变异体。重链和轻链共有序列的FR和其变体提供适用于制备人源化抗CD40抗体的序列。参见例如美国专利号6,037,454和6,054,297。
人类种系序列自然地发现于人类群体中。这些种系基因的组合产生抗体多样性。抗体的轻链的种系抗体序列来自保守人类种系κ或λv基因和j基因。类似地,重链序列来自种系v基因、d基因和j基因(LeFranc,M-P和LeFranc,G,“The Immunoglobulin Facts Book”Academic Press,2001)。
“经分离的”抗体是已自其天然环境的成分鉴别出且分离和/或回收的抗体。抗体的天然环境的污染物成分为可干扰抗体的诊断或治疗用途的那些物质,且可为酶、激素和其他蛋白性或非蛋白性溶质。在一个方面中,将抗体纯化至按抗体的重量计的至少大于95%分离。
分离的抗体包括重组细胞内的重组细胞产生的原位抗体,由于抗体的天然环境的至少一种成分将不存在。然而,经分离的抗体通常将通过至少一个纯化步骤制备,在该步骤中去除重组细胞物质。
术语“抗体效能”是指有助于抗原的抗体识别的因素或抗体的体内有效性。抗体的氨基酸序列的变化可影响抗体特性诸如折叠,且可影响物理因素,诸如抗体结合于抗原的初始速率(ka)、抗体自抗原的解离常数(kd)、抗体对于抗原的亲和力常数(Kd)、抗体的构型、蛋白质稳定性和抗体的半衰期。
抗体也可与前药结合。“前药”为医药学上活性物质的前体细胞或衍生物形式,相较于亲本药物,其对肿瘤细胞具有较少细胞毒性且能够以酶方式活化或转化成活性更高的形式。参见例如Wilman,1986年,“Prodrugs in Cancer Chemotherapy”,BiochemicalSociety Transactions,14,第375-382页,第615版Meeting Belfast和Stella等人,1985,“Prodrugs:A Chemical Approach to Targeted Drug Delivery”,Directed DrugDelivery,Borchardt等人(编),第247-267页,Humana Press。
出于诊断以及治疗性监测目的,用于本发明方法中的抗体也可与标记(单独标记或标记和其他第二药剂(前药和其类似物))结合。区别于其他第二药剂的标记是指作为可检测化合物或组合物且其可直接或间接结合于本发明的人源化抗体的药剂。标记本身可为单独可检测的(例如放射性同位素标记或荧光标记),或在酶标记的情况下,可催化底物化合物或组合物发生可检测的化学变化。经标记的人源化抗CD40抗体可经制备且用于各种应用中,包括体外和体内诊断。
用于本发明的方法中的抗体可配制为脂质体制剂的一部分,以便实现其体内递送。“脂质体”为由各种类型的脂质、磷脂和/或表面活性剂构成的小囊泡。脂质体适用于向哺乳动物递送化合物或配制剂,诸如本文所公开的人源化抗CD40抗体,任选地与一或多种药物活性剂和/或标记偶联或组合。脂质体的组分通常配置为双层形式,类似于生物膜的脂质配置。
出于治疗的目的,术语“哺乳动物”是指归类为哺乳动物的任何动物,包括人类、家畜与农畜和动物园、竞技或宠物动物,诸如狗、马、猫、奶牛和其类似动物。哺乳动物较佳为人类。
如本文所用,“病症”是受益于用本文所描述的人源化抗CD40抗体治疗的任何病况。此病况包括慢性和急性病症或疾病,包括使哺乳动物易患所讨论的病症的那些病理病况。本文中欲治疗的非限制性实例或病症包括癌症、血液恶性病、良性和恶性肿瘤、白血病和淋巴样恶性病以及炎症、血管生成、自身免疫性疾病和免疫病症。
术语“癌症”和“癌性”是指或描述哺乳动物中典型地以不受调节的细胞生长为特征的生理病况。癌症的实例包括但不限于癌瘤、淋巴瘤、母细胞瘤、肉瘤和白血病。
如本文所用,术语“CD40相关病症”或“CD40相关疾病”是指指示表达CD40的细胞的修饰或排除的病况。这些细胞包括表达CD40的细胞,其展现与癌性或恶性生长相关的异常增殖或表达CD40的细胞。展现CD40抗原的异常表达的癌症的更特定实例包括B成淋巴样细胞、伯基特氏淋巴瘤(Burkitt's lymphoma)、多发性骨髓瘤、T细胞淋巴瘤、卡波西氏肉瘤(Kaposi's sarcoma)、骨肉瘤、表皮和内皮肿瘤、胰脏癌、肺癌、乳腺癌、卵巢癌、结肠癌、前列腺癌、头颈癌、皮肤(黑色素瘤)癌、膀胱癌和肾癌。此类病症包括但不限于白血病、淋巴瘤(包括B细胞淋巴瘤和非霍奇金氏淋巴瘤)、多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom's macroglobulinemia);实体肿瘤,包括肉瘤,诸如骨肉瘤、尤文氏肉瘤(Ewing's sarcoma)、恶性黑色素瘤、腺癌(包括卵巢腺癌)、卡波西氏肉瘤/卡堡氏卡波西氏肿瘤和鳞状细胞癌。
CD40相关病症也包括免疫系统的疾病和病症,诸如自身免疫性病症和炎症性病症。此类病况包括但不限于狼疮性肾炎、类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、硬皮病、干燥综合征、多发性硬化症、牛皮癣、炎症性肠病(例如溃疡性结肠炎和克罗恩氏病)、肺炎、哮喘和特发性血小板减少性紫癜(ITP)。
当在本文中使用时,短语“阻止生长”或“生长抑制”是指抑制细胞生长,尤其表达CD40抗原的肿瘤性细胞类型的生长或增殖。因此,生长抑制例如显著降低S期中肿瘤性细胞百分比。
术语“静脉内输注”是指在超过大约15分钟的一段时间内将药剂导入至动物或人类患者的静脉中,该段时间通常介于大约30至90分钟之间。
术语“静脉内快速注射”或“静脉内推注”是指将药物施用动物或人类的静脉中,使得身体在大约15分钟或更短,一般5分钟或更短时间内接受药物。
术语“皮下施用”是指通过自药物容器相对缓慢的持续递送将药剂引入动物或人类患者的皮肤下,优选为皮肤与皮下组织之间的凹穴内。捏起或拉起皮肤且远离皮下组织可产生凹穴。
术语“皮下输注”是指将药物通过自药物容器相对缓慢的持续递送而引入至动物或人类患者的皮肤下,优选为皮肤与下层组织之间的凹穴内,维持包括(但不限于)30分钟或更少、或90分钟或更少的一段时间。任选地,输注可通过皮下植入植入动物或人类患者的皮肤下的药物递送泵制得,其中该泵递送预定量的药物维持预定时段,诸如30分钟、90分钟或跨越治疗方案长度的时段。
术语“皮下推注”是指动物或人类患者的皮肤下方的药物施用,其中推注药物递送小于大约15分钟;在另一方面中,小于5分钟,且在又一方面中,小于60秒。在甚至又一方面中,施用是在皮肤与下层组织之间的凹穴内,其中凹穴可通过捏起或拉起皮肤且远离下层组织而产生。
术语“治疗有效量”用以指缓解或改善所治疗病症的症状中之一或多者的活性剂的量。借此,其为具有有益患者结果,例如生长停滞作用或导致细胞缺失的量。在一方面中,治疗有效量具有细胞凋亡活性,或能够诱导细胞死亡。在另一方面中,治疗有效量是指显示为有效例如减缓疾病进展的目标血清浓度。功效可视待治疗的病况而定以常规方式测量。例如,在以表达CD40的细胞为特征的肿瘤性疾病或病症中,可通过评定疾病进展时间或确定反应率来测量功效。
如本文所用,术语“治疗”和“疗法”和其类似术语意指包括疾病或病症的治疗以及预防,或遏制措施,从而产生任何临床上需要或有益的作用,包括(但不限于)缓解或减轻一或多种症状、消退、减缓或停止疾病或病症的进展。因此,例如,术语治疗包括在疾病或病症的症状发作之前或之后施用药剂,由此预防或移除疾病或病症的一或多种病征。作为另一实例,术语包括在疾病的临床表现之后施用药剂,以对抗疾病的症状。此外,在施用影响疾病或病症的临床参数,诸如组织损伤程度或癌转移的量或程度的情况下,无论治疗是否引起疾病得到改善,在发作之后和已产生临床症状之后施用药剂包含如本文所使用的“治疗”或“疗法”。另外,只要与在不存在使用人源化CD40抗体组合物的情况下的症状相比,单独或与另一治疗剂组合的本发明的组合物减轻或改善所治疗的病症的至少一种症状,则结果应视为对潜在病症的有效治疗,而与病症的所有症状是否得到减轻无关。
术语“包装插页”用以指治疗产品的商业包装中通常包括的包装,其含有关于适应症、用法、施用、禁忌和/或关于使用此类治疗产品的警告的信息。
抗体
人源化抗CD40抗体和结合剂可用于治疗和/或预防以表达CD40表面抗原(诸如狼疮性肾炎)的细胞的增殖为特征的多种疾病或病症。人源化抗CD40抗体和CD40结合剂各包括至少一部分,其特异性识别CD40表位(即,抗原结合片段)。
制造抗CD40抗体的方法先前已描述于US20110243932中,其全部内容以引用的方式并入本文中。
如先前US20110243932中所描述,基于CD40结合表征选择初始表征鼠类抗体。
自这些初始研究,选择具有表1中所示的以下重链可变区和表2中所示的轻链可变区的鼠类抗体:
表1:CD40鼠类前导序列-VH序列
表2:CD40鼠类前导序列-VK序列
基于框架同源性、CDR结构、保守性典型残基、保守性界面填充残基和其他参数针对小鼠前导序列中的每一者选择人类框架序列。
所选各种鼠类抗体的鼠类重链和轻链CDR分别展示于表3和表4中:
表3:重链CDR序列
上文所列的H-CDR1是使用Chothia编号系统的序列(Al-Lazikani等人,(1997)JMB273,927-948)。序列的Kabat编号由粗体斜体文字表示且IMGT编号由上文表中CDR1和CDR2的残基的带下划线的文字展示。2H11、10F2和19B10中的每一者的H-CDR3的序列为TTSYYVGTYGY(SEQ ID NO:77)且20E2为ARQDGYRYAMDY(SEQ ID NO:78)。
表4:
轻链CDR序列
此外,Chothia编号系统用于表4,其中序列的Kabat编号由粗体、斜体文字表示,且IMGT编号由带下划线的文字展示。
选择相较于嵌合亲本Fab展示较佳或相等结合的Fab来转化为IgG。来自20E2系列的克隆转化为两种不同IgG型式:a)IgG4DM(双重突变体)在Fc/铰链区中具有两种突变,减少半分子形成的Ser228Pro和进一步减少FcγR结合的Leu235Glu。b)IgG1KO(效应子功能的敲除)在Fc区中具有两种突变,Leu234Ala和Leu235Ala,其减少效应子功能,诸如FcγR和补体结合。两种IgG型式均描述于文献中。实施例1进一步详细描述三个候选物的人源化。此类人源化的结果产生人源化抗体序列,其具有下文所示的重链和轻链序列:
在一些实施方案中,抗原结合片段可例如阻断增殖或以其他方式阻止细胞生长,或例如经由结合CD40表面抗原而引起其耗竭、死亡或以其他方式其缺失。例如,在T和B细胞恶性病中,当恶性细胞暴露于导致正常淋巴细胞活化的刺激时,通常导致抗肿瘤作用(例如生长停滞,伴随或不伴随细胞缺失或细胞凋亡)。已经由抗原受体或共刺激受体用信号观察到此活化诱导的生长停滞(参见例如Ashwell等人,1987,Science 237:61;Bridges等人.,1987,J.Immunol.139:4242;Page和Defranco,1988,J.Immunol.140:3717;和Beckwith等人.,1990,J.Natl.Cancer Inst.82:501)。由于抗体或可溶性配体特异性结合,CD40刺激抑制B细胞淋巴瘤生长(参见例如Funakoshi等人,1994,Blood 83:2787-2794)。以此方式抑制恶性细胞生长且针对CD40表面抗原的药剂为合适药剂的实例。
CD40特异性药剂包括与CD40(例如人类CD40或其变体)结合的人源化抗CD40抗体的抗原结合片段。CD40特异性药剂和抗体可任选地与细胞毒性剂或化学治疗剂结合或融合。在人源化抗体结合至CD40表面抗原且造成表达CD40的细胞类型耗竭的方面中,结合一般特征为在体内归巢CD40表面抗原细胞。适合的结合剂以足够的亲和力和/或亲合力结合CD40抗原,使得CD40特异性药剂通过特异性靶向表达该抗原的细胞而适用作治疗剂。
在一些方面中,人源化抗体使CD40配体与CD40的结合减少至少45%、至少50%、至少60%或至少75%或至少80%或至少90%或至少95%。
在一些实施方案中,人源化抗CD40抗体,包括其抗原结合片段,诸如重链和轻链可变域,包含上文所描述的衍生自CDR抗体A(重链序列=SEQ ID NO:27;SEQ ID NO:28;SEQID NO:29或SEQ ID NO:30;轻链序列=SEQ ID NO:26),抗体B(重链序列=SEQ ID NO:32;SEQ ID NO:33;SEQ ID NO:34;或SEQ ID NO:35;轻链序列=SEQ ID NO:31)和抗体C(重链序列=SEQ ID NO:37;SEQ ID NO:38;SEQ ID NO:39或SEQ ID NO:40;轻链序列=SEQ IDNO:36;)的氨基酸序列残基和衍生自人类免疫球蛋白框架区的氨基酸残基。人源化抗CD40抗体任选地包括共同或种系框架区中的特异性氨基酸取代。
相对于通过将CDR或HVL“直接交换”至人类种系框架区中所形成的人源化抗体中所展现的效能,这些框架位置处的氨基酸残基的特异性取代可改善抗体效能的各个方面,包括结合亲和力和/或稳定性,如以下实例中所示。
在一些实施方案中,本发明描述具有SEQ ID NO:1至SEQ ID NO:4的重链(VH)序列和SEQ ID NO:5至SEQ ID NO:8的轻链(VL)序列的其他单克隆抗体(参见上表1和2)。这些鼠类抗体的CDR序列展示于表3和表4中,将此类CDR置放于人类共同重链和轻链可变域的FR中将产生本发明的适用人源化抗体。
在一些特异性实施方案中,本文所公开的人源化抗CD40抗体至少包含重链或轻链可变域,该重链或轻链可变域包含如表1至4中所示的鼠类单克隆抗体的CDR或HVL和人类种系重链和轻链可变域的FR。在例示性实施方案中,本文中产生的人源化抗体为:抗体A、抗体B和抗体C和其各种重链和轻链序列展示于SEQ ID NO 26至SEQ ID NO:40中。
在特定实施方案中,涵盖具有SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29或SEQID NO:30中的任一者的重链序列以及SEQ ID NO:26的轻链序列的抗体。替代抗体包括具有SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34或SEQ ID NO:35的重链序列以及SEQ ID NO:31的轻链序列的那些抗体。在其他实施方案中,提供具有SEQ ID NO:37、SEQ ID NO:38、SEQID NO:39或SEQ ID NO:40的重链序列以及SEQ ID NO:36的轻链序列的人源化抗体。
这些序列的CDR展示于表3和表4中。在特定实施方案中,预期在这些示例性免疫球蛋白之间具有转换的CDR区的嵌合抗体(即,例如切换抗体A的一或两个CDR与来自抗体C的类似CDR)可产生有用抗体。
在某些实施方案中,人源化抗CD40抗体为抗体片段。各种抗体片段已在上文进行一般论述且存在已研发用于产生抗体片段的技术。片段可经由完整抗体的蛋白分解消化衍生(参见例如Morimoto等人,1992,Journal of Biochemical and Biophysical Methods24:107-117;和Brennan等人,1985,Science 229:81)。替代地,片段可在重组宿主细胞中直接产生。例如,Fab'-SH片段可自大肠杆菌中直接回收且以化学方式偶合以形成F(ab')2片段(参见例如Carter等人,1992,Bio/Technology 10:163-167)。通过另一方法,F(ab')2片段可自重组宿主细胞培养物直接分离。用于产生抗体片段的其他技术对于本领域技术人员将是显而易知的。
某些实施方案包括人源化抗CD40抗体的F(ab')2片段,其包含SEQ ID NO:27、SEQID NO:28、SEQ ID NO:29或SEQ ID NO:30中的任一者的重链序列以及SEQ ID NO:26的轻链序列。替代抗体包括具有SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34或SEQ ID NO:35的重链序列以及SEQ ID NO:31的轻链序列的那些抗体。在其他实施方案中,提供具有SEQ IDNO:37、SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40的重链序列以及SEQ ID NO:36的轻链序列的人源化抗体。此类实施方案可包括包含此类F(ab')2的完整抗体。
在一些实施方案中,抗体或抗体片段包括介导效应子功能的恒定区。恒定区可针对表达CD40的靶细胞提供抗体依赖性细胞毒性(ADCC)、抗体依赖性细胞吞噬(ADCP)和/或补体依赖性细胞毒性(CDC)反应。效应子域可为例如Ig分子的Fc区。通常,CD40结合剂募集和/或活化细胞毒性白血球(例如自然杀伤(NK)细胞、吞噬细胞(例如巨噬细胞)和/或血清补体成分)。
抗体的效应子结构域可来自任何适合的脊椎动物物种和同型。来自不同动物物种的同型的不同之处在于介导效应子功能的能力。例如,人类免疫球蛋白介导CDC和ADCC/ADCP的能力一般分别按IgM≈IgG1≈IgG3>IgG2>IgG4和IgG1≈IgG3>IgG2/IgM/IgG4次序。鼠类免疫球蛋白一般分别按鼠类IgM≈IgG3>>IgG2b>IgG2a>>IgG1和IgG2b>IgG2a>IgG1>>IgG3次序介导CDC和ADCC/ADCP。在另一实例中,鼠类IgG2a介导ADCC,而鼠类IgG2a和IgM介导CDC。
抗体修饰
人源化抗CD40抗体和药剂可包括人源化抗CD40抗体或其抗原结合片段的修饰。
人源化抗CD40抗体的结合物可使用多种双功能蛋白质偶合剂来制得,诸如N-丁二酰亚胺基-3-(2-吡啶基二硫醇)丙酸酯(SPDP)、亚胺基硫杂环戊烷(IT)、酰亚胺酯的双功能衍生物(诸如己二酰亚胺酸二甲酯HCl)、活性酯(诸如辛二酸二丁二酰亚胺酯)、醛(诸如戊二醛)、双叠氮基化合物(诸如双(对叠氮基苯甲酰基)己二胺)、双重氮化合物衍生物(诸如双-(对重氮鎓苯甲酰基)-乙二胺)、二异氰酸酯(诸如2,6-二异氰酸甲苯酯)和双活性氟化合物(诸如1,5-二氟-2,4-二硝基苯)。例如,蓖麻毒素免疫毒素可如Vitetta等人,1987,Science238:1098中所描述来制备。碳14标记的1-异硫氰基苯甲基-3-甲基二伸乙三胺五乙酸(MX-DTPA)为用于使放射性核苷酸与抗体结合的例示性螯合剂。结合物也可由可裂解接头形成。
本文所公开的人源化抗CD40抗体也可配制成免疫脂质体。含有抗体的脂质体系通过本领域中已知的方法制备,诸如Epstein等人,1985,Proc.Natl.Acad.Sci.USA 82:3688;Hwang等人.,1980,Proc.Natl.Acad.Sci.USA 77:4030;和美国专利第4,485,045号和第4,544,545号中所描述。具有增强循环时间的脂质体揭示于例如美国专利第5,013,556号。
特别适用的脂质体可通过逆相蒸发法而利用包含磷脂酰胆碱、胆固醇和经PEG衍生的磷脂酰乙醇胺(PEG-PE)的脂质组合物产生。脂质体经由孔径经限定的过滤器挤出以产生具有所需直径的脂质体。本文所公开的抗体的Fab'片段可经由二硫键互换反应与脂质体结合,如Martin等人,1982,J.Biol.Chem.257:286-288中所描述。
在其他实施方案中,也包括人源化抗CD40抗体的共价修饰。共价修饰包括半胱氨酰基残基、组氨酰基残基、赖氨酰基和氨基端残基、精氨酰基残基、酪氨酰基残基、羧基侧基(天冬氨酰基或谷氨酰基)、谷酰氨酰基和天冬酰氨酰基残基、或丝氨酰基、或苏氨酰基残基的修饰。另一类型的共价修饰涉及以化学方式或酶促方式将糖苷偶联至抗体。若适用,则此类修饰可通过抗体的化学合成或通过酶促或化学裂解进行。抗体的其他类型的共价修饰通过使抗体的靶向氨基酸残基与能够与所选侧链或氨基端或羧基端残基反应的有机衍生药剂反应而引入至分子中。
存在于抗体上的任何碳水化合物部分的移除可以化学方式或酶促方式实现。化学去糖基化由Hakimuddin等人,1987,Arch.Biochem.Biophys.259:52和Edge等人,1981,Anal.Biochem.118:131描述。抗体上糖类部分的酶促裂解可通过使用如由Thotakura等人,1987,Meth.Enzymol 138:350所描述的各种内切糖苷酶和外切糖苷酶来实现。
另一类型的适用共价修饰包含以美国专利号4,640,835、美国专利号4,496,689、美国专利号4,301,144、美国专利号4,670,417、美国专利号4,791,192和美国专利号4,179,337中之一或多者中所阐述的方式使抗体连接至各种非蛋白质聚合物中之一者,例如聚乙二醇、聚丙二醇或聚氧化烯。
人源化和氨基酸序列变体
抗CD40抗体的氨基酸序列变体可通过将适当核苷酸变化引入至抗CD40抗体DNA中或通过肽合成来制备。此类变体包括例如缺失本文实施例中的抗CD40抗体的氨基酸序列内的残基和/或插入这些残基中和/或取代这些残基。进行缺失、插入和取代的任何组合以获得最终构建体,其限制条件为该最终构建体拥有所需的特征。氨基酸变化也可改变人源化或变体抗CD40抗体的翻译后加工,诸如改变糖基化位点的数目或位置。
一种适用于鉴别抗CD40抗体的作为突变诱发的优选的位置的某些残基或区的方法称作“丙氨酸扫描突变诱发”,如Cunningham和Wells(Science,244:1081-1085(1989))所描述。此处,鉴别出残基或目标残基组(例如带电残基,诸如arg、asp、his、lys和glu),且经中性或带负电荷的氨基酸(通常为丙氨酸)置换以影响氨基酸与CD40抗原的相互作用。然后,通过在取代位点处或为取代位点引入另外的或其他变体来优化对取代表现出功能敏感性的氨基酸位置。因此,虽然用于引入氨基酸序列变异的位点为预先确定的,但突变本身的性质无需预先确定。例如,为分析给定位点的突变的效能,可在目标密码子或目标区进行丙氨酸扫描或随机突变诱发,且针对所需活性筛选所表达的抗CD40抗体变体。
氨基酸序列插入包括长度在一个残基至含有一百个或更多个残基的多肽范围内的氨基末端和/或羧基末端融合,以及单个或多个氨基酸残基的序列内插入。末端插入的实例包括与表位标签融合的抗CD40抗体。抗CD40抗体分子的其他插入变体包括抗CD40抗体的N端或C端与酶或延长抗体的血清半衰期的多肽的融合体。
另一类型的变体为氨基酸取代变体。这些变体在抗CD40抗体分子中移除至少一个氨基酸残基且在其位置插入不同残基。取代型突变诱发的最相关位点包括高可变区,但也考虑FR变化。保守取代以标题“优选的取代”示于表5中。若此类取代导致生物活性变化,则可引入命名为“示例性取代”或如下文关于氨基酸类别所进一步描述的更多实质性变化,且筛选产物。
表5:
在蛋白质化学中,一般可接受的是,抗体的生物特性可通过选择在其作用方面显著不同的取代基来实现,该取代作用是维持(a)取代区域中的多肽主链的结构,例如片层或螺旋状构型;(b)分子在靶位点处的电荷或疏水性;或(c)侧链的主体。基于常见侧链特性,将天然存在的残基划分成下组:
(1)疏水性:正亮氨酸、met、ala、val、leu、ile;
(2)中性亲水性:cys、ser、thr;
(3)酸性:asp、glu;
(4)碱性:asn、gin、his、lys、arg;
(5)影响链取向的残基:gly、pro;和
(6)芳族:trp、tyr、Phe。
非保守取代将引起这些类别中之一者的成员换成另一个类别。
不参与维持人源化或变体抗CD40抗体的适当构型的任何半胱氨酸残基一般也可经丝氨酸取代,以改善分子的氧化稳定性,防止异常交联,或提供与目标化合物的已确立结合点。反之,可将半胱氨酸键添加至抗体以改善其稳定性(尤其在抗体为诸如Fv片段的抗体片段的情况下)。
一种类型的取代型变体涉及取代亲本抗体(例如人源化或人类抗体)的一或多个高可变区残基。一般而言,经选择用于进一步研发的所得变体应相对于产生其的亲本抗体具有经改善的生物特性。产生此类取代型变体的适宜方式为用噬菌体呈现的亲和力成熟。简言之,使若干高可变区位点(例如6-7个位点)突变以在各位点处产生所有可能的氨基酸取代。因此产生的抗体变体以单价方式自丝状噬菌体粒子以与包装在各粒子内的M13的基因III产物的融合物形式呈现。然后,针对噬菌体呈现变体的生物活性(例如结合亲和力)对其进行筛选。为了鉴别用于修饰的候选高可变区位点,可进行丙氨酸扫描突变诱发以鉴别显著有助于抗原结合的高可变区残基。可选地或另外,其可有益于分析抗原-抗体复合物的晶体结构以鉴别抗体与人类CD40之间的接触点。此类接触残基和相邻残基为根据本文中详述的技术用于取代的候选物。在产生这些变体后,如本文所描述对变体组进行筛选,且可在一或多个相关分析中选择具有优良特性的抗体用于进一步研发。
抗体的另一类型的氨基酸变体改变抗体的原始糖基化模式。“改变”意指使抗体中发现的一或多个糖类部分缺失,和/或添加不存在于抗体中的一或多个糖基化位点。
在一些实施方案中,可能需要修饰本发明的抗体以添加糖基化位点。抗体的糖基化通常为N连接型或O连接型。N连接型是指糖类部分与天冬酰胺残基的侧链连接。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸,其中X为除脯氨酸以外的任何氨基酸,为用于糖类部分与天冬酰胺侧链的酶促连接的识别序列。因此,在多肽中这些三肽序列中的任一者的存在产生潜在糖基化位点。O连接型糖基化是指糖N-乙酰基半乳胺糖、半乳糖或木糖中的一者与羟氨基酸,最通常丝氨酸或苏氨酸连接,但也可使用5-羟脯氨酸或5-羟赖氨酸。因此,为了使给定蛋白质(例如抗体)糖基化,蛋白质的氨基酸序列经工程改造以含有上文所描述的三肽序列中的一或多者(针对N连接糖基化位点)。也可通过向原始抗体的序列添加一或多个丝氨酸或苏氨酸残基或用这些残基取代原始抗体的序列来进行改变(针对O连接糖基化位点)。
编码抗CD40抗体的氨基酸序列变体的核酸分子通过本领域中已知的多种方法制备。这些方法包括(但不限于)自天然来源(在天然存在的氨基酸序列变体的情况下)分离或通过寡核苷酸介导的(或定点)突变诱发、PCR突变诱发和先前制备的抗CD40抗体的变体或非变体版本的盒突变诱发制备。
治疗用途
人源化抗CD40抗体或药剂通过任何适合的方式施用,包括肠胃外、皮下、腹膜内、肺内和鼻内,且针对局部免疫抑制治疗视需要包括病灶内施用(包括灌注或在移植之前以其他方式使移植物与抗体接触)。人源化抗CD40抗体或药剂可以例如以输注形式或以推注形式施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内或皮下施用。此外,人源化抗CD40抗体适合通过脉冲输注施用,特别地,在抗体剂量递减的情况下施用。在一个方面中,部分视施用的短期或长期性而定,通过注射,最优选为静脉内或皮下注射给药。
对于疾病的预防或治疗,抗体的适当剂量将视各种因素而定,这些因素施诸如如上文所定义的待治疗的疾病的类型、疾病的严重度和时程、否为预防或治疗目的而施用抗体、先前疗法、患者的临床病史和对抗体的反应和主治医师的判断。一次性或历经一系列治疗适合地向患者施用该抗体。
视疾病的类型和严重度而定,约1μg/kg至20mg/kg(例如0.1-15mg/kg)抗体为向患者施用的初始候选剂量,不论例如通过一或多次分开施用或通过连续输注。典型的每日剂量可在约1μg/kg至100mg/kg或更多范围内,视上文所提及的因素而定。对于历经数天或更长时间的重复施用,视病况而定,持续治疗直至出现疾病症况的所需抑制为止。然而,其他给药方案可为适用的。此疗法的进展易于通过常规技术手段和测定法来监测。示例性给药方案为WO94/04188中所公开的给药方案。
术语“抑制”在本文中在与“改善”和“缓解”相同的情形下使用,意指减轻疾病的一或多个特征。
抗体组合物将以与良好医学实践一致的方式配制、给药和施用。在此情形下考虑的因素包括所治疗的特定病症、所治疗的特定哺乳动物、个别患者的临床病况、病症起因、药剂的递送部位、施用方法、施用时间表和医学从业者已知的其他因素。待施用抗体的“治疗有效量”将通过此类考虑因素控管,且是预防、改善或治疗与CD40表达相关的病症所需的最少量。
抗体并非必须,而是任选地与一或多种当前用于预防或治疗所讨论病症的药剂一起配制。此类其他药剂的有效量视存在于配制剂中的人源化抗CD40抗体的量、病症或治疗的类型和如上文所描述的其他因素而定。这些药剂一般以如上文所使用的相同剂量和施用途径或迄今使用的剂量的约1%至99%使用。
CD40相关的病症
抗CD40抗体或药剂适用于治疗或预防表达CD40的癌症或免疫病症,其特征为CD40的表达,例如通过免疫细胞(例如淋巴细胞或树突状细胞)的不恰当活化。CD40的此类表达可归因于例如细胞表面上CD40蛋白质水平增加和/或所表达CD40的抗原性改变。根据本文所描述的方法治疗或预防免疫病症通过向需要此类治疗或预防的受试者施用有效量的抗CD40抗体或药剂来实现,由此抗体(i)结合至表达CD40且与疾病病况相关的活化免疫细胞,和(ii)对活化免疫细胞施加细胞毒性、细胞生长抑制或免疫抑制作用。
以免疫细胞不当活化为特征且可通过本文所描述的方法治疗或预防的免疫疾病可例如通过构成疾病基础的过敏反应类型来分类。这些反应通常分为四种类型:过敏性反应、细胞毒性(细胞溶解)反应、免疫复合体反应或细胞介导的免疫(CMI)反应(也称为延迟型过敏(DTH)反应)。(参见例如功能性免疫缺乏(William E.Paul编.,雷文出版社(RavenPress),N.Y.,第3版.1993)。)
此类免疫疾病的具体实例包括以下:类风湿性关节炎、自身免疫性疾病脱髓鞘病(例如多发性硬化症、过敏性脑脊髓炎)、内分泌眼病变、葡萄膜视网膜炎、系统性红斑狼疮、重症肌无力、格雷氏病、肾丝球肾炎、自身免疫性肝病、炎症性肠病(例如克罗恩氏病或溃疡性结肠炎)、过敏、过敏反应、干燥综合征、I型糖尿病、原发性胆汁性肝硬化、韦格纳氏肉芽肿病(Wegener's granulomatosis)、肌肉纤维疼痛、多发性肌炎、皮肌炎、炎症性肌炎、多内分泌功能衰竭、施密特氏症候群(Schmidt's syndrome)、自身免疫性葡萄膜炎、爱迪生氏病、肾上腺炎、甲状腺炎、桥本氏甲状腺炎、自身免疫性甲状腺疾病、恶性贫血、胃萎缩症、慢性肝炎、类狼疮肝炎、动脉粥样硬化、亚急性皮肤红斑性狼疮、副甲状腺低能症、德雷斯勒氏症候群(Dressler's syndrome)、自身免疫性疾病血小板减少症、特发性血小板减少性紫癜、溶血性贫血、寻常天疱疮、天疱疮、疱疹样皮炎、斑秃、类天疱疮、硬皮病、进行性系统性硬化症、脊症候群(钙质沉着、雷诺氏现象(Raynaud's phenomenon)、食道蠕动异常、硬皮病)和毛细管扩张)、雄性和雌性自身免疫性疾病不孕症、强直性脊椎炎、溃疡性结肠炎、混合结缔组织病、多动脉炎(polyarteritis nedosa)、全身坏死性脉管炎、异位性皮肤炎、特应性鼻炎、古德帕斯彻综合征(Goodpasture's syndrome)、蔡格司病(Chagas'disease)、类肉瘤病、风湿热、哮喘、习惯性流产、抗磷脂症候群、农夫肺、多形性红斑、心脏切开后症候群、库欣氏症候群(Cushing's syndrome)、自身免疫性疾病慢性活动性肝炎、养鸟人肺(bird-fancier's lung)、中毒性表皮坏死溶解、阿尔波特氏症候群(Alport's syndrome)、肺泡炎、过敏性肺泡炎、纤维化肺泡炎、间质性肺病、结节性红斑、坏疽性脓皮病、输液反应、高安氏动脉炎(Takayasu's arteritis)、风湿性多肌痛、颞动脉炎、血吸虫病、巨大细胞动脉炎、蛔虫病、曲霉病、萨姆普特氏症候群(Sampter's syndrome)、湿疹、类淋巴瘤肉芽肿、白塞氏病(Behcet's disease)、卡普兰氏症候群(Caplan's syndrome)、川崎氏病(Kawasaki's disease)、登革热、脑脊髓炎、心内膜炎、心内膜心肌纤维变性、内眼炎、持久隆起性红斑(erythema elevatum et diutinum)、牛皮癣、胎儿红血球母细胞增多症、嗜酸性筋膜炎、舒尔曼氏症候群(Shulman's syndrome)、费尔蒂氏症候群(Felty's syndrome)、丝虫病、睫状体炎、慢性睫状体炎、异时睫状体炎、法曲氏睫状体炎(Fuch's cyclitis)、IgA肾病、亨诺-舒过敏性紫癜(Henoch-Schonlein purpura)、移植物抗宿主疾病、移植排斥反应、心肌病、伊顿-兰伯特症候群(Eaton-Lambert syndrome)、复发性多软骨炎、冷凝球蛋白血症、瓦尔登斯特伦氏巨球蛋白血症、艾瓦氏症候群(Evan's syndrome)、急性呼吸窘迫症候群、肺炎、骨质疏松症、迟发型过敏反应和自身免疫性性腺功能衰竭。
因此,本文所描述的方法涵盖治疗B淋巴细胞病症(例如系统性红斑狼疮、古德帕斯彻综合征、类风湿性关节炎和I型糖尿病)、Th1-淋巴细胞病症(例如类风湿性关节炎、多发性硬化症、牛皮癣、干燥综合征(Sjorgren's syndrome)、桥本氏甲状腺炎、格雷氏病、原发性胆汁性肝硬化、韦格纳氏肉芽肿病、肺结核或移植物抗宿主疾病),或Th2-淋巴细胞病症(例如特应性皮肤炎、系统性红斑狼疮、特应性哮喘、鼻结膜炎、过敏性鼻炎、欧门氏综合征(Omenn's syndrome)、系统性硬化症或慢性移植物对抗宿主疾病)。通常,涉及树突状细胞的病症涉及Th1-淋巴细胞或Th2-淋巴细胞的病症。
类风湿性关节炎(RA)为影响大约1%群体的最常见炎症性自身免疫性疾病疾病中的一者。虽然可获得有效治疗(例如MTX和抗TNF药剂),但存在大量未满足的医学需要,尤其对于对抗TNF疗法(约30%患者)反应不足的那些患者。另外,5年内至多50%患者中断TNF拮抗剂治疗,主要归因于不良事件,且也因为越来越多患者失去治疗益处。因此,确立靶向RA中的炎症和关节破坏但不仅依赖于TNF的直接抑制的有效疗法是重要的。极具吸引力的方法为靶向共刺激细胞途径。共刺激中的关键受体-配体对中的一者为CD40/CD40L。此系统允许免疫细胞之间和免疫与非免疫细胞之间的互作用,所有免疫细胞在RA发病机制中是重要的。用本发明的拮抗性抗体阻断CD40可在RA中具有以下作用中的一或多者:
1)抑制B细胞分化和抗体同种型转换;
2)抑制T细胞和巨噬细胞中的细胞因子和趋化因子产生和黏附分子上调;
3)抑制树突状细胞的活化,和
4)抑制促炎症性细胞因子、趋化因子、基质金属蛋白酶、前列腺素产生且下调非免疫细胞(例如上皮、内皮和间叶细胞)中的黏附分子。
本文明确地涵盖实现以上效果中的一或多者的方法。除RA以外,本发明的组合物尤其适用于多发性硬化症、牛皮癣(包括牛皮癣性关节炎)、青少年类风湿性关节炎的治疗方法。炎症性肠病、系统性红斑狼疮和实体器官移植。
类风湿性关节炎(RA)为在成人中流行率为大约1%的慢性系统性自身免疫性疾病。该疾病不断引起显著发病率和过早死亡(死亡主要归因于加快的心血管疾病)。现已确认,关节损害在疾病过程中极早发生,其中高达30%的患者在诊断时展示骨骼腐蚀的放射照相证据,在1年之后增加至60%。当前指南建议在已建立明确诊断之后3个月内开始用传统疾病缓解抗风湿性药物(DMARD)治疗。DMARD具有减少或预防关节损害和保存关节功能的潜能。当前,风湿病学家选择甲氨蝶呤(MTX)作为大部分患者的初始DMARD疗法。
TNF拮抗剂依那西普(etanercept,)、英夫利昔单抗(infliximab,)、阿达木单抗(adalimumab,)、CTLA4-拮抗剂阿巴西普(abatacept,)、抗IL-6受体mAb托珠利单抗(tocilizumab)和抗CD20 mAb利妥昔单抗(rituximab,)有效治疗RA。在对传统DMARD反应不足之后,当前指南通常建议使用生物DMARD用于治疗活动性RA。
在无先前MTX治疗的患有早期侵袭性RA的患者中的近期研究展示,MTX与TNF拮抗剂的组合在用作单一疗法时优于彼此。最显著的结果为组合疗法的显著放射学益处。因此,MTX与TNF抑制剂的组合应用于具有侵袭性疾病和侵袭性表型(例如,高活性评分、功能性损伤、类风湿性因子(RF)或抗环瓜氨酸肽抗体(CCP)的血清阳性、升高的CRP、放射照相削弱)的最大风险的患者中。然而,我们预测在临床实践中,TNF拮抗剂将很少用作一线疗法。2005年4月美国风湿病学家进行的研究显示,最影响使用TNF拮抗剂的决定的因素为:MTX或多个DMARD失效、医师整体评估、功能性损伤和放射性照相恶化或削弱。目前,估计20%患有RA的患者接受美国TNF抑制剂疗法。
由于药物不耐受性和毒性或缺乏反应,因此相当大百分比的RA患者未通过包括生物疗法的当前治疗充分帮助。5年内至多50%患者停止TNF拮抗剂治疗,主要归因于不良事件,且也因为越来越多患者失去其反应。
在一些实施方案中,免疫病症为T细胞介导的免疫病症,诸如其中与病症相关的活化的T细胞表达CD40的T细胞病症。可施用抗CD40抗体或药剂以耗竭此类表达CD40的活化的T细胞。在特定实施方案中,施用抗CD40抗体或药剂可耗竭表达CD40的活化的T细胞,而静止T细胞实质上不受抗CD40或药剂耗竭。在此情形下,“实质上不耗竭”意指少于约60%或少于约70%或少于约80%的静止T细胞未耗竭。
如本文所描述的抗CD40抗体和药剂也适用于治疗或预防表达CD40的癌症。根据本文所描述的方法治疗或预防表达CD40的癌症通过向需要此类治疗或预防的受试者施用有效量的抗CD40抗体或药剂来达成,由此抗体或药剂(i)结合于表达CD40的癌细胞且(ii)发挥细胞毒性或细胞生长抑制作用以耗竭或抑制表达CD40的癌细胞的增殖。
可通过本文所描述的方法治疗或预防的表达CD40的癌症包括例如白血病,诸如急性白血病、急性淋巴球性白血病、急性骨髓细胞性白血病(例如成髓细胞性、前髓细胞性、骨髓单核细胞性、单核细胞性或红白血病)、慢性白血病、慢性骨髓细胞性(粒细胞性)白血病或慢性淋巴细胞性白血病;真性红细胞增多症;淋巴瘤(例如霍奇金氏病或非霍奇金氏病);多发性骨髓瘤、瓦尔登斯特伦氏巨球蛋白血症;重链病;实体肿瘤,诸如肉瘤和癌瘤(例如纤维肉瘤、黏液肉瘤、脂肪肉瘤、软骨肉瘤、成骨性肉瘤、骨肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴内皮肉瘤、滑膜瘤、间皮瘤、尤文氏肿瘤(Ewing's tumor)、平滑肌肉瘤、横纹肌肉瘤、结肠癌、结肠直肠癌、胰脏癌、乳癌、卵巢癌、前列腺癌、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊腺癌、髓性癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎性癌、肾母细胞瘤(Wilms'tumor)、宫颈癌、子宫癌、睪丸肿瘤、肺癌、小细胞肺癌、非小细胞肺癌、膀胱癌、上皮癌、神经胶瘤、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血管细胞瘤、听神经瘤、少突神经胶质瘤、脑膜瘤、黑素瘤、成神经细胞瘤、成视网膜细胞瘤、鼻咽癌或食道癌)。
药物组合物及其施用
可向患有免疫病症或表达CD40的癌症或处于患有免疫病症或表达CD40的癌症风险下的受试者施用包含CD40结合剂(例如抗CD40抗体)的组合物。本发明进一步提供CD40结合剂(例如抗CD40抗体)在制造用于预防或治疗表达CD40的癌症或免疫病症的药物中的用途。如本文所用的术语“受试者”意指可施用CD40结合剂的任何哺乳动物患者,包括例如人类和非人类哺乳动物,诸如灵长类动物、啮齿动物和狗。特定旨在使用本文所描述的方法治疗的受试者包括人类。抗体或药剂可单独或与其他组合物组合施用以预防或治疗免疫病症或表达CD40的癌症。
用于此类药物组合物的优选的抗体为包含人源化抗体或抗体片段的那些抗体,该人源化抗体或抗体片段具有SEQ ID NO:1至4、SEQ ID NO:27、SEQ ID NO:28、SEQ ID NO:29、SEQ ID NO:30、SEQ ID NO:32、SEQ ID NO:33、SEQ ID NO:34、SEQ ID NO:35、SEQ IDNO:37、SEQ ID NO:38、SEQ ID NO:39或SEQ ID NO:40中的任一者的重链可变区氨基酸序列。
在一个实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包括向该受试者施用包含抗CD40(抗分化簇40)抗体的组合物,
其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ ID NO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ ID NO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ IDNO:25组成的组的轻链CDR3序列;或
其中该抗CD40抗体包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQ ID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ IDNO:58、SEQ ID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ IDNO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ IDNO:70、SEQ ID NO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ IDNO:41、SEQ ID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:50、SEQ IDNO:51、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQ ID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ IDNO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36;
其中该组合物包含80mg、120mg、180mg或240mg该抗CD40抗体;
其中包含80mg抗CD40抗体的组合物的单剂量施用产生约888至约1550的Cmax(ngmL-1)、约126至约365的AUC0-tz(μg·h mL-1)或约330至约464的AUC0-inf(μg·h mL-1);或
其中包含120mg抗CD40抗体的组合物的单剂量施用产生约5160至约7210的Cmax(ng mL-1)、约1110至约2010的AUC0-tz(μg·h mL-1)或约1120至约2020的AUC0-inf(μg·hmL-1);或
其中包含180mg抗CD40抗体的组合物的单剂量施用产生约8650至约16300的Cmax(ng mL-1)、约2900至约6380的AUC0-tz(μg·h mL-1)或约2020至约2910的AUC0-inf(μg·hmL-1);或
其中包含240mg抗CD40抗体的组合物的单剂量施用产生约15700至约21300的Cmax(ng mL-1)、约5680至约7750的AUC0-tz(μg·h mL-1)或约5610至约7780的AUC0-inf(μg·hmL-1);或
其中包含240mg抗CD40抗体的组合物的多剂量施用(q1w或每周一次)在第一剂量之后产生约23的Cmax,1(μg mL-1)或在第一剂量之后产生约2600的AUCτ,1(μg·h mL-1);或
其中包含240mg抗CD40抗体的组合物的多剂量施用(q1w或每周一次)在第四剂量之后产生约74的Cmax,4(μg mL-1),或在第四剂量之后产生约49的Cmin,4(μg mL-1),或在第四剂量之后产生约10900的AUCτ,4(μg·h mL-1)。
根据以上实施方案的方法,其中自身免疫性疾病或炎症性疾病选自由以下组成的组:狼疮性肾炎、类风湿性关节炎、多发性硬化症、增生性狼疮性肾丝球肾炎、炎症性肠病(IBD)、牛皮癣、特发性血小板减少性紫癜(ITP)、克罗恩氏病和系统性红斑狼疮(SLE)、桥本氏甲状腺炎、原发性黏液性水肿、甲状腺中毒症/格雷氏病、恶性贫血、自身免疫性萎缩性胃炎、自身免疫性心脏炎、爱迪生氏病、过早更年期、1型糖尿病、古德帕斯彻综合征、重症肌无力、自身免疫性溶血性贫血、特发性白血球减少症、原发性胆汁性肝硬化、活动性慢性肝炎(HB Ag阴性)、隐原性肝硬化、干燥综合征、皮肌炎、硬皮病、混合结缔组织病、盘状红斑狼疮和系统性血管炎。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:10的重链CDR1序列、SEQID NO:13的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中该抗体包含SEQ ID NO:19的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:9的重链CDR1序列、SEQ IDNO:14的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中该抗体包含SEQ ID NO:20的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含SEQ ID NO:11的重链CDR1序列、SEQID NO:15的重链CDR2序列和SEQ ID NO:17的重链CDR3序列;且其中该抗体包含SEQ ID NO:21的轻链CDR1序列、SEQ ID NO:23的轻链CDR2序列和SEQ ID NO:25的轻链CDR3序列。
根据以上实施方案的方法,其中该抗体包含重链可变域和轻链可变区,该重链可变域和轻链可变区分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ IDNO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQID NO:35和SEQ ID NO:31;SEQ ID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;SEQ ID NO:40和SEQ ID NO:36。
根据以上实施方案的方法,其中该抗体包含:包含SEQ ID NO:44的重链可变域和包含SEQ ID NO:43的轻链可变域;或包含SEQ ID NO:53的重链可变域和包含SEQ ID NO:52的轻链可变域;或包含SEQ ID NO:58的重链可变域和包含SEQ ID NO:56的轻链可变域。
根据以上实施方案的方法,其中该抗体包含:包含SEQ ID NO:30的重链序列和包含SEQ ID NO:26的轻链序列;或包含SEQ ID NO:35的重链序列和包含SEQ ID NO:31的轻链序列;或包含SEQ ID NO:40的重链序列和包含SEQ ID NO:36的轻链序列。
根据以上实施方案的方法,其中该自身免疫性疾病或炎症性疾病选自由狼疮性肾炎、移植物对抗宿主疾病、自身免疫性疾病或炎症性疾病和CD40相关病症组成的组。
在其他实施方案中,本发明的组合物可经指示用于在对抗TNF药剂反应不足的患有中度至重度活动性RA的患者中减少病征和症状、诱导主要临床反应和减少结构损伤的进展。当前黄金准则:非抗TNF生物疗法。优选地,在此类受试者中,相较于非抗TNF生物(例如阿巴西普、美罗华(Rituxan)),本发明的组合物具有非劣效性,其通过历史比较对抗TNF药剂的反应不足的患者来实现:对于化合物加DMARD,6个月时ACR20>50%(GS:阿巴西普+DMARD 50%对比安慰剂+DMARD 20%)。在其他实施方案中,本发明的组合物在一年内抑制结构损伤的进展,通过用于关节侵蚀和关节间隙变窄的公认X射线评分方法所评定,类似于美罗华(52周之后平均经修改的Sharp评分美罗华+MTX 1.0对比安慰剂+MTX 2.31)。
各种递送系统为已知的且可用于施用CD40结合剂。引入方法包括但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内、硬膜外和经口途径。CD40结合剂可例如通过输注、推注或注射施用,且可与诸如化学治疗剂的其他生物活性剂一起施用。可系统性或局部施用。在优选的实施方案中,施用是通过皮下注射进行的。用于此类注射的配制剂可在例如可每隔一周施用一次的预填充注射器中制备。
将确定本发明的抗体的安全性特征且优选地包括一或多个特征,诸如:与通常用于治疗类风湿性关节炎的其他药物(例如DMARD、类固醇、NSAID)无临床上显著的不良相互作用;与Enbrel相比,没有因安全性或耐受性问题导致的更大的中断;严重感染率不大于抗TNF药剂或其他常用生物药剂;注射部位反应或输注反应的频率和/或严重度与Enbrel相似;重复治疗周期后,没有或极少出现耐药性(小于5%);无中和抗体或较少中和抗体;没有证据表明血小板聚集/活化增强可能导致体内血栓栓塞事件或血小板/内皮功能障碍可能导致出血。
在特定实施方案中,通过注射液、借助于导管、借助于栓剂或借助于植入物施用CD40结合剂组合物,该植入物为多孔、无孔或胶状材料,包括膜,诸如硅橡胶膜或纤维。通常,当施用组合物时,使用抗CD40抗体或药剂不会吸收的材料。
在其他实施方案中,抗CD40抗体或药剂系以控制释放系统递送。在一个实施方案中,可使用泵(参见例如Langer,1990,Science249:1527-1533;Sefton,1989,CRCCrit.Ref.Biomed.Eng.14:201;Buchwald等人,1980,Surgery 88:507;Saudek等人,1989,N.Engl.J.Med.321:574)。在另一实施方案中,可使用聚合材料。(参见例如MedicalApplications of Controlled Release(Langer和Wise编,CRC Press,Boca Raton,Fla.,1974);Controlled Drug Bioavailability,Drug Product Design and Performance(Smolen和Ball编,Wiley,New York,1984);Ranger和Peppas,1983,Macromol.Sci.Rev.Macromol.Chem.23:61。也参见Levy等人,1985,Science 228:190;During等人,1989,Ann.Neurol.25:351;Howard等人,1989,J.Neurosurg.71:105。)其他控制释放系统论述于例如Langer,见上文。
CD40结合剂(例如抗CD40抗体)可以包含治疗有效量的结合剂和一种或多种药学上兼容的成分的药物组合物形式施用。
在典型实施方案中,根据常规程序将药物组合物配制成适用于向人类静脉内或皮下施用的药物组合物。通常,通过注射施用的组合物是在无菌等张水性缓冲液中的溶液。必要时,药物也可包括助溶剂和局部麻醉剂诸如利多卡因(lignocaine)以减轻注射部位的疼痛。一般而言,该成分是单独提供的或以单位剂型混合在一起,例如,以指示活性剂量的气密密封容器(诸如安瓿或药囊)中的干燥冻干粉末或无水浓缩物形式提供。当通过输注施用药物时,其可用含有无菌医药级水或生理食盐水的输注瓶来配药。当通过注射施用药物时,可提供注射用无菌水或生理食盐水的安瓿,以使得该成分可在施用前混合。
此外,药物组合物可以以药用试剂盒形式提供,该药用试剂盒包含(a)含有冻干形式的CD40结合剂(例如抗CD40抗体)的容器和(b)含有药学上可接受的稀释剂用于注射(例如无菌水)的第二容器。药学上可接受的稀释剂可用于对冻干的抗CD40抗体或药剂进行复原或稀释。任选地与此类容器相关的可以是由管理医药或生物产品的制造、使用或销售的政府机构所规定的形式的注意事项,该注意事项反映由人类施用的制造、使用或销售机构的批准。
在一个实施方案中,药物组合物包含浓度为约10mg/ml至约200mg/ml;或约100mg/ml至约200mg/ml;或约120mg/ml至约180mg/ml;或约120mg/ml、130mg/ml、140mg/ml、150mg/ml、160mg/ml、170mg/ml、180mg/ml、190mg/ml或200mg/ml的抗CD40抗体的水性组合物。
除抗CD40抗体之外,药物组合物可进一步包含缓冲液、稳定剂和任选地的pH调节剂。缓冲液的非限制性实例包括一种或多种盐,诸如氯化钠、精氨酸盐酸盐、硫氰酸钠、硫氰酸铵、硫酸铵、氯化铵、氯化钙、氯化锌和乙酸钠;或适合的酸,诸如乙酸和氨基酸的盐。添加量足以提供适合于例如通过注射向患者施用配制剂的黏度的缓冲液。药物组合物可包含约100mM至约200mM盐或缓冲液,或约120mM至约180mM盐或缓冲液。在一个实施方案中,药物组合物包含缓冲液,该缓冲液包含浓度为约20mM至约30mM的乙酸钠和浓度为约120mM至约140mM的氯化钠。在另一实施方案中,药物组合物包含缓冲液,该缓冲液包含浓度为约25mM的乙酸钠和浓度为约130mM的氯化钠。
适合的稳定剂的非限制性实例为聚山梨醇酯20(Tween 20)。稳定剂以足以维持药物组合物的化学和物理稳定性的量存在。药物组合物可包含约0.001%至约0.1%(w/v)的稳定剂;或约0.0015%至约0.015%(w/v)的稳定剂;或约0.01%(w/v)的稳定剂。
在一个实施方案中,药物组合物包含量为约120mg/ml至约180mg/ml的抗CD40抗体;包含浓度为约20mM至约30mM的乙酸钠和浓度为约120mM至约140mM的氯化钠的缓冲液;和浓度为约0.0015至约0.015%(w/v)的聚山梨醇酯20的表面活性剂。在另一实施方案中,抗CD40抗体配制剂包含量为约120mg/ml、130mg/ml、140mg/ml、150mg/ml、160mg/ml、170mg/ml、180mg/ml、190mg/ml或200mg/ml的抗CD40抗体;包含浓度为约25mM的乙酸钠和浓度为约130mM的氯化钠的缓冲液;和浓度为约0.01%(w/v)的聚山梨醇酯20的表面活性剂。
在另一实施方案中,上文所描述的药物组合物中的每一者可包含约70mg至约250mg抗CD40抗体;或约80至240mg抗CD40抗体。在另一实施方案中,上文所描述的药物组合物包含70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg或250mg抗CD40抗体。
上文所描述的药物组合物中的每一者的pH为约4.0至约12.0;或约5至约6.0;或约5.5。pH可通过添加足量的合适的pH调节剂,诸如酸(例如盐酸)或碱(例如氢氧化钠)来调节。
在另一实施方案中,本发明涉及一种使用本文所描述的抗CD40抗体药物组合物中的任一者治疗或预防狼疮性肾炎的方法。
可通过标准临床技术测定有效治疗或预防免疫病症或表达CD40的癌症的CD40结合剂(例如抗CD40抗体)的量。另外,体外测定可任选地用于帮助鉴别最佳剂量范围。待用于配制剂中的精确剂量也将视施用途径和免疫病症或表达CD40的癌症的阶段而定,且应根据医师的判断和各患者的情况来决定。可根据来源于体外或动物模型测试系统的剂量反应曲线外推出有效剂量。
例如,抗CD40抗体或药剂的毒性和治疗功效可通过标准医药程序在细胞培养物或实验动物中测定,测定ED50(在50%群体中治疗上有效的剂量)。表现出较大治疗指数的CD40结合剂(例如抗CD40抗体)是优选的。在CD40结合剂表现出毒性副作用的情况下,使CD40结合剂靶向受影响组织部位的递送系统可用于使潜在损伤非CD40表达细胞降至最低且由此减少副作用。
自细胞培养测定法和动物研究获得的数据可用于配制供人类使用的剂量范围。CD40结合剂的剂量通常处于循环浓度的范围内,包括具有极小毒性或无毒性的ED50。剂量可视所采用的剂型和所利用的施用途径而在此范围内变化。对于该方法中使用的任何CD40结合剂,最初可自细胞培养测定法估算治疗有效剂量。可在动物模型中配制剂量以实现包括如在细胞培养物中所测定的IC50(即,实现症状的最大抑制的一半的测试化合物的浓度)的循环血浆浓度范围。此信息可用于更精确地判定适用于人类的剂量。可例如通过高效液相色谱、ELISA和其类似方法测量血浆中的水平。
一般而言,向患有免疫病症或表达CD40的癌症的患者施用的抗CD40抗体或CD40结合剂的剂量通常为每受试者体重约0.1mg/kg至约100mg/kg。向受试者施用的剂量为每受试者体重约0.1mg/kg至约50mg/kg、约1mg/kg至约30mg/kg、约1mg/kg至约20mg/kg、约1mg/kg至约15mg/kg或约1mg/kg至约10mg/kg。
示例性剂量包括但不限于1ng/kg至100mg/kg。在一些实施方案中,剂量为约0.5mg/kg、约1mg/kg、约2mg/kg、约3mg/kg、约4mg/kg、约5mg/kg、约6mg/kg、约7mg/kg、约8mg/kg、约9mg/kg、约10mg/kg、约11mg/kg、约12mg/kg、约13mg/kg、约14mg/kg、约15mg/kg或约16mg/kg。剂量可例如每日、每周一次(每周)、每周两次、每周三次、每周四次、每周五次、每周六次、两周一次或每月一次、每两个月一次或每三个月一次施用。在特定实施方案中,剂量为约0.5mg/kg/周、约1mg/kg/周、约2mg/kg/周、约3mg/kg/周、约4mg/kg/周、约5mg/kg/周、约6mg/kg/周、约7mg/kg/周、约8mg/kg/周、约9mg/kg/周、约10mg/kg/周、约11mg/kg/周、约12mg/kg/周、约13mg/kg/周、约14mg/kg/周、约15mg/kg/周或约16mg/kg/周。在一些实施方案中,剂量范围介于约1mg/kg/周至约15mg/kg/周。
在另一实施方案中,剂量为每周约70mg至约250mg;或每周约80至240mg。在另一实施方案中,剂量为每周约80mg、每周120mg、每周130mg、每周140mg、每周160mg、每周170mg、每周180mg、每周200mg、每周210mg、每周220mg、每周mg、每周240mg或每周250mg。
在一些实施方案中,包含CD40结合剂的药物组合物可进一步包含结合或未结合至结合剂的治疗剂。抗CD40抗体或CD40结合剂可与一或多种治疗剂组合共施用用于治疗或预防免疫病症或表达CD40的癌症。例如,组合疗法可包括细胞生长抑制剂、细胞毒性剂或免疫抑制剂。组合疗法也可包括例如施用靶向活化的淋巴细胞、树突状细胞或表达CD40的癌细胞的表面上的除CD40以外的受体或受体复合物的药剂。此类药剂的实例包括结合于活化的淋巴细胞、树突状细胞或表达CD40的癌细胞表面处的分子的第二非CD40抗体。另一实例包括靶向此类受体或受体复合物的配体。通常,此类抗体或配体结合于活化的淋巴细胞、树突状细胞或表达CD40的癌细胞上的细胞表面受体且通过将细胞生长抑制或细胞毒性信号递送至活化的淋巴细胞、树突状细胞或表达CD40的癌细胞来增强抗CD40抗体的细胞毒性或细胞生长抑制作用。
此类组合疗法施用对疾病参数(例如症状的严重度、症状数目或复发频率)可具有累加或协同作用。
关于组合性施用的治疗方案,在特定实施方案中,抗CD40抗体或CD40结合剂与治疗剂同时施用。在另一特定实施方案中,在施用抗CD40抗体或CD40结合剂之前或之后,施用治疗剂至少一小时和至多数月,例如至少一小时、五小时、12小时、一天、一周、一个月或三个月,在施用抗CD40抗体或CD40结合剂之前或之后。
适用类别的细胞毒性剂或免疫抑制剂包括例如抗微管蛋白剂、奥瑞他汀(auristatins)(例如MMAE或MMAF)、DNA小沟结合剂、DNA复制抑制剂、烷基化剂(例如铂复合物,诸如顺式-铂、单(铂)、双(铂)和三-核铂复合物和卡铂)、蒽环霉素、抗生素、抗叶酸剂、抗代谢物、化学治疗敏化剂、倍癌霉素、依托泊苷(etoposide)、氟化嘧啶、离子载体、lexitropsin、亚硝基脲、顺氯氨铂(platinol)、预形成的化合物、嘌呤抗代谢物、嘌呤霉素(puromycin)、辐射敏化剂、类固醇、紫杉烷、拓朴异构酶抑制剂、长春花生物碱或其类似物。
个别细胞毒性或免疫抑制剂包括例如雄性激素、安曲霉素(AMC)、天冬酰胺酶、5-氮杂胞苷、硫唑嘌呤、博莱霉素、白消安(busulfan)、丁硫氨酸亚砜胺、喜树碱、卡铂、卡莫司汀(BSNU)、CC-1065、氮芥苯丁酸、顺铂(cisplatin)、秋水仙碱、环磷酰胺、阿糖胞苷、胞苷阿拉伯糖苷、细胞松弛缓素B、达卡巴嗪、放线菌素(dactinomycin)(以前为放射菌素(actinomycin))、道诺霉素、达卡巴嗪、多西他赛(docetaxel)、阿霉素(doxorubicin)、雌性素、5-氟脱氧尿苷、5-氟尿嘧啶、短杆菌素D、羟基脲、伊达霉比星、异环磷酰胺、伊立替康、洛莫司汀(CCNU)、氮芥、美法仑(melphalan)、6-巯基嘌呤、甲氨蝶呤、光神霉素、丝裂霉素C、米托蒽醌、硝基咪唑、紫杉醇、普卡霉素、甲苄肼、链脲霉素、替尼泊苷(tenoposide)、6-硫代鸟嘌呤、噻替派(thioTEPA)、拓朴替康、长春碱、长春新碱、长春瑞宾(vinorelbine)、VP-16和VM-26。
在一些典型实施方案中,治疗剂为细胞毒性剂。适合的细胞毒性剂包括例如海兔毒素(dolastatins)(例如奥瑞他汀E、AFP、MMAF、MMAE、AEB或AEVB)、DNA小沟结合剂(例如烯二炔和lexitropsins)、倍癌霉素、紫杉烷(例如紫杉醇和多西他赛)、嘌呤霉素、长春花生物碱、CC-1065、SN-38、拓朴替康、吗啉代-阿霉素、根霉素、氰基吗啉代-阿霉素、棘霉素、康普瑞汀、纺锤菌素、埃坡霉素A和B、雌莫司汀、cryptophysins、西马多丁(cemadotin)、类美登素、圆皮海绵内脂(discodermolide)、五家素(eleutherobin)或米托蒽醌。
在一些实施方案中,细胞毒性剂为常规的化学治疗剂,诸如阿霉素、紫杉醇、美法仑、长春花生物碱、甲氨蝶呤、丝裂霉素C或依托泊苷。另外,有效药剂,诸如CC-1065类似物、卡奇霉素、美登素、海兔毒素10的类似物、根霉素和海葵毒素可连接至抗CD40抗体或其药剂。
在特定实施方案中,细胞毒性或细胞生长抑制剂为奥瑞他汀E(在本领域中也称为海兔毒素-10)或其衍生物。典型地,奥瑞他汀E衍生物为例如形成在奥瑞他汀E与酮酸之间的酯。例如,可使奥瑞他汀E与对乙酰基苯甲酸或苯甲酰基戊酸反应以分别产生AEB和AEVB。其他典型奥瑞他汀衍生物包括AFP、MMAF和MMAE。奥瑞他汀E和其衍生物的合成和结构描述于例如美国专利申请号2004-0157782A1和2005-0238649;国际专利申请号PCT/US03/24209、国际专利申请案号PCT/US02/13435和美国专利号6,884,869;6,323,315;6,239,104;6,034,065;5,780,588;5,665,860;5,663,149;5,635,483;5,599,902;5,554,725;5,530,097;5,521,284;5,504,191;5,410,024;5,138,036;5,076,973;4,986,988;4,978,744;4,879,278;4,816,444;和4,486,414;其公开内容以引用的方式并入本文中。
在特定实施方案中,细胞毒性剂为DNA小沟结合剂。(参见例如美国专利号6,130,237。)例如,在一些实施方案中,小沟结合剂为CBI化合物。在其他实施方案中,小沟结合剂是烯二炔(例如卡奇霉素)。
抗微管蛋白剂的实例包括但不限于紫杉烷(例如(紫杉醇)、(多西他赛))、T67(Tularik)、长春花生物碱(例如长春新碱、长春碱、长春地辛和长春瑞宾)和海兔毒素(例如奥瑞他汀E、AFP、MMAF、MMAE、AEB、AEVB)。其他抗微管蛋白剂包括例如浆果赤霉素衍生物、紫杉烷类似物(例如埃博霉素A和B)、诺考达唑(nocodazole)、秋水仙碱和秋水酰胺(colcimid)、雌莫司汀、cryptophysins、西马多丁、类美登素、康普瑞汀(combretastatin)、圆皮海绵内脂和五加素。
在一些实施方案中,细胞毒性剂为美登素(另一组抗微管蛋白剂)。例如,在特定实施方案中,类美登素为美登素或DM-1(ImmunoGen,Inc.;还参见Chari等人.,1992,CancerRes.52:127-131)。
在一些实施方案中,治疗剂不为放射性同位素。
在一些实施方案中,细胞毒性或免疫抑制剂为抗代谢物。抗代谢物可为例如嘌呤拮抗剂(例如硫唑嘌呤或霉酚酸吗啉乙酯)、二氢叶酸还原酶抑制剂(例如甲氨蝶呤)、阿昔洛韦、更昔洛韦、齐多夫定、阿糖腺苷、利巴韦林(ribavarin)、叠氮胸苷、胞苷阿拉伯糖苷、金刚烷胺、二脱氧尿苷、碘脱氧尿苷、赤霉苷(poscamet)或曲氟尿苷。
在其他实施方案中,细胞毒性或免疫抑制剂是他克莫司(tacrolimus)、环孢霉素或雷帕霉素。在其他实施方案中,细胞毒性剂为阿地白介素、阿仑单抗(alemtuzumab)、阿利维甲酸(alitretinoin)、异嘌呤醇、六甲蜜胺、阿米福汀、阿那曲唑、三氧化二砷、贝沙罗汀(bexarotene)、贝沙罗汀、卡鲁睾酮(calusterone)、卡培他滨、塞内昔布、克拉屈滨、阿法达贝泊汀、地尼白介素、右雷佐生、丙酸屈他雄酮、表柔比星(epirubicin)、阿法依泊汀、雌莫司汀、依西美坦、非格司亭、氟尿苷、氟达拉宾、氟维司群(fulvestrant)、吉西他滨、吉妥单抗奥佐米星、戈舍瑞林(goserelin)、埃达霉素、异环磷酰胺、甲磺酸伊马替尼、干扰素α-2a、伊立替康、来曲唑、甲酰四氢叶酸、左旋咪唑、氮芥或氮芥、甲地孕酮、美司钠、甲氨蝶呤、甲氧沙林、丝裂霉素C、米托坦、苯丙酸诺龙、奥普瑞白介素、奥沙利铂(oxaliplatin)、帕米膦酸盐、培加酶、培门冬酶、派非格司亭、喷司他丁、哌泊溴烷、普卡霉素、卟吩姆钠、甲苄肼、奎纳克林、拉布立酶、雷利米得、沙格司亭、链脲菌素、它莫昔芬、替莫唑胺、替尼泊甙(teniposide)、睪内酯、硫鸟嘌呤、托瑞米芬、托西莫单抗(Tositumomab)、曲妥珠单抗(Trastuzumab)、维甲酸、尿嘧啶氮芥、伐柔比星(valrubicin)、长春碱、长春新碱、长春瑞宾和唑来膦酸盐。
在额外实施方案中,药物为人源化抗HER2单克隆抗体;美罗华(利妥昔单抗;Genentech,Inc.,South San Francisco,Calif.);嵌合抗CD20单克隆抗体);OVAREX(AltaRex Corporation,MA);PANOREX(Glaxo Wellcome,NC;鼠类IgG2a抗体);西妥昔单抗艾必妥(Cetuximab Erbitux)(Imclone Systems Inc.,NY;抗EGFR IgG嵌合抗体);维他欣(Vitaxin)(MedImmune,Inc.,MD);阿仑单抗I/H(Leukosite,MA;人源化IgG1抗体);SmartMI95(Protein Design Labs,Inc.,CA;人源化抗CD33 IgG抗体);LymphoCide(Immunomedics,Inc.,NJ;人源化抗CD22 IgG抗体);Smart ID10(Protein Design Labs,Inc.,CA;人源化抗HLA-DR抗体);Oncolym(Techniclone,Inc.,CA;放射性标记鼠类抗HLA-Dr10抗体);Allomune(BioTransplant,CA;人源化抗CD2 mAb);安维汀(Avastin)(Genentech,Inc.,CA;抗VEGF人源化抗体);Epratuzamab(Immunomedics,Inc.,NJ和Amgen,CA;抗CD22抗体);和CEAcide(Immunomedics,NJ;人源化抗CEA抗体)。
其他适合的抗体包括但不限于针对以下抗原的抗体:CA125、CA15-3、CA19-9、L6、Lewis Y、Lewis X、α甲胎蛋白、CA 242、胎盘碱性磷酸酶、前列腺特异性抗原、前列腺酸磷酸酶、表皮生长因子、MAGE-1、MAGE-2、MAGE-3、MAGE-4、抗转铁蛋白受体、p97、MUC1-KLH、CEA、gp100、MART1、前列腺特异性抗原、IL-2受体、CD20、CD52、CD33、CD22、人绒毛膜促性腺激素、CD38、黏蛋白、P21、MPG和Neu癌基因产物。
在一些实施方案中,额外治疗剂为免疫抑制剂。免疫抑制剂可为例如更昔洛韦、依那西普、他克莫司、环孢霉素、雷帕霉素、霉酚酸酯(MMF)、环磷酰胺(CyP)、硫唑嘌呤、羟基氯奎、咪唑立宾(mizoribine)、霉酚酸吗啉乙酯或甲氨蝶呤。或者,免疫抑制剂可为例如糖皮质激素(例如皮质醇或醛固酮)或糖皮质激素类似物(例如强的松或地塞米松)。在另一实施方案中,免疫抑制剂可为血管收缩素转化酶(ACE)抑制剂(例如卡托普利(captopril)、喹那普利(quinapril)或依那普利(enalapril))或血管收缩素II受体阻断剂(ARB)(例如,氯沙坦(losartan)或坎地沙坦(candesartan))。
适合的环加氧酶抑制剂包括甲氧芬那酸、甲芬那酸、卡洛芬、双氯芬酸、二氟尼柳、芬布芬、非诺洛芬、布洛芬、吲哚美辛、酮基布洛芬、萘丁美酮、萘普生、舒林酸、替诺昔康、托美汀和乙酰基水杨酸。
适合的脂肪加氧酶抑制剂包括氧化还原抑制剂(例如儿茶酚丁烷衍生物、去甲二氢愈创酸(NDGA)、马索罗酚(masoprocol)、菲尼酮、兰诺帕伦(Ianopalen)、吲唑啉酮、萘甲酮、呋喃酚、烷基羟胺)和非氧化还原抑制剂(例如羟基噻唑、甲氧基烷基噻唑、苯并哌喃和其衍生物、甲氧基四氢哌喃、乳香酸和乳香酸的乙酰化衍生物,和用环烷基基团取代的喹啉甲氧基苯乙酸)以及氧化还原抑制剂的前体。
其他适合的脂肪加氧酶抑制剂包括抗氧化剂(例如苯酚、没食子酸丙酯、类黄酮和/或含有类黄酮的天然存在的底物、黄酮、黄酮醇、二氢槲皮素、木犀草素、高良姜素、奥洛波尔(orobol)、查耳酮的衍生物、4,2',4'-三羟基查耳酮、邻氨基苯酚、N-羟基脲、呋喃酚、依布硒啉(ebselen)和提高还原性硒酶活性之物种)、铁螯合剂(例如异羟肟酸和其衍生物、N-羟基脲、2-苯甲基-1-萘酚、儿茶酚、羟胺、鼠尾草醇抗氧化剂C、儿茶酚、萘酚、柳氮磺胺吡啶、zyleuton、5-邻氨基苯甲酸和4-(Ω-芳基烷基)苯基链烷酸)、含咪唑的化合物(例如酮康唑和伊曲康唑)、吩噻嗪和苯并哌喃衍生物。
其他适合的脂肪加氧酶抑制剂包括类花生酸(例如十八碳四烯酸、二十碳四烯酸、二十二碳五烯酸、二十碳六烯酸和二十二碳六烯酸和其酯、PGE1(前列腺素E1)、PGA2(前列腺素A2)、维前列醇、15-单羟基二十碳四烯酸、15-单羟基二十碳三烯酸和15-单羟基二十碳五烯酸,和白三烯B5、C5和D5)、干扰钙流的化合物、吩噻嗪、二苯基丁胺、维拉帕米(verapamil)、岩藻糖苷、姜黄素、绿原酸、咖啡酸、5,8,11,14-二十碳四烯酸(ETYA)、羟苯基维甲酰胺酚、lonapalen、七叶苷(esculin)、乙胺嗪、邻二氮杂菲、黄芩素、普昔罗米(proxicromil)、硫醚、二烯丙基硫化物和二-(1-丙烯基)硫化物的抑制剂。
白三烯受体拮抗剂包括钙化三醇、昂唑司特(ontazolast)、Bayer Bay-x-1005、Ciba-Geigy CGS-25019C、依布硒啉、Leo Denmark ETH-615、Lilly LY-293111、Ono ONO-4057、Terumo TMK-688、Boehringer Ingleheim BI-RM-270、Lilly LY 213024、Lilly LY264086、Lilly LY 292728、Ono ONO LB457、Pfizer 105696、Perdue Frederick PF 10042、Rhone-Poulenc Rorer RP 66153、SmithKline Beecham SB-201146、SmithKline BeechamSB-201993、SmithKline Beecham SB-209247、Searle SC-53228、Sumitamo SM 15178、American Home Products WAY 121006、Bayer Bay-o-8276、Warner-Lambert CI-987、Warner-Lambert CI-987BPC-15LY 223982、Lilly LY 233569、Lilly LY-255283、MacroNexMNX-160、Merck和Co.MK-591、Merck和Co.MK-886、Ono ONO-LB-448、Purdue Frederick PF-5901、Rhone-Poulenc Rorer RG 14893、Rhone-Poulenc Rorer RP 66364、Rhone-PoulencRorer RP 69698、Shionoogi S-2474、Searle SC-41930、Searle SC-50505、Searle SC-51146、Searle SC-52798、SmithKline Beecham SK和F-104493、Leo Denmark SR-2566、Tanabe T-757和Teijin TEI-1338。
在另一实施方案中,额外治疗剂选自由以下组成的组:霉酚酸酯(MMF)、环磷酰胺(CyP)、糖皮质激素(GC)和皮质类固醇,或其任何组合。
在一个实施方案中,额外治疗剂为霉酚酸酯(MMF)。
在另一实施方案中,额外治疗剂为环磷酰胺(CyP)。
在另一实施方案中,额外治疗剂为糖皮质激素(GC)。
在另一个实施例中,额外治疗剂为皮质类固醇。
制品
在另一方面中,包括含有适用于治疗上文所描述的病症的物质的制品。制品包含容器和标签。适合的容器包括(例如)瓶子、小瓶、注射器和试管。容器可由多种材料(诸如玻璃或塑料)形成。容器容纳有效治疗病况的组合物且可具有无菌接取口。例如,容器可为具有可通过皮下注射针刺穿的塞子的静脉内溶液袋或小瓶。组合物中的活性剂为人源化抗CD40抗体。容器上或与容器相关的标签指示组合物用于治疗所选病况。制品可进一步包含第二容器,该第二容器包含药学上可接受的缓冲液,诸如磷酸盐缓冲盐水、林格氏溶液(Ringer's solution)和右旋糖溶液。其可进一步包括从商业和使用者的角度来看合乎需要的其他材料,包括其他缓冲液、稀释剂、过滤器、针、注射器和带有使用说明书的包装插页。
在与方面或实施方案中的任一者相关的实施方案中,与安慰剂相比,施用引起该受试者中的总SLEDAI或非肾SLEDAI评分得到改善。在一些实施方案中,在第26周或第52周改善为≥5%。在一些实施方案中,在第26周或第52周,改善为≥10%。
在另一实施方案中,本发明涉及一种测定抗CD40抗体在治疗或预防受试者中的自身免疫性疾病或炎症性疾病的治疗功效的方法,该方法包括向该受试者施用包含抗CD40抗体的组合物,测量该受试者中的经活化的B细胞子集的水平,其中经活化的B细胞子集的水平降低(当比较治疗之前和之后的水平时)指示具有功效。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种减少患有自身免疫性疾病或炎症性疾病的受试者中的经活化的B细胞子集的水平的方法,该方法包括向该受试者施用包含抗CD40抗体的组合物,其中经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该受试者施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物,其中该受试者展现(或已经确定展现)经活化的B细胞子集的存在。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包括(a)确定该受试者表现出经活化的B细胞子集的存在(例如通过测试获自受试者的生物样品),(b)向该受试者施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
在另一实施方案中,本发明涉及一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包含向该受试者施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物,其中已确定该受试者表现出经活化的B细胞子集的存在。在相关实施方案中,经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。在相关实施方案中,抗CD40抗体为本文所公开的抗体中的任一者。在相关实施方案中,自身免疫性疾病或炎症性疾病为本文所公开的疾病中的任一者。
本发明在以下实施例中进一步加以描述,其不旨在限制本发明的范围。
实施例
实施例1:人源化抗CD40抗体的产生
本发明的人源化抗CD4抗体可根据US20110243932中所描述的程序制备。抗体A、抗体B和抗体C为衍生自克隆至人IgG1-KO(KO=基因敲除)/κ主链中的小鼠抗体20E2(抗体A和抗体B)或2H11(抗体C)的人源化抗体。IgG1-KO在Fc区中具有两种突变,Leu234Ala和Leu235Ala以减少FcγR和补体结合。
此类人源化的结果产生下文所示的各种人源化重链和轻链可变序列:
SEQ ID NO:41(可变轻链序列):
SEQ ID NO:42(可变重链序列):
SEQ ID NO:43(可变轻链序列)
SEQ ID NO:44(可变重链序列)
SEQ ID NO:45(可变轻链序列)
SEQ ID NO:46(可变重链序列)
SEQ ID NO:47(可变轻链序列)
SEQ ID NO:48(可变重链序列)
SEQ ID NO:49(可变轻链序列)
SEQ ID NO:50(可变轻链序列)
SEQ ID NO:51(可变轻链序列)
SEQ ID NO:52(可变轻链序列)
SEQ ID NO:53(可变重链序列)
SEQ ID NO:54(可变轻链序列)
SEQ ID NO:55(可变轻链序列)
SEQ ID NO:56(可变轻链序列)
SEQ ID NO:57(可变重链序列)
SEQ ID NO:58(可变重链序列)
SEQ ID NO:59(可变重链序列)
SEQ ID NO:60(可变重链序列)
SEQ ID NO:61(可变重链序列)
SEQ ID NO:62(可变重链序列):
SEQ ID NO:63(可变重链序列)
SEQ ID NO:64(可变重链序列)
SEQ ID NO:65(可变重链序列)
SEQ ID NO:66(可变重链序列)
SEQ ID NO:67(可变重链序列)
SEQ ID NO:68(可变重链序列)
SEQ ID NO:69(可变重链序列)
SEQ ID NO:70(可变重链序列)
SEQ ID NO:71(可变重链序列)
SEQ ID NO:72(可变重链序列)
SEQ ID NO:73(可变重链序列)
来自抗体10F2Hum的SEQ ID NO:74(可变轻链序列)1:
来自抗体10F2Hum的SEQ ID NO:75(可变轻链序列)2:
SEQ ID NO:76(可变轻链序列)
本发明的示例性人源化抗体是具有如下表中所示的重链和轻链序列的人源化抗体。下表中的粗体加下划线的序列为可变域,而正常的未经加下划线的序列为恒定域:
将可变区亚克隆至一个或两个不同的合适的IgG表达载体中:
A)在Fc区中具有Leu234Ala、Leu235Ala双重突变以减少诸如FcγR的效应子功能和补体结合的人类IgG1-KO(基因敲除)/κ形式
B)在铰链区中具有Ser228Pro突变以减少IgG4半分子的出现和Leu235Glu突变以进一步减少FcγR结合的人类IgG4-DM(双重突变体)/κ形式
纯化抗体A和抗体B且通过以下准则评估:
-CCF的外观(浊度)
-CCF的过滤特性
-蛋白A的产量
-洗脱和中和时的浊度
-可溶性聚集体(SEC)
-纯度/污染概况(SDS)
-电荷概况(IEF)
实施例2:健康中国和日本受试者中的1期临床试验中的BI 655064的安全性、药物动力学和药效学
摘要
目的:为评估在4周内每周一次施用80-240mg的单剂量和240mg的多剂量之后,健康中国和日本受试者中BI 655064的安全性、药物动力学和药效学。
方法:进行两个1期双盲安慰剂对照研究(中国/日本男性受试者中BI 655064的单上升剂量[n=12/BI 655064剂量组]或中国男性受试者[n=9]中重复240mg BI 655064)。收集血浆样品以研究BI 655064药物动力学、药效学(CD40受体占有率[RO])和免疫原性,以及BI 655064的安全性和耐受性。
结果:BI 655064显示在4周内80-240mg的单剂量施用和重复施用240mg BI655064之后良好的总耐受性。更多中国受试者报告单剂量施用之后与日本受试者相比的不良事件(59.4%相对于3.1%)。BI 655064表现出非线性可饱和动力学,其中较高剂量引起较慢明显清除率(0.514-0.713mL min 1)和不成比例地较高总暴露量(AUC0-inf;5610-7780μg·h mL-1)和240mg BI 655064的最大血浆浓度(15,700-21,300ng mL-1)。CD40 RO的百分之九十抑制以≥120mg的剂量实现,且观察到BI 655064血浆浓度与CD40 RO的抑制之间的直接关系。大部分受试者具有积极治疗引发的抗药物抗体反应。
结论:东亚男性受试者中的BI 655064药物动力学和安全性概况与西方群体中观察到的受试者一致。未来临床试验无需调整BI 655064给药建议。
引言
细胞表面受体CD40与其配体CD40L(CD154)的相互作用在调节体液和细胞免疫和在自身免疫性疾病(诸如类风湿性关节炎(RA)、系统性红斑狼疮(SLE)和狼疮性肾炎(LN))的病理学中发挥重要作用。SLE为一种系统性自身免疫性疾病,其特征在于丧失对各种自身抗原,尤其核酸和其结合蛋白的B细胞耐受性。这些自身抗体形成免疫复合体,其沉积在身体的多种组织中且驱使炎症性细胞和介质募集至肾脏,引起LN。SLE的肾损伤随种族而变化,其中与高加索人(30-38%)相比,患有SLE的东亚患者表现出较高的肾损伤率(50-60%),其中在泰国和斯里兰卡中观察到最高的LN比率(70-100%)。
BI 655064为人源化、非耗竭、拮抗性治疗抗体,其选择性地结合人CD40且阻断CD40-CD40L相互作用。缺乏可结晶(Fc)区域的功能片段的抗CD40L抗体与血栓栓塞事件不相关。将两个突变(Leu234Ala和Leu235Ala)引入BI 655064的Fc区中以防止Fc介导的补体介导的细胞毒性和血小板活化。在患有活动性RA的患者中,BI 655064已与炎症性和骨再吸收标记(IL-6、MMP-3和核因子κB配体的受体活化剂)、自身抗体浓度(IgG、IgM和IgA类风湿性因子)和CD95+活化的B细胞子集的减少相关。目前正在进行中的诱导和维持研究中评定BI 655064在患有LN的患者中的功效和安全性。
BI 655064已以单上升剂量(SRD)和多上升剂量(MRD)形式施用至西方健康志愿者。在SRD研究中,BI 655064以0.2与120mg之间的静脉内(i.v.)施用形式和40与120mg之间的皮下(s.c.)施用形式施用。BI 655064暴露与剂量按前述比例增加,其中给药的终末半衰期在4h至4天i.v.和大约5天s.c.之间。在i.v.和s.c.BI 655064两者给药之后,观察到剂量相关的CD40受体占有率抑制(RO)和CD54上调增加,且增加的单次i.v.和s.c.剂量直至120mg BI 655064;剂量≥20mg i.v.和120mg s.c.显示>90% CD40受体占有率和CD54上调的抑制,其在120mg i.v和s.c.组中持续7天。BI 655064的所有剂量均具有良好耐受性。
在MRD研究中,BI 655064血浆浓度与剂量按前述比例增加,最可能归因于80与120mg之间的剂量的目标介导的清除率,但对于>120mg的剂量接近比例。终末半衰期在6天与8天之间的范围内。在给药4周之后,在所有剂量水平下观察到>90% CD40受体占有率和CD54上调的抑制,在最后一次给药之后持续17天。80-240mg BI 655064的多次递增s.c.给药通常具有良好耐受性,且未观察到急性免疫反应的相关迹象。
在此,我们呈现来自两个研究的结果,所述研究经实施以在4周内每周一次(q1w)施用SRD(80-240mg)和240mg BI 655064的多剂量之后表征BI 655064在健康中国和日本受试者中的安全性、药物动力学(PK)和药效学(PD)。
方法
受试者
符合条件的受试者为以下健康的东亚男性受试者:中国种族(中国人种;出生于中国;或在中国境外出生的中国人种和四名在中国境内出生的中国人种祖父母的后裔)或日本人种(出生于日本,和在日本境外居住<10年且父母和祖父母均出生于日本境内),年龄在20与45岁之间,身体质量指数(BMI)≥18.5且≤25kg m-2。
研究设计
研究1为剂量组内的中国和日本健康男性受试者中的随机双盲安慰剂对照的SRD研究(ClinicalTrials.gov identifier:NCT01917916)。受试者以3:1比率(BI 655064:安慰剂)随机化至四个连续剂量组;每80、120、180和240mg BI 655064剂量组16名受试者(8名中国人、8名日本人)。在各剂量组内,12名受试者(6名中国人,6名日本人)接受BI 655064且4名受试者(2名中国人,2名日本人)接受安慰剂。在各剂量递增之后评估安全性数据。基于高加索人健康志愿者的PK/PD模型,选择用于研究1中的80-240mg BI 655064的剂量,表明每周80mg BI 655064给药对CD40 RO的>90%抑制。
研究2为中国健康男性受试者中的随机双盲安慰剂对照多剂量研究(ClinicalTrials.gov identifier:NCT02331277)。受试者以3:1比率随机分组以在4周内接受240mg BI 655064(9名受试者)或安慰剂(3名受试者)q1w。基于来自健康志愿者的先前临床研究的安全性、PK和PD数据选择240mg剂量。BI 655064在两个研究中均以s.c.注射形式施用。
这些研究的目标为研究在s.c.注射80-240mg的SRD后且在多剂量BI 655064(4周内240mg BI 655064的q1w s.c.注射)后,健康中国和日本男性受试者中BI 655064的安全性、耐受性、PK和PD。
这些研究是在韩国首尔的首尔大学医院临床试验中心(Seoul NationalUniversity Hospital Clinical Trial Centre)对中国人种的受试者进行的,以及在日本东京的Medical Co.LTA Sumida Hospital对日本人种的受试者进行的。所有受试者提供书面知情同意书。根据首尔大学医院机构审查委员会(Seoul National UniversityHospital Institutional Review Board)(华裔)、九州岛临床药理学研究机构审查委员会(Kyushu Clinical Pharmacology Research Institutional Review Board)(日本种族)、临床良好规范和赫尔辛基宣言和其修正进行研究。
安全性评估
安全性通过监测治疗引发的不良事件(AE;使用MedDRA术语)、体检、生命迹象、12导联心电图(ECG)和临床实验室测试(血液学、凝血,包括出血时间、临床化学和尿分析)来评定。
耐受性由研究者根据存在或不存在“肿胀”、“硬结”、“发热”、“泛红”、“疼痛”或“其他发现”来判定。
药物动力学评估
使用留置导管从前臂静脉将用于PK分析的血液样品(2mL)收集至三钾乙二胺四乙酸(K3 EDTA)抗凝剂管中。对于研究1,给药前且以给药后长达1656小时的规则时间间隔收集血液样品。对于研究2,在第一次给药之前、在第一次给药后长达144小时的规则时间间隔、在第二次、第三次和第四次给药之前(分别在第一次给药后168小时、336小时和504小时),且在第一次给药后长多3192小时以规则时间间隔收集血液样品。
收集之后立即将血液样品置于冰上且在4℃-8℃下在样品收集30分钟内离心(2000-4000×g)10分钟。将血浆转移至两个聚丙烯样品小瓶(各大约0.4mL)中且在≤-20℃下储存,直至运送至分析实验室。
BI 655064的血浆浓度在所有访问时使用经验证的夹层酶联免疫吸附测定法(ELISA;Covance Laboratories Inc.,Chantilly,VA,USA)评估,其中定量下限为30ng mL-1。研发ELISA且经验证用于定量人类血浆中的BI 655064。该方法符合系统适合性、准确性、精确性、定量限制、选择性、稀释线性和分析物稳定性的所有前瞻性标准。在六个分析操作中测试准确性和精确性,且所有水平均具有小于30%的总误差(绝对%RE加%CV)。对于此方法,满足分析内和分析间准确性和精确性接受标准±20%;定量(LLOQ)的下限和(定量的上限(ULOQ))±25%。定量范围为30至800ng/mL。稀释线性确立为1/50,000。基于人类血浆中BI 655064的回收率,选择性在正常、溶血的和血脂样品中是可接受的。稳定性评估指示掺入人类血浆中的BI 655064在6次解冻循环之后稳定,在环境室温下持续大约24小时,在2至8℃下持续72小时,且在-60至-80℃下持续长达20个月且在-15至-30℃下持续12个月。BI655064在全血中稳定长达四小时。完整分析法细节由Schwabe等人提供。
血浆BI 655064浓度时间数据通过非分室方法使用 软件(版本6.3,Certara L.P.,Princeton,NJ 08540,USA)分析。参数包括最大血浆浓度(Cmax)、最小血浆浓度(Cmin)、使用标准WinNonlin程序实现Cmax(tmax)和终末半衰期(t1/2)的时间。浓度-时间曲线下面积随着时间零至最后一个可定量血浆浓度(AUC0-tz),且使用WinNonlin线性上调/对数下降算法计算均匀给药间隔τ(AUCτ)内的AUC。在研究1中,表观清除率(CL/F)计算为剂量/AUC0-inf,其中F为系统性可用性且AUC0-inf为从时间0外推至无穷大的剂量时间间隔内的AUC。在研究1中,表观分布体积(Vz/F)测定为(CL/F)/末端消除常数(λz)。在研究2中,累积比率(基于Cmax的RA,Cmax;基于AUCτ的RA,AUC)计算为第四剂量之后的值与第一剂量之后的值的比率。
药效学评估
用于测定CD40 RO(2.7mL)的血液样品是从前臂静脉收集在肝素抗凝剂管中。随后,将1mL全血转移至TransFix稳定管中且在冰上递送至德国Boehringer IngelheimPharma GmbH&Co.KG以进行进一步分析。对于研究1,在给药前和以给药后长达1320小时的规则时间间隔收集血液样品,且对于研究2,在第一次给药前、在第一次给药后72小时、在第二次和第四次给药前和以第一次给药后长达3192小时的规则时间间隔收集血液样品。
如Albach等人所描述,使用经验证的荧光活化的细胞分选(FACS)分析法来分析CD40 RO。使用来自与或不与异硫氰酸荧光素标记的BI 655064一起孵育的样品的所观察到的荧光值的比率来计算CD40 RO。CD40 RO的抑制表示为百分比且通过将来自给药后测量值的CD40 RO值相对于各个别受试者的对应给药前基线值进行计算。
免疫原性评估
用于测量针对BI 655064的抗体(抗药物抗体[ADA])(2mL)的血液样品在K3-EDTA抗凝剂管中自前臂静脉收集。对于研究1,在给药前和在给药后264小时、984小时和1656小时时收集血液样品,对于研究2,在第一次和第四次给药之前和在第一次给药后912小时、1848小时、2520小时、3192小时和5880小时时收集血液样品。
收集之后立即将血液样品置于冰上且在4℃-8℃下在样品收集30分钟内离心(2000-4000×g)10分钟。将血浆转移至两个冷冻管(各大约0.4mL)中且在≤-20℃下储存,直至运送至分析实验室。
使用经验证的桥联测定法在血浆样品中分析针对BI 655064的抗药物抗体(Covance Laboratories Inc.,Chantilly,VA,USA)。用正常人类血浆验证使用生物素标记的BI 655064的电化学发光测定(ECL)测定法以用于检测抗BI 655064抗体。对于验证层,确定健康血浆中的验证截点在外源添加的BI 655064存在下为35.7%抑制。该方法的精确度通过阳性对照测定为具有<10%的CV。在250ng/mL阳性对照抗体水平下,抗BI 655064的BI655064药物耐受性为50g/mL。
如果其在筛检测定中的反应大于或等于板特异性切点且如果其在特异性测试中证实为阳性(通过添加BI 655064阻断的反应),则将样品视为ADA阳性;证实ADA阳性样品在滴度分析中进一步表征。通过分析连续两倍样品稀释度测定滴度。所报告的滴度为产生大于或等于确认切点的平均电化学发光值的最高倍稀释。完整测定法细节由Schwabe等人提供[11]。
统计分析
使用安全性、PK和PD的描述性统计分析研究结果。不进行样本大小的正式计算。安全性群体包括接受BI 655064的所有受试者。PK和PD群体包括已接受BI 655064且在无相关重要治疗方案违规的情况下提供PK和PD分析的可评估数据的所有受试者。功率模型用于探究研究1中的Cmax、AUC0-tz和AUC0-inf的剂量比例。该模型定义为:exp(Yij)=α'*exp(Xi)β+ε'ij。在对数转换之后,将模型转换成线性形式:Yij=α+β*Xi+εij。如果回归线(β)的斜率等于1,则假定剂量比例。
结果
受试者
研究1和2的人口统计和基线特征概述于表6中。研究1入组64名健康男性受试者(32名中国人和32名日本人)且所有受试者完成研究。日本受试者比中国受试者稍大(平均年龄28.5岁相对于25.2岁)。此外,日本受试者相较于中国受试者具有较低体重和BMI(分别为总体平均体重63.9kg相对于69.4kg和总体平均BMI 21.3kg m-2相对于23.0kg m-2)。日本受试者中无一人为吸烟者,而32名中国受试者中的17名为吸烟者。
表6.人口统计和基线特征
结果以年龄、体重和BMI的平均值(标准偏差)显示。结果以吸烟和酒精史的受试者数目(受试者百分比数目)显示。
a每天吸烟不超过10支香烟、3支雪茄或3个烟斗。
b在不干扰研究参与的程度下。
BMI,身体质量指数;CHI,中国受试者;JPN,日本受试者;SD,标准偏差。
中国和日本受试者在不同剂量组之间不存在人口统计特征的相关差异,不同之处在于研究1中240mg剂量组中的日本受试者比中国受试者略微年长(平均年龄36.2相对于23.2岁;表6)。
研究2入组12名健康中国受试者,一名受试者在接受全部四个剂量的安慰剂之后撤回同意书且11名受试者完成研究。
研究2中的治疗组之间不存在人口统计特征的相关差异,不同之处在于安慰剂组仅含有目前或戒烟者的受试者且安慰剂组中无受试者饮酒(表6)。
安全性
BI 655064单剂量上升至240mg经中国和日本受试者良好耐受,且240mg BI655064q1w在4周内的多次给药经中国受试者良好耐受。在这些两个研究中的任一者中未报告严重AE或导致停药的AE,且所有AE的严重程度为轻度或中度且在研究结束时消退(表7)。在研究1中,只有中国人种受试者经历治疗相关AE,且与安慰剂相比,在BI 655064的单剂量施用之后观察到更多治疗相关AE。认为药物相关的最频繁报告的AE为腹泻,其由合并的BI655064剂量组中24名受试者中的两个(8.3%)报告,相比于研究1中经安慰剂治疗的8名中国受试者中无一人(0%)报告。对于研究2,认为药物相关且报告超过一个受试者的唯一AE为胸痛、头痛、关节痛、肢体疼痛和痤疮;其中,头痛是BI 655064组中报告的受试者百分比高于安慰剂组的唯一事件(BI 655064有2名受试者[22.2%]相对于安慰剂有0名受试者)。
表7.AE和治疗相关AE的频率的概述
a包括日本人种中的一名受试者(所有其他具有AE的受试者均为中国种族)。
b定义为导致死亡,立即危及生命,导致持续性或严重残疾或失能,需要或延长受试者住院治疗的AE是先天性异常或出生缺陷、癌症或出于任何其他原因视为严重的。
c定义为失能或导致无法工作或进行日常活动的AE。
d由研究者定义。
e报告超过或等于两个接受BI 655064的受试者中出现的AE。
AE,不良事件。
未观察到关于临床实验室测试的临床相关发现(包括出血时间)、生命征象、ECG、体检或局部耐受性,除了在第三次注射之后经历疼痛和在第四次注射之后经历“其他发现”的研究2的BI 655064 240mg治疗组中所入组的一名受试者以外。
药物动力学
在研究1中SRD施用之后,BI 655064血浆浓度随剂量升高而增加。BI 655064血浆浓度-时间曲线在给药后96-144小时达至峰值,随后至少达到两相下降(图1)。终末消除半衰期(t1/2)通常为97.4-225小时长范围。平均CL/F值较小(范围:0.467-4.04mL min-1)且倾向于随剂量增加而减少。平均Vz/F值也随剂量增加而减少(范围:8.28-40.3L)。120mg-240mg剂量组的Cmax和AUC参数的变化系数通常在40%-90%范围内,表明中等至高可变化性,且对于80mg剂量组,至多为1740%,表明极高可变化性(由具有极低AUC的一名受试者驱动)。日本受试者中的暴露量(Cmax和AUC)通常高于所有剂量组中的中国受试者中的暴露;然而,暴露比率(日本/中国)在最高(240mg)剂量组中较小(Cmax:1.36;AUC0-inf:1.39)。日本受试者中的t1/2值稍微长于中国受试者中的t1/2值,而tmax值显示无明显差异(表8)。
表8.在向研究1中的中国和日本受试者单剂量施用之后选择的BI 655064药物动力学参数的概述。
显示为几何平均值的数据(变化%的几何系数),除了tmax,其呈现为中值(范围)。
an=5。
AUC0-inf,自时间零外推至无穷大的浓度-时间曲线下面积;AUC0-inf,norm,剂量标准化AUC0-inf;AUC0-tz,随时间零至最后一个可定量血浆浓度的浓度-时间曲线下面积;AUC0-tz,norm,剂量标准化AUC0-tz;CL/F,表观清除率;Cmax,最大血浆浓度;Cmax,norm,剂量标准化Cmax;t1/2;终末半衰期;tmax,实现Cmax的时间;Vz/F,表观体积分布。
在整个剂量范围(80-240mg)内分析中国和日本受试者中的剂量比例。BI 655064展示在整个剂量范围(80-240mg)内AUC(斜率β=2.6-3.4)和Cmax(斜率β=2.3-2.5)的大于剂量比例的增加。使用剂量标准化暴露的目视检查也支持BI 655064暴露中的前述比例增加(数据未示出)。
当在120mg-240mg的剂量范围内评估剂量比例时,斜率β估计值保持>1.5,但95%信赖区间包括Cmax(中国和日本受试者)和AUC(日本受试者)的一致性。
在研究2中,在研究1中接受240mg BI 655064的单剂量(在参与研究2之前大约1.5年)的一名受试者罹患ADA。滴度值自16(基线)显著提高至65,536(恰好在240mg BI655064q1w的第四剂量之前)。初步研究表明此受试者提出ADA干扰血浆中BI 655064的生物分析测量;因此,自此受试者的数据自此处呈现的PK分析排除。
在研究2的4周内的240mg BI 655064q1w剂量之后,血浆浓度-时间曲线在最后剂量之后达到峰值84.2小时,随后至少具有247小时的t1/2的两相下降。在第四剂量之后血浆浓度未达到稳定状态(图2)。基于Cmax和AUCτ在第四剂量之后的累积比率分别为3.24和4.19(表9)。
表9.在向研究2中的中国受试者施用多剂量之后选择的BI 655064药物动力学参数的概述。
显示为几何平均值的数据(变化%之几何系数),除了tmax,其呈现为中值(范围)。
aAUCτ与AUC0-168h同义。
AUCτ,1,第一次给药后均匀给药时间间隔内的血浆浓度-时间曲线下面积;AUCτ,4,第四次给药后均匀给药时间间隔内的血浆浓度-时间曲线下面积;Cmax,1,第一次给药后观察到的最大浓度;Cmax,4,第四次给药后观察到的浓度最大值;Cmin,4,第四次给药后血浆中分析物的最低测量浓度;q1w,每周一次;RA,AUC,4,等于第四次给药后的AUCτ除以第一次给药后的AUCτ;RA,Cmax,4,等于第四次给药后的Cmax除以第一次给药后的Cmax;t1/2,4,第四次给药后的终末消除半衰期;tmax,至观察到的浓度最大值的时间;tmax,4,第四次给药后至观察到的浓度最大值的时间。
免疫原性
在研究1中,在BI 655064的单次给药后,在大部分受试者(45/48名受试者)中检测到阳性ADA反应,以及在大部分情况下,BI 655064的终末消除阶段(给药后第42天或第70天)中的反应起始时间(表10)。
表10.在向研究1中的中国和日本受试者单剂量施用之后的阳性ADA的概述。
ADA,抗药物抗体;NC,未计算。
在研究2中重复给药240mg BI 655064之后也检测到阳性ADA反应(表11)。截至第245天,入选BI 655064治疗组中的所有九名受试者具有阳性ADA反应(中值发作时间:第一次给药后105天)。基于Shankar等人2014白皮书关于免疫原性报告的建议,将ADA反应指定为治疗诱导或治疗加强。[13]。7/9名受试者(77.8%)表现出治疗诱导的ADA阳性反应,且具有预先存在的ADA的2/9名受试者(22.2%)表现出治疗增强的ADA阳性反应。在研究中将具有基线滴度1的一名受试者随后基于提高的滴度分类为增强的。也参与研究1的受试者的ADA反应自16显著增强至65,536。
表11.在向研究2中的中国受试者多剂量施用之后阳性ADA的概述。
a在此时间点仅测试八名受试者。
b在此时间点仅测试两名受试者。
ADA,抗药物抗体;NC,未计算;q1w,每周一次。
药效学
在研究1中的安慰剂剂量组中,未观察到CD40 RO的抑制,而RO在所有活性剂剂量组中受到抑制。在中国受试者中,BI 655064以≥120mg的剂量单次s.c.施用导致CD40RO的90%抑制,在日本受试者中,所有BI 655064剂量均实现90%的CD40 RO抑制(图3)。90%抑制的持续时间随着BI 655064剂量增加而增加(120mg:24-168小时;180mg:12-432小时;240mg:12-648小时)。
在研究1中,在BI 655064血浆浓度与CD40 RO抑制之间观察到直接关系。CD40 RO的百分之九十抑制通过BI 655064血浆浓度≥400ng mL-1来实现。此外,中文字受试者与日本受试者之间的BI655064血浆浓度与CD40 RO抑制之间的关系无明显差异(图4)。
在研究2中,自此PD评估排除具有预先存在的ADA和增强的反应(最可能归因于参与研究1)的受试者。初步研究表明ADA可能干扰PD测定法形式的结果,最可能归因于使用FITC标记的BI 655064测定试剂。在4周内q1w s.c.施用240mg BI 655064之后,在BI655064治疗组中观察到CD40 RO之90%抑制,其中在第一剂量之后1848与3192小时之间抑制实质上减少。在安慰剂治疗组中,CD40 RO的抑制随时间推移相对于基线下降(图3)。
讨论
本文所描述的两个阶段1研究评价BI 655064在健康东亚受试者中施用80-240mgBI 655064的SSID和4周内用240mg BI 655064q1w多次给药之后的安全性、PK和PD,且进行以支持将东亚受试者整合至2期临床试验中。
BI 655064显示在4周内施用单次s.c.80-240mg剂量和240mg q1w的多次给药后健康东亚受试者中的良好总体耐受性。所观察到的AE概况与来自在西方群体中进行的类似研究的结果一致。一般而言,具有AE的受试者的比例类似于或低于接受安慰剂的受试者中观察到的那些比例。总体而言,与日本受试者相比,较高比例的中国受试者报告任何AE(59.4相对于3.1%)。观察到接受BI 655064的受试者以及接受安慰剂的受试者的差异。日本受试者中报告的AE频率较低也已在将日本志愿者与其他人种进行比较的文献中报告的其他单剂量和多剂量研究中观察到。然而,报告AE的中国受试者的比例与在西方群体中进行的类似SRD研究中观察到的比例类似,其中在BI 655064s.c.或i.v.施用之后有41%受试者报告AE。
BI 655064在BI 655064的较高剂量下表现出非线性饱和动力学,导致清除较慢且使血浆暴露不成比例地较高(AUC和Cmax)。在240mg剂量下,清除率达到最小0.514-0.713mLmin-1。东亚受试者中观察到的BI 655064PK概况与西方群体中观察到的概况相当且与呈现非线性PK的其他化合物一致,可能归因于靶向介导的途径。
如补充图1中所示,在高加索人、日本人和中国群体中比较受试者之个别BI655064暴露;在所观察到单剂量(分别为补充图1A和1B)和多剂量(分别补充图1c和1D)之后,Cmax和AUC0-168在人种内和人种间存在较大变化。考虑到较大变化,在80-240mg剂量范围内施用SRD之后或在东亚受试者中多次给药后,向中观察到的受试者,BI 655064暴露(AUC、Cmax)与在西方群体中观察到的那些暴露无明显差异。
观察到BI 655064暴露随着体重和BMI增加而减少的趋势。日本受试者中的BI655064暴露(AUC、Cmax)一般高于研究1中的80-240mg剂量范围中的中国受试者。鉴于日本受试者具有比入选研究1中的中国受试者低的基线体重(表1),此可归因于BI 655064暴露与体重之间的相关性。由于每剂量组受试者的数目受到限制,因此需要用较大数目的受试者进一步调查以显示共变数定量(诸如体重或吸烟史)的影响。
CD40 RO的百分之九十抑制在此东亚群体中以BI 655064≥120mg的剂量来实现,且观察到BI 655064血浆浓度与CD40 RO抑制之间的直接关系。可能需要较高剂量的BI655064以实现患有LN的患者中的>90% CD40 RO,因为LN中的炎症不仅由B细胞驱动,而且由全部表达CD40的单核细胞、巨噬细胞、树突状细胞和肾固有细胞(包括肾小球膜细胞、足细胞和近端小管细胞)驱动。
在研究2中,安慰剂组显示CD40 RO抑制下降(在最后一次取样时间点处相对于基线处的0下降至<-100%),其与未染色样品的荧光强度的不寻常下降相关。两个治疗组中出现的下降和此原因是未知的(在样品稳定性、测定实施或样品完整性中未观察到偏差)。因此,应谨慎解释来自研究2的CD40 RO数据。
入选这些研究中的几乎所有东亚受试者均具有阳性的治疗引发的ADA反应。虽然发病率高,但在这些研究中,在随访周期结束时主要观察到ADA反应,其中BI 655064血浆浓度接近测定定量下限且BI 655064很大程度上被消除;因此,无法评价ADA对BI 655064PK的影响。在西方群体中进行的先前研究中,ADA反应为适中的,其中滴度相对较低且高度可变(2-640)[11]。与高加索人受试者相比,用其他单克隆抗体,包括阿达木单抗和依法珠单抗(efalizumab)观察到东亚受试者中ADA的发病率更高。
在研究2中,ADA滴度相对较低(1-64),除了先前在研究1中接受BI 655064且在研究2中在基线处具有预先存在的ADA反应的受试者。此受试者在研究2期间具有显著增强的ADA反应,但未展示与ADA的存在相关的安全性发现。中和ADA测定法当前不可用;因此,未得出关于ADA是否中和的结论。在用人源化抗CD52单克隆抗体阿仑单抗再暴露之后,也已报告增强的ADA反应。
在这些研究中,无法排除ADA对PK和PD测定法的影响。观察到的ADA反应的高发病率的原因是未知的,但可能归因于树突状细胞上CD40的表达。在患有RA与甲氨蝶呤反应不足的患者中的BI 655064的最近临床试验中,ADA的发病率较低(6/44名患者)且所有ADA滴度均≤8。
总之,东亚男性受试者中的BI 655064PK和安全性概况与在西方群体中进行的先前研究中观察到的那些一致;因此,未来临床研究无需调整BI 655064给药建议。在此东亚集体中观察到ADA的高发病率;因此未来临床试验应监测共施用BI 655064与其他免疫抑制剂(即甲氨蝶呤)的患者的免疫原性概况,其可降低ADA反应的发病率,如RA中的其他生物制剂所见。
实施例3:评定BI 655064(一种拮抗性抗CD40抗体)在患有狼疮性肾炎的患者中的功效和安全性的随机剂量范围、安慰剂对照、II期研究
背景:在患有SLE的患者(pts)中,CD40-CD40L途径的活化导致B细胞和其他炎症性细胞类型的刺激和增殖。自身抗体的后续产生和其在肾脏中的沉积,以及骨髓和常驻肾细胞的活化导致局部炎症且最终导致肾损伤。因此,CD40为狼疮性肾炎(LN)中的吸引人的治疗靶标。BI 655064为在摩尔范围内阻断CD40途径且下调经活化的B细胞的人源化抗CD40单克隆抗体。
此研究的目的是为了测试不同剂量的BI 655064是否帮助患有活动性狼疮性肾炎的人群。特别地,我们评定在患有活动性增生性LN(狼疮性肾炎)的患者中,与安慰剂相比,作为霉酚酸酯和类固醇的附加物,在52周(wks)内三次剂量的皮下BI 655064的功效和安全性。
目标
目标为表征剂量反应关系,鉴定III期发展的目标剂量,且研究3种剂量的BI655064在患有活动性狼疮性肾炎的患者中作为标准照护疗法的附属皮下施用52周的安全性和功效。
研究设计/方法
患有活动性LN的患者中的此多中心、随机、安慰剂对照、双盲、平行组II期试验在2016年8月16日与2020年8月18日之间跨越20个国家74个地点进行。将总共121名患者以与安慰剂或BI 655064120mg、180mg或240mg的2:1:1:2比率随机化;所有患者均接受SoC(标准照护)。(图5)根据种族(亚洲人相对于非亚洲人)和筛选时的蛋白尿(尿蛋白/尿肌酐比率[UP/UC]<3或≥3)对随机分组进行分层。在52周的治疗之后进行主要功效分析。在第52周时具有至少部分肾反应或UP/UC<1的患者可决定其是否想要参与维持试验1293.13。
患者数目
计划随机化:120;实际随机化:121。
BI 655064 120mg:随机化:21;经处理:21;经分析:21。
BI 655064 180mg:随机化:20;经处理:20;经分析:20。
BI 655064 240mg:随机化:40;经处理:40;经分析:40。
安慰剂:随机化:40;经处理:40;经分析:40。
总体而言,121名患有LN的患者以与安慰剂或BI 655064 120mg、180mg或240mg的2:1:1:2比率随机化、双盲,且在前3周接受每周起始剂量,随后对于120和180mg剂量每2周给药,且对于240mg组每周给药(120mg)。关键纳入标准包括在筛选之前3个月内的活动性ISN/RPS III类或IV类(±V)肾活检和≥1mg/mg的筛选蛋白/肌酐比。基于人种(亚洲人与非亚洲人)和筛选蛋白/肌酸(UP/UC)比率(<3相对于≥3)对随机分组进行分层。主要功效终点为完全肾反应(CRR),定义为第52周时的24h蛋白尿<0.5g/天和稳定的eGFR。
在试验的初始阶段(第1-26周)期间的SoC包括:剂量为2-3g/天的MMF。若患者经历MMF相关不良事件(AE),则允许剂量<2g/天。高剂量类固醇,其包括脉冲的甲基强的松龙(500mg静脉内[IV],持续3天),随后在随机分组12周内口服类固醇递减至每天10mg强的松当量。在随机分组之前6周内接受≤3g IV类固醇的患者仅接受达至1.5g所需的IV类固醇脉冲的数目。如果研究者认为有必要,则允许每天1000mg甲基强的松龙的最大剂量,持续长达3天(总计≤3000mg)。
试验的第二期(第26-52周)期间的SoC包括MMF(1-2g/天)以及每天≤10mg普赖松当量。经历MMF相关AE的患者允许剂量减少至1g/天。若患者经历疾病恶化或红肿,则允许研究者增加类固醇剂量。
研究终点描述于图5中。完全肾反应(CRR)定义为尿蛋白(UP)<0.5g/天且如果eGFR低于正常范围,则正常估计的肾小球滤过率(eGFR)或相对于基线减少<20%。部分肾反应(PRR)定义为蛋白尿相对于基线和正常eGFR减少≥50%,或如果eGFR低于正常范围,则eGFR相对于基线减少<20%。
诊断
患有狼疮性肾炎的患者(根据ISN/RPS2003分类的III类或IV类)。
主要纳入标准
在第1次访问时年龄为18至70岁的男性和女性患者,通过ACR标准1997诊断系统性红斑狼疮症(SLE)。必须记录至少4个标准,其中的一者必须为在筛选时或诱导疗法开始时的阳性抗dsDNA抗体或阳性抗核抗体(ANA)。患者必须患有III类或IV类狼疮性肾炎(ISN/RPS2003分类),伴有活动性或活动性/慢性疾病,允许共存V类,在筛选之前3个月(在美国6个月)内由肾活检证实,或在倘若针对狼疮性肾炎的诱导疗法尚未开始的筛选期间,以及通过蛋白尿≥1.0g/天(分别为UP/UC≥1)证明的活动性肾病。
研究性产物:BI655064;剂量:剂量组1:120mg,一周一次,持续3周,随后120mg,每2周一次。剂量组2:180mg,一周一次,持续3周,随后180mg,每2周一次。剂量组3:240mg,一周一次,持续3周,随后120mg,一周一次。施用模式:皮下注射。
比较剂产品:安慰剂;剂量:不适用;施用模式:皮下注射。
治疗持续时间:治疗52周,随后8周随访时段。
功效评价标准
此试验中的主要终点为在第52周时患有完全肾反应(CRR)的患者的比例。次要终点为:在第26周具有CRR的患者的比例;在第26周和第52周具有部分肾反应(PRR)的患者的比例;在第26周和第52周具有主要肾反应(MRR)的患者的比例。
安全性评价标准
安全性标准包括不良事件(AE)、安全性实验室测试、体检(包括体重测量)、生命体征(血压、脉搏率)和12导联心电图。
统计方法
此II期剂量发现试验的统计设计为多重比较程序和建模(MCPMod)方法。使用逻辑回归模型分析在52周时的CRR(使用尿蛋白[UP]导出且使用来自24小时尿液集合的UP/UC导出)。模型中的因素包括治疗和共变量种族(亚洲人/非亚洲人)和筛选时的蛋白尿(UP/UC<3或≥3)。根据此模型,估计各活性剂量组的安慰剂调节的治疗估算以及其对应的变量共变量矩阵。这些结果用于MCPMod分析中。对各剂量水平下具有CRR的患者与安慰剂的模型化比例进行成对比较。此外,对各剂量水平下具有CRR的患者与安慰剂的所观察到的比例进行成对比较。使用纽康比(Newcombe)方法计算信赖区间且得出来自关联的巴纳德(Barnard)测试的p值。
在所有患者完成26周治疗之后进行中期分析。
结果:
此试验中的安慰剂反应高于预期(48.3%;表12);BI 655064剂量中无一者相比于安慰剂提高第52周时的CRR比率。然而,使用点点尿样评估,基于肌酐调节的蛋白尿在第52周时的CRR在180mg组(50%)中相对于安慰剂(42.5%)显示更好反应,且180mg剂量显示在第4周时相对于安慰剂随时间相对于基线的更大变化。相对于安慰剂(20.4周),在180mg组(17.3周)中实现CRR的时间更短。180mg组也显示总SLEDAI(SELENA)和其分项评分相较于安慰剂的改善。
表12.在第52周时的功效终点
基于24h蛋白尿的完全肾反应(CRR);在第46和52周基于UP/UC(点尿样)的确认的CRR(cCRR)。*逻辑回归模型包括治疗和筛选时的共变量种族和蛋白尿。
出人意料的高安慰剂反应促使评价确认的CRR(cCRR)的事后分析,由此在第46(对治疗的倒数第二次访问)和52周时均要求确认终点。相对于安慰剂(29.1%),在180mg组(44.3%)中观察到高15.2%的cCRR(p=0.26)。
虽然基于较小样品大小,与安慰剂相比,240mg组中报告更多感染相关重度和严重不良事件和嗜中性球减少症。值得注意的是,在出现嗜中性球减少症的患者中,没有产生临床影响(例如感染增加)。除这些观察结果以外,治疗组中的安全性数据是可比较的。
与安慰剂相比,在180和240mg组中CD27-IgD-CD95+、CD27-IgD+CD95+、CD27+IgD+CD95+和CD27+IgD-CD95+B细胞子集的百分比中观察到较大程度的相对于基线的减少。
在用BI 655054治疗的五名患者中检测到治疗引发的抗药物抗体(ADA),所有患者均处于低滴度,且在接受安慰剂的一名患者中检测到;ADA对药物动力学或安全性没有影响。
概述-结论
试验不符合其主要CRR终点。然而,当在第46和52周时均要求确认CRR时,由此引起的安慰剂反应减少产生分别有利于180mg和240mg BI 655064的15.2%和9.1%的作用大小(表13)。
表13.在第52周时的功效终点
基于24h蛋白尿的CRR;在第46和52周基于UP/UC(点尿样)的cCRR。*逻辑回归模型包括治疗和筛选时的共变量种族和蛋白尿。
试验患者和对临床试验方案的顺应性
总共209位患者参与此试验。其中,将121名患者随机分组至4个治疗组中的1个(BI655064 120mg:21名患者,BI 655064 180mg:20名患者,BI 655064 240mg:40名患者,安慰剂:40名患者)。所有患者均用至少一种剂量的试验药物治疗。过早停止试验药物治疗的患者的比例在120mg组中为33.3%,在180mg组中为15.0%,在240mg组中为12.5%,且在安慰剂组中为17.5%。过早停药的最常见原因为AE(120mg:19.0%,180mg:15.0%,240mg:12.5%,安慰剂:7.5%)。
绝大部分患者为女性(89.3%);然而,与180mg和240mg组(各90.0%)相比,120mg组中女性的比例较低(76.2%)且安慰剂组中女性比例较高(95.0%)。总体而言,52.1%的患者为白人、43.0%为亚洲人、3.3%为黑人或非洲裔美国人,0.8%为多种族,且0.8%种族信息缺失。与在其他治疗组中相比,120mg组中的白人患者的比例略低。约20%的患者为西班牙种族;然而,安慰剂组含有比其他治疗组略低的西班牙患者百分比。患者群体的平均(标准偏差[SD])年龄为34.5(10.2)岁,且平均(SD)体重为63.5(15.2)kg。
治疗组之间在诊断时间<6个月的患者比例(120mg:28.6%,180mg:30.0%,240mg:42.5%,安慰剂:47.5%)、全球IV类狼疮性肾炎患者比例(基于当地肾脏病理学家的评估;120mg:47.6%,180mg:40.0%,240mg:40.0%,安慰剂:32.5%)、基线(120mg:52.4%,180mg:30.0%,240mg:67.5%,安慰剂:55.0%)处的抗dsDNA>ULN的患者比例、基线(120mg:85.9,180mg:99.9,240mg:91.1,安慰剂:88.8)处的平均eGFR[mL/min/1.73m2]和基线(120mg:4.3,180mg:3.0,240mg:3.2,安慰剂:2.8)处的平均UP[g/天]之间存在一些不平衡。
所有患者均使用皮质类固醇(主要为甲基强的松龙、强的松和强的松龙)和霉酚酸酯作为此试验中的标准护理疗法。系统器官类别水平下的其他通常使用的疗法为抗疟疾药、用于消化性溃疡和胃-食道反流病的药物、钙、其他镇痛剂和退热剂和血管收缩素转化酶抑制剂(ACEi)。使用ACEi或血管收缩素受体阻断剂疗法进行治疗的患者比例在安慰剂组(82.5%)中比在BI 655064组(120mg:61.9%,180mg:70.0%,240mg:77.5%)中高。
大多数试验患者暴露于试验药物超过48周。平均(SD)暴露量在120mg组中为41.6(15.9)周,在180mg组中为49.0(7.9)周,在240mg组中为48.7(8.0)周,且在安慰剂组中为46.5(12.6)周。
12.4%的患者(120mg:19.0%,180mg:0%,240mg:15.0%,安慰剂:12.5%)报告重要方案偏差(iPD)。最常见iPD涉及伴随药物使用。
功效结果
主要终点:在第52周时具有完全肾反应的患者比例。
在第52周时实现CRR的经调节的患者比例(基于来自24h尿液收集的UP)在安慰剂组中比在BI 655064治疗组中更高(表14)。在第52周观察到的安慰剂反应率明显高于预期。在MCPMod分析中,所有预定模型均显示平坦剂量反应形状。
表14:在第52周时具有完全肾反应(基于UP 24h)的经调节(基于模型)的患者比例
N=各组中的患者数目,n=所观察到的具有CRR的患者数目
1具有CRR的经调节的患者比例
2通过减去对应概率来计算概率差值。
使用基于来自24小时尿液收集的UP/UC的交替推导的CRR分析产生类似的结果,而在使用来自点尿样的UP/UC的CRR分析中,与安慰剂相比,在180mg和240mg组中观察到的在第52周实现CRR的患者比例更高。(50.0%和47.5%相对于42.5%)。在基于来自2个时间点(第46周和第52周;“确认的CRR”)处的点尿样的UP/UC的CRR的事后分析中,在180mg和240mg组中实现CRR的经调节的患者比例比安慰剂组中明显更高(44.3%和38.2%相对于29.1%)。
次要终点:在第26周时具有完全肾反应的患者比例。
在第26周,180mg组为唯一治疗组,其中较高比例的患者相对于安慰剂实现CRR(基于UP 24h)。所观察到的具有CRR的患者比例在第26周时为37.5%(安慰剂)、28.6%(120mg)、50.0%(180mg)和35.0%(240mg)。在第26周基于UP/UC 24h的CRR分析产生类似结果。
次要终点:在第26周和第52周时具有部分肾反应的患者比例。
在第26周和第52周时,180mg组为唯一治疗组,其中较高比例的患者相对于安慰剂实现PRR(基于UP 24h)。在第26周所观察到的具有PRR的患者比例为62.5%(安慰剂)、42.9%(120mg)、75.0%(180mg)和62.5%(240mg)。在第52周所观察到的具有PRR的患者比例为60.0%(安慰剂)、33.3%(120mg)、65.0%(180mg)和55.0%(240mg)。在第52周基于UP/UC 24h对PRR的分析中,180mg和240mg治疗组显示较高比例的患者相对于安慰剂实现PRR。
次要终点:在第26周和第52周具有主要肾反应的患者比例。
在第26周和第52周,180mg组为唯一治疗组,其中较高比例的患者相对于安慰剂实现MRR(基于UP 24h)。在第26周所观察到的具有MRR的患者比例为50.0%(安慰剂)、28.6%(120mg)、55.0%(180mg)和37.5%(240mg)。在第52周所观察到的具有MRR的患者比例为52.5%(安慰剂)、42.9%(120mg)、55.0%(180mg)和52.5%(240mg)。在第52周时基于UP/UC24h的MRR分析中,240mg组为唯一治疗组,表明较高比例的患者相对于安慰剂实现MRR。
安全性结果
几乎所有患者报告至少1个AE(不良事件)。系统器官类别(SOC)报告频率最高的AE(在任何治疗组中>25%)为感染和传染(120mg:61.9%,180mg:75.0%,240mg:75.0%,安慰剂:60.0%)、皮肤和皮下组织病症(23.8%、30.0%、55.0%、47.5%)、胃肠病症(38.1%、40.0%、40.0%、35.0%)、肌肉骨骼和结缔组织病症(33.3%、20.0%、32.5%、45.0%)、一般疾病和施用部位病况(38.1%、15.0%、25.0%、30.0%)、研究(19.0%、25.0%、40.0%、17.5%)、神经系统病症(14.3%、20.0%、30.0%、30.0%)和血液和淋巴系统病症(14.3%、20.0%、37.5%、10.0%)。优先项(PT)报告的频率最高的AE(在任何治疗组中>15%)为上呼吸道感染(23.8%、35.0%、17.5%、20.0%)、腹泻(23.8%、15.0%、22.5%、15.0%)、脱发(0%、15.0%、22.5%、17.5%)、鼻咽炎(9.5%、5.0%、10.0%、17.5%)和嗜中性白血球减少症(4.8%、15.0%、17.5%、2.5%)。
感染和传染是导致停药的最频繁AE;其在180mg组中报告1名患者(5.0%)且在240mg组中报告3名患者(7.5%)。蛋白尿为导致PT水平停止的唯一AE,其总共报告>1名患者(240mg中1名患者和安慰剂中1名患者)。
药物相关的AE(如由研究者所定义)最常属于SOC感染和传染(120mg:28.6%,180mg:15.0%,240mg:40.0%,安慰剂:22.5%)、研究(14.3%,0%,20.0%,10.0%)、血液和淋巴系统病症(4.8%,5.0%,15.0%,7.5%)和一般病症和施用部位病况(19.0%、0%、7.5%、10.0%)。最常见的药物相关PT(任何治疗组中≥10%)为上呼吸道感染(4.8%、10.0%、12.5%、10.0%)、带状疱疹(4.8%、0%、10.0%、2.5%)和嗜中性白血球减少症(0%、5.0%、10.0%、2.5%)。
最大RCTC 3级的AE最常报告于SOC血液和淋巴系统病症(120mg:4.8%,180mg:5.0%,240mg:12.5%,安慰剂:5.0%)和感染和传染(4.8%、5.0%、5.0%、5.0%);针对任何治疗组中>1名患者报告的RCTC级别3的PT为嗜中性白血球减少症(180mg:5.0%,240mg:5.0%)、淋巴球减少症(240mg:5.0%,安慰剂2.5%)和体重增加(240mg:5.0%)。
最大RCTC 4级的血液和淋巴系统病症最常报告于240mg组中(120mg:4.8%,180mg:5.0%,240mg:7.5%,安慰剂:2.5%);RCTC 4级的感染和传染仅报告于240mg组中(5.0%);任何治疗组中>1名患者报告的RCTC 4级的唯一PT为嗜中性白血球减少症(120mg:4.8%,180mg:5.0%,240mg:7.5%)。
AESI报告于类别机会性感染(120mg:19.0%,180mg:10.0%,240mg:25.0%,安慰剂:12.5%)、重度感染(4.8%、5.0%、7.5%、5.0%)和肝损伤(安慰剂:2.5%)。任何治疗组中>1名患者报告的PT水平得到AESI为带状疱疹(120mg:4.8%,180mg:5.0%,240mg:12.5%,安慰剂:7.5%)、口腔念珠菌病(120mg:9.5%)、胃肠炎(240mg:5.0%)和败血性休克(240mg:5.0%)。
SOC感染和传染中最常报告严重不良事件(SAE)(120mg:9.5%,180mg:10.0%,240mg:20.0%,安慰剂:7.5%)。在PT水平下,治疗组中>1名患者报告的SAE为败血性休克(240mg:5.0%)和嗜中性白血球减少症(120mg:4.8%,180mg:10.0%,240mg:2.5%)。在此试验中报告一例死亡:30岁女性患者死于细菌肺炎、急性呼吸衰竭和心室性心搏过速,其经研究者评定为与研究药物无关。
实验室参数的评价揭示嗜中性粒细胞的治疗组之间的不平衡:240mg组中具有较低嗜中性粒细胞计数的患者的比例高于其他治疗组。
结论
在52周治疗之后,就CRR而言,将BI 655064(在120、180和240mg的剂量下)添加至患有活动性狼疮性肾炎的患者的标准照护疗法中似乎没有超过安慰剂的益处。在安慰剂组中约48%患者实现CRR、120mg组中为38%、180mg组中为45%和240mg组中为45%。在第52周观察到的安慰剂反应率高于预期。
然而,在2个时间点(第46周和第52周)处对确认的CRR的分析导致安慰剂反应减少和超过安慰剂的180mg剂量的大量益处,其与在总SLEDAI-SELENA评分和其分项评分中观察到的改善一致。
尽管用BI 655064治疗在120和180mg的剂量下是安全且良好耐受的,但最高BI655064剂量(240mg)与较高频率的重度和严重感染、机会性感染和嗜中性白血球减少症相关。
事后分析结果和讨论
功效
B 655064对CRR和PRR的作用
基于24小时收集的UP(尿蛋白):在第26周时BI 655064 180mg剂量组中具有CRR的患者比例高于安慰剂组(50.0%相对于37.5%;图6A)。BI 655064 180mg组为唯一治疗组,其中在治疗26周与52周之后,实现CRR或PRR得到患者比例高于安慰剂组(图6B和图6D)。在第52周实现CRR的经调节的患者比例在安慰剂组中比在BI 655064组中的任一者中更高(图6C)。
基于来自点尿样的UP/UC:在第52周BI 655064 180mg和240mg组中实现CRR的患者比例高于安慰剂组中(图7A)。在第46周和第52周时确认的CRR(cCRR)的事后分析中,在BI655064 180mg和240mg组中实现cCRR的经调节的患者比例高于安慰剂组(分别为44.3%和38.2%相对于29.1%;图7B)。
其他终点的评定
在第52周实现CRR的患者中,BI 655064 180mg组中的患者相比其他治疗组中的患者在更短的时段内实现CRR(图8A)。基于点尿样的UP/UC随时间相对于基线额中值变化的分析表明BI 655064180mg的UP/UC随时间比其他组具有更实质性降低(图8B)。在第52周时,在BI 655064 180mg和240mg组中总系统性红斑狼疮疾病活性指数(SLEDAI)相对于基线的降低大于在其他治疗组中(图8C)。在BI 655064组中,非肾SLEDAI平均评分相对于基线的降低大于在安慰剂组中(图8D)。在治疗后第12周和第26周,在BI 655064 180mg和240mg组中的选定活化的B细胞子集中观察到相对于安慰剂组的显著减少(图9A和图9B)。
安全性
所有治疗组的AE频率是可比较的。BI 655064 240mg组中的较高比例患者相比于安慰剂和其他治疗组经历严重感染和嗜中性白血球减少症;然而,嗜中性白血球减少症与感染不相关。4级感染仅报告于BI 655064 240mg组中(两名患者,5.0%)。BI 655064 180mg组中未报告任何所关注的安全性发现。
讨论
此试验的结果表明,CD40-CD40L的抑制显示具有LN的患者中的一些益处,且证明靶向CD40而不引起血栓栓塞事件的可行性。基于来自24小时尿液收集的UP,该试验在第52周时不符合CRR的主要终点。出乎意料地高安慰剂反应促使事后分析以评价cCRR。BI655064 180mg和240mg组在第46周和第52周具有比安慰剂组分别高15.2%和9.1%的cCRR。经BI 655064治疗的患者中SLEDAI评分的改善支持其在治疗具有活动性LN的患者中的潜在应用。
与安慰剂组相比,在BI 655064组中观察到选择活化的记忆B细胞子集显著减少,其支持所观察到的临床作用。BI 655064 180mg相比于240mg组耐受良好。240mg剂量组中的患者中严重和重度感染和嗜中性白血球减少症的发病率高于安慰剂和其他治疗组。来自cCRR事后分析的结果证明BI 655064 180mg可对LN有效。反应者的第二年治疗正在进行中。
BI 655064对患有LN的患者的SLEDAI评分的有利影响和其先前在类风湿性关节炎中证实的功效表明BI 655064可为患有非肾性SLE病况的患者提供益处且保证进一步研究。
尽管已描述本发明的某些方面和实施方案,但这些方面和实施方案仅借助于实施例呈现,且并不旨在限制本发明的范围。实际上,本文所描述的新颖方法和系统在不脱离其精神的情况下可以以多种其他形式实施。随附权利要求书和其等效物旨在涵盖落入本发明的范畴和精神内的此类形式或修改。
本公开中引用的全部专利和/或出版物,包括期刊文章,以引用的方式明确地并入本文中。
序列表
<110> 勃林格殷格翰国际有限公司
<120> 抗CD40抗体用于治疗炎症性病况的用途
<130> 09-0706-WO-1
<150> 63/193776
<151> 2021-05-27
<150> 63/138014
<151> 2021-01-15
<150> 63/080896
<151> 2020-09-21
<160> 78
<170> PatentIn版本3.5
<210> 1
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 2H11的CD40鼠类前导VH序列
<400> 1
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Glu Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 2
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 10F2的CD40鼠类前导VH序列
<400> 2
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 3
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 19B10的CD40鼠类前导VH序列
<400> 3
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Gln Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Glu Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Asn Thr Val Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Leu Thr Val Ser Ser
115
<210> 4
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CD40鼠类前导VH序列
<400> 4
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Ser Val Thr Val Ser Ser
115
<210> 5
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 2H11的CD40鼠类前导VK序列
<400> 5
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Gly Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 6
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 10F2的CD40鼠类前导VK序列
<400> 6
Gln Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Ile Ile Thr Cys Ser Ala Thr Ser Ser Val Ser Tyr Ile
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Ala Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 7
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 19B10的CD40鼠类前导VK序列
<400> 7
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 8
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CD40鼠类前导VK序列
<400> 8
Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr Val Thr Ala Gly
1 5 10 15
Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Asn Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys
<210> 9
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 2H11和19B10的CDR1重链
<400> 9
Gly Phe Asn Ile Lys Asp Tyr Tyr Val His
1 5 10
<210> 10
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 10F2的CDR1重链
<400> 10
Gly Phe Asn Ile Lys Asp Tyr Tyr Ile His
1 5 10
<210> 11
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR1重链
<400> 11
Gly Phe Thr Phe Ser Asp Tyr Gly Met His
1 5 10
<210> 12
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 2H11的CDR2重链
<400> 12
Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 13
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 10F2的CDR2重链
<400> 13
Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
<210> 14
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 19B10的CDR2重链
<400> 14
Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe Gln
1 5 10 15
Gly
<210> 15
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR2重链
<400> 15
Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val Lys
1 5 10 15
Gly
<210> 16
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 2H11, 10F2和19B10的CDR3重链
<400> 16
Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr
1 5
<210> 17
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR3重链
<400> 17
Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr
1 5 10
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 2H11的CDR1轻链
<400> 18
Ser Ala Ser Ser Ser Val Ser Tyr Met Leu
1 5 10
<210> 19
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 10F2的CDR1轻链
<400> 19
Ser Ala Thr Ser Ser Val Ser Tyr Ile Leu
1 5 10
<210> 20
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 19B10的CDR1轻链
<400> 20
Ser Ala Ser Ser Ser Val Ser Tyr Met Leu
1 5 10
<210> 21
<211> 17
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR1轻链
<400> 21
Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu
1 5 10 15
Thr
<210> 22
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 2H11, 10F2和19B10的CDR2轻链
<400> 22
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR2轻链
<400> 23
Trp Thr Ser Thr Arg Glu Ser
1 5
<210> 24
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 2H11, 10F2和19B10的CDR3轻链
<400> 24
Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
1 5
<210> 25
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 20E2的CDR3轻链
<400> 25
Gln Asn Asp Tyr Thr Tyr Pro Leu Thr
1 5
<210> 26
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体A的轻链
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 27
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体A的重链IgG1K0
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Ala Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 28
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体A的重链IgG1
<400> 28
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Ala Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 29
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 抗体A的重链IgG4DM
<400> 29
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Ala Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 30
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体A的重链IgG1K0b
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Ala Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 31
<211> 220
<212> PRT
<213> 人工序列
<220>
<223> 抗体B的轻链
<400> 31
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
115 120 125
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
145 150 155 160
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
180 185 190
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
195 200 205
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215 220
<210> 32
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体B的重链IgG1K0
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 33
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体B的重链IgG1
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 34
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 抗体B的重链IgG4DM
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 35
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体B的重链IgG1K0b
<400> 35
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 36
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 抗体C的轻链
<400> 36
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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 37
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 抗体C的重链IgG1K0
<400> 37
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 38
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 抗体C的重链IgG1
<400> 38
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 39
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 抗体C的重链IgG4DM
<400> 39
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 40
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 抗体C的重链IgG1K0b
<400> 40
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly 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 His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr 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 Ala Leu Pro Ala Pro 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 Arg Asp Glu Leu 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 Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln 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 Pro Gly Lys
435 440 445
<210> 41
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 41
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 42
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 42
Glu Val Gln Leu Val Lys Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 43
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体A中可变轻链
<400> 43
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 44
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变重链抗体A
<400> 44
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Ala Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 45
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 45
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 46
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Arg Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 47
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 47
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 48
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 49
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 49
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 50
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 50
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Arg Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 51
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 51
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 52
<211> 113
<212> PRT
<213> 人工序列
<220>
<223> 抗体B中可变轻链
<400> 52
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
20 25 30
Gly Asn Gln Lys Asn Tyr Leu Thr Trp His Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp Tyr Thr Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 53
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 53
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Asn Arg Ile Ile Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 54
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 54
Gln 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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 55
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 55
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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 56
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 可变轻链
<400> 56
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 Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 57
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 57
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 58
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 抗体C中可变重链
<400> 58
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 59
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 59
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Val Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 60
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 60
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 61
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变重链
<400> 61
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Ser Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 62
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体19B10-Hum的可变重序列版本1
<400> 62
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 63
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 可变 Heavy Sequence Version 2 from 抗体19B10-Hum
<400> 63
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Val Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 64
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体19B10-Hum的可变重序列版本3
<400> 64
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 65
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体19B10-Hum的可变重序列版本4
<400> 65
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 Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 66
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体19B10-Hum的可变重序列版本5
<400> 66
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 Thr Ala Ser Gly Phe Asn Ile Thr Asp Tyr
20 25 30
Tyr Val His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Phe Ala Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala 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
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 67
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本1
<400> 67
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 68
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本2
<400> 68
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 69
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本3
<400> 69
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 70
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本4
<400> 70
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 71
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本5
<400> 71
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 72
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本6
<400> 72
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 73
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变重序列版本7
<400> 73
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Lys Val Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Glu Asp Gly Asp Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Ala Asp Thr Ser Thr Asp Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr Trp Gly Gln Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 74
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变轻序列版本1
<400> 74
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 Ser Ala Thr Ser Ser Val Ser Tyr Ile
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 75
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变轻序列版本2
<400> 75
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 Ser Ala Thr Ser Ser Val Ser Tyr Ile
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 76
<211> 106
<212> PRT
<213> 人工序列
<220>
<223> 来自抗体10F2Hum的可变轻序列版本3
<400> 76
Gln 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 Ser Ala Thr Ser Ser Val Ser Tyr Ile
20 25 30
Leu Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Trp Ile Tyr
35 40 45
Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Arg Thr Phe Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 77
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 2H11, 10F2和19B10的重链CDR3
<400> 77
Thr Thr Ser Tyr Tyr Val Gly Thr Tyr Gly Tyr
1 5 10
<210> 78
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 20E2的重链CDR3
<400> 78
Ala Arg Gln Asp Gly Tyr Arg Tyr Ala Met Asp Tyr
1 5 10
Claims (15)
1.一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,所述方法包括向所述受试者施用包含抗CD40(抗分化簇40)抗体的组合物,
其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ IDNO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ IDNO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ IDNO:25组成的组的轻链CDR3序列;或
其中该抗CD40抗体包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQ ID NO:44、SEQ ID NO:46、SEQ IDNO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ ID NO:58、SEQ IDNO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ IDNO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ ID NO:66、SEQ IDNO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70、SEQ IDNO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ ID NO:41、SEQ ID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQ ID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQ IDNO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36;
其中该组合物包含80mg、120mg、180mg或240mg该抗CD40抗体;
其中包含80mg该抗CD40抗体的该组合物的单剂量施用产生约888至约1550的Cmax(ngmL-1)、约126至约365的AUC0-tz(μg·hmL-1)或约330至约464的AUC0-inf(μg·h mL-1);或
其中包含120mg该抗CD40抗体的该组合物的单剂量施用产生约5160至约7210的Cmax(ngmL-1)、约1110至约2010的AUC0-tz(μg·hmL-1)或约1120至约2020的AUC0-inf(μg·h mL-1);或
其中包含180mg该抗CD40抗体的该组合物的单剂量施用产生约8650至约16300的Cmax(ng mL-1)、约2900至约6380的AUC0-tz(μg·hmL-1)或约2020至约2910的AUC0-inf(μg·h mL-1);或
其中包含240mg该抗CD40抗体的该组合物的单剂量施用产生约15700至约21300的Cmax(ng mL-1)、约5680至约7750的AUC0-tz(μg·h mL-1)或约5610至约7780的AUC0-inf(μg·h mL-1);或
其中包含240mg该抗CD40抗体的该组合物的多剂量施用(q1w或每周一次)在第一剂量之后产生约23的Cmax,1(μg mL-1)或在第一剂量之后产生约2600的AUCT,1(μg·h mL-1);或
其中包含240mg该抗CD40抗体的该组合物的多剂量施用(q1w或每周一次)在第四剂量之后产生约74的Cmax,4(μg mL-1),或在第四剂量之后产生约49的Cmin,4(μg mL-1),或在第四剂量之后产生约10900的AUCT,4(μg·h mL-1)。
2.如权利要求1所述的方法,其中该自身免疫性疾病或炎症性疾病选自由以下组成的组:狼疮性肾炎、类风湿性关节炎、多发性硬化症、增生性狼疮性肾小球性肾炎、炎症性肠病(IBD)、牛皮癣、特发性血小板减少性紫癜(ITP)、克罗恩氏病和系统性红斑狼疮(SLE)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、原发性黏液性水肿、甲状腺中毒症/格雷氏病(Graves disease)、恶性贫血、自身免疫性萎缩性胃炎、自身免疫性心脏炎、爱迪生氏病(Addison's disease)、过早更年期、1型糖尿病、古德帕斯彻综合征(Good pasture'ssyndrome)、重症肌无力、自身免疫性溶血性贫血、特发性白血球减少症、原发性胆汁性肝硬化、活动性慢性肝炎(HB Ag阴性)、隐原性肝硬化、干燥综合征(Sjogren's syndrome)、皮肌炎、硬皮病、混合结缔组织病、盘状红斑狼疮和系统性血管炎。
3.如权利要求1所述的方法,其中该抗体包含SEQ ID NO:10的重链CDR1序列、SEQ IDNO:13的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中所述抗体包含SEQ ID NO:19的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
4.如权利要求1的方法,其中所述抗体包含SEQ ID NO:9的重链CDR1序列、SEQ ID NO:14的重链CDR2序列和SEQ ID NO:16的重链CDR3序列;且其中所述抗体包含SEQ ID NO:20的轻链CDR1序列、SEQ ID NO:22的轻链CDR2序列和SEQ ID NO:24的轻链CDR3序列。
5.如权利要求1所述的方法,其中所述抗体包含SEQ ID NO:11的重链CDR1序列、SEQ IDNO:15的重链CDR2序列和SEQ ID NO:17的重链CDR3序列;且其中所述抗体包含SEQ ID NO:21的轻链CDR1序列、SEQ ID NO:23的轻链CDR2序列和SEQ ID NO:25的轻链CDR3序列。
6.如权利要求1所述的方法,其中该抗体包含重链可变域和轻链可变区,该重链可变域和轻链可变区分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ IDNO:35和SEQ ID NO:31;SEQ ID NO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQID NO:39和SEQ ID NO:36;SEQ ID NO:40和SEQ ID NO:36。
7.如权利要求1所述的方法,其中该抗体包含:
包含SEQ ID NO:44的重链可变域和包含SEQ ID NO:43的轻链可变域;或
包含SEQ ID NO:53的重链可变域和包含SEQ ID NO:52的轻链可变域;或
包含SEQ ID NO:58的重链可变域和包含SEQ ID NO:56的轻链可变域。
8.如权利要求1所述的方法,其中该抗体包含:
包含SEQ ID NO:30的重链序列和包含SEQ ID NO:26的轻链序列;或
包含SEQ ID NO:35的重链序列和包含SEQ ID NO:31的轻链序列;或
包含SEQ ID NO:40的重链序列和包含SEQ ID NO:36的轻链序列。
9.如权利要求1所述的方法,其中该自身免疫性疾病或炎症性疾病选自由以下组成的组:狼疮性肾炎、移植物抗宿主疾病、自身免疫性疾病或炎症性疾病和CD40相关病症。
10.一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,所述方法包括向所述受试者施用包含抗CD40(抗分化簇40)抗体的组合物,
其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ IDNO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ IDNO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ IDNO:25组成的组的轻链CDR3序列;或
其中该抗CD40包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ ID NO:58、SEQID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70、SEQID NO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ ID NO:41、SEQID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ IDNO:49、SEQ ID NO:50、SEQ ID NO:51、SEQID NO:52、SEQ IDNO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQ IDNO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36;
其中该组合物包含120mg或180mg或240mg该抗CD40抗体,且其中与安慰剂相比,施用引起该受试者中的总SLEDAI-SELENA评分和其分项评分得到改善。
11.一种测定抗CD40抗体治疗或预防受试者中的自身免疫性疾病或炎症性疾病的治疗功效的方法,该方法包含在向该受试者施用包含该抗CD40抗体的组合物,测量该受试者中的经活化的B细胞子集的水平,其中该经活化的B细胞子集的水平降低(当比较治疗之前和之后的水平时)指示具有功效,其中该经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。
12.一种减少患有自身免疫性疾病或炎症性疾病的受试者中的经活化的B细胞子集的水平的方法,该方法包括向所述受试者施用包含抗CD40抗体的组合物,其中该经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。
13.一种治疗或预防有此需要的受试者中的自身免疫性疾病或炎症性疾病的方法,该方法包括向所述受试者施用包含80mg、120mg、180mg或240mg抗CD40(抗分化簇40)抗体的组合物,其中该受试者表现出(或已确定表现出)经活化的B细胞子集的存在,其中该经活化的B细胞子集选自由以下组成的组:CD19+IgD-CD27-CD95+、CD19+IgD+CD27-CD95+、CD19+IgD-CD27+CD95+和CD19+IgD+CD27+CD95+。
14.如权利要求11、12或13中任一项所述的方法,其中该抗CD40抗体包含重链和轻链,其中该重链序列和轻链序列选自由以下组成的组:a)选自由SEQ ID NO:9至SEQ ID NO:11组成的组的重链CDR1序列、选自由SEQ ID NO:12至SEQ ID NO:15组成的组的重链CDR2序列和选自由SEQ ID NO:16至SEQ ID NO:17组成的组的重链CDR3序列;和b)轻链CDR1序列具有选自由SEQ ID NO:18至SEQ ID NO:21组成的组的序列、SEQ ID NO:22至SEQ ID NO:23的轻链CDR2序列和选自由SEQ ID NO:24至SEQ ID NO:25组成的组的轻链CDR3序列;或
其中该抗CD40包含可变重链域和可变轻链域,该可变重链域包含SEQ ID NO:42、SEQID NO:44、SEQ ID NO:46、SEQ ID NO:48、SEQ ID NO:53、SEQ ID NO:57、SEQ ID NO:58、SEQID NO:59、SEQ ID NO:60、SEQ ID NO:61、SEQ ID NO:62、SEQ ID NO:63、SEQ ID NO:64、SEQID NO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:70、SEQID NO:71、SEQ ID NO:72、SEQ ID NO:73中的任一者;该可变轻链域包含SEQ ID NO:41、SEQID NO:43、SEQ ID NO:45、SEQ ID NO:47、SEQ IDNO:49、SEQ ID NO:50、SEQ ID NO:51、SEQID NO:52、SEQ IDNO:54、SEQ ID NO:55、SEQ ID NO:56、SEQ ID NO:74、SEQ IDNO:75或SEQID NO:76中的任一者;或
其中该抗CD40抗体包含重链序列和轻链序列,该重链序列和轻链序列分别包含以下氨基酸序列:SEQ ID NO:27和SEQ ID NO:26;SEQ ID NO:28和SEQ ID NO:26;SEQ ID NO:29和SEQ ID NO:26;SEQ ID NO:30和SEQ ID NO:26;SEQ ID NO:32和SEQ ID NO:31;SEQ ID NO:33和SEQ ID NO:31;SEQ ID NO:34和SEQ ID NO:31;SEQ ID NO:35和SEQ ID NO:31;SEQ IDNO:37和SEQ ID NO:36;SEQ ID NO:38和SEQ ID NO:36;SEQ ID NO:39和SEQ ID NO:36;或SEQ ID NO:40和SEQ ID NO:36。
15.如权利要求14所述的方法,其中该组合物包含120mg或180mg或240mg该抗CD40抗体。
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