CN107233569A - 抗体制剂和方法 - Google Patents
抗体制剂和方法 Download PDFInfo
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- CN107233569A CN107233569A CN201710222179.9A CN201710222179A CN107233569A CN 107233569 A CN107233569 A CN 107233569A CN 201710222179 A CN201710222179 A CN 201710222179A CN 107233569 A CN107233569 A CN 107233569A
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Abstract
用于预防或治疗淀粉样变性(包括AA淀粉样变性和AL淀粉样变性)的抗体制剂和方法。
Description
本申请是申请日为2012年10月25日、申请号为201280052471.6、发明名称为“抗体制剂和方法”的发明专利申请的分案申请。
相关申请
要求2011年10月25日提交的美国临时申请No.61/551,406(其通过引用整体并入本文)的优先权。
技术领域
本发明属于免疫学和医学的技术领域。
发明背景
淀粉样变性是描述特征在于病理形式的淀粉样蛋白的存在的许多疾病的一般术语,所述疾病通常牵涉蛋白质原纤维(fibril)的细胞外沉积,这形成了许多“淀粉样蛋白沉积物”或“淀粉样蛋白斑块”,这可在局部部位发生或全身性发生。这些沉积物或斑块主要包含天然存在的可溶性蛋白质或肽,所述蛋白质或肽在多个组织部位中装配成直径为10-100μm的广泛不溶的沉积物。沉积物通常包含直径约10-15nm的原纤维的侧向聚集物。淀粉样蛋白原纤维,当用刚果红染料染色时,在偏振光下产生特征性苹果绿双折射。通常地,这些沉积物的原纤维组分是各种形式的淀粉样蛋白疾病的鉴定性特征。
形成斑块沉积物的肽或蛋白质通常从更大的前体蛋白质产生。更具体地,淀粉样蛋白聚集物例如原纤维沉积物的发病机制通常牵涉“异常”前体蛋白至聚集成反向平行β折叠片的片段的蛋白水解切割。
全身性淀粉样变性是由错误折叠的蛋白质的组织沉积引起的一组复杂的疾病,所述疾病导致进行性器官损伤。最常见的类型,AL淀粉样变性或原发性淀粉样变性,牵涉由产生错误折叠的免疫球蛋白轻链的克隆性浆细胞引起的血液学障碍。浆细胞过度产生错误折叠的轻链导致异常AL蛋白(淀粉样蛋白)在具有AL淀粉样变性的个体的组织和器官中沉积。AL淀粉样变性的临床特征包括一组症状和器官功能障碍,其可包括心脏、肾和肝功能障碍、胃肠受累、神经病和巨舌症。然而,促淀粉样变性的免疫球蛋白轻链籍以导致器官功能障碍的机制尚未被良好表征,据猜测,淀粉样蛋白沉积物和原纤丝(prefibrillar)聚集物可促成在AL淀粉样变性患者中观察到的对器官的细胞毒性作用。AL淀粉样变性是其自身的疾病实体,虽然AL淀粉样变性可在小亚组(达到15%)的多发性骨髓瘤患者中同时存在。
AL淀粉样变性是罕见障碍,其发病率据估计为8/1,000,000人。在美国每年仅报告1200至3200例AL淀粉样变性的新案例。2/3的AL淀粉样变性患者是男性,少于5%的患者年龄在40岁以下。AL淀粉样变性的病因和来源仍然知之甚少。
AL淀粉样变性患者的现有疗法的目的在于,减少或消除骨髓障碍,即负责产生轻链的浆细胞,从而限制或停止淀粉样蛋白的产生。最具侵入性的治疗选择包括,对可耐受其的患者进行干细胞移植和高剂量化学疗法。其它治疗方案包括,通常用于治疗血液肿瘤的药物例如美法仑,泼尼松,地塞米松和蛋白体抑制剂例如硼替佐米的组合,以试图减少轻链产生。目前尚没有经批准的、直接靶向促淀粉样变性的蛋白的潜在毒性形式的AL淀粉样变性的治疗。
不同形式的全身性淀粉样变性,AA淀粉样变性或继发性淀粉样变性,由于其它疾病例如慢性炎性疾病(例如,类风湿性关节炎和强直性脊柱炎)或慢性感染(例如,肺结核或骨髓炎)而“继发性地”发生。在继发性淀粉样变性中,沉积的淀粉样蛋白为淀粉样蛋白A,来源于急性期蛋白血清淀粉样蛋白A。继发性淀粉样变性的治疗涉及治疗基础性疾病。
因此,存在对直接靶向病理性淀粉样蛋白原纤维的、治疗AA淀粉样变性和AL淀粉样变性的疗法的需要。本发明提供了2A4和7D8抗体以及其嵌合和人源化形式的药物制剂,其由于AL和AA淀粉样蛋白的病理形式的共有的免疫原性表位,而显示对这些蛋白的高亲和力结合。
发明概述
本发明提供了用于预防和治疗淀粉样蛋白疾病的抗体制剂。在本发明的一个方面,药物制剂包含,(a)特异性地与2A4或7D8竞争对抗原的结合,和/或针对包含AEDS(SEQID NO:18)的表位的抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的嵌合或人源化形式或其片段,其中所述抗体以在约1mg/mL至约100mg/mL的范围内的浓度存在;(b)以在约20mM至约30mM的范围内的浓度存在的组氨酸缓冲剂;(c)以在约210mM至约250mM的范围内的浓度存在的海藻糖;和(d)以在按重量计约0.005%至约0.05%的范围内的浓度存在的聚山梨醇酯20;其中所述制剂的特征在于在约6至约7的范围内的pH。例如,本发明的代表性制剂包含,具有含有SEQ ID NO:4所示的氨基酸序列的轻链可变区和/或含有SEQ ID NO:5所示的氨基酸序列的重链可变区的抗体。更具体地,此类制剂包含,具有含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,例如,具有含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ IDNO:15所示的氨基酸序列的重链的抗体。
本发明的其它代表性制剂包含,(a)具有含有SEQ ID NO:6、7和8所示的3个互补决定区的轻链可变区和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区的抗体;和(b)具有含有SEQ ID NO:12、7和8所示的3个互补决定区的轻链可变区和含有SEQ IDNO:9、10和11所示的3个互补决定区的重链可变区的抗体。
在本发明的代表性制剂中,抗体以在约5mg/mL至约15mg/mL的范围内的浓度(例如约10mg/mL)存在,或以在约25-75mg/mL的范围内的浓度(例如,50mg/mL)存在。
在本发明的其它代表性制剂中,组氨酸缓冲剂以约25mM的浓度存在。组氨酸缓冲剂可包括L-组氨酸和L-组氨酸HCl一水合物。例如,可以以在约16mM至约22mM的范围内的浓度使用L-组氨酸,以及可以以在约4mM至约8mM的范围内的浓度使用L-组氨酸HCl一水合物。
在本发明的其它代表性制剂中,海藻糖以约230mM的浓度存在。
如本文中所述制备的本发明的代表性制剂,(a)特征在于约300mOsm/kg的重量摩尔渗透压浓度(osmolality);(b)在制剂中包含少于约10%的以聚集物的形式存在的抗体;(c)还包含填充剂;(d)是无菌的;和/或(e)在冷冻和解冻后是稳定的。
在本发明的一个方面,制剂包含,(a)包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且所述抗体以约10mg/mL的浓度存在;(b)以约25mM的浓度存在的组氨酸缓冲剂;(c)以约230mM的浓度存在的海藻糖;(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和(e)约6.5的pH。
在本发明的另一个方面,药物制剂包含,(a)抗体,其为抗体2A4(ATCC登录号PTA-9662)、抗体7D8(ATCC登录号PTA-9468),或特异性地与2A4或7D8竞争对抗原的结合,和/或针对包含AEDS(SEQ ID NO:18)的表位的抗体2A4或抗体7D8的嵌合或人源化形式或其片段,其中所述抗体以在约50mg/mL至约100mg/mL的范围内的浓度存在;(b)缓冲剂;(c)非还原糖;和(d)非离子表面活性剂。在具体的实例中,所公开的制剂的抗体包含,含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:15所示的氨基酸序列的重链。
在本发明的另一个方面,抗体制剂是冷冻干燥的。例如,代表性冻干制剂可包含:(a)抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的人源化形式或其抗原结合片段;(b)组氨酸;(c)海藻糖;和(d)聚山梨醇酯20。冻干制剂,当重构时,可具有约6至约7的pH,例如当重构时pH 6.5。冻干制剂通常包含约100mg至约1000mg的抗体。冻干制剂通常以在按重量计约0.005%至约0.05%的范围内的浓度包含聚山梨醇酯20。重构后,冻干制剂产生水溶液,例如,水溶液包含:(a)包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且所述抗体以约10mg/mL的浓度存在;(b)以约25mM的浓度存在的组氨酸缓冲剂;(c)以约230mM的浓度存在的海藻糖;(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和(e)约6.5的pH。代表性冻干制剂在利用无菌水重构后包含约100mg的抗体。
还提供了编码用于制备公开的制剂的抗体的核酸。例如,此类核酸包括,含有编码SEQ ID NO:13的抗体轻链的核苷酸序列的核酸和含有编码SEQ ID NO:14-16的任一个的抗体重链的核苷酸序列的核酸。例如,SEQ ID NO:19和SEQ ID NO:20(其与SEQ ID NO:19同一并且还包含编码信号肽的序列)所示的核苷酸序列各自编码SEQ ID NO:13的人源化2A4轻链。作为另一个实例,SEQ ID NO:22和SEQ ID NO:23(其与SEQ ID NO:22同一并且还包含编码信号肽的序列)所示的核苷酸序列各自编码SEQ ID NO:15的人源化2A4重链。
为了产生抗体,可将公开的核酸单个地或组合地(例如,编码人源化2A4轻链的核酸和编码人源化2A4重链的核酸的组合)包含在载体中。例如,载体可包含,含有编码SEQ IDNO:13-16、21和24的任一个的核苷酸序列的核酸;含有SEQ ID NO:19-20和22-23的任一个的核苷酸序列的核酸,或其组合。本发明的代表性载体包括,(a)包含编码SEQ ID NO:13或21所示的人源化2A4轻链和SEQ ID NO:15或24所示的人源化2A重链的核酸序列的载体;(b)包含具有SEQ ID NO:19的核苷酸序列的核酸和具有SEQ ID NO:22的核苷酸序列的核酸的载体;和(c)包含具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQ ID NO:23的核苷酸序列的核酸的载体。
还提供了已将本文中公开的一个或多个核酸稳定地掺入它们的基因组的宿主细胞(例如,CHO细胞)。例如,宿主细胞可在其基因组中包含,含有编码SEQ ID NO:13-16、21和24的任一个的核苷酸序列的稳定地整合的核酸;包含SEQ ID NO:19-20和22-23的任一个的核苷酸序列的稳定整合的核酸,或其组合。本发明的代表性宿主细胞包括,(a)包含编码SEQID NO:13或21所示的人源化2A4轻链和SEQ ID NO:15或24所示的人源化2A重链的核酸序列的宿主细胞;(b)包含具有SEQ ID NO:19的核苷酸序列的核酸和SEQ ID NO:22的核苷酸序列的核酸的宿主细胞;和(c)包含具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQ IDNO:23的核苷酸序列的核酸的宿主细胞。
本发明还提供了制备药物制剂的方法。在本发明的一个方面,此类方法包括,(a)培养已将编码鼠,嵌合或人源化2A4抗体或鼠,嵌合或人源化7D8抗体的轻链和重链的核酸稳定地整合进入其基因组的哺乳动物细胞,以便细胞将抗体分泌进入细胞培养基,和从细胞培养基纯化抗体;(b)和制备制剂,所述制剂包含(i)特异性地与2A4或7D8竞争对抗原的结合的抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的嵌合或人源化形式,或其片段,其中抗体以在约1mg/mL至约100mg/mL的范围内的浓度存在;(i i)以在约20mM至约30mM的范围内的浓度存在的组氨酸缓冲剂;(i i i)以在约210mM至约250mM的范围内的浓度存在的海藻糖;和(iv)以在按重量计约0.005%至约0.05%的范围内的浓度存在的聚山梨醇酯20;其中制剂的特征在于,在约6至约7的范围内的pH。例如,在本发明的一个方面,培养已将编码人源化2A4抗体的轻链和重链的核酸稳定地整合进入其基因组的哺乳动物细胞。用于该目的的哺乳动物细胞包括,(a)已将编码SEQ ID NO:13或21所示的人源化2A4轻链和SEQ ID NO:15或24所示的人源化2A重链的核酸序列稳定地整合进入其基因组的宿主细胞;(b)已将具有SEQ ID NO:19的核苷酸序列的核酸和具有SEQ ID NO:22的核苷酸序列的核酸稳定地整合进入其基因组的宿主细胞;和(c)已将具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQ ID NO:23的核苷酸序列的核酸稳定地整合进入其基因组的宿主细胞。在本发明的一些方面,公开的制备药物制剂的方法包括,评价制剂中的抗体的至少一个性质的额外步骤,所述性质例如物理稳定性、化学稳定性和/或生物活性。
还提供了治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维的存在的淀粉样变性或处于患所述疾病的风险中的人患者的方法,所述方法包括,给患者施用有效剂量的本发明的制剂。顺从治疗的患者具有淀粉样蛋白疾病例如淀粉样蛋白A淀粉样变性(其特征在于淀粉样蛋白A蛋白原纤维的存在),或AL淀粉样变性(其特征在于淀粉样蛋白轻链类型蛋白原纤维的存在)。具有AL淀粉样变性的患者还可患有相关的B淋巴细胞谱系的恶液质(dyscrasis),例如恶性肿瘤例如多发性骨髓瘤。
公开的治疗性和预防性治疗法包括,由此引发协同作用结果的联合治疗(即,公开的抗体制剂与一种或多种另外的药物一起施用)。两种或更多种药物同时施用或以任意顺序相继施用,即,在施用第二药物之前,与第二药物同时,或在第二药物施用之后施用本发明的制剂。例如,可将本发明的制剂与美法仑组合同时或相继地施用。作为另一个实例,可将本发明的制剂与硼替佐米、美法仑、来那度胺和卡非佐米中的一种或多种组合同时或相继地施用。
根据公开的治疗性和预防性疗法,本发明的制剂可以以多个剂量施用,例如以约每天一次至约每年一次的频率,例如以约每隔一周一次至约每三个月一次的频率,或例如每月一次。在一个方面,以在约10mg至约5000mg药物的范围内的剂量静脉内施用本发明的抗体制剂。例如,可以以约每隔一周一次至约每隔一月一次的频率,以约30mg至约2500mg人源化2A4药物的剂量施用制剂。用于公开的方法的代表性剂量包括30mg、100mg、300mg、1000mg、2000mg和2500mg的人源化2A4药物。
在本发明的一个方面,治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维、沉积物或原纤丝聚集物的存在的轻链(AL)淀粉样变性或处于患所述疾病的风险中的人患者的方法包括,给患者施用有效剂量的药物制剂,所述药物制剂包含:(a)包含含有SEQ IDNO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且所述抗体以约10mg/mL的浓度存在;(b)以约25mM的浓度存在的组氨酸缓冲剂;(c)以约230mM的浓度存在的海藻糖;(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和(e)约6.5的pH。在此类方法中,剂量通常为以约每周一次至约每季度一次的频率(例如,每28天一次)静脉内或皮下施用的约0.5mg/kg至约30mg/kg的抗体(例如,约0.5mg/kg至约8mg/kg,或约8mg/kg至约30mg/kg)。
本发明还提供了药物产品(pharmaceutical product),其包含:(a)装有100mg以粉剂形式存在的抗体的小瓶;(b)抗体重构说明书;和(c)制备用于输注的重构的抗体的说明书,其中(i)抗体包含,含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链;和(ii)重构说明书要求,利用注射用水重构至10mL的可抽出体积。
附图概述
图1A-1B显示不同的人源化2A4抗体的轻链和重链序列。粗体和下划线标示的是,用于N连接的糖基化的共有序列。
图2显示鼠2A4和7D8的轻链可变区(VL)及重链可变区(VH)的序列。双下划线标示的是,前导序列;下划线标示的是,互补决定区(CDR)序列。
图3显示人源化2A4形式3的轻链可变区(VL)和重链可变区(VH)的序列。小写字母标示的是,回复突变。
图4A-4B显示,编码人源化2A4形式3的重链(图4A)和轻链(图4B)序列的核酸序列。单下划线标示的是,前导序列;无下划线的是,可变区;双下划线标示的是,恒定区。
发明详述
本发明提供了用于预防和治疗淀粉样蛋白疾病的抗体制剂。在本发明的一个方面,药物制剂包含,(a)特异性地与2A4或7D8竞争对抗原的结合,和/或针对包含AEDS(SEQID NO:18)的表位的抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的嵌合或人源化形式或其片段,其中抗体以在约1mg/mL至约100mg/mL的范围内的浓度存在;(b)以在约20mM至约30mM的范围内的浓度存在的组氨酸缓冲剂;(c)以在约210mM至约250mM的范围内的浓度存在的海藻糖;和(d)以在按重量计约0.005%至约0.05%的范围内的浓度存在的聚山梨醇酯20;其中所述制剂的特征在于,在约6至约7的范围内的pH。
在本文描述的本发明的一个方面,人源化2A4为鼠2A4的IgG1,κ同种型形式。在人源化2A4的特异性表征的过程中,发现抗体还以高亲和力和以构象依赖性方式与轻链淀粉样蛋白原纤维中的轻链、但不与循环中的游离轻链反应。
本发明提供了用于静脉内输注靶向AA淀粉样变性和AL淀粉样变性患者中的错误折叠的淀粉样蛋白的人源化2A4和/或人源化7D8抗体的方法。一些人源化2A4抗体特异性结合AL和SAA的病理性淀粉样蛋白形式,但不结合这些病理形式所源自的亲代分子(SAA,天然免疫球蛋白轻链[LC],完整免疫球蛋白[Ig])。
I.药物制剂和产品
I.A.特征
本文中提供了药物制剂,其包含分别与2A4或7D8特异性地竞争对抗原(即,人AA或AL蛋白)的结合,和/或针对表位AEDS(SEQ ID NO:18)的抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的嵌合或人源化形式或其片段。还提供了包含鼠抗体2A4或鼠抗体7D8或其片段的药物制剂。抗体以在约1mg/mL至约100mg/mL的范围内的浓度存在。制剂的特征在于在约6至约7的范围内的pH,并且以在约20mM至约30mM的范围内的浓度包含组氨酸缓冲剂、以在约210mM至约250mM的范围内的浓度包含海藻糖;和以在按重量计约0.005%至约0.05%的范围内的浓包含聚山梨醇酯20。
术语“人源化免疫球蛋白”或“人源化抗体”是指,包含至少一个人源化免疫球蛋白或抗体链(即,至少一个人源化轻链或重链)的免疫球蛋白或抗体。术语“人源化免疫球蛋白链”或“人源化抗体链”(即,“人源化免疫球蛋白轻链”或“人源化免疫球蛋白重链”)是指这样的免疫球蛋白或抗体链(即,分别地轻链或重链),其具有包括大体上来自人免疫球蛋白或抗体的可变构架区和大体上来自非人免疫球蛋白或抗体的互补决定区(CDR)(例如,至少一个CDR,优选两个CDR,更优选三个CDR)的可变区,并且还包括恒定区(例如,在轻链的情况下,至少一个恒定区或其部分,和在重链的情况下优选三个恒定区)。术语“人源化可变区”(例如,“人源化轻链可变区”或“人源化重链可变区”)是指,包括大体上来自人免疫球蛋白或抗体的可变构架区和大体上来自非人免疫球蛋白或抗体的互补决定区(CDR)的可变区。
短语“大体上来自人免疫球蛋白或抗体”或“大体上人”意指,当为了比较目的与人免疫球蛋白或抗体氨基酸序列进行比对时,区域与人构架区或恒定区序列共有至少80-90%,优选90-95%,更优选95-99%的同一性(即,局部序列同一性),允许例如进行保守置换、共有序列置换、种系置换、回复突变等。保守置换、共有序列置换、种系置换、回复突变等的引入通常称为人源化抗体或链的“优化”。短语“大体上来自非人免疫球蛋白或抗体”或“大体上非人”意指,具有与非人生物例如非人哺乳动物的免疫球蛋白或抗体具有至少80-95%,优选90-95%,更优选96%、97%、98%或99%的同一性的免疫球蛋白或抗体序列。
因此,人源化免疫球蛋白或抗体的或人源化免疫球蛋白或抗体链的所有区域或残基(除了可能地CDR外)与一个或多个天然人免疫球蛋白序列的对应区域或残基大体上同一。术语“对应区域”或“对应残基”是指,当为了比较目的将第一与第二序列最佳地比对时,占据与第一氨基酸或核苷酸序列上的区域或残基相同(即,等同)的位置的第二氨基酸或核苷酸序列上的区域或残基。
在一些制剂中,抗体包含含有SEQ ID NO:1、2或4的任一个所示的氨基酸序列的轻链可变区。在一些制剂中,抗体包含含有SEQ ID NO:3或5所示的氨基酸序列的重链可变区。在一些制剂中,抗体包含含有SEQ ID NO:1、2或4的任一个所示的氨基酸序列的轻链可变区和含有SEQ ID NO:3或5所示的氨基酸序列的重链可变区。在一些制剂中,抗体包含含有SEQID NO:1所示的氨基酸序列的轻链可变区和含有SEQ ID NO:3所示的氨基酸序列的重链可变区。在一些制剂中,抗体包含含有SEQ ID NO:4所示的氨基酸序列的轻链可变区和含有SEQ ID NO:5所示的氨基酸序列的重链可变区。在一些制剂中,抗体包含含有SEQ ID NO:2所示的氨基酸序列的轻链可变区和含有SEQ ID NO:3所示的氨基酸序列的重链可变区。
在一些制剂中,抗体包含含有SEQ ID NO:6、7和8所示的3个互补决定区的轻链可变区和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。在其它制剂中,抗体包含含有SEQ ID NO:12、7和8所示的3个互补决定区的轻链可变区和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。
在本发明的其它制剂中,抗体包含鼠,嵌合,或人源化2A4抗体或鼠,嵌合或人源化7D8抗体的轻链和重链可变区,如美国专利No.7,928,203和PCT国际公开案WO 2009/086539(其各自通过引用整体并入本文)中描述的,将所述专利和公开案中描述的轻链和重链可变区序列明确地通过引用并入本文。
在一些制剂中,抗体包含含有SEQ ID NO:13或21所示的氨基酸序列的轻链和含有SEQ ID NO:14-16和24的任一个所示的氨基酸序列的重链。抗体可以包括或可以不包括上述轻链和重链氨基酸序列的前导序列。
在其它制剂中,抗体是2A4或7D8抗体的片段,包括其嵌合和人源化形式,例如Fab片段、Fab'片段、F(ab')2片段、Fv片段或ScFv片段。
在本发明的一些方面,抗体特异性结合聚集的淀粉样蛋白,而不特异性地结合单体淀粉样蛋白(例如,对于淀粉样蛋白的单体形式的特异性结合亲和力,至少10倍和通常至少100倍更低)。
在一些制剂中,抗体以在约5mg/mL至约100mg/mL的范围内的浓度存在。在一些制剂中,抗体以在约5mg/mL至约15mg/mL的范围内的浓度存在。在一些制剂中,抗体以在约25mg/mL至约75mg/mL的范围内的浓度存在。例如,抗体可以以约10mg/mL的浓度存在,或以约50mg/mL的浓度存在。抗体可以以约50mg/瓶至约500mg/瓶或更大的量的无菌液体剂型存在。例如,抗体可以以约100mg/瓶的无菌液体剂型存在。
可将用于公开的制剂的抗体与治疗性部分例如细胞毒性剂、放射治疗剂、免疫调节剂、第二抗体(例如,以形成抗体异缀合物)或促进或增强嵌合或人源化2A4或嵌合或人源化7D8抗体的活性的任何其它生物活性剂偶联。代表性治疗部分包括,已知对于淀粉样蛋白疾病或淀粉样蛋白的症状的治疗、控制或改善是有用的试剂。
还可将用于公开的制剂的抗体与可检测标记物偶联,例如,以用于诊断淀粉样蛋白障碍,监控淀粉样蛋白疾病的进展,和/或评价治疗的效力。如所描述配制的抗体对于在患有AA淀粉样变性或AL淀粉样变性或对所述疾病易感的受试者中,或在获自此类受试者的适当的生物样品中进行此类测定是特别有用的。可被偶联或连接至人源化2A4抗体或人源化7D8抗体的代表性可检测标记物包括,各种酶例如辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶或乙酰胆碱酯酶;辅基,例如链霉抗生物素蛋白/生物素和抗生物素蛋白/生物素;荧光材料例如但不限于伞形酮、荧光素、异硫氰酸荧光素、罗丹明、二氯三嗪基胺荧光素、丹磺酰氯或藻红蛋白;发光材料例如鲁米诺;生物发光材料例如萤光素酶、萤光素和水母荧光素;放射性材料例如但不限于碘(131I、125I、123I、121I,)、碳(14C)、硫(5S)、氚(3H)、铟(115In、113In、112In、111In,)和锝(99Tc)、铊(201Ti)、镓(68Ga、67Ga)、钯(103Pd)、钼(99Mo)、氙(133Xe)、氟(18F)、153Sm、177Lu、159Gd、149Pm、140La、175Yb、166Ho、90Y、47Sc、186Re、188Re、142Pr、105Rh、97Ru、68Ge、57Co、65Zn、85Sr、32P、153Gd、169Yb、51Cr、54Mn、75Se、113Sn和117Tin;使用各种正电子发射断层摄影术的正电子发射金属、非放射性顺磁性金属离子,和放射性标记或缀合至特定放射性同位素的分子。
可使用本领域已知的技术,将治疗性部分和/或可检测的物质直接或通过中间体(例如,接头)间接偶联或缀合至鼠,嵌合或人源化2A4抗体或鼠,嵌合或人源化7D8抗体。参见,例如,Arnon等人,"Monoclonal Antibodies For Immunotargeting Of Drugs InCancer Therapy",in Monoclonal Antibodies And Cancer Therapy,Reisfeld等人(eds.),pp.243-56(Alan R.Liss,Inc.1985);Hellstrom等人,"Antibodies For DrugDelivery",in Controlled Drug Delivery(第2版),Robinson等人(eds.),pp.623-53(Marcel Dekker,Inc.1987);Thorpe,"Antibodies Carriers Of Cytotoxic Agents InCancer Therapy:A Review",in Monoclonal Antibodies84:Biologica lAnd ClinicalApplications,Pinchera等人(eds.),pp.475-506(1985);"Analysis,Results,And FutureProspective Of The Therapeutic Use Of Radiolabeled Antibodies In CancerTherapy",in Monoclonal Antibody For Cancer Detection And Therapy,Baldwin等人(eds.),pp.303-16(Academic Press 1985)和Thorpe等人,Immunol.Rev.,1982,62:119-58。
公开的制剂中使用的抗体还包括,鼠,嵌合或人源化2A4抗体或鼠,嵌合或人源化7D8抗体的修饰形式,所述修饰形式相较于对应的未修饰抗体具有增加的体内半衰期。可以例如通过糖基化、乙酰化、PEG化、磷酸化、酰胺化、衍生化(通过已知的保护/封闭基团)、蛋白水解切割、至细胞配体或其它蛋白质的连接等来制备此类修饰形式。作为一个实例,用于抗体半衰期延长的代表性方法描述于PCT国际公开案No.WO 02/060919中。
本发明包括,具有在38℃-42℃持续至少约30天的稳定性(如通过高效尺寸排阻色谱法(HPSEC)评估的)的抗体制剂,具有在20℃-24℃持续至少约1年的稳定性的制剂,和具有在2℃-4℃具有持续至少约3年的稳定性的制剂。更具体地,公开的制剂显示,低至不可检测的水平的抗体聚集和/或片段化,或高于初始水平的、低的或不可检测的抗体片段化和/或聚集的增加(例如,低于约10%的聚集)。具有低至不可检测的水平的片段化的制剂,例如在单个峰中(如通过高效尺寸排阻色谱法(HPSEC)测定的)或在还原毛细管凝胶电泳(rCGE)的两个(2)峰(对应于抗体重链和抗体轻链的每一个)中,包含至少约80%、85%、90%、95%、98%或99%的总蛋白质(其代表非降解抗体),并且不包含各自具有超过5%、超过4%、超过3%、超过2%、超过1%或超过0.5%的总蛋白质的其它单峰。具有低至不可检测的水平的聚集的制剂包含,按重量计不超过约15%、不超过约10%、不超过约5%、不超过约4%、不超过约3%、不超过约2%、不超过约1%或不超过约0.5%的聚集蛋白质,如通过高效尺寸排阻色谱法(HPSEC)测量的。例如,在一些制剂中,少于约10%的抗-淀粉样蛋白抗体以聚集物的形式存在。本发明的稳定的制剂还显示几乎无或无嵌合或人源化2A4或嵌合或人源化7D8的生物活性(例如可通过ELISA和/或其它功能测定测量的结合亲和力)的丧失,例如至少约50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、98%或99%的给定的活性的初始可测量值。
组氨酸缓冲剂可以以约25mM的浓度存在于一些制剂中。在一些制剂中,组氨酸缓冲剂包含L-组氨酸和L-组氨酸HCl一水合物。例如,在一些制剂中,L-组氨酸以在约16mM至约22mM的范围内的浓度存在并且L-组氨酸HCl一水合物以在约4mM至约8mM的范围内的浓度存在。
在一些制剂中,海藻糖以约210mM至约250mM例如约230mM的浓度存在。在一些制剂中,使用不同的非还原糖例如蔗糖、甘露醇或山梨醇。
在一些制剂中,聚山梨醇酯20以在按重量计约0.005%至约0.05%的范围内的浓度,例如,0.005%、0.01%、0.015%、0.02%、0.025%、0.03%、0.035%、0.04%、0.045%或0.05%的浓度存在。或者,在一些制剂中,聚山梨醇酯20以在约0.05g/L、0.1g/L、0.15g/L、0.2g/L、0.25g/L、0.3g/L、0.35g/L、0.4g/L、0.45g/L或0.5g/L的浓度存在。一些制剂以0.2g/L的浓度包含聚山梨醇酯20。
一些制剂的特征在于,在约6-7的范围内的pH,例如,6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9或7.0的pH。一些制剂具有约6.5的pH。
一些制剂的特征在于约300mOsm/kg的重量摩尔渗透压浓度。
填充剂也可包含在一些制剂中。
通常地,制剂是无菌的,例如,如通过使用0.2μm或0.22μm滤器无菌过滤实现的。本发明的制剂在冷冻和解冻后通常也是稳定的。
任选地,本发明的制剂还可包含其它赋形剂,例如糖、多元醇和氨基酸(例如,精氨酸、赖氨酸和甲硫氨酸)。在其它方面,本发明还提供了大体上不含表面活性剂、无机盐、另外的糖和/或其它赋形剂,即少于约0.0005%、少于0.0003%或少于0.0001%的此类化合物的制剂。
示例性制剂包含抗体,所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14、15或16的任一个所示的氨基酸序列的重链,所述抗体以约10mg/mL的浓度存在;以约25mM的浓度存在的组氨酸缓冲剂;以约230mM的浓度存在的海藻糖;以约0.2g/L的浓度存在的聚山梨醇酯20;并且pH为约6.5。
I.B.药物制剂的制备
本发明还提供制备药物制剂的方法。在本发明的一个方面,此类方法包括,(a)培养已将编码鼠抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)或其嵌合或人源化形式的重链或轻链的核酸稳定地整合进入其基因组的哺乳动物细胞,以便细胞将抗体分泌进入细胞培养基,和从细胞培养基纯化抗体;(b)和制备制剂,所述制剂包含,(i)以在约1mg/mL至约100mg/mL的范围内的浓度存在的纯化的抗体;(ii)以在约20mM至约30mM的范围内的浓度存在的组氨酸缓冲剂;(iii)以在约210mM至约250mM的范围内的浓度存在的海藻糖;和(iv)以在按重量计约0.005%至约0.05%的范围内的浓度存在的聚山梨醇酯20;其中制剂的特征在于在约6至约7的范围内的pH。
在本发明的一些方面,公开的制备药物制剂的方法包括,评价制剂中的抗体的至少一个性质的另外的步骤,所述性质选自物理稳定性、化学稳定性和生物活性。
例如,在本发明的一个方面,培养哺乳动物细胞以产生抗体,其中哺乳动物细胞已将编码人源化2A4抗体的轻链和重链的核酸稳定地整合进入它们的基因组。用于该目的的哺乳动物细胞包括,(a)已将编码SEQ ID NO:13或21所示的人源化2A4轻链和SEQ ID NO:15或24所示的人源化2A重链的核酸序列稳定地整合进入其基因组的宿主细胞;(b)已将具有SEQ ID NO:19的核苷酸序列的核酸和具有SEQ ID NO:22的核苷酸序列的核酸稳定地整合进入其基因组的宿主细胞;和(c)已将具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQID NO:23的核苷酸序列的核酸稳定地整合进入其基因组的宿主细胞。
为了产生抗体,将公开的核酸包含在载体中。在一些实例中,载体包含,有效地连接至能够实现DNA在宿主细胞中表达的适当的控制序列的编码鼠2A4或7D8抗体或其嵌合或人源化形式的核酸。此类控制序列包括,实现转录的启动子(例如,本领域已知的组成型启动子或诱导型启动子)、控制此类转录的任选的操纵子序列、编码适当的mRNA核糖体结合位点的序列、增强子、多腺苷酸化信号以及控制转录和翻译的终止的序列。载体可以是质粒、噬菌体颗粒(例如,病毒载体例如腺病毒、腺相关病毒、逆转录病毒、疱疹病毒、痘苗病毒、慢病毒、痘病毒和巨细胞病毒载体),或仅仅是基因组插入物。当转化进入适当的宿主后,抗体核酸可整合进入宿主的基因组,或载体可以不依赖于宿主基因组而复制和起作用。
可将公开的核酸单独地或组合地(例如,编码抗体轻链的核酸和编码抗体重链的核酸的组合)包含在载体中。例如,载体可包含,含有编码SEQ ID NO:13-16、21或24的任一个的核苷酸序列的核酸;含有SEQ ID NO:19-20和22-23的任一个的核苷酸序列的核酸,或其组合。本发明的代表性载体包括,(a)包含编码SEQ ID NO:13所示的人源化2A4轻链和SEQID NO:15所示的人源化2A重链的核酸序列的载体;(b)包含具有SEQ ID NO:19的核苷酸序列的核酸和具有SEQ ID NO:22的核苷酸序列的核酸的载体;和(c)包含具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQ ID NO:23的核苷酸序列的核酸的载体。
用于制备本发明的抗体制剂的宿主细胞包括哺乳动物细胞(包括人来源的细胞),例如猴肾细胞、人胚胎肾细胞、幼仓鼠肾(BHK)细胞、中国仓鼠卵巢细胞(CHO)、小鼠塞尔托利细胞、人宫颈癌(HeLa)细胞、犬肾细胞、人肺细胞、人肝细胞、小鼠乳房肿瘤细胞和NS0细胞。例如,宿主细胞可在其基因组中包含,含有编码SEQ ID NO:13-16、21和24的任一个的核苷酸序列的稳定地整合的核酸;含有SEQ ID NO:19-20和22-23的任一个的核苷酸序列的稳定整合的核酸,或其组合。本发明的代表性宿主细胞包括,(a)包含编码SEQ ID NO:13或21所示的人源化2A4轻链和SEQ ID NO:15或24所示的人源化2A重链的核酸序列的宿主细胞;(b)包含具有SEQ ID NO:19的核苷酸序列的核酸和具有SEQ ID NO:22的核苷酸序列的核酸的宿主细胞;和(c)包含具有SEQ ID NO:20的核苷酸序列的核酸和具有SEQ ID NO:23的核苷酸序列的核酸的宿主细胞。
在本发明的另一个方面,嵌合或人源化2A4抗体或嵌合或人源化7D8抗体通过化学合成来制备,随后将其用于公开的制剂中。
用于制备公开的制剂的抗体通常是分离的或纯化的,即大体上不含来自产生它们的细胞的细胞材料或其它污染性蛋白质,或当化学合成时,大体上不含化学药物前体或其它化学药物。例如,大体上不含细胞材料的抗体包括,具有少于约30%、25%、20%、15%、10%、8%、5%、2%、1%、0.5%、0.1%或更少(按干重计)的污染性蛋白质的抗体的制剂。当重组产生抗体时,其还大体上不含细胞培养基,从而细胞培养基构成少于约30%、25%、20%、15%、10%、8%、5%、2%、1%、0.5%、0.1%或更少的蛋白质制剂的体积。当通过化学合成产生抗体时,其优选大体上不含化学药物前体或参与蛋白质合成的其它化学药物,或与所述化学药物前体或其它化学药物分离。因此,此类抗体制剂具有少于约30%、25%、20%、15%、10%、8%、5%、2%、1%、0.5%、0.1%或更少(按干重计)的化学药物前体或除抗体药物外的化合物。重组表达的抗体的纯化可利用本领域已知的许多方法中的任何方法,例如亲和层析、酸处理、深度过滤、阴离子交换层析、阳离子交换层析、纳米过滤、超滤、透析和渗滤(diafiltration)。
可将纯化的抗体药物调整成包含本文中描述的任何制剂的溶液,其稀释至期望的浓度并贮存以待使用。任选地,可将制剂以浓缩的形式贮存以待使用。取决于它们的稳定性特征,液体制剂可在冷冻条件下以冰冻的形式贮存,或在室温下贮存,这可根据经验来确定。在一些情况下,使用进一步的过滤步骤。可将本文中描述的一些制剂冷冻干燥并以粉剂形式贮存。取决于它们的稳定性特征,冻干制剂可在冷冻条件下以冰冻形式贮存或在室温下贮存,这可根据经验来确定。例如,可在约2℃至8℃的温度下贮存冻干制剂。在此类情况下,可在给患者施用之前重构制剂,以产生具有以本文中描述的浓度存在的抗体和赋形剂的液体制剂。在一些情况下,在无菌水中重构制剂。在一些情况下,重构制剂,将其添加至用于给患者施用的输液袋中。可在给患者施用之前在冷冻条件下或在室温下贮存重构的制剂,进行与稳定性特征一致的时间。冷冻干燥和重构技术在本领域是已知的并且描述于实施例中。
因此,本发明还包括,包含冻干的抗体药物以及重构和使用说明书的药物产品。例如,代表性药物产品可包括:(a)装有约100mg以粉剂形式存在的抗体的小瓶;(b)抗体重构说明书;和(c)制备用于输注的重构抗体的说明书,其中(i)抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链;和(ii)重构说明书要求,用注射用水重构至10mL的可抽出体积。
II.诊断和治疗的方法
还提供了治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维的存在的淀粉样变性或处于患所述疾病的风险中的人患者的方法,所述方法包括给患者施用有效剂量的本文中描述的制剂的任何制剂。
II.A.顺从诊断和治疗的受试者
人源化2A4药物将用于治疗全身性淀粉样变性,例如牵涉淀粉样蛋白轻链AL或淀粉样蛋白A(AA)蛋白的淀粉样变性。全身性淀粉样变性是由错误折叠的蛋白质的组织沉积引起的一组复杂的疾病,其导致进行性器官损伤。最常见的类型,AL淀粉样变性或原发性淀粉样变性,牵涉由产生错误折叠的免疫球蛋白轻链的克隆性浆细胞引起的血液学障碍。浆细胞过度产生错误折叠的轻链导致异常AL蛋白(淀粉样蛋白)在患有AL淀粉样变性的个体的组织和器官中沉积。AL淀粉样变性的临床特征包括一组症状和器官功能障碍,其可包括心脏、肾和肝功能障碍、GI受累、神经病和巨舌症。不同形式的全身性淀粉样变性,AA淀粉样变性或继发性淀粉样变性,由于其它疾病例如慢性炎性疾病(例如,类风湿性关节炎和强直性脊柱炎)或慢性感染(例如,肺结核或骨髓炎)而“继发性”发生。在继发性淀粉样变性中,沉积的淀粉样蛋白是淀粉样蛋白A,来源于急性期蛋白血清淀粉样蛋白A。
周围淀粉样变性顺从于该类型的淀粉样蛋白-特异性免疫疗法(通过在AA淀粉样蛋白中以及AL淀粉样蛋白中鉴定的新表位的抗体靶向)。AA和AL的动物模型中的研究已显示,合理剂量的抗体能够获得显著的积极治疗作用。
顺从于使用公开的抗体制剂的治疗的受试者或患者包括,处于发生疾病的风险中但未显示症状的个体,以及已显示淀粉样蛋白疾病的症状的患者。因此,可给一般群体预防性施用本发明的方法,而无需对受试患者进行任何风险评估。例如,本发明的方法对于确实具有已知的自身免疫障碍遗传风险的个体是特别有用的。此类个体包括,具有已经历该疾病的亲戚的个体和其风险已通过遗传或生物化学标志物的分析得到确定的个体。作为另一个实例,患有AA淀粉样变性的患者可长期无症状,这使得在淀粉样蛋白沉积物广泛出现之前,AA淀粉样变性的临床诊断通常被耽误或错失。对于无症状的这些患者,据估计仅53%的病例被诊断出来。参见,例如,L.E.K.Consulting,Independent Market Research(2003)。预防性施用公开的抗体制剂可降低AA淀粉样变性的发病率。
本发明的方法对于确实具有已知的患AA淀粉样变性或AL淀粉样变性的风险或怀疑患有所述疾病或已被诊断为患有所述疾病的个体是特别有用的。此类个体包括但不限于,患有慢性炎性疾病、遗传性炎性疾病和慢性微生物感染,例如类风湿性关节炎、幼年型慢性关节炎、强直性脊柱炎、银屑病、银屑病性关节病、Reiter's综合征、成人Still's病、Behcet's综合征、克罗恩病、家族性地中海热、麻疯病、肺结核、支气管扩张症、压力性溃疡、慢性肾盂肾炎、骨髓炎、Whipple's病、骨髓瘤、巨球蛋白血症、免疫细胞恶液质、单克隆丙种球蛋白病、潜隐性恶液质的个体。慢性炎性和感染性病况是AA淀粉样变性发展的前提,并且表现为局部结节性淀粉样变性的AL淀粉样变性可与慢性炎性疾病相关。确实具有已知的患AA淀粉样变性的风险的个体还包括但不限于,具有恶性肿瘤如何杰金氏淋巴瘤、肾癌、肠癌、肺癌和泌尿生殖道癌、基底细胞癌和多毛细胞白血病的那些个体。此外,具有已知的患AA淀粉样变性的风险的个体还包括但不限于,具有淋巴组织增殖性疾病例如Castleman’s病的个体。一些此类患者具有特征在于淀粉样蛋白A蛋白原纤维的存在的AA淀粉样变性。一些此类患者具有特征在于淀粉样蛋白轻链类型蛋白原纤维的存在的AL淀粉样变性。一些患者具有归因于AL淀粉样变性的全身性器官功能障碍,包括心脏、肾、肝、周围神经系统、胃肠系统、自主神经系统、肺和/或软组织或淋巴系统的功能障碍。
顺从于治疗的患者还包括,已接受、目前正接受或以后将接受替代疗法以治疗淀粉样蛋白疾病或相关病况例如炎性疾病、慢性微生物感染、恶性肿瘤、遗传性炎性疾病和淋巴组织增殖性疾病的那些患者。例如,患者还可接受或已接受本文中针对联合治疗而鉴定的一种或多种治疗剂。作为具体的实例,患有AL的患者还可接受或已接受,硼替佐米、美法仑、来那度胺和/或卡非佐米。对于先前已接受用于治疗淀粉样蛋白疾病的替代疗法的那些患者,此类疗法根据相关临床测量可以是成功的或可以是未成功的。
II.B.治疗方案
如本文中所用,术语“治疗”和“医治”是指,与疾病相关的一个或多个症状或效应的缓解或改善,疾病的一个或多个症状或效应的发作的防止、抑制或延迟,疾病的一个或多个症状或效应的严重度或频率的减轻,和/或期望的结果的增加或趋向,如本文中描述的。
本文中公开的治疗的期望结果可根据淀粉样蛋白疾病和患者特征(patientprofile)而变化,并且对于本领域技术人员来说是可容易地确定的。一般而言,期望的结果包括可测量的指标,例如病理性淀粉样蛋白原纤维的减少或清除,减少的或抑制的淀粉样蛋白聚集和/或淀粉样蛋白原纤维的沉积,以及增强的对病理性和/或聚集的淀粉样蛋白原纤维的免疫应答。期望的结果还包括淀粉样蛋白疾病特异性症状的改善。例如,AL淀粉样变性的治疗的期望的结果包括,已知症状包括器官功能障碍、外周和自律神经病变、腕管综合征、巨舌症、限制性心肌病、大关节的关节病、免疫恶液质、骨髓瘤以及潜隐的恶液质的发病率或严重度的降低。作为另一个实例,AA的治疗的期望的结果包括,相关炎症、关节炎、银屑病、微生物感染、恶性肿瘤或AA淀粉样变性所继发自的其它先前存在或共同存在的疾病的症状的减少。
公开的疗法的期望结果,相较于对照或基线测量值,通常是可定量的量度。如本文中所用,相对性术语例如"改善”、"增加"或"减少"表示,相对于对照例如在开始本文中描述的治疗之前相同个体中的测量值或对照个体或组中的测量值的值。对照个体是患有与待治疗的个体相同的淀粉样蛋白疾病的个体,其与待治疗的个体年龄大致相同(以确保被治疗的个体和对照个体中的疾病的分期是相当的),但未曾接受使用公开的抗体制剂的治疗。在该情况下,公开的抗体制剂的效力通过远离未治疗对照中的可测量的指标的偏移或趋势来评估。或者,对照个体是健康个体,其与待治疗的个体年龄大致相同。在该情况下,公开的抗体制剂的效力通过朝向健康对照中的可测量的指标的偏移或趋势来评估。对疗法的反应的变化或改善通常是统计学上显著的,并且通过p-值来描述,小于或等于0.1,小于0.05,小于0.01,小于0.005或小于0.001的p-值可被认为是显著的。
在无症状和有症状的患者中,根据公开的方法的治疗可始于潜在AA或AL淀粉样蛋白疾病的诊断之前或之后的任意时间。治疗通常必需在一段时间内施用多个剂量。治疗可通过随时间过去测定抗体或使用放射性标记的SAP闪烁显像来监测。如果反应下降,可表明需要加强剂量。AL淀粉样变性患者对治疗的反应可通过评估心脏标志物例如NT-proBNP和/或肌钙蛋白、血清肌酸和/或碱性磷酸酶;通过进行无血清轻链(SFLC)测定、定量免疫球蛋白测定、活组织检查、血清蛋白电泳(SPEP)、尿蛋白质电泳(UPEP)、血清、尿免疫固定电泳(IFE)和/或器官成像技术来监测。可根据反应标准例如血清和尿的阴性IFE、正常κ/λ比率和/或骨髓中少于5%的浆细胞来确定示例性完全反应(CR)。可从低于40mg/L的dFLC确定示例性很好的部分反应(VGPR)。可从≥50%的dFLC减少确定示例性部分反应(PR)。在肾中,可以例如在≥25%的eGFR的减少或≥0.5mg/dL的血清肌酸的增加不存在的情况下,从24小时尿蛋白质排泄的≥50%的减少(例如,>0.5g/24小时)确定对治疗的反应。在肝中,可以例如从初始升高的碱性磷酸酶的≥50%的减少或根据CT扫描或MRI的肝尺寸的≥2cm的减小确定对治疗的反应。在心脏中,可以例如从具有>650ng/L的NT-proBNP基线的患者的NT-proBNP的≥30%和300ng/L的减少确定对治疗的反应。
对于所述患者,可在约10mg至约5000mg的剂量范围内,例如以约10mg、约30mg、约100mg、约300mg、约1000mg、约2000mg或约2500mg静脉内施用抗体制剂。还可在约0.1mg/kg至约50mg/kg,或约0.5mg/kg至约30mg/kg宿主体重的剂量范围内静脉内施用抗体制剂。例如,剂量可以为约0.5mg/kg体重、约1.0mg/kg、约1.5mg/kg、约2.0mg/kg、约4.0mg/kg、约5.0mg/kg、约8.0mg/kg、约10mg/kg、约15mg/kg、约16mg/kg、约20mg/kg、约25mg/kg,或约30mg/kg体重。个体患者的剂量增加可由处方医生在不存在任何临床上显著的事件的情况下自行确定,所述临床上显著的事件可被处方医生合理地认为给患者带来过度的安全性风险,例如,等级≥3的非血液学毒性、等级≥3的不受最大止呕吐/抗腹泻疗法控制的恶心、呕吐或腹泻、在生长因子支持不存在的情况下持续>7天的等级4的中性粒细胞减少症、伴随≥38.5℃的发热和/或全身性感染的任何持续时间的等级3或4的中性粒细胞减少症,或其它等级≥4的血液学毒性。
通常在多种情况下施用抗体。示例性治疗方案使得必需进行每两周一次、每月一次或每3-6个月一次的施用。例如,患者可接受每4周一次的抗体制剂(作为一个周期),例如每28天一个周期。取决于抗体制剂在患者中的药代动力学特征(pharmacokineticprofile),可调整给药频率。例如,抗体的半衰期可允许两周的给药频率。在一些方法中,同时施用两种或更多种具有不同结合特异性的单克隆抗体,在该情况下施用的每一种抗体的剂量落在指定的范围内。单次剂量之间的间隔可以是每周1次、每月1次或每年1次。间隔也可以是无规律的,如通过测量患者中针对淀粉样蛋白(例如,AA)的抗体的血液水平所指示的。在一些方法中,调整剂量以达到约1-1000μg/ml或约25-300μg/ml的血浆抗体浓度。或者,可将抗体作为持续释放制剂来进行施用,在该情况下需要更少频率的施用。
剂量和频率取决于抗体在患者中的半衰期而变化。一般而言,人抗体显示最长半衰期,随后为人源化抗体、嵌合抗体和非人抗体。施用的剂量和频率可取决于治疗是预防性的还是治疗性的而变化。在预防性应用中,在长时期内以相对不频繁的间隔施用相对低的剂量。一些患者在其余生中持续接受治疗。在治疗性应用中,有时需要以相对短的间隔施用相对高的剂量,直至疾病的进展减小或终止,直至实现部分或完全反应,和/或直至患者显示疾病症状的减轻或改善。此后,可对患者施用预防性方案。
本文中公开的制剂可以以适合于胃肠外(例如,静脉内、肌内、皮下)施用的剂型提供。视具体应用而定,可以以适合于直肠、经皮肤、经鼻、经阴道、吸入、经眼或其它施用的剂量可选择地提供制剂。通常按照常规药学实践制备药物制剂。参见例如,Remington:TheScience and Practice of Pharmacy,(第19版)ed.A.R.Gennaro,1995,Mack PublishingCompany,Easton,Pa.和Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick和J.C.Boylan,1988-1999,Marcel Dekker,N.Y.。
在本发明的一个方面,治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维、沉积物或原纤丝聚集物的存在的轻链(AL)淀粉样变性或处于患所述疾病的风险中的人患者的方法,包括给患者施用有效剂量的药物制剂,所述药物制剂包含:(a)抗体,其包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一项所示的氨基酸序列的重链,并且其以约10mg/mL的浓度存在;(b)以约25mM的浓度存在的组氨酸缓冲剂;(c)以约230mM的浓度存在的海藻糖;(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和(e)约6.5的pH。在此类方法中,剂量通常为以约每周一次至约每季度一次(例如,每28天一次)的频率静脉内或皮下施用的约0.5mg/kg至约30mg/kg的抗体(例如,约0.5mg/kg至约8mg/kg,或约8mg/kg至约30mg/kg)。
II.C.联合药物疗法治疗方案
本发明还包括,用于治疗或预防淀粉样蛋白疾病,特别地AA淀粉样变性和AL淀粉样变性的联合治疗。此类联合治疗通过将本发明的抗体制剂与一种或多种第二治疗剂(例如视情况而定,治疗或预防AA淀粉样变性或AL淀粉样变性的另一种疗法)结合施用来进行。还可将根据本发明的联合治疗与用于治疗或预防与淀粉样蛋白疾病相关的疾病或病况例如炎性疾病、慢性微生物感染、肿瘤(包括恶性肿瘤)、遗传性炎性疾病和/或淋巴组织增生性障碍的第二疗法结合施用。许多治疗可获得用于商业用途,用于临床评价和用于临床前开发,其任一种可被选择来与公开的抗体制剂组合使用。此类治疗可以是一种或多种化合物或治疗,其选自但不限于几个主要种类,即,(i)非类固醇抗炎药(NSAID;例如,detoprofen、双氯芬酸、二氟尼柳、依托度酸、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、甲氯芬那酸、甲芬那酸、美洛昔康、萘丁美酮、萘普生钠、奥沙普秦、吡罗昔康、舒林酸、托美丁、塞来考昔、罗非昔布、阿司匹林、水杨酸胆碱、salsalte、以及水杨酸钠和水杨酸镁);(ii)类固醇(例如,可的松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙、泼尼松、曲安西龙);(iii)DMARD,即,改善病情抗风湿药(例如,环孢菌素、硫唑嘌呤、甲氨蝶呤、来氟米特、环磷酰胺、羟氯喹、柳氮磺胺吡啶、D-青霉胺、米诺环素和金);(iv)重组蛋白(例如,(依那西普,可溶性TNF受体)和(英夫利昔单抗)嵌合单克隆抗-TNF抗体);(v)干细胞移植;和/或(vi)化学疗法。AL淀粉样变性患者还可接受治疗方案,所述治疗方案包括,以护理标准范围内的剂量施用的、通常用于治疗血液恶性肿瘤的药物或药物的组合,所述药物例如美法仑、泼尼松、地塞米松、来那度胺和蛋白体抑制剂例如硼替佐米和卡非佐米(KYPROLISTM)。
联合治疗的持续时间取决于待治疗的淀粉样蛋白疾病的类型、与淀粉样蛋白疾病相关的任何基础性疾病、患者的年龄和状况、患者疾病的分期和类型、患者对治疗的反应等。医生可密切地观察治疗效果,并根据需要进行任何调整。此外,具有更大的发生AA淀粉样变性或AL淀粉样变性的风险的人(例如,在遗传上易罹患或先前患有炎性病症或其它基础性疾病的人)可接受预防性联合治疗,以抑制或延迟AA AL聚集物例如原纤维的产生,或作为治疗后维持疗法。
当进行联合治疗时,可同时施用或以任意顺序依次施用两种或更多种药物,即在施用第二药物之前,与第二药物同时,或在施用第二药物之后施用本发明的制剂。例如,联合治疗可通过在施用第二试剂/疗法之前(例如,之前1分钟、5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)、与之同时,或在其之后(例如,之后1分钟、5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)施用第一疗法而进行。
可独立地控制组合治疗的每一种组分的施用剂量、频率和模式。例如,可每天3次口服施用一种治疗剂/疗法,而可每天一次肌内施用第二治疗剂/疗法。联合治疗可以以包括休息期的间歇性周期提供。还可将化合物混合或另外配制在一起,以便一次施用递送两种化合物。在该情况下,每一种治疗剂通常以按重量计1-95%的组合物总重量的量存在。或者,可分开地并以单独的剂量配制本发明的抗体制剂和第二治疗剂。用于治疗的药物组合可以以药物包装的组分提供。
优选地,公开的联合治疗引发协同治疗作用,即,大于它们各自的作用或治疗结果之和的作用。可测量的治疗结果描述于本文中。例如,协同治疗作用可以是这样的作用,其为由给定的组合的单一试剂引发的治疗作用之和的至少约2倍,或至少约5倍,或至少约10倍或至少约20倍,或至少约50倍,或至少约100倍。协同治疗作用还可被观察为,相较于由给定的组合的单一试剂引发的治疗作用之和,至少10%、或至少20%、或至少30%、或至少40%、或至少50%、或至少60%、或至少70%、或至少80%、或至少90%或至少100%或更多的治疗作用的增加。协同作用还可以是,当将组合施用治疗剂时,允许减少治疗剂的剂量的作用。
实施例
下列实施例用于举例说明本发明的实施方案。下列实施例的某些方面根据在本发明的实践中良好地工作的、由本申请共同发明人发现或考虑的技术和方法进行描述。基于本公开内容和本领域技术人员的一般水平,本领域技术人员将理解,下列实施例仅意欲为示例性的,并且可进行许多变化、修饰和改变而不背离本发明的范围。
实施例1.用于治疗AL淀粉样变性的人源化2A4的选择
制备IgG1、κ同种型抗体,其为鼠抗体2A4的人源化形式。代表性人源化2A4抗体的轻链和重链序列示于图1A-1B和3中。编码特定人源化2A4抗体形式3(其氨基酸序列示于图3中)的核酸描述于图4A-4B中。
亲代单克隆2A4抗体针对人血清淀粉样蛋白A(sAA)的新-羧基末端表位(其因天然sAA分子在氨基酸残基76上的切割而产生)。鼠抗体不与IgG或游离轻链(LC)交叉反应,并且其已显示针对迄今为止检查的患者来源的AL淀粉样蛋白样品的广泛的同种型识别。2A4识别AL轻链淀粉样蛋白的多种形式,包括可溶性多聚体和不溶性沉积物。此外,已显示,抗体在小鼠异种移植物模型中促进淀粉样瘤的消退。鼠2A4抗体的轻链和重链序列示于图2中。
实施例2.人源化2A4抗体的剂量测定
TRIAD小鼠模型和食蟹猴的非临床研究已利用4和40mg/kg的剂量(在小鼠中)和10、50和100mg/kg的剂量(猴子中)。基于mg/kg的至人等效剂量(HED)的转化(因它们限制于血管空间而为最适当的用于单克隆抗体的转化)给出0.32和3.2(对于小鼠)以及3.2、16和32(对于猴子)的HED。基于目前可获得的数据,预期两个物种中的NOAEL为最高施用剂量。通过使用3.2的小鼠HED(因给药限制而为最敏感的物种)和10X安全系数,在首次人给药中MRSD为约0.32mg/kg。基于动物研究,对人的施用始于0.5mg/kg的剂量。
实施例3.表达载体的制备
为了产生最终的h2A4IgG1HC载体,使用质粒CET1019AS-hygro-h2A4VH3-Sce4.23.07作为模板通过PCR分离重链的可变区。用于扩增的引物在片段的5'末端引入MfeI限制位点和在3'末端引入BlpI限制位点,用于亚克隆。将可变区克隆进入MfeI和BamHI消化的真核生物表达载体pBI-61,所述载体包含G1m(3)同种异型的人IgG1的基因组恒定区。所得的重组表达载体pBI-61/2A4IgG1-REM大小为9,015个碱基对,并且具有在DHFR启动子控制之下的来自仓鼠的可选择标记二氢叶酸还原酶(DHFR)和多腺苷酸化信号。该载体还包含用于在大肠杆菌(E.coli)中进行选择的β-内酰胺酶基因以及大肠杆菌(ColE1ori)、SV40(SV40ori)和丝状噬菌体f1(f1ori)的复制起始点。HC的表达由与来源于仓鼠基因组的转录增强元件(TE)组合的来自人巨细胞病毒(CMV)的立即早期启动子/增强子区域驱动。为了转录终止和稳定,使用来自仓鼠生长激素的多腺苷酸化信号;为了增强转录,使用来源于仓鼠基因组的非编码序列(TE)。
使用质粒CET1019AS-hu2A4VL3-hck-puro-Sce 4.19.07作为模板,通过PCR分离h2A4LC的可变区,并在片段5'末端引入SgrAI限制位点和在3'末端引入KpnI限制位点,用于亚克隆入利用相同限制性内切酶消化的终真核生物表达载体pBI-60。该载体包含人κ链的基因组恒定区。所得的重组表达载体pBI-60/2A4LC大小为7,144个碱基对,并且包含在SV40启动子的控制之下的可选择标记新霉素磷酸转移酶突变体,其赋予对遗传霉素的抗性。为了转录终止,使用来自单纯疱疹(Herpes simplex)的胸苷激酶的多腺苷酸化信号。该载体还包含用于在大肠杆菌中进行选择的β-内酰胺酶基因以及大肠杆菌(ColE1ori)和丝状噬菌体f1(f1ori)的复制起始点。LC的表达由与来源于仓鼠基因组的转录增强元件(TE)组合的来自人巨细胞病毒(CMV)的立即早期启动子/增强子区域驱动。为了转录终止和稳定,使用来自仓鼠生长激素的多腺苷酸化信号;为了增强转录,使用来源于仓鼠基因组的非编码序列(TE)。
实施例4.人源化2A4抗体(混合来源的材料)的产生
在生长于无任何牛来源的组分的化学成分确定的培养基中的中国仓鼠卵巢(CHO)细胞中产生人源化2A4。将来自生产性细胞系最终所源自的稳定转染的细胞的抗体混合。通过蛋白A亲和层析纯化混合来源的材料。将该材料在食蟹猴中用于人组织交叉反应性研究和单剂量药代动力学(PK)研究。人源化2A4抗体的制剂为10mg/mL抗体、25mM L-组氨酸/L-组氨酸HCl一水合物、230mM脱水海藻糖、0.02%(w/v)聚山梨醇酯20,pH=6.5。
实施例5.人源化2A4抗体(克隆来源的材料)的产生
从实施例3中描述的细胞混合物中分离单个CHO细胞克隆,在无任何牛材料的情况下,将其用于建立原始细胞库(Master Cell Bank)(MCB)。使用与人源化2A4的GMP临床形式(2,000L规模)相同的细胞培养和纯化方法(除了按比例放大外),以80L规模生产用于非临床研究的人源化2A4。来自2,000L生产规模的材料也可用于非临床研究。
实施例6.制造人源化2A4抗体的方法
小瓶解冻及接种物扩增。将来自MCB的细胞解冻,转移至适当的细胞培养瓶中。将细胞在约37℃进行温育。将解冻的培养物扩增1至4天(细胞解冻后的第一代)。为了进行传代培养,将等分的生长的细胞培养物(和确定体积的、预加温的、0.22μm或更小过滤的接种培养基)用于在约0.02L至1L工作体积的标准细胞培养容器中达到约0.1-0.5x 106个细胞/mL的接种密度。例如,可在0.125L或0.25L或0.5L培养容器中进行第一代培养,随后在1L培养容器中进行传代。可在该培养阶段起始原种培养。为了制备用于单个生产发酵罐的接种培养物,将原种培养物的等分进行扩增,以产生达到25L体积的培养物。通常地,将细胞培养物从1L培养物按比例放大至2个或更多个1L或2L培养物,随后放大至2个或更多个2L或3L培养物,最终放大至2个或更多个达到25L培养体积/容器的培养物。将来自几个容器的生长细胞悬浮物混合,随后用于接种80L生物反应器。摇瓶、方瓶(T-flask)、转瓶(spinner flask)和袋可用作标准细胞培养容器用于上述培养步骤。
生物反应器中的种子培养物。在用细胞接种之前,将0.22μm或更小过滤的生长培养基添加至生物反应器。将加载的生物反应器的内容物加温至约37℃,并在细胞的整个温育过程中维持在该温度。将来自接种培养物的细胞转移至预加温的培养基中。将初始细胞密度定在0.1-0.5x 106个细胞/mL的范围内。将细胞在80L生物反应器中培养,随后在400L生物反应器中培养。大致每2至4天将细胞传代培养。在该阶段,可将细胞转移至相同或更大体积的另一个容器中。通常地,将细胞培养物从1x 80L生物反应器培养按比例放大至1x400L培养。为了起始生产阶段,将细胞从生长的400L细胞悬浮物转移至约2,000L工作体积的生产生物反应器。
2,000L生物反应器中的生产培养。在接种细胞之前,将0.22μm或更小过滤的生产培养基添加至生产生物反应器。将加载的生产生物反应器的内容物加温至约37℃,并在细胞的整个温育过程中维持在该温度。将生产阶段的初始细胞密度定在0.1-0.5x 106个细胞/mL的范围内。以分批补料方式运行生产生物反应器。为了支持抗体的生产和延长培养持续时间,在生产阶段添加营养补料培养基。通过培养时间或细胞密度确定起始进料的时间点。需要时,可在生产阶段添加葡萄糖溶液和/或谷氨酰胺溶液,以避免这些物质在生产过程中耗尽。2,000L生产生物反应器的运行时间通常为8至14天。体外测试收获前样品的无菌性、支原体和外来病毒。
收获和澄清。在生产阶段培养8至14天后,将细胞培养液体与细胞分离。在收获前取样后并在收获之前,可调整培养物的pH和温度以促进在收获过程中去除细胞、碎片和颗粒。为了除去细胞,将培养物通过离心+死端式过滤部件。将细胞离心和/或通过膜保留。将收获的培养液体通过0.22μm孔径或更小孔径的过滤器,收集在适当的容器中。可通过用磷酸缓冲盐溶液(PBS)冲洗,从收获系统除去残留培养液,以从收获系统回收残留产物。将所得的回收的产物与收获的培养液体收集在一起以形成收获混合物,也称为收获的无细胞培养液(HCCF)。调整HCCF的pH和温度以有利于随后的下游处理步骤。
纯化。通过一系列步骤(包括亲和层析、酸处理、深度过滤、阴离子交换层析、阳离子交换层析、纳米过滤和超滤/渗滤,可以以数个循环进行其中的几个步骤)从HCCF纯化抗体。为了除去污染物,亲和层析处理步骤特异性地结合抗体产物。将HCCF用于填充有MabSelect基质的层析柱。基质在中性pH上结合抗体,而污染则出现在流通液体中并且被除去。在洗脱步骤中,用100mM醋酸/醋酸钠溶液pH 3.5洗脱柱子。为了灭活潜在的病毒污染物,将抗体溶液在pH 3.5±0.1在室温温育最少60分钟。在温育后,使用2M氨丁三醇溶液将酸处理混合物调整至pH 7.2,随后经历深度过滤以进行澄清。对于阴离子交换层析,用注射用水(WFI)将深度过滤的产物混合物调整至≤7mS/cm的电导率。将调整的混合物用于填充有Q Sepharose FF树脂的层析柱。抗体通过阴离子交换基质,而不结合。监测流通液体,基于吸光度测量值收集含有抗体的级分。对于阳离交换层析,通过添加醋酸将产物混合物调整至5.5±0.1的pH,用WFI调整至≤7.5mS/cm的电导率。将调整的产物混合物用于填充有SPSepharose FF阳离子交换树脂的层析柱。以结合-洗脱模式进行该层析步骤。抗体结合阳离子交换基质。在洗脱步骤中,用100mM醋酸/醋酸钠和138.5mM氯化钠溶液pH 5.5洗脱柱子。通过将抗体溶液通过0.1μm预滤器和以Planova 20N纳米过滤器的1bar分压的最大压力通过Planova 20N纳米过滤器来除去潜在病毒污染物。在超滤/渗滤(UF/DF)期间,将产物浓缩至目标浓度,将缓冲液更换为制剂缓冲液。使用具有约30kD的截断值的超滤膜进行浓缩和渗滤。通过将产物浓缩至30-100mg/mL来处理材料。用25mM L-组氨酸,pH 6.5的溶液来对30kD混合物进行渗滤,随后冲洗至约60-70mg/mL的浓度。可立即在-40℃贮存30kD混合物直至进行配制。对于配制,将30kD产物混合物调整至包含17.5mM L-组氨酸/7.5mM L-组氨酸盐酸盐、230mM海藻糖和0.02%(w/v)聚山梨醇酯20,pH=6.5的溶液。最后用配制缓冲液将抗体稀释至10mg/mL的期望的目标浓度。将所得的药物通过0.22μm过滤器过滤以除去任何潜在的外来微生物污染物和颗粒材料。可将药物于-40℃冷冻贮存直至充注。
实施例7.包含人源化2A4抗体的药物的表征
用于制剂的人源化2A4包含两个异二聚体。每一个异二聚体包含约50kDa(449个氨基酸)的重链多肽和约24kDa(219个氨基酸)的κ轻链多肽。抗体蛋白具有人源化氨基酸序列,拥有约147kDa的总分子量。抗体分子的4条多肽链通过二硫键连接在一起。每一个重链多肽包含一个被占据的用于N连接糖基化的共有序列(位置299至301,在图1A中以粗体和下划线突出显示)。每个抗体分子存在2个针对血清淀粉样蛋白A表位的结合部位。
竞争性结合ELISA已被建立来测量人源化2A4对其抗原(CGGHEDT(SEQ ID NO:17),当缀合至卵白蛋白时)的结合,并与参照标准比较。
实施例8.人源化2A4药物的组分和组成
用于临床使用的人源化2A4药物(100mg/瓶)是由25mL小瓶(20R)中的10mL装填物组成的无菌液体剂型。非临床人源化2A4药物(200mg/瓶)为25mL小瓶(20R)中的20mL装填物。表1中提供了人源化2A4的非临床和临床制剂。人源化2A4药物的终制剂在20oC和pH 6.5下具有1.034g/mL的密度。
表1.非临床和临床人源化2A4药物的组成
实施例9.药物产品的批次配方(100mg/ml瓶)
配方被设计用于2,600瓶的药物产品批次,如表2中提供的。
表2.用于2,600瓶的批次配方
成分 | 等级 | 量/批 |
人源化2A4抗体 | - | 260.0g |
L-组氨酸 | USP,Ph.Eur. | 70.72g |
L-组氨酸HCl一水合物 | Ph.Eur. | 40.82g |
脱水海藻糖 | USP/NF,Ph.Eur. | 2,262.52g |
聚山梨醇酯20 | USP/NF,Ph.Eur. | 5.20g |
实施例10.冷冻干燥
Hof Com 26041冷冻干燥器用于在约86小时的时间过程中冷冻干燥配制的人源化2A4药物,其中按照表3中所示的程序通过N2注射,由MKS控制系统(MKS Instruments)调节压力。通过Pirani信号检测终点。在干燥模式过程中,将小瓶直接置于搁板上而无需冻干盘。用制药级无菌N2以约600mbar进行氮气装填。随后密闭小瓶,将其在冷冻干燥器中于5℃贮存。将终药物产品于2-8℃避光贮存。该过程应当产生白色至微黄色冻干饼(lyo cake)。
表3概述了用于人源化2A4药物的冷冻干燥的程序。
表3.冷冻干燥步骤
实施例11.冻干药物产品的重构
在使用之前,必须用无菌注射用水重构冻干粉(lyophlisate)。在层流(laminarair-flow)下,按照下列方法进行h2A4小瓶的重构。除去各个产品小瓶的完全翻转盖(flip-off-cap)。还除去橡皮塞。通过移取必需体积(2x 5mL WFI,使用活塞式移液器)来添加溶剂。当进行该动作时,要确保将溶剂缓慢地添加至冻干产品。小心地涡旋(不要摇动)小瓶,直至冻干产品完全溶解。通过小心地上下倒置小瓶来使溶液均质化。按照表1等分溶解的材料,并将其于-70℃贮存直至分析。
实施例12.人源化2A4药物的临床评价
临床试验被设计来测定人源化2A4药物在具有AL淀粉样变性的受试者中的最大耐受剂量(MTD)和/或2期推荐剂量(P2RD)。给药始于0.5mg/kg并且升高至30mg/kg或总共2500mg(按两者中较低者计算)。最初,将人源化2A4药物作为单一试剂每28天静脉内施用一次,直至器官功能的增进或不可接受的治疗相关毒性或收回知情同意。如果来自初始剂量的人源化2A4药物的半衰期(t1/2)表明不同的给药方案更加合适(例如,每2周一次,或可选择地,比每28天一次频率更低的方案),那么可使用可选择的给药方案来修改随后组群的给药。
本发明的一些实施方案如下:
1.一种药物制剂,其包含:
(a)特异性地与2A4或7D8竞争对抗原的结合的抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的嵌合或人源化形式,或其片段,其中所述抗体以在约1mg/mL至约100mg/mL的范围内的浓度存在;
(b)以在约20mM至约30mM的范围内的浓度存在的组氨酸缓冲剂;
(c)以在约210mM至约250mM的范围内的浓度存在的海藻糖;和
(d)以在按重量计约0.005%至约0.05%的范围内的浓度存的聚山梨醇酯20;
其中所述制剂的特征在于,在约6至约7的范围内的pH。
2.实施方案1的制剂,其中所述抗体是抗体2A4的人源化形式。
3.实施方案1的制剂,其中所述抗体包含含有SEQ ID NO:4所示的氨基酸序列的轻链可变区。
4.实施方案1的制剂,其中所述抗体包含含有SEQ ID NO:5所示的氨基酸序列的重链可变区。
5.实施方案3的制剂,其中所述抗体包含含有SEQ ID NO:5所示的氨基酸序列的重链可变区。
6.实施方案5的制剂,其中所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链。
7.实施方案6的制剂,其中所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:15所示的氨基酸序列的重链。
8.实施方案1的制剂,其中所述抗体包含,含有SEQ ID NO:6、7和8所示的3个互补决定区的轻链可变区,和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。
9.实施方案1的制剂,其中所述抗体是由ATCC登录号PTA-9468产生的抗体7D8的人源化或嵌合形式。
10.实施方案1的制剂,其中所述抗体包含,含有SEQ ID NO:12、7和8所示的3个互补决定区的轻链可变区,和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。
11.实施方案1-10的任一项的制剂,其中所述抗体以在约5mg/mL至约15mg/mL的范围内的浓度存在。
12.实施方案11的制剂,其中所述抗体以约10mg/mL的浓度存在。
13.实施方案1-10的任一项的制剂,其中所述抗体以在约25-75mg/mL的范围内的浓度存在。
14.实施方案13的制剂,其中所述抗体以约50mg/mL的浓度存在。
15.实施方案1-14的任一项的制剂,其中所述组氨酸缓冲剂以约25mM的浓度存在。
16.实施方案15的制剂,其中所述组氨酸缓冲剂包含L-组氨酸和L-组氨酸HCl一水合物。
17.实施方案16的制剂,其中所述L-组氨酸以在约16mM至约22mM的范围内的浓度存在,并且L-组氨酸HCl一水合物以在约4mM至约8mM的范围内的浓度存在。
18.实施方案1-17的任一项的制剂,其中所述海藻糖以约230mM的浓度存在。
19.实施方案1-18的任一项的制剂,其特征在于约300mOsm/kg的重量摩尔渗透压浓度。
20.实施方案1-19的任一项的制剂,其中少于约10%的抗体以聚集物的形式存在于制剂中。
21.实施方案1-20的任一项的制剂,其还包含填充剂。
22.实施方案1-21的任一项的制剂,其是无菌的。
23.实施方案1-22的任一项的制剂,其在冷冻和解冻后是稳定的。
24.一种药物制剂,其包含:
(a)包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且其以约10mg/mL的浓度存在;
(b)以约25mM的浓度存在的组氨酸缓冲剂;
(c)以约230mM的浓度存在的海藻糖;
(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和
(e)约6.5的pH。
25.实施方案24的制剂,其中所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:15所示的氨基酸序列的重链。
26.一种药物制剂,其包含:
(a)抗体,其为抗体2A4(ATCC登录号PTA-9662)、抗体7D8(ATCC登录号PTA-9468),或特异性地与2A4或7D8竞争对抗原的结合的抗体2A4或抗体7D8的嵌合或人源化形式,或其片段,其中所述抗体以在约50mg/mL至约100mg/mL的范围内的浓度存在;
(b)缓冲剂;
(c)非还原糖;和
(d)非离子表面活性剂。
27.一种抗体的冻干制剂,其包含
(a)抗体2A4(ATCC登录号PTA-9662)或抗体7D8(ATCC登录号PTA-9468)的人源化形式或其抗原结合片段;
(b)组氨酸;
(c)海藻糖;和
(d)聚山梨醇酯20。
28.实施方案27的冻干制剂,其中当重构时,所述制剂具有约6至约7的pH。
29.实施方案28的冻干制剂,其中当重构时,所述制剂具有约6.5的pH。
30.实施方案27的冻干制剂,其包含约100mg至约1000mg的抗体。
31.实施方案27的冻干制剂,其中所述聚山梨醇酯20以在按重量计约0.005%至约0.05%的范围内的浓度存在。
32.实施方案27的冻干制剂,其使得能够重构以产生水溶液,所述溶液包含:
(a)包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且其以约10mg/mL的浓度存在;
(b)以约25mM的浓度存在的组氨酸缓冲剂;
(c)以约230mM的浓度存在的海藻糖;
(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和
(e)约6.5的pH。
33.实施方案32的冻干制剂,其中所述冻干制剂包含约100mg的抗体并且使得能够用无菌水重构。
34.一种核酸,其包含编码SEQ ID NO:13的核苷酸序列。
35.实施方案34的核酸,其包含SEQ ID NO:19的核苷酸序列。
36.实施方案35的核酸,其包含SEQ ID NO:20的核苷酸序列。
37.一种核酸,其包含编码SEQ ID NO:14-16的任一个的核苷酸序列。
38.实施方案37的核酸,其包含编码SEQ ID NO:15的核苷酸序列。
39.实施方案38的核酸,其包含SEQ ID NO:22的核苷酸序列。
40.实施方案39的核酸,其包含SEQ ID NO:23的核苷酸序列。
41.一种载体,其包含实施方案34-40的任一项的核酸。
42.一种载体,其包含实施方案34和38的核酸。
43.一种载体,其包含实施方案35和39的核酸。
44.一种载体,其包含实施方案36和40的核酸。
45.一种宿主细胞,其已将实施方案34-40的任一项的核酸稳定地整合进入其基因组。
46.实施方案45的宿主细胞,其中所述宿主细胞是CHO细胞。
47.实施方案45的宿主细胞,其已将包含编码SEQ ID NO:13的核苷酸序列的核酸和包含编码SEQ ID NO:14-16的任一个的核苷酸序列的核酸稳定地整合进入其基因组。
48.实施方案38的宿主细胞,其已将包含编码SEQ ID NO:19的核苷酸序列的核酸和包含编码SEQ ID NO:22的核苷酸序列的核酸稳定地整合进入其基因组。
49.实施方案38的宿主细胞,其已将包含编码SEQ ID NO:20的核苷酸序列的核酸和包含编码SEQ ID NO:23的核苷酸序列的核酸稳定地整合进入其基因组。
50.实施方案47-49的任一项的宿主细胞,其中所述宿主细胞是CHO细胞。
51.一种制备药物制剂的方法,其包括:
(a)培养已将一个或多个编码人源化2A4抗体的轻链和重链的核酸稳定地整合进入其基因组的哺乳动物细胞,以便所述细胞将所述抗体分泌进入细胞培养基,和从所述细胞培养基纯化所述抗体;
(b)和制备实施方案1的制剂。
52.实施方案51的方法,其中所述编码人源化2A4抗体的轻链的核酸包含编码SEQID NO:13的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含编码SEQ IDNO:14-16的任一个的核苷酸序列。
53.实施方案52的方法,其中所述编码人源化2A4抗体的轻链的核酸包含编码SEQID NO:13的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含编码SEQ IDNO:15的核苷酸序列。
54.实施方案53的方法,其中所述编码人源化2A4抗体的轻链的核酸包含SEQ IDNO:19的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含SEQ ID NO:22的核苷酸序列。
55.实施方案54的方法,其中所述编码人源化2A4抗体的轻链的核酸包含SEQ IDNO:20的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含SEQ ID NO:23的核苷酸序列。
56.实施方案51-55的任一项的方法,其还包括评价制剂中的抗体的至少一个性质,所述性质选自物理稳定性、化学稳定性和生物活性。
57.实施方案51-55的任一项的方法,其中所述哺乳动物细胞是CHO细胞。
58.一种方法,所述方法治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维的存在的淀粉样变性或处于患所述疾病的的风险中的人患者,所述方法包括给所述患者施用有效剂量的实施方案1-33的任一项的制剂。
59.实施方案58的方法,其中所述人患者具有特征在于淀粉样蛋白A蛋白原纤维的存在的淀粉样蛋白A淀粉样变性。
60.实施方案59的方法,其中所述制剂是实施方案25的制剂。
61.实施方案60的方法,其中所述人患者具有特征在于淀粉样蛋白轻链类型蛋白原纤维的存在的AL淀粉样变性。
62.实施方案61的方法,其中所述制剂是实施方案25的制剂。
63.实施方案61或62的方法,其中所述患者还用美法仑、硼替佐米、来那度胺或卡非佐米的一种或两种来治疗。
64.实施方案63的方法,其中所述患者在用实施方案1-33的任一项的制剂治疗之前,用美法仑和/或硼替佐米来治疗。
65.实施方案64的方法,其中所述患者在用实施方案1-33的任一项的制剂治疗的同时,用美法仑和/或硼替佐米来治疗。
66.实施方案64的方法,其中所述患者在用实施方案1-33的任一项的制剂治疗之后,用美法仑和/或硼替佐米来治疗。
67.实施方案58-66的任一项的方法,其中所述AL淀粉样变性与B淋巴细胞谱系的恶液质相关。
68.实施方案67的方法,其中所述恶液质是恶性肿瘤。
69.实施方案68的方法,其中所述恶性肿瘤是多发性骨髓瘤。
70.实施方案58-69的任一项的方法,其中所述制剂以多个剂量施用。
71.实施方案70的方法,其中以约每日一次至约每年一次的频率施用所述制剂。
72.实施方案71的方法,其中所述频率在约每隔一周一次至约每三个月一次的范围内。
73.实施方案58-72的任一项的方法,其中以在约10mg至约5000mg人源化2A4药物的范围内的剂量静脉内施用所述制剂。
74.实施方案73的方法,其中以约每隔一周一次至约每隔一月一次的频率,以在约30mg至约2500mg人源化2A4药物的范围内的剂量施用所述制剂。
75.实施方案73或74的方法,其中每月一次施用所述制剂。
76.实施方案73-75的任一项的方法,其中所述剂量为约30mg人源化2A4药物。
77.实施方案73-75的任一项的方法,其中所述剂量为约100mg人源化2A4药物。
78.实施方案73-75的任一项的方法,其中所述剂量为约300mg人源化2A4药物。
79.实施方案73-75的任一项的方法,其中所述剂量为约1000mg人源化2A4药物。
80.实施方案73-75的任一项的方法,其中所述剂量为约2500mg人源化2A4药物。
81.一种方法,所述方法治疗性或预防性治疗患有特征在于淀粉样蛋白原纤维、沉积物或原纤丝聚集物的存在的轻链(AL)淀粉样变性或处于患所述疾病的风险中的人患者,包括给所述患者施用有效剂量的药物制剂,所述制剂包含:
(a)包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链的抗体,并且所述抗体以约10mg/mL的浓度存在;
(b)以约25mM的浓度存在的组氨酸缓冲剂;
(c)以约230mM的浓度存在的海藻糖;
(d)以约0.2g/L的浓度存在的聚山梨醇酯20;和
(e)约6.5的pH。
82.实施方案81的方法,其中所述剂量为,以约每周一次至约每季度一次的频率静脉内或皮下施用约0.5mg/kg至约30mg/kg的所述抗体。
83.实施方案82的方法,其中施用频率为每28天一次。
84.实施方案82的方法,其中所述剂量为约0.5mg/kg至约8mg/kg。
85.实施方案82的方法,其中所述剂量为约8mg/kg至约30mg/kg。
86.一种药物产品,其包含:
(a)装有约100mg的以粉剂形式存在的抗体的小瓶;
(b)抗体重构说明书;和
(c)制备用于输注的重构的抗体的说明书,
其中:
(i)所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16的任一个所示的氨基酸序列的重链;和
(ii)所述重构说明书要求,用注射用水重构至10mL的可抽出体积。
序列表
<110> Onclave Therapeutics Limited
Garidel, Patrick
Klein, Pamela
Henderson, Isaac Craig
<120> 抗体制剂和方法
<130> E090 1040CN
<160> 24
<170> PatentIn version 3.5
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<222> (69)..(87)
<223> CDR 2
<220>
<221> MISC_FEATURE
<222> (120)..(127)
<223> CDR 3
<400> 3
Met Val Leu Gly Leu Lys Trp Val Phe Phe Val Val Phe Tyr Gln Gly
-15 -10 -5
Val His Cys Glu Val Gln Leu Val Glu Ser Gly Gly Arg Leu Val Gln
-1 1 5 10
Pro Lys Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
15 20 25
Asn Thr Tyr Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
30 35 40 45
Glu Trp Val Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr
50 55 60
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Phe Arg Asp Asp Ser
65 70 75
Gln Ser Met Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
80 85 90
Ala Met Tyr Tyr Cys Val Arg Pro Tyr Ser Asp Ser Phe Ala Tyr Trp
95 100 105
Gly Gln Gly Thr Leu Val Thr Val Ser Ala
110 115
<210> 4
<211> 112
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(人源化的2A4轻链可变区形式3)
<400> 4
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Thr Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 5
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(人源化的2A4重链可变区形式3)
<400> 5
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 6
<211> 16
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(16)
<223> 2A4 VL CDR1
<400> 6
Arg Ser Ser Gln Ser Leu Val His Ser Thr Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 7
<211> 7
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(7)
<223> 2A4 VL CDR2
<400> 7
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 8
<211> 9
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(9)
<223> 2A4 VL CDR3
<400> 8
Ser Gln Ser Thr His Val Pro Phe Thr
1 5
<210> 9
<211> 10
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(10)
<223> 2A4 VH CDR1
<400> 9
Gly Phe Thr Phe Asn Thr Tyr Ala Met Tyr
1 5 10
<210> 10
<211> 19
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(19)
<223> 2A4 VH CDR2
<400> 10
Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr Tyr Ala Asp Ser
1 5 10 15
Val Lys Asp
<210> 11
<211> 8
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(8)
<223> 2A4 VH CDR3
<400> 11
Pro Tyr Ser Asp Ser Phe Ala Tyr
1 5
<210> 12
<211> 7
<212> PRT
<213> 小家鼠
<220>
<221> MISC_FEATURE
<222> (1)..(16)
<223> 7D8 VL CDR1
<400> 12
Arg Ser Ser Leu Ser Leu Val His Ser Thr Gly Asn Thr Tyr Leu His
1 5 10 15
<210> 13
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(人源化的2A4 kappa轻链)
<400> 13
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Thr Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 14
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列
(人源化的2A4 IgG1重链变体1 (G1m1同种异型))
<400> 14
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala 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 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> 15
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列
(人源化的2A4 IgG1重链变体2 (G1m3同种异型))
<220>
<221> MISC_FEATURE
<222> (299)..(301)
<223> 糖基化位点
<400> 15
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala 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> 16
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(人源化的2A4 IgG2重链)
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr
20 25 30
Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr Tyr Ala Asp
50 55 60
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
210 215 220
Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 His 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 Phe Arg Val Val Ser Val Leu
290 295 300
Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg 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 Met Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln 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 Pro Gly Lys
435 440 445
<210> 17
<211> 7
<212> PRT
<213> 智人
<400> 17
Cys Gly Gly His Glu Asp Thr
1 5
<210> 18
<211> 4
<212> PRT
<213> 智人
<400> 18
Ala Glu Asp Ser
1
<210> 19
<211> 660
<212> DNA
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列
(Hu2A4 VH3VL3 hcg1, k cDNA 序列 - 不具有信号序列的轻链)
<400> 19
gacgtggtga tgacccagtc ccctctgtcc ctgcctgtga cccctggcga gcctgcctcc 60
atctcctgcc ggtcctccca gtccctggtg cactccaccg gcaacaccta tctgcactgg 120
tatctgcaga agcctggcca gtctcctcag ctgctgatct acaaggtgtc caaccggttc 180
tccggcgtgc ctgaccggtt ctctggctcc ggctccggca ccgacttcac cctgaagatc 240
tcccgggtgg aggccgagga cgtgggcgtg tactactgct cccagtccac ccacgtgcct 300
ttcaccttcg gcggaggcac caaggtggag atcaagcgaa ctgtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgttag 660
<210> 20
<211> 726
<212> DNA
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(Hu2A4 VH3VL3 hcg1, k cDNA 序列 - 轻链)
<220>
<221> sig_肽
<222> (1)..(66)
<220>
<221> CDS
<222> (1)..(726)
<220>
<221> V_区
<222> (67)..(402)
<220>
<221> C_区
<222> (403)..(726)
<400> 20
atg gac atg cgg gtg ccc gca cag ctg ctg ggc ctg ctg atg ctg tgg 48
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp
1 5 10 15
gtg tcc ggc tcc tcc ggc gac gtg gtg atg acc cag tcc cct ctg tcc 96
Val Ser Gly Ser Ser Gly Asp Val Val Met Thr Gln Ser Pro Leu Ser
20 25 30
ctg cct gtg acc cct ggc gag cct gcc tcc atc tcc tgc cgg tcc tcc 144
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
cag tcc ctg gtg cac tcc acc ggc aac acc tat ctg cac tgg tat ctg 192
Gln Ser Leu Val His Ser Thr Gly Asn Thr Tyr Leu His Trp Tyr Leu
50 55 60
cag aag cct ggc cag tct cct cag ctg ctg atc tac aag gtg tcc aac 240
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
cgg ttc tcc ggc gtg cct gac cgg ttc tct ggc tcc ggc tcc ggc acc 288
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
gac ttc acc ctg aag atc tcc cgg gtg gag gcc gag gac gtg ggc gtg 336
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
tac tac tgc tcc cag tcc acc cac gtg cct ttc acc ttc ggc gga ggc 384
Tyr Tyr Cys Ser Gln Ser Thr His Val Pro Phe Thr Phe Gly Gly Gly
115 120 125
acc aag gtg gag atc aag cga act gtg gct gca cca tct gtc ttc atc 432
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
ttc ccg cca tct gat gag cag ttg aaa tct gga act gcc tct gtt gtg 480
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
tgc ctg ctg aat aac ttc tat ccc aga gag gcc aaa gta cag tgg aag 528
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
gtg gat aac gcc ctc caa tcg ggt aac tcc cag gag agt gtc aca gag 576
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
cag gac agc aag gac agc acc tac agc ctc agc agc acc ctg acg ctg 624
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
agc aaa gca gac tac gag aaa cac aaa gtc tac gcc tgc gaa gtc acc 672
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
cat cag ggc ctg agc tcg ccc gtc aca aag agc ttc aac agg gga gag 720
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
tgt tag 726
Cys
<210> 21
<211> 241
<212> PRT
<213> 人工序列
<220>
<223> 合成的构建体
<400> 21
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Met Leu Trp
1 5 10 15
Val Ser Gly Ser Ser Gly Asp Val Val Met Thr Gln Ser Pro Leu Ser
20 25 30
Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser
35 40 45
Gln Ser Leu Val His Ser Thr Gly Asn Thr Tyr Leu His Trp Tyr Leu
50 55 60
Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn
65 70 75 80
Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr
85 90 95
Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val
100 105 110
Tyr Tyr Cys Ser Gln Ser Thr His Val Pro Phe Thr Phe Gly Gly Gly
115 120 125
Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile
130 135 140
Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
145 150 155 160
Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys
165 170 175
Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
180 185 190
Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
195 200 205
Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
210 215 220
His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
225 230 235 240
Cys
<210> 22
<211> 1350
<212> DNA
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列
(Hu2A4 VH3VL3 hcg1, k cDNA 序列 - 不具有信号序列的重链)
<400> 22
gaggtgcagc tggtcgagtc cggcggaggc ctggtgcagc ctggcggctc cctgagactg 60
tcctgcgccg cctccggctt caccttcaac acctacgcca tgtactggat caggcaggct 120
cctggcaagg gactggagtg ggtggcccgg atcaggtcca agtccaacaa ctacgctatc 180
tactacgccg actccgtgaa ggaccggttc accatctccc gggacgactc caagaactcc 240
ctgtatctgc agatgaactc cctgaaaacc gaggacaccg ccgtgtacta ctgcgctcgg 300
ccttactccg actccttcgc ctactggggc cagggcaccc tggtgaccgt gtccagcgcc 360
tccaccaagg gcccatcggt cttccccctg gcaccctcct ccaagagcac ctctgggggc 420
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 480
aactcaggcg ccctgaccag cggcgtgcac accttcccgg ctgtcctaca gtcctcagga 540
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca gcttgggcac ccagacctac 600
atctgcaacg tgaatcacaa gcccagcaac accaaggtgg acaagagagt tgagcccaaa 660
tcttgtgaca aaactcacac atgcccaccg tgcccagcac ctgaactcct ggggggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacatgcg tggtggtgga cgtgagccac gaagaccctg aggtcaagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccgc gggaggagca gtacaacagc 900
acgtaccgtg tggtcagcgt cctcaccgtc ctgcaccagg actggctgaa tggcaaggag 960
tacaagtgca aggtctccaa caaagccctc ccagccccca tcgagaaaac catctccaaa 1020
gccaaagggc agccccgaga accacaggtg tacacgctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctatcccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacgcc tcccgtgctg 1200
gactccgacg gctccttctt cctctatagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtcccc gggtaaatga 1350
<210> 23
<211> 1407
<212> DNA
<213> 人工序列
<220>
<223> 含有鼠和人残基的人源化抗体序列(Hu2A4 VH3VL3 hcg1, k cDNA 序列 - 重链)
<220>
<221> sig_肽
<222> (1)..(57)
<220>
<221> CDS
<222> (1)..(1407)
<220>
<221> V_区
<222> (58)..(414)
<220>
<221> C_区
<222> (415)..(1407)
<400> 23
atg gag ttc ggc ctg tcc tgg ctg ttc ctg gtg gcc atc ctg aag ggc 48
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
gtg cag tgc gag gtg cag ctg gtc gag tcc ggc gga ggc ctg gtg cag 96
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
cct ggc ggc tcc ctg aga ctg tcc tgc gcc gcc tcc ggc ttc acc ttc 144
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
aac acc tac gcc atg tac tgg atc agg cag gct cct ggc aag gga ctg 192
Asn Thr Tyr Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
gag tgg gtg gcc cgg atc agg tcc aag tcc aac aac tac gct atc tac 240
Glu Trp Val Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr
65 70 75 80
tac gcc gac tcc gtg aag gac cgg ttc acc atc tcc cgg gac gac tcc 288
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
85 90 95
aag aac tcc ctg tat ctg cag atg aac tcc ctg aaa acc gag gac acc 336
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
100 105 110
gcc gtg tac tac tgc gct cgg cct tac tcc gac tcc ttc gcc tac tgg 384
Ala Val Tyr Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala Tyr Trp
115 120 125
ggc cag ggc acc ctg gtg acc gtg tcc agc gcc tcc acc aag ggc cca 432
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
tcg gtc ttc ccc ctg gca ccc tcc tcc aag agc acc tct ggg ggc aca 480
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
gcg gcc ctg ggc tgc ctg gtc aag gac tac ttc ccc gaa ccg gtg acg 528
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
gtg tcg tgg aac tca ggc gcc ctg acc agc ggc gtg cac acc ttc ccg 576
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
gct gtc cta cag tcc tca gga ctc tac tcc ctc agc agc gtg gtg acc 624
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
gtg ccc tcc agc agc ttg ggc acc cag acc tac atc tgc aac gtg aat 672
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
cac aag ccc agc aac acc aag gtg gac aag aga gtt gag ccc aaa tct 720
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
225 230 235 240
tgt gac aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg 768
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
ggg gga ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc 816
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
atg atc tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc 864
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
cac gaa gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag 912
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
gtg cat aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg 960
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat 1008
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
ggc aag gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc 1056
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
340 345 350
atc gag aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag 1104
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
gtg tac acg ctg ccc cca tcc cgg gag gag atg acc aag aac cag gtc 1152
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
agc ctg acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg 1200
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
gag tgg gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct 1248
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
ccc gtg ctg gac tcc gac ggc tcc ttc ttc ctc tat agc aag ctc acc 1296
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
gtg gac aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg 1344
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
atg cat gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg 1392
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
tcc ccg ggt aaa tga 1407
Ser Pro Gly Lys
465
<210> 24
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 合成的构建体
<400> 24
Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
35 40 45
Asn Thr Tyr Ala Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ile Tyr
65 70 75 80
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
85 90 95
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Pro Tyr Ser Asp Ser Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
130 135 140
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
145 150 155 160
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
210 215 220
His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser
225 230 235 240
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
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Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
305 310 315 320
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
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Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
Claims (10)
1.一种抗体的冻干制剂,其包含
(a)100mg的ATCC登录号PTA-9662的抗体2A4或ATCC登录号PTA-9468的抗体7D8的人源化形式或者其抗原结合片段;
(b)27.2mg L-组氨酸;
(c)15.7mg L-组氨酸HCl一水合物;
(d)870.2mg海藻糖;和
(e)2mg聚山梨醇酯20。
2.权利要求1的冻干制剂,其中所述抗体包含含有SEQ ID NO:6、7和8所示的3个互补决定区的轻链可变区,和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。
3.权利要求1的冻干制剂,其中所述抗体包含含有SEQ ID NO:12、7和8所示的3个互补决定区的轻链可变区,和含有SEQ ID NO:9、10和11所示的3个互补决定区的重链可变区。
4.权利要求1的冻干制剂,其中所述抗体包含含有SEQ ID NO:4所示的氨基酸序列的轻链可变区,和含有SEQ ID NO:5所示的氨基酸序列的重链可变区。
5.权利要求1的冻干制剂,其中所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:14-16中任一个所示的氨基酸序列的重链。
6.权利要求1的冻干制剂,其中所述抗体包含含有SEQ ID NO:13所示的氨基酸序列的轻链和含有SEQ ID NO:15所示的氨基酸序列的重链。
7.一种制备冻干制剂的方法,其包括:
(a)培养已将一个或多个编码人源化2A4抗体或人源化7D8抗体的轻链和重链的核酸稳定地整合进入其基因组的哺乳动物细胞,以便所述细胞将所述抗体分泌进入细胞培养基,和从所述细胞培养基纯化所述抗体;
(b)和制备权利要求1-6中任一项的冻干制剂。
8.权利要求7的方法,其中所述编码人源化2A4抗体的轻链的核酸包含编码SEQ ID NO:13的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含编码SEQ ID NO:14-16中任一个的核苷酸序列。
9.权利要求7的方法,其中所述编码人源化2A4抗体的轻链的核酸包含编码SEQ ID NO:13的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含编码SEQ ID NO:15的核苷酸序列。
10.权利要求9的方法,其中所述编码人源化2A4抗体的轻链的核酸包含SEQ ID NO:19的核苷酸序列,并且其中所述编码人源化2A4抗体的重链的核酸包含SEQ ID NO:22的核苷酸序列。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113811332A (zh) * | 2019-03-05 | 2021-12-17 | 普罗塞纳生物科学有限公司 | 治疗al淀粉样变性的方法 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
LT3378535T (lt) | 2011-10-28 | 2023-02-27 | Prothena Biosciences Limited | Humanizuoti antikūnai, atpažįstantys alfa-sinukleiną |
WO2013075740A1 (en) | 2011-11-23 | 2013-05-30 | Sanofi | Antibody purification method |
EP2682168A1 (en) * | 2012-07-02 | 2014-01-08 | Millipore Corporation | Purification of biological molecules |
MX368177B (es) * | 2013-05-06 | 2019-09-23 | Sanofi Sa | Proceso continuo de múltiples etapas para purificar anticuerpos. |
US10513555B2 (en) * | 2013-07-04 | 2019-12-24 | Prothena Biosciences Limited | Antibody formulations and methods |
US11326182B2 (en) | 2016-04-29 | 2022-05-10 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
WO2017189964A2 (en) | 2016-04-29 | 2017-11-02 | Voyager Therapeutics, Inc. | Compositions for the treatment of disease |
JP2019519584A (ja) * | 2016-06-30 | 2019-07-11 | プロシーナ バイオサイエンシーズ リミテッド | アミロイドーシスを処置するための組成物 |
US20200233294A1 (en) | 2017-03-23 | 2020-07-23 | Sony Corporation | Beam irradiation apparatus, and projector with detection function |
KR102607629B1 (ko) | 2017-06-29 | 2023-12-01 | 더 트러스티스 오브 콜롬비아 유니버시티 인 더 시티 오브 뉴욕 | 아밀로이드 침착 질환의 치료를 위한 키메라 항체 |
US11382974B2 (en) * | 2017-08-01 | 2022-07-12 | The Trustees Of Columbia University In The City Of New York | Methods and compositions for treatment of amyloid deposition diseases |
CN112040983A (zh) * | 2018-03-23 | 2020-12-04 | 普罗西纳生物科学有限公司 | 淀粉样变性的治疗和预防 |
US12018069B2 (en) | 2018-06-28 | 2024-06-25 | The Trustees Of Columbia University In The City Of New York | Methods and compositions for imaging amyloid deposits |
MA54923A (fr) | 2019-02-12 | 2021-12-22 | Prothena Biosciences Ltd | Traitement de l'amylose al avec la combinaison d'anticorps monoclonaux dirigés contre des chaînes légères d'immunoglobuline et de la molécule de membrane cellulaire cd38 sur des cellules productrices d'anticorps et d'autres cellules immunitaires |
PE20212185A1 (es) | 2019-02-18 | 2021-11-11 | Lilly Co Eli | Formulacion de anticuerpos terapeuticos |
WO2024081329A1 (en) * | 2022-10-12 | 2024-04-18 | Marengo Therapeutics, Inc. | Multifunctional molecules binding to tcr and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040023338A1 (en) * | 2001-10-26 | 2004-02-05 | Heavner George A. | IL-4 mutein proteins, antibodies, compositions, methods and uses |
US20040120956A1 (en) * | 2002-06-27 | 2004-06-24 | Song Xiao-Yu R. | CNGH0004 polypeptides, antibodies, compositions, methods and uses |
CN101172099A (zh) * | 1995-07-27 | 2008-05-07 | 基因技术股份有限公司 | 稳定等渗的冻干蛋白质制剂 |
CN101553504A (zh) * | 2006-12-11 | 2009-10-07 | 豪夫迈·罗氏有限公司 | Aβ抗体胃肠外制剂 |
CN102016059A (zh) * | 2007-12-28 | 2011-04-13 | 依兰制药公司 | 淀粉样变性的治疗和预防 |
Family Cites Families (136)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0229810B1 (en) | 1985-07-09 | 1991-10-16 | Quadrant Bioresources Limited | Protection of proteins and the like |
CA1329760C (en) | 1987-10-29 | 1994-05-24 | Ted C. K. Lee | Plasma and recombinant protein formulations in high ionic strength media |
US4877608A (en) | 1987-11-09 | 1989-10-31 | Rorer Pharmaceutical Corporation | Pharmaceutical plasma protein formulations in low ionic strength media |
GB8921222D0 (en) | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
US5945098A (en) | 1990-02-01 | 1999-08-31 | Baxter International Inc. | Stable intravenously-administrable immune globulin preparation |
US6165500A (en) | 1990-08-24 | 2000-12-26 | Idea Ag | Preparation for the application of agents in mini-droplets |
ES2136620T3 (es) | 1991-04-19 | 1999-12-01 | Lds Technologies Inc | Formulaciones de microemulsiones convertibles. |
US5334380A (en) | 1991-09-27 | 1994-08-02 | Board Of Regents, The University Of Texas System | Anti-endotoxin, interleukin-1 receptor antagonist and anti-tumor necrosis factor antibody with arginine-free formulations for the treatment of hypotension |
ATE174794T1 (de) | 1991-09-27 | 1999-01-15 | Univ Texas | Parenteral anzuwendende aminosäuren enthaltende zubereitungen zur bekämpfung von hypotension und verwandten pathologien |
DE69306755T2 (de) | 1992-01-21 | 1997-04-10 | Stanford Res Inst Int | Verbessertes verfahren zur herstellung von mikronisierter polypeptidarzneimitteln |
AU675930B2 (en) | 1992-02-18 | 1997-02-27 | Pharmos Corp. | Dry compositions for preparing submicron emulsions |
IL101007A (en) | 1992-02-18 | 1997-08-14 | Pharmos Ltd | Dry stable compositions prepared by lyophilization |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
JP3698721B2 (ja) | 1993-02-23 | 2005-09-21 | ジェネンテク・インコーポレイテッド | 有機溶媒を用いて処理したポリペプチドの賦形剤安定化 |
IS1796B (is) | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
JPH09510182A (ja) | 1993-11-17 | 1997-10-14 | エルディーエス・テクノロジーズ・インコーポレーテッド | カプセル封入されたドラッグデリバリー用透明液 |
US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
DE69535127T2 (de) | 1994-03-18 | 2007-02-15 | Supernus Pharmaceuticals, Inc. | Emulgierte arzneistoffabgabesysteme |
DE69530196T2 (de) | 1994-06-02 | 2003-11-20 | Elan Drug Delivery Ltd | Methode zum verhindern der aggregation von proteinen/peptiden bei rehydratation oder auftauen |
US5580856A (en) | 1994-07-15 | 1996-12-03 | Prestrelski; Steven J. | Formulation of a reconstituted protein, and method and kit for the production thereof |
EP1138319A3 (en) | 1994-08-04 | 2003-03-19 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US5593824A (en) | 1994-09-02 | 1997-01-14 | Pharmacia Biotech, Inc. | Biological reagent spheres |
US6524557B1 (en) | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US5654337A (en) | 1995-03-24 | 1997-08-05 | II William Scott Snyder | Topical formulation for local delivery of a pharmaceutically active agent |
US6258341B1 (en) | 1995-04-14 | 2001-07-10 | Inhale Therapeutic Systems, Inc. | Stable glassy state powder formulations |
US6136346A (en) | 1995-04-14 | 2000-10-24 | Inhale Therapeutic Systems | Powdered pharmaceutical formulations having improved dispersibility |
US6309671B1 (en) | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
EP0831790B1 (en) | 1995-06-07 | 2003-05-07 | Elan Drug Delivery Limited | Methods for stably incorporating substances within dry, foamed glass matrices and compositions obtained thereby |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
IL122910A (en) * | 1995-07-27 | 2002-05-23 | Genentech Inc | Stable isotonic protein formulation that has undergone lyophilization |
US6685940B2 (en) | 1995-07-27 | 2004-02-03 | Genentech, Inc. | Protein formulation |
USRE38431E1 (en) | 1995-12-01 | 2004-02-17 | The American National Red Cross | Methods of production and use of liquid formulations of plasma proteins |
PT885002E (pt) | 1996-03-04 | 2011-07-14 | Massachusetts Inst Technology | Materiais e métodos para aumento da internalização celular |
US6632648B1 (en) | 1996-05-14 | 2003-10-14 | Elan Drug Delivery Limited | Methods of terminal sterilization of fibrinogen |
EP0852951A1 (de) | 1996-11-19 | 1998-07-15 | Roche Diagnostics GmbH | Stabile lyophilisierte pharmazeutische Zubereitungen von mono- oder polyklonalen Antikörpern |
GB9705588D0 (en) | 1997-03-18 | 1997-05-07 | Anglia Research Foundation | Stable particle in liquid formulations |
WO1998043610A1 (en) | 1997-04-03 | 1998-10-08 | Elias Hakalehto | A method for producing jelly sweets which contain antibodies |
US7365166B2 (en) | 1997-04-07 | 2008-04-29 | Genentech, Inc. | Anti-VEGF antibodies |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
ATE230277T1 (de) | 1997-06-13 | 2003-01-15 | Genentech Inc | Stabilisierte antikörperformulierung |
JP2002522354A (ja) | 1997-09-19 | 2002-07-23 | シャイア ラボラトリーズ,インコーポレイテッド | 固溶体ビードレット |
US6913745B1 (en) | 1997-12-02 | 2005-07-05 | Neuralab Limited | Passive immunization of Alzheimer's disease |
DE69940051D1 (de) | 1998-06-26 | 2009-01-22 | Otsuka Pharma Co Ltd | Wasserlösliche trockene zusammensetzungen |
US6551613B1 (en) | 1998-09-08 | 2003-04-22 | Alza Corporation | Dosage form comprising therapeutic formulation |
NZ511072A (en) | 1998-10-05 | 2004-03-26 | Penn State Res Found | Method for enhancing receptor-mediated cellular internalization using a composition of an active agent and a viscous material and an enhancer |
NZ511527A (en) | 1998-11-13 | 2002-10-25 | Jago Res A | Dry powder for inhalation |
DK1031347T3 (da) | 1999-01-27 | 2002-07-08 | Idea Ag | Transnasal transport/immunisering med meget tilpasselige bærere |
US7258869B1 (en) | 1999-02-08 | 2007-08-21 | Alza Corporation | Stable non-aqueous single phase viscous vehicles and formulations utilizing such vehicle |
NZ513441A (en) | 1999-02-08 | 2004-01-30 | Alza Corp | Stable non-aqueous single phase viscous drug delivery vehicles comprising a polymer a solvent and a surfactant |
DE60003803T2 (de) | 1999-04-16 | 2004-06-03 | Novo Nordisk A/S | Trockene formbare arzneistoffformulierung |
JP2002543165A (ja) | 1999-05-03 | 2002-12-17 | バテル・メモリアル・インスティテュート | エーロゾル化および吸入のための組成物 |
US7820161B1 (en) | 1999-05-07 | 2010-10-26 | Biogen Idec, Inc. | Treatment of autoimmune diseases |
GB9914412D0 (en) | 1999-06-22 | 1999-08-18 | Worrall Eric E | Method for the preservation of viruses,bacteria and biomolecules |
US6309663B1 (en) | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
DE60019458T2 (de) | 1999-12-14 | 2006-02-23 | Thermo BioStar, Inc., Boulder | Stabilisierendes verdünnungsmittel für polypeptide und antigene |
US7919113B2 (en) | 1999-12-30 | 2011-04-05 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Dispersible concentrate lipospheres for delivery of active agents |
US6465425B1 (en) | 2000-02-10 | 2002-10-15 | Alkermes Controlled Therapeutics, Inc. | Microencapsulation and sustained release of biologically active acid-stable or free sulfhydryl-containing proteins |
US6653062B1 (en) | 2000-07-26 | 2003-11-25 | Wisconsin Alumni Research Foundation | Preservation and storage medium for biological materials |
US7141236B2 (en) | 2000-07-28 | 2006-11-28 | Nektar Therapeutics | Methods and compositions for delivering macromolecules to or via the respiratory tract |
PT1324776E (pt) | 2000-10-12 | 2009-12-23 | Genentech Inc | Formulações de proteína concentradas de viscosidade reduzida |
ES2727425T3 (es) | 2000-12-12 | 2019-10-16 | Medimmune Llc | Moléculas con semividas prolongadas, composiciones y usos de las mismas |
GB0113179D0 (en) | 2001-05-31 | 2001-07-25 | Novartis Ag | Organic compounds |
DK1397155T3 (en) | 2001-06-21 | 2015-12-07 | Genentech Inc | Prolonged release formulation |
US7364736B2 (en) | 2001-06-26 | 2008-04-29 | Amgen Inc. | Antibodies to OPGL |
US6646394B2 (en) * | 2001-07-09 | 2003-11-11 | Nissan Motor Co., Ltd. | Control device for plurality of rotating electrical machines |
JP4317010B2 (ja) * | 2001-07-25 | 2009-08-19 | ピーディーエル バイオファーマ,インコーポレイティド | IgG抗体の安定な凍結乾燥医薬製剤 |
DK1441589T3 (da) | 2001-11-08 | 2012-08-06 | Abbott Biotherapeutics Corp | Stabil, flydende, farmaceutisk sammensætning af IgG-antistoffer |
DE10163459A1 (de) | 2001-12-21 | 2003-07-03 | Merck Patent Gmbh | Lyophilisierte Zubereitung enthaltend Antikörper gegen EGF-Rezeptor |
EP3578168A1 (en) | 2002-02-14 | 2019-12-11 | Chugai Seiyaku Kabushiki Kaisha | Formulation of antibody-containing solutions comprising a sugar as a stabilizer |
SI1946776T1 (sl) | 2002-02-27 | 2017-07-31 | Immunex Corporation | Stabiliziran tnfr-fc sestavek, ki obsega arginin |
US6982080B2 (en) | 2002-03-15 | 2006-01-03 | Wyeth | Hydroxyethyl starch—containing polypeptide compositions |
CA2482448C (en) | 2002-04-11 | 2014-07-08 | Medimmune Vaccines, Inc. | Preservation of bioactive materials by freeze dried foam |
KR20050011741A (ko) | 2002-04-11 | 2005-01-29 | 메드이뮨 백신즈 인코포레이티드 | 분무 건조에 의한 생물학적 활성 물질의 보존 |
US7132100B2 (en) | 2002-06-14 | 2006-11-07 | Medimmune, Inc. | Stabilized liquid anti-RSV antibody formulations |
US7425618B2 (en) | 2002-06-14 | 2008-09-16 | Medimmune, Inc. | Stabilized anti-respiratory syncytial virus (RSV) antibody formulations |
US7601351B1 (en) | 2002-06-26 | 2009-10-13 | Human Genome Sciences, Inc. | Antibodies against protective antigen |
US20040033228A1 (en) | 2002-08-16 | 2004-02-19 | Hans-Juergen Krause | Formulation of human antibodies for treating TNF-alpha associated disorders |
DE60311526T2 (de) | 2002-11-01 | 2007-10-31 | Glaxosmithkline Biologicals S.A. | Immunogene zusammensetzung |
US20040156895A1 (en) | 2002-11-12 | 2004-08-12 | Elan Pharma International Ltd. | Solid dosage forms comprising pullulan |
BRPI0316779B8 (pt) | 2002-12-16 | 2023-02-28 | Genentech Inc | Anticorpo anti-cd20 humano ou fragmento de ligação ao antígeno do mesmo, seus usos, composição, artigo manufaturado e formulação líquida |
JP4680601B2 (ja) | 2002-12-17 | 2011-05-11 | メディミューン・エルエルシー | 生物活性材料の高圧噴霧乾燥 |
ZA200507757B (en) * | 2003-04-04 | 2007-01-31 | Genentech Inc | High concentration antibody and protein formulations |
US7374762B2 (en) | 2003-05-14 | 2008-05-20 | Immunogen, Inc. | Drug conjugate composition |
DE10333317A1 (de) | 2003-07-22 | 2005-02-17 | Biotecon Therapeutics Gmbh | Formulierung für Proteinarzneimittel ohne Zusatz von humanem Serumalbumin (HSA) |
EP2248830A1 (en) | 2003-11-04 | 2010-11-10 | Novartis Vaccines and Diagnostics, Inc. | Use of antagonist anti-CD40 antibodies for treatment of autoimmune and inflammatory diseases and organ transplant rejection |
US20050100965A1 (en) | 2003-11-12 | 2005-05-12 | Tariq Ghayur | IL-18 binding proteins |
DE10355251A1 (de) | 2003-11-26 | 2005-06-23 | Merck Patent Gmbh | Pharmazeutische Zubereitung enthaltend einen Antikörper gegen den EGF-Rezeptor |
SI21639A (sl) | 2003-12-23 | 2005-06-30 | LEK farmacevtska dru�ba d.d. | Farmacevtski pripravek, ki vsebuje nemicelarne sulfobetaine |
NZ549893A (en) | 2004-03-24 | 2010-05-28 | Facet Biotech Corp | Use of anti-alpha5beta1 antibodiesin a stabilising solution to inhibit cancer cell proliferation |
US8043631B2 (en) | 2004-04-02 | 2011-10-25 | Au Jessie L S | Tumor targeting drug-loaded particles |
AU2005249360B2 (en) | 2004-04-12 | 2011-07-21 | Medimmune, Llc | Anti-IL-9 antibody formulations and uses thereof |
GB0409795D0 (en) | 2004-04-30 | 2004-06-09 | Glaxosmithkline Biolog Sa | Drying method |
AU2005259221B2 (en) | 2004-07-01 | 2011-02-10 | Innate Pharma | Antibodies binding to receptors KIR2DL1, -2, 3 but not KIR2DS4 and their therapeutic use |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
AU2005306997B2 (en) * | 2004-10-25 | 2012-07-05 | Merck Sharp & Dohme Corp. | Anti-ADDL antibodies and uses thereof |
KR101319772B1 (ko) | 2004-11-09 | 2013-10-23 | 노바갈리 파르마 에스 에이 | 면역 억제제를 포함하는 안과용 유제 |
US20060124266A1 (en) * | 2004-11-23 | 2006-06-15 | Novozymes North America, Inc. | Use of cyclodextrins for reducing deposits during paper production |
US7919072B1 (en) | 2005-01-04 | 2011-04-05 | Gp Medical, Inc. | Nanoparticles for protein drug delivery |
US7993625B1 (en) | 2005-01-04 | 2011-08-09 | Gp Medical, Inc. | Pharmaceutical composition of nanoparticles |
US7879313B1 (en) | 2005-01-04 | 2011-02-01 | Gp Medical, Inc. | Nanoparticles for protein drug delivery |
US7541046B1 (en) | 2005-01-04 | 2009-06-02 | Gp Medical, Inc. | Nanoparticles for protein drug delivery |
US7910086B1 (en) | 2005-01-04 | 2011-03-22 | Gp Medical, Inc. | Nanoparticles for protein drug delivery |
US8048453B1 (en) | 2005-01-04 | 2011-11-01 | Gp Medical, Inc. | Pharmaceutical composition of nanoparticles for protein drug delivery |
US7897585B1 (en) | 2005-01-04 | 2011-03-01 | Gp Medical, Inc. | Nanoparticles for protein drug delivery |
GT200600031A (es) | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
MY139088A (en) | 2005-02-21 | 2009-08-28 | Lg Life Sciences Ltd | Sustained release composition of protein drug |
WO2006112838A1 (en) | 2005-04-18 | 2006-10-26 | Xtl Biopharmaceuticals Ltd. | Stabilized anti-hepatitis b (hbv) antibody formulations |
JP5070200B2 (ja) | 2005-04-22 | 2012-11-07 | イーライ リリー アンド カンパニー | Tgfベータ1に特異的な抗体 |
PE20061324A1 (es) | 2005-04-29 | 2007-01-15 | Centocor Inc | Anticuerpos anti-il-6, composiciones, metodos y usos |
WO2006131013A2 (en) | 2005-06-07 | 2006-12-14 | Esbatech Ag | STABLE AND SOLUBLE ANTIBODIES INHIBITING TNFα |
JP5396080B2 (ja) | 2005-06-30 | 2014-01-22 | アッヴィ・インコーポレイテッド | IL−12/p40結合蛋白質 |
US7956160B2 (en) | 2005-07-22 | 2011-06-07 | Amgen Inc. | Concentrated protein lyophilates, methods, and uses |
PE20100748A1 (es) * | 2005-12-12 | 2010-11-12 | Hoffmann La Roche | Anticuerpo anti beta-4-amiloide que contiene asparagina glicosilada en la region variable de vh |
EP1962907A2 (en) | 2005-12-21 | 2008-09-03 | Wyeth a Corporation of the State of Delaware | Protein formulations with reduced viscosity and uses thereof |
JP5033868B2 (ja) | 2006-03-23 | 2012-09-26 | バイオアークティック ニューロサイエンス アーベー | 改良型プロトフィブリル選択的抗体及びその使用 |
DE102006030164A1 (de) | 2006-06-29 | 2008-01-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Inhalative Pulver |
TWI551607B (zh) * | 2006-07-14 | 2016-10-01 | Ac免疫公司 | 人類化抗體 |
AU2007309616B2 (en) | 2006-10-20 | 2011-10-06 | Amgen Inc. | Stable polypeptide formulations |
GB0621707D0 (en) | 2006-10-31 | 2006-12-13 | Univ London Pharmacy | Formulations for delivery via pressurised metered dose inhalers |
JP5410985B2 (ja) | 2006-12-05 | 2014-02-05 | クルセル ホランド ベー ヴェー | 液体抗狂犬病抗体製剤 |
US7883664B2 (en) | 2007-06-27 | 2011-02-08 | University Of North Carolina At Charlotte | Microwave drying process for vitrification of biologics |
US8268354B2 (en) | 2007-11-07 | 2012-09-18 | Aridis Pharmaceuticals | Sonic low pressure spray drying |
CN105126099A (zh) | 2007-12-21 | 2015-12-09 | 弗·哈夫曼-拉罗切有限公司 | 抗体制剂 |
PE20091174A1 (es) | 2007-12-27 | 2009-08-03 | Chugai Pharmaceutical Co Ltd | Formulacion liquida con contenido de alta concentracion de anticuerpo |
AR070316A1 (es) | 2008-02-07 | 2010-03-31 | Merck & Co Inc | Antagonistas de pcsk9 (proproteina subtilisina-kexina tipo 9) |
EP2303226B1 (en) | 2008-06-25 | 2016-03-23 | Endo Pharmaceuticals Solutions Inc. | Sustained delivery of exenatide and other polypeptides |
WO2009158432A2 (en) | 2008-06-27 | 2009-12-30 | Amgen Inc. | Ang-2 inhibition to treat multiple sclerosis |
WO2010002862A2 (en) | 2008-07-01 | 2010-01-07 | Aveo Pharmaceuticals, Inc. | Fibroblast growth factor receptor 3 (fgfr3) binding proteins |
CA2734919C (en) | 2008-08-27 | 2016-08-16 | Schering Corporation | Lyophilized formulations of engineered anti-il-23p19 antibodies |
BRPI0918419A2 (pt) | 2008-09-19 | 2015-11-24 | Hoffmann La Roche | nova formulação anticorpo |
BRPI0921947A2 (pt) * | 2008-11-20 | 2018-10-16 | Genentech, Inc. | formulações de proteína terapêutica |
CN201401081Y (zh) | 2009-03-26 | 2010-02-10 | 徐谦 | 一种两折型合页 |
CN201553504U (zh) * | 2009-10-30 | 2010-08-18 | 浙江浦江缆索有限公司 | 一种悬索拉索成圈用120t成圈机 |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101172099A (zh) * | 1995-07-27 | 2008-05-07 | 基因技术股份有限公司 | 稳定等渗的冻干蛋白质制剂 |
US20040023338A1 (en) * | 2001-10-26 | 2004-02-05 | Heavner George A. | IL-4 mutein proteins, antibodies, compositions, methods and uses |
US20040120956A1 (en) * | 2002-06-27 | 2004-06-24 | Song Xiao-Yu R. | CNGH0004 polypeptides, antibodies, compositions, methods and uses |
CN101553504A (zh) * | 2006-12-11 | 2009-10-07 | 豪夫迈·罗氏有限公司 | Aβ抗体胃肠外制剂 |
CN102016059A (zh) * | 2007-12-28 | 2011-04-13 | 依兰制药公司 | 淀粉样变性的治疗和预防 |
Non-Patent Citations (1)
Title |
---|
胡晓苗等: "高免卵黄抗体提纯及提取液冻干的研究", 《安徽农业科学》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113811332A (zh) * | 2019-03-05 | 2021-12-17 | 普罗塞纳生物科学有限公司 | 治疗al淀粉样变性的方法 |
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