CN116981695A - 含工程化铰链区的抗体及其应用 - Google Patents
含工程化铰链区的抗体及其应用 Download PDFInfo
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Abstract
一种工程化二聚体抗体,各单体从N末端至C末端包含Fab结构域和与之操作性连接的工程化铰链区以及Fc区,所述工程化二聚体抗体有利于抗体药物偶联物的生产。
Description
技术领域
本发明主要涉及生物制药领域,尤其工程化抗体以及抗体药物偶联物。
背景技术
抗体药物偶联物(ADC)是一种新型靶向药物,由靶向抗体、用于连接药物的转接子/连接子和作为效应物的高效载荷组成。抗体通过抗体-抗原相互作用将细胞毒性药物带向抗原表达细胞。抗体的靶向作用使药物具有肿瘤特异性而对正常组织的危害较小。因此,毒性很强的细胞毒素可以与抗体连接从而形成可用于临床的ADC。因此,ADC降低了最小有效剂量(MED)并提高了最大耐受剂量(MTD),由此扩大了治疗窗口。
ADC研发成功取决于众多因素,包括抗体的选择、连接子-载荷(linker-payload)的选择、连接子-载荷的偶联方式以及偶联过程的研发。抗体中的半胱氨酸巯基作为强亲核试剂是理想的偶联反应基团。天然抗体中,半胱氨酸残基形成二硫键,抗体轻-重链与重-重链之间二硫键(链间二硫键)的还原为偶联提供了理想的游离半胱氨酸巯基。但是,如果所有的半胱氨酸都被还原并与药物相连,过度修饰的抗体缺乏循环稳定性,PK不良。据报道,平均药物/抗体比(DAR)为4(DAR4)的ADC体内治疗指数最佳。但由于四个链间二硫键之间的还原电位接近,部分还原后IgG1抗体中游离巯基的数量呈σ值较大的正态分布。常规方法生产的ADC是不同DAR的混合物,包含DAR0至DAR8的产物。平均DAR4的ADC混合物中DAR4仅占40%左右,其他副产物占大多数。对于IgG4类抗体而言更是如此,游离巯基/抗体平均值若为4则无游离巯基的和8个游离巯基的抗体百分比更高。如前文所述,载药量过高的ADC其PK不理想而且毒性风险较大;载药量过低则疗效不足。
因此,提高ADC产品的均质性(优选DAR4的均质性)是长久以来的研发目标。通过位点特异性偶联来制备均质ADC最常用的技术是基于点突变的偶联(如非天然氨基酸或ThiomabTM的半胱氨酸)或是基于酶切(如mTG(微生物转谷氨酰胺酶),Sortase或FGE(甲酰甘氨酸生成酶))短肽标签的偶联。然而,这些技术存在应用上的难点。例如,哪个位点更适合突变或加标是未知的。
一直以来始终需要均质性更高、具有理想的DAR的ADC产品以及可靠便利的制备这样的ADC的方法。与此关联的,需要对ADC及其制备方法有利的、更容易制备的工程化抗体。
发明内容
本发明提供一种包含工程化铰链区的工程化抗体,它有利于生产均质性和DAR等品质更优良的ADC。
首先,本发明提供一种工程化二聚体抗体,所述二聚体抗体的各单体从N末端至C末端包含Fab结构域和与之操作性连接的工程化铰链区以及Fc区,其中,所述工程化铰链区包含选自SEQ ID NO:1至9之任一的序列。
另一方面,本发明提供一种核酸分子或核酸分子组合,所述核酸分子或核酸分子组合编码本发明的工程化抗体。
另一方面,本发明提供一种包含本发明的工程化抗体的抗体药物偶联物。
另一方面,本发明提供一种组合物,包含本发明的抗体药物偶联物或由本发明的抗体药物偶联物组成,所述抗体药物偶联物中至少或超过80%、85%、90%或95%其药物/抗体之比为4。
另一方面,本发明提供一种制备抗体药物偶联物的方法,包括经部分还原的本发明抗体与连接子-载荷化合物偶联的步骤。
另一方面,本发明提供一种抗体药物偶联物产品,所述产品由本发明方法获得,所述产品中至少或超过80%、85%、90%或95%的抗体药物偶联物其药物/抗体之比为4。
另一方面,本发明提供了包含工程化铰链区的本发明工程化抗体用于生产ADC的应用。
另一方面,本发明提供为有需要的对象治疗疾患、紊乱或病症的方法,包括给予所述对象治疗有效量的本文所述抗体药物偶联物。本发明还提供用于有需要的对象治疗其疾病、紊乱或病症的本发明抗体药物偶联物。
本发明具有多项优势。尤其,本发明的工程化抗体使用天然免疫球蛋白G铰链序列并在其天然结构位置发生交换而不引入任何全新氨基酸序列,因此,所得的工程化抗体在体内引起的免疫原性会更少。而且,用本发明的工程化抗体能够获得高均质性的ADC产品,并能够在合适的偶联条件下实现最优的4分子连接子-载荷连接,产品中4分子连接子-载荷的ADC的百分比高达80%以上。
本发明使得抗体药物偶联物的制备显著简化。实施方式之一中,抗体药物偶联物的制备可以是简单(一锅式)偶联,包括:首先用温和还原剂进行部分还原,然后在同一缓冲系中进行偶联。采用本发明抗体的偶联反应不需要其他酶。本发明的ADC具有高度的均质性,DAR4抗体药物偶联物百分比可提高至80%以上、85%以上、甚至更高。而且,本发明的ADC对疾病细胞例如带有肿瘤相关抗原(TAA)或肿瘤特异性抗原(TSA)的细胞表现出优异的细胞毒性。
附图说明
以下所述附图属于说明书的一部分,用以进一步说明本发明的相关内容。以下一幅或多幅附图与具体实施方式的详细描述有助于更好地理解本发明。
图1:本发明工程化抗体的示意图。
图2:比较例中用原生IgG1抗体和原生IgG4抗体制备的ADC产品的DAR分布情况。
图3:本发明实施例之一中,抗体886-45的结构和用其制备的ADC产品的DAR分布情况。
图4:本发明实施例之一中,抗体886-50的结构和用其制备的ADC产品的DAR分布情况。
具体实施方式
术语与定义
本文中,“一个”、“一种”和“该/所述”引导的单数形式包括复数含义,除非另作说明。同样,术语“一个”(或“一种”)、“一个(种)或多个(种)”和“至少一个(种)”在本文中可互换使用。
本文中,术语“约”或“大约”指量、水平、值、数目、频率、百分比、维度、尺寸、量、重量或长度相对于参考量、水平、值、数目、频率、百分比、维度、尺寸、量、重量或长度相差至多30%、25%、20%、25%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%。在特定的实施方式中,术语“约”或“大约”在一个数值前面时表示该值加减15%、10%、5%或1%的范围。
本文中一种实施方式中的一项或多项特征可以与另一实施方式中的一项或多项特征组合,这并不背离本发明的构思和概念。
除非另做定义,本发明使用的所有技术和科学术语其意义与本发明所属领域普通技术人员通常所理解的相同。文中列举的公开文献和专利文献都通过援引纳入本文并适用于所有目的。本说明书引用的文献应被视为表明本领域技术人员的技术水平,但这不应理解为承认本发明无权凭借发明在先而早于这种公开。
本文中,“抗体”指特异性结合抗原的免疫球蛋白,例如单克隆抗体、多克隆抗体、多特异性抗体和双特异性(二价)抗体。通常,以二聚体抗体为例,抗体包含两条重链和两条轻链,各单体由一对重链和轻链构成。抗体分5大类,即IgA、IgD、IgE、IgG和IgM,有些可进一步分成若干亚类,诸如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2。
本文中,“Fab”、“Fab结构域”和“Fab臂”可互换使用,指轻链与重链在免疫球蛋白(比如抗体)的可变区和第一恒定区偶合构成的结构域。通常,Fab结构域含一个或多个链间二硫键。Fab结构域负责各种抗原结合活性。
本文中,“Fc区”亦称“可结晶片段”,指重链的第二恒定区(CH2)及此后恒定区构成的片段,或指重链的铰链区的一部分、第二恒定区(CH2)及此后恒定区构成的片段。并且,本文中,在二聚体抗体中,“Fc结构域”指两重链偶合的Fc区。Fc区具有多种效应功能,诸如ADCC和CDC。
本文中,“铰链”和“铰链区”可互换使用,指重链的CH1区的C末端与CH2区的N末端相连的区域。铰链区的长度可以是约12-62个氨基酸残基。人IgG1中铰链区占第216至230位残基,人IgG4中占第219至230位残基,以上编号按照EU编号系统。本文中,在二聚体抗体中,“铰链结构域”指两重链偶合的铰链区。铰链区是抗体Fab与Fc之间的柔性连接。在IgG亚类IgG1、IgG2、IgG3和IgG4之间,铰链区的长度和柔性差异很大。以最常用作治疗用生物药的IgG1和IgG4为例,IgG1的铰链区含15个氨基酸(如EPKSCDKTHTCPPCP(SEQ ID NO:10)),很有柔性,IgG4的铰链区较短,仅12个氨基酸。野生型IgG1和IgG4在核心铰链区(EU编号226-229)相差一个氨基酸:IgG1中为Cys-Pro-Pro-Cys而IgG4中为Cys-Pro-Ser-Cys。天然IgG4在核心铰链区存在链间半胱氨酸二硫键与链内半胱氨酸二硫键之间的平衡,因此可以观察到重链臂交换和分泌后IgG4半抗体分子的存在。业已证实,IgG4的S228P突变(例如ESKYGPPCPPCP(SEQ ID NO:11))可防止自然臂交换从而显著稳定IgG4重链之间的共价相互作用,因此已广泛用于IgG4抗体的开发和生产。S228P突变在IgG4铰链中形成多脯氨酸螺旋(PPCPPCP),配合较短的IgG4铰链长度,与IgG1铰链相比将进一步限制其柔性。不同铰链之间的柔性差异对抗体的生物偶联具有重要意义,因为位于柔性铰链片段中的半胱氨酸残基被认为比位于刚性铰链中的半胱氨酸残基更具反应性。有实验表明,S228P IgG4的重链-轻链间二硫键和重链-重链间二硫键均为弱反应性。
本文中,“特异性结合”指两个分子之间例如抗体和抗原之间的非随机结合反应。本发明的工程化抗体特异性结合抗原的结合亲和力(KD)≤10-6M(例如≤5x10-7 M、≤2x10-7M、≤10-7M、≤5x10-8 M、≤2x10-8 M、≤10-8M、≤5x10-9 M、≤2x10-9 M、≤10-9M、或≤10-10M)。本文中,KD指解离速率与缔合速率之比(koff/kon)。
术语“操作性地连接/相连”指两个或更多个目标生物序列的并置,彼此之间有或没有间隔子或连接子,并置的方式使得它们之间的关系允许各自以预期方式起作用。用于描述多肽时表示多肽序列相连的方式使得连接产物具有预期的生物学功能。例如,抗体可变区可与恒定区操作性地相连得到具有抗原结合活性的稳定产物。该术语也可用于描述多核苷酸。例如,当编码多肽的多核苷酸与调控序列(如启动子、增强子、沉默子序列等)操作性相连时,表示这些多核苷酸序列的连接方式实现所述多核苷酸有调地表达多肽。
本文中,“对象”指人或非人动物对象。非人动物可以是哺乳动物,例如灵长类动物。非人动物对象的例子包括但不限于豢养动物、畜牧动物和动物园动物、竞技动物或宠物,例如犬、猫、豚鼠、兔、大鼠、小鼠、马、猪、牛和熊。优选地,对象是人。“有需要的对象”指需要就疾病、紊乱或病症进行诊断、预后、缓解、预防和/或治疗的对象。
1.工程化抗体
本发明内容之一,提供了一种工程化二聚体抗体,所述二聚体抗体的各单体从N末端至C末端包含Fab结构域和与之操作性连接的工程化铰链区以及Fc区,其中,所述工程化铰链区包含选自SEQ ID NO:1至9之任一的序列。
SEQ ID NO. | 铰链序列 |
1 | EPKSCKSKYGPPCPPCP |
2 | EPKSCKKYGPPCPPCP |
3 | EPKSCKTPPCPPCP |
4 | EPKSCKSKTPPCPPCP |
5 | EPKSCKKTPPCPPCP |
6 | EPKSCSKTPPCPPCP |
7 | EPKSCSKKTPPCPPCP |
8 | EPKSCSKKGPPCPPCP |
9 | EPKSCSKYTPPCPPCP |
二聚体抗体可由两个彼此配对的单体构成,各自包含偶合的重链和轻链。所述工程化抗体可以是IgG型的。单体通过链间结合力(包括链间键和/或链间相互作用)形成二聚体。链间结合力的例子包括但不限于二硫键、氢键、静电相互作用、盐桥、疏水-亲水相互作用和“锁钮-锁孔(Knobs-into-Holes)”机制。总体而言,本发明的工程化抗体具有图1所示的结构。
本发明工程化抗体的特征之一在于本发明的工程化铰链区。所述工程化铰链区有一部分衍生自IgG1铰链区还有一部分衍生自IgG4铰链区,所得工程化铰链结构域含有至少两个链间二硫键。出人意料地,发明人发现这有助于提高ADC产品的均质性,例如提高DAR4抗体药物偶联物的比例。同时,本发明对铰链区半胱氨酸残基的周围残基进行了优化,出人意料地,发明人发现这有助于进一步提高ADC产品的均质性,例如进一步提高DAR4抗体药物偶联物的比例。一些实施方式中,总体ADC产品中DAR4的比例可高达80%以上,甚至高达90%以上。
本发明的工程化抗体可用于二硫键被温和还原剂还原而释放的半胱氨酸残基处的生物偶联。本发明的工程铰链结构域改变了铰链结构域中二硫键的还原反应活性,当使用温和还原剂部分还原抗体时,这导致Fab结构域中的二硫键选择性地被还原。这有利于提供高度均质性的ADC产品,其主要包含有四个连接子-载荷的偶联物,所述四个连接子-载荷大多连接在Fab结构域。一些实施方式中,偶联物总体中DAR4偶联物的比例可高达80%以上,高达90%以上,或甚至更高。
总体而言,据ADC生产和ADC产品本身而言,具有工程化铰链区的工程化抗体具有多项优势,比如高均质性,更可控的DAR,简化生产、理想的药代动力学特性和/或药效动力学特性。
本发明中,Fab结构域可源自任意抗体,尤其治疗用抗体。一些实施方式中,所述Fab结构域源自特异性结合肿瘤抗原(TA)例如肿瘤特异性抗原(TSA)和肿瘤相关抗原(TAA)的抗体。肿瘤抗原的例子包括但不限于:CD20、CD38、CD123、ROR1、ROR2、BCMA、PSMA、SSTR2、SSTR5、CD19、FLT3、CD33、PSCA、ADAM 17、CEA、Her2、EGFR、EGFR-vIII、CD30、FOLR1、GD-2、CA-IX、Trop-2、CD70、CD38、间皮素、EphA2、CD22、CD79b、GPNMB、CD56、CD138、CD52、CD74、CD30、CD123、RON和ERBB2。TA特异性抗体的例子包括但不限于:曲妥珠单抗(Trastuzumab)、利妥昔单抗(Rituximab)、西妥昔单抗(Cetuximab)、贝伐单抗(Bevacizumab)、帕尼图单抗(Panitumumab)、阿仑单抗(Alemtuzumab)、马妥珠单抗(Matuzumab)、吉妥珠单抗(Gemtuzumab)、泊洛妥珠单抗(Polatuzumab)、伊妥珠单抗(Inotuzumab)等。一些实施方式中,Fab结构域源自人IgG抗体,例如IgG1或IgG4亚类的Fab结构域,优选IgG1亚类的Fab结构域。
所述工程化抗体还包含Fc结构域,优选人IgG Fc结构域。一些实施方式中,Fc结构域可以是IgG1或IgG4亚类的。显然,重链的Fc区也是如此。
另一方面,本发明提供一种核酸分子或核酸分子组合,所述核酸分子或核酸分子组合编码本发明的工程化抗体。一些实施方式中,所述核酸分子可以是一个或多个载体,尤其表达载体。本领域技术人员可以看出,重链的编码核酸和轻链的编码核酸可以分别克隆在不同(即非同一)表达载体并共转染到宿主细胞中从而重组表达抗体,也可以将两链的编码序列插入同一表达载体。本领域所知的表达载体和宿主细胞均可用于本发明。例子包括但不限于质粒、病毒载体、合成载体、细菌宿主、酵母、昆虫细胞和动物细胞,如CHO细胞。一些实施方式中,所述核酸分子(如载体)或核酸分子组合可包含在试剂盒中,所述试剂盒还可包含如何用所述核酸分子或核酸分子组合重组生产所述抗体的说明。
2.抗体药物偶联物
2.1.抗体药物偶联物
本发明内容之一,提供的是包含本发明工程化抗体的抗体药物偶联物,其中,本发明的工程化抗体通过连接子与一个或多个药物分子偶联。
本发明对于可用的药物(亦称“载荷”)没有限制。本发明可用的药物包括细胞毒性药物,尤其用于癌症治疗的那些。此类药物包括但不限于DNA损伤剂、DNA结合剂、抗代谢物、酶抑制剂如胸苷酸合成酶抑制剂和拓扑异构酶抑制剂、微管蛋白抑制剂和毒素(如细菌、真菌、植物或动物来源的毒素)。具体例子包括紫杉醇,氨甲蝶呤,甲氨喋呤,二氯氨甲蝶呤,5-氟尿嘧啶,6-巯基嘌呤,阿糖胞苷,美法仑,环氧长春碱,长春西定,放线菌素,柔红霉素,多柔比星,丝裂霉素C,丝裂霉素A,洋红霉素,氨基蝶呤,他利霉素,鬼臼及鬼臼衍生物如足叶乙甙或磷酸足叶乙甙,长春花碱,长春新碱,长春地辛,紫杉烷包括紫杉醇,多西他赛视黄酸,丁酸,N8-乙酰基亚精胺,喜树碱,卡奇霉素,埃斯培拉霉素,烯-二炔,多卡霉素A,多卡霉素SA,卡奇霉素,喜树碱,哈米特林,美登木素(包括DM1,DM2,DM3,DM4)和澳瑞他汀类(包括单甲基澳瑞他汀E(MMAE)、单甲基澳瑞他汀F(MMAF)、单甲基澳瑞他汀D(MMAD))。在一些实施方式中,药物是澳瑞他汀类,如MMAE。可用任意合适的本领域所知方法将药物与连接子连接。一些实施方式中,以连接子-载荷化合物作为中间体来提供药物,例如“MC-vc-PAB-MMAE”。
本发明采用的药物可通过连接子与抗体结合。本领域已知有众多用于ADC的连接子。本发明对于可用的连接子没有特别限制,只要它具有能与抗体上巯基反应从而与抗体相连的基团。例如,本发明采用的连接子可以是氨酰亚胺或卤酰基官能化的连接子。例子包括但不限于-MC-vc-PAB-(“MC”:马来酰亚胺-己酰基;“-vc-”:缬氨酸-瓜氨酸二肽(-Val-Cit-);“PAB”:对氨基苄基),-MC-GGFG-(“-GGFG-”:–Gly-Gly-Phe-Gly-四肽),-MC-vc-,-MC-和-SMCC-(琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯)。一些实施方式中,连接子是-MC-vc-PAB-连接子。
一些实施方案中,连接子-载荷与还原反应选择性打开的链间二硫键的半胱氨酸残基相连。一些实施方式中,本发明偶联物的药物/抗体之比(DAR)可以是约2至约8,优选约2至6,更优选约4。该比例可以是分子群的平均比例,例如ADC群的平均DAR为DAR4。某优选实施方式中,所述偶联物包含主要结合于Fab结构域的药物分子,某些情形中,四个药物分子全部结合在Fab结构域。
2.2.抗体药物偶联物的制备
本发明中,连接子-载荷连接在二硫键被温和还原剂还原而释放的半胱氨酸残基处。尤其,本发明的工程化铰链结构域改变了铰链结构域中二硫键的还原反应活性,因此,在用温和还原剂对抗体进行部分还原时,被选择性还原的是Fab结构域的二硫键。这有利于提供高度均质性的产品,其主要包含有四个连接子-载荷的偶联物,所述四个连接子-载荷大多连接在Fab结构域。
本发明内容之一,提供了一种制备本发明抗体药物偶联物的方法。简而言之,所述方法可包括部分还原的抗体与连接子-载荷偶联。优选地,在还原反应缓冲系中进行偶联反应,所述缓冲系含有作为添加剂的有机溶剂用于促进连接子-载荷的溶解。具体而言,该方法可以包括部分还原的本发明抗体与带有马来酰亚胺或卤代乙酰基基团的连接子-载荷化合物通过迈克尔加成反应(Michael addition)偶联的步骤。部分还原的抗体可通过用温和还原剂对本发明工程化抗体进行部分还原来制备。一些实施方式中,所述方法可以包括:
用温和还原剂对本发明的工程化抗体进行部分还原,以及
部分还原的抗体与带有马来酰亚胺或卤代乙酰基基团的连接子-载荷化合物通过迈克尔加成反应偶联。
一些实施方式中,所述温和还原剂是TCEP或DTT。一些实施方式中,还原剂/抗体之比约为1至20,优选3至10,例如约2至5、约4至10或约9至15。一些实施方式中,部分还原在pH约4.0至8.0的条件下进行,例如约5至6,例如约5.5。一些实施方式中,所述部分还原反应时长约0.5至24小时,例如约1至20小时,约0.5至5小时,约4至10小时或9至15小时。一些实施方式中,所述部分还原在温度约4至37℃的条件下进行,优选4至15℃,例如约5至10℃、约9至15℃、约14至20℃、约19至25℃或约24至30℃。
一些实施方式中,偶联反应在pH约4.0至8.0、例如约pH 5至6、例如pH 5.5的缓冲液中以及可选的有机添加剂(例如有机溶剂或有机助溶剂)存在下进行,所述有机添加剂的量可以是约0.0%至20.0%(重量百分比),例如约5.0%至15.0%或约10.0%至15.0%。一些实施方式中,药物/抗体之比可以是约5至20,例如约4至10、约9至15、或约14至19;反应温度可以是约4至37℃,例如约5至10℃、约9至15℃、约14至20℃、约19至25℃、或约24至30℃;而且/或者,反应时长可以是约0.5至4小时,例如约1至3小时。
一些实施方式中,本发明方法提供包含或由抗体偶联物混合物或由抗体偶联物混合物组成的产品,所述混合物中至少约80%、至少约85%、至少约90%、或至少约95%的DAR为4。一些情形中,DAR4的偶联物中4个药物分子全部连在Fab结构域。
3.组合物
一些实施方式中,本发明方法提供包含抗体偶联物混合物或由抗体偶联物混合物组成的产品,所述混合物中至少约80%、至少约85%、至少约90%、或至少约95%的DAR为4。一些情形中,DAR4的偶联物中4个药物分子都全部连在Fab结构域。
另一方面,本发明还提供一种药物组合物,包含前文所述的抗体药物偶联物或抗体药物偶联物混合物和药学上可接受的载体。
4.治疗
本发明的抗体药物偶联物可用于有需要的对象治疗其疾病、紊乱或病症,包括给与对象治疗有效量的抗体药物偶联物。本发明还提供用于有需要的对象治疗其疾病、紊乱或病症的本发明抗体药物偶联物。治疗的疾病包括但不限于癌症,包括实体瘤和恶性血液病,例如HER2、Trop2、EGFR和/或CD20阳性疾病。这些癌症的例子包括但不限于乳腺癌、卵巢癌、子宫内膜癌、前列腺癌、胃癌、胰腺癌、肝癌、肺癌(如NSCLC)、胶质瘤、膀胱癌、结直肠癌、淋巴瘤(如非霍奇金淋巴瘤(NHL))和白血病。
实施例
以下实施例仅用于本发明展示,不对本发明范围构成限制。
缩写
DMA:N,N’-二甲基乙酰胺
DTT:1,4-二硫苏糖醇
TCEP:三(2-羧基乙基)膦
MC:马来酰亚胺-己酰基
PAB:对氨基苄基
MMAE:单甲基澳瑞他汀E
HIC:疏水作用色谱
HPLC:高效液相色谱
RP-HPLC:反相-高效液相色谱法
SEC:大小排阻色谱
IC50:半数最大抑制浓度
MED:最小有效剂量
MTD:最大耐受剂量
MWCO:截留分子量
DAR:药物/抗体之比
eq:还原剂/抗体的摩尔比或载荷/抗体的摩尔比
通用方法
抗体的制备
本文中全部抗体分子均进行了灰仓鼠(Cricetulus griseus)密码子优化,按照标准分子生物学方法合成并克隆到自有生产载体中,然后由TOP10大肠杆菌中质粒大抽制得。
转染前72小时,将CHO K1宿主细胞按2-4E5个细胞/mL接种在CD CHO培养基中。用Vi-CELL计点宿主细胞计算细胞密度,290g离心7分钟,然后在转染前重悬于预温热的新鲜CD CHO培养基中。重悬的宿主细胞在Kuhner摇床中孵育(36.5℃,75%湿度,6%CO2,120rpm),直至使用。
将总共4mg编码目标抗体的质粒加入宿主细胞重悬液中,然后加12mg聚醚酰亚胺。经转染的培养物在Kuhner摇床中于36.5℃、75%湿度、6% CO2、120rpm培养4小时。加入自有补充培养基后,经转染的培养物在Kuhner摇床中于31℃、75%湿度、6%CO2、120rpm培养9-10天。
在收获日,经转染的培养物先1,000g离心10分钟再10,000g离心40分钟澄清化,然后通过0.22μm过滤器无菌过滤。上清液用ProA色谱纯化。ProA洗脱物通过加入1-2%中和缓冲液(1M Tris-HCl,pH 9.0)中和,然后用pH 5.5的20mM组氨酸-乙酸盐缓冲液进行配制。
偶联之前所有蛋白质均经过质控检测,包括还原和非还原SDS-PAGE、SEC-HPLC、通过LAL凝胶法(LAL gel clot assay)检测内毒素水平,并通过质谱进行分子鉴定。
HIC-HPLC测定DAR
过程:取8μl ADC样品进行HIC-HPLC测定DAR。
SEC-HPLC测定纯度和聚集体
过程:取20μl ADC样品进行SEC-HPLC测定纯度和聚集体。
RP-HPLC测定药物负载
过程:取20μl ADC样品与75μl 8M盐酸胍和5μl Tris-HCl、pH 8.0混合。向混合物中加入1μl的0.5M TCEP溶液。37℃反应30分钟(min),然后RP-HPLC测定抗体上的药物负载。
RP-HLPC测定游离药物
过程:取85μl ADC溶液与15μl DMA混合,然后用100μl沉淀缓冲液(NaCl饱和的37.5%v/v甲醇/乙腈溶液)沉淀蛋白质,22℃以1400rpm漩涡搅拌10分钟(min)。
样品以16000rpm离心10分钟。取上清液与标准品一起进行RP-HPLC检测以测定游离药物。
细胞毒性试验
在培养板上接种培养在培养基(例如加有10%胎牛血清的RPMI-1640培养基)中的肿瘤模型细胞(例如HCC1954细胞、Raji细胞、HCC827细胞),例如,HCC1954细胞的接种密度可以是4000细胞/孔,Raji细胞的接种密度可以是10000细胞/孔,HCC827细胞的接种密度可以是3000细胞/孔。用ADC测试品例如靶向Her2、靶向CD20和靶向EGFR的ADC处理细胞。举例来说,Raji细胞可在板上接种后立即用ADC处理,HCC1954细胞和HCC827细胞可在接种后24小时用ADC处理。然后评价处理效果。例如,可在37℃,ADC处理4天或5天后测定活度,并由此计算最大抑制和IC50。
比较例1
如下所述制备不含结构域亚类交换的原生IgG1抗体和原生IgG4抗体。原生IgG1抗体具有铰链序列EPKSCDKTHTCPPCP(SEQ ID NO:10),原生IgG4抗体具有铰链序列ESKYGPPCPPCP(SEQ ID NO:11)。将两抗体分别溶于含50mM NaCl、2mM EDTA、pH7.0的磷酸缓冲液(PB)和含50mM NaCl、2mM EDTA、pH 6.5的PB缓冲液,抗体浓度均为8.0mg/ml。向IgG1抗体中加入2.7eq的TCEP,混合物在37℃孵育2小时。向IgG4抗体中加入4.1eq的TCEP,混合物在37℃孵育24小时。
然后,在各混合物中,向还原抗体中加入DMA至浓度为10%,然后分别加入7eq(对IgG 1)和9eq(对IgG4)的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。用40KD MWCO脱盐柱纯化偶联产物,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行终产物特征鉴定(图2)。
实施例1
抗体886-45(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCKSKTPPCPPCP(SEQ ID NO:4);重链(HC)序列:SEQ ID NO:16,轻链(LC)序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.6eq的TCEP,混合物于4℃孵育3小时(hr)。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行终产物特征鉴定(图3)。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达80.20%。如图所示,与原生抗体相比,本发明的铰链区工程化显著提高了ADC产品的均质性。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-45 | 2.6/4℃ | 1.10 | 12.0 | 80.20 | 6.70 | 0.00 | 3.85 |
实施例2
抗体886-50(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCSKYTPPCPPCP(SEQ ID NO:9);HC序列:SEQ ID NO:21,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入3.1eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行终产物特征鉴定(图4)。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达87.96%。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-50 | 3.1/4℃ | 0.39 | 7.62 | 87.96 | 4.04 | 0.00 | 3.91 |
实施例3
抗体886-42(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCKSKYGPPCPPCP(SEQ ID NO:1);HC序列:SEQ ID NO:13,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.6eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达79.49%。
实施例4
抗体886-43(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCKKYGPPCPPCP(SEQ ID NO:2);HC序列:SEQ ID NO:14,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.2eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达76.35%。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-43 | 2.2/4℃ | 2.65 | 17.14 | 76.35 | 3.86 | 0.00 | 3.63 |
实施例5
抗体886-44(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCKTPPCPPCP(SEQ ID NO:3);HC序列:SEQ ID NO:15,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入4.2eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达71.51%。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-44 | 4.2/4℃ | 1.83 | 17.14 | 71.51 | 8.79 | 0.73 | 3.79 |
实施例6
抗体886-46(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCKKTPPCPPCP(SEQ ID NO:5);HC序列:SEQ ID NO:17,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.5eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达79.60%。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-46 | 2.5/4℃ | 1.06 | 10.03 | 79.60 | 9.36 | 0.96 | 3.96 |
实施例7
抗体886-47(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCSKTPPCPPCP(SEQ ID NO:6);HC序列:SEQ ID NO:18,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入3.2eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达81.50%。
实施例8
抗体886-48(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCSKKTPPCPPCP(SEQ ID NO:7);HC序列:SEQ ID NO:19,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.5eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达82.44%。
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实施例9
抗体886-49(IgG1-Fab,IgG1-Fc;铰链序列:EPKSCSKKGPPCPPCP(SEQ ID NO:8);HC序列:SEQ ID NO:20,LC序列:SEQ ID NO:12)溶于pH 5.5的20mM组氨酸-乙酸盐缓冲液,浓度4.0mg/ml。向抗体溶液中加入2.5eq的TCEP,混合物于4℃孵育3小时。然后,向还原抗体中加入DMA至浓度为10%,然后加入7eq的MC-vc-PAB-MMAE。偶联反应在4℃进行1小时。偶联产物用40KD MWCO脱盐柱纯化,于pH5.5的20mM组氨酸-乙酸盐缓冲液中保存。用测定DAR和药物分布的HIC-HPLC进行最终产物特征鉴定。铰链区经工程化,ADC产品高度均质,主要含DAR4的ADC,百分比高达81.20%。
mAb | TCEP比/T | D0 | D2 | D4 | D6 | D8 | DAR |
886-49 | 2.5/4℃ | 0.78 | 6.99 | 81.20 | 9.77 | 1.26 | 3.97 |
序列表
<110> 上海药明合联生物技术有限公司(WuXi XDC (Shanghai) Co., Ltd.)
<120> 含工程化铰链区的抗体及其应用
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<170> PatentIn version 3.3
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Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
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Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
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Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Val Asn Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
His Tyr Thr Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
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Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
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Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
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Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
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Met Glu Phe Gly Leu Ser Trp Leu Phe Leu Val Ala Ile Leu Lys Gly
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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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Lys Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
245 250 255
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
260 265 270
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
275 280 285
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
290 295 300
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
305 310 315 320
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
325 330 335
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
340 345 350
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
355 360 365
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
370 375 380
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
385 390 395 400
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
405 410 415
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
420 425 430
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
435 440 445
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
450 455 460
Leu Ser Leu Ser Pro Gly Lys
465 470
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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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Lys Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 15
<211> 468
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-44的重链氨基酸序列
<400> 15
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Lys Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
245 250 255
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
340 345 350
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
<210> 16
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-45的重链氨基酸序列
<400> 16
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Lys Ser Lys Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 17
<211> 469
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-46的重链氨基酸序列
<400> 17
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Lys Lys Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 18
<211> 469
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-47的重链氨基酸序列
<400> 18
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Ser Lys Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
260 265 270
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
275 280 285
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
290 295 300
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
305 310 315 320
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
325 330 335
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
355 360 365
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
370 375 380
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
385 390 395 400
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
405 410 415
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
420 425 430
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
435 440 445
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
450 455 460
Leu Ser Pro Gly Lys
465
<210> 19
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-48的重链氨基酸序列
<400> 19
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Ser Lys Lys Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 20
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-49的重链氨基酸序列
<400> 20
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Ser Lys Lys Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 21
<211> 470
<212> PRT
<213> 人造序列
<220>
<223> 抗体886-50的重链氨基酸序列
<400> 21
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 Asn Ile
35 40 45
Lys Asp Thr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala
65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn
85 90 95
Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
210 215 220
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys
225 230 235 240
Ser Cys Ser Lys Tyr Thr Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
245 250 255
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
305 310 315 320
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
Claims (14)
1.一种工程化二聚体抗体,所述二聚体抗体的各单体从N末端至C末端包含Fab结构域和与之操作性连接的工程化铰链区以及Fc区,其中,所述工程化铰链区包含选自SEQ IDNO:1至9之任一的序列。
2.如权利要求1所述的工程化抗体,其中,所述Fab结构域为IgG1或IgG4亚类,优选IgG1亚类。
3.如权利要求1所述的工程化抗体,其中,所述Fc区为IgG1或IgG4亚类。
4.一种核酸分子或核酸分子组合,所述核酸分子或核酸分子组合编码权利要求1所述的工程化抗体。
5.如权利要求4所述的核酸分子或核酸分子组合,所述核酸分子或所述组合中的各核酸分子是载体。
6.一种抗体药物偶联物,包含权利要求1–3中任一项所述的工程化抗体。
7.一种组合物,包含权利要求6所述的抗体药物偶联物或由权利要求6所述的抗体药物偶联物组成,其中,所述抗体药物偶联物中至少或超过80%、85%、90%或95%其药物/抗体之比为4。
8.一种制备抗体药物偶联物的方法,包括经部分还原的权利要求1所述抗体与连接子-载荷化合物偶联的步骤。
9.如权利要求8所述的方法,进一步包括用温和还原剂对权利要求1所述的工程化抗体进行还原来提供所述部分还原的抗体。
10.如权利要求9所述的方法,具有一项或多项以下特征:
其中,所述温和还原剂是TCEP或DTT;
其中,还原剂/抗体之比为1至20,优选3至10;
其中,所述部分还原步骤的pH为4.0至8.0,优选5至6;
其中,所述部分还原步骤时长0.5至24小时,优选1至20小时;且/或
其中,所述部分还原步骤的温度为4至37℃,优选4至15℃。
11.一种抗体药物偶联物产品,所述产品由权利要求8所述方法获得,所述产品中至少或超过80%、85%、90%或95%的抗体药物偶联物其药物/抗体之比为4。
12.权利要求1所述工程化抗体用于生产ADC的应用。
13.一种为有需要的对象治疗疾患的方法,包括给予所述对象治疗有效量的权利要求6所述抗体药物偶联物。
14.用于为有需要的对象治疗疾患的权利要求6所述的抗体药物偶联物。
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PCT/CN2022/091130 WO2023212906A1 (en) | 2022-05-06 | 2022-05-06 | Antibodis comprising engineered hinge and uses thereof |
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US20110077383A1 (en) * | 2007-07-03 | 2011-03-31 | Medimmune, Llc | Hinge domain engineering |
EP3368579B1 (en) * | 2015-10-30 | 2021-11-24 | F. Hoffmann-La Roche AG | Hinge modified antibody fragments and methods of making |
WO2021013068A1 (en) * | 2019-07-19 | 2021-01-28 | Wuxi Biologics (Shanghai) Co., Ltd. | Polypeptide complex for conjugation and use thereof |
CN116761824A (zh) * | 2021-01-18 | 2023-09-15 | 上海药明合联生物技术有限公司 | 工程化抗-trop2抗体及其抗体-药物偶联物 |
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