CN109790215B - 异源二聚体免疫球蛋白构建体和其制备方法 - Google Patents
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Abstract
本发明提供了一种稳定和高度特异性的异源二聚体免疫球蛋白构建体的制备方法,例如双特异性抗体,其具有所需的天然IgG特点和没有不需要的重轻链错配,该双特异性抗体能同时结合两种靶分子并且在治疗复杂疾病方面会更有效。
Description
对相关申请的交叉引用
本申请要求于2016年9月29日提交了中国专利申请序号CN2016108638147的优先权,其公开内容通过引用全部引入本文。
技术领域
本发明的领域和是稳定且高度特异的异源二聚体免疫球蛋白构建体,其保留天然IgG抗体的所需特点而沒有不需的重轻链错配。
背景技术
具有单特异性并且仅与靶抗原上的单个表位相互作用的单克隆抗体(mAb)已被广泛用于治疗许多疾病,例如癌症、炎症和自身免疫疾病和传染病。然而,迄今为止,此类治疗分子如果单独使用,没有一种能够显示出足够的药效,这是由于疾病的潜在复杂性,例如癌症或炎症性疾病,通常涉及过多种疾病介导的分子通路和信号通路之间的相叉作用。因为这种mAb仅与单个靶抗原相互作用,所以难以提供最佳治疗效果。同时阻断多个靶点或者一个靶点的多个位点能够改善治疗效果。另外,用单个多特异性分子靶向多个抗原/表位使得新药物开发不那么复杂,因为该疗法被简化为单一分子。和使用两个或以上的单特异分子的联合用药相比,对于患者和医疗工作者都是更方便的。
双特异抗体(BsAb)或多特异性分子通常是本领域已知的。最初尝试制备的双特异抗体涉及使用双功能偶联试剂将两个现有的IgG分子、两个Fab’或两个(Fab’)2片段连接的化学偶联。但是,这种化学偶联的BsAb存在很多的局限性,例如生产双特异性分子工作的劳动强度,纯化异源二聚体的困难、去除同源二聚体和原单克隆抗体的困难和低收率。
另一种的BsAb分子是杂种-杂交瘤(hybrid hybridoma)或四源杂交瘤(quadroma),其是通过体细胞融合两种分泌不同抗体的杂交瘤细胞系而生产的。由于免疫球蛋白重链和轻链的随机配对,仅有抗体混合物的1/10是所需要的功能性BsAb,这使纯化过程复杂并使生产收率减少。
WO2013060867描述了一种大规模生产异源二聚体双特异抗体的方法,该方法先还原两种混合的同源二聚体免疫球蛋白,然后通过在这两种同源二聚体的CH3结构域引入不对称突变从而促使Fab臂发生交换,最后通过再氧化链间二硫键。
WO2009089004描述了一种制备异源二聚体蛋白的方法,该方法通过在CH3-CH3界面处引入一个或多个带电荷氨基酸突变,其不利于同源二聚体形成,但通过静电作用力促进异源二聚体形成。
US5173168描述了一种利用“杵-臼”策略来制备异源二聚体IgG的方法。首先通过使用大氨基酸置换小氨基酸来形成第一条链CH3结构域界面处的“杵”;并通过使用小氨基酸置换大氨基酸来形成第二条链上CH3界面处的“臼”。杵和臼的相互作用有利于异源二聚体IgG的形成,而不利于同源二聚体的形成。
WO2012058768描述了一种异源二聚体IgG制备方法。该方法涉及阴性和阳性设计和结构和计算机模型指导的蛋白工程技术引入突变到IgG1 CH3结构域。
新生Fc受体(FcRn)包括一条跨膜重链(p51亚基,alpha链)与一条可溶轻链(p14亚基,beta链),两者以非共价键形式组合在一起。FcRn在结构上与主要组织相容性复合体I(MHC I)类异源二聚体受体家族同源性。FcRn具有多种重要的生物学功能。FcRn作为转运受体与免疫球蛋白IgG和白蛋白结合,并穿越多种细胞屏障。如在妊娠过程中,FcRN将母体的IgG抗体转运到胎儿体内,提供新生儿的体液免疫力。如Adv Drug Deliv Rev.2015 Aug30;91:109-24.J Immunol.2015 May 15;194(10):4595-603.Nat Rev Immunol.2007 Sep;7(9):715-25.所述,FcRn与IgG和白蛋白之间的pH依赖性相互作用对于通过循环回收和减少蛋白的降解以延长血清半衰期是至关重要。如Immunol Rev.2015 Nov;268(1):253-68.Mol Immunol.2015 Oct;67(2Pt A):131-41.所述,FcRn与IgG的结合部位是在CH2-CH3结构域的交界面,而涉及氨基酸残基253、310和435。
发明内容
本公开涉及一种异源二聚体免疫球蛋白构建体,例如双特异性抗体,其具有导致增加的稳定性和特异性的修饰的恒定区,和异源二聚体免疫球蛋白构建体的制备方法和使用方法。
本发明的第一方面涉及一种异源二聚体,其包括Fc受体(FcR)-结合成员和一个或多个与FcR-结合成员共价连接的识别部分。其中FcR-结合成员包括通过一个或多个二硫键链间连接的第一多肽和第二多肽。第一多肽和第二多肽分別包括免疫球蛋白重链恒定区的至少一部分。第一多肽和第二多肽在如下位置包括至少5个氨基酸的置换,
1)第一多肽上366位和399位氨基酸置换和第二多肽上351位、407位和409位氨基酸的置换;或者
2)第一多肽上366位和409位氨基酸置换结构域第二多肽上351位、399位和407位氨基酸置换;
因此,第一多肽与第二多肽彼此之间具有比自身更高的二聚化亲和力。
在一些实施例中,所述至少5个氨基酸的置换包括以下置换中的至少一个:
a)第二多肽上L351位上置换为甘氨酸、酪氨酸、缬氨酸、脯氨酸、天冬氨酸、谷氨酸、赖氨酸或色氨酸;
b)第一多肽上T366位上置换为亮氨酸、脯氨酸、色氨酸或缬氨酸;
c)第一多肽和/或第二多肽上D399位上置换为半胱氨酸、天冬酰胺、异亮氨酸、甘氨酸、精氨酸、苏氨酸或丙氨酸;
d)第二多肽上Y407位上置换为亮氨酸、丙氨酸、脯氨酸、苯丙氨酸、苏氨酸或组氨酸;和
e)第一多肽和/或第二多肽上K409位上置换为半胱氨酸、脯氨酸、丝氨酸、苯丙氨酸、缬氨酸、谷氨酸或精氨酸。
在一些实施例中,所述至少5个氨基酸的置换包括来自第一组a)-h)和第二组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第一组:
a)第一多肽T366L置换和第二多肽L351E,Y407L置换;
b)第一多肽T366L置换和第二多肽L351G,Y407L置换;
c)第一多肽T366L置换和第二多肽L351Y,Y407A置换;
d)第一多肽T366P置换和第二多肽L351V,Y407P置换;
e)第一多肽T366W置换和第二多肽L351D,Y407P置换;
f)第一多肽链T366P置换和第二多肽L351P,Y407F置换;
g)第一多肽T366V置换和第二多肽链L351K,Y407T置换;和
h)第一多肽T366L置换和第二多肽L351W,Y407H置换;
第二组:
a)第一多肽D399R置换和第二多肽K409V置换;
b)第一多肽D399C置换和第二多肽K409C置换;
c)第一多肽D399C置换和第二多肽K409P置换;
d)第一多肽D399N置换和第二多肽K409S置换;
e)第一多肽D399G置换和第二多肽K409S置换;
f)第一多肽D399I置换和第二多肽K409F置换;
g)第一多肽D399T置换和第二多肽K409Q置换;和
h)第一多肽D399A置换和第二多肽K409R置换。
在一些实施例中,所述至少5个氨基酸的置换包括来自第三组a)-h)和第四组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第三组:
a)第一多肽T366L置换和第二多肽L351E,Y407L置换;
b)第一多肽T366L置换和第二多肽L351G,Y407L置换;
c)第一多肽T366L置换和第二多肽L351Y,Y407A置换;
d)第一多肽链T366P置换和第二多肽L351V,Y407P置换;
e)第一多肽T366W置换和第二多肽L351D,Y407P置换;
e)第一多肽T366P置换和第二多肽L351P,Y407F置换;
g)第一多肽T366V置换和第二多肽L351K,Y407T置换;和
h)第一多肽T366L置换和第二多肽L351W,Y407H置换;
第四组:
a)第一多肽K409V置换和第二多肽D399R置换;
b)第一多肽K409C置换和第二多肽D399C置换;
c)第一多肽K409P置换和第二多肽D399C置换;
d)第一多肽K409S置换和第二多肽D399N置换;
e)第一多肽K409S置换和第二多肽D399G置换;
f)第一多肽K409F置换和第二多肽D399I置换;
g)第一多肽K409Q置换和第二多肽D399T置换;和
h)第一多肽K409R置换和第二多肽D399A置换。
在一些实施方案例中,所述至少5个氨基酸的置换包括第五组a)-h)中以下成员中的任何一种:
第五组:
a)第一多肽T366L和D399R置换和第二多肽L351E、Y407L和K409V置换;
b)第一多肽T366L和D399C置换和第二多肽L351G、Y407L和K409C置换;
c)第一多肽T366L和D399C置换和第二多肽L351Y、Y407A和K409P置换;
d)第一多肽T366P和D399N置换和第二多肽L351V、Y407P和K409S置换;
e)第一多肽T366W和D399G置换和第二多肽L351D、Y407P和K409S置换;
f)第一多肽T366P和D399I置换和第二多肽L351P、Y407F和K409F置换;
g)第一多肽T366V和D399T置换和第二多肽L351K、Y407T和K409Q置换;
h)第一多肽T366L和D399A置换和第二多肽L351W、Y407H和K409R置换。
在一些实施方案例中,所述至少5个氨基酸的置换包括第六组a)-h)中以下成员中的任何一种:
第六组:
a)第一多肽T366L和K409V置换和第二多肽L351E、Y407L和D399R置换;
b)第一多肽T366L和K409C置换和第二多肽L351G、Y407L和D399C置换;
c)第一多肽T366L和K409P置换和第二多肽L351Y、Y407A和D399C置换;
d)第一多肽T366P和K409S置换和第二多肽L351V、Y407P和D399N置换;
e)第一多肽T366W和K409S置换和第二多肽L351D、Y407P和D399G置换;
f)第一多肽T366P和K409F置换和第二多肽L351P、Y407F和D399I置换;
g)第一多肽T366V和K409Q置换和第二多肽L351K、Y407T和D399T置换;
h)第一多肽T366L和K409R置换和第二多肽L351W、Y407H和D399A置换。
在一些实施例中,所述至少5个氨基酸的置换包括第一多肽T366L和D399R置换。在一些实施例中,所述至少5个氨基酸的置换包括第二多肽L351E、Y407L和K409V置换。在一些实施例中,所述至少5个氨基酸的置换包括第一多肽T366L和D399R置换和第二多肽L351E,、Y407L和K409V置换。
在一些实施例中,所述FcR-结合成员包括一个Fc结构域。在一些实施例中,所述Fc结构域来源于IgG Fc结构域。在一些实施例中,所述Fc结构域来源于IgG1 Fc结构域、IgG2Fc结构域、IgG3 Fc结构域和IgG4 Fc结构域的其中一种。
在一些实施例中,所述FcR-结合成员能够特异性结合Fc受体。在一些实施例中,所述Fc受体是新生Fc受体(FcRn)。在一些实施例中,所述Fc受体是FcγRI、FcγRIIA、FcγRIIB1、FcγRIIB2、FcγRIIIA、FcγRIIIB、FcεRI、FcεRII、FcαRI、Fcα/μR、FcRn和其组合中的一种。在一些实施例中,与Fc受体的结合引发抗体依赖的细胞介导的细胞毒性作用(ADCC)。
在一些实施例中,第一多肽和第二多肽的至少一种的序列包括以下其中一个SEQID NO:16-31、33、35、37、39、41、43、45、48、49、51、53、55、57、59、61、63、68、69、70和71。
在一些实施例中,所述与FcR结合成员共价连接的一个或多个识别部分包括抗原结合(Fab)片段或多个片段、单链可变(scFv)片段或多个片段、膜受体的细胞外结构域、细胞膜受体的肽配体、细胞因子和亲和力标签的至少一种。在一些实施例中,所述一个或多个识别部分包括一个Fab片段和一个scFv片段。在一些实施例中,所述一个或多个识别部分包括两个scFv片段。在一些实施例中,所述两个scFv片段是不同。在一些实施例中,所述一个或多个识别部分包括两个Fab片段。在一些实施例中,所述两个Fab片段是不同。在一些实施例中,所述异源二聚体包括具有两个不同Fab片段的免疫球蛋白(Ig)样分子。
在一些实施例中,所述一个或多个识别部分识别HER2。在一些实施例中,所述一个或多个识别部分识别PD-L1。在一些实施例中,所述一个或多个识别部分识别Trop2。在一些实施例中,所述一个或多个识别部分识别CD3。在一些实施例中,所述一个或多个识别部分识别CD20。
在一些实施例中,识别包括特异性结合。在一些实施例中,所述一个或多个识别部分特异性结合HER2。在一些实施例中,所述一个或多个识别部分特异性结合PD-L1。在一些实施例中,所述一个或多个识别部分特异性结合Trop2。在一些实施例中,所述一个或多个识别部分特异性结合CD3。在一些实施例中,所述一个或多个识别部分特异性结合CD20。
在一些实施例中,所述一个或多个识别部分包括选自下面的第VII a)-d)组的一对识别部分:
第七组:
a)特异性结合HER2的Fab和特异性结合CD3的scFv;
b)特异性结合Trop2的Fab和特异性结合CD3的scFv;
c)特异性结合CD20的Fab和特异性结合CD3的scFv;和
d)特异性结合PD-L1的Fab和特异性结合CD3的scFv。
在一些实施例中,所述一个或多个识别部分包括一个特异性结合HER2的Fab和特异性结合CD20的Fab。
在一些实施例中,所述异源二聚体包括不同的多个第一重链和不同的多个第二重链,和不同的多个第一轻链和不同的多个第二轻链。
本公开的第二方面涉及一种生产异源二聚体的方法。在一些实施例中,所述方法括步骤:1)将在第一宿主细胞中编码第一多肽的一种或多种核酸和在第二宿主细胞中编码第二多肽的一种或多种核酸进行表达,其中第一宿主细胞和第二宿主细胞彼此分开;2)在分开时还原第一多肽和第二多肽;3)将还原的第一多肽和第二多肽混合以形成所得混合物;4)将混合物进行氧化;和5)回收形成的异源二聚体。
本公开的另一方面涉及一种生产异源二聚体的方法,该异源二聚体包括二价异源免疫球蛋白,所述二价异源免疫球蛋白具有不同的第一重链和第二重链,和不同的第一轻链和第二轻链。在一些实施例中,所述方法包括如下步骤:1)将在第一宿主细胞中编码第一重链和第一轻链的一种或多种核酸和在第二宿主细胞中编码第二重链和第二轻链的一种或多种核酸进行表达,其中第一宿主细胞和第二宿主细胞彼此分开;2)将第一重链与第一轻链还原在一起和将第二重链与第二轻链还原在一起;3)将还原的第一重链、第一轻链、第二重链和第二轻链混合以形成所得混合物;4)将混合物进行氧化;和5)回收形成的异源二聚体。在一些实施例中,所述第一重链和第二重链形成二价异源免疫球蛋白的Fc区。
在一些实施例中,所述Fc区包括至少5个氨基酸置换,其中所述至少5个氨基酸置换包括来自第八组a)-h)和第九组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第八组:
a)第一重链T366L置换和第二重链L351E,Y407L置换;
b)第一重链T366L置换和第二重链L351G,Y407L置换;
c)第一重链T366L置换和第二重链L351Y,Y407A置换;
d)第一重链T366P置换和第二重链L351V,Y407P置换;
e)第一重链T366W置换和第二重链L351D,Y407P置换;
f)第一重链T366P置换和第二重链L351P,Y407F置换;
g)第一重链T366V置换和第二重链L351K,Y407T置换;和
h)第一重链T366L置换和第二重链L351W,Y407H置换;
第九组:
a)第一重链D399R置换和第二重链K409V置换;
b)第一重链D399C置换和第二重链K409C置换;
c)第一重链D399C置换和第二重链K409P置换;
d)第一重链D399N置换和第二重链K409S置换;
e)第一重链D399G置换和第二重链K409S置换;
f)第一重链D399I置换和第二重链K409F置换;
g)第一重链D399T置换和第二重链K409Q置换;和
h)第一重链D399A置换和第二重链K409R置换。
在一些实施方案例中,所述至少5个氨基酸的置换包括来自第十组a)-h)中以下成员中的任何一种:
第十组:
a)第一重链T366L和D399R置换和第二重链L351E、Y407L和K409V置换;
b)第一重链T366L和D399C置换和第二重链L351G、Y407L和K409C置换;
c)第一重链T366L和D399C置换和第二重链L351Y、Y407A和K409P置换;
d)第一重链T366P和D399N置换和第二重链L351V、Y407P和K409S置换;
e)第一重链T366W和D399G置换和第二重链L351D、Y407P和K409S置换;
f)第一重链T366P和D399I置换和第二重链L351P、Y407F和K409F置换;
g)第一重链T366V和D399T置换和第二重链L351K、Y407T和K409Q置换;
h)第一重链T366L和D399A置换和第二重链L351W、Y407H和K409R置换。
在一些实施方案例中,所述至少5个氨基酸的置换包括来自第十一组a)-h)中以下成员中的任何一种:
第十一组:
a)第一重链T366L和K409V置换和第二重链L351E、Y407L和D399R置换;
b)第一重链T366L和K409C置换和第二重链L351G、Y407L和D399C置换;
c)第一重链T366L和K409P置换和第二重链L351Y、Y407A和D399C置换;
d)第一重链T366P和K409S置换和第二重链L351V、Y407P和D399N置换;
e)第一重链T366W和K409S置换和第二重链L351D、Y407P和D399G置换;
f)第一重链T366P和K409F置换和第二重链L351P、Y407F和D399I置换;
g)第一重链T366V和K409Q置换和第二重链L351K、Y407T和D399T置换;
h)第一重链T366L和K409R置换和第二重链L351W、Y407H和D399A置换。
本公开的另一方面涉及一种生产异源二聚体的方法,该异源二聚体包括免疫球蛋白异源二聚体,该免疫球蛋白异源二聚体包括不同的第一重链和第二重链,和不同的第一轻链和第二轻链。在一些实施例中,所述方法包括如下步骤:1)将在第一宿主细胞中编码第一重链和第一轻链的一种或多种核酸和在第二宿主细胞中编码第二重链和第二轻链的一种或多种核酸进行表达,其中第一宿主细胞和第二宿主细胞彼此分开;2)将第一重链与第一轻链还原在一起和将第二重链与第二轻链在一起;3)将还原的第一重链、第一轻链、第二重链和第二轻链混合以形成所得混合物;4)将混合物进行氧化;和5)回收形成的异源二聚体。在一些实施例中,所述第一重链和第二重链形成二价异源免疫球蛋白的Fc区。
在一些实施例中,所述Fc结构域包括至少5个氨基酸置换,其中所述至少5个氨基酸置换包括来自第十二组a)-h)和第十三组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第十二组:
a)第一重链T366L置换和第二重链L351E,Y407L置换;
b)第一重链T366L置换和第二重链L351G,Y407L置换;
c)第一重链T366L置换和第二重链L351Y,Y407A置换;
d)第一重链T366P置换和第二重链L351V,Y407P置换;
e)第一重链T366W置换和第二重链L351D,Y407P置换;
f)第一重链T366P置换和第二重链L351P,Y407F置换;
g)第一重链T366V置换和第二重链L351K,Y407T置换;和
h)第一重链T366L置换和第二重链L351W,Y407H置换;
第十三组:
a)第一重链K409V置换和第二重链D399R置换;
b)第一重链K409C置换和第二重链D399C置换;
c)第一重链K409P置换和第二重链D399C置换;
d)第一重链K409S置换和第二重链D399N置换;
e)第一重链K409S置换和第二重链D399G置换;
f)第一重链K409F置换和第二重链D399I置换;
g)第一重链K409Q置换和第二重链D399T置换;
h)第一重链K409R置换和第二重链D399A置换。
本公开的另一方面涉及一种生产异源二聚体的方法,该异源二聚体包括二价异源蛋白,该二价异源蛋白包括一条重链、一条轻链,和一条与Fc链相连的scFv片段,其中重链的一部分和与scFv片段连接的Fc链形成Fc区。在一些实施例中,所述方法包括如下步骤:1)将编码重链、轻链和与一条Fc链相连的scFv片段的一种或多种核酸在宿主细胞中进行表达;2)回收形成的异源二聚体。
在一些实施例中,所述Fc区包括至少5个氨基酸置换,其中所述至少5个氨基酸置换包括来自第十四组a)-h)和第十五组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第十四组:
a)第一重链T366L置换和第二重链L351E,Y407L置换;
b)第一重链T366L置换和第二重链L351G,Y407L置换;
c)第一重链T366L置换和第二重链L351Y,Y407A置换;
d)第一重链T366P置换和第二重链L351V,Y407P置换;
e)第一重链T366W置换和第二重链L351D,Y407P置换;
f)第一重链T366P置换和第二重链L351P,Y407F置换;
g)第一重链T366V置换和第二重链L351K。Y407T置换;和
h)第一重链T366L置换和第二重链L351W,Y407H置换;
第十五组:
a)第一重链D399R置换和第二重链K409V置换;
b)第一重链D399C置换和第二重链K409C置换;
c)第一重链D399C置换和第二重链K409P置换;
d)第一重链D399N置换和第二重链K409S置换;
e)第一重链D399G置换和第二重链K409S置换;
f)第一重链D399I置换和第二重链K409F置换;
g)第一重链D399T置换和第二重链K409Q置换;和
h)第一重链D399A置换和第二重链K409R置换。
在一些实施例中,所述至少5个氨基酸的置换包括来自第十六组a)-h)和第十七组a)-h)的每一个的任何一个成员的以下组合中的任一种:
第十六组:
a)第一重链T366L置换和第二重链L351E,Y407L置换;
b)第一重链T366L置换和第二重链L351G,Y407L置换;
c)第一重链T366L置换和第二重链L351Y,Y407A置换;
d)第一重链T366P置换和第二重链L351V,Y407P置换;
e)第一重链T366W置换和第二重链L351D,Y407P置换;
f)第一重链T366P置换和第二重链L351P,Y407F置换;
g)第一重链T366V置换和第二重链L351K,Y407T置换;或
h)第一重链T366L置换和第二重链L351W,Y407H置换;
第十七组:
a)第一重链K409V置换和第二重链D399R置换;
b)第一重链K409C置换和第二重链D399C置换;
c)第一重链K409P置换和第二重链D399C置换;
d)第一重链K409S置换和第二重链D399N置换;
e)第一重链K409S置换和第二重链D399G置换;
f)第一重链K409F置换和第二重链D399I置换;
g)第一重链K409Q置换和第二重链D399T置换;
h)第一重链K409R置换和第二重链D399A置换。
在一些实施例的一方面涉及产生异源二聚体的方法,其中核酸位于载体上或载体系统上。在一些实施例中,所述载体或载体系统包括基于pCDNA改造得到的质粒载体pX0GC。
在一些实施例的一方面涉及产生异源二聚体的方法,其中宿主细胞包括人胚肾细胞HEK293或HEK293T、HEK293E、HEK293修饰的HEK293F、中国仓鼠卵巢细胞(CHO)、CHO-S、CHO-dhfr-、CHO/DG44、CHO修饰的ExpiCHO,和其组合。
在一些实施例的一方面涉及产生异源二聚体的方法,其中还原步骤涉及一种或多种还原剂,其包括2-巯基乙胺、二硫苏糖醇、三(2-羧乙基)膦盐酸盐、其他化学衍生物和其组合中的至少一种。在一些实施例中,该方法还包括在约2℃至8℃下进行还原,例如,3℃至6℃和4℃,任选地在约至少3小时进行还原(例如:3小时至8小时、4小时至7小时,和5小时至6小时)。在其他实施例中,所述方法包括除去一种或多种还原剂。在一些实施例中,除去一种或多种还原剂涉及脱盐方法。
在一些实施例的一方面涉及产生异源二聚体的方法,其中氧化步骤涉及一种或多种氧化剂,其包括L-脱氢抗坏血酸、其化学衍生物和其组合中的至少一种。在一些实施例中,该方法还包括在约2℃至8℃下进行氧化,例如,3℃至6℃和4℃,任选地在约至少5小时进行氧化(例如5小时至4天、5小时至3天和5小时至1天。)在一些实施例中,该方法还包括回收和/或纯化。
在另一个方面,本公开涉及编码根据本公开任何方面的异源二聚体的一部分的核酸。在一些实施例中,所述核酸序列包括以下SEQ ID NO之一:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64-67,或者与以下SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64-67的一个或多个具有至少70%,例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、或者99.9%的序列同一性。在一些实施例中,所述核酸序列包括在严格条件下与SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64-67中的一个或多个相杂交的序列。在一些实施例中,所述核酸序列包括与SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64-67中的一个或多个相互补的序列。
在另一方面,本公开涉及载体或载体系统,其包括至少一种编码根据本公开任何方面的异源二聚体的一部分的核酸。在一些实施例中,所述载体或载体系统包括基于pCDNA改造得到的质粒载体pX0GC。
在另一方面,本公开涉及一种宿主细胞,其包括一种载体或载体系统,该载体或载体系统包括编码根据本公开任何方面的异源二聚体的一部分的任何核酸。在一些实施例中,所述的宿主细胞是人胚肾细胞HEK293或HEK293T、HEK293E、HEK293修饰的HEK293F,中国仓鼠卵巢细胞CHO、CHO-S、CHO-dhfr-、CHO/DG44和CHO细胞修饰的ExpiCHO中的其中一种。
在另一方面,本公开涉及重组产生根据本公开何方面的异源二聚体的一部分的方法。在一些实施例中,该方法包括提供含有载体或载体系统的宿主细胞,所述载体或载体系统包括一种或多种编码本公开任一方面的异源二聚体的至少第一重链和第二重链的核酸;表达该核酸;和回收重组产生的异源二聚体。
在另一方面,本公开涉及一种组合物,其包括如上所述的异源二聚体、药学上可接受的载体、防腐剂或赋形剂。
在另一方面,本公开涉及将上述异源二聚体施用有需求的受试者的方法。在一些实施例中,将异源二聚体施用受试者以治疗疾病或病症。在另外一些实施例中,将异源二聚体施用受试者以预防疾病或病症。在一些实施例中,受试者是哺乳动物。在一些实施例中,受试者是人类。
在一些实施例中,所述疾病或病症包括自身免疫性疾病、针对移植物的免疫应答、变态反应、感染、神经退行性疾病、肿瘤和细胞增生性疾病或其组合中的至少一种。在一些实施例中,所述自身免疫性疾病包括关节炎、风湿性关节炎、银屑病、多发性硬化症(MS)、溃疡性结肠炎、克罗恩病、系统性红斑狼疮(SLE)、肾小球肾炎、扩张型心肌病样疾病、斯耶格伦氏综合征、过敏性接触性皮炎、多肌炎、硬皮病、动脉周性多动脉炎、风湿热、白癜风、胰岛素依赖性糖尿病、白塞氏综合征、慢性甲状腺炎和其组合中的至少一种。在一些实施例中,所述神经退行性疾病包括帕金森氏病、亨廷顿氏病、马查多-约瑟夫病、肌萎缩性侧索硬化症(ALS)、克罗伊茨费尔特-雅各布病和其组合中的至少一种。在一些实施例中,所述肿瘤和细胞增生性疾病包括白血病、淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌(NSCLC)、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤和其组合中的至少一种。
另一方面,本公开涉及如上所述的异源二聚体用于药物中的用途。
另一方面,本公开涉及如上所述的异源二聚体用于治疗疾病或病症的用途。在一些实施例中,所述疾病或病症包括自身免疫性疾病、针对移植物的免疫应答、变态反应、感染、神经退行性疾病、肿瘤和细胞增生性疾病或其组合中的至少一种。
另一方面,本公开涉及如上所述的异源二聚体用于制备药物的用途。
另一方面,本公开涉及如上所述的异源二聚体用于制备治疗疾病或病症的药物的用途。在一些实施例中,所述异源二聚体是根据本公开的任何方面的异源二聚体。在一些实施例中,所述疾病或病症包括自身免疫性疾病、针对移植物的免疫应答、变态反应、感染、神经退行性疾病、肿瘤和细胞增生性疾病或其组合中的至少一种。
附图说明
图1示出了pDis3载体结构示意图,其中Cmv是指巨细胞病毒启动子(Cytomegalovirus promoter),sp是指信号肽(signal peptide),SUMO是指类泛素蛋白抗原标签(Small ubiquitin-related modifier tag),Fc是指可结晶片段(fragmentcrystallizable),BGH是指牛生长激素多聚腺苷酸信号(bovine growth hormonepolyadenylation(bgh-PolyA)signal),HA是指人类流感病毒血凝素片段(Humaninfluenza hemagglutinin),PUC ori是指pUC的复制起始位点(origin of replicationof pUC),Hydro是指潮霉素B抗性基因(hygromycin B resistant gene),AmpR是指氨苄青霉素抗性基因(Ampicillin resistant gene),oriP是指埃-巴二氏病毒复制起始位点(TheEpstein–Barr Virus replicationorigin(oriP))。
图2示出了异源二聚体Fc库的结构。
图3示出了同源二聚体和异源二聚体的配对。
图4示出了抗HER2/抗CD3-scFv异源二聚体的通用结构。
图5示出了抗HER2/抗CD3-scFv异源二聚体的洗脱峰。
图6示出了抗HER2/抗CD3-scFv异源二聚体的SDS-PAGE分析。
图7示出了抗HER2/抗CD3-scFv异源二聚体的纯度分析。
图8A和图8B示出了不同含量下的抗HER2/抗CD3-scFv异源二聚体的稳定性,图8A为10mg/mL和40℃,图8B为1mg/mL和40℃。
图9示出了抗HER2/抗CD3-scFv异源二聚体与FcRn的结合亲和力。
图10A、10B、10C和10D示出了抗HER2/抗CD3-scFv异源二聚体与SK-BR-3和Jurkat细胞的同时结合,图10A为同种型,图10B为抗HER2单克隆抗体,图10C为抗HER2/抗CD3四价同源二聚体双特异抗体,图10D为抗HER2/抗CD3二价异源二聚体双特异抗体。
图11A和图11B示出了抗HER2/抗CD3-scFv异源二聚体对不同靶细胞中的体外细胞毒性。图11A为SK-BR 3,图11B为BT-474。
图12示出了通过腹膜内施用的抗HER2/抗CD3-scFv异源二聚体的一剂量药代动力学(PK)谱。
图13示出了抗Trop-2/抗CD3-scFv异源二聚体的SDS-PAGE分析。
图14示出了抗Trop2/抗CD3-scFv异源二聚体的Trop-2结合亲和力。
图15A、图15B、图15C和图15D示出了抗Trop2/抗CD3-scFv异源二聚体与BxPC-3和Jurkat细胞的同时结合。图15A为同种型,图15B为抗CD3单克隆抗体,图15C为抗Trop2单克隆抗体,图15D为抗Trop2/抗CD3异源二聚体双特异抗体。
图16A和图16B示出了抗Trop2/抗CD3-scFv异源二聚体抗体分子的体外细胞毒性。图16A为H1650,图16B为BxPC-3。
图17示出了通过腹膜内施用的抗-Trop2/抗CD3-scFv异源二聚体的一剂量药代动力学(PK)谱。
图18示出了抗CD20/抗CD3-scFv异源二聚体抗体分子的SDS-PAGE分析。
图19A和图19B示出了不同含量下的抗CD20/抗CD3-scFv异源二聚体抗体分子的稳定性。图19A为10mg/mL和40℃,图19B为1mg/mL和40℃。
图20示出了抗PD-L1/抗CD3-scFv异源二聚体抗体分子的SDS-PAGE分析。
图21示出了抗PD-L1/抗CD3-scFv异源二聚体抗体分子的PD-L1结合亲和力。
图22A、图22B、图22C和图22D示出了抗PD-L1/抗CD3-scFv异源二聚体分子与H460和Jurkat细胞的同时结合。图22A为同种型,图22B为抗PD-L1单克隆抗体,图22C为抗CD3单克隆抗体,图22D为抗PD-L1/抗CD3异源二聚体双特异抗体。
图23A和图23B示出了抗PD-L1/抗CD3-scFv异源二聚体对不同靶细胞中的体外细胞毒性。图23A为HCC827,图23B为H1650。
图24示出了抗CD20表达产物的洗脱峰。
图25示出了抗HER2/抗CD20异源二聚体的通用结构。
图26示出了半聚体的通用结构。
图27示出了还原反应产物的SDS-PAGE分析。
图28示出了还原反应产物的尺寸排阻-高效液相色谱(SEC-HPLC)分析。
图29示出了氧化反应产物的SDS-PAGE分析。
图30示出了抗HER2/抗CD20异源二聚体的洗脱峰。
图31示出了抗HER2/抗CD20异源二聚体的SDS-PAGE分析。
图32示出了抗HER2/抗CD20异源二聚体的纯度分析。
图33示出了抗HER2/抗CD20异源二聚体的分析。
图34A和图34B示出了抗HER2/抗CD20异源二聚体的质谱鉴定结果(图34A)以及相关的序列比对结果(图34B)。实线表示氨基酸与第二质谱中的预期氨基酸相同,虚线表示肽与初步质谱中的预期肽相同,和没有阴影的氨基酸表示“未找到”。
具体实施方式
本公开涉及免疫球蛋白样异源二聚体构建体,例如(但不一定)双特异性抗体,其具有修饰的重链恒定区(例如,Fc区),所述修饰的重链恒定区赋予构建体增加的稳定性和治疗功效。可以使这些构建体保留天然IgG的有益特点,并且没有重轻链错配。本公开另外涉及产生免疫球蛋白构建体的方法,通常通过的两个“半抗体”或“半聚体”之间的还原反应和随后的氧化反应来产生异源二聚体。本公开的异源二聚体可被视为由两个不相同的半抗体或半聚体通过一个或多个二硫键相互连接而组成。半聚体含有单链突变的免疫球蛋白重链或其片段和与其关联的识别部分(称为链的“同源”识别部分),该关联在典型的生理条件下是共价键。这些半聚体被设计成在其重链恒定区中具有修饰,使得在还原条件下抑制同源二聚体形成,否则通常有利于支持通过非共价力配对同源二聚体,而在同一还原条件下,两个互补设计的半聚体之间有利于异源二聚体关联没。通过“异源二聚体关联(heterodimeric association)”,意味着包括非共价结合力和共价结合力。如本文所用,"半抗体(half antibody)"或"半抗体(halfmer)"可以指分子或分子复合物,其可以被视为仅含有完全免疫球蛋白异源四聚体的“一半(half)”或免疫球蛋白的衍生物(例如scFv),并且通常在典型的生理条件下构成Fc受体结合成员的在通常的两个多肽链中仅具有一个多肽链,并且一个识别部分与所述一条多肽链关联。例如,半抗体或半聚体可以包括具有特定突变的免疫球蛋白重链(或其片段)和免疫球蛋白轻链(或其片段),所述免疫球蛋白重链和免疫球蛋白轻链通过共价键或非共价相互作用如疏水力和氢键结合在一起,并且所述半抗体分子或半聚体通常可认为是“单价的(monovalent)”。或者,这种“单价”半抗体或半聚体可以包括含有具有特定突变的免疫球蛋白重链的铰链区和CH2和CH3区的单链,所述单链例如通过共价键与非Fab识别部分,例如可变片段(scFv)或受体的结合结构域连接。对应于前一实例的示例性“半聚体”或“半抗体”在图26中示出,图26示出一个免疫球蛋白重链和一个轻链。
本公开的异源二聚体的产品产率与天然抗体类似,方法简单易操作。在一个实施例中,异源二聚体由两种不同的“半抗体”组成的,所述每种半抗体由携带特定突变的完整Ig重链和完整的Ig轻链组成,通常,所述半抗体体分别表达,例如,在两个不同的细胞中,分别纯化,分别通过添加还原剂分别还原,合在一起,然后通过氧化形成异源二聚体。在另一个实施例中,该异源二聚体由两种不同的半聚体组成,其中,一种半聚体由携带特定突变的完整重链和完整轻链,而另一种半聚体是携带与非Fab识别部分连接的特定突变的FcR-结合重链片段,本公开的异源二聚体可以使用单细胞系表达和纯化。示例性还原剂包括,例如,2-巯基乙胺、二硫苏糖醇、三(2-羧乙基)膦盐酸盐、和其他化学衍生物,但还原剂不限于此。示例性氧化剂包括,例如,L-脱氢抗坏血酸和其他化学衍生物,但氧化剂不限于此。
本公开异源二聚体的特征在于异源二聚体上CH3结构域中的五个特异性非半胱氨酸突变。所述突变是T366、D399、L351、Y407和K409。如本文所用,氨基酸残基的编号根据Kabat EU索引编号,例如,如Edelman et al.,1969,Proc Natl Acad Sci USA 63:78-8中所述,通过引用整体并入本文。例如,可以使用Kabat EU索引编号来比较靶抗体的序列与由Kabat EU索引鉴定的共有序列。纯粹作为实例,五种突变可包括T366L、D399R、L351E、Y407L和K409V。然而,本发明严格地不限于此。例如,T366的突变可包括以下任何非限制性实例:T366L、T366P、T366C、T366V、T366S、T366R和T366W。D399的突变可包括以下任何非限制性实例:D399R、D399C、D399H、D399V、D399T、D399A、D399P、D399N、D399I、D399H、D399S、D399G和D399M。L351的突变可包括以下任何非限制性实例:L351E、L351G、L351R、L351Y、L351T、L351K、L351W、L351V、L351P和L351D。Y407的突变可包括以下任何非限制性实例:407L、Y407P、Y407A、Y407R、Y407V、Y407T、Y407H和Y407F。K409的突变可包括以下任何非限制性实例:K409V、K409C、K409P、K409A、K409F、K409Q、K409R、K409T、K409S、K409M、K409Y和K409N。
在示例性实施例中,T366和D399的突变位于第一多肽上,即,在第一重链的CH3结构域中,L351、Y407和K409的突变位于第二个多肽上,即,在第二重链的CH3结构域中。尽管本公开明确地不限于此,但该组合产生具有良好稳定性和结合活性的最佳自发异源二聚体的形成。每个半聚体对其互补半聚体的“伙伴(partner)”或链具有强烈的吸引力,和对自我有强烈的排斥力,因此强烈有利于异源二聚体的形成,并强烈不利于同源二聚体的形成。当在充分还原的生理条件下,当两种组分半聚体中只有一种存在于水性溶液中时,实际存在的多肽形式可包括半聚体形式、两个半聚体通过非共价力连接的同源二聚体形式,和未折叠形式。在所述溶液中,以同源二聚体形式存在的多肽形式的部分被显着抑制,所述水性溶液基本上不含除上述半聚体之外的任何多肽,例如互补的“其他”半聚体。换句话说,当仅含有第一多肽链或第二多肽链中的一个和与其关联得一条识别部分(多肽链的“同源(cognate)”识别部分)在含有足量还原剂的生理条件下被引入水性介质中时,这种多肽链和其同源识别部分不倾向于形成同源二聚体,但倾向水性溶液中保持为半聚体,所述溶液基本上不含任何其他多肽。这种引入水性溶液的行为包括,例如,在宿主细胞中的表达。同样,当含有两条多肽链和其同源识别部分在含有足量还原剂的生理条件下被引入水性溶液中时,可以存在相应的异源二聚体和其组成的半聚体,但同源二聚体的形成受到抑制。基于水性溶液中存在的所有多肽形式(半聚体、同源二聚体、异源二聚体和未折叠物种等)的总重量,在还原剂存在下形成同源二聚体的比例通常小于50%,所述水性溶液基本上不含其他多肽。例如,在还原剂的存在下,由第一多肽、第二多肽、与识别部分共价连接的第一多肽,或与识别部分公价连接的第二多肽所形成的同源二聚体的比例(按重量计)小于50%。例如,小于45%、40%、35%、30%、25%、20%、15%、10%、5%、4%、3%、2%、1%或甚至更少。
在某些实施例中,还原剂选自谷胱甘肽、2-巯基乙醇、2-巯基乙胺、三(2-羧乙基)膦(TCEP)、半胱氨酸、半胱氨酸盐酸盐、二硫苏糖醇(DTT),半胱氨酸二硫苏糖醇、二硫丁胺,二硫赤藓糖醇(DTE)、钠硼氢化物(NaBH4),氰基硼氢化钠(NaCNBH 3)和/或其组合。在一些实施例中,还原剂浓度相对于蛋白质浓度可以是1至100倍(例如,20至50倍)摩尔过量。在某些实施例中,还原剂可以是约0.1mM至约20mM的浓度。可以以足够量使用的代表性还原剂包括1mM或更高的二硫苏糖醇、50mM或更高的2-巯基乙胺和50mM或更高半胱氨酸。在一些实施例中,在蛋白质氧化之前与蛋白质温育后,除去还原剂。
第一多肽和第二多肽可通过共价键或柔性连接体分别连接至识别部分,所述识别部分包括但不限于抗原结合片段、单链抗体片段(scFv)、识别受体的配体或识别配体的受体。共价键包括两个或多个原子之间的化学键,其中两个或多个原子共同使用它们的外层电子。当这些电子达到饱和状态时形成的稳定化学结构称为共价键。换句话说,共价键是原子间通过共用电子对所形成的相互作用。同一种的元素的原子或不同元素的都可以通过共价键结合。本公开中的中第一多肽和第二多肽之间的共价键包括,但不限于,一分子氨基酸的氨基与另一分子氨基酸反应的羧基合成而导致释放一分子水(H2O)的酰胺键,或者乙二醇或聚乙二醇或其他化合物或其多聚物的醛基与一分子氨基酸的氨基相互作用形成酰胺键或亚胺键。柔性连接体可包括短氨基酸序列或多聚体。这种氨基酸序列包括但不限于GGGGSGGGGSGGGGS(SEQ ID NO:72)。
T366、D399、L351、Y407和K409的其他突变组合明确地在本公开的范围内。例如,来自第一组和第二组的a)-h)的以下任何组合:
第一组:
a)第一多肽T366L置换和第二多肽L351E,Y407L置换;
b)第一多肽T366L置换和第二多肽L351G,Y407L置换;
c)第一多肽T366L置换和第二多肽L351Y,Y407A置换;
d)第一多肽T366P置换和第二多肽L351V,Y407P置换;
e)第一多肽T366W置换和第二多肽L351D,Y407P置换;
e)第一多肽T366P置换和第二多肽L351P,Y407F置换;
g)第一多肽T366V置换和第二多肽L351K,Y407T置换;和
h)第一多肽T366L置换和第二多肽L351W,Y407H置换;
第二组:
a)第一多肽D399R置换和第二多肽K409V置换;
b)第一多肽D399C置换和第二多肽K409C置换;
c)第一多肽链D399C置换和第二多肽K409P置换;
d)第一多肽D399N置换和第二多肽K409S置换;
e)第一多肽D399G置换和第二多肽K409S置换;
f)第一多肽D399I置换和第二多肽K409F置换;
g)第一多肽D399T置换和第二多肽K409Q置换;和
h)第一多肽D399A置换和第二多肽K409R置换。
来自第三组和第四组的a)-h)的以下任何组合:
第三组:
a)第一多肽T366L置换和第二多肽L351E,Y407L置换
b)第一多肽T366L置换和第二多肽L351G,Y407L置换;
c)第一多肽T366L置换和第二多肽L351Y,Y407A置换;
d)第一多肽T366P置换和第二多肽L351V,Y407P置换;
e)第一多肽T366W置换和第二多肽L351D,Y407P置换;
e)第一多肽T366P置换和第二多肽L351P,Y407F置换;
g)第一多肽T366V置换和第二多肽L351K,Y407T置换;和
h)第一多肽T366L置换和第二多肽L351W,Y407H置换;第四组:
a)第一多肽K409V置换和第二多肽D399R置换;
b)第一多肽K409C置换和第二多肽D399C置换;
c)第一多肽K409P置换和第二多肽D399C置换;
d)第一多肽K409S置换和第二多肽D399N置换;
e)第一多肽K409S置换和第二多肽D399G置换;
f)第一多肽K409F置换和第二多肽D399I置换;
g)第一多肽K409Q置换和第二多肽D399T置换;和
h)第一多肽K409R置换和第二多肽D399A置换。
来自第五组的以下任何成员a)-h):
第五组:
a)第一多肽T366L和D399R置换和第二多肽L351E、Y407L和K409V置换;
b)第一多肽T366L和D399C置换和第二多肽L351G、Y407L和K409C置换;
c)第一多肽T366L和D399C置换和第二多肽L351Y、Y407A和K409P置换;
d)第一多肽T366P和D399N置换和第二多肽L351V、Y407P和K409S置换;
e)第一多肽T366W和D399G置换和第二多肽L351D、Y407P和K409S置换;
f)第一多肽T366P和D399I置换和第二多肽L351P、Y407F和K409F置换;
g)第一多肽T366V和D399T置换和第二多肽L351K、Y407T和K409Q置换;
h)第一多肽T366L和D399A置换和第二多肽L351W、Y407H和K409R置换。
来自第六组的以下任何成员a)-h):
第六组:
a)第一多肽T366L和K409V置换和第二多肽L351E、Y407L和D399R置换;
b)第一多肽T366L和K409C置换和第二多肽L351G、Y407L和D399C置换;
c)第一多肽T366L和K409P置换和第二多肽L351Y、Y407A和D399C置换;
d)第一多肽T366P和K409S置换和第二多肽L351V、Y407P和D399N置换;
e)第一多肽T366W和K409S置换和第二多肽L351D、Y407P和D399G置换;
f)第一多肽T366P和K409F置换和第二多肽L351P、Y407F和D399I置换;
g)第一多肽T366V和K409Q置换和第二多肽L351K、Y407T和D399T置换;
h)第一多肽T366L和K409R置换和第二多肽L351W、Y407H和D399A置换。
第一多肽和第二多肽可各自包括一条重链。本公开的异源二聚体构建体可以包括双特异性抗体,但显然不限于此。例如,异源二聚体构建体可包括一个或多个scFv片段和一个或多个Fab片段,例如,一个scFv片段和一个Fab片段或两个Fab片段。异源二聚体多肽的示例性序列包括但不特别限于:SEQ ID NO:16-31、33、35、37、39、41、43、45、48、49、51、53、55、57、59、61、63、68、69、70和71中的任一个。还包括与SEQ ID NO:16-31、33、35、37、39、41、43、45、48、49、51、53、55、57、59、61、63、68、69、70和71中的任一个共享至少70%序列同一性(同时保持生物活性)的变体序列。例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99.9%或更好的序列同一性。另外,SEQ ID NO:16-31、33、35、37、39、41、43、45、48、49、51、53、55、57、59、61、63、68、69、70和71中的任一个可以具有一个或多个保守置换,并且仍然在本公开的范围内。
本公开的双特异性异源二聚体抗体在第一重链和第二重链之间形成一个或多个二硫键。二硫键可以在同一个细胞内表达期间形成,或通过体外加入氧化剂进行氧化反应的方法形成。发生在实施例中的二硫键在半聚体表达、纯化、通过添加还原剂还原、混合在一起,然后氧化以形成异源二聚体时发生。
本公开的异源二聚体能够结合Fc受体,例如FcγRI、FcγRIIA、FcγRIIB1、FcγRIIB2、FcγRIIIA、FcγRIIIB、FcεRI、FcεRII、FcαRI、Fcα/μR和FcRn中的一种或多种。在示例性实施例中,异源二聚体具有结合FcRn的能力。如本文所用,FcRn是指在结构上与MHC I类异源二聚体受体家族同源,包括一条I类跨膜重链(p51亚基,alpha链)与一条可溶轻链(p14亚基,beta链),两者以非共价相互作用形式组合在一起。FcRn与IgG的结合部位,在CH2-CH3的交界面。其中最重要的氨基酸位点为253、310和435位。
根据其结构的性质,本发明的异二聚体可以(但不是必须)同时靶向一种或多种抗原。在示例性实施例中,抗原包括HER2,PD-L1,TROP2,CD3和/或CD20中的一种或多种。然而,本发明严格不限于此。这是因为本公开涉及用于改善稳定性、血清半衰期和治疗功效的抗体/免疫球蛋白构建体的恒定区(CH3)的修饰。本公开的技术可以应用于仅与一种靶抗原结合的单克隆抗体。这包括例如已知的治疗性抗体。此类抗体仍可受益于具有修饰的恒定区所改善的稳定性。在这种情况下,第一多肽和第二多肽上(或连接)的识别部分将保持相同,并且“半抗体”或“半聚体”之间的差异可能仅位于CH3区域。
可受益于本公开的修饰的已知治疗性单克隆抗体可包括任何以下非限制性抗体:3F8、8H9、阿巴伏单抗(Abagovomab)、阿昔单抗(Abciximab)、联合西妥昔单抗(Abituzumab)、Abrilumab、Actoxumab、阿达木单抗(Adalimumab)、阿德木单抗(Adecatumumab)、百健单抗(Aducanumab)、Afasevikumab、阿非莫单抗(Afelimomab)、阿托珠单抗(Afutuzumab),培阿珠单抗(Alacizumab pegol)、ALD518、阿仑珠单抗(Alemtuzumab)、Alirocumab、喷替酸阿妥莫单抗(Altumomab pentetate)、Amatuximab、马安莫单抗(Anatumomab mafenatox)、Anetumab ravtansine、Anifrolumab、安芦珠单抗(Anrukinzumab)、阿泊珠单抗(Apolizumab)、阿西莫单(Arcitumomab)、Ascrinvacumab、阿塞珠单抗(Aselizumab)、阿特珠单抗(Atezolizumab)、Atinumab、Atlizumab、阿托木单抗(Atorolimumab)、Avelumab、巴匹珠单抗(Bapineuzumab),巴利昔单抗(Basiliximab)、巴土昔单抗(Bavituximab)、贝妥莫单抗(Bectumomab)、Begelomab、贝利木单抗(Belimumab)、Benralizumab、柏替莫单抗(Bertilimumab)、贝索单抗(Besilesomab)、Bevacizumab、贝茨罗特斯单抗(Bezlotoxumab)、比西单抗(Biciromab)、比玛格鲁单抗(Bimagrumab)、Bimekizumab,Bivatuzumab mertansine、Bleselumab、兰妥莫单抗(Blinatumomab)、布隆妥维单抗(Blontuvetmab)、布鲁宗津单抗(Blosozumab)、Bococizumab、Brazikumab、布妥昔单抗(Brentuximab vedotin)、贝伐珠单抗(Briakinumab)、布达路单抗(Brodalumab)、Brolucizumab、Brontictuzumab、Burosumab、Cabiralizumab、卡那单抗(Canakinumab)、美坎珠单抗(Cantuzumab mertansine)、莫坎妥珠单抗(Cantuzumab ravtansine)、卡普兰珠单抗(Caplacizumab)、卡罗单抗喷地肽(Capromab pendetide)、卡鲁单抗(Carlumab)、Carotuximab、卡妥索单抗(Catumaxomab)、cBR96-多柔比星免疫偶联物(cBR96-doxorubicin immunoconjugate)、西利珠单抗(Cedelizumab)、Cergutuzumabamunaleukin、培舍珠单抗(Certolizumab pegol)、西妥昔单抗(Cetuximab)、泊西他珠单抗(Citatuzumab bogatox)、西妥木单抗(Cixutumumab)、克莱赞珠单抗(Clazakizumab)、克立昔单抗(Clenoliximab)、克莱维足单抗(Clivatuzumab tetraxetan)、Codrituzumab、Coltuximab ravtansine、可那木单抗(Conatumumab)、可那足单抗(Concizumab)、CR6261、克雷内治单抗(Crenezumab)、克洛特单抗(Crotedumab)、达西珠单抗(Dacetuzumab)、达克珠单抗(Daclizumab)、达罗土珠单抗(Dalotuzumab)、Dapirolizumab pegol、达拉土姆单抗(Daratumumab)、Dectrekumab、地莫米佐单抗(Demcizumab)、Denintuzumab mafodotin、地舒单抗(Denosumab)、Depatuxizumab mafodotin、Derlotuximab biotin、地莫单抗(Detumomab)、Dinutuximab、Diridavumab、Domagrozumab、阿托度单抗(Dorlimomabaritox)、德罗图单抗(Drozitumab)、杜力戈图单抗(Duligotumab)、杜丕璐单抗(Dupilumab)、德瓦鲁单抗(Durvalumab)、杜氏图单抗(Dusigitumab)、依美昔单抗(Ecromeximab)、依库珠单抗(Eculizumab)、埃巴单抗(Edobacomab)、依决洛单抗(Edrecolomab)、依法珠单抗(Efalizumab)、依夫单抗(Efungumab)、依德鲁单抗(Eldelumab)、Elgemtumab、埃罗妥珠单抗(Elotuzumab)、艾西莫单抗(Elsilimomab)、Emactuzumab、Emibetuzumab、Emicizumab、埃文单抗(Enavatuzumab)、抗体药物偶联物(Enfortumab vedotin)、培戈赖莫单抗(Enlimomab pegol)、Enoblituzumab、艾诺克单抗(Enokizumab)、艾诺提克单抗(Enoticumab)、埃斯托西单抗(Ensituximab)、西依匹莫单抗(Epitumomab cituxetan)、Epratuzumab,Erenumab,Erlizumab,Ertumaxomab,Etaracizumab,Etrolizumab,依帕珠单抗(Evinacumab)、艾沃单抗(Evolocumab)、艾韦单抗(Exbivirumab)、法索单抗(Fanolesomab)、法拉莫单抗(Faralimomab)、法拉图组单抗(Farletuzumab)、·法希姆单抗(Fasinumab)、BTA05、非维珠单抗(Felvizumab)、非扎奴单抗(Fezakinumab)、菲巴珠单抗(Fibatuzumab)、菲拉特珠单抗(Ficlatuzumab)、弗吉妥姆单抗(Figitumumab)、弗瑞单抗(Firivumab)、弗兰单抗(Flanvotumab)、弗乐提单抗(Fletikumab)、冯特利珠单抗(Fontolizumab)、芙拉单抗(Foralumab)、夫瑞单抗(Foravirumab)、弗瑞索单抗(Fresolimumab)、弗兰单抗(Fulranumab)、弗图希单抗(Futuximab)、Galcanezumab、加利昔单抗(Galiximab)、盖尼塔单抗(Ganitumab)、盖坦德单抗(Gantenerumab)、加维莫单抗(Gavilimomab)、吉妥珠单抗奥佐米星(Gemtuzumabozogamicin)、加沃坦珠单抗(Gevokizumab)、吉仁土希单抗(Girentuximab)、维德汀单抗(Glembatumumab vedotin)、戈利木单抗(Golimumab)、戈利昔单抗(Gomiliximab)、古谢夫单抗(Guselkumab)、替伊立珠单抗(Ibalizumab)、替伊莫单抗(Ibritumomab tiuxetan)、依库单抗(Icrucumab)、Idarucizumab、伊戈伏单抗(Igovomab)、IMAB362、Imalumab、英西单抗(Imciromab)、英戈土珠单抗(Imgatuzumab)、英克拉库单抗(Inclacumab)、依坦希单抗(Indatuximab ravtansine)、Indusatumab vedotin、Inebilizumab、英利昔单抗(Infliximab)、伊诺莫单抗(Inolimomab)、伊珠单抗奥佐米星(Inotuzumab ozogamicin)、英妥木单抗(Intetumumab)、英妥木单抗(Ipilimumab)、英妥木单抗(Iratumumab)、Isatuximab依拓珠单抗(Itolizumab)、希凯珠单抗(Ixekizumab)、凯利昔单抗(Keliximab)、拉贝珠单抗(Labetuzumab)、拉姆帕力珠单抗(Lampalizumab)、Lanadelumab、Landogrozumab、Laprituximab emtansine、来金珠单抗(Lebrikizumab)、来马索单抗(Lemalesomab)、Lendalizumab、Lenzilumab、乐地单抗(Lerdelimumab)、来沙木单抗(Lexatumumab)、利韦单抗(Libivirumab)、Lifastuzumab vedotin、Ligelizumab、Lilotomab satetraxetan、林妥珠单抗(Lintuzumab)、立鲁单抗(Lirilumab)、罗德希珠单抗(Lodelcizumab)、Lokivetmab、劳乌土珠单抗(Lorvotuzumab mertansine)、鲁卡木单抗(Lucatumumab)、Lulizumab pegol、鲁昔单抗(Lumiliximab)、Lumretuzumab、MABp1,马帕木单抗(Mapatumumab)、马格土希单抗(Margetuximab)、马司莫单抗(Maslimomab)、马妥珠单抗(Matuzumab)、美力姆单抗(Mavrilimumab)、美泊利单抗(Mepolizumab)、美替木单抗(Metelimumab)、米拉珠单抗(Milatuzumab)、明瑞莫单抗(Minretumomab)、Mirvetuximabsoravtansine、米妥莫单抗(Mitumomab)、莫格穆里单抗(Mogamulizumab)、Monalizumab、莫罗木单抗(Morolimumab)、莫他珠单抗(Motavizumab)、莫希土姆单抗(Moxetumomabpasudotox)、莫罗单抗-CD3(Muromonab-CD3)、他那可单抗(Nacolomab tafenatox)、纳米路单抗(Namilumab)、他那莫单抗(Naptumomab estafenatox)、纳瑞特单抗(Narnatumab)、那他珠单抗(Natalizumab)、Navicixizumab、Navivumab、奈巴库单抗(Nebacumab)、奈昔木单抗(Necitumumab)、Nemolizumab、奈瑞莫单抗(Nerelimomab)、耐西维单抗(Nesvacumab)、尼妥珠单抗(Nimotuzumab)、妮威禄单抗(Nivolumab)、巯诺莫单抗(Nofetumomabmerpentan)、Obiltoxaximab、Obinutuzumab、奥卡土珠单抗(Ocaratuzumab)、奥瑞珠单抗(Ocrelizumab)、奥度莫单抗(Odulimomab)、奥法木单抗(Ofatumumab)、奥拉图单抗(Olaratumab)、奥鲁凯珠单抗(Olokizumab)、奥马珠单抗(Omalizumab)、欧那土珠单抗(Onartuzumab)、欧土希珠单抗(Ontuxizumab)、Opicinumab、莫奥珠单抗(Oportuzumabmonatox)、奥戈伏单抗(Oregovomab)、奥泰单抗(Orticumab)、奥昔珠单抗(Otelixizumab)、奥特乐土珠单抗(Otlertuzumab)、欧西鲁单抗(Oxelumab)、欧赞尼珠单抗(Ozanezumab)、欧咗立珠单抗(Ozoralizumab)、帕昔单抗(Pagibaximab)、帕利珠单抗(Palivizumab)、Pamrevlumab、帕利珠单抗(Panitumumab)、帕尼库单抗(Pankomab)、帕诺库单抗(Panobacumab)、帕萨土珠单抗(Parsatuzumab)、帕考珠单抗(Pascolizumab)、Pasotuxizumab、帕特立珠单抗(Pateclizumab)、帕图单抗(Patritumab)、Pembrolizumab、帕尼单抗(Pemtumomab)、培拉凯珠单抗(Perakizumab)、培妥珠单抗(Pertuzumab)、培克珠单抗(Pexelizumab)、皮地利珠单抗(Pidilizumab)、平尼土珠单抗(Pinatuzumabvedotin)、平妥莫单抗(Pintumomab)、普拉库鲁单抗(Placulumab)、普拉土珠单抗(Polatuzumab vedotin)、珀珠单抗(Ponezumab)、Prezalizumab、普立昔单抗(Priliximab)、普陀希单抗(Pritoxaximab)、普立木单抗(Pritumumab)、PRO 140、坤立珠单抗(Quilizumab)、雷库图单抗(Racotumomab)、雷德图单抗(Radretumab)、雷韦单抗(Rafivirumab)、Ralpancizumab、雷莫芦单抗(Ramucirumab)、雷珠单抗(Ranibizumab)、雷昔库单抗(Raxibacumab)、Refanezumab、瑞加韦单抗(Regavirumab)、瑞利珠单抗(Reslizumab)、利妥木单抗(Rilotumumab)、Rinucumab、Risankizumab、利妥昔单抗(Rituximab)、罗妥木单抗(Robatumumab)、罗勒杜单抗(Roledumab)、罗姆苏珠单抗(Romosozumab)、罗利珠单抗(Rontalizumab)、Rovalpituzumab tesirine、罗维珠单抗(Rovelizumab)、鲁利珠单抗(Ruplizumab)、Sacituzumab govitecan、沙玛立珠单抗(Samalizumab)、Sapelizumab沙鲁单抗(Sarilumab)、沙妥莫单抗(Satumomab pendetide)、司库钦单抗(Secukinumab)、司瑞斑图单抗(Seribantumab)、斯图希单抗(Setoxaximab)、司韦单抗(Sevirumab)、SGN-CD19A、SGN-CD33A、西罗珠单抗(Sibrotuzumab)、西法木单抗(Sifalimumab)、西图希单抗(Siltuximab)、西姆土珠单抗(Simtuzumab)、西利珠单抗(Siplizumab)、希瑞库单抗(Sirukumab)、Sofituzumab vedotin、苏兰珠单抗(Solanezumab)、苏力图单抗(Solitomab)、松普希珠单抗(Sonepcizumab)、松妥珠单抗(Sontuzumab)、司他芦单抗(Stamulumab)、硫索单抗(Sulesomab)、索维单抗(Suvizumab)、他贝鲁单抗(Tabalumab)、他珠单抗(Tacatuzumab tetraxetan)、他度珠单抗(Tadocizumab)、他利珠单抗(Talizumab)、Tamtuvetmab、他尼珠单抗(Tanezumab)、帕他莫单抗(Taplitumomab paptox)、Tarextumab、替非珠单抗(Tefibazumab)、阿替莫单抗(Telimomab aritox)、替妥莫单抗(Tenatumomab)、替奈昔单抗(Teneliximab)、替利珠单抗(Teplizumab)、替普单抗(Teprotumumab)、Tesidolumab、Tetulomab、Tezepelumab、TGN1412,替西木单抗(Ticilimumab)、替加珠单抗(Tigatuzumab Tildrakizumab)、Timolumab、Tisotumab vedotin、TNX-650、托珠单抗(Tocilizumab)、托利珠单抗(Toralizumab)、Tosatoxumab、托西莫单抗(Tositumomab)、托维图单抗(Tovetumab)、曲洛青木单抗(Tralokinumab)、曲妥珠单抗(Trastuzumab)、Trastuzumab emtansine、TRBS07、曲加立珠(Tregalizumab)、曲美木单抗(Tremelimumab)、Trevogrumab、西莫白介素单抗(Tucotuzumab celmoleukin)、妥韦单抗(Tuvirumab)、乌波利土西单抗(Ublituximab)、Ulocuplumab、乌瑞鲁单抗(Urelumab)、乌珠单抗(Urtoxazumab)、优特克单抗(Ustekinumab)、Utomilumab、Vadastuximab talirine、Vandortuzumab vedotin、伐提克图单抗(Vantictumab)、Vanucizumab、伐利昔单抗(Vapaliximab)、Varlilumab、维特立珠单抗(Vatelizumab)、维多珠单抗(Vedolizumab)、维妥珠单抗(Veltuzumab)、维帕莫单抗(Vepalimomab)、维西库单抗(Vesencumab)、维西珠单抗(Visilizumab)、Vobarilizumab、伏洛昔单抗(Volociximab)、伏妥土珠单抗(Vorsetuzumab mafodotin)、伏妥昔单抗(Votumumab)、Xentuzumab、扎芦木单抗(Zalutumumab)、扎木单抗(Zanolimumab)、扎土希单抗(Zatuximab)、齐拉木单抗(Ziralimumab)、阿佐莫单抗(Zolimomab aritox)和其组合。
目标可包括以下任何非限制性目标:-淀粉样蛋白、4-1BB、5AC、5T4、甲胎蛋白、促血管新生蛋白因子、AOC3、B7-H3、BAFF、c-MET、c-MYC、C242抗原、C5、CA-125、CCL11、CCR2、CCR4、CCR5、CD4、CD8、CD11、CD18、CD125、CD140a、CD127、CD15、CD152、CD140、CD19、CD2、CD20、CD22、CD23、CD25、CD27、CD274、CD276、CD28、CD3、CD30、CD33、CD37、CD38、CD4、CD40、CD41、CD44、CD47、CD5、CD51、CD52、CD56、CD6、CD74、CD80、CEA、CFD、CGRP、CLDN、CSF1R、CSF2、CTGF、CTLA-4、CXCR4、CXCR7、DKK1、DLL3、DLL4、DR5、EGFL7、EGFR、EPCAM、ERBB2、ERBB3、FAP、FGF23、FGFR1、GD2、GD3、GDF-8、GPNMB、GUCY2C、HER1、HER2、HGF、HIV-1、HSP90、ICAM-1、IFN-α、IFN-γ、IgE、CD221、IGF1、IGF2、IGHE、IL-1、IL2、IL-4、IL-5、IL-6、IL-6R、IL-9、IL-12、IL-15、IL-15R、IL-17、IL-13、IL-18、IL-1β、IL-22,、IL-23、IL23A、整合素、ITGA2、IGTB2、Lewis-Y抗原、LFA-1、LOXL2、LTA、MCP-1、MIF、MS5A1、MUC1、MUC16、MSLN、人肌肉生长抑制素、MMP超家族、NCA-90、NFG、NOGO-A、Notch1、NRP1、OX-40、OX-40L、P2X超家族、PCSK9、PD-1、PD-L1、PDCD1、PDGF-R、RANKL、RHD、RON、TRN4、血清白蛋白、SDC1、SLAMF7、SIRPα、SOST、SHP1、SHP2、STEAP1、TAG-72、TEM1、TIGIT、TFPI、TGF-β、TNF-α、TNF超家族、TRAIL超家族、Toll样受体、WNT超家族、VEGF-A、VEGFR-1、VWF、巨细胞病毒(CMV)、呼吸道合胞体病毒(RSV)、乙型肝炎、丙型肝炎、甲型流感血凝素、狂犬病毒(RV)、人类免疫缺陷病毒(HIV)、单纯疱疹病毒(HSV)和其组合。
除了本文公开的CH3结构域中的特定五个氨基酸置换之外,本公开的异源二聚体构建体可以具有一个或多个置换、缺失、添加和/或插入。例如,某些氨基酸可以置换在蛋白质结构中的其它氨基酸而没有明显损失与其它多肽(如抗原)或细胞结合的能力。由于结合能力和蛋白性质决定了蛋白的生物功能活性,可以在蛋白序列上进行某些氨基酸序列的置换而不会明显损失它们的生物效用或活性。在许多情况中,多肽变体含有一个或多个保守置换。
本公开的异源二聚体构建体可以包括药学上可接受的载体,赋形剂或溶剂的药物组合物的形式提供。所述组合物可任选地含有一种或多种另外的药物活性成分,例如另一种抗体或治疗剂。本公开的药物组合物还可以与,例如,另一种免疫刺激剂,抗癌剂,抗病毒剂或疫苗等组合疗法给药。在某些实施例中,所述组合物包括浓度为至少1mg/mL、5mg/mL、10mg/mL、50mg/mL、100mg/mL、150mg/mL或200mg/mL的异源二聚体。在一些实施例中,异源二聚体的浓度可以是1-300mg/mL或100-300mg/mL。
药物组合物可包括任何数量的赋形剂。可以使用的赋形剂包括载体、表面活性剂,增稠剂或乳化剂、固体粘合剂、分散剂或悬浮助剂、增溶剂、着色剂、调味剂、包衣剂、崩解剂、润滑剂、甜味剂、防腐剂、等渗剂和其组合。赋形剂的选择和使用是根据Gennaro,ed.,雷明登:药学的科学与实践(Remington:The Science and Practice of Pharmacy),20thEd.(Lippincott Williams&Wilkins 2003)所述,其公开内容通过引用并入本文。
优选地,药物组合物适用于静脉内,肌肉内,皮下,肠胃外(parenteral),脊柱或表皮施用(例如,通过注射或输注)。根据施用途径,活性化合物可以涂覆在材料中以保护其免受酸和其它自然条件可能使其失活。本文所用的术语"肠胃外施用(parenteraladministration)"是指除肠内和局部给药以外的给药方式,通常通注射,包括但不限于通过静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管内、皮下、表皮下、关节内、包膜下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注。另外,本文所述的抗体可以通过非肠胃外途径施用,例如,局部,表皮或粘膜途径施用,如鼻内,口服,阴道,直肠,舌下或局部施用。
本发明的药物组合物可以是药学上可接受的盐的形式。“药学上可接受的盐(pharmaceutically acceptable salt)”是指保留母体化合物的所需生物活性并且不产生任何不期望的毒理学作用的盐。这些盐的实例包括酸加成盐和碱加成盐。酸加成盐包括衍生自无毒无机酸的盐,例如,盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、磷等,和衍生自无毒有机酸,例如,脂肪族单体和二羧酸、苯基-取代的链烷酸、羟基链烷酸、芳族酸、脂族和芳族磺酸等。碱加成盐包括衍生自碱土金属的盐,例如,钠、钾、镁、钙等,和衍生自无毒有机胺,例如,N'N'-二苄基乙二胺、N-甲基-D-葡糖胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺和普鲁卡因等。
药学上可接受的组合物可以是液体形式或固体形式。固体制剂通常但不是必须冻干并在给药前加入溶液中进行单次或多次给药。所述制剂不应暴露于极端温度或pH值以避免热变性。因此,本公开的抗体组合物应制剂在生物学相关的pH范围内。通常需要缓冲溶液以在储存期间保持适当的pH范围,特别是对于在制剂和给药之间储存较长时间的液体制剂。通常,液体和固体制剂都需要在较低温度(通常为2-8℃)下储存,以保持较长时间的稳定性。制剂成的抗体组合物尤其是液体制剂,可能含有抑菌剂以防止或减少储存期间的蛋白质水解,其包括但不限于苯甲醇、苯酚、甲苯酚、氯丁醇、羟苯甲酯和/或对羟基苯甲酸丙酯的有效浓度(通常<1%w/v)。对于一些患者,抑菌剂可能是不当。因此,冻干制剂可以在含有或不含有这种成分的溶液中重构。可以将其他组分添加到缓冲液体或固体抗体制剂中,包括但不限于作为冷冻保护剂的糖(包括但不限于多羟基烃如山梨糖醇,甘露醇,甘油和半乳糖醇和/或二糖如蔗糖,乳糖,麦芽糖或海藻糖)和在某些情况下包括但不限于相关的盐(包括但不限于NaCl、KCl或LiCl)。这种抗体制剂特别是长期储存的液体制剂,将依赖于有用的总渗透压范围,以在2℃至8℃,或更高的温度下促进长期稳定性,并同时使该制剂可用于肠胃外注射。例如,但不一定,总渗透压的有效范围(溶液中的分子总数)可以为约200mOs/L至约800mOs/L。显而易见的是,诸如蔗糖或山梨糖醇的细胞保护剂的量将取决于制剂中盐的量,以使溶液的总渗透压保持在合适的范围内。因此,无盐制剂可以但不是必须含有约5%至约25%的蔗糖。
或者,无盐山梨糖醇基制剂可以但不是必须含有约3%至约12%的山梨糖醇。当然,无盐制剂将保证各个冷冻保护剂的范围增加,以保持有效的渗透压水平。这些配方还可含有二价阳离子(包括但不限于MgCl2,CaCl2)非离子型表面活性剂(包括但不限于聚山梨酯(吐温80)、聚山梨酯/>(吐温60)、聚山梨酯/>(吐温400)和聚山梨酯/>(吐温20)、聚氧乙烯烷基醚、包括但不限于Brij/>Brij/>和其他如Triton/>Triton X/> Span 85和Pluronic系列非离子表面活性剂(例如Pluronic121))。这些组分的任何可能包括抑菌剂的组合可用于填充本公开的含抗体制剂。本公开的异源二聚体还可以是“化学衍生物”,描述了含有额外化学部分的抗体,所述化学部分通常不是免疫球蛋白分子的一部分(例如聚乙二醇化)。这些部分可以改善基础分子的溶解度,半衰期,吸收等。或者,所述部分可以减弱基础分子的不良副作用或降低基础分子的毒性。本发明的药物组合物可以是无菌水性溶液或分散液的形式。本公开的药物组合物还可以配制成微乳液,脂质体或适于高药物浓度的其他有序结构。
本公开的异源二聚体构建体能够同时结合多个靶分子,因此在治疗复杂疾病方面更有效。本公开的异源二聚体构建体可以施用于需要其的受试者以治疗疾病或病症,例如,病毒或细菌感染、代谢或自身免疫疾病,或癌症或其他细胞增殖性疾病。在一些实施例中,所述自身免疫性疾病包括关节炎、风湿性关节炎、银屑病、多发性硬化症(MS)、溃疡性结肠炎、克罗恩病、系统性红斑狼疮(SLE)、肾小球肾炎、扩张型心肌病样疾病、斯耶格伦氏综合征、过敏性接触性皮炎、多肌炎、硬皮病、动脉周性多动脉炎、风湿热、白癜风、胰岛素依赖性糖尿病、白塞氏综合征、慢性甲状腺炎和其组合中的至少一种。在一些实施例中,所述神经退行性疾病包括帕金森氏病、亨廷顿氏病、马查多-约瑟夫病、肌萎缩性侧索硬化症(ALS)、克罗伊茨费尔特-雅各布病和其组合中的至少一种。在一些实施例中,所述肿瘤和细胞增生性疾病包括白血病、淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌(NSCLC)、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤和其组合中的至少一种。
本公开另外涉及编码本公开的异源二聚体构建体的一种或多种多肽的一种或多种核酸。核酸可编码SEQ ID NO:16-31、33、35、37、39、41、43、45、48、49、51、53、55、57、59、61、63、68、69、70和71中的任一个。在一些实施例中,核酸可包括SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64至67中的任一个。还包括与SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、和64至67中的任一个共享至少70%的序列同一性的变体序列。例如至少75%、80%、85%、90%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%、99.9%或更好的序列同一性。变体核酸序列可以是密码子喜好优化的。如本文所用,密码子优化是指核酸的体外诱变,以增加或最大化基因的表达(例如,相对于未修饰的核酸的转基因,没有改变(或具有最小的改变)对合成蛋白质的氨基酸序列,即同义突变)。密码子优化可以影响蛋白质表达率高达1,000倍,特别是通过倾向于有效的可溶性蛋白质表达。改变的密码子通常是宿主细胞翻译系统通常不使用的密码子。
在本公开发明范围内,提供了能够在中度至高度严格条件下与本本公开的核酸或片段(或互补序列)杂交的核酸序列。杂交技术是分子生物学领域公知的。例如,合适测试的条件包括在5×SSC、0.5%SDS、1.0mM EDTA(pH8.0)的溶液中预洗;在50-60℃、5×SSC、过夜的条件下杂交;再于在20分钟下用含0.1%SDS溶液的2×、0.5×和0.2×的SSC各洗涤两次。另外,合适的高严格杂交条件包括上述的条件,所不同的是杂交温度升高了,例如达到60-65℃或65-70℃。
本公开的核酸可以包括在载体或载体系统中。所述载体可以是,例如,但不一定是质粒。其他明确的非限制性的重组载体可包括穿梭载体和表达载体。通常,质粒构建体也包括复制起点(如复制的ColE1起点)和选择标记(如氨苄青霉素或四环素抗性)。“表达载体”是指包括例如表达本公开的异源二聚体构建体所需要的控制序列或调控元件的载体。其他明确的非限制性的重组载体是本领域已知的,可包括,例如,如λ噬菌体的噬菌体载体、如非复制型腺病毒载体的其他病毒载体、慢病毒载体、pSV、pCMV系列质粒载体、牛痘和逆转录病毒载体、杆状病毒载体、粘粒和人工染色体。所述载体可以是哺乳动物表达载体。例如,载体可以转染到哺乳动物细胞中,并且在稳定转染的情况下,DNA可以通过同源重组整合到基因组中,或者,可以瞬时转染细胞。大多数工程化载体的共同点是复制起始位点、多克隆位点和选择标记,因此只要载体(包括载体系统,例如多个质粒)含有这样的系统,它们就被认为是本发明的范围所涵盖的。哺乳动物表达载体的常见启动子包括CMV和SV40启动子。非病毒启动子如EF-1启动子也是已知的。示例性载体包括基于pCDNA改造得到的质粒载体pX0GC。
本公开还体现了含有根据本发公开一方面的载体或载体系统的宿主细胞。本领域普通技术人员将理解,不同的细胞类型可能导致不同的异源二聚体构建体产物,并且可能影响产物的治疗功效。例如,宿主细胞可以(但不一定)包括以下细胞类型中的任何一种:人胚肾细胞HEK293或以HEK293细胞为基础改造而得到的HEK293T、HEK293E、HEK293F、中国仓鼠卵巢细胞CHO或以CHO细胞为基础改造而得到的CHO-S、CHO-dhfr-、CHO/DG44、ExpiCHO,和相关细胞系。本领域已知的其他细胞系包括NS0鼠骨髓瘤细胞、PER.C6人细胞、酵母细胞如酿酒酵母(S.cerevisiae)、裂殖酵母(S.pombe)和毕赤酵母(P.pastoris),和菌细胞如大肠杆菌。无细胞表达系统也存在,例如,基于大肠杆菌细胞裂解物,含有转录/翻译所必需的细胞组分。真核和哺乳动物无细胞系统在本领域中也是已知的,例如,小麦胚无细胞表达系统,和Brodel et al.(2015),Methods Mol Bio.1261:129-40中所述的,通过引用整体并入本文。一些重组抗体生成系统在收获前在宿主细胞表面上表达重组抗体,而其他重组抗体生成系统仅将抗体释放到用于收集的培养基中。这些变化旨在落入本公开的范围内。
如本文所用,术语“抗体”(Ab)以最广义使用并具体地可包括任何免疫球蛋白,无论是天然的还是部分或完全合成产生的,包括但不限于单克隆抗体,多克隆抗体,多特异性抗体(例如,双特异性抗体和多反应性抗体)和抗体片段。因此,本公开中使用的术语“抗体”意在包括但不限于任何特异性结合成员、免疫球蛋白类和/或同种型(例如,IgG1、IgG2a、IgG2b、IgG3、IgG4、IgM、IgA1、IgA2、IgD,和IgE)和生物相关片段或其特异性结合成员,其包括但不限于Fab、F(ab′)2、scFv(单链或相关实体)和(scFv)2。
如本文所用,术语“抗体片段”可包括使用本领域普通技术人员容易已知和可获得的技术获得的那些抗体片段,如本文所述。因此,除了上文所述的“抗体”的定义之外,术语“抗体”还可包括任何包括完整抗体的一部分的多肽或蛋白质,例如完整抗体的抗原结合区或可变区。这些可以源自天然来源,或者它们可以部分或完全合成产生。抗体片段的实例包括但不限于Fab、Fab'、F(ab′)2、和Fv片段;双抗体和线性抗体。
本文所用,术语"抗体依赖的细胞介导的细胞毒性作用"或"ADCC"可以指细胞介导的反应,其中,表达FcR(如自然杀伤(NK)细胞、中性白细胞和巨噬细胞)的细胞毒性细胞(例如,非特异性的)识别靶细胞上的结合抗体,随后引起靶细胞的裂解。介导ADCC的原代细胞NK细胞表达FcγRIII,而单核细胞表达FcγRI、FcγRII和FcγRIII。
如本文所用,术语“双特异性抗体”是指具有结合单个抗原或两种不同抗原上的两个不同表位的能力的抗体。表位可以由邻接氨基酸(线性表位)或由蛋白质的三级折叠并置的非邻接氨基酸(构象表位)形成。由邻接氨基酸形成的表位通常在暴露于变性溶剂时保留,而通过三级折叠形成的表位通常在用变性溶剂处理时损失。表位通常包括独特空间构象中的至少3个,更通常是,至少5或至少8至10个氨基酸。本公开的双特异性抗体可以是二价、三价或四价的。如本文所用,"价的(valent)"、"价(valence)"、"多价(valencies)"或其他"价"的语法变体是指抗体分子中抗原结合位点的数目。这些抗原识别位点可识别相同的表位或不同的表位。
如本文所用,术语“载体(carriers)”可包括药学上可接受的载体,赋形剂或稳定剂,其在所用剂量(dosage))和浓度对细胞或哺乳动物无毒。药学上可接受的载体通常是水性pH缓冲溶液。生理学上可接受的载体的实例包括但不限于:如磷酸盐,柠檬酸盐和其他有机酸的缓冲剂;抗氧化剂包括但不限于抗坏血酸;低分子量(少于约10个残基)多肽;蛋白质,例如但不限于血清白蛋白,明胶或免疫球蛋白;亲水性聚合物,例如但不限于聚乙烯吡咯烷酮;氨基酸,例如但不限于甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸;单糖,二糖和其他碳水化合物,包括但不限于葡萄糖,甘露糖或糊精;螯合剂,例如但不限于EDTA;糖醇,例如但不限于甘露醇或山梨糖醇;成盐抗衡离子,例如但不限于钠;和/或非离子表面活性剂,例如但不限于TWEEN;聚乙二醇(PEG)和普流罗尼类(PLURONICS)。这些组分的任何组合其可能包括抑菌剂,可用于填充本公开的制剂。
如本文所用的术语“保守序列修饰(conservative sequence modifications)”或“保守置换(conservative substitutions)"可以指对本公开的靶表位或抗体和其抗原结合部分的氨基酸修饰,其不显着影响或改变本公开的异源二聚体免疫球蛋白构建体的结合特征。这种保守修饰包括氨基酸置换,添加和缺失。可以通过本领域已知的标准技术将修饰引入本公开的抗体中,例如,定点突变(site-directed mutagenesis)和PCR介导的突变。保守氨基酸置换是指一个氨基酸残基被具有相似侧链的氨基酸残基所置换。氨基酸置换通常是基于氨基酸侧链取代基的相对相似性,如它们的疏水性、亲水性、电荷、大小等。本领域已经定义了具有相似侧链的氨基酸残基家族。这些家族包括具有碱性侧链的氨基酸(例如,赖氨酸、精氨酸、组氨酸)、酸性侧链的氨基酸(例如,天冬氨酸、谷氨酸)、不带电荷的极性侧链的氨基酸(例如,甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链的氨基酸(例如,丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链的氨基酸(例如,苏氨酸、缬氨酸、异亮氨酸)和芳香侧链的氨基酸(例如,酪氨酸、苯丙氨酸、色氨酸、组氨酸)。
如本文所用,术语“细胞外结构域”或“膜受体的细胞外结构域”是指分子识别序列通常,其包括识别和结合相应抗原或配体的细胞外的细胞外区域,将受体锚定在细胞表面的跨膜结构域上,并参与具有细胞内激酶活性或信号传导途径的细胞内结构域。配体可以指蛋白质,小肽或能被膜受体细胞外结构域识别并结合的化合物。免疫原、丝裂原或其他刺激剂可以诱导多种细胞产生的低分子量可溶性蛋白质。其可以调节固有免疫和适应性免疫、血细胞生成、细胞生长、APSC多能细胞和损伤组织修复。细胞因子可被分为白细胞介素、干扰素、肿瘤坏死因子超家族、集落刺激因子、趋化因子、生长因子。蛋白表达标签指在目标蛋白的N端或C端加入的一段氨基酸序列,可以是小肽也可以是长的氨基酸。标签的加入可以有利于蛋白质的正确折叠,并可以有利于蛋白质的分离纯化。标签的加入更可以有利于降低蛋白质在细胞内的降解。常用的标签包括但不限于HA,SUMO,His,GST,GFP,和Flag。
如本文所用,术语“Fab片段”可以指识别部分,其是抗原结合片段(fragment ofantigen binding,Fab)相当于抗体分子的两个臂,其一个完整的轻链和重链的VH和CH1结构域组成。
如本文所用,术语“Fc”是指"可结晶片段(fragment crystallizable)区域,其由CH2和CH3恒定结构域组成,并且是与效应分子或细胞(例如Fc受体)相互作用的免疫球蛋白的相互作用区域。
如本文所用,术语“Fc受体”或“FcR”用于描述结合Fc区的受体(例如抗体或抗体片段的Fc区)。术语“Fc受体”或“FcR”包括新生受体(FcRn),其负责将母体IgG转移至胎儿。其他Fc受体包括FcγRI、FcγRIIA、FcγRIIB1、FcγRIIB2、FcγRIIIA、FcγRIIIB、FcεRI、FcεRII、FcαRI和Fcα/μR中的任何一种。
本发明使用的术语“同源性(homology)”可以指两种组合物之间存在共有结构。蛋白质的“同源性”可以指两个或更多个氨基酸和/或肽序列之间重叠的量(例如,以百分比表示)。核酸的“同源性”可以指两个或更多个核酸序列之间重叠的量(例如,以百分比表示)。如本文所用,两个序列之间的百分比(%)同源性等同于两个序列之间的同一性百分比。两个序列之间的同一性百分比是序列共有的相同位置的数量的函数(即%同源性=#相同位置的数量/位置总数#×100)考虑到间隙的数量和长度需要引入每个间隙以得到两个序列的最佳比对。可以使用数学算法完成序列的比较和两个序列之间的同一性百分比的确定。通过局部比对工具和/或算法在本领域中充分表示了这种同源性,并且可以包括双序列比对,多序列比对方法,结构比对方法和/或系统发育分析方法。当序列在保守置换不同时,序列同一性百分比可以(但不一定)向上调整以校正置换的保守性质。进行这种调整的方法是本领域技术人员所熟知的。通常,但不是必须的,这涉及将保守置换评分为部分而非完全错配,从而增加序列同一性百分比。因此,例如,当给予相同的氨基酸得分为1且非保守置换得分为零时,保守置换得分为0和1之间的得分。
如本文所用,术语“免疫球蛋白(immunoglobulin)”是指具有四条多肽链的对称结构,其中两条较长、相对分子量较大的重链,含450~550个氨基酸残基,相对分子质量在55,000~70,000Da之间;两条较短、相对分子量较小的轻链(L链),含约210个氨基酸残基,相对分子质量约24,000Da。不同的免疫球蛋白重链和轻链在靠近N端的约110个氨基酸的序列变化很大,称为可变区(variable region,V区),而靠近C端的其余氨基酸序列相对稳定,称为恒定区(constant region,C区)。重链中可变区约占重链长度的1/4,恒定区约占重链长度的3/4。IgG在H链内具有三个恒定区,称为CH1、CH2和CH3。恒定区既是免疫球蛋白分子的骨 架,又是激活免疫反应的部位之一。本发明中的恒定区涉及第一多肽和第二多肽相互作用的区域,其中该区域包括位于CH3区域的氨基酸。这些氨基酸包括但不限于:GLN347、TYR349、THR 350、LEU 351、SER 354、ARG 355、ASP 356、GLU 357、LYS 360、SER 364、THR366、LEU 368、LYS 370、ASN390、LYS392、THR394、PRO395、VAL 397、ASP399、SER400、PHE405、TYR407、LYS409、和LYS439。
如本文所用,术语“纯化的(purified)”或“分离的(isolated)”抗体、肽、多肽或蛋白质可以指已与天然关联的其他蛋白质,脂质和核酸分离的肽、多肽或蛋白质。多肽/蛋白质可佔至少10%(即,10%至100%之间的任何百分比,例如20%、30%、40%、50%、60%、70%、80%、85%、90%、95%和99%)的纯化制剂的干重。纯度可以通过任何合适的标准方法测量,例如,通过柱色谱,聚丙烯酰胺凝胶电泳或HPLC分析。
如本文所用,术语“scFv”可以指单链可变片段。scFv是免疫球蛋白的重链(VH)和轻链(VL)的可变区的融合蛋白,其与连接肽连接。连接肽的长度可为约5至40个氨基酸或约10至30个氨基酸或约5、10、15、20、25、30、35或40个氨基酸。示例性连接肽是GGGGSGGGGSGGGGS(SEQ ID NO:72)。
术语“特异性的结合(specific binding)”、“选择性的结合(selectivebinding)”、“选择性结合(selectively binds)”和“特异性结合(specifically binds)”可以指抗体结合预定抗原上的表位但不结合其他抗原。通常,抗体以约小于10-6M的平衡解离常数(KD)结合,例如约小于10 -7M、10 -8M、10-9M或10-10M或甚至更低当通过,例如,平衡透析或使用预定抗原(例如,Her2,PD-L1,Trop2,CD3和/或CD20上的表位)作为分析物和抗体作为配体的2000表面等离子体共振仪器中的表面等离子体共振(SPR)技术,或抗体与抗原阳性细胞结合的Scatchard分析,和(ii)与预定抗原结合的亲和力比其与预定抗原或密切相关抗原以外的非特异性抗原(例如BSA,酪蛋白)结合的亲和力大至少两倍。
如本文所用,术语“受试者(subject)”或“患者(patient)”可以指可以施用治疗的生物系统。生物系统可包括例如单个细胞,一组细胞(例如细胞培养物),器官,组织或多细胞生物。本公开的受试者可包括鸟类,爬行动物,哺乳动物等。优选地,哺乳动物包括啮齿动物和灵长类动物,包括人。
如本文所用,术语“治疗的(treating)”或“治疗(treatment)”疾病可以指执行方案,其可以包括向患者(人或其他)施用一种或多种药物,以致力缓解疾病的体征或症状。缓解可以在疾病出现的症状或体征之前和出现之后发生。因此,“治疗的(preventing)”或“治疗(prevention)”包括“预防的”或“预防”疾病。另外,“治疗的”或“治疗”不需要完全缓解体征或症状和不需要治愈,并且具体包括可能对患者仅具有边际效应的方案。
如本文所用,术语“变体Fc区(variant Fc region)”是指通过至少一个氨基酸修饰(例如,替換,插入或缺失)而不同于天然序列Fc区(或其部分)的氨基酸序列,“变体Fc区”包括异源二聚体变体,其中重链亚基序列可以彼此不同。本公开的示例性氨基酸修饰包括CH3区域中的T366L,D399R,L351E,Y407L和/或K409V。
在本公开中和所附权利要求中,除非上下文另有明确规定,否则单数形式“a”,“and”和“the”包括复数形式
术语“约(about)”是指本领域普通技术人员不认为与基线值显着不同的一系列值。例如,术语“约”可以指在规定值的20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%或0.01%范围内的值,和这些规定值的期间值上下文将定义的值。
如本文所用的术语“结合成员”是指试剂,例如,特异性结合靶,例如Fc受体的蛋白质或蛋白质复合物(例如抗体或其片段),小分子等。Fc受体结合成员是指特异性结合Fc受体的试剂。术语“特异性的结合(specific binding)”,“特异性结合(specificallybinds)”等是指相对于溶液或反应混合物中的其他分子或部分的分子优先结合。在一些实施例中,结合成员与其特异性结合的靶标之间的亲和力的特征在于10-6M或更低的Kd(解离常数),例如,10-7M、10-8M、10-9M、10-10M或更低。
如本文所用,术语“识别部分(recognition moieties)”是指可以高度选择性与目标分子(如抗原、配体、受体、底物)发生特异性相互作用的试剂区域。代表性识别部分包括:抗体的可变区、抗体可变区的结构变体、受体的结合域、配体结合域或酶的结合域。在本公开中,识别部分被鉴定为与其关联的链的同源识别部分。取决于背景和环境,该关联在本质上可以是共价的或非共价的。例如,本公开的双特异性异源二聚体抗体具有与其各自的链共价连接的识别部分,而这种双特异性抗体的半聚体可以在充分还原的条件下至少部分地与组成链非共价结合。
如本文所用,术语“生理状况(physiological condition)”或“多个生理状况(physiological conditions)”是指自然界中可能发生生物体或细胞系统的周围环境的条件或多个条件,或允许某些变量(例如温度)超出生物体中可观察到的典型范围的条件,但仍然支持本公开的双特异性异源二聚体抗体的一些功能。生理条件的非限制性实例是通常在诸如哺乳动物细胞的细胞中或周围所发现的温度,离子强度(例如,Ca2+或Mg2+),pH和浓度。温度范围约2℃至40℃(例如20℃至40℃)、大气压约1、pH值约为6-8,葡萄糖浓度约1mM至20mM、约大气氧浓度和地球重力也是生理条件的例子。如本文所用,该术语还可以与表征病症的其他特定限制组合。应理解,在这种情况下,该术语应在如此表征的条件的范围内被适当地解释。例如,当本文描述将水性溶液在生理条件下并充分还原,例如含有1mM二硫苏糖醇时,例如在磷酸盐缓冲盐水(PBS)中在2℃至4℃下用1mM二硫苏糖醇,这并不意味着这即使在存在还原剂的情况下,整体溶液实际上支持抗体的功能,但是这意味着除了二硫苏糖醇之外,溶液中的其余元素或变量位于被认为是支持的范围内。
如本文所用,术语“基本上不含(essentially free)”是指特定组分的含量,例如多肽,其在使本领域技术人员已知的常规检测方法和方案下是检测不到的,例如,蛋白质印迹法(Western Blot)、酶联免疫吸附实验(ELISA)、放射免疫分析(RIA)、高效液相色谱法(HPLC)(包括手性HPLC、手性HPLC/MS和LC/MS/MS等)、薄层分析法、质谱法、旋光度测定法、气相色谱-质谱法或其他。
本文公开的出版物仅是为了在本公开的提交日之前的公开内容而提供的。本文中的任何内容均不应被解释为承认本公开无权先于此类出版物。此外,提供的出版日期可能与可能需要独立确认的实际出版日期不同。
本文中引用的每个申请和专利,和每个申请和专利中引用的每个文件或参考文献,专利或非专利文献(包括在每个已发布专利的起诉期间;“申请引用文件”)和与这些申请和专利中的任何一个相对应和/或要求优先权的每个PCT和外国申请或专利,和在每个申请的引用文献中所引用或参考的每个文献在此通过引用全部明确地并入本文。更普遍地,在本文中引用的文件或参考文献,不论在权利声明书之前的参考文献清单中,还是在文本本身,和每一个这些文献或参考文献(“本文引用的参考文献”),和在本文引用的每篇参考文献(包括任何制造商的说明书,指示书等)中引用的每篇文献或参考文献在此明确地并入本文。
下面将通过下述非限制性实施例进一步说明本公开。
VII.实施例
实施例1,用于筛选异源二聚体分子的突变位点
在IgG1重链区的CH3结构域中引入突变以促进异源二聚体化。根据文献J.Biol.Chem.2010,285:19637-19646,,通过引用整体并入本文,分析抗体IgG1的两个同源CH3结构域(以下表示为CH3-A和CH3-B)之间相互作用中起重要作用的氨基酸。通过ProteinData Bank(PDB)数据库,搜索27个抗体序列,并且氨基酸基于接触方法的标准进行筛选,其中界面残基被定义为其侧链重原子距离第二链中任何残基的重原子的规定极限小于4.5A的位置的残基。
另外通过丙氨酸突变筛选CH3界面中的氨基酸,并通过盐酸胍变性的方法检测解离和去折叠的自由能,以找到与野生型相比对自由能影响最大的氨基酸。结果表明,366位苏氨酸、368位亮氨酸、405位苯丙氨酸、407位酪氨酸、409位赖氨酸突变后的自由能变化大于2kcal/mol,参见Biochemistry.1998Jun 30;37(26):9266-73,通过引用整体并入本文。界面上氨基酸的距离用Pymol或DS软件另外进行了分析,结果见表1。界面间的氢键以斜体和下划线表示。基于CH3界面上相互作用的氨基酸的距离和丙氨酸突变扫描结果,选择以下突变位点以促进异源二聚体的形成:第一条多肽上/CH3结构域中的苏氨酸366和天冬氨酸399,和第二条多肽上/CH3结构域中的亮氨酸351,酪氨酸407和赖氨酸409。
表1.CH3界面上重原子距离
实施例2-Fc异源二聚体真核细胞展示文库的构建
2.1-Fc异源二聚体展示载体的构建
Fc异源二聚体的展示载体pDis3是基于展示载体pDisplay(Invitrogen,货号V66020)进行改造得到的。首先将pDisplay载体进行NotI(NEB,货号R0189S)与SfiI(NEB,货号R-0123S)酶切,将载体上的myc和PDGFR基因去掉。以pDisplay质粒为模版,扩增出多克隆位点序列。上游引物为TGGGGCCCAGCCGGCCAGATCT(SEQ ID NO:1),下游引物为ATAAGAATGCGGCCGCGTCGACCTGCA(SEQ ID NO:2)。上下游引物分别带有SfiI和NotI酶切位点。多克隆位点序列经SfiI与NotI酶切后,插入到上述酶切过的载体中。结果得到载体中间产物载体pDis。
通过以下方法将pDis内的F1 ori基因去除和插入Orip。以载体pTT5(Biovetor,货号3574108)为模版,通过使用以下引物扩增出Orip基因片段,所述引物含有SspI(NEB,Cat.No.R1032S)酶切位点:5-ATCGAGTCAATATTAGGGTTAGTAAAAGGGTCCTAAGGAAC(SEQ ID NO:3)和5-CAGTCGATAATATTAAGAATTAATTCTCATGTTTGACAGCTTAT(SEQ ID NO:4)。然后将Orip基因经SspI酶切后,连接到上述SspI酶切过的pDis载体中。结果得到载体中间产物pDis1载体。将中间载体pDis1经AvrII(NEB,货号R0174S)酶切,去除Neo抗性基因片段。通过用以下引物扩增pCEP4(Invitrogen,货号V04450)插入hygro抗性基因并添加AvrII酶切位,上游引物为,TAGCCTCCCCCTAGGGTGGGCGAAGAACTCCAGCATG(SEQ ID NO:5),下游引物为,TTTGGAGGCCTAGGCTTTTGCAAAGATCGATCAAGAGACAGGATGAGGA(SEQ ID NO:6)。hygro抗性基因经酶切后,插入上述pDis1载体中得到中间载体pDis2。
一段DNA序列(SEQ ID NO:7)由中国苏州金唯智合成。在此DNA片段上,从左至右依次为SUMO基因(来源,ChampionTM pET SUMO载体,Invitrogen,cat.No.K30001),人Fc基因(命名为Fc1,含有CH3-A结构域),牛生长激素(BGH)多腺苷酸化信号,信号肽基因(来源,pDisplay载体),流感血凝素(HA)基因(Genbank登录号:NC_007362.1,第98位氨基酸到第106位氨基酸),和人Fc基因序列(命名为Fc2,含有CH3-B结构域)。整条基因序列的两端分别有SfiI与PstI酶切位点。Fc序列,SUMO序列和HA序列按哺乳物细胞的密码子喜好进行优化。Fc1基因序列中有BglII与SacII酶切位点,Fc2基因序列中含有BsrGI与SalI的酶切位点。并且这些酶切位点的存在不改变Fc的氨基酸序列。将合成的基因序列与pDis2分别用SfiI与PstI进行酶切,联接pDis2后得到最终载体pDis3,结构见图1。
2.2异源二聚体Fc库的构建
pUC57-TCZHC(苏州金唯智)含有天然的人Fc基因序列。通过简并密码子NNS的简并引物扩增pUC57-TCZHC以制备第一段定点随机化Fc序列,使得Fc1的第366位氨基酸和第399位氨基酸随机突变为20种不同的天然氨基酸。上游引物为TCCCAGCCGGGATGAGCTGACCAAGAACCAAGTCTCCCTCNNSTGCCTGGTCAAGGGATTCTACCCTTC(SEQ ID NO:8),和下游引物为GTCCACGGTGAGCTTGGAGTACAGGAAGAAGGATCCGTCGCTSNNCAGGACGGGGGGGGTTGTCTT(SEQ ID NO:9)
用以下引物从pUC57-TCZHC扩增第二Fc基因,上游引物为TACTCCAAGCTCACCGTGGACAAGAGC(SEQ ID NO:10),和下游引物为CGATCCAATCGATGGAAGATCTTCATCATTTGCCGGGGCTGAGGCTCAGGCT(SEQ ID NO:11)。
使用以下引物通过重叠延伸将定点随机化的Fc1片段连接起来,引物为5'-CAAGGGCCAGCCGCGGGAACCTCAAGTGTATACCCTCCCTCCCAGCCGGGATGAGCTGACCAAGAACCAA(SEQ ID NO:12)和5'-CGATCCAATCGATGGAAGATCTTCATCATTTGCCGGGGCTGAGGCTCAGGCT(SEQ ID NO:13)。
所述Fc1片段通过BglII(NEB,货号R0144S)与SacII(NEB,货号R0157S)限制性位点亚克隆到pDis3载体中。通过电穿孔装置(Biorad,Gene Pulser Xcell)将脱盐的构建体转化到大肠杆菌Top10菌株细胞中。
将转化体涂在含有浓度100mg/L氨苄青霉素的选择性琼脂培养基上。通过计算菌落数来计算突变库的容量。随机挑选20个菌落并通过DNA序列验证插入的种类。直至通过重复电穿孔达到10^5个容量,以得到Fc1定点随机突变库。
通过质粒提取试剂盒(Qiagen,货号27106)提取Fc1定点随机突变库。所述Fc1定点随机突变库用作Fc1+Fc2定点随机突变库构建的模板。使用简并引物将定点随机突变Fc2片段克隆到Fc1定点随机突变库以分别添加BsrGI和SalI限制性位点5'和3'。
引物两端带有BsrGI和SalI位点。在引物中通过NNS简并密码子将Fc片段中的第351位氨基酸,第407位的氨基酸和第409位氨基酸随机突变为20种不同的天然氨基酸。Fc2片段和线性化的Fc2载体(通过BsrGI(NEB,货号R3575L)和SalI(NEB,货号R3138L)酶切)用电穿孔装置(Bio-Rad Gene Pulser Xcell)共同转化入大肠杆菌Top10中。
将转化体涂在含有浓度100mg/L氨苄青霉素的选择性琼脂培养基上。直至通过重复电转操作至库容达3X10^8个克隆,以得到Fc1+Fc2定点随机突变库。异源二聚体Fc库的构建流程见图2。使用QIAGEN质粒Plus 96试剂盒(Qiagen,货号16181)从选择性琼脂培养基中随机挑选单菌落提取Fc1+Fc2库的质粒。
将纯化的质粒在96孔板中转染FreeStyleTM 293F细胞。(Invitrogen,货号R79007)。在转染前一天,将293-F细胞传代培养并扩增以使细胞过夜生长。在转染当天,将细胞离心收集细胞,并重悬于新鲜的FreeStyleTM 293表达培养基(Gibco,货号12338001)至最终密度为200*105活细胞/mL。将质粒(终浓度为36.67ug/mL)以指定的摩尔比与聚乙烯亚胺(25kDa,终浓度为55ug/mL,Alfa Aesar,货号43896)瞬时共转染,混合并在37℃培养1小时。之后加入19倍转染体积的新鲜培养基并继续培养。收集转染5~6天的细胞培养上清。
如图3所示,带有两个不同的标签的异源二聚体Fc在上清中共有五种结构。使用ELISA方法检测上清中的异源二聚体。简要的说,在pH9.6的碳酸盐缓冲溶液种包被抗HA抗体(Abcam,货号:ab18181)于96孔板上,并用PBST(Sigma,货号:P-3563)洗涤。板表面上的任何非特异性结合位点被含有5%脱脂乳的PBST阻断。并用PBST洗涤该板。用1% BSA的PBST稀释上清并加入板中,在25℃下培养1小时。用PBST洗涤该板以除去未结合的样品。生物素标记的抗SUMO抗体被5%脱脂奶粉的PBST稀释并加入板中,然后在25℃下培养1小时。用PBST洗涤该板。然后第二抗体,链霉素亲和素标记的辣根过氧化物酶(Abcam,货号:ab59653)稀释于含5%脱脂奶粉的PBST中,并加入板中,然后在25℃下培养1小时。用PBST洗涤该板。加入TMB(BD OptEIA,货号:555214)以通过酶转化成显色10分钟。加入1M H2SO4,终止显色。在酶标仪上读取450nm处的吸光度。
每一轮筛选,选取OD值最高的20个克隆,将对应的96孔板中的细胞进行扩大培养。使用ProteinA琼脂糖色谱(ACRO Biosystems,货号MA0422-S1)从培养物上清液中纯化蛋白质,并通过SDS-PAGE分析。在多轮筛选后,选取异源二聚体形成比例最高的克隆,将对应的质粒进行DNA测序分析。结果如下表2所示。阳性克隆的氨基酸序列如SEQ ID NO:16-SEQ IDNO:31所示。
表2.Fc1和Fc2测序结果
实施例3-异源二聚体抗体表达载体的构建
构建编码抗HER2抗体的重链和轻链的X0GC表达载体,其中抗体可变区序列来源于http://www.drugbank.ca/drugs/DB00072。使用的重链恒定结构域是人IgG1(Fc1)。编码可变轻链(VL)的核酸序列是SEQ ID NO:32,氨基酸序列是SEQ ID NO:33。编码轻链(CL)恒定结构域的核酸序列是EQ ID NO.34,氨基酸序列是SEQ ID NO:35。编码可变重链(VH)的核酸序列是SEQ ID NO:36,氨基酸序列是SEQ ID NO:37。编码重链(CH)恒定区的核酸序列是SEQID NO:38,氨基酸序列是SEQ ID NO:39。
通过PCR的方法分别扩增VL,CL,VH,CH。反应体系均为H2O 8.9μl,5×Phusion DNA聚合酶缓冲液4μl,1mM dNTP 4μl,上游引物1μl,下游引物1μl,Phusion DNA聚合酶0.1μl和模板1μl。将可变区和恒定区片段的PCR产物经1.5%琼脂糖凝胶电泳分离,并用DNA纯化试剂盒(Promega,A9282)回收。使用回收的可变和恒定片段作为模板,与可变片段的上游引物和恒定区的片段下游引物一起进行下一轮PCR反应。得到轻链或者重链的全长片段。将全长片段和X0GC载体分別用EcoRI(NEB,货号R3101L)/HindIII(NEB,货号R3104L)限制性位点酶切和连接。酶切反应体系为10×缓冲液3 2μl,EcoRI和HindIII各0.5μl,回片段3μl,H2O14.5μl。反应在37℃下进行3小时。连接体系为10×T4DNA连接酶缓冲液2μl,T4DNA连接酶(NEB,货号M0202V)0.5μl,胶回片段3μl,回收载体3μl,H2O 11.5μl。反应在室温下进行12小时。将构建体转化到大肠杆菌DH5α菌株(天根,CB104,中国),然后产生具有抗体重链(Fc1)或者轻链的质粒,该质粒用于在真核细胞中表达。
构建编码抗HER2的重链的X0GC表达载体。重链恒定区序列为IgG1(Fc2)(SEQ IDNO:40)。氨基酸序列为SEQ ID NO:41。抗体重链的表达质粒用于在真核细胞中表达抗体的重链(Fc2)。
构建编码抗CD20抗体的重链和轻链的X0GC表达载体。抗体可变区序列来源于US5736137,通过引用整体并入本文。重链恒定区序列为人IgG1(Fc1)。编码可变轻链(VL)的核酸序列是SEQ ID NO:42且氨基酸序列如SEQ ID NO:43所示。恒定轻链(CL)的氨基酸序列是SEQ ID NO:35。编码可变重链(VH)的核酸序列是SEQ ID NO:44,氨基酸序列如SEQ IDNO:45所示。编码恒定重链(CH)的核酸序列是SEQ ID NO:46或47,氨基酸序列如SEQ ID NO:48或49所示。如上所述产生表达载体。抗体重链或者轻链的表达质粒用于在真核细胞中表达抗体的重链(Fc1或Fc2)或者轻链。
如上述方法一样,构建抗Trop-2的抗体重链和轻链的X0GC表达载体。其中抗体可变区序列来源于WO2003074566,通过引用整体并入本文。重链恒定区序列为人IgG1(Fc1)。编码可变轻链(VL)的核酸序列是SEQ ID NO:50,氨基酸序列如SEQ ID NO:51所示。恒定轻链(CL)的氨基酸序列是SEQ ID NO:35。编码可变重链(VH)的核酸序列是SEQ ID NO:52,氨基酸序列如SEQ ID NO:53所示。编码恒定重链(CH)的核酸序列是SEQ ID NO:54,氨基酸序列如SEQ ID NO:55所示。
如上述方法一样,构建抗PD-L1的抗体重链和轻链的X0GC表达载体。其中抗体可变区序列来源于US20100203056,通过引用整体并入本文。重链恒定区序列为人IgG1(Fc1)。可变轻链的核酸序列是SEQ ID NO:56,可变轻链的氨基酸序列如SEQ ID NO:57所示。恒定轻链的氨基酸序列如SEQ ID NO:35所示。可变重链的核酸序列是SEQ ID NO:58,可变重链的氨基酸序列如SEQ ID NO:59所示。恒定重链的核酸序列是SEQ ID NO:60,恒定重链的氨基酸序列如SEQ ID NO:61所示。
如上所述,构建编码抗CD3 scFv的与人IgG1(Fc2)融合序列的X0GC表达载体。其中抗体可变区序列来源于US7112324,通过引用整体并入本文。恒定重区序列为人IgG1(Fc2)。可变区的核酸序列是SEQ ID NO:62,可变区氨基酸序列如SEQ ID NO:63所示。恒定区的核酸序列是SEQ ID NO:64或SEQ ID NO:65或SEQ ID NO:66或SEQ ID NO:67,恒定区的氨基酸序列如SEQ ID NO:68或SEQ ID NO:69或SEQ ID NO:70或SEQ ID NO:71所示。抗CD3scFv与人IgG1(Fc2)融合序列的表达载体用于在真核细胞中表达抗CD3scFv与人IgG1(Fc2)融合序列。
实施例4-异源二聚体抗体的表达
抗体重链和轻链的两个表达载体转染293F细胞系(FreeStyleTM 293-F Cells,货号R79007,invitrogen)。在转染前一天,将293-F细胞传代培养并扩增以使细胞过夜生长。在转染当天,将细胞离心收集细胞,并用将细胞重悬于新鲜的FreeStyleTM 293表达培养基(FreeStyleTM 293Expression Medium,货号12338001,Gibco)中至最终密度为200*105活细胞/mL。将质粒(终浓度为36.67ug/mL))以指定的摩尔比与聚乙烯亚胺(25kDa,终浓度为55ug/uL,Alfa Aesar,货号43896)瞬时共转染,轻轻混匀并在120rpm摇床37℃培养1小时。之后加入19倍转染体积的新鲜培养基并继续培养。收集转染5~6天的细胞培养上清。
还将三种表达载体转染到细胞中。抗体A的重链(人IgG1-Fc1)、抗体A的轻链,和将抗体B’scFv与人IgG1-Fc2的融合序列一起转染。在细胞培养上清液中存在Fc1同源二聚体和Fc1/scFv-Fc2同源二聚体。由于Fc1和之间的互斥作用,Fc1/scFv-Fc2同源二聚体是主要产物。加上,Fc1和Fc2更倾向于形成异源二聚体。
通过ELISA的方法测定产量,其中抗HER2-Fc1和抗CD3-Fc2的表产量为70~100mg/L。在应用层析柱纯化之前,以0.22μm滤膜过滤以去除细胞碎片。此步骤在4℃下进行。
实施例5-抗HER2/抗CD3-scFv异源二聚体抗体的纯化
抗HER2/抗CD3-scFv异源二聚体抗体分子的通用结构如图4所示。使用如上述rProtein A Sepharose Fast Flow(16mm I.D.,22ml,GE Healthcare)从培养物上清液中纯化蛋白质。将纯化收集的蛋白溶液通过超滤浓缩管超滤浓缩(标称截留分子量10KDa),将溶液置换为PBS溶液。之后加入该溶液的1/2倍体积的3M(NH4)2SO4(终浓度为1M(NH4)2SO4)。用缓冲液A(20mM磷酸钠,1M(NH4)2SO4,pH 7.0)稀释蛋白。
同样采用AKTA explorer 100型蛋白纯化系统(GE Healthcare)进行以下纯化。使用Source phenyl(16mm I.D.,22ml,GE Healthcare)纯化蛋白。首先将蛋白样品进行上样到预先用缓冲液A(20mM磷酸钠,1M(NH4)2SO4,PH 7.0)平衡的柱上。流速为3ml/min。柱在上样后以缓冲液A进行平衡,之后以在180分钟内通过以缓冲液A(0%B)到100%缓冲液B(20mM磷酸钠,PH 7.0)梯度冲洗15个柱体积。流速为2ml/min。图5所示的分馏通过超滤浓缩管超滤浓缩(标称截留分子量10KDa),并将溶液置换为PBS的磷酸盐溶液。将蛋白过滤0.22μm并在4℃下保存。将纯化蛋白通过SDS-PAGE方法分析。结果如图6所示。经SEC-HPLC纯度分析,结果如图7所示,纯度为97.65%。
实施例6-抗HER2/抗CD3-scFv异源二聚体双特异性抗体的稳定性
将充分密封的HER2/CD3异源二聚体样品(1mg/mL和10mg/mL)放置于40℃恒温箱(BINDER KBF240)。使用高效排阻液相色谱(SEC-HPLC)在不同时间点(基线(第0天)、第1天、第2天、第5天,第7天)用20μg样品测试稳定性。上述SEC-HPLC条件如下:(1)排阻色谱柱:TSKgel G3000SWxl(Tosoh Bioscience),5μm,7.8mm×30cm;(2)缓冲液:5mM PBS,150mMNaCl,pH 6.7;(3)流速:0.6mL/min;(4)紫外检测波长:280nm;(5)采集时间:30min。所用仪器是Agilent 1200Infinity色谱仪,利用Agilent ChemStation记录图谱并计算剩余单体的比例。如图8所示,在40℃实验条件下,所述异源二聚体抗HER2/抗CD3-scFv不会发生明显的聚集。数据证明了所述抗HER2/抗CD3-scFv异源二聚体具备较好的热稳定性。
实施例7-抗HER2/抗CD3-scFv异源二聚体双特异性抗体与FcRn的结合活性
用酶联免疫吸附试验(ELISA)测定抗HER2/抗CD3-scFv异源二聚体与FcRn的结合能力。简单地说,用抗HER2/抗CD3-scFv异源二聚体和对照包被ELISA板上,用pH=9.6的碳酸盐/碳酸氢盐缓冲溶液中,并在4℃过夜进行。将板用PBST(pH=6.0)洗涤5次。加入含0.5%BSA的PBST按300μL/孔封闭,将板在25℃下孵育至少1小时。如上所述洗涤板,然后向每孔加入100μL的稀释在含0.5%BSA的PBST并将板里的FcRn-his tag(北京义翘神州,货号CT009-H08H),1μg/mL,并在25℃下孵育2小时。如上所述洗涤板,然后向每孔加入100μL的1:5000稀释在含0.5%BSA的PBST里的抗小鼠his抗体(康为世纪,货号CW0228A),并在25℃下孵育1小时。如上所述洗涤板,然后向每孔加入100μL的1:10000稀释在含0.5%BSA的PBST(pH=6.0)里辣根过氧化物酶标记(HRP)的抗小鼠IgG抗体(Abcam,货号Ab7068),并在25℃孵育1小时。如上所述洗涤板,然后向每孔加入100μL的TMB并在室温下着色10分钟。向每孔加入100μL的1M H2SO4,终止显色。在酶标仪上读取450nm处的光密度。结果如图9所示,抗HER2/抗CD3-scFv异源二聚体能够与FcRn结合。
实施例8-抗HER2/抗CD3-scFv异源二聚体双特异性抗体的体外结合活性
用流式细胞术(FACS)测定在抗HER2/抗CD3-scFv异源二聚体对高表达HER2的SK-BR-3细胞和高表达CD3的Jurkat细胞的结合能力。
收集SK-BR-3细胞、Jurkat细胞并用含2% FBS(Hyclone,货号SH30084.03)的冷PBS(GIBCO,货号14190-235)分別洗涤一次。然后,将等份的SK-BR-3细胞(每管1×106个细胞)重悬于冷分析缓冲液(200μL含2% FBS的DPBS)中,并与0.5nM的抗HER2/抗CD3-scFv异源二聚体,或四价抗HER2/抗CD3同源二聚体,或HER2抗体,或同型对照(人免疫球蛋白,江西博雅生物制药股份有限公司,国药准字S19993012,中国)在黑暗中于冰上孵育30分钟。对Jurkat细胞的等分试样进行类似处理,除了那些样品的浓度变为5nM。在孵育结束时,用冷分析缓冲液洗涤细胞两次,然后再重悬于冷分析缓冲液中,并与1:50稀释的FITC标记的抗人IgG抗体(北京中杉金桥,货号ZF0306,中国)在黑暗中于冰上孵育30分钟。在孵育结束时,用冷分析缓冲液洗涤细胞两次,然后再重悬于冷PBS中。使用FACS Calibur流式细胞仪(Becton Dickinson)进行流式细胞分析。结果如表3和表4所示。结果表明异二聚体抗HER2/抗CD3-scFv构建体与其抗原HER2和CD3结合,具有良好的活性。
表3.与高表达HER2的SK-BR-3细胞的结合活性
表4.与高表达CD3的Jurkat细胞结合抗
实施例9-抗HER2/抗CD3-scFv异源二聚体双特异性抗体的对HER2和CD3的同时结合活性
通过流式细胞术(FACS)使用SK-BR-3细胞和Jurkat细胞测定抗HER2/抗CD3-scFv异源二聚体对HER2和CD3的同时结合活性。
参照PKH26试剂盒(Sigma,货号SLBH4568V)使用说明书染色SK-BR-3细胞。简要的说,收集SK-BR-3细胞并在无血清培养基洗涤一次后,用PKH26试剂盒里的Diluent C分别将SK-BR-3制备成2×107/mL细胞悬液并将PKH26染料稀释到4μM。然后将细胞悬液和染料1:1混合在一起,此混合悬液的细胞密度为1×107/mL,而PKH26的浓度为2μM。然后将混合悬液在室温下孵育1分钟,再用同等体积的FBS孵育1分钟以终止染色。将混合悬液400g离心10分钟,用完全培养基洗涤两次,再重悬于完全培养基。参照CFSE试剂盒(Life technology,货号C34554)使用说明书染色Jurkat细胞。简要的说,用PBS稀释CFSE到工作浓度0.5μM并在37℃预热。将Jurkat细胞以1000rpm离心5分钟,然后重悬于预热的CFSE工作溶液中,并在37℃下孵育15分钟。将染色的Jurkat细胞以1000rpm离心5分钟,再重悬于完全培养基中,并孵育30分钟。孵化后,用完全培养基洗涤细胞一次,再重悬于完全培养基中。
离心收集以上已经染色的SK-BR-3细胞和Jurkat细胞,并用作为冷分析缓冲液的含2%FBS的冷PBS洗涤一次。将细胞以细胞密度为5×106/mL重悬于分析缓冲液。将SK-BR-3和Jurkat按1:1混合,然后每管加入100μL等分试样的混合物(即2.5×105SK-BR-3和2.5×105Jurkat)。然后加入100μL抗HER2/抗CD3-scFv异源二聚体样品或同型对照(人免疫球蛋白,江西博雅生物制药股份有限公司,国药准字S19993012)。并稀释于冷分析缓冲液,终浓度为5nM。流式管在黑暗中于冰上孵育30分钟,并用冷分析缓冲液洗涤两次,然后重悬于500μL冷PBS中。使用FACS Calibur进行流式细胞检测分析。
结果如图10所示,抗HER2/抗CD3-scFv异源二聚体能够引发同时结合高表达HER2的SK-BR-3细胞和高表达CD3的Jurkat细胞,来引发SK-BR-3和Jurkat细胞的靠近关联,这意味着异源二聚体可以将T细胞募集到肿瘤细胞中,导致改善的癌细胞杀伤活性。
实施例10-抗HER2/抗CD3-scFv异源二聚体双特异性抗体对肿瘤细胞的体外细胞毒性
收集靶细胞(BT-474和SK-BR-3),将其按细胞密度为2×105/mL重悬于完全培养基(RPMI 1640含10%FBS)中。将靶细胞BT-474和SK-BR-3分别接种于96孔板,每孔50μL(1×104细胞每孔),再向加入每孔加入100μL的用所述完全培养基序列稀释的抗HER2/抗CD3-scFv异源二聚体样品和对照。根据预实验,将效靶比(E/T)定为20:1。即将效应细胞(人PBMC细胞,Lonza,货号CC-2702)按细胞密度为4×106/mL重悬于所述完全培养基中,并每孔接种50μL(2×105细胞每孔)。将培养板置于37℃二氧化碳培养箱中孵育4天。孵育结束后,除去上清液和用200μL DPBS清洗细胞两次以洗去效应细胞。加入100μL所述完全培养基和20μLMTS,然后在37℃二氧化碳培养箱中孵育2-3小时。酶标仪在490nm处读取吸光度(OD值)。细胞毒性计算如下:
如图11所示,抗HER2/抗CD3-scFv异源二聚体构建体以浓度依赖性的杀伤HER2高表达的乳腺癌细胞SK-BR-3和BT-474。构建体的细胞毒性远远优于赫赛汀(HER2单抗),显现了很强的肿瘤细胞杀伤活性。
实施例11-抗HER2/抗CD3-scFv异源二聚体双特异性抗体在小鼠体内的药代动力学研究
选用雌性BALB/c小鼠,8周龄,购自北京华阜康生物科技股份有限公司测试抗HER2/抗CD3-scFv异源二聚体的药代动力学研究。小鼠适应环境一周后,随机分为两组,每组21只。分别用单剂量20nmol/kg的单抗赫赛汀、抗HER2/抗CD3异源二聚体抗体腹腔注射给药予小鼠。在0点,给药后1小时、3小时、6小时、10小时、24小时、48小时、72小时、96小时、120小时、168小时、216小时、264小时、312小时,通过眼眶采血将血液样品以交错的方式收集血液样品到没有抗凝血剂的管中。每只小鼠的采血点均为2次。每个时间点使用的小鼠数量是2。每个血液样品在室温下凝结30分钟至1小时,以3000rpm离心10分钟,然后收集血清样品并储存-80℃待测。
使用ELISA分析血清中单抗赫赛汀、HER2/CD3异源二聚体抗体的浓度。简要的说,用pH=9.6的碳酸盐/碳酸氢盐缓冲溶液4℃过夜用100μL/孔的人重组HER2蛋白(北京义翘神州,货号10004-H08H)以1μg/mL包被于96孔NuncMaxisorp分析板上。将板用PBST(Sigma,货号P-3563)洗涤5次。加入300μL/孔的含5%脱脂奶粉的PBST封闭该板,然后将板在25℃下孵育至少1小时。如上述洗涤板,然后在每孔加入每孔100μL的含10%混合小鼠血清、1%BSA的PBST稀释的血清样品,然后将板在25℃下孵育1小时。如上述洗涤板,然后加入每孔100μL的1:2000稀释于含5%脱脂奶粉的PBST中的辣根过氧化物酶标记的抗人IgG-HRP抗体(Chemicon,货号AP309P),然后将板在25℃下孵育1小时。如上述洗涤板,然后加入每孔100μL的TMB(BD OptEIA,货号55214)进行显色,在室温显色10分钟。向每个孔中加入100μL的1MH2SO4,终止显色。在酶标仪上读取450nm处的光密度。
结果如图12所示,单次腹腔注射的剂量为20nmol/kg的单抗赫赛汀,抗HER2/抗CD3-scFv异源二聚体,在小鼠体内显示出了相似的药代动力学特征。抗HER2/抗CD3-scFv异源二聚体的药代动力学参数如下:半衰期t1/2为129小时;药时曲线下面积AUClast为30611nM.hr;达峰时间Tmax为3小时;达峰浓度Cmax为264nM;表观分布容积Vd为85mL/Kg;清除率CL为0.45mL/hr/kg;平均驻留时间MRTlast为88小时。抗HER-2/抗CD3构建体的异源二聚体产生过程的概述见下表5。
表5
实施例12-抗Trop-2/抗CD3-scFv异源二聚体双特异性抗体的纯化
将收获的培养液上清使用如上述实施例5所述方法进行纯化。将纯化产物通过SDS-PAGE方法分析。结果如图13所示。抗Trop-2/抗CD3-scFv异源二聚体产物的纯度高于95%。
实施例13-抗Trop-2/抗CD3-scFv异源二聚体双特异性抗体的稳定性和体外结合活性
用酶联免疫吸附试验(ELISA)测定抗Trop-2/抗CD3-scFv异源二聚体抗体与Trop-2的结合活性。简单地说,用pH=9.6的碳酸盐/碳酸氢盐缓冲液在ELISA板上包被重组人Trop-2(北京义翘神州,货号10004-H08H),包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。将板用PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,并将板在25℃孵育至少1小时。如上述洗涤板,向每个孔中加入100μL的在含1%BSA的PBST里稀释的样品,并将板在25℃孵育1小时。如上述洗涤板,加入1:2000稀释在含1%BSA的PBST里的抗人IgG-HRP抗体(Chemicon,货号AP309P),每孔加入100μL,并25℃孵育1小时。如上述洗涤板,向每个孔中加入100μL TMB(BD OptEIA,货号555214)室温显色10分钟。向每个孔中加入100μL的1MH2SO4,终止显色。在酶标仪上读取450nm处的吸光度。结果如图14所示,抗Trop-2/抗CD3-scFv异源二聚体抗体和Trop-2的结合具有高亲和力。用流式细胞术(FACS)在高表达CD3的Jurkat细胞上测定抗Trop-2/抗CD3-scFv异源二聚体抗体与CD3的结合活性。FACS的具体方法与实施例8相似。结果如表6所示,抗Trop-2/抗CD3-scFv异源二聚体抗体能够良好的结合Jurkat细胞,表明其对抗原具有良好的结合活性。
表6.与高表达CD3的Jurkat细胞的结合活性
实施例14-抗Trop-2/抗CD3-scFv异源二聚体抗体对Trop2和CD3的同时结合活性
通过流式细胞术(FACS)使用BxPC3细胞和Jurkat细胞测定抗Trop-2/抗CD3-scFv异源二聚体对Trop2和CD3的同时结合活性。进行FACS的具体方法与实施例9相似。用PKH26试剂盒的操作说明对BxPC3细胞进行染色,并通过CFSE试剂盒对Jurkat细胞进行染色。结果如图15所示,通过同时结合具有高表达Trop-2的BPCPC3细胞和具有高表达CD3的Jurkat细胞,抗Trop-2/抗CD3-scFv异源二聚体抗体能够引发BxPC3和Jurkat细胞的靠近关联,这意味着异源二聚体可以将T细胞募集到肿瘤细胞中,并导致改善的癌细胞杀伤活性。
实施例15-抗Trop-2/抗CD3-scFv异源二聚体双特异性抗体对肿瘤细胞的体外细胞毒性
收集靶细胞H1650、BxPC-3,将其按细胞密度为1×105/mL,重悬于完全培养基(RPMI 1640含10%FBS)中。将靶细胞H1650,BxPC-3分别接种于96孔板,每孔50μL(5×103细胞每孔),再加入用完全培养基序列稀释的抗Trop2/抗CD3-scFv异源二聚体抗体样品和对照,100μL每孔。将效应细胞(人PBMC细胞,Lonza,货号CC-2702)按细胞密度为2×106/mL或者0.5×106/mL重悬于所述完全培养基中,每孔接种50μL(1×105细胞每孔或者0.25×105细胞每孔)。将培养板置于37℃二氧化碳培养箱中孵育3天。孵育结束后,去除上清液,用200μLDPBS洗涤细胞两次以洗去效应细胞。入100μL所述完全培养基和20μL MTS,将样品在37℃二氧化碳培养箱中孵育2-3小时。酶标仪在490nm处读取吸光度(OD值)。细胞毒性计算如下:
如图16所示(带有效应细胞),抗Trop-2/抗CD3-scFv异源二聚体抗体以浓度依赖性的杀伤Trop-2高表达的癌细胞(非小细胞肺癌细胞H1650和人胰腺癌细胞BxPC3)。双特异抗体的杀伤效果都远优于抗Trop-2mAb,显现了很强的肿瘤细胞杀伤活性。
实施例16-抗Trop-2/抗CD3-scFv异源二聚体双特异性抗体在小鼠体内的药代动力学研究
选用雌性BALB/c小鼠,8周龄,购自北京华阜康生物科技股份有限公司测试抗Trop-2/抗CD3-scFv异源二聚体的药代动力学研究。注射、采血样品和分析方法与所述实施例11相似。通过包被Trop-2(北京义翘神州,货号10004-H08H)用ELISA测定小鼠血清,以确定其中抗Trop-2/抗CD3-scFv异源二聚体抗体分子的浓度。结果如图17所示,单次腹腔注射的剂量为20nmol/kg的抗Trop-2抗体,抗Trop-2/抗CD3-scFv异源二聚体抗,在小鼠体内显示出了相似的药代动力学特征。抗Trop-2/抗CD3-scFv异源二聚体抗体的药代动力学参数如下:半衰期t1/2为165小时;药时曲线下面积AUClast为26072nM.hr;达峰时间Tmax为6小时;达峰浓度Cmax为203nM;表观分布容积Vd为107mL/Kg;清除率CL为0.45mL/hr/kg;平均驻留时间MRTlast为92小时。
实施例17-抗CD20/抗CD3-scFv异源二聚体双特异性抗体的纯化
将收获的培养液上清使用如上述实施例5所述方法进行纯化。将纯化产物通过SDS-PAGE方法分析。结果如图18所示。抗CD20/抗CD3-scFv异源二聚体产物的纯度高于95%。
实施例18-抗CD20/抗CD3-scFv异源二聚体双特异性抗体的稳定性和体外结合活性
将充分密封的抗CD20/抗CD3-scFv异源二聚体分子样品(1mg/mL和10mg/mL)放置于40℃恒温箱(BINDER KBF240)。使用高效排阻液相色谱(SEC-HPLC)在不同时间点(基线(第0天)、第1天、第3天、第6天)用20μg样品测试稳定性。结果如图19所示,在40℃实验条件下,所述抗CD20/抗CD3-scFv异源二聚体不会发生明显的聚集。数据证明了所述抗CD20/抗CD3-scFv异源二聚体构建体具备较好的热稳定性。用流式细胞术(FACS)在高表达CD20的Raji细胞,和高表达CD3的Jurkat细胞上测定抗CD20/抗CD3-scFv异源二聚体抗体的CD20和CD3的结合活性。FACS的具体方法与实施例8相似。结果如表7和表8所示,抗CD20/抗CD3-scFv异源二聚体构建体能够良好的结合高表达CD20的Raji细胞,并且结合高表达CD3的Jurkat细胞,表明所述构建体结合抗原CD20和CD3。
表7.与高表达CD20的Raji细胞的结合。
表8.与高表达CD3的Jurkat细胞的结合。
实施例19-抗PD-L1/抗CD3-scFv异源二聚体双特异性抗体的纯化
将收获的培养液上清使用如上述实施例5所述方法进行纯化。将纯化产物通过SDS-PAGE方法分析。结果如图20所示。抗PD-L1/抗CD3-scFv异源二聚体产物的纯度高于95%。
实施例20-抗PD-L1/抗CD3-scFv异源二聚体双特异性抗体的体外结合活性
用酶联免疫吸附试验(ELISA)测定抗PD-L1/抗CD3-scFv异源二聚体的PD-L1的结合活性。ELISA的具体方法与实施例13相似。用PD-L1(北京义翘神州,货号10084-H08H)包被ELISA板。结果如图21所示,抗PD-L1/抗CD3-scFv异源二聚体和PD-L1的结合具有高亲和力。
用流式细胞术(FACS)在高表达CD3的Jurkat细胞上测定抗PD-L1/抗CD3-scFv异源二聚体与CD3的结合活性。FACS的具体方法与实施例8相似。结果如表9所示,抗PD-L1/抗CD3-scFv异源二聚体能够良好的结合Jurkat细胞,表明其能够结合CD3抗原。
表9.与高表达CD3的Jurkat细胞的结合活性
实施例21-抗PD-L1/CD3-scFv异源二聚体双特异性抗体对PD-L1和CD3的同时结合活性
用流式细胞术(FACS)在H460细胞和Jurkat细胞上测定抗PD-L1/CD3-scFv异源二聚体对PD-L1和CD3的同时结合活性。具体方法与实施例9相似。如图22所示,抗PD-L1/CD3-scFv异源二聚体构建体可以引发高表达PD-L1的H460细胞和高表达CD3的Jurkat细胞的靠近关联,这意味着异源二聚体可以将T细胞募集到肿瘤细胞中,并导致改善的癌细胞杀伤活性。
实施例22-抗PD-L1/CD3-scFv异源二聚体双特异性抗体的体外细胞毒性
收集靶细胞HCC827、H1650,将其按细胞密度为1×105/mL,重悬于完全培养基(RPMI 1640含10%FBS)中。将靶细胞HCC827和H1650分别接种于96孔板,每孔50μL(5×103细胞每孔),再加入用完全培养基序列稀释的抗PD-L1/抗CD3-scFv异源二聚体抗体样品和对照,100μL每孔。将效应细胞(人PBMC细胞,Lonza,货号CC-2702)按细胞密度为2×106/mL重悬于所述完全培养基中,每孔接种50μL(1×105细胞每孔)。将培养板置于37℃二氧化碳培养箱中孵育3天。孵育结束后,除去上清液和用200μL DPBS清洗细胞两次以洗去效应细胞。加入100μL所述完全培养基和20μL MTS,将样品在37℃二氧化碳培养箱中孵育2-3小时。酶标仪在490nm处读取吸光度(OD值)。细胞毒性计算如下:
如图23所示(具有效应细胞),抗PD-L1/CD3-scFv异源二聚体构建体以浓度依赖性的杀伤PD-L1高表达的癌细胞(非小细胞肺癌细胞H1650和HCC827),显现了很强的肿瘤细胞杀伤活性。
实施例23-纯化抗Her2和抗CD20表达产物以产生Fab-Fab形式的双特异性抗体
采用AKTA explorer 100型蛋白纯化系统(GE Healthcare)和亲和色谱柱ProteinA Sepharose Fast Flow(16mm I.D.,22ml,GE Healthcare)于4℃下进行纯化。首先以缓冲液A(20mMPBST,150mM氯化钠,pH 7.4)平衡色谱柱,在基线稳定后将经过上述处理的细胞上清液进行上样,流速为5ml/min,并在上样后以缓冲液A进行平衡。所述样品是具有CH3结构域中氨基酸突变的抗Her2和抗CD20表达产物,其通过上文实施例4中描述的方法表达。之后,首先以缓冲液B1(缓冲液A+0.5M精氨酸)冲洗5个柱体积;然后以缓冲液B2(100mM柠檬酸,pH 3.0)洗脱5个柱体积,以收集洗脱峰即为目的蛋白。以上洗脱步骤流速都为5ml/min。抗CD20产物的代表性色谱图如图24所示,其与抗Her2产物产生类似的结果(未示出)。收集标示的图示灰色区域的洗脱峰,并通过加入1M醋酸钠溶液将pH调至5.0。
实施例24-抗HER2/抗CD20天然IgG样异源二聚体双特异性抗体的纯化
抗HER2/抗CD20异源二聚体的通用结构如图25所示。
将上述实施例23的纯化产物进行体外重组以形成异源二聚体。首先,通过超滤浓缩管超滤浓缩(标称截留分子量10KDa),将缓冲液置换为磷酸盐缓冲液(phosphate buffersaline,PBS)。将每种抗HER2和抗CD20产物的浓度调整到1mg/ml PBS,并加入1/200倍终体积的1M DTT(DTT终浓度分别为0.1mM、0.5mM、1mM、2mM、5mM、10mM或20mM)。然后在4℃条件下进行还原3-8小时。在还原的过程,二硫键如如可能存在于抗HER2和抗CD20同源二聚体分子的铰链区的二硫键打开,形成了含有一条重链和一条轻链的半抗体分子(或半聚体),结构如图26所示。还原的样品在变性条件下经SDS-PAGE分析。抗CD20产物的代表性结果显示在图27中,其与抗Her2产物产生类似的结果(未示出)。在图中,从右侧出现在柱道2-4中的四个主要条带从上到下分別为:LC-HC-HC-LC同源二聚体、HC-LC半聚体、HC,和LC。如图所示,随着DTT浓度的增加,只有两条带(HC和LC)显得突出,并几乎没有观察到同源二聚体。通过在PBS中的1mM DTT存在下,经SEC-HPLC分析抗Her2半聚体产物(A)和抗CD20半聚体产物(B)的结果显示在图28中。如图288所示,在DTT浓度等于或大于1mM的条件下反应,抗Her2和抗CD20产物的同源二聚体分子(半聚体)比例小于10%,半抗体分子比例大于90%所涉及的总多肽种类。
还原的抗HER2和抗CD20半聚体分子以1:1(摩尔比)混合,并在4℃条件下进行重组反应0.5-24小时。在重组的过程中,抗Her2和抗CD20半聚体形成抗Her2/抗CD20异二聚体,其含有两个半聚体,它们通过CH2/CH3之间的非共价相互作用大部分保持在一起。然后,使用超滤浓度(10kDa分子量截留值)将缓冲液更换为PBS。通过空气或者氧化剂驱动的氧化反应终止还原,使异源二聚体的双特异抗体的链间二硫键重新形成。化反应的条件包括空气中放置样品1天、3天、4天,或者加入氧化剂100mM L-脱氢抗坏血酸(蛋白终浓度1mg/ml,氧化剂终浓度0.5mM、1mM、5mM、10mM)在4℃条件下进行氧化反应5小时或24小时。氧化反应完成后,获得的样品进行SDS-PAGE分析。结果如图29所示。
通过超滤浓缩(标称截留分子量10KDa),将从抗HER2和抗CD20半聚体的还原氧化所得到的抗HER2/抗CD20异源二聚体浓缩,和将缓冲溶液置换为10mM PBST,pH 5.8。采用AKTA explorer 100型蛋白纯化系统(GE Healthcare)和离子色谱柱Source 15S(16mmI.D.,17ml,GE Healthcare)于4℃下进行纯化样品。首先以缓冲液A(10mM磷酸钠,pH 7.0)平衡色谱柱,在基线稳定后将经过上述处理的蛋白溶液进行上样,流速为3ml/min,并在上样后以缓冲液A进行平衡。之后以缓冲液A(10mM磷酸钠,pH 5.8)到缓冲液B(10mM磷酸钠,pH5.8)梯度冲洗20个柱体积(0%B-100%B,170min,流速2ml/min)。收集标示的主要洗脱主峰(如图30所示)。集的蛋白缓冲溶液通过超滤浓缩管超滤浓缩(标称截留分子量10KDa),将溶液置换为磷酸盐溶液(PBS,pH=7.4),过滤除菌4℃保存。将纯化产物通过SDS-PAGE方法分析。结果如图31所示。所述产物经SEC-HPLC纯度分析,结果如图32所示。纯度为97.3%。
实施例25-抗HER2/抗CD20异源二聚体的分析方法建立
将下列五种样品采用HPLC方法进行区分:抗HER2半抗体、抗HER2同源二聚体、抗CD20半抗体、抗CD20同源二聚体,和抗HER2/抗CD20异源二聚体。具体实验方法如下:(1)疏水相互作用色谱柱:TSK-GEL Phenyl-5PW,7.5mm ID x 7.5cm,10μm;(2)缓冲液和梯度方法:缓冲液A是20mM PBS缓冲液,pH 7.0,1M(NH4)2SO4;缓冲液B是20mM PBS,pH 7.0;梯度方法是40分钟内40%缓冲液B升至100%缓冲液B;(3)流速:0.5mL/min;(4)温度25℃;(5)检测波长:280nm。结果如图33所示,从图中可知,抗CD20-FC1同源二聚体(如图33的峰1)、抗HER2-FC2同源二聚体(如图34的峰5),和抗HER2/抗CD20异源二聚体(如图34的峰3)在此方法中得到有效的区分,显示为不同的出峰时间。这证实实施例24的产物是异源二聚体,而非同源二聚体。
实施例26-抗HER2/抗CD20异源二聚体的质谱鉴定
将下列三种样品:抗HER2同源二聚体、抗CD20同源二聚体和抗HER2/抗CD20异源二聚体进行液质联用(LC-MS)分析,以确定氨基酸覆盖率。将上述样品进行胰蛋白酶酶切,并在37℃下孵育18小时。LC-MS条件如下:色谱柱:WatersACQUITY UPLC BEH C18,1.7μm,2.1mm x 100mm。柱温:50℃。流速:0.2mL/min。缓冲液A:0.1%甲酸。缓冲液B:0.1%甲酸/100%乙腈。洗脱梯度:2-35%缓冲液B,90分钟;35-45%缓冲液B,20分钟。ESI源:正离子模式。毛细管电压:2.5kV。锥体电压:25V。扫描范围:100-2500Da。MSe电压:20-40V
如图34为抗HER2同源二聚体、抗CD20同源二聚体和抗HER2/抗CD20异源二聚体的基峰离子色谱图(BPI)(图34A),和各自的氨基酸覆盖率(图34B)。抗CD20同源二聚体分子的氨基酸覆盖率为99.7%,抗HER2同源二聚体的氨基酸覆盖率为100%;抗HER2/抗CD20异源二聚体的氨基酸覆盖率为99.4%。从LC-MS获得的抗CD20同源二聚体中包括两个特异性氨基酸置换的抗CD20轻链和重链的氨基酸序列分别显示于SEQ ID NO:73和74。从LC-MS获得的抗HER2同源二聚体中包括三个特异性氨基酸置换的抗HER2轻链和重链的氨基酸序列分别显示于SEQ ID NO:75和76。从LC-MS获得的抗CD20/HER2异源二聚体包括两个特异性氨基酸置换的抗CD20轻链和重链的氨基酸序列分别显示于SEQ ID NO:77和78。从LC-MS获得的抗CD20/HER2异源二聚体包括三个特异性氨基酸置换的抗HER2轻链和重链的氨基酸序列分别显示于SEQ ID NO:79和80。SEQ ID NO:74中第66位的氨基酸甘氨酸和67位的赖氨酸、SEQID NO:78中第66位氨基酸甘氨酸、67位的赖氨酸218位的赖氨酸、第343位的丙氨酸第344位的赖氨酸、和SEQ ID NO:80中第217位的氨基酸赖氨酸、第342位的丙氨酸和第343位的赖氨酸在LC-MS分析中未被发现。结果表明抗HER2/抗CD20异源二聚体具有与预期相同的序列。
本领域技术人员将理解,在不脱离本公开的范围和精神的情况下,可以进行许多和各种修改。因此,应该理解的是,本文描述的本公开的各种实施例仅是说明性的,并不意图限制本公开的范围。本文引用的所有参考文献均通过引用整体并入本文。
序列表
<110> 北京韩美药品有限公司
刘家望
宋楠萌
杨东歌
杨亚平
金孟燮
<120> 异源二聚体免疫球蛋白构建体和其制备方法
<130> LZ1706112CN07
<150> CN 2016108638147
<151> 2016-09-29
<160> 80
<170> PatentIn version 3.5
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gatcttcttc aagatcaaga agaccacccc cctgaggagg ctgatggagg ccttcgccaa 180
gaggcagggc aaggagatgg acagcctgag gttcctgtac gacggcatcc gtattcaagc 240
cgaccagacc cctgaggacc tggacatgga ggacaacgac atcatcgagg cccacaggga 300
gcagatcggc ggcgaaccca agtccagcga taagacccac acatgccctc cctgtcctgc 360
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gatgatcagc aggacccctg aagtgacctg cgtggtcgtg gacgtgagcc acgaggaccc 480
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catcgagaaa accatcagca aggccaaggg ccaaccgcgg gaacctcaag tgtataccct 720
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cctccacaac cactataccc agaagagcct gagcctcagc cccggcaaat gatgaagatc 1020
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ccctcccccg tgccttcctt gaccctggaa ggtgccactc ccactgtcct ttcctaataa 1140
aatgaggaaa ttgcatcgca ttgtctgagt aggtgtcatt ctattctggg gggtggggtg 1200
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ccctgtagcg gcgcagcgcg cgttgacatt gattattgac tagttattaa tagtaatcaa 1380
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aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 1620
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 1680
ctacttggca gtacatctac gtattagtca tcgctattac catggtgatg cggttttggc 1740
agtacatcaa tgggcgtgga tagcggtttg actcacgggg atttccaagt ctccacccca 1800
ttgacgtcaa tgggagtttg ttttggcacc aaaatcaacg ggactttcca aaatgtcgta 1860
acaactccgc cccattgacg caaatgggcg gtaggcgtgt acggtgggag gtctatataa 1920
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gaccgtgctg caccaggatt ggctcaacgg caaggagtac aagtgcaaag tctccaacaa 2400
ggccctgccc gcccccatcg agaagaccat ctccaaggct aagggacagc ccagggagcc 2460
ccaagtgtac accctccctc ccagccggga tgagctgacc aagaaccaag tctccctcac 2520
ctgcctggtc aagggattct acccttccga cattgccgtc gaatgggaga gcaatggcca 2580
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caagctgcag aat 2773
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Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
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Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
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Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser
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Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
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Lys Thr Thr Pro Pro Val Leu Cys Ser Asp Gly Ser Phe Phe Leu Tyr
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Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
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Ser Leu Ser Leu Ser Pro Gly Lys
225 230
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Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
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Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
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Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
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Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
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Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Gly Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Leu
180 185 190
Ser Cys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 18
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 18
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Cys Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 19
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 19
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Tyr Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Ala
180 185 190
Ser Pro Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 20
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 20
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Val Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Thr Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 21
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 21
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Lys Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Thr
180 185 190
Ser Gln Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 22
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 22
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Ala Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 23
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 23
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Trp Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu His
180 185 190
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 24
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 24
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Pro Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asn Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 25
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 25
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Val Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Pro
180 185 190
Ser Ser Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 26
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 26
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Pro Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Ile Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 27
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 27
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Pro Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Phe
180 185 190
Ser Phe Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 28
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 28
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Gly Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 29
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 29
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Asp Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Pro
180 185 190
Ser Ser Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 30
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc1序列
<400> 30
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Arg Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 31
<211> 232
<212> PRT
<213> 人工的
<220>
<223> Fc2序列
<400> 31
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Glu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Leu
180 185 190
Ser Val Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 32
<211> 312
<212> DNA
<213> 人工的
<220>
<223> VL序列
<400> 32
gacattcaga tgactcagag cccttcttca ctgtcagctt ccgtgggcga cagagtcact 60
atcacctgcc gcgcaagtca ggatgtgaac accgcagtcg cctggtacca gcagaagcct 120
ggcaaagctc caaagctgct gatctacagc gcatctttcc tgtattctgg agtgcccagt 180
aggtttagtg ggtcacggtc cggtaccgac ttcacactga ctatctccag cctgcagcct 240
gaggattttg ccacatacta ttgccagcag cactatacca caccccctac tttcggccag 300
ggaaccaaag tg 312
<210> 33
<211> 104
<212> PRT
<213> 人工的
<220>
<223> VL序列
<400> 33
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val
100
<210> 34
<211> 330
<212> DNA
<213> 人工的
<220>
<223> CL序列
<400> 34
gagatcaagc gaactgtggc cgctccaagc gtcttcattt ttccaccctc tgacgaacag 60
ctgaagtcag ggacagcttc cgtggtctgt ctgctgaaca atttttaccc cagggaggcc 120
aaagtgcagt ggaaggtcga taacgctctg cagagcggaa attctcagga gagtgtgaca 180
gaacaggact caaaagattc cacttatagc ctgtctagta ccctgacact gtccaaggca 240
gactacgaaa agcataaagt gtatgcctgt gaggtcacac atcagggtct gtcaagcccc 300
gtcactaagt ccttcaatcg tggcgaatgc 330
<210> 35
<211> 110
<212> PRT
<213> 人工的
<220>
<223> CL序列
<400> 35
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
1 5 10 15
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
20 25 30
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
35 40 45
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
50 55 60
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
65 70 75 80
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
85 90 95
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105 110
<210> 36
<211> 360
<212> DNA
<213> 人工的
<220>
<223> VH序列
<400> 36
gaggtgcagc tggtcgaaag tgggggtggg ctggtgcagc caggcggatc actgaggctg 60
tcctgcgccg ctagcggctt caacatcaaa gacacctata ttcactgggt ccgacaggca 120
ccagggaagg gtctggaatg ggtggctcgt atctacccta caaatggtta cactagatat 180
gccgactccg tgaaaggccg gtttactatt tctgctgata ccagtaagaa cacagcatac 240
ctgcagatga atagcctgag ggctgaggat accgcagtgt actattgctc tcggtggggg 300
ggtgacggct tctacgctat ggattattgg ggccagggaa ctctggtcac cgtgtccagc 360
<210> 37
<211> 120
<212> PRT
<213> 人工的
<220>
<223> VH序列
<400> 37
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 38
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacac tgcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgctgtgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctgtgctcag atggttcctt ctttctgtac agtaaactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 39
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 39
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Cys Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 40
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 40
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacag agcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgacttgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctggactcag atggttcctt ctttctgctg agtgtgctga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 41
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 41
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Glu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Leu Ser Val Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 42
<211> 309
<212> DNA
<213> 人工的
<220>
<223> VL序列
<400> 42
cagatcgtgc tgagccagag ccccgccatc ctgagcgcca gccccggcga gaaggtgacc 60
atgacctgca gggccagcag cagcgtgagc tacatccact ggttccagca gaagcccggc 120
agcagcccca agccctggat ctacgccacc agcaacctgg ccagcggcgt gcccgtgagg 180
ttcagcggca gcggcagcgg caccagctac agcctgacca tcagcagggt ggaggccgag 240
gacgccgcca cctactactg ccagcagtgg accagcaacc cccccacctt cggcggcggc 300
accaagctg 309
<210> 43
<211> 103
<212> PRT
<213> 人工的
<220>
<223> VL序列
<400> 43
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu
100
<210> 44
<211> 363
<212> DNA
<213> 人工的
<220>
<223> VH序列
<400> 44
caggtgcagc tgcagcagcc cggcgccgag ctggtgaagc ccggcgccag cgtgaagatg 60
agctgcaagg ccagcggcta caccttcacc agctacaaca tgcactgggt gaagcagacc 120
cccggcaggg gcctggagtg gatcggcgcc atctaccccg gcaacggcga caccagctac 180
aaccagaagt tcaagggcaa ggccaccctg accgccgaca agagcagcag caccgcctac 240
atgcagctga gcagcctgac cagcgaggac agcgccgtgt actactgcgc caggagcacc 300
tactacggcg gcgactggta cttcaacgtg tggggcgccg gcaccaccgt gaccgtgagc 360
gcc 363
<210> 45
<211> 121
<212> PRT
<213> 人工的
<220>
<223> VH序列
<400> 45
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala
115 120
<210> 46
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 46
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacac tgcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgctgtgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctgtgctcag atggttcctt ctttctgtac agtaaactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 47
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 47
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacac tgcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgctgtgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctgcggtcag atggttcctt ctttctgtac agtaaactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 48
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 48
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Cys Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 49
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 49
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Leu Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Arg Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 50
<211> 312
<212> DNA
<213> 人工的
<220>
<223> VL序列
<400> 50
gatatccagc tgacccagag ccctagcagc ctgagcgcta gcgtgggcga cagggtgagc 60
atcacctgca aggccagcca ggacgtgtcc atcgccgtgg cctggtatca acagaagccc 120
ggcaaggccc ccaagctgct gatctacagc gccagctaca ggtacaccgg cgtgcccgac 180
agatttagcg gcagcggctc cggcacagac ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccgtgtacta ctgccagcag cactacatca cccccctgac ctttggcgcc 300
ggcaccaaag tg 312
<210> 51
<211> 104
<212> PRT
<213> 人工的
<220>
<223> VL序列
<400> 51
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Ile Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln His Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Val
100
<210> 52
<211> 360
<212> DNA
<213> 人工的
<220>
<223> VH序列
<400> 52
gtgcagctgc agcagtccgg cagcgagctg aagaagcctg gcgccagcgt gaaggtgagc 60
tgcaaggcca gcggctacac cttcaccaac tacggcatga actgggtgaa gcaggcccct 120
ggccagggac tgaagtggat gggctggatc aacacctaca ccggcgagcc cacctacacc 180
gacgacttca agggcaggtt cgccttcagc ctggacacca gcgtgtccac cgcctacctg 240
cagatctcca gcctgaaggc cgacgacacc gccgtgtact tctgcgccag aggcggcttc 300
ggcagcagct actggtactt cgacgtgtgg ggccagggaa gcctggtgac cgtgagcagc 360
<210> 53
<211> 120
<212> PRT
<213> 人工的
<220>
<223> VH序列
<400> 53
Val Gln Leu Gln Gln Ser Gly Ser Glu Leu Lys Lys Pro Gly Ala Ser
1 5 10 15
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr Gly
20 25 30
Met Asn Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Lys Trp Met Gly
35 40 45
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe Lys
50 55 60
Gly Arg Phe Ala Phe Ser Leu Asp Thr Ser Val Ser Thr Ala Tyr Leu
65 70 75 80
Gln Ile Ser Ser Leu Lys Ala Asp Asp Thr Ala Val Tyr Phe Cys Ala
85 90 95
Arg Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Ser Leu Val Thr Val Ser Ser
115 120
<210> 54
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 54
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacac tgcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgccctgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctgaactcag atggttcctt ctttctgtac agtaaactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 55
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 55
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Pro Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asn Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 56
<211> 312
<212> DNA
<213> 人工的
<220>
<223> VL序列
<400> 56
gacatccaga tgacccagag ccctagcagc ctgagcgcta gcgtgggcga cagggtgacc 60
atcacctgca gggccagcca ggatgtgagc accgctgtgg cctggtatca acagaagccc 120
ggcaaggccc ccaagctgct gatctacagc gccagcttcc tgtacagcgg cgtgcccagc 180
agatttagcg gcagcggcag cggcaccgat ttcaccctga ccatcagcag cctgcagccc 240
gaggacttcg ccacctacta ctgccagcag tacctgtacc atcccgccac cttcggccag 300
ggcaccaagg tg 312
<210> 57
<211> 104
<212> PRT
<213> 人工的
<220>
<223> VL序列
<400> 57
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Ser Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Leu Tyr His Pro Ala
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val
100
<210> 58
<211> 354
<212> DNA
<213> 人工的
<220>
<223> VH序列
<400> 58
gaggtgcagc tggtggagag cggaggagga ctggtgcagc ctggaggatc cctgagactg 60
agctgcgccg ccagcggctt caccttcagc gacagctgga tccactgggt gagacaggcc 120
cctggcaagg gcctggaatg ggtggcctgg atctcccctt acggcggcag cacctactac 180
gccgacagcg tgaagggcag gttcaccatc agcgccgaca ccagcaagaa caccgcctac 240
ctgcagatga acagcctgag ggccgaggac accgccgtgt actactgcgc cagaagacac 300
tggcccggcg gattcgacta ctggggacag ggcaccctgg tgaccgtgag cgcc 354
<210> 59
<211> 118
<212> PRT
<213> 人工的
<220>
<223> VH序列
<400> 59
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 Ser Asp Ser
20 25 30
Trp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Trp Ile Ser Pro Tyr Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Arg His Trp Pro Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 60
<211> 990
<212> DNA
<213> 人工的
<220>
<223> CH序列
<400> 60
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacac tgcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgtggtgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctgggatcag atggttcctt ctttctgtac agtaaactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 61
<211> 330
<212> PRT
<213> 人工的
<220>
<223> CH序列
<400> 61
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Gly Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 62
<211> 729
<212> DNA
<213> 人工的
<220>
<223> 可变区序列
<400> 62
gatatcaagc tgcagcagag cggtgcagaa ctggccagac ctggcgcttc agtgaaaatg 60
tcctgtaaga ctagcggcta cacattcact cgatatacca tgcactgggt gaagcagcgt 120
ccagggcagg gtctggagtg gatcggatat attaacccct ctcgcgggta caccaactat 180
aatcagaagt ttaaagacaa ggccacactg actaccgata agagctctag tactgcttac 240
atgcagctgt catccctgac cagcgaagac tctgcagtgt actattgcgc ccgatactat 300
gacgatcatt actgtctgga ctactggggc cagggaacaa ctctgactgt cagctctgtg 360
gagggaggaa gtggaggttc aggaggatcc ggaggtagcg gaggagtgga cgatatccag 420
ctgacccagt ctcccgccat tatgtccgct agccctggcg agaaagtcac catgacatgc 480
agagccagtt catccgtgtc ctacatgaat tggtatcagc agaaatctgg aacaagtcca 540
aagaggtgga tctacgacac ttctaaggtc gcaagtgggg tgccctatcg gttttctggg 600
agtggttcag gcacttccta cagcctgacc attagctcta tggaggccga agatgctgca 660
acctactatt gccagcagtg gagtagcaat cctctgacat ttggagcagg gactaaactg 720
gaactgaag 729
<210> 63
<211> 243
<212> PRT
<213> 人工的
<220>
<223> 可变区序列
<400> 63
Asp Ile Lys Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Ser Arg Gly Tyr Thr Asn Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Thr Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Tyr Asp Asp His Tyr Cys Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Thr Leu Thr Val Ser Ser Val Glu Gly Gly Ser Gly Gly Ser Gly
115 120 125
Gly Ser Gly Gly Ser Gly Gly Val Asp Asp Ile Gln Leu Thr Gln Ser
130 135 140
Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys
145 150 155 160
Arg Ala Ser Ser Ser Val Ser Tyr Met Asn Trp Tyr Gln Gln Lys Ser
165 170 175
Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Val Ala Ser
180 185 190
Gly Val Pro Tyr Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser
195 200 205
Leu Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys
210 215 220
Gln Gln Trp Ser Ser Asn Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu
225 230 235 240
Glu Leu Lys
<210> 64
<211> 990
<212> DNA
<213> 人工的
<220>
<223> 恒定区序列
<400> 64
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacag gacctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgacttgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctggactcag atggttcctt ctttctgctc agttgtctga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 65
<211> 990
<212> DNA
<213> 人工的
<220>
<223> 恒定区序列
<400> 65
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacat atcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgacttgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctggactcag atggttcctt ctttctggca agtcctctga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 66
<211> 990
<212> DNA
<213> 人工的
<220>
<223> 恒定区序列
<400> 66
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacag ttcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgacttgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctggactcag atggttcctt ctttctgcca agttcactga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 67
<211> 990
<212> DNA
<213> 人工的
<220>
<223> 恒定区序列
<400> 67
gcttcaacaa aaggaccttc cgtgtttcca ctggcaccct ctagtaagag tacttcagga 60
ggaaccgcag cactgggatg tctggtgaag gactacttcc cagagcccgt caccgtgtct 120
tggaacagtg gagcactgac ctccggggtc catacatttc ctgccgtgct gcagtcatcc 180
ggtctgtata gcctgagctc tgtggtcaca gtcccaagtt catccctggg cacccagaca 240
tacatctgca acgtgaatca caaaccttcc aatactaagg tcgacaagaa agtggaacca 300
aaaagctgtg ataagactca tacctgccca ccttgtcctg caccagagct gctgggaggt 360
ccaagcgtgt tcctgtttcc acccaagccc aaagacacac tgatgatttc tcgcacaccc 420
gaagtcactt gtgtggtcgt ggacgtgtcc cacgaggatc ctgaagtcaa gttcaactgg 480
tacgtggatg gcgtcgaggt gcataatgct aagaccaaac ccagagagga acagtacaac 540
agcacctatc gcgtcgtgtc tgtcctgaca gtgctgcacc aggattggct gaacggaaag 600
gagtacaagt gcaaagtgag caacaaggcc ctgcccgctc ctatcgagaa gaccatttct 660
aaggctaaag gccagcctag agaaccacag gtgtatacag atcctccaag tcgcgacgag 720
ctgacaaaaa accaggtctc cctgacttgt ctggtgaagg gattctaccc tagcgatatc 780
gcagtggagt gggaatctaa tgggcagcca gaaaacaatt ataagaccac accccctgtg 840
ctggactcag atggttcctt ctttctgcca agtagtctga ccgtggacaa gtccaggtgg 900
cagcagggga acgtcttttc ctgcagcgtg atgcatgagg ccctgcacaa tcattacaca 960
cagaaatctc tgagtctgtc accaggaaag 990
<210> 68
<211> 330
<212> PRT
<213> 人工的
<220>
<223> 恒定区序列
<400> 68
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Gly Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Leu Ser Cys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 69
<211> 330
<212> PRT
<213> 人工的
<220>
<223> 恒定区序列
<400> 69
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Tyr Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Ala Ser Pro Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 70
<211> 330
<212> PRT
<213> 人工的
<220>
<223> 恒定区序列
<400> 70
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Val Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Pro Ser Ser Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 71
<211> 330
<212> PRT
<213> 人工的
<220>
<223> 恒定区序列
<400> 71
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Asp Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Pro Ser Ser Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 72
<211> 15
<212> PRT
<213> 人工的
<220>
<223> 合成的
<400> 72
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 73
<211> 213
<212> PRT
<213> 人工的
<220>
<223> 抗CD20同源二聚体中的抗CD20轻链
<400> 73
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 74
<211> 451
<212> PRT
<213> 人工的
<220>
<223> 抗CD20同源二聚体中的抗CD20重链
<400> 74
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Arg Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 75
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 抗HER2同源二聚体中的抗HER2轻链
<400> 75
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 76
<211> 450
<212> PRT
<213> 人工的
<220>
<223> 抗HER2同源二聚体中的抗HER2重链
<400> 76
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Glu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Leu Ser Val Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 77
<211> 213
<212> PRT
<213> 人工的
<220>
<223> 抗CD20/HER2异源二聚体中的抗CD20轻链
<400> 77
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 78
<211> 451
<212> PRT
<213> 人工的
<220>
<223> 抗CD20/HER2异源二聚体中的抗CD20重链
<400> 78
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly
100 105 110
Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Leu Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Arg Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 79
<211> 214
<212> PRT
<213> 人工的
<220>
<223> 抗CD20/HER2异源二聚体中的抗HER2轻链
<400> 79
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Val Asn Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser Phe Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln His Tyr Thr Thr Pro Pro
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 80
<211> 450
<212> PRT
<213> 人工的
<220>
<223> 抗CD20/HER2异源二聚体中的抗HER2重链
<400> 80
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 Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Arg Ile Tyr Pro Thr Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Glu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Leu Ser Val Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
Claims (43)
1.一种异源二聚体,其包括Fc受体(FcR)-结合成员和一条或多条与该FcR-结合成员共价连接的识别部分,其中FcR-结合成员包括第一多肽(Fc1)和第二多肽(Fc2),
其中所述第一多肽和第二多肽的氨基酸序列如以下中的任一组所示:
a)SEQ ID NO:16的第一多肽和SEQ ID NO:17的第二多肽;
b)SEQ ID NO:18的第一多肽和SEQ ID NO:19的第二多肽;
c)SEQ ID NO:20的第一多肽和SEQ ID NO:21的第二多肽;
d)SEQ ID NO:22的第一多肽和SEQ ID NO:23的第二多肽;
e)SEQ ID NO:24的第一多肽和SEQ ID NO:25的第二多肽;
f)SEQ ID NO:26的第一多肽和SEQ ID NO:27的第二多肽;
g)SEQ ID NO:28的第一多肽和SEQ ID NO:29的第二多肽;和
h)SEQ ID NO:30的第一多肽和SEQ ID NO:31的第二多肽。
2.如权利要求1所述的异源二聚体,其中所述FcR-结合成员包括一个Fc结构域。
3.如权利要求2所述的异源二聚体,其中所述Fc结构域来源于IgG Fc结构域。
4.如权利要求3所述的异源二聚体,其中IgG Fc结构域包括选自IgG1Fc结构域、IgG2Fc结构域、IgG3Fc结构域和IgG4Fc结构域中的一种。
5.如权利要求1所述的异源二聚体,其中所述一个或多个识别部分包括抗原结合(Fab)片段或多个片段、单链可变(scFv)片段或多个片段、膜受体的细胞外结构域、细胞膜受体的肽配体、细胞因子、凝血因子、亲和力标签和其组合中的至少一种。
6.如权利要求5所述的异源二聚体,其中所述一个或多个识别部分包括两个识别部分,其中所述两个识别部分各自包括Fab片段。
7.如权利要求6所述的异源二聚体,其中所述两个Fab片段是不同的。
8.如权利要求7所述的异源二聚体,其中所述异源二聚体包括一个免疫球蛋白(Ig)样分子。
9.如权利要求7或8所述的异源二聚体,其中所述异源二聚体包括一个双特异性抗体。
10.如权利要求5所述的异源二聚体,其中所述一个或多个识别部分包括两个识别部分,其中所述两个识别部分包括一个Fab片段和一个scFv片段。
11.如权利要求1所述的异源二聚体,其中,当在含有1mM二硫苏糖醇的生理条件下的水性溶液中存在时,基于溶液中所有多肽形式的重量,由第一多肽、第二多肽、第一多肽和其同源识别部分、或第二多肽和其同源识别部分所形成的同源二聚体的比例小于50%重量,所述溶液基本上不含除所述第一多肽或第二多肽和其同源识别部分以外的肽。
12.如权利要求1所述的异源二聚体,其中所述至少5个氨基酸置换包括第一多肽上T366L和D399R置换和第二多肽上L351E,Y407L和K409V置换。
13.如权利要求7所述的异源二聚体,其中所述异源二聚体包括第一重链和第二重链,以及第一轻链和第二轻链,其中,所述第一重链和第二重链不相同,并且第一轻链和第二轻链不相同。
14.如权利要求10所述的异源二聚体,其中所述Fab片段和scFv片段选自一对选自第七组a)-d)的识别部分:
第七组:
a)特异性结合HER2的Fab和特异性结合CD3的scFv;
b)特异性结合Trop2的Fab和特异性结合CD3的scFv;
c)特异性结合CD20的Fab和特异性结合CD3的scFv;和
d)特异性结合PD-L1的Fab和特异性结合CD3的scFv。
15.如权利要求7所述的异源二聚体,其中,两个不相同的Fab片段包括特异性结合HER2的第一Fab片段和特异性结合CD20的第二Fab片段。
16.如权利要求1所述的异源二聚体,其中,所述FcR-结合成员能够结合Fc受体,所述Fc受体选自Fcγ、FcγRIIA、FcγRIIB1、FcγRIIB2、FcγRIIIA、FcγRIIIB、FcεRI、FcεRII、FcαRI、Fcα/μR、FcRn和其组合中的一种。
17.如权利要求16所述的异源二聚体,其中,所述FcR-结合成员能够结合FcRn。
18.如权利要求16所述的异源二聚体,其中,所述与Fc受体的结合引发抗体依赖的细胞介导的细胞毒性作用(ADCC)。
19.一种生产异源二聚体的方法,该异源二聚体包括二价异源免疫球蛋白,其中,所述二价异源免疫球蛋白具有第一重链、第二重链、第一轻链和第二轻链,所述第一重链和第二重链不相同,所述第一轻链和第二轻链不相同,所述第一重链和第二重链的一部分形成二价异源免疫球蛋白的Fc1区和Fc2区,该方法包括步骤:
1)将在第一宿主细胞中编码第一重链和第一轻链的一种或多种核酸和在第二宿主细胞中编码第二重链和第二轻链的一种或多种核酸进行表达,其中第一宿主细胞和第二宿主细胞彼此分开;
2)将第一重链与第一轻链一起还原和将第二重链与第二轻链一起还原;
3)将还原的第一重链、第一轻链、第二重链和第二轻链混合以形成所得混合物;
4)将混合物进行氧化;和
5)回收形成的异源二聚体,
其中所述Fc1区和Fc2区的氨基酸序列如以下中的任一组所示:
a)SEQ ID NO:16的Fc1区和SEQ ID NO:17的Fc2区;
b)SEQ ID NO:18的Fc1区和SEQ ID NO:19的Fc2区;
c)SEQ ID NO:20的Fc1区和SEQ ID NO:21的Fc2区;
d)SEQ ID NO:22的Fc1区和SEQ ID NO:23的Fc2区;
e)SEQ ID NO:24的Fc1区和SEQ ID NO:25的Fc2区;
f)SEQ ID NO:26的Fc1区和SEQ ID NO:27的Fc2区;
g)SEQ ID NO:28的Fc1区和SEQ ID NO:29的Fc2区;和
h)SEQ ID NO:30的Fc1区和SEQ ID NO:31的Fc2区。
20.如权利要求19所述的方法,其中一种或多种核酸包括在载体上或载体系统上。
21.如权利要求20所述的方法,其中,所述载体或载体系统包括基于pCDNA改造得到的质粒载体pX0GC。
22.如权利要求21所述的方法,其中,所述载体或载体系统被引入一个或多个细胞中。
23.如权利要求22所述的方法,其中,所述一个或多个细胞包括HEK293、HEK293T、HEK293F或CHO、CHO-S、CHO-dhfr-、CHO/DG44和ExpiCHO细胞中的一个。
24.如权利要求19所述的方法,其中还原步骤包括:
1)加入还原剂,所述还原剂包括:2-巯基乙胺、二硫苏糖醇、三(2-羧乙基)膦和其组合中的一种,
2)在4℃下进行还原反应最少3小时;和
3)去除还原剂。
25.如权利要求24所述的方法,所述还原剂包括在0.1mM或更高浓度下的二硫苏糖醇。
26.如权利要求24-25中任一项所述的方法,所述还原剂通过进行脱盐柱去除。
27.如权利要求19所述的方法,其中氧化步骤包括在空气中氧化最少5小时。
28.如权利要求19所述的方法,其中氧化步骤包括:
i)加入氧化剂,所述氧化剂包括L-脱氢抗坏血酸,
ii)在4℃下进行氧化反应最少5小时;和
iii)去除氧化剂。
29.如权利要求28所述的方法,所述氧化剂包括在0.5mM或更高浓度下的L-脱氢抗坏血酸。
30.如权利要求19所述的方法,其还包括分离步骤。
31.一种核酸,其编码如权利要求1中所述的异源二聚体。
32.如权利要求31所述的核酸,所述核酸包括选自SEQ ID NO:32、34、36、38、40、42、44、46、47、50、52、54、56、58、60、62、64-67中的一种。
33.一种载体或载体系统,其包括如权利要求31或32所述的核酸。
34.如权利要求33所述的载体或载体系统,其中所述载体或载体系统包括基于pCDNA改造得到的质粒载体pX0GC。
35.一种细胞,其包括如权利要求33或34所述的载体或载体系统。
36.如权利要求35所述的细胞,所述细胞包括HEK293或CHO细胞。
37.如权利要求36所述的细胞,所述HEK293细胞为HEK293T或HEK293F细胞,并且所述CHO细胞为CHO-S、CHO-dhfr-、CHO/DG44或ExpiCHO细胞。
38.一种药物组合物,其包括
药学上可接受的载体和下列之一:
i)如权利要求1-18中任一项所述的异源二聚体;
ii)如权利要求31或32所述的核酸;
iii)如权利要求33或34所述的载体或载体系统;
iv)如权利要求35-37中任一项所述的细胞;和
v)其组合。
39.如权利要求38所述的药物组合物在制备用于治疗或预防疾病或病症的药物中的用途,其中所述疾病或病症包括以下一种或多种:自身免疫性疾病、针对移植物的免疫应答、变态反应、感染、神经退行性疾病和肿瘤。
40.如权利要求39所述的用途,其中所述自身免疫性疾病选自关节炎、银屑病、多发性硬化症、溃疡性结肠炎、克罗恩病、系统性红斑狼疮、肾小球肾炎、扩张型心肌病样疾病、斯耶格伦氏综合征、过敏性接触性皮炎、多肌炎、硬皮病、动脉周性多动脉炎、风湿热、白癜风、胰岛素依赖性糖尿病、白塞氏综合征、慢性甲状腺炎和其组合。
41.如权利要求40所述的用途,其中所述关节炎为风湿性关节炎。
42.如权利要求39所述的用途,其中所述神经退行性疾病选自帕金森氏病、亨廷顿氏病、马查多-约瑟夫病、肌萎缩性侧索硬化症、克罗伊茨费尔特-雅各布病白血病和其组合。
43.如权利要求39所述的用途,其中所述肿瘤选自淋巴瘤、骨髓瘤、脑肿瘤、头颈部鳞状细胞癌、非小细胞肺癌、鼻咽癌、食道癌、胃癌、胰腺癌、胆囊癌、肝癌、结直肠癌、乳腺癌、卵巢癌、宫颈癌、子宫内膜癌、子宫肉瘤、前列腺癌、膀胱癌、肾细胞癌、黑色素瘤和其组合。
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CL2019000836A1 (es) | 2019-08-02 |
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US11498977B2 (en) | 2022-11-15 |
US20190284299A1 (en) | 2019-09-19 |
JP2019535650A (ja) | 2019-12-12 |
IL265605A (en) | 2019-05-30 |
KR20190055813A (ko) | 2019-05-23 |
PE20190576A1 (es) | 2019-04-22 |
EP3504234A1 (en) | 2019-07-03 |
CA3035681A1 (en) | 2018-04-05 |
ZA201901708B (en) | 2022-11-30 |
PH12019500655A1 (en) | 2019-08-05 |
TN2019000055A1 (en) | 2020-07-15 |
MY194994A (en) | 2022-12-30 |
KR102242990B1 (ko) | 2021-04-22 |
ECSP19022190A (es) | 2019-05-31 |
MX2019003563A (es) | 2019-08-12 |
SG11201901307VA (en) | 2019-03-28 |
AU2017336867B2 (en) | 2024-03-14 |
JP7424727B2 (ja) | 2024-01-30 |
CN109790215A (zh) | 2019-05-21 |
DOP2019000079A (es) | 2019-11-15 |
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