CN108465111A - 免疫球蛋白fc变体 - Google Patents
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Abstract
本发明涉及具有增加的FcRn结合亲和力的免疫球蛋白Fc变体，其特征在于包括选自天然免疫球蛋白Fc片段的恒定区中的307S、308F、380S、380A、428L、429K、430S、433K和434S(该编号是根据EU索引)的一个或更多个氨基酸修饰。由于高的FcRn结合亲和力，根据本发明的免疫球蛋白Fc变体显示更延长的体内半衰期，并且因此可用于制备蛋白质药物的长效剂型。
Description
本申请是分案申请，原申请的申请日为2012年12月28日，中国 申请号为201280066663.2，国际申请号为PCT/KR2012/011739，发明 名称为“免疫球蛋白FC变体”。
技术领域
本发明涉及具有增加的FcRn(新生Fc受体)结合亲和力的免疫球蛋 白Fc变体和使用其增加生理学活性多肽的体内半衰期的方法。本发明 的免疫球蛋白Fc变体特征在于包括选自天然免疫球蛋白Fc片段的恒 定区中的307S、308F、380S、380A、428L、429K、430S、433K和434S (该编号是根据EU索引)的一个或更多个氨基酸修饰。
背景技术
抗体是结合具体抗原的免疫蛋白。抗体由两条多肽轻链和两条多 肽重链组成。每条链由免疫球蛋白结构域组成并且都具有可变区和恒 定区。抗体之间的可变区显示明显的序列多样性并且负责结合靶抗原。 具有相对低的序列多样性的恒定区负责结合许多天然蛋白并且引发重 要的生物化学事件。
在许多之前的文献中公开了抗体的结构、功能和亚类的详细描述 (Burton DR:Immunoglobulin G:functional sites,Mol.Immunol.22: 161-206,1985)。IgG中Fc结构域之间的区域介导与新生Fc受体(FcRn) 的相互作用。FcRn捕获通过内吞作用进入细胞的IgG并且使其从内体 循环回至血流(Raghavan等,Annu.Rev.Cell Dev.Biol.12：181-220,1996)。由于抗体本身的大尺寸，利用肾过滤的排阻，该过程产生范围 从一周至三周的延长的抗体血清半衰期。
大鼠和人Fc结构域的研究已经表明了一些Fc残基对FcRn结合的 重要性。在鼠Fcγ结构域中，在位点T252、T254和T256处的随机突 变和噬菌体展示选择产生三重突变体T252L/T254S/T256F，其具有增加 的FcRn结合亲和力和血清半衰期(Ghetie等,Nat.Biotech.15(7): 637-640,1997)。通过在位点I253、H310和H435处的突变，Fc/FcRn 相互作用的破坏也导致下降的体内半衰期(Medesan等,J.Immunol. 158(5):2211-2217,1997)。
已经证明对于结合FcRn重要的人Fcγ结构域的一些残基的突变增 加血清半衰期。尤其，在人Fcγ1中，当三个残基被其他19个常规氨 基酸替代时，一些点突变显示增加的FcRn结合亲和力(Hinton等,J. Biol.Chem.279(8):6213-6216,2004)。已知Fc的氨基酸，H310和H435， 以及L309和I253主要通过盐桥和疏水键参与结合FcRn。也报道了 T250、M252、S254、T256、V308、E380、M428和N434中的突变增 加或降低FcRn结合亲和力(Roopenian等,Nat.Rview Immunology 7: 715-725,2007)。
韩国专利号10-1027427公开了具有增加的FcRn结合亲和力的曲 妥珠单抗(赫赛汀，Genentech)变体，并且这些变体包含选自257C、 257M、257L、257N、257Y、279Q、279Y、308F和308Y的一个或更 多个氨基酸修饰。韩国专利公开号2010-0099179提供了贝伐单抗(阿瓦 斯汀，Genentech)变体并且这些变体通过包含在N434S、 M252Y/M428L、M252Y/N434S和M428L/N434S的氨基酸修饰显示增 加的体内半衰期。
考虑蛋白质的清除和体内半衰期性质，抗体蛋白作为治疗剂的施 用需要以规定频率注射。更长的体内半衰期允许较不频繁的注射或更 低的剂量，其每一种明显是有优势的。尽管以前报道的Fc结构域中的 突变产生具有增加的FcRn结合亲和力和延长的体内半衰期的一些抗 体变体，但是发现这些突变不是最佳的，并且一些变体未使体内半衰 期提高至满意的水平。
同时，增加体内半衰期的需要不是限于抗体蛋白的问题。治疗性 蛋白，包括低分子量多肽、细胞因子和激素，由于低的稳定性容易变 性，被血液中的蛋白水解酶降解，并且最终通过肾或肝脏的作用去除。 所以，包括多肽作为药学上活性成分的蛋白质药物应频繁施用至患者， 以便维持它们的最佳血液浓度和效价。然而，由于大部分蛋白质药物 以可注射的剂型被施用至患者，用于维持活性多肽的最佳血液浓度的 频繁注射引起巨大的疼痛。
为了解决这些问题，已经尝试连接比如PEG的聚合物或融合比如 白蛋白的蛋白质以增加多肽药物的体内半衰期。然而，即使其连接PEG 或其融合白蛋白，该多肽药物仍显示相对低的生物学活性或其体内半 衰期不能增加至足够的水平。韩国专利号10-0567902公开了一种通过 体外将免疫球蛋白片段与非肽基聚合物连接制备的缀合物。在该方法 中，仅免疫球蛋白片段在大肠杆菌中产生，并且然后通过该非肽基聚 合物连接至生理学活性多肽，其通过使其活性下降最小化导致延长多 肽的半衰期。该方法已经视为可应用至在自然中未发现的非天然的或 合成的生理学活性物质，以及应用至天然肽和蛋白质的一般技术。然 而，仍需要使包括肽和蛋白质的治疗性生理学活性物质的体内半衰期 最大化。
因此，本发明人已经开发了与天然免疫球蛋白Fc片段相比具有增 加的FcRn结合亲和力的免疫球蛋白Fc变体。他们也发现，其中本发 明的免疫球蛋白Fc变体经非肽基聚合物共价连接至生理学活性多肽的 蛋白缀合物由于增加的FcRn结合亲和力显示更延长的体内半衰期。
发明内容
技术问题
本发明的目的是提供具有增加的FcRn结合亲和力的免疫球蛋白 Fc变体。
本发明的另一个目的是提供包括本发明的免疫球蛋白Fc变体的蛋 白缀合物。
本发明的仍另一个目的是提供通过使用本发明的免疫球蛋白Fc变 体增加生理学活性多肽的体内半衰期的方法。
技术方案
在一方面中，本发明提供了具有增加的FcRn结合亲和力的免疫球 蛋白Fc变体，其包括选自天然免疫球蛋白Fc片段的恒定区中的307S、308F、380S、380A、428L、429K、430S、433K和434S(该编号是根 据EU索引)的一个或更多个氨基酸修饰。
在另一方面中，本发明提供了具有增加的体内半衰期的蛋白缀合 物，其中生理学活性多肽经非肽基聚合物共价连接至根据本发明的免 疫球蛋白Fc变体。
在仍另一方面中，本发明提供了增加生理学活性多肽的体内半衰 期的方法，其包括经非肽基聚合物共价连接根据本发明的免疫球蛋白 Fc变体至生理学活性多肽的步骤。
发明的有利效果
因为根据本发明的免疫球蛋白Fc变体显示高的FcRn结合亲和力， 所以它们可增加生理学活性多肽的体内半衰期。因此，具有延长的体 内半衰期的蛋白缀合物——其中本发明的免疫球蛋白Fc变体经非肽基 聚合物共价连接至生理学活性多肽，可有效地用于制备具有显著低的 施用频率的蛋白质药物的长效剂型。
附图说明
图1至3是分析根据本发明的免疫球蛋白Fc变体的FcRn结合亲 和力的ELISA结果，其中左图代表在pH 6.0下的结合亲和力，和右图 代表在pH 7.4下的结合亲和力；和
图4是分析根据本发明的蛋白缀合物的FcRn结合亲和力的ELISA 结果，其中通过经非肽基聚合物连接免疫球蛋白Fc变体和生理学活性 多肽制备蛋白缀合物，左图代表在pH 6.0下的结合亲和力，和右图代 表在pH 7.4下的结合亲和力。
最佳实施方式
在本发明的一方面中，本发明涉及具有增加的FcRn结合亲和力的 免疫球蛋白Fc变体，其包括选自天然免疫球蛋白Fc片段的恒定区中 的307S、308F、380S、380A、428L、429K、430S、433K和434S(该 编号是根据EU索引)的一个或更多个氨基酸修饰。
如本文使用，术语“FcRn”或“新生Fc受体”意思是结合IgG抗 体Fc区域并且至少部分由FcRn基因编码的蛋白质。FcRn可以来自包 括人、小鼠、大鼠、兔和猴但是不限于这些的任何生物体。如本领域 已知，功能FcRn蛋白包括两条多肽，其通常被称为重链和轻链。轻链是β-2-微球蛋白并且重链由FcRn基因编码。除非本文另外指出，FcRn 或FcRn蛋白指FcRn重链与β-2-微球蛋白的复合体。
如本文使用，术语“天然(野生型)多肽”意思是经历修饰以产生变 体的非修饰的多肽。天然多肽是天然出现的多肽或其衍生物或操作的 多肽。天然多肽可实际上指包括其或编码其的氨基酸序列的多肽组合 物。所以，如本文使用，术语“天然免疫球蛋白”意思是非修饰的免 疫球蛋白多肽，其通过氨基酸修饰产生变体。可互换地，也可使用术 语“亲本免疫球蛋白”，其意思是通过氨基酸修饰产生变体的非修饰的 免疫球蛋白多肽。
如本文使用，术语“氨基酸修饰”意思是氨基酸替代、插入和/或 缺失，优选氨基酸序列的替代。如本文使用，术语“氨基酸替代”或 “替代”意思是在天然多肽序列中具体位置上氨基酸用另一个氨基酸 的替代。例如，包括T307S替代的免疫球蛋白Fc变体指其中在天然免 疫球蛋白Fc片段的氨基酸序列中307位的苏氨酸被丝氨酸替代的变 体。
如本文使用，术语“免疫球蛋白Fc变体”意思是与天然免疫球蛋 白Fc片段的那些相比，包括一个或更多个氨基酸修饰。在本发明的优 选的实施方式中，免疫球蛋白Fc变体意思是包括选自307S、308F、 380S、380A、428L、429K、430S、433K和434S(该编号是根据EU索引)的一个或更多个氨基酸修饰的变体，以便与天然免疫球蛋白Fc 片段相比，具有增加的FcRn结合亲和力。
本发明基于识别在免疫球蛋白Fc片段的恒定区中显示改进的 FcRn结合亲和力的一些突变。本发明提供与相应的天然免疫球蛋白Fc 片段相比具有增加的FcRn结合亲和力和/或体内半衰期的免疫球蛋白 Fc变体。抗体和其他生理学活性物质的体内半衰期(即，在对象的血清 或其他组织中的持久性)是确定其施用剂量或频率的重要临床参数。因 此，包括具有延长的体内半衰期的抗体的生理学活性物质是药学上重 要的和有利的。
在这点上，有报道称免疫球蛋白的体内半衰期与Fc和FcRn的结 合相关。在经非特异性胞饮作用摄取进入内皮细胞后，免疫球蛋白Fc 片段被内化进入酸性内体。在内体的酸性pH(<6.5)下FcRn与免疫球 蛋白结合并且在血流的碱性pH(>7.4)下释放其。因此，FcRn使得免疫 球蛋白免于溶酶体降解。当血清免疫球蛋白水平下降时，更多的FcRn 分子可用于免疫球蛋白结合，以便抢救增加量的免疫球蛋白。相反， 如果血清免疫球蛋白水平上升，FcRn变饱和，从而增加被内化和降解 的免疫球蛋白的比例(Ghetie和Ward,Annu.Rev.Immunol.18:739-766, 2000)。
基于免疫球蛋白Fc片段和FcRn的结合与免疫球蛋白的体内半衰 期之间的密切关系，多个突变被引入天然免疫球蛋白Fc片段的恒定区， 以便开发在低pH环境下显示增加的FcRn结合亲和力，但是在高pH 环境下结合亲和力基本上没有变化的免疫球蛋白Fc变体。因此，已发 现修饰选自天然免疫球蛋白Fc片段的恒定区中的氨基酸残基307、 308、380、428、429、430、433和434(该编号是根据EU索引)的一个 或更多个氨基酸增加了FcRn结合亲和力。
因此，本发明提供了包括选自天然免疫球蛋白Fc片段的恒定区中 的307S、308F、380S、380A、428L、429K、430S、433K和434S(该 编号是根据EU索引)的一个或更多个氨基酸修饰的免疫球蛋白Fc变 体。
在一个优选的实施方式中，本发明提供了包括选自天然免疫球蛋 白Fc片段的恒定区中的428L/434S、433K/434S、429K/433K、 428L/433K、308F/380A、307S/380S和380S/434S的氨基酸修饰的免疫 球蛋白Fc变体。
在具体的实施方式中，本发明提供了其中天然免疫球蛋白Fc片段 的恒定区中在428位的甲硫氨酸被亮氨酸替代和在434位的天冬酰胺 被丝氨酸替代的免疫球蛋白Fc变体。包括428L/434S氨基酸修饰的免 疫球蛋白Fc变体具有由SEQ ID NO:74表示，并且通过具有由SEQ ID NO:113表示的碱基序列的核苷酸编码的氨基酸序列。在本发明中，免 疫球蛋白Fc变体命名为HMC002。
在另一个具体的实施方式中，本发明提供了其中天然免疫球蛋白Fc片段的恒定区中在433位的组氨酸被赖氨酸替代和在434位的天冬 酰胺被丝氨酸替代的免疫球蛋白Fc变体。包括433K/434S氨基酸修饰 的免疫球蛋白Fc变体具有由SEQ ID NO:80表示，并且通过具有由 SEQ ID NO:114表示的碱基序列的核苷酸编码的氨基酸序列。在本发 明中，免疫球蛋白Fc变体命名为HMC008。
在仍另一个具体的实施方式中，本发明提供了其中天然免疫球蛋 白Fc片段的恒定区中在429位的组氨酸被赖氨酸替代和在433位的组 氨酸被赖氨酸替代的免疫球蛋白Fc变体。包括429K/433K的氨基酸修 饰的免疫球蛋白Fc变体具有由SEQ ID NO:91表示，并且通过具有由 SEQ ID NO:115表示的碱基序列的核苷酸编码的氨基酸序列。在本发 明中，免疫球蛋白Fc变体命名为HMC019。
在仍另一个具体的实施方式中，本发明提供了其中天然免疫球蛋 白Fc片段的恒定区中在428位的甲硫氨酸被亮氨酸替代和在433位的 组氨酸被赖氨酸替代的免疫球蛋白Fc变体。包括428L/433K氨基酸修 饰的免疫球蛋白Fc变体具有由SEQ ID NO:92表示并且通过具有由 SEQ ID NO:116表示的碱基序列的核苷酸编码的氨基酸序列。在本发 明中，免疫球蛋白Fc变体命名为HMC020。
在仍另一个具体的实施方式中，本发明提供了其中天然免疫球蛋 白Fc片段的恒定区中在308位的缬氨酸被苯丙氨酸替代和在380位的 谷氨酸被丙氨酸替代的免疫球蛋白Fc变体。包括308F/380A氨基酸修 饰的免疫球蛋白Fc变体具有由SEQ ID NO:100表示，并且通过具有 由SEQ ID NO:117表示的碱基序列的核苷酸编码的氨基酸序列。在本 发明中，免疫球蛋白Fc变体命名为HMC028。
在仍另一个具体的实施方式中，本发明提供了其中天然免疫球蛋 白Fc片段的恒定区中在307位的苏氨酸被丝氨酸替代和在380位的谷 氨酸被丝氨酸替代的免疫球蛋白Fc变体。包括307S/380S氨基酸修饰 的免疫球蛋白Fc变体具有由SEQ ID NO:101表示，并且通过具有由 SEQ ID NO:118表示的碱基序列的核苷酸编码的氨基酸序列。在本发 明中，免疫球蛋白Fc变体命名为HMC029。
在仍另一个具体的实施方式中，本发明提供了其中天然免疫球蛋 白Fc片段的恒定区中在380位的谷氨酸被丝氨酸替代和在434位的天 冬酰胺被丝氨酸替代的免疫球蛋白Fc变体。包括380S/434S氨基酸修 饰的免疫球蛋白Fc变体具有由SEQ ID NO:103表示，并且通过具有 由SEQ ID NO:119表示的碱基序列的核苷酸编码的氨基酸序列。在本 发明中，免疫球蛋白Fc变体命名为HMC031。
用于制备上述免疫球蛋白Fc变体的亲本免疫球蛋白Fc片段可以 优选地是从韩国专利号10-824505公开的大肠杆菌转化体HM11201 (Escherichia coli HM11201，保藏编号为KCCM-10660P，于2005年6 月20日被保藏于韩国微生物保藏中心(361-221，Yurim B/D，Hongje-1-dong，Scodaemun-gu，首尔120-861，韩国))产生的HMC001。 HMC001是具有由SEQID NO:73表示的氨基酸序列的免疫球蛋白Fc 片段。
在本发明中，根据引入亲本免疫球蛋白Fc片段的氨基酸修饰定义 免疫球蛋白Fc变体，并且其中氨基酸残基的编号如在Kabat中EU索 引的(Kabat等,Sequence ofproteins of immunological interest,5th Ed., United States Public HealthService,National Institutes of Health, Bethesda,1991)。此时，因为用作在本发明中亲本免疫球蛋白Fc片段 的HMC001是通过当在大肠杆菌转化体中产生时去除一部分N-末端缺 乏初始甲硫氨酸残基的免疫球蛋白Fc片段，其可不根据Kabat编号。 用作本发明中亲本免疫球蛋白Fc片段的HMC001具有脯氨酸为第一个 氨基酸，并且根据本发明的免疫球蛋白Fc变体的氨基酸编号与其符合。 然而，引入本发明的免疫球蛋白Fc变体的突变位置不限于HMC001 并且可根据Kabat编号定义。例如，HCM001的“81T”与根据Kabat 编号的“307T”相同。
本发明的免疫球蛋白Fc变体在内体的低pH下，例如，在pH 6.0 下显示增加的结合亲和力，但是在高pH下，例如，在pH 7.4下没有 增加的结合亲和力。进一步，它们进入内体的内化增加，但是本发明 的免疫球蛋白Fc变体可以在正常速率下被释放，产生增加的体内半衰 期。
在本发明中，天然免疫球蛋白Fc片段可以是衍生自人IgG1、IgG2、 IgG3或IgG4的Fc片段。在本发明中，该天然免疫球蛋白Fc片段优选 地可以是衍生自人IgG4的Fc片段，其不包括可变区和重链，并且是 无糖基化的。
与天然免疫球蛋白Fc片段相比，根据本发明的免疫球蛋白Fc变 体包括一个或更多个氨基酸修饰，并且因此具有不同的氨基酸序列。 根据本发明的免疫球蛋白Fc变体的氨基酸序列与天然免疫球蛋白Fc 片段的氨基酸序列基本上是同源的。例如，根据本发明的免疫球蛋白 Fc变体的氨基酸序列与天然免疫球蛋白Fc片段的氨基酸序列可具有 大约80％或更高的同源性，优选地大约90％或更高的同源性，以及最 优选地大约95％或更高的同源性。氨基酸修饰在遗传方面上可通过分 子生物学方法进行或可通过酶或化学方法进行。
可通过本领域已知的任何常规方法制备根据本发明的免疫球蛋白 Fc变体。在一个实施方式中，根据本发明的免疫球蛋白Fc变体用于创 建编码包括具体氨基酸修饰的多肽序列的核酸，接着如果期望被克隆 到宿主细胞、被表达并且测定。在相关的文献中描述了多种方法 (Molecular Cloning-A Laboratory Manual,第三版,Maniatis,Cold SpringHarbor Laboratory Press,New York,2001；Current Protocols in Molecular Biology,John Wiley&Sons)。
编码根据本发明的免疫球蛋白Fc变体的核酸可被并入用于蛋白质 表达的表达载体。表达载体典型地包括与控制或调控序列、选择标记、 任何融合伴侣和/或另外的元件操作地连接，即以功能关系布置的蛋白 质。根据本发明的免疫球蛋白Fc变体可通过在使得诱导或引起其表达 的适当条件下培养用核酸，优选地用包含编码免疫球蛋白Fc变体的核 酸的表达载体转化的宿主细胞产生。多种适当的宿主细胞包括但不限 于哺乳动物细胞、细菌细胞、昆虫细胞和酵母细胞。将外源核酸引入 宿主细胞内的方法是本领域所熟知的，并且将随着使用的宿主细胞而 不同。大肠杆菌，由于其低的生产成本是有工业价值的，可优选地用 作宿主细胞以产生根据本发明的免疫球蛋白Fc变体。
所以，本发明的范围包括制备免疫球蛋白Fc变体的方法，其包括 以下步骤：
1)在适合蛋白质表达的条件下，培养其中引入编码免疫球蛋白Fc 变体的核酸的宿主细胞；和
2)纯化或分离由宿主细胞表达的免疫球蛋白Fc变体。
可通过本领域已知的多种方法分离或纯化抗体。标准纯化方法包 括色谱技术、电泳、免疫沉淀法、透析、过滤、浓缩和色谱聚焦技术。 如本领域所熟知，多种天然蛋白比如细菌蛋白A、G和L可与抗体结 合，并且因此这些蛋白质可用于抗体的纯化。通常通过使用具体融合 标签(fusion partner)确保纯化。例如，如果采用GST融合可通过使用谷 胱甘肽树脂纯化蛋白质，如果采用His标签可通过使用Ni+2亲和色谱 法纯化蛋白质，或如果使用flag标签可通过使用固定化抗flag抗体纯 化蛋白质。
在另一方面中，本发明涉及具有增加的体内半衰期的蛋白缀合物， 其中生理学活性多肽经非肽基聚合物共价连接至本发明的免疫球蛋白 Fc变体。
根据本发明的免疫球蛋白Fc变体在内体的低pH下，例如，在pH 6.0下显示增加的结合亲和力，而在高pH下，例如，在pH 7.4下没有 相应增加的结合亲和力。因此，它们进入内体的内化增加，但是它们 以正常速率释放，导致增加的体内半衰期(见图1)。因此，根据本发明 的免疫球蛋白Fc变体可用作用于增加包括蛋白质药物的生理学活性多 肽的体内半衰期的载体。因此，本发明的蛋白缀合物可有效地用于制 备由于高的FcRn结合亲和力具有显著增加的体内半衰期的长效药物 剂型。
进一步，本发明提供了通过将本发明的免疫球蛋白Fc变体经非肽 基聚合物共价连接至生理学活性多肽制备长效药物剂型的方法。
根据本发明的制备方法可包括以下步骤：
1)将免疫球蛋白Fc变体经具有末端反应基的非肽基聚合物共价连 接至生理学活性多肽；和
2)分离其中生理学活性多肽、非肽基聚合物和免疫球蛋白Fc变体 彼此共价连接的缀合物。
本发明可用的非肽基聚合物可选自生物可降解聚合物，比如聚乙 二醇、聚丙二醇、乙二醇和丙二醇的共聚物、聚氧乙烯化的多元醇、 聚乙烯醇、多糖、葡聚糖、聚乙烯基乙醚、PLA(聚乳酸)或PLGA(聚 乳酸-乙醇酸)、脂聚合物、几丁质、透明质酸和其组合，并且优选地聚 乙二醇。而且，本领域已知的或使用常规技术可容易制备的它们的衍 生物落在本发明的范围内。
待连接至根据本发明的免疫球蛋白Fc变体的生理学活性多肽可以 是任何一种，没有限制，只要需要具有增加的体内半衰期。例如，可 使用用于治疗或预防人疾病目的的多种生理学活性多肽，比如细胞因 子、白介素、结合白介素的蛋白、酶、抗体、生长因子、转录因子、 血液因子、疫苗、结构蛋白、配体蛋白或受体、细胞表面抗原和受体 拮抗剂，以及其衍生物或类似物。
本发明可用的生理学活性多肽的例子包括人生长激素、生长激素 释放激素、生长激素释放肽、干扰素和干扰素受体(例如，干扰素-α、-β 和-γ、可溶性I型干扰素受体)、粒细胞集落-刺激因子(G-CSF)、粒细胞 -巨噬细胞集落-刺激因子(GM-CSF)、胰高血糖素样肽(GLP-1)、G-蛋白 -偶联受体、白介素(例如，IL-1受体、IL-4受体)、酶(例如，葡糖脑苷 脂酶、艾杜糖醛酸-2-硫酸酯酶、α-半乳糖苷酶-A、半乳糖苷酶α、β、 α-L-艾杜糖苷酸酶、丁酰胆碱酯酶、壳质酶、谷氨酸脱羧酶、伊米苷酶 (imiglucerase)、脂肪酶、尿酸酶、血小板活化因子乙酰水解酶、中性肽 链内切酶、髓过氧物酶)、白介素-和细胞因子-结合蛋白(例如，IL-18bp、 TNF-结合蛋白)、巨噬细胞活化因子、巨噬细胞肽、B-细胞因子、T-细 胞因子、蛋白A、过敏抑制剂、细胞坏死糖蛋白、免疫毒素、淋巴毒 素、肿瘤坏死因子、肿瘤抑制剂、转化生长因子、α-1抗胰蛋白酶、白 蛋白、α-乳蛋白酶、载脂蛋白-E、促红细胞生成素、高糖基化的促红细 胞生成素、血管生成素、血红蛋白、凝血酶、凝血酶受体激活肽、凝 血酶调节素、血液因子VII、血液因子VIIa、血液因子VIII、血液因子 IX和血液因子XIII、纤溶酶原激活物、纤维蛋白-结合肽、尿激酶、链 激酶、水蛭素、蛋白C、C-反应蛋白、肾素抑制剂、胶原酶抑制剂、 超氧化物歧化酶、瘦蛋白(leptin)、血小板衍生的生长因子、上皮生长 因子、表皮生长因子、血管抑制素、内皮抑素血管紧张肽、骨生长因 子、骨刺激蛋白、降钙素、胰岛素、心钠素、软骨诱导因子、依降钙 素、结缔组织活化因子、组织因子途径抑制剂、促卵泡激素、促黄体 激素、促黄体激素释放激素、神经生长因子(例如，神经生长因子、睫 状体神经营养因子、轴突再生因子-1(axogenesisfactor-1)、脑钠肽、胶 质源性神经营养因子、神经生长因子、中性粒细胞抑制因子、神经营 养因子、neuturin)、甲状旁腺激素、松弛素、分泌素、生长调节素、胰 岛素样生长因子、肾上腺皮质激素、胰高血糖素、缩胆囊素、胰腺多 肽、胃泌素释放肽、促肾上腺皮质激素释放因子、促甲状腺激素、自 分泌运动因子、乳铁蛋白、肌肉生长抑制因子、受体(例如，TNFR(P75)、 TNFR(P55)、IL-1受体、VEGF受体、B-细胞激活受体)、受体拮抗剂(例 如，IL1-Ra)、细胞表面抗原(例如，CD 2、3、4、5、7、11a、11b、18、 19、20、23、25、33、38、40、45、69)、单克隆抗体、多克隆抗体、 抗体片段(例如，scFv、Fab、Fab'、F(ab')2和Fd)和病毒衍生的疫苗抗 原，但不限于这些。抗体片段可选自具有与具体抗原结合能力的Fab、 Fab'、F(ab')2、Fd和scFv。
其中生理学活性多肽经非肽基聚合物共价连接至本发明的免疫球 蛋白Fc变体的蛋白缀合物由于高的FcRn结合亲和力显示显著延长的 体内半衰期(见图4)。所以，通过使用作为载体的根据本发明的免疫球 蛋白Fc片段制备的蛋白缀合物可增加在血液中的持久性，并且因此显 著地降低施用频率。
实施例
通过以下实施例进一步阐释本发明。然而，应理解这些实施例仅 用于特别地阐述本发明，而不应以任何形式理解为它们用于限制本发 明。
实施例1：构建表达免疫球蛋白Fc片段的载体
从由大肠杆菌转化体HM11201(KCCM-10660P，韩国专利号 10-0824505)产生的HMC001的氨基酸序列(SEQ ID NO:73)选择参与人 FcRn的结合亲和力的位置，并且在其上诱导突变，以用另一个氨基酸 替代相应位置的氨基酸，以便增加FcRn结合亲和力。为了实现此，使 用核苷酸替代的引物和QuikChangeTM定点突变试剂盒(Stratagene)。在 这点上，在以下表1至3中显示了用于定点突变的引物。
对于通过聚合酶链反应(PCR)的定点突变，将50ng的HMC001表 达载体、每个引物对、dNTP和PfuTurboTM聚合酶(Stratagene)添加在PCR 管中，并且如下进行反应：在95℃下变性30秒，95℃下30秒，55℃ 下1分钟和68℃下14分钟的16个循环，和68℃下最终延伸5分钟。 以上扩增的大约1.2kb的PCR产品通过DNA测序进行碱基序列分析， 并且结果显示在以下表4中。在表4中描述的氨基酸编号是根据EU索 引，并且括号中的编号表示基于HMC001的氨基酸序列(SEQ ID NO: 73)的氨基酸编号。
每个扩增的PCR产品用NdeI或BamHI切割，并且然后插入之前 用相同的限制性内切酶处理的质粒pET22b(Novagen)中，从而获得包 括每个免疫球蛋白Fc变体的表达载体。
表1
表2
表3
表4
实施例2：在大肠杆菌中产生免疫球蛋白Fc变体
通过在42℃下热休克1分钟将实施例1中制备的免疫球蛋白Fc 变体的表达载体分别转化进入大肠杆菌BL21(DE3)感受态细胞 (Invitrogen)，接着在补充氨苄青霉素的LB固体培养基上培养以选择抗 氨苄青霉素的菌落。
因此选择的菌落接种在500ml的2×LB培养基(包含氨苄青霉素) 上，并且在振荡培养器中在37℃和20rpm下培养15小时。在将100ml 的培养液转移至500ml新鲜的2×LB培养基(包含氨苄青霉素)之后， 温育所得溶液直到在600nm(OD600)的光密度达到4至5。将200ml 的培养液以10％(v/v)的比例转移至5L-发酵罐中，向其中注入2×LB 培养基(包含氨苄青霉素)，并且在37℃、500～700rpm和1vvm的通气 速度条件下进行半自动pH恒定(semi-pH stat)分批补料培养45小时。 在发酵期间，当OD600达到90或更高时，将作为诱导物的IPTG(异 丙基-1-硫代-β-D-呋喃半乳糖苷)添加至发酵罐，终浓度为0.1mM，以 便诱导蛋白质合成。
实施例3：免疫球蛋白Fc变体的分离和纯化
实施例2中发酵的培养液在12,000g下离心30分钟以回收细胞团 块。因此回收的细胞团块悬浮在10×体积的裂解缓冲液(20mM Tris(pH 9.0)、1mM EDTA(pH 8.0)、0.2MNaCl、0.5％triton X-100)中，并且然 后在15,000psi的压力下使用微射流机(微射流卡盘)破坏三次。因此获 得的细胞裂解液在6,000g下离心30分钟，以仅获得通过大肠杆菌转化体表达的蛋白质的内含体。
内含体用0.5％Triton X-100和蒸馏水冲洗，并且悬浮在包含10× 体积的20mMTris(pH 9.0)的8M尿素溶液中2小时，以使它们溶解。 为了分离不溶解的固体杂质，溶解内含体的溶液在12,000g下离心30 分钟以收集上清液。然后，将L-半胱氨酸添加至上清液，终浓度为1mM 并在室温下温育1小时，以诱导蛋白质还原。
对于还原的蛋白质的重折叠，用100×体积的重折叠溶液(2M尿素、 0.25M精氨酸、50mM Tris(pH 8.5)、0.5mM Cys)稀释在4℃下溶解24 小时的内含体。
在Akta提纯器(Amersham Pharmacia Biotech)中使用离子交换柱 (IEX柱，GEHealthcare)纯化因此重折叠的蛋白质，从而获得纯度98％ 或更高的免疫球蛋白Fc变体。
实施例4：评估免疫球蛋白Fc变体的人FcRn结合亲和力
为了评估实施例3中分离和纯化的免疫球蛋白Fc变体的FcRn结 合亲和力，进行ELISA。在以下实验中，人FcRn(hFcRn，人新生Fcγ 受体)在293T细胞中表达并且从其纯化，并且GST抗体从Merk Milipore购买。在每个免疫球蛋白Fc变体中测量的FcRn结合亲和力与作为对照组的HMC001或天然IgG的那些对比。
在用30μg/ml的天然IgG和每个10μg/ml的HMC001和免疫球蛋 白Fc变体包被96-孔板后，添加100μl的5μg/ml的FcRn至每个孔。 为了评估结合或解离，在pH 6.0和7.4下进行该实验。用于该实验的 试验缓冲液和冲洗液具有如表5中显示的以下组分，并且结果显示在 图1至3中。
表5
| 组分 | |
| 试验缓冲液 | 磷酸钠(pH 6.0/7.4)、0.5％BSA、0.05％吐温20 |
| 冲洗液 | 磷酸钠(pH 6.0/7.4)、0.05％吐温20 |
如在图1至3中所显示，发现与HMC001或天然IgG相比，根据 本发明制备的免疫球蛋白Fc变体在pH 7.4下显示低的FcRn结合亲和 力，但是在pH 6.0下高的FcRn结合亲和力。
实施例5：评估包括免疫球蛋白Fc变体和exendin-4的缀合物的人FcRn结合亲和力
为了检查根据本发明的免疫球蛋白Fc变体，甚至以与蛋白质药物 的缀合形式，是否显示增加的人FcRn结合亲和力，使用在两端具有乙 醛反应基的PEG将在实施例4中发现显示高的FcRn结合亲和力的免 疫球蛋白Fc变体HMC002和HMC008共价连接至exendin-4，从而制 备蛋白缀合物。根据韩国专利号10-1058290中描述的方法进行蛋白缀 合物的制备。根据如实施例4中描述的相同方法进行ELISA，以评估 上面制备的蛋白缀合物的人FcRn结合亲和力。
如图4中所显示，发现根据本发明的免疫球蛋白Fc变体维持高的 FcRn结合亲和力，即使其每个经非肽基聚合物连接至生理学活性多肽。
所以，通过使用根据本发明的免疫球蛋白Fc变体作为载体制备的 药物缀合物已经大大延长了体内半衰期，由于增加的FcRn结合亲和 力，并且因此它可用作能够显著降低施用频率的长效药物剂型。
给出在本描述使用的特定术语仅为了描述具体的实施方式，并且 不旨在限制本发明。在本描述中使用的单数形式包括复数形式，除非 它们明显地表示相反的意思。在本描述中使用的“包括”或“具有” 的意思旨在包含特定性质、区域、整数、步骤、操作、元件和/或组分， 但不旨在排除其他性质、区域、整数、步骤、操作、元件、组分和/或 基团的存在或添加。
工业适用性
本发明的免疫球蛋白Fc变体显示高的FcRn结合亲和力，并且因 此可增加生理学活性多肽的体内半衰期。所以，具有延长的体内半衰 期的蛋白缀合物——其中本发明的免疫球蛋白Fc变体经非肽基聚合物 共价连接至生理学活性多肽——可有效地用于制备具有显著低的施用 频率的蛋白质药物的长效剂型。
<110> 韩美科学株式会社
<120> 免疫球蛋白Fc变体
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<150> KR10-2011-0147683
<151> 2011-12-30
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gttgtgcaga gcctccttca tcacggagca tgag 34
<210> 33
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203R/H207Kss
<400> 33
catgctccgt gatgcgtgag gctctgaaga accactacac acag 44
<210> 34
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203R/H207Kas
<400> 34
ctgtgtgtag tggttcttca gagcctcacg catcacggag catg 44
<210> 35
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203K/H207Kss
<400> 35
catgctccgt gatgaaggag gctctgaaga accactacac acag 44
<210> 36
<211> 44
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203K/H207Kas
<400> 36
ctgtgtgtag tggttcttca gagcctcctt catcacggag catg 44
<210> 37
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 引物FcM202L/H207Kss
<400> 37
cttctcatgc tccgtgctgc atgaggctct gaagaaccac tacacacag 49
<210> 38
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 引物FcM202L/H207Kas
<400> 38
ctgtgtgtag tggttcttca gagcctcatg cagcacggag catgagaag 49
<210> 39
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203K/N208Tss
<400> 39
ctcatgctcc gtgatgaagg aggctctgca cacccactac acacagaag 49
<210> 40
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203K/N208Tas
<400> 40
cttctgtgtg tagtgggtgt gcagagcctc cttcatcacg gagcatgag 49
<210> 41
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Ess
<400> 41
gtggtcagcg tcctcgaagt cctgcaccag gac 33
<210> 42
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Eas
<400> 42
gtcctggtgc aggacttcga ggacgctgac cac 33
<210> 43
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE154Ass
<400> 43
agcgacatcg ccgtggcgtg ggagagcaat ggg 33
<210> 44
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE154Aas
<400> 44
cccattgctc tcccacgcca cggcgatgtc gct 33
<210> 45
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE154Sss
<400> 45
agcgacatcg ccgtgtcgtg ggagagcaat ggg 33
<210> 46
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE154Sas
<400> 46
cccattgctc tcccacgaca cggcgatgtc gct 33
<210> 47
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcV82Pss
<400> 47
gtcagcgtcc tcacccccct gcaccaggac tgg 33
<210> 48
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcV82Pas
<400> 48
ccagtcctgg tgcagggggg tgaggacgct gac 33
<210> 49
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE204Sss
<400> 49
tgctccgtga tgcattcggc tctgcacaac cac 33
<210> 50
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE204Sas
<400> 50
gtggttgtgc agagccgaat gcatcacgga gca 33
<210> 51
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Sss
<400> 51
gtggtcagcg tcctctccgt cctgcaccag gac 33
<210> 52
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Sas
<400> 52
gtcctggtgc aggacggaga ggacgctgac cac 33
<210> 53
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203A/E204Sss
<400> 53
tcatgctccg tgatggcttc ggctctgcac aacc 34
<210> 54
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203A/E204Sas
<400> 54
ggttgtgcag agccgaagcc atcacggagc atga 34
<210> 55
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH207A/N208Sss
<400> 55
gatgcatgag gctctggcca gccactacac acag 34
<210> 56
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH207A/N208Sas
<400> 56
ctgtgtgtag tggctggcca gagcctcatg catc 34
<210> 57
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE204A/N208Sss
<400> 57
gctccgtgat gcatgcggct ctgcacagcc ac 32
<210> 58
<211> 32
<212> DNA
<213> 人工序列
<220>
<223> 引物FcE204A/N208Sas
<400> 58
gtggctgtgc agagccgcat gcatcacgga gc 32
<210> 59
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203A/N208Sss
<400> 59
ctcatgctcc gtgatggctg aggctctgca cagc 34
<210> 60
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH203A/N208Sas
<400> 60
gctgtgcaga gcctcagcca tcacggagca tgag 34
<210> 61
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcM202A/N208Sss
<400> 61
cttctcatgc tccgtggcgc atgaggctct gcac 34
<210> 62
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcM202A/N208Sas
<400> 62
gtgcagagcc tcatgcgcca cggagcatga gaag 34
<210> 63
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcY93Lss
<400> 63
gctgaatggc aaggagctca agtgcaaggt ctcc 34
<210> 64
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcY93Las
<400> 64
ggagaccttg cacttgagct ccttgccatt cagc 34
<210> 65
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcV82Lss
<400> 65
ggtcagcgtc ctcaccctcc tgcaccagga ctg 33
<210> 66
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 引物FcV82Las
<400> 66
cagtcctggt gcaggagggt gaggacgctg acc 33
<210> 67
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Ass
<400> 67
gtgtggtcag cgtcctcgcc gtcctgcacc agga 34
<210> 68
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcT81Aas
<400> 68
tcctggtgca ggacggcgag gacgctgacc acac 34
<210> 69
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH207L/N208Sss
<400> 69
gatgcatgag gctctgctca gccactacac acag 34
<210> 70
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcH207L/N208Sas
<400> 70
ctgtgtgtag tggctgagca gagcctcatg catc 34
<210> 71
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcY93A/N208Sss
<400> 71
gctgaatggc aaggaggcca agtgcaaggt ctcc 34
<210> 72
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物FcY93A/N208Sas
<400> 72
ggagaccttg cacttggcct ccttgccatt cagc 34
<210> 73
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC001 Fc片段
<400> 73
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 74
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC002 Fc片段衍生物
<400> 74
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 75
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC003 Fc片段衍生物
<400> 75
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Phe Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 76
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC004 Fc片段衍生物
<400> 76
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Thr Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 77
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC005 Fc片段衍生物
<400> 77
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Thr Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 78
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC006 Fc片段衍生物
<400> 78
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Phe His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 79
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC007 Fc片段衍生物
<400> 79
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Leu Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 80
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC008 Fc片段衍生物
<400> 80
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Lys Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 81
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC009 Fc片段衍生物
<400> 81
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 82
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC010 Fc片段衍生物
<400> 82
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Thr Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 83
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC011 Fc片段衍生物
<400> 83
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Phe His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 84
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC012 Fc片段衍生物
<400> 84
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Arg Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 85
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC013 Fc片段衍生物
<400> 85
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Lys Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 86
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC014 Fc片段衍生物
<400> 86
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Arg Ala Leu Lys Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 87
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC015 Fc片段衍生物
<400> 87
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Arg Ala Leu Lys Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 88
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC016 Fc片段衍生物
<400> 88
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Arg Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 89
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC017 Fc片段衍生物
<400> 89
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Lys Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 90
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC018 Fc片段衍生物
<400> 90
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Arg Glu Ala Leu Lys Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 91
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC019 Fc片段衍生物
<400> 91
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Lys Glu Ala Leu Lys Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 92
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC020 Fc片段衍生物
<400> 92
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu Lys Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 93
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC021 Fc片段衍生物
<400> 93
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Lys Glu Ala Leu His Thr
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 94
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC022 Fc片段衍生物
<400> 94
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Glu Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 95
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC023 Fc片段衍生物
<400> 95
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Glu Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 96
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC024 Fc片段衍生物
<400> 96
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ala Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 97
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC025 Fc片段衍生物
<400> 97
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ser Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 98
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC026 Fc片段衍生物
<400> 98
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ala Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 99
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC027 Fc片段衍生物
<400> 99
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Pro Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Ser Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 100
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC028 Fc片段衍生物
<400> 100
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Pro Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ala Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 101
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC029 Fc片段衍生物
<400> 101
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Ser Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ser Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 102
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC030 Fc片段衍生物
<400> 102
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Ala Ser Ala Leu His Asn
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 103
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC031 Fc片段衍生物
<400> 103
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Ala Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 104
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC032 Fc片段衍生物
<400> 104
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Ala Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 105
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC033 Fc片段衍生物
<400> 105
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Ala Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 106
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC034 Fc片段衍生物
<400> 106
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met Ala Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 107
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC035 Fc片段衍生物
<400> 107
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Ala His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 108
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC036 Fc片段衍生物
<400> 108
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Leu Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 109
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC037 Fc片段衍生物
<400> 109
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Leu Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 110
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC038 Fc片段衍生物
<400> 110
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Ala Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 111
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC039 Fc片段衍生物
<400> 111
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu Leu Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 112
<211> 221
<212> PRT
<213> 人工序列
<220>
<223> HMC040 Fc片段衍生物
<400> 112
Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu
1 5 10 15
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
20 25 30
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln
35 40 45
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
50 55 60
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
65 70 75 80
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Ala Lys Cys Lys
85 90 95
Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
100 105 110
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
115 120 125
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
130 135 140
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
145 150 155 160
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
165 170 175
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln
180 185 190
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Ser
195 200 205
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
210 215 220
<210> 113
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC002 Fc片段衍生物
<400> 113
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgctgcatg aggctctgca cagccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 114
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC008 Fc片段衍生物
<400> 114
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgatgcatg aggctctgaa gagccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 115
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC019 Fc片段衍生物
<400> 115
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgatgaagg aggctctgaa gaaccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 116
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC020 Fc片段衍生物
<400> 116
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg agtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgctgcatg aggctctgaa gaaccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 117
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC028 Fc片段衍生物
<400> 117
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
acccccctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgg cgtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgatgcatg aggctctgca caaccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 118
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC029 Fc片段衍生物
<400> 118
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
tccgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgt cgtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgatgcatg aggctctgca caaccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
<210> 119
<211> 663
<212> DNA
<213> 人工序列
<220>
<223> HMC031 Fc片段衍生物
<400> 119
ccatcatgcc cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 60
cccaaggaca ccctcatgat ctcccggacc cctgaggtca catgcgtggt ggtggacgtg 120
agccaggaag accctgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 180
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc 240
accgtcctgc accaggactg gctgaatggc aaggagtaca agtgcaaggt ctccaacaaa 300
ggcctcccat cctccatcga gaaaaccatc tccaaagcca aagggcagcc ccgagaacca 360
caggtgtaca ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 420
tgcctggtca aaggcttcta tcccagcgac atcgccgtgt cgtgggagag caatgggcag 480
ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 540
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaacgtctt ctcatgctcc 600
gtgatgcatg aggctctgca cagccactac acacagaaga gcctctccct gtctctgggt 660
aaa 663
1
Claims (11)
1.蛋白缀合物，其中生理学活性多肽经由非肽基聚合物共价连接至免疫球蛋白Fc变体，
其中所述免疫球蛋白Fc变体包括在野生型免疫球蛋白Fc片段的恒定区中的氨基酸修饰428L/434S(该编号是根据EU索引)。
2.根据权利要求1所述的蛋白缀合物，其中所述蛋白缀合物与包括野生型免疫球蛋白Fc片段的蛋白缀合物相比具有增加的体内半衰期和FcRn结合亲和力。
3.根据权利要求1所述的蛋白缀合物，所述免疫球蛋白Fc变体包括下列氨基酸修饰：所述野生型免疫球蛋白Fc片段的所述恒定区中在428位的甲硫氨酸被亮氨酸替代和在434位的天冬酰胺被丝氨酸替代；并且具有由SEQ ID NO:74表示的氨基酸序列。
4.根据权利要求1所述的蛋白缀合物，其中所述非肽基聚合物选自聚乙二醇单聚合物、聚丙二醇单聚合物、乙二醇-丙二醇共聚物、聚氧乙烯化的多元醇、聚乙烯醇、多糖、葡聚糖、聚乙烯基乙醚、生物可降解聚合物、脂聚合物、几丁质、透明质酸和其组合。
5.根据权利要求1所述的蛋白缀合物，其中所述生理学活性多肽选自人生长激素、生长激素释放激素、生长激素释放肽、干扰素、集落刺激因子、白介素、可溶性白介素受体、可溶性TNF受体、葡糖脑苷脂酶、巨噬细胞活化因子、巨噬细胞肽、B细胞因子、T细胞因子、蛋白A、过敏抑制剂、细胞坏死糖蛋白、免疫毒素、淋巴毒素、肿瘤坏死因子、肿瘤抑制剂、转移生长因子、α-1抗胰蛋白酶、白蛋白、载脂蛋白-E、促红细胞生成素、高糖基化的促红细胞生成素、血液因子VII、血液因子VIII、血液因子IX、血纤维蛋白溶酶原活化因子、尿激酶、链激酶、蛋白C、C-反应蛋白、肾素抑制剂、胶原酶抑制剂、超氧化物歧化酶、瘦蛋白、血小板衍生的生长因子、表皮生长因子、骨生长因子、骨刺激蛋白、降钙素、胰岛素、胰岛素变体、胰高血糖素、胰高血糖素样肽-1、心钠素、软骨诱导因子、结缔组织活化因子、促卵泡激素、促黄体激素、促黄体激素释放激素、神经生长因子、甲状旁腺激素、松弛素、分泌素、生长调节素、胰岛素样生长因子、肾上腺皮质激素、缩胆囊素、胰腺多肽、胃泌素释放肽、促肾上腺皮质激素释放因子、促甲状腺激素、受体、受体拮抗剂、细胞表面抗原、单克隆抗体、多克隆抗体、抗体片段和病毒衍生的疫苗抗原。
6.根据权利要求1所述的蛋白缀合物，其中所述野生型免疫球蛋白Fc片段选自IgG1、IgG2、IgG3和IgG4的Fc片段。
7.根据权利要求6所述的蛋白缀合物，其中所述野生型免疫球蛋白Fc片段是人无糖基化IgG4Fc片段。
8.根据权利要求1所述的蛋白缀合物，其中所述野生型免疫球蛋白Fc片段具有由SEQID NO:73表示的氨基酸序列。
9.根据权利要求1所述的蛋白缀合物，其中所述免疫球蛋白Fc变体不包括所述免疫球蛋白的可变区和轻链。
10.根据权利要求1所述的蛋白缀合物，其中所述免疫球蛋白Fc变体在动物细胞或大肠杆菌中产生。
11.根据权利要求1所述的蛋白缀合物，其中与野生型免疫球蛋白Fc片段相比，所述免疫球蛋白Fc变体在pH 7.4下显示低的FcRn结合亲和力，但是在pH 6.0下显示高的FcRn结合亲和力。
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| WO2013100702A1 (en) | 2013-07-04 |
| TW202012449A (zh) | 2020-04-01 |
| JP6689329B2 (ja) | 2020-04-28 |
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| TW201336865A (zh) | 2013-09-16 |
| JP2019001793A (ja) | 2019-01-10 |
| TWI680137B (zh) | 2019-12-21 |
| US20140357843A1 (en) | 2014-12-04 |
| CN104039831B (zh) | 2018-02-23 |
| EP2802604A1 (en) | 2014-11-19 |
| JP6448368B2 (ja) | 2019-01-09 |
| AR089507A1 (es) | 2014-08-27 |
| JP2015507628A (ja) | 2015-03-12 |
| EP3656792A1 (en) | 2020-05-27 |
| KR20130078633A (ko) | 2013-07-10 |
| CN104039831A (zh) | 2014-09-10 |
| KR102041412B1 (ko) | 2019-11-11 |
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