CN111542540A - 结合瘦蛋白受体和/或gp130的双特异性抗原结合分子及其使用方法 - Google Patents
结合瘦蛋白受体和/或gp130的双特异性抗原结合分子及其使用方法 Download PDFInfo
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Abstract
本发明涉及抗原结合分子，包括结合人GP130和/或人瘦蛋白受体(LEPR)的双特异性抗原结合分子，以及此类抗原结合分子用于治疗与瘦蛋白缺乏或瘦蛋白抵抗相关的病症和障碍的用途。本发明的双特异性抗原结合分子可以是例如双特异性抗体，所双特异性抗体包含特异性结合人GP130的第一抗原结合结构域和特异性结合人LEPR的第二抗原结合结构域。本发明的双特异性抗原结合分子可用于诱导的瘦蛋白和/或LEPR介导的信号传导将是有益的治疗应用，例如，用于治疗肥胖、脂肪营养不良以及与瘦蛋白缺乏或瘦蛋白抵抗相关的或由瘦蛋白缺乏或瘦蛋白抵抗导致的其他疾病和障碍。
Description
技术领域
本发明涉及抗原结合分子，包括结合人GP130和/或人瘦蛋白受体(LEPR)的双特异性抗原结合分子(例如，双特异性抗体)，以及此类抗原结合分子用于治疗与瘦蛋白缺乏或瘦蛋白抵抗相关的病症和障碍的用途。
序列表
序列表的正式副本以ASCII格式的序列表与说明书同时通过EFS-Web以电子方式提交，文件名为“10397WO01_SEQ_LIST_ST25.txt”，创建日期为2018年12月17日，大小为约151KB。该ASCII格式的文档中含有的序列表是说明书的一部分，并且以引用的方式整体并入本文。
背景技术
糖蛋白130(GP130)是受体复合物的组分，所述受体复合物还包含CNTRF-α和LIFR-β。通过这种受体复合物进行的信号传导活化了JAK/STAT信号传导，在某些生物学背景下，这会导致食欲下降、食物摄入减少和体重减轻。
瘦蛋白是一种主要由脂肪组织表达的多肽激素，它涉及代谢、能量平衡和食物摄入的调节。瘦蛋白活性通过与瘦蛋白受体的相互作用和通过瘦蛋白受体的信号传导来介导。瘦蛋白受体(也称为“LEPR”、“WSX”、“OB受体”、“OB-R”和“CD295”)是一种I类细胞因子受体家族的单次跨膜受体，具有较大(818个氨基酸)的胞外结构域。瘦蛋白缺乏、瘦蛋白抵抗和某些LEPR信号传导缺陷/信号传导受损突变与肥胖、2型糖尿病、血脂异常、脂肪营养不良、肝性脂肪变性、非酒精性和酒精性脂肪肝疾病、严重胰岛素抵抗、矮怪病/多诺霍(Donohue)综合征、罗伯森-门登霍尔(Rabson-Mendenhall)综合征和相关的并发症相关联。解决瘦蛋白抵抗、瘦蛋白缺乏和低瘦蛋白血症(例如，脂肪营养不良)的治疗方法主要集中于补充瘦蛋白或瘦蛋白类似物向受影响的个体的递送。然而，这些方法通常显示出有限的功效，尤其是在瘦蛋白抵抗个体中，并且常常与不良副作用相关联。因此，本领域中需要治疗瘦蛋白抵抗和与瘦蛋白缺乏或低瘦蛋白血症相关的其他病症的替代方法。
发明内容
本发明部分涉及LEPR和GP130的抗体介导的异二聚化，以活化两个受体，从而刺激与通过这些受体进行的信号传导相关的厌食作用的概念。因此，本发明提供了结合人GP130和/或人瘦蛋白受体(LEPR)的抗原结合分子(例如，抗体和抗体的抗原结合片段)。根据某些实施方案，本发明提供了双特异性抗原结合分子，所述双特异性抗原结合分子包含特异性结合人GP130的第一抗原结合结构域(D1)和特异性结合人瘦蛋白受体(LEPR)的第二抗原结合结构域(D2)。本发明包括LEPRxGP130双特异性分子(例如，双特异性抗体)。在本发明的某些示例性实施方案中，抗GP130抗原结合结构域(D1)和抗LEPR(D2)抗原结合结构域各自包含与相同的或不同的轻链可变区(LCVR)配对的不同的、独特的重链可变区(HCVR)。
本发明的抗原结合分子(例如，双特异性抗原结合分子)尤其可用于靶向表达LEPR的细胞和/或表达GP130的细胞、或它们二者。根据某些实施方案，本发明的双特异性抗原结合分子可用于使细胞表面上的LEPR和GP130彼此物理连接，以刺激LEPR信号传导。通过这种方式，本发明的双特异性抗原结合分子可以在多种治疗应用中(例如，在肥胖、脂肪营养不良以及与瘦蛋白缺乏或瘦蛋白抵抗相关的或由瘦蛋白缺乏或瘦蛋白抵抗导致的其他疾病和障碍的治疗中)作为LEPR激动剂，在这些治疗应用中瘦蛋白和/或LEPR介导的信号传导将是有利的。
通过参阅接下来的详细说明，其他实施方案将变得显而易见。
附图说明
图1示出了与用同种型对照抗体的进行治疗(实心圆圈)相比，LEPRxGP130双特异性抗体治疗(空心正方形和空心菱形)对喂食高脂肪饮食、表达人LEPR和人GP130的肥胖小鼠的影响。在第0天和第7天(以“剂量”和向上箭头表示)以30mg/kg皮下施用抗体，针对每个治疗组随时间推移，绘制随时间推移的抗体治疗对体重的影响(以从给药前起体重的平均变化百分比表示)图形。空心正方形表示用bsAb21236(或称为“H4H21236D”)治疗的小鼠。空心菱形表示用bsAb21237(或称为“H4H21237D”)治疗的小鼠。(*)表示同种型对照与bsAb21236相比，P<0.05。(#)表示同种型对照与bsAb21237相比，P<0.05。
具体实施方式
在描述本发明前，应当理解，本发明不限于所述的特定方法和实验条件，因为这类方法和条件可以变化。还应当理解，本文所用的术语仅用于描述具体实施方案的目的，而无意进行限制，因为本发明的范围将仅由所附权利要求书限制。
除非另有定义，否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常所理解的相同含义。如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不大于1％。例如，如本文所用，表述“约100”包括99和101以及它们之间的全部值(例如，99.1、99.2、99.3、99.4等)。
尽管与本文中描述的那些方法和材料类似或等效的任何方法和材料均可用于本发明的实践或检验，但现在描述优选的方法和材料。本说明书中提及的所有专利、申请和非专利出版物全文以引用方式并入本文中。
GP130蛋白
如本文所用，表述“糖蛋白130”、“GP130”、“gp130”等等是指包含如SEQ ID NO:185所示的氨基酸序列的人GP130蛋白(另外参见UniProtKB Q17RA0)。表述“GP130”包括单体和多聚体GP130分子二者。如本文所用，表述“单体人GP130”意指不含有或不具有任何多聚化结构域并且在正常条件下作为单个GP130分子(不与另一个GP130分子直接物理连接)存在的GP130蛋白或其部分。示例性单体GP130分子是本文称为包含SEQ ID NO:191的氨基酸序列的“hGP130.mmh”(参见例如本文的实施例3)的分子。如本文所用，表述“二聚体人GP130”意指包含两个GP130分子的构建体，所述两个GP130分子通过接头、共价键、非共价键或通过多聚化结构域(诸如抗体Fc结构域)彼此连接。示例性二聚体GP130分子是本文称为包含SEQID NO:197的氨基酸序列的“hGP130.hFc”或包含SEQ ID NO:190的氨基酸序列的“hGP130.mFc”(参见例如本文的实施例3)的分子。
除非明确指出是来自非人物种，否则本文对蛋白质、多肽和蛋白质片段的所有提及均旨在指相应的蛋白质、多肽或蛋白质片段的人型式。因此，除非指出是来自非人物种，例如，“小鼠GP130”、“猴GP130”等，否则表述“GP130”意指人GP130。
如本文所用，表述“细胞表面表达的GP130”意指在体外或体内细胞表面上表达，以使得GP130蛋白的至少一部分暴露于细胞膜的胞外侧，并且可接近抗体的抗原结合部分的一种或多种GP130蛋白或其胞外结构域。“细胞表面表达的GP130”可以包括在通常表达GP130蛋白的细胞表面上表达的GP130蛋白或由这种GP130蛋白组成。或者，“细胞表面表达的GP130”可以包括在通常在表面上不表达人GP130、但是已经被人工工程化为在表面上表达GP130的细胞表面上表达的GP130蛋白或由这种GP130蛋白组成。
抗GP130抗体及其抗原结合片段
根据本发明的一个方面，提供了抗GP130抗体(例如，单特异性抗GP130抗体)。根据本发明该方面的示例性抗GP130抗体在本文的表1和2中列出。表1示出了示例性抗GP130抗体的重链可变区(HCVR)、轻链可变区(LCVR)、重链互补决定区(HCDR1、HCDR2和HCDR3)和轻链互补决定区(LCDR1、LCDR2和LCDR3)的氨基酸序列标识符，本发明的双特异性抗原结合分子可以衍生自这些示例性抗GP130抗体。表2示出了示例性抗GP130抗体的HCVR、LCVR、HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3的核酸序列标识符。
本发明提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含HCVR，所述HCVR包含选自表1中列出的HCVR氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含LCVR，所述LCVR包含选自表1中列出的LCVR氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含HCVR和LCVR氨基酸序列对(HCVR/LCVR)，所述HCVR和LCVR氨基酸序列对包含与表1中列出的LCVR氨基酸序列中的任一者配对的表1中列出的HCVR氨基酸序列中的任一者。根据某些实施方案，本发明提供了包含表1中列出的示例性抗GP130抗体中的任一者中所含有的HCVR/LCVR氨基酸序列对的抗体或其抗原结合片段。在某些实施方案中，HCVR/LCVR氨基酸序列对是SEQ ID NO:154/10。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含重链CDR1(HCDR1)，所述HCDR1包含选自表1中列出的HCDR1氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含重链CDR2(HCDR2)，所述HCDR2包含选自表1中列出的HCDR2氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含重链CDR3(HCDR3)，所述HCDR3包含选自表1中列出的HCDR3氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含轻链CDR1(LCDR1)，所述LCDR1包含选自表1中列出的LCDR1氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含轻链CDR2(LCDR2)，所述LCDR2包含选自表1中列出的LCDR2氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含轻链CDR3(LCDR3)，所述LCDR3包含选自表1中列出的LCDR3氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含HCDR3和LCDR3氨基酸序列对(HCDR3/LCDR3)，所述HCDR3和LCDR3氨基酸序列对包含与表1中列出的LCDR3氨基酸序列中的任一者配对的表1中列出的HCDR3氨基酸序列中的任一者。根据某些实施方案，本发明提供了包含表1中列出的示例性抗GP130抗体中的任一者中所含有的HCDR3/LCDR3氨基酸序列对的抗体或其抗原结合片段。在某些实施方案中，HCDR3/LCDR3氨基酸序列对是SEQ ID NO:160/16。
本发明还提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含表1中列出的示例性抗GP130抗体中的任一者中所含有的一组六个CDR(即，HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)。在某些实施方案中，HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3氨基酸序列组选自由以下各项组成的组：SEQ ID NO:20-22-24-12-14-16、28-30-32-12-14-16、36-38-40-12-14-16、44-46-48-12-14-16、52-54-56-12-14-16、60-62-64-12-14-16、68-70-72-12-14-16、76-78-80-12-14-16、84-86-88-12-14-16、92-94-96-12-14-16、100-102-104-12-14-16、108-110-112-12-14-16、116-118-120-12-14-16、124-126-128-12-14-16、132-134-136-12-14-16、140-142-144-12-14-16、148-150-152-12-14-16和156-158-160-12-14-16。
在一个相关实施方案中，本发明提供了特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含表1中列出的示例性抗GP130抗体中的任一者所定义的HCVR/LCVR氨基酸序列对中所含有的一组六个CDR(即，HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)。例如，本发明包括特异性结合GP130的抗体或其抗原结合片段，所述抗体或其抗原结合片段包含以下HCVR/LCVR氨基酸序列对中所含有的HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3氨基酸序列组：SEQ ID NO:154/10。
用于鉴定HCVR和LCVR氨基酸序列中的CDR的方法和技术是本领域熟知的，并且可以用于鉴定本文公开的指定HCVR和/或LCVR氨基酸序列中的CDR。可以用于鉴定CDR的边界的示例性惯例包括例如Kabat定义、Chothia定义和AbM定义。一般而言，Kabat定义基于序列差异，Chothia定义基于结构环区域的位置，AbM定义是Kabat和Chothia方法之间的折衷方案。参见例如，Kabat,"Sequences of Proteins of Immunological Interest,"NationalInstitutes of Health,Bethesda,Md.(1991)；Al-Lazikani等人,J.Mol.Biol.273:927-948(1997)；和Martin等人,Proc.Natl.Acad.Sci.USA 86:9268-9272(1989)。公共数据库也可用于鉴定抗体中的CDR序列。
本发明还提供了编码抗GP130抗体或其部分的核酸分子。例如，本发明提供了编码表1中列出的HCVR氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的HCVR核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的LCVR氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的LCVR核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的HCDR1氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的HCDR1核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的HCDR2氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的HCDR2核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的HCDR3氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的HCDR3核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的LCDR1氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的LCDR1核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的LCDR2氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的LCDR2核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码表1中列出的LCDR3氨基酸序列中的任一者的核酸分子；在某些实施方案中，所述核酸分子包含选自表2中列出的LCDR3核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了编码HCVR的核酸分子，其中所述HCVR包含一组三个CDR(即，HCDR1-HCDR2-HCDR3)，其中所述HCDR1-HCDR2-HCDR3氨基酸序列组如表1中列出的示例性抗GP130抗体中的任一者所定义。
本发明还提供了编码LCVR的核酸分子，其中所述LCVR包含一组三个CDR(即，LCDR1-LCDR2-LCDR3)，其中所述LCDR1-LCDR2-LCDR3氨基酸序列组如表1中列出的示例性抗GP130抗体中的任一者所定义。
本发明还提供了编码HCVR和LCVR二者的核酸分子，其中所述HCVR包含表1中列出的HCVR氨基酸序列中的任一者的氨基酸序列，并且其中所述LCVR包含表1中列出的LCVR氨基酸序列中的任一者的氨基酸序列。在某些实施方案中，所述核酸分子包含选自表2中列出的HCVR核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列，以及选自表2中列出的LCVR核酸序列中的任一者的多核苷酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。在根据本发明的该方面的某些实施方案中，所述核酸分子编码HCVR和LCVR，其中所述HCVR和LCVR二者均衍生自表1中列出的相同的抗GP130抗体。
本发明还提供了能够表达包含抗GP130抗体的重链可变区或轻链可变区的多肽的重组表达载体。例如，本发明包括重组表达载体，所述重组表达载体包含上述核酸分子中的任一者，即编码表1所示的HCVR、LCVR和/或CDR序列中的任一者的核酸分子。本发明的范围内还包括已经引入此类载体的宿主细胞，以及通过在允许产生抗体或抗体片段的条件下培养宿主细胞并且回收这样产生的抗体和抗体片段来产生抗体或其部分的方法。
本发明包括具有经修饰的糖基化模式的抗GP130抗体。在一些实施方案中，用于除去不期望的糖基化位点的修饰可以是有用的，或者缺乏岩藻糖部分的抗体存在于寡糖链上，例如，以增加抗体依赖性细胞的细胞毒性(ADCC)功能(参见Shield等人(2002)JBC 277:26733)。在其他应用中，可以进行半乳糖基化的修饰，以修饰补体依赖性细胞毒性(CDC)。
LEPR蛋白
如本文所用，表述“瘦蛋白受体”、“LEPR”等等是指人瘦蛋白受体，所述人瘦蛋白受体包含如SEQ ID NO:186所示的氨基酸序列(另外参见UniProtKB/Swiss-Prot登录号P48357)。科学文献中使用的LEPR的替代名称包括“OB受体”、“OB-R”和“CD295”。LEPR也称为“WSX”(参见例如美国专利号7,524,937)。表述“LEPR”包括单体LEPR分子和多聚体LEPR分子二者。如本文所用，表述“单体人LEPR”意指不含有或不具有任何多聚化结构域并且在正常条件下作为单个LEPR分子(不与另一个LEPR分子直接物理连接)存在的LEPR蛋白或其部分。示例性单体LEPR分子是本文称为包含SEQ ID NO:187的氨基酸序列的“hLEPR.mmh”(参见例如本文的实施例10)的分子。如本文所用，表述“二聚体人LEPR”意指包含两个LEPR分子的构建体，所述两个LEPR分子通过接头、共价键、非共价键或通过多聚化结构域(诸如抗体Fc结构域)彼此连接。示例性二聚体LEPR分子是本文称为包含SEQ ID NO:189的氨基酸序列的“hLEPR.hFc”(参见例如本文的实施例10)的分子。
除非明确指出是来自非人物种，否则本文对蛋白质、多肽和蛋白质片段的所有提及均旨在指相应的蛋白质、多肽或蛋白质片段的人型式。因此，除非指出是来自非人物种，例如，“小鼠LEPR”、“猴LEPR”等，否则表述“LEPR”意指人LEPR。
如本文所用，表述“细胞表面表达的LEPR”意指在体外或体内细胞表面上表达，以使得LEPR蛋白的至少一部分暴露于细胞膜的胞外侧，并且可接近抗体的抗原结合部分的一种或多种LEPR蛋白或其胞外结构域。“细胞表面表达的LEPR”可以包括在通常表达LEPR蛋白的细胞表面上表达的LEPR蛋白或由这种LEPR蛋白组成。或者，“细胞表面表达的LEPR”可以包括在通常在表面上不表达人LEPR、但是已经被人工工程化为在表面上表达LEPR的细胞表面上表达的LEPR蛋白或由这种LEPR蛋白组成。
LEPR的若干同种型通过可变剪接来产生，从而得到长同种型b(LEPR-b)和若干短形式，包括显示出最高和最广泛表达模式的同种型a(LEPR-a)(Tartaglia LA.The leptinreceptor.J Biol Chem 1997；272:6093–6096)。LEPR-b是在大脑中表达的主要同种型，而LEPR-a在肝脏中广泛表达。所有同种型共有相同的胞外结构域、跨膜区和一小段胞质结构域(含有Box 1区)，然后是可变区。长形式含有介导瘦蛋白的所有信号传导能力所需的胞内序列基序，而短形式则缺乏这些区域。短形式的胞外结构域与能够进行信号传导的长形式相同。
LEPRxGP130双特异性抗原结合分子
本发明基于通过使LEPR和GP130在细胞表面上桥接来刺激LEPR和GP130信号传导的概念。具体而言，本发明涉及这样的前提：双特异性抗原结合分子(诸如LEPRxGP130双特异性抗体(如本文别处所详细描述))能够通过使GP130相对接近细胞表面上的瘦蛋白受体来刺激STAT3的LEPR依赖性信号传导，甚至在不存在瘦蛋白的情况下也如此。通过这种方式，本发明的双特异性抗原结合分子可以作为LEPR激动剂，所述LEPR激动剂可用于所诱导的瘦蛋白/LEPR信号传导是有利的和/或所期望的治疗背景。
因此，本发明提供了双特异性抗原结合分子，所述双特异性抗原结合分子包含结合人GP130的第一抗原结合结构域(本文也称为“D1”)和结合人LEPR的第二抗原结合结构域(本文也称为“D2”)。根据本发明，并且如本文的工作例所示，本发明的双特异性抗原结合分子同时结合LEPR和GP130导致LEPR信号传导的刺激。
本发明的双特异性抗原结合分子在本文中可以称为“LEPRxGP130双特异性抗体”或其他相关术语。
本发明的LEPRxGP130双特异性抗原结合分子可以使用衍生自单特异性(常规)抗LEPR抗体和抗GP130抗体的抗原结合结构域来构建。例如，单克隆、单特异性、抗LEPR抗体和/或抗GP130抗体的集合可以使用本领域已知的标准方法来产生，并且这些抗体的抗原结合结构域可以被用于使用本领域已知的常规技术来构建LEPRxGP130双特异性抗原结合分子(例如，双特异性抗体)。
可以在本发明的背景中用于产生LEPRxGP130双特异性抗原结合分子的示例性抗LEPR抗体包括美国专利申请公开号2017/0101477中描述的抗LEPR抗体中的任一者，该专利申请公开的公开内容整体并入本文。可以用于构建本发明的LEPRxGP130双特异性抗原结合分子的抗LEPR抗体可以是激动剂抗体，即结合人LEPR和活化LEPR信号传导的抗体。在其他实施方案中，可以用于构建LEPRxGP130双特异性抗原结合分子的抗LEPR抗体可以是增强抗体，即通过LEPR来增强瘦蛋白介导的信号传导的抗体。可用于构建LEPRxGP130双特异性抗原结合分子的抗LEPR抗体可以是能够与瘦蛋白复合地结合LEPR的抗体。此类抗体包括结合LEPR并且不阻断LEPR:瘦蛋白相互作用的那些抗体。或者，可用于构建LEPRxGP130双特异性抗原结合分子的抗LEPR抗体可以是与瘦蛋白竞争LEPR的结合和/或仅在不存在瘦蛋白的情况下结合LEPR的抗体。可用于构建LEPRxGP130双特异性抗原结合分子的特定抗LEPR抗体的非限制性实例包括本文称为“mAb18445”和“mAb18446”的抗LEPR抗体。
在一些实施方案中，LEPRxGP130双特异性抗原结合分子衍生自抗LEPR抗体，所述抗LEPR抗体通过LEPR-b同种型在体外增强瘦蛋白介导的信号传导。
在一些实施方案中，LEPRxGP130双特异性抗原结合分子衍生自抗LEPR抗体，所述抗LEPR抗体不通过LEPR-α同种型在体外活化瘦蛋白介导的信号传导。
可以在本发明的背景中用于产生LEPRxGP130双特异性抗原结合分子的示例性抗GP130抗体包括本文别处描述的抗GP130抗体中的任一者。可用于构建LEPRxGP130双特异性抗原结合分子的抗GP130抗体包括具有一种或多种以下性质的抗GP130抗体：结合猴GP130，不结合小鼠或大鼠GP130，结合GP130的FNIII结构域内的表位，不抑制GP130配体介导的信号传导，和/或在不存在GP130配体的情况下不活化GP130信号传导。GP130配体包括例如人抑癌素M(OSM)、人白血病抑制因子(LIF)和人睫状神经营养因子(CNTF)。可用于构建LEPRxGP130双特异性抗原结合分子的特定抗GP130抗体的非限制性实例包括本文称为“mAb16683”的抗GP130抗体。
根据本发明，双特异性抗原结合分子可以是单个多功能多肽，或它可以是彼此共价或非共价结合的两个或更多个多肽的多聚体复合物。如通过本公开所显而易见，具有特异性结合人LEPR的抗原结合结构域和特异性结合人GP130的抗原结合结构域的任何抗原结合构建体被视为“双特异性抗原结合分子”。本发明的双特异性抗原结合分子中的任一者或其变体可以使用标准分子生物学技术(例如，重组DNA和蛋白质表达技术)来构建，如本领域的普通技术人员所已知。
本发明的双特异性抗原结合分子可以是“分离的”。如本文所用，“分离的双特异性抗原结合分子”意指已经从天然环境的至少一种组分中鉴定和分离和/或回收的双特异性抗原结合分子。例如，出于本发明的目的，已经从生物体的至少一种组分或从产生抗体的组织或细胞分离或移除的双特异性抗体是“分离的双特异性抗体”。分离的双特异性抗原结合分子还包括在重组细胞内的原位分子。分离的双特异性抗原结合分子是已经经历至少一个纯化或分离步骤的分子。根据某些实施方案，分离的双特异性抗原结合分子可以基本上不含其他细胞物质和/或化学物质。
抗原结合结构域
本发明的双特异性抗原结合分子包含两个单独的抗原结合结构域(D1和D2)。如本文所用，表述“抗原结合结构域”意指能够特异性结合所关注的特定抗原(例如，人LEPR或人GP130)的任何肽、多肽、核酸分子、支架型分子、肽展示分子或含多肽的构建体。如本文参考抗原结合结构域所用，术语“特异性结合”等等意指抗原结合结构域能够与特定抗原形成复合物并且在普通测试条件下不结合其他不相关的抗原。“不相关的抗原”是彼此具有小于95％的氨基酸同一性的蛋白质、肽或多肽。
可以在本发明的语境中使用的抗原结合结构域的示例性种类包括抗体、抗体的抗原结合部分、与特定抗原特异性相互作用的肽(例如，肽体(peptibody))、与特定抗原特异性相互作用的受体分子、包含特异性结合特定抗原的受体的配体结合部分的蛋白质、抗原结合支架(例如，DARPin、HEAT重复序列蛋白、ARM重复序列蛋白、三角形四肽重复序列蛋白和基于天然存在的重复序列蛋白的其他支架等[参见例如，Boersma和Pluckthun，2011,Curr.Opin.Biotechnol.22:849-857，和其中引用的参考文献])，以及它们的适体或部分。
用于确定两个分子是否彼此特异性结合的方法是本领域熟知的并且包括例如平衡透析、表面等离子共振等等。如本文所用，术语“表面等离子共振”是指允许例如使用BIAcoreTM系统(GE Healthcare,Piscataway,NJ的Biacore生命科学部门)，通过对生物传感器基质内的蛋白质浓度改变的检测来进行实时相互作用的分析的光学现象。
如上文所示，“抗原结合结构域”(D1和/或D2)可以包含抗体或抗体的抗原结合片段或由抗体或抗体的抗原结合片段组成。如本文所用，术语“抗体”意指包含与特定抗原(例如，人MET)特异性结合或相互作用的至少一个互补决定区(CDR)的任何抗原结合分子或分子复合物。术语“抗体”包括包含四条多肽链(即通过二硫键相互连接的两条重(H)链和两条轻(L)链)的免疫球蛋白分子，以及它们的多聚体(例如，IgM)。每条重链包含重链可变区(在本文中缩写为HCVR或VH)和重链恒定区。重链恒定区包含三个结构域：CH1、CH2和CH3。每条轻链包含轻链可变区(在本文中缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域(CL1)。VH区和VL区可以进一步细分为高变区(称为互补性决定区(CDR))，所述高变区之间散布有更保守的区(称为框架区(FR))。每个VH和VL由从氨基末端至羧基末端按以下顺序排列的三个CDR和四个FR组成：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本发明的不同实施方案中，本发明抗体的(或其抗原结合部分)的FR可以与人种系序列相同，或可以经天然或人工修饰。可以根据两个或更多个CDR的并行分析来定义氨基酸共有序列。
本发明的双特异性抗原结合分子的D1和/或D2组分可以包含全抗体分子的抗原结合片段或由全抗体分子的抗原结合片段组成。如本文所用，术语抗体的“抗原结合部分”、抗体的“抗原结合片段”等包括特异性结合抗原以形成复合物的任何天然存在的、酶促可获得的、合成性或基因工程化的多肽或糖蛋白。可以例如使用任何合适的标准技术(诸如蛋白水解消化或涉及编码抗体可变结构域和任选地抗体恒定结构域的DNA的操作和表达的重组基因工程技术)从全抗体分子衍生出抗体的抗原结合片段。这种DNA是已知的和/或可从例如商业来源、DNA文库(包括例如噬菌体-抗体文库)容易地获得，或者可以是合成的。可以对所述DNA进行测序并且通过化学方式或通过使用分子生物学技术来操纵所述DNA，例如以将一个或多个可变结构域和/或恒定结构域布置成合适的构型，或者引入密码子、产生半胱氨酸残基、修饰、添加或缺失氨基酸等。
抗原结合片段的非限制性实例包括：(i)Fab片段；(ii)F(ab')2片段；(iii)Fd片段；(iv)Fv片段；(v)单链Fv(scFv)分子；(vi)dAb片段；和(vii)由模拟抗体的高变区的氨基酸残基组成的最小识别单位(例如，分离的互补决定区(CDR)，诸如CDR3肽)，或约束性FR3-CDR3-FR4肽。如本文所用，其他经工程化的分子(诸如结构域特异性抗体、单结构域抗体、结构域缺失抗体、嵌合抗体、CDR移植抗体、双体、三体、四体、微体、纳米体(例如，单价纳米体、二价纳米体等)、小模块免疫药物(SMIP)和鲨鱼可变IgNAR结构域)也被涵盖在表述“抗原结合片段”内。
抗体的抗原结合片段通常将包含至少一个可变结构域。可变结构域可以具有任何尺寸或氨基酸组成并且通常将包含与一个或多个框架序列毗邻或符合读框的至少一个CDR。在具与VL结构域相关的VH结构域的抗原结合片段中，VH结构域和VL结构域可以以任何合适的布置方式彼此相对定位。例如，可变区可以是二聚体并且含有VH-VH、VH-VL或VL-VL二聚体。或者，抗体的抗原结合片段可以含有单体VH或VL结构域。
在某些实施方案中，抗体的抗原结合片段可以含有与至少一个恒定结构域共价连接的至少一个可变结构域。可以存在于本发明的抗体的抗原结合片段内的可变结构域和恒定结构域的非限制性示例性构型包括：(i)VH-CH1；(ii)VH-CH2；(iii)VH-CH3；(iv)VH-CH1-CH2；(v)VH-CH1-CH2-CH3；(vi)VH-CH2-CH3；(vii)VH-CL；(viii)VL-CH1；(ix)VL-CH2；(x)VL-CH3；(xi)VL-CH1-CH2；(xii)VL-CH1-CH2-CH3；(xiii)VL-CH2-CH3；和(xiv)VL-CL。在可变结构域和恒定结构域的任何配置中，包括上文所列的任何示例性配置，可变结构域和恒定结构域可以彼此直接连接或可以由完整或部分的铰链区或接头区连接。铰链区可以由在单个多肽分子中邻近的可变结构域和/或恒定结构域之间产生柔性或半柔性连接的至少2个(例如，5个、10个、15个、20个、40个、60个或更多个)氨基酸组成。此外，抗原结合片段可以包含彼此和/或与一个或多个单体VH结构域或VL结构域非共价缔合(例如，通过一个或多个二硫键)的上文列出的可变结构域和恒定结构域构型中的任一者的同源二聚体或异源二聚体(或其他多聚体)。
本发明的双特异性抗原结合分子可以包含人抗体和/或重组人抗体或其片段，或者由人抗体和/或重组人抗体或其片段组成。如本文所用，术语“人抗体”包括具有源自人种系免疫球蛋白序列的可变区和恒定区的抗体。然而，人抗体可以包含不由人种系免疫球蛋白序列编码的氨基酸残基(例如，通过体外随机诱变或定点诱变或者通过体内体细胞突变来引入的突变)，例如在CDR尤其是CDR3中的这种氨基酸残基。然而，如本文所用，术语“人抗体”不旨在包括已经将衍生自另一个哺乳动物物种(诸如小鼠)的种系的CDR序列植入到人框架序列上的抗体。
本发明的双特异性抗原结合分子可以包含重组人抗体或其抗原结合片段，或者由重组人抗体或其抗原结合片段组成。如本文所用，术语“重组人抗体”意在包括通过重组手段所制备、表达、产生或分离的全部人抗体，如使用转染至宿主细胞(在下文进一步描述)中的重组表达载体表达的抗体、从重组人抗体组合文库(在下文进一步描述)分离的抗体、从相对于人免疫球蛋白基因而言转基因的动物(例如，小鼠)分离的抗体(参见例如，Taylor等人，(1992)Nucl.Acids Res.20:6287-6295)或通过涉及将人免疫球蛋白基因序列剪接至其他DNA序列的任何其他手段所制备、表达、产生或分离的抗体。此类重组人抗体具有源自人种系免疫球蛋白序列的可变区和恒定区。然而，在某些实施方案中，使此类重组人抗体进行体外诱变(或者，当使用针对人Ig序列的转基因动物时，进行体内体细胞诱变)，因此重组抗体的VH区和VL区的氨基酸序列是虽然衍生自并且涉及人种系VH序列和VL序列，但是可以天然不存在于体内人抗体种系库中的序列。
用于制备双特异性抗体的方法是本领域已知的并且可以用于构建本发明的双特异性抗原结合分子。可以在本发明的语境中使用的示例性双特异性形式包括但不限于例如基于scFv的或双体双特异性形式、IgG-scFv融合体、双可变结构域(DVD)-Ig、四源杂交瘤、钮入孔、共同轻链(例如，具有钮入孔的共同轻链等)、CrossMab、CrossFab、(SEED)体、亮氨酸拉链、Duobody、IgG1/IgG2、双重作用Fab(DAF)-IgG和Mab2双特异性形式(关于前述形式的综述，参见例如，Klein等人,2012,mAbs 4:6,1-11，以及其中引用的参考文献)。
可以包含在本发明的LEPRxGP130双特异性抗原结合分子中的示例性抗原结合结构域(D1和D2)包括衍生自本文公开的或本领域已知的抗LEPR抗体和/或抗GP130抗体中的任一者的抗原结合结构域。
例如，本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含HCVR，所述HCVR包含选自表1中列出的HCVR氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含LCVR，所述LCVR包含选自表1中列出的LCVR氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含HCVR和LCVR氨基酸序列对(HCVR/LCVR)，所述HCVR和LCVR氨基酸序列对包含与表1中列出的LCVR氨基酸序列中的任一者配对的表1中列出的HCVR氨基酸序列中的任一者。根据某些实施方案，本发明提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)结构域，所述D1结构域包含表1中列出的示例性抗MET抗体中的任一者中所含有的HCVR/LCVR氨基酸序列对。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含重链CDR1(HCDR1)，所述HCDR1包含选自表1中列出的HCDR1氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含重链CDR2(HCDR2)，所述HCDR2包含选自表1中列出的HCDR2氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含重链CDR3(HCDR3)，所述HCDR3包含选自表1中列出的HCDR3氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含轻链CDR1(LCDR1)，所述LCDR1包含选自表1中列出的LCDR1氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含轻链CDR2(LCDR2)，所述LCDR2包含选自表1中列出的LCDR2氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含轻链CDR3(LCDR3)，所述LCDR3包含选自表1中列出的LCDR3氨基酸序列中的任一者的氨基酸序列，或者与它们具有至少90％、至少95％、至少98％或至少99％的序列同一性的它们的基本上相似的序列。
本发明还提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含HCDR3和LCDR3氨基酸序列对(HCDR3/LCDR3)，所述HCDR3和LCDR3氨基酸序列对包含与表1中列出的LCDR3氨基酸序列中的任一者配对的表1中列出的HCDR3氨基酸序列中的任一者。根据某些实施方案，本发明提供了包含表1中列出的示例性抗MET抗体中的任一者中所含有的HCDR3/LCDR3氨基酸序列对的抗体或其抗原结合片段。
本发明还提供LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含表1中列出的示例性抗MET抗体中的任一者中所含有的一组六个CDR(即，HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)。
在一个相关实施方案中，本发明提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域，所述D1抗原结合结构域包含表1中列出的示例性抗MET抗体中的任一者所定义的HCVR/LCVR氨基酸序列对中所含有的一组六个CDR(即，HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)。
本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D2(LEPR结合)抗原结合结构域，所述D2抗原结合结构域包含衍生自本文所述的、美国专利申请公开号2017/0101477(该专利申请公开的公开内容整体并入本文)中描述的或者本领域已知的抗LEPR抗体中的任一者的可变结构域(HCVR和/或LCVR)和/或互补决定区(HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和/或LCDR3)。
作为非限制性示例性实例，本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)抗原结合结构域和D2(LEPR结合)抗原结合结构域，其中所述D1抗原结合结构域包含SEQ ID NO:154/10的HCVR/LCVR氨基酸序列对，或者包含SEQ ID NO:156-158-160-12-14-16的一组重链和轻链CDR(HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)，其中所述D2(LEPR结合)抗原结合结构域包含SEQ ID NO:170/10或178/10的HCVR/LCVR氨基酸序列对，或者包含SEQ ID NO:172-174-176-12-14-16或180-182-184-12-14-16的一组重链和轻链CDR(HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3)。具有这些序列特征的示例性LEPRxGP130双特异性抗体是称为bsAb21236的双特异性抗体，所述bsAb21236包含衍生自mAb16683的D1和衍生自mAb18445的D2。具有这些序列特征的示例性LEPRxGP130双特异性抗体是称为bsAb21237的双特异性抗体，所述bsAb21237包含衍生自mAb16683的D1和衍生自mAb18446的D2。本发明的双特异性抗体的其他具体实例如本文的实施例9、表20所示。
多聚化组分
在某些实施方案中，本发明的双特异性抗原结合分子还可以包含一种或多种多聚化组分。多聚化组分可以发挥维持抗原结合结构域(D1和D2)之间缔合的作用。如本文所用，“多聚化组分”是具有与具有相同或相似结构或构造的第二多聚化组分缔合的能力的任何大分子、蛋白质、多肽、肽或氨基酸。例如，多聚化组分可以是包含免疫球蛋白CH3结构域的多肽。多聚化组分的非限制性实例是免疫球蛋白的Fc部分，例如，选自同种型IgG1、IgG2、IgG3和IgG4以及每个同种型组内的任何同种异型的IgG的Fc结构域。在某些实施方案中，多聚化组分是含有至少一个半胱氨酸残基的1至约200个氨基酸长度的Fc片段或氨基酸序列。在其他实施方案中，多聚化组分是半胱氨酸残基或含有半胱氨酸的短肽。其他多聚化结构域包括：包含亮氨酸拉链、螺旋-环基序、或卷曲螺旋基序的肽或多肽，或者由亮氨酸拉链、螺旋-环基序、或卷曲螺旋基序组成的肽或多肽。
在某些实施方案中，本发明的双特异性抗原结合分子包含两个多聚化结构域M1和M2，其中D1附接至M1，并且D2附接至M2，并且其中M1与M2的缔合促进了单个双特异性抗原结合分子中D1和D2的彼此物理连接。在某些实施方案中，M1和M2彼此相同。例如，M1可以是具有特定氨基酸序列的Fc结构域，并且M2是具有与M1相同氨基酸序列的Fc结构域。或者，M1和M2可以在一个或多个氨基酸位置彼此不同。例如，M1可以包含第一免疫球蛋白(Ig)CH3结构域，并且M2可以包含第二Ig CH3结构域，其中第一和第二Ig CH3结构域彼此相差至少一个氨基酸，并且其中与具有相同的M1和M2序列的参考构建体相比，至少一个氨基酸差异减少了靶向构建体与蛋白A的结合。在一个实施方案中，M1的Ig CH3结构域结合蛋白A，并且M2的IgCH3结构域含有减少或消除蛋白A结合的突变，诸如H95R修饰(按照IMGT外显子编号；按照EU编号为H435R)。M2的CH3还可以包含Y96F修饰(按照IMGT编号；按照EU编号为Y436F)。可以存在于M2的CH3中的另外的修饰包括：就IgG1 Fc结构域而言，D16E、L18M、N44S、K52N、V57M和V82I(按照IMGT编号；按照EU编号为D356E、L358M、N384S、K392N、V397M和V422I)；就IgG2Fc结构域而言，N44S、K52N和V82I(按照IMGT编号；按照EU编号为N384S、K392N和V422I)；以及就IgG4 Fc结构域而言，Q15R、N44S、K52N、V57M、R69K、E79Q和V82I(按照IMGT编号；按照EU编号为Q355R、N384S、K392N、V397M、R409K、E419Q和V422I)。
变体
与衍生出抗原结合蛋白或抗原结合结构域的相应的种系序列相比，本文公开的双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)可以在重链和轻链可变结构域的框架和/或CDR区中包含一个或多个氨基酸置换、插入和/或缺失。通过将本文公开的氨基酸序列与可从例如公共抗体序列数据库获得的种系序列进行比较，可以容易地确定此类突变。本发明包括本文公开的双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)，所述双特异性抗原结合分子或其抗原结合结构域衍生自本文公开的氨基酸序列中的任一者，其中一个或多个框架和/或CDR区内的一个或多个氨基酸被突变为衍生出抗体的种系序列的一个或多个相应的残基，或者被突变为另一个人种系序列的一个或多个相应的残基，或者被突变为一个或多个相应的种系残基的保守氨基酸置换(此类序列改变在本文中统称为“种系突变”)。从本文公开的重链和轻链可变区序列开始，本领域的普通技术人员可以容易地产生许多双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)，所述双特异性抗原结合分子或其抗原结合结构域包含一个或多个单独的种系突变或其组合。在某些实施方案中，VH和/或VL结构域内的所有框架和/或CDR残基被突变回存在于衍生出抗体的原始种系序列中的残基。在其他实施方案中，仅某些残基被突变回原始种系序列，例如，仅存在于FR1的前8个氨基酸内或FR4的后8个氨基酸内的突变残基，或者仅存在于CDR1、CDR2或CDR3内的突变残基。在其他实施方案中，一个或多个框架和/或CDR残基中的一者或多者被突变为不同的种系序列(即，不同于最初衍生出抗体的种系序列的种系序列)的一个或多个相应的残基。此外，本发明的双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)可以在框架和/或CDR区内含有两个或更多个种系突变的任何组合，例如，其中某些单独的残基被突变为特定种系序列的相应的残基，而某些不同于原始种系序列的其他残基得以维持或被突变为不同的种系序列的相应的残基。一旦获得，即可容易地测试含有一个或多个种系突变的双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)的一种或多种所期望的性质，诸如，改善的结合特异性、增加的结合亲和力、改善或增强的拮抗或激动生物学性质(视情况而定)、减少的免疫原性等。以这种一般方式获得的双特异性抗原结合分子或其抗原结合结构域(D1和/或D2)涵盖在本发明中。
本发明还包括抗LEPR抗体、抗GP130抗体以及包含本文公开的HCVR、LCVR和/或CDR氨基酸序列中的任一者的变体的双特异性抗原结合分子。在本发明的该方面内包括的示例性变体包括具有一个或多个保守置换的本文公开的HCVR、LCVR和/或CDR氨基酸序列中的任一者的变体。例如，本发明包括具有HCVR、LCVR和/或CDR氨基酸序列的抗LEPR抗体、抗GP130抗体和LEPRxGP130双特异性抗原结合分子，相对于本文所示的HCVR、LCVR和/或CDR氨基酸序列组中的任一者，所述HCVR、LCVR和/或CDR氨基酸序列具有例如10个或更少、8个或更少、6个或更少、4个或更少等的保守氨基酸置换。
在本发明的该方面内包括的示例性变体还包括与本文公开的HCVR、LCVR和/或CDR氨基酸序列中的任一者具有基本序列同一性的变体。如本文在氨基酸序列的语境中所用，术语“基本同一性”或“基本上相同”意指当对两个氨基酸序列进行最佳比对时，诸如通过程序GAP或BESTFIT使用默认空位权重进行最佳比对时，这两个氨基酸序列共有至少95％、98％或99％的序列同一性。在某些实施方案中，不相同的残基位置的差异在于保守氨基酸置换。“保守氨基酸置换”是氨基酸残基被含有具有相似的化学性质(例如，电荷或疏水性)的侧链(R基团)的另一个氨基酸残基置换的氨基酸置换。通常，保守氨基酸置换基本上不会改变蛋白质的功能性质。在两个或更多个氨基酸序列的保守置换彼此不同的情况下，可以向上调整序列同一性百分比或相似性程度以校正置换的保守性质。用于进行该调整的手段是本领域的技术人员熟知的。参见例如，Pearson(1994)Methods Mol.Biol.24:307-331，该文献以引用的方式并入本文。含有具有相似的化学性质的侧链的氨基酸组的实例包括：(1)脂族侧链：甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸；(2)脂族-羟基侧链：丝氨酸和苏氨酸；(3)含酰胺的侧链：天冬酰胺和谷氨酰胺；(4)芳族侧链：苯丙氨酸、酪氨酸和色氨酸；(5)碱性侧链：赖氨酸、精氨酸和组氨酸；(6)酸性侧链：天冬氨酸和谷氨酸，以及(7)含硫侧链，即半胱氨酸和甲硫氨酸。优选的保守氨基酸置换组为：缬氨酸-亮氨酸-异亮氨酸、苯丙氨酸-酪氨酸、赖氨酸-精氨酸、丙氨酸-缬氨酸、谷氨酸-天冬氨酸和天冬酰胺-谷氨酰胺。或者，保守替换是在Gonnet等人(1992)Science 256:1443-1445中公开的PAM250对数似然矩阵中具有正值的任何改变，该文献以引用的方式并入本文。“适度保守”替换是在PAM250对数似然矩阵中具有非负值的任何改变。
通常使用序列分析软件来测量两个不同的氨基酸序列之间的序列同一性。序列分析软件使用分配给各种置换、缺失和其他修饰(包括保守氨基酸置换)的相似性度量来匹配相似的序列。例如，GCG软件含有诸如Gap和Bestfit的程序，这些程序可以以默认参数使用，以确定紧密相关的多肽(诸如来自不同物种的生物体的同源多肽)之间，或野生型蛋白及其突变型蛋白之间的序列同源性或序列同一性。参见例如，GCG 6.1版。还可以使用FASTA(GCG6.1版中的程序)使用默认或推荐参数对多肽序列进行比较。FASTA(例如，FASTA2和FASTA3)提供了查询和搜索序列之间的最佳重叠区域的比对和序列同一性百分比(Pearson(2000)，出处同上)。当将本发明的序列与含有大量来自不同生物体的序列的数据库进行比较时，另一种优选的算法是使用默认参数的计算机程序BLAST，尤其是BLASTP或TBLASTN。参见例如，Altschul等人(1990)J.Mol.Biol.215:403-410和Altschul等人(1997)NucleicAcids Res.25:3389-402，每个文献均以引用的方式并入本文。
包含Fc变体的LEPRxGP130双特异性抗原结合分子
根据本发明的某些实施方案，提供了LEPRxGP130双特异性抗原结合蛋白，所述LEPRxGP130双特异性抗原结合蛋白包含Fc结构域，所述Fc结构域包含一个或多个突变，所述突变例如与中性pH相比在酸性pH下增强了或减少了抗体与FcRn受体的结合。例如，本发明包括LEPRxGP130双特异性抗原结合蛋白，所述LEPRxGP130双特异性抗原结合蛋白在Fc结构域的CH2或CH3区中包含突变，其中一个或多个突变在酸性环境下(例如，在pH范围为从约5.5至约6.0的胞内体中)增加了Fc结构域与FcRn的亲和力。当施用于动物时，此类突变可以导致抗体的血清半衰期增加。此类Fc修饰的非限制性实例包括例如，第250位(例如，E或Q)；第250和428位(例如，L或F)；第252位(例如，L/Y/F/W或T)，第254位(例如，S或T)和第256位(例如，S/R/Q/E/D或T)处的修饰；或者第428和/或433位(例如，H/L/R/S/P/Q或K)和/或第434位(例如，H/F或Y)处的修饰；或者第250和/或428位处的修饰；或者第307或308位(例如，308F、V308F)和第434位处的修饰。在一个实施方案中，修饰包括428L(例如，M428L)和434S(例如，N434S)修饰；428L、259I(例如，V259I)和308F(例如，V308F)修饰；433K(例如，H433K)和434(例如，434Y)修饰；252、254和256(例如，252Y、254T和256E)修饰；250Q和428L的修饰(例如，T250Q和M428L)；以及307和/或308修饰(例如，308F或308P)。
例如，本发明包括LEPRxGP130双特异性抗原结合蛋白，所述LEPRxGP130双特异性抗原结合蛋白包含Fc结构域，所述Fc结构域包含一对或多对或者一组或多组选自由以下组成的组的突变：250Q和248L(例如，T250Q和M248L)；252Y、254T和256E(例如，M252Y、S254T和T256E)；428L和434S(例如，M428L和N434S)；以及433K和434F(例如，H433K和N434F)。在本发明的范围内设想了本文公开的抗体可变结构域内的前述Fc结构域突变和其他突变的所有可能的组合。
本发明的LEPRxGP130抗原结合分子的生物学特征
本发明包括以高亲和力结合人LEPR的LEPRxGP130双特异性抗原结合分子。例如，本发明包括LEPRxGP130抗原结合分子，所述LEPRxGP130抗原结合分子以小于约110nM的KD结合单体人LEPR(例如，hLEPR.mmh)，所述KD如通过在25℃下的表面等离子共振，例如，使用本文的实施例10中定义的测定法形式，或基本上类似的测定法所测量。根据某些实施方案，提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子以大于约3分钟的解离半衰期(t1/2)结合单体人LEPR(例如，hLEPR.mmh)，所述解离半衰期如通过在25℃下的表面等离子共振，例如，使用本文的实施例10中定义的测定法形式，或基本上类似的测定法所测量。
本发明包括以高亲和力结合人GP130的LEPRxGP130双特异性抗原结合分子。例如，本发明包括LEPRxGP130抗原结合分子，所述LEPRxGP130抗原结合分子以小于约150nM的KD结合单体人GP130(例如，hGP130.mmh)，所述KD如通过在25℃下的表面等离子共振，例如，使用本文的实施例10中定义的测定法形式，或基本上类似的测定法所测量。根据某些实施方案，提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子以大于约2.5分钟的解离半衰期(t1/2)结合单体人GP130(例如，hGP130.mmh)，所述解离半衰期如通过在25℃下的表面等离子共振，例如，使用本文的实施例10中定义的测定法形式，或基本上类似的测定法所测量。
本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子能够结合表达人LEPR的细胞。在一些方面，LEPRxGP130双特异性抗原结合分子能够结合表达人LEPR同种型b的细胞。在某些实施方案中，提供了在存在和/或不存在瘦蛋白的情况下结合表达人LEPR的细胞的LEPRxGP130双特异性抗原结合蛋白。本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子能够结合表达人GP130的细胞。本发明的双特异性抗原结合分子进行的细胞结合可以通过表达LEPR和/或GP130的细胞上的荧光活化细胞分选(FACS)，例如，使用本文的实施例11中定义的测定法形式，或基本上类似的测定法来评估。
本发明包括活化GP130介导的细胞信号转导的LEPRxGP130双特异性抗原结合分子。在某些实施方案中，本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子以用GP130配体处理所观察到的活化程度的至少20％的效力活化GP130介导的细胞信号转导。例如，本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子以在相同的或类似的实验测定法条件下用人抑癌素M(OSM)处理所观察到的活化程度的至少20％或25％的效力活化GP130介导的细胞信号转导。本发明的双特异性抗原结合分子进行的GP130介导的细胞信号的活化可以通过体外细胞信号测定法，例如，使用本文的实施例12中定义的测定法形式，或基本上类似的测定法来评估。
本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子特异性地或优先地活化通过LEPR同种型‘b’(长形式)进行的信号传导，并且基本上不活化通过LEPR同种型‘a’(短形式)进行的信号传导。根据某些实施方案，提供了LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子特异性地或优先地增强通过LEPR同种型‘b’(长形式)进行的瘦蛋白信号传导，并且基本上不增强通过LEPR同种型‘a’(短形式)进行的瘦蛋白信号传导。通过LEPR同种型‘b’和/或LEPR同种型‘a’进行的信号传导的活化或增强可以通过使用特异性表达LEPR同种型‘b’或LEPR同种型‘a’的报告细胞系进行的体外测定法，例如，使用本文的实施例14中定义的测定法形式，或基本上类似的测定法来评估。
本发明包括LEPRxGP130双特异性抗原结合分子，当施用于动物时，所述LEPRxGP130双特异性抗原结合分子会导致体重减轻。例如，本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子在双特异性抗原结合分子以治疗有效剂量施用于动物后2至14天的动物中导致体重减轻1％至4％。本发明的双特异性抗原结合分子进行的体重减轻诱导可以使用基因工程模型系统，例如，使用本文的实施例13中所示的体内模型，或基本上类似的模型来评估。
本发明的双特异性抗原结合分子可以具有一种或多种前述生物学特征，或它们的任何组合。本发明的双特异性抗原结合分子的生物学特征的前述列表并非旨在是详尽的。在阅读包括本文的工作例的本公开后，本发明的双特异性抗原结合分子的其他生物学特征对于本领域的普通技术人员将是显而易见的。
表位作图、结合结构域和相关的技术
本发明的抗体和抗原结合结构域所结合的表位可以由3个或更多个(例如，3个、4个、5个、6个、7个、8个、9个、10个、11个、12个、13个、14个、15个、16个、17个、18个、19个、20个或更多个)LEPR或GP130蛋白的氨基酸的单个邻接序列组成。或者，相关的表位可以由多个靶蛋白的非邻接氨基酸(或氨基酸序列)组成。
可以使用本领域的普通技术人员已知的各种技术来确定与本发明的抗体和抗原结合结构域相互作用的LEPR和/或GP130上的表位。可以用于确定特定抗体或抗原结合结构域的表位或结合结构域的示例性技术包括例如点诱变(例如，丙氨酸扫描诱变、精氨酸扫描诱变等)、肽印迹分析(Reineke,2004,Methods Mol Biol 248:443-463)、蛋白酶保护和肽切割分析。此外，可以采用诸如抗原的表位切除、表位提取和化学修饰的方法(Tomer,2000,Protein Science 9:487-496)。可以用于鉴定与抗体相互作用的多肽内的氨基酸的另一种方法是通过质谱法检测的氢/氘交换。大体上，氢/氘交换法涉及所关注的蛋白质的氘标记，然后是抗体与氘标记的蛋白质的结合。然后，将蛋白质/抗体复合物转移至水中，以允许氢-氘交换在除抗体保护的残基(仍然是氘标记的)之外的所有残基处发生。在抗体解离后，使靶蛋白进行蛋白酶切割和质谱分析，从而显示对应于与抗体相互作用的特定氨基酸的氘标记的残基。参见例如，Ehring(1999)Analytical Biochemistry 267(2):252-259；Engen和Smith(2001)Anal.Chem.73:256A-265A。还可以使用X射线晶体结构分析来鉴定与抗体相互作用的多肽内的氨基酸。
本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)结构域，所述D1结构域结合至与本文所述的特定示例性抗GP130抗体或抗原结合结构域中的任一者(例如，包含如本文的表1中所示的氨基酸序列中的任一者的抗体)相同的表位。本发明包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D2(LEPR结合)结构域，所述D2结构域结合至与本文所述的特定示例性抗LEPR抗体或抗原结合结构域中的任一者(例如，包含如本文的表18所示的氨基酸序列中的任一者的抗体)相同的表位。同样，本发明还包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D1(GP130结合)结构域，所述D1结构域与本文所述的特定示例性抗GP130抗体中的任一者(例如，包含如本文的表1所示的氨基酸序列中的任一者的抗体)竞争GP130的结合。此外，本发明还包括LEPRxGP130双特异性抗原结合分子，所述LEPRxGP130双特异性抗原结合分子包含D2(LEPR结合)结构域，所述D2结构域与本文所述的特定示例性抗LEPR抗体中的任一者(例如，包含如本文的表18所示的氨基酸序列中的任一者的抗体)竞争LEPR的结合。
通过使用本领域已知的和本文示例的常规方法，可以容易地确定抗体或抗原结合结构域是否结合至与参考抗GP130或抗LEPR抗体相同的表位，或者竞争与参考抗GP130或抗LEPR抗体的结合。例如，为了确定测试抗体是否结合至与本发明的参考抗GP130或抗LEPR抗体相同的表位，使参考抗体结合至靶分子(即，GP130或LEPR蛋白，视情况而定)。然后，评估测试抗体结合至靶分子的能力。如果测试抗体在与参考抗体饱和结合后能够结合至靶分子，则可以得出以下结论：测试抗体结合至与参考抗体不同的表位。在另一个方面，如果测试抗体在与参考抗体饱和结合后不能结合至靶分子，则测试抗体可以结合至与本发明的参考抗体所结合的表位相同的表位。然后可以进行另外的常规实验(例如，肽突变和结合分析)，以确认所观察到的测试抗体结合的缺乏事实上是否是由于结合至与参考抗体相同的表位，或者空间阻断(或另一个现象)是否是造成所观察的结合缺乏的原因。可以使用ELISA、RIA、Biacore、流式细胞术或者本领域可用的任何其他定量或定性抗体结合测定法来进行这类实验。根据本发明的某些实施方案，如果例如1倍、5倍、10倍、20倍或100倍过量的一种抗体抑制另一种抗体的结合至少50％，但优选地75％、90％或甚至99％，如在竞争性结合测定法中所测量，则两种抗体结合至相同的(或重叠)表位(参见例如，Junghans等人,Cancer Res.1990:50:1495-1502)。或者，如果抗原中的减少或消除一种抗体的结合的基本上所有氨基酸突变都减少或消除另一种抗体的结合，则认为两种抗体结合至相同的表位。如果只有减少或消除一种抗体的结合的氨基酸突变的子集减少或消除另一种抗体的结合，则认为两种抗体具有“重叠表位”。
为了确定抗体是否与参考抗GP130或抗LEPR抗体竞争结合(或交叉竞争结合)，在两个方向上进行上述结合方法：在第一方向上，使参考抗体在饱和条件下结合至靶分子，然后评估测试抗体与靶分子的结合。在第二方向上，使测试抗体在饱和条件下结合至靶分子，然后评估参考抗体与靶分子的结合。如果在两个方向上只有第一(饱和)抗体能够结合至靶分子，则可以得出以下结论：测试抗体和参考抗体竞争靶分子的结合。如本领域的普通技术人员所理解，竞争与参考抗体的结合的抗体可能未必结合至与参考抗体相同的表位，但是可能通过重叠或邻近表位的结合来在空间上阻断参考抗体的结合。
可以根据与抗原结合结构域相互作用的GP130或LEPR的结构域来描述本发明的双特异性抗原结合分子的抗原结合结构域(D1和/或D2)。GP130和LEPR蛋白包含称为D1、D2、D3和FNIII的各种结构域。因此，本发明的双特异性抗原结合分子的D1和D2抗原结合结构域可以结合选自由D1、D2、D3或FNIII组成的组的LEPR或GP130的结构域。根据某些示例性实施方案，提供了LEPRxGP130双特异性抗原结合分子，其中D1(抗GP130)抗原结合结构域结合至GP130的FNIII结构域，D2(抗LEPR)抗原结合结构域结合至LEPR的FNIII结构域。在本发明的范围内设想了其他结合结构域组合。
人抗体的制备
本发明的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体可以是完全人抗体。用于产生单克隆抗体(包括完全人单克隆抗体)的方法是本领域已知的。任何此类已知的方法均可用于本发明的背景中，以制备特异性结合至人GP130和/或人LEPR的人抗体。
使用例如VELOCIMMUNETM技术，或用于产生完全人单克隆抗体的任何其他类似的已知方法，初始分离出具有人可变区和小鼠恒定区的针对人GP130和/或人LEPR的高亲和力嵌合抗体。如下文实验部分所述，表征和选择抗体的所期望的特征，包括亲和力、配体阻断活性、选择性、表位等。如果需要，用所期望的人恒定区(例如野生型或经修饰的IgG1或IgG4)替换小鼠恒定区，以产生完全人抗GP130和/或抗LEPR抗体。虽然所选的恒定区可以根据特定用途而变化，但是高亲和力抗原结合和靶标特异性特征留在可变区中。在某些情况下，直接从抗原阳性的B细胞中分离出完全人抗GP130和/或抗LEPR抗体。
生物等效物
本发明包括变体抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体，这些变体抗体的氨基酸序列不同于所描述的抗体的氨基酸序列，但是保持了结合一个或多个相关靶抗原(GP130和/或LEPR)和发挥衍生出此类变体的亲本抗体的一种或多种生物学功能的能力。当与亲本序列相比时，此类变体抗体和抗体片段包含一个或多个氨基酸的添加、缺失或置换，但是表现出基本上相当于所描述的抗体的生物学活性。同样，本发明包括编码本发明的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体的DNA序列，其中当与所公开的亲本序列相比时，此类DNA序列包含一个或多个核苷酸的添加、缺失或置换，但是编码与本文公开的示例性抗体基本上生物等效的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体。此类变体氨基酸和DNA序列的实例在本文别处有所讨论。
如果两种抗原结合蛋白或抗体是药物等效物或药物替代物，并且当在相似的实验条件下以相同的摩尔剂量的单剂量和多剂量给药时，所述药物等效物或药物替代物未显示出吸收速率和程度的显著差异，则它们被视为生物等效物。如果某些抗体在吸收程度上是等效的，但是在吸收速率上不是等效的，则它们将被视为等效物或药物替代物，但是因为吸收速率的这种差异是有意的并且反映在标记中，所以可以被视为生物等效物，这些抗体对于例如在长期使用中达到有效体内药物浓度不是必需的，并且被认为对于所研究的特定药品不具有临床意义。
在一个实施方案中，如果两种抗原结合蛋白在安全性、纯度和效力方面不存在有临床意义的差异，则它们是生物等效物。
在一个实施方案中，如果与不进行参考产品和生物产品之间的切换的连续疗法相比，患者可以进行这种切换一次或多次，而没有预期的不良反应风险的增加，包括免疫原性的临床上显著的变化、或减少的有效性，则两种抗原结合蛋白是生物等效物。
在一个实施方案中，如果两种抗原结合蛋白都通过针对一个或多个使用条件的一种或多种共同作用机制来发挥作用，以达到此类机制是已知的程度，则它们是生物等效物。
生物等效性可以通过体内和体外方法来展示。生物等效性度量包括，例如，(a)在人或其他哺乳动物中的体内试验，其中测量了随时间推移的血液、血浆、血清或其他生物流体中的抗体或其代谢物的浓度；(b)与人体内生物利用率数据相关联并且可以合理地预测人体内生物利用率数据的体外试验；(c)在人或其他哺乳动物中的体内试验，其中测量了随时间推移的抗体(或其靶标)的适当急性药理作用；以及(d)建立抗体的安全性、功效、或者生物利用率或生物等效性的良好对照的临床试验。
物种选择性和物种交叉反应性
根据某些实施方案，本发明提供了结合至人GP130和人LEPR，但是不结合至来自其他物种的相应的蛋白质的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体(以及包含抗GP130和/或抗LEPR抗原结合结构域的其他抗原结合分子)。本发明还包括结合至人GP130和人LEPR并且结合至来自一个或多个非人物种的GP130和LEPR的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体(以及包含抗GP130和/或抗LEPR抗原结合结构域的抗原结合分子)。例如，本发明包括包含第一抗原结合结构域和第二抗原结合结构域的双特异性抗原结合分子，其中所述第一抗原结合结构域结合人和猴(例如，食蟹猕猴(Macacafascicularis))GP130，但是不结合啮齿动物(大鼠和/或小鼠)GP130。本发明包括包含第一抗原结合结构域和第二抗原结合结构域的双特异性抗原结合分子，其中所述第二抗原结合结构域结合人和猴(例如，食蟹猕猴)LEPR，但是不结合啮齿动物(大鼠和/或小鼠)LEPR。
本发明还提供了结合至人GP130和/或人LEPR的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体(以及包含抗GP130和/或抗LEPR抗原结合结构域的其他抗原结合分子)，并且视情况而定，可以结合至或不结合至相应的GP130和/或LEPR蛋白的小鼠、大鼠、豚鼠、仓鼠、沙鼠、猪、猫、狗、兔、山羊、绵羊、奶牛、马、骆驼、食蟹猕猴、狨猴、恒河猴或黑猩猩型式中的一者或多者。
治疗制剂和施用
本发明提供了包含本发明的抗GP130抗体、抗LEPR抗体和LEPRxGP130双特异性抗体(以及包含抗GP130和/或抗LEPR抗原结合结构域的其他抗原结合分子)的药物组合物。本发明的药物组合物可以用合适的载剂、赋形剂、和提供改善的转移、递送、耐受性等等的其他药剂来配制。
抗体的治疗用途
本发明包括这样的方法：所述方法包括将包含LEPRxGP130双特异性抗原结合分子(例如，如本文的表20所示的包含D1和D2组分中的任一者的LEPRxGP130双特异性抗原结合分子)的治疗组合物施用于有需要的受试者(例如，哺乳动物(诸如人))。所述治疗组合物可以包含本文公开的LEPRxGP130双特异性抗原结合分子中的任一者，以及药学上可接受的载剂或稀释剂。
本发明的LEPRxGP130双特异性抗原结合分子尤其可用于治疗、预防和/或改善与瘦蛋白缺乏、瘦蛋白抵抗、低瘦蛋白血症相关的或它们介导的，或者可通过刺激或活化LEPR信号传导或模拟瘦蛋白的体外或体内天然活性来治疗的任何疾病或障碍。例如，本发明的双特异性抗原结合分子可用于治疗脂肪营养不良病症。可通过本发明的双特异性抗原结合分子治疗的示例性脂肪营养不良病症包括，例如，先天性全身脂肪营养不良、获得性全身脂肪营养不良、家族性局部脂肪营养不良、获得性局部脂肪营养不良、离心性腹部脂肪营养不良、环状脂肪萎缩、局部脂肪营养不良和HIV相关的脂肪营养不良。
本发明的LEPRxGP130双特异性抗原结合分子也可用于治疗或预防一种或多种选自由以下各项组成的组的疾病或障碍：肥胖、代谢综合征、饮食引起的食物冲动、功能性下丘脑性闭经、1型糖尿病、2型糖尿病、胰岛素抵抗、严重胰岛素抵抗(包括由于胰岛素受体中的突变而导致的严重胰岛素抵抗、不由胰岛素受体中的突变导致的严重胰岛素抵抗、由下游信号传导通路中的突变导致的或由其他原因导致的严重胰岛素抵抗)、非酒精性和酒精性脂肪肝疾病、阿尔茨海默病、瘦蛋白缺乏、瘦蛋白抵抗、脂肪营养不良、矮怪病/多诺霍综合征、罗伯森-门登霍尔综合征。
在本文所述的治疗方法的背景下，可以将LEPRxGP130双特异性抗原结合分子作为单药疗法(即，作为唯一的治疗剂)或与一种或多种另外的治疗剂(所述治疗剂的实例在本文别处有所描述)组合施用。
组合疗法和制剂
本发明包括包含本文所述的LEPRxGP130双特异性抗原结合分子中的任一者与一种或多种另外的治疗活性组分组合的组合物和治疗制剂，以及包括将此类组合施用于有需要的受试者的治疗方法。
本发明的LEPRxGP130双特异性抗原结合分子可以与一种或多种另外的治疗活性组分(例如，用于治疗肥胖、高胆固醇血症、高脂血症、2型糖尿病、1型糖尿病、食欲控制、不孕等的处方药品)共配制和/或组合施用。此类另外的治疗活性组分的实例包括，例如重组人瘦蛋白(例如，美曲普汀[MYALEPT])、PCSK9抑制剂(例如，抗PCSK9抗体[阿利西尤单抗(alirocumab)、依洛尤单抗(evolocumab)、bococizumab、罗德西珠单抗(lodelcizumab)、拉潘西珠单抗(ralpancizumab)等])、他汀类药物(阿托伐他汀(atorvastatin)、瑞舒伐他汀(rosuvastatin)、西立伐他汀(cerivastatin)、匹伐他汀(pitavastatin)、氟伐他汀(fluvastatin)、辛伐他汀(simvastatin)、洛伐他汀(lovastatin)、普伐他汀(pravastatin)等)、依泽替米贝(ezetimibe)、胰岛素、胰岛素变体、胰岛素促分泌剂、二甲双胍、磺酰脲类、钠葡萄糖协同转运蛋白2(SGLT2)抑制剂(例如，达格列净(dapaglifozin)、卡纳格列净(canaglifozin)、恩格列净(empagliflozin)等)、GLP-1激动剂/类似物(例如，唾液素-4、艾塞那肽、利拉鲁肽、利西拉来、阿比鲁肽、杜拉鲁肽等)、胰高血糖素(GCG)抑制剂(例如，抗GCG抗体)、胰高血糖素受体(GCGR)抑制剂(例如，抗GCGR抗体、小分子GCGR拮抗剂、GCGR特异性反义寡核苷酸、抗GCGR适体[例如，Spiegelmers]等)、血管生成素样蛋白(ANGPTL)抑制剂(例如，抗ANGPTL3抗体、抗ANGPTL4抗体、抗ANGPTL8抗体等)、芬特明(phentermine)、奥利司他(Orlistat)、托吡酯(Topiramate)、安非他酮(bupropion)、托吡酯(Topiramate)/芬特明(phentermine)、安非他酮(bupropion)/那曲酮(naltrexone)、安非他酮(bupropion)/唑尼沙胺(zonisamide)、普兰林肽(Pramlintide)/美曲普汀(Metrelepin)、氯卡色林(Lorcaserin)、西替利司他(Cetilistat)、特索芬辛(Tesofensine)、韦利贝特(Velneperit)等。
一种或多种另外的治疗活性组分，例如上文列出的药剂中的任一者或其衍生物，可以在本发明的LEPRxGP130双特异性抗原结合分子的施用之前、同步或者之后立即施用；(出于本公开的目的，这种施用方案被视为LEPRxGP130双特异性抗原结合分子与另外的治疗活性组分“组合”施用)。本发明包括药物组合物，其中本发明的LEPRxGP130双特异性抗原结合分子与如本文别处所述的一种或多种另外的治疗活性组分共配制。
施用方案
根据本发明的某些实施方案，可以将多剂量的LEPRxGP130双特异性抗原结合分子(或者包含LEPRxGP130双特异性抗原结合分子和本文提及的另外的治疗活性剂中的任一者的组合的药物组合物)在限定的时间范围内施用于受试者。根据本发明的该方面的方法包括将多剂量的本发明的LEPRxGP130双特异性抗原结合分子按顺序施用于受试者。如本文所用，“按顺序施用”意指每个剂量的LEPRxGP130双特异性抗原结合分子在不同的时间点，例如在以预定间隔(例如，小时、日、周或月)分开的不同日施用于受试者。本发明包括这样的方法：所述方法包括将单一初始剂量的LEPRxGP130双特异性抗原结合分子，然后是一个或多个第二剂量的LEPRxGP130双特异性抗原结合分子，以及任选地随后是一个或多个第三剂量的LEPRxGP130双特异性抗原结合分子按顺序施用于患者。
术语“初始剂量”、“第二剂量”和“第三剂量”是指本发明的LEPRxGP130双特异性抗原结合分子的施用的时间顺序。因此，“初始剂量”是在治疗方案开始时施用的剂量(也称为“基线剂量”、“负荷剂量”、“起始剂量”等等)；“第二剂量”是在初始剂量后施用的剂量；“第三剂量”是在第二剂量后施用的剂量。初始、第二和第三剂量都可以含有相同量的LEPRxGP130双特异性抗原结合分子，但是通常在施用频率方面可以彼此不同。然而，在某些实施方案中，在初始、第二和/或第三剂量中含有的LEPRxGP130双特异性抗原结合分子的量在治疗过程中彼此不同(例如，适当上调或下调)。在某些实施方案中，在治疗方案开始时以“负荷剂量”施用两个或更多个(例如，2个、3个、4个或5个)剂量，然后以较低频率施用后续剂量(例如，“维持剂量”)。
装置
本发明还提供了包含本文所示的双特异性抗原结合分子(例如，它们的药物制剂)的器皿(例如，小瓶或色谱柱)或注射装置(例如，注射器、预填充注射器或自动注射器)。器皿或注射装置可以包装成试剂盒。
注射装置是经由肠胃外途径(例如，眼内、玻璃体内、肌肉内、皮下或静脉内途径)将物质引入受试者(例如，人)体内的装置。例如，注射装置可以是注射器(例如，预填充有药物制剂的注射器，诸如自动注射器)，所述注射器例如包括用于容纳待注射的流体(例如，包含抗体或其片段或药物制剂)的筒或桶，用于穿刺皮肤、血管或其他组织以注射液体的针；用于将流体从筒中推出并通过针孔进入受试者体内的柱塞。
本发明包括用于施用本发明的双特异性抗原结合分子的方法，所述方法包括例如通过注射装置将分子引入(例如，注射至)受试者体内。
表达方法
本发明包括用于制备本发明的双特异性抗原结合分子或其免疫球蛋白链的重组方法，所述重组方法包括(i)将一种或多种编码这种双特异性抗原结合分子的免疫球蛋白轻链和/或重链的多核苷酸引入宿主细胞，例如，其中所述多核苷酸在载体中；和/或整合进宿主细胞染色体中和/或可操作地连接至启动子；(ii)在有利于多核苷酸的表达的条件下培养宿主细胞(例如，哺乳动物、真菌、中国仓鼠卵巢(CHO)、毕赤酵母(Pichia)或巴斯德毕赤酵母(Pichia pastoris))，以及(iii)任选地，从宿主细胞和/或宿主细胞在中间生长的培养基分离双特异性抗原结合分子或免疫球蛋白链。这种方法的产物及其药物组合物也形成本发明的一部分。
在本发明的一个实施方案中，用于制备双特异性抗原结合分子的方法包括例如通过柱色谱、沉淀和/或过滤来纯化分子的方法。这种方法的产物及其药物组合物也形成本发明的一部分。
包含本发明的双特异性抗原结合分子和/或编码这种分子的免疫球蛋白链的多核苷酸(例如，在载体中)的宿主细胞也是本发明的一部分。宿主细胞包括例如哺乳动物细胞(诸如中国仓鼠卵巢(CHO)细胞)和真菌细胞(诸如毕赤酵母细胞(例如，巴斯德毕赤酵母))。
实施例
提供以下实施例是为了向本领域的普通技术人员提供完整公开内容和描述如何制备和使用本发明的方法和组合物，而非旨在限制发明人所认为的其发明的范围。已努力确保有关所用的数字(例如，量、温度等)的准确性，但应考虑某些实验误差和偏差。除非另外指明，否则份数是重量份，分子量是平均分子量，温度是按摄氏度计并且压力是大气压或接近大气压。
实施例1.抗GP130抗体的产生
通过用包含重组人GP130胞外结构域的免疫原免疫包含编码人免疫球蛋白重链和κ轻链可变区的DNA的基因工程小鼠来获得抗GP130抗体。用于免疫的小鼠表达“通用轻链”。即，在该小鼠中产生的抗体具有不同的重链可变区，但是具有基本上相同的轻链可变结构域。
通过GP130特异性免疫测定法来监测抗体免疫应答。当实现所期望的免疫应答时，收获脾细胞并与小鼠骨髓瘤细胞融合，以保持它们的活力并来自杂交瘤细胞系。筛选和选择杂交瘤细胞系以鉴定产生GP130特异性抗体的细胞系。使用该技术，获得了若干抗GP130嵌合抗体(即，具有人可变结构域和小鼠恒定结构域的抗体)。此外，如US 2007/0280945A1中所述，直接从不与骨髓瘤细胞融合的抗原阳性的B细胞中分离出若干完全人抗GP130抗体。
根据本实施例的方法产生的示例性抗GP130抗体的某些生物学性质，以及由其构建的双特异性抗体，在下文所示的实施例中有所详细描述。
实施例2.抗GP130的重链和轻链可变区氨基酸和核酸序列。
表1示出了本发明所选的抗LEPR抗体的重链和轻链可变区和CDR的氨基酸序列标识符。(如上所述，实施例1中产生的所有抗体都具有相同的轻链可变区以及相同的轻链CDR序列)。表2示出了相应的核酸序列标识符。
表1：抗GP130氨基酸序列标识符
表1：抗GP130氨基酸序列标识符
表2：抗GP130核酸序列标识符
表2：抗GP130核酸序列标识符
本发明的抗体可以是任何同种型。例如，本发明的抗GP130抗体可以包含表1和表2中所示的可变结构域和CDR序列以及同种型IgG4、IgG1等的人Fc结构域。对于某些应用或实验，Fc结构域可以是小鼠Fc结构域。如本领域的普通技术人员所理解，可以将具有特定Fc同种型的抗体转化为具有不同的Fc同种型的抗体(例如，可以将具有小鼠IgG4 Fc的抗体转化为具有人IgG1等的抗体)，但无论如何，可变结构域(包括CDR)(以表1和2中示出的数字标识符表示)将保持相同，并且预期结合特性相同或基本上相似，无论Fc结构域的性质如何。
实施例3.在25℃和37℃下测量的抗GP130单克隆抗体与不同的GP130试剂结合的Biacore结合动力学。
使用基于实时表面等离子共振的Biacore 4000生物传感器来确定与纯化的抗GP130单克隆抗体结合的不同的GP130试剂的平衡解离常数(KD)。所有结合研究均在25℃和37℃下的10mM HEPES、150mM NaCl、3mM EDTA和0.05％v/v表面活性剂Tween-20pH7.4(HBS-ET)运行缓冲液中进行。Biacore传感器表面首先通过胺与单克隆小鼠抗人Fc抗体(GE,#BR-1008-39)的偶联来衍生化，以捕获抗GP130单克隆抗体。对以下单体和二聚体GP130试剂进行结合研究：用C-末端myc-myc-六组氨酸标签表达的人GP130胞外结构域(hGP130-mmH；SEQID NO:191)、用C-末端myc-myc-六组氨酸标签表达的食蟹猕猴GP130胞外结构域(mfGP130-mmH；SEQ ID NO:194)、用C-末端小鼠IgG2a Fc标签表达的人GP130胞外结构域(hGP130-hFc；SEQ ID NO:197)、用C-末端myc-myc-六组氨酸标签表达的小鼠GP130胞外结构域(mGP130-mmH；SEQ ID NO:196)以及用C-末端myc-myc-六组氨酸标签表达的大鼠GP130胞外结构域(rGP130-mmH；SEQ ID NO:195)。用“mmH”标记的试剂是单体，而用“mFc”标记的试剂是二聚体。因此，例如，“hGP130-mmH”也被称为“单体人GP130”，并且“hGP130-mFc”也被称为“二聚体人GP130”。
首先在HBS-ET运行缓冲液中制备不同浓度的hGP130-mmH、mfGP130-mmH、hGP130-mFc(100nM–3.7nM；3倍连续稀释)或100nM的mGP130-mmH和rGP130-mmH，并且以30μL/分钟的流速在抗人Fc捕获的抗GP130单克隆抗体表面上注射这些抗体4分钟，同时在HBS-ET运行缓冲液中监测单克隆抗体结合的GP130试剂的解离10分钟。使用Scrubber 2.0c曲线拟合软件将实时结合传感图拟合为具有质量传递限制的1:1结合模型，从而确定缔合速率(ka)和解离速率(kd)。从动力学速率计算结合解离平衡常数(KD)和解离半衰期(t1/2)的计算公式为：
表3至12中示出了hGP130-MMH、mfGP130-MMH、hGP130.mFc、mGP130-MMH或rGP130-MMH在25℃和37℃下与本发明的不同抗GP130单克隆抗体结合的结合动力学参数。
表3：hGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表3：hGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表3：hGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
表4：hGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表4：hGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表4：hGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
在25℃下，抗GP130单克隆抗体与hGP130-MMH结合，KD值范围为从663pM至411nM，如表3所示。在37℃下，抗GP130单克隆抗体与hGP130-MMH结合，KD值范围为从1.84nM至225nM，如表4所示。
表5：mfGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表5：mfGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表5：mfGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
IC表示所观察的结合包括端值在内，并且在目前实验条件下不能拟合实时结合数据表示所观察的结合包括端值在内，并且在目前实验条件下不能拟合实时结合数据。
表6：mfGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表6：mfGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
本发明的26种抗GP130单克隆抗体中的23种与mfGP130-MMH结合。在25℃下，抗GP130单克隆抗体与mfGP130-MMH结合，KD值范围为从812pM至233nM，如表5所示。在37℃下，抗GP130单克隆抗体与mfGP130-MMH结合，KD值范围为从2.34nM至239nM，如表6所示。
表7：hGP130-mFc在25℃下与GP130单克隆抗体结合的结合动力学参数。
表7：hGP130-mFc在25℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合
表8：hGP130-mFc在37℃下与GP130单克隆抗体结合的结合动力学参数。
表8：hGP130-mFc在37℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
#意味着未观察到hGP130-mFc从捕获的GP130单克隆抗体的解离，并且在分析过程中将kd值手动固定为1.00E-05。
在25℃下，抗GP130单克隆抗体与hGP130-mFc结合，KD值范围为从36.6pM至8.21nM，如表7所示。在37℃下，抗GP130单克隆抗体与hGP130-mFc结合，KD值范围为从17pM至9.56nM，如表8所示。
表9：mGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表9：mGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
表10：mGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表10：mGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表10：mGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
如表9和10所示，本发明的抗GP130单克隆抗体在25℃或37℃下均不与mGP130-MMH结合。
表11：rGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表11：rGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
表11：rGP130-MMH在25℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
表12：rGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表12：rGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
表12：rGP130-MMH在37℃下与GP130单克隆抗体结合的结合动力学参数。
NB表示在目前实验条件下未观察到结合。
如表11和12所示，本发明的26种抗GP130单克隆抗体中的2种与rGP130-MMH结合。在25℃下，抗GP130单克隆抗体与rGP130-MMH结合，KD值范围为从344nM至460nM，如表11所示。在37℃下，抗GP130单克隆抗体与rGP130-MMH结合，KD值范围为从403nM至950，如表12所示。
实施例4：通过FACS分析来评估抗GP130抗体细胞结合
为了评估本发明的抗GP130抗体的细胞结合，产生了两种细胞系。一种所产生的细胞系是稳定过表达全长(FL)人gp130(登录号P40189的氨基酸1-918，第2位的亮氨酸变为缬氨酸，天然变体)，以及荧光素酶报告基因(Stat3-荧光素酶,Stat3-luc,SA Bioscience,#CLS-6028L)的HEK293细胞。使用流式细胞术来分选高表达gp130的细胞两次。以下称为HEK293/Stat3-luc/gp130-2X分选。还评估了IMR-32细胞(人神经母细胞瘤，ATCC)的细胞结合，因为这些细胞内源性表达gp130，并且被用于生物测定法。产生稳定表达萤光素酶报告基因(Stat3-萤光素酶,Stat3-luc,SA Bioscience,#CLS-6028L)的用于结合的细胞，这些细胞以下称为IMR-32/STAT3-Luc细胞。
对于FACS分析，将10nM抗体用于在含有2％FBS的PBS(不含钙和镁)中在4℃下染色30分钟，每种细胞类型0.5×106个细胞/孔。在添加抗体之前，将IMR-32/STAT3-luc细胞与1mg/mL小鼠IgG一起在4℃下温育30分钟，以阻断Fc受体。为了测试抗gp130抗体结合是否对IMR-32细胞上的gp130具有特异性，在25℃下，将抗体添加至IMR-32/Stat3-luc细胞中30分钟，所述细胞预先结合或不预先结合1000nM融合至myc-myc-his标签的人gp130的胞外结构域的重组蛋白(hgp130.mmh)。在与一抗一起温育后，用8μg/mL的
缀合的二抗(Jackson ImmunoResearch Laboratories Inc.，抗人#109-607-003)对细胞进行染色30分钟。使用BD CytoFixTM(Becton Dickinson,#554655)固定细胞，并且在
流式细胞仪上分析细胞。还针对所有细胞系测试了单独的未染色和二抗对照。使用
软件来分析结果，以确定活细胞的荧光的几何平均值。
如表13所示，在10nM下测试的二十六个本发明的抗gp130抗体显示出以范围为从29倍至159倍的结合比率结合至HEK293/Stat3-luc/gp130-2X分选细胞。抗gp130抗体显示出以4倍至45倍的结合比率结合至HEK293亲代细胞。在不存在hgp130.mmh的情况下，与IMR-32/Stat3-luc细胞的结合比率的范围为从5倍至23倍，在存在hGP130.mmh的情况下，为从4倍至9倍。单独的同种型对照抗体和二抗样品显示出针对HEK293细胞系的结合比率的范围为从1倍至3倍，针对IMR-32/Stat3-luc细胞，为从1倍至8倍。
表13：10nM抗gp130抗体与HEK293/Stat3-luc/gp130-2X分选和IMR-32/Stat3-luc细胞的结合。
表13：10nM抗gp130抗体与HEK293/Stat3-luc/gp130-2X分选和IMR-32/Stat3-luc细胞的结合。
表13：10nM抗gp130抗体与HEK293/Stat3-luc/gp130-2X分选和IMR-32/Stat3-luc细胞的结合。
实施例5：不同的抗GP130单克隆抗体之间的Octet交叉竞争。
在Octet HTX生物传感器平台(Pall ForteBio Corp.)上，使用实时、无标记生物层干涉测量测定法来确定一组抗GP130单克隆抗体之间的结合竞争。整个实验在25℃下在10mM HEPES、150mM NaCl、3mM EDTA、0.05％v/v表面活性剂Tween-20和1mg/mL BSA pH7.4(HBS-EBT)的缓冲液中进行，平板以1000rpm的速度振荡。为了评估2种抗体是否彼此竞争重组人GP130(hGP130-mmH；用C-末端myc-myc-六组氨酸标签表达，SEQ ID:188)上的各自的表位的结合，首先通过将生物传感器尖端浸入含有40-50μg/mL hGP130-MMH溶液的孔中4分钟，将约0.4-0.5nm的hGP130-mmH捕获至抗五His抗体涂覆的Octet生物传感器尖端(Fortebio Inc,#18-5122)上。然后，通过浸入含有50μg/mL mAb-1溶液的孔中4分钟，从而用第一抗GP130单克隆抗体(mAb-1)来饱和抗原捕获的生物传感器尖端。然后将生物传感器尖端浸入含有50μg/mL第二抗GP130单克隆抗体(mAb-2)溶液的孔中3分钟。在实验的每个步骤之间，在HBS-ETB缓冲液中洗涤生物传感器尖端。在整个实验过程中监测实时结合反应，并记录每个步骤结束时的结合反应。比较mAb-2与预先复合有mAb-1的hGP130-MMH的结合反应，并且确定不同的抗GP130单克隆抗体的竞争/非竞争行为，如表14所示。
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
表14：抗GP130单克隆抗体之间的交叉竞争
实施例6：与Luminex-GP130δD1-mmH和GP130δD1-3-mmH CHO上清液中的GP130结构域蛋白结合的单克隆抗体。
为了鉴定与本发明的抗GP130抗体相互作用的人GP130的结合区，利用基于Luminex FLEXMAP(FM3DD,LuminexCorp)流式细胞术的分析来表征重组人GP130蛋白结构域的相互作用。对于该测定法，将约300万个羧化的MicroplexR微球(Luminex,目录号LC1000A)进行洗涤，涡旋并在pH6.2的0.1M NaPO4(活化缓冲液)中超声处理，然后离心除去上清液。将微球重新悬浮在120L的活化缓冲液中，并通过添加15L的50mg/mL N-羟基琥珀酰亚胺(NHS，Thermo Scientific，产品目录号24500)将羧酸酯基团(-COOH)活化。在25℃下15L 50mg/mL的1-乙基-3-[3-二甲基氨基丙基]碳二亚胺(EDC，ThermoScientific，产品目录号22980)。10分钟后，通过添加600L的50mM MES，pH5(偶联缓冲液)将反应的pH降低至5.0，并将微球涡旋，并离心除去上清液。立即将活化的珠子与500L 20g/mL含小鼠IgG的单克隆抗myc单克隆抗体在偶联缓冲液中混合，并在25℃下温育两小时。加入50L 1M TRIS-HCl(pH8.0)淬灭偶联反应，将微球快速涡旋，离心并用1mL Dulbecco的1X磷酸盐缓冲盐水(DPBS，pH7.2，ThermoScientific产品目录号14190136)洗涤四次，以除去未偶联的蛋白质和其他反应组分。
将瞬时表达的GP130蛋白，包括用C-末端myc-myc六组氨酸标签表达的人GP130δD1(人GP130δD1-MMH，SEQ ID NO:192)和用C-末端myc-myc六组氨酸标签表达的人GP130δD1-D3(人GP130ΔD1-D3-MMH，SEQ ID NO:193)，悬浮在无血清CHO-S-SFM II培养基(ThermoFisher，产品目录号31033020)中，然后通过离心进行澄清。用C-末端myc-myc六组氨酸标签表达的纯化的GP130全长胞外结构域(人GP130-MMH，SEQ ID NO:191)在PBS中制备为10ug/mL。将如上所述制备的具有固定化抗myc单克隆抗体的微球等分试样分别添加到1mL每种这些蛋白质上清液和500uL纯化的GP130蛋白中。将微球轻轻混合，在25℃下温育两小时，用1mL DBPS洗涤两次，离心除去上清液，最后重悬于1mL DPBS缓冲液中。分别从与全长人GP130和每个人GP130域蛋白的单个反应中提取的48μL抗myc IgG偶联微球，并在3.6mL PBS+20mg/mL BSA+0.05％叠氮化钠(阻断缓冲液)中混合在一起。
从该混合池中，将75μL微球/孔铺在96孔滤板(Millipore，产品目录号：MSBVN1250)上，并与25μL单个抗人GP130单克隆抗体(0.5或5μg/mL)混合，在25℃下温育2小时，然后用200μL含0.05％Tween 20的DPBS(洗涤缓冲液)洗涤两次。为了检测和定量与单个微球结合的抗GP130抗体水平，可以添加100μL溶于阻断缓冲液的2.5μg/mL R-藻红蛋白缀合的山羊F(ab')2抗人κ(Southern Biotech，产品目录号2063-09)，并在25℃下温育30分钟。在30分钟后，将样品用200μL洗涤缓冲液洗涤两次，然后重悬于150μL洗涤缓冲液中。在Luminex分析仪中测量微球的中位数荧光强度(MFI)。
表15：抗GP130抗体与myc标签结合的Luminex MFI信号捕获了人GP130的全长胞外结构域、分离的人GP130δD1和δD1-D3结构域。
表15：抗GP130抗体与myc标签结合的Luminex MFI信号捕获了人GP130的全长胞外结构域、分离的人GP130δD1和δD1-D3结构域。
表15：抗GP130抗体与myc标签结合的Luminex MFI信号捕获了人GP130的全长胞外结构域、分离的人GP130δD1和δD1-D3结构域。
表15中列出了基于Luminex的分析结果。Luminex MFI信号强度表明，本发明的二十六个抗GP130抗体与人GP130全长胞外结构域结合。
抗GP130抗体mAb16637、mAb16641、mAb16656、mAb16659、mAb16664、mAb16665、mAb16676、mAb16687和MAb16695丧失与这两种缺失蛋白的结合，这表明在人GP130的D1结构域内具有结合表位。
抗GP130抗体mAb16614、mAb16618、mAb16622、mAb16636、mAb16662、mAb16666、mAb16673、mAb16682、mAb16692丧失与GP130δD1-D3的结合，同时保持与GP130δD1的结合，这表明它们的结合表位在人GP130的D2-D3结构域内。
抗GP130抗体mAb16623、mAb16646、mAb16669、mAb16680、mAb16683、mAb16684、mAb16693、mAb16702与GP130δD1和GP130δD1-D3结合，这表明它们的结合结构域位于人GP130的FNIII内。
实施例7：使用IMR-32/Stat3-luc细胞，不使用配体或使用hOncostain M、hLIF或hCNTF进行基于功能细胞的测定法。
为了评估抗GP130抗体的转录活化或抑制作用，产生了稳定表达萤光素酶报告基因(STAT3-Luc；SABiosciences，#CLS-6028L)的IMR-32细胞(人神经母细胞瘤ATCC)。所得的细胞系在下文中称为IMR-32/STAT3-Luc(参见本文的实施例4)。
对于生物测定，将IMR-32/STAT3-Luc细胞以15,000个细胞/孔接种在96孔板中的测定缓冲液中(0.1％FBS，溶于含青霉素/链球菌的Optimem中)，并在5％CO2中于37℃下过夜温育。第二天，将抗gp130抗体或同种型对照在测定缓冲液(加上仅含有不含测试分子的缓冲液的样品)中从100nM连续稀释至24.4pM，添加到细胞中并在25℃下温育30分钟。在30分钟后，使用100pM人抑癌素M(hOSM，R&D System 293-OM)、20pM人白血病抑制因子(hLIF，R&D System 7734-LF)、20pM人睫状神经营养因子(hCNTF，R&D System 257-NT)，或将测定缓冲液添加到细胞中。将hOSM、hLIF和hCNTF在测定缓冲液(加上仅包含不含测试分子的缓冲液的样品)中从10nM连续稀释至0.17pM，并添加到未用抗体处理的细胞中。在5％CO2中于37℃下放置5小时后，用OneGloTM试剂(Promega，#E6031)和VictorTMX多标记酶标仪(PerkinElmer)测量荧光素酶活性。使用非线性回归(4参数对数)和Prism 5软件(GraphPad)对结果进行分析，以获得EC50和IC50值。用抗体实现的RLU的最大范围除以hOSM实现的RLU的最大范围来计算抗体的活化。使用以下公式，用RLU值计算抑制百分比：
在此公式中，“RLU基线”是经过恒定量的无抗体配体(hOSM、hLIF或hCNTF)处理的细胞的发光值。“RLU抑制”是具有特定配体浓度的特定抗体在100nM处的发光值，“RLU背景”是无任何配体或抗体的细胞的发光值。
如表16所示，测试了本发明的二十六个抗人gp130抗体活化或抑制IMR-32/Stat3-luc细胞的活化的能力。如表19所示，在不存在任何添加的配体的情况下，所测试的本发明的抗体均未显示出IMR-32/Stat3-luc细胞的任何活化。本发明的26种抗体中的一种，即MAb16692，表现出对三种配体的完全抑制，hOSM、hLIF和hCNTF的IC50值分别为48pM、140pM和230pM。所测试的本发明的另外十种抗体显示出对至少一种配体的一些抑制，％抑制范围为从17％至95％，抑制抗体的IC50值范围为从＞100nM至88pM。本发明的十五种抗体未显示出对任何测试配体的抑制。同种型对照抗体未显示IMR-32/Stat3-luc细胞有任何可测量的活化或抑制。配体活化的IMR-32/STAT3-luc细胞的EC50值，对于hOSM为54pM，对于hLIF为23pM，对于hCNTF为4pM。
表16
在IMR-32/Stat3-luc细胞中不存在或存在GP130配体的情况下抗gp130抗体的活化和抑制
实施例8：阻断ELISA的GP130纯化抗体
GP130(糖蛋白130)是一种I型细胞因子受体跨膜蛋白，当与CNTFRα(睫状神经营养因子受体α亚基)结合时，会与配体睫状神经营养因子(CNTF)形成高亲和力的三元复合物。使用竞争夹心ELISA来测量抗gp130抗体阻断GP130蛋白与板结合的CNTFRα/CNTF复合物结合的能力。在该测定法中，将各种浓度的抗gp130抗体与恒定量的二聚GP130蛋白预混合，并监测由于抗体存在于固定在板上的CNTFRα/CNTF复合物中而导致的gp130结合的减少。
实验中使用的二聚体gp130蛋白由一部分人gp130胞外结构域(登录号为NP_002175.2的氨基酸E23-E619)和C-末端的小鼠IgG2a蛋白的Fc部分(hGP130-mFc；SEQ ID:190，分子量94,210道尔顿)组成。CNTFRα蛋白购自R&D Systems(登录号6992的氨基酸Q23-P346，分子量36,000道尔顿)。CNTF蛋白购自R&D Systems(登录号6441.1的氨基酸A2-M200，分子量22,800道尔顿)。包括同种型抗体对照、抗Fel d 1和人IgG4P抗体作为IgG背景检测的对照。
使用以下程序进行实验。将人CNTFRα以2mg/mL的浓度在HBSS中于4℃在96孔微量滴定板上涂覆过夜。随后使用1％(w/v)BSA在HBSS中的溶液阻断非特异性结合位点。在室温下，将在HBSS中浓度为1μg/ml的人CNTF加入与板结合的CNTFRα中1小时。在单独的稀释板中，用连续稀释的3.4pM至200nM范围的抗体和无抗体来滴定恒定量的2.5nM人GP130-mFc蛋白。将这些溶液在室温(RT)下温育1小时，然后将其转移至具有CNTFRα/CNTF复合物的微量滴定板中，不进行洗涤。将板在室温温育2小时，用PBST缓冲液洗涤，并且用缀合有辣根过氧化物酶(HRP)的抗mFc多克隆抗体(Jackson ImmunoResearch Inc)检测板结合的hGP130-mFc。用TMB溶液(BD Biosciences，按照制造商的说明按1:1比例混合底物A和B)对样品显影，以产生比色反应，然后用1M硫酸中和，然后在Victor X5读板器上测量450nm的吸光度。
使用PrismTM软件(GraphPad)中的S形剂量响应模型进行数据分析。所计算的IC50值的定义为降低50％的GP130与CNTFRα/CNTF复合物结合所需的抗体浓度，该值被用作阻断效力的指标。计算出在最大测试浓度下的阻断百分比，作为从剂量曲线确定的抗体阻断GP130与平板上的CNTFRα/CNTF结合的能力的指标。从100％阻断中减去在测试浓度最高的200nM抗体存在下观察到的信号减少率，相对于2.5nM GP130无抗体(0％阻断)的信号与仅HRP偶联二抗的背景信号(100％阻断)之间的差值。
阻断ELISA的结果显示在表17中，其中报告了所有抗体存在200nM抗体时的阻断百分比。仅在阻断GP130的30％以上与CNTFRα/CNTF结合的抗体中报告了IC50值。二十六种a-GP130抗体中有十九种阻断<30％的GP130蛋白与板涂覆的CNTFRα/CNTF结合。负数表示在抗体存在下检测到的GP130结合增加。七种抗体阻断GP130蛋白与CNTFRα/CNTF的结合>30％、IC50值范围从1.25nM至6.5nM的定量下限以下，其中四种在测试的最高抗体浓度下阻断信号的90％或更多。不相关的阻断对照抗体在浓度高达200nM时显示出4.5％的阻断。
表17：阻断ELISA的GP130纯化抗体
表17：阻断ELISA的GP130纯化抗体
表17：阻断ELISA的GP130纯化抗体
在该实施例中，100％阻断等于无GP130的OD450nm值的HRP缀合的二抗。
无抗体的2.5nM hGP130-mFc的OD450nm值为0％阻断。
负的最大阻断百分比表示在抗体存在下检测到的GP130结合增加。
-IC50值无法定量，在所测试的最高浓度下阻断<30％的抗体。
*表示该测定法的IC50值小于1.25E-09M的定量下限。
实施例9：LEPR x GP130聚焦方法双特异性筛选。
该实施例描述了与LEPR和GP130都结合以促进STAT3信号转导的双特异性抗体的产生。此类抗体在本文中称为“LEPR x GP130双特异性抗体”或“LEPRx GP130 bsAb”、“抗LEPRx抗GP130双特异性抗体”等等。在该实施例中，若干抗GP130结合臂与四个不同的抗LEPR结合臂配对。用于构建该实施例的双特异性抗体的抗LEPR抗体是称为mAb16679、mAb18445、mAb18446和mAb18449的激动抗体(参见美国专利申请公开号2017/0101477，该专利申请的公开内容以引用的方式整体并入本文)。表18和19分别汇总了在该实施例中使用的抗LEPR抗体的可变结构域和CDR的氨基酸和核酸序列。
表18：抗LEPR氨基酸序列标识符
表19：抗LEPR核酸序列标识符
通过将来自mAb16679的抗LEPR结合臂与来自18种不同的抗GP130抗体的结合臂配对，产生了十八种双特异性抗体。通过将来自抗LEPR抗体mAb18449、mAb18445和mAb18446的结合臂与抗GP130结合臂配对，可以产生六个另外的双特异性抗体。使用标准方法来产生本文所述的双特异性抗体。本实施例中显示的所有LEPR x GP130双特异性抗体均包含相同的(“共有”)轻链(包含SEQ ID NO:10的轻链可变区[LCVR]氨基酸序列和SEQ ID NO:12、14和16的轻链CDR[LCDR1、LCDR2和LCDR3]氨基酸序列)。表20汇总了该实施例的双特异性抗体的组分。
表20：LEPRxGP130双特异性抗体组分汇总。
表20：LEPRxGP130双特异性抗体组分汇总。
表20：LEPRxGP130双特异性抗体组分汇总。
表20：LEPRxGP130双特异性抗体组分汇总。
实施例10：在25℃和37℃下测得的抗LEPRx抗GP130双特异性抗体与不同的GP130试剂结合的Biacore结合动力学。
使用Biacore 4000仪器使用实时表面等离子共振生物传感器来确定LEPR和GP130与纯化的抗LEPR/GP130双特异性抗体结合的平衡解离常数(KD值)。所有结合研究均在25℃和37℃下的10mM HEPES、150mM NaCl、3mM EDTA和0.05％v/v表面活性剂Tween-20pH7.4(HBS-ET)运行缓冲液中进行。Biacore传感器表面首先通过胺与单克隆小鼠抗人Fc抗体(GE,#BR-1008-39)的偶联来衍生化，以捕获抗LEPR/GP130双特异性抗体。对以下试剂进行结合研究：用C-末端myc-myc-六组氨酸标签表达的人LEPR胞外结构域(hLEPR-MMH；SEQ IDNO:187)，用C-末端myc-myc-六组氨酸标签表达的食蟹猕猴LEPR胞外结构域(mfLEPR-MMH；SEQ ID NO:188)，用C-末端myc-myc-六组氨酸标签表达的人GP130胞外结构域(hGP130-MMH；SEQ ID NO:191)和用C-末端myc-myc-六组氨酸标签表达的食蟹猕猴GP130胞外结构域(mfGP130-MMH；SEQ ID NO:194)。首先在HBS-ET运行缓冲液(100nM–3.7nM；3倍系列稀释液)中制备不同浓度的LEPR或GP130试剂，并在抗人Fc捕获的抗LEPR/GP130双特异性抗体表面上注射4分钟,流速为30μL/min，同时在HBS-ET运行缓冲液中监测与双特异性抗体结合的LEPR或GP130试剂的解离10分钟。使用Scrubber 2.0c曲线拟合软件将实时结合传感图拟合为具有质量传递限制的1:1结合模型，从而确定动力学缔合速率(ka)和解离速率(kd)常数。从动力学速率常数计算结合解离平衡常数(KD)和解生活(t1/2)的计算公式恒定为：
表21至28显示了hLEPR-MMH、mfLEPR-MMH、hGP130-MMH或mfGP130-MMH在25℃和37℃下与本发明的不同抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表21
在25℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数
表21
在25℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数
表21
在25℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数
*NB表示在目前实验条件下未观察到结合。
表22
在37℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表22
在37℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表22
在37℃下hLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
在25℃下，抗LEPR/GP130双特异性抗体与hLEPR-MMH结合，KD值在5.91nM至106nM之间，如表21所示。在37℃下，抗LEPR单克隆抗体与hLEPR-MMH结合，KD值范围为从16.2nM至726nM，如表22所示。
表23
在25℃下mfLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表23
在25℃下mfLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
表24：
在37℃下mfLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表24：
在37℃下mfLEPR-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
在25℃下，本发明的22种抗LEPR/GP130双特异性抗体中的21种与mfLEPR-MMH结合，KD值在2.63nM至583nM之间，如表23所示。在37℃下，本发明的22种抗LEPR/GP130双特异性抗体中的20种与mfLEPR-MMH结合，KD值为5.05nM至284nM，如表24所示。
表25：
在25℃下hGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表25：
在25℃下hGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
表26：
在37℃下hGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表26：
在37℃下hGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
在25℃下，本发明的22种抗LEPR/GP130双特异性抗体中的17种与hGP130-MMH结合，KD值在448pM至219nM之间，如表25所示。在37℃下，22种抗LEPR/GP130双特异性抗体中的17种与hGP130-MMH结合，KD值在901pM至358nM之间，如表26所示。
表27
在25℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表27
在25℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表27
在25℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
表28
在37℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表28
在37℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
表28
在37℃下mfGP130-MMH与抗LEPR/GP130双特异性抗体结合的结合动力学参数。
*NB表示在目前实验条件下未观察到结合。
#IC表示观察到的结合信号比同种型对照抗体表面观察到的非特异性结合小三倍以上，和/或数据不能用于测量结合动力学参数。
在25℃下，本发明的22种LEPR x GP130双特异性抗体中的17种与mfGP130-MMH结合，KD值范围为513pnM至188nM，如表27所示。在37℃下，本发明的22种LEPR x GP130双特异性抗体中的16种与mfGP130-MMH结合，KD值为959pM至450nM，如表28所示。
实施例11：通过FACS分析测量LEPR x GP130双特异性抗体细胞结合
为了评估LEPRxGP130双特异性抗体对细胞的结合，产生了HEK293稳定细胞系。产生一种稳定地过表达全长人GP130(登录号P40189的氨基酸1-918，第2位的亮氨酸变为缬氨酸，天然变体)以及萤光素酶报道基因(Stat3-荧光素酶，Stat3-luc，SA Bioscience，#CLS-6028L)的细胞系，并使用流式细胞仪对GP130的高表达进行两次分选。以下将该细胞系称为“HEK293/Stat3-luc/gp130-2X分选”。在该实施例中使用的另一种细胞系，下文称为“HEK293/hLEPR-GPI”，稳定表达具有N-末端myc-myc标签和来自人羧肽酶M的C-末端肽序列的人LEPR的胞外结构域(登录号P48357的氨基酸22-839，同种型B)，所述C-末端肽序列指导GPI(糖基磷脂酰肌醇)的添加，使得蛋白质可以被GPI锚定到膜上。
对于FACS分析，将0.5×106个细胞/孔的HEK293亲本细胞、HEK293/Stat3-luc/gp130-2X分选细胞和HEK293/hLEPR-GPI细胞与200nM的抗GP130或LEPR或用LEPRxGP130双特异性抗体，以及同种型对照抗体在4℃含2％FBS的PBS(不含钙和镁)中温育。
为了测试抗LEPR抗体结合或LEPRxGP130双特异性抗体与细胞的结合是否受到瘦蛋白的存在的影响，将1μM人瘦蛋白(R&D Systems，#398-LP)与细胞温育30分钟，然后加入抗LEPR抗体或同种型对照抗体。在与一抗一起温育后，将细胞用8mg/mL的
缀合的二抗(Jackson ImmunoResearch Laboratories Inc.,#109-607-003)染色30分钟。使用BD CytoFixTM(Becton Dickinson,#554655)固定细胞，并且在
(Intellicyt)流式细胞仪上分析细胞。还针对所有细胞系测试了单独的未染色和二抗对照。使用
(IntelliCyt)和FlowJo version 10软件来分析结果，以确定活细胞的荧光的几何平均值。
如表29所示，在200nM下测试的本发明的两种LEPRxGP130双特异性抗体展示出以132倍和169倍的结合比率结合HEK293/gp130 2X分选细胞，并且以4423倍和6320倍(在无瘦蛋白的情况下)以及3596倍和5932倍(在存在1μM瘦蛋白的情况下)的结合比率结合HEK293/hLEPR-GPI细胞。作为常规抗体(mAb16683)制得的本发明双特异性抗体的GP130结合臂表现出以235倍的结合比率结合HEK293/gp130 2X分选细胞，并且以21倍的结合比率结合HEK293/hLEPR-GPI细胞。作为常规抗体制成的双特异性抗体(mAb18445和mAb18446)的LEPR结合臂显示出与HEK293/hLEPR-GPI细胞的结合比率为4711倍和7023倍(在无瘦蛋白的情况下)以及4246倍和6390倍(在存在1μM瘦蛋白的情况下)。抗GP130和抗LEPR常规抗体和双特异性抗体展示出以3到24倍的结合比率结合HEK293亲代细胞。单独的同种型对照抗体和二抗样品也不显示出与含有或不含有瘦蛋白的任何细胞系的显著结合，结合比率为1-3倍。
表29：通过FACS评估抗体与细胞的结合
实施例12：基于功能细胞的测定法。
细胞因子受体GP130(登录号P40189的氨基酸1-918)和LEPR(登录号P48357的氨基酸1-1165)具有非共价结合的酪氨酸激酶JAK2(结合到其胞质结构域的膜近端区域)。用同源配体或激动抗体进行的治疗最终将活化JAK2，从而使受体胞质区域上的关键酪氨酸残基磷酸化。磷酸化的酪氨酸残基用作信号传导复合物的停靠位点，该复合物在磷酸化后会刺激信号传导通路，诸如STAT3和ERK。对于LEPR，酪氨酸残基Y1141介导STAT3信号传导，并且该残基至苯丙氨酸的突变(Y1141F)消除了STAT3信号传导(Carpenter等人,1998,Proc.Natl.Acad.Sci.USA 95:6061-6066)。
在用LEPR x GP130 bsAb处理后，通过促进GP130和LEPR异源二聚化，开发了检测STAT3的转录活化的生物测定法。具体而言，产生了稳定表达突变型人LEPR(Y1141F)和野生型人GP130、以及STAT3响应性荧光素酶报告基因(STAT3-Luc；Qiagen CLS-6028L)的报告基因细胞系。分离所得的稳定细胞系，称为HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)，并保存在DME培养基中，该培养基中添加了10％FBS、1ug/mL嘌呤霉素、250ug/mL潮霉素B、500ug/mLG418和青霉素/链霉素/L-谷氨酰胺。在此生物测定法中鉴定出两种LEPRxGP130双特异性抗体，bsAb21236和bsAb21237，它们在存在瘦蛋白的情况下可促进STAT3活性。
对于生物测定法，将HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞以20,000个细胞/孔的密度接种，然后第二天，将培养基替换为80uL补充有1％BSA和0.1％FBS(测定缓冲液)的Opti-MEM。随后，将10uL固定浓度的10nM人瘦蛋白(人瘦蛋白；R&D Systems，#398-LP-01M)添加到孔中。在人瘦蛋白处理后，立即将双特异性抗体在测定缓冲液中半对数系列稀释(12个点)至终浓度为500nM至5pM，然后添加到细胞中。将同种型对照和人OSM(hOSM；R&DSystems，#295-OM/CF)在测定缓冲液中半对数稀释(11个点)至终浓度为100nM至1pM，然后添加到细胞中。然后将板在37℃和5％CO2下在培养箱中放置过夜。然后将One-Glo试剂(Promega，#E6051)添加到样品中，并在Envision Multilable酶标仪(Perkin Elmer)上以发光模式测量萤光素酶活性。获得相对光单位(RLU)值，并使用GraphPad Prism软件(GraphPad)使用非线性回归分析结果。从hOSM剂量反应中获得的最大RLU值在基于HEK293.STAT3.Luc.GP130.hLepR(Y1141F)的细胞分析中定义为100％活化。
在基于HEK293.STAT3.Luc.gp130.hLepR(Y1141F)细胞的测定中评估了LEPRxGP130双特异性抗体通过GP130介导的细胞信号活化的能力，表30显示了所得的EC50值和活化百分比。使用hOSM的剂量反应证实了细胞系的反应性，该剂量反应在测定中展示出具有592pM的EC50值。测试的两种LEPRxGP130双特异性抗体bsAb21236和bsAb21237在此测定法中均被活化，EC50值分别为2.11nM和2.46nM。两种双特异性抗体均具有hOSM所观察到的最大活化的大约20％。
表30
LEPRxGP130双特异性抗体对HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞系的活化
为了确认基于HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞的检测中LEPRxGP130双特异性抗体的活化是由于LEPR和GP130的活化，使用可溶性LEPR和GP130蛋白进行竞争生物测定，以阻断双特异性抗体的活化。竞争生物测定法利用过量固定浓度500nM的具有C-末端hFc标签的人LEPR的胞外结构域(hLEPR-hFc；SEQ ID NO:189)、具有C-末端myc-myc-六组氨酸标签的人LEPR的胞外结构域(hLEPR-MMH；SEQ ID NO:187)、具有C-末端hFc标签的人GP130的胞外结构域(hGP130-hFc；SEQ ID NO:197)和具有C-末端myc-myc-六组氨酸标签的人CNTFR的胞外结构域(hCNTFR-MMH；SEQ ID NO:198)。
为了进行测定法，将HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞以20,000个细胞/孔的密度接种，然后在第二天，将培养基替换为70uL补充有1％BSA和0.1％FBS(测定缓冲液)的Opti-MEM。将10nL固定浓度10nM的人瘦蛋白(人瘦蛋白；R&D Systems，#398-LP-01M)添加到孔中。在人瘦蛋白处理后，立即将10nM测定缓冲液中的双特异性抗体添加到细胞中。之后立即将过量500nM的可溶性蛋白hLEPR-hFc、hLEPR-MMH、hGP130-hFc和hCNTFR-MMH添加到适当的指定孔中。然后将板在37℃和5％CO2下在培养箱中放置过夜。然后将One-Glo试剂(Promega，#E6051)添加到样品中，并在Envision Multilable酶标仪(PerkinElmer)上以发光模式测量萤光素酶活性。获得相对光单位(RLU)值，并使用GraphPad Prism软件(GraphPad)分析结果。
竞争测定结果表明，可溶性hLEPR-hFc、hLEPR-MMH和hGP130-hFc能够阻断双特异性抗体的活性，而可溶性hCNTFR.mmh则不能阻断双特异性抗体的活性。单独的双特异性抗体的活性定义为100％，而同种型对照的活性表示0％活性。
下表31显示了在可溶性人LEPR、GP130和CNTFR存在下，双特异性抗体对HEK293.STAT3.Luc.GP130.hLEPR细胞的活化。表32显示了在hLEPR-MMH、hLEPR-hFc、hGP130-hFc或hCNTFR-MMH存在下的RLU产生。
表31
在可溶性人LEPR、GP130和CNTFR存在下，LEPR x GP130双特异性抗体活化HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞
表32
LEPR x GP130双特异性抗体在可溶性人LEPR、GP130和CNTFR存在下对HEK293.STAT3.Luc.GP130.hLEPR(Y1141F)细胞的活化
实施例13：LEPR x GP130双特异性抗体bsAb21236和bsAb21237在饮食诱导的肥胖小鼠中的体内功效。
在体内模型中，使用高脂饮食喂养的肥胖LEPRHu/Hu、IL6STHu/Hu小鼠确定了两种本发明的LEPR x GP130双特异性抗体bsAb21236和bsAb21237对体重的影响，所述小鼠表达由代替鼠LEPR胞外结构域序列的人LEPR胞外结构域序列组成的瘦蛋白受体，以及由代替鼠IL6ST胞外结构域序列的人IL6ST胞外结构域序列组成的GP130蛋白。
在第0天，将高脂饮食喂养12周的二十三只雄性LEPRHu/Hu、IL6STHu/Hu小鼠按体重随机分为三组，每组7至8只小鼠。在第0天和第7天，每组通过皮下注射接受剂量为30mg/kg的同种型对照抗体，剂量为30mg/kg的bsAb21236或剂量为30mg/kg的bsAb21237。使用的同种型对照抗体不结合任何已知的小鼠蛋白质。在研究期间，每天测量每只小鼠的体重。计算每只动物在每个时间点从第0天起的体重变化百分比。图1汇总了每个治疗组中动物的平均体重变化百分比。所有结果均表示为平均值±SEM。
如图1所示，与同种型对照抗体注射的小鼠相比，用bsAb21236以30mg/kg的剂量处理的LEPRHu/Hu、IL6STHu/Hu小鼠从抗体治疗后三天开始以及在随后的其他时间点测量的体重变化百分比均显著降低。与同种型对照抗体注射的小鼠相比，以30mg/kg的bsAb21237治疗的LEPRHu/Hu、IL6STHu/Hu小鼠从抗体治疗后五天开始以及在随后的其他测量时间点体重变化百分比显著降低。
实施例14：用LEPR x GP130 bsAbs治疗后，通过促进GP130和LEPR(短形式)异源二聚体的STAT3的转录活化
GP130是多种细胞因子的协同受体，在人组织中广泛表达(Taga T.,KishimotoT.gp130 and the interleukin-6family of cytokines.Annu.Rev.Immunol 1997；15:797–819)。LEPR的同种型通过可变剪接来产生，从而得到长同种型b(LEPR-b)和若干短形式，包括显示出最高和最广泛表达模式的同种型a(LEPR-a)(Tartaglia LA.The leptinreceptor.J Biol Chem 1997；272:6093–6096)。所有同种型共有相同的胞外结构域、跨膜区和一小段胞质结构域(含有Box 1区)，然后是可变区。长形式含有介导瘦蛋白的所有信号传导能力所需的胞内序列基序，而短形式则缺乏这些区域。由于短形式的胞外结构域与信号传递能力长形式相同，因此双特异性抗体可以结合短形式并与GP130产生复合物。通常，LEPR激动剂(包括LEPRxGP130双特异性抗原结合分子)的主要目标靶组织是主要表达LEPR同种型b的大脑。考虑到GP130和LEPR亚型a的广泛表达，在组织(诸如肝脏)中存在不期望的STAT3活化的潜力。
为了评估由LEPR短同种型a和GP130的复合产生的信号转导结果，开发了在用LEPRx GP130 bsAb处理后通过促进GP130和LEPR(短形式)异二聚化来检测STAT3的转录活化的生物测定法。具体而言，产生稳定表达LEPR(NP_001003679.1)的显性短形式(称为hLEPR(a))和野生型人GP130，以及STAT3响应荧光素酶报告基因(STAT3-Luc；Qiagen CLS-6028L)的报告基因细胞系。分离得到的稳定细胞系，称为HEK293.STAT3.Luc.GP130.hLEPR(a)，并保存在DME培养基中，该培养基中补充有10％FBS、1ug/mL嘌呤霉素、250ug/mL潮霉素B、500ug/mL G418和青霉素/链霉素/L-谷氨酰胺。
对于生物测定法，将HEK293.STAT3.Luc.GP130.hLEPR(a)细胞以20,000个细胞/孔的密度接种，然后第二天，将培养基替换为80uL补充有1％BSA和0.1％FBS(测定缓冲液)的Opti-MEM。随后，将10uL固定浓度的10nM人瘦蛋白(人瘦蛋白；R&D Systems，#398-LP-01M)添加到孔中。在人瘦蛋白处理后，立即将双特异性抗体在测定缓冲液中半对数系列稀释(12个点)至终浓度为500nM至5pM，然后添加到细胞中。作为对照，将人瘦蛋白和OSM(hOSM；R&DSystems，#295-OM/CF)在测定缓冲液中半对数稀释(11个点)至终浓度为100nM至1pM，然后添加到细胞中。然后将板在37℃和5％CO2下在培养箱中放置过夜。然后将One-Glo试剂(Promega，#E6051)添加到样品中，并在Envision Multilable酶标仪(Perkin Elmer)上以发光模式测量萤光素酶活性。获得相对光单位(RLU)值，并使用GraphPad Prism软件(GraphPad)使用非线性回归分析结果。从hOSM剂量反应获得的最大RLU值在基于细胞的测定法中定义为100％活化(在HEK293.STAT3.Luc.GP130.hLEPR(a)中)。
在基于细胞的HEK293.STAT3.Luc.gp130.hLEPR(a)细胞测定法中评估了LEPR xGP130双特异性抗体通过GP130介导的细胞信号转导来活化的能力，所得反应如表33所示。使用hOSM的剂量反应证实了细胞系的反应性，该剂量反应在测定中显示出EC50值为121pM的活化作用，其最大响应被称为100％活化。测试的两个LEPR x GP130双特异性抗体bsAb21236和bsAb21237均未能活化LEPR(a)的STAT3信号传导。类似于瘦蛋白，本发明的双特异性抗原结合蛋白仅在含有长形式的LEPR的细胞类型中产生生产性STAT3信号转导。
表33：
LEPR x GP130双特异性抗体对HEK293.STAT3.Luc.GP130.hLEPR(a)细胞系的活化
总之，数据显示本文提供的LEPRxGP130双特异性抗体不会通过瘦蛋白受体的“短形式”(LEPR-a同种型)活化信号传导，但会通过瘦蛋白受体(LEPR)的“长形式”(LEPR-b同种型)活化信号传导。该发现的相关性表明，这些双特异性抗体将主要在主要表达‘b’同种型的大脑中发挥其活性，而不会在广泛表达‘a’形式的其他组织(诸如肝)中发挥作用。鉴于这些双特异性抗体可通过活化大脑中的LEPR信号传导来治疗肥胖，因此这项工作证实了本文提供的双特异性抗体可有效靶向所需要的瘦蛋白信号传导(在大脑中)，同时避免了身体别处的不期望的信号传导(诸如肝，例如在炎性肝细胞腺瘤中(参见Rebouissou等人，NatureLetters,457(8):200-205,2009))。
本发明在范围上不受本文所述的具体实施方案的限制。实际上，除了本文中所述的那些内容之外，所属领域的技术人员根据前述说明和附图将显而易知本发明的各种修改。此类修改旨在落在所附权利要求书的范围内。
序列表
<110> 瑞泽恩制药公司
J·科洛马达
P·史蒂维斯
J·阿尔塔雷霍斯
<120> 结合瘦蛋白受体和/或GP130的双特异性抗原结合分子及其使用方法
<130> 10397WO01
<140> TBD
<141> 2018-12-17
<150> 62/607,137
<151> 2017-12-18
<150> 62/635,406
<151> 2018-02-26
<160> 198
<170> PatentIn 3.5版
<210> 1
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
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caggtgcagc tggtggagtc cgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
tcctgtacag cgtctggatt caccttcagt agttatgcca tgtactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtgtcagtt atatactatg atggaagtta taaatactat 180
gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatgg acagcctgag agccgaggac acggctgtct attactgtgc gagttataac 300
tggaactact ggtacttcga tttctggggc cgtggcaccc tggtcactgt ctcctca 357
<210> 2
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Tyr Asn Trp Asn Tyr Trp Tyr Phe Asp Phe Trp Gly Arg Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 3
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 3
ggattcacct tcagtagtta tgcc 24
<210> 4
<211> 8
<212> PRT
<213> 人工序列
<220>
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<400> 4
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 5
<211> 24
<212> DNA
<213> 人工序列
<220>
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atatactatg atggaagtta taaa 24
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<220>
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<400> 6
Ile Tyr Tyr Asp Gly Ser Tyr Lys
1 5
<210> 7
<211> 36
<212> DNA
<213> 人工序列
<220>
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gcgagttata actggaacta ctggtacttc gatttc 36
<210> 8
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<212> PRT
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<220>
<223> 合成
<400> 8
Ala Ser Tyr Asn Trp Asn Tyr Trp Tyr Phe Asp Phe
1 5 10
<210> 9
<211> 324
<212> DNA
<213> 人工序列
<220>
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gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180
aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag agttacagta cccctccgat caccttcggc 300
caagggacac gactggagat taaa 324
<210> 10
<211> 108
<212> PRT
<213> 人工序列
<220>
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<400> 10
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 Ser Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln 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 Ser Tyr Ser Thr Pro Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 11
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 11
cagagcatta gcagctat 18
<210> 12
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<220>
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<400> 12
Gln Ser Ile Ser Ser Tyr
1 5
<210> 13
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 13
gctgcatcc 9
<210> 14
<211> 3
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<213> 人工序列
<220>
<223> 合成
<400> 14
Ala Ala Ser
1
<210> 15
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 15
caacagagtt acagtacccc tccgatcacc 30
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 16
Gln Gln Ser Tyr Ser Thr Pro Pro Ile Thr
1 5 10
<210> 17
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 17
caggtgcagc tggtggagtc tgggggaggc gtggtccagc cgggggggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt acttatgaca ttcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtc atatcttttg atggaagtaa tagaaattat 180
ggagactccg tgaagggccg attcaccatc tccagggaca attccgacaa taccctgttt 240
ctggaaatga acaatctgag atttgaagac acggctgtgt attactgtgc gaaagagggc 300
tacggtgttg acttccaaca ctggggccag ggcaccctgg tcaccgtctc ctca 354
<210> 18
<211> 118
<212> PRT
<213> 人工序列
<220>
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<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr
20 25 30
Asp Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Ser Phe Asp Gly Ser Asn Arg Asn Tyr Gly Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Asp Asn Thr Leu Phe
65 70 75 80
Leu Glu Met Asn Asn Leu Arg Phe Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Gly Tyr Gly Val Asp Phe Gln His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 19
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<212> DNA
<213> 人工序列
<220>
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<400> 19
ggattcacct tcagtactta tgac 24
<210> 20
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<220>
<223> 合成
<400> 20
Gly Phe Thr Phe Ser Thr Tyr Asp
1 5
<210> 21
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 21
atatcttttg atggaagtaa taga 24
<210> 22
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 22
Ile Ser Phe Asp Gly Ser Asn Arg
1 5
<210> 23
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 23
gcgaaagagg gctacggtgt tgacttccaa cac 33
<210> 24
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
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Ala Lys Glu Gly Tyr Gly Val Asp Phe Gln His
1 5 10
<210> 25
<211> 384
<212> DNA
<213> 人工序列
<220>
<223> 合成
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caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagt aattactact ggacctggat ccggcagccc 120
ccagggaagg gactggagtg gattgggcat atctctaaca gtgggaccac caactataac 180
ccctccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240
aagctgacct ctgtgaccgc cgcagacacg gccgtgtatt actgtgcgag actccccctc 300
ggtattgcag cagttgatac agattattat tattacttcg gtatggacgt ctggggccaa 360
gggaccacgg tcaccgtctc ctca 384
<210> 26
<211> 128
<212> PRT
<213> 人工序列
<220>
<223> 合成
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Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Tyr
20 25 30
Tyr Trp Thr Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly His Ile Ser Asn Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Leu Pro Leu Gly Ile Ala Ala Val Asp Thr Asp Tyr Tyr Tyr Tyr
100 105 110
Phe Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120 125
<210> 27
<211> 24
<212> DNA
<213> 人工序列
<220>
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<400> 27
ggtggctcca tcagtaatta ctac 24
<210> 28
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 28
Gly Gly Ser Ile Ser Asn Tyr Tyr
1 5
<210> 29
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 29
atctctaaca gtgggaccac c 21
<210> 30
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 30
Ile Ser Asn Ser Gly Thr Thr
1 5
<210> 31
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 31
gcgagactcc ccctcggtat tgcagcagtt gatacagatt attattatta cttcggtatg 60
gacgtc 66
<210> 32
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 32
Ala Arg Leu Pro Leu Gly Ile Ala Ala Val Asp Thr Asp Tyr Tyr Tyr
1 5 10 15
Tyr Phe Gly Met Asp Val
20
<210> 33
<211> 348
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 33
gaggtgcagc tggtggagtc tgggggaggt gtggtacggc ctggggggtc cctgagactc 60
tcctgtacag cctctggatt cacctttgat gattatggca tgagctgggt ccgccaagct 120
ccagggaagg gactggagtg ggtctctggt attaattgga atggtggtag aacagaatat 180
gcagacgctg tgaagggccg attcatcatc tccagagaca acgccaagaa ctccctgtat 240
ctgcaaatga acagtctgag agccgaggac acggccttgt atttctgtgc gagaacggaa 300
ttacggtggg actactgggg ccagggaacc ctggtcaccg tctcctca 348
<210> 34
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asn Trp Asn Gly Gly Arg Thr Glu Tyr Ala Asp Ala Val
50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Phe Cys
85 90 95
Ala Arg Thr Glu Leu Arg Trp Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 35
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 35
ggattcacct ttgatgatta tggc 24
<210> 36
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 36
Gly Phe Thr Phe Asp Asp Tyr Gly
1 5
<210> 37
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 37
attaattgga atggtggtag aaca 24
<210> 38
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 38
Ile Asn Trp Asn Gly Gly Arg Thr
1 5
<210> 39
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 39
gcgagaacgg aattacggtg ggactac 27
<210> 40
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 40
Ala Arg Thr Glu Leu Arg Trp Asp Tyr
1 5
<210> 41
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 41
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggact caccttcagt agttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtttcacac attagtagtg ctggtagtac caaatactac 180
gcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgttt 240
ctgcaaatga acagcctgag agccgaggac acggctattt attactgtgc gggctataac 300
tacgcctact actacttcgg tgtggacgtc tggggccaag ggaccacggt caccgtctcc 360
tca 363
<210> 42
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 42
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 Leu Thr Phe Ser Ser Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser His Ile Ser Ser Ala Gly Ser Thr Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Gly Tyr Asn Tyr Ala Tyr Tyr Tyr Phe Gly Val Asp Val Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 43
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 43
ggactcacct tcagtagtta tgaa 24
<210> 44
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 44
Gly Leu Thr Phe Ser Ser Tyr Glu
1 5
<210> 45
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 45
attagtagtg ctggtagtac caaa 24
<210> 46
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 46
Ile Ser Ser Ala Gly Ser Thr Lys
1 5
<210> 47
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 47
gcgggctata actacgccta ctactacttc ggtgtggacg tc 42
<210> 48
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 48
Ala Gly Tyr Asn Tyr Ala Tyr Tyr Tyr Phe Gly Val Asp Val
1 5 10
<210> 49
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 49
cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60
atttgcactg tctctggtgg ctccatcagc agtaataatt actactgggg ctggatccgc 120
cagcccccag ggaaggggct ggaatggatt gggaatttgt atggtagtgg gagtacctac 180
tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240
tccctgaagc tgagttttgt gaccgccgca gacacggctg tgtatcactg tgcgagatgg 300
gacactaacg ggggggcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 360
<210> 50
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 50
Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Ile Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asn
20 25 30
Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Asn Leu Tyr Gly Ser Gly Ser Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Phe Val Thr Ala Ala Asp Thr Ala Val Tyr His
85 90 95
Cys Ala Arg Trp Asp Thr Asn Gly Gly Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 51
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 51
ggtggctcca tcagcagtaa taattactac 30
<210> 52
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 52
Gly Gly Ser Ile Ser Ser Asn Asn Tyr Tyr
1 5 10
<210> 53
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 53
ttgtatggta gtgggagtac c 21
<210> 54
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 54
Leu Tyr Gly Ser Gly Ser Thr
1 5
<210> 55
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 55
gcgagatggg acactaacgg gggggctttt gatatc 36
<210> 56
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 56
Ala Arg Trp Asp Thr Asn Gly Gly Ala Phe Asp Ile
1 5 10
<210> 57
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 57
caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggtta cacctttacc agccttggaa tcagctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg atcagcgcct acagtggtaa tagagactat 180
gcacagaagt tccagggcag agtcaccatg accacagaca catccacgag cacagcctat 240
atggagctga ggagcctgag atctgacgac acggccgtgt attattgtgc gagatctcta 300
cgttttgact actggggcca gggaaccctg gtcaccgtct cctca 345
<210> 58
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 58
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Leu
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Ser Gly Asn Arg Asp Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Leu Arg Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 59
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 59
ggttacacct ttaccagcct tgga 24
<210> 60
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 60
Gly Tyr Thr Phe Thr Ser Leu Gly
1 5
<210> 61
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 61
atcagcgcct acagtggtaa taga 24
<210> 62
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 62
Ile Ser Ala Tyr Ser Gly Asn Arg
1 5
<210> 63
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 63
gcgagatctc tacgttttga ctac 24
<210> 64
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 64
Ala Arg Ser Leu Arg Phe Asp Tyr
1 5
<210> 65
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 65
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
tcctgtgcag cctcaggatt caccttggat gattttgcca tgcactgggt ccggcaagct 120
ccagggaagg gcctggagtg ggtctcaggt attagttgga atagcggtaa tataggttat 180
gcggactctg tgaagggccg cttcaccatc tccagagaca acgccaggaa ctccctgtat 240
ctgcaaatga acagtctgag agcggaagac acggccttgt attactgcac ctcgggatac 300
tacctctact acgctatgga cgtctggggc caggggacca cggtcaccgt ctcctca 357
<210> 66
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 66
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Asp Asp Phe
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Asn Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Thr Ser Gly Tyr Tyr Leu Tyr Tyr Ala Met Asp Val Trp Gly Gln Gly
100 105 110
Thr Thr Val Thr Val Ser Ser
115
<210> 67
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 67
ggattcacct tggatgattt tgcc 24
<210> 68
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 68
Gly Phe Thr Leu Asp Asp Phe Ala
1 5
<210> 69
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 69
attagttgga atagcggtaa tata 24
<210> 70
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 70
Ile Ser Trp Asn Ser Gly Asn Ile
1 5
<210> 71
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 71
acctcgggat actacctcta ctacgctatg gacgtc 36
<210> 72
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 72
Thr Ser Gly Tyr Tyr Leu Tyr Tyr Ala Met Asp Val
1 5 10
<210> 73
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 73
caggtgcagc tggtgcagtc tgggcctgag gtgaagaagc ctgggtcttc ggtgaaggtc 60
tcctgcaagg cttctggagg caccatcgac agaaatgaaa tcacctgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggagta atcatcccta tcttaggtga ggcacactac 180
gaacgaaaat tccagggcag actcacgatt accatggacg agtccacgag tacagcctat 240
atggaactga gtaatctgag atctgaggac acggccgtat attactgtgc gagagagagg 300
gcagctcgag gctaccttga ctactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 74
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 74
Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Ile Asp Arg Asn
20 25 30
Glu Ile Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Val Ile Ile Pro Ile Leu Gly Glu Ala His Tyr Glu Arg Lys Phe
50 55 60
Gln Gly Arg Leu Thr Ile Thr Met Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Ala Ala Arg Gly Tyr Leu Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 75
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 75
ggaggcacca tcgacagaaa tgaa 24
<210> 76
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 76
Gly Gly Thr Ile Asp Arg Asn Glu
1 5
<210> 77
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 77
atcatcccta tcttaggtga ggca 24
<210> 78
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 78
Ile Ile Pro Ile Leu Gly Glu Ala
1 5
<210> 79
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 79
gcgagagaga gggcagctcg aggctacctt gactac 36
<210> 80
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 80
Ala Arg Glu Arg Ala Ala Arg Gly Tyr Leu Asp Tyr
1 5 10
<210> 81
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 81
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc cgggggggtc cctgagactc 60
tcctgtacag cctctggatt caccttcagt aattatgcta tattctgggt ccgccaggct 120
ccagggaagg gactggaata tgtttcaggt attagtaata atggggttac taaatattat 180
gcagactctg tgagggacag attcaccatc tccagagaca attccaggaa cacggtgtct 240
attcaaatgg acagcctgag aactgaggac atggctgtgt attactgtgc gcgagaaaac 300
tggggatcgg acgatggttt tgatatctgg ggccaaggaa caatggtcac cgtctcttca 360
<210> 82
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 82
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 Thr Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Ala Ile Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val
35 40 45
Ser Gly Ile Ser Asn Asn Gly Val Thr Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Arg Asp Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asn Thr Val Ser
65 70 75 80
Ile Gln Met Asp Ser Leu Arg Thr Glu Asp Met Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asn Trp Gly Ser Asp Asp Gly Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 83
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 83
ggattcacct tcagtaatta tgct 24
<210> 84
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 84
Gly Phe Thr Phe Ser Asn Tyr Ala
1 5
<210> 85
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 85
attagtaata atggggttac taaa 24
<210> 86
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 86
Ile Ser Asn Asn Gly Val Thr Lys
1 5
<210> 87
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 87
gcgcgagaaa actggggatc ggacgatggt tttgatatc 39
<210> 88
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 88
Ala Arg Glu Asn Trp Gly Ser Asp Asp Gly Phe Asp Ile
1 5 10
<210> 89
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 89
caggtgcagt tggtgcagtc tgggactgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggagg caccttcagc acctatccta tcaattgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac ggcaagctac 180
gcacagaagt tccagggcag agtcgcgatt accacggacg aatccacgag cacagcctac 240
atggagctga acagcctgag atctgaggac acggccgtgt attattgtgc gagagagagg 300
ccgaactggg gatctaatga ctactggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 90
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 90
Gln Val Gln Leu Val Gln Ser Gly Thr Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr Tyr
20 25 30
Pro Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Ser Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Ala Ile Thr Thr Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Asn Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Pro Asn Trp Gly Ser Asn Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 91
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 91
ggaggcacct tcagcaccta tcct 24
<210> 92
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 92
Gly Gly Thr Phe Ser Thr Tyr Pro
1 5
<210> 93
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 93
atcatcccta tctttggtac ggca 24
<210> 94
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 94
Ile Ile Pro Ile Phe Gly Thr Ala
1 5
<210> 95
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 95
gcgagagaga ggccgaactg gggatctaat gactac 36
<210> 96
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 96
Ala Arg Glu Arg Pro Asn Trp Gly Ser Asn Asp Tyr
1 5 10
<210> 97
<211> 366
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 97
caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
gcctgtgcag cgtctggatt cacctttaga agttatggca tgcactgggt ccgccaggct 120
ccaggcaagg ggctggagtg ggtggcagtt atctggtatg atggaagtaa taaatactat 180
acagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acagcctgag agccgaggac acggctatgt attactgtgc gatagacaaa 300
tgggctacgg tgactacgta cctgtttgac tactggggcc agggaaccct ggtcaccgtc 360
tcctca 366
<210> 98
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 98
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ala Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Ile Asp Lys Trp Ala Thr Val Thr Thr Tyr Leu Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 99
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 99
ggattcacct ttagaagtta tggc 24
<210> 100
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 100
Gly Phe Thr Phe Arg Ser Tyr Gly
1 5
<210> 101
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 101
atctggtatg atggaagtaa taaa 24
<210> 102
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 102
Ile Trp Tyr Asp Gly Ser Asn Lys
1 5
<210> 103
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 103
gcgatagaca aatgggctac ggtgactacg tacctgtttg actac 45
<210> 104
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 104
Ala Ile Asp Lys Trp Ala Thr Val Thr Thr Tyr Leu Phe Asp Tyr
1 5 10 15
<210> 105
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 105
gaggtgcagc tggtggagtc tgggggaggc ttggtacagt ctggagggtc cctgagactc 60
tcttgtgcag cctctggatt caccttcagt cgttatgaaa tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggttgcatat attagtaata ctggtactac cagggactat 180
tcagactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactatat 240
ctacaaatga gcagcctgag agtcgaggac acggctgttt attattgtgt gagagagaaa 300
tttagtggga cctctgactg gttcgacccc tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 106
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 106
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Glu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Asn Thr Gly Thr Thr Arg Asp Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Glu Lys Phe Ser Gly Thr Ser Asp Trp Phe Asp Pro Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 107
ggattcacct tcagtcgtta tgaa 24
<210> 108
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 108
Gly Phe Thr Phe Ser Arg Tyr Glu
1 5
<210> 109
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 109
attagtaata ctggtactac cagg 24
<210> 110
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 110
Ile Ser Asn Thr Gly Thr Thr Arg
1 5
<210> 111
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 111
gtgagagaga aatttagtgg gacctctgac tggttcgacc cc 42
<210> 112
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 112
Val Arg Glu Lys Phe Ser Gly Thr Ser Asp Trp Phe Asp Pro
1 5 10
<210> 113
<211> 375
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 113
gaggtgcagc tggtggagtc tgggggaggc ttggtgcagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt agctatgcca tgaactgggt ccgccaggct 120
ccagggaagg ggctggaatg ggtctcagct attagtggta gtggtgatag cacatactac 180
acagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
ctgcaaatga acaccctgag agccgaggac acggccgtat attactgtgc gaaagaggag 300
attgttatgt tggtaggtgc taccccgggg tggttcgacc cctggggcca gggaaccctg 360
gtcaccgtct cctca 375
<210> 114
<211> 125
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 114
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 Ser Tyr
20 25 30
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Tyr Tyr Thr Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Glu Glu Ile Val Met Leu Val Gly Ala Thr Pro Gly Trp Phe
100 105 110
Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 115
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 115
ggattcacct ttagtagcta tgcc 24
<210> 116
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 116
Gly Phe Thr Phe Ser Ser Tyr Ala
1 5
<210> 117
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 117
attagtggta gtggtgatag caca 24
<210> 118
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 118
Ile Ser Gly Ser Gly Asp Ser Thr
1 5
<210> 119
<211> 54
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 119
gcgaaagagg agattgttat gttggtaggt gctaccccgg ggtggttcga cccc 54
<210> 120
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 120
Ala Lys Glu Glu Ile Val Met Leu Val Gly Ala Thr Pro Gly Trp Phe
1 5 10 15
Asp Pro
<210> 121
<211> 387
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 121
gaggtgcagc tggtgcagtc tggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60
tcctgtaagg gttctggata cagttttacc agttactgga tcgactgggt gcgccagatg 120
cccgggaaag gcctggagtg gatggggatc atctatcctg atgactctga taccagatac 180
agtccgtcct tccaaggcca ggtcaccatg tcagtcgaca agtccatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggcctcggac accgccatat attactgtgc gagacatgag 300
agaggtatag tagaagctgg tacggattac tactactact acggtatgga cgtctggggc 360
caagggacca cggtcaccgt ctcctca 387
<210> 122
<211> 129
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 122
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Ile Asp Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met
35 40 45
Gly Ile Ile Tyr Pro Asp Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Met Ser Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg His Glu Arg Gly Ile Val Glu Ala Gly Thr Asp Tyr Tyr Tyr
100 105 110
Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser
115 120 125
Ser
<210> 123
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 123
ggatacagtt ttaccagtta ctgg 24
<210> 124
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 124
Gly Tyr Ser Phe Thr Ser Tyr Trp
1 5
<210> 125
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 125
atctatcctg atgactctga tacc 24
<210> 126
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 126
Ile Tyr Pro Asp Asp Ser Asp Thr
1 5
<210> 127
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 127
gcgagacatg agagaggtat agtagaagct ggtacggatt actactacta ctacggtatg 60
gacgtc 66
<210> 128
<211> 22
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 128
Ala Arg His Glu Arg Gly Ile Val Glu Ala Gly Thr Asp Tyr Tyr Tyr
1 5 10 15
Tyr Tyr Gly Met Asp Val
20
<210> 129
<211> 357
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 129
caggttcagc tggtgcagtc tggagctgag gtgatgaagc ctggggcctc agtgaaggtc 60
tcctgcaggg cttctggtta cacctttagc agctatgata tcaactgggt gcgacaggcc 120
cctggacaag gacttgagtg gatgggatgg atcagcactg ccactggtaa cacaaactat 180
ccacagaagg tccagggcag agtcaccatg accacagaca catcaacgaa cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtat attattgtac gagagagggc 300
aattcgaagg gctggctcga cccctggggc cagggaaccc tggtcaccgt ctcctca 357
<210> 130
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 130
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Thr Ala Thr Gly Asn Thr Asn Tyr Pro Gln Lys Val
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Gly Asn Ser Lys Gly Trp Leu Asp Pro Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 131
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 131
ggttacacct ttagcagcta tgat 24
<210> 132
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 132
Gly Tyr Thr Phe Ser Ser Tyr Asp
1 5
<210> 133
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> synthetic
<400> 133
atcagcactg ccactggtaa caca 24
<210> 134
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 134
Ile Ser Thr Ala Thr Gly Asn Thr
1 5
<210> 135
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 135
acgagagagg gcaattcgaa gggctggctc gacccc 36
<210> 136
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 136
Thr Arg Glu Gly Asn Ser Lys Gly Trp Leu Asp Pro
1 5 10
<210> 137
<211> 363
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 137
caggtacagc tgcagcagtc aggtcccgga caaatgaagt cctcgcagac cctcacactc 60
acctgtgcca tctccgggga cagtgtctct agcaacagtg ctatttggta ctggatcagg 120
cagtccccat cgagaggcct tgagtggctg gggaggacaa agttcaggtc caaatggtat 180
aatgattttg cactatctat gaaaagtcga ataaccatca acccagacac atccaagaac 240
cagttctccc tgcacctgaa ctctgtgact cccgaggaca cggctgtata ttactgtgca 300
agatataagt gggaacttta ctttgactac tggggccagg gaaccctggt caccgtctcc 360
tca 363
<210> 138
<211> 121
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 138
Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Gln Met Lys Ser Ser Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30
Ser Ala Ile Trp Tyr Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu
35 40 45
Trp Leu Gly Arg Thr Lys Phe Arg Ser Lys Trp Tyr Asn Asp Phe Ala
50 55 60
Leu Ser Met Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn
65 70 75 80
Gln Phe Ser Leu His Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val
85 90 95
Tyr Tyr Cys Ala Arg Tyr Lys Trp Glu Leu Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 139
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 139
ggggacagtg tctctagcaa cagtgctatt 30
<210> 140
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 140
Gly Asp Ser Val Ser Ser Asn Ser Ala Ile
1 5 10
<210> 141
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 141
acaaagttca ggtccaaatg gtataat 27
<210> 142
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 142
Thr Lys Phe Arg Ser Lys Trp Tyr Asn
1 5
<210> 143
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 143
gcaagatata agtgggaact ttactttgac tac 33
<210> 144
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 144
Ala Arg Tyr Lys Trp Glu Leu Tyr Phe Asp Tyr
1 5 10
<210> 145
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 145
gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagt acctattgga tgaactgggt ccgccaggct 120
ccagggaagg ggctggagtg ggtggccaac ataaaggaag atggaagtga gaaatactat 180
gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagagagggt 300
tttggagtgg ttacctatat ctggggccaa gggacaatgg tcaccgtctc ttca 354
<210> 146
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 146
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 Thr Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Glu Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Phe Gly Val Val Thr Tyr Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 147
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 147
ggattcacct ttagtaccta ttgg 24
<210> 148
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 148
Gly Phe Thr Phe Ser Thr Tyr Trp
1 5
<210> 149
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 149
ataaaggaag atggaagtga gaaa 24
<210> 150
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 150
Ile Lys Glu Asp Gly Ser Glu Lys
1 5
<210> 151
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 151
gcgagagagg gttttggagt ggttacctat atc 33
<210> 152
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 152
Ala Arg Glu Gly Phe Gly Val Val Thr Tyr Ile
1 5 10
<210> 153
<211> 351
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 153
caggtgcagc tggtggagtc tgggggaggc ttggtcaagc ctggagggtc cctgagactc 60
tcctgtgcag cctctggatt caccttcagt gactactata tgacctggat ccgccagact 120
ccagggaagg ggctggattg ggtttcatac attagttcta gtggtactaa caaatacaac 180
gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctcactgtat 240
ctgcaaatga acagcctgcg agccgaggac acggccgtat attactgtgt gagagacccc 300
ccctggggta tggacgtctg gggccaaggg accacggtca ccgtctcctc a 351
<210> 154
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 154
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Thr Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Asp Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Thr Asn Lys Tyr Asn Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Asp Pro Pro Trp Gly Met Asp Val Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 155
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 155
ggattcacct tcagtgacta ctat 24
<210> 156
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 156
Gly Phe Thr Phe Ser Asp Tyr Tyr
1 5
<210> 157
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 157
attagttcta gtggtactaa caaa 24
<210> 158
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 158
Ile Ser Ser Ser Gly Thr Asn Lys
1 5
<210> 159
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 159
gtgagagacc ccccctgggg tatggacgtc 30
<210> 160
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 160
Val Arg Asp Pro Pro Trp Gly Met Asp Val
1 5 10
<210> 161
<211> 360
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 161
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
tcctgtgttg cctctggatt caccttcaat aaatacgaca tgcactgggt ccgccaaact 120
actggaaaag gtctagagtg ggtctcaggt attgatactg atggtgacac atactatcca 180
ggctccgtga agggccgatt caccatctcc agagaaaatg ccgagaactc cctgtatctt 240
caaatgaacg gcctgagagt cggggacacg gctgtgtatt actgtgcaag atggccttgg 300
agtggtttct atggtgcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 360
<210> 162
<211> 120
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 162
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 Val Ala Ser Gly Phe Thr Phe Asn Lys Tyr
20 25 30
Asp Met His Trp Val Arg Gln Thr Thr Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Asp Thr Asp Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Glu Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Gly Leu Arg Val Gly Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Trp Pro Trp Ser Gly Phe Tyr Gly Ala Phe Asp Ile Trp Gly Gln
100 105 110
Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 163
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 163
ggattcacct tcaataaata cgac 24
<210> 164
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 164
Gly Phe Thr Phe Asn Lys Tyr Asp
1 5
<210> 165
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 165
attgatactg atggtgacac a 21
<210> 166
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 166
Ile Asp Thr Asp Gly Asp Thr
1 5
<210> 167
<211> 42
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 167
gcaagatggc cttggagtgg tttctatggt gcttttgata tc 42
<210> 168
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 168
Ala Arg Trp Pro Trp Ser Gly Phe Tyr Gly Ala Phe Asp Ile
1 5 10
<210> 169
<211> 372
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 169
caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60
acctgcactg tctctggtgg ctccatcagc agcggtggtg actactggag ctggatccgc 120
cagctcccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcgcctac 180
tataatccgt ccctcaagag tcgaggtacc atatcaatag acacgtctaa gaaccagttc 240
tccctgaagc tgacctctgt gactgccgcg gacacggccg tatatttctg tgtgaaatta 300
cgatttttgg agtggttctt ggggggctgg ttcggcccct ggggccaggg aaccctggtc 360
accgtctcct ca 372
<210> 170
<211> 124
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 170
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Asp Tyr Trp Ser Trp Ile Arg Gln Leu Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Ala Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Gly Thr Ile Ser Ile Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe
85 90 95
Cys Val Lys Leu Arg Phe Leu Glu Trp Phe Leu Gly Gly Trp Phe Gly
100 105 110
Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 171
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 171
ggtggctcca tcagcagcgg tggtgactac 30
<210> 172
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 172
Gly Gly Ser Ile Ser Ser Gly Gly Asp Tyr
1 5 10
<210> 173
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 173
atctattaca gtgggagcgc c 21
<210> 174
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 174
Ile Tyr Tyr Ser Gly Ser Ala
1 5
<210> 175
<211> 48
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 175
gtgaaattac gatttttgga gtggttcttg gggggctggt tcggcccc 48
<210> 176
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 176
Val Lys Leu Arg Phe Leu Glu Trp Phe Leu Gly Gly Trp Phe Gly Pro
1 5 10 15
<210> 177
<211> 351
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 177
gaggtgcagc tggtggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60
tcctgtgcag cctctggatt cacctttagc aactatggca tgacctgggt ccgccaggct 120
ccagggaagg gcctggaatg ggtctcagct attactggtg gtggtggtag cacatactac 180
tcaaactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacggtgtat 240
ctgcgaatga acagtgtgag agccgaggac acggccgtat attactgtgc gaaatataag 300
tggaacttcg tggacgactg gggccaggga accacggtca ccgtctcctc a 351
<210> 178
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 178
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 Asn Tyr
20 25 30
Gly Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Thr Gly Gly Gly Gly Ser Thr Tyr Tyr Ser Asn Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr
65 70 75 80
Leu Arg Met Asn Ser Val Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Lys Trp Asn Phe Val Asp Asp Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 179
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 179
ggattcacct ttagcaacta tggc 24
<210> 180
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 180
Gly Phe Thr Phe Ser Asn Tyr Gly
1 5
<210> 181
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 181
attactggtg gtggtggtag caca 24
<210> 182
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 182
Ile Thr Gly Gly Gly Gly Ser Thr
1 5
<210> 183
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 183
gcgaaatata agtggaactt cgtggacgac 30
<210> 184
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 184
Ala Lys Tyr Lys Trp Asn Phe Val Asp Asp
1 5 10
<210> 185
<211> 918
<212> PRT
<213> 人工序列
<220>
<223> 人GP130 UniProtKB - Q17RA0
<400> 185
Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu
1 5 10 15
Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser
20 25 30
Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys
35 40 45
Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr
50 55 60
Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr
65 70 75 80
Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser
85 90 95
Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu
100 105 110
Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys
115 120 125
Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys
130 135 140
Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu
145 150 155 160
Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg
165 170 175
Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val
180 185 190
Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr
195 200 205
Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro
210 215 220
Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu
225 230 235 240
Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys
245 250 255
Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile
260 265 270
Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp
275 280 285
Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu
290 295 300
Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile
305 310 315 320
Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile
325 330 335
Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val Gln Leu Val Trp Lys
340 345 350
Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val
355 360 365
Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala
370 375 380
Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu
385 390 395 400
Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile
405 410 415
Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu Lys Ala
420 425 430
Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr Thr Pro Arg Glu
435 440 445
Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Asp Lys Ala
450 455 460
Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly Thr Val His Arg Thr
465 470 475 480
Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val
485 490 495
Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala
500 505 510
Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys
515 520 525
Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val
530 535 540
Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr
545 550 555 560
Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp Ser Ser His Thr Glu
565 570 575
Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu Tyr Met Val Arg Met
580 585 590
Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe
595 600 605
Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro
610 615 620
Val Cys Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys
625 630 635 640
Phe Asn Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro
645 650 655
Asp Pro Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro
660 665 670
Arg His Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser Asp Gly Asn Phe
675 680 685
Thr Asp Val Ser Val Val Glu Ile Glu Ala Asn Asp Lys Lys Pro Phe
690 695 700
Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe Lys Lys Glu Lys Ile Asn
705 710 715 720
Thr Glu Gly His Ser Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser
725 730 735
Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu Asn Glu Ser Ser Gln Asn
740 745 750
Thr Ser Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg
755 760 765
His Gln Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln
770 775 780
Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu Val Asp
785 790 795 800
His Val Asp Gly Gly Asp Gly Ile Leu Pro Arg Gln Gln Tyr Phe Lys
805 810 815
Gln Asn Cys Ser Gln His Glu Ser Ser Pro Asp Ile Ser His Phe Glu
820 825 830
Arg Ser Lys Gln Val Ser Ser Val Asn Glu Glu Asp Phe Val Arg Leu
835 840 845
Lys Gln Gln Ile Ser Asp His Ile Ser Gln Ser Cys Gly Ser Gly Gln
850 855 860
Met Lys Met Phe Gln Glu Val Ser Ala Ala Asp Ala Phe Gly Pro Gly
865 870 875 880
Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Val Gly Met Glu Ala Ala
885 890 895
Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pro Gln Thr Val Arg Gln
900 905 910
Gly Gly Tyr Met Pro Gln
915
<210> 186
<211> 1165
<212> PRT
<213> 人工序列
<220>
<223> 人LEPR (UniProtKB/Swiss-Prot登录号P48357)
<400> 186
Met Ile Cys Gln Lys Phe Cys Val Val Leu Leu His Trp Glu Phe Ile
1 5 10 15
Tyr Val Ile Thr Ala Phe Asn Leu Ser Tyr Pro Ile Thr Pro Trp Arg
20 25 30
Phe Lys Leu Ser Cys Met Pro Pro Asn Ser Thr Tyr Asp Tyr Phe Leu
35 40 45
Leu Pro Ala Gly Leu Ser Lys Asn Thr Ser Asn Ser Asn Gly His Tyr
50 55 60
Glu Thr Ala Val Glu Pro Lys Phe Asn Ser Ser Gly Thr His Phe Ser
65 70 75 80
Asn Leu Ser Lys Thr Thr Phe His Cys Cys Phe Arg Ser Glu Gln Asp
85 90 95
Arg Asn Cys Ser Leu Cys Ala Asp Asn Ile Glu Gly Lys Thr Phe Val
100 105 110
Ser Thr Val Asn Ser Leu Val Phe Gln Gln Ile Asp Ala Asn Trp Asn
115 120 125
Ile Gln Cys Trp Leu Lys Gly Asp Leu Lys Leu Phe Ile Cys Tyr Val
130 135 140
Glu Ser Leu Phe Lys Asn Leu Phe Arg Asn Tyr Asn Tyr Lys Val His
145 150 155 160
Leu Leu Tyr Val Leu Pro Glu Val Leu Glu Asp Ser Pro Leu Val Pro
165 170 175
Gln Lys Gly Ser Phe Gln Met Val His Cys Asn Cys Ser Val His Glu
180 185 190
Cys Cys Glu Cys Leu Val Pro Val Pro Thr Ala Lys Leu Asn Asp Thr
195 200 205
Leu Leu Met Cys Leu Lys Ile Thr Ser Gly Gly Val Ile Phe Gln Ser
210 215 220
Pro Leu Met Ser Val Gln Pro Ile Asn Met Val Lys Pro Asp Pro Pro
225 230 235 240
Leu Gly Leu His Met Glu Ile Thr Asp Asp Gly Asn Leu Lys Ile Ser
245 250 255
Trp Ser Ser Pro Pro Leu Val Pro Phe Pro Leu Gln Tyr Gln Val Lys
260 265 270
Tyr Ser Glu Asn Ser Thr Thr Val Ile Arg Glu Ala Asp Lys Ile Val
275 280 285
Ser Ala Thr Ser Leu Leu Val Asp Ser Ile Leu Pro Gly Ser Ser Tyr
290 295 300
Glu Val Gln Val Arg Gly Lys Arg Leu Asp Gly Pro Gly Ile Trp Ser
305 310 315 320
Asp Trp Ser Thr Pro Arg Val Phe Thr Thr Gln Asp Val Ile Tyr Phe
325 330 335
Pro Pro Lys Ile Leu Thr Ser Val Gly Ser Asn Val Ser Phe His Cys
340 345 350
Ile Tyr Lys Lys Glu Asn Lys Ile Val Pro Ser Lys Glu Ile Val Trp
355 360 365
Trp Met Asn Leu Ala Glu Lys Ile Pro Gln Ser Gln Tyr Asp Val Val
370 375 380
Ser Asp His Val Ser Lys Val Thr Phe Phe Asn Leu Asn Glu Thr Lys
385 390 395 400
Pro Arg Gly Lys Phe Thr Tyr Asp Ala Val Tyr Cys Cys Asn Glu His
405 410 415
Glu Cys His His Arg Tyr Ala Glu Leu Tyr Val Ile Asp Val Asn Ile
420 425 430
Asn Ile Ser Cys Glu Thr Asp Gly Tyr Leu Thr Lys Met Thr Cys Arg
435 440 445
Trp Ser Thr Ser Thr Ile Gln Ser Leu Ala Glu Ser Thr Leu Gln Leu
450 455 460
Arg Tyr His Arg Ser Ser Leu Tyr Cys Ser Asp Ile Pro Ser Ile His
465 470 475 480
Pro Ile Ser Glu Pro Lys Asp Cys Tyr Leu Gln Ser Asp Gly Phe Tyr
485 490 495
Glu Cys Ile Phe Gln Pro Ile Phe Leu Leu Ser Gly Tyr Thr Met Trp
500 505 510
Ile Arg Ile Asn His Ser Leu Gly Ser Leu Asp Ser Pro Pro Thr Cys
515 520 525
Val Leu Pro Asp Ser Val Val Lys Pro Leu Pro Pro Ser Ser Val Lys
530 535 540
Ala Glu Ile Thr Ile Asn Ile Gly Leu Leu Lys Ile Ser Trp Glu Lys
545 550 555 560
Pro Val Phe Pro Glu Asn Asn Leu Gln Phe Gln Ile Arg Tyr Gly Leu
565 570 575
Ser Gly Lys Glu Val Gln Trp Lys Met Tyr Glu Val Tyr Asp Ala Lys
580 585 590
Ser Lys Ser Val Ser Leu Pro Val Pro Asp Leu Cys Ala Val Tyr Ala
595 600 605
Val Gln Val Arg Cys Lys Arg Leu Asp Gly Leu Gly Tyr Trp Ser Asn
610 615 620
Trp Ser Asn Pro Ala Tyr Thr Val Val Met Asp Ile Lys Val Pro Met
625 630 635 640
Arg Gly Pro Glu Phe Trp Arg Ile Ile Asn Gly Asp Thr Met Lys Lys
645 650 655
Glu Lys Asn Val Thr Leu Leu Trp Lys Pro Leu Met Lys Asn Asp Ser
660 665 670
Leu Cys Ser Val Gln Arg Tyr Val Ile Asn His His Thr Ser Cys Asn
675 680 685
Gly Thr Trp Ser Glu Asp Val Gly Asn His Thr Lys Phe Thr Phe Leu
690 695 700
Trp Thr Glu Gln Ala His Thr Val Thr Val Leu Ala Ile Asn Ser Ile
705 710 715 720
Gly Ala Ser Val Ala Asn Phe Asn Leu Thr Phe Ser Trp Pro Met Ser
725 730 735
Lys Val Asn Ile Val Gln Ser Leu Ser Ala Tyr Pro Leu Asn Ser Ser
740 745 750
Cys Val Ile Val Ser Trp Ile Leu Ser Pro Ser Asp Tyr Lys Leu Met
755 760 765
Tyr Phe Ile Ile Glu Trp Lys Asn Leu Asn Glu Asp Gly Glu Ile Lys
770 775 780
Trp Leu Arg Ile Ser Ser Ser Val Lys Lys Tyr Tyr Ile His Asp His
785 790 795 800
Phe Ile Pro Ile Glu Lys Tyr Gln Phe Ser Leu Tyr Pro Ile Phe Met
805 810 815
Glu Gly Val Gly Lys Pro Lys Ile Ile Asn Ser Phe Thr Gln Asp Asp
820 825 830
Ile Glu Lys His Gln Ser Asp Ala Gly Leu Tyr Val Ile Val Pro Val
835 840 845
Ile Ile Ser Ser Ser Ile Leu Leu Leu Gly Thr Leu Leu Ile Ser His
850 855 860
Gln Arg Met Lys Lys Leu Phe Trp Glu Asp Val Pro Asn Pro Lys Asn
865 870 875 880
Cys Ser Trp Ala Gln Gly Leu Asn Phe Gln Lys Pro Glu Thr Phe Glu
885 890 895
His Leu Phe Ile Lys His Thr Ala Ser Val Thr Cys Gly Pro Leu Leu
900 905 910
Leu Glu Pro Glu Thr Ile Ser Glu Asp Ile Ser Val Asp Thr Ser Trp
915 920 925
Lys Asn Lys Asp Glu Met Met Pro Thr Thr Val Val Ser Leu Leu Ser
930 935 940
Thr Thr Asp Leu Glu Lys Gly Ser Val Cys Ile Ser Asp Gln Phe Asn
945 950 955 960
Ser Val Asn Phe Ser Glu Ala Glu Gly Thr Glu Val Thr Tyr Glu Asp
965 970 975
Glu Ser Gln Arg Gln Pro Phe Val Lys Tyr Ala Thr Leu Ile Ser Asn
980 985 990
Ser Lys Pro Ser Glu Thr Gly Glu Glu Gln Gly Leu Ile Asn Ser Ser
995 1000 1005
Val Thr Lys Cys Phe Ser Ser Lys Asn Ser Pro Leu Lys Asp Ser
1010 1015 1020
Phe Ser Asn Ser Ser Trp Glu Ile Glu Ala Gln Ala Phe Phe Ile
1025 1030 1035
Leu Ser Asp Gln His Pro Asn Ile Ile Ser Pro His Leu Thr Phe
1040 1045 1050
Ser Glu Gly Leu Asp Glu Leu Leu Lys Leu Glu Gly Asn Phe Pro
1055 1060 1065
Glu Glu Asn Asn Asp Lys Lys Ser Ile Tyr Tyr Leu Gly Val Thr
1070 1075 1080
Ser Ile Lys Lys Arg Glu Ser Gly Val Leu Leu Thr Asp Lys Ser
1085 1090 1095
Arg Val Ser Cys Pro Phe Pro Ala Pro Cys Leu Phe Thr Asp Ile
1100 1105 1110
Arg Val Leu Gln Asp Ser Cys Ser His Phe Val Glu Asn Asn Ile
1115 1120 1125
Asn Leu Gly Thr Ser Ser Lys Lys Thr Phe Ala Ser Tyr Met Pro
1130 1135 1140
Gln Phe Gln Thr Cys Ser Thr Gln Thr His Lys Ile Met Glu Asn
1145 1150 1155
Lys Met Cys Asp Leu Thr Val
1160 1165
<210> 187
<211> 846
<212> PRT
<213> 人工序列
<220>
<223> hLEPR-MMH
<400> 187
Phe Asn Leu Ser Tyr Pro Ile Thr Pro Trp Arg Phe Lys Leu Ser Cys
1 5 10 15
Met Pro Pro Asn Ser Thr Tyr Asp Tyr Phe Leu Leu Pro Ala Gly Leu
20 25 30
Ser Lys Asn Thr Ser Asn Ser Asn Gly His Tyr Glu Thr Ala Val Glu
35 40 45
Pro Lys Phe Asn Ser Ser Gly Thr His Phe Ser Asn Leu Ser Lys Thr
50 55 60
Thr Phe His Cys Cys Phe Arg Ser Glu Gln Asp Arg Asn Cys Ser Leu
65 70 75 80
Cys Ala Asp Asn Ile Glu Gly Lys Thr Phe Val Ser Thr Val Asn Ser
85 90 95
Leu Val Phe Gln Gln Ile Asp Ala Asn Trp Asn Ile Gln Cys Trp Leu
100 105 110
Lys Gly Asp Leu Lys Leu Phe Ile Cys Tyr Val Glu Ser Leu Phe Lys
115 120 125
Asn Leu Phe Arg Asn Tyr Asn Tyr Lys Val His Leu Leu Tyr Val Leu
130 135 140
Pro Glu Val Leu Glu Asp Ser Pro Leu Val Pro Gln Lys Gly Ser Phe
145 150 155 160
Gln Met Val His Cys Asn Cys Ser Val His Glu Cys Cys Glu Cys Leu
165 170 175
Val Pro Val Pro Thr Ala Lys Leu Asn Asp Thr Leu Leu Met Cys Leu
180 185 190
Lys Ile Thr Ser Gly Gly Val Ile Phe Gln Ser Pro Leu Met Ser Val
195 200 205
Gln Pro Ile Asn Met Val Lys Pro Asp Pro Pro Leu Gly Leu His Met
210 215 220
Glu Ile Thr Asp Asp Gly Asn Leu Lys Ile Ser Trp Ser Ser Pro Pro
225 230 235 240
Leu Val Pro Phe Pro Leu Gln Tyr Gln Val Lys Tyr Ser Glu Asn Ser
245 250 255
Thr Thr Val Ile Arg Glu Ala Asp Lys Ile Val Ser Ala Thr Ser Leu
260 265 270
Leu Val Asp Ser Ile Leu Pro Gly Ser Ser Tyr Glu Val Gln Val Arg
275 280 285
Gly Lys Arg Leu Asp Gly Pro Gly Ile Trp Ser Asp Trp Ser Thr Pro
290 295 300
Arg Val Phe Thr Thr Gln Asp Val Ile Tyr Phe Pro Pro Lys Ile Leu
305 310 315 320
Thr Ser Val Gly Ser Asn Val Ser Phe His Cys Ile Tyr Lys Lys Glu
325 330 335
Asn Lys Ile Val Pro Ser Lys Glu Ile Val Trp Trp Met Asn Leu Ala
340 345 350
Glu Lys Ile Pro Gln Ser Gln Tyr Asp Val Val Ser Asp His Val Ser
355 360 365
Lys Val Thr Phe Phe Asn Leu Asn Glu Thr Lys Pro Arg Gly Lys Phe
370 375 380
Thr Tyr Asp Ala Val Tyr Cys Cys Asn Glu His Glu Cys His His Arg
385 390 395 400
Tyr Ala Glu Leu Tyr Val Ile Asp Val Asn Ile Asn Ile Ser Cys Glu
405 410 415
Thr Asp Gly Tyr Leu Thr Lys Met Thr Cys Arg Trp Ser Thr Ser Thr
420 425 430
Ile Gln Ser Leu Ala Glu Ser Thr Leu Gln Leu Arg Tyr His Arg Ser
435 440 445
Ser Leu Tyr Cys Ser Asp Ile Pro Ser Ile His Pro Ile Ser Glu Pro
450 455 460
Lys Asp Cys Tyr Leu Gln Ser Asp Gly Phe Tyr Glu Cys Ile Phe Gln
465 470 475 480
Pro Ile Phe Leu Leu Ser Gly Tyr Thr Met Trp Ile Arg Ile Asn His
485 490 495
Ser Leu Gly Ser Leu Asp Ser Pro Pro Thr Cys Val Leu Pro Asp Ser
500 505 510
Val Val Lys Pro Leu Pro Pro Ser Ser Val Lys Ala Glu Ile Thr Ile
515 520 525
Asn Ile Gly Leu Leu Lys Ile Ser Trp Glu Lys Pro Val Phe Pro Glu
530 535 540
Asn Asn Leu Gln Phe Gln Ile Arg Tyr Gly Leu Ser Gly Lys Glu Val
545 550 555 560
Gln Trp Lys Met Tyr Glu Val Tyr Asp Ala Lys Ser Lys Ser Val Ser
565 570 575
Leu Pro Val Pro Asp Leu Cys Ala Val Tyr Ala Val Gln Val Arg Cys
580 585 590
Lys Arg Leu Asp Gly Leu Gly Tyr Trp Ser Asn Trp Ser Asn Pro Ala
595 600 605
Tyr Thr Val Val Met Asp Ile Lys Val Pro Met Arg Gly Pro Glu Phe
610 615 620
Trp Arg Ile Ile Asn Gly Asp Thr Met Lys Lys Glu Lys Asn Val Thr
625 630 635 640
Leu Leu Trp Lys Pro Leu Met Lys Asn Asp Ser Leu Cys Ser Val Gln
645 650 655
Arg Tyr Val Ile Asn His His Thr Ser Cys Asn Gly Thr Trp Ser Glu
660 665 670
Asp Val Gly Asn His Thr Lys Phe Thr Phe Leu Trp Thr Glu Gln Ala
675 680 685
His Thr Val Thr Val Leu Ala Ile Asn Ser Ile Gly Ala Ser Val Ala
690 695 700
Asn Phe Asn Leu Thr Phe Ser Trp Pro Met Ser Lys Val Asn Ile Val
705 710 715 720
Gln Ser Leu Ser Ala Tyr Pro Leu Asn Ser Ser Cys Val Ile Val Ser
725 730 735
Trp Ile Leu Ser Pro Ser Asp Tyr Lys Leu Met Tyr Phe Ile Ile Glu
740 745 750
Trp Lys Asn Leu Asn Glu Asp Gly Glu Ile Lys Trp Leu Arg Ile Ser
755 760 765
Ser Ser Val Lys Lys Tyr Tyr Ile His Asp His Phe Ile Pro Ile Glu
770 775 780
Lys Tyr Gln Phe Ser Leu Tyr Pro Ile Phe Met Glu Gly Val Gly Lys
785 790 795 800
Pro Lys Ile Ile Asn Ser Phe Thr Gln Asp Asp Ile Glu Lys His Gln
805 810 815
Ser Asp Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu Gln
820 825 830
Lys Leu Ile Ser Glu Glu Asp Leu His His His His His His
835 840 845
<210> 188
<211> 844
<212> PRT
<213> 人工序列
<220>
<223> MfLEPR-MMH
<400> 188
Phe Asn Leu Ser Tyr Pro Ile Thr Pro Trp Arg Phe Lys Leu Ser Cys
1 5 10 15
Met Pro Pro Asn Ser Thr Tyr Asp Tyr Phe Leu Leu Pro Ala Gly Leu
20 25 30
Ser Lys Asn Thr Ser Asn Leu Asn Gly His Tyr Glu Thr Ala Val Glu
35 40 45
Phe Asn Ser Ser Asp Thr His Phe Ser Asn Leu Ser Lys Thr Thr Phe
50 55 60
His Cys Cys Phe Arg Ser Glu Gln Asp Arg Asn Cys Ser Leu Cys Ala
65 70 75 80
Asp Asn Ile Glu Gly Lys Thr Phe Val Ser Thr Val Asn Ser Ser Val
85 90 95
Phe Gln Gln Met Gly Ala Asn Trp Asn Ile Gln Cys Trp Leu Lys Gly
100 105 110
Asp Leu Lys Leu Phe Ile Cys Tyr Val Glu Ser Leu Phe Lys Asn Pro
115 120 125
Phe Lys Asn Tyr Lys His Lys Val His Leu Leu Tyr Val Leu Pro Glu
130 135 140
Val Leu Glu Asp Ser Pro Leu Val Pro Gln Lys Gly Ser Phe Gln Met
145 150 155 160
Val His Cys Asn Cys Ser Val His Glu Arg Cys Glu Cys Leu Val Pro
165 170 175
Val Pro Thr Ala Lys Leu Asn Asp Thr Leu Leu Met Cys Leu Lys Ile
180 185 190
Thr Ser Gly Gly Val Ile Phe Gln Ser Pro Leu Met Ser Val Gln Pro
195 200 205
Ile Asn Met Val Lys Pro Asp Pro Pro Leu Gly Leu Arg Met Glu Ile
210 215 220
Thr Asp Asp Gly Asn Leu Lys Ile Ser Trp Ser Ser Pro Pro Leu Val
225 230 235 240
Pro Phe Pro Leu Gln Tyr Glu Val Lys Tyr Ser Glu Asn Ser Thr Thr
245 250 255
Val Ile Arg Glu Ala Asp Lys Ile Val Ser Ala Thr Ser Leu Leu Val
260 265 270
Asp Gly Ile Leu Pro Gly Ser Ser Tyr Glu Val Gln Val Arg Gly Lys
275 280 285
Arg Leu Asp Gly Pro Gly Ile Trp Ser Asp Trp Ser Thr Pro His Val
290 295 300
Phe Thr Thr Gln Asp Val Ile Tyr Phe Pro Pro Lys Ile Leu Thr Ser
305 310 315 320
Val Gly Ser Asn Val Ser Phe His Cys Ile Tyr Lys Asn Glu Asn Lys
325 330 335
Ile Val Ser Ser Lys Lys Ile Val Trp Trp Met Asn Leu Ala Glu Lys
340 345 350
Ile Pro Gln Ser Gln Tyr Asp Val Val Ser Asp His Val Ser Lys Val
355 360 365
Thr Phe Phe Asn Leu Asn Glu Thr Lys Pro Arg Gly Lys Phe Thr Tyr
370 375 380
Asp Ala Val Tyr Cys Cys Asn Glu His Glu Cys His His Arg Tyr Ala
385 390 395 400
Glu Leu Tyr Val Ile Asp Val Asn Ile Asn Ile Ser Cys Glu Thr Asp
405 410 415
Gly His Leu Thr Lys Met Thr Cys Arg Trp Ser Thr Asn Thr Ile Gln
420 425 430
Ser Leu Ala Gly Ser Thr Leu Gln Leu Arg Tyr Arg Arg Ser Ser Leu
435 440 445
Tyr Cys Phe Asp Ile Pro Ser Ile His Pro Ile Ser Lys Pro Lys Asp
450 455 460
Cys Tyr Leu Gln Ser Asp Gly Phe Tyr Glu Cys Val Phe Gln Pro Ile
465 470 475 480
Phe Leu Leu Ser Gly Tyr Thr Met Trp Ile Arg Ile Asn His Pro Leu
485 490 495
Gly Ser Leu Asp Ser Pro Pro Thr Cys Val Leu Pro Asp Ser Val Val
500 505 510
Lys Pro Leu Pro Pro Ser Ser Val Lys Ala Glu Ile Ile Lys Asn Ile
515 520 525
Gly Leu Leu Lys Ile Ser Trp Glu Lys Pro Val Phe Pro Glu Asn Asn
530 535 540
Leu Gln Phe Gln Ile Arg Tyr Gly Leu Ser Gly Lys Glu Ile Gln Trp
545 550 555 560
Lys Met Tyr Asp Val Tyr Asp Ala Lys Ser Lys Ser Val Ser Leu Pro
565 570 575
Val Pro Asp Phe Cys Ala Val Tyr Ala Val Gln Val Arg Cys Lys Arg
580 585 590
Ser Asp Gly Leu Gly Leu Trp Ser Asn Trp Ser Asn Pro Ala Tyr Thr
595 600 605
Val Val Met Asp Ile Lys Val Pro Met Arg Gly Pro Glu Phe Trp Arg
610 615 620
Ile Ile Asn Gly Asp Thr Met Lys Lys Glu Lys Asn Val Thr Leu Leu
625 630 635 640
Trp Lys Pro Leu Met Lys Asn Asp Ser Leu Cys Ser Val Gln Arg Tyr
645 650 655
Val Ile Asn His His Thr Ser Cys Asn Gly Thr Trp Ser Glu Asp Val
660 665 670
Gly Asn His Thr Lys Phe Thr Phe Leu Trp Thr Glu Gln Ala His Thr
675 680 685
Val Thr Val Leu Ala Ile Asn Ser Ile Gly Ala Ser Val Ala Asn Phe
690 695 700
Asn Leu Thr Phe Ser Trp Pro Met Ser Lys Val Asn Ile Val Gln Ser
705 710 715 720
Leu Ser Ala Tyr Pro Leu Asn Ser Ser Cys Val Ile Leu Ser Trp Ile
725 730 735
Leu Ser Pro Ser Asp Tyr Lys Leu Met Tyr Phe Ile Ile Glu Trp Lys
740 745 750
Asn Leu Asn Glu Asp Gly Glu Ile Lys Trp Leu Arg Ile Ser Ser Ser
755 760 765
Val Lys Lys Tyr Tyr Ile His Asp His Phe Ile Pro Ile Glu Lys Tyr
770 775 780
Gln Phe Ser Leu Tyr Pro Ile Phe Met Glu Gly Val Gly Lys Pro Lys
785 790 795 800
Ile Ile Asn Ser Phe Ala Gln Asp Asn Thr Glu Lys His Gln Asn Asp
805 810 815
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu Gln Lys Leu
820 825 830
Ile Ser Glu Glu Asp Leu His His His His His His
835 840
<210> 189
<211> 1045
<212> PRT
<213> 人工序列
<220>
<223> hLEPR-hFc
<400> 189
Phe Asn Leu Ser Tyr Pro Ile Thr Pro Trp Arg Phe Lys Leu Ser Cys
1 5 10 15
Met Pro Pro Asn Ser Thr Tyr Asp Tyr Phe Leu Leu Pro Ala Gly Leu
20 25 30
Ser Lys Asn Thr Ser Asn Ser Asn Gly His Tyr Glu Thr Ala Val Glu
35 40 45
Pro Lys Phe Asn Ser Ser Gly Thr His Phe Ser Asn Leu Ser Lys Thr
50 55 60
Thr Phe His Cys Cys Phe Arg Ser Glu Gln Asp Arg Asn Cys Ser Leu
65 70 75 80
Cys Ala Asp Asn Ile Glu Gly Lys Thr Phe Val Ser Thr Val Asn Ser
85 90 95
Leu Val Phe Gln Gln Ile Asp Ala Asn Trp Asn Ile Gln Cys Trp Leu
100 105 110
Lys Gly Asp Leu Lys Leu Phe Ile Cys Tyr Val Glu Ser Leu Phe Lys
115 120 125
Asn Leu Phe Arg Asn Tyr Asn Tyr Lys Val His Leu Leu Tyr Val Leu
130 135 140
Pro Glu Val Leu Glu Asp Ser Pro Leu Val Pro Gln Lys Gly Ser Phe
145 150 155 160
Gln Met Val His Cys Asn Cys Ser Val His Glu Cys Cys Glu Cys Leu
165 170 175
Val Pro Val Pro Thr Ala Lys Leu Asn Asp Thr Leu Leu Met Cys Leu
180 185 190
Lys Ile Thr Ser Gly Gly Val Ile Phe Gln Ser Pro Leu Met Ser Val
195 200 205
Gln Pro Ile Asn Met Val Lys Pro Asp Pro Pro Leu Gly Leu His Met
210 215 220
Glu Ile Thr Asp Asp Gly Asn Leu Lys Ile Ser Trp Ser Ser Pro Pro
225 230 235 240
Leu Val Pro Phe Pro Leu Gln Tyr Gln Val Lys Tyr Ser Glu Asn Ser
245 250 255
Thr Thr Val Ile Arg Glu Ala Asp Lys Ile Val Ser Ala Thr Ser Leu
260 265 270
Leu Val Asp Ser Ile Leu Pro Gly Ser Ser Tyr Glu Val Gln Val Arg
275 280 285
Gly Lys Arg Leu Asp Gly Pro Gly Ile Trp Ser Asp Trp Ser Thr Pro
290 295 300
Arg Val Phe Thr Thr Gln Asp Val Ile Tyr Phe Pro Pro Lys Ile Leu
305 310 315 320
Thr Ser Val Gly Ser Asn Val Ser Phe His Cys Ile Tyr Lys Lys Glu
325 330 335
Asn Lys Ile Val Pro Ser Lys Glu Ile Val Trp Trp Met Asn Leu Ala
340 345 350
Glu Lys Ile Pro Gln Ser Gln Tyr Asp Val Val Ser Asp His Val Ser
355 360 365
Lys Val Thr Phe Phe Asn Leu Asn Glu Thr Lys Pro Arg Gly Lys Phe
370 375 380
Thr Tyr Asp Ala Val Tyr Cys Cys Asn Glu His Glu Cys His His Arg
385 390 395 400
Tyr Ala Glu Leu Tyr Val Ile Asp Val Asn Ile Asn Ile Ser Cys Glu
405 410 415
Thr Asp Gly Tyr Leu Thr Lys Met Thr Cys Arg Trp Ser Thr Ser Thr
420 425 430
Ile Gln Ser Leu Ala Glu Ser Thr Leu Gln Leu Arg Tyr His Arg Ser
435 440 445
Ser Leu Tyr Cys Ser Asp Ile Pro Ser Ile His Pro Ile Ser Glu Pro
450 455 460
Lys Asp Cys Tyr Leu Gln Ser Asp Gly Phe Tyr Glu Cys Ile Phe Gln
465 470 475 480
Pro Ile Phe Leu Leu Ser Gly Tyr Thr Met Trp Ile Arg Ile Asn His
485 490 495
Ser Leu Gly Ser Leu Asp Ser Pro Pro Thr Cys Val Leu Pro Asp Ser
500 505 510
Val Val Lys Pro Leu Pro Pro Ser Ser Val Lys Ala Glu Ile Thr Ile
515 520 525
Asn Ile Gly Leu Leu Lys Ile Ser Trp Glu Lys Pro Val Phe Pro Glu
530 535 540
Asn Asn Leu Gln Phe Gln Ile Arg Tyr Gly Leu Ser Gly Lys Glu Val
545 550 555 560
Gln Trp Lys Met Tyr Glu Val Tyr Asp Ala Lys Ser Lys Ser Val Ser
565 570 575
Leu Pro Val Pro Asp Leu Cys Ala Val Tyr Ala Val Gln Val Arg Cys
580 585 590
Lys Arg Leu Asp Gly Leu Gly Tyr Trp Ser Asn Trp Ser Asn Pro Ala
595 600 605
Tyr Thr Val Val Met Asp Ile Lys Val Pro Met Arg Gly Pro Glu Phe
610 615 620
Trp Arg Ile Ile Asn Gly Asp Thr Met Lys Lys Glu Lys Asn Val Thr
625 630 635 640
Leu Leu Trp Lys Pro Leu Met Lys Asn Asp Ser Leu Cys Ser Val Gln
645 650 655
Arg Tyr Val Ile Asn His His Thr Ser Cys Asn Gly Thr Trp Ser Glu
660 665 670
Asp Val Gly Asn His Thr Lys Phe Thr Phe Leu Trp Thr Glu Gln Ala
675 680 685
His Thr Val Thr Val Leu Ala Ile Asn Ser Ile Gly Ala Ser Val Ala
690 695 700
Asn Phe Asn Leu Thr Phe Ser Trp Pro Met Ser Lys Val Asn Ile Val
705 710 715 720
Gln Ser Leu Ser Ala Tyr Pro Leu Asn Ser Ser Cys Val Ile Val Ser
725 730 735
Trp Ile Leu Ser Pro Ser Asp Tyr Lys Leu Met Tyr Phe Ile Ile Glu
740 745 750
Trp Lys Asn Leu Asn Glu Asp Gly Glu Ile Lys Trp Leu Arg Ile Ser
755 760 765
Ser Ser Val Lys Lys Tyr Tyr Ile His Asp His Phe Ile Pro Ile Glu
770 775 780
Lys Tyr Gln Phe Ser Leu Tyr Pro Ile Phe Met Glu Gly Val Gly Lys
785 790 795 800
Pro Lys Ile Ile Asn Ser Phe Thr Gln Asp Asp Ile Glu Lys His Gln
805 810 815
Ser Asp Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
820 825 830
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
835 840 845
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
850 855 860
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
865 870 875 880
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
885 890 895
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
900 905 910
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
915 920 925
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
930 935 940
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
945 950 955 960
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
965 970 975
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
980 985 990
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
995 1000 1005
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
1010 1015 1020
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
1025 1030 1035
Leu Ser Leu Ser Pro Gly Lys
1040 1045
<210> 190
<211> 830
<212> PRT
<213> 人工序列
<220>
<223> hGP130-mFc
<400> 190
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln
305 310 315 320
Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln
385 390 395 400
Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp
435 440 445
Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp
465 470 475 480
Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525
Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu
565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590
Gln Gly Glu Ile Glu Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro
595 600 605
Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe
610 615 620
Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro
625 630 635 640
Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val
645 650 655
Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr
660 665 670
Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala
675 680 685
Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys
690 695 700
Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser
705 710 715 720
Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro
725 730 735
Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val
740 745 750
Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly
755 760 765
Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp
770 775 780
Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp
785 790 795 800
Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu His
805 810 815
Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys
820 825 830
<210> 191
<211> 625
<212> PRT
<213> 人工序列
<220>
<223> hGP130-MMH
<400> 191
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln
305 310 315 320
Gly Tyr Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln
385 390 395 400
Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp
435 440 445
Gln Gln Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp
465 470 475 480
Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525
Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu
565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590
Gln Gly Glu Ile Glu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly
595 600 605
Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu His His His His His
610 615 620
His
625
<210> 192
<211> 524
<212> PRT
<213> 人工序列
<220>
<223> hGP130 δ D1-MMH
<400> 192
Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly
1 5 10 15
Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu
20 25 30
Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp
35 40 45
Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser
50 55 60
Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala
65 70 75 80
Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys
85 90 95
Val Lys Pro Asn Pro Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu
100 105 110
Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser
115 120 125
Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser
130 135 140
Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser
145 150 155 160
Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile
165 170 175
Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu
180 185 190
Glu Ala Ser Gly Ile Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser
195 200 205
Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val
210 215 220
Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile
225 230 235 240
Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn
245 250 255
Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg
260 265 270
Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala
275 280 285
Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val
290 295 300
Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp
305 310 315 320
Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val
325 330 335
Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly
340 345 350
Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys
355 360 365
Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro
370 375 380
Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro
385 390 395 400
Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp
405 410 415
Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr
420 425 430
Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp
435 440 445
Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu
450 455 460
Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly
465 470 475 480
Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Glu
485 490 495
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu Gln Lys Leu
500 505 510
Ile Ser Glu Glu Asp Leu His His His His His His
515 520
<210> 193
<211> 319
<212> PRT
<213> 人工序列
<220>
<223> hGP130 δ D1-D3-MMH
<400> 193
Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Thr Gln Gly Tyr
1 5 10 15
Arg Thr Val Gln Leu Val Trp Lys Thr Leu Pro Pro Phe Glu Ala Asn
20 25 30
Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys Ser His
35 40 45
Leu Gln Asn Tyr Thr Val Asn Ala Thr Lys Leu Thr Val Asn Leu Thr
50 55 60
Asn Asp Arg Tyr Leu Ala Thr Leu Thr Val Arg Asn Leu Val Gly Lys
65 70 75 80
Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln Ala Thr
85 90 95
His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met Leu Trp
100 105 110
Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile Leu Glu
115 120 125
Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Thr Asp Trp Gln Gln
130 135 140
Glu Asp Gly Thr Val His Arg Thr Tyr Leu Arg Gly Asn Leu Ala Glu
145 150 155 160
Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp Gly Pro
165 170 175
Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro Pro Ser
180 185 190
Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala Val
195 200 205
Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe Ile Arg
210 215 220
Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr Ala Val
225 230 235 240
Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Thr Ser
245 250 255
Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu Gly Gly
260 265 270
Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala Gln Gly
275 280 285
Glu Ile Glu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu
290 295 300
Gln Lys Leu Ile Ser Glu Glu Asp Leu His His His His His His
305 310 315
<210> 194
<211> 625
<212> PRT
<213> 人工序列
<220>
<223> MfGP130-MMH
<400> 194
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ser Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asn Arg Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Arg Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Cys Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
Ser Asp Trp Ser Glu Glu Ala Asn Gly Ile Thr Tyr Glu Asp Arg Pro
290 295 300
Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Ala Gln
305 310 315 320
Gly Tyr Arg Thr Val Gln Leu Met Trp Lys Thr Leu Pro Pro Phe Glu
325 330 335
Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys
340 345 350
Ser His Leu Gln Asn Tyr Thr Val Asn Asp Thr Lys Leu Thr Val Asn
355 360 365
Leu Thr Asn Asp Arg Tyr Val Ala Thr Leu Thr Ala Arg Asn Leu Val
370 375 380
Gly Lys Ser Asp Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln
385 390 395 400
Ala Thr His Pro Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met
405 410 415
Leu Trp Val Glu Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile
420 425 430
Leu Glu Trp Cys Val Leu Ser Asp Lys Ala Pro Cys Ile Ala Asp Trp
435 440 445
Gln Gln Glu Asp Gly Thr Val His Arg Thr His Leu Arg Gly Asn Leu
450 455 460
Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp
465 470 475 480
Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro
485 490 495
Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu
500 505 510
Ala Val Leu Glu Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe
515 520 525
Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr
530 535 540
Ala Val Asn Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu
545 550 555 560
Thr Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu
565 570 575
Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala
580 585 590
Gln Gly Glu Ile Glu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly
595 600 605
Gly Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu His His His His His
610 615 620
His
625
<210> 195
<211> 624
<212> PRT
<213> 人工序列
<220>
<223> rGP130-MMH
<400> 195
Gln Leu Val Glu Pro Cys Gly Tyr Ile Tyr Pro Glu Phe Pro Val Val
1 5 10 15
Gln Arg Gly Ser Asn Phe Thr Ala Thr Cys Val Leu Lys Glu Lys Cys
20 25 30
Leu Gln Val Tyr Ser Val Asn Ala Thr Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Val Ala Val Pro Lys Glu Gln Val Thr Val Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Val Val Phe Gln Asn Val Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Leu Ser Gly Tyr Pro Pro Asp Ile Pro Thr Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Asn Met Leu Cys Gln Trp Asp Pro Gly Arg
115 120 125
Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
Glu Lys Phe Pro Asp Cys Arg Thr Lys His Gly Thr Ser Ser Cys Met
145 150 155 160
Met Gly Tyr Thr Pro Ile Tyr Phe Val Asn Ile Glu Val Trp Val Glu
165 170 175
Ala Glu Asn Ala Leu Gly Asn Val Ser Ser Glu Pro Ile Asn Phe Asp
180 185 190
Pro Val Asp Lys Val Lys Pro Ser Pro Pro His Asn Leu Ser Val Thr
195 200 205
Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Ala Trp Val Asn Ser
210 215 220
Gly Leu Asp Ser Ile Leu Arg Leu Lys Ser Asp Ile Gln Tyr Arg Thr
225 230 235 240
Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu Glu Asp Thr Val Ser
245 250 255
Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu Tyr
260 265 270
Val Phe Arg Ile Arg Ser Ile Lys Glu Asn Gly Lys Gly Tyr Trp Ser
275 280 285
Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr Glu Asp Arg Pro Ser
290 295 300
Lys Ala Pro Ser Phe Trp Tyr Lys Val Asn Ala Asn His Pro Gln Glu
305 310 315 320
Tyr Arg Ser Ala Arg Leu Ile Trp Lys Thr Leu Pro Leu Ser Glu Ala
325 330 335
Asn Gly Lys Ile Leu Asp Tyr Glu Val Val Leu Thr Gln Ser Lys Ser
340 345 350
Val Ser Gln Thr Tyr Thr Val Asn Gly Thr Glu Leu Ile Val Asn Leu
355 360 365
Thr Asn Asn Arg Tyr Val Ala Ser Leu Ala Ala Arg Asn Val Val Gly
370 375 380
Lys Ser Pro Ala Thr Val Leu Thr Ile Pro Gly Ser His Phe Lys Ala
385 390 395 400
Ser His Pro Val Val Asp Leu Lys Ala Phe Pro Lys Asp Asn Leu Leu
405 410 415
Trp Val Glu Trp Thr Pro Pro Ser Lys Pro Val Asn Lys Tyr Ile Leu
420 425 430
Glu Trp Cys Val Leu Ser Glu Asn Ser Pro Cys Ile Pro Asp Trp Gln
435 440 445
Gln Glu Asp Gly Thr Val Asn Arg Thr His Leu Arg Gly Ser Leu Leu
450 455 460
Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr Pro Val Phe Pro Gly Gly
465 470 475 480
Pro Gly Ser Pro Glu Ser Met Lys Ala Tyr Leu Lys Gln Ala Ala Pro
485 490 495
Ser Lys Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala
500 505 510
Val Leu Glu Trp Asp His Leu Pro Val Asp Val Gln Asn Gly Phe Ile
515 520 525
Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val Gly Lys Glu Met Val
530 535 540
Val Arg Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Ser
545 550 555 560
Ser Asp Thr Leu Tyr Met Val His Met Ala Ala Tyr Thr Glu Glu Gly
565 570 575
Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Leu Lys Phe Ala Gln
580 585 590
Gly Glu Ile Glu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly
595 600 605
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu His His His His His His
610 615 620
<210> 196
<211> 623
<212> PRT
<213> 人工序列
<220>
<223> mGP130-MMH
<400> 196
Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr Pro Glu Phe Pro Val Val
1 5 10 15
Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys Val Leu Lys Glu Ala Cys
20 25 30
Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Ala Ala Val Pro Arg Glu Gln Val Thr Val Ile Asn Arg Thr Thr
50 55 60
Ser Ser Val Thr Phe Thr Asp Val Val Leu Pro Ser Val Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu Gln Asn Val Tyr Gly Val
85 90 95
Thr Met Leu Ser Gly Phe Pro Pro Asp Lys Pro Thr Asn Leu Thr Cys
100 105 110
Ile Val Asn Glu Gly Lys Asn Met Leu Cys Gln Trp Asp Pro Gly Arg
115 120 125
Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
Glu Lys Phe Pro Asp Cys Gln Ser Lys His Gly Thr Ser Cys Met Val
145 150 155 160
Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile Glu Val Trp Val Glu Ala
165 170 175
Glu Asn Ala Leu Gly Lys Val Ser Ser Glu Ser Ile Asn Phe Asp Pro
180 185 190
Val Asp Lys Val Lys Pro Thr Pro Pro Tyr Asn Leu Ser Val Thr Asn
195 200 205
Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Ser Trp Val Ser Ser Gly
210 215 220
Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp Ile Gln Tyr Arg Thr Lys
225 230 235 240
Asp Ala Ser Thr Trp Ile Gln Val Pro Leu Glu Asp Thr Met Ser Pro
245 250 255
Arg Thr Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu Tyr Val
260 265 270
Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly Lys Gly Tyr Trp Ser Asp
275 280 285
Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr Glu Asp Arg Pro Ser Arg
290 295 300
Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro Ser His Gly Gln Glu Tyr
305 310 315 320
Arg Ser Val Arg Leu Ile Trp Lys Ala Leu Pro Leu Ser Glu Ala Asn
325 330 335
Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu Thr Gln Ser Lys Ser Val
340 345 350
Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu Leu Thr Val Asn Leu Thr
355 360 365
Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala Arg Asn Lys Val Gly Lys
370 375 380
Ser Ala Ala Ala Val Leu Thr Ile Pro Ser Pro His Val Thr Ala Ala
385 390 395 400
Tyr Ser Val Val Asn Leu Lys Ala Phe Pro Lys Asp Asn Leu Leu Trp
405 410 415
Val Glu Trp Thr Pro Pro Pro Lys Pro Val Ser Lys Tyr Ile Leu Glu
420 425 430
Trp Cys Val Leu Ser Glu Asn Ala Pro Cys Val Glu Asp Trp Gln Gln
435 440 445
Glu Asp Ala Thr Val Asn Arg Thr His Leu Arg Gly Arg Leu Leu Glu
450 455 460
Ser Lys Cys Tyr Gln Ile Thr Val Thr Pro Val Phe Ala Thr Gly Pro
465 470 475 480
Gly Gly Ser Glu Ser Leu Lys Ala Tyr Leu Lys Gln Ala Ala Pro Ala
485 490 495
Arg Gly Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala Val
500 505 510
Leu Ala Trp Asp Gln Ile Pro Val Asp Asp Gln Asn Gly Phe Ile Arg
515 520 525
Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val Gly Lys Glu Met Val Val
530 535 540
His Val Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Ser Ser
545 550 555 560
Asp Thr Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu Gly Gly
565 570 575
Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala Gln Gly
580 585 590
Glu Ile Glu Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu Gly Gly Glu
595 600 605
Gln Lys Leu Ile Ser Glu Glu Asp Leu His His His His His His
610 615 620
<210> 197
<211> 824
<212> PRT
<213> 人工序列
<220>
<223> hGP130-hFc
<400> 197
Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val
1 5 10 15
Gln Leu His Ser Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys
20 25 30
Met Asp Tyr Phe His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn
35 40 45
His Phe Thr Ile Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala
50 55 60
Ser Ser Val Thr Phe Thr Asp Ile Ala Ser Leu Asn Ile Gln Leu Thr
65 70 75 80
Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile
85 90 95
Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys
100 105 110
Ile Val Asn Glu Gly Lys Lys Met Arg Cys Glu Trp Asp Gly Gly Arg
115 120 125
Glu Thr His Leu Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr
130 135 140
His Lys Phe Ala Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys
145 150 155 160
Thr Val Asp Tyr Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val
165 170 175
Glu Ala Glu Asn Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe
180 185 190
Asp Pro Val Tyr Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val
195 200 205
Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn
210 215 220
Pro Ser Ile Lys Ser Val Ile Ile Leu Lys Tyr Asn Ile Gln Tyr Arg
225 230 235 240
Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala
245 250 255
Ser Thr Arg Ser Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu
260 265 270
Tyr Val Phe Arg Ile Arg Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp
275 280 285
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Claims (31)
1.一种分离的双特异性抗原结合分子，包含：
(a)结合人GP130的第一抗原结合结构域(D1)；和
(b)结合人瘦蛋白受体(LEPR)的第二抗原结合结构域(D2)。
2.如权利要求1所述的分离的双特异性抗原结合分子，其中D1和/或D2包含免疫球蛋白可变结构域。
3.如权利要求1所述的分离的双特异性抗原结合分子，其中D1和/或D2包含免疫球蛋白重链可变区(HCVR)和免疫球蛋白轻链可变区(LCVR)。
4.如权利要求1至3中任一项所述的分离的双特异性抗原结合分子，还包含连接D1与D2的多聚化组分。
5.如权利要求4所述的分离的双特异性抗原结合分子，其中所述多聚化组分包含免疫球蛋白的Fc部分。
6.如权利要求1所述的分离的双特异性抗原结合分子，其中D1衍生自抗GP130抗体，所述抗GP130抗体表现出一个或多个选自由以下组成的组的性质：
(i)如通过表面等离子共振所测量，在25℃下以小于约50nM的KD结合单体人GP130；
(ii)如通过表面等离子共振所确定，结合猴GP130，但是基本上不结合大鼠或小鼠GP130；
(iii)在基于细胞的GP130信号传导测定法中不抑制GP130配体介导的信号传导；以及
(iv)在不存在GP130配体的情况下不活化GP130信号传导。
7.如权利要求1所述的分离的双特异性抗原结合分子，其中D2衍生自抗LEPR抗体，所述抗LEPR抗体表现出一个或多个选自由以下组成的组的性质：
(i)如通过表面等离子共振所测量，在25℃下以小于约110nM的KD结合单体人LEPR；以及
(ii)在体外增强瘦蛋白介导的信号传导。
8.如权利要求1至7中任一项所述的分离的双特异性抗原结合分子，其中所述双特异性抗原结合分子表现出一个或多个选自由以下组成的组的性质：
(i)如通过表面等离子共振所测量，在25℃下以小于约110nM的KD结合单体人LEPR；
(ii)如通过表面等离子共振所测量，在25℃下以大于约3分钟的t1/2结合单体人LEPR；
(iii)如通过表面等离子共振所测量，在25℃下以小于约150nM的KD结合单体人GP130；
(iv)如通过表面等离子共振所测量，在25℃下以大于约2.5分钟的t1/2结合单体人GP130；
(v)结合猴LEPR；
(vi)结合猴GP130；
(vii)如通过FACS所测量，在存在或不存在瘦蛋白的情况下结合表达人LEPR的细胞；
(viii)在基于细胞的测定法中活化GP130，效力为相同的或相似的实验测定法条件下由人抑癌素M介导的活化的至少20％或更大；以及
(ix)当以治疗有效剂量施用于动物时，导致体重减轻。
9.如权利要求1至8中任一项所述的分离的双特异性抗原结合分子，其中D1包含来自重链可变区(D1-HCVR)的三个重链互补决定区(D1-HCDR1、D1-HCDR2和D1-HCDR3)和来自轻链可变区(D1-LCVR)的三个轻链互补决定区(D1-LCDR1、D1-LCDR2和D1-LCDR3)，所述重链可变区包含SEQ ID NO:154的氨基酸序列，所述轻链可变区包含SEQ ID NO:10的氨基酸序列。
10.如权利要求9所述的分离的双特异性抗原结合分子，其中D1-HCDR1包含SEQ ID NO:156的氨基酸序列；D1-HCDR2包含SEQ ID NO:158的氨基酸序列；D1-HCDR3包含SEQ ID NO:160的氨基酸序列；D1-LCDR1包含SEQ ID NO:12的氨基酸序列：D1-LCDR2包含SEQ ID NO:14的氨基酸序列；并且D1-LCDR3包含SEQ ID NO:16的氨基酸序列。
11.如权利要求10所述的分离的双特异性抗原结合分子，其中D1-HCVR包含SEQ ID NO:154的氨基酸序列；并且D1-LCVR包含SEQ ID NO:10的氨基酸序列。
12.如权利要求1至11中任一项所述的分离的双特异性抗原结合分子，其中D2包含来自重链可变区(D2-HCVR)的三个重链互补决定区(D2-HCDR1、D2-HCDR2和D2-HCDR3)；和来自轻链可变区(D2-LCVR)的三个轻链互补决定区(D2-LCDR1、D2-LCDR2和D2-LCDR3)，所述重链可变区包含选自由SEQ ID NO:2、162、170和178组成的组的氨基酸序列，所述轻链可变区包含SEQ ID NO:10的氨基酸序列。
13.如权利要求12所述的分离的双特异性抗原结合分子，其中D2-HCVR包含选自由以下各项组成的组的D2-HCDR1、D2-HCDR2、D2-HCDR3氨基酸序列：分别地，SEQ ID NO:4、6、8；分别地，SEQ ID NO:164、166、168；分别地，SEQ ID NO:172、174、176，以及分别地，SEQ ID NO:180、182、184；并且其中D2-LCVR包含分别地SEQ ID NO:12、14、16的D2-LCDR1、D2-LCDR2、D2-LCDR3氨基酸序列。
14.如权利要求13所述的分离的双特异性抗原结合分子，其中D2-HCVR包含选自由SEQID NO:2、162、170和178组成的组的氨基酸序列；并且D1-LCVR包含SEQ ID NO:10的氨基酸序列。
15.如权利要求1所述的分离的双特异性抗原结合分子，其中D2衍生自抗LEPR抗体，所述抗LEPR抗体在体外通过LEPR-b同种型增强瘦蛋白介导的信号传导。
16.如权利要求1所述的分离的双特异性抗原结合分子，其中D2衍生自抗LEPR抗体，所述抗LEPR抗体不在体外通过LEPR-α同种型活化瘦蛋白介导的信号传导。
17.如权利要求1所述的分离的双特异性抗原结合分子，其中所述双特异性抗原结合分子通过所述LEPR-b同种型来活化信号传导，并且基本上不通过所述LEPR-a同种型来活化瘦蛋白介导的信号传导。
18.一种药物组合物，包含如权利要求1至17中任一项所述的分离的双特异性抗原结合分子和药学上可接受的载剂或稀释剂。
19.一种器皿或注射装置，包含如权利要求1至18中任一项所述的分离的双特异性抗原结合分子或其药物组合物。
20.一种分离的核酸，编码如权利要求1-17中任一项所述的双特异性抗原结合分子的免疫球蛋白链。
21.一种分离的载体，包含如权利要求20所述的核酸。
22.一种分离的宿主细胞，包含如权利要求1-21中任一项所述的双特异性抗原结合分子、核酸或载体。
23.如权利要求22所述的宿主细胞，是中国仓鼠卵巢细胞。
24.一种用于治疗受试者的与瘦蛋白缺乏或瘦蛋白抵抗相关的或者由瘦蛋白缺乏或瘦蛋白抵抗导致的疾病或病症的方法，所述方法包括将如权利要求18所述的药物组合物施用于有需要的受试者。
25.如权利要求24所述的方法，其中所述与瘦蛋白缺乏或瘦蛋白抵抗相关的或者由瘦蛋白缺乏或瘦蛋白抵抗导致的疾病或病症选自由以下各项组成的组：脂肪营养不良、肥胖、代谢综合征、饮食引起的食物冲动、功能性下丘脑性闭经、1型糖尿病、2型糖尿病、胰岛素抵抗、由于胰岛素受体突变导致的严重胰岛素抵抗、阿尔茨海默氏病、瘦蛋白缺乏、瘦蛋白抵抗、矮怪病/多诺霍综合征和罗伯森-门登霍尔综合征。
26.一种用于治疗受试者的脂肪营养不良病症的方法，所述方法包括将如权利要求18所述的药物组合物施用于有需要的受试者，其中所述脂肪营养不良病症选自由以下各项组成的组：先天性全身脂肪营养不良、获得性全身脂肪营养不良、家族性局部脂肪营养不良、获得性局部脂肪营养不良、离心性腹部脂肪营养不良、环状脂肪萎缩、局部脂肪营养不良和HIV相关的脂肪营养不良。
27.如权利要求24至26中任一项所述的方法，还包括将第二治疗剂施用于所述受试者，其中所述第二治疗剂选自由以下各项组成的组：重组人瘦蛋白、PCSK9抑制剂、他汀、依泽替米贝、胰岛素、胰岛素变体、胰岛素促分泌剂、二甲双胍、磺酰脲、钠葡萄糖协同转运蛋白2(SGLT2)抑制剂、GLP-1激动剂/类似物、胰高血糖素(GCG)抑制剂、胰高血糖素受体(GCGR)抑制剂、血管生成素样蛋白(ANGPTL)抑制剂、苯丁胺、奥利司他、托吡酯、安非他酮、托吡酯/苯丁胺、安非他酮/纳曲酮、安非他酮/唑尼沙胺、普兰林肽/美曲普汀、氯卡色林、西替利司他、特索芬辛和韦利贝特。
28.一种用于制备如权利要求1-17中任一项所述的双特异性抗原结合分子或其免疫球蛋白链的方法，包括：
(a)将编码所述抗原结合蛋白的免疫球蛋白链的一个或多个多核苷酸引入宿主细胞中；
(b)在有利于所述多核苷酸的表达的条件下培养所述宿主细胞；以及
(c)任选地，从所述宿主细胞和/或所述宿主细胞在其中生长的培养基中分离所述抗原结合蛋白或免疫球蛋白链。
29.一种双特异性抗原结合分子或免疫球蛋白链，是如权利要求28所述的方法的产物。
30.一种用于将如权利要求1-17、18或29中任一项所述的分离的双特异性抗原结合分子或其药物组合物施用于受试者的方法，所述方法包括将所述分子或组合物注射至所述受试者的身体内。
31.如权利要求30所述的方法，其中所述分子或组合物是静脉内注射的、肌肉内注射的或皮下注射的。
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- 2018-12-17 SG SG11202005146VA patent/SG11202005146VA/en unknown
- 2018-12-17 CN CN201880081646.3A patent/CN111542540A/zh active Pending
- 2018-12-17 MX MX2020006508A patent/MX2020006508A/es unknown
- 2018-12-17 US US16/222,800 patent/US11834500B2/en active Active
- 2018-12-17 BR BR112020012011-1A patent/BR112020012011A2/pt unknown
- 2018-12-17 JP JP2020552684A patent/JP2021509021A/ja active Pending
- 2018-12-17 EP EP18830668.2A patent/EP3728315A1/en active Pending
- 2018-12-17 KR KR1020207018709A patent/KR20200100089A/ko not_active Application Discontinuation
- 2018-12-17 AU AU2018390811A patent/AU2018390811A1/en active Pending
- 2018-12-17 MA MA051289A patent/MA51289A/fr unknown
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| CN112190691A (zh) * | 2020-09-23 | 2021-01-08 | 南方医科大学 | Lifr蛋白作为非酒精性脂肪肝生物标记物及治疗靶点的应用 |
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| US20190185562A1 (en) | 2019-06-20 |
| US20240158497A1 (en) | 2024-05-16 |
| KR20200100089A (ko) | 2020-08-25 |
| MA51289A (fr) | 2021-03-24 |
| MX2020006508A (es) | 2020-09-17 |
| AU2018390811A1 (en) | 2020-07-02 |
| BR112020012011A2 (pt) | 2020-11-24 |
| IL275243A (en) | 2020-07-30 |
| WO2019126071A1 (en) | 2019-06-27 |
| US11834500B2 (en) | 2023-12-05 |
| EP3728315A1 (en) | 2020-10-28 |
| CA3084385A1 (en) | 2019-06-27 |
| JP2021509021A (ja) | 2021-03-18 |
| SG11202005146VA (en) | 2020-06-29 |
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