CN112236196A - 心房利钠肽嫁接抗体 - Google Patents
心房利钠肽嫁接抗体 Download PDFInfo
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- CN112236196A CN112236196A CN201980038627.7A CN201980038627A CN112236196A CN 112236196 A CN112236196 A CN 112236196A CN 201980038627 A CN201980038627 A CN 201980038627A CN 112236196 A CN112236196 A CN 112236196A
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Abstract
本发明涉及抗体或其片段，其包含纳入到所述抗体或其片段的至少一个CDR区域中的至少一个异源氨基酸序列，其中所述至少一个异源氨基酸序列包含N端接头序列(Ntls)、心房利钠肽(ANP)和C端接头序列(Ctls)。任选地，所述至少一个CDR区域的至少一部分被所述至少一个纳入其中的异源氨基酸序列所替代。本发明还涉及用于治疗方法中的这种抗体或其片段、包含这种抗体或其片段的组合物、编码这种抗体或其片段的核酸或核酸混合物、包含这种核酸或这种核酸混合物的宿主细胞，以及涉及产生这种抗体或其片段的方法。
Description
技术领域
本发明涉及抗体或其片段，其包含纳入到所述抗体或其片段的至少一个CDR区域内的至少一个异源氨基酸序列，其中所述至少一个异源氨基酸序列包含N端接头序列(Ntls)、心房利钠肽(ANP)和C端接头序列(Ctls)。任选地，所述至少一个CDR区域的至少一部分被所述至少一个纳入到其中的异源氨基酸序列所替代。在以下两者之间存在至少12个氨基酸残基：在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC(重链)res25与ANP的第一个氨基酸残基之间；在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res51与ANP的第一个氨基酸残基之间；在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸序列残基HC res92与ANP的第一个氨基酸残基之间；在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸序列残基LC(轻链)res26与ANP的第一个氨基酸残基之间；在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res49与ANP的第一个氨基酸残基之间；和/或在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res88与ANP的第一个氨基酸残基之间。此外，在ANP的最后一个氨基酸残基和以下之间存在至少9个氨基酸残基：在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res35a；在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸序列残基HC res57；在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res106；在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res 32；在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res57；和/或在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res98。本发明还涉及这种抗体或其片段用于治疗方法中、包含这种抗体或其片段的组合物、编码这种抗体或其片段的核酸或核酸混合物、包含这种核酸或这种核酸混合物的宿主细胞以及产生这种抗体或其片段的方法。
背景技术
利钠肽为具有神经体液作用的三种结构相关肽的家族。心房利钠肽(ANP)为包含由半胱氨酸残基7和23之间的二硫键桥形成的中心环结构的28个氨基酸的肽。人ANP在心房肌细胞中表达为153个氨基酸长的前激素原。信号肽切割产生激素原形式，其随后被进一步切割为成熟的ANP和N端残余物，称为NT-proANP。与ANP相似，脑利钠肽(BNP)和C型利钠肽(CNP)也是由前体蛋白产生的，并包含中心环结构。ANP主要是由左、右心房的心肌细胞产生和释放，而BNP主要是由心室心肌细胞产生。CNP是由血管内皮细胞合成。除了这些位置，还在身体的其他部分产生较小量的利钠肽，例如在大脑、肾脏和肾上腺中。利钠肽由三个独立的基因NPPA、NPPB和NPPC编码。这三种肽的氨基酸序列在哺乳动物中是高度保守的(Potteret al.，Handb Exp Pharmacol.2009；(191)：341-66)。然而，已经记载了利钠肽的显著序列修饰，如截短、氨基酸交换以及嵌合融合(例如CD-NP(McKie et al.，Curr Heart FailRep.2010Sep；7(3)：93-9))以产生有效的利钠肽，其激活或结合细胞受体并能引起相关的生理效果。
利钠肽与三种不同的膜结合受体类型NPR-A、NPR-B和NPR-C结合，从而介导它们的生物学效果。ANP和BNP与NPR-A的结合亲和力最大；相比之下，CNP对NPR-B受体的亲和力最大。NPR-A和NPR-B包含(微粒的)鸟苷酸环化酶结构域(pGC)，其酶活性导致(细胞内)环鸟苷一磷酸(cGMP)的增加。作为第二信使，cGMP调节不同的细胞过程。NPR-C受体没有显示出鸟苷酸环化酶的活性，还被称为“清除”受体，因为它可以结合利钠肽，从而导致其通过内吞作用的降解。已经记载了NPR-C受体通过调节cAMP的额外信号传导功能(Anand-Srivastava，Peptides.2005Jun；26(6)：1044-59)。
心脏激素ANP和BNP在心室和心房伸展时排出，例如由于血浆量过多。它们通过放松血管平滑肌发挥血管舒张效果，并导致血压降低。在肾脏中，ANP会导致尿液排出增加(利尿)，以及尿液中钠离子浓度增加(尿钠增多)。ANP被认为是肾素-血管紧张素-醛固酮系统(RAAS)的代偿性拮抗剂，其在许多心血管疾病中被过度激活。此外，ANP发挥其他神经体液效果，包括对交感神经系统的抑制效果，以及对压力反射的复杂调节效果(Woods et al.，Clin Exp Pharmacol Physiol.2004Nov；31(11)：791-4)。对于ANP以及BNP和CNP，抗炎、抗肥大和抗纤维化效果已在不同疾病的动物模型中得到证实(例如Knowles et al.，2001，J.Clin.Invest.107：975-984；Dahrouj et al.，J Pharmacol Exp Ther.2013Jan；344(1)：96-102；Baliga et al.，Br J Pharmacol.2014Jul；171(14)：3463-75；Mitaka etal.Intensive Care Med Exp.2014Dec；2(1)：28；Werner et al.，Basic ResCardiol.2016Mar；111(2)：22；Kimura et al.，Respir Res.2016Feb 19；17：19)。CNP对NPR-B的激活在骨骼生长(Yasoda et al.，Clin.Calcium.2009Jul；19(7)：1003-8)和血管内皮完整性(Moyes et al.，J Clin Invest.2014Sep；124(9)：4039-51)方面起着重要作用。
利钠肽及其受体的广谱生理效果使它们成为药物开发中的有吸引力的目标(Lumsden et al.，Curr Pharm Des.2010；16(37)：4080-8；Buglioni et al.，Annu RevMed.2016；67：229-43)。例如，利钠cGMP系统可能在各种病理生理条件下被抑制，其可能会导致高血压、细胞增殖增加、纤维化、炎症、内皮功能障碍、糖尿病、代谢综合征、动脉粥样硬化、心机能不全、心肌梗死、肺动脉高压、眼睛和肾脏疾病、骨骼障碍、中风和/或性功能障碍。
利钠肽的治疗用途的主要障碍是它们在生物体中的血浆半衰期很短，只有几分钟(Hunt et al.，J Clin Endocrinol Metab.1994Jun；78(6)：1428-35；Kimura et al.，EurJ Clin Pharmacol.2007Jul；63(7)：699-702)。除了NPR-C受体的内吞作用外，利钠肽还被脑啡肽酶(NEP)和胰岛素降解酶(IDE)有效地蛋白水解降解。所给予的利钠肽的相关短期生物学效果限制了将它们的治疗用途主要限制于急性适应症。例如，在不同的国家，重组卡培立肽(ANP)和奈西立肽(BNP)的输注被批准用于治疗急性失代偿性心力衰竭。
通过提供具有增加的血浆半衰期、提的高蛋白水解稳定性和延长的作用时间的NPR-A和NPR-B激动剂，将大大促进慢性疾病的治疗。
近年来，已经记载了几种利钠肽衍生物和变体，例如CD-NP(McKie et al.，CurrHeart Fail Rep.2010Sep；7(3)：93-9)、ZD100/MANP(McKie et al.，Hypertension.2010Dec；56(6)：1152-9)、PL-3994(Edelson et al.，Pulm PharmacolTher.2013Apr；26(2)：229-38)、乌拉立肽(Anker et al.，Eur Heart J.2015Mar 21；36(12)：715-2)、ANX-042(Pan et al.，Proc Natl Acad Sci USA.2009Jul.7；106(27)：11282-7)和BMN-111(Wendt et al.，J.Pharmacol Exp Ther.2015Apr；353(1)：132-49)。CD-NP的半衰期约为18.5分钟(Lee et al.，BMC Pharmacology 2007，7(Suppl I)：P38)。在US9,193,777和EP2432489 A中分别公开了其他ANP和CNP衍生物。
此外，还记载了利钠肽融合物(包括Fc融合物、白蛋白融合物)和聚乙二醇化利钠肽。例如，US2010/0310561、WO2008/154226、WO2010/117760、WO2006/107124、WO2008/136611和WO2008/079995中公开了利钠肽-Fc融合物。US7,521,424和US2014/0148390中公开了利钠肽-白蛋白融合物，US2014/0148390中公开了聚乙二醇化利钠肽。
WO2005/060642记载了通过将两端具有两个随机侧翼氨基酸的ANP或BNP插入人破伤风类毒素特异性抗体的CDRH3区域而获得的ANP和BNP肽嫁接(engrafted)抗体文库的产生。类似地，WO2005/082004公开了通过将2G12抗体的整个原CDRH3区域替代为两侧侧翼具有两个随机氨基酸残基的ANP模拟肽而获得的ANP模拟嫁接抗体文库的产生。WO2005/060642和WO2005/082004都没有公开任何特定的利钠肽嫁接抗体，更不用说在功能上表征这些抗体。
发明目的
鉴于现有技术，本发明的目的是提供与天然存在的野生型利钠肽相比，在血清中具有增加的稳定性的新的利钠肽受体激动剂。
发明内容
上文所述目的是通过本独立权利要求的教导来实现的。本发明人惊讶地发现，可以通过将利钠肽氨基酸序列纳入到免疫球蛋白分子或其片段的一个CDR区域中来获得与天然存在的野生型利钠肽相比，在血清中的稳定性显著增加的生物活性利钠肽变体，尽管免疫球蛋白CDR区域的长度较短且序列保守性较高，这对生物活性肽的纳入具有相当大的构象抑制作用。然而，纳入到免疫球蛋白CDR区域内的利钠肽的活性显示出极大变化。本发明人已经发现，成功纳入产生生物活性利钠肽变体的决定性因素为纳入的利钠肽和与纳入的利钠肽的最近邻CDR框架连接N端和C端之间的氨基酸残基数量。利钠肽与邻近的CDR框架连接之间的N端和C端侧翼氨基酸残基低于某一数量时，仅得到了没有生物活性或生物活性大大降低的利钠肽免疫球蛋白融合构建体。纳入的利钠肽侧翼的特定接头序列被发现特别有利于实现高的肽活性、良好的表达水平和/或低的蛋白片段化水平。
因此，在第一方面，本发明涉及抗体或其片段，所述抗体或其片段包含纳入到所述抗体或其片段的至少一个CDR区域内的至少一个异源氨基酸序列，其中所述至少一个异源氨基酸序列包含N端接头序列(Ntls)、利钠肽和C端接头序列(Ctls)，其中任选地所述至少一个CDR区域的至少一部分所述至少一个被纳入其中的异源氨基酸序列所替代，其中
a)在以下中存在至少12个氨基酸残基
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres25(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res S25)与利钠肽的第一个氨基酸残基之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres51(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res I51)与利钠肽的第一个氨基酸残基之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres92(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res C96)与利钠肽的第一个氨基酸残基之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres26(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res S25)与利钠肽的第一个氨基酸残基之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres49(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res Y51)与利钠肽的第一个氨基酸残基之间；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres88(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res C90)与利钠肽的第一个氨基酸残基之间；并且其中
b)在利钠肽的最后一个氨基酸残基和以下之间存在至少9个氨基酸残基
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres35a(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res M34)；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres57(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res T58)；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres106(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res G111)；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres 32(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res D34)；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres57(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res G59)；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres98(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res F102)。
在其他方面，本发明涉及这种抗体或其片段用于治疗方法中、包含这种抗体或其片段的组合物、编码这种抗体或其片段的核酸或核酸混合物、包含这种核酸或这种核酸混合物的宿主细胞和产生这种抗体或其片段的方法。
具体实施方式
通过参考以下本发明的详细描述和其中包含的实施例可以更容易地理解本发明。
在第一方面，本发明涉及抗体或其片段，所述抗体或其片段包含纳入到所述抗体或其片段的至少一个CDR区域内的至少一个异源氨基酸序列，其中所述至少一个异源氨基酸序列包含N端接头序列(Ntls)、利钠肽和C端接头序列(Ctls)，其中任选地所述至少一个CDR区域的一部分被至少一个纳入其中的异源氨基酸序列所替代。
本发明人已经发现可以通过将利钠肽氨基酸序列纳入到免疫球蛋白分子或其片段的一个CDR区域来获得与天然存在的野生型利钠肽相比，在血清中具有显著增加的稳定性的生物活性利钠肽变体。该发现是完全预料不到的。如本领域中公知的，免疫球蛋白CDR区的较短的长度和较高的序列保守性(在CDRL1、CDRL2、CDRL3、CDRH1和CDRH2中尤为明显)，对生物活性肽的纳入具有相当大的构象抑制，周围的免疫球蛋白序列可能对纳入的肽的表达、折叠和/或生物活性产生不利影响。事实上，本发明人已经发现，在免疫球蛋白CDR区域内纳入的利钠肽的活性变化很大，这取决于构建利钠肽嫁接抗体的确切方式。产生功能性的(即生物活性的)利钠肽变体的成功纳入的决定性因素，被证明是纳入的利钠肽和与纳入的利钠肽最近邻的CDR框架连接N端和C端之间的氨基酸残基数量。利钠肽与邻近的CDR框架连接之间的N端和C端侧翼氨基酸残基低于某一数量时，没有获得生物活性的利钠肽免疫球蛋白融合构建体。
术语“纳入的”、“插入的”、“整合的”、“嫁接的”和“嵌入的”以及“纳入”、“插入”、“整合”、“嫁接”和“嵌入”在本文可互换使用。在本发明的上下文中，这些术语是指通过在抗体或抗体片段的原始序列中引入异源序列来产生杂交多核酸或杂交多肽。这种纳入可以任何方式进行。通常，包含侧翼为N端和C端接头序列的利钠肽的抗体或其片段是由重组DNA技术产生并如本文所述表达。
将侧翼为N端和C端接头序列的利钠肽纳入到原始抗体或抗体片段序列的CDR区域内可能导致所述CDR区域的至少一部分的缺失。例如，可以进行编码所述包括N端接头序列、利钠肽和C端接头序列的异源氨基酸序列的核酸序列的克隆，使得将部分CDR编码序列被纳入的异源核酸序列替代。在具体的其他实施方案中，包含利钠肽的异源氨基酸序列的纳入不会导致其中插入异源氨基酸序列的CDR区域的氨基酸残基缺失。
在本发明的上下文中，术语“异源氨基酸序列”是指不是来源于初始“空的”抗体或其片段的氨基酸序列，所述抗体或其片段中纳入所述氨基酸序列。将异源氨基酸序列嫁接到抗体或其片段中，从而产生包含不同来源的氨基酸序列的经改造的重组抗体分子。
术语“利钠肽”是指能诱导尿钠增多(即肾脏进行的钠排出)的肽。利钠肽包括心利钠肽(ANP)、脑利钠肽(BNP)、C型利钠肽(CNP)、树眼镜蛇属(Dendroaspis)利钠肽(DNP)和尿扩张素。本发明的含义内的利钠肽可有任何来源。利钠肽包括天然利钠肽(如野生型利钠肽)及其突变形式，以及不同物种的同源利钠肽。然而，该术语还包括经改造的利钠肽，如不同利钠肽的经改造的嵌合变体。已知密码子的使用在物种之间是不同的。因此，当在靶细胞中表达异源蛋白时，改造核酸序列以适应于靶细胞的密码子使用可能是必须的或至少是有益的。设计和构建给定蛋白质的衍生物的方法是任何本领域普通技术人员均熟知的。
在具体的实施方案中，利钠肽选自任何物种的野生型利钠肽和任何这种野生型利钠肽的功能性变体。在本发明的上下文中，术语“利钠肽的功能性变体”或“功能性利钠肽变体”是指任何来源的利钠肽，包括天然肽和经改造的肽，它们在氨基酸序列上和/或编码给定利钠肽(例如给定物种的野生型利钠肽)的氨基酸序列的核酸序列上不同，但仍具有功能活性。在本发明的上下文中，术语“功能活性”指利钠肽变体执行天然存在的利钠肽(特别是野生型利钠肽)的生物学功能的能力。具体地，“功能活性”意指利钠肽变体能够与其各个受体结合。在NPR-A和NPR-B配体的情况下，“功能活性”具体地意指通过与这些受体中的一种或两种结合，介导(细胞内)环鸟苷一磷酸(cGMP)增加的能力。
在具体的实施方案中，功能性利钠肽变体能够执行给定利钠肽(例如任何给定物种的野生型利钠肽)的一种或多种生物学功能的至少约50％、具体地至少约60％、至少约70％、至少约80％、最具体地至少约90％，其中所述一种或多种生物学功能包括但不限于利钠肽与其各个受体的结合和/或诱导细胞内cGMP的增加。
利钠肽的功能活性可以用任何方法(包括体外方法)来测量，这些方法使得有可能测量(细胞内)环鸟苷一磷酸(cGMP)的增加或测量cGMP调节的细胞过程的变化，包括实施例3和5中记载的方法。在具体的实施方案中，如果由实施例3中记载的荧光测定法确定的(非嫁接的)利钠肽变体的EC50值低于500nM，更具体地低于250nM，更具体地低于150nM，更具体地低于100nM，更具体地低于50nM，最具体地低于25nM，则所述(非嫁接的)利钠肽变体被认为具有功能活性。
将这种功能性利钠肽变体纳入到如本文所述的免疫球蛋白分子或其片段的一个CDR区，产生具有利钠肽功能活性的利钠肽嫁接免疫球蛋白，与非嫁接的功能性利钠肽变体相比，所述利钠肽嫁接免疫球蛋白在血清中的稳定性显著增加，如实施例所示。如果在通过评估cGMP调节的细胞过程的变化直接或间接地测量(细胞内)环鸟苷一磷酸(cGMP)的增加的任何方法中，利钠肽嫁接免疫球蛋白给出显著的正信号，则所述利钠肽嫁接免疫球蛋白被认为具有生物活性(即功能性)。具体地，利钠肽嫁接免疫球蛋白的功能活性可通过实施例3和5中记载的方法来评估。在利钠肽嫁接免疫球蛋白的情况下，显著性通常是基于以下评估的：i)与阴性样品的比较，如空的免疫球蛋白支架，例如构建体#209(包括SEQ ID NO65和SEQ ID NO 66的抗体，TPP-5657)，ii)与阳性样品的比较，例如构建体#117(包括SEQID NO 67和SEQ ID NO 66的抗体，TPP-5661)，和iii)剂量依赖性。
尽管与参考利钠肽相比，本发明的功能性利钠肽变体可含有任意数量的包含一个或多个氨基酸的添加、缺失和/或置换的突变，但功能性利钠肽变体通常将保持相应的利钠肽的关键特征，例如中心环结构域内的关键残基。例如在Lincoln R.Potter et al.(HandbExp Pharmacol.2009；(191)：341-366)中描述了利钠肽的保守性残基。因此，在具体的实施方案中，功能性利钠肽变体与下面所示的序列有至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％或至少95％的序列一致性：
X1CFGX2X3X4DRIX5X6X7SX8LGC
其中X1和X5为G或S；
X3为R或K；
X6为A或S；和
X2、X4、X7和X8可为任意氨基酸。
原则上，任何类型的利钠肽都可以纳入到如本文所述的免疫球蛋白或其片段的CDR区域内。具体地，本发明人已经发现，在一种类型的利钠肽中关于嫁接的利钠肽的令人满意的生物活性的最低要求及特别合适的N端和C端氨基酸序列的发现，可以被赋予其他类型的利钠肽。不希望囿于理论，据猜测，在不同的利钠肽类型中这些成功地将利钠肽嵌入免疫球蛋白分子中的类似要求，可能是由于利钠肽家族中的结构相似性和/或作用机制。
在具体的实施方案中，利钠肽选自具有序列SEQ ID NO 23的人ANP、具有序列SEQID NO 24的人BNP、具有序列SEQ ID NO 25的人CNP和与SEQ ID NO 23至25中任一个具有至少60％、65％、70％、75％、80％、85％、90％、95％或至少98％序列同一性的肽。同样，具有偏离野生型人利钠肽ANP、BNP和CNP序列的利钠肽可具有任何天然来源，例如野生型人利钠肽的突变版本或不同物种的同源物或经改造的利钠肽。设计和构建肽变体的方法是本领域任何一个普通技术人员已知的。
在具体的这类实施方案中，与SEQ ID NO 23至25中任一个具有至少60％、65％、70％、75％、80％、85％、90％、95％或至少98％序列同一性的利钠肽为功能性利钠肽变体。
对于参考多核苷酸或多肽序列，“百分比(％)序列同一性”定义为在比对序列和任选引入的空位(如果必要的话)以达到最大百分比序列同一性后，分别在候选序列中的与分别在参考多核苷酸或多肽序列中的核酸或氨基酸残基分别相同的核酸或氨基酸残基的百分比。保守性置换不被视为序列同一性的一部分。在具体的实施方案中，在候选序列和/或参考序列中引入的任何空位，其总量不超过参考序列残基总量的50％、40％、30％、25％、20％、15％或10％。在具体的实施方案中，在不将任何空位引入候选序列或参考序列的情况下(即使用无空位比对)，确定百分比序列同一性。用于确定百分比氨基酸序列同一性比对可以通过本领域技术人员充分掌握的各种方式实现，例如，使用公开可得的计算机软件，如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适当参数，包括在被比较序列的全长上实现最大比对所需的任何算法。
与给定的参考利钠肽(例如具有氨基酸序列SEQ ID NO 23的人ANP)具有给定的序列同一性百分比的利钠肽，与参考利钠肽相比，可含有一个或多个包括一个或多个氨基酸的添加、缺失和/或置换的突变。根据本发明的教导，所述缺失、添加和/或置换的氨基酸可为连续的氨基酸，或可分散在与参考利钠肽(例如具有SEQ ID NO 23氨基酸序列的人ANP)具有给定的序列同一性百分比的利钠肽的氨基酸序列的长度上。在DNA水平上，编码与给定的参考利钠肽具有给定的序列同一性百分比的利钠肽的核酸序列，由于遗传密码的简并性，可在更大程度上不同。
根据本发明的教导，只要保持与参考利钠肽的规定氨基酸序列同一性，可以添加、删除和/或置换任何数量的氨基酸。在具体的实施方案中，保持规定的氨基酸序列同一性，且利钠肽变体具有生物活性，即为功能性利钠肽变体。优选地，与上述测定中测量的参考利钠肽相比，与给定的参考利钠肽(例如具有SEQ ID NO 23氨基酸序列的人ANP)具有给定的序列同一性百分比的利钠肽的生物活性的降低小于90％、小于80％、小于70％、小于60％、小于50％、小于25％或小于10％。
本文使用的术语“抗体”意指免疫球蛋白分子，特别是由四条多肽链组成的二聚体免疫球蛋白分子：两条重(H)链和两条轻(L)链，它们通常由二硫键相互连接。每条重链由重链可变区(本文简称为VH)和重链恒定区组成。重链恒定区可以包括例如三个结构域CH1、CH2和CH3。每条轻链由轻链可变区(本文简称为VL)和轻链恒定区组成。轻链恒定区由一个结构域(CL)组成。VH和VL区域可以进一步细分为高变异区域，称为互补决定区域(CDR)，其间存在更保守的区域，称为框架区域(FR)。每个VH和VL通常包括从氨基端到羧基端排列的三个CDR和四个FR组成，例如按以下顺序：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。
如本文所用，术语“互补决定区域”(CDR；例如CDR1、CDR2和CDR3)是指抗体可变结构域的氨基酸残基，其存在是抗原结合所必需的。每个可变结构域通常有三个CDR区域，识别为CDR1、CDR2和CDR3。每个互补决定区域可以包括由Kabat定义的“互补决定区域”中的氨基酸残基(例如关于轻链可变结构域中的约残基24-34(CDRL1)、50-56(CDRL2)和89-97(CDRL3)，以及重链可变结构域中的31-35(CDRH1)、50-65(CDRH2)和95-102(CDRH3)；(Kabatet al.，Sequences of Proteins of Immulological Interest，5th Ed.Public HealthService，National Institutes of Health，Bethesda，MD.(1991))和/或来自“高变环”的那些残基(例如轻链可变结构域中的约残基26-32(CDRL1)、50-52(CDRL2)和91-96(CDRL3)，重链可变结构域中的残基26-32(CDRH1)、53-55(CDRH2)和96-101(CDRH3)(Chothia andLesk；J Mol Biol 196：901-917(1987))。在某些情况下，互补决定区域可以包括来自根据Kabat定义的的CDR区域和高变环的氨基酸。
根据其重链恒定结构域的氨基酸序列，完整的抗体可以被分配给不同的“类”。完整抗体有五大类：IgA、IgD、IgE、IgG和IgM，其中几种可进一步分为“亚类”(同种型)，例如IgGl、IgG2、IgG3、IgG4、IgA1和IgA2。在本发明的上下文中，术语“抗体”包括从自然界中分离出来或用重组方法制备的任何主类的免疫球蛋白分子(包括IgG、IgE、IgM、IgD、IgA和IgY)和任何亚类的免疫球蛋白分子(包括IgG1、lgG2、lgG3、lgG4、lgA1和lgA2)，并包括所有常规已知的抗体。用于本发明中的免疫球蛋白的一个优选类为IgG。术语“抗体”还延伸到其他蛋白支架，这些支架能够使抗体CDR插入物定向到与天然抗体中存在的活性结合构象相同的活性结合构象中，使得与衍生出CDR的天然抗体的结合活性相比，观察到的靶抗原与这些嵌合蛋白的结合保持不变。
在本发明的上下文中，术语抗体/免疫球蛋白的“片段”是指包含至少一个CDR区域的抗体/免疫球蛋白的任何部分。具体地，本发明的抗体片段保留了增加纳入其中的生物活性肽(优选利钠肽)的血清半衰期的能力。本发明的抗体片段包括Fab、Fab’、Fab’-SH、F(ab’)2和Fv片段；双价抗体(diabody)；单域抗体(Dab)；线性抗体(linear antibody)；单链抗体分子(scFv)；和二硫键稳定的Fv抗体片段(dsFv)；以及由抗体片段形成的多特异性抗体和包含VL或VH结构域的片段，其由完整的免疫球蛋白制备或通过重组方法制备。
可以改造F(ab’)2或Fab以最小化或完全去除CH1和CL结构域之间存在的分子间二硫键相互作用。本发明的抗体片段可以单独包括可变区或包括可变区与以下的全部或部分：铰链区、CH1、CH2、CH3和CL结构域。还包括抗体片段，其包含可变区与铰链区、CH1、CH2、CH3和CL结构域的任意组合。
抗体或其片段构成支架，赋予纳入其中的利钠肽稳定性。例如，与天然存在的利钠肽相比，纳入到本文所述抗体的CDR区域内的利钠肽的血清半衰期可能会增加。
主要地，包含利钠肽的异源氨基酸序列可被纳入到任何免疫球蛋白分子或其片段中。具体地，根据本发明可使用任何物种(包括但不限于人、牛、小鼠、大鼠、猪、狗、鲨鱼、美洲驼(lama)和骆驼)的及任何主类和亚类的免疫球蛋白。然而，对于治疗使用，人或人源化抗体可能是优选的。在本发明的上下文中，术语“人抗体”是指具有人免疫球蛋白氨基酸序列的抗体，包括分离自人免疫球蛋白文库、分离自人B细胞或分离自转基因一种或多种人免疫球蛋白的动物的抗体，以及合成的人抗体。在具体的实施方案中，可变结构域的氨基酸轻链和重链序列分别源自人种系序列LV 1-40和HV 3-23(更多信息，参见实施例1)。
在本发明的上下文中，术语“人源化抗体”或“人源化抗体片段”是指(i)源自非人来源(例如携带异源免疫系统的转基因小鼠)的抗体或其片段，其抗体基于人种系序列；或(ii)嵌合的的抗体或其片段，其中可变结构域源自非人来源，恒定结构域源自人来源，或(iii)CDR嫁接的抗体或其片段，其中可变结构域的CDR来自非人来源，而可变结构域的一个或多个框架为人来源，恒定结构域(如果有的话)为人来源。
本发明的抗体或其片段可为单特异性、双特异性、三特异性或更大的多特异性。
在本发明的上下文中，术语“包括(comprises)或包括(comprising)”意味着“包括但不限于”。该术语的目的是开放式的，以规定存在任何声称的特征、元素、整数、步骤或组分，但不排除存在或添加一个或多个其他特征、元素、整数、步骤、组分或其组。因此，术语“包括”包括更限制性的术语“由...组成”和“基本上由...组成”。在一个实施方案中，在整个申请中且特别是在权利要求中使用的术语“包括”可被替换为术语“由...组成”。
在本发明的上下文中，术语“大约”或“约”意指在给定值的80％至120％之间，或者在90％至110％之间，包括在95％至105％之间。
在本发明的抗体或其片段中，a)在以下中存在至少12个氨基酸残基
i)在CDRH1中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res25(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res S25)与利钠肽的第一个氨基酸残基之间；
ii)在CDRH2中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res51(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res I51)与利钠肽的第一个氨基酸残基之间；
iii)在CDRH3中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res92(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res C96)与利钠肽的第一个氨基酸残基之间；
iv)在CDRL1中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res26(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res S25)与利钠肽的第一个氨基酸残基之间；
v)在CDRL2中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res49(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res Y51)与利钠肽的第一个氨基酸残基之间；和/或
vi)在CDRL3中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res88(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res C90)与利钠肽的第一个氨基酸残基之间；
和b)在利钠肽的最后一个氨基酸残基和以下之间存在至少9个氨基酸残基
i)在CDRH1中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res35a(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res M34)；
ii)在CDRH2中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res57(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res T58)；
iii)在CDRH3中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres106(在具有氨基酸序列SEQ ID NO 65的重链中，其对应于res G111)；
iv)在CDRL1中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res 32(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res D34)；
v)在CDRL2中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res57(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res G59)；和/或
vi)在CDRL3中纳入异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res98(在具有氨基酸序列SEQ ID NO 66的轻链中，其对应于res F102)。
以上列出的氨基酸残基的命名是指在纳入异源氨基酸序列之前，在原始免疫球蛋白分子中的氨基酸位置。在本发明的上下文中，以上列出的氨基酸残基被称为“参考氨基酸”或“参考aa”。这些参考氨基酸残基位于或接近CDR框架连接，但并不必然对应于标准CDR边界定义(标准CDR边界定义为CDRH1的氨基酸残基S25和W36；CDRH2的S49和R67；CDRH3的K98和W108；CDRL1的C22和W37；CDRL2的Y51和G59；CDRL3的C90和F102。Jarasch andSkerra，Proteins 2017Jan；85(1)：65-71)。
插入的利钠肽的N端最近邻的参考aa加上在所述参考aa与插入的利钠肽的第一个氨基酸残基之间存在的氨基酸段在本文被称为“N端序列”。N端序列包含Ntls。在具体的实施方案中，N端序列由Ntls加上相邻的N端参考aa组成。
插入的利钠肽的最后一个氨基酸残基与插入的利钠肽的C端最近邻的参考aa之间存在的氨基酸段加上所述参考aa，在本文称为“C端序列”。C端序列包含Ctls。在具体的实施方案中，C端序列由Ctls加上相邻的C端参考aa组成。
在具体的实施方案中，Ntls包含GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、2或4中任一个的序列，或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、7、9、11、13、15、16、17、19或21中任一个的序列；或与SEQ ID NO6、7、9、11、13、15、16、17、19或21中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列。Ntls还可以包含上文所列氨基酸序列的任意组合。
在具体的这类实施方案中，Ntls包含GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、2或4中任一个的序列，或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、7、9、11、13、15或21中任一个的序列；与SEQ ID NO 6、7、9、11、13、15或21中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列；或其任意组合。
在具体的实施方案中，Ctls包含GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、3或5中任一个的序列，或与SEQ ID NO 1、3或5中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、8、10、12、14、15、17、18、19、20或22中任一个的序列；或与SEQ IDNO 6、8、10、12、14、15、17、18、19、20或22中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列。Ctls还可以包含上文所列氨基酸序列的任意组合。
在具体的实施方案中，Ctls包含GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、3或5中任一个的序列，或与SEQ ID NO 1、3或5中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、8、10、12、14、15、20或22中任一个的序列；与SEQ ID NO 6、8、10、12、14、15、20或22中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列；或其任意组合。
在具体的实施方案中，包含在Ntls和/或Ctls中的序列与SEQ ID NO1至22中任一个之间的序列同一性为至少60％、具体地至少65％、至少70％、至少75％、至少80％、至少85％、至少90％、至少95％或100％。
在本发明的上下文中，术语“GS接头序列”是指主要包含甘氨酸和丝氨酸残基的肽接头。具体地，本发明的GS接头序列的至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％、至少95％或100％的氨基酸残基选自甘氨酸和丝氨酸残基。本发明的GS接头序列可以例如总共包含1至30个氨基酸残基。具体地，本发明的GS接头序列不包含超过3、2或1个非甘氨酸或丝氨酸的氨基酸残基。
在本发明的上下文中，术语“PN接头序列”是指主要包含脯氨酸和天冬酰胺残基的肽接头。具体地，本发明的PN接头序列的至少60％、至少65％、至少70％、至少75％、至少80％、至少85％、至少90％、至少95％或100％的氨基酸残基选自脯氨酸和天冬酰胺残基。本发明的PN接头序列可以例如总共包含1至30个氨基酸残基。具体地，本发明的PN接头序列不包含超过3、2或1个非脯氨酸或天冬酰胺的氨基酸残基。可存在于本发明的PN接头序列中的其他氨基酸残基为例如赖氨酸或谷氨酸残基。
在具体的实施方案中，包含在Ntls和/或Ctls内并选自以下的接头序列包含至少1、2、3、4、5、6、7、8、9或10个氨基酸残基：GS接头序列；PN接头序列；人IgG抗体支架接头序列；人IgG fab结构域支架序列；与人IgG抗体支架接头序列、人IgG fab结构域支架序列或SEQ ID NO 1至5中任一个的序列具有至少80％序列同一性的序列；与SEQ ID NO 6至22中任一个具有至少60％序列同一性的序列。包含在Ntls和/或Ctls内的接头序列可例如包含最多达30、28、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11或10个氨基酸残基。
在包含人IgG抗体支架的序列或与其具有至少80％序列同一性的序列的接头的情况下，使用与纳入异源氨基酸序列的CDR相邻的支架区域的序列可能特别有利。例如，在异源氨基酸序列纳入CDRH2结构域的情况下，Ntls和/或Ctls可包含含有作为框架区域FRH2或FRH3一部分的氨基酸序列的接头。类似地，在异源氨基酸序列纳入CDRL2区域的情况下，Ntls和/或Ctls可包含含有作为框架区域FRH2或FRH3一部分的氨基酸序列的接头。
在具体的实施方案中，Ntls由以下组成：GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、2或4中任一个的序列或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、7、9、11、13、15、16、17、19或21中任一个的序列；与SEQ IDNO 6、7、9、11、13、15、16、17、19或21中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列；或其任意组合。
在具体的实施方案中，Ctls由以下组成：GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、3或5中任一个的序列或与SEQ ID NO 1、3或5中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、8、10、12、14、15、17、18、19、20或22中任一个的序列；与SEQID NO 6、8、10、12、14、15、17、18、19、20或22中任一个具有至少60％、至少70％、至少80％、至少90％或至少95％序列同一性的序列；或其任意组合。
在具体的实施方案中，Ntls和Ctls均包含至少一个以上列出的接头序列或其任意组合。原则上，任何以上列出的Ntls接头序列都可以与任何以上列出的Ctls接头序列相结合。具体地，任何接头序列都可以与GS接头相结合。作为非限制性实施例，GS Ctls接头可以与包含SEQ ID NO 6、9或15中任一个的序列或者与SEQ ID NO 6、9或15中任一个具有至少60％序列同一性的序列的Ntls接头相结合。另一个非限制实施例为GS Ntls接头与包含序列SEQ ID NO 15或者与其具有至少60％序列同一性的序列的Ctls接头相结合。
在N端和C端侧翼序列的总长度足够的情况下，以上列出的接头序列已被证明特别有利于获得良好的利钠肽活性。不希望囿于理论，认为以上列出的连接肽段导致这样的构象/折叠，即其促成了有利于将具有生物活性的利钠肽以最小的空间阻碍呈现给其各自的受体的系统状态。
在具体的实施方案中，i)Ntls包含GS接头序列；PN接头序列；序列SEQ ID NO 2、4、9、11、13或15；与SEQ ID NO 2、4、9、11、13或15具有至少60％序列同一性的序列；或其任意组合，和ii)Ctls包含GS接头序列；PN接头序列；SEQ ID NO 3、5、12、14、15或20的序列；与SEQ ID NO 3、5、12、14、15或20具有至少60％序列同一性的序列；或其任意组合。这些接头序列已被证明是特别有用的，因为它们不仅实现了高的利钠肽活性，而且在重组表达中表达水平良好，并且在表达时不容易发生蛋白质断裂(参见表9)。
在具体的实施方案中，Ntls和Ctls各自包含GS接头序列；Ntls和Ctls各自包含PN接头序列；Ntls和Ctls各自包含作为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，具体地为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更具体地Ntls包含SEQ ID NO 1、2或4中任一个的序列，或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列，Ctls包含SEQ IDNO 1、3或5中任一个的序列或与其具有至少80％序列同一性的序列；Ntls和Ctls各自包含序列SEQ ID NO 6或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 7或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 8或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 10与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 11或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 12或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 13或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 14或与其具有至少60％序列同一性的序列；Ntls和Ctls各自包含序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；Ntls和Ctls各自包含序列SEQID NO 15或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 16或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 17或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 17或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 18或与其具有至少60％序列同一性的序列；Ntls和Ctls各自包含序列SEQ IDNO 19或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 20或与其具有至少60％序列同一性的序列；或Ntls包含序列SEQ ID NO 21或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 22或与其具有至少60％序列同一性的序列。
在具体的这类实施方案中，Ntls和Ctls各自包含GS接头序列；Ntls和Ctls各自包含PN接头序列；Ntls和Ctls各自包含作为人IgG抗体支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，具体地为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更具体地Ntls包含SEQ ID NO 1、2或4中任一个的序列或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列，Ctls包含SEQ IDNO 1、3或5中任一个的序列或与其具有至少80％序列同一性的序列；Ntls和Ctls各自包含序列SEQ ID NO 6或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 7或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 8或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 10与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 11或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 12或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 13或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 14或与其具有至少60％序列同一性的序列；Ntls和Ctls各自包含序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 20或与其具有至少60％序列同一性的序列；或Ntls包含序列SEQ ID NO 21或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 22或与其具有至少60％序列同一性的序列。
在具体的这类实施方案中，Ntls和Ctls各自包含GS接头序列；Ntls和Ctls各自包含PN接头序列；Ntls包含序列SEQ ID NO 2或与其具有至少80％序列同一性的序列，Ctls包含序列SEQ ID NO3或与其具有至少80％序列同一性的序列；Ntls包含序列SEQ ID NO 4或与其具有至少80％序列同一性的序列，Ctls包含序列SEQ ID NO 5或与其具有至少80％序列同一性的序列；Ntls包含序列SEQ ID NO 11或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 12或与其具有至少60％序列同一性的序列；Ntls包含序列SEQ IDNO 13或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 14或与其具有至少60％序列同一性的序列；Ntls和Ctls各自包含序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；或Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，Ctls包含序列SEQ ID NO 20或与其具有至少60％序列同一性的序列。这些接头组合已被证明对获得高利钠肽活性、在重组表达中的良好表达水平以及最小或无蛋白断裂特别有用，如表9所示。
在具体的实施方案中，Ntls还包含在其C终端处的锚定元件A1和/或Ctls还包含在其N终端处的锚定元件A2，其中A1和A2主要包含甘氨酸和丝氨酸残基。在具体的实施方案中，A1和/或A2包含至少1、2、3、4或5个氨基酸残基。A1和/或A2总共可包含最多达10、9、8、7、6或5个氨基酸残基。在具体的实施方案中，A1和/或A2的至少60％、至少70％、至少80％、至少90％或100％的氨基酸残基选自甘氨酸和丝氨酸残基。具体地，A1和/或A2不包含超过3、2或1个非甘氨酸或丝氨酸的氨基酸残基。
在具体的实施方案中，Ntls由以下组成：i)在其C终端的锚定元件A1和ii)GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、2或4中任一个的序列或与SEQ ID NO 1、2或4中任一个具有至少80％的序列同一性的序列；SEQ ID NO 6、7、9、11、13、15、16、17、19或21中任一个的序列；与SEQ ID NO 6、7、9、11、13、15、16、17、19或21中任一个的序列具有至少60％序列同一性的序列；或其任意组合。
在具体的实施方案中，Ctls由以下组成：i)在其N终端处的锚定元件A2和ii)GS接头序列；PN接头序列；作为人IgG抗体支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，特别是作为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、3或5中任一个的序列或与SEQ ID NO1、3或5中任一个具有至少80％序列同一性的序列；SEQ ID NO 6、8、10、12、14、15、17、18、19、20或22中任一个的序列；与SEQ ID NO 6、8、10、12、14、15、17、18、19、20或22中任一个具有至少60％序列同一性的序列；或其任意组合。
在具体的实施方案中，Ntls和/或Ctls总共包含至少3、4、5、6、7、8、9或10个氨基酸残基。Ntls和/或Ctls可例如总共包含最多达30、28、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11或10个氨基酸残基。
在具体的实施方案中，在以下中存在的氨基酸段包含SEQ ID NO 26至38中任一个的序列或与SEQ ID NO 26至38中任一个具有至少80％、85％、90％、95％或至少98％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres25与利钠肽的第一个氨基酸残基之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres51与利钠肽的第一个氨基酸残基之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres92与利钠肽的第一个氨基酸残基之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres26与利钠肽的第一个氨基酸残基之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres49与利钠肽的第一个氨基酸残基之间；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres88与利钠肽的第一个氨基酸残基之间。
在具体的实施方案中，在利钠肽的最后一个氨基酸残基与以下之间存在的氨基酸段包含SEQ ID NO 39至51中任一个的序列或与SEQ ID NO 39至51中任一个具有至少80％、85％、90％、95％或至少98％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres35a；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres57；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres106；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres 32；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres57；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres98。
在具体的实施方案中，异源氨基酸序列由Ntls、利钠肽和Ctls组成。
在具体的实施方案中，在以下中存在的氨基酸段包含SEQ ID NO 52至64中任一个的序列或与SEQ ID NO 52至64中任一个具有至少80％、85％、90％、95％或至少98％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres25与根据Kabat的氨基酸残基HC res35a之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres51和根据Kabat的氨基酸残基HC res57之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres92和根据Kabat的氨基酸残基HC res106之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres26和根据Kabat的氨基酸残基LC res 32之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres49和根据Kabat的氨基酸残基LC res57之间；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LCres88和根据Kabat的氨基酸残基LC res98之间。
在具体的实施方案中，抗体或其片段包含至少两个利钠肽。在具体的实施方案中，两个利钠肽均包含在还包含Ntls和Ctls的异源氨基酸序列中，并被纳入到如本文所述的所述抗体或其片段的CDR区域内。至少两个利钠肽可以被纳入到两条轻链或两条重链的两个相应CDR区域内，或者至少两个利钠肽可以被纳入到两个单独的CDR区域内。至少两个利钠肽可是相同的或不同的。在具体的这类实施方案中，抗体或其片段包含至少两个不同的利钠肽，其被纳入到至少两个CDR区域内。
由于抗体分子的二聚体结构，将编码异源氨基酸序列(Ntls-利钠肽-Ctls)的一个核酸序列插入编码免疫球蛋白分子的轻链或重链的核酸中，通常会产生携带位于两条相同的轻链或两条相同的重链的相应CDR区域的两个利钠肽的抗体蛋白。然而，还想到将两个编码利钠肽的核酸插入编码轻链和/或重链的核酸序列的两个不同的CDR编码区，从而产生抗体分子，其具有位于二聚抗体的两个相应CDR对中的四个利钠肽。还包括其轻链和/或重链不同的二聚免疫球蛋白分子，例如包括携带单个利钠肽的二聚抗体以及携带在两条轻链或两条重链的两个相应CDR区域中的两个不同利钠肽的二聚抗体。
在具体的实施方案中，将利钠肽插入CDRH1和CDRH2、CDRH1和CDRH3、CDRH2和CDRH3、CDRH1和CDRL1、CDRH1和CDRL2、CDRH1和CDRL3、CDRH2和CDRL1或CDRH2和CDRL2中。在具体的实施方案中，抗体或其片段包含一个ANP和一个BNP分子；一个ANP和一个CNP分子；或一个BNP和一个CNP分子。
在具体的实施方案中，包含纳入到所述抗体或其片段的至少一个CDR区域内的至少一个异源氨基酸序列中的利钠肽为ANP，且所述抗体或其片段包含至少一个其他利钠肽。在具体的实施方案中，所述至少一个其他利钠肽也包含在异源氨基酸序列中，所述异源氨基酸序列还包含Ntls和Ctls并被纳入到所述抗体或其片段的CDR区域内。在具体的实施方案中，将ANP和至少一个其他利钠肽纳入到抗体或其片段的两条轻链或两条重链的两个相应CDR区域内。在具体的其他实施方案中，将ANP和至少一个其他利钠肽纳入到至少两个单独的CDR区域内。具体地，所述至少一个其他利钠肽选自ANP、BNP和CNP，更具体地选自BNP和CNP。
不含有包含利钠肽的异源氨基酸序列的，由具有序列SEQ ID NO 65的两条重链和具有序列SEQ ID NO 66的两条轻链组成的“空的”抗体分子称为TPP-5657。在具体的实施方案中，由具有序列SEQ ID NO 65或与其具有至少80％、至少85％、至少90％或至少95％序列同一性的序列的两条重链与具有序列SEQ ID NO 66或与其具有至少80％、至少85％、至少90％或至少95％序列同一性的序列的两条轻链组成的抗体分子作为初始抗体或亲代抗体，包含利钠肽的异源氨基酸序列被纳入其中。在具体的这类实施方案中，包含利钠肽的异源氨基酸序列被纳入到这种抗体分子的一条或两条重链的CDR区域内。
在具体的这类实施方案中，包含至少一个纳入到至少一个其CDR区域内的异源氨基酸序列的重链具有SEQ ID NO 67至79中任一个的序列，或与SEQ ID NO 67至79中任一个具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。在具体的实施方案中，本发明的抗体由两条相同的重链和两条相同的轻链组成，所述重链具有SEQ ID NO 67至79中任一个的序列或与SEQ ID NO 67至79中任一个具有至少80％、至少85％、至少90％或至少95％序列同一性的序列，所述轻链具有序列SEQ ID NO 66或与其具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。
在具体的其他实施方案中，将包含利钠肽的异源氨基酸序列纳入到这类抗体分子的一条或两条轻链的CDR区域内。在具体的这类实施方案中，包含至少一个纳入到至少一个其CDR区域内的异源氨基酸序列的轻链具有SEQ ID NO 80或81中任一个的序列或与SEQ IDNO 80或81中任一个具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。在具体的实施方案中，本发明的抗体由两条相同的轻链和两条相同的重链组成，所述轻链具有SEQ ID NO 80或81中任一个的序列或与SEQ ID NO 80或81中任一个具有至少80％、至少85％、至少90％或至少95％序列同一性的序列，所述重链具有序列SEQ ID NO 65或与其具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。
下表描述了本发明的示例性抗体的重链和轻链组成。
表1：示例性利钠肽嫁接抗体构建体
本发明的抗体或其片段包括天然存在的纯化的产品、化学合成步骤的产品和重组技术生产的产品。基于其来源，本发明的抗体或其片段可以为糖基化的或非糖基化的。
例如，标准重组DNA方法可用于制备和/或获得编码重链和轻链的核酸，将这些核酸纳入到表达载体中，并将载体引入宿主细胞进行重组表达(参见例如Sambrook，Fritschand Maniatis(eds.)，Molecular Cloning；A Laboratory Manual，Second Edition，ColdSpring Harbor，N.Y.，(1989)；Ausubel，F.M.et al.(eds.)Current Protocols inMolecular Biology，Greene Publishing Associates，(1989)；Goeddel，Gene ExpressionTechnology，Methods in Enzymology 185，Academic Press，San Diego，Calif.(1990)；和Boss等人的US 4,816,397)。
因此，在第二方面，本发明涉及编码本发明的抗体或其片段的核酸或核酸混合物。这些核酸序列可能在某些情况下被优化以用于哺乳动物表达。本发明的DNA分子不仅限于本文公开的序列，还包括其变体。
本发明还提供了包含一个或多个本发明的核酸序列的重组核酸构建体。本发明的重组核酸构建体可例如包含核酸载体，例如质粒，其中已插入编码本发明的抗体或其片段的核酸分子。应理解，表达载体的设计(包括调控序列的选择)受到诸如宿主细胞的选择、所需的蛋白质表达水平以及是否需要组成型表达或诱导型表达等因素的影响。
用于细菌使用的可用的表达载体可以通过将一个或多个本发明的核酸序列、合适的翻译起始和终止信号与功能性启动子一起插入可操作阅读相中来构建。细菌表达载体通常包括一个或多个表型选择标记和复制起点，以确保载体的维持以及(如果需要的话)在细菌宿主中提供扩增。细菌表达载体可包含源自市售可得的质粒的元件，如公知的克隆载体pBR322(ATCC37017)。根据所表达的抗体或其片段的预期用途，可以有利地选择许多细菌表达载体。例如，如果需要大量这类抗体，可能需要介导易于纯化的抗体融合蛋白的高水平表达的载体。
预期用于真核宿主细胞中抗体表达的重组核酸构建体可包含能够调控真核细胞中开放阅读框的表达的调控序列，优选启动子和多腺苷酸化信号。优选地选择在预期用于抗体表达的特定细胞类型中具有功能性的启动子和多腺苷酸化信号。合适的启动子的实例包括但不限于来自巨细胞病毒(CMV)(如强的CMV即刻早期启动子)、猿猴病毒40(SV40)、小鼠乳腺肿瘤病毒(MMTV)、人免疫缺陷病毒(HIV)(如HIV长末端重复(LTR)启动子)、莫洛尼病毒、EB病毒(EBV)、腺病毒(如腺病毒主要晚期启动子(ADMLP))、多瘤和劳斯肉瘤病毒(RSV)的启动子、由CMV早期增强子元件、鸡β-肌动蛋白基因的启动子、第一外显子和第一内含子及兔β珠蛋白基因的剪接受体组成的合成CAG启动子；以及来自哺乳动物基因如肌动蛋白、肌球蛋白、血红蛋白、肌肉肌酸和金属硫蛋白的启动子。在具体的实施方案中，真核表达盒包含CMV启动子。在本发明的上下文中，术语“CMV启动子”是指强的即刻早期巨细胞病毒启动子。
合适的多腺苷化信号的实例包括但不限于牛生长激素(BGH)多腺苷酸化位点、SV40多腺苷酸化信号和LTR多腺苷酸化信号。
此外，重组核酸序列可包含一个或多个增强子序列。增强子可以为例如哺乳动物肌动蛋白、肌球蛋白、血红蛋白、肌肉肌酸的增强子或病毒增强子，例如来自CMV、RSV、SV40或EBV的增强子。有关病毒调控元件及其序列的进一步描述，请参见Stinski的US 5,168,062、Bell等人的US 4,510,245和Schaffner等人的US 4,968,615。
调控序列和密码子通常是物种依赖性的，因此为了使蛋白质生产最大化，优选地选择在预期用于抗体表达的物种/细胞类型中有效的调控序列和密码子。本领域技术人员可以生产在给定的受试物种中有功能的重组DNA分子。
哺乳动物重组表达载体还可以包含复制起点和选择性标记(参见例如US 4,399,216、US 4,634,665和US 5,179,017)。合适的选择性标记包括赋予对药物的抗性的基因，所述药物为如G418、嘌呤霉素、潮霉素、杀稻瘟菌素、博莱霉素(zeocin/bleomycin)或甲氨蝶呤，或利用已引入载体的宿主细胞上的营养缺陷型(如谷氨酰胺合成酶)的选择性标记。例如，二氢叶酸还原酶(DHFR)基因赋予对甲氨蝶呤的抗性，新基因赋予对G418的抗性，来自土曲霉(Aspergillus terreus)的bsd基因赋予对杀稻瘟菌素的抗性，嘌呤霉素N-乙酰基转移酶赋予对嘌呤霉素的抗性，Sh ble基因产物赋予对博莱霉素的抗性，大肠杆菌潮霉素抗性基因(hyg或hph)赋予对潮霉素的抗性。选择性标记(如DHFR或谷氨酰胺合成酶)也可与MTX和MSX结合用于扩增技术。
在一些实施方案中，将编码重链和轻链的核酸序列插入到单独的载体中。在其他实施方案中，将编码重链和轻链的核酸序列插入到同一载体中。此外，可以将编码重链和/或轻链的可变区的核酸序列转换为例如编码全长抗体链、Fab片段或scFv的核酸序列。编码VL或VH的DNA片段可为可操作地连接(使得两个DNA片段编码的氨基酸序列在框架内)到另一个编码例如抗体恒定区或柔性接头的DNA片段。作为实例，为了创建编码scFv的多核苷酸序列，可以将编码VH和VL的核酸可操作地连接到编码柔性接头的另一个片段上，使VH和VL序列可以表达为连续的单链蛋白且VL和VH区域由柔性接头连接(参见例如Bird et al.(1988)Science 242：423-426；Huston et al.(1988)Proc.Natl.Acad.Sci.USA 85：5879-5883；McCafferty et al.，Nature(1990)348：552-554)。人重链和轻链恒定区的序列为本领域中已知的(参见例如Kabat，E.A.，el al.(1991)Sequences of Proteins ofImmunological Interest，Fifth Edition，U.S.Department of Health and HumanServices，NIH Publication No.91-3242)，通过标准PCR扩增可以获得包含这些区域的DNA片段。
在具体的实施方案中，编码其中纳入包含利钠肽的异源氨基酸序列的重链的核酸序列包含SEQ ID NO 82或83中任一个的序列，或与SEQ ID NO 82或83中任一个具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。在具体的这类实施方案中，编码轻链的核酸序列包含序列SEQ ID NO 84或与其具有至少80％、至少85％、至少90％或至少95％序列同一性的序列。
在第三方面，本发明涉及包含本发明的核酸或核酸混合物的宿主细胞。在本发明的上下文中，术语“宿主细胞”、“宿主细胞系”和“宿主细胞培养物”可互换使用，并且是指其中已引入外源核酸的细胞，包括这些细胞的子代。宿主细胞包括“转化子”、“转化的细胞”、“转染子”、“转染的细胞”和“转导的细胞”，其包括原代转化/转染/转导的细胞和由其衍生的子代，而不考虑传代次数。子代的核酸含量可能与亲本细胞不完全相同，并且所包含的外源核酸可能含有突变。本文包括具有与在原始转化的细胞中筛选或选择的功能或生物活性相同的功能或生物活性的突变子代。
将表达载体至宿主细胞中的转染可采用标准技术进行，如电穿孔、核转染、磷酸钙沉淀、脂质转染、基于聚阳离子的转染如基于聚乙烯亚胺(PEI)的转染和DEAE-葡聚糖转染。
适合的宿主细胞包括原核细胞和真核细胞。原核宿主细胞的实例为例如细菌，包括但不限于大肠杆菌(Escherichia coli)、枯草芽孢杆菌(Bacillus subtilis)、鼠伤寒沙门氏菌(Salmonella typhimurium)以及假单胞菌属(Pseudomonas)、链霉菌属(Streptomyces)和葡萄球菌属(Staphylococcus)中的多个种。
真核宿主细胞的非限制性实例包括酵母、昆虫和昆虫细胞、植物和植物细胞、转基因动物和哺乳动物细胞。用于抗体表达的适合哺乳动物宿主细胞包括中国仓鼠卵巢(CHO细胞)，如CHO-K1、CHO-S、CHO-K1SV(包括在Urlaub and Chasin，(1980)Proc.Natl.Acad.Sci.USA 77：4216-4220和Urlaub et al.，Cell.1983Jun；33(2)：405-12中所述的dhfr-CHO细胞，与DHFR选择性标记一起使用，例如如R.J.Kaufman and P.A.Sharp(1982)Mol.Biol.159：601-621所述的；以及如Fan et al.，Biotechnol Bioeng.2012Apr；109(4)：1007-15中所示例的其他敲除细胞)、NS0骨髓瘤细胞、COS细胞、HEK293细胞、HKB11细胞、BHK21细胞、CAP细胞、EB66细胞和SP2细胞。
表达在表达系统中还可以为短暂的或半稳定的，如HEK293、HEK293T、HEK293-EBNA、HEK293E、HEK293-6E、HEK293-Freestyle、HKB11、Expi293F、293EBNALT75、CHOFreestyle、CHO-S、CHO-K1、CHO-K1SV、CHOEBNALT85、CHOS-XE、CHO-3E7或CAP-T细胞(例如Durocher et al.，Nucleic Acids Res.2002Jan 15；30(2)：E9)。
在第四方面，本发明涉及产生抗体或其片段的方法，包括培养本发明的宿主细胞。具体地，本发明的宿主细胞是在适合抗体或其片段表达的条件下培养的。
抗体表达可是组成型的或调控型的(例如诱导型的)。对于诱导型抗体表达，本发明的宿主细胞通常生长到适当的细胞密度，然后通过适当的方法(例如温度转换或化学诱导，如添加或去除小分子诱导剂，如与Tet系统结合的四环素)去抑制/诱导所选启动子，并培养宿主细胞一段额外的时间。
在具体的实施方案中，产生本发明的抗体或其片段的方法还包括从宿主细胞培养物中回收抗体或其片段的步骤。细胞可例如通过离心收集，通过物理或化学方法破坏，抗体或其片段可从所得粗提取物中进一步纯化。在一些实施方案中，设计表达载体以使得所表达的抗体或其片段分泌到其中生长宿主细胞的培养基中。在这种情况下，可以使用标准的蛋白质纯化方法直接从培养基中回收抗体或其片段。
在具体的实施方案中，本发明的方法还包括纯化回收抗体或其片段的步骤。具体地，将抗体纯化(1)至大于90％，如例如通过分析色谱或通过SDS-毛细管凝胶电泳(例如在Caliper LabChip GXII、GX90或Biorad生物分析仪装置上)测定，更具体地纯化产生至少为约92.5％、95％、98％或99％的抗体同质性(homogeneity)；或者，将抗体纯化(2)至足以获得N端或内部氨基酸序列的至少15个残基的程度，或(3)在还原或非还原条件下使用考马斯蓝或优选银染色，通过SDS-PAGE至同质性。
可以通过公知的方法从重组细胞培养物中回收和纯化本发明的抗体或其片段，所述方法包括但不限于硫酸铵或乙醇沉淀、酸提取、蛋白质A色谱、蛋白质G色谱、分子筛色谱、阴离子或阳离子交换色谱、磷纤维素色谱、疏水相互作用色谱、亲和色谱、羟基磷灰石色谱和凝集素色谱。高效液相色谱(“HPLC”)还可用于纯化(参见例如Colligan，CurrentProtocols in Immunology或Current Protocols in Protein Science，John Wiley&Sons，NY，N.Y.，(1997-2001)，例如第1、4、6、8、9、10章)。
在第五方面，本发明涉及包含本发明的抗体或其片段的组合物。具体地，本发明的组合物为适合用于治疗方法的药物组合物，其中所包含的本发明的抗体或其片段的量可有效实现预期目的，即预防或治疗特定疾病状态。
组合物任选地还包含至少一种药学上可接受的赋形剂。在本发明的上下文中，术语“赋形剂”是指与药物的活性成分一起配制的天然或合成物质。适宜的赋形剂包括抗粘附剂、粘合剂、涂料、崩解剂、香料、颜料、润滑剂、助流剂、吸着剂、防腐剂和甜味制。药学上可接受的赋形剂的具体实例包括但不限于盐水、缓冲盐水、右旋糖和水。在本发明的上下文中，术语“药学上可接受的”是指在给予哺乳动物(例如人)时，在生理上可耐受的且通常不产生不良反应的分子实体和药物组合物的其他成分。术语“药学上可接受的”还可指经联邦或州政府的监管机构批准或在美国药典或其他公认用于哺乳动物(更具体地人)的药典中列出。
本发明的组合物还可包含一种或多种其他治疗活性剂。
药物组合物可为溶液、悬液、肠溶胶囊、冻干粉的形式或适合预期用途的任何其他形式。
可以使用本领域中公知的药学上可接受的赋形剂，以适合口服给药的剂量配制用于口服给药的药物组合物。这种赋形剂使得药物组合物能够被配制成片剂、丸剂、糖衣丸剂(dragee)、胶囊剂、液体、凝胶、糖浆、浆料(slurry)、悬液等，用于被患者摄入。
可以通过活性化合物与固体赋形剂的组合获得用于口服使用的药物制品，任选地研磨所得混合物，并在添加合适的助剂(如果需要的话)后加工颗粒混合物，以获得片剂或糖衣丸核心。合适的赋形剂为碳水化合物或蛋白质填料，如糖，包括乳糖、蔗糖、甘露醇或山梨醇；来自玉米、小麦、稻、马铃薯或其他植物的淀粉；纤维素，如甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素钠；和胶，包括阿拉伯胶和黄芪胶；和蛋白质，如明胶和胶原。如果需要，可以添加崩解剂或增溶剂，如交联聚乙烯吡咯烷酮、琼脂、海藻酸或其盐，如海藻酸钠。
可以给糖衣丸核心提供合适的包衣(如浓缩糖溶液)，其还可含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、漆液(lacquear solution)以及合适的有机溶剂或溶剂混合物。可将染料或颜料添加到片剂或糖衣丸包衣中，以进行产品鉴定或表征活性化合物的量，即剂量。
可口服使用的药物制品包括明胶制成的推合胶囊，以及明胶和包衣(如甘油或山梨醇)制成的软密封胶囊。推合胶囊可含有与填料或粘合剂(如乳糖或淀粉)、润滑剂(如滑石或硬脂酸镁)和任选的稳定剂混合的活性成分。在软胶囊中，活性化合物可以溶解或悬浮于合适的液体中，如含有或不含稳定剂的脂肪油、液体石蜡或液体聚乙二醇。
用于肠胃外给药的药物制剂包括治疗活性剂的水溶液。对于注射，可以在水溶液中、优选在生理上相容的缓冲液(如Hank溶液、Ringer溶液或生理缓冲盐水)中配制本发明的药物组合物。水性注射悬液可含有增加悬液粘度的物质，如羧甲基纤维素钠、山梨醇或右旋糖酐。此外，活性剂的悬液可被制备为适当的油性注射悬液。合适的亲脂溶剂或载体包括脂肪油(如芝麻油)或合成脂肪酸酯(如油酸乙酯或甘油三酯)或脂质体。任选地，悬液还可含有增加治疗活性剂溶解度的适合稳定剂或试剂，以允许制备高度浓缩的溶液。
对于局部或鼻腔给药，在制品中使用适合于待渗透的特定屏障的渗透剂。这类渗透剂通常为本领域中已知的。
本发明的药物组合物可以本领域中已知的方式制造，例如通过常规的混合、溶解、造粒、制备糖衣丸、悬浮、乳化、包封、包埋或冻干过程。
药物组合物可以盐的形式提供并可用酸形成，所述酸包括但不限于盐酸、硫酸、乙酸、乳酸、酒石酸、苹果酸、琥珀酸等。盐倾向于更易溶于水性或其他质子溶剂，这些溶剂为相应的游离碱形式。在其他情况下，优选的制品可为含有1mM-50mM组氨酸、0.1％-2％蔗糖、2％-7％甘露醇的冻干粉末，pH范围为4.5至7.5，其在使用前与缓冲液结合。
制剂和给药技术的其他细节可以在最新版的Remington′s PharmaceuticalSciences(Ed.Maack Publishing Co，Easton，Pa.)中找到。
制备包含本发明的抗体或其片段的药物组合物后，可将其放置在适当的容器中并标记用于治疗的指定病症。对于本发明的抗体或片段的给药，这种标记将包括给药量、频率和方法。
本发明还提供了包含装有本发明前述组合物的一种或多种成分的一个或多个容器的包装(pack)和试剂盒。伴随这种容器的是由管理药品或生物产品的制造、使用或销售的政府机构规定的形式的通知，反映该机构已批准制造、使用或销售该产品用于人给药。
在第六方面，本发明涉及本发明的抗体或其片段或本发明的组合物用于治疗方法中。
具体地，这种治疗方法涉及向需要其的受试者给予治疗有效量的本发明的抗体或其片段。受试者可为人或非人动物(如兔子、大鼠、小鼠、狗、猴或其他低等灵长类)。
在本发明的上下文中，术语“治疗有效量”被定义为足以预防或减轻本文提到的任何障碍和疾病的疾病症状的本发明抗体或其片段的量，作为单次剂量或根据多剂量方案，单独的或与其他药物联合的。在具体的实施方案中，所述“治疗有效量”为毒理学上可耐受的。有效剂量的确定完全在本领域技术人员的能力范围内。治疗剂的治疗有效量通常在很大程度上取决于具体的患者特征，如年龄、体重、性别和疾病状态，给药时间、频率和途径，药物组合以及正在治疗的障碍的性质。抗体的常用剂量从0.1微克至100,000微克不等，最高达约10g的总剂量，取决于给药途径。
例如，可在国际协调会议的出版物和REMINGTON′S PHARMACEUTICAL SCIENCES的第27和28章，第484-528页(18th ed.，Alfonso R.Gennaro，Ed.，Easton，Pa.：MackPub.Co.，1990)中找到其确定方法的一般性指导。更具体地说，确定治疗有效量将取决于诸如药物的毒性和效能的因素，这些因素可以使用本领域中公知的和前述参考文献中记载的方法来确定。总之，治疗剂的治疗效能和毒性可分别在细胞培养测定或动物模型中确定，例如ED50(50％人群中治疗有效的剂量)和LD50(对50％人群致死的剂量)。ED50与LD50的剂量比为治疗指数。
本发明的抗体或其片段适用于治疗和/或预防心血管、肾、肺、骨骼、眼、血栓栓塞性和纤维变性疾病和障碍、侏儒症、软骨发育不全以及其他与cGMP相关的和/或利钠肽反应性障碍。因此，在具体的实施方案中，抗体或其片段用于治疗和/或预防这些障碍和疾病中的任何一种或其任意组合。
因此，本发明的抗体或其片段可用在治疗和/或预防心血管病症的药物中，例如动脉和肺动脉高压、顽固性和难治性高血压、急慢性心力衰竭、冠心病、闭塞性细支气管炎综合征(BOS)、肿瘤相关的和肿瘤学疾病、移植物抗宿主病、镰状细胞病、稳定和不稳定心绞痛、外周和心脏血管障碍、心律失常、房性和室性心律失常和传导受损(如房室传导阻滞I-III度(AB传导阻滞I-III))、室上性快速性心律失常、心房颤动、心房扑动、心室颤动、心室扑动、室性快速性心律失常、扭转型室性心动过速、房性和室性期外收缩、AV交接区期外收缩、病态窦房结综合征、晕厥、房室结折返性心动过速、Wolff-Parkinson-White综合征、急性冠状动脉综合征(ACS)、自身免疫性心脏病(心包炎、心内膜炎、瓣膜炎、主动脉炎、心肌病)、休克(如心源性休克、感染性休克和过敏性休克)、动脉瘤、拳击手心肌病(心室早发性收缩(PVC))；可用在治疗和/或预防血栓栓塞性障碍和缺血的药物中，例如心肌缺血、心肌梗死、中风、心脏肥大、短暂性缺血性发作、先兆子痫、炎性心血管病症、冠状动脉和外周动脉痉挛、水肿形成(如肺水肿、脑水肿、肾水肿或心力衰竭导致的水肿)、外周循环紊乱、再灌注损伤、动脉和静脉血栓形成、微量白蛋白尿、心肌机能不全、内皮功能障碍、预防例如溶栓治疗后的再狭窄、经皮腔内血管成形术(PTA)、经腔内冠状动脉血管成形术(PTCA)、心脏移植和旁路手术、以及微血管和大血管损伤(血管炎)、纤维蛋白原和低密度脂蛋白(LDL)水平升高、纤溶酶原激活物抑制剂1(PAI-1)浓度升高；以及用在治疗和/或预防勃起功能障碍和女性性功能障碍的药物中。
在本发明的上下文中，术语“心力衰竭”包括急性和慢性心力衰竭，还包括更具体或相关的疾病类型如急性失代偿性心力衰竭、右心衰竭、左心衰竭、全心衰竭、缺血性心肌病、扩张型心肌病、肥大型心肌病、特发性心肌病、先天性心脏缺陷、与心脏瓣膜缺陷有关的心力衰竭、二尖瓣狭窄、二尖瓣闭锁不全、主动脉瓣狭窄、主动脉瓣闭锁不全、三尖瓣狭窄、三尖瓣闭锁不全、肺动脉瓣狭窄、肺动脉瓣闭锁不全、合并心脏瓣膜缺陷、心肌炎症(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心力衰竭、酒精性心肌病、心脏储存障碍(cardiac storage disorder)、舒张期心力衰竭和收缩期心力衰竭、射血分数保留型心力衰竭(HFpEF)、射血分数降低型心力衰竭(HFrEF)和现有慢性心力衰竭的急性恶化期(恶化心力衰竭)。
此外，本发明的抗体或其片段还可用于治疗和/或预防动脉硬化、外周动脉疾病(PAD)、脂质代谢受损、低脂蛋白血症、血脂异常、高甘油三酯血症、高脂血症、高胆固醇血症、无β脂蛋白血症、谷固醇血症、黄瘤病、丹吉尔病、肥胖(adiposity)、肥胖症(obesity)及合并高脂血症和代谢综合征。
本发明的抗体或其片段还可用于治疗和/或预防原发性和继发性雷诺现象、微循环受损、跛行、外周和自主神经病、糖尿病性微血管病、糖尿病性视网膜病、糖尿病四肢溃疡、坏疽、CREST综合征、红斑性肢痛、甲癣、风湿病以及用于促进伤口愈合。
本发明的抗体或其片段还适合用于治疗泌尿障碍，例如良性前列腺综合症(BPS)、良性前列腺增生(BPH)、良性前列腺肥大(BPE)、膀胱出口阻塞(BOO)、下泌尿道综合症(LUTS，包括猫泌尿综合征(FUS))、泌尿生殖系统障碍包括神经源性膀胱过动症(OAB)和(IC)、尿失禁(UI)(例如混合性尿失禁、急迫性尿失禁、应激性尿失禁或充溢性尿失禁(MUI、UUI、SUI、OUI))、骨盆疼痛、男性和女性泌尿生殖系统器官的良性和恶性障碍。
本发明的抗体或其片段还适用于治疗和/或预防肾脏障碍，特别是急性和慢性肾机能不全及急性和慢性肾功能衰竭。在本发明的上下文中，术语“肾机能不全”包括肾机能不全的急性和慢性表现，以及潜在或相关的肾脏障碍如肾灌注不足、透析中低血压、梗阻性尿路病、肾小球病、肾小球肾炎、急性肾小球肾炎、肾小球硬化、肾小管间质性疾病、肾病障碍(如原发性和先天性肾脏疾病)、肾炎、免疫性肾脏障碍(如肾移植排斥和免疫复合物诱发的肾脏障碍、毒性物质诱发的肾病、造影剂诱发的肾病、糖尿病和非糖尿病肾病、肾盂肾炎、肾囊肿、肾硬化、高血压性肾硬化和肾病综合征，其在诊断上可被表征为：例如异常减少的肌酸酐和/或水排泄、异常升高的尿素、氮、钾和/或肌酸酐血浓度、改变的肾酶(例如谷氨酰合成酶)活性、改变的尿渗透压或尿量、升高的微量白蛋白尿、巨量白蛋白尿、肾小球和小动脉病变、肾小管扩张、高磷血症和/或需要透析。本发明还包括本发明的抗体或其片段用于治疗和/或预防肾机能不全后遗症的用途，例如肺水肿、心力衰竭、尿毒症、贫血、电解质紊乱(例如高钾血症、低钠血症)以及骨骼和碳水化合物代谢紊乱。
此外，本发明的抗体或其片段还适用于治疗和/或预防哮喘障碍、肺动脉压过高(PAH)和其他形式的肺动脉高压(PH)包括左心疾病、HIV、镰状细胞贫血、血栓栓塞(CTEPH)、结节病、COPD或肺纤维化相关肺动脉高压、慢性阻塞性肺病(COPD)、急性呼吸窘迫综合征(ARDS)、急性肺损伤(ALI)、α-1-抗胰蛋白酶缺乏症(AATD)、肺纤维化、肺气肿(例如吸烟诱发的肺气肿)、闭塞性细支气管炎综合征(BOS)和囊性纤维化(CF)。
本发明的抗体或其片段还适用于控制特征为NO/cGMP系统紊乱的中枢神经系统障碍。它特别适合于在认知缺损后改善知觉、注意力、学习或记忆，如特别是与以下情况/疾病/综合征有关的那些缺损：如轻度认知缺损、年龄相关学习和记忆缺损、年龄相关记忆丧失、血管性痴呆、颅脑创伤、中风、中风后发生的痴呆(中风后痴呆)、创伤后颅脑创伤、一般注意力障碍、有学习和记忆问题的儿童的注意力障碍、阿尔茨海默病、路易体痴呆、额叶退化性痴呆(包括皮克综合征)、帕金森氏病、进行性核性麻痹、皮质基底节变性痴呆、肌萎缩侧索硬化(ALS)、亨廷顿氏病、脱髓鞘、多发性硬化症、丘脑退化、Creutzfeld-Jacob痴呆、HIV痴呆、痴呆性精神分裂症或Korsakoff精神病。它还适用于治疗和/或预防中枢神经系统障碍，如焦虑、紧张和抑郁状态、CNS相关的性功能障碍和睡眠紊乱，以及用于控制摄入食物、兴奋剂和成瘾物质的病理紊乱。
此外，本发明的抗体或其片段还适用于控制脑血流量，因此是控制偏头痛的有效试剂。它还适用于预防和控制脑梗死(脑卒中)后遗症，如中风、脑缺血和颅脑创伤。它还可以用来控制疼痛和耳鸣的状态。
此外，本发明的抗体或片段具有抗炎作用，因此可用作抗炎剂，用于治疗和/或预防败血症(SIRS)、多器官衰竭(MODS、MOF)、肾脏炎性障碍、慢性肠道炎症(IBD、克罗恩病、UC)、胰腺炎、腹膜炎、类风湿病、炎性皮肤病和炎性眼病。
此外，本发明的抗体或其片段还可用于治疗和/或预防自身免疫性疾病。
抗体或其片段还适用于治疗和/或预防内脏器官的纤维化病症例如肺、心脏、肾脏、生殖系统、骨髓、特别是肝脏，以及皮肤纤维瘤和纤维化眼病。在本发明的上下文中，术语纤维化障碍特别包括以下术语：肝纤维化、肝硬化、肺纤维化、心内膜心肌纤维化、肾病、肾小球肾炎、间质性肾纤维化、糖尿病导致的纤维化损伤、子宫纤维瘤、子宫内膜异位症、骨髓纤维化和类似的纤维化障碍、硬皮病、硬斑病、瘢痕疙瘩、肥大性瘢痕形成(也是手术操作后)、痣、糖尿病视网膜病变、增殖性玻璃体视网膜病变和结缔组织障碍(例如结节病)。
本发明的抗体或其片段还适用于控制术后瘢痕形成，例如青光眼手术导致的。
本发明的抗体或其片段还可以在美容上用于老化和角质化皮肤。
此外，本发明的抗体或其片段适用于治疗和/或预防肝炎、肿瘤、骨质疏松、青光眼和胃轻瘫。
此外，本发明的抗体或其片段适用于治疗和/或预防眼部障碍，例如对利钠肽有反应的眼疾病、视网膜障碍、青光眼包括原发性开角型青光眼(POAG)、闭角型青光眼、先天性/发育性青光眼、视网膜病变、眼外伤、视神经病变、高眼压、眼内压升高、糖尿病视网膜病变、黄斑变性(AMD)、年龄相关性眼病、黄斑水肿、巩膜炎、葡萄膜炎、干眼、角膜上皮磨损、角膜溃疡。
此外，本发明的抗体或其片段适用于治疗骨和软骨障碍，如对利钠肽有反应的骨和软骨疾病、关节炎、软骨组织退行性疾病、骨关节炎、软骨退化、骨折、骨骼发育异常、软骨发育不全、骨质疏松症、成骨不全症、佩吉特骨病(PDB)、代谢性骨病、年龄相关性骨病、骨髓炎、骨坏死、佝偻病、骨软化病、生长板损伤和疾病、关节和骨置换相关缺陷、马方综合征(Marfan syndrome)、运动损伤、肌肉营养不良、迪谢内肌营养不良症(Duchenne musculardystrophy)。
因此，在另一方面，本发明涉及本发明的抗体或其片段用于治疗和/或预防障碍、特别是上述障碍的用途。
在具体的实施方案中，本发明的抗体或其片段可用在治疗和/或预防心力衰竭、心绞痛、高血压、肺动脉高压、缺血、血管病症、肾机能不全、血栓栓塞性障碍、纤维化障碍、骨骼和骨障碍、眼部障碍和动脉硬化的方法中。
在另一方面，本发明涉及本发明的抗体或其片段用于生产治疗和/或预防障碍、特别是上述障碍的药物的用途。
在具体的实施方案中，本发明涉及本发明的抗体或其片段用于生产治疗和/或预防心力衰竭、心绞痛、高血压、肺动脉高压、缺血、血管病症、肾机能不全、血栓栓塞性障碍、纤维化障碍、痴呆症、动脉硬化、骨骼和骨病症、眼部障碍、侏儒症、软骨发育不全和勃起功能障碍的药物的用途。
在另一方面，本发明涉及使用有效量的至少一种本发明的抗体或其片段治疗和/或预防障碍、特别是上述障碍的方法。
在具体的实施方案中，本发明涉及使用有效量的至少一种本发明的抗体或其片段治疗和/或预防心力衰竭、心绞痛、高血压、肺动脉高压、缺血、血管病症、肾机能不全、血栓栓塞性障碍、纤维化障碍、肿瘤和肿瘤学疾病、骨骼和骨障碍、眼部障碍、侏儒症、软骨发育不全和动脉硬化的方法。
本发明的抗体或其片段可作为唯一的药剂给药或可与一种或多种额外治疗剂组合给药，在某些情况下，抗体本身可能被修饰。例如，抗体或其片段可以被缀合至化学实体，例如以进一步提高效能、稳定性和/或半衰期。具体地，本发明的抗体或其片段可被聚乙二醇化和/或羟乙基淀粉化(HESylated)。
因此，在具体的实施方案中，本发明的抗体或其片段与至少一种额外治疗剂组合用于治疗方法中，特别是用于以上记载的目的。
本发明还提供了包含至少一种本发明的抗体或其片段和至少一种额外治疗剂的药物组合。
在本发明的上下文中，术语“药物组合”以本领域技术人员已知的方式使用，这种组合可能是固定组合、非固定组合或组件试剂盒。
在本发明的上下文中，术语“固定组合”以本领域技术人员已知的方式使用，并被定义为这样一种组合，其中例如第一活性成分(如一种或多种本发明的抗体或其片段)，以及另一种活性成分以一个单位剂量或一个单一实体一起存在，例如单一剂量制剂。“固定组合”的一个实例为一种药物组合物，其中第一活性成分和另一种活性成分以混合物存在，以便同时给药，例如在制剂中。“固定组合”的另一个实例为这样一种药物组合，其中第一活性成分和另一种活性成分以一个单元而不是以混合物存在。因此，本发明提供这样的药物组合物，其包含至少一种抗体或其片段和至少一种额外治疗剂，特别用于治疗和/或预防上述障碍。
在本发明的上下文中，使用的术语“非固定组合”和“组件试剂盒”以本领域技术人员已知的方式使用，并被定义为这样一种组合，其中第一活性成分和另一种活性成分以超过一个单元存在，例如以单独的剂量制品。非固定组合或组件试剂盒的一个实例为这样一种组合，其中第一活性成分和另一种活性成分单独存在。
非固定组合或组件试剂盒的组分可以单独、惯序、同时、并发或按时间顺序交错给药。
本发明的抗体或其片段可与所述其他治疗活性剂同时、在其之前或在其之后给药。在本发明的上下文中，术语“同时”是指本发明的抗体或其片段与至少一种其他治疗活性剂在同一天、更特别是在12小时内、更特别是在2小时内给药。
在具体的实施方案中，本发明的抗体或其片段与至少一种其他治疗活性剂的给药发生在连续八周内、更特别是在连续一至六周内。本发明的抗体或其片段与至少一种其他治疗活性剂可以通过相同途径或通过不同途径给药。
本发明的抗体或其片段可例如与同一适应症治疗组的已知试剂组合，例如用于治疗和/或预防与以下有关的疾病和病症的试剂：高血压、心力衰竭、肺动脉高压、COPD、哮喘、囊性纤维化、软骨发育不全、高磷血症、慢性肾脏疾病(CKD)、软组织钙化、慢性肾脏疾病相关钙化、非慢性肾脏疾病相关钙化、中层钙化包括蒙克伯格内侧硬化症(Moenckeberg’smedial sclerosis)、动脉粥样硬化、内膜钙化、CKD相关心脏肥大、CKD相关肾营养不良、骨质疏松症、绝经后骨质疏松症、II型糖尿病、慢性肾脏疾病、衰老、低磷酸盐尿、甲状旁腺功能亢进、维生素D障碍、维生素K缺乏、维生素K拮抗剂凝血剂、川崎病、ACDC(CD73缺乏导致的动脉钙化)、GACI(婴儿全身性动脉钙化)、IBGC(特发性基底节钙化)、PXE(弹性假黄瘤)、类风湿关节炎、Singleton-Merten综合征、P-地中海贫血、钙化防御、异养骨化、早产胎盘钙化、子宫钙化、钙化子宫纤维瘤、法尔病(morbus fahr)、主动脉瓣微钙化和钙化。
与本发明的抗体或其片段组合的适合的其他治疗剂的优选实例：
-有机硝酸酯和NO供体，例如硝普钠、硝酸甘油、单硝酸异山梨酯、二硝酸异山梨酯、吗多明或SIN-1，和吸入的NO；
-抑制环鸟苷单磷酸(cGMP)分解的化合物，例如磷酸二酯酶(PDE)1、2和/或5的抑制剂，特别是PDE 5抑制剂，如西地那非(sildenafil)、伐地那非(vardenafil)、他达拉非(tadalafil)、乌地那非(udenafil)、desantafil、阿伐那非(avanafil)、米罗那非(mirodenafil)、洛地那非(lodenafil)或PF-00489791；
-抗血栓试剂，例如且优选血小板聚集抑制剂、抗凝血剂或促纤溶物质；
-降压活性成分，例如且优选钙拮抗剂、血管紧张素AIl拮抗剂、ACE抑制剂、NEP抑制剂、血管肽酶抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻滞剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、rho激酶抑制剂和利尿剂；
-抗心律失常试剂，例如且优选钠通道阻滞剂、β-受体阻滞剂、钾通道阻滞剂、钙拮抗剂、If通道阻滞剂、洋地黄、抗副交感神经药(vagoliytics)、拟交感神经药和其他抗心律失常药物，如腺苷、腺苷受体激动剂以及维纳卡兰(vernakalant)；
-正性肌力试剂，例如强心苷(Dogoxin)、β-肾上腺素能和多巴胺能激动剂，如异丙肾上腺素、肾上腺素、去甲肾上腺素、多巴胺或多巴酚丁胺；
-血管加压素受体拮抗剂，例如且优选考尼伐坦(conivaptan)、托伐普坦(tolvaptan)、利希普坦(lixivaptan)、莫扎瓦普坦(mozavaptan)、萨塔瓦普坦(satavaptan)、SR-121463、RWJ 676070或BAY 86-8050以及WO 2010/105770、WO2011/104322和WO 2016/071212中记载的化合物；
-改变脂质代谢的活性成分，例如且优选甲状腺受体激动剂、PCSK9抑制剂、胆固醇合成抑制剂，例如且优选HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂、ACAT抑制剂、CETP抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、脂肪酶抑制剂、聚合胆汁酸吸着剂、胆汁酸再吸收抑制剂和脂蛋白(a)拮抗剂。
-抗炎试剂，例如且优选糖皮质激素，例如且优选强的松、强的松龙、甲基强的松龙、去炎松、地塞米松、倍氯米松、倍他米松、氟尼缩松、布地奈德或氟替卡松以及非甾体抗炎试剂(NSAID)，例如且优选乙酰水杨酸(阿司匹林)、布洛芬和萘普生、5-氨基水杨酸衍生物、白三烯拮抗剂、TNF-α-抑制剂和趋化因子受体拮抗剂，如CCR1、2和/或5抑制剂；
-抑制信号转导级联的试剂，例如且优选激酶抑制剂，例如且优选酪氨酸激酶和/或丝氨酸/苏氨酸激酶抑制剂；
-抑制细胞外基质的降解和修饰的试剂，例如且优选基质金属蛋白酶(MMP)抑制剂，例如且优选糜蛋白酶、基质降解酶(stromelysine)、胶原酶、明胶酶和聚蛋白多糖酶(aggrecanase)(优选MMP-1、MMP-3、MMP-8、MMP-9、MMP-10、MMP-11和MMP-13)以及金属弹性蛋白酶(MMP-12)和中性粒细胞弹性蛋白酶(HNE)的抑制剂，例如西维来司他(sivelestat)或DX-890；
-阻断5-羟色胺与其受体结合的试剂，例如且优选5-HT2b受体拮抗剂；
-抗纤维化试剂，例如且优选尼达尼布(nintedanib)、吡非尼酮、腺苷A2b受体拮抗剂、鞘氨醇-1-磷酸酯受体3(S1P3)拮抗剂、自分泌运动因子抑制剂、溶血磷脂酸受体1(LPA-1)和溶血磷脂酸受体2(LPA-2)拮抗剂、赖氨酰氧化酶(LOX)抑制剂、赖氨酰氧化酶样2抑制剂、CTGF抑制剂、IL-13拮抗剂、整合素拮抗剂、TGF-β拮抗剂、wnt信号抑制剂、CCR2-拮抗剂；
-作为支气管扩张剂的试剂，例如且优选5-HT2b受体拮抗剂；β2-肾上腺素能激动剂(短和长效)、抗胆碱能药和茶碱；
-作为细胞因子和趋化因子的拮抗剂的试剂，例如且优选TGF-β、CTGF、IL-1、IL-4、IL-5、IL-6、IL-8、IL-13、IL-25、IL-33、TSLP和整合素的拮抗剂；
-有机硝酸酯和NO供体，例如且优选硝普钠、硝酸甘油、单硝酸异山梨酯、二硝酸异山梨酯、吗多明或SIN-1，以及吸入的NO；
-可溶性鸟苷酸环化酶的不依赖NO但依赖血红素的刺激物，例如且优选WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO2012/028647和WO 2012/059549中所述的化合物；
-可溶性鸟苷酸环化酶的不依赖NO且不依赖血红素的激活剂，例如且优选WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462和WO 02/070510中所述的化合物；
-刺激cGMP合成的试剂，例如sGC调节剂，例如且优选利奥西胍(riociguat)、西那西胍(cinaciguat)、维拉西胍(vericiguat)；
-前列环素类似物或IP受体激动剂，例如且优选伊洛前列素、贝前列素、曲前列素(treprostinil)、依前列素(epoprostenol)或赛乐西帕(Selexipag)；
-内皮素受体拮抗剂，例如且优选波生坦、达卢生坦、安贝生坦(Ambrisentan)或西他生坦；
-抑制可溶性环氧化物水解酶(sEH)的试剂，例如且优选N，N′-二-环己基脲、12-(3-金刚烷-1-基-脲基)-十二烷酸或1-金刚烷-1-基-3-{5-[2-(2-乙氧基乙氧基)乙氧基]戊基}-脲；
-与葡萄糖代谢相互作用的试剂，例如且优选胰岛素、双胍、噻唑烷二酮、磺酰脲、阿卡波糖、DPP4抑制剂、GLP-1类似物或SGLT-1抑制剂；
-利钠肽，例如且优选心利钠肽(ANP，卡培立肽)、脑利钠肽(BNP，奈西立肽)、C型利钠肽(CNP)或尿扩张素；
-利钠肽衍生物，例如且优选伏索利肽(vosoritide)、蛇毒肽(cenderitide)、PL3994；
-心肌肌球蛋白激活剂，例如且优选奥米卡夫韦酯(omecamtiv mecarbil)(CK-1827452)；
-钙敏化剂，例如且优选左西孟旦；
-影响心脏能量代谢的试剂，例如且优选乙莫克舍、二氯乙酸酯、雷诺嗪或曲美他嗪、全部或部分腺苷A1受体激动剂，如GS-9667(以前称为CVT-3619)、卡帕地松(capadenoson)和neladenoson；
-影响心率的试剂，例如且优选伊伐布雷定。
抗血栓试剂优选地被理解为来自血小板聚集抑制剂、抗凝血剂剂或促纤溶物质的化合物。
在具体的实施方案中，将本发明的抗体或其片段与血小板聚集抑制剂组合给药，例如且优选阿司匹林、氯吡格雷、普拉格雷(prasugrel)、替格瑞洛(ticagrelor)、噻氯匹啶或双嘧达莫。
在具体的实施方案中，将本发明的抗体或其片段与凝血酶抑制剂组合给药，例如且优选希美加群(ximelagatran)、达比加群酯(dabigatran)、美拉加群(melagatran)、比伐卢定(bivalirudin)或克赛(clexane)。
在具体的实施方案中，将本发明的抗体或其片段与GPIIb/IIIa拮抗剂组合给药，例如且优选替罗非班或阿昔单抗。
在具体的实施方案中，将本发明的抗体或其片段与Xa因子抑制剂组合给药，例如且优选利伐沙班(rivaroxaban)、DU-176b、阿哌沙班(apixaban)、贝曲沙班(betrixaban)、奥米沙班(otamixaban)、非地沙班(fidexaban)、雷扎沙班(razaxaban)、letaxaban、eribaxaban、磺达肝癸钠(fondaparinux)、艾卓肝素(idraparinux)、PMD-3112、达瑞沙班(darexaban)(YM-150)、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV803、SSR-126512或SSR-128428。
在具体的实施方案中，将本发明的抗体或其片段与肝素或低分子量(LMW)肝素衍生物组合给药。
在具体的实施方案中，将本发明的抗体或其片段与维生素K拮抗剂组合给药，例如且优选香豆素。
降压试剂优选地被理解为来自钙拮抗剂、血管紧张素AlI拮抗剂、ACE抑制剂、内皮素拮抗剂、肾素抑制剂、α-受体阻滞剂、β-受体阻滞剂、盐皮质激素受体拮抗剂、rho激酶抑制剂和利尿剂的化合物。
在具体的实施方案中，将本发明的抗体或其片段与钙拮抗剂组合给药，例如且优选硝苯地平、氨氯地平、戊脉安或地尔硫卓。
在具体的实施方案中，将本发明的抗体或其片段与α-1受体阻滞剂组合给药，例如且优选哌唑嗪。
在具体的实施方案中，将本发明的抗体或其片段与β-受体阻滞剂组合给药，例如且优选普萘洛尔、阿替洛尔、噻吗洛尔、吲哚洛尔、阿普洛尔、氧烯洛尔、喷布洛尔、布拉洛尔、美替洛尔、纳多洛尔、甲吲洛尔、卡拉洛尔、甲磺胺心定、美托洛尔、倍他洛尔、塞利洛尔、比索洛尔、卡替洛尔、艾司洛尔、拉贝洛尔、卡维洛尔、阿达洛尔、兰地洛尔、奈比洛尔、依泮洛尔或布新洛尔。
在具体的实施方案中，将本发明的抗体或其片段与血管紧张素AII拮抗剂组合给药，例如且优选洛沙坦、坎地沙坦、缬沙坦、替米沙坦或恩布沙坦，或双血管紧张素AII拮抗剂/脑啡肽酶(neprilysin)抑制剂，例如且优选LCZ696(缬沙坦/沙必比尔(sacubitril))。
在具体的实施方案中，将本发明的抗体或其片段与ACE抑制剂组合给药，例如且优选依那普利、卡托普利、赖诺普利、雷米普利、地拉普利、福辛普利、喹那普利、培哚普利或泉多普利。
在具体的实施方案中，将本发明的抗体或其片段与内皮素拮抗剂组合给药，例如且优选波生坦、达卢生坦、安贝生坦或西他生坦。
在具体的实施方案中，将本发明的抗体或其片段与肾素抑制剂组合给药，例如且优选阿利吉仑、SPP-600或SPP-800。
在具体的实施方案中，将本发明的抗体或其片段与盐皮质激素受体拮抗剂组合给药，例如且优选非奈利酮(finerenone)、螺内酯或依普利酮。
在具体的实施方案中，将本发明的抗体或其片段与袢利尿剂组合给药，例如速尿灵、托拉塞米、布美他尼和吡咯他尼，与保钾利尿剂组合给药例如阿米洛利和氨苯蝶啶，与醛固酮拮抗剂组合给药，例如螺内酯、坎利酸钾和依普利酮，以及与噻嗪类利尿剂组合给药，例如氢氯噻嗪、氯噻酮、希帕胺和吲达帕胺。
脂质代谢修饰剂优选地被理解为来自CETP抑制剂、甲状腺受体激动剂、胆固醇合成抑制剂如HMG-CoA还原酶抑制剂或角鲨烯合成抑制剂、ACAT抑制剂、MTP抑制剂、PPAR-α、PPAR-γ和/或PPAR-δ激动剂、胆固醇吸收抑制剂、聚合胆汁酸吸着剂、胆汁酸再吸收抑制剂、脂肪酶抑制剂和脂蛋白(a)拮抗剂的化合物。
在具体的实施方案中，将本发明的抗体或其片段与CETP抑制剂组合给药，例如且优选达塞曲匹(dalcetrapib)、安塞曲匹(anacetrapib)、托彻普(torcetrapib)(CP-529414)、JJT-705或CETP疫苗(Avant)。
在具体的实施方案中，将本发明的抗体或其片段与甲状腺受体激动剂组合给药，例如且优选D-甲状腺素、3，5，3′-三碘甲腺原氨酸(T3)、CGS23425或阿昔替罗(CGS 26214)。
在具体的实施方案中，将本发明的抗体或其片段与来自他汀类的HMG-CoA还原酶抑制剂组合给药，例如且优选洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、罗苏伐他汀或匹伐他汀。
在具体的实施方案中，将本发明的抗体或其片段与角鲨烯合成抑制剂组合给药，例如且优选BMS-188494或TAK-475。
在具体的实施方案中，将本发明的抗体或其片段与ACAT抑制剂组合给药，例如且优选阿伐麦布、甲亚油酰胺、帕替麦布(pactimibe)、依鲁麦布(eflucimibe)或SMP-797。
在具体的实施方案中，将本发明的抗体或其片段与MTP抑制剂组合给药，例如且优选英普他派、BMS-201038、R-103757或JTT-130。
在具体的实施方案中，将本发明的抗体或其片段与PPAR-γ激动剂组合给药，例如且优选吡格列酮或罗格列酮。
在具体的实施方案中，将本发明的抗体或其片段与PPAR-δ激动剂组合给药，例如且优选GW 501516或BAY 68-5042。
在具体的实施方案中，将本发明的抗体或其片段与胆固醇吸收抑制剂组合给药，例如且优选依泽替米贝、替奎安或帕马苷。
在具体的实施方案中，将本发明的抗体或其片段与脂肪酶抑制剂组合给药，例如且优选为奥利司他。
在具体的实施方案中，将本发明的抗体或其片段与聚合胆汁酸吸着剂组合给药，例如且优选消胆胺、考来替泊(colestipol)、考来维仑(colesolvam)、考来胶或考来替胺(colestimide)。
在具体的实施方案中，将本发明的抗体或其片段与胆汁酸再吸收抑制剂组合给药，例如且优选ASBT(＝IBAT)抑制剂，例如AZD-7806、S-8921、AK-105、BARI-1741、SC-435或SC-635。
在具体的实施方案中，将本发明的抗体或其片段与脂蛋白(a)拮抗剂组合给药，例如且优选gemcabene calcium(CI-1027)或烟酸。
在具体的实施方案中，将本发明的抗体或其片段与脂蛋白(a)拮抗剂组合给药，例如且优选gemcabene calcium(CI-1027)或烟酸。
在具体的实施方案中，将本发明的抗体或其片段与sGC调节剂组合给药，例如且优选利奥西胍、西那西胍或维拉西胍。
在具体的实施方案中，将本发明的抗体或其片段与影响葡萄糖代谢的试剂组合给药，例如且优选胰岛素、磺酰脲、阿卡波糖、DPP4抑制剂、GLP-1类似物或SGLT-1抑制剂。
在具体的实施方案中，将本发明的抗体或其片段与TGFβ拮抗剂组合给药，例如且优选吡非尼酮、尼达尼布或非苏木单抗(fresolimumab)。
在具体的实施方案中，将本发明的抗体或其片段与CCR2拮抗剂组合给药，例如且优选CCX-140。
在具体的实施方案中，将本发明的抗体或其片段与TGFα拮抗剂组合给药，例如且优选阿达木单抗。
在具体的实施方案中，将本发明的抗体或其片段与半乳凝素-3抑制剂组合给药，例如且优选GCS-100。
在具体的实施方案中，将本发明的抗体或其片段与Nrf-2抑制剂组合给药，例如且优选巴多索隆(bardoxolone)。
在具体的实施方案中，将本发明的抗体或其片段与BMP-7激动剂组合给药，例如且优选THR-184。
在具体的实施方案中，将本发明的抗体或其片段与NOX1/4抑制剂组合给药，例如且优选GKT-137831。
在具体的实施方案中，将本发明的抗体或其片段与影响维生素D代谢的药剂组合给药，例如且优选骨化三醇、阿法骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、胆钙化醇或旁卡西醇。
在具体的实施方案中，将本发明的抗体或其片段与细胞生长抑制剂组合给药，例如且优选环磷酰胺。
在具体的实施方案中，将本发明的抗体或其片段与免疫抑制剂组合给药，例如且优选环孢素。
在具体的实施方案中，将本发明的抗体或其片段与磷酸盐粘合剂组合给药，例如且优选考来替兰(colestilan)、盐酸司维拉姆和碳酸司维拉姆、镧和碳酸镧。
在具体的实施方案中，将本发明的抗体或其片段与肾近端小管磷酸钠共转运蛋白组合给药，例如且优选烟酸或烟酰胺。
在具体的实施方案中，将本发明的抗体或其片段与拟钙剂(calcimimetic)组合给药，用于治疗甲状旁腺功能亢进。
在具体的实施方案中，将本发明的抗体或其片段与用于铁缺乏治疗的试剂组合给药，例如且优选铁产品。
在具体的实施方案中，将本发明的抗体或其片段与用于高尿酸血症(hyperurikaemia)治疗的试剂组合给药，例如且优选别嘌呤醇或拉布立酶。
在具体的实施方案中，将本发明的抗体或其片段与用于贫血症治疗的糖蛋白激素组合给药，例如且优选红细胞生成素。
在具体的实施方案中，将本发明的抗体或其片段与用于免疫治疗的生物制品组合给药，例如且优选阿巴西普(abatacept)、利妥昔单抗(rituximab)、依库丽单抗(eculizumab)或贝利木单抗(belimumab)。
在具体的实施方案中，将本发明的抗体或其片段与用于治疗心力衰竭的加压素拮抗剂(伐普坦类(vaptanes))组合给药，例如且优选托伐普坦、考尼伐坦、利伐普坦(lixivaptan)、莫扎瓦普坦、萨塔瓦普坦或瑞考伐普坦(relcovaptan)。
在具体的实施方案中，将本发明的抗体或其片段与Jak抑制剂组合给药，例如且优选鲁索替尼(ruxolitinib)、托法替尼(tofacitinib)、巴瑞替尼(baricitinib)、CYT387、GSK2586184、来他替尼(lestaurtinib)、帕瑞替尼(pacritinib)(SB1518)或TG101348。
在具体的实施方案中，将本发明的抗体或其片段与用于微血栓治疗的前列环素类似物组合给药。
在具体的实施方案中，将本发明的抗体或其片段与碱治疗组合给药，例如且优选碳酸氢钠。
在具体的实施方案中，将本发明的抗体或其片段与mTOR抑制剂组合给药，例如且优选依维莫司或雷帕霉素。
在具体的实施方案中，将本发明的抗体或其片段与NHE3抑制剂组合给药，例如且优选AZD1722或替纳帕诺(tenapanor)。
在具体的实施方案中，将本发明的抗体或其片段与eNOS调节剂组合给药，例如且优选沙丙蝶呤。
在具体的实施方案中，将本发明的抗体或其片段与CTGF抑制剂组合给药，例如且优选FG-3019。
可使用一种或多种生理上可接受的载体或赋形剂以任何常规方式配制用于本发明治疗方法的抗体或其片段。可通过任何适当的方式给予本发明的抗体或其片段，这些方式可以根据待治疗的障碍类型而改变。可能的给药途径包括肠内(例如口服)、肠胃外(如静脉内、动脉内、腹膜内、肌肉内、皮下、心内、脑室内、鞘内、髓内、病灶内(intralesional))、肺内和鼻内给药。此外，本发明的抗体或其片段可通过脉输注给药，例如以降低的抗体或其片段的剂量。优选地通过注射、最优选地通过静脉注射或皮下注射给药，部分取决于病症是急性还是慢性。待给药的量将取决于多个因素，如个体的临床症状、性别、年龄和/或体重、是否给予其他药物等。技术人员将认识到，给药途径将根据待治疗的障碍或病症而变化。
肠胃外递送方法包括局部、动脉内、瘤内、肌内、皮下、髓内、鞘内、脑室内、静脉内、腹膜内或鼻内给药。
在具体的实施方案中，治疗方法包括抗体或其片段或者包含该抗体或其片段的药物组合物的单次或多次给药。单次给药剂量可相同或不同。具体地，治疗方法包括本发明的抗体或其片段的1、2、3、4、5或6次给药，优选地其中多次给药发生在连续一至六个月内。本发明的抗体或其片段可例如每3至4天、每周、每两周一次或每三周一次给药，这取决于其半衰期和清除率。
附图说明
图1：大鼠静脉给药5mg/kg后TPP-10992和TPP-5661的平均血浆浓度。
图2：小鼠腹膜内给药5mg/kg后TPP-12897的平均血浆浓度。
图3：ANP(A-C)、TPP-10992(D-F)和TPP-5661(G-I)抗蛋白水解降解的稳定性。直接(A、D、G)或在37℃下用0.6μg/ml NEP(B、E、H)或0.6μg/ml IDE(C、F、I)孵育4小时后在稳定的大鼠ANP受体细胞系上检测ANP、TPP-10992和TPP-5661的活性。
图4：BNP(A-C)和TPP-11155(D-F)抗蛋白水解降解的稳定性。直接(A、D)或在37℃下用0.6μg/ml NEP(B、E)或0.6μg/ml IDE(C、F)孵育4小时后在稳定的大鼠BNP受体细胞系上检测BNP和TPP-11155的活性。
图5：CNP(A-C)和TPP-12897(D-F)抗蛋白水解降解的稳定性。直接(A、D)或在37℃下用0.6μg/ml NEP(B、E)或0.6μg/ml IDE(C、F)孵育4小时后在稳定的大鼠CNP受体细胞系上检测CNP和TPP-11155的活性。
图6：ANP肽和TPP-10992在PE收缩的主动脉环内诱导的血管舒张的剂量-反应曲线。通过苯肾上腺素(1μM)收缩的内皮完整的大鼠主动脉环内的ANP肽(空心圆)和TPP-10992(实心圆)的浓度-反应曲线(0.0001-10μM；n＝3只大鼠)。实验值是相对于苯肾上腺素在每个组织中产生的收缩的最大变化(作为100％)计算。ANP肽和TPP-10992的效价分别为-7.4和-6.7(logEC50值)。数据代表2次实验的平均值±S.E.M.。
图7：ANP肽和TPP-5661在PE收缩的主动脉环内诱导的血管舒张的剂量-反应曲线。通过苯肾上腺素(1μM)收缩的内皮完整的大鼠主动脉环内的ANP肽(空心圆)和TPP-5661(实心圆)的浓度-反应曲线(0.0001-10μM；n＝3只大鼠)。实验值是相对于苯肾上腺素在每个组织中产生的收缩的最大变化(作为100％)计算。ANP肽和TPP-5661的效价分别为-7.4和-6.5(logEC50值)。数据代表2次实验的平均值±S.E.M.。
图8：清醒大鼠中ANP的血流动力学效果。在0小时腹膜内给予大鼠ANP。500μg剂量的ANP导致平均动脉血压(MAP)减低约25％，效果持续时间约为6-8小时。
图9：清醒大鼠中TPP-5661的血流动力学效果。在0小时腹膜内给予TPP-5661。15mg/kg剂量导致平均动脉血压(MAP)减低约20％，在施用后24-48小时具有最大效果，效果持续时间超过6天。
图10：清醒大鼠中TPP-10992的血流动力学效果。在0小时腹膜内给予TPP-10992。30mg/kg剂量导致平均动脉血压(MAP)减低约20％，在施用后48小时具有最大效果，效果持续时间超过6天。
图11：BNP嫁接抗体构建体在hNPRA细胞上的活性。通过与参考样品TPP-5661和TPP-5657比较，评估纯化的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。以稀释系列测试样品，一式四份。
图12：不同的人IgG同种型提供同样合适的抗体支架。化合物9、33、65、91、127和191IgG1(分别为TPP-10294、TPP-10277、TPP-10279、TPP-10282、TPP-10269和TPP-10355)、IgG2和IgG4同种型的示例性活性测定。通过与参考样品化合物117人IgG1 TPP-5661和化合物209人IgG1 TPP-5657比较，评估纯化的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。以稀释系列测试样品，一式四份。
图13：来源于不同物种的同样合适的IgG抗体支架。化合物117人IgG1(TPP-5661)和化合物9人IgG1(TPP-10294)及其非人IgG1对应物(counterpart)的示例性活性测定。通过与参考样品化合物209人IgG1(TPP-5657)比较，评估纯化的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。以稀释系列测试样品，一式四份。
图14：来源于不同种系序列的同样合适的人IgG抗体支架。通过与参考样品TPP-10992比较，评估纯化的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。以稀释系列测试样品，一式四份。
图15：通过实时阻抗测量评估TPP-12899对LPS、IL-1β和凝血酶诱导的内皮屏障通透性的保护效果。
图16：TPP-13992对存活率(A)、体重增加(B)、尿蛋白/肌酸酐比值(C)和左心房重量(D)的治疗效果；(n＝8-12(健康对照n＝5)，平均值±SEM，单向ANOVA vs TPP-10155(同种型特异性对照抗体)。
图17：安慰剂、0.1、0.3和1.0mg/kg TPP-10992后的血流动力学评估。TPP-10992显示了血压的剂量依赖性和长效的(＞5d)降低。与安慰剂组相比，＊＊p＜0.01，＊＊＊＊p＜0.0001，采用单向ANOVA检验进行重复测量，然后采用Tukey的多重比较检验。
实施例
实施例1：构建候选TPP-5661
通过用将包含Ntls、野生型大鼠ANP和Ctls的异源氨基酸序列的两个N端残基置换HV 3-23的两个C端残基所述异源氨基酸序列融合到HV 3-23(SEQ ID NO 85)的C端，以及通过用所述异源氨基酸序列的9个C端残基置换IGHJ1的9个N端残基将所述异源氨基酸序列融合到IGHJ1(SEQ ID NO 86)的N端残基，设计候选TPP-5661。相应的SEQ ID NO 67的全长重链序列还包含氨基酸序列恒定H(SEQ ID NO 87)。
将携带插入的大鼠ANP(rANP)的SEQ ID NO 67的全长重链序列与通过组合序列LV1-40(SEQ ID NO 88)、IGLJ2(SEQ ID NO 89)和恒定L(SEQ ID NO 90)构建的SEQ ID NO 66的全长轻链序列配对，产生完整的IgG候选TPP-5661(参见表1)。
以下示出的是全长重链序列(SEQ ID NO 67)；纳入的异源氨基酸序列(Ntls-rANP-Ctls)加下划线；源自HV 3-23和IGHJ1的序列以粗体显示：
按照本领域中公知的方法克隆所设计并合成的抗体构建体，并利用质粒特异性寡核苷酸通过DNA测序确认。
实施例2：将NP插入抗体-CDR中导致血清半衰期增加
测定体内药代动力学参数
对雄性Wistar大鼠(n＝3)静脉给药5mg/kg后，测定TPP-10992(SEQ ID NO 76和SEQ ID NO 66)和TPP-5661(SEQ ID NO 67和SEQ ID NO 66)的药代动力学参数。TPP-10992和TPP-5661经尾静脉以单次快速静脉注射给予。通过先前植入的导管从颈静脉采集血液样品，时间间隔最长达14天(336小时)。将生成的EDTA-血浆储存在-20℃下，直到进行进一步分析。
采用抗人IgG ELISA(酶联免疫吸附测定)方法(format)对血浆样品中的TPP-10992和TPP-5661进行定量。采用非房室数据分析(non-compartmental data analysis)由血浆浓度时间谱计算药代动力学参数。
图1中以图形方式描绘了静脉给药后TPP-10992和TPP-5661随时间的平均血浆浓度。
下表2概述了TPP-10992和TPP-5661的平均清除率和终末半衰期。
表2：大鼠中静脉给药5mg/kg后，TPP-10992和TPP-5661的平均清除率(CL)和终末半衰期(t1/2)。
| 分析物 | TPP-5661 | TPP-10992 | |
| CL | [mL/h/kg] | 0.62 | 0.27 |
| t<sub>1/2</sub> | [h] | 297 | 184 |
测定体内药代动力学参数
对雌性Balb/c小鼠(n＝3)腹膜内给药后，测定TPP-12897的药代动力学参数。在施用后的15分钟至最长达72小时采集血液样品。将生成的EDTA-血浆储存在-20℃下，直到进行进一步分析。用抗人IgG(免疫球蛋白G)ELISA方法对血浆样品中的TPP-12897进行定量。
采用非房室数据分析由血浆浓度时间谱计算药代动力学参数。
图2中以图形方式描绘了腹膜内给药后TPP-12897随时间的平均血浆浓度。
下表3概述了TPP-12897的曲线下平均面积(AUC)和终末半衰期。
表3：小鼠中腹膜内给药5mg/kg后，TPP-12897的曲线下平均面积(AUC)和终末半衰期(t1/2)。
| 分析物 | TPP-12897 | |
| AUC | [mg·h/L] | 7705 |
| t<sub>1/2</sub> | [h] | 194 |
实施例3：NP嫁接抗体的体外、离体和体内效价
ANP嫁接抗体在NPR-A受体细胞系中的活性数据
如前所述，产生了基于发光的大鼠ANP受体(NPR-A)细胞系(Wunder et al.(2013)，Eur J Pharmacol.698：131)。因此，通过用编码CNGA2(cGMP生物传感器)和大鼠NPR-A的质粒构建体共转染CHO细胞系，稳定表达荧光钙传感蛋白GCaMP6，产生了基于荧光的大鼠ANP受体(NPR-A)细胞系。
在黑色透明底384孔微量滴定板上培养ANP受体GCaMP6细胞(2500细胞/孔)一天。去除细胞培养基后，在37℃和5％CO2下，用含有黑色掩蔽染料的Tyrode(130mM NaCl、5mMKCl、2mM CaCl2、20mM HEPES、1mM MgCl2、4.8mM NaHCO3，pH 7.4)负载(load)报告细胞20分钟。采用IBMX(0.2mM)防止内源性磷酸二酯酶进行的cGMP降解。
添加激动剂后直接开始荧光测量(3分钟，动力学模式)。在含有黑色掩蔽染料和0.1％BSA的Tyrode中加入受体配体。在FLIPR 
上进行测量。
ANP(Bachem，H-2100)在NPR-A细胞系上刺激浓度依赖性荧光信号，EC50值为0.22nM。TPP-5661和TPP-10992分别刺激大鼠ANP受体报告细胞系，EC50值为17nM和180nM。对照抗体构建体TPP-5657没有显著刺激NPR-A细胞系(测试最高达460nM的最大浓度)。
为了确定对蛋白水解降解的敏感性，在37℃下用0.6μg/ml中性内肽酶(NEP，R&DSystems，1182-ZNC)或0.6μg/ml胰岛素降解酶(IDE，Merck，407241-50UG)孵育4小时后，还表征了受体配体的活性进行。
图3以图形方式描绘了ANP(A-C)、TPP-10992(D-F)和TPP-5661(G-I)抗蛋白水解降解的稳定性。如图3所示，利钠肽ANP(Bachem，H-2100)对NEP和IDE进行的降解显示出较高的敏感性。相比之下，TPP-5661和TPP-10992对NEP和IDE进行的蛋白水解降解显示出较高的抗性。
BNP嫁接抗体在NPR-A受体细胞系中的活性数据
如前所述，产生了基于发光的大鼠BNP受体(NPR-A)细胞系(Wunder et al.(2013)，Eur J Pharmacol.698：131)。因此，通过用编码CNGA2(cGMP生物传感器)和大鼠NPR-A的质粒构建体共转染CHO细胞系，稳定表达荧光钙传感蛋白GCaMP6，产生了基于荧光的大鼠BNP受体(NPR-A)细胞系。
在黑色透明底384孔微量滴定板上培养BNP受体GCaMP6细胞(2500细胞/孔)一天。去除细胞培养基后，在37℃和5％CO2下，用含有黑色掩蔽染料的Tyrode(130mM NaCl、5mMKCl、2mM CaCl2、20mM HEPES、1mM MgCl2、4.8mM NaHCO3，pH 7.4)负载报告细胞20分钟。采用IBMX(0.2mM)防止内源性磷酸二酯酶进行的cGMP降解。
添加激动剂后直接开始荧光测量(3分钟，动力学模式)。在含有黑色掩蔽染料和0.1％BSA的Tyrode中加入受体配体。在FLIPR 
上进行测量。
BNP(Bachem，H-5968)在NPR-A细胞系上刺激浓度依赖性荧光信号，EC50值为2.9nM。TPP-9902、TPP-11153、TPP-1154、TPP-11155、TPP-11156和TPP-11157分别刺激大鼠BNP受体报告细胞系，EC50值为2.3μM、＞1.9μM、7nM、12nM、1.2μM和11nM。对照抗体构建体TPP-5657没有显著刺激NPR-A细胞系(测试最高达460nM的最大浓度)。
为了确定对蛋白水解降解的敏感性，在37℃下用0.6μg/ml中性内肽酶(NEP，R&DSystems，1182-ZNC)或0.6μg/ml胰岛素降解酶(IDE，Merck，407241-50UG)孵育4小时后，还表征了受体配体的活性。利钠肽BNP(Bachem，H-5968)对NEP和IDE降解进行的显示出较高的敏感性。相比之下，TPP-11155和TPP-11157对NEP和IDE进行的蛋白水解降解显示出较高的抗性。
图4以图形方式描绘了BNP(A-C)和TPP-11155(D-F)抗蛋白水解降解的稳定性。
CNP嫁接抗体在NPR-B受体细胞系中的活性数据
如前所述，产生了基于发光的大鼠CNP受体(NPR-B)报告细胞系，并进行了发光测量(Wunder et al.(2013)，Eur J Pharmacol.698：131)。
在不透明的384孔微量滴定板上培养CNP受体细胞(2500细胞/孔)一天。去除细胞培养基后，在37℃和5％CO2下，用溶于无Ca2+的Tyrode(130mM NaCl、5mM KCl、20mM HEPES、1mM MgCl2、4.8mM NaHCO3，pH 7.4)中2.5μg/ml腔肠素(coelenterazine)负载细胞3小时。在含0.1％BSA的无Ca2+的Tyrode中加入受体配体，持续10分钟。用IBMX(0.2mM)防止内源性磷酸二酯酶进行的cGMP降解。使用电荷耦合器件(CCD)相机在不透光盒中开始发光测量，然后立即加入钙离子(最终浓度3mM)。持续监测发光50秒。
CNP(Bachem，H-1296)在大鼠NPR-B细胞系上刺激浓度依赖性发光信号，EC50值为0.024nM。TPP-9465、TPP-12377、TPP-12378、TPP-12897和TPP-12899分别刺激大鼠CNP受体报告细胞系，EC50值为5.2nM、4.1nM、25nM、10nM和3.2nM。TPP-12374刺激大鼠CNP受体报告细胞系，EC50值为150nM，TPP-12375、TPP-12376仅显示出较弱的活性迹象。
为了确定对蛋白水解降解的敏感性，在37℃下用0.6μg/ml中性内肽酶(NEP，R&DSystems，1182-ZNC)或0.6μg/ml胰岛素降解酶(IDE，Merck，407241-50UG)孵育4小时后，还表征了受体配体的活性。
与利钠肽CNP(Bachem，H-1296)相比，TPP-12377、TPP-12897和TPP-12899对NEP和IDE进行的蛋白水解降解显示出较高的抗性。
图5以图形方式描绘了CNP(A-C)和TPP-12897(D-F)抗蛋白水解降解的稳定性。
用分离的大鼠主动脉环测定的ANP嫁接抗体的活性数据
所有实验都是按照机构指南进行的，并得到当地动物实验委员会的批准。将雄性Sprague-Dawley大鼠(体重250-300g)用戊巴比妥钠(40mg/kg i.p.)麻醉，断头处死，放血。切除胸主动脉，置于具有以下组分的冰冷克雷布斯缓冲液(Krebs buffer)中：130mM NaCl、14.9mM NaHCO3、5.5mM右旋糖、4.7mM KCl、1.18mM KH2PO4、1.17mM MgSO47H2O和1.6mMCaCl22H2O。将血管固定装有冷冻的克雷布斯溶液的Sylgard培养皿中，清除脂肪和结缔组织，并切成长度为约3至4mm的环段。在37℃下，将主动脉环垂直固定在含有克雷布斯溶液的50ml室(ADI仪器)中，用95％O2和5％CO2的混合物持续鼓泡。使用PowerLab数据采集系统(软件Lab Chart 7.0)记录等长收缩力(isometric force)变化。
平衡期后，用80mM KCl刺激主动脉环以检查组织活力。接下来，通过验证用苯肾上腺素(PE，1μM)预收缩的血管中对乙酰胆碱(ACh，1μM)的反应性，确定制品的内皮完整性。洗脱和平衡一段时间后，用苯肾上腺素(PE，1μM)诱导收缩，然后用利钠肽和利钠肽嫁接IgG评估血管舒张。大鼠ANP肽(ADH-GM-10057T，Santai Labs)用作参考。
如图6所示，ANP肽和TPP-10992均在PE收缩的主动脉环内诱导了剂量依赖性血管舒张。
如图7所示，ANP肽和TPP-5661均在PE收缩的主动脉环内诱导了剂量依赖性血管舒张。
在清醒大鼠中获得的ANP嫁接抗体的活性数据
通过无线电遥测术(Data Sciences International)监测自由活动的清醒动物的血压和心率。将体重为210-300g的雌性自发性高血压大鼠(SHR/N Crl BR，Charles River)用于这些研究。所有动物都被安置在环境温度为22-24℃的单独笼子中，并保持12小时的光/暗循环，随意自由获得标准实验室大鼠食物和水。进行最少14天的遥测仪(HD-10，DSI)植入，然后将动物用于血压测量。手术是在无菌条件下进行。刮净腹壁后，做中线腹部切口，将充液传感器导管向上游插入髂动脉分叉与肾动脉之间暴露的降主动脉。根据DSI指南，遥测导管的尖端位于肾动脉的尾部，并由组织粘合剂固定。将发射器体(transmitter body)粘贴在内腹膜壁上，然后闭合腹部。为进行手术保护抵御感染和疼痛，注射单一剂量的抗生素(
10％，60mg/kg s.c.，0.06ml/100g体重，Beta-Pharma GmbH&Co，Germany)和镇痛剂(
4mg/kg s.c.，Pfizer，Germany)。采用DSI软件进行遥测数据采集，预定义为每5分钟重复采集样品血流动力学数据10秒。数据采集至少在给药前2小时开始，在完成测量周期后结束。数据表示为每组至少4只动物的基础值％±SEM。每只动物的基础值是以施用物质前两小时(上午7:00-9:00)测量值的平均值计算。然后，数据被表示为每半小时的平均值，从施用后15分钟开始。所有动物均用单次腹膜内(ip)施用的溶解在磷酸盐缓冲盐水(PBS)中的试验物质处理。上午9:00(0小时)进行给药。
图8以图形方式描绘了ANP肽的血流动力学效果。图9以图形方式描绘了TPP-5661的血流动力学效果。图10以图形方式描绘了TPP-10992的血流动力学效果。
实施例4：产生不同的NP嫁接抗体构建体
对于利钠肽纳入到非CDRH3的CDR区中的构建体，通过将三残基段Leu Thr Gly(IGHD7-27＊01)融合到HV 3-23的C端和IGHJ1的N端(比较实施例1)，设计了推测为功能中性的CDRH3。相应的SEQ ID NO 65的全长重链序列还包含氨基酸序列恒定H(SEQ ID NO87)。
将不合任何利钠肽插入物的SEQ ID NO 65的全长重链序列与实施例1中描述的SEQ ID NO 66的全长轻链序列配对，产生合成的、推测为中性的IgG阴性对照TPP-5657。
按照本领域中公知的方法克隆所设计并合成的抗体构建体，并利用质粒特异性寡核苷酸通过DNA测序确认。
从该抗体支架开始，产生以下ANP嫁接抗体构建体。
表4：设计ANP嫁接抗体构建体
1各个N端参考氨基酸残基与插入的利钠肽的第一个氨基酸之间存在的氨基酸残基数量；
2插入的利钠肽的最后一个氨基酸与各个C端参考氨基酸残基之间存在的氨基酸残基数量；
表4续：设计ANP嫁接抗体构建体
3N端序列对应于插入的利钠肽的N端最近邻的参考aa加上在所述参考aa与插入的利钠肽的第一个氨基酸残基之间存在的氨基酸段
4C端序列对应于插入的利钠肽的最后一个氨基酸残基与插入的利钠肽的C端最近邻的参考aa之间存在的氨基酸段加上所述参考aa
此外，从抗体支架TPP-5657开始，产生了以下BNP嫁接人IgG1抗体构建体。
表5：设计BNP嫁接抗体构建体
1各个N端参考氨基酸残基与插入的利钠肽的第一个氨基酸之间存在的氨基酸残基数量；
2插入的利钠肽的最后一个氨基酸与各个C端参考氨基酸残基之间存在的氨基酸残基数量；
3相应的ANP化合物指具有相同整合基因座并包含相同N端和C端序列的ANP嫁接抗体构建体
表5续：设计BNP嫁接抗体构建体
3N端序列对应于插入的利钠肽的N端最近邻的参考aa加上在所述参考aa与插入的利钠肽的第一个氨基酸残基之间存在的氨基酸段
4C端序列对应于插入的利钠肽的最后一个氨基酸残基与插入的利钠肽的C端最近邻的参考aa之间存在的氨基酸段加上所述参考aa
实施例5：生成的构建体的体外活性
根据本领域中公知的方法在HEK293细胞中瞬时表达所有构建体，靶向细胞密度约为2x10^6个细胞/ml，编码轻链和重链的两种质粒的总DNA浓度约为1μg/ml，孵育5天进行表达。
原始化合物样品(raw compound sample，rcs)以0.4ml培养体积表达，离心分离的上清液直接用于测试。根据本领域中公知的方法，通过IgG-Fc定量ELISA评估化合物浓度。简言之，将1∶1500稀释的上清液和以400ng/ml开始的2倍稀释系列的人参考血清(Bethyl，RS-110-4)在黑色Maxisorp 384微量滴定板(MTP)中于37℃下固定1小时，所述微量滴定板用以1x包被缓冲液(Candor，121125)1∶440稀释的抗人Fc[Sigma I2136]包被。在用100％SMART Block(Candor，113125)封闭后，施用1∶10000稀释的抗人Fc-HRP[Sigma，A0170]，以检测rcs和参考样品中的抗体。参考样品的剂量曲线用于定量评估表7和表8中所示的化合物浓度，“μg/ml rcs”列。所有样品均一式四份施用。
根据本领域中公知的方法，通过以蛋白质-A进行的一步纯化从6ml表达培养物中产生分离的化合物样品(ics)。通过加入8％(v/v)1M Tris/HCl(pH 9.0)中和酸性洗脱液，通过280nm处的吸收定量，并归一化至125nM的浓度。
通过以蛋白质-A和随后的在PBS缓冲液中的SEC进行的两步纯化从至少35ml的表达培养物中产生纯化的化合物样品(pcs)。表7和表8中所示的值，“μg/ml pcs”列，是指通过分析型蛋白A色谱法测定的表达培养物上清液中的化合物浓度。
通过使用根据制造商说明书(cisbio；62GM2PEH)进行的cGMP定量测定，在异源过表达人NPRA(hNPRA)的细胞上测量表7和表8中所示的所有活性。简言之，基于由于以(利钠肽)样品进行的NPRA刺激而由细胞产生的cGMP与d2标记的cGMP之间的竞争结合穴状化合物(Cryptate)标记抗体，该测定法定量了缓冲溶液或细胞培养上清液中的cGMP。样品cGMP和d2标记的cGMP竞争结合穴状化合物标记的抗cGMP抗体上有限数量的位点，因此
特异性荧光信号(即能量转移)与样品中cGMP的浓度成反比。
用GraphPad Prism(Windows版本7.00，GraphPad软件，La Jolla CaliforniaUSA)分析剂量反应曲线数据，并根据对底部、顶部和斜率(各自实验的所有数据集的共享值)施加限制的Y＝底部+(顶部-底部)/(1+10^((LogEC50-X)＊HillSlope)拟合EC50。
通过与阴性对照TPP-5657和阳性样品(特别是TPP-5661)比较，首次评估了原始化合物样品在稳定的hNPRA-CHO k1细胞上的活性。对照和rcs在两种浓度下进行了测试(一式四份)，相对稀释因子为5，目的是在测定的动态范围内的荧光信号。测定窗口被定义为无活性样品信号(最大信号，s_max)和高活性样品信号(最小信号，s_min)的差异，这两种化合物浓度下活性％计算为100＊(s_max-s)/(s_max-s_min)。表7中列出的值，“活性rcs”和“stdev活性rcs”列，表示两种浓度的结果平均值和各自的标准偏差。少于参考化合物TPP-5661信号(36％)一半的rcs信号被评估为无活性(n.a.)。
通过与以5倍稀释开始的参考样品TPP-5661的2.5倍稀释系列(8个浓度)相比，重新评估了几种原始化合物样品在稳定的hNPRA-CHO k1细胞上的活性。通过计算δ“logEC50”_化合物-“logEC50”_TPP-5661，相对于参考rcs TPP-5661的相应值，设置作为rcs活性量度的“logEC50”拟合值；结果值列于表7，“rel.活性rcs”列中。值得注意的是，没有考虑rcs中的化合物浓度，因此给定的值受到等测(equal measure)的化合物活性和浓度的影响。所有样品均一式四份施用。
通过EC50测定和与参考样品TPP-5661的比较，评估了分离的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。样品以从80nM至0.13nM的2.5倍稀释系列进行测试。通过计算δlogEC50_化合物-logEC50_TPP-5661，相对于参考ics TPP-5661的相应值(-8.8)，设置作为ics活性量度的logEC50拟合值；结果值列于表7，“rel.logEC50 ics”列中。所有样品均一式四份施用。
通过EC50测定和与参考样品TPP-5661的比较，在多个实验中评估了纯化的化合物样品在稳定的hNPRA-CHO k1细胞上的活性。样品以稀释系列进行测试，至少一式四份。表7中“rel.logEC50 pcs 1、3和4”列中列出的值来自从20或25nM开始的5倍稀释系列(≥4个浓度)。表7中“rel.logEC50 pcs 2”列中列出的值来自从25nM开始的10倍稀释系列(4个浓度)。表7中“rel.logEC50 pcs 5、6、7、8和9”列中列出的值分别来自从40至200nM开始的2.5倍稀释系列，具有8或12个浓度。通过计算δlogEC50_化合物-logEC50_TPP-5661，相对于各自实验中的参考TPP-5661的相应值(平均值为-9.2，标准偏差为0.5)，设置作为pcs活性量度的logEC50拟合值。
通过EC50测定和与参考样品TPP-5661的比较，在三个实验中评估了纯化的化合物样品在瞬时hNPRA-HEK293细胞上的活性。样品以从1000nM至0.013nM的5倍稀释系列中进行测试。通过计算δlogEC50_化合物-logEC50_TPP-5661，相对于各自实验中的参考TPP-5661的相应值(平均值为-9.0，标准偏差为0.4)，设置作为pcs活性量度的logEC50拟合值；结果值列于表7，“rel.logEC50＊pcs”列中。所有样品均一式四份施用。
在“qualit.活性”列中给出了化合物活性的总结性定性评估，“平均rel.logEC50”列中列出的值计算为给定的rel.logEC50值的平均值。显示EC50值＞参考化合物TPP-566150倍(即平均rel.logEC50＞1.7)的化合物，定性评估为无活性(“-”)；显示相对logEC50在0.7至1.7之间的化合物被评估为有活性(“+”)；显示相对logEC50＜0.7的化合物被评估为非常有活性(“++”)；在相对logEC低于-0.7时观察到最高活性(“+++”)。在显示rcs中活性但未被确认为ics或pcs的化合物被标记为统一的“y”，可能由于它们的非常低的表达水平(≤1μg/ml，“μg/ml”列中的“n.e.”)而被评估为无活性的化合物(“活性rcs”列中的“n.a.”)也相应地标记。
没有获得化合物#104和#135的结论性数据。12种化合物(#54、#61、#89、#139、#162、#168、#170、#171、#172、#173、#176、#196)示出非常低的表达水平(rcs中≤1μg/ml)，因此没有活性；化合物制备(pcs)后示出#61的活性。在大多数情况下，7种化合物(#7、#24、#70、#83、#90、#154、#167)作为rcs示出低活性，尽管它们的表达水平非常低；通过化合物制备(pcs)确认了#24和#90的活性。在化合物#18、#26、#29、#92、#96、#101、#104、#158、#164、#179的rcs中未观察到活性；然而，使用较高浓度时示出了化合物#18、#92、#158、#164的活性(rel.活性rcs)；因此确认了#26缺乏活性。
表8：脑利钠肽嫁接抗体构建体的表达水平和活性
不适用(na)
1各个N端参考氨基酸残基与插入利钠肽的第一个氨基酸之间存在的氨基酸残基数量；
2插入的利钠肽的最后一个氨基酸与各个C端参考氨基酸残基之间存在的氨基酸残基数量；
3相应的ANP Cpd指具有相同整合基因座并包含相同N-端和C-端序列的ANP嫁接抗体构建体
如实施例3所述，在稳定的hNPRA-CHO k1细胞上，对稀释序列的纯化的化合物样品进行测试，一式四份。图11中以图形方式描绘了BNP嫁接抗体构建体的活性。
与TPP-1154、TPP-11155和TPP-11157相比，TPP-11156、TPP-9902和TPP-11153在hNPRA细胞上表现出显著的活性。在rNPRA上观察到相反结果，TPP-1154、TPP-11155和TPP-11157的EC50＜20nM，TPP-9902、TPP-11153和TPP-11156的EC50＞1μM(参见实施例3)。这可以通过TPP-11156、TPP-9902和TPP-11153中存在人BNP序列，而TPP-1154、TPP-11155和TPP-11157包含大鼠BNP序列来解释(参见表5)。与所有其他人BNP嫁接抗体构建体相比，在BNP的N-端和C-端具有较少额外氨基酸数的TPP-18031和TPP-18032在hNPRA上无活性。
实施例6：特定的接头序列特别有利于获得良好的同质性和表达水平
根据制造商的说明书(LabChip GX，Caliper Life Sciences)，在还原条件下，通过毛细管凝胶电泳测定纯化的化合物样品的纯度(实施例5，表7，“％纯度pcs”列)。％纯度计算为对应于完整轻链和重链的峰面积之和相对于观察到的所有峰之和。
包含GS接头序列、PN接头序列或序列SEQ ID NO 2、4、9、11、13或15的Ntls序列，和包含GS接头序列、PN接头序列或序列SEQ ID NO 3、5、12、14、15或20的Ctls序列被证明特别有用，因为它们不仅实现了高利钠肽活性(只要各个N端参考氨基酸残基与插入的利钠肽的第一个氨基酸之间存在至少12个氨基酸残基)，而且实现了良好的表达水平(与例如在化合物#186、#195和#202中使用的序列相比)以及(与化合物6和7中使用的序列相比)较低的不均匀性(参见表9)。使用包含GS接头序列的接头序列以及包含PN接头序列的接头序列时，观察到非常好的纯度，平均值为98％。类似地，对于具有包含序列SEQ ID NO 2、3、4、5、9、11、12、13、14、15和20的接头的化合物，也观察到了良好的值。值得注意的是，具有序列SEQ IDNO 9的Ntls只有在化合物中与具有序列SEQ ID NO 20的Ctls组合时才会实现非常高的纯度；只有在当SEQ ID NO 11的N端侧侧翼为Asp(D)而不是Thr(T)或Val(V)时以及当SEQ IDNO 12VNHLRSEKLT的C端侧侧翼为Gly(G)而不是Tyr(Y)或Phe(F)时，含有具有序列SEQ IDNO 11的Ntls和具有序列SEQ ID NO 12的Ctls的组合的化合物才显示出很高的纯度，如化合物#126和#135中。
实施例7：IgG1、IgG2和IgG4同种型提供了同样合适的抗体支架
生成化合物9、33、65、91、127和191(分别为人IgG1 TPP-10294、TPP-10277、TPP-10279、TPP-10282、TPP-10269和TPP-10355)作为不同IgG同种型。如实施例3所述，在稳定的hNPRA-CHO k1细胞上，对稀释序列的纯化的化合物样品进行测试，一式四份。ANP嫁接人IgG2和IgG4同种型构建体(例如化合物9IgG4 TPP-10992)的活性与其相应的IgG1同种型相似，如图12中以图形方式描绘的。
实施例8：人和非人IgG提供同样合适的抗体支架
生成化合物9(人IgG1 TPP-10294和IgG4 TPP-10992)和化合物117(人IgG1 TPP-5665)作为非人IgG同种型。如实施例3所述，在稳定的hNPRA-CHO k1细胞上，对稀释序列的纯化的化合物样品进行测试，一式四份。ANP嫁接大鼠和小鼠同种型构建体(例如化合物9大鼠IgG1 TPP-13992)的活性与其相应的人IgG同种型相似(图13)。
实施例9：包含不同种系序列的人IgG提供同样合适的抗体支架
构建了22种额外的ANP嫁接IgG4抗体(化合物A至S)。在每一种情况下，ANP都被纳入到CDRH1中。这些构建体的重链包含不同的HV和CDRH3序列，并与不同的λ或κ轻链配对。表10和表11概述了化合物A至S的结构。
表10：设计ANP嫁接抗体构建体A至S
1各个N端参考氨基酸残基与插入的利钠肽的第一个氨基酸之间存在的氨基酸残基数量；
2插入的利钠肽的最后一个氨基酸与各个C端参考氨基酸残基之间存在的氨基酸残基数量；
3N端序列对应于插入的利钠肽的N端最近邻的参考aa加上在所述参考aa与插入的利钠肽的第一个氨基酸残基之间存在的氨基酸段
4C端序列对应于插入的利钠肽的最后一个氨基酸残基与插入的利钠肽的C端最近邻的参考aa之间存在的氨基酸段加上所述参考aa
表11：设计ANP嫁接抗体构建体A至S
| Cmpd | TPP | HV | CDRH3 | LV/KV | 纯度 |
| 9 | TPP-10992 | HV3-23 | KLTGAEYFQHW | LV1-40 | 99 |
| A | TPP-13944 | HV3-23 | KLTGAEYFQHW | LV2-14 | 98 |
| B | TPP-13945 | HV3-23 | KLTGAEYFQHW | LV3-21 | 93 |
| C | TPP-13941 | HV3-23 | KDYGDYAEYFQHW | LV1-40 | 100 |
| D | TPP-13956 | HV3-23 | KLTGAEYFQHW | KV1-5 | 99 |
| E | TPP-13955 | HV3-23 | KLTGAEYFQHW | KV3-20 | 99 |
| F | TPP-13940 | HV3-23 | KVLRFLEWLLYAEYFQHW | LV1-40 | 98 |
| G | TPP-13939 | HV3-23 | KVQLERAEYFQHW | LV1-40 | 100 |
| H | TPP-13943 | HV3-23 | KYNRNHAEYFQHW | LV1-40 | 54 |
| I | TPP-13942 | HV3-23 | KYNWNDAEYFQHW | LV1-40 | 99 |
| J | TPP-14684 | HV3-23 | RGATFALDW | KV3-20 | 97 |
| K | TPP-13958 | HV3-23 | RGRLPDVW | KV1-5 | 99 |
| L | TPP-13957 | HV3-23 | RGRLPDVW | KV3-20 | 97 |
| M | TPP-13948 | HV3-23 | RGRLPDVW | LV1-40 | 98 |
| N | TPP-14289 | HV3-23 | RGRLPDVW | LV1-47 | |
| O | TPP-13946 | HV3-23 | RGRLPDVW | LV2-14 | 97 |
| P | TPP-13947 | HV3-23 | RGRLPDVW | LV3-21 | 96 |
| Q | TPP-13952 | HV5-51 | RGRLPDVW | LV2-14 | 99 |
| R | TPP-13953 | HV5-51 | RGRLPDVW | LV3-21 | 98 |
| S | TPP-13962 | HV5-51 | RGRLPDVW | KV1-5 | 99 |
如实施例3所述，在稳定的hNPRA-CHO k1细胞上，对稀释系列的包含不同种系序列的IgG支架构建体A至S的纯化的化合物样品进行测试，一式四份。图14中以图形方式描绘了示例性活性数据。
实施例10：CNP嫁接IgG保护抵御诱导的内皮屏障通透性
利用微电极覆盖的微量滴定板(E-Plate)，以xCELLigence RTCA系统通过实时阻抗测量评估内皮单层通透性。相对阻抗变化表示为无单位的细胞指数(CI)值。
将原代人肺动脉内皮细胞(HPAEC)在胶原预包被的E-Plate上以低传代数接种。在具有恒定CI值的紧密单层和细胞屏障形成后，用所示浓度的化合物TPP-12899或各自的阴性对照抗体构建体TPP-5657对HPAEC进行预处理，然后用破坏性激动剂LPS(200ng/ml)、IL-1β(0.5ng/ml)或凝血酶(2U/ml)破坏EC屏障。每10分钟记录CI，以监测对细胞生长和单层通透性的影响。将所有细胞指数在最后记录点时进行归一化，然后施用测试物质(＝归一化CI)。
进行实验，n＝4，每个实验3种技术重复。结果以平均值±SEM表示。数据用单向ANOVA和Sidak多重事后检验进行统计分析；p值＜0.05被认为是显著的。
图15以图形方式描绘了以细胞指数值表示的对内皮单层通透性的影响。如图15中所示，用TPP-12899对人内皮单层培养物的预处理以剂量依赖性的方式保护抵御诱导的内皮屏障通透性。这与施用的屏障破坏剂无关；使用快速的和强作用凝血酶，以及长效的促炎性刺激LPS和IL-1β，都观察到显著的效果。各自的阴性对照为显示效果。
实施例11：ANP嫁接IgG在慢性心力衰竭大鼠模型(TGR(mRenR2)27中的长期效果
TGR(mRenR2)27大鼠模型显示出高血压和内皮功能障碍以及终末器官损伤。使用8周龄的雄性肾素转基因大鼠(Ganten D.，Nature.1990；344(6266)：541-4)。在所有研究组中，通过饮用水(20mg/l)长期给予一氧化氮合成酶L-NAME(Nω-硝基-L-精氨酸甲酯)的非选择性抑制剂，以诱导内皮功能障碍。每周一次腹膜内给予在实施例8中使用的TPP-10294的大鼠IgG1对应物TPP-13992和大鼠IgG1同种型对照抗体TPP-10155。评估体重和存活率。从断奶开始，安慰剂组用溶剂(vehicle)(PBS)处理，健康对照组用卡托普利-食物处理。随意进食食物和水。每日观察动物的行为和一般健康状况。实验结束(第14周)时，将大鼠麻醉。然后将大鼠放血，并将心脏从胸腔中取出用于进行分析。在研究结束时收集尿液，以确定不同的尿液参数，例如尿蛋白肌酸酐比率。图16以图形方式描绘了TPP-13992对存活率、体重增加、尿蛋白/肌酸酐比率和左心房重量的治疗效果。
实施例12：ANP嫁接IgG对健康比格犬中的血液动力学效果
在清醒的遥测比格犬中，在主要的药效学研究中，评估了单次皮下给药后TPP-10992对心血管和ECG参数的效果。
手术植入遥测装置(DSITM，USA)以测量血压以及心率，然后经历恢复期以使伤口闭合。在研究当天，激活遥测传感器，用于连续的血流动力学测量。由位于动物设施的遥测接收器采集传输信号。所有采集到的数据都由数据采集程序处理，并在预定的12小时时间段内取平均值。对于TPP-10992，使用NaCl(0.9％)作为溶剂(vehicle)，通过皮下注射施用剂量0.1mg/kg、0.3mg/kg和1.0mg/kg体重。
图17中以图形方式描绘了结果。在健康犬中，TPP-10992示出血压的剂量依赖性和长期的(＞5d)降低，在1.0mg/kg s.c.下是显著的(与安慰剂相比)。没有观察到对心率的效果。
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<120> 心房利钠肽嫁接抗体
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<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 28
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 29
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 29
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 30
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 30
Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro Gly Ser Gly
1 5 10 15
Gly
<210> 31
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 31
Ser Gly Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 32
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 32
Ala Lys Val His Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 33
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 33
Ala Ala Trp Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Gly Gly
1 5 10 15
Ser Gly Gly
<210> 34
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 34
Ala Lys Gly Ile Thr Gly Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 35
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 35
Ser Gly Ser Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 36
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 36
Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 37
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 37
Gly Val Pro Lys Glu Lys Glu Lys Glu Lys Val Ser Thr Ala Val Gly
1 5 10 15
Gly
<210> 38
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（不含参考aa）
<400> 38
Ser Val Val Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly Ser Gly
1 5 10 15
Gly
<210> 39
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 39
Gly Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly
1 5 10
<210> 40
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 40
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly
1 5 10
<210> 41
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 41
Gly Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro
1 5 10 15
Ser
<210> 42
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 42
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
<210> 43
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 43
Gly Ser Asn Pro Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser
1 5 10
<210> 44
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 44
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Gly Ser
1 5 10 15
<210> 45
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 45
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro His Val Asp Val Trp
1 5 10 15
Gly Gln
<210> 46
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 46
Gly Ser Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Val
1 5 10
<210> 47
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 47
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Ala Glu Tyr Phe Gln His Trp
1 5 10 15
Gly Gln
<210> 48
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 48
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Gly Ser
1 5 10
<210> 49
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 49
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Ser
1 5 10
<210> 50
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 50
Gly Ser Ala Pro Leu Glu Val Pro Lys Glu Lys Glu Lys Glu Lys Val
1 5 10 15
<210> 51
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（不含参考aa）
<400> 51
Gly Gly Ser Thr Pro Leu Lys Ser Leu Ala Ser
1 5 10
<210> 52
<211> 54
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 52
Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Gly Ser Gly Gly Ser
1 5 10 15
Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile Gly Ala
20 25 30
Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Gly Ser Gly Gly
35 40 45
Ser Gly Ser Gly Ser Gly
50
<210> 53
<211> 65
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 53
Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Pro Asp Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly
20 25 30
Gly Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser
35 40 45
Phe Arg Tyr Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
50 55 60
Gly
65
<210> 54
<211> 64
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 54
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp
20 25 30
Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly
35 40 45
Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro Ser
50 55 60
<210> 55
<211> 63
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 55
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
20 25 30
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
35 40 45
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
50 55 60
<210> 56
<211> 59
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列(wo ref aas)
<400> 56
Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro Gly Ser Gly
1 5 10 15
Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile
20 25 30
Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser Asn
35 40 45
Pro Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser
50 55
<210> 57
<211> 63
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 57
Ser Gly Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
20 25 30
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
35 40 45
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Gly Ser
50 55 60
<210> 58
<211> 66
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 58
Ala Lys Val His Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
20 25 30
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
35 40 45
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro His Val Asp Val Trp
50 55 60
Gly Gln
65
<210> 59
<211> 61
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 59
Ala Ala Trp Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Gly Gly
1 5 10 15
Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp
20 25 30
Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly
35 40 45
Ser Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Val
50 55 60
<210> 60
<211> 66
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 60
Ala Lys Gly Ile Thr Gly Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
20 25 30
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
35 40 45
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Ala Glu Tyr Phe Gln His Trp
50 55 60
Gly Gln
65
<210> 61
<211> 61
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 61
Ser Gly Ser Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp
20 25 30
Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly
35 40 45
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Gly Ser
50 55 60
<210> 62
<211> 59
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 62
Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg
20 25 30
Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser
35 40 45
Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Ser
50 55
<210> 63
<211> 61
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 63
Gly Val Pro Lys Glu Lys Glu Lys Glu Lys Val Ser Thr Ala Val Gly
1 5 10 15
Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile
20 25 30
Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser Ala
35 40 45
Pro Leu Glu Val Pro Lys Glu Lys Glu Lys Glu Lys Val
50 55 60
<210> 64
<211> 56
<212> PRT
<213> 人工
<220>
<223> N端序列-NP-C端序列（不含参考aas）
<400> 64
Ser Val Val Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly Ser Gly
1 5 10 15
Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile
20 25 30
Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Gly Ser
35 40 45
Thr Pro Leu Lys Ser Leu Ala Ser
50 55
<210> 65
<211> 447
<212> PRT
<213> 人
<400> 65
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Leu Thr Gly Ala Glu Tyr Phe Gln His Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 66
<211> 217
<212> PRT
<213> 人
<400> 66
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
<210> 67
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 67
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Ile
115 120 125
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 68
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 68
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
115 120 125
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 69
<211> 504
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 69
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
50 55 60
Pro Asp Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly
65 70 75 80
Gly Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser
85 90 95
Phe Arg Tyr Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
100 105 110
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
115 120 125
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
130 135 140
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu
145 150 155 160
Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
165 170 175
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
180 185 190
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
195 200 205
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
210 215 220
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
225 230 235 240
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
245 250 255
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
260 265 270
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
275 280 285
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
290 295 300
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
305 310 315 320
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
325 330 335
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
340 345 350
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
355 360 365
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
370 375 380
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
385 390 395 400
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
405 410 415
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
420 425 430
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
435 440 445
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
450 455 460
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
465 470 475 480
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
485 490 495
Lys Ser Leu Ser Leu Ser Pro Gly
500
<210> 70
<211> 504
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 70
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Ser
50 55 60
Pro Asp Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly
65 70 75 80
Gly Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser
85 90 95
Phe Arg Tyr Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro
100 105 110
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
115 120 125
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
130 135 140
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu
145 150 155 160
Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
165 170 175
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
180 185 190
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
195 200 205
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
210 215 220
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
225 230 235 240
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
245 250 255
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
260 265 270
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
275 280 285
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
290 295 300
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
305 310 315 320
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
325 330 335
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
340 345 350
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
355 360 365
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
370 375 380
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
385 390 395 400
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
405 410 415
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
420 425 430
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
435 440 445
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
450 455 460
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
465 470 475 480
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
485 490 495
Lys Ser Leu Ser Leu Ser Pro Gly
500
<210> 71
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 71
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Val His Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
115 120 125
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
130 135 140
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 72
<211> 504
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 72
Glu Val Gln Leu Leu 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 Gly Ser Gly
20 25 30
Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly Ser Gly Gly
35 40 45
Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile Gly
50 55 60
Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser Tyr Gly
65 70 75 80
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Met Ser Trp Val Arg Gln
85 90 95
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly
100 105 110
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
115 120 125
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
130 135 140
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu
145 150 155 160
Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
165 170 175
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser
180 185 190
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
195 200 205
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
210 215 220
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
225 230 235 240
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr
245 250 255
Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys
260 265 270
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
275 280 285
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
290 295 300
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
305 310 315 320
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
325 330 335
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
340 345 350
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
355 360 365
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
370 375 380
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
385 390 395 400
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
405 410 415
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
420 425 430
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
435 440 445
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
450 455 460
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
465 470 475 480
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
485 490 495
Lys Ser Leu Ser Leu Ser Pro Gly
500
<210> 73
<211> 500
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 73
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro
50 55 60
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
65 70 75 80
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
85 90 95
Gly Ser Asn Pro Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser Thr Tyr
100 105 110
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
115 120 125
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
130 135 140
Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu Tyr Phe Gln His
145 150 155 160
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
165 170 175
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
180 185 190
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
195 200 205
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
210 215 220
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
225 230 235 240
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
245 250 255
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
260 265 270
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
275 280 285
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
290 295 300
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
305 310 315 320
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
325 330 335
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
340 345 350
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
355 360 365
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
370 375 380
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
385 390 395 400
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
405 410 415
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
420 425 430
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
435 440 445
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
450 455 460
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
465 470 475 480
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
485 490 495
Leu Ser Pro Gly
500
<210> 74
<211> 502
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 74
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Thr Tyr Ile Ser Asn Val Asn His Lys Pro
50 55 60
Asp Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly
65 70 75 80
Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe
85 90 95
Arg Tyr Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Gly Ser
100 105 110
Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
115 120 125
Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
130 135 140
Asp Thr Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu Tyr Phe
145 150 155 160
Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
165 170 175
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser
180 185 190
Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
195 200 205
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
210 215 220
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
225 230 235 240
Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys
245 250 255
Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
260 265 270
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
275 280 285
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
290 295 300
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
305 310 315 320
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
325 330 335
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
340 345 350
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
355 360 365
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
370 375 380
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
385 390 395 400
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
405 410 415
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
420 425 430
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
435 440 445
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
450 455 460
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
465 470 475 480
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
485 490 495
Leu Ser Leu Ser Pro Gly
500
<210> 75
<211> 500
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 75
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp
50 55 60
Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg
65 70 75 80
Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg
85 90 95
Tyr Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Ser Thr Tyr
100 105 110
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
115 120 125
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
130 135 140
Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu Tyr Phe Gln His
145 150 155 160
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
165 170 175
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
180 185 190
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
195 200 205
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
210 215 220
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
225 230 235 240
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
245 250 255
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
260 265 270
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
275 280 285
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
290 295 300
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
305 310 315 320
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
325 330 335
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
340 345 350
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
355 360 365
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
370 375 380
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
385 390 395 400
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
405 410 415
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
420 425 430
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
435 440 445
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
450 455 460
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
465 470 475 480
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
485 490 495
Leu Ser Pro Gly
500
<210> 76
<211> 501
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 76
Glu Val Gln Leu Leu 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 Gly Ser Gly
20 25 30
Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly Ser Gly Gly
35 40 45
Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile Gly
50 55 60
Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser Tyr Gly
65 70 75 80
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Met Ser Trp Val Arg Gln
85 90 95
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly
100 105 110
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
115 120 125
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
130 135 140
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu
145 150 155 160
Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala
165 170 175
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser
180 185 190
Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe
195 200 205
Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly
210 215 220
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
225 230 235 240
Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr
245 250 255
Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg
260 265 270
Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
275 280 285
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
290 295 300
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
305 310 315 320
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
325 330 335
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
340 345 350
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
355 360 365
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
370 375 380
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
385 390 395 400
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
405 410 415
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
420 425 430
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
435 440 445
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
450 455 460
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
465 470 475 480
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
485 490 495
Ser Leu Ser Leu Gly
500
<210> 77
<211> 493
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 77
Glu Val Gln Leu Leu 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 Gly Ser Gly
20 25 30
Ser Gly Ser Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe
35 40 45
Gly Gly Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn
50 55 60
Ser Phe Arg Tyr Gly Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Met
65 70 75 80
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala
85 90 95
Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
100 105 110
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
115 120 125
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys
130 135 140
Leu Thr Gly Ala Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val
145 150 155 160
Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala
165 170 175
Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
180 185 190
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
195 200 205
Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
210 215 220
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
225 230 235 240
Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr
245 250 255
Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
260 265 270
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
275 280 285
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
290 295 300
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
305 310 315 320
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
325 330 335
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
340 345 350
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
355 360 365
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
370 375 380
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
385 390 395 400
Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
405 410 415
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
420 425 430
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
435 440 445
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
450 455 460
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
465 470 475 480
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
485 490
<210> 78
<211> 497
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 78
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Val Val Val Thr Ser His Gln Ala Pro Gly Glu Gly
50 55 60
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
65 70 75 80
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
85 90 95
Gly Gly Ser Thr Pro Leu Lys Ser Leu Ala Ser Thr Tyr Tyr Ala Asp
100 105 110
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
115 120 125
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
130 135 140
Tyr Cys Ala Lys Leu Thr Gly Ala Glu Tyr Phe Gln His Trp Gly Gln
145 150 155 160
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
165 170 175
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
180 185 190
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
195 200 205
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
210 215 220
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
225 230 235 240
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
245 250 255
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
260 265 270
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
275 280 285
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
290 295 300
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
305 310 315 320
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
325 330 335
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
340 345 350
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
355 360 365
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
370 375 380
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
385 390 395 400
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
405 410 415
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
420 425 430
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
435 440 445
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
450 455 460
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
465 470 475 480
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
485 490 495
Gly
<210> 79
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 79
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ile Thr Gly Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly Arg Met
115 120 125
Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe Arg Tyr
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Ala Glu Tyr Phe Gln His Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 80
<211> 267
<212> PRT
<213> 人工
<220>
<223> NP嫁接的LC
<400> 80
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asn Pro Asn
85 90 95
Pro Asn Pro Asn Pro Asn Pro Asn Gly Gly Ser Gly Gly Ser Leu Arg
100 105 110
Arg Ser Ser Cys Phe Gly Gly Arg Met Asp Arg Ile Gly Ala Gln Ser
115 120 125
Gly Leu Gly Cys Asn Ser Phe Arg Tyr Gly Ser Asn Pro Asn Pro Asn
130 135 140
Pro Asn Pro Asn Pro Asn Val Phe Gly Ser Gly Thr Lys Val Thr Val
145 150 155 160
Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser
165 170 175
Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser
180 185 190
Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser
195 200 205
Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn
210 215 220
Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp
225 230 235 240
Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr
245 250 255
Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
260 265
<210> 81
<211> 274
<212> PRT
<213> 人工
<220>
<223> NP嫁接的LC
<400> 81
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro
50 55 60
Asp Gly Gly Ser Gly Gly Ser Leu Arg Arg Ser Ser Cys Phe Gly Gly
65 70 75 80
Arg Met Asp Arg Ile Gly Ala Gln Ser Gly Leu Gly Cys Asn Ser Phe
85 90 95
Arg Tyr Gly Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn
100 105 110
Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr
115 120 125
Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp
130 135 140
Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu Ser Gly Val Val Phe Gly
145 150 155 160
Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser
165 170 175
Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala
180 185 190
Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val
195 200 205
Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr
210 215 220
Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu
225 230 235 240
Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln
245 250 255
Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu
260 265 270
Cys Ser
<210> 82
<211> 366
<212> DNA
<213> 人工
<220>
<223> NP嫁接的HC编码构建体
<400> 82
gaagtgcagc tgctggaaag cggcggaggc ctggtgcagc ctggcggatc tctgagactg 60
agctgtgccg ccagcggctt caccttcagc agctacgcca tgagctgggt gcgccaggcc 120
cctggaaaag gcctggaatg ggtgtccgcc atctctggca gcggcggcag cacctactac 180
gccgattctg tgaagggccg gttcaccatc agccgggaca acagcaagaa caccctgtac 240
ctgcagatga acagcctgcg ggccgaggac accgccgtgt actactgtac aagcgtgcac 300
caggaaacaa agaagtacca gagcagcccc gacggcggca gtggcggaag tctgagaaga 360
agctcc 366
<210> 83
<211> 525
<212> DNA
<213> 人工
<220>
<223> NP嫁接的HC编码构建体
<400> 83
gaagttcagc tgctggaatc tggcggcgga ctggttcaac ctggcggatc tctgagactg 60
agctgtgccg ccagcggctt tacatttggc agcggctctg gatctggctc cggaagcgga 120
tctcctgatg gtggaagcgg aggcagcctg agaagaagca gctgtttcgg cggcagaatg 180
gacagaatcg gcgcccaatc tggcctgggc tgcaacagct ttagatacgg cagctacggc 240
tccggcagtg gttccggtag tggctctgga atgagctggg ttcgacaggc ccctggcaaa 300
ggccttgaat gggtgtccgc catttctggc agcggaggct ctacctacta cgccgatagc 360
gtgaagggca gattcaccat cagccgggac aacagcaaga acaccctgta cctgcagatg 420
aactccctga gagccgagga caccgccgtg tactattgcg ccaaactgac aggcgccgag 480
tacttccagc attggggaca gggaaccctg gtcacagtct cttca 525
<210> 84
<211> 333
<212> DNA
<213> 人
<400> 84
cagtctgtgc tgacacagcc tcctagtgtg tctggcgccc ctggccagag agtgaccatc 60
agctgtaccg gcagcagctc caacatcgga gccggctatg acgtgcactg gtatcagcag 120
ctgcctggca ccgcccccaa actgctgatc tacggcaaca gcaaccggcc cagcggcgtg 180
cccgatagat tttccggcag caagagcggc accagcgcca gcctggctat tactggactg 240
caggccgagg acgaggccga ctactactgc cagagctacg acagcagcct gagcggcgtg 300
gtgtttggcg gcggaacaaa gctgaccgtg cta 333
<210> 85
<211> 98
<212> PRT
<213> 人
<400> 85
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys
<210> 86
<211> 17
<212> PRT
<213> 人
<400> 86
Ala Glu Tyr Phe Gln His Trp Gly Gln Gly Thr Leu Val Thr Val Ser
1 5 10 15
Ser
<210> 87
<211> 329
<212> PRT
<213> 人
<400> 87
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225 230 235 240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 88
<211> 99
<212> PRT
<213> 人
<400> 88
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Ser Gly
<210> 89
<211> 12
<212> PRT
<213> 人
<400> 89
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
1 5 10
<210> 90
<211> 106
<212> PRT
<213> 人
<400> 90
Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser
1 5 10 15
Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp
20 25 30
Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro
35 40 45
Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn
50 55 60
Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys
65 70 75 80
Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val
85 90 95
Glu Lys Thr Val Ala Pro Thr Glu Cys Ser
100 105
<210> 91
<211> 18
<212> PRT
<213> 人工
<220>
<223> NP变体
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可为任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (5)..(7)
<223> Xaa可为任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (11)..(13)
<223> Xaa可为任何天然存在的氨基酸
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa可为任何天然存在的氨基酸
<400> 91
Xaa Cys Phe Gly Xaa Xaa Xaa Asp Arg Ile Xaa Xaa Xaa Ser Xaa Leu
1 5 10 15
Gly Cys
<210> 92
<211> 7
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 92
Ser Gly Phe Thr Phe Ser Ser
1 5
<210> 93
<211> 10
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 93
Ser Gly Phe Thr Phe Gly Ser Gly Ser Gly
1 5 10
<210> 94
<211> 6
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 94
Gly Ser Gly Ser Gly Met
1 5
<210> 95
<211> 13
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 95
Ser Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10
<210> 96
<211> 9
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 96
Ser Gly Ser Gly Ser Gly Ser Gly Met
1 5
<210> 97
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 97
Ser Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Gly Ser Gly Gly
1 5 10 15
<210> 98
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 98
Gly Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Met
1 5 10
<210> 99
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 99
Ser Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly
1 5 10 15
Ser Gly Gly
<210> 100
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 100
Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Met
1 5 10
<210> 101
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 101
Ser Pro Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 102
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 102
Gly Ser Gly Arg Glu Val Pro Ile Ser Asn Gly Ser Gly Phe Val Val
1 5 10 15
Ala Met
<210> 103
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 103
Ser Gly Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 104
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 104
Ser Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu
1 5 10 15
Leu Thr Ala Pro Arg
20
<210> 105
<211> 24
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 105
Ser Gly Phe Thr Phe Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly
1 5 10 15
Ser Pro Asp Gly Gly Ser Gly Gly
20
<210> 106
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 106
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Met
1 5 10 15
<210> 107
<211> 25
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 107
Ser Gly Phe Thr Phe Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys
1 5 10 15
Leu Arg Ala Leu Leu Thr Ala Pro Arg
20 25
<210> 108
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 108
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Met
1 5 10
<210> 109
<211> 4
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 109
Ile Ser Gly Ser
1
<210> 110
<211> 4
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 110
Gly Gly Ser Thr
1
<210> 111
<211> 8
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 111
Ile Ser Gly Ser Gly Ser Gly Ser
1 5
<210> 112
<211> 8
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 112
Gly Ser Gly Ser Gly Gly Ser Thr
1 5
<210> 113
<211> 9
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 113
Ile Ser Gly Ser Gly Ser Gly Ser Gly
1 5
<210> 114
<211> 10
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 114
Gly Ser Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 115
<211> 11
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 115
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly
1 5 10
<210> 116
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 116
Gly Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 117
<211> 12
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 117
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly
1 5 10
<210> 118
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 118
Gly Glu Lys Glu Lys Glu Lys Val Ser Thr Ala Val Gly Ser Thr
1 5 10 15
<210> 119
<211> 13
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 119
Ile Ser Gly Ser Ala Val Val Asn Gly Gly Ser Gly Gly
1 5 10
<210> 120
<211> 9
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 120
Gly Lys Ile Ala Ile Gly Gly Ser Thr
1 5
<210> 121
<211> 14
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 121
Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Gly Gly
1 5 10
<210> 122
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 122
Gly Ser Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser Thr
1 5 10
<210> 123
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 123
Ile Ser Gly Ser Val Val Val Thr Ser His Gly Gly Ser Gly Gly
1 5 10 15
<210> 124
<211> 10
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 124
Gly Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 125
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 125
Ile Ser Gly Ser Ala Val Val Asn Val Arg Gly Gly Ser Gly Gly
1 5 10 15
<210> 126
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 126
Gly Gly Asp Lys Ile Ala Ile Gly Gly Ser Thr
1 5 10
<210> 127
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 127
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Ser Gly Gly
1 5 10 15
<210> 128
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 128
Ile Ser Gly Leu Ala Val Gln Ile Arg Arg Gly Gly Ser Gly Gly
1 5 10 15
<210> 129
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 129
Gly Gly Ser Gly Arg Glu Thr Leu Thr Leu Tyr Val Gly Ser Thr
1 5 10 15
<210> 130
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 130
Ile Ser Gly Ser Ala Val Val Asn Val Arg Ala Gly Gly Ser Gly Gly
1 5 10 15
<210> 131
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 131
Ile Ser Gly Ser Tyr Ala Met Ser Trp Val Arg Gly Gly Ser Gly Gly
1 5 10 15
<210> 132
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 132
Gly Ser Tyr Ala Met Ser Trp Val Arg Gln Gly Ser Thr
1 5 10
<210> 133
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 133
Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro Gly Gly
1 5 10 15
<210> 134
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 134
Gly Ser Asn Pro Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser Thr
1 5 10 15
<210> 135
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 135
Ile Ser Gly Ser Ala Val Val Asn Val Arg Ala Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 136
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 136
Gly Ser Gly Asp Lys Ile Ala Ile Gly Gly Ser Thr
1 5 10
<210> 137
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 137
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 138
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 138
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Ser Gly
1 5 10 15
Gly
<210> 139
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 139
Ile Ser Gly Ser Val Val Val Thr Ser His Gln Ala Pro Gly Ser Gly
1 5 10 15
Gly
<210> 140
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 140
Gly Ser Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr Gly Ser Thr
1 5 10 15
<210> 141
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 141
Ile Ser Gly Arg Tyr Asn Ile Leu Lys Ile Gln Lys Val Gly Ser Gly
1 5 10 15
Gly
<210> 142
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 142
Gly Gly Ser Gly Glu Tyr Leu Ile Thr Tyr Gln Ile Met Gly Ser Thr
1 5 10 15
<210> 143
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 143
Ile Ser Gly Arg Gln Leu Leu Phe Cys Arg Val Thr Leu Gly Ser Gly
1 5 10 15
Gly
<210> 144
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 144
Gly Gly Ser Gly Glu Gln Ala Tyr Pro Glu Tyr Leu Ile Thr Tyr Gly
1 5 10 15
Ser Thr
<210> 145
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 145
Ile Ser Val Val Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly Ser
1 5 10 15
Gly Gly
<210> 146
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 146
Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Ser Thr
1 5 10
<210> 147
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 147
Ile Ser Gly Val Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly Ser
1 5 10 15
Gly Gly
<210> 148
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 148
Gly Glu Lys Lys Lys Leu Lys Ser Leu Gly Ser Thr
1 5 10
<210> 149
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 149
Gly Glu Lys Lys Lys Leu Lys Ser Gly Gly Ser Thr
1 5 10
<210> 150
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 150
Ile Ser Gly Ser Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly Ser
1 5 10 15
Gly Gly
<210> 151
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 151
Gly Glu Lys Lys Lys Gly Lys Ser Gly Gly Ser Thr
1 5 10
<210> 152
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 152
Ile Ser Val Val Val Thr Ser His Gln Ala Pro Gly Ser Gly Gly Ser
1 5 10 15
Gly Gly
<210> 153
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 153
Ile Ser Val Val Val Thr Ser His Gln Ala Pro Thr Ser Gly Gly Ser
1 5 10 15
Gly Gly
<210> 154
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 154
Ile Ser Val Val Val Thr Ser His Gln Ser Pro Thr Pro Gly Gly Ser
1 5 10 15
Gly Gly
<210> 155
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 155
Gly Gly Ser Thr Pro Leu Lys Ser Leu Ala Ser Thr
1 5 10
<210> 156
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 156
Gly Ser Thr Pro Lys Leu Lys Ser Leu Ala Ser Thr
1 5 10
<210> 157
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 157
Ile Ser Val Val Val Thr Ser His Pro Thr Pro Gly Glu Gly Gly Ser
1 5 10 15
Gly Gly
<210> 158
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 158
Ile Ser Val Val Val Thr Ser His Gln Ala Pro Ser Pro Gly Ser Thr
1 5 10 15
Gly Gly
<210> 159
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 159
Ile Ser Val Val Val Thr Ser His Gln Ala Asn Gly Ser Gly Gly Ser
1 5 10 15
Gly Gly
<210> 160
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 160
Ile Ser Gly Ser Ala Val Val Asn Val Arg Ala Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 161
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 161
Gly Ser Lys Gly Asp Lys Ile Ala Ile Gly Gly Ser Thr
1 5 10
<210> 162
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 162
Ile Ser Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 163
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 163
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Ser Thr
1 5 10
<210> 164
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 164
Ile Ser Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 165
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 165
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Ser Thr
1 5 10
<210> 166
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 166
Ile Ser Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu Thr Ala
1 5 10 15
Pro Gly
<210> 167
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 167
Gly Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 168
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 168
Ile Ser Gly Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Gly Gly Ser
1 5 10 15
Gly Gly
<210> 169
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 169
Gly Ser Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Gly Ser Thr
1 5 10 15
<210> 170
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 170
Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro Gly Ser
1 5 10 15
Gly Gly
<210> 171
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 171
Ile His Pro Leu Gln Asn Arg Trp Ala Leu Trp Phe Phe Lys Gly Ser
1 5 10 15
Gly Gly
<210> 172
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 172
Gly Gly Ser Gly Asn Leu Arg Leu Ile Ser Lys Phe Asp Thr Val Thr
1 5 10 15
<210> 173
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 173
Ile Ser Gly Ser Val Thr Ile Phe Ser Leu Ala Thr Asn Glu Gly Ser
1 5 10 15
Gly Gly
<210> 174
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 174
Gly Gly Ser Gly Lys Thr Thr Trp His Arg Ile Ser Val Phe Gly Gly
1 5 10 15
Ser Thr
<210> 175
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 175
Ile Tyr Leu Glu Gly Lys Ile Asp Tyr Gly Glu Tyr Met Asp Gly Ser
1 5 10 15
Gly Gly
<210> 176
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 176
Gly Gly Ser Asn Val Arg Arg Gln Ala Thr Thr Ile Ile Ala Asp Asn
1 5 10 15
Ile Thr
<210> 177
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 177
Ile Ser Gly Ser Val Gln Gly Ile Ile Asn Phe Glu Gln Lys Gly Ser
1 5 10 15
Gly Gly
<210> 178
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 178
Gly Gly Ser Gly Pro Val Lys Val Trp Gly Ser Ile Lys Gly Gly Gly
1 5 10 15
Ser Thr
<210> 179
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 179
Ile Ser Gly Val Val Val Thr Ser His Gln Ala Pro Gly Glu Gly Gly
1 5 10 15
Ser Gly Gly
<210> 180
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 180
Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Gly Ser Thr
1 5 10
<210> 181
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 181
Ile Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 182
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 182
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Ser Thr
1 5 10
<210> 183
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 183
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 184
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 184
Gly Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 185
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 185
Ile Ser Gly Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 186
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 186
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Ser Thr
1 5 10
<210> 187
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 187
Ile Ser Gly Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 188
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 188
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Ser Thr
1 5 10
<210> 189
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 189
Ile Ser Gly Ser Val Val Val Thr Ser His Gln Ala Pro Gly Gly Gly
1 5 10 15
Ser Gly Gly
<210> 190
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 190
Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr Gly Ser Thr
1 5 10
<210> 191
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 191
Gly Glu Lys Pro Lys Pro Lys Pro Leu Ala Tyr Gly Ser Thr
1 5 10
<210> 192
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 192
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Ser Thr
1 5 10
<210> 193
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 193
Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Pro Gly Gly
1 5 10 15
Ser Gly Gly
<210> 194
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 194
Ile Ser Gly Asp Ile Tyr Leu Ala Ile Asn Ile Thr Asn Gly Glu Gly
1 5 10 15
Ser Gly Gly
<210> 195
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 195
Gly Gly Ser Gly Asp Ile Tyr Leu Ala Ile Asn Ile Thr Asn Gly Glu
1 5 10 15
Ser Thr
<210> 196
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 196
Ile Ser Gly Ser Ala Thr Lys Ala Val Ser Val Leu Lys Gly Asp Gly
1 5 10 15
Ser Gly Gly
<210> 197
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 197
Gly Gly Ser Gly Val Gln Gly Ile Ile Asn Phe Glu Gln Lys Gly Gly
1 5 10 15
Ser Thr
<210> 198
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 198
Ile Ser Gly Ser Val Pro Lys Glu Lys Glu Lys Glu Lys Val Ser Thr
1 5 10 15
Ala Val Gly Gly
20
<210> 199
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 199
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10
<210> 200
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 200
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10 15
<210> 201
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 201
Ile Ser Gly Ser Ser Gly Ala Val Val Asn Val Arg Ala Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 202
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 202
Gly Ser Lys Gly Asp Lys Ile Ala Ile Trp Thr Thr Gly Ser Thr
1 5 10 15
<210> 203
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 203
Ile Ser Gly Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 204
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 204
Ile Ser Gly Ser Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 205
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 205
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Gly Ser Thr
1 5 10 15
<210> 206
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 206
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 207
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 207
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 208
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 208
Gly Ser Tyr Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10 15
<210> 209
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 209
Ile Ser Thr Gln Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 210
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 210
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Thr
1 5 10 15
<210> 211
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 211
Ile Ser Gly Ser Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 212
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 212
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Gly Ser Thr
1 5 10 15
<210> 213
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 213
Ile Ser Gly Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 214
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 214
Gly Ser Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Gly Ser Thr
1 5 10 15
<210> 215
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 215
Ile Ser Ala Val Gln Val Lys Leu Glu Leu Gly His Arg Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 216
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 216
Gly Ser Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Ser Thr
1 5 10 15
<210> 217
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 217
Ile Ser Gly Phe Ile Leu Pro Ile Glu Val Tyr Phe Lys Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 218
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 218
Gly Ser Pro Arg Lys Val Arg Phe Asp Tyr Asp Leu Phe Ser Thr
1 5 10 15
<210> 219
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 219
Ile Ser Gly Ser Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 220
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 220
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Gly Ser Thr
1 5 10 15
<210> 221
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 221
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10 15
<210> 222
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 222
Ile Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu
1 5 10 15
Thr Ala Pro Arg
20
<210> 223
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 223
Gly Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Ser Thr
1 5 10 15
<210> 224
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 224
Ile Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu
1 5 10 15
Thr Ala Pro Gly
20
<210> 225
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 225
Gly Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Thr
1 5 10 15
<210> 226
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 226
Ile Ser Gly Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 227
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 227
Gly Ser Lys Thr His Thr Ser Pro Pro Ser Pro Gly Gly Ser Thr
1 5 10 15
<210> 228
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 228
Ile Ser Gly Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 229
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 229
Gly Ser Tyr Ser Ser Tyr Ala Met Ser Trp Val Arg Gly Gly Ser Thr
1 5 10 15
<210> 230
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 230
Gly Ser Tyr Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Gly Ser Thr
1 5 10 15
<210> 231
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 231
Ile Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 232
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 232
Ile Ser Gly Ser Pro Asn Pro Asn Pro Asn Pro Asn Pro Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 233
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 233
Gly Ser Tyr Pro Asn Pro Asn Pro Asn Pro Asn Pro Ser Gly Ser Thr
1 5 10 15
<210> 234
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 234
Ile Ser Gly Pro Asn Pro Asn Lys Asn Pro Asn Pro Asn Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 235
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 235
Gly Ser Tyr Asn Pro Asn Glu Asn Pro Asn Pro Asn Pro Gly Ser Thr
1 5 10 15
<210> 236
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 236
Ile Ser Gly Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 237
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 237
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Gly Ser Thr
1 5 10 15
<210> 238
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 238
Ile Ser Gly Ser Val Val Val Thr Ser His Gln Ala Pro Gly Gly Ser
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 239
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 239
Ile Ser Gly Ser Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 240
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 240
Gly Ser Gly Arg Glu Val Pro Ile Ser Asn Gly Ser Gly Gly Ser Thr
1 5 10 15
<210> 241
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 241
Ile Ser Gly Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 242
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 242
Ile Ser Pro Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 243
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 243
Gly Ser Gly Arg Glu Val Pro Ile Ser Asn Gly Ser Gly Phe Ser Thr
1 5 10 15
<210> 244
<211> 11
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 244
Cys Ala Lys Ser Pro Asp Gly Gly Ser Gly Gly
1 5 10
<210> 245
<211> 4
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 245
Gly Ser Tyr Gly
1
<210> 246
<211> 9
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 246
Gly Ser Tyr Gln His Trp Gly Gln Gly
1 5
<210> 247
<211> 13
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 247
Cys Ala Lys Val His Gln Glu Thr Gly Gly Ser Gly Gly
1 5 10
<210> 248
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 248
Gly Ser Trp His Val Gln His Trp Gly Gln Gly
1 5 10
<210> 249
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 249
Cys Ala Lys Val His Gln Glu Thr Pro Asp Gly Gly Ser Gly Gly
1 5 10 15
<210> 250
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 250
Gly Ser Tyr Glu Trp His Val Gln His Trp Gly Gln Gly
1 5 10
<210> 251
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 251
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Gly Gly
1 5 10 15
<210> 252
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 252
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
1 5 10 15
Gly Gln Gly
<210> 253
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 253
Cys Thr Ser Val His Gln Glu Thr Ser Ser Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 254
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 254
Gly Ser Tyr Ser Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly
1 5 10 15
<210> 255
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 255
Cys Ala Lys Thr His Thr Ser Pro Pro Ser Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 256
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 256
Gly Ser Ser Pro Pro Ser Pro Tyr Phe Gln His Trp Gly Gln Gly
1 5 10 15
<210> 257
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 257
Cys Thr Ser Val His Gln Glu Thr Lys Ser Ser Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 258
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 258
Gly Ser Tyr Ser Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln Gly
1 5 10 15
<210> 259
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 259
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly
<210> 260
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 260
Cys Thr Ser Val His Gln Glu Thr Lys Lys Ser Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 261
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 261
Gly Ser Tyr Ser Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly Gln
1 5 10 15
Gly
<210> 262
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 262
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Gly Gly
1 5 10 15
Ser Gly Gly
<210> 263
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 263
Cys Thr Ser Val His Gln Glu Thr Lys Lys Gln Ser Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 264
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 264
Gly Ser Tyr Ser Tyr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly
1 5 10 15
Gln Gly
<210> 265
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 265
Cys Ala Lys Val His Pro Asn Pro Asn Pro Asn Pro Asn Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 266
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 266
Gly Ser Asn Pro Asn Pro Asn Pro Asn Pro His Val Asp Val Trp Gly
1 5 10 15
Gln Gly
<210> 267
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 267
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly
20
<210> 268
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 268
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 269
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 269
Cys Ala Lys Leu Thr Val Val Val Thr Ser His Gln Ala Pro Gly Glu
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 270
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 270
Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr Phe Gln His Trp Gly
1 5 10 15
Gln Gly
<210> 271
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 271
Cys Ala Lys Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 272
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 272
Gly Ser Lys Thr His Thr Ser Pro Pro Ser Pro Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 273
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 273
Cys Ala Lys Val Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 274
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 274
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Val Gln His Trp Gly Gln
1 5 10 15
Gly
<210> 275
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 275
Cys Ala Lys Val His Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 276
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 276
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr His Val Gln His Trp Gly Gln
1 5 10 15
Gly
<210> 277
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 277
Cys Ala Lys Leu Thr Val Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 278
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 278
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 279
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 279
Cys Ala Lys Leu Thr Ala Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 280
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 280
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Asn Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 281
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 281
Cys Ala Lys Gly Ile Thr Gly Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 282
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 282
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Ala Glu Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 283
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 283
Gly Ser Tyr Asp Tyr Val Trp Gly Ser Tyr Ala Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 284
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 284
Cys Ala Lys Leu Thr Ser Val Val Val Thr Ser His Gln Ala Pro Gly
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 285
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 285
Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 286
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 286
Cys Ala Lys Val His Pro Asn Pro Asn Pro Asn Pro Asn Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 287
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 287
Gly Ser Tyr Asn Pro Asn Pro Asn Pro Asn Pro His Val Asp Val Trp
1 5 10 15
Gly Gln Gly
<210> 288
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 288
Cys Ala Lys Leu Thr Gln Val Lys Leu Glu Leu Gly His Arg Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 289
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 289
Gly Ser Asn His Leu Arg Ser Glu Lys Leu Thr Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 290
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 290
Cys Ala Lys Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 291
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 291
Cys Ala Lys Thr Gln Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 292
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 292
Gly Ser Asn Thr Lys Val Asp Lys Lys Ala Glu Tyr Phe Gln His Trp
1 5 10 15
Gly Gln Gly
<210> 293
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 293
Gly Ser Tyr Ser Tyr Thr Thr Tyr Asn Tyr Glu Trp His Val Asp Val
1 5 10 15
Trp Gly Gln Gly
20
<210> 294
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 294
Cys Ala Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 295
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 295
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val His
1 5 10 15
Trp Gly Gln Gly
20
<210> 296
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 296
Cys Ala Lys Leu Thr Ala Glu Glu Trp Lys Lys Lys Tyr Glu Lys Glu
1 5 10 15
Lys Glu Lys Asn Lys Gly Ser
20
<210> 297
<211> 21
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 297
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ala Glu Tyr Phe Gln
1 5 10 15
His Trp Gly Gln Gly
20
<210> 298
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 298
Cys Ala Asp Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg
1 5 10 15
Ala Leu Leu Thr Ala Pro Arg
20
<210> 299
<211> 21
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 299
Gly Ser Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Tyr Phe Gln
1 5 10 15
His Trp Gly Gln Gly
20
<210> 300
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 300
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Tyr Gln Ser Ser
1 5 10 15
Pro Asp Gly Gly Ser Gly Gly
20
<210> 301
<211> 21
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 301
Gly Ser Tyr Ser Tyr Thr Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp
1 5 10 15
Val Trp Gly Gln Gly
20
<210> 302
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 302
Cys Ala Lys Leu Thr Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg
1 5 10 15
Ala Leu Leu Thr Ala Pro Arg
20
<210> 303
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 303
Cys Ala Lys Leu Thr Ala Val Gln Val Lys Leu Glu Leu Gly His Arg
1 5 10 15
Pro Asp Gly Gly Ser Gly Gly
20
<210> 304
<211> 25
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 304
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Tyr Gln
1 5 10 15
Ser Ser Pro Asp Gly Gly Ser Gly Gly
20 25
<210> 305
<211> 23
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 305
Gly Ser Tyr Ser Tyr Thr Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His
1 5 10 15
Val Asp Val Trp Gly Gln Gly
20
<210> 306
<211> 25
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 306
Cys Ala Lys Leu Thr Ala Val Gln Val Lys Leu Glu Leu Gly His Arg
1 5 10 15
Ala Gln Pro Asp Gly Gly Ser Gly Gly
20 25
<210> 307
<211> 23
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 307
Gly Ser Pro Val Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Tyr
1 5 10 15
Phe Gln His Trp Gly Gln Gly
20
<210> 308
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 308
Ser Ser Ser Asn Ile Gly Ser Lys Leu Arg Ala Leu Leu Thr Ala Pro
1 5 10 15
Arg
<210> 309
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 309
Gly Ser Gly Ser Gly Gly Ser Gly Gly Ser Gly Ser Gly Tyr Asp
1 5 10 15
<210> 310
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 310
Gly Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asp
1 5 10
<210> 311
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 311
Ser Ser Leu Gly Gln Ile Gln Leu Thr Ile Arg His Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 312
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 312
Gly Ser Asn Lys Leu Ile Val Val Val His Ala Ser Arg Asn Leu Ile
1 5 10 15
Gly Tyr Asp
<210> 313
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 313
Ser Pro Leu Gly Gln Ile Gln Leu Thr Ile Arg His Ser Ser Gln Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 314
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 314
Gly Ser Arg Asn Lys Leu Ile Val Val Val His Ala Ser Arg Asn Leu
1 5 10 15
Ile Ala Tyr Asp
20
<210> 315
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 315
Ser Ser Leu Gly Gln Ile Gln Leu Thr Ile Arg His Ser Ser Gln Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 316
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 316
Gly Ser Arg Asn Lys Leu Ile Val Val Val His Ala Ser Arg Asn Leu
1 5 10 15
Ile Gly Tyr Asp
20
<210> 317
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 317
Ser Ser Ser Asn Ile Gly Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala
1 5 10 15
Leu Leu Thr Ala Pro Arg
20
<210> 318
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 318
Gly Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu
1 5 10 15
Leu Thr Ala Asp
20
<210> 319
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 319
Gly Ser Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Ser Gly
1 5 10 15
Ser Gly Tyr Asp
20
<210> 320
<211> 24
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 320
Ser Ser Ser Asn Ile Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly
1 5 10 15
Ser Pro Asp Gly Gly Ser Gly Gly
20
<210> 321
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 321
Gly Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Tyr Asp
1 5 10 15
<210> 322
<211> 7
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 322
Asn Ser Asn Arg Pro Ser Gly
1 5
<210> 323
<211> 6
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 323
Tyr Gly Gly Ser Gly Ser
1 5
<210> 324
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 324
Gly Ser Gly Ser Asn Ser Asn Arg Pro Ser Gly
1 5 10
<210> 325
<211> 13
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 325
Tyr Gly Lys Thr His Thr Ser Pro Pro Ser Pro Gly Gly
1 5 10
<210> 326
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 326
Gly Gly Lys Thr His Thr Ser Pro Pro Ser Pro Gly Asn Arg Pro Ser
1 5 10 15
Gly
<210> 327
<211> 14
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 327
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly
1 5 10
<210> 328
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 328
Gly Gly Lys Thr His Thr Ser Pro Pro Ser Pro Ser Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 329
<211> 14
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 329
Tyr Gly Ser Lys Thr His Thr Ser Pro Pro Ser Pro Gly Gly
1 5 10
<210> 330
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 330
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly Ser Gly Gly
1 5 10 15
<210> 331
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 331
Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro Ser Gly
1 5 10 15
<210> 332
<211> 16
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 332
Tyr Gly Ser Ser Asp Lys Thr His Thr Ser Pro Pro Ser Pro Gly Gly
1 5 10 15
<210> 333
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 333
Gly Gly Ser Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn
1 5 10 15
Arg Pro Ser Gly
20
<210> 334
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 334
Tyr Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 335
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 335
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Asn Arg Pro Ser Gly
1 5 10 15
<210> 336
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 336
Tyr Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 337
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 337
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Asn Arg Pro Ser Gly
1 5 10 15
<210> 338
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 338
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly
<210> 339
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 339
Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro Ser
1 5 10 15
Gly
<210> 340
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 340
Tyr Gly Val Pro Lys Glu Lys Glu Lys Glu Lys Val Ser Thr Ala Val
1 5 10 15
Gly Gly
<210> 341
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 341
Gly Ser Ala Pro Leu Glu Val Pro Lys Glu Lys Glu Lys Glu Lys Val
1 5 10 15
Gly
<210> 342
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 342
Tyr Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 343
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 343
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Asn Arg Pro Ser
1 5 10 15
Gly
<210> 344
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 344
Tyr Gly Gly Ser Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 345
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 345
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly
1 5 10 15
Gly Gly
<210> 346
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 346
Gly Ser Tyr Glu Lys Glu Lys Glu Lys Asn Lys Thr Leu Lys Asn Val
1 5 10 15
Gly
<210> 347
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 347
Tyr Gly Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 348
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 348
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Asn Arg Pro Ser
1 5 10 15
Gly
<210> 349
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 349
Tyr Gly Ala Glu Glu Trp Lys Lys Lys Tyr Glu Lys Glu Lys Glu Lys
1 5 10 15
Gly Gly
<210> 350
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 350
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly
<210> 351
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 351
Tyr Gly Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 352
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 352
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Asn Arg Pro Ser
1 5 10 15
Gly
<210> 353
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 353
Tyr Gly Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu Thr Ala
1 5 10 15
Pro Gly
<210> 354
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 354
Gly Ser Asp Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 355
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 355
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 356
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 356
Tyr Gly Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 357
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 357
Gly Ser Asp Arg Phe Ser Gly Ser Lys Ser Gly Gly Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 358
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 358
Tyr Gly Gly Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 359
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 359
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Gly Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 360
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 360
Tyr Thr Gln Thr Tyr Ile Ser Asn Val Asn His Lys Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 361
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 361
Gly Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Asn Arg Pro
1 5 10 15
Ser Gly
<210> 362
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 362
Tyr Gly Gly Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 363
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 363
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 364
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 364
Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 365
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 365
Gly Ser Tyr Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn Arg Pro
1 5 10 15
Ser Gly
<210> 366
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 366
Tyr Gly Ser Gln Val Lys Leu Glu Leu Gly His Arg Ala Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 367
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 367
Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu Thr Ser Gly Asn Arg
1 5 10 15
Pro Ser Gly
<210> 368
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 368
Tyr Pro Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 369
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 369
Gly Ser Gly Arg Glu Val Pro Ile Ser Asn Gly Ser Gly Phe Asn Arg
1 5 10 15
Pro Ser Gly
<210> 370
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 370
Tyr Gly Gly Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 371
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 371
Gly Ser Gly Arg Glu Val Pro Ile Ser Asn Gly Ser Gly Gly Asn Arg
1 5 10 15
Pro Ser Gly
<210> 372
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 372
Tyr Gly Ala Val Val Tyr Ile Glu Ile Leu Asp Arg His Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 373
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 373
Tyr Gly Ser Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu
1 5 10 15
Thr Ala Pro Arg
20
<210> 374
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 374
Gly Ser Asp Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Ser Gly Asn
1 5 10 15
Arg Pro Ser Gly
20
<210> 375
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 375
Tyr Gly Ser Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu
1 5 10 15
Thr Ala Pro Gly
20
<210> 376
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 376
Tyr Gly Ser Ala Val Gln Val Lys Leu Glu Leu Gly His Arg Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 377
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 377
Gly Ser Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Ser Gly Asn
1 5 10 15
Arg Pro Ser Gly
20
<210> 378
<211> 15
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 378
Cys Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly Gly Ser Gly Gly
1 5 10 15
<210> 379
<211> 10
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 379
Gly Ser Gly Ser Gly Ser Gly Ser Gly Phe
1 5 10
<210> 380
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 380
Cys Gln Ser Tyr Asp Ile Leu Pro Ile Glu Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 381
<211> 11
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 381
Gly Ser Arg Phe Asp Tyr Asp Gly Val Val Phe
1 5 10
<210> 382
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 382
Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly Gly Ser Gly
1 5 10 15
Gly
<210> 383
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 383
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Phe
1 5 10
<210> 384
<211> 17
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 384
Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly
<210> 385
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 385
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Phe
1 5 10
<210> 386
<211> 18
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 386
Cys Gln Ser Tyr Asp Lys Leu Glu Leu Gly His Pro Asp Gly Gly Ser
1 5 10 15
Gly Gly
<210> 387
<211> 12
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 387
Gly Ser His Leu Arg Ser Glu Lys Gly Val Val Phe
1 5 10
<210> 388
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 388
Cys Gln Ser Tyr Asp Ile Leu Pro Ile Glu Val Tyr Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 389
<211> 13
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 389
Gly Ser Lys Val Arg Phe Asp Tyr Asp Gly Val Val Phe
1 5 10
<210> 390
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 390
Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Pro Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 391
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 391
Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Asp Gly Gly
1 5 10 15
Ser Gly Gly
<210> 392
<211> 19
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 392
Cys Gln Ser Tyr Asp Gly Phe Ile Leu Pro Ile Glu Val Tyr Gly Gly
1 5 10 15
Ser Gly Gly
<210> 393
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 393
Gly Ser Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Val Val Phe
1 5 10 15
<210> 394
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 394
Cys Gln Ser Tyr Asp Lys Leu Glu Leu Gly His Arg Ala Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 395
<211> 14
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 395
Gly Ser Val Asn His Leu Arg Ser Glu Lys Gly Val Val Phe
1 5 10
<210> 396
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 396
Cys Gln Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 397
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 397
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Val Phe
1 5 10 15
<210> 398
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 398
Cys Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 399
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 399
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Phe
1 5 10 15
<210> 400
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 400
Cys Gln Ser Tyr Asp Pro Asn Pro Asn Pro Asn Pro Asn Pro Asp Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 401
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 401
Gly Ser Asn Pro Asn Pro Asn Pro Asn Pro Ser Gly Val Val Phe
1 5 10 15
<210> 402
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 402
Cys Ala Ala Trp Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 403
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 403
Gly Ser Asn Pro Asn Pro Asn Pro Asn Pro Asn Pro Asn Val Phe
1 5 10 15
<210> 404
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 404
Cys Gln Ser Tyr Asp Gln Val Lys Leu Glu Leu Gly His Arg Ala Gly
1 5 10 15
Gly Ser Gly Gly
20
<210> 405
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 405
Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu Thr Gly Val Val Phe
1 5 10 15
<210> 406
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 406
Cys Gln Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 407
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 407
Cys Gln Ser Tyr Asp Gln Val Lys Leu Glu Leu Gly His Arg Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 408
<211> 15
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 408
Gly Ser Asn His Leu Arg Ser Glu Lys Leu Thr Gly Val Val Phe
1 5 10 15
<210> 409
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 409
Cys Gln Ser Tyr Asp Gly Phe Ile Leu Pro Ile Glu Val Tyr Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 410
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 410
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Phe
1 5 10 15
<210> 411
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 411
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Val Val Phe
1 5 10 15
<210> 412
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 412
Cys Gly Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly
20
<210> 413
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 413
Gly Ser Tyr Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Gly Phe
1 5 10 15
<210> 414
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 414
Cys Gln Ser Tyr Asp Ser Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala
1 5 10 15
Leu Leu Thr Ala Pro Arg
20
<210> 415
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 415
Cys Gln Ser Ala Val Gln Val Lys Leu Glu Leu Gly His Arg Ala Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 416
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 416
Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Val Phe
1 5 10 15
<210> 417
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 417
Cys Gln Ser Tyr Asp Gln Val Lys Leu Glu Leu Gly His Arg Ala Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 418
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 418
Cys Gln Ser Tyr Asp Gly Phe Ile Leu Pro Ile Glu Val Tyr Phe Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 419
<211> 16
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 419
Gly Ser Arg Lys Val Arg Phe Asp Tyr Asp Leu Phe Gly Val Val Phe
1 5 10 15
<210> 420
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 420
Cys Gln Ser Tyr Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro
1 5 10 15
Asp Gly Gly Ser Gly Gly
20
<210> 421
<211> 17
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 421
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Gly Val Val
1 5 10 15
Phe
<210> 422
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 422
Cys Gln Ser Tyr Asp Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser
1 5 10 15
Pro Asp Gly Gly Ser Gly Gly
20
<210> 423
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 423
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Ser Gly Val
1 5 10 15
Val Phe
<210> 424
<211> 24
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 424
Cys Gln Ser Tyr Asp Ala Val Gln Val Lys Leu Glu Leu Gly His Arg
1 5 10 15
Ala Pro Asp Gly Gly Ser Gly Gly
20
<210> 425
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 425
Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu Thr Phe Asn Gly Val
1 5 10 15
Val Phe
<210> 426
<211> 25
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 426
Cys Gln Ser Tyr Asp Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys
1 5 10 15
Leu Arg Ala Leu Leu Thr Ala Pro Arg
20 25
<210> 427
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 427
Gly Ser Gly Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu Thr Gly
1 5 10 15
Val Val Phe
<210> 428
<211> 21
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 428
Gly Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys Leu Arg Ala Leu Leu
1 5 10 15
Thr Ala Val Val Phe
20
<210> 429
<211> 25
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 429
Cys Gln Ser Tyr Asp Ser Ser Asp Arg Ser Ala Leu Leu Lys Ser Lys
1 5 10 15
Leu Arg Ala Leu Leu Thr Ala Pro Glu
20 25
<210> 430
<211> 23
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 430
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly Ser Gly
20
<210> 431
<211> 20
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 431
Gly Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val
1 5 10 15
Trp Gly Gln Gly
20
<210> 432
<211> 18
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 432
Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp Gly
1 5 10 15
Gln Gly
<210> 433
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 433
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp
1 5 10 15
Gly Gly Ser Gly Gly Ser
20
<210> 434
<211> 24
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 434
Gly Ser Gly Gly Tyr Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp
1 5 10 15
His Val Asp Val Trp Gly Gln Gly
20
<210> 435
<211> 21
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 435
Cys Gln Ser Tyr Asp Gln Val Lys Leu Glu Leu Gly His Arg Ala Gly
1 5 10 15
Gly Ser Gly Gly Ser
20
<210> 436
<211> 21
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 436
Gly Ser Gly Gly Ser Gly Ser Val Asn His Leu Arg Ser Glu Lys Leu
1 5 10 15
Thr Gly Val Val Phe
20
<210> 437
<211> 24
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 437
Gly Ser Gly Gly Ser Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp
1 5 10 15
His Val Asp Val Trp Gly Gln Gly
20
<210> 438
<211> 23
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 438
Gly Gly Gly Ser Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His
1 5 10 15
Val Asp Val Trp Gly Gln Gly
20
<210> 439
<211> 22
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 439
Cys Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Tyr
1 5 10 15
Lys Gly Ala Asn Lys Lys
20
<210> 440
<211> 20
<212> PRT
<213> 人工
<220>
<223> N端序列（含参考aa）
<400> 440
Ile Ser Gly Ser Val Val Val Thr Ser His Gln Ala Pro Gly Gly Gly
1 5 10 15
Ser Gly Gly Ser
20
<210> 441
<211> 19
<212> PRT
<213> 人工
<220>
<223> C端序列（含参考aa）
<400> 441
Gly Ser Gly Gly Ser Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr
1 5 10 15
Gly Ser Thr
<210> 442
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 442
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Met Val Gln Gly Ser Gly Cys Phe Gly Arg Lys Met
115 120 125
Asp Arg Ile Ser Ser Ser Ser Gly Leu Gly Cys Lys Val Leu Arg Arg
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 443
<211> 500
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 443
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Val Val Val Thr Ser His Gln Ala Pro Gly
50 55 60
Gly Gly Ser Gly Gly Met Val Gln Gly Ser Gly Cys Phe Gly Arg Lys
65 70 75 80
Met Asp Arg Ile Ser Ser Ser Ser Gly Leu Gly Cys Lys Val Leu Arg
85 90 95
Arg Gly Glu Lys Lys Lys Leu Lys Ser Leu Ala Tyr Gly Ser Thr Tyr
100 105 110
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
115 120 125
Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
130 135 140
Ala Val Tyr Tyr Cys Ala Lys Leu Thr Gly Ala Glu Tyr Phe Gln His
145 150 155 160
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
165 170 175
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
180 185 190
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
195 200 205
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
210 215 220
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
225 230 235 240
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
245 250 255
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
260 265 270
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
275 280 285
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
290 295 300
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
305 310 315 320
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
325 330 335
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
340 345 350
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
355 360 365
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
370 375 380
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
385 390 395 400
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
405 410 415
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
420 425 430
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
435 440 445
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
450 455 460
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
465 470 475 480
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
485 490 495
Leu Ser Pro Gly
500
<210> 444
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 444
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Gly Ile Thr Gly Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Met Val Gln Gly Ser Gly Cys Phe Gly Arg Lys Met
115 120 125
Asp Arg Ile Ser Ser Ser Ser Gly Leu Gly Cys Lys Val Leu Arg Arg
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Ala Glu Tyr Phe Gln His Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 445
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 445
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Tyr Lys
100 105 110
Gly Ala Asn Lys Lys Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu
115 120 125
Asp Arg Ile Gly Ser Met Ser Gly Leu Gly Cys Gly Ser Gly Gly Ser
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 446
<211> 499
<212> PRT
<213> 人工
<220>
<223> NP嫁接的HC
<400> 446
Glu Val Gln Leu Leu 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 Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr 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 Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Val His Gln Glu Thr Lys Lys Tyr Gln Ser Ser Pro Asp Gly
100 105 110
Gly Ser Gly Gly Ser Gly Leu Ser Lys Gly Cys Phe Gly Leu Lys Leu
115 120 125
Asp Arg Ile Gly Ser Met Ser Gly Leu Gly Cys Gly Ser Gly Gly Tyr
130 135 140
Gly Ser Tyr Ser Tyr Thr Tyr Asn Tyr Glu Trp His Val Asp Val Trp
145 150 155 160
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
165 170 175
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
180 185 190
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
195 200 205
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
210 215 220
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
225 230 235 240
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
245 250 255
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
260 265 270
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
275 280 285
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
290 295 300
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
305 310 315 320
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
325 330 335
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
340 345 350
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
355 360 365
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
370 375 380
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
385 390 395 400
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
405 410 415
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
420 425 430
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
435 440 445
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
450 455 460
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
465 470 475 480
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
485 490 495
Ser Pro Gly
<210> 447
<211> 217
<212> PRT
<213> 人
<400> 447
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly
20 25 30
Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
35 40 45
Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser
85 90 95
Leu Asp Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly
100 105 110
Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu
115 120 125
Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe
130 135 140
Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val
145 150 155 160
Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys
165 170 175
Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser
180 185 190
His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu
195 200 205
Lys Thr Val Ala Pro Thr Glu Cys Ser
210 215
Claims (18)
1.一种抗体或其片段，其包含纳入到所述抗体或其片段的至少一个CDR区域内的至少一个异源氨基酸序列，其中所述至少一个异源氨基酸序列包含N端接头序列(Ntls)、心房利钠肽(ANP)和C端接头序列(Ctls)，其中任选地所述至少一个CDR区域的至少一部分被所述至少一个纳入其中的异源氨基酸序列所替代，其中
a)在以下中存在至少12个氨基酸残基
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res25与所述ANP的第一个氨基酸残基之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res51与所述ANP的第一个氨基酸残基之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res92与所述ANP的第一个氨基酸残基之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res26与所述ANP的第一个氨基酸残基之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res49与所述ANP的第一个氨基酸残基之间；
和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res88与所述ANP的第一个氨基酸残基之间；
并且其中
b)在所述ANP的最后一个氨基酸残基和以下之间存在至少9个氨基酸残基
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res35a；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res57；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres106；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res32；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res57；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res98。
2.根据权利要求1所述的抗体或其片段，其中所述ANP选自具有序列SEQ ID NO 23的人ANP及与其具有至少80％序列同一性的肽。
3.根据权利要求1或2所述的抗体或其片段，其中
a)所述Ntls包含
i)GS接头序列；
ii)PN接头序列；
iii)为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更特别是SEQ ID NO 1、2或4中任一个的序列，或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列；
iv)序列S EQ ID NO 6或与其具有至少60％序列同一性的序列；
v)序列SEQ ID NO 7或与其具有至少60％序列同一性的序列；
vi)序列SEQ ID NO 9或与其具有至少60％序列同一性的序列；
vii)序列SEQ ID NO 11或与其具有至少60％序列同一性的序列；
viii)序列SEQ ID NO 13或与其具有至少60％序列同一性的序列；
ix)序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；
x)序列SEQ ID NO 21或与其具有至少60％序列同一性的序列；
或
xi)其任意组合，并且其中
b)所述Ctls包含
i)GS接头序列；
ii)PN接头序列；
iii)为人IgG抗体支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，特别是为人IgG抗体的fab结构域支架的一部分的氨基酸序列，或与其具有至少80％序列同一性的序列，更特别是为SEQ ID NO 1、3或5中任一个的序列，或与SEQ ID NO 1、3或5中任一个具有至少80％序列同一性的序列；
iv)序列SEQ ID NO 6或与其具有至少60％序列同一性的序列；
v)序列SEQ ID NO 8或与其具有至少60％序列同一性的序列；
vi)序列SEQ ID NO 10或与其具有至少60％序列同一性的序列；
vii)序列SEQ ID NO 12或与其具有至少60％序列同一性的序列；
viii)序列SEQ ID NO 14或与其具有至少60％序列同一性的序列；
ix)序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；
x)序列SEQ ID NO 20或与其具有至少60％序列同一性的序列；
xi)序列SEQ ID NO 22或与其具有至少60％序列同一性的序列；
或
xii)其任意组合。
4.根据权利要求3所述的抗体或其片段，其中
i)所述Ntls和所述Ctls各自包含GS接头序列；
ii)所述Ntls和所述Ctls各自包含PN接头序列；
iii)所述Ntls和所述Ctls各自包含为人IgG抗体支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，具体地是为人IgG抗体的fab结构域支架的一部分的氨基酸序列或与其具有至少80％序列同一性的序列，更具体地所述Ntls包含SEQ ID NO 1、2或4中任一个的序列，或与SEQ ID NO 1、2或4中任一个具有至少80％序列同一性的序列，所述Ctls包含SEQ ID NO 1、3或5中任一个的序列或与SEQ ID NO 1、3或5中任一个具有至少80％序列同一性的序列；
iv)所述Ntls和所述Ctls各自包含序列SEQ ID NO 6或与其具有至少60％序列同一性的序列；
v)所述Ntls包含序列SEQ ID NO 7或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 8或与其具有至少60％序列同一性的序列；
vi)所述Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 10与其具有至少60％序列同一性的序列；
vii)所述Ntls包含序列SEQ ID NO 11或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 12或与其具有至少60％序列同一性的序列；
viii)所述Ntls包含序列SEQ ID NO 13或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 14或与其具有至少60％序列同一性的序列；
ix)所述Ntls和所述Ctls各自包含序列SEQ ID NO 15或与其具有至少60％序列同一性的序列；
x)所述Ntls包含序列SEQ ID NO 9或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 20或与其具有至少60％序列同一性的序列；或者
xi)所述Ntls包含序列SEQ ID NO 21或与其具有至少60％序列同一性的序列，所述Ctls包含序列SEQ ID NO 22或与其具有至少60％序列同一性的序列。
5.根据前述权利要求中任一项所述的抗体或其片段，其中所述Ntls还包含在其C终端处的锚定元件A1和/或其中所述Ctls还包含在其N终端处的锚定元件A2，其中A1和A2主要包含甘氨酸和丝氨酸残基，具体地其中A1和/或A2的至少60％氨基酸残基选自甘氨酸和丝氨酸残基。
6.根据前述权利要求中任一项所述的抗体或其片段，其中在以下中存在的氨基酸段包含SEQ ID NO 26至38中任一个的序列或与SEQ ID NO 26至38中任一个具有至少80％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res25与ANP的第一个氨基酸残基之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res51与ANP的第一个氨基酸残基之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res92与ANP的第一个氨基酸残基之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res26与ANP的第一个氨基酸残基之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res49与ANP的第一个氨基酸残基之间；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res88与ANP的第一个氨基酸残基之间；
并且其中在所述ANP的最后一个氨基酸残基与以下之间存在的氨基酸段包含SEQ IDNO 39至51中任一个的序列或与SEQ ID NO 39至51中任一个具有至少80％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res35a；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res57；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HCres106；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res32；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res57；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res98。
7.根据前述权利要求中任一项所述的抗体或其片段，其中所述Ntls和/或所述Ctls总共包含至少3、4、5、6、7、8、9或10个以及最多达30、28、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11或10个氨基酸残基。
8.根据前述权利要求中任一项所述的抗体或其片段，其中在以下中存在的氨基酸段包含SEQ ID NO 52至64中任一个的序列或与SEQ ID NO 52至64中任一个具有至少80％序列同一性的序列
i)在CDRH1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res25与根据Kabat的氨基酸残基HC res35a之间；
ii)在CDRH2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res51与根据Kabat的氨基酸残基HC res57之间；
iii)在CDRH3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基HC res92与根据Kabat的氨基酸残基HC res106之间；
iv)在CDRL1中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res26与根据Kabat的氨基酸残基LC res 32之间；
v)在CDRL2中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res49与根据Kabat的氨基酸残基LC res57之间；和/或
vi)在CDRL3中纳入所述异源氨基酸序列的情况下，根据Kabat的氨基酸残基LC res88与根据Kabat的氨基酸残基LC res98之间。
9.根据前述权利要求中任一项所述的抗体或其片段，包含至少一个其他利钠肽，具体地其中所述ANP和所述至少一个其他利钠肽被纳入到至少两个单独的CDR区域内，更具体地其中所述至少一个其他利钠肽选自ANP、BNP和CNP，最具体地选自BNP和CNP。
10.根据前述权利要求中任一项所述的抗体或其片段，其中所述抗体或其片段为人或人源化抗体或其片段，具体地其中所述抗体或其片段为IgG类。
11.根据前述权利要求中任一项所述的抗体或其片段，其中
(i)所述轻链包含或由氨基酸序列SEQ ID NO 66组成，所述重链包含或由SEQ ID NO67至79中任一个的氨基酸序列组成；或
(ii)所述重链包含或由氨基酸序列SEQ ID NO 65组成，所述轻链包含或由SEQ ID NO80和81中任一个的氨基酸序列组成。
12.根据前述权利要求中任一项所述的抗体片段，其中所述抗体片段选自Fab、Fab’、Fab’-SH、F(ab’)2和Fv片段；双价抗体；单域抗体(Dab)；线性抗体；单链抗体分子(ScFv)；和二硫键稳定性Fv抗体片段(dsFv)。
13.一种组合物，其包含根据权利要求1至12中任一项所述的抗体或其片段及任选地药学上可接受的载体的化合物。
14.一种编码根据权利要求1至12中任一项所述的抗体或其片段的核酸或核酸混合物。
15.一种包含根据权利要求14所述的核酸或核酸混合物的宿主细胞。
16.一种产生抗体或其片段的方法，包括在适合表达所述抗体或其片段的条件下培养根据权利要求15所述的宿主细胞。
17.根据权利要求1至12中任一项所述的抗体或其片段用于治疗方法中。
18.根据权利要求1至12中任一项所述的抗体或其片段，用于治疗心血管、肾、肺、骨骼、眼、血栓栓塞或纤维化疾病或障碍、侏儒症、软骨发育不全或其他与cGMP相关的和/或利钠肽反应性障碍。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113332423A (zh) * | 2021-05-26 | 2021-09-03 | 华中科技大学同济医学院附属协和医院 | 一种pcsk9抑制剂在心脏移植术后抗排斥反应中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| US20210139555A1 (en) | 2021-05-13 |
| AU2019250363A1 (en) | 2020-11-12 |
| IL277868A (en) | 2020-11-30 |
| PE20210020A1 (es) | 2021-01-07 |
| KR20210003787A (ko) | 2021-01-12 |
| CA3096750A1 (en) | 2019-10-17 |
| JP2024050750A (ja) | 2024-04-10 |
| SG11202009413WA (en) | 2020-10-29 |
| EP3773901A1 (en) | 2021-02-17 |
| EP3553081A1 (en) | 2019-10-16 |
| SA520420339B1 (ar) | 2024-02-26 |
| MX2020010684A (es) | 2020-11-06 |
| BR112020020037A2 (pt) | 2021-01-05 |
| TW201943734A (zh) | 2019-11-16 |
| JP2021520801A (ja) | 2021-08-26 |
| AR114481A1 (es) | 2020-09-09 |
| WO2019197470A1 (en) | 2019-10-17 |
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