CN110092837B - Uti融合蛋白 - Google Patents
Uti融合蛋白 Download PDFInfo
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- CN110092837B CN110092837B CN201910282497.3A CN201910282497A CN110092837B CN 110092837 B CN110092837 B CN 110092837B CN 201910282497 A CN201910282497 A CN 201910282497A CN 110092837 B CN110092837 B CN 110092837B
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Abstract
本发明提供UTI融合蛋白、用于产生所述融合蛋白的DNA序列,及使用所述融合蛋白的药物组合物及方法。
Description
本申请是2015年2月23日提交的同名发明专利申请201580014645.3的分案申请。
【发明领域】
本发明涉及分子生物学、药理学及医学。
【发明背景】
尿胰蛋白酶抑制剂(UTI),还称为乌司他丁、尿抑制素(uristatin/urinastatin/ulistin)、人抑制剂30(HI-30)、明京(mingin)及比库蛋白,为具有约40kD分子量的蛋白酶抑制剂。UTI存在于人尿液及血液(hUTI)中并且具有各种生理活性诸如对于丝氨酸蛋白酶家族,诸如胰蛋白酶、α-胰凝乳蛋白酶、胞浆素、组织蛋白酶-G及白细胞弹性蛋白酶的抑制效应。UTI还具有免疫调节效应,且其可下调促炎性细胞因子,诸如肿瘤坏死因子-α(TNF-α)、白介素-1(IL-1)及白介素(IL-6)的释放。另外,UTI还干扰PDGF-D(PDGF-DD)/PDGF-BBR活性二聚体介导的信号传导途径,此干扰是通过中和该二聚体来实现的。
hUTI已经收到上市授权并且一种产品在日本以商标名Miraclid销售并且从人尿液分离。事实上,从人尿液分离的hUTI当前由多个制造商销售以治疗胰腺炎及由休克造成的急性循环衰竭。
UTI首先在人体内以被称为AMBP(α1-微球蛋白/比库蛋白前体)的前体蛋白形式产生,其编码于人染色体9上。AMBP的蛋白水解产生含有143个氨基酸的游离UTI。UTI包括已知抑制丝氨酸蛋白酶的两个Kunitz结构域,其由UTI的N及C末端上的非结构化氨基酸侧接。预期两个结构域赋予蛋白酶抑制的不同特异性,这归因于涉及蛋白酶结合的不同氨基酸。通过与其他丝氨酸蛋白酶抑制剂(例如BPTI、牛胰腺胰蛋白酶抑制剂)类比的方法,可估计用于蛋白酶抑制的两个关键氨基酸包括Met26(Kunitz结构域1)及Arg88(Kunitz结构域2)。关于UTI的不同部分在抑制不同蛋白酶期间的牵涉所知甚少,但是移除Kunitz结构域1已被证明可改变蛋白酶特异性,从而揭示针对因子Xa及血浆激肽释放酶的新抑制活性。全长UTI不展示此两种蛋白酶的抑制(Morishita等人,Thrombosis Research 1994,第73卷(3/4)第193-204页)。UTI还包括两个连接糖,一个糖O连接于Ser10处并且一个糖N连接于Asn45处。UTI在啮齿动物及人中的半衰期为4-30分钟(Fries等人,International Journal ofBiochemistry and Cell Biology,2000,第32卷,第125-137页)。
UTI融合蛋白应含有氨基酸的优化序列,包括任何UTI结构域的最佳开始及终止点,且可融合至另一种蛋白质以增强性质诸如表达、纯化、半衰期及稳定性。融合配偶体的确切序列需要确定并且可包括可改变融合配偶体的功能性质的连接子、开始/终止点和/或突变的变化。
已知自尿液获得的乌司他丁的变体WO199856916、US5792629、US5407915、US5409895、US7019123及US6583108。已经公开乌司他丁的融合蛋白(及其变化形式)的概念US20080181892、US5541288及US20080255025。某些UTI融合蛋白描述于CN 103044554A中。CN103044554A的融合蛋白涉及Fc结构域中的特异性变体,大概用于避免任何Fc介导药理学作用(ADCC,CDC)。已经意外地发现具有野生型IgG1的UTI-Fc耐受良好并且提供半衰期的显著增加。另外,与CN 103044554A的UTI融合蛋白相比,本发明UTI融合蛋白,尤其SEQ ID NO:1,展现更大热稳定性。
本发明提供UTI融合蛋白、包含该融合蛋白的药物组合物、制备方法及其用途。
【发明概述】
本发明提供包含UTI结构域及融合配偶体的UTI融合蛋白,其中UTI结构域可操作地连接至融合配偶体。本发明提供包含UTI结构域及Fc结构域的UTI融合蛋白,其中UTI结构域可操作地连接至Fc结构域。本发明还提供如本文描述的分离的UTI融合蛋白。
在一些实施方案中,本发明提供UTI融合蛋白,其包含包括SEQ ID NO:1、3、5、7、9、11、13、15、17、19、21、23、25、27及29的序列。在一个实施方案中,本发明提供包含SEQ IDNO:1的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:3的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:5的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:7的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:9的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:11的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:13的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:15的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:17的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:19的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:21的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:23的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:25的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:27的UTI融合蛋白。在一个实施方案中,本发明提供包含SEQ ID NO:29的UTI融合蛋白。
根据本发明的另一实施方案,本发明提供编码UTI融合蛋白的核酸序列,所述UTI融合蛋白包括本文所述UTI融合蛋白。此外,本发明提供如SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28及30所阐述的DNA序列。在一个实施方案中,编码UTI融合蛋白的核酸进一步包括含有核酸可操作地与其连接的控制序列的载体。在另一实施方案中,本发明提供包含编码UTI融合蛋白的核酸序列的宿主细胞,如哺乳动物、昆虫、大肠杆菌或酵母细胞,且将宿主细胞保持在融合蛋白分子得以表达的条件下。
在另一实施方案中,本发明提供包含本文所述的UTI融合蛋白及药学上可接受的载体或赋形剂的药物组合物。
根据本发明的另一实施方案,提供治疗UTI相关病症的方法,其包括向有需要的患者施用有效量的本文所述的UTI融合蛋白。
即,本发明提供UTI融合蛋白作为药物的用途,包括制造药物,和本文所述的UTI融合蛋白用于治疗本文所述的UTI相关病症的用途。
【附图简述】
图1是UTI结构域结构及糖基化位点。
图2是展示不同连接子的两种UTI-Fc构建体。
图3是本发明的各种UTI-Fc构建体。
图4是用于UTI融合构建中的DNA装配策略(SLIC)。
图5是UTI及UTI-Fc1、SEQ ID NO:1对于蛋白酶活性(胰蛋白酶)的抑制
图6是UTI-Fc1、UFC1、SEQ ID NO:1对于蛋白酶活性(胰凝乳蛋白酶)的抑制。
图7是UTI-Fc1、UFC1、SEQ ID NO:1对于蛋白酶活性(多种蛋白酶)的抑制。
图8是UTI及UTI-Fc1、UTI-Fc、SEQ ID NO:1对于细胞因子分泌(IL-6)的抑制。
图9是UTI融合蛋白的纯化产量。
图10是在C3H小鼠中,SEQ ID NO:1对于LPS诱导的C5a的作用。
【发明详述】
本发明提供包含UTI结构域及融合配偶体的UTI融合蛋白,其中UTI结构域可操作地连接至融合配偶体。本发明的UTI融合蛋白对于蛋白酶,包括胰蛋白酶具有抑制作用。
在一些实施方案中,融合配偶体为Fc多肽。在一些实施方案中,融合配偶体为人Fc多肽。在一些实施方案中,融合配偶体为人Fc多肽的类似物。在一些实施方案中,融合配偶体为人Fc多肽的片段。在其他实施方案中,融合配偶体为小鼠Fc多肽。在其他实施方案中,融合配偶体为大鼠Fc多肽。
在一些实施方案中,融合配偶体为人白蛋白。在一些实施方案中,融合配偶体为人白蛋白的类似物。在一些实施方案中,融合配偶体为经修饰的人白蛋白。在一些实施方案中,融合配偶体为人白蛋白的片段。
在一些实施方案中,UTI结构域为人UTI(hUTI)。在一些实施方案中,UTI结构域为hUTI的类似物。在一些实施方案中,UTI结构域为hUTI的片段。在一些实施方案中,UTI融合蛋白包含野生型hUTI结构域。
在一些实施方案中,UTI融合蛋白包含野生型人UTI结构域及人Fc结构域。在一些实施方案中,UTI融合蛋白包含野生型hUTI结构域,及连接子结构域,及人Fc结构域。
在一些实施方案中,UTI融合蛋白包含野生型人UTI结构域及人白蛋白或其类似物或其片段。在一些实施方案中,UTI融合蛋白包含野生型hUTI结构域、连接子结构域,及人白蛋白或其类似物或其片段。
在一些实施方案中,Fc结构域结合至人细胞上的Fc受体。在一些实施方案中,分子的血清半衰期显著长于单独UTI结构域的血清半衰期。在一些实施方案中,分子的UTI结构域的蛋白酶抑制活性与单独UTI结构域相同或大于单独UTI结构域。在一些实施方案中,将分子施用于小鼠减少炎症反应,包括但不限于,降低免疫细胞的活化或降低细胞因子或趋化因子的产生、分泌或活性。
应了解UTI结构域可通过连接子结构域可操作地连接至融合配偶体。
本发明提供UTI融合蛋白,其包含融合至多肽的UTI结构域,所述多肽选自由以下组成的组:a)Fc结构域,b)Fc结构域的类似物,及c)Fc结构域的片段,其中UTI结构域通过连接子结构域融合至Fc结构域、其类似物或其片段。本发明提供UTI融合蛋白,其包含融合至多肽的hUTI结构域,所述多肽选自由以下组成的组:a)Fc结构域,b)Fc结构域的类似物,及c)Fc结构域的片段,其中hUTI结构域通过连接子结构域融合至Fc结构域、其类似物或其片段。
本发明融合蛋白涵盖具有单体及多聚体形式的蛋白质,不论通过完整抗体的消化制备或通过其他方法产生。
术语“多聚体”及“多聚体的”是指其中Fc结构域或包含Fc结构域的分子具有共价、非共价缔合,或同时具有共价及非共价相互作用的两个或更多个多肽链的蛋白质。术语多聚体包括术语二聚体。
术语“二聚体”是指其中Fc结构域或包含Fc结构域的分子具有共价、非共价缔合,或同时具有共价及非共价相互作用的两个多肽链的蛋白质。即,术语“二聚体”是指其中两个Fc结构域共价、非共价缔合,或同时具有共价及非共价相互作用的UTI融合蛋白。更具体而言,术语“二聚体”是指其中两个Fc结构域共价缔合的UTI融合蛋白。
本发明提供UTI融合蛋白,其包含融合至多肽的UTI结构域,所述多肽选自由以下组成的组:a)白蛋白、b)白蛋白类似物、c)白蛋白的片段。本发明还提供UTI融合蛋白,其包含融合至多肽的hUTI结构域,所述多肽选自由以下组成的组:a)人白蛋白、b)白蛋白类似物、c)人白蛋白的片段,其中hUTI通过连接子结构域融合至白蛋白、其类似物或其片段。
【术语定义】
用于本说明书及权利要求中的术语如以下阐明来定义,除非另外指示。
如本文使用,术语“连接(的)”、“融合(的)”或“融合”可互换使用。
这些术语指的是通过无论何种手段包括化学偶联或重组手段将两个以上元件或组分或结构域连接在一起。化学偶联方法在本领域中为已知的。
“融合蛋白”是指具有共价连接在一起的两个或更多个部分的多肽,其中一个或多个部分来源于不同蛋白质。两个部分可通过单一肽键来直接连接(例如,各部分彼此直接连接)或经由含有一个或多个氨基酸残基的肽连接子(例如在各部分之间具有介入氨基酸或氨基酸序列)来连接。总体上,编码两个部分及连接子的DNA彼此处于阅读框中并且使用重组技术来产生。
“UTI结构域”是模拟UTI活性的蛋白质或肽。应了解可改变本发明的UTI结构域以使得其与其所衍生的天然存在或原始序列的序列不同,同时保持原始序列的所需活性。优选UTI结构域为原始人UTI(hUTI)、其类似物及变体。hUTI的变体包括替换或修饰原始hUTI的一个或多个并非所需结构特征或提供功能活性的氨基酸,所述替换或修饰包括保守取代。hUTI的变体包括在原始hUTI中移除或插入的一个或多个并非所需结构特征或提供功能活性的氨基酸。hUTI的变体包括替换或修饰原始hUTI的一个或多个氨基酸以改变一种或多种性质或活性。hUTI的变体包括在原始hUTI中移除或插入一个或多个氨基酸以改变一种或多种UTI性质或活性。hUTI的变体包括移除或改变原始人UTI中的糖基化位点。hUTI的变体包括移除或改变一个或多个Kunitz结构域。hUTI的变体可通过标准技术,如定点诱变及PCR介导的诱变来引入。
重组hUTI结构域的氨基酸残基序列如SEQ ID NO:31所阐述。总体上,UTI结构域包括与如SEQ ID NO:31所阐述的重组hUTI结构域具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的序列。
“Fc结构域”为包含抗体的恒定区排除第一恒定区免疫球蛋白结构域和在一些情况下,包含铰链的一部分或全部的多肽。因此,Fc结构域是指抗体的非抗原结合部分,不论是否呈单体或多聚体形式。产生Fc结构域的抗体优选为人来源并且可为任何免疫球蛋白,但是优选IgG1及IgG2。
Fc结构域包括重链的铰链区。本文中的“铰链”或“铰链区”或“抗体铰链区”或“免疫球蛋白铰链区”意指可挠性多肽,其包含介于抗体的第一恒定结构域与第二恒定结构域之间的氨基酸,恰好在木瓜蛋白酶裂解上游。因此,对于IgG,Fc结构域包含免疫球蛋白结构域CH2及CH3以及CH1与CH2之间的铰链区。虽然Fc区的边界可能变化,但人IgG重链Fc区通常被界定为包括残基C226或P230至其羧基末端,其中编号是根据如Kabat中的EU指数。在一些实施方案中,如下文更全面所述,对Fc结构域进行氨基酸修饰,例如用以改变与一个或多个FcγR受体或与FcRn受体的结合。
因此,在某些实施方案中,术语Fc结构域包括可截短,通过置换、缺失和/或插入来修饰的铰链区并且此外经修饰或未经修饰的铰链区可为位连接子结构域的连接点。
“Fc结构域的类似物”是指自原始Fc修饰但是仍然包含拯救受体的结合位点的分子或序列。术语Fc结构域的类似物包括自非人原始Fc人源化的分子或序列。术语Fc结构域的类似物还包括缺少一个或多个原始Fc残基,或具有该Fc残基的修饰的分子或序列,该Fc残基影响或涉及二硫化物形成、与宿主细胞的不兼容性、表达后的N末端多样性、稳定性、糖基化、与补体的相互作用、结合至Fc拯救受体和/或与Fcγ受体相互作用。
术语“Fc结构域的多个片段”或“Fc结构域的片段”是指其中一个或多个位点已经从其移除的原始Fc,其中所移除的位点不构成本发明的融合蛋白所需要的结构特征或功能活性。Fc结构域的片段包括从原始Fc缺失残基或截短原始Fc并且可包括其余残基的取代。插入或改变残基(例如,取代的残基)可为天然氨基酸或改变的氨基酸、模拟肽、非天然氨基酸或D氨基酸。
总体上,Fc结构域包括与IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM,尤其人IgG1或IgG2至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一的序列。
术语Fc结构域包括原始Fc及Fc的类似物并且包括单体及多聚体形式,不论通过完整抗体的消化制备或通过其他方法产生。
在某些实施方案中,Fc结构域包含至少铰链结构域(上部、中间和/或下部铰链区)、CH2结构域(或变体或其片段)及CH3结构域(或变体或其片段)。在另一实施方案中,Fc结构域由铰链结构域(上部、中间和/或下部铰链区)、CH2结构域(或变体或其片段)及CH3结构域(或变体或其片段)组成。在某些其它实施方案中,Fc结构域由铰链结构域(上部、中间和/或下部铰链区)、CH2结构域(或变体或其片段)、CH3结构域(或变体或其片段)及CH4结构域(或变体或其片段)组成。在另一实施方案中,Fc结构域由铰链结构域(上部、中间和/或下部铰链区)及CH2结构域组成。在另一实施方案中,Fc结构域由铰链结构域(上部、中间和/或下部铰链区)及CH3结构域(或变体或其片段)组成。在另一实施方案中,Fc结构域由CH2结构域(或变体或其片段)及CH3结构域(或变体或其片段)组成。在另一实施方案中,Fc结构域由完整CH2结构域及完整CH3结构域组成。在另一实施方案中,Fc结构域由完整CH2结构域及完整CH3结构域组成。在一个实施方案中,本发明的Fc结构域包括Fc分子的在本领域中已知为FcRn结合所需要的至少一部分。在另一实施方案中,本发明的Fc结构域包括Fc分子的在本领域中已知为蛋白质A结合所需要的至少一部分。在另一实施方案中,本发明的Fc结构域包括Fc分子的在本领域中已知为蛋白质G结合所需要的至少一部分。
根据本发明,Fc结构域总体上是指包含免疫球蛋白重链的Fc结构域的全部或一部分的多肽。如以上论述,这包括但不限于包含整个铰链区、CH1、CH2和/或CH3结构域的多肽以及包含例如铰链、CH2及CH3结构域的这些肽的片段。Fc结构域可来源于任何物种和/或亚型的任何免疫球蛋白,包括但不限于人IgG1、IgG2、IgG3、IgG4、IgD、IgA、IgE或IgM抗体。因此,Fc结构域包括IgA、IgD及IgG的最后两个恒定区免疫球蛋白结构域,IgE及IgM的最后三个恒定区免疫球蛋白结构域,以及该结构域的可挠性铰链N末端。对于IgA及IgM而言,Fc可包括J链。
如本文使用的Fc结构域包括原始Fc及Fc变体分子。与Fc变体及原始Fc蛋白质一样,术语Fc结构域包括单体及多聚体形式的分子,不论自抗体消化或通过其他手段产生。
如在本文中阐明,应了解,可修饰任何Fc结构域以使得其在氨基酸序列方面与天然存在的免疫球蛋白分子的原始Fc结构域不同。在某些示例性实施方案中,Fc结构域保留效应功能,例如,FcγR结合。在某些示例性实施方案中,Fc结构域缺少效应功能,例如,FcγR结合。
本发明的Fc结构域可来源于不同的免疫球蛋白分子。举例而言,Fc结构域可包括来源于IgG1的CH2和/或CH3结构域及来源于IgG3的铰链区。
在一些实施方案中,UTI融合蛋白包括Fc结构域。适用于产生本发明的UTI融合蛋白的Fc结构域可自许多不同来源获得。在优选实施方案中,UTI融合蛋白的Fc结构域来源于人免疫球蛋白。然而,应了解,Fc结构域可来源于另一个哺乳动物物种的免疫球蛋白,包括例如啮齿动物(例如小鼠、大鼠、兔、豚鼠)或非人灵长类动物(例如黑猩猩、弥猴)物种。此外,UTI融合蛋白Fc结构域或其一部分可来源于任何免疫球蛋白种类。
本文所用的术语“野生型”或“wt”或“原始”意指自然界中所见的氨基酸序列或核苷酸序列,包括等位基因变异。野生型蛋白质、多肽、抗体、免疫球蛋白、IgG、多核苷酸、DNA、RNA等具有未经有意修饰的氨基酸序列或核苷酸序列。
在某些实施方案中,本发明的UTI融合蛋白可使用连接子结构域。连接子结构域用于可操作地将UTI结构域连接至融合配偶体。
术语“连接子结构域”是指多肽连接子、非肽连接子及其组合。具体而言,连接子结构域可为多肽。如本文使用,术语“连接子结构域”是指将两个结构域以线性序列来连接的序列。如本文使用,术语“多肽连接子”是指将两个结构域以多肽链的线性氨基酸序列来连接的肽或多肽序列(例如,合成肽或多肽序列)。举例而言,多肽连接子可用于将UTI结构域连接至Fc结构域。优选地,这些多肽连接子可为多肽分子提供可挠性。本发明的UTI融合蛋白可包含连接子结构域,包括肽连接子。
举例而言,连接子结构域可用于将两个结构域以多肽连接子的线性氨基酸序列来连接,诸如将UTI结构域与Fc结构域连接。在某些实施方案中,连接子结构域可用于将UTI结构域连接至Fc结构域。连接子结构域可用于将结构域以任何顺序连接。举例而言,在一些实施方案中,连接子以顺序UTI-连接子-Fc来连接UTI结构域与Fc结构域,而在其他实施方案中连接子以顺序Fc-连接子-UTI来连接UTI结构域与Fc结构域,其中多肽区域自N末端至C末端指示。示例性多肽连接子包括由甘氨酸及丝氨酸残基组成的那些,即所谓的Gly-Ser多肽连接子。如本文使用,术语“Gly-Ser多肽连接子”是指由甘氨酸及丝氨酸残基组成的肽。示例性Gly-Ser多肽连接子包括氨基酸序列Ser(Gly4Ser)n,其中n为1至10的整数,分别为SEQID NO:33-42。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=1。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=2。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=3。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=4。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=5。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=6。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=7。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=8。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=9。在一个实施方案中,UTI融合蛋白包括一个或两个Gly-Ser多肽连接子,其中n=10。
另一示例性连接子在SEQ ID NO:43中给出。
术语“包括”意指化合物,即,融合蛋白可在N-或C-末端中的一者或两者上包括额外氨基酸。当然,这些额外氨基酸不应显著干扰化合物,即,融合蛋白的活性。
术语“氨基酸”是指天然存在的及合成的氨基酸以及以与天然存在的氨基酸类似方式起作用的氨基酸类似物及氨基酸模拟物。天然存在的氨基酸为通过遗传密码编码的那些,以及后来经修饰的那些编码氨基酸,例如,羟基脯氨酸及磷酸丝氨酸。氨基酸类似物意指具有与天然存在氨基酸相同的碱性化学结构的化合物,即,融合蛋白,即,结合至氢原子的碳原子、羧基、氨基及R基团。氨基酸类似物具有经修饰的R基团,或产生经修饰的肽骨架,但是保持与天然存在氨基酸相同的基本化学结构。
术语“氨基酸取代”是指预定或原始氨基酸序列中的至少一个现有氨基酸残基用不同的“置换”氨基酸置换。
术语“氨基酸插入”是指将一个或多个额外氨基酸插入预定或原始氨基酸序列中。插入可为一个、两个、三个、四个、五个或直至二十个氨基酸残基。
术语“氨基酸缺失”是指将至少一个氨基酸自预定或原始氨基酸序列移除。缺失可为一个、两个、三个、四个、五个或直至二十个氨基酸残基。
术语“多肽”、“肽”及“蛋白质”在本文中互换使用并且指氨基酸残基的聚合物。该术语适用于其中一个或多个氨基酸为非天然氨基酸、合成氨基酸或氨基酸模拟物的氨基酸聚合物。
术语“核酸”是指脱氧核糖核苷酸或核糖核苷酸及其呈单链或双链形式的聚合物。术语“核酸”可与基因、核苷酸、多核苷酸、cDNA、DNA及mRNA互换使用。除非特别限制,该术语包括含有具有与天然核酸类似结合性质的天然核苷酸的已知类似物的核酸。除非特别限制,具体核苷酸序列还包括其保守修饰变体(例如,含有简并密码子取代的那些)及互补序列以及具体描述的序列。
本发明的多核苷酸可主要由任何多核糖核苷酸或多脱氧核糖核苷酸组成,其可为未经修饰的RNA或DNA或经修饰的RNA或DNA。举例而言,多核苷酸可主要由单或双链区域、混合单或双链区域组成。另外,多核苷酸可为含有RNA或DNA或RNA及DNA二者的三链区域。经修饰的多核苷酸包括经修饰的碱基,如三苯甲基化碱基或不寻常碱基如肌苷。可对RNA及DNA产生各种修饰,因而多核苷酸包括经化学、酶或代谢修饰的形式。
术语“衍生”或“衍生物”是指具有例如在半胱氨酰基残基之间交联的环状部分的化合物,即融合蛋白,所述化合物,即融合蛋白得以交联,一个或多个肽基键合由非肽键置换,或N末端由NRR1、NRC(O)R1、NRC(O)OR1、NHC(O)NHR1、NRS(O)2R2、琥珀酰胺或其他基团置换,其中R及R1在本文中定义和/或C末端由C(O)R3或NR4R5置换,以及其中氨基酸部分通过用能够与选定侧链或终端残基反应的试剂处理来修饰的化合物,即融合蛋白。R选自由氢及C1-6烷基组成的组,R1选自由氢及C1-6烷基组成的组,R2选自由C1-6烷基、C3-8环烷基及任选取代的苯基组成的组;R3选自由氢、C1-6烷基及C3-8环烷基组成的组;R4选自由氢及C1-6烷基组成的组;R5选自由氢、C1-6烷基及C3-8环烷基组成的组;或R4及R5与其连接的氮结合以形成4至7员饱和环,该环任选具有选自基团N、O及S的1个额外环杂原子。
术语“C1-6烷基”是指具有1至6个碳原子的直链或分支烷基链。
术语“C3-8环烷基”是指具有3至8个碳原子的单环或双环饱和或部分(但不完全)不饱和烷基环,且包括环丙基、环丁基、环戊基、环己基等。应了解该术语包括苯并稠合环戊基及环己基。
术语“任选取代的苯基”是指用1至3个独立地选自由以下组成的组的取代基任选取代的苯基:卤基、C1-6烷基、C1-6烷氧基、氰基及三氟甲基。
【制备】
本发明的化合物,即,融合蛋白,可通过标准合成方法、重组DNA技术或制备肽及融合蛋白的其他方法来制备。在示例性过程中,hUTI结构域通过编码UTI结构域及Fc结构域及任何连接子结构域的DNA构建体的表达来共价连接至Fc结构域。
预想构建UTI融合蛋白的替代方法。在一些实施方案中,可改变结构域定向来构建保留FcR结合并且具有活性UTI结构域的Fc-UTI分子或UTI-Fc分子或UTI-Fc-UTI分子。
在一些实施方案中,UTI融合蛋白包括野生型Fc结构域,其可允许融合蛋白在结合FcRn(Fc新生儿受体)之后经历胞吞。因此,本发明进一步提供产生所公开UTI融合蛋白的方法。该方法涵盖培养含有编码本发明UTI融合蛋白的分离核酸的宿主细胞。如本领域的技术人员了解,取决于UTI融合蛋白的性质,这可用各种方法进行。在一些实施方案中,产生并且可分离本发明的UTI融合蛋白。
一般而言,提供编码本发明UTI融合蛋白的核酸。此多核苷酸编码UTI结构域、融合配偶体及任何连接子结构域。本发明还涵盖来源于所公开的多核苷酸的寡核苷酸片段及与这些多核苷酸互补的核酸序列。
该多核苷酸可呈RNA或DNA的形式。呈DNA、cDNA、基因组DNA、核酸类似物及合成DNA形式的多核苷酸在本发明的范围内。DNA可为双链或单链,且若为单链,则可为编码链(有义链)或非编码链(反义链)。编码多肽的编码序列可与本文提供的编码序列相同或者可为不同编码序列,该序列由于遗传密码的冗余性或简并性而编码与本文提供的DNA相同的多肽。
在一些实施方案中,将编码本发明的UTI融合蛋白的核酸并入表达载体中,该表达载体可为染色体外载体或者经设计以整合到其所引入的宿主细胞的基因组中。表达载体可含有许多适当调节序列(包括但不限于转录及翻译控制序列、启动子、核糖体结合位点、增强子、复制起点等)或其他组分(选择基因等),其皆如本领域中众所熟知经可操作地连接。在一些情况下,使用两个核酸并且各自置于不同的表达载体中(例如,重链在第一表达载体中,轻链在第二表达载体中),或替代地其可置于相同的表达载体中。本领域的技术人员将了解,该表达载体的设计,包括调节序列的选择,可取决于诸如宿主细胞的选择、所要的蛋白质表达水平等因素。
一般而言,核酸和/或表达可引入适合的宿主细胞中以产生重组宿主细胞,该引入使用适合于所选宿主细胞的任何方法(例如转化、转染、电穿孔、感染),以使得该核酸分子可操作地连接至一个或多个表达控制元件(例如载体中、细胞中通过诸过程产生的构建体中、整合到宿主细胞基因组中)。所得重组宿主细胞可保持在适合于表达的条件下(例如,在诱导剂存在下,在合适非人动物中,在补充有合适盐、生长因子、抗生素、营养补充剂等的合适培养基中),由此产生所编码的多肽。在一些情况下,重链于一种细胞中产生且轻链于另一细胞中产生。
可作为表达宿主获得的哺乳动物细胞系在本领域中为已知的且包括可自美国典型培养物保藏中心(ATCC)(Manassas,VA)获得的许多永生化细胞系,包括但不限于中国仓鼠卵巢(CHO)细胞、HEK 293细胞、NSO细胞、HeLa细胞、幼仓鼠肾脏(BHK)细胞、猴肾脏细胞(COS)、人肝细胞癌细胞(例如Hep G2),及许多其他细胞系。还可使用非哺乳动物细胞来表达重组抗体,该非哺乳动物细胞包括但不限于细菌、酵母、昆虫及植物细胞。在一些实施方案中,抗体可于诸如牛或鸡的转基因动物中产生。
在一个实施方案中,本发明的融合蛋白由核苷酸序列编码。本发明的核苷酸序列可适用于许多应用,包括:克隆、基因疗法、蛋白质表达及纯化、突变引入、有需要的宿主的DNA疫苗接种、用于例如被动免疫的抗体产生、PCR、引物及探针产生、siRNA设计及产生等。在一个实施方案中,本发明的核苷酸序列包括选自SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30或32的核苷酸序列,由其组成,或基本上由其组成。
在一个实施方案中,核苷酸序列包括与在SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30或32中阐述的核苷酸序列具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的核苷酸序列。在一个实施方案中,核苷酸序列包括与在SEQ ID NO:2、4、6、8、10、12、14、16、18、20、22、24、26、28、30或32中阐述的连续核苷酸序列具有至少80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%同一性的连续核苷酸序列。
本发明的优选UTI融合蛋白包含来源于人免疫球蛋白序列的序列(例如,至少一个Fc结构域)。然而,序列可包括来自另一个哺乳动物物种的一个或多个序列。举例而言,灵长类动物Fc结构域或核酸酶结构域可包含于靶标序列中。或者,一个或多个鼠氨基酸可存在于多肽中。在一些实施方案中,本发明的多肽序列不具有免疫原性和/或具有降低的免疫原性。本发明的UTI融合蛋白可包含在一个或多个氨基酸残基处,例如,在必需或非必需氨基酸残基处的保守氨基酸取代。“保守氨基酸取代”为其中氨基酸残基经具有类似侧链的氨基酸残基置换的氨基酸取代。具有类似侧链的氨基酸残基的家族已在本领域中加以定义,包括碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支侧链(例如苏氨酸、缬氨酸、异亮氨酸)及芳族侧链(例如酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此,结合多肽中的非必需氨基酸残基优选用来自相同侧链家族的另一个氨基酸残基置换。在另一实施方案中,一串氨基酸可经侧链家族成员的顺序和/或组成不同的在结构上类似的串置换。或者,在另一实施方案中,突变可沿着全部或一部分编码序列,如通过饱和诱变来随机引入,且所得突变体可并入本发明的结合多肽中并且针对其结合至所需靶的能力来进行筛选。
【使用】
在一个实施方案中,本发明提供诊断及治疗UTI相关病状的方法。如本文所用,术语“病状”、“病症”及“疾病”涉及任何不健康或异常状态。术语“UTI相关病状”包括其中UTI提供治疗益处的病状、病症及疾病。术语“UTI相关病状”包括以免疫调节或炎症效应为特征的病状。具体而言,术语UTI相关病状包括胰腺炎,包括急性胰腺炎及慢性胰腺炎,全身炎症反应综合症,急性循环衰竭(例如,由休克造成),弥散性血管内凝血,及多器官功能障碍综合症。术语UTI相关病状还包括用于高风险手术患者中。术语UTI相关病状还包括肺、肝、心或肾的感染。术语UTI相关病状还包括严重败血症。术语UTI相关病状还包括由SARS病毒造成的急性肺损伤(ALI)或急性呼吸窘迫综合症(ARDS)。
在一个实施方案中,本发明提供治疗UTI相关病状的方法,包括向有需要的患者施用有效量,例如,药学上有效量的所公开UTI融合蛋白。在某些实施方案中,病状为本文具体提到病状。
本发明的药物组合物以药学领域中熟知的方式制备且包括至少一种本发明UTI融合蛋白作为活性成分。根据本发明使用的UTI融合蛋白的药物组合物通过将具有所需纯度的UTI融合蛋白与任选药学上可接受的赋形剂混合来制备。术语“药学上可接受的赋形剂”是指通常用于制备药物组合物且应为药学上纯净的并在所用量下无毒的赋形剂。其通常为合计可充当活性成分的媒介物或介质的固体、半固体或液体物质。药学上可接受的赋形剂的一些实例见于Remington’s Pharmaceutical Sciences and the Handbook ofPharmaceutical Excipients中,且包括稀释剂、媒介物、载体、持续释放基质、稳定剂、防腐剂、溶剂、悬浮剂、缓冲剂、乳化剂、染料、推进剂、包衣剂及其他赋形剂。总体上对于注射或静脉内施用,本发明的UTI融合蛋白呈冻干制剂或水溶液形式。
药学上可接受的赋形剂在所用量下对接受者无毒,且包括:缓冲剂,诸如磷酸盐、柠檬酸盐及其他有机酸;抗氧化剂,包括抗坏血酸及甲硫氨酸;防腐剂(诸如氯化十八烷基二甲基苯甲基铵;氯化六羟季铵;氯化苯甲烃铵;苄索氯铵;苯酚、丁醇或苯甲醇;对羟基苯甲酸烃酯,诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯;儿茶酚(catechol);间苯二酚;环己醇;3-戊醇;及间甲酚);低分子量(少于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯啶酮;氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸;单糖、二糖及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合剂,诸如EDTA;糖,诸如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成盐抗衡离子,诸如钠;金属复合物(例如Zn-蛋白质复合物);和/或非离子表面活性剂,诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。
本文中的药物组合物还可含有所治疗的特定适应症所需要的一种以上活性化合物,即融合蛋白,优选为具有互补活性且不会对彼此有不利影响的那些。这些分子适当地以对预期的目的有效的量组合存在。
待体内施用的药物组合物应当无菌或接近无菌。此可通过经无菌过滤膜过滤来容易地达成。
本发明的UTI融合蛋白根据已知方法施用至受试者,该已知方法诸如作为丸剂形式或经连续输注一段时间的静脉内施用、通过肌肉内、腹膜内、脑脊髓内、皮下、关节内、滑膜内或鞘内注射或输注,或通过局部或吸入途径。UTI融合蛋白的静脉内或皮下施用为优选的。
术语“治疗(treat/treatment/treating)”包括改善本文所述的病状。术语“治疗”包括提供减缓、间断、遏止、控制或停止本文所述的病状的状态或进展的所有过程,但未必指示完全消除病状的所有症状或治愈病状。术语“治疗”意欲包括治疗性治疗这些病症。术语“治疗”意欲包括防治性治疗这些病症。
如本文所用,术语“患者”及“受试者”包括人及非人动物,例如哺乳动物,诸如小鼠、大鼠、天竺鼠、狗、猫、兔、母牛、马、绵羊、山羊及猪。该术语还包括禽类、鱼类、爬行动物、两栖动物等。应了解更特定患者为人。此外,更特定患者及受试者为非人哺乳动物,诸如小鼠、大鼠及狗。
如本文所用,术语“有效量”是指在施用单次或多次剂量后,本发明化合物治疗罹患提及的病状的患者的量。有效量可易于由如本领域的技术人员的照护诊断医师诸如医师或兽医通过使用已知技术及通过观测在类似情况下获得的结果来确定。例如,医师或兽医可以低于达成所要治疗作用的所需水平的水平起始药物组合物中采用的药剂的剂量且逐步增加剂量直至达成所要作用。
在确定有效量,即剂量时,照护诊断医师考虑许多因素,包括但不限于:患者的物种;其身材、年龄及一般健康状况;涉及的特定病状、病症或疾病;病状、病症或疾病的程度或牵连或严重性;个别患者的反应;施用的特定化合物,即融合蛋白;施用模式;施用的制剂的生物可用度特征;所选剂量方案;相伴药物的使用;及其他相关情况。特定量可由熟练人员确定。虽然这些剂量是基于具有约60kg至约70kg的平均质量的人受试者,但医师将能够确定用于质量属于此重量范围外的患者(例如,婴儿)的适当剂量。
调节剂量方案以提供所需反应。例如,可施用单次丸剂,可随时间施用几次分开剂量,或者可按照治疗情形的紧张程度所指示,按比例减少或增加剂量。
为施用方便及剂量均匀,肠胃外组合物可配制成剂量单位形式。本文使用的剂量单位形式是指对于待治疗的受试者适合作为单位剂量的物理离散单位;每一单位含有经计算产生所要治疗作用的与所需药物载体结合的预定量的活性化合物即融合蛋白。
本发明药物组合物优选以单位剂型配制,其中各剂通常含有约0.5mg至约100mg本发明UTI融合蛋白。术语“单位剂型”是指含有预定量的活性成分以及适合的药物赋形剂的物理离散单位,在整个给药方案期间使用一个或多个该物理离散单位来产生所要治疗效应。可采用一个或多个“单位剂型”以实现治疗剂量。
用于本发明的UTI融合蛋白的有效量的示例性、非限制性范围为约0.1-100mg/kg,如约0.1-50mg/kg,例如约0.1-20mg/kg,如约0.1-10mg/kg,例如约0.5mg/kg,约如0.3mg/kg,约1mg/kg,或约3mg/kg。在另一实施方案中,UTI融合蛋白以1mg/kg或更多的剂量,如1至20mg/kg的剂量,例如5至20mg/kg的剂量,例如8mg/kg的剂量施用。用于本发明的UTI融合蛋白的有效量的示例性、非限制性范围为约1-500mg/剂量,如约1-100mg/剂量,例如约1-50mg/剂量,如约1-10mg/剂量,例如约1mg/剂量,或约3mg/剂量,或约5mg/剂量。
在一个实施方案中,UTI融合蛋白通过输注以每3天或每周10至500mg/剂量的剂量施用。必要时,此施用可重复以保持所需治疗效应。
作为非限制性实例,根据本发明的治疗可以每天或每天至少一次约0.1-100mg/kg,诸如0.5、0.9、1.0、1.1、1.5、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、40、45、50、60、70、80、90或100mg/kg的量提供UTI融合蛋白的剂量;于治疗起始后以1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40mg/kg的量,或者以1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20mg/kg的量每周至少一次,或其任何组合来提供。作为非限制性实例,根据本发明的治疗可以以约1-100mg/剂量,如1、5、10、20、30、40、45、50、60、70、80、90、100、150、200、250、300、350或400mg/剂量的量提供UTI融合蛋白剂量。于治疗起始后以1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40mg/kg的量每天至少一次,或其任何组合提供UTI融合蛋白的剂量。或者于治疗起始后以1、10、20、30、40、50、60、70、80、90或100mg/kg的量每周至少一次,或其任何组合。
本发明的UTI融合蛋白适用于各种应用,包括治疗UTI相关疾病。本发明的UTI融合蛋白可适用于治疗涉及免疫系统的疾病、自身免疫疾病、炎症疾病、手术后炎症响应、溶酶体相关疾病、凝血疾病蛋白酶相关疾病以及作为手术期间的辅助疗法。本发明的UTI融合蛋白可适用于治疗胰腺炎(包括内窥镜检查诱导的胰腺炎及急性胰腺炎)、关节炎、SARS、全身炎症反应综合症、急性循环衰竭、败血症、肝炎、阑尾炎、结肠炎、器官衰竭、器官损伤(包括胰腺、肾脏、肺)、再灌注损伤、斯蒂文斯-约翰逊综合症、毒性表皮坏死溶解、休克、缺血性损伤、急性肺损伤(包括由急性主动脉夹层造成的急性肺损伤)、哮喘、肺炎症、肺炎(包括呼吸器相关的)、弥散性血管内凝血(DIC)、急性呼吸窘迫综合症(ARDS)及全身炎症反应综合症。
本发明的UTI融合蛋白可适用于抑制蛋白酶,包括丝氨酸蛋白酶,包括胰蛋白酶,胰凝乳蛋白酶,凝血酶,激肽释放酶,胞浆素,弹性蛋白酶,组织蛋白酶,脂肪酶,透明质酸酶,因子IXa、Xa、XIa及XlIa,及分叶核白细胞弹性蛋白酶。
本发明的UTI融合蛋白可适用于抑制促炎性介体,如细胞因子、肿瘤坏死因子-α、白介素-1、-1β、-4、-6及-8、-10及趋化因子。
本发明的UTI融合蛋白可适用于治疗癌症,包括预防肿瘤侵入及转移,改变细胞凋亡速率,及在顺铂治疗中减少肾功能损失。
本发明的UTI融合蛋白可适用于治疗AIDS,包括作为辅助治疗。
【实施例】
以下为执行本发明的具体实施方案的实施例。提供实施例仅是为说明性的目的,而非打算以任何方式限制本发明的范围。已努力确保关于所用数值(例如量、温度等)的准确性,但应虑及一些实验误差及偏差。除非另外指示,本发明的实践将使用本领域的技能范围内的蛋白质化学、生物化学、重组DNA技术及药理学的常规方法。此类技术在文献中得到完全解释。参见例如T.E.Creighton,Proteins:Structure and Molecular Properties(W.H.Freeman and Company,1993);A.L.Lehninger,Biochemistry(Worth Publishers,Inc.);Sambrook等人,Molecular Cloning:A Laboratory J\1anual(第2版,1989);Methods In Enzymology(S.Colowlck及N.Kaplan编,Academic Press,Inc.);Remington’sPharmaceutical Sciences,第18版(Easton,Pennsylvania:Mack Publishing Company,1990);Carey及Sundberg Advanced Organic Chemistry第3版(Plenum Press)第A及B卷(l992)。
【实施例1:构建编码UTI融合蛋白的DNA载体】
执行分子生物学的方法在本领域中为已知的并且可发现例如于MolecularCloning:A laboratory Manual第4版(Micheal Green及Joseph Sambrook,Cold SpringHarbor Press,2012)中。
编码UTI-Fc1的基因使用来自Life Technologies(Carlsbad,CA)的GeneArt密码子优化基因合成服务来测序。蛋白质序列如SEQ ID NO:1中列出,其中添加信号肽,MGWSCIILFLVATATGVHS,用于分泌。图1示出用于融合的UTI的一般区域。编码UTI-Fc1的基因连接至哺乳动物表达载体中。哺乳动物表达载体在本领域中为已知的,包括pSecTag2/HygroA、pcDNA4及pcDNA6载体(Life Technologies,Carlsbad CA)。载体用限制酶,来自NewEngland Biolabs(NEB)的HindIII-HF及EcoRI来消化。将此片段连接至表达载体,其提供羟苄青霉素抗性并且用相同两种限制酶消化。1:3的载体:插入物摩尔比用于连接反应。将连接的DNA转化至来自NEB的10-β化学感受态大肠杆菌细胞中,且铺板于LB-羟苄青霉素板上生长过夜。集落在LB中与羟苄青霉素一起生长过夜并且miniprep DNA通过Qiagen’sQIAprep Spin Miniprep试剂盒(Qiagen,Hilden,Germany)制备。然后,DNA使用来自BioApplied Technologies Joint(BATJ,San Diego)的DNA测序服务来测序。随后,序列验证集落与羟苄青霉素一起生长于LB培养基中,使用BenchPro2100仪器及来自LifeTechnologies的MaxiCard来进行DNA纯化。
【实施例2:构建编码UTI-Fc融合蛋白的变体的DNA载体】
SEQ ID NO:1-28列出一些UTI-Fc融合蛋白的DNA及蛋白质序列。这些UTI融合蛋白包括修饰,该修饰改变Ig同种型、连接子、UTI结构域、UTI及Fc结构域顺序(N-或C-末端)、UTI种类、Fc种类、UTI开始/终止残基、糖连接、蛋白酶敏感位点及Fc效应功能。一些UTI-Fc蛋白质描绘于图2及3中。包含Ser的三个氨基酸修饰(IgG1Fc3Ser,C154S/P172S/P265S)的UTI-Fc融合蛋白包含改变二硫键形成及FcγR功能的突变。
【产生UTI-Fc表达构建体】
将UTI(例如野生型、S10A及K21S K22S变体)及人Fc3Ser结构域的核苷酸序列进行密码子优化用于CHO细胞表达并且通过Life Technologies(Carlsbad,CA)合成。通过经由与序列及连接反应无关的克隆(SLIC)方法(Li及Elledge 2007Nature Methods 4(3):251-256)来装配UTI及Fc3Ser结构域在CHO表达载体中建立以下构建体:UTI-Fc3Ser、UTI S10A-Fc3Ser、UTI K21S K22S-Fc3Ser、UTI m2-Fc3Ser、UTI L1-Fc3Ser、UTI L2-Fc3Ser(图4A)。通过将线性化载体(30ng)、UTI(100ng)及Fc3Ser(100ng)PCR产物与用于同源重组的合适突出端序列,及T4DNA聚合酶(0.5U)在含有NEBuffer2及BSA(New England Biolabs)的5μL体积中混合来进行基于SLIC的DNA装配。在室温下孵育30min之后,T4DNA聚合酶的外切核酸酶活性通过添加2mM的dCTP来淬灭。然后,体外同源重组通过在30min内的75C至37C的温度梯度来进行。含有装配DNA的反应混合物化学转化至TOP10大肠杆菌(Invitrogen)中,且铺板于含有羟苄青霉素的LB-琼脂中。将其余构建体的开放阅读框(UTI m1-Fc3Ser、UTI d1-Fc3Ser、UTI d2-Fc3Ser、UTI L3-Fc3Ser、UTI-Fc IgG2、Fc3Ser-UTI,及小鼠UTI-小鼠IgG1)进行密码子优化并且合成为融合构建体。这些构建体使用如上所述SLIC方法克隆至表达载体中(图4B)。载体中的所有13个构建体的DNA序列通过Sanger DNA测序来验证。
【实施例3:在CHO细胞中表达UTI-Fc融合】
编码UTI-Fc1的DNA载体使用Invitrogen的Freestyle MAX试剂稳定转染至CHO-S细胞中。大量培养物铺板至T烧瓶中并且使用补充有50-100μM范围内的不同浓度的甲硫氨酸砜亚胺(MSX)的CD CHO来选择。一旦培养物自选择回收,将其扩增以用于产生及冷冻保存。进行多重产生批次以支持体外及体内测试。产生过程为使用来自Invitrogen的CDFortiCHO、CD Efficient Feed B及CD Efficient Feed C的10-14天分批补料培养。产生体积为1L–3L范围内,且培养物通过在3500rpm下离心1-2小时随后将上清液无菌过滤来收获并且所得细胞上清液用于纯化。
【实施例4:纯化UTI-Fc融合蛋白】
2批次UTI-Fc1的纯化通过将具有所表达的UTI-Fc1的2.3升CHO细胞条件培养基施加至在25mM柠檬酸三钠(pH 8.1),125mM NaCl中平衡的30ml蛋白质A mAb select lx(GEhealthcare)来进行。柱用2柱体积(60ml)25mM柠檬酸三钠(pH 8.1),125mM NaCl,然后用2柱体积(60ml)25mM柠檬酸三钠(pH 8.1),2000mM NaCl清洗。然后,柱用2柱体积(60ml)25mM柠檬酸三钠(pH 8.1),125mM NaCl平衡。UTI-Fc1用7柱容积(210ml)梯度洗脱至100%25mM柠檬酸(pH2.9),125mM NaCl。UTI-Fc1洗脱为两个峰,近似5.5pH下的宽阔的侧接峰及近似3.5pH下的较尖峰。然后,使用具有30K M.W.C.O.的Amicon Ultra离心浓缩机将浓的UTI-Fc缓冲液交换至TBS pH 7.4最终缓冲液(25mM三(羟甲基)氨基甲烷,130mM NaCl,2.7mM KClpH7.4)中。纯化蛋白质产量展示于表1中并且蛋白质储存于-80℃下以进一步使用。
【表1】
【实施例5:表达及纯化额外UTI-Fc融合蛋白】
转染当天,将CHO细胞计数并且以2.2x106个活的细胞/毫升的密度接种于90%总体积900mL中并且在33℃下在摇瓶中生长直到转染为止。将冷冻DNA解冻并且添加至PEI(聚乙烯亚胺-阳离子聚合物)及AKT。以0.625ug/1百万个细胞添加DNA。1L细胞需要1.25mg。添加的总DNA的90%为所关注的DNA=1.125mg。其余10%为AKT(编码抗凋亡蛋白质)=0.125mg。以2.5ug/1百万个细胞添加PEI。对于1L转染,此为5mg。将PEI溶液添加至稀释DNA并且在室温下孵育15分钟,然后将DNA复合物添加至细胞。
培养物在33℃下,5%CO2,及125rpm下生长。转染后1至4小时,添加0.6mM丙戊酸。对于1L转染,此为2mL的300mM储备物。第1天,添加1:250抗凝集剂,即4mL/1L及15%v/v CDEfficient Feed C即150mL/1L。第5天及第9天,添加15%CD Efficient Feed C。
细胞上清液在第14天收获,将细胞计数并且确定蛋白质滴度。细胞通过在3000rpm下在4℃下30分钟离心来旋转沉降。上清液经由0.2微米过滤器过滤并且储存于4℃下或冷冻于-20℃下。
纯化UTI-Fc融合通过蛋白质A层析进行。200mL细胞培养物上清液与2ml的MabSelect Sure Protein A Sepharose珠粒混合并且在4℃下振荡过夜。然后,珠粒混合物在50ml管中在1200rpm下离心5分钟并且将上清液丢弃。将珠粒添加至柱并且用结合缓冲液(Biorad,Hercules,CA)洗涤三次。将UTI融合物用8ml MAPS II洗脱缓冲液(Biorad,Hercules,CA)洗脱。添加2ml中和溶液(1M Tris-HCl pH 8)。样本然后通过使用AmiconCentrifugal单元(30MWCO,15mL,Millipore)以缓冲液重复浓缩并稀释来缓冲液交换至25mM柠檬酸,125mM NaCl,pH 5.5中。图9列出各种UTI融合蛋白的纯化结果。
【实施例6:通过UTI融合蛋白抑制蛋白酶】
胰蛋白酶通过UTI-Fc融合蛋白来抑制的体外酶法测定。
各种浓度(≤200nM最终浓度)的UTI-Fc1溶液在50mM HEPES,150mM NaCl,20mMCaCl2及0.01%Brij L23(pH 7.4)中制备。活性测定在Greiner384-孔小体积板中执行。所有步骤在环境温度下进行。
将人胰腺胰蛋白酶(1.5nM最终浓度)(Athens Research&Technology,Inc)添加至稀释液,然后与测试UTI-Fc一起预孵育15分钟。随后,反应以100μM(最终)基质N-苯甲酰基-L-精氨酸-7-酰氨基-4-甲基香豆素盐酸盐SIGMA B7260-25MG开始。反应混合物总体积为20l。胰蛋白酶活性经由荧光来确定。举例而言,荧光强度在30至60分钟的窗口内、在BMGPHERAstar FS或PHERAstar plus上使用370nm的激发波长及470nm的发射波长在动力学模式下测定。胰蛋白酶活性与所观察到的荧光线性成比例地变化(最终–初始)。在给定UTI-Fc浓度下的胰蛋白酶的抑制百分比定义为:
抑制百分比=100*(1-((Fi–Fp)/(Fn-Fp)))
其中:Fi为在测试UTI-Fc的给定浓度下所观察到的荧光。
Fp为阳性对照的所观察到的荧光,即不存在胰蛋白酶时的2至6个测定的平均值。
Fn为阴性对照的所观察到的荧光,即在存在单独媒介物时的胰蛋白酶的2至6个测定的平均值。
测试化合物,即,融合蛋白的IC50(产生50%抑制的化合物,即,融合蛋白的摩尔浓度)通过方程抑制百分比=底部+((顶部-底部)/(1+((IC50/[UTI-Fc])^Hill)))的非线性最小平方曲线拟合来计算。包含在UTI-Fc的图内的为一个阳性对照。如图5所述,人UTI具有约3nM的IC50。
其他蛋白酶通过UTI-Fc1的抑制的测量还测量于Reaction Biology Corporation(Malvern,PA)。图6展示UTI-Fc1对于胰凝乳蛋白酶的抑制。图7列出UTI-Fc1对于多种蛋白酶的抑制常数。UTI-Fc1适度地抑制胰凝乳蛋白酶及胞浆素并且示出半胱天冬酶-1、组织蛋白酶C及木瓜蛋白酶的微弱抑制。
【实施例7:用UTI融合蛋白处理的细胞效应】
细胞因子释放的UTI-Fc1抑制在基于细胞的测定中测量。BEAS2B细胞以20,000细胞/孔的密度接种于96孔板中并且使用完全BEGM Bullet试剂盒(Lonza)在CO2恒温箱中培养。24小时之后,培养基置换为普通DMEM以进行饥饿处理并且将细胞培养过夜。然后细胞与含有100nM胰蛋白酶与各种浓度人尿液UTI或重组UTI-Fc1蛋白质的新制普通DMEM一起孵育。8小时之后,将培养上清液收集并且使用人IL-6DuoSet(R&D Systems)来评估IL-6蛋白质水平。
结果证明在BEAS2B细胞中,UTI及UTI-Fc均降低胰蛋白酶诱导的IL-6产生。如图8展示,抑制为剂量依赖性的,其中IC50值分别为0.40和0.41μg/mL。
【实施例8:UTI-Fc分子的稳定性测量-热变性】
执行测定来测量热及实时稳定性。所有分子在胰蛋白酶抑制中展示活性。热稳定性在Microcal VP-DSC量热计上通过差示扫描量热法来测量。样本以1mg/ml制备并且在0.25mM Tris(pH7.4),0.13M NaCl及0.0027M KCl中缓冲。样本以每小时200℃的速率自25℃加热至110℃。将UTI-Fc1与分别包含IgG2或IgG1Fc结构域的申请公开案第CN103044554A号,SEQ ID 2及6比较。结果呈现于表2中。
【表2】
蛋白质 | DSC Tm1(℃) | DSC Tm2(℃) |
UTI-Fc1(SEQ ID NO:1) | 70.86 | 85.79 |
CN 103044554A SEQ ID 6 | 68.72 | 86.38 |
CN 103044554A SEQ ID 2 | 68.47 | 79.22 |
【实施例9:实时稳定性测量】
实时稳定性测量通过在TBS,pH7.4缓冲液中将SEQ ID NO:1(UTI-Fc1)或CN103044554A,SEQ ID 2或6在2-8℃及40℃下孵育0、2及4周来执行。较高及较低分子量物质的形成通过尺寸排除层析(SEC)来确定并且以聚丙烯酰胺凝胶电泳(PAGE)来观测。每个UTI-Fc的浓度还通过使用通过蛋白质组成来确定的消光系数来确定280nm下的溶液的吸光率(A280)来监测。当通过SEC分析时,UTI-Fc分子产生两个部分重叠峰。通过SEC测量的每个UTI-Fc样本中的峰面积百分比在表3中在时间=0周、2周及4周来报告。还显示在时间=2周及4周时通过A280(%Δ(mg/ml))测量的浓度的变化百分比。每个样本的初始T0浓度为UTI-Fc1=33.5mg/mL,CN 103044554A SEQ ID 2=8.5mg/mL及CN 103044554A SEQ ID 6=5.6mg/mL。3%的可变性对于SEC为典型的并且对于个别UV测量为15%。通过PAGE的分析显示每个UTI-Fc分子显示全长UTI-Fc的预期带型。
【表3】
【实施例10:补体抑制的体内测试】
在体内测量UTI-Fc1(SEQ ID NO:1)对于补体系统的影响。雌性C3h/HeJ小鼠购自Jackson Laboratories。动物根据实验设计表4来给药。在零时给予LPS后15分钟,将动物腹膜内注射(100ul/小鼠)。在LPS注射后2及4小时,将动物通过CO2超剂量来安乐死并且通过心脏穿刺来收集血液。将血液转移至血清分离微管并且使其在室温下凝结30分钟。随后,微管在12,000rpm下离心5分钟并且将血清移除并且分装至96孔板。迷迭香酸用作阳性对照并且以盐水中3mg/ml使用。96孔板在-20℃下冷冻。血清样本通过duoset对C5a含量进行分析。统计显著性使用Prism制图软件来确定并且若p<0.05,则作用视为统计上显著。如图10所示,在LPS给药后4小时,SEQ ID NO:1(UTI-Fc1)在20、50及100mg/kg下显著降低C5a。
【表4:实验设计(UTI-Fc1为SEQ ID:1)】
【序列表】
SEQ ID NO:1UTI-Fc 1蛋白质序列
SEQ ID NO:2UTI-Fc 1DNA序列
SEQ ID NO:3UTI-Fc IgG1 3Ser蛋白质序列
SEQ ID NO:4UTI-Fc IgG1 3Ser DNA序列
SEQ ID NO:5UTI-Fc IgG2Ser蛋白质序列
SEQ ID NO:6UTI-Fc IgG2Ser DNA序列
SEQ ID NO:7UTI-Fc IgG2蛋白质序列
SEQ ID NO:8 UTI-Fc IgG2 DNA序列
SEQ ID NO:9 UTI-Fc IgG1 3Ser S10A蛋白质序列
SEQ ID NO:10 UTI-Fc IgG1 3Ser S10A DNA序列
SEQ ID NO:11 UTI-Fc IgG1 3Ser m2蛋白质序列
SEQ ID NO:12UTI-Fc IgG1 3Ser m2DNA序列
SEQ ID NO:13UTI-Fc IgG1 3Ser m1蛋白质序列
SEQ ID NO:14UTI-Fc IgG1 3Ser m1DNA序列
SEQ ID NO:15UTI-Fc IgG1 3Ser连接子3蛋白质序列
SEQ ID NO:16UTI-Fc IgG1 3Ser连接子3DNA序列
SEQ ID NO:17UTI-Fc IgG1 3Ser连接子2蛋白质序列
SEQ ID NO:18UTI-Fc IgG1 3Ser连接子2DNA序列
SEQ ID NO:19UTI-Fc IgG1 3Ser连接子1蛋白质序列
SEQ ID NO:20UTI-Fc IgG1 3Ser连接子1DNA序列
SEQ ID NO:21UTI-Fc IgG1 3Ser K21S K22S蛋白质序列
SEQ ID NO:22UTI-Fc IgG1 3Ser K21S K22S DNA序列
SEQ ID NO:23UTI-Fc IgG1 3Ser d2蛋白质序列
SEQ ID NO:24UTI-Fc IgG1 3Ser d2DNA序列
SEQ ID NO:25UTI-Fc IgG1 3Ser d1蛋白质序列
SEQ ID NO:26UTI-Fc IgG1 3Ser d1DNA序列
SEQ ID NO:27mUTI-mFc mIgG1蛋白质序列
SEQ ID NO:28mUTI-mFc mIgG1DNA序列
SEQ ID NO:29Fc IgG1 3Ser UTI蛋白质序列
SEQ ID NO:30Fc IgG1 3Ser UTI DNA序列
SEQ ID NO:31hUTI蛋白质序列
SEQ ID NO:32AMBP前原蛋白序列
本说明书还包括下列内容:
1.一种UTI融合蛋白,其包含SEQ ID NO:1。
2.一种分离的UTI融合蛋白,其包含SEQ ID NO:1。
3.根据实施方式1或2所述的融合蛋白,其中所述融合蛋白为二聚体,其中所述Fc结构域共价缔合。
4.一种药物组合物,其包含根据实施方式1、2或3所述的UTI融合蛋白及药学上可接受的赋形剂。
5.根据实施方式1、2或3所述的UTI融合蛋白作为药物的用途。
6.一种治疗UTI相关病状的方法,其包括向有需要的患者施用有效量的根据实施方式1、2或3所述的UTI融合蛋白。
7.一种核酸,其包含编码SEQ ID NO:1的多核苷酸序列。
8.一种表达载体,其包含根据实施方式6所述的核酸。
9.一种重组宿主细胞,其包含如实施方式7所述的表达载体。
10.一种产生UTI融合蛋白的方法,其包括:将如实施方式8所述的重组宿主细胞放置于生长培养基中,以使得所述重组融合蛋白得以表达,且将所述融合蛋白自所述细胞或生长培养基分离。
序列表
<110> TAKEDA CALIFORNIA, INC.
<120> UTI融合蛋白质
<130> UTI-5001-WO
<140>
<141>
<150> 61/943,617
<151> 2014-02-24
<160> 48
<170> PatentIn 3.5版
<210> 1
<211> 375
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 1
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Gly
130 135 140
Ser Gly Gly Gly Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
145 150 155 160
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
165 170 175
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
180 185 190
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
195 200 205
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
210 215 220
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
225 230 235 240
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
245 250 255
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
260 265 270
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
275 280 285
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
290 295 300
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
305 310 315 320
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
325 330 335
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
340 345 350
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
355 360 365
Ser Leu Ser Leu Ser Pro Gly
370 375
<210> 2
<211> 1125
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 2
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgg gatcaggcgg cggaggcgac aagacccata cctgtccacc ttgccctgcc 480
cccgagctgc tgggaggacc ttctgtgttc ctgttccccc caaagcccaa ggacaccctg 540
atgatctccc ggacccctga agtgacctgc gtggtggtgg atgtgtccca cgaggatccc 600
gaagtgaagt tcaattggta cgtggacggc gtggaagtgc acaacgccaa gaccaagccc 660
agagaggaac agtacaactc cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag 720
gattggctga acggcaaaga gtacaagtgc aaggtgtcca acaaggccct gcctgccccc 780
atcgaaaaga ccatctccaa ggccaagggc cagccccggg aaccccaggt gtacacactg 840
ccccctagcc gggaagagat gacaaagaac caggtgtccc tgacctgtct cgtgaaggga 900
ttctacccct ccgatatcgc cgtggaatgg gagtccaacg gccagcctga gaacaactac 960
aagaccaccc cccctgtgct ggactccgac ggctcattct tcctgtactc caagctgaca 1020
gtggacaagt cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggcc 1080
ctgcacaacc actacaccca gaagtccctg tccctgagcc ccggc 1125
<210> 3
<211> 375
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 3
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
145 150 155 160
Pro Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro
165 170 175
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
180 185 190
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
195 200 205
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
210 215 220
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
225 230 235 240
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
245 250 255
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
260 265 270
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
275 280 285
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
290 295 300
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
305 310 315 320
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
325 330 335
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
340 345 350
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
355 360 365
Ser Leu Ser Leu Ser Pro Gly
370 375
<210> 4
<211> 1125
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 4
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc gggagcccaa atcttccgac aagacccata cctgtccacc ttgccctgcc 480
cccgagctgc tgggaggatc ctctgtgttc ctgttccccc caaagcccaa ggacaccctg 540
atgatctccc ggacccctga agtgacctgc gtggtggtgg atgtgtccca cgaggatccc 600
gaagtgaagt tcaattggta cgtggacggc gtggaagtgc acaacgccaa gaccaagccc 660
agagaggaac agtacaactc cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag 720
gattggctga acggcaaaga gtacaagtgc aaggtgtcca acaaggccct gcctgcctcc 780
atcgaaaaga ccatctccaa ggccaagggc cagccccggg aaccccaggt gtacacactg 840
ccccctagcc gggaagagat gacaaagaac caggtgtccc tgacctgtct cgtgaaggga 900
ttctacccct ccgatatcgc cgtggaatgg gagtccaacg gccagcctga gaacaactac 960
aagaccaccc cccctgtgct ggactccgac ggctcattct tcctgtactc caagctgaca 1020
gtggacaagt cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggcc 1080
ctgcacaacc actacaccca gaagtccctg tccctgagcc ccggc 1125
<210> 5
<211> 370
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 5
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Lys Ser Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
145 150 155 160
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
165 170 175
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
180 185 190
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met Glu Val His
195 200 205
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
210 215 220
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
225 230 235 240
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
245 250 255
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
260 265 270
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
275 280 285
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
290 295 300
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
305 310 315 320
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
325 330 335
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
340 345 350
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
355 360 365
Gly Lys
370
<210> 6
<211> 1110
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 6
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc ggaaatcctg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 480
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 540
gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 600
tacgtggacg gcatggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 660
agcacgttcc gtgtggtcag cgtcctcacc gtcgtgcacc aggactggct gaacggcaag 720
gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 780
aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 840
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 900
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 960
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1020
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 1080
cagaagagcc tctccctgtc tccgggtaaa 1110
<210> 7
<211> 370
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 7
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
145 150 155 160
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
165 170 175
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
180 185 190
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met Glu Val His
195 200 205
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
210 215 220
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
225 230 235 240
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
245 250 255
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
260 265 270
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
275 280 285
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
290 295 300
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
305 310 315 320
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
325 330 335
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
340 345 350
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
355 360 365
Gly Lys
370
<210> 8
<211> 1110
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 8
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc ggaaatgttg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 480
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 540
gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 600
tacgtggacg gcatggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 660
agcacgttcc gtgtggtcag cgtcctcacc gtcgtgcacc aggactggct gaacggcaag 720
gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 780
aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 840
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 900
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 960
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1020
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 1080
cagaagagcc tctccctgtc tccgggtaaa 1110
<210> 9
<211> 375
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 9
Ala Val Leu Pro Gln Glu Glu Glu Gly Ala Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
145 150 155 160
Pro Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro
165 170 175
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
180 185 190
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
195 200 205
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
210 215 220
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
225 230 235 240
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
245 250 255
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
260 265 270
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
275 280 285
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
290 295 300
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
305 310 315 320
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
325 330 335
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
340 345 350
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
355 360 365
Ser Leu Ser Leu Ser Pro Gly
370 375
<210> 10
<211> 1125
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 10
gctgtgctgc ctcaggaaga ggaaggcgca ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc gggagcccaa atcttccgac aagacccata cctgtccacc ttgccctgcc 480
cccgagctgc tgggaggatc ctctgtgttc ctgttccccc caaagcccaa ggacaccctg 540
atgatctccc ggacccctga agtgacctgc gtggtggtgg atgtgtccca cgaggatccc 600
gaagtgaagt tcaattggta cgtggacggc gtggaagtgc acaacgccaa gaccaagccc 660
agagaggaac agtacaactc cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag 720
gattggctga acggcaaaga gtacaagtgc aaggtgtcca acaaggccct gcctgcctcc 780
atcgaaaaga ccatctccaa ggccaagggc cagccccggg aaccccaggt gtacacactg 840
ccccctagcc gggaagagat gacaaagaac caggtgtccc tgacctgtct cgtgaaggga 900
ttctacccct ccgatatcgc cgtggaatgg gagtccaacg gccagcctga gaacaactac 960
aagaccaccc cccctgtgct ggactccgac ggctcattct tcctgtactc caagctgaca 1020
gtggacaagt cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggcc 1080
ctgcacaacc actacaccca gaagtccctg tccctgagcc ccggc 1125
<210> 11
<211> 353
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 11
Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala Gly Pro Cys Met Gly Met
1 5 10 15
Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser Met Ala Cys Glu Thr Phe
20 25 30
Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn Asn Phe Val Thr Glu Lys
35 40 45
Glu Cys Leu Gln Thr Cys Arg Thr Val Ala Ala Cys Asn Leu Pro Ile
50 55 60
Val Arg Gly Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala Phe Asp Ala
65 70 75 80
Val Lys Gly Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys Gln Gly Asn
85 90 95
Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr Cys Gly Val
100 105 110
Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg Glu Pro Lys Ser Ser Asp
115 120 125
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
130 135 140
Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
145 150 155 160
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
165 170 175
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
180 185 190
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
195 200 205
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
210 215 220
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu
225 230 235 240
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
245 250 255
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
260 265 270
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
275 280 285
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
290 295 300
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
305 310 315 320
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
325 330 335
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
340 345 350
Gly
<210> 12
<211> 1059
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 12
gaggactcct gccagctggg ctactctgcc ggcccttgta tgggcatgac ctcccggtac 60
ttctacaacg gcacctccat ggcctgcgag acattccagt acggcggctg catgggcaac 120
ggcaacaact ttgtgacaga gaaagagtgc ctgcagacct gcagaaccgt ggccgcctgt 180
aacctgccta tcgtgcgggg accctgtcgg gcctttatcc agctgtgggc cttcgacgcc 240
gtgaagggca aatgcgtgct gttcccctat ggcggctgcc agggaaatgg aaacaagttc 300
tactccgaga aagaatgccg cgagtactgt ggcgtgccag gcgacgggga tgaggaactg 360
ctgcgggagc ccaaatcttc cgacaagacc catacctgtc caccttgccc tgcccccgag 420
ctgctgggag gatcctctgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 480
tcccggaccc ctgaagtgac ctgcgtggtg gtggatgtgt cccacgagga tcccgaagtg 540
aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 600
gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggattgg 660
ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc ctccatcgaa 720
aagaccatct ccaaggccaa gggccagccc cgggaacccc aggtgtacac actgccccct 780
agccgggaag agatgacaaa gaaccaggtg tccctgacct gtctcgtgaa gggattctac 840
ccctccgata tcgccgtgga atgggagtcc aacggccagc ctgagaacaa ctacaagacc 900
accccccctg tgctggactc cgacggctca ttcttcctgt actccaagct gacagtggac 960
aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 1020
aaccactaca cccagaagtc cctgtccctg agccccggc 1059
<210> 13
<211> 253
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 13
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Pro Lys Ser Ser Asp Lys Thr His Thr
20 25 30
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Ser Ser Val Phe
35 40 45
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
50 55 60
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
65 70 75 80
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
85 90 95
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
100 105 110
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
115 120 125
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
130 135 140
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
145 150 155 160
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
165 170 175
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
180 185 190
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
195 200 205
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
210 215 220
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
225 230 235 240
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
245 250
<210> 14
<211> 759
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 14
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagc ccaaatcttc cgacaagacc catacctgtc caccttgccc tgcccccgag 120
ctgctgggag gatcctctgt gttcctgttc cccccaaagc ccaaggacac cctgatgatc 180
tcccggaccc ctgaagtgac ctgcgtggtg gtggatgtgt cccacgagga tcccgaagtg 240
aagttcaatt ggtacgtgga cggcgtggaa gtgcacaacg ccaagaccaa gcccagagag 300
gaacagtaca actccaccta ccgggtggtg tccgtgctga ccgtgctgca ccaggattgg 360
ctgaacggca aagagtacaa gtgcaaggtg tccaacaagg ccctgcctgc ctccatcgaa 420
aagaccatct ccaaggccaa gggccagccc cgggaacccc aggtgtacac actgccccct 480
agccgggaag agatgacaaa gaaccaggtg tccctgacct gtctcgtgaa gggattctac 540
ccctccgata tcgccgtgga atgggagtcc aacggccagc ctgagaacaa ctacaagacc 600
accccccctg tgctggactc cgacggctca ttcttcctgt actccaagct gacagtggac 660
aagtcccggt ggcagcaggg caacgtgttc tcctgctccg tgatgcacga ggccctgcac 720
aaccactaca cccagaagtc cctgtccctg agccccggc 759
<210> 15
<211> 384
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 15
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Ser Asp Lys
145 150 155 160
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Ser
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys
260 265 270
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
<210> 16
<211> 1152
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 16
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgg gaggtggtgg atcaggtggc ggaggatcag agcccaaatc ttccgacaag 480
acccatacct gtccaccttg ccctgccccc gagctgctgg gaggatcctc tgtgttcctg 540
ttccccccaa agcccaagga caccctgatg atctcccgga cccctgaagt gacctgcgtg 600
gtggtggatg tgtcccacga ggatcccgaa gtgaagttca attggtacgt ggacggcgtg 660
gaagtgcaca acgccaagac caagcccaga gaggaacagt acaactccac ctaccgggtg 720
gtgtccgtgc tgaccgtgct gcaccaggat tggctgaacg gcaaagagta caagtgcaag 780
gtgtccaaca aggccctgcc tgcctccatc gaaaagacca tctccaaggc caagggccag 840
ccccgggaac cccaggtgta cacactgccc cctagccggg aagagatgac aaagaaccag 900
gtgtccctga cctgtctcgt gaagggattc tacccctccg atatcgccgt ggaatgggag 960
tccaacggcc agcctgagaa caactacaag accacccccc ctgtgctgga ctccgacggc 1020
tcattcttcc tgtactccaa gctgacagtg gacaagtccc ggtggcagca gggcaacgtg 1080
ttctcctgct ccgtgatgca cgaggccctg cacaaccact acacccagaa gtccctgtcc 1140
ctgagccccg gc 1152
<210> 17
<211> 365
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 17
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Ser Ser Val Phe
145 150 155 160
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
165 170 175
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
180 185 190
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
195 200 205
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
210 215 220
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
225 230 235 240
Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser
245 250 255
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
260 265 270
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
275 280 285
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
290 295 300
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
305 310 315 320
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
325 330 335
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
340 345 350
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
355 360 365
<210> 18
<211> 1095
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 18
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc ggtgtccacc ttgccctgcc cccgagctgc tgggaggatc ctctgtgttc 480
ctgttccccc caaagcccaa ggacaccctg atgatctccc ggacccctga agtgacctgc 540
gtggtggtgg atgtgtccca cgaggatccc gaagtgaagt tcaattggta cgtggacggc 600
gtggaagtgc acaacgccaa gaccaagccc agagaggaac agtacaactc cacctaccgg 660
gtggtgtccg tgctgaccgt gctgcaccag gattggctga acggcaaaga gtacaagtgc 720
aaggtgtcca acaaggccct gcctgcctcc atcgaaaaga ccatctccaa ggccaagggc 780
cagccccggg aaccccaggt gtacacactg ccccctagcc gggaagagat gacaaagaac 840
caggtgtccc tgacctgtct cgtgaaggga ttctacccct ccgatatcgc cgtggaatgg 900
gagtccaacg gccagcctga gaacaactac aagaccaccc cccctgtgct ggactccgac 960
ggctcattct tcctgtactc caagctgaca gtggacaagt cccggtggca gcagggcaac 1020
gtgttctcct gctccgtgat gcacgaggcc ctgcacaacc actacaccca gaagtccctg 1080
tccctgagcc ccggc 1095
<210> 19
<211> 343
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 19
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Ser Ser Val Phe Leu Phe Pro Pro Lys Pro
130 135 140
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
145 150 155 160
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
165 170 175
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
180 185 190
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
195 200 205
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
210 215 220
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
225 230 235 240
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
245 250 255
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
260 265 270
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
275 280 285
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
290 295 300
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
305 310 315 320
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
325 330 335
Ser Leu Ser Leu Ser Pro Gly
340
<210> 20
<211> 1029
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 20
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgtcctctgt gttcctgttc 420
cccccaaagc ccaaggacac cctgatgatc tcccggaccc ctgaagtgac ctgcgtggtg 480
gtggatgtgt cccacgagga tcccgaagtg aagttcaatt ggtacgtgga cggcgtggaa 540
gtgcacaacg ccaagaccaa gcccagagag gaacagtaca actccaccta ccgggtggtg 600
tccgtgctga ccgtgctgca ccaggattgg ctgaacggca aagagtacaa gtgcaaggtg 660
tccaacaagg ccctgcctgc ctccatcgaa aagaccatct ccaaggccaa gggccagccc 720
cgggaacccc aggtgtacac actgccccct agccgggaag agatgacaaa gaaccaggtg 780
tccctgacct gtctcgtgaa gggattctac ccctccgata tcgccgtgga atgggagtcc 840
aacggccagc ctgagaacaa ctacaagacc accccccctg tgctggactc cgacggctca 900
ttcttcctgt actccaagct gacagtggac aagtcccggt ggcagcaggg caacgtgttc 960
tcctgctccg tgatgcacga ggccctgcac aaccactaca cccagaagtc cctgtccctg 1020
agccccggc 1029
<210> 21
<211> 375
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 21
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Ser Ser Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
145 150 155 160
Pro Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro
165 170 175
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
180 185 190
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
195 200 205
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
210 215 220
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
225 230 235 240
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
245 250 255
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
260 265 270
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
275 280 285
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
290 295 300
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
305 310 315 320
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
325 330 335
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
340 345 350
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
355 360 365
Ser Leu Ser Leu Ser Pro Gly
370 375
<210> 22
<211> 1125
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 22
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
tcctccgagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag aaccgtggcc 240
gcctgtaacc tgcctatcgt gcggggaccc tgtcgggcct ttatccagct gtgggccttc 300
gacgccgtga agggcaaatg cgtgctgttc ccctatggcg gctgccaggg aaatggaaac 360
aagttctact ccgagaaaga atgccgcgag tactgtggcg tgccaggcga cggggatgag 420
gaactgctgc gggagcccaa atcttccgac aagacccata cctgtccacc ttgccctgcc 480
cccgagctgc tgggaggatc ctctgtgttc ctgttccccc caaagcccaa ggacaccctg 540
atgatctccc ggacccctga agtgacctgc gtggtggtgg atgtgtccca cgaggatccc 600
gaagtgaagt tcaattggta cgtggacggc gtggaagtgc acaacgccaa gaccaagccc 660
agagaggaac agtacaactc cacctaccgg gtggtgtccg tgctgaccgt gctgcaccag 720
gattggctga acggcaaaga gtacaagtgc aaggtgtcca acaaggccct gcctgcctcc 780
atcgaaaaga ccatctccaa ggccaagggc cagccccggg aaccccaggt gtacacactg 840
ccccctagcc gggaagagat gacaaagaac caggtgtccc tgacctgtct cgtgaaggga 900
ttctacccct ccgatatcgc cgtggaatgg gagtccaacg gccagcctga gaacaactac 960
aagaccaccc cccctgtgct ggactccgac ggctcattct tcctgtactc caagctgaca 1020
gtggacaagt cccggtggca gcagggcaac gtgttctcct gctccgtgat gcacgaggcc 1080
ctgcacaacc actacaccca gaagtccctg tccctgagcc ccggc 1125
<210> 23
<211> 320
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 23
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Thr Val Ala Ala Cys Asn Leu Pro Ile Val
20 25 30
Arg Gly Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala Phe Asp Ala Val
35 40 45
Lys Gly Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys Gln Gly Asn Gly
50 55 60
Asn Lys Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr Cys Gly Val Pro
65 70 75 80
Gly Asp Gly Asp Glu Glu Leu Leu Arg Glu Pro Lys Ser Ser Asp Lys
85 90 95
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Ser
100 105 110
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
115 120 125
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
130 135 140
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
145 150 155 160
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
165 170 175
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
180 185 190
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Ser Ile Glu Lys
195 200 205
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
210 215 220
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
225 230 235 240
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
245 250 255
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
260 265 270
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
275 280 285
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
290 295 300
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
305 310 315 320
<210> 24
<211> 960
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 24
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaaaccg tggccgcctg taacctgcct atcgtgcggg gaccctgtcg ggcctttatc 120
cagctgtggg ccttcgacgc cgtgaagggc aaatgcgtgc tgttccccta tggcggctgc 180
cagggaaatg gaaacaagtt ctactccgag aaagaatgcc gcgagtactg tggcgtgcca 240
ggcgacgggg atgaggaact gctgcgggag cccaaatctt ccgacaagac ccatacctgt 300
ccaccttgcc ctgcccccga gctgctggga ggatcctctg tgttcctgtt ccccccaaag 360
cccaaggaca ccctgatgat ctcccggacc cctgaagtga cctgcgtggt ggtggatgtg 420
tcccacgagg atcccgaagt gaagttcaat tggtacgtgg acggcgtgga agtgcacaac 480
gccaagacca agcccagaga ggaacagtac aactccacct accgggtggt gtccgtgctg 540
accgtgctgc accaggattg gctgaacggc aaagagtaca agtgcaaggt gtccaacaag 600
gccctgcctg cctccatcga aaagaccatc tccaaggcca agggccagcc ccgggaaccc 660
caggtgtaca cactgccccc tagccgggaa gagatgacaa agaaccaggt gtccctgacc 720
tgtctcgtga agggattcta cccctccgat atcgccgtgg aatgggagtc caacggccag 780
cctgagaaca actacaagac caccccccct gtgctggact ccgacggctc attcttcctg 840
tactccaagc tgacagtgga caagtcccgg tggcagcagg gcaacgtgtt ctcctgctcc 900
gtgatgcacg aggccctgca caaccactac acccagaagt ccctgtccct gagccccggc 960
<210> 25
<211> 308
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 25
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Glu Pro Lys
65 70 75 80
Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
85 90 95
Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
100 105 110
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
115 120 125
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
130 135 140
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
145 150 155 160
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
165 170 175
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
180 185 190
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
195 200 205
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
210 215 220
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
225 230 235 240
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
245 250 255
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
260 265 270
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
275 280 285
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
290 295 300
Leu Ser Pro Gly
305
<210> 26
<211> 924
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 26
gctgtgctgc ctcaggaaga ggaaggctct ggcggaggcc agctcgtgac cgaagtgacc 60
aagaaagagg actcctgcca gctgggctac tctgccggcc cttgtatggg catgacctcc 120
cggtacttct acaacggcac ctccatggcc tgcgagacat tccagtacgg cggctgcatg 180
ggcaacggca acaactttgt gacagagaaa gagtgcctgc agacctgcag agagcccaaa 240
tcttccgaca agacccatac ctgtccacct tgccctgccc ccgagctgct gggaggatcc 300
tctgtgttcc tgttcccccc aaagcccaag gacaccctga tgatctcccg gacccctgaa 360
gtgacctgcg tggtggtgga tgtgtcccac gaggatcccg aagtgaagtt caattggtac 420
gtggacggcg tggaagtgca caacgccaag accaagccca gagaggaaca gtacaactcc 480
acctaccggg tggtgtccgt gctgaccgtg ctgcaccagg attggctgaa cggcaaagag 540
tacaagtgca aggtgtccaa caaggccctg cctgcctcca tcgaaaagac catctccaag 600
gccaagggcc agccccggga accccaggtg tacacactgc cccctagccg ggaagagatg 660
acaaagaacc aggtgtccct gacctgtctc gtgaagggat tctacccctc cgatatcgcc 720
gtggaatggg agtccaacgg ccagcctgag aacaactaca agaccacccc ccctgtgctg 780
gactccgacg gctcattctt cctgtactcc aagctgacag tggacaagtc ccggtggcag 840
cagggcaacg tgttctcctg ctccgtgatg cacgaggccc tgcacaacca ctacacccag 900
aagtccctgt ccctgagccc cggc 924
<210> 27
<211> 374
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 27
Ala Val Leu Pro Gln Glu Ser Glu Gly Ser Gly Thr Glu Pro Leu Ile
1 5 10 15
Thr Gly Thr Leu Lys Lys Glu Asp Ser Cys Gln Leu Asn Tyr Ser Glu
20 25 30
Gly Pro Cys Leu Gly Met Gln Glu Arg Tyr Tyr Tyr Asn Gly Ala Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Leu Gly Asn Gly Asn
50 55 60
Asn Phe Ile Ser Glu Lys Asp Cys Leu Gln Thr Cys Arg Thr Ile Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Gln Gly Pro Cys Arg Ala Phe Ile Lys
85 90 95
Leu Trp Ala Phe Asp Ala Ala Gln Gly Lys Cys Ile Gln Phe His Tyr
100 105 110
Gly Gly Cys Lys Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Lys Glu Tyr Cys Gly Val Pro Gly Asp Gly Tyr Glu Glu Leu Ile Arg
130 135 140
Ser Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr
145 150 155 160
Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp
165 170 175
Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp
180 185 190
Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp
195 200 205
Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn
210 215 220
Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp
225 230 235 240
Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro
245 250 255
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala
260 265 270
Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp
275 280 285
Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile
290 295 300
Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn
305 310 315 320
Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys
325 330 335
Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys
340 345 350
Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu
355 360 365
Ser His Ser Pro Gly Lys
370
<210> 28
<211> 1122
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 28
gcagtgctgc cccaagagag tgaggggtca gggactgagc cactaataac tgggaccctc 60
aagaaagaag actcctgcca gctcaattac tcagaaggcc cctgcctagg gatgcaagag 120
aggtattact acaacggcgc ttccatggcc tgcgagacct ttcaatatgg gggttgccta 180
ggcaacggca acaacttcat ctctgagaag gactgtctgc agacatgtcg gaccatagcg 240
gcctgcaatc tccccatagt ccaaggcccc tgccgagcct tcataaagct ctgggcattt 300
gatgcagcac aagggaagtg catccaattc cactacgggg gctgcaaagg caacggcaac 360
aaattctact ctgagaagga atgcaaagag tactgtggag tccctggtga tgggtacgag 420
gaactaatac gcagtaaaat cgtgcctcgg gactgcggct gcaagccctg catctgcacc 480
gtgcccgagg tgtcctccgt gttcatcttc ccacccaagc ccaaggacgt gctgaccatc 540
accctgaccc ccaaagtgac ctgcgtggtg gtggacatct ccaaggacga ccccgaggtg 600
cagttcagtt ggttcgtgga cgacgtggaa gtgcacaccg cccagaccca gcccagagag 660
gaacagttca actccacctt cagatccgtg tccgagctgc ccatcatgca ccaggactgg 720
ctgaacggca aagagttcaa gtgcagagtg aactccgccg ccttcccagc ccccatcgaa 780
aagaccatct ccaagaccaa gggcagaccc aaggcccccc aggtgtacac catcccccca 840
cccaaagaac agatggccaa ggacaaggtg tccctgacct gcatgatcac cgatttcttc 900
ccagaggaca tcaccgtgga atggcagtgg aacggccagc ccgccgagaa ctacaagaac 960
acccagccca tcatggacac cgacggctcc tacttcgtgt actccaagct gaacgtgcag 1020
aagtccaact gggaggccgg caacaccttc acctgtagcg tgctgcacga gggcctgcac 1080
aaccaccaca ccgagaagtc cctgtcccac tcccccggca ag 1122
<210> 29
<211> 391
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 29
Glu Pro Lys Ser Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Ser Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Gly Gly Gly Gly Ser Ala Val Leu Pro Gln Glu Glu Glu Gly
245 250 255
Ser Gly Gly Gly Gln Leu Val Thr Glu Val Thr Lys Lys Glu Asp Ser
260 265 270
Cys Gln Leu Gly Tyr Ser Ala Gly Pro Cys Met Gly Met Thr Ser Arg
275 280 285
Tyr Phe Tyr Asn Gly Thr Ser Met Ala Cys Glu Thr Phe Gln Tyr Gly
290 295 300
Gly Cys Met Gly Asn Gly Asn Asn Phe Val Thr Glu Lys Glu Cys Leu
305 310 315 320
Gln Thr Cys Arg Thr Val Ala Ala Cys Asn Leu Pro Ile Val Arg Gly
325 330 335
Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala Phe Asp Ala Val Lys Gly
340 345 350
Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys Gln Gly Asn Gly Asn Lys
355 360 365
Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr Cys Gly Val Pro Gly Asp
370 375 380
Gly Asp Glu Glu Leu Leu Arg
385 390
<210> 30
<211> 1173
<212> DNA
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多核苷酸"
<400> 30
gagcccaaat cttccgacaa gacccatacc tgtccacctt gccctgcccc cgagctgctg 60
ggaggatcct ctgtgttcct gttcccccca aagcccaagg acaccctgat gatctcccgg 120
acccctgaag tgacctgcgt ggtggtggat gtgtcccacg aggatcccga agtgaagttc 180
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcccag agaggaacag 240
tacaactcca cctaccgggt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 300
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgcctccat cgaaaagacc 360
atctccaagg ccaagggcca gccccgggaa ccccaggtgt acacactgcc ccctagccgg 420
gaagagatga caaagaacca ggtgtccctg acctgtctcg tgaagggatt ctacccctcc 480
gatatcgccg tggaatggga gtccaacggc cagcctgaga acaactacaa gaccaccccc 540
cctgtgctgg actccgacgg ctcattcttc ctgtactcca agctgacagt ggacaagtcc 600
cggtggcagc agggcaacgt gttctcctgc tccgtgatgc acgaggccct gcacaaccac 660
tacacccaga agtccctgtc cctgagcccc ggcaagggag gtggtggatc aggaggtgga 720
ggttccggtg gcggaggatc agctgtgctg cctcaggaag aggaaggctc tggcggaggc 780
cagctcgtga ccgaagtgac caagaaagag gactcctgcc agctgggcta ctctgccggc 840
ccttgtatgg gcatgacctc ccggtacttc tacaacggca cctccatggc ctgcgagaca 900
ttccagtacg gcggctgcat gggcaacggc aacaactttg tgacagagaa agagtgcctg 960
cagacctgca gaaccgtggc cgcctgtaac ctgcctatcg tgcggggacc ctgtcgggcc 1020
tttatccagc tgtgggcctt cgacgccgtg aagggcaaat gcgtgctgtt cccctatggc 1080
ggctgccagg gaaatggaaa caagttctac tccgagaaag aatgccgcga gtactgtggc 1140
gtgccaggcg acggggatga ggaactgctg cgg 1173
<210> 31
<211> 147
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 31
Ala Val Leu Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val
1 5 10 15
Thr Glu Val Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala
20 25 30
Gly Pro Cys Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser
35 40 45
Met Ala Cys Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn
50 55 60
Asn Phe Val Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala
65 70 75 80
Ala Cys Asn Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln
85 90 95
Leu Trp Ala Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr
100 105 110
Gly Gly Cys Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys
115 120 125
Arg Glu Tyr Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg
130 135 140
Phe Ser Asn
145
<210> 32
<211> 352
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 32
Met Arg Ser Leu Gly Ala Leu Leu Leu Leu Leu Ser Ala Cys Leu Ala
1 5 10 15
Val Ser Ala Gly Pro Val Pro Thr Pro Pro Asp Asn Ile Gln Val Gln
20 25 30
Glu Asn Phe Asn Ile Ser Arg Ile Tyr Gly Lys Trp Tyr Asn Leu Ala
35 40 45
Ile Gly Ser Thr Cys Pro Trp Leu Lys Lys Ile Met Asp Arg Met Thr
50 55 60
Val Ser Thr Leu Val Leu Gly Glu Gly Ala Thr Glu Ala Glu Ile Ser
65 70 75 80
Met Thr Ser Thr Arg Trp Arg Lys Gly Val Cys Glu Glu Thr Ser Gly
85 90 95
Ala Tyr Glu Lys Thr Asp Thr Asp Gly Lys Phe Leu Tyr His Lys Ser
100 105 110
Lys Trp Asn Ile Thr Met Glu Ser Tyr Val Val His Thr Asn Tyr Asp
115 120 125
Glu Tyr Ala Ile Phe Leu Thr Lys Lys Phe Ser Arg His His Gly Pro
130 135 140
Thr Ile Thr Ala Lys Leu Tyr Gly Arg Ala Pro Gln Leu Arg Glu Thr
145 150 155 160
Leu Leu Gln Asp Phe Arg Val Val Ala Gln Gly Val Gly Ile Pro Glu
165 170 175
Asp Ser Ile Phe Thr Met Ala Asp Arg Gly Glu Cys Val Pro Gly Glu
180 185 190
Gln Glu Pro Glu Pro Ile Leu Ile Pro Arg Val Arg Arg Ala Val Leu
195 200 205
Pro Gln Glu Glu Glu Gly Ser Gly Gly Gly Gln Leu Val Thr Glu Val
210 215 220
Thr Lys Lys Glu Asp Ser Cys Gln Leu Gly Tyr Ser Ala Gly Pro Cys
225 230 235 240
Met Gly Met Thr Ser Arg Tyr Phe Tyr Asn Gly Thr Ser Met Ala Cys
245 250 255
Glu Thr Phe Gln Tyr Gly Gly Cys Met Gly Asn Gly Asn Asn Phe Val
260 265 270
Thr Glu Lys Glu Cys Leu Gln Thr Cys Arg Thr Val Ala Ala Cys Asn
275 280 285
Leu Pro Ile Val Arg Gly Pro Cys Arg Ala Phe Ile Gln Leu Trp Ala
290 295 300
Phe Asp Ala Val Lys Gly Lys Cys Val Leu Phe Pro Tyr Gly Gly Cys
305 310 315 320
Gln Gly Asn Gly Asn Lys Phe Tyr Ser Glu Lys Glu Cys Arg Glu Tyr
325 330 335
Cys Gly Val Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg Phe Ser Asn
340 345 350
<210> 33
<211> 6
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成
肽"
<400> 33
Ser Gly Gly Gly Gly Ser
1 5
<210> 34
<211> 11
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成
肽"
<400> 34
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 35
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成
肽"
<400> 35
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 36
<211> 21
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成
肽"
<400> 36
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser
20
<210> 37
<211> 26
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成
肽"
<400> 37
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25
<210> 38
<211> 31
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 38
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
<210> 39
<211> 36
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 39
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25 30
Gly Gly Gly Ser
35
<210> 40
<211> 41
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 40
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40
<210> 41
<211> 46
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 41
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
<210> 42
<211> 51
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成多肽"
<400> 42
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
20 25 30
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
35 40 45
Gly Gly Ser
50
<210> 43
<211> 16
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 43
Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 44
<211> 19
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 44
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 45
<211> 19
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 45
Pro Gly Asp Gly Asp Glu Glu Leu Leu Arg Glu Pro Lys Ser Ser Asp
1 5 10 15
Lys Thr His
<210> 46
<211> 19
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 46
Pro Gly Asp Gly Asp Glu Glu Leu Leu Gly Ser Gly Gly Gly Gly Asp
1 5 10 15
Lys Thr His
<210> 47
<211> 10
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 47
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 48
<211> 15
<212> PRT
<213> 人工序列
<220>
<221> 来源
<223> /注释="人工序列的描述: 合成肽"
<400> 48
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
Claims (14)
1.UTI-Fc融合蛋白,其由以下(a)和(b)组成:
(a)SEQ ID NO:1的氨基酸1~149,其可操作地连接至
(b)野生型IgG1 Fc结构域,其中所述Fc结构域包含排除第一恒定区免疫球蛋白结构域的抗体的恒定区。
2.二聚体,其由2个分离的权利要求1的UTI-Fc融合蛋白组成,其中所述Fc结构域共价缔合。
3.药物组合物,其包含:
权利要求1的UTI-Fc融合蛋白或者权利要求2的二聚体,及
药学可接受的赋形剂。
4.核酸,其编码权利要求1的UTI-Fc融合蛋白或者权利要求2的二聚体。
5.表达载体,其包含权利要求4的核酸。
6.重组宿主细胞,其包含权利要求5的表达载体。
7.权利要求6的重组宿主细胞,其中所述细胞选自:哺乳动物细胞、昆虫细胞、大肠杆菌细胞及酵母细胞。
8.权利要求7的重组宿主细胞,其中所述哺乳动物细胞选自:中国仓鼠卵巢细胞、HEK293细胞、NSO细胞、HeLa细胞、幼仓鼠肾脏细胞、猴肾脏细胞及人肝细胞癌细胞。
9.产生权利要求1的UTI-Fc融合蛋白的方法,其包括:
将权利要求6~8之任一项的重组宿主细胞放入生长培养基,从而表达重组融合蛋白,及
从所述细胞或生长培养基分离所述重组融合蛋白。
10.权利要求1的UTI-Fc融合蛋白或者权利要求2的二聚体用于制造治疗UTI相关病症的药物的用途。
11.权利要求10的用途,其中所述UTI相关病症选自:胰腺炎、关节炎、SARS、全身炎症反应综合征、急性循环衰竭、败血症、肝炎、阑尾炎、结肠炎、器官衰竭、器官损伤、再灌注损伤、斯蒂文斯-约翰逊综合征、毒性表皮坏死溶解、休克、缺血性损伤、哮喘、肺炎症(lunginflammation)、弥散性血管内凝血及急性呼吸窘迫综合征。
12.由SEQ ID NO:1组成的尿胰蛋白酶抑制剂-Fc(UTI-Fc)融合蛋白用于制造治疗UTI相关病症的药物的用途,其中所述UTI相关病症选自:胰腺炎、关节炎、SARS、全身炎症反应综合征、急性循环衰竭、败血症、肝炎、阑尾炎、结肠炎、器官衰竭、器官损伤、再灌注损伤、斯蒂文斯-约翰逊综合征、毒性表皮坏死溶解、休克、缺血性损伤、哮喘、肺炎症(lunginflammation)、弥散性血管内凝血及急性呼吸窘迫综合征。
13.权利要求11或12的用途,
其中所述胰腺炎是急性胰腺炎或内窥镜检查诱导的胰腺炎;
其中所述器官损伤是胰腺损伤、肾脏损伤或肺损伤;且
其中所述肺炎症(lunginflammation)是肺炎(pneumonia)。
14.权利要求13的用途,
其中所述肺损伤是急性肺损伤或由急性主动脉夹层造成的肺损伤;且
其中所述肺炎(pneumonia)是呼吸器相关的肺炎。
Priority Applications (1)
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CN201910282497.3A CN110092837B (zh) | 2014-02-24 | 2015-02-23 | Uti融合蛋白 |
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US201461943617P | 2014-02-24 | 2014-02-24 | |
US61/943,617 | 2014-02-24 | ||
CN201580014645.3A CN106232135B (zh) | 2014-02-24 | 2015-02-23 | Uti融合蛋白 |
CN201910282497.3A CN110092837B (zh) | 2014-02-24 | 2015-02-23 | Uti融合蛋白 |
PCT/US2015/017152 WO2015127391A1 (en) | 2014-02-24 | 2015-02-23 | Uti fusion proteins |
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CN201580014645.3A Division CN106232135B (zh) | 2014-02-24 | 2015-02-23 | Uti融合蛋白 |
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CN110092837A CN110092837A (zh) | 2019-08-06 |
CN110092837B true CN110092837B (zh) | 2024-01-02 |
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PL3110434T3 (pl) * | 2014-02-24 | 2019-01-31 | Takeda Gmbh | Białka fuzyjne uti |
EP3635108A4 (en) * | 2017-06-07 | 2021-03-31 | Spark Therapeutics, Inc. | REINFORCEMENT AGENT FOR IMPROVED CELL TRANSFECTION AND / OR RAV VECTOR PRODUCTION |
WO2020106881A1 (en) * | 2018-11-20 | 2020-05-28 | Diamedica Inc. | Modified ulinastatin polypeptides |
JP2021050161A (ja) | 2019-09-25 | 2021-04-01 | 武田薬品工業株式会社 | 複素環化合物及びその用途 |
JP2021080177A (ja) | 2019-11-14 | 2021-05-27 | 武田薬品工業株式会社 | 複素環化合物及びその用途 |
US11725043B2 (en) | 2020-03-05 | 2023-08-15 | DiaMedica USA Inc. | Ulinastatin polypeptides |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101124248A (zh) * | 2004-08-11 | 2008-02-13 | 特鲁比昂药品公司 | 结合域融合蛋白 |
CN101721699A (zh) * | 2008-10-13 | 2010-06-09 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗伴随vegf升高的炎症反应的药物中的应用 |
CN102580085A (zh) * | 2008-10-13 | 2012-07-18 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗脓毒症药物中的应用 |
CN103044554A (zh) * | 2012-05-14 | 2013-04-17 | 旭华(上海)生物研发中心有限公司 | 重组二聚化人尿胰蛋白酶抑制剂、其制备方法及其应用 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5663143A (en) * | 1988-09-02 | 1997-09-02 | Dyax Corp. | Engineered human-derived kunitz domains that inhibit human neutrophil elastase |
ES2066033T3 (es) | 1989-05-13 | 1995-03-01 | Bayer Ag | Inhibidores de las proteinasas, procedimiento para su preparacion y composiciones farmaceuticas que los contienen. |
US5409895A (en) | 1990-11-13 | 1995-04-25 | Mochida Pharmaceutical Co., Ltd. | Protease inhibitory polypeptides derived from urinary trypsin inhibitor and compositions thereof |
JP2769083B2 (ja) | 1993-02-22 | 1998-06-25 | 日清食品株式会社 | エラスターゼ阻害活性を有する新規ペプチドおよびその製造方法 |
CA2247888A1 (en) | 1996-03-11 | 1997-09-18 | Bayer Corporation | Human bikunin |
DE19725014A1 (de) | 1997-06-13 | 1998-12-17 | Bayer Ag | Aprotininvarianten mit verbesserten Eigenschaften und Bikunine von Aprotininvarianten |
DK1730191T3 (da) * | 2004-03-30 | 2011-10-17 | Glaxo Group Ltd | Immunglobulin som binder HOSM |
WO2006129849A1 (ja) * | 2005-06-03 | 2006-12-07 | Mochida Pharmaceutical Co., Ltd. | 抗cd14抗体融合蛋白質 |
PT1981519T (pt) | 2005-12-29 | 2018-02-23 | Dyax Corp | Inibição de protéases |
PL2334705T3 (pl) * | 2008-09-26 | 2017-06-30 | Ucb Biopharma Sprl | Produkty biologiczne |
MX2011011815A (es) * | 2009-05-05 | 2012-01-27 | Amgen Inc | Mutantes fgf21 y usos de los mismos. |
IL300276B1 (en) * | 2011-04-29 | 2024-07-01 | Univ Washington | Therapeutic nuclease preparations and methods |
US8619331B2 (en) | 2011-07-19 | 2013-12-31 | Xerox Corporation | Simulated paper texture using clear toner and glossmark on texture-less stock |
CN104159926B (zh) * | 2011-12-01 | 2019-02-01 | 圆祥生命科技有限公司 | 补体和vegf途径的蛋白质抑制剂及其使用方法 |
ES2671631T3 (es) * | 2012-04-23 | 2018-06-07 | Nrl Pharma, Inc. | Proteína de fusión de lactoferrina y método para la preparación de la misma |
JP2013253079A (ja) * | 2012-05-14 | 2013-12-19 | Xuhua (Shanghai) Biological Research & Development Center Co Ltd | 生物学的に活性なヒト尿中トリプシンインヒビターのFc融合タンパク質並びにその調製および使用 |
PL3110434T3 (pl) * | 2014-02-24 | 2019-01-31 | Takeda Gmbh | Białka fuzyjne uti |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101124248A (zh) * | 2004-08-11 | 2008-02-13 | 特鲁比昂药品公司 | 结合域融合蛋白 |
CN101721699A (zh) * | 2008-10-13 | 2010-06-09 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗伴随vegf升高的炎症反应的药物中的应用 |
CN102580085A (zh) * | 2008-10-13 | 2012-07-18 | 成都康弘生物科技有限公司 | Vegf受体融合蛋白在制备治疗脓毒症药物中的应用 |
CN103044554A (zh) * | 2012-05-14 | 2013-04-17 | 旭华(上海)生物研发中心有限公司 | 重组二聚化人尿胰蛋白酶抑制剂、其制备方法及其应用 |
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