CN115028727A - 靶向msln的三特异性蛋白质及使用方法 - Google Patents
靶向msln的三特异性蛋白质及使用方法 Download PDFInfo
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Abstract
本文提供了包含与CD3结合的结构域、半衰期延长结构域和与MSLN结合的结构域的靶向间皮素(MSLN)的三特异性蛋白质。还提供了其药物组合物，以及用于制备这类靶向MSLN的三特异性蛋白质的核酸、重组表达载体和宿主细胞。还公开了使用所公开的靶向MSLN的三特异性蛋白质预防和/或治疗疾病、病况和病症的方法。
Description
本申请是申请日为2018年05月11日、申请号为201880046561.1、发明名称为“靶向MSLN的三特异性蛋白质及使用方法”的中国专利申请(其对应PCT申请的申请日为2018年05月11日、申请号为PCT/US2018/032427)的分案申请。
序列表
本申请包含序列表，该序列表已经以ASCII格式通过电子方式提交，并且通过引用整体并入本文。所述ASCII副本创建于2018年5月11日，被命名为47517-720_601_SL.txt，大小为293,251字节。
背景技术
在多种临床环境中常常需要选择性破坏单个细胞或特定的细胞类型。例如，癌症疗法的首要目标是特定地破坏肿瘤细胞，同时使健康细胞和组织保持完整且不受损伤。一种这样的方法是诱导针对肿瘤的免疫应答，使得免疫效应细胞如自然杀伤(NK)细胞或细胞毒性T淋巴细胞(CTL)攻击并破坏肿瘤细胞。
间皮素(MSLN)是在卵巢癌、胰腺癌、肺癌和三阴性乳腺癌以及间皮瘤中过表达的GPI连接的膜结合肿瘤抗原MSLN。MSLN的正常组织表达局限于内衬于胸膜腔、心包腔和腹膜腔的单细胞间皮层。MSLN的过表达与肺腺癌和三阴性乳腺癌的预后不良相关。MSLN已被用作用于大量方式的癌抗原，包括免疫毒素、疫苗、抗体药物缀合物和CAR-T细胞。临床疗效的早期迹象已确认MSLN为靶标，但是需要疗效改善的疗法来治疗表达MSLN的癌症。
发明内容
一个实施方案提供了结合间皮素的三特异性蛋白质，其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A)；
(b)第二结构域(B)，其为半衰期延长结构域；和
(c)与MSLN特异性结合的第三结构域(C)，
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。在一些实施方案中，第一结构域包含各自能够与人CD3特异性结合的可变轻结构域和可变重结构域。在一些实施方案中，第一结构域是人源化的或人的。在一些实施方案中，第二结构域结合白蛋白。在一些实施方案中，第二结构域包含scFv、可变重结构域(VH)、可变轻结构域(VL)、肽、配体或小分子。在一些实施方案中，第三结构域包含与MSLN特异性结合的VHH结构域、scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。在一些实施方案中，第三结构域包含VHH结构域。在一些实施方案中，所述VHH结构域包含一个或多个保守区，所述保守区包含与SEQ ID NO:41、42、43或44相同或相对于SEQ ID NO:41、42、43或44包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:41相同或相对于SEQ ID NO:41包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:42相同或相对于SEQ ID NO:42包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:43相同或相对于SEQ ID NO:43包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:44相同或相对于SEQ ID NO:44包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含(i)对应于SEQ ID NO:41的一段氨基酸；(ii)对应于SEQ ID NO:42的一段氨基酸；(iii)对应于SEQ ID NO:43的一段氨基酸；和(iv)对应于SEQ ID NO:44的一段氨基酸；在一些实施方案中，所述VHH结构域包含下式：
f1-r1-f2-r2-f3-r3-f4
其中，r1与SEQ ID NO:51相同或相对于SEQ ID NO:51包含一个或多个氨基酸残基置换；r2与SEQ ID NO:52相同或相对于SEQ ID NO:52包含一个或多个氨基酸残基置换；且r3与SEQ ID NO:53相同或相对于SEQ ID NO:53包含一个或多个氨基酸残基置换；并且其中f1、f2、f3和f4是框架残基。在一些实施方案中，所述VHH结构域包含与选自SEQ ID NO:1-29的序列至少80％相同的序列。在一些实施方案中，第三结构域包含选自SEQ ID NO:1-29的序列。在一些实施方案中，第三结构域是人源化的VHH结构域。在一些实施方案中，所述人源化的VHH结构域包含一个或多个保守区，所述保守区包含与SEQ ID NO:45、46、47、48、49或50相同或相对于SEQ ID NO:45、46、47、48、49或50包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:45相同或相对于SEQ ID NO:45包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:46相同或相对于SEQ ID NO:46包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:47相同或相对于SEQ ID NO:47包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:48相同或相对于SEQ ID NO:48包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:49相同或相对于SEQ ID NO:49包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:50相同或相对于SEQ ID NO:50包含一个或多个氨基酸残基置换的序列。在一些实施方案中，所述VHH结构域包含(i)对应于SEQ ID NO:45的一段氨基酸，(ii)对应于SEQ ID NO:46的一段氨基酸，(iii)对应于SEQ ID NO:47的一段氨基酸，(iv)对应于SEQID NO:48的一段氨基酸，(v)对应于SEQ ID NO:49的一段氨基酸，和(vi)对应于SEQ ID NO:50的一段氨基酸；在一些实施方案中，所述人源化的VHH结构域包含下式：
f1-r1-f2-r2-f3-r3-f4
其中，r1与SEQ ID NO:54相同或相对于SEQ ID NO:54包含一个或多个氨基酸残基置换；r2与SEQ ID NO:55相同或相对于SEQ ID NO:55包含一个或多个氨基酸残基置换；且r3与SEQ ID NO:56相同或相对于SEQ ID NO:56包含一个或多个氨基酸残基置换；并且其中f1、f2、f3和f4是框架残基。在一些实施方案中，第三结构域包含选自SEQ ID NO:30-40和102-105的序列。在一些实施方案中，第三结构域与包含SEQ ID NO:57所示序列的人间皮素蛋白质结合。在一些实施方案中，第三结构域与间皮素的表位结合，其中所述表位位于包含SEQ ID NO:57的氨基酸残基296-390的区域I、包含SEQ ID NO:57的氨基酸残基391-486的区域II或包含SEQ ID NO:57的氨基酸残基487-598的区域III中。在一些实施方案中，连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:87)、(GGS)n(SEQ ID NO:88)、(GGGS)n(SEQ IDNO:89)、(GGSG)n(SEQ ID NO:90)、(GGSGG)n(SEQ ID NO:91)或(GGGGS)n(SEQ ID NO:92)，其中n为1、2、3、4、5、6、7、8、9或10。在一些实施方案中，连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:95)或(GGGGS)3(SEQ ID NO:96)。在一些实施方案中，所述结构域以H2N-(C)-(B)-(A)-COOH的顺序连接。在一些实施方案中，所述蛋白质小于约80kDa。在一些实施方案中，所述蛋白质为约50kDa至约75kDa。在一些实施方案中，所述蛋白质小于约60kDa。在一些实施方案中，所述蛋白质具有至少约50小时的消除半衰期。在一些实施方案中，所述蛋白质具有至少约100小时的消除半衰期。在一些实施方案中，与针对相同MSLN的IgG相比，所述蛋白质具有增加的组织穿透。在一些实施方案中，所述蛋白质包含选自SEQ ID NO:58-86、98、100和101的序列。一个实施方案提供了结合间皮素的三特异性蛋白质，其包含如SEQ IDNO:98所示的序列。一个实施方案提供了结合间皮素的三特异性蛋白质，其中所述蛋白质包含：(a)与人CD3特异性结合的第一结构域(A)；(b)第二结构域(B)，其为半衰期延长结构域；和(c)与MSLN特异性结合的第三结构域(C)，其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接，其中所述第三结构域包含一个或多个选自SEQ ID No:51-56和106-222的CDR序列。在一些实施方案中，所述第三结构域包含CDR1，该CDR1包含如SEQ ID No.:51、54和106-144中任一个所示的序列。在一些实施方案中，所述第三结构域包含CDR2，该CDR2包含如SEQ ID No.:52、55和145-183中任一个所示的序列。在一些实施方案中，所述第三结构域包含CDR2，该CDR2包含如SEQ ID No.:53、56和184-222中任一个所示的序列。在一些实施方案中，所述第三结构域包含框架区1(f1)，该框架区1包含如SEQ ID No.:262-300中任一个所示的序列。在一些实施方案中，所述第三结构域包含如SEQ ID No.:301-339中任一个所示的框架区(f2)序列。在一些实施方案中，所述第三结构域包含如SEQ ID No.:340-378中任一个所示的框架区(f3)序列。在一些实施方案中，所述蛋白质包含选自SEQ ID NO:58-86、98、100和101的序列。在一些实施方案中，所述蛋白质包含如SEQ ID NO:98所示的序列。
一个实施方案提供了一种药物组合物，其包含(i)根据上述实施方案中任一项的结合MSLN的三特异性蛋白质，和(ii)药学上可接受的载剂。
一个实施方案提供了一种产生根据上述实施方案中任一项的结合间皮素的三特异性蛋白质的方法，所述方法包括在允许表达结合间皮素的三特异性蛋白质并从培养物中回收和纯化所产生的蛋白质的条件下培养用载体转化或转染的宿主，该载体包含编码根据上述实施方案中任一项的结合间皮素的三特异性蛋白质的核酸序列。
一个实施方案提供了一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括向有需要的受试者施用根据上述实施方案中任一项的结合间皮素的三特异性蛋白质。在一些实施方案中，所述受试者是人。在一些实施方案中，该方法进一步包括将药剂与根据上述实施方案中任一项的单结构域间皮素结合蛋白质联合施用。在一些实施方案中，所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。在一些实施方案中，所述结合间皮素的三特异性蛋白质介导T细胞对表达间皮素的肿瘤细胞的杀伤。在一些实施方案中，所述肿瘤性疾病包括实体瘤疾病。在一些实施方案中，该实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。在一些实施方案中，该实体瘤疾病是转移性的。
一个实施方案提供了一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含选自SEQ ID NO:58-86、98、100和101的序列的结合间皮素的三特异性蛋白质。在一些实施方案中，所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。在一些实施方案中，所述结合间皮素的三特异性蛋白质引导T细胞对表达间皮素的肿瘤细胞的杀伤。在一些实施方案中，所述肿瘤性疾病包括实体瘤疾病。在一些实施方案中，该实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。在一些实施方案中，该实体瘤疾病是转移性的。
一个实施方案提供了一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含如SEQ ID NO:98所示的序列的结合间皮素的三特异性蛋白质。在一些实施方案中，该方法包括以至多10mg/kg的剂量施用所述结合间皮素的三特异性蛋白质。在一些实施方案中，该蛋白质每周施用一次。在一些实施方案中，该蛋白质每周施用两次。在一些实施方案中，该蛋白质每隔一周施用一次。在一些实施方案中，该蛋白质每三周施用一次。
援引并入
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附图说明
本发明的新特征在随附的权利要求书中具体阐述。通过参考以下对利用到本发明原理的说明性实施方案加以阐述的详细描述及其附图，将会对本发明的特征和优点获得更好的理解，在这些附图中：
图1是示例性的靶向MSLN的三特异性抗原结合蛋白质的示意图，其中该蛋白质具有包含抗-CD3ε单链可变片段(scFv)和抗-ALB可变重链区的恒定核心元件；以及抗MSLN结合域，该抗MSLN结合域可以是VHH、VH、scFv、非Ig结合物或配体。
图2示出了示例性TriTAC分子(2A2和2A4)在杀伤表达靶蛋白MSLN的OVCAR8细胞中的效力。
图3示出了本公开的示例性TriTAC分子(MH6T TriTAC)能够引导来自五名供体(供体02；供体86；供体41；供体81；和供体35)的T细胞杀死Caov3细胞。该图还示出了对照TriTAC分子(GFP TriTAC)无法引导来自这五名供体(供体02；供体86；供体41；供体81；和供体35)的T细胞杀死Caov3细胞。
图4示出了本公开的示例性TriTAC分子(MH6T TriTAC)能够引导来自五名供体(供体02；供体86；供体41；供体81；和供体35)的T细胞杀死OVCAR3细胞。该图还示出了对照TriTAC分子(GFP TriTAC)无法引导来自这五名供体(供体02；供体86；供体41；供体81；和供体35)的T细胞杀死OVCAR3细胞。
图5示出了本公开的示例性TriTAC分子(MH6T TriTAC)能够引导来自健康供体的T细胞杀死表达MSLN的细胞(OVCAR3细胞；Caov4细胞；OVCAR3细胞；和OVCAR8细胞)。该图还示出了MH6T TriTAC无法引导来自健康供体的T细胞杀死不表达MSLN的细胞(MDAPCa2b细胞；和NCI-H510A细胞)。
图6示出了本公开的示例性TriTAC分子(MH6T TriTAC)能够引导来自食蟹猴的T细胞杀死人卵巢癌细胞系(OVCAR3细胞；Caov3细胞)。该图还示出了对照TriTAC分子(GFPTriTAC)无法引导来自食蟹猴的T细胞杀死人卵巢癌细胞系(OVCAR3细胞；Caov3细胞)。
图7示出了在存在或不存在人血清白蛋白(HSA)的情况下，本公开的示例性TriTAC分子(MH6T TriTAC)能够引导T细胞杀死表达MSLN的NCI-H2052间皮瘤细胞。
图8示出了在MH6T TriTAC和表达MSLN的Caov4细胞的存在下，本公开的示例性TriTAC分子(MH6T TriTAC)能够激活来自四名健康供体(供体2；供体86；供体35；和供体81)的T细胞，如通过T细胞分泌TNF-α所证明的。
图9示出了在MH6T TriTAC和表达MSLN的OVCAR8细胞的存在下，本公开的示例性TriTAC分子(MH6T TriTAC)能够激活来自四名健康供体(供体2；供体86；供体35；和供体81)的T细胞，如通过T细胞上CD69表达的活化所证明的。
图10示出了本公开的示例性TriTAC分子(MH6T TriTAC)与表达MSLN的细胞系或不表达MSLN的细胞系的结合。图10A显示了MH6T TriTAC与表达MSLN的细胞(Caov3细胞-左上图；Caov4细胞-右上图；OVCAR3细胞-左下图；OVCAR8细胞-右下图)的结合；图10A进一步示出了对照TriTAC(GFP TriTAC)无法与相同细胞系结合。图10B显示了MH6T TriTAC和GFPTriTAC均无法与不表达MSLN的细胞系(MDCA2b细胞-左图；NCI-H510A细胞-右图)结合。
图11示出了本公开的示例性TriTAC分子(MH6T TriTAC)与来自四名健康供体(供体2-左上图；供体35-右上图；供体41-左下图；供体81-右下图)的T细胞的结合。
图12示出了本公开的示例性TriTAC分子(MH6T TriTAC)能够在植入表达MSLN的NCI-H292细胞的NCG小鼠中抑制肿瘤生长。
图13示出了本公开的示例性TriTAC分子MH6T TriTAC的药代动力学曲线。图中显示了在注射至两只食蟹猴后的不同时间点，MH6TTriTAC分子的血清水平。
图14显示了本公开的两个示例性三特异性分子TriTAC 74和TriTAC 75的结合亲和力测量的结果，以及这两个TriTAC分子杀死SKOV3和OVCAR细胞的EC50值。
图15示出了本公开的两个示例性TriTAC分子TriTAC 75和TriTAC74的药代动力学曲线。图中显示了在注射至食蟹猴后的不同时间点，TriTAC分子的血清水平。
具体实施方式
本文描述了靶向间皮素(MSLN)的三特异性蛋白质，其药物组合物，以及用于制备其这类蛋白质的核酸、重组表达载体和宿主细胞。还提供了使用所公开的靶向MSLN的三特异性蛋白质预防和/或治疗疾病、病况和病症的方法。所述靶向MSLN的三特异性蛋白质能够特异性结合MSLN以及CD3，并且具有半衰期延长结构域，如与人白蛋白(ALB)结合的结构域。图1描绘了三特异性MSLN结合蛋白质的一个非限制性实例。
在一方面，所述靶向MSLN的三特异性蛋白质包含与CD3特异性结合的结构域(A)、与人白蛋白(ALB)特异性结合的结构域(B)以及与MSLN特异性结合的结构域(C)。靶向MSLN的三特异性蛋白质中的这三个结构域以任意顺序排列。因此，预计所述靶向MSLN的三特异性蛋白质的结构域顺序为：
H2N-(A)-(B)-(C)-COOH、
H2N-(A)-(C)-(B)-COOH、
H2N-(B)-(A)-(C)-COOH、
H2N-(B)-(C)-(A)-COOH、
H2N-(C)-(B)-(A)-COOH或
H2N-(C)-(A)-(B)-COOH。
在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(A)-(B)-(C)-COOH的结构域顺序。在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(A)-(C)-(B)-COOH的结构域顺序。在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(B)-(A)-(C)-COOH的结构域顺序。在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(B)-(C)-(A)-COOH的结构域顺序。在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(C)-(B)-(A)-COOH的结构域顺序。在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有H2N-(C)-(A)-(B)-COOH的结构域顺序。
在一些实施方案中，所述靶向MSLN的三特异性蛋白质具有HSA结合域作为中间结构域，使得结构域顺序为H2N-(A)-(B)-(C)-COOH或H2N-(C)-(B)-(A)-COOH。预计在ALB结合域作为中间结构域的这类实施方案中，赋予CD3和MSLN结合域额外的柔性以结合其各自的靶标。
在一些实施方案中，本文描述的靶向MSLN的三特异性蛋白质包含具有表1中所述序列(SEQ ID NO:58-86、98、100和101)及其子序列的多肽。在一些实施方案中，该三特异性抗原结合蛋白质包含与表1中所述序列(SEQ ID NO:58-86、98、100和101)具有至少70％-95％或更高同源性的多肽。在一些实施方案中，该三特异性抗原结合蛋白质包含与表1中所述序列(SEQ ID NO:58-86、98、100和101)具有至少70％、75％、80％、85％、90％、95％或更高同源性的多肽。
本文所述的靶向MSLN的三特异性蛋白质被设计为允许通过募集细胞毒性T细胞来特异性靶向表达MSLN的细胞。这与ADCC(抗体依赖性细胞介导的细胞毒性)相比提高了功效，ADCC利用针对唯一抗原的全长抗体并且不能直接募集细胞毒性T细胞。相反，通过接合在这些细胞上特异性表达的CD3分子，所述靶向MSLN的三特异性蛋白质可使细胞毒性T细胞与表达MSLN的细胞以高度特异性的方式交联，从而将T细胞的细胞毒性潜能引导至靶细胞。本文所述的靶向MSLN的三特异性蛋白质经由与表面表达的CD3蛋白质结合而接合细胞毒性T细胞，这形成TCR的一部分。数个MSLN三特异性抗原结合蛋白质与CD3和特定细胞表面上表达的MSLN的同时结合引起T细胞活化，并介导特定MSLN表达细胞的后续裂解。因此，预期靶向MSLN的三特异性蛋白质显示强烈的、特异的和有效的靶细胞杀伤。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质刺激细胞毒性T细胞杀死靶细胞以消除致病细胞(例如，表达MSLN的肿瘤细胞)。在一些这样的实施方案中，细胞被选择性地消除，从而减小毒副作用的可能性。
与传统单克隆抗体和其它较小的双特异性分子相比，本文所述的靶向MSLN的三特异性蛋白质提供进一步的治疗优点。通常，重组蛋白质药物的有效性在很大程度上取决于蛋白质本身的内在药代动力学。一种这样的益处在于，本文所述的靶向MSLN的三特异性蛋白质由于具有半衰期延长结构域，如对HAS具有特异性的结构域，而具有延长的药代动力学消除半衰期。就此而言，在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质具有约两天、三天、约五天、约七天、约10天、约12天或约14天的延长的血清消除半衰期。这与具有相对短得多的消除半衰期的其它结合蛋白质如BiTE或DART分子形成对照。例如，BiTE CD19×CD3双特异性scFv-scFv融合分子由于其消除半衰期短而需要连续的静脉内输注(i.v.)药物递送。所述靶向MSLN的三特异性蛋白质的较长的内在半衰期解决了这个问题，从而允许增加治疗潜力，如低剂量药物制剂、减少的定期给药和/或新的药物组合物。
本文所述的靶向MSLN的三特异性蛋白质还具有对于增强的组织穿透和组织分布而言最优的大小。较大的大小限制或阻止蛋白质在靶组织中的穿透或分布。本文所述的靶向MSLN的三特异性蛋白质通过具有允许增强的组织穿透和分布的小尺寸而避免了这一问题。因此，在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质具有约50kD至约80kD、约50kD至约75kD、约50kD至约70kD或约50kD至约65kD的大小。因此，所述靶向MSLN的三特异性蛋白质的大小优于约150kD的IgG抗体以及约55kD但半衰期没有延长并因此快速通过肾脏清除的BiTE和DART双抗体分子。
在进一步的实施方案中，本文所述的靶向MSLN的三特异性蛋白质具有对于增强的组织穿透和分布而言最优的大小。在这些实施方案中，靶向MSLN的三特异性蛋白质被构建为尽可能小，同时保留对其靶标的特异性。因此，在这些实施方案中，本文所述的靶向MSLN的三特异性蛋白质具有约20kD至约40kD，或约25kD至约35kD至约40kD、至约45kD、至约50kD、至约55kD、至约60kD、至约65kD的大小。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质具有约50kD、49kD、48kD、47kD、46kD、45kD、44kD、43kD、42kD、41kD、40kD、约39kD、约38kD、约37kD、约36kD、约35kD、约34kD、约33kD、约32kD、约31kD、约30kD、约29kD、约28kD、约27kD、约26kD、约25kD、约24kD、约23kD、约22kD、约21kD或约20kD的大小。获得小尺寸的示例性方法是对每个结构域都采用单结构域抗体(sdAb)片段。例如，特定的三特异性抗原结合蛋白质具有抗-CD3 sdAb、抗-ALB sdAb和针对MSLN的sdAb。这使得示例性MSLN三特异性抗原结合蛋白质的大小减小至60kD以下。因此，在一些实施方案中，所述靶向MSLN的三特异性蛋白质的结构域都是单结构域抗体(sdAb)片段。在其它实施方案中，本文所述的靶向MSLN的三特异性蛋白质包含针对ALB和/或MSLN的小分子实体(SME)结合物。SME结合物是大小平均为约500Da至2000Da的小分子，并且通过已知方法如分选酶连接或缀合而附接至靶向MSLN的三特异性蛋白质。在这些情况下，MSLN三特异性抗原结合蛋白质的结构域之一为分选酶识别序列，例如，LPETG(SEQ ID NO:97)。为了将SME结合物附接至具有分选酶识别序列的MSLN三特异性抗原结合蛋白质，将该蛋白质与分选酶和SME结合物一起孵育，从而分选酶将SME结合物附接至该识别序列。已知的SME结合物包括与间皮素结合的MIP-1072和MIP-1095。在另外其它的实施方案中，本文所述的靶向MSLN的三特异性蛋白质中与MSLN结合的结构域包含用于结合MSLN的knottin肽。Knottin是具有半胱氨酸结支架(knotscaffold)的二硫键稳定的肽，并且具有约3.5kD的平均大小。预期Knottin与某些肿瘤分子如MSLN结合。在进一步的实施方案中，本文所述的靶向MSLN的三特异性蛋白质中与MSLN结合的结构域包含天然MSLN配体。
本文所述的靶向MSLN的三特异性蛋白质的另一个特征是，它们是具有其结构域的柔性连接的单多肽设计。这允许容易地产生并制备靶向MSLN的三特异性蛋白质，因为它们可以由易于引入载体中的单个cDNA分子编码。另外，由于本文所述的靶向MSLN的三特异性蛋白质是单体单多肽链，因此不存在链配对问题或不需要二聚化。预计本文所述的靶向MSLN的三特异性蛋白质的聚集趋势减小，不同于其它报道的分子，如具有Fc-γ免疫球蛋白结构域的双特异性蛋白质。
在本文所述的靶向MSLN的三特异性蛋白质中，结构域通过内部连接体L1和L2连接，其中L1连接靶向MSLN的三特异性蛋白质的第一和第二结构域，而L2连接靶向MSLN的三特异性蛋白质的第二和第三结构域。连接体L1和L2具有优化的长度和/或氨基酸组成。在一些实施方案中，连接体L1和L2具有相同的长度和氨基酸组成。在其它实施方案中，L1和L2不同。在某些实施方案中，内部连接体L1和/或L2是“短的”，即，由0、1、2、3、4、5、6、7、8、9、10、11或12个氨基残基组成。因此，在某些情况下，内部连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下，内部连接体为肽键。在某些实施方案中，内部连接体L1和/或L2是“长的”，即，由15、20或25个氨基残基组成。在一些实施方案中，这些内部连接体由约3个至约15个，例如8、9或10个连续氨基酸残基组成。关于内部连接体L1和L2的氨基酸组成，选择具有以下性质的肽，即，能赋予靶向MSLN的三特异性蛋白质柔性，不干扰结合域，以及抵抗蛋白酶切割。例如，甘氨酸和丝氨酸残基通常提供蛋白酶抗性。适合于连接靶向MSLN的三特异性蛋白质中的结构域的内部连接体的实例包括但不限于(GS)n(SEQ ID NO:87)、(GGS)n(SEQ ID NO:88)、(GGGS)n(SEQ ID NO:89)、(GGSG)n(SEQ ID NO:90)、(GGSGG)n(SEQID NO:91)、(GGGGS)n(SEQ ID NO:92)、(GGSGG)n(SEQ ID NO:93)或(GGG)n(SEQ ID NO:94)，其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中，内部连接体L1和/或L2为(GGGGS)4(SEQ ID NO:95)或(GGGGS)3(SEQ ID NO:96)。
CD3结合域
T细胞应答的特异性由TCR对抗原(在主要组织相容性复合体MHC的环境中展示)的识别来介导。作为TCR的一部分，CD3是包含CD3γ(gamma)链、CD3δ(delta)链和存在于细胞表面上的两条CD3ε(epsilon)链的蛋白质复合物。CD3与TCR的α(alpha)和β(beta)链缔合，并与CD3ζ(zeta)一起构成完整的TCR。CD3在T细胞上诸如通过固定化抗CD3抗体的簇集导致T细胞活化，这类似于T细胞受体的接合，但不依赖于其克隆特有的特异性。
在一个方面，本文所述的靶向MSLN的三特异性蛋白质包含与CD3特异性结合的结构域。在一个方面，本文所述的靶向MSLN的三特异性蛋白质包含与人CD3特异性结合的结构域。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质包含与CD3γ特异性结合的结构域。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质包含与CD3δ特异性结合的结构域。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质包含与CD3ε特异性结合的结构域。
在进一步的实施方案中，本文所述的靶向MSLN的三特异性蛋白质包含与TCR特异性结合的结构域。在某些情况下，本文所述的靶向MSLN的三特异性蛋白质包含特异性结合TCR的α链的结构域。在某些情况下，本文所述的靶向MSLN的三特异性蛋白质包含特异性结合TCR的β链的结构域。
在某些实施方案中，本文所述的靶向MSLN的三特异性蛋白质的CD3结合域不仅表现出有效的对人CD3的CD3结合亲和力，而且还显示出与相应的食蟹猴CD3蛋白质的优异的交叉反应性。在一些情况下，靶向MSLN的三特异性蛋白质的CD3结合域与来自食蟹猴的CD3具有交叉反应性。在某些情况下，针对CD3的人:食蟹猴KD比例为5至0.2。
在一些实施方案中，所述MSLN三特异性抗原结合蛋白质的CD3结合域可以是与CD3结合的任何结构域，包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些情况下，CD3结合域来源于该MSLN三特异性抗原结合蛋白质最终将在其中使用的相同物种是有益的。例如，对于人用而言，MSLN三特异性抗原结合蛋白质的CD3结合域包含来自抗体或抗体片段的抗原结合域的人或人源化残基可能是有益的。
因此，在一方面，所述抗原结合域包含人源化或人抗体或抗体片段，或者鼠抗体或抗体片段。在一个实施方案中，人源化或人抗CD3结合域包含本文所述的人源化或人抗CD3结合域的轻链互补决定区1(LC CDR1)、轻链互补决定区2(LC CDR2)和轻链互补决定区3(LCCDR3)中的一个或多个(例如，全部三个)，以及/或者本文所述的人源化或人抗CD3结合域的重链互补决定区1(HC CDR1)、重链互补决定区2(HC CDR2)和重链互补决定区3(HC CDR3)中的一个或多个(例如，全部三个)，例如，人源化或人抗CD3结合域包含一个或多个，例如全部三个LC CDR，以及一个或多个，例如全部三个HC CDR。
在一些实施方案中，人源化或人抗CD3结合域包含对CD3具有特异性的人源化或人轻链可变区，其中对CD3具有特异性的轻链可变区在人轻链框架区中包含人或非人轻链CDR。在某些情况下，该轻链框架区为λ(lamda)轻链框架。在其它情况下，该轻链框架区为κ(kappa)轻链框架。
在一些实施方案中，人源化或人抗CD3结合域包含对CD3具有特异性的人源化或人重链可变区，其中对CD3具有特异性的重链可变区在人重链框架区中包含人或非人重链CDR。
在某些情况下，重链和/或轻链的互补决定区衍生自已知的抗CD3抗体，例如，莫罗单抗-CD3(OKT3)、奥昔珠单抗(TRX4)、替利珠单抗(MGA031)、维西珠单抗(Nuvion)、SP34、TR-66或X35-3、VIT3、BMA030(BW264/56)、CLB-T3/3、CRIS7、YTH12.5、F111-409、CLB-T3.4.2、TR-66、WT32、SPv-T3b、11D8、XIII-141、XIII-46、XIII-87、12F6、T3/RW2-8C8、T3/RW2-4B6、OKT3D、M-T301、SMC2、F101.01、UCHT-1和WT-31。
在一个实施方案中，抗CD3结合域为包含本文提供的氨基酸序列的轻链和重链的单链可变片段(scFv)。如本文所用的，“单链可变片段”或“scFv”是指包含轻链可变区的抗体片段和至少一个包含重链可变区的抗体片段，其中该轻链和重链可变区经由短的柔性多肽连接体连续连接，并且能够表达为单多肽链，并且其中该scFv保留其所衍生自的完整抗体的特异性。在一个实施方案中，抗CD3结合域包含：轻链可变区，其包含具有本文提供的轻链可变区的氨基酸序列的至少一个、两个或三个修饰(例如，置换)但不超过30、20或10个修饰(例如，置换)的氨基酸序列，或与本文提供的氨基酸序列具有95％-99％同一性的序列；和/或重链可变区，其包含具有本文提供的重链可变区的氨基酸序列的至少一个、两个或三个修饰(例如，置换)但不超过30、20或10个修饰(例如，置换)的氨基酸序列，或与本文提供的氨基酸序列具有95％-99％同一性的序列。在一个实施方案中，人源化或人抗CD3结合域为scFv，并且包含本文所述氨基酸序列的轻链可变区经由scFv连接体附接至包含本文所述氨基酸序列的重链可变区。scFv的轻链可变区和重链可变区可以是例如以下方向中的任何一种：轻链可变区-scFv连接体-重链可变区或重链可变区-scFv连接体-轻链可变区。
在一些情况下，根据已知方法制备与CD3结合的scFv。例如，可通过利用柔性多肽连接体将VH和VL区连接在一起来产生scFv分子。该scFv分子包含具有优化的长度和/或氨基酸组成的scFv连接体(例如，Ser-Gly连接体)。因此，在一些实施方案中，该scFv连接体的长度使得VH或VL结构域可以与其它可变域进行分子间缔合，从而形成CD3结合位点。在某些实施方案中，这样的scFv连接体是“短的”，即，由0、1、2、3、4、5、6、7、8、9、10、11或12个氨基酸残基组成。因此，在某些情况下，该scFv连接体由约12个或更少的氨基酸残基组成。在0个氨基酸残基的情况下，该scFv连接体为肽键。在一些实施方案中，这些scFv连接体由约3个至约15个，例如8、9或10个连续氨基酸残基组成。关于scFv连接体的氨基酸组成，选择能赋予柔性、不干扰可变域以及允许链间折叠以使两个可变域一起形成功能性CD3结合位点的肽。例如，包含甘氨酸和丝氨酸残基的scFv连接体通常提供蛋白酶抗性。在一些实施方案中，scFv中的连接体包含甘氨酸和丝氨酸残基。该scFv连接体的氨基酸序列可通过例如噬菌体展示法进行优化，以提高scFv的CD3结合和产率。适合于连接scFv中可变轻结构域和可变重结构域的肽scFv连接体的实例包括但不限于(GS)n(SEQ ID NO:87)、(GGS)n(SEQ IDNO:88)、(GGGS)n(SEQ ID NO:89)、(GGSG)n(SEQ ID NO:90)、(GGSGG)n(SEQ ID NO:91)、(GGGGS)n(SEQ ID NO:92)、(GGSGG)n(SEQ ID NO:93)或(GGG)n(SEQ ID NO:94)，其中n为1、2、3、4、5、6、7、8、9或10。在一个实施方案中，该scFv连接体可以是(GGGGS)4(SEQ ID NO:95)或(GGGGS)3(SEQ ID NO:96)。连接体长度的变化可以保持或增强活性，从而在活性研究中产生优异的功效。
在一些实施方案中，MSLN三特异性抗原结合蛋白质的CD3结合域对表达CD3的细胞上的CD3具有亲和力，其KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或者0.5nM或更低。在一些实施方案中，MSLN三特异性抗原结合蛋白质的CD3结合域对CD3ε、CD3γ或CD3δ具有亲和力，其KD为1000nM或更低、500nM或更低、200nM或更低、100nM或更低、80nM或更低、50nM或更低、20nM或更低、10nM或更低、5nM或更低、1nM或更低或者0.5nM或更低。在进一步的实施方案中，MSLN三特异性抗原结合蛋白质的CD3结合域对CD3具有低亲和力，即，约100nM或更高。
与CD3结合的亲和力可通过例如MSLN三特异性抗原结合蛋白质本身或其CD3结合域与测定板上包被的CD3、微生物细胞表面上展示的CD3、溶液中的CD3等结合的能力来确定。本公开的MSLN三特异性抗原结合蛋白质本身或其CD3结合域与CD3的结合活性可以如下测定：将配体(例如，CD3)或MSLN三特异性抗原结合蛋白质本身或其CD3结合域固定至珠子、基底、细胞等。可将试剂添加至合适的缓冲液中并将结合配偶体在给定的温度下孵育一段时间。洗涤以去除未结合的物质后，可采用例如SDS、高pH缓冲液等释放结合的蛋白质，并通过例如表面等离子体共振(SPR)进行分析。
半衰期延长结构域
本文涉及延长抗原结合域的半衰期的结构域。预期这样的结构域包括但不限于白蛋白结合域、Fc结构域、小分子和本领域已知的其它半衰期延长结构域。
人白蛋白(ALB)(分子量约为67kDa)是血浆中最丰富的蛋白质，以约50mg/ml(600μM)存在，并且在人体中具有大约20天的半衰期。ALB用来维持血浆pH，对胶体血压有贡献，起到许多代谢物和脂肪酸的载剂的作用，并且充当血浆中主要的药物转运蛋白。
与白蛋白的非共价缔合延长了短寿命蛋白质的消除半衰期。例如，与仅施用Fab片段相比，当分别静脉内施用于小鼠和兔时，白蛋白结合域与Fab片段的重组融合体导致25倍和58倍的体内清除率，以及26倍和37倍的半衰期延长。在另一个实例中，当用脂肪酸对胰岛素进行酰化以促进与白蛋白的缔合时，在兔或猪中皮下注射时观察到持久的效果。总之，这些研究证明了白蛋白结合与延长的作用之间存在联系。
在一个方面，本文所述的靶向MSLN的三特异性蛋白质包含半衰期延长结构域，例如与ALB特异性结合的结构域。在一些实施方案中，MSLN三特异性抗原结合蛋白质的ALB结合域可以是与ALB结合的任何结构域，包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中，该ALB结合域是对HSA具有特异性的单链可变片段(scFv)、单结构域抗体如重链可变域(VH)、轻链可变域(VL)和骆驼科来源的单结构域抗体的可变域(VHH)、肽、配体或小分子实体。在某些实施方案中，该ALB结合域是单结构域抗体。在其它实施方案中，该HSA结合域是肽。在进一步的实施方案中，该HSA结合域是小分子。在一些实施方案中，设想MSLN三特异性抗原结合蛋白质的HSA结合域相当小并且不超过25kD、不超过20kD、不超过15kD或不超过10kD。在某些情况下，该ALB结合蛋白质如果是肽或小分子实体，则为5kD或更小。
MSLN三特异性抗原结合蛋白质的半衰期延长结构域导致MSLN三特异性抗原结合蛋白质本身的药效学和药代动力学改变。如上所述，半衰期延长结构域延长了消除半衰期。半衰期延长结构域还改变药效学性质，包括三特异性抗原结合蛋白质的组织分布、穿透和扩散的改变。在一些实施方案中，与没有半衰期延长结构域的蛋白质相比，半衰期延长结构域提供改善的组织(包括肿瘤)靶向、组织分布、组织穿透、组织内的扩散和增强的功效。在一个实施方案中，治疗方法有效且高效地利用减少量的三特异性抗原结合蛋白质，从而导致副作用减小，如非肿瘤细胞的细胞毒性降低。
此外，可以选择半衰期延长结构域的结合亲和力，以便针对特定三特异性抗原结合蛋白质中的特定消除半衰期。因此，在一些实施方案中，该半衰期延长结构域具有高结合亲和力。在其它实施方案中，该半衰期延长结构域具有中等结合亲和力。在另外其它的实施方案中，该半衰期延长结构域具有低或微小的结合亲和力。示例性的结合亲和力包括10nM或更低(高)、10nM至100nM(中等)和大于100nM(低)的KD浓度。如上所述，通过已知方法如表面等离子体共振(SPR)测定与ALB的结合亲和力。
在一些实施方案中，本文描述的ALB结合域包含单结构域抗体。
间皮素(MSLN)结合域
间皮素是存在于腹膜、胸膜和心包体腔的间皮内衬细胞表面上的糖蛋白。间皮素基因(MSLN)编码71kD的前体蛋白，该蛋白质被加工成被称为间皮素的40kD蛋白质，该蛋白质是存在于细胞表面上的糖基磷脂酰肌醇锚定的糖蛋白(Chang等人，Proc Natl Acad SciUSA(1996)93:136-40)。从由HPC-Y5细胞系制备的文库中克隆间皮素cDNA(Kojima等人(1995)J.Biol.Chem.270:21984-21990)。还使用识别间皮瘤的单克隆抗体K1来克隆cDNA(Chang和Pastan(1996)Proc.Natl.Acad.Sci.USA 93:136-40)。间皮素是分化抗原，其在正常人体组织中的表达仅限于内衬于诸如胸膜、心包膜和腹膜等体腔的间皮细胞。间皮素在包括间皮瘤、胰腺腺癌、卵巢癌、胃和肺腺癌在内的几种不同的人类癌症中也高度表达。(Hassan等人,Eur J Cancer(2008)44:46-53)(Ordonez,Am J Surg Pathol(2003)27:1418-28；Ho等人,Clin Cancer Res(2007)13:1571-5)。间皮素在绝大多数原发性胰腺腺癌中过表达，在良性胰腺组织中可见罕有且微弱的表达。Argani P等人.Clin CancerRes.2001；7(12):3862-3868。上皮恶性胸膜间皮瘤(MPM)普遍表达间皮素，而肉瘤样MPM可能不表达间皮素。大多数浆液性上皮性卵巢癌和相关的原发性腹膜癌均表达间皮素。
间皮素还可以用作某些类型癌症的诊断和预后的标志物，因为在一些间皮素阳性癌症患者的血液中可以检测到痕量的间皮素(Cristaudo等人,Clin.Cancer Res.13:5076-5081,2007)。据报道，间皮素可通过在其羧基末端缺失或通过从其膜结合形式蛋白水解裂解而释放到血清中(Hassan等人,Clin.Cancer Res.10:3937-3942,2004)。在暴露于石棉的工人中发生恶性间皮瘤之前数年，可检测到间皮素的可溶性形式增加(Creaney和Robinson,Hematol.Oncol.Clin.North Am.19:1025-1040,2005)。此外，卵巢癌、胰腺癌和肺癌患者血清中的可溶性间皮素也升高(Cristaudo等人,Clin.Cancer Res.13:5076-5081,2007；Hassan等人,Clin.Cancer Res.12:447-453,2006；Croso等人,CancerDetect.Prev.30:180-187,2006)。因此，间皮素是疾病预防或治疗方法的合适的靶标，并且需要有效的间皮素特异性抗体。
已经显示，细胞表面成熟间皮素包含三个不同的结构域，即区域I(包含残基296-390)、II(包含残基391-486)和III(包含残基487-598)。(Tang等人,A human single-domain antibody elicits potent antitumor activity by targeting an epitope inmesothelin close to the cancer cell surface,Mol.Can.Therapeutics,12(4):416-426,2013)。针对治疗性干预生成的第一批抗间皮素抗体被设计为干扰间皮素与CA-125之间的相互作用。噬菌体展示鉴定了Fv SS，对Fv SS进行了亲和力优化，并用其产生靶向间皮素的重组免疫毒素SS1P。同样使用SS1的MORAb-009抗体amatuximab识别间皮素区域I内的氨基末端64个氨基酸中的非线性表位。还使用SS1Fv生成了嵌合抗原受体工程化的T细胞。最近，已经报道了识别间皮素蛋白质其它区域的新抗间皮素抗体。
仍然需要用于治疗与间皮素过表达有关的实体瘤疾病如卵巢癌、胰腺癌、间皮瘤、肺癌、胃癌和三阴性乳腺癌的其它可用选择。在某些实施方案中，本公开提供了靶向MSLN的三特异性蛋白质，其包含与肿瘤靶细胞表面上的MSLN特异性结合的结合域。
本文所述的靶向MSLN的三特异性蛋白质的设计允许MSLN结合域为柔性的，因为该MSLN结合域可以是任何类型的结合域，包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中，该MSLN结合域为单链可变片段(scFv)、单结构域抗体如重链可变域(VH)、轻链可变域(VL)和骆驼科来源的单结构域抗体的可变域(VHH)。在其它实施方案中，该MSLN结合域为非Ig结合域，即，抗体模拟物，如anticalin、affilin、affibody分子、affimer、affitin、alphabody、avimer、DARPin、fynomer、kunitz结构域肽和单抗体(monobody)。在进一步的实施方案中，该MSLN结合域为与MSLN结合或缔合的配体或肽。在更进一步的实施方案中，该MSLN结合域为knottin。在更进一步的实施方案中，该MSLN结合域为小分子实体。
在一些实施方案中，所述MSLN结合域与包含SEQ ID NO:57的序列的蛋白质结合。在一些实施方案中，所述MSLN结合域与包含与SEQ ID NO:57相比截短的序列的蛋白质结合。
在一些实施方案中，本文公开的MSLN结合域识别全长间皮素。在某些情况下，本文公开的MSLN结合域识别间皮素区域I(包含SEQ ID NO:57的氨基酸残基296-390)、区域II(包含SEQ ID NO:57的氨基酸残基391-486)或区域III(包含SEQ ID NO:57的氨基酸残基487-598)中的表位。预期在一些实施方案中，本公开的MSLN结合域可以识别并结合位于间皮素的区域I、II或III外部的表位。在另外其它的实施方案中，公开了识别并结合不同于MORAb-009抗体的表位的MSLN结合域。
在一些实施方案中，所述MSLN结合域为抗MSLN抗体或抗体变体。如本文所用的，术语“抗体变体”是指本文所述抗体的变体和衍生物。在某些实施方案中，涉及本文所述的抗MSLN抗体的氨基酸序列变体。例如，在某些实施方案中，预期本文所述的抗MSLN抗体的氨基酸序列变体改善抗体的结合亲和力和/或其它生物学性质。用于制备氨基酸变体的示例性方法包括但不限于将适当的修饰引入编码抗体的核苷酸序列中，或者通过肽合成。这样的修饰包括，例如，抗体的氨基酸序列内的残基的缺失和/或插入和/或置换。
可进行缺失、插入和置换的任意组合以得到最终构建体，条件是最终构建体具有期望的特性，例如抗原结合。在某些实施方案中，提供了具有一个或多个氨基酸置换的抗体变体。用于置换诱变的感兴趣的位点包括CDR和框架区。以下描述了此类置换的实例。可将氨基酸置换引入感兴趣的抗体中，并针对所需活性，例如，保留/改善的抗原结合、降低的免疫原性或改善的T细胞介导的细胞毒性(TDCC)来筛选产物。保守和非保守的氨基酸置换均考虑用于制备抗体变体。
在用来产生变异抗MSLN抗体的置换的另一个实例中，亲本抗体的一个或多个高变区残基被置换。通常，之后基于与亲本抗体相比的所需性质的改善，例如，增加的亲和力、降低的亲和力、降低的免疫原性、增加的结合的pH依赖性来选择变体。
在一些实施方案中，所述靶向MSLN的三特异性蛋白质的MSLN结合域是单结构域抗体，诸如对间皮素具有特异性的重链可变域(VH)、美洲驼(llama)来源的sdAb的可变域(VHH)、肽、配体或小分子实体。在一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质的间皮素结合域是与间皮素结合的任何结构域，包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在某些实施方案中，该MSLN结合域为单结构域抗体。在其它实施方案中，该MSLN结合域为肽。在进一步的实施方案中，该MSLN结合域为小分子。
通常，应当注意，本文中以其最广泛的含义使用的术语单结构域抗体不限于特定的生物学来源或特定的制备方法。单结构域抗体是其互补决定区是单结构域多肽的一部分的抗体。实例包括但不限于重链抗体、天然不含轻链的抗体、衍生自常规4链抗体的单结构域抗体、工程抗体以及与衍生自抗体的那些不同的单结构域支架。单结构域抗体可以是本领域的任何单结构域抗体，或任何未来的单结构域抗体。单结构域抗体可来源于任何物种，包括但不限于小鼠、人、骆驼、美洲驼、山羊、兔、牛。例如，在一些实施方案中，通过以下方法获得本公开的单结构域抗体：(1)通过分离天然存在的重链抗体的VHH结构域；(2)通过表达编码天然存在的VHH结构域的核苷酸序列；(3)通过天然存在的VHH结构域的“人源化”或通过表达编码这样的人源化VHH结构域的核酸；(4)通过来自任何动物物种，特别是来自哺乳动物物种，如来自人类的天然存在的VH结构域的“骆驼化”，或通过表达编码这样的骆驼化VH结构域的核酸；(5)通过“结构域抗体”或“Dab”的“骆驼化”，或通过表达编码这样的骆驼化VH结构域的核酸；(6)通过使用合成或半合成技术制备蛋白质、多肽或其它氨基酸序列；(7)通过使用本领域已知的核酸合成技术制备编码单结构域抗体的核酸，然后表达由此获得的核酸；以及/或者(8)通过前述一种或多种的任意组合。
在一个实施方案中，单结构域抗体对应于针对MSLN的天然存在的重链抗体的VHH结构域。如本文进一步描述的，这样的VHH序列通常可以通过以下方法来生成或获得：用MSLN适当地免疫美洲驼物种(即，以产生针对MSLN的免疫应答和/或重链抗体)，获得来自所述美洲驼的合适的生物样品(如血液样品、血清样品或B细胞样品)，并使用本领域已知的任何合适技术从所述样品开始生成针对MSLN的VHH序列。
在另一个实施方案中，这类天然存在的针对MSLN的VHH结构域从骆驼科VHH序列的幼稚文库获得，例如通过使用本领域已知的一种或多种筛选技术使用MSLN或其至少一个部分、片段、抗原决定簇或表位筛查这样的文库。这类文库和技术例如在WO 99/37681、WO 01/90190、WO 03/025020和WO 03/035694中描述。或者，使用衍生自幼稚VHH文库的改进的合成或半合成文库，如通过诸如随机诱变和/或CDR改组等技术从幼稚VHH文库获得的VHH文库，例如WO 00/43507所述。
在进一步的实施方案中，又一种获得针对MSLN的VHH序列的技术涉及适当地免疫能够表达重链抗体的转基因哺乳动物(即，以产生针对MSLN的免疫应答和/或重链抗体)，从所述转基因哺乳动物获得合适的生物样品(如血液样品、血清样品或B细胞样品)，然后使用本领域已知的任何合适技术从所述样品开始生成针对MSLN的VHH序列。例如，为此目的，可以使用表达重链抗体的大鼠或小鼠以及在WO 02/085945和WO 04/049794中描述的其它方法和技术。
在一些实施方案中，所述靶向MSLN的三特异性蛋白质的抗MSLN单结构域抗体包括单结构域抗体，其具有对应于天然存在的VHH结构域的氨基酸序列的氨基酸序列，但是已经“人源化”，即通过用存在于来自人类的常规4链抗体(例如，如上所述)的VH结构域中相应位置处的一个或多个氨基酸残基替换所述天然存在的VHH序列(特别是框架序列中)的氨基酸序列中的一个或多个氨基酸残基。这可以按本领域已知的方式进行，该方式对于本领域技术人员将会是显而易见的，例如基于本文的进一步描述。此外，应当注意，本公开的此类人源化抗MSLN单结构域抗体以本质上已知的任何合适的方式获得(即，如以上(1)-(8)点所示)，因此不严格限于使用包含天然存在的VHH结构域的多肽作为起始材料获得的多肽。在一些另外的实施方案中，如本文所述的单结构域抗MSLN抗体包括单结构域抗体，其具有对应于天然存在的VH结构域的氨基酸序列的氨基酸序列，但是已经“骆驼化”，即通过用存在于重链抗体的VHH结构域中的相应位置处的一个或多个氨基酸残基替换来自常规4链抗体的天然存在的VH结构域的氨基酸序列中的一个或多个氨基酸残基。此类“骆驼化”置换优选地在形成VH-VL界面和/或存在于VH-VL界面处的氨基酸位置处以及/或者在所谓的骆驼科标志残基处插入(参见例如WO 94/04678，以及Davies和Riechmann(1994和1996))。优选地，用作生成或设计骆驼化单结构域的起始材料或起始点的VH序列优选地是来自哺乳动物的VH序列，更优选地是人类的VH序列，如VH3序列。然而，应当注意，在某些实施方案中，本公开的此类骆驼化抗MSLN单结构域抗体以本领域已知的任何合适的方式获得(即，如以上(1)-(8)点所示)，因此不严格限于使用包含天然存在的VH结构域的多肽作为起始材料获得的多肽。例如，如本文进一步描述的，“人源化”和“骆驼化”均通过分别提供编码天然存在的VHH结构域或VH结构域的核苷酸序列，然后分别以新核苷酸序列编码“人源化”或“骆驼化”单结构域抗体的方式改变所述核苷酸序列中的一个或多个密码子来进行。然后可以表达该核酸，以提供本公开的期望的抗MSLN单结构域抗体。或者，在其它实施方案中，分别基于天然存在的VHH结构域或VH结构域的氨基酸序列，分别设计本公开的期望的人源化或骆驼化抗MSLN单结构域抗体的氨基酸序列，然后使用已知的肽合成技术从头合成。在一些实施方案中，分别基于天然存在的VHH结构域或VH结构域的氨基酸序列或核苷酸序列，分别设计编码本公开的期望的人源化或骆驼化抗MSLN单结构域抗体的核苷酸序列，然后使用已知的核酸合成技术从头合成，之后使用已知的表达技术表达由此获得的核酸，以提供本公开的期望的抗MSLN单结构域抗体。
用于从天然存在的VH序列或VHH序列开始获得本公开的抗MSLN单结构域抗体和/或编码该抗MSLN单结构域抗体的核酸的其它合适方法和技术包括例如以合适的方式组合一个或多个天然存在的VH序列(诸如一个或多个框架(FR)序列和/或互补决定区(CDR)序列)的一个或多个部分、一个或多个天然存在的VHH序列(诸如一个或多个FR序列或CDR序列)的一个或多个部分以及/或者一个或多个合成或半合成序列，以提供本公开的抗MSLN单结构域抗体或编码该抗MSLN单结构域抗体的核苷酸序列或核酸。
在一些实施方案中，所述MSLN结合域是抗MSLN特异性抗体，其包含重链可变互补决定区CDR1、重链可变CDR2、重链可变CDR3、轻链可变CDR1、轻链可变CDR2和轻链可变CDR3。在一些实施方案中，该MSLN结合域包含与MSLN结合的任何结构域，包括但不限于来自以下的结构域：单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体，或者抗原结合片段如单结构域抗体(sdAb)、Fab、Fab'、F(ab)2和Fv片段，由一个或多个CDR组成的片段、单链抗体(例如，单链Fv片段(scFv))、二硫键稳定的Fv(dsFv)片段、异缀合抗体(例如，双特异性抗体)、pFv片段、重链单体或二聚体、轻链单体或二聚体，以及由一条重链和一条轻链组成的二聚体。在一些实施方案中，该MSLN结合域是单结构域抗体。在一些实施方案中，抗MSLN单结构域抗体包含重链可变互补决定区(CDR)，CDR1、CDR2和CDR3。
在一些实施方案中，所述MSLN结合域是包含氨基酸序列的多肽，该氨基酸序列由被三个互补决定区/序列中断的四个框架区/序列(f1-f4)组成，如下式所示：f1-r1-f2-r2-f3-r3-f4，其中r1、r2和r3分别是互补决定区CDR1、CDR2和CDR3，并且f1、f2、f3和f4是框架残基。本公开的MSLN结合蛋白质的框架残基包含例如75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93或94个氨基酸残基，并且互补决定区包含例如24、25、26、27、28、29、30、31、32、33、34、35或36个氨基酸残基。在一些实施方案中，该MSLN结合域包含选自SEQ ID NO:1-40和102-105的氨基酸序列。在一些实施方案中，本公开的结合MSLN的三特异性蛋白质的框架区1包含SEQ ID NO:223-261中任一个的序列。在一些实施方案中，本公开的结合MSLN的三特异性蛋白质的框架区2包含SEQ ID NO:262-300中任一个的序列。在一些实施方案中，本公开的结合MSLN的三特异性蛋白质的框架区3包含SEQ ID NO:301-339中任一个的序列。在一些实施方案中，本公开的结合MSLN的三特异性蛋白质的框架区4包含SEQID NO:340-378中任一个的序列。
在一些实施方案中，所述CDR1包含如SEQ ID NO:51所示的氨基酸序列，或在SEQID NO:51中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR2包含如SEQ ID NO:52所示的序列，或在SEQ ID NO:52中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR3包含如SEQ ID NO:53所示的序列，或在SEQ ID NO:53中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。
在一些实施方案中，所述CDR1包含如SEQ ID NO:54所示的氨基酸序列，或在SEQID NO:54中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR2包含如SEQ ID NO:55所示的序列，或在SEQ ID NO:55中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR3包含如SEQ ID NO:56所示的序列，或在SEQ ID NO:56中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。
在一些实施方案中，所述CDR1包含如SEQ ID NO:106-144中任一个所示的氨基酸序列，或在SEQ ID NO:106-144的任一个中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR2包含如SEQ ID NO:145-183中任一个所示的序列，或在SEQ ID NO:145-183的任一个中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。在一些实施方案中，所述CDR3包含如SEQ ID NO:184-222中任一个所示的序列，或在SEQ ID NO:184-222的任一个中具有一个、两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸置换的变体。
在某些实例中，本公开的MSLN结合域包含一个或多个保守区。所述保守区包含如SEQ ID NO:41-49所示的序列，或相对于所述序列包含一个或多个氨基酸残基置换的变体。示例性的实施方案包括MSLN结合蛋白质，其包含一个或多个选自SEQ ID NO:41-44的保守区，或相对于所述序列包含一个或多个氨基酸残基置换的变体。在一些情况下，所述MSLN结合域包含(i)对应于SEQ ID NO:41的一段氨基酸，(ii)对应于SEQ ID NO:42的一段氨基酸，(iii)对应于SEQ ID NO:43的一段氨基酸，和(iv)对应于SEQ ID NO:44的一段氨基酸。
其它示例性实施方案包括MSLN结合域，其包含一个或多个选自SEQ ID NO:45-50的保守区，或相对于所述序列包含一个或多个氨基酸残基置换的变体。在一些情况下，所述MSLN结合域包含(i)对应于SEQ ID NO:45的一段氨基酸，(ii)对应于SEQ ID NO:46的一段氨基酸，(iii)对应于SEQ ID NO:47的一段氨基酸，(iv)对应于SEQ ID NO:48的一段氨基酸，(v)对应于SEQ ID NO:49的一段氨基酸，和(vi)对应于SEQ ID NO:50的一段氨基酸。
在各个实施方案中，本公开的MSLN结合域与选自SEQ ID NO:1-29的氨基酸序列至少约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同。
在各个实施方案中，本公开的MSLN结合域与选自SEQ ID NO:30-40和102-105的氨基酸序列至少约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同。
在各个实施方案中，本公开的MSLN结合域的互补决定区与SEQ ID NO:51、SEQ IDNO:54或SEQ ID No.:106-144中任一个所示的氨基酸序列至少约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同。
在各个实施方案中，本公开的MSLN结合域的互补决定区与SEQ ID NO:52、SEQ IDNO:55或SEQ ID No.:145-183中任一个所示的氨基酸序列至少约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同。
在各个实施方案中，本公开的MSLN结合域的互补决定区与SEQ ID NO:53、SEQ IDNO:56或SEQ ID No.:184-222中任一个所示的氨基酸序列至少约10％、约20％、约30％、约40％、约50％、约60％、约70％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同。
在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:1的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:2的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:3的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:4的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:5的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:6的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:7的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:8的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:9的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:10的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:11的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:12的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:13的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:14的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:15的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:16的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:17的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:18的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:19的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:20的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:21的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:22的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:23的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:24的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:25的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:26的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:27的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:28的序列的单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:29的序列的单结构域抗体。
在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ IDNO:30的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:31的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:32的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQID NO:33的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:34的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:35的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQID NO:36的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:37的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:38的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQID NO:39的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:40的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:102的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:103的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:104的序列的人源化单结构域抗体。在一些实施方案中，根据上述实施方案中任一项的MSLN结合蛋白质是包含SEQ ID NO:105的序列的人源化单结构域抗体。
在一些实施方案中，所述MSLN结合域对人和食蟹猴间皮素具有交叉反应性。在一些实施方案中，该MSLN结合域对人间皮素是特异性的。在某些实施方案中，本文公开的MSLN结合域以人Kd(hKd)与人间皮素结合。在某些实施方案中，本文公开的MSLN结合域以食蟹猴Kd(cKd)与食蟹猴间皮素结合。在某些实施方案中，本文公开的MSLN结合域分别以食蟹猴Kd(cKd)和人Kd(hKd)与食蟹猴间皮素和人间皮素结合。在一些实施方案中，该MSLN结合蛋白质以相当的结合亲和力(即，hKd和cKd值相差不超过±10％)与人和食蟹猴间皮素结合。在一些实施方案中，所述hKd和cKd在约0.1nM至约500nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约450nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约400nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约350nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约300nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约250nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约200nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约150nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约100nM的范围内。在一些实施方案中，所述hKd和cKd在约0.1nM至约90nM的范围内。在一些实施方案中，所述hKd和cKd在约0.2nM至约80nM的范围内。在一些实施方案中，所述hKd和cKd在约0.3nM至约70nM的范围内。在一些实施方案中，所述hKd和cKd在约0.4nM至约50nM的范围内。在一些实施方案中，所述hKd和cKd在约0.5nM至约30nM的范围内。在一些实施方案中，所述hKd和cKd在约0.6nM至约10nM的范围内。在一些实施方案中，所述hKd和cKd在约0.7nM至约8nM的范围内。在一些实施方案中，所述hKd和cKd在约0.8nM至约6nM的范围内。在一些实施方案中，所述hKd和cKd在约0.9nM至约4nM的范围内。在一些实施方案中，所述hKd和cKd在约1nM至约2nM的范围内。
在一些实施方案中，任何前述MSLN结合域(例如，SEQ ID NO:1-40的抗MSLN单结构域抗体)是为了易于纯化而标记的亲和肽。在一些实施方案中，亲和肽标签是六个连续的组氨酸残基，也称为6X-his(SEQ ID NO:379)。
在某些实施方案中，本公开的MSLN结合域相对于可溶性间皮素优先结合膜结合的间皮素。膜结合的间皮素是指在表达间皮素的细胞的细胞膜表面之中或之上存在间皮素。可溶性间皮素是指不再存在于正表达或已表达间皮素的细胞的细胞膜表面之中或之上的间皮素。在某些情况下，可溶性间皮素存在于受试者的血液和/或淋巴循环中。在一个实施方案中，所述MSLN结合域与膜结合的间皮素的结合至少是与可溶性间皮素的结合的5倍、10倍、15倍、20倍、25倍、30倍、40倍、50倍、100倍、500倍或1000倍。在一个实施方案中，本公开的靶向MSLN的三特异性抗原结合蛋白质优先结合膜结合的间皮素，是与可溶间皮素的结合的30倍。使用本领域公知的测定可以容易地确定抗原结合蛋白质与膜结合的MSLN相对于可溶性MSLN的优先结合。
TriTAC分子
本公开的各个实施方案提供了包含如本文所述的MSLN结合域的三特异性分子(本文中也称为TriTAC分子)。在一些实施方案中，该TriTAC分子包含如SEQ ID No:58-86、98、100和101中任一个所示的氨基酸序列。在一些实施方案中，本公开的TriTAC分子包含与选自SEQ ID No:58-86、98、100和101的氨基酸序列至少约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。在一些实施方案中，本公开的TriTAC分子包含与选自SEQ ID No:58-86、98、100和101的氨基酸序列全长至少约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。在一些实施方案中，本公开的TriTAC分子包含与选自SEQ ID No:58-86、98、100和101的氨基酸序列全长的一部分至少约75％、约76％、约77％、约78％、约79％、约80％、约81％、约82％、约83％、约84％、约85％、约86％、约87％、约88％、约89％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或约100％相同的氨基酸序列。
向嵌合抗原受体(CAR)中的整合
在某些实例中，本公开的靶向MSLN的三特异性抗原结合蛋白质可以并入嵌合抗原受体(CAR)中。工程化的免疫效应细胞，例如T细胞或NK细胞，可以用来表达CAR，该CAR包括抗MSLN靶向三特异性蛋白质，该蛋白质含有本文所述的抗MSLN单结构域抗体。在一个实施方案中，包括本文所述的抗MSLN靶向三特异性蛋白质的CAR经由铰链区连接至跨膜域，并进一步连接至共刺激域，例如获自OX40、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)或4-1BB的功能性信号传导域。在一些实施方案中，该CAR进一步包含编码细胞内信号传导域如4-1BB和/或CD3ζ的序列。
肿瘤生长减少性质
在某些实施方案中，当施用于具有表达间皮素的肿瘤细胞的受试者时，本公开的靶向MSLN的三特异性蛋白质在体内减少肿瘤细胞的生长。肿瘤细胞生长减少的测量可以通过本领域公知的多种不同方法来确定。非限制性实例包括直接测量肿瘤尺寸，测量切除的肿瘤块并与对照对象进行比较，通过可能使用或可能不使用同位素或发光分子(例如萤光素酶)增强分析的成像技术(例如CT或MRI)进行测量，等等。在特定实施方案中，与对照抗原结合剂相比，本公开的三特异性蛋白质的施用导致肿瘤细胞的体内生长减少至少约10％、20％、30％、40％、50％、60％、70％、80％、90％或100％，肿瘤生长减少约100％表明完全反应和肿瘤消失。在进一步的实施方案中，与对照抗原结合剂相比，本公开的三特异性蛋白质的施用导致肿瘤细胞的体内生长减少约50-100％、约75-100％或约90-100％。在进一步的实施方案中，与对照抗原结合剂相比，本公开的三特异性蛋白质的施用导致肿瘤细胞的体内生长减少约50-60％、约60-70％、约70-80％、约80-90％或约90-100％。
MSLN三特异性蛋白质修饰
本文所述的靶向MSLN的三特异性蛋白质包括衍生物或类似物，其中(i)氨基酸被不是由遗传密码编码的氨基酸残基置换，(ii)成熟多肽与另一化合物如聚乙二醇融合，或(iii)额外的氨基酸与该蛋白质融合，如前导序列或分泌序列或用于纯化该蛋白质的序列。
典型的修饰包括但不限于乙酰化、酰化、ADP-核糖基化、酰胺化、黄素的共价附接、血红素部分的共价附接、核苷酸或核苷酸衍生物的共价附接、脂质或脂质衍生物的共价附接、磷脂酰肌醇的共价附接、交联、环化、二硫键形成、脱甲基化、共价交联的形成、胱氨酸的形成、焦谷氨酸的形成、甲酰化、γ羧化、糖基化、GPI锚形成、羟基化、碘化、甲基化、肉豆蔻酰化、氧化、蛋白水解加工、磷酸化、异戊二烯化、外消旋化、硒化、硫酸化、转移RNA介导的向蛋白质添加氨基酸，如精氨酰化和泛素化。
在本文所述的靶向MSLN的三特异性蛋白质中的任何位置进行修饰，所述位置包括肽骨架、氨基酸侧链和氨基或羧基末端。可用于修饰靶向MSLN的三特异性蛋白质的某些常见肽修饰包括糖基化、脂质附接、硫酸化、谷氨酸残基的γ-羧化、羟基化、多肽中的氨基或羧基或两者被共价修饰的封闭，以及ADP-核糖基化。
编码靶向MSLN的三特异性蛋白质的多核苷酸
在一些实施方案中，还提供了编码本文所述的抗MSLN三特异性结合蛋白质的多核苷酸分子。在一些实施方案中，该多核苷酸分子以DNA构建体的形式提供。在其它实施方案中，该多核苷酸分子以信使RNA转录物的形式提供。
所述多核苷酸分子通过已知方法构建，例如通过将编码由肽连接体隔开，或在其它实施方案中通过肽键直接连接的三个结合域的基因组合成单个基因构建体，该单个基因构建体与合适的启动子以及可选的合适的转录终止子可操作地连接，并且将其在细菌或其它合适的表达系统例如CHO细胞中表达。在MSLN结合域为小分子的实施方案中，该多核苷酸含有编码CD3结合域和半衰期延长结构域的基因。在半衰期延长结构域为小分子的实施方案中，该多核苷酸含有编码与CD3和MSLN结合的结构域的基因。根据所采用的载体系统和宿主，可使用任何数目的合适的转录和翻译元件，包括组成型和诱导型启动子。选择启动子使得其驱动该多核苷酸在相应宿主细胞中的表达。
在一些实施方案中，将所述多核苷酸插入载体中，优选表达载体中，这代表进一步的实施方案。该重组载体可根据已知方法来构建。特别感兴趣的载体包括质粒、噬菌粒、噬菌体衍生物、病毒(virii)(例如，逆转录病毒、腺病毒、腺伴随病毒、疱疹病毒、慢病毒等)和粘粒。
可利用多种表达载体/宿主系统，以包含并表达编码所述三特异性抗原结合蛋白质的多肽的多核苷酸。表达载体的实例是用于在大肠杆菌中表达的pSKK(Le Gall等人,JImmunol Methods.(2004)285(1):111-27)或用于在哺乳动物细胞中表达的pcDNA5(Invitrogen)。
因此，在一些实施方案中，如本文所述的靶向MSLN的三特异性蛋白质通过以下步骤产生：将编码如上所述蛋白质的载体引入宿主细胞中，并在允许蛋白质结构域表达的条件下培养所述宿主细胞，可将其分离并任选地进一步纯化。
药物组合物
在一些实施方案中，还提供了药物组合物，其包含本文所述的抗MSLN三特异性结合蛋白质、包含编码靶向MSLN的三特异性蛋白质的多肽的多核苷酸的载体或被该载体转化的宿主细胞，以及至少一种药学上可接受的载剂。术语“药学上可接受的载剂”包括但不限于不干扰成分的生物活性的有效性且对所施用的患者无毒的任何载剂。合适的药物载剂的实例是本领域公知的，并且包括磷酸盐缓冲盐水溶液、水、乳液如水包油乳液、各种类型的润湿剂、无菌溶液等。这样的载剂可通过常规方法配制，并且可以以合适的剂量施用于受试者。优选地，该组合物是无菌的。这些组合物还可含有辅料如防腐剂、乳化剂和分散剂。可通过包含各种抗细菌剂和抗真菌剂来确保阻止微生物的作用。另一个实施方案提供了一种或多种上述靶向MSLN的三特异性蛋白质，其以冻干形式包装或包装在水性介质中。
在药物组合物的一些实施方案中，本文所述的靶向MSLN的三特异性蛋白质被包封在纳米颗粒中。在一些实施方案中，该纳米颗粒是富勒烯、液晶、脂质体、量子点、超顺磁纳米颗粒、树状聚体或纳米棒。在药物组合物的其它实施方案中，将MSLN三特异性抗原结合蛋白质附接至脂质体。在一些情况下，MSLN三特异性抗原结合蛋白质与脂质体表面缀合。在一些情况下，MSLN三特异性抗原结合蛋白质被包封在脂质体的壳内。在一些情况下，该脂质体为阳离子脂质体。
本文所述的靶向MSLN的三特异性蛋白质被考虑用作药物。给药通过不同方式实现，例如，通过静脉内、腹膜内、皮下、肌肉内、局部或真皮内给药。在一些实施方案中，给药途径取决于疗法的种类和药物组合物中包含的化合物的种类。给药方案将由主治医师根据其它临床因素来确定。对于任何一名患者的剂量依赖于许多因素，包括患者体型、体表面积、年龄、性别、待施用的具体化合物、给药时间和途径、疗法的种类、总体健康和其它同时施用的药物。“有效剂量”是指活性成分的量，该量足以影响疾病的病程和严重程度，从而导致这种病理学的减轻或缓解，并且可使用已知方法来确定。
在一些实施方案中，本公开的靶向MSLN的三特异性蛋白质以至多10mg/kg的剂量以每周一次的频率施用。在一些情况下，剂量范围为约1ng/kg至约10mg/kg。在一些实施方案中，该剂量为约1ng/kg至约10ng/kg、约5ng/kg至约15ng/kg、约12ng/kg至约20ng/kg、约18ng/kg至约30ng/kg、约25ng/kg至约50ng/kg、约35ng/kg至约60ng/kg、约45ng/kg至约70ng/kg、约65ng/kg至约85ng/kg、约80ng/kg至约1μg/kg、约0.5μg/kg至约5μg/kg、约2μg/kg至约10μg/kg、约7μg/kg至约15μg/kg、约12μg/kg至约25μg/kg、约20μg/kg至约50μg/kg、约35μg/kg至约70μg/kg、约45μg/kg至约80μg/kg、约65μg/kg至约90μg/kg、约85μg/kg至约0.1mg/kg、约0.095mg/kg至约10mg/kg。在一些情况下，该剂量为约0.1mg/kg至约0.2mg/kg、约0.25mg/kg至约0.5mg/kg、约0.45mg/kg至约1mg/kg、约0.75mg/kg至约3mg/kg、约2.5mg/kg至约4mg/kg、约3.5mg/kg至约5mg/kg、约4.5mg/kg至约6mg/kg、约5.5mg/kg至约7mg/kg、约6.5mg/kg至约8mg/kg、约7.5mg/kg至约9mg/kg或约8.5mg/kg至约10mg/kg。在一些实施方案中，给药频率约为少于每天一次、每隔一天一次、少于每天一次、每周两次、每周一次、7天一次、两周一次、两周一次、三周一次、每四周一次或每月一次。在一些情况下，给药频率为每周一次。在一些情况下，给药频率为每周一次，剂量最高为10mg/kg。在一些情况下，给药持续时间为约1天至约4周或更长
治疗方法
在一些实施方案中，本文还提供了用于刺激有需要的个体的免疫系统的方法和用途，其包括施用本文所述的抗MSLN靶向三特异性蛋白质。在一些情况下，本文所述的抗MSLN靶向三特异性蛋白质的施用诱导和/或保持对表达靶抗原的细胞的细胞毒性。在一些情况下，表达靶抗原的细胞是癌细胞或肿瘤细胞、病毒感染的细胞、细菌感染的细胞、自身反应性T或B细胞、受损红细胞、动脉斑块或纤维化组织。
本文还提供了用于治疗与靶抗原相关的疾病、病症或病况的方法和用途，其包括向有需要的个体施用本文所述的抗MSLN靶向三特异性蛋白质。与靶抗原相关的疾病、病症或病况包括但不限于病毒感染、细菌感染、自身免疫病、移植排斥、动脉粥样硬化或纤维化。在其它实施方案中，与靶抗原相关的疾病、病症或病况为增生性疾病、肿瘤性疾病、炎性疾病、免疫性病症、自身免疫病、传染性疾病、病毒性疾病、变态反应、寄生虫反应、移植物抗宿主病或宿主抗移植物病。在一个实施方案中，与靶抗原相关的疾病、病症或病况为癌症。可以用本公开的MSLN结合蛋白质治疗、预防或控制的癌症及其使用方法包括但不限于上皮细胞起源的癌症。此类癌症的实例包括以下：白血病，例如但不限于急性白血病，急性淋巴细胞白血病，急性髓细胞性白血病，如成髓细胞性、早幼粒细胞性、骨髓单核细胞性、单核细胞性和红白血病，以及骨髓增生异常综合征；慢性白血病，例如但不限于慢性髓细胞性(粒细胞性)白血病、慢性淋巴细胞性白血病、毛细胞白血病；真性红细胞增多症；淋巴瘤，例如但不限于霍奇金病、非霍奇金病；多发性骨髓瘤，例如但不限于郁积型多发性骨髓瘤、非分泌性骨髓瘤、骨硬化性骨髓瘤、浆细胞白血病、孤立性浆细胞瘤和髓外浆细胞瘤；瓦尔登斯特伦巨球蛋白血症；意义不明的单克隆丙种球蛋白病；良性单克隆丙种球蛋白病；重链病；骨和结缔组织肉瘤，例如但不限于骨骼的肉瘤、骨肉瘤、软骨肉瘤、尤因肉瘤、恶性巨细胞瘤、骨纤维肉瘤、脊索瘤、骨膜肉瘤、软组织肉瘤、血管肉瘤、纤维肉瘤、卡波西肉瘤、平滑肌肉瘤、脂肪肉瘤、淋巴管肉瘤、神经鞘瘤、横纹肌肉瘤、滑膜肉瘤；脑瘤，例如但不限于神经胶质瘤、星形细胞瘤、脑干神经胶质瘤、室管膜瘤、少突神经胶质瘤、非神经胶质瘤、听神经鞘瘤、颅咽管瘤、髓母细胞瘤、脑膜瘤、松果体细胞瘤、松果体母细胞瘤、原发性脑淋巴瘤；乳腺癌，包括但不限于导管癌、腺癌、小叶(小细胞)癌、导管内癌、髓样乳腺癌、粘液性乳腺癌、小管性乳腺癌、乳头状乳腺癌、佩吉特病和炎性乳腺癌；肾上腺癌，例如但不限于嗜铬细胞瘤和肾上腺皮质癌；甲状腺癌，例如但不限于乳头状或滤泡状甲状腺癌、髓样甲状腺癌和间变性甲状腺癌；胰腺癌，例如但不限于胰岛素瘤、胃泌素瘤、胰高血糖素瘤、病毒瘤、分泌促生长素抑制素的肿瘤以及类癌或胰岛细胞瘤；垂体癌，例如但不限于库欣病、分泌催乳素的肿瘤、肢端肥大症和尿崩症；眼癌，例如但不限于眼黑素瘤，如虹膜黑素瘤、脉络膜黑素瘤和睫状体黑素瘤，以及视网膜母细胞瘤；阴道癌，如鳞状细胞癌、腺癌和黑素瘤；外阴癌，如鳞状细胞癌、黑素瘤、腺癌、基底细胞癌、肉瘤和佩吉特病；宫颈癌，例如但不限于鳞状细胞癌和腺癌；子宫癌，例如但不限于子宫内膜癌和子宫肉瘤；卵巢癌，例如但不限于卵巢上皮癌、交界瘤、胚细胞瘤和基质肿瘤；食管癌，例如但不限于鳞状癌、腺癌、腺样囊性癌、粘液表皮样癌、腺鳞癌、肉瘤、黑素瘤、浆细胞瘤、疣状癌和燕麦细胞(小细胞)癌；胃癌，例如但不限于腺癌、蕈状(息肉样)、溃疡性、浅表扩散、弥散性扩散、恶性淋巴瘤、脂肪肉瘤、纤维肉瘤和癌肉瘤；结肠癌；直肠癌；肝癌，例如但不限于肝细胞癌和肝母细胞瘤；胆囊癌，如腺癌；胆管癌，例如但不限于乳头状、结节状和弥漫性；肺癌，如非小细胞肺癌、鳞状细胞癌(表皮样癌)、腺癌、大细胞癌和小细胞肺癌；睾丸癌，例如但不限于生殖细胞瘤、精原细胞瘤、间变性、经典(典型)、精细胞癌、非精原细胞瘤、胚胎性癌、畸胎瘤、绒毛膜癌(卵黄囊瘤)，前列腺癌，例如但不限于前列腺上皮内瘤样病变、腺癌、平滑肌肉瘤和横纹肌肉瘤；松果体癌；口腔癌，例如但不限于鳞状细胞癌；基底癌；唾液腺癌，例如但不限于腺癌、粘液表皮样癌和腺样囊性癌；咽癌，例如但不限于鳞状细胞癌和疣状；皮肤癌，例如但不限于基底细胞癌、鳞状细胞癌和黑素瘤，浅表扩散性黑素瘤、结节性黑素瘤、痣样恶性黑素瘤、肢端着色斑性黑素瘤；肾癌，例如但不限于肾细胞癌、腺癌、肾上腺样瘤、纤维肉瘤、移行细胞癌(肾盂和/或子宫)；维尔姆斯瘤；膀胱癌，例如但不限于移行细胞癌、鳞状细胞癌、腺癌、癌肉瘤。此外，癌症包括粘液肉瘤、成骨性肉瘤、内皮肉瘤、淋巴管内皮肉瘤、间皮瘤、滑膜瘤、血管母细胞瘤、上皮癌、囊腺癌、支气管原癌、汗腺癌、皮脂腺癌、乳头状癌和乳头状腺癌(关于这类病症的综述，参见Fishman等人,1985,Medicine,第2版,J.B.Lippincott Co.,Philadelphia，以及Murphy等人,1997,Informed Decisions:The Complete Book of Cancer Diagnosis,Treatment,and Recovery,Viking Penguin,Penguin Books U.S.A.,Inc.,United States ofAmerica)。
本公开的靶向MSLN的三特异性蛋白质也可用于治疗或预防多种癌症或其它异常增生性疾病，包括(但不限于)以下：癌，包括膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌和皮肤癌；包括鳞状细胞癌；淋巴谱系的血液系统肿瘤，包括白血病、急性淋巴细胞白血病、急性淋巴母细胞白血病、B细胞淋巴瘤、T细胞淋巴瘤、伯基特淋巴瘤；骨髓谱系的血液系统肿瘤，包括急性和慢性髓性白血病和早幼粒细胞白血病；间充质起源的肿瘤，包括纤维肉瘤和横纹肌肉瘤；其它肿瘤，包括黑素瘤、精原细胞瘤、四癌、神经母细胞瘤和神经胶质瘤；中枢和周围神经系统的肿瘤，包括星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤；间充质起源的肿瘤，包括纤维肉瘤、横纹肌瘤和骨肉瘤；以及其它肿瘤，包括黑素瘤、着色性干皮病、角膜动化瘤、精原细胞瘤、甲状腺滤泡癌和畸胎瘤。还想到由凋亡异常引起的癌症也可以通过本公开的方法和组合物治疗。此类癌症可包括但不限于滤泡性淋巴瘤，具有p53突变的癌，乳腺、前列腺和卵巢的激素依赖性肿瘤，以及癌前病变，如家族性腺瘤性息肉病和骨髓增生异常综合征。在特定的实施方案中，在皮肤、肺、结肠、乳房、前列腺、膀胱、肾、胰腺、卵巢或子宫中治疗或预防恶性或增生异常改变(如化生和发育异常)或过度增生性疾病。在其它具体的实施方案中，治疗或预防肉瘤、黑素瘤或白血病。
在一些实施方案中，如本文所用的，“治疗”或“处理”是指治疗性处理，其中目的是减缓(减轻)不期望的生理病况、病症或疾病，或是获得有益或期望的临床结果。对于本文所述的目的，有益或期望的临床结果包括但不限于症状的减轻；病况、病症或疾病程度的减小；病况、病症或疾病状态的稳定(即不恶化)；病况、病症或疾病的延迟发作或进展减缓；病况、病症或疾病状态的改善；以及病况、病症或疾病的增强或改善的可检测到的或不可检测的(部分或全部的)缓解。治疗包括引发临床上显著的反应，而没有过高水平的副作用。治疗还包括与不接受治疗的情况下预期的生存期相比延长生存期。在其它实施方案中，“治疗”或“处理”是指预防性措施，其中目的是例如在易患疾病的人(例如，携带诸如乳腺癌等疾病的遗传标志物的个体)中，延迟不希望的生理病况、病症或疾病的发作或者降低其严重程度。
在本文所述的方法的一些实施方案中，如本文所述的靶向MSLN的三特异性蛋白质与用于治疗特定疾病、病症或病况的药剂联合施用。药剂包括但不限于涉及抗体、小分子(例如，化疗药物)、激素(甾体、肽等)的疗法、放射疗法(γ射线、X射线，和/或放射性同位素、微波、UV辐射等的定向递送)、基因疗法(例如，反义，逆转录病毒疗法等)和其它免疫疗法。在一些实施方案中，本文所述的抗MSLN靶向三特异性蛋白质与止泻剂、止吐剂、镇痛药、阿片类药物和/或非甾体抗炎剂联合施用。在一些实施方案中，本文所述的抗MSLN靶向三特异性蛋白质与抗癌剂联合施用。可在本公开的各个实施方案(包括本公开的药物组合物和剂型和试剂盒)中使用的抗癌剂的非限制性实例包括：阿西维辛；阿柔比星；盐酸阿考达唑；阿克罗宁；阿多来新；阿地白介素；六甲蜜胺；安波霉素；醋酸阿美蒽醌；氨鲁米特；安吖啶；阿那曲唑；安曲霉素；天冬酰胺酶；曲林菌素；阿扎胞苷；阿扎替派；阿佐霉素；巴马司他；苯佐替派；比卡鲁胺；盐酸比生群；二甲磺酸双奈法德；比折来新；硫酸博来霉素；布喹那钠；溴匹立明；白消安；放线菌素C；卡鲁睾酮；卡醋胺；卡贝替姆；卡铂；卡莫司汀；盐酸卡柔比星；卡折来新；西地芬戈；苯丁酸氮芥；西罗霉素；顺铂；克拉屈滨；甲磺酸克雷斯托；环磷酰胺；阿糖胞苷；达卡巴嗪；放线菌素D；盐酸柔红霉素；地西他滨；右奥马铂；地扎胍宁；甲磺酸地扎胍宁；地吖醌；多西他赛；多柔比星；盐酸多柔比星；屈洛昔芬；柠檬酸屈洛昔芬；丙酸屈他雄酮；达佐霉素；依达曲沙；盐酸依氟乌氨酸；依沙芦星；恩洛铂；恩普氨酯；依匹哌啶；盐酸表柔比星；厄布洛唑；盐酸依索比星；雌莫司汀；雌莫司汀磷酸钠；依他硝唑；依托泊苷；磷酸依托泊苷；艾托卜宁；盐酸法倔唑；法扎拉滨；芬维A胺；氟尿苷；磷酸氟达拉滨；氟尿嘧啶；氟西他滨；磷喹酮；福司曲星钠；吉西他滨；盐酸吉西他滨；羟基脲；盐酸依达比星；异环磷酰胺；伊莫福新；白介素II(包括重组白介素II或rIL2)；干扰素α-2a；干扰素α-2b；干扰素α-n1；干扰素α-n3；干扰素β-I a；干扰素γ-I b；异丙铂；盐酸伊立替康；醋酸兰瑞肽；来曲唑；醋酸亮丙瑞林；盐酸利阿唑；洛美曲索钠；洛莫司汀；盐酸洛索蒽醌；马索罗酚；美坦辛；盐酸氮芥；醋酸甲地孕酮；醋酸美伦孕酮；美法仑；美诺立尔；巯基嘌呤；甲氨蝶呤；甲氨蝶呤钠；氯苯氨啶；美妥替哌；米丁度胺；米托克星(mitocarcin)；丝裂红素(mitocromin)；米托洁林；丝裂马星；丝裂霉素；米托司培；米托坦；盐酸米托蒽醌；霉酚酸；诺考达唑；诺加霉素；奥马铂；奥昔舒仑；紫杉醇；培门冬酶；培利霉素；戊氮芥；硫酸培洛霉素；培磷酰胺；哌泊溴烷；哌泊舒凡；盐酸吡罗蒽醌；普卡霉素；普洛美坦；卟吩姆钠；泊非霉素；泼尼莫司汀；盐酸丙卡巴肼；嘌呤霉素；盐酸嘌呤霉素；吡唑呋喃菌素；利波腺苷；罗谷亚胺；沙芬戈；盐酸沙芬戈；司莫司汀；辛曲秦；斯帕膦酸钠；司帕霉素；盐酸螺旋锗；螺莫司汀；螺铂；链黑菌素；链脲霉素；磺氯苯脲；他利霉素；替可加兰钠；替加氟；盐酸替洛蒽醌；替莫泊芬；替尼泊苷；替罗昔隆；睾内酯；硫咪嘌呤；硫鸟嘌呤；噻替哌；噻唑羧胺核苷；替拉扎明；柠檬酸托瑞米芬；醋酸曲托龙；磷酸曲西立滨；三甲曲沙；葡糖醛酸三甲曲沙；曲普瑞林；盐酸妥布氯唑；乌拉莫司汀；乌瑞替派；伐普肽；维替泊芬；硫酸长春碱；硫酸长春新碱；长春地辛；硫酸长春地辛；硫酸长春匹定；硫酸长春甘酯；硫酸长春罗新；酒石酸长春瑞滨；硫酸长春罗定；硫酸长春利定；伏氯唑；折尼铂；净司他丁；盐酸佐柔比星。抗癌药的其它实例包括但不限于：20-表-1,25二羟基维生素D3；5-乙炔基尿嘧啶；阿比特龙；阿柔比星；酰基富烯；腺环戊醇；阿多来新；阿地白介素；ALL-TK拮抗剂；六甲蜜胺；氨莫司汀；amidox；氨磷汀；氨基酮戊酸；氨柔比星；安吖啶；阿那格雷；阿那曲唑；穿心莲内酯；血管生成抑制剂；拮抗剂D；拮抗剂G；安雷利克斯；抗背侧化形态发生蛋白-1(anti-dorsalizing morphogenetic protein-1)；抗雄激素；前列腺癌；抗雌激素；抗瘤酮；反义寡核苷酸；甘氨酸阿非科林；凋亡基因调节剂；凋亡调节剂；无嘌呤酸；ara-CDP-DL-PTBA；精氨酸脱氨酶；芥子碱(asulacrine)；阿他美坦；阿莫司汀；阿奇他汀(axinastatin)1；阿奇他汀2；阿奇他汀3；阿扎司琼；阿扎毒素；重氮络氨酸；浆果赤霉素III衍生物；balanol；巴马司他；BCR/ABL拮抗剂；苯并二氢扑酚(benzochlorins)；苯甲酰基星状孢菌素(benzoylstaurosporine)；β-内酰胺衍生物；β-alethine；betaclamycin B；桦木酸；bFGF抑制剂；比卡鲁胺；比生群；双吖丙啶基精胺；双奈法德；双曲群A(bistratene A)；比折来新；breflate；溴匹立明；布朵替坦；丁硫氨酸硫酸亚胺；卡泊三醇；钙磷酸蛋白C；喜树碱衍生物；金丝雀痘IL-2；卡培他滨；羧酰胺-氨基-三唑；羧胺三唑；CaRest M3；CARN 700；软骨衍生抑制剂；卡折来新；酪蛋白激酶抑制剂(ICOS)；栗树精胺；天蚕抗菌肽B；西曲瑞克；二氢卟酚；氯喹喔啉磺酰胺；西卡前列素；顺式卟啉；克拉屈滨；氯米芬类似物；克霉唑；collismycin A；collismycin B；康普瑞汀A4；康普瑞汀类似物；conagenin；crambescidin 816；克雷斯托；念珠藻素8；念珠藻素A衍生物；curacin A；环戊蒽醌；环铂(cycloplatam)；塞匹霉素；阿糖胞苷十八烷基磷酸盐；溶细胞因子；磷酸己烷雌酚(cytostatin)；达昔单抗；地西他滨；脱氢膜海鞘素B；地洛瑞林；地塞米松；右异环磷酰胺；右雷佐生；右维拉帕米；地吖醌；膜海鞘素B；didox；二乙基去甲精胺；二氢-5-氮杂胞苷；9-二氢泰素；二氧杂霉菌素(dioxamycin)；二苯基螺莫司汀；多西他赛；廿二醇；多拉司琼；去氧氟尿苷；屈洛昔芬；屈大麻酚；多卡米星SA；依布硒；依考莫司汀；依地福新；依决洛单抗(edrecolomab)；依氟鸟氨酸；榄香烯；乙嘧替氟；表柔比星；爱普列特；雌莫司汀类似物；雌激素激动剂；雌激素拮抗剂；依他硝唑；磷酸依托泊苷；依西美坦；法倔唑；法扎拉滨；芬维A胺；非格司亭；非那雄胺；夫拉平度；氟卓斯汀；fluasterone；氟达拉滨；盐酸氟道诺霉素(fluorodaunorunicin hydrochloride)；福酚美克；福美坦；福司曲星；福莫司汀；德卟啉钆(gadolinium texaphyrin)；硝酸镓；加洛他滨；加尼瑞克；明胶酶抑制剂；吉西他滨；谷胱甘肽抑制剂；hepsulfam；调蛋白；六亚甲基双乙酰胺；金丝桃素；伊班膦酸；伊达比星；艾多昔芬；伊决孟酮；伊莫福新；伊洛马司他；咪唑并吖啶酮；咪喹莫特；免疫刺激肽；胰岛素样生长因子-I受体抑制剂；干扰素激动剂；干扰素；白介素；碘苄胍；碘代多柔比星；4-甘薯苦醇；伊罗普拉；伊索拉定；异邦格唑；异高软海绵素B；伊他司琼；加斯普拉诺利得(jasplakinolide)；卡哈拉里德F(kahalalide F)；三乙酸片螺素-N；兰瑞肽；雷那霉素；来格司亭；硫酸香菇多糖；雷波斯他汀；来曲唑；白血病抑制因子；白细胞α干扰素；亮丙瑞林+雌激素+黄体酮；亮丙瑞林；左旋咪唑；利阿唑；线性多胺类似物；亲脂性二糖肽；亲脂性铂化合物；lissoclinamide 7；洛铂；蚯蚓磷脂；洛美曲索；氯尼达明；洛索蒽醌；HMG-CoA还原酶抑制剂(诸如但不限于洛伐他汀、普伐他汀、氟伐他汀、他汀类、辛伐他汀和阿托伐他汀)；洛索立宾；勒托替康；lutetium texaphyrin；lysofylline；裂解肽；美坦辛；曼诺他汀A；马立马司他；马索罗酚；乳腺丝抑蛋白；基质溶解因子抑制剂；基质金属蛋白酶抑制剂；美诺立尔；美巴龙(merbarone)；阿伏瑞林；甲硫氨酸酶(methioninase)；甲氧氯普胺；MIF抑制剂；米非司酮；米替福星；米立司亭；错配的双链RNA；米托胍腙；二溴卫矛醇；丝裂霉素类似物；米托萘胺；迈托毒素成纤维细胞生长因子-皂草素；米托蒽醌；莫法罗汀；莫拉司亭；人绒毛膜促性腺激素单克隆抗体；单磷酰脂质A+分支杆菌细胞壁sk；莫哌达醇；多重耐药基因抑制剂；基于多肿瘤抑制物1的疗法；芥子抗癌剂；印度洋海绵B(mycaperoxide B)；分枝杆菌细胞壁提取物；myriaporone；N-乙酰地那林；N-取代的苯甲酰胺；那法瑞林；nagrestip；纳洛酮+喷他佐辛；napavin；naphterpin；那托司亭；奈达铂；奈莫柔比星；奈立膦酸；中性内肽酶；尼鲁米特；尼萨霉素；一氧化氮调节剂；硝基氧抗氧化剂；nitrullyn；O6-苄基鸟嘌呤；奥曲肽；okicenone；寡核苷酸；奥那司酮；昂丹司琼；昂丹司琼；oracin；口服细胞因子诱导剂；奥马铂；奥沙特隆；奥沙利铂；oxaunomycin；紫杉醇；紫杉醇类似物；紫杉醇衍生物；palauamine；palmitoylrhizoxin；帕米膦酸；人参三醇；帕诺米芬；parabactin；泊泽普汀；培门冬酶；培得星(peldesine)；戊聚糖多硫酸钠；喷司他丁；喷曲唑；全氟溴烷；培磷酰胺；紫苏醇；吩嗪霉素(phenazinomycin)；苯乙酸盐；磷酸酶抑制剂；溶链菌制剂(picibanil)；盐酸毛果芸香碱；吡柔比星；吡曲克辛；placetin A；placetin B；纤溶酶原激活物抑制剂；铂络合物；铂化合物；铂-三胺络合物；卟吩姆钠；泊非霉素；强的松；丙基双吖啶酮；前列腺素J2；蛋白酶体抑制剂；基于蛋白质A的免疫调节剂；蛋白激酶C抑制剂；蛋白激酶C抑制剂；微藻；蛋白酪氨酸磷酸酶抑制剂；嘌呤核苷磷酸化酶抑制剂；红紫素；甲氧基吡唑啉吖啶；吡哆基化血红蛋白聚氧乙烯缀合物；raf拮抗剂；雷替曲塞；雷莫司琼；ras法尼基蛋白转移酶抑制剂；ras抑制剂；ras-GAP抑制剂；去甲基化瑞替普汀；铼Re 186依替膦酸盐；根霉素；核糖酶；RII异维A酰胺；罗谷亚胺；罗希吐碱；罗莫肽；罗喹美克；rubiginone B1；ruboxyl；沙芬戈；saintopin；SarCNU；肌植醇A；沙格司亭；Sdi 1模拟物；司莫司汀；衰老衍生的抑制剂1；有义寡核苷酸；信号转导抑制剂；信号转导调节剂；单链抗原结合蛋白；西佐喃；索布佐生；硼卡钠；苯乙酸钠；solverol；生长调节素结合蛋白；索纳明；膦门冬酸；穗霉素D(spicamycin D)；螺莫司汀；斯耐潘定；海绵抑素1(spongistatin 1)；角鲨胺；干细胞抑制剂；干细胞分裂抑制剂；stipiamide；溶基质蛋白酶抑制剂；sulfinosine；强效血管活性肠肽拮抗剂；suradista；苏拉明；苦马豆素；合成的糖胺聚糖；他莫司汀；它莫西芬甲硫碘化物；牛磺莫司汀；他扎罗汀；替可加兰钠；替加氟；tellurapyrylium；端粒酶抑制剂；替莫泊芬；替莫唑胺；替尼泊苷；四氯十氧化物(tetrachlorodecaoxid)；tetrazomine；菌体胚素(thaliblastine)；噻可拉林(thiocoraline)；血小板生成素；血小板生成素模拟物；胸腺法新；胸腺生成素受体激动剂；胸腺曲南；促甲状腺激素；本紫红素乙酯锡(tin ethyletiopurpurin)；替拉扎明；二氯化二茂钛(titanocene bichloride)；topsentin；托瑞米芬；全能干细胞因子；翻译抑制剂；维甲酸；三乙酰尿苷；曲西立宾；三甲曲沙；曲普瑞林；托烷司琼；妥罗特来；酪氨酸激酶抑制剂；酪氨酸磷酸化抑制剂(tyrphostin)；UBC抑制剂；乌苯美司；泌尿生殖窦衍生的生长抑制因子；尿激酶受体拮抗剂；伐普肽；variolin B；载体系统；红细胞基因疗法；维拉雷琐；藜芦胺；verdins；维替泊芬；长春瑞滨；vinxaltine；
伏罗唑；扎诺特隆；折尼铂；亚苄维C(zilascorb)；和净司他丁斯酯。其它抗癌药物是5-氟尿嘧啶和亚叶酸。当在使用沙利度胺和拓扑异构酶抑制剂的方法中使用时，这两种药剂特别有用。在一些实施方案中，本公开的抗MSLN靶向三特异性蛋白质与吉西他滨联合使用。
在一些实施方案中，本文所述的抗MSLN靶向三特异性蛋白质在手术之前、期间或之后施用。
间皮素表达的检测方法和间皮素相关癌症的诊断
根据本公开的另一个实施方案，提供了用于在体外或体内检测间皮素表达的试剂盒。该试剂盒包括前述的靶向MSLN的三特异性蛋白质(例如，含有标记的抗MSLN单结构域抗体或其抗原结合片段的三特异性蛋白质)，以及一种或多种用于检测标记物的化合物。在一些实施方案中，该标记物选自荧光标记物、酶标记物、放射性标记物、核磁共振活性标记物、发光标记物和发色团标记物。
在一些情况下，在生物样品中检测间皮素表达。该样品可以是任何样品，包括但不限于来自活检、尸检和病理学标本的组织。生物样品还包括组织切片，例如，用于组织学目的冷冻切片。生物样品还包括体液，如血液、血清、血浆、痰、脊髓液或尿液。生物样品通常获自哺乳动物，如人或非人灵长类动物。
在一个实施方案中，提供了一种通过使来自受试者的样品与本文公开的抗MSLN单结构域抗体接触并检测该单结构域抗体与样品的结合来确定受试者是否患有癌症的方法。与抗体与对照样品的结合相比，抗体与样品的结合的增加确定该受试者患有癌症。
在另一个实施方案中，提供了一种通过使来自被诊断出患有癌症的受试者的样品与本文公开的抗MSLN单结构域抗体接触并检测该抗体与样品的结合来确认受试者中癌症的诊断的方法。与抗体与对照样品的结合相比，抗体与样品的结合的增加确认了受试者中癌症的诊断。
在所公开方法的一些实例中，三特异性蛋白质的MSLN单结构域抗体被直接标记。
在一些实例中，所述方法进一步包括使与所述抗MSLN单结构域抗体特异性结合的第二抗体与所述样品接触；以及检测第二抗体的结合。与第二抗体与对照样品的结合相比，第二抗体与样品的结合的增加检测出受试者中的癌症或证实了受试者中癌症的诊断。
在一些情况下，所述癌症是间皮瘤、前列腺癌、肺癌、胃癌、鳞状细胞癌、胰腺癌、胆管癌、三阴性乳腺癌或卵巢癌，或表达间皮素的任何其它类型的癌症。
在一些实例中，对照样品是来自没有癌症的受试者的样品。在特定的实例中，样品是血液或组织样品。
在一些情况下，结合(例如特异性结合)间皮素的抗体直接用可检测标记物标记。在另一个实施方案中，结合(例如，特异性结合)间皮素的抗体(第一抗体)未被标记，而第二抗体或可以结合特异性结合间皮素的抗体的其它分子被标记。选择第二抗体，使其能够特异性结合特定种类和类别的第一抗体。例如，如果第一抗体是美洲驼IgG，则第二抗体可以是抗美洲驼IgG。可以与抗体结合的其它分子包括但不限于蛋白A和蛋白G，两者均可商购获得。抗体或第二抗体的合适的标记物如上所述，并且包括各种酶、辅基、荧光材料、发光材料、磁性剂和放射性材料。合适的酶的非限制性实例包括辣根过氧化物酶、碱性磷酸酶、β-半乳糖苷酶或乙酰胆碱酯酶。合适的辅基复合物的非限制性实例包括链霉亲和素/生物素和抗生物素蛋白/生物素。合适的荧光材料的非限制性实例包括伞形酮、荧光素、异硫氰酸荧光素、罗丹明、二氯三嗪胺荧光素、丹磺酰氯或藻红蛋白。非限制性的示例性发光材料是鲁米诺；非限制性的示例性磁性剂是钆，而非限制性的示例性放射性标记物包括125I、131I、35S或3H。
在备选的实施方案中，可以通过竞争性免疫测定在生物样品中测定间皮素，该测定采用以可检测物质标记的间皮素标准品和特异性结合间皮素的未标记抗体。在该测定中，将生物样品、标记的间皮素标准品和特异性结合间皮素的抗体混合在一起，并测定与未标记的抗体结合的标记的间皮素标准品的量。生物样品中间皮素的量与同特异性结合间皮素的抗体结合的标记间皮素标准品的量成反比。
本文公开的免疫测定和方法可以用于多种目的。在一个实施方案中，特异性结合间皮素的抗体可用来检测细胞培养物中的细胞中间皮素的产生。在另一个实施方案中，该抗体可以用来检测生物样品如组织样品或血液或血清样品中间皮素的量。在一些实例中，该间皮素是细胞表面间皮素。在其它实例中，该间皮素是可溶性间皮素(例如，细胞培养上清液中的间皮素或体液样品如血液或血清样品中的间皮素。
在一个实施方案中，提供了用于检测生物样品如血液样品或组织样品中的间皮素的试剂盒。例如，为了确认受试者中的癌症诊断，可以进行活检以获得用于组织学检查的组织样品。或者，可以获取血液样品以检测可溶性间皮素蛋白质或片段的存在。根据本公开内容，用于检测多肽的试剂盒通常将包含特异性结合间皮素的单结构域抗体。在一些实施方案中，该试剂盒中包括抗体片段，如scFv片段、VH结构域或Fab。在进一步的实施方案中，该抗体被标记(例如，用荧光、放射性或酶标记物标记)。
在一个实施方案中，试剂盒包括说明材料，其公开了使用结合间皮素的抗体的手段。该说明材料可以用电子形式(如计算机软盘或光盘)书写，也可以是可视的(如视频文件)。试剂盒还可以包括其它组件，以方便试剂盒设计所针对的特定应用。因此，例如，该试剂盒可以另外包含检测标记物的手段(例如用于酶标记物的酶底物，用于检测荧光标记物的滤光器套件，合适的第二标记物，如第二抗体等)。该试剂盒可以另外包括常规用于实施特定方法的缓冲液和其它试剂。这样的试剂盒和合适的内容物是本领域技术人员熟知的。
在一实施方案中，诊断试剂盒包括免疫测定。尽管免疫测定的细节可随所采用的特定形式而不同，但是检测生物样品中间皮素的方法通常包括使生物样品与在免疫反应性条件下与间皮素多肽特异性反应的抗体接触的步骤。使抗体在免疫反应性条件下特异性结合以形成免疫复合物，并直接或间接检测免疫复合物(结合的抗体)的存在。
确定细胞表面标志物存在与否的方法是本领域公知的。例如，抗体可以与包括但不限于酶、磁珠、胶体磁珠、半抗原、荧光染料、金属化合物、放射性化合物或药物的其它化合物缀合。抗体也可用于免疫测定，例如但不限于放射免疫测定(RIA)、ELISA或免疫组织化学测定中。抗体也可用于荧光激活的细胞分选(FACS)。FACS使用多个颜色通道、低角度和钝角光散射检测通道以及阻抗通道，以及其它更复杂的检测级别，来对细胞进行分离或分类(参见第5,061,620号美国专利)。如本文所公开的，结合间皮素的任何单结构域抗体均可在这些测定中使用。因此，这些抗体可以用于常规的免疫测定中，包括但不限于ELISA、RIA、FACS、组织免疫组织化学、Western印迹法或免疫沉淀。
本发明提供了包括但不限于以下实施方式：
1.一种结合间皮素(MSLN)的三特异性蛋白质，其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A)；
(b)第二结构域(B)，其为半衰期延长结构域；和
(c)与MSLN特异性结合的第三结构域(C)，
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。
2.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻结构域和可变重结构域。
3.根据实施方式1所述的结合MSLN的蛋白质，其中所述第一结构域是人源化的或人的。
4.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第二结构域结合白蛋白。
5.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第二结构域包含scFv、可变重结构域(VH)、可变轻结构域(VL)、肽、配体或小分子。
6.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含与MSLN特异性结合的VHH结构域、scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
7.根据实施方式6所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含VHH结构域。
8.根据实施方式7所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含一个或多个保守区，所述保守区包含与SEQ ID NO:41、42、43或44相同或相对于SEQ ID NO:41、42、43或44包含一个或多个氨基酸残基置换的序列。
9.根据实施方式8所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:41相同或相对于SEQ ID NO:41包含一个或多个氨基酸残基置换的序列。
10.根据实施方式8所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:42相同或相对于SEQ ID NO:42包含一个或多个氨基酸残基置换的序列。
11.根据实施方式8所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:43相同或相对于SEQ ID NO:43包含一个或多个氨基酸残基置换的序列。
12.根据实施方式8所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:44相同或相对于SEQ ID NO:44包含一个或多个氨基酸残基置换的序列。
13.根据实施方式7所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含(i)对应于SEQ ID NO:41的一段氨基酸；(ii)对应于SEQ ID NO:42的一段氨基酸；(iii)对应于SEQ ID NO:43的一段氨基酸；和(iv)对应于SEQ ID NO:44的一段氨基酸。
14.根据实施方式7所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含下式：
f1-r1-f2-r2-f3-r3-f4
其中，r1与SEQ ID NO:51相同或相对于SEQ ID NO:51包含一个或多个氨基酸残基置换；r2与SEQ ID NO:52相同或相对于SEQ ID NO:52包含一个或多个氨基酸残基置换；且r3与SEQ ID NO:53相同或相对于SEQ ID NO:53包含一个或多个氨基酸残基置换；并且其中f1、f2、f3和f4是框架残基。
15.根据实施方式7所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含与选自SEQ ID NO:1-29的序列至少80％相同的序列。
16.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含选自SEQ ID NO:1-29的序列。
17.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述第三结构域是人源化的VHH结构域。
18.根据实施方式17所述的结合MSLN的三特异性蛋白质，其中所述人源化的VHH结构域包含一个或多个保守区，所述保守区包含与SEQ ID NO:45、46、47、48、49或50相同或相对于SEQ ID NO:45、46、47、48、49或50包含一个或多个氨基酸残基置换的序列。
19.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:45相同或相对于SEQ ID NO:45包含一个或多个氨基酸残基置换的序列。
20.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守区，所述保守区包含与SEQ ID NO:46相同或相对于SEQ ID NO:46包含一个或多个氨基酸残基置换的序列。
21.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:47相同或相对于SEQ ID NO:47包含一个或多个氨基酸残基置换的序列。
22.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:48相同或相对于SEQ ID NO:48包含一个或多个氨基酸残基置换的序列。
23.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:49相同或相对于SEQ ID NO:49包含一个或多个氨基酸残基置换的序列。
24.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含保守域，所述保守域包含与SEQ ID NO:50相同或相对于SEQ ID NO:50包含一个或多个氨基酸残基置换的序列。
25.根据实施方式18所述的结合MSLN的三特异性蛋白质，其中所述VHH结构域包含(i)对应于SEQ ID NO:45的一段氨基酸，(ii)对应于SEQ ID NO:46的一段氨基酸，(iii)对应于SEQ ID NO:47的一段氨基酸，(iv)对应于SEQ ID NO:48的一段氨基酸，(v)对应于SEQID NO:49的一段氨基酸，和(vi)对应于SEQ ID NO:50的一段氨基酸。
26.根据实施方式17所述的结合MSLN的三特异性蛋白质，其中所述人源化的VHH结构域包含下式：
f1-r1-f2-r2-f3-r3-f4
其中，r1与SEQ ID NO:54相同或相对于SEQ ID NO:54包含一个或多个氨基酸残基置换；r2与SEQ ID NO:55相同或相对于SEQ ID NO:55包含一个或多个氨基酸残基置换；且r3与SEQ ID NO:56相同或相对于SEQ ID NO:56包含一个或多个氨基酸残基置换；并且其中f1、f2、f3和f4是框架残基。
27.根据实施方式17-26中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含选自SEQ ID NO:30-40和102-105的序列。
28.根据实施方式1-27中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域与包含SEQ ID NO:57所示序列的人间皮素蛋白质结合。
29.根据实施方式1-28中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域与间皮素的表位结合，其中所述表位位于包含SEQ ID NO:57的氨基酸残基296-390的区域I、包含SEQ ID NO:57的氨基酸残基391-486的区域II或包含SEQ ID NO:57的氨基酸残基487-598的区域III中。
30.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中连接体L1和L2各自独立地选自(GS)n(SEQ ID NO:87)、(GGS)n(SEQ ID NO:88)、(GGGS)n(SEQ ID NO:89)、(GGSG)n(SEQ ID NO:90)、(GGSGG)n(SEQ ID NO:91)或(GGGGS)n(SEQ ID NO:92)，其中n为1、2、3、4、5、6、7、8、9或10。
31.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中连接体L1和L2各自独立地为(GGGGS)4(SEQ ID NO:95)或(GGGGS)3(SEQ ID NO:96)。
32.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述结构域以H2N-(C)-(B)-(A)-COOH的顺序连接。
33.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质小于约80kDa。
34.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质为约50kDa至约75kDa。
35.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质小于约60kDa。
36.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质具有至少约50小时的消除半衰期。
37.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质具有至少约100小时的消除半衰期。
38.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中与针对相同MSLN的IgG相比，所述蛋白质具有增加的组织穿透。
39.根据实施方式1所述的结合MSLN的三特异性蛋白质，其中所述蛋白质包含选自SEQ ID NO:58-86、98、100和101的序列。
40.一种药物组合物，其包含(i)根据实施方式1-39中任一项所述的结合MSLN的三特异性蛋白质，和(ii)药学上可接受的载剂。
41.一种产生根据实施方式1-39中任一项所述的结合间皮素的三特异性蛋白质的方法，所述方法包括在允许表达结合间皮素的三特异性蛋白质并从培养物中回收和纯化所产生的蛋白质的条件下培养用载体转化或转染的宿主，该载体包含编码根据实施方式1-39中任一项所述的结合间皮素的三特异性蛋白质的核酸序列。
42.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括向有需要的受试者施用根据实施方式1-39中任一项所述的结合间皮素的三特异性蛋白质。
43.根据实施方式42所述的方法，其中所述受试者是人。
44.根据实施方式43所述的方法，其中所述方法进一步包括将药剂与根据实施方式1-39中任一项所述的结合间皮素的三特异性蛋白质联合施用。
45.根据实施方式42-44中任一项所述的方法，其中所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。
46.根据实施方式45所述的方法，其中所述结合间皮素的三特异性蛋白质介导T细胞对表达间皮素的肿瘤细胞的杀伤。
47.根据实施方式42-46中任一项所述的方法，其中所述肿瘤性疾病包括实体瘤疾病。
48.根据实施方式47所述的方法，其中所述实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。
49.根据实施方式48所述的方法，其中所述实体瘤疾病是转移性的。
50.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含选自SEQ ID NO:58-86、98、100和101的序列的结合间皮素的三特异性蛋白质。
51.根据实施方式50所述的方法，其中所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。
52.根据实施方式51所述的方法，其中所述结合间皮素的三特异性蛋白质引导T细胞对表达间皮素的肿瘤细胞的杀伤。
53.根据实施方式50-52中任一项所述的方法，其中所述肿瘤性疾病包括实体瘤疾病。
54.根据实施方式53所述的方法，其中所述实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。
55.根据实施方式54所述的方法，其中所述实体瘤疾病是转移性的。
56.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含SEQID NO:98所示序列的结合间皮素的三特异性蛋白质。
57.根据实施方式50-56中任一项所述的方法，其包括以至多10mg/kg的剂量施用所述结合间皮素的三特异性蛋白质。
58.根据实施方式50-57中任一项所述的方法，其中所述蛋白质每周施用一次。
59.根据实施方式50-57中任一项所述的方法，其中所述蛋白质每周施用两次。
60.根据实施方式50-57中任一项所述的方法，其中所述蛋白质每隔一周施用一次。
61.根据实施方式50-57中任一项所述的方法，其中所述蛋白质每三周施用一次。
62.一种结合间皮素(MSLN)的三特异性蛋白质，其包含SEQ ID NO:98所示的序列。
63.一种结合间皮素(MSLN)的三特异性蛋白质，其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A)；
(b)第二结构域(B)，其为半衰期延长结构域；和
(c)与MSLN特异性结合的第三结构域(C)，
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接，其中所述第三结构域包含一个或多个选自SEQ ID No:51-56和106-222的CDR序列。
64.根据实施方式63所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含CDR1，该CDR1包含SEQ ID No.:51、54和106-144中任一个所示的序列。
65.根据实施方式63或64所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含CDR2，该CDR2包含SEQ ID No.:52、55和145-183中任一个所示的序列。
66.根据实施方式63-65中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含CDR2，该CDR2包含SEQ ID No.:53、56和184-222中任一个所示的序列。
67.根据实施方式63-66中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含框架区1(f1)，该框架区1包含SEQ ID No.:262-300中任一个所示的序列。
68.根据实施方式63-67中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含SEQ ID No.:301-339中任一个所示的框架区(f2)序列。
69.根据实施方式63-68中任一项所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含SEQ ID No.:340-378中任一个所示的框架区(f3)序列。
70.根据实施方式63-69中任一项所述的结合MSLN的三特异性蛋白质，其中所述蛋白质包含选自SEQ ID NO:58-86、98、100和101的序列。
71.根据实施方式63-70中任一项所述的结合MSLN的三特异性蛋白质，其中所述蛋白质包含SEQ ID NO:98所示的序列。
72.一种药物组合物，其包含(i)根据实施方式63-71中任一项所述的结合MSLN的三特异性蛋白质，和(ii)药学上可接受的载剂。
73.一种产生根据实施方式63-71中任一项所述的结合间皮素的三特异性蛋白质的方法，所述方法包括在允许表达结合间皮素的三特异性蛋白质并从培养物中回收和纯化所产生的蛋白质的条件下培养用载体转化或转染的宿主，该载体包含编码根据实施方式63-71中任一项所述的结合间皮素的三特异性蛋白质的核酸序列。
74.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括向有需要的受试者施用根据实施方式63-71中任一项所述的结合间皮素的三特异性蛋白质。
75.根据实施方式74所述的方法，其中所述受试者是人。
76.根据实施方式75所述的方法，其中所述方法进一步包括将药剂与根据实施方式63-71中任一项所述的结合间皮素的三特异性蛋白质联合施用。
77.根据实施方式74-76中任一项所述的方法，其中所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。
78.根据实施方式77所述的方法，其中所述结合间皮素的三特异性蛋白质介导T细胞对表达间皮素的肿瘤细胞的杀伤。
79.根据实施方式74-78中任一项所述的方法，其中所述肿瘤性疾病包括实体瘤疾病。
80.根据实施方式79所述的方法，其中所述实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。
81.根据实施方式80所述的方法，其中所述实体瘤疾病是转移性的。
82.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用根据实施方式63-71中任一项所述的结合间皮素的三特异性蛋白质。
83.根据实施方式82所述的方法，其中所述结合间皮素的三特异性蛋白质选择性地结合表达间皮素的肿瘤细胞。
84.根据实施方式83所述的方法，其中所述结合间皮素的三特异性蛋白质引导T细胞对表达间皮素的肿瘤细胞的杀伤。
85.根据实施方式82-84中任一项所述的方法，其中所述肿瘤性疾病包括实体瘤疾病。
86.根据实施方式85所述的方法，其中所述实体瘤疾病包括间皮瘤、肺癌、胃癌、卵巢癌或三阴性乳腺癌。
87.根据实施方式86所述的方法，其中所述实体瘤疾病是转移性的。
实施例
实施例1：评估数种示例性靶向MSLN的三特异性抗原结合蛋白质的结合和细胞毒
活性的方法
蛋白质产生
将三特异性分子的序列克隆到哺乳动物表达载体pCDNA 3.4(Invitrogen)中，其之前是前导序列，之后是6x组氨酸标签。将Expi293F细胞(Life Technologies A14527)以0.2-8×1e6个细胞/ml悬浮保持在Optimum Growth Flasks(Thomson)中的Expi 293培养基中。根据Expi293Expression System Kit(Life Technologies，A14635)方案，将纯化的质粒DNA转染到Expi293细胞中，并在转染后保持4-6天。在条件培养基中，使用带有蛋白A尖端的Octet仪器，且使用对照三特异性蛋白质制作标准曲线，对条件培养基中来自转染的Expi293细胞的所测示例性三特异性蛋白质的量进行定量。
细胞毒性测定
使用人T细胞依赖性细胞毒性(TDCC)测定来测量T细胞接合物(包括三特异性分子)引导T细胞杀伤肿瘤细胞的能力(Nazarian等人,2015.J Biomol Screen.20:519-27)。在该测定中，将T细胞和目标癌细胞系细胞在384孔板中以10:1的比例混合在一起，并添加不同量的所测三特异性蛋白质。将肿瘤细胞系工程化为表达萤光素酶蛋白质。48小时后，为了对剩余的存活肿瘤细胞进行定量，使用
Luminescent Assay(Promega)。
在本研究中，将条件培养基的滴定添加到TDCC测定(T细胞依赖性细胞毒性测定)中，以评估抗MSLN单结构域抗体是否能够在T细胞与表达间皮素的卵巢癌细胞系OVCAR8之间形成突触。48小时后测量OVCAR8细胞的活力。可以看出，所述三特异性蛋白质介导了T细胞杀伤。图2显示了用所测三特异性蛋白质2A2和2A4进行的示例细胞活力测定。以下表1列出了所测三特异性蛋白质的TDCC活性的EC50。
表1：靶向MSLN的三特异性蛋白质(TriTAC)的TDCC活性
此外，观察到所测靶向MSLN的三特异性蛋白质的TDCC活性对表达间皮素的细胞是特异性的，因为所测三特异性蛋白质不介导T细胞对不表达间皮素的LNCaP细胞的杀伤。特别是，三特异性蛋白质2A2、11F3、9H2、5C2、10B3、2F4、5F2、7F1、2F4、5H1、3B4和7H2对LnCaP细胞不显示TDCC活性。
实施例2：异种移植肿瘤模型
在异种移植模型中评价前述实施例的靶向MSLN的三特异性蛋白质。
向雌性免疫缺陷NOD/scid小鼠进行亚致死照射(2Gy)，并将1X106个NCI-H28细胞皮下接种到它们的右背侧。当肿瘤达到100至200mm3时，将动物分成3个处理组。第2组和第3组(各8只动物)腹膜内注射1.5×107个活化的人T细胞。三天后，用50μg实施例1的MSLN三特异性抗原结合蛋白质的总共9个静脉内剂量(qdx9d)处理第3组的动物。第1组和第2组仅用媒介物处理。测量体重和肿瘤体积30天。
预计与相应媒介物处理的对照组相比，用前述实施例的靶向MSLN的三特异性蛋白质处理的动物具有统计学上显著的肿瘤生长延迟。
实施例3：关于向卵巢癌患者施用实施例1的MSLN三特异性抗原结合蛋白质的概念
验证临床试验方案
这是用于研究实施例1的MSLN三特异性抗原结合蛋白质作为卵巢癌治疗方法的I/II期临床试验。
研究结果：
主要：前述实施例的靶向MSLN的三特异性蛋白质的最大耐受剂量
次要：确定前述实施例的靶向MSLN的三特异性蛋白质的体外反应是否与临床反应相关
I期
最大耐受剂量(MTD)在该试验的I期部分确定。
1.1最大耐受剂量(MTD)在该试验的I期部分确定。
1.2满足合格性标准的患者加入针对前述实施例的靶向MSLN的三特异性蛋白质的试验。
1.3目标是确定前述实施例的靶向MSLN的三特异性蛋白质可以在参与者中安全施用而没有严重的或难以处理的副作用的最高剂量。给定的剂量取决于之前已经入选该研究的参与者的数目以及剂量耐受程度。并非所有参与者都接受相同的剂量。
II期
2.1随后的II期部分以MTD进行治疗，目的是确定采用前述实施例的靶向MSLN的三特异性蛋白质的疗法是否会导致至少20％的反应率。
II期的主要结果---确定采用前述实施例的靶向MSLN的三特异性蛋白质的疗法是否会致使至少20％的患者实现临床反应(强烈反应(blast response)、轻微反应、部分反应或完全反应)。
合格性
2014年，根据当前的世界卫生组织分类，经组织学证实的卵巢癌表面上皮-间质肿瘤
性索-间质肿瘤
生殖细胞肿瘤
恶性，未另外指定
年龄≥18岁
预期寿命≥6周
虽然本文已经显示并描述了本发明的优选实施方案，但是对于本领域技术人员显而易见的是，这些实施方案仅以示例的方式提供。在不脱离本发明的情况下，本领域技术人员现将想到许多变化、改变和替换。应当理解，本文所述的本发明实施方案的各种替代方案均可用于实施本发明。以下权利要求旨在限定本发明的范围，并由此涵盖这些权利要求范围内的方法和结构及其等同物。
实施例4：MH6T TriTAC引导T细胞杀死表达MSLN的卵巢癌细胞
使用人T细胞依赖性细胞毒性(TDCC)测定来测量T细胞接合物(包括三特异性分子)引导T细胞杀死肿瘤细胞的能力(Nazarian等人.2015.J Biomol Screen.20:519-27)。该测定中使用的Caov3细胞被工程化为表达萤光素酶。将来自5名不同健康供体(供体02、供体86、供体41、供体81和供体34)的T细胞和目标癌细胞Caov3混合在一起，并加入不同量的本公开的示例性三特异性分子MH6T TriTAC(SEQ ID NO:98)，将混合物在37℃下孵育48小时。Caov3细胞和T细胞也与靶向GFP的对照三特异性分子GFP TriTAC(SEQ ID NO:99)在37℃下孵育48小时。48小时后，通过发光测定对剩余的活肿瘤细胞进行定量。
观察到MH6 TriTAC分子能够引导来自所有5名健康供体的T细胞杀死目标癌细胞Caov3(如图3所示)，而对照GFP TriTAC分子则不能引导来自这5名健康供体中任一名的T细胞杀死Caov3细胞(也显示在图3中)。
使用与上述相同的方案，使用OVCAR3细胞进行进一步的测定。观察到，MH6 TriTAC分子能够引导来自所有5名健康供体的T细胞杀死目标癌细胞OVCAR3(如图4所示)，而对照GFP TriTAC分子则不能引导来自这5名健康供体中任一名的T细胞杀死OVCAR3细胞(也显示在图4中)。
以下表II中列出了关于杀死表达MSLN的靶细胞的EC50值。
表II：MH6T TriTAC引导来自5名不同健康供体的T细胞杀死表达MSLN的卵巢癌细胞系的EC50值。原始数据的代表图示在图3和图4中提供。
实施例5：MH6T TriTAC引导T细胞杀死表达MSLN的细胞，但不引导杀死不表达MSLN的细胞
在该试验中，将来自健康供体的T细胞与表达MSLN的目标癌细胞(Caov3细胞、Caov4细胞、OVCAR3细胞和OVCAR8细胞)或不表达MSLN的目标癌细胞(NCI-H510A细胞、MDAPCa2b细胞)一起孵育。本研究中使用的每个靶细胞均被工程化为表达萤光素酶。将不同量的MH6T TriTAC(SEQ ID NO:98)分子添加到上面列出的T细胞与目标癌细胞的混合物中。将混合物在37℃下孵育48小时。48小时后，使用发光测定对剩余的活目标癌细胞进行定量。
观察到MH6 TriTAC分子能够引导T细胞杀死表达MSLN的目标癌细胞(即，Caoc3、Caov4、OVCAR3和OVCAR8细胞，如图5所示)。然而，MH6T TriTAC分子不能引导T细胞杀死不表达MSLN的目标癌细胞(MDAPCa2b和NCI-H510A细胞)，也如图5所示。
以下表III中列出了关于杀死表达MSLN的癌细胞的EC50值。
表III：MH6T TriTAC引导T细胞杀死表达MSLN的癌细胞系的EC50值。
实施例6：MH6T TriTAC引导来自食蟹猴的T细胞杀死人卵巢癌细胞系
在该试验中，将来自食蟹猴供体的外周血单个核细胞(PBMC；T细胞是PBMC的组成部分)与表达MSLN的目标癌细胞(CaOV3细胞和OVCAR3细胞)混合，将不同量的MH6T TriTAC分子(SEQ ID NO:98)加入混合物中，并在37℃下孵育48小时。平行地，如上所述，将食蟹猴PBMC与表达MSLN的细胞的混合物与不同量的靶向GFP的对照TriTAC分子GFP TriTAC(SEQID NO:99)在37℃下孵育48小时。该试验中使用的目标癌细胞被工程为表达萤光素酶。48小时后，使用发光测定对剩余的活靶细胞进行定量。
观察到MH6 TriTAC分子能够有效地引导食蟹猕猴PBMC杀死表达MSLN的细胞(即Caov3和OVCAR，如图6所示)，而对照GFP TriTAC分子却无法引导食蟹猕猴PBMC杀死所述细胞(也显示在图6中)。MH6T TriTAC分子的EC50值对于OVCAR3细胞为2.9pM，而对于Caov3细胞为3.0pM，与使用人T细胞观察到的EC50值没有显著差异，如表II中所示。
实施例7：在存在或不存在人血清白蛋白的情况下，MH6T TriTAC分子引导T细胞杀死表达MSLN的NCI-H2052间皮瘤细胞
本研究的目的是评估MH6T TriTAC分子与人血清白蛋白(HSA)的结合是否影响MH6T TriTAC分子引导T细胞杀死表达MSLN的细胞的能力。本研究中使用的NCI-H2052间皮瘤细胞被工程化为表达萤光素酶。将来自健康供体的T细胞和表达MSLN的细胞(NCI-H2052)混合，并将不同量的MH6T TriTAC(SEQ ID NO:98)分子添加至该混合物中。在存在或不存在HSA的情况下，将混合物在37℃下孵育48小时。还在存在或不存在HSA的情况下，将NCI-H2052细胞与T细胞的混合物与靶向GFP的对照三特异性分子GFP TriTAC(SEQ ID NO:99)在37℃下孵育48小时。48小时后，使用发光测定对剩余的活靶细胞进行定量。
观察到在存在或不存在HSA的情况下，MH6 TriTAC分子能够有效引导T细胞杀死NCI-H2052细胞(如图7所示)，而对照GFP TriTAC分子则无法实现(同样如图7所示)。还观察到在HSA的存在下，细胞杀伤的EC50值增加了约3.2倍(如表IV中所示)
在存在或不存在15mg/ml HSA的情况下，采用另外的表达MSLN的细胞系，使用MH6TTriTAC分子进行进一步的TDCC测定，其EC50值在表IV中呈现。
表IV：在存在或不存在HSA的情况下，MH6T TriTAC引导T细胞杀死表达MSLN的癌细胞的EC50值
实施例8：在MH6T TriTAC和表达MSLN的Caov4细胞的存在下，来自4名不同供体的T细胞分泌TNF-α
在该试验中使用的目标癌细胞CaOv4被工程化为表达萤光素酶。在该试验中，将来自4名不同健康供体(供体02、供体86、供体35和供体81)的T细胞和Caov4细胞混合在一起，添加不同量的MH6TTriTAC分子(SEQ ID NO:98)，并将混合物在37℃下孵育48小时。还将Caov4细胞和T细胞与靶向GFP的对照三特异性分子GFP TriTAC(SEQ ID NO:99)在37℃下孵育48小时。在48小时时收集来自TDCC测定的条件培养基，之后使用发光测定来测量目标癌细胞的活力。使用AlphaLISA测定试剂盒(Perkin Elmer)测定条件培养基中TNF-α的浓度。
观察到在Caov4细胞和MH6T TriTAC分子的存在下，TNF-α分泌到培养基中，而在Caov4细胞和对照GFP TriTAC分子的存在下则不分泌，如图8所示。
此外，在MH6T TriTAC分子的存在下，对于来自所有4名健康供体的T细胞观察到有效杀伤，但在对照GFP TriTAC分子的存在下未观察到有效杀伤。还针对其它表达MSLN的细胞系(Caov3细胞、OVCAR3细胞和OVCAR8细胞)建立了TDCC测定，并观察到类似的TNF-α表达。MH6T TriTAC诱导TNF-α表达的EC50值在表V中呈现。但是，当使用不表达MSLN的癌细胞(NCI-H510A细胞或MDAPCa2b细胞)进行测定时，没有观察到MH6T TriTAC引导TNF-α分泌(数据未示出)。因此，该研究表明，在表达MSLN的目标癌细胞的存在下，MH6T TriTAC分子能够激活T细胞。
表V：MH6T TriTAC分子诱导来自4名不同T细胞供体的T细胞和4种不同的表达MSLN的细胞系表达TNF-α的EC50值
实施例9：在MH6T TriTAC和表达MSLN的OVCAR8细胞的存在下，来自4名不同供体的T细胞上CD69表达的活化
该试验中使用的OVCAR8细胞被工程化为表达萤光素酶。在该试验中，将来自4名不同健康供体(供体02、供体86、供体35和供体81)的T细胞和OVCAR8细胞混合在一起，添加不同量的MH6T TriTAC分子(SEQ ID NO:98)，并将混合物在37℃下孵育48小时。OVCAR8细胞和T细胞也与靶向GFP的对照三特异性分子GFP TriTAC(SEQ ID NO:99)在37℃下孵育48小时。48小时后，收集T细胞，并通过流式细胞术测量T细胞上的CD69表达。
如图9所示，在OVCAR8细胞和MH6T TriTAC分子的存在下，在来自所有4名健康供体的T细胞上检测到CD69表达，但在阴性对照GFP TriTAC和OVCAR8细胞的存在下未检测到CD69表达。还针对其它表达MSLN的细胞(Caov3细胞、OVCAR3细胞和OVCAR8细胞)建立了TDCC测定，并观察到类似的CD69表达。表VI中呈现了MH6TTriTAC诱导Caov3细胞和OVCAR8细胞中CD69活化的EC50值。
表VI：在MH6T TriTAC分子和表达MSLN的OVCAR8细胞或Caov3细胞的存在下，来自4名不同供体的T细胞上CD69表达活化的EC50值。
当使用不表达MSLN的癌细胞(NCI-H510A细胞或MDAPCa2b细胞)进行该试验时，未观察到MH6T诱导的CD69活化(数据未示出)。因此，该研究表明，在表达MSLN的目标癌细胞的存在下，MH6T TriTAC分子能够激活T细胞。
实施例10：MH6T TriTAC与表达MSLN/不表达MSLN的细胞系的结合的测量
对于本研究，将某些表达MSLN的目标癌细胞(Caov3细胞、CaOV4细胞、OVCAR3细胞和OVCAR8细胞)和某些不表达MSLN的癌细胞(MDAPCa2b细胞和NCI-H510A细胞)与MH6TriTAC分子(SEQ ID NO:98)或对照GFP TriTAC分子(SEQ ID NO:99)一起孵育。孵育后，洗涤细胞以除去未结合的MH6T或GFP TriTAC分子，并进一步与与同Alexa Fluor 647缀合的第二抗体一起孵育，该第二抗体能够识别TriTAC分子中的抗白蛋白结构域。通过流式细胞术测量MH6T TriTAC或GFP TriTAC与表达MSLN或不表达MSLN的细胞的结合。
观察到MH6T TriTAC分子与表达MSLN的细胞系(Caov3、Caov4、OVCAR3和OVCAR8)的牢固结合，如图10A所示(左上图显示MH6TTriTAC与Caov3细胞的结合；右上图显示MH6TTriTAC与Caov4细胞的结合；左下图显示MH6T TriTAC与OVCAR3细胞的结合；右下图显示MH6T TriTAC与OVCAR8细胞的结合)；而如图10B所示，在不表达MSLN的细胞系中未观察到结合(左图显示MH6T TriTAC无法与MDAPCa2b细胞结合，右图显示MH6T TriTAC无法与NCI-H510A细胞结合)。此外，当将任何细胞类型与GFP TriTAC分子一起孵育时，均未观察到结合，如图10A和图10B所示。
实施例11：MH6T TriTAC与来自供体的T细胞的结合的测量
对于本研究，将来自4名健康供体的T细胞与MH6 TriTAC分子(SEQ ID NO:98)或缓冲液(作为阴性对照)一起孵育。孵育后，洗涤细胞以去除未结合的MH6T TriTAC分子，并与Alexa Fluor 647缀合的第二抗体进一步孵育，该抗体能够识别MH6T TriTAC分子中的抗白蛋白结构域。通过流式细胞术测量MH6T TriTAC与细胞的结合。
观察到MH6T TriTAC与用MH6T TriTAC分子处理的来自所有四名供体的T细胞的牢固结合，如图11所示(左上图显示MH6T TriTAC与来自供体2的T细胞的结合；右上图显示MH6T TriTAC与来自供体35的T细胞的结合；左下图显示MH6T TriTAC与来自供体41的T细胞的结合；右下图显示MH6T TriTAC与来自供体81的T细胞的结合)。
实施例12：用MH6T TriTAC分子处理的小鼠中肿瘤生长的抑制
对于该研究，将107个NCI-H292细胞和107个人PBMC共同皮下植入两组NCG小鼠中(每组8只小鼠)。5天后，每天以0.25mg/kg的剂量向一组小鼠注射MH6T TriTAC分子(SEQ IDNO:98)，持续10天(第5-14天)；而另一组小鼠则注射媒介物对照。每隔几天测量一次肿瘤体积，并在第36天终止研究。与注射媒介物对照的小鼠相比，在注射MH6 TriTAC分子的小鼠中观察到显著的肿瘤生长抑制，如图12所示。
实施例13：MH6T TriTAC在食蟹猴中的药代动力学
对于该研究，向两只食蟹猴静脉内注射10mg/kg剂量的MH6TTriTAC分子(SEQ IDNO:98)，并在注射后的不同时间点收集血清样品。在电化学发光测定中，使用识别MH6TTriTAC分子的抗独特型抗体测量血清中MH6T TriTAC的量。图13显示了在不同时间点的血清M6HT TriTAC水平的图。然后使用这些数据计算MH6T TriTAC分子的药代动力学性质，如表VII中所示。
表VII：MH6T TriTAC的药代动力学参数
实施例14：针对本公开的两个示例性三特异性分子的最大活性和暴露，对CD3ε结合亲和力的优化
对于该研究，测量了本公开的两个示例性三特异性分子TriTAC 74(SEQ ID NO:100)和TriTAC 75(SEQ ID NO:101)的CD3ε、MSLN和白蛋白结合亲和力。观察到尽管这两个分子对肿瘤靶标(MSLN)和白蛋白的结合亲和力相似，但TriTAC74在结合人CD3ε方面的有效性是TriTAC75的大约5倍，如图14所示。另外，使用SKOV3和OVCAR细胞，用TriTAC 74和TriTAC 75分子进行TDCC测定。图14显示了在TDCC测定中获得的EC50值。
如在向食蟹猴注射TriTAC分子(静脉内浓注剂量为0.02mg/kg)后在药代动力学测定中所测量的，与TriTAC 75相比，在TriTAC 74中，发现CD3ε亲和力的差异导致AUC大约增加了30％至50％，如表VIII所示。在注射后的不同时间点，使用采用抗独特型抗体的MesoScale Discovery(MSD)测定来测量TriTAC分子的血清水平。使用n＝2个重复进行MSD测定。在MSD测定中观察到的血清浓度在图15中示出，而药代动力学参数在表VIII中列出。
表VIII：TriTAC 74和TriTAC 75的药代动力学参数
序列表
本公开的示例性结合间皮素的三特异性蛋白质的CDR的序列表
本公开的示例性结合间皮素的三特异性蛋白质的CDR2的序列表
本公开的示例性结合间皮素的三特异性蛋白质的CDR3的序列表
本公开的示例性MSLN三特异性结合蛋白质的框架区1(f1)
本公开的示例性MSLN三特异性结合蛋白质的框架区2(f2)
本公开的示例性MSLN三特异性结合蛋白质的框架区3(f3)
本公开的示例性MSLN三特异性结合蛋白质的框架区4(f4)
序列表
<110> 哈普恩治疗公司
<120> 靶向MSLN的三特异性蛋白质及使用方法
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<150> 62/657,434
<151> 2018-04-13
<150> 62/505,747
<151> 2017-05-12
<160> 379
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Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Pro Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ala Thr Ser Ala Ile Thr
20 25 30
Asn Leu Gly Trp Tyr Arg Arg Ala Pro Gly Gln Val Arg Glu Met Val
35 40 45
Ala Arg Ile Ser Val Arg Glu Asp Lys Glu Asp Tyr Glu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Gln Asn Leu Val Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Gln Pro His Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Gly Ala Gln Arg Trp Gly Arg Gly Pro Gly Thr Thr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 17
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 17
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Arg Ile Arg
20 25 30
Val Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Asp Ser Gly Ile Ala Arg Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 18
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 18
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu
1 5 10 15
Ser Arg Arg Leu Ser Cys Ala Val Ser Gly Asp Thr Ser Lys Phe Lys
20 25 30
Ala Val Gly Trp Tyr Arg Gln Ala Pro Gly Ala Gln Arg Glu Leu Leu
35 40 45
Ala Trp Ile Asn Asn Ser Gly Val Gly Asn Thr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Arg Leu Thr Pro Glu Asp Thr Asp Val Tyr Tyr Cys Arg
85 90 95
Phe Tyr Arg Arg Phe Gly Ile Asn Lys Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser
115
<210> 19
<211> 122
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 19
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asn Lys
20 25 30
Pro Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Ser Ser Asp Gly Gly Ser Thr Arg Tyr Ala Ala Leu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Glu Ser Leu Val Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Leu Arg Thr Tyr Tyr Leu Asn Asp Pro Val Val Phe Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser
115 120
<210> 20
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 20
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Leu Arg Gly Thr Leu His Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 21
<211> 115
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 21
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Asp Arg Ile Thr
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Asn Arg Gly Thr Ser Asn Tyr Ala Asn Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Arg Lys Trp Gly Arg Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser
115
<210> 22
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 22
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Arg Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Arg Thr Ile Gly Ile Asn
20 25 30
Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Leu Val
35 40 45
Ala Thr Ile Thr Lys Gly Gly Thr Thr Asp Tyr Ala Asp Ser Val Asp
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Lys Arg Arg Glu Trp Ala Lys Asp Phe Glu Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 23
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 23
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Ile Gly Ser Ile Asn Ser
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Pro Val Ala
35 40 45
Val Ile Thr Asp Arg Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
85 90 95
Ile Ala Asp Trp Arg Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 24
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 24
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Arg Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 25
<211> 114
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 25
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Thr Ser Thr Thr Phe Ser Ile Asn Ser
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Pro Val Ala
35 40 45
Val Ile Thr Asn Arg Gly Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
85 90 95
Ile Ala Asp Trp Arg Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser
<210> 26
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 26
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser
115
<210> 27
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 27
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Ser Thr Ile Asp
20 25 30
Thr Met Tyr Trp His Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val
35 40 45
Ala Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Val Arg Thr Thr Ser Tyr Pro Val Asp Phe Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser
115
<210> 28
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 28
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser
115
<210> 29
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 29
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Asp Trp Ser Ala Asn
20 25 30
Phe Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Val Ala Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
100 105 110
<210> 30
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 30
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Asp Trp Ser Ala Asn
20 25 30
Phe Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Val Ala Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 31
<211> 111
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Asp Trp Ser Ala Asn
20 25 30
Phe Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Val Ala Ser Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
<210> 32
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 32
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 33
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 33
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 34
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 34
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 35
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 35
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly
115
<210> 36
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 36
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly
115
<210> 37
<211> 118
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 37
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly
115
<210> 38
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 38
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Ser Thr Ile Asp
20 25 30
Thr Met Tyr Trp His Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val
35 40 45
Ala Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Val Arg Thr Thr Ser Tyr Pro Val Asp Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser
115
<210> 39
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Thr Ile Asp
20 25 30
Thr Met Tyr Trp His Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Val Arg Thr Thr Ser Tyr Pro Val Asp Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 40
<211> 117
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 40
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Ser Thr Ile Asp
20 25 30
Thr Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Val Arg Thr Thr Ser Tyr Pro Val Asp Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 41
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 41
Glu Ser Gly Gly Gly Leu Val
1 5
<210> 42
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 42
Leu Ser Cys
1
<210> 43
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 43
Gly Arg Phe
1
<210> 44
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 44
Val Thr Val Ser Ser
1 5
<210> 45
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 45
Gln Leu Val Glu Ser Gly Gly Gly
1 5
<210> 46
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 46
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
1 5 10
<210> 47
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 47
Ala Ser Gly
1
<210> 48
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 48
Arg Gln Ala Pro Gly
1 5
<210> 49
<211> 33
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 49
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
1 5 10 15
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
20 25 30
Cys
<210> 50
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 50
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 51
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 51
Gly Arg Thr Phe Ser Val Arg Gly Met Ala
1 5 10
<210> 52
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 52
Ile Asn Ser Ser Gly Ser Thr Asn Tyr Gly
1 5 10
<210> 53
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 53
Asn Ala Gly Gly Gly Pro Leu Gly Ser Arg
1 5 10
<210> 54
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 54
Gly Gly Asp Trp Ser Ala Asn Phe Met Tyr
1 5 10
<210> 55
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 55
Ile Ser Ser Gly Gly Ser Thr Asn Val Arg
1 5 10
<210> 56
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 56
Asn Ala Asp Thr Ile Gly Thr Ala Arg Asp
1 5 10
<210> 57
<211> 630
<212> PRT
<213> 智人（Homo sapiens）
<400> 57
Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro
1 5 10 15
Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln
20 25 30
Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu
35 40 45
Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg
50 55 60
Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu
65 70 75 80
Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu
85 90 95
Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro
100 105 110
Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro
115 120 125
Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr Arg Phe Phe Ser Arg Ile
130 135 140
Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln
145 150 155 160
Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu
165 170 175
Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu
180 185 190
Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu
195 200 205
Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg
210 215 220
Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp
225 230 235 240
Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly
245 250 255
Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg
260 265 270
Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile
275 280 285
Leu Arg Pro Arg Phe Arg Arg Glu Val Glu Lys Thr Ala Cys Pro Ser
290 295 300
Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys
305 310 315 320
Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln Met
325 330 335
Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu
340 345 350
Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val
355 360 365
Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp Ile
370 375 380
Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Glu
385 390 395 400
Val Asn Lys Gly His Glu Met Ser Pro Gln Ala Pro Arg Arg Pro Leu
405 410 415
Pro Gln Val Ala Thr Leu Ile Asp Arg Phe Val Lys Gly Arg Gly Gln
420 425 430
Leu Asp Lys Asp Thr Leu Asp Thr Leu Thr Ala Phe Tyr Pro Gly Tyr
435 440 445
Leu Cys Ser Leu Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser Ser
450 455 460
Ile Trp Ala Val Arg Pro Gln Asp Leu Asp Thr Cys Asp Pro Arg Gln
465 470 475 480
Leu Asp Val Leu Tyr Pro Lys Ala Arg Leu Ala Phe Gln Asn Met Asn
485 490 495
Gly Ser Glu Tyr Phe Val Lys Ile Gln Ser Phe Leu Gly Gly Ala Pro
500 505 510
Thr Glu Asp Leu Lys Ala Leu Ser Gln Gln Asn Val Ser Met Asp Leu
515 520 525
Ala Thr Phe Met Lys Leu Arg Thr Asp Ala Val Leu Pro Leu Thr Val
530 535 540
Ala Glu Val Gln Lys Leu Leu Gly Pro His Val Glu Gly Leu Lys Ala
545 550 555 560
Glu Glu Arg His Arg Pro Val Arg Asp Trp Ile Leu Arg Gln Arg Gln
565 570 575
Asp Asp Leu Asp Thr Leu Gly Leu Gly Leu Gln Gly Gly Ile Pro Asn
580 585 590
Gly Tyr Leu Val Leu Asp Leu Ser Met Gln Glu Ala Leu Ser Gly Thr
595 600 605
Pro Cys Leu Leu Gly Pro Gly Pro Val Leu Thr Val Leu Ala Leu Leu
610 615 620
Leu Ala Ser Thr Leu Ala
625 630
<210> 58
<211> 498
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 58
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Val Arg
20 25 30
Gly Met Ala Trp Tyr Arg Gln Ala Gly Asn Asn Arg Ala Leu Val Ala
35 40 45
Thr Met Asn Pro Asp Gly Phe Pro Asn Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Trp Asp Ile Ala Glu Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Asn Ser Glu Asp Thr Thr Val Tyr Tyr Cys Asn Ser
85 90 95
Gly Pro Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly
100 105 110
Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
115 120 125
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
130 135 140
Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro
145 150 155 160
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp
165 170 175
Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
180 185 190
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
195 200 205
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser
210 215 220
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
245 250 255
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
260 265 270
Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
275 280 285
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
290 295 300
Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
305 310 315 320
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
325 330 335
Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile
340 345 350
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
370 375 380
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
385 390 395 400
Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
405 410 415
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
420 425 430
Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser
435 440 445
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
450 455 460
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg
465 470 475 480
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His
485 490 495
His His
<210> 59
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 59
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Pro Ser Ile Glu
20 25 30
Gln Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ala Leu Thr Ser Gly Gly Arg Ala Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Gly Asp Asn Val Arg Asn Met Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Ser
85 90 95
Ala Gly Arg Phe Lys Gly Asp Tyr Ala Gln Arg Ser Gly Met Asp Tyr
100 105 110
Trp Gly Lys Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr
180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
195 200 205
Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 60
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 60
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Phe Ser Gly Thr Thr Tyr Thr Phe Asp
20 25 30
Leu Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Thr Val Val
35 40 45
Ala Ser Ile Ser Ser Asp Gly Arg Thr Ser Tyr Ala Asp Ser Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Gly Glu Asn Gly Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Leu
85 90 95
Gly Gln Arg Ser Gly Val Arg Ala Phe Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 61
<211> 511
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 61
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Ser Thr Ser Asn Ile Asn
20 25 30
Asn Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Val Ile Thr Arg Gly Gly Tyr Ala Ile Tyr Leu Asp Ala Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Ala Ile Tyr Leu
65 70 75 80
Glu Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn
85 90 95
Ala Asp Arg Val Glu Gly Thr Ser Gly Gly Pro Gln Leu Arg Asp Tyr
100 105 110
Phe Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
130 135 140
Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
145 150 155 160
Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
165 170 175
Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr
180 185 190
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
195 200 205
Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala
210 215 220
Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly
225 230 235 240
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
245 250 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
260 265 270
Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr
275 280 285
Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp
305 310 315 320
Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
325 330 335
Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr
340 345 350
Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp
355 360 365
Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val
385 390 395 400
Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu
405 410 415
Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn
420 425 430
Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly
435 440 445
Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu
450 455 460
Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp
465 470 475 480
Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe
485 490 495
Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 62
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 62
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Ile Asn
20 25 30
Ala Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Ser Arg Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Val Ser Leu
65 70 75 80
Gln Met Asn Thr Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys Asn
85 90 95
Ala Arg Thr Tyr Thr Arg His Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 63
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 63
Gln Val Arg Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ile Ser Ala Phe Arg Leu Met
20 25 30
Ser Val Arg Trp Tyr Arg Gln Asp Pro Ser Lys Gln Arg Glu Trp Val
35 40 45
Ala Thr Ile Asp Gln Leu Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ala Ile Ser Lys Asp Ser Thr Arg Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Met Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Gly Gly Gly Pro Leu Gly Ser Arg Trp Leu Arg Gly Arg His Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
145 150 155 160
Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
165 170 175
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
245 250 255
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
260 265 270
Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala
275 280 285
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
290 295 300
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
305 310 315 320
Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala
325 330 335
Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala
355 360 365
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr
385 390 395 400
Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr
405 410 415
Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp
420 425 430
Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr
435 440 445
Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu
450 455 460
Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu
465 470 475 480
Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly
485 490 495
Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 64
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 64
Gln Val Arg Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Pro Phe Ser Ile Asn
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Ser Ile Ser Ser Ser Gly Asp Phe Thr Tyr Thr Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Arg Arg Thr Tyr Leu Pro Arg Arg Phe Gly Ser Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 65
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 65
Gln Val Gln Pro Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Ser Asp Phe Thr Glu Asp
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Ser Gly Lys Glu Arg Glu Ser Val
35 40 45
Ala Phe Val Ser Lys Asp Gly Lys Arg Ile Leu Tyr Leu Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Ile Asp Lys Lys Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Asn Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys
85 90 95
Asn Ser Ala Pro Gly Ala Ala Arg Asn Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met
145 150 155 160
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
165 170 175
Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
210 215 220
Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
245 250 255
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys
260 265 270
Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg
275 280 285
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys
290 295 300
Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
325 330 335
Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly
340 345 350
Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly
355 360 365
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
385 390 395 400
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
405 410 415
Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
435 440 445
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
450 455 460
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
465 470 475 480
Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
485 490 495
Thr Val Leu His His His His His His
500 505
<210> 66
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 66
Gln Val Gln Pro Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser Gly Ser Asp Phe Thr Glu Asp
20 25 30
Ala Met Ala Trp Tyr Arg Gln Ala Ser Gly Lys Glu Arg Glu Ser Val
35 40 45
Ala Phe Val Ser Lys Asp Gly Lys Arg Ile Leu Tyr Leu Asp Ser Val
50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Ile Tyr Lys Lys Thr Val Tyr
65 70 75 80
Leu Gln Met Asp Asn Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys
85 90 95
Asn Ser Ala Pro Gly Ala Ala Arg Asn Val Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met
145 150 155 160
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
165 170 175
Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
210 215 220
Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
245 250 255
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys
260 265 270
Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg
275 280 285
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys
290 295 300
Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
325 330 335
Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly
340 345 350
Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly
355 360 365
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
385 390 395 400
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
405 410 415
Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
435 440 445
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
450 455 460
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
465 470 475 480
Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
485 490 495
Thr Val Leu His His His His His His
500 505
<210> 67
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 67
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
165 170 175
Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
210 215 220
Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu His His His His His His
500
<210> 68
<211> 512
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 68
Gln Val Gln Ile Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Leu Thr Tyr Ser Ile Val
20 25 30
Ala Val Gly Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Met Val
35 40 45
Ala Asp Ile Ser Pro Val Gly Asn Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Lys Glu Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys His
85 90 95
Ile Val Arg Gly Trp Leu Asp Glu Arg Pro Gly Pro Gly Pro Ile Val
100 105 110
Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
130 135 140
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
145 150 155 160
Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
165 170 175
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu
180 185 190
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
195 200 205
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln
225 230 235 240
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
260 265 270
Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys
275 280 285
Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
290 295 300
Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala
305 310 315 320
Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn
325 330 335
Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val
340 345 350
Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr
355 360 365
Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val
385 390 395 400
Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr
405 410 415
Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro
420 425 430
Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly
435 440 445
Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser
450 455 460
Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu
465 470 475 480
Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val
485 490 495
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 69
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 69
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Thr Phe Gly Val Tyr
20 25 30
Gly Met Glu Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val
35 40 45
Ala Ser His Thr Ser Thr Gly Tyr Val Tyr Tyr Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Lys
85 90 95
Ala Asn Arg Gly Ser Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
165 170 175
Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
210 215 220
Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu His His His His His His
500
<210> 70
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 70
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Thr Thr Ser Ser Ile Asn Ser
20 25 30
Met Ser Trp Tyr Arg Gln Ala Gln Gly Lys Gln Arg Glu Pro Val Ala
35 40 45
Val Ile Thr Asp Arg Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
85 90 95
Ile Ala Asp Trp Arg Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
165 170 175
Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
210 215 220
Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
His His His His His His
500
<210> 71
<211> 508
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 71
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Thr Leu Ser Arg Tyr
20 25 30
Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Gln Phe Val
35 40 45
Ala Ala Ile Ser Arg Ser Gly Gly Thr Thr Arg Tyr Ser Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Ala Asn Thr Phe Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Arg Pro Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Val Arg Arg Arg Gly Trp Gly Arg Thr Leu Glu Tyr Trp Gly Gln
100 105 110
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
145 150 155 160
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
245 250 255
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys
260 265 270
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn
275 280 285
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile
290 295 300
Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu
325 330 335
Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val
340 345 350
Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu
385 390 395 400
Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly
405 410 415
Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln
420 425 430
Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe
435 440 445
Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly
450 455 460
Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu
465 470 475 480
Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly
485 490 495
Thr Lys Leu Thr Val Leu His His His His His His
500 505
<210> 72
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 72
Gln Val Gln Leu Gly Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Ile Phe Ser Pro Asn
20 25 30
Ala Met Ile Trp His Arg Gln Ala Pro Gly Lys Gln Arg Glu Pro Val
35 40 45
Ala Ser Ile Asn Ser Ser Gly Ser Thr Asn Tyr Gly Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Val Ser Arg Asp Ile Val Lys Asn Thr Met Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Tyr Ser Asp Phe Arg Arg Gly Thr Gln Tyr Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met
145 150 155 160
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
165 170 175
Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
210 215 220
Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
245 250 255
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys
260 265 270
Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg
275 280 285
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys
290 295 300
Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
325 330 335
Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly
340 345 350
Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly
355 360 365
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
385 390 395 400
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
405 410 415
Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
435 440 445
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
450 455 460
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
465 470 475 480
Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
485 490 495
Thr Val Leu His His His His His His
500 505
<210> 73
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 73
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Pro Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ala Thr Ser Ala Ile Thr
20 25 30
Asn Leu Gly Trp Tyr Arg Arg Ala Pro Gly Gln Val Arg Glu Met Val
35 40 45
Ala Arg Ile Ser Val Arg Glu Asp Lys Glu Asp Tyr Glu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Gln Asn Leu Val Tyr
65 70 75 80
Leu Gln Met Asn Asn Leu Gln Pro His Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Gly Ala Gln Arg Trp Gly Arg Gly Pro Gly Thr Thr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 74
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 74
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Arg Ile Arg
20 25 30
Val Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Asp Ser Gly Ile Ala Arg Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 75
<211> 506
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 75
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu
1 5 10 15
Ser Arg Arg Leu Ser Cys Ala Val Ser Gly Asp Thr Ser Lys Phe Lys
20 25 30
Ala Val Gly Trp Tyr Arg Gln Ala Pro Gly Ala Gln Arg Glu Leu Leu
35 40 45
Ala Trp Ile Asn Asn Ser Gly Val Gly Asn Thr Ala Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Arg Leu Thr Pro Glu Asp Thr Asp Val Tyr Tyr Cys Arg
85 90 95
Phe Tyr Arg Arg Phe Gly Ile Asn Lys Asn Tyr Trp Gly Gln Gly Thr
100 105 110
Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
115 120 125
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
130 135 140
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly
145 150 155 160
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
165 170 175
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
180 185 190
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
195 200 205
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
210 215 220
Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val
225 230 235 240
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
245 250 255
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
260 265 270
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val
275 280 285
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
290 295 300
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg
305 310 315 320
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
325 330 335
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
340 345 350
Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
355 360 365
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser
385 390 395 400
Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser
405 410 415
Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys
420 425 430
Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala
435 440 445
Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala
450 455 460
Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr
465 470 475 480
Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys
485 490 495
Leu Thr Val Leu His His His His His His
500 505
<210> 76
<211> 510
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 76
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Gly Asn Lys
20 25 30
Pro Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Val Ile Ser Ser Asp Gly Gly Ser Thr Arg Tyr Ala Ala Leu Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Glu Ser Leu Val Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Ala Leu Arg Thr Tyr Tyr Leu Asn Asp Pro Val Val Phe Ser Trp
100 105 110
Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
145 150 155 160
Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
165 170 175
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala
180 185 190
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
195 200 205
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
210 215 220
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr
225 230 235 240
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu
245 250 255
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser
260 265 270
Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala
275 280 285
Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
290 295 300
Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser
305 310 315 320
Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala
325 330 335
Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr
340 345 350
Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala
355 360 365
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr
385 390 395 400
Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr
405 410 415
Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp
420 425 430
Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr
435 440 445
Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu
450 455 460
Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu
465 470 475 480
Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly
485 490 495
Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
500 505 510
<210> 77
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 77
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Leu Arg Gly Thr Leu His Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 78
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 78
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Asp Arg Ile Thr
20 25 30
Thr Met Gly Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Thr Ile Ser Asn Arg Gly Thr Ser Asn Tyr Ala Asn Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Ala Arg Lys Trp Gly Arg Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
165 170 175
Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
210 215 220
Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu His His His His His His
500
<210> 79
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 79
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Arg Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Arg Thr Ile Gly Ile Asn
20 25 30
Asp Met Ala Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Leu Val
35 40 45
Ala Thr Ile Thr Lys Gly Gly Thr Thr Asp Tyr Ala Asp Ser Val Asp
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Lys Arg Arg Glu Trp Ala Lys Asp Phe Glu Tyr Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 80
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 80
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Ile Gly Ser Ile Asn Ser
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Pro Val Ala
35 40 45
Val Ile Thr Asp Arg Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
85 90 95
Ile Ala Asp Trp Arg Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
165 170 175
Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
210 215 220
Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
His His His His His His
500
<210> 81
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 81
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Leu Val
35 40 45
Ala Thr Ile Asn Arg Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Arg Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 82
<211> 502
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 82
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Thr Ser Thr Thr Phe Ser Ile Asn Ser
20 25 30
Met Ser Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Pro Val Ala
35 40 45
Val Ile Thr Asn Arg Gly Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu Gln
65 70 75 80
Met Asp Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
85 90 95
Ile Ala Asp Trp Arg Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
130 135 140
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val
145 150 155 160
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
165 170 175
Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr
180 185 190
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
195 200 205
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
210 215 220
Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
225 230 235 240
Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
245 250 255
Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser
260 265 270
Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro
275 280 285
Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn
290 295 300
Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser
305 310 315 320
Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys
325 330 335
Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly
340 345 350
Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val
355 360 365
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser
385 390 395 400
Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val
405 410 415
Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala
420 425 430
Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro
435 440 445
Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu
450 455 460
Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp
465 470 475 480
Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu
485 490 495
His His His His His His
500
<210> 83
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 83
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Gln Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 84
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 84
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Arg Thr Ser Thr Ile Asp
20 25 30
Thr Met Tyr Trp His Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val
35 40 45
Ala Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser
85 90 95
Val Arg Thr Thr Ser Tyr Pro Val Asp Phe Trp Gly Gln Gly Thr Gln
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe Gly Met
145 150 155 160
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
165 170 175
Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
210 215 220
Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu
245 250 255
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys
260 265 270
Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg
275 280 285
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys
290 295 300
Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe
305 310 315 320
Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn
325 330 335
Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly
340 345 350
Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly
355 360 365
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu
385 390 395 400
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr
405 410 415
Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro
420 425 430
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro
435 440 445
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
450 455 460
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
465 470 475 480
Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
485 490 495
Thr Val Leu His His His His His His
500 505
<210> 85
<211> 507
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 85
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Ser Ser Ile Asn
20 25 30
Thr Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn
85 90 95
Thr Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe Trp Gly Gln Gly
100 105 110
Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
115 120 125
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
130 135 140
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
145 150 155 160
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
165 170 175
Ser Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val
180 185 190
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Thr Ile Gly Gly Ser Leu Ser Arg Ser Ser Gln Gly Thr Leu Val Thr
225 230 235 240
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
245 250 255
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu
260 265 270
Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Met Asn Trp
275 280 285
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg
290 295 300
Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp
305 310 315 320
Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln
325 330 335
Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg
340 345 350
His Gly Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly
355 360 365
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro
385 390 395 400
Ser Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser
405 410 415
Ser Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu
435 440 445
Ala Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys
450 455 460
Ala Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr
465 470 475 480
Tyr Cys Val Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr
485 490 495
Lys Leu Thr Val Leu His His His His His His
500 505
<210> 86
<211> 499
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 86
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Gly Asp Trp Ser Ala Asn
20 25 30
Phe Met Tyr Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Val Ala Ser Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
115 120 125
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
130 135 140
Ser Gly Phe Thr Phe Ser Ser Phe Gly Met Ser Trp Val Arg Gln Ala
145 150 155 160
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Ser
165 170 175
Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
180 185 190
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
195 200 205
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Arg
210 215 220
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
245 250 255
Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr
260 265 270
Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly
275 280 285
Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr
290 295 300
Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp
305 310 315 320
Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp
325 330 335
Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr
340 345 350
Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
355 360 365
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly
385 390 395 400
Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly
405 410 415
Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly
420 425 430
Leu Ile Gly Gly Thr Lys Phe Leu Ala Pro Gly Thr Pro Ala Arg Phe
435 440 445
Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val
450 455 460
Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val Leu Trp Tyr Ser Asn
465 470 475 480
Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His
485 490 495
His His His
<210> 87
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<220>
<221> MISC_FEATURE
<222> (1)..(20)
<223> 该序列可包含1-10个"Gly Ser"重复单元
<400> 87
Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser
1 5 10 15
Gly Ser Gly Ser
20
<210> 88
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(30)
<223> 该序列可包含1-10个"Gly Gly Ser"重复单元
<400> 88
Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly
1 5 10 15
Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser Gly Gly Ser
20 25 30
<210> 89
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Gly Ser"重复单元
<400> 89
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
20 25 30
Gly Gly Gly Ser Gly Gly Gly Ser
35 40
<210> 90
<211> 40
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(40)
<223> 该序列可包含1-10个"Gly Gly Ser Gly"重复单元
<400> 90
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly
20 25 30
Gly Gly Ser Gly Gly Gly Ser Gly
35 40
<210> 91
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Ser Gly Gly"重复单元
<400> 91
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
20 25 30
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40 45
Gly Gly
50
<210> 92
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Gly Gly Ser"重复单元
<400> 92
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
35 40 45
Gly Ser
50
<210> 93
<211> 50
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(50)
<223> 该序列可包含1-10个"Gly Gly Gly Gly Gly"重复单元
<400> 93
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
1 5 10 15
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
20 25 30
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
35 40 45
Gly Gly
50
<210> 94
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<220>
<221> MISC_FEATURE
<222> (1)..(30)
<223> 该序列可包含1-10个"Gly Gly Gly"重复单元
<400> 94
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
1 5 10 15
Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly
20 25 30
<210> 95
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 95
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Gly Gly Gly Ser
20
<210> 96
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 96
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 97
<211> 5
<212> PRT
<213> 未知
<220>
<223> “未知”的描述：分选酶识别域
<400> 97
Leu Pro Glu Thr Gly
1 5
<210> 98
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 98
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 99
<211> 503
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 99
Gln Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Val Asn Arg Tyr
20 25 30
Ser Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val
35 40 45
Ala Gly Met Ser Ser Ala Gly Asp Arg Ser Ser Tyr Glu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Arg Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Val Asn Val Gly Phe Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
165 170 175
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
210 215 220
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu His His His His His His
500
<210> 100
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 100
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Asn Thr Phe Asn Lys Tyr Ala Met Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Gly Asn
340 345 350
Phe Gly Asp Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly
405 410 415
Ala Val Thr His Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Val Leu Ala Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Val
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 101
<211> 504
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 101
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln
115 120 125
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
130 135 140
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
145 150 155 160
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
165 170 175
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg
180 185 190
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
195 200 205
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
210 215 220
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
245 250 255
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala
260 265 270
Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln
275 280 285
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr
290 295 300
Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr
305 310 315 320
Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn
325 330 335
Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn
340 345 350
Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr
355 360 365
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
370 375 380
Gly Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr
385 390 395 400
Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly
405 410 415
Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly
420 425 430
Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly
435 440 445
Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu
450 455 460
Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr
465 470 475 480
Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
485 490 495
Val Leu His His His His His His
500
<210> 102
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 102
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 103
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 103
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 104
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 104
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val
35 40 45
Ala Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 105
<211> 116
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
多肽
<400> 105
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ser Thr Phe Ser Ile Arg
20 25 30
Ala Met Arg Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
65 70 75 80
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
85 90 95
Asp Thr Ile Gly Thr Ala Arg Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 106
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 106
Gly Arg Thr Phe Ser Val Arg Gly Met Ala
1 5 10
<210> 107
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 107
Gly Ser Ile Pro Ser Ile Glu Gln Met Gly
1 5 10
<210> 108
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 108
Gly Thr Thr Tyr Thr Phe Asp Leu Met Ser
1 5 10
<210> 109
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 109
Gly Ser Thr Ser Asn Ile Asn Asn Met Arg
1 5 10
<210> 110
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 110
Gly Ser Thr Phe Gly Ile Asn Ala Met Gly
1 5 10
<210> 111
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 111
Ile Ser Ala Phe Arg Leu Met Ser Val Arg
1 5 10
<210> 112
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 112
Gly Arg Pro Phe Ser Ile Asn Thr Met Gly
1 5 10
<210> 113
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 113
Gly Ser Asp Phe Thr Glu Asp Ala Met Ala
1 5 10
<210> 114
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 114
Gly Ser Asp Phe Thr Glu Asp Ala Met Ala
1 5 10
<210> 115
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 115
Gly Phe Thr Phe Ser Ser Phe Gly Met Ser
1 5 10
<210> 116
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 116
Gly Leu Thr Tyr Ser Ile Val Ala Val Gly
1 5 10
<210> 117
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 117
Gly Leu Thr Phe Gly Val Tyr Gly Met Glu
1 5 10
<210> 118
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 118
Thr Thr Ser Ser Ile Asn Ser Met Ser
1 5
<210> 119
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 119
Gly Arg Thr Leu Ser Arg Tyr Ala Met Gly
1 5 10
<210> 120
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 120
Gly Ser Ile Phe Ser Pro Asn Ala Met Ile
1 5 10
<210> 121
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 121
Gly Ala Thr Ser Ala Ile Thr Asn Leu Gly
1 5 10
<210> 122
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 122
Gly Ser Thr Phe Arg Ile Arg Val Met Arg
1 5 10
<210> 123
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 123
Gly Asp Thr Ser Lys Phe Lys Ala Val Gly
1 5 10
<210> 124
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 124
Gly Ser Thr Phe Gly Asn Lys Pro Met Gly
1 5 10
<210> 125
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 125
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 126
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 126
Gly Arg Thr Asp Arg Ile Thr Thr Met Gly
1 5 10
<210> 127
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 127
Gly Arg Thr Ile Gly Ile Asn Asp Met Ala
1 5 10
<210> 128
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 128
Ala Ile Gly Ser Ile Asn Ser Met Ser
1 5
<210> 129
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 129
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 130
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 130
Thr Thr Phe Ser Ile Asn Ser Met Ser
1 5
<210> 131
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 131
Gly Ser Thr Phe Ser Ile Arg Ala Met Arg
1 5 10
<210> 132
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 132
Gly Arg Thr Ser Thr Ile Asp Thr Met Tyr
1 5 10
<210> 133
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 133
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 134
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 134
Gly Gly Asp Trp Ser Ala Asn Phe Met Tyr
1 5 10
<210> 135
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 135
Gly Gly Asp Trp Ser Ala Asn Phe Met Tyr
1 5 10
<210> 136
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 136
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 137
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 137
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 138
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 138
Gly Ser Thr Ser Ser Ile Asn Thr Met Tyr
1 5 10
<210> 139
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 139
Gly Ser Thr Phe Ser Ile Arg Ala Met Arg
1 5 10
<210> 140
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 140
Gly Ser Thr Phe Ser Ile Arg Ala Met Arg
1 5 10
<210> 141
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 141
Gly Ser Thr Phe Ser Ile Arg Ala Met Arg
1 5 10
<210> 142
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 142
Gly Arg Thr Ser Thr Ile Asp Thr Met Tyr
1 5 10
<210> 143
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 143
Gly Arg Thr Ser Thr Ile Asp Thr Met Tyr
1 5 10
<210> 144
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 144
Gly Arg Thr Ser Thr Ile Asp Thr Met Tyr
1 5 10
<210> 145
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 145
Thr Met Asn Pro Asp Gly Phe Pro Asn Tyr Ala Asp Ala Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 146
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 146
Ala Leu Thr Ser Gly Gly Arg Ala Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 147
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 147
Ser Ile Ser Ser Asp Gly Arg Thr Ser Tyr Ala Asp Ser Val Arg Gly
1 5 10 15
Arg Phe Thr
<210> 148
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 148
Val Ile Thr Arg Gly Gly Tyr Ala Ile Tyr Leu Asp Ala Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 149
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 149
Val Ile Ser Arg Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 150
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 150
Thr Ile Asp Gln Leu Gly Arg Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Ala
<210> 151
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 151
Ser Ile Ser Ser Ser Gly Asp Phe Thr Tyr Thr Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 152
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 152
Phe Val Ser Lys Asp Gly Lys Arg Ile Leu Tyr Leu Asp Ser Val Arg
1 5 10 15
Gly Arg Phe Thr
20
<210> 153
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 153
Phe Val Ser Lys Asp Gly Lys Arg Ile Leu Tyr Leu Asp Ser Val Arg
1 5 10 15
Gly Arg Phe Thr
20
<210> 154
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 154
Ser Ile Ser Gly Ser Gly Ser Asp Thr Leu Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly Arg Phe Thr
20
<210> 155
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 155
Asp Ile Ser Pro Val Gly Asn Thr Asn Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 156
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 156
Ser His Thr Ser Thr Gly Tyr Val Tyr Tyr Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 157
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 157
Val Ile Thr Asp Arg Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 158
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 158
Ala Ile Ser Arg Ser Gly Gly Thr Thr Arg Tyr Ser Asp Ser Val Lys
1 5 10 15
Gly Arg Phe Thr
20
<210> 159
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 159
Ser Ile Asn Ser Ser Gly Ser Thr Asn Tyr Gly Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 160
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 160
Arg Ile Ser Val Arg Glu Asp Lys Glu Asp Tyr Glu Asp Ser Val Lys
1 5 10 15
Gly Arg Phe Thr
20
<210> 161
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 161
Val Ile Ser Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg
1 5 10 15
Phe Thr
<210> 162
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 162
Trp Ile Asn Asn Ser Gly Val Gly Asn Thr Ala Glu Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 163
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 163
Val Ile Ser Ser Asp Gly Gly Ser Thr Arg Tyr Ala Ala Leu Val Lys
1 5 10 15
Gly Arg Phe Thr
20
<210> 164
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 164
Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Ser
<210> 165
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 165
Thr Ile Ser Asn Arg Gly Thr Ser Asn Tyr Ala Asn Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 166
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 166
Thr Ile Thr Lys Gly Gly Thr Thr Asp Tyr Ala Asp Ser Val Asp Gly
1 5 10 15
Arg Phe Thr
<210> 167
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 167
Val Ile Thr Asp Arg Gly Ser Thr Ser Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 168
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 168
Thr Ile Asn Arg Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Ser
<210> 169
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 169
Val Ile Thr Asn Arg Gly Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 170
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 170
Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly Arg
1 5 10 15
Phe Thr
<210> 171
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 171
Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 172
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 172
Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Ser
<210> 173
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 173
Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 174
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 174
Arg Ile Ser Gly Arg Gly Val Val Asp Tyr Val Glu Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 175
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 175
Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 176
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 176
Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 177
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 177
Phe Ile Ser Ser Gly Gly Ser Thr Asn Val Arg Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 178
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 178
Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly Arg
1 5 10 15
Phe Thr
<210> 179
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 179
Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly Arg
1 5 10 15
Phe Thr
<210> 180
<211> 18
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 180
Val Ile Tyr Gly Ser Ser Thr Tyr Tyr Ala Asp Ala Val Lys Gly Arg
1 5 10 15
Phe Thr
<210> 181
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 181
Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 182
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 182
Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 183
<211> 19
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 183
Tyr Val Thr Ser Arg Gly Thr Ser Asn Val Ala Asp Ser Val Lys Gly
1 5 10 15
Arg Phe Thr
<210> 184
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 184
Gly Pro Tyr
1
<210> 185
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 185
Gly Arg Phe Lys Gly Asp Tyr Ala Gln Arg Ser Gly Met Asp Tyr
1 5 10 15
<210> 186
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 186
Gln Arg Ser Gly Val Arg Ala Phe
1 5
<210> 187
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 187
Asp Arg Val Glu Gly Thr Ser Gly Gly Pro Gln Leu Arg Asp Tyr
1 5 10 15
<210> 188
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 188
Arg Thr Tyr Thr Arg His Asp Tyr
1 5
<210> 189
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 189
Gly Gly Gly Pro Leu Gly Ser Arg Trp Leu Arg Gly Arg His
1 5 10
<210> 190
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 190
Arg Arg Thr Tyr Leu Pro Arg Arg Phe Gly Ser
1 5 10
<210> 191
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 191
Ala Pro Gly Ala Ala Arg Asn Tyr
1 5
<210> 192
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 192
Ala Pro Gly Ala Ala Arg Asn Val
1 5
<210> 193
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 193
Gly Gly Ser Leu Ser Arg Ser Ser
1 5
<210> 194
<211> 16
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 194
Val Arg Gly Trp Leu Asp Glu Arg Pro Gly Pro Gly Pro Ile Val Tyr
1 5 10 15
<210> 195
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 195
Asn Arg Gly Ser Tyr Glu Tyr
1 5
<210> 196
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 196
Ile Ala Asp Trp Arg Gly Tyr
1 5
<210> 197
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 197
Arg Arg Arg Gly Trp Gly Arg Thr Leu Glu Tyr
1 5 10
<210> 198
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 198
Ser Asp Phe Arg Arg Gly Thr Gln Tyr
1 5
<210> 199
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 199
Gln Arg Trp Gly Arg Gly Pro Gly Thr Thr
1 5 10
<210> 200
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 200
Asp Asp Ser Gly Ile Ala Arg Asp Tyr
1 5
<210> 201
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 201
Tyr Arg Arg Phe Gly Ile Asn Lys Asn Tyr
1 5 10
<210> 202
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 202
Leu Arg Thr Tyr Tyr Leu Asn Asp Pro Val Val Phe Ser
1 5 10
<210> 203
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 203
Tyr Ile Pro Leu Arg Gly Thr Leu His Asp Tyr
1 5 10
<210> 204
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 204
Arg Lys Trp Gly Arg Asn Tyr
1 5
<210> 205
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 205
Lys Arg Arg Glu Trp Ala Lys Asp Phe Glu Tyr
1 5 10
<210> 206
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 206
Ile Ala Asp Trp Arg Gly Tyr
1 5
<210> 207
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 207
Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe
1 5 10
<210> 208
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 208
Ile Ala Asp Trp Arg Gly Tyr
1 5
<210> 209
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 209
Asp Thr Ile Gly Thr Ala Arg Asp Tyr
1 5
<210> 210
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 210
Arg Thr Thr Ser Tyr Pro Val Asp Phe
1 5
<210> 211
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 211
Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe
1 5 10
<210> 212
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 212
Ala Ser Tyr
1
<210> 213
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 213
Ala Ser Tyr
1
<210> 214
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 214
Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe
1 5 10
<210> 215
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 215
Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe
1 5 10
<210> 216
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 216
Tyr Ile Pro Tyr Gly Gly Thr Leu His Asp Phe
1 5 10
<210> 217
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 217
Asp Thr Ile Gly Thr Ala Arg Asp Tyr
1 5
<210> 218
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 218
Asp Thr Ile Gly Thr Ala Arg Asp Tyr
1 5
<210> 219
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 219
Asp Thr Ile Gly Thr Ala Arg Asp Tyr
1 5
<210> 220
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 220
Arg Thr Thr Ser Tyr Pro Val Asp Phe
1 5
<210> 221
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 221
Arg Thr Thr Ser Tyr Pro Val Asp Phe
1 5
<210> 222
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 222
Arg Thr Thr Ser Tyr Pro Val Asp Phe
1 5
<210> 223
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 223
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 224
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 224
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 225
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 225
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Phe Ser
20 25
<210> 226
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 226
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 227
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 227
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 228
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 228
Gln Val Arg Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 229
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 229
Gln Val Arg Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 230
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 230
Gln Val Gln Pro Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser
20 25
<210> 231
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 231
Gln Val Gln Pro Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Val Ser
20 25
<210> 232
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 232
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 233
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 233
Gln Val Gln Ile Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 234
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 234
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Thr Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 235
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 235
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 236
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 236
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 237
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 237
Gln Val Gln Leu Gly Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 238
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 238
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Pro Ser Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 239
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 239
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 240
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 240
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Glu
1 5 10 15
Ser Arg Arg Leu Ser Cys Ala Val Ser
20 25
<210> 241
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 241
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 242
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 242
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 243
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 243
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 244
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 244
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Arg Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser
20 25
<210> 245
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 245
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 246
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 246
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 247
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 247
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Thr Ser
20 25
<210> 248
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 248
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Thr Leu Ser Cys Ala Ala Ser
20 25
<210> 249
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 249
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 250
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 250
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 251
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 251
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 252
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 252
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 253
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 253
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 254
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 254
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 255
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 255
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 256
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 256
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 257
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 257
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 258
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 258
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 259
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 259
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser
20 25
<210> 260
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 260
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 261
<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 261
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser
20 25
<210> 262
<211> 13
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 262
Trp Tyr Arg Gln Ala Gly Asn Asn Arg Ala Leu Val Ala
1 5 10
<210> 263
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 263
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 264
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 264
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Thr Val Val Ala
1 5 10
<210> 265
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 265
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 266
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 266
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 267
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 267
Trp Tyr Arg Gln Asp Pro Ser Lys Gln Arg Glu Trp Val Ala
1 5 10
<210> 268
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 268
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 269
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 269
Trp Tyr Arg Gln Ala Ser Gly Lys Glu Arg Glu Ser Val Ala
1 5 10
<210> 270
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 270
Trp Tyr Arg Gln Ala Ser Gly Lys Glu Arg Glu Ser Val Ala
1 5 10
<210> 271
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 271
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 272
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 272
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Met Val Ala
1 5 10
<210> 273
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 273
Trp Phe Arg Gln Ala Pro Gly Lys Gln Arg Glu Trp Val Ala
1 5 10
<210> 274
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 274
Trp Tyr Arg Gln Ala Gln Gly Lys Gln Arg Glu Pro Val Ala
1 5 10
<210> 275
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 275
Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Gln Phe Val Ala
1 5 10
<210> 276
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 276
Trp His Arg Gln Ala Pro Gly Lys Gln Arg Glu Pro Val Ala
1 5 10
<210> 277
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 277
Trp Tyr Arg Arg Ala Pro Gly Gln Val Arg Glu Met Val Ala
1 5 10
<210> 278
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 278
Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val Ala
1 5 10
<210> 279
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 279
Trp Tyr Arg Gln Ala Pro Gly Ala Gln Arg Glu Leu Leu Ala
1 5 10
<210> 280
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 280
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 281
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 281
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 282
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 282
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 283
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 283
Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Leu Val Ala
1 5 10
<210> 284
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 284
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Pro Val Ala
1 5 10
<210> 285
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 285
Trp Phe Arg Gln Ala Pro Gly Glu Glu Arg Glu Leu Val Ala
1 5 10
<210> 286
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 286
Trp Tyr Arg Gln Ala Pro Gly Asn Gln Arg Glu Pro Val Ala
1 5 10
<210> 287
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 287
Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val Ala
1 5 10
<210> 288
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 288
Trp His Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val Ala
1 5 10
<210> 289
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 289
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 290
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 290
Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala
1 5 10
<210> 291
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 291
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 292
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 292
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 293
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 293
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 294
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 294
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 295
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 295
Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Asp Leu Val Ala
1 5 10
<210> 296
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 296
Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 297
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 297
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 298
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 298
Trp His Arg Gln Ala Pro Gly Asn Glu Arg Glu Leu Val Ala
1 5 10
<210> 299
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 299
Trp His Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala
1 5 10
<210> 300
<211> 14
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 300
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
1 5 10
<210> 301
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 301
Ile Ser Trp Asp Ile Ala Glu Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Asn Ser Glu Asp Thr Thr Val Tyr Tyr Cys Asn Ser
20 25
<210> 302
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 302
Ile Ser Gly Asp Asn Val Arg Asn Met Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Ser Ala
20 25
<210> 303
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 303
Ile Ser Gly Glu Asn Gly Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Leu Glu Asp Thr Ala Val Tyr Tyr Cys Leu Gly
20 25
<210> 304
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 304
Ile Ser Arg Asp Asn Ala Asn Asn Ala Ile Tyr Leu Glu Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn Ala
20 25
<210> 305
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 305
Ile Ser Arg Asp Asn Ala Glu Asn Thr Val Ser Leu Gln Met Asn Thr
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Phe Cys Asn Ala
20 25
<210> 306
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 306
Ile Ser Lys Asp Ser Thr Arg Asn Thr Val Tyr Leu Gln Met Asn Met
1 5 10 15
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 307
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 307
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 308
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 308
Ile Ser Arg Asp Ile Asp Lys Lys Thr Val Tyr Leu Gln Met Asp Asn
1 5 10 15
Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ser
20 25
<210> 309
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 309
Ile Ser Arg Asp Ile Tyr Lys Lys Thr Val Tyr Leu Gln Met Asp Asn
1 5 10 15
Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ser
20 25
<210> 310
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 310
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
20 25
<210> 311
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 311
Ile Ser Lys Glu Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys His Ile
20 25
<210> 312
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 312
Ile Ser Arg Asp Asn Ala Lys Ser Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Lys Ala
20 25
<210> 313
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 313
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
20 25
<210> 314
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 314
Ile Ser Arg Asp Asn Ala Ala Asn Thr Phe Tyr Leu Gln Met Asn Asn
1 5 10 15
Leu Arg Pro Asp Asp Thr Ala Val Tyr Tyr Cys Asn Val
20 25
<210> 315
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 315
Val Ser Arg Asp Ile Val Lys Asn Thr Met Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser Tyr
20 25
<210> 316
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 316
Ile Ser Arg Asp Asn Thr Gln Asn Leu Val Tyr Leu Gln Met Asn Asn
1 5 10 15
Leu Gln Pro His Asp Thr Ala Ile Tyr Tyr Cys Gly Ala
20 25
<210> 317
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 317
Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Asn
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 318
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 318
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Arg
1 5 10 15
Leu Thr Pro Glu Asp Thr Asp Val Tyr Tyr Cys Arg Phe
20 25
<210> 319
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 319
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Glu Ser
1 5 10 15
Leu Val Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 320
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 320
Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Thr Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 321
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 321
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 322
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 322
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 323
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 323
Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
20 25
<210> 324
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 324
Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu Gln Met Asn Arg
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 325
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 325
Ile Ser Arg Asp Asn Ala Arg Asn Thr Val Tyr Leu Gln Met Asp Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Ile Tyr Thr Cys His Val
20 25
<210> 326
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 326
Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Asn
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 327
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 327
Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Ser Val
20 25
<210> 328
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 328
Val Ser Arg Asp Ser Ala Lys Asn Ile Val Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 329
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 329
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val
20 25
<210> 330
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 330
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Val
20 25
<210> 331
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 331
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 332
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 332
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 333
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 333
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Thr
20 25
<210> 334
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 334
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 335
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 335
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 336
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 336
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Asn Ala
20 25
<210> 337
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 337
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Val
20 25
<210> 338
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 338
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Val
20 25
<210> 339
<211> 29
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 339
Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser
1 5 10 15
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ser Val
20 25
<210> 340
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 340
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 341
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 341
Trp Gly Lys Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 342
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 342
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 343
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 343
Phe Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 344
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 344
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 345
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 345
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 346
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 346
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 347
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 347
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 348
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 348
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 349
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 349
Gln Gly Thr Leu Val Thr Val Ser Ser
1 5
<210> 350
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 350
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 351
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 351
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 352
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 352
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 353
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 353
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 354
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 354
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
1 5 10
<210> 355
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 人工序列的描述：合成
肽
<400> 355
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
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Claims (10)
1.一种结合间皮素(MSLN)的三特异性蛋白质，其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A)；
(b)第二结构域(B)，其为半衰期延长结构域；和
(c)与MSLN特异性结合的第三结构域(C)，
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接。
2.根据权利要求1所述的结合MSLN的三特异性蛋白质，其中所述第一结构域包含各自能够与人CD3特异性结合的可变轻结构域和可变重结构域。
3.根据权利要求1所述的结合MSLN的蛋白质，其中所述第一结构域是人源化的或人的。
4.根据权利要求1所述的结合MSLN的三特异性蛋白质，其中所述第二结构域结合白蛋白。
5.根据权利要求1所述的结合MSLN的三特异性蛋白质，其中所述第二结构域包含scFv、可变重结构域(VH)、可变轻结构域(VL)、肽、配体或小分子。
6.根据权利要求1所述的结合MSLN的三特异性蛋白质，其中所述第三结构域包含与MSLN特异性结合的VHH结构域、scFv、VH结构域、VL结构域、非Ig结构域、配体、knottin或小分子实体。
7.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含选自SEQ IDNO:58-86、98、100和101的序列的结合间皮素的三特异性蛋白质。
8.一种治疗或改善增生性疾病或肿瘤性疾病的方法，该方法包括施用包含SEQ ID NO:98所示序列的结合间皮素的三特异性蛋白质。
9.一种结合间皮素(MSLN)的三特异性蛋白质，其包含SEQ ID NO:98所示的序列。
10.一种结合间皮素(MSLN)的三特异性蛋白质，其中所述蛋白质包含
(a)与人CD3特异性结合的第一结构域(A)；
(b)第二结构域(B)，其为半衰期延长结构域；和
(c)与MSLN特异性结合的第三结构域(C)，
其中所述结构域以H2N-(A)-(C)-(B)-COOH、H2N-(B)-(A)-(C)-COOH、H2N-(C)-(B)-(A)-COOH的顺序或者通过连接体L1和L2连接，其中所述第三结构域包含一个或多个选自SEQ IDNo:51-56和106-222的CDR序列。
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| PCT/US2018/032427 WO2018209304A1 (en) | 2017-05-12 | 2018-05-11 | Msln targeting trispecific proteins and methods of use |
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| CA3063362A1 (en) | 2018-11-15 |
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| EP3621648A1 (en) | 2020-03-18 |
| AU2018265860A1 (en) | 2020-01-16 |
| BR112019023856A2 (pt) | 2020-06-09 |
| US10730954B2 (en) | 2020-08-04 |
| JP7209936B2 (ja) | 2023-01-23 |
| CN110913908B (zh) | 2022-05-27 |
| AU2018265860B2 (en) | 2022-08-11 |
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