CN117979977A - 用于细胞疗法的b细胞扩增方法 - Google Patents
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Abstract
本文所公开的本发明涉及用于扩增细胞群体,具体地B细胞群体的经改进的方法。本发明进一步涉及经改进的B细胞扩增培养基、包括经扩增的B细胞的组合物以及使用此类经扩增的B细胞的方法。本发明进一步涉及治疗疾病或病症的方法,其中获得并且培养B细胞群体,并且其中所述B细胞被工程化以表达有效载荷和/或嵌合受体,并且其中所述B细胞被施用于受试者。
Description
背景技术
B细胞是免疫细胞,负责多种功能,包含帮助身体抵抗传染和疾病。所述细胞能够分泌响应于所识别抗原的抗体,呈递抗原,并且还分泌细胞因子。在癌症中,已经在某些肿瘤周围的三级淋巴结构(“TLS”)中发现了B细胞。TLS包括免疫细胞(包含T细胞和B细胞两者)的聚集体。所述聚集体在肿瘤中的存在与更好的患者预后相关。参见例如,Helmink,B.A.等人,《自然(Nature)》,2020,577(7791),549-555;Petitprez F等人,《自然》,2020,577(7791),556-560。
LPS激活的脾细胞(包含B细胞)与检查点抑制剂的组合的瘤内注射已经显示出产生抗肿瘤应答。Soldevilla等人,《肿瘤免疫学(Oncoimmunology)》,2018,7:8,e1450711。进一步,鉴于B细胞具有呈递抗原和分泌蛋白质的天然能力,作为用于靶向某些患病细胞类型并分泌治疗性有效载荷的细胞疗法具有很大的潜力。
然而,扩大用于细胞疗法的工程化B细胞的生产规模是一个具有挑战性的过程。几十年来,已经通过表达CD40配体(“CD40L”)的饲养细胞层系统实现了B细胞的体外激活和增殖。Banchereau,J.等人(1991)《科学(Science)》251:70–72;Schultze,J.L.等人(1997)《临床研究杂志(J.Clin.Invest.)》100:2757–2765;Liebig,T.M.等人(2009)《视觉实验杂志(J.Vis.Exp.)》32:1373。这些系统都有一个共同的缺点,即它们依赖表达CD40L的饲养细胞层。饲养细胞的使用阻碍了激活和增殖过程的标准化,并且在方案中引入了变量。
使用CD40L已经描述了B细胞的扩增,具有混合的结果。参见例如,Wennhold等人,2019,《移注医学和血液疗法(Transfus Med Hemother)》,46:36–46。一些方法导致低扩增产量,产生的B细胞数量不足以用于细胞工程化和用于将B细胞用作治疗剂以施用于患者。因此,需要改进的B细胞扩增技术、生长培养基等。
发明内容
本发明总体上提供了用于扩增细胞群体,具体地B细胞群体的改进的方法。本发明进一步涉及改进的细胞培养基、其组合物以及使用此类经扩增的B细胞的方法。这种新型方法包含使用新型CD40L融合蛋白、交联抗体和IL-4和/或IL-21。此类方法对工程化B细胞的有效激活和增殖至关重要,使得功能性扩增B细胞的期望水平增加200倍。
本文所提供的用于扩增B细胞的方法优于常规方法,因为迄今为止的常规扩增方法导致不期望的低细胞扩增,并且因此降低了工程化B细胞的产量。适当的细胞功能和产量在细胞疗法中是至关重要的,对于同种异体治疗,并且具体地在自体治疗环境中,其中通常仅一次机会来采集患者的细胞、培养、扩增、工程化和施用有效剂量的此类细胞。
在各个实施例中,本发明涉及一种治疗有需要的受试者的疾病或病症的方法,所述方法包括:从来源获得B细胞群体;在包括CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞;对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者;以及向所述受试者施用所述B细胞。在各个实施例中,所述来源是哺乳动物。在各个实施例中,所述来源是包括外周单核血细胞的生物样品。
在各个实施例中,所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。在各个实施例中,所述CD40L包括与SEQ ID NO:3至少95%相同的氨基酸序列。在各个实施例中,所述CD40L融合蛋白包括SEQ ID NO:3融合蛋白的氨基酸序列。在各个实施例中,所述CD40L交联剂是抗体。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQID NO:7至少95%相同的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
在各个实施例中,在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。在各个实施例中,在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。在各个实施例中,所述方法进一步涉及在存在IL-4的情况下培养所述B细胞。在各个实施例中,所述方法进一步涉及在存在IL-21的情况下培养所述B细胞。
在各个实施例中,所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。在各个实施例中,所述疾病或病症选自由以下组成的组:癌症、心脏疾病、炎性疾病、肌肉萎缩疾病或神经疾病中的至少一种。在各个实施例中,所述癌症是以下中的至少一种:乳腺癌、结肠癌、直肠癌、食管癌;肺癌、胰腺癌、胃癌、肝癌、肝细胞癌、间质瘤如GIST、胶质母细胞瘤和神经胶质瘤。在各个实施例中,至少约3×107个B细胞被施用于所述受试者。在各个实施例中,所述B细胞群体被培养至少14天。
在各个实施例中,本发明涉及一种治疗有需要的受试者的疾病或病症的方法,所述方法包括:从来源获得B细胞群体;在包括CD40L融合蛋白和CD40L交联抗体的培养基中培养所述B细胞,其中所述CD40L融合蛋白包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同;以及向所述受试者施用所述B细胞。
在各个实施例中,所述来源是哺乳动物。在各个实施例中,所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。在各个实施例中,本发明进一步包括对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。
在各个实施例中,在含有CD40L和CD40L交联抗体的培养基中培养所述B细胞之前,所述B细胞被工程化。在各个实施例中,在含有CD40L和CD40L交联抗体的培养基中培养所述B细胞之后,所述B细胞被工程化。在各个实施例中,本发明进一步包括在存在IL-4的情况下培养所述B细胞。在各个实施例中,本发明进一步包括在存在IL-21的情况下培养所述B细胞。在各个实施例中,所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。在各个实施例中,所述疾病或病症选自由以下组成的组:癌症、心脏疾病、炎性疾病、肌肉萎缩疾病或神经疾病中的至少一种。在各个实施例中,所述癌症是以下中的至少一种:乳腺癌、结肠癌、直肠癌、食管癌;肺癌、胰腺癌、胃癌、肝癌、肝细胞癌、间质瘤如GIST、胶质母细胞瘤和神经胶质瘤。在各个实施例中,至少约3×107个B细胞被施用于所述受试者。在各个实施例中,所述B细胞群体被培养至少14天。
在各个实施例中,本发明涉及一种用于制备工程化B细胞的方法,所述方法包括:从来源获得B细胞群体;在包括CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞;以及对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。在各个实施例中,所述来源是哺乳动物。在各个实施例中,所述来源是包括外周单核血细胞的生物样品。
在各个实施例中,所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。在各个实施例中,所述CD40L包括与SEQ ID NO:3至少95%相同的氨基酸序列。在各个实施例中,所述CD40L融合蛋白包括SEQ ID NO:3融合蛋白的氨基酸序列。在各个实施例中,所述CD40L交联剂是抗体。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQID NO:7至少95%相同的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
在各个实施例中,在含有CD40L和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。在各个实施例中,在含有CD40L和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。在各个实施例中,所述方法进一步涉及在存在IL-4的情况下培养所述B细胞。在各个实施例中,所述方法进一步涉及在存在IL-21的情况下培养所述B细胞。在各个实施例中,所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。在各个实施例中,所述来源是哺乳动物。在各个实施例中,所述来源是包括外周单核血细胞的生物样品。
在各个实施例中,所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。在各个实施例中,所述CD40L包括与SEQ ID NO:3至少95%相同的氨基酸序列。在各个实施例中,所述CD40L融合蛋白包括SEQ ID NO:3融合蛋白的氨基酸序列。在各个实施例中,所述CD40L交联剂是抗体。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQID NO:7至少95%相同的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
在各个实施例中,所述方法进一步包括在存在IL-4的情况下培养所述B细胞。在各个实施例中,所述方法进一步包括在存在IL-21的情况下培养所述B细胞。在各个实施例中,所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。在各个实施例中,至少约3×107个B细胞被获得。在各个实施例中,所述B细胞群体被培养至少14天。
在各个实施例中,提供了一种制备工程化B细胞的方法,所述方法包括:从来源获得B细胞群体;在包括CD40L和CD40L交联抗体的培养基中培养所述B细胞,其中所述CD40L融合蛋白包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同;以及向所述受试者施用所述B细胞。在各个实施例中,所述来源是哺乳动物。在各个实施例中,所述CD40L融合蛋白包括SEQ IDNO:3的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和轻链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述轻链可变区包括SEQ ID NO:7的氨基酸序列。
在各个实施例中,所述方法进一步包括对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。在各个实施例中,在含有CD40L和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。在各个实施例中,在含有CD40L和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。在各个实施例中,所述方法进一步包括在存在IL-4的情况下培养所述B细胞。在各个实施例中,所述方法进一步包括在存在IL-21的情况下培养所述B细胞。在各个实施例中,所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。在各个实施例中,至少约3×107个B细胞被获得。在各个实施例中,所述B细胞群体被培养至少14天。
在各个实施例中,本发明涉及一种B细胞扩增培养基,其包括:CD40L融合蛋白和CD40L交联抗体,其中所述CD40L融合蛋白包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同;以及向所述受试者施用所述B细胞。
在各个实施例中,所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。在各个实施例中,所述培养基进一步包括IL-4。在各个实施例中,所述培养基进一步包括IL-21。
附图说明
图1示出了人B细胞可以在含有HELA-CD40饲养细胞的培养基中生长和扩增,但在存在MEGA-CD40L的情况下不扩增(恩佐生命科学公司(Enzo Life Sciences))。纯化的B细胞在第0天以大约10,000个细胞/ml的等效密度开始,并且在HELA-CD40L饲养细胞上生长。在第4天,将培养物分成两组,并且一组继续在含有HELA-CD40L饲养细胞的相同培养基中生长,而另一组在补充有MEGA-CD40L(0.1μg/ml)但没有HELA饲养细胞的培养基中生长。在第8天,将另外的100ng/ml MEGA-CD40L添加到MEGA-CD40L条件下的生长培养基中。箭头指示MEGA-CD40L处理发生的时间。此数据表明,当在HELA-CD40L饲养细胞上生长时,B细胞到第11天有显著的增殖,但是如果用MEGA-CD40L生长,在第11天没有观察到显著的生长。
图2示出了,甚至在不存在HELA-CD40L饲养细胞的情况下,仅两周后,人细胞可以在包括CD40L和CD40L交联剂的培养基中至少生长和扩增至约3×107个细胞。在整个研究过程中维持两种密度(150K和1MM)。较低密度的培养物能够维持较高的生长速率,并且产生较大的相对总质量。甚至仅在两周内,细胞就能够扩增至少200倍。
图3展示了经扩增的工程化B细胞可以维持转基因表达。图3A展示了在腺病毒载体转染后72小时,67%的经扩增的工程化B细胞表现出GPC B细胞受体表达。图3B示出了用空载体(其不表达GPC3的载体)转染的细胞中的表达GPC-BCR的细胞的百分比。图3C示出了根本没有用任何载体转导的细胞。
图4示出了Ad5RGD-GFP转导后的B细胞扩增和生长速率。Ad5RGD-GFP导致B细胞中的高效GFP表达。约60%的总B细胞的表达维持至少8-10天。GFP+B细胞在转导后继续增殖,持续超过一周。
图5示出了通过RGD(601)用鼠GPC3构建体转导的人B细胞的成功扩增。图5A描绘了经转导的抗GPC3 scFV嵌合受体的结构,所述嵌合受体包括抗GPC3 scFv、CD8铰链结构域、CD28跨膜结构域和CD79a信号传导结构域。图5B示出了表达经转导的GPC3嵌合受体的B细胞的相对百分比。
图6示出了通过RGD(602)用鼠GPC3构建体转导的人B细胞的成功扩增。图6A描绘了经转导的抗GPC3 scFV嵌合受体的结构,所述嵌合受体包括抗GPC3 scFv、CD8铰链结构域、CD28跨膜结构域和CD79b信号传导结构域。图6B示出了表达经转导的GPC3嵌合受体的B细胞的相对百分比。
图7示出了用RGD功能化的非病毒基因递送载体转导的人B细胞的扩增,所述载体表达靶向GPC3的嵌合受体。图7A描绘了此嵌合受体的结构,所述嵌合受体包括抗GPC3scFv、CD8铰链结构域、CD28跨膜结构域和CD79b或CD79a信号传导结构域。图7B示出了表达经转导的GPC3嵌合受体的B细胞的相对百分比。
图8示出了通过RGD(463)用鼠GPC3构建体转导的人B细胞的成功扩增。图8A描绘了经转导的抗GPC3 scFV嵌合受体的结构,所述嵌合受体包括抗GPC3 scFv、CD8铰链结构域、CD28跨膜结构域和CD79b信号传导结构域。图8B示出了表达经转导的GPC3嵌合受体的B细胞的相对百分比。
图9示出了用RGD功能化的非病毒基因递送载体转导的人B细胞的扩增,所述载体表达靶向肌聚糖的嵌合受体(394)。图9A描绘了此嵌合受体的结构,所述嵌合受体包括抗肌聚糖scFv、鼠G2a Fc结构域、跨膜结构域和胞质尾部。图9B展示了在B细胞转导和扩增之后,被证明表达嵌合受体的细胞的百分比。
图10示出了在携带HPEG2肿瘤的小鼠中,经工程化和经扩增的人B细胞体内归巢至肿瘤引流淋巴结(“TDLN”)。
具体实施方式
应当理解,本文中的描述仅是示例性和说明性的,并且不限制所要求保护的本发明。在本申请中,除非另外特别说明,否则单数的使用包含复数。
I.概述
应当理解,本发明涉及产生、扩增和/或分离工程化B细胞群体的方法。例如,本发明方法可以用于产生例如多种工程化B细胞,如2020年9月2日提交的美国临时专利申请第63/073799号和2020年3月31日提交的美国临时专利申请第63/003120号中所描述。这些包含但不限于:
1)已经使用例如结合结构域(如scFv、抗体、配体、受体或其片段)修饰成所关注位点/靶标的B细胞;
2)已经用归巢结构域修饰的B细胞,所述B细胞进一步包括激活以及任选地共刺激结构域,使得所述B细胞可以在与期望的靶标相互作用时归巢和激活;
3)被工程化以能够产生期望的蛋白质有效载荷的B细胞,如抗体、治疗蛋白、多肽、核酸序列(如RNAi)等;
4)包括归巢结构域/结合结构域、激活结构域、任选的共刺激结构域的经工程化的B细胞,并且所述经工程化的B细胞进一步被工程化以表达期望的蛋白质有效载荷,如抗体、治疗蛋白、多肽、核酸序列(如RNAi)等;
5)已经被修饰以表达整联蛋白、归巢抗体、蛋白质或受体的B细胞,使得所述B细胞被吸引至所关注的特异性位点/靶标(例如,归巢组织)处的特异性配体、趋化因子或引诱剂,并且由此可以归巢到所关注位点/靶标,例如,以递送期望的有效载荷;
6)已经被修饰以表达免疫抑制分子的B细胞,使得局限于所关注位点/靶标的B细胞的炎症和自身免疫活性得到降低,由此产生阳性治疗应答;
7)已经用化合物或其衍生物处理的B细胞,使得所述B细胞的转运通过特异性B细胞整联蛋白和/或归巢受体的表达而改变;
8)已经(i)用Toll样受体(TLR)激动剂处理,和/或(ii)被工程化以表达组成型活性TLR的B细胞,用于增强B细胞和/或产生有效的效应B细胞以便增加受试者的免疫应答;
9)已经用与溶酶体蛋白的靶向信号融合的编码所关注的特异性抗原的mRNA电穿孔的B细胞,使得所述B细胞可以同时且有效地在HLA I类和II类分子两者中呈递所关注的特异性抗原和/或抗原衍生的表位。
10)已经用自扩增RNA电穿孔的B细胞,所述自扩增RNA编码此前根据1至9中所述的任何项。
将理解,本申请的经工程化或经修饰的B细胞的各个实施例不是互相排斥的,并且除非明确指出,否则可以以任何方式且不受任何限制彼此组合,以便实现促进本文所设想的任何结果和/或治疗应答。
更具体地,本发明方法可以用作制备技术,以在产生以下B细胞实施例中产生B细胞的改良扩增。这些在2020年9月2日提交的美国临时专利申请第63/073799号和2020年3月31日提交的美国临时专利申请第63/003120号中描述,所述专利申请的内容特此通过引用整体并入本文。用于制备本发明的构建体和经工程化的免疫细胞的某些方法描述于PCT申请PCT/US2015/14520中,所述申请的内容特此通过引用整体并入。制备构建体和细胞的另外的方法可以在美国临时专利申请第62/244,036号中找到,所述美国临时专利申请的内容特此进一步通过引用整体并入。
本发明还涉及使用通过本文所描述的方法产生的工程化B细胞治疗疾病或病症的方法。适于治疗的疾病或病症的实例包含但不限于癌症、心脏疾病、炎性疾病、肌肉萎缩疾病、神经疾病等。
II.定义
本文所使用的章节标题仅出于组织目的,而不应被解释为对所描述的主题进行限制。在本申请中引用的所有文件或文件的部分,包含但不限于专利、专利申请、论文、书籍和专著,均特此出于任何目的通过引用整体明确地并入。如根据本公开所用,除非另外指示,否则以下术语应理解为具有以下含义:
在本申请中,除非另有说明,否则“或”的使用意指“和/或”。此外,术语“包含(including)”以及如“包含(includes)”和“包含(included)”等其它形式的使用不是限制性的。此外,除非另外特别说明,否则如“元件”或“组分”等术语涵盖包括一个单元的元件和组分以及包括多于一个亚单元的元件和组分两者。
术语“多核苷酸”、“核苷酸”或“核酸”包含单链核苷酸聚合物和双链核苷酸聚合物两者。包括多核苷酸的核苷酸可以是核糖核苷酸或脱氧核糖核苷酸或任一种核苷酸类型的经修饰形式。所述修饰包含碱基修饰,如溴尿嘧啶核苷和肌苷衍生物;核糖修饰,如2',3'-二脱氧核糖;以及核苷酸间键合修饰,如硫代磷酸酯、二硫代磷酸酯、硒代磷酸酯、二硒代磷酸酯、硫代苯胺磷酸酯(phosphoro-anilothioate)、苯胺磷酸酯(phoshoraniladate)和氨基磷酸酯。
术语“寡核苷酸”是指包括200个或更少核苷酸的多核苷酸。寡核苷酸可以是单链或双链,例如,用于构建突变基因。寡核苷酸可以是有义或反义寡核苷酸。寡核苷酸可以包含用于检测测定的标记,所述标记包含放射性标记、荧光标记、半抗原或抗原标记。寡核苷酸可以用作例如PCR引物、克隆引物或杂交探针。
术语“控制序列”是指可以影响与其连接的编码序列的表达和加工的多核苷酸序列。此类控制序列的性质可以取决于宿主生物体。在特定实施例中,原核生物的控制序列可以包含启动子、核糖体结合位点和转录终止序列。例如,真核生物的控制序列可以包含包括一个或多个转录因子识别位点的启动子、转录增强子序列和转录终止序列。“控制序列”可以包含前导序列(信号肽)和/或融合配偶体序列。
如本文所使用的,“可操作地连接”意指所述术语所应用的组分处于允许其在合适条件下执行其固有功能的关系。
术语“载体”意指用于将蛋白质编码信息转移到宿主细胞中的任何分子或实体(例如,核酸、质粒、噬菌体或病毒)。术语“表达载体”或“表达构建体”是指合于转化宿主细胞并且含有指导和/或控制(与宿主细胞结合)与其可操作地连接的一个或多个异源编码区的表达的核酸序列的载体。表达构建体可以包含但不限于影响或控制转录、翻译,并且如果存在内含子,影响与其可操作地连接的编码区的RNA剪接的序列。
术语“宿主细胞”是指已经被核酸序列转化或能够被转化并由此表达所关注基因的细胞。所述术语包含亲本细胞的后代,无论后代与原始亲本细胞在形态上或遗传构成上是否相同,只要存在所关注基因即可。
术语“转化”是指细胞的遗传特性的变化,并且当细胞已经被修饰为含有新的DNA或RNA时,所述细胞已经被转化。例如,在细胞通过转染、转导或其它技术引入新的基因物质从其天然状态被基因修饰时,所述细胞被转化。在转染或转导后,转化DNA可以通过物理整合到细胞的染色体中而与细胞的DNA重组,或者可以作为附加型元件短暂地维持而不被复制,或者可以作为质粒独立复制。当转化DNA随着细胞分裂而复制时,认为细胞已经被稳定转化。
术语“转染”是指细胞摄取外来或外源DNA。许多转染技术是本领域熟知的并且在本文中公开。参见例如,Graham等人1973《病毒学(Virology)》,1973,52:456;Sambrook等人,《分子克隆:实验室手册(Molecular Cloning,a laboratory manual)》,2001,同上;Davis等人,《分子生物学基本方法(Basic Methods in Molecular Biology)》,1986,爱思唯尔出版社(Elsevier);Chu等人,1981,《基因(Gene)》,13:197。
术语“转导”是指通过病毒载体将外来DNA引入到细胞中的过程。参见例如,Jones等人,《基因学:原理和分析(Genetics:Principles and Analysis)》,1998,波士顿:琼斯和巴特利特出版社(Boston:Jones&Bartlett Publ.)。
术语“多肽”或“蛋白质”是指具有蛋白质的氨基酸序列的大分子,包含天然序列的一个或多个氨基酸的缺失、添加和/或取代。术语“多肽”和“蛋白质”具体地涵盖抗原结合分子、抗体或具有抗原结合蛋白的一个或多个氨基酸的缺失、添加和/或取代的序列。术语“多肽片段”是指与全长天然蛋白相比,具有氨基末端缺失、羧基末端缺失和/或内部缺失的多肽。与天然蛋白相比,此类片段还可以含有经修饰的氨基酸。有用的多肽片段包含抗原结合分子的免疫功能片段。
术语“分离的”意指(i)不含通常发现的至少一些其它蛋白质;(ii)基本上不含来自同一来源,例如来自同一物种的其它蛋白质;(iii)与至少约50%的多核苷酸、脂质、碳水化合物或与其天然缔合的其它物质分离;(iv)和不与其天然缔合的多肽可操作地缔合(通过共价或非共价相互作用);或(v)在自然界中不存在。
多肽(例如,抗原结合分子)的“变体”包括氨基酸序列,其中相对于另一个多肽序列,一个或多个氨基酸残基被插入到氨基酸序列中、从氨基酸序列缺失和/或取代到氨基酸序列中。变体包含融合蛋白。
术语“同一性”是指两个或更多个多肽分子或两个或更多个核酸分子的序列之间的关系,如通过比对和比较序列确定的。“同一性百分比”意指比较分子中氨基酸或核苷酸之间的相同残基的百分比,并且是基于所比较的分子中的最小分子的大小计算的。对于这些计算,优选地通过特定的数学模型或计算机程序(即,“算法”)来解决比对中的空位(如果有的话)。
为了计算同一性百分比,被比较的序列通常以使序列之间的匹配最大的方式进行比对。可以用于确定同一性百分比的计算机程序的一个实例是GCG程序包,所述程序包包含GAP(Devereux等人,《核酸研究(Nucl.Acid Res.)》,1984,12,387;威斯康星州麦迪逊威斯康星大学遗传学计算机组(Genetics Computer Group,University of Wisconsin,Madison,Wis.))。计算机算法GAP用于比对要确定百分比序列同一性的两个多肽或多核苷酸。对序列进行比对,以实现其相应氨基酸或核苷酸的最佳匹配(“匹配范围”,如由算法确定的)。在某些实施例中,标准比较矩阵(参见例如,Dayhoff等人,1978,《蛋白序列和结构图谱学(Atlas of Protein Sequence and Structure)》,5:345-352中关于PAM 250比较矩阵的内容;Henikoff等人,1992,《美国国家科学院院刊(Proc.Natl.Acad.Sci.U.S.A.)》,89,10915-10919中关于BLO-SUM 62比较矩阵的内容)也被算法使用。
如本文所使用的,二十种常规(例如,天然存在的)氨基酸及其缩写遵循常规用法。参见例如,《免疫学合成(Immunology A Synthesis)》(第2版,Golub和Green编辑,马萨诸塞州桑德兰Sinauer Assoc.出版社(Sinauer Assoc.,Sunderland,Mass.)(1991)),所述文献出于任何目的通过引用并入本文。二十种常规氨基酸、非天然氨基酸(如α-、α-二取代的氨基酸、N-烷基氨基酸、乳酸和其它非常规氨基酸)的立体异构体(例如,D-氨基酸)也可以是本发明的多肽的合适的组分。非常规氨基酸的实例包含:4-羟基脯氨酸、γ-羧基-谷氨酸盐、ε-N,N,N-三甲基赖氨酸、e-N-乙酰基赖氨酸、0-磷酸丝氨酸、N-乙酰基丝氨酸、N-甲酰基甲硫氨酸、3-甲基组氨酸、5-羟基赖氨酸、σ-N-甲基精氨酸以及其它类似的氨基酸和亚氨基酸(例如,4-羟基脯氨酸)。在本文所使用的多肽标记中,根据标准使用和惯例,左手方向是氨基末端方向,并且右手方向是羧基末端方向。
保守氨基酸取代可以涵盖非天然存在的氨基酸残基,所述氨基酸残基通常通过化学肽合成而不是通过生物系统中的合成来并入。这些包含肽模拟物和氨基酸部分的其它反向或倒置的形式。可以基于共同的侧链性质将天然存在的残基分为几类:
a)疏水性:正亮氨酸、Met、Ala、Val、Leu、Ile;
b)中性亲水性:Cys、Ser、Thr、Asn、Gln;
c)酸性:Asp、Glu;
d)碱性:His、Lys、Arg;
e)影响链定向的残基:Gly、Pro;以及
f)芳香族:Trp、Tyr、Phe。
例如,非保守取代可以涉及用这些种类之一的成员交换来自另一种类的成员。
根据某些实施例,在对抗原结合分子、经工程化的T细胞的共刺激结构域或激活结构域进行改变时,可以考虑氨基酸的亲水指数。根据氨基酸的疏水性和电荷特性已经为每个氨基酸分配了亲水指数。所述氨基酸是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸/胱氨酸(+2.5);蛋氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。参加例如,Kyte等人,1982,《分子生物学杂志(J.Mol.Biol.)》,157,105-131。已知某些氨基酸可以取代具有类似亲水指数或评分的其它氨基酸,并且仍然保留类似的生物活性。在本领域中还应理解,可以在亲水性的基础上有效地进行相似氨基酸的取代,特别是当由此产生的生物功能性蛋白质或肽旨在用于免疫学实施例时,如在本发明的情况中。表1中阐述了示例性氨基酸取代。
表1
术语“衍生物”是指包含除了氨基酸(或核酸)插入、缺失或取代之外的化学修饰的分子。在某些实施例中,衍生物包括共价修饰,包含但不限于与聚合物、脂质或其它有机或无机部分的化学键合。在某些实施例中,经化学修饰的抗原结合分子的循环半衰期可以大于未经化学修饰的抗原结合分子的循环半衰期。在一些实施例中,衍生的抗原结合分子被共价修饰以包含一个或多个水溶性聚合物连接,包含但不限于聚乙二醇、聚氧乙二醇(polyoxyethylene glycol)或聚丙二醇。
肽类似物通常在制药工业中用作具有类似于模板肽的那些性质的性质的非肽药物。这些类型的非肽化合物被称为“肽模拟物(peptide mimetics)”或“拟肽(peptidomimetics)”。Fauchere,J.L.,1986,《药物研究进展(Adv.Drug Res.)》,1986,15,29;Veber,D.F.和Freidinger,R.M.,1985,《神经科学趋势(Trends in Neuroscience)》,8,392-396;以及Evans,B.E.等人,1987,《药物化学杂志(J.Med.Chem.)》,30,1229-1239,所述文献出于任何目的通过引用并入本文中。
术语“治疗有效量”是指确定在哺乳动物中产生治疗应答的免疫细胞或其它治疗剂的量。此类治疗有效量由本领域的普通技术人员容易地确定。
术语“患者”和“受试者”可互换使用,并且包含人和非人动物受试者以及患有正式诊断的病症的受试者、未患有正式辨别的病症的受试者、接受医疗护理的受试者、有罹患病症的风险的受试者等。
术语“治疗(treat)”和“治疗(treatment)”包含治疗性治疗、预防性治疗和在其中降低受试者罹患病症的风险或其它风险因素的应用。治疗不需要完全治愈病症并且涵盖减轻症状或潜在风险因素的实施例。术语“预防”并不要求100%消除事件发生的可能性。相反,所述术语表示在化合物或方法存在的情况下,事件发生的可能性已经降低。
标准技术可以用于重组DNA、寡核苷酸合成以及组织培养和转化(例如,电穿孔、脂质转染)。酶反应和纯化技术可以根据制造商的说明书或如本领域中通常实现或如本文所描述的来执行。前述技术和程序通常可以根据本领域熟知的常规方法并且如在整个本说明书中引用和讨论的各种一般的和更具体的参考文献中所描述那样执行。参见例如,Sambrook等人,《分子克隆:实验室手册》(第2版,纽约州冷泉港的冷泉港实验室出版社(Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.)(1989)),所述文献出于任何目的通过引用并入本文中。
如本文所使用的,术语“大体上”或“基本上”是指相较于参考数量、水平、数值、数目、频率、百分比、尺寸、大小、量、重量或长度,数量、水平、数值、数目、频率、百分比、尺寸、大小、量、重量或长度为约90%、91%、92%、93%、94%、95%、96%、97%、98%或99%或更高。在一个实施例中,术语“基本上相同”或“大体上相同”是指与参考数量、水平、数值、数目、频率、百分比、尺寸、大小、量、重量或长度大约相同的数量、水平、数值、数目、频率、百分比、尺寸、大小、量、重量或长度的范围。
如本文所使用的,术语“大体上不含”和“基本上不含”可互换使用,且当用于描述组合物(例如细胞群或培养基)时,是指不含所指定物质的组合物,例如95%不含、96%不含、97%不含、98%不含、99%不含所指定物质,或检测不到,如通过常规方式所测量。类似的含义可以应用于术语“不存在”,其中是指组合物中不存在特定物质或组分。
如本文所使用的,术语“明显的”是指数目、水平、值、数量、频率、百分比、尺寸、大小、量、重量或长度的范围,或者可通过一种或多种标准方法容易检测到的事件。术语“不明显的(not-appreciable)”和“不明显的(not appreciable)”以及等效物是指数目、水平、值、数量、频率、百分比、尺寸、大小、量、重量或长度的范围,或者是通过标准方法不容易检测到或检测不到的事件。在一个实施例中,如果事件发生的时间少于5%、4%、3%、2%、1%、0.1%、0.001%或更少,则所述事件是不明显的。
在本说明书通篇,除非上下文另外要求,否则“包含(comprise/comprises/comprising)”一词应理解为暗指包括所述步骤或要素或一组步骤或要素,但不排除任何其它步骤或要素或任何其它组步骤或要素。在特定实施例中,术语“包含”、“具有”、“含有”和“包括”同义地使用。
如本文所使用的,“由…组成”意指包含且限于短语“由…组成”之后的事物。因此,短语“由…组成”表示所列元件是必需的或强制性的,并且可以不存在其它元件。
“基本上由…组成”意指包含在所述短语之后列出的任何元件,并且限于不干扰或促进本公开中对所列元件指定的活动或动作的其它元件。因此,短语“基本上由……组成”指示所列要素是需要或必需的,但其它要素是任选的并且可视其是否影响所列要素的活性或作用而存在或不存在。
贯穿本说明书提及“一个实施例”、“一实施例”、“特定实施例”、“相关实施例”、“某一实施例”、“另外的实施例”或“另一实施例”或其组合意指结合实施例描述的特定特征、结构或特性包含在本发明的至少一个实施例中。因此,贯穿本说明书中的各处出现的前述短语不一定全部指代同一实施例。此外,特定特征、结构或特性可以在一个或多个实施例中以任何合适的方式组合。
如本文所使用的,术语“约”或“大约”是指某一数量、水平、值、数量、频率、百分比、尺寸、大小、量、重量或长度相对于参考数量、水平、值、数量、频率、百分比、尺寸、大小、量、重量或长度变化多达30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%。在特定实施例中,术语“约”或“大约”在数字值之前时指示所述值加上或减去15%、10%、5%或1%的范围或其任何中间范围。
如本文所使用的,术语“引入”是指包括使细胞与多核苷酸、多肽或小分子接触的过程。引入步骤还可以包括将多核苷酸或多肽显微注射到细胞中,使用脂质体将多核苷酸或多肽递送到细胞中,或将多核苷酸或多肽与细胞可渗透部分融合以将它们引入到细胞中。
扩增B淋巴细胞群体以进行细胞疗法的方法
在各个实施例中,设想了扩增工程化B淋巴细胞群体的改进方法。所述方法涉及通过包括CD40配体和交联抗体的细胞培养基交联在B细胞上表达的CD40。将CD40L与IL-4(一种已知的用于激活的B细胞的生长因子)组合已经显示出对B细胞的有效激活和增殖至关重要。Banchereau,J.等人(1991)《科学》251:70–72;Schultze,J.L.等人(1997)《临床研究杂志》100:2757–2765。同样,据报告,IL-21也是B细胞激活和增殖的有效刺激物。然而,另外地,IL-21驱动向浆细胞表型的B细胞成熟。值得注意的是,本发明的各个实施例的细胞培养基和方法使得经工程化的B细胞能够实现激活和增殖结果,这与经典的基于饲养细胞的NIH3T3/tCD40L方案相当。
1.CD-40配体
在各个实施例中,工程化B细胞在存在CD40配体(“CD40L”)的情况下扩增。在各个实施例中,CD40L是
MQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL(SEQ ID NO:1)。
在各个实施例中,工程化B细胞在存在包括CD40L序列和多聚化结构域的融合蛋白存在下扩增。在各个实施例中,所述多聚化结构域源自腱生蛋白。在各个实施例中,所述多聚化结构域包括:
ACGCAAAPDIKDLLSRLEELEGLVSSLREQ(SEQ ID NO:2)。
在各个实施例中,所述多聚化结构域是SEQ ID NO:2并且CD40L是SEQ ID NO:1。在各个实施例中,包括多聚化结构域和CD40L的融合蛋白包括:
VGDGSSHHHHHHSSGGGRGSHHHHHHGGACGCAAAPDIKDLLSRLEELEGLVSSLREQGGGSGGGSGGGSMQKGDQNPQIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSNREASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVNVTDPSQVSHGTGFTSFGLLKL(SEQ ID NO:3)。
在优选的实施例中,所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。在各个实施例中,所述CD40L融合蛋白包括与SEQ ID NO:3至少95%相同的氨基酸序列。在各个实施例中,所述CD40L包括SEQ ID NO:3的氨基酸序列。
交联剂
设想了本发明的B细胞将在存在CD40L交联剂的情况下扩增。在各个实施例中,所述CD40L交联剂是抗体。在各个实施例中,交联抗体的轻链区包括:
DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQRNYLAWYQQKPGQPPKLLIHGASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHRYPLTFGAGTKLELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQ ID NO:4)。
在各个实施例中,交联抗体的轻链可变区包括:
DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQRNYLAWYQQKPGQPPKLLIHGASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHRYPLTFGAGTKLELK(SEQ ID NO:5)。
在各个实施例中,交联抗体的重链区包括:
EVQLQQFGAELVKPGASVKISCKASGYTFTDYNMDWVKQSHGKSLEWIGDINPNYGSTSYNQKFKGKATLTVDKSSSTAYMELRSLTSEDTAVYYCARDWTGAMDYWGQGTSVTVSSAKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK(SEQ ID NO:6)。
在各个实施例中,交联抗体的轻链可变区包括:
EVQLQQFGAELVKPGASVKISCKASGYTFTDYNMDWVKQSHGKSLEWIGDINPNYGSTSYNQKFKGKATLTVDKSSSTAYMELRSLTSEDTAVYYCARDWTGAMDYWGQGTSVTVSS(SEQ ID NO:7)。
在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQ ID NO:7至少95%相同的氨基酸序列。在各个实施例中,所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。在各个实施例中,所述抗体包括SEQ ID NO:4的轻链和SEQ ID NO:6的重链。在各个实施例中,所述抗体包括轻链和重链,所述轻链包括与SEQ ID NO:4至少85%相同的氨基酸序列,所述重链包括与SEQ ID NO:6至少85%相同的氨基酸序列。在各个实施例中,所述抗体包括轻链和重链,所述轻链包括与SEQ ID NO:4至少95%相同的氨基酸序列,所述重链包括与SEQ IDNO:6至少95%相同的氨基酸序列。
III.工程化B细胞
如本文所使用的,术语“工程化B细胞”是指已经被基因改变以表达期望蛋白质或分子的B细胞。此类蛋白质或分子可以是内源性或嵌合受体。此类工程化B细胞可以被基因改变以表达“归巢”受体,所述归巢受体靶向特定组织/器官类型或靶向肿瘤或特定细胞类型。
1.抗原
肿瘤抗原.在某些实施例中,B细胞的所关注位点/靶标是肿瘤抗原。本发明的抗原结合结构域(部分)的选择将取决于待治疗的癌症的具体类型。一些肿瘤抗原可以是膜结合的,而另一些肿瘤抗原可以是分泌的。例如,肿瘤抗原可以分泌并积聚在胞外基质中,或者肿瘤抗原可以表达为MHC复合物的一部分。肿瘤抗原是本领域熟知的,并且可以包含例如CD19、KRAS、HGF、CLL、胶质瘤相关抗原、癌胚抗原(CEA)、β-人绒毛膜促性腺激素、α-胎甲球蛋白(AFP)、凝集素反应性AFP、甲状腺球蛋白、RAGE-1、MN-CA IX、人端粒酶逆转录酶、RU1、RU2(AS)、肠羧基酯酶、mut hsp70-2、M-CSF、前列腺酶、前列腺特异性抗原(PSA)、PAP、NY-ESO-1、LAGE-1a、p53、蛋白质、PSMA、Her2/neu、生存素和端粒酶、前列腺癌肿瘤抗原-1(PCTA-1)、MAGE、ELF2M、嗜中性粒细胞弹性蛋白酶、ephrinB2、CD22、胰岛素生长因子(IGF)-I、IGF-II、IGF-I受体、间皮素、EGFR、BCMA、KIT和IL-13。
传染病抗原.在某些实施例中,所关注位点/靶标是传染病抗原,针对所述传染病抗原,可能期望免疫应答。传染病抗原是本领域熟知的,并且可以包含但不限于病毒、细菌、原生生物和寄生虫抗原,如寄生虫、真菌、酵母、支原体、病毒蛋白、细菌蛋白和碳水化合物,以及真菌蛋白和碳水化合物。另外,传染病抗原的传染病的类型没有特别限制,并且可以包含但不限于病毒性传染病中的难治性疾病,如AIDS、乙型肝炎、艾普斯登-巴尔病毒(Epstein Barr Virus,EBV)感染、HPV感染、HCV感染等。寄生虫抗原可以包含但不限于疟疾寄生虫子孢子蛋白。
在某些实施例中,经修饰的B细胞表达经工程化的B细胞受体(CAR-B),所述经工程化的B细胞受体包括胞外结构域、跨膜结构域和胞内结构域。在某些实施例中,胞外结构域包括结合结构域和铰链结构域。
在某些实施例中,胞外结构域包括结合结构域,如scFv、配体、抗体、受体或其片段,所述结合结构域允许经修饰的B细胞通过与在那些细胞表面上表达的蛋白质结合来靶向特异性靶细胞。在某些实施例中,经修饰的肿瘤细胞靶向在肿瘤细胞表面上表达的蛋白质/抗原并与其结合。在某些实施例中,经修饰的B细胞进一步表达有效载荷。在某些实施例中,有效载荷能够增加肿瘤中交叉呈递树突状细胞(DC)的数量。在某些实施例中,有效载荷能够激活T细胞并且将T细胞吸引到肿瘤中。在某些实施例中,有效载荷能够在肿瘤中促进三级淋巴结构(TLS)的形成。在本发明的某些实施例中,经修饰的B细胞表达CAR-B和有效载荷两者。在某些实施例中,CAR-B包括刺激结构域,当与在肿瘤细胞表面上表达的抗原或蛋白质结合时,所述刺激结构域激活有效载荷的表达。
B细胞中的嵌合抗原受体(CAR-B)的设计和结构域定向
在各个实施例中,本发明提供了一种嵌合B细胞受体(CAR-B)。应当理解,嵌合B细胞受体(CAR-B)是经基因工程化的受体。根据本领域已知的技术,这些经工程化的受体可以容易地插入到B细胞中并且由B细胞表达。用CAR-B,单个受体可以被编程以识别在肿瘤细胞上表达的特异性蛋白质或抗原,并且当与所述蛋白质或抗原结合时引发抗肿瘤应答。在各个实施例中,CAR-B部分用作归巢机制,以将B细胞递送到靶组织。
应当理解,相对于携带受体的细胞,本发明的嵌合B细胞受体将包括胞外结构域(所述胞外结构域将包括抗原结合结构域,并且可以包括胞外信号传导结构域和/或铰链结构域)、跨膜结构域和胞内结构域。胞内结构域至少包括激活结构域,优选地包含CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和/或MyD88。应当进一步理解的是,抗原结合结构域被工程化使得所述抗原结合结构域位于分子/构建体的胞外部分中,使得所述抗原结合结构域能够识别其一个或多个靶标并且与所述一个或多个靶标结合。
在结构上,应当理解,这些结构域与相对于免疫细胞的位置相对应。表2中阐述了根据本发明的示例性CAR-B构建体:
表2
在各个实施例中,嵌合B细胞受体包含胞外结构域、跨膜结构域和胞质结构域。在各个实施例中,胞质结构域包括激活结构域。在各个实施例中,胞质结构域还可以包括共刺激结构域。在各个实施例中,胞外结构域包括抗原结合结构域。在各个实施例中,胞外结构域进一步包括抗原结合结构域与跨膜结构域之间的铰链区。
胞外结构域.许多胞外结构域可以与本发明一起使用。在各个实施例中,胞外结构域包括抗原结合结构域。在各个实施例中,胞外结构域还可以包括铰链区和/或信号传导结构域。在各个实施例中,含有IgG1恒定结构域的胞外结构域还可以包括IgG1(臼)或IgG1(杵)以促进定向cBCR形成。
抗原结合结构域和结合结构域.如本文所使用的,“抗原结合结构域(antigenbinding domain)”、“抗原结合结构域(antigen-binding domain)”或“结合结构域”是指B-CAR的能够与在细胞表面上表达的抗原或蛋白质结合的一部分。在一些实施例中,抗原结合结构域与涉及过度增殖性疾病的细胞上的抗原或蛋白质结合。在优选的实施例中,抗原结合结构域与在肿瘤细胞表面上表达的抗原或蛋白质结合。鉴于下面的定义和描述,将进一步理解抗原结合分子。
当解离常数(Kd)为1x 10-7M时,抗原结合结构域被称为与其靶抗原或蛋白质“特异性结合”。当Kd为1-5×10-9M时,抗原结合结构域以“高亲和力”与抗原特异性结合,并且当Kd为1-5×10-10M时,抗原结合结构域以“非常高的亲和力”与抗原特异性结合。在一个实施例中,抗原结合结构域的Kd为10-9M。在一个实施例中,解离速率<1×10-5。在其它实施例中,抗原结合结构域将与Kd介于约10-7M与10-13M之间的抗原或蛋白质结合,并且在又另一个实施例中,抗原结合结构域将以Kd 1.0-5.0x10结合。
当抗原结合结构域与一个靶标的结合比其与第二靶标的结合更紧密时,所述抗原结合结构域被称为是“选择性的”。
术语“中和”是指与配体结合并防止或减少所述配体的生物效应的抗原结合结构域。这可以通过例如直接阻断配体上的结合位点或通过与配体结合并且通过间接手段(如配体中的结构或能量改变)改变配体的结合能力来实现。在一些实施例中,所述术语还可以表示防止与其结合的蛋白质执行生物功能的抗原结合结构域。
术语“靶标”或“抗原”是指能够被抗原结合分子结合的分子或分子的一部分。在某些实施例中,靶标可以具有一个或多个表位。
术语“抗体”是指由免疫系统产生以识别特定抗原的所谓的免疫球蛋白、Y形蛋白。术语“抗体片段”是指抗体的抗原结合片段和Fc片段。抗原结合片段的类型包含:F(ab')2、Fab、Fab'和Fv分子。Fc片段完全由免疫球蛋白的重链恒定区产生。
胞外信号传导结构域.胞外结构域有益于淋巴细胞对抗原的信号传导和有效应答。在本发明中特别有用的胞外结构域可以源自(即,包括)CD28、CD28T(参见例如,美国专利申请US2017/0283500Al)、OX40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、诱导型T细胞共刺激分子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT(TNFSF14)、NKG2C、CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白、细胞因子受体、整联蛋白、信号传导淋巴细胞性激活分子(SLAM蛋白)、激活NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(触觉的)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、与CD83特异性结合的配体或其任何组合。胞外结构域可以源自天然的或合成的来源。
铰链结构域.如本文所描述,胞外结构域通常包括铰链部分。这是胞外结构域靠近细胞膜的一部分。胞外结构域可以进一步包括间隔子区。根据本发明可以使用多种铰链,包含如上所讨论的共刺激分子,以及免疫球蛋白(Ig)序列、3X strep II间隔子或其它合适的分子,以实现与靶细胞的期望的特殊距离。在一些实施例中,整个胞外区包括铰链区。在一些实施例中,铰链区包括如本文所描述的CD28或CD8或其部分的胞外结构域。
跨膜结构域.B-CAR可以被设计成包括与B-CAR的胞外结构域融合或以其它方式连接的跨膜结构域。B-CAR可以类似地与B-CAR的胞内结构域融合。在一个实施例中,使用天然与B-CAR中的结构域之一相关的跨膜结构域。在一些实例中,跨膜结构域可以通过氨基酸取代来选择或修饰,以避免此类结构域与相同或不同表面膜蛋白的跨膜结构域结合,从而使与受体复合物的其它成员的相互作用最小化。跨膜结构域可以源自天然的或合成的来源。在来源是天然的情况下,所述结构域可以源自任何膜结合的蛋白或跨膜蛋白。在本发明中特别有用的跨膜区可以源自(即,包括)CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、诱导型T细胞共刺激分子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT(TNFSF14)、NKG2C、CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白、细胞因子受体、整联蛋白、信号传导淋巴细胞性激活分子(SLAM蛋白)、激活NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(触觉的)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、与CD83特异性结合的配体或其任何组合。
任选地,短连接子可以在B-CAR的胞外结构域、跨膜结构域和胞内结构域中的任何或一些结构域之间形成连接。
在某些实施例中,本发明的B-CAR中的跨膜结构域是CD28跨膜结构域。在一个实施例中,本发明的B-CAR中的跨膜结构域是CD8跨膜结构域。
胞内(胞质)结构域.本发明的B-CAR受体的胞内(IC,或胞质)结构域可以提供免疫细胞的正常效应子功能中的至少一种正常效应子功能的激活。
应当理解,合适的胞内分子包含但不限于CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和MyD88。胞内分子可以进一步包含CD28、CD28T、OX-40、4-1BB/CD137、CD2、CD7、CD27、CD30、CD40、程序性死亡-1(PD-1)、诱导型T细胞共刺激分子(ICOS)、淋巴细胞功能相关抗原-1(LFA-1、CD1-1a/CD18)、CD3γ、CD3δ、CD3ε、CD247、CD276(B7-H3)、LIGHT(TNFSF14)、NKG2C、Igα(CD79a)、DAP-10、Fcγ受体、MHC 1类分子、TNF受体蛋白、免疫球蛋白、细胞因子受体、整联蛋白、信号传导淋巴细胞性激活分子(SLAM蛋白)、激活NK细胞受体、BTLA、Toll配体受体、ICAM-1、B7-H3、CDS、ICAM-1、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8α、CD8β、IL-2Rβ、IL-2Rγ、IL-7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(触觉的)、CEACAM1、CRT AM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、与CD83特异性结合的配体或其任何组合。本发明的CAR-B的胞质信号传导部分内的胞质信号传导序列可以以随机或指定顺序彼此连接。
如本文所使用的,术语“共刺激”结构域或分子是指用于放大或抵消细胞的初始激活信号的细胞表面分子的异质组。
在一个优选的实施例中,胞质结构域被设计成包括hCD19的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD40的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD40和hCD79b的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD40和hCD137的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD40和hFcγr2a的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD40和hMyd88的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD79a的信号传导结构域。在另一个实施例中,胞质结构域被设计成包括hCD79b的信号传导结构域。这些实施例优选地是人来源的,但可以源自其它物种。
B.表达有效载荷的经修饰的B细胞.
在本发明的各个实施例中,提供了能够表达有效载荷的经修饰的B细胞。如本文所使用的,术语“有效载荷”是指用作治疗剂的氨基酸序列、编码肽或蛋白质的核酸序列或RNA分子。在某些实施例中,有效载荷用于递送至肿瘤或肿瘤微环境。在某些实施例中,令人期望的是B细胞向肿瘤或肿瘤微环境递送有效载荷,所述有效载荷能够例如增加肿瘤中交叉呈递树突状细胞(DC)的数量。交叉呈递DC将允许改善肿瘤抗原的呈递。在各个实施例中,有效载荷可以能够激活T细胞并将其吸引到肿瘤中。在肿瘤中激活更多的T细胞将补充交叉呈递的DC以重塑肿瘤环境,从而具有更有效的抗肿瘤免疫能力。有效载荷还可以促进肿瘤中三级淋巴结构(TLS)的形成。临床研究已经证明,B细胞、TLS与免疫检查点阻断的应答之间存在关系。
本发明的有效载荷的非排他性实例包含:IL-1、IL-7、IL-8、IL-10、IL-12、IL-13、IL-17、IL-18、IL-21、干扰素α、干扰素β、干扰素γ、TSLP、CCL21、FLT3L、XCL1、LIGHT(TNFSF14)、OX40L、CD137L、CD40L、ICOSL、抗CD3抗体、CD47、TIM4-FC、CXCL13、CCL21、CD80、CD40L、IFNαA2、LIGHT、4-1BBL、MDGF(C19orf10)、FGF10、PDGF、集聚蛋白、TNF-α、GM-CSF、抗FAP抗体、抗TGF-β抗体;TGF-β陷阱、诱饵或其它抑制分子;抗BMP抗体;BMP陷阱、诱饵或其它抑制分子。
有效载荷表达的信号传导.在本发明的各个实施例中,有效载荷作为DNA构建体在经激活的转录途径的控制下在经修饰的B细胞中表达。在某些实施例中,有效载荷的表达受经激活的T细胞的核因子(“NFAT”)途径控制。NFAT途径是在免疫应答期间激活的转录因子途径并且由NFκΒ激活。在各个实施例中,经修饰的B细胞表达有效载荷和CAR-B两者。在各个实施例中,在经修饰的B细胞表达有效载荷和CAR-B两者的情况下,CAR-B可以进一步编码诱导NFκΒ途径的激活的信号传导分子。此类分子包含但不限于:CD79a(免疫球蛋白α)、CD79b(免疫球蛋白β)、CD40、CD19、CD137、Fcγr2a和MyD88。
在各个实施例中,本发明涉及表达至少一个有效载荷的分离的B细胞。在各个实施例中,本发明涉及表达多于一个有效载荷的分离的B细胞。在各个实施例中,本发明涉及表达1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个不同的有效载荷的分离的B细胞。
B细胞进行归巢的修饰.在本发明的各个实施例中,经工程化的B细胞可以用归巢结构域进行修饰(例如,如图2所示),使得B细胞可以归巢到所关注位点/靶标并且在与所述靶标相互作用时激活。另外,在B细胞膜上表达的识别靶组织上的地址素和配体的B细胞归巢受体、改变B细胞到特定位点的转运的化合物或其衍生物以及B细胞的抑制分子炎症和自身免疫活性可以在B细胞归巢以及专门免疫应答的发展中起作用。
表达所关注整联蛋白的经修饰的B细胞.由淋巴细胞表达的主要归巢受体是整联蛋白,所述整联蛋白是特征在于α和β链的异源二聚体结构的一大类分子。通常,整联蛋白的特异性α链和β链的配对决定归巢受体的类型。例如,α4链与β7链的配对表征主要整联蛋白分子(α4β7),所述主要整联蛋白分子负责淋巴细胞与在派伊尔结(PP)和胃肠(GI)道固有层内皮小静脉(LPV)中的高内皮小静脉(HEV)上表达的粘膜地址素细胞粘附分子1(MAdCAM-1)结合。类似地,α4链与β1链的配对表征皮肤的归巢受体(α4β1)。
在本发明的各个实施例中,可以预先选择具有介导优选定位的特定性状的待修饰的B细胞。例如,可以富集表达CXCR3的记忆B细胞,并且然后进行工程化。CXCR3细胞可以吸引到在炎症位点处表达的配体。因此,经修饰的B细胞可以优先地定位于此类位点。
在本发明的各个实施例中,提供了表达整联蛋白的α4链和β7链的经修饰的B细胞。令人期望的是,α4β7整联蛋白的表达将促进经修饰的B细胞归巢至结肠。在各个实施例中,提供了表达整联蛋白的α4链和β1链的经修饰的B细胞。令人期望的是,α4β1整联蛋白的表达将促进经修饰的B细胞归巢至皮肤。在各个实施例中,提供了一种经修饰的B细胞,其表达整联蛋白的α链和β链的所期望的配对,使得所表达的整联蛋白促进经修饰的B细胞归巢至所期望的所关注位点/靶标。因此,在各个实施例中,考虑在B细胞中表达整联蛋白的α链和β链的任何所期望的组合,使得表达特异性整联蛋白的经修饰的B细胞靶向所期望的所关注位点/靶标。
表达所关注归巢受体的经修饰的B细胞.B细胞具有归巢至炎性组织的能力,并且改变其归巢受体表达可以补充其天然归巢倾向。B细胞定位还通过引诱剂分子(例如,靶标,如配体和趋化因子)在特定位置或组织中的炎性位点处的表达来驱动。此类分子还可以包含抗体,如将细胞靶向外周淋巴结地址素(PNAd)的MECA79抗体。Bahmani等人,《临床研究杂志》2018;128(11):4770-4786;Azzi等人,《细胞报告(Cell Rep.)》2016;15(6):1202-13。因此,B细胞可以被工程化以表达促进B细胞归巢至所关注位点/靶标以及此类B细胞与所期望的靶标的相互作用的某些抗体、蛋白质和受体。在某些情况下,此类受体的表达将B细胞重定向到所关注组织。
在本发明的各个实施例中,提供了一种经修饰的B细胞,其能够表达归巢抗体、蛋白质或受体,所述归巢抗体、蛋白质或受体的表达能够将B细胞定向到所关注的特异性位点/靶标。使用特异性归巢受体/配体对将T细胞示例性归巢至特异性归巢组织(靶组织)如表3中所阐述。相同的特异性归巢受体/配体对也能够促进B细胞归巢至特异性归巢组织(靶组织)。因此,在本发明的各个实施例中,使用如表3中所阐述的对应归巢受体/配体对促进经修饰的B细胞归巢至示例性归巢组织(靶组织)。
表3
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表4中阐述了根据本发明的示例性归巢组织(靶组织)类型以及能够实现组织限制的B细胞归巢的配体或趋化因子。
表4
归巢组织类型 | 配体/趋化因子 |
CNS | VCAM-1、CD62P、用于CCR1、2、5的配体、CXCR3 |
肝脏 | CD62P、VAP-1、CXCL16 |
小肠 | MAdCAM、CD62P、CCL25 |
结肠 | MAdCAM、CD62P、CCL20、GPR15L |
皮肤 | CD62E、CD62P、CCL17(22)、ICAM-1 |
胸腺 | VCAM、CD62P、CCL25 |
外周淋巴结 | PNAd、CCL21、ICAM-1 |
派伊尔结 | MAdCAM、CCL21、CXCL13 |
骨髓 | VCAM、CD62P、CXCL12、ICAM-1 |
在本发明的各个实施例中,提供了一种经修饰的B细胞,其表达抗体、蛋白质或受体中的一种或多种,所述抗体、蛋白质或受体使用如表3中所阐述的特异性归巢受体/配体对促进经修饰的B细胞归巢至示例性靶组织/归巢组织。在本发明的各个实施例中,提供了一种经修饰的B细胞,其表达归巢受体中的一种或多种归巢受体,所述归巢受体使用如表3和/或4中所阐述的配体或趋化因子促进经修饰的B细胞归巢至示例性靶组织/归巢组织。如本文所使用的,术语“B细胞归巢”是指将本申请的B细胞定位、靶向、转运、定向或重定向到所关注位点/靶标,例如,归巢组织或靶组织、特定位置或组织中的炎性位点、或肿瘤或肿瘤微环境,其中治疗性有效载荷的递送是令人期望的。如在B细胞归巢的上下文中所使用的,术语“抗体”、“蛋白质”或“受体”是指用作治疗剂的氨基酸序列、编码肽或蛋白质的核酸序列、或RNA分子,所述治疗剂当在本发明的经修饰的B细胞中表达时将B细胞定向到所关注位点/靶标。
在某些实施例中,归巢抗体、蛋白质或受体分子用于将表达此类分子的经修饰的B细胞归巢/靶向至所关注位点/靶标。在某些实施例中,归巢抗体、蛋白质或受体分子用于将表达此类分子的经修饰的B细胞归巢/靶向至特定位置或组织中的炎性位点。在某些实施例中,归巢抗体、蛋白质或受体用于将B细胞靶向肿瘤或肿瘤微环境。在某些实施例中,将B细胞靶向至特定位置是令人期望的,使得本发明的经工程化或经修饰的B细胞可以将治疗性有效载荷递送到所期望的所关注位置,例如,归巢组织或靶组织、特定位置或组织中的炎性位点、或肿瘤或肿瘤微环境。因此,在某些实施例中,令人期望的是B细胞归巢至所关注位点/靶标,例如,肿瘤或肿瘤微环境,并且将有效载荷递送至所关注位点/靶标,所述有效载荷能够例如增加所关注位点/靶标(例如,在肿瘤中)处的交叉呈递树突状细胞(DC)的数量。
在各个实施例中,归巢抗体、蛋白质或受体作为DNA构建体在经修饰或经工程化的B细胞中表达。在各个实施例中,归巢抗体、蛋白质或受体作为DNA构建体在组成型地激活的转录途径的控制下在经修饰的B细胞中表达。在各个实施例中,涉及B细胞归巢/靶向的归巢抗体、蛋白质或受体不在B细胞中天然表达或者以比在B细胞中天然表达的水平高的水平表达。表4中阐述了根据本发明的使用特异性归巢受体/配体对将经修饰的B细胞示例性归巢至特异性归巢组织/靶组织。应当理解,尽管表4中阐述了示例性归巢组织、归巢受体和配体对,但本发明的经修饰的B细胞可以被工程化以表达任何归巢抗体、蛋白质或受体(例如,表5中所示的任何归巢受体),使得经修饰的B细胞可以定向到所关注的特异性位点/靶标。
表5
归巢组织类型 | 归巢受体 | 配体/趋化因子 |
肝脏 | CXCR6 | CXCL16 |
小肠 | CCR9 | CCL25 |
大肠(结肠) | CCR6 | CCL20 |
淋巴结 | CCR7 | CCL21 |
骨髓 | CXCR4 | CXCL12 |
派伊尔结 | CCR7和CXCR5 | 分别为CCL21和CXCL13 |
皮肤 | CCR4 | CCL17(22) |
用于本发明的特异性归巢受体/配体对的归巢(靶)组织类型的非排他性实例包含:皮肤、肠道(肠、结肠、肠系膜淋巴结(mLN)、派伊尔结(PP)、小肠)、肝脏、肺、骨髓、心脏、外周淋巴结(LN)、CNS、胸腺和骨髓。
可以与本发明的特异性或对应的引诱剂/配体/趋化因子配对的归巢受体的非排他性实例包含:CLA(PSGL-1糖型)、CLA(PSGL-1糖型)、CCR10、CCR3、CCR4、CCR5、CCR6、CCR9、CD43E、CD44、c-Met、CXCR3、CXCR4、LFA-1、LFA-1(αLβ2)、选择蛋白配体、VLA-4、VLA-4(α4β1)和α4β7。
可以与本发明的特异性或对应的归巢受体配对的配体/趋化因子的非排他性实例包含:CXCL16、CCL17、CCL17(22)、CCL20(MIP-3α)、CCL21、CCL25、CCL27、CCL28、CCL4、CCL5、CD62E、CD62P、CXCL10、CXCL12、CXCL13、CXCL16、CXCL9/CXCL10、CXCR3、E/P选择蛋白、E选择蛋白、GPR15L、HGF、透明质酸盐、ICAM-1、用于CCR1、2、5的配体、MAdCAM、MAdCAM-1、PNAd、VAP-1、VCAM和VCAM-1。
在本发明的某些实施例中,提供了一种经修饰的B细胞,其表达或具有增加的示例性B细胞归巢受体(例如,如表3所阐述)的表达,使得经修饰的B细胞靶向表达对应配体/趋化因子的对应的所关注归巢组织(例如,如表3和/或4所阐述)。在本发明的某些实施例中,提供了一种经修饰的B细胞,其与特异性α链和β链配对和特异性B细胞归巢受体(例如,如表3和/或4所阐述)共表达整联蛋白,所述整联蛋白和/或归巢受体的表达促使或促进经修饰的B细胞归巢/靶向至所关注位点/靶标。在一些实施例中,提供了一种经修饰的B细胞,其共表达α4β7整联蛋白和CCR9。令人期望的是,α4β7和CCR9的共表达将促进本发明的经修饰的B细胞的小肠归巢。在一些实施例中,提供了一种经修饰的B细胞,其共表达α4β1整联蛋白和CCR4。令人期望的是,α4β1和CCR4的共表达将促进本发明的经修饰的B细胞的小肠归巢。
表达免疫抑制分子的经修饰的B细胞.B细胞是许多自身免疫疾病的关键促成因素。然而,B细胞可以在治疗上用于拮抗自身免疫。具体地,B细胞可以被工程化以表达至少一个或多个免疫抑制分子,所述免疫抑制分子可以降低B细胞的自身免疫活性,从而导致自身免疫疾病减少。免疫抑制分子是本领域熟知的。此类抑制分子可以包含但不限于IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3。在本发明的某些实施例中,提供了一种经修饰的B细胞,其被工程化以表达选自以下的抑制分子中的至少一个或多个:IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3或其任何组合,使得位点处的炎症和定位于位点的B细胞的自身免疫活性降低,由此产生阳性治疗应答。
改变B细胞转运的化合物.在本发明的某些实施例中,提供了一种经修饰的B细胞,其用至少一种或多种化合物或其衍生物处理,所述至少一种或多种化合物或其衍生物通过诱导特异性B细胞整联蛋白和/或归巢受体的表达来改变B细胞的转运。改变B细胞转运的化合物或其衍生物是本领域熟知的。在某些实施例中,提供了一种经修饰的B细胞,其用全反式视黄酸(ATRA)或其衍生物处理,所述ATRA或其衍生物由于α4β7整联蛋白和CCR9归巢受体的表达增加而促进B细胞归巢至肠道(小肠)。如本文所使用的,术语“化合物”是指以所期望的方式改变B细胞转运的化学品、药物、治疗剂或其衍生物。
在本发明的各个实施例中,将工程化以共表达特异性整联蛋白(例如,具有特异性α链和β链配对)和所关注的特异性B细胞归巢受体的经修饰的B细胞用至少一种或多种化合物或其衍生物处理,所述化合物或其衍生物改变经修饰的B细胞的转运并且由于特异性整联蛋白和/或归巢受体的表达增加而促进细胞归巢至所关注的特异性位点/靶标。在各个实施例中,经修饰以与特异性α链和β链配对和特异性B细胞归巢受体共表达整联蛋白的B细胞进一步表达至少一个或多个免疫抑制分子,使得靶向特定炎症位点的经修饰的B细胞的自身免疫活性降低,从而导致自身免疫疾病减少。在一些实施例中,将工程化以表达一个或多个免疫抑制分子,例如IL-10、TGF-β、PD-L1、PD-L2、LAG-3和TIM-3或其组合的经修饰的B细胞用ATRA或其衍生物处理指定时间段,使得α4β7整联蛋白和CCR9归巢受体的表达被诱导以促进B细胞归巢至所关注的特异性位点/靶标(例如,肠道),但位点处的炎症和定位于位点的B细胞的自身免疫活性降低,从而产生阳性治疗应答。在一个实施例中,将工程化以表达一个或多个免疫抑制分子,例如IL-10、TGF-β或其组合的经修饰的B细胞用ATRA或其衍生物处理指定时间段,使得α4β7整联蛋白和CCR9归巢受体的表达被诱导以促进B细胞归巢至所关注的特异性位点/靶标(例如,肠道),但位点处的炎症和定位于位点的B细胞的自身免疫活性降低,从而产生阳性治疗应答。
应当理解,经修饰以共表达特异性B细胞整联蛋白和将B细胞靶向所关注的特定归巢组织/靶组织的归巢受体的本发明的任何B细胞可以被进一步工程化以表达一个或多个免疫抑制分子,用于减少定位于位点的B细胞的炎症和自身免疫活性,和/或用通过诱导特异性B细胞整联蛋白和/或归巢受体的表达而改变经修饰的B细胞的归巢/靶向的化合物处理。
用TLR激动剂和TLR激活B细胞.B细胞具有摄取和呈递由其特异性B细胞受体(BCR)识别的抗原的天然能力。由Toll样受体(TLR)激活的B细胞导致有效的效应B细胞在免疫应答中防御身体。TLR在B细胞中的表达或增加所述表达可以提供用于增强B细胞调节适应性免疫应答的先天信号的机制。
用TLR激动剂激活B细胞.在本发明的各个实施例中,提供了一种B细胞,其中所述B细胞用至少一种TLR激动剂体外或离体处理。在各个实施例中,TLR可以是TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和/或TLR13。在各个实施例中,TLR激动剂优先地与一种或多种选自由以下组成的组的TLR结合:TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和TLR13。TLR激动剂是本领域熟知的,并且可以包含但不限于富含CpG的寡核苷酸和双链RNA模拟物、聚肌苷酸:聚胞苷酸(poly-I:C)。在各个实施例中,TLR激动剂可以是CpG寡核苷酸。
在各个实施例中,每个B细胞可以用一种TLR激动剂处理。在各个实施例中,每个B细胞可以用多于一种TLR激动剂处理。例如,每个B细胞可以用1种、2种、3种、4种、5种、6种、7种、8种、9种、10种、11种或12种不同的TLR激动剂处理。可替代地,可以向患者施用B细胞的异质群体,每个B细胞用独特的TLR激动剂或TLR激动剂的组合处理。在一些实施例中,在向有需要的受试者或患者施用B细胞的同时或之前,将用作治疗剂的B细胞用一种或多种TLR激动剂处理。在某些实施例中,用一种或多种TLR激动剂进行的处理能够产生更有效的效应B细胞,以在免疫应答中防御身体。在某些实施例中,用一种或多种TLR激动剂进行的处理能够增强B细胞的免疫应答。在一些实施例中,用至少一种或多种TLR激动剂处理本发明的B细胞诱导一种或多种TLR的表达或激活。
用TLR表达激活B细胞.在本发明的各个实施例中,提供了能够表达组成型活性TLR的经修饰的B细胞。在各个实施例中,TLR作为DNA构建体在组成型激活的转录途径的控制下在经修饰或经工程化的B细胞中表达。在各个实施例中,TLR不在B细胞中天然表达或者以比在B细胞中天然表达的水平高的水平表达。在各个实施例中,TLR可以是TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12和/或TLR13。
在各个实施例中,每个B细胞可以表达多于一种组成型活性TLR。例如,每个B细胞可以表达1种、2种、3种、4种、5种、6种、7种、8种、9种、10种、11种、12种或13种不同的组成型活性TLR。可替代地,可以向患者施用B细胞的异质群体,每个B细胞能够表达和/或分泌独特的TLR或TLR的组合,所述TLR是组成型活性的。在各个实施例中,可以通过B细胞的异质群体向受试者或患者施用1种、2种、3种、4种、5种、6种、7种、8种、9种、10种、11种、12种或13种不同的组成型活性TLR。
在本发明的某些实施例中,B细胞是表达至少一种组成型活性TLR的经修饰的B细胞。在某些实施例中,用一种或多种TLR激动剂处理表达至少一种组成型活性TLR的经修饰的B细胞。在某些实施例中,组成型活性TLR的表达能够产生更有效的效应B细胞,以在免疫应答中防御身体。在某些实施例中,组成型活性TLR的表达能够增强B细胞的免疫应答。在某些实施例中,经修饰的B细胞表达组成型活性的TLR和本申请的任何CAR-B两者。在各个实施例中,在向有需要的受试者或患者施用经修饰的B细胞的同时或之前,用一种或多种TLR激动剂进一步处理表达组成型活性的TLR和/或CAR-B的经修饰的B细胞。在某些实施例中,B细胞可以被工程化以在不存在CAR-B的情况下表达有效载荷和修饰因子,如TLR,以进行瘤内施用。
在HLA I类和II类分子中同时呈递抗原的经修饰的B细胞.B细胞,除了其在抗体产生中的功能之外,还表达高水平的人白细胞抗原(HLA)II类分子并且可以抗原呈递至CD4+T细胞。Hong等人,2018,《免疫力(Immunity)》49,695–708。在本发明的各个实施例中,提供了一种经修饰的B细胞,其能够在HLA I类和II类分子两者中同时呈递特异性抗原和/或抗原衍生的所关注表位,如肿瘤抗原或传染病抗原。肿瘤抗原和传染病抗原是本领域熟知的,并且描述于前述部分中。在某些实施例中,所关注的特异性抗原,例如,肿瘤抗原或传染病抗原,与溶酶体蛋白的靶向信号融合,所述溶酶体蛋白将抗原靶向溶酶体并且在HLA I类和II类分子两者中同时且有效地呈递抗原。在一些实施例中,靶向信号是溶酶体相关膜蛋白-1(LAMP1)的靶向信号。在一些实施例中,靶向信号能够进入核内体再循环隔室。Clec9A的c末端序列是这种靶向部分。如本文所使用的,与靶向信号融合的特异性肿瘤抗原或传染病抗原是指用作治疗剂的氨基酸序列、编码肽或蛋白质的核酸序列、或RNA分子(例如,mRNA分子)。在一个实施例中,与靶向信号融合的特异性肿瘤抗原或传染病抗原是指用作治疗剂的mRNA分子。在某些实施例中,令人期望的是,与靶向信号(如LAMP1或Clec9A的靶向信号)融合的特异性肿瘤抗原和/或传染病抗原被靶向溶酶体或核内体,并且在HLA I类和II类分子两者中同时且有效地呈递。在某些实施例中,令人期望的是,在成熟之前或之后,用与靶向信号(如LAMP1或Clec9A的靶向信号)融合的编码所关注的特异性肿瘤抗原和/或传染病抗原的mRNA电穿孔B细胞(例如,人B细胞)能够在HLA I类和II类分子两者中同时且有效地呈递特异性抗原和/或抗原衍生的表位。在各个实施例中,所关注的特异性肿瘤抗原和/或传染病抗原不是由B细胞天然呈递的,不是由B细胞同时在HLA I类和II类分子两者中天然呈递的,或者不是由B细胞以高效率在HLA I类和II类分子两者中天然呈递的。设想的是,将此类电穿孔的B细胞引入到受试者(例如,人宿主)体内将通过在HLA I类和II类分子两者中同时且有效地呈递特异性抗原和/或抗原衍生的所关注表位来促进抗原特异性免疫应答的发展或增强抗原特异性免疫应答。
在各个实施例中,本发明涉及与靶向信号(如LAMP1的靶向信号)融合的编码至少一种所关注的特异性抗原(例如,肿瘤抗原或传染病抗原)的核酸序列(例如,mRNA序列),所述核酸序列用作B细胞电穿孔中的治疗剂,用于在HLA I类和II类分子两者中同时且有效地呈递特异性抗原和/或抗原衍生的表位。在各个实施例中,本发明涉及与靶向信号融合的编码多于一种(例如,1种、2种、3种、4种、5种或更多种)特异性肿瘤抗原和/或所关注的传染病抗原的核酸序列,例如,mRNA序列。在各个实施例中,本发明涉及不同核酸序列的池(例如,不同mRNA序列的池),用作如上所述的B细胞电穿孔中的治疗剂,其中每个池编码至少一种所关注的特异性抗原(例如,肿瘤抗原或传染病抗原),所述特异性抗原与不同于其它mRNA序列的池的靶向信号融合。因此,在一些实施例中,可以向受试者施用B细胞的同质群体,其中每个B细胞用与靶向信号融合的编码至少一种所关注的特异性抗原的mRNA电穿孔。在一些实施例中,可以向受试者施用B细胞的同质群体,其中每个B细胞用与靶向信号融合的编码多于一种所关注的特异性抗原的mRNA电穿孔。在一些实施例中,可以向受试者施用B细胞的异质群体,其中每个B细胞用mRNA的组合电穿孔,每个mRNA编码与不同靶向信号融合的至少一种所关注的特异性抗原。
在一些实施例中,如上所述的用于电穿孔的B细胞可以是本申请的任何经修饰的B细胞。在一些实施例中,经修饰的B细胞包括B细胞的嵌合抗原受体(CAR-B)。在各个实施例中,经修饰的B细胞可以表达CAR-B并且在HLA I类和II类分子两者中同时且有效地呈递所关注的特异性抗原和/或抗原衍生的表位。
在各个实施例中,本发明涉及一种向有需要的患者施用分离的B细胞的方法。在各个实施例中,可以向患者施用B细胞的群体。在各个实施例中,每个B细胞可以表达多于一个有效载荷肽或蛋白质。例如,每个B细胞可以表达1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个不同的有效载荷。可替代地,可以向患者施用B细胞的异质群体,每个B细胞能够表达和/或分泌独特的有效载荷或有效载荷的组合。在各个实施例中,可以通过B细胞的异质群体向患者施用1个、2个、3个、4个、5个、6个、7个、8个、9个、10个、11个或12个不同的有效载荷。
IV.治疗方法
在本发明的各个方面,经扩增的B细胞群体将作为治疗剂递送到有需要的患者。在各个实施例中,经扩增的B细胞群体将能够治疗或预防各种疾病或病症,包含癌症。
在一些实施例中,本发明涉及在受试者体内产生B细胞介导的免疫应答,包括向受试者施用有效量的本申请的经扩增的和/或经工程化的B细胞。在一些实施例中,B细胞介导的免疫应答针对一个或多个靶细胞。在一些实施例中,经工程化的免疫细胞包括B细胞的嵌合抗原受体(B-CAR)。在一些实施例中,靶细胞是肿瘤细胞。在一些方面,本发明包括一种用于治疗或预防恶性肿瘤的方法,所述方法包括向有需要的受试者施用有效量的至少一种本文所描述的分离的抗原结合分子。在一些方面,本发明包括治疗或预防恶性肿瘤的方法,所述方法包括向有需要的受试者施用有效量的至少一个免疫细胞,其中所述免疫细胞包括至少一种嵌合抗原受体。
在一些方面,本发明包括一种药物组合物,所述药物组合物包括经扩增的工程化B细胞群体,所述细胞群体包括至少一种如本文所描述的抗原结合分子和药学上可接受的赋形剂。在一些实施例中,所述药物组合物进一步包括另外的活性剂。
在一些实施例中,受试者被诊断患有局限于肝脏的转移性疾病。在其它实施例中,转移性疾病是癌症。在仍其它实施例中,癌症从乳房、结肠、直肠、食道、肺、胰腺和/或胃中的原发性肿瘤转移。在仍其它实施例中,受试者被诊断为患有不可切除的转移性肝肿瘤。在又其它实施例中,受试者被诊断为患有来自原发性结直肠癌的不可切除的转移性肝肿瘤。在一些实施例中,受试者被诊断为患有肝细胞癌。
应当理解,经修饰的B细胞的靶剂量的范围可以优选地为1×106-2×1010个细胞/kg,更优选地为2×106个细胞/kg。应当理解,高于和低于此范围的剂量可能适用于某些受试者,并且适当的剂量水平可以由医疗保健提供者根据需要确定。另外,可以根据本发明提供多剂量的细胞。
还提供了用于减小受试者的肿瘤大小的方法,所述方法包括向受试者施用本发明的经修饰的B细胞,其中所述细胞包括CAR-B受体,所述CAR-B受体包括与肿瘤上的抗原、有效载荷或CAR-B和有效载荷两者结合的抗原结合结构域。在一些实施例中,受试者患有实体瘤或血液恶性肿瘤,如淋巴瘤或白血病。在一些实施例中,将经修饰的B细胞递送到肿瘤床。在一些实施例中,癌症存在于受试者的骨髓中。
还提供了用于将B细胞归巢至受试者体内的所关注位点/靶标的方法,所述方法包括向受试者施用本发明的经修饰的B细胞,其中所述细胞包括在所关注位点/靶标处被吸引到配体、趋化因子或引诱剂的整联蛋白、归巢抗体、蛋白质或受体。在一些实施例中,所关注位点/靶标是例如归巢组织或靶组织、特定位置或组织中的炎性位点、或肿瘤或肿瘤微环境,其中治疗性有效载荷的递送是令人期望的。
还提供了用于减少受试者体内的所关注位点/靶标处的B细胞的炎症和自身免疫活性的方法,所述方法包括向受试者施用本发明的经修饰的B细胞,其中所述细胞包括免疫抑制分子。在一些实施例中,所关注位点/靶标是例如归巢组织或靶组织、特定位置或组织中的炎性位点、或肿瘤或肿瘤微环境,其中治疗性有效载荷的递送是令人期望的。
在一些实施例中,经扩增的工程化B细胞群体是自体B细胞。在一些实施例中,经修饰的B细胞是同种异体B细胞。在一些实施例中,经修饰的B细胞是异源B细胞。在一些实施例中,本申请的经修饰的B细胞在体内转染或转导。在其它实施例中,经工程化的细胞离体转染或转导。
如本文所使用的,术语“受试者”或“患者”是指个体。在一些方面,受试者是哺乳动物,如人。在一些方面,受试者可以是非人灵长类动物。非人灵长类动物包含狨猴、猴、黑猩猩、大猩猩、猩猩和长臂猿,仅举几例。术语“受试者”还包含家养动物,如猫、狗等;家畜(例如,美洲驼、马、牛);野生动物(例如,鹿、麋鹿、驼鹿等);实验室动物(例如,小鼠、兔、大鼠、沙鼠、豚鼠等);以及禽类(例如,鸡、火鸡、鸭等)。优选地,受试者是人受试者。更优选地,受试者是人患者。
在某些实施例中,包括本文所公开的表达CAR的免疫效应细胞的组合物可以与任何数量的化疗剂联合施用。化疗剂的实例包含:烷化剂,如噻替哌和环磷酰胺(CYTOXANTM);烷基磺酸盐,如白消安、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮杂环丙烷,如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和乌瑞替哌(uredopa);亚乙基亚胺和甲基胺类(methylamelamines),包含六甲蜜胺、曲他胺、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)和三羟甲密胺(trimethylolomelamine resume);氮芥类(nitrogen mustard),如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌氮芥(cholophosphamide)、依弗酰胺(ifosfamide)、氮芥(mechlorethamine)、盐酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲(nitrosurea),如卡莫司汀(carmustine)、氯脲霉素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,如阿克拉霉素(aclacinomysins)、放线菌素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycin)、放线菌素C(cactinomycin)、卡奇霉素(calicheamicin)、卡拉比星(carabicin)、洋红霉素(carminomycin)、嗜癌菌素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-二氮-5-氧代-L-正亮氨酸、阿霉素(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、去甲氧基柔红霉素(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素(mitomycin)、菌酚酸(mycophenolic acid)、诺加霉素(nogalamycin)、橄榄霉素(olivomycin)、培洛霉素(peplomycin)、泊非霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(que-lamycin)、罗多比星(rodorubicin)、链黑菌素(streptonigrin)、链脲菌素(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,如甲氨蝶呤和5-氟脲嘧啶(5-FU);叶酸类似物,如二甲叶酸(denopterin)、甲氨蝶呤、蝶罗呤、三甲曲沙(trimetrexate);嘌呤类似物,如氟达拉滨、6-巯基嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,如安西他滨(ancitabine)、阿扎胞苷、6-氮杂尿苷、卡莫氟(carmofur)、阿糖胞苷、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷、5-FU;雄激素类,如卡普睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类,如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂,如亚叶酸;醋葡醛内酯;醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);安吖啶(amsacrine);百垂布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elformithine);依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基酰肼;丙卡巴肼;雷佐生(razoxane);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三环乙亚胺醌(triaziquone);2,2',2”-三氯三乙胺;乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);盖克托辛(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派;紫杉烷,例如紫杉醇(/>百时美施贵宝(Bristol-Myers Squibb))和多西紫杉醇(/>罗纳普朗克乐安(Rhone-Poulenc Rorer));苯丁酸氮芥(chlorambucil);吉西他滨(gemcitabine);6-硫鸟嘌呤;巯基嘌呤;甲氨蝶呤;铂类似物,如顺铂和卡铂;长春碱;铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);丝裂霉素C;米托蒽醌;长春新碱;长春瑞宾(vinorelbine);诺维本(navelbine);诺安托(novantrone);替尼泊苷(teniposide);道诺霉素(daunomycin);氨蝶呤;希罗达(xeloda);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);视黄酸衍生物,如TARGRETINTM(贝沙罗汀(bexarotene))、PANRETINTM(阿利维A酸);ONTAKTM(地尼白介素-毒素连接物(denileukin diftitox));埃斯波霉素(esperamicin);卡培他滨(capecitabine);以及以上药物中的任何药物的药学上可接受的盐、酸或衍生物。此定义还包含用于调节或抑制对肿瘤的激素作用的抗激素剂,如:抗雌激素类,包含例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)、芳香酶抑制4(5)-咪唑、4-羟基他莫西芬、曲沃昔芬(trioxifene)、雷洛西芬(keoxifene)、LY117018、奥那司酮(onapristone)和托瑞米芬(toremifene)(法乐通(Fareston));和抗雄激素类,如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;以及以上药物中的任何药物的药学上可接受的盐、酸或衍生物。在适当的情况下,还可以施用化疗剂的组合,包含但不限于CHOP,即,环磷酰胺/>阿霉素(羟基多柔比星)、氟达拉滨、长春新碱/>和泼尼松(Prednisone)。
多种另外的治疗剂可以与本文所描述的组合物结合使用。例如,潜在有用的另外的治疗剂包含PD-1(或PD-L1)抑制剂,如纳武单抗(nivolumab)派姆单抗(pembrolizumab)/>派姆单抗、皮地利珠单抗(pidilizumab)和阿特珠单抗(atezolizumab)/>
适于与本发明组合使用的另外的治疗剂包含但不限于依鲁替尼(ibrutinib)奥法木单抗(ofatumumab)/>利妥昔单抗(rituximab)贝伐珠单抗(bevacizumab)/>曲妥珠单抗(trastuzumab)/>曲妥珠单抗美坦新偶联物(trastuzumab emtansine)/>伊马替尼(imatinib)/>西妥昔单抗(cetuximab)/>帕尼单抗(panitumumab)/>卡妥索单抗(catumaxomab)、替伊莫单抗(ibritumomab)、奥法木单抗、托西莫单抗(tositumomab)、本妥昔单抗(brentuximab)、阿仑单抗(alemtuzumab)、吉妥珠单抗(gemtuzumab)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、来那替尼(neratinib)、阿昔替尼(axitinib)、马赛替尼(masitinib)、帕唑帕尼(pazopanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、托西尼布(toceranib)、来他替尼(lestaurtinib)、阿昔替尼(axitinib)、西地尼布(cediranib)、乐伐替尼(lenvatinib)、尼达尼布(nintedanib)、帕唑帕尼、瑞戈非尼(regorafenib)、司马沙尼(semaxanib)、索拉非尼(sorafenib)、舒尼替尼、替沃扎尼(tivozanib)、托西尼布(toceranib)、凡德他尼、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊马替尼、达沙替尼(dasatinib)、尼罗替尼(nilotinib)、帕纳替尼(ponatinib)、拉多替尼(radotinib)、博舒替尼(bosutinib)、来他替尼、鲁索替尼(ruxolitinib)、帕克替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、比美替尼(binimetinib)、艾乐替尼(alectinib)、色瑞替尼(ceritinib)、克唑替尼(crizotinib)、阿柏西普(aflibercept)、adipotide、地尼白介素-毒素连接物、mTOR抑制剂,如依维莫司(Everolimus)和西罗莫司(Temsirolimus)、刺猬抑制剂,如索尼德吉(sonidegib)和维莫德吉(vismodegib)、CDK抑制剂,如CDK抑制剂(帕博西尼(palbociclib))。
在另外的实施例中,包括含有CAR的免疫的组合物可以与抗炎剂一起施用。抗炎剂或药物包含但不限于类固醇和糖皮质激素(包含倍他米松、布地奈德、地塞米松、醋酸氢化可的松、氢化可的松、氢化可的松、甲基强的松龙、泼尼松龙、泼尼松、曲安奈德)、包含阿司匹林的非甾体类抗炎药(NSAIDS)、布洛芬、萘普生、甲氨蝶呤、柳氮磺胺吡啶、来氟米特、抗TNF药物、环磷酰胺和霉酚酸酯。示例性NSAID包含布洛芬、萘普生、萘普生钠、Cox-2抑制剂和唾液酸化物(sialylate)。示例性镇痛药包含对乙酰氨基酚、羟考酮、盐酸丙氧芬的曲马多。示例性糖皮质激素包含可的松、地塞米松、氢化可的松、甲基强的松龙、泼尼松龙或泼尼松。示例性生物应答调节剂包含针对细胞表面标志物(例如,CD4、CD5等)的分子、细胞因子抑制剂如TNF拮抗剂(例如,依那西普(etanercept)阿达木单抗和英利昔单抗(infliximab)/>趋化因子抑制剂和粘附分子抑制剂。生物应答调节剂包含单克隆抗体以及重组形式的分子。示例性DMARD包含硫唑嘌呤、环磷酰胺、环孢菌素、甲氨蝶呤、青霉胺、来氟米特、柳氮磺胺吡啶、羟氯喹、金(口服(金诺芬)和肌内)和米诺环素。
在某些实施例中,本文所描述的组合物与细胞因子结合施用。如本文所使用的,“细胞因子”意指由一种细胞群体释放的蛋白质,所述细胞群作用于另一个作为细胞间介质的细胞。细胞因子的实例是淋巴因子、单核因子和传统的多肽激素。细胞因子中包含生长激素,如人生长激素、N-甲硫氨酰基人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛激素;松弛素原;糖蛋白激素,如促卵泡激素(FSH)、促甲状腺激素(TSH)和促黄体激素(LH);肝细胞生长因子(HGF);成纤维细胞生长因子(FGF);催乳素;胎盘催乳素;副中肾管抑制物质;小鼠促性腺激素相关肽;抑制素;激活素;血管内皮生长因子;整联蛋白;血小板生成素(TPO);神经生长因子(NGF),如NGF-β;血小板生长因子;转化生长因子(TGF),如TGF-α和TGF-β;胰岛素样生长因子I和胰岛素样生长因子II;促红细胞产生素(EPO);骨诱导因子;干扰素,如干扰素α、干扰素β和干扰素γ;集落刺激因子(CSF),如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);以及粒细胞-CSF(G-CSF);白介素(IL),如IL-1、IL-lα、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12;IL-15,一种肿瘤坏死因子,如TNF-α或TNF-β;以及包含LIF和试剂盒配体(KL)的其它多肽因子。如本文所使用的,术语细胞因子包含来自天然来源或来自重组细胞培养物的蛋白质以及天然序列细胞因子的生物活性等效物。
实例
尽管上文所描述的发明已经出于清楚理解的目的通过说明和举例的方式进行了一些详细描述,但是根据本发明的教导,对于本领域普通技术人员而言应当容易了解到,可以在不偏离随附权利要求书的精神或范围的情况下对本发明进行某些改变和修改。仅通过说明的方式而不是通过限制的方式提供以下实例。本领域技术人员将容易认识到可以被改变或修改以产生本质上类似的结果的各种非关键参数。
实例1:人B细胞的纯化和富集
根据以下方案从PBMC中收集和富集人B细胞。如下从血沉棕黄层制备PBMC。将每供体(大约25ml)体积用PBS升高到120ml。接下来,在四个50ml管中将30ml分层到15ml的Ficoll上。这然后以450g旋转20分钟。然后去除并丢弃上层。然后分离第一层正下方的PBMC界面(嗜中性粒细胞密度最大,并且数量向层底部增加)。从每个供体取出4个管中的每个管的接口,并且转移到两个50ml锥形管中。使用PBS将每个管升高到每管50ml。然后将两个管中的每一个在500g下旋转5分钟。
通过抽吸沉淀物并且使针对ACK裂解缓冲液的两种沉淀物组合的总体积达到10ml来进行RBC裂解。然后将溶液在室温下保持五分钟。接下来,添加40ml PBS,将溶液混合,并且然后以500g离心,持续5分钟。然后在PBS中使此混合物达到40ml体积,以计算PBMC的产量。每个B细胞富集制剂使用1.5亿个PBMC。
根据用于人B细胞的产品ID 17954纯化的说明(干细胞技术公司(Stem Cell Technologies))进行B细胞的富集。将溶液离心,并且将1.5亿个PBMC重悬于3ml/>分离缓冲液中。将沉淀物重悬于15ml管中的3ml/>缓冲液中。添加150μl的混合物增强剂。添加150μl分离混合物,并且将管混合并在室温下温育5分钟。将快速球体涡旋30秒,并且将150μl添加管中,并且然后混合,并且移动至磁体中。3分钟之后,将其倒入新管中,并且重复磁体步骤。
实例2:使用HELA-CD40L饲养细胞或MEGA-CD40L扩增B细胞
由于人外周血中的B细胞的低频率,很难获得足够数量的B细胞用于临床细胞疗法目的。因此,B细胞扩增是制备临床级B细胞的重要步骤。人B细胞的生长需要CD40L。已经证实,如果在表达CD40L的单层HEL细胞上生长,B细胞可以存活和扩增。然而,有必要建立不依赖于饲养细胞的B细胞生长方法。为了确定是否存在用于此目的的可商购获得的工具或试剂,与HELA-CD40L饲养细胞上进行的生长比较之下,对Enzo MEGA-CD40L进行了测试。
HeLa-CD40L饲养细胞的生长培养基条件.饲养细胞板通过在24孔板上以每板5×106个照射CD40L HeLa细胞来制备。基础培养基包含RPMI-1640+10% FCS;Penn/strep(100u/ml,100ug/ml);亚硒酸钠(100nM);以及IL-4(2ng/ml)(R&D 204-IL)。在铺板B细胞之前,允许饲养细胞生长至少24小时。
含有MEGA-CD40L的生长培养基条件.培养基条件与上文相同,除了没有饲养细胞。而是,将B细胞铺板在包括RPMI-1640+10% FCS;Penn/strep(100u/ml,100ug/ml);亚硒酸钠(100nM);IL-4(2ng/ml)(R&D 204-IL);以及MEGA-CD40L(100ng/ml)的培养基中。
HeLa-CD40L和MEGA-CD40L条件下的B细胞生长速率在图1中描绘。此研究证明,人B细胞可以在含有HELA-CD40L饲养细胞的培养基中生长和扩增,但在存在MEGA-CD40L的情况下不扩增。
纯化的B细胞在第0天以大约10,000个细胞/ml的等效密度开始,并且在HELA-CD40L饲养细胞上生长。在第4天,将培养物分成两组,并且一组继续在含有HELA-CD40L饲养细胞的相同培养基中生长,而另一组在补充有MEGA-CD40L(0.1μg/mL)但没有HELA饲养细胞的培养基中生长。在第8天,将另外的100ng/mL MEGA-CD40L添加到MEGA-CD40L条件下的生长培养基中。图1中的箭头指示MEGA-CD40L处理发生的时间。
数据表明,当在HELA-CD40L饲养细胞上生长时,B细胞到第11天有显著的增殖,但是如果用MEGA-CD40L生长,在第11天没有观察到显著的生长。
实例3:在不使用饲养细胞的情况下扩增B细胞
在此实例中,B细胞在不存在HELA-CD40L表达性饲养细胞的情况下被扩增。将B细胞铺板在包括IL-4(5μg;5000IU/μg溶解于100μL H2O中以获得2.5×105IU/ml);CD40L(SEQID NO:140,500μg重悬于500μL);CD40L交联抗体(SEQ ID NO:143和144);人AB血清(IC092938249 VWR);以及10μL青霉素链霉素的扩增培养基中。B细胞以(i)100,000至150,000/ml;或(ii)1,000,000/mL的密度铺板并且扩增至少15天,每七天补充新鲜培养基。
维持在100,000至150,000个细胞/mL密度的细胞能够在两周内扩增超过200倍;而维持在1,000,000个细胞/ml密度的细胞显示出显著更少的细胞生长。参见图2。
实例4:经扩增的B细胞的工程化
使用腺病毒载体对经扩增的人B细胞进行工程化以表达各种嵌合受体。首先使用实例1和3中描述的技术纯化、富集和扩增B细胞。B细胞在实例3的扩增培养基中培养10天,并且然后用表6中列出的腺病毒转导。
表6
然后使用如本文所描述的B细胞扩增培养基体外培养包括B细胞的Ad5腺病毒,持续10天。然后按照以下方案用腺病毒转导经扩增的B细胞。
B细胞生长10天,并且达到大约1400万个细胞的产量。测试了若干种编码人BCR的腺病毒F35病毒构建体。一个实例如下。使用编码GPC3特异性BCR的腺病毒。还使用腺病毒空载体对照。也没有使用病毒模拟对照。
在以下条件下,将20μl 109/ml病毒颗粒添加到50万个B细胞中:
将B细胞铺板在24孔板上的200μl含有0.2% BSA和CD40L+Xlinker(美天旎公司产品编号130-098-775,具有与上文所概述的扩增培养基中所描述的相同的浓度)、IL-4(如扩增培养基中所描述)和0.5μg/ml凝聚胺的中。添加病毒之后,将板以1100g离心,持续1小时,然后转移到培养箱中,持续2.5小时,并且给予2mL新鲜的扩增培养基。3天之后,细胞用GPC3-BV染色以检测表达BCR的B细胞。结果如图2A-2C所阐述,并且显示转导后72小时,至少67%的细胞表达GPC3 BCR。
实例5:Ad5RGD-GFP在人B细胞中的表达
来自PBMC的B细胞在培养基中生长10天。用编码GFP的Ad5-RGD构建体转导B细胞,并且置于含有0.2% BSA、CD40L+Xlinker、5%人AB血清和IL-4的中。然后添加病毒,并且以1100g离心,持续1小时,然后在37℃下温育3小时。然后将培养基转换成正常人B细胞生长培养基,直到进行分析。
GFP多个时间点的表达检测结果如下:
72 | 120 | 144 | 192 | 240 |
为了解决病毒对细胞活力的影响,在第6天、第8天和第10天通过和FACS测试总细胞计数和GFP阳性计数的分数。结果如图4所阐述。Ad5-RGD修饰的GFP转导导致B细胞中的高效GFP表达。大约60%的总B细胞的表达维持至少10天。经转导的B细胞在转导后继续增殖,持续至少一周。
实例6:通过用腺病毒进行的转导得到鼠BCR构建体或IL-10在人B细胞中的表达
源自PBMC的B细胞在培养基中生长10天。然后用编码鼠IL-10的Ad5-RGD构建体或若干种形式的鼠BCR转导B细胞。(在等待人类形式时使用鼠类)。然后在包括含0.2% BSA、CD40L+Xlinker、5%人AB血清和IL-4的的条件下培养B细胞。添加病毒并以1100g离心,持续1小时,然后在37℃下温育3小时,然后转换成正常人B细胞生长培养基,直到进行分析。以两种比率(20μl:50万个B细胞和2μl:50万个B细胞)测试病毒。
在转导后96小时,即第4天进行表达测试。在-80℃下储存IL-10上清液。通过与人GPC3-BV结合检测GPC3构建体。通过与FITC strep标签结合检测肌聚糖构建体。图5至9中阐述了结果。
实例7:监测通过腺病毒递送后人BCR在人B细胞中的体内归巢和表达
来自PBMC的B细胞在培养基中生长10天。然后用编码荧光素酶+/-GPC3-BCR的Ad5f35构建体转导B细胞。PWF-524/PWWF-684(Luc+GPC3 CAR)和PWF-684(Luc)被转导,并且然后在Wennhold培养基中培养过夜,以便有时间表达BCR和Luc。此后,将大约90万个细胞IV递送到患有HEPG2肿瘤的小鼠。通过生物发光监测Luc。
数据在图10中示出,所述图示出了GPC3 CAR(524)使人B细胞到携带HEPG2肿瘤的SHORN小鼠的TDLN的归巢富集了100倍。具体地,SHORN小鼠缺乏T细胞、B细胞和NK细胞,这使得人B细胞不会被排斥。相对于肺部,在TDLN中发现了100倍的富集。在肺中观察到2-5倍高的信号,这可能是由于HEPG2转移。图10示出了经工程化的GPC3 CARS可以帮助指导B细胞归巢到发炎的淋巴器官。
序列表
<110> 步行鱼治疗学股份有限公司(WALKING FISH THERAPEUTICS, INC.)
<120> 用于细胞疗法的B细胞扩增方法
<130> 109036-0060
<140> 尚未指定
<141> 与此同时
<150> US 63/176,463
<151> 2021-04-19
<160> 142
<170> PatentIn 3.5版
<210> 1
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 1
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagaagat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 2
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 2
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagaggat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 3
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 3
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggctg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 4
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 4
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagatttgt attcatgaaa acgatacaga gatgcaacac aggagaaaga tccttatcct 240
tactgaactg tgaggagatt aaaagccagt ttgaaggctt tgtgaaggat ataatgttaa 300
acaaagagga gacgaagaaa gaaaacagct ttgaaatgca aaaaggtgat cagaatcctc 360
aaattgcggc acatgtcata agtgaggcca gcagtaaaac aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 5
<211> 784
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 5
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatagag atgcaacaca ggagaaagat ccttatcctt 240
actgaactgt gaggagatta aaagccagtt tgaaggcttt gtgaaggata taatgttaaa 300
caaagaggag acgaagaaag aaaacagctt tgaaatgcaa aaaggtgatc agaatcctca 360
aattgcggca catgtcataa gtgaggccag cagtaaaaca acatctgtgt tacagtgggc 420
tgaaaaagga tactacacca tgagcaacaa cttggtaacc ctggaaaatg ggaaacagct 480
gaccgttaaa agacaaggac tctattatat ctatgcccaa gtcaccttct gttccaatcg 540
ggaagcttcg agtcaagctc catttatagc cagcctctgc ctaaagtccc ccggtagatt 600
cgagagaatc ttactcagag ctgcaaatac ccacagttcc gccaaacctt gcgggcaaca 660
atccattcac ttgggaggag tatttgaatt gcaaccaggt gcttcggtgt ttgtcaatgt 720
gactgatcca agccaagtga gccatggcac tggcttcacg tcctttggct tactcaaact 780
ctga 784
<210> 6
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 6
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgaaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 7
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 7
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgagaagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 8
<211> 775
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 8
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacgaagaaa gaaaacagct ttgaaatgca aaaaggtgat cagaatcctc aaattgcggc 360
acatgtcata agtgaggcca gcagtaaaac aacatctgtg ttacagtggg ctgaaaaagg 420
atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc tgaccgttaa 480
aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc gggaagcttc 540
gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat tcgagagaat 600
cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac aatccattca 660
cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg tgactgatcc 720
aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac tctga 775
<210> 9
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 9
atgatcgaaa catacaacca aacttctccc tgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 10
<211> 782
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 10
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa aacagctttg aaatgcaaaa aggtgatcag aatcctcaaa 360
ttgcggcaca tgtcataagt gaggccagca gtaaaacaac atctgtgtta cagtgggctg 420
aaaaaggata ctacaccatg agcaacaact tggtaaccct ggaaaatggg aaacagctga 480
ccgttaaaag acaaggactc tattatatct atgcccaagt caccttctgt tccaatcggg 540
aagcttcgag tcaagctcca tttatagcca gcctctgcct aaagtccccc ggtagattcg 600
agagaatctt actcagagct gcaaataccc acagttccgc caaaccttgc gggcaacaat 660
ccattcactt gggaggagta tttgaattgc aaccaggtgc ttcggtgttt gtcaatgtga 720
ctgatccaag ccaagtgagc catggcactg gcttcacgtc ctttggctta ctcaaactct 780
ga 782
<210> 11
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 11
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacaga tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 12
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 12
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgagg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 13
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 13
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgtgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 14
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 14
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg catatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 15
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 15
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcgt aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 16
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 16
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagagaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 17
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 17
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtggggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 18
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 18
atgatcgaaa catacaacca aacttctccc cgatctgtgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 19
<211> 783
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 19
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa catctgtgtt acagtgggct 420
gaaaaaggat actacaccat gagcaacaac ttggtaaccc tggaaaatgg gaaacagctg 480
accgttaaaa gacaaggact ctattatatc tatgcccaag tcaccttctg ttccaatcgg 540
gaagcttcga gtcaagctcc atttatagcc agcctctgcc taaagtcccc cggtagattc 600
gagagaatct tactcagagc tgcaaatacc cacagttccg ccaaaccttg cgggcaacaa 660
tccattcact tgggaggagt atttgaattg caaccaggtg cttcggtgtt tgtcaatgtg 720
actgatccaa gccaagtgag ccatggcact ggcttcacgt cctttggctt actcaaactc 780
tga 783
<210> 20
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 20
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagggg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 21
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 21
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtag 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 22
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 22
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
cctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 23
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 23
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaacg gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 24
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 24
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag aatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 25
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 25
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacaa catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 26
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 26
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa cccaggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 27
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 27
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccccggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 28
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 28
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaaagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 29
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 29
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctgttat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 30
<211> 783
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 30
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctatatc tatgcccaag tcaccttctg ttccaatcgg 540
gaagcttcga gtcaagctcc atttatagcc agcctctgcc taaagtcccc cggtagattc 600
gagagaatct tactcagagc tgcaaatacc cacagttccg ccaaaccttg cgggcaacaa 660
tccattcact tgggaggagt atttgaattg caaccaggtg cttcggtgtt tgtcaatgtg 720
actgatccaa gccaagtgag ccatggcact ggcttcacgt cctttggctt actcaaactc 780
tga 783
<210> 31
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 31
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgcct aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 32
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 32
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
caggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 33
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 33
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
ccggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 34
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 34
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaact ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 35
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 35
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccctggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 36
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 36
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat aaccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 37
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 37
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacattc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 38
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 38
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcaggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 39
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 39
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggtaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 40
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 40
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
taatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 41
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 41
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgagagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 42
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 42
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagt agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 43
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 43
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtgtttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 44
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 44
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatctgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 45
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 45
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtccttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 46
<211> 784
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 46
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcagt 720
gactgatcca agccaagtga gccatggcac tggcttcacg tcctttggct tactcaaact 780
ctga 784
<210> 47
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 47
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca agtcctttgg cttactcaaa 780
ctctga 786
<210> 48
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 48
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca tgtcctttgg cttactcaaa 780
ctctga 786
<210> 49
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 49
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctctgg cttactcaaa 780
ctctga 786
<210> 50
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 50
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg ctcactcaaa 780
ctctga 786
<210> 51
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 51
atgatcaaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 52
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 52
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt gcttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 53
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 53
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagataat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 54
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 54
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tggatcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 55
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 55
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgatcttcat agaaggttgg acaagataga agatgaaagg aatcttcatg 180
aagattttgt attcatgaaa acgatacaga gatgcaacac aggagaaaga tccttatcct 240
tactgaactg tgaggagatt aaaagccagt ttgaaggctt tgtgaaggat ataatgttaa 300
acaaagagga gacgaagaaa gaaaacagct ttgaaatgca aaaaggtgat cagaatcctc 360
aaattgcggc acatgtcata agtgaggcca gcagtaaaac aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 56
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 56
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag acccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 57
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 57
atgatcgaaa catacaacca aacttttccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 58
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 58
atgatcgaaa catacaacca aacttctccc caatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 59
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 59
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatctc 360
aaattgcggc acatgtcata agtgaggcca gcagtaaaac aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 60
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 60
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcag cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 61
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 61
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacagtcata agtgaggcca gcagtaaaac aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 62
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 62
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagcgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 63
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 63
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgagcca gcagtaaaac aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 64
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 64
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa aacatctgtg ttacagtggg 420
ctgaaaaagg atactacacc atgagcaaca acttggtaac cctggaaaat gggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 65
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 65
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagcgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 66
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 66
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaaa gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 67
<211> 785
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 67
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tggaaacagc 480
tgaccgttaa aagacaagga ctctattata tctatgccca agtcaccttc tgttccaatc 540
gggaagcttc gagtcaagct ccatttatag ccagcctctg cctaaagtcc cccggtagat 600
tcgagagaat cttactcaga gctgcaaata cccacagttc cgccaaacct tgcgggcaac 660
aatccattca cttgggagga gtatttgaat tgcaaccagg tgcttcggtg tttgtcaatg 720
tgactgatcc aagccaagtg agccatggca ctggcttcac gtcctttggc ttactcaaac 780
tctga 785
<210> 68
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 68
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccatta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 69
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 69
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atccatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 70
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 70
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagcta cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 71
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 71
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt tgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 72
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 72
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagttaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 73
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 73
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tgcatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 74
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 74
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccagtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 75
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 75
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ctcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 76
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 76
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagacaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 77
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 77
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgtaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 78
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 78
atgattgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 79
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 79
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgctttggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 80
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 80
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttatca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttga cttactcaaa 780
ctctga 786
<210> 81
<211> 786
<212> DNA
<213> 人工序列
<220>
<223> 合成
<400> 81
atgatcgaaa catacaacca aacttctccc cgatctgcgg ccactggact gcccatcagc 60
atgaaaattt ttatgtattt acttactgtt tttcttaaca cccagatgat tgggtcagca 120
ctttttgctg tgtatcttca tagaaggttg gacaagatag aagatgaaag gaatcttcat 180
gaagattttg tattcatgaa aacgatacag agatgcaaca caggagaaag atccttatcc 240
ttactgaact gtgaggagat taaaagccag tttgaaggct ttgtgaagga tataatgtta 300
aacaaagagg agacgaagaa agaaaacagc tttgaaatgc aaaaaggtga tcagaatcct 360
caaattgcgg cacatgtcat aagtgaggcc agcagtaaaa caacatctgt gttacagtgg 420
gctgaaaaag gatactacac catgagcaac aacttggtaa ccctggaaaa tgggaaacag 480
ctgaccgtta aaagacaagg actctattat atctatgccc aagtcacctt ctgttccaat 540
cgggaagctt cgagtcaagc tccatttata gccagcctct gcctaaagtc ccccggtaga 600
ttcgagagaa tcttactcag agctgcaaat acccacagtt ccgccaaacc ttgcgggcaa 660
caatccattc acttgggagg agtatttgaa ttgcaaccag gtgcttcggt gtttgtcaat 720
gtgactgatc caagccaagt gagccatggc actggcttca cgtcctttgg cttactcaaa 780
ctctga 786
<210> 82
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 82
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 83
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 83
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Arg Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 84
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 84
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 85
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 85
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Lys Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 86
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 86
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Lys Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 87
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 87
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Arg Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 88
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 88
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Glu Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 89
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 89
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Val Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 90
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 90
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala Tyr Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 91
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 91
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Val Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 92
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 92
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Arg
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 93
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 93
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Gly Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 94
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 94
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Val Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 95
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 95
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Gly Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 96
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 96
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Pro Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 97
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 97
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Asn Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 98
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 98
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Glu
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 99
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 99
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Asn Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 100
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 100
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Gln Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 101
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 101
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Pro Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 102
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 102
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Cys Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 103
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 103
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Gln Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 104
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 104
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Pro Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 105
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 105
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 106
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 106
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Asn His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 107
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 107
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Arg Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 108
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 108
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Arg Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 109
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 109
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Val Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 110
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 110
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 111
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 111
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Ser Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 112
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 112
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Pro Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 113
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 113
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Lys Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 114
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 114
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Met Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 115
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 115
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Ser
245 250 255
Gly Leu Leu Lys Leu
260
<210> 116
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 116
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Ser Leu Lys Leu
260
<210> 117
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 117
Met Ile Lys Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 118
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 118
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 119
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 119
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Ile Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 120
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 120
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 121
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 121
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Pro Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 122
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 122
Met Ile Glu Thr Tyr Asn Gln Thr Phe Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 123
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 123
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Gln Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 124
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 124
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 125
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 125
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 126
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 126
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Arg Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 127
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 127
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Arg
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 128
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 128
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Ile Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 129
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 129
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile His Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 130
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 130
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Thr Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 131
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 131
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Leu Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 132
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 132
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Ala Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 133
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 133
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Ser Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 134
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 134
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Leu Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 135
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 135
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Thr Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 136
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 136
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 137
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 137
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Leu Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 138
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 138
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Ile Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Asp Leu Leu Lys Leu
260
<210> 139
<211> 261
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 139
Met Ile Glu Thr Tyr Asn Gln Thr Ser Pro Arg Ser Ala Ala Thr Gly
1 5 10 15
Leu Pro Ile Ser Met Lys Ile Phe Met Tyr Leu Leu Thr Val Phe Leu
20 25 30
Asn Thr Gln Met Ile Gly Ser Ala Leu Phe Ala Val Tyr Leu His Arg
35 40 45
Arg Leu Asp Lys Ile Glu Asp Glu Arg Asn Leu His Glu Asp Phe Val
50 55 60
Phe Met Lys Thr Ile Gln Arg Cys Asn Thr Gly Glu Arg Ser Leu Ser
65 70 75 80
Leu Leu Asn Cys Glu Glu Ile Lys Ser Gln Phe Glu Gly Phe Val Lys
85 90 95
Asp Ile Met Leu Asn Lys Glu Glu Thr Lys Lys Glu Asn Ser Phe Glu
100 105 110
Met Gln Lys Gly Asp Gln Asn Pro Gln Ile Ala Ala His Val Ile Ser
115 120 125
Glu Ala Ser Ser Lys Thr Thr Ser Val Leu Gln Trp Ala Glu Lys Gly
130 135 140
Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr Leu Glu Asn Gly Lys Gln
145 150 155 160
Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr Ile Tyr Ala Gln Val Thr
165 170 175
Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln Ala Pro Phe Ile Ala Ser
180 185 190
Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu Arg Ile Leu Leu Arg Ala
195 200 205
Ala Asn Thr His Ser Ser Ala Lys Pro Cys Gly Gln Gln Ser Ile His
210 215 220
Leu Gly Gly Val Phe Glu Leu Gln Pro Gly Ala Ser Val Phe Val Asn
225 230 235 240
Val Thr Asp Pro Ser Gln Val Ser His Gly Thr Gly Phe Thr Ser Phe
245 250 255
Gly Leu Leu Lys Leu
260
<210> 140
<211> 219
<212> PRT
<213> 人工序列
<220>
<223> 合成
<400> 140
Val Gly Asp Gly Ser Ser His His His His His His Ser Ser Gly Gly
1 5 10 15
Gly Arg Gly Ser His His His His His His Gly Gly Ala Cys Gly Cys
20 25 30
Ala Ala Ala Pro Asp Ile Lys Asp Leu Leu Ser Arg Leu Glu Glu Leu
35 40 45
Glu Gly Leu Val Ser Ser Leu Arg Glu Gln Gly Gly Gly Ser Gly Gly
50 55 60
Gly Ser Gly Gly Gly Ser Met Gln Lys Gly Asp Gln Asn Pro Gln Ile
65 70 75 80
Ala Ala His Val Ile Ser Glu Ala Ser Ser Lys Thr Thr Ser Val Leu
85 90 95
Gln Trp Ala Glu Lys Gly Tyr Tyr Thr Met Ser Asn Asn Leu Val Thr
100 105 110
Leu Glu Asn Gly Lys Gln Leu Thr Val Lys Arg Gln Gly Leu Tyr Tyr
115 120 125
Ile Tyr Ala Gln Val Thr Phe Cys Ser Asn Arg Glu Ala Ser Ser Gln
130 135 140
Ala Pro Phe Ile Ala Ser Leu Cys Leu Lys Ser Pro Gly Arg Phe Glu
145 150 155 160
Arg Ile Leu Leu Arg Ala Ala Asn Thr His Ser Ser Ala Lys Pro Cys
165 170 175
Gly Gln Gln Ser Ile His Leu Gly Gly Val Phe Glu Leu Gln Pro Gly
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Glu Val Gln Leu Gln Gln Phe Gly Ala Glu Leu Val Lys Pro Gly Ala
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Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
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Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Asn Tyr Gly Ser Thr Ser Tyr Asn Gln Lys Phe
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Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Arg Asp Trp Thr Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser
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Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu
115 120 125
Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys
130 135 140
Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val Thr Trp Asn Ser
145 150 155 160
Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala Leu Leu Gln Ser
165 170 175
Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp
180 185 190
Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro Ala Ser Ser Thr
195 200 205
Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn
210 215 220
Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro Ala Pro Asn Leu
225 230 235 240
Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn Ile Lys Asp Val
245 250 255
Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Val
260 265 270
Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val
275 280 285
Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser
290 295 300
Thr Ile Arg Val Val Ser Thr Leu Pro Ile Gln His Gln Asp Trp Met
305 310 315 320
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ser
325 330 335
Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu Val Arg Ala Pro
340 345 350
Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys Asp
355 360 365
Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro Gly Asp Ile Ser
370 375 380
Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn Tyr Lys Asp Thr
385 390 395 400
Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu
405 410 415
Asn Met Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys Asn
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Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile Ser
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450
<210> 142
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Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Val Ser Ala Gly
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Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser
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Gly Asn Gln Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile His Gly Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn
85 90 95
Asp His Arg Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu
100 105 110
Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser
115 120 125
Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn
130 135 140
Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu
145 150 155 160
Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp
165 170 175
Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr
180 185 190
Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr
195 200 205
Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215 220
Claims (65)
1.一种治疗有需要的受试者的疾病或病症的方法,所述方法包括:
a.从来源获得B细胞群体;
b.在包括CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞;
c.对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者;以及
d.向所述受试者施用所述B细胞。
2.根据权利要求1所述的方法,其中所述来源是哺乳动物。
3.根据权利要求2所述的方法,其中所述来源是包括外周单核血细胞的生物样品。
4.根据权利要求1所述的方法,其中所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。
5.根据权利要求1所述的方法,其中所述CD40L融合蛋白包括与SEQ ID NO:3至少95%相同的氨基酸序列。
6.根据权利要求1所述的方法,其中所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。
7.根据权利要求1所述的方法,其中所述CD40L交联剂是抗体。
8.根据权利要求7所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQ IDNO:7至少95%相同的氨基酸序列。
9.根据权利要求8所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
10.根据权利要求1所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。
11.根据权利要求1所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。
12.根据权利要求1所述的方法,其进一步包括在存在IL-4的情况下培养所述B细胞。
13.根据权利要求1所述的方法,其进一步包括在存在IL-21的情况下培养所述B细胞。
14.根据权利要求1所述的方法,其中所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。
15.根据权利要求1所述的方法,其中所述疾病或病症选自由以下组成的组:癌症、心脏疾病、炎性疾病、肌肉萎缩疾病或神经疾病中的至少一种。
16.根据权利要求15所述的方法,其中所述癌症是以下中的至少一种:乳腺癌、结肠癌、直肠癌、食管癌;肺癌、胰腺癌、胃癌、肝癌、肝细胞癌、间质瘤如GIST、胶质母细胞瘤和神经胶质瘤。
17.根据权利要求1所述的方法,其中至少约3×107个B细胞被施用于所述受试者。
18.根据权利要求1所述的方法,其中所述B细胞群体被培养至少14天。
19.一种治疗有需要的受试者的疾病或病症的方法,所述方法包括:
a.从来源获得B细胞群体;
b.在包括CD40L融合蛋白和CD40L交联抗体的培养基中培养所述B细胞,其中所述CD40L融合蛋白包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同;以及
c.向所述受试者施用所述B细胞。
20.根据权利要求19所述的方法,其中所述来源是哺乳动物。
21.根据权利要求19所述的方法,其中所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。
22.根据权利要求19所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
23.根据权利要求19所述的方法,其进一步包括对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。
24.根据权利要求19所述的方法,其中在含有CD40L融合蛋白和CD40L交联抗体的培养基中培养所述B细胞之前,所述B细胞被工程化。
25.根据权利要求19所述的方法,其中在含有CD40L融合蛋白和CD40L交联抗体的培养基中培养所述B细胞之后,所述B细胞被工程化。
26.根据权利要求19所述的方法,其进一步包括在存在IL-4的情况下培养所述B细胞。
27.根据权利要求19所述的方法,其进一步包括在存在IL-21的情况下培养所述B细胞。
28.根据权利要求19所述的方法,其中所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。
29.根据权利要求19所述的方法,其中所述疾病或病症选自由以下组成的组:癌症、心脏疾病、炎性疾病、肌肉萎缩疾病或神经疾病中的至少一种。
30.根据权利要求29所述的方法,其中所述癌症是以下中的至少一种:乳腺癌、结肠癌、直肠癌、食管癌;肺癌、胰腺癌、胃癌、肝癌、肝细胞癌、间质瘤如GIST、胶质母细胞瘤和神经胶质瘤。
31.根据权利要求19所述的方法,其中至少约3×107个B细胞被施用于所述受试者。
32.根据权利要求19所述的方法,其中所述B细胞群体被培养至少14天。
33.一种用于制备工程化B细胞的方法,所述方法包括:
a.从来源获得B细胞群体;
b.在包括CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞;以及
c.对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。
34.根据权利要求33所述的方法,其中所述来源是哺乳动物。
35.根据权利要求33所述的方法,其中所述来源是包括外周单核血细胞的生物样品。
36.根据权利要求33所述的方法,其中所述CD40L融合蛋白包括与SEQ ID NO:3至少85%相同的氨基酸序列。
37.根据权利要求33所述的方法,其中所述CD40L融合蛋白包括与SEQ ID NO:3至少95%相同的氨基酸序列。
38.根据权利要求33所述的方法,其中所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。
39.根据权利要求33所述的方法,其中所述CD40L交联剂是抗体。
40.根据权利要求39所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括与SEQ ID NO:5至少95%相同的氨基酸序列,所述重链可变区包括与SEQ IDNO:7至少95%相同的氨基酸序列。
41.根据权利要求40所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
42.根据权利要求33所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。
43.根据权利要求33所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。
44.根据权利要求33所述的方法,其进一步包括在存在IL-4的情况下培养所述B细胞。
45.根据权利要求33所述的方法,其进一步包括在存在IL-21的情况下培养所述B细胞。
46.根据权利要求33所述的方法,其中所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。
47.根据权利要求33所述的方法,其中获得了至少约3×107个B细胞。
48.根据权利要求33所述的方法,其中所述B细胞群体被培养至少14天。
49.一种用于制备工程化B细胞的方法,所述方法包括:
a.从来源获得B细胞群体;以及
b.在包括CD40L融合蛋白和CD40L交联抗体的培养基中培养所述B细胞,其中所述CD40L包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同。
50.根据权利要求49所述的方法,其中所述来源是哺乳动物。
51.根据权利要求49所述的方法,其中所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。
52.根据权利要求49所述的方法,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
53.根据权利要求49所述的方法,其进一步包括对所述B细胞进行工程化以表达有效载荷、嵌合受体或两者。
54.根据权利要求49所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之前,所述B细胞被工程化。
55.根据权利要求49所述的方法,其中在含有CD40L融合蛋白和CD40L交联剂的培养基中培养所述B细胞之后,所述B细胞被工程化。
56.根据权利要求49所述的方法,其进一步包括在存在IL-4的情况下培养所述B细胞。
57.根据权利要求49所述的方法,其进一步包括在存在IL-21的情况下培养所述B细胞。
58.根据权利要求49所述的方法,其中所培养的B细胞表达以下标志物中的至少一种标志物:CD62L、CCR7、CD80、CD86、CD54、ICAM、CD58或CD27。
59.根据权利要求49所述的方法,其中获得了至少约3×107个B细胞。
60.根据权利要求49所述的方法,其中所述B细胞群体被培养至少14天。
61.一种B细胞扩增培养基,其包括:
a.CD40L,其中所述CD40L融合蛋白包括与SEQ ID NO:3的氨基酸序列至少95%相同的氨基酸序列,以及
b.CD40L交联抗体,所述CD40L交联抗体的轻链可变区与SEQ ID NO:5的氨基酸序列至少95%相同,并且所述CD40L交联抗体的重链可变区与SEQ ID NO:7的氨基酸序列至少95%相同;以及
c.向所述受试者施用所述B细胞。
62.根据权利要求61所述的培养基,其中所述CD40L融合蛋白包括SEQ ID NO:3的氨基酸序列。
63.根据权利要求61所述的培养基,其中所述抗体包括轻链可变区和重链可变区,所述轻链可变区包括SEQ ID NO:5的氨基酸序列,所述重链可变区包括SEQ ID NO:7的氨基酸序列。
64.根据权利要求61所述的培养基,其进一步包括IL-4。
65.根据权利要求61所述的培养基,其进一步包括IL-21。
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