CN114341189A - 全新il-15前药及其应用 - Google Patents
全新il-15前药及其应用 Download PDFInfo
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Abstract
本发明提供IL‑15细胞因子前药及其制备和应用。
Description
相关申请交叉引用
本申请同时要求2019年6月12日提交的美国临时申请号62/860,635、2019年8月17日提交的美国临时申请号62/888,444、2019年8月23日提交的美国临时申请号62/891,190、2020年1月11日提交的美国临时申请号62/959,973及2020年5月23日提交的美国临时申请号63/029,473的优先权，上述优先权文件均全文被引。
序列清单
本申请包含一个已以ASCII格式电子提交的序列清单，序列表在此通过引用全文合并。创建于2020年6月8日的ASCII副本名为025471_WO004_SL.txt，大小为359,580字节。
背景技术
白细胞介素-15(IL-15)是一种由单核巨噬细胞或病毒感染后的免疫细胞分泌的，在结构上和IL-2类似的细胞因子，IL-15可以诱导自然杀伤性细胞(NK)及免疫系统其它细胞的增殖，并可参与杀死病毒感染的细胞或肿瘤细胞。和IL-2一样，IL-15以KD约为1nM和IL-2的β/γ受体复合物(IL-2Rβ/γ)结合，其为具有中间亲和力的受体(Giri et al.,EMBOJ.(1994)13:2822-30)。IL-15以更高的亲和力(KD＝～0.05nM)结合到IL-15α受体(IL-15Rα)，IL-15Rα和IL-2Rβ/γ结合在一起形成一个对IL-15具有特异性和高亲和力的受体(αβγ)(Minami et al.,Annu Rev Immunol.(1993)11:245-67；Giri et al.,J Leukoc Biol.(1995)5745:763-6；and Lehours et al.,Eur Cytokine Netw.(2000)11:207-15)。
IL-15Rα的胞外域包括一个Sushi域，一种蛋白分子间相互作用的常见结构。有文献表明IL-15Rα的N末端片段的前65个氨基酸具有部分活性，而片段的前85个氨基酸具有全部功能(Wei et al.,J Immunol.(2001)167(1):277-82).
突变的手段可以用来研究IL-15和其受体的相互作用，有文献表明D8和Q108分别参与IL-15结合到IL-2Rβ和γ亚基的过程中(Pettit et al.,J Biol Chem.(1997)272:2312-18)。IL-15的进一步突变研究表明IL-15的L45,Q48,S51,L52,E64,N65,I68和L69的氨基酸残基参与IL-15与IL-15Rα或IL-2Rβ的结合(U.S.Pat.7,858,081)。具有以下突变E64K,N65K,N65D,L66D,L66E,I67D,I67E或I68D的IL-15突变体在细胞活性分析中具有降低了的生物学活性(Zhu et al.,J Immnol.(2009)183(6):3598；and WO2005/085282A1)。以IL-15和IL-15Rα相互作用的突变研究表明E46,V49,L45,S51及L52和与IL-15α的结合有关(Bernard et al.,J Biol Chem.(2004)279:24313-22)，E46位点具有十分重要的作用，用碱性氨基酸取代它的酸性氨基酸(E46K)会使IL-15丧失生物学功能，完全不能和IL-15Rα结合。
然而，作为候选药物的IL-15明显的副作用限制了此类药物的使用剂量。该药物对T细胞、NK细胞及其他免疫细胞的激活并不具有位点特异性，另外，尽管IL-15突变体对IL-15/2受体的亲和力明显降低，但仍存在“PK渗漏”，并且在以IL-15为基础的蛋白治疗的生产制备存在很多困难。上述问题均对提高以IL-15为基础的治疗的相关技术提出了更高的要求。
发明内容
本发明提供一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中，掩蔽部分融合到载体部分，Sushi域也融合到载体部分，IL-15细胞因子部分和Sushi域融合在一起，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，掩蔽部分通过第一肽连接物融合到载体部分，Sushi域通过第二肽连接物融合到载体部分，IL-15细胞因子部分通过第三肽连接物融合到Sushi域，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的；在一些特定的实施例中，第三肽连接物至少有15,20,25或30个氨基酸长度(比如可以为15-50个氨基酸长度或15-100个氨基酸长度)所述第三肽连接物可选择地包含SEQ ID NO:139或140。
本发明同时提供了一种前药，包括一个IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中IL-15细胞因子部分融合到载体部分，Sushi域也融合到载体部分，掩蔽部分和Sushi域融合在一起，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，IL-15细胞因子部分通过第一肽连接物融合到载体部分，Sushi域通过第二肽连接物融合到载体部分，掩蔽部分通过第三肽连接物融合到Sushi域，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的。
本发明进一步提供了一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中掩蔽部分融合到载体部分，IL-15细胞因子部分也融合到载体部分，Sushi域融合到IL-15细胞因子部分，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，掩蔽部分通过第一肽连接物融合到载体部分，IL-15细胞因子部分通过第二肽连接物融合到载体部分，Sushi域通过第三肽连接物融合到IL-15细胞因子部分，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的。在一些特定的实施例中，第三肽连接物至少有15,20,25或30个氨基酸长度(比如可以为15-50个氨基酸长度或15-100个氨基酸长度)所述第三肽连接物可选择地包含SEQID NO:139或140。
本发明同时提供了一种前药，包括一个IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中IL-15细胞因子部分融合到载体部分，掩蔽部分也融合到载体部分，Sushi域和掩蔽部分融合在一起，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，IL-15细胞因子部分通过第一肽连接物融合到载体部分，掩蔽部分通过第二肽连接物融合到载体部分，Sushi域通过第三肽连接物融合到掩蔽部分，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的。
本发明同时提供了一种前药，包括一个IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中IL-15细胞因子部分融合到载体部分，掩蔽部分融合到IL-15细胞因子部分，Sushi域和载体融合在一起，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，IL-15细胞因子部分通过第一肽连接物融合到载体部分，掩蔽部分通过第二肽连接物融合到IL-15细胞因子部分，Sushi域通过第三肽连接物融合到载体部分，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的。
本发明同时也提供了一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中掩蔽部分融合到载体部分，IL-15细胞因子部分融合到掩蔽部分，Sushi域和载体部分融合在一起，且掩蔽部分可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。在一些实施例中，掩蔽部分通过第一肽连接物融合到载体部分，IL-15细胞因子部分通过第二肽连接物融合到掩蔽部分，Sushi域通过第三肽连接物融合到载体部分，其中至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是可切割的；在一些实施例中，至少一个肽连接物(比如一个肽连接物、两个肽连接物或三个肽连接物)是不可切割的；在一些实施例中，所有肽连接物均为不可切割的。
在一些实施例中，掩蔽部分包括IL-15细胞因子部分的受体胞外域。例如，在一些实施例中，掩蔽部分包括人源IL-2Rβ的胞外域或其功能类似物，和/或人源IL-2Rγ的胞外域或其功能类似物。在一些具体的实施例中，人源IL-2Rγ或其功能类似物的胞外域包括SEQ ID NO:6或与其至少有90％同源性的氨基酸序列。在一些其他实施例中，人源IL-2Rβ胞外域或其功能类似物包括SEQ ID NO:3、4、5或与其至少有90％同源性的氨基酸序列。在一些其他实施例中，掩蔽部分包括一个可结合到IL-15细胞因子部分的抗体片段。
本发明进一步提供了一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)以及可选的Sushi域(S)，掩蔽部分可选择地通过一个肽连接物融合到载体部分、IL-15细胞因子部分或Sushi域，其中掩蔽部分包括的抗体片段可通过结合到IL-15细胞因子部分以抑制IL-15细胞因子部分的生物学活性。
在一些实施例中，前药的抗体片段为包括抗IL-15抗体重链CDR1-3和轻链CDR1-3的ScFv或Fab，所述抗IL-15抗体选自146B7,146H5,404E4,and 404A8。例如，抗体片段包括含有SEQ ID NO:100的重链CDR(HCDR)1、含有SEQ ID NO:101的HCDR2、含有SEQ ID NO:102或106的HCDR3、含有SEQ ID NO:103的轻链CDR(LCDR)1、含有SEQ ID NO:104的LCDR2、以及含有SEQ ID NO:105的LCDR3。在一些具体实施例中，,抗体片段包括(i)含有SEQ ID NO:107的或与其具有至少95％同源氨基酸序列的重链可变区和含有SEQ ID NO:108或123的或与其具有至少95％同源氨基酸序列的轻链可变区；(ii)SEQ ID NO:109；(iii)SEQ ID NO:110或(iv)SEQ ID NO:124。在某些实施例中,重链CDR3(SEQ ID NO:102)的半胱氨酸残基突变为Ser,Thr,Met,Ala,Gly,Asn或Gln。.
在一些实施例中，掩蔽部分对IL-15细胞因子部分结合到IL-15Rα的影响很小，甚至可忽略不计。
在一些实施例中，所述IL-15细胞因子部分为含有SEQ ID NO:2序列或其突变体的人源IL-15多肽。在一些特定的实施例中,人源IL-15多肽相比于SEQ ID NO:2具有选自以下一个或多个突变：N1A,N1D,N4A,N4D,I6T,S7A,D8A,D8T,D8E,D8N,K10A,K10D,K11A,K11D,E46,V49,L45,S51,L52,D61A,D61N,T62L,T62A,E64A,E64L,E64K,E64Q,N65A,N65L,N65D,L66D,L66E,I 67D,I67E,I68S,I68E,L69S,L69E,N72A,N72D,V63E,V63D,L66E,L66D,I67E,I67D,Q108E,N112A,N1D/D61N,N1D/E64Q,N4D/D61N,N4D/E64Q,D8N/D61N,D8N/E64Q,D61N/E64Q,E64Q/Q108E,N1D/N4D/D8N,D61N/E64Q/N65D,N1D/D61N/E64Q,N1D/Q108E,N1D/D61N/E64Q/Q108E,N4D/D61N/E64Q/Q108E,及D30N/E64Q/N65D。
在一些实施例中，载体部分为聚乙二醇分子，白蛋白，白蛋白片段，抗体Fc结构域，抗体或抗原结合片段。在更多的实施例中,载体部分为抗体Fc结构域或含有L234A及L235A(“LALA”)(EU编号)突变的抗体。在一些实施例中，载体部分为抗体Fc结构域或含有球孔突变(knobs-into-holes)的抗体，其中IL-15细胞因子部分和掩蔽部分融合到抗体Fc结构域不同多肽链上或抗体的不同重链上。在一些实施例中，所述knobs-into-holes突变包括在Fc结构域多肽链或抗体重链上的T366Y“knob”突变，和在Fc结构域其他多肽链或抗体另一条重链上的Y407T“hole”突变；或者所述knobs-into-holes突变包括在“knob链”的CH3区的Y345C和/或T366W突变和在“hole链”CH3区的E356C,T366S,L368A,和或Y407V突变(EU编码)。在一些实施例中，载体部分为IgG4的Fc结构域，其中所述第一多肽链包括和SEQ IDNOs：80,81或87具有至少99％同源性的氨基酸序列，所述第二多肽链包括和SEQ ID NOs：82-86具有至少99％同源性的氨基酸序列。
在一些实施例中，载体部分为抗PD-1抗体，其包含一条与SEQ ID NO:55或56具有至少99％同源氨基酸序列的轻链，与SEQ ID NO:54,60或61具有至少99％同源氨基酸序列的第一重链，和与SEQ ID NO:52,53,58,59,62,63或69具有至少99％同源氨基酸序列的第二重链。在更多实施例中，所述载体部分为包含一条与SEQ ID NO:55具有至少99％同源氨基酸序列的轻链，与SEQ ID NO:66具有至少99％同源氨基酸序列的第一重链，和与SEQ IDNO:64,65,67或68具有至少99％同源氨基酸序列的第二重链的抗PD-1抗体。
在一些实施例中，所述载体部分为包含一条与SEQ ID NO:50或51具有至少99％同源氨基酸序列的轻链，与SEQ ID NO:47,48或49具有至少99％同源氨基酸序列的第一重链，和与SEQ ID NO:45或46具有至少99％同源氨基酸序列的第二重链的抗PD-L1抗体。
在一些实施例中，所述载体部分为可特异性结合选自PD-1,PD-L1,CTLA-4,LAG-3,TIM-3,及TIGIT中一个或多个抗原的抗体或抗原结合片段。
在一些实施例中，所述载体部分为抗体或抗体的Fc结构域，所述前药包括以下多肽链配对(顺序由N末端到C末端):C1-A和C2-S-M，A-C1和M-S-C2，C1-S-A和C2-M，C1-A-S和C2-M，S-A-C1和M-C2，或者，A-S-C1和M-C2；其中C1和C2分别为Fc结构域的第一和第二多肽链，或者分别为抗体的第一或第二重链；“-”为直接肽键相连或肽连接物。
在一些实施例中，所述Sushi域包括SEQ ID NO:7或9，或与其具有至少90％同源性的氨基酸序列。
在一些实施例中，第一、第二、第三肽连接物中至少一个为不可切割的肽连接物，优选地为选自SEQ ID NOs：11-16的序列。
在一些实施例中，第一、第二、第三肽连接物中至少一个为可切割肽连接物，其包括尿激酶型纤溶酶原激活物(uPA)，蛋白裂解酶(matriptase)，基质金属肽酶(MMP)2或MMP9的底物序列。例如所述可切割肽连接物可包括(i)uPA和MMP2，(ii)uPA和MMP9，(iii)uPA、MMP2和MMP9，或(iv)MMP2和蛋白裂解酶的底物序列。在一些特定的实施例中，所述可切割肽连接物的氨基酸序列选自SEQ ID NO:17-36。所述可切割肽连接物可被位于肿瘤部位或其周围环境的一个或多个蛋白酶裂解，从而活化在肿瘤部位或其周围环境中的前药。
另一方面，本发明提供了一种包括所述前药及药学上可接受的赋形剂的药物组合物；用于编码所述前药的多核苷酸；包含所述多核苷酸的表达载体；包含所述表达载体的宿主细胞。在一些实施例中，宿主细胞中编码uPA、蛋白裂解酶、MMP2和/或MMP9的基因被敲除。
同时，本发明也提供了一种制备所述前药的方法，所述方法包括在允许表达前药的条件下培养哺乳动物宿主细胞，以及分离前药。
另一方面，本发明对需要其的患者提供了治疗癌症，或感染性疾病，或刺激免疫系统的方法，包括向患者施用治疗有效量的包括所述前药的药物组合物。患者可能患有，例如HIV感染，或乳腺癌，肺癌，胰腺癌，食道癌，髓样甲状腺癌，卵巢癌，子宫癌，前列腺癌，睾丸癌，结直肠癌和胃癌中的任一癌症。同时也提供了IL-15前药在治疗癌症或感染性疾病或刺激免疫系统的用途，以及IL-15前药在制备治疗以上疾病药物中的应用。
本发明的其他特征，目的和有益效果可显而易见于下述的详细描述中，应当理解，说明本发明的实施例和方面的详细描述仅用来说明，而并非用于限制。本发明范围内的各种变化和修改对于本领域技术人员来说是显而易见的。
附图说明
图1A-C为载体部分为Fc结构域的IL-15前药的结构示意图。图1A为IL-15RαSushi域的多肽可选择地通过一个不可切割的肽连接物融合到Fc结构域一条多肽的C末端，IL-15多肽可选择地通过一个不可切割的连接物融合到Sushi域的C末端，掩蔽部分通过一个可切割的连接物融合到Fc另一条多肽的C末端。图1B为IL-15多肽可选择地通过一个不可切割的肽连接物融合到Fc其中一条多肽的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到IL-15多肽的C末端，掩蔽部分通过一个可切割的连接物融合到Fc另一条多肽的C末端。图1C为IL-15多肽可选择地通过一个不可切割的肽连接物融合到Fc其中一条多肽的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到Fc另一条多肽的C末端，掩蔽部分通过一个可切割的连接物融合到Sushi域的C末端。以上三个图示的Fc结构域均含有knobs-into-holes突变。
图2A-C为载体部分为Fc结构域的IL-15前药的结构示意图。图2A为IL-15RαSushi域的多肽可选择地通过一个不可切割的肽连接物融合到Fc结构域一条多肽的N末端，IL-15多肽可选择地通过一个不可切割的连接物融合到Sushi域的N末端，掩蔽部分通过一个可切割的连接物融合到Fc另一条多肽的N末端。图2B为IL-15多肽可选择地通过一个不可切割的肽连接物融合到Fc其中一条多肽的N末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到IL-15多肽的N末端，掩蔽部分通过一个可切割的连接物融合到Fc另一条多肽的N末端。图2C为IL-15多肽可选择地通过一个不可切割的肽连接物融合到Fc其中一条多肽的N末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到Fc另一条多肽的N末端，掩蔽部分通过一个可切割的连接物融合到Sushi域的N末端。以上三个图示的Fc结构域均含有knobs-into-holes突变。
图3A-C为抗体(有两个抗原结合位点)作为其载体部分的IL-15前药的结构示意图。图3A为IL-15多肽可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到IL-15多肽的C末端，掩蔽部分通过一个可切割连接物融合到抗体另一条重链的C末端。图3B为IL-15RαSushi域可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15多肽可选择地通过一个不可切割的连接物融合到Sushi域的C末端，掩蔽部分通过一个可切割的连接物融合到抗体另一条重链的C末端。图3C为IL-15多肽可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到抗体另一条重链的C末端，掩蔽部分通过一个可切割连接物融合到Sushi域的C末端。以上三个图示的抗体均含有knobs-into-holes突变。
图4A和4B为单抗原结合位点的抗体作为其载体部分的IL-15前药的结构示意图。图4A为IL-15多肽可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到IL-15多肽的C末端，掩蔽部分通过一个可切割连接物融合到抗体另一条重链的C末端。图4B为IL-15RαSushi域可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15多肽可选择地通过一个不可切割的连接物融合到Sushi域的C末端，掩蔽部分通过一个可切割的连接物融合到抗体另一条重链的C末端。以上两个图示的抗体均含有knobs-into-holes突变且掩蔽部分和抗体重链的可变区位于同一条多肽链上。
图5A和5B为单抗原结合位点的抗体作为其载体部分的IL-15前药的结构示意图。图5A为IL-15多肽可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15RαSushi域可选择地通过一个不可切割的连接物融合到IL-15多肽的C末端，掩蔽部分通过一个可切割连接物融合到抗体另一条重链的C末端。图5B为IL-15RαSushi域可选择地通过一个不可切割的肽连接物融合到所述抗体的其中一条重链的C末端，IL-15多肽可选择地通过一个不可切割的连接物融合到Sushi域的C末端，掩蔽部分通过一个可切割的连接物融合到抗体另一条重链的C末端。以上两个图示的抗体均含有knobs-into-holes突变且IL-15多肽和Sushi域和抗体重链的可变区位于同一条多肽链上。
图6A为Fc-IL-15前药(JR3.68.1,JR3.68.2及JR3.68.3)及对照分子((Fc-IL-15融合多肽,JR3.68.4及JR3.68.5)的序列信息
图6B为图6A分子的结构图示，所有上述分子均以Fc结构域作为载体部分，JR3.68.1，Sushi域通过不可切割连接物融合到Fc其中一条多肽的C末端，IL-15多肽通过一个不可切割的连接物融合到Sushi域的C末端，掩蔽部分通过可切割的连接物融合到Fc另一条多肽的C末端。JR3.68.2，IL-15多肽通过一条不可切割的连接物融合到Fc其中一条多肽的C末端，Sushi域通过一条不可切割的连接物融合到IL-15多肽的C末端，掩蔽部分通过一条可切割连接物融合到Fc另一条多肽的C末端。JR3.68.3，IL-15多肽通过一条不可切割的连接物融合到Fc其中一条多肽的C末端，Sushi域通过一条不可切割的连接物融合到Fc另一条多肽的C末端，掩蔽部分通过一条可切割连接物融合到Sushi域。JR3.68.4和JR3.68.5分别是JR3.68.1和JR3.68.2的活化状态(其结构中未设计掩蔽部分)。
图7A和图7B为图6B所示的融合蛋白在活化前和活化后的SDS-PAGE胶检测分析。
图8A-C分别为经蛋白A柱纯化的Fc-IL-15/Sushi域融合蛋白JR3.68.1,JR3.68.2及JR3.68.3的分子排阻色谱SEC-HPLC分析。
图9A-C为可活化的Fc-IL-15融合多肽JR3.68.1,JR3.68.2及JR3.68.3分别在活化前后的细胞生物活性检测结果，其中三组数据均采用IL-15作为阳性对照。
图10A以表格形式列出抗体-IL-15融合多肽JR3.74.1和JR3.74.2(不含掩蔽部分)及可活化的抗体-IL-15融合多肽JR3.73.2and JR3.73.4的序列信息。
图10B为图10A分子的结构图示。
图11A和图11B分别为经蛋白A柱纯化的JR3.74.1,JR3.74.2,JR3.73.2及JR3.73.4分子排阻色谱SEC-HPLC分析。
图11C显示了前药样品在经蛋白酶处理而活化前后对CTLL2细胞增殖影响的分析结果。
图12A和图12B为抗-IL-15抗体146B7的scFv(scFv1或scFv2)作为其掩蔽部分的IL-15前药对NK92细胞增殖的作用分析结果。图12A为可活化的IL-15融合蛋白的序列信息；图12B为NK92细胞增殖结果分析。其中，
Reference X1:
IL-15/IL-15受体α亚基的复合物和XmAb的Fc结构域的融合物(IL-15/IL-15Rα-Fc)；
Fc-IL-15*：以IL-2Rβ的胞外域(ECD)作为掩蔽部分的可活化的IL-15融合蛋白；
Fc-IL-15：不含有掩蔽部分的Fc-IL-15融合蛋白；
RLU：相对荧光响应值。
图13A和13B为可活化的IL-15融合蛋白在活化前后对NK92细胞活性的影响结果。图13A为包括野生型IL-15的IL-15融合蛋白对NK92细胞活性的影响。图13B为包括N65D突变的IL-15突变体的IL-15融合多肽对NK92细胞活性的影响。其中，Reference X1:
IL-15/IL-15受体α亚基复合物和Xm Ab的Fc结构域的融合物(IL-15/IL-15Rα-Fc)；
LUC:荧光信号单位；
ACT:活化状态。
图14A用图标列出了可活化的IL-15融合蛋白的序列信息。
图14B-D为可活化的IL-15融合蛋白在活化前后对NK92增殖的作用结果。图14B是由IL-2Rβ胞外域和IL-2Rγ胞外域为掩蔽部分的野生型IL-15的作用结果。图14C是由IL-2Rβ胞外域和IL-2Rγ胞外域为掩蔽部分的IL-15突变体的作用结果，其中突变位点为Q108E。图14D是不含有Sushi域的可活化的Fc-IL-15融合蛋白(JR2.145.1)和一个在Sushi域和IL-15多肽之间有一个较长连接物的融合蛋白(JR2.145.2)的作用结果。其中，
Reference X1：
IL-15/IL-15受体α亚基复合物和Xm Ab的Fc结构域的融合物(IL-15/IL-15Rα-Fc)；
Reference X2：不含有Sushi域的PD-1抗体和IL-15突变体的融合蛋白。
发明的具体说明
本发明及附权利要求书中使用的单数形式“一个”，“或”和“这”包括复数所指物，除非上下文另有明确规定。
此处“约”一个值或参数的引用包括(并描述了)该值或参数本身的变体。例如，“约X”的描述包括“X”的描述。此外，在任何一组数字前面使用“约”也包括在这一组所引用的数字中使用“约”。例如，“约X、Y或Z”的描述意在描述“约X、约Y或约Z”。
术语“抗原结合部分”是指多肽或一组相互作用的多肽，其与抗原特异性结合，其包括但不限于抗体(例如，单克隆抗体、多克隆抗体、多特异性抗体、双特异性抗体、抗独特型抗体或双功能混合抗体)，或其抗原结合片段(例如Fab，Fab’，F(ab’)2，Fv，二硫键连接的Fv，scFv，单域抗体(dAb)或双抗体)，或单链抗体和含Fc的多肽，比如免疫粘附素。在一些实施例中，抗体可以是任何重链种型(例如，IgG，IgA，IgM，IgE或IgD)或亚型(例如，IgG1，IgG2，IgG3或IgG4)。在一些实施方案中，抗体可以是任何轻链种型(例如kappa或lambda)。抗体可以是人的，非人的(例如，来自小鼠，大鼠，兔，山羊或另种非人的动物)，嵌合的(例如，具有非人可变区和人源恒定区)或人源化的(例如，具有非人CDR，人源构架和恒定区)。在一些实施例中，抗体是衍生的抗体。
“细胞因子激动剂多肽”一词是指野生型细胞因子或其类似物。野生型细胞因子的类似物与野生型细胞因子具有相同的生物学特异性(例如，结合到相同的受体并激活相同的靶细胞)，尽管其活性水平可能与野生型细胞因子不同。类似物可能，例如，一个野生型细胞因子的突变蛋白质(即突变多肽),并可能相对于野生型细胞因子包括至少1个、至少2个、至少3个、至少有4个、至少5个、至少6个、至少7个、至少8个、至少九个或者至少10个突变。
“细胞因子拮抗剂”或“细胞因子掩蔽部分”是指与细胞因子结合，从而抑制细胞因子与靶细胞表面受体结合和/或在拮抗剂或掩蔽部分的作用下发挥其生物学功能的部分(如多肽)。细胞因子拮抗剂或掩蔽部分的例子，包括但不仅限于从细胞因子自然受体的细胞外区域衍生的与细胞因子作用的多肽。
术语“有效量”或“治疗有效量”是指足以治疗特定失调、状况或疾病(如改善、缓和、减轻和/或延缓一种或多种症状)的化合物或组合物的量。关于疾病如癌症，有效量可能是一个足以延缓癌症发展或进展(例如减少肿瘤的生长速度，和/或延迟或阻止肿瘤血管生成、转移、或肿瘤细胞渗透到周边器官)，减少上皮样细胞，达到癌症消退(例如减少或消除肿瘤)，和/或防止或延缓癌症的发生或复发。有效剂量可一次或多次给予。
“功能性类似物”是指具有与对照分子相同的生物学特异性(如与相同配体结合)和/或活性(如激活或抑制靶细胞)的分子。
关于两个多肽序列的术语“融合(fused)”或融合(fusion)，其是指两个多肽序列通过主链肽键的连接。两个多肽可以直接融合，亦可以通过一个或多个氨基酸长的连接肽融合。融合多肽可以通过重组技术，由包含着两个融合部份体的各自编码序列的一段编码序列制备，其间可具或不具连接肽的编码序列。在一些实施方案中，融合涵盖化学缀合。
“可接受药用赋形剂”指的是用来指一个成分组合中的一个成分，适用于给予受试者，包括人体，对受试者没有过度的有害副作用、不影响药物活性成分(API)的生物活性。
“受试者”一词指哺乳动物，包括但不限于人类、宠物(如犬、猫)、农场动物(如牛、马)、啮齿动物或灵长类动物。
此处使用的“治疗(treatment)”或“治疗(treating)”是一种获得有益或预期临床结果的方法。有益或期望的临床结果包括但不限于以下一项或多项：减轻疾病带来的一个或多个症状,减少疾病的程度，改善疾病状态，稳定疾病(例如预防或延缓疾病的恶化或进展)，预防或延迟一种疾病的传播(如转移)，预防或延缓疾病的复发，实现疾病部分或全部缓解,减少治疗疾病所需的一个或多个其他药物剂量,提高患者的生活质量和/或延长生存。本发明方法思考了治疗的一个或多个方面。
应该理解，这里描述的各种实施例中的一个、一些或所有属性可以组合起来形成本发明的其他实施例。此处使用的章节标题为了组织的目的而并不应该被解释成限定本申请所描述的主题。
I.IL-15前药
本发明披露的IL-15前药可在体内代谢成为活化的IL-15治疗药物。IL-15前药与之前的IL-15疗法相比副作用更少，体内PK更好(如更长的半衰期)，靶向特异性更好，更有效。本发明披露的IL-15前药能够降低聚体含量，提高生产效率，从而进一步克服了融合分子和双特异性分子制备过程中遇到的困难。
所述前药包括IL-15多肽(A)(比如，细胞因子激动剂多肽或IL-15细胞因子部分)，可选的IL-15RαSushi域(S)，掩蔽部分(M)(比如，细胞因子拮抗剂)以及一个载体部分(C)，这些部分通过肽连接物相互连接，其中一个为可在肿瘤位点被蛋白酶活化的可切割肽连接物，活化后的肽连接物使掩蔽部分(IL-15拮抗剂)和IL-15细胞因子部分彼此分离。在一些实施例中，掩蔽部分(IL-15拮抗剂)，例如可以为IL-15受体胞外域或可结合到所述细胞因子的抗体片段、，通过可切割连接物(比如，可切割的肽连接物)连接到细胞因子部分、Sushi域或载体部分。在其他实施例中，掩蔽部分通过不可切割的连接物连接到其他部分。
掩蔽部分通过和IL-15细胞因子部分结合来抑制其生物学功能。在一些实施例中，所述前药的掩蔽部分特异性地结合到和IL-15多肽相互作用结构域的IL-2Rβ和/或γ链的抗原表位上。前药中可切割连接物在蛋白酶水解作用下，掩蔽部分和细胞因子部分分开，所述掩蔽部分的抑制作用消除。在一些实施例中，所述前药的掩蔽部分并不阻止或抑制IL-15多肽(A)和IL-15Rα的结合。所述前药在患者的靶位点(比如，在肿瘤位点或其周围环境，或感染位点)通过切割连接物被活化，并随之释放所述前药其他部分的细胞因子掩蔽部分或IL-15细胞因子部分，暴露出被预先掩蔽的IL-15细胞因子部分并使IL-15细胞因子和其在靶细胞上的受体结合并发挥其生物学功能。在一些实施例中，前药的载体部分为抗原结合部分，比如，可以结合靶位点抗原的抗体。
在一些本发明披露的IL-15前药的实施例中，所述Sushi域通过一个肽连接物(可切割的或不可切割的)融合到载体部分、掩蔽部分，和/或IL-15细胞因子部分。在一些实施例中，所述IL-15细胞因子部分通过一个肽连接物(可切割的或不可切割的)融合到载体部分、掩蔽部分，和/或Sushi域。在一些实施例中，所述掩蔽部分通过一个肽连接物(可切割的或不可切割的)融合到载体部分、细胞因子部分，和/或Sushi域。
在一些实施例中，所述前药通过载体靶向递送到靶点并代谢成有活性的、促炎的IL-15细胞因子。在进一步实施例中，前药的载体为可靶向到肿瘤抗原的抗体，通过切割连接细胞因子掩蔽部分和载体部分或细胞因子部分的连接物、可将所述前药递送到患者的肿瘤位点实现局部代谢(例如，肿瘤微环境的内部或周围)，让促发炎的细胞因子部分和靶细胞相应受体发生作用并在局部刺激靶向免疫细胞。
A.前药的IL-15部分
所述IL-15前药中，IL-15细胞因子部分可以为野生型的IL-15多肽，如具有SEQ IDNO:2序列的野生型人源IL-15多肽，或IL-15突变体，如源自野生型IL-15并相较于野生型IL-15对IL-2Rβ(CD122)具有较低亲和力的IL-15突变体。IL-15突变体相较于野生型IL-15对CD122或IL-2R二聚体具有明显降低的亲和力。
在一些实施例中，所述IL-15部分被掩蔽时，其生物学活性降低至少5倍、至少10倍、至少20倍、至少50倍、或至少100倍；或其EC50值增加至少5倍、至少10倍、至少20倍、至少50倍或至少100倍。
在一些实施例中，所述IL-15部分为在以下位点至少包括1、2、3、4、或5个突变的IL-15突变体：人源IL-15的N1,N4,I6,S7,D8,K10,K11,E46,D61,T62,E64,N65,I68,L69,N72,V63,L66,I67,A70,N71,Q108,N112。示例性地，IL-15突变体包括以下一个或多个突变：N1A,N1D,N4A,N4D,I6T,S7A,D8A,DAT,D8E,D8N,K10A,K10D,K11A,K11D,D61A,D61N,T62L,T62A,E64A,E64L,E64K,E64Q,N65A,N65L,N65D,L66D,L66E,I 67D,I67E,I68S,I68E,L69S,L69E,N72A,N72D,V63E,V63D,L66E,L66D,I67E,I67D,Q108E及N112A。在一些实施例中，所述IL-15部分包括选自E46,V49,L45,S51,及L52位置的突变。除非另有说明，IL-15和IL-15突变体涉及到的氨基酸序号和SEQ ID NO:2中的序号一致。在其他实施例中，IL-15部分包括和SEQ ID NO:2具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％或99％同源性的氨基酸序列。
在一些特定实施例中，所述IL-15突变体包括选自N1D/D61N，N1D/E64Q，N4D/D61N，N4D/E64Q，D8N/D61N，D8N/E64Q，D30N/E64Q/N65D，D61N/E64Q，E64Q/Q108E，N1D/N4D/D8N，D61N/E64Q/N65D，N1D/D61N/E64Q，N1D/D61N/E64Q/Q108E，和N4D/D61N/E64Q/Q108E的突变。
B.IL-15受体α亚基Sushi域
在一些实施例中，所述IL-15前药包括IL-15RαSushi域。所述Sushi域直接或可选地通过一个连接物(比如，可切割或不可切割的肽连接物)融合到载体部分或IL-15细胞因子部分；所述掩蔽部分通过一个可切割或不可切割的肽连接物融合到Sushi域或载体部分。在一些特定实施例中，通过肽连接物，Sushi域融合到载体部分，细胞因子部分融合到Sushi域。所述IL-15前药中，Sushi域可为野生型的Sushi域，或Sushi域包含如SEQ ID NO:7或9的氨基酸序列。在其他实施例中，Sushi域包含和SEQ ID NO:7或SEQ ID NO:9具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％或99％同源性的氨基酸序列。
在一些实施例中，人源IL-15受体α亚基(IL-15Rα)具有如SEQ ID NO:8所示的氨基酸序列，在一些实施例中，编码人源IL-15Rα的序列如SEQ ID NO:137所示。所述前药一个示例性的IL-15Rα蛋白可包括或由SEQ ID NO:8的Sushi域(比如，SEQ ID NO:8的第31-95位或31-105位氨基酸序列)构成，或可以为包括或由SEQ ID NO:9或SEQ ID NO:7所示的氨基酸序列构成。在一些实施例中，IL-15Rα蛋白具有SEQ ID NO:7的氨基酸序列和选自D96,P97，A98,D96/P97，D96/C97，D96/P97/A98，D96/P97/C98及D96/C97/A98的氨基酸嵌入，其中，氨基酸位置编号与全长人源IL-15Rα或SEQ ID NO:8相对应。例如，IL-15Rα(比如，SEQ ID NO:9)的C末端可增加D，P，A，DP，DC，DPA，DPC，或DCA氨基酸。在一些实施例中，IL-15Rα蛋白为SEQ ID NO:9中含有一个或多个选自K34C，A37C，G38C，S40C及L42C取代的氨基酸序列，其中，氨基酸位置编号与SEQ ID NO:9相对应。在一些实施例中，IL-15类似物及Sushi域包括一组分别选自E87C:D96/P97/C98；E87C:D96/C97/A98；V49C:S40C；L52C:S40C；E89C:K34C；Q48C:G38C；E53C:L42C；C42S:A37C；和L45C:A37C的氨基酸取代或插入(冒号前的为IL-15的突变，冒号后的为Sushi域的突变)。
C.前药的掩蔽部分
所述前药中的细胞因子拮抗剂，如掩蔽部分，包括可结合到所述前药的细胞因子部分以掩蔽细胞因子及抑制其生物学功能的肽、抗体或抗体片段。在一些实施例中，掩蔽部分包括可结合到人源IL-15多肽并抑制其生物学活性的结合抗原部分或抗体的结合片段。
举一个例子,IL-15拮抗剂包括可结合IL-15并阻止IL-15结合到其受体部分的肽或抗体，当IL-15被掩蔽时，其生物学活性降低。在一些实施例中，所述IL-15拮抗剂包括IL-2Rβ或IL-2Rγ胞外域或其功能类似物，比如衍生自人源IL-2Rβ或IL-2Rγ的序列(比如，SEQID NO:3-6序列其中之一)。在一些实施例中，IL-15拮抗剂是一个从肽库里筛选出来的一个肽。在一些实施例中，所述IL-15拮抗剂包括可阻止IL-15或IL-15突变体结合到IL-15受体的抗体或其片段。在其他实施例中，所述拮抗剂抑制IL-15多肽的生物学活性。在一些实施例中，所述拮抗剂包括scFv，Fab或其他为本领域技术人员所了解的抗体片段。在一些优选实施例中，所述抗体片段是对IL-15具有特异性的scFv。在其他优选的实施例中，所述拮抗剂特异地结合到IL-15活性肽与β-链或γ-链结合的位点。在一些特定的实施例中，所述掩蔽部分并未阻止或抑制IL-15多肽和IL-15Rα的结合，举例来说，所述IL-15结合抗体可选自146B7，146H5，404E4及404A8。在一些实施例中，IL-15拮抗剂的scFv或Fab包含的重链CDR1，CDR2和CDR3结构域选自146B7，146H5，404E4及404A8的IL-15抗体的重链；且轻链CDR1，CDR2和CDR3结构域来自所述抗体的轻链；所述抗体的具体描述参见WO2003/017935A2。
在一些实施例中，所述IL-15拮抗剂包括分别如SEQ ID NO:100，101及102氨基酸序列的重链CDR1，CDR2及CDR3结构域，及分别如SEQ ID NO:103，104及105氨基酸序列的轻链CDR1，CDR2及CDR3结构域。在一些实施例中，重链CDR3结构域的SEQ ID NO:102序列中包括一个半胱氨酸残基的取代突变。SEQ ID NO:102序列中CDR3结构域的半胱氨酸残基可突变为Ser，Thr，Ala，Asn或Gln。在另一实施例中，所述CDR3结构域包括SEQ ID NO:106的氨基酸序列。在一些实施例中，所述拮抗剂或掩蔽部分为包括序列SEQ ID NO:107或与其具有至少95％同源性氨基酸序列的重链可变区及包括序列SEQ ID NO:108或123或与其具有至少95％同源性氨基酸序列的轻链可变区的scFv或Fab。在一些特别的实施例中，所述掩蔽部分包括如SEQ ID NO:110或124的氨基酸序列。
D.前药的载体部分
所述前药的载体部分可以为抗原结合部分或非抗原结合部分。载体部分可改善PK情况，如提高血浆中细胞因子激动剂多肽的血浆半衰期，并将细胞因子激动剂多肽靶向递送至身体的靶位点部位，如肿瘤位点。
在一些实施例中，所述载体部分(C)为包括第一和第二多肽链(比如，两条不同重链)的Fc结构域，其中所述多肽链(从N末端到C末端)为一组选自以下组合的分子结构：
a)F1-PL1-A-PL2-S,F2-CL-M(FIG.1A)；
b)F1-PL1-S-PL2-A,F2-CL-M(FIG.1B)；及
c)F1-PL1-S-PL2-A,F2-CL-M(FIG.1C)；
其中，F1和F2为可形成为一个异二聚体的所述载体部分(比如，Fc结构域)的亚基；PL1和PL2为肽连接物；CL为可切割肽连接物；S为Sushi域；A为IL-15多肽。
在一些实施例中，所述载体部分(C)为包括第一和第二多肽链(比如，两条不同重链)的Fc结构域，其中所述多肽链(从N末端到C末端)为一组选自以下组合的分子结构：
a)A-PL1-S-F1,M-CL-F2(FIG.2A)；
b)S-PL1-A-F1,M-CL-F2(FIG.2B)；及
c)A-PL1-F1,M-CL-S-F2(FIG.2C)；
其中，F1和F2为可形成为一个异二聚体的所述载体部分(比如，Fc结构域)的亚基；PL1和PL2为肽连接物；CL为可切割肽连接物；S为Sushi域；A为IL-15多肽。
在一些实施例中，所述载体部分(C)为包括两条抗体轻链、第一抗体重链和第二抗体重链的抗体，其中，
a)第一重链包括C1-CL-M的分子结构(从N末端到C末端)，
b)第二重链包括C2-PL1-S-PL2-A的分子结构(从N末端到C末端)，其中C1和C2为抗体重链；PL1和PL2为肽连接物；CL为可切割的肽连接物；S为Sushi域；A为IL-15多肽。在其他实施例中，上述第一和第二重链的顺序为相反的(如图3A和3B所示)。
在一些实施例中，所述载体部分(C)为包括两条抗体轻链、第一抗体重链和第二抗体重链的抗体，其中，
a)第一重链包括C1-A的分子结构(从N末端到C末端)，
b)第二重链包括C2-PL1-S-CL-M的分子结构(从N末端到C末端)，其中C1和C2为抗体重链；PL1和PL2为肽连接物；CL为可切割的肽连接物；S为Sushi域；且A为IL-15多肽(如图3C所示)。
在一些实施例中，本发明披露的前药包括三条多肽链-一条抗体轻链和两条重链，其中第一条多肽链为抗体轻链可变区，第一重链包括抗体抗体重链可变区和恒定区，第二重链包括CH2和CH3结构域，其中所述第一和第二重链包括选自如下组合的分子结构(从N末端到C末端)：
a)F-PL1-A-PL2-S,HC-CL-M(FIG.4A)；
b)F-PL1-S-PL2-A,HC-CL-M(FIG.4B)；
c)HC-PL1-A-PL2-S,F-CL-M(FIG.5A)；及
d)HC-PL1-S-PL2-A,F-CL-M(FIG.5B)。
其中，F为Fc结构域(包括CH2和CH3结构域)的亚基；HC为可以和所述轻链形成抗原结合部分的重链；PL1和PL2为肽连接物；CL为可切割肽连接物；S为Sushi域；且A为IL-15多肽。
1、抗原-结合的载体部分
载体部分可以是抗体或抗原结合片段，或免疫粘附素。在一些实施例中，抗原结合部分是具有两条重链和两条轻链的全长抗体、Fab片段、Fab’片段、F(ab’)2片段、Fv片段、二硫键连接的Fv片段、单域抗体、纳米体或单链可变片段(scFv)。在一些实施例中，抗原结合部分为双特异性抗原结合部分，可与两种不同抗原或同一抗原上的两种不同表位结合。抗原结合部分可能为细胞因子激动剂多肽提供附加和潜在的协同治疗效果。
所述细胞因子多肽(IL-15)和其掩蔽物可融合到抗原结合部分轻链和/或重链的N末端或C末端。举例来说，所述细胞因子多肽(比如IL-15)和其掩蔽物融合到抗体重链或抗原结合片段，或融合到抗体轻链或抗原结合片段。在一些实施例中，细胞因子多肽(IL-15)融合到一条或两条抗体重链的C末端，且所述细胞因子掩蔽部分通过可切割的或不可切割的肽连接物融合到重链的另一末端或融合到细胞因子激动剂多肽的C末端。在一些实施例中，所述细胞因子多肽(IL-15)融合到其中一条抗体重链的C末端，且所述细胞因子掩蔽部分通过可切割的肽连接物融合到另一条抗体重链的C末端，其中两条重链可选地包括使得两条不同重链配对的突变。
形成Fc-融合蛋白或双特异性抗体的异二聚体的策略是众所周知的(参见，例如，Spies et al.,Mol Imm.67(2)(A):95-106(2015))。例如，前药中的两个重链多肽可以通过“knobs-into-holes”突变形成稳定的异二聚体。进行“knobs-into-holes”突变以促进抗体重链的异二聚体的形成，并且普遍用于制造双特异性抗体(参见，例如，美国专利号8,642,745)。例如，抗体的Fc结构域可在“knob chian”的CH3结构域中包含T366W突变，而在“holechain”的CH3结构域中包含T366S，L368A和/或Y407V突变。还可以使用CH3域之间的另一个链间二硫桥，例如，通过将Y349C突变引入“knobs chain”的CH3域，并将E356C或S354C突变引入“hole chain”的CH3域中(参见，例如，Merchant et al.,Nature Biotech 16:677-81(1998))。在其他实施方案中，抗体部分可在两个CH3结构域之一中包含Y349C和/或T366W突变，在另一个CH3结构域中包含E356C，T366S，L368A和/或Y407V突变。在某些特定实施例中，抗体部分可在两个CH3结构域之一中包含Y349C和/或T366W突变，在另一个CH3结构域中包含S354C(或E356C)，T366S，L368A和/或Y407V突变；另外以一个CH3结构域上额外的Y349C突变，和另一个CH3结构域上额外的E356C或S354C突变，形成一个链间二硫键(编号始终根据Kabat的EU索引编号；Kabat et al.,“Sequences of Proteins of ImmunologicalInterest,”5th ed.,Public Health Service,National Institutes of Health,Bethesda,Md.(1991))。其他knobs-in-holes技术，比如EP1870459A1中所述的，均可以替代或附加地使用。于是，抗体部分的knobs-in-holes突变的另一个例子是在“knob chain”的CH3域中带有R409D/K370E突变，在“hole chain”的CH3域中带有D399K/E357K突变(EU编号)
在一些实施例中，前药的抗体部分包括Fc结构域的L234A和L235A(“LALA”)突变。LALA突变可消除补体结合和固定以及Fcγ依赖性ADCC(见Hezareh et al.J.Virol.(2001)75(24):12161-8)。在进一步实施例中，除了knobs-into-holes突变外，抗体部分还存在LALA突变。
在一些实施例中，该抗体部分包括Fc结构域的M252Y/S254T/T256E(“YTE”)突变。YTE突变允许同时调节血清半衰期、组织分布和IgG1活性(见Dall’Acqua et al.,J BiolChem.(2006)281:23514-24；and Robbie et al.,Antimicrob Agents Chemother.(2013)57(12):6147-53)。在进一步实施例中，除了knobs-into-holes突变外，在抗体部分中还存在YTE突变。在具体实施例中，抗体部分具有YTE、LALA和knobs-into-holes突变或它们的任何组合。
抗原结合部分可与细胞表面的抗原结合，如免疫细胞，例如T细胞、NK细胞和巨噬细胞，或与细胞因子结合。例如，抗原结合部分可以与PD-1、LAG-3、TIM-3、TIGIT、CTLA-4或TGF-beta，抗原结合部分可以为抗体。该抗体可能具有激活免疫细胞并增强其抗癌活性的能力。
抗原结合部分可与肿瘤细胞表面的抗原结合。例如，抗原结合部分可与FAPα、5T4、Trop-2、PD-L1、HER-2、EGFR、Claudin 18.2、DLL-3、GCP3或癌胚抗原(CEA)，抗原结合部分可以为抗体。该抗体可能具有或不具有ADCC活性。该抗体还可以进一步偶联到细胞毒性药物上。
在一些实施例中，抗原结合部分可结合于脒基环化酶C(GCC)，糖类抗原19-9(CA19-9)，糖蛋白A33(gpA33)，粘蛋白1(MUC1)、胰岛素样生长因子1受体(IGF1-R),人类表皮生长因子受体2(HER2)，人类表皮生长因子受体3(HER3)，delta-like蛋白3(DLL3)，delta-like蛋白4(DLL4)、表皮生长因子受体(EGFR)，蛋白多糖-3(GPC3)，c-MET，血管内皮生长因子受体1(VEGFR1)，血管内皮生长因子受体2(VEGFR2)、Nectin-4、Liv-1、糖蛋白NMB(GPNMB)、前列腺特异性膜抗原(PSMA)、Trop-2、碳酸酐酶IX(CA9)，内皮素B受体(ETBR)，前列腺1的6个跨膜上皮抗原(STEAP1)，叶酸受体α(FR-α)，SLIT和NTRK类蛋白6(SLITRK6)碳酸酐酶VI(CA6)，磷酸二酯酶家族成员3(ENPP3)，间皮素，滋养层糖蛋白(TPBG)，CD19，CD20，CD22，CD33，CD40，CD56，CD66e，CD70，CD74，CD79b，CD98，CD123，CD138，CD352，CD47，信号调节蛋白(SIRPα),Claudin 18.2,Claudin 6，BCMA或EPCAM。在一些实施例中，抗原结合部分与DLL3的表皮生长因子(EGF)-样结构域结合。在一些实施例中，抗原结合部分与DLL3的Delta/Serrate/Lag2(DSL)-样结构域结合。在一些实施例中，抗原结合部分与位于GPC3的第374个氨基酸后的一个表位结合。在一些实施例中，抗原结合部分与GPC3的硫酸肝素聚糖结合。在一些实施例中，抗原结合部分与Claudin 18.2结合，但不与Claudin 18.1结合。在一些实施例中，抗原结合部分与Claudin 18.1的结合亲和力，比与Claudin 18.2的结合亲和力至少弱10倍。
在一些实施例中，所述抗原结合部分(载体部分)包括可结合到PD-1并通过抑制PD-1和其配体(PD-L1)相互作用来促进抗肿瘤免疫反应的抗体或本领域技术人员所了解的相关抗体片段。在一些实施例中，抗体或抗原结合片段形式特异性结合PD-1，例如一些靶向PD-1并应用于本发明的抗体，包括但不限于：nivolumab(BMS-936558,Bristol-MyersSquibb)，pembrolizumab(lambrolizumab,MK03475 or MK-3475,Merck)，人源化抗PD-1抗体JS001(上海君实)，单克隆抗PD-1抗体TSR-042(Tesaro,Inc.),pidilizumab(抗PD-1单抗CT-011,Medivation)，单克隆抗PD-1抗体BGB-A317(百济神州)，和/或抗PD-1抗体SHR-1210(上海恒瑞),人源单克隆抗体REGN2810(Regeneron)，人源单克隆抗体MDX-1106(Bristol-Myers Squibb)，和/或人源抗PD-1IgG4抗体PDR001(Novartis)。在一些实施例中，PD-1抗体来自RMP1-14(rat IgG)-BioXcell cat#BP0146克隆。专利号为8,008,449的美国专利公开了一些其他可采用的PD-1抗体。在一些实施例中，所述抗体或抗原结合部分能够特异性地和PD-L1结合并抑制其与PD-1的相互作用，进而增加免疫活性。本领域技术人员所了解的一切能够和PD-L1结合并干扰PD-1和PD-L1相互作用、促进抗肿瘤免疫应答的抗体均可以用于本发明披露的联合治疗应用中，例如，可以靶向PD-L1的抗体BMS-936559(Bristol-MyersSquibb)和MPDL3280A(Genetech；currently in human trials)。专利号为7,943,743的美国专利披露了其他可采用的靶向PD-L1的抗体。本领域技术人员应当理解，所有可特异性结合PD-1或PD-L1，干扰PD-1/PD-L1相互作用，促进抗肿瘤免疫应答的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述载体部分为选自ASKB1296，avelumab，阿特珠单抗(atezolizumab)和度伐单抗(durvalumab)的抗PD-L1抗体。
在一些实施例中，所述载体为可结合到肿瘤细胞表达抗原的抗体。在一些实施例中，所述载体抗体具有ADCC功能。在一些实施例中，所述载体抗体和选自HER2，HER3，EGFR，CMET，Trop-2，GPC3，Claudin 18.2，Claudin 6，5T4，BCMA，CD38，CD20，CD30，CD47及VEGFR2的抗原相结合
在一些实施例中，所述载体为可以和两个抗原结合的双特异性抗体，所述抗原选自PD-1，PD-L1，CTLA-4，LAG-4，TIM-3，CD47及TIGIT。
在一些实施例中，所述载体抗体和人源PD-1结合，其中所述PD-1抗体包括与nivolumab，pembrolizumab，toripalimab，sintilimab或tislelizumab具有相同CDR1，CDR2和CDR3结构域的重链及具有相同CDR1，CDR2和CDR3结构域的轻链。
在一些实施例中，所述载体抗体和人源PD-1结合，其中，轻链包括和SEQ ID NO:55或56任一序列具有至少99％同源性的氨基酸序列，第一重链包括和SEQ ID NO:54，60或61任一序列具有至少99％同源性的氨基酸序列，第二重链包括和SEQ ID NO:52,53,58,59,62,63或69任一序列具有至少99％同源性的氨基酸序列。
在一些实施例中，抗体和人源PD-1结合，其中，轻链包括和SEQ ID NO:55具有至少99％同源性的氨基酸序列，第一重链包括和SEQ ID NO:66具有至少99％同源性的氨基酸序列，第二重链包括和SEQ ID NO:64,65,67或68任一序列具有至少99％同源性的氨基酸序列。
在一些实施例中，所述载体抗体和PD-1结合，其中，轻链包括和SEQ ID NO:55或56任一序列具有至少99％同源性的氨基酸序列，第一重链包括和SEQ ID NO:80,81或87任一序列具有至少99％同源性的氨基酸序列，第二重链包括和SEQ ID NO:52,53,58,59,62,63或69任一序列具有至少99％同源性的氨基酸序列
在一些实施例中，所述载体抗体和PD-1结合，其中，轻链包括和SEQ ID NO:55或56任一序列具有至少99％同源性的氨基酸序列，第一重链包括和SEQ ID NO:54，60或61任一序列具有至少99％同源性的氨基酸序列，第二重链包括和SEQ ID NO:82,83,84,85和86任一序列具有至少99％同源性的氨基酸序列
在一些实施例中，所述载体抗体和人源PD-L1结合，其中，轻链包括和SEQ ID NO:50或51任一序列具有至少99％同源性的氨基酸序列，第一重链包括和SEQ ID NO:47,48或49任一序列具有至少99％同源性的氨基酸序列，第二重链包括和SEQ ID NO:45或46任一序列具有至少99％同源性的氨基酸序列
在一些实施例中，所述载体抗体为可结合两个抗原的双特异性抗体，所述抗原选自HER2，HER3，EGFR，CMET，Trop-2，GPC3，Claudin 18.2，Claudin 6，5T4，BCMA，CD38，CD20，CD30及VEGFR2。在一些实施例中，所述载体为可以和cMet和EGFR结合的双特异性抗体，其中EGFR结合域包括来自于SEQ ID NO:88或90的轻链CDR1，CDR2和CDR3，以及来自于SEQ IDNO:89或91的重链CDR1，CDR2和CDR3。
在一些实施例中，所述载体部分为IgG1的Fc结构域，其中第一条多肽包括和SEQID NO:37,70-72及73具有至少99％同源性的氨基酸序列，第二条多肽链包括和SEQ ID NO:38,39,75-78和79具有至少99％同源性的氨基酸序列。
在一些实施例中，所述载体部分为IgG4的Fc结构域，其中第一条多肽包括和SEQID NO:80,81及87具有至少99％同源性的氨基酸序列，第二条多肽链包括和SEQ ID NO:82-85和86具有至少99％同源性的氨基酸序列。.
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合CTLA-4并抑制其与CD80和CD86相互作用的抗体或其片段。例如靶向CTLA-4的抗体包括FDA已经批准上市的ipilimumab(MDX-010,MDX-101,BMS)以及正在进行人体试验的ticilimumab(CP-675、206，Pfizer)。公开/公告号为WO 2012/120125，US 6,984,720和US6,682,7368及申请号为US2002/0039581，US2002/0086014和US2005/0201994的美国专利申请披露了其他可采用的能够靶向CTLA-4的抗体。本领域技术人员应当理解，任何可以与CTLA-4结合，抑制其与CD80和CD86相互作用并促进抗肿瘤免疫反应的抗体均可用于本发明披露的联合治疗应用中
在一些实施例中，所述联合治疗包括使用本领域技术人员所了解的能够和LAG-3结合的抗体并抑制其与MHC II的相互作用。一个示例性的靶向LAG-3的抗体为IMP321(Immutep)，其目前正在进行临床试验。美国专利申请2011/0150892披露了其他可采用的能够靶向LAG-3的抗体，本领域技术人员应当理解，任何可以与LAG-3结合，抑制其与与MHC II相互作用，并促进抗肿瘤免疫反应的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合TIM-3并抑制其与半乳糖凝集素-9相互作用的抗体或其片段。美国专利申请2013/0022623披露了可采用的能够靶向TIM-3的抗体。本领域技术人员应当理解，任何可以与TIM-3结合，抑制其与半乳糖凝集素-9相互作用，并促进抗肿瘤免疫反应的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合4-1BB/CD137并抑制其与CD137L相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与4-1BB/CD137结合，抑制其与CD137L或其他配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合GITR并抑制与其配体相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与GITR结合，抑制与GITRL或其他配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用,的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合OX40并抑制与其配体相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与OX40结合，抑制与OX40L或其他配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合CD40并抑制与其配体相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与CD40结合，抑制与其配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合ICOS并抑制与其配体相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与ICOS结合，抑制与其配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用的抗体均可用于本发明披露的联合治疗应用中。
在一些实施例中，所述抗原结合部分包括本领域技术人员所了解的可以结合CD28并抑制与其配体相互作用的抗体或其片段。本领域技术人员应当理解，任何可以与CD28结合，抑制与其配体相互作用，并促进抗肿瘤免疫应答或免疫刺激反应而达到总的抗癌作用的抗体均可用于本发明披露的联合治疗应用中。
其他示例性的抗原结合部分包括曲妥珠单抗、利妥昔单抗、本妥昔单抗(brentuximab)、西妥昔单抗、帕尼单抗、GC33(或其人源化版本)、抗EGFR抗体mAb806(或其人源化版本)在一些实施例中，抗原结合部分至少有90％、91％、92％、93％、94％、95％、96％、97％、98％或99％与曲妥珠单抗、利妥昔单抗、本妥昔单抗(brentuximab)、西妥昔单抗或帕尼单抗、GC33(或其人源化版本)、抗EGFR抗体mAb806(或其人源化版本)或其片段一致。在一些实施例中，抗原结合部分有一个抗体重链，其至少有90％，91％，92％，93％，94％，95％，96％，97％，98％或99％与曲妥珠单抗，利妥昔单抗，本妥昔单抗，西妥昔单抗，帕尼单抗，GC33(或其人源化版本),抗-EGFR抗体mAb806(或其人源化版本)及片段形式一致的同源性。在一些实施例中，抗原结合部分有一个抗体轻链，其至少有90％，91％，92％，93％，94％，95％，96％，97％，98％或99％与曲妥珠单抗，利妥昔单抗，本妥昔单抗，西妥昔单抗，帕尼单抗，GC33(或其人源化版本)，抗-EGFR抗体mAb806(或其人源化版本)及片段形式一致的同源性。所述抗原结合部分和IL-15多肽融合。在一些实施例中，抗原结合部分包括曲妥珠单抗、利妥昔单抗、本妥昔单抗、西妥昔单抗、帕尼单抗、GC33或抗EGFR抗体mAb806的6个互补决定区(CDRs)
许多CDR描述是本领域已知的，并引用至本文中。本领域技术人员可以基于重链或轻链可变区的序列，轻易地确定所给定描述的CDR。“Kabat”CDR乃基于序列可变性且最为常用(Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.PublicHealth Service,National Institutes of Health,Bethesda,Md.(1991))。“Chothia”CDR是指结构环的位置(Chothia&Lesk,Canonical structures for the hypervariableregions of immunoglobulins,J.Mol.Biol.,vol.196,pp.901-917(1987))。“AbM”CDR代表了Kabat CDR和Chothia结构环之间的折衷，其亦被牛津分子(Oxford Molecular)的AbM抗体建模软件使用。“Contact”CDR为基于对可用复杂晶体结构的分析。参考常见的抗体编号方案，这些CDR的各个残基在下表1中列出。除非本文另有说明，否则抗体中的氨基酸编号是指如上文Kabat等人所述的Kabat编号方案，其包括当参照Kabat，Chothia，AbM或Contact方案进行CDR描述时。使用该编号系统，实际的线性氨基酸序列可以包含较少或额外的氨基酸，其对应于可变结构域的框架区(FR)或CDR的缩短或插入。例如，重链可变域可以包括在H2的残基52之后的单个氨基酸插入(根据Kabat的残基52a)，亦包括在重链FR残基82之后的插入的残基(例如，根据Kabat的残基82a，82b和82c等)。对于所给定的抗体，通过在抗体序列同源区域与“标准”Kabat编号序列进行比对，可以确定其抗体残基的Kabat编号。
表1.根据各种方案的CDR描述
在一些实施例中，CDRs是“扩展的CDRs”，包含根据不同方案开始或结束区域。例如，扩展的CDR可如下所示:L24-L36，L26-L34，或L26-L36(VL-CDR1)；L46-L52，L46-L56，或L50-L55(VL-CDR2)；L91-L97(VL-CDR3)；H47-H55,H47-H65，H50-H55，H53-H58，或H53-H65(VH-CDR2；和/或H93-H102(VH-CDR3)。
在一些实施例中，与EGFR结合的抗原结合部分，包括与SEQ ID NO:88的氨基酸序列或其片段具有至少90％,91％，92％，93％，94％，95％，96％，97％，98％，或99％同源性的轻链，和与SEQ ID NO:89的氨基酸序列或其片段具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％,或99％同源性的重链。在一些实施例中，抗原结合域包括SEQ IDNO:88的CDR1、CDR2和CDR3，以及SEQ ID NO:89的CDR1、CDR2和CDR3。
在一些实施例中，与EGFR结合的抗原结合部分，包括与SEQ ID NO:90的氨基酸序列或其片段具有至少90％,91％，92％，93％，94％，95％，96％，97％，98％，或99％同源性的轻链，和与SEQ ID NO:91的氨基酸序列或其片段具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％,或99％同源性的重链。在一些实施例中，抗原结合域包括SEQ IDNO:90的CDR1、CDR2和CDR3，以及SEQ ID NO:91的CDR1、CDR2和CDR3。
在一些实施例中，与c-MET结合的抗原结合部分，包括与SEQ ID NO:92的氨基酸序列或其片段具有至少90％,91％，92％，93％，94％，95％，96％，97％，98％，或99％同一性的轻链，和与SEQ ID NO:93的氨基酸序列或其片段具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％,或99％同一性的重链。在一些实施例中，抗原结合域包括SEQ IDNO:92的CDR1、CDR2和CDR3，以及SEQ ID NO:93的CDR1、CDR2和CDR3。
在一些实施例中，与GPC3结合的抗原结合部分，包括与SEQ ID NO:94的氨基酸序列或其片段具有至少90％,91％，92％，93％，94％，95％，96％，97％，98％，或99％同一性的轻链，和与SEQ ID NO:95的氨基酸序列或其片段具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％,或99％同一性的重链。在一些实施例中，抗原结合域包括SEQ IDNO:94的CDR1、CDR2和CDR3，以及SEQ ID NO:95的CDR1、CDR2和CDR3。
在一些实施例中，与5T4结合的抗原结合部分，包括与SEQ ID NO:98或99的氨基酸序列具有至少90％,91％，92％，93％，94％，95％，96％，97％，98％，或99％同一性的轻链可变区，和与SEQ ID NO:96或97的氨基酸序列或其片段具有至少90％，91％，92％，93％，94％，95％，96％，97％，98％,或99％同一性的重链可变区。在一些实施例中，抗原结合域包括SEQ ID NO:98或99的CDR1、CDR2和CDR3，以及SEQ ID NO:96或97的CDR1、CDR2和CDR3。
在一些实施例中，与Trop-2结合的抗原结合部分，包含轻链可变区和重链可变区，所述轻链可变区包含KASQDVSIAVA(SEQ ID NO:125)氨基酸序列的CDR1，SASYRYT(SEQ IDNO:126)氨基酸序列的CDR2，QQHYITPLT(SEQ ID NO:127)氨基酸序列的CDR3；所述重链可变区，包括NYGMN(SEQ ID NO:128)氨基酸序列的CDR1、WINTYTGEPTYTDDFKG(SEQ ID NO:129)氨基酸序列的CDR2，和GGFGSSYWYFDV(SEQ ID NO:130)氨基酸序列的CDR3。
在一些实施例中，与间皮素结合的抗原结合部分，包含轻链可变区和重链可变区，所述轻链可变区包含SASSSVSYMH(SEQ ID NO:131)氨基酸序列的CDR1，DTSKLAS(SEQ IDNO:132)氨基酸序列的CDR2，QQWSGYPLT(SEQ ID NO:133)氨基酸序列的CDR3；所述重链可变区包括GYTMN(SEQ ID NO:134)氨基酸序列的CDR1、LITPYNGASSYNQKFRG(SEQ ID NO:135)氨基酸序列的CDR2，和GGYDGRGFDY(SEQ ID NO:136)氨基酸序列的CDR3。
在一些实施例中，抗原结合部分包括一个、两个或三个抗原结合结构域。例如，抗原结合部分是双特异性的，可与两种不同的抗原结合，这两种抗原选自HER2、HER3、EGFR、5T4、FAPα、Trop-2、GPC3、VEGFR2、Claudin 18.2和PD-L1。在一些实施例中，上述抗原结合的双特异性部分可以与同一抗原的两个不同表位结合，比如与HER2的两个不同表位结合。
2.其他载体部分
其他非抗原结合的载体部分亦可以用于本发明的前药。例如，抗体Fc结构域(例如人IgG1，IgG2，IgG3或IgG4 Fc)，聚合物(例如PEG)，白蛋白(例如人白蛋白)，或其片段，或纳米颗粒，均可使用。
举例来说，可以将IL-15多肽、Sushi域和IL-15拮抗剂与抗体Fc结构域融合，形成Fc融合蛋白。在一些实施例中Sushi域可选地融合到Fc结构域其中一条重链的C末端或N末端，IL-15多肽通过不可切割连接物融合到Sushi域的C末端或N末端，且掩蔽部分通过可切割的肽或不可切割的连接物融合到Fc结构域的另一条重链的C末端或N末端。在一些实施例中，每一条重链的Fc结构域均包括允许其形成配对的突变。在一些实施例中，所述突变包括knobs-into-holes、YTE和/或LALA突变。
前药的载体部分可包含白蛋白(例如人血清白蛋白)或其片段。在一些实施例中，白蛋白或其片段，与人血清白蛋白或其片段相比具有约85％或更多，约90％或更多，约91％或更多，约92％或更多，约93％或更多，约94％或更多，约95％或更多，约96％或更多，约97％或更多，约98％或更多，约99％或更多，约99.5％或更多，约99.8％或更多的同源性。
在一些实施例中，载体部分包括约10或更多，20或更多，30或更多，40或更多，50或更多，60或更多，70或更多，80或更多，90或更多，100或更多，120或更多，140或更多，160或更多，180或更多，200或更多，250或更多，300或更多，350或更多，400或更多长度为450或更多，500或更多或550或更多氨基酸长度的白蛋白片段(例如，人血清白蛋白)。在一些实施例中，白蛋白片段为约10个氨基酸长度与约584个氨基酸长度之间(例如在约10与约20，约20与约40，约40与约80，约80与约160，约160与约250，约250和约350，约350和约450，或约450和约550个氨基酸之间)。在一些实施例中，白蛋白片段包括Sudlow I结构域或其片段，或是Sudlow II结构域或其片段。
D.前药连接物的构成
IL-15多肽及Sushi域可以在具有或不具有连接肽的情况下与载体部分融合，连结肽可以是不可切割的。在一些实施例中，连接肽选自SEQ ID NO:11-16。在一些特定的实施例中，连接肽包含氨基酸序列GGGGSGGGGSGGGGS(SEQ ID NO:13)。
在一些实施例中，IL-15多肽(A)通过连接肽和Sushi域(S)融合，所述肽连接物为至少25、30或35个氨基酸长度。在一些实施例中。肽连接物为25-45个氨基酸。在一些实施例中，肽连接物为25，26，27，28，29，30，31，32，33，34，35，36，37，38，39，40，41，42，43，44或45个氨基酸。在一些实施例中，连接物包括氨基酸序列GSAGSAAGSGEF(SEQ ID NO:138)。在一些实施例中，连接物包括氨基酸序列(GGGGS)n1GSAGSAAGSGEF(GGGGS)n2(SEQ ID NO:139)，其中n1＝1，2或3且n2＝1，2或3。在一些实施例中，连接物包括氨基酸序列(GGGGS)n1AA(GGGGS)n2(SEQ ID NO:140)，其中n1＝2或3，n2＝2或3。
掩蔽部分通过可切割连接物融合到载体，所述可切割连接物包括一个或多个(例如两个或三个)可切割部分(CM)。每个CM可以为选自天冬酰胺内肽酶(legumain),血纤维蛋白溶酶(plasmin)，TMPRSS-3/4,MMP-2,MMP-9,MT1-MMP,组织蛋白酶(cathepsin)，含半胱氨酸的天冬氨酸蛋白水解酶(caspase)，人嗜中性粒细胞弹性蛋白酶(human neutrophilelastase)，β分泌酶(beta-secretase)，uPA,或PSA的酶底物或蛋白酶底物。比如可切割连接物包括但不限于包含选自SEQ ID NO:17-35及36的氨基酸序列
在一些实施例中，本发明披露的IL-15前药包括通过肽连接物和IL-15多肽融合的IL-15受体αSushi域(S)。在一些实施例中，所述肽连接物包括至少20个氨基酸、至少25个氨基酸、至少30个氨基酸、至少35个氨基酸、至少40个氨基酸；或者为27个氨基酸、32个氨基酸、37个氨基酸、42个氨基酸或47个氨基酸。
II.IL-15前药举例
在一些实施例中，可活化的IL-15前药具有任一如图1A-1C及图2A-2C所示的分子结构。在一些特定的实施例中，IL-15前药具有任一如图1B或图2B所示的分子结构。在一些实施例中，IL-15前药包括任一如图3A-3C所示的结构。在一些特定的实施例中，IL-15前药包括如图3B所示的结构。在一些实施例中，载体部分为包括如图4A、4B、5A或5B所示的抗原结合部分的抗体。在一个优选的实施例中，IL-15前药包括如图4B或5B所示的结构。
IL-15前药可以不含Sushi域或任何其功能类似物。在一些实施例中，所述IL-15前药包括具有一个或多个突变位点的IL-15多肽，突变位点选自E46，V49，L45，S51及L52(序号和SEQ ID NO:2一致)。在一些实施例中，所述IL-15多肽包括突变E46K(序号和SEQ ID NO:2一致)。在其他实施例中，所述IL-15多肽包括突变E46K/N65D(序号和SEQ ID NO:2一致)。在另外其他实施例中，所述IL-15多肽包括突变E46K/Q108E(序号和SEQ ID NO:2一致)。
在一些实施例中，本发明披露的IL-15前药包括IgG1 Fc结构域作为其载体部分，例如，IL-15前药可选自表2。在其他实施例中，本发明披露的IL-15前药包括IgG4 Fc结构域，例如，IL-15前药可选自表3。在一些实施例中，本发明披露的IL-15包括可结合人源PD-L1的抗体作为载体部分，例如，IL-15前药可选自表4.在一些实施例中，本发明披露的IL-15前药包括可结合人源PD-1的抗体作为载体部分，例如，IL-15前药可选自表5。
表2.可活化的IgG1 Fc-IL-15融合多肽举例
表3.可激活的IgG4 Fc-IL-15融合多肽举例
表4.可激活的PD-L1抗体/IL-15融合多肽举例
表5.可激活的PD-1抗体-IL-15融合多肽举例
下述序列表并非具有限定意义地列举了一些特定的IL-15多肽，Sushi域，细胞因子的拮抗剂/掩蔽部分，载体，肽连接物，和前药。此外，本发明的前药通过众所周知的重组技术制备。例如，可将包含编码前药中多肽链的序列的一个或多个表达载体，转染至哺乳动物宿主细胞(例如，CHO细胞)中，在允许编码序列表达并将表达的多肽组装成前药复合物的条件下培养细胞。为了使前药保持无活性，可以使用不表达或微量表达uPA，MMP-2和/或MMP-9的宿主细胞。在一些实施例中，宿主细胞可包含这些蛋白酶基因的无效突变(敲除)。
III.药物组合物
对包含了本发明中前药和突变蛋白(例如，活性药物成分或API)的药物组合物，可藉将所需纯度的API与一或多种可选择的药学上可接受赋形剂混合来制备(参见，例如，Remington's Pharmaceutical Sciences,16th Edition.,Osol,A.Ed.(1980))in theform of lyophilized formulations or aqueous solutions.)，其形式为冻干制剂或水溶液。药学上可接受的赋形剂(或载体)通常在使用的剂量和浓度下对给予者无毒，包括但不限于：缓冲剂含有例如包括，磷酸盐，柠檬酸盐，琥珀酸盐，组氨酸，乙酸盐或另一种无机或有机酸或其盐；抗氧化剂，包括抗坏血酸和蛋氨酸；防腐剂(例如十八烷基二甲基苄基氯化铵；六甲基氯化铵；苯扎氯铵；苄索氯铵；苯酚，丁醇或苄醇；对羟基苯甲酸烷基酯如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯；邻苯二酚；间苯二酚；间苯二酚；3-戊醇和间甲酚)；低分子量(少于约10个残基)多肽；蛋白质，例如血清白蛋白，明胶或免疫球蛋白；亲水性聚合物，例如聚乙烯吡咯烷酮；氨基酸，例如甘氨酸，谷氨酰胺，天冬酰胺，组氨酸，精氨酸或赖氨酸；单糖，二糖和其他碳水化合物，包括蔗糖，葡萄糖，甘露糖或糊精；螯合剂，如EDTA；糖，例如蔗糖，甘露醇，海藻糖或山梨糖醇；成盐的抗衡离子，例如钠；金属配合物(例如锌-蛋白配合物)；和/或非离子表面活性剂，例如聚乙二醇(PEG)。
缓冲剂用于将pH控制在最佳的治疗效果范围内，特别是当稳定性依赖于pH时。缓冲液浓度最好在50mM到250mM之间。适用于与本发明一起使用的缓冲剂包括有机和无机酸及其盐类，如柠檬酸盐、磷酸盐、琥珀酸盐、酒石酸盐、富马酸盐、葡萄糖酸盐、草酸盐、乳酸盐和醋酸盐。此外，缓冲液可包括组氨酸和三甲胺盐，如三羟甲基氨基甲烷。
添加防腐剂以减缓微生物的生长，通常在0.2％-1.0％(w/v)范围内存在。本发明使用的适用防腐剂包括十八烷基二甲基苄基氯化铵；六甲铵氯化物；苯扎卤铵(如氯、溴、碘)、苯扎氯铵；硫柳汞、苯酚、丁基或苄醇；羟苯甲酸甲酯或羟苯甲酸丙酯；邻苯二酚；间苯二酚；环己醇，3-戊醇和间甲酚。
张度剂，有时称为“稳定剂”，是用以调节或维持成分中液体的张力。当其与带电荷的生物大分子(如蛋白质和抗体)一起使用时，它们通常被称为“稳定剂”，因其可与氨基酸侧链的带电基团相互作用，从而降低了分子间和分子内相互作用的可能性。当考虑其他成分的相对量时，张度剂可在0.1％至25％重量比之间的任何量使用，或更优选于1％至5％重量比之间。优选的张度剂包括多元糖醇，更优选地为三元或更高级的糖醇，例如甘油，赤藓糖醇，阿拉伯糖醇，木糖醇，山梨糖醇和甘露糖醇。
非离子表面活性剂或去污剂(也称为“湿润剂”)，被用以帮助溶解治疗剂，并保护治疗蛋白避免因搅动所导致的聚集，其亦允许了该制剂配方可暴露于剪切表面应力而不引起活性治疗性蛋白或抗体的变性。非离子表面活性剂的使用范围为约0.05mg/ml至约1.0mg/ml，优选地为约0.07mg/ml至约0.2mg/ml。
合适的非离子表面活性剂包括聚山梨酸酯(20、40、60、65、80等)，泊咯沙姆(184、188等)，普朗尼克多元醇，曲拉通，聚氧乙烯山梨糖醇单醚(吐温-20，吐温-80等)，聚桂醇400，聚氧化烯硬脂酸酯40，聚氧乙烯氢化蓖麻油10、50和60，单硬脂酸甘油酯，蔗糖脂肪酸酯，甲基纤维素和羧甲基纤维素。可使用的阴离子去污剂包括月桂基硫酸钠，磺基琥珀酸二辛酯钠和磺酸二辛基钠。阳离子去污剂包括苯扎氯铵或苄索氯铵。
药物载体、赋形剂或稀释剂的选择可根据预定的给药途径和标准制药实践。药物组合物还可包括适合的粘合剂、润滑剂、悬浮剂、涂层剂或增溶剂。
根据不同的药物传递系统，可能需要不同的成分/处方要求。举例来说，本发明中有用的药物组合物可被配制成适用于微型泵或通过粘膜途径传递，例如，作为鼻用喷雾剂或气雾剂用于吸入或可吸收溶液，亦或配制成注射形式的成分以肠胃外地给药，其藉由例如静脉内，肌内或皮下途径传递。
在一些实施例中，本发明的药物组合是一种冻干蛋白制剂。在其他实施例中，所述药物组合物可以是水溶剂制剂。
IV.治疗方法
IL-15前药可用于治疗疾病，其取决于抗原结合结构域所结合的抗原。在一些实施例中，IL-15前药前药用于治疗癌症。在一些实施方案中，例如当药物分子为抗菌药或抗病毒药时，IL-15前药用于治疗感染。
在一些实施例中，治疗受试者疾病(例如癌症，病毒感染或细菌感染)的方法包含向对象施用有效量的IL-15前药。在其他实施例中，治疗方法进一步包括联合IL-15前药(在前药施用前、施用后，或同时施用)施用额外的治疗剂，所述额外的治疗剂可以为抗体或其片段，小分子药或其他类型的治疗用药，本发明中已披露其中一些药物。
在一些实施例中，癌症是实体癌。在一些实施例中，癌症是血液癌或实体瘤。可治疗的示例性癌症包括但不限于，白血病，淋巴瘤，肾癌，膀胱癌，泌尿道癌，子宫颈癌，脑癌，头颈癌，皮肤癌，子宫癌，睾丸癌，食道癌，肝癌，大肠癌，胃癌，鳞状细胞癌，前列腺癌，胰腺癌，肺癌，例如非小细胞肺癌，胆管癌，乳腺癌和卵巢癌。
在一些实施例中，IL-15前药用于治疗细菌感染，如脓毒症。在一些实施例中，引起细菌感染的细菌是耐药细菌。在一些实施例中，抗原结合部分与细菌抗原结合。
在一些实施例中，IL-15前药用于治疗病毒感染。在一些实施例中，引起病毒感染的病毒是丙型肝炎病毒(HCV)、乙型肝炎病毒(HBV)、人体免疫缺陷病毒(HIV)或人类乳头瘤病毒(HPV)。在一些实施例中,抗原结合部分与病毒抗原相结合。
一般来说，现有药物的给药剂量和给药途径是根据受试者的情况和条件，按照标准的药学实践确定。在一些实施例中，药物成分给予是通过任一给药路径，包括口服、皮下、吸入、静脉注射、动脉内的、肌内、直接应用于伤口，应用手术部位、腹腔内、栓剂、皮下、皮内注射、经皮、雾化、胸膜腔内、脑室、关节内的、眼内、颅内或脊柱内。在一些实施例中，药物被静脉注射给受试者。
在一些实施例中，药物组合物的剂量是单剂量或重复剂量。在一些实施例中，剂量为每天一次，每天两次，每天三次，或每天四次或更多次给予给药对象。在一些实施方案中，一周内给予约1次或更多(例如约2、3、4、5、6或7或更多)剂量。在一些实施例中，药物组合物以每周一次，每两周一次，每三周一次，每四周一次，每周一次，每三周中的两周，或每四周中的三周，来实施给药。在一些实施例中，多次剂量于几天，几周，几个月或几年的过程中给予。在一些实施方案中，治疗过程为约1或更多剂量(例如约2、3、4、5、7、10、15或20或更多剂量)。
除非本文另外定义，否则与本发明相关的科学和技术术语，应具有本领域普通技术人员通常理解的含义。示例性方法和材料如下所描述，但与本文描述的那些类似或等同的方法和材料亦可被用于本发明的实践或试验。如有冲突，以本规范说明，包括定义，为准。通常，本文所述相关于细胞和组织培养，分子生物学，免疫学，微生物学，遗传学，分析化学，合成有机化学，医学和药物化学，以及蛋白质和核酸化学，以及杂交混合的命名法和技术均为本领域众所周知和常用的。酶促反应和纯化技术乃根据制造商的规范说明执行，如本领域通常达成的或如本文所述。此外，除非上下文另外要求，否则单数术语应包括复数，并且复数术语应包括单数。在整个规范说明和实施方案中，词语“具有”和“包含”，或其同义、替代词及变体，将被理解为暗示着包括了所述整数或整数组，但不排除任何其他整数或整数组。应当理解，本文所述发明的方面和变化包括"由……组成"和/或"基本上由……组成"的方面和变化。尽管本文引用了许多文件，但该引用并不构成承认这些文件中的任何文件形成本领域公知常识的一部分。
具体实施例
HEK293细胞的瞬时转染
使用PEI(聚乙烯亚胺)将表达质粒以2.5–3μg/ml转染到3x106活细胞/ml的自由式(Freestyle)HEK293细胞中。对于基于Fc的IL-15前药，所述Fc-IL-15突变体融合多肽和Fc-掩蔽部分融合多肽的比例为1：2。对于基于抗体的IL-15前药，knob重链(包含IL-15多肽)和hole重链(包含掩蔽部分)与轻链DNA的摩尔比为2：1：2。转染后6天，通过在9,000rpm下离心45分钟，而后0.22μM过滤，来收获细胞培养物。
蛋白纯化
大体来说，Fc-和基于抗体的IL-15融合多肽依次经过Protein A亲和层析、离子交换层析、疏水作用层析，和/或尺寸排阻色谱进行纯化。在一些实施例中，基于抗体的IL-15前药的纯化操作包括四个层析步骤：1)Protein A亲和层析，2)以流穿模式进行的CaptoTMAdhere，3)CaptoTM MMC ImpRes，以及4)以流穿模式进行的Q 
HP。CaptoTMAdhere用含有50mM醋酸，30mM氯化钠(pH 5.5)的缓冲液进行平衡，CaptoTM MMC ImpRes用缓冲液A(50mM醋酸，30mM氯化钠，pH 5.5)进行平衡并用缓冲液B(50mM醋酸，0.5M精氨酸，pH5.5)以30柱体积的线性梯度进行洗脱。Q
HP用40mM Bis Tris,pH 6.5进行平衡。
SEQ-HPLC分析
SEC-HPLC的分析是在Agilent 1100系列HPLC系统上进行并配以TosohBioscience的
色谱柱(7.8mmIDX 30cm，粒径5μm)。上样至多100μl，色谱柱的流动相为200mM K3PO4、250mM KCl，pH 6.5的缓冲液。，流速设定为0.5ml/min。柱温为室温。蛋白质洗脱的检测UV为220nm和280nm。
SDS-PAGE分析
将10μl培养物上清液或20μg纯化后的蛋白样品与具有或不具有还原剂的BoltTMLDS样品缓冲液(Novex)混合。样品于70℃加热3分钟，然后加载到NuPAGETM 4-12％BisTris凝胶(Invitrogen)上。该凝胶在NuPAGETM MOPS SDS运行缓冲液(Invitrogen)中以200伏特运行40分钟，然后使用考马斯染色。
蛋白水解处理
将1μg的蛋白酶，人MMP-2(R&D systems)，人MMP-9(R&D systems)，鼠MMP-2(R&Dsystems)或鼠MMP-9(R&D systems)加入到50μg的蛋白前体，并在37℃条件下过夜。
CTLL2分析
CTLL2细胞在RPMI-1640培养基中生长，培养基中添加L-谷氨酰胺、10％胎牛血清、10％非必需氨基酸、10％丙酮酸钠和55μM巯基乙醇。CTLL2细胞不贴壁，在IL-15浓度为100ng/ml的培养基中维持在5x104-1x106细胞/ml。一般来说，细胞每周分裂两次,对于生物测定，最好使用传代后不少于48小时的细胞。
在96孔板中以50μL每孔将样品以2x浓度稀释。于12个孔中，将IL-15标准品从20ng/mL(2倍浓度)滴定至3x连续稀释。适当地对样品进行滴定度测试。将CTLL2细胞清洗5次以去除IL-15，向每孔的50μl中分配5000个细胞，并与样品一起培养过夜或至少18个小时。随后，每孔加入100μl Cell Titer Glo试剂(Promega)并测定荧光强度。
NK92增殖分析
NK92细胞增值分析根据如下实验方案进行。
NK92细胞系为因子依赖型的细胞系，其需要IL-2来维持生长和存活。在分析检测前，清洗所述细胞以去除IL-2，并在没有生长因子的条件下培养过夜。收集细胞并再次清洗以去除残留的生长因子，并将其(20000细胞/孔)加入含有连续稀释的待测样品和对照品的96孔板中。将上述细胞培养板培养过夜并加入Cell Titer Glo试剂(Promega)，测定其荧光值。本实验提供了一种利用ATP水平作为细胞活性指标的方法。
多个IL-15前药进行前述分析，所述IL-15前药分别用IL-2Rβ胞外域(ECD)，IL-2RβECD和IL-2RγECD，以及来自于IL-15抗体146B7的scFv分子掩蔽。
pSTAT5分析
NK92/pSTAT5稳定细胞系在添加有0.1％FBS的RPMI 1640培养基中饥饿培养过夜，以每孔5x105个细胞的密度将其接种植96孔板中并在37℃和5％CO2的条件下培养过夜。将IL-15融合多肽加入细胞中并在培养箱中培养5-6个小时。随后，向其加入100μl的PierceTMFirefly Luc One-Step Glow Assay检测试剂并利用光度计读取其生物荧光度。
酶联免疫吸附测定(ELISA)
向96孔板的每孔加入100μl浓度为10μg/ml的IL-15融合蛋白，其中IL-15融合蛋白溶于PBS中，并于4℃下过夜包被。每孔用PBS清洗3次并用100μl含2％脱脂奶粉的PBS缓冲液封闭1个小时，再将每孔用PBS清洗3次并加入100μl，3倍梯度稀释的蛋白样品，并于室温(RT)培养1个小时。经过3次PBS清洗后，向其加入100μl的HRP偶联抗IgG抗体并于室温培养1个小时。随后培养孔用PBS再清洗3次，加入检测试剂并在检测波长405nm下检测OD值。
实施例1：IL-15前药的表达及测定
发明人构建大量的前药并使其在HEK293细胞(如图6A和图10A)中重组表达。在所述IL-15前药中，表达的IL-15多肽作为融合多肽的一部分，其生物学活性被检测。其中一些表达的IL-15融合多肽的序列如图6A，图10A及图12A所示。
表达的IL-15融合多肽在活化前后分别进行SDS-PAGE检测(图7A，非还原性；及图7B，还原性)，结果显示样品JR3.68.1，JR3.68.2及JR3.68.3的掩蔽部分在蛋白酶处理后被成功水解下来。
实施例2：可活化的IL-15前药组分的纯化
利用Protein A柱纯化可活化的IL-15前药：JR3.68.1，JR3.68.2和JR3.68.3，并利用SEC-HPLC进行分析。JR3.68.1(图1A)包括一个通过肽连接物融合到Fc结构域其中一条重链C末端的Sushi域，IL-15多肽通过肽连接物融合到Sushi域的C末端，掩蔽部分(IL2RβECD)融合到Fc结构域另一条重链的C末端。JR3.68.2如图1B所示，JR3.63.3如图1C所示。
当用Protein A亲和柱层析纯化时，发明人惊喜地发现，前药分子的多个组分间的结构、排列、相对位置及布局对药物聚集程度有显著影响。Fc-Sushi-IL-15结构(包括两条多肽链：SEQ ID NO:37及SEQ ID NO:38)(JR3.68.1)相较于Fc-IL-15-Sushi结构(JR3.68.2，包括两条多肽链SEQ ID NO:37及SEQ ID NO:40)明显具有较高的纯度(具有较高的主峰，图8A)以及具有较低的聚集程度(图8B)。同时，Sushi域和细胞因子分别位于Fc结构域两条不同重链上的结构的SEC-HPLC主峰纯度比JR3.68.2(JR3.68.3，图8C)高，比JR3.68.1(图8A)低。当载体为抗体(如，nivolumab，抗人源PD-1抗体；图11B，JR3.73.2vsJR3.73.4)时，其现象具有和上述相同的趋势。
发明人出乎意料地发现增加掩蔽部分后，融合多肽的纯度明显提高。以抗体作为载体的IL-15前药JR3.73.2相较于JR3.74.1的激活形式(图11A和图11B)具有更高的SEC-HPLC单体纯度。而JR3.74.1的单体峰具有一个明显的肩峰(图11A)，表明在进一步纯化过程中存在潜在的挑战。
实施例3.IL-15前药的细胞活性
CTLL2分析
IL-15前药JR3.68.1，JR3.68.2及JR3.68.3在活化前后对CTLL2细胞活性的影响如图9A-9C所示，结果表明，JR3.68.1在蛋白酶处理后具有明显的活化作用。以抗体作为载体部分的IL-15前药的细胞活性如图11C所示，结果表明，IL-15前药JR3.73.被活化。
NK92分析
研究分析分别被scFv分子(来自IL-15抗体146B7)、IL-2RβECD或IL-2RβECD和联合IL-2RγECD掩蔽的多个IL-15前药对NK92细胞增殖的影响。分别被来自IL-15抗体146B7的scFv1或scFv2掩蔽的IL-15前药对NK92细胞增殖分析结果表明，scFv2和scFv1均明显抑制了IL-15WT及具有N65D突变的IL-15突变体的活性(图12B)。
通过pSTAT5方法研究可活化的IL-15融合蛋白在活化前后对NK92细胞活性的影响。图13A显示scFv2和scFv1对野生型IL-15具有相同的抑制程度，且经蛋白酶处理后的融合多肽为活化状态。图13B显示scFv2能够显著地抑制具有N65D突变的IL-15突变体活性。结果也表明scFv1能有效地抑制IL-15突变体的活性。发明人出乎意料地发现在体外通过蛋白酶处理，但并不需要进一步纯化以去除水解下来的scFv分子在前提下，两种IL-15前药分子仍可被活化。发明人也惊喜地注意到scFv2相较于scFv1对N65D的IL-15突变体具有更强的抑制效果。
研究分析被IL-2Rβ或被IL-2Rβ联合IL-2Rγ掩蔽的可活化的IL-15融合多肽对NK92细胞活性的影响。在这些融合多肽中，野生型的IL-15被IL-2RβECD和IL-2RγECD掩蔽，结果表明，IL-2RβECD联合IL-2RγECD形成一个有效的野生型IL-15掩蔽部分，所述前药在蛋白酶处理后被活化(图14A)。具有Q18E突变的IL-15突变体(其在蛋白酶处理后被活化)被IL-2RβECD和IL-2RγECD掩蔽(图14C)
同样地，我们研究分析了不含有Sushi域的可活化的Fc-IL-15融合多肽(JR2.145.1)及在Sushi域和IL-15多肽部分之间具有较长连接物的融合多肽(JR2.145.2)对NK92细胞活性的影响。结果表明，上述两种情况对具有N65D突变的IL-15突变体具有明显掩蔽作用，说明在IL-15多肽缺少Sushi域的前提下，scFv2掩蔽部分有效抑制其活性。在Sushi域和IL-15多肽之间存在较长连接物(32个氨基酸)时，掩蔽部分同样很好地发挥其功能。
上述非限制性示例仅出于说明性目的而提供，以便于更全面地理解所公开的主题。这些示例不应被解释为限制本说明书中描述的任何实施方案，包括那些涉及抗体，药物组合物，或用于治疗癌症，神经变性或感染性疾病的方法和用途的实施方案。
序列表
下述序列中，加框的残基表示为突变；下划线标示的可切割的连接物表示为蛋白酶底物序列。
SEQ ID NO:1–人源IL-2
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
SEQ ID NO:2–人源IL-15
NWVNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISLESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQSFVHIVQMFINT
SEQ ID NO:3–人源IL-2受体β亚基胞外域(uniprot/P14784)
AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT
SEQ ID NO:4–含突变D68E的人源IL-2受体β亚基胞外域(uniprot/P14784)
AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPESQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFERHLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT
SEQ ID NO:5–含突变E136Q/H138R的人源IL-2受体β亚基胞外(uniprot/P14784)
AVNGTSQFTCFYNSRANISCVWSQDGALQDTSCQVHAWPDRRRWNQTCELLPVSQASWACNLILGAPDSQKLTTVDIVTLRVLCREGVRWRVMAIQDFKPFENLRLMAPISLQVVHVETHRCNISWEISQASHYFQRRLEFEARTLSPGHTWEEAPLLTLKQKQEWICLETLTPDTQYEFQVRVKPLQGEFTTWSPWSQPLAFRTKPAALGKDT
SEQ ID NO:6–人源IL-2受体γ亚基胞外域(uniprot/P31785)
LNTTILTPNG NEDTTADFFL TTMPTDSLSV STLPLPEVQC FVFNVEYMNC TWNSSSEPQPTNLTLHYWYK NSDNDKVQKC SHYLFSEEIT SGCQLQKKEI HLYQTFVVQL QDPREPRRQA TQMLKLQNLVIPWAPENLTL HKLSESQLEL NWNNRFLNHC LEHLVQYRTD WDHSWTEQSV DYRHKFSLPS VDGQKRYTFRVRSRFNPLCG SAQHWSEWSH PIHWGSNTSK ENPFLFALEA
SEQ ID NO:7–IL-15受体α亚基胞外域
ITCPPPMSVE HADIWVKSYS LYSRERYICN SGFKRKAGTS SLTECVLNKA TNVAHWTTPSLKCIRDPALV HQRPA
SEQ ID NO:8–IL-15受体α的氨基酸序列
MAPRRARGCR TLGLPALLLL LLLRPPATRG ITCPPPMSVE HADIWVKSYS LYSRERYICNSGFKRKAGTS SLTECVLNKA TNVAHWTTPS LKCIRDPALV HQRPAPPSTV TTAGVTPQPE SLSPSGKEPAASSPSSNNTA ATTAAIVPGS QLMPSKSPST GTTEISSHES SHGTPSQTTA KNWELTASAS HQPPGVYPQGHSDTTVAIST STVLLCGLSA VSLLACYLKS RQTPPLASVE MEAMEALPVT WGTSSRDEDL ENCSHHL
SEQ ID NO:9–IL-15受体α的Sushi域的氨基酸序列
ITCPPPMSVE HADIWVKSYS LYSRERYICN SGFKRKAGTS SLTECVLNKA TNVAHWTTPSLKCIR
SEQ ID NO:10–人源CCL19氨基酸序列
TNDAEDCC LSVTQKPIPG YIVRNFHYLL IKDGCRVPAV VFTTLRGRQL CAPPDQPWVERIIQRLQRTS AKMKRRSS
SEQ ID NOs:11-16肽连接物(不可切割的)
GGGGS(SEQ ID NO:11)
GGGGSGGGGS(SEQ ID NO:12)
GGGGSGGGGSGGGGS(SEQ ID NO:13)
GGGGSGGGGSXGGGGSGGGGS(SEQ ID NO:14),X＝A或N
GGGGSGGGGSXGGGGYGGGGS(SEQ ID NO:15),X＝S,A或N,Y＝A或N
GGGGSGGGGSGGGGSAAGGGGSGGGGSGGGGS(SEQ ID NO:16)
SEQ ID NOs:17-23–MMP-2/MMP-9可切割的肽连接物
GPLGVR(SEQ ID NO:17)
PLGMWSR(SEQ ID NO:18)
PLGLWAR(SEQ ID NO:19)
PQGIAGQR(SEQ ID NO:20)
PLGLAG(SEQ ID NO:21)
LALGPR(SEQ ID NO:22)
GGPLGMLSQS(SEQ ID NO:23)
SEQ ID NOs:24-32–尿激酶纤溶酶原激活剂(uPA)可切割的肽连接物GGGGRRGGS(SEQ ID NO:24)
TGRGPSWV(SEQ ID NO:25)
SARGPSRW(SEQ ID NO:26)
TARGPSFK(SEQ ID NO:27)
TARGPSW(SEQ ID NO:28)
GGWHTGRN(SEQ ID NO:29)
HTGRSGAL(SEQ ID NO:30)
PLTGRSGG(SEQ ID NO:31)
LTGRSGA(SEQ ID NO:32)
SEQ ID NO:33–蛋白裂解酶可切割的肽连接物
RQARVVNG
SEQ ID NO:34–蛋白裂解酶-MMP2/9双可切割的肽连接物
VHMPLGFLGPRQARVVNG
SEQ ID NO:35–可切割的肽连接物
GGSLSGRSDNHGGGGS
SEQ ID NO:36–可切割的连接物
GGGGSGGGGSGGGGSISSGLLSSGGSGGSLSGRSDNHGGGGS
SEQ ID NO:37–IgG1 Fc与IL-2Rβ的融合的氨基酸序列；Fc具有hole突变和LALA突变(CX5.51.1)
SEQ ID NO:38–IgG1 Fc与IL-15RαSushi和IL-15多肽的融合的氨基酸序列；Fc具有knob突变和LALA突变(CX5.51.4)
其中X1为选自N和D的氨基酸，X2为选自Q和E的氨基酸。
SEQ ID NO:39–Fc与IL-15RαSushi和IL-15多肽的融合的氨基酸序列；Fc具有knob突变；A和S之间具有较长连接物。
其中X1为选自N和D的氨基酸，X2选自Q和E的氨基酸。
SEQ ID NO:40 Fc-IL-15-Sushi knob
CX5.51.5
SEQ ID NO:41 Fc-IL-15 knob
CX5.51.6
SEQ ID NO:42 Fc-Sushi-beta hole(CX5.51.7)
SEQ ID NO:43 IgG1 Fc-Hole(CX5.43.8)
SEQ ID NO:44 Fc-IL-15 knob,含有E46K/N65D突变的IL-15
SEQ ID NO:45重链融合Sushi和IL-15多肽的PD-L1抗体1296，Fc具有Knob突变(CX5.48.1)。
其中，X1为选自N和D的氨基酸，X2选自Q和E的氨基酸
SEQ ID NO:46PD-L1抗体1296重链-IL-15融合Sushi域，Fc具有Knob突变(CX5.48.2)。
SEQ ID NO:47重链融合IL-2RβECD的PD-L1抗体1296,Fc具有Hole突变。
SEQ ID NO:48重链和可以结合IL-15的scFv1(VH-VL)融合的PD-L1抗体1296，Fc具有Hole突变。
SEQ ID NO:49重链和可以结合IL-15的scFv2(VL-VH)融合的PD-L1抗体1296，Fc具有Hole突变。
SEQ ID NO:50PD-L1抗体1296轻链
DIQMTQspSSLSASvGDRVTItCRASQDISNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSRFSGSGSGTDYtLTISsLqpEDIATYFCQQGKTLPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:51和basal IL-2v融合的PD-L1抗体1296轻链
SEQ ID NO:52重链融合Sushi域和IL-15多肽的PD-1抗体，Fc具有Knob突变(CX5.48.3)
SEQ ID NO:53PD-1抗体重链-IL-15然后Sushi域，Fc具有Knob突变(CX5.48.4)
SEQ ID NO:54PD-1抗体重链-beta hole(CX3.58.3)
SEQ ID NO:55PD-1抗体轻链(CX5.17.1)
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:56融合基础IL-2v的PD-1抗体轻链
SEQ ID NO:57PD-1 HC hole(CX3.58.4)
SEQ ID NO:58 PD-1抗体重链和Sushi域及N65D突变的IL-15多肽融合，Fc具有Knob突变。
SEQ ID NO:59 PD-1抗体重链和Sushi域及Q108E突变的IL-15多肽融合，Fc具有Knob突变。
SEQ ID NO:60 PD-1抗体重链-scFV1(VH-VL)hole
SEQ ID NO:61 PD-1抗体重链-scfv2(VL-VH)hole
SEQ ID NO:62 PD-1抗体重链和E46K突变的IL-15多肽融合，Fc具有Knob突变；；不含Sushi域。
SEQ ID NO:63 PD-1抗体重链和E46K/N65D突变的IL-15多肽融合，Fc具有Knob突变；；不含Sushi域。
SEQ ID NO:64 CX7_71_1PD1-IL-15vE46K,不含Sushi域,不含KIH
SEQ ID NO:65 PD1-IL-15vE46K/N65D,不含Sushi域,不含KIH
SEQ ID NO:66_CX7_53_2 PD1-ScFv2不含KIH
SEQ ID NO:67_CX7_53_1 PD1-Sushi-IL-15vN65D不含KIH
SEQ ID NO:68_CX7_53_1 PD1-Sushi-IL-15vN65D不含KIH,含长连接物
SEQ ID NO:69PD-1抗体重链和Sushi域融合，并结合N65D突变的IL-15多肽，Fc具有Knob突变,含长连接物
SEQ ID NO:70和抗IL-15的scFv融合的IgG1 Fc的氨基酸序列，Fc具有hole突变
SEQ ID NO:71第二种和抗IL-15的scFv融合的IgG1 Fc的氨基酸序列，Fc具有hole突变
SEQ ID NO:72第三种和抗IL-15的scFv融合的Fc的氨基酸序列，Fc具有hole突变
SEQ ID NO:73第四种和抗IL-15的scFv融合的Fc的氨基酸序列，Fc具有hole突变
SEQ ID NO:74IgG1 Fc-knob-Sushi-IL-15 IgG1_allotype EEM,LALA突变H435RY436F
SEQ ID NO:75IgG1 Fc-knob-IL-15(E46K/N65D)IgG1_allotype EEM,LALA突变
SEQ ID NO:76IgG1 Fc-knob-Sushi-IL-15(N65D)IgG1_allotype EEM,LALA突变H435R/Y436F
SEQ ID NO:77IgG1 Fc-knob-Sushi-IL-15 IgG1_allotype EEM,LALA突变H435RY436F
5’XbaI,3’PmeI
ASKGD111_CX5_75_3
SEQ ID NO:78 IgG1 Fc-knob-Sushi-IL-15(D30N,E64Q,N65D)IgG1_allotypeEEM,LALA突变H435R/Y436F
5’XbaI,3’PmeI
ASKGD111_CX5_74_1
SEQ ID NO:79IgG1 Fc-knob-Sushi-IL-15(N65D)IgG1_allotype EEM,LALA突变H435R/Y436F
5’XbaI,3’PmeI
ASKGD111_CX5_74_2
SEQ ID NO:80 IgG4 FC-scFV1(VH-VL)hole
SEQ ID NO:81 IgG4 FC-scfv2(VL-VH)hole
SEQ ID NO:82IgG4 Fc-knob-Sushi-IL-15(N65D)
SEQ ID NO:83IgG4 Fc-knob-Sushi-IL-15(N65D),长连接物
SEQ ID NO:84IgG4 Fc-knob-Sushi-IL-15(Q108E)
SEQ ID NO:85IgG4 Fc-knob-IL-15E46K,不含Sushi域
SEQ ID NO:86IgG4 Fc-knob-IL-15 E46K/N65D,不含Sushi域
SEQ ID NO:87IgG4 FC-IL2R_beta ECD hole
SEQ ID NO:88西妥昔单抗轻链
DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:89西妥昔单抗重链
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:90帕尼单抗轻链
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYFCQHFDHLPLAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:91帕尼单抗重链
GHIYYSGNTNYNPSLKSRLTISIDTSKTQFSLKLSSVTAADTAIYYCVRDRVTGAFDIWGQGTMVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDERKCCVECPAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:92抗-cMET抗体轻链
DIVMTQAAPSVPVTPGESVSISCRSSKSLLHSNGNTYLYWFLQRPGQSPQVLIYRMSNLASGVPDRFSGSGSGTAFTLRIRRVEAEDVGVYYCMQNLEYPFTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:93抗-cMET抗体重链
QVQLQQSGPELVKSGASVKMSCKASGNTLKDDHVHWVKQRPGQGLEWIGWIYPGGGRTRYNEKFKGKTTLTADKPSSTVNMLLSSLTSEDSAIYFCTNLVFDVWGAGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:94抗GPC3抗体轻链
DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSNANTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQNTHVPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:95抗GPC3抗体重链
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYEMHWVRQAPGQGLEWMGALDPKTGDTAYSQKFKGRVTLTADKSTSTAYMELSSLTSEDTAVYYCTRFYSYTYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:96第一种人源化的H8抗5T4的VH(蛋白序列)
QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVKQSPGQGLEWIGRINPNNGVTLYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSTMITNYVMDYWGQGTLWTVSS
SEQ ID NO:97第二种人源化的H8抗5T4的VH(蛋白序列)
QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYYMHWVRQAPGQGLEWMGRINPNNGVTLYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSTMITNYVMDYWGQGTLVTVSS
SEQ ID NO:98第一种人源化的H8抗5T4的VL(蛋白序列)
DIVMTQSPDSLAVSLGERATINCKASQSVSNDVAWYQQKPGQSPKLLISYTSSRYAGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCQQDYNSPPTFGGGTKLEIK
SEQ ID NO:99第二种人源化的H8抗5T4的VL(蛋白序列)
DIVMTQSPDSLAVSLGERATINCKASQSVSNDVAWYQQKPGQPPKLLIYYTSSRYAGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQDYNSPPTFGGGTKLEIK
SEQ ID NO:100抗IL-15抗体146B7 HC CDR1(蛋白序列)
TYWIG
SEQ ID NO:101抗IL-15抗体146B7 HC CDR2(蛋白序列)
IIYPGDSDTRYSPSFQG
SEQ ID NO:102抗IL-15抗体146B7 HC CDR3(蛋白序列)
GNWNCFDY
SEQ ID NO:103抗IL-15抗体146B7 LC CDR1(蛋白序列)
RASQSVSSSYLA
SEQ ID NO:104抗IL-15抗体146B7 LC CDR2(蛋白序列)
GASRRAT
SEQ ID NO:105抗IL-15抗体146B7 LC CDR3(蛋白序列)
QRYGSSHT
SEQ ID NO:106第二种抗IL-15抗体146B7 HC CDR3(蛋白序列)
GNWNSFDY
SEQ ID NO:107抗IL-15抗体146B7 HC可变区(蛋白序列)
EVQLVQSGAEVKKPGESLKISCKVSGYFFTTYWIGWVRQMPGKGLEYMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGNWNCFDYWGQGTLVTVSS
SEQ ID NO:108抗IL-15抗体146B7 LC可变区(蛋白序列)
EIVLTQSPGTLSLSPGREATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQRYGSSHTFGQGTKLEISRTVAAPSVFIFP
SEQ ID NO:109 anti-IL-15 scFv1
EVQLVQSGAEVKKPGESLKISCKVSGYFFTTYWIGWVRQMPGKGLEYMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGNWNCFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGREATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQRYGSSHTFGQGTKLEISR
SEQ ID NO:110 anti-IL-15 scFv2
EIVLTQSPGTLSLSPGREATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQRYGSSHTFGQGTKLEISRGGGGSGGGGSGGGGSEVQLVQSGAEVKKPGESLKISCKVSGYFFTTYWIGWVRQMPGKGLEYMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGNWNCFDYWGQGTLVTVSS
SEQ ID NO:111 IgG1 Fc-hole-Hv-Lv
ASKGD111_CX5_101_1
SEQ ID NO:112 IgG1 Fc-hole-Lv-Hv
ASKGD111_CX5_101_2
SEQ ID NO:113Fc-hole Fc-hole IgG1,LALA突变-IL2Rbeta-gamma
ASKGD111_CX5_105_1
SEQ ID NO:114Fc-hole IgG1,LALA突变-IL2R-gamma-beta
ASKGD111_CX5_105_2
SEQ ID NO:115Fc-hole Fc-hole IgG1,LALA突变-IL2R-beta-Ctergamma
ASKGD111_CX5_105_3
SEQ ID NO:116Fc-knob-Sushi-IL-15(Q108E)IgG1_allotype EEM,LALA突变H435R/Y436F
5’XbaI,3’PmeI
ASKGD111_CX5_74_3
SEQ ID NO:117Fc-hole IgG1,LALA mutation-IL2Rbeta D68E,不可切割
ASKGD111_CX5_76_2
SEQ ID NO:118Fc-Sushi-IL-15vN65D IgG1_allotype EEM,LALA突变,YTE.
ASKD215_CX7.40.1
SEQ ID NO:119IgG1 Fc-hole-MMP/matriptase-VL-VH
ASKD215_CX7_40_2
SEQ ID NO:120IgG1 Fc-hole-MMP/matriptase-VL-VH，其第2个切割位于VL和VH之间
ASKD215_CX7_40_3
SEQ ID NO:121 Fc-IL-15vN65D,Knob链,不含Sushi域
ASKD215_CX7.56.2，
SEQ ID NO:122在Sushi域和IL-15v之间具有较长连接物的Fc knob链
ASKD215_CX7_56_3
SEQ ID NO:123第二种抗IL-15抗体146B7 LC可变区(蛋白序列)
EIVLTQSPGTLSLSPGREATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQRYGSSHTFGQGTKLE
SEQ ID NO:124抗IL-15scFv1 ver2
EVQLVQSGAEVKKPGESLKISCKVSGYFFTTYWIGWVRQMPGKGLEYMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGGNWNCFDYWGQGTLVTVSSGGGGSGGGGSGGGGSEIVLTQSPGTLSLSPGREATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASRRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQRYGSSHTFGQGTKLE
SEQ ID NO:125抗Trop-2抗体轻链CDR1
KASQDVSIAVA
SEQ ID NO:126抗Trop-2抗体轻链CDR2
SASYRYT
SEQ ID NO:127抗Trop-2抗体轻链CDR3
QQHYITPLT
SEQ ID NO:128抗Trop-2抗体重链CDR1
NYGMN
SEQ ID NO:129抗Trop-2抗体重链CDR2
WINTYTGEPTYTDDFKG
SEQ ID NO:130抗Trop-2抗体重链CDR3
GGFGSSYWYFDV
SEQ ID NO:131抗间皮素抗体轻链CDR1
SASSSVSYMH
SEQ ID NO:132抗间皮素抗体轻链CDR2
DTSKLAS
SEQ ID NO:133抗间皮素抗体轻链CDR3
QQWSGYPLT
SEQ ID NO:134抗间皮素抗体重链CDR1
GYTMN
SEQ ID NO:135抗间皮素抗体重链CDR2
LITPYNGASSYNQKFRG
SEQ ID NO:136抗间皮素抗体重链CDR3
GGYDGRGFDY
SEQ ID NO:137人源白介素15受体Α亚基，(IL-15RΑ)，转录因子1,mRNA
ctgggcagcg ctcgcccggg gagtccagcg gtgtcctgtg gagctgccgc catggccccgcggcgggcgc gcggctgccg gaccctcggt ctcccggcgc tgctactgct gctgctgctc cggccgccggcgacgcgggg catcacgtgc cctcccccca tgtccgtgga acacgcagac atctgggtca agagctacagcttgtactcc agggagcggt acatttgtaa ctctggtttc aagcgtaaag ccggcacgtc cagcctgacggagtgcgtgt tgaacaaggc cacgaatgtc gcccactgga caacccccag tctcaaatgc attagagaccctgccctggt tcaccaaagg ccagcgccac cctccacagt aacgacggca ggggtgaccc cacagccagagagcctctcc ccttctggaa aagagcccgc agcttcatct cccagctcaa acaacacagc ggccacaacagcagctattg tcccgggctc ccagctgatg ccttcaaaat caccttccac aggaaccaca gagataagcagtcatgagtc ctcccacggc accccctctc agacaacagc caagaactgg gaactcacag catccgcctcccaccagccg ccaggtgtgt atccacaggg ccacagcgac accactgtgg ctatctccac gtccactgtcctgctgtgtg ggctgagcgc tgtgtctctc ctggcatgct acctcaagtc aaggcaaact cccccgctggccagcgttga aatggaagcc atggaggctc tgccggtgac ttgggggacc agcagcagag atgaagacttggaaaactgc tctcaccacc tatgaaactc ggggaaacca gcccagctaa gtccggagtg aaggagcctctctgctttag ctaaagacga ctgagaagag gtgcaaggaa gcgggctcca ggagcaagct caccaggcctctcagaagtc ccagcaggat ctcacggact gccgggtcgg cgcctcctgc gcgagggagc aggttctccgcattcccatg ggcaccacct gcctgcctgt cgtgccttgg acccagggcc cagcttccca ggagagaccaaaggcttctg agcaggattt ttatttcatt acagtgtgag ctgcctggaa tacatgtggt aatgaaataaaaaccctgcc ccgaatcttc cgtccctcat cctaactttc agttcacaga gaaaagtgac atacccaaagctctctgtca attacaaggc ttctcctggc gtgggagacg tctacaggga agacaccagc gtttgggcttctaaccaccc tgtctccagc tgctctgcac acatggacag ggacctggga aaggtgggag agatgctgagcccagcgaat cctctccatt gaaggattca ggaagaagaa aactcaactc agtgccattt tacgaatatatgcgtttata tttatacttc cttgtctatt atatctatac attatatatt atttgtattt tgacattgtaccttgtataa acaaaataaa acatctattt tcaata
SEQ ID NO:138不可切割的肽连接物
GSAGSAAGSGEF
SEQ ID NO:139不可切割的肽连接物，其中,n1＝1，2或3，n2＝1，2，或3.
(GGGGS)n1GSAGSAAGSGEF(GGGGS)n2
SEQ ID NO:140不可切割的肽连接物
(GGGGS)n1AA(GGGGS)n2；wherein n1＝2或3,n2＝2或3.
序列表
<110> 奥美药业有限公司
<120> 全新IL-15前药及其应用
<130> 025471.WO004
<140>
<141>
<150> 63/029,473
<151> 2020-05-23
<150> 62/959,973
<151> 2020-01-11
<150> 62/891,190
<151> 2019-08-23
<150> 62/888,444
<151> 2019-08-17
<150> 62/860,635
<151> 2019-06-12
<160> 140
<170> PatentIn version 3.5
<210> 1
<211> 133
<212> PRT
<213> 智人(Homo sapiens)
<400> 1
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr
130
<210> 2
<211> 113
<212> PRT
<213> 智人(Homo sapiens)
<400> 2
Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile
1 5 10 15
Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His
20 25 30
Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln
35 40 45
Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu
50 55 60
Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val
65 70 75 80
Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile
85 90 95
Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn
100 105 110
Thr
<210> 3
<211> 214
<212> PRT
<213> 智人(Homo sapiens)
<400> 3
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
1 5 10 15
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
20 25 30
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
35 40 45
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
50 55 60
Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
65 70 75 80
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
85 90 95
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
100 105 110
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
115 120 125
Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg
130 135 140
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
145 150 155 160
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
165 170 175
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
180 185 190
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
195 200 205
Ala Leu Gly Lys Asp Thr
210
<210> 4
<211> 214
<212> PRT
<213> 智人(Homo sapiens)
<400> 4
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
1 5 10 15
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
20 25 30
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
35 40 45
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
50 55 60
Gly Ala Pro Glu Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
65 70 75 80
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
85 90 95
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
100 105 110
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
115 120 125
Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg
130 135 140
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
145 150 155 160
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
165 170 175
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
180 185 190
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
195 200 205
Ala Leu Gly Lys Asp Thr
210
<210> 5
<211> 214
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
1 5 10 15
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
20 25 30
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
35 40 45
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
50 55 60
Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
65 70 75 80
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
85 90 95
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
100 105 110
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
115 120 125
Ser Gln Ala Ser His Tyr Phe Gln Arg Arg Leu Glu Phe Glu Ala Arg
130 135 140
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
145 150 155 160
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
165 170 175
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
180 185 190
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
195 200 205
Ala Leu Gly Lys Asp Thr
210
<210> 6
<211> 240
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly Asn Glu Asp Thr Thr Ala
1 5 10 15
Asp Phe Phe Leu Thr Thr Met Pro Thr Asp Ser Leu Ser Val Ser Thr
20 25 30
Leu Pro Leu Pro Glu Val Gln Cys Phe Val Phe Asn Val Glu Tyr Met
35 40 45
Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro Gln Pro Thr Asn Leu Thr
50 55 60
Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn Asp Lys Val Gln Lys Cys
65 70 75 80
Ser His Tyr Leu Phe Ser Glu Glu Ile Thr Ser Gly Cys Gln Leu Gln
85 90 95
Lys Lys Glu Ile His Leu Tyr Gln Thr Phe Val Val Gln Leu Gln Asp
100 105 110
Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln Met Leu Lys Leu Gln Asn
115 120 125
Leu Val Ile Pro Trp Ala Pro Glu Asn Leu Thr Leu His Lys Leu Ser
130 135 140
Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn Arg Phe Leu Asn His Cys
145 150 155 160
Leu Glu His Leu Val Gln Tyr Arg Thr Asp Trp Asp His Ser Trp Thr
165 170 175
Glu Gln Ser Val Asp Tyr Arg His Lys Phe Ser Leu Pro Ser Val Asp
180 185 190
Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg Ser Arg Phe Asn Pro Leu
195 200 205
Cys Gly Ser Ala Gln His Trp Ser Glu Trp Ser His Pro Ile His Trp
210 215 220
Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe Leu Phe Ala Leu Glu Ala
225 230 235 240
<210> 7
<211> 75
<212> PRT
<213> 智人(Homo sapiens)
<400> 7
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala
65 70 75
<210> 8
<211> 267
<212> PRT
<213> 智人(Homo sapiens)
<400> 8
Met Ala Pro Arg Arg Ala Arg Gly Cys Arg Thr Leu Gly Leu Pro Ala
1 5 10 15
Leu Leu Leu Leu Leu Leu Leu Arg Pro Pro Ala Thr Arg Gly Ile Thr
20 25 30
Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser
35 40 45
Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys
50 55 60
Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala
65 70 75 80
Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp
85 90 95
Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Thr Val Thr Thr
100 105 110
Ala Gly Val Thr Pro Gln Pro Glu Ser Leu Ser Pro Ser Gly Lys Glu
115 120 125
Pro Ala Ala Ser Ser Pro Ser Ser Asn Asn Thr Ala Ala Thr Thr Ala
130 135 140
Ala Ile Val Pro Gly Ser Gln Leu Met Pro Ser Lys Ser Pro Ser Thr
145 150 155 160
Gly Thr Thr Glu Ile Ser Ser His Glu Ser Ser His Gly Thr Pro Ser
165 170 175
Gln Thr Thr Ala Lys Asn Trp Glu Leu Thr Ala Ser Ala Ser His Gln
180 185 190
Pro Pro Gly Val Tyr Pro Gln Gly His Ser Asp Thr Thr Val Ala Ile
195 200 205
Ser Thr Ser Thr Val Leu Leu Cys Gly Leu Ser Ala Val Ser Leu Leu
210 215 220
Ala Cys Tyr Leu Lys Ser Arg Gln Thr Pro Pro Leu Ala Ser Val Glu
225 230 235 240
Met Glu Ala Met Glu Ala Leu Pro Val Thr Trp Gly Thr Ser Ser Arg
245 250 255
Asp Glu Asp Leu Glu Asn Cys Ser His His Leu
260 265
<210> 9
<211> 65
<212> PRT
<213> 智人(Homo sapiens)
<400> 9
Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp Val
1 5 10 15
Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly
20 25 30
Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn
35 40 45
Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile
50 55 60
Arg
65
<210> 10
<211> 76
<212> PRT
<213> 智人(Homo sapiens)
<400> 10
Thr Asn Asp Ala Glu Asp Cys Cys Leu Ser Val Thr Gln Lys Pro Ile
1 5 10 15
Pro Gly Tyr Ile Val Arg Asn Phe His Tyr Leu Leu Ile Lys Asp Gly
20 25 30
Cys Arg Val Pro Ala Val Val Phe Thr Thr Leu Arg Gly Arg Gln Leu
35 40 45
Cys Ala Pro Pro Asp Gln Pro Trp Val Glu Arg Ile Ile Gln Arg Leu
50 55 60
Gln Arg Thr Ser Ala Lys Met Lys Arg Arg Ser Ser
65 70 75
<210> 11
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 11
Gly Gly Gly Gly Ser
1 5
<210> 12
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 12
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 13
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 13
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 14
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> VARIANT
<222> (11)..(11)
<223> /replace="Asn"
<220>
<221> SITE
<222> (1)..(21)
<223> /note="变体（variant）中所涉突变位点的突变残基无偏好性"
<400> 14
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Gly Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Gly Ser
20
<210> 15
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> VARIANT
<222> (11)..(11)
<223> /replace="Ala" or "Asn"
<220>
<221> VARIANT
<222> (16)..(16)
<223> /replace="Asn"
<220>
<221> SITE
<222> (1)..(21)
<223> /note="变体（variant）中所涉突变位点的突变残基无偏好性"
<400> 15
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Gly Gly Ala
1 5 10 15
Gly Gly Gly Gly Ser
20
<210> 16
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 16
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
<210> 17
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 17
Gly Pro Leu Gly Val Arg
1 5
<210> 18
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 18
Pro Leu Gly Met Trp Ser Arg
1 5
<210> 19
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 19
Pro Leu Gly Leu Trp Ala Arg
1 5
<210> 20
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 20
Pro Gln Gly Ile Ala Gly Gln Arg
1 5
<210> 21
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 21
Pro Leu Gly Leu Ala Gly
1 5
<210> 22
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 22
Leu Ala Leu Gly Pro Arg
1 5
<210> 23
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 23
Gly Gly Pro Leu Gly Met Leu Ser Gln Ser
1 5 10
<210> 24
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 24
Gly Gly Gly Gly Arg Arg Gly Gly Ser
1 5
<210> 25
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 25
Thr Gly Arg Gly Pro Ser Trp Val
1 5
<210> 26
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 26
Ser Ala Arg Gly Pro Ser Arg Trp
1 5
<210> 27
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 27
Thr Ala Arg Gly Pro Ser Phe Lys
1 5
<210> 28
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 28
Thr Ala Arg Gly Pro Ser Trp
1 5
<210> 29
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 29
Gly Gly Trp His Thr Gly Arg Asn
1 5
<210> 30
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 30
His Thr Gly Arg Ser Gly Ala Leu
1 5
<210> 31
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 31
Pro Leu Thr Gly Arg Ser Gly Gly
1 5
<210> 32
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 32
Leu Thr Gly Arg Ser Gly Ala
1 5
<210> 33
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 33
Arg Gln Ala Arg Val Val Asn Gly
1 5
<210> 34
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 34
Val His Met Pro Leu Gly Phe Leu Gly Pro Arg Gln Ala Arg Val Val
1 5 10 15
Asn Gly
<210> 35
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 35
Gly Gly Ser Leu Ser Gly Arg Ser Asp Asn His Gly Gly Gly Gly Ser
1 5 10 15
<210> 36
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 36
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile
1 5 10 15
Ser Ser Gly Leu Leu Ser Ser Gly Gly Ser Gly Gly Ser Leu Ser Gly
20 25 30
Arg Ser Asp Asn His Gly Gly Gly Gly Ser
35 40
<210> 37
<211> 467
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 37
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu
225 230 235 240
Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn
245 250 255
Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser
260 265 270
Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val
275 280 285
His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu
290 295 300
Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro
305 310 315 320
Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu
325 330 335
Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys
340 345 350
Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val
355 360 365
His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala
370 375 380
Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser
385 390 395 400
Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys
405 410 415
Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu
420 425 430
Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser
435 440 445
Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly
450 455 460
Lys Asp Thr
465
<210> 38
<211> 448
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> VARIANT
<222> (399)..(399)
<223> /replace="Asp"
<220>
<221> VARIANT
<222> (442)..(442)
<223> /replace="Glu"
<220>
<221> SITE
<222> (1)..(448)
<223> /note="变体（variant）中所涉突变位点的突变残基无偏好性"
<400> 38
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp
245 250 255
Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser
260 265 270
Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu
275 280 285
Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys
290 295 300
Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Gly
305 310 315 320
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Trp
325 330 335
Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser
340 345 350
Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser
355 360 365
Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile
370 375 380
Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu Asn Leu
385 390 395 400
Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu
405 410 415
Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu
420 425 430
Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn Thr Ser
435 440 445
<210> 39
<211> 465
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> VARIANT
<222> (416)..(416)
<223> /replace="Asp"
<220>
<221> VARIANT
<222> (459)..(459)
<223> /replace="Glu"
<220>
<221> SITE
<222> (1)..(465)
<223> /note="变体（variant）中所涉突变位点的突变残基无偏好性"
<400> 39
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile Trp
245 250 255
Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser
260 265 270
Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val Leu
275 280 285
Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys Cys
290 295 300
Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro Pro Ser Gly
305 310 315 320
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala
325 330 335
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn
340 345 350
Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln
355 360 365
Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro
370 375 380
Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val
385 390 395 400
Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val Glu Asn
405 410 415
Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr
420 425 430
Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys
435 440 445
Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile Asn Thr
450 455 460
Ser
465
<210> 40
<211> 451
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 40
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
245 250 255
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
260 265 270
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
275 280 285
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
290 295 300
Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn
305 310 315 320
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
325 330 335
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
340 345 350
Asn Thr Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
355 360 365
Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His
370 375 380
Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr
385 390 395 400
Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr
405 410 415
Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro
420 425 430
Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala
435 440 445
Pro Pro Ser
450
<210> 41
<211> 355
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 41
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
245 250 255
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
260 265 270
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu Leu
275 280 285
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
290 295 300
Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn
305 310 315 320
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
325 330 335
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
340 345 350
Asn Thr Ser
355
<210> 42
<211> 563
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 42
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
225 230 235 240
Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His
245 250 255
Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr
260 265 270
Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr
275 280 285
Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro
290 295 300
Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala
305 310 315 320
Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro Leu
325 330 335
Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn
340 345 350
Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser
355 360 365
Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val
370 375 380
His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu
385 390 395 400
Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro
405 410 415
Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu
420 425 430
Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys
435 440 445
Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val
450 455 460
His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala
465 470 475 480
Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser
485 490 495
Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys
500 505 510
Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu
515 520 525
Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser
530 535 540
Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly
545 550 555 560
Lys Asp Thr
<210> 43
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 43
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 44
<211> 355
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 44
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly
225 230 235 240
Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp Leu
245 250 255
Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp Val
260 265 270
His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Lys Leu
275 280 285
Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr Val
290 295 300
Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly Asn
305 310 315 320
Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys Asn
325 330 335
Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe Ile
340 345 350
Asn Thr Ser
355
<210> 45
<211> 692
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> VARIANT
<222> (643)..(643)
<223> /replace="Asp"
<220>
<221> VARIANT
<222> (686)..(686)
<223> /replace="Glu"
<220>
<221> SITE
<222> (1)..(692)
<223> /note="变体（variant）中所涉突变位点的突变残基无偏好性"
<400> 45
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala
465 470 475 480
Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile
485 490 495
Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu
500 505 510
Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser
515 520 525
Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro
530 535 540
Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu Asp
580 585 590
Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser Asp
595 600 605
Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu Glu
610 615 620
Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp Thr
625 630 635 640
Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn Gly
645 650 655
Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu Lys
660 665 670
Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met Phe
675 680 685
Ile Asn Thr Ser
690
<210> 46
<211> 690
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 46
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
450 455 460
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
465 470 475 480
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
485 490 495
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
500 505 510
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
515 520 525
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
530 535 540
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
545 550 555 560
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
565 570 575
Met Phe Ile Asn Thr Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
580 585 590
Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
595 600 605
Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala
610 615 620
Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile
625 630 635 640
Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu
645 650 655
Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser
660 665 670
Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro Ala Pro
675 680 685
Pro Ser
690
<210> 47
<211> 694
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 47
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
485 490 495
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
500 505 510
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
515 520 525
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
530 535 540
Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
545 550 555 560
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
565 570 575
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
580 585 590
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
595 600 605
Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg
610 615 620
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
625 630 635 640
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
645 650 655
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
660 665 670
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
675 680 685
Ala Leu Gly Lys Asp Thr
690
<210> 48
<211> 721
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 48
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
485 490 495
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
500 505 510
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
515 520 525
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
530 535 540
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
545 550 555 560
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
565 570 575
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
580 585 590
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
595 600 605
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
610 615 620
Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln
625 630 635 640
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
645 650 655
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile
660 665 670
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
675 680 685
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg
690 695 700
Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser
705 710 715 720
Arg
<210> 49
<211> 721
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 49
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Ile Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala Arg Phe Gly Tyr Phe Tyr Gly Ser Ser Phe Tyr Ala Val Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
115 120 125
Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly
130 135 140
Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
145 150 155 160
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
165 170 175
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
180 185 190
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn
195 200 205
Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro
210 215 220
Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
325 330 335
Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn
355 360 365
Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
485 490 495
Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
500 505 510
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
515 520 525
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
530 535 540
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
545 550 555 560
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His
565 570 575
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg Gly Gly Gly Gly
580 585 590
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
595 600 605
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser
610 615 620
Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val
625 630 635 640
Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro
645 650 655
Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr
660 665 670
Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser
675 680 685
Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn
690 695 700
Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
705 710 715 720
Ser
<210> 50
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 50
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 51
<211> 362
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 51
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Lys Thr Leu Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln
225 230 235 240
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
245 250 255
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ser Met Leu Thr Ala Lys
260 265 270
Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
275 280 285
Glu Glu Ala Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
290 295 300
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Glu Ile Asn Val
305 310 315 320
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
325 330 335
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
340 345 350
Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr
355 360
<210> 52
<211> 665
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 52
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val
450 455 460
Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu
465 470 475 480
Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser
485 490 495
Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr
500 505 510
Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg
515 520 525
Pro Ala Pro Pro Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
530 535 540
Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu
545 550 555 560
Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu
565 570 575
Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys
580 585 590
Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala
595 600 605
Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser
610 615 620
Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu
625 630 635 640
Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His
645 650 655
Ile Val Gln Met Phe Ile Asn Thr Ser
660 665
<210> 53
<211> 665
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 53
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu
450 455 460
Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu
465 470 475 480
Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys
485 490 495
Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala
500 505 510
Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser
515 520 525
Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu
530 535 540
Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His
545 550 555 560
Ile Val Gln Met Phe Ile Asn Thr Ser Gly Gly Ser Gly Gly Gly Gly
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro
580 585 590
Pro Met Ser Val Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu
595 600 605
Tyr Ser Arg Glu Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala
610 615 620
Gly Thr Ser Ser Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val
625 630 635 640
Ala His Trp Thr Thr Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu
645 650 655
Val His Gln Arg Pro Ala Pro Pro Ser
660 665
<210> 54
<211> 680
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 54
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser
465 470 475 480
Arg Ala Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp
485 490 495
Thr Ser Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln
500 505 510
Thr Cys Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu
515 520 525
Ile Leu Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val
530 535 540
Thr Leu Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala
545 550 555 560
Ile Gln Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile
565 570 575
Ser Leu Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp
580 585 590
Glu Ile Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu
595 600 605
Ala Arg Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu
610 615 620
Thr Leu Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro
625 630 635 640
Asp Thr Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu
645 650 655
Phe Thr Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys
660 665 670
Pro Ala Ala Leu Gly Lys Asp Thr
675 680
<210> 55
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 55
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 56
<211> 362
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 56
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Ser Asn Trp Pro Arg
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Ala Pro Ala Ser Ser Ser Thr Lys Lys Thr Gln
225 230 235 240
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
245 250 255
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Ser Met Leu Thr Ala Lys
260 265 270
Phe Ala Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
275 280 285
Glu Glu Ala Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
290 295 300
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Glu Ile Asn Val
305 310 315 320
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
325 330 335
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
340 345 350
Phe Ser Gln Ser Ile Ile Ser Thr Leu Thr
355 360
<210> 57
<211> 440
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 57
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Lys
435 440
<210> 58
<211> 661
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 58
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu
450 455 460
His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg
465 470 475 480
Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu
485 490 495
Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr
500 505 510
Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro
515 520 525
Ala Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
530 535 540
Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
545 550 555 560
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
565 570 575
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
580 585 590
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
595 600 605
Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
610 615 620
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
625 630 635 640
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met
645 650 655
Phe Ile Asn Thr Ser
660
<210> 59
<211> 661
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 59
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu
450 455 460
His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg
465 470 475 480
Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu
485 490 495
Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr
500 505 510
Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro
515 520 525
Ala Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
530 535 540
Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
545 550 555 560
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
565 570 575
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
580 585 590
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
595 600 605
Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
610 615 620
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
625 630 635 640
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Glu Met
645 650 655
Phe Ile Asn Thr Ser
660
<210> 60
<211> 702
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 60
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Pro Leu
435 440 445
Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
450 455 460
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys
465 470 475 480
Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly
485 490 495
Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile
500 505 510
Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln
515 520 525
Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp
530 535 540
Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly
545 550 555 560
Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
565 570 575
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
580 585 590
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
595 600 605
Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
610 615 620
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
625 630 635 640
Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg
645 650 655
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
660 665 670
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser
675 680 685
Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg
690 695 700
<210> 61
<211> 702
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 61
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Pro Leu
435 440 445
Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val
450 455 460
Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Arg Glu Ala
465 470 475 480
Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly
500 505 510
Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp
530 535 540
Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe Gly
545 550 555 560
Gln Gly Thr Lys Leu Glu Ile Ser Arg Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly
580 585 590
Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val
595 600 605
Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met
610 615 620
Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser
625 630 635 640
Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala
645 650 655
Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala
660 665 670
Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys
675 680 685
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
690 695 700
<210> 62
<211> 568
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 62
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
450 455 460
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
465 470 475 480
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
485 490 495
Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
500 505 510
Ile His Asp Thr Val Glu Glu Leu Ile Ile Leu Ala Asn Asn Ser Leu
515 520 525
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
530 535 540
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
545 550 555 560
Val Gln Met Phe Ile Asn Thr Ser
565
<210> 63
<211> 568
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 63
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
450 455 460
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
465 470 475 480
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
485 490 495
Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
500 505 510
Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu
515 520 525
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
530 535 540
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
545 550 555 560
Val Gln Met Phe Ile Asn Thr Ser
565
<210> 64
<211> 569
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 64
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu
450 455 460
Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu
465 470 475 480
Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys
485 490 495
Cys Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala
500 505 510
Ser Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser
515 520 525
Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu
530 535 540
Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His
545 550 555 560
Ile Val Gln Met Phe Ile Asn Thr Ser
565
<210> 65
<211> 569
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 65
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu
450 455 460
Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu
465 470 475 480
Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys
485 490 495
Cys Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala
500 505 510
Ser Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser
515 520 525
Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu
530 535 540
Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His
545 550 555 560
Ile Val Gln Met Phe Ile Asn Thr Ser
565
<210> 66
<211> 706
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 66
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Pro Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser
465 470 475 480
Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser
485 490 495
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg
500 505 510
Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg
515 520 525
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg
530 535 540
Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser
545 550 555 560
Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Gly Gly Gly
565 570 575
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
580 585 590
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile
595 600 605
Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp
610 615 620
Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr
625 630 635 640
Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val
645 650 655
Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser
660 665 670
Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly
675 680 685
Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
690 695 700
Ser Ser
705
<210> 67
<211> 651
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 67
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val
450 455 460
Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu
465 470 475 480
Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser
485 490 495
Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr
500 505 510
Thr Pro Ser Leu Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser
530 535 540
Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala
545 550 555 560
Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala
565 570 575
Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly
580 585 590
Asp Ala Ser Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn
595 600 605
Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu
610 615 620
Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe
625 630 635 640
Val His Ile Val Gln Met Phe Ile Asn Thr Ser
645 650
<210> 68
<211> 668
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 68
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val
450 455 460
Glu His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu
465 470 475 480
Arg Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser
485 490 495
Leu Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr
500 505 510
Thr Pro Ser Leu Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser
530 535 540
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile
545 550 555 560
Ser Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp
565 570 575
Ala Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr
580 585 590
Ala Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser
595 600 605
Gly Asp Ala Ser Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala
610 615 620
Asn Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys
625 630 635 640
Glu Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser
645 650 655
Phe Val His Ile Val Gln Met Phe Ile Asn Thr Ser
660 665
<210> 69
<211> 678
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 69
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Asp Cys Lys Ala Ser Gly Ile Thr Phe Ser Asn Ser
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Ser Lys Arg Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Asn Asp Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser
115 120 125
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp
130 135 140
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr
145 150 155 160
Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr
165 170 175
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys
180 185 190
Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp
195 200 205
Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala
210 215 220
Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
225 230 235 240
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
245 250 255
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val
260 265 270
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
275 280 285
Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
290 295 300
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
305 310 315 320
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
325 330 335
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr
340 345 350
Lys Asn Gln Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser
355 360 365
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
370 375 380
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
385 390 395 400
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe
405 410 415
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
420 425 430
Ser Leu Ser Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu
450 455 460
His Ala Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg
465 470 475 480
Tyr Ile Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu
485 490 495
Thr Glu Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr
500 505 510
Pro Ser Leu Lys Cys Ile Arg Asp Pro Ala Leu Val His Gln Arg Pro
515 520 525
Ala Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
530 535 540
Gly Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
545 550 555 560
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
565 570 575
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
580 585 590
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
595 600 605
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
610 615 620
Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
625 630 635 640
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
645 650 655
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
660 665 670
Met Phe Ile Asn Thr Ser
675
<210> 70
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 70
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu
225 230 235 240
Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
260 265 270
Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe
275 280 285
Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly
290 295 300
Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr
305 310 315 320
Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile
325 330 335
Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala
340 345 350
Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Gly Thr Leu Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys
405 410 415
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg
435 440 445
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
450 455 460
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
465 470 475 480
Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys
485 490 495
Leu Glu Ile Ser Arg
500
<210> 71
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 71
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu
225 230 235 240
Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
260 265 270
Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
275 280 285
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
290 295 300
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro
305 310 315 320
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr
340 345 350
Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
370 375 380
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
385 390 395 400
Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp
405 410 415
Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly
420 425 430
Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
435 440 445
Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu
450 455 460
Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala
465 470 475 480
Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
485 490 495
Val Thr Val Ser Ser
500
<210> 72
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 72
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr
20 25 30
Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu
225 230 235 240
Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
260 265 270
Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe
275 280 285
Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly
290 295 300
Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr
305 310 315 320
Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile
325 330 335
Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala
340 345 350
Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp
355 360 365
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser
385 390 395 400
Pro Gly Thr Leu Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys
405 410 415
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln
420 425 430
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg
435 440 445
Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
450 455 460
Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr
465 470 475 480
Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys
485 490 495
Leu Glu Ile Ser Arg
500
<210> 73
<211> 501
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 73
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr
20 25 30
Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe Leu
225 230 235 240
Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser
260 265 270
Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser
275 280 285
Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala
290 295 300
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro
305 310 315 320
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr
340 345 350
Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
370 375 380
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
385 390 395 400
Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp
405 410 415
Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly
420 425 430
Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
435 440 445
Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu
450 455 460
Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala
465 470 475 480
Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
485 490 495
Val Thr Val Ser Ser
500
<210> 74
<211> 438
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 74
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
245 250 255
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
260 265 270
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
275 280 285
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
290 295 300
Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
305 310 315 320
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
325 330 335
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
340 345 350
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
355 360 365
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
370 375 380
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
385 390 395 400
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
405 410 415
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
420 425 430
Met Phe Ile Asn Thr Ser
435
<210> 75
<211> 438
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 75
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
245 250 255
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
260 265 270
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
275 280 285
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
290 295 300
Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
305 310 315 320
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
325 330 335
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
340 345 350
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
355 360 365
Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
370 375 380
Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
385 390 395 400
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
405 410 415
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
420 425 430
Met Phe Ile Asn Thr Ser
435
<210> 76
<211> 438
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 76
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
245 250 255
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
260 265 270
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
275 280 285
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
290 295 300
Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
305 310 315 320
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
325 330 335
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
340 345 350
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
355 360 365
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
370 375 380
Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
385 390 395 400
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
405 410 415
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
420 425 430
Met Phe Ile Asn Thr Ser
435
<210> 77
<211> 438
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 77
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Tyr
20 25 30
Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp Ile
245 250 255
Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys Asn
260 265 270
Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys Val
275 280 285
Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu Lys
290 295 300
Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly
305 310 315 320
Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile
325 330 335
Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu
340 345 350
Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu
355 360 365
Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His
370 375 380
Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser
385 390 395 400
Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu
405 410 415
Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln
420 425 430
Met Phe Ile Asn Thr Ser
435
<210> 78
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 78
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp
260 265 270
Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys
275 280 285
Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys
290 295 300
Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu
305 310 315 320
Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
340 345 350
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
355 360 365
Glu Ser Asn Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
370 375 380
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
385 390 395 400
His Asp Thr Val Gln Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
405 410 415
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
420 425 430
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
435 440 445
Gln Met Phe Ile Asn Thr Ser
450 455
<210> 79
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 79
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp
260 265 270
Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys
275 280 285
Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys
290 295 300
Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu
305 310 315 320
Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
340 345 350
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
355 360 365
Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
370 375 380
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
385 390 395 400
His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
405 410 415
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
420 425 430
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
435 440 445
Gln Met Phe Ile Asn Thr Ser
450 455
<210> 80
<211> 503
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 80
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly
225 230 235 240
Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu
260 265 270
Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly
275 280 285
Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly
290 295 300
Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr
305 310 315 320
Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys
325 330 335
Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp
340 345 350
Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp
355 360 365
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr
385 390 395 400
Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu
405 410 415
Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr
420 425 430
Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser
435 440 445
Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
450 455 460
Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala
465 470 475 480
Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe Gly Gln Gly
485 490 495
Thr Lys Leu Glu Ile Ser Arg
500
<210> 81
<211> 503
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 81
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly
225 230 235 240
Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
260 265 270
Leu Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser
275 280 285
Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly
290 295 300
Gln Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly
305 310 315 320
Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
325 330 335
Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln
340 345 350
Arg Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
355 360 365
Ser Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly
385 390 395 400
Glu Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr
405 410 415
Tyr Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr
420 425 430
Met Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser
435 440 445
Phe Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala
450 455 460
Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr
465 470 475 480
Cys Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly
485 490 495
Thr Leu Val Thr Val Ser Ser
500
<210> 82
<211> 440
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 82
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala
245 250 255
Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile
260 265 270
Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu
275 280 285
Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser
290 295 300
Leu Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
325 330 335
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
340 345 350
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
355 360 365
Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
370 375 380
Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu
385 390 395 400
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
405 410 415
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
420 425 430
Val Gln Met Phe Ile Asn Thr Ser
435 440
<210> 83
<211> 459
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 83
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala
245 250 255
Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile
260 265 270
Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu
275 280 285
Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser
290 295 300
Leu Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Ala Ala Gly Gly Ser Gly Gly Gly Gly Ser
325 330 335
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser
340 345 350
Asp Leu Lys Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala
355 360 365
Thr Leu Tyr Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala
370 375 380
Met Lys Cys Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly
385 390 395 400
Asp Ala Ser Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn
405 410 415
Asn Ser Leu Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu
420 425 430
Cys Glu Glu Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe
435 440 445
Val His Ile Val Gln Met Phe Ile Asn Thr Ser
450 455
<210> 84
<211> 440
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 84
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala
245 250 255
Asp Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile
260 265 270
Cys Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu
275 280 285
Cys Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser
290 295 300
Leu Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
305 310 315 320
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
325 330 335
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
340 345 350
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
355 360 365
Phe Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
370 375 380
Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu
385 390 395 400
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
405 410 415
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
420 425 430
Val Glu Met Phe Ile Asn Thr Ser
435 440
<210> 85
<211> 360
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 85
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
245 250 255
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
260 265 270
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
275 280 285
Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
290 295 300
Ile His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu
305 310 315 320
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
325 330 335
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
340 345 350
Val Gln Met Phe Ile Asn Thr Ser
355 360
<210> 86
<211> 360
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 86
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Cys Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
225 230 235 240
Ser Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys
245 250 255
Lys Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr
260 265 270
Thr Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys
275 280 285
Phe Leu Leu Lys Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser
290 295 300
Ile His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu
305 310 315 320
Ser Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu
325 330 335
Leu Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile
340 345 350
Val Gln Met Phe Ile Asn Thr Ser
355 360
<210> 87
<211> 481
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 87
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Cys Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly
225 230 235 240
Phe Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn Gly Thr
260 265 270
Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val
275 280 285
Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala
290 295 300
Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val
305 310 315 320
Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser
325 330 335
Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg
340 345 350
Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe
355 360 365
Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val
370 375 380
Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His
385 390 395 400
Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly
405 410 415
His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu
420 425 430
Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln
435 440 445
Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp
450 455 460
Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp
465 470 475 480
Thr
<210> 88
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 88
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 89
<211> 449
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 89
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 90
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 91
<211> 385
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 91
Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe Ser Leu
20 25 30
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys Val
35 40 45
Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
50 55 60
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
65 70 75 80
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys
85 90 95
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
100 105 110
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
115 120 125
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn
130 135 140
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn
145 150 155 160
Thr Lys Val Asp Glu Arg Lys Cys Cys Val Glu Cys Pro Ala Gly Pro
165 170 175
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
180 185 190
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
195 200 205
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
210 215 220
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
225 230 235 240
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
245 250 255
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
260 265 270
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
275 280 285
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
290 295 300
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
305 310 315 320
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
325 330 335
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
340 345 350
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
355 360 365
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
370 375 380
Lys
385
<210> 92
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 92
Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly
1 5 10 15
Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Gln Val Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile
65 70 75 80
Arg Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Asn
85 90 95
Leu Glu Tyr Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 93
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 93
Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Ser Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Asn Thr Leu Lys Asp Asp
20 25 30
His Val His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Tyr Pro Gly Gly Gly Arg Thr Arg Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Thr Thr Leu Thr Ala Asp Lys Pro Ser Ser Thr Val Asn
65 70 75 80
Met Leu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ile Tyr Phe Cys
85 90 95
Thr Asn Leu Val Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val
100 105 110
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
115 120 125
Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys
130 135 140
Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu
145 150 155 160
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
165 170 175
Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr
180 185 190
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val
195 200 205
Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro
210 215 220
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
245 250 255
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
260 265 270
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
275 280 285
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
290 295 300
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
305 310 315 320
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
325 330 335
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
340 345 350
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
355 360 365
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
370 375 380
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
385 390 395 400
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
405 410 415
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
420 425 430
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
<210> 94
<211> 219
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 94
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Ala Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Asn
85 90 95
Thr His Val Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 95
<211> 445
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 95
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Ala Leu Asp Pro Lys Thr Gly Asp Thr Ala Tyr Ser Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Phe Tyr Ser Tyr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro
115 120 125
Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
130 135 140
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala
145 150 155 160
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly
165 170 175
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly
180 185 190
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys
195 200 205
Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys
210 215 220
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
245 250 255
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
260 265 270
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
275 280 285
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
290 295 300
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 96
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 96
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Lys Gln Ser Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Trp Thr Val Ser Ser
115 120
<210> 97
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 97
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe
50 55 60
Lys Asp Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 98
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 98
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Ser Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Phe Cys Gln Gln Asp Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 99
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 99
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Asp Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 100
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 100
Thr Tyr Trp Ile Gly
1 5
<210> 101
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 101
Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
1 5 10 15
Gly
<210> 102
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 102
Gly Asn Trp Asn Cys Phe Asp Tyr
1 5
<210> 103
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 103
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 104
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 104
Gly Ala Ser Arg Arg Ala Thr
1 5
<210> 105
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 105
Gln Arg Tyr Gly Ser Ser His Thr
1 5
<210> 106
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 106
Gly Asn Trp Asn Ser Phe Asp Tyr
1 5
<210> 107
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 107
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 108
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 108
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro
115
<210> 109
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 109
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg
210 215 220
Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser
225 230 235 240
Arg
<210> 110
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 110
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser Arg Gly Gly Gly Gly
100 105 110
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
115 120 125
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser
130 135 140
Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val
145 150 155 160
Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro
165 170 175
Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr
180 185 190
Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser
195 200 205
Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn
210 215 220
Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
225 230 235 240
Ser
<210> 111
<211> 510
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 111
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro
245 250 255
Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val
260 265 270
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser Leu
275 280 285
Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile
290 295 300
Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile
305 310 315 320
Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly
325 330 335
Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln
340 345 350
Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg
355 360 365
Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
370 375 380
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
385 390 395 400
Gly Gly Ser Gly Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu
405 410 415
Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val
420 425 430
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro
435 440 445
Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp
450 455 460
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
465 470 475 480
Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly
485 490 495
Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser
500 505 510
<210> 112
<211> 510
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 112
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro
245 250 255
Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Ile
260 265 270
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
275 280 285
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
290 295 300
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
305 310 315 320
Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
325 330 335
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
340 345 350
Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe
355 360 365
Gly Gln Gly Thr Lys Leu Glu Ile Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Gln Ser Gly
385 390 395 400
Ala Glu Val Lys Lys Pro Gly Glu Ser Leu Lys Ile Ser Cys Lys Val
405 410 415
Ser Gly Tyr Phe Phe Thr Thr Tyr Trp Ile Gly Trp Val Arg Gln Met
420 425 430
Pro Gly Lys Gly Leu Glu Tyr Met Gly Ile Ile Tyr Pro Gly Asp Ser
435 440 445
Asp Thr Arg Tyr Ser Pro Ser Phe Gln Gly Gln Val Thr Ile Ser Ala
450 455 460
Asp Lys Ser Ile Ser Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala
465 470 475 480
Ser Asp Thr Ala Met Tyr Tyr Cys Ala Arg Gly Gly Asn Trp Asn Cys
485 490 495
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
500 505 510
<210> 113
<211> 710
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 113
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Pro Leu Gly Val Arg Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn Gly Thr Ser Gln
260 265 270
Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp Ser
275 280 285
Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp Pro
290 295 300
Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser Gln
305 310 315 320
Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln Lys
325 330 335
Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu Gly
340 345 350
Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu Asn
355 360 365
Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu Thr
370 375 380
His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr Phe
385 390 395 400
Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His Thr
405 410 415
Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp Ile
420 425 430
Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val Arg
435 440 445
Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser Gln
450 455 460
Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr Gly
465 470 475 480
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
485 490 495
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
500 505 510
Gly Ser Gly Gly Gly Gly Ser Pro Leu Pro Glu Val Gln Cys Phe Val
515 520 525
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
530 535 540
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
545 550 555 560
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
565 570 575
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
580 585 590
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
595 600 605
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
610 615 620
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
625 630 635 640
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
645 650 655
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
660 665 670
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
675 680 685
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
690 695 700
Ser His Pro Ile His Trp
705 710
<210> 114
<211> 710
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 114
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Pro Leu Gly Val Arg Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Pro Leu Pro Glu Val Gln Cys
260 265 270
Phe Val Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser
275 280 285
Glu Pro Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser
290 295 300
Asp Asn Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu
305 310 315 320
Ile Thr Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln
325 330 335
Thr Phe Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala
340 345 350
Thr Gln Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu
355 360 365
Asn Leu Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp
370 375 380
Asn Asn Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg
385 390 395 400
Thr Asp Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His
405 410 415
Lys Phe Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg
420 425 430
Val Arg Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser
435 440 445
Glu Trp Ser His Pro Ile His Trp Gly Gly Gly Gly Ser Gly Gly Gly
450 455 460
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
465 470 475 480
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
485 490 495
Ala Val Asn Gly Thr Ser Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala
500 505 510
Asn Ile Ser Cys Val Trp Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser
515 520 525
Cys Gln Val His Ala Trp Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys
530 535 540
Glu Leu Leu Pro Val Ser Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu
545 550 555 560
Gly Ala Pro Asp Ser Gln Lys Leu Thr Thr Val Asp Ile Val Thr Leu
565 570 575
Arg Val Leu Cys Arg Glu Gly Val Arg Trp Arg Val Met Ala Ile Gln
580 585 590
Asp Phe Lys Pro Phe Glu Asn Leu Arg Leu Met Ala Pro Ile Ser Leu
595 600 605
Gln Val Val His Val Glu Thr His Arg Cys Asn Ile Ser Trp Glu Ile
610 615 620
Ser Gln Ala Ser His Tyr Phe Glu Arg His Leu Glu Phe Glu Ala Arg
625 630 635 640
Thr Leu Ser Pro Gly His Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu
645 650 655
Lys Gln Lys Gln Glu Trp Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr
660 665 670
Gln Tyr Glu Phe Gln Val Arg Val Lys Pro Leu Gln Gly Glu Phe Thr
675 680 685
Thr Trp Ser Pro Trp Ser Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala
690 695 700
Ala Leu Gly Lys Asp Thr
705 710
<210> 115
<211> 610
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 115
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Pro Leu Gly Val Arg Gly
245 250 255
Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn Gly Thr Ser Gln
260 265 270
Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp Ser
275 280 285
Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp Pro
290 295 300
Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser Gln
305 310 315 320
Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln Lys
325 330 335
Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu Gly
340 345 350
Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu Asn
355 360 365
Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu Thr
370 375 380
His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr Phe
385 390 395 400
Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His Thr
405 410 415
Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp Ile
420 425 430
Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val Arg
435 440 445
Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser Gln
450 455 460
Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr Gly
465 470 475 480
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
485 490 495
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
500 505 510
Gly Ser Gly Gly Gly Gly Ser Ala Pro Glu Asn Leu Thr Leu His Lys
515 520 525
Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn Arg Phe Leu Asn
530 535 540
His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp Trp Asp His Ser
545 550 555 560
Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe Ser Leu Pro Ser
565 570 575
Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg Ser Arg Phe Asn
580 585 590
Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp Ser His Pro Ile
595 600 605
His Trp
610
<210> 116
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 116
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp
260 265 270
Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys
275 280 285
Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys
290 295 300
Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu
305 310 315 320
Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
340 345 350
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
355 360 365
Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
370 375 380
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
385 390 395 400
His Asp Thr Val Glu Asn Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
405 410 415
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
420 425 430
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
435 440 445
Glu Met Phe Ile Asn Thr Ser
450 455
<210> 117
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 117
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Ala Val Asn Gly Thr Ser Gln Phe
260 265 270
Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp Ser Gln
275 280 285
Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp Pro Asp
290 295 300
Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser Gln Ala
305 310 315 320
Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Glu Ser Gln Lys Leu
325 330 335
Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu Gly Val
340 345 350
Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu Asn Leu
355 360 365
Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu Thr His
370 375 380
Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr Phe Glu
385 390 395 400
Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His Thr Trp
405 410 415
Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp Ile Cys
420 425 430
Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val Arg Val
435 440 445
Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser Gln Pro
450 455 460
Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr
465 470 475
<210> 118
<211> 455
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 118
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp
260 265 270
Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys
275 280 285
Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys
290 295 300
Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu
305 310 315 320
Lys Cys Ile Arg Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser
325 330 335
Gly Gly Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys
340 345 350
Ile Glu Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr
355 360 365
Glu Ser Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe
370 375 380
Leu Leu Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile
385 390 395 400
His Asp Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser
405 410 415
Ser Asn Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu
420 425 430
Glu Glu Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val
435 440 445
Gln Met Phe Ile Asn Thr Ser
450 455
<210> 119
<211> 517
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 119
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Val His Met Pro Leu Gly Phe
245 250 255
Leu Gly Pro Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser
260 265 270
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
275 280 285
Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln
290 295 300
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
305 310 315 320
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile
325 330 335
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
340 345 350
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg
355 360 365
Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
385 390 395 400
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu Ser
405 410 415
Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr Trp
420 425 430
Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met Gly
435 440 445
Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe Gln
450 455 460
Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr Leu
465 470 475 480
Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys Ala
485 490 495
Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr Leu
500 505 510
Val Thr Val Ser Ser
515
<210> 120
<211> 518
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 120
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Cys Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Pro
245 250 255
Leu Gly Val Arg Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile
260 265 270
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg
275 280 285
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu
290 295 300
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr
305 310 315 320
Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser
325 330 335
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu
340 345 350
Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His Thr Phe
355 360 365
Gly Gln Gly Thr Lys Leu Glu Ile Ser Gly Gly Gly Gly Ser Gly Gly
370 375 380
Gly Gly Ser Arg Gln Ala Arg Val Val Asn Gly Gly Gly Gly Gly Ser
385 390 395 400
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
405 410 415
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
420 425 430
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
435 440 445
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
450 455 460
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
465 470 475 480
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
485 490 495
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
500 505 510
Leu Val Thr Val Ser Ser
515
<210> 121
<211> 373
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 121
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
260 265 270
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
275 280 285
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
290 295 300
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
305 310 315 320
Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
325 330 335
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
340 345 350
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met
355 360 365
Phe Ile Asn Thr Ser
370
<210> 122
<211> 469
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 122
Met Gly Val Lys Val Leu Phe Ala Leu Ile Cys Ile Ala Val Ala Glu
1 5 10 15
Ala Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
20 25 30
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
35 40 45
Tyr Ile Thr Arg Glu Pro Glu Val Thr Cys Val Val Val Asp Val Ser
50 55 60
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
65 70 75 80
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
85 90 95
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
100 105 110
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
115 120 125
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
130 135 140
Val Tyr Thr Leu Pro Pro Cys Arg Glu Glu Met Thr Lys Asn Gln Val
145 150 155 160
Ser Leu Trp Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
165 170 175
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
180 185 190
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
195 200 205
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
210 215 220
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
225 230 235 240
Ser Pro Gly Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Ile Thr Cys Pro Pro Pro Met Ser Val Glu His Ala Asp
260 265 270
Ile Trp Val Lys Ser Tyr Ser Leu Tyr Ser Arg Glu Arg Tyr Ile Cys
275 280 285
Asn Ser Gly Phe Lys Arg Lys Ala Gly Thr Ser Ser Leu Thr Glu Cys
290 295 300
Val Leu Asn Lys Ala Thr Asn Val Ala His Trp Thr Thr Pro Ser Leu
305 310 315 320
Lys Cys Ile Arg Gly Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly
325 330 335
Gly Ser Ala Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
340 345 350
Gly Gly Ser Asn Trp Val Asn Val Ile Ser Asp Leu Lys Lys Ile Glu
355 360 365
Asp Leu Ile Gln Ser Met His Ile Asp Ala Thr Leu Tyr Thr Glu Ser
370 375 380
Asp Val His Pro Ser Cys Lys Val Thr Ala Met Lys Cys Phe Leu Leu
385 390 395 400
Glu Leu Gln Val Ile Ser Leu Glu Ser Gly Asp Ala Ser Ile His Asp
405 410 415
Thr Val Glu Asp Leu Ile Ile Leu Ala Asn Asn Ser Leu Ser Ser Asn
420 425 430
Gly Asn Val Thr Glu Ser Gly Cys Lys Glu Cys Glu Glu Leu Glu Glu
435 440 445
Lys Asn Ile Lys Glu Phe Leu Gln Ser Phe Val His Ile Val Gln Met
450 455 460
Phe Ile Asn Thr Ser
465
<210> 123
<211> 105
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 123
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg Tyr Gly Ser Ser His
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu
100 105
<210> 124
<211> 238
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 124
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu
1 5 10 15
Ser Leu Lys Ile Ser Cys Lys Val Ser Gly Tyr Phe Phe Thr Thr Tyr
20 25 30
Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Tyr Met
35 40 45
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
50 55 60
Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Asn Trp Asn Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
115 120 125
Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu
130 135 140
Ser Leu Ser Pro Gly Arg Glu Ala Thr Leu Ser Cys Arg Ala Ser Gln
145 150 155 160
Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
165 170 175
Ala Pro Arg Leu Leu Ile Tyr Gly Ala Ser Arg Arg Ala Thr Gly Ile
180 185 190
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
195 200 205
Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Arg
210 215 220
Tyr Gly Ser Ser His Thr Phe Gly Gln Gly Thr Lys Leu Glu
225 230 235
<210> 125
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 125
Lys Ala Ser Gln Asp Val Ser Ile Ala Val Ala
1 5 10
<210> 126
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 126
Ser Ala Ser Tyr Arg Tyr Thr
1 5
<210> 127
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 127
Gln Gln His Tyr Ile Thr Pro Leu Thr
1 5
<210> 128
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 128
Asn Tyr Gly Met Asn
1 5
<210> 129
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 129
Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Thr Asp Asp Phe Lys
1 5 10 15
Gly
<210> 130
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 130
Gly Gly Phe Gly Ser Ser Tyr Trp Tyr Phe Asp Val
1 5 10
<210> 131
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 131
Ser Ala Ser Ser Ser Val Ser Tyr Met His
1 5 10
<210> 132
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 132
Asp Thr Ser Lys Leu Ala Ser
1 5
<210> 133
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 133
Gln Gln Trp Ser Gly Tyr Pro Leu Thr
1 5
<210> 134
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 134
Gly Tyr Thr Met Asn
1 5
<210> 135
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 135
Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe Arg
1 5 10 15
Gly
<210> 136
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 136
Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr
1 5 10
<210> 137
<211> 1566
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成多聚核苷酸"
<400> 137
ctgggcagcg ctcgcccggg gagtccagcg gtgtcctgtg gagctgccgc catggccccg 60
cggcgggcgc gcggctgccg gaccctcggt ctcccggcgc tgctactgct gctgctgctc 120
cggccgccgg cgacgcgggg catcacgtgc cctcccccca tgtccgtgga acacgcagac 180
atctgggtca agagctacag cttgtactcc agggagcggt acatttgtaa ctctggtttc 240
aagcgtaaag ccggcacgtc cagcctgacg gagtgcgtgt tgaacaaggc cacgaatgtc 300
gcccactgga caacccccag tctcaaatgc attagagacc ctgccctggt tcaccaaagg 360
ccagcgccac cctccacagt aacgacggca ggggtgaccc cacagccaga gagcctctcc 420
ccttctggaa aagagcccgc agcttcatct cccagctcaa acaacacagc ggccacaaca 480
gcagctattg tcccgggctc ccagctgatg ccttcaaaat caccttccac aggaaccaca 540
gagataagca gtcatgagtc ctcccacggc accccctctc agacaacagc caagaactgg 600
gaactcacag catccgcctc ccaccagccg ccaggtgtgt atccacaggg ccacagcgac 660
accactgtgg ctatctccac gtccactgtc ctgctgtgtg ggctgagcgc tgtgtctctc 720
ctggcatgct acctcaagtc aaggcaaact cccccgctgg ccagcgttga aatggaagcc 780
atggaggctc tgccggtgac ttgggggacc agcagcagag atgaagactt ggaaaactgc 840
tctcaccacc tatgaaactc ggggaaacca gcccagctaa gtccggagtg aaggagcctc 900
tctgctttag ctaaagacga ctgagaagag gtgcaaggaa gcgggctcca ggagcaagct 960
caccaggcct ctcagaagtc ccagcaggat ctcacggact gccgggtcgg cgcctcctgc 1020
gcgagggagc aggttctccg cattcccatg ggcaccacct gcctgcctgt cgtgccttgg 1080
acccagggcc cagcttccca ggagagacca aaggcttctg agcaggattt ttatttcatt 1140
acagtgtgag ctgcctggaa tacatgtggt aatgaaataa aaaccctgcc ccgaatcttc 1200
cgtccctcat cctaactttc agttcacaga gaaaagtgac atacccaaag ctctctgtca 1260
attacaaggc ttctcctggc gtgggagacg tctacaggga agacaccagc gtttgggctt 1320
ctaaccaccc tgtctccagc tgctctgcac acatggacag ggacctggga aaggtgggag 1380
agatgctgag cccagcgaat cctctccatt gaaggattca ggaagaagaa aactcaactc 1440
agtgccattt tacgaatata tgcgtttata tttatacttc cttgtctatt atatctatac 1500
attatatatt atttgtattt tgacattgta ccttgtataa acaaaataaa acatctattt 1560
tcaata 1566
<210> 138
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<400> 138
Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe
1 5 10
<210> 139
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> SITE
<222> (1)..(15)
<223> /note="所述区域可包括1至3个'Gly Gly Gly Gly Ser'重复单元"
<220>
<221> SITE
<222> (28)..(42)
<223> /note="所述区域可包括1至3个'Gly Gly Gly Gly Ser'重复单元"
<400> 139
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
1 5 10 15
Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe Gly Gly Gly Gly Ser
20 25 30
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
35 40
<210> 140
<211> 32
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> source
<223> /note="人工序列说明：合成肽"
<220>
<221> SITE
<222> (1)..(15)
<223> /note="所述区域可包括2或3个'Gly Gly Gly Gly Ser'重复单元"
<220>
<221> SITE
<222> (18)..(32)
<223> /note="所述区域可包括2或3个'Gly Gly Gly Gly Ser'重复单元"
<400> 140
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
20 25 30
Claims (44)
1.一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中，
所述掩蔽部分和所述IL-15细胞因子部分结合并抑制IL-15细胞因子部分的生物活性，
所述掩蔽部分与所述载体部分融合，
所述Sushi域与所述载体部分融合，
所述IL-15细胞因子部分和所述Sushi域融合。
2.如权利要求1所述的前药，其特征在于，
所述掩蔽部分通过第一肽连接物与所述载体部分融合，
所述Sushi域通过第二肽连接物与所述载体部分融合，
所述IL-15细胞因子部分通过第三肽连接物与所述Sushi域融合，其中三个肽连接物中至少一个为可切割的。
3.如权利要求2所述的前药，其特征在于，所述第三肽连接物至少为15,20,25,或30个氨基酸长度，优选地，所述第三肽连接物包括SEQ ID NO:139或140。
4.一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和Sushi域(S)，其中，
所述掩蔽部分和所述IL-15细胞因子部分结合并抑制IL-15细胞因子部分的生物活性，
所述IL-15细胞因子与所述载体部分融合，
所述Sushi域与所述载体部分融合，
所述掩蔽部分和所述Sushi域融合。
5.如权利要求4所述的前药，其特征在于，
所述IL-15细胞因子部分通过第一肽连接物与所述载体部分融合，
所述Sushi域通过第二肽连接物与所述载体部分融合，
所述掩蔽部分通过第三肽连接物与Sushi域融合，优选地，其中三个肽连接物中至少一个为可切割的。
6.如权利要求1至5任一项所述的前药，其特征在于，所述掩蔽部分包括IL-15细胞因子部分受体的胞外域(ECD)。
7.如权利要求6所述的前药，其特征在于，所述掩蔽部分包括人源IL-2Rβ胞外域或其功能类似物，和/或人源IL-2Rγ胞外域或其功能类似物。
8.如权利要求7所述的前药，其特征在于，所述人源IL-2Rγ胞外域或其功能类似物包含SEQ ID NO:6或与其具有至少90％同源性的氨基酸序列。
9.如权利要求7所述的前药，其特征在于，所述人源IL-2Rβ胞外域或其功能类似物包含SEQ ID NO:3，4或5，或与其具有至少90％同源性的氨基酸序列。
10.如权利要求1至5任一项所述的前药，其特征在于，所述掩蔽部分包括可结合IL-15细胞因子部分的抗体片段。
11.一种前药，包括IL-15细胞因子部分(A)，掩蔽部分(M)，载体部分(C)和可选的Sushi域(S)，其中，
所述掩蔽部分包括可结合IL-15细胞因子部分并抑制IL-15细胞因子部分的一种生物学活性的抗体片段，
所述掩蔽部分通过肽连接物与所述载体部分、IL-15细胞因子部分，或Sushi域融合。
12.如权利要求10或11任一项所述的前药，其特征在于，所述抗体片段为包括抗IL-15抗体的重链CDR1-3及轻链CDR1-3的ScFv或Fab，所述抗IL-15抗体选自146B7、146H5、404E4和404A8。
13.如权利要求10或11任一项所述的前药，其特征在于，所述抗体片段具有包含SEQ IDNO:100的重链CDR(HCDR)1，包含SEQ ID NO:101的HCDR2，包含SEQ ID NO:102或106的HCDR3；包含SEQ ID NO:103的轻链CDR(LCDR)1，包含SEQ ID NO:104的LCDR2，包含SEQ IDNO:105的LCDR3。
14.如权利要求10或11任一项所述的前药，其特征在于，所述抗体片段具有(i)包含SEQID NO:107或与其具有至少95％同源性氨基酸序列的重链可变区，包含SEQ ID NO:108或123或与其具有至少95％同源性氨基酸序列的轻链可变区；(ii)SEQ ID NO:109；(iii)SEQID NO:110；或(iv)SEQ ID NO:124。
15.如权利要求13或14任一项所述的前药，其特征在于，所述重链CDR3的半胱氨酸残基突变为Ser，Thr，Met，Ala，Gly，Asn或Gln。
16.前述权利要求任一项所述的前药，其特征在于，所述掩蔽部分对IL-15细胞因子部分和IL-15Rα的结合不存在影响或为最低程度影响。
17.前述权利要求任一项所述的前药，其特征在于，所述IL-15细胞因子部分为包括SEQID NO:2或其突变体的人源IL-15多肽。
18.如权利要求17所述的前药，其特征在于，所述人源IL-15多肽相对于SEQ ID NO:2包括一个或多个选自N1A，N1D，N4A，N4D，I6T，S7A，D8A，D8T，D8E，D8N，K10A，K10D，K11A，K11D，E46，V49，L45，S51，L52，D61A，D61N，T62L，T62A，E64A，E64L，E64K，E64Q，N65A，N65L，N65D，L66D，L66E，I 67D，I67E，I68S，I68E，L69S，L69E，N72A，N72D，V63E，V63D，L66E，L66D，I67E，I67D，Q108E，N112A，N1D/D61N，N1D/E64Q，N4D/D61N，N4D/E64Q，D8N/D61N，D8N/E64Q，D61N/E64Q，E64Q/Q108E，N1D/N4D/D8N，D61N/E64Q/N65D，N1D/D61N/E64Q，N1D/Q108E，N1D/D61N/E64Q/Q108E，N4D/D61N/E64Q/Q108E，和D30N/E64Q/N65D的突变。
19.前述任一项所述的前药，其特征在于，所述载体部分为PEG分子、白蛋白、白蛋白片段、抗体Fc结构域、或抗体或其抗原结合片段。
20.如权利要求19所述的前药，其特征在于，所述载体部分为Fc结构域或抗体，包含L234A和L234A突变(“LALA”)(EU编号)。
21.如权利要求19或20所述的前药，其特征在于，所述载体部分为包含球孔突变的抗体Fc结构域或抗体，其中，所述IL-15细胞因子部分和掩蔽部分分别融合到抗体Fc结构域的两条不同多肽链，或分别融合到抗体的不同重链。
22.如权利要求21所述的前药，其特征在于，
所述球孔突变包括位于Fc结构域或抗体重链上的T366Y“knob”突变，和位于Fc结构域另一条多肽或抗体另一条重链上的Y407T“hole”突变；或
所述球孔突变包括位于CH3结构域“knob链”的Y349C和/或T366W突变，和位于CH3结构域“hole链”的E356C，T366S，L368A和/或Y407V突变。
23.如权利要求19所述的前药，其特征在于，所述载体部分为IgG4 Fc结构域，其中第一条多肽包括和SEQ ID NO:80，81或87至少有99％同源性的氨基酸序列，第二条多肽链包括和选自SEQ ID NO:82-86具有至少99％同源性的氨基酸序列。
24.如权利要求19或20任一项所述的前药，其特征在于，所述载体部分为抗PD-1抗体，其包括和SEQ ID NO:55或56具有至少99％同源性氨基酸序列的轻链，和SEQ ID NO:54，60或61具有至少99％同源性氨基酸序列的第一重链，以及和SEQ ID NO:52,53,58,59,62,63或69具有至少99％同源性氨基酸序列的第二重链。
25.如权利要求19或20任一项所述的前药，其特征在于，所述载体部分为抗PD-1抗体，其包括和SEQ ID NO:55具有至少99％同源性氨基酸序列的轻链，和SEQ ID NO:66具有至少99％同源性氨基酸序列的第一重链，以及和SEQ ID NO:64,65,67或68具有至少99％同源性氨基酸序列的第二重链。
26.如权利要求19或20任一项所述的前药，其特征在于，所述载体部分为抗PD-L1抗体，其包括和SEQ ID NO:50或51具有至少99％同源性氨基酸序列的轻链，和SEQ ID NO:47,48或49具有至少99％同源性氨基酸序列的第一重链，以及和SEQ ID NO:45或46具有至少99％同源性氨基酸序列的第二重链。
27.如权利要求19或20任一项所述的前药，其特征在于，所述载体部分为抗体或抗原结合片段，所述抗体或抗原结合片段特异性结合一个或多个选自PD-1，PD-L1，CTLA-4，LAG-3，TIM-3，CD47，以及TIGIT的抗原。
28.如权利要求19-27任一项所述的前药，其特征在于，所述载体部分为抗体Fc结构域或抗体，所述前药(从N末端到C末端)包括选自如下的多肽组合：
a)C1-A和C2-S-M，
b)A-C1和M-S-C2，
c)C1-S-A和C2-M，
d)C1-A-S和C2-M，
e)S-A-C1和M-C2，或
f)A-S-C1和M-C2；
其中，所述C1和C2分别为Fc结构域的第一和第二肽链，或分别为抗体第一和第二重链，“-”为直接肽键或肽连接物。
29.前述权利要求任一项所述的前药，其特征在于，所述Sushi域包括SEQ ID NO:7或9，或与其具有至少90％同源性的氨基酸序列。
30.前述权利要求任一项所述的前药，其特征在于，所述第一、第二、第三肽连接物中至少一个为不可切割的肽连接物，优选地，选自SEQ ID NO:11-16。
31.前述任一项所述的前药，其特征在于，所述第一、第二、第三肽连接物中至少一个为可切割肽连接物，其包括尿激酶型纤溶酶原激活物(uPA)，蛋白裂解酶，基质金属肽酶(MMP)2或MMP9的底物序列。
32.如权利要求31所述的前药，其特征在于，所述肽连接物包括(i)uPA和MMP2的底物序列，(ii)uPA和MMP9的底物序列，(iii)uPA、MMP2和MMP9的底物序列，或(iv)MMP2和蛋白裂解酶的底物序列。
33.如权利要求31所述的前药，其特征在于，所述可切割肽连接物包括选自SEQ ID NO:17-36的氨基酸序列。
34.前述权利要求任一项所述的前药，其特征在于，所述可切割肽连接物可被位于肿瘤部位或其周围环境的一个或多个蛋白酶裂解，所述裂解导致前药在肿瘤部位或周围环境被活化。
35.一种药物组合物，其包含权利要求1-34中任一项所述的前药，以及药学上可接受的赋形剂。
36.编码如权利要求1-34中任一项所述前药的多核苷酸。
37.包含如权利要求36所述的多核苷酸的表达载体。
38.包含如权利要求37所述载体的宿主细胞。
39.如权利要求38所述的宿主细胞，其特征在于，编码uPA、蛋白裂解酶、MMP2和/或MMP9的基因在宿主细胞中被敲除。
40.一种制备如权利要求1-34任一项所述前药的方法，包括
在允许前药表达的条件下，培养权利要求38或39的宿主细胞，其中所述宿主细胞是哺乳动物细胞，以及
分离前药。
41.一种于有需要的患者中治疗癌症或感染性疾病或刺激免疫系统的方法，其包括向所述患者施用治疗有效量的权利要求35的药物组合物。
42.IL-15前药用于治疗用途，所述治疗为权利要求41所述方法中的治疗癌症或感染性疾病或刺激免疫系统。
43.IL-15前药在制备治疗药物中的应用，所述治疗为权利要求41所述方法中的治疗癌症或感染性疾病或刺激免疫系统。
44.如权利要求41所述的方法，权利要求42所述的前药用途，或权利要求43所述的应用，其特征在于，患者为病毒感染，或患有选自乳腺癌、肺癌、胰腺癌、食道癌、甲状腺髓样癌、卵巢癌、子宫癌、前列腺癌、睾丸癌、结肠直肠癌和胃癌的癌症。
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| US20200392235A1 (en) | 2020-12-17 |
| KR20220020879A (ko) | 2022-02-21 |
| EP3983432A1 (en) | 2022-04-20 |
| WO2020252264A1 (en) | 2020-12-17 |
| US20240067739A1 (en) | 2024-02-29 |
| AU2020291012A1 (en) | 2021-12-16 |
| JP2022536898A (ja) | 2022-08-22 |
| US11845801B2 (en) | 2023-12-19 |
| CA3141626A1 (en) | 2020-12-17 |
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