具体实施方式

本文公开了将包含诱导型细胞因子的构建体工程化并使用所述构建体的方法和组合物。细胞因子是有效的免疫激动剂，这导致它们被认为是有前途的肿瘤治疗剂。然而，细胞因子被证明具有非常狭窄的治疗窗。细胞因子的血清半衰期短，并且也被认为是高效的。因此，细胞因子的治疗性施用产生了不期望的全身作用和毒性。为了在预期的细胞因子作用位点(例如，肿瘤)处达到所期望细胞因子水平需要施用大量细胞因子，这加剧了这些问题。不幸的是，由于细胞因子的生物学特性以及不能有效地靶向并控制其活性，因此细胞因子在肿瘤的治疗中未达到所希望的临床优势。

本文公开了克服毒性和半衰期短的问题的融合蛋白，所述问题严重限制了细胞因子在肿瘤学中的临床应用。融合蛋白含有具有受体激动剂活性的细胞因子多肽。但是在融合蛋白的情况下，细胞因子受体激动剂的活性减弱并且循环半衰期延长。融合蛋白包含蛋白酶裂解位点，所述位点由与所期望细胞因子活性位点(例如，肿瘤)相关的蛋白酶裂解，并且通常富集于或选择性地存在于具有所期望活性的位点。因此，在所期望活性位点处优先(或选择性)且有效地裂解融合蛋白，以将细胞因子的活性基本上限制在所期望活性位点，诸如肿瘤微环境。蛋白酶在所期望活性位点(诸如肿瘤微环境中)的裂解从融合蛋白中释放出一种形式的细胞因子，所述细胞因子作为细胞因子受体激动剂的活性远大于融合蛋白(通常比融合蛋白大至少约100倍的活性)。在裂解融合蛋白时释放的细胞因子形式通常具有较短的半衰期，所述半衰期通常基本上相似于天然存在的细胞因子的半衰期，从而将细胞因子活性进一步限制到肿瘤微环境。即使融合蛋白的半衰期延长，但是因为循环融合蛋白减弱并且活性细胞因子靶向肿瘤微环境，所以毒性显著降低或消除。本文所述的融合蛋白首次使得能够施用有效治疗剂量的细胞因子来治疗肿瘤，其中细胞因子的活性基本上限制到肿瘤微环境，并且显著降低或消除细胞因子的不需要的全身作用和毒性。

除非另外定义，否则本文使用的所有技术术语、标记法和其他科学术语均意图具有本发明所属的领域的技术人员通常所理解的含义。在一些情况下，为了清楚和/或易于参考，本文定义了具有通常理解的含义的术语，并且本文中包括此类定义不一定应被解释为表示与本领域通常理解的内容的区别。本领域技术人员通常很好地理解本文所述或参考的技术和程序并通常使用常规方法来应用所述技术和程序，所述方法诸如Sambrook等人,Molecular Cloning:A Laboratory Manual第4版(2012)Cold Spring Harbor LaboratoryPress,Cold Spring Harbor,NY中所述的广泛应用的分子克隆方法。适当地，除非另外说明，否则通常根据制造商定义的方案和条件进行涉及使用可商购获得的试剂盒和试剂的程序。

“细胞因子”是熟知的技术术语，是指由细胞(尤其是免疫系统的细胞)分泌的并且是免疫系统的调节剂的任何一类免疫调节蛋白(诸如白介素或干扰素)。可用于本文所公开的融合蛋白中的细胞因子多肽包括但不限于转化生长因子，诸如TGF-α和TGF-β(例如，TGFβ1、TGFβ2、TGFβ3)；干扰素，诸如干扰素-α、干扰素-β、干扰素-γ、干扰素-κ和干扰素-ω；白介素，诸如IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21和IL-25；肿瘤坏死因子，诸如肿瘤坏死因子α和淋巴毒素；趋化因子(例如，C-X-C基序趋化因子10(CXCL10)、CCL19、CCL20、CCL21)和粒细胞巨噬细胞集落刺激因子(GM-CS)，以及活化细胞因子同源受体的此类多肽的片段(即前述功能片段)。“趋化因子”是本领域的术语，是指具有诱导附近的反应性细胞定向趋化的能力的任何小细胞因子家族。

众所周知，细胞因子的血清半衰期较短，经常只有几分钟或几小时。即使已经改变旨在延长血清半衰期但保留受体激动剂活性的氨基酸序列的细胞因子形式也通常具有较短的血清半衰期。如本文所用，“半衰期细胞因子”是指在受试者的血清中具有基本上短暂的半衰期循环的细胞因子，诸如小于10分钟、小于15分钟、小于30分钟、小于60分钟、小于90分钟、小于120分钟、小于240分钟或小于480分钟的血清半衰期。如本文所用，半衰期短的细胞因子包括其序列尚未修饰来在受试者体内实现比正常半衰期更长的半衰期的细胞因子，以及已经改变旨在延长血清半衰期但保留受体激动剂活性的氨基酸序列的多肽。通常，短半衰期细胞因子多肽诸如IL-2多肽的血清半衰期与天然存在的IL-2相当，例如在天然存在的IL-2的5倍、4倍、3倍或2倍内。后一种情况并不意味着包括添加异源蛋白结构域，诸如真正的半衰期延长元件，诸如血清白蛋白。

“分选酶”是通过识别并裂解嵌入或末端连接于靶蛋白或肽的羧基端分选信号来修饰蛋白质的转肽酶。分选酶A催化靶蛋白上的Thr和Gly残基之间的LPXTG基序(SEQ IDNO:125)(其中X为任何标准氨基酸)的裂解，其中Thr残基短暂连接到所述酶上的活性位点Cys残基，从而形成酶硫酰基中间体。为了完成转肽作用并创建肽-单体缀合物，具有N端亲核基团(通常为寡甘氨酸基序)的生物分子攻击中间体，从而替代分选酶A并连接两个分子。

如本文所用，术语“空间阻断剂”是指可通过诸如接头的其他部分(例如呈嵌合多肽(融合蛋白)形式)直接或间接地共价键合到细胞因子多肽但不以其他方式共价键合到细胞因子多肽的多肽或多肽部分。空间阻断剂可例如通过静电键合、疏水键合、离子键合或氢键键合来非共价键合到细胞因子多肽。空间阻断剂通常由于其靠近细胞因子部分和相对大小而抑制或阻断细胞因子部分的活性。空间阻断剂还可通过募集大蛋白结合配偶体来阻断。空间阻断剂的实例是与血清白蛋白结合的抗体；虽然抗体本身可能足够大或可能不足以大到自行阻止活化或结合，但白蛋白募集允许足够的空间阻断。

如本文所用和描述的，“半衰期延长元件”是嵌合多肽的一部分，其例如通过改变其大小(例如，使其高于肾脏滤过界限)、形状、流体动力学半径、电荷、或吸收、生物分布、代谢和消除的参数来增加血清半衰期并改善pK。

如本文所用，术语“可活化的”、“活化”、“诱导”和“可诱导的”是指作为融合蛋白的一部分的蛋白质(即细胞因子)结合其受体并在从融合蛋白裂解其他元件时实现活性的能力。

如本文所用，“质粒”或“病毒载体”是将所公开的核酸运输到细胞中而不降解的剂，并且包含核酸分子和/或多肽在其所递送到的细胞中产生表达的启动子。

如本文所用，术语“肽”、“多肽”或“蛋白质”广泛地用于指由肽键连接的两个或更多个氨基酸。蛋白质、肽和多肽在本文中也可互换使用，以指示氨基酸序列。应当认识到，术语多肽在本文中并不用于暗示构成所述分子的氨基酸的特定大小或数量，并且本发明的肽可含有至多几个氨基酸残基或更多。

如通篇所用，“受试者”可为脊椎动物，更具体地为哺乳动物(例如人、马、猫、狗、牛、猪、绵羊、山羊、小鼠、兔、大鼠和豚鼠)、鸟类、爬行动物、两栖动物、鱼类和其他任何动物。术语不表示特定的年龄或性别。因此，旨在涵盖无论雄性还是雌性的成年和新生受试者。

如本文所用，“患者”或“受试者”可互换使用，并且可指患有疾病或病症(例如癌症)的受试者。术语患者或受试者包括人和兽医学受试者。

如本文所用，术语“治疗(treatment\treat\treating)”是指减少疾病或病状的作用或者疾病或病状的症状的方法。因此，在所公开的方法中，治疗可指确立的疾病或病状或疾病或病状的症状的严重程度至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％或基本上完全减少。例如，如果与对照相比，受试者疾病的一个或多个症状减少10％，则认为用于治疗疾病的方法是一种治疗。因此，与天然或对照水平相比，减少可为10％、20％、30％、40％、50％、60％、70％、80％、90％、100％或10％与100％之间的任何减少百分比。应理解，治疗不必指治愈或完全消除疾病、病状或者疾病或病状的症状。

如本文所用，术语“预防(prevent\preventing\prevention)”疾病或病症是指例如在受试者开始显示疾病或病症的一种或多种症状之前或大约同时发生的施用嵌合多肽或编码嵌合多肽的核酸序列的作用，其抑制或延迟疾病或病症的一种或多种症状的发作或加剧。

如本文所用，对“降低”、“减少”或“抑制”的提及包括与合适的对照水平相比，至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％或更大的变化。此类术语可包括但不一定包括完全消除功能或特性，诸如激动剂活性。

“减弱的细胞因子受体激动剂”是与细胞因子受体的天然存在的激动剂相比，具有降低的受体激动剂活性的细胞因子受体激动剂。与受体的天然存在的激动剂相比，减弱的细胞因子激动剂可具有至少约10倍、至少约50倍、至少约100倍、至少约250倍、至少约500倍、至少约1000倍或更低的激动剂活性。当含有如本文所述的细胞因子多肽的融合蛋白被描述为“减弱的”或具有“减弱的活性”时，意指融合蛋白是减弱的细胞因子受体激动剂。

“完整融合蛋白”是其中结构域没有例如通过蛋白酶裂解去除的融合蛋白。结构域可通过蛋白酶裂解或其他酶活性去除，但是当融合蛋白为“完整的”时，这并没有发生。

如本文所用，“部分”是指分子的在该分子内具有不同功能的部分，并且该功能可在另一分子的情况下由该部分来执行。部分可为具有特定功能的化学实体，或具有特定功能的生物分子的一部分。例如，融合蛋白内的“阻断部分”是融合蛋白的能够阻断一些或所有融合多肽的活性的部分。这可能是蛋白质结构域，诸如血清白蛋白。阻断可通过空间阻断剂或特定阻断剂来完成。空间阻断剂通过大小和位置而不是基于特定结合来阻断；一个实例是血清白蛋白。特定的阻断剂通过与待阻断部分发生特定相互作用来阻断。必须针对具体细胞因子或活性结构域来调整特定阻断剂；无论有效载荷如何，都可使用空间阻断剂，只要其足够大。

一般来讲，细胞因子的治疗应用受到其全身毒性的强烈限制。例如，最初发现TNF具有诱导一些肿瘤的出血性坏死的能力，并且对不同肿瘤细胞系具有体外细胞毒性作用，但它后来被证明具有很强的促炎活性，这可在过度产生的情况下对人体产生危险的影响。由于全身毒性是在人体中使用药物活性量的细胞因子的基本问题，因此目前正在评估新型衍生物和治疗策略，旨在降低此类生物效应物的毒性作用，同时保持其治疗功效。

IL-2在免疫系统中发挥刺激和调节功能，并且与共同γ链(γc)细胞因子家族的其他成员一起对免疫稳态起至关重要的作用。IL-2通过结合IL-2受体(IL-2R)来介导其作用，所述IL-2受体由以IL-2Rα(CD25)、IL-2Rβ(CD122)和IL-2Rγ(γc,CD132)链制成的三聚体受体IL-2或二聚体βγIL-2R(1,3)组成。两种IL-2R变体都能够在IL-2结合后传输信号。然而，三聚体αβγIL-2R对IL-2的亲和力比二聚体βγIL-2R(3)高约10至100倍，这暗示CD25赋予IL-2与其受体高亲和力结合，但对信号转导不重要。在活化的T细胞和CD4+叉头框P3(FoxP3)+T调节细胞(Treg)上发现三聚体IL-2R，它们在体外和体内对IL-2敏感。相反，抗原刺激过的(记忆)CD8+、CD44高记忆表型(MP)CD8+和自然杀伤(NK)细胞被赋予高水平的二聚体βγIL-2R，并且这些细胞也在体外和体内对IL-2作出有力反应。

高亲和力IL-2R的表达对于赋予T细胞对体内瞬时可用的低浓度IL-2的反应至关重要。IL-2Rα表达在原初和记忆T细胞上不存在，但在抗原活化后被诱导。IL-2Rβ由NK、NKT和记忆CD8+T细胞组成性表达，但在抗原活化后也在原初T细胞上被诱导。γc的调节不那么严格，并且由所有淋巴样细胞组成性表达。一旦抗原诱导高亲和力IL-2R后，IL-2R信号传导就部分通过Stat5依赖性调节Il2ra转录来上调IL-2Rα的表达(Kim等人,2001)。此过程代表了维持高亲和力IL-2R表达并保持IL-2信号传导，同时仍保留IL-2的来源的机制。

IL-2Rα通过被极性周边包围的大的疏水性结合表面捕获IL-2，从而导致相对较弱的相互作用(Kd 10-8M)和快速开关的结合动力学。然而，IL-2Rα-IL-2二元复合物导致IL-2的构象变化非常小，从而通过IL-2和IL-2Rβ之间明显的极性相互作用促进与IL-2Rβ的缔合。IL2/α/β三聚体复合物的假高亲和力(即Kd约300pM)清楚地指示，三聚体复合物比单独与α链(Kd＝10nM)或单独与β链(Kd＝450nM)结合的IL2更稳定，如Ciardelli的数据所示。无论如何，IL2/α/β三聚体接着将γ链募集到能够进行信号传导的四元复合物中，这通过γ链在IL2结合的β链上的大复合结合位点所促进。

换句话讲，三元IL-2Rα-IL-2Rβ-IL-2复合物接着通过与IL-2的弱相互作用和与IL-2Rβ的强相互作用而募集γc，以产生稳定的四元高亲和力IL-2R(Kd 10-11M，即10pM)。高亲和力的四元IL-2-IL-2R复合物的形成导致通过酪氨酸激酶Jak1和Jak3进行信号转导，所述酪氨酸激酶分别与IL-2Rβ和γc缔合(Nelson和Willerford，1998)。四元IL-2-IL-2R复合物被快速内在化，其中IL-2、IL-2Rβ和γc迅速降解，但IL-2Rα循环到细胞表面(Hémar等人,1995；Yu和Malek,2001)。因此，需要持续的IL-2R信号传导的那些功能性活动需要持续的IL-2来源来与IL-2Rα接合并形成额外IL-2-IL-2R信号传导复合物。

调节性T细胞主动抑制免疫系统的活化，并预防病理性自身反应和随后的自身免疫性疾病。开发选择性地活化调节性T细胞以治疗自身免疫性疾病的药物和方法是热门研究的主题，并且在很大程度上是不成功的，直到能够在炎症部位选择性地递送活性白介素的本发明的发展。调节性T细胞(Treg)是一类抑制其他免疫细胞活性的CD4+CD25+T细胞。Treg是免疫系统稳态的关键，并且在维持对自身抗原的耐受性和调节对外来抗原的免疫应答方面起主要作用。多种自身免疫性和炎性疾病，包括1型糖尿病(T1D)、系统性红斑狼疮(SLE)和移植物抗宿主病(GVHD)，已显示出缺乏Treg细胞数量或Treg功能。

因此，人们对开发增强Treg细胞数量和/或功能的疗法非常感兴趣。一种正在研究的针对自身免疫性疾病的治疗方法是移植自体、离体扩增的Treg细胞(Tang,Q.等人,2013,Cold Spring Harb.Perspect.Med.,3:1-15)。虽然这种方法在治疗动物疾病模型和多个早期人类临床试验方面具有前景，但它需要使用患者自身的T细胞进行个性化治疗，具有侵入性并且技术复杂。另一种方法是用低剂量白介素-2(IL-2)治疗。Treg细胞特征性表达高组成性水平的高亲和力IL-2受体IL2Rαβγ，所述受体由亚基IL2Rα(CD25)、IL2Rβ(CD122)和IL2Rγ(CD132)组成，并且已显示出Treg细胞的生长依赖于IL-2(Malek,T.R.等人,2010,Immunity,33:153-65)。

相反，也使用IL-2来实现免疫活化，并且已批准重组IL-2()用于治疗某些癌症。高剂量IL-2用于治疗患有转移性黑色素瘤和转移性肾细胞癌的患者，这对总体存活率有长期影响。

低剂量IL-2治疗慢性GVHD(Koreth,J.等人,2011,N Engl J Med.,365:2055-66)和HCV相关性自身免疫性血管炎患者(Saadoun,D.等人,2011,N Engl J Med.,365:2067-77)的临床试验已证明Treg水平的增加和临床功效的迹象。已开始研究IL-2在多种其他自身免疫性和炎性疾病中的功效的新临床试验。使用所谓的低剂量IL-2的基本原理是利用在Treg上组成性表达的三聚体IL-2受体的高IL-2亲和力，同时使其他不表达高亲和力受体的T细胞处于失活状态。这些试验中使用的IL-2的重组形式阿地白介素(Aldesleukin)(由Prometheus Laboratories,San Diego,CA以出售)与高毒性有关。已批准阿地白介素用于治疗转移性黑色素瘤和转移性肾癌，但其副作用非常严重，以至仅建议在有重症监护室的医院中使用(网址：www.proleukin.com/assets/pdf/proleukin.pdf)。

IL-2在自身免疫性疾病中的临床试验采用了较低剂量的IL-2来靶向Treg细胞，因为Treg细胞由于表达IL2Rα而与许多其他免疫细胞类型相比，对更低浓度的IL-2作出反应(Klatzmann D,2015Nat Rev Immunol.15:283-94)。然而，即使这些较低的剂量也会导致安全性和耐受性问题，并且所使用的治疗方法长期地或在间歇性5天疗程中采用每天皮下注射。因此，对增强Treg细胞数量和功能、比IL-2更特异性地靶向Treg细胞、更安全且更耐受、并且施用频率更低的自身免疫性疾病疗法存在需要。

已提出一种用于改善基于IL-2的疗法的自身免疫性疾病治疗指数的方法是使用相对于其他免疫细胞对Treg细胞具有选择性的IL-2变体。IL-2受体表达于多种不同的免疫细胞上，所述细胞包括T细胞、NK细胞、嗜酸性粒细胞和单核细胞，并且这种广泛的表达模式可能有助于其对免疫系统的多效作用和高全身毒性。特别地，活化的T效应细胞与肺上皮细胞一样表达IL2Rαβγ。但是，活化T效应细胞与下调并控制免疫应答的目标直接相反，并且活化肺上皮细胞会导致已知的IL-2剂量限制性副作用，包括肺水肿。事实上，高剂量IL-2免疫疗法的主要副作用是血管渗漏综合征(VLS)，它导致血管内流体在诸如肺和肝的器官中积聚，随后引起肺水肿和肝细胞损伤。除了停用IL-2外，没有其他治疗VLS的方法。已在患者中测试了低剂量IL-2方案以避免VLS，然而，这是以次最佳治疗结果为代价。

根据文献，VLS被认为是由IL-2活化的NK细胞释放促炎性细胞因子引起的。然而，有强有力的证据表明，肺水肿是由IL-2与表达低至中等水平的功能性αβγIL-2R的肺内皮细胞的直接结合引起的。并且，通过在CD25缺陷型宿主小鼠中用抗CD25单克隆抗体(mAb)阻断与CD25的结合或通过使用CD122特异性IL-2/抗IL-2mAb(IL-2/mAb)复合物来消除与IL-2和肺内皮细胞相互作用相关联的肺水肿，从而预防VLS。

用除IL-2以外的白介素细胞因子进行治疗受到更多的限制。IL-15表现出与IL-2相似的免疫细胞刺激活性，但没有相同的抑制作用，因此使其成为有前景的免疫治疗候选物。重组人IL-15治疗转移性恶性黑色素瘤或肾细胞癌的临床试验表明免疫细胞分布、增殖和活化发生了明显变化，并暗示潜在的抗肿瘤活性(Conlon等人，2014)。IL-15目前正在临床试验中，以治疗各种形式的癌症。然而，已知IL-15治疗与不期望和毒性作用，诸如加剧某些白血病、移植物抗宿主病、低血压、血小板减少和肝损伤相关联。(Mishra A.等人,CanceCell,2012,22(5):645-55；Alpdogan O.等人,Blood,2005,105(2):866-73；Conlon KC等人,J Clin Oncol,2015,33(1):74-82。)

由于IL-2具有充分证明的治疗风险，例如其血清半衰期短且毒性高，因此直接使用IL-2作为激动剂来结合IL-2R并治疗性地调节免疫应答一直存在问题。这些风险也限制了其他细胞因子的治疗开发和使用。需要降低这些风险的新形式的细胞因子。本文公开了包含IL-2和IL-15和其他细胞因子、细胞因子的功能片段和突变蛋白以及被设计为解决这些风险并提供所需免疫调节治疗剂的条件活性细胞因子的组合物和方法。

本发明被设计为解决直接IL-2疗法和使用其他细胞因子的疗法的缺点，例如使用细胞因子阻断部分，例如空间阻断多肽、血清半衰期延长多肽、靶向多肽、连接多肽(包含蛋白酶可裂解的接头)及其组合。细胞因子当施用于患者时具有很高的效力，所述细胞因子包括白介素(例如IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、IL-23)、干扰素(IFN，包括IFNα、IFNβ和IFNγ)、肿瘤坏死因子(例如，TNFα、淋巴毒素)、转化生长因子(例如，TGFβ1、TGFβ2、TGFβ3)、趋化因子(C-X-C基序趋化因子10(CXCL10)、CCL19、CCL20、CCL21)以及粒细胞-巨噬细胞集落刺激因子(GM-CS)。如本文所用，“趋化因子”意指具有诱导邻近反应性细胞中定向趋化能力的小细胞因子家族。细胞因子可提供有力的治疗，但伴随着临床上难以控制且限制细胞因子的临床使用的不期望的作用。本公开涉及可在不期望作用减少或消除的情况下在患者中使用的新形式的细胞因子。特别地，本公开涉及药物组合物，其包含嵌合多肽(融合蛋白)、编码融合蛋白的核酸的药物组合物和它们的药物制剂，其含有与相应细胞因子相比细胞因子受体活化活性降低的细胞因子或细胞因子的活性片段或突变蛋白。然而，在选定条件下或在选定生物环境中，嵌合多肽常常以与相应天然存在的细胞因子相同或更高的效力活化其同源受体。如本文所述，这通常使用细胞因子阻断部分来实现，所述细胞因子阻断部分在一般条件下而不是在选定条件下阻断或抑制细胞因子、其活性片段或突变蛋白(诸如在所期望细胞因子活性位点(例如，炎症位点或肿瘤)处存在的那些)的受体活化功能。

嵌合多肽和编码嵌合多肽的核酸可使用任何合适的方法来制备。例如，编码嵌合多肽的核酸可使用重组DNA技术、合成化学或这些技术的组合来制备，并在合适的表达系统诸如CHO细胞中表达。可类似地制备嵌合多肽，例如通过使用合成或半合成化学技术等表达合适的核酸来制备。在一些实施方案中，可通过分选酶介导的缀合将阻断部分连接到细胞因子多肽。“分选酶”是通过识别并裂解嵌入或末端连接于靶蛋白或肽的羧基端分选信号来修饰蛋白质的转肽酶。分选酶A催化靶蛋白上Thr和Gly残基之间的LPXTG基序(SEQ ID No.:125)(其中X为任何标准氨基酸)的裂解，其中Thr残基与酶上的活性位点Cys残基短暂连接，从而形成酶-硫酰基中间体。为了完成转肽作用并创建肽-单体缀合物，具有N端亲核基团(通常为寡甘氨酸基序)的生物分子攻击中间体，从而替代分选酶A并连接两个分子。

为了形成细胞因子-阻断部分融合蛋白，首先在N端用聚甘氨酸序列标记细胞因子多肽，或可替代地在C端用LPXTG基序(SEQ ID NO.:125)标记细胞因子多肽。阻断部分或其他元件具有连接的用作标记多肽的受体位点的相应肽。对于与通过其N端连接的携带LPXTG受体肽(SEQ ID NO.:125)的结构域的缀合，多肽将标记有N端聚甘氨酸拉伸物。对于与通过其C端连接的携带聚甘氨酸肽的结构域的缀合，多肽将在其C端用LPXTG分选酶识别序列(SEQ ID NO.:125)进行标记。识别聚甘氨酸和LPXTG(SEQ ID NO.:125)序列，分选酶将在聚合物多肽和标记多肽之间形成肽键。分选酶反应裂解甘氨酸残基作为中间体，并在室温下发生。

可利用多种机制来去除或减少由阻断部分引起的抑制。例如，药物组合物可包含具有蛋白酶可裂解的接头的IL-2多肽部分和阻断部分，例如空间阻断部分，所述蛋白酶可裂解的接头包含位于IL-2多肽和IL-2阻断部分之间或IL-2阻断部分内的蛋白酶裂解位点。当蛋白酶裂解位点被裂解时，阻断部分可与细胞因子解离，并且然后细胞因子可活化细胞因子受体。细胞因子部分也可通过结合在相关细胞因子上发现的表位的特定阻断部分(诸如抗体)阻断。

可使用任何合适的接头。例如，接头可包含甘氨酸-甘氨酸、分选酶识别基序或分选酶识别基序和肽序列(Gly₄Ser)_n(SEQ ID NO.:126)或(Gly₃Ser)_n(SEQ ID NO.:127)，其中n为1、2、3、4或5。通常，分选酶识别基序包含肽序列LPXTG(SEQ ID NO.:125)，其中X为任何氨基酸。在一些实施方案中，共价键是在连接到细胞因子多肽的C端的反应性赖氨酸残基与连接到阻断剂或其他结构域的N端的反应性天冬氨酸之间。在其他实施方案中，共价键是在连接到细胞因子多肽的N端的反应性天冬氨酸残基与连接到所述阻断剂或其他结构域的C端的反应性赖氨酸残基之间。

因此，如本文中详细描述的，所使用的细胞因子阻断部分(例如IL-2阻断部分)可为空间阻断剂。如本文所用，“空间阻断剂”是指可直接或通过诸如接头的其他部分(例如呈嵌合多肽(融合蛋白)的形式)间接地共价键合到细胞因子多肽但不以其他方式共价键合到细胞因子多肽的多肽或多肽部分。空间阻断剂可例如通过静电键合、疏水键合、离子键合或氢键键合来非共价键合到细胞因子多肽。空间阻断剂通常由于其靠近细胞因子部分和相对大小而抑制或阻断细胞因子部分的活性。可通过在空间上分离细胞因子部分与空间阻断剂，诸如通过在空间阻断剂和细胞因子多肽之间的位点处酶促裂解包含空间阻断剂和细胞因子多肽的融合蛋白来去除细胞因子部分的空间抑制作用。

如本文中更详细描述的，阻断功能可与药物组合物中的额外功能性组分(诸如靶向结构域、血清半衰期延长元件和蛋白酶可裂解的连接多肽)组合或由于所述组分存在。例如，血清半衰期延长多肽也可为空间阻断剂。

各种元件确保IL-2在所期望IL-2活性位点的优先递送和活性，并通过优先与血清半衰期延长策略相关的阻断和/或靶向策略严重限制对白介素的全身暴露。在此血清半衰期延长策略中，白介素的阻断版本的循环时间延长(优选地1至2周或更多周)，但活化版本具有典型的白介素血清半衰期。

与血清半衰期延长版本相比，静脉内施用IL-2的血清半衰期仅为约10分钟，这是由于其分布在全身细胞外空间中，所述空间很大，在平均体型的成年人中为约15L。随后，IL-2被肾脏代谢，其半衰期为约2.5小时。(Smith,K.“Interleukin 2immunotherapy.”Therapeutic Immunology 240(2001))。通过其他测量，IL-2具有非常短的血浆半衰期，对于静脉内施用为85分钟，并且对于皮下施用为3.3小时(Kirchner,G.I.等人,1998,Br JClin Pharmacol.46:5-10)。在本发明的一些实施方案中，半衰期延长元件通过接头连接到白介素，所述接头在作用位点被裂解(例如通过炎症特异性或肿瘤特异性蛋白酶)，从而在所期望位点释放白介素的全部活性，并还将其与未裂解版本的半衰期延长分离。在此类实施方案中，完全活性和游离白介素将具有非常不同的药代动力学(pK)特性，半衰期为数小时而不是数周。此外，暴露于活性细胞因子仅限于所期望的细胞因子活性位点(例如，炎症位点或肿瘤)以及全身暴露于活性细胞因子及相关毒性和副作用降低。

本发明中设想的其他细胞因子(例如，由Blood 2011117:4787-4795；doi:doi.org/10.1182/blood-2010-10-311456报告的IL-15)具有与IL-2类似的药理学，并且因此，本发明的设计解决了直接使用这些剂的缺点，并提供了可具有延长的半衰期和/或靶向所期望活性位点(例如，炎症位点或肿瘤)的嵌合多肽。

如果需要的话，可将IL-2工程化来以与相应野生型IL-2不同的亲和力特异性结合通常为IL-2R复合物或三个IL-2R亚基中的一个，以例如选择性地活化Treg或Teff。例如，与野生型IL-2相比，被认为相对于Il-2受体的二聚体β/γ形式，对IL-2受体的三聚体形式具有更高亲和力的IL-2多肽可具有氨基酸序列，所述氨基酸序列包含相对于SEQ ID NO:1(成熟IL-2蛋白，其包含人IL-2的氨基酸21-153，具有Uniprot登录号P60568-1)的以下突变组中的一组：(a)K64R、V69A和Q74P；(b)V69A、Q74P和T101A；(c)V69A、Q74P和I128T；(d)N30D、V69A、Q74P和F103S；(e)K49E、V69A、A73V和K76E；(f)V69A、Q74P、T101A和T133N；(g)N30S、V69A、Q74P和I128A；(h)V69A、Q74P、N88D和S99P；(i)N30S、V69A、Q74P和I128T；(j)K9T、Q11R、K35R、V69A和Q74P；(k)A1T、M46L、K49R、E61D、V69A和H79R；(l)K48E、E68D、N71T、N90H、F103S和I114V；(m)S4P、T10A、Q11R、V69A、Q74P、N88D和T133A；(n)E15K、N30S Y31H、K35R、K48E、V69A、Q74P和I92T；(o)N30S、E68D、V69A、N71A、Q74P、S75P、K76R和N90H；(p)N30S、Y31C、T37A、V69A、A73V、Q74P、H79R和I128T；(q)N26D、N29S、N30S、K54R、E67G、V69A、Q74P和I92T；(r)K8R、Q13R、N26D、N30T、K35R、T37R、V69A、Q74P和I92T；以及(s)N29S、Y31H、K35R、T37A、K48E、V69A、N71R、Q74P、N88D和I89V。这种方法也可用于制备其他细胞因子的突变蛋白，所述细胞因子包括白介素(例如，IL-2、IL-7、IL-12、IL-15、IL-18、IL-23)、干扰素(IFN，包括IFNα、IFNβ和IFNγ)、肿瘤坏死因子(例如，TNFα、淋巴毒素)、转化生长因子(例如，TGFβ1、TGFβ2、TGFβ3)和粒细胞-巨噬细胞集落刺激因子(GM-CS)。例如，可制备对同源受体具有所期望的结合亲和力的突变蛋白。

如上文所述，本文所公开的任何突变体IL-2多肽都可包含所述序列；它们也可限于所述序列并另外与SEQ ID NO:1相同。此外，本文所公开的任何突变体IL-2多肽可任选地包含用另一个残基(例如，丝氨酸)取代位置125处的半胱氨酸残基和/或可任选地包含在SEQ ID NO:1的位置1处的丙氨酸残基的缺失。

改善基于IL-2的疗法的治疗指数的另一种方法是优化所述分子的药代动力学以最大程度地活化Treg细胞。早期对IL-2作用的研究表明，IL-2在体外刺激人T细胞增殖需要至少5至6小时暴露于有效浓度的IL-2(Cantrell,D.A.等人,1984,Science,224:1312-1316)。当向人患者施用时，IL-2具有非常短的血浆半衰期，对于静脉内施用为85分钟，并且对于皮下施用为3.3小时(Kirchner,G.I.等人,1998,Br J Clin Pharmacol.46:5-10)。由于IL-2半衰期短，因此持续必要的时间段将循环IL-2维持在或高于刺激T细胞增殖所必需的水平需要高剂量来使IL-2峰值水平显著高于Treg细胞的EC50或将需要频繁施用。这些高IL-2峰值水平可活化IL2Rβγ受体并产生其他意外或不利影响，例如如上文所述的VLS。其中循环半衰期比IL-2长的IL-2类似物或的多功能蛋白(其中IL-2连接到能够与FcRn受体结合的结构域)可持续指定的时间段以低于IL-2的剂量达到目标药物浓度，并且其峰值水平更低。因此，此种IL-2类似物将需要比IL-2更低剂量或更低施用频率来有效地刺激Treg细胞。更低频率地皮下施用IL-2药物也将使患者更耐受。具有这些特征的治疗剂将在临床上转化为改善的药理功效、降低的毒性以及改善的患者对治疗的依从性。可替代地，IL-2或IL-2的突变蛋白(在本文中为“IL-2*”)可选择性地靶向预期的作用位点(例如炎症位点)。可通过若干种策略中的一种，包括将结构域添加到包含被裂解的IL-2(或突变蛋白)的阻断剂的所施用剂上，或通过靶向结构域或两者组合来实现这种靶向。

在一些实施方案中，可根据期望的靶标将IL-2*部分激动剂调整为以更高或更低的亲和力结合；例如，可将IL-2*工程化为以增强的亲和力与受体亚基中的一个结合而不与其他亚基结合。与完全激动剂或完全拮抗剂不同，这些类型的部分激动剂提供了将信号传导特性调整至引起所期望功能特性的幅度，同时不满足不期望特性的阈值的能力。鉴于部分激动剂的活性不同，可将一系列IL-2变体工程化以表现出甚至更好的独特信号传导活性，范围从几乎完全激动到部分激动到完全拮抗。

在一些实施方案中，IL-2*改变了对IL-2Rα的亲和力。在一些实施方案中，与野生型IL-2相比，IL-2*对IL-2Rα的亲和力更高。在其他实施方案中，IL-2*改变了对IL-2Rβ的亲和力。在一个实施方案中，IL-2*对IL-2Rβ(例如IL-2Rβ的N端)具有增强的结合亲和力，这消除了对IL-2Rα的功能需求。在另一个实施方案中，生成的IL-2*对IL-2Rβ具有增加的结合亲和力但表现出与IL-2Rγ的结合降低，并且因此是缺陷型IL-2Rβγ异源二聚体和信号传导。

在下文进一步详细描述的阻断部分也可用于促进与一种或多种受体的结合或所述受体的活化。在一个实施方案中，添加阻断部分，使得IL-2Rβγ结合或活化被阻断，但IL-2Rα结合或活化不改变。在另一个实施方案中，添加阻断部分，使得IL-2Rα结合或活化减少。在另一个实施方案中，添加阻断部分，使得与所有三个受体的结合和或所述受体的活化均受到抑制。可通过去除特定环境中的阻断部分，例如通过对将一个或多个阻断部分连接至细胞因子的接头进行蛋白水解裂解来消除这种阻断。

可应用类似方法来改善其他细胞因子，特别是用作免疫刺激剂，例如用于治疗癌症。例如，在此方面，可调整细胞因子(例如，IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、IL-23、IFNα、IFNβ和IFNγ、TNFα、淋巴毒素、TGFβ1、TGFβ2、TGFβ3、GM-CSF、CXCL10、CCL19、CCL20和CCL21)的药代动力学和/或药效动力学以在所期望活性的位点(诸如肿瘤中，但优选不是全身性)处最大程度地活化效应细胞(例如，效应T细胞、NK细胞)和/或细胞毒性免疫应答促进细胞(例如，诱导树突状细胞成熟)。

因此，本文所提供的药物组合物包含至少一种细胞因子多肽，诸如白介素(例如，IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、IL-23)、干扰素(IFN，包括IFNα、IFNβ和IFNγ)、肿瘤坏死因子(例如，TNFα、淋巴毒素)、转化生长因子(例如，TGFβ1、TGFβ2、TGFβ3)、趋化因子(例如CXCL10、CCL19、CCL20、CCL21)和粒细胞-巨噬细胞集落刺激因子(GM-CS)或前述任一种的功能片段或突变蛋白。多肽通常还包含至少一个接头氨基酸序列，其中在某些实施方案中，氨基酸序列能够被内源蛋白酶裂解。在一个实施方案中，接头包含有包含HSSKLQ(SEQID NO.:25)、GPLGVRG(SEQ ID NO.:128)、IPVSLRSG(SEQ ID NO.:129)、VPLSLYSG(SEQ IDNO.130)或SGESPAYYTA(SEQ ID NO.131)的氨基酸序列。在其他实施方案中，嵌合多肽还含有能够阻断白介素多肽活性的阻断部分，例如空间阻断多肽部分。例如，阻断部分可包含人血清白蛋白(HSA)结合结构域或任选地分支或多臂的聚乙二醇(PEG)。可替代地，药物组合物包含第一细胞因子多肽或其片段以及阻断部分，例如空间阻断多肽部分，其中阻断部分阻断在细胞因子受体上的细胞因子多肽的活性，并且其中在某些实施方案中，阻断部分包含蛋白酶可裂解的结构域。在一些实施方案中，仅通过将具有非常短的接头的额外结构域连接到白介素结构域的N端或C端来实现细胞因子活性的阻断和降低。在此类实施方案中，预期通过蛋白酶消化阻断部分或将阻断剂连接至白介素的短接头来减轻阻断。一旦结构域被剪断或释放，它将不再能够实现细胞因子活性的阻断。

药物组合物例如嵌合多肽可包含两种或更多种细胞因子，其可为相同的细胞因子多肽或不同的细胞因子多肽。例如，两种或更多种不同类型的细胞因子具有互补功能。在一些实例中，第一细胞因子为IL-2，并且第二细胞因子为IL-12。在一些实施方案中，两种或更多种不同类型的细胞因子多肽中的每一种都具有调节其他细胞因子多肽活性的活性。在含有两个细胞因子多肽的嵌合多肽的一些实例中，第一细胞因子多肽为T细胞活化的，并且第二细胞因子多肽为非T细胞活化的。在含有两个细胞因子多肽的嵌合多肽的一些实例中，第一细胞因子为趋化剂，例如CXCL10，并且第二细胞因子为免疫细胞活化剂。

优选地，本文所公开的融合蛋白中所包含的细胞因子多肽(包括功能片段)未经突变或工程化来改变天然存在的细胞因子的特性，包括受体结合亲和力和特异性或血清半衰期。然而，可接受天然存在的(包括野生型)细胞因子的氨基酸序列的改变，以例如促进克隆和实现所期望的表达水平。

CD25结合

CD25结合在修饰的IL-2构建体中受到阻止。相比之下，本文所述的IL-2多肽优选地未被修饰成避免CD25结合。优选地，本文所述的IL-2多肽结合CD25。通常，本文所述的IL-2融合蛋白能够进行CD25结合并且阻断涉及与IL-2Rβ和γ(CD 122和CD 132)相互作用。

阻断部分

阻断部分可为抑制细胞因子结合和/或活化其受体的能力的任何部分。阻断部分可抑制细胞因子结合和/或活化其受体从而在空间上阻断和/或通过非共价结合至细胞因子的能力。合适的阻断部分的实例包括细胞因子同源受体的全长或细胞因子结合片段或突变蛋白。也可使用结合细胞因子的抗体及其片段，包括多克隆抗体、重组抗体、人抗体、人源化抗体、单链可变片段(scFv)、单结构域抗体(诸如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼型纳米抗体的可变结构域(VHH))、dAb等。也可使用结合细胞因子的其他合适的抗原结合结构域，包括模拟抗体结合和/或结构的非免疫球蛋白蛋白，诸如anticalin、遍在蛋白(affilin)、亲和体(affibody)分子、亲和性多聚体(affimer)、affitin、α体(alphabody)、高亲合性多聚体(avimer)、DARPin、菲诺体(fynomer)、库尼茨型(kunitz)结构域多肽、单体(monobody)，以及基于其他工程化支架诸如SpA、GroEL、纤维连接蛋白、脂质体和CTLA4支架的结合结构域。合适的阻断多肽的其他实例包括在空间上抑制或阻断细胞因子与其同源受体的结合的多肽。有利地，此类部分还可用作半衰期延长元件。例如，通过与水溶性聚合物诸如PEG缀合而修饰的肽可在空间上抑制或阻止细胞因子与其受体的结合。也可使用具有较长血清半衰期的多肽或其片段，诸如血清白蛋白(人血清白蛋白)、免疫球蛋白Fc、转铁蛋白等，以及此类多肽的片段和突变蛋白。与例如具有较长血清半衰期的蛋白质(诸如HSA、免疫球蛋白或转铁蛋白)结合或与循环到质膜的受体(诸如FcRn或转铁蛋白受体)结合的抗体和抗原结合结构域也可抑制细胞因子，特别是当结合其抗原时。此类抗原结合多肽的实例包括单链可变片段(scFv)、单结构域抗体(诸如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼型纳米抗体的可变结构域(VHH))、dAb等。也可使用结合细胞因子的其他合适的抗原结合结构域，包括模拟抗体结合和/或结构的非免疫球蛋白蛋白，诸如anticalin、affilin、亲和体分子、亲和性多聚体、affitin、α体、高亲合性多聚体、DARPin、菲诺体、库尼茨型结构域多肽、单体，以及基于其他工程化支架诸如SpA、GroEL、纤维连接蛋白、脂质体和CTLA4支架的结合结构域。

在示例性实例中，当IL-2为嵌合多肽中的细胞因子时，阻断部分可为IL-2受体的α链(IL-2Rα)或IL-2受体的β链(IL-2Rβ)或γ链(IL-2Rγ)的全长或片段或突变蛋白、抗IL-2单结构域抗体(dAb)或scFv、Fab、抗CD25抗体或其片段以及抗HAS dAb或scFv等。

本发明的额外方面

1.一种融合蛋白，所述融合蛋白包含与结合部分可操作地连接的细胞因子部分，所述结合部分包含非CDR环和可裂解的接头，其中所述结合部分能够掩蔽所述细胞因子与其受体的结合和/或所述细胞因子对所述受体的活化。

2.如方面1所述的融合蛋白，其中所述结合部分为天然肽、合成肽、工程化支架或工程化大血清蛋白。

3.如方面1或2所述的融合蛋白，其中所述工程化支架包括sdAb、scFv、Fab、VHH、纤连蛋白III型结构域、免疫球蛋白样支架、DARPin、胱氨酸结肽、脂质运载蛋白、三螺旋束支架、蛋白G相关白蛋白结合模块、或DNA或RNA适体支架。

4.如方面1至2中任一项所述的融合蛋白，其中所述结合部分能够结合大血清蛋白。

5.如方面1至3中任一项所述的融合蛋白，其中所述非CDR环来自可变结构域、恒定结构域、C1组结构域、C2组结构域、I结构域或其任何组合。

6.如方面1至4中任一项所述的融合蛋白，其中所述结合部分还包含互补决定区(CDR)。

7.如方面5所述的融合蛋白，其中所述结合部分能够结合大血清蛋白。

8.如方面6所述的融合蛋白，其中所述大血清蛋白为半衰期延长蛋白。

9.如方面6或7所述的融合蛋白，其中所述大血清蛋白为白蛋白、转铁蛋白、XIII因子或纤维蛋白原。

10.如方面5至8中任一项所述的融合蛋白，其中所述CDR环提供对大血清蛋白或免疫球蛋白轻链或其任何组合具有特异性的结合位点。

11.如方面1至9中任一项所述的融合蛋白，其中所述可裂解的接头包含裂解位点。

12.如方面10所述的融合蛋白，其中所述裂解位点由蛋白酶识别。

13.如方面11所述的融合蛋白，其中所述结合部分结合至所述细胞因子。

14.如方面11或11所述的融合蛋白，其中所述结合部分与所述细胞因子共价连接。

15.如方面11、11或14所述的融合蛋白，其中所述结合部分能够通过所述结合部分和所述细胞因子之间的特异性分子间相互作用来掩蔽所述细胞因子与其靶标的结合。

16.如方面11至14中任一项所述的融合蛋白，其中所述非CDR环提供对所述部分和所述细胞因子的结合具有特异性的结合位点。

17.如方面11至15中任一项所述的融合蛋白，其中在裂解所述可裂解的接头后，所述结合部分与所述细胞因子分离，并且所述细胞因子与其靶标结合。

18.如方面1至16中任一项所述的融合蛋白，其中所述细胞因子结合细胞因子受体。

19.如方面17所述的融合蛋白，其中所述细胞因子受体包括I型细胞因子受体、I型IL受体、II型IL受体、趋化因子受体或肿瘤坏死受体超家族受体。

20.如方面1至18中任一项所述的融合蛋白，其中所述可裂解的接头包含裂解位点。

21.如方面20所述的融合蛋白，其中所述裂解位点由蛋白酶识别。

22.如方面21所述的融合蛋白，其中所述蛋白酶裂解位点由丝氨酸蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶、苏氨酸蛋白酶、谷氨酸蛋白酶、金属蛋白酶、明胶酶或天冬酰胺肽裂解酶识别。

23.如方面21所述的融合蛋白，其中所述蛋白酶裂解位点由以下蛋白酶识别：组织蛋白酶B、组织蛋白酶C、组织蛋白酶D、组织蛋白酶E、组织蛋白酶K、组织蛋白酶L、激肽释放酶、hK1、hK10、hK15、纤溶酶(plasmin)、胶原酶、IV型胶原酶、溶基质素、Xa因子、糜蛋白酶样蛋白酶、胰蛋白酶样蛋白酶、弹性蛋白酶样蛋白酶、枯草杆菌蛋白酶样蛋白酶、猕猴桃蛋白酶、菠萝蛋白酶、钙蛋白酶、半胱天冬酶、半胱天冬酶-3、Mir1-CP、木瓜蛋白酶、HIV-1蛋白酶、HSV蛋白酶、CMV蛋白酶、凝乳酶、肾素、胃蛋白酶、蛋白裂解酶、豆荚蛋白、纤溶酶(plasmepsin)、猪笼草蛋白酶、金属外肽酶、金属内肽酶、基质金属蛋白酶(MMP)、MMP1、MMP2、MMP3、MMP8、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、ADAM10、ADAM17、ADAM12、尿激酶纤溶酶原活化剂(uPA)、肠激酶、前列腺特异性靶标(PSA、hK3)、白介素-1β转化酶、凝血酶、FAP(FAP-α)、二肽基肽酶或二肽基肽酶IV(DPPIV/CD26)、II型跨膜丝氨酸蛋白酶(TTSP)、中性粒细胞弹性蛋白酶、组织蛋白酶G、蛋白酶3、中性粒细胞丝氨酸蛋白酶4、肥大细胞糜酶、肥大细胞类胰蛋白酶、二肽基肽酶和二肽基肽酶IV(DPPIV/CD26)。

24.一种条件活性结合蛋白，其包含结合部分(M)，所述结合部分包含非CDR环、细胞因子和可裂解的接头(L)，其中所述非CDR环能够结合所述细胞因子，并且其中所述结合部分能够抑制所述细胞因子与其受体的结合和/或抑制所述细胞因子对所述受体的活化。

25.如方面24所述的条件活性结合蛋白，其中所述结合部分能够结合半衰期延长蛋白。

26.如方面24或25所述的条件活性结合蛋白，其中所述结合部分为天然肽、合成肽、工程化支架或工程化大血清蛋白。

27.如方面26所述的条件活性结合蛋白，其中所述工程化支架包括sdAb、scFv、Fab、VHH、纤连蛋白III型结构域、免疫球蛋白样支架、DARPin、胱氨酸结肽、脂质运载蛋白、三螺旋束支架、蛋白G相关白蛋白结合模块、或DNA或RNA适体支架。

28.如方面24至27中任一项所述的条件活性结合蛋白，其中所述非CDR环来自可变结构域、恒定结构域、C1组结构域、C2组结构域、I结构域或其任何组合。

29.如方面24至28中任一项所述的条件活性结合蛋白，其中所述结合部分还包含互补决定区(CDR)。

30.如方面24至29中任一项所述的条件活性结合蛋白，其中所述结合部分包含对大血清蛋白具有特异性的结合位点。

31.如方面30所述的条件活性结合蛋白，其中所述大血清蛋白为白蛋白、转铁蛋白、XIII因子或纤维蛋白原。

32.如方面29至31中任一项所述的条件活性结合蛋白，其中所述CDR提供对大血清蛋白或免疫球蛋白轻链或其任何组合具有特异性的结合位点。

33.如方面29至32中任一项所述的条件活性结合蛋白，其中所述结合部分能够通过结合部分和细胞因子之间的特异性分子间相互作用来掩蔽细胞因子与其靶标的结合。

34.如方面29至33中任一项所述的条件活性结合蛋白，其中所述非CDR环提供对结合部分和细胞因子的结合具有特异性的结合位点。

35.如方面24至34中任一项所述的条件活性结合蛋白，其中所述细胞因子结合细胞因子受体。

36.如方面35所述的条件活性结合蛋白，其中所述细胞因子受体包含I型细胞因子受体、I型IL受体、II型IL受体、趋化因子受体或肿瘤坏死受体超家族受体。

37.如方面24至36中任一项所述的条件活性结合蛋白，其中所述可裂解的接头包含裂解位点。

38.如方面37所述的条件活性结合蛋白，其中所述裂解位点由蛋白酶识别。

39.如方面38所述的条件活性结合蛋白，其中所述蛋白酶裂解位点由丝氨酸蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶、苏氨酸蛋白酶、谷氨酸蛋白酶、金属蛋白酶、明胶酶或天冬酰胺肽裂解酶识别。

40.如方面38所述的条件活性结合蛋白，其中所述蛋白酶裂解位点由以下蛋白酶识别：组织蛋白酶B、组织蛋白酶C、组织蛋白酶D、组织蛋白酶E、组织蛋白酶K、组织蛋白酶L、激肽释放酶、hK1、hK10、hK15、纤溶酶、胶原酶、IV型胶原酶、溶基质素、Xa因子、糜蛋白酶样蛋白酶、胰蛋白酶样蛋白酶、弹性蛋白酶样蛋白酶、枯草杆菌蛋白酶样蛋白酶、猕猴桃蛋白酶、菠萝蛋白酶、钙蛋白酶、半胱天冬酶、半胱天冬酶-3、Mir1-CP、木瓜蛋白酶、HIV-1蛋白酶、HSV蛋白酶、CMV蛋白酶、凝乳酶、肾素、胃蛋白酶、蛋白裂解酶、豆荚蛋白、纤溶酶、猪笼草蛋白酶、金属外肽酶、金属内肽酶、基质金属蛋白酶(MMP)、MMP1、MMP2、MMP3、MMP8、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、ADAM10、ADAM17、ADAM12、尿激酶纤溶酶原活化剂(uPA)、肠激酶、前列腺特异性靶标(PSA、hK3)、白介素-1β转化酶、凝血酶、FAP(FAP-α)、二肽基肽酶或二肽基肽酶IV(DPPIV/CD26)、II型跨膜丝氨酸蛋白酶(TTSP)、中性粒细胞弹性蛋白酶、组织蛋白酶G、蛋白酶3、中性粒细胞丝氨酸蛋白酶4、肥大细胞糜酶、肥大细胞类胰蛋白酶、二肽基肽酶和二肽基肽酶IV(DPPIV/CD26)。

41.如方面24所述的条件活性结合蛋白，其还包含结合至所述结合部分的半衰期延长结构域，其中所述半衰期延长结构域为结合蛋白提供安全开关，并且其中在所述接头裂解时，通过分离所述结合部分和所述半衰期延长结构域与所述细胞因子来活化所述结合蛋白，并且由此将所述结合蛋白与所述安全开关分离。

42.如方面41所述的条件活性结合蛋白，其中所述接头的裂解位于肿瘤微环境中。

43.一种条件活性结合蛋白，其包含通过结合部分内的非CDR环与细胞因子结合的结合部分，其中所述结合部分进一步连接至半衰期延长结构域并包含可裂解的接头，其中所述结合蛋白在其通过裂解接头而活化之前具有延长的半衰期，并且其中在活化时，所述结合部分和所述半衰期延长结构域与所述细胞因子分离，并且其中所述结合蛋白在活化状态下不具有延长的半衰期。

44.如方面43所述的条件活性结合蛋白，其中所述接头的裂解位于肿瘤微环境中。

体内半衰期延长元件

优选地，嵌合多肽包含体内半衰期延长元件。增加天然地具有短半衰期的治疗分子的体内半衰期允许更可接受且可管理的给药方案而不牺牲有效性。如本文所用，“半衰期延长元件”是嵌合多肽的一部分，其例如通过改变其大小(例如，使其高于肾脏滤过界限)、形状、流体动力学半径、电荷、或吸收、生物分布、代谢和消除的参数来增加体内半衰期并改善pK。改善多肽pK的示例性方式是通过在多肽链中表达与受体结合的元件，所述受体再循环到细胞质膜而不是在溶酶体中降解，诸如内皮细胞上的FcRn受体和转铁蛋白受体。三种类型的蛋白质(例如人IgG、HSA(或片段)和转铁蛋白)在人血清中的存留时间比仅由其大小预测的时间长得多，这是它们与再循环而不是在溶酶体中降解的受体结合的能力的功能。保留FcRn结合的这些蛋白质或它们的片段通常与其他多肽连接，以延长其血清半衰期。在一个实施方案中，半衰期延长元件为人血清白蛋白(HSA)结合结构域。HSA(SEQ ID NO:2)也可直接结合至药物组合物或通过短接头结合。也可使用HSA的片段。HSA及其片段可用作阻断部分和半衰期延长元件。人IgG和Fc片段也可执行类似的功能。

血清半衰期延长元件也可为与具有较长血清半衰期的蛋白质诸如血清白蛋白、转铁蛋白等结合的抗原结合多肽。此类多肽的实例包括抗体及其片段，包括多克隆抗体、重组抗体、人抗体、人源化抗体、单链可变片段(scFv)、单结构域抗体(诸如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼型纳米抗体的可变结构域(VHH))、dAb等。其他合适的抗原结合结构域包括模拟抗体结合和/或结构的非免疫球蛋白蛋白，诸如anticalin、affilin、亲和体分子、亲和性多聚体、affitin、α体、高亲合性多聚体、DARPin、菲诺体、库尼茨型结构域多肽、单体，以及基于其他工程化支架诸如SpA、GroEL、纤维连接蛋白、脂质体和CTLA4支架的结合结构域。抗原结合多肽的其他实例包括所期望受体的配体、受体的配体结合部分、凝集素和与一种或多种靶抗原结合或缔合的肽。

一些优选的血清半衰期延长元件是包含互补决定区(CDR)和任选地非CDR环的多肽。有利地，此类血清半衰期延长元件可延长细胞因子的血清半衰期，并且还用作细胞因子的抑制剂(例如，通过空间阻断、非共价相互作用或其组合)和/或作为靶向结构域。在一些情况下，血清半衰期延长元件是衍生自免疫球蛋白分子(Ig分子)或模拟抗体结构和/或结合活性的工程化蛋白支架的结构域。Ig可为任何类别或子类(IgG1、IgG2、IgG3、IgG4、IgA、IgE、IgM等)。Ig分子的多肽链折叠成一系列由环连接的平行β链。在可变区中，三个环构成确定分子的抗原结合特异性的“互补决定区”(CDR)。IgG分子包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链或其抗原结合片段。每条重链由重链可变区(本文中缩写为VH)和重链恒定区构成。重链恒定区包含三个结构域CH1、CH2和CH3。每条轻链由轻链可变区(本文中缩写为VL)和轻链恒定区构成。轻链恒定区包含一个结构域CL。VH和VL区可进一步细分为高变区，称为互补决定区(CDR)，其在序列上具有高变异性和/或参与抗原识别和/或通常形成结构明确的环，中间穿插有更保守的区域，称为框架区(FR)。每个VH和VL由三个CDR和四个FR构成，以下列顺序由氨基端至羧基端排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。在本公开的一些实施方案中，FR1、FR2、FR3和FR4的氨基酸序列中的至少一些或所有是本文所述的结合部分的“非CDR环”的一部分。如图5所示，免疫球蛋白分子的可变结构域具有排列成两股的几条β链。轻免疫球蛋白链和重免疫球蛋白链的可变结构域含有三个高变环或互补决定区(CDR)。V结构域的三个CDR(CDR1、CDR2、CDR3)在β桶的一端聚簇。CDR是连接免疫球蛋白折叠的β链B-C、C’-C”和F-G的环，而连接免疫球蛋白折叠的β链AB、CC’、C”-D和E-F的底部环和连接免疫球蛋白折叠的D-E链的顶部环是非CDR环。在本公开的一些实施方案中，恒定结构域、CH1、CH2或CH3的至少一些氨基酸残基是本文所述的结合部分的“非CDR环”的一部分。在一些实施方案中，非CDR环包含Ig或Ig样分子的C1组结构域的AB、CD、EF和DE环中的一个或多个；Ig或Ig样分子的C2组结构域的AB、CC’、EF、FG、BC和EC’环；Ig或Ig样分子的I(中间)组结构域的DE、BD、GF、A(A1A2)B和EF环。

在可变结构域内，CDR被认为负责抗原识别和结合，而FR残基被认为是CDR的支架。然而，在某些情况下，一些FR残基在抗原识别和结合中起重要作用。影响Ag结合的框架区残基分为两类。第一类是与抗原接触的FR残基，因此是结合位点的一部分，并且这些残基中的一些在序列上与CDR接近。其他残基是在序列上远离CDR但在分子的3-D结构中与其紧邻的残基，例如重链中的环。血清半衰期延长结构域(例如，包含CDR的结构域)可包含至少一个非CDR环。在一些实施方案中，非CDR环提供用于结合细胞因子、大血清蛋白或其他靶抗原的结合位点。

除含有CDR之外或可替代地含有CDR，血清半衰期延长元件还包含非CDR环。在一些实施方案中，修饰非CDR环以产生对所期望靶抗原(诸如大血清蛋白，诸如白蛋白)或对细胞因子部分或其他靶向抗原具有特异性的抗原结合位点。设想可使用各种技术来修饰非CDR环，例如定点诱变、随机诱变、插入非CDR环氨基酸序列外来的至少一个氨基酸、氨基酸取代。在一些实例中，抗原肽被插入非CDR环。在一些实例中，抗原性肽取代非CDR环。在一些情况下，仅产生一个非CDR环的修饰以产生抗原结合位点。在其他情况下，对多于一个非CDR环进行修饰。例如，修饰在图5所示的非CDR环(即AB、CC’、C”D、EF和D-E)中的任一个。在一些情况下，修饰DE环。在其他情况下，修饰AB、CC’、C”–D、E-F环中的所有四个。

在一些实例中，血清半衰期延长元件具有双重结合特异性，并含有特异性结合大血清蛋白(诸如血清白蛋白)的CDR和特异性结合并阻断细胞因子结构域的非CDR环。在其他实例中，血清半衰期延长元件含有特异性结合靶抗原诸如细胞因子结构域或其他靶抗原的CDR和特异性结合大血清蛋白诸如血清白蛋白的非CDR环。优选地，血清半衰期延长元件例如通过空间闭塞、通过特定分子间相互作用或两者的组合来抑制细胞因子结构域与同源细胞因子受体的结合。

在一些实施方案中，血清半衰期延长元件非共价地直接结合细胞因子并抑制其活性。

在某些实例中，结合部分通过AB、CC’、C”D和E-F环中的一个或多个与细胞因子结合，并通过BC、C’C”和FG中的一个或多个与大血清蛋白诸如白蛋白结合。在某些实例中，结合部分通过其AB、CC’、C”D或EF环与大血清蛋白诸如白蛋白结合，并通过其BC、C’C”或FG环与细胞因子结合。在某些实例中，结合部分通过其AB、CC’、C”D和EF环与大血清蛋白诸如白蛋白结合，并通过其BC、C’C”和FG环与细胞因子结合。在某些实例中，结合部分通过AB、CC’、C”D和E-F环中的一个或多个与大血清蛋白诸如白蛋白结合，并通过BC、C’C”和FG中的一个或多个与细胞因子结合。

结合部分为任何种类的多肽。例如，在某些情况下，结合部分为天然肽、合成肽或纤连蛋白支架或工程大血清蛋白。大血清蛋白包括例如白蛋白、纤维蛋白原或球蛋白。在一些实施方案中，结合部分为工程化支架。工程化支架包括例如sdAb、scFv、Fab、VHH、III型纤连蛋白结构域、免疫球蛋白样支架(如Halaby等人，1999.Prot Eng12(7):563-571中提出的那样)、DARPin、胱氨酸结肽、脂质运载蛋白、三螺旋束支架、蛋白G相关白蛋白结合模块、或DNA或RNA适体支架。

在一些情况下，血清半衰期延长元件通过其非CDR环结合细胞因子结构域，并且如本文所述，细胞因子结构域进一步连接至靶向结构域。在一些情况下，血清半衰期延长元件包含大血清蛋白的结合位点。在一些实施方案中，CDR提供大血清蛋白的结合位点。在一些实例中，大血清蛋白为球蛋白、白蛋白、转铁蛋白、IgG1、IgG2、IgG4、IgG3、IgA单体、XIII因子、纤维蛋白原、IgE或五聚体IgM。在一些实施方案中，CDR形成免疫球蛋白轻链(诸如Igκ游离轻链或Igλ游离轻链)的结合位点。

一种示例性条件活性蛋白在图6中示出。在所示实例中，血清白蛋白结合结构域(例如dAb)中的非CDR环可形成细胞因子IL-2的结合位点。在此实例中，血清白蛋白的结合位点可由血清白蛋白结合结构域的CDR形成。

血清半衰期延长元件可为任何类型的结合结构域，包括但不限于来自单克隆抗体、多克隆抗体、重组抗体、人抗体、人源化抗体的结构域。在一些实施方案中，结合部分为单链可变片段(scFv)、单结构域抗体，诸如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼衍生纳米抗体的可变结构域(VHH)。在其他实施方案中，结合部分为非Ig结合结构域，即抗体模拟物，诸如anticalin、affilin、亲和体分子、亲和性多聚体、affitin、α体、高亲合性多聚体、DARPin、菲诺体、库尼茨型结构域多肽和单体。

在其他实施方案中，血清半衰期延长元件可为水溶性聚合物或与水溶性聚合物(诸如PEG)缀合的肽。如本文所用，“PEG”、“聚乙二醇”和“聚(乙二醇)”是可互换的，并包含任何非肽水溶性聚(环氧乙烷)。术语“PEG”也意指含有大部分，即大于50％的-OCH₂CH₂-重复亚基的聚合物。关于特定形式，PEG可采用多种分子量中的任何数量，以及将在下文更详细描述的结构或几何形状，诸如“分支”、“线性”、“叉状”、“多功能”等。PEG不限于特定的结构，并且可为线性的(例如，封端的，例如，烷氧基PEG或双官能PEG)、分支或多臂的(例如，叉状PEG或与多元醇核连接的PEG)、树突状(或星形)结构，每个结构具有或不具有一个或多个可降解的连接部分。此外，PEG的内部结构可以任何数量的不同重复模式来组织，并且可选自由均聚物、交替共聚物、无规共聚物、嵌段共聚物、交替三元共聚物、无规三元共聚物和嵌段三元共聚物组成的组。PEG可通过任何合适的方法与多肽和肽缀合。通常，使反应性PEG衍生物(诸如N-羟基琥珀酰亚胺酯PEG)与包含具有侧链的氨基酸的肽或多肽反应，所述侧链含有胺、巯基、羧酸或羟基官能团，所述氨基酸诸如半胱氨酸、赖氨酸、天冬酰胺、谷氨酰胺、苏氨酸、酪氨酸、丝氨酸、天冬氨酸和谷氨酸。

靶向结构域和保留结构域

对于某些应用，可能需要使构建体在其体内期望位置存在的时间最大化。这可通过在嵌合多肽(融合蛋白)中包含另一个结构域以影响其在体内的运动来实现。例如，嵌合核酸可编码将多肽引导至体内某个位置(例如肿瘤细胞或炎症位点)的结构域；此结构域被称为“靶向结构域”和/或编码将多肽保留在体内某个位置(例如肿瘤细胞或炎症位点)的结构域；此结构域称为“保留结构域”。在一些实施方案中，结构域可用作靶向结构域和保留结构域。在一些实施方案中，靶向结构域和/或保留结构域对富含蛋白酶的环境具有特异性。在一些实施方案中，编码的靶向结构域和/或保留结构域对调节性T细胞(Treg)具有特异性，例如靶向CCR4或CD39受体。其他合适的靶向和/或保留结构域包括具有在炎症组织中过表达的同源配体的那些，例如IL-1受体或IL-6受体。在其他实施方案中，合适的靶向和/或保留结构域包括具有在肿瘤组织中过表达的同源配体的那些，例如Epcam、CEA或间皮素。在一些实施方案中，靶向结构域通过接头与白介素连接，所述接头在作用位点被裂解(例如通过炎症或癌症特异性蛋白酶)，从而在期望的位点释放白介素的全部活性。在一些实施方案中，靶向和/或保留结构域通过接头与白介素连接，所述接头不在作用位点被裂解(例如通过炎症或癌症特异性蛋白酶)，从而使细胞因子保留在所期望位点。

在一些情况下，选择的抗原在病变细胞或组织(例如肿瘤或癌细胞)的表面上表达。可用于肿瘤靶向和保留的抗原包括但不限于EpCAM、EGFR、HER-2、HER-3、c-Met、FOLR1和CEA。本文所公开的药物组合物还包含含有两个靶向和/或保留结构域的蛋白质，所述两个靶向和/或保留结构域与已知在病变细胞或组织上表达的两个不同靶抗原结合。示例性抗原结合结构域对包括但不限于EGFR/CEA、EpCAM/CEA和HER-2/HER-3。

合适的靶向和/或保留结构域包括抗原结合结构域，诸如抗体及其片段，包括多克隆抗体、重组抗体、人抗体、人源化抗体、单链可变片段(scFv)、单结构域抗体(诸如重链可变结构域(VH)、轻链可变结构域(VL)和骆驼型纳米抗体的可变结构域(VHH))、dAb等。其他合适的抗原结合结构域包括模拟抗体结合和/或结构的非免疫球蛋白蛋白，诸如anticalin、affilin、亲和体分子、亲和性多聚体、affitin、α体、高亲合性多聚体、DARPin、菲诺体、库尼茨型结构域多肽、单体，以及基于其他工程化支架诸如SpA、GroEL、纤维连接蛋白、脂质体和CTLA4支架的结合结构域。抗原结合多肽的其他实例包括所期望受体的配体、受体的配体结合部分、凝集素和与一种或多种靶抗原结合或缔合的肽。

在一些实施方案中，靶向和/或保留结构域特异性结合细胞表面分子。在一些实施方案中，靶向和/或保留结构域特异性结合肿瘤抗原。在一些实施方案中，靶向多肽特异性地且独立地结合选自以下至少一种的肿瘤抗原：成纤维细胞活化蛋白α(FAPa)、滋养层细胞糖蛋白(5T4)、肿瘤相关钙信号转导子2(Trop2)、纤连蛋白EDB(EDB-FN)、纤连蛋白EIIIB结构域、CGS-2、EpCAM、EGFR、HER-2、HER-3、cMet、CEA和FOLR1。在一些实施方案中，靶向多肽特异性地且独立地结合两个不同的抗原，其中抗原中的至少一个为选自成纤维细胞活化蛋白α(FAPa)、滋养层细胞糖蛋白(5T4)、肿瘤相关钙信号转导蛋白2(Trop2)、纤连蛋白EDB(EDB-FN)、纤连蛋白EIIIB结构域、CGS-2、EpCAM、EGFR、HER-2、HER-3、cMet、CEA和FOLR1的肿瘤抗原。

靶向和/或保留抗原可为在肿瘤细胞上表达的肿瘤抗原。肿瘤抗原是本领域中熟知的，并且包括例如EpCAM、EGFR、HER-2、HER-3、c-Met、FOLR1、PSMA、CD38、BCMA和CEA、5T4、AFP、B7-H3、钙粘蛋白-6、CAIX、CD117、CD123、CD138、CD166、CD19、CD20、CD205、CD22、CD30、CD33、CD352、CD37、CD44、CD52、CD56、CD70、CD71、CD74、CD79b、DLL3、EphA2、FAP、FGFR2、FGFR3、GPC3、gpA33、FLT-3、gpNMB、HPV-16E6、HPV-16E7、ITGA2、ITGA3、SLC39A6、MAGE、间皮素、Muc1、Muc16、NaPi2b、连接素-4、P-钙粘蛋白、NY-ESO-1、PRLR、PSCA、PTK7、ROR1、SLC44A4、SLTRK5、SLTRK6、STEAP1、TIM1、Trop2、WT1。

靶向和/或保留抗原可为免疫检查点蛋白。免疫检查点蛋白的实例包括但不限于CD27、CD137、2B4、TIGIT、CD155、ICOS、HVEM、CD40L、LIGHT、TIM-1、OX40、DNAM-1、PD-L1、PD1、PD-L2、CTLA-4、CD8、CD40、CEACAM1、CD48、CD70、A2AR、CD39、CD73、B7-H3、B7-H4、BTLA、IDO1、IDO2、TDO、KIR、LAG-3、TIM-3或VISTA。

靶向和/或保留抗原可为细胞表面分子，诸如蛋白质、脂质或多糖。在一些实施方案中，靶向和/或保留抗原是在肿瘤细胞、病毒感染的细胞、细菌感染的细胞、受损的红细胞、动脉斑块细胞、发炎或纤维化组织细胞上。靶向和/或保留抗原可包含免疫应答调节剂。免疫应答调节剂的实例包括但不限于粒细胞-巨噬细胞集落刺激因子(GM-CSF)、巨噬细胞集落刺激因子(M-CSF)、粒细胞集落刺激因子(G-CSF)、白介素2(IL-2)、白介素3(IL-3)、白介素12(IL-12)、白介素15(IL-15)、B7-1(CD80)、B7-2(CD86)、GITRL、CD3或GITR。

靶向和/或保留抗原可为细胞因子受体。细胞因子受体的实例包括但不限于I型细胞因子受体，诸如GM-CSF受体、G-CSF受体、I型IL受体、Epo受体、LIF受体、CNTF受体、TPO受体；II型细胞因子受体，诸如IFN-α受体(IFNAR1、IFNAR2)、IFB-β受体、IFN-γ受体(IFNGR1、IFNGR2)、II型IL受体；趋化因子受体，诸如CC趋化因子受体、CXC趋化因子受体、CX3C趋化因子受体、XC趋化因子受体；肿瘤坏死受体超家族受体，诸如TNFRSF5/CD40、TNFRSF8/CD30、TNFRSF7/CD27、TNFRSF1A/TNFR1/CD120a、TNFRSF1B/TNFR2/CD120b；TGF-β受体，诸如TGF-β受体1、TGF-β受体2；Ig超家族受体，诸如IL-1受体、CSF-1R、PDGFR(PDGFRA、PDGFRB)、SCFR。

接头

如上文所述，药物组合物包含一个或多个接头序列。接头序列用于提供多肽之间的柔性，使得例如阻断部分能够抑制细胞因子多肽的活性。接头序列可位于细胞因子多肽、血清半衰期延长元件和/或阻断部分中的任何或所有之间。如本文所述，接头中的至少一个为蛋白酶可裂解的，并且含有(一种或多种)所期望蛋白酶的(一个或多个)裂解位点。优选地，所期望蛋白酶在所期望的细胞因子活性位点(例如肿瘤微环境)富集或选择性表达。因此，融合蛋白在所期望细胞因子活性的位点被优选地或选择性地裂解。

合适的接头可具有不同的长度，诸如1个氨基酸(例如，Gly)至20个氨基酸、2个氨基酸至15个氨基酸、3个氨基酸至12个氨基酸，包括4个氨基酸至10个氨基酸、5个氨基酸至9个氨基酸、6个氨基酸至8个氨基酸或7个氨基酸至8个氨基酸，并且可为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59或60个氨基酸。

药物组合物的组分的取向在很大程度上是设计选择的问题，并且已经认识到多种取向是可能的，并且所有取向都旨在由本公开涵盖。例如，阻断部分可位于细胞因子多肽的C端或N端。

已知与患病细胞或组织相关的蛋白酶包括但不限于丝氨酸蛋白酶、半胱氨酸蛋白酶、天冬氨酸蛋白酶、苏氨酸蛋白酶、谷氨酸蛋白酶、金属蛋白酶、天冬酰胺肽裂解酶、血清蛋白酶、组织蛋白酶、组织蛋白酶B、组织蛋白酶C、组织蛋白酶D、组织蛋白酶E、组织蛋白酶K、组织蛋白酶L、激肽释放酶、hKl、hK10、hK15、纤溶酶、胶原酶、IV型胶原酶、溶基质素、Xa因子、糜蛋白酶样蛋白酶、胰蛋白酶样蛋白酶、弹性蛋白酶样蛋白酶、枯草杆菌蛋白酶样蛋白酶、猕猴桃蛋白酶、菠萝蛋白酶、钙蛋白酶、半胱天冬酶、半胱天冬酶-3、Mir1-CP、木瓜蛋白酶、HIV-1蛋白酶、HSV蛋白酶、CMV蛋白酶、凝乳酶、肾素、胃蛋白酶、蛋白裂解酶、豆荚蛋白、纤溶酶、猪笼草蛋白酶、金属外肽酶、金属内肽酶、基质金属蛋白酶(MMP)、MMP1、MMP2、MMP3、MMP8、MMP9、MMP13、MMP11、MMP14、尿激酶纤溶酶原活化剂(uPA)、肠激酶、前列腺特异性靶标(PSA，hK3)、白介素-1β转化酶、凝血酶、FAP(FAP-a)、二肽基肽酶、跨膜肽酶、颗粒酶和二肽基肽酶IV(DPPIV/CD26)。能够裂解由本文所提供的嵌合核酸序列编码的氨基酸序列的蛋白酶可例如选自由以下组成的组：前列腺特异性抗原(PSA)、基质金属蛋白酶(MMP)、A双歧蛋白和金属蛋白酶(ADAM)、纤溶酶原活化剂、组织蛋白酶、半胱天冬酶、肿瘤细胞表面蛋白酶和弹性蛋白酶。MMP可为例如基质金属蛋白酶2(MMP2)或基质金属蛋白酶9(MMP9)。

表1列出了可用于本文所公开的方法的蛋白酶，并且表1a列出了示例性蛋白酶及其裂解位点：

表1.与炎症和癌症相关的蛋白酶

表1a：示例性蛋白酶和蛋白酶识别序列

本文提供包含多肽序列的药物组合物。与所有肽、多肽和蛋白质(包括其片段)一样，应当理解，嵌合多肽的氨基酸序列中可能发生另外的修饰(氨基酸序列变体)，但这些修饰不会改变肽、多肽或蛋白质的性质或功能。此类修饰包括保守性氨基酸取代，并在下文更详细地讨论。

本文提供的组合物具有所期望的功能。组合物至少包含IL-2多肽；阻断部分，例如空间阻断多肽；和任选的血清半衰期延长元件，以及任选的靶向多肽，其中一个或多个接头连接组合物中的每个多肽。提供第一多肽(例如IL-2突变蛋白)作为活性剂。提供阻断部分以阻断白介素的活性。提供接头多肽，例如蛋白酶可裂解多肽，以被在活性剂的预期靶标上特异性表达的蛋白酶裂解。任选地，阻断部分通过结合白介素多肽来阻断第一多肽的活性。在一些实施方案中，阻断部分(例如空间阻断肽)通过蛋白酶可裂解的接头与白介素连接，所述蛋白酶可裂解的接头在作用位点被裂解(例如通过炎症特异性或肿瘤特异性蛋白酶)，从而在所期望位点释放细胞因子的全部活性。

蛋白酶裂解位点可为天然存在的蛋白酶裂解位点或人工工程化的蛋白酶裂解位点。人工工程化的蛋白酶裂解位点可被多于一种对将发生裂解的所期望环境(例如肿瘤)具有特异性的蛋白酶裂解。蛋白酶裂解位点可被至少一种蛋白酶、至少两种蛋白酶、至少三种蛋白酶或至少四种蛋白酶裂解。

在一些实施方案中，接头包含甘氨酸-甘氨酸、分选酶识别基序或分选酶识别基序和肽序列(Gly₄Ser)_n(SEQ ID NO:126)或(Gly₃Ser)_n(SEQ ID NO:127)，其中n为1、2、3、4或5。在一个实施方案中，分选酶识别基序包含肽序列LPXTG(SEQ ID NO.:125)，其中X为任何氨基酸。在一个实施方案中，共价键是在连接到细胞因子多肽的C端的反应性赖氨酸残基与连接到阻断部分或其他部分的N端的反应性天冬氨酸之间。在一个实施方案中，共价键是在连接到细胞因子多肽的N端的反应性天冬氨酸残基与连接到阻断部分或其他部分的C端的反应性赖氨酸残基之间。

裂解和诱导性

如本文所述，在融合蛋白的情况下，细胞因子多肽的活性减弱，并且在所期望的活性位点(诸如在肿瘤微环境中)进行蛋白酶裂解，从融合蛋白中释放出一种形式的细胞因子，所述细胞因子作为细胞因子受体激动剂比融合蛋白的活性高得多。例如，融合多肽的细胞因子-受体活化(激动剂)活性可比作为单独的分子实体的细胞因子多肽的细胞因子受体活化活性低至少约10倍、至少约50倍、至少约100倍、至少约250倍、至少约500倍或至少约1000倍。当作为融合蛋白的一部分的细胞因子多肽含有与细胞因子多肽基本相同且基本上不包含额外氨基酸并且不与其他分子缔合(通过共价或非共价键)的氨基酸时，则作为单独的分子实体存在。如果必要的话，作为单独的分子实体的细胞因子多肽可包含一些额外氨基酸序列，诸如标签或短序列，以帮助表达和/或纯化。

在其他实例中，融合多肽的细胞因子-受体活化(激动剂)活性比含有通过裂解融合蛋白中的蛋白酶可裂解的接头而产生的细胞因子多肽的多肽的细胞因子受体活化活性低至少约10倍、至少约50倍、至少约100倍、至少约250倍、至少约500倍或约1000倍。换句话讲，含有通过裂解融合蛋白中的蛋白酶可裂解的接头而产生的细胞因子多肽的多肽的细胞因子受体活化(激动剂)活性比融合蛋白的细胞因子受体活化活性高至少约10倍、至少约50倍、至少约100倍、至少约250倍、至少约500倍或至少约1000倍。

多肽取代

本文所述的多肽可包含具有与相应天然存在的蛋白质(例如，IL-2、IL-15、HSA)相同的氨基酸序列或只要保持所期望的功能可具有不同于天然存在的蛋白质的氨基酸序列的组分(例如，细胞因子、阻断部分)。应当理解，对所公开的蛋白质和编码它们的核酸的任何已知修饰和衍生物或可能出现的修饰和衍生物进行定义的一种方式是通过根据与特定已知参考序列的同一性来定义序列变体。具体公开的多肽和核酸与本文所提供的嵌合多肽具有至少70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性。例如，提供的多肽或核酸与本文所述的任何核酸或多肽的序列具有至少70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％同一性。本领域技术人员容易理解如何确定两个多肽或两个核酸的同一性。例如，可在比对两个序列之后计算同一性，以使同一性处于其最高水平。

计算同一性的另一种方式可通过公布的算法执行。用于比较的最佳序列比对可通过以下方法进行：Smith和Waterman Adv.Appl.Math.2:482(1981)的局部同一性算法；Needleman和Wunsch,J.Mol.Biol.48:443(1970)的同一性比对算法；Pearson和Lipman,Proc.Natl.Acad.Sci.USA 85:2444(1988)的相似性探索方法；这些算法的计算机化实现(在Wisconsin Genetics软件包中的GAP、BESTFIT、FASTA和TFASTA，Genetics ComputerGroup,575Science Dr.,Madison,Wis.)；或检查。

对于核酸，相同类型的同一性可通过例如Zuker,Science244:48-52(1989)；Jaeger等人,Proc.Natl.Acad.Sci.USA86:7706-7710(1989)；Jaeger等人,MethodsEnzymol.183:281-306(1989)中公开的算法获得，所述文献中关于至少与核酸比对相关的材料以引用的方式并入本文。应当理解，通常可使用任何方法，并且在某些情况下，这些各种方法的结果可能不同，但是技术人员理解，如果使用这些方法中的至少一种发现同一性，则可认为序列具有所述同一性，并在本文中公开。

蛋白质修饰包括氨基酸序列修饰。氨基酸序列的修饰可能自然出现为等位基因变异(例如，由于遗传多态性)，可能由于环境影响(例如，通过暴露于紫外线)而出现，或可能由人为干预(例如，通过诱变克隆的DNA序列)产生，诸如诱导点、缺失、插入和取代突变体。这些修饰可导致氨基酸序列发生变化，提供沉默突变，修饰限制性位点或提供其他特异性突变。氨基酸序列修饰通常属于三种类别中的一种或多种：取代、插入或缺失修饰。插入包括氨基和/或羧基端融合以及单个或多个氨基酸残基的序列内插入。插入通常将比氨基或羧基端融合的插入小，例如约一至四个残基。缺失的特征在于从蛋白质序列中去除一个或多个氨基酸残基。通常，在蛋白质分子内的任一位点处缺失不超过约2至6个残基。氨基酸取代通常是单个残基，但是也可同时在多个不同位置处出现；插入通常为约1至10个氨基酸残基；并且缺失的范围是约1至30个残基。缺失或插入优选在相邻对中进行，即2个残基缺失或2个残基插入。取代、缺失、插入或其任何组合可以进行组合以得到最终构建体。突变不能将序列置于阅读框外，并且优选地将不创建可以产生二级mRNA结构的互补区。取代修饰是其中至少一个残基已被去除并且在其位置插入不同残基的修饰。此类取代通常根据下表2进行，并将其称为保守取代。

表2.示例性氨基酸取代

通过已知方法进行修饰，包括特定氨基酸取代。例如，通过对编码多肽的DNA中的核苷酸进行位点特异性诱变来进行修饰，从而产生编码所述修饰的DNA，并随后在重组细胞培养物中表达DNA。用于在具有已知序列的DNA的预先确定位点处进行取代突变的技术是熟知的，例如M13引物诱变和PCR诱变。

可选择修饰以优化结合。例如，亲和力成熟技术可用于通过在互补决定区(CDR)内引入随机突变来改变scFv的结合。可使用多种技术引入此类随机突变，所述技术包括放射、化学诱变剂或易错PCR。可使用例如噬菌体展示进行多轮突变和选择。

本公开还涉及编码本文所述的嵌合多肽的核酸，并且涉及此类核酸产生嵌合多肽以及用于治疗目的的用途。例如，本发明包括编码嵌合多肽的DNA和RNA分子(例如，mRNA、自我复制RNA)，以及此类DNA和RNA分子的治疗用途。

示例性组合物

本发明的示例性融合蛋白以多种取向组合上文所述的元件。本节中描述的取向仅作为实例，并且不应视为限制性的。

在一些实施方案中，融合蛋白包含IL-2多肽、阻断部分和半衰期延长元件。在一些实施方案中，IL-2多肽位于半衰期延长元件和阻断部分之间。在一些实施方案中，IL-2多肽位于阻断部分和半衰期延长元件的N端。在一些此类实施方案中，IL-2多肽位于阻断部分近端；在一些此类实施方案中，IL-2多肽位于半衰期延长元件近端。在所有实施方案中必须包括至少一种蛋白酶可裂解的接头，使得IL-2多肽可在裂解时具有活性。在一些实施方案中，IL-2多肽位于阻断部分和半衰期延长元件的C端。额外元件可通过可裂解的接头、不可裂解的接头或通过直接融合来彼此连接。在一些情况下，有益的是包含两个相同的细胞因子以促进二聚化。

在一些实施方案中，所使用的阻断结构域能够延长半衰期，并且IL-2多肽位于两个此类阻断结构域之间。在一些实施方案中，IL-2多肽位于两个阻断结构域之间，其中一个能够延长半衰期。

在一些实施方案中，两种细胞因子包含在同一构建体中，至少一个细胞因子为IL-2。在一些实施方案中，细胞因子各自连接到两个阻断结构域(一个分子中总共三个)，其中阻断结构域位于两个细胞因子结构域之间。在一些实施方案中，可包括一个或多个额外半衰期延长结构域来优化药代动力学特性。

在一些实施方案中，三种细胞因子包含在同一构建体中。在一些实施方案中，第三种细胞因子可代替其他两种细胞因子之间的阻断结构域来起到阻断其他两种细胞因子的作用。

用于融合蛋白的优选的半衰期延长元件为人血清白蛋白(HSA)、结合血清白蛋白的抗体或抗体片段(例如scFV、dAb)、人或人源化IgG、或前述任一种的片段。在一些优选的实施方案中，阻断部分为人血清白蛋白(HSA)、或结合血清白蛋白的抗体或抗体片段、结合细胞因子并阻止结合活化或细胞因子受体即另一种细胞因子活化的抗体、或前述任一种的片段。在包含额外靶向结构域的优选的实施方案中，靶向结构域为结合富集在癌细胞表面上的细胞表面蛋白(诸如EpCAM、FOLR1和纤连蛋白)的抗体。

治疗方法和药物组合物

还提供了治疗患有疾病或病症或处于发展所述疾病或病症的风险下的受试者的方法，所述疾病或病症诸如增殖性疾病、肿瘤性疾病、炎性疾病、免疫性病症、自身免疫性疾病、感染性疾病、病毒性疾病、过敏反应、寄生虫反应或移植物抗宿主疾病。所述方法向有此需要的受试者施用有效量的如本文所公开的融合蛋白，所述融合蛋白通常作为药物组合物施用。在一些实施方案中，所述方法还包括选择患有此种疾病或病症或处于发展所述疾病或病症的风险下的受试者。药物组合物优选地包含在炎症或肿瘤位点处活化的阻断的细胞因子、其片段或突变蛋白。在一个实施方案中，嵌合多肽包含细胞因子多肽、其片段或突变蛋白以及血清半衰期延长元件。在另一个实施方案中，嵌合多肽包含细胞因子多肽、其片段或突变蛋白以及阻断部分，例如空间阻断多肽，其中空间阻断多肽能够在空间上阻断细胞因子多肽、其片段或突变蛋白的活性。在另一个实施方案中，嵌合多肽包含细胞因子多肽、其片段或突变蛋白、阻断部分以及血清半衰期延长元件。

炎症是人体组织对有害刺激(诸如病原体、受损细胞或刺激物)的复杂生物应答的一部分，并且是涉及免疫细胞、血管和分子介质的保护性应答。炎症的功能是消除细胞损伤的初始原因，清除最初损伤和炎症过程中受损的坏死细胞和组织，并开始组织修复。炎症可由感染引起，作为症状或疾病出现，例如癌症、动脉粥样硬化、过敏、肌病、HIV、肥胖症或自身免疫性疾病。自身免疫性疾病是由对自身抗原的异常免疫应答引起的慢性病状。可用本文所公开的多肽治疗的自身免疫性疾病包括但不限于狼疮、腹腔疾病、1型糖尿病、格雷氏病(Graves disease)、炎性肠病、多发性硬化、牛皮癣、类风湿性关节炎和系统性红斑狼疮。

药物组合物可包含一种或多种蛋白酶可裂解的接头序列。接头序列用于提供多肽之间的柔性，使得每个多肽能够抑制第一多肽的活性。接头序列可位于细胞因子多肽、其片段或突变蛋白、阻断部分和血清半衰期延长元件中的任何或所有之间。任选地，组合物包含两个、三个、四个或五个接头序列。所述接头序列即两个、三个或四个接头序列可为相同或不同的接头序列。在一个实施方案中，接头序列包含GGGGS(SEQ ID NO.:132)、GSGSGS(SEQID NO.:133)或G(SGGG)₂SGGT(SEQ ID NO.:134)。在另一个实施方案中，接头包含选自由以下组成的组的蛋白酶可裂解的序列：HSSKLQ(SEQ ID NO.:25)、GPLGVRG(SEQ ID NO.:128)、IPVSLRSG(SEQ ID NO.:129)、VPLSLYSG(SEQ ID NO.:130)和SGESPAYYTA(SEQ ID NO.:131)。

在一些实施方案中，接头被选自由以下组成的组的蛋白酶裂解：激肽释放酶、凝血酶、糜酶、羧肽酶A、组织蛋白酶G、弹性蛋白酶、PR-3、颗粒酶M、钙蛋白酶、基质金属蛋白酶(MMP)、纤溶酶原活化剂、组织蛋白酶、半胱天冬酶、类胰蛋白酶或肿瘤细胞表面蛋白酶。

合适的接头可具有不同的长度，诸如1个氨基酸(例如，Gly)至20个氨基酸、2个氨基酸至15个氨基酸、3个氨基酸至12个氨基酸，包括4个氨基酸至10个氨基酸、5个氨基酸至9个氨基酸、6个氨基酸至8个氨基酸或7个氨基酸至8个氨基酸，并且可为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59或60个氨基酸。

还提供了治疗患有癌症或处于发展癌症的风险下的受试者的方法。所述方法包括向有此需要的受试者施用有效量的如本文所公开的嵌合多肽(融合蛋白)，所述嵌合多肽通常作为药物组合物施用。在一些实施方案中，所述方法还包括选择患有癌症或处于发展癌症的风险下的受试者。药物组合物优选地包含在肿瘤位点处活化的阻断的细胞因子、其片段或突变蛋白。优选地，肿瘤为实体肿瘤。癌症可以是但不限于结肠癌、肺癌、黑色素瘤、肉瘤、肾细胞癌和乳腺癌。

所述方法还可包括施用一种或多种额外剂来治疗癌症，所述一种或多种额外剂诸如化学治疗剂(例如，阿霉素(Adriamycin)、柔红霉素(Cerubidine)、博莱霉素(Bleomycin)、马法兰(Alkeran)、长春碱(Velban)、长春新碱(Oncovin)、氟尿嘧啶、噻替派、甲氨蝶呤、比生群、米托蒽醌(Noantrone)、硫鸟嘌呤(Thiguanine)、阿糖胞苷(Cytaribine)、丙卡巴肼(Procarabizine))、免疫肿瘤剂(例如，抗PD-L1、抗CTLA4、抗PD-1、抗CD47、抗GD2)、细胞疗法(例如，CAR-T、T细胞疗法)、溶瘤病毒等。

本文提供含有嵌合多肽和药学上可接受的载剂的药物制剂或组合物。本文所提供的组合物适合于体外或体内施用。药学上可接受的载剂意指不为在生物学上或另外不合需要的材料，即所述材料向受试者施用而不引起不期望的生物作用或以有害方式与含有所述材料的药物制剂或组合物的其他组分相互作用。选择载剂以使活性成分的降解最小化并使受试者的不良副作用最小化。

合适的载剂及其制剂描述于Remington:The Science and Practice ofPharmacy,第21版,David B.Troy编,Lippicott Williams&Wilkins(2005)中。通常，在制剂中使用适当量的药学上可接受的盐以使制剂等渗，尽管在需要时制剂可为高渗或低渗的。药学上可接受的载剂的实例包括但不限于无菌水、盐水、缓冲溶液(如林格氏溶液)和右旋糖溶液。溶液的pH通常为约5至约8或约7至7.5。其他载剂包括持续释放制剂，诸如含有免疫原性多肽的固体疏水性聚合物的半透性基质。基质呈成形制品的形式，例如膜、脂质体或微粒。根据例如施用途径和所施用组合物的浓度，某些制剂可能为更优选的。载剂是适合于将嵌合多肽或编码嵌合多肽的核酸序列施用于人或其他受试者的那些载剂。

药物制剂或组合物根据是需要局部治疗或全身治疗以及待治疗的区域来以多种方式施用。通过若干种施用途径中的任一种施用组合物，所述施用途径包括局部、口服、肠胃外、静脉内、关节内、腹膜内、肌肉内、皮下、腔内、经皮、肝内、颅内、雾化/吸入或通过经由支气管镜检安装。在一些实施方案中，组合物局部(非全身性)施用，包括肿瘤内、关节内、鞘内等。

用于肠胃外施用的制剂包括无菌水性或非水性溶液、悬浮液以及乳液。非水性溶剂的实例为丙二醇、聚乙二醇、植物油(诸如橄榄油)和可注射有机酯(诸如油酸乙酯)。水性载剂包括水、醇/水性溶液、乳液或悬浮液，包括盐水和缓冲介质。肠胃外媒介物包括氯化钠溶液、林格氏右旋糖、右旋糖和氯化钠、乳酸化林格氏溶液或不挥发性油。静脉内媒介物包括流体和营养补充剂、电解质补充剂(如基于林格氏右旋糖的那些)等。任选地存在防腐剂和其他添加剂，诸如例如抗微生物剂、抗氧化剂、螯合剂和惰性气体等。

局部施用的制剂包括软膏、洗剂、乳膏、凝胶、滴剂、栓剂、喷雾剂、液体和粉末。常规药物载剂、水性、粉末或油性基质、增稠剂等任选地为必需或期望的。

用于口服施用的组合物包括粉末或颗粒、水或非水性介质中的悬浮液或溶液、胶囊、囊剂或片剂。增稠剂、调味料、稀释剂、乳化剂、分散助剂或结合剂任选地为期望的。

任选地，嵌合多肽或编码嵌合多肽的核酸序列由载体施用。有许多组合物和方法可用于通过例如表达载体在体外或体内将核酸分子和/或多肽递送至细胞。这些方法和组合物主要可分为两类：基于病毒的递送系统和基于非病毒的递送系统。此类方法为本领域中熟知的，并且易于适用于本文所述的组合物和方法。此类组合物和方法可用于体外或体内转染或转导细胞，以例如产生表达并优选地分泌编码的嵌合多肽的细胞系或将核酸治疗性地递送至受试者。本文所公开的嵌合核酸的组分通常在框架内可操作地连接以编码融合蛋白。

如本文所用，质粒或病毒载体是将所公开的核酸运输到细胞中而不降解的剂，并且包括使核酸分子和/或多肽在其所递送到的细胞中产生表达的启动子。病毒载体为例如腺病毒、腺相关病毒、疱疹病毒、痘苗病毒、脊髓灰质炎病毒、辛德毕斯(Sindbis)和其他RNA病毒，包括具有HIV骨架的这些病毒。还优选共享这些病毒的特性而使其适合用作载体的任何病毒家族。逆转录病毒载体通常由Coffin等人,Retroviruses,Cold Spring HarborLaboratory Press(1997)描述，其中载体及其制备方法以引用的方式并入本文。已经描述了复制缺陷型腺病毒的构建(Berkner等人,J.Virol.61:1213-20(1987)；Massie等人,Mol.Cell.Biol.6:2872-83(1986)；Haj-Ahmad等人,J.Virol.57:267-74(1986)；Davidson等人,J.Virol.61:1226-39(1987)；Zhang等人,BioTechniques 15:868-72(1993))。这些病毒作为载体的益处和用途是它们可扩散到其他细胞类型上的程度受到限制，因为它们可以在初始感染的细胞内复制，但不能形成新的感染性病毒颗粒。重组腺病毒已显示在直接体内递送至气道上皮、肝细胞、血管内皮、CNS实质和许多其他组织位点之后实现高效率。其他有用的系统包括例如复制型和宿主限制性非复制型痘苗病毒载体。

所提供的多肽和/或核酸分子可通过病毒样颗粒递送。病毒样颗粒(VLP)由衍生自病毒结构蛋白的一种或多种病毒蛋白组成。用于制备和使用病毒样颗粒的方法描述于例如Garcea和Gissmann,Current Opinion in Biotechnology 15:513-7(2004)。

所提供的多肽可通过亚病毒致密体(DB)递送。DB通过膜融合将蛋白质运输到靶细胞中。用于制备和使用DB的方法描述于例如Pepperl-Klindworth等人,Gene Therapy 10:278-84(2003)。

所提供的多肽可通过外皮聚集体递送。用于制备和使用外皮聚集体的方法描述于国际公布号WO 2006/110728中。

基于非病毒的递送方法可包括含有核酸分子和编码多肽的核酸序列的表达载体，其中核酸可操作地连接到表达控制序列。合适的载体骨架包括例如本领域常规使用的那些，诸如质粒、人工染色体、BAC、YAC或PAC。许多载体和表达系统可从诸如Novagen(Madison,Wis.)、Clonetech(Pal Alto,Calif.)、Stratagene(La Jolla,Calif.)和Invitrogen/Life Technologies(Carlsbad,Calif.)的公司商购获得。载体通常含有一个或多个调节区。调节区包括但不限于启动子序列、增强子序列、应答元件、蛋白质识别位点、诱导性元件、蛋白质结合序列、5’和3’非翻译区(UTR)、转录起始位点、末端序列、聚腺苷酸化序列和内含子。此类载体还可用于通过在合适宿主细胞诸如CHO细胞中表达来制备嵌合多肽。

控制哺乳动物宿主细胞中载体转录的优选启动子可获自各种来源，例如病毒的基因组，诸如多瘤病毒、猿猴病毒40(SV40)、腺病毒、逆转录病毒、乙型肝炎病毒和最优选的巨细胞病毒(CMV)；或获自异源哺乳动物启动子，例如β-肌动蛋白启动子或EF1α启动子；或获自杂合或嵌合启动子(例如，融合至β-肌动蛋白启动子的CMV启动子)。当然，来自宿主细胞或相关物种的启动子也可用于本文。

增强子通常是指DNA中距转录起始位点不固定距离处起作用的序列，并且可位于转录单元的5’或3’。此外，增强子可位于内含子内以及在编码序列本身内。它们的长度通常在10个与300个碱基对(bp)之间，并且它们以顺式起作用。增强子通常起到增加附近启动子转录的作用。增强子还可含有介导转录调节的应答元件。虽然已知许多增强子序列来自哺乳动物基因(球蛋白、弹性蛋白酶、白蛋白、甲胎蛋白和胰岛素)，但人们通常将使用来自真核细胞病毒的增强子进行一般表达。优选的实例为复制起点后侧上的SV40增强子、巨细胞病毒早期启动子增强子、复制起点后侧上的多瘤增强子以及腺病毒增强子。

启动子和/或增强子可为可诱导型的(例如化学或物理调节的)。化学调节的启动子和/或增强子可例如通过醇、四环素、类固醇或金属的存在来调节。物理调节的启动子和/或增强子可例如由环境因素诸如温度和光来调节。任选地，启动子和/或增强子区可充当组成型启动子和/或增强子，以最大化待转录的转录单元区的表达。在某些载体中，启动子和/或增强子区域可以细胞类型特异性方式具有活性。任选地，在某些载体中，启动子和/或增强子区域可在所有真核细胞中具有活性，而与细胞类型无关。这种类型的优选启动子为CMV启动子、SV40启动子、β-肌动蛋白启动子、EF1α启动子和逆转录病毒长末端重复序列(LTR)。

载体还可包含例如复制起点和/或标记。标记基因可在细胞上赋予可选择表型，例如抗生素抗性。标记产物用于确定载体是否已被递送至细胞，并且一旦递送就被表达。哺乳动物细胞的可选择标记的实例为二氢叶酸还原酶(DHFR)、胸苷激酶、新霉素、新霉素类似物G418、潮霉素、嘌呤霉素和杀稻瘟菌素。当此类可选择标记成功地转移到哺乳动物宿主细胞中时，如果置于选择压力下，则转化的哺乳动物宿主细胞可存活。其他标记的实例包括例如大肠杆菌(E.coli)lacZ基因、绿色荧光蛋白(GFP)和荧光素酶。另外，表达载体可包括被设计为促进表达的多肽的操纵或检测(例如，纯化或定位)的标签序列。标签序列诸如GFP、谷胱甘肽S-转移酶(GST)、聚组氨酸、c-myc、血凝素或FLAG^TM标签(Kodak；New Haven,Conn.)序列通常表达为与编码的多肽的融合物。此类标签可插入多肽内的任何位置，包括羧基端或氨基端。

如本文所用，术语肽、多肽或蛋白质广泛地用于指由肽键连接的两个或更多个氨基酸。蛋白质、肽和多肽在本文中也可互换使用，以指氨基酸序列。应当认识到，术语多肽在本文中并不用于暗示构成所述分子的氨基酸的特定大小或数量，并且本发明的肽可含有至多几个氨基酸残基或更多。如通篇所用，受试者可为脊椎动物，更具体地为哺乳动物(例如人、马、猫、狗、牛、猪、绵羊、山羊、小鼠、兔、大鼠和豚鼠)、鸟类、爬行动物、两栖动物、鱼类和其他任何动物。术语不表示特定的年龄或性别。因此，旨在涵盖无论雄性还是雌性的成年和新生受试者。如本文所用，患者或受试者可互换使用，并且可指患有疾病或病症(例如癌症)的受试者。术语患者或受试者包括人和兽医学受试者。

处于发展疾病或病症的风险下的受试者可能在遗传上易患所述疾病或病症，例如具有家族史或具有引起所述疾病或病症的基因的突变，或表现出所述疾病或病症的早期体征或症状。当前患有疾病或病症的受试者具有疾病或病症的一种或多于一种症状，并且可能已诊断为患有所述疾病或病症。

如本文所述的方法和剂可用于预防性治疗和治疗性治疗。为了预防性应用，在发作之前(例如，在癌症或炎症的明显体征之前)或在早发期间(例如，在癌症或炎症的早期体征和症状时)向受试者施用治疗有效量的本文所述的嵌合多肽或编码所述嵌合多肽的嵌合核酸序列。预防性施用可在表现癌症或炎症症状之前发生若干天至若干年。例如，预防性施用可用于预防性治疗诊断为患有癌症遗传倾向的受试者。治疗性治疗涉及在诊断或发展为癌症或炎症(例如，自身免疫性疾病)后，向受试者施用治疗有效量的本文所述的嵌合多肽或编码所述嵌合多肽的核酸序列。当患者正在接受预期会发炎的治疗(例如，化学疗法)时，也可使用预防性应用。

根据本文教导的方法，向受试者施用有效量的剂(例如，嵌合多肽)。术语有效量和有效剂量可互换使用。术语有效量定义为产生所期望的生理应答所必需的任何量。可凭经验确定施用所述剂的有效量和方案，并且进行此类确定是在本领域技术范围内的。施用的剂量范围是足够大以产生所期望的效果的剂量范围，其中疾病或病症的一种或多种症状受到影响(例如，减少或延迟)。剂量不应大到导致严重的不良副作用，诸如不需要的交叉反应、过敏反应等。一般来讲，剂量随着年龄、病状、性别、疾病类型、疾病或病症程度、施用途径或方案中是否包含其他药物而变化，并且可由本领域技术人员确定。在任何禁忌症的情况下，可由个体医师调节剂量。剂量可变化，并且可以每日一个或多个剂量施用来施用，历时一天或几天。关于给定类别药物产品的适当剂量，指导可发现于文献中。

如本文所用，术语治疗(treatment、treat或treating)是指减少疾病或病状的作用或者疾病或病状的症状的方法。因此，在公开的方法中，治疗可指确立的疾病或病状或者疾病或病状的症状的严重程度的10％、20％、30％、40％、50％、60％、70％、80％、90％或100％减少。例如，如果与对照相比，受试者疾病的一个或多个症状减少10％，则认为用于治疗疾病的方法是一种治疗。因此，与天然或对照水平相比，减少可为10％、20％、30％、40％、50％、60％、70％、80％、90％、100％或10％与100％之间的任何减少百分比。应理解，治疗不必指治愈或完全消除疾病、病状或者疾病或病状的症状。

如本文所用，术语疾病或病症的预防(prevent、preventing和prevention)是指例如在受试者开始显示疾病或病症的一种或多种症状之前或大约同时发生的施用嵌合多肽或编码嵌合多肽的核酸序列的作用，其抑制或延迟疾病或病症的一个或多个症状的发作或加剧。如本文所用，对降低、减少或抑制的提及包括与对照水平相比10％、20％、30％、40％、50％、60％、70％、80％、90％或更大的变化。此类术语可包括但不一定包括完全消除。

已经开发了相对于IL2Rβγ对IL2Rαβγ具有选择性的IL-2变体(Shanafelt,A.B.等人,2000,Nat Biotechnol.18:1197-202；Cassell,D.J.等人,2002,Curr Pharm Des.,8:2171-83)。这些变体具有氨基酸取代，这降低了它们对IL2Rβ的亲和力。由于IL-2对IL2Rγ具有无法检测到的亲和力，因此这些变体降低了对IL2Rβγ受体复合物的亲和力，并且降低了活化IL2Rβγ表达细胞的能力，但保留了结合IL2Rα的能力以及结合并活化IL2Rαβγ受体复合物的能力。

基于表达IL2Rβγ的NK细胞是导致毒性的主要因素的假说，这些变体中的一种IL2/N88R(Bay 50-4798)作为免疫系统刺激物的IL-2低毒版本进行临床测试。Bay 50-4798已显示选择性地刺激活化的T细胞相对于NK细胞的增殖，并在癌症患者(Margolin,K.等人,2007,Clin Cancer Res.,13:3312-9)和HIV患者(Davey,R.T.等人,2008,J InterferonCytokine Res.,28:89-100)的I/II期临床试验中进行评估。这些临床试验表明，Bay 50-4798比阿地白介素更安全且更耐受，并且还表明它增加了CD4+CD25+T细胞(富含Treg细胞的细胞群)的水平。在这些试验之后，本领域的研究更充分地确立了Treg细胞的身份，并证明Treg细胞选择性表达IL2Rαβγ(回顾于Malek,T.R.等人,2010,Immunity,33:153-65中)。

另外，可制备相对于天然IL-2选择性地改变对CD25链的亲和力的突变体。

IL-2可被工程化以产生通常结合IL-2R复合物或特异性结合IL-2Rα亚基的突变体，其亲和力不同于相应的野生型IL-2或目前可用的突变体(称为C125S，因为位置125处的半胱氨酸残基被丝氨酸残基替代)的亲和力。

因此，本发明的特征在于突变体白介素-2(IL-2*)多肽，其包括与野生型IL-2具有至少80％同一性(例如，85％、87％、90％、95％、97％、98％或99％同一性)的氨基酸序列，并且与WT IL-2相比，其与IL-2三聚体受体的结合相对于二聚体IL-2受体更高。通常，突变蛋白还将以比野生型IL-2结合IL-2Rα的亲和力更大的亲和力结合IL-2受体α亚基(IL-2Rα)。由于含有(或仅含有)一个或多个氨基酸取代(其可视为保守或非保守取代)，突变体IL-2多肽内的氨基酸序列可与SEQ ID NO:1(UniProtKB登录号P60568)不同。也可并入非天然存在的氨基酸。可替代地或另外，由于含有和添加和/或缺失一个或多个氨基酸残基，氨基酸序列可与SEQ ID NO:1(其可视为“参考”序列)不同。更具体地，氨基酸序列可由于SEQ ID NO:1的以下位置中的至少一个位置处的突变而不同于SEQ ID NO:1：1、4、8、9、10、11、13、15、26、29、30、31、35、37、46、48、49、54、61、64、67、68、69、71、73、74、75、76、79、88、89、90、92、99、101、103、114、125、128或133(或其组合)。如所指出的，可能这些位置中只有一个可改变，可能位置中的两个、三个、四个、五个、六个、七个、八个、九个、十个或11个或更多个(包括至多所有)可改变。例如，氨基酸序列可在位置69和74以及进一步在位置30、35和128中的一个或多个处不同于SEQ ID NO:1。氨基酸序列也可在以下组的位置中的一组处不同于SEQID NO:2(如US 7569215中所公开的，所述专利以引用的方式并入本文)：(a)位置64、69和74；(b)位置69、74和101；(c)位置69、74和128；(d)位置30、69、74和103；(e)位置49、69、73和76；(f)位置69、74、101和133；(g)位置30、69、74和128；(h)位置69、74、88和99；(i)位置30、69、74和128；(j)位置9、11、35、69和74；(k)位置1、46、49、61、69和79；(l)位置48、68、71、90、103和114；(m)位置4、10、11、69、74、88和133；(n)位置15、3031、35、48、69、74和92；(o)位置30、68、69、71、74、75、76和90；(p)位置30、31、37、69、73、74、79和128；(q)位置26、29、30、54、67、69、74和92；(r)位置8、13、26、30、35、37、69、74和92；和(s)位置29、31、35、37、48、69、71、74、88和89。除了这些位置的突变之外，突变体IL-2多肽的氨基酸序列可以在其他方面与SEQ ID NO:1相同。关于特异性取代，由于具有以下突变中的一种或多种，所述氨基酸序列可不同于SEQ ID NO:1：A1T、S4P、K8R、K9T、T10A、Q11R、Q13R、E15K、N26D、N29S、N30S、N30D、N30T、Y31H、Y31C、K35R、T37A、T37R、M46L、K48E、K49R、K49E、K54R、E61D、K64R、E67G、E68D、V69A、N71T、N71A、N71R、A73V、Q74P、S75P、K76E、K76R、H79R、N88D、I89V、N90H、I92T、S99P、T101A、F103S、I114V、I128T、I128A、T133A或T133N。我们的命名法与科学文献的命名法一致，其中野生型或参考序列中氨基酸的单字母代码紧接其在序列中的位置，然后紧接替代它的氨基酸的单字母代码。因此，A1T表示用苏氨酸取代位置1的丙氨酸残基。本发明范围内的其他突变体多肽包括那些包括在V69(例如A)和Q74(例如P)处具有取代的突变体SEQ IDNO:2的突变体多肽。例如，氨基酸序列可包含相对于SEQ ID NO:2的以下组突变中的一组：(a)K64R、V69A和Q74P；(b)V69A、Q74P和T101A；(c)V69A、Q74P和I128T；(d)N30D、V69A、Q74P和F103S；(e)K49E、V69A、A73V和K76E；(f)V69A、Q74P、T101A和T133N；(g)N30S、V69A、Q74P和I128A；(h)V69A、Q74P、N88D和S99P；(i)N30S、V69A、Q74P和I128T；(j)K9T、Q11R、K35R、V69A和Q74P；(k)A1T、M46L、K49R、E61D、V69A和H79R；(l)K48E、E68D、N71T、N90H、F103S和I114V；(m)S4P、T10A、Q11R、V69A、Q74P、N88D和T133A；(n)E15K、N30S Y31H、K35R、K48E、V69A、Q74P和I92T；(o)N30S、E68D、V69A、N71A、Q74P、S75P、K76R和N90H；(p)N30S、Y31C、T37A、V69A、A73V、Q74P、H79R和I128T；(q)N26D、N29S、N30S、K54R、E67G、V69A、Q74P和I92T；(r)K8R、Q13R、N26D、N30T、K35R、T37R、V69A、Q74P和I92T；以及(s)N29S、Y31H、K35R、T37A、K48E、V69A、N71R、Q74P、N88D和I89V。SEQ ID NO:2作为可用于本发明的示例性IL-2多肽序列公开于US 7569215中，所述专利以引用的方式并入本文。

如上文所述，本文所公开的任何突变体IL-2多肽都可包含所述序列；它们也可限于所述序列并在其他方面与SEQ ID NO:1相同。此外，本文所描述的任何突变体IL-2多肽可任选地包含用另一个残基(例如，丝氨酸)取代位置125处的半胱氨酸残基和/或可任选地包含在SEQ ID NO:1的位置1处的丙氨酸残基的缺失。

本文所公开的突变体IL-2多肽可以结合至IL-2Rα亚基的K_d小于约28nM(例如，小于约25nM；小于约5nM；约1nM；小于约500pM；或小于约100pM)。更具体地，突变体IL-2多肽可具有小于1.0nM(例如，约0.8nM、0.6nM、0.4nM或0.2nM)的亲和力平衡常数。亲和力也可表示为与IL-2Rα亚基或IL-2受体复合物(例如，在细胞表面表达或以其他方式结合膜的复合物)解离的相对速率。例如，相对于野生型多肽或基于IL-2的治疗剂例如IL-2*，突变体IL-2多肽与例如IL-2Rα解离的速率降低。可替代地，亲和力可表征为IL-2*多肽在例如表达IL-2R的细胞表面上持续存在的时间或平均时间。例如，IL-2*多肽可在受体上持续存在至少约2、5、10、50、100或250次(或更多)。

所公开的材料、组合物以及组分可用于所公开的方法和组合物，可与所公开的方法和组合物联用，可用来制备所公开的组合物，或者是所公开的方法和组合物的产品。本文公开了这些材料及其他材料，并且应理解，在公开了这些材料的组合、子组、相互作用、群组等，而没有明确地具体提及各种个体和集体组合的每一种组合以及这些化合物的排列方式时，每种情况均具体地涵盖并描述在本文中。例如，如果公开并讨论了方法并且讨论了可对多个分子(包括所述方法)进行的多种修改，除非明确地相反指示，否则明确涵盖了所述方法的每一种组合和排列以及可能的修改。同样，还特别预期并公开这些的任何子集或组合。这个概念适用于本公开的所有方面，包括但不限于使用所公开的组合物的方法中的步骤。因此，如果有多种附加步骤可进行，那么应理解，这些附加步骤中的每一个可与所公开的方法的任何具体方法步骤或方法步骤的组合一起实施，并且每种此类组合或组合的子集都在本发明的预想之中并应视为得到公开。

本文引用的出版物和引用它们的材料特此以引用的方式整体明确地并入。

实施例

以下是本发明的方法和组合物的实例。应理解，鉴于本文所提供的一般描述，可实施各种其他实施方案。

实施例1：通过ELISA检测融合蛋白中的IL-2、IL-2突变蛋白、IL-2Rα和IL-2Rγ

用可商购获得的抗体(例如抗IL-2单克隆抗体(JES6-1A12)(BD Pharmingen；SanJose,Calif.))检测IL-2突变蛋白。阳性对照用于显示单克隆抗体是否识别细胞因子或突变蛋白。还使用针对IL-2Rα和IL-2Rγ链的抗体。使用PBS中的抗体(2.5μg/ml)涂覆96孔板的孔。用具有0.2％20的PBS中的5％脱脂牛奶(PBS-M-Tw)阻断孔，并在37℃下添加融合蛋白1至2小时。洗涤后，添加抗IL-2生物素标记的抗体，例如JES5H4(BD Pharmingen)，并使用Strepavidin HRP(Southern Biotechnology Associates；Birmingham,Ala.)检测结合。通过在0.1M柠檬酸盐pH 4.5和0.04％H₂O₂中添加50μl邻苯二胺(OPD)(Sigma-Aldrich)来使ELISA板显影，通过添加50μl/孔2N H₂SO₄停止ELISA，并在490nm处读取吸光度。

实施例2：通过MMP9蛋白酶对融合蛋白进行蛋白酶裂解

本领域技术人员将熟悉建立蛋白质裂解测定的方法。用1ug活性MMP9(Sigma目录号SAE0078-50或Enzo目录BML-SE360)裂解1xPBS pH 7.4中的100ug蛋白质，并在室温下孵育至多16小时。随后将消化的蛋白质用于功能测定或在测试之前储存于-80℃下。使用本领域中熟知的方法通过SDS PAGE监测裂解的程度。如图10所示，查看MMP9蛋白酶完全裂解融合蛋白。

实施例3：CTLL-2测定

将CTLL2细胞(ATCC)以500,000个细胞/孔的浓度的悬浮液接种在含有或不含40mg/ml人血清白蛋白(HSA)的培养基中，并在37℃和5％CO₂下用系列稀释的重组hIL2或可活化hIL2刺激72小时。测试未裂解和裂解的可活化hIL2的活性。通过用活性MMP9孵育产生裂解的可活化hIL2。使用基于CellTiter-Glo(Promega)发光的细胞活力测定评定细胞活力。结果在图7至9中示出。

实施例4：IL-2/IL-2Rα/IL-2Rγ嵌合多肽的蛋白酶裂解导致对抗体和生物活性IL-2突变蛋白的可及性增加。

在用蛋白酶(例如PSA)裂解之前和之后，对IL-2突变蛋白融合蛋白进行生物化学表征。免疫印迹分析将显示融合蛋白可被PSA裂解，并且在用PSA处理样品后，约20kDa预测的低分子量裂解产物与抗IL-2抗体反应的强度增加。裂解程度取决于PSA的量以及孵育时间。有趣的是，当在PSA处理之前和之后通过ELISA对融合蛋白进行分析时，发现在PSA裂解后IL-2的表观量增加。在此实验中，根据构建体的不同，使用这种夹心ELISA检测到的IL-2表观量增加约2或4倍，这表明抗体结合在完整融合蛋白中受到部分阻碍。在PSA处理后，还使用CTLL-2细胞系(其生长和存活需要IL-2)对相同样品的等分试样进行分析，并且可使用比色MTT测定法确定细胞的活力。在此测定中，可稀释上清液越多，其所含的生物活性IL-2越多，并且PSA裂解后生物活性IL-2的数量会增加。IL-2突变蛋白的量增加将表明，在PSA裂解后，与抗IL-2抗体反应的约20kDa预测的低分子量裂解片段增加，抗体可及性增加，并且最重要的是，生物活性IL-2突变蛋白的数量增加。

实施例5.蛋白酶活化的融合蛋白的体内递送导致肿瘤生长减少

检查嵌合多肽以确定其在体内是否可具有生物作用。对于这些实验，使用一种系统，其中腹膜内注射的肿瘤细胞快速且优先附着于乳白色斑点并在其上开始生长，所述乳白色斑点是在网膜上发现的一系列有组织的免疫聚集体(Gerber等人,Am.J.Pathol.169:1739-52(2006))。这种系统提供了一种方便的方式来检查融合蛋白治疗对肿瘤生长的影响，因为融合蛋白可多次经腹膜内递送，并且可通过检查解离的网膜细胞来分析肿瘤生长。对于这些实验，可使用在体外表达MMP2和MMP9的快速生长的肿瘤细胞系结肠38细胞系。网膜组织通常表达相对少量的MMP2和MMP9，但是当网膜上出现结肠38肿瘤时，MMP水平升高。使用此肿瘤模型，检查IL-2突变蛋白融合蛋白影响肿瘤生长的能力。腹膜内注射结肠38细胞，使其附着并生长1天，并且然后每天用融合蛋白腹膜内处理。在第7天，处死动物，并且使用流式细胞术并通过集落形成测定法检查网膜的肿瘤生长。

实施例6：靶向CD20的示例性可活化IL2蛋白的构建

产生可活化IL2结构域

如下产生能够与存在于肿瘤中或肿瘤细胞上的CD20多肽结合的IL-2多肽。产生含有以下核酸序列的核酸：(1)编码IL-2多肽序列和(2)一个或多个多肽接头。可活化的白介素质粒构建体可具有任选的Flag、His或其他亲和标签，并且被电穿孔到HEK293或其他合适的人或哺乳动物细胞系中并被纯化。验证测定包括使用在蛋白酶存在下对IL-2刺激产生反应的T细胞进行的T细胞活化测定。

产生scFv CD20结合结构域

CD20是存在于B淋巴细胞上的细胞表面蛋白中的一种。CD20抗原存在于正常和恶性的前B和成熟B淋巴细胞中，包括超过90％的B细胞非霍奇金氏淋巴瘤(NHL)中的那些。抗原在造血干细胞、活化的B淋巴细胞(浆细胞)和正常组织中不存在。这样，已经描述了几种主要来源于鼠类的抗体：1F5、2B8/C2B8、2H7和1H4。

因此，人或人源化抗CD20抗体用于产生可活化白介素蛋白的CD20结合结构域的scFv序列。获得编码人或人源化VL和VH结构域的DNA序列，并且任选地优化构建体的密码子以在智人的细胞中表达。VL和VH结构域在scFv中出现的顺序是变化的(即VL-VH或VH-VL取向)，并且“G4S”或“G₄S”亚基(G₄S)₃的三个拷贝连接可变结构域以创建scFv结构域。抗CD20scFv质粒构建体可具有任选的Flag、His或其他亲和标签，并且被电穿孔到HEK293或其他合适的人或哺乳动物细胞系中并被纯化。验证测定包括通过FACS进行的结合分析、使用Proteon进行的动力学分析和对CD20表达细胞进行的染色。

克隆编码可活化IL2蛋白的DNA表达构建体

具有蛋白酶裂解位点结构域的可活化IL2构建体用于构建可活化白介素蛋白与抗CD20 scFv结构域和血清半衰期延长元件(例如，HSA结合肽或VH结构域)的组合。为了在CHO细胞中表达可活化白介素蛋白，将所有蛋白结构域的编码序列克隆到哺乳动物表达载体系统中。简言之，单独合成并亚克隆编码可活化白介素结构域的基因序列、血清半衰期延长元件和CD20结合结构域以及肽接头L1和L2。然后将所得构建体按CD20结合结构域–L1–IL2亚基1–L2–蛋白酶裂解结构域–L3–IL2亚基2–L4–抗CD20 scFv–L5–血清半衰期延长元件的顺序连接在一起，以产生最终构建体。所有表达构建体被设计为含有N端信号肽和C端六聚组氨酸(6xHis)标签的编码序列，以分别促进蛋白质分泌和纯化。

在稳定转染的CHO细胞中表达可活化IL2蛋白

使用CHO-K1中国仓鼠卵巢细胞(ATCC，CCL-61)的衍生物CHO细胞表达系统((,Life Technologies)(Kao和Puck,Proc.Natl.Acad Sci USA 1968；60(4):1275-81)。根据Life Technologies提供的标准细胞培养方案对贴壁细胞进行传代培养。

为了适应悬浮液中的生长，将细胞与组织培养瓶分离，并将其置于无血清培养基中。将悬浮液适应的细胞冷冻保存在含10％DMSO的培养基中。

通过转染悬浮液适应的细胞来产生稳定表达分泌的可活化白介素蛋白的重组CHO细胞系。在用抗生素潮霉素B进行选择期间，每周两次测量活细胞密度，并且将细胞离心分离并以0.1x10⁶个活细胞/mL的最大密度悬浮于新鲜的选择培养基中。选择2至3周后，回收稳定表达可活化白介素蛋白的细胞库，此时将细胞转移至摇瓶中的标准培养基中。通过进行蛋白凝胶电泳或流式细胞术来确认重组分泌蛋白的表达。将稳定的细胞库冷冻保存在含有DMSO的培养基中。

在稳定转染的CHO细胞系的10天分批补料培养中通过分泌到细胞培养上清液中产生可活化IL2蛋白。10天后以通常>75％培养活力收获细胞培养上清液。每隔一天从生产培养物中收集样品，并评定细胞密度和活力。在收获当天，通过离心和真空过滤清除细胞培养上清液，之后进一步使用。

通过SDS-PAGE分析细胞培养上清液中的蛋白质表达滴度和产物完整性。

纯化可活化IL2蛋白

以两步程序从CHO细胞培养上清液中纯化可活化IL2蛋白。在第一步中对构建体进行亲和色谱，之后在第二步中在Superdex 200上进行制备性尺寸排阻色谱法(SEC)。对样品进行缓冲液交换，并通过超滤浓缩至>1mg/mL的典型浓度。通过在还原和非还原条件下进行SDS PAGE来评定最终样品的纯度和均质性(通常>90％)，之后分别通过使用抗HSA或抗独特型抗体进行免疫印迹以及通过分析型SEC来评定。纯化的蛋白质以等分形式储存于-80℃下直至使用。

实施例7：通过流式细胞术确定抗原亲和力

测试实施例6的可活化IL2蛋白与人CD20⁺细胞和食蟹猴CD20⁺细胞的结合亲和力。

将CD20⁺细胞与100μL实施例6的可活化白介素蛋白的连续稀释液和至少一种蛋白酶一起孵育。用FACS缓冲液洗涤三次后，将细胞与0.1mL的10μg/mL小鼠单克隆抗独特型抗体一起在同一缓冲液中于冰上孵育45min。在第二次洗涤循环后，将细胞与0.1mL的15μg/mLFITC缀合的山羊抗小鼠IgG抗体一起在与之前相同的条件下孵育。作为对照，将细胞与抗His IgG一起孵育，之后与不含可活化IL2蛋白的FITC缀合的山羊抗小鼠IgG抗体一起孵育。然后将细胞再次洗涤，并重悬于含有2μg/mL碘化丙啶(PI)的0.2mL FACS缓冲液中，以便排除死细胞。用使用MXP软件(Beckman-Coulter,Krefeld,Germany)的Beckman-CoulterFC500 MPL流式细胞仪或用使用Incyte软件(Merck Millipore,Schwalbach,Germany)的Millipore Guava EasyCyte流式细胞仪测量1x10⁴个活细胞的荧光。使用CXP软件(Beckman-Coulter,Krefeld,Germany)或Incyte软件(Merck Millipore,Schwalbach,Germany)计算细胞样品的平均荧光强度。在减去仅用二级和三级试剂染色的细胞的荧光强度值之后，然后将这些值用于利用GraphPad Prism(Windows版本6.00，GraphPad软件，LaJolla California USA)的单点结合(双曲线)方程计算K_D值。

评定在人CD20⁺肿瘤细胞系上的CD20结合和交叉反应性。使用在表达重组人或重组食蟹猴抗原的CHO细胞系上确定的K_D值计算交叉反应性的K_D比。

实施例8：细胞毒性测定

体外评估实施例6的可活化IL2蛋白对CD20⁺靶细胞的免疫应答的调节。

将荧光标记的CD20⁺REC-1细胞(被套细胞淋巴瘤细胞系，ATCC CRL-3004)与随机供体的分离的PBMC或作为效应细胞的CB15 T细胞(标准化T细胞系)一起在实施例5的可活化IL2蛋白和至少一种蛋白酶的存在下孵育。在湿润的培养箱中于37℃下孵育4h后，在荧光分光光度计中测定荧光染料从靶细胞到上清液中的释放。在不使用实施例1的可活化IL2蛋白的情况下孵育的靶细胞和在孵育结束时通过添加皂苷完全溶解的靶细胞分别充当阴性和阳性对照。

基于测量的剩余活靶细胞，根据以下公式计算特定细胞裂解的百分比：[1-(活靶_(样品)数目/活靶_(自发)数目)]×100％。使用GraphPad软件通过非线性回归/4参数逻辑拟合计算S型剂量应答曲线和EC₅₀值。使用对于给定的抗体浓度所获得的裂解值，以通过使用Prism软件的4参数对数拟合分析来计算S型剂量应答曲线。

实施例9：可活化IL2蛋白的药代动力学

在动物研究中评估实施例5的可活化IL2蛋白的半衰期消除。

将可活化IL2蛋白以0.5mg/kg团注到隐静脉以施用于食蟹猴。另一个食蟹猴组接受大小相当的IL2构建体，但缺少血清半衰期延长元件。第三组和第四组分别接受具有血清半衰期延长元件的IL2构建体和具有CD20和血清半衰期延长元件的细胞因子，并且两者的大小均与可活化白介素蛋白相当。每个测试组由5只猴子组成。在指定的时间点采集血清样品，进行连续稀释，并使用CD20的结合ELISA测定蛋白质的浓度。

使用测试制品的血浆浓度进行药代动力学分析。当针对给药后的时间作图时，每个测试制品的组平均血浆数据符合多指数曲线。数据通过具有用于分布阶段和消除阶段的团注输入和一级速率常数的标准两室模型拟合。静脉内施用数据的最佳拟合的一般方程为：c(t)＝Ae^-αt+Be^-βt，其中c(t)是时间t时的血浆浓度，A和B是Y轴上的截距，并且α和β分别是分布阶段和消除阶段的表观一级速率常数。α阶段是初始清除阶段并且反映蛋白质在动物所有细胞外流体中的分布，而衰减曲线的第二或β阶段代表真正的血浆清除。用于拟合此类方程的方法是本领域中熟知的。例如，A＝D/V(α-k21)/(α-β)，B＝D/V(β-k21)/(α-β)，并且α和β(对于α>β)是二次方程的根r²+(k12+k21+k10)r+k21k10＝0，其使用以下估计参数：V＝分布体积，k10＝消除速率，k12＝从房室1到房室2的传输速率，k21＝从房室2到房室1的传输速率，以及D＝施用的剂量。

数据分析：使用KaleidaGraph(KaleidaGraph^TMV.3.09Copyright 1986-1997Synergy Software.Reading,Pa.)制得浓度相对于时间曲线的曲线图。报告为小于可报告(LTR)的值不包括在PK分析中，并且不以图形表示。使用WinNonlin软件(Professional V.3.1WinNonlin^TMCopyright 1998-1999.PharsightCorporation.Mountain View,Calif.)通过房室分析确定药代动力学参数。药代动力学参数的计算如Ritschel W A和Kearns G L,1999的Handbook Of Basic PharmacokineticsIncluding Clinical Applications,第5版,American Pharmaceutical Assoc.,Washington,D.C中所述。

预期与缺乏血清半衰期延长元件的蛋白质相比，实施例5的可活化IL2蛋白具有改善的药代动力学参数，诸如消除半衰期增加。

实施例10：异种移植肿瘤模型

在异种移植模型中评估实施例5的可活化IL2蛋白。

雌性免疫缺陷型NOD/scid小鼠经亚致死性照射(2Gy)，并且在右背侧皮下接种4x10⁶个Ramos RA1细胞。当肿瘤达到100至200mm³时，将动物分为3个处理组。将第2组和第3组(每组8只动物)腹膜内注射1.5x10⁷个活化的人T细胞。三天后，随后用总共9个50μg静脉内剂量的实施例1的可活化白介素蛋白(qdx9d)处理第3组的动物。第1组和第2组仅使用载体处理。持续30天测定体重和肿瘤体积。

预期与相应载体处理的对照组相比，用实施例5的可活化IL2蛋白处理的动物在肿瘤生长上具有统计学上显著的延迟。

尽管本文已示出并描述了本发明的优选实施方案，但对于本领域技术人员来说将显而易见的是，此类实施方案仅作为实例提供。本领域技术人员现在将想到许多变化、改变和替换而不偏离本发明。应理解，本文所述的本发明的实施方案的各种替代方案可用于实行本发明。所意图的是，以下权利要求限定本发明的范围以及由此涵盖这些权利要求及其等同物范围内的方法和结构。

实施例11：HEK Blue测定

将HEK-Blue IL2细胞(InvivoGen)以50,000个细胞/孔浓度的悬浮液接种在含有或不含15mg/ml至40mg/ml人血清白蛋白(HSA)的培养基中，并在37℃和5％的CO₂下用系列稀释的重组hIL2或可活化hIL2刺激24小时。测试未裂解和裂解的可活化hIL2的活性。通过用活性MMP9孵育产生裂解的可诱导hIL2。通过使用试剂QUANTI-Blue(InvivoGen)对分泌型碱性磷酸酶(SEAP)活性进行定量(即基于比色的测定)来评定IL12活性。结果在图11中示出。

实施例12：MC38实验

使用在体外表达MMP9的快速生长的结肠腺癌细胞系MC38细胞系。使用此肿瘤模型，检查融合蛋白影响肿瘤生长的能力。

实施例12a MC38 IL-2POC

剂和处理：

#-对照组

实施例12b：MC38 IL-2

剂和处理：

#-对照组

实施例12c：用ACP16、ACP132和ACP21处理

用异氟烷麻醉小鼠以植入细胞以减少溃疡将CR雌性C57BL/6小鼠的侧腹皮下建立有0％Matrigel中的5x10⁵个MC38肿瘤细胞。细胞注射体积为0.1mL/小鼠。在开始日期时小鼠年龄为8至12周。当肿瘤的平均大小达到100-150mm³并开始治疗时，进行配对。ACP16以17、55、70或230ug/动物给药；ACP132以9、28、36或119ug/动物给药；ACP21以13、42、54或177ug/动物给药。体重在开始时测量，并且然后每两周测量一次直到结束。每两周进行一次卡尺测量直到结束。任何不良反应都应立即报告。对单次观察体重减轻超过30％或连续三次体重减轻超过25％的任何个体动物实施安乐死。平均体重减轻>20％或死亡率>10％的任何组均停止给药；此组并不实施安乐死，并且使其恢复。在体重减轻>20％的组中，对达到体重减轻终点的个体实施安乐死。如果与组治疗相关的体重减轻恢复到原始体重的10％以内，则以较低剂量或较不频繁的给药方案恢复给药。非治疗体重％恢复的例外在个案基础上是允许的。终点是肿瘤生长延迟(TGD)。单独地监测动物。实验的终点是肿瘤体积达到1500mm³或45天，以先到者为准。响应者的追踪时间更长。当达到终点时，将对动物实施安乐死。结果在图17中示出。

实施例12d：MC38再激发

通过肿瘤植入再激发实施例12b的治愈的小鼠(经ACP16处理的)，以确定是否从初始处理建立了抗肿瘤记忆。

剂和处理：

#-对照组

程序：

用异氟烷麻醉小鼠以植入细胞以减少溃疡研究的这一部分开始于植入当天(第1天)。将由33只CR雌性C57BL/6小鼠组成的第1组的侧腹皮下建立有0％Matrigel中的5x10⁵个MC38肿瘤细胞。将由33只CR雌性C57BL/6小鼠组成的第2组至第6组的左侧腹皮下建立有0％Matrigel中的5x10⁵个MC38肿瘤细胞。将先前的MC38实验(实施例12b)的肿瘤植入每只动物的右侧腹。细胞注射体积为0.1mL/小鼠。在开始时对照小鼠的年龄为14至17周。这些小鼠与先前的MC38实验(实施例12b)的小鼠年龄匹配。再激发期间未发生活性剂给药。每两周测量一次体重直到结束，卡尺测量也一样。立即报告任何不良反应或死亡。对单次观察体重减轻超过30％或连续三次体重减轻超过25％的任何个体动物实施安乐死。终点是肿瘤生长延迟(TGD)。单独地监测动物。实验的终点是肿瘤体积达到1000mm³或45天，以先到者为准。在可能的情况下，响应者的追踪时间更长。当达到终点时，对动物实施安乐死。结果在图15中示出。

实施例13.条件活性融合蛋白含有作为血清白蛋白结合结构域的阻断部分

此实施例描述了通常通过在阻断部分和活性部分之间的接头裂解后将阻断部分从活性部分中分离出来而具有可诱导活性(即它们在被诱导之前是无活性的)的融合蛋白(优选细胞因子)的产生和活性。融合蛋白含有单个抗体可变结构域(dAb)，其通过CDR环结合血清白蛋白，并通过一个或多个非CDR环(例如C环)结合到活性部分(此处为抗CD3scFV)。血清白蛋白结合阻断部分通过蛋白酶可裂解的接头可操作地连接到活性部分，并且活性部分通过非蛋白酶可裂解的接头可操作地连接到靶向结构域(此处为抗表皮生长因子受体(EGFR)dAb或抗前列腺特异性膜抗原(PSMA)dAb)。这些融合蛋白可作为非活性蛋白施用，所述非活性蛋白在裂解蛋白酶可裂解的接头并随后释放抑制性白蛋白结合结构域时被活化。融合蛋白中的抗CD3 scFV是本公开中描述的融合蛋白中所期望的细胞因子的替代物。可使用本文描述和例证的方法制备含有所期望的细胞因子(例如IL-2、IL-12、干扰素)或其功能片段或突变蛋白、靶向结构域和白蛋白结合dAb(也结合并抑制细胞因子或其功能片段或突变蛋白)的类似融合蛋白。结合并抑制所期望的细胞因子或其功能片段或突变蛋白的活性的抗血清白蛋白dAb可提供细胞因子的空间掩蔽(通过接近结合血清白蛋白的细胞因子)和细胞因子的特异性掩蔽(通过经由非CDR环(例如，C环)结合细胞因子))。可使用合适的方法获得结合并抑制所期望的细胞因子或其功能片段或突变蛋白活性的抗血清白蛋白dAb，所述方法诸如通过将氨基酸序列多样性引入到抗血清白蛋白结合dAb的非CDR环(例如，C环)中并筛选与所期望的细胞因子的结合。任何合适的方法都可用于选择，诸如噬菌体展示。例如，可使用的示例性抗血清白蛋白dab具有以下序列，并且C环中的氨基酸序列(加粗下划线)可多样化(例如，随机化)，并且筛选通过CDR相互作用与血清白蛋白结合和通过非CDR环相互作用与细胞因子结合的所得dAb。如果需要的话，可将已知细胞因子结合肽的氨基酸序列移植到C环中。

A.蛋白酶活化ProTriTAC导致体外活性显著增强

测试纯化的ProTriTAC(前药)、不可裂解的ProTriTAC[前药(不可裂解)]和模仿蛋白酶活化的ProTriTAC(活性药物)的重组活性药物片段在ELISA测定中与重组人CD3的结合，在流式细胞术测定中与纯化的人原代T细胞的结合，以及在T细胞依赖性细胞毒性测定中的功能效价。

对于ELISA，将指定浓度的可溶性ProTriTAC蛋白与固定化的重组人CD3e(R&DSystems)一起在室温下在补充有15mg/ml人血清白蛋白的PBS中孵育1h。使用SuperBlock(Thermo Fisher)阻断板，使用具有0.05％Tween-20的PBS洗涤，并使用非竞争性抗CD3独特型单克隆抗体11D3，之后使用过氧化物酶标记的二抗和TMB-ELISA底物溶液(ThermoFisher)进行检测。

对于流式细胞术，将指定浓度的可溶性ProTriTAC蛋白与纯化的人原代T细胞一起在具有2％胎牛血清和15mg/ml人血清白蛋白的PBS存在下于4℃下孵育1h。用具有2％胎牛血清的PBS洗涤板，使用AlexaFluor 647标记的非竞争性抗CD3独特型单克隆抗体11D3检测，并使用FlowJo 10(FlowJo,LLC)分析数据。

对于在T细胞依赖性细胞毒性测定中的功能效价，将指定浓度的可溶性ProTriTAC蛋白与纯化的静息人T细胞(效应细胞)和HCT116癌细胞(靶细胞)一起以10:1的效应子:靶细胞比例在37℃下孵育48h。HCT116靶细胞系已被荧光素酶报告基因稳定转染，从而允许通过ONE-Glo(Promega)测量特异性T细胞介导的细胞杀伤。

B.ProTriTAC在啮齿动物肿瘤异种移植模型中表现出强大的蛋白酶依赖性抗肿瘤 活性

在免疫受损的NCG小鼠中，在与扩增的人T细胞混合的HCT116皮下异种移植肿瘤中评估ProTriTAC的体内抗肿瘤活性。具体地，在第0天将每只小鼠的5x106个HCT116细胞与2.5x106个扩增的T细胞混合。从第二天开始，通过腹膜内注射以q.d.x 10方案进行ProTriTAC的给药。使用卡尺测量确定肿瘤体积测量，并在指定时间使用公式V＝(长度x宽度x宽度)/2计算。

C.示例性ProTriTAC三特异性分子的表达、纯化和稳定性蛋白质生产

将编码诱导型融合蛋白分子的序列克隆到哺乳动物表达载体pcDNA 3.4(Invitrogen)中，在这之前是前导序列，并且之后是6x组氨酸标签(SEQ ID NO.:136)。将Expi293F细胞(Life Technologies A14527)以0.2至8x 1e6个细胞/ml之间的悬浮液保持在Expi 293培养基中的Optimum Growth Flasks(Thomson)中。按照Expi293表达系统试剂盒(Life Technologies，A14635)的方案将纯化的质粒DNA转染到Expi293细胞中，并将其在转染后保持4至6天。可替代地，将编码融合蛋白分子的序列克隆到转染到CHO-DG44 dhfr-细胞中的哺乳动物表达载体pDEF38(CMC ICOS)中，产生稳定的库，并在纯化之前在生产培养基中培养多达12天。使用具有蛋白A尖端((ForteBio/Pall)的Octet RED 96仪器，使用标准曲线的对照融合蛋白对条件培养基中示例性融合蛋白的量进行定量。过滤来自任一宿主细胞的条件培养基，并通过亲和和脱盐色谱法进行部分纯化。随后通过离子交换对融合蛋白进行抛光，并在级分合并后配制成含有赋形剂的中性缓冲液。通过使用溶解于水/有机流动相中的Acquity BEH SEC 200 1.7u 4.6x150mm柱(Waters Corporation)的SDS-PAGE和分析SEC评定最终纯度，其中赋形剂在1290LC系统上的中性pH条件下，并且峰集成有Chemstation CDS软件(Agilent)。从CHO宿主细胞纯化的融合蛋白在以下描述的SDS-PAGE中示出。

稳定性评定

将两种制剂中纯化的融合蛋白再分装到无菌管中，并通过五个冻融循环施加压力，每个循环包括在-80℃和室温下超过1小时或在37℃下孵育1周。通过使用UV透明96孔板(Corning 3635)使用SpectraMax M2和SoftMaxPro软件(Molecular Devices)进行的UV光谱法、SDS-PAGE和分析SEC来对应力样品的浓度和浊度进行评估，并与对照的非应力样品的相同分析进行比较。下文描述了从293个宿主细胞纯化的单个示例性ProTriTAC分子的对照样品和应力样品的分析SEC色谱图的覆盖图。

结果表明，ProTriTAC的产量与CHO稳定库中的常规TriTAC的产量相当；并且在反复冻融并在37℃下1周后，蛋白质是稳定的。

D.在三周食蟹猴药代动力学研究中证明ProTriTAC在体内的功能性掩蔽和稳定性

将单剂量靶向PSMA的ProTriTAC(SEQ ID NO:119)、不可裂解的ProTriTAC(SEQ IDNO:120)、不可掩蔽/不可裂解的TriTAC(SEQ ID NO:123)和模仿蛋白酶活化的ProTriTAC(SEQ ID NO:121)的活性药物以0.1mg/kg的剂量通过静脉内注射到食蟹猴中。在指定时间点收集血浆样品。使用利用生物素化重组人PSMA(R&D systems)和MSD测定(Meso ScaleDiagnostic，LLC)中磺基标记的抗CD3独特型抗体克隆11D3的配体结合测定来确定ProTriTAC浓度。使用Phoenix WinNonlin药代动力学软件，使用与静脉推注施用途径一致的非房室方法，估计药代动力学参数。

为了计算体内前药转化率，通过求解以下微分方程组来估计循环中的活性药物浓度，其中P为前药的浓度，A为活性药物的浓度，k_a为循环中前药活化率，k_c,P为前药的清除率，并且k_c,A为活性药物的清除率。

凭经验确定食蟹猴的前药、活性药物和不可裂解的前药对照(k_c,NCLV)的清除率。为了估计循环中前药活化率，假设可裂解前药和不可裂解前药的清除率之间的差异仅源于循环中的非特异性活化。因此，通过从不可裂解前药中减去可裂解前药的清除率来估计前药在循环中转化为活性药物的比率。

k_a＝k_C，NCLV-k_c，P

凭经验确定循环中前药的初始浓度，并假设活性药物的初始浓度为零。

结果和讨论

实施例13的结果表明，可制备包含具有所期望治疗活性的多肽的融合蛋白，诸如细胞因子或其功能片段或突变蛋白或抗CD3 scFV，其中治疗活性被结合血清白蛋白和活性多肽的掩蔽结构域掩蔽。掩蔽结构域通过蛋白酶可裂解的接头可操作地连接到活性结构域。结果表明，此类型的融合蛋白可作为失活蛋白施用，所述失活蛋白在所期望的治疗活性位置诸如肿瘤处被蛋白酶裂解后被活化。

实施例13中使用的融合蛋白的氨基酸序列以SEQ ID NO:116-123给出。

表3中详细描述了样品融合蛋白构建体。在表3中，“L”为“接头”的缩写，并且“cleav.link.”为“可裂解的接头”的缩写。其他缩写“mIFNg”指示小鼠干扰素γ(IFNg)；“hAlbumin”指示人血清白蛋白(HSA)；“mAlbumin”指示小鼠血清白蛋白。

表3：构建体置换表

序列表

以引用的方式并入

本文引用的所有专利和非专利出版物的全部公开内容各自出于所有目的以引用的方式整体并入本文。

其他实施方案

上文阐述的公开内容可包括具有独立效用的多种不同的发明。虽然已经以其一个或多个优选的形式公开了这些发明中的每一种，但是本文公开并例示的它们的特定实施方案不应被认为是限制意义的，因为多种变化是可能的。本发明的主题包括本文所公开的各种元件、特征、功能和/或性质的全部新颖的和不明显的组合和子组合。以下权利要求特别指出被视为新颖的和不明显的某些组合和子组合。在本申请中、在要求本申请优先权的申请中或在相关申请中，可要求保护以特征、功能、元件和/或特性的其他组合和子组合体现的发明。此类权利要求与原始权利要求相比无论是针对不同的发明还是相同的发明，以及无论在范围上更宽、更窄、等同或不同都被认为包括在本公开的发明主题内。

序列表

<110> 狼人治疗公司

<120> 可活化白介素-2多肽及其使用方法

<130> 105365-0021

<140>

<141>

<150> 62/756,507

<151> 2018-11-06

<150> 62/756,504

<151> 2018-11-06

<150> 62/671,225

<151> 2018-05-14

<160> 137

<170> PatentIn version 3.5

<210> 1

<211> 153

<212> PRT

<213> 智人(Homo sapiens)

<400> 1

Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu

1 5 10 15

Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu

20 25 30

Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile

35 40 45

Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe

50 55 60

Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu

65 70 75 80

Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys

85 90 95

Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile

100 105 110

Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala

115 120 125

Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe

130 135 140

Cys Gln Ser Ile Ile Ser Thr Leu Thr

145 150

<210> 2

<211> 609

<212> PRT

<213> 智人(Homo sapiens)

<400> 2

Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala

1 5 10 15

Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala

20 25 30

His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu

35 40 45

Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val

50 55 60

Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp

65 70 75 80

Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp

85 90 95

Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala

100 105 110

Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln

115 120 125

His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val

130 135 140

Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys

145 150 155 160

Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro

165 170 175

Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys

180 185 190

Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu

195 200 205

Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Gly Leu Lys Cys

210 215 220

Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val

225 230 235 240

Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser

245 250 255

Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly

260 265 270

Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile

275 280 285

Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu

290 295 300

Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp

305 310 315 320

Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Gly Ser

325 330 335

Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly

340 345 350

Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val

355 360 365

Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys

370 375 380

Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu

385 390 395 400

Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys

405 410 415

Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu

420 425 430

Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val

435 440 445

Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His

450 455 460

Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Cys Leu Ser Val Phe

465 470 475 480

Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg

485 490 495

Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Gly Arg Pro Cys Phe

500 505 510

Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala

515 520 525

Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu

530 535 540

Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys

545 550 555 560

Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala

565 570 575

Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe

580 585 590

Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly

595 600 605

Leu

<210> 3

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP7裂解结构域序列”

<400> 3

Lys Arg Ala Leu Gly Leu Pro Gly

1 5

<210> 4

<211> 40

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP7裂解结构域序列”

<400> 4

Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu

1 5 10 15

Arg Pro Leu Ala Leu Trp Arg Ser Asp Arg Asp Arg Asp Arg Asp Arg

20 25 30

Asp Arg Asp Arg Asp Arg Asp Arg

35 40

<210> 5

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP9裂解结构域序列”

<220>

<221> VARIANT

<222> (3)..(3)

<223> /置换="Thr"

<220>

<221> VARIANT

<222> (4)..(4)

<223> /置换=“Ile”

<220>

<221> VARIANT

<222> (5)..(5)

<223> /置换=“Thr”

<220>

<221> SITE

<222> (1)..(5)

<223> /注释="序列中给出的变体残基相对于变体位置的注释中的那些残基没有偏好"

<400> 5

Pro Arg Ser Leu Ser

1 5

<210> 6

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP9裂解结构域序列”

<400> 6

Leu Glu Ala Thr Ala

1 5

<210> 7

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP11裂解结构域序列”

<400> 7

Gly Gly Ala Ala Asn Leu Val Arg Gly Gly

1 5 10

<210> 8

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP14裂解结构域序列”

<400> 8

Ser Gly Arg Ile Gly Phe Leu Arg Thr Ala

1 5 10

<210> 9

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<400> 9

Pro Leu Gly Leu Ala Gly

1 5

<210> 10

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<220>

<221> MOD_RES

<222> (6)..(6)

<223> 任何氨基酸

<400> 10

Pro Leu Gly Leu Ala Xaa

1 5

<210> 11

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<220>

<221> MOD_RES

<222> (4)..(4)

<223> Cys(me)

<400> 11

Pro Leu Gly Xaa Ala Gly

1 5

<210> 12

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<400> 12

Glu Ser Pro Ala Tyr Tyr Thr Ala

1 5

<210> 13

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<400> 13

Arg Leu Gln Leu Lys Leu

1 5

<210> 14

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP裂解结构域序列”

<400> 14

Arg Leu Gln Leu Lys Ala Cys

1 5

<210> 15

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

MMP2、MMP9、MMP14裂解结构域序列”

<220>

<221> MOD_RES

<222> (3)..(3)

<223> Cit

<220>

<221> MOD_RES

<222> (5)..(5)

<223> Hof

<400> 15

Glu Pro Xaa Gly Xaa Tyr Leu

1 5

<210> 16

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

尿激酶纤溶酶原活化物(uPA)裂解结构域序列"

<400> 16

Ser Gly Arg Ser Ala

1 5

<210> 17

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

尿激酶纤溶酶原活化物(uPA)裂解结构域序列"

<400> 17

Asp Ala Phe Lys

1

<210> 18

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

尿激酶纤溶酶原活化物(uPA)裂解结构域序列"

<400> 18

Gly Gly Gly Arg Arg

1 5

<210> 19

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

溶酶体酶裂解结构域序列”

<400> 19

Gly Phe Leu Gly

1

<210> 20

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

溶酶体酶裂解结构域序列”

<400> 20

Ala Leu Ala Leu

1

<210> 21

<211> 2

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

溶酶体酶裂解结构域序列”

<400> 21

Phe Lys

1

<210> 22

<211> 3

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

组织蛋白酶B裂解结构域序列”

<400> 22

Asn Leu Leu

1

<210> 23

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

组织蛋白酶D裂解结构域序列”

<220>

<221> MOD_RES

<222> (3)..(3)

<223> Cys(et)

<400> 23

Pro Ile Xaa Phe Phe

1 5

<210> 24

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

组织蛋白酶K裂解结构域序列”

<400> 24

Gly Gly Pro Arg Gly Leu Pro Gly

1 5

<210> 25

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

前列腺特异性抗原裂解结构域序列”

<400> 25

His Ser Ser Lys Leu Gln

1 5

<210> 26

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

前列腺特异性抗原裂解结构域序列”

<400> 26

His Ser Ser Lys Leu Gln Leu

1 5

<210> 27

<211> 9

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

前列腺特异性抗原裂解结构域序列”

<400> 27

His Ser Ser Lys Leu Gln Glu Asp Ala

1 5

<210> 28

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

单纯疱疹病毒蛋白酶裂解结构域序列"

<400> 28

Leu Val Leu Ala Ser Ser Ser Phe Gly Tyr

1 5 10

<210> 29

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

HIV蛋白酶裂解结构域序列"

<400> 29

Gly Val Ser Gln Asn Tyr Pro Ile Val Gly

1 5 10

<210> 30

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

CMV蛋白酶裂解结构域序列"

<400> 30

Gly Val Val Gln Ala Ser Cys Arg Leu Ala

1 5 10

<210> 31

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

凝血酶裂解结构域序列"

<220>

<221> MOD_RES

<222> (2)..(2)

<223> 2-羧基哌啶

<400> 31

Phe Xaa Arg Ser

1

<210> 32

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

凝血酶裂解结构域序列"

<400> 32

Asp Pro Arg Ser Phe Leu

1 5

<210> 33

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

凝血酶裂解结构域序列"

<400> 33

Pro Pro Arg Ser Phe Leu

1 5

<210> 34

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

半胱天冬酶-3裂解结构域序列”

<400> 34

Asp Glu Val Asp

1

<210> 35

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

半胱天冬酶-3裂解结构域序列”

<400> 35

Asp Glu Val Asp Pro

1 5

<210> 36

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

半胱天冬酶-3裂解结构域序列”

<400> 36

Lys Gly Ser Gly Asp Val Glu Gly

1 5

<210> 37

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

白介素1β转化酶裂解结构域序列”

<400> 37

Gly Trp Glu His Asp Gly

1 5

<210> 38

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

肠激酶裂解结构域序列”

<400> 38

Glu Asp Asp Asp Asp Lys Ala

1 5

<210> 39

<211> 9

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

FAP裂解结构域序列”

<400> 39

Lys Gln Glu Gln Asn Pro Gly Ser Thr

1 5

<210> 40

<211> 6

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

激肽释放酶2裂解结构域序列”

<400> 40

Gly Lys Ala Phe Arg Arg

1 5

<210> 41

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

纤溶酶裂解结构域序列”

<400> 41

Asp Ala Phe Lys

1

<210> 42

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

纤溶酶裂解结构域序列”

<400> 42

Asp Val Leu Lys

1

<210> 43

<211> 4

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

纤溶酶裂解结构域序列”

<400> 43

Asp Ala Phe Lys

1

<210> 44

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

TOP裂解结构域序列”

<400> 44

Ala Leu Leu Leu Ala Leu Leu

1 5

<210> 45

<211> 652

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 45

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

130 135 140

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

145 150 155 160

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

165 170 175

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

180 185 190

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

195 200 205

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

210 215 220

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

225 230 235 240

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

245 250 255

Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

260 265 270

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

275 280 285

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

290 295 300

Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

305 310 315 320

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu

325 330 335

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

340 345 350

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

355 360 365

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

405 410 415

Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser

420 425 430

Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro

435 440 445

Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr

450 455 460

Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn

465 470 475 480

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

485 490 495

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp

500 505 510

Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly

515 520 525

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

530 535 540

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

545 550 555 560

Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln

565 570 575

Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe

580 585 590

Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr

595 600 605

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

610 615 620

Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly

625 630 635 640

Thr Lys Val Glu Ile Lys His His His His His His

645 650

<210> 46

<211> 652

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 46

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

130 135 140

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser

145 150 155 160

Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

165 170 175

Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val

180 185 190

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

195 200 205

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

210 215 220

Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr

225 230 235 240

Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

245 250 255

Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

260 265 270

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln

275 280 285

Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala

290 295 300

Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro

305 310 315 320

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

325 330 335

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr

340 345 350

Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

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 Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser

385 390 395 400

Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly

405 410 415

Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser

420 425 430

Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys

435 440 445

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu

450 455 460

Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr

465 470 475 480

Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val

485 490 495

Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly

500 505 510

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

515 520 525

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

530 535 540

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

545 550 555 560

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

565 570 575

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

580 585 590

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

595 600 605

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

610 615 620

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

625 630 635 640

Ile Ile Ser Thr Leu Thr His His His His His His

645 650

<210> 47

<211> 553

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 47

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn

145 150 155 160

Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr

210 215 220

Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly

260 265 270

Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser

275 280 285

Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp

290 295 300

Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu

305 310 315 320

Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu

325 330 335

Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu

340 345 350

Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp

355 360 365

Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu

370 375 380

Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu

385 390 395 400

Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu

405 410 415

Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser

420 425 430

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

435 440 445

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

450 455 460

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

465 470 475 480

Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val

485 490 495

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

500 505 510

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

515 520 525

Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr

530 535 540

Val Ser Ser His His His His His His

545 550

<210> 48

<211> 553

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 48

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn

145 150 155 160

Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr

210 215 220

Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln

260 265 270

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg

275 280 285

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser

290 295 300

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile

305 310 315 320

Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg

325 330 335

Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met

340 345 350

Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly

355 360 365

Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser

370 375 380

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser

385 390 395 400

Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro

405 410 415

Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu

420 425 430

Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro

435 440 445

Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala

450 455 460

Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu

465 470 475 480

Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro

485 490 495

Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly

500 505 510

Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile

515 520 525

Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser

530 535 540

Thr Leu Thr His His His His His His

545 550

<210> 49

<211> 553

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 49

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

145 150 155 160

Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr

165 170 175

Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly

180 185 190

Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr

195 200 205

Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

210 215 220

Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala

225 230 235 240

Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly

245 250 255

Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

260 265 270

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

275 280 285

Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

290 295 300

Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

305 310 315 320

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr

325 330 335

Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly

340 345 350

Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro

355 360 365

Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

370 375 380

Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

385 390 395 400

Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly

405 410 415

Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

420 425 430

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

435 440 445

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys

450 455 460

Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro

465 470 475 480

Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser

485 490 495

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

500 505 510

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys

515 520 525

Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val

530 535 540

Glu Ile Lys His His His His His His

545 550

<210> 50

<211> 682

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 50

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

130 135 140

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

145 150 155 160

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

165 170 175

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

180 185 190

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

195 200 205

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

210 215 220

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

225 230 235 240

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

245 250 255

Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

260 265 270

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

275 280 285

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

290 295 300

Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

305 310 315 320

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu

325 330 335

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

340 345 350

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

355 360 365

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

405 410 415

Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

420 425 430

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

435 440 445

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

450 455 460

Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys

465 470 475 480

Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser

485 490 495

Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

500 505 510

Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

515 520 525

Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp

530 535 540

Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

545 550 555 560

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

565 570 575

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

580 585 590

Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys

595 600 605

Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr

610 615 620

Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

625 630 635 640

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

645 650 655

Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys

660 665 670

Val Glu Ile Lys His His His His His His

675 680

<210> 51

<211> 667

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 51

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

130 135 140

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

145 150 155 160

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

165 170 175

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

180 185 190

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

195 200 205

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

210 215 220

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

225 230 235 240

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

245 250 255

Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

260 265 270

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

275 280 285

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

290 295 300

Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

305 310 315 320

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu

325 330 335

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

340 345 350

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

355 360 365

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

405 410 415

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

420 425 430

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

435 440 445

Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly

450 455 460

Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr

465 470 475 480

Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

485 490 495

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

500 505 510

Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr

515 520 525

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly Pro Gly

530 535 540

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile Gln Met Thr Gln

545 550 555 560

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

565 570 575

Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln

580 585 590

Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg

595 600 605

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

610 615 620

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

625 630 635 640

Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr

645 650 655

Lys Val Glu Ile Lys His His His His His His

660 665

<210> 52

<211> 682

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 52

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

180 185 190

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

195 200 205

Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

210 215 220

Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr

225 230 235 240

Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu

245 250 255

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

260 265 270

Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly

275 280 285

Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

305 310 315 320

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser

325 330 335

Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys

340 345 350

Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val

355 360 365

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

370 375 380

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

385 390 395 400

Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile

405 410 415

Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

420 425 430

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

435 440 445

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

450 455 460

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

465 470 475 480

Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val

485 490 495

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

500 505 510

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

515 520 525

Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr

530 535 540

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

545 550 555 560

Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala

565 570 575

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser

580 585 590

Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu

595 600 605

Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser

610 615 620

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val

625 630 635 640

Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr

645 650 655

Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val

660 665 670

Thr Val Ser Ser His His His His His His

675 680

<210> 53

<211> 393

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 53

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

145 150 155 160

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr

165 170 175

Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly

180 185 190

Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro

195 200 205

Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn

210 215 220

Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

225 230 235 240

Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly

245 250 255

Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

260 265 270

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro

275 280 285

Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys

290 295 300

Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro

305 310 315 320

Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser

325 330 335

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

340 345 350

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys

355 360 365

Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val

370 375 380

Glu Ile Lys His His His His His His

385 390

<210> 54

<211> 423

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 54

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

180 185 190

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

195 200 205

Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

210 215 220

Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr

225 230 235 240

Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu

245 250 255

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

260 265 270

Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly

275 280 285

Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

305 310 315 320

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser

325 330 335

Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys

340 345 350

Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val

355 360 365

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

370 375 380

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

385 390 395 400

Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile

405 410 415

Lys His His His His His His

420

<210> 55

<211> 682

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 55

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

165 170 175

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

180 185 190

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

195 200 205

Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

210 215 220

Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr

225 230 235 240

Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu

245 250 255

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

260 265 270

Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly

275 280 285

Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

305 310 315 320

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser

325 330 335

Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys

340 345 350

Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val

355 360 365

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

370 375 380

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

385 390 395 400

Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile

405 410 415

Lys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser

420 425 430

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

435 440 445

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

450 455 460

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

465 470 475 480

Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val

485 490 495

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

500 505 510

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

515 520 525

Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr

530 535 540

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

545 550 555 560

Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala

565 570 575

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser

580 585 590

Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu

595 600 605

Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser

610 615 620

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val

625 630 635 640

Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr

645 650 655

Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val

660 665 670

Thr Val Ser Ser His His His His His His

675 680

<210> 56

<211> 682

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 56

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly

1 5 10 15

Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Ser

20 25 30

Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val

35 40 45

Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn

85 90 95

Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly

115 120 125

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

130 135 140

Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser

145 150 155 160

Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

165 170 175

Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val

180 185 190

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

195 200 205

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

210 215 220

Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr

225 230 235 240

Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

245 250 255

Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

260 265 270

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln

275 280 285

Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala

290 295 300

Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro

305 310 315 320

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

325 330 335

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr

340 345 350

Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

355 360 365

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

370 375 380

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly

385 390 395 400

Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln

405 410 415

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg

420 425 430

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser

435 440 445

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile

450 455 460

Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg

465 470 475 480

Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met

485 490 495

Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly

500 505 510

Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser

515 520 525

Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala

530 535 540

Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu

545 550 555 560

Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn

565 570 575

Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys

580 585 590

Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro

595 600 605

Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg

610 615 620

Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys

625 630 635 640

Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr

645 650 655

Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile

660 665 670

Ser Thr Leu Thr His His His His His His

675 680

<210> 57

<211> 393

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 57

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn

145 150 155 160

Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr

210 215 220

Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser

225 230 235 240

Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro

245 250 255

Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu

260 265 270

Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro

275 280 285

Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala

290 295 300

Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu

305 310 315 320

Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro

325 330 335

Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly

340 345 350

Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile

355 360 365

Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser

370 375 380

Thr Leu Thr His His His His His His

385 390

<210> 58

<211> 423

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 58

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser

130 135 140

Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn

145 150 155 160

Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

165 170 175

Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr

210 215 220

Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

245 250 255

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly

260 265 270

Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser

275 280 285

Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp

290 295 300

Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu

305 310 315 320

Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu

325 330 335

Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu

340 345 350

Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp

355 360 365

Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu

370 375 380

Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu

385 390 395 400

Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu

405 410 415

Thr His His His His His His

420

<210> 59

<211> 669

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 59

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

130 135 140

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

145 150 155 160

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

165 170 175

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

180 185 190

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

195 200 205

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

210 215 220

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

225 230 235 240

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

245 250 255

Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

260 265 270

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

275 280 285

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

290 295 300

Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

305 310 315 320

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu

325 330 335

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

340 345 350

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

355 360 365

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu

405 410 415

Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val

420 425 430

Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp

435 440 445

Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn

450 455 460

Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala

465 470 475 480

Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser

485 490 495

Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg

500 505 510

Gly Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr

515 520 525

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

530 535 540

Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala

545 550 555 560

Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser

565 570 575

Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro

580 585 590

Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser

595 600 605

Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

610 615 620

Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys

625 630 635 640

Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu

645 650 655

Glu Ile Lys His His His His His His Glu Pro Glu Ala

660 665

<210> 60

<211> 669

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 60

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp

20 25 30

Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val

35 40 45

Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn

85 90 95

Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val

100 105 110

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu

130 135 140

His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr

145 150 155 160

Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro

165 170 175

Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu

180 185 190

Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His

195 200 205

Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu

210 215 220

Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr

225 230 235 240

Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser

245 250 255

Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

260 265 270

Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

275 280 285

Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

290 295 300

Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys

305 310 315 320

Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu

325 330 335

Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

340 345 350

Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr

355 360 365

Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu

405 410 415

Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr

420 425 430

Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr

435 440 445

Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

450 455 460

Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly

465 470 475 480

Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val Glu Glu

485 490 495

Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr

500 505 510

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser

515 520 525

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln

530 535 540

Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys

545 550 555 560

Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys

565 570 575

Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly

580 585 590

Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu

595 600 605

Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu

610 615 620

Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp

625 630 635 640

Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr

645 650 655

Val Ser Ser His His His His His His Glu Pro Glu Ala

660 665

<210> 61

<211> 689

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 61

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln

165 170 175

Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys

180 185 190

Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu

195 200 205

Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile

210 215 220

Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys

225 230 235 240

Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu

245 250 255

Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp

260 265 270

Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr

275 280 285

Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

290 295 300

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

305 310 315 320

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln

325 330 335

Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys

340 345 350

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu

355 360 365

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

370 375 380

Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr

385 390 395 400

Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys

405 410 415

Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

420 425 430

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

435 440 445

Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

450 455 460

Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

465 470 475 480

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala

485 490 495

Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr

500 505 510

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val

515 520 525

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr

530 535 540

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

545 550 555 560

Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu

565 570 575

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg

580 585 590

Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys

595 600 605

Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr

610 615 620

Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

625 630 635 640

Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly

645 650 655

Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly

660 665 670

Thr Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu

675 680 685

Ala

<210> 62

<211> 689

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 62

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 Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val

165 170 175

Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala

180 185 190

Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser

195 200 205

Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu

210 215 220

Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser

225 230 235 240

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val Glu

245 250 255

Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro

260 265 270

Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly

275 280 285

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln

290 295 300

Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser

305 310 315 320

Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val

325 330 335

Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro

340 345 350

Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr

355 360 365

Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser

370 375 380

Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly

385 390 395 400

Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val

405 410 415

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

420 425 430

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

435 440 445

Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

450 455 460

Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

465 470 475 480

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala

485 490 495

Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr

500 505 510

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val

515 520 525

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr

530 535 540

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

545 550 555 560

Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu

565 570 575

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg

580 585 590

Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys

595 600 605

Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr

610 615 620

Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

625 630 635 640

Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly

645 650 655

Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly

660 665 670

Thr Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu

675 680 685

Ala

<210> 63

<211> 272

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

IL2Ra序列”

<400> 63

Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val

1 5 10 15

Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro

20 25 30

His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn

35 40 45

Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr

50 55 60

Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys

65 70 75 80

Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro

85 90 95

Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro

100 105 110

Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro

115 120 125

Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val

130 135 140

Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His

145 150 155 160

Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg

165 170 175

Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln

180 185 190

Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu

195 200 205

Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr

210 215 220

Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln

225 230 235 240

Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu

245 250 255

Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile

260 265 270

<210> 64

<211> 551

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

IL2Rb序列”

<400> 64

Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu

1 5 10 15

Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser

20 25 30

Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp

35 40 45

Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp

50 55 60

Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser

65 70 75 80

Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln

85 90 95

Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu

100 105 110

Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu

115 120 125

Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu

130 135 140

Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr

145 150 155 160

Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His

165 170 175

Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp

180 185 190

Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val

195 200 205

Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser

210 215 220

Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr

225 230 235 240

Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly

245 250 255

Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys Arg Asn Thr Gly Pro

260 265 270

Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe

275 280 285

Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu

290 295 300

Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro

305 310 315 320

Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu

325 330 335

Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn

340 345 350

His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His

355 360 365

Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln Val Tyr Phe Thr Tyr

370 375 380

Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly Val Ala Gly Ala Pro

385 390 395 400

Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu Ser Gly Glu Asp Asp

405 410 415

Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu Leu Leu Phe Ser Pro

420 425 430

Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr Ala Pro Gly Gly Ser

435 440 445

Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu Gln Glu Arg Val Pro

450 455 460

Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro Thr Pro Gly Val Pro

465 470 475 480

Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu Val Leu Arg Glu Ala

485 490 495

Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu Gly Val Ser Phe Pro

500 505 510

Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg Ala Leu Asn Ala Arg

515 520 525

Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly

530 535 540

Gln Asp Pro Thr His Leu Val

545 550

<210> 65

<211> 369

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

IL2Rg序列”

<400> 65

Met Leu Lys Pro Ser Leu Pro Phe Thr Ser Leu Leu Phe Leu Gln Leu

1 5 10 15

Pro Leu Leu Gly Val Gly Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly

20 25 30

Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp

35 40 45

Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val

50 55 60

Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro

65 70 75 80

Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn

85 90 95

Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr

100 105 110

Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe

115 120 125

Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln

130 135 140

Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu

145 150 155 160

Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn

165 170 175

Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp

180 185 190

Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe

195 200 205

Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg

210 215 220

Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp

225 230 235 240

Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe

245 250 255

Leu Phe Ala Leu Glu Ala Val Val Ile Ser Val Gly Ser Met Gly Leu

260 265 270

Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro

275 280 285

Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His

290 295 300

Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser

305 310 315 320

Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro

325 330 335

Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn

340 345 350

Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu

355 360 365

Thr

<210> 66

<211> 276

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 66

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr

65 70 75 80

Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

85 90 95

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Val Gly Ala Phe Arg Pro Tyr

115 120 125

Arg Lys His Glu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser

145 150 155 160

Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val

165 170 175

Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp

180 185 190

Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys

195 200 205

Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser

210 215 220

Gly Asn Thr Ala Ser Leu Thr Thr Thr Gly Ala Gln Ala Glu Asp Glu

225 230 235 240

Ala Asp Tyr Tyr Cys Asn Ser Ser Pro Phe Glu His Asn Leu Val Val

245 250 255

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His

260 265 270

Glu Pro Glu Ala

275

<210> 67

<211> 674

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 67

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

210 215 220

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

225 230 235 240

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

245 250 255

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

260 265 270

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

290 295 300

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

305 310 315 320

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

325 330 335

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

340 345 350

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

355 360 365

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

370 375 380

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

385 390 395 400

Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

420 425 430

Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala

435 440 445

Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala

450 455 460

Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg

465 470 475 480

Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

485 490 495

Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

500 505 510

Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val

515 520 525

Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

530 535 540

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu

545 550 555 560

Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys

565 570 575

Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg

580 585 590

Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly

595 600 605

Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

610 615 620

Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys

625 630 635 640

Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp

645 650 655

Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His

660 665 670

His His

<210> 68

<211> 674

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 68

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly

130 135 140

Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

165 170 175

Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro

180 185 190

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp

195 200 205

Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

210 215 220

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

225 230 235 240

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser

245 250 255

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro

260 265 270

Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser

275 280 285

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

290 295 300

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln

305 310 315 320

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser

325 330 335

Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg

340 345 350

Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala

355 360 365

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala

370 375 380

Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly

385 390 395 400

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln

405 410 415

Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val

420 425 430

Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp

435 440 445

Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala

450 455 460

Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser

465 470 475 480

Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe

485 490 495

Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly

500 505 510

Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro Gly Pro Ala Gly

515 520 525

Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

530 535 540

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

545 550 555 560

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

565 570 575

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

580 585 590

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

595 600 605

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

610 615 620

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

625 630 635 640

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

645 650 655

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His

660 665 670

His His

<210> 69

<211> 425

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 69

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile

20 25 30

Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu

35 40 45

Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu

50 55 60

Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln

65 70 75 80

Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr

85 90 95

Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser

100 105 110

Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu

115 120 125

Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val

130 135 140

Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu

145 150 155 160

His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr

165 170 175

Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser

180 185 190

Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro

195 200 205

Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln

210 215 220

Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr

225 230 235 240

Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

245 250 255

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser

260 265 270

Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro

275 280 285

Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu

290 295 300

Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro

305 310 315 320

Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala

325 330 335

Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu

340 345 350

Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro

355 360 365

Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly

370 375 380

Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile

385 390 395 400

Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser

405 410 415

Thr Leu Thr His His His His His His

420 425

<210> 70

<211> 425

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 70

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro

195 200 205

Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr

210 215 220

Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly

225 230 235 240

Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp

245 250 255

Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln

260 265 270

Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met

275 280 285

Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys

290 295 300

Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His

305 310 315 320

Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg

325 330 335

Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly

340 345 350

Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu

355 360 365

Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly

370 375 380

Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln

385 390 395 400

Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr

405 410 415

Glu Tyr Gln His His His His His His

420 425

<210> 71

<211> 555

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 71

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

65 70 75 80

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

85 90 95

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

130 135 140

Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro

145 150 155 160

Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr

165 170 175

Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly

180 185 190

Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp

195 200 205

Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln

210 215 220

Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met

225 230 235 240

Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys

245 250 255

Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His

260 265 270

Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg

275 280 285

Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly

290 295 300

Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu

305 310 315 320

Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly

325 330 335

Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln

340 345 350

Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr

355 360 365

Glu Tyr Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

370 375 380

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

385 390 395 400

Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser

405 410 415

Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His

420 425 430

Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys

435 440 445

Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys

450 455 460

Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys

465 470 475 480

Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu

485 490 495

Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu

500 505 510

Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala

515 520 525

Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile

530 535 540

Ile Ser Thr Leu Thr His His His His His His

545 550 555

<210> 72

<211> 555

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 72

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro

195 200 205

Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr

210 215 220

Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly

225 230 235 240

Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp

245 250 255

Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln

260 265 270

Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met

275 280 285

Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys

290 295 300

Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His

305 310 315 320

Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg

325 330 335

Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly

340 345 350

Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu

355 360 365

Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly

370 375 380

Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln

385 390 395 400

Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr

405 410 415

Glu Tyr Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

435 440 445

Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

450 455 460

Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

465 470 475 480

Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu

485 490 495

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr

500 505 510

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr

515 520 525

Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu

530 535 540

Val Thr Val Ser Ser His His His His His His

545 550 555

<210> 73

<211> 555

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 73

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro

195 200 205

Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr

210 215 220

Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly

225 230 235 240

Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp

245 250 255

Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln

260 265 270

Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met

275 280 285

Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys

290 295 300

Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His

305 310 315 320

Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg

325 330 335

Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly

340 345 350

Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu

355 360 365

Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly

370 375 380

Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln

385 390 395 400

Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr

405 410 415

Glu Tyr Gln Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro

420 425 430

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

435 440 445

Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

450 455 460

Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

465 470 475 480

Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu

485 490 495

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr

500 505 510

Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr

515 520 525

Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu

530 535 540

Val Thr Val Ser Ser His His His His His His

545 550 555

<210> 74

<211> 575

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 74

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

65 70 75 80

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

85 90 95

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala

130 135 140

Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly

145 150 155 160

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

165 170 175

Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala

180 185 190

Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr

195 200 205

Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp

210 215 220

Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

225 230 235 240

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu

245 250 255

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly

260 265 270

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

275 280 285

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

290 295 300

Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr

305 310 315 320

Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser

325 330 335

Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

340 345 350

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

355 360 365

Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly

370 375 380

Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly

385 390 395 400

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

405 410 415

Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

420 425 430

Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu

435 440 445

Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile

450 455 460

Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe

465 470 475 480

Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu

485 490 495

Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys

500 505 510

Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile

515 520 525

Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala

530 535 540

Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe

545 550 555 560

Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His His

565 570 575

<210> 75

<211> 704

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 75

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

195 200 205

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

210 215 220

Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala

225 230 235 240

Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr

245 250 255

Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp

260 265 270

Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

275 280 285

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu

290 295 300

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly

305 310 315 320

Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile Gln Met

325 330 335

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

340 345 350

Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr

355 360 365

Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser

370 375 380

Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

385 390 395 400

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

405 410 415

Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly

420 425 430

Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly

435 440 445

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

450 455 460

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

465 470 475 480

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

485 490 495

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

500 505 510

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

515 520 525

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

530 535 540

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

545 550 555 560

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

565 570 575

Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

580 585 590

Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

595 600 605

Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala

610 615 620

Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr

625 630 635 640

Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

645 650 655

Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu

660 665 670

Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp

675 680 685

Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His His His

690 695 700

<210> 76

<211> 689

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 76

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu

435 440 445

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu

450 455 460

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp

465 470 475 480

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp

485 490 495

Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr

500 505 510

Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser

515 520 525

Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn

530 535 540

Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser

545 550 555 560

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

565 570 575

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

580 585 590

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

595 600 605

Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile

610 615 620

Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

625 630 635 640

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

645 650 655

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr

660 665 670

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His

675 680 685

His

<210> 77

<211> 545

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 77

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

210 215 220

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

225 230 235 240

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

245 250 255

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

260 265 270

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

275 280 285

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

290 295 300

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

305 310 315 320

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

325 330 335

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

340 345 350

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

355 360 365

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

370 375 380

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

385 390 395 400

Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

420 425 430

Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala

435 440 445

Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala

450 455 460

Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg

465 470 475 480

Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

485 490 495

Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

500 505 510

Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val

515 520 525

Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His

530 535 540

His

545

<210> 78

<211> 575

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 78

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

195 200 205

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

210 215 220

Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala

225 230 235 240

Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr

245 250 255

Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp

260 265 270

Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

275 280 285

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu

290 295 300

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly

305 310 315 320

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

325 330 335

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

340 345 350

Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr

355 360 365

Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser

370 375 380

Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

385 390 395 400

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

405 410 415

Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly

420 425 430

Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly

435 440 445

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

450 455 460

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

465 470 475 480

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

485 490 495

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

500 505 510

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

515 520 525

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

530 535 540

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

545 550 555 560

Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His His

565 570 575

<210> 79

<211> 421

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 79

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

65 70 75 80

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

85 90 95

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

115 120 125

Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala

130 135 140

Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys

145 150 155 160

Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile

165 170 175

Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu

180 185 190

Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu

195 200 205

Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu

210 215 220

Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn

225 230 235 240

Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met

245 250 255

Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg

260 265 270

Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly

275 280 285

Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu

290 295 300

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

305 310 315 320

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp

325 330 335

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

340 345 350

Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe

355 360 365

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

370 375 380

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

385 390 395 400

Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His

405 410 415

His His His His His

420

<210> 80

<211> 806

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 80

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser

130 135 140

Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly

145 150 155 160

Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala

165 170 175

Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala

180 185 190

Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg

195 200 205

Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

210 215 220

Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

225 230 235 240

Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val

245 250 255

Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly

260 265 270

Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gln Val Gln Leu Gln

275 280 285

Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser

290 295 300

Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr

305 310 315 320

Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg

325 330 335

Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile

340 345 350

Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu

355 360 365

Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr

370 375 380

Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly

385 390 395 400

Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln

405 410 415

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg

420 425 430

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala

435 440 445

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile

450 455 460

Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe

465 470 475 480

Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn

485 490 495

Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser

500 505 510

Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val

515 520 525

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

530 535 540

Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val

545 550 555 560

Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr

565 570 575

Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu

580 585 590

Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser

595 600 605

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln

610 615 620

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro

625 630 635 640

Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro

645 650 655

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser

660 665 670

Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu

675 680 685

Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr

690 695 700

Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu

705 710 715 720

Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val

725 730 735

Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu

740 745 750

Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr

755 760 765

Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe

770 775 780

Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr

785 790 795 800

His His His His His His

805

<210> 81

<211> 676

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 81

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser

130 135 140

Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly

145 150 155 160

Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala

165 170 175

Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala

180 185 190

Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg

195 200 205

Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

210 215 220

Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

225 230 235 240

Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val

245 250 255

Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly

260 265 270

Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val

275 280 285

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

290 295 300

Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val

305 310 315 320

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser

325 330 335

Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile

340 345 350

Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu

355 360 365

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp

370 375 380

Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

385 390 395 400

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

405 410 415

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

420 425 430

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val

435 440 445

Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr

450 455 460

Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

465 470 475 480

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

485 490 495

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr

500 505 510

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro Gly Pro

515 520 525

Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr

530 535 540

Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met

545 550 555 560

Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met

565 570 575

Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His

580 585 590

Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn

595 600 605

Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser

610 615 620

Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe

625 630 635 640

Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn

645 650 655

Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His

660 665 670

His His His His

675

<210> 82

<211> 421

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 82

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser

130 135 140

Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly

145 150 155 160

Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala

165 170 175

Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala

180 185 190

Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg

195 200 205

Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

210 215 220

Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro

225 230 235 240

Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val

245 250 255

Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly

260 265 270

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser

275 280 285

Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln

290 295 300

Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg

305 310 315 320

Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys

325 330 335

His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu

340 345 350

Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile

355 360 365

Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr

370 375 380

Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu

385 390 395 400

Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His

405 410 415

His His His His His

420

<210> 83

<211> 420

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 83

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly

130 135 140

Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His

405 410 415

His His His His

420

<210> 84

<211> 550

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 84

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

165 170 175

Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro

180 185 190

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp

195 200 205

Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

210 215 220

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

225 230 235 240

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser

245 250 255

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro

260 265 270

Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr

275 280 285

Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met

290 295 300

Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met

305 310 315 320

Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His

325 330 335

Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn

340 345 350

Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser

355 360 365

Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe

370 375 380

Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn

385 390 395 400

Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly

405 410 415

Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln

420 425 430

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg

435 440 445

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser

450 455 460

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile

465 470 475 480

Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg

485 490 495

Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met

500 505 510

Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly

515 520 525

Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser

530 535 540

His His His His His His

545 550

<210> 85

<211> 420

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 85

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His

405 410 415

His His His His

420

<210> 86

<211> 290

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 86

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His

275 280 285

His His

290

<210> 87

<211> 291

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 87

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His

275 280 285

His His His

290

<210> 88

<211> 689

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 88

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly

130 135 140

Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu

435 440 445

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu

450 455 460

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp

465 470 475 480

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp

485 490 495

Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr

500 505 510

Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser

515 520 525

Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn

530 535 540

Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser

545 550 555 560

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

565 570 575

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

580 585 590

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

595 600 605

Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile

610 615 620

Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

625 630 635 640

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

645 650 655

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr

660 665 670

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His

675 680 685

His

<210> 89

<211> 704

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 89

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

180 185 190

Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

195 200 205

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

210 215 220

Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala

225 230 235 240

Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr

245 250 255

Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp

260 265 270

Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu

275 280 285

Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu

290 295 300

Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly

305 310 315 320

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

325 330 335

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

340 345 350

Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr

355 360 365

Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser

370 375 380

Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

385 390 395 400

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

405 410 415

Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly

420 425 430

Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly

435 440 445

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

450 455 460

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

465 470 475 480

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

485 490 495

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

500 505 510

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

515 520 525

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

530 535 540

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

545 550 555 560

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

565 570 575

Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

580 585 590

Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala

595 600 605

Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr

610 615 620

Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser

625 630 635 640

Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

645 650 655

Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu

660 665 670

Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp

675 680 685

Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His

690 695 700

<210> 90

<211> 674

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 90

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly

50 55 60

Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr

100 105 110

Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ala Pro Thr Ser Ser Ser Thr Lys

130 135 140

Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile

145 150 155 160

Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu

165 170 175

Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu

180 185 190

Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu

195 200 205

Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn

210 215 220

Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met

225 230 235 240

Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg

245 250 255

Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly

260 265 270

Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu

275 280 285

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

290 295 300

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp

305 310 315 320

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

325 330 335

Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe

340 345 350

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

355 360 365

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

370 375 380

Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

385 390 395 400

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln

420 425 430

Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg

435 440 445

Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala

450 455 460

Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile

465 470 475 480

Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe

485 490 495

Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn

500 505 510

Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser

515 520 525

Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val

530 535 540

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

545 550 555 560

Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val

565 570 575

Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr

580 585 590

Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu

595 600 605

Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser

610 615 620

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln

625 630 635 640

Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro

645 650 655

Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His

660 665 670

His His

<210> 91

<211> 704

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 91

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr

245 250 255

Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

260 265 270

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

275 280 285

Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro

290 295 300

Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu

305 310 315 320

Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn

325 330 335

Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met

340 345 350

Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu

355 360 365

Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe

370 375 380

His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu

385 390 395 400

Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu

405 410 415

Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln

420 425 430

Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met

435 440 445

Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

450 455 460

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

465 470 475 480

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

485 490 495

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

500 505 510

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

515 520 525

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

530 535 540

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

545 550 555 560

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

565 570 575

Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

580 585 590

Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala

595 600 605

Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr

610 615 620

Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser

625 630 635 640

Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

645 650 655

Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu

660 665 670

Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp

675 680 685

Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His

690 695 700

<210> 92

<211> 704

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 92

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly

50 55 60

Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr

100 105 110

Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

145 150 155 160

Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser

165 170 175

Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro

180 185 190

Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp

195 200 205

Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

210 215 220

Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu

225 230 235 240

Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser

245 250 255

Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro

260 265 270

Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser

275 280 285

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

290 295 300

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln

305 310 315 320

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser

325 330 335

Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg

340 345 350

Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala

355 360 365

Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala

370 375 380

Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly

385 390 395 400

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln

405 410 415

Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val

420 425 430

Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp

435 440 445

Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala

450 455 460

Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser

465 470 475 480

Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe

485 490 495

Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly

500 505 510

Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly

515 520 525

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

530 535 540

Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

545 550 555 560

Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln

565 570 575

Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly

580 585 590

Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys

595 600 605

Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu

610 615 620

Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser

625 630 635 640

Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val

645 650 655

Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr

660 665 670

Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr

675 680 685

Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His His

690 695 700

<210> 93

<211> 689

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 93

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr

245 250 255

Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

260 265 270

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

275 280 285

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

290 295 300

Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

305 310 315 320

Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

325 330 335

Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala

340 345 350

Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr

355 360 365

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val

370 375 380

Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr

385 390 395 400

Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys

405 410 415

Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln

420 425 430

Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly

435 440 445

Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys

450 455 460

Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu

465 470 475 480

Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser

485 490 495

Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val

500 505 510

Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr

515 520 525

Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr

530 535 540

Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly

545 550 555 560

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser

565 570 575

Gly Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala

580 585 590

Ala Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln

595 600 605

Thr Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly

610 615 620

Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

625 630 635 640

Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro

645 650 655

Glu Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr

660 665 670

Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His

675 680 685

His

<210> 94

<211> 700

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 94

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Arg Gly Glu Thr Gly

290 295 300

Pro Ala Ala Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

305 310 315 320

Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

325 330 335

Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly

340 345 350

Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr

355 360 365

Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

370 375 380

Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp

385 390 395 400

Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser

405 410 415

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

420 425 430

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

435 440 445

Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly

450 455 460

Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser

465 470 475 480

Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro

485 490 495

Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr

500 505 510

Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn

515 520 525

Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

530 535 540

Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp

545 550 555 560

Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly

565 570 575

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

580 585 590

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

595 600 605

Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln

610 615 620

Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe

625 630 635 640

Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr

645 650 655

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

660 665 670

Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly

675 680 685

Thr Lys Val Glu Ile Lys His His His His His His

690 695 700

<210> 95

<211> 276

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 95

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr

65 70 75 80

Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

85 90 95

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

100 105 110

Thr Ala Val Tyr Tyr Cys Ala Arg Gly Val Gly Ala Phe Arg Pro Tyr

115 120 125

Arg Lys His Glu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser

145 150 155 160

Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val

165 170 175

Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp

180 185 190

Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys

195 200 205

Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser

210 215 220

Gly Asn Thr Ala Ser Leu Thr Thr Thr Gly Ala Gln Ala Glu Asp Glu

225 230 235 240

Ala Asp Tyr Tyr Cys Asn Ser Ser Pro Phe Glu His Asn Leu Val Val

245 250 255

Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His

260 265 270

Glu Pro Glu Ala

275

<210> 96

<211> 279

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 96

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Glu

20 25 30

Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly

35 40 45

Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly

50 55 60

Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr

65 70 75 80

Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys

85 90 95

Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp

100 105 110

Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala

115 120 125

Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

145 150 155 160

Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg

165 170 175

Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp

180 185 190

Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

195 200 205

Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe

210 215 220

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val

225 230 235 240

Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp

245 250 255

Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys His His His

260 265 270

His His His Glu Pro Glu Ala

275

<210> 97

<211> 279

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 97

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Glu

20 25 30

Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly

35 40 45

Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly

50 55 60

Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr

65 70 75 80

Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys

85 90 95

Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp

100 105 110

Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala

115 120 125

Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ser

130 135 140

Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile

145 150 155 160

Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg

165 170 175

Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp

180 185 190

Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

195 200 205

Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe

210 215 220

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val

225 230 235 240

Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp

245 250 255

Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys His His His

260 265 270

His His His Glu Pro Glu Ala

275

<210> 98

<211> 279

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 98

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser

20 25 30

Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser

35 40 45

Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln

50 55 60

Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu

65 70 75 80

Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

85 90 95

Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr

100 105 110

Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr

115 120 125

Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val

145 150 155 160

Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala

165 170 175

Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr

195 200 205

Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser

210 215 220

Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala

225 230 235 240

Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe

245 250 255

Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser His His His

260 265 270

His His His Glu Pro Glu Ala

275

<210> 99

<211> 279

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 99

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser

20 25 30

Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser

35 40 45

Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln

50 55 60

Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu

65 70 75 80

Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

85 90 95

Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr

100 105 110

Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr

115 120 125

Lys Leu Glu Ile Lys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly

130 135 140

Leu Pro Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val

145 150 155 160

Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala

165 170 175

Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly

180 185 190

Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr

195 200 205

Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser

210 215 220

Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala

225 230 235 240

Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe

245 250 255

Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser His His His

260 265 270

His His His Glu Pro Glu Ala

275

<210> 100

<211> 295

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 100

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His

275 280 285

His His His Glu Pro Glu Ala

290 295

<210> 101

<211> 765

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 101

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu

165 170 175

Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu

180 185 190

Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp

195 200 205

His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val

210 215 220

Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe

225 230 235 240

Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu

245 250 255

Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe

260 265 270

Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro

275 280 285

Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe

290 295 300

Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr

305 310 315 320

Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr

325 330 335

Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu

340 345 350

Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu

355 360 365

Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp

370 375 380

Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu

385 390 395 400

Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys

405 410 415

His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys

420 425 430

Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys

435 440 445

Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu

450 455 460

Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val

465 470 475 480

Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe

485 490 495

Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser

500 505 510

Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu

515 520 525

Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe

530 535 540

Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln

545 550 555 560

Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala

565 570 575

Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr

580 585 590

Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys

595 600 605

Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser

610 615 620

Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser

625 630 635 640

Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro

645 650 655

Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe

660 665 670

Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu

675 680 685

Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys

690 695 700

His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp

705 710 715 720

Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr

725 730 735

Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala

740 745 750

Leu Gly Leu His His His His His His Glu Pro Glu Ala

755 760 765

<210> 102

<211> 765

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 102

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu

165 170 175

Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu

180 185 190

Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp

195 200 205

His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val

210 215 220

Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe

225 230 235 240

Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu

245 250 255

Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe

260 265 270

Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro

275 280 285

Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe

290 295 300

Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr

305 310 315 320

Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr

325 330 335

Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu

340 345 350

Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu

355 360 365

Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp

370 375 380

Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu

385 390 395 400

Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys

405 410 415

His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys

420 425 430

Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys

435 440 445

Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu

450 455 460

Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val

465 470 475 480

Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe

485 490 495

Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser

500 505 510

Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu

515 520 525

Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe

530 535 540

Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln

545 550 555 560

Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala

565 570 575

Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr

580 585 590

Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys

595 600 605

Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser

610 615 620

Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser

625 630 635 640

Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro

645 650 655

Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe

660 665 670

Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu

675 680 685

Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys

690 695 700

His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp

705 710 715 720

Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr

725 730 735

Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala

740 745 750

Leu Gly Leu His His His His His His Glu Pro Glu Ala

755 760 765

<210> 103

<211> 765

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 103

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ala His Lys Ser Glu

165 170 175

Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu

180 185 190

Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp

195 200 205

His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val

210 215 220

Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe

225 230 235 240

Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu

245 250 255

Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe

260 265 270

Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro

275 280 285

Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe

290 295 300

Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr

305 310 315 320

Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr

325 330 335

Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu

340 345 350

Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu

355 360 365

Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp

370 375 380

Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu

385 390 395 400

Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys

405 410 415

His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys

420 425 430

Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys

435 440 445

Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu

450 455 460

Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val

465 470 475 480

Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe

485 490 495

Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser

500 505 510

Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu

515 520 525

Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe

530 535 540

Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln

545 550 555 560

Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala

565 570 575

Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr

580 585 590

Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys

595 600 605

Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser

610 615 620

Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser

625 630 635 640

Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro

645 650 655

Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe

660 665 670

Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu

675 680 685

Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys

690 695 700

His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp

705 710 715 720

Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr

725 730 735

Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala

740 745 750

Leu Gly Leu His His His His His His Glu Pro Glu Ala

755 760 765

<210> 104

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 104

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

275 280 285

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly

305 310 315 320

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

325 330 335

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

340 345 350

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

355 360 365

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

370 375 380

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

385 390 395 400

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

405 410 415

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

420 425 430

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

435 440 445

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

450 455 460

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

465 470 475 480

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

485 490 495

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

500 505 510

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

515 520 525

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

530 535 540

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

545 550 555 560

Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly

565 570 575

Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

580 585 590

Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala

595 600 605

Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr

610 615 620

Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser

625 630 635 640

Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

645 650 655

Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu

660 665 670

Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp

675 680 685

Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 105

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 105

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly

50 55 60

Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr

100 105 110

Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

435 440 445

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

450 455 460

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

465 470 475 480

Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val

485 490 495

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser

500 505 510

Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile

515 520 525

Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu

530 535 540

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp

545 550 555 560

Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

565 570 575

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

580 585 590

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

595 600 605

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val

610 615 620

Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr

625 630 635 640

Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

645 650 655

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

660 665 670

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr

675 680 685

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 106

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 106

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly

50 55 60

Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr

100 105 110

Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly

130 135 140

Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

435 440 445

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

450 455 460

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

465 470 475 480

Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val

485 490 495

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser

500 505 510

Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile

515 520 525

Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu

530 535 540

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp

545 550 555 560

Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

565 570 575

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

580 585 590

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

595 600 605

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val

610 615 620

Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr

625 630 635 640

Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

645 650 655

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

660 665 670

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr

675 680 685

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 107

<211> 161

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 107

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His

145 150 155 160

His

<210> 108

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 108

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

275 280 285

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly

305 310 315 320

Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu

325 330 335

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

340 345 350

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

355 360 365

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

370 375 380

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

385 390 395 400

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

405 410 415

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

420 425 430

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

435 440 445

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

450 455 460

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

465 470 475 480

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

485 490 495

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

500 505 510

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

515 520 525

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

530 535 540

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

545 550 555 560

Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly

565 570 575

Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly

580 585 590

Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala

595 600 605

Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala

610 615 620

Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr

625 630 635 640

Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

645 650 655

Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu

660 665 670

Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp

675 680 685

Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 109

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 109

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

435 440 445

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

450 455 460

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

465 470 475 480

Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val

485 490 495

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser

500 505 510

Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile

515 520 525

Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu

530 535 540

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp

545 550 555 560

Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

565 570 575

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

580 585 590

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

595 600 605

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val

610 615 620

Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr

625 630 635 640

Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

645 650 655

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

660 665 670

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr

675 680 685

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 110

<211> 708

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 110

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys

115 120 125

Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly

130 135 140

Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys

145 150 155 160

Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu

165 170 175

Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr

180 185 190

Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln

195 200 205

Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala

210 215 220

Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile

225 230 235 240

Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys

245 250 255

Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp

260 265 270

Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro

275 280 285

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

290 295 300

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

305 310 315 320

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

325 330 335

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

340 345 350

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

355 360 365

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

370 375 380

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

385 390 395 400

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

405 410 415

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

420 425 430

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

435 440 445

Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val

450 455 460

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser

465 470 475 480

Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val

485 490 495

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser

500 505 510

Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile

515 520 525

Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu

530 535 540

Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp

545 550 555 560

Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

565 570 575

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

580 585 590

Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp

595 600 605

Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val

610 615 620

Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr

625 630 635 640

Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser

645 650 655

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu

660 665 670

Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr

675 680 685

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His

690 695 700

Glu Pro Glu Ala

705

<210> 111

<211> 579

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 111

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly

145 150 155 160

Pro Ala Gly Leu Tyr Ala Gln Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

275 280 285

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly

305 310 315 320

Pro Ala Gly Leu Tyr Ala Gln Pro Gly Ser Glu Val Gln Leu Val Glu

325 330 335

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

340 345 350

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

355 360 365

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

370 375 380

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

385 390 395 400

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

405 410 415

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

420 425 430

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

435 440 445

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

450 455 460

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

465 470 475 480

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

485 490 495

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

500 505 510

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

515 520 525

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

530 535 540

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

545 550 555 560

Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu

565 570 575

Pro Glu Ala

<210> 112

<211> 579

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 112

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro

145 150 155 160

Gly Gly Pro Ala Gly Ile Gly Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

275 280 285

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Pro

305 310 315 320

Gly Gly Pro Ala Gly Ile Gly Pro Gly Ser Glu Val Gln Leu Val Glu

325 330 335

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

340 345 350

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

355 360 365

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

370 375 380

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

385 390 395 400

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

405 410 415

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

420 425 430

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

435 440 445

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

450 455 460

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

465 470 475 480

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

485 490 495

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

500 505 510

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

515 520 525

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

530 535 540

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

545 550 555 560

Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu

565 570 575

Pro Glu Ala

<210> 113

<211> 579

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 113

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Ala

145 150 155 160

Leu Phe Lys Ser Ser Phe Pro Pro Gly Ser Glu Val Gln Leu Val Glu

165 170 175

Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys

180 185 190

Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg

195 200 205

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser

210 215 220

Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile

225 230 235 240

Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu

245 250 255

Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu

260 265 270

Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

275 280 285

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

290 295 300

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Ala

305 310 315 320

Leu Phe Lys Ser Ser Phe Pro Pro Gly Ser Glu Val Gln Leu Val Glu

325 330 335

Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys

340 345 350

Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg

355 360 365

Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser

370 375 380

Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser

385 390 395 400

Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

405 410 415

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp

420 425 430

Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly

435 440 445

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

450 455 460

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

465 470 475 480

Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly

485 490 495

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser

500 505 510

Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly

515 520 525

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

530 535 540

Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe

545 550 555 560

Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu

565 570 575

Pro Glu Ala

<210> 114

<211> 581

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 114

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro

145 150 155 160

Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu Val

165 170 175

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

180 185 190

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

195 200 205

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

210 215 220

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

225 230 235 240

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

245 250 255

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

260 265 270

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

275 280 285

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

290 295 300

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

305 310 315 320

Pro Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu

325 330 335

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu

340 345 350

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp

355 360 365

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp

370 375 380

Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr

385 390 395 400

Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser

405 410 415

Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn

420 425 430

Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser

435 440 445

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

450 455 460

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

465 470 475 480

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

485 490 495

Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile

500 505 510

Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

515 520 525

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

530 535 540

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr

545 550 555 560

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His

565 570 575

His Glu Pro Glu Ala

580

<210> 115

<211> 613

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 115

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr

20 25 30

Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn

35 40 45

Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe

50 55 60

Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys

65 70 75 80

Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln

85 90 95

Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn

100 105 110

Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu

115 120 125

Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile

130 135 140

Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro

145 150 155 160

Gly Gly Pro Ala Gly Ile Gly Ala Leu Phe Lys Ser Ser Phe Pro Pro

165 170 175

Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu Val

180 185 190

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser

195 200 205

Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val

210 215 220

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly

225 230 235 240

Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr

245 250 255

Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser

260 265 270

Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser

275 280 285

Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

290 295 300

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

305 310 315 320

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro

325 330 335

Pro Gly Gly Pro Ala Gly Ile Gly Ala Leu Phe Lys Ser Ser Phe Pro

340 345 350

Pro Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu

355 360 365

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu

370 375 380

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp

385 390 395 400

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp

405 410 415

Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr

420 425 430

Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser

435 440 445

Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn

450 455 460

Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser

465 470 475 480

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

485 490 495

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

500 505 510

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

515 520 525

Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile

530 535 540

Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

545 550 555 560

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

565 570 575

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr

580 585 590

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His

595 600 605

His Glu Pro Glu Ala

610

<210> 116

<211> 534

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 116

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn

35 40 45

Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly

50 55 60

Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

65 70 75 80

Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser

100 105 110

Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Lys Pro Leu Gly Leu Gln Ala Arg Val Val Gly Gly Gly Gly Thr Gln

130 135 140

Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr

145 150 155 160

Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn

165 170 175

Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu

180 185 190

Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser

195 200 205

Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln

210 215 220

Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg

225 230 235 240

Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly

245 250 255

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val

260 265 270

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser

275 280 285

Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val

290 295 300

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser

305 310 315 320

Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg

325 330 335

Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met

340 345 350

Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His

355 360 365

Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

405 410 415

Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser

420 425 430

Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe

435 440 445

Val Val Ala Ile Asn Trp Ala Ser Gly Ser Thr Tyr Tyr Ala Asp Ser

450 455 460

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu

465 470 475 480

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

485 490 495

Cys Ala Ala Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp

500 505 510

Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

515 520 525

His His His His His His

530

<210> 117

<211> 534

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 117

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn

35 40 45

Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly

50 55 60

Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

65 70 75 80

Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser

100 105 110

Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Val Val Gly Gly Gly Gly Thr Gln

130 135 140

Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr

145 150 155 160

Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn

165 170 175

Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu

180 185 190

Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser

195 200 205

Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln

210 215 220

Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg

225 230 235 240

Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly

245 250 255

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val

260 265 270

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser

275 280 285

Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val

290 295 300

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser

305 310 315 320

Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg

325 330 335

Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met

340 345 350

Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His

355 360 365

Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

405 410 415

Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser

420 425 430

Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe

435 440 445

Val Val Ala Ile Asn Trp Ala Ser Gly Ser Thr Tyr Tyr Ala Asp Ser

450 455 460

Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu

465 470 475 480

Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr

485 490 495

Cys Ala Ala Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp

500 505 510

Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

515 520 525

His His His His His His

530

<210> 118

<211> 398

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 118

Val Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser

1 5 10 15

Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser

20 25 30

Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys

35 40 45

Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val

50 55 60

Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala

65 70 75 80

Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr

85 90 95

Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys

100 105 110

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

130 135 140

Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

165 170 175

Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr

180 185 190

Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser

195 200 205

Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile

225 230 235 240

Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

245 250 255

Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

260 265 270

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala

275 280 285

Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Gly Trp Phe Arg Gln

290 295 300

Ala Pro Gly Lys Glu Arg Glu Phe Val Val Ala Ile Asn Trp Ala Ser

305 310 315 320

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

325 330 335

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

340 345 350

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Tyr Gln Ile Asn

355 360 365

Ser Gly Asn Tyr Asn Phe Lys Asp Tyr Glu Tyr Asp Tyr Trp Gly Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser His His His His His His

385 390 395

<210> 119

<211> 518

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 119

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn

35 40 45

Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly

50 55 60

Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

65 70 75 80

Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser

100 105 110

Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Lys Pro Leu Gly Leu Gln Ala Arg Val Val Gly Gly Gly Gly Thr Gln

130 135 140

Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr

145 150 155 160

Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn

165 170 175

Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu

180 185 190

Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser

195 200 205

Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln

210 215 220

Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg

225 230 235 240

Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly

245 250 255

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val

260 265 270

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser

275 280 285

Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val

290 295 300

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser

305 310 315 320

Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg

325 330 335

Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met

340 345 350

Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His

355 360 365

Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

405 410 415

Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu

420 425 430

Tyr His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

435 440 445

Val Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val

450 455 460

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

465 470 475 480

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

485 490 495

Asp Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser

500 505 510

His His His His His His

515

<210> 120

<211> 518

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 120

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn

35 40 45

Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly

50 55 60

Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

65 70 75 80

Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser

100 105 110

Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Gly Gly Val Val Gly Gly Gly Gly Thr Gln

130 135 140

Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr

145 150 155 160

Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn

165 170 175

Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu

180 185 190

Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser

195 200 205

Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln

210 215 220

Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg

225 230 235 240

Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly

245 250 255

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val

260 265 270

Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser

275 280 285

Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val

290 295 300

Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser

305 310 315 320

Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg

325 330 335

Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met

340 345 350

Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His

355 360 365

Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln

370 375 380

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

385 390 395 400

Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly

405 410 415

Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu

420 425 430

Tyr His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp

435 440 445

Val Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val

450 455 460

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

465 470 475 480

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

485 490 495

Asp Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser

500 505 510

His His His His His His

515

<210> 121

<211> 382

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 121

Val Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser

1 5 10 15

Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser

20 25 30

Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys

35 40 45

Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val

50 55 60

Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala

65 70 75 80

Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr

85 90 95

Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys

100 105 110

Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln

130 135 140

Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

145 150 155 160

Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

165 170 175

Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr

180 185 190

Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser

195 200 205

Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr

210 215 220

Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile

225 230 235 240

Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

245 250 255

Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

260 265 270

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala

275 280 285

Ala Ser Arg Phe Met Ile Ser Glu Tyr His Met His Trp Val Arg Gln

290 295 300

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Asn Pro Ala Gly

305 310 315 320

Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg

325 330 335

Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro

340 345 350

Glu Asp Thr Ala Val Tyr Tyr Cys Asp Ser Tyr Gly Tyr Arg Gly Gln

355 360 365

Gly Thr Gln Val Thr Val Ser Ser His His His His His His

370 375 380

<210> 122

<211> 503

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 122

Gln Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Val Asn Arg Tyr

20 25 30

Ser Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val

35 40 45

Ala Gly Met Ser Ser Ala Gly Asp Arg Ser Ser Tyr Glu Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Arg Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Asn Val Asn Val Gly Phe Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu

115 120 125

Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu

130 135 140

Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp

145 150 155 160

Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser

165 170 175

Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe

180 185 190

Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn

195 200 205

Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly

210 215 220

Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly

225 230 235 240

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

245 250 255

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala

260 265 270

Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala

275 280 285

Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn

290 295 300

Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile

305 310 315 320

Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu

325 330 335

Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe

340 345 350

Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu

355 360 365

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

370 375 380

Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val

385 390 395 400

Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala

405 410 415

Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln

420 425 430

Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr

435 440 445

Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr

450 455 460

Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu

465 470 475 480

Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val

485 490 495

Leu His His His His His His

500

<210> 123

<211> 509

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 123

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Val

115 120 125

Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser Leu

130 135 140

Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr

145 150 155 160

Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro

165 170 175

Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro

180 185 190

Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala

195 200 205

Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys

210 215 220

Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu

225 230 235 240

Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

245 250 255

Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

260 265 270

Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn

275 280 285

Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu

290 295 300

Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr

305 310 315 320

Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys

325 330 335

Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala

340 345 350

Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile Ser

355 360 365

Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

370 375 380

Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly

385 390 395 400

Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala Ala

405 410 415

Ser Arg Phe Met Ile Ser Glu Tyr His Met His Trp Val Arg Gln Ala

420 425 430

Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Asn Pro Ala Gly Thr

435 440 445

Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp

450 455 460

Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu

465 470 475 480

Asp Thr Ala Val Tyr Tyr Cys Asp Ser Tyr Gly Tyr Arg Gly Gln Gly

485 490 495

Thr Gln Val Thr Val Ser Ser His His His His His His

500 505

<210> 124

<211> 267

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 124

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly

50 55 60

Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr

245 250 255

Lys Val Glu Ile Lys His His His His His His

260 265

<210> 125

<211> 5

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

分选酶A裂解位点"

<220>

<221> MOD_RES

<222> (3)..(3)

<223> 任何氨基酸

<400> 125

Leu Pro Xaa Thr Gly

1 5

<210> 126

<211> 25

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<220>

<221> SITE

<222> (1)..(25)

<223> /注释="此序列可包含1-5个‘Gly Gly Gly Gly Ser’重复单元"

<400> 126

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 127

<211> 20

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<220>

<221> SITE

<222> (1)..(20)

<223> /注释="此序列可包含1-5个‘Gly Gly Gly Ser’重复单元"

<400> 127

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser

20

<210> 128

<211> 7

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

蛋白酶可裂解的序列”

<400> 128

Gly Pro Leu Gly Val Arg Gly

1 5

<210> 129

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

蛋白酶可裂解的序列”

<400> 129

Ile Pro Val Ser Leu Arg Ser Gly

1 5

<210> 130

<211> 8

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

蛋白酶可裂解的序列”

<400> 130

Val Pro Leu Ser Leu Tyr Ser Gly

1 5

<210> 131

<211> 10

<212> PRT

<213> 未知(Unknown)

<220>

<221> 来源

<223> /注释=“未知描述：

蛋白酶可裂解的序列”

<400> 131

Ser Gly Glu Ser Pro Ala Tyr Tyr Thr Ala

1 5 10

<210> 132

<211> 5

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<400> 132

Gly Gly Gly Gly Ser

1 5

<210> 133

<211> 6

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<400> 133

Gly Ser Gly Ser Gly Ser

1 5

<210> 134

<211> 13

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<400> 134

Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Thr

1 5 10

<210> 135

<211> 15

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成肽”

<400> 135

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 136

<211> 6

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：6xHis标签”

<400> 136

His His His His His His

1 5

<210> 137

<211> 124

<212> PRT

<213> 人工序列(Artificial Sequence)

<220>

<221> 来源

<223> /注释=“人工序列描述：合成多肽”

<400> 137

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn

35 40 45

Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly

50 55 60

Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

65 70 75 80

Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

85 90 95

Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser

100 105 110

Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser

115 120