CN114106173A - 抗ox40抗体、其药物组合物及应用 - Google Patents

抗ox40抗体、其药物组合物及应用 Download PDF

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CN114106173A
CN114106173A CN202010872934.XA CN202010872934A CN114106173A CN 114106173 A CN114106173 A CN 114106173A CN 202010872934 A CN202010872934 A CN 202010872934A CN 114106173 A CN114106173 A CN 114106173A
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黄诗亨
李建良
李福彬
蔡薇
严晓华
田梦
张俊霞
毕艳侠
王彩虹
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Shanghai Taijin Biotechnology Co ltd
Zhongshan Hengdong Biopharmaceutical Co ltd
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Suzhou Jinglian Medical Technology Co ltd
Shanghai Taijin Biotechnology Co ltd
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Priority to CN202180052313.XA priority patent/CN116457463B/zh
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Abstract

本发明涉及抗OX40抗体、其药物组合物及应用。本发明抗OX40抗体的序列文中所述。本发明的抗OX40抗体或其抗原结合片段及其药物组合物可用于治疗T细胞相关的疾病。

Description

抗OX40抗体、其药物组合物及应用
技术领域
本发明涉及抗OX40抗体、其药物组合物及应用。
背景技术
肿瘤免疫治疗的突破和发展是肿瘤治疗领域的巨大进步，被《科学》杂志评选为2013年“年度突破”。目前主要有四种手段可以利用免疫系统的力量来对抗肿瘤：1)针对肿瘤抗原的抗体被输入到肿瘤患者体内杀灭肿瘤细胞，其中部分机制是肿瘤细胞结合了抗体之后被表达Fc受体的免疫细胞杀灭；2)从肿瘤病人分离的抗肿瘤免疫细胞在体外扩增，然后回输到病人体内发挥抗肿瘤作用；3)T细胞被基因工程修饰后表达识别肿瘤抗原的嵌合抗原受体(Chimeric Antigen Receptor，CAR)被输入到肿瘤病人体内；4)针对限制免疫细胞活性的免疫抑制信号通路靶点(被称为“免疫检查点”)的单克隆抗体(如抗CTLA-4与抗PD-1/PD-L1)，通过阻断免疫抑制信号增强免疫系统针对肿瘤细胞产生的杀伤性T细胞应答杀伤肿瘤。
尽管上述方法已经用于临床，肿瘤免疫治疗领域对于新的、通过不同机制发挥作用的免疫疗法依然有着迫切的需求。这是因为:1)并非全部的肿瘤种类都对现有的肿瘤免疫治疗手段有反应；2)即使是对现有免疫治疗有反应的肿瘤种类，也并非这些肿瘤种类的全部病人都对这些免疫治疗有反应；3)组合治疗被预测具有更强的治疗效果；4)肿瘤很可能会产生逃脱这些治疗手段的突变。
针对免疫共刺激分子的激动型抗体，能够通过结合免疫细胞表面传递免疫激活信号的靶标分子并激活其控制的免疫激活信号通路，进而增强抗肿瘤免疫应答杀死肿瘤细胞，属于一类具有广泛前景的治疗方法。在众多免疫共刺激分子中，OX40是最早被发现和验证具有干预抗肿瘤应答的分子之一。
OX40是一个TNF受体超家族成员，主要表达于活化的T细胞表面，包括各活化的CD4和CD8 T细胞功能亚群，如Th1，Th2，TFH，Th17，以及调节性T细胞(Tregs)。OX40在中性粒细胞、NK和NKT细胞上也被报道有少量表达。OX40不表达于幼稚T细胞、特异表达于活化T细胞的特点使得靶向OX40具有一定的选择性，而不会无差别的激活所有T细胞(比如靶向表达更加广泛的CD28)。OX40L/CD252是OX40的天然配体，主要表达于B细胞、树突状细胞(DCs)和巨噬细胞等抗原提呈细胞细胞。OX40L和OX40的都是在抗原诱导表达的，OX40L的表达由CD40-CD40L信号、Toll样受体(TLRs)和炎性细胞因子诱导。OX40的表达则由抗原提呈细胞给T细胞提呈抗原激活的T细胞受体下游信号激活，受到CD28-B7.1/2信号的正向调控，表达水平峰值出现在T细胞活化后12小时～6天之间。OX40/OX40L的结构分析支持OX40与OX40L相互作用候发生三聚化，以及OX40/OX40L的结合很可能是直接参与细胞相互作用的。OX40的三聚化使得其胞内段能够招募TRAF2/3/5，并激活NF-kB信号，上调Bcl-2和Bcl-xL等抗凋亡分子的表达，从而抑制细胞凋亡增强细胞存活。OX40还被发现能够协同TCR信号共同通过PI3K/Akt影响T细胞的存活和增殖，以及通过NFAT调控IL-2、IL-4、IL-5和IFN-g等细胞因子的表达。因此，OX40的激活能够抑制活化T细胞凋亡，促进其增殖并产生细胞因子。这些都是能够激活OX40信号的激动型抗OX40的功能。
抗OX40(和OX40L-Fc融合蛋白)已经被报道在黑色素瘤、直肠癌、纤维肉瘤、B细胞和T细胞淋巴瘤、以及白血病等多种肿瘤模型中能够抑制肿瘤生长，包括在部分小鼠中建立对肿瘤的抵抗力。在此基础上，多个抗人OX40单克隆抗体已经进入临床研究，包括辉瑞的PF04518600，施贵宝的BMS-986178，以及MedImmune的多个抗OX40抗体。但是抗OX40作为抗肿瘤药物的研发进展并不顺利，从2013年报道第一项临床研究之后至今，多家公司的药物都停滞不前，尚未有抗体进入临床三期研究，提示抗肿瘤抗体的免疫效应通路和设计原则尚需进一步研究。
发明内容
本发明提供抗OX40抗体或其抗原结合片段，所述抗OX40抗体至少含有一个选自以下序列的CDR：SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5和SEQID NO:6。
在一个或多个实施方案中，所述抗OX40抗体含有如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:2所示的HCDR2和如SEQ ID NO:3所示的HCDR3，和/或含有如SEQ ID NO:4所示的LCDR1、如SEQ ID NO:5所示的LCDR2和如SEQ ID NO:6所示的LCDR3。
在一个或多个实施方案中，所述抗OX4抗体含有如SEQ ID NO:7-38中任一所示的HCDR1，如SEQ ID NO:39-65中任一所示的HCDR2，和如SEQ ID NO:66-114中任一所示的HCDR3，和/或如SEQ ID NO:115-145中任一所示的LCDR1，如SEQ ID NO:146-159中任一所示的LCDR2和如SEQ ID NO:160-199中任一所示的LCDR3。
在一个或多个实施方案中，所述抗OX40抗体含有以下组a1到组a71中任一组所示的HCDR1、HCDR2和HCDR3：
Figure BDA0002651709260000031
Figure BDA0002651709260000041
和/或以下组b1到组b71中任一组所示的LCDR1、LCDR2和LCDR3：
Figure BDA0002651709260000042
Figure BDA0002651709260000051
Figure BDA0002651709260000061
更优选地，所述抗OX40抗体含有表1的组c1到组c71中任一组的HCDR和LCDR。
在一个或多个实施方案中，所述抗OX40抗体VH的FR1可选自表2中各抗体编号的VH的FR1，VH的FR2可选自表2中各抗体编号的VH的FR2，VH的FR3可选自表2中各抗体编号的VH的FR3，VH的FR4可选自表2中各抗体编号的VH的FR4；和/或VL的FR1可选自表2中各抗体编号的VL的FR1，VL的FR2可选自表2中各抗体编号的VL的FR2，VL的FR3可选自表2中各抗体编号的VL的FR3，VL的FR4可选自表2中各抗体编号的VL的FR4。
在一个或多个实施方案中，所述抗OX40抗体VH的FR区为选自抗体SEQ ID NO:200-270的任一VH的FR区，和VL的FR区为选自抗体SEQ ID NO:271-341的任一VL的FR区。
在一个或多个实施方案中，所述抗OX40抗体的VH的氨基酸序列如SEQ ID NO:200-270中任一所示，和/或VL的氨基酸序列如SEQ ID NO:271-341中任一所示。优选地，抗OX40抗体的VH的氨基酸序列和VL的氨基酸序列如表2的任一行所示。
在一些实施方案中，本发明抗体的重链恒定区的氨基酸序列如SEQ ID NO:342-344中任一项所示，和/或轻链恒定区的氨基酸序列如SEQ ID NO:345所示。
在一个或多个实施方案中，本发明任一实施方案所述的抗OX40抗体为嵌合抗体或完全人抗体；优选为完全人抗体。
本发明还提供一种药物组合物，所述药物组合物含有本发明任一实施方案所述的抗OX40抗体或其抗原结合片段，和药学上可接受的赋形剂或载剂。
本发明还提供本发明任一实施方案所述的抗OX40抗体或其抗原结合片段在制备治疗T细胞相关疾病中的应用；优选地，所述T细胞相关的疾病为T细胞相关的肿瘤或OX40介导的病症。
在一个或多个实施方案中，所述OX40介导的病症包括OX40介导的变态反应、哮喘、COPD、类风湿关节炎、牛皮癣、自体免疫疾病和炎症相关疾病。
本发明还提供一种治疗或预防T细胞相关疾病的方法，所述方法包括给予需要的患者治疗有效量的本发明任一实施方案所述的抗OX40抗体或其抗原结合片段，或含有本发明任一实施方案所述的抗OX40抗体或其抗原结合片段的药物组合物。优选地，所述T细胞相关的疾病为T细胞相关的肿瘤或自体免疫疾病。
附图说明
图1显示酶联免疫吸附实验(ELISA)方法测定单细胞测序来源的抗人OX40抗体与人OX40胞外段抗原的结合能力。结果显示，来源于单细胞测序的抗人OX40的抗体，除少数抗体外，一定浓度的纯化后的单细胞测序抗体(A)浓度为3.16μg/ml，(B)浓度为0.316μg/ml，(C)梯度稀释(3.16μg/ml-1ng/ml)均对人OX40胞外段抗原具有一定的结合能力。
图2A-C显示利用流式细胞仪检测抗人OX40抗体结合OX40过表达细胞表面OX40的结果。
图3是抗原结合活性检测结果，显示杂交瘤上清中的抗人OX40抗体能够特异结合人OX40胞外段抗原。杂交瘤上清中的抗人OX40抗体与人OX40胞外段抗原的结合由ELISA分析，显示的是将上清1:100稀释的各种抗体结合包被的人OX40之后被HRP标记的抗鼠IgG Fc检测到的ELISA信号(A650)。
图4显示在人外周血单个核细胞(PBMC)中检测杂交瘤上清中的抗人OX40抗体激活T细胞并促进其增殖的激动活性。将杂交瘤上清进行1:5稀释，或将对照抗体浓度调至1μg/ml，并用含0.1μg/ml抗人CD3的原代细胞培养液培养细胞72小时，然后用流式技术分析小鼠CD4+T细胞的CFSE的平均荧光强度(MFI)。CFSE会随细胞的分裂增殖而荧光强度等倍稀释，故CD4+T细胞的CFSE的MFI与细胞增殖活化负相关，即与抗OX40抗体的活性负相关。
图5显示在hOX40Tg小鼠脾脏细胞中检测杂交瘤上清中的抗人OX40抗体激活T细胞并促进其增殖的激动活性。将杂交瘤上清进行1:4稀释，或将对照抗体浓度调至1μg/ml，并用含0.1μg/ml抗鼠CD3的原代细胞培养液培养细胞72小时，然后用流式技术分析小鼠CD4+T细胞(A)和CD8+T细胞(B)的CFSE的平均荧光强度(MFI)以及CFSE MFI较低的CD4+T细胞(C)和CD8+T细胞(D)所占比例。CFSE会随细胞的分裂增殖而荧光强度等倍稀释，故CFSE的MFI与细胞增殖活化负相关，而CFSE较低细胞群的比例与抗OX40抗体的活性正相关。
具体实施方式
除非另有定义，本发明的实施将采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术，这些都在本领域的技术范围内。这些技术在文献中有充分解释，诸如Molecular Cloning：A Laboratory Manual，第二版(Sambrook等，1989)；Oligonucleotide Synthesis(M.J.Gait编辑，1984)；Animal Cell Culture(R.I.Freshney编辑，1987)；Methods in Enzymology(Academic Press，Inc.)；Current Protocols inMolecular Biology(F.M.Ausubel等编辑，1987版及其定期更新版本)；PCR：ThePolymerase Chain Reaction(Mullis等编辑，1994)；A Practical Guide to MolecularCloning(Perbal Bernard V.，1988)；Phage Display：A Laboratory Manual(Barbas等，2001)。
OX40是结合OX40L(CD252，TNFSF4)的细胞表面受体或包含OX40的受体复合物。人OX40(hOX40)的氨基酸序列的NCBI登录号为(NP_003318)。OX40蛋白也可包括变体及片段。所述片段包括不具有全部或部分跨膜的胞外结构域，和/或胞内结构域以及胞外结构域的片段。可溶性形式的hOX40包括保持结合BAFF和/或APRIL的能力的胞外结构域或胞外结构域的片段。“OX40”也包括OX40氨基酸序列的翻译后修饰。翻译后修饰包括但不限于N-和O-连接糖基化。
OX40主要在活化的效应T细胞(Teffs)和调节性T细胞(Tregs)上表达，也在NKT细胞、NK细胞和嗜中性粒细胞上表达。在癌症中，在肿瘤浸润淋巴细胞中发现表达OX40的活化T细胞。OX40及其配体OX40L在诱导及维持T细胞反应中起关键作用。增强抗肿瘤T细胞功能可用于抵抗癌症以及其他OX40介导的病症，包括例如OX40介导的变态反应、哮喘、COPD、类风湿关节炎、牛皮癣、自体免疫疾病和炎症相关疾病。
抗OX40抗体
本发明提供特异性地结合OX40的抗体。
本文中，术语“抗体”包括单克隆抗体(包括全长抗体，其具有免疫球蛋白Fc区)，具有多表位特异性的抗体组合物，多特异性抗体(例如，双特异性抗体)，双抗体和单链分子，以及抗体片段，尤其是抗原结合片段，例如，Fab，F(ab’)2和Fv)。本文中，术语“免疫球蛋白”(Ig)和“抗体”可互换地使用。
基本的4链抗体单元是由两条相同的轻链(L)和两条相同的重链(H)构成的异四聚体糖蛋白。IgM抗体由5个基本的异四聚体单元及称作J链的另外多肽组成，包含10个抗原结合位点；而IgA抗体包含2-5个基本的4链单元，其可与J链组合聚合形成多价装配物。在IgG的情况中，4链单元通常约150,000道尔顿。每条轻链通过一个共价二硫键与重链相连，而两条重链通过一个或多个二硫键彼此相连，二硫键的数目取决于重链的同种型。每条重链和轻链还具有间隔规律的链内二硫桥。每条重链在N-末端具有可变结构域(VH)，接着是三个(对于每种α和γ链)和四个(对于μ和ε同种型)恒定结构域(CH)。每条轻链在N-末端具有可变结构域(VL)，接着是其另一端的恒定结构域。VL与VH排列在一起，而CL与重链的第一恒定结构域(CH1)排列在一起。特定的氨基酸残基被认为在轻链和重链可变结构域之间形成界面。成对的VH和VL一起形成一个抗原结合位点。关于不同类别抗体的结构和性质，参见如Basic and Clinical Immunology，第八版，Daniel P.Sties，Abba I.Terr和TristramG.Parsolw编辑，Appleton&Lange，Norwalk，CT，1994，第71页和第6章。来自任何脊椎动物物种的轻链，根据其恒定结构域氨基酸序列，可归入两种称作κ和λ的截然不同型中的一种。根据其重链恒定结构域(CH)氨基酸序列，免疫球蛋白可归入不同的类或同种型。有五类免疫球蛋白：IgA、IgD、IgE、IgG和IgM，分别具有称作α、δ、ε、γ和μ的重链。根据CH序列和功能的相对较小差异，γ和α类可进一步分为亚类，例如人表达下列亚类：IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgA2。
抗体的“可变区”或“可变结构域”是指抗体的重链或轻链的氨基末端结构域。重链和轻链的可变结构域可分别称为“VH”和“VL”。这些结构域通常是抗体的最可变的部分(相对于相同类型的其它抗体)并含有抗原结合位点。
术语“可变的”指可变结构域中的某些区段在抗体序列中差异广泛的情况。可变结构域介导抗原结合并限定特定抗体对其特定抗原的特异性。然而，变异性并非均匀分布于可变结构域跨越的全部氨基酸。相反，其集中在三个称为高变区(HVR)的区段(在轻链和重链可变结构域中均有)，即分别为重链可变区的HCDR1、HCDR2、HCDR3以及轻链可变区的LCDR1、LCDR2和LCDR3。可变结构域中更为高度保守的部分称为构架区(FR)。天然重链和轻链的可变结构域各自包含四个FR区(FR1、FR2、FR3和FR4)，它们大多采取β-折叠构象，通过形成环状连接且在有些情况中形成β-折叠结构一部分的三个HVR连接。每条链中的HVR通过FR区非常接近的保持在一起，并与另一条链的HVR一起促成抗体的抗原结合位点的形成(参见Kabat等，Sequences of Immunological Interest，第五版，国立卫生研究所，Bethesda，MD，1991)。通常，轻链可变区的结构为FR1-LCDR1-FR2-LCDR2-FR3-LCDR3-FR4，重链可变区的结构为FR1-HCDR1-FR2-HCDR2-FR3-HCDR3-FR4。恒定结构域不直接参与抗体与抗原的结合，但展现出多种效应子功能，如在抗体依赖性细胞介导的细胞毒性中抗体的参与。
本发明中，部分抗体是激动型抗体，部分抗体是非激动型抗体。优选的，本发明所述激动型抗体的各CDR之间可以任意组合，从而构成激动型抗体CDR组或用于形成激动型抗体可变区；本发明所述非激动型抗体的各CDR之间可以任意组合，形成有效的CDR组，从而构成非激动型抗体CDR组或用于形成非激动型抗体可变区。本文中，“激动型抗体可变区”是指以完整抗体的形式对抗原具有激动活性的可变区，例如OX40激动型抗体可变区或激动型OX40抗体可变区；“非激动型抗体可变区”是指以完整抗体的形式不具有任何激动活性的抗体可变区，例如OX40非激动型抗体可变区或非激动型OX40抗体可变区。
本文中，术语“单克隆抗体”指从一群基本上同质的抗体中获得的抗体，即除了可能以少量存在的可能的天然出现的突变和/或翻译后修饰(例如异构化、酰胺化)之外，构成群体的各个抗体是相同的。单克隆抗体是高度特异性的，针对单个抗原位点。与多克隆抗体制剂(其典型地包括针对不同决定簇(表位)的不同抗体)相比，每个单克隆抗体针对抗原上的单个决定簇。除它们的特异性外，单克隆抗体的优势在于它们通过杂交瘤培养合成，未受到其它免疫球蛋白的污染。修饰语“单克隆”表明抗体从基本上同质的抗体群获得的特征，不应解释为要求通过任何特定方法来生产抗体。例如，将根据本发明使用的单克隆抗体可通过多种技术来生成，包括例如杂交瘤法(例如，Kohler和Milstein，Nature，256：495-97(1975)；Hongo等，Hybridoma，14(3)：253-260(1995)，Harlow等，Antibodies：A LaboratoryManual，Cold Spring Harbor Laboratory Press，第二版.1988；Hammerling等，在：Monoclonal Antibodies and T-Cell Hybridomas，563-681，Elsevier，N.Y.，1981)、重组DNA法(例如US 4,816,567)、噬菌体展示技术(例如，Clackson等，Nature，352：624-628(1991)；Marks等，J.Mol.Biol.，222：581-597(1992)；Sidhu等，J.Mol.Biol.，338(2)：299-310(2004)；Lee等，J.Mol.Biol.，340(5)：1073-1093(2004)；Fellouse，Proc.Natl.Acad.Sci.USA，101(34)：12467-12472(2004)；和Lee等J.Immunol.Methods，284(1-2)：119-132(2004))、及用于从具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物生成人或人样抗体的技术(例如，WO1998/24893；WO1996/34096；WO1996/33735；WO 1991/10741；Jakobovits等，Proc.Natl.Acad.Sci.USA，90：2551(1993)；Jakobovits等，Nature，362：255-258(1993)；Bruggemann等，Year in Immunol.，7：33(1993)；US 5,545,807；US 5,545,806；US 5,569,825；US 5,625,126；US 5,633,425；和US5,661,016；Marks等，Bio/Technology，10：779-783(1992)；Lonberg等，Nature，368：856-859(1994)；Morrison，Nature，368：812-813(1994)；Fishwild等，Nature Biotechnol.，14：845-851(1996)；Neuberger，Nature Biotechnol.，14：826(1996)；和Lonberg和Huszar，Intern.Rev.Immunol.，13：65-93(1995)、单细胞测序法(Nat Biotechnol.2013Feb；31(2):166-9.)。
术语“全长抗体”、“完整抗体”或“完全抗体”可互换地使用，是指基本上是其完整形式的抗体(与抗体片段相对比)。具体而言，完全抗体包括那些具有重链和轻链包括Fc区的抗体。恒定结构域可以是天然序列恒定结构域(例如，人天然序列恒定结构域)或其氨基酸序列变体。在一些情况中，完整抗体可具有一种或多种效应子功能。
“抗体片段”包含完整抗体的一部分，优选完整抗体的抗原结合区和/或可变区。抗体片段优选为抗体的抗原结合片段。抗体片段的例子包括Fab、Fab’、F(ab’)2和Fv片段；双抗体；线性抗体(参见美国专利5,641,870，实施例2；Zapata等，Protein Eng.，8(10)：1057-1062，1995)；单链抗体分子；scFv-Fc片段；由抗体片段形成的多特异性抗体；以及通过化学修饰或通过掺入脂质体中应能够增加半衰期的任何片段。用木瓜蛋白酶消化抗体产生称作“Fab”片段的两个相同的抗原结合片段，和一个残余“Fc”片段，其名称反映了它易于结晶的能力。Fab片段由完整轻链及重链可变结构域(VH)和一条重链第一恒定结构域(CH1)组成。每个Fab片段在抗原结合方面是单价的，即其具有单个抗原结合位点。胃蛋白酶处理抗体产生一个较大F(ab’)2片段，它粗略相当于两个通过二硫键相连的Fab片段，具有不同抗原结合活性且仍能够交联抗原。Fab’片段因在CH1结构域的羧基末端增加了一些另外的残基(包括来自抗体铰链区的一个或多个半胱氨酸)而与Fab片段有所不同。F(ab’)2抗体片段最初是作为成对Fab’片段生成的，在Fab’片段之间具有铰链半胱氨酸。抗体片段的其它化学偶联也是已知的。Fc片段包含通过二硫键保持在一起的两条重链的羧基末端部分。抗体的效应子功能是由Fc区中的序列决定的，该区还是由在某些类型细胞上发现的Fc受体(FcR)所识别的区。
“Fv”是含有完整抗原识别和结合位点的最小抗体片段。该片段由紧密、非共价结合的一个重链可变结构域和一个轻链可变结构域的二聚体组成。从这两个结构域的折叠中突出了六个高变环(重链和轻链各3个环)，贡献出抗原结合的氨基酸残基并赋予抗体以抗原结合特异性。然而，即使是单个可变结构域(或只包含对抗原特异的三个HVR的半个Fv)也具有识别和结合抗原的能力，尽管亲合力低于完整结合位点。
“单链Fv”也可缩写为“sFv”或“scFv”，是包含抗体VH和VL结构域的连接成一条多肽链的抗体片段。优选的是，sFv多肽在VH和VL结构域之间还包含多肽接头，使得sFv形成期望的抗原结合结构。关于sFv的综述参见The Pharmacology of Monoclonal Antibodies，第113卷，Rosenburg和Moore编辑，Springer-Verlag，New York，pp.269-315(1994)。
所述片段的“化学修饰”包括添加聚(亚烷基)二醇如聚乙二醇(“聚乙二醇化，PEG化”)，包括Fv、scFv、Fab、F(ab’)2和Fab'的聚乙二醇化片段，即Fv-PEG、scFv-PEG、Fab-PEG、F(ab’)2-PEG和Fab'-PEG。这类片段具有EGFR结合活性。
优选地，所述抗体片段，尤其是抗原结合片段，由其来源抗体的重链可变区或轻链可变区的部分序列构成或者包含它们，所述部分序列足以保留与其来源抗体相同的结合特异性和充分的亲和力，对于OX40，优选至少等于其来源抗体亲和力的1/100，在更优选方式中至少等于1/10。这种抗体片段将包含最少5个氨基酸，优选其来源的抗体序列的10、15、25、50和100个连续氨基酸。
单克隆抗体在本文中也包括“嵌合”抗体(免疫球蛋白)，其中重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源，而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源，以及此类抗体的片段，只要它们展现出期望的生物学活性(US4,816,567；Morrison等，Proc.Nat.Acad.Sci.USA，81：6851-6855，1984)。
非人(例如鼠)抗体的“人源化”形式指最低限度包含衍生自非人免疫球蛋白的序列的嵌合抗体。因此，“人源化抗体”通常指可变结构域构架区与在人抗体中发现的序列交换的非人抗体。通常在人源化抗体中，整个抗体(除CDR以外)由人来源的多核苷酸编码或与这种抗体相同(除CDR以外)。CDR(其中一些或全部由源自非人生物体的核酸编码)被移植到人抗体可变区的β-折叠骨架中以产生抗体，其特异性由被移植的CDR来决定。这类抗体的产生例如在WO92/11018；Jones，1986，Nature，321：522-525；Verhoeyen等，1988，Science，239：1534-1536中有描述。人源化抗体也可以使用具有基因工程免疫系统的小鼠而产生(见Roque等，2004，Biotechnol.Prog.，20：639-654)。
“人抗体”指这样的抗体，其具有与由人生成的抗体的氨基酸序列对应的氨基酸序列和/或使用本文所公开的用于生成人抗体的任何技术产生。人抗体的这种定义明确排除包含非人抗原结合残基的人源化抗体。人抗体可使用本领域已知的多种技术来生成，包括噬菌体展示文库。这类技术可参见Hoogenboom和Winter，分子生物学杂志，227：381(1991)；Marks等，分子生物学杂志，222：581(1991)。可获得的制备人单克隆抗体的方法在Cole等，单克隆抗体和癌症治疗，Alan R.Liss，p.77(1985)；Boerner等，免疫学杂志，147(1)：86-95(1991)中描述。还参见van Dijk和van de Winkel，现代药学评论，5：368-74(2001)。人抗体可以如下制备，即将抗原施用于转基因动物，其经修饰而应答抗原激发生成此类抗体，但是其内源基因座已经失去能力，例如经免疫的异种移植小鼠(xenomice)(参见例如US 6,075,181和6,150,584，关于XENOMOUSETM技术)。还可参见例如Li等，美国国家科学院学报，103：3557-3562(2006)，关于经人B细胞杂交瘤技术产生的人抗体。
本发明的抗OX40抗体也可以是微型抗体。微型抗体是包含与CH3结构域连接的scFv的最小化抗体样蛋白(Hu等，1996，Cancer Res.，56：3055-3061)。本发明的抗OX40抗体还可以是结构域抗体，参见例如US 6,248,516。结构域抗体(dAb)是抗体的功能结合结构域，对应于人抗体dAB的重链(VH)或轻链(VL)的可变区，具有约13kDa的分子量或小于完整抗体的十分之一尺寸。dAB在包括细菌、酵母和哺乳动物细胞系统的多种宿主中充分表达。另外，即使在经受严酷条件，诸如冷冻干燥或热变性后，dAb仍高度稳定且保持活性。参见例如US 6,291,158；US 6,582,915；US 6,593,081；US 6,172,197；US 2004/0110941；EP0368684；US 6,696,245、WO04/058821、WO04/003019和WO03/002609。
本发明抗OX40抗体的HCDR1可含有X1X2X3X4X5X6X7X8X9X10(SEQ ID NO:1)，其中，X1为G或S，X2为A、D、F、G、V或Y，X3为S、T或I，X4为I、L或F，X5为I、S、D、N、T或A，X6为N、S、T、D、R或G，X7为N、S、T、Y、A、G或F，X8为N、Y、A、G、W、S、I、K、F、T或D，X9为W、V或无，X10为N、G或无。示例性的HCDR1的氨基酸序列如SEQ ID NO:7-38中任一所示。在一个或多个实施方案中，X1为G或S，X2为D、F、G或Y，X3为S或T，X4为I、L或F，X5为S、D或T，X6为N、S、T或D，X7为S、T或Y，X8为N、Y、A、G或I，X9为W、V或无，X10为N或无。优选地，HCDR1的氨基酸序列如SEQ ID NO:9、10、12、13、19、21、23、33、34、38中任一所示。
本发明抗OX40抗体的HCDR2可含有X1X2X3X4X5X6X7X8X9X10(SEQ ID NO:2)，其中，X1为M或I；X2为N、Y、S、K、H或F；X3为P、W、Q、H、S、G、A或R；X4为N、S、G、Y、K或D；X5为S、D、G、N、A或T；X6为T、N、S、D或G；X7为N、K、T、S、D、Y、H、G、A或E；X8为T、I、K、G或无；X9为T或无；X10为T、I或无。在一个或多个实施方案中，X1为I；X2为N、Y、S、H或F；X3为W、H、S或A；X4为N、S、G或Y；X5为S、D、G或N；X6为T、N、S、D或G；X7为N、K、T、S或D；X8为T、I、K或无；X9和X10为无。示例性的HCDR2的氨基酸序列如SEQ ID NO:39-65中任一所示。优选地，HCDR2的氨基酸序列如SEQ ID NO:42、43、46、47、50、58、59、63、64中任一所示。
本发明抗OX40抗体的HCDR3可含有CX1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18(SEQ ID NO:3)，其中，X1为V、T、S或A，X2为R、K、I、G、A、T、S、H、Q、N或E，X3为S、D、W、G、Y、A、E、R、L、V、T、M或K，X4为G、Y、F、V、L、A、P、D、S、W、R、Q、E、N或K，X5为D、Y、G、S、R、F、T、V、A、P、L、I、E、W或N，X6为W、G、E、D、S、R、P、Y、N、L、A、T、I或V，X7为H、S、L、A、T、Y、G、F、W、V、E、D或M，X8为C、G、L、F、Y、S、W、D、M、T、N、R、H、V或P，X9为F、S、D、Y、W、G、T、E、P、L、R、N或无，X10为D、Y、F、I、N、W、V、P、E、L、G、S、Q或无，X11为Y、G、D、W、F、A、I、Q、S、N或无，X12为W、D、Y、F、N、G、R、P或无，X13为I、W、Y、D、S、F、G、L或无，X14为Q、W、I、Y、F、D、V、H或无，X15为H、W、M、D、Y、F或无，X16为W、D、S、Y或无，X17为V、W、Y或无，X18为W或无。在一个或多个实施方案中，X1为V或A，X2为R、K、S或Q，X3为S、D、G、Y、A或E，X4为G、Y、D、S、W或N，X5为Y、S、F、T、A、L、I或W，X6为G、D、P、Y、N、L或T，X7为S、L、T、Y、F、W、E或D，X8为G、F、Y、S、W、M、T或H，X9为F、S、D、Y、E、L或无，X10为D、Y、V、L、G或无，X11为Y、G、W、F、Q、N或无，X12-X18为无。示例性的LCDR1的氨基酸序列如SEQ ID NO:66-114中任一所示。优选地，HCDR3的氨基酸序列如SEQ ID NO:67、78、79、80、86、93、96、99、100、107、108中任一所示。
本发明抗OX40抗体的LCDR1可含有X1X2X3X4X5X6X7X8X9X10X11X12(SEQ IDNO:4)，其中，X1为H或Q，X2为G、D、S或T，X3为S、I、L、T或V，X4为S、N、R、W、L、V或F，X5为T、D、N、S、H、Y或G，X6为Y、D、W、S、R、N、G或T，X7为N、D、S、Y或无，X8为G、N或无，X9为Y、N、D、H、S或无，X10为N、T、R、K或无，X11为Y、F、S、N或无，X12为Y或无。在一个或多个实施方案中，X1为H或Q，X2为G、D或S，X3为S、I、L或V，X4为S、N、W、L或F，X5为T、N、S、H、Y或G，X6为Y、D、S、R或N，X7为N、D、Y或无，X8为G或无，X9为Y、N、D或无，X10为N、T或无，X11为Y或无，X12为无。示例性的LCDR1的氨基酸序列如SEQID NO:115-145中任一所示。优选地，LCDR1的氨基酸序列如SEQ ID NO:115、116、120、122、124、126、130、134、135、140、141中任一所示。
本发明抗OX40抗体的LCDR2可含有X1X2X3(SEQ ID NO:5)，其中，X1为T、K、G、W、E、M、L、D、A或Q；X2为V、A、T或G；X3为S或A。在一个或多个实施方案中，X1为K、G、L、D或A；X2为V、A或G；X3为S。示例性的LCDR2的氨基酸序列如SEQ ID NO:146-159中任一所示。优选地，LCDR2的氨基酸序列如SEQ ID NO:147、148、153、154、155中任一所示。
本发明抗OX40抗体的LCDR3可含有CX1QX2X3X4X5X6X7X8X9X10X11(SEQ IDNO:6)，其中，X1为M、Q、L或H，X2为G、Y、A、V、H、T、F或S，X3为T、G、Y、N、L、D或S，X4为H、S、T、Q、D、N、G、I或R，X5为W、S、T、Y、L、I或N，X6为P、S、M、I、W或T，X7为W、F、L、P、I、Y、R或T，X8为T、L、A、F或W，X9为F、L、T或无，X10为T、F或无，X11为F或无。在一个或多个实施方案中，X1为M、Q或L，X2为G、Y、A或S，X3为T、G、Y、N、L或D，X4为H、S、Q或N，X5为W、S、T、Y、L、I或N，X6为P或I，X7为W、F、L、I、Y、R或T，X8为T或F，X9为F或无，X10和X11为无。示例性的LCDR3的氨基酸序列如SEQ ID NO:160-199中任一所示。优选地，LCDR3的氨基酸序列如SEQ ID NO:160、161、166、168、172、182、192、193、195、198中任一所示。
在一些实施方案中，本发明的抗OX40抗体含有如SEQ ID NO:1所示的HCDR1、如SEQID NO:2所示的HCDR2和如SEQ ID NO:3所示的HCDR3，和/或如SEQ ID NO:4所示的LCDR1、如SEQ ID NO:5所示的LCDR2和如SEQ ID NO:6所示的LCDR3。优选地，本发明的抗OX40抗体含有如SEQ ID NO:7-38中任一所示的HCDR1，如SEQ ID NO:39-65中任一所示的HCDR2，和如SEQ ID NO:66-114中任一所示的HCDR3，和/或如SEQ ID NO:115-145中任一所示的LCDR1，如SEQ ID NO:146-159中任一所示的LCDR2和如SEQ ID NO:160-199中任一所示的LCDR3。
更优选地，本发明的抗OX40抗体含有如SEQ ID NO:9、10、12、13、19、21、23、33、34、38任一所示的HCDR1，如SEQ ID NO:42、43、46、47、50、58、59、63、64任一所示的HCDR2，和如SEQ ID NO:67、78、79、80、86、93、96、99、100、107、108任一所示的HCDR3，和/或如SEQ IDNO:115、116、120、122、124、126、130、134、135、140、141任一所示的LCDR1，如SEQ ID NO:147、148、153、154、155中任一所示的LCDR2和如SEQ ID NO:160、161、166、168、172、182、192、193、195、198任一所示的LCDR3。
进一步优选地，本发明的抗OX40抗体含有以下组a1到组a71中任一组所示的HCDR1、HCDR2和HCDR3：
Figure BDA0002651709260000161
Figure BDA0002651709260000171
Figure BDA0002651709260000181
优选含有选自以下的任一组所示的HCDR1、HCDR2和HCDR3：a3、a5、a11、a16、a19、a20、a21、a41、a59、a63、a65、a68、a69；
和/或以下组b1到组b71中任一组所示的LCDR1、LCDR2和LCDR3：
Figure BDA0002651709260000182
Figure BDA0002651709260000191
优选选自以下的任一组所示的LCDR1、LCDR2和LCDR3：b3、b5、b11、b16、b19、b20、b21、b41、b59、b63、b65、b68、b69。
更优选地，本发明抗OX40抗体含有表1的组c1到组c71中任一组的HCDR和LCDR：
表1
Figure BDA0002651709260000201
Figure BDA0002651709260000211
在一个或多个实施方案中，本发明抗OX40抗体含有表1中选自以下的任一组的HCDR和LCDR：c3、c5、c11、c16、c19、c20、c21、c41、c59、c63、c65、c68、c69。
本发明抗OX40抗体VH的FR1可选自表2中各抗体编号的VH的FR1，FR2可选自表2中各抗体编号的VH的FR2，FR3可选自表2中各抗体编号的VH的FR3，FR4可选自表2中各抗体编号的VH的FR4；和/或VL的FR1可选自表2中各抗体编号的VL的FR1，FR2可选自表2中各抗体编号的VL的FR2，FR3可选自表2中各抗体编号的VL的FR3，FR4可选自表2中各抗体编号的VL的FR4。
表2
Figure BDA0002651709260000221
Figure BDA0002651709260000231
在优选的实施方案中，本发明抗OX40抗体VH的FR区为选自抗体SEQ ID NO:200-270的任一VH的FR区，和VL的FR区为选自抗体SEQ ID NO:271-341的任一VL的FR区。进一步优选地，这类抗体的HCDR选自前述组a1到组a71中的任一组，LCDR选自前述组b1到组b71中的任一组；更优选地，这类抗体的CDR选自前述组c1到组c71中的任一组。
在一些实施方案中，本发明的抗OX40抗体的VH的氨基酸序列如SEQ ID NO:200-270中任一所示，和/或VL的氨基酸序列如SEQ ID NO:271-341中任一所示。优选地，本发明的抗OX40抗体的VH的氨基酸序列和VL的氨基酸序列如表1的任一行所示。
在一些实施方案中，本发明抗体的重链恒定区的氨基酸序列如SEQ ID NO:342-345中任一项所示，和/或轻链恒定区的氨基酸序列如SEQ ID NO:346或347所示。在一些实施方案中，表2中组d1-d40的抗体的重链恒定区的氨基酸序列如SEQ ID NO:345所示，和/或轻链恒定区的氨基酸序列如SEQ ID NO:347所示。在其他实施方案中，表2中组d41-d71的抗体的重链恒定区的氨基酸序列如SEQ ID NO:342-344中任一项所示，和/或轻链恒定区的氨基酸序列如SEQ ID NO:346所示；优选地，表2中组d41-d71的抗体的重链恒定区的氨基酸序列如下表中各对应组所示。本文中，各抗体的重链和轻链恒定区可使用本领域中任何其他重链和轻链恒定区而不影响抗体与抗原的结合能力。
Figure BDA0002651709260000241
Figure BDA0002651709260000251
本发明的抗体可以是嵌合抗体、人源化抗体或完全人抗体；优选为完全人抗体。应理解，本发明实施例所提供的抗体为完全人抗体。
在不实质性影响抗体活性的前提下，本领域技术人员可以对本发明的序列取代、添加和/或缺失一个或更多个(例如1、2、3、4、5、6、7、8、9或10个或更多个)氨基酸，以获得所述抗体或其功能性片段序列的变体。它们都被视为包括在本发明保护的范围内。如在可变区的FR和/或CDR区中将具有类似性质的氨基酸进行取代。取代优选是保守性取代；可进行保守性取代的氨基酸残基为本领域所周知。在一些实施方案中，本发明所述变体的序列可以与其来源序列有至少有95％、96％、97％、98％或99％的一致性。本发明所述的序列一致性可以使用序列分析软件测量。例如使用缺省参数的计算机程序BLAST，尤其是BLASTP或TBLASTN。
本发明的抗OX40抗体可以被修饰以影响功能。本发明包括具有修饰的糖基化模式的抗OX40抗体。可进行修饰以除去不期望的糖基化位点，或在寡糖链上不存在岩藻糖部分以增强抗体的依赖性细胞毒性(ADCC)功能，或可进行半乳糖基化修饰以改变补体依赖性细胞毒性(CDC)。
本发明抗OX40抗体的通常可具备约10-9至约10-13M的亲和力常数。
可采用本领域常规的方法制备本发明的抗OX40抗体，如本领域熟知的杂交瘤技术。或者，本发明的抗OX40抗体可在除杂交瘤细胞系以外的细胞系中表达。可用编码本发明抗体的序列转化合适的哺乳动物宿主细胞。转化可采用任何已知的方法进行，例如包括将多核苷酸包装在病毒(或病毒载体中)并用病毒(或载体)转导宿主细胞。所用的转化程序取决于将转化的宿主。用于将异源多核苷酸引入哺乳动物细胞中的方法为本领域所熟知，包括葡聚糖介导的转染、磷酸钙沉淀、聚凝胺介导的转染、原生质体融合、电穿孔、将多核苷酸囊封在脂质体中和将DNA直接微注射至核中等。可用作用于表达的宿主的哺乳动物细胞系为本领域所熟知，包括但不限于可从美国典型培养物保藏中心(ATCC)获得的多种永生化细胞系，包括但不限于中国仓鼠卵巢(CHO)细胞、HeLa细胞、幼仓鼠肾(BHK)细胞、猴肾细胞(COS)、人肝细胞癌细胞(例如，HepG2)等。尤其优选的细胞系通过确定哪些细胞系具有高表达水平并产生具有基本OX40结合特性的抗体来进行选择。
编码抗OX40抗体的多核苷酸序列
本发明提供核酸分子，其包括编码本发明所述抗OX40抗体的多核苷酸序列。本文提供编码重链可变区、轻链可变区、重链、轻链以及各CDR的多核苷酸序列。
本发明的核酸分子包括单链和双链形式的DNA和RNA，以及相应的互补序列。DNA包括例如cDNA、基因组DNA、化学合成的DNA、PCR扩增的DNA及其组合。本发明的核酸分子包括全长基因或cDNA分子以及其片段的组合。本发明的核酸优选地源自人来源，但本发明也包括源自非人的核酸。
本发明中，分离的核酸分子指独立片段形式或作为较大核酸构建体组分的核酸分子。在一个优选的实施方案中，核酸基本上不含污染性的内源物质。核酸分子优选地源自以基本上纯的形式至少分离一次的DNA或RNA且其量或浓度使得能够通过标准生物化学方法来识别、操纵和回收其组分核苷酸序列。所述序列优选地以未受内部非翻译序列或内含子(典型地在真核基因中存在)中断的开放阅读框形式来提供和/或构建。非翻译DNA的序列可存在于开放阅读框的5'或3'处，其同样不影响编码区的操纵或表达。
本发明还包括在适度严苛的条件下、优选在高度严苛的条件下与如本文中所述编码抗OX40抗体的核酸杂交的核酸。影响杂交条件选择的基本参数和关于设计合适条件的指导可参见Sambrook,Fritsch和Maniatis(1989，Molecular Cloning：A LaboratoryManual，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，N.Y.，第9章和第11章；和Current Protocols in Molecular Biology，1995，Ausubel等编，John Wiley&Sons,Inc.，章节2.10和6.3-6.4)。
如本文中所概述，通常使用盒式诱变或PCR诱变或本领域中熟知的其它技术在编码抗OX40抗体的DNA中通过核苷酸的位点特异性诱变以产生编码变体的DNA，且此后在细胞培养物中表达重组DNA来制备根据本发明的变体。然而，可以通过使用确定的技术体外合成来制备包含具有多达约100-150个残基的的抗原结合片段。
如本领域技术人员将了解，由于遗传密码的简并性，可制得极大量的核酸，它们全部编码本发明的抗OX40抗体或其抗原结合片段。因此，在已鉴定特定氨基酸序列的情况下，本领域技术人员可通过以不改变编码蛋白质的氨基酸序列的方式简单地修饰一个或多个密码子的序列来制得任何数量的不同的核酸。
本发明还提供包含至少一个如上述多核苷酸的质粒、表达载体、转录盒或表达盒形式的表达系统和构建体。另外，本发明提供包含所述表达系统或构建体的宿主细胞。
任何宿主细胞中所用的表达载体通常含有用于质粒维系和用于克隆与表达外源性核苷酸序列的序列。所述序列(在某些实施方案中总称为“侧翼序列”)通常包括一个或多个以下核苷酸序列：启动子、一个或多个增强子序列、复制起点、转录终止序列、含有供体和受体剪接位点的完全内含子序列、编码用于多肽分泌的前导序列的序列、核糖体结合位点、聚腺苷酸化序列、用于插入编码将要表达的抗体的核酸的多连接子区和可选标记元件。下文论述每个这些序列。
载体可任选地含有“标签”编码序列，即位于抗OX40抗体编码序列的5'或3'末端的寡核苷酸分子；寡核苷酸序列编码聚组氨酸(诸如6His)或另一种“标签”，诸如FLAG、HA(血球凝集素流感病毒)或myc，它们存在市场上有售的抗体中。此标签在表达多肽时典型地与多肽融合，且可充当用于从宿主细胞亲和力纯化或检测抗OX40抗体的一种方式。亲和力纯化例如可通过使用针对此标签的抗体作为亲和力基质的柱色谱法来完成。标签任选地可随后通过诸如使用某些用于裂解的肽酶的各种方式从经过纯化的OX40抗OX40抗体除去。
侧翼序列可以是同源的(即，来自与宿主细胞相同的物种和/或菌株)、异源的(即，来自除宿主细胞物种或菌株以外的物种)、杂合的(即，来自一种以上来源的侧翼序列的组合)、合成的或天然的。同样地，侧翼序列的来源可以是任何原核或真核生物体、任何脊椎动物或无脊椎动物生物体或任何植物，条件是侧翼序列在宿主细胞机制中起作用且可由宿主细胞机制活化。
复制起点典型地是在市场上购买的那些原核表达载体的一部分，且此起点有助于载体在宿主细胞中扩增。如果选择的载体不含复制起点位点，则可以基于已知的序列来化学合成并连接到载体中。举例来说，来自质粒pBR322(New England Biolabs，Beverly，MA)的复制起点适合于大多数革兰氏阴性细菌，且各种病毒起点(例如，SV40、多瘤病毒、腺病毒、水泡性口炎病毒(VSV)或乳头瘤病毒，诸如HPV或BPV)适用于在哺乳动物细胞中克隆载体。哺乳动物表达载体通常不需要复制起点组分(例如，常常只使用SV40起点，因为它也含有病毒早期启动子)。
转录终止序列典型地位于多肽编码区的3'末端，用以终止转录。原核细胞中的转录终止序列通常是富含G-C的片段，接着是多聚胸苷酸序列。
可选的标记基因编码对于在选择性培养基中生长的宿主细胞的存活和生长而言必要的一种蛋白质。典型的选择标记基因编码(a)赋予对于抗生素或其它毒素(例如，对于原核宿主细胞而言为氨苄青霉素、四环素或卡那霉素)的抗性；(b)补足细胞的营养缺陷型；或(c)提供无法从复合物或确定的培养基获得的重要营养素的蛋白质。特异性的可选标记是卡那霉素抗性基因、氨苄青霉素抗性基因和四环素抗性基因。有利的是，新霉素抗性基因也可以用于在原核和真核宿主细胞中进行选择。
核糖体结合位点对于mRNA的翻译起始而言通常是必要的而且由Shine-Dalgarno序列(原核生物)或Kozak序列(真核生物)来表征。此元件典型地位于启动子的3'和将要表达的多肽的编码序列的5'。
本发明的表达和克隆载体将典型地含有由宿主生物体识别并与编码抗OX40抗体的分子可操作性连接的启动子。启动子是位于控制结构基因转录的结构基因(通常在约100至1000bp以内)的起始密码子上游的非转录序列。
本领域中也熟知与酵母宿主一起使用的合适启动子。酵母增强子有利地与酵母启动子一起使用。熟知与哺乳动物宿主细胞一起使用的合适启动子且包括但不限于由诸如多瘤病毒、鸡痘病毒、腺病毒(诸如腺病毒2)、牛乳头瘤病毒、禽肉瘤病毒、巨细胞病毒、反转录病毒、B型肝炎病毒和最优选的猿猴病毒40(SV40)的病毒基因组获得的些启动子。其它合适的哺乳动物启动子包括异源哺乳动物启动子，例如热休克启动子和肌动蛋白启动子。
可将增强子序列插入载体中以通过高等真核生物增加编码组成本发明的抗OX40抗体的轻链或重链的DNA的转录。增强子是作用于启动子以增加转录的DNA的顺式作用元件，长度通常约为10-300bp。增强子具有相对的方向和位置独立性，已在转录单元的5’和3’位置处发现增强子。已知可获自哺乳动物基因的若干种增强子序列，例如球蛋白、弹性蛋白酶、白蛋白、甲胎蛋白和胰岛素的增强子序列。然而，典型地使用来自病毒的增强子。本领域中已知的SV40增强子、巨细胞病毒早期启动子增强子、多瘤病毒增强子和腺病毒增强子是用于活化真核启动子的示例性增强元件。
本发明的表达载体可以由起始载体(诸如市售载体)来构建。这类载体可含有或可不含所有所需的侧翼序列。如果本文所述侧翼序列的一个或多个并非已存在于载体中，则其可单独获得并与载体连接。本领域技术人员熟知用于获得各个侧翼序列的方法。
在构建载体并将编码包含抗OX40抗体的轻链、重链或轻链和重链的核酸分子插入载体的适当位点后，可将已完成的载体插入合适的宿主细胞中用于扩增和/或多肽表达。可通过众所周知的方法将抗OX40抗体的表达载体转化至所选的宿主细胞中，所述方法包括转染、感染、磷酸钙共沉淀、电穿孔、微注射、脂转染、DEAE-葡聚糖介导的转染或其它已知的技术。所选方法部分可随待使用的宿主细胞类型而变化。
当培养在适当的条件下培养宿主细胞，使其合成抗OX40抗体，抗OX40抗体随后可从培养基收集(如果宿主细胞将其分泌到培养基中)或直接从产生其的宿主细胞中收集(如果不分泌的话)。适当的宿主细胞如前文所述。
抗OX40抗体用于治疗目的的用途
本文所述的抗OX40抗体的所有方面都可用于制备用以治疗本文所述各种病况和疾病的药物，所述病况和疾病尤其病况与表达OX40的免疫细胞(尤其是T细胞、NK细胞和嗜中性粒细胞)相关的疾病或病况。在一些实施方案中，所述病况和疾病是T细胞相关癌症，包括但不限于：膀胱癌、乳腺癌、子宫/子宫颈癌、卵巢癌、前列腺癌、睾丸癌、食道癌、胃肠癌、胰脏癌、结肠直肠癌、结肠癌、肾癌、头颈癌、肺癌、胃癌、生殖细胞癌、骨癌、肝癌、甲状腺癌、皮肤癌、中枢神经系统的新生物、淋巴瘤、白血病、骨髓瘤、尿生殖系统癌症、尿路上皮癌、肾细胞癌、胃腺癌、非小细胞肺癌、弥漫大B细胞淋巴瘤、头颈部鳞状细胞癌、霍奇金淋巴瘤、胃食管交界腺癌、黑色素瘤、肉瘤及病毒相关癌症。在某些实施方案中，癌症为转移性癌症、难治性癌症或复发性癌症。所述病况和疾病还可以是其他OX40介导的病症，包括例如OX40介导的变态反应、哮喘、COPD、类风湿关节炎、牛皮癣、溃疡性结肠炎、特应性皮炎、自体免疫疾病和炎症相关疾病。
诊断用途、测定和试剂盒
本发明的抗OX40抗体可用于诊断测定，例如结合测定来检测和/或定量在组织(诸如骨髓)或细胞(诸如浆细胞)中表达的OX40。抗OX40抗体可用在进一步研究OX40在疾病中的作用的研究中。抗OX40抗体可用来进一步研究OX40在形成均聚和/或异聚受体复合物中的作用和所述OX40受体复合物在疾病中的作用。
OX40的血清含量可以是预后的。本发明的实施方案包括诊断测定和试剂盒以测量可溶性OX40是肿瘤细胞上的膜结合OX40的潜在替代品。
本发明的抗OX40抗体可用于诊断目的，用来检测、诊断或监控与OX40相关的疾病和/或病况。本发明提供使用本领域技术人员已知的经典免疫组织学方法检测样本中OX40的存在。可以体内或体外进行OX40的检测。适用于检测OX40的存在的方法实例包括ELISA、FACS、RIA等。
对于诊断应用来说，通常用可检测的标记基团来标记抗OX40抗体。合适的标记基团包括(但不限于)以下：放射性同位素或放射性核素(例如，3H、14C、15N、35S、90Y、99Tc、111In、125I、131I)、荧光基团(例如，FITC、罗丹明、镧系元素磷光体)、酶促基团(例如，辣根过氧化物酶、β根半乳糖苷酶、荧光素酶、碱性磷酸酶)、化学发光基团、生物素基基团或由二级报导体识别的预定多肽表位(例如，亮氨酸拉链对序列、用于二级抗体的结合位点、金属结合结构域、表位标签)。在一些实施方案中，标记基团通过各种长度的间隔子臂与抗OX40抗体偶合以减小潜在的位阻。用于标记蛋白质的各种方法在本领域中已知且可用来进行本发明。
本发明的一个方面提供识别表达OX40的细胞。在一个具体实施方案中，用标记基团标记抗体并检测经过标记的抗体与OX40的结合。在另一个具体实施方案中，体内检测抗体与OX40的结合。在另一个具体实施方案中，使用本领域中已知的技术来分离和测量抗体-OX40。
本发明的另一方面提供检测与本发明的抗体竞争结合OX40的测试分子的存在。一种所述测定的实例将涉及在存在或不存在测试分子的情形下检测含有一定量OX40的溶液中的游离抗体的量。游离抗体(即，未结合OX40的抗体)的量增加将表示测试分子能与该抗体竞争结合OX40。在一个实施方案中，用标记基团标记抗体。或者，标记测试分子并在存在或不存在抗体的情形下监控游离测试分子的量。
药物组合物、施用途径
本发明提供药物组合物，其包含治疗有效量的一种或多种本发明的抗OX40抗体以及药学上可接受的稀释剂、载剂、增溶剂、乳化剂、防腐剂和/或佐剂。
在某些实施方案中，药物组合物中可接受的稀释剂、载剂、增溶剂、乳化剂、防腐剂和/或佐剂等优选地在所采用的剂量和浓度下对接受者无毒。在某些实施方案中，药物组合物可含有用于改善、维持或保留例如组合物的pH、渗透性、粘度、澄清度、颜色、等渗性、气味、无菌性、稳定性、溶解或释放速率、吸收或渗透的这类物质。这些物质为现有技术已知，例如可参见REMINGTON'S PHARMACEUTICAL SCIENCES，第18版，A.R.Genrmo编，1990，MackPublishing Company。可视预期的施用途径、递送方式和所需的剂量来确定最佳的药物组合物。
可选择本发明的药物组合物用于肠胃外递送。或者，可选择组合物用于吸入或通过消化道(诸如经口)递送。所述药学上可接受的组合物的制备在本领域的技术内。
其它药物组合物将为本领域技术人员显而易见，包括在持续或控制释放递送配制物中包含抗OX40抗体的配制物。用于配制多种其它持续或可控传递方式的技术(诸如脂质体载剂、生物易蚀微粒或多孔珠粒和积存注射)也为本领域技术人员所知。
用于体内施用的药物组合物通常以无菌制剂的形式提供。通过经无菌过滤膜过滤来实现灭菌。在组合物冻干时，可在冻干和复水之前或之后使用此方法进行灭菌。用于肠胃外施用的组合物可以冻干形式或在溶液中储存。肠胃外组合物通常放在具有无菌进入孔的容器中，例如具有皮下注射针可刺穿的塞子的静脉内溶液带或小瓶。
药物组合物一经配制，就以溶液、悬浮液、凝胶、乳液、固体、晶体或以脱水或冻干粉末的形式储存在无菌小瓶中。所述配制物可储存成即用形式或在施用前复水的形式(例如，冻干)。本发明还提供用于产生单剂量施用单位的试剂盒。本发明的试剂盒可各自含有具有干燥蛋白的第一容器和具有含水配制物的第二容器。在本发明的某些实施方案中，提供含有单腔和多腔预填充注射器(例如，液体注射器和冻干注射器)的试剂盒。
本发明也提供通过施用本发明任一实施方案所述的抗OX40抗体或其抗原结合片段或其药物组合物来治疗患者(尤其是患者的T细胞相关疾病，如T细胞相关癌症以及自体免疫疾病)的方法。
本文中，术语“患者”、“受试者”、“个体”、“对象”在本文中可互换使用，包括任何生物体，优选动物，更优选哺乳动物(例如大鼠、小鼠、狗、猫、兔等)，且最优选的是人。“治疗”指向受试者采用本文所述治疗方案以达到至少一种阳性治疗效果(比如，癌症细胞数目减少、肿瘤体积减小、癌细胞浸润至周边器官的速率降低或肿瘤转移或肿瘤生长的速率降低)。有效治疗患者的治疗方案可根据多种因素(比如患者的疾病状态、年龄、体重及疗法激发受试者的抗癌反应的能力)而变。
将采用的含有本发明抗OX40抗体或其抗原结合片段的药物组合物的治疗有效量将取决于例如治疗程度和目标。本领域技术人员将了解，用于治疗的适当剂量水平将部分取决于所递送的分子、适应症、施用途径和患者的大小(体重、体表或器官大小)和/或状况(年龄和一般健康状况)而变化。在某些实施方案中，临床医生可滴定剂量并改变施用途径来获得最佳的治疗效果。
给药频率将取决于所用配制物中特定抗OX40抗体的药物动力学参数。临床医生典型地施用组合物直到达到实现所需效果的剂量。组合物因此可作为单次剂量施用，或随时间以作为两次或多次剂量(可含有或不含有相同量的所需分子)施用，或通过植入装置或导管以连续输液的方式施用。
药物组合物的施用途径是根据已知方法，例如经口、通过静脉内、腹膜内、脑内(脑实质内)、脑室内、肌肉内、眼内、动脉内、门静脉或病灶内途径注射；通过持续释放系统或通过植入装置。
下文将以具体实施例的方式阐述本发明。应理解，这些实施例仅仅是阐述性的，并非意图限制本发明的范围。实施例中所用到的方法和材料，除非另有说明，否则均为本领域常规的材料和方法。
实施例
材料与方法
1)免疫球蛋白可变区基因人源化小鼠AceMouseGBTM源自湖南华康恒健生物技术有限公司。该小鼠均在湖南华康恒健生物技术有限公司饲养，相关动物实验的开展均符合我国法律和各级规章，并获得湖南华康恒健生物技术有限公司动物护理和使用委员会的许可。
2)OX40人源化小鼠(hOX40Tg小鼠)：人鼠嵌合Tnfrsf4(OX40)cDNA-wpre-polyA(其中OX40基因胞外区域(约2.3kb)和跨膜区域前半部分为人源，包括Exon1-5和Exon6的前半部分，跨膜区域后面半部和胞内区域为鼠源，包括Exon7和Exon6的后半部分。)该品系小鼠为上海南方模式生物科技股份有限公司利用CRISPR/Cas9技术获得。此种基因型的小鼠适用于对鼠源抗人OX40抗体的研究。
所有小鼠均饲养在上海交通大学医学院动物科学实验中心，所有动物实验的开展均符合我国法律和各级规章，并获得上海交通大学医学院动物护理和使用委员会的许可。
实施例1，免疫小鼠使其产生抗人OX40的单克隆抗体
第一次免疫采用商品化的重组人OX40抗原蛋白(6His标签，货号CK60，供应商Novoprotein)和标准的弗氏完全佐剂按照40微克人重组OX40蛋白抗原/20克小鼠体重的剂量进行。第二次至第四次免疫采用表达人OX40全长蛋白(序列参考NCBI数据库，编号NM_003327.2)的专有表达载体对6周龄大的小鼠进行免疫。第五次免疫采用商品化的重组人OX40抗原蛋白(6His标签，货号CK60，供应商Novoprotein)和PBS按照25微克人重组OX40蛋白抗原/小鼠的剂量进行。
实施例2，对免疫后的小鼠血清进行酶联免疫反应检测
将人重组OX40抗原蛋白(Novoprotein，货号CK60)用PBS稀释成0.5纳克/微升，在Maxisorp的96孔平底ELISA板加入100微升/孔抗原，用保鲜膜密封后置4℃过夜。隔天倾去抗原后，用PBS(200微升/孔)洗一遍，倾去PBS后在吸水纸上拍干并在每孔加入200微升封闭液(含有10％胎牛血清的PBS)置室温封闭2小时。封闭结束后倾去封闭液后在吸水纸上拍干。加入50微升稀释液(含有5％胎牛血清的PBS)将血清进行浓度梯度稀释并加入96孔板，置室温1小时，之后倾去样品，用洗涤液(含0.05％Tween-20的PBS)洗3遍液，最后倾去洗涤液后在吸水纸上拍干。加入50微升稀释液(含有5％胎牛血清的PBS)稀释HRP羊抗小鼠IgG二抗(终浓度0.4微克/毫升；生产商Biolegend，货号405306)置室温1小时,之后倾去液体，用洗涤液(含0.05％Tween-20的PBS)洗5遍(200微升/孔)，最后倾去洗涤液后在吸水纸上拍干。加入50微升/孔TMB-过氧化氢尿素溶液(生产商Thermo ScientificTM，货号34029)底物液置室温避光放置3-5分钟，加入50微升/孔0.25M硫酸终止反应，之后在多功能酶标仪上检测450nm波长光吸收。
Figure BDA0002651709260000331
实施例3，单细胞测序产生单克隆抗体
IgG可变区人源化小鼠经His标记的人OX40胞外段蛋白(hOX40-EC-His，Novoprotein，Cat.No.CK60，Lot.No.0331348)免疫后，取小鼠脾脏、腹股沟和腘窝淋巴结细胞进行流式分选，将分选出的IgD阴性的B谱系细胞进行单细胞测序(10x Genomics)。根据免疫后抗原特异性B细胞克隆扩张的特点从众多序列中挑出目的序列(轻链可变区和重链可变区序列)，并将其构建成带有恒定区(轻链为Cκ，重链恒定区为IgG恒定区)的完整抗体结构。将抗体序列插入至表达载体，以共转的形式转入悬浮293细胞中，收集上清，并用蛋白G珠进行亲和纯化。纯化后的抗体经分子筛(Size-Exclusion Chromatography，SEC)去除多聚体，所得单体抗体置于4℃或-20℃冰箱保存、待用。
实施例4，ELISA测定单细胞测序抗体结合hOX40-EC的能力
1)在96孔高吸附性酶标检测板(nunc)中包被100μl hOX40-EC-His(Novoprotein)，浓度为2μg/ml，置于四度冰箱孵育过夜；
2)弃去板中液体，用PBST(含0.05％Tween 20的PBS)洗板2次，加入200μl1％BSA(PBS配制)，室温封闭2小时；
3)将纯化的单细胞测序抗体、阴性对照抗体Ctrl hIgG及阳性对照抗体IBI101、Pogalizumab适当稀释(3.16μg/ml-1ng/ml)，各取100μl至上述封闭后的孔中(PBST洗3遍，弃去液体)，室温孵育1小时；
4)PBST洗板4遍，拍干液体，每孔加入100μl检测抗体羊抗人IgG Fc HRP(1:100000，Bethyl)室温孵育1小时；
5)PBST洗板5遍，拍干液体，每孔加入100μl HRP的底物TMB(A液与B液等体积混合，KPL)，显色10-30分钟后用酶标仪读取OD650的信号值。
如图1所示，单细胞测序抗体具有OX40结合能力。
实施例5，利用电融合技术从免疫后的小鼠脾脏细胞获得杂交瘤细胞
提前复苏SP2/0小鼠骨髓瘤细胞；融合当天取SP2/0小鼠骨髓瘤细胞计数；将免疫成功后的OX40小鼠脾脏放置运输培养基HB培养基(含1％P/S)中并且立刻提取分离脾脏中的细胞计数备用；取1.5x 108个脾细胞与1.5x 108个SP2/0小鼠骨髓瘤的比例混合；混合后200G离心5分钟,弃上清，用20毫升的融合液洗两遍备用；200G室温离心5分钟，弃上清并加入6.4毫升电融合缓冲液重悬沉淀；准备一个50毫升离心管，加入13毫升预热的HB培养基；将混合细胞悬液加入已经用75％酒精消毒并凉干的CUY497X10电极并采用ECFG21电融合仪(生产商NEPAGENE，型号ECFG21)的标准操作流程进行细胞电融合；融合完成后将细胞吸出并放进之前在培养箱里预热的13毫升HB培基中；用HAT培养基重悬细胞，按照5×105细胞/孔铺96孔平底板；将96孔板放在37℃培养箱静置培养，每天观察细胞，第10天，取上清进行ELISA初筛。
实施例6，利用酶联免疫反应筛选杂交瘤抗人OX40单克隆抗体
将OX40抗原(Novoprotein cat：CK60)用PBS稀释成0.5纳克/微升；在Maxisorp的96孔平底ELISA板加入100微升/孔抗原，用保鲜膜密封后置4℃过夜；隔天倾去抗原后，用PBS(200微升/孔)洗一遍，倾去PBS后在吸水纸上拍干并在每孔加入200微升封闭液置室温封闭2小时；封闭结束后倾去封闭液后在吸水纸上拍干；加入50微升样本(实施例5中获得的OX40杂交瘤细胞培养上清)，置室温1小时，之后倾去样品，用洗涤液洗3遍液，最后倾去洗涤液后在吸水纸上拍干；加入50微升用稀释液(含有5％胎牛血清的PBS)稀释HRP羊抗小鼠IgG二抗置室温1小时,之后倾去液体，用洗涤液洗5遍(200微升/孔)，最后倾去洗涤液后在吸水纸上拍干；加入50微升/孔TMB-过氧化氢尿素溶液底物液置室温避光放置3-5分钟，加入50微升/孔0.25M硫酸终止反应，之后在多功能酶标仪上检测450nm波长光吸收。结果如下表所示：
Figure BDA0002651709260000351
Figure BDA0002651709260000361
实施例7，利用流式细胞仪检测抗人OX40抗体结合OX40过表达细胞表面OX40分析
200G离心收集OX40过表达细胞下来后用含3％FCS的PBS洗一遍，然后重悬在2.5毫升含3％FCS的PBS中，将细胞加入96孔板中，每孔25微升细胞(2.5×105)，各加入75微升样本(实施例5中获得的OX40杂交瘤细胞培养上清)，设置阳参孔加入75微升抗-OX40抗体(克隆ACT35，生产商Biolegend终浓度1微克/毫升)；阴参孔1加入75微升IgG2a同种型对照(克隆MG2a-53，生产商Biolegend，终浓度1微克/毫升)；阴参孔2加入75微升含3％FCS的PBS，置4℃冰箱孵育1小时，之后用含3％FCS的PBS洗两遍；倾去上清后，样品孔、阳参孔、阴参孔1和阴参孔2加入50微升500纳克/毫升浓度的二抗(生产商Ebioscience，羊抗小鼠IgG-PE，货号12-4010-82)；之后将板置4℃冰箱避光孵育30分钟之后用含3％FCS的PBS洗两遍，最后将细胞重悬在50微升含3％FCS的PBS中用流式细胞仪进行检测。结果如下表和图2A-C所示。
Figure BDA0002651709260000362
Figure BDA0002651709260000371
实施例8，ELISA检测杂交瘤上清中anti-hOX40鼠源抗体结合hOX40-EC的能力
1)在96孔高吸附性酶标检测板(nunc)中包被100μl hOX40-EC-His(Novoprotein)，浓度为1μg/ml，置于四度冰箱孵育过夜；
2)弃去板中液体，用PBST(含0.05％Tween 20的PBS)洗板2次，加入200μl1％BSA(PBS配制)，室温封闭2小时；
3)将杂交瘤上清梯度稀释(1:10/1:100/1:1000/1:10000)，各取100μl至上述封闭后的孔中(PBST洗2遍，弃去液体)，室温孵育1小时；
4)PBST洗板4遍，拍干液体，每孔加入100μl检测抗体羊抗小鼠IgG Fc HRP(1:5000，Jackson ImmunoResearch)室温孵育1小时；
5)PBST洗板5遍，拍干液体，每孔加入100μl HRP的底物TMB(A液与B液等体积混合，KPL)，一段时间后用酶标仪读取OD650的信号值；
6)选取样本1:100稀释时的信号值进行结果统计。
结果如下表和图3所示，表明杂交瘤抗体克隆具有结合OX40的能力。
Figure BDA0002651709260000372
Figure BDA0002651709260000381
Figure BDA0002651709260000391
实施例9，杂交瘤上清中抗人OX40抗体体外免疫激活活性分析(PBMC法)
1)制备PBMC悬液：-80℃冰箱取出冻存的正常献血员PBMC(Ficoll分离获得健康人外周血单个核细胞)，迅速置于37℃水浴中复苏融解。用预热PBS洗2遍后，用适量PBS重悬细胞，并用改良纽鲍尔计数板对细胞进行计数；
2)CFSE标记PBMC：根据实验需要取出部分细胞，用PBS稀释，使得细胞密度在(2-4)*10^7/ml，体积小于5ml，加入CFSE，使得其终浓度为5μM。混匀后置于37℃培养箱中孵育15min。随后用含有9ml 5％FBS的洗液清洗细胞2次，400g离心5min，弃上清。加入适量原代细胞培养基(RPMI+10％FBS+1％Pen/Strep+1％HEPES+1％丙酮酸钠+0.1％2ME(终浓度50uM))重悬细胞，并计数；
3)除对照(未处理、仅CD3、CD3+CD28)外，用含0.2μg/ml的抗人CD3(克隆:H001，Sino Biological)原代细胞培养基重悬上述CFSE标记细胞，使其细胞密度为2*10^6/ml。根据实验设计向96孔细胞培养平底板中加入100μl上述细胞，使得每孔的细胞数为2*10^5个。未处理组加未用CFSE标记的细胞，且不加抗人CD3及其他抗体。仅CD3组加CFSE标记的细胞和抗人CD3，但不加其他抗体。CD3+CD28组加CFSE标记的细胞和抗人CD3，并加入浓度为2μg/ml的抗人CD28抗体(克隆:H001，Sino Biological)(经步骤4等体积稀释后，抗鼠CD3和CD28终浓度分别为0.1μg/ml和1μg/ml)；
4)用原代培养基稀释杂交瘤上清(1:5)，1μg/ml的ctrl hIgG和IBI101分别作为抗体的阴性对照和阳性对照。各取100μl加至上述加有抗人CD3抗体和CFSE标记PBMC的孔板中。对照组各加100μl培养基；
5)将上述细胞置于37℃培养箱中培养3天；
6)流式细胞术检测T细胞的增殖：将上述培养后的细胞转移至96孔U底板中，用PBS洗2遍，500g离心5分钟，甩去上清，将细胞重悬在含有PE-Cy7抗人CD4(克隆:SK3，1:500，BDPharmingenTM)和APC抗人CD8(克隆:RPA-T8(RUO)，1:500，BD PharmingenTM)的50μl FACS缓冲液(含有0.5％FBS，2mM EDTA的PBS)中，冰上避光孵育15分钟，然后PBS缓冲液洗涤细胞两次，重悬于含有DAPI(0.5μg/ml，Invitrogen)的200μl FACS缓冲液中，并通过流式细胞仪分析。
如图4所示，杂交瘤抗体克隆具有体外免疫激活活性(PBMC系统)。
实施例10，杂交瘤上清中抗人OX40抗体体外免疫激活活性分析(脾细胞法)
1)制备hOX40Tg小鼠脾脏白细胞单细胞悬液：无菌条件下取hOX40Tg小鼠的脾脏，研磨后用5ml红细胞裂解液ACK冰上裂解5分钟，加9ml PBS终止裂解并清洗脾脏细胞，400g离心5min，用2ml PBS重悬脾脏细胞，即获得脾脏单细胞悬液。取少量单细胞悬液进行1:100稀释，用改良纽鲍尔计数板对细胞进行计数；
2)CFSE标记脾细胞：根据实验需要取出部分细胞，用PBS稀释，使得细胞密度在(2-4)*10^7/ml，体积小于5ml，加入CFSE，使得其终浓度为5μM。混匀后置于37℃培养箱中孵育15min。随后用含有9ml 5％FBS的洗液清洗细胞2次，400g离心5min，弃上清。加入2ml原代细胞培养基(RPMI+10％FBS+1％Pen/Strep+1％HEPES+1％丙酮酸钠+0.1％2ME(终浓度50uM))重悬细胞，并计数；
3)除对照(未处理、仅CD3、CD3+CD28)外，用含0.2μg/ml的抗小鼠CD3原代细胞培养基重悬上述CFSE标记细胞，使其细胞密度为2*10^6/ml。根据实验设计向96孔细胞培养平底板中加入100μl上述细胞，使得每孔的细胞数为2*10^5个。未处理组加未用CFSE标记的细胞，且不加抗鼠CD3及其他抗体。仅CD3组加CFSE标记的细胞和抗鼠CD3，但不加其他抗体。CD3+CD28组加CFSE标记的细胞和抗鼠CD3，并加入浓度为2μg/ml的抗鼠CD28抗体(经步骤4等体积稀释后，抗鼠CD3和CD28终浓度分别为0.1μg/ml和1μg/ml)；
4)用原代培养基稀释杂交瘤上清(1:4)，1μg/ml的ctrl hIgG和IBI101分别作为抗体的阴性对照和阳性对照。各取100μl加至上述加有抗鼠CD3抗体和CFSE标记脾细胞的孔板中。对照组各加100μl培养基；
5)将上述细胞置于37℃培养箱中培养3天；
6)流式细胞术检测T细胞的增殖：将上述培养后的细胞转移至96孔U底板中，用PBS洗2遍，500g离心5分钟，甩去上清，将细胞重悬在含有PE抗小鼠CD4(克隆:GK1.5，1:500，BD)和APC抗小鼠CD8a(克隆:53-6.7，1:500，BioLegend)的50μl FACS缓冲液(含有0.5％FBS，2mM EDTA的PBS)中，冰上避光孵育15分钟，然后PBS缓冲液洗涤细胞两次，重悬于含有DAPI(0.5μg/ml，Invitrogen)的200μl FACS缓冲液中，并通过流式细胞仪分析。
图5显示杂交瘤抗体克隆具有体外免疫激活活性。
序列表
<110> 湖南华康恒健生物技术有限公司
苏州景涞医疗科技有限公司
<120> 抗OX40抗体、其药物组合物及应用
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<221> MUTAGEN
<222> (9)..(9)
<223> Xaa为Y、N、D、H、S或无
<220>
<221> MUTAGEN
<222> (10)..(10)
<223> Xaa为N、T、R、K或无
<220>
<221> MUTAGEN
<222> (11)..(11)
<223> Xaa为Y、F、S、N或无
<220>
<221> MUTAGEN
<222> (12)..(12)
<223> Xaa为Y或无
<400> 4
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 5
<211> 3
<212> PRT
<213> Artificial Sequence
<220>
<221> MUTAGEN
<222> (1)..(1)
<223> Xaa为T、K、G、W、E、M、L、D、A或Q
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为V、A、T或G
<220>
<221> MUTAGEN
<222> (3)..(3)
<223> Xaa为S或A
<400> 5
Xaa Xaa Xaa
1
<210> 6
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<221> MUTAGEN
<222> (1)..(1)
<223> Xaa为M、Q、L或H
<220>
<221> MUTAGEN
<222> (2)..(2)
<223> Xaa为G、Y、A、V、H、T、F或S
<220>
<221> MUTAGEN
<222> (3)..(3)
<223> Xaa为T、G、Y、N、L、D或S
<220>
<221> MUTAGEN
<222> (4)..(4)
<223> Xaa为H、S、T、Q、D、N、G、I或R
<220>
<221> MUTAGEN
<222> (5)..(5)
<223> Xaa为W、S、T、Y、L、I或N
<220>
<221> MUTAGEN
<222> (6)..(6)
<223> Xaa为P、S、M、I、W或
<220>
<221> MUTAGEN
<222> (7)..(7)
<223> Xaa为W、F、L、P、I、Y、R或T
<220>
<221> MUTAGEN
<222> (8)..(8)
<223> Xaa为T、L、A、F或W
<220>
<221> MUTAGEN
<222> (9)..(9)
<223> Xaa为F、L、T或无
<220>
<221> MUTAGEN
<222> (10)..(10)
<223> Xaa为T、F或无
<220>
<221> MUTAGEN
<222> (11)..(11)
<223> Xaa为F或无
<400> 6
Cys Xaa Gln Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 7
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 7
Gly Ala Ser Ile Ile Asn Asn Asn Trp
1 5
<210> 8
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 8
Gly Asp Ser Ile Ser Ser Ser Tyr Trp
1 5
<210> 9
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 9
Gly Asp Ser Ile Ser Ser Thr Asn Trp
1 5
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 10
Gly Phe Ser Leu Ser Thr Ser Ala Val Asn
1 5 10
<210> 11
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 11
Gly Phe Ser Leu Ser Thr Ser Gly Val Gly
1 5 10
<210> 12
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 12
Gly Phe Thr Phe Asp Asp Tyr Ala
1 5
<210> 13
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 13
Gly Phe Thr Phe Ser Asp Tyr Tyr
1 5
<210> 14
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 14
Gly Phe Thr Phe Ser Asn Ala Trp
1 5
<210> 15
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 15
Gly Phe Thr Phe Ser Asn Tyr Trp
1 5
<210> 16
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 16
Gly Gly Ser Ile Asn Ser Ser Ser Trp
1 5
<210> 17
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 17
Gly Gly Ser Ile Asn Ser Thr Asn Trp
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 18
Gly Gly Ser Ile Ser Asn Gly Asn Trp
1 5
<210> 19
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 19
Gly Gly Ser Ile Ser Asn Ser Asn Trp
1 5
<210> 20
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 20
Gly Gly Ser Ile Ser Arg Ser Asn Trp
1 5
<210> 21
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 21
Gly Gly Ser Ile Ser Ser Ser Ile Trp
1 5
<210> 22
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 22
Gly Gly Ser Ile Ser Ser Ser Lys Trp
1 5
<210> 23
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 23
Gly Gly Ser Ile Ser Ser Ser Asn Trp
1 5
<210> 24
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 24
Gly Gly Ser Ile Ser Ser Thr Asn Trp
1 5
<210> 25
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 25
Gly Gly Ser Ile Ser Ser Tyr Asn Trp
1 5
<210> 26
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 26
Gly Val Ser Ile Ser Ser Ser Asn Trp
1 5
<210> 27
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 27
Gly Tyr Ile Phe Thr Arg Tyr Ala
1 5
<210> 28
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 28
Gly Tyr Ile Phe Thr Ser Tyr Ala
1 5
<210> 29
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 29
Gly Tyr Thr Phe Ala Asn Phe Gly
1 5
<210> 30
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 30
Gly Tyr Thr Phe Ile Gly Tyr Tyr
1 5
<210> 31
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 31
Gly Tyr Thr Phe Thr Gly Tyr Phe
1 5
<210> 32
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 32
Gly Tyr Thr Phe Thr Gly Tyr Tyr
1 5
<210> 33
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 33
Gly Tyr Thr Phe Thr Asn Tyr Ala
1 5
<210> 34
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 34
Gly Tyr Thr Phe Thr Asn Tyr Gly
1 5
<210> 35
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 35
Gly Tyr Thr Phe Thr Arg Tyr Thr
1 5
<210> 36
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 36
Gly Tyr Thr Phe Thr Ser Tyr Asp
1 5
<210> 37
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 37
Gly Tyr Thr Phe Thr Ser Tyr Gly
1 5
<210> 38
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 38
Ser Gly Ser Ile Ser Ser Ser Ile Trp
1 5
<210> 39
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 39
Met Asn Pro Asn Ser Gly Asn Thr
1 5
<210> 40
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 40
Ile Tyr Trp Ser Asp Asp Lys
1 5
<210> 41
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 41
Ile Tyr Gln Ser Gly Ser Thr
1 5
<210> 42
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 42
Ile Tyr His Ser Gly Ser Thr
1 5
<210> 43
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 43
Ile Tyr His Ser Gly Asn Thr
1 5
<210> 44
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 44
Ile Tyr His Ser Gly Asp Thr
1 5
<210> 45
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 45
Ile Tyr His Gly Gly Ser Thr
1 5
<210> 46
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 46
Ile Ser Trp Asn Ser Gly Ser Ile
1 5
<210> 47
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 47
Ile Ser Ser Ser Gly Thr Thr Ile
1 5
<210> 48
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 48
Ile Ser His Asn Gly Ser Thr
1 5
<210> 49
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 49
Ile Ser Gly Ser Asp Ser Thr Ile
1 5
<210> 50
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 50
Ile Ser Ala Tyr Ser Gly Asp Lys
1 5
<210> 51
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 51
Ile Ser Ala Tyr Asn Gly Tyr Thr
1 5
<210> 52
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 52
Ile Ser Ala Tyr Asn Gly Asn Thr
1 5
<210> 53
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 53
Ile Ser Ala Tyr Asn Gly His Thr
1 5
<210> 54
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 54
Ile Asn Pro Asn Ser Gly Gly Thr
1 5
<210> 55
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 55
Ile Asn Pro Asn Ser Gly Ala Thr
1 5
<210> 56
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 56
Ile Asn Pro Asn Asn Gly Asp Thr
1 5
<210> 57
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 57
Ile Asn His Ser Gly Asn Thr
1 5
<210> 58
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 58
Ile Asn His Asn Gly Ser Thr
1 5
<210> 59
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 59
Ile Asn Ala Gly Asn Gly Asn Thr
1 5
<210> 60
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 60
Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile
1 5 10
<210> 61
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 61
Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr
1 5 10
<210> 62
<211> 8
<212> PRT
<213> Artificial Sequence
<400> 62
Ile Lys Gln Asp Gly Ser Glu Lys
1 5
<210> 63
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 63
Ile His His Ser Gly Asn Thr
1 5
<210> 64
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 64
Ile Phe Trp Asn Asp Asp Lys
1 5
<210> 65
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 65
Ile Phe His Ser Gly Thr Thr
1 5
<210> 66
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 66
Cys Val Arg Ser Gly Asp Trp His Cys Phe Asp Tyr Trp
1 5 10
<210> 67
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 67
Cys Val Lys Asp Tyr Tyr Gly Ser Gly Ser Tyr Gly Asp Ile Gln His
1 5 10 15
Trp
<210> 68
<211> 14
<212> PRT
<213> Artificial Sequence
<400> 68
Cys Val Ile Trp Phe Gly Glu Leu Leu Ser Phe Asp Tyr Trp
1 5 10
<210> 69
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 69
Cys Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp
1 5 10
<210> 70
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 70
Cys Val Ala Tyr Val Ser Gly Thr Tyr Tyr Asn Phe Asp Tyr Trp
1 5 10 15
<210> 71
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 71
Cys Thr Thr Asp Leu Tyr Ser Ser Ser Trp Asp Ala Phe Asp Ile Trp
1 5 10 15
<210> 72
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 72
Cys Thr Ser Asp Tyr Gly Asp Tyr Trp
1 5
<210> 73
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 73
Cys Thr Ser Ala Ala Arg Arg Gly Tyr Phe Asp Ile Trp
1 5 10
<210> 74
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 74
Cys Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp
1 5 10
<210> 75
<211> 14
<212> PRT
<213> Artificial Sequence
<400> 75
Cys Thr His Arg Pro Gly Tyr Thr Tyr Gly Tyr Gly Tyr Trp
1 5 10
<210> 76
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 76
Cys Ser Arg Glu Gly Gly Asn Ala Phe Phe Asp Tyr Trp
1 5 10
<210> 77
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 77
Cys Ala Thr Leu Pro Gly Tyr Ser Ser Gly Trp Phe Asp Ser Trp
1 5 10 15
<210> 78
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 78
Cys Ala Ser Ser Gly Ser Leu Tyr Met Asp Val Trp
1 5 10
<210> 79
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 79
Cys Ala Ser Glu Asp Phe Asp Tyr Trp
1 5
<210> 80
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 80
Cys Ala Arg Tyr Ser Thr Pro Phe Phe Asp Tyr Trp
1 5 10
<210> 81
<211> 14
<212> PRT
<213> Artificial Sequence
<400> 81
Cys Ala Arg Val Val Val Ala Ser Tyr Tyr Phe Asp Asn Trp
1 5 10
<210> 82
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 82
Cys Ala Arg Val Gly Ala Asn Trp Phe Asp Pro Trp
1 5 10
<210> 83
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 83
Cys Ala Arg Thr Gly Pro Thr Val Thr Thr Asp Tyr Trp
1 5 10
<210> 84
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 84
Cys Ala Arg Thr Gly Pro Ile Val Thr Thr Glu Tyr Trp
1 5 10
<210> 85
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 85
Cys Ala Arg Ser Gly Thr Thr His Thr Phe Asp Ile Trp
1 5 10
<210> 86
<211> 19
<212> PRT
<213> Artificial Sequence
<400> 86
Cys Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met
1 5 10 15
Asp Val Trp
<210> 87
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 87
Cys Ala Arg Met Gly Tyr Tyr Tyr Gly Ser Gly Ser Asp Tyr Trp
1 5 10 15
<210> 88
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 88
Cys Ala Arg Lys Gly Tyr Asn Trp Asn Tyr Asp Tyr Phe Asp Tyr Trp
1 5 10 15
<210> 89
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 89
Cys Ala Arg Gly Gly Thr Thr Phe Asp Tyr Trp
1 5 10
<210> 90
<211> 18
<212> PRT
<213> Artificial Sequence
<400> 90
Cys Ala Arg Gly Gly Leu Tyr Leu Tyr Ser Ser Ser Trp Phe Phe Asp
1 5 10 15
Ser Trp
<210> 91
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 91
Cys Ala Arg Gly Gly Ala Val Ala Leu Asp Tyr Trp
1 5 10
<210> 92
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 92
Cys Ala Arg Gly Asp Val Leu Leu Trp Phe Gly
1 5 10
<210> 93
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 93
Cys Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly
1 5 10
<210> 94
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 94
Cys Ala Arg Glu Trp Phe Gly Glu Leu Trp Gln Ile Phe Phe Asp Tyr
1 5 10 15
Trp
<210> 95
<211> 14
<212> PRT
<213> Artificial Sequence
<400> 95
Cys Ala Arg Glu Gly Val Gly Ala Thr Pro Phe Asp Tyr Trp
1 5 10
<210> 96
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 96
Cys Ala Arg Glu Asp Tyr Tyr Tyr Met Asp Val Trp
1 5 10
<210> 97
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 97
Cys Ala Arg Asp Trp Glu Gly Phe Gly Glu Ser Ile Gly Asp Tyr Trp
1 5 10 15
<210> 98
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 98
Cys Ala Arg Asp Trp Ala Gly Asp Arg Tyr Tyr Phe Asp Tyr Trp
1 5 10 15
<210> 99
<211> 15
<212> PRT
<213> Artificial Sequence
<400> 99
Cys Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp
1 5 10 15
<210> 100
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 100
Cys Ala Arg Asp Ser Ser Thr Trp Tyr Glu Gly Asn Tyr Phe Asp Tyr
1 5 10 15
Trp
<210> 101
<211> 19
<212> PRT
<213> Artificial Sequence
<400> 101
Cys Ala Arg Asp Arg Asp Val Tyr Gly Tyr Ser Gly Tyr Gly Tyr Phe
1 5 10 15
Asp Tyr Trp
<210> 102
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 102
Cys Ala Arg Asp Gln Asp Tyr Tyr Gly Ser Gly Asn Phe Tyr Tyr Trp
1 5 10 15
<210> 103
<211> 17
<212> PRT
<213> Artificial Sequence
<400> 103
Cys Ala Arg Asp Gln Ala Asp Tyr Phe Gly Ser Gly Asn Tyr Val Tyr
1 5 10 15
Trp
<210> 104
<211> 18
<212> PRT
<213> Artificial Sequence
<400> 104
Cys Ala Arg Asp Pro Tyr Gly Ser Gly Thr Tyr Tyr Arg Leu Phe Asp
1 5 10 15
Tyr Trp
<210> 105
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 105
Cys Ala Arg Asp Pro Pro Ser Asp Tyr Trp
1 5 10
<210> 106
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 106
Cys Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp
1 5 10 15
<210> 107
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 107
Cys Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp
1 5 10
<210> 108
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 108
Cys Ala Gln Tyr Asn Trp Asn Ser Ser Phe Asp Tyr Trp
1 5 10
<210> 109
<211> 9
<212> PRT
<213> Artificial Sequence
<400> 109
Cys Ala Asn Glu Asp Phe Asp Tyr Trp
1 5
<210> 110
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 110
Cys Ala Lys Ser Gly Thr Tyr Gly Tyr Phe Asp Tyr Trp
1 5 10
<210> 111
<211> 16
<212> PRT
<213> Artificial Sequence
<400> 111
Cys Ala Lys Asp Lys Gly Ile Met Val Arg Gly Gly Pro Asp Tyr Trp
1 5 10 15
<210> 112
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 112
Cys Ala His Tyr Ser Asn Tyr Asp Tyr Trp
1 5 10
<210> 113
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 113
Cys Ala Gly Glu Asp Thr Gly Trp Pro Phe Asp Phe Trp
1 5 10
<210> 114
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 114
Cys Ala Glu Thr Ser Thr Ile Thr Thr Asn Tyr Trp
1 5 10
<210> 115
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 115
His Gly Ser Ser Thr Tyr
1 5
<210> 116
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 116
Gln Asp Ile Asn Thr Tyr
1 5
<210> 117
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 117
Gln Asp Ile Ser Asp Tyr
1 5
<210> 118
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 118
Gln Asp Ile Ser Asn Tyr
1 5
<210> 119
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 119
Gln Gly Ile Arg Asn Asp
1 5
<210> 120
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 120
Gln Gly Ile Trp Asn Asp
1 5
<210> 121
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 121
Gln Ser Ile Ser Asn Trp
1 5
<210> 122
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 122
Gln Ser Ile Ser Asn Tyr
1 5
<210> 123
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 123
Gln Ser Ile Ser Ser Trp
1 5
<210> 124
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 124
Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr
1 5 10
<210> 125
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 125
Gln Ser Leu Val Tyr Arg Asp Gly Asn Thr Phe
1 5 10
<210> 126
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 126
Gln Ser Leu Val Tyr Ser Asp Gly Asp Thr Tyr
1 5 10
<210> 127
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 127
Gln Ser Leu Val Tyr Ser Asp Gly His Thr Ser
1 5 10
<210> 128
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 128
Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Phe
1 5 10
<210> 129
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 129
Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Asn
1 5 10
<210> 130
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 130
Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr
1 5 10
<210> 131
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 131
Gln Ser Thr Ser Ser Tyr
1 5
<210> 132
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 132
Gln Ser Val Phe Tyr Ser Ser Asn Ser Arg Asn Tyr
1 5 10
<210> 133
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 133
Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr
1 5 10
<210> 134
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 134
Gln Ser Val Ser Gly Asp Tyr
1 5
<210> 135
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 135
Gln Ser Val Ser Gly Asn Tyr
1 5
<210> 136
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 136
Gln Ser Val Ser Gly Ser Tyr
1 5
<210> 137
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 137
Gln Ser Val Ser Ser Gly Tyr
1 5
<210> 138
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 138
Gln Ser Val Ser Ser Asn
1 5
<210> 139
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 139
Gln Ser Val Ser Ser Asn Tyr
1 5
<210> 140
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 140
Gln Ser Val Ser Ser Arg Tyr
1 5
<210> 141
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 141
Gln Ser Val Ser Ser Ser Tyr
1 5
<210> 142
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 142
Gln Ser Val Ser Ser Thr Tyr
1 5
<210> 143
<211> 6
<212> PRT
<213> Artificial Sequence
<400> 143
Gln Thr Ile Ser Ser Tyr
1 5
<210> 144
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 144
Gln Thr Val Ser Gly Asn Tyr
1 5
<210> 145
<211> 7
<212> PRT
<213> Artificial Sequence
<400> 145
Gln Thr Val Ser Ser Ser Tyr
1 5
<210> 146
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 146
Thr Val Ser
1
<210> 147
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 147
Lys Val Ser
1
<210> 148
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 148
Gly Ala Ser
1
<210> 149
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 149
Trp Ala Ser
1
<210> 150
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 150
Glu Val Ser
1
<210> 151
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 151
Met Ala Ser
1
<210> 152
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 152
Gly Thr Ser
1
<210> 153
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 153
Leu Gly Ser
1
<210> 154
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 154
Asp Ala Ser
1
<210> 155
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 155
Ala Ala Ser
1
<210> 156
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 156
Trp Thr Ser
1
<210> 157
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 157
Asp Ala Phe
1
<210> 158
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 158
Gln Val Ser
1
<210> 159
<211> 3
<212> PRT
<213> Artificial Sequence
<400> 159
Lys Ala Ala
1
<210> 160
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 160
Cys Met Gln Gly Thr His Trp Pro Trp Thr Phe
1 5 10
<210> 161
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 161
Cys Gln Gln Tyr Gly Ser Ser Pro Phe Thr Phe
1 5 10
<210> 162
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 162
Cys Gln Gln Tyr Tyr Ser Thr Pro Leu Thr Phe
1 5 10
<210> 163
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 163
Cys Met Gln Gly Thr His Trp Pro Pro Thr Phe
1 5 10
<210> 164
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 164
Cys Gln Gln Tyr Asn Ser Tyr Ser Leu Thr Phe
1 5 10
<210> 165
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 165
Cys Gln Gln Tyr Gly Thr Ser Pro Ile Thr Phe
1 5 10
<210> 166
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 166
Cys Met Gln Ala Leu Gln Thr Pro Tyr Thr Phe
1 5 10
<210> 167
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 167
Cys Gln Gln Tyr Asp Asp Leu Pro Leu Thr Phe
1 5 10
<210> 168
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 168
Cys Gln Gln Tyr Gly Ser Ser Pro Leu Thr Phe
1 5 10
<210> 169
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 169
Cys Gln Gln Tyr Asp Asn Leu Pro Ile Thr Phe
1 5 10
<210> 170
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 170
Cys Gln Gln Tyr Gly Gly Ser Pro Pro Leu Leu Thr Phe
1 5 10
<210> 171
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 171
Cys Met Gln Val Leu Gln Thr Pro Tyr Thr Phe
1 5 10
<210> 172
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 172
Cys Met Gln Gly Thr His Trp Pro Arg Thr Phe
1 5 10
<210> 173
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 173
Cys Gln Gln Tyr Gly Ser Ser Met Phe Thr Phe
1 5 10
<210> 174
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 174
Cys Met Gln Ala Leu Gln Thr Pro Leu Thr Phe
1 5 10
<210> 175
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 175
Cys Leu Gln His Asn Ser Tyr Pro Trp Thr Phe
1 5 10
<210> 176
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 176
Cys Gln Gln Tyr Tyr Ser Ser Pro Trp Thr Phe
1 5 10
<210> 177
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 177
Cys Gln Gln Tyr Asn Asn Trp Pro Leu Thr Phe
1 5 10
<210> 178
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 178
Cys Gln Gln Tyr Asp Ile Leu Pro Tyr Thr Phe
1 5 10
<210> 179
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 179
Cys Gln Gln Tyr Tyr Ser Thr Pro Tyr Thr Phe
1 5 10
<210> 180
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 180
Cys Gln Gln Tyr Tyr Ser Ile Pro Leu Thr Phe
1 5 10
<210> 181
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 181
Cys Gln Gln Tyr Gly Asn Ser Pro Leu Thr Phe
1 5 10
<210> 182
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 182
Cys Gln Gln Tyr Gly Ser Ser Pro Ile Thr Phe
1 5 10
<210> 183
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 183
Cys Gln Gln Tyr Gly Ser Leu Pro Leu Thr Phe
1 5 10
<210> 184
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 184
Cys Gln Gln Tyr Ser Ser Ser Pro Ile Thr Phe
1 5 10
<210> 185
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 185
Cys Leu Gln Tyr Gly Ser Ser Pro Leu Thr Phe
1 5 10
<210> 186
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 186
Cys Gln Gln Tyr Gly Arg Ser Pro Leu Thr Phe
1 5 10
<210> 187
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 187
Cys Gln Gln Thr Tyr Ser Ile Pro Ile Thr Phe
1 5 10
<210> 188
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 188
Cys Gln Gln Tyr Gly Asn Ser Pro Ile Thr Phe
1 5 10
<210> 189
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 189
Cys Gln Gln Tyr Asp Asn Leu Pro Phe Thr Phe
1 5 10
<210> 190
<211> 13
<212> PRT
<213> Artificial Sequence
<400> 190
Cys Met Gln Gly Thr His Trp Pro Pro Ala Leu Thr Phe
1 5 10
<210> 191
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 191
Cys Gln Gln Phe Gly Ser Ser Pro Leu Thr Phe
1 5 10
<210> 192
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 192
Cys Gln Gln Tyr Asp Asn Leu Ile Thr Phe
1 5 10
<210> 193
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 193
Cys Gln Gln Ser Tyr Ser Ile Pro Ile Thr Phe
1 5 10
<210> 194
<211> 10
<212> PRT
<213> Artificial Sequence
<400> 194
Cys Gln Gln Tyr Tyr Asp Tyr Trp Thr Phe
1 5 10
<210> 195
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 195
Cys Leu Gln Tyr Asn Asn Tyr Pro Leu Thr Phe
1 5 10
<210> 196
<211> 12
<212> PRT
<213> Artificial Sequence
<400> 196
Cys His Gln Tyr Asn Asn Trp Pro Pro Trp Thr Phe
1 5 10
<210> 197
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 197
Cys Gln Gln Tyr Gly Ser Leu Pro Ile Thr Phe
1 5 10
<210> 198
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 198
Cys Gln Gln Ser Tyr Asn Asn Pro Leu Thr Phe
1 5 10
<210> 199
<211> 11
<212> PRT
<213> Artificial Sequence
<400> 199
Cys Gln Gln Tyr Asn Asn Tyr Thr Phe Thr Phe
1 5 10
<210> 200
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 200
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 201
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 201
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Thr Val Ser Tyr Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 202
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 202
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Ser Cys Ala Phe Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Ser Gly Asn Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Arg Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 203
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 203
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Thr Val Ser Tyr Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 204
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 204
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Ser Phe Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Leu Ser
65 70 75 80
Leu Asn Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 205
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 205
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 206
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 206
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Ser His Asn Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 207
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 207
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 208
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 208
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Ser Gly Asp Lys Lys Tyr Glu Gln Lys Phe
50 55 60
Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 209
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 209
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 210
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 210
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Arg Tyr
20 25 30
Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Ser Gly Thr Tyr Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 211
<211> 113
<212> PRT
<213> Artificial Sequence
<400> 211
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 212
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 212
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Arg Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Asp Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 213
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 213
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Ile Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Glu Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 214
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 214
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Ser Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Gly Gly Gly Tyr Asp Ala Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 215
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 215
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Arg
20 25 30
Asp Gly Asn Thr Phe Leu Phe Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Val Tyr Glu Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Asp Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 216
<211> 115
<212> PRT
<213> Artificial Sequence
<400> 216
Gln Val Pro Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Asn Pro Asn Asn Gly Asp Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Gly Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Pro Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 217
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 217
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Arg Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Met Ala Ser Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 218
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 218
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Phe Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Ser Ile Leu Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Thr Thr His Thr Phe Asp Ile Trp Gly Gln Gly Thr
100 105 110
Met Val Thr Val Ser Ser
115
<210> 219
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 219
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 220
<211> 122
<212> PRT
<213> Artificial Sequence
<400> 220
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Val Lys Asp Tyr Tyr Gly Ser Gly Ser Tyr Gly Asp Ile Gln His Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 221
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 221
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Arg Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 222
<211> 123
<212> PRT
<213> Artificial Sequence
<400> 222
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Arg Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Leu Tyr Ser Ser Ser Trp Asp Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 223
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 223
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asp Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg
100 105
<210> 224
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 224
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Trp Ala Gly Asp Arg Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 225
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 225
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 226
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 226
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Val Gly Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Leu Ile Tyr Trp Ser Asp Asp Lys Arg Tyr Ser Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asn Gln Val
65 70 75 80
Val Leu Thr Met Thr Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Thr His Arg Pro Gly Tyr Thr Tyr Gly Tyr Gly Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 227
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 227
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Phe Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Leu Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 228
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 228
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Ser His Asn Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 229
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 229
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 230
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 230
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile His His Ser Gly Asn Thr Asn Cys Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 231
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 231
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asp
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Lys Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 232
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 232
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 233
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 233
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asp Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Leu Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asp Leu Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Arg
100 105
<210> 234
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 234
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Met Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Asn Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 235
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 235
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asp Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Thr Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ala Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Met Gln Gly
85 90 95
Thr His Trp Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 236
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 236
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Ser Gly Asp Lys Lys Tyr Glu Gln Lys Phe
50 55 60
Gln Gly Arg Val Ser Val Thr Thr Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Trp Ala Gly Asp His Tyr Tyr Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 237
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 237
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Val Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 238
<211> 124
<212> PRT
<213> Artificial Sequence
<400> 238
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met Asp
100 105 110
Val Trp Gly Ile Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 239
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 239
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu
65 70 75 80
Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 240
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 240
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Ser Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 241
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 241
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu
65 70 75 80
Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 242
<211> 123
<212> PRT
<213> Artificial Sequence
<400> 242
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Leu Tyr Leu Tyr Ser Ser Ser Trp Phe Phe Asp Ser
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 243
<211> 110
<212> PRT
<213> Artificial Sequence
<400> 243
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Gly Ser Pro
85 90 95
Pro Leu Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 244
<211> 124
<212> PRT
<213> Artificial Sequence
<400> 244
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Trp Ile Asn Ala Gly Asn Gly Asn Thr Lys Tyr Ser Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Phe Tyr Cys
85 90 95
Ala Arg Ser Gly Leu Tyr Glu Trp Glu Leu Gln Tyr Tyr Tyr Met Asp
100 105 110
Val Trp Gly Ile Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 245
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 245
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Phe Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Val
85 90 95
Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 246
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 246
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Phe Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Ala Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Val Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Arg Leu Arg Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 247
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 247
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly His Thr Ser Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Asp Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Leu Glu Ala Glu Asp Val Gly Val Tyr Cys Cys Met Gln Gly
85 90 95
Thr His Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 248
<211> 123
<212> PRT
<213> Artificial Sequence
<400> 248
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Thr
20 25 30
Asn Trp Trp Gly Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr Gln Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Pro Tyr Gly Ser Gly Thr Tyr Tyr Arg Leu Phe Asp Tyr
100 105 110
Trp Gly Gln Gly Ile Leu Val Thr Val Ser Ser
115 120
<210> 249
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 249
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Met
85 90 95
Phe Thr Phe Gly Pro Gly Thr Asn Val Asp Ile Lys
100 105
<210> 250
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 250
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Met Asn Pro Asn Ser Gly Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Lys Gly Tyr Asn Trp Asn Tyr Asp Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 251
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 251
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 252
<211> 115
<212> PRT
<213> Artificial Sequence
<400> 252
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala His Tyr Ser Asn Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser
115
<210> 253
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 253
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 254
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 254
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Phe Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Ala Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Val Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Arg Leu Arg Phe Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Glu Ala Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 255
<211> 113
<212> PRT
<213> Artificial Sequence
<400> 255
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ser Ser Gln Ser Val Phe Tyr Ser
20 25 30
Ser Asn Ser Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Leu Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 256
<211> 122
<212> PRT
<213> Artificial Sequence
<400> 256
Gln Val Gln Leu Val His Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ile Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Thr Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Trp Phe Gly Glu Leu Trp Gln Ile Phe Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 257
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 257
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Phe Gly Ala Ser Thr Arg Ala Thr Gly Thr Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Ile Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 258
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 258
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
85 90 95
Ala Lys Asp Lys Gly Ile Met Val Arg Gly Gly Pro Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 259
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 259
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Arg
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Ile Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 260
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 260
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Glu Gly Gly Asn Ala Phe Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 261
<211> 113
<212> PRT
<213> Artificial Sequence
<400> 261
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Met Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Thr Pro Tyr Thr Phe Gly Gln Gly Thr Gln Leu Glu Ile
100 105 110
Lys
<210> 262
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 262
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile His His Ser Gly Asn Thr Asn Cys Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Tyr Val Thr Asp Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 263
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 263
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asp
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Lys Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 264
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 264
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile His His Ser Gly Asn Thr Asn Cys Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 265
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 265
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asp
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 266
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 266
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Cys Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 267
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 267
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asp
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Leu Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Lys Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 268
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 268
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Cys Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 269
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 269
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asp
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Lys Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 270
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 270
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Ser Gly Ser Ile Ser Ser Ser
20 25 30
Ile Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ala Gly Thr Gly Thr Thr Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 271
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 271
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 272
<211> 123
<212> PRT
<213> Artificial Sequence
<400> 272
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Ser Lys Ala Asp Gly Gly Thr Ile Asp Tyr Ala Ala
50 55 60
Pro Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Arg Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Thr Asp Leu Tyr Ser Ser Ser Trp Asp Ala Phe Asp Ile
100 105 110
Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
115 120
<210> 273
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 273
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 274
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 274
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Gly Ala Asn Trp Phe Asp Pro Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 275
<211> 113
<212> PRT
<213> Artificial Sequence
<400> 275
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser
20 25 30
Ser Asn Asn Lys Asn Tyr Leu Val Trp Tyr Gln Gln Thr Pro Gly Gln
35 40 45
Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Ser Ile Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 276
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 276
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Val Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Ser Thr Leu Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Glu Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 277
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 277
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Gly Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Phe Arg Ala Thr Gly Ile Pro Asp Asn Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Thr Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 278
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 278
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Asn Gly
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Arg Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Arg Ser Gly Asp Trp His Cys Phe Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 279
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 279
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Glu
65 70 75 80
Pro Glu Asp Phe Val Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro
85 90 95
Leu Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 280
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 280
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Asp Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Val Ser
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 281
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 281
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 282
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 282
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 283
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 283
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Thr Lys
100 105
<210> 284
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 284
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Asp Tyr Tyr Gly Ser Gly Asn Phe Tyr Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 285
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 285
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 286
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 286
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Ser Gln Ile Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Arg Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 287
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 287
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Ser Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Thr Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 288
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 288
Gln Val Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Lys Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 289
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 289
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Trp Ala Ser Gln Ser Val Ser Ser Thr
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 290
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 290
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Thr Thr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 291
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 291
Glu Ile Val Leu Met Gln Tyr Pro Gly Thr Leu Ser Leu Ser Ser Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Ser Gly Met Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys
100 105
<210> 292
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 292
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Gly Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Thr Leu Pro Gly Tyr Ser Ser Gly Trp Phe Asp Ser Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 293
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 293
Glu Ile Val Leu Met Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ser Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Arg Val Glu Ile Lys
100 105
<210> 294
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 294
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Leu Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Cys Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Ile Pro Gly Lys Arg Ala Gly Val
35 40 45
Asp Trp Gly Asn Leu Ser Trp Glu His Gln Leu Gln Pro Ala Pro Gln
50 55 60
Glu Ser Ser His His Ile Ser Arg Gln Val Gln Glu Pro Val Leu Pro
65 70 75 80
Glu Ala Glu Leu Cys Asp Arg Arg Gly His Asp Arg Val Leu Leu Cys
85 90 95
Glu Asn Gly Val Leu Leu Trp Phe Gly Glu Leu Leu Gly Pro Gly Asn
100 105 110
Pro Gly His Arg Leu Leu
115
<210> 295
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 295
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Phe Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys
100 105
<210> 296
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 296
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ala Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Pro Thr Val Thr Thr Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 297
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 297
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Tyr Arg Ala Thr Gly Met Pro Glu Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Tyr Gly Arg Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 298
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 298
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Val Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Glu Thr Ser Thr Ile Thr Thr Asn Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 299
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 299
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr Ser Ile Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 300
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 300
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Asn Ser Thr
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ala Val Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 301
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 301
Glu Ile Val Leu Thr Gln Ser Pro Gly Pro Leu Ser Leu Ser Pro Gly
1 5 10 15
Asp Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Thr Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Leu Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Asn Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 302
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 302
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Asp Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Val Ser
65 70 75 80
Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Ile Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 303
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 303
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Phe Asn Leu Glu Val Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 304
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 304
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly His Thr Asn Tyr Ala Gln Lys Leu
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr
65 70 75 80
Met Glu Leu Trp Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Asp Tyr Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
100 105 110
Ser Ser
<210> 305
<211> 114
<212> PRT
<213> Artificial Sequence
<400> 305
Asp Val Val Val Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Asn Leu Tyr Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Gln Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro Ala Leu Thr Phe Gly Gly Gly Thr Glu Val Glu
100 105 110
Ile Lys
<210> 306
<211> 116
<212> PRT
<213> Artificial Sequence
<400> 306
Gln Val Gln Met Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Ile Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Lys Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Ile Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Arg Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Asp Val Leu Leu Trp Phe Gly Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 307
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 307
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Phe Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Thr Lys
100 105
<210> 308
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 308
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Asn Leu Ser Leu Thr Cys Val Val Ser Gly Ala Ser Ile Ile Asn Asn
20 25 30
Asn Trp Trp Thr Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Phe His Ser Gly Thr Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Asn Arg Val Thr Ile Ser Val Asp Lys Ala Lys Asn Gln Phe Ser
65 70 75 80
Leu Asn Leu Lys Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Val Ala Tyr Val Ser Gly Thr Tyr Tyr Asn Phe Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 309
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 309
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Phe Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 310
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 310
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asp Phe Ala Gln Lys Phe
50 55 60
Gln Ala Arg Val Thr Met Thr Arg Asp Thr Ala Ile Asn Ile Val Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Val Val Ala Ser Tyr Tyr Phe Asp Asn Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 311
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 311
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 312
<211> 124
<212> PRT
<213> Artificial Sequence
<400> 312
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Ile
35 40 45
Ser Tyr Ile Ser Gly Ser Asp Ser Thr Ile Tyr Tyr Glu Asp Ser Val
50 55 60
Met Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Asp Val Tyr Gly Tyr Ser Gly Tyr Gly Tyr Phe Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 313
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 313
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 314
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 314
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Thr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Thr Gly Pro Ile Val Thr Thr Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 315
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 315
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Gly
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 316
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 316
Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Ala Val Asn Val Gly Trp Ile Arg Gln Pro His Gly Lys Ala Leu Glu
35 40 45
Trp Leu Ala Leu Ile Phe Trp Asn Asp Asp Lys Arg Tyr Ser Pro Ser
50 55 60
Leu Lys Asn Arg Leu Thr Ile Thr Lys Asp Thr Ser Lys Asp Gln Val
65 70 75 80
Val Leu Thr Met Ser Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Gln Tyr Asn Trp Asn Ser Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 317
<211> 106
<212> PRT
<213> Artificial Sequence
<400> 317
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Asn Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Phe Tyr Cys Gln Gln Tyr Asp Asn Leu Ile Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 318
<211> 120
<212> PRT
<213> Artificial Sequence
<400> 318
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Lys Arg Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Thr
50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser Lys Asn Thr
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Thr Ser Ala Ala Arg Arg Gly Tyr Phe Asp Ile Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 319
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 319
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Arg
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Asn Arg Ala Thr Gly Met Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 320
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 320
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Arg Ser
20 25 30
Asn Trp Trp Thr Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Leu Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Ser Gly Ser Leu Tyr Met Asp Val Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 321
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 321
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Thr Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ile Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 322
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 322
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 Asn Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Val Gly Ala Thr Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Ser Leu Val Thr Val Ser Ser
115
<210> 323
<211> 106
<212> PRT
<213> Artificial Sequence
<400> 323
Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Lys Ala Ala Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
65 70 75 80
Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Asp Tyr Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 324
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 324
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Asp Ser Ile Ser Ser Thr
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Asn His Asn Gly Ser Thr Tyr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Arg Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Tyr Tyr Tyr Met Asp Val Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 325
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 325
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Thr Ser Gln Gly Ile Trp Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Glu Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Asn Asn Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 326
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 326
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Glu Asp Tyr Tyr Gly Ser Gly Asn Tyr Tyr His Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 327
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 327
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ile Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Tyr Asn Asn Trp Pro Pro
85 90 95
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 328
<211> 122
<212> PRT
<213> Artificial Sequence
<400> 328
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Tyr Ile Ser Ser Ser Gly Thr Thr Ile Tyr Cys Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Ser Ser Thr Trp Tyr Glu Gly Asn Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 329
<211> 112
<212> PRT
<213> Artificial Sequence
<400> 329
Asp Val Val Val Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val Tyr Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 330
<211> 122
<212> PRT
<213> Artificial Sequence
<400> 330
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Asn Ser Ser
20 25 30
Ser Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asp Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Ala Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gln Ala Asp Tyr Phe Gly Ser Gly Asn Tyr Val Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 331
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 331
Glu Ile Val Leu Met Gln Tyr Pro Gly Thr Leu Ser Leu Ser Ser Gly
1 5 10 15
Glu Arg Arg Val Leu Ser Cys Arg Pro Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Leu Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Val Glu Ile Lys
100 105
<210> 332
<211> 121
<212> PRT
<213> Artificial Sequence
<400> 332
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Ala Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Trp Glu Gly Phe Gly Glu Ser Ile Gly Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 333
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 333
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Phe Ser Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile His Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Leu Gln Tyr Gly Ser Ser Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 334
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 334
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Asn Ser
20 25 30
Asn Trp Trp Asn Trp Val Arg Gln Pro Pro Gly Arg Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Tyr Ser Thr Pro Phe Phe Asp Tyr Trp Gly Gln Gly Asn Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 335
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 335
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Gln Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Cys Cys Gln Gln Ser Tyr Asn Asn Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 336
<211> 117
<212> PRT
<213> Artificial Sequence
<400> 336
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Ser Gly Gly Ser Ile Ser Ser Ser
20 25 30
Asn Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Asn Thr Ile Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Leu Asp Lys Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Ser Gly Ser Leu Tyr Met Asp Val Trp Gly Lys Gly Thr Thr
100 105 110
Val Thr Val Ser Ser
115
<210> 337
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 337
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Leu Ser Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser His Gly Ser Ser Thr Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Gly Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Phe Gly Thr Asp Phe Ile Leu Thr Ile Ser Ser Met Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ile Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 338
<211> 119
<212> PRT
<213> Artificial Sequence
<400> 338
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ala Asn Phe
20 25 30
Gly Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Trp Ile Ser Ala Tyr Asn Gly Tyr Thr Asn Tyr Ala Gln Gln Phe
50 55 60
Gln Gly Arg Ile Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Val Ile Trp Phe Gly Glu Leu Leu Ser Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 339
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 339
Asp Ile Gln Met Thr Gln Phe Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly
50 55 60
Asn Gly Phe Gly Thr Asp Phe Thr Phe Pro Leu Ser Arg Met Gln Pro
65 70 75 80
Glu Asp Phe Ala Ser Ser Tyr Cys Gln Gln Tyr Asn Asn Tyr Thr Phe
85 90 95
Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys
100 105
<210> 340
<211> 118
<212> PRT
<213> Artificial Sequence
<400> 340
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gly
1 5 10 15
Thr Leu Ser Leu Thr Cys Ala Val Phe Gly Asp Ser Ile Ser Ser Ser
20 25 30
Tyr Trp Trp Ser Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Glu Ile Tyr His Ser Gly Ser Thr His Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Lys Ser Lys Asn His Leu Ser
65 70 75 80
Leu Lys Leu Ile Ser Val Thr Asp Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Gly Glu Asp Thr Gly Trp Pro Phe Asp Phe Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 341
<211> 108
<212> PRT
<213> Artificial Sequence
<400> 341
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro
85 90 95
Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 342
<211> 336
<212> PRT
<213> Artificial Sequence
<400> 342
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly
1 5 10 15
Asp Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Ser Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Ser Val His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val
65 70 75 80
Thr Cys Ser Val Ala His Pro Ala Ser Ser Thr Thr Val Asp Lys Lys
85 90 95
Leu Glu Pro Ser Gly Pro Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys
100 105 110
Lys Glu Cys His Lys Cys Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser
115 120 125
Val Phe Ile Phe Pro Pro Asn Ile Lys Asp Val Leu Met Ile Ser Leu
130 135 140
Thr Pro Lys Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro
145 150 155 160
Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala
165 170 175
Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Ile Arg Val Val
180 185 190
Ser Thr Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe
195 200 205
Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr
210 215 220
Ile Ser Lys Ile Lys Gly Leu Val Arg Ala Pro Gln Val Tyr Ile Leu
225 230 235 240
Pro Pro Pro Ala Glu Gln Leu Ser Arg Lys Asp Val Ser Leu Thr Cys
245 250 255
Leu Val Val Gly Phe Asn Pro Gly Asp Ile Ser Val Glu Trp Thr Ser
260 265 270
Asn Gly His Thr Glu Glu Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp
275 280 285
Ser Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser
290 295 300
Lys Trp Glu Lys Thr Asp Ser Phe Ser Cys Asn Val Arg His Glu Gly
305 310 315 320
Leu Lys Asn Tyr Tyr Leu Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys
325 330 335
<210> 343
<211> 335
<212> PRT
<213> Artificial Sequence
<400> 343
Ala Lys Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly
1 5 10 15
Gly Thr Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Thr Ser Asn Thr Trp Pro Ser Gln Thr Ile
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Glu Pro Arg Val Pro Ile Thr Gln Asn Pro Cys Pro Pro Leu Lys
100 105 110
Glu Cys Pro Pro Cys Ala Ala Pro Asp Leu Leu Gly Gly Pro Ser Val
115 120 125
Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser
130 135 140
Pro Met Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp
145 150 155 160
Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln
165 170 175
Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser
180 185 190
Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys
195 200 205
Cys Lys Val Asn Asn Arg Ala Leu Pro Ser Pro Ile Glu Lys Thr Ile
210 215 220
Ser Lys Pro Arg Gly Pro Val Arg Ala Pro Gln Val Tyr Val Leu Pro
225 230 235 240
Pro Pro Ala Glu Glu Met Thr Lys Lys Glu Phe Ser Leu Thr Cys Met
245 250 255
Ile Thr Gly Phe Leu Pro Ala Glu Ile Ala Val Asp Trp Thr Ser Asn
260 265 270
Gly Arg Thr Glu Gln Asn Tyr Lys Asn Thr Ala Thr Val Leu Asp Ser
275 280 285
Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Gln Lys Ser Thr
290 295 300
Trp Glu Arg Gly Ser Leu Phe Ala Cys Ser Val Val His Glu Val Leu
305 310 315 320
His Asn His Leu Thr Thr Lys Thr Ile Ser Arg Ser Leu Gly Lys
325 330 335
<210> 344
<211> 324
<212> PRT
<213> Artificial Sequence
<400> 344
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Glu Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Pro Arg Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 345
<211> 326
<212> PRT
<213> Artificial Sequence
<400> 345
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 346
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 346
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
1 5 10 15
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
20 25 30
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
35 40 45
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
65 70 75 80
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
85 90 95
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 347
<211> 107
<212> PRT
<213> Artificial Sequence
<400> 347
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105

Claims (10)

1.抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体含有如SEQ ID NO:1所示的HCDR1、如SEQ ID NO:2所示的HCDR2和如SEQ ID NO:3所示的HCDR3，和/或含有如SEQID NO:4所示的LCDR1、如SEQ ID NO:5所示的LCDR2和如SEQ ID NO:6所示的LCDR3。
2.如权利要求1所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体含有如SEQ ID NO:7-38中任一所示的HCDR1，如SEQ ID NO:39-65中任一所示的HCDR2，和如SEQ ID NO:66-114中任一所示的HCDR3，和/或如SEQ ID NO:115-145中任一所示的LCDR1，如SEQ ID NO:146-159中任一所示的LCDR2和如SEQ ID NO:160-199中任一所示的LCDR3。
3.如权利要求1所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体含有以下组a1到组a71中任意一组所示的HCDR1、HCDR2和HCDR3：
Figure FDA0002651709250000011
Figure FDA0002651709250000021
Figure FDA0002651709250000031
和/或以下组b1到组b71中任意一组所示的LCDR1、LCDR2和LCDR3：
Figure FDA0002651709250000032
Figure FDA0002651709250000041
4.如权利要求1所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体含有表1的组c1到组c71中任一组所示的HCDR和LCDR。
5.如权利要求1-4中任一项所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体VH的各FR区为选自SEQ ID NO:200-270所示VH中任一VH的FR区，和VL的各FR区为选自SEQ ID NO:271-341所示VL中任一VL的FR区；更优选地，所述抗OX40抗体VH和VL的各FR区为选自表2中任意一个抗体的VH和VL的FR区。
6.如权利要求1所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体的VH的氨基酸序列如SEQ ID NO:200-270中任一所示，和/或VL的氨基酸序列如SEQ ID NO:271-341中任一所示；优选地，所述抗OX40抗体的VH的氨基酸序列和VL的氨基酸序列如表2的任一抗体编号所示。
7.如权利要求1-6中任一项所述的抗OX40抗体或其抗原结合片段，其特征在于，所述抗OX40抗体为嵌合抗体或完全人抗体；优选为完全人抗体。
8.一种药物组合物，其特征在于，所述药物组合物含有权利要求1-7中任一项所述的抗OX40抗体或其抗原结合片段，和药学上可接受的赋形剂或载剂。
9.一种核酸分子或含有该核酸分子的载体，选自：
(1)编码权利要求1-7中任一项所述的抗OX40抗体或其抗原结合片段的多核苷酸序列；
(2)(1)所述多核苷酸序列的互补序列。
10.权利要求1-7中任一项所述的抗OX40抗体或其抗原结合片段在制备治疗T细胞相关疾病中的应用；优选地，所述T细胞相关的疾病为T细胞相关的肿瘤或OX40介导的疾病；更优选地，所述OX40介导的疾病包括OX40介导的变态反应、哮喘、COPD、类风湿关节炎、牛皮癣、自体免疫疾病和炎症相关疾病。
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