CN109415436A - 抗il-33抗体及其组合物、方法及用途 - Google Patents

抗il-33抗体及其组合物、方法及用途 Download PDF

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CN109415436A
CN109415436A CN201780026021.2A CN201780026021A CN109415436A CN 109415436 A CN109415436 A CN 109415436A CN 201780026021 A CN201780026021 A CN 201780026021A CN 109415436 A CN109415436 A CN 109415436A
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L·布卢姆
K·H·诺卡
J·R·阿普加
M·A·法梅尔
M·A·兰伯特
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Pfizer Corp
Pfizer Inc
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Abstract

本发明提供特异性结合IL‑33的抗体和其抗原结合片段及其用途和相关方法。

Description

抗IL-33抗体及其组合物、方法及用途
技术领域
本发明涉及特异性结合白细胞介素-33的抗体及其抗原结合片段，以及其组合物、方法及用途。
背景技术
IL-33为关键的IL-1家族成员，其放大涉及哮喘和特应性炎症的许多细胞类型的应 答。IL-33以高亲和力与白细胞介素-1受体样1(IL1RL1；亦称为致癌抑制因子2[ST2])结合，并与IL1RAcP形成三元复合体以形成信号传导复合体。此信号传导复合体导致一 系列依赖Myddosome(具有MyD88和IRAK家族成员)的事件。此信号传导最终导致 NFκb活化及细胞和细胞因子环境特异性背景中的其他通路。当细胞(例如肥大细胞或嗜 碱性粒细胞)受到IL-33刺激时，产生2型细胞因子，例如IL-4、5和13。
IL-33已在许多哮喘和过敏性疾病的临床前模型中显示出当其活性被药理学或遗传 学方法阻断时具有关键作用。通路的阻断已可通过中和针对IL-33的抗体或受体IL1RL1、 IL-33或IL1RL1的遗传缺失或受体IL1RL1与Fc偶联的融合蛋白的可溶形式来完成(Coyle et al.,1999,J.Exper.Med 190(7):895-902)。在大多数使用含有蛋白水解过敏原的 生理过敏原(例如尘螨、蟑螂或链格孢属(alternaria)真菌)的模型系统中，IL-33在驱动 炎症和气道重塑的其他方面中具有重要作用(Chu et al.,2013,J.Allergy Clin.Immunol.131:187-200)。在依赖用于致敏化的佐剂(例如氢氧化铝(明矾)或尿酸钠晶体)的药理学模型中，IL-33在模型的致敏期和诱导2型细胞因子(例如IL-5和IL13)中具有 重要作用(Hara et al.,2014,J.Immunol.192(9):4032-4042)。IL-33亦被发现在与气道中的病毒感染相关的炎症应答中具有重要作用。由病毒感染对气道上皮造成的损伤可引发 IL-33释放并修改免疫应答的类型。
疾病例如慢性鼻窦炎并鼻息肉(chronic rhinosinusitis with nasal polyps)(CRSwNP)、 特应性皮炎(AD)和哮喘是其中可能有多种细胞因子涉及发病机理的疾病。IL-33受体 ST2表达于许多与2型炎症相关的细胞类型中，包括肥大细胞、嗜碱性粒细胞、Th2-T细 胞、2型先天性淋巴样细胞，等(Cayrol&Girard,2014,Current Opinion in Immunology31:31-37；Molofsky et al..2015,Immunity 42(6):1005-1019)。这些细胞类型对IL-33的初 次应答是产生炎性细胞因子，尤其是与2型炎症相关的那些，包括IL-5、IL-13、IL-4、IL-31和IL-9(Molofsky et al.,2015,Immunity 42(6):1005-1019；Rivelleseet al,2014,Eur.J. Immunol.44(10):3045-3055；Suzukawaet al.,2008,J.Immunology 181(9):5981-5989； Vocca et al.Immunobiology 220(8):954-963；Maier et al.,2014,J.Immunology 193(2):645-654)。亦产生其他细胞因子及趋化因子，其在驱动募集另外的炎性细胞类型 至组织部位上具重要作用(Cayrol&Girard,2014；Molofsky et al.,2015)。IL-33最初释放 由身体或黏膜表面的上皮损伤触发。疾病相关的触发因素包括具有蛋白水解活性的过敏 原、上皮的物理损伤、病毒及身体表面常见的真菌和细菌。在其中该组织富含嗜酸性粒 细胞和肥大细胞的疾病中，对上皮的损伤引发级联反应，从而释放IL-33，作用在局部 靶细胞上，并驱动产生多种对2型炎症应答极为重要的细胞因子。
发明内容
本发明提供特异性结合IL-33的抗体(和其抗原结合片段)，以及其用途和相关方法。 本领域技术人员使用不超过常规实验将认识到或能够确定许多本文所描述的本发明的 具体实施方案的等价物。该类等价物意图由下列实施方案(E)涵盖。
E1.一种特异性结合人IL-33的分离的抗体或其抗原结合片段。
E2.E1的抗体或其抗原结合片段，该抗体包含以下组之一的CDR-H1、CDR-H2和CDR-H3序列：SEQ ID NO：14、32、90、94、97、113、118、121、124、126、129、 132、135、138、141、144、147、150、152、155、158、161、163、165、167、170、 173、176、179、182、184、186、201、204、210、213、216、219、222、225、228、 231和234。
E3.E1至E2中任一项的抗体或其抗原结合片段，包含以下组之一的CDR-L1、 CDR-L2和CDR-L3序列：SEQ ID NO：19、36、81、91、98、115、189、192、195、198 和207。
E4.如E1至E3中任一项的抗体或其抗原结合片段，包含(i)至(vi)的一或多者：
(i)选自以下组的CDR-L1：SEQ ID NO：20、37、190、193、257、258、259和260，
(ⅱ)选自以下组的CDR-L2：SEQ ID NO：21、196、199、261、262、263和264，
(ⅲ)选自以下组的CDR-L3：SEQ ID NO：22、38、208、265、26、267和268，
(ⅳ)选自以下组的CDR-H1：SEQ ID NO：16、33、269、270和271，
(v)选自以下组的CDR-H2：SEQ ID NO：17、34、168、171、174、180、202、205、 211、214、217、220、223、226、229、232、235、272、273、274和275，
(ⅵ)选自以下组的CDR-H3：SEQ ID NO：18、35、114、119、122、127、130、 133、136、139、142、145、148、153、156、159、177、187、276、277、278和279。
E5.如E1至E4中任一项的抗体或其抗原结合片段，包含
(i)选自以下组的CDR-L1：SEQ ID NO：257、258、259和260，
(ⅱ)选自以下组的CDR-L2：SEQ ID NO：261、262、263和264，
(ⅲ)选自以下组的CDR-L3：SEQ ID NO：265、266、267和268，
(ⅳ)选自以下组的CDR-H1：SEQ ID NO：269、270和271，
(v)选自以下组的CDR-H2：SEQ ID NO：272、273、274和275，
(ⅵ)选自以下组的CDR-H3：SEQ ID NO：276、277、278和279。
E6.如E1至E5中任一项的抗体或其抗原结合片段，包含
(i)CDR-L1，其包含SEQ ID NO：257，
(ⅱ)CDR-L2，其包含SEQ ID NO：261，
(ⅲ)CDR-L3，其包含SEQ ID NO：265，
(ⅳ)CDR-H1，其包含SEQ ID NO：269，
(v)CDR-H2，其包含SEQ ID NO：272，
(ⅵ)CDR-H3，其包含SEQ ID NO：276。
E7.如E1至E6中任一项的抗体或其抗原结合片段，包含
(i)CDR-L1，其包含SEQ ID NO：258，
(ⅱ)CDR-L2，其包含SEQ ID NO：262，
(ⅲ)CDR-L3，其包含SEQ ID NO：266，
(ⅳ)CDR-H1，其包含SEQ ID NO：270，
(v)CDR-H2，其包含SEQ ID NO：273，
(ⅵ)CDR-H3，其包含SEQ ID NO：277。
E8.如E1至E7中任一项的抗体或其抗原结合片段，包含
(i)CDR-L1，其包含SEQ ID NO：259，
(ⅱ)CDR-L2，其包含SEQ ID NO：263，
(ⅲ)CDR-L3，其包含SEQ ID NO：267，
(ⅳ)CDR-H1，其包含SEQ ID NO：271，
(v)CDR-H2，其包含SEQ ID NO：274，
(ⅵ)CDR-H3，其包含SEQ ID NO：278。
E9.如E1至E8中任一项的抗体或其抗原结合片段，包含
(i)CDR-L1，其包含SEQ ID NO：260，
(ⅱ)CDR-L2，其包含SEQ ID NO：264，
(ⅲ)CDR-L3，其包含SEQ ID NO：268，
(ⅳ)CDR-H1，其包含SEQ ID NO：271，
(v)CDR-H2，其包含SEQ ID NO：275，
(ⅵ)CDR-H3，其包含SEQ ID NO：278。
E10.如E1至E9中任一项的抗体或其抗原结合片段，包含
(i)CDR-L1，其包含SEQ ID NO：20，
(ⅱ)CDR-L2，其包含SEQ ID NO：21，
(ⅲ)CDR-L3，其包含SEQ ID NO：208，
(ⅳ)CDR-H1，其包含SEQ ID NO：16，
(v)CDR-H2，其包含SEQ ID NO：226，
(ⅵ)CDR-H3，其包含SEQ ID NO：18。
E11.E1至E10中任一项的抗体或其抗原结合片段，包含SEQ ID NO：225的CDR-H1、CDR-H2和CDR-H3序列。
E12.E1至E11中任一项的抗体或其抗原结合片段，包含SEQ ID NO：207的CDR-L1、CDR-L2和CDR-L3序列。
E13.E1至E12中任一项的抗体或其抗原结合片段，包含下列取代的一或多者：
(i)CDR L1中的1、2、3、4、5或6个取代成人种系VL序列的相应残基，
(ii)CDR L2中的1、2、3、4或5个取代成人VL种系序列的相应残基，
(iii)CDR L3中的1、2、3、4、5或6个取代成人种系VL序列的相应残基，
(iv)CDR H1中的1个取代成人种系VH序列的相应残基，
(v)CDR H2中的1、2、3、4、5、6、7或8个取代成人种系VH序列的相应残基，
其中该人种系VL序列选自以下组：DPK9、DPK12、DPK18、DPK24、HK102_V1、 DPK1、DPK8、DPK3、DPK21、Vg_38K、DPK22、DPK15、DPL16、DPL8、V1-22、 Vλ共有序列、Vλ1共有序列、Vλ3共有序列、Vκ共有序列、Vκ1共有序列、Vκ2共 有序列及Vκ3，且该人种系VH选自以下组：DP54、DP47、DP50、DP31、DP46、DP71、 DP75、DP10、DP7、DP49、DP51、DP38、DP79、DP78、DP73、VH3、VH5、VH1及 VH4。
E14.E1至E13中任一项的抗体或其抗原结合片段，包含衍生自人种系VH序列的 VH框架序列，该人种系VH序列选自以下组：DP54、DP47、DP50、DP31、DP46、 DP71、DP75、DP10、DP7、DP49、DP51、DP38、DP79、DP78、DP73、VH3、VH5、 VH1及VH4。
E15.E1至E14中任一项的抗体或其抗原结合片段，包含衍生自人VH3种系序列的框架VH序列。
E16.E1至E15中任一项的抗体或其抗原结合片段，包含衍生自人种系VH序列的框架VH序列，该人种系VH序列选自以下组：DP54、DP47、DP50、DP31、DP46、DP49 和DP51。
E17.E1至E16中任一项的抗体或其抗原结合片段，包含衍生自人种系VH序列的框架VH序列，该人种系VH序列选自以下组：DP54、DP47、DP50和DP31。
E18.E1至E17中任一项的抗体或其抗原结合片段，包含衍生自人种系DP54序列的VH框架序列。
E19.E1至E18中任一项的抗体或其抗原结合片段，包含衍生自人种系VL序列的 VL框架序列，该人种系VL序列选自以下组：DPK9、DPK12、DPK18、DPK24、HK102_V1、 DPK1、DPK8、DPK3、DPK21、Vg_38K、DPK22、DPK15、DPL16、DPL8、V1-22、 Vλ共有序列、Vλ1共有序列、Vλ3共有序列、Vκ共有序列、Vκ1共有序列、Vκ2共 有序列及Vκ3。
E20.E1至E19中任一项的抗体或其抗原结合片段，包含衍生自人种系VL序列的 VL框架序列，该人种系VL序列选自以下组：DPK9、DPK12、DPK18、DPK24、HK102_V1、 DPK1、DPK8、DPK3、DPK21、Vg_38K、DPK22、DPK15、Vκ共有序列、Vκ1共有 序列、Vκ2共有序列及Vκ3。
E21.E1至E20中任一项的抗体或其抗原结合片段，包含衍生自人种系Vκ1序列的VL框架序列。
E22.E1至E21中任一项的抗体或其抗原结合片段，包含衍生自人种系VL序列的 VL框架序列，该人种系VL序列选自以下组：DPK9、HK102_V1、DPK1和DPK8。
E23.E1至E22中任一项的抗体或其抗原结合片段，包含衍生自人种系DPK9序列的VL框架序列。
E24.E1至E23中任一项的抗体或其抗原结合片段，包含VL框架序列和VH框架序列，其中VL框架序列或VH框架序列的一或二者与其衍生自的人种系序列至少90％相 同。
E25.E1至E24中任一项的抗体或其抗原结合片段，包含VL框架序列和VH框架序列，其中VL框架序列或VH框架序列的一或二者与其衍生自的人种系序列至少66％、 76％、80％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同。
E26.E1至E25中任一项的抗体或其抗原结合片段，包含VL框架序列和VH框架序列，其中VL框架序列或VH框架序列的一或二者与其衍生自的人种系序列相同。
E27.E1至E26中任一项的抗体或其抗原结合片段，包含VH，该VH包含与SEQ ID NO：225至少90％相同的氨基酸序列。
E28.E1至E27中任一项的抗体或其抗原结合片段，包含VH，该VH包含与SEQ ID NO：225至少92％相同的氨基酸序列。
E29.E1至E28中任一项的抗体或其抗原结合片段，包含VH，该VH包含SEQ ID NO：225的氨基酸序列。
E30.E1至E29中任一项的抗体或其抗原结合片段，包含VL，该VL包含与SEQ ID NO：207至少66％相同的氨基酸序列。
E31.E1至E30中任一项的抗体或其抗原结合片段，包含VL，该VL包含与SEQ ID NO：207至少66％、76％、80％、91％、92％、93％、94％、95％、96％、97％、98％或 99％相同的氨基酸序列。
E32.E1至E31中任一项的抗体或其抗原结合片段，包含VL，该VL包含SEQ ID NO：207的氨基酸序列。
E33.E1至E32中任一项的抗体或其抗原结合片段，包含Fc结构域。
E34.E33的抗体或其抗原结合片段，其中该Fc结构域为IgA(例如IgA1或IgA2)、IgD、IgE、IgM或IgG(例如IgG1、IgG2、IgG3或IgG4)的Fc结构域。
E35.E34的抗体或其抗原结合片段，其中该Fc结构域为IgG的Fc结构域。
E36.E35的抗体或其抗原结合片段，其中该IgG选自以下组：IgG1、IgG2、IgG3或IgG4。
E37.E36的抗体或其抗原结合片段，其中该IgG为IgG1。
E38.E1至E37中任一项的抗体或其抗原结合片段，包含重链，该重链包含与SEQ IDNO：244至少90％相同的氨基酸序列。
E39.E1至E38中任一项的抗体或其抗原结合片段，包含重链，该重链包含与SEQ IDNO：244至少91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序 列。
E40.E1至E39中任一项的抗体或其抗原结合片段，包含重链，该重链包含SEQ IDNO：244的氨基酸序列。
E41.E1至E40中任一项的抗体或其抗原结合片段，包含LC)，该LC包含与SEQ IDNO：209至少90％相同的氨基酸序列。
E42.E1至E41中任一项的抗体或其抗原结合片段，包含LC)，该LC包含与SEQ IDNO：209至少91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序 列。
E43.E1至E42中任一项的抗体或其抗原结合片段，包含LC)，该LC包含SEQ ID NO：209的氨基酸序列。
E44.E1至E43中任一项的抗体或其抗原结合片段，包含由保藏于ATCC且具有 ATCC登录编号为PTA-122724的质粒编码的VH序列。
E45.E1至E44中任一项的抗体或其抗原结合片段，包含由保藏于ATCC且具有 ATCC登录编号为PTA-122725的质粒编码的VL序列。
E46.一种抗体或其抗原结合片段，与E1至E45中任一项的抗体或其抗原结合片段竞争结合人IL-33。
E47.一种抗体或其抗原结合片段，与下列之一或多者竞争结合人IL-33：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、 9B3_1、9B3_2A、9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、 9B3_31V2、9B3_36、9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、 IL33-12、IL33-13、IL33-45、IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、 IL33-68、IL33-74、IL33-75、IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、 IL33-154、IL33-155、IL33-156、IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、 IL33-170、IL33-171、IL33-172、IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、 IL33-167-153、IL33-158LS及IL33-167LS。
E48.一种抗体或其抗原结合片段，与IL33-158LS或IL33-158LS的抗原结合片段竞争结合人IL-33。
E49.E1至E48中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段为Fc融合蛋白、单抗体(monobody)、大抗体(maxibody)、双功能抗体、scFab、scFv、肽体(peptibody)。
E50.E1至E49中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段以 约为或低于选自以下组的值的KD与人IL-33结合：约10nM、5nM、2nM、1nM、900pM、 800pM、700pM、600pM、500pM、400pM、300pM、250pM、200pM、150pM、100pM、 50pM、40pM、30pM、25pM、20pM、15pM、10pM、5pM及1pM。
E51.E1至E50中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段以 约为或低于选自以下组的值的KD与食蟹猴IL-33结合：约10nM、5nM、2nM、1nM、 900pM、800pM、700pM、600pM、500pM、400pM、300pM、250pM、200pM、150pM、 100pM、50pM、40pM、30pM、25pM、20pM、15pM、13pM、10pM、5pM及1pM。
E52.E1至E51中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33结合的KD是在该抗体或其抗原结合片段与人IL-33结合的KD的1个数量级之内。
E53.E1至E52中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与人 IL-33结合的KD相较于与食蟹猴IL-33结合的KD的比率介于5：1至1：5。
E54.E1至E53中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与人 IL-33结合的KD相较于与食蟹猴IL-33结合的KD的比例率介于2：1至1：2。
E55.E1至E54中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段与 活性IL-33结合的KD低于与无活性IL-33结合的KD。
E56.E1至E55中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段与 活性IL-33结合的KD较与无活性IL-33结合的KD低至少10倍。
E57.E1至E56中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段与 活性IL-33结合的KD较与无活性形式的IL-33结合的KD低至少10、100、1×103、1×104、 1×105、1×106、1×107倍。
E58.E1至E57中任一项的抗体或其抗原结合片段，其中该抗体或其抗原结合片段与 活性IL-33结合，但不与无活性IL-33结合。
E59.E55至E58中任一项的抗体或其抗原结合片段，其中该活性IL-33的KD的测量使用IL-33变体，其中在位置208的半胱氨酸(C208)(根据SEQ ID NO：396编号)氨基酸 残基被非半胱氨酸氨基酸残基取代。
E60.E55至E59中任一项的抗体或其抗原结合片段，其中该活性IL-33的KD的测量使用IL-33变体，其中C208和C232(根据SEQ ID NO：396编号)被非半胱氨酸氨基酸 残基取代。
E61.E55至E60中任一项的抗体或其抗原结合片段，其中该活性IL-33的KD的测量使用还原形式的野生型IL-33。
E62.E55至E61中任一项的抗体或其抗原结合片段，其中该无活性IL-33的KD的测量使用非还原形式的野生型IL-33。
E63.E55至E62中任一项的抗体或其抗原结合片段，其中该IL-33为人IL-33。
E64.E55至E62中任一项的抗体或其抗原结合片段，其中该IL-33为食蟹猴IL-33。
E65.E1至E64中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率是在范围的下限值选自以下组 的范围之内：0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、 1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、 3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5和6.2，且范围的上限值选自以下组的 范围之内：1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、 2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、 6.2、9、9.2和10。
E66.E1至E55中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率介于约0.5至约3.0之间。
E67.E1至E56中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率介于约1.2至约2.4之间。
E68.E1至E57中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率介于约1至约2之间。
E69.E1至E58中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率介于约1.3至约2.3之间。
E70.E1至E59中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与食 蟹猴IL-33的结合KD相较于与人IL-33的结合KD的比率介于约1.3至约1.8之间。
E71.E1至E70中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：5的食蟹猴IL-33的结合KD相较于与SEQ ID NO：3的人IL-33的结合KD的比率介于约1.0至约2.3之间。
E72.E1至E71中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：5的食蟹猴IL-33的结合KD相较于与SEQ ID NO：3的人IL-33的结合KD的比率介于约1.0至约2.0之间。
E73.E1至E72中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：5的食蟹猴IL-33的结合KD相较于与SEQ ID NO：3的人IL-33的结合KD的比率介于约1.3至约1.8之间。
E74.E1至E73中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：5的食蟹猴IL-33的结合KD相较于与SEQ ID NO：3的人IL-33的结合KD的比率的测量是通过比较用于中和食蟹猴和人IL-33的HEK293 ST2 NFκB报告分子分 析的结果来进行。
E75.E1至E74中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率介于约4至约10之间。
E76.E1至E75中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率介于约4.2至约9.2之间。
E77.E1至E76中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率为约4.2。
E78.E1至E77中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率为约6.2。
E79.E1至E78中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率为约9.2。
E80.E1至E79中任一项的抗体或其抗原结合片段，其中该抗体或抗原结合片段与SEQ ID NO：397的食蟹猴IL-33的结合KD相较于与SEQ ID NO：1的人IL-33的结合 KD的比率的测量是通过比较用于中和食蟹猴和人IL-33的HEK293 ST2 NFκB报告分子 分析的结果来进行。
E81.E50至E80中任一项的抗体或其抗原结合片段，其中该KD值是通过表面等离子共振(SPR)测量。
E82.E50至E81中任一项的抗体或其抗原结合片段，其中该KD值是通过表面等离子共振(SPR)测量且该IL-33为固定的。
E83.E1至E82中任一项的抗体或其抗原结合片段，其中在食蟹猴中终末半衰期为至 少约15天。
E84.E1至E83中任一项的抗体或其抗原结合片段，其中在食蟹猴中终末半衰期为至 少约16天。
E85.E1至E84中任一项的抗体或其抗原结合片段，其中在食蟹猴中终末半衰期为至 少约18天。
E86.E1至E85中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约30天。
E87.E1至E86中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约50天。
E88.E1至E87中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约55天。
E89.E1至E88中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约60天。
E90.E1至E89中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约65天。
E91.E1至E90中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约70天。
E92.E1至E91中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约75天。
E93.E1至E92中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约80天。
E94.E1至E93中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约85天。
E95.E1至E94中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少 约90天。
E96.E1至E95中任一项的抗体或其抗原结合片段，其中该抗体在亲和力捕获自身相 互作用纳米颗粒光谱分析法(affinity-capture self-interaction nanoparticlespectroscopy assay)中的最大吸收波长相对于空白小于15nm。
E97.E1至E96中任一项的抗体或其抗原结合片段，其中该抗体在亲和力捕获自身相 互作用纳米颗粒光谱分析法中的最大吸收波长相对于空白小于10nm。
E98.E1至E97中任一项的抗体或其抗原结合片段，其中该抗体在亲和力捕获自身相 互作用纳米颗粒光谱分析法中的最大吸收波长相对于空白小于5nm。
E99.E1至E98中任一项的抗体或其抗原结合片段，其中该抗体在亲和力捕获自身相 互作用纳米颗粒光谱分析法中的最大吸收波长相对于空白小于1nm。
E100.E1至E99中任一项的抗体或其抗原结合片段，其中该抗体的DNA结合分数 相对于空白标准化低于19。
E101.E1至E100中任一项的抗体或其抗原结合片段，其中该抗体的DNA结合分数相对于空白标准化低于15。
E102.E1至E101中任一项的抗体或其抗原结合片段，其中该抗体的DNA结合分数相对于空白标准化低于10。
E103.E1至E102中任一项的抗体或其抗原结合片段，其中该抗体的DNA结合分数相对于空白标准化低于7.55。
E104.一种抗体或其抗原结合片段，该抗体与E1至E103中任一项的抗体或其抗原结合片段竞争结合。
E105.一种抗体或其抗原结合片段，该抗体与E1至E104中任一项的抗体或其抗原结合片段结合相同的表位。
E106.一种抗体或其抗原结合片段，包含选自以下组抗体的CDR：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、9B3_1、 9B3_2A、9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、 9B3_36、9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、 IL33-45、IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、 IL33-75、IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、 IL33-156、IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、 IL33-172、IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、 IL33-158LS及IL33-167LS。
E107.一种抗体或其抗原结合片段，包含选自以下组抗体的VL和VH：7E8_嵌合 体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、 9B3_1、9B3_2A、9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、 9B3_31V2、9B3_36、9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、 IL33-12、IL33-13、IL33-45、IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、 IL33-154、IL33-155、IL33-156、IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、 IL33-170、IL33-171、IL33-172、IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、 IL33-167-153、IL33-158LS及IL33-167LS。
E108.一种抗体或其抗原结合片段，选自以下组：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、9B3_1、9B3_2A、9B3_2B、 9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、9B3_79、 9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、IL33-55、 IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、IL33-80、 IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、 IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、 IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS 及IL33-167LS。
E109.一种分离的核酸分子，其包含一或多个编码E1至E108中任一项的抗体或其抗原结合片段的核苷酸序列。
E110.一种分离的核酸分子，其包含SEQ ID NO：398、399、400和401之一或多者 所示的核酸序列。
E111.一种分离的核酸分子，其包含SEQ ID NO：398所示的核酸序列。
E112.一种分离的核酸分子，其包含核酸序列分离的核酸分子，其包含如SEQ IDNO：398、399、400和401中的一或多者所示的核酸序列，如SEQ ID NO：399所示。
E113.一种分离的核酸分子，其包含SEQ ID NO：400所示的核酸序列。
E114.一种分离的核酸分子，其包含SEQ ID NO：401所示的核酸序列。
E115.一种分离的核酸分子，其包含保藏于ATCC且具有ATCC登录编号为 PTA-122724的核酸分子的编码序列。
E116一种分离的核酸分子，其包含保藏于ATCC且具有ATCC登录编号为 PTA-122725的核酸分子的编码序列。
E117.一种载体，其包含E109至E116中任一项的核酸分子。
E118.一种宿主细胞，其包含E109至E116中任一项的核酸分子或E117的载体。
E119.E118的宿主细胞，其中该细胞为哺乳动物细胞。
E120.E119的宿主细胞，其中该宿主细胞为CHO细胞、HEK-293细胞或Sp2.0细胞。
E121.一种制造抗体或其抗原结合片段的方法，其包含在该抗体或其抗原结合片段 由E119至E120中任一项的宿主细胞表达的条件下培养所述宿主细胞。
E122.E121的方法，其进一步包含分离该抗体或其抗原结合片段。
E123.一种药物组合物，其包含E1至E108中任一项的抗体或其抗原结合片段及药物上可接受的运载体或赋形剂。
E124.一种降低IL-33活性的方法，其包含对有需要降低IL-33活性的对象施用治疗 有效量的E1至E108中任一项的抗体或其抗原结合片段，或E123的药物组合物。
E125.一种治疗炎性疾病的方法，其包含对有需要治疗炎性疾病的对象施用治疗有 效量的E1至E108中任一项的抗体或其抗原结合片段，或E123的药物组合物。
E126.一种治疗特应性皮炎的方法，其包含对有需要治疗特应性皮炎的对象施用治 疗有效量的E1至E108中任一项的抗体或其抗原结合片段，或E123的药物组合物。
E127.一种治疗炎性肠病的方法，其包含对有需要治疗炎性肠病的对象施用治疗有 效量的E1至E108中任一项的抗体或其抗原结合片段，或E123的药物组合物。
E128.E121至E127中任一项的方法，其中该对象为人。
E129.E121至E128中任一项的方法，其包含静脉内施用所述抗体或其抗原结合片段 或药物组合物。
E130.E121至E128中任一项的方法，其包含皮下施用所述抗体或其抗原结合片段或 药物组合物。
E131.E121至E130中任一项的方法，其中所述抗体或其抗原结合片段或药物组合物 约每周施用二次、每周施用一次、每二周施用一次、每三周施用一次、每四周施用一次、每五周施用一次、每六周施用一次、每七周施用一次、每八周施用一次、每九周施用一 次、每十周施用一次、每月施用二次、每月施用一次、每二个月施用一次、每三个月施 用一次或每四个月施用一次。
E132.E1至E108中任一项的抗体或其抗原结合片段或E123的药物组合物，其用作药物。
E133.E1至E108中任一项的抗体或其抗原结合片段或E123的药物组合物，其用于降低对象的IL-33的活性。
E134.E1至E108中任一项的抗体或其抗原结合片段或E123的药物组合物，其用于治疗对象的炎性疾病。
E135.E1至E108中任一项的抗体或其抗原结合片段或E123的药物组合物，其用于治疗对象的特应性皮炎。
E136.一种治疗医学病况的方法，其包含对有需要治疗医学病况的对象施用治疗有 效量的E1至E108中任一项的抗体或其抗原结合片段或E123的药物组合物。
E137.E106的方法，其中该病况选自以下组：炎性肠病、过敏症、过敏性鼻炎、过 敏性结膜炎、春季型角膜结膜炎(vernal keratoconjunctivitis)、季节性过敏、宠物过敏、哮喘、食物过敏、花生过敏、特应性皮炎、慢性鼻窦炎伴鼻息肉(CRSwNP)、过敏性鼻 炎、支气管炎、慢性阻塞性肺病(COPD)、呼吸系统疾病病毒性恶化、儿童和成人的病 毒感染(呼吸道合胞病毒(RSV)、鼻病毒、流感)、荨麻疹、嗜酸性粒细胞食道炎、慢性 纤维化、肝纤维化、非酒精性脂肪性肝炎(NASH)、慢性肾脏病、特发性肺纤维化(IPF)、 硬皮病、系统性硬化症、急性肾损伤、败血症、胰腺炎、1型糖尿病、移植物抗宿主病 (GVHD)、组织移植、阿兹海默氏症、类风湿性关节炎：肠易激症候群(IBS)、克罗恩(Crohn) 氏病、溃疡性结肠炎、多发性硬化症、牛皮癣、乳糜泻及雷诺(Raynaud)氏病或现象。
附图说明
图1A至1C的图形显示与经捕获的大鼠7E8 Fab结合的IL-33的表面等离子共振痕迹。 图1A显示大鼠7E8 Fab与经固定的人IL-33(mm2)的结合。图1B显示在没有还原剂之 存在下，大鼠7E8 Fab与经固定的人IL-33(WT)的结合。图1C显示在还原剂(DTT)的 存在下，大鼠7E8 Fab与经固定的人IL-33(WT)的结合。
图2A至2B的图形显示经优化的抗IL-33可变区与人DP-54/DPK9种系的序列比对。图2A显示IL33-158-152/IL33-158LS的VH(SEQ ID NO：225)和VL(SEQ ID NO：207) 与人种系序列DP-54/JH4(SEQ ID NO：7)和DPK9/JK4(SEQ ID NO：11)的比对。图 2B显示IL33-167-153/IL33-167LS的VH(SEQ ID NO：210)和VL(SEQ ID NO：91)与 人种系序列DP-54/JH4(SEQID NO：7)和DPK9/JK4(SEQ ID NO：11)的比对。
图3A至3B的图形显示细胞因子与固定在芯片上的本发明抗体的结合。图3A显示细胞因子与经固定的IL33-158LS Fab的结合。图3B显示细胞因子与经固定的7E8 Fab 的结合。
具体实施方式
抗体
抗体的“抗原结合片段”是指保留特异性结合抗原的能力(优选为具有基本上相同的 结合亲和力)的全长抗体的片段。抗原结合片段的实例包括(i)Fab片段，其是由VL、 VH、CL和CH1结构域所组成的单价片段；(ii)F(ab')2片段，其为包含二个通过铰链区 的二硫桥连接的Fab片段的二价片段；(iii)Fd片段，其是由VH和CH1结构域所组成； (iv)Fv片段，其是由抗体单臂的VL和VH结构域所组成，(v)dAb片段(Ward et al.,1989 Nature 341:544-546)，其由VH结构域所组成；及(vi)分离的互补决定区(CDR)、二硫键 连接的Fvs(dsFv)和抗独特型(抗-Id)抗体和胞内抗体。此外，虽然Fv片段的二个结构 域VL和VH是由不同的基因编码，它们可使用重组方法通过合成的接头接合而使得它 们制成单一蛋白链，其中该VL和VH区配对以形成单价分子(称为单链Fv(scFv))；参 见，例如Bird et al.Science 242:423-426(1988)及Huston et al.,1988,Proc.Natl.Acad.Sci. USA 85:5879-5883。其他形式的单链抗体，例如双功能抗体(diabody)亦涵盖在内。双 功能抗体为二价双特异性抗体，其中VH和VL结构域表达在单一多肽链上，但使用因 太短而无法允许在同一链上的该二个结构域之间形成配对的接头，从而迫使该结构域与 另一链的互补结构域配对并产生二个抗原结合位点(参见，例如Holliger et al,1993,.Proc. Natl.Acad.Sci.USA 90:6444-6448；Poljak et al.,1994,Structure 2:1121-1123)。
抗体“可变结构域”是指抗体轻链(VL)的可变区或抗体重链(VH)的可变区(单独或组合的)。如本领域所已知，重链和轻链的可变区各自由四个框架区(FR)组成，该四个 框架区通过三个互补决定区(CDR)连接，并促成抗体的抗原结合位点的形成。
“互补决定区”(CDR)可根据Kabat、Chothia、Kabat和Chothia二者的累积、AbM、 接触、North的定义和/或构象定义或本领域所熟知的任何CDR测定方法鉴别。参见， 例如Kabat et al.,1991,Sequences of Proteins of Immunological Interest,5th ed.(高度可变 区)；Chothia et al.,1989,Nature 342:877-883(结构环结构)。特定抗体中构成CDR的氨 基酸残基的相同性(identity)可使用本领域所熟知的方法测定。CDR的AbM定义为Kabat 和Chothia之间的折衷且是使用Oxford Molecular的AbM抗体建模软件CDR的“接触”定义是基于MacCallum et al.,1996,J.Mol.Biol.,262:732-745中所示的观察列的抗原接触。CDR的“构型”定义是基于对抗原结合具有焓贡献的残基(参见，例如Makabe et al.,2008,J.Biol.Chem.,283:1156-1166)。North已使用不同的优选CDR定义组来鉴定典型的CDR构型(North et al.,2011,J.Mol.Biol.406:228-256)。于另一方法中(本文称为CDR的“构型定义”)，CDR的位置可被鉴定为是对抗原结合具有焓贡献的残 基(Makabe et al.,2008,J Biol.Chem.283:1156-1166)。还有其他CDR边界定义可能未严 格遵循上述方法其中一者，但仍将与至少一部分的Kabat CDR重迭，尽管CDR可能因 鉴于预测或实验发现而缩短或延长，使得特定的残基或残基组甚至整个CDR并不会显 著影响抗原结合。如本文所使用的CDR可指由本领域已知的任何方法(包括方法的组合) 定义的CDR。本文所使用的方法可利用根据这些方法任一者所定义的CDR。对于任一 指定的包含多于一个的CDR的实施方案，该CDR(或抗体的其他残基)可根据Kabat、 Chothia、North、延伸的、AbM、接触和/或构型定义的任一者定义。
可变结构域中的残基是根据Kabat编号，Kabat为用于编译抗体的重链可变结构域或轻链可变结构域的编号系统。参见Kabat et al.,1991,Sequences of Proteins ofImmunological Interest,5th Ed.Public Health Service,National Institutes ofHealth, Bethesda,MD.。使用此编号系统，该实际线性氨基酸序列可含有相应于缩短的可变结构 域的FR或CDR的较少氨基酸或插入可变结构域的FR或CDR的额外氨基酸。例如， 重链可变结构域可在H2的残基52之后包括单一氨基酸插入物(根据Kabat为残基52a)及 在重链FR残基82之后包括插入的残基(例如根据Kabat为残基82a、82b和82c)。指定抗 体的残基的Kabat编号可通过比对抗体序列与“标准”Kabat编号序列的同源区来测定。 可用于指派Kabat编号的算法有多种。本文使用Abysis发布的2.3.3版本(www.abysis.org) 中执行的算法来指派可变区CDR-L1、CDR-L2、CDR-L3、CDR-H2和CDR-H3的Kabat 编号。Abm定义用于CDR-H1。
抗体中的特定氨基酸残基位置亦可根据Kabat编号。
“框架”(FR)残基为除了CDR残基之外的抗体可变结构域残基。VH或VL结构域 框架包含下列结构的四个框架亚区FR1、FR2、FR3和FR4，其间穿插着CDR： FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4。
“表位”是指与抗体特异性结合的抗原范围或区域，例如包含与抗体相互作用的残基 的范围或区域。表位可为线性或构型的。
“优选结合”或“特异性结合”(本文中可互换使用)表位的抗体为本领域中充分了解 的术语，而测定该等特异性或优选结合的方法亦为本领域所熟知。相较于分子与其他细胞或物质的结合，若该分子更频繁地、更快速地、以更长的持续时间和/或以较高的亲 和力与特定的细胞或物质反应或联结，则该分子被称为显示出“特异性结合”或“优选结 合”。相较于抗体与其他物质的结合，若该抗体以较高的亲和力、亲合力、更容易和/或 以更长的持续时间与靶结合，则该抗体“特异性结合”或“优选结合”靶。例如特异性或优 选结合IL-33表位的抗体是以较该抗体与其他IL-33表位或非IL-33表位结合的更高亲和 力、亲合力、更容易和/或以更长的持续时间与IL-33表位结合。经由阅读此定义亦可理 解，例如特异性或优选结合第一靶的抗体(或部分或表位)可能或可能不特异性或优选 结合第二靶。因此，“特异性结合”或“优选结合”不一定需要(尽管其可包括)排他性结合。 一般而言，但不一定，对结合的引用意味着优选结合。“特异性结合”或“优选结合”包括 识别并结合样品中的特异性分子，但基本上不识别或结合其他分子的化合物，例如蛋白 质、核酸、抗体，等。例如识别并结合样品中的同源配体或结合伴侣(例如与肿瘤抗原 结合的抗人肿瘤抗原抗体)，但基本上不识别或结合样品中的其他分子的抗体或肽受体 与该同源配体或结合伴侣特异性结合。因此，在指定的分析条件下，该特异性结合部分 (例如抗体或其抗原结合部分或受体或其配体结合部分)优选结合特定的靶分子且不以 显著量与存在于该测试样品中的其他组分结合。
可用来选择特异性结合感兴趣的分子的抗体或肽的分析格式有多种。例如固相ELISA免疫分析、免疫沉淀、BIAcoreTM(GE Healthcare，Piscataway，NJ)、荧光活化的 细胞分选(FACS)、OctetTM(FortéBio，Inc.，Menlo Park，CA)和蛋白质印迹分析等多种 分析可用来鉴定与抗原特异性反应的抗体，或与同源配体或结合伴侣特异性结合的受体 或其配体结合部分。通常，特异性或选择性反应将至少为背景信号或干扰的二倍，更常 为超过背景的10倍，甚至更具体地，当该平衡解离常数(KD)≤1μM(优选为≤100nM，更 优选为≤10nM，再更优选为≤100pM，再更优选为≤10pM，且甚至更佳为≤1pM)时，抗 体被说是与抗原“特异性结合”。
当与抗体有关时，本文所使用的术语“竞争”意指第一抗体或其抗原结合部分与抗原 的结合减少随后该相同抗原与第二抗体或其抗原结合部分的结合。一般而言，第一抗体与抗原的结合创造空间位阻、构型改变，或结合至共有的表位(或其部分)，从而使第二 抗体与相同抗原的结合减少。标准竞争分析可用于测定二种抗体是否彼此竞争。一种用 于抗体竞争的合适分析涉及使用Biacore技术，此Biacore技术可使用表面等离子共振 (SPR)技术(通常使用生物传感器系统(例如系统))来测量相互作用的程度。 例如，SPR可用于体外竞争性结合抑制分析中以测定一抗体抑制第二抗体的结合的能力。 另一种用于测量抗体竞争的分析是使用基于ELISA的方法。
此外，国际专利申请案第WO2003/48731号中描述基于抗体的竞争的用于“分类(binning)”抗体的高通量过程。若一抗体(或片段)减少另一抗体(或片段)与IL-33的结合，则存在竞争。例如可通过依次加入不同抗体来使用依序结合竞争分析。可添加第一 抗体以达到接近饱和的结合。然后，加入第二抗体。若未检测到第二抗体与IL-33结合， 或与无第一抗体存在的平行分析(该值可以设定为100％)相比较时结合显著减少(例如 减少至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至 少约70％、至少约80％或至少约90％)，则该两种抗体被认为彼此竞争。实施例4中提供 通过SPR进行的示例性抗体竞争分析(及重迭的表位分析)。
“Fc融合”蛋白为其中一或多个多肽可操作地连接Fc多肽的蛋白质。Fc融合将免疫球蛋白的Fc区与融合伴侣结合。
术语“治疗”包括预防性和/或治疗性治疗。若该治疗是在病况的临床表现之前施用， 则该治疗被认为是预防性的。治疗性治疗包括，例如改善或降低疾病的严重性或缩短疾 病的长度。
结合亲和力
抗体的结合亲和力可以KD值表示，该KD值是指特定的抗原-抗体相互作用的解离速率。KD为解离的速率(亦称为“解离速率(koff)”)对结合的速率(或“结合速率(kon)”的比率。因此，KD等于koff/kon且以摩尔浓度(M)表示，KD值越小，该结合亲和力越强。抗 体的KD值可使用本领域完善设立的方法测定。用于测量KD的一种示例性方法为表面 等离子共振(SPR)，其通常使用生物传感器系统，例如系统。BIAcore动力 学分析包含分析抗原与该表面上具有固定分子(例如包含表位结合结构域的分子)的芯 片的结合及解离。用于测定抗体的Kd的另一方法是使用生物膜干涉技术(Bio-Layer Interferometry)，通常使用技术(Octet QKe系统，ForteBio)。此外或另外，亦 可使用可从SapidyneInstruments(Boise，Id)取得的(动力学排除分析(Kinetic Exclusion Assay))分析。
在一些方面中，该KD值是通过表面等离子共振(SPR)测量。该IL-33可被固定住。该IL-33可被固定在固体表面上。该IL-33可，例如通过共价偶联(例如胺偶联)被固定 在在芯片上。该芯片可为CM5传感器芯片。
当分析物与配体结合时，蛋白质累积在传感器表面上导致折射率增加。该折射率变 化是实时测量(在动力学分析实验中的采样是每0.1s进行一次)，结果以应答单位相对于 时间来绘制(RU)(称为传感图)。重要的是，若运行和样品缓冲剂的折射率存有差异亦会产生应答(背景应答)。必须从传感图减去此背景应答以取得实际结合应答。背景应答是 经由注射分析物通过对照流动池或参考流动池(flow cell)来记录，该流动池不具有配体 或具有不相关配体固定在传感器表面上。实时测量结合相互作用的结合和解离允许计算 结合和解离速率常数及相应的亲和常数。一个RU代表每平方毫米结合1pg蛋白质。在 实践中通常需要每平方毫米结合超过50pg的分析物以产生良好的可重复应答。可固定 的IL-33介于85至370RU。可固定的IL-33介于85至225RU。
抗体与IL-33的解离可监测约3600秒。可进行SPR分析并在约15℃至约37℃之间收集数据。可进行SPR分析并在约25℃至37℃之间收集数据。可进行SPR分析并在约37℃ 收集数据。可进行SPR分析并在37℃收集数据。该KD值可使用BIAcore T200仪器，通 过SPR测量。该SPR速率及亲和力可通过将所得的传感图数据拟合至BIAcore T200评 估软件1.0版中的1：1模型来测定。收集速率可为约1Hz。
术语“IL-33分子”是指显示出与野生型IL-33的序列相同性高于与细胞因子IL-1家族 的另一成员的序列相同性(该比较是在相同物种内进行)。术语IL-33分子包括突变体、 变体、截短、片段、剪接变体及融合蛋白的IL-33样部分。
IL-33是以前体形式产生，该前体形式具有负责转位至细胞核和与染色质结合的N端结构域，及与ST2受体相互作用并负责IL-33的生物活性的C端12-链β-三叶形结构域。 由UniProtKB/Swiss-Prot登录编号O95760.1所代表的人IL-33的全长形式在本文中以 SEQID NO：396提供。
当IL-33从细胞释放后，该N端结构域被切割，导致C端结构域释放，具有较全长 蛋白质更高的活性。许多不同蛋白酶，包括IL-33的细胞来源的内源性蛋白酶(例如钙蛋 白酶(calpain))及衍生自炎症细胞(例如肥大细胞和嗜中性粒细胞)的外源性蛋白酶均可 切割IL-33前体分子。该IL-33的精确切割位点将根据存在的蛋白酶而变化。来自SEQ ID NO：396的氨基酸112至270的重组型IL-33 C端结构域为代表性IL-33活性C端形式， 并被指定为SEQ ID NO：1。
IL-33的结构表明其为具有四个游离半胱氨酸残基(C208、C232、C227和C259，根据SEQ ID NO：396的编号)的β-三叶蛋白。证据表明IL-33以活性形式(这四个半胱氨 酸被还原)及无活性形式(半胱氨酸残基对之间具有二硫键，包括介于C208-C259和 C227-C232对之间的二硫键)存在，这似乎与实质的构型变化(包括对高亲和力ST2结合 位点的破坏)相一致，从而对丧失ST2结合提供潜在的结构解释(Cohen et al.,2015, NatureCommunications 6:8327；doi:10.1038/ncomms9327)。突变证据进一步表明半胱氨 酸残基C208和C232亦可能形成二硫键从而导致IL-33去活化(Cohen et al.,2015)。
IL-33的组成上活性形式可通过将一或多个半胱氨酸残基突变成非半胱氨酸残基来 产生。残基C208已被发现对去活化过程特别重要，残基C232的突变亦似乎赋予对去活化的抗性。证据亦表明介于C208-C259和C227-C232之间的可能的二硫键并非去活化的 全部来源，因为C227和C259中的突变不能赋予相似水平的对去活化的抗性；因此IL-33 的二硫键形成可能有几种方式。(Cohen_2015)。
“活性IL-33”可被定义为能够与ST2结合的IL-33分子。活性IL-33可被定义为缺乏一或二个分子内共价键的IL-33分子，该分子内共价键是介于位置208、227、232和259(根据SEQ ID NO：396的编号)的残基对之间。活性IL-33可被定义为缺乏二个分子内共价 键的IL-33分子，该分子内共价键是介于位置208、227、232和259(根据SEQ ID NO：396 的编号)的残基对之间。在一些方面中，活性IL-33为缺乏介于残基208和259之间的共 价键的IL-33分子。在一些方面中，活性IL-33为缺乏介于残基227和232之间的共价键的 IL-33分子。在一些方面中，活性IL-33为缺乏残基208和227之间的共价键的IL-33分子。 在一些方面中，活性IL-33为缺乏残基208和232之间的共价键的IL-33分子。在一些方面 中，活性IL-33为缺乏残基对208/259和227/232、或残基对208/232和227/229之间的共价 键的IL-33分子。因此，活性IL-33包括还原形式的野生型IL-33和突变形式的IL-33，其 中在位置编号208、227、232和259处至少有一、二、三或四个残基不是半胱氨酸。在一 些方面中，残基208和232至少一者不是半胱氨酸。在一些方面中，至少残基208不是半 胱氨酸。在一些方面中，至少残基208和232不是半胱氨酸。在一些方面中，残基208、 227、232和259无一为半胱氨酸。在一些方面中，残基208、227、232和259的一或多者 为丝氨酸。该共价键可为二硫键。上述残基编号是根据SEQ ID NO：1的编号。在一些 方面中，活性IL-33包含含有SEQ ID NO：1的完全还原分子。在一些方面中，活性IL-33 包含含有SEQ ID NO：4的完全还原分子。在一些方面中，活性IL-33包含含有SEQ ID NO： 3的分子。在一些方面中，活性IL-33包含含有SEQ IDNO：5的分子。
无活性IL-33可被定义为以低于活性IL-33的亲和力至少10倍的亲和力与ST2结合的IL-33分子。在一些方面中，无活性IL-33以低于活性IL-33至少100倍的亲和力与ST2 结合。在一些方面中，无活性IL-33以低于活性IL-33至少1000倍的亲和力与ST2结合。 在一些方面中，无活性IL-33以低于活性IL-33至少4个数量级的亲和力与ST2结合。在 一些方面中，无活性IL-33以低于活性IL-33至少5个数量级的亲和力与ST2结合。在一 些方面中，无活性IL-33在残基对208/259和227/232之一或二者之间包含共价键。在一些 方面中，无活性IL-33在残基对208/232和227/259之一或二者之间包含共价键。在一些方 面中，无活性IL-33在残基208和232之间包含共价键。在一些方面中，无活性IL-33在残 基208和259之间包含共价键。在一些方面中，无活性IL-33在残基227和232之间包含共 价键。在一些方面中，无活性IL-33在残基对208/259和227/232二者之间包含共价键。该 残基之一或多者可为半胱氨酸。该共价键之一或二者可为可为二硫键。前述残基编号是 根据SEQ ID NO：396的编号。
在一些方面中，该IL-33为人IL-33。在一些方面中，该野生型IL-33的序列为SEQID NO：1。在一些方面中，该IL-33为大鼠IL-33。在一些方面中，该IL-33为小鼠IL-33。 在一些方面中，该IL-33为灵长类动物IL-33。在一些方面中，该IL-33为猿IL-33。在一 些方面中，该IL-33为猴IL-33。于一某些方面中，该IL-33为食蟹猴IL-33。
活性IL-33的KD可使用IL-33变体测量，其中至少C208被另一氨基酸残基取代。在一些方面中，活性IL-33的KD可使用IL-33变体测量，其中至少C232被另一氨基酸残基 取代。在一些方面中，活性IL-33的KD可使用IL-33变体测量，其中至少C208和C232 被取代。在一些方面中，活性IL-33的KD可使用IL-33变体测量，其中至少C208、C227、 C232和C259被取代。在一些方面中，该半胱氨酸残基之一或多者被丝氨酸取代。
针对IL-33的抗体
在一些方面中，本发明提供拮抗性IL-33抗体。IL-33途径的高亲和力拮抗剂可能对 多种细胞类型和多个组织区室有效，在该多种细胞类型和多个组织隔室中IL-33被认为作用于其靶细胞上。在一些方面中，本发明的抗体可接近IL-33从细胞(尤其是上皮细胞 和内皮细胞)释放的部位。在一些方面中，本发明提供可分在肺和其他组织内的胞外空 间的IL-33抗体，该IL-33抗体可有效地与细胞表面受体竞争结合IL-33并具有相当长的 半衰期，以允许不频繁地给药。本发明的抗体具有潜力修饰驱动与哮喘相关的发展及炎 症的重要途径。
中和或“阻断”抗体是指与IL-33的结合具有下列情况的抗体：(i)干扰、限制或抑制 IL-33或IL-33片段与IL-33受体组分(例如ST2、IL-1RAcP，等)之间的相互作用；和/ 或(ii)导致IL-33的至少一种生物学功能受抑制。测定本发明抗体的中和作用的分析描 述于本文他处且为本领域所熟知。
本发明提供特异性结合IL-33的抗体。在一些方面中，本发明提供中和至少50％的IL-33的抗体或其抗原结合片段。在一些方面中，本发明提供中和至少60％的IL-33的抗 体或其抗原结合片段。在一些方面中，本发明提供中和至少70％的IL-33的抗体或其抗 原结合片段。在一些方面中，本发明提供中和至少80％的IL-33的抗体或其抗原结合片 段。在一些方面中，本发明提供中和至少90％的IL-33的抗体或其抗原结合片段。在一 些方面中，本发明提供中和至少95％的IL-33的抗体或其抗原结合片段。在一些方面中， 本发明提供中和至少96％的IL-33的抗体或其抗原结合片段。在一些方面中，本发明提 供中和至少97％的IL-33的抗体或其抗原结合片段。在一些方面中，本发明提供中和至 少98％的IL-33的抗体或其抗原结合片段。在一些方面中，本发明提供中和至少99％的 IL-33的抗体或其抗原结合片段。
该抗体或其抗原结合片段可选自以下组：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体 _huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、9B3_1、9B3_2A、9B3_2B、 9B3_3、9B3_5、9B3_7、9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、 9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、 IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、 IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、 IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、 IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS 和IL33-167LS、其抗原结合片段及其突变体、变体、衍生物和基本上相似的版本。
CDR共有序列
在一些方面中，该CDR包含SEQ ID NO：257、261、265、269、272和276。这些 CDR序列基于所有可用数据(ABS加突变加大鼠组库)、测试的VH种系及基于建模的突 变掺入共有序列以保留/改善与IL-33的结合或减少多重反应性或序列不利条件(liability)， 但不会破坏结合。
CDR H1：基于总体可用信息，用于CDR H1的广泛共有序列为SEQ ID NO：269。 用于CDR H1的共有序列的进一步细化子集为SEQ ID NO：270，包括从优化亲代大鼠 抗体7E8和9B3及扩增的二元取代(ABS)所得的结果。用于优化的7E8的共有CDR H1序 列为26GF(T/E)F(S/E)(N/S)YWMY32(SEQ ID NO：270)。从9B3进行的CDR H1取代(其 引入S31N突变或引入T28E或S30E突变)允许保留全部活性。扩增的二元取代诱变显 示出对位置35的Y具强烈偏好而非DP54种系残基S。用于优化的7E8，处理位置31处 的9B3序列及位置35处的ABS偏好的共有CDR H1序列为SEQ ID NO：271。
CDR H2：基于总体可用信息，用于CDR H2的广泛共有序列为SEQ ID NO：272。 用于CDR H2的共有序列的进一步细化子集为SEQ ID NO：273，包括从优化7E8和9B3 及扩增的二元取代(ABS)所得的结果。用于优化的7E8的共有CDR H2序列为 50(S/A)I(T/N)(P/N)(N/D)(G/A)(G/S/H)(N/D/E)(T/K/D/E)YY(P/V/L)(D/E)SV(K/Q) G66(SEQ ID NO：273)。引入突变S50A、G55A、G56H、N57D、N57E、T58D、T58E、 D62E或K65Q允许保留人IL-33中和效力，而不会实质增加非特异性结合。N54I、N54L、 N54V、N54Y和N54W允许保留人IL-33中和效力，但引入增加的非特异性结合。将 CDR H2从9B3取代成7E8，此取代引入四个变化(T52N、P53N、N54D和P61L)，允许 保留对人IL-33的强中和作用，但导致对食蟹猴IL-33的中和效力降低。扩增的二元取代 诱变显示出位置50、52和53处对S、T和P具强烈偏好而非DP54种系残基N、K和Q，但容许掺入DP54种系突变N54D、G56S、N57E、T58K和P61V。用于优化的7E8，处 理位置52和53处的ABS偏好及容许用于中和人IL-33的9B3序列的共有CDR H2序列为 SEQ ID NO：274。用于优化的7E8，处理位置52和53处的ABS偏好的共有CDR H2序 列为SEQ ID NO：275。
CDR H3：基于总体可用信息，用于CDR H3的广泛共有序列为SEQ ID NO：276。 用于CDR H3的共有序列的进一步细化子集为SEQ ID NO：277，包括从优化7E8和9B3 及分析来自以人IL-33免疫化的大鼠抗体组库的序列所得的结果。用于优化的7E8的共 有CDR H3序列为99G(H/Y)Y(Y/S)(Y/H)(T/S/N)(S/A)YS(L/F)(G/S)Y110(SEQ ID NO： 278)。引入突变H100Y、Y103H、T104N、T104S或S105A允许保留人IL-33的中和效 力，而不会实质增加非特异性结合。突变S105D和S105N导致损失人IL-33中和效力。 将CDR H3从9B3取代成7E8，此取代引入突变Y102S、T104S、L108F和G109S，允许 保留对人IL-33的强中和效力，但导致对食蟹猴IL-33的中和效力降低。掺入从以人IL-33 免疫化的大鼠的抗体组库鉴定的7E8相关CDRH3序列显示出下列氨基酸与高度的人 IL-33中和效力兼容：R100、F101、N104、I108、A109、H110、N110、S110和F110。 用于优化的7E8，处理容许用于中和人IL-33的9B3序列的共有CDRH3序列为SEQ ID NO：279。
CDR L1：基于总体可用信息，用于CDR L1的广泛共有序列为SEQ ID NO：257。 用于CDR L1的共有序列的进一步细化子集为SEQ ID NO：258，包括从优化7E8和9B3 及扩增的二元取代(ABS)所得的结果。用于优化的7E8的共有CDR L1序列为24(K/R) AS(Q/H)(N/S)I(N/S)(K/S)HLD34(SEQ ID NO：259)。扩增的二元取代诱变显示出位置 32和34处对H和D具强烈偏好而非DPK9种系残基Y32和N34，但容许掺入DPK9种系 突变K24R、N28S、N30S和K31S。将9B3轻链取代成7E8轻链(其包括轻链序列变异Q27H) 允许保留IL-33中和效力，但不引入非特异性结合。引入突变N30H、K31R和H32Y允 许保留人IL-33中和效力，但增加非特异性结合，而突变N30Y、N30D、N30W、K31E 和K31D会降低效力和/或引入更高的非特异性结合。用于优化的7E8，处理位置32和34 处的ABS偏好而不允许位置27处的轻链序列变化的共有CDR L1序列为SEQ ID NO： 260。
CDR L2：基于总体可用信息，用于CDR L2的广泛共有序列为SEQ ID NO：261。 用于CDR L2的共有序列的进一步细化子集为SEQ ID NO：262，包括从优化7E8和9B3 及扩增的二元取代(ABS)所得的结果。用于优化的7E8的共有CDR L2序列为50F(T/A) (N/S)(N/S)LQ(T/S)56(SEQ ID NO：263)。扩增的二元取代诱变显示出位置50处对F具 强烈偏好而非DPK9种系残基A，但容许掺入DPK9种系突变T51A、N52S、N53S和 T56S。引入突变N52Y或N53R允许保留人IL-33中和效力，但增加非特异性结合，而 突变F50H、T56D、T56E和T56Q降低效力和/或引入更高的非特异性结合。用于优化 的7E8而不容许位置53处的变化的共有CDR L2序列为SEQ ID NO：264。
CDR L3：基于总体可用信息，用于CDR L3的广泛共有序列为SEQ ID NO：265。 用于CDR L3的共有序列的进一步细化子集为SEQ ID NO：266，包括从优化7E8和9B3 及扩增的二元取代(ABS)所得的结果。用于优化的7E8的共有CDR L3序列为89(F/Q) QY(N/Y)(N/S/Q/R)GWT96(SEQ ID NO：267)。引入突变N93Q允许保留人IL-33中和效 力但不会实质增加非特异性结合，而突变N93R允许人IL-33中和效力且少量增加非特 异性结合。突变N92R和G94R允许保留人IL-33中和效力，但导致非特异性结合增加。 将9B3轻链取代成7E8轻链(其包括轻链序列变异N93S)允许保留IL-33中和效力而不引 入非特异性结合。扩增的二元取代诱变显示出位置91和94处对Y和G具强烈偏好而非 DPK9种系残基S和T，但容许掺入DPK9种系突变F89Q、N92Y和N93S。保留大鼠J 区段残基W95强烈优于取代人JK4残基W95L。用于优化的7E8，处理位置91和94处的 ABS偏好而不允许掺入位置93处的R的共有CDR L3序列为SEQ IDNO：268。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：257、CDR-L2含有SEQ ID NO：261、 CDR-L3含有SEQ ID NO：265、CDR-H1含有SEQ ID NO：269、CDR-H2含有SEQ ID NO： 272且CDR-H3含有SEQID NO：276。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：258、CDR-L2含有SEQ ID NO：262、 CDR-L3含有SEQ ID NO：266、CDR-H1含有SEQ ID NO：270、CDR-H2含有SEQ ID NO： 273且CDR-H3含有SEQID NO：277。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：259、CDR-L2含有SEQ ID NO：263、 CDR-L3含有SEQ ID NO：267、CDR-H1含有SEQ ID NO：271、CDR-H2含有SEQ ID NO： 274且CDR-H3含有SEQID NO：278。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：260、CDR-L2含有SEQ ID NO：264、CDR-L3含有SEQ ID NO：268、CDR-H1含有SEQ ID NO：271、CDR-H2含有SEQ ID NO： 275且CDR-H3含有SEQID NO：279。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：20、CDR-L2含有SEQ ID NO：21、 CDR-L3含有SEQID NO：208、CDR-H1含有SEQ ID NO：16、CDR-H2含有SEQ ID NO： 226且CDR-H3含有SEQ IDNO：18。
在一些方面中，该抗体或其抗原结合片段包含SEQ ID NO：225的CDR-H1、CDR-H2和CDR-H3序列。
在一些方面中，该抗体或其抗原结合片段包含SEQ ID NO：207的CDR-L1、CDR-L2和CDR-L3序列。
该抗体或抗原结合片段可包含VH，该VH包含与SEQ ID NO：225至少90％相同 的氨基酸序列。该VH可包含与SEQ ID NO：225至少91％、92％、93％、94％、95％、 96％、97％、98％或99％相同的氨基酸序列。该VH可包含SEQ ID NO：225的氨基酸序 列。
该抗体或抗原结合片段可包含VL，该VL包含与SEQ ID NO：207至少90％相同的 氨基酸序列。该VL可包含与SEQ ID NO：207至少91％、92％、93％、94％、95％、96％、 97％、98％或99％相同的氨基酸序列。该VL可包含SEQ ID NO：207的氨基酸序列。
该抗体或抗原结合片段可包含HC，该HC包含与SEQ ID NO：244至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列。该HC可包含SEQ ID NO：244的氨基酸序列。
该抗体或抗原结合片段包含LC，该LC包含与SEQ ID NO：209至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列。该LC可包含SEQ ID NO：209的氨基酸序列。
在一些方面中，该抗体或其抗原结合片段包含CDR-L1、CDR-L2、CDR-L3、CDR-H1、CDR-H2和CDR-H3，该CDR-L1含有SEQ ID NO：20、CDR-L2含有SEQ ID NO：21、 CDR-L3含有SEQID NO：22、CDR-H1含有SEQ ID NO：16、CDR-H2含有SEQ ID NO： 211且CDR-H3含有SEQ IDNO：18。
在一些方面中，该抗体或其抗原结合片段包含SEQ ID NO：210的CDR-H1、CDR-H2和CDR-H3序列。
在一些方面中，该抗体或其抗原结合片段包含SEQ ID NO：91的CDR-L1、CDR-L2 和CDR-L3序列。
该抗体或抗原结合片段可包含VH，该VH包含与SEQ ID NO：210至少90％相同 的氨基酸序列。该VH可包含与SEQ ID NO：210至少91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列。该VH可包含SEQ ID NO：210的氨基酸序 列。
该抗体或抗原结合片段可包含VL，该VL包含与SEQ ID NO：91至少90％相同的 氨基酸序列。该VL可包含与SEQ ID NO：91至少91％、92％、93％、94％、95％、96％、 97％、98％或99％相同的氨基酸序列。该VL可包含SEQ ID NO：91的氨基酸序列。
该抗体或抗原结合片段可包含HC，该HC包含与SEQ ID NO：245至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列。该HC可包含SEQ ID NO：245的氨基酸序列。
该抗体或抗原结合片段可包含LC，该LC包含与SEQ ID NO：93至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同的氨基酸序列。该LC可包含SEQ ID NO：93的氨基酸序列。
种系取代
在某些实施方案中，该抗体或其抗原结合片段包含下列重链CDR序列：(ⅰ)包含SEQ ID NO：16的CDR-H1，包含SEQ ID NO：226的CDR-H2和包含SEQ ID NO：18 的CDR-H3；和/或(ii)下列轻链CDR序列：包含SEQ ID NO：20的CDR-L1、包含SEQ ID NO：21的CDR-L2和包含SEQ ID NO：208的CDR-L3。
在某些实施方案中，在CDR-L1中做出相对于SEQ ID NO：20而言不超过11个、或 不超过10个、不超过9个、不超过8个、不超过7个、不超过6个、不超过5个、不超过4 个、不超过3个、不超过2个或不超过1个取代。在某些实施方案中，在CDR-L2中做出 相对于SEQ ID NO：21而言不超过6个、不超过5个、不超过4个、不超过3个、不超过2 个或不超过1个取代。在某些实施方案中，在CDR-L3中做出相对于SEQ ID NO：208 而言不超过8个、不超过7个、不超过6个、不超过5个、不超过4个、不超过3个、不超过 3个、不超过2个或不超过1个取代。在一些实施方案中，在CDR-H1中做出相对于SEQ ID NO：16而言不超过10个、不超过9个、不超过8个、不超过7个、不超过6个、不超过5 个、不超过4个、不超过3个、不超过2个或不超过1个取代。在一些实施方案中，在CDR-H2 中做出相对于SEQ ID NO：211而言不超过17个、不超过16个、不超过15个、不超过14 个、不超过13个、不超过12个、不超过11个、或不超过10个、不超过9个、不超过8个、 不超过7个、不超过6个、不超过5个、不超过4个、不超过3个、不超过2个、或不超过1 个取代。在一些实施方案中，在CDR-H3中做出相对于SEQ ID NO：18而言不超过12 个、不超过11个、或不超过10个、不超过9个、不超过8个、不超过7个、不超过6个、不 超过5、不超过4个、不超过3个、不超过2个、或不超过1个取代。在某些实施方案中， 该(一个或多个)取代所改变的结合亲和力(KD)值不超过1000倍、不超过100倍或10倍。
在某些实施方案中，该取代为根据表1的保守取代。
表1:保守取代
残基 保守取代 残基 保守取代
Ala Ser Leu Ile,Val
Arg Lys Lys Arg,Gln
Asn Gln；His Met Leu,Ile
Asp Glu Phe Met,Leu,Tyr
Cys Ser Ser Thr；Gly
Gln Asn Thr Ser,Val
Glu Asp Trp Tyr
Gly Pro Tyr Trp,Phe
His Asn,Gln Val Ile,Leu
Ile Leu,Val Pro -
在某些实施方案中，该取代为人种系取代，其中CDR残基被相应的人种系残基取代以增加人氨基酸含量并潜在地降低抗体的致免疫性。例如若使用人种系DPK9框架及 示例性抗体IL-33-158LS，则该IL33-158LS抗体的CDR-L1(SEQ ID NO：20)与人种系 DPK9的比对如下：
对于位置25、26、27、29、33和34，该人种系残基和相应的IL33-158LS残基相同 且种系取代是不可能的。对于位置24、28、30、31和32(粗体且下划线)，该人种系残基 和相应的IL33-158LS残基不相同。这些位置处的IL33-158LS的残基可被相应的人种系 DPK9残基替代以进一步增加人残基含量。
用于在抗体CDR中引入人种系残基的方法和文库详细描述于美国临时申请案 62/162,905及(Townsend et al.,2015,Proc.Natl.Acad.Sci.USA.112(50)：15354-15359)中，其全部内容以引用方式并入本文。
该抗体或其抗原结合片段可包含VH框架，该VH框架可包含人种系VH框架序列。 该VH框架序列可来自人VH3种系、VH1种系、VH5种系或VH4种系。优选的人种系 重链框架为衍生自VH1、VH3或VH5种系的框架。例如可使用来自下列种系的VH框 架：IGHV3-23、IGHV3-7或IGHV1-69(种系名称基于IMGT种系定义)。优选的人种系 轻链框架为衍生自Vκ或Vλ种系的框架。例如可使用来自下列种系的VL框架： IGKV1-39或IGKV3-20(种系名称基于IMGT种系定义)。另外或此外，该构架序列可为 人种系共有框架序列，例如人Vλ1共有序列、Vκ1共有序列、Vκ2共有序列，Vκ3共有 序列、VH3种系共有序列、VH1种系共有序列、VH5种系共有序列或VH4种系共有序列 的框架。人种系框架的序列可从各种公开的数据库取得，例如V-base、IMGT、NCBI 或Abysis。
该抗体或其抗原结合片段可包含VL框架，该VL框架包含人种系VL框架序列。 该VL框架可包含一或多个氨基酸取代、添加或缺失，同时仍保留与该抗体衍生的种系 的功能和结构相似性。在一些方面中，该VL框架与人种系VL框架序列至少90％、至 少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、 至少99％或100％相同。在一些方面中，该抗体或其抗原结合片段包含VL框架，该VL 框架相对于人种系VL框架序列而言包含1、2、3、4、5、6、7、8、9、10个氨基酸取 代、添加或缺失。在一些方面中，该1、2、3、4、5、6、7、8、9或10个氨基酸取代、 添加或缺失仅在框架区中。在一些方面中，该％相同性是基于与VL的相似性，不包括 本文定义为CDR的那些部分。
该人种系VL框架可为DPK9(IMGT名称：IGKV1-39)的框架。该人种系VL框架 可为DPK12(IMGT名称：IGKV2D-29)的框架。该人种系VL框架可为DPK18(IMGT 名称：IGKV2-30)的框架。该人种系VL框架可为DPK24(IMGT名称：IGKV4-1)的框 架。该人种系VL框架可为HK102_V1(IMGT名称：IGKV1-5)的框架。该人种系VL 框架可为DPK1(IMGT名称：IGKV1-33)的框架。该人种系VL框架可为DPK8(IMGT 名称：IGKV1-9)的框架。该人种系VL框架可为DPK3(IMGT名称：IGKV1-6)的框架。 该人种系VL框架可为DPK21(IMGT名称：IGKV3-15)的框架。该人种系VL框架可 为Vg_38K(IMGT名称：IGKV3-11)的框架。该人种系VL框架可为DPK22(IMGT名 称：IGKV3-20)的框架。该人种系VL框架可为DPK15(IMGT名称：IGKV2-28)的框 架。该人种系VL框架可为DPL16(IMGT名称：IGLV3-19)的框架。该人种系VL框架 可为DPL8(IMGT名称：IGLV1-40)的框架。该人种系VL框架可为V1-22(IMGT名称： IGLV6-57)的框架。该人种系VL框架可为人Vλ共有序列的框架。该人种系VL框架 可为人Vλ1共有序列的框架。该人种系VL框架可为人Vλ3共有序列的框架。该人种系 VL框架可为人Vκ共有序列的框架。该人种系VL框架可为人Vκ1共有序列的框架。 该人种系VL框架可为人Vκ2共有序列的框架。该人种系VL框架可为人Vκ3共有序列 的框架。
在一些方面中，该VL框架为DPK9。其他相似的框架区亦被预测来递送本发明的 有益抗体，本发明的有益抗体包含下列CDR：SEQ ID NO：257、261和265；或SEQ ID NO：258、262和266；或SEQ ID NO：259、263和267；或SEQ ID NO：260、264、268； 或SEQ ID NO：20、21和208；包括DPK5、DPK4、DPK1、IGKV1-5*01、DPK24、DPK21、 DPK15、IGKV1-13*02、IGKV1-17*01、DPK8、IGKV3-11*01和DPK22，其与DPK-9 的FW区分别具有99、97、97、96、80、76、66、97、97、96、76和74％相同性且在下 列共同结构特征(Kabat编号)中包含一或更少个氨基酸差异：(A)紧接在CDR之下(游 标区)的残基L2、L4、L35、L36、L46、L47、L48、L49、L64、L66、L68、L69、L71， (B)VH/VL链包装残基：L36、L38、L44、L46、L87及(C)典型CDR结构支持残基L2、 L48、L64、L71(参见Lo,“Antibody Humanization by CDR移植物ing”,(2004)AntibodyEngineering,Vol.248,Methods in Molecular Biology pp 135-159；以及O’Brien andJones, “Humanization of Monoclonal Antibodies by CDR移植物ing”,(2003)Recombinant Antibodies for Cancer Therapy,Vol.207,Methods in MolecularBiology pp 81-100)。特别优 选为分别与DPK9具有99、97、97、96、80、76、66％相同性的DPK5、DPK4、DPK1、 IGKV1-5*01、DPK24、DPK21、DPK15的框架区，且在这些常见的结构特征中不具有 氨基酸差异。在一些方面中，该％相同性基于与VL的相似性，不包括本文定义为CDR的那些部分。
本发明抗体(及片段)的CDR-L1、CDR-L2和CDR-L3中的残基可被如表2中所示的 相应的种系残基所取代。
表2
提供替代序列用于具有和不具有缺口的共有序列。在没有共有序列的位置处，()中的残基与最常见的残基并列(tied).
该抗体或其抗原结合片段可包含VH框架，该VH框架包含人种系VH框架序列。 该VH框架可包含一或多个氨基酸取代、添加或缺失，同时仍保留与该抗体衍生的种系 的功能和结构相似性。在一些方面中，该VH框架与人种系VH框架序列至少90％、至 少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、 至少99％或100％相同。在一些方面中，该抗体或其抗原结合片段包含VH框架，该VH 框架相对于人种系VH框架序列而言包含1、2、3、4、5、6、7、8、9、10个氨基酸取 代、添加或缺失。在一些方面中，该1、2、3、4、5、6、7、8、9或10个氨基酸取代、 添加或缺失仅在框架区中。在一些方面中，该％相同性基于与VH的相似性，不包括本 文定义为CDR的那些部分。
该人种系VH框架可为DP54或IGHV3-7的框架。该人种系VH框架可为DP47或 IGHV3-23的框架。该人种系VH框架可为DP71或IGHV4-59的框架。该人种系VH框 架可为DP75或IGHV1-2_02的框架。该人种系VH框架可为DP10或IGHV1-69的框架。 该人种系VH框架可为DP7或IGHV1-46的框架。该人种系VH框架可为DP49或 IGHV3-30的框架。该人种系VH框架可为DP51或IGHV3-48的框架。该人种系VH框 架可为DP38或IGHV3-15的框架。该人种系VH框架可为DP79或IGHV4-39的框架。 该人种系VH框架可为DP78或IGHV4-30-4的框架。该人种系VH框架可为DP73或 IGHV5-51的框架。该人种系VH框架可为DP50或IGHV3-33的框架。该人种系VH框 架可为DP46或IGHV3-30-3的框架。该人种系VH框架可为DP31或IGHV3-9的框架。 该人种系VH框架可为人VH种系共有序列的框架。该人种系VH框架可为人VH3种系 共有序列的框架。该人种系VH框架可为人VH5种系共有序列的框架。该人种系VH框 架可为人VH1种系共有序列的框架。该人种系VH框架可为人VH4种系共有序列的框 架。
在一些方面中，该VH框架为DP-54。其他相似的框架区亦被预测来递送本发明的有益抗体，本发明的有益抗体包含下列CDR：SEQ ID NO：269、272和276；或SEQ ID NO:270、273和277；或SEQ ID NO：271、274和278；或SEQ ID NO：271、275和278； 或SEQ ID NO：16、226和18；包括DP-50、IGHV3-30*09、IGHV3-30*15、IGHV3-48*01、 DP-77、DP-51、IGHV3-66*01、DP-53、DP-48、IGHV3-53*01、IGHV3-30*02和DP-49， 其与DP-54的FW区分别具有93、92、92、99、97、97、96、96、94、94、93和92％相 同性且在下列共同结构特征(Kabat编号)中包含一或更少个氨基酸差异(A)紧接在 CDR之下(游标区)的残基、H2、H47、H48和H49、H67、H69、H71、H73、H93、H94， (B)VH/VL链包装残基：H37、H39、H45、H47、H91、H93及(C)典型CDR结构支持 残基H24、H71、H94(参见Lo 2004、和O'Brien and Jones 2003)。特别优选为分别与DP-54 具有93、92和92％相同性的DP-50、IGHV3-30*09、IGHV3-30*15的框架区且在这些共 同结构特征中没有氨基酸差异。在一些方面中，该％相同性基于与VH的相似性，不包 括本文定义为CDR的那些部分。
本发明抗体(及片段)的CDR-H1、CDR-H2和CDR-H3中的残基可被如表3中所示的 相应种系残基所取代。
表3
提供替代序列用于具有和不具有缺口的共有序列。在没有共有序列的位置处，()中的残基与最常见的残基并列(tied).
在某些实施方案中，本文所描述的抗体或其抗原结合片段包含(i)VH，其包含与SEQ ID NO：225至少50％、至少60％、至少70％、至少75％、至少80％、至少85％、至 少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、 至少98％、至少99％或100％相同的氨基酸序列，和/或(ii)VL，其包含与SEQ ID NO： 207至少50％、至少60％、至少66％、至少70％、至少75％、至少76％、至少80％、至少 85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至 少97％、至少98％、至少99％或100％相同的氨基酸序列。这些VL和VH序列的任何组 合亦包含在本发明中。
在某些实施方案中，本文所描述的抗体或其抗原结合片段包含(i)HC，其包含与SEQ ID NO：244至少50％、至少60％、至少70％、至少75％、至少80％、至少85％、至 少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、 至少98％、至少99％或100％相同的氨基酸序列；和/或(ii)LC，其包含与SEQ ID NO： 209至少50％、至少60％、至少70％、至少75％、至少80％、至少85％、至少90％、至少 91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至 少99％或100％相同的氨基酸序列。这些HC和LC序列的任何组合亦包含在本发明中。
在某些实施方案中，本文所描述的抗体或其抗原结合片段包含Fc结构域。该Fc 结构域可衍生自IgA(例如IgA1或IgA2)、IgD、IgE或IgG(例如IgG1、IgG2、IgG3或IgG4)。
在一些实施方案中，本文所描述的抗体或其抗原结合片段包含(i)VH，其包含与下组的其中一者至少50％、至少60％、至少70％、至少75％、至少80％、至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、 至少99％或100％相同的氨基酸序列：SEQ ID NO：14、32、43、54、61、72、90、94、 97、101、106、111、113、118、121、124、126、129、132、135、138、141、144、147、 150、152、155、158、161、163、165、167、170、173、176、179、182、184、186、 201、204、210、213、216、219、222、225、228、231和234，和/或(ii)VL，其包含与 下组的任一者具有至少50％、至少60％、至少70％、至少75％、至少80％、至少85％、至 少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、 至少98％、至少99％或100％相同性的氨基酸序列：SEQ ID NO：19、36、47、56、65、 76、81、84、86、88、91、98、103、108、115、189、192、195、188和207。这些VL和VH序列的任何组合亦包含在本发明中。在一些方面中，该VH并非选自以下组的一 或多者：SEQ ID NO：43、54和101。在一些方面中，该VL并非选自以下组的一或多 者：SEQ ID NO：47、56和103。
本发明亦提供与本文所描述的任何抗体或其抗原结合片段竞争结合人IL-33的抗体 或其抗原结合片段，例如本文所提供的任一抗体(或其抗原结合片段)。例如若抗体或其抗原结合部分与人IL-33的结合阻碍随后IL33-158LS与人IL-33的结合，则该抗体或其 抗原结合部分与IL33-158LS竞争结合人IL-33。
本发明亦提供与本文所描述的任何抗体或其抗原结合片段结合至相同的人IL-33表 位的抗体或其抗原结合片段，例如本文所提供的抗体或其抗原结合片段的任一者。例如， 抗体竞争分析(和重迭表位分析)可通过如本文所详细描述的SPR评估。
本发明提供的抗体及抗原结合片段包括单克隆抗体、多克隆抗体、抗体片段(例如Fab、Fab'、F(ab')2、Fv、Fc、等)、嵌合抗体、双特异性抗体、异缀合抗体(heteroconjugateantibody)、单链(ScFv)、其突变体、包含抗体部分的融合蛋白、结构域抗体(dAb)、人源 化抗体及包含具有所需特异性的抗原识别位点的免疫球蛋白分子的任何其他修饰构型 (包括抗体的糖基化变体、抗体的氨基酸序列变体及经共价修饰的抗体)。该抗体和抗原 结合片段可为小鼠、大鼠、人或任何其他来源(包括嵌合抗体或人源化抗体)。在一些实 施方案中，该抗体为单克隆抗体。在一些实施方案中，该抗体为嵌合抗体、人源化抗体 或人抗体。在某些实施方案中，该抗体为人抗体。在某些实施方案中，该抗体为人源化 抗体。
生物保藏物
本发明的代表性材料于2015年12月23日保藏于美国典型培养物保藏中心，美国弗吉 尼亚州马纳萨斯大学大道10801号，20110-2209(American Type Culture Collection,10801 University Boulevard,Manassas,Va.20110-2209)。具有ATCC编号PTA-122724的载体 VH-IL33-158LS包含编码抗体IL33-158LS的重链可变区的DNA插入物，而具有ATCC 编号PTA-122725的载体VL-IL33-158LS包含编码抗体IL33-158LS的轻链可变区的DNA 插入物。这些保藏物根据国际承认用于专利程序的微生物保藏布达佩斯条约(布达佩斯 条约，Budapest Treaty)的规定进行。这确保从保藏日起30年该存活培养物的维持。该保 藏物将根据布达佩斯条约的条款由ATCC提供并受辉瑞公司和ATCC之间的协议管制， 此协议确保该保藏的培养物后代在相关的美国专利案公布时或在任何美国或外国专利 申请案(以先到者为准)开放给公众时的永久和无限制可用性，并确保由美国专利和商 标专员(U.S.Commissioner of Patents and Trademarks)依据35USC第122条及据此的监理 规则(Commissioner’s rules)(包括37CFR 1.14节，特别参考886OG 638(37C.F.R.Section1.14with particular reference to 886OG 638))决定具有权利者可取得该后代。
本申请案的受让人已同意若该保藏材料的培养物在合适的条件下培养时死亡或遗 失或受损，该物质将在通知时及时被更换成另一相同材料。保藏物质的可用性不应被理解为允许在违背任何政府当局根据其专利法所授予的权利下实施本发明。
核酸
本发明亦提供编码本文所描述的任一抗体(包括抗体部分和修饰的抗体)的多核苷 酸。本发明亦提供制备本文所描述的任何多核苷酸的方法。多核苷酸可通过本领域已知的程序制备和表达。
所需抗体、定义的抗体片段或其抗原结合片段的序列及编码该等抗体或其片段的核 酸可使用标准测序技术测定。编码所需抗体、定义的抗体片段或其抗原结合片段的核酸序列可被插入用于重组生产和表征的各种载体(例如克隆和表达载体)中。编码该重链、 定义的抗体片段或该重链的抗原结合片段的核酸，及编码该轻链、定义的抗体片段或该 轻链的抗原结合片段的核酸可被克隆在相同的载体或不同的载体中。
在一方面中，本发明提供多核苷酸，该多核苷酸编码下列任一IL-33抗体及其抗原结合部分的氨基酸序列：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移 植物、IL33-10、9B3 CDR移植物、9B3_1、9B3_2A、9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、9B3_79、9B3_124、9B3_162、 7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、IL33-55、IL33-56、IL33-57、 IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、IL33-80、IL33-81、IL33-103、 IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、IL33-157、IL33-158、 IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、IL33-175、IL33-186、 IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS和IL33-167LS。
本发明提供编码抗体或其抗原结合片段的氨基酸序列的多核苷酸，该抗体或其抗原 结合片段与选自以下组的抗体结合至基本上相同的表位：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、9B3_1、9B3_2A、 9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、 9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、 IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、 IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、 IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、 IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS 和IL33-167LS。
本发明提供编码抗体或其抗原结合片段的氨基酸序列的多核苷酸，该抗体或其抗原 结合片段与选自以下组的抗体竞争结合IL-33：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体 _huJseg、7E8 CDR移植物、IL33-10、9B3 CDR移植物、9B3_1、9B3_2A、9B3_2B、 9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、9B3_79、 9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、IL33-55、 IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、IL33-80、 IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、 IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、 IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS 和IL33-167LS。
本发明提供编码一或多种蛋白质的多核苷酸，该蛋白质包含选自以下组的氨基酸序 列：(i)SEQ ID NO：1至279。
本发明提供多核苷酸，其包含如SEQ ID NO：398、399、400和401之一或多者所 示的核酸序列。本发明提供包含如SEQ ID NO：398所示的核酸序列的多核苷酸。本发 明提供包含如SEQ ID NO：399所示的核酸序列的多核苷酸。本发明提供包含如SEQ ID NO：400所示的核酸序列的多核苷酸。本发明提供包含如SEQ ID NO：401所示的核酸 序列的多核苷酸。
本发明提供多核苷酸，其包含保藏于ATCC且具有登录编号PTA-122724及登录编号PTA-122725的核酸分子的DNA插入物的编码序列的一或二者。本发明提供多核苷酸， 其包含保藏于ATCC且具有登录编号PTA-122724的核酸分子。本发明提供多核苷酸， 其包含保藏于ATCC且具有登录编号PTA-122725的核酸分子。
本发明提供包含一或多个如SEQ ID NO：398、399、400和401之一或多者所示的 核酸分子的细胞。本发明提供包含一或多个如SEQ ID NO：398和399所示的核酸分子 的细胞。本发明提供包含一或多个如SEQ ID NO：400和401所示的核酸分子的细胞。
在另一方面中，本发明提供编码抗IL-33抗体的多核苷酸及其变体，其中这些变体多核苷酸与本文所公开的任一具体的核酸序列具有至少70％、至少75％、至少80％、至 少85％、至少87％、至少89％、至少90％、至少91％、至少92％、至少93％、至少94％、 至少95％、至少96％、至少97％、至少98％或至少99％序列相同性。这些量并不意图限 制，且所列举的百分比之间的增量被具体设想为本公开内容的一部分。
本发明提供由本文所描述的核酸分子编码的多肽。
在一实施方案中，该VH和VL结构域或其抗原结合部分或全长HC或LC是由分 别的多核苷酸编码。或者，VH和VL二者或其抗原结合部分，或HC和LC是由单一 多核苷酸编码。
与任一这些序列互补的多核苷酸亦包含在本公开内容内。多核苷酸可为单链(编码 或反义)或双链且可为DNA(基因组、cDNA或合成的)或RNA分子。RNA分子包括 HnRNA分子，该HnRNA分子含有内含子并以一对一的方式相应于DNA分子，及不含 有内含子的mRNA分子。另外的编码或非编码序列可以，但不必要存在于本公开内容 的多核苷酸内，且多核苷酸可以，但不必连接其他分子和/或支持材料。
多核苷酸可包含天然序列(即，编码抗体或其部分的内源序列)或可包含这种序列的变体。多核苷酸变体含有一或多个取代、添加、缺失和/或插入，从而使得所编码的 多肽的免疫反应性相对于天然免疫反应性分子未减弱。对编码的多肽的免疫反应性的影 响通常可依本文的描述进行评估。与编码天然抗体或其部分的多核苷酸序列相比，在一 些实施方案中，变体显示出具有至少约70％相同性，在一些实施方案中，至少约80％相 同性，在一些实施方案中，至少约90％相同性，且在一些实施方案中，至少约95％相同 性。这些量并不意图限制，且所列举的百分比之间的增量被具体设想为本公开内容的一 部分。
当如下所述比对最大相应时，若二个序列中的核苷酸或氨基酸序列相同，该二个多 核苷酸或多肽序列被称为“完全相同”。二个序列之间的比较通常通过比较在比较窗口中 的序列来进行，以识别并比较序列局部区域的相似性。本文所使用的“比较窗口”是指具有至少约20个连续位置(通常为30至约75个，或40至约50个)的区段，其中可在将二个 序列最佳比对后，将序列与具有相同数目的连续位置的参考序列进行比较。
用于比较的序列的最佳比对可使用生物信息软件套装(Inc.，Madison，WI)中的程序，利用默认参数进行。该程序体现下列参考 文献中描述的几种比对方案：Dayhoff,M.O.,1978,Amodel of evolutionary change inproteins-Matrices for detecting distant relationships.In Dayhoff,M.O.(ed.)Atlas of Protein Sequence and Structure,National Biomedical ResearchFoundation,Washington DC Vol.5, Suppl.3,pp.345-358；Hein J.,1990,UnifiedApproach to Alignment and Phylogenes pp.626-645Methods in Enzymology vol.183,Academic Press,Inc.,San Diego,CA；Higgins, D.G.and Sharp,P.M.,1989,CABIOS 5:151-153；Myers,E.W.and Muller W.,1988, CABIOS 4:11-17；Robinson,E.D.,1971,Comb.Theor.11:105；Santou,N.,Nes,M.,1987, Mol.Biol.Evol.4:406-425；Sneath,P.H.A.and Sokal,R.R.,1973,Numerical Taxonomy the Principles and Practice ofNumerical Taxonomy,Freeman Press,San Francisco,CA；Wilbur, W.J.and Lipman,D.J.,1983,Proc.Natl.Acad.Sci.USA 80:726-730。
在一些实施方案中，“序列相同性的百分比”是通过在至少20个位置的比较窗口上比 较二个经最佳比对的序列来测定，其中在比较窗口中的多核苷酸或多肽序列的部分相较 于用于二个序列的最佳比对的参考序列(其不包含添加或缺失)而言可包含20％或更少(通常为5％至15％，或10％到12％)的添加或缺失(即，缺口)。百分比的计算是通过测定 位置(出现在二个序列中的完全相同的核酸碱基或氨基酸残基的位置)的数目以产生匹 配位置的数目，将匹配的位置数目除以参考序列中的位置的总数目(即，窗口大小)并 将结果乘以100以得到序列相同性的百分比。
变体亦可能，或者基本上与天然基因或其一部分或补体同源。这种多核苷酸变体能 够在中等严格条件下与编码天然抗体的天然存在的DNA序列(或其互补序列)杂交。
合适的“中等严格条件”包括在5X SSC、0.5％SDS、1.0mM EDTA(pH8.0)的溶液中预先洗涤；在50℃至65℃，5X SSC中杂交过夜；接着在65℃洗涤二次，20分钟，各以 含有0.1％SDS的2X、0.5X和0.2X SSC洗涤。
如本文所使用的“高度严格条件”或“高严格性条件”是指以下：(1)采用低离子强度 和高温进行洗涤，例如在50℃的0.015M氯化钠/0.0015M柠檬酸钠/0.1％十二烷基硫酸钠；(2)在杂交过程中采用变性剂，例如甲酰胺，例如42℃的50％(v/v)甲酰胺加上0.1％ 牛血清白蛋白/0.1％Ficoll/0.1％聚乙烯吡咯啶酮/50mM磷酸钠缓冲剂，pH 6.5加750mM 氯化钠、75mM柠檬酸钠；或(3)采用42℃的50％甲酰胺、5X SSC(0.75M氯化钠、0.075M 柠檬酸钠)、50mM磷酸钠(pH 6.8)、0.1％焦磷酸钠、5X Denhardt氏溶液、经超音波处 理的鲑鱼精子DNA(50μg/mL)、0.1％SDS和10％硫酸葡聚醣，并以42℃0.2X SSC(氯化 钠/柠檬酸钠)及55℃的50％甲酰胺中洗涤，随后以55℃的由含有EDTA的0.1X SSC组 成的进行高严格性洗涤。本领域技术人员将理解如何依需要调整温度、离子强度等以适 应因子例如探针长度等。
本领域的一般技术人士将理解由于遗传密码的简并性，有许多的核苷酸序列编码如 本文所描述的多肽。这些多核苷酸中有些仅与任何天然基因的核苷酸序列具最少的同源 性。尽管如此，本公开内容具体考虑由于密码子使用的差异而有不同变化的多核苷酸。此外，包含本文所提供的多核苷酸序列的基因的等位基因在本发明的范围内。等位基因 为由于一或多个突变，例如缺失、添加和/或取代核苷酸而被改变的内源基因。所产生 的mRNA和蛋白质可能，但不一定具有改变的结构或功能。等位基因可使用标准技术(例 如杂交、扩增和/或数据库序列比较)鉴定。
本公开内容的多核苷酸可使用化学合成、重组方法或PCR取得。化学多核苷酸合成的方法为本领域所熟知，不需要在此详细描述。本领域技术人员可使用本文提供的序 列及市售的DNA合成仪来产生所需的DNA序列。
为了使用重组方法制备多核苷酸，可将包含所需序列的多核苷酸插入合适的载体中， 且该载体可再被引入用于复制和扩增的合适的宿主细胞中，本文中将进一步讨论。多核 苷酸可通过本领域已知的任何方式插入宿主细胞中。细胞可通过直接摄取、内吞作用(endocytosis)、转染、F接合或电穿孔引入外源多核苷酸来转化。一旦引入后，该外源 多核苷酸可以未整合的载体(例如质粒)形式保持在细胞内或被整合入宿主细胞基因组 中。如此扩增的多核苷酸可通过本领域所熟知的方法从宿主细胞中分离。参见，例如 Sambrooket al.,1989。
或者，PCR允许复制DNA序列。PCR技术为本领域所熟知且描述于美国专利案第 4,683,195、4,800,159、4,754,065和4,683,202号及PCR:The Polymerase Chain Reaction,Mullis et al.eds.,Birkauswer Press,Boston,1994中。
RNA可通过下述方法取得：使用在合适的载体中的分离的DNA并将其插入合适的宿主细胞中。当该细胞复制时，该DNA被转录成RNA，RNA随后可使用本领域技术 人员所熟知的方法(例如Sambrook et al.,1989中所示者)分离。
合适的克隆和表达载体可包括各种组分，例如启动子、增强子及其他转录调控序列。 该载体亦可经建构以允许随后将抗体可变结构域克隆入不同的载体中。合适的克隆载体 可根据标准技术构建，或可从本领域中可用的大量克隆载体中选择。虽然所选择的克隆载体可能根据所欲使用的宿主细胞而有变化，有用的克隆载体通常将具有自我复制的能力，可能拥有用于特定的限制性内切酶的单一靶，和/或可能携带用于可用来选择含有 该载体的克隆株的标记物的基因。合适的实例包括质粒和细菌病毒，例如pUC18、pUC19、Bluescript(例如pBS SK+)和其衍生物、mp18、mp19、pBR322、pMB9、ColE1、pCR1、 RP4、噬菌体DNA及穿梭载体，例如pSA3和pAT28。这些和许多其他克隆载体可从商 品供货商，例如BioRad、Strategene和Invitrogen公司取得。进一步提供表达载体。表 达载体通常为可复制的多核苷酸构建体，其含有根据本公开内容的多核苷酸。这暗示表 达载体在宿主细胞中必须以附加体或染色体DNA的整合部分形式复制。合适的表达载 体包括，但不限于质粒、病毒载体(包括腺病毒、腺相关病毒、逆转录病毒)、黏粒及公 开于PCT公开第WO 87/04462号中的表达载体。载体组分通常可包括，但不限于下组 之一或多者：信号序列；复制起点；一或多个标记基因；合适的转录控制元件(例如启 动子、增强子和终止子)。为了表达(即，翻译)，时常亦需要一或多个翻译控制元件，例 如核糖体结合位点、翻译起始位点和终止密码子。
含有感兴趣的多核苷酸的载体和/或该多核苷酸本身可通过任何数目的适当方法(包括电穿孔、利用氯化钙、氯化铷、磷酸钙、DEAE-葡聚醣或其他物质进行转染；基 因枪(microprojectile bombardment)；脂质体转染(lipofection)；及感染(例如其中该载体为感染剂，例如牛痘病毒)引入宿主细胞中。引入载体或多核苷酸的选择通常将取决于 该宿主细胞的特性。
该抗体或其抗原结合片段可利用合适的宿主细胞重组制备。编码该抗体或其抗原结 合片段的核酸可克隆入表达载体中，然后该表达载体可再被引入宿主细胞(例如大肠杆菌(E.coli)细胞、酵母细胞、昆虫细胞、猿猴COS细胞、中国仓鼠卵巢(CHO)细胞或 骨髓瘤细胞(其中该细胞不另外产生免疫球蛋白))中以获得在重组宿主细胞中合成抗体。 本领域所熟知的多种细胞中，优选的宿主细胞包括CHO细胞、人胚胎肾(HEK)293细胞 或Sp2.0细胞。抗体片段可通过蛋白水解或其他降解全长抗体的方法、通过重组方法、 或通过化学合成产生。抗体的多肽片段，尤其是至多约50个氨基酸的较短的多肽可通过 化学合成很方便地制备。用于化学合成蛋白质和肽类的方法为本领域所已知且可从市场 取得。
本发明的抗体或其抗原结合片段可为亲和力成熟的。例如，亲和力成熟抗体可通过 本领域中已知的程序(Marks et al.,1992,Bio/Technology,10:779-783；Barbas etal.,1994, Proc Nat.Acad.Sci,USA91:3809-3813；Schier et al.,1995,Gene,169:147-155；Yelton et al., 1995,J.Immunol.,155:1994-2004；Jackson et al.,1995,J.Immunol.,154(7):3310-9； Hawkins et al.,1992,J.Mol.Biol.,226:889-896；和WO2004/058184)产生。
用途和医学疗法
在一些方面中，本发明提供使用抗IL-33抗体或其抗原结合片段抑制IL-33活性的治 疗方法，其中该治疗方法包含施用治疗有效量的包含抗体或其抗原结合片段的药物组合 物。受治疗的病症是通过除去、抑制或降低IL-33活性或信号传导而被提高、改善、抑 制或预防的任何疾病或病况。
在一些方面中，该病症为炎性疾病或病症、或具有至少一种与该炎性疾病或病症相 关的症状的病况。该炎性疾病或病症或症状的严重性、持续时间或发生频率可被缓解或减少。
本发明的抗体及其抗原结合片段可能在其中发挥效力的黏膜或身体表面的过敏及 其他疾病包括：过敏症、过敏性鼻炎、过敏性结膜炎、春季型角膜结膜炎(vernalkeratoconjunctivitis)、季节性过敏、宠物过敏、哮喘、食物过敏、花生过敏、特应性皮 炎、慢性鼻窦炎(rhinosinusitis)伴鼻息肉(CRSwNP)、过敏性鼻炎、支气管炎、慢性阻塞 性肺病(COPD)、呼吸系统疾病病毒性恶化、儿童和成人病毒感染(呼吸道合胞病毒(RSV))、 鼻病毒、流感)、荨麻疹(urticarias)和嗜酸粒细胞性食管炎。涉及慢性纤维化的疾病亦 可通过本发明的抗体及其抗原结合片段治疗。这些包括：肝纤维化、非酒精性脂肪性肝 炎(NASH)、慢性肾脏病、特发性肺纤维化(IPF)、硬皮病、系统性硬化症。涉及急性组 织损伤的疾病亦可通过本发明的抗体及其抗原结合片段治疗，包括：急性肾损伤、败血 症、胰腺炎、1型糖尿病、移植物抗宿主病(GVHD)、组织移植。可以本发明的抗体及其 抗原结合片段治疗的其他慢性退化性或慢性炎性疾病包括：阿兹海默氏症、类风湿性关 节炎、炎性肠病：肠易激症候群(irritable bowel syndrome)(IBS)、克罗恩氏(Crohn)症、 溃疡性结肠炎。可以本发明的抗体及其抗原结合片段治疗的其他疾病包括多发性硬化症、 牛皮癣、乳糜泻(celiacdisease)和雷诺(Raynaud)氏病。
该抗体及其抗体片段可与一或多种另外的治疗活性化合物组合施用。该另外的治疗 活性化合物包括针对IL-1a、IL-1b、IL-2、IL-3、IL-4、IL-5、IL-6、IL-8、IL-9、IL-10、IL-12、IL-13、IL-17、IL-18、IL-21、IL-23、IL-25、IL-26、IL-31、IL36、IFNα、IFNγ 的拮抗剂或其各自受体的的拮抗剂、NSAID、类固醇和皮质类固醇。
本发明的抗IL-33抗体亦可用于检测和/或测量样品中的IL-33或IL-33表达细胞，例 如用于诊断目的。例如抗IL-33抗体或其片段可用来诊断特征为IL-33异常表达(例如过表达、表达不足、缺乏表达，等)的病况或疾病。用于IL-33的示例性诊断分析可包含 例如将从患者取得的样品与本发明的抗IL-33抗体接触，其中该抗IL-33抗体被可检测的 标记或报告分子标记。
如本文所使用的“药物上可接受的运载体”或“药物上可接受的赋形剂”包括任何当 与活性成分组合时允许该成分保留生物活性且与该对象的免疫系统不反应的材料。实例 包括，但不限于任何标准药学运载体，例如磷酸盐缓冲盐水溶液、水、乳剂(例如油/水乳剂)及各种类型的润湿剂。用于雾化剂或肠胃道外施用的优选稀释剂是磷酸盐缓冲盐 水(PBS)或生理(0.9％)盐水。包含这种运载体的组合物通过为人熟知的常规方法配制 (参见，例如Remington's Pharmaceutical Sciences,18th edition,A.Gennaro,ed.,MackPublishing Co.,Easton,PA,1990；及Remington,The Science and Practice ofPharmacy,20th Ed.,Mack Publishing,2000)。
组合物
本发明的抗体或其抗原结合片段可配制成药物组合物。在冻干制剂或水溶液的形式 中，该药物组合物可进一步包含药物上可接受的运载体、赋形剂和/或稳定剂(Remington: The Science and practice of Pharmacy 20th Ed.,2000,LippincottWilliams and Wilkins,Ed. K.E.Hoover)。可接受的运载体、赋形剂或稳定剂在施用接受者的剂量和浓度下是无毒 的，且可包含缓冲剂，例如磷酸盐、柠檬酸盐和其他有机酸；抗氧化剂，包括抗坏血酸 和甲硫氨酸；防腐剂(例如十八烷基二甲苄基氯化铵；氯化六甲双铵；苯扎氯铵、苄索 氯铵；苯酚、丁醇或苄醇；对羟基苯甲酸烷基酯，例如对羟基苯甲酸甲酯或对羟基苯甲 酸丙酯；儿茶酚；间苯二酚；环己醇；3-戊醇；及间甲酚)；低分子量(少于约10个残基) 多肽；蛋白质，例如血清白蛋白、明胶或免疫球蛋白；亲水性聚合物，例如聚乙烯吡咯啶酮；氨基酸，例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸；单糖、 双糖及其他碳水化合物，包括葡萄糖、甘露糖或葡聚糖；螯合剂，例如EDTA；糖类， 例如蔗糖、甘露醇、海藻糖或山梨糖醇；形成盐的抗衡离子，例如钠；金属复合体(例 如Zn-蛋白复合体)；和/或非离子性表面活性剂，例如TWEENTM、PLURONICSTM或 聚乙二醇(PEG)。本文中进一步描述药物上可接受的赋形剂。
剂量
如本文所使用的药物、化合物或药物组合物的“有效剂量”、“有效量”或“治疗有效量”是足以使任何一或多种有益或期望的结果起作用的量。对于预防性用途，有益或期 望的结果包括排除或降低疾病的风险、减轻疾病的严重性或延迟疾病发作，包括疾病的 生物化学、组织学和/或行为症状、其并发症及在该疾病发展过程中呈现的中间病理表 型。对于治疗用途，有益或期望的结果包括临床结果，例如减少炎症或由活性IL-33高 度表达所导致之一或多种症状、减少治疗该疾病所需的其他药物的剂量、增强另一种药 物的效果和/或推迟患者疾病的进展。有效剂量可在一或多次施用中施用。为了本发明 的目的，药物、化合物或药物组合物的有效剂量为足以直接或间接完成预防或治疗性治 疗的量。如在临床背景下所理解的，药物、化合物或药物组合物的有效剂量可与或可不 与另一药物、化合物或药物组合物联合来达成。因此，在施用一或多种治疗剂的背景下， 可考虑“有效剂量”，而单一试剂若与一或多种其他试剂联合时，则可考虑以有效量给予 以可能实现或实现理想的结果。
“个体”或“对象”为哺乳动物，更优选为人。哺乳动物亦包括，但不限于农场动物、运动动物、宠物、灵长类动物、马、狗、猫、小鼠和大鼠。
在一些实施方案中，该方法或用途包含施用初始剂量为约0.025mg/kg至约20mg/kg 的本发明的抗体、或其抗原结合片段、或药物组合物。初始剂量之后可为一或多个后续剂量。在一些实施方案中，可以至少任一下列频率施用一或多个后续剂量：每周、每隔 一周、每三周、每四周、每五周、每六周、每七周、每八周、每九周、每十周、每十一 周或每十二周。
在一些实施方案中，该方法或用途包含施用初始剂量为约0.25mg至约2000mg的本发明的抗体或其抗原结合片段。在一些实施方案中，该抗体或其抗原结合片段是每周、 每隔一周、每三周、每四周、每五周、每六周、每七周、每八周、每九周、每十周、每 十一周或每十二周施用。
试剂盒
本发明亦提供包含本发明的抗体或其抗原结合片段及使用用法说明的试剂盒或制 品。因此，在一些实施方案中，提供试剂盒或制品，该试剂盒或制品包含容器、该容器 内的包含抗IL-33拮抗剂抗体的组合物及药品说明书(package insert)，该药品说明书含有施用治疗有效量的抗-IL-33拮抗剂抗体以治疗有需要治疗的患者的用法说明。
在某些实施方案中，该试剂盒可含有具有干燥蛋白质的第一容器及具有水性制剂的 第二容器。在某些实施方案中，包括含有单室和多室的经预填充的注射器(例如液体注射器和冻干剂注射器(lyosyringe))的试剂盒。
关于本发明的抗体或其抗原结合片段的用途的用法说明通常包括关于用于所欲治 疗的剂量、给药方案和施用途径的信息。该容器可为单位剂量、散装(例如多剂量包装)或亚单位剂量。本发明的试剂盒中所提供的用法说明通常书写在标签或药品说明书(例 如包含在该试剂盒中的纸张)上的用法说明，但机器可阅读的用法说明(例如磁盘或光 盘上所记载的用法说明)亦可接受。
本发明的试剂盒是在合适的包装中。合适的包装包括，但不限于小瓶、瓶子、罐子、软性包装(例如密封的聚酯薄膜(Mylar)或塑料袋)，等。用于与特定装置，例如吸入器、 鼻部施用装置(例如雾化器)或输注装置例如微型泵组合使用的包装，亦在考虑之内。 试剂盒可具有无菌进入口(例如该容器可能为静脉内溶液袋或具有可被皮下注射针刺穿 的塞子的小瓶)。该容器亦可具有无菌进入口(例如该容器可为静脉内溶液袋或具有可被 皮下注射针刺穿的塞子的小瓶)。该容器可进一步包含第二药学活性剂。
试剂盒任选地提供额外组分，例如缓冲剂和解释信息。通常，该试剂盒包含容器和在该容器上或与该容器联结的标签或药品说明书。
定义
当与可测量的数字变量一起使用时，“约”或“近似”是指该变量的指示值及该变量的 所有在该指示值的实验误差内(例如在平均值的95％置信区间内)或在该指示值的10％以内(以较大者为准)的数值。数字范围包括界定该范围的数字。
如本文所使用的“载体”意指能够递送且优选地，在宿主细胞中表达感兴趣的之一或 多个基因或序列的构建体。载体的实例包括，但不限于病毒载体、裸DNA或RNA表 达载体、质粒、黏粒或噬菌体载体、与阳离子缩合剂联结的DNA或RNA表达载体、 包封在脂质体中的DNA或RNA表达载体及某些真核细胞，如生产细胞。
如本领域所已知的术语“相同性”是指通过比较序列所测定的二或更多个多肽分子 或二或更多个核酸分子的序列之间的关系。本领域中，“相同性”亦意指通过将核苷酸或氨基酸序列的字符串间进行匹配所测定的多肽或核酸分子序列(视情况而定)之间的序 列相关程度。“相同性”测量二或更多个具有缺口对齐的序列之间的完全相同匹配百分比， 缺口对齐是通过计算机程序的特定数学模型(即“算法”)处理。
术语“相似性”为相关概念，但相对于“相同性”，其是指相似性的测量，该相似性的测量包括完全相同匹配和保守性取代匹配。由于保守性取代适用于多肽，且不适用于核 酸分子，故相似性仅涉及多肽序列比较。若二个多肽序列具有，例如10/20个完全相同 的氨基酸，且其余部分均为非保守性取代，则该相同性和相似性百分比均为50％。若在 该相同实例中，多出5个位置为保守性取代，则该相同性百分比仍为50％，但相似性百 分比将为75％(15/20)。因此，在其中存在保守性取代的情况中，二个多肽序列之间的相 似程度将高于该二个序列之间的相同性百分比。
实施例
本文描述示例性方法和材料，但亦可使用相似或等价于本文所描述的方法和材料者 来实践或测试本发明。该材料、方法及实施例仅用于说明而不意图用来限制。
实施例1分离与人IL-33结合的大鼠单克隆抗体
通过多次皮下注射，以在明矾佐剂中的重组人IL-33(SEQ ID NO：1)，氨基酸S112-T270(R&D Systems，Minneapolis，MN；目录编号3625-IL/CF)将Sprague-Dawley 大鼠免疫化。亦筛选显示出对固定在经链亲和素涂层的ELISA盘上的生物素化的人 IL-33具结合活性的血清，以用于阻断10ng/ml生物素化的人IL-33与人ST2-Fc(SEQ ID NO：2)结合，该人ST2-Fc(SEQ ID NO：2)已被固定在ELISA盘上的抗人Fc捕获。 为了进行分析，通过用二硫苏糖醇(DTT)将野生型IL-33还原或使用人IL-33变体mm2 (SEQ ID NO：3)(其中所有四个半胱氨酸残基经突变成丝氨酸)来维持细胞因子活性。 从具有最高效价的大鼠中，将富集在经IL-33涂层的小珠上的杂交瘤和培养的B细胞进 行筛选以选出与人IL-33结合、阻断人IL-33/ST2-Fc结合、及中和人IL-33对稳定表达 ST2的HEK-293细胞和受NFκB反应性启动子控制的表达分泌型碱性磷酸酶的质粒的活 性的抗体。鉴定出227种IL-33结合抗体，其中6种抗体(30A1、30B11、7E8、9B3、12F9 和14D8)亦中和IL33-ST2结合及报告细胞活性，且选出这种抗体以用于分子克隆和随 后的分析。
实施例2克隆大鼠抗IL-33抗体重链和轻链可变区
使用cDNA合成系统(Clontech Laboratories Inc.of Mountain View，加州) 克隆中和抗IL-33抗体的重链和轻链可变区，然后进行PCR扩增。使用RNEasy试剂盒(Qiagen)和ⅡA oligo(Clontech Laboratories Inc.)与SuperscriptⅡTM逆转录酶 (Clontech Laboratories Inc.)从1μg总RNA合成cDNA，该1μg总RNA是从约500,000个克隆的B细胞(14D8、12F9)或7E8、9B3、30A1、30B11杂交瘤细胞分离出。然后使用 与SMARTⅡA oligo序列退火的引物及大鼠恒定区特异性引物(用于轻链的大鼠κ和用于 重链的大鼠IgG1)与GoTaq Green聚合酶主混合物(Promega)，通过PCR扩增cDNA。 将重链和轻链PCR产物亚克隆入pCR4-TOPO载体(Invitrogen)中并测定该核酸序列。 该方法的优点在于不需要预先知道DNA序列。此外，所得的DNA序列未由使用简并 PCR引物而被改变。
然后，将可变重链区克隆入含有经过突变以消除效应子功能的人IgG1恒定区(SEQID NO：9)的pSMED2哺乳动物表达载体(Leu234Ala、Leu235Ala和Gly237Ala，EU编 号；美国专利案第5,624,821号))中，产生嵌合重链。将可变轻链区克隆入含有人κ恒定 区(SEQ IDNO：30)的pSMEN3哺乳动物表达载体中以产生嵌合轻链。在抗体9B3、14D8、 30A1和30B11的情况中，亦使用最接近的人κ链J区段(SEQ ID NO：12、82)来替代大 鼠κ链J区段，以提高该嵌合抗体的表达。
实施例3通过抗人IL-33抗体中和IL-33
在实施例1中描述的基于HEK293 ST2 NFκB细胞的报告子分析中，该六个嵌合抗体显示出与人IL-33结合并中和其活性，如表4中所示。
表4.亲本大鼠抗IL-33抗体和大鼠/人嵌合体对HEK293 ST2 NFκB报告子细胞分析中IL-33(mm2)活 性的抑制
亦使用HEK293 ST2 NFκB分析，以食蟹猴IL-33的变体(其中该变体的三个半胱氨酸残基经突变成丝氨酸(SEQ ID NO：5))测试该嵌合抗体以测定其中和食蟹猴IL33的能力。7E8、30A1和30B11能分别在IC50为0.21、2.95和0.20nM时中和食蟹猴IL-33，而12F8 和14B8则不，且9B3仅显示出微弱的中和作用(表5)。
表5.抗IL-33抗体对对HEK293 ST2 NFκB报告子细胞分析中食蟹猴IL-33活性的抑制。IL33针对 0.1ng/ml食蟹猴IL33滴定抗体
实施例4抗IL-33抗体的表位分组
根据使用Octet生物传感器的竞争分析将六个中和抗体分组到表位小组中。在经链 亲和素涂层的Octet尖端装填10μg/ml生物素-hIL-33(mm2)150秒，转移至阻断封闭缓冲剂(1％BSA，在PBS中)中50秒，然后转移到含有该六个抗体其中一者的孔内290秒以 允许第一抗体与IL-33结合。然后将尖端转移到含有第二抗体的第二孔中290秒。若该第 二抗体显示出生物传感器信号增加高于前述由第一抗体所产生者，则抗体被评分为非竞 争性，而若该第二抗体未产生额外增加的信号，则该抗体被评分为竞争性(表6)。基于 这些竞争数据，抗体7E8、9B3、30A1和30B11定义为一个表位组，而12F9和14D8定义 为第二个非重迭表位组。
表6.通过Octet生物传感器表位分组抗IL-33抗体
实施例5人源化大鼠抗IL-33抗体
通过互补决定区(CDR)移植(以下称为“CDR移植”)产生中和大鼠抗体7E8、9B3、12F9和30B11的人源化形式。将重链CDR移植到具有JH4区段(SEQ ID NO：8)的人 DP-54框架区(VH3子群；SEQ ID NO：7)上，而将轻链CDR移植到具有JK4区段(SEQ ID NO：12)的人DPK9框架区(VKI子群；SEQ ID NO：11)上。将人源化VH区接合 到效应子功能突变的人IgG1恒定区(SEQ ID NO：9)，然后亚克隆入专有表达载体中以 产生CDR移植的重链SEQ ID NO：92(7E8 CDR移植物)、99(9B3 CDR移植物)、104(12F9 CDR移植物)和109(30B11 CDR移植物)。CDR移植的30B11的第二种形式在重链的位 置71处掺入大鼠残基(缬氨酸)，而非种系精氨酸残基，所产生的重链称为SEQ ID NO： 112。将人源化VL区与人κ恒定区(SEQ ID NO：13)融合，然后亚克隆入专有表达载 体以产生CDR移植的轻链SEQ ID NO：93(7E8 CDR移植物)、SEQ ID NO：100(9B3 CDR 移植物)、SEQ ID NO：105(12F8 CDR移植物)和SEQ ID NO：110(30B11 CDR移植物)。 7E8亦被移植在其他VH3种系框架(DP47，登录编号CAA78217.1；DP31，登录编号 CAA78203.1；DP50，登录编号CAA78220.1)并与CDR移植的7E8(SEQ ID NO：92、93)具有相似的基于细胞的活性和非特异性结合。
实施例6通过人源化IL-33抗体中和重组和天然人IL-33及重组食蟹猴IL-33
CDR移植的7E8、9B3、12F9和30B11在实施例1所描述的HEK293 ST2 NFκB报告 子分析中显示出中和人IL-33的活性。尤其是，CDR移植的7E8显示出IC50为0.019nM， 与7E8杂交瘤7E8(表7)所表达的0.024nM IC50几乎一致。CDR移植的12F9显示出在高浓 度下仅部分抑制(表7)，而非完全抑制，嵌合型12F9(表4)所观察到的IC50为2.71nM。 CDR移植的9B3和30B11的IC50值分别为0.520和0.368nM(表7)，相对于这些抗体的嵌合 形式，活性约降低10倍(表4)。含有重链框架回复突变R71V的CDR移植的30B11的第 二形式显示出与该嵌合体相较下效力的降低情况相似(0.278nM vs 0.028nM IC50)(表7、 表4)。
表7:通过CDR移植的IL-33抗体在HEK293 ST2 NFκB报告子细胞分析中中和人IL-33(mm2) 活性
CDR移植的7E8和7E8杂交瘤在以食蟹猴IL-33进行的ST2 NFκB报告子分析中进一步显示出具有相似的中和效力(分别为0.069nM和0.032nM；表8)，相似于它们在以人 IL-33(mm2)进行的ST2 NFκB报告子分析中的活性(CDR移植的7E8和7E8杂交瘤二者 均为0.043nMIC50；表8)。CDR移植的7E8和可溶性人IL-33受体ST2-Fc显示出对人 IL-33(mm2)具有相似的中和效力(分别为0.043nM和0.056nM)，并对保留野生型半胱 氨酸残基的人IL-33具有相似的中和效力(分别为3.21nM和1.89nM；表8)。
表8:通过杂交瘤衍生的抗体和CDR移植的7E8在HEK293 ST2 NFκB报告子细胞分析中抑制 IL-33中和.
表8:通过大鼠亲本杂交瘤衍生的抗体和人源化CDR-移植的7E8在HEK293 ST2 NFκB分析中抑制IL-33的中和。 针对0.1ng/ml IL-33(mm2)、0.1ng/ml食蟹猴IL-33和2ng/ml人IL-33(R&D)测试稀释系列的抗体。测定进行三次重 复，剂量范围为0.0018-30nM IL-33(R&D)。ND，未测定。
实施例7通过IL-33抗体中和来自人细胞提取物的天然IL-33的活性
CDR移植的7E8进一步显示中和由培养的人肺纤维母细胞产生的天然人IL-33的活性。将人肺纤维母细胞系HFL-1(ATCC)的早期传代生长在DMEM+10％经热去活化的 胎牛血清(FBS)+L-谷胺酰胺/青霉素/链霉素+1/100HEPES中。当细胞达到95至100％汇 合时，移除培养基并以不含血清的相同培养基替换，再孵育24小时。然后移除培养基， 以20ng/mlTNF-α替换，再另外孵育14小时。通过胰蛋白酶处理来收获细胞，将细胞离 心沉淀成小丸(pelleted)并在无血清的培养基中冷冻。通过在-20℃下进行5次冻融循环来 制备裂解物，使其达到10mM DTT并将样品离心再稀释以评估IL-33活性。HFL-1细胞 裂解物显示出在HEK293 ST2 NFκB报告子分析中活化NFκB报告基因且该活性可部分 被可溶性人ST2-Fc(SEQ ID NO：2)和多克隆抗IL-33中和抗体阻断。大鼠抗体7E8、9B3、 30A11和30B11和嵌合体完全阻断活性，且嵌合型14D8完全阻断活性，表示这些抗体可 识别并中和在人原代细胞中产生的内源性IL-33。
表9.通过抗IL-33抗体抑制来自人肺纤维母细胞裂解物的天然人IL-33
表9.将64倍稀释的人肺纤维母细胞(HFL-1)裂解物与0.1、1或10nM抗体一起在HEK293 ST2 NFκB分析中孵育。 单独的裂解物仅在培养基中产生3.9倍的信号增加。抑制百分比计算为100×(1-(测试样品-仅培养基)/(单独裂解 物-仅培养基))。
实施例8抗IL-33抗体以高效力中和IL-33
为了在不受配体浓度影响的分析中测量抗体与IL-33的结合亲和力，以HEK293ST2 NFκB报告子分析系统设计实验，其中可进行Schild分析以计算分析独立性和配体浓度独立性的7E8对IL-33的亲和力测量(Arunlakshana and Schild，1959)。在NFκB ST2报告子分析中，在多个7E8 CDR移植物(SEQ ID NOS：92、93)的浓度测定IL-33的EC50， 并计算出IL-33(mm2)的κB为6.01pM，野生型IL-33(R&D)的kB为83.45pM(表10)。
当共刺激物为IL-12时，IL-33亦为从血液中的天然杀手细胞产生IFNγ的有效共刺 激剂。通过Ficoll从新鲜的肝素化人血中纯化人外周血单核细胞(PBMC)，再以IL-12处理2小时，然后以5pM的IL-33和抗IL-33抗体的剂量滴定混合物处理。加入IL-33后20 小时收集培养上清液，并通过MSD盘式分析仪(Meso Scale Diagnostics，Rockville，MD) 测量IFNγ的水平。在人PBMC中，相似于在HEK293 ST2 NFκB报告子分析中的观察， 7E8抑制二个供体中的IL-33(mm2)所得的kB计算为1.04pM和6.64pM。因此，7E8 CDR 移植物对IL-33(mm2)的表观亲和力非常高，而在野生型IL-33方面是在个位数皮摩尔 范围内且低于100pM。
表10.7E8 CDR移植物在HEK293 ST2 NFκB报告子细胞和人PBMC中抑制IL-33活性的Schild分析
表10:0.028pM-55.5nM(n＝3次重复)。ND，未测定。以特定浓度的7E8-CDR移植物在HEK293 ST2 NFkB报告 子细胞或人PBMC上对IL-33(mm2)或野生型IL-33(R&D Systems)的中和的Schild分析。以log([A']/[A])-1)对 -log[B]作图，其中A'是抗体存在的IL-33的EC50，A是抗体不存在的IL-33的EC50，B是抗体浓度，产生的X截距 等于kB，是抗体与IL-33结合的平衡常数的近似值。
实施例9 IL-33抗体对人和食蟹猴IL-33的结合亲和力
使用BIAcore T200仪器通过表面等离子共振测量与人和食蟹猴IL-33的结合。将抗 人Fc抗体固定在CM5芯片上并捕获抗IL-33抗体。将人IL-33(mm2)或食蟹猴IL-33在3.9-125nM的浓度范围内以50μl/min流过芯片45秒并允许解离240-1500秒。如下列表11 中所示，测定亲和力值。所有抗体与人IL-33结合，亲和力范围是在171至540pM。经捕 获的嵌合型12F9和嵌合型14D8不与溶液中的125nM食蟹猴IL-33结合，而CDR移植的 7E8、嵌合型9B3、嵌合型30A1和嵌合型30B11与溶液相的人和食蟹猴IL-33结合。
表11.通过以IgG捕获形式的表面等离子共振测量抗IL-33 IgG与人和食蟹猴IL-33结合的亲和 力
实施例10使用表面等离子共振和KinExATM方法的7E8动力学评估
由于以捕获的IgG测量的抗体的表观亲和力较其在溶液相中的IL-33中和效力明显 更低(实施例11)，进行二种替换方式来测定亲和力。为了除去IgG分子的2个结合臂的二价存在的影响，通过木瓜蛋白酶切割CDR移植的7E8(SEQ ID NO：92、93)来制备 单价抗IL-33抗体Fab片段。通过二种方法测量Fab片段亲和力，使用BIAcore仪器， 通过捕获在芯片上的Fab或IL-33进行表面等离子共振，并使用KinExA仪器与溶液中 Fab和IL-33测量溶液平衡亲和力。
表面等离子共振实验是以二种形式进行。当通过抗人Fab捕获试剂盒(GEHealthcare 公司目录编号28958325)捕获7E8 Fab时，所测得的对IL-33(mm2)的亲和力为249.5pM， 而对IL-33(R&D)的亲和力为290pM(表12)，相似于以相似形式捕获的IgG所取得的结 果(表11)。然而，当生物素化的hIL-33(mm2)被捕获在经链亲和素涂层的BIAcore生物传感器上并将7E8 Fab滴定系列注射在传感器表面上，所测得的7E8 Fab对IL-33(mm2) 的亲和力为3.06pM(表12)。不欲受任何特定理论的束缚，这二种形式的结果之间的差异 可能来自基质效果，例如在pH 7.4，预期溶液中的带正电荷的Fab(pI 8.52)对带负电荷 的CM5传感器芯片具吸引力，同样地，溶液中带负电荷的IL-33(IL-33mm2为pI 5.2，IL-33 WT为pI4.45，生物素化的IL-33mm2为pI 5.48)对带负电荷的CM5传感器芯片具排斥 力(Drake etal.2012,Anal.Biochem.429(1):58-69)。测量亲和力的正交方法描述于下列实 施例10中。
为了评估7E8与野生型IL33的结合，根据制造商的方案使用胺偶联试剂盒(目录编号BR100050，GE Healthcare)将具有野生型半胱氨酸残基的重组IL33蛋白(SEQ ID NO： 4)与CM5传感器芯片(目录编号BR100530，GE Healthcare)共价偶联。以非还原的IL-33 和在固定之前已经在室温以3mM DTT还原3小时的IL-33样品进行平行研究。相似水平 的IL-33被固定(对于非还原和还原IL-33，分别为293和370个共振单位)。活化并封闭流 动池1以用作参考流动池。使用10mM HEPES pH 7.4、0.15M NaCl、3mM EDTA、 0.05％P-20(HBS-EP+)作为运行和样品缓冲剂，流速为每分钟50μl，将大鼠亲本Fab 7E8 进行系列滴定。监控解离3600秒。在37℃，在Biacore T200仪器(GE Healthcare)上，以 1Hz的收集速率进行Biacore动力学分析。经由将所得的传感图数据拟合至Biacore T200 评估软件版本1.0(GEHealthcare)的1：1模型来测定速率常数和亲和力。大鼠7E8 Fab对 已用DTT预处理的野生型人IL-33的亲和力经测量为44.23pM(表12)，而7E8 Fab并未 与非还原的IL-33结合(图1)。此观察表明7E8选择性地与活性IL-33结合，而不与已通过 氧化被去活化的IL-33结合，并表明在治疗设置中存有经去活化的IL-33将不会干扰从 7E8衍生的抗体与活性IL-33结合的能力。
表12.通过在Fab捕获形式中和固定的IL-33的表面等离子共振测量7E8 Fab与人IL-33结合的 亲和力
表12.通过表面等离振子共振测量7E8 Fab与人IL33的结合亲和力。溶液相Fab在0.78-12.5nM测 试，溶液相IL-33在0.78-25nM测试。
为了处理在不同试剂取向中通过等离振子共振测量的亲和力中与形式依赖性差异， 使用正交方法来评估7E8 Fab对IL-33的亲和力，二种结合伙伴均在溶液中。使用动力学排除分析(KinExA)仪器(型号3200，Sapidyne)来测定7E8 Fab对huIL-33(mm2)(SEQ IDNO：3)和huIL33wt(SEQ ID NO：4)的结合亲和力。在使用前将HuIL33wt在3mM DTT中还原至少2小时。在室温使用固定的抗原分析形式进行亲和力测定。通过在25℃ 孵育72小时来达到平衡结合。使用KinExAPro软件版本3.6.5(Sapidyne)进行数据分析。 使用“亲和力标准”模型来分析数据并测定huIL33mm2和还原的huIL33wt的表观KD及 表观活性浓度。适当时，使用“漂移校正”。在独立实验中取得多条曲线(包括受体和控 制的KD二者)并使用“n曲线分析”工具分析以取得KD和活性浓度的全局最佳拟合值。 该软件报告具95％置信区间的各个最佳拟合值。KinExA分析显示出7E8 Fab以非常高的 亲和力与人IL-33结合，hIL-33的mm2形式测得的KD为0.35pM，还原WT形式测得的 KD为4.04pM(表13)。这些结果与通过Schild分析所分析的基于细胞的分析的结果一致 (实施例8)，其显示出在溶液平衡条件下，7E8CDR移植物在溶液中以低皮摩尔亲和力 与IL-33结合。
表13.通过KinExA测量7E8与IL-33(mm2)和人IL-33(WT)的亲和力
表13.使用固定抗原分析形式进行亲和力测定。将7E8 Fab从15fM至0.25nM滴定到固定浓度为4pM和 100pM huIL-33(mm2)中，并将其从244fM至2nM滴定到固定浓度为100pM和500pM hu IL-33(WT)中。 通过KinExA软件基于理论结合方程与测量信号的最小二乘拟合来计算具有kD的括号中所示的95％置信 区间和百分误差。
实施例11通过扩增的二元取代抗原互补位测定抗IL-33抗体的抗体
使用三种方法来鉴定对抗体7E8的功能至关重要的氨基酸。首先，进行系统性检查大鼠mAb-CDR序列和人种系CDR序列之间的不同CDR残基以测定哪些位置需要原始 大鼠序列及哪些位置容许改变。此方法处理重链CDR-H1和CDR-H2及轻链CDR-L1、 CDR-L2和CDR-L3中的序列。第二种方法(实施例12)处理CDR-H3中序列变异(未在种 系中编码)的容许度。通过下一代测序(NGS)测定存在于经免疫化的大鼠的脾脏B细 胞(亲本7E8衍生于此)中的序列变异并测定在CDR-H3的各个位置处的变异频率。测试 变体CDR序列的子集的功能以彻底所观察的序列变化的影响。检查功能性CDR残基的 第三种方法为在抗体工程化过程中检查特定的工程化的氨基酸变体(参见实施例14至 16)。
用于测定关键CDR残基的方法已有描述，通过该方法从含有人种系残基或在各CDR位置(除了CDR-H3外)处的相应的啮齿动物残基的文库中选择功能性抗体变体(Townsend et al.,2015)。构建噬菌体scFv文库，其中将7E8的所有与人种系(DP54/DPK9)不同的CDR位置随机处理，从而使得约50％的克隆株编码大鼠7E8氨基酸，而约50％的 克隆株编码该位置的人种系氨基酸(表14)。制备文库并对人IL-33(mm2)进行3至4轮选 择。回收保留与IL-33结合的克隆株并测定其序列。从该实验，其中可观察到人序列的 结合克隆株少于约20％的位置被定义为大鼠必须残基。大鼠残基被优选保留在11个位置 (重链残基Y35、S50、T52和P53；轻链残基H32、D34、F50、N53、Y91、G94和W95)， 表示这些残基被人种系残基替代是极不利的。轻链中的F50被A取代的情况并未观察到， 这表明F为该位置的强烈优选的氨基酸。大鼠和人残基被发现在重链残基54(N/D)、56、 (G/S)、57(N/E)、58(T/K)和61(P/V)和轻链残基24(K/R)、28(N/S)、30(N/S)、31(K/S)、 52(N/S)、56(T/S)、89(F/Q)、92(N/Y)和93(N/S)的频率相似，表示这些位置的大鼠序 列不具关键性。轻链中的位置51编码大鼠7E8克隆株中的苏氨酸残基，但在人类DPK9 种系序列中则偏好编码的丙氨酸，86％的结合克隆株中有掺入此氨基酸(表14)。虽然文 库中位置51处丙氨酸密码子的起始频率为68％，高于大多数，但相似于数种其他残基， 在所选择的克隆株中其他具有相似的起始偏好的位置(例如在起始文库中位置L24的精 氨酸密码子的频率为65％，而位置L30的丝氨酸密码子的频率为63％)具有几乎相等的 氨基酸分布。此观察表明丙氨酸在位置51的强烈偏好。
表14.通过扩增二元取代测试的7E8 CDR位置中人氨基酸的掺入频率
表14.基于SEQ ID NO：94和SEQ ID NO：91分别将位点编号为重链(H)或轻链(L)可变区。
实施例12在以人IL33免疫化的大鼠中抗IL33抗体CDR-H3序列可容许的变化。
抗体相关于实施例1中所描述的IL-33中和抗体所能容许的CDR H3序列变异是通过 将与该抗体来源相同的动物的免疫组库测序来进行检查。从经免疫化的大鼠的脾组织分 离出RNA，依实施例2中的描述通过逆转录-RACE PCR制备并在Roche FLX+仪器上进 行下一代定序。从62,484个序列reads鉴定出具有与实施例1中的那些中和抗体相关的 CDR3序列的VH基因的组。计算在该独特CDR3序列的组内各位置处的氨基酸与中和 抗体序列分岐的频率，不调整该群体中各CDR3序列的频率(表15)。来自7E8和9B3的 CDR3中被强烈保守的序列(未加权样品中的变化<15％)为G99、H100、Y101、Y103、 S105、Y106和S107。在大鼠组库中所鉴定出的72个序列变体中并未观察到Y106中的变 化，且来自Y103、S105和S107的变化仅在少于3％的序列中观察到。
表15:在经免疫的大鼠免疫组库中存在的变体中发现来自7E8和9B3 CDR-H3的氨基酸差异频率
表15.数字表示在获得这些抗体的免疫大鼠的组库中鉴定的独特7E8-和9B3-相关CDR H3序列组内的 CDR H3的每个位置处观察到的氨基酸变化的频率。在该计算中未考虑在组库中观察到给定CDR H3序 列的频率。
将表16中所显示的与9B3和7E8相关的CDRH3序列子集克隆入嵌合型9B3重链的框架中，产生的重链由SEQ ID NO：116、120、123、125、128、131、134、137、140、 143、146、149、151、154、157和160指代。将这些重链与嵌合型9B3轻链(SEQ ID NO： 117)共转染，表达所产生的抗体，纯化并通过BIAcore分析来分析IL-33解离速率及在 HEK293 ST2 NFκB报告分析中抑制IL-33信号传导。在与125nM IL-33(mm2)结合后， 依实施例9中的描述使用被固定的抗人Fc抗体捕获的完整IgG测量解离速率。二种分析 均显示出与亲本9B3的相比较，存在于大鼠组库中的大多数CDRH3序列变体的解离速 率或中和效力的变化很少或没有变化，表示所观察到的序列变化是被充分容许的变化。 所有测试的18种抗体的解离速率均在9B3的解离速率的2.5倍以内。在18种抗体中有4种 可观察到基于细胞的效力降低高达4倍。效力的较大变化不能归因于特定的单一变化， 因为这四种抗体全部含有在其他变体中所观察到的具有最小功能影响的突变。在这些抗 体中的另外取代的背景下，以化学上相似的侧链取代二个高度保守的氨基酸(抗体 9B3-22中的芳香族侧链取代Y101F及抗体9B3-7中的带正电荷的侧链取代H100R)不会 导致抗体功能显著变化。综合而论，在免疫化组库中观察到的氨基酸序列变化表明在抗 体9B3及与其密切相关的7E8的CDR H3中，残基G99、H100、Y101、Y103、S105、Y106 和S107或具有化学上相似的侧链的残基是有利的。
表16.从经免疫的大鼠组库中鉴定的含有CDR-H3的9B3嵌合体变体的IL-33中和活性和解离速率。
表16.从经免疫的大鼠组库中鉴定的含有CDR-H3的9B3嵌合体变体的IL-33中和活性和解离速率。频率是指在来 自经免疫的大鼠组库的下一代测序运行中获得CDR3序列的次数。与9B3分歧的序列以粗体下划线文字显示。框 架3的C端末端的序列以小写文本显示。
实施例13评估抗IL-33抗体的非特异性结合
抗体与除了其靶外的分子的非特异性结合已被提出为体内快速清除的机制( et al.,2010,MAbs 4(6):753-760)。这种多重反应性非靶结合的证据可透过测量与膜制剂 (Xu et al.,2013,Protein Eng.Des.Select.26(10):663-70；)、杆状病毒颗粒(et al.,2012, mAbs 4:753-60)或带负电荷的物质，例如DNA、胰岛素和肝素(Tilleret al.,2008,J. Immunol.Methods 329(1-2):112-124)的结合来取得。
用于DNA和胰岛素的ELISA是使用低严格性方案，该低严格性方案最初是研发用于检测来自狼疮患者的低亲和力自身抗体(Tiller et al.,2008)。将在PBS中的5μg/ml胰岛 素或10μg/ml单链或双链DNA涂层在Nunc Maxisorp ELISA盘上过夜。以水洗涤孔3次，然后在室温下以ELISA缓冲剂(PBS/0.05％Tween/1mM EDTA)封闭1小时。将在ELISA 缓冲剂中的3-10μg/ml抗体在孔中在室温孵育1小时，并以水洗涤孔3次，在室温下与在 ELISA缓冲剂中与HRP缀合的山羊抗人IgG1 1:5000一起孵育1小时。以水洗涤3次后， 以TMB显色5分钟，再以0.1M硫酸终止反应。用于结合杆状病毒(BV)颗粒的ELISA 是根据Hotzel，2012中所描述的方法。在每个孔中加入在50mM碳酸钠缓冲剂(pH9.6)中 的4％BV悬浮液以将抗原固定在Nunc Maxisorp ELISA盘中，并允许颗粒在4℃吸附在 盘上过夜。以封闭缓冲剂(PBS/0.5％BSA)在室温下将孔封闭1小时。以PBS洗涤3次后， 将在封闭缓冲剂中的10μg/ml抗体加入ELISA孔中并在室温下孵育1小时。以PBS洗涤 盘6次并与20ng/ml HRP-山羊抗人抗体(Jackson ImmunoResearch Cat No.109-035-008) 在室温下孵育1小时。将盘在PBS中洗涤6次，在每个孔中加入25μl的TMB物质并允 许显色15分钟，然后通过在每个孔中加入1M磷酸终止。在任何步骤中缓冲剂中均未添 加洗涤剂。将10μg/ml Ab的A450信号相对来自空白孔的信号标准化以用于比较样品。
嵌合型和CDR移植的7E8被发现在低严格性多重反应性ELISA中与DNA和胰岛 素适度结合，而嵌合型9B3显示出DNA和胰岛素结合接近阴性对照抗体，尽管序列相 似于7E8(表17)。7E8的CDR-H2被其9B3负体替代可造成多重反应性部分降低，而替换 CDR H1或CDR H3的影响最小。
9B3的人IL-33(mm2)阻断活性低于7E8的(在HEK293 ST2 NFκB分析中9B3的人 IL-33(mm2)阻断活性为0.264nM，而7E8的人IL-33(mm2)阻断活性为0.059nM)。此差 异在抑制食蟹猴IL-33时更显著：7E8的抑制效力(0.131nM)相似于其对人IL-33的抑制 效力，而9B3对食蟹猴IL-33的抑制效力实质上较弱，在20nM时仅部分阻断。以9B3 CDR H2替代7E8 CDRH2导致对食蟹猴IL-33的效力大为损失(0.131nM IC50降至3.46nM)，相 似地，以9B3 CDR H3替代7E8 CDR H3导致对食蟹猴IL-33的效力损失(7.65nM)。因此， CDR H2同时携带7E8/9B3族的IL-33中和抗体的特异性和非特异性活性的决定簇，而 CDR H3携带特异性活性的决定簇。
表17.DNA结合活性和7E8的CDR移植物变体对人和食蟹猴IL-33的中和作用
实施例14评估7E8的CDR变体的非特异性结合及活性
多重反应性与CDR中的正电荷不平衡有关(Datta-Mannan et al.,2015,MAbs 7(3):483-493)。7E8和9B3的轻链之间无电荷差异。检查7E8和9B3的CDR-H2和CDR-H3 序列(SEQ ID NO：17、34、18和35)显示出四个CDR-H2和四个CDR-H3差异，其中仅 有一个(在位置54，7E8的N及9B3的D)会导致电荷差异。以N54D突变修饰7E8以产 生IL33-45(重链SEQ IDNO：169)，其仅对多重反应性具有适度效果，但显著降低食蟹 猴IL-33中和效力，该方式相似于以9B3的CDR H2取代7E8的CDR H2所观察到的(表18)。 为此，需要另外的序列变体以鉴定允许保留7E8对人和食蟹猴IL-33的活性，同时降低 7E8的多重反应性的序列变化。
表18.通过掺入来自9B3的CDR H2序列的7E8的变体对人和食蟹猴IL-33的DNA结合活性和中和
实施例15优化抗IL-33抗体7E8
在7E8中制造一系列突变以鉴定可降低多重反应性但不损失活性的变化。尽管以天 冬氨酸取代CDR H2中的N54略微降低多重反应性，但导致基于细胞的活性降低，以其 他氨基酸(I、L、V、W、Y)替代N54增加与杆状病毒的非特异性结合，同时使基于细 胞的活性保持完整。
如同通过与杆状病毒颗粒、DNA或胰岛素结合所测量的，以二个带负电荷的残基(天冬氨酸或谷氨酸)的任一者替代CDR H2残基N57会导致多重反应性显著降低，但这 些突变不会降低中和活性(表19)。令人惊讶的是，对重链的CDR3(S105D)添加负电荷 会同时导致多重反应性和基于细胞的活性的不良变化，而对轻链添加负电荷(突变N30D、 K31D、T56D或T56E)增加多重反应性。因此，N57D和N57E变体的不寻常在于它们 提高多重反应性而不损害与人或食蟹猴IL-33中和。这些结果表明负电荷的位置，而非 仅可变结构域上的总电荷，是重要的。
表19.CDR移植的7E8的单个氨基酸变体对杆状病毒结合活性和人和食蟹猴IL-33的中和
将一系列被预测将引入负电荷、除去疏水残基或修饰位置57附近的残基的另外的重 链CDR突变连同N57E一起检查。在CDR-H2掺入个别突变(S50A、T58D；表20)的具 有N57E突变的7E8的多重反应性大致上维持低下，而在基于HEK293 ST2 NFκB细胞 的分析中(表21)，具有N57E突变的7E8的效力通过掺入S50A或T58D而基本上没有变 化。相似地，具有N57E突变的7E8的多重反应性通过在CDR H1(T28E)、H2(G56H、 T58D、D62E、S63A或K65Q)或H3(H100Y、Y102H、Y103H、Y103W、T104N或T104S) 中掺入另外的个别突变而大致上维持低下。同样地，在基于HEK293 ST2 NFκB细胞的 分析中，具有N57E突变的7E8的效力通过在CDRH1(T28E)、H2(K65Q)或H3(H100Y、 T104N或T104S)中掺入另外的个别突变而基本上没有变化。
在几乎与实施例8中所描述的用于PBMC分析所使用者完全相同的形式中，通过IL-12的共刺激，IL-33可刺激在人全血中产生IFNγ，所不同的是与用于PBMC的5pM IL-33相比较，全血应答所需的IL-33的浓度较高(100pM)。相似于在HEK293 ST2 NFκB 分析中所观察到的结果，通过掺入个别突变S50A或T58D，具有N57E突变的7E8的全 血效力基本上没有变化(表21)。同样地，通过在CDR H1(T28E)、H2(S63A或K65Q)或 H3(Y103H、T104N或T104S)中掺入另外的个别突变，具有N57E突变的7E8的效力基 本上没有变化。
将设计用来排除翻译后修饰的可能位点的突变(轻链N93Q，其除去可能的NG天冬酰胺脱酰胺位点(Chelius et al.,2005,Anal.Chem.77(18):6004-6011))与抗体IL33-136中 的重链突变N57E组合，结果发现导致保留基于细胞的活性(表21)并部分保留提高的多重反应性(表20)。
表20.通过CDR移植的7E8的CDR H2和CDR L3变体与杆状病毒、DNA和胰岛素结合
表21.CDR移植的7E8的CDR H2和CDR L3变体的基于细胞的活性
检查这些突变与二个另外的重链突变(G55A，其允许除去可能的NG天冬酰胺脱酰胺位点，及D62E，其除去可能的DS天冬氨酸异构化位点(Chelius,D.,et al.(2005))的 组合的活性和多重反应性，并鉴定一组克隆株，该组克隆株具有约为起始克隆株7E8 CDR移植物的二倍的基于细胞的活性(在HEK293 ST2 NFκB报告子分析、人全血和人 PBMC分析中)及在阴性对照抗体的二倍内的多重反应性(表22、表23)。
表22.通过含有多个CDR H2和CDR L3突变的CDR移植的7E8的变体与杆状病毒、DNA和胰岛素 结合
表23.含有多个CDR H2和CDR L3突变的CDR移植的7E8的变体的基于细胞的的活性
实施例17在优化的抗体7E8变体中加入半衰期延长突变
产生抗体IL33-158和IL33-167的二种重链变体形式，一种变体Fc(SEQ ID NO：237) 在Fc中含有突变L234A L235A和G237A以降低效应子功能(描述于美国专利案第 5,624,821号)并缺失C端的赖氨酸残基以降低产物异质性，另一变体(SEQ ID NO：238) 含有L234A L235A和G237A突变，C端赖氨酸缺失和双突变M432L N438S以增进在 酸性pH下与新生儿Fc受体FcRn结合，预期将导致体内半衰期延长(Zalevsky et al.,2010, NatureBiotechnol.28(2):157-159)。在载体pRY19中建立各构建体并将其稳定转染入 CHO细胞中。所产生的抗体为IL33-158-152(SEQ ID NO：241、SEQ ID NO：209)、 IL33-167-153(SEQID NO：242、SEQ ID NO：93)、IL33-158LS(SEQ ID NO：244SEQ ID NO：209)和IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)。该经优化的抗体与相应 的人种系序列的可变区的序列比对显示于图2中。
实施例18降低经优化的分子中的多重反应性
由经稳定转染的CHO细胞产生的抗体L33-158LS(SEQ ID NO：244、SEQ ID NO：209)和IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)显示出与阴性对照单克隆抗体 贝伐单抗(bevacizumab)(表24)相当的多重反应性水平。这些水平与IL33-158(SEQ ID NO：227、SEQ ID NO：209)和IL33-167(SEQ ID NO：212、SEQ ID NO：93)的水平 相当(显示于表22中)，表示加入恒定区突变L234A、L235A、G237A、M432L和N438S 突变并缺失C端赖氨酸基本上不会改变所产生的分子的多重反应性。
表24.通过CDR-移植的7E8的优化变体与DNA和胰岛素结合
实施例19经优化的抗IL-33抗体在基于细胞的分析中的人和食蟹猴IL-33中和活性
由经稳定转染的CHO细胞产生的抗体IL33-158-152(SEQ ID NO：241、SEQ ID NO：209)、IL33-167-153(SEQ ID NO：242、SEQ ID NO：93)、IL33-158LS(SEQ ID NO：244、 SEQID NO：209)和IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)显示出在HEK293 ST2 NFκB报告子分析中对人IL-33(mm2)、人IL-33(WT)和食蟹猴IL-33(半胱氨酸突变) 的IL-33中和作用相似于亲本抗体7E8 CDR移植物(SEQ ID NO：92、SEQ ID NO：93)。 表25.在HEK293 ST2 NFκB报道子细胞分析中CDR-移植的7E8的优化变体的中和活性
实施例20经优化的抗IL-33抗体在PBMC和全血中的IL-33中和活性
从经稳定转染的CHO细胞产生的抗体IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)和IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)显示出在人PBMC中的 IL-33(mm2)中和作用相似于亲本抗体7E8 CDR移植物(SEQ ID NO：92、SEQ ID NO： 93)。
表26.在人PBMC中CDR-移植的7E8的优化变体的中和活性
抗体 HC SEQ NO LC SEQ NO IC<sub>50</sub>(nM)±SEM(n)
IL33-158LS 244 209 0.0014±0.0001(4)
IL33-167LS 245 93 0.0011±0.0002(4)
7E8 CDR移植物 92 93 0.0014±0.0004(4)
表26:中和PBMC中IFN-γ的产生。用16.67pM IL-12引发人PBMC，然后用5μM人IL-33(mm2)处理。.
从经稳定转染的CHO细胞产生的抗体IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)和IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)显示出在人全血中对人 IL-33(mm2)和人IL-33(WT)的由IL-33刺激的IFN-γ产生的中和作用相似于亲本抗体 7E8 CDR移植物(SEQ ID NO：92、SEQ ID NO：93)的作用。
表27.在人全血中CDR-移植的7E8的优化变体的中和活性
表27:用IL-12刺激全血，然后用125nM人IL-33(mm2或R&D)刺激。
从经稳定转染的CHO细胞产生的抗体IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)显示出人IL-33(mm2)和人IL-33(R&D)中和作用，而市售的Nessy-1未显示出显 著的中和作用。市售的单克隆抗体19G8显示出对人IL-33(mm2)的中和作用较 IL33-158LS弱，与对人IL-33(R&D)的中和作用相当(表28)。因此，对由IL-33(mm2)所 代表的人IL-33的活性形式的强烈选择性中和作用为IL33-158LS的特征性质。
表28.与商业抗IL-33抗体相比，IL33-158LS在HEK293 ST2 NFκB分析中的中和活性
结论：
在一系列使用细胞系、原代人单核细胞和人全血的生物分析中，人源化的经优化的 抗人IL-33抗体IL33-158-152、IL33-167-153、IL33-158LS和IL33-167LS为有效的IL-33生物活性中和剂。
实施例21使用表面等离子共振进行优化的抗IL-33抗体的动力学评估
在37℃，在Biacore T200仪器(GE Healthcare)上，以1Hz的收集速率进行Biacore动力学分析。根据制造商的方案，使用胺偶联试剂盒(目录编号BR100050，GE Healthcare)将人IL33(mm2)、食蟹猴IL-33和经还原的huIL33wt与CM5传感器芯片(目录号 BR100530，GEHealthcare)共价偶联。固定水平为260RU的人IL-33(mm2)、85RU的食 蟹猴IL-33及108-225RU的经还原的huIL33(WT)。将流动池1活化并封闭的以作为参考 流动池。以每分钟50ul的流速注射引导抗IL-33 Fab 158LS、167LS和亲本Fab 7E8的滴 定系列并监测解离3600秒。稀释和运行缓冲剂为HBS-EP+(10mM HEPES pH 7.4、0.15M NaCl、3mM EDTA、0.05％P-20)。将所得的传感图数据拟合在Biacore T200评估软件1.0 版(GE Healthcare)中的1：1模型以测定速率常数和亲和力。
依实施例10中的描述通过表面等离振子共振，以固定在传感器芯片上的IL-33和在 溶液相的Fab片段测量该经优化的抗体IL33-158LS和IL33-167LS的Fab片段的亲和力。二种经优化的抗体均显示出与人IL33(mm2)、人IL33(WT)和食蟹猴IL33的结合亲和力 相当于该亲本CDR移植的7E8的Fab所表现的亲和力(表29)。
表29.通过表面等离子共振测量测量的7E8 CDR移植物、IL33-158LS和IL33-167LS的Fab片段与人 和食蟹猴IL-33结合的动力学参数
实施例22抗IL-33的细胞因子特异性
为了评估抗IL-33抗体7E8和IL33-158LS的细胞因子特异性，通过表面等离子共振， 以BIAcore T-200评估一组非靶细胞因子与这些抗体的结合。该细胞因子组包括IL-1α、 IL-1β、IL-18、IL-36α和IL-36γ。结果(表30，图3)显示出100nM的无关细胞因子并无 结合，而抗IL-33抗体7E8和IL33-158LS以非常相似的％RMAX值与IL-33mm2和还原 的IL-33WT结合。在无还原的情况下，未观察到与IL-33结合。
表30. 7E8和IL33-158LS的细胞因子选择性
实施例23与人ST2竞争与IL33结合
在Octet结合分析中测试IL33-158LS阻断ST2受体与IL-33结合的能力。将抗体或人ST2-Fc(SEQ ID NO：6)捕获在涂覆抗人Fc的Octet尖端上，以过量的人IgG1对照 抗体封闭游离结合位点并将IL-33(R&D)和第二抗体或ST2-Fc的混合物施于尖端。该 IL33-158LS和人IL-33的复合体能够与捕获在Octet尖端的对照的非中和抗IL-33抗体 IL33-271(SEQID NO：254，SEQ ID NO：256)结合，相反地，IL33-271和人IL-33的复 合体能够与经固定的IL33-158LS结合。同样地，人ST2-Fc和IL33-271能够同时以任一 取向与人IL-33结合。然而，经固定的IL33-158LS无法与IL-33和ST2-Fc的复合体结合， 相反地，经固定的ST2-Fc无法与IL-33和IL33-158LS的复合体结合。这些结果指示 IL33-158LS与ST2-Fc竞争在IL-33上的重迭结合位点。
表31.IL33-158LS与IL-33受体ST2竞争结合IL-33
表31:(+)表示第二抗体和IL-33的复合物与在Octet尖端上捕获的第一抗体结合。(-)表示加入IL-33和第二抗体的 混合物后未观察到信号增加。
实施例24经优化的抗IL-33抗体的热稳定性
使用差示扫描量热法来测定IL33-158-152、IL33-158LS、IL33-167-153和IL33-167LS 的稳定性。对于此分析，用自动进样器(Malvern仪器公司)将0.3mg/ml的样品分配在MicroCal VP-Capillary DSC的样品托盘中，在10℃平衡5分钟，然后以每小时100℃的速率扫描达到110℃。选择16秒的过滤期。将原始数据进行基线校正并将蛋白质浓度标准 化。使用Origin软件7.0(OriginLab公司，Northampton，MA)以适当的转换数将数据拟 合至MN2态模型。下列表32显示在20mM组氨酸pH5.8、8.5％蔗糖、0.05mg/ml EDTA 中的分子的熔化温度(Tm1-Tm3)。所有四个分子显示出良好的稳定性，在CH2结构域中 的第一次转换(Tm1)高于65℃。此外，引入LS突变对该分子的稳定性的影响非常小(≤ 1℃)。
表32.优化的7E8变体的热稳定性
表32:通过差示扫描量热法测定的20mM组氨酸pH5.8、8.5％蔗糖、0.05mg/ml EDTA中IL33-158和 IL33-167衍生分子的热转变。
实施例25通过体内施用抗IL-33抗体捕获食蟹猴IL-33
测试IL33-158LS捕获天然食蟹猴IL-33的能力。在静脉内对食蟹猴给药0.14或14mg/kg的IL33-158LS后，通过腹膜内注射施用氢氧化铝(明矾)(1mg，在0.1ml中)。 注射明矾后达72小时抽取血液样品。使用免疫亲和LC\MS\MS法测量与IL33-158LS结 合的总食蟹猴IL-33。将与生物素-缀合的抗人Fc抗体与各血浆样品一起孵育，并在4℃ 孵育过夜以与所有与抗IL-33抗体结合的细胞因子结合。在各样品中添加链亲和素小珠 并孵育30分钟，洗涤，再使用低pH洗脱缓冲剂将该细胞因子从抗体释放，然后以Tris 缓冲剂中和。然后将具有用于IL-33的特征序列的延长的稳定的经同位素标记的肽加入 各样品中，再以DTT还原所有样品，以碘乙酰胺烷基化并以胰蛋白酶消化。然后以2D 纳米UPLC串联质谱仪系统鉴定该胰蛋白酶肽。对使用20μL血浆的食蟹猴IL-33而言， 此分析的定量极限为50pg/mL。与低剂量的0.14mg/kg IL33-158LS相比较，在施用14.3 mg/kg的IL33-158LS和明矾攻击后，与IL33-158LS结合的IL-33随时间增加(表33)。这 些结果表示IL33-158LS是以剂量依赖方式与天然食蟹猴IL-33结合，并产生可用于人类 药效学建模的可测量的效果。
IL33-158LS在食蟹猴中的终末血清半衰期为18天，这容许二室PK模型的参数化。对于清除率，异速指数为0.75的速率常数的异速生长比例(allometric scaling)导致预测的 人血清终末半衰期为41天。与抗体在人体中通常观察到的半衰期为20天(Brekke andSandlie(2003),Nature Reviews,Vol 2,pp 52-62)及人类或人源化生物治疗性IgG抗体通常观察到的半衰期为17天(从Singh,et al.(Chapter 5.Application of mechanisticpharmacokinetic-pharmacodynamic modeling towards the development ofbiologics.In: Kumar S,Kumar Singh S,editors.Developability ofBiotherapeutics: ComputationalApproaches.CRC Press；2015:p.109-34)所报告的PK参数衍生)相比较， 此半衰期显著更长。
出人意料的是，在健康志愿者中的初步评估指出IL33-158LS的血清排除(β相)半衰期为至少50天。在本发明的一些方面中，该抗体或其抗原结合部分的终末半衰期为至 少约50天。在本发明的一些方面中，该抗体或其抗原结合部分的终末半衰期为至少约55 天。在本发明的一些方面中，该抗体或其抗原结合部分的终末半衰期为至少约60天。在 本发明的一些方面中，该抗体或其抗原结合部分的终末半衰期为至少约65天。在本发明 的一些方面中，该抗体或其抗原结合部分的终末半衰期为至少约70天。在本发明的一些 方面中，该抗体或其抗原结合部分的终末半衰期为至少约75天。在本发明的一些方面中， 该抗体或其抗原结合部分的终末半衰期为至少约80天。在本发明的一些方面中，该抗体 或其抗原结合部分的终末半衰期为至少约85天。在本发明的一些方面中，该抗体或其抗 原结合部分的终末半衰期为至少约90天。该出乎意料地高半衰期可能是由于可变区和 CDR区及Fc结构域中的修饰。
表33.用IL33-158LS给药并用氢氧化铝(明矾)攻击的食蟹猴中总循环IL-33浓度的时间过程
实施例26比较品IL-33抗体的产生和测试
产生WO2014164959中所描述的多种hIgG4抗体的IgG1形式(表35)(该分离的Fab片段的结合特性与Fc区无关，而该完整IgG4的结合性质预期与IgG1基本上相同)。H4H9675P(相应于IL33-265)、H4H9659P(相应于IL33-266)和H4H9665P(相应于 IL33-267)已被公开对37℃的人IL-33或猴子IL-33具有最高亲和力(WO2014164959的 表3&6)。初始的功能评估显示IL33-267较IL33-265和IL-33-266更低效。更详细的评估 显示出IL33-265的效力较IL33-266高8-10倍(表36)。BIAcore分析IgG与固定的野生型 人IL-33的结合显示出IL33-265仅与还原型IL-33结合，而不与非还原型IL-33结合。
表35
表36
产生IgG1抗体IL33-310(SEQ ID NO：287(HC)和SEQ ID NO：288(LC))并衍生自WO2016077381的10C12.38.H6.87Y.581 IgG4(其被公开为对人和食蟹猴IL-33具有高亲 和力)。
10C12.38.H6.87Y.581由WO2016077381的SEQ ID NO：306(HC)和SEQ ID NO： 307(LC)组成。为了取得用于表达的核苷酸序列，使用Vector NTI软件将可变区序列进 行逆翻译。使用标准恒定κ区的核苷酸序列(其编码与WO2016077381的SEQ ID NO： 307的氨基酸序列相一致的氨基酸序列)用于表达构建体。该标准IgG4恒定区的核苷酸 序列编码的氨基酸序列与WO2016077381的SEQ ID NO：306具有三个不同处，且在此 三个密码子被修饰以编码WO2016077381的SEQ ID NO：306的恒定区。将编码前导序 列SEQ ID NO：402的核苷酸序列置于VH和VL编码序列的框内上游。表37显示比较 IL-167/LS、IL-158/LS、IL33-265和IL33-310的基于细胞的分析的数据。
表37
IgG1抗体IL33-244是基于APE04909，该APE04909被公开为WO2015/106080的SEQID NO：136和SEQ ID NO：171。APE04909为例如实施例2(体外基于细胞的分析)和实 施例5(小鼠中的人IL-33依赖性嗜酸性粒细胞增殖的体内研究，实施例5)中所详细描述 的中和抗体。然而，当根据WO2015/106080的SEQ ID NO：136/171产生抗体时，该抗 体的表达很差且具有异质SEC谱。为了排除密码子不良施用而促成表达差的可能性， 使用来自相似、充分表达的抗体的DNA序列作为起点，并经过调节以使用其中需要改 变的高频率人类密码子编码上述序列。然而，此步骤之后表达仍然不佳且SEC样式仍 显示异质性(表38)。
表38
IL33-248在WO2015/099175被描述为3H04和A25(参见图8)，而IL33-247在WO2015/099175中被描述为1C04和A10(参见图9)。合成来自WO 2015/099175的可变区 核苷酸序列并克隆入人IgG1和人λ表达载体(参见表39的来自WO2015/099175的序列)。 IL33-247和IL33-248具有不同的表位IL-158/LS和IL33-167/LS，对于IL33-247，产生 90.75mgLCM和100％的曲线下面积，而对于IL33-248，产生36mg/L CM和85.3％的曲 线下面积，这亦显示具有宽持留时间的不对称峰。
表39
IgG1抗体IL33-312是根据WO16156440的33_640087-7B(SEQ ID NO：615和SEQ IDNO：617)(参见，例如图52及实施例11至12)。IgG1抗体IL33-313是根据WO16156440 的33640237-2B(SEQ ID NO：623和SEQ ID NO：625)。
实施例27经优化的抗IL-33抗体和比较品抗体在基于细胞的分析中的人IL-33和食蟹猴IL-33中和活性
在HEK293 ST2 NFκB报告分析中测试抗体IL33-158LS(SEQ ID NO：244、SEQ IDNO：209)、IL33-167LS(SEQ ID NO：245、SEQ ID NO：93)、IL33-265(SEQ ID NO： 403、SEQ IDNO：404)和IL33-310(SEQ ID NO：405、SEQ ID NO：406)对人IL-33 和食蟹猴IL-33的中和作用(表40)。IL33-158LS(SEQ ID NO：244SEQ ID NO：209)显 示出对人IL-33和食蟹猴IL-33的半胱氨酸突变体形式具相似的中和效力(食蟹猴IC50： 人IC50比率为1.8)。同样地，IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)对野生 型人IL-33和食蟹猴IL-33(SEQ ID NO：397)具相似的中和效力(食蟹猴IC50：人IC50比 率为4.2)。IL33-167LS(SEQ ID NO：245、SEQID NO：93)显示出对食蟹猴IL-33和人 IL-33同样接近的中和效力。其他二种抗体，IL33-265(SEQ ID NO：403、SEQ ID NO： 404)和IL33-310(SEQ ID NO：405、SEQ ID NO：406)显示出对人IL-33和食蟹猴IL-33 的中和效力之间具有较大的差异(猴IC50：人IC50比率为28.7至超过250)。
第二个实验中，在HEK293 ST2 NFκB报告子分析中测试IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)、IL33-310(SEQ ID NO：405、SEQ ID NO：406)、IL33-312(SEQ ID NO：407、SEQ ID NO：408)和IL33-313(SEQ ID NO：409、SEQ ID NO：410)对 人IL-33和食蟹猴IL-33的中和作用(表41)。IL33-158LS和IL33-312对食蟹猴IL-33和人 IL-33半胱氨酸突变体具有同样接近的相对中和效力(食蟹猴IC50：人IC50比率分别为1.4 和1.1)。IL33-158LS和IL33-312对野生型人IL-33和食蟹猴IL-33的相关中和作用亦相似 (食蟹猴IC50：人IC50比率分别为9.2和5.4)。IL33-310和IL33-313显示出对人IL-33和食 蟹猴IL-33的中和效力之间具有较大的差异(猴子IC50：人IC50比率为29.2至528.1；表41)。 综合而论，该数据显示在此高效力的抗人IL-33抗体组内，IL33-158LS(SEQ ID NO：244、 SEQ ID NO：209)具有最相似的野生型人IL-33和食蟹猴IL-33的中和效力，与IL33-312 相当。
表40.在HEK293 ST2 NFkB报道子细胞分析中人和食蟹猴IL-33的中和
表41.在HEK293 ST2 NFkB报道子细胞分析中人和食蟹猴IL-33的中和
实施例28使用表面等离子共振进行抗IL-33抗体的动力学评估
在37℃，在Biacore T200仪器(GE Healthcare)上以1Hz的收集速率进行Biacore动 力学分析。根据制造商的方案，使用胺偶联试剂盒(目录编号BR100050，GE Healthcare)将还原和非还原的野生型人IL-33及经还原的野生型食蟹猴IL-33共价偶联在CM5传感 器芯片(产品目录编号BR100530，GE Healthcare)上。将流动池1活化并封闭以作为参 考流动池。在一实验中，固定量为218RU的还原的野生型人IL-33及248RU的还原的 野生型食蟹猴IL-33。在该实验中，以每分钟50ul的流速注射抗IL-33 Fab 158LS和167LS 的滴定系列并监测解离3600秒。在第二实验中，固定量为130RU的还原的野生型人IL-33、 97RU的非还原的野生型人IL-33、88RU的还原的野生型食蟹猴IL-33。在该实验中， 以每分钟50ul的流速注射抗IL-33 Fab 158LS、167LS和IL33-265的滴定系列并监测解 离900秒。该稀释和运行缓冲剂为HBS-EP+(10mM HEPES pH 7.4、0.15M NaCl、3mM EDTA、0.05％P-20)。将所得的传感图数据拟合在Biacore T200评估软件1.0版(GE Healthcare)中的1：1模型以测定速率常数和亲和力。亦以此形式测试完整IL33-0310 IgG 并观察到其与还原的人IL-33和还原的食蟹猴IL-33快速结合，以非常慢的速度解离，但 不与非还原的人IL-33结合(表Y)。二价IgG的动力学性质不能直接与单价Fab片段的 动力学性质相比较且并未呈现于本文中。
抗IL33 Fab 158LS、167LS、IL33-265和抗IL33 IgG抗体IL33-310均与经DTT处理的野生型人IL33和食蟹猴IL33强力结合。相反地，这些抗体无一与非还原的野生型人 IL-33结合(表42)。
IL33-158LS(SEQ ID NO：244SEQ ID NO：209)的Fab与野生型人IL-33和食蟹猴IL-33(SEQ ID NO：397)的亲和力相似(在二个独立的实验中，猴子KD：人KD比率为 1.3和2.3)。IL33-167LS(SEQ ID NO：245，SEQ ID NO：93)显示出与猴子IL-33和人IL-33 的亲和力同样接近。IL33-265(SEQ ID NO：403、SEQ ID NO：1003)显示出与野生型 人IL33和食蟹猴IL33的亲和力之间有较大的差异，猴子KD：人KD比率为57.8(表42)。
表42.通过表面等离子体共振测量的Fab 158LS、167LS和IL33-265的Fab片段与野生型人和食蟹猴 IL-33结合的动力学参数
实施例29经优化的抗IL-33抗体和比较品抗体的自身相互作用和多重反应性
测试抗体IL33-158(SEQ ID NO：227、SEQ ID NO：209)、IL33-158LS(SEQ ID NO：244、SEQ ID NO：209)和IL33-312(SEQ ID NO：407、SEQ ID NO：408)与DNA和 胰岛素的结合，并另外在AC-SINS分析中测试自身相互作用(affinity-capture self-interactionnanoparticle spectroscopy；Liu et al.,2014,mAbs 6:483-92)。在AC-SINS 分析中，捕获在金纳米球上的mAb若彼此结合将引起最大吸光度移动，并因此引起小 珠聚集，在该分析中的高得分已表明与溶解度和非特异性膜相互作用关联(Liu et al., 2014,mAbs 6:483-92)。IL33-158和IL33-158LS具有非常低的AC-SINS得分，与阴性对 照组的得分相当，而IL33-312的得分与阳性对照组的得分相当(表43)。IL33-312亦具有 高DNA结合分数，与阳性对照组的得分相当，而IL33-158和IL33-158LS显示出较适 度的得分。综合而论，这些结果指示与IL33-312相比较，IL33-158和IL33-158LS具有 实质上较低的非特异性结合指标。
表43.IL-33抗体的非特异性结合和自身相互作用
因此，本发明已参考上述的代表性实施方案广泛公开和说明。本领域技术人员将认 知可在不背离本发明的精神和范围的前提下对本发明做出各种修改。本文中的所有出版 物、专利申请案及核发的专利以引用方式并入本文，其程度如同个别出版物、专利申请案或核发的专利的全部内容各自被具体且个别被指明以引用方式并入本发明中。包含在以引用方式并入本文的文本中的定义的排除程度为其与本发明中的定义相抵触。
可理解的是，为了清楚起见，在分别的实施方案的背景下所描述的本发明的某些特 性亦可组合提供在单一实施方案中。相反地，为了简明起见，在单一实施方案的背景下所描述的本发明的各种特性亦可分别提供或以任何合适的次组合提供。
相关于本发明的一种实施方案所讨论的任何限制可具体考虑应用于本发明的任何 其他实施方案。此外，本发明的任何组合物可用于本发明的任何方法，且本发明的任何方法可用于制造或利用本发明的任何组合物。尤其是，应了解，申请专利范围中所描述 的本发明的任何方面(单独或与一或多个另外的权利要求和/或说明书的方面组合)可与 权利要求和/或说明书和/或序列表和/或附图以外所提出的本发明的其他方面组合。
如本文中所发现的具体实施例不在本发明的范围内，该具体实施例可被明确放弃。
在权利要求书中使用的术语“或”意味“和/或”，除非明确指出仅指替代项或这种替代 项相互排斥，尽管本公开内容支持仅指替代项和“和/或”的定义。如本文的权利要求书 中所使用的，除非另有明确说明，“一(a或an)”可意指一或多项。如本文的权利要求书中所使用的，当与字语“包含”结合使用时，本文中使用的字语“一(a或an)”可意指一项 或多于一项。如本文所使用的“另一”可意指至少第二或更多项。除非本文中另外定义， 否则与本发明联合使用的科学和技术术语应具有领域之一般技术人士所通常理解的含 义。此外，除非上下文另有要求，单数术语应包括复数且复数术语应包括单数。本文中 参照本发明使用的字语“包含(comprises/comprising)”和字语“具有/包括”是用于具体指 定所陈述的特性、整数、步骤或组分的存在，但不预先排除存在或添加一或多种其他特 性、整数、步骤、组分或其群组。
尽管所公开的教导已参照各种应用、方法和组合物描述，应理解的是，在不背离本教导和下文中的本发明的权利要求书的前提下可做出各种变化和修改。所提供的实施例是为更充分说明所公开的教导，而不意图限制本文所呈现的教导的范围。虽然本教导已 就这些示例性实施方案描述，对这些示例性实施方案进行多种变化和修改而无需过度实 验是可行的。所有这种变化和修改都在本教导的范围内。
当本发明的方面或实施方案是就马库什(Markush)组或其他替代项组描述时，本发 明不仅包括整体列出的整个组，亦包括个别组别的各成员和主要组别的所有可能的亚组， 还有缺少一或多个该组成员的主要组。本发明亦设想明确排除申请专利的发明中的一或 多个任一组员。
本文所引用的所有参考数据，包括专利、专利申请案、论文、教科书，等及其中所引用的参考数据的全部内容在此以引用方式并入本文，其程度为它们并非已并入本文。 在该并入的文献和相似物中有一或多项与本申请案不同或矛盾的情况中(包括，但不限 于定义的术语、术语用法、描述的技术，等)，以本申请案为准。
本说明和实施例详细描述本发明的某些具体实施方案并描述本发明者所考虑的最 佳模式。然而，应理解的是，无论前述内容可能会多么详细地出现在文本中，本发明可以多种方式实施且本发明应当根据所附的权利要求书及其任何等同物来解释。
序列表
序列表
<110> 辉瑞公司
<120> 抗IL-33抗体及其组合物、方法及用途
<130> PC72256A
<150> 62/328,294
<151> 2016-04-27
<150> 62/483,781
<151> 2017-04-10
<160> 410
<170> PatentIn version 3.5
<210> 1
<211> 159
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 1
Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser
1 5 10 15
Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr
20 25 30
Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val
35 40 45
Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp
50 55 60
Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp
65 70 75 80
Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys
85 90 95
Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met
100 105 110
His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe
115 120 125
Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser
130 135 140
Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr
145 150 155
<210> 2
<211> 553
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 2
Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val
1 5 10 15
Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr
20 25 30
Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe
35 40 45
Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Glu Val Ala Asp Ser
50 55 60
Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly
65 70 75 80
Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro
85 90 95
Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys
100 105 110
Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu
115 120 125
Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His
130 135 140
Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp
145 150 155 160
Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val
165 170 175
Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu
180 185 190
Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu
195 200 205
Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly
210 215 220
Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile
225 230 235 240
Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln
245 250 255
Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala
260 265 270
Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu
275 280 285
Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn
290 295 300
Pro Ser Lys Glu Cys Phe Ile Glu Gly Arg Met Asp Pro Lys Ser Cys
305 310 315 320
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
325 330 335
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
340 345 350
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
355 360 365
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
370 375 380
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
385 390 395 400
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
405 410 415
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
420 425 430
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
435 440 445
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
450 455 460
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
465 470 475 480
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
485 490 495
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
500 505 510
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
515 520 525
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
530 535 540
Pro Gly Lys His His His His His His
545 550
<210> 3
<211> 166
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 3
Met Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu
1 5 10 15
Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser
20 25 30
Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys
35 40 45
Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly
50 55 60
Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys
65 70 75 80
Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His
85 90 95
Lys Ser Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn
100 105 110
Met His Ser Asn Ser Val Ser Phe Glu Ser Lys Thr Asp Pro Gly Val
115 120 125
Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser
130 135 140
Ser Glu Asn Leu Ser Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr
145 150 155 160
His His His His His His
165
<210> 4
<211> 169
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 4
Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser
1 5 10 15
Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr
20 25 30
Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val
35 40 45
Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp
50 55 60
Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp
65 70 75 80
Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys
85 90 95
Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met
100 105 110
His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe
115 120 125
Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser
130 135 140
Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr Leu
145 150 155 160
Glu Asp Tyr Lys Asp Asp Asp Asp Lys
165
<210> 5
<211> 166
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 5
Met Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu
1 5 10 15
Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser
20 25 30
Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys
35 40 45
Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly
50 55 60
Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys
65 70 75 80
Asp Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His
85 90 95
Lys Ser Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn
100 105 110
Arg Ser Phe Asn Ser Val Ser Phe Glu Ser Lys Thr Asp Pro Gly Val
115 120 125
Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr
130 135 140
Ser Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile
145 150 155 160
His His His His His His
165
<210> 6
<211> 533
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 6
Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val
1 5 10 15
Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr
20 25 30
Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe
35 40 45
Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser
50 55 60
Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly
65 70 75 80
Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro
85 90 95
Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys
100 105 110
Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu
115 120 125
Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His
130 135 140
Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp
145 150 155 160
Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val
165 170 175
Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu
180 185 190
Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu
195 200 205
Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly
210 215 220
Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile
225 230 235 240
Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln
245 250 255
Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala
260 265 270
Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu
275 280 285
Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn
290 295 300
Pro Ser Lys Glu Cys Phe Val Glu Cys Pro Pro Cys Pro Ala Pro Pro
305 310 315 320
Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
325 330 335
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
340 345 350
Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met
355 360 365
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
370 375 380
Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu
385 390 395 400
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala
405 410 415
Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
420 425 430
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
435 440 445
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
450 455 460
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
465 470 475 480
Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
485 490 495
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
500 505 510
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
515 520 525
Leu Ser Pro Gly Lys
530
<210> 7
<211> 113
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 7
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
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 Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
100 105 110
Ser
<210> 8
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 8
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 9
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 9
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 10
<211> 330
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 10
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 11
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 11
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 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 Gly 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 Ser Tyr Ser Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 12
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 12
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 13
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 13
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
<210> 14
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 14
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Lys Thr Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Ile Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Ser Leu Val Thr Val Ser Ser
115 120
<210> 15
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 15
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 16
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 16
Gly Phe Thr Phe Ser Ser Tyr Trp Met Tyr
1 5 10
<210> 17
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 17
Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 18
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 18
Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr
1 5 10
<210> 19
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 19
Glu Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Cys Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Gly Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp
100 105
<210> 20
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 20
Lys Ala Ser Gln Asn Ile Asn Lys His Leu Asp
1 5 10
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 21
Phe Thr Asn Asn Leu Gln Thr
1 5
<210> 22
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 22
Phe Gln Tyr Asn Asn Gly Trp Thr
1 5
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 23
Trp Gly Gln Gly Ser Leu Val Thr Val Ser Ser
1 5 10
<210> 24
<211> 98
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 24
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val
<210> 25
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 25
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
1 5 10 15
<210> 26
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 26
Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 27
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 27
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
100 105
<210> 28
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 28
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Lys Thr Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Glu Asn Thr Ile Tyr
65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Phe Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Ser Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 29
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 29
Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp
1 5 10
<210> 30
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 30
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
<210> 31
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 31
Glu Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Leu Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Cys Thr Leu Thr Ile Asn Ser Leu Gln Pro
65 70 75 80
Gly Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Asp Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 32
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 32
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 33
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 33
Gly Phe Thr Phe Ser Asn Tyr Trp Met Tyr
1 5 10
<210> 34
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 34
Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val Lys
1 5 10 15
Gly
<210> 35
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 35
Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr
1 5 10
<210> 36
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 36
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 37
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 37
Lys Ala Ser His Asn Ile Asn Lys His Leu Asp
1 5 10
<210> 38
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 38
Phe Gln Tyr Asn Ser Gly Trp Thr
1 5
<210> 39
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 39
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
1 5 10
<210> 40
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 40
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 41
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 41
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
1 5 10
<210> 42
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 42
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 43
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 43
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Ile Phe Lys Asn Tyr
20 25 30
Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 44
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 44
Gly Phe Ile Phe Lys Asn Tyr Trp Met Thr
1 5 10
<210> 45
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 45
Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 46
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 46
Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr
1 5 10
<210> 47
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 47
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ala Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Ser
20 25 30
Leu Ile Trp Phe Gln Gln Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg
100 105
<210> 48
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 48
Arg Ala Ser Gln Ser Ile Ser Asn Ser Leu Ile
1 5 10
<210> 49
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 49
Ser Ser Ser Thr Leu Glu Ser
1 5
<210> 50
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 50
Leu Gln Tyr Ala Thr Tyr Pro Trp Thr
1 5
<210> 51
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 51
Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Ile Phe Lys Asn Tyr
20 25 30
Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Glu Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 52
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 52
Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg
1 5 10
<210> 53
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 53
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Ala Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Ser Ile Ser Asn Ser
20 25 30
Leu Ile Trp Phe Gln Gln Lys Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 54
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 54
Glu Val Gln Leu Val Asp Ser Gly Gly Asp Gln Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Lys Asn Tyr
20 25 30
Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 55
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 55
Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 56
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 56
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile
35 40 45
Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 57
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 57
Arg Thr Ser Gln Ser Ile Asn Asn Asn Leu Cys
1 5 10
<210> 58
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 58
Ser Thr Ser Thr Leu Glu Ser
1 5
<210> 59
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 59
Glu Val Gln Leu Val Asp Ser Gly Gly Asp Gln Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Ile Phe Lys Asn Tyr
20 25 30
Trp Met Thr Trp Ile Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Ala Ser Ile Thr Asn Ser Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asp Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Asp Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 60
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 60
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile
35 40 45
Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 61
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 61
Gln Val Asn Leu Leu Gln Ser Gly Ala Thr Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 62
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 62
Gly Tyr Ser Phe Thr Asp Tyr Trp Val Ser
1 5 10
<210> 63
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 63
Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe Lys
1 5 10 15
Asp
<210> 64
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 64
Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr
1 5 10
<210> 65
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 65
Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Lys
100 105
<210> 66
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 66
Lys Ala Ser Gln Asn Val Gly Asn Asn Ile Ala
1 5 10
<210> 67
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 67
Tyr Ala Ser Asn Arg Tyr Thr
1 5
<210> 68
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 68
Gln Arg Ile Tyr Asn Ser Pro Pro Thr
1 5
<210> 69
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 69
Gln Val Asn Leu Leu Gln Ser Gly Ala Thr Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Met Lys Met Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asn Asn Phe Asn Lys Glu Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Thr Arg Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Gly Pro Tyr Tyr Tyr Ser Ser Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 70
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 70
Phe Gly Gly Gly Thr Lys Val Glu Leu Lys
1 5 10
<210> 71
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 71
Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 72
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 72
Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Ala Thr Ser Gly Phe Ser Phe Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 73
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 73
Gly Phe Ser Phe Thr Asp Tyr Trp Val Ser
1 5 10
<210> 74
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 74
Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe Lys
1 5 10 15
Gly
<210> 75
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 75
Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr
1 5 10
<210> 76
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 76
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Arg
100 105
<210> 77
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 77
Lys Ala Ser Gln Asn Val Gly Asn Asn Leu Ala
1 5 10
<210> 78
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 78
Gln Val Lys Leu Leu Gln Ser Gly Ala Ala Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Ala Thr Ser Gly Phe Ser Phe Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Thr Ser Glu Asp Ser Ala Ile Tyr Tyr Cys
85 90 95
Thr Arg Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 79
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 79
Phe Gly Gly Gly Thr Lys Val Glu Leu Arg
1 5 10
<210> 80
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 80
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Leu Arg Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 81
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 81
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 82
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 82
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
1 5 10
<210> 83
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 83
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Cys Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 84
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 84
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile
35 40 45
Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 85
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 85
Asp Ile Gln Leu Thr Gln Ser Pro Ser Thr Leu Pro Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Ser Cys Arg Thr Ser Gln Ser Ile Asn Asn Asn
20 25 30
Leu Cys Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Arg Leu Ile
35 40 45
Tyr Ser Thr Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Ser Ile Ser Ser Leu Glu Ser
65 70 75 80
Gln Asp Phe Ala Met Tyr Tyr Cys Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 86
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 86
Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 87
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 87
Ile Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Ile Ala Trp Tyr Arg Gln Lys Pro Gly Gln Ser Pro Glu Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 88
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 88
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 89
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 89
Asn Ile Val Met Thr Gln Ser Pro Lys Ser Met Ser Ile Ser Val Gly
1 5 10 15
Asp Arg Val Thr Met Asn Cys Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Gly Gly Tyr Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Val Gln Ala
65 70 75 80
Glu Asp Ala Ala Phe Tyr Tyr Cys Gln Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 90
<211> 123
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 90
His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
1 5 10 15
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
Ser Tyr Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Val Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 91
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 91
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 92
<211> 453
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 92
His Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
1 5 10 15
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
20 25 30
Ser Tyr Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
35 40 45
Trp Val Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro Asp
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
85 90 95
Tyr Cys Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala
225 230 235 240
Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 93
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 93
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 94
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 94
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 95
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 96
<211> 110
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 96
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
100 105 110
<210> 97
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 97
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 Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu 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 Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 98
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 98
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 Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 99
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 99
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 Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu 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 Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 100
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 100
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 Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 101
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 101
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 Lys Asn Tyr
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro 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 Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 102
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 102
Gly Phe Thr Phe Lys Asn Tyr Trp Met Thr
1 5 10
<210> 103
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 103
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 Ser
20 25 30
Leu Ile Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 104
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 104
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 Lys Asn Tyr
20 25 30
Trp Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Asn Thr Gly Gly Ala Thr Tyr Tyr Pro 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 Arg Arg Tyr Asn Ser Gly Ser Pro Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 105
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 105
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 Ser
20 25 30
Leu Ile Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ser Ser Thr Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Leu Gln Tyr Ala Thr Tyr Pro Trp
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 106
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 106
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 Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
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 Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 107
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 107
Gly Phe Thr Phe Thr Asp Tyr Trp Val Ser
1 5 10
<210> 108
<211> 107
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 108
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 Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 109
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 109
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 Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
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 Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 110
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 110
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 Lys Ala Ser Gln Asn Val Gly Asn Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Arg Ile Tyr Asn Ser Pro Pro
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 111
<211> 122
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 111
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 Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Val 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 Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 112
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 112
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 Thr Asp Tyr
20 25 30
Trp Val Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Tyr Pro Asn Ser Gly Ala Asp Asn Phe Asn Glu Asn Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Val 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 Gly Pro Tyr Tyr Tyr Ser Thr Gln Ile Ile Phe Ala Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 113
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 113
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 114
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 114
Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr
1 5 10
<210> 115
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 115
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 116
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 116
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 117
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 117
Asp Ile Gln Met Thr Gln Ser Pro Ser Val Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Leu Ser Cys Lys Ala Ser His Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Val Gly Glu Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Val Ala Thr Tyr Phe Cys Phe Gln Tyr Asn Ser Gly Trp Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 118
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 118
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 119
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 119
Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr
1 5 10
<210> 120
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 120
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 121
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 121
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 122
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 122
Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr
1 5 10
<210> 123
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 123
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Val Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 124
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 124
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 125
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 125
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Ile Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 126
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 126
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 127
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 127
Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr
1 5 10
<210> 128
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 128
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 129
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 129
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 130
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 130
Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr
1 5 10
<210> 131
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 131
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly Arg Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 132
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 132
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 133
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 133
Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His
1 5 10
<210> 134
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 134
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Asn Ser Tyr Ser Phe Ala His Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 135
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 135
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 136
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 136
Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn
1 5 10
<210> 137
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 137
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ala Asn Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 138
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 138
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 139
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 139
Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser
1 5 10
<210> 140
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 140
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Ser Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 141
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 141
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 142
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 142
Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr
1 5 10
<210> 143
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 143
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Phe Ser Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 144
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 144
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 145
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 145
Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe
1 5 10
<210> 146
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 146
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Phe Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 147
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 147
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 148
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 148
Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr
1 5 10
<210> 149
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 149
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 150
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 150
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 151
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 151
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 152
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 152
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 153
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 153
Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr
1 5 10
<210> 154
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 154
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 155
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 155
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 156
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 156
Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr
1 5 10
<210> 157
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 157
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 158
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 158
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 159
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 159
Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr
1 5 10
<210> 160
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 160
Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Tyr Trp Ile Arg Gln Ala Pro Gly Met Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asn Asn Ala Glu Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ser Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Lys Gly His Tyr Tyr Tyr Ser Ser Tyr Ser Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 161
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 161
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 Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 162
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 162
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 Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 163
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 163
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 164
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 164
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Asn Asn Asp Gly Gly Asn Thr Tyr Tyr Leu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 165
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 165
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 166
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 166
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Ser Tyr Ser Ser Tyr Ser Phe Ser Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 167
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 167
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 168
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 168
Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 169
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 169
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asp Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 170
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 170
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 171
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 171
Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 172
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 172
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 173
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 173
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 174
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 174
Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 175
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 175
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 176
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 176
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 177
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 177
Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr
1 5 10
<210> 178
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 178
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 179
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 179
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 180
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 180
Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 181
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 181
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Leu Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 182
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 182
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 183
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 183
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 184
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 184
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 185
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 185
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asp Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Asp Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 186
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 186
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 187
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 187
Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr
1 5 10
<210> 188
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 188
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Asn Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ala Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 189
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 189
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 Lys Ala Ser Gln Asn Ile Asn Asp His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 190
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 190
Lys Ala Ser Gln Asn Ile Asn Asp His Leu Asp
1 5 10
<210> 191
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 191
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 Lys Ala Ser Gln Asn Ile Asn Asp His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 192
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 192
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 Lys Ala Ser Gln Asn Ile Asp Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 193
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 193
Lys Ala Ser Gln Asn Ile Asp Lys His Leu Asp
1 5 10
<210> 194
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 194
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 Lys Ala Ser Gln Asn Ile Asp Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 195
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 195
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 196
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 196
Phe Thr Asn Asn Leu Gln Asp
1 5
<210> 197
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 197
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 198
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 198
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 199
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 199
Phe Thr Asn Asn Leu Gln Glu
1 5
<210> 200
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 200
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Asn Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 201
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 201
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 202
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 202
Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 203
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 203
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 204
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 204
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 205
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 205
Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 206
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 206
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 207
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 207
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Gln Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 208
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 208
Phe Gln Tyr Asn Gln Gly Trp Thr
1 5
<210> 209
<211> 213
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 209
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 Lys Ala Ser Gln Asn Ile Asn Lys His
20 25 30
Leu Asp Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Phe Thr Asn Asn Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly 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 Phe Gln Tyr Asn Gln Gly Trp Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 210
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 210
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 211
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 211
Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 212
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 212
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 213
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 213
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 214
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 214
Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys
1 5 10 15
Gly
<210> 215
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 215
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 216
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 216
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 217
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 217
Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 218
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 218
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 219
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 219
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 220
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 220
Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys
1 5 10 15
Gly
<210> 221
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 221
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 222
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 222
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 223
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 223
Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 224
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 224
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 225
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 225
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 226
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 226
Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu Ser Val Lys
1 5 10 15
Gly
<210> 227
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 227
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 228
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 228
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 229
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 229
Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu Ser Val Lys
1 5 10 15
Gly
<210> 230
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 230
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 231
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 231
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 232
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 232
Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu Ser Val Lys
1 5 10 15
Gly
<210> 233
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 233
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Gly Gly Glu Thr Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 234
<211> 121
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 234
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 235
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 235
Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro Asp Ser Val Lys
1 5 10 15
Gly
<210> 236
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 236
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Thr Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 237
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 237
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 238
<211> 329
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 238
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly 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 Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 239
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 239
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser
<210> 240
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
100 105
<210> 241
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 241
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 242
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 242
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 243
<211> 106
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 243
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
1 5 10 15
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
20 25 30
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
35 40 45
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
50 55 60
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
65 70 75 80
Asn Val Phe Ser Cys Ser Val Leu His Glu Ala Leu His Ser His Tyr
85 90 95
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
100 105
<210> 244
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 244
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro Glu 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
420 425 430
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 245
<211> 450
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 245
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Trp Met Tyr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ser Ile Thr Pro Asn Ala Gly Glu Asp Tyr Tyr Pro 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 Gly His Tyr Tyr Tyr Thr Ser Tyr Ser Leu Gly Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly
225 230 235 240
Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Leu
420 425 430
His Glu Ala Leu His Ser His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 246
<211> 117
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 246
Gln Val Leu Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Val Ser Cys Lys Ala Ser Gly Ser 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 Trp Ile Asn Pro Asn Asn 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 Arg Glu Leu Arg Tyr Asn Trp Lys Ser Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 247
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 247
Gly Ser Thr Phe Thr Gly Tyr Tyr Met His
1 5 10
<210> 248
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 248
Trp Ile Asn Pro Asn Asn Gly Gly Thr Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 249
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 249
Glu Leu Arg Tyr Asn Trp Lys Ser
1 5
<210> 250
<211> 108
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 250
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Arg Pro
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser
50 55 60
Gly Asn 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 Asp Asn Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105
<210> 251
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 251
Arg Ala Ser Gln Ser Val Gly Arg Pro Tyr Leu Ala
1 5 10
<210> 252
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 252
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 253
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 253
Gln Gln Tyr Asp Asn Ser Pro Tyr Thr
1 5
<210> 254
<211> 447
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 254
Gln Val Leu Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Thr Val Lys Val Ser Cys Lys Ala Ser Gly Ser 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 Trp Ile Asn Pro Asn Asn 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 Arg Glu Leu Arg Tyr Asn Trp Lys Ser Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu
115 120 125
Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys
130 135 140
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser
145 150 155 160
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
165 170 175
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser
180 185 190
Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn
195 200 205
Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His
210 215 220
Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Ala Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 255
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 255
Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
1 5 10
<210> 256
<211> 215
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 256
Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Arg Pro
20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Gly Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser
50 55 60
Gly Asn 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 Asp Asn Ser Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 257
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be K, S, H, T, Q, W, Y, F or R
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be A, S or G
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be S, A or D
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Q, H, S, E, D, or T
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, S, D, R, K, Y, E or G
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be I or V
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be N, F, K, H, R, L, M, I, E or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be K, Q, E, R, W, F, Y, N, A, S or H
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be H, F, R or W
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be L, I, V or A
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be D, S or A
<400> 257
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 258
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be K or R
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Q or H
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be I or V
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be K, S or N
<400> 258
Xaa Ala Ser Xaa Xaa Xaa Xaa Xaa His Leu Asp
1 5 10
<210> 259
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be K or R
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Q or H
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be K or S
<400> 259
Xaa Ala Ser Xaa Xaa Ile Xaa Xaa His Leu Asp
1 5 10
<210> 260
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be K or R
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be K or S
<400> 260
Xaa Ala Ser Gln Xaa Ile Xaa Xaa His Leu Asp
1 5 10
<210> 261
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F, W, Y, D, E, G or S
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be T, G, R, A, N or V
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be N, W, Y, R, F, K,Q, E, D, H or S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N, F, Y, I, M, Q, L, A, R, G, P or S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be L, I, V or R
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be Q, R, K, F, H, L, W, Y, A or E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be T, S, N or Y
<400> 261
Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 262
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F or Y
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be A or T
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be Q or E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be T or S
<400> 262
Xaa Xaa Xaa Xaa Leu Xaa Xaa
1 5
<210> 263
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa cn be T or A
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa cn be N or S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa cn be N or S
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa cn be T or S
<400> 263
Phe Xaa Xaa Xaa Leu Gln Xaa
1 5
<210> 264
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be A or T
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be N or S
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be T or S
<400> 264
Phe Xaa Xaa Asn Leu Gln Xaa
1 5
<210> 265
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F, Q, W, H or A
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be Q, S, T or A
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be Y, H or F
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N, W, F, Y, R, K, H or D
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, S,Q, W, K, R, H, Y, D, G, T or V
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G, R, P, K, W, F, I, N or Q
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be W or H
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be T, S or Q
<400> 265
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 266
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F or Q
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be Y or F
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N or Y
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, S, Q, R or Y
<400> 266
Xaa Gln Xaa Xaa Xaa Gly Trp Thr
1 5
<210> 267
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F or Q
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N or Y
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, S, Q or R
<400> 267
Xaa Gln Tyr Xaa Xaa Gly Trp Thr
1 5
<210> 268
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be F or Q
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be N or Y
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, S or Q
<400> 268
Xaa Gln Tyr Xaa Xaa Gly Trp Thr
1 5
<210> 269
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be F, Y or H
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be T, Q, N, S, E, D, R or Y
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be F, Y or H
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be S, E, D, T or W
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be N, S, T, E, D, H, L, I, Y, R, K or G
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be Y, F or H
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be W, H, Y, A or G
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be M, E, Q or I
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be Y, F, H or N
<400> 269
Gly Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 270
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be T or E
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be S or E
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be N or S
<400> 270
Gly Phe Xaa Phe Xaa Xaa Tyr Trp Met Tyr
1 5 10
<210> 271
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be N or S
<400> 271
Gly Phe Thr Phe Ser Xaa Tyr Trp Met Tyr
1 5 10
<210> 272
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be S, A or T
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be I or V
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be T, H, N or S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be P, N, F or M
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N, I, D, Y or W
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G or A
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be G, H, D, E, R, K, Y or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N, Y, D, E, Q or H
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be T, K, E, S, I, A or D
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be Y, H or W
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be Y, F or H
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be P, V, L, D or S
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa can be D, E, Q or A
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa can be S, A, N or D
<220>
<221> MISC_FEATURE
<222> (15)..(15)
<223> Xaa can be V, D or T
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa can be K, N, D, S, E or Q
<400> 272
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10 15
Gly
<210> 273
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be S or A
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be T or N
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be P or N
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or D
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G or A
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be G, S or H
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N, D or E
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be T, K, D or E
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be P, V or L
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa can be D or E
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa can be K or Q
<400> 273
Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Xaa
1 5 10 15
Gly
<210> 274
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be S or A
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be T or N
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be P or N
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or D
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G or A
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be G or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or E
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be T, K or D
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be P, V or L
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa can be D or E
<400> 274
Xaa Ile Xaa Xaa Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Lys
1 5 10 15
Gly
<210> 275
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be S or A
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be N or D
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G or A
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be G or S
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or E
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be T, K or D
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be P or V
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa can be D or E
<400> 275
Xaa Ile Thr Pro Xaa Xaa Xaa Xaa Xaa Tyr Tyr Xaa Xaa Ser Val Lys
1 5 10 15
Gly
<210> 276
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be G, S, A, T or D
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be H, K, R or Y
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be Y, H, F or S
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Y, H, R or S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be Y, H, W, F, R or S
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be T, N, V, I, S, A, G or Y
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be S, N, A, Q, D, G, R or Y
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be Y, W,H, F, G, D or N
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be S, A or G
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be L, M, F or I
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be G, A, Y, S or D
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be Y, N, S, F, E, D, H, I or V
<400> 276
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5 10
<210> 277
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be H, R or Y
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa can be Y or F
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Y or S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be Y or H
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be T, S or N
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be S or A
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be L, F or I
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be G, S or A
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be Y, H, N, S or F
<400> 277
Gly Xaa Xaa Xaa Xaa Xaa Xaa Tyr Ser Xaa Xaa Xaa
1 5 10
<210> 278
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be H or Y
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Y or S
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be Y or H
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be T, S or N
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be S or A
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be L or F
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be G or S
<400> 278
Gly Xaa Tyr Xaa Xaa Xaa Xaa Tyr Ser Xaa Xaa Tyr
1 5 10
<210> 279
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be Y or S
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be T or S
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be L or F
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be G or S
<400> 279
Gly His Tyr Xaa Tyr Xaa Ser Tyr Ser Xaa Xaa Tyr
1 5 10
<210> 280
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 280
Arg Ala Ser Gln Ser Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 281
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 281
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 282
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 282
Gln Gln Ser Tyr Ser Thr Pro
1 5
<210> 283
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 283
Lys Ser Ser Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr Leu Tyr
1 5 10 15
<210> 284
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 284
Glu Val Ser Asn Arg Phe Ser
1 5
<210> 285
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 285
Met Gln Ser Ile Gln Leu Pro
1 5
<210> 286
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 286
Arg Ser Ser Gln Ser Leu Val Tyr Ser Asp Gly Asn Thr Tyr Leu Asn
1 5 10 15
<210> 287
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 287
Lys Val Ser Asn Arg Asp Ser
1 5
<210> 288
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 288
Met Gln Gly Thr His Trp Pro
1 5
<210> 289
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 289
Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 290
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 290
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 291
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 291
Gln Gln Tyr Tyr Ser Thr Pro
1 5
<210> 292
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 292
Arg Ala Ser Gln Ser Ile Ser Ser Trp Leu Ala
1 5 10
<210> 293
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 293
Asp Ala Ser Ser Leu Glu Ser
1 5
<210> 294
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 294
Gln Gln Tyr Asn Ser Tyr Ser
1 5
<210> 295
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 295
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 296
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 296
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 297
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 297
Gln Gln Tyr Asp Asn Leu Pro
1 5
<210> 298
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 298
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 299
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 299
Ala Ala Ser Thr Leu Gln Ser
1 5
<210> 300
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 300
Gln Gln Leu Asn Ser Tyr Pro
1 5
<210> 301
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 301
Arg Ala Ser Gln Ser Val Ser Ser Asn Leu Ala
1 5 10
<210> 302
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 302
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 303
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 303
Gln Gln Tyr Asn Asn Trp Pro
1 5
<210> 304
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 304
Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala
1 5 10
<210> 305
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 305
Asp Ala Ser Asn Arg Ala Thr
1 5
<210> 306
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 306
Gln Gln Arg Ser Asn Trp Pro
1 5
<210> 307
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 307
Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala
1 5 10
<210> 308
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 308
Gly Ala Ser Ser Arg Ala Thr
1 5
<210> 309
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 309
Gln Gln Tyr Gly Ser Ser Pro
1 5
<210> 310
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 310
Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 311
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 311
Leu Gly Ser Asn Arg Ala Ser
1 5
<210> 312
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 312
Met Gln Ala Leu Gln Thr Pro
1 5
<210> 313
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 313
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser
1 5 10
<210> 314
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 314
Gly Lys Asn Asn Arg Pro Ser
1 5
<210> 315
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 315
Asn Ser Arg Asp Ser Ser Gly Asn His
1 5
<210> 316
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 316
Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His
1 5 10
<210> 317
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 317
Gly Asn Ser Asn Arg Pro Ser
1 5
<210> 318
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 318
Gln Ser Tyr Asp Ser Ser Leu Ser Gly
1 5
<210> 319
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 319
Thr Arg Ser Ser Gly Ser Ile Ala Ser Asn Tyr Val Gln
1 5 10
<210> 320
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 320
Glu Asp Asn Gln Arg Pro Ser
1 5
<210> 321
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 321
Gln Ser Tyr Asp Ser Ser Asn
1 5
<210> 322
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 322
Thr Gly Ser Ser Ser Gly Gly Ser Tyr Tyr Val Ser
1 5 10
<210> 323
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 323
Thr Gly Ser Ser Ser Asp Val Gly Gly Ser Tyr Tyr Val Ser
1 5 10
<210> 324
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 324
Glu Asn Asp Ser Asn Arg Pro Ser
1 5
<210> 325
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be S or D
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be Q or G
<400> 325
Glu Asp Ser Asn Arg Xaa Lys Xaa Gln Lys Pro Ser
1 5 10
<210> 326
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or T
<400> 326
Gln Ser Trp Asp Ser Ser Ala Xaa
1 5
<210> 327
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or T
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be F or V
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be G or V
<400> 327
Gln Ser Trp Asp Ser Ser Ala Xaa Phe Xaa Xaa
1 5 10
<210> 328
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa can be A or Y
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa can be N, H or S
<400> 328
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Xaa Val Xaa
1 5 10
<210> 329
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa can be A or Y
<220>
<221> MISC_FEATURE
<222> (14)..(14)
<223> Xaa can be N, H or S
<400> 329
Ser Gly Ser Ser Ser Asn Ile Ile Gly Asn Asn Xaa Val Xaa
1 5 10
<210> 330
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be K, N or Q
<400> 330
Gly Asn Asn Xaa Arg Pro Ser
1 5
<210> 331
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or S
<400> 331
Ala Ala Trp Asp Asp Ser Leu Xaa Gly
1 5
<210> 332
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> Xaa can be A or V
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be K or S
<400> 332
Cys Ser Gly Asp Xaa Leu Gly Xaa Lys Tyr Ala His
1 5 10
<210> 333
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 333
Lys Asp Ser Glu Arg Pro Ser
1 5
<210> 334
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N, D, T or A
<400> 334
Gln Ser Trp Asp Ser Ser Gly Xaa
1 5
<210> 335
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N, D, T, or A
<400> 335
Gln Ser Trp Asp Ser Ser Gly Xaa His
1 5
<210> 336
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 336
Arg Ala Ser Gln Ser Leu Leu His Ser Asp Gly Ile Ser Ser Tyr Leu
1 5 10 15
Ala
<210> 337
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 337
Arg Ala Ser Gln Gly Ile Ser Ser Tyr Leu Ala
1 5 10
<210> 338
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 338
Ala Ala Ser Ser Arg Ala Ser
1 5
<210> 339
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 339
Gln Gln Tyr Asn Ser Tyr Pro
1 5
<210> 340
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or S
<400> 340
Arg Ala Ser Gln Gly Ile Ser Xaa Tyr Leu Ala
1 5 10
<210> 341
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 341
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 342
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 342
Gln Gln Tyr Asn Ser Tyr Pro
1 5
<210> 343
<211> 16
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 343
Arg Ser Ser Gln Ser Leu Leu His Ser Asp Gly Asn Thr Tyr Leu Asp
1 5 10 15
<210> 344
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 344
Arg Ser Ser Gln Ser Leu Leu His Ser Asp Asp Gly Asn Thr Tyr Leu
1 5 10 15
Asp
<210> 345
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa can be K or T
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be V or I
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be A or F
<400> 345
Xaa Xaa Ser Asn Arg Xaa Ser
1 5
<210> 346
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 346
Met Gln Ala Thr Gln Phe Pro
1 5
<210> 347
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be S or V
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa can be S or V
<400> 347
Arg Ala Ser Gln Ser Xaa Xaa Ser Ser Tyr Leu Ala
1 5 10
<210> 348
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 348
Gly Ala Ser Thr Arg Ala Thr
1 5
<210> 349
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa can be S, N, G or H
<400> 349
Gln Gln Tyr Xaa Asn Trp Pro
1 5
<210> 350
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 350
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 351
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 351
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 352
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 352
Leu Gln Asp Tyr Asn Tyr Pro Leu Thr
1 5
<210> 353
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 353
Gly Phe Thr Phe Ser Ser Tyr Trp Met Ser
1 5 10
<210> 354
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 354
Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
1 5 10 15
Lys Gly
<210> 355
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 355
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5 10
<210> 356
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 356
Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 357
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 357
Gly Gly Ser Ile Ser Ser Tyr Tyr Trp Ser
1 5 10
<210> 358
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 358
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 359
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 359
Gly Tyr Thr Phe Thr Gly Tyr Tyr Met His
1 5 10
<210> 360
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 360
Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe
1 5 10 15
Gln Gly
<210> 361
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 361
Gly Gly Thr Phe Ser Ser Tyr Ala Ile Ser
1 5 10
<210> 362
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 362
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
1 5 10 15
Gln Gly
<210> 363
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 363
Gly Tyr Thr Gly Thr Ser Tyr Tyr Met His
1 5 10
<210> 364
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 364
Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
1 5 10 15
Gln Gly
<210> 365
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 365
Gly Phe Thr Phe Ser Ser Tyr Gly Met His
1 5 10
<210> 366
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 366
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 367
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 367
Gly Phe Thr Phe Ser Ser Tyr Ser Met Asn
1 5 10
<210> 368
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 368
Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 369
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 369
Gly Phe Thr Phe Ser Asn Ala Trp Met Ser
1 5 10
<210> 370
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 370
Gly Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala
1 5 10 15
Pro Val Lys Gly
20
<210> 371
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 371
Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr Trp Gly
1 5 10
<210> 372
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 372
Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 373
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 373
Gly Gly Ser Ile Ser Ser Gly Asp Tyr Tyr Trp Ser
1 5 10
<210> 374
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 374
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 375
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 375
Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Gly
1 5 10
<210> 376
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 376
Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
1 5 10 15
Gln Gly
<210> 377
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be H or S
<400> 377
Gly Phe Thr Phe Ser Ser Tyr Ala Met Xaa
1 5 10
<210> 378
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be H or S
<400> 378
Gly Phe Thr Phe Ser Ser Tyr Ala Met Xaa Trp Ser
1 5 10
<210> 379
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 379
Gly Trp Ile Ser Pro Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 380
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 380
Gly Trp Ile Ser Pro Lys Ala Asn Gly Gly Ser Thr Tyr Tyr Ala Asp
1 5 10 15
Ser Val Lys Gly
20
<210> 381
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 381
Gly Phe Thr Phe Ser Ser Tyr Ala Met Ser
1 5 10
<210> 382
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be G or S
<400> 382
Ser Val Ile Ser Ser Asp Gly Xaa Ser Thr Tyr Tyr Ala Asp Ser Val
1 5 10 15
Lys Gly
<210> 383
<211> 20
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be G or S
<400> 383
Ser Val Ile Ser Ser Lys Ala Asp Gly Xaa Ser Thr Tyr Tyr Ala Asp
1 5 10 15
Ser Val Lys Gly
20
<210> 384
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa can be S, G or H
<400> 384
Gly Tyr Ser Phe Thr Ser Tyr Trp Ile Xaa
1 5 10
<210> 385
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa can be R, I or S
<400> 385
Gly Xaa Ile Tyr Pro Gly Asp Ser Asp Thr Arg Tyr Ser Pro Ser Phe
1 5 10 15
Gln Gly
<210> 386
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be A or Y
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa can be I or M
<400> 386
Gly Tyr Thr Phe Thr Ser Tyr Xaa Xaa His
1 5 10
<210> 387
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa can be G or Y
<400> 387
Gly Trp Ile Asn Pro Xaa Asn Gly Asn Thr Asn Tyr Ala Gln Lys Phe
1 5 10 15
Gln
<210> 388
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa can be N or Y
<400> 388
Gly Gly Ser Ile Ser Ser Gly Xaa Tyr Tyr Trp Ser
1 5 10
<210> 389
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 389
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 390
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 390
Gly Phe Thr Phe Ser Ser Tyr Gly Met His
1 5 10
<210> 391
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 391
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Ala Lys
1 5 10 15
Gly
<210> 392
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 392
Gly Phe Thr Phe Ser Ser Tyr Ala Met His
1 5 10
<210> 393
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 393
Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 394
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 394
Gly Phe Thr Phe Asp Asp Tyr Ala Met His
1 5 10
<210> 395
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 395
Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys
1 5 10 15
Gly
<210> 396
<211> 270
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 396
Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys
1 5 10 15
Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser
20 25 30
Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg
35 40 45
Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr
50 55 60
Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu
65 70 75 80
Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe
85 90 95
Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser
100 105 110
Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr
115 120 125
Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu
130 135 140
Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu
145 150 155 160
Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly
165 170 175
Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe
180 185 190
Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys
195 200 205
Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His
210 215 220
Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile
225 230 235 240
Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu
245 250 255
Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr
260 265 270
<210> 397
<211> 165
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 397
Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu Ser
1 5 10 15
Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr
20 25 30
Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys Val
35 40 45
Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly Asp
50 55 60
Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp
65 70 75 80
Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys
85 90 95
Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Arg
100 105 110
Ser Phe Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe
115 120 125
Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr Ser
130 135 140
Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile His
145 150 155 160
His His His His His
165
<210> 398
<211> 639
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 398
gacatccaga tgacccagtc cccctcttct ctgtctgcct ctgtgggcga cagagtgacc 60
atcacctgta aagcaagtca gaatattaat aaacacttag actggtatca gcagaagcct 120
ggcaaggctc ccaagctgct gatctacttt acaaacaatt tacaaactgg cgtgccttcc 180
agattctccg gctctggctc tggcaccgat ttcaccctga ccatctcctc cctccagcct 240
gaggatttcg ccacctacta ctgctttcag tataaccagg ggtggacctt tggcggcgga 300
acaaaggtgg agatcaagcg tacggtggct gcaccatctg tcttcatctt cccgccatct 360
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600
agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639
<210> 399
<211> 1350
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 399
gaggtgcagc tggtggagtc tggcggcgga ctggtgcagc ctggcggctc tctgagactg 60
tcttgtgccg cctccggctt caccttcagt tcctactgga tgtactgggt gaggcaggcc 120
cctggcaagg gcctggagtg ggtggccgcc attactccta atgccggtga ggactactat 180
ccagagtctg tgaaaggccg gttcaccatc tccagggaca acgccaagaa ctccctgtac 240
ctccagatga actccctgag ggccgaggat accgccgtgt actactgtgc cagaggccat 300
tattactata ccagctattc gcttggatac tggggccagg gcaccctggt gaccgtgtcc 360
tctgcgtcga ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga agccgctggg 720
gcaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgttgcatg aggctctgca ctcccactac 1320
acgcagaaga gcctctccct gtccccggga 1350
<210> 400
<211> 639
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 400
gacatccaga tgacccagtc cccctcttct ctgtctgcct ctgtgggcga cagagtgacc 60
atcacctgta aagcaagtca gaatattaat aaacacttag actggtatca gcagaagcct 120
ggcaaggctc ccaagctgct gatctacttt acaaacaatt tacaaactgg cgtgccttcc 180
agattctccg gctctggctc tggcaccgat ttcaccctga ccatctcctc cctccagcct 240
gaggatttcg ccacctacta ctgctttcag tataacaatg ggtggacctt tggcggcgga 300
acaaaggtgg agatcaagcg tacggtggct gcaccatctg tcttcatctt cccgccatct 360
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600
agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639
<210> 401
<211> 1350
<212> DNA
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 401
gaggtgcagc tggtggagtc tggcggcgga ctggtgcagc ctggcggctc tctgagactg 60
tcttgtgccg cctccggctt caccttcagt tcctactgga tgtactgggt gaggcaggcc 120
cctggcaagg gcctggagtg ggtggcctcc attactccta atgccggtga ggactactat 180
ccagactctg tgaaaggccg gttcaccatc tccagggaca acgccaagaa ctccctgtac 240
ctccagatga actccctgag ggccgaggat accgccgtgt actactgtgc cagaggccat 300
tattactata ccagctattc gcttggatac tggggccagg gcaccctggt gaccgtgtcc 360
tctgcgtcga ccaagggccc atcggtcttc cccctggcac cctcctccaa gagcacctct 420
gggggcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgccct gaccagcggc gtgcacacct tcccggctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcagctt gggcacccag 600
acctacatct gcaacgtgaa tcacaagccc agcaacacca aggtggacaa gaaagttgag 660
cccaaatctt gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga agccgctggg 720
gcaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 900
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 960
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1020
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1200
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgttgcatg aggctctgca ctcccactac 1320
acgcagaaga gcctctccct gtccccggga 1350
<210> 402
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 402
Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Ala His Ser
<210> 403
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 403
Glu Val Gln Leu Val Glu Ser Gly Gly Asn Leu Glu Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Arg Ser
20 25 30
Ala Met Asn Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Gly Ser Gly Gly Arg Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Ser Ala Glu Asp Thr Ala Ala Tyr Tyr Cys
85 90 95
Ala Lys Asp Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Met Asp Val Trp
100 105 110
Gly His Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 404
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 404
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Phe 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 Ala 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 Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Ile Tyr Tyr Cys Gln Gln Ala Asn Ser Val Pro Ile
85 90 95
Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 405
<211> 445
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 405
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Phe
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Ser Gly Gly Lys Thr Phe Thr Asp Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 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
Thr Arg Ala Asn Tyr Gly Asn Trp Phe Phe Glu Val Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
210 215 220
Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser
325 330 335
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Val Ser Arg Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
435 440 445
<210> 406
<211> 218
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 406
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Glu Ser Val Ala Lys Tyr
20 25 30
Gly Leu Ser Leu Leu Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Arg Leu Leu Ile Phe Ala Ala Ser Asn Arg Gly Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Lys
85 90 95
Glu Val Pro Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
115 120 125
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
130 135 140
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
145 150 155 160
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
180 185 190
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
195 200 205
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 407
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 407
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ser Ala Ile Asp Gln Ser Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 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 Gln Lys Phe Met Gln Leu Trp Gly Gly Gly Leu Arg Tyr Pro
100 105 110
Phe Gly Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 408
<211> 212
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 408
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Glu Gly Met Gly Asp Lys Tyr Ala
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Arg Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gly Val Ile Gln Asp Asn Thr Gly Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala
100 105 110
Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn
115 120 125
Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val
130 135 140
Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu
145 150 155 160
Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser
165 170 175
Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser
180 185 190
Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro
195 200 205
Thr Glu Cys Ser
210
<210> 409
<211> 456
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 409
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Gly Ile Ala Asp Asp Phe Thr Ser Thr Tyr Tyr Ala Asp Pro Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 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 Leu Trp Met Met Asn Tyr Ala Gly Gly Leu Arg Tyr Pro
100 105 110
Phe Gly Tyr Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser
115 120 125
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr
130 135 140
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
145 150 155 160
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
165 170 175
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
180 185 190
Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile
195 200 205
Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val
210 215 220
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
225 230 235 240
Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
245 250 255
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
260 265 270
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
275 280 285
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
290 295 300
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
305 310 315 320
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
325 330 335
Leu Pro Ala Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
340 345 350
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
355 360 365
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
370 375 380
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
385 390 395 400
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
405 410 415
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
420 425 430
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
435 440 445
Ser Leu Ser Leu Ser Pro Gly Lys
450 455
<210> 410
<211> 212
<212> PRT
<213> Artificial Sequence
<220>
<223> Synthetic Construct
<400> 410
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln
1 5 10 15
Thr Ala Ser Ile Thr Cys Ser Gly Glu Arg Met Gly Asp Lys Tyr Ala
20 25 30
Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr
35 40 45
Arg Asp Thr Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60
Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met
65 70 75 80
Asp Glu Ala Asp Tyr Tyr Cys Gly Val Leu Lys Gln Asp Thr Gly Val
85 90 95
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala
100 105 110
Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn
115 120 125
Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val
130 135 140
Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu
145 150 155 160
Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser
165 170 175
Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser
180 185 190
Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro
195 200 205
Thr Glu Cys Ser
210

Claims (25)

1.一种特异性结合人IL-33的抗体或其抗原结合片段，其包含下列(i)至(vi)中任一：
(i)选自以下组的CDR-L1：根据Kabat编号的SEQ ID NO：20、37、190、193、257、258、259和260，
(ⅱ)选自以下组的CDR-L2：根据Kabat编号的SEQ ID NO：21、196、199、261、262、263和264，
(ⅲ)选自以下组的CDR-L3：根据Kabat编号的SEQ ID NO：22、38、208、265、26、267和268，
(ⅳ)选自以下组的CDR-H1：根据Kabat编号的SEQ ID NO：16、33、269、270和271，
(v)选自以下组的CDR-H2：根据Kabat编号的SEQ ID NO：17、34、168、171、174、180、202、205、211、214、217、220、223、226、229、232、235、272、273、274和275，及
(ⅵ)选自以下组的CDR-H3：根据Kabat编号的SEQ ID NO：18、35、114、119、122、127、130、133、136、139、142、145、148、153、156、159、177、187、276、277、278和279。
2.如权利要求1的抗体或其抗原结合片段，其包含SEQ ID NO：225的CDR-H1、CDR-H2和CDR-H3序列，及SEQ ID NO：207的CDR-L1、CDR-L2和CDR-L3序列。
3.如权利要求1-2任一项的抗体或其抗原结合片段，其包含
(i)包含根据Kabat编号的SEQ ID NO：20的CDR-L1，
(ⅱ)包含根据Kabat编号的SEQ ID NO：21的CDR-L2，
(ⅲ)包含根据Kabat编号的SEQ ID NO：208的CDR-L3，
(ⅳ)包含根据Kabat编号的SEQ ID NO：16的CDR-H1，
(v)包含根据Kabat编号的SEQ ID NO：226的CDR-H2，及
(ⅵ)包含根据Kabat编号的SEQ ID NO：18的CDR-H3。
4.如权利要求1至3中任一项的抗体或其抗原结合片段，其包含VL框架序列和VH框架序列，并且其中所述VL框架序列或VH框架序列的一或二者与其衍生自的人种系序列至少90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同，且其中所述VL框架序列衍生的人种系VL序列选自以下组：DPK9、DPK12、DPK18、DPK24、HK102_V1、DPK1、DPK8、DPK3、DPK21、Vg_38K、DPK22、DPK15、DPL16、DPL8、V1-22、Vλ共有序列、Vλ1共有序列、Vλ3共有序列、Vκ共有序列、Vκ1共有序列、Vκ2共有序列及Vκ3，且其中所述VH框架序列衍生的人种系VH序列选自以下组：DP54、DP47、DP50、DP31、DP46、DP71、DP75、DP10、DP7、DP49、DP51、DP38、DP79、DP78、DP73、VH3、VH5、VH1及VH4。
5.如权利要求1至4中任一项的抗体或其抗原结合片段，其包含VH和VL，所述VH包含与SEQ ID NO：225至少90％相同的氨基酸序列，所述VL包含与SEQ ID NO：207至少90％相同的氨基酸序列。
6.如权利要求1至5中任一项的抗体或其抗原结合片段，其包含VH和VL，所述VH包含SEQID NO：225的氨基酸序列，所述VL包含SEQ ID NO：207的氨基酸序列。
7.如权利要求1至6中任一项的抗体或其抗原结合片段，其包含Fc结构域且其中所述Fc结构域为IgA1、gA2、IgD、IgE、IgM、IgG1、IgG2、IgG3或IgG4的Fc结构域。
8.如权利要求7的抗体或其抗原结合片段，其中所述Fc为IgG1。
9.如权利要求1至8中任一项的抗体或其抗原结合片段，其包含重链和LC，所述HC包含与SEQ ID NO：244至少90％相同的氨基酸序列，且所述LC包含与SEQ ID NO：209至少90％相同的氨基酸序列。
10.如权利要求1至9中任一项的抗体或其抗原结合片段，其包含重链和LC，所述重链包含SEQ ID NO：244的氨基酸序列且所述LC包含SEQ ID NO：209的氨基酸序列。
11.一种抗体或其抗原结合片段，其包含由保藏于ATCC且具有ATCC登录编号为PTA-122724的质粒编码的VH序列及由保藏于ATCC且ATCC登录编号为PTA-122725的质粒编码的VL序列。
12.一种抗体或其抗原结合片段，其与如权利要求1至11中任一项的抗体或其抗原结合片段竞争结合人IL-33。
13.一种抗体或其抗原结合片段，其与下组之一或多者竞争结合人IL-33：7E8_嵌合体、9B3_嵌合体、9B3_嵌合体_huJseg、7E8CDR移植物、IL33-10、9B3CDR移植物、9B3_1、9B3_2A、9B3_2B、9B3_3、9B3_5、9B3_7 9B3_13、9B3_15、9B3_17、9B3_22、9B3_31V2、9B3_36、9B3_79、9B3_124、9B3_162、7E8H/9B3K、9B3_563、IL33-11、IL33-12、IL33-13、IL33-45、IL33-55、IL33-56、IL33-57、IL33-58、IL33-61、IL33-62、IL33-68、IL33-74、IL33-75、IL33-80、IL33-81、IL33-103、IL33-117、IL33-136、IL33-153、IL33-154、IL33-155、IL33-156、IL33-157、IL33-158、IL33-167、IL33-168、IL33-169、IL33-170、IL33-171、IL33-172、IL33-175、IL33-186、IL33-187、IL33-188、IL33-158-152、IL33-167-153、IL33-158LS及IL33-167LS。
14.如权利要求1至13中任一项的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段以约为或低于选自以下组的值的KD与人IL-33结合：约10nM、5nM、2nM、1nM、900pM、800pM、700pM、600pM、500pM、400pM、300pM、250pM、200pM、150pM、100pM、50pM、40pM、30pM、25pM、20pM、15pM、10pM、5pM及1pM。
15.如权利要求1至14中任一项的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段以约为或低于选自以下组的值的KD与食蟹猴IL-33结合：约10nM、5nM、2nM、1nM、900pM、800pM、700pM、600pM、500pM、400pM、300pM、250pM、200pM、150pM、100pM、50pM、40pM、30pM、25pM、20pM、15pM、13pM、10pM、5pM及1pM。
16.如权利要求1至15中任一项的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段与食蟹猴IL-33结合的KD是在与人IL-33结合的KD的10倍之内。
17.如权利要求1至16中任一项的抗体或其抗原结合片段，其中所述抗体或其抗原结合片段与活性IL-33结合的KD低于其与无活性IL-33结合的KD。
18.如权利要求1至17中任一项的抗体或其抗原结合片段，其中在人体中终末半衰期为至少约31天。
19.一种分离的核酸分子，其包含：
(i)一或多个编码如权利要求1至18中任一项的抗体或其抗原结合片段的核苷酸序列；或者
(ⅱ)如SEQ ID NO：398、399、400和401之一或多者所示的核酸序列；或者
(ⅲ)保藏于ATCC且具有登录编号PTA-122724或登录编号PTA-122725的核酸分子的编码序列。
20.一种载体，其包含如权利要求19的核酸分子。
21.一种宿主细胞，其包含如权利要求19的核酸分子或如权利要求20的载体。
22.一种制备抗体或其抗原结合片段的方法，其包含在所述抗体或其抗原结合片段被权利要求21的宿主细胞表达的条件下培养所述宿主细胞。
23.一种药物组合物，其包含如权利要求1至18中任一项的抗体或其抗原结合片段及药物上可接受的运载体或赋形剂。
24.一种治疗医学病况的方法，包含向需要治疗医疗病况的对象施用治疗有效量的权利要求1至18中任一项的抗体或其抗原结合片段，或权利要求23的药物组合物。
25.如权利要求24的方法，其中所述医学病况选自以下组：炎性肠病、过敏症、过敏性鼻炎、过敏性结膜炎、春季型角膜结膜炎、季节性过敏、宠物过敏、哮喘、食物过敏、花生过敏、特应性皮炎、慢性鼻窦炎伴鼻息肉(CRSwNP)、过敏性鼻炎、支气管炎、慢性阻塞性肺病(COPD)、呼吸系统疾病病毒性恶化、儿童和成人的病毒感染(呼吸道合胞病毒(RSV)、鼻病毒、流感)、荨麻疹、嗜酸性粒细胞食道炎、慢性纤维化、肝纤维化、非酒精性脂肪性肝炎(NASH)、慢性肾脏病、特发性肺纤维化(IPF)、硬皮病、系统性硬化症、急性肾损伤、败血症、胰腺炎、1型糖尿病、移植物抗宿主病(GVHD)、组织移植、阿兹海默氏症、类风湿性关节炎：肠易激症候群(IBS)、克罗恩氏病、溃疡性结肠炎、多发性硬化症、牛皮癣、乳糜泻及雷诺氏病或现象。
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