抗IL-33抗体及其组合物、方法及用途与流程

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(coyleetal.,1999,j.exper.med190(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(chuetal.,2013,j.allergyclin.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(haraetal.,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(chronicrhinosinusitiswithnasalpolyps)(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,currentopinioninimmunology31:31-37；molofskyetal..2015,immunity42(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(molofskyetal.,2015,immunity42(6):1005-1019；rivelleseetal,2014,eur.j.immunol.44(10):3045-3055；suzukawaetal.,2008,j.immunology181(9):5981-5989；voccaetal.immunobiology220(8):954-963；maieretal.,2014,j.immunology193(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；molofskyetal.,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。技术实现要素：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：seqidno：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：seqidno：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：seqidno：20、37、190、193、257、258、259和260，(ⅱ)选自以下组的cdr-l2：seqidno：21、196、199、261、262、263和264，(ⅲ)选自以下组的cdr-l3：seqidno：22、38、208、265、26、267和268，(ⅳ)选自以下组的cdr-h1：seqidno：16、33、269、270和271，(v)选自以下组的cdr-h2：seqidno：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：seqidno：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：seqidno：257、258、259和260，(ⅱ)选自以下组的cdr-l2：seqidno：261、262、263和264，(ⅲ)选自以下组的cdr-l3：seqidno：265、266、267和268，(ⅳ)选自以下组的cdr-h1：seqidno：269、270和271，(v)选自以下组的cdr-h2：seqidno：272、273、274和275，(ⅵ)选自以下组的cdr-h3：seqidno：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seqidno：257，(ⅱ)cdr-l2，其包含seqidno：261，(ⅲ)cdr-l3，其包含seqidno：265，(ⅳ)cdr-h1，其包含seqidno：269，(v)cdr-h2，其包含seqidno：272，(ⅵ)cdr-h3，其包含seqidno：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seqidno：258，(ⅱ)cdr-l2，其包含seqidno：262，(ⅲ)cdr-l3，其包含seqidno：266，(ⅳ)cdr-h1，其包含seqidno：270，(v)cdr-h2，其包含seqidno：273，(ⅵ)cdr-h3，其包含seqidno：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seqidno：259，(ⅱ)cdr-l2，其包含seqidno：263，(ⅲ)cdr-l3，其包含seqidno：267，(ⅳ)cdr-h1，其包含seqidno：271，(v)cdr-h2，其包含seqidno：274，(ⅵ)cdr-h3，其包含seqidno：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seqidno：260，(ⅱ)cdr-l2，其包含seqidno：264，(ⅲ)cdr-l3，其包含seqidno：268，(ⅳ)cdr-h1，其包含seqidno：271，(v)cdr-h2，其包含seqidno：275，(ⅵ)cdr-h3，其包含seqidno：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seqidno：20，(ⅱ)cdr-l2，其包含seqidno：21，(ⅲ)cdr-l3，其包含seqidno：208，(ⅳ)cdr-h1，其包含seqidno：16，(v)cdr-h2，其包含seqidno：226，(ⅵ)cdr-h3，其包含seqidno：18。e11.e1至e10中任一项的抗体或其抗原结合片段，包含seqidno：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seqidno：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)cdrl1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)cdrl2中的1、2、3、4或5个取代成人vl种系序列的相应残基，(iii)cdrl3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)cdrh1中的1个取代成人种系vh序列的相应残基，(v)cdrh2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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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seqidno：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seqidno：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seqidno：5的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：5的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：5的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：5的食蟹猴il-33的结合kd相较于与seqidno：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hek293st2nfκb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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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seqidno：397的食蟹猴il-33的结合kd相较于与seqidno：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hek293st2nfκb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-captureself-interactionnanoparticlespectroscopyassay)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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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seqidno：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seqidno：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seqidno：398、399、400和401中的一或多者所示的核酸序列，如seqidno：399所示。e113.一种分离的核酸分子，其包含seqidno：400所示的核酸序列。e114.一种分离的核酸分子，其包含seqidno：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(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7e8fab结合的il-33的表面等离子共振痕迹。图1a显示大鼠7e8fab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7e8fab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7e8fab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(seqidno：225)和vl(seqidno：207)与人种系序列dp-54/jh4(seqidno：7)和dpk9/jk4(seqidno：11)的比对。图2b显示il33-167-153/il33-167ls的vh(seqidno：210)和vl(seqidno：91)与人种系序列dp-54/jh4(seqidno：7)和dpk9/jk4(seqidno：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il33-158lsfab的结合。图3b显示细胞因子与经固定的7e8fab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(wardetal.,1989nature341:544-546)，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birdetal.science242:423-426(1988)及hustonetal.,1988,proc.natl.acad.sci.usa85:5879-5883。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holligeretal,1993,.proc.natl.acad.sci.usa90:6444-6448；poljaketal.,1994,structure2:1121-1123)。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kabatetal.,1991,sequencesofproteinsofimmunologicalinterest,5thed.(高度可变区)；chothiaetal.,1989,nature342:877-883(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oxfordmolecular的abm抗体建模软件cdr的“接触”定义是基于maccallumetal.,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makabeetal.,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(northetal.,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(makabeetal.,2008,jbiol.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kabatcdr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kabatetal.,1991,sequencesofproteinsofimmunologicalinterest,5thed.publichealthservice,nationalinstitutesofhealth,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(gehealthcare，piscataway，nj)、荧光活化的细胞分选(facs)、octettm(fortébio，inc.，menlopark，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-layerinterferometry)，通常使用技术(octetqke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(kineticexclusionassay))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(flowcell)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biacoret200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biacoret200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seqidno：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seqidno：396的氨基酸112至270的重组型il-33c端结构域为代表性il-33活性c端形式，并被指定为seqidno：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seqidno：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(cohenetal.,2015,naturecommunications6:8327；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(cohenetal.,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seqidno：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seqidno：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seqidno：1的编号。在一些方面中，活性il-33包含含有seqidno：1的完全还原分子。在一些方面中，活性il-33包含含有seqidno：4的完全还原分子。在一些方面中，活性il-33包含含有seqidno：3的分子。在一些方面中，活性il-33包含含有seqidno：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seqidno：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seqidno：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、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seqidno：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。cdrh1：基于总体可用信息，用于cdrh1的广泛共有序列为seqidno：269。用于cdrh1的共有序列的进一步细化子集为seqidno：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cdrh1序列为26gf(t/e)f(s/e)(n/s)ywmy32(seqidno：270)。从9b3进行的cdrh1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cdrh1序列为seqidno：271。cdrh2：基于总体可用信息，用于cdrh2的广泛共有序列为seqidno：272。用于cdrh2的共有序列的进一步细化子集为seqidno：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cdrh2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(seqidno：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cdrh2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cdrh2序列为seqidno：274。用于优化的7e8，处理位置52和53处的abs偏好的共有cdrh2序列为seqidno：275。cdrh3：基于总体可用信息，用于cdrh3的广泛共有序列为seqidno：276。用于cdrh3的共有序列的进一步细化子集为seqidno：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cdrh3序列为99g(h/y)y(y/s)(y/h)(t/s/n)(s/a)ys(l/f)(g/s)y110(seqidno：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cdrh3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seqidno：279。cdrl1：基于总体可用信息，用于cdrl1的广泛共有序列为seqidno：257。用于cdrl1的共有序列的进一步细化子集为seqidno：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cdrl1序列为24(k/r)as(q/h)(n/s)i(n/s)(k/s)hld34(seqidno：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cdrl1序列为seqidno：260。cdrl2：基于总体可用信息，用于cdrl2的广泛共有序列为seqidno：261。用于cdrl2的共有序列的进一步细化子集为seqidno：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cdrl2序列为50f(t/a)(n/s)(n/s)lq(t/s)56(seqidno：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cdrl2序列为seqidno：264。cdrl3：基于总体可用信息，用于cdrl3的广泛共有序列为seqidno：265。用于cdrl3的共有序列的进一步细化子集为seqidno：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cdrl3序列为89(f/q)qy(n/y)(n/s/q/r)gwt96(seqidno：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cdrl3序列为seqidno：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seqidno：257、cdr-l2含有seqidno：261、cdr-l3含有seqidno：265、cdr-h1含有seqidno：269、cdr-h2含有seqidno：272且cdr-h3含有seqidno：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seqidno：258、cdr-l2含有seqidno：262、cdr-l3含有seqidno：266、cdr-h1含有seqidno：270、cdr-h2含有seqidno：273且cdr-h3含有seqidno：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seqidno：259、cdr-l2含有seqidno：263、cdr-l3含有seqidno：267、cdr-h1含有seqidno：271、cdr-h2含有seqidno：274且cdr-h3含有seqidno：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seqidno：260、cdr-l2含有seqidno：264、cdr-l3含有seqidno：268、cdr-h1含有seqidno：271、cdr-h2含有seqidno：275且cdr-h3含有seqidno：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seqidno：20、cdr-l2含有seqidno：21、cdr-l3含有seqidno：208、cdr-h1含有seqidno：16、cdr-h2含有seqidno：226且cdr-h3含有seqidno：18。在一些方面中，该抗体或其抗原结合片段包含seqidno：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seqidno：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seqidno：225至少90％相同的氨基酸序列。该vh可包含与seqidno：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seqidno：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seqidno：207至少90％相同的氨基酸序列。该vl可包含与seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：20、cdr-l2含有seqidno：21、cdr-l3含有seqidno：22、cdr-h1含有seqidno：16、cdr-h2含有seqidno：211且cdr-h3含有seqidno：18。在一些方面中，该抗体或其抗原结合片段包含seqidno：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seqidno：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seqidno：210至少90％相同的氨基酸序列。该vh可包含与seqidno：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seqidno：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seqidno：91至少90％相同的氨基酸序列。该vl可包含与seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：16的cdr-h1，包含seqidno：226的cdr-h2和包含seqidno：18的cdr-h3；和/或(ii)下列轻链cdr序列：包含seqidno：20的cdr-l1、包含seqidno：21的cdr-l2和包含seqidno：208的cdr-l3。在某些实施方案中，在cdr-l1中做出相对于seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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seqidno：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alaserleuile,valarglyslysarg,glnasngln；hismetleu,ileaspgluphemet,leu,tyrcysserserthr；glyglnasnthrser,valgluasptrptyrglyprotyrtrp,phehisasn,glnvalile,leuileleu,valpro-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(seqidno：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(townsendetal.,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：seqidno：257、261和265；或seqidno：258、262和266；或seqidno：259、263和267；或seqidno：260、264、268；或seqidno：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,“antibodyhumanizationbycdr移植物ing”,(2004)antibodyengineering,vol.248,methodsinmolecularbiologypp135-159；以及o’brienandjones,“humanizationofmonoclonalantibodiesbycdr移植物ing”,(2003)recombinantantibodiesforcancertherapy,vol.207,methodsinmolecularbiologypp81-100)。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：seqidno：269、272和276；或seqidno:270、273和277；或seqidno：271、274和278；或seqidno：271、275和278；或seqidno：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lo2004、和o'brienandjones2003)。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seqidno：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seqidno：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seqidno：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seqidno：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：seqidno：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：seqidno：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：seqidno：43、54和101。在一些方面中，该vl并非选自以下组的一或多者：seqidno：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(americantypeculturecollection,10801universityboulevard,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，budapesttreaty)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.commissionerofpatentsandtrademarks)依据35usc第122条及据此的监理规则(commissioner’srules)(包括37cfr1.14节，特别参考886og638(37c.f.r.section1.14withparticularreferenceto886og638))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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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、7e8cdr移植物、il33-10、9b3cdr移植物、9b3_1、9b3_2a、9b3_2b、9b3_3、9b3_5、9b3_79b3_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)seqidno：1至279。本发明提供多核苷酸，其包含如seqidno：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seqidno：398所示的核酸序列的多核苷酸。本发明提供包含如seqidno：399所示的核酸序列的多核苷酸。本发明提供包含如seqidno：400所示的核酸序列的多核苷酸。本发明提供包含如seqidno：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seqidno：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seqidno：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seqidno：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,amodelofevolutionarychangeinproteins-matricesfordetectingdistantrelationships.indayhoff,m.o.(ed.)atlasofproteinsequenceandstructure,nationalbiomedicalresearchfoundation,washingtondcvol.5,suppl.3,pp.345-358；heinj.,1990,unifiedapproachtoalignmentandphylogenespp.626-645methodsinenzymologyvol.183,academicpress,inc.,sandiego,ca；higgins,d.g.andsharp,p.m.,1989,cabios5:151-153；myers,e.w.andmullerw.,1988,cabios4:11-17；robinson,e.d.,1971,comb.theor.11:105；santou,n.,nes,m.,1987,mol.biol.evol.4:406-425；sneath,p.h.a.andsokal,r.r.,1973,numericaltaxonomytheprinciplesandpracticeofnumericaltaxonomy,freemanpress,sanfrancisco,ca；wilbur,w.j.andlipman,d.j.,1983,proc.natl.acad.sci.usa80:726-730。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5xssc、0.5％sds、1.0mmedta(ph8.0)的溶液中预先洗涤；在50℃至65℃，5xssc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0.2xssc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，ph6.5加750mm氯化钠、75mm柠檬酸钠；或(3)采用42℃的50％甲酰胺、5xssc(0.75m氯化钠、0.075m柠檬酸钠)、50mm磷酸钠(ph6.8)、0.1％焦磷酸钠、5xdenhardt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℃0.2xssc(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0.1xssc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sambrooketal.,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:thepolymerasechainreaction,mullisetal.eds.,birkauswerpress,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sambrooketal.,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pbssk+)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wo87/04462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(microprojectilebombardment)；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(marksetal.,1992,bio/technology,10:779-783；barbasetal.,1994,procnat.acad.sci,usa91:3809-3813；schieretal.,1995,gene,169:147-155；yeltonetal.,1995,j.immunol.,155:1994-2004；jacksonetal.,1995,j.immunol.,154(7):3310-9；hawkinsetal.,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(irritablebowelsyndrome)(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'spharmaceuticalsciences,18thedition,a.gennaro,ed.,mackpublishingco.,easton,pa,1990；及remington,thescienceandpracticeofpharmacy,20thed.,mackpublishing,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:thescienceandpracticeofpharmacy20thed.,2000,lippincottwilliamsandwilkins,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(packageinsert)，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(seqidno：1)，氨基酸s112-t270(r&dsystems，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(seqidno：2)结合，该人st2-fc(seqidno：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(seqidno：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(clontechlaboratoriesinc.ofmountainview，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ⅱaoligo(clontechlaboratoriesinc.)与superscriptⅱtm逆转录酶(clontechlaboratoriesinc.)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smartⅱaoligo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gotaqgreen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(seqidno：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(seqidno：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(seqidno：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hek293st2nfκb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hek293st2nfκb报告子细胞分析中il-33(mm2)活性的抑制亦使用hek293st2nfκb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(seqidno：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hek293st2nfκb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(seqidno：8)的人dp-54框架区(vh3子群；seqidno：7)上，而将轻链cdr移植到具有jk4区段(seqidno：12)的人dpk9框架区(vki子群；seqidno：11)上。将人源化vh区接合到效应子功能突变的人igg1恒定区(seqidno：9)，然后亚克隆入专有表达载体中以产生cdr移植的重链seqidno：92(7e8cdr移植物)、99(9b3cdr移植物)、104(12f9cdr移植物)和109(30b11cdr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seqidno：112。将人源化vl区与人κ恒定区(seqidno：13)融合，然后亚克隆入专有表达载体以产生cdr移植的轻链seqidno：93(7e8cdr移植物)、seqidno：100(9b3cdr移植物)、seqidno：105(12f8cdr移植物)和seqidno：110(30b11cdr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(seqidno：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-33cdr移植的7e8、9b3、12f9和30b11在实施例1所描述的hek293st2nfκb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0.024nmic50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(0.278nmvs0.028nmic50)(表7、表4)。表7:通过cdr移植的il-33抗体在hek293st2nfκb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st2nfκb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st2nfκb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hek293st2nfκb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hek293st2nfκb分析中抑制il-33的中和。针对0.1ng/mlil-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0.0018-30nmil-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10mmdtt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hek293st2nfκb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(seqidno：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hek293st2nfκb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hek293st2nfκb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(arunlakshanaandschild，1959)。在nfκbst2报告子分析中，在多个7e8cdr移植物(seqidnos：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(mesoscalediagnostics，rockville，md)测量ifnγ的水平。在人pbmc中，相似于在hek293st2nfκb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，7e8cdr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10.7e8cdr移植物在hek293st2nfκb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hek293st2nfkb报告子细胞或人pbmc上对il-33(mm2)或野生型il-33(r&dsystems)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9il-33抗体对人和食蟹猴il-33的结合亲和力使用biacoret200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-33igg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(seqidno：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7e8fab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7e8fab滴定系列注射在传感器表面上，所测得的7e8fab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ph7.4，预期溶液中的带正电荷的fab(pi8.52)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pi5.2，il-33wt为pi4.45，生物素化的il-33mm2为pi5.48)对带负电荷的cm5传感器芯片具排斥力(drakeetal.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，gehealthcare)将具有野生型半胱氨酸残基的重组il33蛋白(seqidno：4)与cm5传感器芯片(目录编号br100530，gehealthcare)共价偶联。以非还原的il-33和在固定之前已经在室温以3mmdtt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10mmhepesph7.4、0.15mnacl、3mmedta、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fab7e8进行系列滴定。监控解离3600秒。在37℃，在biacoret200仪器(gehealthcare)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biacoret200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7e8fab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7e8fab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7e8fab与人il-33结合的亲和力表12.通过表面等离振子共振测量7e8fab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7e8fab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7e8fab对huil-33(mm2)(seqidno：3)和huil33wt(seqidno：4)的结合亲和力。在使用前将huil33wt在3mmdtt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7e8fab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7e8fab从15fm至0.25nm滴定到固定浓度为4pm和100pmhuil-33(mm2)中，并将其从244fm至2nm滴定到固定浓度为100pm和500pmhuil-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(townsendetal.,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7e8cdr位置中人氨基酸的掺入频率表14.基于seqidno：94和seqidno：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cdrh3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-racepcr制备并在rocheflx+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9b3cdr-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cdrh3序列组内的cdrh3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cdrh3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seqidno：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(seqidno：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hek293st2nfκb报告分析中抑制il-33信号传导。在与125nmil-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cdrh3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(etal.,2010,mabs4(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(xuetal.,2013,proteineng.des.select.26(10):663-70；)、杆状病毒颗粒(etal.,2012,mabs4:753-60)或带负电荷的物质，例如dna、胰岛素和肝素(tilleretal.,2008,j.immunol.methods329(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(tilleretal.,2008)。将在pbs中的5μg/ml胰岛素或10μg/ml单链或双链dna涂层在nuncmaxisorpelisa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/1mmedta)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igg11:5000一起孵育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nuncmaxisorpelisa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/mlhrp-山羊抗人抗体(jacksonimmunoresearchcatno.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/mlab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cdrh1或cdrh3的影响最小。9b3的人il-33(mm2)阻断活性低于7e8的(在hek293st2nfκb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9b3cdrh2替代7e8cdrh2导致对食蟹猴il-33的效力大为损失(0.131nmic50降至3.46nm)，相似地，以9b3cdrh3替代7e8cdrh3导致对食蟹猴il-33的效力损失(7.65nm)。因此，cdrh2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cdrh3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-mannanetal.,2015,mabs7(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(seqidno：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seqidno：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cdrh2取代7e8的cdrh2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cdrh2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cdrh2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cdrh2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hek293st2nfκb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cdrh1(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hek293st2nfκb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5pmil-33相比较，全血应答所需的il-33的浓度较高(100pm)。相似于在hek293st2nfκb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cdrh1(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(cheliusetal.,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cdrh2和cdrl3变体与杆状病毒、dna和胰岛素结合表21.cdr移植的7e8的cdrh2和cdrl3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.,etal.(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7e8cdr移植物的二倍的基于细胞的活性(在hek293st2nfκb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cdrh2和cdrl3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cdrh2和cdrl3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(seqidno：237)在fc中含有突变l234al235a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(seqidno：238)含有l234al235a和g237a突变，c端赖氨酸缺失和双突变m432ln438s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(zalevskyetal.,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(seqidno：241、seqidno：209)、il33-167-153(seqidno：242、seqidno：93)、il33-158ls(seqidno：244seqidno：209)和il33-167ls(seqidno：245、seqidno：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(seqidno：244、seqidno：209)和il33-167ls(seqidno：245、seqidno：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(seqidno：227、seqidno：209)和il33-167(seqidno：212、seqidno：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(seqidno：241、seqidno：209)、il33-167-153(seqidno：242、seqidno：93)、il33-158ls(seqidno：244、seqidno：209)和il33-167ls(seqidno：245、seqidno：93)显示出在hek293st2nfκb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7e8cdr移植物(seqidno：92、seqidno：93)。表25.在hek293st2nfκb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(seqidno：244、seqidno：209)和il33-167ls(seqidno：245、seqidno：93)显示出在人pbmc中的il-33(mm2)中和作用相似于亲本抗体7e8cdr移植物(seqidno：92、seqidno：93)。表26.在人pbmc中cdr-移植的7e8的优化变体的中和活性抗体hcseqnolcseqnoic50(nm)±sem(n)il33-158ls2442090.0014±0.0001(4)il33-167ls245930.0011±0.0002(4)7e8cdr移植物92930.0014±0.0004(4)表26:中和pbmc中ifn-γ的产生。用16.67pmil-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(seqidno：244、seqidno：209)和il33-167ls(seqidno：245、seqidno：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7e8cdr移植物(seqidno：92、seqidno：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(seqidno：244、seqidno：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hek293st2nfκb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biacoret200仪器(gehealthcare)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，gehealthcare)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-33fab158ls、167ls和亲本fab7e8的滴定系列并监测解离3600秒。稀释和运行缓冲剂为hbs-ep+(10mmhepesph7.4、0.15mnacl、3mmedta、0.05％p-20)。将所得的传感图数据拟合在biacoret200评估软件1.0版(gehealthcare)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7e8cdr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biacoret-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(seqidno：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(seqidno：254，seqidno：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microcalvp-capillarydsc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/mledta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/mledta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/kgil33-158ls相比较，在施用14.3mg/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(allometricscaling)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(brekkeandsandlie(2003),naturereviews,vol2,pp52-62)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,etal.(chapter5.applicationofmechanisticpharmacokinetic-pharmacodynamicmodelingtowardsthedevelopmentofbiologics.in:kumars,kumarsinghs,editors.developabilityofbiotherapeutics:computationalapproaches.crcpress；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(seqidno：287(hc)和seqidno：288(lc))并衍生自wo2016077381的10c12.38.h6.87y.581igg4(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seqidno：306(hc)和seqidno：307(lc)组成。为了取得用于表达的核苷酸序列，使用vectornti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seqidno：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seqidno：306具有三个不同处，且在此三个密码子被修饰以编码wo2016077381的seqidno：306的恒定区。将编码前导序列seqidno：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37igg1抗体il33-244是基于ape04909，该ape04909被公开为wo2015/106080的seqidno：136和seqidno：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seqidno：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38il33-248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wo2015/099175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/lcm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39igg1抗体il33-312是根据wo16156440的33_640087-7b(seqidno：615和seqidno：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(seqidno：623和seqidno：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hek293st2nfκb报告分析中测试抗体il33-158ls(seqidno：244、seqidno：209)、il33-167ls(seqidno：245、seqidno：93)、il33-265(seqidno：403、seqidno：404)和il33-310(seqidno：405、seqidno：406)对人il-33和食蟹猴il-33的中和作用(表40)。il33-158ls(seqidno：244seqidno：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(seqidno：244、seqidno：209)对野生型人il-33和食蟹猴il-33(seqidno：397)具相似的中和效力(食蟹猴ic50：人ic50比率为4.2)。il33-167ls(seqidno：245、seqidno：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(seqidno：403、seqidno：404)和il33-310(seqidno：405、seqidno：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hek293st2nfκb报告子分析中测试il33-158ls(seqidno：244、seqidno：209)、il33-310(seqidno：405、seqidno：406)、il33-312(seqidno：407、seqidno：408)和il33-313(seqidno：409、seqidno：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(seqidno：244、seqidno：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hek293st2nfkb报道子细胞分析中人和食蟹猴il-33的中和表41.在hek293st2nfkb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biacoret200仪器(gehealthcare)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，gehealthcare)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，gehealthcare)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-33fab158ls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-33fab158ls、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+(10mmhepesph7.4、0.15mnacl、3mmedta、0.05％p-20)。将所得的传感图数据拟合在biacoret200评估软件1.0版(gehealthcare)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il33-0310igg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il33fab158ls、167ls、il33-265和抗il33igg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(seqidno：244seqidno：209)的fab与野生型人il-33和食蟹猴il-33(seqidno：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(seqidno：245，seqidno：93)显示出与猴子il-33和人il-33的亲和力同样接近。il33-265(seqidno：403、seqidno：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fab158ls、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(seqidno：227、seqidno：209)、il33-158ls(seqidno：244、seqidno：209)和il33-312(seqidno：407、seqidno：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-captureself-interactionnanoparticlespectroscopy；liuetal.,2014,mabs6:483-92)。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(liuetal.,2014,mabs6:483-92)。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>patentinversion3.5<210>1<211>159<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>1serilethrglyileserproilethrglutyrleualaserleuser151015thrtyrasnaspglnserilethrphealaleugluaspglusertyr202530gluiletyrvalgluaspleulyslysaspglulyslysasplysval354045leuleusertyrtyrgluserglnhisproserasngluserglyasp505560glyvalaspglylysmetleumetvalthrleuserprothrlysasp65707580phetrpleuhisalaasnasnlysgluhisservalgluleuhislys859095cysglulysproleuproaspglnalaphephevalleuhisasnmet100105110hisserasncysvalserpheglucyslysthraspproglyvalphe115120125ileglyvallysaspasnhisleualaleuilelysvalaspserser130135140gluasnleucysthrgluasnileleuphelysleusergluthr145150155<210>2<211>553<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>2lyspheserlysglnsertrpglyleugluasnglualaleuileval151015argcysproargglnglylysprosertyrthrvalasptrptyrtyr202530serglnthrasnlysserileprothrglngluargasnargvalphe354045alaserglyglnleuleulyspheleuproalagluvalalaaspser505560glyiletyrthrcysilevalargserprothrpheasnargthrgly65707580tyralaasnvalthriletyrlyslysglnseraspcysasnvalpro859095asptyrleumettyrserthrvalserglyserglulysasnserlys100105110iletyrcysprothrileaspleutyrasntrpthralaproleuglu115120125trpphelysasncysglnalaleuglnglyserargtyrargalahis130135140lysserpheleuvalileaspasnvalmetthrgluaspalaglyasp145150155160tyrthrcyslyspheilehisasngluasnglyalaasntyrserval165170175thralathrargserphethrvallysaspgluglnglypheserleu180185190pheprovalileglyalaproalaglnasngluilelysgluvalglu195200205ileglylysasnalaasnleuthrcysseralacyspheglylysgly210215220thrglnpheleualaalavalleutrpglnleuasnglythrlysile225230235240thrasppheglygluproargileglnglnglugluglyglnasngln245250255serpheserasnglyleualacysleuaspmetvalleuargileala260265270aspvallysglugluaspleuleuleuglntyraspcysleualaleu275280285asnleuhisglyleuargarghisthrvalargleuserarglysasn290295300proserlysglucyspheilegluglyargmetaspprolyssercys305310315320asplysthrhisthrcysproprocysproalaprogluleuleugly325330335glyproservalpheleupheproprolysprolysaspthrleumet340345350ileserargthrprogluvalthrcysvalvalvalaspvalserhis355360365gluaspprogluvallyspheasntrptyrvalaspglyvalgluval370375380hisasnalalysthrlysproargglugluglntyrasnserthrtyr385390395400argvalvalservalleuthrvalleuhisglnasptrpleuasngly405410415lysglutyrlyscyslysvalserasnlysalaleuproalaproile420425430glulysthrileserlysalalysglyglnproarggluproglnval435440445tyrthrleuproproserargaspgluleuthrlysasnglnvalser450455460leuthrcysleuvallysglyphetyrproseraspilealavalglu465470475480trpgluserasnglyglnprogluasnasntyrlysthrthrpropro485490495valleuaspseraspglyserphepheleutyrserlysleuthrval500505510asplysserargtrpglnglnglyasnvalphesercysservalmet515520525hisglualaleuhisasnhistyrthrglnlysserleuserleuser530535540proglylyshishishishishishis545550<210>3<211>166<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>3metserilethrglyileserproilethrglutyrleualaserleu151015serthrtyrasnaspglnserilethrphealaleugluaspgluser20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gluservalthrgluglnaspserlysaspserthrtyrserleuser165170175serthrleuthrleuserlysalaasptyrglulyshislysvaltyr180185190alacysgluvalthrhisglnglyleuserserprovalthrlysser195200205pheasnargglyglucys210<210>90<211>123<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>90hissergluvalglnleuvalgluserglyglyglyleuvalglnpro151015glyglyserleuargleusercysalaalaserglyphethrpheser202530sertyrtrpmettyrtrpvalargglnalaproglylysglyleuglu354045trpvalalaserilethrproasnglyglyasnthrtyrtyrproasp505560servallysglyargphethrileserargaspasnalalysasnser65707580leutyrleuglnmetasnserleuargalagluaspthralavaltyr859095tyrcysalaargglyhistyrtyrtyrthrsertyrserleuglytyr100105110trpglyglnglythrleuvalthrvalserser115120<210>91<211>106<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>91aspileglnmetthrglnserproserserleuseralaservalgly151015aspargvalthrilethrcyslysalaserglnasnileasnlyshis202530leuasptrptyrglnglnlysproglylysalaprolysleuleuile354045tyrphethrasnasnleuglnthrglyvalproserargphesergly505560serglyserglythraspphethrleuthrileserserleuglnpro65707580gluaspphealathrtyrtyrcyspheglntyrasnasnglytrpthr859095pheglyglyglythrlysvalgluilelys100105<210>92<211>453<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>92hissergluvalglnleuvalgluserglyglyglyleuvalglnpro151015glyglyserleuargleusercysalaalaserglyphethrpheser202530sertyrtrpmettyrtrpvalargglnalaproglylysglyleuglu354045trpvalalaserilethrproasnglyglyasnthrtyrtyrproasp505560servallysglyargphethrileserargaspasnalalysasnser65707580leutyrleuglnmetasnserleuargalagluaspthralavaltyr859095tyrcysalaargglyhistyrtyrtyrthrsertyrserleuglytyr100105110trpglyglnglythrleuvalthrvalserseralaserthrlysgly115120125proservalpheproleualaproserserlysserthrserglygly130135140thralaalaleuglycysleuvallysasptyrpheprogluproval145150155160thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe165170175proalavalleuglnserserglyleutyrserleuserservalval180185190thrvalproserserserleuglythrglnthrtyrilecysasnval195200205asnhislysproserasnthrlysvalasplyslysvalgluprolys210215220sercysasplysthrhisthrcysproprocysproalaprogluala225230235240alaglyalaproservalpheleupheproprolysprolysaspthr245250255leumetileserargthrprogluvalthrcysvalvalvalaspval260265270serhisgluaspprogluvallyspheasntrptyrvalaspglyval275280285gluvalhisasnalalysthrlysproargglugluglntyrasnser290295300thrtyrargvalvalservalleuthrvalleuhisglnasptrpleu305310315320asnglylysglutyrlyscyslysvalserasnlysalaleuproala325330335proileglulysthrileserlysalalysglyglnproargglupro340345350glnvaltyrthrleuproproserarggluglumetthrlysasngln355360365valserleuthrcysleuvallysglyphetyrproseraspileala370375380valglutrpgluserasnglyglnprogluasnasntyrlysthrthr385390395400proprovalleuaspseraspglyserphepheleutyrserlysleu405410415thrvalasplysserargtrpglnglnglyasnvalphesercysser420425430valmethisglualaleuhisasnhistyrthrglnlysserleuser435440445leuserproglylys450<210>93<211>213<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>93aspileglnmetthrglnserproserserleuseralaservalgly151015aspargvalthrilethrcyslysalaserglnasnileasnlyshis202530leuasptrptyrglnglnlysproglylysalaprolysleuleuile354045tyrphethrasnasnleuglnthrglyvalproserargphesergly505560serglyserglythraspphethrleuthrileserserleuglnpro65707580gluaspphealathrtyrtyrcyspheglntyrasnasnglytrpthr859095pheglyglyglythrlysvalgluilelysargthrvalalaalapro100105110servalpheilepheproproseraspgluglnleulysserglythr115120125alaservalvalcysleuleuasnasnphetyrproargglualalys130135140valglntrplysvalaspasnalaleuglnserglyasnserglnglu145150155160servalthrgluglnaspserlysaspserthrtyrserleuserser165170175thrleuthrleuserlysalaasptyrglulyshislysvaltyrala180185190cysgluvalthrhisglnglyleuserserprovalthrlysserphe195200205asnargglyglucys210<210>94<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>94gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>95<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>95gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalglupr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50<210>121<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>121gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095vallysglyhistyrsertyrsersertyrserileasptyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>122<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>122glyhistyrsertyrsersertyrserileasptyr1510<210>123<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>123gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095vallysglyhistyrsertyrsersertyrserileasptyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>124<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>124gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrsersertyrserileasptyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>125<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>125gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrsersertyrserileasptyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>126<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>126gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrthrsertyrserpheglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>127<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>127glyhistyrsertyrthrsertyrserpheglytyr1510<210>128<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>128gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrthrsertyrserpheglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>129<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>129gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyargtyrtyrtyrsersertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>130<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>130glyargtyrtyrtyrsersertyrserphealatyr1510<210>131<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>131gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyargtyrtyrtyrsersertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>132<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>132gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrasnsertyrserphealahistrpgly100105110glnglythrleuvalthrvalserser115120<210>133<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>133glyhistyrtyrtyrasnsertyrserphealahis1510<210>134<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>134gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrasnsertyrserphealahistrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>135<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>135gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrsersertyrserphealaasntrpgly100105110glnglythrleuvalthrvalserser115120<210>136<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>136glyhistyrsertyrsersertyrserphealaasn1510<210>137<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>137gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrsertyrsersertyrserphealaasntrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>138<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>138gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrsersertyrserpheglysertrpgly100105110glnglythrleuvalthrvalserser115120<210>139<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>139glyhistyrtyrtyrsersertyrserpheglyser1510<210>140<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>140gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrsersertyrserpheglysertrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>141<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>141gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhisphesertyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>142<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>142glyhisphesertyrthrsertyrserphealatyr1510<210>143<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>143gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhisphesertyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>144<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>144gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrsersertyrserphealaphetrpgly100105110glnglythrleuvalthrvalserser115120<210>145<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>145glyhistyrtyrtyrsersertyrserphealaphe1510<210>146<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>146gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrsersertyrserphealaphetrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>147<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>147gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>148<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>148glyhistyrtyrtyrthrsertyrserphealatyr1510<210>149<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>149gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>150<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>150gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>151<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>151gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserl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l354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrsersertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>159<211>12<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>159glyhistyrtyrtyrsersertyrserphealatyr1510<210>160<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>160gluvalglnleuvalgluthrglyglyglyleuvalglnproglyarg151015serleulysleusercysvalalaserglyphethrpheserasntyr202530trpmettyrtrpileargglnalaproglymetglyleuglutrpval354045serserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargasnasnalagluasnthrvaltyr65707580leuglnmetasnserleuargsergluaspthralathrtyrtyrcys859095alalysglyhistyrtyrtyrsersertyrserphealatyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaproglualaalagly225230235240alaproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>161<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>161gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrpheserasntyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>162<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>162gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrpheserasntyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>163<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>163gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>164<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>164gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserileasnasnaspglyglyasnthrtyrtyrleuaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>165<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>165gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrsertyrsersertyrserphesertyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>166<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>166gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrsertyrsersertyrserphesertyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>167<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>167gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproaspglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>168<211>17<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>168serilethrproaspglyglyasnthrtyrtyrproaspservallys151015gly<210>169<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>169gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproaspglyglyasnthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>170<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>170gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyaspthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>171<211>17<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>171serilethrproasnglyglyaspthrtyrtyrproaspservallys151015gly<210>172<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>172gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglyaspthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyvalgluval275280285hisasnalalysthrlysproargglugluglntyrasnserthrtyr290295300argvalvalservalleuthrvalleuhisglnasptrpleuasngly305310315320lysglutyrlyscyslysvalserasnlysalaleuproalaproile325330335glulysthrileserlysalalysglyglnproarggluproglnval340345350tyrthrleuproproserarggluglumetthrlysasnglnvalser355360365leuthrcysleuvallysglyphetyrproseraspilealavalglu370375380trpgluserasnglyglnprogluasnasntyrlysthrthrpropro385390395400valleuaspseraspglyserphepheleutyrserlysleuthrval405410415asplysserargtrpglnglnglyasnvalphesercysservalmet420425430hisglualaleuhisasnhistyrthrglnlysserleuserleuser435440445proglylys450<210>173<211>121<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>173gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglygluthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserser115120<210>174<211>17<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>174serilethrproasnglyglygluthrtyrtyrproaspservallys151015gly<210>175<211>451<212>prt<213>artificialsequence<220><223>syntheticconstruct<400>175gluvalglnleuvalgluserglyglyglyleuvalglnproglygly151015serleuargleusercysalaalaserglyphethrphesersertyr202530trpmettyrtrpvalargglnalaproglylysglyleuglutrpval354045alaserilethrproasnglyglygluthrtyrtyrproaspserval505560lysglyargphethrileserargaspasnalalysasnserleutyr65707580leuglnmetasnserleuargalagluaspthralavaltyrtyrcys859095alaargglyhistyrtyrtyrthrsertyrserleuglytyrtrpgly100105110glnglythrleuvalthrvalserseralaserthrlysglyproser115120125valpheproleualaproserserlysserthrserglyglythrala130135140alaleuglycysleuvallysasptyrpheprogluprovalthrval145150155160sertrpasnserglyalaleuthrserglyvalhisthrpheproala165170175valleuglnserserglyleutyrserleuserservalvalthrval180185190proserserserleuglythrglnthrtyrilecysasnvalasnhis195200205lysproserasnthrlysvalasplyslysvalgluprolyssercys210215220asplysthrhisthrcysproprocysproalaprogluleuleugly225230235240glyproservalpheleupheproprolysprolysaspthrleumet245250255ileserargthrprogluvalthrcysvalvalvalaspvalserhis260265270gluaspprogluvallyspheasntrptyrvalaspglyval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