TW202302634A - 用於治療不正常子宮出血之IL-11或IL-11Ra抑制劑 - Google Patents
用於治療不正常子宮出血之IL-11或IL-11Ra抑制劑 Download PDFInfo
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Abstract
本發明係關於能夠結合至IL-11及/或IL-11RA且抑制或拮抗其作用之藥劑,該等藥劑用於治療及/或預防不正常子宮出血(其包含大量月經出血、長期出血、出血模式改變、痛經)以及原有疾病平滑肌瘤及子宮內膜異位;及該藥劑用於抑制月經之用途。此外,本發明提供新穎IL-11抗體。
Description
本發明提供呈介白素-11 (IL-11)及/或介白素-11受體α (IL-11RA)之抑制劑及拮抗劑形式之藥劑,包括用於治療及/或預防不正常子宮出血之異位抑制劑及拮抗劑。本發明提供呈抗體、片段及其衍生物、抗體、模擬物、核酸、適體或小分子形式之抑制劑或拮抗劑。本發明亦提供用於發現此類藥劑之分析及篩選技術。
此外,本發明提供結合至人類介白素-11 (IL-11)之經分離之抗體或其抗原結合片段;包含該等經分離之抗體或其抗原結合片段之醫藥組合物及組合;及該等經分離之抗體或其抗原結合片段之用途,其用於製造供治療或預防尤其哺乳動物之疾病,諸如(但不限於)不正常子宮出血(AUB),諸如大量月經出血及月經過多以及與AUB相關之痛經的醫藥組合物。
當女性經歷月經失血(MBL)變化或MBL程度或陰道出血模式與年齡匹配一般女性群體所經歷不同時,可診斷為不正常子宮出血(AUB) (國家婦女和兒童健康合作中心(National Collaborating Centre for Women's and Children's Health,NCCWCH):國家臨床卓越研究所(National Institute for Clinical Excellence,NICE)指南.CG44大量月經出血:完全指南.2007年1月24日)。正常月經以28±7天之週期出現,持續4±2天,平均MBL為40±20 ml。AUB呈現不正常月經出血模式範圍,包括不規則、大量或長期月經出血或出血模式改變。AUB可能與排卵或無卵性週期相關。所使用之術語為功能異常子宮出血(DUB)、月經過多(menorrhagia) (亦可能延長之規則間隔之異常大量月經出血)、子宮出血(不規則時間間隔之子宮出血,尤其預期月經期之間)及月經過多(metromenorrhagia) (兩者之組合)。AUB為一般從業者及婦科醫生所觀測到之最常見婦科疾病之一。
大量月經出血(HMB)在醫學文獻中廣泛定義為每次月經期80 ml或超過80 ml之月經失血(MBL) (Hallberg & Nilsson 1964, Hallberg等人(1966))。在本發明之含義中,HMB定義為每週期60 ml或超過60 ml之月經失血,例如每週期60至80 ml,尤其每週期超過80 ml。根據NICE,HMB出於臨床目的應定義為干擾女性身體、情緒、社交及物質生活品質且可單獨或與其他症狀組合發生的過度月經失血。任何干預應旨在改良生活品質量度。基於18個流行病研究,HMB之全球盛行率在4%至52%範圍內(Fraser等人,2009)。可藉由不同評定方法及各研究所使用之群體樣品考慮廣泛變量。已發現使用主觀評定之研究中之盛行率相比於直接量測MBL之研究中之9-11%始終更高。然而,估算30%女性罹患HMB似乎更具代表性(El-Hemaidi等人(2007))。HMB在處於生殖年齡範圍最末端之女性(亦即,接近或經歷閉經之青少年女童及婦女)中更普遍(Shapley等人(2004))。
可能診斷出潛在器質性病因,諸如良性子宮贅瘤,尤其子宮頸及子宮內膜息肉及平滑肌瘤、子宮腺肌症及宮頸及子宮內膜之惡性病。實際上,AUB及HMB之最顯著病因為平滑肌瘤且極大比例患有症狀性平滑肌瘤之女性遭受HMB。
大量月經出血經常為潛在出血病症,諸如血友病及馮威里氏病(von Willebrand's disease)、血小板病症/功能障礙(如格蘭茨曼氏血小板無力症(Glantzmann's thrombasthenia))及血小板減少症以及纖維蛋白溶酶原活化抑制劑1 PAI-1缺乏症之呈現症狀且可為女性之唯一出血症狀。儘管AUB及HMB之女性健康治療方法之較大影響仍為未滿足的醫療需求。
平滑肌瘤(亦已知為子宮纖維瘤或肌瘤)為生殖年齡女性之最常見良性婦科腫瘤。大致5-10%生殖年齡女性具有子宮纖維瘤症狀且需要治療。平滑肌瘤由肌肉細胞及子宮(uterus/womb)壁中及周圍之其他組織組成。其通常特徵在於大量月經出血、疼痛及整體症狀。症狀可在輕度至重度範圍內且具有影響女性日常生活之可能。平滑肌瘤為婦科疾病住院之主要病因之一且為子宮切除術之主要指示。子宮切除術為適於不希望保留其生育力或其子宮之女性的平滑肌瘤之唯一永久性治療。存在極小侵襲性手術干預,但與復發風險相關且需要額外干預。手術干預與併發症風險相關。當前醫學治療選項限於症狀短期減輕。缺乏長期使用當前藥物之持續效益之證據且顯著不良事件與一些治療相關。避免平滑肌瘤之手術或侵襲性程序需要有效的長期醫學治療選項,其仍為未滿足的醫療需求。
痛經(亦已知為疼痛性時間段或月經絞痛)為月經期間的疼痛。其通常在月經開始時發作。症狀典型地持續短於三天。疼痛通常位於骨盆或下腹部。其他症狀可包括背痛、腹瀉或噁心。(Osayande & Mehulic (2014))。其為最常見月經病症,盛行率視生殖年齡女性之16%與91%之間的研究而不同,嚴重疼痛為2%-29% (Ju等人(2014))。痛經經常歸因於諸如平滑肌瘤或子宮內膜異位(繼發性痛經)之潛在問題,後者佔所有痛經患者中70%之潛在原因(Janssen等人(2013))。此外,痛經更常見於月經大量、月經不規則或月經在十二歲之前開始之彼等女性中(Wikipedia: https://en.wikipedia.org/wiki/dysmenorrhea)。
歸因於月經週期結束時子宮內膜細胞之破壞,在月經期間釋放前列腺素及其他發炎介體(Lethaby等人(2013))。此等因子引起子宮肌層收縮(Wright & Solange (2003))。當子宮肌肉收縮時,其壓縮對子宮內膜組織之血液供應,轉而分解且進一步死亡。總之,此等收縮及對鄰近組織之最終暫時性氧剝奪對月經期間經歷之疼痛或「絞痛」負責。
當前治療選項為用於減輕原發性痛經之疼痛之非類固醇消炎藥(NSAID) (Marjoribanks等人(2015))。然而,其可具有噁心、消化不良、消化性潰瘍及腹瀉之副作用。
用於痛經之其他治療選項為組合口服避孕藥。然而,Wong等人(2009)之系統回顧描述含有較低劑量或中等劑量雌激素之組合口服避孕藥減輕與痛經相關之疼痛的有限證據。僅孕激素激素治療可能更有效,因為經常實現月經減少(Power等人(2007);Sachedina & Todd (2020))。然而,連續僅孕激素施用極經常造成滴血與不可預測的時間模式,亦限制生活品質及接受性。更佳及更可接受的治療選項為必需的,對於不願激素治療之彼等患者亦為必需的。
子宮內膜異位為藉由子宮外部,例如腹腔中存在子宮內膜組織(病變)所定義之慢性婦科病症,其誘導慢性發炎反應,導致慢性骨盆疼痛及不孕症(Giudice & Kao (2004))。在大致5-10%之女性群體之盛行率之情況下,估計子宮內膜異位在世界範圍內影響1.76億女性(Adamson等人(2010))。子宮內膜異位可嚴重影響女性生活。因為許多症狀如此嚴重以至於其一年平均臥床18天(Kjerulff等人(1996))。病變為激素反應性的且可能在月經期間出血。
患有子宮內膜異位之女性可罹患慢性、週期性骨盆疼痛(痛經)及/或非週期性骨盆疼痛,削弱生育力及在性交期間經受疼痛(性交困難)。其中,痛經經常報導為最常見症狀(Sinaii等人(2008))。其他症狀可包括腸胃紊亂、泌尿問題及疲乏。子宮內膜異位如何產生之最可接受的理論為在月經子宮內膜組織期間經由輸卵管脫落且植入腹膜表面上(Sampson (1927)、Giudice (2010))。在接受腹腔鏡診斷之前,通常用非類固醇消炎藥(NSAID)、類鴉片及/或憑經驗與組合口服避孕藥(COC)或孕激素一起治療患有子宮內膜異位之女性。COC之使用為仿單核准適應症外,而若干孕激素在一些國家已核准用於此適應症。其他基於激素之療法涉及促性腺素釋放激素(GnRH)類似物或拮抗劑。雖然基於激素之治療可減少病變生長,但其經常具有有限功效或潛在不良作用(DiVasta & Laufer (2013))。出於安全問題,不存在用GnRH類似物或GnRH拮抗劑長期連續治療之選項以及目前不使用疼痛抑制劑,例如布洛芬。手術移除病變為另一選項;然而,症狀典型地在兩年內在高達75%女性中復發(Olive (2002))。避免子宮內膜異位之手術或侵襲性程序需要有效長期醫學治療選項,其仍為未滿足的醫療需求。
對於治療諸如大量月經出血、月經過多及痛經之不正常子宮出血及諸如平滑肌瘤及子宮內膜異位之原有疾病存在未滿足的醫療需求。本發明之目標為提供實現前述疾病治療之手段。
介白素-11 (IL-11)及IL-11RA信號傳導之生理作用存在爭議討論。IL-11 (介白素11 UniProtKB-P20809)亦已知為AGIF,其描述為屬於多效性及冗餘細胞介素家族之基質細胞衍生之細胞介素,其使用其高親和力多次單元受體複合物(細胞介素之gp130家族)中之介白素6信號轉導子(IL6ST)/醣蛋白130 (gp130)轉導次單元。IL-11細胞介素展示刺激產生免疫球蛋白之B細胞之T細胞依賴性產生。亦發現,支持造血幹細胞及巨核細胞祖細胞之增殖且誘導巨核細胞成熟,導致血小板產量提高(Paul等人(1990))。IL-11亦促進肝細胞響應於肝損傷之增殖。結合至其受體IL-11RA或sIL-11RA及gp130活化促進細胞增殖之信號級聯(Harmegnies等人(2003))。信號傳導導致『信號轉導與轉錄活化因子3』(STAT3)之細胞內蛋白激酶及磷酸化之活化。對於IL11基因,已發現編碼不同同功異型物之替代剪接轉錄物變異體。
IL-11RA (介白素-11受體α(A),UniProtKB-Q14626)亦已知為CRSDA,其為介白素-11之受體,其為造血細胞介素受體家族之成員。在結構上,此特定受體與睫狀神經營養因子受體類似,因為兩者均含有細胞外區域,其具有由免疫球蛋白樣域及細胞介素受體樣域構成之2域結構。介白素6之受體系統(IL-6)、白血病抑制因子(LIF)、抑瘤素M (OSM)、睫狀神經營養因子(CNTF)、IL-11及心營養素1 (CT1)可利用用於起動信號傳遞之IL6ST。已發現此基因之多次替代剪接轉錄物變異體。在嚙齒動物中,人類IL-11RA存在兩種直系同源物IL-11RA1及IL-11RA2。膜結合IL-11RA受體可裂解,導致可溶性同功異型物sIL-11RA釋放。與膜結合IL-11RA/IL-11/IL6ST之經典信號傳導(順式信號傳導)相反,可溶性IL-11RA可介導反式信號傳導:在IL-11結合至受體之後,IL-11/sIL-11RA複合物結合至表現膜結合IL6ST之細胞且IL-11R/sIL-11RA/IL6ST複合物可引發與經典膜結合IL-11RA類似之細胞內信號傳導。對於反式信號傳導,在靶細胞中IL-11RA不表現為必需的(Lokau等人,2017)。
Cork等人2002描述,IL-11在子宮內膜中由基質細胞及上皮細胞兩者產生,且在蛻膜化期間基質細胞產量提高。另外,IL-11RA存在於人類子宮內膜中,貫穿月經週期受體表現變化極少。專利申請案WO9603143A1揭示,如馮威里氏病(von Willebrand's disease)、血液凝固疾病或具有無法解釋的出血時間延長之患者的出血病症應用IL-11細胞介素治療。Ragni等人2011報導患有輕度馮威里氏病之女性中之臨床試驗,該等女性經人類重組IL-11治療。治療使71%受試者中之月經出血嚴重程度降低。因此先前技術描述,月經出血可藉由施用IL-11減少。然而,先前技術中不存在證據表明不正常子宮出血或月經之治療係藉由拮抗或抑制IL-11或IL-11RA。
已展示,在若干其他失調因子中,在平滑肌瘤組織(Luo等人(2005))中IL-11表現上調,且其表現可能為平滑肌瘤之相關診斷性標記物或用於監測平滑肌瘤治療之診斷性標記物(WO2005/098041A2)。然而,文獻中無適應症,IL-11及/或IL-11RA之抑制或拮抗可為治療選項。
對於子宮內膜異位,關於IL-11及/或IL-11RA之表現之資料為有爭論的,一種研究描述與可育女性相比患有子宮內膜異位之不育女性之子宮內膜中IL-11及IL-11RA下調(Dimitriadis等人(2006))。然而,關於不孕症而非子宮內膜異位自身之發病機制論述此發現。此外,此發現不可在單獨非依賴型研究(Mikolajczyk等人(2006))中確認。另一研究描述患有子宮內膜異位及對照物之女性之腹膜液中分泌IL-11;然而,展示與子宮內膜異位或子宮內膜異位之疾病階段無相關性(Gazvani等人(2000))。此外,Gazvani等人陳述,不存在證據表明IL-11在骨盆子宮內膜異位之發病機制中之作用。
IL-11之功能阻斷抗體或拮抗IL-11之重組蛋白,例如衍生自IL-11RA之受體已描述於科學及專利文獻中,然而,未描述諸如大量月經出血、長期出血或出血模式改變以及痛經之不正常子宮出血及原有疾病平滑肌瘤及子宮內膜異位及月經的治療及/或預防。
用作IL-11信號傳導之拮抗劑之抑制性受體之實例描述於專利申請案WO 9959608中。用作IL-11及IL-11信號傳導之拮抗劑之抑制性抗體之實例描述於專利申請案WO2018109170、WO2018109174、WO2017103108、WO2019238882及WO2019238884中。藉由市售供應商,例如來自R&D Systems, Inc之MAB218及Mab418提供人類及鼠類IL-11之功能阻斷抗體。
本發明之一個態樣為非激素治療,藉由抑制介白素11 (IL-11)或其受體(IL-11RA)之作用及信號傳導預防或緩解患有或未患有平滑肌瘤之女性中諸如大量月經出血之不正常子宮出血、月經過多及痛經。本發明之另一態樣為平滑肌瘤之非激素治療、預防或緩解。本發明之另一態樣為子宮內膜異位之非激素治療、預防或緩解。本發明之另一態樣為痛經之非激素治療、預防或緩解。本發明之另一態樣為月經自身之非激素預防或緩解。
此外,本發明係關於新穎抗體或其抗原結合抗體片段,其對人類、小鼠、大鼠及/或獼猴IL-11蛋白呈現高親和力且其抑制IL-11介導之信號傳導。本發明之一些IL-11抗體或其抗原結合抗體片段抑制IL-11與IL-11Ra之相互作用及IL-11/IL-11Ra/gp130複合物形成。本發明之其他抗體或其抗原結合抗體片段抑制IL-11/IL-11Ra/gp130複合物形成且不會抑制IL-11與IL-11Ra之相互作用。此外,本發明係關於新穎雙特異性抗體或其抗原結合抗體片段,其對人類、小鼠、大鼠及/或獼猴IL-11蛋白質呈現高親和力且其抑制IL-11介導之信號傳導。另外,本發明之抗體或其抗原結合抗體片段不會結合至IL-2Ra。
本發明之高度較佳IL-11抗體描繪於表9及10且藉由其結構特徵表徵。
本發明亦涉及編碼本發明之抗體或其抗原結合片段之聚核苷酸、表現本發明之抗體或其抗原結合片段之細胞、用於產生本發明之抗體或其抗原結合片段之方法。本發明亦關於經分離之核酸序列,其中之每一者可編碼前述抗體或其抗原結合片段。本發明之核酸適用於重組產生抗體或抗原結合抗體片段。因此,本發明亦關於含有本發明之核酸序列之載體及宿主細胞。
本發明之抗體或其抗原結合抗體片段適用於治療、預防或緩解患有或不患有平滑肌瘤之女性中之不正常子宮出血,諸如大量月經出血、月經過多及痛經,治療、預防或緩解平滑肌瘤及子宮內膜異位。此外,本發明之抗體或其抗原結合抗體片段適用於預防或緩解月經。
本發明之組合物可用於治療性或防治性應用。因此,本發明包括一種醫藥組合物,其包含本發明抗體或其抗原結合片段及因此醫藥學上可接受之載劑或賦形劑。
此等及其他目的以根據本發明之獨立項之方法及手段滿足。附屬項與具體實施例相關。
應理解,本發明不限於所描述之裝置或組合物之特定組件部分或結構特徵或所描述之方法的方法步驟,因為此類裝置及方法可改變。亦應理解,本文所使用之術語僅出於描述特定實施例之目的,且並不意欲為限制性的。在彼此不同之依附技術方案中敍述某些方法的純粹實情並非表明此等方法不能有利地組合使用。申請專利範圍中之任何參考符號均不應視為限制範疇。此外應理解,倘若給定由數值定界之參數範圍,則認為範圍包括此等限制值。
此外應理解本文所揭示之實施例不意欲理解為彼此不相關之單獨實施例。用一個實施例論述之特徵意謂亦結合本文中展示之其他實施例揭示。若在一種情況下,具體特徵不用一個實施例而用另一實施例揭示,則熟習此項技術者將理解不必意謂該特徵不意欲用該另一實施例揭示。熟習此項技術者應瞭解,亦針對另一實施例揭示該特徵為本申請案之要旨,但僅出於清晰性之目的及為保持本說明書之長度可管理。應進一步理解,例如出於啟用目的本文所提及之先前技術文獻的內容以全文引用之方式併入,亦即例如當論述一種方法時其細節描述於該先前技術文獻中。此途徑用以保持本說明書之長度可管理。
定義除非另外定義,否則本說明書、圖式及申請專利範圍所用之所有科學及技術術語均具有其如一般熟習此項技術者通常所理解的含義。本文所提及之所有公開案、專利申請案、專利及其他參考案均以全文引用的方式併入本文中。在相矛盾之情況下,將以本說明書(包括定義)為準。若兩個或多於兩個以引用的方式併入之文獻相對於彼此包括衝突及/或不一致的揭示內容,則應以具有更遲有效日期之文獻為準。材料、方法和實例僅為例示性的,用並不意欲為限制性的。
除非另外陳述,否則用於本文檔(包括說明書及申請專利範圍)之以下術語具有下文給出之定義。
術語「包含(comprising)」、「包括(including)」、「含有(containing)」、「具有(having)」等應解讀為廣泛性或開放式且非限制性地。術語「包含」當用於本說明書中時包括「由……組成」。
除非上下文另外明確指示,否則單數形式,諸如「一(a/an)」或「該(the)」包括複數個參考物。因此,舉例而言,提及「單株抗體」包括相同或不同的單一單株抗體以及複數個單株抗體。同樣,提及「細胞」包括單一細胞以及複數個細胞。
如本文所使用,表述「約」或「~」係指在如藉由一般熟習此項技術者所測定之特定值的可接受之誤差範圍內的值,其將部分地視如何量測或測定值而定,亦即,量測系統之限制。舉例而言,根據此項技術中之實踐,「約」可意謂在1或大於1個標準偏差內。術語「約」亦用於指示,所討論之量或值可為所指定值或大致相同之一些其他值。該片語意欲傳達,類似值促成如本文所描述之等效結果或效果。在此上下文中,「約」可指高於及/或低於至多10%之範圍。每當針對某一分析或實施例指定術語「約」時,該定義對於特定情境為佔優勢的。
如本文所使用,術語「胺基酸」或「胺基酸殘基」典型地係指天然存在之胺基酸。本文使用一個字母代碼指代各別胺基酸。如本文所使用,「帶電荷胺基酸」為帶負電荷或帶正電荷之胺基酸。「帶負電荷胺基酸」為天冬胺酸(D)及麩胺酸(E)。「帶正電荷胺基酸」為精胺酸(R)、離胺酸(K)及組胺酸(H)。「極性胺基酸」為形成氫鍵作為供體或接受體之所有胺基酸。此等為所有帶電荷胺基酸及天冬醯胺酸(N)、麩醯胺酸(Q)、絲胺酸(S)、蘇胺酸(T)、酪胺酸(Y)及半胱胺酸(C)。「極性不帶電荷胺基酸」為天冬醯胺酸(N)、麩醯胺酸(Q)、絲胺酸(S)、蘇胺酸(T)、酪胺酸(Y)及半胱胺酸(C)。「兩性胺基酸」為色胺酸(W)、酪胺酸(Y)及甲硫胺酸(M)。「芳族胺基酸」為苯丙胺酸(F)、酪胺酸(Y)及色胺酸(W)。「疏水性胺基酸」為甘胺酸(G)、丙胺酸(A)、纈胺酸(V)、白胺酸(L)、異白胺酸(I)、脯胺酸(P)、苯丙胺酸(F)、甲硫胺酸(M)及半胱胺酸。「小胺基酸」為甘胺酸(G)、丙胺酸(A)、絲胺酸(S)、脯胺酸(P)、蘇胺酸(T)、天冬胺酸(D)及天冬醯胺酸(N)。
如本文所使用,術語「肽」、「多肽」及「蛋白質」可互換地使用,且係指由藉由肽鍵共價連接之胺基酸殘基構成之化合物。蛋白質或肽必須含有至少兩個胺基酸,且對於胺基酸之最大數目無限制。多肽包括包含藉由肽鍵彼此接合之兩個或多於兩個胺基酸之任何肽或蛋白質。如本文所使用,術語係指短鏈(其在此項技術中亦通常稱作例如肽、寡肽及寡聚物)及長鏈(其在此項技術中一般稱作蛋白質,其存在多種類型)。「多肽」包括例如生物活性片段、實質上同源多肽、寡肽、均二聚體、雜二聚體、多肽變異體、經修飾之多肽、衍生物、類似物、融合蛋白以及其他物質。多肽包括天然肽、重組肽、合成肽或其組合。
若未另外陳述或顯然不相容,則一般提及來自特定物種(諸如小鼠)之基因或蛋白質,將同樣地意謂來自人類之類似物。此尤其適用於生物標記之情形中。
術語「經分離」在應用於核酸、多肽、蛋白質或抗體時表示核酸、多肽、蛋白質或抗體基本上不含與天然狀態相關之其他細胞組分。其較佳為均質狀態。其可為乾燥或水溶液形式。純度及均質性典型地使用諸如聚丙烯醯胺凝膠電泳或高效液相層析之分析化學技術來測定。作為製劑中存在之主要物質的蛋白質、多肽或抗體經實質上純化。詳言之,經分離基因與側接該基因且編碼除相關基因外之蛋白質的開放閱讀框架分離。然而,經分離之多肽可例如經由適合連接子固定於例如珠粒或顆粒上。
術語「純化」表示核酸或蛋白質基本上在電泳凝膠中產生一個條帶。特定言之,其意謂核酸或蛋白質至少85%純、更佳至少95%純且最佳至少99%純。
如本文所使用,關於例如合成核酸分子或合成基因或合成肽之術語「合成」係指藉由重組方法及/或藉由化學合成方法產生的核酸分子或多肽分子。如本文所使用,藉由重組方式藉由使用重組DNA方法產生意謂用於表現由經選殖之DNA編碼之蛋白質的熟知分子生物學方法之使用。
「轉譯後修飾」(PTM)係指在天然條件下在蛋白質生物合成之後引入的肽或蛋白質之共價修飾。該術語包括(但不限於)糖基化、磷酸化、醯化、腺苷酸化、法呢基化、泛素化及硫酸化。轉譯後修飾可影響肽或蛋白質之活性。
「序列一致性」或「一致性百分比」為描述查詢序列與標靶序列之類似程度的數字,更精確而言,各序列中多少字元在比對之後一致。計算序列一致性之最流行工具為BLAST (基本局部比對檢索工具,https://blast.ncbi.nlm.nih.gov/),其進行序列對之間的比較,檢索具有局部類似性之區域。適合比對方法為此項技術中已知的,例如用於全域比對之尼德曼-翁施算法(Needleman-Wunsch algorithm),使用BLOSUM62矩陣,其中空隙開放罰分為11且空隙擴展罰分為1。隨後,可對比對相同殘基對進行計數且隨後除以比對之總長度(包括空隙、內部以及外部)以獲得一致性百分比值。
對於「類似性百分比」或「序列類似性」值,可使用與一致性百分比值相同的途徑,不同之處在於計數之物不為一致殘基對而是與非陰性BLOSUM62值(亦即,≥0)配對之比對殘基。
「同型對照」為不結合標靶但與識別標靶之參考抗體或片段具有相同類別及類型的抗體或片段。
若抗體或片段結合來自兩種或多於兩種不同物種之抗原,例如以1.0 E-07 M或更低、更佳低於1.0 E-08 M、甚至更佳低於1.0 E-09 M、甚至更佳低於1.0 E-10 M之
K D值,則抗體或片段稱為「交叉反應性(cross-reactive)」或「交叉反應性(cross reactive)」。
如本文中關於抗體所使用之術語「特異性結合」、「特定針對於/用於」或「尤其識別」意謂一種抗體,其識別特異性抗原,但實質上不識別或結合樣品中之其他分子:藉由實質性非特異性結合表徵的抗體將缺乏治療適用性,使得排除此等實施例。然而,如此項技術中已知,抗體或結合子之特異性結合未必排除結合至其他抗原/標靶分子之抗體或結合子。特異性結合至來自一種物質之抗原之抗體亦可結合至來自一或多種其他物質之抗原。此類跨物種反應性自身並不改變抗體特異性分類。
在一些情況下,可參考抗體、蛋白質或肽與第二化學物質之相互作用使用術語「特異性結合(specific binding/specifically binding)」來意謂相互作用視化學物質上特定結構(例如抗原決定子或抗原決定基)之存在而定;舉例而言,抗體識別且與特定蛋白質結構結合而非與一般蛋白質結合。若抗體對抗原決定基「A」具有特異性,則在含經標記「A」及該抗體之反應中,含抗原決定基A (或未經標記之游離A)之分子的存在將減少結合至該抗體之經標記A的量。
術語「脫靶結合」係指抗體結合與預期標靶不同之單獨蛋白質,例如標靶蛋白質家族之蛋白質的能力。脫靶結合可使用此項技術中已知之商業分析(諸如Retrogenix脫靶特徵分析)評估。簡言之,在含有HEK293細胞之微陣列上測試抗體,該等HEK293細胞獨立地表現數千個人類膜蛋白及分泌蛋白。抗體與潛在脫靶之結合必須藉由FACS使用過度表現潛在脫靶之細胞來證實。
術語「親和力」為此項技術之術語且描述結合子、抗體或抗體片段與標靶之間的結合強度。抗體及其片段對標靶之「親和力」可使用此項技術中熟知或本文所描述之技術,例如藉由ELISA、等溫滴定量熱法(ITC)、表面電漿子共振(SPR)、流式細胞量測術或螢光偏振分析測定。較佳地,親和力以解離常數
K D形式提供。
「解離常數」或「
K D」或「KD」具有莫耳單位[M]且對應於一半靶蛋白在平衡時佔據之結合子/抗體的濃度。解離常數愈小,結合子或抗體與其標靶之間的親和力愈高。
「半數最大有效濃度」或「EC50」或「EC
50」係指在指定培育時間之後誘導介於基線與最大值之間一半反應的藥物、抗體、片段、結合物或分子的濃度。在抗體結合之情形下,EC50因此反映半數最大結合所需之抗體濃度。若反曲點可藉由描述所應用藥物、抗體、片段、共軛物或分子濃度與信號之間的關係的劑量反應曲線之數學建模(例如非線性回歸)來測定EC50。舉例而言,若S形曲線遵循劑量-反應曲線,則可測定EC50。在反應為抑制的情況下,EC50稱為半數最大抑制濃度(IC50)。
術語「抗體」(Ab)係指特異性結合至特定抗原或免疫學上可與特定抗原反應之免疫球蛋白分子(例如(但不限於)人類IgG1、IgG2、IgG3、IgG4、IgM、IgD、IgE、IgA1、IgA2、小鼠IgG1、IgG2a、IgG2b、IgG2c、IgG3、IgA、IgD、IgE或IgM、大鼠IgG1、IgG2a、IgG2b、IgG2c、IgA、IgD、IgE或IgM、兔IgA1、IgA2、IgA3、IgE、IgG、IgM、山羊IgA、IgE、IgG1、IgG2、IgE、IgM或雞IgY)。抗體或抗體片段在輕鏈及重鏈可變域兩者中包含互補決定區(CDR,亦稱為高變區)。可變域之更高度保守部分稱為構架(FR)。如此項技術中所知,描繪抗體高變區之胺基酸位置/邊界可取決於情形及此項技術中已知之各種定義而變化。如本文所使用,免疫球蛋白胺基酸殘基之編號係根據Kabat等人之免疫球蛋白胺基酸殘基編號系統進行。天然重鏈及輕鏈之可變域各自包含四個FR區。各鏈中之三個CDR藉由FR區緊密結合在一起且與來自另一條鏈之CDR一起有助於形成抗體之抗原結合位點,參見Kabat, E. A.等人,「Sequences of Proteins of Immunological Interest (Natl. Inst. Health, Bethesda, MD), GPO Publ.」No165-462 (1987)。如本文所使用之術語抗體亦指抗體片段,除非以其他方式明確陳述。視各別情形而定,術語抗體亦可指具有免疫球蛋白樣功能之任何蛋白質結合分子。
術語「CDR」係指抗體之互補決定區。如此項技術中已知,互補決定區(CDR)為抗體及T細胞受體中之可變鏈的一部分。一組CDR構成互補位。CDR對抗原特異性之多樣性至關重要。通常存在六個可共同與抗原接觸之CDR。輕鏈之CDR為LCDR1、LCDR2及LCDR3。重鏈之CDR稱為HCDR1、HCDR2及HCDR3。HCDR3為最可變互補決定區(參見例如Chothia、Cyrus及Arthur M. Lesk.「Canonical structures for the hypervariable regions of immunoglobulins.」 Journal of molecular biology 196.4 (1987): 901-917.;Kabat, E. A.等人「Sequences of proteins of immunological interest. Bethesda, MD: US Department of Health and Human Services.」公共衛生處(Public Health Service),國立衛生研究院(National Institutes of Health) (1991): 103-511.)。
「恆定區」係指抗體分子中賦予效應功能之部分。重鏈恆定區可選自五種同型中之任一者:alpha (α)、delta (δ)、epsilon (ε)、gamma (g)或mu (μ)。
如本文所使用之術語「Fc域」、「Fc區」或「Fc部分」係指含有恆定區之至少一部分的抗體重鏈之C端區。該術語包括原生序列Fc區及變異體Fc區。舉例而言,人類IgG重鏈Fc區可自Cys226或自Pro230延伸至重鏈之羧基末端。
根據本發明之抗體或結合片段可經修飾以改變至少一種恆定區介導之生物效應功能。舉例而言,在一些實施例中,抗體可經修飾以相對於未經修飾之抗體降低或增強至少一種恆定區介導之生物效應功能,例如減少或改良與Fc受體(FcγR)之結合。可例如藉由在FcγR相互作用所必需之特定區域處使抗體之免疫球蛋白恆定區鏈段突變來減少FcγR結合(參見例如Canfield、Stephen M.及Sherie L. Morrison.「The binding affinity of human IgG for its high affinity Fc receptor is determined by multiple amino acids in the CH2 domain and is modulated by the hinge region.」 The Journal of experimental medicine 173.6 (1991): 1483-1491;及Lund、John等人「Human Fc gamma RI and Fc gamma RII interact with distinct but overlapping sites on human IgG.」 The Journal of Immunology 147.8 (1991): 2657-2662.)。可例如藉由去岩藻糖基化增強FcγR結合。減少FcγR結合亦可降低依賴於FcγR相互作用之其他效應功能,該等相互作用諸如助噬作用、吞噬作用及抗原依賴性細胞毒性(「ADCC」)。
此外,解決Fc與FcRn之相互作用允許在活體內調節抗體之半衰期。藉由例如引入突變H435A消除相互作用導致極短半衰期,因為抗體不再受藉由FcRn再循環保護而免於溶酶體降解。在根據所有態樣之一些較佳實施例中,根據本發明之抗體包含突變H435A或為縮短半衰期已另外經工程改造。
術語「抗IL-11抗體」或「IL-11抗體」及「結合至IL-11之抗體」係指能夠以足夠親和力結合IL-11以使得抗體適用作靶向IL-11之診斷劑及/或治療劑的抗體。根據本發明,抗體較佳具有低於1.0 E-08 M(以KD值形式)、更佳低於1.0 E-09 M、甚至更佳低於5.0 E-10 M、甚至更佳低於1.0 E-10 M、甚至更佳低於5.0 E-11 M、甚至更佳低於2.5 E-11 M、甚至更佳低於1.0 E-11 M之目標親和力。可較佳藉由例如如本文中其他地方所描述之表面電漿子共振光譜分析之途徑測定KD值。在某些實施例中,IL-11抗體結合至在來自不同物種之IL-11中為保守性的IL-11之抗原決定基。
術語「抗IL-11Ra抗體」或「IL-11Ra抗體」及「結合至IL-11Ra之抗體」係指能夠以足夠親和力結合IL-11Ra以使得抗體適用作靶向IL-11Ra之診斷劑及/或治療劑的抗體。根據本發明,抗體之目標親和力較佳為至少1.0 E-07 M(以KD值形式),更佳為至少1.0 E-08 M,甚至更佳在1.0 E-09 M至1.0 E-10 M範圍內。可較佳藉由表面電漿子共振光譜分析之途徑或ELISA測定KD值。
如本文所使用之抗體之「片段」為必需的以實質上保留全長抗體之所需親和力。因而,例如抗人類IL-11抗體之適合片段將保留例如與人類IL-11受體結合之能力。抗體之片段包含全長抗體之一部分,一般為其抗原結合或可變區。抗體片段之實例包括(但不限於) Fab、Fab'、F(ab')2及Fv片段、單鏈抗體分子、雙功能抗體及域抗體,參見Holt、Lucy J.等人「Domain antibodies: proteins for therapy.」 Trends in biotechnology 21.11 (2003): 484-490。
「Fab片段」含有輕鏈之恆定域及重鏈之第一恆定域(CH2)。
「Fab'片段」與Fab片段的不同之處在於在重鏈CH2域之羧基末端添加幾個殘基,包括一或多個來自抗體鉸鏈區之半胱胺酸。
藉由F(ab')2胃蛋白酶消化產物之鉸鏈半胱胺酸處二硫鍵之裂解來產生「F(ab')片段」。一般熟習此項技術者已知抗體片段之其他化學偶合。Fab及F(ab')2片段缺乏完整抗體之Fc片段,自動物循環更快速清除,且相比於完整抗體可具有更少非特異性組織結合,參見例如Wahl、Richard L.、Charles W. Parker及Gordon W. Philpott.「Improved radioimaging and tumor localization with monoclonal F (ab') 2.」核醫學雜誌:官方公開案(Journal of nuclear medicine: official publication), 核子醫學學會(Society of Nuclear Medicine) 24.4 (1983): 316-325。
「Fv片段」為含有完全目標識別及結合位點之抗體的最小片段。此區域由緊密非共價締合之一個重鏈可變域及一個輕鏈可變域的二聚體組成(VH-VL二聚體)。在此組態中,各可變域之三個CDR相互作用以界定VH-VL二聚體表面上之抗原結合位點。通常,六個CDR賦予抗體抗原結合特異性。然而,在一些情況下,即使單一可變域(或僅包含三個對標靶具有特異性之CDR之Fv的一半)能夠識別及結合抗原,但親和力低於完整結合位點。
「單鏈Fv」或「scFv」抗體片段在單一多肽鏈中包含抗體之VH及VL域。一般而言,Fv多肽進一步在VH與VL域之間包含多肽連接子,該多肽連接子使得scFv能夠形成用於抗原結合之所需結構。
「雙特異性抗體」為對相同或不同抗原上之至少兩種不同抗原決定基具有結合特異性的單株抗體。在本發明中,結合特異性可針對例如IL-11之兩個不同抗原決定基。結合特異性中之一者亦有可能針對例如IL-11,另一者可針對任何其他抗原,例如(但不限於)細胞表面蛋白質、受體、受體次單元、組織特異性抗原、病毒衍生之蛋白質、病毒編碼之包膜蛋白、細菌衍生之蛋白質或細菌表面蛋白質。
「衍生抗體」典型地藉由糖基化、乙醯化、聚乙二醇化、磷酸化、硫酸化、醯胺化、由已知保護/封端基團衍生化、蛋白水解分裂、與細胞配位體或其他蛋白質鍵聯修飾。許多化學修飾中之任一者可藉由已知技術進行,包括(但不限於)特異性化學裂解、乙醯化、甲醯化、衣黴素之代謝合成等。另外,衍生物可含有一或多種非天然胺基酸,例如使用安博生物(ambrx)技術,參見例如Wolfson、Wendy.「Amber codon flashing ambrx augments proteins with unnatural amino acids.」 Chemistry & biology 13.10 (2006): 1011-1012。根據本發明之抗體可經衍生化,例如經糖基化或硫酸化。
如本文所使用,術語「衍生物」應指蛋白質構築體在結構上與共同抗體概念不同,但仍具有一定結構關係,例如scFv、Fab及/或F(ab)
2,以及雙特異性、三特異性或更高特異性抗體構築體,且進一步保留IL-11或IL-11RA結合能力。
熟習此項技術者已知之其他抗體衍生物為雙功能抗體、駱駝科抗體、奈米抗體、域抗體、具有由scFvs、IgAs (由J鏈及分泌組分接合之兩種IgG結構)組成之兩條鏈之二價均二聚體、鯊魚抗體、由新世界靈長類動物框架加非新世界靈長類動物CDR組成之抗體、包含CH3+VL+VH之二聚構築體及抗體結合物(例如抗體或與毒素相關之片段或衍生物、細胞介素、放射性同位素或標籤)。此等類型詳細描述於文獻中且可基於本發明由熟習此項技術者使用,進一步增加本發明活性。
如本文所使用,術語「抗體模擬物」係關於有機分子,最常為特異性結合至靶蛋白之蛋白質,其與抗體類似但在結構上不與抗體相關。抗體模擬物通常係莫耳質量為約3至20 kDa之人工肽或蛋白質。定義尤其涵蓋親和抗體分子、阿非林(affilins)、親和體(affimers)、阿非汀(affitins)、阿爾法體(alphabodies)、抗運載蛋白(anticalins)、高親和性多聚體(avimers)、達爾潘蛋白(DARPins)、非諾莫(fynomers)、孔尼茲(kunitz)域肽、單功能抗體及奈米CLAMP。
「單株抗體」為結合特定抗原之抗體之實質上同源群體。單株免疫球蛋白可藉由熟習此項技術者熟知之方法獲得(參見例如Köhler、Georges及Cesar Milstein.「Continuous cultures of fused cells secreting antibody of predefined specificity.」 nature 256.5517 (1975): 495-497.及美國專利第4,376,110號)。可自原核或真核生物體分離、富集或純化具有特異性結合親和力之免疫球蛋白或免疫球蛋白片段。熟習此項技術者已知之常規方法使得能夠在原核及真核生物體兩者中產生免疫球蛋白或免疫球蛋白片段及具有免疫球蛋白樣功能之蛋白質結合分子兩者。根據本發明之抗體較佳為單株抗體。
「人類化抗體」含有來源於非人類物種(諸如小鼠)之CDR區,其已例如連同任何必需構架回復突變一起移植至人類序列衍生V區中。因此,在極大程度上,人類化抗體為人類免疫球蛋白(受體抗體),其中來自受體的高變區之殘基經來自諸如具有所需特異性、親和力及能力之小鼠、大鼠、家兔或非人類靈長類動物之非人類物種(供體抗體)的高變區之殘基置換。參見例如美國專利第5,225,539號、第5,585,089號、第5,693,761號、第5,693,762號、第5,859,205號,各自以引用的方式併入本文中。在一些情況下,人類免疫球蛋白之構架殘基經對應非人類殘基置換。此外,人類化抗體可包含在受體抗體或供體抗體中未發現之殘基。進行此等修飾以進一步改進抗體效能(例如,獲得所需親和力)。一般而言,人類化抗體將包含實質上全部至少一個且典型地兩個可變域,其中全部或實質上全部高變區與非人類免疫球蛋白之彼等區域相對應且全部或基本上全部構架區為人類免疫球蛋白序列之彼等區域。人類化抗體視情況包含免疫球蛋白恆定區(Fc)之至少一部分,典型地人類免疫球蛋白之恆定區的至少一部分。關於其他細節,參見Jones、Peter T.等人「Replacing the complementarity-determining regions in a human antibody with those from a mouse.」 Nature 321.6069 (1986): 522-525.;Riechmann、Lutz等人「Reshaping human antibodies for therapy.」 Nature 332.6162 (1988): 323-327.;及Presta, Leonard G.「Antibody engineering.」 Current Opinion in Structural Biology 2.4 (1992): 593-596.,各自以引用之方式併入本文中。
完全人類抗體(人類抗體)包含人類來源之CDR,亦即,人源之CDR。較佳地,根據本發明之完全人類抗體為與最接近人類VH生殖系基因具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.5%或100%序列一致性之抗體(例如自推薦清單提取且在IMGT/域-間隙比對中分析之序列)。
如由諸如生效的INN物種子系統之常見命名法系統在2017年之前所接受,完全人類抗體可包含與基於IMGT資料庫測定之最近人類生殖系參考物相比較低數目之生殖系偏差(http://www.imgt.org,2019年11月29日)。舉例而言,根據本發明之完全人類抗體與最近人類生殖系參考物相比可在CDR中包含至多1、2、3、4、5、6、7、8、9、10、12、13、14或15個生殖系偏差。完全人類抗體可藉由選殖技術以及細胞富集或永生化步驟自人類來源之B細胞產生。然而,臨床使用中之大部分完全人類抗體自針對人類IgG基因座經轉殖基因之免疫接種小鼠分離或來自藉由噬菌體呈現之複雜組合庫(Brüggemann, Marianne等人「Human antibody production in transgenic animals.」 Archivum immunologiae et therapiae experimentalis 63.2 (2015): 101-108.;Carter、Paul J.「Potent antibody therapeutics by design.」 Nature reviews immunology 6.5 (2006): 343-357.;Frenzel、André、Thomas Schirrmann及Michael Hust.「Phage display-derived human antibodies in clinical development and therapy.」 MAbs.第8卷第7期. Taylor & Francis, 2016.;Nelson、Aaron L.、Eugen Dhimolea及Janice M. Reichert.「Development trends for human monoclonal antibody therapeutics.」 Nature reviews drug discovery 9.10 (2010): 767-774.)。
可使用若干技術來產生完全人類抗體或產生包含人類來源之CDR的抗體(參見WO2008112640)。劍橋抗體技術(CAT)及Dyax已獲得來自自免疫接種人類分離之周邊B細胞的抗體cDNA序列且設計用於鑑別具有特定特異性之人類可變區序列的噬菌體呈現集合庫。簡言之,抗體可變區序列與M13噬菌體之基因III或基因VIII結構融合。此等抗體可變區序列在攜載各別序列之噬菌體的尖端處表現為Fab或單鏈Fv (scFv)結構。經由使用不同程度之抗原結合條件(嚴格)之數輪淘選過程,可選擇且分離表現對相關抗原具有特異性之Fab或scFv結構的噬菌體。可隨後使用標準定序程序闡明所選噬菌體之抗體可變區cDNA序列。可隨後使用已建立之抗體工程改造技術來重構具有所需同型之完整抗體。根據此方法構築之抗體視為完全人類抗體(包括CDR)。為了改良所選抗體之免疫反應性(抗原結合親和力及特異性),可引入活體外成熟過程,包括不同重鏈及輕鏈之組合結合、重鏈及輕鏈之CDR3處的缺失/添加/突變(模擬V-J及V-D-J重組)及隨機突變(模擬體細胞超突變)。由此方法產生之「完全人類」抗體之實例為抗腫瘤壞死因子α抗體、修美樂(Humira) (阿達木單抗(adalimumab))。
術語「聚核苷酸」係指以重組方式或以合成方式產生的聚合去氧基核糖核苷酸或其類似物或經修飾之聚核苷酸。該術語包含雙股及單股DNA或RNA。聚核苷酸可整合至例如微環、質體、黏質體、袖珍染色體或人造染色體中。聚核苷酸可分離或整合於另一核酸分子中,例如真核宿主細胞之表現載體或染色體中。
如本文所使用,術語「載體」係指核酸分子,其能夠將核酸分子傳播至其所連接之核酸分子。該術語進一步包含質體(非病毒)及病毒載體。某些載體能夠導引與其可操作地連接之核酸或聚核苷酸之表現。此類載體在本文中稱作「表現載體」。真核用途之表現載體可藉由將編碼至少一種相關蛋白質(POI)之聚核苷酸序列插入適合載體主鏈中來構築。載體主鏈可包含必需元件以確保載體之維護及(若需要)提供宿主內之擴增。對於病毒載體,例如慢病毒或反轉錄病毒載體,可需要其他病毒特異性元件,諸如結構元件或其他元件,且為此項技術中所熟知。此等元件可例如以順式(在同一質體上)或反式(在獨立質體上)提供。病毒載體可能需要輔助病毒或包裝株用於大規模轉染。載體可含有其他元件,諸如強化子元件(例如病毒、真核)、內含子及用於哺乳動物細胞中複製之質體複製之病毒來源。根據本發明,表現載體典型地具有驅動POI表現之啟動子序列。POI及/或選擇性標記蛋白之表現可為組成性或調節的(例如,可藉由添加或移除小分子誘導子誘導)。哺乳動物宿主細胞表現之較佳調節序列包括引導哺乳動物細胞中高水準POI表現之病毒元件,諸如衍生自細胞巨大病毒(CMV)、猴病毒40 (SV40)、腺病毒(例如腺病毒主要晚期啟動子Ad LP)或多瘤病毒之調節元件、啟動子及/或強化子。關於病毒調節元件及其序列之其他描述,參見例如U.S. 5,168,062、U.S. 4,510,245及U.S. 4,968,615。
「宿主細胞」為用於接收、維持、再生及擴增載體之細胞。宿主細胞亦可用於表現多肽,例如由載體編碼之抗體或其片段。當宿主細胞分裂時,載體中所含有之核酸複製,藉此擴增核酸。較佳宿主細胞為哺乳動物細胞,諸如CHO細胞或HEK細胞。
「多肽之連接子」可經由醯胺鍵或任何其他功能性殘基附接。多肽之連接子可附接多肽之N端或C端或可經由反應性官能基或胺基酸側鏈附接。多肽可例如與生物素、蛋白質(諸如人類血清白蛋白(HSA))、載體蛋白(諸如匙孔螺血氰蛋白(KLH)、卵白蛋白(OVA)或牛血清白蛋白(BSA))、螢光染料、短胺基酸序列(諸如UNK標籤、HA標籤、Myc標籤或His標籤)、反應性標籤(諸如順丁烯二醯亞胺、碘乙醯胺、烷基鹵化物、3-巰基丙基或4-疊氮基丁酸)或各種其他適合部分偶合。適合連接子,例如用於結合多肽之非限制性實例包括β-丙胺酸、4-胺基丁酸(GABA)、(2-胺基乙氧基)乙酸(AEA)、5-胺基戊酸(Ava)、6-胺基己酸(Ahx)、PEG2間隔子(8-胺基-3,6-二氧雜辛酸)、PEG3間隔子(12-胺基-4,7,10-三氧雜十二酸)、PEG4間隔子(15-胺基-4,7,10,13-四氧雜戊癸酸)及Ttds (三氧雜十三烷-丁二醯胺酸)。在一些情況下,連接子可來源於反應性部分,例如順丁烯二醯亞胺、碘乙醯胺、烷基鹵化物、3-巰基丙基或4-疊氮基丁酸。在一些情況下,連接子可包含聚乙二醇(PEG)、聚丙二醇、聚氧化烯或聚乙二醇或聚丙二醇之共聚物。
「治療」受試者之疾病或「治療」患有疾病之受試者係指對受試者進行醫藥治療,例如投與藥物,以使得該疾病之至少一種症狀減少或預防惡化。
術語「預防(prevent)」、「預防(preventing)」、「預防(prevention)」及其類似術語係指使未患有但有發展疾病、病症或病況之風險或易發展疾病、病症或病況之受試者發展疾病、病症或病況之機率降低。
術語「有效量」或「治療有效量」在本文中可互換使用且係指足以達成特定生物結果或調節或改善受試者之症狀或症狀發作時間之量。對於治療大量月經出血、不正常子宮出血或繼發於平滑肌瘤或子宮內膜異位之大量月經出血,典型有效量為導致出血減少至少約35%、通常減少至少約50%、較佳至少約60%或更佳至少約70%的量。特定受試者之有效量可視以下因素而變化:諸如所治療之病況、受試者之整體健康狀況、投與方法、途徑及劑量以及副作用之嚴重程度。當組合時,有效量與組分之組合呈比率且該效應不限於單獨的個別組分。
抗體、片段或結合物之「醫藥組合物」(亦為「治療性調配物」)可藉由將具有所需純度之抗體與視情況選用之生理學上可接受之載劑、賦形劑或穩定劑混合來製備,例如根據雷明頓氏醫藥科學(Remington's Pharmaceutical Sciences) (第18版;Mack Pub. Co.: Eaton, Pa., 1990),例如呈凍乾調配物或水溶液形式。可接受之載劑、賦形劑或穩定劑在所利用之劑量及濃度下對受體無毒性,且包括緩衝劑,諸如磷酸鹽、檸檬酸鹽及其他有機酸;抗氧化劑,包括抗壞血酸及甲硫胺酸;防腐劑(諸如十八烷基二甲基苯甲基氯化銨;氯化六羥季銨;苯紮氯銨、苄索氯銨;苯酚、丁醇或苯甲醇;烷基對羥苯甲酸酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯;兒茶酚;間苯二酚;環己醇;3-戊醇;及間甲酚);低分子量(小於約10個殘基)多肽;蛋白質,諸如血清白蛋白、明膠或免疫球蛋白;親水性聚合物,諸如聚乙烯吡咯啶酮;胺基酸,諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、雙醣及其他碳水化合物,包括葡萄糖、甘露糖或糊精;螯合劑,諸如EDTA;糖,諸如蔗糖、甘露糖醇、海藻糖或山梨糖醇;成鹽抗衡離子,諸如鈉;金屬錯合物(例如Zn-蛋白質複合物);及/或非離子界面活性劑,諸如Tween®、Pluronic®或聚乙二醇(PEG)。
根據本發明之典型的「受試者」包括人類及非人類受試者。受試者可為哺乳動物,諸如小鼠、大鼠、貓、犬、靈長類動物及/或人類。
如本文所使用,術語「不正常子宮出血」(AUB)定義為與年齡匹配之一般女性群體所經歷不同的女性月經失血(MBL)或MBL程度或陰道出血模式。不正常子宮出血包括大量月經出血或經常與痛經相關之月經過多。
如本文所使用,術語「子宮內膜異位」定義為(i)外在性子宮內膜異位,其在子宮外部(子宮內膜異位病變)具有含有子宮內膜腺(子宮內膜上皮細胞)及子宮內膜基質之子宮內膜組織,典型地存在於(但不限於)腹腔內;及(ii)內在性子宮內膜異位,亦稱為子宮腺肌症,其在子宮肌層內具有含有子宮內膜腺(子宮內膜上皮細胞)及子宮內膜基質之子宮內膜組織。
如本文所使用,術語「平滑肌瘤」(亦稱為子宮纖維瘤或肌瘤)為生殖年齡女性之最常見良性婦科腫瘤,且由在子宮壁中生長或在子宮壁周圍生長之肌肉細胞及其他組織界定。
如本文所使用,術語「痛經」亦已知為疼痛期或月經絞痛,定義為月經期間的疼痛。
如本文所使用,術語「介白素11」、「IL-11」或「IL11」亦已知為AIGF (脂肪細胞生成抑制因子),其係指具有UniProt ID P20809 (人類)、P47873 (小鼠)、P20808 (長尾獼猴/食蟹獼猴)或Q99MF5 (大鼠)之蛋白質,如表1中所列。IL-11為基於其常見輔受體gp130之使用區分的屬於IL-6類型細胞介素家族之細胞介素。人類IL-11以兩種同功異型物表現(表1)且人類IL-11基因至少剪接成兩種主要變異體(表2)。人類、小鼠、食蟹獼猴及大鼠之典型介白素11 mRNA序列之NCBI參考識別符展示於表2中。
表1:IL-11蛋白質序列識別符
表2:IL-11 mRNA序列識別符
同功異型物 | UniProt 識別符 | 物種 | SEQ ID NO | 批註 |
1 | P20809-1 | 人類 | 1 | 『典型』序列(人類IL-11);包括信號序列aa 1-21 |
2 | P20809-2 | 人類 | 2 | 不同於如下典型序列:1至79缺失。 |
1 | P47873 | 小鼠 | 16 | 包括信號序列aa 1-21之『典型』序列(小鼠IL-11) |
1 | P20808 | 食蟹獼猴 | 17 | 包括信號序列aa 1-21之『典型』序列(食蟹獼猴IL-11) |
1 | Q99MF5 | 大鼠 | 18 | 包括信號序列aa 1-21之『典型』序列(大鼠IL-11) |
變異體 | NCBI 參考序列 | 物種 | SEQ ID NO | 批註 |
1 | NM_000641.4 | 人類 | 5 | 『全長』序列 |
2 | NM_001267718.1 | 人類 | 6 | 不具有外顯子2 (5'編碼區中之外顯子),相比於變異體1產生下游框內起始密碼子 |
1 | NM_008350.4 | 小鼠 | 19 | 『全長』序列 |
X1 | XM_045380640.1 | 食蟹獼猴 | 20 | 『全長』序列 |
1 | NM_133519.5 | 大鼠 | 21 | 『全長』序列 |
如本文所使用,術語「IL-11RA」或「IL-11Ra」(UniProt Q14626(人類) P70225(小鼠))為介白素11受體之次單元且亦已知為CRSDA、介白素11受體α次單元、介白素11受體次單元α。介白素11受體為結合介白素11之I型細胞介素受體。其為由介白素11受體α次單元及信號轉導次單元gp130構成之雜二聚體。膜結合IL-11RA受體可裂解,導致可溶性同功異型物sIL-11RA釋放。IL-11RA表現於2種同功異型物中(表3)。人類IL-11RA基因在若干變異體中剪接,其中變異體3與編碼蛋白質同功異型物相關(表4)。存在兩種鼠類IL11Ra基因:Il11ra1 (人類IL-11RA之同源物)及Il11ra2 (人類現有無同源物)及經編碼之蛋白質展示於表3中。對於Ilra1三個轉錄物變異體存在,全部編碼相同蛋白質,僅Ilra1之轉錄物變異體2提供於表4中。對於食蟹獼猴IL11RA,不存在UniProt ID。因此,吾人使用NCBI參考蛋白質ID (表3),展示與人類IL11Ra之最高同源性(Uniprot ID Q14626-1)以及對應食蟹獼猴IL11RA NCBI參考mRNA ID (表4)。
表3:IL-11受體α蛋白質序列識別符
表4:IL-11受體α核酸序列標識符
同功異型物 | UniProt / NCBI RefSeq 識別符 | 物種 | 同義名 | SEQ ID NO | 批註 |
1 | Q14626-1 | 人類 | HCR1 | 3 | 『典型』序列(IL-11RA) |
2 | Q14626-2 | 人類 | HCR2 | 4 | 可溶性形式(sIL-11RA):不同於如下典型序列:391-422缺失 |
1 | Q64385 | 小鼠 | 8 | 由與人類同源之小鼠基因Il11ra1編碼 | |
1 | P70225 | 小鼠 | 9 | 由小鼠基因Il11ra2編碼 | |
1 | XP_045229354.1 | 食蟹獼猴 | 22 | 『全長』序列 | |
1 | Q99MF4 | 大鼠 | 23 | 『全長』序列 |
變異體 | NCBI 參考序列 | 物種 | SEQ ID NO | 批註 |
3 | NM_001142784.3 | 人類 | 7 | 編碼受體蛋白 |
2 | NM_001163401.1 | 小鼠 | 10 | Il11ra1 (轉錄物變異體2 cDNA) |
NM_010550.3 | 小鼠 | 11 | Il11ra2 cDNA | |
X4 | XM_045373419.1 | 食蟹獼猴 | 24 | 『全長』序列 |
1 | NM_139116.1 | 大鼠 | 25 | 『全長』序列 |
術語「gp130」係指醣蛋白gp130,亦已知為介白素-6-信號轉導子、IL6ST、CD130、CDW130、GP130或IL-6RB (UniProt.P40189 (人類);Q00560 (小鼠))。Gp130為跨膜蛋白且形成IL-6受體家族內I型細胞介素受體之一個次單元。其通常稱為常見gp130次單元且對於細胞介素接合之後的信號轉導至關重要。如同其他I型細胞介素受體,gp130具有確保正確蛋白質摺疊及配位體結合之WSXWS胺基酸模體。其在受體與其配位體相互作用之後與傑納斯激酶相互作用以誘發細胞內信號。在結構上,gp130由其細胞外部分中五個纖維結合蛋白III型域及一個免疫球蛋白樣C2型(免疫球蛋白樣)域構成。IL-11結合至IL-11Ra。此等兩種蛋白質之複合物隨後與gp130締合。3種蛋白質之此複合物隨後均二聚體化以形成可產生下游信號之六聚複合物。gp130不具有內源性酪胺酸激酶活性。相反,其在與其他蛋白質複合之後在酪胺酸殘基上磷酸化。磷酸化導致與JAK/Tyk酪胺酸激酶及STAT蛋白質轉錄因子締合。特定言之,STAT3經活化,其引起許多下游基因之活化。
表5:不同物種之介白素6信號轉導子蛋白序列之UniProt/NCBI RefSeq識別符
表6:不同物種之介白素6信號轉導子mRNA序列之NCBI RefSeq識別符
同功異型物 | UniProt / NCBI RefSeq 識別符 | 物種 | SEQ ID NO | 批註 |
1 | P40189-1 | 人類 | 12 | 『典型』序列(介白素-6受體次單元β) |
2 | P40189-2 | 人類 | n.a. | 此同功異型物序列與如下典型序列不同:325-329:RPSKA→NIASF及330-918:缺失 |
3 | P40189-3 | 人類 | 13 | 此同功異型物序列與如下典型序列不同:423-483:缺失 |
1 | Q6PDI9 | 小鼠 | 26 | |
X1 | XP_045249657.1 | 食蟹獼猴 | 27 | 四種同功異型物(aa)中之最長者:924 |
1 | P40190 | 大鼠 | 28 |
同功異型物 | NCBI 參考序列 | 物種 | SEQ ID NO | 批註 |
1 | NM_002184.4 | 人類 | 14 | 編碼介白素-6受體次單元β之『典型序列』 |
2 | NM_175767.3 | 人類 | n.a. | 編碼介白素-6受體次單元β之同功異型物3 |
3 | NM_001190981.2 | 人類 | 15 | 編碼介白素-6受體次單元β之同功異型物3 |
NM_010560.3 | 小鼠 | 29 | ||
1 | XM_045393722.1 | 食蟹獼猴 | 30 | |
1 | NM_001008725.3 | 大鼠 | 31 |
如本文所使用,術語「IL-11介導之信號傳導」係指在IL-11結合至IL-11RA及gp130後開始之信號轉導,促進涉及gp130:IL-11:IL-11RA複合物之二聚體的高階結構形成。此允許例如gp130相關下游傑納斯激酶(JAK)活化、STAT介導之轉錄活性、非典型MAPK/ERK依賴性信號傳導之活化及介導之依賴性轉錄活性。可溶性或膜結合IL-11Ra可與IL-11形成複合物。因此,IL-11有可能在結合細胞表面gp130之前結合至可溶性IL-11Ra,其在表現gp130而非IL-11Ra之細胞中促進IL-11介導之信號傳導(Lokau等人,2016 Cell Reports 14, 1761-1773)。因為IL-11Ra表現僅在少數細胞類型中觀測到,而gp130在廣泛範圍之細胞類型中表現,所謂IL-11反信號傳導可能為IL-11介導之信號傳導之最常見形式。
術語「IL-11功能阻斷抗體」、「抗IL-11功能阻斷抗體」係指抑制IL-11介導之信號轉導之IL-11抗體。
治療及 / 或預防不正常子宮出血已發現藉由功能阻斷IL-11抗體抑制IL-11信號傳導路徑對兩種大量月經出血展示極強作用(例如實例1、圖2;實例5、圖6;實例6、圖7;實例7、圖8;實例10、圖11;實例11、圖13;實例12、圖14;實例13、圖15)及子宮重量(例如實例2、圖3;實例10、圖12)。此等出人意料的結果導致以下結論:結合至IL-11及/或IL-11RA及抑制或拮抗IL-11信號傳導減弱月經及不正常子宮出血,包括大量月經出血。
此外,已發現IL-11顯著誘導VEGF-A分泌。此藉由用IL-11功能阻斷抗體額外處理而得到完全抑制。VEGF-A為熟知的促血管生成介體,藉由IL-11誘導可能引起平滑肌瘤血管形成增加及平滑肌瘤生長增強(實例3,圖4)。
另外,已發現,與用對照抗體處理之動物相比,患有HMB之經IL-11抗體處理之動物在月經期間展示體重損失之減少(實例4,圖5),且與用對照抗體處理之動物相比,經IL-11抗體處理之動物展示探索行為增加,如在行進距離及直立所見(實例8;圖9)。其指示用IL-11功能阻斷抗體處理使得患有HMB之經處理之動物在月經期間活動增加且健康提高。
使得不正常子宮出血,諸如大量月經出血、月經過多及痛經以及諸如平滑肌瘤及子宮內膜異位或月經本身之原有疾病減少的IL-11及/或IL-11RA藥劑之抑制或拮抗作用因此為出人意料的且驚人的。
根據第一態樣,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據另一態樣,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導之藥劑的用途,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據另一態樣,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導之藥劑的用途,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位之方法中。
根據另一態樣,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導之藥劑的用途,其用於製備治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位之醫藥組合物,較佳藥物。
根據另一態樣,本發明涵蓋使用有效量之能夠結合至IL-11及IL-11RA及/或抑制或拮抗IL-11介導之信號傳導的藥劑治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位之方法。
根據本發明之所有態樣之一個實施例,涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血為大量月經出血、長期出血或出血模式改變之出血。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血為大量月經出血且其中大量月經出血繼發於平滑肌瘤或子宮內膜異位。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血與痛經相關。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血與繼發於子宮平滑肌瘤或子宮內膜異位之痛經相關。
根據另一態樣,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導之藥劑的用途,其用於抑制或調節月經。
根據本發明之一個實施例,能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用之藥劑為異位抑制劑或拮抗劑。如本文所使用,術語「異位抑制劑」或「異位拮抗劑」係關於藉由結合至靶蛋白之異位位點改變標靶之活性位點中之蛋白質構形且因此改變活性位點形狀之藥劑。因此,標靶(例如配位體)不再能夠結合至其特定受體或經歷結合其受體之能力降低。
根據本發明之一個實施例,能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用的藥劑為保留IL-11及/或IL-11RA結合能力之單株抗體或IL-11及/或IL-11RA結合片段或其衍生物或特異性結合至IL-11及/或IL-11RA蛋白質之抗體模擬物。
藥劑根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11或IL-11Ra且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位,其中該等藥劑為異位抑制劑或拮抗劑。
異位抑制劑或拮抗劑包括(但不限於)
● IL-11或IL-11Ra抗體或IL-11或IL-11Ra抗體片段或其衍生物
● 核酸分子,諸如(但不限於) siRNA (小干擾RNA)或shRNA (短髮夾RNA)
● 特異性結合至IL-11或IL-11Ra之適體
● 特異性結合至IL-11或IL-11Ra之小分子
根據本發明之抗體、抗體片段、抗體-模擬物或其衍生物
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中該等藥劑為IL-11及/或IL-11RA抗體、IL-11及/或IL-11RA抗體片段、IL-11及/或IL-11RA抗體-模擬物或其衍生物。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中該等藥劑為IL-11單株抗體且其中該單株抗體以≤1.0 E-08 M、≤1.0 E-09 M、≤5.0 E-10 M、≤1.0 E-10 M、≤5.0 E-11 M、≤2.5 E-11 M或≤1.0 E-11 M之解離常數(
K D)結合至人類IL-11。
IL-11及/或IL-11RA抗體已描述於科學或專利文獻中,尚未用於治療不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據本發明,IL-11及/或IL-11RA抗體包括(但不限於)描述於科學及專利文獻中之IL-11及/或IL-11RA抗體,例如特異性結合至IL-11及/或IL-11RA之重組抗體。
用於人類及小鼠IL-11及/或IL-11RA之功能阻斷抗體由商業供應商提供。已知抗lL-11抗體之實例包括單株抗體純系6D9A (Abbiotec或Genetex)、純系KT8 (Abbiotec或LS-bio)、純系M3103F11 (BioLegend)、純系1F1 (Merck)、純系3C6 (Abnova Corporation)、純系GF1 (LifeSpan Biosciences)、純系22616 (Thermo Fisher Scientific)、純系9T27 (Genetex)、純系12 (Thermo Fisher Scientific)、未知純系(LS-bio, #LS-C104441)、純系9 (Thermo Fisher Scientific)、純系13455 (Source BioScience)及純系22626 (R & D Systems,用於Bockhorn等人(2013);單株小鼠lgG2A;目錄號MAB218;R&D Systems, MN, USA)。已知抗lL-11RA抗體之實例包括US 2014/0219919 A1中所描述之單株抗體純系025 (Sino Biological)、純系EPR5446 (Abcam)、純系473143 (R & D Systems)、純系8E2及8E4及Blanc等人(2000)中所描述之單株抗體。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11介導之信號傳導的藥劑,其用於治療及/或預防不正常子宮出血,其中該藥劑為IL-11及/或IL-11RA單株抗體或保留IL-11及/或IL-11RA結合能力之IL-11及/或IL-11RA結合抗體片段或其衍生物或特異性結合至IL-11及/或IL-11RA蛋白質之抗體模擬物。
如上文所論述,IL-11及/或IL-11RA經充分說明以使得熟習此項技術者能夠在彼此製得單株抗體。常規方法涵蓋融合瘤、嵌合/人類化、噬菌體呈現/轉殖基因哺乳動物及其他抗體工程改造技術。
用於產生融合瘤細胞之方法揭示於Köhler & Milstein (1975)中。基本上,例如小鼠在B細胞分離及與骨髓瘤細胞融合之後經人類IL-11及/或IL-11RA蛋白質免疫。
用於產生及/或選擇嵌合或人類化mAb之方法為此項技術中已知的。基本上,例如來自不涉及IL-11及/或IL-11RA結合之鼠類抗IL-11及/或IL-11RA抗體之蛋白質序列經對應人類序列置換。舉例而言,Genentech之US6331415描述嵌合抗體之產生,同時醫學研究委員會(Medical Research Council)之US6548640描述CDR接枝技術且Celltech之US5859205描述人類化抗體之產生。
用於產生及/或選擇全人類mAb之方法為此項技術中已知的。此等可涉及經人類IL-11及/或IL-11RA免疫之轉殖基因動物之用途或適合呈現技術,如酵母呈現、噬菌體呈現、B細胞呈現或核糖體呈現之用途,其中來自集合庫之抗體在固定相上針對人類IL-11及/或IL-11RA進行篩選。
活體外抗體庫尤其揭示於MorphoSys之US6300064及MRC/Scripps/Stratagene之US6248516中。噬菌體呈現技術例如揭示於Dyax之US5223409中。轉殖基因哺乳動物平台例如描述於TaconicArtemis之EP1480515A2中。
IgG、scFv、Fab及/或F(ab)
2為熟習此項技術者熟知之抗體型式。能夠實現之相關技術可獲自各別教科書。
經修飾之抗體型式為例如雙特異性或三特異性抗體構築體、基於抗體之融合蛋白、免疫共軛物及其類似者。此等類型詳細描述於文獻中且可基於本發明由熟習此項技術者使用,進一步增加本發明活性。
基於不同IL-11及/或IL-11RA同功異型物之胺基酸序列之公眾可用性,發現能夠例如藉由結合至IL-11RA、IL-11或IL6ST相互作用位點而充當IL-11及/或IL-11RA之抑制劑或拮抗劑的適合抗體或片段或衍生物因此對於熟習此項技術者而言係慣例問題。
針對用於科學研究之IL-11及/或IL-11RA之多株抗體例如可購自R&D Systems, Inc.,強調熟習此項技術者亦能夠製得針對該等標靶之治療抗體。
核酸根據本發明之一個實施例,能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用的藥劑包含特異性結合至第二核酸分子的第一核酸分子,其中該第二核酸分子編碼IL-11及/或IL-11RA蛋白質。
該第二核酸分子可為自編碼IL-11及/或IL-11RA蛋白質之基因轉錄的mRNA。該第二核酸不含內含子,但歸因於替代性剪接,轉錄自編碼IL-11及/或IL-11RA蛋白質之基因的不同mRNA可彼此不同。在此類情況下,第一核酸分子可為siRNA (小干擾RNA)或shRNA (短髮夾RNA)。
siRNA係可經化學修飾以增強穩定性之短人造RNA分子。因為siRNA係雙股的,所以亦應用『有義』及『反義』之原理。有義股具有與經轉錄之mRNA相同之鹼基序列且反義股具有互補序列。技術上,向患者投與之siRNA分子與稱為Argonaut之胞內酶結合以形成所謂的RNA誘導靜默錯合物(RNA-induced silencing complex;RISC)。siRNA之反義股將RISC引導至標靶mRNA,其中反義股與標靶mRNA雜交,隨後由RISC裂解。以此方式,各別mRNA之轉譯經中斷。RISC可隨後使其他mRNA裂解。遞送技術例如揭示於Xu及Wang (2015)中。基於IL-11及/或IL-11R之不同mRNA同功異型物之公眾可用性,發現siRNA之適合序列對於熟習此項技術者而言係慣例問題。
shRNA係可用於經由RNA干擾(RNAi)靜默靶基因表現之具有緊密髮夾圈之人工RNA分子。shRNA可例如藉助於質體或經由病毒或細菌載體遞送至細胞。shRNA係有利的RNAi介體,因為其具有相對較低的降解及轉化速率。各別質粒包含適合之啟動子以表現shRNA,如聚合酶III啟動子,諸如U6及H1,或聚合酶II啟動子。在質體或載體已整合於宿主基因組中之後,shRNA經轉錄於細胞核中。產物模仿pri-微RNA (pri-miRNA)且藉由Drosha處理。所得pre-shRNA藉由輸出蛋白5自細胞核導出。此產物隨後藉由內切酶(Dicer)處理且裝載於RNA誘導靜默錯合物(RISC)中,其後相同的靜默出現在siRNA中。基於IL-11或IL-11RA之不同mRNA同功異型物之公眾可用性,發現shRNA之適合序列對於熟習此項技術者而言係慣例問題。
該第二核酸分子亦可為編碼IL-11及/或IL-11RA蛋白質之基因中所包含的基因組DNA。該基因包含若干非編碼內含子,因此其序列不同於本文所揭示之mRNA或cDNA之序列。
在此情況下,第一核酸分子可為CRISPR Cas系統之引導RNA (參見例如Jinek等人(2012)),該引導RNA包含能夠與IL11及/或IL11RA基因之基因組股雜交的標靶特異性crRNA (「小干擾CRISPR RNA」) (或第一核酸分子可為單獨crRNA)。引導RNA/crRNA能夠將Cas酶(其為核酸內切酶)引導至IL11及/或IL11RA基因,其中Cas酶進行序列特異性股斷裂。藉由產生一或多個雙股斷裂,因此可使IL11及/或IL11RA基因沉默。為例如在不同子宮內膜組織細胞中針對IL11及/或IL-11RA之活體內基因沉默使用該系統,需要專用遞送技術,其包含遞送媒劑,諸如脂質奈米粒子,如例如Yin等人(2016)中所論述。基於IL-11及/或IL-11RA基因之基因組序列之公眾可用性,發現引導RNA中包含之crRNA之適合序列對於熟習此項技術者而言係慣例問題。
在另一實施例中,該第一核酸分子亦可為CRISPR Cpf系統之引導RNA (Zetsche等人(2015)),該引導RNA包含標靶特異性crRNA (「小干擾CRISPR RNA」)。類似於CRISPR Cas,引導RNA能夠將Cpf酶(其為核酸內切酶)引導至IL11及/或IL11RA基因。關於技術考慮,例如用於活體內應用之遞送及發現第一核酸分子之適合序列,如同CRISPR Cas之相似態樣適用。
CRISPR技術之其他實施例目前處於研發中,具有不同核酸內切酶。然而,全部此等途徑使用與靶序列雜交之標靶特異性RNA (如CRISPR Cas中之引導RNA或crRNA)。在全部此等情況中,標靶特異性RNA在本文所論述之較佳實施例之含義中稱為第一核酸分子。關於技術考慮,例如用於活體內應用之遞送及發現第一核酸分子之適合序列,如同CRISPR Cas之相似態樣適用。
根據本發明之一個實施例,能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用的藥劑為特異性結合至IL-11及/或IL-11RA蛋白質之適體。
適體為對預定標靶具有特異性結合特性之寡核苷酸。其經由稱為SELEX (「指數富集配位體之系統進化」)之組合製程獲自含有達至10
15種不同序列之隨機合成程式庫。適體特性由其3D形狀決定,該形狀由分子內摺疊產生,該分子內摺疊由其一級序列驅動。適體3D結構經由氫鍵鍵合、靜電及堆疊相互作用極其適用於其同源標靶之識別。適體一般呈現高親和力(對於小分子約微莫耳及對於蛋白質皮莫耳之K
d)。
關於產生標靶特異性適體之技術譜系之概述例如在Blind及Blank (2015)中給出。適體亦可遞送至細胞內空間中,如Thiel & Giangrande (2010)中所揭示。
基於不同IL-11及/或IL-11RA同功異型物之胺基酸序列之公眾可用性,發現能夠例如藉由結合至其活性中心或異位位點而充當IL-11及/或IL-11RA之抑制劑或拮抗劑的適合抗體因此對於熟習此項技術者而言係慣例問題。
根據本發明之一個實施例,能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用的藥劑為特異性結合至IL-11及/或IL-11RA蛋白質之一或多種同功異型物的小分子(SMol)。
用於適合抑制性或拮抗小化學分子(SMol)之鑑別及/或選擇及/或最佳化之方法為此項技術中已知的。此等可涉及但不限於諸如以下之方法:例如藉由量測例如IL-11/IL-11RA募集中之螢光共振能量轉移(FRET)或時間分辨螢光共振能量轉移(TR-FRET)對人類或非人類或經修飾之人類或經修飾之非人類IL-11及/或IL-11RA之此類SMol或SMol庫的結合分析或置換分析。
所有此等分子有可能用作IL-11及/或IL-11RA之抑制劑或拮抗劑以用於治療及/或預防不正常子宮出血,諸如大量月經出血或月經過多、痛經以及原有疾病平滑肌瘤及子宮內膜異位及月經。
根據本發明之一個實施例,拮抗劑或抑制劑可藉助於IL-11/IL-11RA結合分析、抑制分析、募集分析或活化分析發現。
根據本發明之一個實施例,抗體、片段或衍生物、抗體模擬物、適體或小分子結合之IL-11及/或IL-11RA蛋白質包含SEQ ID No 1至4、8、9中之任一者中所包含之序列。
根據本發明之一個實施例,編碼IL-11及/或IL-11RA蛋白質之第二核酸分子包含SEQ ID No. 5至7、10、11或其衍生物中之任一者中所包含之核苷酸序列。
醫藥組合物根據本發明之另一態樣,提供能夠結合至之IL-11及/或IL-11RA且根據上述描述抑制或拮抗IL-11及/或IL-11RA之作用的藥劑(用於製造藥物)之用途,其用於治療診斷或罹患不正常子宮出血、大量月經出血痛經以及原有疾病平滑肌瘤及子宮內膜異位及月經之人類受試者。
根據本發明之另一態樣,提供一種醫藥組合物,其包含能夠結合至IL-11及/或IL-11RA且根據上述描述抑制或拮抗IL-11及/或IL-11RA之作用的藥劑及一或多種醫藥學上可接受之賦形劑。
本發明進一步提供醫藥組合物,其包含能夠結合至IL-11及/或IL-11RA且根據上述描述抑制或拮抗IL-11及/或IL-11RA之作用的藥劑及至少一種或多於一種其他活性成分,該等醫藥組合物尤其用於治療及/或防治前述疾病。此類其他活性成分之較佳實例包括(但不限於):選擇性雌激素受體調節劑(SERM)、雌激素受體(ER)拮抗劑、芳香酶抑制劑、17β-HSD1抑制劑、類固醇硫酸酯酶(STS)抑制劑、GnRH促效劑及拮抗劑、吻素受體(KISSR)拮抗劑、選擇性雄激素受體調節劑(SARM)、雄激素、5α-還原酶抑制劑、選擇性孕酮受體調節劑(SPRM)、促孕素、抗雌激素、口服避孕藥、有絲分裂原活化蛋白質(MAP)激酶之抑制劑及MAP激酶(Mkk3/6、Mek1/2、Erk1/2)之抑制劑、蛋白激酶B (PKBα/β/γ;Akt1/2/3)之抑制劑、磷酸肌醇3-激酶(PI3K)之抑制劑、細胞週期素依賴性激酶(CDK1/2)之抑制劑、低氧誘導之信號傳導路徑之抑制劑(HIF1α抑制劑,脯胺醯基羥化酶之活化劑)、組蛋白脫乙醯基酶(HDAC)抑制劑、前列腺素F受體(FP) (PTGFR)拮抗劑及非類固醇發炎抑制劑(NSAID)。
舉例而言,本發明之藥劑可與已知抗過度增殖、細胞生長抑制或細胞毒素物質組合以用於治療癌症。另外,本發明藥劑亦可與放射線療法及/或手術干預組合使用。
適合組合活性成分之實例包括(但不限於):
131I-chTNT、阿巴瑞克(abarelix)、阿比特龍(abiraterone)、阿柔比星(aclarubicin)、阿地介白素(aldesleukin)、阿倫單抗(alemtuzumab)、亞利崔托寧(alitretinoin)、六甲蜜胺(altretamine)、胺魯米特(aminoglutethimide)、胺柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、阿加來濱(arglabin)、三氧化二砷、天冬醯胺酶、阿紮胞苷(azacitidine)、巴利昔單抗(basiliximab)、RDEA 119、貝洛替康(belotecan)、苯達莫司汀(bendamustine)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、比生群(bisantrene)、博萊黴素(bleomycin)、硼替佐米(bortezomib)、布舍瑞林(buserelin)、白消安(busulfan)、卡巴他賽(cabazitaxel)、亞葉酸鈣、左亞葉酸鈣、卡培他濱(capecitabine)、卡鉑(carboplatin)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡托莫西單抗(catumaxomab)、塞內昔布(celecoxib)、西莫白介素(celmoleukin)、西妥昔單抗(cetuximab)、苯丁酸氮芥(chlorambucil)、氯地孕酮(chlormadinone)、氮芥(chlormethine)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯膦酸、氯法拉濱(clofarabine)、克立他酶(crisantaspase)、環磷醯胺、環丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、達卡巴𠯤(dacarbazine)、放線菌素d (dactinomycin)、達貝汀α (darbepoetin alfa)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼白介素迪夫托斯(denileukin diftitox)、德諾單抗(denosumab)、地洛瑞林(deslorelin)、二溴螺氯銨(dibrospidium chloride)、多西他賽(docetaxel)、脫氧氟尿苷(doxifluridine)、小紅莓(doxorubicin)、小紅莓+雌酮(doxorubicin+estrone)、艾庫組單抗(eculizumab)、依決洛單抗(edrecolomab)、依利醋銨(elliptinium acetate)、艾曲波帕(eltrombopag)、內皮抑制素(endostatin)、依諾他濱(enocitabine)、表柔比星(epirubicin)、環硫雄醇(epitiostanol)、艾伯汀α (epoetin alfa)、艾伯汀β (epoetin beta)、依鉑(eptaplatin)、艾瑞布林(eribulin)、埃羅替尼(erlotinib)、雌二醇(estradiol)、雌莫司汀(oestramustine)、依託泊苷(etoposide)、依維莫司(everolimus)、依西美坦(exemestane)、法屈唑(fadrozole)、非格司亭(filgrastim)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、福美司坦(formestane)、福莫司汀(fotemustine)、氟維司群(fulvoestrant)、硝酸鎵、加尼瑞克(ganirelix)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥單抗(gemtuzumab)、氧化型谷胱甘肽(glutoxim)、戈舍瑞林(goserelin)、二鹽酸組胺、組胺瑞林(histrelin)、羥基脲(hydroxycarbamide)、I-125粒(I-125 pellets)、伊班膦酸(ibandronic acid)、替伊莫單抗(ibritumomab tiuxetan)、伊達比星(idarubicin)、異環磷醯胺(ifosfamide)、伊馬替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、干擾素α (interferon alfa)、干擾素β (interferon beta)、干擾素γ (interferon gamma)、伊匹單抗(ipilimumab)、伊立替康(irinotecan)、伊沙匹隆(ixabepilone)、蘭瑞肽(lanreotide)、拉帕替尼(lapatinib)、來那度胺(lenalidomide)、來格司亭(lenograstim)、香菇多糖(lentinan)、來曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、麥角乙脲(lisuride)、洛鉑(lobaplatin)、洛莫司汀(lomustine)、氯尼達明(lonidamine)、馬索羅酚(masoprocol)、甲羥孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美法侖(melphalan)、美雄烷(mepitiostan)、巰嘌呤、甲胺喋呤(methotrexate)、甲氧沙林(methoxsalen)、胺基乙醯丙酸甲酯、甲睾酮(methyltestosterone)、米伐木肽(mifamurtide)、米替福新(miltefosine)、米鉑(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴衛矛醇(mitolactol)、絲裂黴素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈達鉑(nedaplatin)、奈拉濱(nelarabine)、尼羅替尼(nilotinib)、尼魯胺(nilutamide)、尼妥珠單抗(nimotuzumab)、尼莫司汀(nimustine)、尼曲吖啶(nitracrine)、奧伏托默單抗(ofatumumab)、奧美拉唑(omeprazole)、奧賽力鉑(oxaliplatin)、p53基因療法、太平洋紫杉醇(paclitaxel)、帕利夫明(palifermin)、鈀-103粒(palladium-103 pellets)、帕米膦酸(pamidronic acid)、帕尼單抗(panitumumab)、帕佐泮尼(pazopanib)、培門冬酶(pegaspargase)、pEG-艾伯汀β (甲氧基PEG-艾伯汀β)、派非格司亭(pegfilgrastim)、聚乙二醇化干擾素α-2b (peginterferon alfa-2b)、培美曲唑(pemetrexed)、戊唑星(pentazocine)、噴司他汀(pentostatin)、培洛黴素(peplomycin)、培磷醯胺(perfosfamid)、皮西板尼(picibanil)、吡柔比星(pirarubicin)、普樂沙福(plerixafor)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、聚磷酸雌二醇(polyoestradiol phosphate)、多醣-K、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、潑尼莫司汀(prednimustine)、丙卡巴肼(procarbazine)、喹高利特(quinagolide)、氯化鐳-223 (radium-223 chloride)、雷洛昔芬(raloxifen)、雷替曲賽(raltitrexed)、雷莫司汀(ranimustine)、雷佐生(razoxane)、瑞戈非尼(regorafenib)、利塞膦酸(risedronic acid)、利妥昔單抗(rituximab)、羅米地辛(romidepsin)、羅米司亭(romiplostim)、沙格司亭(sargramostim)、西普亮塞-T (sipuleucel-T)、西佐喃(sizofiran)、索布佐生(sobuzoxan)、甘胺雙唑鈉(sodium glycididazole)、索拉非尼(sorafenib)、鏈脲菌素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、他米巴羅汀(tamibarotene)、他莫昔芬(tamoxifen)、他索那明(tasonermin)、替西白介素(teceleukin)、喃氟啶(tegafur)、喃氟啶+吉美拉西+奧特拉西(tegafur+gimeracil+oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、坦西莫司(temsirolimus)、替尼泊苷(teniposide)、睪固酮(testosterone)、替曲膦(tetrofosmin)、沙立度胺(thalidomide)、噻替派(thiotepa)、胸腺法新(thymalfasin)、硫鳥嘌呤、托西利單抗(tocilizumab)、拓朴替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲貝替定(trabectedin)、曲妥珠單抗(trastuzumab)、曲奧舒凡(treosulfan)、維甲酸(tretinoin)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲洛磷胺(trofosfamide)、色胺酸(tryptophan)、烏苯美司(ubenimex)、伐柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、維羅非尼(vemurafenib)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)、長春瑞濱(vinorelbine)、伏立諾他(vorinostat)、伏羅唑(vorozole)、釔-90玻璃微球體(yttrium-90 glass microsphere)、淨司他丁(zinostatin)、淨司他丁司他美(zinostatin stimalamer)、唑來膦酸(zoledronic acid)、左柔比星(zorubicin)。
本發明較佳係關於藥物,其包含至少一種能夠結合至IL-11及/或IL-11RA且根據上述描述抑制或拮抗IL-11介導之信號傳導的藥劑及以下活性成分中之一或多者,該等藥物尤其用於治療及/或防治類固醇受體依賴性增殖性病症:
- LHRH (促黃體素釋放激素)促效劑、
- LHRH (促黃體素釋放激素)拮抗劑、
- C(17,20)裂解酶抑制劑、
- I型5-α-還原酶抑制劑、
- II型5-α-還原酶抑制劑、
- 混合I/II型5-α-還原酶抑制劑、
- 用於治療骨轉移瘤之α輻射發射之放射性藥品,例如氯化鐳-223、
- 細胞抑制劑、
- VEGF (血管內皮生長因子)激酶抑制劑、
- 抗雌激素、
- 抗雌激素劑、
- EGF抗體、
- 雌激素或
- 聚(ADP-核糖)聚合酶I抑制劑或
- 偶合至細胞表面蛋白質之雙特異性T細胞接合子(BiTE),例如前列腺特異性膜抗原(PSMA)。
根據另一態樣,本發明涵蓋醫藥組合,其包含:
(a) 一或多種能夠結合至IL-11及/或IL-11RA且根據上述描述抑制或拮抗IL-11介導之信號傳導的藥劑,及
(b) 一或多種其他活性成分。
本發明之另一態樣為用於鑑別用於治療及/或預防罹患不正常子宮出血、處於罹患不正常子宮出血風險下之患者的方法中之藥劑,該方法包含在適合分析中篩選一或多種測試藥劑。
根據一個實施例,此類方法進一步包含創造及/或提供測試化合物庫之先前步驟。
根據所有態樣之另一實施例,本發明涵蓋用於判定人類或動物受試者是否適合於用根據上述描述之藥劑、醫藥組合物或組合治療之方法,該方法包含
a. 提供來自該受試者之組織或液體樣品,及
b. 測定該樣品是否由IL-11及/或IL-11RA之表現或過度表現表徵。
根據本發明之其他態樣,提供一種用於治療或預防不正常子宮出血之方法,其包含向有需要之受試者投與有效量之能夠抑制或拮抗IL-11及/或IL-11RA之作用的藥劑、根據上述描述之醫藥組合物或根據上述描述之組合。
根據所有態樣之另一實施例,本發明涵蓋用於判定人類或動物受試者是否適合於用根據上述描述之藥劑、醫藥組合物或組合治療之方法,該方法包含
a. 提供來自該受試者之組織或液體樣品,及
b. 測定該樣品是否由IL-11之表現或過度表現表徵,其中該表現IL-11係如下測定
i. 在mRNA水準上(例如RT-PCR、原位PCR及/或螢光原位雜交(FISH),
ii. 在蛋白質水準上(例如,利用免疫組織化學、免疫墨點法、ELISA及其類似者)。
根據本發明之另一態樣,提供一種用於根據上述描述之方法的伴隨診斷,其中該伴隨診斷包含至少一種選自由以下組成之群的藥劑:能夠與編碼IL-11及/或IL-11RA蛋白質之核酸(DNA或RNA)雜交的核酸探針或引子。
a. 能夠結合至IL-11及/或IL-11RA蛋白質之抗體,及/或
b. 能夠結合至IL-11及/或IL-11RA蛋白質之適體。
篩選及標靶抑制分析
用於鑑別及/或選擇及/或最佳化能夠結合至IL-11及/或IL-11RA且抑制或拮抗IL-11及/或IL-11RA之作用的適合藥劑之方法為此項技術中已知的。此等可涉及(但不限於)諸如能夠抑制或拮抗IL-11及/或IL-11RA對人類或非人類或經修飾之人類或經修飾之非人類IL-11及/或IL-11RA之作用的此類藥劑之結合分析的方法。存在熟習此項技術者已知的許多類型之配位體結合分析,放射性及非放射性分析。可藉由使用例如固定化IL-11或IL-11RA及經標記之藥劑,例如藉由用放射性同位素進行放射性標記或添加例如螢光部分來量測藥劑結合,在肽藥劑之情況下,可添加其他標籤作為例如Fc (免疫球蛋白之片段可結晶區域)標籤或Avi標籤(鏈黴抗生物素蛋白標籤)。另外,結合分析可涉及(但不限於)諸如天然或人造結合搭配物之募集之抑制或拮抗的置換分析之方法,諸如人類或非人類IL-11或其衍生物在人類或非人類IL-11RA或其衍生物上之募集。募集及募集抑制可藉由熟習此項技術者藉由若干方法量測,例如量測此類IL-11/IL-11RA募集中例如螢光共振能量轉移(FRET)或時間分辨螢光共振能量轉移(TR-FRET)。在一個實施例中,可量測IL-11或IL-11RA或IL-11/IL-11RA複合體對IL6ST募集之抑制及/或拮抗。在另一實施例中,募集之結合或抑制/拮抗可藉由人類或非人類細胞中之細胞分析來量測,該等細胞自然地表現IL-11RA (或IL-11RA及IL6ST)或表現重組人類或非人類IL-11RA (或IL-11RA及IL6ST)或其衍生物之細胞中。
根據本發明之一個實施例,拮抗劑或抑制劑可藉助於IL-11及/或IL-11RA抑制分析或活化分析發現。在一個實施例中,此類方法可包括(但不限於)藉由分析IL-11/IL-11RA信號傳導路徑之下游標記物,諸如傑納斯激酶(JAK)或信號轉導子及轉錄活化子蛋白(STAT)至IL-11/IL-11RA/IL6ST信號傳導複合物之募集來量測抑制或拮抗IL-11信號傳導的細胞分析,例如利用來自MSD (中尺度)之市售分析『磷脂醯-STAT3 (Tyr705)分析鹼套組』或Stat3依賴性報導子分析,例如來自Biocompare之『藉由螢光素酶之STAT3報導子分析』。在另一實施例中,STAT3或MEK/ERK激酶之磷酸化可藉由例如天然表現IL-11RA及IL6ST之人類或非人類細胞中或表現重組人類或非人類IL-11RA (或IL-11RA及IL6ST)或其衍生物之細胞中的ELISA技術量測。
IL - 11 之新穎治療性抗體及其醫療用途根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段能夠減少不正常子宮出血期間之失血。
經分離之抗體或其抗原結合片段在月經期間失血減少可在如實例1中所描述之鼠類HMB模型中分析。
根據所有態樣之另一實施例,本發明涵蓋經分離之抗體或其抗原結合片段,其中該經分離之抗體或其抗原結合片段使在月經期間失血減少至少約35%、或減少至少約50%、或較佳減少至少約60%、或更佳減少至少約70%。
能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段能夠如實例2中所描述減少子宮分化。如在所描述之子宮出血動物模型中誘導之子宮分化導致月經及在移除孕酮之後的子宮出血。在所描述之鼠類HMB模型之第12天降低子宮重量可解釋為預測如實例2中所描述之鼠類HMB模型在第12天與第15天之間所量測之子宮出血減少。
大量月經出血或月經通常特徵為健康狀況下降。避免或減少月經及大量月經出血為針對原發性及繼發性痛經之有效治療。能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段能夠使健康狀況下降之徵象縮減為如實例4中所描述在月經及大量月經出血期間體重減輕降低或縮減如實例8中所示月經及大量月經出血時之探索行為減少。
用於減少鼠類HMB模型出血之另一替代標記物為在第12天如實例9中所示之分化子宮中活化受體複合物下游之IL-11介導之Stat3磷酸化減少。
根據另一態樣,本發明涵蓋能夠抑制纖維瘤組織分泌VEGF-A之經分離之抗體或其抗原結合片段。
藉由經分離之抗體或其抗原結合片段抑制纖維瘤組織分泌VEGF-A可如實例3中所描述分析。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段以≤1.0 E-08 M、≤1.0 E-09 M、≤5.0 E-10 M、≤1.0 E-10 M、≤5.0 E-11 M、≤2.5 E-11 M或≤1.0 E-11 M之解離常數(KD)結合至人類IL-11。
經分離之抗體或其抗原結合片段與IL-11之結合可藉由如實例16中所描述來自Biacore系統之表面電漿子共振(SPR)或如實例23及24所描述之ELISA方法分析。測定經分離之抗體或其抗原結合片段與IL-11之結合的其他方法包括(但不限於)使用經由中尺度發現(MSD)之電化學螢光方法(ELC)、流式螢光檢測術xMAP®平台、免疫PCR (Lasseter HC等人,2020, Cytokine X; 28;2)、放射免疫分析(RIA)、螢光免疫分析(FIA)、熱轉移分析、LC-MS偵測及來自Octet系統之生物膜層干涉量測術(BLI)及動力排除分析技術,例如KinExA
®(Sapidyne Instruments, Inc., Boise, ID)。KinExA提供允許量測平衡結合親和力及在溶液相中使用未經修飾之分子之動力學的平台。此藉由在允許足夠的時間達到平衡(親和力量測結果)之後或在預平衡條件(動力學)下使用固相固定化分子探測一種相互作用成分之自由濃度來實現(Darling RJ等人(2004). ASSAY and Drug Development Technologies.
2(6): 647-657)。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段以≤100 nM、≤50 nM、≤25 nM、≤10 nM、≤1 nM、≤0.5 nM或≤0.1 nM之IC
50抑制人類IL-11介導之信號傳導。
活體外IL-11功能阻斷分析可為如實例17中所描述之分析。另外,其他活體外IL-11功能阻斷分析描述於文獻中。相比於在藉由本質上或編碼各別受體且使其在經轉染細胞中表現之DNA暫時或穩定轉染之後表現IL-11Ra及gp130初級細胞或細胞株中之重組或經誘導IL-11來誘導下游信號傳導之後的基於西方墨點之分析中之總STAT3,可藉由分析磷酸化STAT3之量之STAT3下游磷酸化來量測及定量IL-11信號傳導及藉由功能阻斷抗體之其信號傳導抑制。適合的初級細胞為例如如Sumida等人2015所描述之健康供體之PBMC。在用重組IL-11 (例如10 ng/ml)誘導之後,可藉由使用特異性抗體之免疫墨點評估總STAT3、磷酸化STAT3 (pSTAT3)及作為例如α-微管蛋白之對照蛋白質。
另外,活體外IL-11功能阻斷分析可量測且定量例如人類或鼠類IL-11在T11小鼠漿細胞瘤細胞株中以劑量依賴性方式所誘導之細胞增殖,如R&D系統(https://www.rndsystems.com/products/human-il-11-antibody_af-218-na或Nordan, R. P.等人(1987) J. Immunol. 139:813)所描述。由重組IL-11 (例如1 ng/mL)引發之增殖可藉由功能阻斷抗體抑制。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段抑制IL-11與IL-11Ra之相互作用且其中該經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物形成。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中如藉由使用雙複合物ELISA所測定,該等經分離之抗體或其抗原結合片段以≤1000 nM、≤100 nM、≤10 nM之IC
50抑制IL-11與IL-11Ra之相互作用,且其中如藉由使用三複合物ELISA所測定,該等經分離之抗體或其抗原結合片段以≤1000 nM、≤100 nM、≤10 nM之IC
50抑制IL-11/IL-11Ra/gp130複合物形成。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段抑制IL-11與IL-11Ra之相互作用且其中該經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物形成。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中如藉由使用三複合物ELISA所測定,該等經分離之抗體或其抗原結合片段以≤1000 nM、≤100 nM、≤10 nM之IC
50抑制IL-11/IL-11Ra/gp130複合物形成,且其中如藉由使用雙複合物ELISA所測定,該等經分離之抗體或其抗原結合片段不抑制IL-11與IL-11Ra之相互作用。
IL-11信號傳導之抑制可歸因於IL-11與IL-11Ra之相互作用位點之阻斷,或歸因於在IL-11:IL-11Ra複合物與細胞膜結合gp130相互作用後gp130活化之抑制。複合IL-11:IL-11Ra可包含可溶性或膜結合IL-11Ra。
可藉由各種分析方法分析藉由抗體或其抗原結合片段對IL-11與可溶性或膜結合IL-11Ra之相互作用之抑制。方法包括(但不限於)例如ELISA、FACS、經由中尺度發現(MSD)之電化學螢光方法(ELC)、流式螢光檢測術xMAP®平台、免疫PCR (Lasseter HC等人,2020, Cytokine X; 28;2)、放射免疫分析(RIA)、螢光免疫分析(FIA)、熱轉移分析、LC-MS偵測及來自Octet系統之生物膜層干涉量測術(BLI)及動力排除分析技術,例如KinExA
®。一種較佳分析型式為ELISA,其中可溶性IL-11Ra在存在或不存在IL-11抗體的情況下結合至固定化IL-11,且IL-11:IL-11Ra複合物形成可藉由經標記之偵測試劑(例如結合至IL-11Ra之抗體-酶結合物)偵測。干擾IL-11Ra:IL11複合物形成之抗體將減少分析中之最終讀取信號。為了促進偵測試劑之結合,IL-11Ra可用作融合蛋白,其中IL-11Ra已藉由重組DNA技術融合至例如抗體之Fc部分或小肽序列,尤其適合於藉由偵測試劑,例如cMyc標籤、His標籤或其他標籤識別。IL-11Ra亦可經化學修飾,例如經生物素標記,以便允許藉由尤其識別化學修飾之試劑,例如鏈黴抗生物素蛋白辣根過氧化酶偵測。採用IL-11Ra-Fc融合蛋白之ELISA型式描述於實例18中。為了允許測試人類IgG以及鼠類IgG對IL-11:IL-Ra複合物形成之抑制,利用兩種不同IL11Ra-Fc融合蛋白。當測試鼠類IgG時,使用融合至人類Fc之犬類IL-11Ra (Sino Biological;#70078-D02H),且當測試人類IgG時,使用融合至小鼠Fc之小鼠IL-11Ra (R&D System,#7405-MR)。顯而易見,歸因於物種之間的高IL-11Ra同源性,犬類IL-11Ra可用於與人類(SEQ ID NO: 1,aa 22-199;例如Invigate,例如批次號C121021-19)或鼠類IL-11 (SEQ ID NO: 16;aa 22-199,例如Invigate,例如批次號C210819-09)之複合物形成,且鼠類IL-11Ra可用於與人類(SEQ ID NO: 1;aa 22-199,例如Invigate,例如批次號C121021-19)或鼠類Il-11 (SEQ ID NO: 16;aa 22-199,例如Invigate,例如批次號C210819-09)之複合物形成。雙複合物分析型式之示意圖展示於17 (a、b)中。
可藉由如上文所描述之用於抑制IL-11:IL-11Ra雙複合物形成之分析測試及用於抑制IL-11Ra:IL-11:gp130三複合物形成之分析測試的組合來分析IL-11結合抗體或其抗原結合片段對IL-11:IL-11Ra複合物與gp130之相互作用的特定抑制。若抗體干擾三複合物分析中IL-11Ra:IL11:gp130三複合物形成而非雙複合物分析中IL-11:IL-11Ra雙複合物形成,則得出結論,抗體結合至IL-11與gp130之相互作用相關而非IL-11與IL-11Ra之相互作用相關的IL-11上之抗原決定基。相比之下,干擾雙複合物分析中IL-11:IL-11Ra複合物形成之抗體預期同樣干擾三複合物分析中IL-11Ra:IL-11:gp130複合物形成。重要地,因為抗體干擾雙複合物形成,所以得出結論,抗體結合至IL-11與IL-11Ra之相互作用相關的IL-11上之抗原決定基。
可藉由各種分析方法分析抗體或其抗原結合片段對IL-11:IL-11Ra複合物與可溶性或膜結合gp130之相互作用之抑制。方法包括(但不限於)例如ELISA、FACS、經由中尺度發現(MSD)之電化學螢光方法(ELC)、流式螢光檢測術xMAP®平台、免疫PCR (Lasseter HC等人,2020, Cytokine X; 28;2)、放射免疫分析(RIA)、螢光免疫分析(FIA)、熱轉移分析、LC-MS偵測、來自Octet系統之生物膜層干涉量測術(BLI)及均相時間分辨螢光(HTRF)分析。一種較佳分析型式為ELISA,其中可溶性IL-11Ra-Fc (例如R&D Systems, #7405-MR)、人類IL-11 (例如Invigate,例如批次號C121021-19)或鼠類IL-11 (例如Invigate,例如批次號C210819-09)及鼠類(例如R&D Systems, #468-MG)或人類gp130-Fc (例如R&D Systems, #671-GP)在存在或不存在IL-11抗體的情況下混合。視是否測試人類或鼠類IL-11抗體對三複合物形成之抑制而定,藉由固定化抗小鼠Fc或抗人類Fc捕捉試劑捕捉所形成之IL-11Ra:IL-11:gp130三複合物。最後,在測試人類IL-11 IgG對三複合物形成抑制之分析中,藉由針對人類或小鼠gp130之生物素標記抗體偵測所捕捉之三複合物。當測試小鼠IL-11 IgG對三複合物形成之抑制時,針對鼠類IL-11Ra經生物素標記之抗體用作偵測試劑。在兩種分析型式中,對於人類及小鼠IgG,藉由鏈黴抗生物素蛋白-POD試劑及受質使生物素標記偵測試劑之存在可見。若測試抗體抑制三複合物形成,則讀取信號將降低。三複合物分析型式之示意圖展示於18 (a、b)中。
抗體TPP-16478、TPP-18068、TPP-27159、TPP-29386、TPP-29528、TPP-29536在雙複合物及三複合物ELISA兩者中展示活性。另外,競爭者抗體TPP-23552及TPP-23580以及具有至少一些功能活性之所有測試市售抗體同樣在雙複合物及三複合物ELISA兩者中具有活性。
所測試市售抗體及競爭者抗體TPP-23552及TPP-23580中無一者在三複合物ELISA中展示活性且在雙複合物ELISA中未展示活性。相比之下,抗體TPP-18087、TPP-29519、TPP-29520、TPP-29521、TPP-29522、TPP-29523、TPP-29680、TPP-30000、TPP-30001、TPP-30002、TPP-30003、TPP-31325及TPP-31385在三複合物ELISA中展示活性且在雙複合物ELISA中未展示活性,表明此等抗體識別與gp130而非IL-11Ra之相互作用相關的IL-11上之新穎抗原決定基。
另外,實例39中可展示,增加濃度之競爭性抗體TPP-29536 (TPP-18068之衍生物(在雙複合體及三複合體ELISA兩者中具有活性))完全阻斷TPP-18068與IL-11之結合,而TPP-29680 (TPP-18087之衍生物(在三複合體ELISA中具有活性但在雙複合體ELISA中無活性))無影響(圖21a)。此外,增加濃度之競爭性抗體TPP-29680完全阻斷TPP-18087與IL-11之結合,而TPP-29536無影響(圖21b)。此等資料指示TPP-18068之抗原決定基(在雙複合物及三複合物ELISA兩者中具有活性)及其衍生物為獨特的且不與TPP-18087之抗原決定基(在三複合物ELISA中具有活性但在雙複合物ELISA中無活性)及其衍生物重疊。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段且其中該等經分離之抗體或其抗原結合片段抑制IL-11與IL-11Ra之結合且其中該等經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物形成。
雙複合物ELISA及三複合物ELISA中本發明之經分離之抗體或其抗原結合片段之不同活性指示此等抗體或其抗原結合片段形成結合至不同IL-11抗原決定基之兩種類別IL-11抗體。因此,各類別抗體可與結合至兩種不同IL-11抗原決定基之雙特異性抗體組合。此類雙特異性抗體包含抑制IL-11與IL-11Ra之相互作用之抗體的CDR's及抑制IL-11:IL-11Ra複合物與gp130之相互作用之抗體的CDR's。此類抗體之實例為TPP-20489、TPP-26195、TPP-29603及TPP-29697。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為雙特異性抗體或其抗原結合片段能夠結合至兩種不同IL-11抗原決定基,且其中雙特異性抗體或其抗原結合片段包含:包含第一IL-11抗原決定基之第一結合位點之第一單鏈片段(scFv)及包含第二IL-11抗原決定基之第二結合位點之第二單鏈片段(scFv)。各scFv片段可經由連接子,諸如肽連接子,例如GG GGSGGGGSGG GGSG (例如SEQ ID NO: 74,aa 240-256)融合至單獨Fc域(例如IgG Fc域)。一個FcR域可包含杵突變且另一Fc域可包含對應臼突變。(亦參見圖20)。在兩條鏈在宿主細胞中表現後,形成雙特異性抗體,其可藉由習知方法自培養物上清液純化。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段且其中雙特異性抗體或其抗原結合片段包含
i) 第一鏈,該第一鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 33之H-CDR1、包含SEQ ID NO: 34之H-CDR2及包含SEQ ID NO: 35之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 37之L-CDR1、包含SEQ ID NO: 38之L-CDR2及包含SEQ ID NO: 39之L-CDR3;及
ii) 第二鏈,該第二鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 55之H-CDR1、包含SEQ ID NO: 56之H-CDR2及包含SEQ ID NO: 57之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 59之L-CDR1、包含SEQ ID NO: 60之L-CDR2及包含SEQ ID NO: 61之L-CDR3;或
iii) 第一鏈,該第一鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 121之H-CDR1、包含SEQ ID NO: 122之H-CDR2及包含SEQ ID NO: 123之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 125之L-CDR1、包含SEQ ID NO: 126之L-CDR2及包含SEQ ID NO: 127之L-CDR3;及
iv) 第二鏈,該第二鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 107之H-CDR1、包含SEQ ID NO: 108之H-CDR2及包含SEQ ID NO: 109之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 111之L-CDR1、包含SEQ ID NO: 112之L-CDR2及包含SEQ ID NO: 113之L-CDR3。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段且其中雙特異性抗體或其抗原結合片段包含
i) 第一鏈,該第一鏈包含:包含SEQ ID NO: 32之可變重鏈域及包含SEQ ID NO: 36之可變輕鏈域;及
ii) 第二鏈,該第二鏈包含:包含SEQ ID NO: 54之可變重鏈域及包含SEQ ID NO: 58之可變輕鏈域;或
iii) 第一鏈,該第一鏈包含:包含SEQ ID NO:120之可變重鏈域及包含SEQ ID NO:124之可變輕鏈域;及
iv) 第二鏈,該第二鏈包含:包含SEQ ID NO: 106之可變重鏈域及包含SEQ ID NO: 110之可變輕鏈域。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段且其中雙特異性抗體或其抗原結合片段包含
i) 包含SEQ ID NO: 74之第一鏈及包含SEQ ID NO:75之第二鏈;或
ii) 包含SEQ ID NO:132之第一鏈及包含SEQ ID NO:133之第二鏈。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該人類IL-11具有SEQ ID NO: 1之序列aa 22-199;其中該人類IL-11Ra具有SEQ ID NO: 3之序列及/或其中該人類gp130為序列SEQ ID 12。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段與小鼠、大鼠及食蟹獼猴IL-11交叉反應,尤其對食蟹獼猴IL-11具有與人類IL-11相差小於100倍、小於30倍、小於15倍或小於5倍的親和力。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該IL-11為人類IL-11,尤其SEQ ID NO 1之序列aa 22-199之人類IL-11。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該IL-11為鼠類IL-11,尤其SEQ ID NO:16之序列aa 22-199之鼠類IL-11。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該IL-11為食蟹獼猴IL-11,尤其SEQ ID NO:17之序列aa 22-199之食蟹獼猴IL-11。
經分離之抗體或其抗原結合片段與IL-11之結合可藉由如實例16中所描述來自Biacore系統之表面電漿子共振(SPR)或如實例23及24所描述之ELISA方法分析。測定經分離之抗體或其抗原結合片段與IL-11之結合的其他方法包括(但不限於)使用經由中尺度發現(MSD)之電化學螢光方法(ELC)、流式螢光檢測術xMAP®平台、免疫PCR (Lasseter HC等人,2020, Cytokine X; 28;2)、放射免疫分析(RIA)、螢光免疫分析(FIA)、熱轉移分析、LC-MS偵測及來自Octet系統之生物膜層干涉量測術(BLI)及動力排除分析技術,例如KinExA
®(Sapidyne Instruments, Inc., Boise, ID)。KinExA提供允許量測平衡結合親和力及在溶液相中使用未經修飾之分子之動力學的平台。此藉由在允許足夠的時間達到平衡(親和力量測結果)之後或在預平衡條件(動力學)下使用固相固定化分子探測一種相互作用成分之自由濃度來實現(Darling RJ等人(2004). ASSAY and Drug Development Technologies.
2(6): 647-657)。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段不結合至IL-2Ra。
如實例20及26中所示,一些IL-11抗體展示與IL-2受體α (IL-2Ra或IL2Ra)之交叉反應性。然而,根據本發明之抗體,尤其TPP-29603、TPP-29697、TPP-18087、TPP-29536、TPP-29528、TPP-29519、TPP-29520、TPP-29521、TPP-29522、TPP-29523及TPP-23580不結合至IL2Ra (參見實例33)。
根據本發明之經分離之抗體或抗原結合片段可展現上文所描述之特徵之任何組合。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段包含
i. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 33之H-CDR1、包含SEQ ID NO: 34之H-CDR2及包含SEQ ID NO: 35之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 37之L-CDR1、包含SEQ ID NO: 38之L-CDR2及包含SEQ ID NO: 39之L-CDR3;或
ii. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO:43之H-CDR1、包含SEQ ID NO: 44之H-CDR2及包含SEQ ID NO: 45之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 47之L-CDR1、包含SEQ ID NO: 48之L-CDR2及包含SEQ ID NO: 49之L-CDR3;或
iii. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 55之H-CDR1、包含SEQ ID NO: 56之H-CDR2及包含SEQ ID NO: 57之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 59之L-CDR1、包含SEQ ID NO: 60之L-CDR2及包含SEQ ID NO: 61之L-CDR3;或
iv. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 65之H-CDR1、包含SEQ ID NO: 66之H-CDR2及包含SEQ ID NO: 67之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 69之L-CDR1、包含SEQ ID NO: 70之L-CDR2及包含SEQ ID NO: 71之L-CDR3;或
v. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 83之H-CDR1、包含SEQ ID NO: 84之H-CDR2及包含SEQ ID NO: 85之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 87之L-CDR1、包含SEQ ID NO: 88之L-CDR2及包含SEQ ID NO: 89之L-CDR3;或
vi. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 107之H-CDR1、包含SEQ ID NO: 108之H-CDR2及包含SEQ ID NO: 109之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 111之L-CDR1、包含SEQ ID NO: 112之L-CDR2及包含SEQ ID NO: 113之L-CDR3;或
vii. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 121之H-CDR1、包含SEQ ID NO:122之H-CDR2及包含SEQ ID NO: 123之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 125之L-CDR1、包含SEQ ID NO: 126之L-CDR2及包含SEQ ID NO: 127之L-CDR3;或
viii. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 137之H-CDR1、包含SEQ ID NO: 138之H-CDR2及包含SEQ ID NO: 139之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 141之L-CDR1、包含SEQ ID NO: 142之L-CDR2及包含SEQ ID NO: 143之L-CDR3;或
ix. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 149之H-CDR1、包含SEQ ID NO: 150之H-CDR2及包含SEQ ID NO: 151之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 153之L-CDR1、包含SEQ ID NO: 154之L-CDR2及包含SEQ ID NO: 155之L-CDR3;或
x. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 161之H-CDR1、包含SEQ ID NO: 162之H-CDR2及包含SEQ ID NO: 163之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 165之L-CDR1、包含SEQ ID NO: 166之L-CDR2及包含SEQ ID NO: 167之L-CDR3;或
xi. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 173之H-CDR1、包含SEQ ID NO: 174之H-CDR2及包含SEQ ID NO: 175之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 177之L-CDR1、包含SEQ ID NO: 178之L-CDR2及包含SEQ ID NO: 179之L-CDR3;或
xii. 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 185之H-CDR1、包含SEQ ID NO: 186之H-CDR2及包含SEQ ID NO: 187之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 189之L-CDR1、包含SEQ ID NO: 190之L-CDR2及包含SEQ ID NO: 191之L-CDR3。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段包含
i. 包含SEQ ID NO: 32之可變重鏈域及包含SEQ ID NO: 36之可變輕鏈域;或
ii. 包含SEQ ID NO: 42之可變重鏈域及包含SEQ ID NO: 46之可變輕鏈域;或
iii. 包含SEQ ID NO: 54之可變重鏈域及包含SEQ ID NO: 58之可變輕鏈域;或
iv. 包含SEQ ID NO: 64之可變重鏈域及包含SEQ ID NO: 68之可變輕鏈域;或
v. 包含SEQ ID NO: 82之可變重鏈域及包含SEQ ID NO: 86之可變輕鏈域;或
vi. 包含SEQ ID NO: 106之可變重鏈域及包含SEQ ID NO: 110之可變輕鏈域;或
vii. 包含SEQ ID NO: 120之可變重鏈域及包含SEQ ID NO: 124之可變輕鏈域;或
viii. 包含SEQ ID NO: 136之可變重鏈域及包含SEQ ID NO: 140之可變輕鏈域;或
ix. 包含SEQ ID NO: 148之可變重鏈域及包含SEQ ID NO: 152之可變輕鏈域;或
x. 包含SEQ ID NO: 160之可變重鏈域及包含SEQ ID NO: 164之可變輕鏈域;或
xi. 包含SEQ ID NO: 172之可變重鏈域及包含SEQ ID NO: 176之可變輕鏈域;或
xii. 包含SEQ ID NO: 184之可變重鏈域及包含SEQ ID NO: 188之可變輕鏈域。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段包含
i. 包含SEQ ID NO: 40之重鏈及包含SEQ ID NO: 41之輕鏈;或
ii. 包含SEQ ID NO: 90之重鏈及包含SEQ ID NO: 91之輕鏈;或
iii. 包含SEQ ID NO: 92之重鏈及包含SEQ ID NO: 33之輕鏈;或
iv. 包含SEQ ID NO: 116之重鏈及包含SEQ ID NO: 117之輕鏈;或
v. 包含SEQ ID NO: 130之重鏈及包含SEQ ID NO: 131之輕鏈;或
vi. 包含SEQ ID NO: 146之重鏈及包含SEQ ID NO: 147之輕鏈;或
vii. 包含SEQ ID NO: 158之重鏈及包含SEQ ID NO: 159之輕鏈;或
viii. 包含SEQ ID NO: 170之重鏈及包含SEQ ID NO: 171之輕鏈;或
ix. 包含SEQ ID NO: 182之重鏈及包含SEQ ID NO: 183之輕鏈;或
x. 包含SEQ ID NO: 192之重鏈及包含SEQ ID NO: 193之輕鏈;或
xi. 包含SEQ ID NO: 194之重鏈及包含SEQ ID NO: 195之輕鏈;或
xii. 包含SEQ ID NO: 196之重鏈及包含SEQ ID NO: 197之輕鏈。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗體或其抗原結合片段為單株抗體或抗原結合片段。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗體或其抗原結合片段為IgG抗體,尤其IgG1或IgG4抗體。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗原結合片段為scFv、Fab、Fab'片段或F(ab')2片段。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗體或其抗原結合片段為人類、人類化或嵌合抗體或其抗原結合片段,更尤其完全人類抗體或其抗原結合片段。
根據另一態樣,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等經分離之抗體或其抗原結合片段與根據本發明之經分離之抗體或抗原結合片段競爭結合至IL-11。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗體或其抗原結合片段為結合至IL-11及至少一種其他抗原之單特異性抗體或多特異性抗體,諸如雙特異性、三特異性或四特異性抗體。
根據所有態樣之另一實施例,本發明涵蓋能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段,其中該等抗體或其抗原結合片段與根據本發明之經分離之抗體或其抗原結合片段競爭結合至IL-11。
表7:市售抗體之簡要說明:
表8:抗體之簡要說明:
目錄號 | 公司 | 純系 | 同型 | 宿主 | 雙 / 三複合物 ELISA |
MAB218 | R&D Systems | 22626 | IgG2a | 小鼠 | 在雙複合物ELISA及三複合物ELISA中具有活性 |
MAB418 | R&D Systems | 188520 | IgG2a | 大鼠 | 未測試 |
AF-418 | R&D Systems | NA | IgG | 山羊 | 未測試 |
GTX34009 | Genetex | 6D9A1 | IgG1 | 小鼠 | 無活性 |
GTX52814 | Genetex | 9T27 | IgG2 | 小鼠 | 在雙複合物ELISA及三複合物ELISA中具有活性 |
LS-C104441 | LS-bio | 未知 | IgG1 | 小鼠 | 在雙複合物ELISA及三複合物ELISA中具有活性 |
LS-C193526 | LS-bio | KT8 | IgG1 | 小鼠 | 在雙複合物ELISA及三複合物ELISA中具有活性 |
MA5-30696 | Thermo Fisher Scientific | 12 | IgG1 | 小鼠 | 無活性 |
MA5-30695 | Thermo Fisher Scientific | 9 | IgG1 | 小鼠 | 無活性 |
MA5-23711 | Thermo Fisher Scientific | 22616 | IgG2b | 小鼠 | 在雙複合物ELISA及三複合物ELISA中具有活性 |
抗體 | 同型 | 雙 / 三複合物 ELISA | 描述 |
TPP-12904 | 不適用 | 同型對照 | |
TPP-10159 | mIgG1,λ | 不適用 | 同型對照 |
TPP-10748 | mIgG2a,λ | 不適用 | 同型對照 |
TPP-10750 | rIgG2a,λ | 不適用 | 同型對照 |
TPP-27360 | scFv-mIgG1 | 不適用 | 同型對照 |
TPP-16478 | hIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-18063 | mIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-18068 | mIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-18087 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-19528 | mIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-23552 | hIgG1,κ | 在雙複合物ELISA及三複合物ELISA中具有活性 | BSN 3C6 WO2019238882 |
TPP-23580 | hIgG1,κ | 在雙複合物ELISA及三複合物ELISA中具有活性 | BSN 3C6 WO2019238882 |
TPP-27159 | hIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-29386 | hIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-29519 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-29520 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-29521 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-29522 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-29523 | mIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-29528 | mIgG1,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-29536 | hIgG-λ-HS | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-29680 | hIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-30000 | hIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-30001 | hIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-30002 | hIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-30003 | hIgG1,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-31325 | hIgG4-SPLE,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-31385 | hIgG4-SPLE,λ | 在三複合物ELISA中具有活性,但在雙複合物ELISA中無活性 | |
TPP-31391 | hIgG4-SPLE,λ | 在雙複合物ELISA及三複合物ELISA中具有活性 | |
TPP-26195 | scFv-kih-mIgG1 | 在雙複合物ELISA及三複合物ELISA中具有活性 | 包含TPP-18068及TPP-18087之CDR's之雙特異性 |
TPP-20489 | scFv-kih-hIgG1 | 在雙複合物ELISA及三複合物ELISA中具有活性 | 包含TPP-18068及TPP-18087之CDR's之雙特異性 |
TPP-29697 | scFv-kih-hIgG1 | 在雙複合物ELISA及三複合物ELISA中具有活性 | 包含TPP-29528及TPP-29519之CDR's之雙特異性 |
TPP-29603 | scFv-kih-mIgG1 | 在雙複合物ELISA及三複合物ELISA中具有活性 | 包含TPP-29528及TPP-29519之CDR's之雙特異性 |
本申請案經由電子歸檔提供之序列表的全文包括於本文中。SEQ ID NO: 1至SEQ ID NO: 31係關於IL-11、IL-11Ra及介白素-6信號轉導子(參見表1-6)。SEQ ID NO: 32至SEQ ID NO:75及SEQ ID NO: 80至SEQ ID NO:197係關於本發明抗體(參見表9-12)。SEQ ID NO: 76至SEQ ID NO: 79係關於競爭者抗體(參見表9)。
在表8中列出根據本發明之較佳單特異性抗體之胺基酸序列,且在表9中列出根據本發明之較佳雙特異性抗體之胺基酸序列。
表9:根據本發明之較佳單特異性抗體之胺基酸序列
表10:根據本發明之較佳雙特異性抗體之胺基酸序列
抗體 | SEQ ID NO: VH | SEQ ID NO: HCDR1 | SEQ ID NO: HCDR2 | SEQ ID NO: HCDR3 | SEQ ID NO: VL | SEQ ID NO: LCDR1 | SEQ ID NO: LCDR2 | SEQ ID NO: LCDR3 | SEQ ID NO: 重鏈 | SEQ ID NO: 輕鏈 |
TPP-16478 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 40 | 41 |
TPP-18063 | 42 | 43 | 44 | 45 | 46 | 47 | 48 | 49 | 50 | 51 |
TPP-18068 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 52 | 53 |
TPP-18087 | 54 | 55 | 56 | 57 | 58 | 59 | 60 | 61 | 62 | 63 |
TPP-19528 | 64 | 65 | 66 | 67 | 68 | 69 | 70 | 71 | 72 | 73 |
TPP-23552 競爭者AB | 76 | 77 | ||||||||
TPP-23580 競爭者AB | 78 | 79 | ||||||||
TPP-27159 | 82 | 83 | 84 | 85 | 86 | 87 | 88 | 89 | 90 | 91 |
TPP-29386 | 106 | 107 | 108 | 109 | 110 | 111 | 112 | 113 | 92 | 93 |
TPP-29519 | 120 | 121 | 122 | 123 | 124 | 125 | 126 | 127 | 94 | 95 |
TPP-29520 | 136 | 137 | 138 | 139 | 140 | 141 | 142 | 143 | 96 | 97 |
TPP-29521 | 148 | 149 | 150 | 151 | 152 | 153 | 154 | 155 | 98 | 99 |
TPP-29522 | 160 | 161 | 162 | 163 | 164 | 165 | 166 | 167 | 100 | 101 |
TPP-29523 | 172 | 173 | 174 | 175 | 176 | 177 | 178 | 179 | 102 | 103 |
TPP-29528 | 106 | 107 | 108 | 109 | 110 | 111 | 112 | 113 | 104 | 105 |
TPP-29536 | 106 | 107 | 108 | 109 | 110 | 111 | 112 | 113 | 116 | 117 |
TPP-29680 | 120 | 121 | 122 | 123 | 124 | 125 | 126 | 127 | 130 | 131 |
TPP-30000 | 136 | 137 | 138 | 139 | 140 | 141 | 142 | 143 | 146 | 147 |
TPP-30001 | 148 | 149 | 150 | 151 | 152 | 153 | 154 | 155 | 158 | 159 |
TPP-30002 | 160 | 161 | 162 | 163 | 164 | 165 | 166 | 167 | 170 | 171 |
TPP-30003 | 172 | 173 | 174 | 175 | 176 | 177 | 178 | 179 | 182 | 183 |
TPP-31325 | 184 | 185 | 186 | 187 | 188 | 189 | 190 | 191 | 192 | 193 |
TPP-31385 | 54 | 55 | 56 | 57 | 58 | 59 | 60 | 61 | 194 | 195 |
TPP-31391 | 64 | 65 | 66 | 67 | 68 | 69 | 70 | 71 | 196 | 197 |
抗體 | SEQ ID NO: VH | SEQ ID NO: HCDR1 | SEQ ID NO: HCDR2 | SEQ ID NO: HCDR3 | SEQ ID NO: VL | SEQ ID NO: LCDR1 | SEQ ID NO: LCDR2 | SEQ ID NO: LCDR3 | SEQ ID NO: 鏈1 | SEQ ID NO: 鏈2 |
TPP-20489 鏈1 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 74 | |
TPP-20489 鏈2 | 54 | 55 | 56 | 57 | 58 | 59 | 60 | 61 | 75 | |
TPP-26195 鏈1 | 32 | 33 | 34 | 35 | 36 | 37 | 38 | 39 | 80 | |
TPP-26195 鏈2 | 54 | 55 | 56 | 57 | 58 | 59 | 60 | 61 | 81 | |
TPP-29603 鏈1 | 120 | 121 | 122 | 123 | 124 | 125 | 126 | 127 | 118 | |
TPP-29603 鏈2 | 106 | 107 | 108 | 109 | 110 | 111 | 112 | 113 | 119 | |
TPP-29697 鏈1 | 120 | 121 | 122 | 123 | 124 | 125 | 126 | 127 | 132 | |
TPP-29697 鏈2 | 106 | 107 | 108 | 109 | 110 | 111 | 112 | 113 | 133 |
在表11中列出根據本發明之較佳抗體之核酸序列。
表11:根據本發明之較佳抗體之核酸序列
抗體 | SEQ ID NO: 重鏈 | SEQ ID NO: 輕鏈 |
TPP-29536 | 114 | 115 |
TPP-29680 | 128 | 129 |
TPP-29697 | 134 鏈1 | 135 鏈2 |
TPP-30000 | 144 | 145 |
TPP-30001 | 156 | 157 |
TPP-30002 | 168 | 169 |
TPP-30003 | 180 | 181 |
肽變異體本發明之抗體或抗原結合片段不限於本文所提供之特異性肽序列。實際上,本發明亦體現此等多肽之變異體。參考本發明及習知獲得之技術及參考文獻,熟習此項技術者將能夠製備、測試及利用本文所揭示之抗體之功能變異體,同時瞭解能夠結合至IL-11之此等變異體在本發明之範疇內。
變異體可包括例如與本文所揭示之肽序列相比具有至少一個改變互補決定區(CDR) (高變)及/或構架(FR) (可變)域/位置的抗體。
藉由改變CDR或FR區域中之一或多個胺基酸殘基,熟習此項技術者通常可產生突變或多樣化抗體序列,其可針對抗原進行篩選,例如用於新的或改良之特性。
本發明之另一較佳實施例為其中如表8中所示選擇VH及VL序列之抗體或抗原結合片段。熟習此項技術者可使用表8中之資料設計本發明之範疇內的肽變異體。較佳地,變異體係藉由改變一或多個CDR區內之胺基酸來構築;變異體亦可具有一或多個改變之構架區。亦可在構架區中進行改變。舉例而言,可能改變肽FR域,其中與生殖系序列相比會出現殘基偏差。
或者,熟習此項技術者可藉由使用例如由Knappik A.等人,JMB 2000, 296:57-86所描述之程序,比對本文所揭示之胺基酸序列與此類抗體之相同類別之已知序列來進行相同分析。
此外,可藉由使用一種抗體作為起始點用於進一步最佳化來獲得變異體,其係使抗體中之一或多個胺基酸殘基,較佳為一或多個CDR中之胺基酸殘基多樣化,且在所得抗體變異體之集合中篩選具有改良特性之變異體。尤其較佳為VL及/或VH之CDR3中之一或多個胺基酸殘基之多樣化。可例如藉由使用三核苷酸突變誘發(TRIM)技術合成一系列DNA分子集合進行多樣化(Virnekäs B.等人,Nucl. Acids Res. 1994, 22: 5600)。抗體或其抗原結合片段包括具有修飾/變異之分子,包括(但不限於)例如導致半衰期改變之修飾(例如Fc部分之修飾或諸如PEG之 其他分子之連接)、改變之結合親和力、或改變之ADCC或CDC活性。
保守性胺基酸變異體可製得保留本文所描述之抗體肽序列之總體分子結構的多肽變異體。鑒於個別胺基酸之特性,熟習此項技術者將識別一些合理取代。可例如基於所涉及之殘基之極性、電荷、溶解度、疏水性、親水性及/或兩性性質之類似性而進行胺基酸取代,亦即「保守取代」。
舉例而言,(a)非極性(疏水性)胺基酸包括丙胺酸、白胺酸、異白胺酸、纈胺酸、脯胺酸、苯丙胺酸、色胺酸及甲硫胺酸;(b)極性中性胺基酸包括甘胺酸、絲胺酸、蘇胺酸、半胱胺酸、酪胺酸、天冬醯胺酸及麩醯胺酸;(c)帶正電(鹼性)胺基酸包括精胺酸、離胺酸及組胺酸;且(d)帶負電(酸性)胺基酸包括天冬胺酸及麩胺酸。該等取代通常地可在(a)至(d)群組內進行。另外,甘胺酸及脯胺酸可基於其破壞α-螺旋之能力彼此取代。類似地,某些胺基酸,諸如丙胺酸、半胱胺酸、白胺酸、甲硫胺酸、麩胺酸、麩醯胺酸、組胺酸及離胺酸更常出現於α-螺旋中,而纈胺酸、異白胺酸、苯丙胺酸、酪胺酸、色胺酸及蘇胺酸更常出現於β摺疊片中。甘胺酸、絲胺酸、天冬胺酸、天冬醯胺酸及脯胺酸通常輪流出現。一些較佳取代可在以下群組中進行:(i) S及T;(ii) P及G;及(iii) A、V、L及I。鑒於已知基因密碼及重組及合成DNA技術,熟練科學家易於構築編碼保守性胺基酸變異體之DNA。
糖基化變異體在抗體包含Fc區之情況下,可改變附著於其上之碳水化合物。由哺乳動物細胞產生之原生抗體典型地包含分支鏈雙觸角寡醣,其通常藉由N鍵連接至Asn297,使用Fc區之CH2域之Kabat EU編號;參見例如Wright等人Trends Biotechnol. 15: 26-32 (1997)。
在某些實施例中,對本文所提供之抗體進行改變以增加或降低抗體糖基化之程度。向抗體添加糖基化位點或使抗體缺失糖基化位點可藉由改變表現系統(例如宿主細胞)及/或藉由改變胺基酸序列以使得產生或移除一或多個糖基化位點來便利地實現。
在本發明之一個實施例中,藉由在原核宿主中表現來製備具有降低之效應功能或抗體衍生物的糖基抗體。適合原核宿主包括(但不限於)大腸桿菌(E. coli)、枯草桿菌(Bacillus subtilis)、鼠傷寒沙門桿菌(Salmonella typhimurium)及屬假單胞菌、鏈黴菌及葡萄球菌內之各種物種。
在一個實施例中,提供具有降低之效應功能的抗體變異體,其特徵為在該抗體之Fc部分之CH2域中的保守性N-連接位點處的修飾。在本發明之一個實施例中,修飾包含重鏈糖基化位點處之突變以防止該位點處之糖基化。因此,在本發明之一個較佳實施例中,藉由重鏈糖基化位點之突變,亦即使用Kabat EU編號之N297突變製備糖基抗體或抗體衍生物且在適當宿主細胞中表現。
在本發明之另一實施例中,糖基抗體或抗體衍生物具有降低之效應功能,其中在該抗體或抗體衍生物之Fc部分之CH2域中的保守性N-連接位點處之修飾包含CH2域聚糖之移除,亦即去糖基化。此等糖基抗體可由習知方法產生,且隨後以酶促方式去糖基化。用於抗體之酶促去糖基化之方法為此項技術中熟知的(例如Winkelhake & Nicolson (1976), J Biol Chem. 251(4):1074-80)。
在本發明之另一實施例中,去糖基化可使用糖基化抑制劑衣黴素實現(Nose & Wigzell (1983), Proc Natl Acad Sci USA, 80(21):6632-6)。亦即,修飾為預防該抗體之Fc部分之CH2域中的保守性N-連接位點處的糖基化。
在一個實施例中,提供無岩藻醣連接(直接或間接)至Fc區之碳水化合物結構的抗體變異體。舉例而言,此類抗體中之岩藻醣量可為1%至80%、1%至65%、5%至65%,或20%至40%。岩藻糖之量係藉由相對於如藉由MALDI-TOF質譜分析量測之附著至Asn 297之所有糖結構(例如複合、混雜及高甘露糖結構)的總和,計算糖鏈內Asn297處之岩藻糖之平均量來確定,如例如WO 2008/077546中所描述。Asn297係指位於Fc區中約位置297之天冬醯胺酸殘基(Fc區殘基之Eu編號);然而,歸因於抗體中微小序列變化,Asn297亦可位於位置294與300之間的位置297之上游或下游約±3個胺基酸處。此類岩藻糖基化變異體可具有改良之ADCC功能。
涉及「去岩藻糖基化」或「岩藻糖缺乏」抗體變異體之公開案之實例包括Okazaki等人J Mol. Biol. 336: 1239-1249 (2004);Yamane-Ohnuki等人Biotech. Bioeng. 87: 614 (2004)。
能夠產生去岩藻糖基化抗體之細胞株之實例包括缺乏蛋白質岩藻糖基化之Lec13 CHO細胞(Ripka等人Arch. Biochem. Biophys. 249:533-545 (1986);及WO 2004/056312),及基因剔除細胞株,諸如α-1,6-岩藻糖基轉移酶基因FUT8基因剔除CHO細胞(參見例如Yamane-Ohnuki等人Biotech. Bioeng. 87: 614 (2004);Kanda, Y.等人,Biotechnol. Bioeng., 94(4):680-688 (2006))。
抗體變異體進一步具備平分寡醣,例如其中附著至抗體之Fc區的雙觸角寡醣藉由GlcNAc平分。此類抗體變異體可具有減少之岩藻糖基化及/或改良之ADCC功能。此類抗體變異體之實例描述於例如WO 2003/011878;美國專利第6,602,684號;及US 2005/0123546中。
亦提供寡醣中之至少一個半乳糖殘基與Fc區附接之抗體變異體。此類抗體變異體可具有改良之CDC功能。此類抗體變異體描述於例如WO1997/30087;WO1998/58964;及WO1999/22764中。
FC 區變異體在某些實施例中,一或多個胺基酸修飾(例如取代)可引入本文所提供之抗體之Fc區(例如人類IgG1、IgG2、IgG3或IgG4 Fc區),藉此產生Fc區變異體。
在某些實施例中,本發明涵蓋具有一些而非所有效應功能之抗體變異體,此使得該抗體成為合乎應用需要之候選物,在該等應用中,活體內抗體半衰期至關重要,而某些效應功能(諸如補體及ADCC)為不必要或有害的。可進行活體外及/或活體內細胞毒性分析以確認CDC及/或ADCC活性之降低/損耗。舉例而言,可進行Fc受體(FcR)結合分析以確保抗體缺乏FcγR結合(因此可能缺乏ADCC活性),但保留FcRn結合能力。在一些實施例中,在Fc區中進行改變,其致使C1q結合及/或補體依賴性細胞毒性(CDC)改變(亦即,改良或減弱)。
在一些實施例中,根據本發明之經分離之抗體或抗原結合片段在抗體之Fc部分中包含沉默突變。抗體之Fc部分中之此類沉默突變為例如(但不限於) E233P、L234V、L235A、∆G236、D265G、A327Q或A330S,或更佳E233P、L234V、L235A、∆G236、D265G、A327Q及A330S (Durben等人,2015, Mol Ther. 2015年4月;23(4):648-55及EP2794658)。其他Fc工程改造實例包括人類IgG4變異體L235E或F234A/L235A及人類IgG1變異體L234A/L235A (「LALA」;Xu等人,Cell Immunol 2000年2月25日;200(1):16-26)。意欲降低效應功能之另一早期途徑為用諸如N297A、N297Q及N297G之突變使N297處之糖基化位點突變(「非糖基化」;Bolt等人,Eur J Immunol. 1993年2月;23(2):403-11;Tao及Morrison, J Immunol. 1989年10月15日;143(8):2595-601;Walker等人,Biochem J. 1989年4月15日;259(2):347-53;Leabman等人,MAbs 2013年11月-12月;5(6):896-903)。另一變化形式為減少如藉由審批通過之抗C5治療艾庫組單抗例示之效應功能的交叉子類別方法,該艾庫組單抗攜有來自IgG2之CH1及鉸鏈區,但攜有來自IgG4之CH2及CH3。其他實例包括人類IgG1中之L234F/L235E/P331S (「FES」;Oganesyan等人,Acta Crystallogr D Biol Crystallogr. 2008年6月;64(Pt 6):700-4)、人類IgG1中之P329G/L234A/L235A (「PG-LALA」;Schlothauer等人,Protein Eng Des Sel 2016年10月;29(10):457-466)、「IgG1sigma」(L234A/L235A/G237A/P238S/H268A/A330S/P331S,Tam等人,Antibodies (Basel) 2017年9月1日;6(3):12)、「IgG1-NNAS」(S298N/T299A/Y300S,Zhou等人,MAbs 2020年1月-12月;12(1):1814583) (根據Eu命名法編號;Edelman等人,Proc Natl Acad Sci USA. 1969年5月; 63(1): 78-85;Kabat等人, 1991, Sequences of Proteins of Immunological Interest,第5版.美國衛生與公共服務部(U.S. Department of Health and Human Services), 公共衛生處(Public Health Service),國立衛生研究院(National Institutes of Health), NIH公開案第91-3242號)。
在一些實施例中,根據本發明之經分離雙特異性抗體或抗原結合片段在抗體之Fc部分中包含對應杵/臼(杵臼)突變。杵臼途徑為藉由驅動與各半抗體CH3域中之突變雜二聚而產生雙特異性抗體的有效方式,該等突變諸如(但不限於)使若干CH3胺基酸殘基發生突變,亦即,對於「杵」半抗體,蘇胺酸(T) 366突變成色胺酸(W),且對於「臼」半抗體,蘇胺酸(T) 366突變成絲胺酸(S),白胺酸(L) 368突變成丙胺酸(A),且酪胺酸(Y) 407突變成纈胺酸(V)。
在某些實施例中,本發明涵蓋具有增加或減少之半衰期之抗體變異體。半衰期延長且與負責將母體IgG轉移至胎兒之新生兒Fc受體(FcRn)之結合改良的抗體(Guyer等人,J Immunol. 117:587 (1976)及Kim等人,J Immunol. 24:249 (1994))描述於US2005/0014934 (Hinton等人)中。彼等抗體包含具有一或多個取代之Fc區,在其中Fc區與FcRn之結合得以改良。舉例而言(但不限於),突變「YTE」(M252Y/S254T/T256E)及等效突變藉由自臨床前物種以及人類兩者中之核內體更高效再循環已展示顯著延長半衰期。藉由例如H435A消除FcRn與抗體之Fc部分之間的相互作用產生極短的半衰期,因為抗體不再受FcRn再循環保護而免受溶酶體降解。
根據另一態樣,本發明涵蓋抗體結合物,其包含根據本發明之經分離之抗體或抗原結合片段。
抗體產生本發明之抗體可衍生自重組抗體集合庫,該重組抗體集合庫係基於已自許多健康志願者之抗體分離的胺基酸序列,例如使用n-CoDeR®技術,將全人類CDR重組成新抗體分子(Carlson & Söderlind, Expert Rev Mol Diagn. 2001年5月;1(1):102-8)。或者,舉例而言,作為Hoet RM等人,Nat Biotechnol 2005;23(3):344-8)中所描述之完全人類抗體噬菌體呈現集合庫的抗體集合庫可用於分離IL-11特異性抗體。自人類抗體集合庫分離之抗體或抗體片段在本文中視為人類抗體或人類抗體片段。
人類抗體可藉由向已經修飾以響應於抗原攻擊而產生完整人類抗體或具有人類可變區之完整抗體的轉殖基因動物投與免疫原來製備。此類動物典型地含有人類免疫球蛋白基因座的全部或一部分,其置換內源性免疫球蛋白基因座,或存在於染色體外或隨機整合至動物染色體中。舉例而言,可進行經基因工程改造之小鼠的免疫接種,尤其hMAb小鼠(例如VelocImmune mouse®或XENOMOUSE®)的免疫接種。
可使用融合瘤技術產生其他抗體(例如參見Köhler及Milstein Nature. 1975年8月7日;256(5517):495-7),產生例如可轉化成嵌合或人類化抗體之鼠類、大鼠或兔抗體。人類化抗體及其製得方法評述於例如Almagro及Fransson, Front. Biosci. 13:1619-1633 (2008)中,且進一步描述於例如Riechmann等人, Nature 332:323-329 (1988);Queen等人,Proc. Natl Acad. Sci. USA 86:10029-10033 (1989);美國專利第5, 821,337號、第7,527,791號、第6,982,321號及第7,087,409號;Kashmiri等人, Methods 36:25-34 (2005) (描述特異性決定區(SDR)移植);Padlan, Mol. Immunol. 28:489-498 (1991) (描述「表面再塑」);Dall' Acqua等人, Methods 36:43-60 (2005) (描述「FR改組」);及Osboum等人, Methods 36:61-68 (2005)及Klimka等人, Br. J. Cancer, 83:252-260 (2000) (描述FR改組之「導引選擇」方法)。
提供用於使用重組抗體集合庫產生抗體之實例。
根據本發明之 DNA 分子根據另一態樣,本發明涵蓋編碼根據本發明之抗體或其抗原結合片段之經分離之核酸序列。
根據另一態樣,本發明涵蓋包含根據本發明之核酸序列之載體。
本發明亦關於編碼根據本發明之抗體或抗原結合片段之經分離之核酸序列。編碼根據本發明之抗體或抗原結合片段之經分離之核酸序列可例如藉由Sambrook等人,1989及Ausubel等人,1989中所描述之技術或替代地藉由以化學方式合成產生。(例如寡核苷酸合成(1984, Gait編, IRL Press, Oxford)中所描述之技術)。表2中給出用於所表現之抗體的DNA序列。此等序列在某些情況下針對哺乳動物表現最佳化。本發明之DNA分子不限於本文所揭示之序列,且亦包括其變異體。本發明內之DNA變異體可藉由參考其在雜交中之物理特性來描述。熟習此項技術者將認識到,使用核酸雜交技術,DNA可用於鑑別其互補序列,且由於DNA為雙股,因此其等效物或同源物。亦將認識到,雜交可以小於100%互補性進行。然而,鑒於病況之適當選擇,可使用雜交技術基於其與特定探針之結構相關性來區分DNA序列。關於此類病況之指導,參見上文Sambrook等人,1989及Ausubel等人,1995 (Ausubel, F. M., Brent, R., Kingston, R. E., Moore, D. D., Sedman, J. G., Smith, J. A., & Struhl, K.編(1995). Current Protocols in Molecular Biology. New York: John Wiley and Sons)。
兩個聚核苷酸序列之間的結構相似性可表現為兩個序列將彼此雜交的條件之「嚴格度」的函數。如本文所使用,術語「嚴格度」係指條件不利於雜交之程度。嚴格條件很大程度上不利於雜交,且僅大多數結構上相關之分子將在此類條件下彼此雜交。相反地,非嚴格條件促進顯示較小程度之結構相關性之分子雜交。因此,雜交嚴格度與兩個核酸序列之結構關係直接相關。
雜交嚴格度為許多因素之函數,包括總DNA濃度、離子強度、溫度、探針尺寸及破壞氫鍵結之試劑的存在。促進雜交之因子包括高DNA濃度、高離子強度、低溫、較長探針尺寸及破壞氫鍵之試劑的不存在。雜交典型地在兩個階段中進行:「結合」階段及「洗滌」階段。
功能等效 DNA 變異體本發明範疇內之DNA變異體之又一類別可參考其編碼產物來描述。此等功能等效聚核苷酸之特徵在於其歸因於遺傳密碼之簡併而編碼相同肽序列的事實。
應認識到,本文所提供之DNA分子之變異體可以若干不同方法構築。舉例而言,其可構築為完全合成DNA。有效合成寡核苷酸之方法為廣泛可用的。參見Ausube等人,章節2.11,附錄21 (1993)。重疊寡核苷酸可以Khorana等人,J. Mol. Biol. 72:209 217 (1971)首先報導之方式合成且組裝;亦參見Ausubel等人,上文, 章節8.2。合成DNA較佳設計成具有在基因之5'及3'端經工程改造以便於選殖至適當載體中的適宜限制位點。
如所指示,產生變異體之方法係以本文所揭示之DNA中之一者開始,且隨後進行定點突變誘發。參見Ausubel等人,上文,第8章,附錄37 (1997)。在典型方法中,將靶DNA選殖入單股DNA噬菌體媒劑中。單股DNA經分離且與含有所需核苷酸改變之寡核苷酸雜交。合成互補股,且將雙股噬菌體引入宿主中。一些所得後代將含有所需突變體,其可使用DNA定序來確認。另外,可獲得增加後代噬菌體將為所需突變體之概率的各種方法。此等方法為本領域中之彼等方法所熟知,且套組可商購用於產生此類突變體。
重組 DNA 構築體及表現根據另一態樣,本發明涵蓋包含根據本發明之核酸序列之載體。
根據另一態樣,本發明涵蓋表現根據本發明之抗體或其抗原結合片段的經分離之細胞,其包含根據本發明之核酸或根據本發明之載體。
根據所有態樣之另一實施例,本發明涵蓋表現根據本發明之抗體或其抗原結合片段之經分離之細胞,其包含根據本發明之核酸或根據本發明之載體,其中該細胞為原核或真核細胞。
根據另一態樣,本發明涵蓋產生根據本發明之經分離之抗體或抗原結合片段的方法,其包含培養根據本發明之細胞及視情況純化該等抗體或抗原結合片段。
本發明進一步提供重組DNA構築體,其包含一或多個根據本發明之核苷酸序列。本發明之重組構築體可與載體(諸如質體、噬菌粒、噬菌體或病毒載體)結合使用,編碼本發明抗體或其抗原結合片段或其變異體的DNA分子插入至該載體中。
因此,在一個態樣中,本發明係關於一種包含根據本發明之核酸序列之載體。
本文所提供之抗體、抗原結合部分或其變異體可藉由在宿主細胞中重組表現編碼輕鏈及重鏈或其部分之核酸序列來製備。為以重組方式表現抗體、抗原結合部分或其變異體,可用攜載編碼輕鏈及/或重鏈或其部分之DNA片段之一或多個重組表現載體轉染宿主細胞,使得輕鏈及重鏈在宿主細胞中表現。使用標準重組DNA方法來製備及/或獲得編碼重鏈及輕鏈之核酸,將此等核酸併入重組表現載體且將載體引入寄主細胞中,諸如描述於Sambrook, Fritsch及Maniatis(編), Molecular Cloning; A Laboratory Manual, 第二版, Cold Spring Harbor, N.Y., (1989)、Ausubel, F. M.等人(編) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989)中及Boss等人之美國專利第4,816,397號中之彼等者。
另外,編碼重鏈及/或輕鏈之可變區之核酸序列可轉化成例如編碼全長抗體鏈、Fab片段之核酸序列或轉化成scFv。編碼VL或VH之DNA片段可以可操作方式連接(使得由兩個DNA片段編碼之胺基酸序列處於框內)至編碼例如抗體恆定區或可撓性連接子之另一DNA片段。人類重鏈及輕鏈恆定區之序列為此項技術中已知的(參見例如Kabat, E. A.等人, (1991) Sequences of Proteins of Immunological Interest, 第五版, U.S. Department of Health and Human Services, NIH公開案第91-3242號)且涵蓋此等區域之DNA片段可藉由標準PCR擴增來獲得。
為建立編碼scFv之聚核苷酸序列,編碼VH及VL之核酸可以操作方式連接至編碼柔性連接子之另一片段,使得VH及VL序列可表示為連續單鏈蛋白,其中VL及VH區係藉由柔性連接子接合(參見例如Bird等人(1988) Science 242:423-426;Huston等人(1988) Proc. Natl. Acad. Sci. USA 85:5879-5883;McCafferty等人, Nature (1990) 348:552-554)。
為表現抗體、其抗原結合片段或其變異體,可使用標準重組DNA表現方法(參見例如Goeddel;Gene Expression Technology. Methods in Enzymology 185,Academic Press,San Diego,Calif. (1990))。舉例而言,可將編碼所需多肽之DNA插入至隨後轉染至適合宿主細胞中之表現載體中。適合宿主細胞為原核細胞及真核細胞。原核宿主細胞之實例為例如細菌,真核宿主細胞之實例為酵母、昆蟲及昆蟲細胞、植物及植物細胞、轉殖基因動物或哺乳動物細胞。重組構築體引入宿主細胞中可使用標準技術(諸如磷酸鈣轉染、DEAE聚葡萄糖介導之轉染、電穿孔、轉導或噬菌體感染)進行。
在一些實施例中,將編碼重鏈及輕鏈之DNA插入至單獨載體中。在其他實施例中,將編碼重鏈及輕鏈之DNA插入至相同載體中。應理解,表現載體之設計,包括調節序列之選擇,受諸如宿主細胞之選擇、所需蛋白質之表現水準及表現是否為組成型或誘導型之因素影響。
因此,在另一態樣中,本發明係關於表現根據本發明之抗體或抗原結合片段及/或包含根據本發明之核酸或根據本發明之載體的經分離之細胞。
經分離之細胞可為幾乎任何可用於表現載體之細胞。經分離之細胞可例如為高級真核宿主細胞,諸如哺乳動物細胞、低級真核宿主細胞,諸如酵母細胞,且可為原核細胞,諸如細菌細胞。
在另一態樣中,本發明係關於一種產生根據本發明之經分離之抗體或抗原結合片段的方法,其包含培養根據本發明之細胞。在特定實施例中,在適合於抗體表現之條件下培養根據本發明之細胞,且回收抗體或抗原結合片段。在特定實施例中,抗體或抗原結合片段經純化,尤其純化至至少95重量%均質性。
細菌表現藉助功能性啟動子在可操作讀取階段中藉由插入編碼所需蛋白質之DNA序列連同適合之轉譯起始及終止信號來構築用於細菌用途之適用表現載體。載體將包含一或多種表現型可選標記物及複製起點以確保維護載體,且視需要,以提供宿主內之擴增。用於轉形之適合原核宿主包括(但不限於)大腸桿菌、枯草桿菌、鼠傷寒沙門桿菌及屬假單胞菌、鏈黴菌及葡萄球菌內之各種物種。
細菌載體可(例如)以噬菌體、質體或噬菌粒為主。此等載體可含有衍生自通常含有熟知選殖載體pBR322 (ATCC 37017)之元素的市售質體之可選標記物及細菌複製起點。在適合宿主菌株轉形及宿主菌株生長至適合細胞密度之後,所選啟動子係藉由適當手段(例如,溫度變換或化學誘導)去抑制/誘導且將細胞培養持續額外時段。細胞典型地藉由離心搜集,藉由物理或化學手段破壞且保留所得粗提取物以供進一步純化。
在細菌系統中,多個表現載體可宜視所表現之蛋白質的預期用途而選擇。舉例而言,當要產生大量此類蛋白質時,為產生抗體或為篩選肽庫,例如引導易純化之高水準融合蛋白產物之表現的載體可為所需的。
因此,本發明之一實施例為包含編碼本發明之新穎抗體之核酸序列的表現載體。
本發明之抗體或其抗原結合片段或其變異體包括經天然純化之產物、化學合成程序之產物及藉由重組技術由原核宿主產生之產物,該原核宿主包括例如大腸桿菌、枯草桿菌、鼠傷寒沙門桿菌及屬假單胞菌、鏈黴菌及葡萄球菌內之各種物種,較佳來自大腸桿菌細胞。
哺乳動物表現用於哺乳動物宿主細胞表現之較佳調節序列包括引導哺乳動物細胞中高水準蛋白質表現之病毒元素,諸如衍生自細胞巨大病毒(CMV) (諸如CMV啟動子/增強子)、猿猴病毒40 (SV40) (諸如SV40啟動子/增強子)、腺病毒(例如,腺病毒主要晚期啟動子(AdMLP))及多瘤病毒之啟動子及/或增強子。抗體之表現可為組成型或調節型的(例如,可藉由添加或移除諸如與Tet系統結合之四環素的小分子電感器誘導)。對於病毒調節性元素及其序列之進一步描述,參見例如Stinski之U.S. 5,168,062、Bell等人之U.S. 4,510,245及Schaffner等人之U.S. 4,968,615。重組表現載體亦可包括複製起點及可選標記物(參見例如U.S. 4,399,216、U.S. 4,634,665及U.S. 5,179,017)。適合可選標記物包括在引入載體之宿主細胞上賦予藥物抗性之基因,該等藥物諸如G418、嘌呤黴素、潮黴素、殺稻瘟菌素(blasticidin)、勻黴素/博萊黴素或甲胺喋呤,或諸如麩醯胺酸合成酶的利用營養缺陷型之可選標記物(Bebbington等人,Biotechnology (N Y). 1992年2月;10(2):169-75)舉例而言,二氫葉酸還原酶(DHFR)基因賦予對甲胺喋呤之抗性、neo基因賦予對G418之抗性、來自土麴菌之bsd基因賦予對殺稻瘟菌素之抗性、嘌呤黴素N-乙醯基-轉移酶賦予對嘌呤黴素之抗性、Sh ble基因產物賦予對勻黴素之抗性,且大腸桿菌潮黴素抗性基因(hyg或hph)賦予對潮黴素之抗性。類似於DHFR或麩醯胺酸合成酶之可選標記物亦適用於與MTX及MSX結合之擴增技術。
可使用標準技術進行將表現載體轉染至宿主細胞中,諸如電致孔、核轉染、磷酸鈣沈澱、脂質體轉染、諸如基於聚乙烯亞胺之轉染的基於聚陽離子之轉染及DEAE-聚葡萄糖轉染。
用於表現本文所提供之抗體、其抗原結合片段或其變異體的適合哺乳動物寄主細胞包括:中國倉鼠卵巢(CHO細胞),諸如CHO-K1、CHO-S、CHO-K1SV [包括dhfr-CHO細胞,描述於Urlaub及Chasin,(1980) Proc. Natl. Acad. Sci. USA 77:4216-4220及Urlaub等人,Cell. 1983年6月;33(2):405-12中,與DHFR可選標記物(例如,如R. J. Kaufman及P. A. Sharp (1982) Mol. Biol. 159:601-621中所描述)一起使用;及例示於Fan等人,Biotechnol Bioeng. 2012年4月;109(4):1007-15中之其他基因剔除細胞];NS0骨髓瘤細胞;COS細胞;HEK293細胞;HKB11細胞;BHK21細胞;CAP細胞;EB66細胞及SP2細胞。
表現在表現系統中亦可為暫時或半穩定的,該等表現系統諸如HEK293、HEK293T、HEK293-EBNA、HEK293E、HEK293-6E、HEK293-自由式(HEK293-Freestyle)、HKB11、Expi293F、293EBNALT75、CHO自由式、CHO-S、CHO-K1、CHO-K1SV、CHOEBNALT85、CHOS-XE、CHO-3E7或CAP-T細胞(例如,Durocher等人, Nucleic Acids Res. 2002年1月15日; 30(2):E9)。
在一些實施例中,表現載體經設計使得將經表現之蛋白質分泌至寄主細胞生產所處之培養基中。可使用標準蛋白質純化方法自培養基回收抗體、其抗原結合片段或其變異體。
純化可藉由熟知方法自重組細胞培養基回收且純化本發明之抗體或其抗原結合片段或其變體,該等方法包括(但不限於)硫酸銨或乙醇沈澱、酸提取、蛋白質A層析法、蛋白質G層析法、陰離子或陽離子交換層析法、磷酸纖維素層析法、疏水相互作用層析法、親和性層析法、羥磷灰石層析法及凝集素層析法。亦可採用高效液相層析法(「HPLC」)以供純化。參見例如Colligan,Protocols in Immunology或Current Protocols in Protein Science,John Wiley & Sons,NY, N.Y., (1997-2001),例如第1章、第4章、第6章、第8章、第9章、第10章,各自以全文引用之方式併入本文中。
本發明之抗體或其抗原結合片段或其變體包括經天然純化之產物、化學合成程序之產物及藉由重組技術由真核宿主產生之產物,該真核宿主包括例如酵母、高等植物、昆蟲及哺乳動物細胞。視重組產生程序中所利用之宿主而定,本發明之抗體可經糖基化或可未經糖基化。此類方法描述於許多標準實驗室手冊,諸如上文Sambrook,章節17.37-17.42;上文Ausubel,第10章、第12章、第13章、第16章、第18章及第20章中。
在較佳實施例中,抗體經純化(1)至超過95重量%抗體,如例如洛瑞方法(Lowry method)、UV-Vis光譜分析或藉由SDS-毛細管凝膠電泳(例如在測徑規(Caliper) LabChip GXII、GX 90或伯樂生物分析儀裝置(Biorad Bioanalyzer device)上)所測定,且在另外較佳實施例中,超過99重量%,(2)在一定程度上足以獲得N端或內部胺基酸序列之至少15個殘基,或(3)在還原性或非還原性條件下使用庫馬斯藍(Coomassie blue)或較佳銀色染料達到藉由SDS-PAGE之均質性。經分離天然存在之抗體包括重組細胞內之原位抗體,此係因為抗體之天然環境之至少一種組分將不存在。然而,通常而言,經分離抗體將藉由至少一個純化步驟來製備。
治療方法治療方法涉及向有需要治療之受試者投與治療有效量之本發明所涵蓋之抗體或其抗原結合片段或其變異體。在此,「治療有效」量定義為抗體或其抗原結合片段之量,其具有足以單獨或與其他藥劑組合減少單次給藥或根據多次給藥方案,減少繼發於平滑肌瘤或子宮內膜異位之大量月經出血、不正常子宮出血或大量月經出血,該等藥劑導致不良病況緩解,但該量為毒理學可耐受的。受試者可為人類或非人類動物(例如,家兔、大鼠、小鼠、犬、猴或其他低等靈長類動物)。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段,或包含根據本發明之經分離之抗體或抗原結合片段的結合物,或包含根據本發明之經分離之抗體或抗原結合片段的醫藥組合物,其用於治療或預防疾病。
根據本發明之經分離之抗體或抗原結合片段可用作各種IL-11相關疾病及/或與不正常子宮出血相關之疾病中之治療或診斷工具。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段或根據本發明之抗體結合物的用途,其用作診斷劑。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段的用途,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段的用途,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段的用途,其用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位之方法中。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段的用途,其用於製備醫藥組合物,較佳藥物,用於治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位。
根據另一態樣,本發明涵蓋使用根據有效量之本發明之經分離之抗體或抗原結合片段治療及/或預防不正常子宮出血、痛經、平滑肌瘤或子宮內膜異位的方法。
根據所有態樣之一個實施例,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血為大量月經出血、長期出血或出血模式改變之出血。
根據所有態樣之另一實施例,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血為大量月經出血,且其中大量月經出血繼發於平滑肌瘤或子宮內膜異位。
根據所有態樣之另一實施例,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血與痛經相關。
根據所有態樣之另一實施例,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段,其用於治療及/或預防不正常子宮出血,其中不正常子宮出血與繼發於子宮平滑肌瘤或子宮內膜異位之痛經相關。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或抗原結合片段或根據本發明之結合物或根據本發明之醫藥組合物的用途,其用於抑制或調節月經。
根據本發明之抗體或抗原結合片段或其變異體可能與已知藥物一起共同投與,且在一些情況下,抗體或其抗原結合片段可能自身經修飾。舉例而言,抗體或其抗原結合片段或其變異體可與藥物或另一肽或蛋白質結合以潛在地進一步提高功效。
本發明之抗體或其抗原結合片段或其變異體可以唯一醫藥劑或與一或多種額外治療劑組合投與,其中組合未造成不可接受之不良作用。
因此,在另一態樣中,本發明係關於根據本發明之經分離之抗體或抗原結合片段或根據本發明之結合物或根據本發明之醫藥組合物,其用於與一或多種其他治療活性化合物之同時、單獨或連續組合中。
此類其他活性化合物之較佳實例包括(但不限於):選擇性雌激素受體調節劑(SERM)、雌激素受體(ER)拮抗劑、芳香酶抑制劑、17β-HSD1抑制劑、類固醇硫酸酯酶(STS)抑制劑、GnRH促效劑及拮抗劑、吻素受體(KISSR)拮抗劑、選擇性雄激素受體調節劑(SARM)、雄激素、5α-還原酶抑制劑、選擇性孕酮受體調節劑(SPRM)、促孕素、抗雌激素、口服避孕藥、有絲分裂原活化蛋白質(MAP)激酶之抑制劑及MAP激酶(Mkk3/6、Mek1/2、Erk1/2)之抑制劑、蛋白激酶B (PKBα/β/γ;Akt1/2/3)之抑制劑、磷酸肌醇3-激酶(PI3K)之抑制劑、細胞週期素依賴性激酶(CDK1/2)之抑制劑、低氧誘導之信號傳導路徑之抑制劑(HIF1α抑制劑,脯胺醯基羥化酶之活化劑)、組蛋白脫乙醯基酶(HDAC)抑制劑、前列腺素F受體(FP) (PTGFR)拮抗劑及非類固醇發炎抑制劑(NSAID)。
舉例而言,本發明之抗體或其片段可與已知抗過度增殖、細胞生長抑制或細胞毒素物質組合以用於治療癌症。另外,本發明藥劑亦可與放射線療法及/或手術干預組合使用。
適合組合活性成分之實例包括(但不限於):
131I-chTNT、阿巴瑞克、阿比特龍、阿柔比星、阿地介白素、阿倫單抗、亞利崔托寧、六甲蜜胺、胺魯米特、胺柔比星、安吖啶、阿那曲唑、阿加來濱、三氧化二砷、天冬醯胺酶、阿紮胞苷、巴利昔單抗、RDEA 119、貝洛替康、苯達莫司汀、貝伐單抗、貝沙羅汀、比卡魯胺、比生群、博萊黴素、硼替佐米、布舍瑞林、白消安、卡巴他賽、亞葉酸鈣、左亞葉酸鈣、卡培他濱、卡鉑、卡莫氟、卡莫司汀、卡托莫西單抗、塞內昔布、西莫白介素、西妥昔單抗、苯丁酸氮芥、氯地孕酮、氮芥、順鉑、克拉屈濱、氯膦酸、氯法拉濱、克立他酶、環磷醯胺、環丙孕酮、阿糖胞苷、達卡巴𠯤、放線菌素d 、達貝汀α、達沙替尼、道諾黴素、地西他濱、地加瑞克、地尼白介素迪夫托斯、德諾單抗、地洛瑞林、二溴螺氯銨、多西他賽、脫氧氟尿苷、小紅莓、小紅莓+雌酮、艾庫組單抗、依決洛單抗、依利醋銨、艾曲波帕、內皮抑制素、依諾他濱、表柔比星、環硫雄醇、艾伯汀α、艾伯汀β、依鉑、艾瑞布林、埃羅替尼、雌二醇、雌莫司汀、依託泊苷、依維莫司、依西美坦、法屈唑、非格司亭、氟達拉濱、氟尿嘧啶、氟他胺、福美司坦、福莫司汀、氟維司群、硝酸鎵、加尼瑞克、吉非替尼、吉西他濱、吉妥單抗、氧化型谷胱甘肽、戈舍瑞林、二鹽酸組胺、組胺瑞林、羥基脲、I-125粒、伊班膦酸、替伊莫單抗、伊達比星、異環磷醯胺、伊馬替尼、咪喹莫特、英丙舒凡、干擾素α、干擾素β、干擾素γ、伊匹單抗、伊立替康、伊沙匹隆、蘭瑞肽、拉帕替尼、來那度胺、來格司亭、香菇多糖、來曲唑、亮丙瑞林、左旋咪唑、麥角乙脲、洛鉑、洛莫司汀、氯尼達明、馬索羅酚、甲羥孕酮、甲地孕酮、美法侖、美雄烷、巰嘌呤、甲胺喋呤、甲氧沙林、胺基乙醯丙酸甲酯、甲睾酮、米伐木肽、米替福新、米鉑、二溴甘露醇、米托胍腙、二溴衛矛醇、絲裂黴素、米托坦、米托蒽醌、奈達鉑、奈拉濱、尼羅替尼、尼魯胺、尼妥珠單抗、尼莫司汀、尼曲吖啶、奧伏托默單抗、奧美拉唑、奧賽力鉑、p53基因療法、太平洋紫杉醇、帕利夫明、鈀-103粒、帕米膦酸、帕尼單抗、帕佐泮尼、培門冬酶、pEG-艾伯汀β (甲氧基PEG-艾伯汀β)、派非格司亭、聚乙二醇化干擾素α-2b、培美曲唑、戊唑星、噴司他汀、培洛黴素、培磷醯胺、皮西板尼、吡柔比星、普樂沙福、普卡黴素、聚胺葡糖、聚磷酸雌二醇、多醣-K、卟吩姆鈉、普拉曲沙、潑尼莫司汀、丙卡巴肼、喹高利特、氯化鐳-223、雷洛昔芬、雷替曲賽、雷莫司汀、雷佐生、瑞戈非尼、利塞膦酸、利妥昔單抗、羅米地辛、羅米司亭、沙格司亭、西普亮塞-T、西佐喃、索布佐生、甘胺雙唑鈉、索拉非尼、鏈脲菌素、舒尼替尼、他拉泊芬、他米巴羅汀、他莫昔芬、他索那明、替西白介素、喃氟啶、喃氟啶+吉美拉西+奧特拉西、替莫泊芬、替莫唑胺、坦西莫司、替尼泊苷、睪固酮、替曲膦、沙立度胺、噻替派、胸腺法新、硫鳥嘌呤、托西利單抗、拓朴替康、托瑞米芬、托西莫單抗、曲貝替定、曲妥珠單抗、曲奧舒凡、維甲酸、曲洛司坦、曲普瑞林、曲洛磷胺、色胺酸、烏苯美司、伐柔比星、凡德他尼、伐普肽、維羅非尼、長春鹼、長春新鹼、長春地辛、長春氟甯、長春瑞濱、伏立諾他、伏羅唑、釔-90玻璃微球體、淨司他丁、淨司他丁司他美、唑來膦酸、左柔比星。
本發明較佳係關於包含至少一種根據本發明之抗體或其抗體片段及以下活性成分中之一或多者的藥物,其尤其用於治療及/或防治類固醇受體依賴性增殖性病症:
- LHRH (促黃體素釋放激素)促效劑、
- LHRH (促黃體素釋放激素)拮抗劑、
- C(17,20)裂解酶抑制劑、
- I型5-α-還原酶抑制劑、
- II型5-α-還原酶抑制劑、
- 混合I/II型5-α-還原酶抑制劑、
- 用於治療骨轉移瘤之α輻射發射之放射性藥品,例如氯化鐳-223、
- 細胞抑制劑、
- VEGF (血管內皮生長因子)激酶抑制劑、
- 抗雌激素、
- 抗雌激素劑、
- EGF抗體、
- 雌激素或
- 聚(ADP-核糖)聚合酶I抑制劑或
- 偶合至細胞表面蛋白質之雙特異性T細胞接合子(BiTE),例如前列腺特異性膜抗原(PSMA)。
根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或其抗原結合片段或包含根據本發明之經分離之抗體或抗原結合片段的結合物或包含根據本發明之經分離之抗體或抗原結合片段的醫藥組合物,其用於與一或多種其他治療活性化合物之同時、單獨或連續組合中。
組合療法包括投與包含根據本發明之抗體或抗原結合片段或其變異體及一或多種額外治療劑的單一醫藥劑型以及投與根據本發明之抗體或抗原結合片段及呈其自身單獨醫藥劑型之各額外治療劑。舉例而言,本發明抗體或其抗原結合片段或其變異體及治療劑可一起以單一液體組合物形式向患者投與,或各藥劑可以單獨劑型投與。
在使用單獨劑量調配物的情況下,根據本發明之抗體或抗原結合片段或其變異體及一或多種額外治療劑可在基本上相同時間(例如同時)或在單獨交錯時間(例如依次)投與。
根據本發明之抗體或其抗原結合片段或其變異體可與手術干預組合使用,諸如(但不限於)肌瘤切除術、子宮動脈栓塞或腹腔鏡或子宮內膜異位病變之習知手術,尤其用於此類手術干預之後的治療。
診斷方法根據另一態樣,本發明涵蓋根據本發明之經分離之抗體或其抗原結合片段或包含根據本發明之經分離之抗體或抗原結合片段的結合物,其用作診斷劑。
此外,根據本發明之抗體或抗原結合片段可按原樣利用或用於組合物、研究及診斷或用作分析參考標準物及其類似者。IL-11抗體或其抗原結合片段可用於偵測IL-11之存在。
醫藥組合物及投與根據另一態樣,本發明涵蓋包含根據本發明之經分離之抗體或抗原結合片段或根據本發明之抗體結合物及視情況一或多種醫藥學上可接受之賦形劑的醫藥組合物。
為治療前述疾病中之任一者,根據本發明使用之醫藥組合物可使用一或多種生理學上可接受之載劑、賦形劑或助劑以任何習知方式調配。關於調配及投與之其他細節可見於最新版的Remington's Pharmaceutical Sciences (Maack Publishing Co, Easton, Pa.出版)中。
根據本發明之抗體或抗原結合片段可藉由任何適合手段投與,其可視所治療之病症之類型而變化。可能的投與途徑包括經口、非經腸及局部投與。非經腸遞送方法包括(但不限於)動脈內、肌肉內、皮下、髓內、鞘內、心室內、靜脈內、腹膜內、眼內或鼻內投與。另外,根據本發明之抗體或抗原結合片段可藉由例如降低劑量之抗體脈衝輸注投與。較佳地,部分視投與是否為短暫或長期而定,藉由注射,最佳靜脈內或皮下注射投與。待投與之量將視多種因素而定,諸如臨床症狀、個體體重、是否投與其他藥物及其類似因素。熟習此項技術者將認識到,投與途徑將視所治療之病症或病況而變化。
根據本發明之醫藥組合物包含單獨或與至少一種其他藥劑(諸如穩定化合物)組合的根據本發明之抗體或抗原結合片段。根據本發明之抗體或其抗原結合片段可在任何無菌、生物相容性醫藥載劑中投與,該醫藥載劑包括(但不限於)生理食鹽水、緩衝生理食鹽水、右旋糖及水。在特定實施例中,根據本發明之醫藥組合物可包含一或多種其他醫藥學上活性之化合物,尤其適合於治療IL-11相關病症及/或與不正常子宮出血相關之病症的一或多種其他醫藥學上活性之化合物。此等藥劑中之任一者可在其與賦形劑或醫藥學上可接受之載劑混合的醫藥組合物中單獨或與其他藥劑或藥物組合投與患者。在特定實施例中,醫藥學上可接受之載劑為醫藥學上惰性的。
可使用此項技術中熟知的醫藥學上可接受之載劑以適用於經口投與之劑量調配用於經口投與之醫藥組合物。此等載劑使得醫藥組合物能夠調配成錠劑、丸劑、糖衣藥丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液及其類似物,以便患者攝入。
口服使用之醫藥製劑可經由組合活性化合物與固體賦形劑,視情況研磨所得混合物且視需要在添加適合的助劑之後處理顆粒之混合物以獲得錠劑或糖衣藥丸核心來獲得。適合的賦形劑為碳水化合物或蛋白質填充劑,諸如糖,包括乳糖、蔗糖、甘露糖醇或山梨糖醇;來自玉米、小麥、大米、馬鈴薯或其他植物之澱粉;纖維素,諸如甲基纖維素、羥基丙基甲基纖維素或羧基甲基纖維素鈉;及膠,包括阿拉伯膠及黃蓍膠;及蛋白質,諸如明膠及膠原蛋白。視需要,可添加崩解劑或增溶劑,諸如交聯聚乙烯吡咯啶酮、瓊脂及海藻酸或其鹽,諸如海藻酸鈉。
糖衣藥丸核心可提供有適合的包衣,諸如濃縮糖溶液,其亦可含有阿拉伯膠、滑石、聚乙烯吡咯啶酮、卡波莫膠(carbopol gel)、聚乙二醇及/或二氧化鈦、漆液及適合的有機溶劑或溶劑混合物。可將染料或顏料添加至錠劑或糖衣藥丸包衣中以鑑別或表徵活性劑之量,亦即劑量。
可經口使用之醫藥製劑包括由明膠製成之配合插入式膠囊以及由明膠及包衣(諸如甘油或山梨糖醇)製成之軟密封膠囊。配合插入式膠囊可含有活性成分與以下之混合物:填充劑或結合劑(諸如乳糖或澱粉)、潤滑劑(諸如滑石或硬脂酸鎂)及視情況選用之穩定劑。在軟膠囊中,活性化合物可在存在或不存在穩定劑之情況下溶解或懸浮於諸如脂肪油、液體石蠟或液體聚乙二醇之適合的液體中。
用於非經腸投與之醫藥調配物包括活性化合物之水溶液。對於注射,本發明之醫藥組合物可在水性溶液中,較佳在生理學上相容的緩衝液(諸如漢克氏溶液(Hank's solution)、林格氏溶液(Ringer's solution)或生理緩衝食鹽水)中調配。水性注射懸浮液可含有增加懸浮液黏度之物質,諸如羧甲基纖維素鈉、山梨糖醇或聚葡萄糖。另外,活性化合物之懸浮液可視需要製備成油性注射懸浮液。適合親脂性溶劑或媒劑包括脂肪油,諸如芝麻油;或合成脂肪酸酯,諸如油酸乙酯或三酸甘油酯;或脂質體。視情況,懸浮液亦可含有適合穩定劑或增加化合物溶解性以允許製備高度濃縮溶液之藥劑。
對於局部或經鼻投與,在調配物中使用適於待滲透之特定障壁的滲透劑。此類滲透劑通常為此項技術中已知的。
本發明之醫藥組合物可以此項技術中已知的方式製造,例如藉助於習知混合、溶解、粒化、糖衣藥丸製造、水磨、乳化、囊封、包覆或凍乾過程。
醫藥組合物可以鹽形式提供且可由酸形成,包括(但不限於)鹽酸、硫酸、乙酸、乳酸、酒石酸、蘋果酸、丁二酸等。與相應的游離鹼形式相比,鹽傾向於更可溶於水性及其他質子溶劑中。在其他情況下,較佳製劑可為pH在4.5至7.5範圍內的1 mM至50 mM組胺酸或磷酸鹽或Tris、0.1%至2%蔗糖及/或2%至7%甘露醇中之凍乾粉末,視情況包含額外物質,如聚山梨醇酯,其在使用之前與緩衝劑組合。
在製備包含調配於可接受載劑中之本發明化合物的醫藥組合物之後,其可置於適當容器中且經標記以用於治療指定病況。為投與IL-11抗體或其抗原結合片段,此類標記將包括投與之量、頻率及方法。
治療學上有效劑量適用於根據本發明之醫藥組合物包括其中活性成分以有效量含有以達成預期目的之組合物,例如治療以局部或完全血管閉塞所致之缺血事件為特徵之特定疾病病況。
有效劑量之確定完全在熟習此項技術者之能力範圍內。確定本發明之新穎抗體或其抗原結合片段或其變異體之治療有效量很大程度上將視特定患者特徵、投與途徑及所治療之病症的性質而定。一般指導可見於例如國際協調會議(International Conference on Harmonization)之出版物及REMINGTON'S PHARMACEUTICAL SCIENCES, 第27章及第28章, 第484頁-第528頁 (第18版, Alfonso R. Gennaro編, Easton, Pa.: Mack Pub. Co., 1990)中。更具體言之,確定治療有效量將視諸如藥物之毒性及功效之因素而定。毒性可使用此項技術中熟知且見於前述參考文獻中之方法測定。功效可利用相同指導結合以下實例中所描述之方法來確定。
對於任何化合物,治療學上有效劑量最初可在細胞培養分析中或在通常為小鼠、兔、狗、豬或猴之動物模型中估算。動物模型亦用於實現所需濃度範圍及投與途徑。此類資訊隨後可用來確定用於在人類中投與的適用劑量及途徑。
治療學上有效劑量係指改善症狀或病況之抗體或其抗原結合片段之量。此類化合物之治療功效及毒性可藉由標準醫藥程序在細胞培養物或實驗動物中測定,例如測定ED50 (在50%群體中治療上有效的劑量)及LD50 (在50%群體中致死之劑量)。治療效應與毒性效應之間的劑量比為治療指數,且其可表示為比率ED50/LD50。展現較大治療指數之醫藥組合物為較佳的。自細胞培養分析法及動物研究獲得之資料用於調配用於人類用途之劑量範圍。此類化合物之劑量較佳在包括具有極少毒性或無毒性之ED50的循環濃度範圍內。劑量視所用劑型、患者之敏感性及投與途徑而定在此範圍內變化。
個別醫師考慮待治療之患者而選擇準確劑量。調節劑量及投與以提供充足量之活性部分或維持所需效果。可考慮之額外因素包括疾病病況之嚴重程度、患者之年齡、體重及性別;飲食、投與之時間及頻率、藥物組合、反應敏感性及對療法之耐受性/反應。視特定調配物之半衰期及清除速率而定,長效醫藥組合物可例如每3至4天、每週一次、每兩週一次或每三週一次投與。
視投與途徑而定,正常劑量可在0.1至100,000微克範圍內變化,至多為約10 g之總劑量。關於特定劑量及遞送方法之指導提供於文獻中。參見美國專利第4,657,760號;第5,206,344號;或第5,225,212號。
套組根據另一態樣,本發明套組包含根據本發明之經分離之抗體或抗原結合片段或根據本發明之抗體結合物或根據本發明之醫藥組合物及使用說明書。
在特定實施例中,套組包含一或多個填充有一或多種本發明之前述組合物之成分的容器。與此類容器視情況相關聯的可為由管理藥品或醫藥產物之製造、使用或銷售之政府機構所規定形式的注意事項,該注意事項反映由用於人類投與之製造、使用或銷售機構的批准。
實例及圖式雖然已在附圖及前述描述中詳細地說明及描述了本發明,但此類說明及描述應被視為說明性或例示性的,而非限定性的;本發明不限於所揭示實施例。所揭示之實施例的其他變體可由熟習此項技術者自附圖、揭示內容及所附申請專利範圍的研究中藉由實踐所主張之本發明而理解且實現。任何參考符號均不應視為限制範疇。本文所揭示之全部胺基酸序列均自N端至C端展示;本文所揭示之全部核酸序列均展示5'->3'。
實例本文中展示之實驗明顯支持IL-11及/或IL-11RA作為目標,其抑制(包括異位抑制)提供不正常子宮出血之療法選項,諸如大量月經出血、長期出血或出血模式改變以及平滑肌瘤、子宮內膜異位或月經及與AUB相關之痛經。
實例 1 : 用 AF418 處理之鼠類 HMB 模型之血液減少在大量月經出血之小鼠模型中,測試功能阻斷IL-11抗體對月經之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1中。簡言之,雌性Scid beige小鼠[Charles River Sulzfeld, Deutschland]在卵巢切除後六天開始接受對照抗體或IL-11功能阻斷多株抗體[來自R&D Systems, Inc.之AF-418-NA]之9 mg/kg每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Scid beige小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
結果展示於圖2中。相比於對照抗體組TPP-12904 (失血76.4 µl+/-17.9 µl SD),可測定功能阻斷抗體處理組AF418 (失血17.9 µl+/-12.7 µl SD)之失血顯著減少(雙尾t檢驗,p<0.0001)。
實例 2 : 用 AF418 處理之鼠類 HMB 模型之子宮重量減輕在月經之小鼠模型中,測試功能阻斷IL-11抗體[來自R&D Systems, Inc.之AF-418-NA]對子宮重量之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導。用子宮內油施用進一步誘導組織蛻膜化,如其他地方(例如Menning, 2012中)所描述且概述於圖1中。簡言之,雌性Scid beige小鼠在卵巢切除後六天開始接受對照抗體或IL-11功能阻斷抗體之9 mg/kg每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Scid beige小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之s.c.注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/d) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中。四天後,移除P4植入以起始P4停藥。在實驗結束後(第15天)四天處死小鼠,且將子宮稱重且搜集用於進一步分析。
對子宮重量之作用結果展示於圖3中。相比於對照抗體[來自R&D Systems, Inc.之AB-108-C] (70.1 mg +/- 25.5 mg SD (AF418)對比297.9 mg +/-162.1 mg SD (AB-108-C (TPP12904))),可測定功能阻斷抗體處理組中之子宮重量之顯著減輕。
藉由功能阻斷IL-11抗體[來自R&D Systems, Inc.之AF-418-NA]抑制IL-11/IL-11RA信號傳導路徑展示對大量月經出血(實例1,圖2)及子宮重量(實例2,圖3)兩者之極強作用。因此,此等出人意料的結果得出IL-11/IL-11RA功能阻斷在很大程度上減少月經之結論。因此,對於子宮內膜異位之逆行月經模型(Sampson, 1927),逆行月經為子宮內膜異位之發病機制中之前提條件。另外,逆行月經不為例外,但通常在月經中發生。然而,已展示且懷疑,大量月經亦展示增加的逆行月經,且因此與罹患子宮內膜異位之更高風險相關(關於綜述參見Laux-Biehlmann等人, 2015)。除子宮內膜異位之發病機制中之重要性之外,逆行月經促使腹膜發炎、疼痛及發炎性疼痛。可設想,月經減少或完全抑制亦將很大程度上減少逆行月經且藉此減少子宮內膜異位及子宮內膜異位相關症狀。另外,子宮內膜異位熟知,腹腔中異位子宮內膜中之活性病變(例如紅色病變)亦藉由月經週期調節。此異位組織使子宮內膜脫落且展示腹膜內出血(Burney & Lathi, 2009)。藉此,除逆行月經之外,『腹膜內月經』進一步促使腹膜發炎、疼痛及發炎性疼痛(Laux-Biehlmann等人,2015)。『腹膜內月經』可進一步在腹腔內散播新異位病變。逆行月經及『腹膜內月經』將很大程度上藉由抑制IL-11/IL-11RA信號傳導預防。隨後,腹膜中新病變之建立以及子宮內膜異位相關之腹膜炎症及發炎性疼痛將減弱。實際上,促性腺激素釋放激素(GnRH)類似物或拮抗劑之當前可用短期治療性干預亦消除促成其總體有益作用之月經。然而,對例如骨骼代謝之強副作用阻止長期治療。在IL-11/IL-11RA之相反拮抗劑或抑制劑中將不具有此類限制。
實例 3 : 用 AF418 處理之原發性人類纖維瘤切片分析中 VEGFA 分泌之抑制在原發性人類纖維瘤切片分析中,測試IL-11 [來自R&D Systems, Inc.之218-IL]及功能阻斷IL-11抗體[來自R&D Systems, Inc.之AF-418-NA]對血管生成介體之作用。血管生成之誘導增加血管形成,其可能造成平滑肌瘤生長增強。用Krumdick組織切片機將來自41歲患者之原發性人類纖維瘤組織以0.4 mm切片(直徑5 mm)切開且在PBS中洗滌。在不具有L-Tryp、含有5%胎牛血清(FCS)之細胞培養基中培育切片隔夜。將切片在48孔培養盤中在400 µl培養基中用IL-11 [來自R&D Systems, Inc.之218-IL]、對照抗體[來自R&D Systems, Inc.之AB-108-C]或IL-11功能阻斷抗體[來自R&D Systems, Inc.之AF-418-NA]進一步培育24小時。
結果展示於圖4中。IL-11顯著誘導VEGF-A (72.2 ng/mg蛋白質+/- 29.8 ng/mg蛋白質SD)分泌,其藉由用IL-11功能阻斷抗體[來自R&D Systems, Inc.之AF-418-NA] (17.3 ng/mg蛋白質+/- 6.4 ng/mg蛋白質SD)額外處理而完全抑制。VEGF-A為熟知的促血管生成介體,藉由IL-11誘導可能引起平滑肌瘤血管形成增加及平滑肌瘤生長增強。統計檢驗:藉由多重比較之一般單向ANOVA與Bonferroni校正(****p<0.0001)。
實例 4 : 用 AF418 處理之鼠類 HMB 模型之動物重量如實例1及2中所指出,藉由功能阻斷IL-11抗體抑制IL-11信號傳導路徑展示對大量月經出血(圖2)及子宮重量(圖3)之顯著作用。因此,此等結果得出IL-11功能阻斷很大程度上減少月經且引起閉經之結論。對於專家而言,已知避免或減少月經及誘導閉經為如持續施用孕激素而展現有效治療原發性及繼發性痛經(Power等人,2007; Sachedina & Todd, 2020)。因此,能夠結合至IL-11且抑制或拮抗IL-11作用之藥劑將為原發性及繼發性痛經之有效治療。為驗證此假設,在大量月經出血模型(圖1)中量測開始月經之前(第12天)及出血期結束(第15天)的動物體重作為健康標記。
如圖5中所示,相比於經TPP-12904對照抗體處理之動物(21% +/- 4.5% SD。統計檢驗:雙尾t檢驗,**** p<0.0001),經AF414 IL-11拮抗抗體處理之動物之動物重量展示體重損失減輕(12.1% +/- 2.4% SD)。
實例 5 : 用 AF418 及 MAB218 處理之鼠類 HMB 模型之血液減少在大量月經出血之小鼠模型中,測試市售功能阻斷IL-11抗體對月經之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Scid beige小鼠[Charles River Sulzfeld, Deutschland]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體[來自R&D Systems, Inc.之Mab-218]或小鼠IgG2A對照抗體[TPP-10748]、IL-11功能阻斷單株抗體[來自R&D Systems, Inc.之Mab-418]或其大鼠IgG2A對照抗體[TPP-10750]之20 mg/kg每週兩次皮下(s.c.)注射,或IL-11功能阻斷多株抗體[來自R&D Systems, Inc.之AF-418-NA]之5 mg/kg每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Scid beige小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
結果展示於圖6中,在Scid beige小鼠中,在MAb218人類IL-11功能阻斷抗體處理組(45µl +/- 18µl SD對比86µl +/- 43µl SD之對照(mAb) TPP-10748;p<0.05)中而非在Mab418小鼠IL-11功能阻斷抗體處理組(79µl +/- 18µl SD對比99µl +/-36µl SD之對照(rAb) TPP-10750)中大量月經出血(HMB)顯著減少。多株AF-418小鼠IL-11功能阻斷抗體再次展示較強抑制(23µl +/- 10µl SD對比99µl +/- 36µl SD之對照(rAb) TPP-10750;p<0.0001)。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性。
實例 6 : 用 TPP - 18068 及 TPP - 18063 處理之鼠類 HMB 模型之血液減少在大量月經出血之小鼠模型中,測試功能阻斷IL-11抗體對月經之作用。此等抗體藉由抗體淘選鑑別且展示與例如對重組IL-11之結合效能不同的活體外活性。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體TPP-18063或TPP-18068或小鼠IgG1對照抗體[TPP-10159]之20 mg/kg每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖7展示藉由單株抗體抑制Balb/c小鼠中之月經出血,其中相比於同型對照抗體TPP-10159 (失血50 µl +/- 29 µl SD),藉由IL-11功能阻斷抗體TPP-18068 (失血17 µl +/- 12 µl SD)而非IL-11功能阻斷抗體TPP-18063 (失血36 µl +/- 28 µl SD)之月經出血之顯著抑制。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(**p<0.01)
實例 7 : 用 TPP - 18068 處理之鼠類 HMB 模型之劑量依賴性血液減少實例7展示活性IL-11功能阻斷抗體TPP-18068相比於同型對照抗體(TPP-10159)之月經出血之劑量依賴性作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體TPP-18068之20 mg/kg、5 mg/kg或1 mg/kg每週兩次皮下(s.c.)注射,與20 mg/kg IgG對照抗體[TPP-10159]進行比較,持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖8展示藉由IL-11功能阻斷抗體TPP-18068之Balb/c小鼠中之大量月經出血模型之月經出血之劑量依賴性抑制,藉由1 mg/kg TPP-18068 (失血39 µl +/- 14 µl SD)無抑制,但藉由5 mg/kg (失血19 µl +/- 11 µl SD)或20 mg/kg (失血19 µl +/- 9 µl SD)對比20 mg/kg對照抗體TPP-10159 (失血37 µl +/- 12 µl SD)每週兩次s.c.注射之顯著抑制。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(**p<0.01)
實例 8 : 用 TPP - 18068 處理之鼠類 HMB 模型之動物活性如實例1及2中所指出,藉由功能阻斷IL-11抗體抑制IL-11信號傳導路徑展示對大量月經出血(圖2)及子宮重量(圖3)之顯著作用。因此,此等結果得出IL-11功能阻斷很大程度上減少月經且減少出血或甚至引起閉經之結論。對於專家而言,已知避免或減少月經及誘導閉經為如持續施用孕激素而展現有效治療原發性及繼發性痛經(Power等人,2007; Sachedina & Todd, 2020)。因此,能夠結合至IL-11且抑制或拮抗IL-11作用之藥劑將為原發性及繼發性痛經之有效治療。除了如實例4中所描述之體重之量測以外,健康之量測亦可在評估曠場分析中之行動及探索之主要行為測試中解決(Murbach等人,2014)。動物在曠場情況中暴露於新環境。在ActiMoT (TSE系統)中監測水平及垂直活動。具有較少壓力、疼痛或更健康之動物活動更多。
在大量月經出血之小鼠模型中,評估阻斷IL-11抗體之功能在曠場分析中對行動及探索之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/c小鼠[Janvier實驗室]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體TPP-18068或IgG對照抗體[TPP-10159]之20 mg/kg每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。在P4停藥後兩天,在ActiMoT (TSE系統)中在五分鐘時間段期間監測水平及垂直活動。
如圖9中所示,用IL-11拮抗抗體TPP-18068處理之動物活動更多。其展示探索行為增加,如行進距離(以米計之每5分鐘水平活動) (30.6 m/5 min +/- 11.6 m/5 min SD;雙尾t檢驗:*p<0.05)及直立(在5分鐘內直立次數之垂直活動) (分別26.4/5 min +/- 12.2/5 min;雙尾t檢驗:**p<0.01)所見,該兩者相比於經TPP-10159對照Ab處理之動物顯著提高(水平活動19.1 m/5 min +/- 3.6 m/5 min;直立12.5/5 min +/- 7.0/5 min),表明壓力更小、疼痛更少或一般更健康。
實例 9 : 用 TPP - 18068 處理之動物 ( 鼠類 HMB 模型 ) 之蛻膜化子宮角中之 Stat3 磷酸化IL-11結合至IL-11受體。二聚體結合至負責進一步下游信號傳導之Gp130。信號傳導導致『信號轉導與轉錄活化因子3』(STAT3)之細胞內蛋白激酶及磷酸化之活化(Harmegnies等人(2003))。子宮內膜分化中之IL-11活化提高STAT3磷酸化。在導致鼠類子宮內膜分化之經修飾之大量月經出血小鼠模型中分析此結果。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括在鼠類子宮之僅一個角中用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體TPP-18063或TPP-18068或IgG對照抗體[TPP-10159]之20 mg/kg每週兩次皮下(s.c.)注射,持續13天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除子宮,稱重且分離角。緊接將蛻膜化子宮角及未蛻膜化子宮角之分離片段單獨地轉移在含有具有磷酸基之裂解液(cisbio目錄號64KL1FDF)及總蛋白質阻斷試劑(cisbio目錄號64KB1AAD)之小試管中之後且速凍在液氮中。對於樣品製備,組織在冰上解凍且均質化。使用溶解/阻斷緩衝液測定蛋白質濃度以產生2 mg/ml蛋白質稀釋液。隨後根據製造商方案,藉由使用來自cisbio之磷酸基-STAT3 (Tyr705)細胞套組#62AT3PEG及總STAT3細胞套組#64NT3PEG量測磷酸化及總Stat3。
圖10展示子宮內膜分化對子宮Stat3磷酸化之作用及藉由IL-11阻塞抑制此信號傳導。在第12天,相比於用對照抗體TPP-10159處理之未分化角(相對值1.18 +/- 0.03 SD),用對照抗體TPP-10159處理之動物(相對值2.07 +/ 0.13 SD)之分化子宮角中Stat3磷酸化顯著提高。在蛻膜化子宮角(經TPP-18068處理之動物中之相對值1.56+/-0.25 SD對比經TPP-10159處理之動物中之相對值2.07 +/ 0.13 SD)中而非在d12在HMB模型中在未蛻膜化子宮角中(經TPP-18068處理之動物中之相對值1.2+/-0.04對比經TPP-10159處理之動物中之相對值1.18+/0.03 SD),IL-11功能阻斷抗體TPP-18068相比於對照抗體TPP-10159 (相對值2.07+/0,13 SD)降低Stat3磷酸化。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(**p<0.01;***p<0.001)。
實例 10 : 用 TPP - 18068 或 TPP - 26195 處理之鼠類 HMB 模型之血液減少及子宮重量減輕IL-11功能阻斷抗體TPP-18068展示對鼠類大量月經出血模型中大量月經出血減少、子宮內IL-11信號傳導及小鼠健康徵象之劑量依賴性顯著作用,如實例6-9中所示。作為經典IgG抗體,此抗體具有兩個針對IL-11結合之一致結合位點。藉由與不同抗原決定基之結合位點組合,產生雙互補位IL-11功能阻斷抗體TPP-26195,如實例34中所示。在Balb/cAnN小鼠[Janvier]之鼠類大量月經出血模型中測試單特異性TPP-18068及衍生雙互補位IL-11功能阻斷抗體TPP-26195對月經出血之作用,與其各別對照IgG抗體及另外WO2019238882中描述為IL-11功能阻斷且此處命名為BSN 3C6 2.2-2.1-mIgG1κ (TPP-23580)之IL-11抗體之小鼠IgG1版本進行比較。
另外,在第12天製備各自經IL-11功能阻斷雙互補位抗體TPP-26195或對照抗體處理之四個動物之大量月經出血模型的子宮。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷單株抗體TPP-18068、TPP-26195之15 mg/kg每週兩次皮下(s.c.)注射,與15 mg/kg其各別IgG對照抗體[TPP-10159及TPP-27360]進行比較,持續16天之時間段。另外,測試WO2019238882中描述為IL-11功能阻斷且此處命名為BSN 3C6 2.2-2.1-mIgG1κ (TPP-23580)之IL-11抗體之小鼠IgG1版本。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖11展示分別每週兩次15 mg/kg s.c.給藥之Balb/c小鼠中IL-11功能阻斷抗體TPP-18068 (失血20.7 µl +/- 5.6 µl SD;** p<0.01)及藉由衍生雙互補位IL-11功能阻斷抗體TPP-26195 (失血16.4 µl +/- 1.2 µl SD;*** p<0.001)相比於其對照IgG抗體TPP-10159 (失血36.8 µl+/-12.2 SD)或TPP-27360 (失血41.2 µl+/-17.0 µl)的月經出血之顯著減少。WO2019238882中描述為IL-11功能阻斷且此處命名為BSN 3C6 2.2-2.1-mIgG1κ (TPP-23580)之IL-11抗體之小鼠IgG1版本在每週兩次15 mg/kg之所選s.c.劑量下(失血30.8 µl+/-19 µl SD)相比於對照IgG抗體TPP-10159 (失血36.8 µl+/-12.2 µl SD)對大量月經出血未展示顯著作用。藉由雙尾曼-惠特尼檢驗測定顯著性。
圖12展示Balb/c小鼠中雙互補位IL-11功能阻斷抗體TPP-26195相比於對照IgG抗體的子宮分化衰減,如藉由鼠類大量月經出血模型之第12天的子宮重量所量測(n=4)。相比於對照抗體TPP-27360處理組(454.8 mg +/- 339.8 mg SD),雙互補位抗體TPP-26195很大程度上抑制子宮內膜分化,如藉由子宮重量極大減輕所指示(55.6 mg +/- 20.8 mg SD)。藉由單尾t檢驗測定顯著性:*p<0.05。
實例 11 : 用 TPP - 26195 處理之鼠類 HMB 模型中的劑量依賴性血液減少在大量月經出血之小鼠模型中,相比於小鼠IgG1對照抗體,以劑量依賴性方式測試雙互補位IL-11功能阻斷抗體TPP-26195對月經之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷雙互補位抗體TPP-26195之10 mg/kg或3 mg/kg或1 mg/kg或0.3 mg/kg每週兩次皮下(s.c.)注射或10 mg/kg每週兩次其小鼠IgG1對照抗體[TPP-27360],持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖13展示每週兩次s.c.給藥10 mg/kg (失血14.4 µl +/- 7.0 µl SD;** p<0.01)、3 mg/kg (失血11.7 µl +/- 1.1 µl SD;*** p<0.001)、1 mg/kg (失血17.4 µl +/- 9.2 µl SD;** p<0.01)及0.3 mg/kg (失血27.5 µl +/- 21.9 µl SD)之Balb/c小鼠中雙互補位IL-11功能阻斷抗體TPP-26195相比於用10 mg/kg對照IgG抗體TPP-27360 (失血41.8 µl +/- 26.8µl SD)每週兩次處理之群組的月經出血之劑量依賴性減少,其中在10、3或1 mg/kg每週兩次s.c.給藥下顯著抑制。藉由多重比較之單向ANOVA與Bonferroni校正計算顯著性。
實例 12 : 用 TPP - 29603 、 TPP - 29528 及 TPP - 29519 處理之鼠類 HMB 模型之血液減少在大量月經出血之小鼠模型中,相比於小鼠IgG1對照抗體(TPP-10159),測試雙互補位IL-11功能阻斷抗體TPP-29603或IL-11功能阻斷抗體TPP-29528或TPP-29519對月經之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始分別接受IL-11功能阻斷雙互補位抗體TPP-29603 (1 mg/kg)或IL-11功能阻斷抗體TPP-29528 (1.39 mg/kg)或TPP-29519 (1.4 mg/kg)或相比於1.4 mg/kg每週兩次小鼠IgG1對照抗體[TPP-10159]更低劑量之每週兩次抗體TPP-29519 (0.42 mg/kg)的等莫耳每週兩次皮下(s.c.)注射,持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖14展示Balb/c小鼠中雙互補位IL-11功能阻斷抗體TPP-29603 (失血13.8 µl+/-4.1 µl SD)及抗體TPP-29528 (失血26.5 µl+/-20.2 µl SD)及TPP-29519 (失血12.7 µl+/-2.4 µl SD)之等莫耳給藥相比於對照IgG抗體TPP-10159 (失血35.5 µl+/-27.2 µl SD)之月經出血減少。另外,亦展示更低劑量之抗體TPP-29519 (失血33.5 µl +/- 19.0 µl SD)。實驗展現等莫耳劑量之IL-11功能阻斷抗體TPP-29603及TPP-29519對月經出血之顯著抑制。藉由多重比較之單向ANOVA與鄧奈特校正計算顯著性(對數標準化值):**P<0.01。
實例 13 : 用 TPP - 29523 處理之鼠類 HMB 模型之劑量依賴性血液減少在大量月經出血之小鼠模型中,相比於其小鼠IgG1對照抗體(TPP-10159)及極低劑量之雙互補位IL-11功能阻斷抗體TPP-29603,以劑量依賴性方式測試IL-11功能阻斷抗體TPP-29523對月經之作用。切除卵巢之小鼠的人工月經週期階段藉由雌二醇(E2)及孕酮(P4)補充/停藥時程誘導,包括用子宮內油施用誘導蛻膜化,如例如Menning (2012)中所描述且概述於圖1及實例1中。簡言之,雌性Balb/cAnN小鼠[Janvier]在卵巢切除後六天開始接受IL-11功能阻斷抗體TPP-29523之2 mg/kg或0.7 mg/kg或0.3 mg/kg每週兩次皮下(s.c.)注射或每週兩次2 mg/kg其小鼠IgG1對照抗體TPP-10159或0.143 mg/kg雙互補位IL-11功能阻斷抗體TPP-29603,持續16天之時間段。在卵巢切除後一週,雌性Balb/c小鼠連續三天接受含100 ng 17α-雌二醇(E2)之乙醇/花生油(1:9)之皮下(s.c.)注射(圖1)。在中斷三天之後,將孕酮(P4)釋放矽橡膠管(0.5 mg P4/天) s.c.植入小鼠背部中,繼而連續三天進一步施用5 ng E2。伴隨最後一次E2處理,將50 µl芝麻油注射至一個子宮角中以誘發蛻膜化。四天後,移除P4植入以起始P4停藥。為了對失血總量進行定量,在P4停藥時將棉塞樣棉墊(4-4.8 mm直徑,Roeko, Coltene/Whaledent, Altstatten, Switzerland)插入小鼠陰道中。每日兩次更換棉塞且針對各小鼠分別收集三天。藉由其他地方報導之鹼性蘇木精方法定量血液體積(Hallberg & Nilsson, 1964)。簡言之,使棉塞在室溫下乾燥。使血色原溶解於1000 µl 5% NaOH (w/v)中且在室溫下旋轉隔夜。在546 nm波長下之ELISA讀取器中量測溶離液之光密度。基於由靜脈血製備之標準物的回歸曲線計算棉簽中所含之血液體積。
圖15展示每週兩次s.c.給藥2 mg/kg (失血22.9 µl+/-1.5 µl SD)、0.7 mg/kg (失血21.0 µl+/-3.1 µl SD)及0.3 mg/kg (失血24.5 µl+/-3.5 µl SD)之Balb/c小鼠中IL-11功能阻斷抗體TPP-29523相比於2 mg/kg給藥之對照IgG抗體TPP-10159 (失血43.5.8 µl+/-27.9 µl SD)的月經出血之劑量依賴性減少。另外,測試0.143 mg/kg雙互補位IL-11功能阻斷抗體TPP-29603之每週兩次s.c.給藥(失血43.11 µl+/-7.9 µl SD)。資料展現已在所有測試之每週兩次給藥下IL-11功能阻斷抗體TPP-29523之月經出血之顯著抑制(** p < 0.01)。藉由多重比較之單向ANOVA與鄧奈特事後檢驗計算顯著性。
實例
14
-
20
展示
TPP
-
18068
、
TPP
-
18087
及
TPP
-
19528
之產生及特徵化
實例
14
:
來自
BioInvent
抗體集合庫之
TPP
-
18068
、
TPP
-
18087
及
TPP
-
19528
之產生
藉由針對可溶性經生物素標記之IL11抗原之選擇,完全人類抗體噬菌體呈現集合庫(BioInvent n-CoDeR Fab λ集合庫)用於分離人類單株抗體。自商業來源使用IL-11:人類IL-11 (Invigate,例如批次號C121021-19)、鼠類IL-11 (Invigate,例如批次號C210819-09)、食蟹獼猴IL-11 (Invigate,例如批次號C290621-19)。抗原使用磺基-NHS-LC-生物素套組(Thermo Scientific™;目錄號A39257)經生物素標記。藉由針對適當的緩衝劑透析來自反應物中移除游離生物素。
對於圖16中示意性地展示之淘選程序,應用以下方案:在室溫(RT)下分別用經生物素標記之抗原(1個試管)及經生物素標記之脫靶(3個試管)塗佈鏈黴抗生物素蛋白偶合戴諾珠粒(Dynabead) M-280 (Invitrogen™)一小時。洗滌戴諾珠粒且隨後在室溫下用底蓋翻轉阻斷1小時。為消耗脫靶結合子,將經阻斷噬菌體集合庫添加至阻斷脫靶裝載戴諾珠粒中且在室溫下用底蓋翻轉培育10分鐘。此消耗步驟重複2次。將耗盡之噬菌體集合庫添加至阻斷標靶裝載戴諾珠粒中且在室溫下用底蓋翻轉培育60分鐘。在嚴格洗滌(含3×阻斷緩衝液及9×PBS (150 mM NaCl;8 mM Na2HPO4;1.5 mM KH2PO4;調節至pH =7.4-7.6)之0.05% Tween-20)之後,具有尤其結合至經塗佈之標靶之Fab噬菌體之戴諾珠粒直接用於感染大腸桿菌菌株HB101。隨後,噬菌體使用M13KO7輔助噬菌體(Invitrogen™)在大腸桿菌菌株HB101中擴增。在以下選擇輪中,目標濃度降低以加強針對高親和力結合子之選擇壓力。
在此集合庫淘選期間,進行兩種不同選擇策略以鑑別展示針對人類、小鼠及/或食蟹獼猴IL-11之交叉反應性之抗體,在第一策略中,人類標靶用於前兩輪淘選,而在第二策略中,鼠類標靶用於前兩輪淘選。在兩種策略中,第二輪之擴增噬菌體隨後在第三輪中針對人類、鼠類及食蟹獼猴IL-11並行淘選。
對於第一定性評估,隨機挑選來自各純系池之88種Fab-噬菌體純系且接種至用補充有100 µg/ml安比西林及1%葡萄糖之100 µl LB培養基填充的平底96孔盤中。在37℃下隔夜培養之後,用補充有100 µl安比西林之100 µl LB培養基填充之新平底96孔盤接種有5 μl隔夜培養物。在37℃下培育經接種之培養盤3小時。在3小時之後,添加補充有100 µl/ml安比西林、200 µM異丙基-β-D-硫代半乳糖苷(IPTG)及M13KO7輔助噬菌體(6×10
9個蝕斑形成單位/ml)之100 µl LB培養基,且將培養盤在37℃下進一步培育30分鐘,繼而在30℃下培育隔夜。次日,針對淘選之前使用的各別標靶之結合(人類、小鼠及食蟹獼猴IL-11),測試包括所表現之Fab-噬菌體分子之上清液。「結合子」已定義為Fab-噬菌體分子,展示在ELISA分析(參見下文)中非結合對照Fab-噬菌體分子之平均信號強度之至少信號強度加上標準差之10倍(非標靶結合Fab-噬菌體之平均+10×標準差)。ELISA分析如下進行:在4℃下用經生物素標記之人類或小鼠IL-11 (30 µl之1 µg/ml PBS溶液)或經生物素標記之非標靶對照蛋白質(30 µl之1 µg/ml PBS溶液)塗佈384孔鏈黴抗生物素蛋白培養盤(Greiner)隔夜。丟棄塗佈溶液,使用包括0.05% Tween (PBST)之磷酸鹽緩衝鹽水(PBS)洗滌培養盤,且隨後使用溶解於PBST中之3%無脂肪奶粉阻斷1小時。在使用PBST之單一洗滌步驟之後,添加來自表現培養物之含有30 µl/孔Fab-噬菌體之上清液,且在室溫(RT)下培育培養盤一小時。在使用PBST之另一單一洗滌步驟之後,將與辣根過氧化酶(GE Healthcare)結合之30 µl 1/5000 PBST稀釋抗M13抗體添加至各孔中,且隨後在室溫下培育一小時。使用PBST之最後一次單一洗滌步驟之後添加30 µl基質溶液(Amplex Red, Invitrogen),在暗處在室溫下15分鐘培育步驟之後,在使用535 nm激發及590 nm處發射偵測之螢光微量培養盤讀取器(Tecan)中量測螢光信號。
提取且純化來自第三輪6池(其展示顯著命中率)之質體DNA。隨後藉助於限制酶自質體切出基因III,再次接合質體且將其轉型成大腸桿菌TOP10。藉由移除基因III,表現形式自Fab-噬菌體變為可溶性Fab。可溶性Fab產生如下:自轉化培養盤選取單一細菌群落且接種於用補充有100 µg/ml安比西林及1%葡萄糖之50 µL LB培養基填充的384孔平底培養盤中,繼而在37℃下培育步驟隔夜。次日,將2 µl/孔隔夜培養物轉移至用補充有100 µg/ml安比西林及200 µM IPTG之50 µl/孔LB培養基預填充之新384孔平底表現培養盤中。在30℃下培育表現培養盤隔夜。次日,在人類及鼠類IL-11之基於ELISA之高通量篩檢(HTS-ELISA)中分別測試10 µl Fab表現培養物。HTS-ELISA之結構及實施方式類似於具有以下變化之先前所描述之Fab-噬菌體ELISA。使用Smart Block (Candor)作為阻斷試劑且使用抗c-myc抗體辣根過氧化酶結合物(Bethyl)作為偵測抗體。
實例 15 : 重組 DNA 構築體及全長抗體之表現、純化及定量自淘選操作,選擇兩個潛在抗體候選物以用於進一步表徵。將相應Fab片段再格式化成全長鼠類IgG1分子。將重鏈及輕鏈選殖至pTT5載體系統(加拿大國家研究委員會(National Research Council Canada),NRC檔案11266)中且使用標準暫時轉染程序在HEK293細胞中表現。簡言之,針對小規模轉染,在轉染之前兩天,在125 mL聚碳酸酯愛倫美氏(Erlenmeyer)搖瓶(Corning, #CLS431143)中用補充有10 mL/L 10% Pluronic F68 (Invitrogen;#24040-32)溶液之F17培養基(Invitrogen,#A13835-01)將HEK293細胞稀釋至0.5×10
6個細胞/mL直至22.5 mL之總體積。在轉染當天之細胞密度應為1.7×10
6個細胞/mL。在轉染當天,在1.25 mL轉染培養基(如上所述之F17培養基+Pluoronic)中使25 µg DNA解凍,且將1 mg/mL (亦即,50 µg)之50 µl聚伸乙基亞胺(Polysciences, #23966)添加至另一1.25 ml轉染培養基中。將兩種溶液渦旋且隨後將聚伸乙基亞胺(PEI)溶液轉移至DNA溶液中。再次渦旋混合物且在室溫下培育15分鐘。在將DNA-PEI混合物添加至細胞中且立即渦旋燒瓶之後,將細胞在含濕氣培育箱中在37℃下在5% CO2下培育五天。
收集上清液且藉由蛋白質A層析法來純化抗體,繼而進行尺寸排阻層析法。在收集之後,濃縮上清液且過濾(孔徑0.2 µm)且裝載至HiTrap MabSelect SuRe管柱(Cytiva)上。在DPBS (pH 7.4)中平衡管柱,與Äkta Pure 25系統(Cytiva) 偶合。用10 CV洗滌管柱且用6 CV溶離緩衝液(50 mM乙酸+50 mM NaCl,pH 3.0)進行溶離。彙集峰溶離份且使用3 M Tris pH 9.0中和。濃縮池(Vivaflow 200 30 kDa膜[Hydrosart 30kDa])且經由0.2 μm過濾器過濾。藉由分析型SEC分析捕捉步驟池(SEC樣品用DPBS pH 7.4稀釋至2 mg/ml)。隨後,使用偶合至Äkta Pure 25系統之Superdex 200 SEC管柱(Cytiva)進行製備型SEC操作。使用2 CV DPBS (pH 7.4)平衡SEC管柱,裝載樣品,且用1.5 CV DPBS (pH 7.4)溶離管柱。彙集峰溶離份。濃縮池且無菌過濾(孔徑0.2 µm)。使用Nanodrop UV分光光度計(Thermo),使用280 nm處之吸光度測定抗體溶液之最終濃度。將抗體等分,在液氮中速凍且儲存於-80℃下。
最終,獲得所得抗體TPP-18063、TPP-18068、TPP18087及TPP-19528。
實例 16 : 藉由 SPR 分析之 TPP - 18063 、 TPP - 18068 、 TPP18087 及 TPP - 19528 之結合親和力測定TPP-18068、TPP-18087、TPP-19528以及市售IL-11抗體TPP-14250 (R&D Systems, #MAB218)之結合親和力之基於SPR之實驗在Biacore T200儀器(GE Healthcare)上在25℃下使用分析緩衝液HBS EP+、300 mM NaCl、1 mg/ml BSA、0.05%NaN3運行。抗體經由共價胺偶合至S系列CM5感測器晶片(Cytiva)之抗小鼠Fc IgG (「小鼠抗體捕捉套組」,訂單號BR100383,Cytiva)捕獲。根據製造商說明書,使用1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(EDC)、N-羥基丁二醯亞胺(NHS)及乙醇胺HCl (pH 8.5) (「胺偶合套組」 BR-1000-50, Cytiva.)進行胺偶合。人類IL-11 (Invigate,例如批次號C121021-19)及鼠類IL-11 (Invigate,例如批次號C210819-09)用作分析物。首先,使用200 nM IL-11進行單一濃度結合實驗以測定粗略親和力。基於彼實驗,選擇IL-11濃度範圍以最佳測定多週期動力學模式中抗IL-11抗體之動力學及親和力。在每次抗原注射之後用甘胺酸(pH 1.7)使感測器表面再生。雙參考所得感測器圖譜(減去參考流動池信號及緩衝液注射)且擬合至1:1朗繆爾結合模型以使用Biacore T200評估軟體或Biacore洞察軟體導出動力學資料。結果展示於表E1中。
表E1:TPP-18063、TPP-18068、TPP18087、TPP-19528及TPP-14250之結合親和力
抗體 | K D [M] :人類 IL11 | K D [M] :小鼠 IL11 |
TPP-14250 | 1.9E-08 | 3.8E-09 |
TPP-18063 | 5.3E-08 | 1.0E-08 |
TPP-18068 | 4.8E-08 | 7.2E-10 |
TPP-18087 | 5.3E-08 | 4.2E-08 |
TPP-19528 | 1.1E-08 | 9.0E-09 |
實例 17 : 藉由使用報導基因分析之 TPP - 18063 、 TPP - 18068 、 TPP18087 及 TPP - 19528 之 IL - 11 介導之信號傳導 之抑制在報導基因分析中量測TPP-18063、TPP-18068、TPP-18087、TPP-19528、商業IL-11抗體TPP-14250 (MAB218)及同型對照TPP-10159對人類IL-11及小鼠IL-11介導之Stat3信號傳導的阻斷活性。簡言之,藉由重組DNA技術先前產生之對應人類IL11RA (SEQ ID NO: 7)或小鼠Il11ra (SEQ ID NO: 10)表現質體與報導基因質體(pNL[NlucP/SIE/Hygro]載體,Promega #CS189701)共轉染至HEK 293F細胞中。10000 將每孔轉染之細胞接種於平底384孔培養盤(Corning, #354660)中,且隨後在37℃、5% CO
2下培育隔夜。次日,在含有固定濃度0.78 [nM]人類IL-11 (Invigate,例如批次號C121021-19)或3.13 [nM]鼠類IL-11 (Invigate,例如批次號C210819-09)之細胞培養基中製備4E-7至5.5E-10[M] (最終分析稀釋度)之TPP-18068、TPP-18087、TPP-19528、TPP-14250及TPP-10159的連續稀釋液。固定人類/鼠類IL11濃度應等於報導基因分析中之人類/鼠類IL劑量反應治癒的EC40值且已預先測定。在室溫下培育抗體/抗原之混合物30分鐘。作為陰性對照,亦在抗體及IL11不存在下培育細胞。其後,丟棄細胞上方之培養基,每孔25 µl添加混合物且與細胞一起在37℃下培育5小時。其後,將在Nano-Luc緩衝液(Promega,N1120)中稀釋(1:50)之Nano-Luc基質(Promega,N1120)每孔25 µl添加至培養盤中。在室溫下在暗處培育培養盤3分鐘,且隨後藉由微量滴定盤讀取器量測發光。來自劑量反應之信號用於藉由GraphPad Prism (GraphPad Software, San Diego)計算IC50值。功效經計算為[(在無抗體存在下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在無抗體存在下量測之信號-在無IL11存在下量測之信號)。結果展示於表E2中。
表E2:TPP-18063、TPP-18068、TPP18087及TPP-19528對IL-11介導之信號傳導之抑制
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值);
* 功效經計算為[(在無抗體存在下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在無抗體存在下量測之信號-在無IL11存在下量測之信號)。
抗體 | hIL-11 | mIL-11 | ||
IC50 [M] | 功效(%)* | IC50 [M] | 功效(%)* | |
TPP-14250 | 2.41E-10 | 27.1 | 1.42E-07 | 69.1 |
TPP-18063 | 1.1E-07 | 54.3 | 9.5E-08 | 60.0 |
TPP-18068 | 4.83E-09 | 20.7 | 2.67E-09 | 84.1 |
TPP-18087 | 1.07E-07 | 51.5 | 3.31E-07 | 49.0 |
TPP-19528 | 1.5E-08 | 65.6 | 9.6E-09 | 80.7 |
TPP-10159 | NM | 0 | NM | 9.4 |
實例 18 : 雙複合物 ELISA 中分析之 TPP - 18063 、 TPP - 18068 、 TPP18087 及 TPP - 19528 對 IL - 11 與 IL - 11Ra 之相互作用的抑制在雙複合物ELISA型式中,測試抗IL-11抗體干擾由固定化鼠類IL-11 (Invigate,例如批次號C210819-09)或人類IL-11 (Invigate,例如批次號C121021-19)及鼠類IL11RA-Fc融合蛋白或犬類IL11RA-人類-F
C融合蛋白組成之複合物之形成的能力(圖17a、b)。
為了測試鼠類IL-11抗體干擾固定化鼠類或人類IL-11與犬類IL11RA-人類-Fc融合蛋白之複合物形成的能力,如允許偵測之下文針對犬類IL11RA-Fc (Sino Biological, #70078-D02H)及抗人類-POD (Sigma, #A0170)所描述進行分析。
為了測試人類IL-11抗體干擾固定化鼠類或人類IL-11與鼠類IL11RA-Fc融合蛋白之複合物形成的能力,除了使用鼠類IL11RA-Fc融合蛋白(R&D System, #7405-MR)而非犬類IL11RA-Fc融合蛋白,允許用抗鼠類IgG (Fc特異性)-過氧化酶(Jackson, #715-035-)而非抗人類POD進行偵測以外,如下文所描述進行分析。
使用鏈黴抗生物素蛋白塗佈之微量滴定培養盤(Greiner bio-one, # 781997)進行分析。在第一步驟中,在25 µl PBS中在培養盤上在4℃下塗佈10nM經生物素標記之小鼠IL-11 (Invigate,Germany,例如批次號C210819-09)或人類IL-11 (Invigate,Germany,例如批次號C121021-19)隔夜。次日,用50 µl PBST洗滌培養盤三次,且隨後在室溫(RT)下用50 µl SmartBlock (Candor, #113125)阻斷一小時。在用PBST額外洗滌三次之後,將鼠類抗IL-11抗體及重組犬類IL11RA-Fc融合蛋白(Sino Biological, #70078-D02H)於PBS-T中之25 µl混合物、10% Smartblock同時添加至培養盤中且在室溫下培育一小時。為了產生劑量反應,針對2 nM犬類IL11RA-Fc將抗體自1E-07滴定至1.6E-10[M],其為大致在抗體不存在下結合至固定化IL-11之受體之劑量反應滴定的EC50。在用PBS-T額外洗滌三次之後,添加含25 µl抗人類-POD (Sigma, # A0170)之PBS-T、10% Smartblock,且在室溫下培育1小時。在用PBS-T最終洗滌三次之後,添加含25 µl AmplexRed (Fisher Scientific, A12222)之1/1000 PBS、0.003% H
2O
2作為基質且在室溫下在暗處培育15分鐘。隨後,在535/595 nm處用培養盤讀取器量測螢光。使用來自劑量反應之信號計算IC50值(GraphPad Prism)。功效經計算為[(在最低抗體濃度下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在最低抗體濃度下量測之信號-在IL11Ra不存在下量測之信號)。結果展示於表E3中。
表E3:在雙複合物ELISA中分析之TPP-18068、TPP18087及TPP-19528對人類IL-11與人類IL-11Ra之相互作用的抑制
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值);
* 功效經計算為[(在最低抗體濃度下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在最低抗體濃度下量測之信號-在IL11Ra不存在下量測之信號)。
**鼠類IgG1-IL-11抗體
抗體** | hIL11 | mIL11 | ||
IC50 [M] | 功效(%)* | IC50 [M] | 功效(%)* | |
TPP-14250 | 7.4E-09 | 67.2 | 1.3E-09 | 92.3 |
TPP-18063 | 5.4E-08 | 42.0 | 1.2E-08 | 68.9 |
TPP-18068 | NM | 19.6 | 2.5E-09 | 72.7 |
TPP-18087 | NM | 10.7 | NM | 13.4 |
TPP-19528 | 3.0E-09 | 57.0 | 2.4E-08 | 79.0 |
TPP-10159 | NM | 10.3 | NM | 10.2 |
實例 19 : 在三複合物 ELISA 中分析之 TPP - 18063 、 TPP - 18068 、 TPP - 18087 及 TPP - 19528 對 IL - 11 / IL - 11Ra / gp130 複合物 之形成的抑制在三複合物ELISA型式中,測試IL-11抗體抑制由鼠類或人類gp130-Fc融合蛋白與鼠類或人類IL-11及鼠類IL11RA-Fc融合蛋白組成之複合物之形成的能力。視是否測試鼠類或人類IL-11 IgG抗體而定,根據圖18 (a、b)調適分析型式。
使用高結合微量滴定培養盤(Greiner, #781077)進行分析。在第一步驟中,在培養盤上在4℃下塗佈在塗佈緩衝劑(Candor,#121125)中經1:1000稀釋之25 µl山羊抗人類IgG (Sigma, #I2136)隔夜。次日,將培養盤用50 µl PBST洗滌一次,且隨後在室溫(RT)下用50 µl SmartBlock (Candor, # 113125)阻斷一小時。同時,在96孔微量滴定盤(Nunc, #267334)中在室溫下預培育含2.5E-07 [M]至4.1E-10 [M]鼠類IL-11抗體之濃度範圍之混合物及固定濃度之人類IL11 (例如Invigate,Germany [8 nM],例如批次號C121021-19),分別鼠類IL-11 (例如Invigate,Germany [8 nM],例如批次號C210819-09)、人類gp130-人類-Fc (R&D Systems, #671-GP, [2 NM]),分別鼠類gp130-人類-Fc (R&D Systems, #468-MG, [2 nM])及重組鼠類IL11RA-鼠類-Fc融合蛋白(R&D System, #7405-MR, [2 nM])之PBS-T、10% SmartBlock一小時。在用PBS-T額外洗滌經塗佈及阻斷之微量滴定盤三次之後,添加25 µl各混合物且在室溫下培育分析盤一小時。在額外洗滌三次之後,添加含經抗小鼠-gp130生物素標記之抗體(R&D, #BAF468)或經抗人類gp130生物素標記之抗體(R&D, #BAF228) (在10% SmartBlock PBS-T中均1:1000)且在室溫下培育1小時。在額外洗滌三次之後,添加含鏈黴抗生物素蛋白-過氧化酶結合物(Sigma, #S5512)之1:1000 SmartBlock PBS-T且在室溫下培育一小時。在最終洗滌三次之後,添加含AmplexRed (Fisher Scientific, A12222)之1/1000 PBS、0.003% H
2O
2作為基質且在室溫下在暗處培育15分鐘。隨後,在535/595 nm處用培養盤讀取器量測螢光。使用來自劑量反應之信號計算IC50值(使用GraphPad Prism軟體)。功效經計算為[(在最低抗體濃度下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在最低抗體濃度下量測之信號-在8.2E-11[M]之IL11濃度下在抗體不存在下量測之信號)。結果展示於表E4中。
表E4:在三複合物ELISA中分析之TPP-18068、TPP-18087及TPP-19528對人類IL-11/IL-11Ra/gp130複合物之形成的抑制
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值);
* 功效經計算為[(在最低抗體濃度下量測之信號-在最高抗體濃度下量測之信號)×100]除以(在最低抗體濃度下量測之信號-在8.2E-11[M]之IL11濃度下在抗體不存在下量測之信號)。
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效(%)* | IC50 [M] | 功效(%)* | |
TPP-14250 | 3.8E-08 | 67.2 | 1.7E-08 | 60.9 |
TPP-18063 | 9.2E-08 | 60.6 | 1.7E-07 | 36.3 |
TPP-18068 | NM | 7.3 | 6.6E-08 | 37.1 |
TPP-18087 | 5.5E-08 | 60.4 | NM | 5.5 |
TPP-19528 | 2.0E-08 | 57.0 | 1.4E-08 | 76.6 |
TPP-10159 | NM | 13.7 | NM | 12.3 |
實例 20 : 藉由 ELISA 分析之 TPP - 18068 、 TPP - 18087 及 TPP - 19528 與 IL2Ra 之結合吾等測試TPP-18068、TPP-18087及TPP-19528與一組蛋白之結合且發現TPP-18068與人類IL2Ra之特異性結合,其在人類IL2Ra直接結合ELISA中進一步分析。以每孔1或0 µg/ml (僅緩衝劑對照組)在30 µl塗佈緩衝劑(Candor, #113500)中在384孔微量滴定盤(Maxisorb, Nunc, #460518)上在4-8℃下塗佈IL2RA (Peprotech, Germany, #200-02RC)。在具有50 µl/孔洗滌緩衝液(PBS + 0.05% Tween,pH 7.4)之兩次洗滌之後,在室溫下用50 µl/孔SmartBlock (Candor, #113500)培育培養盤兩小時。阻斷後,用洗滌緩衝液洗滌培養盤三次。隨後,將30 µl含各別抗體之稀釋系列(1E-7[M]降至2E-13[M])之PBS+0.05% Tween、10% SmartBlock添加至微量滴定盤中,且在室溫下培育90分鐘。在三次額外洗滌之後,每孔添加在PBS+0.05% Tween (pH 7.4)中經1:1000稀釋之30 µl抗小鼠IgG HRP結合抗體(Biotechne, HAF007)且培育一小時。在三次額外洗滌之後,添加1:1000稀釋於PBS中之Amplex red (Invitrogen,#12222,10 mM儲備溶液於DMSO中)及1:10000稀釋於PBS中之H2O2 (30%, Merck,#107209)之混合物作為基質,其中每孔30 µl且在暗處培育20分鐘。在535/590 nm處用微量滴定盤讀取器量測相對螢光。
TPP-18068在抗體濃度3.3E-7[M]下對比同型對照TPP-10159獲得之信號之比率經計算為256,表明TPP-18068對hIL2Ra之較強及顯著結合,而TPP-18087及TPP-19528僅展示分別2.4、0.8之比率,表明無顯著結合。
實例
21
-
24
展示生殖系、序列最佳化
(
PTM
移除及
TPP
-
18087
之親和力成熟
實例
21
:
第
1
輪生殖系化
(
單一突變
)
及
TPP
-
18087
之
PTM
移除
使抗體TPP-18087經受旨在以下之主要最佳化程序:(i)最佳化其親和力;(ii)提高其功能效率;(iii)降低基於序列之免疫原性的風險;及(iv)提高與下游開發過程的相容性。
生殖系化設計、 PTM 移除設計及質體構築將親本抗體之序列與IMGT之人類生殖系序列譜系(Lefranc 2003)比對。選擇在構架中對應位置及CDR相對於TPP-18087具有最小胺基酸差異數目之人類生殖系序列作為生殖系化模板。TPP-18087之VL序列與人類生殖系基因共有最高水準一致性:hIGLV1-47*01生殖系基因。TPP-18087之VH序列與人類生殖系基因共有最高水準一致性:hIGHV3-30*03生殖系基因。選擇非人類生殖系位置上之單一回復突變以構成第1輪生殖系化變異體。
針對以下類型之關鍵轉譯後修飾(PTM)位點掃描TPP-18087之序列:CDR中之天冬醯胺脫醯胺(Asn-Gly及Asn-Ser)、CDR中之天冬胺酸異構化(Asp-Gly)、CDR中及構架中之不成對Cys及CDR中及構架中之N-連接糖基化位點(Asn-Xxx-Ser/Thr,其中Xxx可為除Pro之外的任何胺基酸)。TPP-18087在VL中具有一個Asn-Gly(NG)位點且在VH中具有一個Asp-Gly(DG)位點。為了移除NG位點,進行三種單一突變:天冬醯胺酸轉化成麩醯胺酸或絲胺酸,而甘胺酸轉化成丙胺酸。為移除DG位點,進行三種單一突變:天冬胺酸轉化成麩胺酸,而甘胺酸轉化成丙胺酸或絲胺酸。對於TPP-18087,鑑別TPP-18087之兩個PTM熱點:VL中之一個Asn-Gly(NG)位點及VH中之一個Asp-Gly(DG)位點。NG位點突變成QG、SG及NA。DG位點突變成EG、DA及DS。以組合方式使用WT及單一突變之所有組合探測兩個PTM風險位點
嵌合抗體之質體經密碼子最佳化以用於哺乳動物表現,且隨後在Genewiz (South Plainfield, NJ, USA)合成。將親本抗體及生殖系化變異體之V基因選殖至人類IgG表現載體(中國無錫)中以產生所需同型之人類IgG構築體(VH域與人類IgG4 SPLE變異體融合,且VL域與人類Ig λ CL域融合)。各構築體含有相同恆定片段,但賦予不同VH或VL域,以及不同位點突變。
抗體產生含有VH及VL基因之質體共轉染至Expi293F細胞中。培養細胞5天且收集上清液以用於使用蛋白A管柱(GE Healthcare,目錄175438)之單步驟蛋白質純化。藉由A280/消光係數使用Nanodrop 2000測定來自溶離之蛋白質濃度。藉由SDS-PAGE及HPLC-SEC分析純化三十六個抗體,包括一個嵌合抗體、二十個生殖系化抗體變異體及十五個PTM抗體變異體,且隨後儲存在-80℃下或用於後續分析中。
SPR 對人類 / 小鼠 IL - 11 之親和力使用Biacore 8K偵測對hIL-11 (Invigate,Germany,例如批次號C121021-19)及mIL-11 (Invigate,Germany,例如批次號C210819-09)之抗體結合親和力。在抗人類IgG Fc抗體固定化CM5感測器晶片(GE)上捕捉各抗體。在1×HBS-EP+ (pH 7.4) (GE Healthcare)中不同濃度(0、5、15.82及50 nM)之hIL-11及mIL-11以30 µL/min之流動速率注射於感測器晶片上,締合階段為120秒,繼而200秒解離階段。隨後在各結合週期之後,藉由10 mM甘胺酸(pH 1.5)使晶片再生。
自測試感測器圖譜減去空白表面及緩衝通道之感測器圖譜。使用朗格繆爾分析藉由1:1模型擬合實驗資料。使用19.3 kDa之分子量計算人類及小鼠IL-11之莫耳濃度。第1輪生殖系化及PTM突變體之SPR結果展示於表E5中。
表E5:人類/小鼠IL-11之第1輪生殖系化及PTM移除突變體之SPR結果
* 使用胺基酸殘基之連續編號
下劃線=與人類/小鼠抗原之結合親和力改良;斜體=類似結合;粗體=顯著降低結合;星號(*) =相較於WT抗體,結合親和力稍微降低(降低1.5至2.5倍)
抗體 | K D[M]: hIL-11 | K D[M]: mIL-11 | 突變重鏈 | 突變輕鏈 |
TPP-18087 | 5.2E-09 | 1.2E-08 | VH-WT | VL-WT |
TPP-31312 | 9.2E-09 | 1.3E-08 | VH-WT | VL-WT |
TPP-31277 | 9.4E-09 | 1.2E-08 | VH-WT | VL-N31S |
TPP-31278 | 2.0E-09 | 1.2E-09 | VH-WT | VL-A33Y |
TPP-31279 | 無結合 | 1.4E-07 | VH-WT | VL-N35Y |
TPP-31280 | 6.0E-07 | 無結合 | VH-WT | VL-Y51R |
TPP-31281 | 1.7E-07 | 1.3E-07 | VH-WT | VL-D52N |
TPP-31282 | 1.3E-08 | 1.9E-08 | VH-WT | VL-D53N* |
TPP-31283 | 4.8E-08 | 4.1E-08 | VH-WT | VL-L54Q |
TPP-31284 | 1.1E-08 | 1.5E-08 | VH-WT | VL-L55R |
TPP-31285 | 7.6E-09 | 1.8E-08 | VH-WT | VL-S90A |
TPP-31286 | 9.1E-09 | 1.2E-08 | VH-E1Q | VL-WT |
TPP-31287 | 9.3E-09 | 1.3E-08 | VH-L5V | VL-WT |
TPP-31288 | 1.1E-08 | 1.5E-08 | VH-L11V | VL-WT |
TPP-31289 | 9.6E-09 | 1.4E-08 | VH-G16R | VL-WT |
TPP-31290 | 2.9E-07 | 3.0E-07 | VH-H31S | VL-WT |
TPP-31291 | 無結合 | 無結合 | VH-D33G | VL-WT |
TPP-31292 | 1.1E-08 | 1.9E-08 | VH-N35H* | VL-WT |
TPP-31293 | 4.8E-09 | 1.2E-08 | VH-L37V | VL-WT |
TPP-31294 | 1.1E-08 | 1.7E-08 | VH-G49A | VL-WT |
TPP-31295 | 2.0E-08 | 3.3E-08 | VH-F59Y* | VL-WT |
TPP-31296 | 9.4E-09 | 1.2E-08 | VH-F63S | VL-WT |
TPP-31312 | 9.2E-09 | 1.3E-08 | VH-WT | VL-WT |
TPP-31297 | 8.7E-09 | 1.4E-08 | VH-WT | VL-N97Q |
TPP-31298 | 9.3E-09 | 1.3E-08 | VH-WT | VL-N97S |
TPP-31299 | 1.8E-08 | 1.6E-08 | VH-WT | VL-G98A |
TPP-31300 | 3.8E-09 | 3.0E-09 | VH-D54E | VL-WT |
TPP-31301 | 3.6E-09 | 2.9E-09 | VH-D54E | VL-N97Q |
TPP-31302 | 3.8E-09 | 3.2E-09 | VH-D54E | VL-N97S |
TPP-31303 | 6.9E-09 | 3.6E-09 | VH-D54E | VL-G98A |
TPP-31304 | 1.5E-08 | 2.3E-08 | VH-G55A | VL-WT |
TPP-31305 | 1.5E-08 | 2.5E-08 | VH-G55A | VL-N97Q |
TPP-31306 | 1.5E-08 | 2.3E-08 | VH-G55A | VL-N97S |
TPP-31307 | 3.1E-08 | 2.8E-08 | VH-G55A | VL-G98A |
TPP-31308 | 4.0E-08 | 4.7E-08 | VH-G55S | VL-WT |
TPP-31309 | 4.1E-08 | 5.3E-08 | VH-G55S | VL-N97Q |
TPP-31310 | 4.0E-08 | 4.3E-08 | VH-G55S | VL-N97S |
TPP-31311 | 8.7E-08 | 5.8E-08 | VH-G55S | VL-G98A |
生殖系化突變體TPP-31277至TPP-31296就其人類及小鼠IL-11結合親和力之變化而言分為四個類別。以下弧線突出顯示之突變體展示與WT抗體相比,對人類/小鼠抗原之結合親和力提高。
以斜體突出顯示之突變體與WT抗體相比展示類似的人類/小鼠抗原結合親和力。以粗體突出顯示之突變體展示與WT抗體相比,對人類/小鼠抗原之結合親和力顯著降低。用星號(*)標記之突變體與WT抗體相比展示略微降低之結合親和力(降低1.5至2.5倍)。
對於第1輪PTM移除突變體TPP-31297至TPP-31311,TPP-31300 (VH-D54E)為根據SPR結果在PTM移除之15種變異體中人類/小鼠抗原結合親和力的最佳純系(表E5)。TPP-31298純系之突變位點為VL-N97S,其亦為生殖系突變位點,且此純系與TPP-31312相比展示類似的人類/小鼠抗原結合親和力(表E5)。包括兩個突變位點VH-D54E/VL-N97S之TPP-31302純系展示與人類及小鼠IL11之結合提高,因此兩個突變位點VH-D54E/VL-N97S涉及第2輪CDR生殖系化。
人類及小鼠 IL - 11 RGA 分析除了進行兩次RGA分析以外,如實例17中所描述在人類及小鼠IL-11 RGA分析中測試純化抗體。第1輪生殖系化突變體及PTM移除突變體之人類及小鼠IL-11 RGA分析之結果概述於表E6中。所有突變體展示就SPR結合親和力及RGA效能之變化而言之一致趨勢。
表E6:第1輪生殖系化及對人類/小鼠IL-11之PTM移除突變體之RGA結果
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值);
* 使用胺基酸殘基之連續編號;
下劃線=與人類/小鼠抗原之結合親和力改良;斜體=類似結合;粗體=顯著降低結合;星號(*) =相較於WT抗體,結合親和力稍微降低(降低1.5至2.5倍)
抗體 | IC50 (nM): hIL-11 | IC50 (nM): mIL-11 | 突變位點 | |||
RGA 1 | RGA 2 | RGA 1 | RGA 2 | 重鏈 | 輕鏈 | |
TPP-18087 | 93 | 12 | 231 | 21 | NA | |
TPP-31312 | 171 | 80 | 75 | 20 | VH-WT | VL-WT |
TPP-31277 | 211 | 47 | 43 | 27 | VH-WT | VL-N31S |
TPP-31278 | 22 | 2.36 | 0.13 | 0.08 | VH-WT | VL-A33Y |
TPP-31279 | >500 | >500 | 196 | >500 | VH-WT | VL-N35Y |
TPP-31280 | >500 | NM | >500 | NM | VH-WT | VL-Y51R |
TPP-31281 | >500 | NM | >500 | NM | VH-WT | VL-D52N |
TPP-31282 | 345 | 287 | 70 | 28 | VH-WT | VL-D53N* |
TPP-31283 | >500 | 200 | 247 | 118 | VH-WT | VL-L54Q |
TPP-31284 | 101 | 131 | 65 | 17 | VH-WT | VL-L55R |
TPP-31285 | 50 | 16 | 111 | 23 | VH-WT | VL-S90A |
TPP-31286 | 59 | 37 | 18 | 13 | VH-E1Q | VL-WT |
TPP-31287 | 127 | 56 | 41 | 15 | VH-L5V | VL-WT |
TPP-31288 | 67 | 141 | 47 | 23 | VH-L11V | VL-WT |
TPP-31289 | 61 | 76 | 27 | 23 | VH-G16R | VL-WT |
TPP-31290 | >500 | NM | >500 | NM | VH-H31S | VL-WT |
TPP-31291 | >500 | NM | >500 | NM | VH-D33G | VL-WT |
TPP-31292 | 234 | 107 | 52 | 39 | VH-N35H* | VL-WT |
TPP-31293 | 58 | 13 | 31 | 13 | VH-L37V | VL-WT |
TPP-31294 | 96 | 38 | 41 | 28 | VH-G49A | VL-WT |
TPP-31295 | 364 | 92 | 60 | 37 | VH-F59Y* | VL-WT |
TPP-31296 | 46 | 158 | 20 | 22 | VH-F63S | VL-WT |
TPP-18087 | 111 | 12 | 204 | 21 | VH-WT | VL-WT |
TPP-31312 | 163 | 80 | 31 | 20 | VH-WT | VL-N97Q |
TPP-31297 | 181 | 22 | 37 | 7.93 | VH-WT | VL-N97S |
TPP-31298 | 135 | 33 | 21 | 6.22 | VH-WT | VL-G98A |
TPP-31299 | 238 | 114 | 44 | 14 | VH-D54E | VL-WT |
TPP-31300 | 1.09 | 4.75 | 3.42 | 0.81 | VH-D54E | VL-N97Q |
TPP-31301 | 18.9 | 9.71 | 4.43 | 1.77 | VH-D54E | VL-N97S |
TPP-31302 | 14.5 | 7.13 | 3.49 | 1.17 | VH-D54E | VL-G98A |
TPP-31303 | 9.08 | 11 | 4.38 | 2.49 | VH-G55A | VL-WT |
TPP-31304 | 104 | 35 | 42 | 21 | VH-G55A | VL-N97Q |
TPP-31305 | 182 | 47 | 30 | 29 | VH-G55A | VL-N97S |
TPP-31306 | 126 | 23 | 57 | 60 | VH-G55A | VL-G98A |
TPP-31307 | >500 | 126 | 45 | 37 | VH-G55S | VL-WT |
TPP-31308 | >500 | >500 | 63 | 170 | VH-G55S | VL-N97Q |
TPP-31309 | 261 | 122 | 108 | 68 | VH-G55S | VL-N97S |
TPP-31310 | >500 | >500 | 144 | 75 | VH-G55S | VL-G98A |
TPP-31311 | >500 | 34 | 76 | 127 | VH-G55S | VL-G98A |
實例
22
:
TPP
-
18087
之第
2
輪生殖系化
(
組合突變
)
生殖系化設計、
PTM
移除設計及質體構築
基於第1輪生殖系化之結果,12個生殖系單位點突變體VH-E1Q、VH-L5V、VH-L11V、VH-G16R、VH-N35H、VH-L37V、VH-G49A、VH-F63S、VL-N31S、VL-A33Y、VL-L55R及VL-S90A展示<1.9E-08 M之SPR結合親和力及<1.7E-07 M之RGA效能(平均值)。組合此等12個突變位置以產生用於第2輪生殖系化之模板,命名為基本主鏈(FB)。為評估每一生殖系化突變對FB活性的作用,構成12個向上FB之單一位置回復突變變異體(FB-1)。另兩種突變體(VH-F59Y及VL-D53N)展示SPR結合活性及RGA效能略微降低。同樣以組合方式探測此兩個位點。因此,選擇總計16個利用PTM拋光主鏈(VH-D54E/VL-N97S)之突變體以構成第2輪生殖系化變異體。第2輪生殖系化抗體變異體之DNA經密碼子最佳化以用於哺乳動物表現,且隨後在Genewiz (South Plainfield, NJ, USA)合成。將編碼親本抗體及生殖系化變異體之可變區之基因選殖至人類IgG表現載體(中國無錫)中以產生所需同型之人類IgG構築體(VH域與人類IgG4 SPLE變異體融合,且VL域與人類Ig λ CL域融合)。
SPR 對人類 / 小鼠 IL - 11 之親和力16 如實例21中所描述產生AB且使用SPR分析純化AB與人類及小鼠IL-11之結合,如實例21中所描述。第2輪生殖系化突變體之SPR結果概述於表E7中。
表E7:人類/小鼠IL-11之第2輪生殖系化突變體之SPR分析結果
* 使用胺基酸殘基之連續編號
抗體 | K D [M]: hIL-11 | K D [M]: mIL-11 | 突變位點 |
TPP-31312 | 5.3E-09 | 9.3E-09 | WT |
TPP-31313 | 8.9E-10 | 6.4E-10 | FB |
TPP-31314 | 8.7E-10 | 5.9E-10 | FB-1,回復突變VH-Q1E |
TPP-31315 | 8.7E-10 | 6.5E-10 | FB-1,回復突變VH-V5L |
TPP-31316 | 8.5E-10 | 6.2E-10 | FB-1,回復突變VH-V11L |
TPP-31317 | 8.3E-10 | 5.8E-10 | FB-1,回復突變VH-R16G |
TPP-31318 | 8.9E-10 | 3.0E-10 | FB-1,回復突變VH-H35N |
TPP-31319 | 8.3E-10 | 5.9E-10 | FB-1,回復突變VH-V37L |
TPP-31320 | 9.5E-10 | 5.6E-10 | FB-1,回復突變VH-A49G |
TPP-31321 | 8.5E-10 | 6.7E-10 | FB-1,回復突變VH-S63F |
TPP-31322 | 8.1E-10 | 6.9E-10 | FB-1,回復突變VL-S31N |
TPP-31323 | 2.4E-09 | 1.7E-09 | FB-1,回復突變VL-Y33A |
TPP-31324 | 7.9E-10 | 5.0E-10 | FB-1,回復突變VL-R55L |
TPP-31325 | 5.9E-10 | 3.5E-10 | FB-1,回復突變VL-A90S |
TPP-31326 | 1.7E-09 | 1.2E-09 | FB+1,加VH-F59Y |
TPP-31327 | 1.0E-09 | 8.5E-10 | FB+1,加VL-D53N |
TPP-31328 | 1.8E-09 | 1.8E-09 | FB+2,加VH-F59Y & VL-D53N |
TPP-31325 (具有回復突變VL-A90S之FB)展示針對hIL-11及mIL-11之最高結合親和力,因此參與作為主鏈模板之第2輪親和力最佳化。
人類及小鼠 IL - 11 RGA 分析除了僅進行一個RGA運作且結果概述於表E8中以外,使用如實例21中所描述之純化第2輪生殖系化突變體抗體進行人類及小鼠IL-11 RGA分析。
表E8:第2輪生殖系化突變體對人類/小鼠IL-11之RGA結果
抗體 | IC50 (nM): hIL-11 | IC50 (nM): mIL-11 | 突變位點 |
TPP-31312 | 8.9 | 9.8 | WT |
TPP-31313 | 5.4 | 1.6 | FB |
TPP-31314 | 2.4 | 1.2 | FB-1,回復突變VH-Q1E |
TPP-31315 | 2.9 | 1.7 | FB-1,回復突變VH-V5L |
TPP-31316 | 3.2 | 1.1 | FB-1,回復突變VH-V11L |
TPP-31317 | 2.9 | 1.5 | FB-1,回復突變VH-R16G |
TPP-31318 | 3.8 | 1.2 | FB-1,回復突變VH-H35N |
TPP-31319 | 2.3 | 1.6 | FB-1,回復突變VH-V37L |
TPP-31320 | 2.8 | 1.1 | FB-1,回復突變VH-A49G |
TPP-31321 | 2.8 | 1.0 | FB-1,回復突變VH-S63F |
TPP-31322 | 1.7 | 1.4 | FB-1,回復突變VL-S31N |
TPP-31323 | 7.1 | 3.5 | FB-1,回復突變VL-Y33A |
TPP-31324 | 2.9 | 1.0 | FB-1,回復突變VL-R55L |
TPP-31325 | 1.2 | 0.6 | FB-1,回復突變VL-A90S |
TPP-31326 | 3.6 | 3.3 | FB+1,加VH-F59Y |
TPP-31327 | 3.1 | 2.1 | FB+1,加VL-D53N |
TPP-31328 | 7.9 | 2.1 | FB+2,加VH-F59Y & VL-D53N |
實例
23
:
TPP
-
18087
之第
1
輪親和力成熟
(
單胺基酸突變
)
親和力最佳化設計及突變體構築
使抗體TPP-18087經受主要最佳化程序,旨在最佳化其親和力且提高其功能效率。親本TPP-18087純系之六個互補決定區(CDR)之各胺基酸使用定點突變誘發方法單獨地突變成所有20個胺基酸。使用含有編碼20個胺基酸之NNS密碼子的DNA引子將突變引入至各靶向CDR位置。簡併引子用於定點突變誘發反應中。簡言之,各簡併引子經磷酸化。PCR條件為94℃持續2分鐘,(94℃持續30秒,55℃持續30秒,72℃持續5分鐘),16次循環,72℃持續10分鐘。將PCR產物純化,且隨後轉化成BL21以產生含有c-Myc標籤繼而His標籤之scFv片段。周質提取物用於進一步特徵化。
第 1 輪篩選 ELISA如下設定第1輪篩選ELISA:在4℃下,在塗佈緩衝劑(PBS,pH 7.4)中用100 µl 0.25 µg/ml山羊抗c-myc抗體塗佈96孔Maxisorp免疫盤之單獨孔隔夜。次日,培養盤用300 µl洗滌緩衝液(PBS-T)洗滌三次且在25℃下用200 µl含1%酪蛋白之PBS阻斷1小時。在三次額外洗滌之後,TPP-18087集合庫scFv之周質提取物(PE)用含1%酪蛋白之PBS/0.05% Tween 20 (體積比為1:1)稀釋,且將100 µl/孔添加至培養盤中,在25℃下培育1小時。同時,在25℃下將0.5 µg/ml hIL-11或mIL-11抗原及1.875 µg/ml IL11抗體TPP-31391預混合1小時。TPP-31391含有可變域,其在雙複合物ELISA中為活性的且其不與抗體TPP-18087競爭IL-11結合。在用300 µl洗滌緩衝液洗滌分析盤三次之後,將100 µl hIL-11/TPP-31391或mIL11/TPP-31391混合物添加至孔中,在25℃下培育1小時。在三次額外洗滌之後,此繼而與100 µl/孔抗hFc-IgG-辣根過氧化酶(HRP)結合物(1:5000於PBS-T中)一起在25℃下培育1小時。用300 µl洗滌緩衝液最終洗滌六次之後,用四甲基-聯苯胺(TMB)基質偵測HRP活性且用2 M HCl淬滅反應物。在450 nM處讀取培養盤。
經受篩選ELISA之5368個純系中187個純系展示ELISA OD450信號相比於表現為scFv抗體之野生型抗體TPP-18087提高5至6倍。187個純系之DNA定序揭示在12個CDR胺基酸位置具有獨特序列之24個純系。藉由scFv捕捉ELISA進一步證實此等純系。
scFv 捕獲 ELISA來自TPP-18087集合庫初級篩選之24個命中物的EC50值係藉由使用scFv捕捉ELISA測定。簡言之,將100 µl 1 μg/ml之PBS(pH 7.4)中之IL-11單株抗體TPP-31391添加至96孔Maxisorp免疫盤之單獨孔中且在4℃下培育分析盤隔夜。次日,在25℃下用1%酪蛋白阻斷培養盤1小時。隨後將2 μg/ml hIL-11或mIL-11添加至培養盤中且在25℃下培育1小時。隨後來自TPP-18087集合庫初級篩選之24個命中物的周質提取物用含1%酪蛋白之PBS/0.05% Tween 20連續稀釋3.16倍,添加至培養盤中且在25℃下培育1小時。此後在25℃下與山羊抗c-myc HRP結合物一起在PBS-T中培育1小時。用TMB基質偵測HRP活性且用2 M HCl淬滅反應物。在450 nm處讀取培養盤且用GraphPad Prism測定EC50值。
選擇使用scFv捕捉ELISA展示hIL-11及mIL-11之結合改良的八個突變體用於組合集合庫設計(圖19)。
實例
24
:
第
2
輪親和力成熟
(
組合突變
)
組合集合庫構築
初級篩選中所鑑別且圖19中所示之親和力改良突變用於組合集合庫構築中。
具有最終生殖系TPP-31325 (在PTM移除及第2輪生殖系化後)質體之CJ236菌株用於生成尿嘧啶化單股DNA (ssDNA),其用作TPP-18087組合集合庫構築之模板。簡言之,合成編碼特定CDR位置處之所有所鑑別之突變以及野生型胺基酸的引子且以等莫耳比混合。對於含有超過一個突變位點之引子,合成引子區內含有所有可能突變組合之引子且以等莫耳比混合。為了構築組合集合庫,進行昆克(Kunkel)反應。簡言之,將混合物加熱至85℃持續5分鐘,隨後歷經1小時自64℃冷卻至55℃。其後,添加T4接合酶及T4 DNA聚合酶且混合。且隨後在37℃下培育1.5小時。典型地,200 ng組合集合庫DNA電穿孔至BL21中以用於產生含有c-Myc標籤繼而His標籤之scFv片段。
第 2 輪篩選捕捉 scFv ELISA篩選所構築集合庫以鑑別在結合改良方面產生協同作用的突變組合。藉由捕捉scFv ELISA,用經生物素標記之hIL-11及mIL-11篩選總共1848個純系。簡言之,在4℃下在pH 7.4下在塗佈緩衝液PBS中用0.2 µg/ml山羊抗c-myc抗體塗佈96孔Maxisorp免疫盤之孔隔夜。次日,培養盤用300 µl洗滌緩衝液(PBS-T)洗滌三次,且隨後在25℃下用含200 µl 1%酪蛋白之PBS阻斷1小時。在三次額外洗滌之後,根據1:1體積比用含1%酪蛋白之0.05% Tween 20稀釋組合突變scFv純系之周質(PE),隨後將100 µl添加至培養盤中且在25℃下培育一小時。在三次洗滌之後,將0.25 µg/ml經生物素標記之hIL-11或mIL-11添加至孔中且在25℃下培育1小時。在三次洗滌之後,此繼而與SA-辣根過氧基酶(HRP)結合物一起在25℃下培育1小時。在最終六次洗滌之後,用四甲基-聯苯胺(TMB)基質偵測HRP活性且用2 M HCl淬滅反應物。在450 nM處讀取培養盤。對在450 nm處展現比未突變最終生殖系scFv變異體TPP-31466大2倍之光密度(OD)信號之純系進行定序且藉由SPR進一步確認。
藉由 k 離 排序 SPR 確證組合 scFv 突變體集合庫使用Biacore 8K測定結合至hIL-11及mIL-11之20個scFv命中物之
k d(1/s)。在CM5感測器晶片上經由抗his抗體及抗c-Myc抗體之預固定化混合物捕捉來自周質提取物之各scFv抗體。在感測器晶片上以30 μL/min之流動速率注射含5 nM hIL-11或mIL-11之1×HBS-EP+ (pH 7.4)緩衝劑持續120秒之締合階段,繼而600秒解離階段。隨後在各結合週期之後,藉由10 mM甘胺酸(pH 1.5)使晶片再生。自測試感測圖譜減去用於參考通道及緩衝通道之感測器圖譜。使用朗格繆爾分析藉由1:1模型擬合實驗資料。使用19.3 kDa之分子量計算分析物之莫耳濃度。針對TPP-31466展示來自SPR實驗之
k a、
k d及
K D值,其為最終生殖系變異體TPP-31325之scFv型式以及表E9中之scFv命中物TPP-31413至TPP-31432。
表E9:第2親和力成熟之20次篩選命中物的SPR結果
抗體 | 人類 IL-11 | 小鼠 IL-11 | ||||
k a (1/Ms) | k d (1/s) | K D (M) | k a (1/Ms) | k d (1/s) | K D (M) | |
TPP-31466 | 9.7E+06 | 4.2E-03 | 4.3E-10 | 7.4E+06 | 2.5E-03 | 3.3E-10 |
TPP-31426 | 7.9E+06 | 1.6E-04 | 2.0E-11 | 8.5E+06 | 1.4E-04 | 1.6E-11 |
TPP-31424 | 5.1E+06 | 1.8E-04 | 3.5E-11 | 5.4E+06 | 1.5E-04 | 2.8E-11 |
TPP-31414 | 5.2E+06 | 2.1E-04 | 4.1E-11 | 5.1E+06 | 1.8E-04 | 3.6E-11 |
TPP-31428 | 5.3E+06 | 2.3E-04 | 4.4E-11 | 6.1E+06 | 2.0E-04 | 3.2E-11 |
TPP-31416 | 7.0E+06 | 2.4E-04 | 3.4E-11 | 5.6E+06 | 3.5E-04 | 6.3E-11 |
TPP-31415 | 6.8E+06 | 2.4E-04 | 3.6E-11 | 5.7E+06 | 2.5E-04 | 4.4E-11 |
TPP-31420 | 4.3E+06 | 2.6E-04 | 6.1E-11 | 4.4E+06 | 2.3E-04 | 5.2E-11 |
TPP-31431 | 5.4E+06 | 2.8E-04 | 5.1E-11 | 5.5E+06 | 2.5E-04 | 4.6E-11 |
TPP-31418 | 8.7E+06 | 2.9E-04 | 3.3E-11 | 7.7E+06 | 2.1E-04 | 2.7E-11 |
TPP-31423 | 6.1E+06 | 2.9E-04 | 4.8E-11 | 5.4E+06 | 2.5E-04 | 4.7E-11 |
TPP-31419 | 4.7E+06 | 2.9E-04 | 6.3E-11 | 4.6E+06 | 2.8E-04 | 6.0E-11 |
TPP-31425 | 3.7E+06 | 3.0E-04 | 8.0E-11 | 4.5E+06 | 2.7E-04 | 6.1E-11 |
TPP-31417 | 5.8E+06 | 3.0E-04 | 5.2E-11 | 5.4E+06 | 2.2E-04 | 4.1E-11 |
TPP-31429 | 5.9E+06 | 3.0E-04 | 5.1E-11 | 6.4E+06 | 2.8E-04 | 4.4E-11 |
TPP-31432 | 4.8E+06 | 3.1E-04 | 6.5E-11 | 5.3E+06 | 2.7E-04 | 5.0E-11 |
TPP-31430 | 5.0E+06 | 3.6E-04 | 7.3E-11 | 4.8E+06 | 3.5E-04 | 7.2E-11 |
TPP-31413 | 4.9E+06 | 3.7E-04 | 7.4E-11 | 4.7E+06 | 3.2E-04 | 6.8E-11 |
TPP-31421 | 5.1E+06 | 7.6E-04 | 1.5E-10 | 4.7E+06 | 2.8E-04 | 6.0E-11 |
TPP-31422 | 5.4E+06 | 9.9E-04 | 1.8E-10 | 4.7E+06 | 1.8E-04 | 3.8E-11 |
TPP-31427 | 6.0E+06 | 1.6E-03 | 2.6E-10 | 4.8E+06 | 1.8E-04 | 3.7E-11 |
IgG 轉化將編碼來自第2輪親和力成熟之五個scFv之可變區的基因選殖至鼠類IgG1表現載體pTT5 (VH域與鼠類IgG1變異體融合,且VL域與鼠類Ig λ CL域融合)以產生TPP-29519、TPP-29520、TPP-29521、TPP-29522及TPP-29523之鼠類IgG1表現載體。另外,將五個scFv選殖至人類表現載體中以產生TPP-29680、TPP-30000、TPP-30001、TPP-30002及TPP-30003之所需同型之人類IgG構築體(VH域與人類IgG1 HS變異體融合,其中引入Fc沉默突變(E233P/L234V/L235A/ DG236/D265G/A327Q/A330),且VL域與人類Ig λ CL域融合)。
實例
25
-
27
展示
TPP
-
18068
之生殖系化、序列最佳化
(
PTM
移除
)
及親和力成熟
實例
25
:
TPP
-
18068
之生殖系化及
PTM
移除
使抗體TPP-18068經受旨在以下之主要最佳化程序:(i)最佳化其親和力;(ii)提高其功能效率;(iii)降低基於序列之免疫原性的風險;及(iv)提高與下游開發過程的相容性。
對於TPP-18068 (mIgG1) (分別為TPP-16478(hIgG1))之生殖系化及序列最佳化程序,選擇輕鏈及重鏈之最接近生殖系家族且針對潛在CMC相關殘基進行細閱。CDR區及FW區中之最接近人類生殖系之偏差及CDR區中之潛在CMC相關殘基藉由根據標準分子方案之定點突變誘發來調節或購買自DNA合成提供者。所產生之DNA構築體藉由哺乳動物細胞之暫時性轉染表現且如實例15中所描述純化。隨後如實例16中所描述,藉由SPR測試人類IL-11及鼠類IL-11結合抗體。所量測之
K D值展示於表E10中。
表E10:第1輪生殖系化及TPP-18068之PTM移除之SPR結果
* 使用胺基酸殘基之連續編號
抗體 | K D [M]: hIL-11 | K D [M]: mIL-11 | Mut VH | Mut VL |
TPP-16478 | 6.6E-09 | 8.3E-10 | WT | WT |
TPP-19841 | 6.3E-09 | 7.9E-10 | WT | T23S |
TPP-19842 | 7.3E-09 | 6.6E-10 | WT | A31S |
TPP-19843 | 1.7E-08 | 7.5E-09 | WT | Y33N |
TPP-19844 | 無結合 | 1.1E-08 | WT | D34Y |
TPP-19845 | 2.0E-08 | 5.0E-09 | WT | H36Y |
TPP-19846 | 無結合 | 1.8E-08 | WT | D34T |
TPP-19847 | 9.0E-09 | 2.1E-09 | WT | H36N |
TPP-19848 | 5.2E-08 | 2.4E-09 | WT | E55Q |
TPP-19849 | 5.9E-09 | 6.8E-10 | WT | R81Q |
TPP-19850 | 6.5E-09 | 1.6E-09 | WT | N98S |
TPP-19861 | 1.7E-08 | 2.8E-08 | G33A | WT |
TPP-19862 | 1.9E-08 | 4.7E-09 | H35S | WT |
TPP-19863 | 4.7E-09 | 6.4E-10 | V50A | WT |
TPP-19864 | 1.3E-08 | 無結合 | Y53G | WT |
TPP-19865 | 2.5E-08 | 3.6E-09 | D54S | WT |
TPP-19866 | 8.5E-09 | 1.4E-09 | S56G | WT |
TPP-19867 | 2.7E-08 | 3.4E-09 | Y57S | WT |
TPP-19868 | 6.2E-09 | 7.2E-10 | K58T | WT |
TPP-19869 | 無結合 | 9.3E-09 | A98K | WT |
TPP-19870 | 無結合 | 6.5E-09 | V100Y | WT |
TPP-19871 | 無結合 | 4.7E-08 | P101F | WT |
TPP-19872 | 5.5E-09 | 4.7E-10 | S49A | WT |
TPP-19873 | 2.1E-08 | 4.0E-09 | Y57N | WT |
TPP-19874 | 9.9E-08 | 9.9E-09 | A98R | WT |
對於第2輪生殖系化,隨後在DNA水準上組合單一逆轉,如實例15中所描述進行表現及純化,且如實例16中所描述藉由SPR進行測試。所量測之
K D值展示於表E11中。
表E11:第2輪生殖系化及TPP-18068之PTM移除的SPR結果
* 使用胺基酸殘基之連續編號
抗體 | K D [M]: hIL-11 | K D [M]: mIL-11 | Mut VH | Mut VL |
TPP-16478 | 7.3E-09 | 6.0E-10 | WT | WT |
TPP-21150 | 5.6E-09 | 1.4E-09 | WT | T23S, A31S, N98S |
TPP-21151 | 無結合 | 1.2E-07 | WT | T23S, A31S, S52D, N98S |
TPP-21153 | 1.0E-08 | 3.6E-09 | WT | T23S, A31S, E55Q, N98S |
TPP-21157 | 1.3E-08 | 7.3E-08 | WT | T23S, A31S, E55Q, N98S, P100V |
TPP-21158 | 4.7E-08 | 1.3E-08 | S49A, A98R | WT |
TPP-27154 | 5.4E-09 | 1.3E-09 | WT | N98S |
TPP-27155 | 5.8E-09 | 6.5E-10 | WT | T23S, A31S |
TPP-27156 | 6.6E-09 | 4.5E-10 | S49A | WT |
TPP-27157 | 5.1E-09 | 1.1E-09 | S49A | N98S |
TPP-27158 | 5.9E-09 | 4.0E-10 | S49A | T23S, A31S |
TPP-27159 | 5.4E-09 | 1.1E-09 | S49A | T23S, A31S, N98S |
TPP-27160 | 1.8E-07 | 5.6E-08 | S49A | T23S, A31S, S52D, N98S |
TPP-27162 | 7.4E-09 | 3.2E-09 | S49A | T23S, A31S, E55Q, N98S |
TPP-27163 | 1.2E-08 | 2.8E-08 | S49A | T23S, A31S, E55Q, N98S, P100V |
TPP-27164 | 5.7E-08 | 2.4E-08 | S49A, A98 | N98S |
TPP-27165 | 4.9E-08 | 1.4E-08 | S49A, A98 | T23S, A31S |
TPP-27167 | 無結合 | 8.1E-09 | S49A, A98 | T23S, A31S, S52D, N98S |
TPP-27169 | 1.0E-07 | 4.1E-08 | S49A, A98 | T23S, A31S, E55Q, N98S |
TPP-27170 | 無結合 | 8.4E-09 | S49A, A98 | T23S, A31S, E55Q, N98S, P100V |
另外,在人類及鼠類IL-11報導基因分析中測試第2輪生殖系化及PTM移除之變異體,除了使用固定濃度之1, 9[nM]人類IL-11(Invigate,例如批次號C121021-19)及5.6 [nM]鼠類IL-11 (Invigate,例如批次號C210819-09)以外,如實例17中所描述。結果展示於表E12中。
表E12:第2輪生殖系化及TPP-18068之PTM移除的RGA結果
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | 人類 IL-11 | 小鼠 IL-11 | 突變位點 | |||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | VH | VL | |
TPP-16478 | 5.6E-09 | 51.4 | 9.6E-10 | 90.8 | WT | WT |
TPP-21150 | 1.2E-08 | 46.9 | 1.6E-09 | 92.2 | WT | T23S, A31S, N98S |
TPP-21151 | NM | 19.4 | 5.5E-08 | 65.3 | WT | T23S, A31S, S52D, N98S |
TPP-21153 | 2.6E-08 | 34.0 | 3.4E-09 | 81.2 | WT | T23S, A31S, E55Q, N98S |
TPP-21157 | NM | 13.4 | 4.4E-08 | 59.2 | WT | T23S, A31S, E55Q, N98S, P100V |
TPP-21158 | NM | 19.4 | 2.4E-09 | 73.2 | S49A, A98R | WT |
TPP-27154 | 2.4E-08 | 58.7 | 1.8E-09 | 92.9 | WT | N98S |
TPP-27155 | 2.0E-08 | 56.5 | 1.1E-09 | 94.3 | WT | T23S, A31S |
TPP-27156 | 1.5E-08 | 50.4 | 1.2E-09 | 90.6 | S49A | WT |
TPP-27157 | 1.3E-08 | 51.2 | 1.4E-09 | 86.4 | S49A | N98S |
TPP-27158 | 2.0E-08 | 55.8 | 1.4E-09 | 89.9 | S49A | T23S, A31S |
TPP-27159 | 1.9E-08 | 43.2 | 1.9E-09 | 82.4 | S49A | T23S, A31S, N98S |
TPP-27160 | NM | -2.8 | 1.0E-08 | 63.8 | S49A | T23S, A31S, S52D, N98S |
TPP-27162 | 9.1E-08 | 36.0 | 3.3E-09 | 77.6 | S49A | T23S, A31S, E55Q, N98S |
TPP-27163 | NM | 2.9 | 5.2E-08 | 52.3 | S49A | T23S, A31S, E55Q, N98S, P100V |
TPP-27164 | NM | 13.9 | 4.1E-08 | 63.2 | S49A, A98 | N98S |
TPP-27165 | NM | 17.5 | 4.2E-09 | 75.1 | S49A, A98 | T23S, A31S |
TPP-27167 | NM | 2.5 | 2.1E-09 | 29.3 | S49A, A98 | T23S, A31S, S52D, N98S |
TPP-27169 | NM | 4.0 | 2.0E-09 | 50.2 | S49A, A98 | T23S, A31S, E55Q, N98S |
TPP-27170 | NM | 0.3 | NM | 41.9 | S49A, A98 | T23S, A31S, E55Q, N98S, P100V |
SPR及RGA結果之分析產生最終生殖系化且序列最佳化分子TPP-27159。與TPP-18068相比,TPP-27159在輕鏈之可變區及重鏈中之S49A中攜帶回復T23S、A31S及N98S。
實例
26
:
第
1
輪親和力及效能成熟
親和力最佳化設計及突變體構築
藉由第一輪單一突變聚集進行親和力成熟,繼而在生殖系化且序列最佳化抗體主鏈中最具親和力及效能逐漸增加之胺基酸交換之再組合。
對於突變聚集,藉由使用包括NNK之合成寡核苷酸之定點突變誘發在以下單獨胺基酸位置處產生NNK隨機化(N=A或G或C或T,K=G或T)以用於密碼子多樣化。對於TPP-18068,分析以下區域對親和力及效能之作用:SYGMH (VH SEQ ID NO: 32之殘基31至35)、VISYDGSYKYYADSVKG (VH SEQ ID NO: 32之殘基50至66)、GVPDY (VH SEQ ID NO: 32之殘基99至103)、TGSSSNIGAGYDVH (VL SEQ ID NO: 36之殘基23至36)、SNNERPS (VL SEQ ID NO: 36之殘基52至58)及AAWDDSLNGPV (VL SEQ ID NO: 36之殘基91至101)。
對所得單一NNK集合庫進行定序且鑑別約800個TPP-18068之單一胺基酸交換變異體。
親本純系 TPP - 18068 之突變變異體在 µ 級別型式中之表現為了在基於ELISA之分析設置中測試親本純系之突變變異體,藉由哺乳動物細胞之暫時性表現此等變異體之所產生之DNA pTT5構築體。為了轉染細胞,在96孔聚苯乙烯圓底培養盤(ThermoFisher Scientific, #268152)之各孔中用移液管移取7,5 µl重鏈(HC)及輕鏈(LC)編碼質體(25 µg/ml,各自稀釋於Opti-MEM [Invitrogen, #11058-02]細胞培養基,Gibco)中之每一者,繼而添加15µl/孔Transfectin (ThermoFisher Scientific,目錄號12347019) (1:12,5次稀釋於Opti-MEM中,(ThermoFisher Scientific,目錄號12347019))及在室溫下培育階段持續20分鐘。人類胚胎腎(HEK)細胞在補充有2 mM GlutaMAX (ThermoFisher Scientific,目錄號35050061)及0.1%Pluronic F-68 (ThermoFisher Scientific,目錄號35050061)之FreeStyle F17培養基(Gibco)中稀釋至1E6 個細胞/ml之細胞計數。將380 µl/孔經稀釋之細胞轉移至1 ml深孔培養盤(Hj-Bioanalytik, #750289)中。隨後,將20 µl來自圓底培養盤之DNA混合物添加至深孔培養盤中之細胞中,繼而四小時培育步驟(37℃,5% CO2,70%濕度,700轉/分鐘振盪)。在培育之後,將青黴素(最終濃度:100 U/ml)鏈黴素(最終濃度:100 µg/ml)及明膠蛋白腖N3 (OrganoTechnie,#19554,最終濃度:0.25%)添加至各孔中。隨訪5天培育期,之後將培養盤離心(5分鐘,1000×g)且移除含有表現抗體之上清液且儲存於4℃下以用於進一步測試。
抗 IL - 11 主要最佳化變異體之測試之分析設置使用以下基於ELISA之分析設置來測試親本純系之突變變異體結合至其標靶。在4℃下,將384孔培養盤塗佈隔夜,其中20 µl/孔 1 µg/ml抗小鼠IgG (Fc特異性)溶液(塗佈緩衝劑:Candor,抗小鼠IgG:Sigma #M3534)。次日,培養盤用50 µl/孔PBST洗滌三次且隨後在室溫下使用50 µl 100% smart block (Candor)阻斷一小時,繼而再次如先前所述之三個洗滌步驟。此後,添加20 µl/孔待測試突變變異體(1 µg/ml,於含10% smart block之PBST中)或親本對照TPP-18068且在室溫下培育培養盤一小時。再次洗滌培養盤三次,之後添加25 µl/孔經生物素標記之IL-11溶液(0.5 nM人類IL-11 (Invigate,例如批次號C121021-19);0.3 nM鼠類IL-11 (Invigate,例如批次號C210819-09))且在室溫下培育培養盤一小時。此後接著三個洗滌步驟,隨後添加25 µl/孔鏈黴抗生物素蛋白-辣根過氧化酶結合物(Sigma,1:1000稀釋於含10% smart block之PBST中)。使用PBST之最後三次洗滌步驟後,接著添加30 µl基質溶液(Amplex Red,Invitrogen)。在暗處在室溫下15分鐘培育步驟之後,在螢光微量培養盤讀取器(Envision)中使用535 nm之激發光及偵測590 nm之發射光來量測螢光信號。計算每一突變變異體獲得之OD值與已表現為集合庫中一部分之TPP-16478 WT抗體之OD之間的比率。高比率指示已改善與人類分別小鼠IL-11之結合性。
用於測試 IL - 2Rα 結合之分析設置採用以下基於ELISA之分析設置來測試特異性結合至IL-2Rα (Peprotech, Germany, #200-02RC)之親本純系之突變變異體。在4℃下,在384孔微量滴定盤(Maxisorb, Nunc, #460518)上,由IL-2Rα於30 µl塗佈緩衝劑(Candor, #113500)中,依每孔0.5 µg/ml塗佈隔夜。在用50 µl/孔洗滌緩衝液PBST洗滌三次之後,在室溫下用50 µl/孔SmartBlock (Candor, #113500)培育培養盤一小時。阻斷後,用洗滌緩衝液洗滌培養盤三次。添加30 µl/孔(4 µg/ml,含於PBS+0.05% Tween,10% SmartBlock)待測試抗體後,接著為室溫下之60分鐘培育期。隨後,再洗滌三次之後,每孔添加30 µl抗小鼠IgG HRP結合抗體(Sigma,A0168,1:1000稀釋於PBST中)且培育一小時。最後使用PBST之三次洗滌步驟後,接著添加30 µl基質溶液(Amplex Red,Invitrogen)。在暗處在室溫下15分鐘培育步驟之後,在螢光微量培養盤讀取器(Envision)中使用535 nm之激發光及偵測590 nm之發射光來量測螢光信號。計算針對每一突變變異體獲得之OD值與已表現為集合庫之一部分之陰性對照之同型對照抗體的OD之間的比率。小比率指示損失IL-2Ra結合性。
從第 1 親和力成熟及 IL2Ra 結合之所選拔命中物之表現及特徵分析選擇來自IL-11及IL-2Ra篩選分析之42個命中物,其藉由哺乳動物細胞之暫時性轉染表現且如實例15中所描述純化。隨後如實例16中所描述,藉由SPR測試人類IL-11及鼠類IL-11結合抗體。所量測之
K D值展示於表E13中。
表E13:42個選自第1輪親和力成熟篩選之命中物之SPR結果
抗體 | KD [M]: hIL-11 | KD [M]: mIL-11 | Mut VH | Mut VL |
TPP-18068 | 1.2E-08 | 8.6E-10 | WT | WT |
TPP-26290 | 8.6E-09 | 5.4E-10 | WT | Y33M |
TPP-26291 | 9.7E-09 | 9.4E-10 | WT | D95P |
TPP-26292 | 1.3E-08 | 4.8E-10 | WT | D95E |
TPP-26293 | 1.1E-08 | 2.6E-10 | WT | G32W |
TPP-26294 | 1.1E-08 | 8.2E-10 | WT | G32A |
TPP-26295 | 9.8E-09 | 6.5E-10 | WT | D95H |
TPP-26296 | 1.4E-08 | 7.1E-10 | WT | D95N |
TPP-26297 | 1.3E-08 | 8.9E-10 | WT | D94Q |
TPP-26298 | 1.3E-08 | 7.3E-10 | WT | T23L |
TPP-26299 | 1.1E-08 | 6.3E-10 | WT | N98Y |
TPP-26300 | 9.2E-09 | 4.5E-10 | WT | D95S |
TPP-26301 | 無結合 | 1.0E-09 | WT | G32D |
TPP-26302 | 1.3E-08 | 7.0E-10 | WT | A91S |
TPP-26303 | 1.3E-08 | 6.5E-10 | WT | S58E |
TPP-26304 | 1.2E-08 | 6.4E-10 | WT | G30W |
TPP-26306 | 1.2E-08 | 6.5E-10 | WT | D95Q |
TPP-26307 | 1.6E-08 | 1.6E-09 | WT | D95I |
TPP-26308 | 1.7E-08 | 1.3E-09 | WT | D95V |
TPP-26309 | 8.2E-09 | 8.0E-10 | WT | D95F |
TPP-26310 | 1.3E-08 | 6.6E-10 | WT | S58W |
TPP-26311 | 無結合 | 3.3E-09 | WT | V35H |
TPP-26312 | 1.0E-08 | 8.0E-10 | WT | Y33L |
TPP-26313 | 9.1E-09 | 4.6E-10 | WT | G32Y |
TPP-26314 | 8.3E-09 | 5.6E-10 | WT | D95W |
TPP-26315 | 1.4E-08 | 9.5E-10 | WT | G32H |
TPP-26316 | 8.4E-09 | 7.2E-10 | WT | D95M |
TPP-26317 | 8.1E-09 | 9.0E-10 | WT | G32E |
TPP-26318 | 1.4E-08 | 8.1E-09 | WT | D34F |
TPP-26319 | 1.2E-08 | 1.4E-09 | WT | R56K |
TPP-26320 | 1.3E-08 | 8.3E-10 | WT | N54E |
TPP-26321 | 9.3E-09 | 9.4E-10 | WT | D95L |
TPP-26323 | 1.0E-08 | 5.8E-10 | WT | D95G |
TPP-26324 | 1.3E-08 | 1.2E-09 | A61R | WT |
TPP-26325 | 6.4E-09 | 無結合 | S31W | WT |
TPP-26326 | 9.3E-09 | 1.2E-09 | S31Y | WT |
TPP-26327 | 無結合 | 1.3E-09 | S52R | WT |
TPP-26328 | 1.2E-08 | 1.3E-09 | G99T | WT |
TPP-26329 | 1.4E-08 | 9.2E-10 | Y32W | WT |
TPP-26330 | 9.5E-09 | 1.7E-09 | S31F | WT |
TPP-26331 | 1.5E-08 | 9.5E-10 | M34G | WT |
TPP-26332 | 無結合 | 1.5E-09 | G33K | WT |
TPP-26333 | 1.1E-08 | 無結合 | M34F | WT |
另外,藉由如實例17中所描述之報導基因分析測試42個命中物對人類IL-11及鼠類IL-11介導之Stat3信號傳導之抑制。如實例17中所描述計算效能(IC50 [M])及功效(%),且值展示於表E14中。
表E 14:42個選自第1輪親和力成熟篩選之命中物之RGA結果
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | 人類 IL-11 | 小鼠 IL-11 | 突變位點 | |||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | VH | VL | |
TPP-18068 | 6.7E-09 | 60.3 | 1.0E-09 | 93.1 | WT | WT |
TPP-26290 | 4.7E-09 | 75.9 | 9.7E-10 | 95.1 | WT | Y33M |
TPP-26291 | 4.1E-09 | 68.9 | 1.6E-09 | 92.1 | WT | D95P |
TPP-26292 | 5.6E-09 | 74.0 | 9.4E-10 | 94.7 | WT | D95E |
TPP-26293 | 2.8E-09 | 73.7 | 9.5E-10 | 96.9 | WT | G32W |
TPP-26294 | 9.8E-09 | 69.4 | 1.5E-09 | 97.9 | WT | G32A |
TPP-26295 | 1.3E-08 | 69.2 | 2.1E-09 | 93.9 | WT | D95H |
TPP-26296 | 2.0E-08 | 71.0 | 2.9E-09 | 93.1 | WT | D95N |
TPP-26297 | 3.7E-09 | 57.1 | 1.8E-09 | 93.5 | WT | D94Q |
TPP-26298 | 4.1E-09 | 62.9 | 1.5E-09 | 96.3 | WT | T23L |
TPP-26299 | 3.1E-09 | 70.1 | 9.4E-10 | 96.9 | WT | N98Y |
TPP-26300 | 3.3E-09 | 75.5 | 1.1E-09 | 94.9 | WT | D95S |
TPP-26301 | 2.6E-09 | 76.1 | 1.5E-09 | 91.8 | WT | G32D |
TPP-26302 | 2.2E-08 | 65.8 | 1.1E-09 | 94.3 | WT | A91S |
TPP-26303 | 2.2E-08 | 70.2 | 2.3E-09 | 95.7 | WT | S58E |
TPP-26304 | 5.9E-09 | 70.4 | 1.2E-09 | 95.2 | WT | G30W |
TPP-26306 | 2.2E-09 | 70.0 | 1.5E-09 | 96.4 | WT | D95Q |
TPP-26307 | 5.3E-09 | 52.7 | 1.9E-09 | 92.3 | WT | D95I |
TPP-26308 | 5.9E-09 | 63.6 | 1.3E-09 | 91.6 | WT | D95V |
TPP-26309 | 1.5E-09 | 63.9 | 9.4E-10 | 92.2 | WT | D95F |
TPP-26310 | 4.5E-09 | 59.5 | 1.1E-09 | 94.3 | WT | S58W |
TPP-26311 | 1.9E-09 | 38.1 | 2.2E-09 | 86.2 | WT | V35H |
TPP-26312 | 3.8E-09 | 68.6 | 1.2E-09 | 87.3 | WT | Y33L |
TPP-26313 | 1.7E-09 | 76.1 | 6.6E-10 | 96.2 | WT | G32Y |
TPP-26314 | 1.1E-09 | 69.3 | 8.0E-10 | 94.4 | WT | D95W |
TPP-26315 | 1.7E-09 | 68.3 | 1.5E-09 | 91.5 | WT | G32H |
TPP-26316 | 1.6E-09 | 69.4 | 1.0E-09 | 90.4 | WT | D95M |
TPP-26317 | 9.9E-10 | 69.9 | 1.2E-09 | 93.2 | WT | G32E |
TPP-26318 | 2.4E-09 | 45.9 | 4.7E-09 | 82.3 | WT | D34F |
TPP-26319 | 7.4E-09 | 48.6 | 1.5E-09 | 91.1 | WT | R56K |
TPP-26320 | 7.4E-09 | 70.3 | 1.5E-09 | 100.3 | WT | N54E |
TPP-26321 | 2.1E-09 | 71.3 | 1.1E-09 | 93.5 | WT | D95L |
TPP-26323 | 2.0E-09 | 57.6 | 9.2E-10 | 95.9 | WT | D95G |
TPP-26324 | 1.5E-09 | 59.0 | 1.3E-09 | 92.4 | A61R | WT |
TPP-26325 | 1.7E-09 | 81.4 | 1.3E-09 | 93.0 | S31W | WT |
TPP-26326 | 5.4E-09 | 72.0 | 2.0E-09 | 83.0 | S31Y | WT |
TPP-26327 | NM | 15.0 | 4.7E-07 | 38.0 | S52R | WT |
TPP-26328 | NM | 18.6 | 6.4E-08 | 70.8 | G99T | WT |
TPP-26329 | 2.6E-09 | 67.1 | 1.0E-09 | 95.5 | Y32W | WT |
TPP-26330 | 3.4E-09 | 64.8 | 1.3E-09 | 88.2 | S31F | WT |
TPP-26331 | 5.4E-09 | 54.9 | 1.5E-09 | 90.9 | M34G | WT |
TPP-26332 | NM | 0.8 | NM | 0.9 | G33K | WT |
TPP-26333 | 1.3E-08 | 64.7 | 1.2E-09 | 94.1 | M34F | WT |
42 個選自 第 1 親和力成熟之抗體之 IL - 2Ra 結合隨後,使42種抗體經受IL2Ra結合ELISA,如實例20中所描述。計算IL-2Ra結合相對於同型對照之比率且展示於表E15中。
表E15:選自第1輪親和力成熟篩選之42個所選命中物之IL2Ra結合結果
抗體 | hIL2RA ELISA 結合:與同型之比率 |
TPP-18068 | 398 |
TPP-26290 | 52 |
TPP-26291 | 334 |
TPP-26292 | 557 |
TPP-26293 | 384 |
TPP-26294 | 275 |
TPP-26295 | 385 |
TPP-26296 | 379 |
TPP-26297 | 183 |
TPP-26298 | 474 |
TPP-26299 | 96 |
TPP-26300 | 447 |
TPP-26301 | 15 |
TPP-26302 | 522 |
TPP-26303 | 481 |
TPP-26304 | 436 |
TPP-26306 | 232 |
TPP-26307 | 176 |
TPP-26308 | 188 |
TPP-26309 | 234 |
TPP-26310 | 231 |
TPP-26311 | 292 |
TPP-26312 | 62 |
TPP-26313 | 195 |
TPP-26314 | 455 |
TPP-26315 | 205 |
TPP-26316 | 221 |
TPP-26317 | 31 |
TPP-26318 | 267 |
TPP-26319 | 235 |
TPP-26320 | 260 |
TPP-26321 | 182 |
TPP-26323 | 256 |
TPP-26324 | 247 |
TPP-26325 | 542 |
TPP-26326 | 516 |
TPP-26327 | 11 |
TPP-26328 | 27 |
TPP-26329 | 247 |
TPP-26330 | 264 |
TPP-26331 | 107 |
TPP-26332 | 19 |
TPP-26333 | 436 |
相較於野生型抗體TPP-18068,若干突變體,例如TPP-26301、TPP-26317、TPP-26327、TPP-26328及TPP-26332展現很大程度上減少之IL2RA結合。
實例 27 : 第 2 輪親和力成熟 ( 組合突變 )對於TPP-18068之最終再組合集合庫,選擇NNK集合庫篩選步驟中所示的展現改良之親和力、功能效率或減少之IL-2Ra結合的十二個單取代變異體。VL突變G30W、G32Y、G32D、Y33L、N54E、A91S、D95F、D95P、D95S及S98Y及VH區中之突變M34G、V50L在最終生殖系TPP-27159 (連續胺基酸命名法,參考如由SEQ ID NO: XX-VH及XX-VL所定義之TPP-27159)中組合在一個再組合集合庫中。
對於TPP-27159,產生寡核苷酸以在各所選位置引入所選突變或對應野生型胺基酸。使用連續輪標準重疊延伸PCR進行集合庫構築(Sambrook J, Russell DW (2001) Molecular cloning: a laboratory manual,第3版.Sambrook)。
以彼方式產生TPP-27159之超過800種獨特組合胺基酸交換變異體,如實例26中所描述藉由短暫轉染哺乳動物細胞表現,且如實例26中所描述針對鼠類及人類IL-11結合及IL-2Ra結合篩選所得表現上清液。
選擇18個具有最高人類及小鼠IL-11結合但具有最低IL-2Ra結合之命中物用於進行如實例15中所描述之小規模表現及純化。隨後如實例16中所描述,藉由SPR測試人類IL-11及鼠類IL-11結合抗體。所量測之
K D值展示於表E16中。
表E16:在第2輪親和力成熟之後18個人類IgG1命中物的SPR結果
TPP-ID | K D [M]: hIL-11 | K D [M]: mIL-11 | K D [M]: ratIL-11 | K D [M]: cynoL-11 | Mut VH | Mut VL |
TPP-16478 | 2.2E-09 | 6.2E-10 | 3.3E-10 | 1.8E-09 | WT | WT |
TPP-29381 | 6.2E-10 | 5.7E-10 | 3.0E-10 | 4.3E-10 | WT | G32D, A91S, D95S |
TPP-29382 | 4.4E-10 | 5.6E-10 | 2.0E-10 | 4.6E-10 | WT | G32D, Y33L, D95F, S98Y |
TPP-29383 | 1.1E-09 | 6.2E-10 | 3.1E-10 | 1.3E-09 | WT | G32D, Y33L, N54E, D95P, S98Y |
TPP-29384 | 9.8E-10 | 3.0E-10 | 1.8E-10 | 8.6E-10 | WT | N54E, D95P |
TPP-29386 | 2.7E-10 | 3.0E-10 | 1.5E-10 | 3.1E-10 | WT | G32D, N54E, A91S, D95S |
TPP-29389 | 2.3E-10 | 1.2E-10 | 8.3E-11 | 9.1E-10 | WT | G32Y, N54E, D95P, S98Y |
TPP-29391 | 3.6E-10 | 1.7E-10 | 7.1E-11 | 6.9E-10 | WT | G32D, D95S, S98Y |
TPP-29392 | 9.2E-10 | 1.1E-09 | 9.5E-10 | 8.5E-10 | WT | G30W, G32D, N54E, D95S |
TPP-29393 | 6.6E-10 | 3.9E-10 | 1.8E-10 | 7.2E-10 | WT | G32D, Y33L, N54E, S98Y |
TPP-29394 | 1.2E-09 | 6.5E-10 | 3.7E-10 | 6.7E-10 | WT | G32D, D95F, S98Y |
TPP-29396 | 7.8E-10 | 7.0E-10 | 4.4E-10 | 9.2E-10 | WT | G30W, G32D, N54E, D95F, S98Y |
TPP-29397 | 3.5E-10 | 1.1E-10 | 5.7E-11 | 8.0E-10 | WT | G30W, N54E, D95S, S98Y |
TPP-29399 | 5.6E-10 | 9.3E-10 | 5.3E-10 | 5.7E-10 | WT | G32D, D95S |
TPP-29400 | 5.0E-10 | 9.6E-10 | 7.5E-10 | 3.5E-10 | M34G, V50L | G32D, D95F |
TPP-29401 | 6.9E-10 | 1.1E-10 | 5.8E-11 | 2.3E-10 | M34G | G32Y, N54E |
TPP-29402 | 1.9E-10 | 4.5E-11 | 1.8E-11 | 3.2E-10 | M34G, V50L | Y33L, N54E, D95S, S98Y |
TPP-29403 | 7.7E-10 | 1.8E-10 | 1.1E-10 | 2.6E-10 | M34G, V50L | G32Y |
TPP-29404 | 2.0E-10 | 9.1E-11 | 6.7E-11 | 1.4E-10 | M34G, V50L | G32Y, D95S |
另外,藉由如實例17中所描述之報導基因分析測試18個命中物之人類IL-11及鼠類IL-11結合。如實例17中所描述計算效能(IC50[M])及功效(%)。結果展示於表E17中。
表E17:在第2輪親和力成熟之後18個人類IgG1命中物的RGA結果
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | 人類 IL-11 | 小鼠 IL-11 | 突變位點 | |||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | VH | VL | |
TPP-16478 | 1.6E-08 | 50.9 | 2.4E-10 | 89.0 | WT | WT |
TPP-29381 | 4.8E-10 | 75.3 | 4.5E-10 | 94.8 | WT | G32D, A91S, D95S |
TPP-29382 | 6.4E-10 | 81.4 | 2.6E-10 | 87.5 | WT | G32D, Y33L, D95F, S98Y |
TPP-29383 | 1.6E-09 | 86.0 | 5.7E-10 | 94.2 | WT | G32D, Y33L, N54E, D95P, S98Y |
TPP-29384 | 2.8E-09 | 81.9 | 3.3E-10 | 97.2 | WT | N54E, D95P |
TPP-29386 | 6.4E-10 | 88.9 | 1.2E-10 | 97.9 | WT | G32D, N54E, A91S, D95S |
TPP-29389 | 8.4E-10 | 87.3 | 2.9E-10 | 97.4 | WT | G32Y, N54E, D95P, S98Y |
TPP-29391 | 5.4E-10 | 84.0 | NM | 96.9 | WT | G32D, D95S, S98Y |
TPP-29392 | 1.2E-09 | 80.2 | NM | 89.3 | WT | G30W, G32D, N54E, D95S |
TPP-29393 | 6.1E-10 | 87.3 | 2.4E-10 | 96.2 | WT | G32D, Y33L, N54E, S98Y |
TPP-29394 | 1.7E-09 | 89.8 | 4.8E-10 | 93.9 | WT | G32D, D95F, S98Y |
TPP-29396 | 6.5E-10 | 78.9 | 3.9E-10 | 96.1 | WT | G30W, G32D, N54E, D95F, S98Y |
TPP-29397 | 5.3E-10 | 71.0 | 3.1E-10 | 93.8 | WT | G30W, N54E, D95S, S98Y |
TPP-29399 | 7.3E-10 | 70.2 | NM | 90.0 | WT | G32D, D95S |
TPP-29400 | 4.6E-10 | 59.6 | NM | 87.3 | M34G, V50L | G32D, D95F |
TPP-29401 | 1.3E-09 | 83.3 | 1.5E-10 | 96.9 | M34G | G32Y, N54E |
TPP-29402 | 5.3E-10 | 80.7 | 1.9E-10 | 95.5 | M34G, V50L | Y33L, N54E, D95S, S98Y |
TPP-29403 | 1.7E-09 | 82.4 | 2.7E-10 | 94.3 | M34G, V50L | G32Y |
TPP-29404 | 7.2E-10 | 71.8 | 1.9E-10 | 91.8 | M34G, V50L | G32Y, D95S |
基於此等分析中之結果,針對野生型抗體TPP-16478比較突變體且歸類為『改良』或『未改良』,且選擇最終候選物TPP-29386 (hIgG1) SEQ ID NO:92、重鏈及SEQ ID NO:93、輕鏈。
IgG 轉化將來自第2輪親和力成熟之編碼TPP-29386可變區之基因選殖至鼠類IgG1表現載體pTT5 (VH域與鼠類IgG1變異體融合,且VL域與鼠類Ig λ CL域融合)以產生TPP-29528之鼠類IgG1表現載體。另外,將編碼TPP-29386可變區之基因選殖至人類表現載體pTT5中以產生TPP-29536之所需同型之人類IgG構築體(VH域與引入FcR沉默突變之人類IgG1 HS變異體融合(E233P/L234V/L235A/DG236/D265G/A327Q/A330),且VL域與人類Ig λ CL域融合)。
實例
28
-
31
描述由最佳化
TPP
-
18068
及
TPP
-
18087
產生之經
IgG
轉化之抗體的活體外特徵化
實例
28
:抗體產生
對於TPP-29519、TPP-29520、TPP-29521、TPP-29522、TPP-29523、TPP-29528、TPP-29680、TPP-30000、TPP-30001、TPP-30002、TPP-30003及TPP-29536,含有各別VH及VL基因之質體共轉染至Expi293F細胞中。培養細胞5天且收集上清液以用於使用蛋白A管柱(GE Healthcare,目錄175438)之蛋白質純化。藉由A280/消光係數使用Nanodrop 2000測定來自溶離之蛋白質濃度。藉由SDS-PAGE及HPLC-SEC分析純化抗體,且隨後儲存於-80℃下。
實例 29 : SPR 對人類 / 小鼠 / 獼猴及大鼠 IL - 11 之親和力為評定抗IL-11抗體之結合動力學及親和力以及其物種交叉反應性概況,使用表面電漿子共振(SPR)進行結合分析。在Biacore T200儀器上或在Biacore 8K儀器(Cytiva)上在37℃下使用分析緩衝液HBS EP+、300 mM NaCl、1 mg/ml BSA、0.05% NaN3進行結合分析。經由共價胺偶合至S系列CM5感測器晶片(Cytiva)之抗人類Fc IgG (「人類抗體捕捉套組」,訂單號BR100839,Cytiva)或經由抗小鼠Fc IgG (「小鼠抗體捕捉套組」,訂單號BR100383,Cytiva)捕捉抗體,視同型而定。根據製造商說明書,使用1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(EDC)、N-羥基丁二醯亞胺(NHS)及乙醇胺HCl (pH 8.5) (「胺偶合套組」 BR-1000-50, Cytiva.)進行胺偶合。人類、小鼠、食蟹獼猴或大鼠IL-11在0.05至200 nM濃度範圍內之若干稀釋度下用作分析物。關於結合分析,使用僅一個濃度200 nM IL-11。在每次抗原注射之後用甘胺酸(pH 1.7)使感測器表面再生。雙參考所得感測器圖譜(減去參考流動池信號及緩衝液注射)且擬合至1:1朗繆爾結合模型以使用Biacore T200評估軟體或Biacore洞察軟體導出動力學資料。結果展示於表E18中。若未報導值,則不存在結合或存在極低結合及多相結合行為。低於1E-12的值視為低於儀器之動態範圍且設定為<1E-12。
表E18:由TPP-18068及TPP-18087與親本(TPP-18068及TPP-18087)及競爭者(TPP-23552及TPP-23580)抗體相比最佳化產生之IgG轉化抗體之SPR結果
抗體 | SPR: K D[M] hIL11 | SPR: K D[M] mIL11 | SPR: K D[M] cIL11 | SPR: K D[M] rIL11 |
TPP-18068 | 無結合 | 4.1E-10 | 5.0E-09 | 5.8E-10 |
TPP-18087 | 無結合 | 4.1E-08 | 無結合 | |
TPP-29536 | 1.8E-10 | 1.3E-10 | 2.4E-10 | 2.5E-10 |
TPP-29680 | 1.6E-12 | < 1E-12 | 3.5E-10 | 9.0E-12 |
TPP-30000 | 1.8E-11 | 3.9E-11 | 3.2E-08 | 2.1E-10 |
TPP-30001 | 6.4E-11 | 5.5E-11 | 無結合 | 1.1E-09 |
TPP-30002 | 7.4E-12 | 1.3E-11 | 1.0E-08 | 1.8E-10 |
TPP-30003 | < 1E-12 | < 1E-12 | 4.9E-10 | 6.7E-12 |
TPP-23552 | 1.4E-09 | 1.8E-09 | 無結合 | 3.2E-09 |
TPP-29528 | 3.4E-10 | 2.3E-10 | 2.0E-10 | 3.3E-10 |
TPP-29519 | 1.0E-11 | 3.5E-12 | 6.1E-10 | 2.3E-11 |
TPP-29520 | 9.0E-11 | 1.1E-10 | 無結合 | 2.9E-10 |
TPP-29521 | 1.8E-10 | 9.8E-11 | 無結合 | 2.1E-09 |
TPP-29522 | 3.4E-11 | 2.9E-11 | 2.4E-08 | 3.4E-10 |
TPP-29523 | 2.6E-12 | 4.0E-12 | 1.1E-09 | 2.0E-11 |
TPP-23580 | 2.1E-09 | 2.4E-09 | 無結合 | 4.1E-09 |
實例 30 : 人類、小鼠、食蟹獼猴及大鼠 IL - 11 報導基因分析在生長培養基1N (BPS Biosciences, #79801)中使Stat3報導子HEK293細胞(BPS Biosciences, #79800-P)生長。在第1天,以每孔含有40.000個細胞之50 µl體積在白色384er細胞培養盤(BD BioCoat™聚D-離胺酸384孔,#354660)中在生長培養基1 N中接種細胞。
在同一天,視待測試之IL-11物種而定,藉由在Optimem (Invitrogen, #11058-02)中將人類受體質體(PJF-2813;TPP-14223;SEQ ID:no)或小鼠受體質體(PJF-2809-1;TPP-14189;SEQ ID:no)或大鼠受體質體(PJF2811;TPP-14222;SEQ ID:no)稀釋至0.2 µg/ml進行脂質體轉染。隨後,在Optimem中將LF2000 (Invitrogen, 11668-027)1:50稀釋。以1:1比率混合各別經稀釋之質體及經稀釋之LF2000。在室溫下培育20分鐘之後,將每孔25 µl複合物混合物添加至細胞中,且在37℃、5% CO
2下培育培養盤隔夜。
次日,在生長培養基1 N中將人類IL-11 (Invigate,例如批次號C121021-19)、小鼠IL-11 (Invigate,例如批次號C210819-09)、食蟹獼猴IL-11 (Invigate,批次號C290621-19)或大鼠IL-11 (Invigate,例如批次號C301019-19)稀釋至6 nM之恆定最終濃度。另外,在生長培養基1 N中,自100[nM]開始3倍降至0.137[nM]製備待測試之抗IL11抗體之最終分析連續稀釋液,包括不具有任何抗體之陰性對照。將IL11及抗體連續稀釋液以1: 1比率混合且在室溫下在微量滴定盤中培育30分鐘。隨後,丟棄細胞上方之細胞培養基且將25 µl/孔混合物添加至細胞中。其後,培養盤在5% CO
2下在37℃下培育五小時。最終,將25 µL/孔螢光素酶基質Bright Glo (Promega;#E2620)添加至細胞中,且在室溫下在暗處培育培養盤3分鐘,之後在培養盤讀取器上量測發光。使用來自劑量反應之信號計算功效及IC50值,如實例17中所描述。結果展示於表E19中。
表E19:由TPP-18068及TPP-18087與親本(TPP-18068及TPP-18087)及競爭者(TPP-23552及TPP-23580)抗體相比最佳化產生之IgG轉化抗體之RGA結果
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | hIL11 | mIL11 | cIL11 | rIL11 | ||||
IC50 | 功效 (%) | IC50 | 功效 (%) | IC50 | 功效 (%) | IC50 | 功效 (%) | |
TPP-18068 | 6.5E-09 | 46.1 | 1.2E-09 | 93.6 | 4.1E-09 | 70.0 | 1.8E-09 | 94.0 |
TPP-18087 | NM | 47.8 | 1.6E-08 | 59.4 | NM | 47.7 | NM | 31.8 |
TPP-29536 | 1.2E-09 | 85.1 | 1.4E-09 | 97.2 | 1.0E-09 | 89.7 | 1.3E-09 | 90.9 |
TPP-29680 | 1.5E-09 | 98.4 | 6.6E-10 | 96.2 | 2.9E-10 | 97.5 | 1.1E-09 | 98.5 |
TPP-30000 | 1.8E-09 | 97.8 | 6.6E-10 | 97.9 | NM | 64.6 | 1.4E-09 | 100.1 |
TPP-30001 | 1.3E-09 | 96.5 | 9.3E-10 | 101.0 | 5.6E-09 | 56.6 | 2.1E-09 | 98.9 |
TPP-30002 | 1.2E-09 | 96.5 | NM | 97.2 | NM | 72.8 | 1.1E-09 | 99.1 |
TPP-30003 | 1.8E-09 | 100.4 | 7.5E-10 | 97.1 | NM | 97.1 | 7.2E-10 | 99.5 |
TPP-23552 | 3.7E-09 | 76.7 | 8.1E-09 | 90.9 | NM | 52.4 | 8.8E-09 | 81.3 |
TPP-29528 | NM | 81.2 | 8.9E-10 | 96.9 | 4.4E-10 | 87.8 | 1.8E-09 | 89.9 |
TPP-29519 | 1.8E-09 | 100.1 | 1.2E-09 | 101.2 | 8.9E-10 | 99.2 | 1.0E-09 | 99.7 |
TPP-29520 | 1.7E-09 | 99.7 | 9.1E-10 | 100.2 | NM | 58.6 | 1.3E-09 | 101.2 |
TPP-29521 | 1.9E-09 | 99.2 | 7.6E-10 | 103.0 | NM | 60.0 | 1.8E-09 | 98.9 |
TPP-29522 | 1.6E-09 | 98.6 | 7.8E-10 | 100.8 | NM | 52.0 | 1.6E-09 | 100.7 |
TPP-29523 | 1.6E-09 | 100.3 | 1.4E-09 | 100.7 | 6.8E-10 | 97.2 | 1.4E-09 | 100.7 |
TPP-23580 | NM | 64.0 | 7.9E-09 | 88.9 | NM | 21.9 | 1.4E-08 | 62.2 |
實例 31 : 在雙複合物 ELISA 中分析之 IgG 轉化抗體對 IL - 11 與 IL - 11Ra 之相互作用的抑制使IgG轉化抗體經受實例18中所描述之實驗分析程序。因此計算IC50[M]、分別功效(%)且結果展示於表E20中。
表E20:在雙複合物ELISA中分析之IgG轉化抗體對人類IL-11與人類IL-11Ra之相互作用的抑制
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | |
TPP-18068 | 1.2E-08 | 17.4 | 2.9E-09 | 64.2 |
TPP-18087 | NM | 0.0 | NM | 2.4 |
TPP-29536 | 8.8E-10 | 37.6 | 5.5E-10 | 42.2 |
TPP-29680 | NM | 12.2 | NM | 8.6 |
TPP-30000 | NM | 0.0 | NM | 3.5 |
TPP-30001 | NM | 5.2 | NM | 10.1 |
TPP-30002 | NM | 3.5 | NM | -3.3 |
TPP-30003 | NM | 8.4 | NM | 4.1 |
TPP-23552 | 2.9E-09 | 97.2 | 3.3E-09 | 98.4 |
TPP-29528 | NM | 36.3 | 2.6E-09 | 43.4 |
TPP-29519 | NM | 6.8 | NM | 12.8 |
TPP-29520 | NM | 0.3 | NM | 1.1 |
TPP-29521 | NM | 1.7 | NM | 12.1 |
TPP-29522 | NM | 0.0 | NM | 3.6 |
TPP-29523 | NM | 2.0 | NM | 4.8 |
TPP-23580 | 1.0E-08 | 93.3 | 6.8E-09 | 93.0 |
TPP-14250 | 6.8E-09 | 75.7 | 3.3E-09 | 91.6 |
TPP-18068、TPP-29536、TPP-23552、TPP-29528、TPP-23580及TPP-14250在雙複合物ELISA中展示活性,而TPP-18087、TPP-29680、TPP-30000、TPP-30001、TPP-30002、TPP-30003、TPP-29519、TPP-29520、TPP-29521、TPP-29522及TPP-29523未展示活性。
實例 32 : 在三複合物 ELISA 中分析之 IgG 轉化抗體對 IL - 11 / IL - 11Ra / gp130 複合物 之形成的抑制使IgG轉化抗體經受實例19中所描述之實驗分析程序,且因此計算IC50[M]、分別功效(%)。結果展示於表E21中。
表E21:在三複合物中分析之IgG轉化抗體對人類IL-11/IL-11Ra/gp130複合物之形成的抑制
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | |
TPP-18068 | 1.7E-06 | 84.9 | 3.9E-09 | 84.9 |
TPP-18087 | 1.5E-09 | 25.0 | 3.3E-08 | 25.0 |
TPP-29536 | 1.0E-09 | 98.7 | 6.4E-10 | 102.8 |
TPP-29680 | 7.0E-09 | 78.8 | 1.1E-10 | 100.7 |
TPP-30000 | 5.7E-09 | 86.0 | 1.2E-10 | 98.8 |
TPP-30001 | 1.1E-08 | 81.0 | 1.1E-10 | 99.7 |
TPP-30002 | 4.9E-09 | 86.2 | 7.3E-11 | 102.4 |
TPP-30003 | 7.4E-09 | 85.4 | 1.0E-10 | 101.7 |
TPP-23552 | 6.8E-09 | 90.6 | 2.3E-08 | 90.7 |
TPP-29528 | 1.0E-09 | 94.7 | 6.0E-10 | 94.7 |
TPP-29519 | 2.4E-09 | 81.3 | 1.4E-10 | 81.3 |
TPP-29520 | 1.3E-09 | 81.8 | 1.3E-10 | 81.8 |
TPP-29521 | 1.8E-09 | 85.7 | 9.2E-11 | 85.7 |
TPP-29522 | 2.0E-09 | 85.4 | 1.1E-10 | 85.4 |
TPP-29523 | 2.1E-09 | 84.3 | 1.2E-10 | 84.3 |
TPP-23580 | 3.4E-09 | 45.8 | 3.1E-08 | 45.8 |
TPP-14250 | 1.5E-08 | 81.1 | 8.0E-09 | 81.1 |
所有測試抗體在三複合物ELISA中為活性的。
實例 33 : 最佳化及 IgG 轉化抗體與 IL2Ra 之結合測試IgG轉化抗體TPP結合至IL2Ra,如實例20中所描述。計算針對IgG轉化抗體與同型對照TPP-10159在3.3 E-7[M]之抗體濃度下獲得之信號的比率且展示於表E22中。
表E22:IgG轉化抗體對比同型對照抗體結合之IL-2R結合比率
抗體 | IL -2Ra 結合信號之抗體 / 同型對照比率 |
TPP-18068 | 377.3 |
TPP-18087 | 0.6 |
TPP-29536 | 1.1 |
TPP-29528 | 24.2 |
TPP-29519 | 0.7 |
TPP-29520 | 0.6 |
TPP-29521 | 0.7 |
TPP-29522 | 0.7 |
TPP-29523 | 1.2 |
TPP-23580 | 2.2 |
除了TPP-18068以外,所有測試抗體不結合至IL2RA。
實例 34 : 雙特異性 IL - 11 抗體之產生雙及三複合物ELISA資料指示,TPP-18068及TPP-18087結合至IL-11上兩個不同抗原決定基。為了產生能夠結合至兩種抗原決定基之抗體,產生由各自一組TPP-18068及TPP-18087組成之雙特異性scFv-kih構築體。因此,藉由使用標準重組DNA技術(Sambrook, J.等人編, MOLECULAR CLONING: A LABORATORY MANUAL (第2版1989) Cold Spring Harbor Laboratory Press, NY.第1卷-第3卷)將TPP-18068及TPP-18087之可變區轉換成scFv型式。VH序列藉由15個胺基酸GGGGS GGGGSGGGGS (例如SEQ ID NO: 74,aa 114-129)連接子連接至各別VL序列。經由序列GG GGSGGGGSGG GGSG (例如SEQ ID NO: 74,aa 240 - 256),由TPP-18068產生之scFv融合至含有杵突變之人類IgG Fc域且由TPP-18087產生之scFv融合至含有臼突變之人類IgG Fc域,(圖20)。使用標準短暫轉染程序將所得構築體選殖至載體pTT5中以在HEK293-6E細胞中表現,且如實例15中所描述經由蛋白A及尺寸排阻層析法自細胞培養物上清液純化所得人類IgG抗體TPP-20489。對於各別鼠類變異體TPP-26195,使用具有杵及臼突變之鼠類IgG Fc域。
以類似方式,TPP-29603及TPP-29697藉由組合衍生自TPP-29528之抗IL11 scFv (基於TPP-18086之最佳化抗體)及TPP-29519 (基於TPP-18087之最佳化抗體)而產生。TPP-29603具有含杵臼突變之鼠類IgG1型式,而TPP-29697具有人類IgG1型式,其中Fc含有緊鄰杵臼突變之沉默突變(E233P/L234V/L235A/DG236/D265G/A327Q/A330S突變)。
實例 33 : 藉由 SPR 之 雙特異性抗體之親和力為評定抗IL-11雙特異性抗體之結合動力學及親和力以及其物種交叉反應性概況,使用表面電漿子共振(SPR)進行結合分析。使用分析緩衝液HBS EP+、300 mM NaCl、1 mg/ml BSA、0.05% NaN3,在Biacore T200儀器上或在Biacore 8K+儀器(Cytiva)上在25℃下(對於TPP-26195及TPP-20489)及在37℃下(對於TPP-29603及TPP-29697)進行結合分析。經由共價胺偶合至S系列CM5感測器晶片(Cytiva)之抗人類Fc IgG (「人類抗體捕捉套組」,訂單號BR100839,Cytiva)或經由抗小鼠Fc IgG (「小鼠抗體捕捉套組」,訂單號BR100383,Cytiva)捕捉抗體,視同型而定。根據製造商說明書,使用1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(EDC)、N-羥基丁二醯亞胺(NHS)及乙醇胺HCl (pH 8.5) (「胺偶合套組」 BR-1000-50, Cytiva.)進行胺偶合。人類、小鼠、食蟹獼猴或大鼠IL-11在0.05至200 nM濃度範圍內之若干稀釋度下用作分析物。關於結合分析,使用僅一個濃度200 nM IL-11。在每次抗原注射之後用甘胺酸(pH 1.7)使感測器表面再生。雙參考所得感測器圖譜(減去參考流動池信號及緩衝液注射)且擬合至1:1朗繆爾結合模型以使用Biacore T200評估軟體或Biacore洞察軟體導出動力學資料。
TPP-26195及TPP-20489之結果展示於表E23中,且TPP-29603及TPP-29697之結果展示於表E24中。若未報導值,則不存在結合或存在極低結合及多相結合行為。
表E23:自非最佳化親本抗體TPP-18068及TPP-18087產生之雙特異性抗體之SPR結果。在25℃下進行SPR實驗
*在穩定狀態下測定
表E24:自最佳化抗體TPP-29528及TPP-29519產生之雙特異性抗體之SPR結果。在37℃下進行SPR實驗
抗體 | SPR: K D[M] hIL11 | SPR: K D[M] mIL11 | SPR: K D[M] cIL11 | SPR: K D[M] rIL11 |
TPP-18068 | 2.50E-08 | 3.50E-10 | 3.80E-09 | 2.90E-10 |
TPP-18087* | 1.30E-08 | 3.30E-08 | 5.60E-08 | 3.40E-08 |
TPP-26195 | 8.30E-11 | 4.60E-11 | 7.40E-11 | 4.50E-11 |
TPP-20489 | 1.10E-11 | 5.00E-12 | 2.50E-11 | 2.60E-12 |
抗體 | SPR: K D[M] hIL11 | SPR: K D[M] mIL11 | SPR: K D[M] cIL11 | SPR: K D[M] rIL11 |
TPP-18068 | 無結合 | 4.1E-10 | 5.0E-09 | 5.8E-10 |
TPP-18087 | 無結合 | 4.1E-08 | 無結合 | 無結合 |
TPP-29536 | 1.8E-10 | 1.3E-10 | 2.4E-10 | 2.5E-10 |
TPP-29680 | 1.6E-12 | < 1E-12 | 3.5E-10 | 9.0E-12 |
TPP-29697 | < 1E-12 | < 1E-12 | < 1E-12 | < 1E-12 |
TPP-29528 | 3.4E-10 | 2.3E-10 | 2.0E-10 | 3.3E-10 |
TPP-29519 | 1.0E-11 | 3.5E-12 | 6.1E-10 | 2.3E-11 |
TPP-29603 | 1.9E-12 | 1.7E-12 | 2.2E-12 | 3.4E-12 |
實例 35 : 藉由雙特異性 IL - 11 抗體之人類 / 小鼠 IL - 11 阻斷之報導基因分析相比於先前技術抗體TPP-14250、TPP23580及TPP-23552,在實例17中所描述之Stat3報導基因分析中測試非最佳化雙特異性抗體TPP-20489及TPP-26195對IL-11介導之信號傳導之抑制。使用GraphPad Prism計算效能值(IC50[M])。如實例17中所描述計算功效。結果展示於表E25中。
表E25:自非最佳化親本抗體TPP-18068及TPP-18087產生之雙特異性抗體TPP-20489及TPP-26195之RGA結果
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | |
TPP-18068 | 4.8E-09 | 20.7 | 2.7E-09 | 84.1 |
TPP-18087 | 1.1E-07 | 51.5 | 3.3E-07 | 49 |
TPP-20489 | 3.1E-10 | 102 | 1.0E-09 | 93.9 |
TPP-26195 | 6.5E-10 | 88.5 | 1.8E-09 | 96.9 |
TPP-14250 | 2.4E-10 | 27.1 | 1.4E-07 | 69.1 |
TPP-23580 | 8.7E-09 | 68.6 | 2.8E-08 | 46.7 |
TPP-23552 | 1.8E-08 | 87.9 | 2.2E-08 | 76 |
最終,除了同樣測試食蟹獼猴IL-11 (Invigate,例如批次號C290621-19)及大鼠IL-11 (Invigate,例如批次號C301019-19)且在分析中在6[nM]下使用所有抗原以外,在實例17中所描述之Stat3報導基因分析中測試最佳化雙特異性抗體TPP-29603及TPP-29697對IL-11介導之信號傳導之抑制。為了比較,先前技術抗體TPP23580及TPP-23552包括於分析中。結果展示於表E26中。 表E26:自最佳化親本抗體TPP-29528及TPP-29519產生之雙特異性抗體TPP-29603及TPP-29697的RGA結果。
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | hIL11 | mIL11 | cIL11 | rIL11 | ||||
IC50 | 功效 (%) | IC50 | 功效 (%) | IC50 | 功效 (%) | IC50 | 功效 (%) | |
TPP-18068 | 6.5E-09 | 46.1 | 1.2E-09 | 93.6 | 4.1E-09 | 70.0 | 1.8E-09 | 94.0 |
TPP-18087 | NM | 47.8 | 1.6E-08 | 59.4 | NM | 47.7 | NM | 31.8 |
TPP-29528 | NM | 81.2 | 8.9E-10 | 96.9 | 4.4E-10 | 87.8 | 1.8E-09 | 89.9 |
TPP-29519 | 1.8E-09 | 100.1 | 1.2E-09 | 101.2 | 8.9E-10 | 99.2 | 1.0E-09 | 99.7 |
TPP-29603 | 4.1E-09 | 101.0 | 2.0E-09 | 101.7 | 1.7E-09 | 101.3 | 2.0E-09 | 99.9 |
TPP-29536 | 1.2E-09 | 85.1 | 1.4E-09 | 97.2 | 1.0E-09 | 89.7 | 1.3E-09 | 90.9 |
TPP-29680 | 1.5E-09 | 98.4 | 6.6E-10 | 96.2 | 2.9E-10 | 97.5 | 1.1E-09 | 98.5 |
TPP-29697 | 2.0E-09 | 99.1 | 1.4E-09 | 99.6 | 7.5E-10 | 100.5 | ~ 1.2e-09 | 97.6 |
TPP-23552 | 3.7E-09 | 76.7 | 8.1E-09 | 90.9 | NM | 52.4 | 8.8E-09 | 81.3 |
TPP-23580 | NM | 64.0 | 7.9E-09 | 88.9 | NM | 21.9 | 1.4E-08 | 62.2 |
實例 35 : 在雙複合物 ELISA 中分析之雙特異性 IL - 11 抗體對 IL - 11 與 IL - 11Ra 之相互作用的抑制使雙特異性抗體經受實例18中所描述之實驗分析程序,且因此計算IC50[M]、分別功效(%)。結果展示於表E27中。
表E27:在雙複合物ELISA中分析之雙特異性抗體對人類IL-11與人類IL-11Ra之相互作用的抑制
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | |
TPP-20489 | NM | 13.3 | 3.5E-08 | 45.6 |
TPP-26195 | 6.3E-09 | 28.6 | 4.1E-09 | 59.7 |
TPP-29697 | 1.6E-09 | 46.7 | 1.4E-09 | 52.3 |
TPP-29603 | 1.7E-09 | 35.6 | 3.9E-09 | 53.3 |
實例 36 : 在三複合物 ELISA 中分析之雙特異性抗體對 IL - 11 / IL - 11Ra / gp130 複合物 之形成的抑制使雙特異性抗體經受實例19中所描述之實驗分析程序,且因此計算IC50[M]、分別功效(%)。結果展示於表E28中
表E 28:在三複合物ELISA中分析之雙特異性抗體對人類IL-11/IL-11Ra/gp130複合物之形成的抑制
抗體 | hIL11 | mIL11 | ||
IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) | |
TPP-20489 | 6.28E-09 | 104.7 | 1.81E-09 | 94.0 |
TPP-26195 | 1.28E-09 | 98.0 | 2.58E-10 | 98.0 |
TPP-29697 | 1.60E-09 | 104.1 | 6.22E-11 | 104.5 |
TPP-29603 | 6.96E-10 | 98.5 | 1.70E-10 | 98.5 |
實例 37 : 雙特異性 IL - 11 抗體與 IL2Ra 之結合使雙特異性抗體經受實例20中所描述之實驗分析程序。計算藉由對應雙特異性抗體在1E-07[M]之抗體濃度下產生之信號與同型對照抗體之信號的比率且展示於表E29中。雙特異性抗體未展示結合至IL-2 Ra。
表E29:雙特異性抗體結合IL-2R對比同型對照抗體結合之比率
抗體 | IL -2Ra 結合信號抗體 / 同型對照之比率 |
TPP-26195 | 146.4 |
TPP-20489 | 851.9 |
TPP-29603 | 1.9 |
TPP-29697 | 0.8 |
TPP-29603及TPP-29697不結合至IL2Ra。
實例 38 : 藉由 SPR 、 RGA 、雙複合物及三複合物 ELISA 表徵額外市售抗體在SPR、RGA及ELISA分析中根據實例16、17及18中所描述之實驗程序分析對識別人類IL-11所描述之市售抗體(參見表E30)。
表E30:SPR、RGA、雙複合物及三複合物ELISA中測試之額外市售抗IL-11抗體之清單
目錄號 | 公司 | 應用 | 反應性 | 抗原 | 同型 | 純系 |
GTX34009 | Genetex | WB | 人類 | IL11 | IgG1 | 6D9A1 |
GTX52814 | Genetex | WB,中和/抑制 | 人類 | IL11 | IgG2 | 9T27 |
LS-C104441 | LS-bio | WB,ELISA | 人類 | IL11 | IgG1 | |
MA5-30696 | Thermo Fisher Scientific | ELISA | 人類 | IL11 | IgG1 | 12 |
MA5-30695 | Thermo Fisher Scientific | ELISA | 人類 | IL11 | IgG1 | 9 |
MA5-23711 | Thermo Fisher Scientific | WB,ELISA | 人類 | IL11 | IgG2b | 22616 |
LS-C193526 | LS-bio | WB,ELISA | 人類 | IL11 | IgG1 | KT8 |
除了分別人類、小鼠IL-11僅在200[nM]之單一濃度下量測以外,表E30中所列出之市售抗體經受如實例16中所描述之SPR。結果展示於表E31中。
表E31:藉由SPR測試之市售抗體
抗體目錄號 | SPR: hIL-11 KD [M] | SPR: mIL-11 KD [M] |
GTX34009 | 無結合 | 無結合 |
GTX52814 | 3.3E-09 | 2.0E-09 |
LS-C104441 | 3.9E-09 | 2.2E-09 |
MA5-30696 | 無結合 | 無結合 |
MA5-30695 | 無結合 | 無結合 |
MA5-23711 | 3.6E-09 | 2.0E-09 |
LS-C193526 | 6.3E-09 | 6.2E-09 |
SPR中僅四種測試商業抗體展示結合至人類或小鼠IL-11 (GTX52814、LS-C104441、MA5-23711及LS-C193526)。
表E30中所列出之市售抗體經受如實例17中所描述之RGA。結果展示於表E32中。
表E32:藉由RGA測試之市售抗體
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
目錄號 | hIL-11 | mIL-11 | ||
IC50 [M] | 功效 (%)* | IC50 [M] | 功效 (%)* | |
GTX34009 | NM | 21.3 | NM | 0.0 |
GTX52814 | NM | 5.1 | NM | 75.5 |
LS-C104441 | NM | 42.6 | 3.9E-09 | 88.0 |
MA5-30696 | NM | 4.9 | NM | 17.2 |
MA5-30695 | NM | 23.9 | NM | 15.6 |
MA5-23711 | NM | 19.9 | NM | 47.6 |
LS-C193526 | 5.0E-08 | 52.7 | 5.6E-09 | 88.3 |
表E30中所列出之市售抗體經受如實例18中所描述之雙複合物ELISA。結果展示於表E33中。
表E33:藉由雙複合物ELISA測試之市售抗體
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
人類 IL-11 | 小鼠 IL-11 | |||
抗體 | IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) |
GTX34009 | NM | 10.3 | NM | 11.7 |
GTX52814 | 1.9E-09 | 74.9 | 4.7E-09 | 89.9 |
LS-C104441 | 5.3E-09 | 71.5 | 3.5E-09 | 91.2 |
MA5-30696 | NM | 8.1 | NM | 3.1 |
MA5-30695 | NM | 0.0 | NM | 0.0 |
MA5-23711 | 6.0E-08 | 51.1 | 2.9E-08 | 70.5 |
LS-C193526 | 1.0E-08 | 90.1 | 6.5E-09 | 96.2 |
表E30中所列出之市售抗體經受如實例19中所描述之三複合物。結果展示於表E34中。
表E34:藉由三複合物ELISA測試之市售抗體
NM=無意義(=若可計算功效<20%或無IC
50值,則未報導值)
人類 IL-11 | 小鼠 IL-11 | |||
抗體 | IC50 [M] | 功效 (%) | IC50 [M] | 功效 (%) |
GTX34009 | NM | 1.1 | NM | 0.0 |
GTX52814 | 1.4E-08 | 36.9 | 1.7E-08 | 105.9 |
LS-C104441 | 2.0E-08 | 65.6 | 3.8E-09 | 98.4 |
MA5-30696 | NM | 4.7 | NM | 4.3 |
MA5-30695 | NM | 0.0 | NM | 1.5 |
MA5-23711 | 1.9E-08 | 34.1 | NM | 62.3 |
LS-C193526 | 1.0E-08 | 78.5 | 6.6E-09 | 90.3 |
在所有分析中測試之商業抗體在SPR及RGA分析中為非活性的(GTX34009、MA5-30696及MA5-30695)或在SPR、RGA、雙複合物ELISA及三複合物ELISA中為活性的(GTX52814、LS-C104441、MA5-23711、LS-C193526)。如針對根據本發明之抗體所描述,所測試之商業抗體中無一者在三複合物ELISA中具有活性,而在雙複合物ELISA中並非如此。
實例 39 : 在增加濃度之其親和力成熟衍生物存在下 TPP - 18068 或 TPP - 18087 與 IL - 11 之結合將含25 µl/孔20[nM]經生物素標記之人類IL-11 (Invigate,例如批次號C121021-19)之塗佈緩衝劑(pH 9.6) (Candor, #121125)添加至經鏈黴抗生物素蛋白塗佈之384孔微量滴定盤(Greiner bio-one, #781997)中,且在室溫下培育一小時。在用50 µl/孔PBS-t洗滌三次之後,培養盤用50 µl/孔SmartBlock溶液(Candor, #113125)阻斷且在室溫下再次培育一小時。在用PBS-T額外洗滌三次之後,在1E-08[M]之恆定濃度之鼠類IgG TPP-18068或TPP18087存在下以25 µl/孔將2.5E-07[M]至1.6E-11[M]範圍內之人類IgG稀釋系列,亦即,含TPP-29536、TPP-29680或同型對照抗體TPP-5657之10% SmartBlock PBS-T添加至培養盤中且在室溫下培育一小時。在額外三次洗滌之後,將1:5000稀釋於10% SmartBlock PBS-T中之25 µl抗小鼠(Jackson, #715-035-150)添加至培養盤中且在室溫下培育一小時。在最終三次洗滌之後,添加1:1000稀釋於PBS中之25 µl AmplexRed (Fisher Scientific, #VXA12222)、0.003% H
2O
2且在室溫下在暗處培育15分鐘。在535/595 nm處用培養盤讀取器量測相對螢光且將信號轉移至GraphPad Prism以用於分析。
如圖21a)中所示,增加濃度之競爭性抗體TPP-29536 (TPP-18068之衍生物(在雙複合體及三複合體ELISA兩者中具有活性))完全阻斷TPP-18068與IL-11之結合,而TPP-29680 (TPP-18087之衍生物(在三複合體ELISA中具有活性但在雙複合體ELISA中無活性))無影響。此外,增加濃度之競爭性抗體TPP-29680完全阻斷TPP-18087與IL-11之結合,而TPP-29536無影響(圖21b)。此等資料指示TPP-18068之抗原決定基(在雙複合物及三複合物ELISA兩者中具有活性)及其衍生物為獨特的且不與TPP-18087之抗原決定基(在三複合物ELISA中具有活性但在雙複合物ELISA中無活性)及其衍生物重疊。
序列表IL-11、IL-11Ra及gp130之序列
抗體序列
編號 | 類型 | 序列 |
1 | IL-11 AA 序列 同功異型物1 | MNCVCRLVLVVLSLWPDTAVAPGPPPGPPRVSPDPRAELDSTVLLTRSLLADTRQLAAQLRDKFPADGDHNLDSLPTLAMSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRL |
2 | IL-11 AA 序列 同功異型物2 | MSAGALGALQLPGVLTRLRADLLSYLRHVQWLRRAGGSSLKTLEPELGTLQARLDRLLRRLQLLMSRLALPQPPPDPPAPPLAPPSSAWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRL |
3 | IL-11RA AA 序列同功異型物1 | MSSSCSGLSRVLVAVATALVSASSPCPQAWGPPGVQYGQPGRSVKLCCPGVTAGDPVSWFRDGEPKLLQGPDSGLGHELVLAQADSTDEGTYICQTLDGALGGTVTLQLGYPPARPVVSCQAADYENFSCTWSPSQISGLPTRYLTSYRKKTVLGADSQRRSPSTGPWPCPQDPLGAARCVVHGAEFWSQYRINVTEVNPLGASTRLLDVSLQSILRPDPPQGLRVESVPGYPRRLRASWTYPASWPCQPHFLLKFRLQYRPAQHPAWSTVEPAGLEEVITDAVAGLPHAVRVSARDFLDAGTWSTWSPEAWGTPSTGTIPKEIPAWGQLHTQPEVEPQVDSPAPPRPSLQPHPRLLDHRDSVEQVAVLASLGILSFLGLVAGALALGLWLRLRRGGKDGSPKPGFLASVIPVDRRPGAPNL |
4 | IL-11RA AA 序列同功異型物2 | MSSSCSGLSRVLVAVATALVSASSPCPQAWGPPGVQYGQPGRSVKLCCPGVTAGDPVSWFRDGEPKLLQGPDSGLGHELVLAQADSTDEGTYICQTLDGALGGTVTLQLGYPPARPVVSCQAADYENFSCTWSPSQISGLPTRYLTSYRKKTVLGADSQRRSPSTGPWPCPQDPLGAARCVVHGAEFWSQYRINVTEVNPLGASTRLLDVSLQSILRPDPPQGLRVESVPGYPRRLRASWTYPASWPCQPHFLLKFRLQYRPAQHPAWSTVEPAGLEEVITDAVAGLPHAVRVSARDFLDAGTWSTWSPEAWGTPSTGTIPKEIPAWGQLHTQPEVEPQVDSPAPPRPSLQPHPRLLDHRDSVEQVAVLASLGILSFLGLVAGALALGLW |
編號 | 類型 | 序列 |
5 | IL11 cDNA 序列同功異型物1 | ACTGCCGCGGCCCTGCTGCTCAGGGCACATGCCTCCCCTCCCCAGGCCGCGGCCCAGCTGACCCTCGGGGCTCCCCCGGCAGCGGACAGGGAAGGGTTAAAGGCCCCCGGCTCCCTGCCCCCTGCCCTGGGGAACCCCTGGCCCTGTGGGGACATGAACTGTGTTTGCCGCCTGGTCCTGGTCGTGCTGAGCCTGTGGCCAGATACAGCTGTCGCCCCTGGGCCACCACCTGGCCCCCCTCGAGTTTCCCCAGACCCTCGGGCCGAGCTGGACAGCACCGTGCTCCTGACCCGCTCTCTCCTGGCGGACACGCGGCAGCTGGCTGCACAGCTGAGGGACAAATTCCCAGCTGACGGGGACCACAACCTGGATTCCCTGCCCACCCTGGCCATGAGTGCGGGGGCACTGGGAGCTCTACAGCTCCCAGGTGTGCTGACAAGGCTGCGAGCGGACCTACTGTCCTACCTGCGGCACGTGCAGTGGCTGCGCCGGGCAGGTGGCTCTTCCCTGAAGACCCTGGAGCCCGAGCTGGGCACCCTGCAGGCCCGACTGGACCGGCTGCTGCGCCGGCTGCAGCTCCTGATGTCCCGCCTGGCCCTGCCCCAGCCACCCCCGGACCCGCCGGCGCCCCCGCTGGCGCCCCCCTCCTCAGCCTGGGGGGGCATCAGGGCCGCCCACGCCATCCTGGGGGGGCTGCACCTGACACTTGACTGGGCCGTGAGGGGACTGCTGCTGCTGAAGACTCGGCTGTGACCCGGGGCCCAAAGCCACCACCGTCCTTCCAAAGCCAGATCTTATTTATTTATTTATTTCAGTACTGGGGGCGAAACAGCCAGGTGATCCCCCCGCCATTATCTCCCCCTAGTTAGAGACAGTCCTTCCGTGAGGCCTGGGGGGCATCTGTGCCTTATTTATACTTATTTATTTCAGGAGCAGGGGTGGGAGGCAGGTGGACTCCTGGGTCCCCGAGGAGGAGGGGACTGGGGTCCCGGATTCTTGGGTCTCCAAGAAGTCTGTCCACAGACTTCTGCCCTGGCTCTTCCCCATCTAGGCCTGGGCAGGAACATATATTATTTATTTAAGCAATTACTTTTCATGTTGGGGTGGGGACGGAGGGGAAAGGGAAGCCTGGGTTTTTGTACAAAAATGTGAGAAACCTTTGTGAGACAGAGAACAGGGAATTAAATGTGTCATACATATCCACTTGAGGGCGATTTGTCTGAGAGCTGGGGCTGGATGCTTGGGTAACTGGGGCAGGGCAGGTGGAGGGGAGACCTCCATTCAGGTGGAGGTCCCGAGTGGGCGGGGCAGCGACTGGGAGATGGGTCGGTCACCCAGACAGCTCTGTGGAGGCAGGGTCTGAGCCTTGCCTGGGGCCCCGCACTGCATAGGGCCTTTTGTTTGTTTTTTGAGATGGAGTCTCGCTCTGTTGCCTAGGCTGGAGTGCAGTGAGGCAATCTGAGGTCACTGCAACCTCCACCTCCCGGGTTCAAGCAATTCTCCTGCCTCAGCCTCCCGATTAGCTGGGATCACAGGTGTGCACCACCATGCCCAGCTAATTATTTATTTCTTTTGTATTTTTAGTAGAGACAGGGTTTCACCATGTTGGCCAGGCTGGTTTCGAACTCCTGACCTCAGGTGATCCTCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACACCTGACCCATAGGTCTTCAATAAATATTTAATGGAAGGTTCCACAAGTCACCCTGTGATCAACAGTACCCGTATGGGACAAAGCTGCAAGGTCAAGATGGTTCATTATGGCTGTGTTCACCATAGCAAACTGGAAACAATCTAGATATCCAACAGTGAGGGTTAAGCAACATGGTGCATCTGTGGATAGAACGCCACCCAGCCGCCCGGAGCAGGGACTGTCATTCAGGGAGGCTAAGGAGAGAGGCTTGCTTGGGATATAGAAAGATATCCTGACATTGGCCAGGCATGGTGGCTCACGCCTGTAATCCTGGCACTTTGGGAGGACGAAGCGAGTGGATCACTGAAGTCCAAGAGTTCGAGACCGGCCTGCGAGACATGGCAAAACCCTGTCTCAAAAAAGAAAGAATGATGTCCTGACATGAAACAGCAGGCTACAAAACCACTGCATGCTGTGATCCCAATTTTGTGTTTTTCTTTCTATATATGGATTAAAACAAAAATCCTAAAGGGAAATACGCCAAAATGTTGACAATGACTGTCTCCAGGTCAAAGGAGAGAGGTGGGATTGTGGGTGACTTTTAATGTGTATGATTGTCTGTATTTTACAGAATTTCTGCCATGACTGTGTATTTTGCATGACACATTTTAAAAATAATAAACACTATTTTTAGAATAACAGAA |
編號 | 類型 | 序列 |
6 | IL11 cDNA 序列同功異型物2 | ACTGCCGCGGCCCTGCTGCTCAGGGCACATGCCTCCCCTCCCCAGGCCGCGGCCCAGCTGACCCTCGGGGCTCCCCCGGCAGCGGACAGGGAAGGGTTAAAGGCCCCCGGCTCCCTGCCCCCTGCCCTGGGGAACCCCTGGCCCTGTGGGGACATGAACTAGGGACAAATTCCCAGCTGACGGGGACCACAACCTGGATTCCCTGCCCACCCTGGCCATGAGTGCGGGGGCACTGGGAGCTCTACAGCTCCCAGGTGTGCTGACAAGGCTGCGAGCGGACCTACTGTCCTACCTGCGGCACGTGCAGTGGCTGCGCCGGGCAGGTGGCTCTTCCCTGAAGACCCTGGAGCCCGAGCTGGGCACCCTGCAGGCCCGACTGGACCGGCTGCTGCGCCGGCTGCAGCTCCTGATGTCCCGCCTGGCCCTGCCCCAGCCACCCCCGGACCCGCCGGCGCCCCCGCTGGCGCCCCCCTCCTCAGCCTGGGGGGGCATCAGGGCCGCCCACGCCATCCTGGGGGGGCTGCACCTGACACTTGACTGGGCCGTGAGGGGACTGCTGCTGCTGAAGACTCGGCTGTGACCCGGGGCCCAAAGCCACCACCGTCCTTCCAAAGCCAGATCTTATTTATTTATTTATTTCAGTACTGGGGGCGAAACAGCCAGGTGATCCCCCCGCCATTATCTCCCCCTAGTTAGAGACAGTCCTTCCGTGAGGCCTGGGGGGCATCTGTGCCTTATTTATACTTATTTATTTCAGGAGCAGGGGTGGGAGGCAGGTGGACTCCTGGGTCCCCGAGGAGGAGGGGACTGGGGTCCCGGATTCTTGGGTCTCCAAGAAGTCTGTCCACAGACTTCTGCCCTGGCTCTTCCCCATCTAGGCCTGGGCAGGAACATATATTATTTATTTAAGCAATTACTTTTCATGTTGGGGTGGGGACGGAGGGGAAAGGGAAGCCTGGGTTTTTGTACAAAAATGTGAGAAACCTTTGTGAGACAGAGAACAGGGAATTAAATGTGTCATACATATCCACTTGAGGGCGATTTGTCTGAGAGCTGGGGCTGGATGCTTGGGTAACTGGGGCAGGGCAGGTGGAGGGGAGACCTCCATTCAGGTGGAGGTCCCGAGTGGGCGGGGCAGCGACTGGGAGATGGGTCGGTCACCCAGACAGCTCTGTGGAGGCAGGGTCTGAGCCTTGCCTGGGGCCCCGCACTGCATAGGGCCTTTTGTTTGTTTTTTGAGATGGAGTCTCGCTCTGTTGCCTAGGCTGGAGTGCAGTGAGGCAATCTGAGGTCACTGCAACCTCCACCTCCCGGGTTCAAGCAATTCTCCTGCCTCAGCCTCCCGATTAGCTGGGATCACAGGTGTGCACCACCATGCCCAGCTAATTATTTATTTCTTTTGTATTTTTAGTAGAGACAGGGTTTCACCATGTTGGCCAGGCTGGTTTCGAACTCCTGACCTCAGGTGATCCTCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGTGTGAGCCACCACACCTGACCCATAGGTCTTCAATAAATATTTAATGGAAGGTTCCACAAGTCACCCTGTGATCAACAGTACCCGTATGGGACAAAGCTGCAAGGTCAAGATGGTTCATTATGGCTGTGTTCACCATAGCAAACTGGAAACAATCTAGATATCCAACAGTGAGGGTTAAGCAACATGGTGCATCTGTGGATAGAACGCCACCCAGCCGCCCGGAGCAGGGACTGTCATTCAGGGAGGCTAAGGAGAGAGGCTTGCTTGGGATATAGAAAGATATCCTGACATTGGCCAGGCATGGTGGCTCACGCCTGTAATCCTGGCACTTTGGGAGGACGAAGCGAGTGGATCACTGAAGTCCAAGAGTTCGAGACCGGCCTGCGAGACATGGCAAAACCCTGTCTCAAAAAAGAAAGAATGATGTCCTGACATGAAACAGCAGGCTACAAAACCACTGCATGCTGTGATCCCAATTTTGTGTTTTTCTTTCTATATATGGATTAAAACAAAAATCCTAAAGGGAAATACGCCAAAATGTTGACAATGACTGTCTCCAGGTCAAAGGAGAGAGGTGGGATTGTGGGTGACTTTTAATGTGTATGATTGTCTGTATTTTACAGAATTTCTGCCATGACTGTGTATTTTGCATGACACATTTTAAAAATAATAAACACTATTTTTAGAATAACAGAAAAA |
編號 | 類型 | 序列 |
7 | IL11RA cDNA 序列同功異型物3 | AGAGGGCGAGGGCGAGGGCAGAGGGCGCTGGCGGCAGCGGCCGCGGAAGATGAGCAGCAGCTGCTCAGGGCTGAGCAGGGTCCTGGTGGCCGTGGCTACAGCCCTGGTGTCTGCCTCCTCCCCCTGCCCCCAGGCCTGGGGCCCCCCAGGGGTCCAGTATGGGCAGCCAGGCAGGTCCGTGAAGCTGTGTTGTCCTGGAGTGACTGCCGGGGACCCAGTGTCCTGGTTTCGGGATGGGGAGCCAAAGCTGCTCCAGGGACCTGACTCTGGGCTAGGGCATGAACTGGTCCTGGCCCAGGCAGACAGCACTGATGAGGGCACCTACATCTGCCAGACCCTGGATGGTGCACTTGGGGGCACAGTGACCCTGCAGCTGGGCTACCCTCCAGCCCGCCCTGTTGTCTCCTGCCAAGCAGCCGACTATGAGAACTTCTCTTGCACTTGGAGTCCCAGCCAGATCAGCGGTTTACCCACCCGCTACCTCACCTCCTACAGGAAGAAGACAGTCCTAGGAGCTGATAGCCAGAGGAGGAGTCCATCCACAGGGCCCTGGCCATGCCCACAGGATCCCCTAGGGGCTGCCCGCTGTGTTGTCCACGGGGCTGAGTTCTGGAGCCAGTACCGGATTAATGTGACTGAGGTGAACCCACTGGGTGCCAGCACACGCCTGCTGGATGTGAGCTTGCAGAGCATCTTGCGCCCTGACCCACCCCAGGGCCTGCGGGTAGAGTCAGTACCAGGTTACCCCCGACGCCTGCGAGCCAGCTGGACATACCCTGCCTCCTGGCCGTGCCAGCCCCACTTCCTGCTCAAGTTCCGTTTGCAGTACCGTCCGGCGCAGCATCCAGCCTGGTCCACGGTGGAGCCAGCTGGACTGGAGGAGGTGATCACAGATGCTGTGGCTGGGCTGCCCCATGCTGTACGAGTCAGTGCCCGGGACTTTCTAGATGCTGGCACCTGGAGCACCTGGAGCCCGGAGGCCTGGGGAACTCCGAGCACTGGGACCATACCAAAGGAGATACCAGCATGGGGCCAGCTACACACGCAGCCAGAGGTGGAGCCTCAGGTGGACAGCCCTGCTCCTCCAAGGCCCTCCCTCCAACCACACCCTCGGCTACTTGATCACAGGGACTCTGTGGAGCAGGTAGCTGTGCTGGCGTCTTTGGGAATCCTTTCTTTCCTGGGACTGGTGGCTGGGGCCCTGGCACTGGGGCTCTGGCTGAGGCTGAGACGGGGTGGGAAGGATGGATCCCCAAAGCCTGGGTTCTTGGCCTCAGTGATTCCAGTGGACAGGCGTCCAGGAGCTCCAAACCTGTAGAGGACCCAGGAGGGCTTCGGCAGATTCCACCTATAATTCTGTCTTGCTGGTGTGGATAGAAACCAGGCAGGACAGTAGATCCCTATGGTTGGATCTCAGCTGGAAGTTCTGTTTGGAGCCCATTTCTGTGAGACCCTGTATTTCAAATTTGCAGCTGAAAGGTGCTTGTACCTCTGATTTCACCCCAGAGTTGGAGTTCTGCTCAAGGAACGTGTGTAATGTGTACATCTGTGTCCATGTGTGACCATGTGTCTGTGAGGCAGGGAACATGTATTCTCTGCATGCATGTATGTAGGTGCCTGGGGAGTGTGTGTGGGTCCTTGGCTCTTGGCCTTTCCCCTTGCAGGGGTTGTGCAGGTGTGAATAAAGAGAATAAGGAAGTTCTTGGAGATTATACTCAGAAAAAAAAA |
編號 | 類型 | 序列 | |
8 | mIL-11RA1 AA 序列同功異型物1 | MSSSCSGLTRVLVAVATALVSSSSPCPQAWGPPGVQYGQPGRPVMLCCPGVSAGTPVSWFRDGDSRLLQGPDSGLGHRLVLAQVDSPDEGTYVCQTLDGVSGGMVTLKLGFPPARPEVSCQAVDYENFSCTWSPGQVSGLPTRYLTSYRKKTLPGAESQRESPSTGPWPCPQDPLEASRCVVHGAEFWSEYRINVTEVNPLGASTCLLDVRLQSILRPDPPQGLRVESVPGYPRRLHASWTYPASWRRQPHFLLKFRLQYRPAQHPAWSTVEPIGLEEVITDAVAGLPHAVRVSARDFLDAGTWSAWSPEAWGTPSTGPLQDEIPDWSQGHGQQLEAVVAQEDSPAPARPSLQPDPRPLDHRDPLEQVAVLASLGIFSCLGLAVGALALGLWLRLRRSGKDGPQKPGLLAPMIPVEKLPGIPNLQRTPENFS | |
9 | mIL-11RA2 AA 序列同功異型物1 | MSSSCSGLTRVLVAVATALVSSSSPCPQAWGPPGVQYGQPGRPVMLCCPGVSAGTPVSWFRDGDSRLLQGPDSGLGHRLVLAQVDSPDEGTYVCQTLDGVSGGMVTLKLGFPPARPEVSCQAVDYENFSCTWSPGQVSGLPTRYLTSYRKKTLPGAESQRESPSTGPWPCPQDPLEASRCVVHGAEFWSEYRINVTEVNPLGASTCLLDVRLQSILRPDPPQGLRVESVPGYPRRLHASWTYPASWRRQPHFLLKFRLQYRPAQHPAWSTVEPIGLEEVITDTVAGLPHAVRVSARDFLDAGTWSAWSPEAWGTPSTGLLQDEIPDWSQGHGQQLEAVVAQEDSLAPARPSLQPDPRPLDHRDPLEQVAVLASLGIFSCLGLAVGALALGLWLRLRRSGKEGPQKPGLLAPMIPVEKLPGIPNLQRTPENFS |
編號 | 類型 | 序列 |
10 | mIl11RA1 cDNA 序列同功異型物2 | TATTGGCGCTGGGAGGAGCCGCCCCCACTGCCTGCGCTCAGCACTGGAGGGAGCAGAGGCCGGGGCAGAGGGTGAGGGCGGAGGGCGCTGGCGGCGGCTGCCGCAGAAGATGAGCAGCAGCTGCTCAGGGCTGACCAGGGTCCTGGTGGCCGTGGCTACAGCCCTGGTGTCTTCCTCCTCCCCCTGCCCCCAAGCTTGGGGTCCTCCAGGGGTCCAGTATGGACAACCTGGCAGGCCCGTGATGCTGTGCTGCCCCGGAGTGAGTGCTGGGACTCCAGTGTCCTGGTTTCGGGATGGAGATTCAAGGCTGCTCCAGGGACCTGACTCTGGGTTAGGACACAGACTGGTCTTGGCCCAGGTGGACAGCCCTGATGAAGGCACTTATGTCTGCCAGACCCTGGATGGTGTATCAGGGGGCATGGTGACCCTGAAGCTGGGCTTTCCCCCAGCACGTCCTGAAGTCTCCTGCCAAGCGGTAGACTATGAAAACTTCTCCTGTACTTGGAGTCCAGGCCAGGTCAGCGGTTTGCCCACCCGCTACCTTACTTCCTACAGGAAGAAGACGCTGCCAGGAGCTGAGAGTCAGAGGGAAAGTCCATCCACCGGGCCTTGGCCGTGTCCACAGGACCCTCTGGAGGCCTCCCGATGTGTGGTCCATGGGGCAGAGTTCTGGAGTGAGTACCGGATCAATGTGACCGAGGTGAACCCACTGGGTGCCAGCACGTGCCTACTGGATGTGAGATTACAGAGCATCTTGCGTCCTGATCCACCCCAAGGACTGCGGGTGGAATCCGTACCTGGTTACCCGAGACGCCTGCATGCCAGCTGGACATACCCTGCCTCCTGGCGTCGCCAACCCCACTTTCTGCTCAAGTTCCGGTTGCAATACCGACCAGCACAGCATCCAGCCTGGTCCACGGTGGAGCCCATTGGCTTGGAGGAAGTGATAACAGATGCTGTGGCTGGGCTGCCACACGCGGTACGAGTCAGTGCCAGGGACTTTCTGGATGCTGGCACCTGGAGCGCCTGGAGCCCAGAGGCCTGGGGTACTCCTAGCACTGGTCCCCTGCAGGATGAGATACCTGATTGGAGCCAGGGACACGGACAGCAGCTAGAGGCAGTAGTAGCTCAGGAGGACAGCCCGGCTCCTGCAAGGCCTTCCTTGCAGCCGGACCCAAGGCCACTTGATCACAGGGACCCCTTGGAGCAAGTAGCTGTGTTAGCGTCTCTGGGAATCTTCTCTTGCCTTGGCCTGGCTGTTGGAGCTCTGGCACTGGGGCTCTGGCTGAGGCTGAGACGGAGTGGGAAGGATGGACCGCAAAAACCTGGGCTCTTGGCACCCATGATCCCGGTGGAAAAGCTTCCAGGAATTCCAAACCTGCAGAGGACCCCAGAGAACTTCAGCTGATTTCATCTGTAACCCGGTCAGACTTGGGTGGTTAAAAGGACAGGCAGAAAGAGGCGGGGCAGTGGATCCCTGTGGATGGAGGTCTCAGCTGAAAGTCTGAGCTCTTTTCTTTGACACCTATACTCCAAACTTGCTGCCGGCTGAAGGCTGTCTGGACTTCCGATGTCCTGAGGTGGAAGTCCACCTGAGGAATGTGTACAGAAGTCTGTGTTCCTGTGATCGTGTGTGTATGTGAGACAGGGAGCAAAAGTTCTCTGCATGTGTGTACAGATGATTGGAGAGTGTGTGCGGTCTTGGGCTTGGCCCTTCTGGGAAGTGTGAAGAGTTGAAATAAAAGAGACGGAAGTTTTTGG |
編號 | 類型 | 序列 |
11 | mIl11RA2 cDNA 序列 | GACTCAGTCCAGACCCCTTCCCCCCCGCCTGGGGTCAGGGCTGGACAGGGAGGAGAAGCGAGCTCCTTGCAAGACGAGTTGGGGACGAGATAGCTAGTGACCCTGGCCTTGGCTGACCCGAAAGAGGCCTGGAGACATCTGTCCTCAAAGGATTGTCCACTTCCGGTGACTCCCTGCTGCTGATAATAGGGCCCATGTTTCCCAGAAGGCCCGAGGTTATCCCAAGACTGCTTCTCTCCCTTCACCTCCCATGGCTTCATTCCTGAAGAGCCTGTGATCACTTAGGGTCAGAAATAGACGGATGAGCAGCAGCTGCTCAGGGCTGACCAGGGTCCTGGTGGCCGTGGCTACAGCCCTGGTGTCTTCCTCCTCCCCCTGCCCCCAAGCTTGGGGTCCTCCAGGGGTCCAGTATGGACAACCTGGCAGGCCCGTGATGCTGTGCTGCCCCGGAGTGAGTGCTGGGACTCCAGTGTCCTGGTTTCGGGATGGAGATTCAAGGCTGCTCCAGGGACCTGACTCTGGGTTAGGACACAGACTGGTCTTGGCCCAGGTGGACAGCCCTGATGAAGGCACTTATGTCTGCCAGACCCTGGATGGTGTATCAGGGGGCATGGTGACCCTGAAGCTGGGCTTTCCCCCAGCACGTCCTGAAGTCTCTTGCCAAGCGGTAGACTATGAAAACTTCTCCTGTACTTGGAGTCCAGGCCAGGTCAGCGGTTTGCCCACCCGCTACCTTACTTCCTACAGGAAGAAGACGCTGCCAGGAGCTGAGAGTCAGAGGGAAAGTCCATCCACCGGGCCTTGGCCGTGTCCACAGGACCCTCTGGAGGCCTCCCGATGTGTGGTCCATGGGGCAGAGTTCTGGAGTGAGTACCGGATCAATGTGACCGAGGTGAACCCACTGGGTGCCAGCACGTGCCTACTGGATGTGAGATTACAGAGCATCTTGCGTCCCGATCCACCCCAAGGACTGCGGGTGGAATCCGTACCTGGTTACCCAAGACGCCTGCATGCCAGCTGGACATACCCTGCCTCCTGGCGTCGCCAACCCCACTTTCTGCTCAAGTTCCGGTTGCAATACCGACCAGCACAGCATCCAGCCTGGTCCACGGTGGAGCCCATTGGCTTGGAGGAAGTGATAACAGATACTGTGGCTGGGCTGCCCCACGCGGTACGAGTCAGTGCCAGGGACTTTCTGGATGCTGGCACCTGGAGCGCCTGGAGCCCAGAGGCCTGGGGTACTCCTAGCACTGGTCTCCTGCAGGATGAGATACCTGATTGGAGCCAGGGACATGGACAGCAGCTAGAGGCAGTAGTAGCTCAGGAGGACAGCCTGGCTCCTGCAAGGCCTTCCTTGCAGCCAGACCCAAGGCCACTTGATCACAGGGATCCCTTGGAGCAAGTAGCTGTGTTAGCATCTCTGGGAATCTTCTCTTGCCTTGGCCTGGCTGTTGGAGCCCTGGCACTGGGGCTCTGGCTGAGGCTGAGACGGAGTGGGAAGGAAGGACCGCAAAAACCTGGGCTCTTGGCACCCATGATCCCGGTGGAAAAGCTTCCAGGAATTCCAAACCTGCAGAGGACCCCAGAGAACTTCAGCTGATTTCATCTGTAACCCGGTCAGACTTGGGTGGTTAAAAGGACAGGCAGAAAGAGGCGGGGCAGTGGATCCCTGTGGATGGAGGTCTCAGCTGGAAGTCTGAGCTCTTTTCTTTGACACCTATACTCCAAACTTGCTGCCGGCTGAAGGCTGTCTGGACTTCTGATGTCCTGAGGTGGAAGTCCACCTGAGGAATGTGTACAGAAGTCTGTGTTCCTGTGATCGTGTGTGTATGTGAGACAGGGAGCAAAAGTTCTCTGCATGTGTGTACACATGATTGGAGAGTGTGTGCGGTCTTGGGCTTGGCCCTTCTGGGGAGTGTGAAGAGTTGAAATAAAAGAGACGGAAGTTTTTGGAGATTGTCGTCTAATGTTGCTTTATTAGTTTTGCTGTTGGGGGTGTGAGTACATTTTCTTTTGTAGTACCAGATTTAAACTGGGTACAGTTCCTTGGAGCCTTTTCCCTTGGCGTTCTAACCACCGAGCCAGGCTGCGGTTCTGGGGATGAACACAGACACTGCGCCGAGCCAGGTGAAGCCTGAGAAGGGAAAAGTCCAAAGCTAGGCTCACATTTGGGGGATGAGCTTAGGTAGGGTTCAGGGGTTAGGGGTAAAAGCCCGATGAAAATCCGGGTAGGTATTAGAGTTAGTAAAGGGGCTAGGGATGAATATTGGGGGTTCGGACTGAGGGCAGAGTTAGAGGTATCAAAGTTGGGGGCAGAGCTCACACGACAGCCTGGAGGTGACAGTCCCCATCAGCCTCCTGCAGTTCCATGTGGACAATCCTCCTCAGCAGCCTGCTTGGGAGTGGCTGTCTATAGAGCTGAGTACAGCAGCTAGTGCTGGAGGGCAGAGGCAAGGCTGGAGAACAATAGGGCCACACTTCAGAGAGGTCTGGACCCACAAGCTGCTCTGATTACATAGCTAGAGGTCCAACTTTCTGGGCCCTGTTCCCTGTAGTCCCCTCGCTCAGCATTCATTCTATGGCCTCTGAGAACTTACCTGCTTCAGGAGCCGGGCTCAGAAGCAACAGTAACAGCGGGAGGCTGCTGGCGGGGGAGAGCCCCTCCATCATGCTCACTCAG |
編號 | 類型 | 序列 |
12 | hIL-6受體次單元β AA 序列 | MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDRPSKAPSFWYKIDPSHTQGYRTVQLVWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNATKLTVNLTNDRYLATLTVRNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCITDWQQEDGTVHRTYLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFNKRDLIKKHIWPNVPDPSKSHIAQWSPHTPPRHNFNSKDQMYSDGNFTDVSVVEIEANDKKPFPEDLKSLDLFKKEKINTEGHSSGIGGSSCMSSSRPSISSSDENESSQNTSSTVQYSTVVHSGYRHQVPSVQVFSRSESTQPLLDSEERPEDLQLVDHVDGGDGILPRQQYFKQNCSQHESSPDISHFERSKQVSSVNEEDFVRLKQQISDHISQSCGSGQMKMFQEVSAADAFGPGTEGQVERFETVGMEAATDEG MPKSYLPQTVRQGGYMPQ |
13 | h IL-6R次單元β 同功異型物2;AA seq. | MLTLQTWLVQALFIFLTTESTGELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDIASLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWDGGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIILKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRIRCMKEDGKGYWSDWSEEASGITYEDNIASF |
16 | mIL-11 AA序列 | MNCVCRLVLVVLSLWPDRVVAPGPPAGSPRVSSDPRADLDSAVLLTRSLLADTRQLAAQMRDKFPADGDHSLDSLPTLAMSAGTLGSLQLPGVLTRLRVDLMSYLRHVQWLRRAGGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAPDQPVIPLGPPASAWGSIRAAHAILGGLHLTLDWAVRGLLLLKTRL |
17 | 獼猴IL-11 AA序列 | MNCVCRLVLVVLSLWPDTAVAPGPPPGSPRASPDPRAELDSTVLLTRSLLEDTRQLTIQLKDKFPADGDHNLDSLPTLAMSAGALGALQLPSVLTRLRADLLSYLRHVQWLRRAMGSSLKTLEPELGTLQTRLDRLLRRLQLLMSRLALPQLPPDPPAPPLAPPSSTWGGIRAAHAILGGLHLTLDWAVRGLLLLKTRL |
18 | 大鼠IL-11 AA序列 | MNCVCRLVLVVLSLWPDRVVAPGPPAGSPRVSSDPRADLDSAVLLTRSLLADTRQLAAQMRDKFPADGDHNLDSLPTLAMSAGTLGSLQLPGVLTRLRVDLMSYFRHVQWLRRAAGPSLKTLEPELGALQARLERLLRRLQLLMSRLALPQAAPDQPAVPLGPPASAWGSIRAAHAILGGLHLTLDWAVRGLLLLKTRL |
編號 | 類型 | 序列 |
22 | 獼猴IL-11Ra同功異型物X4;AA序列 | MSSGCSGLSRVLVAVATALVSASSSCPQAWGPPGVQYGQPGRSVKLCCPGVTAGDPVSWFRDGEPRLLQGPDSGLGHELVLTQADSTDEGTYICQTLDGALGGTVTLQLGYPPARPVVSCQAADYENFSCTWSPSQISGLPTRYLTSYRKKTVLGADSQRRSPSTGPWPCPQDPLGAARCVVHGAEFWSQYRINVTEVNPLGASTRLLDVSLQSILRPDPPQGLRVESVPGFPRRLRASWTYPASWPRQPHFLLKFRLQYRPAQHPAWSTVRPGVEPAGLEEMITDAVAGLPHAVRVSARDFLDAGTWSTWSPEAWGTPSTGTVPKEVPAWGQLHMQPEVEPQVDSPAPPSPSLQPHPRLLDHRDSVEQVAVLASLGILSFLGLMAGALALGLWSSKPIEDPGGLRQSPLIILSCWCGWMDSRSLWLGLSWKFCLEPISVRPCISNLPAERCLYL |
23 | 大鼠IL-11Ra AA序列 | MSSSRSGLTRVLVAVATALVSSSTPCPQAWGPPGVQYGQPGRPVMLCCPGVNAGTPVSWFRDGDSRLLQGPDSGLGHRLVLAQVDSRDEGTYVCRTLDGVFGGMVTLKLGSPPARPEVSCQAVDYENFSCTWSPGRVSGLPTRYLTSYRKKTLPGAESQRESPSTGPWPCPQDPLEASRCVVHGAEFWSEYRINVTEVNPLGASTCLLDVRLQRILRPDPPQGLRVESVPGYPRRLHASWTYPASWRRQPHFLLKFRLQYRPAQHPAWSTVEPIGLEELITDAVAGLPHAVRVSARDFLDAGTWSAWSPEAWGTPSTGPLRDEVPDGSRGHEQKLEAAAQEDSPAPPSPSLQPDPRPLDHRDPLEQVAVLASLGIFSFLGLAVGALALGLWLRLRRSGKDGPQKPGFLAPMIPGDKLPGIPNLQRTPENFS |
26 | mIL-6ST AA序列 | MSAPRIWLAQALLFFLTTESIGQLLEPCGYIYPEFPVVQRGSNFTAICVLKEACLQHYYVNASYIVWKTNHAAVPREQVTVINRTTSSVTFTDVVLPSVQLTCNILSFGQIEQNVYGVTMLSGFPPDKPTNLTCIVNEGKNMLCQWDPGRETYLETNYTLKSEWATEKFPDCQSKHGTSCMVSYMPTYYVNIEVWVEAENALGKVSSESINFDPVDKVKPTPPYNLSVTNSEELSSILKLSWVSSGLGGLLDLKSDIQYRTKDASTWIQVPLEDTMSPRTSFTVQDLKPFTEYVFRIRSIKDSGKGYWSDWSEEASGTTYEDRPSRPPSFWYKTNPSHGQEYRSVRLIWKALPLSEANGKILDYEVILTQSKSVSQTYTVTGTELTVNLTNDRYVASLAARNKVGKSAAAVLTIPSPHVTAAYSVVNLKAFPKDNLLWVEWTPPPKPVSKYILEWCVLSENAPCVEDWQQEDATVNRTHLRGRLLESKCYQITVTPVFATGPGGSESLKAYLKQAAPARGPTVRTKKVGKNEAVLAWDQIPVDDQNGFIRNYSISYRTSVGKEMVVHVDSSHTEYTLSSLSSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFNKRDLIKKHIWPNVPDPSKSHIAQWSPHTPPRHNFNSKDQMYSDGNFTDVSVVEIEANNKKPCPDDLKSVDLFKKEKVSTEGHSSGIGGSSCMSSSRPSISSNEENESAQSTASTVQYSTVVHSGYRHQVPSVQVFSRSESTQPLLDSEERPEDLQLVDSVDGGDEILPRQSYFKQNCSQPEACPEISHFERSNQVLSGNEEDFVRLKQQQVSDHISQPYGSEQRRLFQEGSTADALGTGADGQMERFESVGMETTIDEEIPKSYLPQTVRQGGYMPQ |
編號 | 類型 | 序列 |
27 | 獼猴IL6R次單元β同功異型物X1 AA序列 | MKYPHKMLTLQTWVVQALFIFLTTESIGELLDPCGYISPESPVVQLHSNFTAVCVLKEKCMDYFHVNANYIVWKTNHFTIPKEQYTIINRTASSVTFTDISSLNIQLTCNILTFGQLEQNVYGITIISGLPPEKPKNLSCIVNEGKKMRCEWNRGRETHLETNFTLKSEWATHKFADCKAKRDTPTSCTVDYSTVYFVNIEVWVEAENALGKVTSDHINFDPVYKVKPNPPHNLSVINSEELSSILKLTWTNPSIKSVIRLKYNIQYRTKDASTWSQIPPEDTASTRSSFTVQDLKPFTEYVFRICCMKEDGKGYWSDWSEEANGITYEDRPSKAPSFWYKIDPSHAQGYRTVQLMWKTLPPFEANGKILDYEVTLTRWKSHLQNYTVNDTKLTVNLTNDRYVATLTARNLVGKSDAAVLTIPACDFQATHPVMDLKAFPKDNMLWVEWTTPRESVKKYILEWCVLSDKAPCIADWQQEDGTVHRTHLRGNLAESKCYLITVTPVYADGPGSPESIKAYLKQAPPSKGPTVRTKKVGKNEAVLEWDQLPVDVQNGFIRNYTIFYRTIIGNETAVNVDSSHTEYTLSSLTSDTLYMVRMAAYTDEGGKDGPEFTFTTPKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFNKRDLIKKHIWPNVPDPSKSHIAQWSPHTPPRHNFSSKDQMYSDGNFTDVSVVEIEANDKKPFPEDLKSLDLFKKEKINTEGHSSGIGGSSCMSSSRPSISSSDENESSQNTSSTVQYSTVVHSGYRHQVPSVQVFSRSESTQPLLDSEERPEDLQLVDHVDGSDDILPRQQYFKQNCSQHESSPDISHFERSKQVSSVNEEDFVRLKQQISDHISQSCGSGEMKMFQEVSAADPFGPGTEGQIERFETIGMEAAIDEGMPKSYLPQTVRQGGYMPQ |
28 | 大鼠IL6R 次單元β AA序列 | MSALRIWLMQALLIFLTTESIGQLVEPCGYIYPEFPVVQRGSNFTATCVLKEKCLQVYSVNATYIVWKTNHVAVPKEQVTVINRTASSVTFTDVVFQNVQLTCNILSFGQIEQNVYGITILSGYPPDIPTNLSCIVNEGKNMLCQLDPGRETYLETNYTLKSEWATEKFPDCRTKHGTSSCMMGYTPIYFVNIEVWVEAENALGNVSSEPINFDPVDKVKPSPPHNLSVTNSEELSSILKLAWVNSGLDSILRLKSDIQYRTKDASTWIQVPLEDTVSPRTSFTVQDLKPFTEYVFRIRSIKENGKGYWSDWSEEASGTTYEDRPSKAPSFWYKVNANHPQEYRSARLIWKTLPLSEANGKILDYEVVLTQSKSVSQTYTVNGTELIVNLTNNRYVASLAARNVVGKSPATVLTIPGSHFKASHPVVDLKAFPKDNLLWVEWTPPSKPVNKYILEWCVLSENSPCIPDWQQEDGTVNRTHLRGSLLESKCYLITVTPVFPGGPGSPESMKAYLKQAAPSKGPTVRTKKVGKNEAVLEWDHLPVDVQNGFIRNYSISYRTSVGKEMVVRVDSSHTEYTLSSLSSDTLYMVHMAAYTEEGGKDGPEFTFTTLKFAQGEIEAIVVPVCLAFLLTTLLGVLFCFNKRDLIKKHIWPNVPDPSKSHIAQWSPHTPPRHNFNSKDQMYSDANFTDVSVVEIEANNKKPCPDDLKSLDLFKKEKISTEGHSSGIGGSSCMSSSRPSISSSEENESAQSTASTVQYSTVVHSGYRHQVPSVQVFSRSESTQPLLDSEERPEDLQLVDSVDSGDEILPRQQYFKQSCSQPGASPDVSHFGRSSQVPSGSEEDFVRLKQQQVSDHISEPYGSEQRRLFQEGSVADALGTGTDGQIERFESVGMETAMDEDISKSYLPQTVRQGGYMPQ |
類型 | SEQ ID NO | 序列 |
PRT | 32 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSS |
PRT | 33 | SYGMH |
PRT | 34 | VISYDGSYKYYADSVKG |
PRT | 35 | GVPDY |
PRT | 36 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVL |
PRT | 37 | TGSSSNIGAGYDVH |
PRT | 38 | SNNERPS |
PRT | 39 | AAWDDSLNGPV |
PRT | 40 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
PRT | 41 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 42 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSGINWNGGSTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWDGPFDYWGQGTLVTVSS |
PRT | 43 | DYYMS |
PRT | 44 | GINWNGGSTGYADSVKG |
PRT | 45 | WDGPFDY |
PRT | 46 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLGGSVFGGGTKLTVL |
PRT | 47 | TGSSSNIGAGYDVH |
PRT | 48 | YDDLLPS |
PRT | 49 | QSYDSSLGGSV |
PRT | 50 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSGINWNGGSTGYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATWDGPFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 51 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLGGSVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 52 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 53 | QSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 54 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYDMNWLRQAPGKGLEWVGVISYDGSNKFYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSS |
PRT | 55 | HYDMN |
PRT | 56 | VISYDGSNKFYADFVKG |
PRT | 57 | TPGSHFDY |
PRT | 58 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLNGVVFGGGTKLTVL |
PRT | 59 | SGSSSNIGNNAVN |
PRT | 60 | YDDLLPS |
PRT | 61 | SAWDDSLNGVV |
PRT | 62 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYDMNWLRQAPGKGLEWVGVISYDGSNKFYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 63 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLNGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 64 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSSISDTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSNWGSLDYWGQGTLVTVSS |
PRT | 65 | IYAMS |
PRT | 66 | SISDTGDRTYYADSVKG |
PRT | 67 | SNWGSLDY |
PRT | 68 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGRVFGGGTKLTVL |
PRT | 69 | SGSSSNIGSNYVY |
PRT | 70 | YDDLLPS |
PRT | 71 | AAWDDSLSGRV |
PRT | 72 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSSISDTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSNWGSLDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 73 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGRVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 74 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
PRT | 75 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYDMNWLRQAPGKGLEWVGVISYDGSNKFYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLNGVVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG |
PRT | 76 | EVQLVQSGAEVKKPGASVKISCKASGYTFTDYNMDWVKQAPGQRLEWIGDINPHNGGPIYNQKFTGRATLTVDKSASTAYMELSSLRSEDTAVYYCARGELGHWYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 77 | DIVLTQSPASLALSPGERATLSCRASKSVSTSGYSYIHWYQQKPGQPPRLLIYLASNLDSGVPARFSGSGSGTDFTLNIHPLEEEDFATYYCQHSRDLPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
PRT | 78 | EVQLVQSGAEVKKPGASVKISCKASGYTFTDYNMDWVKQAPGQRLEWIGDINPHNGGPIYNQKFTGRATLTVDKSASTAYMELSSLRSEDTAVYYCARGELGHWYFDVWGQGTTVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 79 | DIVLTQSPASLALSPGERATLSCRASKSVSTSGYSYIHWYQQKPGQPPRLLIYLASNLDSGVPARFSGSGSGTDFTLNIHPLEEEDFATYYCQHSRDLPPTFGQGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC |
PRT | 80 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCTGSSSNIGAGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGPVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLWCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 81 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYDMNWLRQAPGKGLEWVGVISYDGSNKFYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLNGVVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLSCAITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVVSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 82 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSS |
PRT | 83 | SYGMH |
PRT | 84 | VISYDGSYKYYADSVKG |
PRT | 85 | GVPDY |
PRT | 86 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGPVFGGGTKLTVL |
PRT | 87 | SGSSSNIGSGYDVH |
PRT | 88 | SNNERPS |
PRT | 89 | AAWDDSLSGPV |
PRT | 90 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 91 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSGYDVHWYQQLPGTAPKLLIYSNNERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 92 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 93 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 94 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYHGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 95 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 96 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYSGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 97 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 98 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 99 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 100 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 101 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 102 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 103 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 104 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 105 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVLGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS |
PRT | 106 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSS |
PRT | 107 | SYGMH |
PRT | 108 | VISYDGSYKYYADSVKG |
PRT | 109 | GVPDY |
PRT | 110 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVL |
PRT | 111 | SGSSSNIGSDYDVH |
PRT | 112 | SNEERPS |
PRT | 113 | SAWDSSLSGPV |
DNA | 114 | GAAGTTCAGCTGCTGGAATCTGGCGGCGGACTGGTTCAACCTGGCGGATCTCTGAGACTGAGCTGTGCCGCCAGCGGCTTCACCTTTAGCAGCTATGGCATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACGACGGCAGCTACAAGTACTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCTGCTGGCGTGCCAGATTACTGGGGCCAGGGAACACTGGTCACAGTGTCATCA |
DNA | 115 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCGACTATGACGTGCACTGGTATCAGCAGCTGCCTGGCACAGCCCCTAAACTGCTGATCTACAGCAACGAGGAACGGCCTAGCGGCGTGCCCGATAGATTTTCTGGCAGCAAGAGCGGCACAAGCGCCAGCCTGGCTATCTCTGGACTGAGATCTGAGGACGAGGCCGACTACTACTGCAGCGCCTGGGATTCTTCTCTGTCTGGCCCTGTTTTTGGCGGAGGCACCAAGCTGACAGTGCTA |
PRT | 116 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 117 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 118 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYHGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPCKEQMAKDKVSLWCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 119 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVCTIPPPKEQMAKDKVSLSCAITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVVSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK |
PRT | 120 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYHGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSS |
PRT | 121 | HYDMH |
PRT | 122 | VISYHGSVKFYADSVKG |
PRT | 123 | TPGFHFDY |
PRT | 124 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 125 | SGSSSNIGSNYVS |
PRT | 126 | YDDLRPS |
PRT | 127 | SAWDDSLSGVV |
DNA | 128 | CAGGTTCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGAAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACCACGGCAGCGTGAAGTTCTACGCCGACTCCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAACACCCGGCTTCCACTTCGACTATTGGGGCCAGGGAACCCTGGTCACAGTCTCTTCA |
DNA | 129 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCAACTACGTGTCCTGGTATCAGCAGCTGCCTGGCACAGCCCCTAAACTGCTGATCTACTACGACGACCTGCGGCCTAGCGGCGTGCCAGATAGATTTTCTGGCAGCAAGAGCGGCACCTCTGCCAGCCTGGCTATCTCTGGACTGAGAAGCGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATGATAGCCTGTCCGGCGTTGTGTTTGGCGGAGGCACAAAGCTGACAGTGCTA |
PRT | 130 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYHGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 131 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 132 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYHGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 133 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSYKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAAGVPDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSSSNIGSDYDVHWYQQLPGTAPKLLIYSNEERPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDSSLSGPVFGGGTKLTVLGGGGSGGGGSGGGGSGVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
DNA | 134 | CAGGTGCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGATCCCTGAGACTGTCTTGTGCCGCCTCCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATCTCCTACCACGGCTCCGTGAAGTTCTACGCCGACAGCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCTAGAACCCCTGGCTTCCACTTCGACTATTGGGGCCAGGGCACACTGGTCACAGTTTCTAGCGGAGGCGGAGGAAGTGGCGGCGGAGGATCTGGCGGTGGTGGTTCTCAGTCTGTGCTGACCCAACCTCCTTCCGCTTCTGGCACACCTGGCCAGAGAGTGACCATCTCTTGCTCCGGCTCCTCCTCCAACATCGGCTCCAATTACGTGTCCTGGTATCAGCAGCTGCCCGGCACAGCTCCCAAACTGCTGATCTACTACGACGACCTGCGGCCTTCTGGCGTGCCCGATAGATTCTCCGGCTCTAAGTCTGGCACCTCTGCCAGCCTGGCTATCTCCGGACTGAGATCTGAGGACGAGGCCGACTACTACTGCTCTGCCTGGGACGATTCTCTGTCCGGCGTTGTGTTTGGCGGAGGCACCAAACTGACAGTGCTCGGAGGTGGTGGCTCTGGTGGCGGAGGAAGTGGCGGAGGCGGTTCTGGTGTTGAATGTCCTCCATGTCCTGCTCCTCCAGTGGCTGGCCCTTCCGTGTTTCTGTTCCCTCCAAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGTGTGGTCGTGGGAGTGTCTCACGAGGATCCCGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGCAGCTGCCCTCTCCAATCGAAAAGACCATCTCCAAGGCCAAGGGACAGCCCAGAGAACCCCAGGTGTACACACTGCCTCCATGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGTGGTGTCTGGTCAAGGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCTAATGGCCAGCCTGAGAACAACTACAAGACCACACCTCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACTCCAAGCTGACAGTGGACAAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGTCCCTGTCTCTGTCCCCTGGCAAG |
DNA | 135 | GAAGTGCAGCTGCTGGAATCTGGCGGAGGATTGGTTCAGCCTGGCGGCTCTCTGAGACTGTCTTGTGCCGCTTCCGGCTTCACCTTCTCCAGCTACGGAATGCACTGGGTCCGACAGGCCCCTGGCAAAGGATTGGAATGGGTCGCCGTGATCTCCTACGACGGCTCCTACAAGTACTACGCCGACTCCGTGAAGGGCAGATTCACCATCTCTCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGAGAGCCGAGGACACCGCCGTGTACTATTGTGCTGCTGGCGTGCCAGATTACTGGGGCCAGGGAACACTGGTCACAGTGTCTAGCGGCGGAGGTGGAAGCGGAGGCGGAGGTTCTGGTGGTGGTGGATCTCAGTCTGTGCTGACCCAGCCTCCTTCTGCTTCTGGCACACCTGGCCAGAGAGTGACCATCTCTTGCTCCGGCTCCTCCTCCAACATCGGCTCTGACTACGACGTGCACTGGTATCAGCAGCTCCCTGGCACAGCTCCCAAACTGCTGATCTACTCCAACGAGGAACGGCCTAGCGGCGTGCCCGATAGATTCTCCGGATCTAAGTCCGGCACCTCTGCCAGCCTGGCTATCTCTGGCCTGAGATCTGAGGACGAGGCCGACTACTACTGCTCCGCCTGGGACTCTTCTCTGTCTGGCCCTGTTTTTGGCGGAGGCACCAAGCTGACAGTGCTCGGAGGTGGTGGCTCTGGTGGCGGAGGAAGTGGCGGAGGCGGTTCTGGTGTTGAATGTCCTCCATGTCCTGCTCCTCCAGTGGCTGGCCCTTCCGTGTTTCTGTTCCCTCCAAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCTGAAGTGACCTGTGTGGTCGTGGGAGTGTCTCACGAGGATCCCGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACAACTCCACCTACAGAGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGCAGCTGCCCTCTCCAATCGAAAAGACCATCTCCAAGGCCAAGGGACAGCCCCGGGAACCTCAAGTCTGTACCTTGCCTCCTAGCCGGGACGAGCTGACCAAGAATCAGGTGTCCCTGTCCTGTGCCGTGAAGGGCTTCTACCCTTCCGATATCGCCGTGGAATGGGAGTCCAATGGCCAGCCTGAGAACAACTACAAGACCACACCTCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGTCCAAGCTGACAGTGGACAAGTCCAGATGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGTCCCTGAGCCTGTCTCCTGGCAAG |
PRT | 136 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYSGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSS |
PRT | 137 | HYDMH |
PRT | 138 | VISYSGSVKFYADSVKG |
PRT | 139 | TPGSHFDY |
PRT | 140 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 141 | SGSSSNIGSNYVN |
PRT | 142 | YDDLRPS |
PRT | 143 | SAWDDSLSGVV |
DNA | 144 | CAGGTTCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGAAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACAGCGGCAGCGTGAAGTTCTACGCCGACTCCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAACACCTGGCAGCCACTTCGACTATTGGGGCCAGGGAACACTGGTCACCGTTAGCTCA |
DNA | 145 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCAACTACGTGAACTGGTATCAGCAGCTGCCCGGCACAGCCCCTAAACTGCTGATCTACTACGACGACCTGCGGCCTAGCGGCGTGCCAGATAGATTTTCTGGCAGCAAGAGCGGCACCTCTGCCAGCCTGGCTATCTCTGGACTGAGAAGCGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATGATAGCCTGTCCGGCGTTGTGTTTGGCGGAGGCACAAAGCTGACAGTGCTA |
PRT | 146 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYSGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 147 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 148 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSS |
PRT | 149 | HYDMH |
PRT | 150 | VISYEGSNKFYADSVKG |
PRT | 151 | TPGFHFDY |
PRT | 152 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 153 | SGSSSNIGSNYVS |
PRT | 154 | YDDLRPS |
PRT | 155 | SAWDDSLSGVV |
DNA | 156 | CAGGTTCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGAAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACGAGGGCAGCAACAAGTTCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAACACCCGGCTTCCACTTCGACTATTGGGGCCAGGGAACCCTGGTCACAGTCTCTTCA |
DNA | 157 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCAACTACGTGTCCTGGTATCAGCAGCTGCCTGGCACAGCCCCTAAACTGCTGATCTACTACGACGACCTGCGGCCTAGCGGCGTGCCAGATAGATTTTCTGGCAGCAAGAGCGGCACCTCTGCCAGCCTGGCTATCTCTGGACTGAGAAGCGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATGATAGCCTGTCCGGCGTTGTGTTTGGCGGAGGCACAAAGCTGACAGTGCTA |
PRT | 158 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 159 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVSWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 160 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSS |
PRT | 161 | HYDMH |
PRT | 162 | VISYEGSNKFYADSVKG |
PRT | 163 | TPGFHFDY |
PRT | 164 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 165 | SGSSSNIGSNYVN |
PRT | 166 | YDDLRPS |
PRT | 167 | SAWDDSLSGVV |
DNA | 168 | CAGGTTCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGAAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACGAGGGCAGCAACAAGTTCTACGCCGACAGCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAACACCCGGCTTCCACTTCGACTATTGGGGCCAGGGAACCCTGGTCACAGTCTCTTCA |
DNA | 169 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCAACTACGTGAACTGGTATCAGCAGCTGCCCGGCACAGCCCCTAAACTGCTGATCTACTACGACGACCTGCGGCCTAGCGGCGTGCCAGATAGATTTTCTGGCAGCAAGAGCGGCACCTCTGCCAGCCTGGCTATCTCTGGACTGAGAAGCGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATGATAGCCTGTCCGGCGTTGTGTTTGGCGGAGGCACAAAGCTGACAGTGCTA |
PRT | 170 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 171 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 172 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSS |
PRT | 173 | HYDMH |
PRT | 174 | VISYEGSVKFYADSVKG |
PRT | 175 | TPGFHFDY |
PRT | 176 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 177 | SGSSSNIGSNYVN |
PRT | 178 | YDDLRPS |
PRT | 179 | SAWDDSLSGVV |
DNA | 180 | CAGGTTCAGCTGGTGGAATCTGGTGGCGGAGTTGTGCAGCCTGGCAGAAGCCTGAGACTGTCTTGTGCCGCCAGCGGCTTCACCTTCAGCCACTACGATATGCACTGGGTCCGACAGGCCCCTGGCAAAGGACTTGAATGGGTCGCCGTGATCAGCTACGAGGGCAGCGTGAAGTTCTACGCCGACTCCGTGAAGGGCAGATTCACCATCAGCCGGGACAACAGCAAGAACACCCTGTACCTGCAGATGAACAGCCTGAGAGCCGAGGACACCGCCGTGTACTACTGTGCCAGAACACCCGGCTTCCACTTCGACTATTGGGGCCAGGGAACCCTGGTCACAGTCTCTTCA |
DNA | 181 | CAGTCTGTTCTGACACAGCCTCCTAGCGCCTCTGGCACACCTGGACAGAGAGTGACCATCAGCTGTAGCGGCAGCAGCTCCAACATCGGCAGCAACTACGTGAACTGGTATCAGCAGCTGCCCGGCACAGCCCCTAAACTGCTGATCTACTACGACGACCTGCGGCCTAGCGGCGTGCCAGATAGATTTTCTGGCAGCAAGAGCGGCACCTCTGCCAGCCTGGCTATCTCTGGACTGAGAAGCGAGGACGAGGCCGACTACTACTGTAGCGCCTGGGATGATAGCCTGTCCGGCGTTGTGTTTGGCGGAGGCACAAAGCTGACAGTGCTA |
PRT | 182 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSVKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVGVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKQLPSPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK |
PRT | 183 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 184 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSS |
PRT | 185 | HYDMH |
PRT | 186 | VISYEGSNKFYADSVKG |
PRT | 187 | TPGSHFDY |
PRT | 188 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVL |
PRT | 189 | SGSSSNIGSNYVN |
PRT | 190 | YDDLRPS |
PRT | 191 | SAWDDSLSGVV |
PRT | 192 | QVQLVESGGGVVQPGRSLRLSCAASGFTFSHYDMHWVRQAPGKGLEWVAVISYEGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK |
PRT | 193 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVNWYQQLPGTAPKLLIYYDDLRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLSGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 194 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYDMNWLRQAPGKGLEWVGVISYDGSNKFYADFVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARTPGSHFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK |
PRT | 195 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNAVNWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSAWDDSLNGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
PRT | 196 | EVQLLESGGGLVQPGGSLRLSCAASGFTFSIYAMSWVRQAPGKGLEWVSSISDTGDRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSNWGSLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK |
PRT | 197 | QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVYWYQQLPGTAPKLLIYYDDLLPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSGRVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS |
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圖1描述大量月經出血之小鼠模型。其展示具有如實例1中所描述經誘導之子宮內膜分化模擬月經及月經子宮出血之卵巢切除且雌激素及孕酮取代之小鼠中之孕酮(P4)退出。藉由分析棉塞中之血液含量監測失血。藉由分析子宮重量或組織學或與例如增殖標記物相比之組織降解標記物表現來監測對月經之其他作用。1)移除卵巢;2)雌激素取代;3)孕酮/雌激素取代;4)子宮內施用油;5)孕酮退出(在第12天(d));6)剖檢(在第16天)。
圖2展示實例1之實驗之結果:其展現HMB小鼠模型中功能阻斷多株IL-11抗體(IL11-fbAb AF418;三角形)對比同型對照抗體(ctrl-Ab;TPP-12904;圓形)對月經之作用。與同型對照抗體組相比,IL-11抗體處理組中失血[µL]顯著(雙尾t檢驗,****p<0.0001)減少。
圖3展示實例2之實驗之結果:其展現HMB小鼠模型中功能阻斷IL-11抗體(多株IL11-fbAb AF418;三角形)對比同型對照抗體(ctrl-Ab;TPP-12904;圓形)對子宮重量之作用。與對照抗體相比,藉由IL-11功能阻斷抗體子宮重量[mg]顯著(雙尾t檢驗,***t<0.001)減少。
圖4展示實例3之結果:原發性人類類纖維切片分析中3 ng/ml人類IL-11 (hIL-11 [來自R&D Systems, Inc.之218-IL]),空心三角形)及1 µg/ml人類IL-11功能阻斷抗體(hIL11-fbAb AF418;方形)對比同型對照抗體(ctrl-Ab;TPP-12904;圓形)對血管內皮生長因子(VEGF;[ng VEGF/mg組織)之分泌之作用。展示VEGF (血管生成IL-11之關鍵介體)。藉由用IL-11功能阻斷抗體AF418 (實心三角形)額外處理來完全抑制藉由hIL-11之血管生成介體VEGF-A之顯著誘導分泌。統計檢驗:單向ANOVA,****p<0.0001。
圖5展示實例4之實驗之結果:HMB小鼠模型中在月經期間功能阻斷IL-11抗體(IL11-fbAb;AF418;三角形)對比同型對照抗體(ctrl-Ab;TPP-12904;圓形)對體重改變百分比(%;d12/d16)之作用。與同型對照抗體處理組相比,IL-11抗體處理組中體重減輕顯著(雙尾t檢驗,****p<0.0001)減少。
圖6:展示實例5之實驗之結果:相比於多株功能阻斷抗體AF418 (菱形),ScidBeige小鼠中市售單株IL-11功能阻斷抗體Mab-218 (實心三角形)相比於其IgG對照抗體TPP-10748 (圓形)及Mab-418 (空心三角形)相比於其IgG對照抗體TPP-10750 (方形)對月經之作用。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(*p<0.05;****p<0.0001)
圖7:藉由單株抗體之Scid beige小鼠中月經出血之效能依賴性抑制。IL-11功能阻斷抗體TPP-18068 (三角形)而非IL-11功能阻斷抗體TPP-18063 (方形)相比於同型對照抗體TPP-10159 (圓形)對月經失血之顯著作用。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(**p<0.01)
圖8:Balb/c小鼠之大量月經出血模型中月經出血之劑量依賴性抑制:藉由1 mg/kg TPP-18068 (方形)無抑制,但藉由5 mg/kg (三角形)或20 mg/kg (菱形)對比20 mg/kg對照抗體TPP-10159 (圓形)顯著抑制。藉由多重比較之單向ANOVA與Bonferroni校正測試顯著性(**p<0.01)
圖9:相比於對照抗體TPP-TPP10159 (方形),在月經期間功能阻斷IL-11抗體(TPP-18068,圓形)對藉由行進距離(水平活性)及直立(垂直活動)量測之自發性活動的作用,A:在5分鐘內,如以米計之行進距離之水平活動;B:在5分鐘內,垂直活動(直立)次數。在A及B中,用IL-11拮抗抗體TPP-18068處理之動物活動更多(雙尾t檢驗:分別*p<0.05;**p<0.01)。
圖10:在d12,在HMB模型中,相比於蛻膜化(圓形)及未蛻膜化子宮角(方形)中之對照抗體TPP-10159,IL-11功能阻斷抗體TPP-18068降低蛻膜化(三角形)而非未蛻膜化(菱形)子宮角中之Stat3磷酸化。統計檢驗:多重比較之單向ANOVA與Bonferroni校正,**p<0.01;***p<0.001。
圖11:藉由單株抗體減少Balb/c小鼠中之月經出血。TPP-18068 (實心三角形)、TPP-26195 (菱形)及TPP-23580 (空心三角形)。相比於其各別對照IgG-抗體TPP-27360 (方形)及TPP-10159 (圓形)。TPP-18068及TPP-26195而非TPP-23580展示在每週兩次15 mg/kg之劑量下對大量月經出血之顯著作用。統計檢驗:雙向曼-惠特尼檢驗(Mann-Whitney test),***p<0.001;**p<0.01;ns=不顯著
圖12展示,如藉由子宮重量在鼠類大量月經出血模型之第12天所量測,相比於對照IgG-抗體(方形),在每週兩次15 mg/kg之劑量下Balb/c小鼠中藉由雙互補位IL-11功能阻斷抗體TPP-26195 (圓形)之子宮分化減少。統計檢驗:單尾t檢驗,*p <0.05
圖13展示相比於10 mg/kg對照IgG-抗體TPP-27360 (方形),在具有10 mg/kg (圓形)、3 mg/kg (菱形)、1 mg/kg (實心三角形)及0.3 mg/kg (空心三角形)之劑量的Balb/c小鼠中藉由雙互補位IL-11功能阻斷抗體TPP-26195的月經出血劑量依賴性減少,證明已每週兩次1 mg/kg給藥之此IL-11功能阻斷抗體之顯著抑制(p<0.01)。統計檢驗:多重比較之單向ANOVA與Bonferroni校正,* *p<0.01;* * *p<0.001;ns=不顯著
圖14展示藉由Balb/c小鼠中雙互補位IL-11功能阻斷抗體TPP-29603 (圓形)及抗體TPP-29528 (菱形)及TPP-29519 (實心三角形)之等莫耳給藥之月經出血相比於對照IgG-抗體TPP-10159 (方形)減少。另外,亦展示較低劑量之抗體TPP-29519 (空心三角形)。實驗展現尤其等莫耳劑量之IL-11功能阻斷抗體TPP-29603及TPP-29519對月經出血之顯著抑制。顯著性檢驗:多重比較(對數標準化值)之單向ANOVA與鄧奈特事後檢驗(Dunnett's post-hoc test),* *p<0.01
圖15展示相比於2 mg/kg對照IgG-抗體TPP-10159 (方形)及0.143 mg/kg給藥之雙互補位IL-11功能阻斷TPP-29603 (空心三角形),Balb/c小鼠中每週兩次皮下給藥2 mg/kg(圓形)、0.7 mg/kg(菱形)及0.3 mg/kg(實心三角形) IL-11功能阻斷抗體TPP-29523的月經出血劑量依賴性減少,證明藉由所有測試劑量之IL-11功能阻斷抗體TPP-29523之顯著抑制(**p<0.01)。統計檢驗:多重比較之單向ANOVA與鄧奈特事後檢驗。
圖16:主要發現之淘選策略:描繪用於選擇經生物素標記之抗原的2種重要策略。在各輪選擇之前,包括關於不相關經生物素標記之蛋白質之消耗步驟。
圖17:用於測試人類抗IL-11抗體(a)或鼠類抗IL-11抗體(b)之雙複合物ELISA之示意圖。圖a)展示在競爭性IL-11抗體具有人類IgG型式時之雙複合物分析原理。首先,藉由微量滴定盤表面上之固定化鏈黴抗生物素蛋白捕獲經生物素標記之人類或鼠類IL-11。除非競爭性抗體以阻斷IL-11Ra之結合位點之方式結合至IL-11,否則鼠類IL-11Ra-小鼠-Fc融合蛋白將結合至所捕獲之經生物素標記之IL-11。結合至IL-11之鼠類IL-11Ra-小鼠-Fc的相對量係用抗小鼠POD試劑及基質偵測。圖b)展示在競爭性IL-11抗體具有鼠類IgG型式時之雙複合物分析原理。首先,藉由微量滴定盤表面上之固定化鏈黴抗生物素蛋白捕獲經生物素標記之人類或鼠類IL-11。除非競爭性抗體以阻斷IL-11Ra之結合位點之方式結合至IL-11,否則犬類IL-11Ra-人類-Fc融合蛋白將結合至所捕獲之經生物素標記之IL-11。結合至IL-11之犬類IL-11Ra-小鼠-Fc的相對量係用抗小鼠POD試劑及基質偵測。
圖18:用於測試人類抗IL-11抗體(a)或鼠類抗IL-11抗體(b)之三複合物分析型式之示意圖。圖a)展示在競爭性IL-11抗體具有人類IgG型式時之三複合物分析原理。首先,將抗小鼠Fc抗體作為捕捉試劑塗佈於微量滴定盤之表面上。隨後,向盤中添加小鼠IL-11Ra-小鼠-Fc融合蛋白、小鼠或人類IL-11、小鼠或人類gp130-人類-Fc融合蛋白及競爭性IL-11抗體之混合物。視測試小鼠還是人類IL-11而定,使用物種匹配之小鼠或人類gp130融合蛋白。小鼠-IL-11Ra、小鼠或人類IL-11及小鼠或人類gp130將形成三分子複合物,其將由經塗佈之抗小鼠Fc抗體捕獲且由經標記之抗小鼠或人類gp130抗體偵測(經由生物素標記及鏈黴抗生物素蛋白-POD標記)。然而,在以阻斷小鼠IL-11Ra與IL-11之間的相互作用或gp130與IL-11之間的相互作用的方式分別結合至小鼠之人類IL-11的競爭性抗體存在下,將不產生三分子複合物,且由鏈黴抗生物素蛋白過氧化酶產生之信號將減弱。值得注意的是,gp130融合蛋白中之人類Fc標籤不以此分析型式使用。
圖b)展示在競爭性IL-11抗體具有鼠類IgG型式時之三複合物分析原理。首先,將抗人類Fc抗體作為捕捉試劑塗佈於微量滴定盤之表面上。隨後,向盤中添加小鼠IL-11Ra-小鼠-Fc融合蛋白、小鼠或人類IL-11、小鼠或人類gp130-人類-Fc融合蛋白及競爭性IL-11抗體之混合物。視測試小鼠還是人類IL-11而定,使用物種匹配之小鼠或人類gp130-人類-Fc融合蛋白。小鼠-IL-11Ra、小鼠或人類IL-11及小鼠或人類gp130將形成三分子複合物,其將由經塗佈之抗人類Fc抗體捕獲且由經標記之抗小鼠IL-11Ra抗體偵測(經由生物素標記及鏈黴抗生物素蛋白-POD標記)。然而,在以阻斷小鼠IL-11Ra與IL-11之間的相互作用或gp130與IL-11之間的相互作用的方式分別結合至小鼠之人類IL-11的競爭性抗體存在下,將不產生三分子複合物,且由鏈黴抗生物素蛋白過氧化酶產生之信號將減弱。值得注意的是,小鼠Il-11Ra融合蛋白中之小鼠Fc標籤不以此分析型式使用。
圖19:第2輪親和力成熟TPP-18087之組合庫設計之圖示。所選突變展示在VHCDR2、VHCDR3、VLCDR1及VLCDR3之序列下方。
圖20:如實例34中所產生之雙特異性抗體的通用組成。將第一抗體(例如TPP-18068)之可變區轉移至scFv,該scFv融合至含有杵突變之人類IgG Fc域。將第二抗體(例如TPP-18087)之可變區轉移至scFv,該scFv融合至含有臼突變之人類IgG Fc域。在兩條鏈在宿主細胞中表現後,形成雙特異性抗體,其可藉由習知方法自培養物上清液純化。
圖21:二及三複合物ELISA中之IL-11抗體活性與三複合物而非雙複合物ELISA中之IL-11抗體活性之間缺乏競爭。圖a)展示由TPP-18068與塗佈在微量滴定盤上之人類IL-11之結合產生的相對螢光,及經由抗小鼠Fc抗體-POD結合物之後續偵測。在增加量之TPP-29536、含有TPP-18068衍生物之親和力成熟及人類Fc存在下信號減弱且在最高抗體濃度下完全阻斷。TPP-18068及TPP-29536在二及三複合物ELISA中為活性的。相比之下,增加濃度之TPP-29680、含有TPP-18087衍生物之親和力成熟及人類Fc不導致信號強度顯著降低。TPP-18087及TPP-29680在三複合物中而非雙複合物ELISA中為活性的。圖b)展示由TPP-18087與塗佈在微量滴定盤上之人類IL-11之結合產生的相對螢光,及經由抗小鼠Fc抗體-POD結合物之後續偵測。在增加量之TPP-29680存在下,信號減弱且在最高抗體濃度下完全阻斷。相比之下,增加濃度之TPP-29536不導致信號強度顯著降低。
<![CDATA[<110> 德商拜耳廠股份有限公司(Bayer AG)]]> <![CDATA[<120> 用於治療不正常子宮出血之IL-11或IL-11Ra抑制劑 ]]> <![CDATA[<130> BHC213043]]> <![CDATA[<140> TW 111107054]]> <![CDATA[<141> 2022-02-25]]> <![CDATA[<150> EP21159569.9]]> (151> 2021-02-26]]> <br/> <br/><![CDATA[<160> 197 ]]> <br/> <br/><![CDATA[<170> PatentIn version 3.5]]> <br/> <br/><![CDATA[<210> 1]]> <br/><![CDATA[<211> 199]]> <br/><![CDATA[<212> PRT]]> <br/><![CDATA[<213> 智人]]> <br/> <br/><![CDATA[<400> 1]]> <br/> <br/><![CDATA[Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Thr Ala Val Ala Pro Gly Pro Pro Pro Gly Pro Pro Arg Val Ser 20 25 30 Pro Asp Pro Arg Ala Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Leu Arg Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Gly Val Leu Thr Arg 85 90 95 Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Gly Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr 115 120 125 Leu Gln Ala Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro Pro 145 150 155 160 Leu Ala Pro Pro Ser Ser Ala Trp Gly Gly Ile Arg Ala Ala His Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 <![CDATA[<210> 2]]> <![CDATA[<211> 120]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Met Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Gly Val Leu Thr 1 5 10 15 Arg Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu 20 25 30 Arg Arg Ala Gly Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly 35 40 45 Thr Leu Gln Ala Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu 50 55 60 Met Ser Arg Leu Ala Leu Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro 65 70 75 80 Pro Leu Ala Pro Pro Ser Ser Ala Trp Gly Gly Ile Arg Ala Ala His 85 90 95 Ala Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly 100 105 110 Leu Leu Leu Leu Lys Thr Arg Leu 115 120 <![CDATA[<210> 3]]> <![CDATA[<211> 422]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Met Ser Ser Ser Cys Ser Gly Leu Ser Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ala Ser Ser Pro Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Ser Val Lys Leu Cys Cys 35 40 45 Pro Gly Val Thr Ala Gly Asp Pro Val Ser Trp Phe Arg Asp Gly Glu 50 55 60 Pro Lys Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Glu Leu Val 65 70 75 80 Leu Ala Gln Ala Asp Ser Thr Asp Glu Gly Thr Tyr Ile Cys Gln Thr 85 90 95 Leu Asp Gly Ala Leu Gly Gly Thr Val Thr Leu Gln Leu Gly Tyr Pro 100 105 110 Pro Ala Arg Pro Val Val Ser Cys Gln Ala Ala Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Ser Gln Ile Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Val Leu Gly Ala Asp Ser Gln Arg 145 150 155 160 Arg Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Gly 165 170 175 Ala Ala Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Gln Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Arg Leu Leu 195 200 205 Asp Val Ser Leu Gln Ser Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Tyr Pro Arg Arg Leu Arg Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Pro Cys Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Glu 260 265 270 Pro Ala Gly Leu Glu Glu Val Ile Thr Asp Ala Val Ala Gly Leu Pro 275 280 285 His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp Ala Gly Thr Trp 290 295 300 Ser Thr Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser Thr Gly Thr Ile 305 310 315 320 Pro Lys Glu Ile Pro Ala Trp Gly Gln Leu His Thr Gln Pro Glu Val 325 330 335 Glu Pro Gln Val Asp Ser Pro Ala Pro Pro Arg Pro Ser Leu Gln Pro 340 345 350 His Pro Arg Leu Leu Asp His Arg Asp Ser Val Glu Gln Val Ala Val 355 360 365 Leu Ala Ser Leu Gly Ile Leu Ser Phe Leu Gly Leu Val Ala Gly Ala 370 375 380 Leu Ala Leu Gly Leu Trp Leu Arg Leu Arg Arg Gly Gly Lys Asp Gly 385 390 395 400 Ser Pro Lys Pro Gly Phe Leu Ala Ser Val Ile Pro Val Asp Arg Arg 405 410 415 Pro Gly Ala Pro Asn Leu 420 <![CDATA[<210> 4]]> <![CDATA[<211> 390]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Met Ser Ser Ser Cys Ser Gly Leu Ser Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ala Ser Ser Pro Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Ser Val Lys Leu Cys Cys 35 40 45 Pro Gly Val Thr Ala Gly Asp Pro Val Ser Trp Phe Arg Asp Gly Glu 50 55 60 Pro Lys Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Glu Leu Val 65 70 75 80 Leu Ala Gln Ala Asp Ser Thr Asp Glu Gly Thr Tyr Ile Cys Gln Thr 85 90 95 Leu Asp Gly Ala Leu Gly Gly Thr Val Thr Leu Gln Leu Gly Tyr Pro 100 105 110 Pro Ala Arg Pro Val Val Ser Cys Gln Ala Ala Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Ser Gln Ile Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Val Leu Gly Ala Asp Ser Gln Arg 145 150 155 160 Arg Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Gly 165 170 175 Ala Ala Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Gln Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Arg Leu Leu 195 200 205 Asp Val Ser Leu Gln Ser Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Tyr Pro Arg Arg Leu Arg Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Pro Cys Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Glu 260 265 270 Pro Ala Gly Leu Glu Glu Val Ile Thr Asp Ala Val Ala Gly Leu Pro 275 280 285 His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp Ala Gly Thr Trp 290 295 300 Ser Thr Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser Thr Gly Thr Ile 305 310 315 320 Pro Lys Glu Ile Pro Ala Trp Gly Gln Leu His Thr Gln Pro Glu Val 325 330 335 Glu Pro Gln Val Asp Ser Pro Ala Pro Pro Arg Pro Ser Leu Gln Pro 340 345 350 His Pro Arg Leu Leu Asp His Arg Asp Ser Val Glu Gln Val Ala Val 355 360 365 Leu Ala Ser Leu Gly Ile Leu Ser Phe Leu Gly Leu Val Ala Gly Ala 370 375 380 Leu Ala Leu Gly Leu Trp 385 390 <![CDATA[<210> 5]]> <![CDATA[<211> 2378]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> actgccgcgg ccctgctgct cagggcacat gcctcccctc cccaggccgc ggcccagctg 60 accctcgggg ctcccccggc agcggacagg gaagggttaa aggcccccgg ctccctgccc 120 cctgccctgg ggaacccctg gccctgtggg gacatgaact gtgtttgccg cctggtcctg 180 gtcgtgctga gcctgtggcc agatacagct gtcgcccctg ggccaccacc tggcccccct 240 cgagtttccc cagaccctcg ggccgagctg gacagcaccg tgctcctgac ccgctctctc 300 ctggcggaca cgcggcagct ggctgcacag ctgagggaca aattcccagc tgacggggac 360 cacaacctgg attccctgcc caccctggcc atgagtgcgg gggcactggg agctctacag 420 ctcccaggtg tgctgacaag gctgcgagcg gacctactgt cctacctgcg gcacgtgcag 480 tggctgcgcc gggcaggtgg ctcttccctg aagaccctgg agcccgagct gggcaccctg 540 caggcccgac tggaccggct gctgcgccgg ctgcagctcc tgatgtcccg cctggccctg 600 ccccagccac ccccggaccc gccggcgccc ccgctggcgc ccccctcctc agcctggggg 660 ggcatcaggg ccgcccacgc catcctgggg gggctgcacc tgacacttga ctgggccgtg 720 aggggactgc tgctgctgaa gactcggctg tgacccgggg cccaaagcca ccaccgtcct 780 tccaaagcca gatcttattt atttatttat ttcagtactg ggggcgaaac agccaggtga 840 tccccccgcc attatctccc cctagttaga gacagtcctt ccgtgaggcc tggggggcat 900 ctgtgcctta tttatactta tttatttcag gagcaggggt gggaggcagg tggactcctg 960 ggtccccgag gaggagggga ctggggtccc ggattcttgg gtctccaaga agtctgtcca 1020 cagacttctg ccctggctct tccccatcta ggcctgggca ggaacatata ttatttattt 1080 aagcaattac ttttcatgtt ggggtgggga cggaggggaa agggaagcct gggtttttgt 1140 acaaaaatgt gagaaacctt tgtgagacag agaacaggga attaaatgtg tcatacatat 1200 ccacttgagg gcgatttgtc tgagagctgg ggctggatgc ttgggtaact ggggcagggc 1260 aggtggaggg gagacctcca ttcaggtgga ggtcccgagt gggcggggca gcgactggga 1320 gatgggtcgg tcacccagac agctctgtgg aggcagggtc tgagccttgc ctggggcccc 1380 gcactgcata gggccttttg tttgtttttt gagatggagt ctcgctctgt tgcctaggct 1440 ggagtgcagt gaggcaatct gaggtcactg caacctccac ctcccgggtt caagcaattc 1500 tcctgcctca gcctcccgat tagctgggat cacaggtgtg caccaccatg cccagctaat 1560 tatttatttc ttttgtattt ttagtagaga cagggtttca ccatgttggc caggctggtt 1620 tcgaactcct gacctcaggt gatcctcctg cctcggcctc ccaaagtgct gggattacag 1680 gtgtgagcca ccacacctga cccataggtc ttcaataaat atttaatgga aggttccaca 1740 agtcaccctg tgatcaacag tacccgtatg ggacaaagct gcaaggtcaa gatggttcat 1800 tatggctgtg ttcaccatag caaactggaa acaatctaga tatccaacag tgagggttaa 1860 gcaacatggt gcatctgtgg atagaacgcc acccagccgc ccggagcagg gactgtcatt 1920 cagggaggct aaggagagag gcttgcttgg gatatagaaa gatatcctga cattggccag 1980 gcatggtggc tcacgcctgt aatcctggca ctttgggagg acgaagcgag tggatcactg 2040 aagtccaaga gttcgagacc ggcctgcgag acatggcaaa accctgtctc aaaaaagaaa 2100 gaatgatgtc ctgacatgaa acagcaggct acaaaaccac tgcatgctgt gatcccaatt 2160 ttgtgttttt ctttctatat atggattaaa acaaaaatcc taaagggaaa tacgccaaaa 2220 tgttgacaat gactgtctcc aggtcaaagg agagaggtgg gattgtgggt gacttttaat 2280 gtgtatgatt gtctgtattt tacagaattt ctgccatgac tgtgtatttt gcatgacaca 2340 ttttaaaaat aataaacact atttttagaa taacagaa 2378 <![CDATA[<210> 6]]> <![CDATA[<211> 2208]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> actgccgcgg ccctgctgct cagggcacat gcctcccctc cccaggccgc ggcccagctg 60 accctcgggg ctcccccggc agcggacagg gaagggttaa aggcccccgg ctccctgccc 120 cctgccctgg ggaacccctg gccctgtggg gacatgaact agggacaaat tcccagctga 180 cggggaccac aacctggatt ccctgcccac cctggccatg agtgcggggg cactgggagc 240 tctacagctc ccaggtgtgc tgacaaggct gcgagcggac ctactgtcct acctgcggca 300 cgtgcagtgg ctgcgccggg caggtggctc ttccctgaag accctggagc ccgagctggg 360 caccctgcag gcccgactgg accggctgct gcgccggctg cagctcctga tgtcccgcct 420 ggccctgccc cagccacccc cggacccgcc ggcgcccccg ctggcgcccc cctcctcagc 480 ctgggggggc atcagggccg cccacgccat cctggggggg ctgcacctga cacttgactg 540 ggccgtgagg ggactgctgc tgctgaagac tcggctgtga cccggggccc aaagccacca 600 ccgtccttcc aaagccagat cttatttatt tatttatttc agtactgggg gcgaaacagc 660 caggtgatcc ccccgccatt atctccccct agttagagac agtccttccg tgaggcctgg 720 ggggcatctg tgccttattt atacttattt atttcaggag caggggtggg aggcaggtgg 780 actcctgggt ccccgaggag gaggggactg gggtcccgga ttcttgggtc tccaagaagt 840 ctgtccacag acttctgccc tggctcttcc ccatctaggc ctgggcagga acatatatta 900 tttatttaag caattacttt tcatgttggg gtggggacgg aggggaaagg gaagcctggg 960 tttttgtaca aaaatgtgag aaacctttgt gagacagaga acagggaatt aaatgtgtca 1020 tacatatcca cttgagggcg atttgtctga gagctggggc tggatgcttg ggtaactggg 1080 gcagggcagg tggaggggag acctccattc aggtggaggt cccgagtggg cggggcagcg 1140 actgggagat gggtcggtca cccagacagc tctgtggagg cagggtctga gccttgcctg 1200 gggccccgca ctgcataggg ccttttgttt gttttttgag atggagtctc gctctgttgc 1260 ctaggctgga gtgcagtgag gcaatctgag gtcactgcaa cctccacctc ccgggttcaa 1320 gcaattctcc tgcctcagcc tcccgattag ctgggatcac aggtgtgcac caccatgccc 1380 agctaattat ttatttcttt tgtattttta gtagagacag ggtttcacca tgttggccag 1440 gctggtttcg aactcctgac ctcaggtgat cctcctgcct cggcctccca aagtgctggg 1500 attacaggtg tgagccacca cacctgaccc ataggtcttc aataaatatt taatggaagg 1560 ttccacaagt caccctgtga tcaacagtac ccgtatggga caaagctgca aggtcaagat 1620 ggttcattat ggctgtgttc accatagcaa actggaaaca atctagatat ccaacagtga 1680 gggttaagca acatggtgca tctgtggata gaacgccacc cagccgcccg gagcagggac 1740 tgtcattcag ggaggctaag gagagaggct tgcttgggat atagaaagat atcctgacat 1800 tggccaggca tggtggctca cgcctgtaat cctggcactt tgggaggacg aagcgagtgg 1860 atcactgaag tccaagagtt cgagaccggc ctgcgagaca tggcaaaacc ctgtctcaaa 1920 aaagaaagaa tgatgtcctg acatgaaaca gcaggctaca aaaccactgc atgctgtgat 1980 cccaattttg tgtttttctt tctatatatg gattaaaaca aaaatcctaa agggaaatac 2040 gccaaaatgt tgacaatgac tgtctccagg tcaaaggaga gaggtgggat tgtgggtgac 2100 ttttaatgtg tatgattgtc tgtattttac agaatttctg ccatgactgt gtattttgca 2160 tgacacattt taaaaataat aaacactatt tttagaataa cagaaaaa 2208 <![CDATA[<210> 7]]> <![CDATA[<211> 1728]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> agagggcgag ggcgagggca gagggcgctg gcggcagcgg ccgcggaaga tgagcagcag 60 ctgctcaggg ctgagcaggg tcctggtggc cgtggctaca gccctggtgt ctgcctcctc 120 cccctgcccc caggcctggg gccccccagg ggtccagtat gggcagccag gcaggtccgt 180 gaagctgtgt tgtcctggag tgactgccgg ggacccagtg tcctggtttc gggatgggga 240 gccaaagctg ctccagggac ctgactctgg gctagggcat gaactggtcc tggcccaggc 300 agacagcact gatgagggca cctacatctg ccagaccctg gatggtgcac ttgggggcac 360 agtgaccctg cagctgggct accctccagc ccgccctgtt gtctcctgcc aagcagccga 420 ctatgagaac ttctcttgca cttggagtcc cagccagatc agcggtttac ccacccgcta 480 cctcacctcc tacaggaaga agacagtcct aggagctgat agccagagga ggagtccatc 540 cacagggccc tggccatgcc cacaggatcc cctaggggct gcccgctgtg ttgtccacgg 600 ggctgagttc tggagccagt accggattaa tgtgactgag gtgaacccac tgggtgccag 660 cacacgcctg ctggatgtga gcttgcagag catcttgcgc cctgacccac cccagggcct 720 gcgggtagag tcagtaccag gttacccccg acgcctgcga gccagctgga cataccctgc 780 ctcctggccg tgccagcccc acttcctgct caagttccgt ttgcagtacc gtccggcgca 840 gcatccagcc tggtccacgg tggagccagc tggactggag gaggtgatca cagatgctgt 900 ggctgggctg ccccatgctg tacgagtcag tgcccgggac tttctagatg ctggcacctg 960 gagcacctgg agcccggagg cctggggaac tccgagcact gggaccatac caaaggagat 1020 accagcatgg ggccagctac acacgcagcc agaggtggag cctcaggtgg acagccctgc 1080 tcctccaagg ccctccctcc aaccacaccc tcggctactt gatcacaggg actctgtgga 1140 gcaggtagct gtgctggcgt ctttgggaat cctttctttc ctgggactgg tggctggggc 1200 cctggcactg gggctctggc tgaggctgag acggggtggg aaggatggat ccccaaagcc 1260 tgggttcttg gcctcagtga ttccagtgga caggcgtcca ggagctccaa acctgtagag 1320 gacccaggag ggcttcggca gattccacct ataattctgt cttgctggtg tggatagaaa 1380 ccaggcagga cagtagatcc ctatggttgg atctcagctg gaagttctgt ttggagccca 1440 tttctgtgag accctgtatt tcaaatttgc agctgaaagg tgcttgtacc tctgatttca 1500 ccccagagtt ggagttctgc tcaaggaacg tgtgtaatgt gtacatctgt gtccatgtgt 1560 gaccatgtgt ctgtgaggca gggaacatgt attctctgca tgcatgtatg taggtgcctg 1620 gggagtgtgt gtgggtcctt ggctcttggc ctttcccctt gcaggggttg tgcaggtgtg 1680 aataaagaga ataaggaagt tcttggagat tatactcaga aaaaaaaa 1728 <![CDATA[<210> 8]]> <![CDATA[<211> 432]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 8]]> Met Ser Ser Ser Cys Ser Gly Leu Thr Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ser Ser Ser Pro Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Pro Val Met Leu Cys Cys 35 40 45 Pro Gly Val Ser Ala Gly Thr Pro Val Ser Trp Phe Arg Asp Gly Asp 50 55 60 Ser Arg Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Arg Leu Val 65 70 75 80 Leu Ala Gln Val Asp Ser Pro Asp Glu Gly Thr Tyr Val Cys Gln Thr 85 90 95 Leu Asp Gly Val Ser Gly Gly Met Val Thr Leu Lys Leu Gly Phe Pro 100 105 110 Pro Ala Arg Pro Glu Val Ser Cys Gln Ala Val Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Gly Gln Val Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Leu Pro Gly Ala Glu Ser Gln Arg 145 150 155 160 Glu Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Glu 165 170 175 Ala Ser Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Glu Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Cys Leu Leu 195 200 205 Asp Val Arg Leu Gln Ser Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Tyr Pro Arg Arg Leu His Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Arg Arg Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Glu 260 265 270 Pro Ile Gly Leu Glu Glu Val Ile Thr Asp Ala Val Ala Gly Leu Pro 275 280 285 His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp Ala Gly Thr Trp 290 295 300 Ser Ala Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser Thr Gly Pro Leu 305 310 315 320 Gln Asp Glu Ile Pro Asp Trp Ser Gln Gly His Gly Gln Gln Leu Glu 325 330 335 Ala Val Val Ala Gln Glu Asp Ser Pro Ala Pro Ala Arg Pro Ser Leu 340 345 350 Gln Pro Asp Pro Arg Pro Leu Asp His Arg Asp Pro Leu Glu Gln Val 355 360 365 Ala Val Leu Ala Ser Leu Gly Ile Phe Ser Cys Leu Gly Leu Ala Val 370 375 380 Gly Ala Leu Ala Leu Gly Leu Trp Leu Arg Leu Arg Arg Ser Gly Lys 385 390 395 400 Asp Gly Pro Gln Lys Pro Gly Leu Leu Ala Pro Met Ile Pro Val Glu 405 410 415 Lys Leu Pro Gly Ile Pro Asn Leu Gln Arg Thr Pro Glu Asn Phe Ser 420 425 430 <![CDATA[<210> 9]]> <![CDATA[<211> 432]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 9]]> Met Ser Ser Ser Cys Ser Gly Leu Thr Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ser Ser Ser Pro Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Pro Val Met Leu Cys Cys 35 40 45 Pro Gly Val Ser Ala Gly Thr Pro Val Ser Trp Phe Arg Asp Gly Asp 50 55 60 Ser Arg Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Arg Leu Val 65 70 75 80 Leu Ala Gln Val Asp Ser Pro Asp Glu Gly Thr Tyr Val Cys Gln Thr 85 90 95 Leu Asp Gly Val Ser Gly Gly Met Val Thr Leu Lys Leu Gly Phe Pro 100 105 110 Pro Ala Arg Pro Glu Val Ser Cys Gln Ala Val Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Gly Gln Val Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Leu Pro Gly Ala Glu Ser Gln Arg 145 150 155 160 Glu Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Glu 165 170 175 Ala Ser Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Glu Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Cys Leu Leu 195 200 205 Asp Val Arg Leu Gln Ser Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Tyr Pro Arg Arg Leu His Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Arg Arg Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Glu 260 265 270 Pro Ile Gly Leu Glu Glu Val Ile Thr Asp Thr Val Ala Gly Leu Pro 275 280 285 His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp Ala Gly Thr Trp 290 295 300 Ser Ala Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser Thr Gly Leu Leu 305 310 315 320 Gln Asp Glu Ile Pro Asp Trp Ser Gln Gly His Gly Gln Gln Leu Glu 325 330 335 Ala Val Val Ala Gln Glu Asp Ser Leu Ala Pro Ala Arg Pro Ser Leu 340 345 350 Gln Pro Asp Pro Arg Pro Leu Asp His Arg Asp Pro Leu Glu Gln Val 355 360 365 Ala Val Leu Ala Ser Leu Gly Ile Phe Ser Cys Leu Gly Leu Ala Val 370 375 380 Gly Ala Leu Ala Leu Gly Leu Trp Leu Arg Leu Arg Arg Ser Gly Lys 385 390 395 400 Glu Gly Pro Gln Lys Pro Gly Leu Leu Ala Pro Met Ile Pro Val Glu 405 410 415 Lys Leu Pro Gly Ile Pro Asn Leu Gln Arg Thr Pro Glu Asn Phe Ser 420 425 430 <![CDATA[<210> 10]]> <![CDATA[<211> 1761]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 10]]> tattggcgct gggaggagcc gcccccactg cctgcgctca gcactggagg gagcagaggc 60 cggggcagag ggtgagggcg gagggcgctg gcggcggctg ccgcagaaga tgagcagcag 120 ctgctcaggg ctgaccaggg tcctggtggc cgtggctaca gccctggtgt cttcctcctc 180 cccctgcccc caagcttggg gtcctccagg ggtccagtat ggacaacctg gcaggcccgt 240 gatgctgtgc tgccccggag tgagtgctgg gactccagtg tcctggtttc gggatggaga 300 ttcaaggctg ctccagggac ctgactctgg gttaggacac agactggtct tggcccaggt 360 ggacagccct gatgaaggca cttatgtctg ccagaccctg gatggtgtat cagggggcat 420 ggtgaccctg aagctgggct ttcccccagc acgtcctgaa gtctcctgcc aagcggtaga 480 ctatgaaaac ttctcctgta cttggagtcc aggccaggtc agcggtttgc ccacccgcta 540 ccttacttcc tacaggaaga agacgctgcc aggagctgag agtcagaggg aaagtccatc 600 caccgggcct tggccgtgtc cacaggaccc tctggaggcc tcccgatgtg tggtccatgg 660 ggcagagttc tggagtgagt accggatcaa tgtgaccgag gtgaacccac tgggtgccag 720 cacgtgccta ctggatgtga gattacagag catcttgcgt cctgatccac cccaaggact 780 gcgggtggaa tccgtacctg gttacccgag acgcctgcat gccagctgga cataccctgc 840 ctcctggcgt cgccaacccc actttctgct caagttccgg ttgcaatacc gaccagcaca 900 gcatccagcc tggtccacgg tggagcccat tggcttggag gaagtgataa cagatgctgt 960 ggctgggctg ccacacgcgg tacgagtcag tgccagggac tttctggatg ctggcacctg 1020 gagcgcctgg agcccagagg cctggggtac tcctagcact ggtcccctgc aggatgagat 1080 acctgattgg agccagggac acggacagca gctagaggca gtagtagctc aggaggacag 1140 cccggctcct gcaaggcctt ccttgcagcc ggacccaagg ccacttgatc acagggaccc 1200 cttggagcaa gtagctgtgt tagcgtctct gggaatcttc tcttgccttg gcctggctgt 1260 tggagctctg gcactggggc tctggctgag gctgagacgg agtgggaagg atggaccgca 1320 aaaacctggg ctcttggcac ccatgatccc ggtggaaaag cttccaggaa ttccaaacct 1380 gcagaggacc ccagagaact tcagctgatt tcatctgtaa cccggtcaga cttgggtggt 1440 taaaaggaca ggcagaaaga ggcggggcag tggatccctg tggatggagg tctcagctga 1500 aagtctgagc tcttttcttt gacacctata ctccaaactt gctgccggct gaaggctgtc 1560 tggacttccg atgtcctgag gtggaagtcc acctgaggaa tgtgtacaga agtctgtgtt 1620 cctgtgatcg tgtgtgtatg tgagacaggg agcaaaagtt ctctgcatgt gtgtacagat 1680 gattggagag tgtgtgcggt cttgggcttg gcccttctgg gaagtgtgaa gagttgaaat 1740 aaaagagacg gaagtttttg g 1761 <![CDATA[<210> 11]]> <![CDATA[<211> 2680]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 11]]> gactcagtcc agaccccttc ccccccgcct ggggtcaggg ctggacaggg aggagaagcg 60 agctccttgc aagacgagtt ggggacgaga tagctagtga ccctggcctt ggctgacccg 120 aaagaggcct ggagacatct gtcctcaaag gattgtccac ttccggtgac tccctgctgc 180 tgataatagg gcccatgttt cccagaaggc ccgaggttat cccaagactg cttctctccc 240 ttcacctccc atggcttcat tcctgaagag cctgtgatca cttagggtca gaaatagacg 300 gatgagcagc agctgctcag ggctgaccag ggtcctggtg gccgtggcta cagccctggt 360 gtcttcctcc tccccctgcc cccaagcttg gggtcctcca ggggtccagt atggacaacc 420 tggcaggccc gtgatgctgt gctgccccgg agtgagtgct gggactccag tgtcctggtt 480 tcgggatgga gattcaaggc tgctccaggg acctgactct gggttaggac acagactggt 540 cttggcccag gtggacagcc ctgatgaagg cacttatgtc tgccagaccc tggatggtgt 600 atcagggggc atggtgaccc tgaagctggg ctttccccca gcacgtcctg aagtctcttg 660 ccaagcggta gactatgaaa acttctcctg tacttggagt ccaggccagg tcagcggttt 720 gcccacccgc taccttactt cctacaggaa gaagacgctg ccaggagctg agagtcagag 780 ggaaagtcca tccaccgggc cttggccgtg tccacaggac cctctggagg cctcccgatg 840 tgtggtccat ggggcagagt tctggagtga gtaccggatc aatgtgaccg aggtgaaccc 900 actgggtgcc agcacgtgcc tactggatgt gagattacag agcatcttgc gtcccgatcc 960 accccaagga ctgcgggtgg aatccgtacc tggttaccca agacgcctgc atgccagctg 1020 gacataccct gcctcctggc gtcgccaacc ccactttctg ctcaagttcc ggttgcaata 1080 ccgaccagca cagcatccag cctggtccac ggtggagccc attggcttgg aggaagtgat 1140 aacagatact gtggctgggc tgccccacgc ggtacgagtc agtgccaggg actttctgga 1200 tgctggcacc tggagcgcct ggagcccaga ggcctggggt actcctagca ctggtctcct 1260 gcaggatgag atacctgatt ggagccaggg acatggacag cagctagagg cagtagtagc 1320 tcaggaggac agcctggctc ctgcaaggcc ttccttgcag ccagacccaa ggccacttga 1380 tcacagggat cccttggagc aagtagctgt gttagcatct ctgggaatct tctcttgcct 1440 tggcctggct gttggagccc tggcactggg gctctggctg aggctgagac ggagtgggaa 1500 ggaaggaccg caaaaacctg ggctcttggc acccatgatc ccggtggaaa agcttccagg 1560 aattccaaac ctgcagagga ccccagagaa cttcagctga tttcatctgt aacccggtca 1620 gacttgggtg gttaaaagga caggcagaaa gaggcggggc agtggatccc tgtggatgga 1680 ggtctcagct ggaagtctga gctcttttct ttgacaccta tactccaaac ttgctgccgg 1740 ctgaaggctg tctggacttc tgatgtcctg aggtggaagt ccacctgagg aatgtgtaca 1800 gaagtctgtg ttcctgtgat cgtgtgtgta tgtgagacag ggagcaaaag ttctctgcat 1860 gtgtgtacac atgattggag agtgtgtgcg gtcttgggct tggcccttct ggggagtgtg 1920 aagagttgaa ataaaagaga cggaagtttt tggagattgt cgtctaatgt tgctttatta 1980 gttttgctgt tgggggtgtg agtacatttt cttttgtagt accagattta aactgggtac 2040 agttccttgg agccttttcc cttggcgttc taaccaccga gccaggctgc ggttctgggg 2100 atgaacacag acactgcgcc gagccaggtg aagcctgaga agggaaaagt ccaaagctag 2160 gctcacattt gggggatgag cttaggtagg gttcaggggt taggggtaaa agcccgatga 2220 aaatccgggt aggtattaga gttagtaaag gggctaggga tgaatattgg gggttcggac 2280 tgagggcaga gttagaggta tcaaagttgg gggcagagct cacacgacag cctggaggtg 2340 acagtcccca tcagcctcct gcagttccat gtggacaatc ctcctcagca gcctgcttgg 2400 gagtggctgt ctatagagct gagtacagca gctagtgctg gagggcagag gcaaggctgg 2460 agaacaatag ggccacactt cagagaggtc tggacccaca agctgctctg attacatagc 2520 tagaggtcca actttctggg ccctgttccc tgtagtcccc tcgctcagca ttcattctat 2580 ggcctctgag aacttacctg cttcaggagc cgggctcaga agcaacagta acagcgggag 2640 gctgctggcg ggggagagcc cctccatcat gctcactcag 2680 <![CDATA[<210> 12]]> <![CDATA[<211> 918]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 12]]> Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu 1 5 10 15 Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser 20 25 30 Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys 35 40 45 Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr 50 55 60 Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr 65 70 75 80 Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser 85 90 95 Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu 100 105 110 Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys 115 120 125 Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys 130 135 140 Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu 145 150 155 160 Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg 165 170 175 Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val 180 185 190 Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr 195 200 205 Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro 210 215 220 Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu 225 230 235 240 Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys 245 250 255 Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile 260 265 270 Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp 275 280 285 Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu 290 295 300 Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile 305 310 315 320 Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Ile 325 330 335 Asp Pro Ser His Thr Gln Gly Tyr Arg Thr Val Gln Leu Val Trp Lys 340 345 350 Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val 355 360 365 Thr Leu Thr Arg Trp Lys Ser His Leu Gln Asn Tyr Thr Val Asn Ala 370 375 380 Thr Lys Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Leu Ala Thr Leu 385 390 395 400 Thr Val Arg Asn Leu Val Gly Lys Ser Asp Ala Ala Val Leu Thr Ile 405 410 415 Pro Ala Cys Asp Phe Gln Ala Thr His Pro Val Met Asp Leu Lys Ala 420 425 430 Phe Pro Lys Asp Asn Met Leu Trp Val Glu Trp Thr Thr Pro Arg Glu 435 440 445 Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Asp Lys Ala 450 455 460 Pro Cys Ile Thr Asp Trp Gln Gln Glu Asp Gly Thr Val His Arg Thr 465 470 475 480 Tyr Leu Arg Gly Asn Leu Ala Glu Ser Lys Cys Tyr Leu Ile Thr Val 485 490 495 Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser Pro Glu Ser Ile Lys Ala 500 505 510 Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly Pro Thr Val Arg Thr Lys 515 520 525 Lys Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp Gln Leu Pro Val 530 535 540 Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr Thr Ile Phe Tyr Arg Thr 545 550 555 560 Ile Ile Gly Asn Glu Thr Ala Val Asn Val Asp Ser Ser His Thr Glu 565 570 575 Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr Leu Tyr Met Val Arg Met 580 585 590 Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe 595 600 605 Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro 610 615 620 Val Cys Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys 625 630 635 640 Phe Asn Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro 645 650 655 Asp Pro Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro 660 665 670 Arg His Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser Asp Gly Asn Phe 675 680 685 Thr Asp Val Ser Val Val Glu Ile Glu Ala Asn Asp Lys Lys Pro Phe 690 695 700 Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe Lys Lys Glu Lys Ile Asn 705 710 715 720 Thr Glu Gly His Ser Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser 725 730 735 Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu Asn Glu Ser Ser Gln Asn 740 745 750 Thr Ser Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg 755 760 765 His Gln Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln 770 775 780 Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu Val Asp 785 790 795 800 His Val Asp Gly Gly Asp Gly Ile Leu Pro Arg Gln Gln Tyr Phe Lys 805 810 815 Gln Asn Cys Ser Gln His Glu Ser Ser Pro Asp Ile Ser His Phe Glu 820 825 830 Arg Ser Lys Gln Val Ser Ser Val Asn Glu Glu Asp Phe Val Arg Leu 835 840 845 Lys Gln Gln Ile Ser Asp His Ile Ser Gln Ser Cys Gly Ser Gly Gln 850 855 860 Met Lys Met Phe Gln Glu Val Ser Ala Ala Asp Ala Phe Gly Pro Gly 865 870 875 880 Thr Glu Gly Gln Val Glu Arg Phe Glu Thr Val Gly Met Glu Ala Ala 885 890 895 Thr Asp Glu Gly Met Pro Lys Ser Tyr Leu Pro Gln Thr Val Arg Gln 900 905 910 Gly Gly Tyr Met Pro Gln 915 <![CDATA[<210> 13]]> <![CDATA[<211> 329]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 13]]> Met Leu Thr Leu Gln Thr Trp Leu Val Gln Ala Leu Phe Ile Phe Leu 1 5 10 15 Thr Thr Glu Ser Thr Gly Glu Leu Leu Asp Pro Cys Gly Tyr Ile Ser 20 25 30 Pro Glu Ser Pro Val Val Gln Leu His Ser Asn Phe Thr Ala Val Cys 35 40 45 Val Leu Lys Glu Lys Cys Met Asp Tyr Phe His Val Asn Ala Asn Tyr 50 55 60 Ile Val Trp Lys Thr Asn His Phe Thr Ile Pro Lys Glu Gln Tyr Thr 65 70 75 80 Ile Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Ile Ala Ser 85 90 95 Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu Thr Phe Gly Gln Leu Glu 100 105 110 Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser Gly Leu Pro Pro Glu Lys 115 120 125 Pro Lys Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Lys Met Arg Cys 130 135 140 Glu Trp Asp Gly Gly Arg Glu Thr His Leu Glu Thr Asn Phe Thr Leu 145 150 155 160 Lys Ser Glu Trp Ala Thr His Lys Phe Ala Asp Cys Lys Ala Lys Arg 165 170 175 Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr Ser Thr Val Tyr Phe Val 180 185 190 Asn Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Thr 195 200 205 Ser Asp His Ile Asn Phe Asp Pro Val Tyr Lys Val Lys Pro Asn Pro 210 215 220 Pro His Asn Leu Ser Val Ile Asn Ser Glu Glu Leu Ser Ser Ile Leu 225 230 235 240 Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys Ser Val Ile Ile Leu Lys 245 250 255 Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ser Gln Ile 260 265 270 Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser Ser Phe Thr Val Gln Asp 275 280 285 Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Cys Met Lys Glu 290 295 300 Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Ile 305 310 315 320 Thr Tyr Glu Asp Asn Ile Ala Ser Phe 325 <![CDATA[<210> 14]]> <![CDATA[<211> 9027]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 14]]> ggatctgaca gtgttccgga gccggggcga gcagccaaaa ggcccgcgga gtcgcgctgg 60 gccgccccgg cgcagctgaa ccgggggccg cgcctgccag gccgacgggt ctggcccagc 120 ctggcgccaa ggggttcgtg cgctgtggag acgcggaggg tcgaggcggc gcggcctgag 180 tgaaacccaa tggaaaaagc atgacattta gaagtagaag acttagcttc aaatccctac 240 tccttcactt actaattttg tgatttggaa atatccgcgc aagatgttga cgttgcagac 300 ttggctagtg caagccttgt ttattttcct caccactgaa tctacaggtg aacttctaga 360 tccatgtggt tatatcagtc ctgaatctcc agttgtacaa cttcattcta atttcactgc 420 agtttgtgtg ctaaaggaaa aatgtatgga ttattttcat gtaaatgcta attacattgt 480 ctggaaaaca aaccatttta ctattcctaa ggagcaatat actatcataa acagaacagc 540 atccagtgtc acctttacag atatagcttc attaaatatt cagctcactt gcaacattct 600 tacattcgga cagcttgaac agaatgttta tggaatcaca ataatttcag gcttgcctcc 660 agaaaaacct aaaaatttga gttgcattgt gaacgagggg aagaaaatga ggtgtgagtg 720 ggatggtgga agggaaacac acttggagac aaacttcact ttaaaatctg aatgggcaac 780 acacaagttt gctgattgca aagcaaaacg tgacaccccc acctcatgca ctgttgatta 840 ttctactgtg tattttgtca acattgaagt ctgggtagaa gcagagaatg cccttgggaa 900 ggttacatca gatcatatca attttgatcc tgtatataaa gtgaagccca atccgccaca 960 taatttatca gtgatcaact cagaggaact gtctagtatc ttaaaattga catggaccaa 1020 cccaagtatt aagagtgtta taatactaaa atataacatt caatatagga ccaaagatgc 1080 ctcaacttgg agccagattc ctcctgaaga cacagcatcc acccgatctt cattcactgt 1140 ccaagacctt aaacctttta cagaatatgt gtttaggatt cgctgtatga aggaagatgg 1200 taagggatac tggagtgact ggagtgaaga agcaagtggg atcacctatg aagatagacc 1260 atctaaagca ccaagtttct ggtataaaat agatccatcc catactcaag gctacagaac 1320 tgtacaactc gtgtggaaga cattgcctcc ttttgaagcc aatggaaaaa tcttggatta 1380 tgaagtgact ctcacaagat ggaaatcaca tttacaaaat tacacagtta atgccacaaa 1440 actgacagta aatctcacaa atgatcgcta tctagcaacc ctaacagtaa gaaatcttgt 1500 tggcaaatca gatgcagctg ttttaactat ccctgcctgt gactttcaag ctactcaccc 1560 tgtaatggat cttaaagcat tccccaaaga taacatgctt tgggtggaat ggactactcc 1620 aagggaatct gtaaagaaat atatacttga gtggtgtgtg ttatcagata aagcaccctg 1680 tatcacagac tggcaacaag aagatggtac cgtgcatcgc acctatttaa gagggaactt 1740 agcagagagc aaatgctatt tgataacagt tactccagta tatgctgatg gaccaggaag 1800 ccctgaatcc ataaaggcat accttaaaca agctccacct tccaaaggac ctactgttcg 1860 gacaaaaaaa gtagggaaaa acgaagctgt cttagagtgg gaccaacttc ctgttgatgt 1920 tcagaatgga tttatcagaa attatactat attttataga accatcattg gaaatgaaac 1980 tgctgtgaat gtggattctt cccacacaga atatacattg tcctctttga ctagtgacac 2040 attgtacatg gtacgaatgg cagcatacac agatgaaggt gggaaggatg gtccagaatt 2100 cacttttact accccaaagt ttgctcaagg agaaattgaa gccatagtcg tgcctgtttg 2160 cttagcattc ctattgacaa ctcttctggg agtgctgttc tgctttaata agcgagacct 2220 aattaaaaaa cacatctggc ctaatgttcc agatccttca aagagtcata ttgcccagtg 2280 gtcacctcac actcctccaa ggcacaattt taattcaaaa gatcaaatgt attcagatgg 2340 caatttcact gatgtaagtg ttgtggaaat agaagcaaat gacaaaaagc cttttccaga 2400 agatctgaaa tcattggacc tgttcaaaaa ggaaaaaatt aatactgaag gacacagcag 2460 tggtattggg gggtcttcat gcatgtcatc ttctaggcca agcatttcta gcagtgatga 2520 aaatgaatct tcacaaaaca cttcgagcac tgtccagtat tctaccgtgg tacacagtgg 2580 ctacagacac caagttccgt cagtccaagt cttctcaaga tccgagtcta cccagccctt 2640 gttagattca gaggagcggc cagaagatct acaattagta gatcatgtag atggcggtga 2700 tggtattttg cccaggcaac agtacttcaa acagaactgc agtcagcatg aatccagtcc 2760 agatatttca cattttgaaa ggtcaaagca agtttcatca gtcaatgagg aagattttgt 2820 tagacttaaa cagcagattt cagatcatat ttcacaatcc tgtggatctg ggcaaatgaa 2880 aatgtttcag gaagtttctg cagcagatgc ttttggtcca ggtactgagg gacaagtaga 2940 aagatttgaa acagttggca tggaggctgc gactgatgaa ggcatgccta aaagttactt 3000 accacagact gtacggcaag gcggctacat gcctcagtga aggactagta gttcctgcta 3060 caacttcagc agtacctata aagtaaagct aaaatgattt tatctgtgaa ttcagatttt 3120 aaaaagtctt cactctctga agatgatcat ttgcccttaa ggacaaaaat gaactgaagt 3180 ttcacatgag ctatttccat tccagaatat ctgggattct actttaagca ctacataaac 3240 tgactttatc ctcagactag ctgaatgatt ttgtgctgtt tcaggatgtt tgcactgaag 3300 aaaaacagaa agcttatctg aaatttataa aactttttgt tttgctacat agaaaacaga 3360 aggtatttga ataataagca gtgatatgct tagtgagcac agctatactg attttgatta 3420 gaatagtcat cagagtggct tagggacagt taatataaaa gaggagcaag gtgtagacca 3480 tcatctactt ctgctaaaat aacttaaaaa gaggtccata ggccataact acatgagccc 3540 agcttttgta atctgacaaa aaaatgagga gcagcttcgt gtatatcagt gtacacggta 3600 ttccttaggt cccttccatt ggtagtgatg ctgcgagtta ttactggaga aaaggaattc 3660 tagagcttta acttggcaga ttaaaagtac tcatttttta ttcatcaata attagtaatc 3720 tcactagttt tcaaaaattt gcatattatt gacaacctct ttgaagatgc atttcacaaa 3780 ctcaacagag tgccatgata agagctaggg atcccccaaa ctatctcaag catctaaaaa 3840 attgccattt ttaaaggctt aaattgtagt agtaaagggg aaaacaggaa gtagtagtaa 3900 aggggaaaaa aaaccaataa agcatctaaa aaattggcat gttaaaaggc ttaaattgct 3960 aatgtgtgta tatatatata tatatataca cacacatatc attgactttt cttaagactt 4020 cagagtactg ggtagatgaa cactttatac agtatatatc ttcagcttaa atttgttttg 4080 agtatttttt ttatttttaa ataagtaggc aaagatttaa atttttttat ttttagtaaa 4140 tgtttgaggc acactaagac aacttgggca atatttgcca aaacaaaaca gaaccccaaa 4200 aaatgtacat cttgttctta gcaaatatca ttattgtaga gacacttaat aaagagatgg 4260 tattttaatg tctgcagttc tgaggtaggg tggaacttag ttctacattg tgatttagga 4320 atttttaaaa ccttttttct tcaagggaga agtgacccag gcctcgagtt tagtgctaaa 4380 gccgctagtg tacttatgct gtcccctaac caccacgtgc gatatggaag cagatgctaa 4440 atataggggt tttcttagaa agtaagagga aattagcaag cgttattagt gattgactac 4500 tgctatcaag tgaattcaaa ggaaacaggt ttttatgcca tatttaagtt acagaaacca 4560 ggcatgctta gaatagtttc tagaggttat tggagaatag aaagctaaga aaacttggta 4620 tacatttaca atggaaatat aattacactt tttactctca gaatattgtt cacattagac 4680 ttcctgttta tcttttatat tcttgcattt atataatgcc tcatcctttc aaagttcttt 4740 cacatattat atgatcttct ttatgaaaaa aatagatgtt tcattctgat atattcagtt 4800 tcccacttta ggcaaaagta gattaataga atgacgaatt caaagtagat gaggaaaatc 4860 aggcacagag aagtaaaggt agggatagac ccaaatttac acaacaagat aatgacatct 4920 ccagctttta agttgatcat caaaggctgg gctggatttg tcttgctgta tgtgtcagga 4980 aatttatacc tattacattt tccattttct caaaatttaa gtcacatgac taatatttag 5040 ctgcaacttt cctcataaca aatagtgtca tgaagaatgt tgtagtgtga agtttgtaca 5100 tttcagggtc agatatacaa tatgaactct taatctacag gaatgagaat ggaggatcat 5160 tgaaggccat gatataaaca aatttgcatg ttgaagcctg tataaaacat ggtacagtga 5220 gtgaatatac ccccatcccc aagaacactt tatacatatt aaatggatat atgattactg 5280 tgcaaaaatt cattctggaa atgaacatat atttgagcac taatatgtaa tgtacacctg 5340 ccctaaggag aaaataaatt ataaaacttt ttacattcaa aattactttc ccaagcatgt 5400 cttagaataa tctatgtgtt gatgcatgta aattgtactt taggtaggca aagaaatctg 5460 gttatttatg taaaaactag tctaataaag ttagttagtg gctttatcac tttaaatctt 5520 tagtgtccaa aagtggtgtt taaagtaata gcacatcaga aaaccttgtc tggacaaaac 5580 tagttcactc actgcttctg cacctgcagt tgctcccttt agggttataa aataatgacc 5640 caaatgttac atgtgttgat attataactt gtcagttact gatgtctgtg gtatcctacc 5700 ctcatctctg aaagggataa tactgaataa ttattagaaa actataaaac ttcacacttt 5760 gtaccattaa aacctaaaat tttaatcttg tcctttttta ctatggatca gtcggcactc 5820 gggaacagca gcaaggaaaa aaagcaaatt tcattcacat gttctgtgtt catacctctt 5880 ctctacctaa ttgttcattt aaatttcagc cttattcctt gataagggat tttaccacat 5940 gaagtcatcc agtgacccta gctcttattg tgaagttagt ggagtatact tagaaatgtt 6000 acaactttaa aatgttacaa aacattcatt aaagctcata tttaaagtag agcatctagt 6060 ttgagaaata gaaatcaatt attaaagatg tcttttttct acccatttaa ctagttaaaa 6120 ccatgacatg taaatgtaga agtagaataa tcatagaatt ccctaaaata tttctgttta 6180 ctaacatata ttgaccaagt acatcaagca ggagagatct tccttcattc tgttatagtc 6240 cacatcattc taattttgct cagttgttat taagagcata ttcctaaacc atacactttt 6300 gtttcaataa agttttattt tgttgagatg aataaaataa caaagttata agctgcataa 6360 gacaaaagtt caattgttca aaaaaaattt actgggatag ctttctatta caggtattgt 6420 tagattatat tgtgctgata agattacttt ctaaaaaatt tgtacttttc tgtaaattaa 6480 aagaatatgg agtcataaaa tggcaagtgt tttaggatta gcctaaaatt ggacattgtc 6540 attgatttca aagaaggtat gaactagcag tcttacagcc taattcttct ttggactggt 6600 ccttggcagc agttcctttt cagactcgat aaacagaatt cagatgatgt aagtcaaaac 6660 aaaactttac aaagccaagc gtattatctt ttgcattaac ctattttttt ccatcataca 6720 tgctactagt atgtgcatta gcatgatatt ctcatataca ttgcattaaa aattaaaagg 6780 tggcagctca gggtgagctc ttctgttgct catttgttcc taaattttta agggcttttt 6840 ctcagtcaat agtttgtaca aactggttag tttaacttca ttacccattt cattaaagtt 6900 gatgggtcgt gtgatgagat gcatttaagg ccgatagtga tagatgtttt ttttatttct 6960 tgaacacagg ctttgtctga atgatgttct tttatctctt gaacacaagc tttgaatgat 7020 aactacaggt tttaagtgct gttacattaa taccataatg tgatgtgtta gaaacaaagg 7080 gatatttcaa aggtagatat ttgaaaattc tctagtctca atatgtatgt gtattgaata 7140 tactctaaaa ataaatgtgc aatttgctag taggacaatg cagtgactga ctagcattag 7200 gtatgtttct tttatatcct agctatgtcc cactttcttc taagtgcaat cctttcatgt 7260 tcacttgctg ttttacccca tctactctaa cttcatttgg aaggcttgtc tagagtatag 7320 catgtatttt tacctttgca gtgaattgca tgtgctaatt gtaaccacag ctatttttat 7380 gttgacataa ctccaaatgt tatattaaat gttctattat atattagctc taatccctta 7440 agtaaatttt aagaaataaa tacttgttca aatttttttt ctgtatgtgg ttactatcat 7500 ctgactatgc atatttgtaa cagcatttat cattagtggt gttagctaaa taagcatctt 7560 agtgtaaatg agatgcttcg tgtgggtttt gtgacatttt aaatgacata atggaatgtg 7620 atttaaaaga aaaccagtac actatcttgg tcttaataac atagaatgga gatggcaaat 7680 ttatccacta gttttccaga tttactattt aatagctgag gtctgaaatc gtagcatcct 7740 ccctcctagt ggacattaaa aaaaaaaaaa aaaaaaaaaa cctacttggt tgtcaagagc 7800 ccaagtatgg aggtgctgcg ccatcttgtg gcctgtctgt gcccaccctg cactctgctg 7860 gagtctccat ccttgttgca gtgagacttg aagttcaaga ttgatacatg gcatcctcct 7920 gctacttctt gaggttacta agtagtatat gaaactaatc agtcagcaag tccacctgga 7980 aggaaaagaa aatctcaact attaatgtgc cttcacattg tgattttgtc taaaaaaatg 8040 tagtgagtca aaaaacccac aagccagcca acagtaactc cttcacatat ataccagagt 8100 ttatagaaat aacatgtcag ctttgggcta tgtgctcctt tgtttaaaat cttctatttg 8160 gttatggctt gtataggctc aagcctgatt tctttaaggt gtggtggctc atcttatcct 8220 aatgtgtatg atagatacag tccatcctgc tttggaaaag attatgtaac tccttgagag 8280 catactcttt ctctagccca aaggcagtga gagagttttc ttgttcagga ttgcttaact 8340 ttccatttaa gctttttctt tttaaattaa tacaaacttc tacactttca aaatacgaaa 8400 tatattacaa ctgcgtatag gctcttccat acttaagtcc agtgcttggg caagttaatg 8460 gagtgaaaga ctacaagcaa agaggaactg aggtagaaaa agaagaatgt gtgaaagcag 8520 caggaagctc agccaactcg aaagcagggt gaacagcttg agtcctgttg ctgctgatcg 8580 gggttggctc ttggacaact tagtaagatc atggaaaggc tgcttgggtt ctccatagaa 8640 aagttctgtc tccatcaagg gaggaaaatg tacctttcaa ctcaaaattc aatatttgtt 8700 tttaaatata gctattttcc ccaaccgcta aagattttca acagatacga agccagagct 8760 tagttttaga aacctgtgga cattcaaacc tgattcttta ttccctgtga ctatggttat 8820 gtcattttac atgtcaaaaa agtgtatcta gaattgtcat ttcttatttt tgagcttttt 8880 ttagtgagaa ttatcccctc acttaaatgg ctttttattt aaacatctgt gcattctgta 8940 tgaaattgta gtctttctgg gataacatgg tgagctatat ggtggtaatc cacacacaca 9000 aaaataaaag ccaaaaaaaa accaaaa 9027 <![CDATA[<210> 15]]> <![CDATA[<211> 8844]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 15]]> ggatctgaca gtgttccgga gccggggcga gcagccaaaa ggcccgcgga gtcgcgctgg 60 gccgccccgg cgcagctgaa ccgggggccg cgcctgccag gccgacgggt ctggcccagc 120 ctggcgccaa ggggttcgtg cgctgtggag acgcggaggg tcgaggcggc gcggcctgag 180 tgaaacccaa tggaaaaagc atgacattta gaagtagaag acttagcttc aaatccctac 240 tccttcactt actaattttg tgatttggaa atatccgcgc aagatgttga cgttgcagac 300 ttggctagtg caagccttgt ttattttcct caccactgaa tctacaggtg aacttctaga 360 tccatgtggt tatatcagtc ctgaatctcc agttgtacaa cttcattcta atttcactgc 420 agtttgtgtg ctaaaggaaa aatgtatgga ttattttcat gtaaatgcta attacattgt 480 ctggaaaaca aaccatttta ctattcctaa ggagcaatat actatcataa acagaacagc 540 atccagtgtc acctttacag atatagcttc attaaatatt cagctcactt gcaacattct 600 tacattcgga cagcttgaac agaatgttta tggaatcaca ataatttcag gcttgcctcc 660 agaaaaacct aaaaatttga gttgcattgt gaacgagggg aagaaaatga ggtgtgagtg 720 ggatggtgga agggaaacac acttggagac aaacttcact ttaaaatctg aatgggcaac 780 acacaagttt gctgattgca aagcaaaacg tgacaccccc acctcatgca ctgttgatta 840 ttctactgtg tattttgtca acattgaagt ctgggtagaa gcagagaatg cccttgggaa 900 ggttacatca gatcatatca attttgatcc tgtatataaa gtgaagccca atccgccaca 960 taatttatca gtgatcaact cagaggaact gtctagtatc ttaaaattga catggaccaa 1020 cccaagtatt aagagtgtta taatactaaa atataacatt caatatagga ccaaagatgc 1080 ctcaacttgg agccagattc ctcctgaaga cacagcatcc acccgatctt cattcactgt 1140 ccaagacctt aaacctttta cagaatatgt gtttaggatt cgctgtatga aggaagatgg 1200 taagggatac tggagtgact ggagtgaaga agcaagtggg atcacctatg aagatagacc 1260 atctaaagca ccaagtttct ggtataaaat agatccatcc catactcaag gctacagaac 1320 tgtacaactc gtgtggaaga cattgcctcc ttttgaagcc aatggaaaaa tcttggatta 1380 tgaagtgact ctcacaagat ggaaatcaca tttacaaaat tacacagtta atgccacaaa 1440 actgacagta aatctcacaa atgatcgcta tctagcaacc ctaacagtaa gaaatcttgt 1500 tggcaaatca gatgcagctg ttttaactat ccctgcctgt gactttcaag ggaacttagc 1560 agagagcaaa tgctatttga taacagttac tccagtatat gctgatggac caggaagccc 1620 tgaatccata aaggcatacc ttaaacaagc tccaccttcc aaaggaccta ctgttcggac 1680 aaaaaaagta gggaaaaacg aagctgtctt agagtgggac caacttcctg ttgatgttca 1740 gaatggattt atcagaaatt atactatatt ttatagaacc atcattggaa atgaaactgc 1800 tgtgaatgtg gattcttccc acacagaata tacattgtcc tctttgacta gtgacacatt 1860 gtacatggta cgaatggcag catacacaga tgaaggtggg aaggatggtc cagaattcac 1920 ttttactacc ccaaagtttg ctcaaggaga aattgaagcc atagtcgtgc ctgtttgctt 1980 agcattccta ttgacaactc ttctgggagt gctgttctgc tttaataagc gagacctaat 2040 taaaaaacac atctggccta atgttccaga tccttcaaag agtcatattg cccagtggtc 2100 acctcacact cctccaaggc acaattttaa ttcaaaagat caaatgtatt cagatggcaa 2160 tttcactgat gtaagtgttg tggaaataga agcaaatgac aaaaagcctt ttccagaaga 2220 tctgaaatca ttggacctgt tcaaaaagga aaaaattaat actgaaggac acagcagtgg 2280 tattgggggg tcttcatgca tgtcatcttc taggccaagc atttctagca gtgatgaaaa 2340 tgaatcttca caaaacactt cgagcactgt ccagtattct accgtggtac acagtggcta 2400 cagacaccaa gttccgtcag tccaagtctt ctcaagatcc gagtctaccc agcccttgtt 2460 agattcagag gagcggccag aagatctaca attagtagat catgtagatg gcggtgatgg 2520 tattttgccc aggcaacagt acttcaaaca gaactgcagt cagcatgaat ccagtccaga 2580 tatttcacat tttgaaaggt caaagcaagt ttcatcagtc aatgaggaag attttgttag 2640 acttaaacag cagatttcag atcatatttc acaatcctgt ggatctgggc aaatgaaaat 2700 gtttcaggaa gtttctgcag cagatgcttt tggtccaggt actgagggac aagtagaaag 2760 atttgaaaca gttggcatgg aggctgcgac tgatgaaggc atgcctaaaa gttacttacc 2820 acagactgta cggcaaggcg gctacatgcc tcagtgaagg actagtagtt cctgctacaa 2880 cttcagcagt acctataaag taaagctaaa atgattttat ctgtgaattc agattttaaa 2940 aagtcttcac tctctgaaga tgatcatttg cccttaagga caaaaatgaa ctgaagtttc 3000 acatgagcta tttccattcc agaatatctg ggattctact ttaagcacta cataaactga 3060 ctttatcctc agactagctg aatgattttg tgctgtttca ggatgtttgc actgaagaaa 3120 aacagaaagc ttatctgaaa tttataaaac tttttgtttt gctacataga aaacagaagg 3180 tatttgaata ataagcagtg atatgcttag tgagcacagc tatactgatt ttgattagaa 3240 tagtcatcag agtggcttag ggacagttaa tataaaagag gagcaaggtg tagaccatca 3300 tctacttctg ctaaaataac ttaaaaagag gtccataggc cataactaca tgagcccagc 3360 ttttgtaatc tgacaaaaaa atgaggagca gcttcgtgta tatcagtgta cacggtattc 3420 cttaggtccc ttccattggt agtgatgctg cgagttatta ctggagaaaa ggaattctag 3480 agctttaact tggcagatta aaagtactca ttttttattc atcaataatt agtaatctca 3540 ctagttttca aaaatttgca tattattgac aacctctttg aagatgcatt tcacaaactc 3600 aacagagtgc catgataaga gctagggatc ccccaaacta tctcaagcat ctaaaaaatt 3660 gccattttta aaggcttaaa ttgtagtagt aaaggggaaa acaggaagta gtagtaaagg 3720 ggaaaaaaaa ccaataaagc atctaaaaaa ttggcatgtt aaaaggctta aattgctaat 3780 gtgtgtatat atatatatat atatacacac acatatcatt gacttttctt aagacttcag 3840 agtactgggt agatgaacac tttatacagt atatatcttc agcttaaatt tgttttgagt 3900 atttttttta tttttaaata agtaggcaaa gatttaaatt tttttatttt tagtaaatgt 3960 ttgaggcaca ctaagacaac ttgggcaata tttgccaaaa caaaacagaa ccccaaaaaa 4020 tgtacatctt gttcttagca aatatcatta ttgtagagac acttaataaa gagatggtat 4080 tttaatgtct gcagttctga ggtagggtgg aacttagttc tacattgtga tttaggaatt 4140 tttaaaacct tttttcttca agggagaagt gacccaggcc tcgagtttag tgctaaagcc 4200 gctagtgtac ttatgctgtc ccctaaccac cacgtgcgat atggaagcag atgctaaata 4260 taggggtttt cttagaaagt aagaggaaat tagcaagcgt tattagtgat tgactactgc 4320 tatcaagtga attcaaagga aacaggtttt tatgccatat ttaagttaca gaaaccaggc 4380 atgcttagaa tagtttctag aggttattgg agaatagaaa gctaagaaaa cttggtatac 4440 atttacaatg gaaatataat tacacttttt actctcagaa tattgttcac attagacttc 4500 ctgtttatct tttatattct tgcatttata taatgcctca tcctttcaaa gttctttcac 4560 atattatatg atcttcttta tgaaaaaaat agatgtttca ttctgatata ttcagtttcc 4620 cactttaggc aaaagtagat taatagaatg acgaattcaa agtagatgag gaaaatcagg 4680 cacagagaag taaaggtagg gatagaccca aatttacaca acaagataat gacatctcca 4740 gcttttaagt tgatcatcaa aggctgggct ggatttgtct tgctgtatgt gtcaggaaat 4800 ttatacctat tacattttcc attttctcaa aatttaagtc acatgactaa tatttagctg 4860 caactttcct cataacaaat agtgtcatga agaatgttgt agtgtgaagt ttgtacattt 4920 cagggtcaga tatacaatat gaactcttaa tctacaggaa tgagaatgga ggatcattga 4980 aggccatgat ataaacaaat ttgcatgttg aagcctgtat aaaacatggt acagtgagtg 5040 aatatacccc catccccaag aacactttat acatattaaa tggatatatg attactgtgc 5100 aaaaattcat tctggaaatg aacatatatt tgagcactaa tatgtaatgt acacctgccc 5160 taaggagaaa ataaattata aaacttttta cattcaaaat tactttccca agcatgtctt 5220 agaataatct atgtgttgat gcatgtaaat tgtactttag gtaggcaaag aaatctggtt 5280 atttatgtaa aaactagtct aataaagtta gttagtggct ttatcacttt aaatctttag 5340 tgtccaaaag tggtgtttaa agtaatagca catcagaaaa ccttgtctgg acaaaactag 5400 ttcactcact gcttctgcac ctgcagttgc tccctttagg gttataaaat aatgacccaa 5460 atgttacatg tgttgatatt ataacttgtc agttactgat gtctgtggta tcctaccctc 5520 atctctgaaa gggataatac tgaataatta ttagaaaact ataaaacttc acactttgta 5580 ccattaaaac ctaaaatttt aatcttgtcc ttttttacta tggatcagtc ggcactcggg 5640 aacagcagca aggaaaaaaa gcaaatttca ttcacatgtt ctgtgttcat acctcttctc 5700 tacctaattg ttcatttaaa tttcagcctt attccttgat aagggatttt accacatgaa 5760 gtcatccagt gaccctagct cttattgtga agttagtgga gtatacttag aaatgttaca 5820 actttaaaat gttacaaaac attcattaaa gctcatattt aaagtagagc atctagtttg 5880 agaaatagaa atcaattatt aaagatgtct tttttctacc catttaacta gttaaaacca 5940 tgacatgtaa atgtagaagt agaataatca tagaattccc taaaatattt ctgtttacta 6000 acatatattg accaagtaca tcaagcagga gagatcttcc ttcattctgt tatagtccac 6060 atcattctaa ttttgctcag ttgttattaa gagcatattc ctaaaccata cacttttgtt 6120 tcaataaagt tttattttgt tgagatgaat aaaataacaa agttataagc tgcataagac 6180 aaaagttcaa ttgttcaaaa aaaatttact gggatagctt tctattacag gtattgttag 6240 attatattgt gctgataaga ttactttcta aaaaatttgt acttttctgt aaattaaaag 6300 aatatggagt cataaaatgg caagtgtttt aggattagcc taaaattgga cattgtcatt 6360 gatttcaaag aaggtatgaa ctagcagtct tacagcctaa ttcttctttg gactggtcct 6420 tggcagcagt tccttttcag actcgataaa cagaattcag atgatgtaag tcaaaacaaa 6480 actttacaaa gccaagcgta ttatcttttg cattaaccta tttttttcca tcatacatgc 6540 tactagtatg tgcattagca tgatattctc atatacattg cattaaaaat taaaaggtgg 6600 cagctcaggg tgagctcttc tgttgctcat ttgttcctaa atttttaagg gctttttctc 6660 agtcaatagt ttgtacaaac tggttagttt aacttcatta cccatttcat taaagttgat 6720 gggtcgtgtg atgagatgca tttaaggccg atagtgatag atgttttttt tatttcttga 6780 acacaggctt tgtctgaatg atgttctttt atctcttgaa cacaagcttt gaatgataac 6840 tacaggtttt aagtgctgtt acattaatac cataatgtga tgtgttagaa acaaagggat 6900 atttcaaagg tagatatttg aaaattctct agtctcaata tgtatgtgta ttgaatatac 6960 tctaaaaata aatgtgcaat ttgctagtag gacaatgcag tgactgacta gcattaggta 7020 tgtttctttt atatcctagc tatgtcccac tttcttctaa gtgcaatcct ttcatgttca 7080 cttgctgttt taccccatct actctaactt catttggaag gcttgtctag agtatagcat 7140 gtatttttac ctttgcagtg aattgcatgt gctaattgta accacagcta tttttatgtt 7200 gacataactc caaatgttat attaaatgtt ctattatata ttagctctaa tcccttaagt 7260 aaattttaag aaataaatac ttgttcaaat tttttttctg tatgtggtta ctatcatctg 7320 actatgcata tttgtaacag catttatcat tagtggtgtt agctaaataa gcatcttagt 7380 gtaaatgaga tgcttcgtgt gggttttgtg acattttaaa tgacataatg gaatgtgatt 7440 taaaagaaaa ccagtacact atcttggtct taataacata gaatggagat ggcaaattta 7500 tccactagtt ttccagattt actatttaat agctgaggtc tgaaatcgta gcatcctccc 7560 tcctagtgga cattaaaaaa aaaaaaaaaa aaaaaaacct acttggttgt caagagccca 7620 agtatggagg tgctgcgcca tcttgtggcc tgtctgtgcc caccctgcac tctgctggag 7680 tctccatcct tgttgcagtg agacttgaag ttcaagattg atacatggca tcctcctgct 7740 acttcttgag gttactaagt agtatatgaa actaatcagt cagcaagtcc acctggaagg 7800 aaaagaaaat ctcaactatt aatgtgcctt cacattgtga ttttgtctaa aaaaatgtag 7860 tgagtcaaaa aacccacaag ccagccaaca gtaactcctt cacatatata ccagagttta 7920 tagaaataac atgtcagctt tgggctatgt gctcctttgt ttaaaatctt ctatttggtt 7980 atggcttgta taggctcaag cctgatttct ttaaggtgtg gtggctcatc ttatcctaat 8040 gtgtatgata gatacagtcc atcctgcttt ggaaaagatt atgtaactcc ttgagagcat 8100 actctttctc tagcccaaag gcagtgagag agttttcttg ttcaggattg cttaactttc 8160 catttaagct ttttcttttt aaattaatac aaacttctac actttcaaaa tacgaaatat 8220 attacaactg cgtataggct cttccatact taagtccagt gcttgggcaa gttaatggag 8280 tgaaagacta caagcaaaga ggaactgagg tagaaaaaga agaatgtgtg aaagcagcag 8340 gaagctcagc caactcgaaa gcagggtgaa cagcttgagt cctgttgctg ctgatcgggg 8400 ttggctcttg gacaacttag taagatcatg gaaaggctgc ttgggttctc catagaaaag 8460 ttctgtctcc atcaagggag gaaaatgtac ctttcaactc aaaattcaat atttgttttt 8520 aaatatagct attttcccca accgctaaag attttcaaca gatacgaagc cagagcttag 8580 ttttagaaac ctgtggacat tcaaacctga ttctttattc cctgtgacta tggttatgtc 8640 attttacatg tcaaaaaagt gtatctagaa ttgtcatttc ttatttttga gcttttttta 8700 gtgagaatta tcccctcact taaatggctt tttatttaaa catctgtgca ttctgtatga 8760 aattgtagtc tttctgggat aacatggtga gctatatggt ggtaatccac acacacaaaa 8820 ataaaagcca aaaaaaaacc aaaa 8844 <![CDATA[<210> 16]]> <![CDATA[<211> 199]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 16]]> Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Arg Val Val Ala Pro Gly Pro Pro Ala Gly Ser Pro Arg Val Ser 20 25 30 Ser Asp Pro Arg Ala Asp Leu Asp Ser Ala Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Met Arg Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Ser Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Thr Leu Gly Ser Leu Gln Leu Pro Gly Val Leu Thr Arg 85 90 95 Leu Arg Val Asp Leu Met Ser Tyr Leu Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Gly Gly Pro Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Ala 115 120 125 Leu Gln Ala Arg Leu Glu Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Ala Ala Pro Asp Gln Pro Val Ile Pro 145 150 155 160 Leu Gly Pro Pro Ala Ser Ala Trp Gly Ser Ile Arg Ala Ala His Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 <![CDATA[<210> 17]]> <![CDATA[<211> 199]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 17]]> Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Thr Ala Val Ala Pro Gly Pro Pro Pro Gly Ser Pro Arg Ala Ser 20 25 30 Pro Asp Pro Arg Ala Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Glu Asp Thr Arg Gln Leu Thr Ile Gln Leu Lys Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Ser Val Leu Thr Arg 85 90 95 Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Met Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr 115 120 125 Leu Gln Thr Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Leu Pro Pro Asp Pro Pro Ala Pro Pro 145 150 155 160 Leu Ala Pro Pro Ser Ser Thr Trp Gly Gly Ile Arg Ala Ala His Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 <![CDATA[<210> 18]]> <![CDATA[<211> 199]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 18]]> Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro 1 5 10 15 Asp Arg Val Val Ala Pro Gly Pro Pro Ala Gly Ser Pro Arg Val Ser 20 25 30 Ser Asp Pro Arg Ala Asp Leu Asp Ser Ala Val Leu Leu Thr Arg Ser 35 40 45 Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Met Arg Asp Lys Phe 50 55 60 Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met 65 70 75 80 Ser Ala Gly Thr Leu Gly Ser Leu Gln Leu Pro Gly Val Leu Thr Arg 85 90 95 Leu Arg Val Asp Leu Met Ser Tyr Phe Arg His Val Gln Trp Leu Arg 100 105 110 Arg Ala Ala Gly Pro Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Ala 115 120 125 Leu Gln Ala Arg Leu Glu Arg Leu Leu Arg Arg Leu Gln Leu Leu Met 130 135 140 Ser Arg Leu Ala Leu Pro Gln Ala Ala Pro Asp Gln Pro Ala Val Pro 145 150 155 160 Leu Gly Pro Pro Ala Ser Ala Trp Gly Ser Ile Arg Ala Ala His Ala 165 170 175 Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu 180 185 190 Leu Leu Leu Lys Thr Arg Leu 195 <![CDATA[<210> 19]]> <![CDATA[<211> 1949]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 19]]> tgcctggccc ttgctgctca cactcacaaa cctcccctcc ccaggccgag gcccagctga 60 ccccctgggt cccccggcag cggacaggga agggttaaag cccccccccc cggctccctg 120 ccccctgccc tggggaaccc ctggcctgtg gggacatgaa ctgtgtttgt cgcctggtcc 180 tggtggtgct gagcctctgg ccagatagag tcgttgcccc tgggccacca gctggctccc 240 ctcgagtctc ttcagaccct cgagcagatc tggacagcgc tgttctccta acccgatccc 300 tcctggcaga cacacggcaa ctagctgcac agatgagaga caaattccca gctgacggag 360 atcacagtct ggactccctg cccaccttgg ccatgagcgc tgggacattg ggatctttgc 420 agcttcctgg tgtgctgaca aggcttcgag tagacttgat gtcctacctc cggcatgtac 480 aatggctgcg ccgtgcaggt ggtccttccc taaagactct ggagccagag ctgggtgccc 540 tgcaagcccg actggaacgg ctactccgcc gtttacagct cttgatgtct cgcctggcct 600 tgccccaggc agccccagac caacctgtga tccccctggg ccctcctgcc tcagcctggg 660 gaagcatccg ggcagctcat gccatcctag gagggctgca cctgaccttg gactgggccg 720 tgcggggcct gctgttgtta aagactcgac tgtgactcgg gactgaaaac caccatcgat 780 accgcccttt aaaaccagat cttatttatt tatttatttt ggtacttgga ggggggcatg 840 atgatcaggg gcatgccaca ccccaaacaa ccgccccaca cccagctaga cagtctttcc 900 agtagacctg ggtgaggggg atcacctgtg gcttatttat acttatttat ttaaacaatt 960 ggggggtggg tgggtgcatc tgagaccctg aagagcaggg aactgagatc ctgggttctg 1020 gggtctctat gaaatctgtt cacagtgtct tcctcacttc ctacattatt tattaaacga 1080 ttacttttta tattaagagg aggaaggagg gaagccgggc gtggtggcgc atgcctttaa 1140 tcccagcact cgggaggcag aggcaggcag atttctgagt tcgaggccag cctggtctaa 1200 gagtgagttc gtgagttcca ggacagccag ggctacacag agaaaccctg tctcgaaaaa 1260 ccaaaaaaaa aaaaaaaaaa aaagaggagg aaggaggggg aaaaaggaag cctggggttt 1320 tataccaaaa tgtgagtttt tttttgtgag tcagagaagt gagaggattt aaatacatat 1380 ctatttagag gttattagca ggagtatgcc gaaaggatcg gagtctaaac tggtacccta 1440 gcatttcaaa ggtcctcaac agatacttaa caaaaagttc cagagcatca ccttataact 1500 aatagcacct gtatggtaca gagctgtaag gtacaaggtt ttttgtttca gcaaaattca 1560 cgatgaccaa tgggaaacaa tctaggcttt ctggggggcg ggcaggggat ggatgaataa 1620 agctagggat acatccgcat gatgaagttc tagctcgcca accataaaaa ggcaagttcc 1680 aggcgaagac tgctttagat attgaacgtc tctgcgaccc aggagcagca gatggtagaa 1740 ctactctccc tatacatgag tatggactgt ttggtttttc aaaatggaaa caccatgatg 1800 ttgacgatag ctgcctcagg gctgaaaaca agcaatggca cagtgggtga ctgttactgt 1860 ttgtgtttgc attttccaga gttttcacca tgactgtatt ttgcaggaca catttataaa 1920 cattaataaa cactattttt agaaaaaaa 1949 <![CDATA[<210> 20]]> <![CDATA[<211> 2550]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 20]]> cgaccacccc cccctttccc ttttcaactt ttccaacttt tccttccgtg ccctcctccg 60 agcgcggcgg cgtgagccct gcaaggcagc cgctccgtgt gaatggaaaa ggcaggcagg 120 gagggtgagt caggatgtgt caggccgccc tcccctgccg cctgcccccc gcccgcccgc 180 cccagccccc tatataaccc cccaggcgtc cacactccct cactgcctcg gccctgctgc 240 tgacgggcac atgcctcccc tccccaggcc gcggcccagc tgacccccgg ggctcccccg 300 gcagcggaca gggaagggtt aaaggccccc ggctccctgc cccctgccct ggggaacccc 360 tggccctgcg gggacatgaa ctgtgtttgc cgcctggtcc tggtcgtgct gagcctgtgg 420 ccagatacag ctgttgcccc tgggccacca cctggctccc ctcgagcttc cccagaccct 480 cgggccgagc tggacagcac cgtgctcctg acccgctctc tcctggagga cacgcggcag 540 ctgactatac agctgaagga caaattccca gctgacgggg accacaacct ggattccctg 600 cccaccctgg ccatgagcgc gggggcactg ggagctctac agctcccgag tgtgctgaca 660 aggctgcgag cggacctact gtcctacctg cggcatgtgc agtggctgcg tcgggcaatg 720 ggctcttccc tgaagaccct ggagcctgag ctgggcaccc tgcagacccg gctggaccgg 780 ctgctgcgcc ggctgcagct cctgatgtcc cgcctggccc tgccccagct gcccccagac 840 ccgccggcgc ccccgctggc gcccccctcc tcaacctggg ggggcatcag ggccgcccac 900 gccatcctgg gggggctgca cctgacactt gactgggccg tgagggggct actgctgctg 960 aagactcggc tgtgacccga ggcccagagc caccaccgtc cttccaaagc cacatcttat 1020 ttatttattt atttcggtac tgggggcgaa acagccaggt gatccccctg cctttatctc 1080 cccctagtta gagacagtcc ttccgtgagg ctggggggca tctgtgcctt atttatactt 1140 atttatttca ggagcggggg tgggctcctg ggtccccgag gaggagggag ttggggtccc 1200 ggattcttgt gtccacagac ttctgccctg gctcctcccg ctcgaggcct gggcaggaat 1260 acatactatt tatttaagca attacttttc atgttggggt ggggagggag gggaaaggga 1320 agcctgggtt tttgtacaaa aatgtgagaa acctttgtga gacgaagaac aaggaattaa 1380 atgtgtcata catatccact tgagggcgac ttgtctgaga gctggggctg gatgctcggg 1440 taactggggc agggcaggtg gaggtcccga gtgggcgggg cagggactgg gagatgggtc 1500 agtcacccag acagctctgg ggaggcagag tttgagcctc gcctggggcc ccacactgca 1560 cagggctctt tgttttttga gatggagact ggctctgttg cctaggttgg agtgcagtgg 1620 cgcaatctaa actcactgca acctccacct cccgggttta atcgattctc ctgcctcagc 1680 ctcccgatta gctgggatca caggcgtgca ccaccacgcc cggctaatta tttatttctt 1740 ttgtattttc agtagagaca aggtttcacc atgttgacca ggctggtttc gaactcctga 1800 cctcaggtga tcctcctgcc ttggcctccc aaagtgctgg gattacaggt gtgagccacc 1860 gcacctgacc tatataggtc ttcaataaat atttaatgga aggttccaga agtcaccctg 1920 cgattaacgg tacccgtatg tgacaaagct gcaaggtcaa gatggttcat tatggctgtg 1980 ttgaccgtag caaattggaa acaatccaga tatccaacag gtgagggtta agcaacatgg 2040 tgcatcggtg gatggaatgc cacccggcca cccagagcag ggactagcat tcagggaggc 2100 taaggagaga ggcctgcttc ggatatagaa agatagcctg acattggcca ggcatggtgg 2160 tcacgcctgt aatcctagca ctctgggagg acgaagcaag tggatcactg aagtccaata 2220 gtttgagacc agcctgggag acgtggcgaa accctgtctc aaaagagaaa aaacgatgtc 2280 ctgacgtgaa acagctacaa aaccactgca tgatgcgatt ccaatttttg tgtttttctt 2340 tctatatatg gattaaaaaa aaaaaaaaaa ccctaaaggg aaataagcca aatgttgaca 2400 aggactgtct ccaggtcaaa ggagagaggt gggattgtgg gtgacttttg atgtttatga 2460 ttgtctgtat tttacagaat ttctgccatg actgtgtatt ttgcatgaca tattttaaaa 2520 ataataaaca ctatttttag aagaacagaa 2550 <![CDATA[<210> 21]]> <![CDATA[<211> 1675]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 21]]> gccgaggccc agctgacccc ctgggctccc ccggcagcgg acagggaagg gttaaaggcc 60 ccctcccccc ggctccctgc cccctgccct ggggaacccc tggcctgtgg ggacatgaac 120 tgtgtttgtc acctggtcct ggtggtgctg agcctctggc cagatagagt cgttgcccct 180 gggccaccag ctggctcccc tcgagtgtct tcagaccctc gtgcagatct ggatagcgct 240 gtcctcttga ccaggtccct cctggcagac acacggcaac tagctgcaca gatgagagac 300 aaattcccag ctgatggaga ccacaatctg gactccctac ctaccttggc catgagcgct 360 gggacactgg gatctttgca gcttcctgga gtgctgacaa ggcttcgagt agacttaatg 420 tcctacttcc gacatgtaca gtggttgcgc cgggcagctg gtccttccct aaagactctg 480 gagccagagc tgggtgccct gcaagcccga ctggaacggc tacttcgtcg cttacagctc 540 ttgatgtctc gcctagcctt gccccaggca gccccggacc aacctgcggt ccctctgggc 600 cctcctgcct cggcctgggg aagcatccgg gcagctcatg ccatcctagg agggctgcac 660 ctgaccttgg actgggccgt gcggggcctg ctgttgttaa agactcggct gtaactcagg 720 actgaaagcc accatcgaca tcgtccttta aagccagatc ttatttattt atttattttg 780 gtacttggag cgggggagca tgatgaacag gggcatgcca caccccaaac agccacaccc 840 agctagataa agtccttcca ggagacctgg gtgagggggc tcacctgtgg cttatttata 900 cttatttatt taaagaattg gggtgggtgc atctgagacc ctgaggagca gggaactgag 960 atcctgggtc ctgggtcttt acgaagtcta ttcacagtgt cttcctcact tttttattat 1020 ttattaaaca attacttttt atattaggag gatggagggg gggaaaggaa gcctggggtt 1080 tttataccaa aatgtgattt tttttttgtg acacagagaa gtggggtatt taactattaa 1140 tgtggggtat ataactattt agaggttatt agcaggaata ttccaaaggg atctgagtgt 1200 aaaccggtac cctagcactt caaaggtcct caacagatac ttagcaaacg gaccgaaaca 1260 cctcatgtct aacagcacct gcatggtaca gagatagcaa ggttcaaggt gtttcagcaa 1320 gagtcacgca ccctggcaaa tgggaaacaa cttaggtttt cggggggggg gggggggcag 1380 gggacggatg aatctagtta gggaagttcc aggcaaagac ttctttagat gttgaacgtc 1440 cctgtgcccc gagagcagca gaggatagaa cctctctttc tatacatgga tatagatttt 1500 ttttgttttt caaaatggaa acaccaaaat gttgacaaca gctgcctcag ggttgaaaac 1560 aagagatggc actgtgggtg actgttattg tttgtgcttg cattttccag agtttccacc 1620 atgactgtat tttgcatgac acgtttacaa acaataataa acactatttt tagaa 1675 <![CDATA[<210> 22]]> <![CDATA[<211> 455]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 22]]> Met Ser Ser Gly Cys Ser Gly Leu Ser Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ala Ser Ser Ser Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Ser Val Lys Leu Cys Cys 35 40 45 Pro Gly Val Thr Ala Gly Asp Pro Val Ser Trp Phe Arg Asp Gly Glu 50 55 60 Pro Arg Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Glu Leu Val 65 70 75 80 Leu Thr Gln Ala Asp Ser Thr Asp Glu Gly Thr Tyr Ile Cys Gln Thr 85 90 95 Leu Asp Gly Ala Leu Gly Gly Thr Val Thr Leu Gln Leu Gly Tyr Pro 100 105 110 Pro Ala Arg Pro Val Val Ser Cys Gln Ala Ala Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Ser Gln Ile Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Val Leu Gly Ala Asp Ser Gln Arg 145 150 155 160 Arg Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Gly 165 170 175 Ala Ala Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Gln Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Arg Leu Leu 195 200 205 Asp Val Ser Leu Gln Ser Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Phe Pro Arg Arg Leu Arg Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Pro Arg Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Arg 260 265 270 Pro Gly Val Glu Pro Ala Gly Leu Glu Glu Met Ile Thr Asp Ala Val 275 280 285 Ala Gly Leu Pro His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp 290 295 300 Ala Gly Thr Trp Ser Thr Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser 305 310 315 320 Thr Gly Thr Val Pro Lys Glu Val Pro Ala Trp Gly Gln Leu His Met 325 330 335 Gln Pro Glu Val Glu Pro Gln Val Asp Ser Pro Ala Pro Pro Ser Pro 340 345 350 Ser Leu Gln Pro His Pro Arg Leu Leu Asp His Arg Asp Ser Val Glu 355 360 365 Gln Val Ala Val Leu Ala Ser Leu Gly Ile Leu Ser Phe Leu Gly Leu 370 375 380 Met Ala Gly Ala Leu Ala Leu Gly Leu Trp Ser Ser Lys Pro Ile Glu 385 390 395 400 Asp Pro Gly Gly Leu Arg Gln Ser Pro Leu Ile Ile Leu Ser Cys Trp 405 410 415 Cys Gly Trp Met Asp Ser Arg Ser Leu Trp Leu Gly Leu Ser Trp Lys 420 425 430 Phe Cys Leu Glu Pro Ile Ser Val Arg Pro Cys Ile Ser Asn Leu Pro 435 440 445 Ala Glu Arg Cys Leu Tyr Leu 450 455 <![CDATA[<210> 23]]> <![CDATA[<211> 431]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 23]]> Met Ser Ser Ser Arg Ser Gly Leu Thr Arg Val Leu Val Ala Val Ala 1 5 10 15 Thr Ala Leu Val Ser Ser Ser Thr Pro Cys Pro Gln Ala Trp Gly Pro 20 25 30 Pro Gly Val Gln Tyr Gly Gln Pro Gly Arg Pro Val Met Leu Cys Cys 35 40 45 Pro Gly Val Asn Ala Gly Thr Pro Val Ser Trp Phe Arg Asp Gly Asp 50 55 60 Ser Arg Leu Leu Gln Gly Pro Asp Ser Gly Leu Gly His Arg Leu Val 65 70 75 80 Leu Ala Gln Val Asp Ser Arg Asp Glu Gly Thr Tyr Val Cys Arg Thr 85 90 95 Leu Asp Gly Val Phe Gly Gly Met Val Thr Leu Lys Leu Gly Ser Pro 100 105 110 Pro Ala Arg Pro Glu Val Ser Cys Gln Ala Val Asp Tyr Glu Asn Phe 115 120 125 Ser Cys Thr Trp Ser Pro Gly Arg Val Ser Gly Leu Pro Thr Arg Tyr 130 135 140 Leu Thr Ser Tyr Arg Lys Lys Thr Leu Pro Gly Ala Glu Ser Gln Arg 145 150 155 160 Glu Ser Pro Ser Thr Gly Pro Trp Pro Cys Pro Gln Asp Pro Leu Glu 165 170 175 Ala Ser Arg Cys Val Val His Gly Ala Glu Phe Trp Ser Glu Tyr Arg 180 185 190 Ile Asn Val Thr Glu Val Asn Pro Leu Gly Ala Ser Thr Cys Leu Leu 195 200 205 Asp Val Arg Leu Gln Arg Ile Leu Arg Pro Asp Pro Pro Gln Gly Leu 210 215 220 Arg Val Glu Ser Val Pro Gly Tyr Pro Arg Arg Leu His Ala Ser Trp 225 230 235 240 Thr Tyr Pro Ala Ser Trp Arg Arg Gln Pro His Phe Leu Leu Lys Phe 245 250 255 Arg Leu Gln Tyr Arg Pro Ala Gln His Pro Ala Trp Ser Thr Val Glu 260 265 270 Pro Ile Gly Leu Glu Glu Leu Ile Thr Asp Ala Val Ala Gly Leu Pro 275 280 285 His Ala Val Arg Val Ser Ala Arg Asp Phe Leu Asp Ala Gly Thr Trp 290 295 300 Ser Ala Trp Ser Pro Glu Ala Trp Gly Thr Pro Ser Thr Gly Pro Leu 305 310 315 320 Arg Asp Glu Val Pro Asp Gly Ser Arg Gly His Glu Gln Lys Leu Glu 325 330 335 Ala Ala Ala Gln Glu Asp Ser Pro Ala Pro Pro Ser Pro Ser Leu Gln 340 345 350 Pro Asp Pro Arg Pro Leu Asp His Arg Asp Pro Leu Glu Gln Val Ala 355 360 365 Val Leu Ala Ser Leu Gly Ile Phe Ser Phe Leu Gly Leu Ala Val Gly 370 375 380 Ala Leu Ala Leu Gly Leu Trp Leu Arg Leu Arg Arg Ser Gly Lys Asp 385 390 395 400 Gly Pro Gln Lys Pro Gly Phe Leu Ala Pro Met Ile Pro Gly Asp Lys 405 410 415 Leu Pro Gly Ile Pro Asn Leu Gln Arg Thr Pro Glu Asn Phe Ser 420 425 430 <![CDATA[<210> 24]]> <![CDATA[<211> 3389]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 24]]> agagggcgag ggcagagggc gctggcggca gcggccgcgg aaggtgaggc ctggtgtaga 60 cgccaaagtc ttgtcacgag tgggcggggc agggtgatgt atgatctgaa aggccgagag 120 tgactgacga ctgtcagtgt gtgtgtgcct gtgagtctgt gtctgtgtga cagtatcatt 180 gtgtgcgatt ctgagtgtca cttggtgcag ctgtcagcta atgtgactgc gtgtgtcagt 240 gtgcatggag ctggggctgc atgtggctgt gcaagtgtgg gattatgtgt gtatctgtca 300 atgcacattt ttggtgggac tgggttgtgt gtttgtgtga gagggactgt gaccacatta 360 gggaatgtgt tttgggaagg tctctgtggg gtttgagacc atgtctgcca gcatgagagt 420 gggtggctgg ctttgtgtgt gccaatgtgt gacttcagca gtagcagagc aaaagtgagg 480 tttgtgacta tgtgtgtgtg ctgggtccta acttaaaccg tgtgggagta cagctgtatt 540 catgtattgg gggacctact tcaagagccc ataggactga cctttctctt aagtgtccag 600 catggacgga cacacccaca acacacgtgg cttcccctcc ttcttcctct gctcaagaat 660 ccccagcatc aggtctactg ctccttactt tctgtttccc tgcttgactc agtttccctt 720 acatgccgtt ttctctccct gttgctgtct tactagggat atctctgcgt gtttcttcat 780 agctttgttc ccctggtctc tgtgtggtgc atttccagtt ttgcctctcc tgtctctttg 840 tttctccctg tgcccctatg cctgccttcc ctgctgatct tgatctcttt ggctagttgg 900 gggcctgtaa cagtgatgag atgcaggtct gccactgcta agagctccct gagagagggg 960 gcttagaccg tgatgaggag ttgcttttag gcggtgctgt gagccctggt agggggctgt 1020 gtatgtgtgt gactgcgtga gtttatgaat atgtgtaagt gtatctgagt ctgaggctgt 1080 gtggctgtgc ctgtgtgact gtgagtgacc gcatgtgaga gtgtgtaagt ctgagggtaa 1140 ctgtgggtct tgtgtatctg gcaccaaggg accaaaggca tttcctggtg ctggggccca 1200 aagagtggag ggggaggtga gaaatggctg gaacttccag gggaggggga actgcactct 1260 ctggcctctc cttatatccc ccaacttggg gcctgctttc ccctggaagc acagccagct 1320 gtgccctaag gaaacatttg gtgaggagtg aaaagaggag gagtttatat ctgatttttc 1380 atttgattgt gtccacgtgt gttcaaaggc atgccctttt gttaactgtg cgtcatgagt 1440 ccatgtgtga atgtgactat gtctggctgt gtgaaaacac agggcatctc tcactgacag 1500 ggacataagt attagccacc ctcttttccc tcttgctggc cttggctgtg tctgtggctt 1560 cctttccaga cttgggggag gcctcttccc ttcacagggc cttgggtggg agggaaggag 1620 ggaggaggca gaagcgggga gggggcctgg ctaggggcgg cggagctcca gggcttagag 1680 ggggcggggc agggaagggg aaggagggga tggctttggg gtcccagaac tgagtggagt 1740 aggagacagg ggctgtagct ggtgagaagt cctggaggcc atggacactc tgctgctggg 1800 atcaccgaga tgagcagcgg ctgctcaggg ctgagcaggg tcctggtggc cgtggctaca 1860 gccctggtgt ctgcctcctc ctcctgcccc caggcctggg gccccccagg ggtccagtat 1920 gggcagcccg gcaggtccgt gaagctgtgt tgtcctggag tgactgctgg ggacccagtg 1980 tcctggtttc gggacgggga gccaaggctg ctccagggac ctgactctgg gctagggcat 2040 gaactggtcc tgacccaggc agacagcact gatgagggca cctacatctg ccagacgctg 2100 gatggtgcac ttgggggcac agtgaccctg cagctgggct accctccagc ccgccctgtt 2160 gtctcctgcc aagcagctga ctatgagaac ttctcttgca cttggagtcc cagccagatc 2220 agcggtttac ccacccgcta cctcacctcc tacaggaaga agacagttct aggagctgat 2280 agccagagga ggagtccatc cacagggccc tggccatgcc cacaggatcc cttaggtgct 2340 gcccgctgtg ttgtccacgg ggctgagttc tggagccagt accggattaa tgtgactgag 2400 gtgaacccac tgggcgccag cacacgcctg ctggatgtga gcttgcagag catcttgcgc 2460 cctgacccac cccagggcct gcgggtagag tcggtaccag gtttcccccg acgcctgcga 2520 gccagctgga cataccctgc ctcctggccg cgccagcccc atttcctgct caagttccgt 2580 ttgcagtacc gtccggcaca gcatccagcc tggtccacgg tgaggcctgg agtggagcca 2640 gctggactgg aggagatgat cacagatgct gtggctgggc tgccccatgc cgtacgagtc 2700 agtgcccggg actttctgga tgctggcacc tggagcacct ggagcccgga ggcctgggga 2760 actccgagca ctgggaccgt accaaaggag gtaccagctt ggggccagct acacatgcag 2820 ccagaggtgg agcctcaggt ggacagccct gctcctccaa gcccctccct ccaaccacac 2880 cctcggctac ttgatcacag ggactctgtg gagcaggtag ctgtgctggc gtctttggga 2940 atcctttctt tcctgggact gatggctgga gccctggcac tggggctctg gagctccaaa 3000 cctatagagg acccaggagg gcttcggcag agtccactta taattctgtc ttgctggtgt 3060 ggatggatgg acagtagatc cctatggttg ggtctcagct ggaagttctg tttggagccc 3120 atttctgtga gaccctgtat ttcaaatttg ccagctgaaa ggtgcctgta cctctgattt 3180 caccccagag ttggagttct gctcgaggaa tgtgtgtaat gtgtacatct gtgtccatgt 3240 gtgaccatgt gtctgtgagg cagggaacat atattctctg catgcatgta tgtaggtgcc 3300 tggggagtgt gtgtgggtcc ttggctcttg gcctttcccc ttgcaggggt tgcgcaggtg 3360 tgaataaaga gaataaggaa gttcttgga 3389 <![CDATA[<210> 25]]> <![CDATA[<211> 1713]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 25]]> ctcctgtagg agggagtctt ggaggccatg agcactcagt cactgtgatt ttcaagatga 60 gcagcagccg ctcagggctg accagggtcc tggtggccgt ggctacagcc ctggtgtctt 120 cctccacccc ctgcccccaa gcttggggtc ctccaggggt ccagtatggg cagcctggca 180 ggcccgtgat gctgtgctgc cccggagtga atgctgggac tccggtgtcc tggtttcggg 240 atggggactc gaggctgctc cagggacctg actctggact aggacacaga ctggtcttgg 300 cccaggtgga cagccgtgac gagggcactt acgtctgtcg gacgctggat ggtgtatttg 360 ggggcatggt gaccctgaag ctgggctccc ccccagctcg gccggaggtc tcctgccaag 420 cagtagacta tgaaaacttt tcttgtactt ggagtccagg ccgggtcagc ggtttgccca 480 cccgctacct tacttcctac aggaagaaga ccctgccagg agctgagagt cagagggaga 540 gtccgtctac cgggccttgg ccatgcccac aagaccccct ggaggcttcc cgatgtgtgg 600 tccacggggc agagttctgg agtgaatacc ggatcaatgt gactgaggtg aacccactgg 660 gcgccagcac gtgcctactg gatgtgagat tacagaggat cttacgtcct gatccacccc 720 aagggctgcg ggtggaatca gtacctggct acccgagacg cctgcatgcc agctggacat 780 accctgcctc ctggcgtcgc cagccccact tcctgctcaa gttccggttg caataccgtc 840 cagcacagca tccagcctgg tccacggtgg agcccattgg cttggaggag ttgataacag 900 atgccgtggc tgggctgccc catgcggtac gagtcagcgc cagggacttt ctggatgctg 960 gcacctggag tgcttggagc ccagaggcct ggggtactcc tagcaccggt cccctgcggg 1020 atgaggtacc tgatgggagc cggggacacg aacagaagct agaggcagca gctcaggagg 1080 acagccccgc tcctccaagc ccttccttgc agccagaccc aaggccactt gatcacaggg 1140 accccttgga gcaagtggct gtgttagcat ctctgggaat cttctctttc cttggcctgg 1200 ctgttggagc cctggctctg gggctctggc tgaggctgag gcggagtggg aaggacgggc 1260 ctcaaaagcc tggcttcttg gcaccaatga tcccagggga caagcttcca ggaatcccaa 1320 acctgcagag gaccccagag aacttcagct gatctcatct gcaaccctgt cagactgggg 1380 tggttaaatg gacaggcagg aggaggcagg acagcggatc cctatggatg gaggtctcag 1440 ttcgaagtct ggagcacttt tctttgacac ctgaactcca aacttgctgc cagctgctca 1500 ctctctggac ctctgatgcc gtccttgagg tggaagtccg cctgaggagc gtgtatcgaa 1560 gtctgtgtcc ctgtgactgt gtgtgtgtgt gatggggaga gcacgttctc cgtatgtgtg 1620 tgtatagatg attggagagt gtgtgtgtgg tcttgggctt ggctctcctg gggagcatgg 1680 agcgtgaaat aaagaggcgg acgtttttgg aaa 1713 <![CDATA[<210> 26]]> <![CDATA[<211> 917]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 26]]> Met Ser Ala Pro Arg Ile Trp Leu Ala Gln Ala Leu Leu Phe Phe Leu 1 5 10 15 Thr Thr Glu Ser Ile Gly Gln Leu Leu Glu Pro Cys Gly Tyr Ile Tyr 20 25 30 Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Ile Cys 35 40 45 Val Leu Lys Glu Ala Cys Leu Gln His Tyr Tyr Val Asn Ala Ser Tyr 50 55 60 Ile Val Trp Lys Thr Asn His Ala Ala Val Pro Arg Glu Gln Val Thr 65 70 75 80 Val Ile Asn Arg Thr Thr Ser Ser Val Thr Phe Thr Asp Val Val Leu 85 90 95 Pro Ser Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110 Gln Asn Val Tyr Gly Val Thr Met Leu Ser Gly Phe Pro Pro Asp Lys 115 120 125 Pro Thr Asn Leu Thr Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140 Gln Trp Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu 145 150 155 160 Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Gln Ser Lys His 165 170 175 Gly Thr Ser Cys Met Val Ser Tyr Met Pro Thr Tyr Tyr Val Asn Ile 180 185 190 Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Lys Val Ser Ser Glu 195 200 205 Ser Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Thr Pro Pro Tyr 210 215 220 Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys Leu 225 230 235 240 Ser Trp Val Ser Ser Gly Leu Gly Gly Leu Leu Asp Leu Lys Ser Asp 245 250 255 Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro Leu 260 265 270 Glu Asp Thr Met Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu Lys 275 280 285 Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Asp Ser Gly 290 295 300 Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr Tyr 305 310 315 320 Glu Asp Arg Pro Ser Arg Pro Pro Ser Phe Trp Tyr Lys Thr Asn Pro 325 330 335 Ser His Gly Gln Glu Tyr Arg Ser Val Arg Leu Ile Trp Lys Ala Leu 340 345 350 Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Ile Leu 355 360 365 Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Thr Gly Thr Glu 370 375 380 Leu Thr Val Asn Leu Thr Asn Asp Arg Tyr Val Ala Ser Leu Ala Ala 385 390 395 400 Arg Asn Lys Val Gly Lys Ser Ala Ala Ala Val Leu Thr Ile Pro Ser 405 410 415 Pro His Val Thr Ala Ala Tyr Ser Val Val Asn Leu Lys Ala Phe Pro 420 425 430 Lys Asp Asn Leu Leu Trp Val Glu Trp Thr Pro Pro Pro Lys Pro Val 435 440 445 Ser Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Glu Asn Ala Pro Cys 450 455 460 Val Glu Asp Trp Gln Gln Glu Asp Ala Thr Val Asn Arg Thr His Leu 465 470 475 480 Arg Gly Arg Leu Leu Glu Ser Lys Cys Tyr Gln Ile Thr Val Thr Pro 485 490 495 Val Phe Ala Thr Gly Pro Gly Gly Ser Glu Ser Leu Lys Ala Tyr Leu 500 505 510 Lys Gln Ala Ala Pro Ala Arg Gly Pro Thr Val Arg Thr Lys Lys Val 515 520 525 Gly Lys Asn Glu Ala Val Leu Ala Trp Asp Gln Ile Pro Val Asp Asp 530 535 540 Gln Asn Gly Phe Ile Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser Val 545 550 555 560 Gly Lys Glu Met Val Val His Val Asp Ser Ser His Thr Glu Tyr Thr 565 570 575 Leu Ser Ser Leu Ser Ser Asp Thr Leu Tyr Met Val Arg Met Ala Ala 580 585 590 Tyr Thr Asp Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr Thr 595 600 605 Pro Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro Val Cys 610 615 620 Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys Phe Asn 625 630 635 640 Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro Asp Pro 645 650 655 Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro Arg His 660 665 670 Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser Asp Gly Asn Phe Thr Asp 675 680 685 Val Ser Val Val Glu Ile Glu Ala Asn Asn Lys Lys Pro Cys Pro Asp 690 695 700 Asp Leu Lys Ser Val Asp Leu Phe Lys Lys Glu Lys Val Ser Thr Glu 705 710 715 720 Gly His Ser Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser Ser Arg 725 730 735 Pro Ser Ile Ser Ser Asn Glu Glu Asn Glu Ser Ala Gln Ser Thr Ala 740 745 750 Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg His Gln 755 760 765 Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln Pro Leu 770 775 780 Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu Val Asp Ser Val 785 790 795 800 Asp Gly Gly Asp Glu Ile Leu Pro Arg Gln Ser Tyr Phe Lys Gln Asn 805 810 815 Cys Ser Gln Pro Glu Ala Cys Pro Glu Ile Ser His Phe Glu Arg Ser 820 825 830 Asn Gln Val Leu Ser Gly Asn Glu Glu Asp Phe Val Arg Leu Lys Gln 835 840 845 Gln Gln Val Ser Asp His Ile Ser Gln Pro Tyr Gly Ser Glu Gln Arg 850 855 860 Arg Leu Phe Gln Glu Gly Ser Thr Ala Asp Ala Leu Gly Thr Gly Ala 865 870 875 880 Asp Gly Gln Met Glu Arg Phe Glu Ser Val Gly Met Glu Thr Thr Ile 885 890 895 Asp Glu Glu Ile Pro Lys Ser Tyr Leu Pro Gln Thr Val Arg Gln Gly 900 905 910 Gly Tyr Met Pro Gln 915 <![CDATA[<210> 27]]> <![CDATA[<211> 924]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 27]]> Met Lys Tyr Pro His Lys Met Leu Thr Leu Gln Thr Trp Val Val Gln 1 5 10 15 Ala Leu Phe Ile Phe Leu Thr Thr Glu Ser Ile Gly Glu Leu Leu Asp 20 25 30 Pro Cys Gly Tyr Ile Ser Pro Glu Ser Pro Val Val Gln Leu His Ser 35 40 45 Asn Phe Thr Ala Val Cys Val Leu Lys Glu Lys Cys Met Asp Tyr Phe 50 55 60 His Val Asn Ala Asn Tyr Ile Val Trp Lys Thr Asn His Phe Thr Ile 65 70 75 80 Pro Lys Glu Gln Tyr Thr Ile Ile Asn Arg Thr Ala Ser Ser Val Thr 85 90 95 Phe Thr Asp Ile Ser Ser Leu Asn Ile Gln Leu Thr Cys Asn Ile Leu 100 105 110 Thr Phe Gly Gln Leu Glu Gln Asn Val Tyr Gly Ile Thr Ile Ile Ser 115 120 125 Gly Leu Pro Pro Glu Lys Pro Lys Asn Leu Ser Cys Ile Val Asn Glu 130 135 140 Gly Lys Lys Met Arg Cys Glu Trp Asn Arg Gly Arg Glu Thr His Leu 145 150 155 160 Glu Thr Asn Phe Thr Leu Lys Ser Glu Trp Ala Thr His Lys Phe Ala 165 170 175 Asp Cys Lys Ala Lys Arg Asp Thr Pro Thr Ser Cys Thr Val Asp Tyr 180 185 190 Ser Thr Val Tyr Phe Val Asn Ile Glu Val Trp Val Glu Ala Glu Asn 195 200 205 Ala Leu Gly Lys Val Thr Ser Asp His Ile Asn Phe Asp Pro Val Tyr 210 215 220 Lys Val Lys Pro Asn Pro Pro His Asn Leu Ser Val Ile Asn Ser Glu 225 230 235 240 Glu Leu Ser Ser Ile Leu Lys Leu Thr Trp Thr Asn Pro Ser Ile Lys 245 250 255 Ser Val Ile Arg Leu Lys Tyr Asn Ile Gln Tyr Arg Thr Lys Asp Ala 260 265 270 Ser Thr Trp Ser Gln Ile Pro Pro Glu Asp Thr Ala Ser Thr Arg Ser 275 280 285 Ser Phe Thr Val Gln Asp Leu Lys Pro Phe Thr Glu Tyr Val Phe Arg 290 295 300 Ile Cys Cys Met Lys Glu Asp Gly Lys Gly Tyr Trp Ser Asp Trp Ser 305 310 315 320 Glu Glu Ala Asn Gly Ile Thr Tyr Glu Asp Arg Pro Ser Lys Ala Pro 325 330 335 Ser Phe Trp Tyr Lys Ile Asp Pro Ser His Ala Gln Gly Tyr Arg Thr 340 345 350 Val Gln Leu Met Trp Lys Thr Leu Pro Pro Phe Glu Ala Asn Gly Lys 355 360 365 Ile Leu Asp Tyr Glu Val Thr Leu Thr Arg Trp Lys Ser His Leu Gln 370 375 380 Asn Tyr Thr Val Asn Asp Thr Lys Leu Thr Val Asn Leu Thr Asn Asp 385 390 395 400 Arg Tyr Val Ala Thr Leu Thr Ala Arg Asn Leu Val Gly Lys Ser Asp 405 410 415 Ala Ala Val Leu Thr Ile Pro Ala Cys Asp Phe Gln Ala Thr His Pro 420 425 430 Val Met Asp Leu Lys Ala Phe Pro Lys Asp Asn Met Leu Trp Val Glu 435 440 445 Trp Thr Thr Pro Arg Glu Ser Val Lys Lys Tyr Ile Leu Glu Trp Cys 450 455 460 Val Leu Ser Asp Lys Ala Pro Cys Ile Ala Asp Trp Gln Gln Glu Asp 465 470 475 480 Gly Thr Val His Arg Thr His Leu Arg Gly Asn Leu Ala Glu Ser Lys 485 490 495 Cys Tyr Leu Ile Thr Val Thr Pro Val Tyr Ala Asp Gly Pro Gly Ser 500 505 510 Pro Glu Ser Ile Lys Ala Tyr Leu Lys Gln Ala Pro Pro Ser Lys Gly 515 520 525 Pro Thr Val Arg Thr Lys Lys Val Gly Lys Asn Glu Ala Val Leu Glu 530 535 540 Trp Asp Gln Leu Pro Val Asp Val Gln Asn Gly Phe Ile Arg Asn Tyr 545 550 555 560 Thr Ile Phe Tyr Arg Thr Ile Ile Gly Asn Glu Thr Ala Val Asn Val 565 570 575 Asp Ser Ser His Thr Glu Tyr Thr Leu Ser Ser Leu Thr Ser Asp Thr 580 585 590 Leu Tyr Met Val Arg Met Ala Ala Tyr Thr Asp Glu Gly Gly Lys Asp 595 600 605 Gly Pro Glu Phe Thr Phe Thr Thr Pro Lys Phe Ala Gln Gly Glu Ile 610 615 620 Glu Ala Ile Val Val Pro Val Cys Leu Ala Phe Leu Leu Thr Thr Leu 625 630 635 640 Leu Gly Val Leu Phe Cys Phe Asn Lys Arg Asp Leu Ile Lys Lys His 645 650 655 Ile Trp Pro Asn Val Pro Asp Pro Ser Lys Ser His Ile Ala Gln Trp 660 665 670 Ser Pro His Thr Pro Pro Arg His Asn Phe Ser Ser Lys Asp Gln Met 675 680 685 Tyr Ser Asp Gly Asn Phe Thr Asp Val Ser Val Val Glu Ile Glu Ala 690 695 700 Asn Asp Lys Lys Pro Phe Pro Glu Asp Leu Lys Ser Leu Asp Leu Phe 705 710 715 720 Lys Lys Glu Lys Ile Asn Thr Glu Gly His Ser Ser Gly Ile Gly Gly 725 730 735 Ser Ser Cys Met Ser Ser Ser Arg Pro Ser Ile Ser Ser Ser Asp Glu 740 745 750 Asn Glu Ser Ser Gln Asn Thr Ser Ser Thr Val Gln Tyr Ser Thr Val 755 760 765 Val His Ser Gly Tyr Arg His Gln Val Pro Ser Val Gln Val Phe Ser 770 775 780 Arg Ser Glu Ser Thr Gln Pro Leu Leu Asp Ser Glu Glu Arg Pro Glu 785 790 795 800 Asp Leu Gln Leu Val Asp His Val Asp Gly Ser Asp Asp Ile Leu Pro 805 810 815 Arg Gln Gln Tyr Phe Lys Gln Asn Cys Ser Gln His Glu Ser Ser Pro 820 825 830 Asp Ile Ser His Phe Glu Arg Ser Lys Gln Val Ser Ser Val Asn Glu 835 840 845 Glu Asp Phe Val Arg Leu Lys Gln Gln Ile Ser Asp His Ile Ser Gln 850 855 860 Ser Cys Gly Ser Gly Glu Met Lys Met Phe Gln Glu Val Ser Ala Ala 865 870 875 880 Asp Pro Phe Gly Pro Gly Thr Glu Gly Gln Ile Glu Arg Phe Glu Thr 885 890 895 Ile Gly Met Glu Ala Ala Ile Asp Glu Gly Met Pro Lys Ser Tyr Leu 900 905 910 Pro Gln Thr Val Arg Gln Gly Gly Tyr Met Pro Gln 915 920 <![CDATA[<210> 28]]> <![CDATA[<211> 918]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 28]]> Met Ser Ala Leu Arg Ile Trp Leu Met Gln Ala Leu Leu Ile Phe Leu 1 5 10 15 Thr Thr Glu Ser Ile Gly Gln Leu Val Glu Pro Cys Gly Tyr Ile Tyr 20 25 30 Pro Glu Phe Pro Val Val Gln Arg Gly Ser Asn Phe Thr Ala Thr Cys 35 40 45 Val Leu Lys Glu Lys Cys Leu Gln Val Tyr Ser Val Asn Ala Thr Tyr 50 55 60 Ile Val Trp Lys Thr Asn His Val Ala Val Pro Lys Glu Gln Val Thr 65 70 75 80 Val Ile Asn Arg Thr Ala Ser Ser Val Thr Phe Thr Asp Val Val Phe 85 90 95 Gln Asn Val Gln Leu Thr Cys Asn Ile Leu Ser Phe Gly Gln Ile Glu 100 105 110 Gln Asn Val Tyr Gly Ile Thr Ile Leu Ser Gly Tyr Pro Pro Asp Ile 115 120 125 Pro Thr Asn Leu Ser Cys Ile Val Asn Glu Gly Lys Asn Met Leu Cys 130 135 140 Gln Leu Asp Pro Gly Arg Glu Thr Tyr Leu Glu Thr Asn Tyr Thr Leu 145 150 155 160 Lys Ser Glu Trp Ala Thr Glu Lys Phe Pro Asp Cys Arg Thr Lys His 165 170 175 Gly Thr Ser Ser Cys Met Met Gly Tyr Thr Pro Ile Tyr Phe Val Asn 180 185 190 Ile Glu Val Trp Val Glu Ala Glu Asn Ala Leu Gly Asn Val Ser Ser 195 200 205 Glu Pro Ile Asn Phe Asp Pro Val Asp Lys Val Lys Pro Ser Pro Pro 210 215 220 His Asn Leu Ser Val Thr Asn Ser Glu Glu Leu Ser Ser Ile Leu Lys 225 230 235 240 Leu Ala Trp Val Asn Ser Gly Leu Asp Ser Ile Leu Arg Leu Lys Ser 245 250 255 Asp Ile Gln Tyr Arg Thr Lys Asp Ala Ser Thr Trp Ile Gln Val Pro 260 265 270 Leu Glu Asp Thr Val Ser Pro Arg Thr Ser Phe Thr Val Gln Asp Leu 275 280 285 Lys Pro Phe Thr Glu Tyr Val Phe Arg Ile Arg Ser Ile Lys Glu Asn 290 295 300 Gly Lys Gly Tyr Trp Ser Asp Trp Ser Glu Glu Ala Ser Gly Thr Thr 305 310 315 320 Tyr Glu Asp Arg Pro Ser Lys Ala Pro Ser Phe Trp Tyr Lys Val Asn 325 330 335 Ala Asn His Pro Gln Glu Tyr Arg Ser Ala Arg Leu Ile Trp Lys Thr 340 345 350 Leu Pro Leu Ser Glu Ala Asn Gly Lys Ile Leu Asp Tyr Glu Val Val 355 360 365 Leu Thr Gln Ser Lys Ser Val Ser Gln Thr Tyr Thr Val Asn Gly Thr 370 375 380 Glu Leu Ile Val Asn Leu Thr Asn Asn Arg Tyr Val Ala Ser Leu Ala 385 390 395 400 Ala Arg Asn Val Val Gly Lys Ser Pro Ala Thr Val Leu Thr Ile Pro 405 410 415 Gly Ser His Phe Lys Ala Ser His Pro Val Val Asp Leu Lys Ala Phe 420 425 430 Pro Lys Asp Asn Leu Leu Trp Val Glu Trp Thr Pro Pro Ser Lys Pro 435 440 445 Val Asn Lys Tyr Ile Leu Glu Trp Cys Val Leu Ser Glu Asn Ser Pro 450 455 460 Cys Ile Pro Asp Trp Gln Gln Glu Asp Gly Thr Val Asn Arg Thr His 465 470 475 480 Leu Arg Gly Ser Leu Leu Glu Ser Lys Cys Tyr Leu Ile Thr Val Thr 485 490 495 Pro Val Phe Pro Gly Gly Pro Gly Ser Pro Glu Ser Met Lys Ala Tyr 500 505 510 Leu Lys Gln Ala Ala Pro Ser Lys Gly Pro Thr Val Arg Thr Lys Lys 515 520 525 Val Gly Lys Asn Glu Ala Val Leu Glu Trp Asp His Leu Pro Val Asp 530 535 540 Val Gln Asn Gly Phe Ile Arg Asn Tyr Ser Ile Ser Tyr Arg Thr Ser 545 550 555 560 Val Gly Lys Glu Met Val Val Arg Val Asp Ser Ser His Thr Glu Tyr 565 570 575 Thr Leu Ser Ser Leu Ser Ser Asp Thr Leu Tyr Met Val His Met Ala 580 585 590 Ala Tyr Thr Glu Glu Gly Gly Lys Asp Gly Pro Glu Phe Thr Phe Thr 595 600 605 Thr Leu Lys Phe Ala Gln Gly Glu Ile Glu Ala Ile Val Val Pro Val 610 615 620 Cys Leu Ala Phe Leu Leu Thr Thr Leu Leu Gly Val Leu Phe Cys Phe 625 630 635 640 Asn Lys Arg Asp Leu Ile Lys Lys His Ile Trp Pro Asn Val Pro Asp 645 650 655 Pro Ser Lys Ser His Ile Ala Gln Trp Ser Pro His Thr Pro Pro Arg 660 665 670 His Asn Phe Asn Ser Lys Asp Gln Met Tyr Ser Asp Ala Asn Phe Thr 675 680 685 Asp Val Ser Val Val Glu Ile Glu Ala Asn Asn Lys Lys Pro Cys Pro 690 695 700 Asp Asp Leu Lys Ser Leu Asp Leu Phe Lys Lys Glu Lys Ile Ser Thr 705 710 715 720 Glu Gly His Ser Ser Gly Ile Gly Gly Ser Ser Cys Met Ser Ser Ser 725 730 735 Arg Pro Ser Ile Ser Ser Ser Glu Glu Asn Glu Ser Ala Gln Ser Thr 740 745 750 Ala Ser Thr Val Gln Tyr Ser Thr Val Val His Ser Gly Tyr Arg His 755 760 765 Gln Val Pro Ser Val Gln Val Phe Ser Arg Ser Glu Ser Thr Gln Pro 770 775 780 Leu Leu Asp Ser Glu Glu Arg Pro Glu Asp Leu Gln Leu Val Asp Ser 785 790 795 800 Val Asp Ser Gly Asp Glu Ile Leu Pro Arg Gln Gln Tyr Phe Lys Gln 805 810 815 Ser Cys Ser Gln Pro Gly Ala Ser Pro Asp Val Ser His Phe Gly Arg 820 825 830 Ser Ser Gln Val Pro Ser Gly Ser Glu Glu Asp Phe Val Arg Leu Lys 835 840 845 Gln Gln Gln Val Ser Asp His Ile Ser Glu Pro Tyr Gly Ser Glu Gln 850 855 860 Arg Arg Leu Phe Gln Glu Gly Ser Val Ala Asp Ala Leu Gly Thr Gly 865 870 875 880 Thr Asp Gly Gln Ile Glu Arg Phe Glu Ser Val Gly Met Glu Thr Ala 885 890 895 Met Asp Glu Asp Ile Ser Lys Ser Tyr Leu Pro Gln Thr Val Arg Gln 900 905 910 Gly Gly Tyr Met Pro Gln 915 <![CDATA[<210> 29]]> <![CDATA[<211> 5452]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<400> 29]]> ggggccgtgg ggggcggagc taggagagcc cgggtcagcg gcggacggag ggtggcgtgt 60 gcggtcggga ggccagagct tcgagccatc cgggctgcgg ctccgctgag ggaccggtgg 120 tgtgggccgg gatccgcggg gctgagggac gctcaggagc ggcgaggctc gcgtccggaa 180 ggaagacccg atagaaggaa catgacatct agaggcagcg aacttgtttc cgattcatgc 240 tttatcattt cttaatttcg tatgttggga acatccctgc aagatgtcag caccaaggat 300 ttggctagcg caagctttgc tttttttcct caccactgaa tctataggtc aacttttgga 360 accgtgtggt tacatctacc ctgaatttcc agttgtccag cgcggctcga acttcactgc 420 catttgtgtg ctgaaggagg cgtgtctgca gcattactac gtgaatgcca gctacatcgt 480 gtggaagacc aaccatgctg ctgttcccag ggagcaggtc actgtcatca acagaaccac 540 gtccagtgtc acgttcacag acgtggtcct cccgagcgtg cagctcacct gcaacatcct 600 gtcctttggg cagatcgagc agaatgtgta tggagtcacc atgctttcag gctttcctcc 660 agataaacct acaaatttga cttgcattgt gaatgagggg aagaatatgc tgtgccagtg 720 ggaccccgga agggagactt accttgaaac aaactacact ttgaaatcag agtgggcaac 780 agagaagttt cctgattgcc agtcaaagca tggcacttca tgtatggtca gctacatgcc 840 cacctattat gtcaacattg aagtctgggt ggaagcagag aatgcccttg ggaaggtctc 900 ctcagagtct atcaattttg accccgtgga taaagtgaaa cccaccccac catataattt 960 atcagtgacc aactcagaag aattatccag tatattaaag ctatcatggg tcagttcagg 1020 gctgggcggt cttttagatc taaagtctga catccaatat aggaccaaag atgcctcaac 1080 ttggatccag gtccctcttg aagatacaat gtctcctcga acttccttca ctgtgcagga 1140 cctcaagcct tttacagaat atgtgtttag gatccggtcc attaaggaca gtgggaaggg 1200 ctactggagt gactggagtg aggaggctag tgggaccaca tacgaagaca gaccatccag 1260 accaccaagt ttctggtata agacaaatcc atcccatggg caggaatata gatctgtacg 1320 gctcatatgg aaggcactgc ctctttctga agccaatggg aaaatcttgg attatgaagt 1380 gattcttacg cagtcaaagt ccgtctcaca aacgtacaca gtcactggca cagagctgac 1440 cgtgaatctc accaatgacc gctatgtcgc gtctctagca gcaagaaaca aggtgggcaa 1500 atcagctgca gctgtcctca ccatccccag cccccacgtc acagctgctt attctgtagt 1560 gaatcttaaa gcatttccaa aagataacct gctctgggtg gaatggacac ctccacctaa 1620 acccgtgagc aagtacatct tagagtggtg tgtgttgtca gagaacgcac cctgtgttga 1680 agactggcag caggaagacg ctaccgtgaa tcggacccac ttgagaggac gcctcctgga 1740 gagcaagtgc tatcaaatca cagtaactcc cgtattcgcc acggggcccg gaggctctga 1800 gtccttgaag gcgtacctca aacaagccgc tcctgccaga ggaccgactg ttcggacaaa 1860 gaaagtgggg aaaaatgaag ctgtcttagc gtgggaccag attcctgtgg acgaccagaa 1920 tggcttcatt agaaactact ccatatctta cagaaccagc gtgggaaagg agatggttgt 1980 gcatgtggat tcttctcaca cggagtacac gctgtcctct ctgagtagtg atacgttgta 2040 catggtccga atggccgcgt acacagatga aggtgggaaa gatgggccgg aattcacttt 2100 tacaacacca aagttcgctc aaggagaaat agaagccata gtcgtgcctg tgtgcttagc 2160 cttcctcctg acaaccctgc tgggcgtctt gttctgcttt aacaaacgag acctaattaa 2220 aaaacacatc tggcctaatg ttcctgatcc ttccaagagt catattgccc agtggtcacc 2280 tcacaccccc ccaaggcaca attttaactc caaagatcaa atgtactcgg acggcaattt 2340 cactgatgta agcgttgtgg aaatagaagc aaacaacaag aagccttgtc cagatgacct 2400 gaagtccgtg gacctgttca agaaggagaa agtgagtaca gaagggcaca gcagtggcat 2460 cgggggctct tcatgcatgt cctcctccag gcccagcatc tccagcaacg aggagaatga 2520 gtctgctcag agcaccgcca gcacggtgca gtactccact gtggtgcaca gcggctacag 2580 gcaccaggtc ccgtccgtgc aagtgttctc aaggtccgag tccacccagc ccctgctaga 2640 ctcggaggag cggccagaag acctgcagct ggtggatagt gtagacggtg gggatgagat 2700 cttgcccagg caaccgtatt tcaagcagaa ctgcagtcag cctgaagcct gtccagagat 2760 ttcacatttt gaaaggtcaa accaggtttt gtccggcaat gaggaggatt ttgtcagact 2820 gaagcagcag caggtttcag atcacatttc tcagccctat ggatccgagc aacggaggct 2880 gtttcaggaa ggctctacag cggatgctct tggcacgggg gctgatggac agatggagag 2940 atttgaatct gttggaatgg agaccacaat tgatgaagaa attcccaaaa gttacttgcc 3000 acagactgta agacaaggtg gctacatgcc gcagtgaagg actggctcct gaacttcagc 3060 aggaactgca aaataaagct aaagacgagt ggcttcagat gagaaacagt cctcactccc 3120 tgaagatagg cattgcctct aaggacaaag tcacacctgg gccgtctcca ttccagagta 3180 gctggaattc tccttcaagc actacatgaa ctgactttat cctctatagc tggaggactc 3240 tgtgctcttt cagaatgttt gcactgccga aaacaaagtg tgtctgagtt tataaagctg 3300 ttggtttgct acatagaaaa cgggggattt aaatgagcca caatgtcatg gcatcgttca 3360 gctgggctgg ttttgatgag actgaccatc cagatgccag cgagaaggcc agcagcatca 3420 tttaaaagtg ccctgtggca cagtgtccag attatgtcat ctagaagacg aaagaatgga 3480 ggggtggctc gtttctgggt ctgtcagaga agcatggcct gctccttgct gttggtatcg 3540 atgccggtta ctactgagga agaggataaa ctttaaagag aagcaacata gaagcacccg 3600 ctttcttata gtcacctaca gcctcccaag aaactgctta ttattgaaaa tgtctttccg 3660 agtcaatttc atccacccta tagtggacca ggctggcctc aaactcagag atctgtctgc 3720 ctctgcctct gcctctgcct ccagagtacc gggatgaaag gcagtgcacc accactgctc 3780 cacttacgaa gattgctgtt tttaaagact taagttgttg acatttttct gaacacacat 3840 aaccacacca gggacagatg attctagaga ctggttgagg aagcacttta tccagaatgt 3900 cttcaacttt aaattacttt aattgactcc accttgtttt gattttcaag aatagcaggg 3960 tgtttgttga agggtggcat ttcccagagc ctcatgcagt cccagaacac acatcccaac 4020 catgtcagcg accaccacaa tgacagaagt cctcctacag agctgaggaa gctggaaggg 4080 tcctgctagt ttgcagggtg ggctttgaac ccacagccct gtgcatgcta gacattcact 4140 ctaccgctga gctgctcctc cgcccggctc attatgtcat ctaggctctc gtgatcctcc 4200 tggcccagct tcctgactgt ctgggactgt ggatgtgtgc tgtcacacac ccaaccaggt 4260 ctttttaata tctgccattt atgaggtaga gtttttacac gacttaggac tatcttaaac 4320 ctattccttc tagttgcttt attaaggaat agcctaggca tccagtgttt agcactaaag 4380 ccattaatgt atttgtgcct aacttcccag tgtgacatgg aggtgggggc taaaggtaga 4440 cactgggcag acaggaattg gctgagcgcc gttagaggct gatcactaag tgtgctcaca 4500 ggaaaagggt tgaagtttca gagcatgggc acccagatca tttatagcgg ttaccacaca 4560 gtgcctagga ggagttgata tgcacttagt tggatgcagt ttcacctttt actctcagaa 4620 ggttgtttat attctacttg ctgatgtgtt atcatttata tttttatact gggtagtcct 4680 tttctgtgtt ctttcacatg tataatcctc gtgagactgt acatgctttg ctctggtata 4740 ttcagttgcc tccttggcaa aaccagcctg gaattgccaa aatgccggaa gtgaagggag 4800 atggtgaaag tcgggcacag gaaggccagg tcaggggcag agagaccaga attcacacta 4860 caaggctggc accattgcca ttcaagttgg acgtcaaagc ctgatcccag ttaggactga 4920 gttttctatg tatatatctg ccaggaagtt aacacttgct gaatttctca tcttctcaca 4980 gtaagcagtc tagttatggg actctatcca tgttcagctg tgacttccct catatcagac 5040 agtggtgctg tgaacgttgc agtgtgaagt ctgtactggc tagggatggt agcccagcgt 5100 gagttcaggc atgaacatag aggccactga aggaagagcc tcctggaagc aagttggcac 5160 gttaaatccc agacagaaag tgtcccaggg agccagggcc tccgccagca gggagggggt 5220 gtgctcactg caggaacgtt catttagaag atgtaccatg gagcacctcc ctttgctcta 5280 agagaaaacc catcttaaag ttcatcttga atacagactt cgctcgagca tgttttagaa 5340 taatctggat gctgtacctt gtaccttagg tagcagagaa agtaatctgg cgtctttctg 5400 taaaaccgtc taataaagct agttctgccc gtgggctcgt attctttcgt gt 5452 <![CDATA[<210> 30]]> <![CDATA[<211> 7509]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 食蟹獼猴]]> <![CDATA[<400> 30]]> ggggagcgcc ccgccccgcc gcgggactgg ggcggcgcgc tacctctgcg gagaaggatc 60 cgcgagcgtt ccggagccgg ggcgagcagc caaaaggccc gcggagccgc gctgggccgc 120 cccggtgcag ctgaaccggg ggccgcgcct gccaggccga cggctctggc ccagcctggc 180 gccaagggtt tcgtgcgctg tggagacgcg gagggtcgag gcggcgcggc ctgagtgaaa 240 cccaatggaa aaagcatgac atttagaagc agaagactta gcttcaaatc cctactcctt 300 cacttagtga ttttgtgatt tgggtatctt ttaaggagac atattatgaa atatccgcac 360 aagatgttga cgttgcagac ttgggtagtg caagccttgt ttatttttct caccactgaa 420 tcaataggtg aacttctaga tccatgtggt tatatcagtc ctgaatctcc agttgtacaa 480 cttcattcta atttcactgc agtttgtgtg ctaaaggaaa aatgtatgga ttattttcat 540 gtaaatgcta attacattgt ctggaaaaca aaccatttta ctattcctaa ggagcaatat 600 actatcataa acagaacagc ctccagtgtc acctttacag atatatcttc attaaatatt 660 cagctcactt gcaacatcct tacatttgga cagcttgaac agaatgttta tggaatcaca 720 ataatttcag gcttgcctcc agaaaaacct aaaaatttga gttgcattgt gaatgaggga 780 aagaaaatga ggtgtgagtg gaatcgtgga agggaaacac acttggagac aaacttcact 840 ttaaaatctg aatgggcaac acacaagttt gctgattgca aagcaaaacg tgacaccccc 900 acctcatgca ctgttgatta ttctactgtg tattttgtca acattgaagt ctgggtagaa 960 gcagagaatg cccttgggaa ggttacatca gatcatatca attttgatcc tgtatataaa 1020 gtgaagccca atccgccaca taatttatca gtgatcaact cagaggaact gtctagtatc 1080 ttaaaattga catggaccaa cccaagtatt aagagtgtta taagactaaa atataacatt 1140 caatatagga ccaaagatgc ctcaacttgg agccagattc cccctgaaga tacagcatcc 1200 acccgatctt cattcactgt ccaagacctt aaacctttta cagaatatgt gtttaggatt 1260 tgctgtatga aggaagatgg taagggatac tggagtgact ggagtgaaga agcaaatggg 1320 atcacctatg aagatagacc atctaaagca ccaagtttct ggtataaaat agatccatcc 1380 catgctcaag gatatagaac tgtacaactc atgtggaaga cattgcctcc ttttgaagcc 1440 aatggaaaaa tcttggatta tgaagtgact ctcacaagat ggaaatcaca tttacaaaat 1500 tatacagtta atgacacaaa actgacagta aatctcacaa atgatcgcta tgtagcaacc 1560 ctaacagcaa ggaatcttgt tggcaaatca gatgcagctg ttttaactat ccctgcctgt 1620 gactttcaag ctactcaccc tgtaatggat cttaaagcat tccccaaaga taacatgctt 1680 tgggtagaat ggactactcc aagggaatct gtaaagaaat atatacttga gtggtgtgtg 1740 ttatcagata aagcgccctg tatcgcagac tggcaacagg aagatggtac tgtgcatcgc 1800 acccatttaa gagggaactt agcagagagc aaatgctatt tgataacagt tactccagta 1860 tatgctgacg gaccaggaag ccctgaatcc ataaaggcat accttaaaca agctccacct 1920 tccaaaggac ctactgttcg gacaaagaaa gtagggaaaa acgaagctgt cttagagtgg 1980 gaccaacttc ctgttgatgt tcagaatgga tttatcagaa attatactat attttataga 2040 accatcattg gaaatgaaac cgctgtgaat gtggattctt cccacacaga atatacattg 2100 tcctctttga ctagtgacac attgtacatg gtacgaatgg cagcatacac agatgaaggt 2160 gggaaggatg gtccagaatt cacttttact accccaaagt ttgctcaagg agaaattgaa 2220 gccatagtcg tgcctgtttg cttagcgttc ctattgacaa ctcttctggg agtgctgttc 2280 tgctttaata agcgagacct aattaaaaaa cacatctggc ctaatgttcc agatccttca 2340 aagagtcata ttgcccagtg gtcacctcac actcctccaa ggcacaactt tagttcaaaa 2400 gatcaaatgt attcagatgg caatttcact gatgtaagtg ttgtggaaat agaagcaaat 2460 gacaaaaaac cttttccaga agatctgaaa tcattggacc tgttcaaaaa ggaaaaaatt 2520 aatactgaag gacacagcag tggtattggg ggttcttcat gcatgtcatc ttctaggcca 2580 agcatttcta gcagtgatga aaatgaatct tcacaaaaca cttcgagcac tgtccagtat 2640 tctactgtgg tgcacagtgg ctacagacac caagttccat ccgtgcaagt cttctcaaga 2700 tccgagtcta cccagccctt gttagattca gaggagcggc cagaagatct acaattagta 2760 gatcatgtag atggcagtga tgacattttg cccaggcaac agtatttcaa acagaactgc 2820 agtcagcatg aatccagtcc cgatatttca cattttgaaa ggtcaaagca agtttcatca 2880 gtcaatgagg aagattttgt tagacttaaa caacagattt cagatcatat ttcacaatcc 2940 tgtggatctg gggaaatgaa aatgtttcag gaagtttctg cagcagatcc ttttggtcca 3000 ggtactgagg gacaaataga aagatttgaa acaattggga tggaggctgc cattgatgaa 3060 ggaatgccta aaagttactt accacagact gtacggcaag gtggctacat gcctcagtga 3120 aggactagta gttcctgctg caacttcagc agtacctata aagtaaagct aaaattattt 3180 tatctgtgaa ttcagatttc aaaaagtctt cactctctga agatgatcat ttgcccttaa 3240 ggacaaaaat gaactgaagt ttcacatgag ctatttccat tccagaatat ctgggattct 3300 actttaagca ctacataaac tgacttcatc ctcagactag ctgaatgatt ttgtgctgtt 3360 tcaggatgtt tgcactgaag aaaaatagaa agcttatctg aaatttataa aactttttgt 3420 tttgctacat aaaaaacaag gtatttaaat aataagcagt gatatgctta gtgagcacag 3480 ctatactgat tttgatgagt catcaaagtg gcttagggac agttaatata aaagattaga 3540 ggagcaaggt gtagaccatc tacttcagct aaaataactt aaaaagagat ccataggcca 3600 taactatatg agcccagctt ttgtaatctg ccaaaaaaaa atgagcagcc tcgtgtatat 3660 caatgtacac aatattcctt aggtcccttc cattggtagt gatgctgcca gttattactg 3720 gagaaaagga attctagagc tttaacttgg caggttaaaa gtactcattt tttattcatc 3780 aataattagt aatctcacta gttttcaaaa atttgcatat tattgacaac ctctttgaag 3840 aactatttca caaactcaac agagtgccat gataagagct agggatcccc caaactatct 3900 caagcatcta aaaaattgcc atttttaaag gcttaaattg tagtaataaa gggggaaaaa 3960 gtggtagtaa agaggaaaaa aaaaaacaaa gcatctaaaa aaatggcatt tttaaaggct 4020 taaattgctg atgtttatat atatatacac acacatatat acacacatat cattgacctt 4080 aagacttcag agaattgggt agatgaagca ctttatatag tatatatctt cagcttaaat 4140 ttgtttagag tactttttaa aatttttaag taggtaaaga tttaaaactt tttattttta 4200 gtgaatgttt gaagcaaact aagatgactt gggcaatatt taccaaaaca aaacagaacc 4260 ccaaaaaatg tacatcttga tcttagcaaa tatccttatt gtagagacag taaagagatg 4320 gtattttaat atctgcagtt ctgaggtagg gtggaactta gttctacatt gtgatttagg 4380 aatttttaaa accctttttc ttcaagggag aagtgaccca ggcctcaagt ttaatgctaa 4440 agccactagt gtacttatgc tgtcccctaa ccaccacttg gcattatgga gacagaggct 4500 aaatataggg gctttcttaa gaaagtaaga ggaaattagc aagcattatt agtgattgac 4560 tactgctatc aagtgaattc aaaggaaaca gatttttaat gccatattta agttacagaa 4620 accaggcatg cttagaatag tttctagagg ttattggaga atagaaagct aagaaaactt 4680 ggtatacatt tacaattgaa atataattac actttttact ctcagaatat tattcacatt 4740 aggcttcctg tttcttttat attcttgcat ttatataaca cctgatcctt tcaaagttct 4800 ttcacatatt atatgatcgt ctttatgaaa aaaaatgctt ttttctgata tattcagttt 4860 cccacttgag acaaaattag attaatagag tcactaattc aaagtagatg aggaaaatca 4920 ggcacagaga agtaaaggta gagatagacc caaatttaca caacaagata atgatattgc 4980 caccgtttaa gttggtcatc aaaggctggg ctggatttgt cttgctatat gtgtcaggaa 5040 atttatacct attacatttt ccattttctc aaaataagtc acatgactgt aatgtttagc 5100 tgcaacttat aacaaatagt gtcatgaaga atgttttagt gtgaggtttg tacatttcag 5160 agtcagttat acaatgtgaa ctcttgatct atgggaatga gaatggagga tcattgaagg 5220 ccatgataca aacaaatgta catgttaaag cctgtataaa acatggtaca gtgagtgaat 5280 acccccatcc ccaagaacac ttgatacata ttaaatgggt atatgattac tgtccagaaa 5340 tgcattccgg agatgaacat tcatttgagc actaatatat aatgtacatc ttctgcccta 5400 aggagaaaat aaattataaa acttgtttta cattcaaaat tactttcccg agcatgtctt 5460 agaataatct gtgtgttgat gcatgtaaat tgtactttag gtaggcaaag aaacaaattt 5520 ggttatttat gtaaaaacta atctaataaa gttagtgact ttatcacttt aaatctttag 5580 agtctaaaag tggtgtttaa agtaacacta gcacatcaga gaaccttgtc tggacaaaac 5640 tagttcactc actgcttctg caactgcagt tgctcccttc agggttatag aaaaaggacc 5700 caaatgttac atgtgttgat attataactt gtcagttact gatgtctgta gtatcctacc 5760 ctcacctctg aaagggataa tactgaataa ttattagaaa actataaaac ttcacacttt 5820 gtaccattaa gacctaaaat tttaatccta tcctttttta tgatggatca gtcagcactc 5880 gaacagcagc aaggaaaaaa agcaaatttc attcacatat tctgtgttca tctctcttct 5940 ctacctaatt gttcatttaa tttcagcctt gttccttgat aagggatttt accacatgaa 6000 gtcatccagt gtccctagct cttactgtga agttagtgga gtataattac aaatgttaca 6060 acttaaaaat gttacaaaac atttatcaaa gctcatattt agagtatcta gtttgagaaa 6120 tagaaatcaa ttattaaaga tgtctttttt ctacccaatt taactagtta aaaccatgac 6180 atgtaaatgt agaagtagaa taatcataca gaattcccta aaatgtttct gtttactaac 6240 attgagcaag tacatcaagt agagagatct tccttcattc tgttatagtc cacatcattc 6300 taattttgct cagttattat taagagcata ttcctaaacc atacactttt atttcaataa 6360 agttttattt tgttgagatg aataaaatat caaagttata agctacataa gacaaaagtt 6420 caattgttca aacaaattta ctgggatagc tttctattat agggattgtt agattatatt 6480 gctctggtaa gattactttc taaaaagttt gtacttttct gtaaaataaa agaatatgga 6540 atcataaaat ggcacgtgtt ttagggttag cctaaaattg ggcattgtca tcgatttcaa 6600 agaaggtatg aactagcagg cttacagcct aatctttgga ctggtccttg gcagcagttc 6660 cttttcagac tcaaacagaa ttcagataga tgtaagtcaa aacaaaactt cacaaagcca 6720 agcatattat cttttgcatt aacctatttc tccatcatac atgatactag tatgtgcatt 6780 agcatgatat tctcatatac attatattaa aaattaaaag gtggcagctc agggtgagct 6840 cttctgttat tcatttgttc ctaaattttt aagggctttt tctcagtcaa tagtttgtac 6900 aaactggtta gtttaacttc attatccatt tctttaaagt tgatggatcg tgataagatg 6960 catttaaggc caatagtgat agattttttt tatctcttga acacaagctt tgtctgaatg 7020 atactcttat ctcttaaaca caagctttga atgataacta caggttttaa gtgctgttac 7080 attaatacca taatgtgatg tgttagaaac aaagggatat ttcaaaggta ggtatttgaa 7140 aattctctag tctcaatgta tatgtgtatt gaatatactc taaaaataaa tgtgcaattt 7200 gctagtagga caatgcagtg attagcatta ggtatgtctc ttttatatcc tagctgtgtc 7260 ccactttctt ctaagtgcaa tcctttcatg ttcacttgct gttttattcc atctactctt 7320 aactgcattt ggaaggcttg tctagagtat agcatgtatt tttacctttg cagtgaattg 7380 catgtgctaa ttgtaaccac agctattttt atgttgacat aactccaaat gttatattaa 7440 atgttctatt acatatcagc tctaatccct taagtaaagt ttaagaaata aattcttgtt 7500 caaattgtt 7509 <![CDATA[<210> 31]]> <![CDATA[<211> 7454]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 褐家鼠]]> <![CDATA[<400> 31]]> gagcatccct tgcaagatgt ccgcactaag gatctggcta atgcaagctt tgcttatttt 60 cctcactact gagtctatag gtcaacttgt ggaaccatgt ggttatatct accctgagtt 120 tccagttgtc cagcgtggct ctaacttcac tgccacttgt gtgctaaagg agaagtgtct 180 gcaggtgtac tccgtgaatg ccacttacat cgtgtggaag acaaaccatg ttgccgttcc 240 taaggagcag gtcacagtca tcaacagaac ggcatccagt gtcacattca cagacgtggt 300 ctttcagaac gtccagctca cctgcaatat cctgtcattt ggacagatcg agcagaatgt 360 gtatggaatc accatacttt caggctatcc tccagatata cctacaaatt tgagttgcat 420 tgtgaatgag gggaagaaca tgctgtgtca gtgggaccca ggaagggaga cataccttga 480 aacaaactac actttgaagt cagagtgggc aacagagaag tttcctgatt gtcgaacaaa 540 gcatggcacg agctcctgca tgatgggcta tacccccatc tattttgtca acatcgaggt 600 ctgggtggag gccgagaatg cccttgggaa tgtctcctca gagcctatca attttgaccc 660 cgtggataaa gtgaaaccca gcccacctca taatttgtca gtgaccaact cagaagaatt 720 atccagtata ttaaaactag catgggtcaa ttcaggtttg gacagtattt taaggctgaa 780 gtcggacatc caatatagga ccaaagatgc ctcaacttgg attcaggtcc ctcttgaaga 840 tacagtgtct ccccggactt cgttcactgt tcaggatctc aagcctttta cagaatatgt 900 gtttaggatt cggtccatta aggagaatgg gaagggctac tggagtgact ggagtgagga 960 ggcgagcggg accacatatg aagacagacc atccaaagcg ccaagtttct ggtataaggt 1020 aaatgcaaac catccacagg agtataggtc tgcacggctc atatggaaga cattgcccct 1080 ttctgaagcc aatgggaaga tcttggatta tgaagtggtt cttacacagt ccaagtcagt 1140 ttcgcaaact tacacagtta acggcacaga gttgatagta aacctcacca ataaccgcta 1200 tgtagcgtct ctagcagcaa gaaatgtggt cggcaagtcc cctgcaaccg tcctcaccat 1260 ccccggctcc cacttcaaag cttctcaccc cgtagtggat cttaaagcat ttccaaaaga 1320 taacctgctc tgggtagaat ggacaccgcc atctaaacct gtgaacaaat acatactaga 1380 gtggtgtgtg ttgtcagaga actcaccctg catcccagac tggcagcaag aagatggcac 1440 tgtgaatcgg acccacttaa gaggaagcct actggagagc aagtgctatc tgatcacagt 1500 aaccccagtg tttcccggtg ggcctggaag ccctgagtcc atgaaggcgt acctcaaaca 1560 agcagctcct tctaaaggac cgactgttcg gacaaagaaa gtggggaaaa atgaagctgt 1620 cttagagtgg gaccatcttc ctgttgatgt ccagaacgga ttcattagaa actactccat 1680 atcttataga accagtgttg gaaaagaaat ggttgtgcgt gtggattctt ctcacacaga 1740 atacacactg tcctctttga gtagcgatac actgtacatg gtccacatgg cagcatacac 1800 agaagaaggt gggaaggatg ggccggaatt cacttttaca acactaaagt ttgctcaagg 1860 agaaatcgaa gccatagtcg tgcctgtgtg cttagctttc ctcctgacaa cgctgctggg 1920 agtcttgttc tgctttaata aacgagacct aattaaaaaa cacatctggc cgaatgtccc 1980 agatccttca aagagtcata ttgcccagtg gtcacctcac acccccccaa ggcacaattt 2040 taactccaaa gatcagatgt actcagatgc caatttcact gacgtaagcg ttgtggaaat 2100 agaagcaaac aacaaaaagc cttgtccaga tgacctgaaa tccttggacc tgttcaagaa 2160 ggagaaaata agtacagaag ggcacagcag tggcattggg gggtcctcgt gcatgtcctc 2220 ttctaggccc agcatctcca gcagtgagga gaacgagtct gctcagagca ccgcaagcac 2280 ggtgcagtac tccaccgtgg tgcacagcgg ctacaggcac caggtgccgt cagtgcaagt 2340 gttctcaagg tctgagtcca cccagcccct gctagactcc gaggagcggc cagaggacct 2400 gcagctggtg gatagtgtgg acagcggtga cgagatctta cccaggcaac agtatttcaa 2460 acaaagctgc agtcagcctg gagccagtcc agatgtttca cacttcgaaa ggtcaagcca 2520 ggttccgtca ggcagtgagg aggattttgt cagactgaaa cagcagcagg tttcagatca 2580 catttcagag ccctatggct ccgagcaacg gaggctgttt caggaaggtt ctgtggcaga 2640 tgctcttggc acagggactg atggacagat agagagattc gaatctgttg gaatggagac 2700 agcgatggat gaagacattt ccaaaagtta cttgccacag actgtaagac aaggtggcta 2760 catgccacag tgagggaccg gctcctgcgg gacctcagcg ggactgcgaa gtaaagctaa 2820 aatgctcgtg acttcagatg ggaaataatc ttcagtccct gatgataacc attgccttta 2880 aggacaaagt cacaactggg ccatctccat tccagagtat ctgggattct ccttcaagca 2940 ctacatgaac tgactttatc ctctgaatag ctggaggact ctgcgctgtt tcagaatgtt 3000 tgcactgctg aaaactaagt gtgtctgagt ttgtaaagct tttgttttgc tccatagaaa 3060 gtggggaatt taaatgagcc gagccgagcc atggcgtcgc tcagctgtgc tggtggtgag 3120 actgaccatt cagatgccgg gagcaaaggt ctaaccctcc tcagccagca gcttcatgtc 3180 agagttcccc gggcagactg cccagattgt gtcacctatc aaaaaaaaaa aaaaaagagt 3240 ggagggggca gggtggctca tttctgggtt tgttattaga gaatcttggc ttgtttggtg 3300 ccgttggtat cgatgcttcc agttattact gaagaaaagg acgaactttc aagagaagca 3360 gcatagaaga acccattacc ttatattcac ctaaaacctc acagaaacct gcttattagt 3420 gataacattt ttcaaagtca gtttcaccaa cactctagtg gaccgggctg gcctcaaact 3480 cacagagatt tgtctgcctc agcctccgga gtactggggt taaaggcatg taccaccacc 3540 accacttgac ttaaaaattt gctgttttta aagacttaag ttgctgacat ttttctgaac 3600 gtatataaac acaccaggga cagatgattc cagatgttgg tggaggaagc actttatcca 3660 gaatgtcttc aactgtacat tactttaatt gactccacct tgtttttgtt tttaagacta 3720 gcaaggtgtt tgctgaaggg tggcattgcc cagaggctca ggcgagtccc agagctcacg 3780 caccgatgtc tgtgaccacc accgtggcag aagtcctcct acaaagctga cgaagccgtg 3840 agggttttgt tagtttgctg ggcggggatt gagcccacag ccttgtacat gctagacact 3900 accactgagc tcacctacac atctcactat gttatgtagg ctcaagcgat cctcctgtct 3960 cagcttcctg agtgttggga cttcgggtgt gcgctgccac acacccgacc aggtagtttt 4020 aatatctgcc atttatgagg tagagtttta cacaggattt aggactatct taaacctgtt 4080 ccttaggttg ctttgttaag gaatagcctg gacatccggt gtttagcact aaagccatta 4140 tgtatgcgcc taactttcca gtgacatgtc ctgggtgggc aggagttgac tgagcgccat 4200 tagtggttga ttaccaccaa gtgtgcgcac aggaaaagga ttaaagtttc agaacatggc 4260 ccttaatcat tcatagccgc tgccccacgg tggctgagga ggagttgatg tgcactgagc 4320 tggatgtggt tttgccgttc actcagagga ctgtttatac tctacttgtg atgtgttatc 4380 gttatatttt tatactaggt aatcctgttc tgagtccttt cacgtgtata atcctcatgg 4440 gactgtacgt gctttgctct ggtattcagt tgccttcttg gcaaaaccag cctagaattg 4500 ctaaaatgcc aggattgaag ttagatgatg aaagtcgggc acaggaaggc caggtcaggg 4560 tcagagagac cagaattcac actacaaggc tggcaccatc accattcaag ttgggcatgg 4620 aagcctgggc ccggcaggac tgagctccct atgtatgtgt atctgccagg aaattaacac 4680 ttgctaaatt tcccatcctc tcacagcgag cagtgtacct gtgcgctgct gtgaacgttg 4740 tagtgtgaag tctgtcctgg ggtagggagt taccagcgtg aggtcaggga tgaacacagc 4800 tcactgaaga cgagcctggt ggaagagagt ttgccattgt gcccactgca tgaacattcc 4860 ctcgggggat gtatcatgga gcacctctct ttgctctaag aaagagtctt agaattcatc 4920 ttaaatacag actttgctac agcatgttta agaataatct ggatgcacgt aacttgtatt 4980 ttaggtaggc agagaaacta atctggctgc tttctgtaaa accagtctaa taaagctaat 5040 tctatacatg ttcttttctt ctctcgtgtg taaaactgta gtttaaggca atcagaaaac 5100 aacctatctt gtggccaaaa ctagttcact gtagtttaag gcaatcagaa aacaacctat 5160 cttgtggcca aaactagttc actgcttctg atgcagttgc ctgcttagga gtcatagaca 5220 aagaaggttt aatgtaatca atattaccaa acagagttcc catcttttac tcaccaaaca 5280 aagtcagtcc ttcgaaaagc ataagtcagt actggcggac acagagaagc caaagtagga 5340 aaagtgcaac cccatcctgg ttctcctgtc tacagttcat tcagcttctg catagttcct 5400 gaactgtagg gttttttgct tttcgggttt tttttgtttt gttttggggt ttgtttgttt 5460 gttttgtttt tggggatttt gggggggtgt ttttggtttt ttaagatagg gtttctctgt 5520 gtggccttgg ctgtcctgga tctgccagcc tggtgtgcca ccactgtctg gtgagaccat 5580 agttcttact gtgaacttaa agggctgaag aggtagaagg gcttatggga cggactgcag 5640 cttctaattt tttctcaacc ctactttaat aatggttctt aaatgcttta accttccttc 5700 tagcccacca cccattaggg gtagtggaaa agagaggata caggtgaagt ggacctgttt 5760 agaaatggtt ctttggagca aatcctgtct gcactgtcag gaaatcagca gttcggttca 5820 ctggtcagca gtggcagccc cactcgagaa cacacttcct ggatgcacca gcagtccagt 5880 tcagtagtgt cgggagagca gcagcggtgg cccgacctag caggagtggc caggcctcag 5940 cctcagcaca agtcagcaga aagaaccaga agttctcagc tgtgcctctc agtgaaatga 6000 aaatatccaa gactgttgag tcctatatat actgcctcca aatatcatgt gtccgtgggt 6060 gtggtctccc cacgtgtctt gcctcagtat gtgagtctgt atcagctgac atgactgcca 6120 atcgacccag gtcaaggaat tcgcaagaag ccaccagaac acacgttttt tggtgtttct 6180 ctttatggag tcctgacaaa tggcgcacaa tgatacatgt gaggcaaacc aatatgtgtg 6240 ttattacaaa gaatccttca tcatgtgtcc tttcgaatgc tttctgtagc aaaatatcct 6300 ttcacctgtg tctgctttag caaaacaccg tccaacacaa ctgactttcc aaagaacctt 6360 aagtttccat tccacaggac actgtcaaag ccaggactgc taacgtccca ttagacatcg 6420 cactgttttt aaagctgtct tctttttcct gcccacagaa ttagagctac agcattcctc 6480 agtgtttgtc atagacatgt attaaccagg tagaacaagc caggaggttt tagactatta 6540 agtttactct cctgcttcat gttactgagt ttcctttaaa agcaagcttt taacacaact 6600 tctggttagt agagattttc atgacatgag tagaatcagt gagctgcaaa aaaaagtgta 6660 aaggtgaatt gttaaaaata accccttggg ctagctctgc tctaggcact gttgttacat 6720 tacccaggta agattacgtt ttaaaatgtg cctttctatg agttagaaaa cacactatat 6780 ggcaaactat ataattaatt catagacaaa gtcttctcaa gccagatgta ctatctctca 6840 ggttcatggt ttgttctgtc acatgcaggt tagcctatgc tcactccggt aaagctaaaa 6900 cggtgatggc tgtaggtgtt actcgctcta acttttttag ggctttttgt caccagtaag 6960 ctcccacaga ctggtcagtt ttttgtttgt tttttgtttg tttgttttaa ttagttgtca 7020 acaccagtga gggggtcagc atgaaaacgc accaggccgg ttgggtagag attcttagtc 7080 ctgtgatcac cagcttagtc tggtaaccac agactgcaaa tgctgttacg taactagaaa 7140 catgggacgt atcagaacaa ggggatgcta cacaggtgtt tgtgtaatat acagtgcacc 7200 ttgctgctag tgtgacagta ggcattccct gtggcccctt atgcctttgc tctcctgtac 7260 tccacgtgag ccctgttctc tcaactctgc cccacccacc catgcagctt cacatgggaa 7320 gcttgcccgt gttagcgctg tagtaagttg catgtgctga gtataaccaa agctatcatt 7380 tttatgttga ccctgtcata aatgtcttac tatatcagct ctaatccttt ttaaataaat 7440 ttgagaaaga aact 7454 <![CDATA[<210> 32]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 32]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <![CDATA[<210> 33]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 33]]> Ser Tyr Gly Met His 1 5 <![CDATA[<210> 34]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 34]]> Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 35]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 35]]> Gly Val Pro Asp Tyr 1 5 <![CDATA[<210> 36]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 36]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 37]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 37]]> Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <![CDATA[<210> 38]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 38]]> Ser Asn Asn Glu Arg Pro Ser 1 5 <![CDATA[<210> 39]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 39]]> Ala Ala Trp Asp Asp Ser Leu Asn Gly Pro Val 1 5 10 <![CDATA[<210> 40]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 40]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 <![CDATA[<210> 41]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 41]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 42]]> <![CDATA[<211> 116]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 42]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Trp Asp Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <![CDATA[<210> 43]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 43]]> Asp Tyr Tyr Met Ser 1 5 <![CDATA[<210> 44]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 44]]> Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 45]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 45]]> Trp Asp Gly Pro Phe Asp Tyr 1 5 <![CDATA[<210> 46]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 46]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Gly Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 47]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 47]]> Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly Tyr Asp Val His 1 5 10 <![CDATA[<210> 48]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 48]]> Tyr Asp Asp Leu Leu Pro Ser 1 5 <![CDATA[<210> 49]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 49]]> Gln Ser Tyr Asp Ser Ser Leu Gly Gly Ser Val 1 5 10 <![CDATA[<210> 50]]> <![CDATA[<211> 440]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 50]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Trp Asp Gly Pro Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala 115 120 125 Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu 130 135 140 Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly 145 150 155 160 Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp 165 170 175 Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro 180 185 190 Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys 195 200 205 Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile 210 215 220 Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro 225 230 235 240 Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val 245 250 255 Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val 260 265 270 Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln 275 280 285 Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln 290 295 300 Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala 305 310 315 320 Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro 325 330 335 Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala 340 345 350 Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu 355 360 365 Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr 370 375 380 Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr 385 390 395 400 Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe 405 410 415 Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys 420 425 430 Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 51]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 51]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Gly Gly Ser Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe 130 135 140 Tyr Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val 145 150 155 160 Thr Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg 180 185 190 His Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu 195 200 205 Lys Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 52]]> <![CDATA[<211> 438]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 52]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly 115 120 125 Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys 130 135 140 Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu 145 150 155 160 Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr 165 170 175 Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu 180 185 190 Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 195 200 205 Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr 210 215 220 Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp 225 230 235 240 Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp 245 250 255 Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp 260 265 270 Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn 275 280 285 Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp 290 295 300 Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro 305 310 315 320 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala 325 330 335 Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp 340 345 350 Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile 355 360 365 Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn 370 375 380 Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys 385 390 395 400 Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys 405 410 415 Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu 420 425 430 Ser His Ser Pro Gly Lys 435 <![CDATA[<210> 53]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 53]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe 130 135 140 Tyr Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val 145 150 155 160 Thr Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg 180 185 190 His Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu 195 200 205 Lys Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 54]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 54]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met Asn Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 55]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 55]]> His Tyr Asp Met Asn 1 5 <![CDATA[<210> 56]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 56]]> Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val Lys 1 5 10 15 Gly <![CDATA[<210> 57]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 57]]> Thr Pro Gly Ser His Phe Asp Tyr 1 5 <![CDATA[<210> 58]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 58]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 59]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 59]]> Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Ala Val Asn 1 5 10 <![CDATA[<210> 60]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 60]]> Tyr Asp Asp Leu Leu Pro Ser 1 5 <![CDATA[<210> 61]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 61]]> Ser Ala Trp Asp Asp Ser Leu Asn Gly Val Val 1 5 10 <![CDATA[<210> 62]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 62]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met Asn Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 63]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 63]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 64]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 64]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Asp Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Asn Trp Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 65]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 65]]> Ile Tyr Ala Met Ser 1 5 <![CDATA[<210> 66]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 66]]> Ser Ile Ser Asp Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 67]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 67]]> Ser Asn Trp Gly Ser Leu Asp Tyr 1 5 <![CDATA[<210> 68]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 68]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 69]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 69]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Tyr 1 5 10 <![CDATA[<210> 70]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 70]]> Tyr Asp Asp Leu Leu Pro Ser 1 5 <![CDATA[<210> 71]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 71]]> Ala Ala Trp Asp Asp Ser Leu Ser Gly Arg Val 1 5 10 <![CDATA[<210> 72]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 72]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Asp Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Asn Trp Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 73]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 73]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 74]]> <![CDATA[<211> 479]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 74]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly 130 135 140 Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala 145 150 155 160 Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys 165 170 175 Leu Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg 180 185 190 Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly 195 200 205 Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp 210 215 220 Ser Leu Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser 260 265 270 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg 275 280 285 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro 290 295 300 Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 305 310 315 320 Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 325 330 335 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr 340 345 350 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr 355 360 365 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 370 375 380 Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys 385 390 395 400 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser 405 410 415 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 420 425 430 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 435 440 445 Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 450 455 460 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 465 470 475 <![CDATA[<210> 75]]> <![CDATA[<211> 481]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 75]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met Asn Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly 130 135 140 Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn 145 150 155 160 Ile Gly Asn Asn Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro 180 185 190 Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile 195 200 205 Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp 210 215 220 Asp Asp Ser Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 225 230 235 240 Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Gly Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 260 265 270 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 275 280 285 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 290 295 300 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 305 310 315 320 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 325 330 335 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 340 345 350 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 355 360 365 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys 370 375 380 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 385 390 395 400 Ser Cys Ala Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 405 410 415 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 420 425 430 Leu Asp Ser Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp 435 440 445 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 450 455 460 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 465 470 475 480 Gly <![CDATA[<210> 76]]> <![CDATA[<211> 449]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 76]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro His Asn Gly Gly Pro Ile Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Glu Leu Gly His Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125 Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 145 150 155 160 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190 Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205 Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys 210 215 220 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445 Lys <![CDATA[<210> 77]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 77]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 20 25 30 Gly Tyr Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Asn Leu Asp Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Leu Glu Glu Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Arg 85 90 95 Asp Leu Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 115 120 125 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 130 135 140 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 145 150 155 160 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 180 185 190 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 195 200 205 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <![CDATA[<210> 78]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 78]]> Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile 35 40 45 Gly Asp Ile Asn Pro His Asn Gly Gly Pro Ile Tyr Asn Gln Lys Phe 50 55 60 Thr Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Glu Leu Gly His Trp Tyr Phe Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr 115 120 125 Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu 130 135 140 Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp 145 150 155 160 Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175 Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser 180 185 190 Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205 Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys 210 215 220 Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr 245 250 255 Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser 260 265 270 Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg 275 280 285 Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile 290 295 300 Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn 305 310 315 320 Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys 325 330 335 Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu 340 345 350 Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe 355 360 365 Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala 370 375 380 Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr 385 390 395 400 Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly 405 410 415 Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His 420 425 430 Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 79]]> <![CDATA[<211> 218]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 79]]> Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Lys Ser Val Ser Thr Ser 20 25 30 Gly Tyr Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Arg Leu Leu Ile Tyr Leu Ala Ser Asn Leu Asp Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His 65 70 75 80 Pro Leu Glu Glu Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His Ser Arg 85 90 95 Asp Leu Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln 115 120 125 Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr 130 135 140 Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln 145 150 155 160 Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr 165 170 175 Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg 180 185 190 His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro 195 200 205 Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <![CDATA[<210> 80]]> <![CDATA[<211> 479]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 80]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly 130 135 140 Gln Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala 145 150 155 160 Gly Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys 165 170 175 Leu Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg 180 185 190 Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly 195 200 205 Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp 210 215 220 Ser Leu Asn Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 260 265 270 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 275 280 285 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 290 295 300 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 305 310 315 320 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 325 330 335 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 340 345 350 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro 370 375 380 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Trp Cys Met 385 390 395 400 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 405 410 415 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 420 425 430 Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn 435 440 445 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 450 455 460 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 465 470 475 <![CDATA[<210> 81]]> <![CDATA[<211> 481]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 81]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met Asn Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly 130 135 140 Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn 145 150 155 160 Ile Gly Asn Asn Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro 180 185 190 Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile 195 200 205 Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp 210 215 220 Asp Asp Ser Leu Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 225 230 235 240 Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Gly Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 260 265 270 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 275 280 285 Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp 290 295 300 Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr 305 310 315 320 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 325 330 335 Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu 340 345 350 Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys 355 360 365 Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr 370 375 380 Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Ser 385 390 395 400 Cys Ala Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 405 410 415 Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met 420 425 430 Asp Thr Asp Gly Ser Tyr Phe Val Val Ser Lys Leu Asn Val Gln Lys 435 440 445 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 450 455 460 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly 465 470 475 480 Lys <![CDATA[<210> 82]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 82]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <![CDATA[<210> 83]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 83]]> Ser Tyr Gly Met His 1 5 <![CDATA[<210> 84]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 84]]> Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 85]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 85]]> Gly Val Pro Asp Tyr 1 5 <![CDATA[<210> 86]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 86]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 87]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 87]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Gly Tyr Asp Val His 1 5 10 <![CDATA[<210> 88]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 88]]> Ser Asn Asn Glu Arg Pro Ser 1 5 <![CDATA[<210> 89]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 89]]> Ala Ala Trp Asp Asp Ser Leu Ser Gly Pro Val 1 5 10 <![CDATA[<210> 90]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 90]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 91]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 91]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Asn Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 92]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 92]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 340 345 350 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 93]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 93]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 94]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 94]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 95]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 95]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 96]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 96]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Ser Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 97]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 97]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 98]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 98]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 99]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 99]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 100]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 100]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 101]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 101]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 102]]> <![CDATA[<211> 441]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 102]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu 115 120 125 Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys 130 135 140 Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser 145 150 155 160 Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp 180 185 190 Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr 195 200 205 Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys 210 215 220 Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys 225 230 235 240 Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val 245 250 255 Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe 260 265 270 Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu 275 280 285 Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His 290 295 300 Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala 305 310 315 320 Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg 325 330 335 Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met 340 345 350 Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro 355 360 365 Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn 370 375 380 Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val 385 390 395 400 Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr 405 410 415 Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu 420 425 430 Lys Ser Leu Ser His Ser Pro Gly Lys 435 440 <![CDATA[<210> 103]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 103]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe Tyr 130 135 140 Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val Thr 145 150 155 160 Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg His 180 185 190 Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu Lys 195 200 205 Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 104]]> <![CDATA[<211> 438]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 104]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly 115 120 125 Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys 130 135 140 Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu 145 150 155 160 Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr 165 170 175 Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu 180 185 190 Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp 195 200 205 Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr 210 215 220 Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp 225 230 235 240 Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp 245 250 255 Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp 260 265 270 Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn 275 280 285 Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp 290 295 300 Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro 305 310 315 320 Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala 325 330 335 Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp 340 345 350 Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile 355 360 365 Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn 370 375 380 Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys 385 390 395 400 Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys 405 410 415 Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu 420 425 430 Ser His Ser Pro Gly Lys 435 <![CDATA[<210> 105]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 105]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr Ile Thr Asp Phe 130 135 140 Tyr Pro Gly Val Val Thr Val Asp Trp Lys Val Asp Gly Thr Pro Val 145 150 155 160 Thr Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg Ala Trp Glu Arg 180 185 190 His Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly His Thr Val Glu 195 200 205 Lys Ser Leu Ser Arg Ala Asp Cys Ser 210 215 <![CDATA[<210> 106]]> <![CDATA[<211> 114]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 106]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser <![CDATA[<210> 107]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 107]]> Ser Tyr Gly Met His 1 5 <![CDATA[<210> 108]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 108]]> Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 109]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 109]]> Gly Val Pro Asp Tyr 1 5 <![CDATA[<210> 110]]> <![CDATA[<211> 111]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 110]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 111]]> <![CDATA[<211> 14]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 111]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asp Tyr Asp Val His 1 5 10 <![CDATA[<210> 112]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 112]]> Ser Asn Glu Glu Arg Pro Ser 1 5 <![CDATA[<210> 113]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 113]]> Ser Ala Trp Asp Ser Ser Leu Ser Gly Pro Val 1 5 10 <![CDATA[<210> 114]]> <![CDATA[<211> 342]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 114]]> gaagttcagc tgctggaatc tggcggcgga ctggttcaac ctggcggatc tctgagactg 60 agctgtgccg ccagcggctt cacctttagc agctatggca tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctacg acggcagcta caagtactac 180 gccgacagcg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actattgtgc tgctggcgtg 300 ccagattact ggggccaggg aacactggtc acagtgtcat ca 342 <![CDATA[<210> 115]]> <![CDATA[<211> 333]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 115]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcgactatg acgtgcactg gtatcagcag 120 ctgcctggca cagcccctaa actgctgatc tacagcaacg aggaacggcc tagcggcgtg 180 cccgatagat tttctggcag caagagcggc acaagcgcca gcctggctat ctctggactg 240 agatctgagg acgaggccga ctactactgc agcgcctggg attcttctct gtctggccct 300 gtttttggcg gaggcaccaa gctgacagtg cta 333 <![CDATA[<210> 116]]> <![CDATA[<211> 443]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 116]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser 115 120 125 Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys 130 135 140 Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu 145 150 155 160 Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu 165 170 175 Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr 180 185 190 Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val 195 200 205 Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro 210 215 220 Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro 225 230 235 240 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 245 250 255 Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 260 265 270 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 275 280 285 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 290 295 300 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 305 310 315 320 Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 325 330 335 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 340 345 350 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 355 360 365 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 370 375 380 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 385 390 395 400 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 405 410 415 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 420 425 430 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 <![CDATA[<210> 117]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 117]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asp 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 65 70 75 80 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser Ser 85 90 95 Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu 115 120 125 Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe 130 135 140 Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val 145 150 155 160 Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys 165 170 175 Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser 180 185 190 His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu 195 200 205 Lys Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 118]]> <![CDATA[<211> 481]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 118]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly 130 135 140 Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn 145 150 155 160 Ile Gly Ser Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro 180 185 190 Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile 195 200 205 Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp 210 215 220 Asp Asp Ser Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 225 230 235 240 Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Gly Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 260 265 270 Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr 275 280 285 Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp 290 295 300 Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr 305 310 315 320 Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser 325 330 335 Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu 340 345 350 Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys 355 360 365 Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr 370 375 380 Ile Pro Pro Cys Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Trp 385 390 395 400 Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln 405 410 415 Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met 420 425 430 Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys 435 440 445 Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu 450 455 460 Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly 465 470 475 480 Lys <![CDATA[<210> 119]]> <![CDATA[<211> 479]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 119]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly 130 135 140 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 145 150 155 160 Asp Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys 165 170 175 Leu Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg 180 185 190 Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly 195 200 205 Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser 210 215 220 Ser Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 260 265 270 Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr 275 280 285 Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu 290 295 300 Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln 305 310 315 320 Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser 325 330 335 Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys 340 345 350 Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Cys Thr Ile Pro 370 375 380 Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Ser Cys Ala 385 390 395 400 Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn 405 410 415 Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr 420 425 430 Asp Gly Ser Tyr Phe Val Val Ser Lys Leu Asn Val Gln Lys Ser Asn 435 440 445 Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu 450 455 460 His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys 465 470 475 <![CDATA[<210> 120]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 120]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 121]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 121]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 122]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 122]]> Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 123]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 123]]> Thr Pro Gly Phe His Phe Asp Tyr 1 5 <![CDATA[<210> 124]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 124]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 125]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 125]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Ser 1 5 10 <![CDATA[<210> 126]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 126]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 127]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 127]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 128]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 128]]> caggttcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagaag cctgagactg 60 tcttgtgccg ccagcggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctacc acggcagcgt gaagttctac 180 gccgactccg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaacaccc 300 ggcttccact tcgactattg gggccaggga accctggtca cagtctcttc a 351 <![CDATA[<210> 129]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 129]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcaactacg tgtcctggta tcagcagctg 120 cctggcacag cccctaaact gctgatctac tacgacgacc tgcggcctag cggcgtgcca 180 gatagatttt ctggcagcaa gagcggcacc tctgccagcc tggctatctc tggactgaga 240 agcgaggacg aggccgacta ctactgtagc gcctgggatg atagcctgtc cggcgttgtg 300 tttggcggag gcacaaagct gacagtgcta 330 <![CDATA[<210> 130]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 130]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 131]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 131]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 132]]> <![CDATA[<211> 481]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 132]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr His Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 115 120 125 Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly 130 135 140 Thr Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn 145 150 155 160 Ile Gly Ser Asn Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala 165 170 175 Pro Lys Leu Leu Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro 180 185 190 Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile 195 200 205 Ser Gly Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp 210 215 220 Asp Asp Ser Leu Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr 225 230 235 240 Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 245 250 255 Ser Gly Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro 260 265 270 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 275 280 285 Arg Thr Pro Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp 290 295 300 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 305 310 315 320 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 325 330 335 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 340 345 350 Tyr Lys Cys Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys 355 360 365 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 370 375 380 Leu Pro Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp 385 390 395 400 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 405 410 415 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 420 425 430 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 435 440 445 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 450 455 460 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 465 470 475 480 Lys <![CDATA[<210> 133]]> <![CDATA[<211> 479]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 133]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ala Gly Val Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 115 120 125 Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly 130 135 140 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser 145 150 155 160 Asp Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys 165 170 175 Leu Leu Ile Tyr Ser Asn Glu Glu Arg Pro Ser Gly Val Pro Asp Arg 180 185 190 Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly 195 200 205 Leu Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Ser 210 215 220 Ser Leu Ser Gly Pro Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 225 230 235 240 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 260 265 270 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 275 280 285 Pro Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu 290 295 300 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 305 310 315 320 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 325 330 335 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 340 345 350 Cys Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro 370 375 380 Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala 385 390 395 400 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 405 410 415 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 420 425 430 Asp Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 450 455 460 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 465 470 475 <![CDATA[<210> 134]]> <![CDATA[<211> 1443]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 134]]> caggtgcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagatc cctgagactg 60 tcttgtgccg cctccggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gattggaatg ggtcgccgtg atctcctacc acggctccgt gaagttctac 180 gccgacagcg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgag agccgaggac accgccgtgt actactgtgc tagaacccct 300 ggcttccact tcgactattg gggccagggc acactggtca cagtttctag cggaggcgga 360 ggaagtggcg gcggaggatc tggcggtggt ggttctcagt ctgtgctgac ccaacctcct 420 tccgcttctg gcacacctgg ccagagagtg accatctctt gctccggctc ctcctccaac 480 atcggctcca attacgtgtc ctggtatcag cagctgcccg gcacagctcc caaactgctg 540 atctactacg acgacctgcg gccttctggc gtgcccgata gattctccgg ctctaagtct 600 ggcacctctg ccagcctggc tatctccgga ctgagatctg aggacgaggc cgactactac 660 tgctctgcct gggacgattc tctgtccggc gttgtgtttg gcggaggcac caaactgaca 720 gtgctcggag gtggtggctc tggtggcgga ggaagtggcg gaggcggttc tggtgttgaa 780 tgtcctccat gtcctgctcc tccagtggct ggcccttccg tgtttctgtt ccctccaaag 840 cctaaggaca ccctgatgat ctctcggacc cctgaagtga cctgtgtggt cgtgggagtg 900 tctcacgagg atcccgaagt gaagttcaat tggtacgtgg acggcgtgga agtgcacaac 960 gccaagacca agcctagaga ggaacagtac aactccacct acagagtggt gtccgtgctg 1020 accgtgctgc accaggattg gctgaacggc aaagagtaca agtgcaaggt gtccaacaag 1080 cagctgccct ctccaatcga aaagaccatc tccaaggcca agggacagcc cagagaaccc 1140 caggtgtaca cactgcctcc atgcagagat gagctgacca agaaccaggt gtccctgtgg 1200 tgtctggtca agggcttcta cccctccgat atcgccgtgg aatgggagtc taatggccag 1260 cctgagaaca actacaagac cacacctcct gtgctggact ccgacggctc attcttcctg 1320 tactccaagc tgacagtgga caagtccaga tggcagcagg gcaacgtgtt ctcctgctcc 1380 gtgatgcacg aggccctgca caatcactac acccagaagt ccctgtctct gtcccctggc 1440 aag 1443 <![CDATA[<210> 135]]> <![CDATA[<211> 1437]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 135]]> gaagtgcagc tgctggaatc tggcggagga ttggttcagc ctggcggctc tctgagactg 60 tcttgtgccg cttccggctt caccttctcc agctacggaa tgcactgggt ccgacaggcc 120 cctggcaaag gattggaatg ggtcgccgtg atctcctacg acggctccta caagtactac 180 gccgactccg tgaagggcag attcaccatc tctcgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgag agccgaggac accgccgtgt actattgtgc tgctggcgtg 300 ccagattact ggggccaggg aacactggtc acagtgtcta gcggcggagg tggaagcgga 360 ggcggaggtt ctggtggtgg tggatctcag tctgtgctga cccagcctcc ttctgcttct 420 ggcacacctg gccagagagt gaccatctct tgctccggct cctcctccaa catcggctct 480 gactacgacg tgcactggta tcagcagctc cctggcacag ctcccaaact gctgatctac 540 tccaacgagg aacggcctag cggcgtgccc gatagattct ccggatctaa gtccggcacc 600 tctgccagcc tggctatctc tggcctgaga tctgaggacg aggccgacta ctactgctcc 660 gcctgggact cttctctgtc tggccctgtt tttggcggag gcaccaagct gacagtgctc 720 ggaggtggtg gctctggtgg cggaggaagt ggcggaggcg gttctggtgt tgaatgtcct 780 ccatgtcctg ctcctccagt ggctggccct tccgtgtttc tgttccctcc aaagcctaag 840 gacaccctga tgatctctcg gacccctgaa gtgacctgtg tggtcgtggg agtgtctcac 900 gaggatcccg aagtgaagtt caattggtac gtggacggcg tggaagtgca caacgccaag 960 accaagccta gagaggaaca gtacaactcc acctacagag tggtgtccgt gctgaccgtg 1020 ctgcaccagg attggctgaa cggcaaagag tacaagtgca aggtgtccaa caagcagctg 1080 ccctctccaa tcgaaaagac catctccaag gccaagggac agccccggga acctcaagtc 1140 tgtaccttgc ctcctagccg ggacgagctg accaagaatc aggtgtccct gtcctgtgcc 1200 gtgaagggct tctacccttc cgatatcgcc gtggaatggg agtccaatgg ccagcctgag 1260 aacaactaca agaccacacc tcctgtgctg gactccgacg gctcattctt cctggtgtcc 1320 aagctgacag tggacaagtc cagatggcag cagggcaacg tgttctcctg ctccgtgatg 1380 cacgaggccc tgcacaatca ctacacccag aagtccctga gcctgtctcc tggcaag 1437 <![CDATA[<210> 136]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 136]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Ser Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 137]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 137]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 138]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 138]]> Val Ile Ser Tyr Ser Gly Ser Val Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 139]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 139]]> Thr Pro Gly Ser His Phe Asp Tyr 1 5 <![CDATA[<210> 140]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 140]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 141]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 141]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn 1 5 10 <![CDATA[<210> 142]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 142]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 143]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 143]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 144]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 144]]> caggttcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagaag cctgagactg 60 tcttgtgccg ccagcggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctaca gcggcagcgt gaagttctac 180 gccgactccg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaacacct 300 ggcagccact tcgactattg gggccaggga acactggtca ccgttagctc a 351 <![CDATA[<210> 145]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 145]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcaactacg tgaactggta tcagcagctg 120 cccggcacag cccctaaact gctgatctac tacgacgacc tgcggcctag cggcgtgcca 180 gatagatttt ctggcagcaa gagcggcacc tctgccagcc tggctatctc tggactgaga 240 agcgaggacg aggccgacta ctactgtagc gcctgggatg atagcctgtc cggcgttgtg 300 tttggcggag gcacaaagct gacagtgcta 330 <![CDATA[<210> 146]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 146]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Ser Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 147]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 147]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 148]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 148]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 149]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 149]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 150]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 150]]> Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 151]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 151]]> Thr Pro Gly Phe His Phe Asp Tyr 1 5 <![CDATA[<210> 152]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 152]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 153]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 153]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Ser 1 5 10 <![CDATA[<210> 154]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 154]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 155]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 155]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 156]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 156]]> caggttcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagaag cctgagactg 60 tcttgtgccg ccagcggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctacg agggcagcaa caagttctac 180 gccgacagcg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaacaccc 300 ggcttccact tcgactattg gggccaggga accctggtca cagtctcttc a 351 <![CDATA[<210> 157]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 157]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcaactacg tgtcctggta tcagcagctg 120 cctggcacag cccctaaact gctgatctac tacgacgacc tgcggcctag cggcgtgcca 180 gatagatttt ctggcagcaa gagcggcacc tctgccagcc tggctatctc tggactgaga 240 agcgaggacg aggccgacta ctactgtagc gcctgggatg atagcctgtc cggcgttgtg 300 tttggcggag gcacaaagct gacagtgcta 330 <![CDATA[<210> 158]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 158]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 159]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 159]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 160]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 160]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 161]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 161]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 162]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 162]]> Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 163]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 163]]> Thr Pro Gly Phe His Phe Asp Tyr 1 5 <![CDATA[<210> 164]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 164]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 165]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 165]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn 1 5 10 <![CDATA[<210> 166]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 166]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 167]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 167]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 168]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 168]]> caggttcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagaag cctgagactg 60 tcttgtgccg ccagcggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctacg agggcagcaa caagttctac 180 gccgacagcg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaacaccc 300 ggcttccact tcgactattg gggccaggga accctggtca cagtctcttc a 351 <![CDATA[<210> 169]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 169]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcaactacg tgaactggta tcagcagctg 120 cccggcacag cccctaaact gctgatctac tacgacgacc tgcggcctag cggcgtgcca 180 gatagatttt ctggcagcaa gagcggcacc tctgccagcc tggctatctc tggactgaga 240 agcgaggacg aggccgacta ctactgtagc gcctgggatg atagcctgtc cggcgttgtg 300 tttggcggag gcacaaagct gacagtgcta 330 <![CDATA[<210> 170]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 170]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 171]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 171]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 172]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 172]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 173]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 173]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 174]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 174]]> Val Ile Ser Tyr Glu Gly Ser Val Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 175]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 175]]> Thr Pro Gly Phe His Phe Asp Tyr 1 5 <![CDATA[<210> 176]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 176]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 177]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 177]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn 1 5 10 <![CDATA[<210> 178]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 178]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 179]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 179]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 180]]> <![CDATA[<211> 351]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 180]]> caggttcagc tggtggaatc tggtggcgga gttgtgcagc ctggcagaag cctgagactg 60 tcttgtgccg ccagcggctt caccttcagc cactacgata tgcactgggt ccgacaggcc 120 cctggcaaag gacttgaatg ggtcgccgtg atcagctacg agggcagcgt gaagttctac 180 gccgactccg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240 ctgcagatga acagcctgag agccgaggac accgccgtgt actactgtgc cagaacaccc 300 ggcttccact tcgactattg gggccaggga accctggtca cagtctcttc a 351 <![CDATA[<210> 181]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 181]]> cagtctgttc tgacacagcc tcctagcgcc tctggcacac ctggacagag agtgaccatc 60 agctgtagcg gcagcagctc caacatcggc agcaactacg tgaactggta tcagcagctg 120 cccggcacag cccctaaact gctgatctac tacgacgacc tgcggcctag cggcgtgcca 180 gatagatttt ctggcagcaa gagcggcacc tctgccagcc tggctatctc tggactgaga 240 agcgaggacg aggccgacta ctactgtagc gcctgggatg atagcctgtc cggcgttgtg 300 tttggcggag gcacaaagct gacagtgcta 330 <![CDATA[<210> 182]]> <![CDATA[<211> 446]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 182]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Val Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Phe His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Gly Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Gln Leu Pro Ser Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <![CDATA[<210> 183]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 183]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 184]]> <![CDATA[<211> 117]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 184]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <![CDATA[<210> 185]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 185]]> His Tyr Asp Met His 1 5 <![CDATA[<210> 186]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 186]]> Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <![CDATA[<210> 187]]> <![CDATA[<211> 8]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 187]]> Thr Pro Gly Ser His Phe Asp Tyr 1 5 <![CDATA[<210> 188]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 188]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 <![CDATA[<210> 189]]> <![CDATA[<211> 13]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 189]]> Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Tyr Val Asn 1 5 10 <![CDATA[<210> 190]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 190]]> Tyr Asp Asp Leu Arg Pro Ser 1 5 <![CDATA[<210> 191]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 191]]> Ser Ala Trp Asp Asp Ser Leu Ser Gly Val Val 1 5 10 <![CDATA[<210> 192]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 192]]> Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Glu Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <![CDATA[<210> 193]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 193]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 194]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 194]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser His Tyr 20 25 30 Asp Met Asn Trp Leu Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Val Ile Ser Tyr Asp Gly Ser Asn Lys Phe Tyr Ala Asp Phe Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Thr Pro Gly Ser His Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <![CDATA[<210> 195]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 195]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala Trp Asp Asp Ser Leu 85 90 95 Asn Gly Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215 <![CDATA[<210> 196]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 196]]> Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ile Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Asp Thr Gly Asp Arg Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Asn Trp Gly Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro 210 215 220 Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 <![CDATA[<210> 197]]> <![CDATA[<211> 216]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 抗體序列]]> <![CDATA[<400> 197]]> Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85 90 95 Ser Gly Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Thr Glu Cys Ser 210 215
Claims (37)
- 一種能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段能夠減少不正常子宮出血期間之失血。
- 如請求項1之能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段以≤1.0 E-08 M、≤1.0 E-09 M、≤5.0 E-10 M、≤1.0 E-10 M、≤5.0 E-11 M、≤2.5 E-11 M或≤1.0 E-11 M之解離常數( K D)結合至人類IL-11。
- 如請求項1至2之能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段以≤100 nM、≤ 50 nM、≤ 25 nM、≤10 nM、≤1 nM、≤ 0.5 nM或≤ 0.1 nM之IC 50抑制人類IL-11介導之信號傳導。
- 如請求項1至3之能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段抑制IL-11與IL-11Ra之相互作用,且 其中該經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物之形成。
- 如請求項1至3之能夠結合至IL-11且抑制IL-11介導之信號傳導的經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物之形成,且 其中該經分離之抗體或其抗原結合片段不抑制IL-11與IL-11Ra之相互作用。
- 如請求項1至3之經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段為能夠結合至兩種不同IL-11抗原決定基之雙特異性抗體或其抗原結合片段。
- 如請求項6之經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段抑制IL-11結合至IL-11Ra,且 其中該經分離之抗體或其抗原結合片段抑制IL-11/IL-11Ra/gp130複合物之形成。
- 如請求項1至7之經分離之抗體或其抗原結合片段, 其中該人類IL-11具有SEQ ID NO: 1之序列aa 22-199; 其中該人類IL-11Ra具有SEQ ID NO: 3之序列及/或 其中該人類gp130為序列SEQ ID 12。
- 如請求項1至3之經分離之抗體或其抗原結合片段, 其中該經分離之抗體或其抗原結合片段不結合至IL-2Ra。
- 如請求項1至9中任一項之經分離之抗體或其抗原結合片段,其包含 i) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 33之H-CDR1、包含SEQ ID NO: 34之H-CDR2及包含SEQ ID NO: 35之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 37之L-CDR1、包含SEQ ID NO: 38之L-CDR2及包含SEQ ID NO: 39之L-CDR3;或 ii) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO:43之H-CDR1、包含SEQ ID NO: 44之H-CDR2及包含SEQ ID NO: 45之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 47之L-CDR1、包含SEQ ID NO: 48之L-CDR2及包含SEQ ID NO: 49之L-CDR3;或 iii) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 55之H-CDR1、包含SEQ ID NO: 56之H-CDR2及包含SEQ ID NO: 57之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 59之L-CDR1、包含SEQ ID NO: 60之L-CDR2及包含SEQ ID NO: 61之L-CDR3;或 iv) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 65之H-CDR1、包含SEQ ID NO: 66之H-CDR2及包含SEQ ID NO: 67之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 69之L-CDR1、包含SEQ ID NO: 70之L-CDR2及包含SEQ ID NO: 71之L-CDR3;或 v) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 83之H-CDR1、包含SEQ ID NO: 84之H-CDR2及包含SEQ ID NO: 85之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 87之L-CDR1、包含SEQ ID NO: 88之L-CDR2及包含SEQ ID NO: 89之L-CDR3;或 vi) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 107之H-CDR1、包含SEQ ID NO: 108之H-CDR2及包含SEQ ID NO: 109之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 111之L-CDR1、包含SEQ ID NO: 112之L-CDR2及包含SEQ ID NO: 113之L-CDR3;或 vii) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 121之H-CDR1、包含SEQ ID NO:122之H-CDR2及包含SEQ ID NO: 123之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 125之L-CDR1、包含SEQ ID NO: 126之L-CDR2及包含SEQ ID NO: 127之L-CDR3;或 viii) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 137之H-CDR1、包含SEQ ID NO: 138之H-CDR2及包含SEQ ID NO: 139之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 141之L-CDR1、包含SEQ ID NO: 142之L-CDR2及包含SEQ ID NO: 143之L-CDR3;或 ix) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 149之H-CDR1、包含SEQ ID NO: 150之H-CDR2及包含SEQ ID NO: 151之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 153之L-CDR1、包含SEQ ID NO: 154之L-CDR2及包含SEQ ID NO: 155之L-CDR3;或 x) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 161之H-CDR1、包含SEQ ID NO: 162之H-CDR2及包含SEQ ID NO: 163之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 165之L-CDR1、包含SEQ ID NO: 166之L-CDR2及包含SEQ ID NO: 167之L-CDR3;或 xi) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 173之H-CDR1、包含SEQ ID NO: 174之H-CDR2及包含SEQ ID NO: 175之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 177之L-CDR1、包含SEQ ID NO: 178之L-CDR2及包含SEQ ID NO: 179之L-CDR3;或 xii) 重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 185之H-CDR1、包含SEQ ID NO: 186之H-CDR2及包含SEQ ID NO: 187之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 189之L-CDR1、包含SEQ ID NO: 190之L-CDR2及包含SEQ ID NO: 191之L-CDR3。
- 如請求項1至10中任一項之經分離之抗體或其抗原結合片段,其包含 xiii) 包含SEQ ID NO: 32之可變重鏈域及包含SEQ ID NO: 36之可變輕鏈域;或 xiv) 包含SEQ ID NO: 42之可變重鏈域及包含SEQ ID NO: 46之可變輕鏈域;或 xv) 包含SEQ ID NO: 54之可變重鏈域及包含SEQ ID NO: 58之可變輕鏈域;或 xvi) 包含SEQ ID NO: 64之可變重鏈域及包含SEQ ID NO: 68之可變輕鏈域;或 xvii) 包含SEQ ID NO: 82之可變重鏈域及包含SEQ ID NO: 86之可變輕鏈域;或 xviii) 包含SEQ ID NO: 106之可變重鏈域及包含SEQ ID NO: 110之可變輕鏈域;或 xix) 包含SEQ ID NO: 120之可變重鏈域及包含SEQ ID NO: 124之可變輕鏈域;或 xx) 包含SEQ ID NO: 136之可變重鏈域及包含SEQ ID NO: 140之可變輕鏈域;或 xxi) 包含SEQ ID NO: 148之可變重鏈域及包含SEQ ID NO: 152之可變輕鏈域;或 xxii) 包含SEQ ID NO: 160之可變重鏈域及包含SEQ ID NO: 164之可變輕鏈域;或 xxiii) 包含SEQ ID NO: 172之可變重鏈域及包含SEQ ID NO: 176之可變輕鏈域;或 xxiv) 包含SEQ ID NO: 184之可變重鏈域及包含SEQ ID NO: 188之可變輕鏈域。
- 如請求項1至11中任一項之經分離之抗體, 其為IgG抗體,尤其IgG1或IgG4抗體。
- 如請求項1至9中任一項之經分離之抗體,其包含 xxv) 包含SEQ ID NO: 40之重鏈及包含SEQ ID NO: 41之輕鏈;或 xxvi) 包含SEQ ID NO: 90之重鏈及包含SEQ ID NO: 91之輕鏈;或 xxvii) 包含SEQ ID NO: 92之重鏈及包含SEQ ID NO: 33之輕鏈;或 xxviii) 包含SEQ ID NO: 116之重鏈及包含SEQ ID NO: 117之輕鏈;或 xxix) 包含SEQ ID NO: 130之重鏈及包含SEQ ID NO: 131之輕鏈;或 xxx) 包含SEQ ID NO: 146之重鏈及包含SEQ ID NO: 147之輕鏈;或 xxxi) 包含SEQ ID NO: 158之重鏈及包含SEQ ID NO: 159之輕鏈;或 xxxii) 包含SEQ ID NO: 170之重鏈及包含SEQ ID NO: 171之輕鏈;或 xxxiii) 包含SEQ ID NO: 182之重鏈及包含SEQ ID NO: 183之輕鏈;或 xxxiv) 包含SEQ ID NO: 192之重鏈及包含SEQ ID NO: 193之輕鏈;或 xxxv) 包含SEQ ID NO: 194之重鏈及包含SEQ ID NO: 195之輕鏈;或 xxxvi) 包含SEQ ID NO: 196之重鏈及包含SEQ ID NO: 197之輕鏈。
- 如請求項6或7之經分離之雙特異性抗體或其抗原結合片段,其包含 xxxvii) 第一鏈,該第一鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 33之H-CDR1、包含SEQ ID NO: 34之H-CDR2及包含SEQ ID NO: 35之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 37之L-CDR1、包含SEQ ID NO: 38之L-CDR2及包含SEQ ID NO: 39之L-CDR3;及 第二鏈,該第二鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 55之H-CDR1、包含SEQ ID NO: 56之H-CDR2及包含SEQ ID NO: 57之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 59之L-CDR1、包含SEQ ID NO: 60之L-CDR2及包含SEQ ID NO: 61之L-CDR3;或 xxxviii) 第一鏈,該第一鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 121之H-CDR1、包含SEQ ID NO: 122之H-CDR2及包含SEQ ID NO: 123之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 125之L-CDR1、包含SEQ ID NO: 126之L-CDR2及包含SEQ ID NO: 127之L-CDR3;及 第二鏈,該第二鏈包含:重鏈抗原結合區,該重鏈抗原結合區包含:包含SEQ ID NO: 107之H-CDR1、包含SEQ ID NO: 108之H-CDR2及包含SEQ ID NO: 109之H-CDR3;及輕鏈抗原結合區,該輕鏈抗原結合區包含:包含SEQ ID NO: 111之L-CDR1、包含SEQ ID NO: 112之L-CDR2及包含SEQ ID NO: 113之L-CDR3。
- 如請求項6、7或14之經分離之雙特異性抗體或其抗原結合片段,其包含 xxxix) 第一鏈,該第一鏈包含:包含SEQ ID NO: 32之可變重鏈域及包含SEQ ID NO: 36之可變輕鏈域;及 第二鏈,該第二鏈包含:包含SEQ ID NO: 54之可變重鏈域及包含SEQ ID NO: 58之可變輕鏈域;或 xl) 第一鏈,該第一鏈包含:包含SEQ ID NO:120之可變重鏈域及包含SEQ ID NO:124之可變輕鏈域;及 第二鏈,該第二鏈包含:包含SEQ ID NO: 106之可變重鏈域及包含SEQ ID NO: 110之可變輕鏈域。
- 如請求項6、7、14或15之經分離之雙特異性抗體,其包含 xli) 包含SEQ ID NO: 74之第一鏈及包含SEQ ID NO:75之第二鏈;或 xlii) 包含SEQ ID NO:132之第一鏈及包含SEQ ID NO:133之第二鏈。
- 如請求項1至11或14至15中任一項之抗原結合片段, 其為scFv、Fab、Fab'片段或F(ab')2片段。
- 如請求項1至16中任一項之經分離之抗體或抗原結合片段, 其為單株抗體或抗原結合片段。
- 如請求項1至18中任一項之經分離之抗體或抗原結合片段, 其為人類、人類化或嵌合抗體或抗原結合片段。
- 一種經分離之抗體或其抗原結合片段,其與如請求項1至19中任一項之經分離之抗體或抗原結合片段競爭結合至IL-11。
- 一種抗體結合物,其包含如請求項1至20中任一項之經分離之抗體或抗原結合片段。
- 一種經分離之核酸序列,其編碼如請求項1至20中任一項之抗體或抗原結合片段。
- 一種載體,其包含如請求項22之核酸序列。
- 一種經分離之細胞,其表現如請求項1至20中任一項之抗體或抗原結合片段及/或包含如請求項22之核酸或如請求項23之載體。
- 如請求項24之經分離之細胞, 其中該細胞為原核或真核細胞。
- 一種產生如請求項1至20中任一項之經分離之抗體或抗原結合片段的方法,其包含培養如請求項24或25中任一項之細胞且視情況純化該抗體或抗原結合片段。
- 一種醫藥組合物,其包含如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之抗體結合物及視情況選用之一或多種醫藥學上可接受之賦形劑。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防疾病。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之抗體結合物,其用作診斷劑。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防不正常子宮出血(AUB)、痛經、平滑肌瘤或子宮內膜異位。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防如請求項30之不正常子宮出血(AUB)、痛經、平滑肌瘤或子宮內膜異位, 其中不正常子宮出血為大量月經出血、長期出血或出血模式改變。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防如請求項30或31之不正常子宮出血(AUB)、痛經、平滑肌瘤或子宮內膜異位, 其中不正常子宮出血為大量月經出血,且 其中大量月經出血繼發於平滑肌瘤或子宮內膜異位。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防如請求項30至31之不正常子宮出血(AUB)、痛經、平滑肌瘤或子宮內膜異位, 其中不正常子宮出血與痛經相關。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於治療或預防如請求項30至33之不正常子宮出血(AUB)、痛經、平滑肌瘤或子宮內膜異位, 其中不正常子宮出血與繼發於平滑肌瘤或子宮內膜異位之痛經相關。
- 一種如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物的用途,其用於抑制或調節月經。
- 如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物,其用於與一或多種其他治療活性化合物之同時、單獨或連續組合。
- 一種套組,其包含如請求項1至20中任一項之經分離之抗體或抗原結合片段或如請求項21之結合物或如請求項27之醫藥組合物及使用說明書。
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EP (2) | EP4298123A2 (zh) |
JP (1) | JP2024512279A (zh) |
KR (1) | KR20230150287A (zh) |
CN (1) | CN117157317A (zh) |
AR (1) | AR124989A1 (zh) |
AU (1) | AU2022225064A1 (zh) |
CA (1) | CA3211686A1 (zh) |
IL (1) | IL305131A (zh) |
MX (1) | MX2023009946A (zh) |
PE (1) | PE20231503A1 (zh) |
TW (1) | TW202302634A (zh) |
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-
2022
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- 2022-02-24 JP JP2023552086A patent/JP2024512279A/ja active Pending
- 2022-02-24 AU AU2022225064A patent/AU2022225064A1/en active Pending
- 2022-02-24 CA CA3211686A patent/CA3211686A1/en active Pending
- 2022-02-24 IL IL305131A patent/IL305131A/en unknown
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IL305131A (en) | 2023-10-01 |
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US20240124572A1 (en) | 2024-04-18 |
AU2022225064A1 (en) | 2023-08-10 |
PE20231503A1 (es) | 2023-09-26 |
WO2022180172A1 (en) | 2022-09-01 |
CA3211686A1 (en) | 2022-09-01 |
JP2024512279A (ja) | 2024-03-19 |
EP4298123A2 (en) | 2024-01-03 |
CN117157317A (zh) | 2023-12-01 |
WO2022180145A3 (en) | 2022-10-27 |
AR124989A1 (es) | 2023-05-24 |
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