TW202246318A - 犬抗體恆定區中之突變 - Google Patents
犬抗體恆定區中之突變 Download PDFInfo
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Abstract
本發明大體上係關於犬抗體變異體及其用途。特定言之,本發明係關於犬抗體之恆定區中用於改良各種特徵之突變。
Description
本發明大體上係關於犬抗體變異體及其用途。特定言之,本發明係關於犬抗體之Fc恆定區中用於改良各種特徵之一個或多個突變。
犬IgG單株抗體(mAb)將研發作為獸醫學中之有效治療劑。幾年前,鑑別且表徵四種犬IgG子類別(Bergeron等人,2014,
Vet Immunol Immunopathol.第157(1-2)卷,第31-41頁)。然而,並未對延長犬IgG之半衰期進行許多研究。
經由再循環機制,新生兒Fc受體(FcRn)以與其片段可結晶(Fc)區之pH依賴性相互作用延長IgG之半衰期。特定言之,跨越CH2及CH3域之界面的Fc區與細胞表面上之FcRn相互作用以調節IgG內環境穩定。IgG胞飲之後的酸性相互作用有助於此相互作用且因此避免IgG降解。內吞IgG接著再循環回至細胞表面且以鹼性pH釋放進入血流中,藉此保持用於恰當功能之足夠血清IgG。因此,IgG之藥物動力學概況視其Fc區之結構及功能特性而定。
三種犬IgG子類別結合犬FcRn且已經與人類IgG類似物進行比較。犬IgG之半衰期仍需要進行充分研究,因為在無任何實驗支援的情況下,吾人不能預期或預測其是否將與人類IgG緊密對準。
延長IgG之半衰期可允許抗體藥物之不太頻繁給藥及/或較低劑量,其繼而減少獸醫問診,提高患者順應性,且減少濃度依賴性細胞毒性/不良事件。
因此,需要鑑別Fc恆定區中用以改良半衰期之突變。
本發明係關於突變犬IgG,相對於野生型犬IgG,該突變犬IgG提供更高的FcRn親和力。特定言之,本申請案之本發明人已發現,取代一個或多個胺基酸殘基驚人且出乎意料地增強對FcRn之親和力。
在一個範疇中,本發明提供經修飾之IgG,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之Eu索引編號。
在一些實施例中,恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
在另一範疇中,本發明提供一種多肽,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之Eu索引編號。
在又一範疇中,本發明提供一種抗體,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之Eu索引編號。
在另一範疇中,本發明提供一種用於產生或製造抗體或分子之方法,該方法包含:提供具有包含犬IgG恆定域之抗體的載體或宿主細胞,相對於野生型犬IgG恆定域,該犬IgG恆定域包含一個或多個胺基酸取代,其中該一個或多個取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439或其組合處。
在另一範疇中,本發明提供一種融合分子,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之Eu索引編號。
在另一範疇中,本發明提供一種用於延長狗之抗體血清半衰期之方法,該方法包含:向該狗投與治療有效量之包含犬IgG恆定域之抗體,相對於野生型犬IgG恆定域,該犬IgG恆定域包含至少一個胺基酸取代,其中該取代處於胺基酸殘基252、254、256、311、434或439處,根據如Kabat中之EU索引編號。在一個例示性實施例中,犬IgG恆定域包含以下突變中之一者或多者:L252F、L252R、L252Y、L252M、A254T、A254S、T256E、Q311W、N434H、N434Y及E439K。在另一例示性實施例中,犬IgG恆定域包含選自以下群組之一個或多個突變:(1) L252F;(2) L252R、N434H及Q311W;(3) L252R;(4) Q311W;(5) L252R、A254T、T256E及N434H;(6) L252Y及A254T;或(7) L252M、A254S及E439K。
本發明之其他特徵及優勢將自以下實施方式實例及圖式變得顯而易知。然而,應理解,實施方式及特定實例雖然指示本發明之較佳實施例,但僅以說明方式給出,因為熟習此項技術者將由此實施方式而變得顯而易知本發明的精神及範疇內的各種改變及修改。
相關申請案之交叉參考
本申請案主張2021年1月28日申請的美國臨時專利申請案第63/142,774號的優先權及權益,該美國臨時專利申請案以全文引用的方式併入本文中。
參考形成本發明之一部分的以下實施方式,可更容易地理解本發明之主題。應理解,本發明不限於本文所描述及/或展示之具體產物、方法、條件或參數,且本文所用之術語係出於僅借助於實例描述特定實施例的目的,且不意欲限制所主張之本發明。
除非本文中另外定義,否則結合本申請案使用之科學與技術術語應具有由一般技術者通常理解之含義。另外,除非上下文另外需要,否則單數術語應包括複數且複數術語應包括單數。
如在本發明中使用,除非另外指明,否則以下術語及縮寫應理解具有以下含義。
定義
在本發明中,除非上下文另外明確指示,否則單數形式「一(a/an)」及「該(the)」包括複數個參考物,且特定數值之引用包括至少該特定值。因此,舉例而言,提及「一分子」或「一化合物」係提及一種或多種此類分子或化合物及熟習此項技術者已知之其等效物等。如本文所用,術語「複數個(種)」意謂多於一個(種)。當表示值範圍時,另一實施例包括自一個特定值及/或至另一個特定值。類似地,當藉由在前面使用「約」以近似值表示值時,應理解,該特定值形成另一實施例。所有範圍皆為包括性且可組合的。
在說明書及申請專利範圍中,免疫球蛋白重鏈中之胺基酸殘基之編號係如Kabat等人, Sequences of Proteins of Immunological Interest, 第5版. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)中之Eu索引的編號。「如Kabat中之Eu索引」係指IgG抗體之殘基編號且反映於本文中之圖2中。
術語「經分離」在結合核酸使用時為自其天然來源中通常與其相關之至少一種污染物核酸中鑑別且分離出之核酸。經分離之核酸可以與自然界中發現的形式或環境不同的形式或環境存在。因此,經分離之核酸分子區別於在天然細胞中存在的核酸分子。經分離之核酸分子包括細胞中含有之通常表現本文中所編碼之多肽的核酸分子,其中例如該核酸分子處於與天然細胞之質粒或染色體位置不同的質粒或染色體位置。經分離之核酸可以單股或雙股形式存在。當經分離之核酸分子用以表現蛋白質時,寡核苷酸或聚核苷酸將含有最小有義或編碼股,但可含有有義股及反義股兩者(亦即,可為雙股)。
當核酸分子與另一核酸分子以函數關係置放時,該核酸分子經「可操作地連接(operably linked/ operably attached)」。舉例而言,若啟動子或強化子影響序列之轉錄,則該啟動子或強化子係可操作地連接至核酸之編碼序列;或若核糖體結合位點經定位以促進轉譯,則核糖體結合位點係可操作地連接至核酸之編碼序列。若編碼變異Fc區之核酸分子經定位而使得經表現之融合蛋白包含與變異Fc區多肽上游或下游鄰接之異源蛋白質或其功能片段,則其可操作地連接於編碼異源蛋白質(亦即,當其存在於自然界中時不包含Fc區的蛋白質或其功能片段)之核酸分子;異源蛋白質可緊鄰變異Fc區多肽或可藉由任何長度及組成之連接子序列與其間隔開。同樣地,當多肽(在本文中與「蛋白質」同義地使用)分子與另一多肽以函數關係置放時,該多肽分子「可操作地連接」。
如本文中所使用,術語「功能片段」參考多肽或蛋白質(例如,變異Fc區或單株抗體)時,係指保留全長多肽之至少一個功能的彼蛋白質片段。片段之大小可介於六個胺基酸至全長多肽之全部胺基酸序列減一個胺基酸的範圍內。本發明之變異Fc區多肽之功能片段保留至少一個如本文所定義之「胺基酸取代」。變異Fc區多肽之功能片段保留此項技術中已知的與Fc區相關之至少一個功能(例如,ADCC、CDC、Fc受體結合、Clq結合、細胞表面受體之下調或可例如增加與其可操作連接之多肽之活體內或活體外半衰期)。
術語「經純化」或「純化」係指自樣品實質性移除至少一種污染物。舉例而言,抗原特異性抗體可藉由完全或實質性移除(至少90%、91%、92%、93%、94%、95%,或更佳地至少96%、97%、98%或99%)至少一種污染性非免疫球蛋白蛋白質來純化;其亦可藉由移除不結合於相同抗原之免疫球蛋白蛋白質來純化。移除非免疫球蛋白蛋白質及/或移除並未結合特定抗原之免疫球蛋白使得樣品中抗原特異性免疫球蛋白之百分比增加。在另一實例中,細菌性宿主細胞中表現之多肽(例如,免疫球蛋白)藉由完全或實質性移除宿主細胞蛋白質來純化;藉此增加樣品中多肽之百分比。
術語「天然的」在指代多肽(例如,Fc區)時在本文中用以指示該多肽具有由自然界中通常存在之多肽或其天然存在之多晶型之胺基酸序列組成的胺基酸序列。天然多肽(例如,天然Fc區)可藉由重組方式製備或可自天然存在源分離。
如本文所使用,術語「表現載體」係指含有所需編碼序列及在特定宿主生物體中表現可操作地連接之編碼序列所需之適當核酸序列的重組DNA分子。
如本文中所使用,術語「宿主細胞」係指位於活體外或原位或活體內的任何真核或原核細胞(例如,細菌細胞,諸如大腸桿菌;CHO細胞、酵母細胞、哺乳動物細胞、禽類細胞、兩棲動物細胞、植物細胞、魚細胞及昆蟲細胞)。
如本文中所使用,術語「Fc區」係指免疫球蛋白重鏈之C端區。「Fc區」可為天然序列Fc區或變異Fc區。儘管免疫球蛋白重鏈之Fc區之一般可接受的界限可不同,但犬IgG重鏈Fc區通常被限定以例如自位置231之胺基酸殘基延伸至其羧基端。在一些實施例中,變異體僅包含Fc區之部分且可包括或不包括羧基端。免疫球蛋白之Fc區一般包含兩個恆定域:CH2及CH3。在一些實施例中,涵蓋具有一個或多個恆定域之變異體。在其他實施例中,涵蓋不含此類恆定域(或僅含此類恆定域之部分)之變異體。
犬IgG Fc區之「CH2域」通常自例如約胺基酸231延伸至約胺基酸340 (參見圖2)。CH2域的獨特之處在於其不與另一域緊密配對。兩個N連接之分支鏈碳水化合物鏈插入於完整天然IgG分子之兩個CH2域之間。
犬IgG Fc區之「CH3域」通常為Fc區延伸中C端至CH2域之殘基延伸段,例如自約胺基酸殘基341至約胺基酸殘基447 (參見圖2)。
「功能性Fc區」具有天然序列Fc區之「效應功能」。相對於包含天然Fc區或變異體之親本Fc區的多肽,包含本發明之變異Fc區的多肽之至少一種效應功能可增強或減弱。效應功能之實例包括但不限於:C1q結合;補體依賴性細胞毒性(CDC);Fc受體結合;抗體依賴性細胞介導之細胞毒性(ADCC);吞噬作用;細胞表面受體(例如B細胞受體)之下調等。此類效應功能可能需要Fc區可操作地連接至結合域(例如抗體可變域),且可使用各種檢定(例如Fc結合檢定、ADCC檢定、CDC檢定、來自全血或分級分離之血液樣本的目標細胞耗乏等)來評定。
「天然序列Fc區」或「野生型Fc區」係指與在自然界中通常發現之Fc區之胺基酸序列具有一致性之胺基酸序列。例示性天然序列犬Fc區展示於圖2中且包括犬IgG Fc區之天然序列。
「變異Fc區」包含與天然序列Fc區(或其片段)之胺基酸序列相差至少一個如本文所定義之「胺基酸取代」的胺基酸序列。在較佳實施例中,變異Fc區相比於天然序列Fc區或在親本多肽之Fc區中具有至少一個胺基酸取代,較佳地在天然序列Fc區中或在親本多肽之Fc區中具有1、2、3、4或5個胺基酸取代。在一替代實施例中,變異Fc區可根據本文中所揭示之方法產生且此變異Fc區可與所選異源多肽(諸如抗體可變域或非抗體多肽(例如,受體或配位體之結合域))融合。
如本文中所使用,在多肽之上下文中的術語「衍生物」係指包含已藉由引入胺基酸殘基取代而變異之胺基酸序列的多肽。如本文中所使用,術語「衍生物」亦指已藉由任何類型之分子與多肽之共價附接經修飾的多肽。舉例而言(但不以限制方式),抗體可例如藉由糖基化、乙醯化、聚乙二醇化、磷酸化、醯胺化、由已知保護/封端基團進行之衍生化、蛋白水解裂解、與細胞配位體或其他蛋白質連接等來修飾。衍生物多肽可藉由使用熟習此項技術者已知之技術進行多種化學修飾來產生,該等技術包括但不限於特異性化學裂解、乙醯化、甲醯化、在衣黴素存在下進行代謝合成等。此外,衍生物多肽擁有與其所衍生之多肽類似或相同的功能。應瞭解包含本發明之變異Fc區的多肽可為如本文所定義之衍生物,較佳地,衍生化發生在Fc區內。
如本文中所使用,關於多肽(例如,Fc區或單株抗體)之「實質上之犬來源」指示該多肽具有與天然犬胺基多肽之胺基酸序列至少80%、至少85%、更佳地至少90%、91%、92%、93%、94%或甚至更佳地至少95%、96%、97%、98%或99%同源性的胺基酸序列。
術語「Fc受體」或「FcR」用於描述結合至Fc區(例如,抗體之Fc區)的受體。較佳FcR係天然序列FcR。此外,較佳FcR為結合IgG抗體(γ受體)且包括FcγRI、FcγRII及FcγRIII子類之受體(包括此等受體之對偶基因變異體及交替剪接形式)的FcR。另一較佳FcR包括新生兒受體FcRn,其負責將母體IgG轉移至胎兒(Guyer等人,J. Immunol.117:587 (1976)及Kim等人,J. Immunol. 24:249 (1994))。其他FcR,包括將來鑑別之彼等FcR,由本文中之術語「FcR」涵蓋。
片語「抗體依賴性細胞介導之細胞毒性」及「ADCC」係指細胞介導之反應,其中表現FcR之非特異性細胞毒性細胞(例如,非特異性) (例如,自然殺手(「NK」)細胞、嗜中性球及巨噬細胞)識別目標細胞上之經結合抗體且隨後使得目標細胞裂解。用於介導ADCC之原代細胞NK細胞僅表現FcγRIII,而單核球表現FcγRI、FcγRII及FcγRIII。
如本文中所使用,片語「效應細胞」係指表現一種或多種FcR且執行效應功能之白血球(較佳地犬)。較佳地,該等細胞至少表現FcγRIII且執行ADCC效應功能。介導ADCC之白血球之實例包括PBMC、NK細胞、單核球、細胞毒性T細胞及嗜中性球。效應細胞可自天然來源(例如自血液或PBMC)分離。
具有「變化」FcRn結合親和力之變異多肽為在pH 6.0下量測時,與變異體之親本多肽或包含天然Fc區之多肽相比,具有增強(亦即,增加的、更大的或更高的)或減弱(亦即降低的、更小的或更低的) FcRn結合親和力之多肽。顯示與FcRn之結合增加或結合親和力增加的變異多肽以相比於親本多肽更大的親和力結合FcRn。顯示與FcRn之結合減小或結合親和力減小的變異多肽以相比於其親本多肽更低的親和力結合FcRn。顯示與FcRn之結合減小的此類變異體可具有與FcRn很少或沒有可觀的結合,例如與親本多肽相比,0%至20%與FcRn之結合。與其親本多肽相比,以「增強親和力」結合FcRn之變異多肽為當結合分析中變異多肽及親本多肽之量基本上相同,且所有其他條件一致時,以比親本多肽更高之結合親和力結合FcRn的多肽。舉例而言,具有增強FcRn結合親和力之變異多肽可顯示相比於親本多肽,FcRn結合親和力增加約1.10倍至約100倍(更通常約1.2倍至約50倍),其中例如在ELISA分析或一般熟習此項技術者可用之其他方法中測定FcRn結合親和力。
如本文中所使用,「胺基酸取代」係指給定胺基酸序列中之至少一個現有胺基酸殘基經另一不同「替代」胺基酸殘基替換。該或該等置換殘基可為「天然存在之胺基酸殘基」(亦即,由遺傳密碼編碼)且選自:丙胺酸(Ala);精胺酸(Arg);天冬醯胺(Asn);天冬胺酸(Asp);半胱胺酸(Cys);麩醯胺酸(Gln);麩胺酸(Glu);甘胺酸(Gly);組胺酸(His);異白胺酸(Ile):白胺酸(Leu);離胺酸(Lys);甲硫胺酸(Met);苯丙胺酸(Phe);脯胺酸(Pro);絲胺酸(Ser);蘇胺酸(Thr);色胺酸(Trp);酪胺酸(Tyr);及纈胺酸(Val)。本文中之胺基酸取代定義亦涵蓋一個或多個非天然存在之胺基酸殘基取代。「非天然存在之胺基酸殘基」係指除上文所列之彼等天然存在之胺基酸殘基以外的能夠共價結合多肽鏈中之一個或多個相鄰胺基酸殘基的殘基。非天然存在之胺基酸殘基之實例包括正白胺酸、鳥胺酸、正纈胺酸、高絲胺酸及其他胺基酸殘基類似物,諸如Ellman等人,Meth. Enzym. 202:301-336 (1991)中所述者。
術語「分析信號」係指偵測蛋白質-蛋白質相互作用之任何方法的輸出,包括但不限於比色分析之吸光度量測、螢光強度或衰變數/分鐘。分析格式可包括ELISA、facs或其他方法。「分析信號」之變化可反映細胞存活率之變化及/或動力學解離速率、動力學締合速率或兩者之變化。「更高分析信號」係指所量測的大於另一數值之輸出數值(例如,在ELISA分析中,與親本多肽相比,變異體可具有更高(更大)的量測數值)。「更低」分析信號係指所量測的小於另一數值之輸出數值(例如,在ELISA分析中,與親本多肽相比,變異體可具有更低的(較小)量測數值)。
術語「結合親和力」係指與各Fc受體-Fc結合相互作用相關之平衡解離常數(以濃度單位表述)。結合親和力直接與動力學解離速率(通常以倒數時間單位報導,例如秒
-1)除以動力學締合速率(通常以每單位時間之濃度單位報導,例如莫耳/秒)之比率相關。一般而言,不可能明確地表明平衡解離常數之變化是否是由於締合速率、解離速率或兩者之差異而導致,除非此等參數中之每一者以實驗方式經測定(例如,藉由BIACORE或SAPIDYNE量測)。
如本文中所使用,術語「鉸鏈區」係指犬IgG延伸中之胺基酸延伸,例如犬IgG之位置216至位置230。其他IgG同型之鉸鏈區可藉由將形成重鏈間二硫(S-S)鍵之半胱胺酸殘基置放在相同位置而與IgG序列對齊。
「Clq」為包括針對免疫球蛋白之Fc區之結合位點的多肽。Clq連同兩個絲胺酸蛋白酶Clr及Cls形成複合體Cl (CDC路徑之第一組分)。
如本文中所使用,術語「抗體」可與「免疫球蛋白」互換使用或「Ig」以最廣泛的意義使用且特定地涵蓋單株抗體(包括全長單株抗體)、多株抗體、多特異性抗體(例如雙特異性抗體)及抗體片段,只要其展現所需生物活性或功能活性。本發明及術語「抗體」亦涵蓋包含來源於不同物種之部分的單鏈抗體及嵌合、犬或犬類化抗體,以及嵌合或CDR移植之單鏈抗體等。此等抗體之各種部分可藉由習知技術化學地、合成地連接在一起或可使用基因工程改造技術製備為連續蛋白。舉例而言,編碼嵌合或犬類化鏈之核酸可表現以產生連續蛋白質。參見例如美國專利第4,816,567號;美國專利第4,816,397號;WO86/01533;美國專利第5,225,539號;及美國專利第5,585,089號及第5,698,762號。另外參見Newman, R.等人,BioTechnology, 10:1455-1460, 1993 (關於靈長類化抗體),及Ladner等人,美國專利第4,946,778號及Bird, R. E.等人,Science, 242:423-426, 1988 (關於單鏈抗體)。應瞭解,包含Fc區(或其部分)之抗體之所有形式涵蓋於本文中之術語「抗體」中。此外,抗體可用可偵測標記來標記,固定於固相上及/或根據此項技術中已知之方法與異源化合物(例如,酶或毒素)共軛。
如本文中所使用,術語「抗體片段」係指完整抗體之一部分。抗體片段之實例包括但不限於直鏈抗體;單鏈抗體分子;Fc或Fc之肽、Fab及Fab片段,及由抗體片段形成之多特異性抗體。抗體片段較佳地保留鉸鏈之至少一部分及視情況IgG重鏈之CH1區。在其他較佳實施例中,抗體片段包含CH2區之至少一部分或全部CH2區。
如本文中所使用,當術語「功能片段」關於單株抗體使用時欲指代單株抗體仍保留功能活性之部分。功能活性可為例如抗原結合活性或特異性、受體結合活性或特異性、效應功能活性等。單株抗體功能片段包括例如單獨的重鏈或輕鏈及其片段,諸如VL、VH及Fd;單價片段,諸如Fv、Fab及Fab';二價片段,諸如F(ab')
2;單鏈Fv (scFv);及Fc片段。此類術語描述於例如Harlowe及Lane,Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York (1989);Molec.Biology and Biotechnology: A Comprehensive Desk Reference (Myers, R. A. (編), New York:VCH Publisher, Inc.);Huston等人, Cell Biophysics, 22:189-224 (1993);Pluckthun及Skerra, Meth.Enzymol., 178:497-515 (1989)及Day, E. D., Advanced Immunochemistry, 第二版, Wiley-Liss, Inc., New York, N.Y. (1990)中。術語功能片段意欲包括例如藉由單株抗體之蛋白酶消化或還原及藉由熟習此項技術者已知之重組DNA方法產生之片段。
如本文中所使用,術語「片段」係指包含另一多肽之胺基酸序列之至少5、15、20、25、40、50、70、90、100或更多個相鄰胺基酸殘基之胺基酸序列的多肽。在一較佳實施例中,多肽之片段保留全長多肽之至少一個功能。
如本文中所使用,術語「嵌合抗體」包括單價、二價或多價免疫球蛋白。單價嵌合抗體為由嵌合重鏈經由與嵌合輕鏈之二硫橋鍵締合形成的二聚體。二價嵌合抗體為由兩個重鏈-輕鏈二聚體經由至少一個二硫橋鍵締合形成的四聚體。用於犬之抗體之嵌合重鏈包含來源於非犬抗體之重鏈的抗原結合區,該非犬抗體連接至犬重鏈恆定區之至少一部分,諸如CH1或CH2。用於犬之抗體之嵌合輕鏈包含來源於非犬抗體之輕鏈的與犬輕鏈恆定區(CL)之至少一部分連接的抗原結合區。具有相同或不同可變區結合特異性之嵌合重鏈及輕鏈的抗體、片段或衍生物亦可藉由個別多肽鏈根據已知方法步驟之適當締合來製備。藉由此途徑,將表現嵌合重鏈之宿主與表現嵌合輕鏈之宿主單獨培養,且單獨地回收免疫球蛋白鏈且接著進行締合。替代地,宿主可進行共培養且使各鏈在培養基中自發地締合,接著回收經組裝之免疫球蛋白或片段,或重鏈及輕鏈均可在相同宿主細胞中表現。用於產生嵌合抗體之方法為此項技術中所熟知(參見例如美國專利第6,284,471號;第5,807,715號;第4,816,567號;及第4,816,397號)。
如本文中所使用,非犬(例如鼠類)抗體之「犬類化」形式(亦即,犬類化抗體)為含有來源於非犬免疫球蛋白之最少序列或沒有來源於非犬免疫球蛋白之序列的抗體。在極大程度上,犬類化抗體係犬免疫球蛋白(接受者抗體),其中來自接受者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、兔、人類或非人類靈長類動物之非犬物種(供者抗體)的高變區之殘基置換。在一些情況下,犬免疫球蛋白之構架區(FR)殘基經相應的非犬殘基置換。此外,犬類化抗體可包含在接受者抗體或供者抗體中未發現之殘基。通常進行此等修飾以進一步改進抗體效能。一般而言,犬類化抗體將包含基本上全部至少一個,且通常兩個可變域,其中全部或基本上全部高變環(CDR)對應於非犬免疫球蛋白之彼等高變環且全部或基本上全部FR殘基為犬免疫球蛋白序列之彼等FR殘基。犬類化抗體亦可包含免疫球蛋白恆定區之至少一部分(Fc),通常犬免疫球蛋白之至少一部分。
如本文中所使用,術語「免疫黏附素」表示將異源「黏附素」蛋白質(例如,受體、配位體或酶)之結合域與免疫球蛋白恆定域組合之抗體樣分子。在結構上,免疫黏附素包含除抗體(亦即,為「異源」)之抗原識別及結合位點(抗原組合位點)以外的黏附素胺基酸序列以所需結合特異性與免疫球蛋白恆定域序列之融合。
如本文中所使用,術語「配位體結合域」係指任何天然受體或保持對應天然受體之至少一種定性配位體結合能力的其任何區或衍生物。在某些實施例中,受體來自具有與免疫球蛋白超基因家族成員同源之胞外域的細胞表面多肽。不為免疫球蛋白超基因家族成員,但此定義仍然特定涵蓋之其他受體為細胞因子之受體,且特定言之具有酪胺酸激酶活性之受體(受體酪胺酸激酶) (造血素及神經生長因子受體超家族之成員),及細胞黏附分子(例如,E-選擇素、L-選擇素及P-選擇素)。
如本文中所使用,術語「受體結合域」係指受體之任何天然配位體,包括例如細胞黏附分子,或此類天然配位體之保持對應天然配位體之至少一種定性受體結合能力的任何區或衍生物。
如本文中所使用,「經分離之」多肽為自其天然環境之組分鑑別及分離及/或回收之多肽。其天然環境之污染組分為將干擾多肽之診斷或治療用途之物質,且可包括酶、激素及其他蛋白質或非蛋白質溶質。在某些實施例中,經分離之多肽經純化(1)至大於95重量%之多肽,如藉由洛瑞法(Lowry method)所測定,且更佳大於99重量%,(2)在一定程度上藉由使用旋轉杯式定序儀(spinning cup sequenator)足以獲得至少15個N端殘基或內部胺基酸序列,或(3)藉由SDS-page在還原或非還原條件下使用庫馬斯藍或銀染色(Coomassie blue or silver stain)達至均質性。經分離之多肽包括原位存在於重組細胞內之多肽,因為多肽之天然環境中的至少一種組分將不存在。然而,通常經分離之多肽將藉由至少一個純化步驟來製備。
如本文中所使用,術語「病症」及「疾病」可互換地使用以指代將得益於用變異多肽(一種包含本發明之變異Fc區的多肽)治療之任何病狀,包括慢性及急性病症或疾病(例如,使患者易患特定病症之病理學病狀)。
如本文中所使用,術語「受體」係指能夠結合至少一種配位體之多肽。較佳受體為具有胞外配位體結合域及視情況其他域(例如,跨膜域、胞內域及/或膜錨)之細胞表面或可溶性受體。在本文中所描述之分析中評估之受體可為完整受體或其片段或衍生物(例如,包含與一種或多種異源多肽融合之受體之結合域的融合蛋白)。此外,用於評估受體之結合性質的受體可存在於細胞中或經分離且視情況塗佈於分析培養盤或某一其他固相上或經直接標記且用作探針。
犬野生型IgG
犬IgG為此項技術中熟知的且充分描述於例如Bergeron等人, 2014,
Vet Immunol Immunopathol., 第157 (1-2)卷, 第31-41頁中。在一個實施例中,犬IgG為IgG
A。在另一實施例中,犬gG為IgG
B。在又另一實施例中,犬IgG為IgG
C。在另一實施例中,犬IgG為IgG
D。在一特定實施例中,犬IgG為IgG
B。
IgG
A、IgG
B、IgG
C及IgG
D之胺基酸及核酸序列在此項技術中亦為熟知的。
在一個實例中,本發明之IgG包含恆定域,例如CH1、CH2或CH3域,或其組合。在另一實例中,本發明之恆定域包含Fc區,包括例如CH2或CH3域,或其組合。
在一特定實例中,野生型恆定域包含SEQ ID NO.: 1、2、3或4中所闡述之胺基酸序列。在一些實施例中,野生型IgG恆定域為SEQ ID NO.: 1、2、3或4之同源物、變異體、異構體或功能片段,但無本文所描述之任何突變。各種可能性代表本發明之各別實施例。
IgG恆定域亦包括具有與重鏈及/或輕鏈之胺基酸序列實質上類似的胺基酸序列之多肽。實質上相同的胺基酸序列在本文中定義為與比較胺基酸序列具有至少70%、75%、80%、85%、90%、95%或99%一致性的序列,如藉由根據Pearson及Lipman,Proc. Natl. Acad. Sci. USA 85:2444-2448 (1988)之FASTA搜索法所測定。
本發明亦包括本文中所描述之編碼IgG或其部分之核酸分子。在一個實施例中,核酸可編碼包含例如CH1、CH2、CH3區或其組合之抗體重鏈。在另一實施例中,核酸可編碼包含例如VH區中之任一者或其部分,或VH CDR中之任一者,包括其任何變異體之抗體重鏈。本發明亦包括編碼抗體輕鏈之核酸分子,該抗體輕鏈包含例如CL區中之任一者或其部分、VL區中之任一者或其部分,或VL CDR中之任一者,包括其任何變異體。在某些實施例中,核酸編碼重鏈及輕鏈兩者或其部分。
SEQ ID NO.: 1、2、3或4中闡述的野生型恆定域之胺基酸序列由其對應核酸序列編碼。舉例而言,SEQ ID NO.: 2中所闡述的野生型恆定域之胺基酸序列由SEQ ID NO.: 5或6中所闡述的核酸序列編碼。在一些實施例中,SEQ ID NO.: 1、2、3或4中闡述的野生型恆定域之胺基酸序列分別由SEQ ID NO.: 16、5、17或18中闡述的核酸序列編碼。
經修飾之犬IgG
本申請案之本發明人已發現,取代一個或多個胺基酸殘基驚人且出乎意料地增強對FcRn之親和力。如本文中所使用,胺基酸位置編號係指根據如在Kabat中之Eu索引編號的位置(Kabat等人, Sequences of Proteins of Immunological Interest, 第5版. Public Health Service, National Institutes of Health, Bethesda, Md. (1991))。
因此,在一個實施例中,本發明提供經修飾之IgG,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之Eu索引編號。
在一些實施例中,恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
在一特定實例中,本發明在SEQ ID NO.: 1、2、3或4中所闡述的野生型胺基酸序列中包含本文所描述之一個或多個突變。在一些實施例中,突變IgG恆定域為具有本文中所描述之一個或多個突變的同源物、變異體、異構體或功能片段。各種可能性代表本發明之各別實施例。
突變恆定域之胺基酸序列由其對應突變核酸序列編碼。
用於製備本發明之抗體分子的方法
用於製備抗體分子的方法為此項技術中熟知的且充分描述於美國專利8,394,925;8,088,376;8,546,543;10,336,818;及9,803,023及美國專利申請案公開案20060067930中,該等專利以全文引用之方式併入本文中。可使用熟習此項技術者已知的任何適合之方法、製程或技術。具有本發明之變異Fc區的抗體分子可根據此項技術中熟知的方法來產生。在一些實施例中,變異Fc區可與所選異源多肽,諸如抗體可變域或受體或配位體之結合域融合。
隨著分子生物學及重組技術方法之出現,熟習此項技術之人員可藉由重組方式產生抗體及抗體樣分子且藉此產生編碼在抗體之多肽結構中發現之特異性胺基酸序列的基因序列。此類抗體可藉由選殖編碼該等抗體之多肽鏈的基因序列或藉由直接合成該等多肽鏈及組裝合成鏈以形成針對特定抗原決定基及抗原決定子具有親和力之活性四聚(H2L2)結構來製備。此允許準備產生具有來自不同物種及來源之中和抗體之序列特徵的抗體。
無論抗體之來源如何,或其如何以重組方式構築,或其如何在活體外或活體內使用轉殖基因動物、實驗室或商購大小之大細胞培養物,使用轉殖基因植物或藉由在製程之任何階段不採用活生物體而直接進行化學合成來合成,所有抗體具有整體類似的3維結構。此結構通常以H2L2形式提供且指代抗體通常包含兩條輕(L)胺基酸鏈及2條重(H)胺基酸鏈的事實。兩條鏈具有能夠與結構上互補之抗原性目標交互的區。與目標交互之區稱為「可變」或「V」區且其特徵在於具有不同抗原特異性之抗體的胺基酸序列不同。H或L鏈之可變區含有能夠特異性結合於抗原目標之胺基酸序列。
如本文中所使用,術語「抗原結合區」係指抗體分子之含有與抗原相互作用且向抗體賦予其針對抗原之特異性及親和力之胺基酸殘基的部分。抗體結合區包括保持抗原結合殘基之恰當構形所必需的「構架」胺基酸殘基。在提供抗原結合區之H或L鏈之可變區內為稱為「高變」之小序列,因為其在不同特異性抗體之間具有極高變異性。此類高變區亦稱為「互補決定區」或「CDR」區。此等CDR區造成抗體針對特定抗原決定子結構之基本特異性。
CDR表示可變區內之非相鄰胺基酸延伸,但與物種無關,已發現此等重要胺基酸序列在可變重鏈及輕鏈區內之位置在可變鏈之胺基酸序列內具有類似位置。所有抗體之可變重鏈及輕鏈各自具有三個彼此不相鄰的CDR區。在所有哺乳動物物種中,抗體肽含有恆定(亦即,高度保守性)及可變區,且在後者中存在CDR,且所謂的「構架區」由在重鏈或輕鏈之可變區內但在CDR之外的胺基酸序列構成。
本發明進一步提供包括上文所描述之核酸中之至少一者的載體。因為遺傳密碼係簡併的,所以可使用超過一個密碼子編碼特定胺基酸。使用遺傳密碼,可鑑別出一種或多種不同核苷酸序列,其中之每一者將能夠編碼胺基酸。特定寡核苷酸實際上將構成實際編碼序列之機率可藉由考慮異常鹼基配對關係及在表現抗體或部分之真核或原核細胞中實際上使用(編碼特定胺基酸的)特定密碼子的頻率來估算。此類「密碼子使用規則」由Lathe等人, 183 J. Molec. Biol. 1-12 (1985)揭示。使用Lathe之「密碼子使用規則」,可鑑別出含有理論上能夠編碼犬IgG序列之「最可能」核苷酸序列的單核苷酸序列或核苷酸序列之集合。亦預期用於本發明之抗體編碼區亦可藉由使用產生本文中所描述之抗體及肽之變異體的標準分子生物技術改變現有抗體基因來提供。此類變異體包括(但不限於)抗體或肽之胺基酸序列的缺失、添加及取代。
舉例而言,一類取代為保守性胺基酸取代。此類取代為犬抗體肽中之既定胺基酸經另一具有類似特徵之胺基酸取代的彼等取代。通常視為保守性取代的係脂族胺基酸Ala、Val、Leu及lie中之一個置換成另一個;羥基殘基Ser及Thr之互換;酸性殘基Asp及Glu之交換;醯胺殘基Asn與Gin之間的取代;鹼性殘基Lys及Arg之交換;芳族殘基Phe、Tyr等中之置換。關於哪些胺基酸變化有可能在表現型上沉默之指南發現於Bowie等人,247
Science1306-10 (1990)。
變異犬抗體或肽可能為全功能或可能在一個或多個活動中缺乏功能。全功能變異體通常僅含有保守性變型或非關鍵殘基或非關鍵區之變型。功能變異體亦可含有使得功能無變化或不明顯變化的類似胺基酸取代。替代地,此類取代可能在一定程度上對功能產生正面或負面影響。非功能性變異體通常含有一個或多個非保守性胺基酸取代、缺失、插入、反轉或截短,或關鍵殘基或關鍵區中之取代、插入、反轉或缺失。
功能必需的胺基酸可藉由此項技術中已知的方法來鑑別,諸如定點突變誘發或丙胺酸掃描突變誘發。Cunningham
等人, 244
Science1081-85 (1989)。後一程序在分子中之每個殘基處引入單丙胺酸突變。隨後測試所得突變分子之生物活性,諸如抗原決定基結合或活體外ADCC活性。配體-受體結合之關鍵位點亦可藉由結構分析來確定,諸如晶體學、核磁共振或光親和性標記。Smith
等人, 224
J. Mol.Biol.899-904 (1992);de Vos
等人, 255
Science306-12 (1992)。
此外,多肽通常含有除二十種「天然存在」胺基酸以外之胺基酸。此外,包括末端胺基酸之許多胺基酸可藉由天然過程(諸如加工及其他轉譯後修飾)或藉由此項技術中熟知的化學修飾技術來修飾。已知修飾包括(但不限於)乙醯化、醯化、ADP-核糖基化、醯胺化、黃素之共價附接、血紅素部分之共價附接、核苷酸或核苷酸衍生物之共價附接、脂質或脂質衍生物之共價附接、磷脂醯肌醇之共價附接、交聯、環化、雙硫鍵形成、去甲基化、共價交聯之形成、胱胺酸之形成、焦麩胺酸之形成、甲醯化、伽瑪羧化、糖基化、GPI錨形成、羥基化、碘化、甲基化、豆蔻醯化、氧化、蛋白水解加工、磷酸化、異戊烯化、外消旋化、硒化、硫酸化、轉移RNA介導之胺基酸添加至蛋白質(諸如精氨醯化)及泛蛋白化。此類修飾已為熟習此項技術者所熟知且非常詳細地描述於科學文獻中。舉例而言,幾種特定地常見修飾糖基化、脂質附接、硫酸化、麩胺酸殘基之伽瑪羧化、羥基化及ADP核糖基化描述於大部分基礎本文中,諸如蛋白質結構及分子性質(Proteins-Structure and Molecular Properties) (第2版,T. E. Creighton, W. H. Freeman & Co., N.Y., 1993)。可獲得關於此主題之許多詳細綜述,諸如Wold,Posttranslational Covalent Modification of proteins, 1-12 (Johnson編, Academic Press, N.Y., 1983);Seifter等人,182 Meth.
Enzymol.626-46 (1990);及Rattan
等人,663
Ann. NY Acad. Sci. 48-62 (1992)。
在另一範疇中,本發明提供抗體衍生物。抗體之「衍生物」含有通常並非蛋白質之一部分的其他化學部分。蛋白質之共價修飾包括於本發明之範疇內。可藉由使抗體之目標胺基酸殘基與有機衍生劑反應將此類修飾引入分子中,該有機衍生劑能夠與所選側鏈或末端殘基反應。舉例而言,用此項技術中熟知的雙官能性試劑進行衍生化適用於將抗體或片段與水不可溶載體基質或與其他巨分子載劑交聯。
衍生物亦包括經標記之放射性標記的單株抗體。舉例而言,放射性碘(251、1311)、碳(4C)、硫(35S)、銦、氚(H
3)或類似者;單株抗體與生物素或抗生素蛋白、與酶(諸如辣根過氧化物酶、鹼性磷酸酶、β-D-半乳糖苷酶、葡萄糖氧化酶、澱粉酶、羧酸脫水酶、乙醯膽鹼酯酶、溶菌酶、蘋果酸脫氫酶或葡萄糖6-磷酸酯脫氫酶)之結合物;以及單株抗體與生物發光劑(諸如螢光素酶)、靜默變化劑(諸如吖啶酯)或螢光劑(諸如藻膽蛋白)之結合物。
本發明之另一衍生物雙官能性抗體為藉由組合兩種單獨抗體之識別兩種不同抗原基團的部分而產生的雙特異性抗體。此可藉由交聯或重組技術來實現。另外,各部分可添加至抗體或其部分中以增加活體內半衰期(例如,藉由延長達至血流清除之時間)。此類技術包括例如添加PEG部分(亦稱為PEG化)且為此項技術中眾所周知的。參見美國專利申請案公開案第20030031671號。
在一些實施例中,將編碼主題抗體之核酸直接引入宿主細胞中,且在足以誘導所編碼抗體表現之條件下培育細胞。在主題核酸已引入至細胞中之後,典型地通常在37℃下(有時在選擇下)培育細胞約1至24小時的時間段以便允許抗體表現。在一個實施例中,抗體經分泌於細胞生長之培養基之上清液中。傳統上,在鼠類雜交瘤株中產生呈天然分子形式之單株抗體。除了彼技術之外,本發明提供抗體之重組DNA表現。此允許在所選宿主物種中產生抗體,以及一系列抗體衍生物及融合蛋白質。
編碼本發明之至少一種抗體、部分或多肽之核酸序列可根據習知技術與載體DNA重組,該等技術包括用於連接之平端式或交錯端式末端、提供適當末端之限制酶消化、黏合末端視需要之填充、避免不當連接之鹼性磷酸酶處理及利用適當連接酶之連接。用於此操作之技術揭示於例如Maniatis等人,MOLECULAR CLONING,LAB. MANUAL, (Cold Spring Harbor Lab. Press,NY,1982及1989)及Ausubel等人,1993,同前文獻中,可用於構築一種抗體分子或其抗原結合區之核酸序列。
若諸如DNA之核酸分子含有含轉錄及轉譯調節資訊之核苷酸序列且此類序列「可操作地連接」至編碼多肽之核苷酸序列,則該核酸分子稱為「能夠表現」該多肽。可操作鍵聯為其中視圖表現之調節DNA序列及DNA序列以允許基因表現為可回收量的肽或抗體部分之方式連接的鍵聯。基因表現所需之調節區之精確性質可能因不同生物體而不同,如類似技術中所熟知。參見例如Sambrook
等人, 2001,同前文獻;Ausubel
等人, 1993,同前文獻。
因此,本發明涵蓋原核或真核細胞中之抗體或肽之表現。適合之宿主包括細菌或真核宿主,包括活體內或原位的細菌、酵母、昆蟲、真菌、鳥類及哺乳動物細胞,或哺乳動物、昆蟲、鳥類或酵母來源之宿主細胞。哺乳動物細胞或組織可屬於人類、靈長類、倉鼠、兔、嚙齒類動物、乳牛、豬、綿羊、馬、山羊、狗或貓來源。亦可使用此項技術中已知的任何其他適合之哺乳動物細胞。
在一個實施例中,本發明之核苷酸序列將併入至能夠在接受者宿主中自發複製的質體或病毒載體中。廣泛多種載體中之任一者可用於此目的。參見例如Ausubel等人,1993,同前文獻。選擇特定質體或病毒載體之重要因素包括:可自不含有載體之彼等接受者細胞中識別且選擇出含有載體之接受者細胞的容易性;特定宿主中所需要的載體複本數目;及是否期望能夠在不同物種之宿主細胞之間「穿梭」載體。
此項技術中已知之實例原核載體包括質體,諸如能夠在大腸桿菌中複製之彼等質體(諸如(例如) pBR322、CoIE1、pSC101、184、.pi.vX)。舉例而言,此類質體藉由Maniatis等人,1989,同前文獻;Ausubel等人,1993,同前文獻揭示。芽孢桿菌質體包括pC194、pC221、pT127等。此類質體藉由Gryczan,THE MOLEC. BIO. OF THE BACILLI 307-329 (Academic Press, NY, 1982)揭示。適合之鏈黴菌質體包括p1J101 (Kendall等人,169 J.Bacteriol. 4177-83 (1987),及鏈黴菌噬菌體,諸如phLC31 (Chater等人,在SIXTH INT'L SYMPOSIUM ON ACTINOMYCETALES BIO.45-54 (Akademiai Kaido,Budapest,Hungary 1986)中。假單胞菌質體綜述於John等人,8 Rev. Infect.Dis. 693-704 (1986);lzaki, 33 Jpn. J. Bacteriol. 729-42 (1978);及Ausubel等人, 1993,同前文獻中。
替代地,適用於表現編碼抗體或肽之cDNA的基因表現元件包含但不限於(a)病毒轉錄促進劑及其強化子元件,諸如SV40早期啟動子(Okayama等人,3 Mol. Cell. Biol. 280 (1983),勞氏肉瘤病毒LTR (Gorman等人, 79 Proc. Natl. Acad. Sci., USA 6777 (1982),及莫洛尼鼠類白血病病毒LTR(Grosschedl等人,41 Cell 885 (1985);(b)剪接區及聚腺苷酸化位點,諸如來源於SV40晚期區之彼等(Okayarea等人,1983)及(c)聚腺苷酸化位點,諸如SV40 (Okayama等人,1983)。
可如Weidle等人,51 Gene 21 (1987)所描述,使用SV40早期啟動子及其強化子、小鼠免疫球蛋白H鏈啟動子強化子、SV40晚期區mRNA剪接、兔S-血球蛋白插入序列、免疫球蛋白及兔S-血球蛋白聚腺苷酸化位點及SV40聚腺苷酸化元件作為表現元件來表現免疫球蛋白cDNA基因。對於由部分cDNA、部分基因體DNA (Whittle等人,1 Protein Engin. 499 (1987))構成之免疫球蛋白基因,轉錄啟動子可為人類細胞巨大病毒,啟動子強化子可為細胞巨大病毒及小鼠/人類免疫球蛋白,且mRNA剪接及聚腺苷酸化區可為天然染色體免疫球蛋白序列。
在一個實施例中,針對嚙齒類動物細胞中之cDNA基因表現,轉錄啟動子為病毒LTR序列,轉錄啟動子強化子為小鼠免疫球蛋白重鏈強化子及病毒LTR強化子中之任一者或兩者,剪接區含有大於31 bp之內含子,且聚腺苷酸化及轉譯終止區衍生自與將合成之免疫球蛋白鏈相對應的天然染色體序列。在其他實施例中,編碼其他蛋白質之cDNA序列與上文列舉之表現元件組合以實現哺乳動物細胞中之蛋白質表現。
各融合基因可組裝於表現載體中或插入至表現載體中。能夠表現免疫球蛋白鏈基因產物之接受者細胞隨後僅傳染有肽或H或L鏈編碼基因,或共轉染有H及L鏈基因。經轉染之接受者細胞在允許表現併入基因之條件下培養,且自培養物回收所表現之免疫球蛋白鏈或完整抗體或片段。
在一個實施例中,編碼肽或H及L鏈或其部分之融合基因經組裝於個別表現載體中,該等表現載體隨後用以共轉染接受者細胞。替代地,編碼H及L鏈之融合基因可組裝於相同表現載體上。對於表現載體之轉染及抗體之產生,接受者細胞株可為骨髓瘤細胞。骨髓瘤細胞可合成、組裝及分泌由經傳染之免疫球蛋白基因編碼之免疫球蛋白且具有使免疫球蛋白糖基化之機制。骨髓瘤細胞可在培養物中或在小鼠之腹腔中生長,其中分泌之免疫球蛋白可自腹水流體中獲得。其他適合之接受者細胞包括淋巴細胞,諸如犬或非犬來源之B淋巴球;犬或非犬來源之融合瘤細胞;或種間異種融合瘤細胞。
攜載本發明之抗體構築體或多肽的表現載體可藉由多種適合之方式中之任一者引入至適當宿主細胞中,該等方式包括生物化學方式,諸如轉化、轉染、共軛、原生質體融合、磷酸鈣-沈澱及施用諸如二乙胺基乙基(DEAE)葡聚糖的聚陽離子;及機械方式,諸如電穿孔、直接顯微注射及微彈轟擊。Johnston等人,240 Science 1538 (1988)。
對於免疫球蛋白H及L鏈之產生,酵母菌可提供優於細菌之明顯優勢。酵母會進行包括糖基化之轉譯後肽修飾。目前存在多種利用強啟動子序列及高質體複本數之重組DNA策略,該等強啟動子序列及高質體複本數可用於在酵母菌中產生所需蛋白質。酵母菌識別經選殖哺乳動物基因產物之前導序列且分泌攜帶前導序列之肽(亦即前肽)。Hitzman
等人, 11th Int'l Conference on Yeast, Genetics & Molec. Biol. (Montpelier, France, 1982)。
可常規地評估酵母菌基因表現系統之肽、抗體、其片段及區的產生量、分泌量及穩定性。當酵母菌在富含葡萄糖之培養基中生長時,可利用一系列酵母菌基因表現系統中之任一者,該等系統併入了來自編碼大量產生之糖分解酶之有效表現基因的啟動子及終止元件。已知糖分解基因亦可提供極有效的轉錄控制信號。舉例而言,可利用磷酸甘油酸激酶(PGK)基因之啟動子及終止子信號。可採取多種方法來評估用於在酵母中表現經選殖之免疫球蛋白cDNA的最佳表現質體。參見Vol. II DNA Cloning, 45-66, (Glover編) IRL Press, Oxford, UK 1985)。
細菌菌株亦可用作用以產生本發明所述之抗體分子或肽的宿主。將含有衍生自與宿主細胞相容之物種之複製子及控制序列的質體載體結合此等細菌宿主使用。載體通常攜帶複製位點以及能夠在轉型細胞中提供表型選擇之特定基因。可採用多種方法來評估用於產生由在細菌中選殖之免疫球蛋白cDNAs編碼之抗體、片段及區或抗體鏈的表現質體(參見Glover,1985,同前文獻;Ausubel,1993,同前文獻;Sambrook,2001,同前文獻;Colligan等人編,Current Protocols in Immunology, John Wiley & Sons, NY, N.Y. (1994-2001);Colligan等人編,Current Protocols in Protein Science, John Wiley & Sons, NY, N.Y. (1997-2001)。
宿主哺乳動物細胞可活體外或活體內生長。哺乳動物細胞提供針對免疫球蛋白蛋白分子之轉譯後修飾,包括前導肽移除、H及L鏈之摺疊及組裝、抗體分子之糖基化及功能性抗體蛋白質之分泌。除了上文所描述之淋巴來源之細胞之外,可用作產生抗體蛋白之宿主的哺乳動物細胞包括纖維母細胞來源之細胞,諸如Vero (ATCC CRL 81)或CHO-K1 (ATCC CRL 61)細胞。許多載體系統可用於在哺乳動物細胞中表現選殖肽H及L鏈基因(參見Glover,1985,同前文獻)。可遵循不同途徑以獲得完全H2L2抗體。可能在相同細胞中共表現H及L鏈以實現H及L鏈胞內締合及鍵聯成完全四聚體H2L2抗體及/或肽。可藉由在相同宿主中使用相同或不同的質體來進行共表現。H及L鏈及/或肽之基因可置放於相同質體中,隨後將該質體轉染至細胞中,藉此直接選擇表現該兩條鏈之細胞。替代地,細胞可首先轉染有編碼一條鏈(例如L鏈)之質體,接著使所得細胞株轉染有含第二可選標記之H鏈質體。經由任一途徑產生肽及/或H2L2分子之細胞株可轉染有編碼其他肽複本、H、L或H加L鏈以及前他可選標記之質體以產生具有增強特性之細胞株,諸如更高的產生經組裝H2L2抗體分子或經轉染細胞株之穩定性增強。
為長期、高產率產生重組型抗體,可使用穩定表現。舉例而言,可對穩定表現抗體分子之細胞株進行工程改造。而非使用含有病毒複製起點之表現載體,宿主細胞可用免疫球蛋白表現卡匣及可選標記轉化。在引入外來DNA後,可使經工程改造之細胞在富集培養基中生長1至2天,且隨後切換成選擇性培養基。重組型質體中之可選標記賦予對選擇之抵抗性且允許細胞將質體穩定整合至染色體中並生長以形成又可選殖且擴展至細胞株中的變異區(foci)。此類經工程改造之細胞株可特別適用於篩選及評估直接地或間接地與抗體分子相互作用的化合物/組分。
一旦產生本發明抗體,則可藉由此項技術中已知的用於純化免疫球蛋白分子之任何方法,例如藉由層析法(例如離子交換、親和力、針對蛋白質A之後的特定抗原之特定親和力及篩分管柱層析法)、離心、差異溶解性或藉由用於純化蛋白質之任何其他標準技術來將其純化。在許多實施例中,抗體自細胞分泌至培養基中且自培養基中收集。
醫藥學及獸醫學應用
本發明亦提供一種醫藥組合物,其包含本發明之分子及一種或多種醫藥學上可接受之載劑。更特定言之,本發明提供一種醫藥組合物,其包含醫藥學上可接受之載劑或稀釋劑及作為活性成分的本發明之抗體或肽。
「醫藥學上可接受之載劑」包括對於以所採用劑量及濃度暴露於其中之細胞或動物為無毒的任何賦形劑。醫藥組合物可包括一種或額外治療劑。
「醫藥學上可接受」係指彼等化合物、材料、組合物及/或劑型在合理醫學判斷之範疇內,適於與動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題併發症,與合理的效益/風險比相稱。
醫藥學上可接受之載劑包括溶劑、分散介質、緩衝液、包衣、抗菌劑及抗真菌劑、潤濕劑、防腐劑、傢夥(bugger)、螯合劑、抗氧化劑、等張劑及吸收延遲劑。
醫藥學上可接受之載劑包括水;生理食鹽水;磷酸鹽緩衝鹽水;右旋糖;甘油;醇,諸如乙醇及異丙醇;磷酸、檸檬酸及其他有機酸;抗壞血酸;低分子量(少於約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、天冬胺酸、精胺酸或離胺酸;單醣、雙醣及包括葡糖、甘露糖或糊精之其他碳水化合物;EDTA;形成鹽之相對離子,諸如鈉;及/或非離子界面活性劑,諸如TWEEN、聚乙二醇(PEG)及PLURONICS;等張劑,諸如糖、多元醇(諸如甘露醇及山梨醇)及氯化鈉;以及其組合。
本發明之醫藥組合物可以多種方式調配,包括例如液體、半固體及固體劑型,諸如液體溶液(例如可注射溶液及可輸注溶液)、分散液或懸浮液、脂質體、栓劑、錠劑、丸劑或散劑。在一些實施例中,組合物係呈可注射或可輸注溶液形式。組合物可呈適於靜脈內、動脈內、肌肉內、皮下、非經腸、經黏膜、經口、局部或經皮投與之形式。組合物可調配為立即、控制、延長或延遲釋放組合物。
本發明之組合物可以單獨的治療劑形式或與其他治療劑組合形式投與。其可單獨投與,但通常與基於所選投藥途徑及標準醫藥實踐選擇的醫藥學載劑一起投與。本文所揭示之抗體之投藥可藉由任何適合之方式進行,包括非經腸注射(諸如腹膜內、皮下或肌肉內注射)、經口,或藉由將抗體(典型地攜載於醫藥調配物中)局部投與至呼吸道表面。局部投與至呼吸道表面可藉由鼻內投藥(例如藉由使用滴管、拭子或吸入劑)來進行。抗體局部投與至呼吸道表面亦可藉由吸入投藥,諸如藉由形成呈氣霧懸浮液形式的含有抗體之醫藥調配物之可吸入粒子,且接著使個體吸入該等可吸入粒子來進行。用於投與醫藥調配物之可吸入粒子的方法及裝置為吾人所熟知的,且可採用任何習知技術。
在一些所需實施例中,抗體藉由非經腸注射來投與。對於非經腸投與,抗體或分子可結合醫藥學上可接受之非經腸媒劑調配為溶液、懸浮液、乳液或凍乾粉形式。舉例而言,媒劑可為抗體或其溶解於可接受之載劑(諸如水性載劑)中的混合物的溶液,此類媒劑為水、生理鹽水、林格氏溶液(Ringer's solution)、右旋糖溶液、海藻糖或蔗糖溶液或5%血清白蛋白、0.4%生理鹽水、0.3%甘胺酸及類似者。亦可使用脂質體及非水性媒劑,諸如不揮發性油。此等溶液為無菌的且一般不含顆粒物質。此等組合物可藉由習知熟知滅菌技術來滅菌。組合物可含有醫藥學上可接受之輔助物質,如大致生理條件所需要,諸如pH調節劑及緩衝劑、毒性調節劑及其類似者,例如乙酸鈉、氯化鈉、氯化鉀、氯化鈣、乳酸鈉等。此等調配物中之抗體濃度可廣泛變化,例如自小於約0.5重量%,通常為或至少約為1重量%至高達15重量%或20重量%,且將根據所選擇之特定投藥模式主要基於液體體積、黏度等來選擇。媒劑或凍乾粉可含有維持等張性之添加劑(例如氯化鈉、甘露醇)及維持化學穩定性之添加劑(例如緩衝液及防腐劑)。調配物藉由常用技術來滅菌。用於製備可非經腸投與之組合物的實際方法將為熟習此項技術者已知或顯而易知的且較詳細地描述在例如雷明頓氏醫藥科學(REMINGTON'S PHARMA.SCI. (第15版, Mack Pub. Co., Easton, Pa., 1980))中。
本發明之抗體或分子可凍乾以便儲存且在使用之前在適合之載劑中復原。此技術已顯示對習知免疫球蛋白有效。可採用任何適合的凍乾及復原技術。熟習此項技術者應瞭解,凍乾及復原可引起不同程度的抗體活性損失且可必須調整使用量以補償。可投與含有本發明抗體或其混合物之組合物以預防現有疾病之復發及/或治療性治療現有疾病。適合之醫藥學載劑描述於最近版本之雷明頓氏醫藥科學(此技術領域中之標準參考本文)中。在治療性應用中,向已經患有疾病之個體投與足以治癒或至少部分地遏制或減輕疾病及其併發症之量的組合物。
用於治療如本文所描述之病狀或疾病的本發明之組合物的有效劑量視許多不同因素而變化,該等因素包括例如但不限於特定藥劑之藥效學特徵及其投藥模式及途徑;目標位點;動物之生理狀態;所投與之其他藥物;治療為預防性的抑或治療性的;接受者之年齡、健康狀況及體重;症狀之性質及程度、並行治療之類別、治療頻率及所需效果。
單次或多次投與組合物可以在治療獸醫所選之劑量及模式下進行。在任何情況下,醫藥調配物應提供足以有效治療個體之量的一種或多種本發明抗體。
治療劑量可使用熟習此項技術者已知之常規方法來滴定以使安全性及功效最佳化。
本發明之醫藥組合物可包括「治療有效量」。「治療有效量」係指在所需劑量及時間段下,有效達成所需治療結果之量。治療有效量之分子可根據諸如個體之疾病病況、年齡、性別及體重,及分子在個體中引起所需反應之能力的因素而變化。治療有效量亦為抗體分子之治療有益效應超過其任何毒性或有害效應的量。
在另一範疇中,本發明之組合物可用於例如治療狗之各種疾病及病症。如本文中所使用,術語「治療(treat/treatment)」係指治療性治療,包括防治性或預防性措施,其中目標係預防或減緩(減輕)非所要的與疾病或病狀相關之生理變化。不論可偵測或不可偵測,有益的或所需的臨床結果包括(但不限於)症狀緩解、疾病或病狀之程度減弱、疾病或病狀穩定(亦即,其中疾病或病狀不再惡化)、疾病或病狀之進程延遲或減緩、疾病或病狀改善或緩和及疾病或病狀緩解(不論部分或總體)。需要治療之彼等者包括已患有該疾病或病狀以及易於患有該疾病或病狀之彼等者或應預防該疾病或病狀之彼等者。
本說明書中引用之所有專利及文獻參考以全文引用之方式併入本文中。
提供以下實例以補充先前揭示內容且提供對本文所描述之主題的較佳理解。此等實例不應視為限制所描述之主題。應理解,本文所描述之實例及實施例僅用於說明之目的,且鑒於其各種修改或改變對於熟習此項技術者將為顯而易見的且欲包括於本發明之真正範疇內且可在不脫離本發明之真正範疇的情況下進行。
實例 實例 1 構築犬 IgG Fc 突變體
全部犬IgG (
圖 1)之構築如Bergeron等人(Bergeron等人,2014,
Vet Immunol Immunopathol.,第157(1-2)卷,第31-41頁)所描述來進行,其中利用含有編碼IgGB(65)子類之犬恆定區之序列的質體且本文所研究之各mAb之VH/VL序列插入編碼恆定域之核苷酸的上游及框內。突變藉由將恆定區直接DNA合成為基因片段而併入各質體之CH1、CH2或CH3域(
圖 2)之各各別位置中,且隨後次選殖至各別所關注可變區中。
表現及純化
單株抗體(mAb)突變體在獲自Thermo Fisher之哺乳動物懸浮液細胞系統EXPICHO-S (Chinese Hamster Ovary)細胞中表現。懸浮EXPICHO-S細胞在EXPICHO表現培養基(Gibco)中維持於0.14與8.0×10e6個細胞/毫升之間。細胞在第-1天及轉染日遵循ExpiCHO方案使用者手冊進行稀釋。使用來源於ExpiFectamine CHO轉染套組(Gibco)之試劑,按照最大效價條件,如方案中所述轉染經稀釋之細胞。培育12至14天之後,採集培養物且進行澄清。經由蛋白質A層析在已藉由PBS預平衡之MabSelect Sure LX (GE Healthcare)上自澄清之上清液純化抗體。在樣本裝載之後,將樹脂用PBS洗滌,且隨後用20 mM乙酸鈉pH 5.5洗滌。用20 mM乙酸pH 3.5自管柱溶離樣本。溶離之後,進行彙集且藉由添加1 M乙酸鈉中和至4%。視可用體積及預期用途而定,有時將樣本交換至最終緩衝液(例如PBS、其他)中。藉由在280 nm下之吸光度來量測濃度。
SDS-PAGE
使用4至12%含Bis-Tris NuPAGE凝膠之MES-SDS操作緩衝劑及SeeBlue Plus 2標準物(均來自Invitrogen)執行非還原性(nr)及還原性十二烷基硫酸鈉聚丙烯醯胺電泳(SDS-PAGE)。對於非還原性樣本,添加1mM之烷化劑N-乙基順丁烯二醯亞胺(NEM),對於還原性樣本,添加還原劑二硫蘇糖醇(DTT)。用庫馬斯藍對凝膠進行染色以偵測蛋白質帶。
分析型SEC
使用來自TOSOH BioScience之TSK凝膠SuperSW3000、4.6mm、10×30 cm、4μm管柱在200mM磷酸鈉pH 7.2操作緩衝劑中以0.25毫升/分鐘進行分析型SEC。
NR-CGE
使用Beckman Coulter PA800 plus分析器使用A55625毛細管筒按照製造商說明書來執行非還原性毛細管凝膠電泳(nrCGE)。
SMAC
使用Sepax Zenix SEC-300、4.6×300mm管柱在200mM磷酸鈉pH 7.2操作緩衝劑中以0.35ml/min進行立式單層吸收層析(SMAC)。
HIC
使用Sepax Proteomix HIC Butyl-NP5、4.6×100mm管柱進行疏水性相互作用層析(HIC)。以0.75ml/min施加自含100% 1.8M硫酸銨之0.1M磷酸鈉pH 6.5至100% 0.1M磷酸鈉pH 6.5之線性梯度持續20min。
Octet-BLI
使用Forte Bio's Octet QKe藉由胺反應性第二代生物感測器進行此分析。將樣本更換為無鈣及鎂之1× Gibco PBS,且稀釋至0.5mg/mL之濃度。在建立生物感測器基線之後,將生物感測器浸沒至100uL之樣本中600秒。
經由Octet QKe定量(Pall ForteBio Corp, Menlo Park, CA, USA)篩檢結合於蛋白質A或蛋白G感測器之抗體。針對蛋白質品質,如Bergeron等人中所描述來純化且定量結合於蛋白質A之構築體。
實例 2 FcRn 結合分析
分離、製備犬FcRn,且根據上文所論述之Bergeron等人分析針對犬FcRn之突變Fc IgG。使用標準PCR來擴增犬FcRn-α次單元及β-微球蛋白。FcRn-α次單元及β-微球蛋白經共轉染至HEK 293細胞中且FcRn複合體係藉由經由c端His標籤進行IMAC親和純化來純化。FcRn複合體經由BirA酶促生物素醯化反應來進行生物素標記。藉由Biacore 3000或Biacore T200 (GE Healthcare,Pittsburgh, PA, USA)使用SA感測器晶片量測KD。
使用修改之SA捕獲方法將FcRn捕獲於感測器表面上。10mM MES;150mM NaCl;0.005% Tween20;0.5 mg/mL BSA;pH6用作捕獲方法操作操作緩衝液及滴定。1×HB-P、0.5 mg/mL BSA;pH7.4亦用於方法操作緩衝液及滴定。Fc突變IgG在受體表面上流動且使用Scrubber2軟體分析(BioLogic Software Pty, Ltd., Campbell, Australia)或T200評估軟體測定親和力(
表 1)。自所有操作中減去僅含有緩衝液之空白操作。流通池使用50 mM Tris pH8進行再生。在15℃下進行操作。
在各別位置產生的突變對於pH6下IgG針對FcRn之親和力具有明顯影響。IgG之FcRn親和力的增加並不依賴於VHVL域,且針對任何犬IgG為通用的。
藉由表面電漿子共振(Biacore)量測野生型(WT)及突變IgG與犬FcRn之結合。亦進行生物物理學表徵。
結果清楚地顯示在各別位置產生的突變對於IgG針對FcRn之親和力具有明顯影響。
實例 3 對狗之 Fc 突變 IgG PK 研究
實施藥物動力學(PK)研究以展示各種犬IgG點突變之半衰期延長之效應:(1) L252F;(2) L252R、N434H、Q311W;(3) L252R;(4) L252Y、N434Y、Q311W;(5) Q311W;(6) L252R、A254T、T256E、N434H;(7) L252Y、A254T;及(8) L252M、A254S、E439K。
將表5中所列出之八種Fc修飾之犬類化單株抗體以及野生型犬類化單株抗體用於實驗中。八種Fc修飾之犬類化單株抗體以單次1 mg/kg皮下投與至約4歲的米格魯犬(n=2)。使用配位體結合方法分析彼等分子之血清濃度。
使用非房室途徑(用於AUC計算之線性梯形法則)藉助於Watson™在狗中評估五種Fc修飾之犬單株抗體之藥物動力學特性。藉由Excel™進行其他計算,包括校正第2次及第3次注射藥物之後的濃度-時間特徵曲線之重疊的AUC。使用Excel™或Watson™計算濃度-時間資料及藥物動力學資料在簡單統計下之彙總(均值、標準偏差、變化係數)。不進行其他統計分析。
結果顯示Fc區之某些修飾對其半衰期時間具有顯著影響,如上表中所示。特定言之,相對於野生型,犬IgG點突變(1) L252F;(2) L252R、N434H、Q311W;(3) L252R;(5) Q311W;(6) L252R、A254T、T256E、N434H;(7) L252Y、A254T;及(8) L252M、A254S、E439K有效於增強半衰期。
野生型mAb ZTS-8183之半衰期(T1/2)為約11天。然而,Fc修飾之犬單株抗體ZTS-00530712、ZTS-00530713、ZTS-00530714、ZTS-00530716、ZTS-00530717、ZTS-00530718及ZTS-00530719之半衰期(T1/2)分別為23.0、4.23、13.9、22.2、31.4、27.8及25.3。
如上表5及圖4中所示,Fc修飾之犬單株抗體ZTS-00530715 (亦即,突變L252Y、N434Y及Q311W之組合)之半衰期(T1/2)無效。
總之,結果清楚地顯示犬IgG點突變(1) L252F;(2) L252R、N434H、Q311W;(3) L252R;(5) Q311W;(6) L252R、A254T、T256E、N434H;(7) L252Y、A254T;及(8) L252M、A254S、E439K高度有效於增強犬之半衰期。
已描述本發明之較佳實施例,應理解,本發明不限於確切實施例,且各種變化及修改可由熟習此項技術者在不偏離本發明之如所附申請專利範圍中定義的範疇或精神之情況下於其中實現。
本專利或申請案檔案含有至少一張彩製圖。在申請且支付必要的費用後,專利局將提供具有彩色圖式之此專利或專利申請公開案之複本。
[圖1]展示IgG之域結構。
[圖2]展示野生型(WT)人類IgG1 WT犬1gGA、WT犬IgGB、WT犬IgGC及WT犬IgGD之胺基酸序列之比對。胺基酸殘基係根據如Kabat中之Eu索引編號。CH1、鉸鏈、CH2及CH3胺基酸殘基分別呈紅色、紫色、藍色及綠色。
[圖3]展示犬Fc IgGB WT核苷酸序列。
[圖4]展示某些犬IgG點突變增加狗之半衰期。突變1係指L252F;突變2係指突變L252R、N434H及Q311W之組合;突變3係指L252R;突變4係指突變L252Y、N434Y及Q311W之組合;突變5係指Q311W;突變6係指突變L252R、A254T、T256E及N434H之組合;突變7係指突變L252Y及A254T之組合;及突變8係指突變L252M、A254S及E439K之組合。
序列表之簡要說明
SEQ ID NO.: 1係指野生型犬IgGA恆定區之胺基酸序列。
SEQ ID NO.: 2係指野生型犬IgGB (65)恆定區之胺基酸序列。
SEQ ID NO.: 3係指野生型犬IgGC恆定區之胺基酸序列。
SEQ ID NO.: 4係指野生型犬IgGD恆定區之胺基酸序列。
SEQ ID NO.: 5係指根據一個實施例經密碼子最佳化之野生型犬IgGB (65)之核酸序列。
SEQ ID NO.: 6係指根據一個實施例之野生型犬IgGB (65)恆定域之核酸序列。
SEQ ID NO.: 7係指野生型犬IgGB CH1域之胺基酸序列。
SEQ ID NO.: 8係指野生型犬IgGB鉸鏈域之胺基酸序列。
SEQ ID NO.: 9係指野生型犬IgGB CH2域之胺基酸序列。
SEQ ID NO.: 10係指野生型犬IgGB CH3域之胺基酸序列。
SEQ ID NO.: 11係指野生型犬IgGB CH1域之核酸序列。
SEQ ID NO.: 12係指野生型犬IgGB鉸鏈域之核酸序列。
SEQ ID NO.: 13係指野生型犬IgGB CH2域之核酸序列。
SEQ ID NO.: 14係指野生型犬IgGB CH3域之核酸序列。
SEQ ID NO.: 15係指野生型人類IgG1恆定區之胺基酸序列。
SEQ ID NO.: 16係指野生型犬IgGA恆定區之核酸序列。
SEQ ID NO.: 17係指野生型犬IgGC恆定區之核酸序列。
SEQ ID NO.: 18係指野生型犬IgGD恆定區之核酸序列。
SEQ ID NO.: 19係指野生型人類IgG1恆定區之核酸序列。
SEQ ID NO.: 20係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR1之核酸序列。
SEQ ID NO.: 21係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR1之胺基酸序列。
SEQ ID NO.: 22係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR2之核酸序列。
SEQ ID NO.: 23係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR2之胺基酸序列。
SEQ ID NO.: 24係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR3之核酸序列。
SEQ ID NO.: 25係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈CDR3之胺基酸序列。
SEQ ID NO.: 26係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR1之核酸序列。
SEQ ID NO.: 27係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR1之胺基酸序列。
SEQ ID NO.: 28係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR2之核酸序列。
SEQ ID NO.: 29係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR2之胺基酸序列。
SEQ ID NO.: 30係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR3之核酸序列。
SEQ ID NO.: 31係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈CDR3之胺基酸序列。
SEQ ID NO.: 32係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈之核酸序列。
SEQ ID NO.: 33係指在本文中稱為ZTS-8183之抗IL31抗體之可變輕鏈之胺基酸序列。
SEQ ID NO.: 34係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈之核酸序列。
SEQ ID NO.: 35係指在本文中稱為ZTS-8183之抗IL31抗體之可變重鏈之胺基酸序列。
<![CDATA[<110> 美商碩騰服務公司(Zoetis Services LLC)]]> <![CDATA[<120> 犬抗體恆定區中之突變]]> <![CDATA[<140> TW 111104187]]> <![CDATA[<141> 2022-01-28]]> <![CDATA[<160> 35 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 331]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGA恆定區]]> <![CDATA[<400> 1]]> Ala Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly 1 5 10 15 Ser Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu His Ser 50 55 60 Leu Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr 65 70 75 80 Phe Thr Cys Asn Val Val His Pro Ala Ser Asn Thr Lys Val Asp Lys 85 90 95 Pro Val Phe Asn Glu Cys Arg Cys Thr Asp Thr Pro Pro Cys Pro Val 100 105 110 Pro Glu Pro Leu Gly Gly Pro Ser Val Leu Ile Phe Pro Pro Lys Pro 115 120 125 Lys Asp Ile Leu Arg Ile Thr Arg Thr Pro Glu Val Thr Cys Val Val 130 135 140 Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val 145 150 155 160 Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Ser Arg Glu Gln Gln 165 170 175 Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu His Gln 180 185 190 Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile Asp 195 200 205 Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Arg Ala 210 215 220 His Lys Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser 225 230 235 240 Ser Ser Asp Thr Val Ser Ile Thr Cys Leu Ile Lys Asp Phe Tyr Pro 245 250 255 Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu 260 265 270 Arg Lys His Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr 275 280 285 Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly 290 295 300 Asp Pro Phe Thr Cys Ala Val Met His Glu Thr Leu Gln Asn His Tyr 305 310 315 320 Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys 325 330 <![CDATA[<210> 2]]> <![CDATA[<211> 335]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGB恆定區]]> <![CDATA[<400> 2]]> Ala Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly 1 5 10 15 Ser Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr 65 70 75 80 Phe Thr Cys Asn Val Ala His Pro Ala Ser Lys Thr Lys Val Asp Lys 85 90 95 Pro Val Pro Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys 100 105 110 Pro Lys Cys Pro Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile 115 120 125 Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu 130 135 140 Val Thr Cys Val Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln 145 150 155 160 Ile Ser Trp Phe Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln 165 170 175 Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu 180 185 190 Pro Ile Gly His Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys 195 200 205 Val Asn Asn Lys Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys 210 215 220 Ala Arg Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser 225 230 235 240 Arg Glu Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys 245 250 255 Asp Phe Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln 260 265 270 Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu 275 280 285 Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg 290 295 300 Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu 305 310 315 320 His Asn His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys 325 330 335 <![CDATA[<210> 3]]> <![CDATA[<211> 333]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGC恆定區]]> <![CDATA[<400> 3]]> Ala Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly 1 5 10 15 Ser Gln Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr 20 25 30 Ile Pro Glu Pro Val Thr Val Ser Trp Asn Ser Val Ser Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr 65 70 75 80 Phe Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys Val Asp Lys 85 90 95 Pro Val Ala Lys Glu Cys Glu Cys Lys Cys Asn Cys Asn Asn Cys Pro 100 105 110 Cys Pro Gly Cys Gly Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro 115 120 125 Pro Lys Pro Lys Asp Ile Leu Val Thr Ala Arg Thr Pro Thr Val Thr 130 135 140 Cys Val Val Val Asp Leu Asp Pro Glu Asn Pro Glu Val Gln Ile Ser 145 150 155 160 Trp Phe Val Asp Ser Lys Gln Val Gln Thr Ala Asn Thr Gln Pro Arg 165 170 175 Glu Glu Gln Ser Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile 180 185 190 Gly His Gln Asp Trp Leu Ser Gly Lys Gln Phe Lys Cys Lys Val Asn 195 200 205 Asn Lys Ala Leu Pro Ser Pro Ile Glu Glu Ile Ile Ser Lys Thr Pro 210 215 220 Gly Gln Ala His Gln Pro Asn Val Tyr Val Leu Pro Pro Ser Arg Asp 225 230 235 240 Glu Met Ser Lys Asn Thr Val Thr Leu Thr Cys Leu Val Lys Asp Phe 245 250 255 Phe Pro Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu 260 265 270 Pro Glu Ser Lys Tyr Arg Met Thr Pro Pro Gln Leu Asp Glu Asp Gly 275 280 285 Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln 290 295 300 Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn 305 310 315 320 His Tyr Thr Gln Ile Ser Leu Ser His Ser Pro Gly Lys 325 330 <![CDATA[<210> 4]]> <![CDATA[<211> 331]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGD恆定區]]> <![CDATA[<400> 4]]> Ala Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly 1 5 10 15 Ser Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Thr Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr 65 70 75 80 Phe Thr Cys Asn Val Val His Pro Ala Ser Asn Thr Lys Val Asp Lys 85 90 95 Pro Val Pro Lys Glu Ser Thr Cys Lys Cys Ile Ser Pro Cys Pro Val 100 105 110 Pro Glu Ser Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro 115 120 125 Lys Asp Ile Leu Arg Ile Thr Arg Thr Pro Glu Ile Thr Cys Val Val 130 135 140 Leu Asp Leu Gly Arg Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val 145 150 155 160 Asp Gly Lys Glu Val His Thr Ala Lys Thr Gln Pro Arg Glu Gln Gln 165 170 175 Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Pro Ile Glu His Gln 180 185 190 Asp Trp Leu Thr Gly Lys Glu Phe Lys Cys Arg Val Asn His Ile Gly 195 200 205 Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala 210 215 220 His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Pro Lys Glu Leu Ser 225 230 235 240 Ser Ser Asp Thr Val Thr Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro 245 250 255 Pro Glu Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Pro Glu Pro Glu 260 265 270 Ser Lys Tyr His Thr Thr Ala Pro Gln Leu Asp Glu Asp Gly Ser Tyr 275 280 285 Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln Gln Gly 290 295 300 Asp Thr Phe Thr Cys Ala Val Met His Glu Ala Leu Gln Asn His Tyr 305 310 315 320 Thr Asp Leu Ser Leu Ser His Ser Pro Gly Lys 325 330 <![CDATA[<210> 5]]> <![CDATA[<211> 1005]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB恆定域-經密碼子最佳化。]]> <![CDATA[<400> 5]]> gccagcacca cagctccctc cgtgttcccc ctggctccta gctgcggctc tacctccggc 60 agcacagtgg ccctggcttg tctggtgtcc ggctacttcc ctgagccagt gaccgtgagc 120 tggaactccg gctccctgac ctccggagtg cacacatttc caagcgtgct gcagtcttcc 180 ggcctgtatt ctctgagctc tatggtgacc gtgccttcca gcaggtggcc atctgagaca 240 ttcacctgca acgtggccca tcccgcttcc aagacaaagg tggacaagcc cgtgcctaag 300 agggagaatg gaagggtgcc ccggccccct gattgcccta agtgtccagc tccagagatg 360 ctgggaggac catccgtgtt catctttcca cccaagccca aggataccct gctgatcgct 420 agaacccctg aggtgacatg cgtggtggtg gacctggatc cagaggaccc cgaggtgcag 480 atctcttggt tcgtggatgg caagcagatg cagaccgcca agacacagcc tagggaggag 540 cagtttaacg gcacctacag ggtggtgtcc gtgctgccaa tcggccacca ggactggctg 600 aagggcaagc agtttacctg caaggtgaac aataaggctc tgccttctcc aatcgagaga 660 acaatctcca aggccagggg ccaggctcat cagcctagcg tgtacgtgct gcctccatcc 720 agagaggagc tgagcaagaa caccgtgtct ctgacatgtc tgatcaagga tttctttccc 780 cctgacatcg atgtggagtg gcagagcaat ggccagcagg agccagagtc taagtatcgc 840 accacaccac cccagctgga cgaggatggc agctacttcc tgtatagcaa gctgtctgtg 900 gacaagtcta gatggcagcg cggcgatacc tttatctgtg ccgtgatgca cgaggcactg 960 cacaatcact acacccagga gagtctgagc cacagcccag gaaaa 1005 <![CDATA[<210> 6]]> <![CDATA[<211> 1005]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB恆定域]]> <![CDATA[<400> 6]]> gcctcaacaa ctgctcctag cgtgtttccc ctggccccta gctgcggaag tacctcaggc 60 agcacagtgg ccctggcttg tctggtgtct ggatatttcc ctgagccagt gaccgtgagt 120 tggaacagcg gctctctgac ctccggggtg cacacatttc catctgtgct gcagtctagt 180 ggcctgtact ccctgtcaag catggtgact gtgccttcct ctaggtggcc atcagaaact 240 ttcacctgca acgtggccca tcccgccagc aagaccaaag tggacaagcc cgtgcctaaa 300 agggagaatg gaagggtgcc aagaccacct gattgcccta agtgtccagc tccagaaatg 360 ctgggaggac caagcgtgtt catctttcca cccaagccca aagacacact gctgattgct 420 agaactcccg aggtgacctg cgtggtggtg gacctggatc cagaggaccc cgaagtgcag 480 atctcctggt tcgtggatgg gaagcagatg cagacagcca aaactcagcc tcgggaggaa 540 cagtttaacg gaacctatag agtggtgtct gtgctgccaa ttggacacca ggactggctg 600 aagggcaaac agtttacatg caaggtgaac aacaaggccc tgcctagtcc aatcgagagg 660 actatttcaa aagctagggg acaggctcat cagccttccg tgtatgtgct gcctccatcc 720 cgggaggaac tgtctaagaa cacagtgagt ctgacttgtc tgatcaaaga tttctttccc 780 cctgacattg atgtggagtg gcagagcaat gggcagcagg agccagaatc caagtacaga 840 accacaccac cccagctgga cgaagatggc tcctatttcc tgtacagtaa gctgtcagtg 900 gacaaatcta ggtggcagcg cggggatacc tttatctgcg ccgtgatgca cgaggctctg 960 cacaatcatt acacacaaga aagtctgtca catagccccg gcaag 1005 <![CDATA[<210> 7]]> <![CDATA[<211> 98]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGB CH1域]]> <![CDATA[<400> 7]]> Ala Ser Thr Thr Ala Pro Ser Val Phe Pro Leu Ala Pro Ser Cys Gly 1 5 10 15 Ser Thr Ser Gly Ser Thr Val Ala Leu Ala Cys Leu Val Ser Gly Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ser Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ser Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Met Val Thr Val Pro Ser Ser Arg Trp Pro Ser Glu Thr 65 70 75 80 Phe Thr Cys Asn Val Ala His Pro Ala Ser Lys Thr Lys Val Asp Lys 85 90 95 Pro Val <![CDATA[<210> 8]]> <![CDATA[<211> 18]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGB鉸鏈域]]> <![CDATA[<400> 8]]> Pro Lys Arg Glu Asn Gly Arg Val Pro Arg Pro Pro Asp Cys Pro Lys 1 5 10 15 Cys Pro <![CDATA[<210> 9]]> <![CDATA[<211> 110]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGB CH2域]]> <![CDATA[<400> 9]]> Ala Pro Glu Met Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Leu Ile Ala Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Leu Asp Pro Glu Asp Pro Glu Val Gln Ile Ser Trp Phe 35 40 45 Val Asp Gly Lys Gln Met Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu 50 55 60 Gln Phe Asn Gly Thr Tyr Arg Val Val Ser Val Leu Pro Ile Gly His 65 70 75 80 Gln Asp Trp Leu Lys Gly Lys Gln Phe Thr Cys Lys Val Asn Asn Lys 85 90 95 Ala Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ala Arg 100 105 110 <![CDATA[<210> 10]]> <![CDATA[<211> 109]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型犬IgGB CH3域]]> <![CDATA[<400> 10]]> Gly Gln Ala His Gln Pro Ser Val Tyr Val Leu Pro Pro Ser Arg Glu 1 5 10 15 Glu Leu Ser Lys Asn Thr Val Ser Leu Thr Cys Leu Ile Lys Asp Phe 20 25 30 Phe Pro Pro Asp Ile Asp Val Glu Trp Gln Ser Asn Gly Gln Gln Glu 35 40 45 Pro Glu Ser Lys Tyr Arg Thr Thr Pro Pro Gln Leu Asp Glu Asp Gly 50 55 60 Ser Tyr Phe Leu Tyr Ser Lys Leu Ser Val Asp Lys Ser Arg Trp Gln 65 70 75 80 Arg Gly Asp Thr Phe Ile Cys Ala Val Met His Glu Ala Leu His Asn 85 90 95 His Tyr Thr Gln Glu Ser Leu Ser His Ser Pro Gly Lys 100 105 <![CDATA[<210> 11]]> <![CDATA[<211> 294]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB CH1域]]> <![CDATA[<400> 11]]> gcctcaacaa ctgctcctag cgtgtttccc ctggccccta gctgcggaag tacctcaggc 60 agcacagtgg ccctggcttg tctggtgtct ggatatttcc ctgagccagt gaccgtgagt 120 tggaacagcg gctctctgac ctccggggtg cacacatttc catctgtgct gcagtctagt 180 ggcctgtact ccctgtcaag catggtgact gtgccttcct ctaggtggcc atcagaaact 240 ttcacctgca acgtggccca tcccgccagc aagaccaaag tggacaagcc cgtg 294 <![CDATA[<210> 12]]> <![CDATA[<211> 54]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB鉸鏈域]]> <![CDATA[<400> 12]]> cctaaaaggg agaatggaag ggtgccaaga ccacctgatt gccctaagtg tcca 54 <![CDATA[<210> 13]]> <![CDATA[<211> 330]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB CH2域]]> <![CDATA[<400> 13]]> gctccagaaa tgctgggagg accaagcgtg ttcatctttc cacccaagcc caaagacaca 60 ctgctgattg ctagaactcc cgaggtgacc tgcgtggtgg tggacctgga tccagaggac 120 cccgaagtgc agatctcctg gttcgtggat gggaagcaga tgcagacagc caaaactcag 180 cctcgggagg aacagtttaa cggaacctat agagtggtgt ctgtgctgcc aattggacac 240 caggactggc tgaagggcaa acagtttaca tgcaaggtga acaacaaggc cctgcctagt 300 ccaatcgaga ggactatttc aaaagctagg 330 <![CDATA[<210> 14]]> <![CDATA[<211> 327]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGB CH3域]]> <![CDATA[<400> 14]]> ggacaggctc atcagccttc cgtgtatgtg ctgcctccat cccgggagga actgtctaag 60 aacacagtga gtctgacttg tctgatcaaa gatttctttc cccctgacat tgatgtggag 120 tggcagagca atgggcagca ggagccagaa tccaagtaca gaaccacacc accccagctg 180 gacgaagatg gctcctattt cctgtacagt aagctgtcag tggacaaatc taggtggcag 240 cgcggggata cctttatctg cgccgtgatg cacgaggctc tgcacaatca ttacacacaa 300 gaaagtctgt cacatagccc cggcaag 327 <![CDATA[<210> 15]]> <![CDATA[<211> 330]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 野生型人類IgG1恆定區]]> <![CDATA[<400> 15]]> Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110 Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125 Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140 Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp 145 150 155 160 Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175 Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190 His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205 Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220 Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu 225 230 235 240 Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255 Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270 Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285 Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300 Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr 305 310 315 320 Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330 <![CDATA[<210> 16]]> <![CDATA[<211> 993]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGA恆定區]]> <![CDATA[<400> 16]]> gcctccacca cggcgccctc ggttttccca ctggccccca gctgcgggtc cacttccggc 60 tccacggtgg ccctggcctg cctggtgtca ggctacttcc ccgagcctgt aactgtgtcc 120 tggaactccg gctccttgac cagcggtgtg cacaccttcc cgtccgtcct gcagtcctca 180 gggcttcact ccctcagcag catggtgaca gtgccctcca gcaggtggcc cagcgagacc 240 ttcacctgca acgtggtcca cccagccagc aacactaaag tagacaagcc agtgttcaat 300 gaatgcagat gcactgatac acccccatgc ccagtccctg aacctctggg agggccttcg 360 gtcctcatct ttcccccgaa acccaaggac atcctcagga ttacccgaac acccgaggtc 420 acctgtgtgg tgttagatct gggccgtgag gaccctgagg tgcagatcag ctggttcgtg 480 gatggtaagg aggtgcacac agccaagacc cagtctcgtg agcagcagtt caacggcacc 540 taccgtgtgg tcagcgtcct ccccattgag caccaggact ggctcacagg gaaggagttc 600 aagtgcagag tcaaccacat agacctcccg tctcccatcg agaggaccat ctctaaggcc 660 agagggaggg cccataagcc cagtgtgtat gtcctgccgc catccccaaa ggagttgtca 720 tccagtgaca cagtcagcat cacctgcctg ataaaagact tctacccacc tgacattgat 780 gtggagtggc agagcaatgg acagcaggag cccgagagga agcaccgcat gaccccgccc 840 cagctggacg aggacgggtc ctacttcctg tacagcaagc tctctgtgga caagagccgc 900 tggcagcagg gagacccctt cacatgtgcg gtgatgcatg aaactctaca gaaccactac 960 acagatctat ccctctccca ttctccgggt aaa 993 <![CDATA[<210> 17]]> <![CDATA[<211> 999]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> mi]]>sc_feature <![CDATA[<223> 野生型犬IgGC恆定區]]> <![CDATA[<400> 17]]> gcctccacca cggcgccctc ggttttccca ctggccccca gctgtgggtc ccaatccggc 60 tccacggtgg ccctggcctg cctggtgtca ggctacatcc ccgagcctgt aactgtgtcc 120 tggaactccg tctccttgac cagcggtgtg cacaccttcc cgtccgtcct gcagtcctca 180 gggctctact ccctcagcag catggtgaca gtgccctcca gcaggtggcc cagcgagacc 240 ttcacctgca atgtggccca cccggccacc aacactaaag tagacaagcc agtggccaaa 300 gaatgcgagt gcaagtgtaa ctgtaacaac tgcccatgcc caggttgtgg cctgctggga 360 gggccttcgg tcttcatctt tcccccaaaa cccaaggaca tcctcgtgac tgcccggaca 420 cccacagtca cttgtgtggt ggtggatctg gacccagaaa accctgaggt gcagatcagc 480 tggttcgtgg atagtaagca ggtgcaaaca gccaacacgc agcctcgtga ggagcagtcc 540 aatggcacct accgtgtggt cagtgtcctc cccattgggc accaggactg gctttcaggg 600 aagcagttca agtgcaaagt caacaacaaa gccctcccat cccccattga ggagatcatc 660 tccaagaccc cagggcaggc ccatcagcct aatgtgtatg tcctgccgcc atcgcgggat 720 gagatgagca agaatacggt caccctgacc tgtctggtca aagacttctt cccacctgag 780 attgatgtgg agtggcagag caatggacag caggagcctg agagcaagta ccgcatgacc 840 ccgccccagc tggatgaaga tgggtcctac ttcctataca gcaagctctc cgtggacaag 900 agccgctggc agcggggaga caccttcata tgtgcggtga tgcatgaagc tctacacaac 960 cactacacac agatatccct ctcccattct ccgggtaaa 999 <![CDATA[<210> 18]]> <![CDATA[<211> 993]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 家犬]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型犬IgGD恆定區]]> <![CDATA[<400> 18]]> gcctccacca cggcgccctc ggttttccca ctggccccca gctgcgggtc cacttccggc 60 tccacggtgg ccctggcctg cctggtgtca ggctacttcc ccgagcctgt aactgtgtcc 120 tggaactccg gctccttgac cagcggtgtg cacaccttcc cgtccgtcct gcagtcctca 180 gggctctact ccctcagcag cacggtgaca gtgccctcca gcaggtggcc cagcgagacc 240 ttcacctgca acgtggtcca cccggccagc aacactaaag tagacaagcc agtgcccaaa 300 gagtccacct gcaagtgtat atccccatgc ccagtccctg aatcactggg agggccttcg 360 gtcttcatct ttcccccgaa acccaaggac atcctcagga ttacccgaac acccgagatc 420 acctgtgtgg tgttagatct gggccgtgag gaccctgagg tgcagatcag ctggttcgtg 480 gatggtaagg aggtgcacac agccaagacg cagcctcgtg agcagcagtt caacagcacc 540 taccgtgtgg tcagcgtcct ccccattgag caccaggact ggctcaccgg aaaggagttc 600 aagtgcagag tcaaccacat aggcctcccg tcccccatcg agaggactat ctccaaagcc 660 agagggcaag cccatcagcc cagtgtgtat gtcctgccac catccccaaa ggagttgtca 720 tccagtgaca cggtcaccct gacctgcctg atcaaagact tcttcccacc tgagattgat 780 gtggagtggc agagcaatgg acagccggag cccgagagca agtaccacac gactgcgccc 840 cagctggacg aggacgggtc ctacttcctg tacagcaagc tctctgtgga caagagccgc 900 tggcagcagg gagacacctt cacatgtgcg gtgatgcatg aagctctaca gaaccactac 960 acagatctat ccctctccca ttctccgggt aaa 993 <![CDATA[<210> 19]]> <![CDATA[<211> 990]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 智人]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 野生型人類IgG1恆定區]]> <![CDATA[<400> 19]]> gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg 60 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120 tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240 tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagaa agttgagccc 300 aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 360 ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540 agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600 gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660 aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 720 ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840 ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 900 cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960 cagaagagcc tctccctgtc tccgggtaaa 990 <![CDATA[<210> 20]]> <![CDATA[<211> 15]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 重鏈CDR1]]> <![CDATA[<400> 20]]> aactacggca tgagc 15 <![CDATA[<210> 21]]> <![CDATA[<211> 5]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 重鏈CDR1]]> <![CDATA[<400> 21]]> Asn Tyr Gly Met Ser 1 5 <![CDATA[<210> 22]]> <![CDATA[<211> 51]]> <![CDATA[<212> ]]> DNA <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<22]]>3> 重鏈CDR2]]> <br/> <br/><![CDATA[<400> 22]]> <br/><![CDATA[accatcagct acggcggcag ctacacctac taccccgaca acatcaaggg c 51 <![CDATA[<210> 23]]> <![CDATA[<211> 17]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 重鏈CDR2]]> <![CDATA[<400> 23]]> Thr Ile Ser Tyr Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Asn Ile Lys 1 5 10 15 Gly <![CDATA[<210> 24]]> <![CDATA[<211> 33]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 重鏈CDR3]]> <![CDATA[<400> 24]]> gtgcggggct acggctacga cacaatggac tac 33 <![CDATA[<210> 25]]> <![CDATA[<211> 11]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 重鏈CDR3]]> <![CDATA[<400> 25]]> Val Arg Gly Tyr Gly Tyr Asp Thr Met Asp Tyr 1 5 10 <![CDATA[<210> 26]]> <![CDATA[<211> 45]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 輕鏈CDR1]]> <![CDATA[<400> 26]]> aaggccagcc agagcgtgtc cttcgccggc acaggcctga tgcac 45 <![CDATA[<210> 27]]> <![CDATA[<211> 15]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 輕鏈CDR1]]> <![CDATA[<400> 27]]> Lys Ala Ser Gln Ser Val Ser Phe Ala Gly Thr Gly Leu Met His 1 5 10 15 <![CDATA[<210> 28]]> <![CDATA[<211> 21]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 輕鏈CDR2]]> <![CDATA[<400> 28]]> cgggccagca acctggaagc c 21 <![CDATA[<210> 29]]> <![CDATA[<211> 7]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 輕鏈CDR2]]> <![CDATA[<400> 29]]> Arg Ala Ser Asn Leu Glu Ala 1 5 <![CDATA[<210> 30]]> <![CDATA[<211> 27]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<223> 輕鏈CDR3]]> <![CDATA[<400> 30]]> cagcagagca gagagtaccc ctggacc 27 <![CDATA[<210> 31]]> <![CDATA[<211> 9]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小家鼠]]> <![CDATA[<220>]]> <![CDATA[<221> MISC_FEATURE]]> <![CDATA[<223> 輕鏈CDR3]]> <![CDATA[<400> 31]]> Gln Gln Ser Arg Glu Tyr Pro Trp Thr 1 5 <![CDATA[<210> 32]]> <![CDATA[<211> 657]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ZTS-8183 –可變輕鏈核酸序列-犬類化]]> <![CDATA[<400> 32]]> gagatcgtga tgacccagag ccccgccagc ctgagcctga gccaggaaga gaaagtcacc 60 atcacatgca aggccagcca gagcgtgtcc ttcgccggca caggcctgat gcactggtat 120 cagcagaagc ccggccaggc ccccaagctg ctgatctacc gggccagcaa cctggaagcc 180 ggcgtgccaa gcagattcag cggcagcggc tccggcaccg acttcagctt caccatcagc 240 agcctcgaac ccgaggacgt ggccgtgtac tactgccagc agagcagaga gtacccctgg 300 accttcggcc agggtaccaa gctggaaatc aagcggaacg acgcccagcc cgccgtgtac 360 ctgttccagc ccagccccga tcagctgcac accggcagcg cttcagtcgt ctgcctgctg 420 aacagcttct accccaagga catcaacgtg aagtggaagg tggacggcgt gatccaggac 480 accggcatcc aggaaagcgt caccgagcag gacaaggaca gcacctacag cctgagcagc 540 accctgacca tgtccagcac cgagtacctg agccacgagc tgtatagctg cgagatcacc 600 cacaagagcc tgcctagcac cctgatcaag agcttccagc ggagcgagtg ctagtag 657 <![CDATA[<210> 33]]> <![CDATA[<211> 217]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ZTS-8183 –可變輕鏈胺基酸序列-犬類化]]> <![CDATA[<400> 33]]> Glu Ile Val Met Thr Gln Ser Pro Ala Ser Leu Ser Leu Ser Gln Glu 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Phe Ala 20 25 30 Gly Thr Gly Leu Met His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 35 40 45 Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ala Gly Val Pro Ser 50 55 60 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Phe Thr Ile Ser 65 70 75 80 Ser Leu Glu Pro Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Ser Arg 85 90 95 Glu Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 110 Asn Asp Ala Gln Pro Ala Val Tyr Leu Phe Gln Pro Ser Pro Asp Gln 115 120 125 Leu His Thr Gly Ser Ala Ser Val Val Cys Leu Leu Asn Ser Phe Tyr 130 135 140 Pro Lys Asp Ile Asn Val Lys Trp Lys Val Asp Gly Val Ile Gln Asp 145 150 155 160 Thr Gly Ile Gln Glu Ser Val Thr Glu Gln Asp Lys Asp Ser Thr Tyr 165 170 175 Ser Leu Ser Ser Thr Leu Thr Met Ser Ser Thr Glu Tyr Leu Ser His 180 185 190 Glu Leu Tyr Ser Cys Glu Ile Thr His Lys Ser Leu Pro Ser Thr Leu 195 200 205 Ile Lys Ser Phe Gln Arg Ser Glu Cys 210 215 <![CDATA[<210> 34]]> <![CDATA[<211> 1365]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ZTS-8183 –可變重鏈核酸序列-犬類化]]> <![CDATA[<400> 34]]> gaggtgcagc tggtggaatc tggcggcgac ctggtcaagc ctggcggcag cctgagactg 60 agctgtgtgg ccagcggctt caccttcagc aactacggca tgagctgggt ccgacaggcc 120 cctggcaagg gactgcagtg ggtggccacc atcagctacg gcggcagcta cacctactac 180 cccgacaaca tcaagggccg gttcaccatc agccgggaca acgccaagaa caccctgtac 240 ctgcagatga acagcctgcg ggccgaggac accgccatgt actactgcgt gcggggctac 300 ggctacgaca caatggacta ctggggccag ggcaccctcg tgaccgtctc gagcgcctca 360 acaactgctc ctagcgtgtt tcccctggcc cctagctgcg gaagtacctc aggcagcaca 420 gtggccctgg cttgtctggt gtctggatat ttccctgagc cagtgaccgt gagttggaac 480 agcggctctc tgacctccgg ggtgcacaca tttccatctg tgctgcagtc tagtggcctg 540 tactccctgt caagcatggt gactgtgcct tcctctaggt ggccatcaga aactttcacc 600 tgcaacgtgg cccatcccgc cagcaagacc aaagtggaca agcccgtgcc taaaagggag 660 aatggaaggg tgccaagacc acctgattgc cctaagtgtc cagctccaga aatgctggga 720 ggaccaagcg tgttcatctt tccacccaag cccaaagaca cactgctgat tgctagaact 780 cccgaggtga cctgcgtggt ggtggacctg gatccagagg accccgaagt gcagatctcc 840 tggttcgtgg atgggaagca gatgcagaca gccaaaactc agcctcggga ggaacagttt 900 aacggaacct atagagtggt gtctgtgctg ccaattggac accaggactg gctgaagggc 960 aaacagttta catgcaaggt gaacaacaag gccctgccta gtccaatcga gaggactatt 1020 tcaaaagcta ggggacaggc tcatcagcct tccgtgtatg tgctgcctcc atcccgggag 1080 gaactgtcta agaacacagt gagtctgact tgtctgatca aagatttctt tccccctgac 1140 attgatgtgg agtggcagag caatgggcag caggagccag aatccaagta cagaaccaca 1200 ccaccccagc tggacgaaga tggctcctat ttcctgtaca gtaagctgtc agtggacaaa 1260 tctaggtggc agcgcgggga tacctttatc tgcgccgtga tgcacgaggc tctgcaccat 1320 cattacacac aagaaagtct gtcacatagc cccggcaagt agtag 1365 <![CDATA[<210> 35]]> <![CDATA[<211> 453]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> ZTS-8183 –可變重鏈胺基酸序列-犬類化]]> <![CDATA[<400> 35]]> Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Gln Trp Val 35 40 45 Ala Thr Ile Ser Tyr Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Asn Ile 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Val Arg Gly Tyr Gly Tyr Asp Thr Met Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala Ser Thr Thr Ala Pro Ser Val Phe Pro 115 120 125 Leu Ala Pro Ser Cys Gly Ser Thr Ser Gly Ser Thr Val Ala Leu Ala 130 135 140 Cys Leu Val Ser Gly Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 145 150 155 160 Ser Gly Ser Leu Thr Ser Gly Val His Thr Phe Pro Ser Val Leu Gln 165 170 175 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Met Val Thr Val Pro Ser Ser 180 185 190 Arg Trp Pro Ser Glu Thr Phe Thr Cys Asn Val Ala His Pro Ala Ser 195 200 205 Lys Thr Lys Val Asp Lys Pro Val Pro Lys Arg Glu Asn Gly Arg Val 210 215 220 Pro Arg Pro Pro Asp Cys Pro Lys Cys Pro Ala Pro Glu Met Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Thr Leu Leu 245 250 255 Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Leu Asp Pro 260 265 270 Glu Asp Pro Glu Val Gln Ile Ser Trp Phe Val Asp Gly Lys Gln Met 275 280 285 Gln Thr Ala Lys Thr Gln Pro Arg Glu Glu Gln Phe Asn Gly Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Pro Ile Gly His Gln Asp Trp Leu Lys Gly 305 310 315 320 Lys Gln Phe Thr Cys Lys Val Asn Asn Lys Ala Leu Pro Ser Pro Ile 325 330 335 Glu Arg Thr Ile Ser Lys Ala Arg Gly Gln Ala His Gln Pro Ser Val 340 345 350 Tyr Val Leu Pro Pro Ser Arg Glu Glu Leu Ser Lys Asn Thr Val Ser 355 360 365 Leu Thr Cys Leu Ile Lys Asp Phe Phe Pro Pro Asp Ile Asp Val Glu 370 375 380 Trp Gln Ser Asn Gly Gln Gln Glu Pro Glu Ser Lys Tyr Arg Thr Thr 385 390 395 400 Pro Pro Gln Leu Asp Glu Asp Gly Ser Tyr Phe Leu Tyr Ser Lys Leu 405 410 415 Ser Val Asp Lys Ser Arg Trp Gln Arg Gly Asp Thr Phe Ile Cys Ala 420 425 430 Val Met His Glu Ala Leu His His His Tyr Thr Gln Glu Ser Leu Ser 435 440 445 His Ser Pro Gly Lys 450
Claims (72)
- 一種經修飾之IgG,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之EU索引編號。
- 如請求項1之經修飾之IgG,其中該恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
- 如請求項1之經修飾之IgG,其中相比於具有該野生型犬IgG恆定域之IgG,該經修飾之IgG具有針對FcRn之更高親和力。
- 如請求項1之經修飾之IgG,其中該經修飾之IgG為犬或犬類化IgG。
- 如請求項1之經修飾之IgG,其中該IgG為IgG A、IgG B、IgG C或IgG D。
- 如請求項1之經修飾之IgG,其中該IgG恆定域為IgG A、IgG B、IgG C或IgG D之恆定域。
- 如請求項1之經修飾之IgG,其中該IgG恆定域包含具有CH3域之Fc恆定區。
- 如請求項1之經修飾之IgG,其中該IgG恆定域包含具有CH2及CH3域之Fc恆定區。
- 如請求項1之經修飾之IgG,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1中所闡述之胺基酸序列。
- 一種醫藥組合物,其包含如請求項1之經修飾之IgG及醫藥學上可接受之載劑。
- 一種套組,其包含於容器中之如請求項1之經修飾之IgG,及使用說明書。
- 一種多肽,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之EU索引編號。
- 如請求項12之多肽,其中該恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
- 如請求項12之多肽,其中相比於具有該野生型犬IgG恆定域之IgG之多肽,該多肽具有針對FcRn之更高親和力。
- 如請求項12之多肽,其中該多肽為犬或犬類化IgG之多肽。
- 如請求項12之多肽,其中該IgG為IgG A、IgG B、IgG C或IgG D。
- 如請求項12之多肽,其中該IgG恆定域為IgG A、IgG B、IgG C或IgG D之恆定域。
- 如請求項12之多肽,其中該IgG恆定域包含具有CH3域之Fc恆定區。
- 如請求項12之多肽,其中該IgG恆定域包含具有CH2及CH3域之Fc恆定區。
- 如請求項12之多肽,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1中所闡述之胺基酸序列。
- 一種抗體,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之EU索引編號。
- 如請求項21之抗體,其中該恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
- 如請求項21之抗體,其中相比於具有該野生型犬IgG恆定域之IgG之多肽,該多肽具有針對FcRn之更高親和力。
- 如請求項21之抗體,其中該多肽為犬或犬類化IgG之多肽。
- 如請求項21之抗體,其中該IgG為IgG A、IgG B、IgG C或IgG D。
- 如請求項21之抗體,其中該IgG恆定域為IgG A、IgG B、IgG C或IgG D之恆定域。
- 如請求項21之抗體,其中該IgG恆定域包含具有CH3域之Fc恆定區。
- 如請求項21之抗體,其中該IgG恆定域包含具有CH2及CH3域之Fc恆定區。
- 如請求項21之抗體,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1中所闡述之胺基酸序列。
- 一種醫藥組合物,其包含如請求項29之抗體及醫藥學上可接受之載劑。
- 一種套組,其包含於容器中之如請求項29之抗體,及使用說明書。
- 一種載體,其包含編碼如請求項21之抗體之胺基酸序列的核酸序列,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1中所闡述之胺基酸序列。
- 一種經分離之細胞,其包含如請求項32之載體。
- 一種製造抗體或分子之方法,該方法包含:提供如請求項33之細胞;及培養該細胞。
- 一種製造抗體之方法,該方法包含:提供如請求項21至29中任一項之抗體。
- 一種融合分子,其包含:相對於野生型犬IgG恆定域包含至少一個胺基酸取代之犬IgG恆定域,其中該取代處於胺基酸殘基247、252、254、256、311、312、314、431、434或439處,根據如Kabat中之EU索引編號。
- 如請求項36之分子,其中該恆定域包含以下取代中之一者或多者:P247V、L252Y、L252P、L252W、L252A、L252D、L252G、L252H、L252I、L252K、L252M、L252N、L252Q、L252S、L252T、L252V、L252F、L252R、A254F、A254G、A254H、A254N、A254Q、A254R、A254W、A254C、A254D、A254I、A254K、A254L、A254M、A254P、A254S、A254T、A254V、A254Y、T256H、T256I、T256K、T256L、T256Q、T256Y、T256A、T256C、T256D、T256F、T256G、T256M、T256N、T256P、T256R、T256S、T256V、T256W、T256E、Q311H、Q311R、Q311Y、Q311W、D312P、L314K、A431K、N434A、N434C、N434D、N434E、N434F、N434G、N434H、N434I、N434K、N434L、N434M、N434P、N434Q、N434R、N434S、N434T、N434V、N434W、N434Y及E439K。
- 如請求項36之分子,其中相比於具有該野生型犬IgG恆定域之IgG之多肽,該多肽具有針對FcRn之更高親和力。
- 如請求項36之分子,其中該多肽為犬或犬類化IgG之多肽。
- 如請求項36之分子,其中該IgG為IgG A、IgG B、IgG C或IgG D。
- 如請求項36之分子,其中該IgG恆定域為IgG A、IgG B、IgG C或IgG D之恆定域。
- 如請求項36之分子,其中該IgG恆定域包含具有CH3域之Fc恆定區。
- 如請求項36之分子,其中該IgG恆定域包含具有CH2及CH3域之Fc恆定區。
- 如請求項36之分子,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1中所闡述之胺基酸序列。
- 一種醫藥組合物,其包含如請求項36之分子及醫藥學上可接受之載劑。
- 一種套組,其包含於容器中之如請求項36之分子,及使用說明書。
- 如請求項1之經修飾之IgG,其中該等突變中之至少一者改良生物物理學特性。
- 如請求項47之經修飾之IgG,其中該生物物理學特性為多反應性。
- 如請求項12之多肽,其中該等突變中之至少一者改良生物物理學特性。
- 如請求項49之多肽,其中該生物物理學特性為多反應性。
- 如請求項21之抗體,其中該等突變中之至少一者改良生物物理學特性。
- 如請求項51之抗體,其中該生物物理學特性為多反應性。
- 如請求項36之分子,其中該等突變中之至少一者改良生物物理學特性。
- 如請求項53之分子,其中該生物物理學特性為多反應性。
- 一種用於延長狗之抗體血清半衰期之方法,該方法包含:向該狗投與治療有效量之包含犬IgG恆定域之抗體,相對於野生型犬IgG恆定域,該犬IgG恆定域包含至少一個胺基酸取代,其中該取代處於胺基酸殘基252、254、256、311、434或439處,根據如Kabat中之EU索引編號。
- 如請求項55之方法,其中該犬IgG恆定域包含以下突變中之一者或多者:L252F、L252R、L252Y、L252M、A254T、A254S、T256E、Q311W、N434H、N434Y及E439K。
- 如請求項55之方法,其中該犬IgG恆定域包含選自以下群組之突變:(1) L252F;(2) L252R、N434H及Q311W;(3) L252R;(4) Q311W;(5) L252R、A254T、T256E及N434H;(6) L252Y及A254T;或(7) L252M、A254S及E439K。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252F。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252R、N434H及Q311W之組合。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252R或Q311W。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252R、A254T、T256E及N434H之組合。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252Y及A254T之組合。
- 如請求項55之方法,其中該犬IgG恆定域包含突變L252M、A254S及E439K之組合。
- 如請求項55之方法,其中相較於具有該野生型犬IgG恆定域之IgG,該犬IgG恆定域具有更高的血清半衰期。
- 如請求項55之方法,其中該IgG為IgGA、IgGB、IgGC或IgGD。
- 如請求項55之方法,其中該IgG恆定域為IgGA、IgGB、IgGC或IgGD之恆定域。
- 如請求項55之方法,其中該IgG恆定域包含具有CH3域之Fc恆定區。
- 如請求項55之方法,其中該IgG恆定域包含具有CH2及CH3域之Fc恆定區。
- 如請求項55之方法,其中該野生型犬IgG恆定域包含SEQ ID NO.: 1、2、3或4中所闡述之胺基酸序列。
- 如請求項55之方法,其中該抗體為抗IL31抗體。
- 一種治療犬個體之IL-31介導之瘙癢或過敏性病狀的方法,該方法包含:向該個體投與治療有效量之如請求項55之抗IL31抗體,藉此治療該犬個體之該IL-31介導之瘙癢或過敏性病狀。
- 如請求項55之方法,其中該IL-31介導之瘙癢或過敏性病狀為選自由以下所組成之群組的瘙癢病狀:異位性皮膚炎、濕疹、牛皮癬、硬皮病及瘙癢性皮炎。
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GB8308235D0 (en) | 1983-03-25 | 1983-05-05 | Celltech Ltd | Polypeptides |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
GB8422238D0 (en) | 1984-09-03 | 1984-10-10 | Neuberger M S | Chimeric proteins |
US5225539A (en) | 1986-03-27 | 1993-07-06 | Medical Research Council | Recombinant altered antibodies and methods of making altered antibodies |
US4946778A (en) | 1987-09-21 | 1990-08-07 | Genex Corporation | Single polypeptide chain binding molecules |
US5530101A (en) | 1988-12-28 | 1996-06-25 | Protein Design Labs, Inc. | Humanized immunoglobulins |
US6284471B1 (en) | 1991-03-18 | 2001-09-04 | New York University Medical Center | Anti-TNFa antibodies and assays employing anti-TNFa antibodies |
US5698762A (en) | 1994-12-09 | 1997-12-16 | Dauerman; Leonard | Microwave-assisted pyrolysis of waste polyaromatic hydrocarbons |
US20030031671A1 (en) | 2001-08-01 | 2003-02-13 | Sydney Welt | Methods of treating colon cancer utilizing tumor-specific antibodies |
BRPI0515230A (pt) | 2004-08-19 | 2008-07-15 | Genentech Inc | polipeptìdeos, anticorpos e ácidos nucléicos isolados, composições, vetor de expressão, células hospedeiras isoladas, método para a produção de um anticorpo, artigos manufaturados, métodos de tratamento e para o alìvio de disfunções, métodos de produção e de seleção de um polipeptìdeo, anticorpo de ligação cd20 humanizado, anticorpo anti-her2 isolado e usos de um anticorpo |
US8367805B2 (en) | 2004-11-12 | 2013-02-05 | Xencor, Inc. | Fc variants with altered binding to FcRn |
US8546543B2 (en) | 2004-11-12 | 2013-10-01 | Xencor, Inc. | Fc variants that extend antibody half-life |
EP2845865A1 (en) | 2004-11-12 | 2015-03-11 | Xencor Inc. | Fc variants with altered binding to FcRn |
US8790651B2 (en) | 2011-07-21 | 2014-07-29 | Zoetis Llc | Interleukin-31 monoclonal antibody |
EP3526246A1 (en) * | 2016-10-17 | 2019-08-21 | Vetoquinol SA | Modified antibody constant region |
AU2019360271A1 (en) * | 2018-10-18 | 2021-04-29 | Elanco Us Inc. | Fc variants with altered binding to neonatal Fc receptor (FcRn) for veterinary use |
SG11202106478UA (en) * | 2019-01-03 | 2021-07-29 | Invetx Inc | Compositions for increasing half-life of a therapeutic agent in canines and methods of use |
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AU2022214843A1 (en) | 2023-07-20 |
US20240059777A1 (en) | 2024-02-22 |
KR20230136604A (ko) | 2023-09-26 |
CO2023009994A2 (es) | 2023-08-09 |
CL2023002202A1 (es) | 2024-01-12 |
JP2024505072A (ja) | 2024-02-02 |
WO2022165067A3 (en) | 2022-09-22 |
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