TWI717319B - 得自類桿菌屬之岩藻糖苷酶及其用途 - Google Patents

得自類桿菌屬之岩藻糖苷酶及其用途 Download PDF

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TWI717319B
TWI717319B TW104117110A TW104117110A TWI717319B TW I717319 B TWI717319 B TW I717319B TW 104117110 A TW104117110 A TW 104117110A TW 104117110 A TW104117110 A TW 104117110A TW I717319 B TWI717319 B TW I717319B
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fucosidase
fucose
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翁啟惠
蔡宗義
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中央研究院
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Abstract

本揭示係關於具有α-(1,2)、α-(1,3)、α-(1,4)及α-(1,6)岩藻糖苷酶活性之α-岩藻糖苷酶。本揭示亦關於包括該α-岩藻糖苷酶之組合物，及產生該α-岩藻糖苷酶及使用該α-岩藻糖苷酶裂解糖偶聯物中之α-(1,2)、α-(1,3)、α-(1,4)及/或α-(1,6)-連接岩藻糖之方法。

Description

得自類桿菌屬之岩藻糖苷酶及其用途 相關申請案
本申請案主張2014年7月2日提出申請之美國臨時申請案USSN 62/020,199之權益。其全部內容之內容併入本文中。
岩藻糖係糖偶聯物之許多O-或N-連接寡糖結構之重要組份。含岩藻糖聚糖涉及諸多生物事件(包含發育及細胞凋亡)，且涉及發炎、癌症及囊性纖維化之發病機制。糖偶聯物之去岩藻糖基化係理解糖偶聯物之生物效應之重要過程。
α-L-岩藻糖苷酶(α-岩藻糖苷酶)係糖苷外切酶，其負責藉由水解岩藻糖中主要附接至半乳糖或N-乙醯基葡糖胺之α-(1,2)、α-(1,3)、α-(1,4)及α-(1,6)鏈接自糖偶聯物之非還原端去除岩藻糖殘基。
眾所周知，人類血清IgG及治療抗體可發生重度岩藻糖基化。已發現，抗體依賴性細胞毒性(ADCC)係負責治療抗體之臨床功效之重要效應物功能之一。在淋巴球受體(FccR)結合至抗體Fc區後，ADCC得以觸發。ADCC活性取決於經由α-(1,6)鏈接附接至N-連接Fc寡糖之最內GlcNAc之岩藻糖之量。
因此，本發明提供用於在活體外改良岩藻糖之酶水解之組合物及方法。特定而言，本發明可用於有效裂解天然糖蛋白中之核心岩藻 糖且糖蛋白並無變性或功能劣化。本發明之組合物及方法可促進Fc融合蛋白或抗體(例如治療抗體)之Fc糖改造。本發明亦應用聚糖測序來辨別糖偶聯物上之岩藻糖位置。糖偶聯物可為糖脂、糖蛋白、寡糖或糖肽。
在一態樣中，本發明係關於包括與SEQ ID NO：1具有至少85%序列一致性之多肽之α-岩藻糖苷酶。在一些實施例中，α-岩藻糖苷酶包括與SEQ ID NO：1具有至少88%序列一致性之多肽。在一些實施例中，α-岩藻糖苷酶包括與SEQ ID NO：1具有序列一致性之多肽。在某些實施例中，α-岩藻糖苷酶包括與SEQ ID NO：2具有序列一致性之多肽。SEQ ID NO：1及2共有88%序列一致性。
本文所闡述之岩藻糖苷酶可水解一或多種α(1,2)、α(1,3)、α(1,4)及α(1,6)-連接岩藻糖。岩藻糖可存在於糖偶聯物中之N-及/或O-連接聚糖中。在某些實施例中，α-岩藻糖苷酶係重組類桿菌屬(Bacteroides)α-岩藻糖苷酶。
在較佳實施例中，α-岩藻糖苷酶展現4-9之最佳pH。
在另一態樣中，本發明係關於包括上文所闡述α-岩藻糖苷酶之組合物。該組合物可進一步包括至少一種糖苷酶。在一些實施例中，糖苷酶可為糖苷外切酶。糖苷外切酶包含但不限於唾液酸酶、半乳糖苷酶、α-岩藻糖苷酶及其變體。在一些實施例中，糖苷酶可為糖苷內切酶。糖苷內切酶包含但不限於內-β-N-乙醯基胺基葡萄糖苷酶(NAG)、EndoA、EndoF1、EndoF2、EndoF3、EndoH、EndoM、EndoS及其變體。
本發明組合物可用於在活體外對糖偶聯物進行去岩藻糖基化。特定而言，本文所闡述之組合物可用於在活體外對糖蛋白進行核心去岩藻糖基化。在一些實施例中，核心去岩藻糖基化係核心α(1,6)去岩藻糖基化。在某些實施例中，核心去岩藻糖基化係核心α(1,3)去岩藻 糖基化。去岩藻糖基化可在糖蛋白並無變性或功能劣化下實施。
本發明之另一態樣提供在活體外對糖偶聯物進行去岩藻糖基化之方法。發明性方法包括使糖偶聯物與上文所闡述本發明之α-岩藻糖苷酶接觸之步驟。糖偶聯物包括一或多種選自α(1,2)、α(1,3)、α(1,4)及α(1,6)-連接岩藻糖之岩藻糖。岩藻糖可存在於糖偶聯物中之N-及/或O-連接聚糖中。
在一些實施例中，糖偶聯物係糖蛋白。在一些實施例中，糖蛋白包括核心岩藻糖。在一些實施例中，核心岩藻糖係核心α-(1,3)-連接岩藻糖或核心α-(1,6)-連接岩藻糖。
在一些實施例中，該方法進一步包括使糖偶聯物與至少一種糖苷酶接觸。在某些實施例中，糖苷酶係糖苷內切酶。使用糖苷內切酶修剪N-聚糖中之寡糖之可變部分。本文所使用之糖苷內切酶之實例包含但不限於Endo-β-N-乙醯基胺基葡萄糖苷酶(NAG)、EndoA、EndoF1、EndoF2、EndoF3、EndoH、EndoM、EndoS及其變體。糖苷外切酶
對於核心去岩藻糖基化而言，可使用糖苷內切酶及α-岩藻糖苷酶依序或同時處理糖偶聯物。核心去岩藻糖基化可為核心α(1,3)去岩藻糖基化或α(1,6)去岩藻糖基化。
本發明一或多個實施例之詳細內容陳述於下文說明書中。根據下列圖式及若干實施例之詳細說明亦及隨附申請專利範圍，本發明之其他特徵或優點將顯而易見。
圖1.展示BfFucH之生物化學性質。
圖2.(a)BfFucH之pH特徵(b)對BfFucH之酶活性之溫度效應(c)對BfFucH之酶活性之金屬離子效應。
圖3.展示Rituxan之BfFucH處理之時間過程。
在Fc聚糖中不存在核心岩藻糖殘基已知會實質上增加IgG之ADCC活性，此乃因非岩藻糖基化抗體以顯著增加之親和力結合至FcgRIIIα受體。為改良FcgRIIIα結合及ADCC，已研發若干策略來減小IgG之岩藻糖基化，包含研發之廢除或減小α-(1,6)岩藻糖基轉移酶之表現程度之細胞系產生。減小岩藻糖基化之替代策略包含使用RNAi使α-(1,6)岩藻糖基轉移酶基因沉默。然而，N-聚糖之核心去岩藻糖基化不能在活體外以酶方式達成，此主要係由於N-聚糖埋入兩個Fc結構域之間。酶去岩藻糖基化效率因空間阻礙(亦即，α-岩藻糖苷酶至岩藻糖殘基之接近由Fc結構域之位置阻斷)而極低。
業內已知諸多α-岩藻糖苷酶。實例包含來自角蠑螺(Turbo cornutus)、白法螺(Charonia lampas)、類炭疽桿菌(Bacillus fulminans)、黑麯黴(Aspergillus niger)、產氣莢膜梭菌(Clostridium perfringens)、牛腎(Glyko)、雞肝之α-岩藻糖苷酶(Tyagarajan等人，1996,Glycobiology 6：83-93)及來自木薯單孢萎蔫病(Xanthomonas manihotis)之α-岩藻糖苷酶II(Glyko,PROzyme)。一些岩藻糖苷酶亦市面有售(尤其係Glyko,Novato,Calif.；PROzyme,San Leandro,Calif.；Calbiochem-Novabiochem公司，San Diego,Calif.)。該等α-岩藻糖苷酶不能有效裂解自N-連接聚糖之核心岩藻糖且糖蛋白並不首先變性。
WO 2013/12066揭示藉由來自牛腎之α-岩藻糖苷酶對(Fucαl,6)GlcNAc-利妥昔單抗實施去岩藻糖基化。如WO 2013/12066中所闡述，將(Fuc αl,6)GlcNAc-利妥昔單抗之反應混合物與來自牛腎之α-岩藻糖苷酶(自Prozyme購得)在37℃下一起培育20天以完全去除(Fucαl,6)GlcNAc-利妥昔單抗中之岩藻糖。業內已知免疫球蛋白之熱不穩定性(Vermeer等人，Biophys J.Jan 78：394-404(2000))。Fab片段對熱處理最敏感，而Fc片段對降低之pH最敏感。預計在延長熱處理 (例如在37℃下20天)之後，抗體顯著損失對CD20之結合親和力，如WO 2013/12066中所闡述。
當前已知α-岩藻糖苷酶之侷限性已妨礙某些N-連接聚糖之有效處理。因此，仍需要適於Fc糖改造用於研發人類治療劑之Fc融合蛋白或抗體之新α-岩藻糖苷酶。
本揭示內容係關於能夠有效裂解來自N-連接聚糖之核心岩藻糖之細菌α-岩藻糖苷酶之意外發現。
本揭示內容係關於能夠有效裂解來自N-連接聚糖之核心岩藻糖之細菌α-岩藻糖苷酶之意外發現。
在一些實例中，α-岩藻糖苷酶可為來自脆弱類桿菌(Bacteroides fragilis)之α-岩藻糖苷酶(BfFucH)。在一些實例中，α-岩藻糖苷酶可為來自多形類桿菌(Bacteroides thetaiotaomicron)之α-岩藻糖苷酶(BtFucH)。可自細菌、酵母、桿狀病毒/昆蟲或哺乳動物細胞表現α-岩藻糖苷酶。在一些實施例中，α-岩藻糖苷酶可為重組類桿菌屬α-岩藻糖苷酶。在一些實施例中，α-岩藻糖苷酶可為自大腸桿菌(E.coli)表現之重組類桿菌屬α-岩藻糖苷酶。
α-岩藻糖苷酶可水解一或多種α(1,2)、α(1,3)、α(1,4)及α(1,6)-連接岩藻糖。岩藻糖可存在於糖偶聯物中之N-及/或O-連接聚糖中。岩藻糖可為核心α-(1,3)岩藻糖或核心α-(1,6)岩藻糖。
反應圖1展示各種含岩藻糖糖偶聯物。
Figure 104117110-A0305-02-0008-1
適用於酶之受質之實例包含但不限於乳寡糖、癌症相關性碳水化合物抗原(例如Globo H)、路易斯血型(a、b、x、y)及唾液酸基路易斯a(SLea)及x(SLex)。與業內已知報導不同，α-岩藻糖苷酶可水解唾液酸基路易斯a(SLea)及x(SLex)且並不裂解末端唾液酸。乳寡糖可具有α-(1,2)、α-(1,3)及/或α-(1,4)連接岩藻糖。
組合物
本發明亦係關於上文所闡述α-岩藻糖苷酶之組合物。α-岩藻糖苷酶包括與SEQ ID NO：1具有至少85%序列一致性之多肽。在一些實施例中，α-岩藻糖苷酶包括與SEQ ID NO：1有至少88%一致性之多肽具或其功能變體。在一些實施例中，α-岩藻糖苷酶包括具有SEQ ID NO：1之胺基酸序列之多肽。在一些實施例中，α-岩藻糖苷酶包括具有SEQ ID NO：2之胺基酸序列之多肽。SEQ ID NO：2與SEQ ID NO：1具有88%序列一致性。
如本文所闡述之變體多肽係彼等胺基酸序列自SEQ ID NO：1或2中之胺基酸序列有所變化者，但與包括具有SEQ ID NO：1或2之胺基酸序列之多肽之酶展現相同或類似功能。
Figure 104117110-A0305-02-0009-2
如本文中所使用，關於序列之序列一致性百分比(%)定義為在比對序列且引入間隙(若需要)以達成最大百分比序列之後，候選多肽序列中與參考多肽序列中之胺基酸殘基相同之胺基酸殘基之一致性百分比。出於確定序列一致性百分比之目的，比對可以熟習此項技術者所熟知之多種方式來達成，例如使用可公開獲得之電腦軟體，例如BLAST、ALIGN或Megalign(DNASTAR)軟體。彼等熟習此項技術者可測定用於量測比對之適當參數，包含在所比較序列之全長範圍內達成最大比對所需要之任何演算法。
應理解，本發明之α-岩藻糖苷酶之多肽可進行衍生或改質以有助於其分離或純化。因此，在本發明之一實施例中，藉由添加能夠直接及特異性結合分離構件之配體來衍生或改質用於本發明之多肽。另一選擇為，藉由添加結合對之一個成員來衍生或改質多肽且分離構件包括藉由添加結合對之另一成員來衍生或改質之試劑。可使用任何適宜結合對。在藉由添加結合對之一個成員來衍生或改質用於本發明之多肽之一較佳實施例中，多肽較佳地加組胺酸標籤或加生物素標籤。通常，在基因層面上包含組胺酸或生物素標籤之胺基酸編碼序列且蛋白質重組表現於大腸桿菌中。組胺酸或生物素標籤通常存在於多肽之一端(在N-末端或C-末端處)。組胺酸標籤通常係由6個組胺酸殘基組成，但其可長於此長度(通常長達7、8、9、10或20個胺基酸)或較短(例如5、4、3、2或1個胺基酸)。另外，組胺酸標籤可含有一或多種胺基酸取代、較佳地如上文所定義之保守取代。
組合物應用
本發明組合物可用於活體外對糖偶聯物進行去岩藻糖基化。本發明方法包括使糖偶聯物與上文所述本發明之α-岩藻糖苷酶接觸之步驟。糖偶聯物包括一或多種選自α-(1,2)、α-(1,3)、α-(1,4)及α-(1,6)-連接岩藻糖之岩藻糖。岩藻糖可存在於糖偶聯物中之N-及/或O-連接聚 糖中。
在一些實施例中，糖偶聯物係糖蛋白。在一些實施例中，糖蛋白包括核心岩藻糖。在一些實施例中，核心岩藻糖係核心α-(1,3)-連接岩藻糖或核心α-(1,6)連接岩藻糖。
在一些實施例中，該方法進一步包括使糖偶聯物與至少一種糖苷酶接觸。在某些實施例中，糖苷酶係糖苷內切酶。使用糖苷內切酶剪掉N-聚糖中之寡糖之可變部分。本文所使用之糖苷內切酶之實例包含(但不限於)內-β-N-乙醯基胺基葡萄糖苷酶(NAG)、EndoA、EndoF1、EndoF2、EndoF3、EndoH、EndoM、EndoS及其變體。
對於核心去岩藻糖基化而言，可使用糖苷內切酶及α-岩藻糖苷酶依序或同時處理糖偶聯物。核心去岩藻糖基化可為核心α(1,3)去岩藻糖基化或α(1,6)去岩藻糖基化。
本發明方法可用於自單株抗體進行Fc糖改造。改造之實例性方法闡述於例如Wong等人USSN12/959,351中，其內容以引用方式併入本文中。較佳地，單株抗體係治療性單株抗體。在一些實例中，製備均質糖基化單株抗體之方法包括以下步驟：(a)使單株抗體與α-岩藻糖苷酶及至少一種糖苷內切酶接觸，由此得到具有單一N-乙醯基葡糖胺(GlcNAc)之去岩藻糖基化抗體，及(b)在適宜條件下向GlcNAc中添加碳水化合物部分。在某些實施例中，可藉由使用Endo-GlcNAC酶及實例性岩藻糖苷酶，然後使用實例性Endo-S突變體及聚糖噁唑啉處理來製備聚糖。
在一個特定實例中，本發明方法之單株抗體係利妥昔單抗(Rituximab)。在某些實施例中，本發明方法之碳水化合物部分係選自由以下組成之群：Sia2(α2-6)Gal2GlcNAc2Man3GlcNAc、Sia2(α2-6)Gal2GlcNAc3Man3GlcNAc、Sia2(α2-3)Gal2GlcNAc2Man3GlcNAc、Sia2(α2-3)Gal2GlcNAc3Man3GlcNAc、Sia2(α2-3/α2- 6)Gal2GlcNAc2Man3GlcNAc、Sia2(α2-6/α2-3)Gal2GlcNAc2Man3GlcNAc、Sia2(α2-3/α2-6)Gal2GlcNAc3Man3GlcNAc、Sia2(α2-6/α2-3)Gal2GlcNAc3Man3GlcNAc、Sia(α2-6)Gal2GlcNAc2Man3GlcNAc、Sia(α2-3)Gal2GlcNAc2Man3GlcNAc、Sia(α2-6)Gal2GlcNAc3Man3GlcNAc、Sia(α2-3)Gal2GlcNAc3Man3GlcNAc、Sia(α2-6)GalGlcNAc2Man3GlcNAc、Sia(α2-3)GalGlcNAc2Man3GlcNAc、Sia(α2-6)GalGlcNAc3Man3GlcNAc、Sia(α2-3)GalGlcNAc3Man3GlcNAc、Gal2GlcNAc2Man3GlcNAc及Gal2GlcNAc3Man3GlcNAc。
在一些實施例中，碳水化合物部分係糖噁唑啉。
本發明方法中之步驟(b)可引起糖鏈延伸。糖鏈延伸之一種方法係經由酶催化糖基化反應。業內眾所周知，使用糖噁唑啉作為酶催化糖基化反應中之糖供體進行糖基化可用於合成寡糖，此乃因糖基化反應係加成反應且其進行並不伴隨酸、水或諸如此類之任何消除。 (Fujita等人，Biochim.Biophys.Acta 2001,1528,9-14)
步驟(b)中之適宜條件包含將反應混合物培育至少20分鐘、30分鐘、40分鐘、50分鐘、60分鐘、70分鐘、80分鐘、90分鐘或100分鐘、較佳地小於60分鐘。培育較佳地發生於室溫下、更佳地在大約20℃、25℃、30℃、35℃、40℃或45℃下及最佳地在大約37℃下。
如本文中所使用，術語「岩藻糖」及「L-岩藻糖」可互換使用。
如本文中所使用，術語「核心岩藻糖」及「核心岩藻糖殘基」可互換使用且係指在α1,3-位或α1,6-位連接至天門冬醯胺酸結合之N-乙醯基葡糖胺之岩藻糖。
如本文中所使用，術語「α-(1,2)岩藻糖苷酶」係指特異性催化來自寡糖之α-(1,2)連接L-岩藻糖殘基之水解之糖苷外切酶。
如本文中所使用，術語「α-(1.4)岩藻糖苷酶」係指特異性催化來自寡糖之α-(1.4)連接L-岩藻糖殘基之水解之糖苷外切酶。
如本文中所使用，術語「聚糖」係指多糖、寡糖或單糖。聚糖可為糖殘基之單體或聚合物且可為直鏈或具支鏈。聚糖可包含天然糖殘基(例如葡萄糖、N-乙醯基葡糖胺、N-乙醯基神經胺酸、半乳糖、甘露糖、岩藻糖、己糖、阿拉伯糖、核糖、木糖等)及/或改質糖(例如2'-氟核糖、2'-去氧核糖、磷酸甘露糖、6'硫N-乙醯基葡糖胺等)。
如本文中所使用，術語「N-聚糖」、「N-連接聚糖」、「N-連接糖基化」、「Fc聚糖」及「Fc糖基化」可互換使用且係指由連接至含Fc多肽中天門冬醯胺殘基之醯胺氮之N-乙醯基葡糖胺(GlcNAc)附接之N-連接寡糖。術語「含Fc多肽」係指包括Fc區之多肽(例如抗體)。
如本文中所使用，術語「糖基化模式」及「糖基化特徵」可互換使用且係指以酶方式或以化學方式自糖蛋白或抗體釋放且然後(例如)使用LC-HPLC或MALDI-TOF MS及諸如此類分析碳水化合物結構之N-聚糖物質之特徵性「指紋」。例如參見Curren Analytical Chemistry，第1卷，第1期(2005)，第28-57頁中之綜述；其全部內容以引用方式併入本文中。
如本文中所使用，術語「糖改造Fc」在本文中使用時係指擣c區上之N-聚糖以酶方式或以化學方式發生改變或改造。本文所用之術語「Fc糖改造」係指用於製備糖改造Fc之酶或化學製程。
在Fc區糖基化特徵背景中之術語「均質」、「均勻」、「均勻地」及「均質性」可互換使用且欲指由一種期望N-聚糖物質代表之單一糖基化模式，其中並無痕量前體N-聚糖。
如本文中所使用，術語「IgG」、「IgG分子」、「單株抗體」、「免疫球蛋白」及「免疫球蛋白分子」可互換使用。
如本文中所使用，本文所用之術語「糖偶聯物」涵蓋至少一種 個部分共價連接至至少一個另一部分之所有分子。該術語具體涵蓋具有共價附接糖部分之所有生物分子，包含(例如)N-連接糖蛋白、O-連接糖蛋白、糖脂、蛋白聚糖等。
如本文中所使用，術語「糖脂」係指含有一或多個共價連接糖部分(亦即聚糖)之脂質。糖部分可呈單糖、二糖、寡糖及/或多糖之形式。糖部分可包括糖殘基之單一無支鏈鏈或可包括一或多種具支鏈。在某些實施例中，糖部分可包含硫酸根基及/或磷酸根基。在某些實施例中，糖蛋白含有O-連接糖部分；在某些實施例中，糖蛋白含有N-連接糖部分。
如本文中所使用，術語「糖蛋白」係指包含一或多種共價附接至其上之寡糖鏈(例如聚糖)之胺基酸序列。實例性胺基酸序列包含多肽、多肽及蛋白質。實例性糖蛋白包含糖基化抗體及抗體樣分子(例如Fc融合蛋白)。實例性抗體包含單株抗體及/或其片段、多株抗體及/或其片段及含有Fc結構域之融合蛋白(例如含有IgG1之Fc區之融合蛋白或其糖基化部分)。
如本文中所使用，術語「N-聚糖」係指自糖偶聯物釋放但先前經由氮鏈接連接至糖偶聯物之糖聚合物(參見下文N-連接聚糖之定義)。
如本文中所使用，術語「O-聚糖」係指自糖偶聯物釋放但先前經由氧鏈接連接至糖偶聯物之糖聚合物(參見下文O-連接聚糖之定義)。
如本文中所使用，野生型酶之功能變體與野生型對等部分擁有相同酶活性且通常共有高胺基酸序列同源性(例如與野生型對等部分之胺基酸序列至少約80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%一致)。使用Karlin及Altschul Proc.Natl.Acad.Sci. USA 87：2264-68,1990之算法(如Karlin及Altschul Proc.Natl.Acad.Sci.USA 90：5873-77,1993中所修改)測定兩個胺基酸序列之「一致性百分比」。此一算法納入Altschul等人，J.Mol.Biol.215：403-10,1990之NBLAST及XBLAST程式(2.0版)中。可使用XBLAST程式(評分=50，字長=3)實施BLAST蛋白質搜索以獲得與所關注蛋白質分子同源之胺基酸序列。在兩個序列之間存在間隙之情形下，可利用Gapped BLAST，如Altschul等人，Nucleic Acids Res.25(17)：3389-3402,1997中所闡述。在利用BLAST及Gapped BLAST程式時，可使用各別程式(例如XBLAST及NBLAST)之缺設參數。功能變體可具有各種突變，包含一或多種胺基酸殘基之添加、缺失或取代。此一變體通常在對於野生型酶之酶活性並不至關重要之區中含有突變且在功能結構域中可不含突變或僅含有y保守胺基酸取代。熟習此項技術者應認識到，可在硫辛酸連接酶突變體中進行保守胺基酸取代以提供功能等效變體，亦即該等變體保留特定硫辛酸連接酶突變體之功能能力。
如本文中所使用，「保守胺基酸取代」係指並不改變進行胺基酸取代之蛋白質中之相對電荷或大小特性之胺基酸取代。可根據熟習此項技術者已知之改變多肽序列之方法來製備變體，諸如發現於編輯該等方法之參考文獻中者：例如Molecular Cloning：A Laboratory Manual,J.Sambrook等人編，第二版，Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York,1989或Current Protocols in Molecular Biology,F.M.Ausubel等人編，John Wiley & Sons,Inc.,New York。胺基酸之保守取代包含在下列群組內之胺基酸中進行之取代：(a)M、I、L、V；(b)F、Y、W；(c)K、R、H；(d)A、G；(e)S、T；(f)Q、N；及(g)E、D。可經由常規技術製備涉及去糖基化系統之任一酶。在一個實例中，自天然來源分離酶。在其他實例中，藉由常規重組技術製備酶。在需要時，可基於用於產生酶之宿主細胞對 靶酶之編碼序列實施密碼子最佳化。舉例而言，在使用大腸桿菌細胞作為經由重組技術產生酶之宿主時，可修改編碼該酶之基因，使其含有大腸桿菌中常用之密碼子。本發明之一或多個實施例之詳細內容陳述於下文說明中。由下列圖式及若干實施例之詳細說明及亦由隨附申請專利範圍，本發明之其他特徵或優點將顯而易見。
本發明包含下列實例以證明本發明之較佳實施例。熟習此項技術者應瞭解，下列實例中揭示之技術代表本發明人發現在實踐本發明中運行良好之技術，且因此可認為構成其實踐之較佳方式。然而，熟習此項技術者由本揭示應瞭解，在不背離本發明之精神及範圍下，所揭示特定實施例中可作多種改變且仍獲得相同或類似結果。
實例 實例1：蛋白質表現構築體
藉由PCR分別自脆弱類桿菌NCTC 9343基因組DNA(ATCC 25285)及多形類桿菌VPI-5482(ATCC 29148)擴增α-岩藻糖苷酶，且選殖至pET47b+(EMD Biosciences,San Diego,CA)(具有N端聚組胺酸(poly-histine)(具有內部AcTEV蛋白酶切割位點)。將研究中所使用之其他酶(例如Endo F1(基因庫(GenBank)：AAA24922.1)、Endo F2(基因庫：AAA24923.1)、Endo F3(基因庫：AAA24924.1)、Endo H(基因庫：AAA26738.1)及PNGase F(基因庫：J05449.1))針對大腸桿菌實施密碼子最佳化，且分別選殖至pET28a(N端具有MBP融合)。所有純系序列首先藉由Applied Biosystems 3730 DNA分析儀證實。
用於大腸桿菌中之蛋白質表現構築體之引物列示於下表中。
Figure 104117110-A0305-02-0016-29
Figure 104117110-A0305-02-0017-4
Figure 104117110-A0305-02-0018-5
 a 用於擴增每一基因之編碼序列之正向(F)及反向(R)PCR反應之引物對。 b 粗體下劃線意指限制性酶識別位點。 c 用於大腸桿菌之密碼子最佳化。例如參見Puigbò等人，Nucleic Acids Research(2007)35(S2)：W126-W130。
蛋白質表現及純化
使用0.2mM異丙基β-D-半乳糖硫吡喃糖苷(IPTG)在16℃經24小時將蛋白質表現構築體轉變成用於蛋白質表現之BL21(DE3)(EMD Biosciences,San Diego,CA)。藉由微射流機破裂細胞且然後離心。收 集上清液且載於Ni-NTA瓊脂糖管柱(QIAGEN GmbH,Hilden,Germany)上並使用10倍洗滌緩衝劑(磷酸鈉緩衝劑(pH 7.0)、300mM氯化鈉及10mM咪唑)洗滌。藉由兩倍洗脫緩衝劑(磷酸鈉緩衝劑(pH 7.0)、300mM氯化鈉及250mM咪唑)來採用洗脫，隨後藉由Amicon Ultra-15 10K(EMD Millipore Chemicals,Billerica,MA)將緩衝劑更換成反應緩衝劑。藉由SDS-PAGE檢驗蛋白質純度且藉由Qubit®蛋白質分析套組(Invitrogen,Carlsbad,CA)量測定量蛋白質濃度。對重組岩藻糖苷酶加his標籤(SEQ ID NO：19)，隨後實施Ni-NTA管柱純化以得到60mg/L之產量且純度大於95%。根據Brandford方法(Protein Assay；Bio-Rad,Hercules,CA,USA)使用牛血清白蛋白作為標準測定蛋白質濃度。藉由SDS-PAGE檢驗酶之純度及分子質量。
來自脆弱類桿菌之經純化岩藻糖苷酶在十二烷基硫酸鈉-聚丙烯醯胺凝膠電泳(SDS-PAGE)中展現約50kDa之分子質量，此接近於47.3kDa之理論分子量。
實例2：酶分析
酶特性
不同於來自哺乳動物或細菌之岩藻糖苷酶(其在酸條件(pH 4.0-6.0)下具有最佳pH)，BfFucH在溫和條件(pH 7.0-7.5)下實施良好。此外，BfFucH不受某些二價金屬離子影響，且外源性添加金屬離子並不影響活性。然而，Ni2+可顯著減小酶活性60%。另外，Zn2+及Cu2+可完全廢除酶活性。螯合劑EDTA展示對酶活性並無效應，從而指示金屬離子並不參與催化反應。酶在室溫及4℃下具有功能活性且較為穩定。
對N-連接聚糖之酶活性
可使用本文所闡述之岩藻糖苷酶測定N-聚糖中之岩藻糖位置。評估具有附接於不同位置處之各種岩藻糖之N-聚糖之BfFucH水解活 性。製備兩種合成糖肽0800F及0823F。兩種糖肽具有分別在糖基化位點處結合至外GlcNAc及最內GlcNAc之岩藻糖。
酶分析揭示，岩藻糖可僅自試樣0800F中之外GlcNAc釋放，但在岩藻糖結合至最內GlcNAc之糖肽0823F中並不如此。此結果指示，N-聚糖中G0結構之空間阻礙可屏蔽且保護岩藻糖免受岩藻糖苷酶水解。與之相反，若使用BfFucH及內-β-N-乙醯基乙醯基胺基葡萄糖苷酶(endo M)同時以一鍋式反應處理0823F，則可容易地去除核心岩藻糖。此結果指示，可使用α-岩藻糖苷酶辨別岩藻糖結合至聚糖之位置。
對寡糖之酶活性
大腸桿菌菌株之血清型O86、0128及O111之脂多糖(LPS)含有各種單糖，例如Gal、GalNAc及岩藻糖。藉由甲醛去氫酶(FDH)偶合分析證實，BfFucH可以劑量依賴性方式自大腸桿菌O128：B12菌株之LPS釋放L-岩藻糖。亦測試酶對各種受質(包含2'-岩藻糖基乳糖(2'FL)、3'-岩藻糖基乳糖(3’FL)、乳糖-N-岩藻五糖I(LNPT I)、Globo H、路易斯a(Lea)、路易斯x(Lex)、路易斯b(Leb)、路易斯y(Ley)、唾液酸基路易斯a(SLea)、唾液酸基路易斯x(SLex)及pNP(對-硝基苯酚)-α-L-岩藻糖苷)之酶活性。結果展示，α-岩藻糖苷酶能夠水解所有受質。
實例3：糖蛋白之核心去岩藻糖基化
橙黃網胞盤菌(Aleuria aurantia)擁有廣泛用作岩藻糖之特異性探針之岩藻糖特異性凝集素(AAL)。AAL識別且特異性結合至複合寡糖及糖偶聯物之岩藻糖及末端岩藻糖殘基。可使用AAL測定核心去岩藻糖基化。糖苷內切酶可用於修剪N-聚糖中之寡糖之可變部分。在處理糖苷內切酶混合劑(Endo F1、Endo F2、Endo F3及Endo H)之後，抗體(Humira或Rituxan)展示高AAL印跡信號，從而指示在抗體中存在核心岩藻糖。然而，在處理糖苷內切酶混合劑(Endo F1、Endo F2、Endo F3及Endo H)及BfFucH之組合之後，抗體(Humira或Rituxan)因核心岩藻糖水解而損失AAL印跡信號。該等結果顯示，BfFucH對於核心去岩藻糖基化較為活躍。
材料及方法
除非另外陳述，否則自Sigma-Aldrich或Merck購買所有化合物及試劑。自(North Chicago,IL)購買抗腫瘤壞死因子-α(TNFα)抗體阿達木單抗(Adalimumab)(Humira®)。自Genentech公司(South San Francisco,CA)/IDEC Pharmaceutical(San Diego,CA)購買抗人類CD20小鼠/人類嵌合IgG1利妥昔單抗(Rituxan®)。自Wyeth Pharmaceuticals(Hampshire,UK)購買TNF受體-Fc融合蛋白Etanercept(Enbrel®)。自Hoffmann-La Roche有限公司(Basel,Switzerland)購買阿法依伯汀(Epoetin beta)(Recormon®)。自EMD Serono公司(Boston,MA)購買干擾素β1a(Rebif®)。
自Carbosynth有限公司(Berkshire,UK)購買對-硝基苯基α-或β-單糖、路易斯糖、血型糖及人類乳寡糖。自Chemicon(EMD Millipore Chemicals,Billerica,MA)購買針對IgG Fc區之一級抗體、Recormon®及Rebif®。自Vector實驗室(Burlingame,CA)購買生物素化橙黃網胞盤菌凝集素(AAL)及HRP-偶聯鏈黴抗生物素。觀察蛋白質印跡之化學發光且使用ImageQuant LAS 4000 biomolecular成像儀系統進行量化。
BfFucH活性分析方法
在25℃下於50mM pH 7.0磷酸鈉緩衝劑中使用pNP-α-L-Fuc(p-硝基苯基-α-L-Fuc)作為受質(作為標準分析條件)來量測酶活性。將α-L-岩藻糖苷酶活性之一個單位定義為在25℃下於50mM pH 7.0磷酸鈉緩衝劑中每分鐘自pNP-α-L-Fuc形成1μmol pNP及Fuc。自Michaelis-Menten方程式藉由非線性回歸分析且藉由GraphPad Prism v5軟體(La Jolla,CA)計算pNP-α-L-Fuc之米氏常數(Michaelis constant)(Km)、周 轉數(Kcat)及Vmax之值。
BfFucH之最佳pH之活性量測。
在上述標準酶分析中於pH範圍4.0-10.0(包含乙酸鈉、MES、MOPS、HEPES、Tris-HCl、CHES緩衝劑)中測定岩藻糖苷酶活性之最佳pH。一式三份實施所有反應以進行統計學評估。
BfFucH之最佳二價金屬離子之活性量測
在標準分析條件中實施金屬需求分析。將酶與金屬離子(Mg2+、Mn2+、Ca2+、Zn2+、Co2+或Ni2+、Fe2+、Cu2+)以5mM之最終濃度在存在及不存在EDTA下混合。一式三份實施所有反應以進行統計學評估。
BfFucH之最佳溫度之活性量測
藉由將足夠量之經純化岩藻糖苷酶與pNP-α-L-Fuc在磷酸鈉緩衝劑(pH 7.0)中一起培育來測定溫度對酶活性之效應。為保持分析一致，所有組份皆充分混合且在分析溫度下預加熱10min，且藉由添加酶來開始反應且藉由多模式板讀取器(SpectraMax M5,Molecular Devices)在恆定溫度下記錄。溫度介於4℃至80℃之間。一式三份實施所有反應以進行統計學評估。
基於岩藻糖去氫酶(FDH)之分析
基於岩藻糖去氫酶之分析自先前報導略有改變。不同於藉由Sigma-Aldrich出售之來自假單胞菌屬(Pseudomonas sp)之其他岩藻糖去氫酶(其僅在與NADP+反應下具有活性)，來自百脈根根瘤菌(Mesorhizobium loti)之重組形式之FDH僅在NAD+下具有功能。藉由在使用340nm激發時約450nm下之NADPH螢光且藉由多模式板讀取器(SpectraMax M5,Molecular Devices)在25℃下量測所形成NADH。藉由使用此方法，在5min內量化各種寡糖(例如路易斯糖及人類乳寡糖(HMO))中之岩藻糖基偶聯物。
免疫球蛋白G、Fc-融合蛋白、EPO、干擾素(IFNβ1a)及流感血凝素(HA)之單-GlcNAc或GlcNAc-(Fuc α-1,6)之生成
藉由反應緩衝劑50mM磷酸鈉緩衝劑(pH 7.0)緩衝劑交換所有糖蛋白。首先，添加糖苷內切酶混合劑溶液(包含EndoF1、EndoF2、EndoF3、EndoH及EndoS(1mg/mL))以去除除結合至糖蛋白之Asn之GlcNAc外之所有N-聚糖鏈，隨後添加適宜量之岩藻糖苷酶。在37℃下培育48小時以完全去除結合至糖蛋白之GlcNAc之核心-岩藻糖。
<110> 中央研究院
<120> 得自類桿菌屬之岩藻糖苷酶及其用途
<130> PCT/US2015/032744
<140> 104117110
<141> 2015-05-27
<150> 62/110,338
<151> 2015-01-30
<150> 62/020,199
<151> 2014-07-02
<150> 62/003,908
<151> 2014-05-28
<150> 62/003,104
<151> 2014-05-27
<150> 62/003,136
<151> 2014-05-27
<160> 19
<170> PatentIn version 3.5
<210> 1
<211> 414
<212> PRT
<213> Bacteroides sp.
<400> 1
Figure 104117110-A0305-02-0024-6
Figure 104117110-A0305-02-0025-7
Figure 104117110-A0305-02-0026-8
<210> 2
<211> 414
<212> PRT
<213> Bacteroides sp.
<400> 2
Figure 104117110-A0305-02-0026-9
Figure 104117110-A0305-02-0027-10
Figure 104117110-A0305-02-0028-11
<210> 3
<211> 38
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 3
Figure 104117110-A0305-02-0029-12
<210> 4
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 4
Figure 104117110-A0305-02-0029-13
<210> 5
<211> 38
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 5
Figure 104117110-A0305-02-0029-14
<210> 6
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 6
Figure 104117110-A0305-02-0030-15
<210> 7
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 7
Figure 104117110-A0305-02-0030-16
<210> 8
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 8
Figure 104117110-A0305-02-0030-17
<210> 9
<211> 38
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 9
Figure 104117110-A0305-02-0030-18
<210> 10
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 10
Figure 104117110-A0305-02-0031-19
<210> 11
<211> 36
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 11
Figure 104117110-A0305-02-0031-20
<210> 12
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 12
Figure 104117110-A0305-02-0031-21
<210> 13
<211> 37
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 13
Figure 104117110-A0305-02-0031-22
<210> 14
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 14
Figure 104117110-A0305-02-0032-23
<210> 15
<211> 38
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 15
Figure 104117110-A0305-02-0032-24
<210> 16
<211> 41
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 16
Figure 104117110-A0305-02-0032-25
<210> 17
<211> 37
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 17
Figure 104117110-A0305-02-0032-26
<210> 18
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 引物
<400> 18
Figure 104117110-A0305-02-0033-27
<210> 19
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 人工序列之敘述：合成 6xHis標籤
<400> 19
Figure 104117110-A0305-02-0033-28

Claims (20)

  1. 一種組合物，其包括：(a)具有與SEQ ID NO：1至少99%序列一致性且具有酶活性之多肽之α-岩藻糖苷酶；(b)至少一種糖苷酶，其係選自由以下組成之群：內-β-N-乙醯基胺基葡萄糖苷酶(NAG)、EndoA、EndoF1、EndoF2、EndoF3、EndoH、EndoM及EndoS；及(c)糖蛋白，其係選自由以下組成之群：免疫球蛋白G、Fc-融合蛋白、EPO、干擾素及流感血凝素；其中該組合物之pH介於7至9。
  2. 如請求項1之組合物，其中該糖蛋白包含N-連接聚糖。
  3. 如請求項1或2之組合物，其中該α-岩藻糖苷酶包括具有SEQ ID NO：1中所述胺基酸序列之分離多肽。
  4. 如請求項1或2之組合物，其中該免疫球蛋白G包含抗CD20抗體或抗TNFα抗體。
  5. 如請求項4之組合物，其中該抗CD20抗體為嵌合IgG1。
  6. 如請求項5之組合物，其中該抗CD20抗體為利妥昔單抗(Rituximab)。
  7. 如請求項4之組合物，其中該抗TNFα抗體為阿達木單抗(Adalimumab)。
  8. 如請求項1或2之組合物，其中該α-岩藻糖苷酶係重組類桿菌屬(Bacteroides)α-L-岩藻糖苷酶。
  9. 如請求項1或2之組合物，其中該α-岩藻糖苷酶可水解存在於糖偶聯物中之N-及/或O-連接聚糖中之α-(1,2)、α-(1,3)、α-(1,4)及α-(1,6)-連接岩藻糖。
  10. 如請求項1或2之組合物，其中該α-岩藻糖苷酶具有4至9之最適pH。
  11. 一種去除糖偶聯物中之一或多種岩藻糖之方法，該方法包括使該糖偶聯物與包括與SEQ ID NO：1具有至少99%序列一致性且具有酶活性之多肽之α-岩藻糖苷酶接觸；其中該α-岩藻糖苷酶來自脆弱類桿菌(Bacteroides fragilis)之α-岩藻糖苷酶(BfFucH)並在溫和條件(pH 7.0-7.5)下實施。
  12. 如請求項11之方法，其中該α-岩藻糖苷酶包括具有SEQ ID NO：1中所述胺基酸序列之分離多肽。
  13. 如請求項11之方法，其中該糖偶聯物包括一或多種選自α-(1,2)、α-(1,3)、α-(1,4)及α-(1,6)-連接岩藻糖之岩藻糖。
  14. 如請求項13之方法，其中該等α-(1,2)、α-(1,3)、α-(1,4)及/或α-(1,6)-連接岩藻糖存在於糖偶聯物中之N-及/或O-連接聚糖中。
  15. 如請求項11之方法，其中該糖偶聯物係糖脂、糖蛋白、寡糖或糖肽。
  16. 如請求項15之方法，其中該糖偶聯物係糖蛋白。
  17. 如請求項16之方法，其中該糖蛋白包括核心岩藻糖。
  18. 如請求項17之方法，其中該核心岩藻糖係核心α-(1,3)-連接岩藻糖或核心α-(1,6)-連接岩藻糖。
  19. 如請求項11之方法，其進一步包括一或多種糖苷內切酶。
  20. 如請求項19之方法，其中該一或多種糖苷內切酶係選自由以下組成之群：內-β-N-乙醯基胺基葡萄糖苷酶(NAG)、EndoA、EndoF1、EndoF2、EndoF3、EndoH、EndoM及EndoS。
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