TWI727884B - 利用醣苷內切酶突變體重塑醣蛋白及其使用方法 - Google Patents
利用醣苷內切酶突變體重塑醣蛋白及其使用方法 Download PDFInfo
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Abstract
醣苷內切酶S2 (endoglycosidase, EndoS2)突變體包含:野生型醣苷內切酶S2序列(序列編號:1)內的一或多個突變點,其中該一或多個突變點是位於殘基133-143、殘基177-182、殘基184-189、殘基221-231、及/或殘基227-237內的胜肽區域內。其中,相較於野生型醣苷內切酶S2,該醣苷內切酶S2突變體具有較低的水解活性以及較高的轉醣苷化活性。一種使用醣苷內切酶S2突變體來製備一經醣工程改造的醣蛋白之方法,其包含將一活化寡醣耦合至一醣蛋白受體上。活化的寡糖為聚醣噁唑啉。
Description
相關申請案之交互參照
本申請主張美國專利申請案於2016年8月24日申請之第 62/378,806號之優先權,該申請案之完整內容納入為本揭示內容的一部分以供參照。
本發明是關於一種從釀膿鏈球菌(
Streptococcus Pyogenes)挑選的醣苷內切酶S2 (endoglycosidase S2, EndoS2)突變體,其於合成具有各種明確定義之N-聚醣 (高甘露糖型(high mannose type)、混合型(hybrid type)以及複合型(complex type))的醣蛋白或醣肽時,具有改善的轉醣苷化(tranglycosylation)-活性及降低的水解活性。特別是,本發明的一或多個實施方式亦提供EndoS2突變體於有效重塑治療性抗體的聚醣之用途,藉此在Fc區域形成同質的聚醣組合物以增進其效用功能(effector function)。
自從1986年批准第一個治療單株抗體以來,這一類生物製藥產品的商業管道逐漸蓬勃發展(1)。到了2015年,總共有47株單株抗體產品在美國或歐洲被批准用以治療多種疾病,包括癌症、自體免疫疾病以及傳染性疾病。若持續以目前的速度批准,預計在2020年將會有70株單株抗體產品打入市場,且全球銷售量將達到1250億美元(2)。對於單株抗體療法來說,由於其臨床活性取決於Fc所介導的效用功能,在Fc區域上N-聚醣的組成對藥物安全性及效率至關重要。多樣的醣苷化狀態也會影響對藥效學及藥物動力學,而其他Fc聚醣結構單元則可能涉及到不良免疫反應。然而,對Fc(區域)醣苷化的控制仍是一大挑戰。
典型的IgG由兩個抗原結合片段(Fabs)構成,並且透過彈性區域與穩定區域(Fc)連結。Fab區域負責抗原辨識,而Fc區域Asn297位置的N-聚醣則與效用細胞上個別Fcγ受器(例如FcγRIIIa及FcγRIIb)以及補體C1q組分進行反應,藉以活化諸如抗體依賴型細胞介導的細胞毒性作用(antibody-dependent cellular cytotoxicity, ADCC)及補體依賴細胞毒性作用(complement-dependent cytotoxicity, CDC)等效用功效(5-7)。幾乎所有治療性抗體之位於各同型二聚體Fc的保留性天冬醯胺酸殘基(N297)皆經N-醣苷化修飾。這些以N-連接的聚醣可產生超過30種不同的醣型,且有著相當程度結構異質性的典型雙分枝複合體形式,其中該核心七醣可以由核心海藻糖(fucose, Fuc)、等分N-乙醯葡萄糖胺(bisecting N-acetyl glucosamine, GlcNAc)、末端半乳糖(galactose, Gal)以及末端唾液酸(sialic acid, Sia)來進行各種修飾(8-9)。N-聚醣的組合物會影響Fc區域構型,進而調控抗體穩定性、藥物動力學特徵、免疫原性、效用功能、抗體介導發炎反應以及補體活性(10)。舉例來說,缺乏核心海藻糖,甚或缺乏等分GlcNAc基位,都會劇烈地增強抗體對效用細胞的FcγIIIa受器(FcγRIIIa)之親和力,導致對目標更好的消除效果(10-11)。此外,末端2,6-唾液酸化聚醣(抗體及靜脈內免疫球蛋白(intravenous immunoglobulin, IVIG)的次要成分)是可增進抗發炎反應特質的優化結構(12-13)。
N-醣苷化是最複雜的後轉譯修飾之一,重組表現系統的不同會產生包含高甘露糖型、混合型及複合型等具顯著異質性之聚醣結構 (14-15)。市售的治療性抗體通常是以醣型混合物的形式存在,而該存在形式不利於各別的治療活性。近來,為了增進效率,醣工程學已經聚集了極大的關注以控制Fc區域的醣苷化。其中一個最普遍的方法是對表現宿主的合成路徑進行活體內醣工程修飾。然而,透過此方法產生的醣型有限,且無法達成完全控制所需的醣型之目標。另一個產生醣苷化異質性的替代方法是透過海藻醣酶或不透過海藻醣酶介導,利用醣苷內切酶[內-N-乙醯胺基葡萄醣苷酶(endo-N-acetyl glucosaminidase,ENGase)]將所有異質性的N-聚醣修剪掉,僅在IgGs的醣苷化位置保留第一個GlcNAc或Fuc-GlcNAc,且接著可將明確定義的噁唑啉(oxazoline)形式之活化聚醣轉移回到GlcNAc受體上以形成天然的β-1,4鍵結(16)。
醣苷內切酶(EndoS及EndoS2)是來自人類病原釀膿鏈球菌(
Streptococcus pyogenes)的第18家族醣苷水解酶(glycoside hydrolase, GH),且近年來逐漸成為治療性抗體醣工程學的關注重點(17-18)。儘管EndoS及EndoS2彼此只有37%的序列相似度,兩者均可催化人類IgG的N-鍵結聚醣核心內部兩個N-乙醯葡萄糖胺(N-acetylglucosamines,GlcNAcs)之間的β-1, 4鍵結的水解作用。此外,兩種酶均可移除在Fc區域上的複合型醣苷。然而,與EndoS相比,EndoS2對於混合型及寡甘露醣結構具有更大的水解能力(19)。更甚者,在醣-噁唑啉作為受質的情況下,部分的GH18及GH85的醣苷內切酶會轉變成醣苷合成酶以催化穀質雙糖鍵結。然而,這些醣苷合成酶酵素原有的水解活性會降低整體產率。
為了進一步提升酵素活性,進而發展了醣苷內切酶突變體,其包含EndoS突變體D233Q及D233A (16)。這揭示了在ENGase活性位點上的重要基位(motif):GH18的D-X-E。此基位可輔助與參與的鄰近基團進行雙置換反應的ENGase催化機制。在本機制中, GlcNAc的2-乙醯胺基團作為親核劑以取代在異構體中心的脫離基團,同時天冬醯胺(Asp)之羧酸鹽促進噁唑啉離子中間物的形成。催化殘基(麩胺酸鹽)可當作一般酸/鹼 (general acid/base),作用為質子化該聚醣脫離基團並將水(H
2O)去質子化使具親核性,藉此導致噁唑啉離子中間物的水解。也有報導指出天門冬胺酸鹽的羧酸鹽(也就是E的N-端的第二個殘基)可促進噁唑啉離子中間物的穩定成形。EndoS的D233Q突變則被指出可增進轉醣苷化活性並減少水解活性。
前述的EndoS D233Q突變體是目前為止已知的最佳醣苷合成酶。他們具有合成同質性抗體的強大潛力。然而,起始材料完全轉換成產物須非常大量的酶,生產大規模酶類及反應之後為了移除殘餘酶類的純化步驟非常繁瑣且耗費人力,如此會對整體醣工程製程產生較大的成本。此外,EndoS突變體的轉醣苷化活性受限於特定對稱的雙分枝複合型醣型,但不限於廣泛的高甘露糖型、混合型及三分枝與四分枝複合型醣型(該些類型具有額外的原生修飾體,例如GlcNAc的α-1,3-海藻糖、Gal的α-1,2-海藻糖、延伸的聚乙醯基乳糖胺基位、以及在末端(termini)的不對稱唾液酸化分枝(antennae))使運用受限。
因為EndoS2具有可水解各種IgG聚醣的潛能,IgG醣工程學領域對其產生了極大的興趣。根據EndoS及EndoS2的序列比對結果,推測EndoS2的D184位點與EndoS的D233位點相同。因此,可預期Endo S2的D184位點的突變形式可能可增進EndoS2的轉醣苷化活性以及消弱水解活性的能力。鑒於上述先前技術,若可在野生型EndoS2的活性位置附近進行定點誘變,則應有利於改善EndoS2的醣苷合成酶活性。本揭示內容提供具有優異醣苷合成酶活性及已降低的水解活性之EndoS2突變體。更重要的是,本發明的新穎EndoS2突變體提供廣泛的受質範圍,並且能夠將高甘露糖型、混合型及雙分枝及三分枝複合型的N-聚醣轉化成具有活性的聚醣噁唑啉(glycan oxazoline)。本發明的EndoS2突變體有利於製備多樣的醣苷化同質抗體,特別是那些預期應獲得抗發炎活性的全唾液酸化多分枝醣型的抗體,藉以進行生物物理及結構的研究。
本揭示內容的實施方式是關於選定的EndoS2突變體,該突變體對廣泛範圍的高甘露糖型、混合型以及複合型N-聚醣具有較少的水解活性及優異的轉醣苷化活性。這些EndoS2突變體可用於製備同質性醣苷化醣肽、醣蛋白以及治療性抗體或其Fc片段。本發明的實施方式可有效重塑該些於抗體Fc區域具有高甘露糖型、混合型以及複合型等醣型的治療性抗體或是其Fc片段。經醣工程改造的抗體可增進其效用功能(諸如FcγIIIA結合及抗體依賴型細胞介導的細胞毒性作用等)及其藥理特性。此外,本揭示內容的實施方式能夠快速地評估多種治療性抗體的Fc醣苷化在其效用功能上的作用,特別是那些預期要獲得抗發炎活性的高唾液酸化複合型醣型的治療性抗體之作用。
本揭示內容的一態樣提供數種EndoS2突變體,其中該些突變體具有至少 80%的同源性且可增加各種諸如高甘露糖型、混合型以及複合型等N-聚醣對海藻糖化或非海藻糖化之GlcNAc受體的轉醣甘化活性,其中該突變體能夠有效率地將活化寡糖供體轉移至海藻糖化或非海藻糖化的GlcNAc受體上,藉以形成新的醣肽、醣蛋白或治療性抗體的同質性醣型。
在另一個態樣中,本發明提供具有優異轉醣苷化活性但水解活性較弱的EndoS2突變體,其中該突變體較佳包含T138、D182、D226、T227及T228等定點突變(site specific mutation),但不限於T138D (序列編號:6)、T138E (序列編號:7)、T138F (序列編號:8)、T138H (序列編號:9)、T138K (序列編號:10)、T138L (序列編號:11)、T138M (序列編號:12)、T138N (序列編號:13)、T138Q (序列編號:14)、T138R (序列編號:15)、T138V (序列編號:16)、T138W (序列編號:17)、D182Q (序列編號: 2)、D226Q (序列編號: 3)、T227Q (序列編號: 4)、以及T228Q (序列編號: 5)。
在另一態樣中,本揭示內容提供了具有優異轉醣苷化活性及較低水解活性之EndoS2突變體於將活化寡糖供體轉移到海藻糖化或非海藻糖化之GlcNAc受體的用途,其中該活化寡糖供體包含合成的聚醣噁唑啉。在一實施方式中,包含高甘露糖型、混合型以及複合型等N-聚醣的合成聚醣噁唑啉具有以下之化學式:
,
其中,R
1是透過β-1, 4鍵結的-H或N-乙醯葡萄糖胺,且R
2及R
3可以相同或不同,且係獨立地選自由:
所組成之群組。
承前段,為了更明確顯示R
2及R
3之化學結構式,以下以化學式表達,R
2及R
3可以相同或不同,且係獨立地選自由:
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及
所組成之群組。
在另一個態樣中,本發明提供在核心海藻糖化或非海藻糖化的GlcNAc受體上進行轉醣苷化作用的EndoS2突變體,其中該核心海藻糖化或非海藻糖化的GlcNAc受體包含核心海藻糖化或非海藻糖化的GlcNAc胜肽、蛋白質及IgG的Fc區域或其片段。
在進一步的態樣中,本發明提供在核心海藻糖化或非海藻糖化的GlcNAc-IgG上進行轉醣苷化作用的EndoS2突變體,其中該IgG是單株抗體且選自由西妥昔單抗(cetuximab)、利妥昔單抗(rituximab)、莫羅莫那-CD3(muromonab-CD3)、阿昔單抗(abciximab)、達昔單抗(daclizumab)、巴利昔單抗(basiliximab)、帕利珠單抗(palivizumab)、英夫利西單抗(infliximab)、曲妥珠單抗(trastuzumab)、吉妥單抗 奧佐米星(gemtuzumab ozogamicin)、阿來組單抗(alemtuzumab)、ibritumomab tiuxetan、阿達木單抗(adalimumab)、奧馬珠單抗(omalizumab)、托西莫單抗(tositumomab)、I-131 托西莫單抗(I-131 tositumomab)、依法利珠單抗(efalizumab)、貝伐單抗(bevacizumab)、帕尼單抗(panitumumab)、帕妥珠單抗(pertuzumab)、那他珠單抗(natalizumab)、依那西普(etanercept)、IGN101、伏洛昔單抗(volociximab)、抗-CD80 mAb、抗-CD23 mAb、CAT-3888、CDP-791、eraptuzumab、MDX-010、MDX-060、MDX-070、馬妥珠單抗、CP-675,206、CAL、SGN-30、扎木單抗(zanolimumab)、阿德木單抗(adecatumumab)、奧果伏單抗(oregovomab)、尼妥珠單抗(nimotuzumab)、ABT-874、地諾單抗(denosumab)、AM 108、AMG 714、芳妥珠單抗(fontolizumab)、達昔單抗(daclizumab)、利木單抗(golimumab)、CNTO 1275、奧瑞珠單抗(ocrelizumab)、HuMax-CD20、貝利單抗(belimumab)、依帕珠單抗(epratuzumab)、MLN1202、維西珠單抗(visilizumab)、托西珠單抗(tocilizumab)、ocrerlizumab、certolizumab pegol、艾庫組單抗(eculizumab)、沛瑟珠單抗(pexelizumab)、阿昔單抗(abciximab)及蘭尼單抗(ranibizimumab)所組成的群組。
在另一獨立態樣中,本發明提供用以重塑核心海藻糖化或非海藻糖化之GlcNAc-胜肽、蛋白質以及IgG或IgG-Fc片段的方法,其中該方法包含:提供胜肽/蛋白質/抗體-GlcNAc受體或Fc片段,且在釀膿鏈球菌(
Streptococcus Pyogenes) EndoS2突變體的催化下與活化的寡醣供體反應,藉此製備具有異質性醣苷化狀態之胜肽、蛋白質及單株抗體的實質上純醣型。
在另一態樣中,本發明提供使用EndoS2突變體來聚醣重塑治療性IgG或其Fc片段的方法,其中該方法包含:
A. 以醣苷內切酶(野生型EndoS2)及細菌α海藻醣酶一同處理或僅以醣苷內切酶(野生型EndoS2)單獨處理帶有異質性N-聚醣之天然或重組核心海藻糖化或非海藻糖化的治療性IgG或IgG-Fc片段,藉以水解在兩個還原端GlcNAc殘基之間的鍵結,並形成核心海藻糖化或非海藻醣化的GlcNAc-IgG受體;
B. 將活化寡醣供體形式之不同預定義寡醣建構單元轉移至核心海藻糖化或非海藻糖化GlcNAc-IgG受體,利用釀膿鏈球菌(
Streptococcus Pyogenes)EndoS2突變體進行轉醣苷化作用以重新建構天然β-1,4鍵結,藉此將預定義寡醣附接至重塑核心海藻糖化或非海藻糖化的IgG或其Fc片段。
在又一態樣中,本揭示內容提供一種組合物,其包含海藻糖化或非海藻糖化之經醣工程改造的抗體或抗原結合片段,其中該抗體或抗原結合片段由在每側Fc區域具有相同N-聚醣結構的IgG分子組成,其中N-聚醣是高甘露糖型、混合型及複合型,且選自由:
所組成之群組。其中,R
1是透過β-1,4鍵結的–H或N-乙醯葡萄糖胺,且R
2及R
3可以相同或不同,且係獨立地選自由:
所組成之群組。
承前段,為了更明確顯示R
2及R
3之化學結構式,以下以化學式表達,R
2及R
3可以相同或不同,且係獨立地選自由:
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及
所組成之群組。
在另一個態樣中,本揭示內容提供經醣工程改造的抗體,其相較於未經修飾的抗體,具有較佳之效用功能(例如與FcγIIIA結合之能力及ADCC)。
本揭示內容的另一個態樣揭示一種用於治療癌症病患的藥學組合物,其包含本揭示內容所述之經醣工程改造抗體的組合物以及藥學上可接受的載體。
前述癌症包含,但不限於:B細胞淋巴瘤(B cell lymphomas)、NHL、前驅B細胞淋巴母細胞性白血病(precursor B cell lymphoblastic leukemia)或前驅B細胞淋巴胚細胞性淋巴瘤(precursor B cell lymphoblastic lymphoma)及成熟B細胞瘤(mature B cell neoplasms)、B細胞慢性淋巴球性白血病(B cell chronic lymphocytic leukemia,CLL)/小淋巴細胞性淋巴瘤(small lymphocytic lymphoma,SLL)、B細胞幼淋巴球性白血病(B cell prolymphocytic leukemia)、淋巴漿細胞性淋巴瘤(lymphoplasmacytic lymphoma)、外套細胞淋巴瘤(mantle cell lymphoma,MCL)、濾泡性淋巴瘤(follicular lymphoma,FL)、低度、中度及高度FL、皮膚毛囊中心淋巴瘤(cutaneous follicle center lymphoma)、邊緣區B細胞淋巴瘤(marginal zone B cell lymphoma)、MALT型邊緣區B細胞淋巴瘤(MALT type marginal zone B cell lymphoma)、節點邊緣區B細胞淋巴瘤(nodal marginal zone B cell lymphoma)、脾型邊緣區B細胞淋巴瘤(splenic type marginal zone B cell lymphoma)、毛細胞白血病(hairy cell leukemia)、瀰漫性大細胞淋巴瘤(diffuse large B cell lymphoma)、柏基特氏淋巴瘤(Burkitt's lymphoma)、漿細胞瘤(plasmacytoma)、漿細胞骨髓瘤(plasma cell myeloma)、移植後淋巴增生性疾病(post-transplant lymphoproliferative disorder)、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)以及退行性變化大細胞淋巴瘤(anaplastic large-cell lymphoma,ALCL)。
本發明欲進行醣工程改造的抗體係選自由西妥昔單抗(cetuximab)、利妥昔單抗(rituximab)、莫羅莫那-CD3(muromonab-CD3)、阿昔單抗(abciximab)、達昔單抗(daclizumab)、巴利昔單抗(basiliximab)、帕利珠單抗(palivizumab)、英夫利西單抗(infliximab)、曲妥珠單抗(trastuzumab)、吉妥單抗 奧佐米星(gemtuzumab ozogamicin)、阿來組單抗(alemtuzumab)、ibritumomab tiuxetan、阿達木單抗(adalimumab)、奧馬珠單抗(omalizumab)、托西莫單抗(tositumomab)、I-131 托西莫單抗(I-131 tositumomab)、依法利珠單抗(efalizumab)、貝伐單抗(bevacizumab)、帕尼單抗(panitumumab)、帕妥珠單抗(pertuzumab)、那他珠單抗(natalizumab)、依那西普(etanercept)、IGN101、伏洛昔單抗(volociximab)、抗-CD80 mAb、抗-CD23 mAb、CAT-3888、CDP-791、eraptuzumab、MDX-010、MDX-060、MDX-070、馬妥珠單抗、CP-675,206、CAL、SGN-30、扎木單抗(zanolimumab)、阿德木單抗(adecatumumab)、奧果伏單抗(oregovomab)、尼妥珠單抗(nimotuzumab)、ABT-874、地諾單抗(denosumab)、AM 108、AMG 714、芳妥珠單抗(fontolizumab)、達昔單抗(daclizumab)、利木單抗(golimumab)、CNTO 1275、奧瑞珠單抗(ocrelizumab)、HuMax-CD20、貝利單抗(belimumab)、依帕珠單抗(epratuzumab)、MLN1202、維西珠單抗(visilizumab)、托西珠單抗(tocilizumab)、ocrerlizumab、certolizumab pegol、艾庫組單抗(eculizumab)、沛瑟珠單抗(pexelizumab)、阿昔單抗(abciximab)、以及蘭尼單抗(ranibizimumab)所組成之群組。
在參閱下文實施方式以及後附的申請專利範圍之後,本發明所屬技術領域中具有通常知識者當可輕易瞭解本發明的其他態樣及優勢。
本發明的實施方式是關於選定的多種EndoS2突變體,該突變體展現出優異的轉醣苷化活性,藉以將來自活化寡醣噁唑啉的廣泛範圍高甘露糖型、混合型或複合型之N-聚醣轉移至經海藻糖化或非經海藻糖化的GlcNAc-胜肽、蛋白質或IgGs受體上,同時具有很少或微不足道的水解產物。新穎EndoS2突變體有效地發揮作用以使同質性醣苷化的醣肽、醣蛋白以及治療性抗體及其Fc片段具有各種確定的醣型。此外,本發明之實施方式可提供效用功能改善的醣工程改造抗體(諸如FcγIIIA結合及抗體依賴型細胞介導的細胞毒性作用(ADCC)等)及其藥理特性。本發明之實施方式也能夠快速地評估多種治療性抗體的Fc醣苷化在其效用功能上的效果。
配合參考形成本文一部分的圖式進行以下說明,同時藉由可實踐的具體實施例而揭露本發明的實施方式。詳細描述這些實施方式以使所屬技術領域具有通常知識者能夠實踐本發明。應當理解的是,可設計其他實施方式,或是可在不背離本發明本發明的範疇之情況下進行結構、邏輯及電學的變更。以下實施方式之實施例的描述因此不應被認為具有限制意味,且本發明的範疇應在後附的申請專利範圍中進行界定。
除非本文另有定義,本文所有的技術及科學術語與本發明所屬技術領域具有通常知識者習知的術語的意思相同。儘管與本文所描述相同或等同的方法及材料可以用於本發明的實施方式或測試中,以下將描述本發明的較佳方法及材料。出於各種目的,本文具體提到的所有出版物和專利文件(包括描述和揭示可以結合本發明使用的出版物中報導的化學物、細胞株、載體、動物、儀器、統計分析以及方法)藉由引用而併入本文。在說明書中引用的參考文獻可被視為所屬技術領域具有通常知識者的指示。本文中的任何內容都不應被解釋為本發明沒有權利憑藉現有發明而使本發明早於這樣的公開內容。
描述本材料以及方法之前,應當理解的是,本發明不限於描述的特定方法、程序、材料以及試劑,特別是這些方法、程序、材料以及試劑可千變萬化。應當被理解的是本文使用的術語是為了描述特定實施方式之目的,而非旨在限制本發明的範疇,而本發明的範疇應僅被限定在附加的申請專利範圍中。
定義
除非上下文另有明確說明,應注意的是,如本文和後附的申請專利範圍所使用的,單數形式「一」(a, an)以及「該」(the)包含複數形式。
本文所使用的「聚醣」(glycan)一詞是指多醣、寡醣或單醣。聚醣可以是糖殘基(residue)的單體或聚合物,也可以為直鏈或支鏈。聚醣可包含天然糖基團(residue)(例如:葡萄糖、N-乙醯葡萄糖胺、N-乙醯神經胺酸(N-acetyl neuraminic acid)、半乳糖、甘露糖、海藻糖、六碳醣、阿拉伯糖、核糖、木糖等)及/或經修飾的糖(例如:2'-氟代核醣(2′-fluororibose)、2'-去氧核糖(2′-deoxyribose)、磷甘露糖(phosphomannose)、6'磺基N-乙醯葡萄糖胺(6′ sulfo N-acetylglucosamine)等)。
本文所使用的「海藻糖」(fucose)、「核心海藻糖」(core fucose)以及「核心海藻糖殘基」(core fucose residue)這些術語可交互地使用,並且用來指稱海藻糖的α-1,6位置連接至N-乙醯葡萄糖胺。
本文所使用的「N-聚醣」(N-glycan)、「N-鍵結聚醣」(N-linked glycan)、「Fc聚醣」(Fc glycan)以及「Fc醣苷化」(Fc glycosylation)該些術語是可交互使用,且被用以指稱藉由與含Fc多肽天冬醯胺酸殘基之醯胺氮鍵結的N-乙醯葡萄糖胺(GlcNAc)所附著的N-鍵結寡醣。術語「含Fc多肽」(Fc-containing polypeptide)是指稱包含Fc區域的多肽,像是抗體。
本文使用的「醣苷化模式」(glycosylation pattern)以及「醣苷化特徵」(glycosylation profile)之詞語可交互使用,並用以指稱N-聚醣種類的特徵「指紋」(fingerprint),N-聚醣是已經從醣蛋白或抗體釋出(不論是透過酵素處理地或是化學性地),接著經LC-HPLC、或 MALDI-TOF MS等分析其碳水化合物結構。舉例來說,可參閱在Current Analytical Chemistry, Vol. 1, No. 1 (2005), pp. 28-57中的評論文章;在此透過引用將全文併入。
本文使用的「經醣工程改造的Fc」(glycoengineered Fc)一詞是指稱Fc區域上被改變或是被改造的N-聚醣,不論是經酵素處理地或是化學地。本文所使用的「Fc醣工程改造」(Fc glycoengineering)術語是指用於製作經工程改造的Fc之酵素處理程序或是化學程序。
Fc區域的醣苷化特徵的內文中,「同質的」(homogeneous)、「均質」(uniform)、「均質地」(uniformly)以及「同質性」(homogeneity)可交互使用,且旨在表示以一種期望的N-聚醣種類為代表,且沒有極微量前驅物N-聚醣的單一醣苷化模式。
本文使用的術語「IgG」、「IgG分子」(IgG molecule)、「單株抗體」(monoclonal antibody)、「免疫球蛋白」(immunoglobulin)以及「免疫球蛋白分子」(immunoglobulin molecule)可交互地使用。
本文所載之「Fc受體」(Fc receptor)或「FcR」一詞描述與抗體之Fc區域結合的受體。較佳的FcR是一人類FcR的天然序列。此外,較佳的FcR是結合IgG抗體的受體(γ受體),且包含FcγRI、FcγRII和FcγRIII亞類的受體(包括這些受體的對偶基因變體和選擇性剪接型)。FcγRII受體包括具有相似胺基酸序列的FcγRIIA(「活化受體」(activating receptor))及FcγRIIB(「抑制受體」(inhibiting receptor)),其主要區別在於其細胞質內區域。活化受體FcγRIIA在其細胞質內區域中含有免疫受體酪胺酸為基礎的活化基位(activation motif,ITAM)。抑制受體FcγRIIB在其細胞質內區域中含有免疫受體酪胺酸爲基礎的抑制基序(inhibition motif,ITIM)。(請參閱總論M. in Daëron,
Annu. Rev. Immunol. 15:203-234 (1997))。FcRs的總論則參照Ravetch and Kinet,
Annu. Rev. Immunol9:457-92 (1991);Capel et al.,
Immunomethods4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995)。本文「FcR」一詞亦包含其他將來將要被鑒定的FcR。該術語還包括負責將母體IgGs轉移到胎兒的新生兒受體:FcRn (Guyer et al.,
J. Immunol. 117:587 (1976) and Kim et al.,
J. Immunol.24:249 (1994))。
本文使用的「效用功能」(effector function)是指抗體Fc區域與Fc受體或配體之交互作用所造成的生化事件。例示性的「效用功能」包含C1q結合;補體依賴性細胞毒性;Fc受體結合;抗體依賴型細胞介導的細胞毒性作用(ADCC);吞噬作用;細胞表面受體的下調(例如:B細胞受體;BCR)。可以使用所屬技術領域中具有通常知識者已知的各種測定方法來評估此類的效用功能。
本文使用的「抗體依賴型細胞介導的細胞毒性作用」(Antibody-dependent cell-mediated cytotoxicity)或「ADCC」是指一種細胞毒性作用。在該作用中,經分泌之Ig會結合到在特定效用細胞(effector cell)(例如:自然殺手細胞、嗜中性球以及巨噬細胞)所表現之Fc受體後,促使該些效用細胞特異性的辨認抗原的標的細胞,並以細胞毒素(cytotoxin)殺死該些標的細胞。抗體「武裝」(arm)該些效用細胞對於這種殺傷作用中是絕對需要的。介導ADCC的NK細胞主要表現FcγRIII,而單核球則表現 FcγRI、FcγRII及FcγRIII。在造血細胞上表現的FcR總結在Ravetch and Kinet,
Annu. Rev. Immunol.9:457-92 (1991)第464頁的表三中。為了達成感興趣分子的ADCC活性,可執行美國專利號:5,500,362或美國專利號:5,821,337所描述的活體外ADCC測定方法。有效的效用細胞包括外周血單核細胞(PBMC)以及自然殺手細胞(NK)。或者是,可在活體內評估感興趣的分子之ADCC活性,例如,揭露在Clynes et al.
PNAS (USA)95:652-656 (1998)中的動物模型中。
在市面上可取得及/或近來在各階段臨床試驗中的治療性蛋白,大約有二分之三是單株抗體,該些單株抗體中的30個抗體以及其衍生物被批准作為不同病症(主要是腫瘤疾病、發炎反應以及自體免疫疾病)的治療用途。然而,天然和重組醣蛋白的聚醣微異質性是開發以醣蛋白為基礎之藥物的主要障礙。蛋白質或抗體表現通常產生只有在側邊寡糖結構有所差異的醣型混合物,而且該些混合物可能具有不同的生物活性,因此在蛋白質或抗體表現的過程中控制醣苷化階段是相當困難的。近來引起人們對治療性抗體的醣工程之高度關注的兩個酵素是來自人類病原體釀膿鏈球菌的EndoS及EndoS2 (Collin and Olsén 2001;Sjögren et al. 2013)。首先發現此酵素是作為可藉由水解抗體的N-鍵結聚醣以取消免疫球蛋白G (IgG)之效用功能的細菌迴避因子。
在IgGs的每個CH2區域上的複合體N-鍵結寡醣的結構對Fc區域的結構是至關重要的,同時也事關與Fc受體的交互作用(Krapp et al. 2003;Woof and Burton 2004)。在IgG-Fc區域的寡糖鏈含有一些N-乙醯基-葡萄糖胺(N-Acetyl-Glucosamine,GlcNAc)及甘露糖(Man)殘基,最後是半乳糖(Gal)及海藻糖(Fuc)殘基以及唾液酸(Sia或N-乙醯基神經胺酸(N-acetylneuraminic acid,NANA)。GlcNAc不論有沒有α1-6 Fuc都附接至Asn297。GlcNAcβ1-4則附接至前述第一個GlcNAc。接著兩個Manα1-6及Manα1-3雙臂彼此附接以形成Manβ1-4。雙臂均包含額外的GlcNAcβ1-2,而Galβ1-4可附接或可不附接在GlcNAcβ1-2上。如此,醣鏈可含有0、1或2個半乳糖殘基,其分別定義為G0、G1、及G2醣型。醣型也可產生其他變異,其包括雙分支GlcNAcβ1-4及以唾液酸或甚至是Galα1-3殘基對其中一分支或雙分支的末端半乳糖殘基加帽。以醣苷內切酶對Fc-聚醣進行酶切割造成Fc區域的變形,且會劇烈地降低IgG與Fcγ受體結合的能力(Allhorn et al. 2008)。雖然EndoS及EndoS2彼此的序列有37%的相似度,兩者均可催化人類IgG的N-鍵結聚醣核心內部兩個N-乙醯葡萄糖胺(N-acetylglucosamines,GlcNAcs)之間的β-1, 4鍵結的水解作用。然而,除了複合型聚醣之外,EndoS2比起EndoS,可水解混合型結構及寡甘露醣結構的程度更甚 (Sjögren et al. 2015)。
自從1980年代首個抗體治療問世以來,在臨床試驗有超過240種治療性抗體且此領域穩定地發展(Chan and Carter 2010)。IgG-Fc聚醣在抗體功能性上扮演的角色已經吸引單株治療性抗體之成長領域中巨大的注意。因此,為了增進治療性抗體的效能,主要焦點將轉移到可特異性地與所挑選的Fcγ受體反應的Fc-聚醣醣工程學。(Sondermann et al. 2013; Bournazos et al. 2014; Monnet et al. 2014; Quast and Lünemann 2014)。某些重要的聚醣修飾可顯著地影響效用功能,包括i)缺乏核心海藻糖殘基附接至減少的末端GlcNAc殘基會導致Fcγ RIIIa的親和力增加且接著增加抗體依賴型細胞毒性(Iidaet al. 2006);ii)IgG富含唾液酸的聚醣則聲稱會透過增加與樹突細胞及巨噬細胞上DC-SIGN受體的交互作用而增加IgGs的抗發炎反應(Anthony et al. 2008;Anthony and Ravetch 2010; Pincetic et al. 2014);iii)具有雙分支的GlcNAc的其中一分支相較於另一個同源的對應物具有較強的ADCC。近年來,控制Fc-醣苷化狀態之生物技術工具的改善促進預定義醣型的治療性抗體的發展。因此,為著功能性及結構性研究,將感興趣的胜肽、蛋白質以及抗體附接至廣泛範圍的高甘露糖型、混合型以及複合型N-聚醣的醣工程領域中,本發明的EndoS2突變體可說是取得重大的進步。
本發明的特徵及優點將透過以下非限制性的實施例更清楚地說明。本發明所屬技術領域中具有通常知識者應當理解到,這些實施例僅用於說明,且不背離本發明之範疇的情形下,當可對其進行各種更動與修飾。
實施例
製備用以醣工程改造胜肽、治療性蛋白質及完整IgGs或其Fc片段的EndoS2突變體
目前為止,可藉由在水解過程中負責促進噁唑啉離子中間物形成的關鍵天冬醯胺酸殘基的定點誘變,而從一些GH85醣苷內切酶(ENGases,包含:EndoA、EndoM以及EndoD)生產醣苷合成酶。
來自釀膿鏈球菌(
Streptococcus pyogenes)的EndoS屬於醣苷水解酶第18族(GH18),該族也包括EndoFl、EndoF2及EndoF3。這些GH18酵素裂解人類IgGs的天冬醯胺酸-鍵結雙分支聚醣以產生單GlcNAc抗體的高效率水解活性廣為人知。即便EndoS也可做為醣苷合成酶,將聚醣噁唑啉作為受質來合成穀質雙糖鍵結,但這些酶類的內生水解活性將造成主要的阻礙,這導致合成醣蛋白的產量顯著地下降。酵素活性的進一步改善則導致醣苷內切酶突變體的產生,其包括D233Q。這ENGase活性位點上提供重要基位(motif):GH18的D-X-E。此基位對參與的鄰近基團進行雙置換反應的ENGase催化機制提供支持。在本機制中, GlcNAc的2-乙醯胺基團作為親核劑以取代在異構體中心的脫離基團,同時Asp之羧酸鹽促進噁唑啉離子中間物的形成。催化殘基(麩胺酸鹽)則作為可質子化該聚醣脫離基團並去質子化親核性的H
2O的一般酸/鹼,藉此造成噁唑啉離子中間物的水解作用,以形成水解產物。也有報導指出天門冬胺酸鹽的羧酸鹽(也就是E的N-端的兩個殘基)可促進噁唑啉離子中間物的穩定成形。EndoS的D突變成Q則被指出可增進轉醣苷化作用並減少水解活性。
雖然EndoS D233Q突變體及D233A突變體均展現合成同質性抗體的強大潛力,為了達成更有效的反應還是需要額外添加大量的酵素。酵素的製備以及反應之後去除酵素的後續步驟將變得繁瑣且耗費人力。近來,EndoS2作為一種新的酵素,從另一種釀膿鏈球菌(
Streptococcus pyogenes)的血清型中被定義出來。除了在EndoS催化的所有物中,內-β-N-乙醯葡萄糖胺苷酶對複合型N-聚醣之活性之外,EndoS2相較於EndoS可具有更大程度的切割N-聚醣的混合型及寡甘露醣結構(Jonathan et al., 2013 and 2015)。
EndoS2與EndoS僅有37%的序列相似度,而EndoS的結構採用催化域常用的(β/α)8桶狀構型。根據這兩種酶類的序列排列結果,位於EndoS2第四個β褶板的殘基E186對應於EndoS的一般酸/鹼性D235殘基。
為了探索EndoS2轉醣苷化作用的催化效率,著手進行檢測在催化位點附近的胺基酸轉化是否會調控其轉醣苷化活性。發明人選擇在催化域附近的一些殘基,以定點誘變進行突變。突變的殘基包含第三個β褶板上的T138、在第四個β褶板上的 D182、在第五個β褶板上的D226、T227及T228(第3圖A小圖)。進行測試的EndoS2突變體包含 T138D (序列編號:6)、T138E (序列編號:7)、T138F (序列編號:8)、T138H (序列編號:9)、T138K (序列編號:10)、T138L (序列編號:11)、T138M (序列編號:12)、T138N (序列編號:13)、T138Q (序列編號:14)、T138R (序列編號:15)、T138V (序列編號:16)、T138W (序列編號:17)、D182Q (序列編號: 2)、D226Q (序列編號: 3)、T227Q (序列編號: 4)、以及T228Q (序列編號: 5)(第2圖及表1)。這些突變體在大腸桿菌(
E. coli)中以高產率表現His-tag融合蛋白,其可以透過Ni-NTA親和管柱進行純化。結果顯示靠近活性位點的突變會劇烈地增進轉醣苷化活性且降低醣苷內切酶活性,而導致顯著的醣苷合成酶效率。此外,這些突變體能夠將複合型N-聚醣由活化聚醣噁唑啉轉移至去醣基化的完整抗體上,同時不產生水解反應。
表1顯示各種EndoS2突變體的序列
序列編號:1 (野生型) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQTIGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:6 (T138D) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ D IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:7 (T138E) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ E IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:8 (T138F) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ F IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:9 (T138H) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ H IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:10 (T138K) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ K IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:11 (T138L) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ L IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:12 (T138M) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ M IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:13 (T138N) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ N IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:14 (T138Q) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ Q IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:15 (T138R) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ R IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:16 (T138V) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ V IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:17 (T138W) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQ W IGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:2 (D182Q) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQTIGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGL QIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:3 (D226Q) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQTIGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIM QTTLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:4 (T227Q) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQTIGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMD Q TLSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
序列編號:5 (T228Q) 1 MDKHLLVKRTLGCVCAATLMGAALATHHDSLNTVKAEEKTVQTGKTD QQVGAKLVQEIREGKRGPLYAGYFRTWHDRASTGIDGKQQHPENTMAE VPKEVDILFVFHDHTASDSPFWSELKDSYVHKLHQQGTALVQTIGVNE LNGRTGLSKDYPDTPEGNKALAAAIVKAFVTDRGVDGLDIDIEHEFTNKR TPEEDARALNVFKEIAQLIGKNGSDKSKLLIMDT Q LSVENNPIFKGIAEDLD YLLRQYYGSQGGEAEVDTINSDWNQYQNYIDASQFMIGFSFFEESASKGN LWFDVNEYDPNNPEKGKDIEGTRAKKYAEWQPSTGGLKAGIFSYAIDRD GVAHVPSTYKNRTSTNLQRHEVDNISHTDYTVSRKLKTLMTEDKRYDVID QKDIPDPALREQIIQQVGQYKGDLERYNKTLVLTGDKIQNLKGLEKLSKL QKLELRQLSNVKEITPELLPESMKKDAELVMVGMTGLEKLNLSGLNRQTL DGIDVNSITHLTSFDISHNSLDLSEKSEDRKLLMTLMEQVSNHQKITVKNT AFENQKPKGYYPQTYDTKEGHYDVDNAEHDILTDFVFGTVTKRNTFIGDE EAFAIYKEGAVDGRQYVSKDYTYEAFRKDYKGYKVHLTASNLGETVTSK VTATTDETYLVDVSDGEKVVHHMKLNIGSGAIMMENLAKGAKVIGTSGD FEQAKKIFDGEKSDRFFTWGQTNWIAFDLGEINLAKEWRLFNAETNTEIK TDSSLNVAKGRLQILKDTTIDLEKMDIKNRKEYLSNDENWTDVAQMDDA KAIFNSKLSNVLSRYWRFCVDGGASSYYPQYTELQILGQRLSNDVANTLD 843 |
根據本發明的實施方式,新穎的EndoS2突變體包含選自序列編號:2至17之序列。這些突變體展現出改善的轉醣苷化活性以及減少的水解活性。因此,他們可有效地催化活性寡糖供體對核心GlcNAc受體(其可為海藻糖化或非海藻糖化)的轉移。
根據某些較佳實施方式,EndoS2突變體可與序列編號2至17的序列或其具有轉醣苷化活性之片段具有至少80% (例如:80%、85%、90%、95%或98%)的序列相似性,且具有期望的轉醣苷化活性。
在其他的較佳實施方式中,本發明的EndoS2突變體中,該突變位點是位於選自由殘基133-143、殘基177-187及殘基221-233所組成的區域中。
在其他較佳的實施方式中,本發明的EndoS2突變體包含 T138D (序列編號:6)、T138E (序列編號:7)、T138F (序列編號:8)、T138H (序列編號:9)、T138K (序列編號:10)、T138L (序列編號:11)、T138M (序列編號:12)、T138N (序列編號:13)、T138Q (序列編號:14)、T138R (序列編號:15)、T138V (序列編號:16)、T138W (序列編號:17)、D182Q (序列編號: 2)、D226Q (序列編號: 3)、T227Q (序列編號: 4)、以及T228Q (序列編號: 5)。
EndoS2及其突變體的聚醣水解活性
透過使用市售的利妥昔單抗(Rituximab)作為受質以檢測EndoS2突變體的聚醣水解活性。利妥昔單抗是一種治療性的抗CD20單株抗體,常作為模式mAb來檢測水解活性以及潛在EndoS2突變體的轉醣苷化活性。市售利妥昔單抗主要的Fc聚醣是核心海藻糖化的雙分支複合型寡糖,同時攜帶0至2個半乳糖基位,分別名為G0F、G1F、以及G2F 醣型。以1:1000 (酵素:利妥昔單抗)的莫耳比例將利妥昔單抗與野生型EndoS2及EndoS2突變體混合處理。透過十二烷基磺酸鈉-聚丙烯醯胺凝膠電泳(sodium dodecylsulfate polyacrylamide gel electrophoresis, SDS-PAGE)監控聚醣水解過程。
以野生型EndoS2處理會導致快速去醣苷化,藉此在醣苷化位點(N297)上產生相應的GlcNAc-Fc N-聚醣。這些結果確認野生型EndoS2對完整IgG的優異Fc聚醣-水解活性,卻也意味著其無法應用於醣苷化重塑mAbs第一步驟(水解作用)。然而,相較於野生型(WT)EndoS2, EndoS2突變體則具有降低的水解活性。具體來說,在長達2小時的處理期間,T138及D226的突變均展現相當低的N-聚醣水解能力或幾乎沒有N-聚醣水解能力,而在D182Q的突變則顯示較低的反應速率(與WT EndoS2相比是低超過60倍)。這些結果顯示殘基D182、T138及D226對醣苷水解酶活性極為重要 (第3圖)。
利用2.6唾液酸化的雙分支複合型(SCT)噁唑啉作為供體受質來檢測EndoS2以其突變體的轉醣苷化作用。
接著使用GlcNAc-利妥昔單抗作為受體,而α-2,6-唾液酸化雙分支複合型(SCT)噁唑啉作為供體受質來檢測EndoS2及其突變體的轉醣苷化能力,如第4圖所繪示。透過SDS-PAGE監控醣苷化重塑過程。將GlcNAc-利妥昔單抗及SCT-噁唑啉(供體/受體以1:1的重量比)與野生型EndoS2及其突變體(酵素/抗體之體積莫耳比為1:1000)一起反應,並以SDS-PAGE監測的條件下顯示相應的野生型EndoS2的轉醣苷化產物的短暫成形,這有可能是肇因於野生型酵素在原位快速水解該產物。儘管缺乏水解能力,所有突變體(T138Q、D182Q、D226Q、T227Q及T228Q)皆具有顯著的轉醣苷化活性。這些結果指出EndoS2突變體為一種新穎之有效醣苷合成酶,可使去醣苷化的完整IgG在不產生水解作用的情況下與複合型N-聚醣進行醣苷化反應。
T138上的各種胺基酸殘基對其轉醣苷化活性的效應
為了鑑別在T138位點上具潛力的轉醣苷化活性且較低之水解活性的最佳胺基酸殘基,在該位點上執行多種突變。接著使用GlcNAc-利妥昔單抗作為受體,而α-2,6-唾液酸化雙分支複合型(SCT)噁唑啉作為供體受質來檢測這些突變體的轉醣苷化能力(第5圖)。在T138 (67.5 nM)的各種突變體是與67.5 µM的GlcNAc-利妥昔單抗及2.5 mM的SCT-噁唑啉同時反應2小時。以SDS-PAGE分析產物,且第5圖顯示GlcNAc-利妥昔單抗(IgG)及利妥昔單抗-SCT (IgG-聚醣)的相對百分比。在眾多檢測的突變體中,T138E、T138R、T138W、T138M以及T138Q具有最大的轉醣苷化潛力。
使用高甘露糖型、混合型以及複合型的N-聚醣的EndoS2突變體的轉醣苷化效能
人類IgGs分子的每個Fc CH2區域上含有N-聚醣。這些聚醣包含高甘露糖型、混合型以及複合型。已經有研究指出Fc N-聚醣成分是抗體促發炎反應及抗發炎反應的重要決定因素。舉例來說,缺乏核心海藻糖,或缺乏等分GlcNAc部分的附接,會劇烈地增進抗體對負責抗體依賴型細胞介導的細胞毒性作用(ADCC)的FcγIIIa受器(FcγRIIIa)之親和力。已顯示含有高甘露糖聚醣的重組IgG分子在人類血液中清除更快,且具有降低的熱穩定性。此外,含有高甘露糖型及混合型聚醣的IgG分子的CH2區域具有更多的構形可撓性。個別生產高甘露糖型、混合型及複合型Fc聚醣的IgGs的最常規方法是使用各種表現系統,包括哺乳類、植物及酵母宿主細胞。然而,這些表現系統通常產生醣型混合物,而非產生單一聚醣結構。因此,對於聚醣改造工程領域的技術人員來說有極大的興趣要獲得可用於生物物理及結構研究的治療性抗體之純醣型。因此,需要能夠有效地將個別高甘露糖型、混合型及複合型聚醣轉移到胜肽、蛋白質及IgGs的GlcNAc受體的醣苷合成酶。
接著,使用一系列的高甘露糖型、混合型及複合型聚醣噁唑啉來評估本發明的EndoS2突變體的轉醣苷化能力(表2)。結果則表明,針對抗體的醣工程改造用途,除了唾液酸化複合型N-聚醣噁唑啉之外,EndoS2突變體也可同樣有效地轉移高甘露糖型系列Man
5GlcNAc-噁唑啉(G1)、Man
9GlcNAc-噁唑啉(G2)、混合型聚醣G3及 G4、以及雙分支及三分支複合型系列聚醣G5-G16,藉此形成相應的同質醣型的成形。此研究使用利妥昔單抗作為模式抗體。然而,本發明所屬技術領域中具有通常知識者應當理解到,也可以相似方式對其他醣蛋白進行修飾。這些結果顯示,除了唾液酸化複合型N-聚醣噁唑啉之外,EndoS2突變體也同樣可有效地轉移高甘露糖型、混合型聚醣及三分支複合型聚醣。
表2列出用於評估EndoS2突變體之轉醣苷化活性的多種聚醣噁唑啉結構
表2
聚醣噁唑啉的通式 | ||
聚醣類型 | 聚醣編號 | 結構 |
高甘露糖型 | G1 | |
G2 | ||
混合型 | G3 | |
G4 | ||
三分支複合型 | G5 | |
G6 | ||
雙分支複合型 | G7 | |
G8 | ||
G9 | ||
G10 | ||
G11 | ||
G12 | ||
G13 | ||
G14 | ||
G15 | ||
G16 | ||
基於在Man-GlcNAc-GlcNAc核心上的分支數量將複合型的聚醣區分成雙分支、三分支及四分支類型。較特別的是,雖然三分支或四分支的聚醣結構龐大,但一般來說只接受雙分支聚醣噁唑啉的醣苷合成酶也可接受三分支或四分支的聚醣噁唑啉。為了證明這些新穎EndoS2突變體的有效性,使用一系列複合型聚醣噁唑啉(表2)檢測轉醣苷化作用,其中使用利妥昔單抗作為模式抗體。第7圖及第8圖顯示結果。這些結果證明EndoS2醣苷合成酶突變體具有將多種高甘露糖型、混合型及複合型聚醣轉移至IgG-Fc區域的優異轉醣苷化效率。因此,由於本發明的新穎EndoS2醣苷合成酶突變體缺乏(或具有非常少的)產物水解活性,因此該突變體可對不同治療性抗體有效且完整地進行轉醣苷化作用,藉此以增強其效用功能。
本發明揭示對廣泛種類N-聚糖(其包含高甘露糖型、混合型以及複合型)具有優異的轉醣苷化活性的選定EndoS2突變體。
在較佳實施方式中,N-聚醣的高甘露糖型、混合型及複合型是活化的噁唑啉形式,如表2所列的通式。
在某些實施方式中,本揭示內容的高甘露類型的N-聚醣可選自由Man
3GlcNAc、Man
5GlcNAc、Man
6GlcNAc、Man
7GlcNAc、Man
8GlcNAc及Man
9GlcNAc所組成之群組。在較佳的實施方式中,高甘露糖型的N-聚醣是Man
5GlcNAc。
在某些實施方式中,本揭示內容的混合型N-聚醣的α-1,3臂上包含至少一個α-2,6- 或 α-2,3末端唾液酸,其中α-1,6臂含有三甘露糖殘基。
在某些實施方式,本文的混合型N-聚醣包含在α-1,3臂上的末端半乳糖,其中α-1,6臂含有三甘露糖殘基。
在某些實施方式,本文的混合型N-聚醣包含在α-1,3臂上的末端GlcNAc,其中α-1,6臂含有三甘露糖殘基。
在某些實施方式中,複合型聚醣是雙分支、三分支及四分支複合型。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一α-2,6或α-2,3末端唾液酸。在較佳實施方式中,N-聚醣包含兩個α-2,6及/或α-2,3末端唾液酸。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個末端半乳糖或GlcNAc。在較佳實施方式中,N-聚醣包含兩個末端半乳糖及/或GlcNAc。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個α-1,2-海藻糖。在某些實施方式中,N-聚醣包含兩個α-1,2-海藻糖。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個α-1,2-海藻糖。在某些實施方式中,N-聚醣包含兩個α-1,3-海藻糖。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含等分GlcNAc。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一LacNAc重複單元。在較佳實施方式中,N-聚醣包含兩個LacNAc重複單元。
在較佳實施方式中,本揭示內容的三分支複合體類型N-聚醣包含至少一 α-2,6 或 α-2,3末端唾液酸。在較佳實施方式中,N-聚醣包含三個α-2,6及/或 α-2,3末端唾液酸。
在某些實施方式中,本揭示內容的三分支複合型N-聚醣包含至少一個末端半乳糖或GlcNAc。在較佳實施方式中,N-聚醣包含三個末端半乳糖及/或GlcNAc。
在某些實施方式中,複合型聚醣是包含在α-1,3臂或α-1,6臂上不對稱分支的雙分支及三分支複合型。
在某些實施方式中,本揭示內容的雙分支及三分支複合型N-聚醣包含α-2,6 或α-2,3末端唾液酸。在較佳的實施方式中,混合型及雙分支及三分支複合型N-聚醣包含α-2,6末端唾液酸。
對利妥昔單抗進行醣工程改造以提供可增進效用功能的多種非海藻糖化醣型
利妥昔單抗是一種標的CD20蛋白質(其主要可見於95%的B細胞淋巴瘤上)的單株抗體。利妥昔單抗摧毀B細胞,藉此用於治療病徵為過多數量的B細胞、過度活化的B細胞、或功能異常的B細胞的疾病。在中國倉鼠卵巢細胞(CHO)中產生的利妥昔單抗通常包含異質性的聚醣混合物模式,而各種聚醣不會顯示相似的生物特質。由於IgG分子對Fc受體及C1q補體的結合會因抗體上不同醣苷化而產生巨大差異,從而影響抗體效用功能並且可能引發病患的不良反應,如此則產生安全性的疑慮。
因此,有需要以改善的抗CD20抗體增進單株抗體療法。在醣苷化模式的異質性混合物中,已知一些特異的醣型可賦予所需的生物功能。此外,在複合型醣型的情況下,除了一些修飾物像是核心海藻糖及等分GlcNAc之外,多種天然修飾物(像是在外圍GlcNAc的α-1,2 海藻糖、在半乳糖上的α-1,3海藻糖、聚LacNAc基位以及三分支及四分支)對生物活性的效應從未被揭露。如此一來,因治療目的,本領域相關技術人員對生產含有明確定義之聚醣結構及序列的所需醣型治療性抗體具有相當大的興趣。
本揭示內容是包含最適醣型的功能性活化經醣工程改造的抗-CD20抗體,其相較於治療性單株抗體展現更強的生物活性。
本揭示內容揭露一種新穎之抗-CD20抗體,其可藉由Fc醣工程從抗-CD20單株抗體來製備。該些經醣工程改造的抗-CD20抗體包含同質性族群及含有明確的聚醣結構及序列的相同Fc聚醣。根據本發明,經醣工程改造的抗-CD20抗體可以向其親代抗體一樣特異性地結合至細胞膜上的人類CD20抗原之相同表位。此外,相同抗體的同質性族群都具有相同的效用物結合位置。
本文使用的「親代抗體」(parental antibody)一詞是指抗-CD20單株抗體,其用於產生經醣工程改造的抗-CD20抗體。可透過細胞培養(像是哺乳類細胞培養、畢赤酵母(
Pichia pastoris)或昆蟲細胞株)獲得親代抗體。較佳地,親代抗體是在哺乳類細胞培養中生產。例示性親代抗體包括,但不限於:利妥昔單抗、奧法木單抗(Ofatumumab)、托西莫單抗(Tositumomab)、奧瑞珠單抗(Ocrelizumab)、11B8或7D8 (揭露於專利號WO2004/035607)。
在某些實施方式中,本揭示內容描述的例示性經醣工程改造的抗-CD20抗體包含具有胺基酸序列如序列編號:18的重鏈,以及具有如序列編號:19的胺基酸序列的輕鏈。在較佳的實施方式中,每個經醣工程改造的抗-CD20抗體包含利妥昔單抗的輕鏈序列及重鏈序列。
下表3顯示利妥昔單抗的重鏈及輕鏈序列。
表3
利妥昔單抗 |
商品編號:DB00073 |
來源:http://www.drugbank.ca/drugs/DB00073 |
利妥昔單抗重鏈 |
序列編號18:QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K |
利妥昔單抗輕鏈 |
序列編號19: QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC |
在某些實施方式中,N-聚醣是連接至利妥昔單抗的Fc區域的Asn-297。
根據本發明的N-聚醣可具有高甘露糖型、混合型及雙分支及三分支複合型結構,其中N-聚醣結構具有下列通式:
其中,R
1是透過β-1,4鍵結的–H或N-乙醯葡萄糖胺,且R
2及R
3是相同或相異,且獨立地選自由:
所組成之群組。
承前段,為了更明確顯示R
2及R
3之化學結構式,以下以化學式表達,R
2及R
3可以相同或不同,且係獨立地選自由:
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
及
所組成之群組。
在某些實施方式中,本揭示內容的N-聚醣可具有額外的鏈內取代基,其包含「等分」(bisecting)的GlcNAc,α-1,2海藻糖、α-1,3海藻糖(不論有沒有α-2,3及/或α-2,6唾液酸),且可以是延伸的聚LacNAc基位。
在某些實施方式中,本揭示內容的高甘露類型的N-聚醣可選自由Man
3GlcNAc、Man
5GlcNAc、Man
6GlcNAc、Man
7GlcNAc、Man
8GlcNAc及Man
9GlcNAc所組成之群組。在較佳的實施方式中,高甘露糖型的N-聚醣是Man
5GlcNAc。
在某些實施方式中,本文描述的混合型的N-聚醣包含至少一個α-2,6或α-2,3末端唾液酸或至少一個末端半乳糖,或至少一個在α-1,3臂上的末端GlcNAc,而α-1,6臂含有三甘露糖殘基。
在某些實施方式中,複合型聚醣是雙分支、三分支及四分支複合型。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一 α-2,6 或 α-2,3末端唾液酸。在較佳實施方式中,N-聚醣包含兩個α-2,6及/或 α-2,3末端唾液酸。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個末端半乳糖或GlcNAc。在較佳實施方式中,N-聚醣包含兩個末端半乳糖及/或GlcNAc。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個α-1,2-海藻糖。在較佳實施方式中,N-聚醣包含兩個α-1,2-海藻糖。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一個α-1,3-海藻糖。在較佳實施方式中,N-聚醣包含兩個α-1,3-海藻糖。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含等分GlcNAc。
在某些實施方式中,本揭示內容的雙分支複合型N-聚醣包含至少一LacNAc重複單元。在較佳實施方式中,N-聚醣包含兩個LacNAc重複單元。
在較佳實施方式中,本揭示內容的三分支複合體類型N-聚醣包含至少一α-2,6或 -2,3末端唾液酸。在較佳實施方式中,N-聚醣包含三個α-2,6及/或α-2,3末端唾液酸。
在某些實施方式中,本揭示內容的三分支複合型N-聚醣包含至少一個末端半乳糖或GlcNAc。在較佳實施方式中,N-聚醣包含三個末端半乳糖及/或GlcNAc。
在某些實施方式中,複合型的聚糖是雙分支、三分支或四分支複合型,其包含在不論α-1,3或在α-1,6臂上的不對稱的分支。
在某些實施方式中,本揭示內容的雙分支及三分支複合型N-聚醣包含α-2,6或α-2,3末端唾液酸。在較佳的實施方式中,混合型及雙分支、三分支及四分支複合型N-聚醣包含α-2,6末端唾液酸。
較佳地,根據本發明之實施方式的N-聚醣是不含核心海藻糖。
表4列出經醣工程改造的抗-CD20抗體之例示性N-聚醣。本揭示內容的實施方式可包含或排除任何表列的N-聚醣。
表4
聚醣類型 | 經醣工程改造的利妥昔單抗 | Fc-醣型 |
高甘露糖型 | Rtx-G1 | |
Rtx-G2 | ||
混合型 | Rtx-G3 | |
Rtx-G4 | ||
三分支複合型 | Rtx-G5 | |
Rtx-G6 | ||
雙分支複合型 | Rtx-G7 | |
Rtx-G8 | ||
Rtx-G9 | ||
Rtx-G10 | ||
Rtx-G11 | ||
Rtx-G12 | ||
Rtx-G13 | ||
Rtx-G14 | ||
Rtx-G15 | ||
Rtx-G16 | ||
經醣工程改造的利妥昔單抗之生物功能
各種抗體的Fc-醣苷化作用會顯著地影響諸如ADCC、CDC及循環半衰期等效用物介導(effector-mediated)作用。增強的ADCC是用於改善治療性抗體藥物效率的重要策略。其具有降低有效藥物劑量的潛能,進而降低藥物之成本。本揭示內容經醣工程改造的抗-CD20抗體具有細胞生長抑制活性,包括造成人類CD20表現細胞的細胞凋亡。在某些實施方式中,經醣工程改造的抗-CD20抗體相較於其親代抗體而言,具有更強的細胞生長抑制能力。
FcγRIIIA和經醣工程改造的利妥昔單抗之間的結合
表5列出經醣工程改造的抗-CD20抗體及利妥昔單抗的例示性FcγRIIIA結合。
表5
使用ELISA測定FcγRIIIA對經醣工程改造的利妥昔單抗之結合 | ||||
醣型 | EC 50(ng/mL) | 最大結合(A450nm) | EC50的增強倍數 | 備註 |
市售利妥昔單抗 | 1045 | 1.2 | 1 | A類別: 增加>30 % B類別: 增加>15-30 % C類別: 增加>5-10 % D類別:無變化 |
Rtx-G1 | 160 | 1.4 | 6.5 | |
Rtx-G2 | 1050 | 1.1 | ~1 | |
Rtx-G3 | 320 | 1.3 | 3.2 | |
Rtx-G4 | 394 | 1.2 | 2.7 | |
Rtx-G5 | 31 | 2.6 | 35 | |
Rtx-G6 | 32 | 2.8 | 34 | |
Rtx-G7 | 31 | 2.5 | 35 | |
Rtx-G8 | 34 | 2.3 | 32 | |
Rtx-G9 | 61 | 2.4 | 17 | |
Rtx-G10 | 43 | 2.2 | 26 | |
Rtx-G11 | 199 | 2.4 | 5.4 | |
Rtx-G12 | 33 | 2.6 | 33 | |
Rtx-G13 | 48 | 2.6 | 22 | |
Rtx-G14 | 33 | 2.4 | 33 | |
Rtx-G15 | 34 | 2.3 | 32 | |
Rtx-G16 | 32 | 2.5 | 34 |
可使用習知的測定方法來測定FcγRIIIA結合。實施例闡述例示性的測定方法。可藉由醣工程改造之抗-CD20抗體及利妥昔單抗的相對比例來測定Fc受體的結合。例示性實施方式的Fc受體結合至少增加2.5倍、3倍、4倍, 5倍、 6倍、7倍、8倍、9倍、10倍、11倍或20倍、30倍或更高。高甘露糖系列的Man
9GlcNAc
2醣型不具有預期的結合能力。然而,Man
5GlcNAc
2醣型比不經修飾的利妥昔單抗要佳。兩種混合型醣型僅可增強2-3倍與FcγRIIIA的結合能力。有趣的是,相較於原有的利妥昔單抗,所有的複合型醣型(包括雙分支及三分支類型)與FcγRIIIA的結合能力均增強超過30倍。在GlcNAc上帶有α-1,3海藻醣不會影響FcγRIIIA結合能力。然而,1,2海藻糖會些微地減少該結合能力。此外,具有多種分支(例如三分支醣類型)不會顯著影響結合能力。然而,一直以來被認為若增加聚醣內的唾液酸含量則可獲得抗發炎反應的活性。
相較於利妥昔單抗,結合能力數據顯示經醣工程改造的抗-CD20抗體(特別是那些具有複合型醣型的抗體)對FcγRIIIA具有較強的結合親和力。
經醣工程改造的利妥昔單抗之ADCC活性
根據本發明,經醣工程改造的利妥昔單抗之ADCC活性相較於其親代抗體的ADCC活性,至少增加3倍,較佳地增加至少9倍、更佳地增加至少10倍的ADCC活性、更佳地增加至少12倍的ADCC活性、更佳地增加至少20倍的ADCC活性、更佳地至少增加30倍的ADCC活性。
表6列出選定的經醣工程改造之抗-CD20抗體及市售利妥昔單抗的例示性改善ADCC活性。實施例闡述了例示性的測定方法。
表6
醣型 | R 2 | EC 50[ng/mL] | 最大細胞溶解(%) | 倍數 |
市售利妥昔單抗 | 0.987 | 13.55 | 27.79 | 1 |
Rtx-G5 | 0.946 | 2.181 | 32.02 | 6.55 |
Rtx-G6 | 0.954 | 2.927 | 39.18 | 4.6 |
Rtx-G14 | 0.942 | 2.323 | 38.76 | 5.8 |
Rtx-G15 | 0.968 | 1.911 | 37.98 | 7.0 |
相較於親代抗體(利妥昔單抗),本揭示內容一系列經醣工程改造的抗-CD20抗體(特別是那些含有複合醣型抗體)具有較強的ADCC活性。本發明經醣工程改造的抗體可作為治療劑,藉以對B細胞介導之惡性腫瘤及免疫疾病產生優異的治療效果,其中該些惡性腫瘤及免疫疾病是與B細胞或B細胞產生之抗體相關。本發明目的在於使用經醣工程改造的抗-CD20抗體以發展治療劑。
總結來說,相較於利妥昔單抗,經醣工程改造的抗-CD20抗體具有較佳的ADCC活性及較強的FcγRIIIA結合親和力。本發明醣抗體不論單獨使用或在含有兩個以上類似抗體的組合物中,且可選地與其他療程(像是化學療法)組合,均可提供優異的臨床反應。ADCC-增強之經醣工程改造的抗-CD20抗體為B細胞淋巴瘤及其他疾病提供替代性的療法。本發明經醣工程改造之抗體具有增強的效用意味著其可以較低的濃度及較低的頻率投予至個體體內,藉以降低抗體毒性的可能性及/或抗體耐受性的發展;據此,該些抗體可用以改變目前的給藥途徑及目前的治療方案。此外,改善的效用功能對以前在重組宿主系統所生產的相應抗-CD20單株抗體的治療具有抗性或頑性的臨床適應症,產生新的治療方法。
抗-CD20抗體之醣工程改造方法
可藉由Fc醣工程學從任何抗-CD20單株抗體(親代抗體)製得本發明之經醣工程改造的抗-CD20抗體,其中該抗-20單株抗體可以購自供應商或正在臨床前期或臨床開發。Fc醣工程學可經酵素處理或化學酵素處理。在較佳的實施方式中,親代抗體是利妥昔單抗。
本發明之經醣工程改造之抗體中的N-聚醣較佳是去海藻醣化的。
本揭示內容包含用以製備經醣工程改造之抗體(例如經醣工程改造的抗-CD20抗體)的改善方法。本發明之方法可包含下列步驟:(a)將α-海藻醣酶及醣苷內切酶與一抗-CD20單株抗體接觸,藉以產生具有單一N-乙醯葡萄糖胺(GlcNAc)的去海藻醣化的抗體;以及(b)在合適條件下將一碳水化合物(醣)基團加入GlcNAc中。
在某些實施方式中,根據本發明之方法,該抗-CD20單株抗體是利妥昔單抗。
任何合適的醣苷內切酶可用於剔除N-聚醣中各種部份的寡醣。本文使用的醣苷內切酶之實例包含EndoS2。
本發明方法之步驟(a)可產生一具有單一個N-乙醯葡萄糖胺(GlcNAc) 去海藻醣化抗體。之後,EndoS2突變體介導轉醣苷化作用,將廣泛的選定碳水化合物基團加到GlcNAc上以延展醣鏈。藉此可產生醣抗體的同質性族群。例示性之本揭示內容所述之轉醣苷酶包含具有序列編號:2至17任一胺基酸序列的EndoS2突變體。
在某些實施方式中,本揭示內容的碳水化合物基團可包含多種高甘露糖型、混和型以及複合型的N-聚醣,其具有以下化學式:
其中,R
1是透過β-1,4鍵結的–H或N-乙醯葡萄糖胺,且R
2及R
3可以相同或不同,且係獨立選自由:
所組成之群組。
承前段,為了更明確顯示R
2及R
3之化學結構式,以下以化學式表達,R
2及R
3可以相同或不同,且係獨立地選自由:
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所組成之群組。
在某些實施方式中,碳水化合物基團是糖噁唑啉。
合適的條件也包含將反應混合物反應至少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,較佳可少於60分鐘。較佳的反應條件是在室溫下進行,較佳約為20℃、25℃、30℃、35℃、40℃或 45℃,且較佳約為37℃。
藥學製劑
含有本發明抗體的治療製劑可藉由將具有所需純化程度的抗體與一或多種自選的生理上可接受的載體、賦形劑或安定劑混合,以水溶液、凍乾或其他乾燥形式製劑的形式以儲存待用(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980))。對接受者執行的可接受的載體、賦形劑或安定劑的劑量及濃度必須是無毒的,且包含緩衝液/緩衝劑,像是磷酸鹽、檸檬酸鹽、以及其他有機酸;抗氧化劑(包括抗壞血酸以及甲硫胺酸);防腐劑(例如:十八烷二甲基苄基氯化銨(octadecyldimethylbenzyl ammonium chloride)、氯化六甲雙銨(hexamethonium chloride)、氯化苯甲烷銨(benzalkonium chloride)、氯化本索寧(benzethonium chloride)、酚、丁基或苄基醇類);烷基對羥基苯甲酸酯例如:甲基或丙基對羥基苯甲酸酯;兒茶酚;間苯二酚(resorcinol);環己醇(cyclohexanol);3-戊醇(3-pentanol);及間甲酚(m-cresol);低分子量(小於約10個基團)的多肽;蛋白質,像是血清白蛋白、明膠、或免疫球蛋白;親水性聚合物例如聚乙烯氫吡咯酮;胺基酸例如甘胺酸、穀醯胺、天冬醯胺酸、組胺酸、精胺酸或離胺酸;單醣、雙醣以及其他碳水化合物例如:葡萄糖、甘露糖或糊精;螯合劑例如EDTA;糖類例如蔗糖、甘露醇、海藻糖或山梨醇;成鹽相對離離子,例如鈉;金屬複合物(例如:鋅-蛋白質(Zn-protein)複合物);以及/或非離子型界面活性劑,例如TWEEN™、PLURONICS™或聚乙二醇(PEG)。
本揭示內容的藥學製劑也可含有對特定治療的病症所需的一種以上有效化合物,其包含,但不限於,有互補活性也不會不利地影響彼此的有效化合物。這類分子適合以對預期目的有效量的組合形式存在。
舉例來說,在膠質藥物遞送系統(例如:微脂體、白蛋白微球體、微乳液、奈米顆粒及奈米膠囊)或在巨乳液中,也可將活性成分包埋在分別藉由凝聚技術或藉由界面聚合作用(例如:羥甲基纖維素或明膠微膠囊及聚(甲基丙烯酸甲酯)微膠囊)製備的微膠囊中。Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)已公開此類技術。
用於活體內投藥的藥學製劑必須為無菌狀態。可透過無菌過濾膜進行過濾來完成滅菌。
可製備持續釋放製劑。持續釋放製劑的合適實施例包括含有本發明之免疫球蛋白的固體疏水性聚合物之半透性基質,其中該基質是以有形固體存在,例如膜、或微膠囊。持續釋放基質的實例包含聚酯、水膠(舉例來說:聚(2-羥乙基-甲基丙烯酸酯(poly(2-hydroxyethyl-methacrylate))、或聚(乙烯醇)(poly(vinylalcohol))、聚乳酸酯(polylactides)(美國專利號:3,773,919))、L-麩胺酸與γ乙基-L-麩胺酸鹽的共聚物、非降解型乙烯乙酸乙酯(ethylene-vinyl acetate)、降解型乳酸-羥乙酸共聚物,例如 LUPRON DEPOT™(含有乳酸-羥乙酸共聚物以及利普安(leuprolide acetate)的可注射微球體)、以及聚-D-(-)-3-羥丁酸(poly-D-(-)-3-hydroxybutyric acid)。雖然聚合物(像是乙烯乙酸乙酯及乳酸-羥乙酸)能夠釋放分子超過100天,特定的水膠只能在較短的時效內釋放蛋白質。當密封的免疫球蛋白在體內停留長時間,暴露在37℃的潮濕環境將造成免疫球蛋白變性或聚集,導致其生物活性的損失及免疫原性的可能變化。根據所涉及的機制,可設計合理的策略來實現免疫球蛋白的穩定性。舉例來說,若已發現聚集作用的機制是透過硫代二硫化物互換形成分子間S-S鍵結,可藉由修飾氫硫基殘基、從酸性溶液凍乾、控制含水量、使用合適的添加劑以及發展特定聚合物基質組合物來達成分子間的穩定性。
可依據所需的劑量體積、給藥模式等因素來決定預凍乾製劑中抗體的含量。例示性的初始蛋白質濃度是從每毫升約2毫克至每毫升約50毫克,較佳地是從每毫升約5毫克至每毫升約40毫克,而最佳的是從每毫升約20毫克至每毫升約30毫克,其中所選的蛋白質是完整抗體(全長抗體)。蛋白質通常存於溶液中。舉例來說,蛋白質可存於pH值從約4至8 (較佳地從5-7)的pH緩衝溶液中。例示性緩衝溶液包含組胺酸、磷酸鹽、Tris緩衝液、檸檬酸鹽、琥珀酸鹽及其他有機酸類。舉例來說,取決於緩衝液及製劑(如:回溶的製劑)所需的等滲性,緩衝液濃度可從約1 mM至約 20 mM、或從約3 mM至約15 mM。如下所述,較佳的緩衝液是可具有凍乾保護性能的組胺酸。琥珀酸鹽也是另一個有效的緩衝液。
將凍乾保護劑加入預凍乾製劑中。在較佳實施方式中,凍乾保護劑是諸如蔗糖或海藻糖等非還原糖。在預凍乾製劑中的凍乾保護劑的量通常是使得在回溶時所得的製劑是等張的。然而,上述也可適用於高張的回溶製劑。此外,凍乾保護劑的量必不能過低使得在凍乾作用時發生不可接受的蛋白質變性或聚集的量。雖然凍乾保護劑是糖(諸如蔗糖或海藻糖)且蛋白質是抗體,在預凍乾製劑中的例示性凍乾保護劑濃度是從約10 mM至約400 mM,且較佳地是從約 30 mM至約 300 mM,且最佳的是從約 50 mM至約 100 mM。
根據蛋白質與凍乾保護劑之組合選定蛋白質與凍乾保護劑的比例。在抗體作為所選蛋白質而糖類(例如蔗糖或海藻糖)作為凍乾保護劑用以產生有高蛋白質濃度的等張回溶製劑的情況下,凍乾保護劑與抗體之莫耳比率是從約100至約1500莫耳的凍乾保護劑比1莫耳的抗體,且較佳地是約從200至約1000莫耳的凍乾保護劑比1莫耳的抗體,舉例來說,從約200至約600莫耳的凍乾保護劑至1莫耳的抗體。
在本發明的較佳實施方式中,是將一界面活性劑加入預凍乾製劑中。或者是或此外,將界面活性劑添加到凍乾製劑及/或回溶製劑中。例示性界面活性劑包含非離子型界面活性劑,像是聚山梨醇酯(polysorbates)(例如:聚山梨醇酯20或聚山梨醇酯80);泊洛沙姆(poloxamer)(例如:泊洛沙姆188);Triton;十二基硫酸鈉(SDS);月桂硫酸鈉;辛基醣苷鈉;月桂硫代甜菜鹼(lauryl-sulfobetaine)、肉豆蔻硫代甜菜鹼(myristyl-sulfobetaine)、亞麻硫代甜菜鹼(linoleyl-sulfobetaine)、或硬脂醯硫代甜菜鹼(stearyl-sulfobetaine);月桂肌胺酸(lauryl-sarcosine)、肉豆蔻肌胺酸(myristyl-sarcosine)、亞麻肌胺酸(linoleyl-sarcosine)或硬脂醯肌胺酸(stearyl-sarcosine);亞麻甜菜鹼(linoleyl-betaine)、肉豆蔻甜菜鹼(myristyl-betaine)、或鯨蠟基甜菜鹼(cetyl-betaine);月桂醯胺丙基甜菜鹼(lauroamidopropyl-betaine)、椰油醯胺丙基甜菜鹼(cocamidopropyl-betaine)、亞麻醯胺丙基甜菜鹼(linoleamidopropyl-betaine)、肉豆蔻醯胺丙基甜菜鹼(myristamidopropyl-betaine)、棕櫚醯胺丙基甜菜鹼(palmidopropyl-betaine)或異硬脂醯胺丙基(isostearamidopropyl-betaine)(例如:月桂醯胺丙基二甲胺(lauroamidopropyl-dimethylamine)、肉豆蔻醯胺丙基二甲胺(myristamidopropyl-dimethylamine)、棕櫚醯胺丙基二甲胺(palmidopropyl-dimethylamine)或異硬脂醯胺丙基二甲胺(isostearamidopropyl-dimethylamine);椰油甲基牛磺酸鈉(sodium methyl cocoyl-taurate)或油基甲基牛磺酸二鈉(disodium methyl oleyl-taurate);以及MONAQUAT™ 系列(Mona Industries, Inc., Paterson, N.J.)、丙二醇(polyethyl glycol)、聚丙二醇(polypropyl glycol)以及乙烯及丙二醇共聚物(例如:Pluronics, PF68等)。添加的界面活性劑的量使得其降低重構蛋白的聚集且最小化回溶之後的顆粒形成。舉例來說,界面活性劑可占預凍乾製劑約0.001%至0.5%的量,較佳是占約0.005%至0.05%的量。
在本發明的特定實施方式中,製備預凍乾製劑的時候使用凍乾保護劑的混合物(像是蔗糖或海藻糖)及填充劑(例如:甘露醇或甘胺酸)。填充劑可產生其中沒有多餘孔洞的均一凍乾餅。
在Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)所揭示的其他藥學上可接受的載體、賦形劑或穩定劑可被包含在預凍乾製劑(及/或凍乾製劑及/或回溶製劑)中,前提是該些成分對製劑所需性質沒有產生不良影響。對受體採用的可接受的載體、賦形劑或穩定劑之劑量及濃度是無毒的,且可接受的載體、賦形劑或穩定劑包括其他緩衝液、防腐劑、共溶劑、抗氧化劑(包括抗壞血酸及甲硫胺酸)、螯合劑例如EDTA;金屬複合物(例如:Zn-蛋白質複合物)、生物可降解聚合物(例如聚酯)及/或諸如成鹽相對離子如鈉。
較佳的情況下,本揭示內容的藥學組合物及製劑是穩定的。一「穩定」(stable)的製劑/組合物的其中一種是在儲存狀態下可實質上保留其物理及化學穩定性與整體性的抗體。Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, N.Y., Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993)總結出本領域中可用以測量蛋白質穩定性的各種分析技術。可在選定的溫度下以選定的時間測量穩定性。
用於活體內投藥的藥學製劑必須為無菌狀態。可在凍乾及回溶之前或之後可透過無菌過濾膜進行過濾來完成滅菌。舉例來說,或是可藉由約120℃高壓蒸氣滅菌該些成分(除了蛋白質)約30分鐘來完成整個混合物的滅菌狀態。.
將蛋白質、凍乾保護劑及其他可選的成分混合在一起之後,將該製劑凍乾。可採用不同的冷凍乾燥機來實現前述目的,例如Hull50®型冷凍乾燥機(Hull,美國)或GT20®型冷凍乾燥機(Leybold-Heraeus,德國)。冷凍乾燥機是先將製劑冷凍,隨後在適合初步乾燥的溫度下使冷凍內容物的冰昇華。在此條件下,産物溫度低於製劑的共熔點或崩潰溫度。通常初步乾燥的擱架溫度為約-30℃至25℃(在初步乾燥期間産物應保持冷凍狀態),合適的壓力通常為50至250mTorr。乾燥所需的時間主要由製劑、放置樣品的容器(如玻璃瓶)的大小和類型以及液體的體積來決定,而該時間可從幾小時至幾天(如40-60小時)。主要根據所用的容器的類型和尺寸以及蛋白質的種類,在約0至40℃下進行第二乾燥步驟。然而, 本文也指出第二乾燥步驟是非必要的。舉例來說,在整個凍乾作用中用以除去全部水相的擱架溫度為約15-30℃(如約20℃)。取決於溫度及其他參數,第二乾燥步驟所需的時間和壓力能生成合適的凍乾餅。第二乾燥步驟時間由産物中所需殘餘濕潤程度來決定,通常需要至少5小時(如10-15小時)。壓力可與初步乾燥步驟中所執行的壓力相同。冷凍乾燥條件可根據製劑和瓶的尺寸而變化。
在一些例子中,較理想的是在容器中對蛋白質製劑進行凍乾,如此則可在該容器中回溶(重構)蛋白質以避免轉移步驟。該例子中的容器可以是,舉例來說,3、5、10、20、50或100cc的小瓶。通常來說,凍乾作用應使凍乾製劑中的水分含量約小於5%,較佳約小於3%。
在所需步驟時,特別是需要對病患投予該蛋白質時,可以稀釋劑來回溶該凍乾製劑,使得回溶製劑中的蛋白質濃度至少為每毫升50 毫克、舉例來說從每毫升50毫克至每毫升400毫克,更佳是從約每毫升80毫克至每毫升300毫克,且最佳是從約每毫升90毫克至約每毫升150毫克。回溶製劑中的高蛋白濃度有利於皮下投予回溶製劑。然而,對於其它給藥途徑,如靜脈內給藥,則需要較低的回溶製劑之蛋白質濃度(例如回溶製劑中的蛋白質濃度為約每毫升5毫克至50毫克,或約為每毫升10毫克至40毫克)。在特定實施方式中,回溶製劑中的蛋白質濃度顯著地高於預凍乾製劑中的蛋白質濃度。例如,回溶製劑的蛋白質濃度是預凍乾製劑蛋白質濃度的約2至40倍,較佳為3至10倍,最佳為3至6倍(如至少3倍或至少4倍)。
回溶通常是在約25℃的溫度下進行以保證完全水合,但也可依照需求採用其它溫度。回溶所需的時間與,例如稀釋劑的種類、賦形劑和蛋白質的量有關。例示性稀釋劑包括無菌水、注射用抑菌溶液(BWFI)、一種pH緩衝液(如磷酸鹽緩衝液)、無菌食鹽水、林格氏溶液或葡萄糖溶液。稀釋劑可非必要地含有防腐劑。例示性防腐劑如上所述,較佳的防腐劑是有芳香醇如苯基或酚基醇。藉由測定不同的防腐劑濃度下與蛋白質的相容性和防腐效力來決定防腐劑的用量。舉例來說,如果防腐劑是芳香醇(如苯甲醇),其含量可從約0.1%至2.0%,較佳為0.5%至1.5%,最佳為1.0%至1.2%。較佳地,每一瓶回溶製劑中尺寸大於10 微米的顆粒應少於6000個。
治療應用
本揭示內容中經醣工程改造的抗體可用於治療患有癌症的病患。該治療方法包含對該病患投予本發明一有效量之經醣工程改造的抗體或一藥學組合物。該癌症包含,但不限於:B細胞淋巴瘤(B cell lymphomas)、NHL、前驅B細胞淋巴母細胞性白血病(precursor B cell lymphoblastic leukemia)或前驅B細胞淋巴胚細胞性淋巴瘤(precursor B cell lymphoblastic lymphoma)及成熟B細胞瘤(mature B cell neoplasms)、B細胞慢性淋巴球性白血病(B cell chronic lymphocytic leukemia,CLL)/小淋巴細胞性淋巴瘤(small lymphocytic lymphoma,SLL)、B細胞幼淋巴球性白血病(B cell prolymphocytic leukemia)、淋巴漿細胞性淋巴瘤(lymphoplasmacytic lymphoma)、外套細胞淋巴瘤(mantle cell lymphoma,MCL)、濾泡性淋巴瘤(follicular lymphoma,FL)、低度、中度及高度FL、皮膚毛囊中心淋巴瘤(cutaneous follicle center lymphoma)、邊緣區B細胞淋巴瘤(marginal zone B cell lymphoma)、MALT型邊緣區B細胞淋巴瘤(MALT type marginal zone B cell lymphoma)、節點邊緣區B細胞淋巴瘤(nodal marginal zone B cell lymphoma)、脾型邊緣區B細胞淋巴瘤(splenic type marginal zone B cell lymphoma)、毛細胞白血病(hairy cell leukemia)、瀰漫性大細胞淋巴瘤(diffuse large B cell lymphoma)、柏基特氏淋巴瘤(Burkitt's lymphoma)、漿細胞瘤(plasmacytoma)、漿細胞骨髓瘤(plasma cell myeloma)、移植後淋巴增生性疾病(post-transplant lymphoproliferative disorder)、華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)以及退行性變化大細胞淋巴瘤(anaplastic large-cell lymphoma,ALCL)。
在特定實施方式中,癌症是B細胞淋巴瘤像是非霍奇金淋巴瘤(non-Hodgkin's lymphoma)。
此外,本揭示內容之經醣工程改造的抗體可用於治療患有自體免疫疾病或發炎性疾病的病患。該治療方法包含對該病患投予本發明一有效量之經醣工程改造的抗體或一藥學組合物。自體免疫性疾病或發炎性疾病的實例包括,但不限於:類風溼性關節炎(rheumatoid arthritis)、青少年期的類風溼性關節炎(juvenile rheumatoid arthritis)、全身性紅斑性狼瘡(systemic lupus erythematosus,SLE)、華格納氏疾病(Wegener's disease)、炎症性腸病(inflammatory bowel disease)、特發性血小板減少性紫癲(idiopathic thrombocytopenic purpura,ITP)、栓塞性血小板減少性紫癲(thrombotic thrombocytopenic purpura,TTP)、自體免疫性血小板減少症(autoimmune thrombocytopenia)、多發性硬化症(multiple sclerosis)、乾癬(psoriasis)、IgA腎病變(IgA nephropathy)、IgM多發性神經病變(IgM polyneuropathies)、重症肌無力(myasthenia gravis)、血管炎(vasculitis)、糖尿病(diabetes mellitus)、雷諾氏綜合症(Reynaud's syndrome)、克隆氏症(Crohn's disease)、潰瘍性結腸炎(ulcerative colitis)、胃炎(gastritis)、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、僵直性脊椎炎(ankylosing spondylitis)、C型肝炎相關的冷凝球蛋白血管炎(hepatitis C-associated cryoglobulinemic vasculitis)、慢性局部腦炎(chronic focal encephalitis)、大疱性類天疱瘡(bullous pemphigoid)、甲型血友病(hemophilia A)、膜性增生性腎絲球腎炎(membranoproliferative glomerulnephritis)、成人型和青少年型皮肌炎(adult and juvenile dermatomyositis)、成人多發性肌炎(adult polymyositis)、慢性蕁麻疹(chronic urticaria)、原發性膽性肝硬化(primary biliary cirrhosis)、視神經脊隨炎(neuromyelitis optica)、葛瑞夫茲氏甲狀腺發育不良疾病(Graves' dysthyroid disease)、大疱性類天疱瘡(bullous pemphigoid)、膜性增生性腎絲球腎炎(membranoproliferative glonerulonephritis)、Churg-Strauss二氏症候群(Churg-Strauss syndrome)、氣喘(asthma)、牛皮癬性關節炎(psoriatic arthritis)、皮膚炎(dermatitis)、呼吸窘迫症候群(respiratory distress syndrome)、腦膜炎(meningitis)、腦炎(encephalitits)、眼色素層炎(uveitis)、濕疹(eczema)、動脈粥樣硬化(atherosclerosis)、白血球黏附缺陷(leukocyte adhesion deficiency)、青少年型糖尿病(juvenile onset diabetes)、Reiter氏病(Reiter's disease)、白塞氏病(Behcet's disease)、溶血性貧血(hemolytic anemia)、異位性皮膚炎(atopic dermatitis)、華格納氏肉芽病(Wegener's granulomatosis)、Omenn氏症候群(Omenn's syndrome)、慢性腎衰竭(chronic renal failure)、急性傳染性單核白血球增多症(acute infectious mononucleosis)、HIV及皰疹相關疾病(HIV and herpes-associated disease)、全身性硬化症(systemic sclerosis)、薛格連氏症候群及腎絲球腎炎(Sjorgen's syndrome and glomerulonephritis)、皮肌炎(dermatomyositis)、ANCA、再生不良性貧血(aplastic anemia)、自體免疫溶血性貧血(autoimmune hemolytic anemia,AIHA)、第八凝血因子缺陷(factor VIII deficiency)、甲型血友病(hemophilia A)、自體免疫性嗜中性白血球減少症(autoimmune neutropenia)、Castleman氏症(Castleman's syndrome)、Goodpasture氏症候群(Goodpasture's syndrome)、實體器官移植排斥(solid organ transplant rejection)、移植物抗宿主病(graft versus host disease,GVHD)、自體免疫性肝炎(autoimmune hepatitis)、淋巴細胞性間質性肺炎(lymphoid interstitial pneumonitis,HIV)、阻塞性細支氣管炎(非移植性)(bronchiolitis obliterans (non-transplant))、格巴二氏症候群(Guillain-Barre Syndrome)、大血管血管炎(large vessel vasculitis)、巨細胞(Takayasu氏)動脈炎(giant cell (Takayasu's) arteritis)、中血管血管炎(medium vessel vasculitis)、川崎病(Kawasaki's Disease)以及結節性多動脈炎(polyarteritis nodosa)。
在特定實施方式中,自體免疫疾病或發炎性疾病是類風溼性關節炎。
在這些治療方法中,可單獨投予經醣工程改造的抗-CD20抗體,或是將經醣工程改造的抗-CD20抗體與第二治療劑合併投予,該第二治療劑可為一第二抗體、一化學治療劑或一免疫抑制劑。第二抗體可與CD20或其他B細胞抗原、或NK細胞或T細胞抗原結合。
將透過以下特定的實施例進一步說明本發明的實施方式。本發明所屬技術領域中具有通常知識者應當理解到,這些實施例僅用於說明,且不悖離本發明之範疇的情形下,當可對其進行各種更動與修飾。舉例來說,本發明EndoS2突變體可用於對任何醣蛋白或醣肽(包含抗體)進行醣工程改造。本文描述的特定實施例是使用抗-CD20抗體。然而,本發明所述技術領域中具有通常知識者應當理解到,也可以相似方法使用其他醣蛋白或抗體。
材料與方法
從外部供應商獲得或從內部生產單株抗體利妥昔單抗。根據前述的程序合成高甘露糖型、混合型及複合型的N-聚醣(20, 21)。
EndoS2及其突變體之轉殖株建構、過表現及純化
合成來自釀膿鏈球菌(
Streptococcus pyogenes)GAS NZ131菌株的EndoS2編碼基因:
ndoS2,並在pET28a表現載體中進行次轉殖。
ndoS2的訊號胜肽序列(胺基酸1-36)的N端被His6-標籤取代。根據供應商的使用操作說明(Agilent Technologies)(其透過使用
ndoS2表現載體作為模板,以含有所需突變的寡核苷酸對做為引子來執行PCR反應),以定點誘變方式產生
ndoS2的突變體。接著,以DpnI處理擴增的DNA,並將其轉形至DH5α勝任細胞中。利用DNA定序(基因體)確認突變的序列。在為了表現而轉形至BL21 (DE3)勝任細胞之後,以0.1 mM的異丙基-β-D-硫代半乳糖苷(isopropyl-β-D-thiogalactopyranoside,IPTG)誘導該細胞,並在20℃之溫度反應16小時使重組EndoS2突變體蛋白與其His6標籤表現,接著以6500 rpm離心30分鐘沉澱蛋白質顆粒(pelleted)。將細胞在在裂解緩衝液(30 mM的HEPES,pH值8.0、300 mM的NaCl)中再懸浮,並使用超音波震盪器(ChromTech)震碎細胞(10分鐘,開啟4秒/關閉5秒)。以10000 rpm對全部的細胞溶胞產物(裂解後產物)進行離心45分鐘,並以固定化金屬離子色層分析法的Ni-NTA管柱(GE Healthcare)純化重組EndoS2蛋白及其突變體蛋白。使用離心過濾器(Amicon ultra centrifugal filters 10 kDa)收集洗脫的蛋白質分液並在儲存緩衝液(30 mM的HEPES、pH值為8.0、100 mM的NaCl)中進行濃縮。以SDS-PAGE分析濃縮的蛋白質樣品,並使用分光光度計(Nano-Drop 2000c)定量蛋白質濃度。野生型EndoS2的過表現之產量大約為每升35毫克;而突變體的產物產量大約為每升25毫克。
從市售的利妥昔單抗製備GlcNAc-利妥昔單抗
將市售的利妥昔單抗(2.5毫克)溶於pH值7.0、濃度為50 mM的1.25毫升磷酸鈉緩衝液中,並與EndoS2(125微克)及海藻醣酶(2.5 毫克)在37℃之溫度下反應22小時。以SDS-PAGE分析確認重鏈上的N-聚醣被完全剪切後,將反應混合物通過1毫升的蛋白質A-瓊脂糖樹酯(protein A-agarose resin)管柱(事先以pH值7.0、濃度為20mM的磷酸鈉進行平衡)進行親和力層析。洗滌之後,以pH值3.0、濃度50mM的10ml甘胺酸鹽酸溶液洗脫被結合的IgG。接著立即以pH值8.3、濃度1 M的Tris-Cl中和該洗脫液的分液,並藉由離心過濾器(Amicon Ultra centrifugal filter)濃縮該分液以獲得GlcNAc-利妥昔單抗(1.93 毫克)。以胰蛋白酶處理產物,而使用電噴灑游離質譜儀(儀器名:nanospray LC/MS)分析醣肽(TKPREEQYNSTYR及EEQYNSTYR)以確認GlcNAc-利妥昔單抗的醣苷化模式。
聚醣-噁唑啉的製備
將各別聚醣(3-5毫克)的溶液、2-氯基-1,3-二甲基咪唑啉氯化物(2-chloro-1,3-dimethylimidazolinium chloride,DMC)(6-10 毫克)及Et
3N(10-20微升)溶於水(300-500微升)中,並於4℃攪拌1小時。將反應混合物通過Sephadex G-25管柱,以0.05%的水性Et3N洗脫,以執行凝膠過濾色層分析法。可將含有該產物G1-G16(聚醣噁唑啉)的分液組合,並凍乾以獲得白色粉末(2.5-4 毫克,產率~80-90%)。
EndoS2及其突變體的水解活性測定
將含有52 µM的利妥昔單抗(400微克)及52 nM的EndoS2(或其選定的突變蛋白質)溶於pH值7.0、濃度為100 mM的HEPES緩衝液中,並在37℃下以700 rpm的搖動該溶液。在指定的時間點以10%的SDS-PAGE收集並分析2微克的等分試樣。有水解聚醣的利妥昔單抗在PAGE膠片上移動較快。可使用圖像處理軟體(Image J)根據在SDS-PAGE上條帶的光強度計算水解產物的相對百分比(第3圖)。
利用SCT-噁唑啉作為供體受質測定EndoS2及其突變體的轉醣苷化活性
將含有67.5 µM的單體GlcNAc-利妥昔單抗(400 微克)及濃度2.5 mM的唾液酸化複合型聚醣 (SCT)-噁唑啉(200 微克)之HEPES緩衝液(pH值7.0、濃度為100 mM)與67.5 nM的EndoS2或選定的突變蛋白質在37℃下混合,並以700 rpm搖動使該溶液反應。在指定的時間點以10%的SDS-PAGE收集並分析2微克的等分試樣。醣苷化的利妥昔單抗在PAGE膠片上移動較慢。使用圖像處理軟體(Image J)基於在SDS-PAGE上條帶的光強度計算利妥昔單抗-SCT的相對百分比。
利用EndoS2突變體對含有各種聚醣噁唑啉的GlcNAc-利妥昔單抗進行轉醣苷化作用
常規程序:將聚醣噁唑啉(2-3 毫克)添加至溶有EndoS2突變體(16.8 µM)及GlcNAc-利妥昔單抗(2 毫克、0.337 mM)之混合物的HEPES緩衝液(濃度:100 mM,pH值7.0)中,並該混合液中,於37℃之溫度下以700 rpm搖動該混合液1至2小時。將0.1 mM的EDTA溶液加入該混合液中以終止反應。以Protein A親和管柱純化反應混合物,隨後通過一陰離子交換管柱(capto Q)收集所需的產物:經醣工程改造的抗-CD20之利妥昔單抗。以胰蛋白酶處理產物,且使用電噴灑游離質譜儀(儀器名:nanospray LC/MS)分析醣肽(TKPREEQYNSTYR及EEQYNSTYR)以確認預期的醣苷化模式。
表7列出用於製備每種利妥昔單抗醣型的最適反應條件
表7
起始材料 | 利妥昔單抗醣型 | EndoS2突變體 | 酵素比例 | 聚醣噁唑啉 | 聚醣含量 | 反應時間 |
GlcNAc-利妥昔單抗 (2毫克,0.337 mM) | Rtx-G1 | D226Q | 16.8 µM | G1 | 2 毫克 | 30分鐘 |
Rtx-G2 | T138Q | 33.7 µM | G2 | 3 毫克 | 30分鐘 | |
Rtx-G3 | D182Q | 16.8 µM | G3 | 2 毫克 | 30分鐘 | |
Rtx-G4 | D226Q | 16.8 µM | G4 | 2 毫克 | 60分鐘 | |
Rtx-G5 | D182Q | 16.8 µM | G5 | 3 毫克 | 30分鐘 | |
Rtx-G6 | D138Q | 33.7 µM | G6 | 3 毫克 | 30分鐘 | |
Rtx-G7 | T138Q | 16.8 µM | G7 | 2 毫克 | 30分鐘 | |
Rtx-G8 | T138Q | 16.8 µM | G8 | 2 毫克 | 30分鐘 | |
Rtx-G9 | D182Q | 16.8 µM | G9 | 2 毫克 | 30分鐘 | |
Rtx-G10 | D182Q | 16.8 µM | G10 | 2 毫克 | 30分鐘 | |
Rtx-G11 | D182Q | 16.8 µM | G11 | 2 毫克 | 60分鐘 | |
Rtx-G12 | D182Q | 16.8 µM | G12 | 2 毫克 | 60分鐘 | |
Rtx-G13 | D138Q | 16.8 µM | G13 | 2 毫克 | 30分鐘 | |
Rtx-G14 | D182Q | 16.8 µM | G14 | 3 毫克 | 60分鐘 | |
Rtx-G15 | D182Q | 16.8 µM | G15 | 2 毫克 | 60分鐘 | |
Rtx-G16 | D182Q | 16.8 µM | G15 | 2 毫克 | 60分鐘 |
經醣工程改造之抗-CD20抗體對FcγRIIIA的結合親和力
以ELISA測定利妥昔單抗之重塑醣型對FcγIIA受體的親和力。
以每孔50 ng的重組可溶性FcγRIIIA(經50mM的重碳酸鹽/碳酸鹽塗層緩衝液(pH值10)稀釋)對微量滴定板(型號:Corning®#9018,聚苯乙烯高結合之96孔透明平底盤)於4℃進行塗層並放置隔夜。以PBST溶液 (0.05%的Tween 20溶於PBS)洗滌三次,並以含有5% BSA的PBST在室溫下反應1小時以阻斷反應。以八次連續稀釋測定經醣工程改造的抗體(Rtx G1-G16)的結合活性,2%的BSA/PBST中初始濃度為每毫升100 微克,並稀釋雙重複。使微量滴定板在室溫下反應1小時,並以PBST洗滌三次。接著,在每個孔中加入100微升之與山葵過氧化酶共軛的山羊抗人類IgG(溶於2%的BSA/PBST中)(商品名:Jackson immune, #109-035-088),並於室溫下反應30分鐘。以PBST洗滌該滴定板5次,並接著在每個孔中加入100微升的TMB受質(eBioscience, #00-4201-56),並將該滴定板在室溫下進行暗反應15分鐘。在酵素免疫測定法讀取器(Molecular Devices Corporation, Sunnyvale, CA,美國)中以波長450 nm測定吸光值。
經醣工程改造的抗CD-20抗體之ADCC活性
使用鈣黃綠素釋放測定法(calcein release assay)評估抗體介導的ADCC。將從BCRC取得的Raji氏細胞(一種人類柏基特氏淋巴瘤(Burkitt’s lymphoma)細胞株)作為標的細胞。使用單核球細胞分離液(商品名:Ficoll-Paque (GE healthcare))從健康受試者的血液中分離外周血單核球(Peripheral blood-mononuclear cells,PBMC)作為效用細胞。以10 μM的鈣黃綠素-乙醯氧基甲基酯(Thermo Fisher Scientific)在37℃下標記標的細胞(每毫升1×10
6)30分鐘。洗滌之後,將經標記的標的細胞以每孔50微升體積中含有1×10
4個細胞數的密度分布在96孔盤中。接著加入各種濃度的抗體以及加入E/T比例為25:1的效用細胞(每孔2.5×10
5個)。在37℃之溫度靜置4小時之後,離心沉積細胞並收集150微升的上清液,並使用螢光微量盤分析儀分析該上清液以測量鈣黃綠素之釋放量。為了最大的程度的釋放量,以1%的Triton X-100裂解細胞。實驗結果的螢光值要先消除培養基背景的螢光值。
雖然僅根據有限的實施方式來描述本發明,所屬技術領域具有通常知識者(特別是受益於本揭示內容的那些)應當理解可在不背離本發明範疇之情況下設計其他的實施方式。因此,本發明之範疇應限定於後附的申請專利範圍中。
無
第1圖是關於野生型EndoS2之序列以及欲進行定點誘變的潛在胺基酸殘基。
第2圖根據本發明一實施方式所闡述之EndoS2突變體T138D (序列編號:6)、T138E (序列編號:7)、T138F (序列編號:8)、T138H (序列編號:9)、T138K (序列編號:10)、T138L (序列編號:11)、T138M (序列編號:12)、T138N (序列編號:13)、T138Q (序列編號:14)、T138R (序列編號:15)、T138V (序列編號:16)、T138W (序列編號:17)、D182Q (序列編號: 2)、D226Q (序列編號: 3)、T227Q (序列編號: 4)及T228Q (序列編號: 5)之胺基酸序列。
第3圖(A)小圖:基於與EndoS序列比對的結果,卡通圖顯示EndoS2催化區域的推想第三個β褶板、第四個β褶板以及第五個β褶板。催化殘基為E186,而圍繞在E186周圍的突變胺基酸包含T138、D182、D226、T227及T228。(B)小圖:使用市售利妥昔單抗作為受質以測定野生型EndoS2以及每個選定位點的突變體之聚醣水解活性之結果。將EndoS2突變體(52 nM)與市售利妥昔單抗(52 µM)併同反應120分鐘,並以SDS-PAGE分析。圖示顯示原始利妥昔單抗(Rtx-聚醣)之相對百分比。使用突變體D184Q作為對照。
第4圖繪示使用GlcNAc-利妥昔單抗(67.5 µM)作為受體而α-2,6 唾液酸化雙分支複合型聚醣(SCT)-噁唑啉(2.5 mM)作為供體測試野生型EndoS2及每個選定位點突變體的(67.5 nM)的轉醣苷化活性之結果。反應進行2小時,並以SDS-PAGE分析。結果顯示利妥昔單抗及Fc區域的α-2,6 唾液酸化雙分支複合型聚醣(Rtx-SCT)之相對百分比。使用突變體D184Q作為對照。
第5圖繪示使用GlcNAc-利妥昔單抗作為受體且α-2, 6唾液酸化雙分支複合型聚醣(SCT)-噁唑啉作為供體,在T138位點突變的轉醣苷化活性比較結果。將含有T138突變體(67.5 nM)、GlcNAc-利妥昔單抗(67.5 µM)以及SCT-噁唑啉(2.5 mM)的反應物進行反應2小時且以SDS-PAGE分析。結果顯示利妥昔單抗及Fc區域的α-2,6 唾液酸化雙分支複合型聚醣(Rtx-SCT)之相對百分比。
第6圖是藉由使用GlcNAc-利妥昔單抗作為受體以及聚醣-噁唑啉(G1-G4)做為供體受質以測定選定的EndoS2突變體對高甘露糖型Man5GlcNAc2 (聚醣G1)、Man9GlcNAc2 (聚醣 G2)以及混合型醣型系列聚醣 (G3及G4)之轉醣苷化活性結果。以十二基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE)監測該反應過程。電泳道(Lane) 1:標記物:電泳道2: GlcNAc-利妥昔單抗;時間點以分鐘計;產物百分比(%)顯示於底部。
第7圖是選定的EndoS2突變體對三分支複合型聚醣G5(末端為半乳糖殘基)及G6(末端為α-2,6唾液酸)的轉醣苷化活性結果。使用GlcNAc-利妥昔單抗作為受體,而聚醣-噁唑啉(G4-G5)作為供體受質以執行該反應。以十二基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE)監測該反應過程。電泳道(Lane) 1:標記物:電泳道2: GlcNAc-利妥昔單抗;時間點以分鐘計;產物百分比(%)顯示於底部。
第8圖是選定的EndoS2突變體對一系列雙分支複合型醣型結構的轉醣苷化活性之結果。聚醣G7是末端有二個半乳糖的雙分支聚醣;聚醣G8是有等分GlcNAc且末端有二個半乳糖的雙分支聚醣;聚醣G9是在二個半乳糖末端之一上帶有α-1, 2海藻糖的雙分支聚醣;以及聚醣G10是在 GlcNAc及末端二半乳糖上都有α-1, 3海藻糖的雙分支聚醣。使用GlcNAc-利妥昔單抗作為受體,而聚醣-噁唑啉(G7-G10)作為供體受質以執行該轉醣苷化作用。以十二基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE)監測該反應過程。電泳道1:標記物;電泳道2:GlcNAc-利妥昔單抗;時間點以分鐘計。
第9圖是選定的EndoS2突變體對二分支複合型聚醣G7(末端為半乳糖殘基)及G16(末端為α-2, 6唾液酸)的轉醣苷化活性結果。使用Fuc(α-1, 6)-GlcNAc-利妥昔單抗作為受體,而聚醣-噁唑啉(G4-G16)作為供體受質以執行該反應。以十二基硫酸鈉聚丙烯醯胺凝膠電泳(sodium dodecyl sulfate polyacrylamide gel electrophoresis,SDS-PAGE)監測該反應過程。電泳道1:標記物:電泳道2: GlcNAc-利妥昔單抗;時間點以分鐘計;產物百分比(%)顯示於底部。
第10圖繪示選定的EndoS2突變體對廣泛範圍的高甘露糖型、混合醣型、複合醣型聚醣的受質特異性。
第11圖繪示利妥昔單抗與其Fc區域上多樣醣型的結構。醣型包含一系列高甘露糖型、混合型以及雙、三分支複合型結構。
第12圖是經醣工程改造利妥昔單抗(Rtx G1-G16)、GlcNAc-利妥昔單抗以及市售利妥昔單抗的SDS-PAGE分析結果。
序列表 <![CDATA[<110> 醣基生醫股份有限公司]]> 中央研究院 <![CDATA[<120> 利用醣苷內切酶突變體重塑醣蛋白及其使用方法]]> <![CDATA[<130> 106128522]]> <![CDATA[<150> US62/378,806]]> <![CDATA[<151> ]]> 2016-08-24 <![CDATA[<160> 19 ]]> <![CDATA[<170> PatentIn version 3.5 ]]> <![CDATA[<210> 1]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 釀膿鏈球菌(Streptococcus pyogenes)]]> <![CDATA[<400> 1]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Thr Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 2]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 2]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Thr Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Gln Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 3]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 3]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Thr Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Gln Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 4]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 4]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Thr Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Gln Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 5]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 5]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Thr Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Gln Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 6]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 6]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Asp Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 7]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 7]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Glu Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 8]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 8]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Phe Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 9]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 9]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln His Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 10]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 10]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Lys Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 11]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 11]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Leu Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 12]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 12]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Met Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 13]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 13]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Asn Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 14]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 14]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Gln Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 15]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 15]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Arg Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 16]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 16]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Val Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 17]]> <![CDATA[<211> 842]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 17]]> Met Asp Lys His Leu Leu Val Lys Arg Thr Leu Gly Cys Val Cys Ala 1 5 10 15 Ala Thr Leu Met Gly Ala Ala Leu Ala Thr His His Asp Ser Leu Asn 20 25 30 Thr Val Lys Ala Glu Glu Lys Thr Val Gln Thr Gly Lys Thr Asp Gln 35 40 45 Gln Val Gly Ala Lys Leu Val Gln Glu Ile Arg Glu Gly Lys Arg Gly 50 55 60 Pro Leu Tyr Ala Gly Tyr Phe Arg Thr Trp His Asp Arg Ala Ser Thr 65 70 75 80 Gly Ile Asp Gly Lys Gln Gln His Pro Glu Asn Thr Met Ala Glu Val 85 90 95 Pro Lys Glu Val Asp Ile Leu Phe Val Phe His Asp His Thr Ala Ser 100 105 110 Asp Ser Pro Phe Trp Ser Glu Leu Lys Asp Ser Tyr Val His Lys Leu 115 120 125 His Gln Gln Gly Thr Ala Leu Val Gln Trp Ile Gly Val Asn Glu Leu 130 135 140 Asn Gly Arg Thr Gly Leu Ser Lys Asp Tyr Pro Asp Thr Pro Glu Gly 145 150 155 160 Asn Lys Ala Leu Ala Ala Ala Ile Val Lys Ala Phe Val Thr Asp Arg 165 170 175 Gly Val Asp Gly Leu Asp Ile Asp Ile Glu His Glu Phe Thr Asn Lys 180 185 190 Arg Thr Pro Glu Glu Asp Ala Arg Ala Leu Asn Val Phe Lys Glu Ile 195 200 205 Ala Gln Leu Ile Gly Lys Asn Gly Ser Asp Lys Ser Lys Leu Leu Ile 210 215 220 Met Asp Thr Thr Leu Ser Val Glu Asn Asn Pro Ile Phe Lys Gly Ile 225 230 235 240 Ala Glu Asp Leu Asp Tyr Leu Leu Arg Gln Tyr Tyr Gly Ser Gln Gly 245 250 255 Gly Glu Ala Glu Val Asp Thr Ile Asn Ser Asp Trp Asn Gln Tyr Gln 260 265 270 Asn Tyr Ile Asp Ala Ser Gln Phe Met Ile Gly Phe Ser Phe Phe Glu 275 280 285 Glu Ser Ala Ser Lys Gly Asn Leu Trp Phe Asp Val Asn Glu Tyr Asp 290 295 300 Pro Asn Asn Pro Glu Lys Gly Lys Asp Ile Glu Gly Thr Arg Ala Lys 305 310 315 320 Lys Tyr Ala Glu Trp Gln Pro Ser Thr Gly Gly Leu Lys Ala Gly Ile 325 330 335 Phe Ser Tyr Ala Ile Asp Arg Asp Gly Val Ala His Val Pro Ser Thr 340 345 350 Tyr Lys Asn Arg Thr Ser Thr Asn Leu Gln Arg His Glu Val Asp Asn 355 360 365 Ile Ser His Thr Asp Tyr Thr Val Ser Arg Lys Leu Lys Thr Leu Met 370 375 380 Thr Glu Asp Lys Arg Tyr Asp Val Ile Asp Gln Lys Asp Ile Pro Asp 385 390 395 400 Pro Ala Leu Arg Glu Gln Ile Ile Gln Gln Val Gly Gln Tyr Lys Gly 405 410 415 Asp Leu Glu Arg Tyr Asn Lys Thr Leu Val Leu Thr Gly Asp Lys Ile 420 425 430 Gln Asn Leu Lys Gly Leu Glu Lys Leu Ser Lys Leu Gln Lys Leu Glu 435 440 445 Leu Arg Gln Leu Ser Asn Val Lys Glu Ile Thr Pro Glu Leu Leu Pro 450 455 460 Glu Ser Met Lys Lys Asp Ala Glu Leu Val Met Val Gly Met Thr Gly 465 470 475 480 Leu Glu Lys Leu Asn Leu Ser Gly Leu Asn Arg Gln Thr Leu Asp Gly 485 490 495 Ile Asp Val Asn Ser Ile Thr His Leu Thr Ser Phe Asp Ile Ser His 500 505 510 Asn Ser Leu Asp Leu Ser Glu Lys Ser Glu Asp Arg Lys Leu Leu Met 515 520 525 Thr Leu Met Glu Gln Val Ser Asn His Gln Lys Ile Thr Val Lys Asn 530 535 540 Thr Ala Phe Glu Asn Gln Lys Pro Lys Gly Tyr Tyr Pro Gln Thr Tyr 545 550 555 560 Asp Thr Lys Glu Gly His Tyr Asp Val Asp Asn Ala Glu His Asp Ile 565 570 575 Leu Thr Asp Phe Val Phe Gly Thr Val Thr Lys Arg Asn Thr Phe Ile 580 585 590 Gly Asp Glu Glu Ala Phe Ala Ile Tyr Lys Glu Gly Ala Val Asp Gly 595 600 605 Arg Gln Tyr Val Ser Lys Asp Tyr Thr Tyr Glu Ala Phe Arg Lys Asp 610 615 620 Tyr Lys Gly Tyr Lys Val His Leu Thr Ala Ser Asn Leu Gly Glu Thr 625 630 635 640 Val Thr Ser Lys Val Thr Ala Thr Thr Asp Glu Thr Tyr Leu Val Asp 645 650 655 Val Ser Asp Gly Glu Lys Val Val His His Met Lys Leu Asn Ile Gly 660 665 670 Ser Gly Ala Ile Met Met Glu Asn Leu Ala Lys Gly Ala Lys Val Ile 675 680 685 Gly Thr Ser Gly Asp Phe Glu Gln Ala Lys Lys Ile Phe Asp Gly Glu 690 695 700 Lys Ser Asp Arg Phe Phe Thr Trp Gly Gln Thr Asn Trp Ile Ala Phe 705 710 715 720 Asp Leu Gly Glu Ile Asn Leu Ala Lys Glu Trp Arg Leu Phe Asn Ala 725 730 735 Glu Thr Asn Thr Glu Ile Lys Thr Asp Ser Ser Leu Asn Val Ala Lys 740 745 750 Gly Arg Leu Gln Ile Leu Lys Asp Thr Thr Ile Asp Leu Glu Lys Met 755 760 765 Asp Ile Lys Asn Arg Lys Glu Tyr Leu Ser Asn Asp Glu Asn Trp Thr 770 775 780 Asp Val Ala Gln Met Asp Asp Ala Lys Ala Ile Phe Asn Ser Lys Leu 785 790 795 800 Ser Asn Val Leu Ser Arg Tyr Trp Arg Phe Cys Val Asp Gly Gly Ala 805 810 815 Ser Ser Tyr Tyr Pro Gln Tyr Thr Glu Leu Gln Ile Leu Gly Gln Arg 820 825 830 Leu Ser Asn Asp Val Ala Asn Thr Leu Asp 835 840 <![CDATA[<210> 18]]> <![CDATA[<211> 451]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 18]]> Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Asn Met His Trp Val Lys Gln Thr Pro Gly Arg Gly Leu Glu Trp Ile 35 40 45 Gly Ala Ile Tyr Pro Gly Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Thr Tyr Tyr Gly Gly Asp Trp Tyr Phe Asn Val Trp Gly 100 105 110 Ala Gly Thr Thr Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <![CDATA[<210> 19]]> <![CDATA[<211> 212]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 合成]]> <![CDATA[<400> 19]]> Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Tyr Ile 20 25 30 His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr 35 40 45 Ala Thr Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser Gly 50 55 60 Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu Asp 65 70 75 80 Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Pro Thr Phe 85 90 95 Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser 100 105 110 Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala 115 120 125 Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val 130 135 140 Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser 145 150 155 160 Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr 165 170 175 Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys 180 185 190 Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn 195 200 205 Arg Gly Glu Cys 210
Claims (11)
- 一種醣苷內切酶S2 (endoglycosidase, EndoS2)突變體,其於一野生型醣苷內切酶S2 (序列編號:1)序列中包含一或多個突變點,其中該一或多個突變點是位於殘基T228,其中該醣苷內切酶S2突變體的水解活性低於該野生型醣苷內切酶S2的水解活性,且該醣苷內切酶S2突變體的轉醣苷化活性高於該野生型醣苷內切酶S2的轉醣苷化活性。
- 如請求項1所述之醣苷內切酶S2突變體,其中該一或多個突變點包含T228Q。
- 如請求項1所述之醣苷內切酶S2突變體,其中該醣苷內切酶S2突變體包含序列編號: 5之序列。
- 一種使用如請求項1-3所述之任一種醣苷內切酶S2突變體來製備一經醣工程改造的醣蛋白之方法,包含將一活化寡醣耦合至一醣蛋白受體。
- 如請求項4所述之方法,其中該活化寡醣是一聚醣噁唑啉。
- 如請求項4所述之方法,其中該醣蛋白受體含有一GlcNAc單醣。
- 如請求項4所述之方法,其中該醣蛋白受體是一非海藻糖化GlcNAc-受體。
- 如請求項4所述之方法,其中該醣蛋白受體是一醣肽、一醣蛋白、一抗體或其片段。
- 如請求項4所述之方法,其中該醣蛋白受體為一核心海藻糖化或非海藻糖化之GlcNAc-IgG受體或其片段。
- 如請求項10所述之方法,其中該GlcNAc-IgG受體係源自一單株抗體,其是選自由西妥昔單抗(cetuximab)、利妥昔單抗(rituximab)、莫羅莫那-CD3(muromonab-CD3)、阿昔單抗(abciximab)、達昔單抗(daclizumab)、巴利昔單抗(basiliximab)、帕利珠單抗(palivizumab)、英夫利西單抗(infliximab)、曲妥珠單抗(trastuzumab)、吉妥單抗 奧佐米星(gemtuzumab ozogamicin)、阿來組單抗(alemtuzumab)、ibritumomab tiuxetan、阿達木單抗(adalimumab)、奧馬珠單抗(omalizumab)、托西莫單抗(tositumomab)、I-131 托西莫單抗(I-131 tositumomab)、依法利珠單抗(efalizumab)、貝伐單抗(bevacizumab)、帕尼單抗(panitumumab)、帕妥珠單抗(pertuzumab)、那他珠單抗(natalizumab)、依那西普(etanercept)、IGN101、伏洛昔單抗(volociximab)、抗-CD80 mAb、抗-CD23 mAb、CAT-3888、CDP-791、eraptuzumab、MDX-010、MDX-060、MDX-070、馬妥珠單抗、CP-675,206、CAL、SGN-30、扎木單抗(zanolimumab)、阿德木單抗(adecatumumab)、奧果伏單抗(oregovomab)、尼妥珠單抗(nimotuzumab)、ABT-874、地諾單抗(denosumab)、AM 108、AMG 714、芳妥珠單抗(fontolizumab)、達昔單抗(daclizumab)、利木單抗(golimumab)、CNTO 1275、奧瑞珠單抗(ocrelizumab)、HuMax-CD20、貝利單抗(belimumab)、依帕珠單抗(epratuzumab)、MLN1202、維西珠單抗(visilizumab)、托西珠單抗(tocilizumab)、ocrerlizumab、certolizumab pegol、艾庫組單抗(eculizumab)、沛瑟珠單抗(pexelizumab)、阿昔單抗(abciximab)以及蘭尼單抗(ranibizimumab)所組成之群組。
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CA2950577A1 (en) * | 2014-05-27 | 2015-12-03 | Academia Sinica | Fucosidase from bacteroides and methods using the same |
KR20220025721A (ko) * | 2019-08-05 | 2022-03-03 | 초 파마 인크. | 항체 글리코폼을 리모델링하기 위한 융합 단백질 |
TW202227479A (zh) | 2020-09-02 | 2022-07-16 | 日商第一三共股份有限公司 | 新穎內-β-N-乙醯葡萄糖胺苷酶 |
EP4337254A1 (en) * | 2021-05-11 | 2024-03-20 | Northeastern University | Site-specific modification of glycoproteins through transglutaminase-mediated conjugation |
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Title |
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Li et. al., "Glycosynthase Mutants of Endoglycosidase S2 Show Potent Transglycosylation Activity and Remarkably Relaxed Substrate Specificity for Antibody Glycosylation Remodeli" THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 291, NO. 32, pp. 16508–16518, June 7, 2016 Published * |
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TW202115251A (zh) | 2021-04-16 |
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IL264873B1 (en) | 2023-04-01 |
IL264873B2 (en) | 2023-08-01 |
US20180057804A1 (en) | 2018-03-01 |
CN110234341A (zh) | 2019-09-13 |
JP2020500549A (ja) | 2020-01-16 |
EP3532090A4 (en) | 2021-01-13 |
CA3034876A1 (en) | 2018-03-01 |
US10000747B2 (en) | 2018-06-19 |
KR20190039580A (ko) | 2019-04-12 |
AU2017315677B2 (en) | 2021-03-11 |
TW202117012A (zh) | 2021-05-01 |
CA3034876C (en) | 2022-10-04 |
EP3532090A1 (en) | 2019-09-04 |
AU2017315677A1 (en) | 2019-04-11 |
IL264873A (zh) | 2019-04-30 |
TWI727883B (zh) | 2021-05-11 |
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