TW201706312A - 用以治療疾病的分子構建體 - Google Patents
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Abstract
本揭示內容提出了多種分子構建體,這些分子構建體具有一標的元件與一效應元件。此處亦揭示了利用所述分子構建體來治療多種疾病的方法。
Description
本揭示內容是關於藥學領域;更明確地說,是關於多功能的分子構建體,譬如具有標的元件與效應元件以將效應元件(如治療藥物)遞送至標的部位的分子構建體。
近年來,本領域發展出多種篩檢與選擇以抗原為標的之單株抗體(monoclonal antibodies,mAbs)的方法,進而帶動許多治療用抗體的研發,為一些不久前還被認為是不治之症的疾病帶來曙光。根據治療性抗體資料庫(Therapeutic Antibody Database)的統計,有多達2,800種左右的抗體已經或即將投入人體臨床試驗研發,而由政府藥物管理機構核准可用於臨床治療的抗體則約有80種。從與抗體療效相關的大量數據中可知抗體是基於何種藥理機制而發揮療效。
以抗體作為治療藥劑時,其主要的藥理機制是以抗體來中和或誘捕造成疾病的介質;所述介質可能是存在於血液循環、間質空間(interstitial space)或淋巴結中的細胞介素或免疫成分。中和所述介質的活性可抑制造成疾病的介質和其受體之間的互動。此外,可將細胞介素的可溶性受體或受體的細胞外部分和免疫球蛋白IgG的Fc部分製成融合蛋白,此種融合蛋白可利用類似中和抗體的機制來中和上述細胞介素或免疫因子;因此目前也開發出多種融合蛋白治療劑。
另外,某些取得臨床使用許可或正在進行臨床研究的治療性抗體則是採用了與上述主要抗體機制不同的機制,來發揮其藥理作用,譬如可藉由和受體結合以阻斷這些受體和其配體之間的互動。對此類抗體藥物來說,其主要的藥理機制並非由Fc-介導的機制(如抗體依賴性細胞毒性(antibody-dependent cellular cytotoxicity,ADCC)或是補體介導的細胞溶解(complement-mediated cytolysis,CMC)等)。
另一些治療性抗體可和目標細胞上的某些表面抗原結合,並藉此在目標細胞上發揮Fc介導的功能以及其他機制。最重要的Fc介導的機制為抗體依賴性細胞毒性(ADCC)以及補體介導的細胞溶解(CMC),這兩種機制都會將與抗體結合的目標細胞溶解。這些抗體和特定的細胞表面抗原結合後,可使得與其結合的目標細胞發生細胞凋亡。
製備具有雙重專一性的抗體的概念與方法,早在三十年前就已萌芽。近年來,隨著重組抗體工程方法的進步、以及對於更好藥物的需求驅使下,發展出多種具有不同結構構形的雙專一性抗體。
舉例來說,雙價或多價抗體可能帶有二或更多種抗原結合位。已知有多種方法可用以製備多價抗體,這些方法通常利用連接結構將三或四種抗原結合片段(antigen-binding fragment,Fab)共價連接在一起。舉例來說,已透過重組工程製備出能表現三或四個串聯(tandem)的Fab重複片段的抗體。
此外,利用合成的交聯物(crosslinker),透過化學方法將不同的抗體或結合部位連接在一起,以製造出多價抗體的方法也是本領域公知的技術。其中一種方式是利用不同的接合物(linker),將三、四或更多個分離的Fab片段,透過化學交聯的方式彼此接合。另一種方式是先製備一個具有多個Fab的構建體,將這些Fab組裝成一維的DNA支架(one-dimensional DNA scaffold)。這些經設計可和目標分子結合的各種多價抗體構建體彼此的尺寸、半衰期、構形彈性以及調節免疫系統的能力各不相同。
基於以上說明,已有部分研究著眼於製備效應元件數目固定的分子構建體或具有二或更多種不同功能性元件(譬如至少一標的元件與至少一效應元件)的分子構建體。然而,通常很難利用化學合成或重組技術等方法,來建立具有特定標的與效應元件組合的分子構建體。因此,本領域亟需一種新穎的分子平台,其可用以建構適用於多種疾病的各種分子。
發明內容旨在提供本揭示內容的簡化摘要,以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述,且其用意並非在指出本發明具體實施例的重要/關鍵元件或界定本發明的範圍。發明內容的唯一目的在於對此處揭示的某些概念提供簡化的說明,以利理解後文所述的實施方式。
< I >
用以治療中樞神經系統疾病的分子構建體及其用途
本揭示內容的此一態樣是關於以可結晶片段(fragment crystallizable,Fc)為基礎的分子構建體(下文稱為Fc型分子構建體),其具有直接或間接連接到免疫球蛋白CH2-CH3區域的至少一標的元件與至少一效應元件。藉由審慎選擇所述Fc型分子構建體的標的與效應元件,所得到的Fc型分子構建體可用以治療中樞神經系統(central nerveous system,CNS)疾病,或可用以製備用於治療CNS疾病的藥物。當可想見,利用此種Fc型分子構建體來治療CNS疾病的方法亦屬於本揭示內容的一種態樣。
根據本揭示內容某些實施方式,Fc型分子構建體包含一對IgG.Fc的CH2-CH3區段、一對效應元件及一對標的元件。成對的效應元件可以是干擾素β1a (interferon β1a,INF-β1a)或干擾素β1b (INF-β1b)或是對整合素α4 (integrin α4)或β-類澱粉蛋白(β-amyloid)專一的抗體片段,而成對標的元件則可以是對人類運鐵蛋白受器或人類胰島素受器專一的抗體片段。
當成對效應元件連接於成對CH2-CH3區段的N-端時,成對標的元件則連接於成對CH2-CH3區段的C-端,反之亦然。或者是,當成對效應元件與成對標的元件都是單鏈可變片段(single-chain variable fragment,scFv)的形式時,則成對標的元件以串聯雙抗體(tandem)或雙抗體(diabody)的構形而連接於成對效應元件的N-端,因而形成一對連接於成對CH2-CH3區段N-端的雙專一性scFv。
於一些實施方式中,該成對CH2-CH3區段衍生自人類IgG重鏈γ4或人類IgG重鏈γ1。
在某些例子中,成對的效應元件或成對的標的元件形成抗原結合片段(antigen-binding fragment,Fab)的構形(即,由VH
-CH1區域以及VL-Cκ區域所組成);此種Fab片段連接於第一與第二重鏈的N-端,而使得Fc型分子構建體形成IgG構形。在這些情形中,未採用Fab構形的該對元件則連接於成對CH2-CH3區段的C-端。
根據某些視需要而採用的實施方式,所述效應元件是INF-β1a、INF-β1b或對整合素α4專一的scFv,而所述標的元件則是對人類運鐵蛋白受器專一的scFv。具體來說,此一分子構建體可用以治療多發性硬化症。
根據其他視需要而採用的實施方式,所述效應元件是對β-類澱粉蛋白專一的,而所述標的元件則是對人類運鐵蛋白受器專一的scFv。具體來說,此種分子構建體適用於治療阿滋海默症。
用以對有需要的個體治療CNS疾病的方法包含以下步驟:對所述個體投予有效量的本態樣之分子構建體。適用於此一治療方法的CNS疾病包括多發性硬化症與阿滋海默症。
< II >
用以治療感染性疾病的分子構建體
本揭示內容的此一態樣是關於一種Fc型分子構建體,此種Fc型分子構建體具有直接或間接地連接到免疫球蛋白的CH2-CH3區域的至少一標的元件與至少一效應元件。藉由選擇本發明Fc型分子構建體的效應元件與標的元件,所述分子構建體可用於治療多種與病毒或細菌感染相關的疾病/症狀,或可用以製備用於治療所述感染疾病/症狀的藥物。當可想見,利用此種Fc型分子構建體來治療病毒或細菌感染的方法亦屬於本揭示內容的一種態樣。
根據本揭示內容多種實施方式,所述Fc型分子構建體包含一對IgG.Fc的CH2-CH3區段、一對效應元件及一對標的元件。成對效應元件是對CD32或CD16b專一的抗體片段,而成對標的元件則是對病毒蛋白或細菌蛋白專一的抗體片段。
當成對效應元件連接於成對CH2-CH3區段的N-端時,成對標的元件則連接於成對CH2-CH3區段的C-端,反之亦然。或者是,當成對效應元件與成對標的元件都是單鏈可變片段(single-chain variable fragment,scFv)的形式時,則成對標的元件以串聯雙抗體(tandem)或雙抗體(diabody)的構形而連接於成對效應元件的N-端,因而形成一對連接於成對CH2-CH3區段N-端的雙專一性scFv。
於一些實施方式中,上述成對的CH2-CH3區段是衍生自人類IgG重鏈γ4或人類IgG重鏈γ1。
在某些例子中,成對的效應元件或成對的標的元件形成抗原結合片段(antigen-binding fragment,Fab)的構形(即,由VH
-CH1區域以及VL
-Cκ區域所組成);此種Fab片段連接於第一與第二重鏈的N-端,而使得Fc型分子構建體形成IgG構形。在這些情形中,未採用Fab構形的該對元件則連接於成對CH2-CH3區段的C-端。
根據某些視需要而採用的實施方式,效應元件是對CD32或CD16b專一的scFv,而標的元件則是對病毒蛋白專一的scFv。譬如,病毒蛋白可以是呼吸道融合病毒(respiratory syncytial virus,RSV)的F蛋白、人類免疫缺陷病毒第I型(human immunodeficiency virus type 1 HIV-1)的gp120蛋白、A型流感病毒(influenza A virus)的血球凝集素A (hemagglutinin A,HA)蛋白或巨細胞病毒(cytomegalovirus)的醣蛋白。具體來說,此種分子構建體適用於治療病毒感染。
根據其他視需要而採用的實施方式,效應元件是對CD32或CD16b專一的scFv,而標的元件則是對細菌蛋白專一的scFv。而細菌蛋白的實施例包括但不限於:革蘭氏陰性菌(Gram(-) bacteria)的內毒素(endotoxin)、困難梭狀芽孢桿菌(Clostridium difficile
)的表面抗原、金黃葡萄球菌(Staphylococcus aureus
)的壁脂酸(lipoteichoic acid)、炭疽桿菌(Bacillus anthracis
)的炭疽毒素(anthrax toxin)或大腸桿菌(Escherichia coli
)的第I型或第II型類志賀毒素(Shiga-like toxin type I or II)。具體來說,此種分子構建體適用於治療細菌感染。
用以對有需要的個體治療與感染(如,病毒與細菌感染)相關的疾病/症狀的方法包含以下步驟:對所述個體投予有效量的本態樣之分子構建體。
為了使本揭示內容的敘述更加詳盡與完備,下文針對了本發明的實施態樣與具體實施例提出了說明性的描述;但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而,亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
為了便於說明,此處整理了說明書、實施例與附隨申請專利範圍中所用的某些詞彙。除非本說明書另有定義,此處所用的科學與技術詞彙的含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。
在不和上下文衝突的情形下,本說明書所用的單數名詞涵蓋該名詞的複數型;而所用的複數名詞時亦涵蓋該名詞的單數型。此外,在本說明書與申請專利範圍中,「至少一」與「一或更多」等表述方式的意義相同,兩者都代表包含了一、二、三或更多。更有甚者,在本說明書與申請專利範圍中,「A、B及C其中至少一者」、「A、B或C其中至少一者」以及「A、B和/或C其中至少一者」係指涵蓋了僅有A、僅有B、僅有C、A與B兩者、B與C兩者、與C兩者、以及A、B與C三者。
雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值,此處已盡可能精確地呈現具體實施例中的相關數值。然而,任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處,「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是,「約」一詞代表實際數值落在平均值的可接受標準誤差之內,視本發明所屬技術領域中具有通常知識者的考量而定。當可理解,除了實驗例之外,或除非另有明確的說明,此處所用的所有範圍、數量、數值與百分比(例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此,除非另有相反的說明,本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值,且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。在此處,將數值範圍表示成由一端點至另一端點或介於二端點之間;除非另有說明,此處所述的數值範圍皆包含端點。
本揭示內容一般係關於多種分子構建體,其中每一分子構建體包含一標的元件(T)與一效應元件(E),在本說明書中有時將這些分子構建體稱為「T-E分子」、「T-E藥物」或「T-E藥品」。
在此處,「標的元件(targeting element)」一詞係指分子構建體能夠直接或間接結合到一目標標的(如,一細胞表面上的受體或一組織中的蛋白質)的部分,因而能夠協助將本發明分子構建體遞送到目標標的。在某些例子中,標的元件可將所述分子構建體導引至鄰近目標細胞處。在其他情形中,標的元件可專一地結合到目標細胞表面上的分子;或標的元件可和第二分子專一地結合,而此一第二分子能夠專一地結合到目標細胞表面上的分子。在某些例子中,一旦標的元件與目標標的接合之後,標的元件可將本發明分子構建體內化,而使其移動到目標細胞的細胞質內。標的元件可以是細胞表面受體的抗體或配體;或者是可和上述抗體或配體結合的分子,因而能夠間接地將本發明分子構建體標的到目標部位(譬如所選定的細胞表面)。相較於沒有標的功能的治療藥物,利用本發明分子構建體能夠加強或有利於效應元件(治療藥劑)在疾病部位的局部化(localization)。上述局部化是一種程度或相對的比例,而不是讓效應元件在疾病部位絕對或完全的局部化。
根據本發明,「效應元件(effector element)」一詞係指一旦分子構建體到達目標部位後,所述分子構建體中能夠發揮生物活性(譬如,誘發免疫反應、發揮細胞毒性及與其相似者)或其他功能活性(譬如招募其他經半抗原標記的治療用分子)的部分。「效應」可指治療性或診斷性的效果。效應元件包含能夠和細胞和/或細胞外免疫調節因子結合的元件。上述效應元件包含如蛋白質、核酸、脂質、碳水化合物、醣蛋白、藥物部分(包含小分子藥與生物製劑)、化合物元素及同位素等物質,也包含上述物質的片段。
雖然在此處利用「第一」、「第二、「第三」等詞彙來描述多種元件、部件、區域和/或區段,這些元件(以及部件、區域和/或區段)不受上述修飾詞的限制。此外,除非上下文有明示的說明,使用這些序數並未隱含序列或順序。反之,這些詞彙僅是用來區分各元件。因此,亦可將下文所述的第一元件命名為第二元件,而不會悖離例示性實施方式所揭示的內容。
在此處,「連接(link)」、「耦接(couple)」以及「複合(conjugate)」等詞可互換使用,且都是用來指稱透過直接或間接的連接關係,將兩個元件連接在一起。
「多肽(polypeptide)」一詞在此係指具有至少兩個胺基酸殘基的聚合物。一般來說,多肽包含2到200個胺基酸殘基;在較佳的情形中,是2到50個殘基。在本說明書中所提及的胺基酸序列涵蓋了此種序列的L-、D-或β-胺基酸等形式。多肽亦包括胺基酸聚合物,其中有一或多個胺基酸殘基是與一天然胺基酸相應的人工化學類似物,當然也包括天然產生的胺基酸聚合物。此外,此一詞彙亦涵蓋以多肽鏈或其他方式連接的胺基酸,上述其他方式如經修飾的連接(modified linkage),譬如以α-酯(α-ester)、β-酯(β-ester)、硫醯胺(thioamide)、磷醯胺(phosphoramide)、氨基甲酸酯(carbomate)、羥基酯(hydroxylate)鍵、以及與其相似者來取代多肽鍵。
於一些實施方式中,本發明範圍亦涵蓋了其他相較於所述序列具有保守性置換的蛋白。於多種實施方式中,有一、二、三、四或五個不同的殘基經過置換。在此處,「保守性置換(conservative substitution)」一詞是指所述胺基酸置換不會明顯地改變分子活性(譬如生物或功能活性和/或專一性)。一般來說,保守性胺基酸置換是利用另一種具有相似化學性質(如電荷或疏水性)的胺基酸來取代某一胺基酸。某些保守性置換包括「類似物置換」,亦即以非標準(如罕見或合成等)胺基酸來取代標準胺基酸,而上述非標準胺基酸和被取代的原有胺基酸之間的差異極小。可由標準胺基酸經人工修飾而在不會大幅改變原有胺基酸結構的前提下,得到所述的胺基酸類似物,譬如異構物或代謝前驅物等皆屬之。
於一些實施方式中,本案的範圍亦涵蓋和任何所述序列具有至少80%序列相似度的任何序列,上述序列相似度較佳為至少85%或90%、更佳為至少95%或98%。
此處針對多肽序列所述的「胺基酸序列相似度百分比(Percentage (%) amino acid sequence identity)」係指候選序列的胺基酸殘基與參考多肽序列的胺基酸殘基完全相同的百分比;於進行上述比對時,可將所述的候選多肽片段與所述的特定多肽片段並排,並於必要時引入間隙,以使二序列形成最高的序列相似度;在計算相似度時,保守性置換的胺基酸殘基視為不同的殘基。相關領域已有多種方法可用以進行上述並排,譬如可公開取得的軟體如BLAST、BLAST-2、ALIGN或Megalign (DNASTAR)等。本發明所屬技術領域中具有通常知識者在進行並排時,可選擇適當的參數與計算方式,以得到最佳的排列方式。在本說明書中,二多肽序列間的序列比較是採用美國國家生物科技資訊中心(Nation Center for Biotechnology Information,NCBI)所提供的蛋白質-蛋白質BLAST分析資料庫Blastp來進行。候選多肽序列A相較於參考多肽序列B的胺基酸序列相似度(在本說明書中亦稱之為多肽序列A與多肽序列B具有特定百分比(%)的胺基酸序列相似度)的計算方式如下:% 其中X是利用BLAST序列並排程式對序列A、B進行排列後所得到的相同胺基酸殘基數目(identical matches),而Y是A、B二序列中較短者的胺基酸殘基總數。
「聚乙二醇化胺基酸(PEGylated amino acid)」一詞在此係指帶有一個胺基(amino group)與一個羧基(carboxyl group)的聚乙二醇(polyethylene glycol,PEG)鏈。一般來說,聚乙二醇化胺基酸的結構式為NH2
-(CH2
CH2
O)n
-COOH。在本揭示內容中,n值介於1到20之間;較佳是介於2至12。
在此處一多肽的「端」係指位於該多肽N-或C-端點的胺基酸殘基。在描述一聚合物(譬如此處所述的聚乙二醇)的組成單元時時,「端」則是指在聚合物骨架末端的部分。在本說明書與申請專利範圍中,「自由端」一詞是用來指稱並未與另一個分子形成化學鍵結的末端胺基酸殘基或構成單元。
「抗原(antigen或Ag)」一詞係指能夠導致免疫反應的分子。此種免疫反應可能涉及分泌性(secretory)、荷爾蒙性(humoral)和/或細胞級(cellular)的抗原專一反應。在本揭示內容中,「抗原」一詞係指蛋白質、多肽(包括其突變株或具有生物活性的片段)、多醣、醣蛋白、醣脂質、核酸或上述之組合。
在本說明書與申請專利範圍中,「抗體(antibody)」一詞應以廣義方式解釋,且包含完整組裝的抗體、可和抗原結合的抗體片段,譬如抗原結合片段(Fab/Fab’)、F(ab’)2
片段(具有彼此以雙硫鍵連接的兩個Fab部分)、可變片段(variable fragment,Fv)、單鏈可變片段(scFv)、雙專一性單鏈可變片段(bi-scFv)、奈米抗體(nanobodies)、單抗體(unibodies)以及雙體抗體(diabodies)。「抗體片段」包含完整抗體的一部分,較佳為包括完整抗體的抗原結合區域或可變區域。在典型的例子中,「抗體」係指實質上由免疫球蛋白基因或其片段所編碼的一或多種多肽所組成的蛋白質。習知的免疫球蛋白基因包括κ (kappa)、λ (lambda)、α (alpha)、γ (gamma)、δ (gamma)、ε (epsilon)與μ (mu)等恆定區基因(constant region gene)、以及無數的免疫球蛋白可變區基因(variable region genes)。輕鏈通常歸類為κ (kappa)或λ (lambda)。重鏈通常歸類為γ (gamma)、μ (mu)、α (alpha)、δ (gamma)或ε (epsilon),基於這些結構,定義出了以下類型的免疫球蛋白:IgG、IgM、IgA、IgD以及IgE。典型的免疫球蛋白抗體結構是一種四聚物(tetramer)。每一個四聚物是由兩條相同的多肽鏈所組成,且每一對分別有一「輕」鏈(約25 kDa)與一「重」鏈(約50-70 kDa)。每一鏈的N-端界定了一個可變區域,包含約100至110個或更多的胺基酸,其主要負責抗原辨識。可變輕鏈(variable light chain,VL
)與可變重鏈(variable heavu chain,VH
)等詞就是分別指上述的輕鏈與重鏈。根據本揭示內容的實施方式,可藉由改變天然抗體或利用重組DNA方式重新合成上述抗體片段。於本揭示內容一些實施方式中,上述抗體和/或抗體片段可具有雙專一性,且可有多種不同的構形。舉例來說,雙專一性抗體可包含二個不同的抗原結合部位(可變區域)。於多種實施方式中,可利用融合瘤技術或重組DNA技術來製備雙專一性抗體。於一些實施方式中,雙專一性抗體對至少兩種不同的表位(epitope)有結合專一性。
「專一地結合(specifically bind)」一詞在此處係指抗體或其抗原結合片段能夠和抗原結合的能力,上述結合的解離常數(dissociation constant,Kd)小於約1×10− 6
M、1×10− 7
M、1×10− 8
M、1×10− 9
M、1×10− 10
M、1×10− 11
M或1×10− 12
M;或者是或額外地,相較於其對於非專一性抗原的結合親和力,上述抗體或其抗原結合片段與抗原結合的親和力為兩倍以上。
「治療(treatment)」一詞係指預防性(如,預防用藥)、療癒性或緩和性的處置,藉以達到所欲的藥學和/或生理學效果;而治療的行為在此包括上述預防性、療癒性或緩和性的處置。具體來說,治療在此係指對於可能患有一醫療疾患、症狀、疾病或與疾患相關的異常、或易於罹患一疾患的個體施用或投予本發明分子構建體或包含此分子構建體的藥學組合物,以期能部分地或完全地緩和、改善、減輕特定異常和/或病症的一或多種症狀或特徵,或是延緩其發生、阻礙其進展、減輕其嚴重性和/或減低發生率。亦可對尚未表出現疾病、異常和/或病症徵兆的個體和/或出現早期徵兆的個體進行治療,以期降低發展出與該疾病、異常和/或病症相關的病理變化的風險。
在此處,「有效量(effective amount)」一詞係指本發明分子構建體的用量足以招致所欲的治療反應。藥劑的有效量不必然能夠治癒疾病或病症,但能夠延緩、阻礙或防止該疾病或病症的發生,或是可緩減與疾病或病症相關的病徵。可將治療有效量可分成一、二或更多劑,而以適當的劑型在指定期間內施用一次、二次或更多次。具體的治療有效量取決於多種因素,例如欲治療的特定狀況、個體的生理條件(如,個體體重、年齡或性別)、接受治療的個體類型、治療持續時間、併行治療(如果有的話)的本質以及所用的具體配方和化合物或其衍生物的結構。舉例來說,可將治療有效量表示成活性成分的總重量,譬如以克、毫克或微克來表示;或表示成活性成分重量相對於體重的比例,譬如表示為每公斤體重多少毫克(mg/kg)。
所述「施用(application)」與「投予(administration)」等詞在此可交替使用,其係指將本發明之分子構建體或藥學組合物提供給需要治療的個體。
「個體(subject)」或「患者(patient)」等詞在此可交互使用,且是指可接受本揭示內容之分子構建體、藥學組合物和/或方法處置的動物(包含人類)。除非另有指明,「個體」或「患者」一般包含雄性與雌性。「個體」或「患者」包含任何可因本揭示內容的處置而獲益的哺乳類動物。所述「個體」或「患者」的例示包含,但不限於:人類、大鼠、小鼠、天竺鼠、猴子、豬、山羊、牛、馬、狗、貓、鳥和禽類。在一實例中,所述患者為人類。所述哺乳類動物涵蓋哺乳動物綱的所有成員,包括人類、靈長類動物、家畜和農畜(如兔子、豬、綿羊和牛)、動物園動物或競賽用動物、寵物,以及齧齒類動物(如,小鼠和大鼠)。「非人類哺乳動物」一詞則涵蓋除了人類以外的所有哺乳動物綱成員。
本揭示內容至少部分是基於建構出了T–E藥物,此種T-E藥物可被遞送至目標細胞、目標組織或器官,且其在這些部位的比例相對高於在血液循環、淋巴系統以及其他細胞、組織和器官中的比例。當實現上述情境時,即可提升T-E藥物的療效,且其副作用與毒性的數目和嚴重性都會降低。相較於不含標的元件的藥物,以T-E分子的形式來投遞藥物時,發揮療效的效應物所用的濃度可能較低。因此,可在較低的劑量下施用治療用的效應物而不會減損其有效性,但卻能同時降低其副作用與毒性。
可因較佳藥物標的而獲益的疾病
若是可將藥物標的到疾病部位,亦即若是可使藥物在疾病部位(相對於在正常組織或器官)局部化或有較優勢的濃度,就能夠改善用以治療許多疾病的藥物,使其具備較佳的療效與安全性。某些抗體藥物是以感染性微生物或其毒素產物為標的,若使這些抗體藥物具備招募免疫細胞的能力,以吞噬或清除與抗體結合的粒子,就能夠提升其療效。下文提出一些主要的例示性疾病,若是能使得這些疾病所用藥物在疾病部位或細胞有較佳的分布比例或能夠招募可吞噬細胞的免疫細胞,就可以改善這些藥物。
I
中樞神經系統疾病
於治療中樞神經系統(CNS)疾病時,通常需要讓治療藥劑通過血腦障礙(blood-brain barrier,BBB)以進入中樞神經系統。某些治療藥劑不會進入中樞神經系統;此類藥物藉由調節周邊的某些活性(如免疫活性),再藉由這些活性進一步調控中樞神經系統中的病況。BBB是由襯接CNS中微血管的內皮細胞所形成。和周邊組織與器官中的微血管不同,BBB中的微血管內皮細胞是由緊連蛋白(occludin)、密連蛋白(claudin)與間隙連接(junctional adhesion)分子形成的緊密連接(tight junction)將其連接在一起。
β-類澱粉蛋白是引發阿滋海默症的主因之一,目前臨床應用中已開發出至少六種對β-類澱粉蛋白專一的抗體,分別是:阿度卡尼單抗(aducanumab)、巴匹珠單抗(bapineuzumab)、克雷內治單抗(crenezumab)、蓋坦德單抗(gantenerumab)、拍珠單抗(ponezumab)與蘇蘭珠單抗(solanezumab)。這些抗體對於改善阿滋海默症的療效通常未臻理想。據信這是因為若要讓這些抗體發會療效,必須要有非常大量的抗體通過BBB進入CNS中的受損部位才行。然而,只有非常少量的抗體能夠通過BBB。
已知可運用干擾素-β-1a (IFN-β-1a)與干擾素-β-1b (IFN-β-1b)來治療多發性硬化症(MS)。IFN-β-1a是由哺乳類細胞所生產,而IFN-β-1b則是由大腸桿菌所生產;這些藥品是由166個胺基酸殘基所組成的單鏈蛋白,其帶有一個雙硫鍵。據稱上述治療藥劑可使受治療患者的MS復發率降低至18-38%。IFN-β-1a與IFN-β-1b的作用機制非常複雜且並未完全為研究人員所瞭解,其過程涉及了抗發炎免疫細胞與因子的正向調控以及促發炎T細胞與因子的負向調控。對MS患者施予IFN-β治療也會降低通過BBB的促發炎T細胞數量。但目前仍不明瞭IFN-β-1a與IFN-β-1b是否至少部分藉由進到CNS中的受損部位而發揮其藥效。
當將抗體或蛋白藥物施用至身體的周邊系統中時,僅有一小部分(約0.1%)會到達CNS,因為只有很小一部分的蛋白藥物能夠穿透BBB。然,已知在許多CNS疾病(包括阿滋海默症與多發性硬化症)中,在患病部位的發炎反應會使得BBB防線崩解,進而提升該部位的通透性。因此,本發明認為若可將較為大量的抗β-類澱粉蛋白或IFN-β-1a與IFN-β-1b抗體導引至BBB,治療藥劑就有較高的機會通過BBB進而提升療效。
更有甚者,已開發出一些治療藥劑能用以抑制發炎性免疫細胞通過BBB。最著名的例子之一就是對細胞黏著分子整合素α4專一的那他珠單抗(natalizumab)。所述抗體能夠抑制發炎性免疫細胞附著到襯接內皮層的BBB並穿透BBB,進而發揮其功能。雖然已證實那他珠單抗有一定的療效,但此種藥物有嚴重的免疫抑制副作用。具體來說,那他珠單抗會導致進行性多處腦白質病(progressive multifocal leukoencephalopathy),這是由JC病毒(John Cunningham virus)引發的伺機性感染。因此,本發明認為若能將大量的抗整合素α4抗體招募至BBB,就可以在較低給藥劑量下達到較佳的療效,因而可降低副作用。
形成BBB的微血管中的內皮細胞能夠表現運鐵蛋白受器與胰島素受器,這些受器可分別調控運鐵蛋白與胰島素分子的胞吞轉送作用(transcytosis)而使其到達大腦薄壁(cerebral parenchyma)。當使用運鐵蛋白受器作為運輸通道時,僅有一小部分可穿透而剩餘的絕大多數都會被困住或降解。因為在脈管系統其他部分中襯接微血管的內皮細胞不會表現運鐵蛋白受器,BBB中內皮細胞上的運鐵蛋白受器可作為部位專一的抗原,而能夠用以招募所投予的治療藥劑。一旦治療藥劑集中在BBB中,就會有較高比例的治療藥劑能夠穿透微血管。
本發明亦體認到,一旦建立了將藥物導向至BBB的機制,就可以進一步探討利用各種抗發炎藥物來治療多種CNS疾病的療效;上述藥物譬如抗TNF-α、抗-IL12/IL-23、抗-IL17以及抗CD3。
對於對整合素α4專一的抗體藥物,可利用運鐵蛋白受器作為目標部位招募者。於治療阿滋海默症時,效應部分可以是數個對β-類澱粉蛋白專一的scFv;於治療多發性硬化症時,效應部分可以是數個IFN-β-1a或IFN-β-1b或數個對整合素α4專一的scFv。
本揭示內容的多種實施方式揭示了數種T-E分子,這些分子可以是單一個多臂接合物構形或是聯合接合物(joint-linker)構形,其各自帶有對運鐵蛋白受器專一的scFv (作為標的元件)以及IFN-β-1a或IFN-β-1b或對整合素α-4專一的scFv (作為效應元件)。替代性的實施方式揭露了多種T-E分子,這些分子可以是單一個多臂接合物構形或是聯合接合物構形,其各自帶有對運鐵蛋白受器專一的scFv (作為標的元件)以及對β-類澱粉蛋白專一的scFv (作為效應元件)。
芬戈莫德是一種免疫抑制藥物,這是一種分離自某些真菌的天然產物—多球殼菌素(myriocin)的衍生物。芬戈莫德已取得許可能用以減少復發-緩解型多發性硬化症的復發。在活體內,芬戈莫德會被磷酸化以形成芬戈莫德磷酸鹽,其結構與天然存在的神經鞘胺醇-1-磷酸鹽(sphingosine-1-phosphate,S1P)相似;芬戈莫德磷酸鹽是一種細胞外脂質介質,且可和5種S1P受器中的4種結合。S1P受器表現於淋巴細胞上,且參與了淋巴細胞遷移。芬戈莫德常見的藥理機制之一是抑制淋巴細胞離開淋巴樣組織而進入循環(並因此進入CNS)。芬戈莫德可以穿過BBB而進入CNS,且CNS中許多類型的細胞會表現S1P受器,這些受器與細胞擴增、型態與遷移等作用相關。據信芬戈莫德可直接作用於CNS上。施用芬戈莫德所導致的常見副作用包括頭痛、疲勞;也會造成嚴重的副作用如皮膚癌、黃斑部水腫與致命的感染(如出血性局部腦炎)。
一個芬戈莫德分子帶有一個NH2
基,可透過此官能基和帶有NHS基的雙功接合臂耦接。根據本揭示內容的一較佳實施方式,可製備一T-E構建體,其帶有一標的元件可將構建體遞送至BBB,並帶有一芬戈莫德的載藥束以作為效應元件。對於芬戈莫德載藥束,一接合單元中可加入5至10個芬戈莫德分子;譬如可利用可裂解接合臂(cleavable linker)或不可裂解合臂(non-cleavable linker)將芬戈莫德分子耦接至接合單元的連接臂。由於患者攝入芬戈莫德之後,會將其轉換成活性形式的芬戈莫德磷酸鹽(類似S1P),因此也可利用芬戈莫德磷酸鹽來製備載藥束。可將帶有芬戈莫德或芬戈莫德磷酸鹽載藥束的接合單元耦接上一或兩個對運鐵蛋白受器I專一的scFv。在施用所述分子構建體之後,一部分的分子構建體會被帶到BBB。從可裂解接合臂上釋出的芬戈莫德分子可通過BBB並進入CNS。或者是,有部分完整的構建體可進入CNS。可運用多種裂解機制來設計可裂解接合臂。一種常見的方式是加入S-S鍵,在標的組織部位可藉由還原反應使S-S雙硫鍵裂解。在接合物設計的領域中,另一種常用的可裂解鍵是使用胺基酸之間對於蛋白酶(如基質金屬蛋白酶)敏感的多肽鍵。
II
感染性疾病
雖然已針對各種會對人類或動物造成嚴重感染的病毒、細菌與真菌製備出大量的單株抗體,卻只有為數不多的單株抗體經許可能夠作為預防性或治療性藥物來對抗感染。此一不足可歸因於幾個主要因素,其中最主要的一個是這些感染性微生物及其產物有多種不同的血清型,且對於特定抗體會有不同的反應程度。另一個原因是所標的之微生物會發生突變,因而躲過特定抗體所引發的反應。
本發明提出的T-E分子設計亦可用於預防與治療感染性疾病。複數個連接臂可提升其對標的感染性微生物或其產物的結合親和力與專一性,並可誘發免疫功能以利廓清微生物及其產物。本發明認為提升結合親和力以及招致免疫廓清功能能夠在某種程度上克服血清型差異與突變的問題。此種改良能夠提升候選抗體預防與治療感染性疾病的效果。可根據本發明來重新設計許多在臨床試驗中無法達到預期效果的抗體,並再次測試其效果。
本發明一組較佳的實施方式使用了聯合接合物構形,其帶有一個用於標的之接合單元、以及一個用於招募效應功能的接合單元。另一組較佳的實施方式使用了單一接合單元,其具有複數個連接臂以供連接標的元件、以及一個耦合臂以供連接效應元件。所述標的元件可以是以下兩大類中的任一種:(1)對微生物表面成分或微生物的產物專一的scFv或sdAb,譬如人類免疫缺陷病毒第I型(HIV-1)的膜蛋白gp120、呼吸道融合病毒(RSV)F蛋白、困難梭狀芽孢桿菌或金黃葡萄球菌的表面抗原、或是革蘭氏陰性菌的內毒素或大腸桿菌的類志賀毒素;或(2)病毒的細胞表面受器的細胞外部分,譬如HIV-1的gp120-結合CD4域。
效應元件可以是一或兩個對IgG的Fc受器專一的scFv或sdAb;上述受器譬如:FcγRIIA (CD32)、FcγRIIIB (CD16b)或FcγRI (CD64)。這些受器表現於嗜中性白血球、巨噬菌體與嗜伊紅白血球上,且是調控與抗體結合之微生物的吞噬作用的主要分子。FcγRIIA與FcγRIIIB可和IgG結合,但親和力較低(Kd約為10-6
至10-7
);而FcγRI可和IgG1與IgG3結合,且親和力較高(Kd約10-9
)。在較佳的情形中,可使用對FcγRIIA或FcγRIIIB專一的scFv或sdAb,因為這些分子在和IgG競爭與受器結合時較有優勢。
對細菌表面上的碳水化合物抗原專一的抗體通常親和力不佳,且主要表現於IgM上而非IgG上。IgM分子有10個Fv (抗原結合部位)。然而,一個IgM分子的分子量約為1,000 kDa,其無法穿過微血管而到達血管外空間。當使用本發明提出的構形時,帶有六個scFv或10個sdAb的分子構建體的分子量約為150 kDa。
於使用抗體藥物來消滅病毒時,關鍵之一在於藥物不能引發透過FcR介導進而促進病毒感染。在這類情形中,結合後的病毒粒子不會被吞噬與消化。有些病毒(譬如登革熱病毒)在吞噬細胞內會擴增。因此,若病毒粒子能夠接近細胞並進入結合後的細胞而不會被消滅,病毒就可在受感染細胞內擴增。因此,根據本發明一組較佳的實施方式,所述分子構建體帶有二或更多個對Fcγ受器專一的scFv,其可和吞噬細胞表面上多個Fcγ受器分子結合,而使得結合後的病毒分子必定會進入吞噬作用路徑中。
已有多種對病毒、細菌或其產物專一的抗體進入臨床試驗,但只有一種對RSV專一的抗體取得上市許可。即使是上述對於RSV專一的抗體,經許可的用途也僅限於預防而無法用以治療正在發生中的感染。本領域亟需設計出能夠用以治療已受感染的個體的抗-RSV抗體。其他抗體仍在臨床開發階段,或無法通過臨床試驗。利用本發明提出的分子構建體平台,可以使用這些抗體並改良其藥效。所述抗體至少包括以下抗體: (1) 對呼吸道融合病毒F蛋白專一的帕利珠單抗(palivizumab)與非維珠單抗(felvizumab); (2) 對人類免疫缺陷病毒第I型gp120專一的蘇韋珠單抗(suvizumab); (3)對B型肝炎病毒B型肝炎表面抗原(HBsAg)專一的利韋單抗(libivirumab)、艾韋單抗(exbivirumab)與妥韋單抗(tuvirumab); (4) 對A型流感病毒血球凝集素A專一的CR6261單抗與非力弗單抗(firivumab); (5) 對巨細胞病毒醣蛋白專一的瑞加韋單抗(regavirumab)與司韋單抗(sevirumab); (6) 對狂犬病病毒醣蛋白專一的雷韋單抗(rafivirumab); (7) 對困難梭狀芽孢桿菌表面抗原專一的阿克托克單抗(actoxumab)與貝挫妥單抗(bezlotoxumab); (8) 對炭疽桿菌炭疽專一的歐必妥昔單抗(obiltoxaximab)與雷昔庫單抗(raxibacumab); (9) 對綠膿桿菌(Pseudomonas aeruginosa
)血清型IATS O11專一的帕諾庫單抗(panobacumab;是一種人類IgM單株抗體); (10) 對金黃葡萄球菌凝集因子A (clumping factor A)專一的替非珠單抗(tefibazumab)與托沙妥單抗(tosatoxumab); (11) 對格蘭氏陰性菌內毒素專一的埃巴單抗(edobacomab;用以治療敗血症); (12) 對金黃葡萄球菌壁脂酸專一的帕昔單抗(pagibaximab;用以治療葡萄球菌敗血症); (13) 對炭疽毒素專一的雷昔庫單抗(raxibacumab;人類單株抗體); (14) 對大腸桿菌第I型或第II型類志賀毒素專一的普托昔單抗(pritoxaximab)、司托昔單抗(setoxaximab)與烏珠單抗(urtoxazumab)。
用以治療中樞神經系統疾病或感染性疾病的
Fc
型分子構建體
以廣義的Fc構形來看,可利用免疫球蛋白抗體作為一標的或效應元件的基礎,並將與其搭配的效應或標的元件以scFv區域的形式引入其兩條γ重鏈的C-端。以傳統的「Fc」構形來看,可利用雙鏈IgG.Fc作為分子平台的基礎。每一多肽鏈可和一或兩個標的元件以及一或兩個效應元件融合,使得每一鏈共帶有二至三個元件。具有Fc構形的T-E分子總計可帶有四至六個元件(譬如scFv或任何其他抗體片段)。在可任選的實施方式中,所述分子構建體的Fc部分亦帶有Fc介導的效應功能,如ADCC和/或補體介導的活化作用。然而在某些其他應用中,不會出現此種Fc介導的效應功能。
在設計Fc型分子構建體時,標的元件可位於N-或C-端。若效應元件透過和細胞表面元件結合而發揮功用,應將效應元件設於構建體的末端。若效應元件是透過和可溶性因子結合並中和其功效而發揮作用,則可位於末端的標的或效應元件和CH2-CH3之間。
藉由挑選本案Fc型分子構建體的T-E元件,所得到的分子構建體可用於治療中樞神經系統(CNS)疾病或感染性疾病。在某些實施方式中,本揭示內容的優點還包括使用了本揭示內容第一態樣所述的接合單元,因而提供了一種能夠輕易控制此處提出的Fc型分子構建體的標的與效應元件數量的方法。隨著所選用的標的和/或效應元件不同,本Fc型分子構建體可採用不同的構形,茲分述如下。
在本案提出的Fc型分子構建體中,標的元件與效應元件都是抗體或其片段。
第1A圖繪示了根據本揭示內容某些實施方式的Fc型分子構建體800A。如圖所示,Fc型分子構建體800A包含兩條相同的CH2-CH3鏈810、連接於CH2-CH3鏈810的N-端的一對效應元件E1、以及連接於CH2-CH3鏈810的C-端的一對標的元件T1。在此一例示性的構形中,標的元件T1與效應元件E1都是scFv。
第1B圖所示的Fc型分子構建體800B與第1A圖的Fc型分子構建體800A結構非常相似,不同之處在於兩個效應元件E1分別連接於CH2-CH3鏈810的C-端,而兩個標的元件T1則分別連接於CH2-CH3鏈810的N-端。
根據某些實施方式,效應元件和標的元件兩者皆連接於CH2-CH3鏈的N-端。舉例來說,當效應元件與標的元件都是單鏈可變片段(scFv)時,可將效應元件與標的元件以串聯雙抗體(tandem)或雙抗體(diabody)的構形連接,因而形成連接於CH2-CH3鏈N-端的雙專一性scFv。
Fc型分子構建體800C (第1C圖)包含一Fc部分,且因此,每一CH2-CH3鏈810的N-端上接有T1-E1雙專一性scFv。
在某些例子中,成對的效應元件或成對的標的元件形成Fab構形(即,由VH
-CH1區域與VL
-Cκ區域組成);此種Fab片段係連接於CH2-CH3鏈的N-端,而使得Fc型分子構建體成為IgG 構形。在這些情形中,不具備Fab構形的該對元件可連接於成對CH2-CH3區段的C-端。
舉例來說,在第2圖所示的Fc型分子構建體900中,兩個標的元件T1分別包含VH
-CH1區域820與VL-
Cκ區域825,因而形成連接於CH2-CH3鏈810的N-端的Fab構形830,而使得Fc型分子構建體900成為IgG構形。在本例中,成對的效應元件E1是連接於成對CH2-CH3鏈810的C-端。
根據某些實施方式,本發明Fc型分子構建體的效應元件為多肽。
譬如,根據本揭示內容某些實施方式,效應元件可以是具有一定療效的多肽,而標的元件則是抗體或其片段(參見,第3A與3B圖)。如第3A圖所示,Fc型分子構建體1000A包含連接於成對CH2-CH3鏈1210之N-端的一對標的元件T1 (此元件為一scFv),以及連接於成對CH2-CH3鏈1210之C-端的一對效應元件E1 (此元件為治療性多肽)。
相似地,在第3B圖的Fc型分子構建體1000B中,成對的標的元件T1 (此元件為一scFv)係連接於CH2-CH3鏈1210之C-端;而成對的效應元件E1 (此元件為治療性多肽)則是連接於成對CH2-CH3鏈1210之N-端。
當可理解,對於使用多肽作為效應元件的Fc型分子構建體,可將標的元件構建為Fab片段的形式,而使得此分子構建體具有IgG構形。
在第1A至3B圖所繪示的構形中,CH2-CH3鏈是來自人類免疫球蛋白γ1或γ4。一般來說,當想要發揮Fc介導的功能(如抗體依賴性細胞毒性(ADCC)以及補體介導活性(發炎活化或目標細胞溶解))時,可以選擇γ1。當想要避免Fc介導的功能時,可以選用γ4來建構本發明Fc型分子構建體。
適用於
Fc
型分子構建體的功能性元件
在討論了本案Fc型分子構建體的基本結構之後,下文進一步說明某些由特定效應元件(們)與標的元件(們)所形成的組合。
欲治療中樞神經系統(CNS)疾病時,可使用對運鐵蛋白受器專一的抗體(或其片段)作為標的元件,並搭配適用於治療特定CNS疾病的效應元件。譬如,用以治療多發性硬化症的Fc型分子構建體可使用對整合素-α4專一的scFv作為效應元件。於治療阿滋海默症時,例示性的型分子構建體可使用對β-類澱粉蛋白專一的scFv作為效應元件。上述可用以治療CNS疾病的Fc型分子構建體可採用第1A至1C圖以及第2圖任一者所示的構形。
用以治療多發性硬化症的Fc型分子構建體也可以使用INF-β1a或INF-β1b作為效應元件。在這種情形中,Fc型分子構建體可採用如第3A與3B圖所示的構形。
在構建用以治療與感染(如病毒感染或細菌感染)相關的疾病/症狀的Fc型分子構建體時,可以使用對病毒蛋白或細菌蛋白專一的抗體(或其片段)作為標的元件。用於治療感染的效應元件則可以使用對CD32或CD16b專一的抗體(或其片段)。這些Fc型分子構建體可採用第3A至3C圖以及第2圖任一者所示的構形。
本發明的精髓在於採用特定標的與效應元件的組合或搭配。在較佳的實施方式中,所述分子構建體採用了Fc融合構形。本發明所屬技術領域具有通常知識者當可想見,亦可利用其他分子平台來連接此處提出的標的與效應元件的組合;上述分子平台諸如多肽、蛋白質(譬如白蛋白)、聚醣、聚乙二醇以及其他類型的聚合物,只要其能夠作為連接多個分子元件的結構基礎即可。
Fc
型分子構建體的用途
本揭示內容亦涉及了利用適當Fc型分子構建體來治療CNS疾病的方法。一般來說,上述方法涉及了對需要此一治療的個體投予治療有效量的Fc型分子構建體,所述Fc型分子構建體可以是根據本揭示內容各實施方式所述的任一種Fc型分子構建體。
本揭示內容也涉及了利用適當Fc型分子構建體來治療感染的方法。一般來說,上述方法涉及了對需要此一治療的個體投予治療有效量的Fc型分子構建體,所述Fc型分子構建體可以是根據本揭示內容各實施方式所述的任一種Fc型分子構建體。
實驗例
實驗例
1
:構建編碼有對
RSV
蛋白
F
專一的
scFv
與對
CD32a
胞外域
專一的
scFv
之雙鏈
IgG1.Fc
融合蛋白的基因片段
藉由融合兩個scFv來建構scFv1-CH2-CH3-scFv2 (人類γ1)重組鏈;其中透過一個可撓性鉸鏈區(flexible hinge region)將對RSV蛋白F專一的scFv連接到IgG1.Fc的CH2域N-端;並透過可撓性接合物((GGGGS)3
)將對CD32a胞外域專一的scFv連接到CH3域C-端。
上述兩個scFv的方向都是VL
-接合物-VH
。這兩個scFv中各別的VL
與VH
是透過親水性接合物(GSTSGSGKPGSGEGSTKG)而連接。IgG1.Fc融合蛋白分子構建體中重組鏈的序列如序列編號:37所示。
上述雙鏈Fc-融合分子構建體(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)的構形如下圖所示。
實驗例
2
:
重組雙鏈
(scFv α
RSV)-hIgG1.Fc-(
scFv α
CD32)
融合蛋白的表現與純化
在本實驗例中,將編碼的基因序列置於pcDNA3表現匣中。將Expi293F細胞以每毫升2.0 × 106
個活細胞的密度播於Expi293F表現培養基中,並維持18至24小時後進行轉染,以確保進行轉染時細胞處於分裂狀態。進行轉染時,將帶有7.5×108
個細胞的255毫升培養基置於2-L艾氏燒瓶中,並加入ExpiFectamine™ 293轉染試劑。於轉染後,將轉染細胞在37°C下以定軌搖動器(125 rpm)培育16至18小時;之後在燒瓶中加入ExpiFectamine™ 293轉染強化劑1與強化劑2,並繼續培育7天。收集培養上清液,並使用蛋白A親和力層析法純化培養基中的重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白。將緩衝液置換為PBS,之後利用12% SDS-PAGE測定(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)蛋白的濃度並進行分析;參見第4A圖。在約85 kDa的位置觀察到含Fc-融合分子構建體的主要電泳條,其大小與預期相符。
實驗例
3
:重組雙鏈
(scFv α RSV)-hIgG1.Fc-(scFv α CD32)
融合蛋白結合力的
ELISA
分析
透過ELISA來分析重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白對RSV蛋白F與CD32a胞外域的結合能力。以2 μg/mL的RSV蛋白F (ino biological Inc.)塗覆在ELISA盤上。利用HRP標記的山羊抗人類IgG1.Fc來偵測重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白。第4B圖的ELISA結果顯示,重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白可和RSV蛋白F結合;此處以阿達木單抗scFv為對照組scFv。
第4C圖是重組Fc融合蛋白對CD32a胞外域的結合活性。以5 μg/mL的重組CD32a胞外域塗覆在ELISA盤上。利用HRP標記的山羊抗人類IgG1.Fc來偵測重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白。第4C圖的ELISA結果顯示,重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32a)融合蛋白可和CD32a胞外域結合;此處以重組雙鏈(scFv α 內毒素)-IgG1.Fc蛋白為對照組scFv。
實驗例
4
:製備帶有對內毒素專一的
scFv
與對
CD32a
胞外域
專一的
scFv
之雙鏈
IgG1.Fc
融合蛋白
藉由融合兩個scFv來建構scFv1-CH2-CH3-scFv2 (人類γ1)重組鏈;其中透過一個可撓性鉸鏈區(flexible hinge region)將對內毒素專一的scFv連接到IgG1.Fc的CH2域N-端;並透過可撓性接合物((GGGGS)3
)將對CD32a胞外域專一的scFv連接到CH3域C-端。
上述兩個scFv的方向都是VL
-接合物-VH
。這兩個scFv中各別的VL
與VH
是透過親水性接合物(GSTSGSGKPGSGEGSTKG)而連接。
IgG1.Fc融合蛋白分子構建體中重組鏈的序列如序列編號:38所示。利用上文實驗例所述的方法,在Expi293F細胞中表現所建構的基因並純化所表現的融合蛋白。利用SDS-PAGE與ELISA分析來定性所製備的新構建體。第5A圖的SDA-PAGE結果顯示新構建體的重組鏈大小約為85 kDa,和預期大小相符。
第5B圖的ELISA結果則顯示上述重組雙鏈(scFv α 內毒素)-(scFv α CD32a)-hIgG1.Fc對大腸桿菌人類LPS 0111:B4 (Sigma Aldrich)有結合活性。以50 μg/ml的聚-L-離胺酸塗覆ELISA盤。接著,進一步以10 μg/ml的大腸桿菌人類LPS 0111:B4塗覆於上述覆有聚-L-離胺酸的ELISA盤上。利用HRP標記的山羊抗人類IgG1.Fc來偵測重組融合蛋白。第5C圖顯示,重組Fc融合蛋白可和CD32a胞外域結合。
上述雙鏈Fc-融合分子構建體(scFv α內毒素)-hIgG1.Fc-(scFv α CD32a)的構形如下圖所示。
實驗例
5
:構建編碼有對干擾素
-β-1a
專一的
scFv
與對
TfR1
胞外域
專一的
scFv
之雙鏈
IgG4.Fc
融合蛋白的基因片段
在重組鏈中配置(干擾素-β-1a)-CH2-CH3-(scFv α TfR1) (人類γ4)以製備雙鏈IgG.Fc 融合蛋白。透過連接物(GGGGSGGGASGGS)將干擾素-β-1a的C-端融合到CH2的N-端。透過可撓性連接物((GGGGS)3
)將對TfR1受器胞外域對專一的scFv連接到CH3域的C-端。
上述scFv (對TfR1受器胞外域對專一的scFv)的方向是VL
-接合物-VH
。此scFv中的VL
與VH
是透過親水性接合物(GSTSGSGKPGSGEGSTKG)而連接。IgG4.Fc融合蛋白分子構建體中重組鏈的序列如序列編號:39所示。
上述雙鏈(干擾素-β-1a)-IgG4.Fc-(scFv α TfR1)分子構建體的構形如下圖所示。
實驗例
6
:重組雙鏈
(
干擾素
-β-1a)-hIgG4.Fc-(scFv α TfR1)
融合蛋白
的表現與純化
在本實驗例中,將編碼的基因序列置於pcDNA3表現匣中。將Expi293F細胞以每毫升2.0 × 106
個活細胞的密度播於Expi293F表現培養基中,並維持18至24小時後進行轉染,以確保進行轉染時細胞處於分裂狀態。進行轉染時,將帶有7.5×108
個細胞的255毫升培養基置於2-L艾氏燒瓶中,並加入ExpiFectamine™ 293轉染試劑。於轉染後,將轉染細胞在37°C下以定軌搖動器(125 rpm)培育16至18小時;之後在燒瓶中加入ExpiFectamine™ 293轉染強化劑1與強化劑2,並繼續培育7天。收集培養上清液,並使用蛋白A親和力層析法純化培養基中的重組雙鏈(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)融合蛋白。將緩衝液置換為PBS,之後利用8% SDS-PAGE測定(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)蛋白的濃度並進行分析;參見第6A圖。在約80 kDa的位置觀察到含Fc-融合分子構建體的主要電泳條,其大小與預期相符。
實驗例
7
:利用
ELISA
和流式細胞儀來分析重組雙鏈
(
干擾素
-β-1a)-hIgG1.Fc-(scFv α TfR1)
融合蛋白的結合力
透過ELISA來分析重組(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)的結合能力。在96孔盤上塗覆5 μg/mL的重組(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)蛋白,每孔100 μl。以對TfR1胞外域專一的scFv作為陰性對照組。利用HRP標記的兔抗人類干擾素-β多株抗體(Santa Cruz Biotechnology, Dallas, USA)來偵測重組雙鏈(干擾素-β-1a)-hIgG1.Fc-(scFv α TfR1)。接著,加入50 μl的TMB受質以進行顯色。加入50 μl的1M HCl使反應停止。利用盤式儀測量450 nm下的吸光值。每一直方條的數據是兩次試驗的平均OD450值。
第6B圖的ELISA結果顯示,(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)融合蛋白可專一地和重組TfR1胞外域結合。
實驗例
8
:製備帶有對整合素
α4
專一的
scFv
與對
TfR1
胞外域
專一的
scFv
的
雙鏈
IgG4.Fc
融合蛋白
對整合素α4專一的scFv的VL
與VH
來自那他珠單抗。在重組鏈中配置(scFv α 整合素α4)-CH2-CH3-(scFv α TfR1) (人類γ4)以製備雙鏈IgG.Fc融合蛋白。透過連接物(GGGGSGGGASGGS)將對整合素α4專一的scFv融合到CH2的N-端。透過可撓性連接物((GGGGS)3
)將對TfR1受器胞外域對專一的scFv連接到CH3域的C-端。第7A圖所示的8% SDS-PAGE分析結果顯示,此一新穎構建體之重組鏈大小約為85 kDa (如箭頭所指),與預期大小相符
上述兩個scFv的方向都是VL
-接合物-VH
。這兩個scFv中各別的VL
與VH
是透過親水性接合物(GSTSGSGKPGSGEGSTKG)而連接。IgG4.Fc融合蛋白分子構建體中重組鏈的序列如序列編號:40所示。
上述雙鏈(scFv α 整合素α4)-IgG4.Fc-(scFv α TfR1)分子構建體的構形如下圖所示。
為了研究重組雙鏈(scFv α 整合素α4)-IgG4.Fc-(scFv α TfR1)蛋白對表現整合素α4的Jurkat T細胞的結合能力,利用流式細胞分析技術來進行細胞結合分析。
將1x106
個Jurkat T細胞以1x105
的密度維持在添加10% FBS的 RPMI1640培養基中。將細胞置於37°C含5% CO2
的加濕腔室中。以結合緩衝液(PBS添加0.1% FBS、2mM EDTA與and 20ng/ml NaN3
)將1x106
個Jurkat T細胞沖洗兩次。將10 μg/ml的Human BD Fc blockTM
(BD Biosciences, San Jose, US) 加入沖洗後的Jurkat T細胞,以阻斷Fc受體介導的Ig Fc結合。沖洗細胞後將其 10 μg/ml的重組(scFv α 整合素α4)-IgG4.Fc-(scFv α TfR1)蛋白在冰上培育15分鐘,並以重組雙鏈(干擾素-β-1a)-IgG4.Fc-(scFv α TfR1)作為陰性對照組。再次沖洗細胞,並和FITC-複合山羊抗-人IgG.Fc (Caltag, Buckingham, UK) (以阻斷緩衝液稀釋1:200倍)在冰上於黑暗中培育15分鐘。利用FACSCanto II流式細胞儀(BD Biosciences)來分析染色的細胞。
第7B圖是重組雙鏈(scFv α 整合素α4)-IgG4.Fc-(scFv α TfR1)蛋白在表現整合素α4的Jurkat T細胞上的細胞染色分析結果。構建體實質上可正向地與Jurkat T細胞結合。
實驗例
9
:帶有對內毒素專一的
scFv
與對
CD32a
胞外域
專一的
scFv
之雙鏈
IgG1.Fc
在似巨噬
細胞
U937
細胞上的生物活性分析
為了測試重組雙鏈(scFv α內毒素)-hIgG1.Fc-(scFv α CD32a)融合蛋白抑制TNF-α分泌的效果,進行ELISA以決定似巨噬菌
細胞U937 細胞上分泌至上清液中的分泌性
TNF-α量。
將U937細胞維持在RPMI1640培養基中(添加10% FBS (Gibco)與100 U/ml盤尼西林-鏈黴素(Gibco)),細胞密度為每毫升3x105
至2x106
個。將細胞置於37°C含5% CO2
的加濕腔室中。將每毫升1x106
個U937細胞和10 ng/ml的13乙酸-12肉豆蔻酸佛波醇酯(phorbol 12-myristate 13-acetate,簡稱PMA,購自Sigma Aldrich)一起培育,以促使U937細胞分化為似巨噬細胞。經過48小時後,移除未貼附細胞,並於沖洗貼附細胞後將其播於96孔盤上。
在分析前一天,以每孔5x104
個細胞的密度將分化的U937細胞播於96孔盤上。利用以下成分刺激細胞:單獨給予1 μg/ml的E. coli
LPS 0111:B4 (Sigma Aldrich),或LPS與10 μg/ml之(scFv α內毒素)-hIgG1Fc、15 μg/ml之(scFv α內毒素)-hIgG1Fc-(scFv α CD32a)或2.5 μg/ml之抗-CD32a scFv的預混物。上述刺激進行兩小時候,收集上清液。利用商用ELISA套組(Biolegend)測量TNF-α產量。
利用來自R&D Systems的ELISA套組測量U937上清液中的TNF-α含量。以4 μg/mL的捕獲抗體(於PBS中)在4°C下將ELISA盤(Greiner Bio-One)處理一夜,以使蛋白塗覆於孔盤上。隨後將其置於0.5%的PBS中1小時,以使反應終止,再以稀釋的培養上清液培育2小時。使用400 ng/mL的生物素-標記偵測抗體,隨後加入卵白素-HRP,以偵測結合的TNF-α。使用TMB基質(Clinical Science Products)進行顯色反應,之後加入1N HCl使反應停止。於450 nm下測量孔盤的吸光值。利用製造商提供的標準蛋白稀釋液得到四-參數邏輯擬和標準曲線(four-parameter logistic fit standard curves),再以外插法決定TNF-α濃度。
第8圖的資料顯示,相較於對照組抗體雙鏈(scFv α內毒素)-hIgG1Fc蛋白與抗-CD32a scFv或單獨使用培養基,重組雙鏈(scFv α內毒素)-hIgG1Fc-(scFv α CD32a)可顯著降低由E. coli
LPS 0111:B4刺激的TNF-α分泌。
當可理解,上文實施方式的說明僅為例示,且本發明所屬技術領域具有通常知識者可對其進行各種修飾。上文的說明、實驗例與資料完整地說明了本發明例示性實施方式的結構與用途。雖然上文實施方式中揭露了本發明的具體實施例,然其並非用以限定本發明,本發明所屬技術領域中具有通常知識者,在不悖離本發明之原理與精神的情形下,當可對其進行各種更動與修飾,因此本發明之保護範圍當以附隨申請專利範圍所界定者為準。
主要元件符號如下:
800A‧‧‧Fc型分子構建體
810‧‧‧CH2-CH3區段
T1‧‧‧標的元件
E1‧‧‧效應元件
800A‧‧‧Fc型分子構建體
810‧‧‧CH2-CH3區段
T1‧‧‧標的元件
E1‧‧‧效應元件
為讓本發明的上述與其他目的、特徵、優點與實施例能更明顯易懂,茲將所附圖式簡單說明如下。
第1A圖至1C為根據本揭示內容多種實施方式的Fc型分子構建體的示意圖。
第2圖為根據本揭示內容多種實施方式的Fc型分子構建體的示意圖。
第3A圖與3B圖為根據本揭示內容多種實施方式的Fc型分子構建體的示意圖。
第4A圖是純化重組雙鏈(scFv α RSV)-hIgG1.Fc-(scFv α CD32)融合蛋白的SDS-PAGE分析結果;而第4B圖與第4C圖的ELISA分析結果分別說明了第4A圖的純化重組融合蛋白對RSV蛋白F (第4B圖)與CD32a胞外域(第4C圖)的結合活性。
第5A圖是純化重組雙鏈(scFv α 內毒素)-hIgG1.Fc-(scFv α CD32)融合蛋白的SDS-PAGE分析結果;而第5B圖與第5C圖的ELISA分析結果分別說明了第5A圖的純化重組融合蛋白對內毒素(第5B圖)與CD32a胞外域(第5C圖)的結合活性。
第6A圖與第6B圖分別是純化重組雙鏈(干擾素-β-1a)-hIgG4.Fc-(scFv α TfR1)融合蛋白的SDS-PAGE分析結果與ELISA分析結果。
第7A圖與第7B圖分別是純化重組雙鏈(scFv α整合素α4)-hIgG4.Fc-(scFv α TfR1)融合蛋白的SDS-PAGE分析結果與染色結果。
第8圖的ELISA分析結果說明了純化重組雙鏈(scFv α內毒素)-hIgG1.Fc-(scFv α CD32a)融合蛋白於抑制TNF-α分泌的效果。
根據慣常的作業方式,圖中各種特徵與元件並未依比例繪製,其繪製方式是為了以最佳的方式呈現與本發明相關的具體特徵與元件。此外,在不同圖式間,儘可能以相同或相似的元件符號來指稱相似的元件/部件。
<110> 免疫功坊股份有限公司 <120> 用以治療疾病的分子構建體 <130> P2953-TW <150> US 62/164,400 <151> 2015-05-20 <150> US/62/213,012 <151> 2015-09-01 <150> US 62/308,349 <151> 2016-03-15 <160> 4 <170> BiSSAP 1.3 <210> 1 <211> 737 <212> PRT <213> 人工序列 <220> <223> (anti-RSV scfv)-IgG1.Fc-(anti-CD32 scFv) <400> 1 Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Cys Gln Leu Ser Val Gly Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Asp 65 70 75 80 Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly Ser Gly Tyr Pro Phe Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Thr Ser Gly 100 105 110 Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val Thr 115 120 125 Leu Arg Glu Ser Gly Pro Ala Leu Val Lys Pro Thr Gln Thr Leu Thr 130 135 140 Leu Thr Cys Thr Phe Ser Gly Phe Ser Leu Ser Thr Ser Gly Met Ser 145 150 155 160 Val Gly Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu Ala 165 170 175 Asp Ile Trp Trp Asp Asp Lys Lys Asp Tyr Asn Pro Ser Leu Lys Ser 180 185 190 Arg Leu Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Val Leu Lys 195 200 205 Val Thr Asn Met Asp Pro Ala Asp Thr Ala Thr Tyr Tyr Cys Ala Arg 210 215 220 Ser Met Ile Thr Asn Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr 225 230 235 240 Val Thr Val Ser Ser Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly 245 250 255 Gly Gly Gly Ser Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 260 265 270 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 275 280 285 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 290 295 300 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 305 310 315 320 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 325 330 335 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Asp Tyr Lys Cys 340 345 350 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 355 360 365 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 370 375 380 Ser Arg Asp Glu Leu Thr Arg Asn Gln Val Ser Leu Thr Cys Leu Val 385 390 395 400 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 405 410 415 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 420 425 430 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 435 440 445 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 450 455 460 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly 465 470 475 480 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ile Gln 485 490 495 Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val 500 505 510 Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Ala Leu Ala Trp 515 520 525 Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala 530 535 540 Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser 545 550 555 560 Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe 565 570 575 Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro His Thr Phe Gly 580 585 590 Gln Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Thr Ser Gly Ser Gly 595 600 605 Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val His Leu Val 610 615 620 Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu Ser 625 630 635 640 Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp Val 645 650 655 Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp Tyr 660 665 670 Asp Gly Ser Asn Tyr Tyr Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr 675 680 685 Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser 690 695 700 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu Gly 705 710 715 720 Ala Ala Ala Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser 725 730 735 Ser <210> 2 <211> 738 <212> PRT <213> 人工序列 <220> <223> (anti-endotoxin scfv)-IgG1.Fc-(anti-CD32 scFv) <400> 2 Asp Ile Gln Met Asn Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Thr Ile Ser Ile Thr Cys Arg Ala Ser Gln Asn Ile Asn Ile Trp 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Pro Gly Asn Val Pro Lys Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Tyr Cys Leu Gln Gly Gln Ser Tyr Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Thr Ser 100 105 110 Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Glu Val 115 120 125 Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu 130 135 140 Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr Tyr Met 145 150 155 160 Thr Trp Val Arg Gln Ala Pro Gly Lys Ala Pro Glu Trp Leu Ala Leu 165 170 175 Ile Arg Asn Lys Arg Asn Gly Asp Thr Ala Glu Tyr Ser Ala Ser Val 180 185 190 Lys Gly Arg Phe Thr Ile Ser Arg Asp Tyr Ser Arg Ser Ile Leu His 195 200 205 Leu Gln Met Asn Ala Leu Arg Thr Glu Asp Ser Ala Thr Tyr Tyr Cys 210 215 220 Val Arg Gln Gly Arg Gly Tyr Thr Leu Asp Tyr Trp Gly Gln Gly Thr 225 230 235 240 Ser Val Thr Val Ser Ser Ala Ser Gly Gly Ser Gly Gly Gly Gly Ser 245 250 255 Gly Gly Gly Gly Ser Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 260 265 270 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 275 280 285 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 290 295 300 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 305 310 315 320 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 325 330 335 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Asp Tyr Lys 340 345 350 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 355 360 365 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 370 375 380 Pro Ser Arg Asp Glu Leu Thr Arg Asn Gln Val Ser Leu Thr Cys Leu 385 390 395 400 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 405 410 415 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 420 425 430 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 435 440 445 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 450 455 460 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly 465 470 475 480 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Ile 485 490 495 Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg 500 505 510 Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Asn Ser Ala Leu Ala 515 520 525 Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp 530 535 540 Ala Ser Ser Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 545 550 555 560 Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp 565 570 575 Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro His Thr Phe 580 585 590 Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Thr Ser Gly Ser 595 600 605 Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Gln Val His Leu 610 615 620 Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg Leu 625 630 635 640 Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His Trp 645 650 655 Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Val Ile Trp 660 665 670 Tyr Asp Gly Ser Asn Tyr Tyr Tyr Thr Asp Ser Val Lys Gly Arg Phe 675 680 685 Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn 690 695 700 Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Leu 705 710 715 720 Gly Ala Ala Ala Ser Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 725 730 735 Ser Ser <210> 3 <211> 658 <212> PRT <213> 人工序列 <220> <223> (IFN-beta)Avonex-IgG4.Fc-(anti-TfR scFv) <400> 3 Met Ser Tyr Asn Leu Leu Gly Phe Leu Gln Arg Ser Ser Asn Phe Gln 1 5 10 15 Cys Gln Lys Leu Leu Trp Gln Leu Asn Gly Arg Leu Glu Tyr Cys Leu 20 25 30 Lys Asp Arg Met Asn Phe Asp Ile Pro Glu Glu Ile Lys Gln Leu Gln 35 40 45 Gln Phe Gln Lys Glu Asp Ala Ala Leu Thr Ile Tyr Glu Met Leu Gln 50 55 60 Asn Ile Phe Ala Ile Phe Arg Gln Asp Ser Ser Ser Thr Gly Trp Asn 65 70 75 80 Glu Thr Ile Val Glu Asn Leu Leu Ala Asn Val Tyr His Gln Ile Asn 85 90 95 His Leu Lys Thr Val Leu Glu Glu Lys Leu Glu Lys Glu Asp Phe Thr 100 105 110 Arg Gly Lys Leu Met Ser Ser Leu His Leu Lys Arg Tyr Tyr Gly Arg 115 120 125 Ile Leu His Tyr Leu Lys Ala Lys Glu Tyr Ser His Cys Ala Trp Thr 130 135 140 Ile Val Arg Val Glu Ile Leu Arg Asn Phe Tyr Phe Ile Asn Arg Leu 145 150 155 160 Thr Gly Tyr Leu Arg Asn Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser 165 170 175 Gly Gly Ser Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly 180 185 190 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 195 200 205 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 210 215 220 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 225 230 235 240 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 245 250 255 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 260 265 270 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 275 280 285 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 290 295 300 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 305 310 315 320 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 325 330 335 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 340 345 350 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 355 360 365 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 370 375 380 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 385 390 395 400 Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 405 410 415 Gly Ser Asp Ile Val Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 420 425 430 Leu Gly Asp Thr Ile Leu Ile Thr Cys His Ala Ser Gln Asn Ile Asn 435 440 445 Val Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Asn Ala Pro Lys Leu 450 455 460 Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe 465 470 475 480 Ser Gly Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu 485 490 495 Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Ser Tyr 500 505 510 Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser 515 520 525 Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly 530 535 540 Gln Val Gln Leu Gln Gln Pro Gly Ala Ala Leu Val Arg Pro Gly Ala 545 550 555 560 Ser Met Arg Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 565 570 575 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Leu Ile 580 585 590 Gly Met Ile His Pro Ser Asp Ser Glu Val Arg Leu Asn Gln Lys Phe 595 600 605 Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 610 615 620 Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 625 630 635 640 Ala Arg Phe Gly Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 645 650 655 Ser Ser <210> 4 <211> 738 <212> PRT <213> 人工序列 <220> <223> (anti-integrin a4 scfv)--IgG4.Fc-(anti-TfR scFv) <400> 4 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Thr Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser Thr Ser 100 105 110 Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly Val Lys 115 120 125 Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala Ser Val Lys 130 135 140 Leu Phe Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr Tyr Met His 145 150 155 160 Trp Val Lys Gln Arg Pro Gln Gln Gly Leu Glu Trp Ile Gly Arg Ile 165 170 175 Asp Pro Ala Ser Gly Asp Thr Lys Tyr Asp Pro Lys Phe Gln Val Lys 180 185 190 Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Trp Leu Gln Leu 195 200 205 Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Asp Gly 210 215 220 Met Trp Val Ser Thr Gly Tyr Ala Leu Asp Phe Trp Gly Gln Gly Thr 225 230 235 240 Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ala Ser 245 250 255 Gly Gly Ser Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly 260 265 270 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 275 280 285 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 290 295 300 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 305 310 315 320 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 325 330 335 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 340 345 350 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 355 360 365 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 370 375 380 Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 385 390 395 400 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 405 410 415 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 420 425 430 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 435 440 445 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 450 455 460 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 465 470 475 480 Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 485 490 495 Gly Ser Asp Ile Val Ile Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser 500 505 510 Leu Gly Asp Thr Ile Leu Ile Thr Cys His Ala Ser Gln Asn Ile Asn 515 520 525 Val Trp Leu Ser Trp Phe Gln Gln Lys Pro Gly Asn Ala Pro Lys Leu 530 535 540 Leu Ile Tyr Lys Ala Ser Asn Leu His Thr Gly Val Pro Ser Arg Phe 545 550 555 560 Ser Gly Ser Gly Ser Gly Thr Gly Phe Thr Leu Thr Ile Ser Ser Leu 565 570 575 Gln Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Gly Gln Ser Tyr 580 585 590 Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Gly Ser 595 600 605 Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr Lys Gly 610 615 620 Gln Val Gln Leu Gln Gln Pro Gly Ala Ala Leu Val Arg Pro Gly Ala 625 630 635 640 Ser Met Arg Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr 645 650 655 Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Leu Ile 660 665 670 Gly Met Ile His Pro Ser Asp Ser Glu Val Arg Leu Asn Gln Lys Phe 675 680 685 Lys Asp Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Ala Tyr 690 695 700 Met Gln Leu Asn Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 705 710 715 720 Ala Arg Phe Gly Leu Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val 725 730 735 Ser Ser
800A‧‧‧Fc型分子構建體
810‧‧‧CH2-CH3區段
T1‧‧‧標的元件
E1‧‧‧效應元件
Claims (15)
- 一種分子構建體包含: 一對IgG.Fc的CH2-CH3區段; 一對效應元件,其中每一效應元件為干擾素 β1a (INF-β1a)或INF-β1b、或對整合素α4、β-類澱粉蛋白、CD16b或CD32專一的一抗體片段;以及 一對標的元件,其中每一標的元件為對人類運鐵蛋白受器、人類胰島素受器、病毒蛋白或細菌蛋白專一的一抗體片段,其中: 當該對效應元件連接於該成對CH2-CH3區段的N-端時,該對標的元件連接於該成對CH2-CH3區段的C-端,反之亦然;或 當該對效應元件與該對標的元件皆為單鏈可變片段(single-chain variable fragment,scFv)的形式時,該對標的元件以串聯雙抗體(tandem)或雙抗體(diabody)的構形而連接於該對效應元件的N-端,因而形成連接於該對CH2-CH3區段的N-端的一對雙專一性scFv。
- 如請求項1所述的分子構建體,其中該對CH2-CH3區段係衍生自人類γ1或γ4免疫球蛋白。
- 如請求項2所述的分子構建體,其中當該對效應元件為一抗原結合片段(antigen-binding fragment,Fab)的形式且當該對標的元件為scFv的形式時,該Fab以及scFv分別連接於該CH2-CH3區段的N-與C-端,而使得該分子構建體形成一延伸IgG構形,反之亦然。
- 如請求項1所述的分子構建體,其中: 該效應元件為INF-β1a或INF-β1b、或對整合素α4專一的一scFv;以及 該標的元件為對人類運鐵蛋白受器專一的一scFv。
- 如請求項1所述的分子構建體,其中: 該效應元件為對β-類澱粉蛋白專一的一scFv;以及 該標的元件為對人類運鐵蛋白受器專一的一scFv。
- 如請求項1所述的分子構建體,其中: 該效應元件為對CD16b或CD32專一的一scFv;以及 該標的元件為對一病毒蛋白或細菌蛋白專一的一scFv。
- 如請求項4所述的分子構建體,其中該病毒蛋白為呼吸道融合病毒(respiratory syncytia virus,RSV)的F蛋白、人類免疫缺陷病毒第I型(human immunodeficiency virus type 1,HIV-1)的gp120蛋白、A型流感病毒的血球凝集素A (hemagglutinin A,HA)蛋白或巨細胞病毒的醣蛋白。
- 如請求項4所述的分子構建體,其中該細菌蛋白是革蘭氏陰性菌(Gram(-) bacteria)的內毒素(endotoxin)、困難梭狀芽孢桿菌(Clostridium difficile )的表面抗原、金黃葡萄球菌(Staphylococcus aureus )的壁脂酸(lipoteichoic acid)、炭疽桿菌(Bacillus anthracis )的炭疽毒素(anthrax toxin)或大腸桿菌(Escherichia coli )的第I型或第II型類志賀毒素(Shiga-like toxin type I or II)。
- 一分子構建體用於製備用以治療一有需要個體的中樞神經系統(central nervous system,CNS)疾病的藥物的用途,其中該分子構建體如請求項1所述。
- 如請求項9所述的用途,其中: 該CNS疾病為多發性硬化症; 該對CH2-CH3區段係衍生自人類γ4免疫球蛋白; 該效應元件為INF-β1a或INF-β1b、或對整合素α4專一的一抗體片段;以及 該標的元件為對人類運鐵蛋白受器專一的一抗體片段。
- 如請求項9所述的用途,其中: 該CNS疾病為阿滋海默症; 該對CH2-CH3區段係衍生自人類γ4免疫球蛋白; 該效應元件為對β-類澱粉蛋白專一的一抗體片段;以及 該標的元件為對人類運鐵蛋白受器專一的一抗體片段。
- 一分子構建體用於製備用以治療一有需要個體的感染性疾病的藥物的用途,其中該分子構建體如請求項1所述。
- 如請求項12所述的分子構建體,其中: 該效應元件為對CD16b或CD32專一的一scFv;以及 該標的元件為對一病毒蛋白或細菌蛋白專一的一scFv。
- 如請求項13所述的用途,其中該病毒蛋白為呼吸道融合病毒(respiratory syncytia virus,RSV)的F蛋白、人類免疫缺陷病毒第I型(human immunodeficiency virus type 1,HIV-1)的gp120蛋白、A型流感病毒的血球凝集素A (hemagglutinin A,HA)蛋白或巨細胞病毒的醣蛋白。
- 如請求項13所述的用途,其中該細菌蛋白是革蘭氏陰性菌(Gram(-) bacteria)的內毒素(endotoxin)、困難梭狀芽孢桿菌(Clostridium difficile )的表面抗原、金黃葡萄球菌(Staphylococcus aureus )的壁脂酸(lipoteichoic acid)、炭疽桿菌(Bacillus anthracis )的炭疽毒素(anthrax toxin)或大腸桿菌(Escherichia coli )的第I型或第II型類志賀毒素(Shiga-like toxin type I or II)。
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