TWI520746B - 使用免疫球蛋白片段之胰島素接合物 - Google Patents
使用免疫球蛋白片段之胰島素接合物 Download PDFInfo
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- TWI520746B TWI520746B TW100111784A TW100111784A TWI520746B TW I520746 B TWI520746 B TW I520746B TW 100111784 A TW100111784 A TW 100111784A TW 100111784 A TW100111784 A TW 100111784A TW I520746 B TWI520746 B TW I520746B
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- insulin
- conjugate
- immunoglobulin
- region
- peptidyl polymer
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Description
本發明係有關具有改良之活體內作用時效及穩定性之胰島素接合物、含其之長效製劑與其製法,該胰島素接合物係胰島素藉由非肽基聚合物而與免疫球蛋白Fc區共價連結所製成。本發明提供治療患有胰島素缺陷(insulin-deficiency)疾病(如:糖尿病)之個體之方法。本發明之胰島素接合物可維持相當高之該胜肽活體內活性,且顯著延長其血清半衰期,藉以大幅改善使用胰島素治療時之藥物順應性(drug compliance)。
胰島素係一種由胰臟β細胞分泌之胜肽,其在體內之血糖濃度控制中扮演中心角色。當胰島素分泌不當或所分泌之胰島素無法在身體內運作時,血糖濃度即失調,因此出現糖尿病。此種糖尿病稱為II型糖尿病。當胰臟無法製造足量胰島素來提高血糖濃度時,即發生I型糖尿病。
II型糖尿病通常使用口服之化學合成降血糖劑治療,有些病例則使用胰島素治療患者。而I型糖尿病則需要胰島素治療。
目前採用之胰島素治療法為在進餐前/後注射胰島素。然而,此等胰島素注射需持續每日投藥三次,如此會造成患者疼痛或不適。曾有人嘗試許多方法來克服此問題。其中一個方法為藉由改善其膜通透性而經由口或鼻吸入法,來傳送胜肽藥物。但該方法所展現之傳送效率卻較注射製劑低的多,因此為了使胜肽藥物之活體內活性維持在所需程度仍有許多困難。
同時還有一種在皮下注射大量藥物後延緩藥物吸收之方法,如此只要一天注射一次即可維持血中濃度。有些已開發之藥物(,Sanofi-aventis)已核准且現已提供患者使用。此外,已進行研究來延長效用,結果開發出Levemir(Novo Nordisk),其係以脂肪酸修飾胰島素所製成,其透過胰島素分子在注射位置之自行結合(self-association)及透過與血液中白蛋白之可逆性結合,而產生延緩效用。然而,此等方法均在注射位置造成疼痛,而且每日注射仍會造成患者相當不適。
已有許多努力試圖改善胜肽藥物於血清中之穩定性並使血中藥物長期維持在高濃度,藉以使藥物之醫藥效力達最佳程度。此等長效性胜肽藥物製劑需要在不會造成患者免疫反應下提高肽藥物之穩定性,並維持夠高之效價。製備長效性胜肽藥物製劑時,通常採用具有高溶解度之聚合物(如:聚乙二醇(PEG))來化學性修飾胜肽藥物之表面。
PEG非專一性結合在標靶胜肽之特定位置或各種不同位置,造成增加胜肽分子量之效果,因此抑制被腎臟排出,並避免水解,不會引起任何副作用。例如:WO 2006/076471描述會結合NPR-A以活化cGMP之產生,造成動脈血壓下降,而可作為充血性心臟衰竭治療劑之B-型排鈉利尿胜肽(BNP),係與PEG結合,藉以維持其生理活性。美國專利第6,924,264號描述PEG結合在腸促胰島素(exendin)-4之離胺酸殘基,以延長其活體內滯留時間。此方法增加PEG之分子量,因此延長胜肽藥物之活體內滯留時間。然而,當增加分子量時,會顯著降低胜肽藥物之效價,亦因此降低與胜肽之反應性。因此反而會出現產量下降之不期望結果。
WO 02/46227說明一種融合蛋白質,其係採用基因重組技術,令GLP-1、腸促胰島素-4或其類似物,與人類血清白蛋白或免疫球蛋白片段(Fc)偶合製成。美國專利第6,756,480號說明一種Fc融合蛋白質,其係由副甲狀腺激素(PTH)及其類似物與Fc區偶合製成。此等方法可以解決諸如:低聚乙二醇化(pegylation)產率及非專一性等問題,但其在延長血液半衰期之效果上仍有效果不如預期之問題,且有時候其效價亦低。為了達到延長血液半衰期之最佳效果,已採用各種不同胜肽連結體(linker),但卻可能引發免疫反應。此外,若使用具有雙硫鍵之胜肽(如:BNP)時,極有可能出現錯誤折疊,且若採用具有非天然胺基酸殘基之胜肽時,其可利用基因重組法製造,但困難度高。
有鑑於此,促使本發明深入研究發展可以儘可能延長胰島素之血清半衰期並同時提高活體內活性之方法,因而發現由免疫球蛋白Fc區、非肽基聚合物及胰島素利用共價鍵彼此進行位置-選擇性連結時,可以比已知之同義融合(inframe fusion)方法更顯著延長其血清半衰期。
本發明之目的係提供可以維持胰島素之活體內活性並顯著延長其血清半衰期之優越胰島素接合物,含其之長效性製劑,及其製法。
達成上述目的之一態樣中,本發明提供一種胰島素接合物,其係利用非肽基聚合物使胰島素連結免疫球蛋白Fc區所製成,其中該非肽基聚合物係連結在胰島素β鏈之胺基末端。
本發明中,胰島素為一種由胰臟因應血液中葡萄糖濃度提高所分泌之胜肽,以使肝臟、肌肉或脂肪組織吸收葡萄糖,進而轉化成肝糖,並停止利用脂肪作為能量來源,因此其功能在於控制血糖濃度。此胜肽包括其促效劑、前驅物、衍生物、片段及變異體,且以天然、短效性或長效性胰島素較佳。
天然胰島素為一種由胰臟分泌之激素,用於促進葡萄糖吸收及抑制脂肪降解,因此具有控制血糖濃度之功能。胰島素係由不具調節血糖濃度功能之前驅物(稱為胰島素原)經過修飾(processing)後形成。胰島素之胺基酸序列如下:
α鏈:
Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asn(SEQ ID NO. 1)
β鏈:
Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr(SEQ ID NO. 2)
胰島素促效劑意指會與胰島素受體結合,以展現與胰島素相同生物活性之化合物,其與胰島素之結構無關。
胰島素衍生物意指與天然胰島素之胺基酸序列具有至少80%同質性之胜肽,其胺基酸殘基上有些基團可能經過化學性取代(例如:α-甲基化、α-羥基化)、刪除(例如:脫胺基化)或修飾(例如:N-甲基化),且具有調節體內血糖濃度之功能。
胰島素片段意指在天然胰島素之N-末端或C-末端增加或刪除一個或多個胺基酸之片段,其中可增加非天然胺基酸(例如:D-型胺基酸),且具有調節體內血糖濃度之功能。
胰島素變異體意指具有一個或多個不同於天然胰島素之胺基酸序列且具有調節體內血糖濃度之功能之胜肽。
可分別或組合採用胰島素之促效劑、衍生物、片段及變異體之各製法。例如:本發明包括具有一個或多個不同於天然胜肽之胺基酸,其N-末端胺基酸殘基已脫胺基化,且具有調節體內血糖濃度之功能之胜肽。
一項明確具體實施例中,本發明所採用胰島素可採用重組技術製造,且亦可採用固相合成法合成。此外,本發明所採用胰島素之特徵在於該非肽基聚合物係連結在胰島素β鏈之胺基末端。本發明使用此非肽基聚合物作為連結體。修飾胰島素之α鏈會降低活性及安全性。因此本發明中,作為連結體之非肽基聚合物係連結在胰島素β鏈之胺基末端,以維持胰島素活性及改善安全性。
本文所採用“活性”一詞意指胰島素與胰島素受體結合之能力,且意指該胰島素透過與胰島素受體結合而發揮其效用。
非肽基聚合物與胰島素β鏈之胺基末端之此等結合可藉由控制pH來達成,較佳係控制在4.5至7.5之範圍內。
本文所採用“N-末端”可與“N-末端區”交換使用。
一項明確實例中,本發明者製備胰島素-PEG-免疫球蛋白Fc接合物,其係由PEG連結免疫球蛋白Fc區之N-末端,並選擇性偶合至胰島素β鏈之N-末端。本發明所製備胰島素-PEG-免疫球蛋白Fc接合物之血清半衰期已顯著延長至約18小時,且在罹患疾病之動物模式中展現降血糖效應。因此,可以製備能維持活體內胰島素活性之新穎長效性胰島素製劑。
免疫球蛋白Fc區可安全用為藥物載劑,因為其係一種可在活體內代謝之生物可降解性多肽。此外,相對於完整之免疫球蛋白分子,該免疫球蛋白Fc區具有相對低之分子量,因此其有利於製備、純化及產生接合物。免疫球蛋白Fc區不包含Fab片段(根據抗體之次分類,其因具有不同胺基酸序列,而呈高度非同源性),因此免疫球蛋白Fc區應可大幅提高物質之均源性,且降低抗原性。
本文所採用“免疫球蛋白Fc區”一詞係指包含免疫球蛋白之重鏈恆定區(constant region)2(CH2)及重鏈恆定區3(CH3),但不包含免疫球蛋白之重鏈及輕鏈之可變區、重鏈恆定區1(CH1)及輕鏈恆定區1(CL1)之蛋白質。其可能進一步包括重鏈恆定區之鉸鏈區。此外,本發明免疫球蛋白Fc區可能包含一部份或所有Fc區,包括重鏈恆定區1(CH1)與/或輕鏈恆定區1(CL1),但不包括重鏈及輕鏈之可變區,只要其能具有實質上類似或更優於天然蛋白質之生理功能即可。此外,其可能為在CH2與/或CH3之胺基酸序列中相對長的部份具有缺失之片段。亦即本發明之免疫球蛋白Fc區可能包含1)CH1功能域(domain)、CH2功能域、CH3功能域及CH4功能域,2)CH1功能域及CH2功能域,3)CH1功能域及CH3功能域,4)CH2功能域及CH3功能域,5)一或多個功能域與免疫球蛋白鉸鏈區(或一部份鉸鏈區)之組合,及6)重鏈恆定區與輕鏈恆定區之各功能域之二聚體。
此外,本發明之免疫球蛋白Fc區包括其序列衍生物(突變體)及天然胺基酸序列。胺基酸序列衍生物之序列,因一或多個胺基酸殘基之缺失、插入、非保留性或保留性取代或其組合,而不同於天然胺基酸序列。例如:在IgG Fc中,已知對結合很重要之位置214至238、297至299、318至322或327至331,可作為修飾之合適目標。此外,可能產生其他各種不同衍生物,包括具有一個可能形成雙硫鍵之區域的缺失、在天然Fc型之N-末端上有數個胺基酸殘基之缺失、或在天然Fc型之N-末端上增加甲硫胺酸殘基之衍生物。此外,為了移除效應子(effector)功能,可能在補體結合位置如:Clq-結合位置及ADCC位置,發生缺失。製備此等免疫球蛋白Fc區之序列衍生物之技術揭示於WO 97/34631及WO 96/32478。
相關技述領域已知,蛋白質及胜肽中之胺基酸交換通常不會改變分子之活性(H. Neurath,R. L. Hill,The Proteins,Academic Press,New York,197 9)。最常見之交換法為Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Thy/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu及Asp/Gly,包括兩種方向之操作。
若需要時,Fc區可經由磷酸化、硫酸化、丙烯酸化、糖基化、甲基化、法呢基化(farnesylation)、乙醯基化、醯胺化,等等方式修飾。
上述Fc衍生物為具有與本發明之Fc區相同之生物活性或改良之結構穩定性(例如:對抗熱、pH等等)之衍生物。
此外,此等Fc區可得自從人類及其他動物(包括牛、羊、豬、小鼠、兔、倉鼠、大鼠及天竺鼠)單離之天然型,或可為得自轉型動物細胞或微生物之其重組體或衍生物。本文中,其可得自天然免疫球蛋白,其係藉由自人體或動物生物體中單離完整免疫球蛋白,並使用蛋白質分解酵素處理而得。木瓜酵素可分解天然免疫球蛋白形成Fab及Fc區,及胃蛋白酶之處理可產生pF’c及F(ab)2片段。此等片段可經過例如:分子大小排阻層析法,(size-exclusion chromatography),以單離出Fc或pF’c。
衍生自人類之Fc區較佳為得自微生物之重組免疫球蛋白Fc區。
此外,本發明之免疫球蛋白Fc區可呈具有天然糖鏈、比天然型增加糖鏈或比天然型減少糖鏈之型式,或可呈脫糖基化型式。可採用相關領域已知之方法增加、減少或脫除免疫球蛋白Fc糖鏈,如:化學法、酵素法及使用微生物之遺傳工程法。脫除Fc區之糖鏈之結果會大幅降低其對補體(c1q)之結合親和性,及降低或喪失抗體依賴性細胞媒介之細胞毒性或補體依賴性細胞毒性,因此不會在活體內誘發不必要之免疫反應。基於此點,脫糖基化或無糖基化型式之免疫球蛋白Fc區可能更適於本發明之目的而能作為藥物載劑。
本文所採用“脫糖基化(deglycosylation)”一詞意指酵素性脫除Fc區之糖部份(moiety),且本文所採用“無糖基化(aglycosylation)”一詞意指由原核生物(較佳指大腸桿菌(E. coli.))產生之未糖基化型式之Fc區。
此外,免疫球蛋白Fc區可為衍生自IgG、IgA、IgD、IgE及IgM之Fc區,或由其組合或其雜合體(hybrid)製成者。較佳係衍生自IgG或IgM,其係屬於人類血液中含量最多之蛋白質,且最佳係衍生自IgG,已知其可延長配體結合性蛋白質之半衰期。
本文所採用“組合”一詞意指令編碼相同來源之單鏈免疫球蛋白Fc區之多肽連結不同來源之單鏈多肽,形成二聚體或多聚體。亦即可由選自IgG Fc、IgA Fc、IgM Fc、IgD Fc及IgE Fc片段所組成之群組中的二個或更多個片段形成二聚體或多聚體。
本文所採用“雜合體”一詞意指在單鏈免疫球蛋白Fc區中出現編碼不同來源之兩種或更多種免疫球蛋白Fc區之序列。本發明中,可能有各種不同型式之雜合體。亦即,功能域雜合體可能由選自IgG Fc、IgM Fc、IgA Fc、IgE Fc及IgD Fc之CH1、CH2、CH3及CH4所組成之群組中的1至4個功能域組成,且可能包括鉸鏈區。
另一方面,IgG分成IgG1、IgG2、IgG3及IgG4次分類,本發明包括其組合或雜合體。較佳為IgG2及IgG4次分類,最佳為幾乎沒有效應子功能之IgG4之Fc區,如:CDC(補體依賴性細胞毒性)。
作為本發明之藥物載劑之最佳免疫球蛋白Fc區為衍生自人類IgG4之非糖基化Fc區。衍生自人類之Fc區更優於非衍生自人類之Fc區,後者可能成為人體之抗原,造成不期望之免疫反應,如:針對抗原產生新抗體。
本文所採用“非肽基聚合物”一詞意指生物可相容之聚合物,含有利用肽鍵以外之任何共價鍵相互連結之二個或更多個重覆單位。
可用於本發明之非肽基聚合物可選自下列各者所組成之群組:聚乙二醇、聚丙二醇、乙二醇與丙二醇之共聚物、聚氧乙基化多元醇、聚乙烯醇、多醣、葡聚糖、聚乙烯乙醚、生物可降解性聚合物如PLA(聚(乳酸))及PLGA(聚乳酸-乙醇酸)、脂質聚合物、幾丁質、玻尿酸及其組合,且以聚乙二醇較佳。相關領域已知且很容易由相關領域之技藝人士製備之其衍生物亦包括在本發明範圍內。
由習知同義融合(inframe fusion)方法製得之融合蛋白質所使用之肽連結體之缺點在於其很容易在活體內被蛋白質水解酵素裂解,因此無法如預期獲得藉由載劑充份延長活性藥物血清半衰期之效力。然而本發明中,仍可採用會抗拒蛋白質水解酵素之聚合物,以如同載劑般維持肽之血清半衰期。因此任何非肽基聚合物不受任何限制均可使用,只要其為具有上述功能之聚合物,亦即為可抗拒活體內蛋白質水解酵素之聚合物。該非肽基聚合物之分子量範圍在1至100 kDa,較佳為1至20 kDa。本發明連結至免疫球蛋白Fc區之非肽基聚合物可為一種聚合物或不同種類聚合物之組合。
用於本發明之非肽基聚合物具有可與免疫球蛋白Fc區及蛋白質藥物結合之反應性基團。
非肽基聚合物在兩端均具有反應性基團,其較佳係選自下列各者所組成之群組:反應性醛基、丙醛基、丁醛基、馬來醯亞胺基及琥珀醯亞胺衍生物。琥珀醯亞胺衍生物可為琥珀醯亞胺基丙酸根、羥基琥珀醯亞胺基、琥珀醯亞胺基羧甲基、或琥珀醯亞胺基碳酸根。特定言之,當非肽基聚合物之兩個末端具有反應性醛基時,其可在最低之非專一性反應下,於兩個末端有效連結生理活性多肽及免疫球蛋白。經由還原性烷化法,利用醛鍵產生之終產物之安定性遠高於利用醯胺鍵連結產生之產物。醛反應性基團在低pH下選擇性結合N-末端,但在高pH(如:pH 9.0)下結合離胺酸殘基,形成共價鍵。
在非肽基聚合物之二個末端之反應性基團可彼此相同或相異。例如:非肽聚合物可在其中一端具有馬來醯亞胺基團,而在另一端具有醛基、丙醛基或丁醛基。當使用兩端均具有反應性羥基之聚乙二醇作為非肽基聚合物時,該羥基可藉由已知化學反應活化成各種不同反應性基團,或可使用具有市售之經修飾反應性基團之聚乙二醇來製備本發明之蛋白質接合物。
本發明另一態樣中,本發明提供一種包含本發明之胰島素接合物之長效性胰島素製劑。
本文所採用“投藥”一詞意指經由某些適當方法將預定量物質送入患者體內。本發明之長效製劑可經由任何常見途徑投藥,只要其可到達所需組織即可。有各種不同投藥模式,包括經腹膜內、靜脈內、肌內、皮下、皮內、經口、局部、鼻內、肺內及經直腸內,但本發明並不受限於此等例舉之投藥模式。然而,由於胜肽經口投與時會被消化,因此經口投與之組成物中的活性成份應經過包覆或調配成可防止被胃分解之保護型式。較佳為該接合物可呈注射型式投藥。此外,本發明之長效製劑可使用某些能傳送活性成份進入標靶細胞中之裝置投藥。
包含本發明之接合物之長效製劑可包括醫藥上可接受之載劑。經口投藥時,該醫藥上可接受之載劑可包括結合劑、潤滑劑、崩解劑、賦形劑、溶解劑、分散劑、安定劑、懸浮劑、著色劑及香料。注射製劑中,醫藥上可接受之載劑可包括緩衝劑、防腐劑、止痛劑、溶解劑、等滲劑、及安定劑。局部投藥之製劑中,醫藥上可接受之載劑可包括基質、賦形劑、潤滑劑及防腐劑。本發明之長效製劑可組合使用上述醫藥上可接受之載劑,調配成各種不同劑型。例如:供經口投藥時,長效製劑可調配成錠劑、口含錠、膠囊、酏劑、懸浮液、糖漿或粉片。供注射製劑用之長效製劑可調配成單劑量安瓿或多劑量容器。長效製劑亦可調配成溶液、懸浮液、錠劑、丸劑、膠囊及持續釋放製劑。
適合該製劑之載劑、賦形劑及稀釋劑之實例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤蘚糖醇、麥芽糖醇、澱粉、阿拉伯膠、藻酸鹽、明膠、磷酸鈣、矽酸鈣、纖維素、甲基纖維素、微晶纖維素、聚乙烯吡咯啶酮、水、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂及礦物油。此外,該等製劑可進一步包括填料、抗凝結劑、潤滑劑、保濕劑、香料及消毒劑。
本發明長效製劑可經由許多相關因素決定,包括所治療疾病型態、投藥途徑、患者之年齡、性別、體重及疾病嚴重性,及作為活性成份之藥物種類。由於本發明之醫藥組成物具有優越之活體內作用時效及效價,因此其可顯著降低本發明藥物之投藥頻率及劑量。
本發明之長效製劑可維持極高之胰島素活體內作用時效及穩定性,因此可有效用於治療胰島素依賴型糖尿病。
另一態樣中,本發明提供一種製備胰島素接合物之方法,其包括下列步驟:
(1)使在各端具有醛、馬來醯亞胺或琥珀醯亞胺衍生物等反應性基團之非肽基聚合物,與免疫球蛋白Fc區之胺基或硫醇基共價連結;
(2)自(1)之反應混合物中單離出接合物,其中該接合物包含與非肽基聚合物共價連結之免疫球蛋白Fc區;及
(3)使胰島素與所單離接合物之非肽基聚合物之另一端共價連結,以產生肽接合物,其包含分別連結在非肽基聚合物各端之免疫球蛋白Fc區及胰島素。
較佳為步驟(1)之非肽基聚合物在其末端具有反應性醛衍生物,更佳為具有3個反應性醛基團。
另一態樣中,本發明提供一種製備胰島素接合物之方法,其包括下列步驟:
(1)使各端具有醛反應性基團之非肽基聚合物,於pH 6.0與免疫球蛋白Fc之N-末端共價連結;
(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含在其N-末端與非肽基聚合物共價連結之免疫球蛋白Fc區;及
(3)使胰島素與所單離接合物之非肽基聚合物之另一端共價連結,以產生肽接合物,其包含分別連結在非肽基聚合物各端之免疫球蛋白Fc區及胰島素。
另一態樣中,本發明提供一種製備胰島素接合物之方法,其包括下列步驟:
(1)使各端具有醛、馬來醯亞胺或琥珀醯亞胺衍生物等反應性基團之非肽基聚合物,與胰島素之胺基或硫醇基共價連結;
(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含與非肽基聚合物共價連結之胰島素;及
(3)使免疫球蛋白Fc區與所單離接合物之非肽基聚合物之另一末端共價連結,以產生肽接合物,其包含分別連結在非肽基聚合物各端之免疫球蛋白Fc區及胰島素。
另一態樣中,本發明提供一種製備胰島素接合物之方法,其包括下列步驟:
(1)使在各端上具有醛反應性基團之非肽基聚合物與胰島素之胺基共價連結;
(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含與非肽基聚合物共價連結之胰島素;及
(3)由免疫球蛋白Fc區與所單離接合物之非肽基聚合物之另一末端共價連結,以產生肽接合物,其包含分別連結在非肽基聚合物各端之免疫球蛋白Fc區及胰島素。
另一態樣中,本發明提供一種治療罹患胰島素缺陷疾病之個體之方法,該方法包括對該個體投與有效量之長效製劑。該胰島素缺陷疾病較佳為糖尿病。
本文所採用之個體可為哺乳動物,例如:人類、非人類靈長類、馬、羊、貓、狗、牛或豬。
下文中,可透過下列實施例更了解本發明,然該等實施例係用於例示而欲意限制本發明之範圍。
實施例1.聚乙二醇化免疫球蛋白Fc區之純化
在免疫球蛋白Fc之N-末端進行聚乙二醇化(pegylation)時,採用5K PropionALD(3)PEG(具有3個丙醛基之PEG,NOF.,日本)進行聚乙二醇化,其係由免疫球蛋白Fc及PEG,依1:2之莫耳比例,免疫球蛋白Fc濃度為10毫克/毫升(mg/ml),於4℃,反應4.5小時。此時,該反應係在100毫莫耳(mM)磷酸鉀緩衝液中,於pH 6.0進行,並添加20 mM SCB(NaCNBH3)作為還原劑。使用Source 15Q(GE Heal thcare)管柱,自反應溶液中純化單-聚乙二醇化免疫球蛋白Fc。
實施例2.胰島素-PEG-免疫球蛋白Fc接合物之製備
製備在胰島素β鏈之苯丙胺酸(B1F)處具90%或以上聚乙二醇化之胰島素-PEG-免疫球蛋白Fc接合物時,由實施例1所得之單-聚乙二醇化免疫球蛋白Fc與胰島素係依4:1之莫耳比例,總蛋白質濃度20 mg/ml,於4℃反應20小時。此時,該反應係在100 mM磷酸鉀緩衝溶液中,於pH 6.0進行,並添加20 mM SCB作為還原劑。反應結束後,反應溶液使用Source 15Q管柱進行初次純化。然後,使用Source 15ISO管柱進行二次純化,得到胰島素-PEG-免疫球蛋白Fc接合物。採用分子大小排阻管柱分析所得胰島素-PEG-免疫球蛋白Fc接合物之B1F處90%或以上之聚乙二醇化,其結果示於第3圖。
實
施例3.胰島素lispro(
)-PEG-免疫球蛋白Fc接合物之製備
由實施例1所得單-聚乙二醇化免疫球蛋白Fc與胰島素lispro係依4:1之莫耳比例,總蛋白質濃度20 mg/ml,於4℃反應20小時。此時,該反應係在100 mM磷酸鉀緩衝溶液中,於pH 6.0進行,並添加20 mM SCB作為還原劑。反應結束後,依實施例2之相同方式進行純化。
實施例4.胰島素glargine(
)-PEG-免疫球蛋白Fc接合物之製備
由實施例1所得單-聚乙二醇化免疫球蛋白Fc與胰島素glargine係依4:1之莫耳比例,總蛋白質濃度20 mg/ml,於4℃反應20小時。此時,該反應係在100 mM磷酸鉀緩衝溶液中,於pH 6.0進行,並添加20 mM SCB作為還原劑。反應結束後,依實施例2之相同方式進行純化。
實施例5.胰島素detemir(
)-PEG-免疫球蛋白Fc接合物之製備
由實施例1所得單-聚乙二醇化免疫球蛋白Fc與胰島素detemir係依4:1之莫耳比例,總蛋白質濃度20 mg/ml,於4℃反應20小時。此時,該反應係在100 mM磷酸鉀緩衝溶液中,於pH 6.0進行,並添加20 mM SCB作為還原劑。反應結束後,依實施例2之相同方式進行純化。
實施例6.長效性胰島素接合物之活體內消除半衰期測定
分析長效性胰島素接合物之活體內作用時效時,採用正常雄性SD大鼠進行藥物動力學分析。在正常雄性SD大鼠皮下注射一次天然胰島素及長效性胰島素接合物,劑量為100微克/公斤(μg/kg)(以胰島素為基準計),然後採用ELISA套組測定血清濃度隨時間之變化,並採用Winnolin 5.2軟體,由測定值計算藥物動力學參數。該長效性胰島素接合物之活體內消除半衰期為17.67小時,比天然胰島素之0.58小時延長約30倍(第1圖)。
實施例7.胰島素衍生物接合物之活體內效力試驗
為了比較胰島素衍生物之接合物之間的活體內效力,採用被鏈佐黴素誘發糖尿病之大鼠來分析其降血糖效應。讓正常大鼠空腹16小時後,經腹膜內注射10 mM鏈佐黴素之檸檬酸緩衝溶液(pH 4.5),劑量為60 mg/kg,以誘發糖尿病。當大鼠血糖濃度達到500毫克/分升(mg/dL)或更高時,在大鼠皮下注射一次胰島素接合物、胰島素detemir接合物或胰島素lispro接合物,劑量為0.5 mg/kg,然後比較其降血糖效應。胰島素接合物與胰島素lispro接合物降血糖效應在注射後維持約4天,且在注射後5天時,血糖濃度上升。胰島素detemir接合物亦顯示降血糖效應,但該效應低於相同劑量之胰島素接合物或胰島素lispro接合物(第2圖)。
實施例8. 胰島素-5 K PEG-免疫球蛋白Fc接合物之結合位置判別
為了判別胰島素與5 K PEG-免疫球蛋白Fc之結合位置,進行Glu-C圖譜分析。取20微克(μg)內切蛋白酶Glu-C(1 mg/ml)加至100μg胰島素-5 K PEG-免疫球蛋白Fc(1 mg/ml)中。反應溶液為50 mM HEPES,pH 7.5,混合物於25℃反應8小時。隨後,添加10微升(μl)1 N HCL中止反應。採用逆相HPLC層析法進行圖譜分析。結果顯示胰島素β鏈之N-末端出現波峰變化,此表示5 K PEG-免疫球蛋白Fc係結合至胰島素β鏈之N-末端(第4a-c圖)。
管柱:Jupiter C18 4.6x250(毫米)mm,5微米(μm)(Phenomenex)
移動相A:20% 0.1莫耳(M)NaSO4(pH 2.0),10% CAN
移動相B:20% 0.1 M NaSO4(pH 2.0),40% CAN
梯度0%B,10分鐘內>0-10%B,5分鐘內>10-70%B,60分鐘內
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<120> 使用免疫球蛋白片段之胰島素接合物
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<151> 2010-04-02
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<211> 30
<212> PRT
<213> 智人
<400> 2
第1圖為胰島素-PEG-免疫球蛋白Fc接合物之藥物動力學分析結果;
第2圖為胰島素衍生物-PEG-免疫球蛋白Fc接合物之間的活體內效力比較結果;及
第3圖為利用分子大小排阻管柱分析胰島素-PEG-免疫球蛋白Fc接合物之β鏈之苯丙胺酸(B1F)處90%或以上聚乙二醇化之結果。
第4a至4c圖為分析胰島素-PEG-免疫球蛋白Fc接合物之β鏈-專一性結合的結果。
無元件符號說明
Claims (18)
- 一種胰島素接合物,其係胰島素藉由非肽基聚合物而與免疫球蛋白Fc區連結所製成,該非肽基聚合物係選自下列各者所組成之群組:聚乙二醇、聚丙二醇、乙二醇與丙二醇之共聚物、聚氧乙基化多元醇、聚乙烯醇、多醣、葡聚糖、聚乙烯乙醚、生物可降解性聚合物、脂質聚合物、幾丁質、玻尿酸及其組合,其中該非肽基聚合物係連結至該胰島素β鏈之胺基末端位置1的苯丙胺酸;其中該免疫球蛋白Fc區為非糖基化,其中該非肽基聚合物之反應性基團係選自下列各者所組成之群組:醛基、丙醛基、丁醛基、馬來醯亞胺基及琥珀醯亞胺衍生物,以及其中非肽基聚合物在兩端具有反應性醛基。
- 如申請專利範圍第1項所述之胰島素接合物,其中該胰島素為天然胰島素,或由天然胰島素之胺基酸透過取代、增加、刪除及修飾之任一方法或其組合而製成之其變異體、衍生物或片段。
- 如申請專利範圍第1項所述之胰島素接合物,其中該免疫球蛋白Fc區係由選自下列各者所組成之群組的1至4個功能域組成:CH1、CH2、CH3及CH4功能域。
- 如申請專利範圍第3項所述之胰島素接合物,其中該免疫球蛋白Fc區進一步包括鉸鏈區。
- 如申請專利範圍第1項所述之胰島素接合物,其中該免疫球蛋白Fc區為衍生自IgG、IgA、IgD、IgE或IgM之Fc區。
- 如申請專利範圍第5項之胰島素接合物,其中該免疫球蛋白Fc區之各功能域為衍生自選自IgG、IgA、IgD、IgE及IgM所組成之群組的免疫球蛋白之不同來源功能域雜合體。
- 如申請專利範圍第5項所述之胰島素接合物,其中該免疫球蛋白Fc區為由相同來源之單鏈免疫球蛋白所組成之二聚體或多聚體。
- 如申請專利範圍第5項所述之胰島素接合物,其中該免疫球蛋白Fc區為IgG4 Fc區。
- 如申請專利範圍第8項所述之胰島素接合物,其中該免疫球蛋白Fc區為人類非糖基化IgG4 Fc區。
- 如申請專利範圍第1項所述之胰島素接合物,其中該琥珀醯亞胺衍生物為琥珀醯亞胺基丙酸根、琥珀醯亞胺基羧甲基、羥基琥珀醯亞胺基或琥珀醯亞胺基碳酸根。
- 一種具有改良活體內作用時效及穩定性之長效性胰島素製劑,其包含如申請專利範圍第1至10項中任一項所述之胰島素接合物。
- 如申請專利範圍第11項所述之長效性胰島素製劑,其中該製劑係用於治療糖尿病。
- 一種製備如申請專利範圍第1項所述之胰島素接合物之方法,其包括下列步驟:(1)使在各端具有醛之反應性基團之非肽基聚合物,與免疫球蛋白Fc區之胺基或硫醇基共價連結;(2)自(1)之反應混合物中單離出接合物,其中該接 合物包含與該非肽基聚合物共價連結之該免疫球蛋白Fc區;及(3)使所單離接合物之非肽基聚合物之另一端共價連結至胰島素β鏈之N-末端位置1的苯丙胺酸,產生肽接合物,其包含分別連結在該非肽基聚合物各端之該免疫球蛋白Fc區及該胰島素。
- 一種製備如申請專利範圍第1項所述之胰島素接合物之方法,其包括下列步驟:(1)使各端具有醛反應性基團之非肽基聚合物,於pH 6.0與免疫球蛋白Fc之N-末端共價連結;(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含在其N-末端與該非肽基聚合物共價連結之該免疫球蛋白Fc區;及(3)使所單離接合物之非肽基聚合物之另一端共價連結至胰島素β鏈之N-末端位置1的苯丙胺酸,產生肽接合物,其包含分別連結在該非肽基聚合物各端之該免疫球蛋白Fc區及該胰島素。
- 一種製備如申請專利範圍第1項所述之胰島素接合物之方法,其包括下列步驟:(1)使各端具有醛之反應性基團之非肽基聚合物,與胰島素β鏈之N-末端位置1的苯丙胺酸的胺基共價連結;(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含與該非肽基聚合物共價連結之該胰島素;及 (3)使免疫球蛋白Fc區與所單離接合物之非肽基聚合物之另一末端共價連結,產生肽接合物,其包含分別連結在該非肽基聚合物各端之該免疫球蛋白Fc區及該胰島素。
- 一種製備如申請專利範圍第1項所述之胰島素接合物之方法,其包括下列步驟:(1)使在各端上具有醛反應性基團之非肽基聚合物與胰島素β鏈之N-末端位置1的苯丙胺酸的胺基共價連結;(2)自(1)之反應混合物中單離出該接合物,其中該接合物包含與該非肽基聚合物共價連結之該胰島素;及(3)由免疫球蛋白Fc區與所單離接合物之非肽基聚合物之另一末端共價連結,產生肽接合物,其包含分別連結在該非肽基聚合物各端之該免疫球蛋白Fc區及該胰島素。
- 一種申請專利範圍第1至10項中任一項之胰島素接合物的用途,其係用於製造用以治療具有胰島素缺陷疾病之個體的醫藥。
- 如申請專利範圍第17項所述之用途,其中該胰島素缺陷疾病為糖尿病。
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