TWI609697B - 高濃度抗體及蛋白質調配物 - Google Patents
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- TWI609697B TWI609697B TW102131180A TW102131180A TWI609697B TW I609697 B TWI609697 B TW I609697B TW 102131180 A TW102131180 A TW 102131180A TW 102131180 A TW102131180 A TW 102131180A TW I609697 B TWI609697 B TW I609697B
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Abstract
本發明提供一種高濃度、無鹽抗體及其他蛋白質調配物,其實質上等滲性及低黏度。亦提供利用所揭示調配物治療疾病之方法。
Description
本揭示內容一般係有關高濃度抗體與其他蛋白質之調配物,其係等滲性及低黏度,包括適用於注射及一般投藥法之調配物。
血友病患者具有流血異常病變,在受傷或手術後造成血液延遲凝結。流血時間延長係由一或多種凝血因子之基因缺陷所致。已知有兩種常見血友病--血友病A及血友病B。血友病A係由因子VIII缺陷引起,而血友病B係由因子IX缺陷引起。總血友病患者中約75-80%為血友病A。
組織因子途徑抑制劑(TFPI)為人類外因性凝血途徑之抑制劑,且具有抗凝血功能。已努力開發一種針對TFPI之抗體,包括抗TFPI單株抗體(aTFPI mAb),以阻斷TFPI功能。其中一種aTFPI mAb為人類IgG2抗TFPI mAb,已開發用於治療血友病A及B患者。
抗體及其他蛋白質可經由靜脈內、肌內與/或皮下注射投與患者。為了確保患者適應性,該肌內及皮下注射劑型可為等滲性,且包括小注射體積(每個注射部位<2.0ml)。為了降低注射體積,蛋白質經常以20mg/ml至150mg/ml之高濃度範圍注射。
雖然目前市面上基於抗體及其他蛋白質之藥品係採用液態及冷凍乾燥劑型,但仍以冷凍乾燥劑型較常用於具有高蛋白質濃度之蛋白質及抗體藥品。
高濃度蛋白質及抗體劑型對調配物之發展產生許多挑戰性,尤其用於液態調配物時。當調配物中之蛋白質濃度接近其表觀溶解限值時,可能透過沉澱、膠凝與/或結晶而出現分層現象。在高蛋白質濃度下,抗體或其他蛋白質
之安定性可能因形成可溶性及不溶性蛋白質-蛋白質凝集物而出現問題。高濃縮蛋白質調配物經常呈高黏度,很難加工處理,如:超濾及無菌過濾,且很難注射劑量溶液。而且在計畫用於肌內或皮下投藥之調配物所要求之高蛋白質濃度下,需要成比例之高濃度安定劑(如:蔗糖及氯化鈉)來達成長期蛋白質安定性。所得高張性溶液經常因傷害組織而造成注射疼痛。因此必需在用於安定之安定劑用量與高蛋白質濃度調配物之滲透壓之間取得平衡。
基於此等理由,相關技藝上需要不會出現蛋白質顯著增加凝集、滲透壓或黏度與/或降低之蛋白質安定性之呈液態且具有高蛋白質濃度之基於抗體及其他蛋白質之醫療性調配物。因此希望該基於高濃度抗體及其他蛋白質調配物含有限量賦形劑且體積小,以方便投與或傳送醫療劑。亦需要該基於高濃度抗體及其他蛋白質之醫療調配物可以進行冷凍乾燥,以加強其在長期儲存條件下之蛋白質安定性。
本發明揭示內容提供一種高濃度液態及冷凍乾燥之基於抗體及蛋白質調配物,其實質上呈等滲性及低黏度,且實質上不含無機鹽。本文所提出該抗體及其他蛋白質調配物包含約0mM至約30mM組胺酸;約50ppm至約200ppm之非離子性表面活性劑,如,例如:聚山梨酸酯(Tween®)80或聚山梨酸酯(Tween®)20;約88mM至約292mM之糖或糖醇,如,例如:甘露糖醇、右旋糖、葡萄糖、海藻糖、與/或蔗糖;約0mM至約50mM精胺酸;約0mM至約50mM離胺酸;約0mM至約133mM甘胺酸或丙胺酸;約0mM至約10mM甲硫胺酸;及約20mg/ml至約150mg/ml之蛋白質,其pH為約pH 4.0至約pH 6.0。本文所揭示調配物之黏度範圍為22℃下之約1mPa-S至約20mPa-S,或22℃下之約1mPa-S至約15mPa-S,或22℃下之約1mPa-S至約10mPa-S,或22℃下之約1mPa-S至約8mPa-S,22℃下之約1mPa-S至約6mPa-S,及滲透壓範圍為約240至約380mmol/kg。
其他態樣中,本發明揭示內容提供一種治療患者之病變之方法,其包括對該患者投與醫療有效量之一或多種本文說明之調配物。例如:提供一種治
療患者之病變之方法,其包括對該患者投與醫療有效量之本文更詳細說明之抗體或其他蛋白質調配物。
本教示內容之此等及其他特色將說明於本文中。
熟悉此相關技術者咸了解,下文說明之圖示僅供說明用。該等圖示並無意以任何方式限制本發明之教示範圍。
圖1出示氯化鈉(NaCl)濃度對20mg/ml抗TFPImAb調配物於pH 5.5下之混濁度之影響。
圖2出示pH對該抗TFPI mAb藥物混濁度之影響。
如上述,本發明揭示內容提供一種抗體及其他蛋白質調配物,其可於所計畫儲存條件下安定該呈液態型或冷凍乾燥型之高蛋白質濃度之抗體或其他蛋白質。本文所說明調配物包括一或多種醫藥上可接受之賦形劑或安定劑,且係含在合適pH下之緩衝介質中,且與生理體液呈實質上等滲性。供全身投藥時,其中一種投藥途徑為注射,包括肌內、靜脈內、腹膜內及皮下注射。
由於其黏度低,本發明所揭示之蛋白質調配物適合經由例如:超濾法及無菌過濾處理,且可經由注射投與患者,包括靜脈內及皮下兩種注射法。此外,由於其呈實質上等滲性,本發明所揭示之抗體及蛋白質調配物降低組織傷害或其他不良生理效應,藉以達成有利之患者耐受性,及提高患者順應性。
本文所說明調配物之特徵在於實質上沒有添加鹽,此作法提供提高其他安定劑(如:蔗糖)濃度之彈性,同時維持調配物之滲透壓,供改良活體內耐受性,因此可提高患者順應性。此外,本文所說明調配物之低黏度方便處理過程,包括(但不限於):超濾及無菌過濾,及通過針頭注射藥品溶液。
本文所採用術語「黏度」係指液態調配物對流動(如:在通過針頭注射投與患者期間)之阻抗。黏度測定法係採用錐與平板技術,利用設定在指定溫度(如:本文說明之22℃)下之控溫平台(Peltier element)進行。通常,在液態調配物
上施加確立之剪切應力梯度,並測定所得之剪切應變速率。黏度為剪切應力與剪切應變速率之比值。本文所採用黏度以22℃下之mPa-S單位表示,其中1mPa-S=1Cp。本文所揭示高濃度、低黏度、實質上等滲性調配物之典型特徵在於其22℃下之黏度範圍為約1mPa-S至約20mPa-S,或22℃下之約1mPa-S至約15mPa-S,或22℃下之約1mPa-S至約10mPa-S,或22℃下之約1mPa-S至約8mPa-S,或22℃下之約1mPa-S至約6mPa-S。
本文所採用術語「滲透壓」係指溶質濃度,其定義為每公斤溶液之溶質毫莫耳數。可藉由添加一或多種安定劑(如:糖或糖醇,包括(但不限於):甘露糖醇、右旋糖、葡萄糖、海藻糖、與/或蔗糖)來達成所需之滲透壓程度。其他適合提供滲透壓之安定劑說明於參考書中,如:醫藥賦形劑手冊(the handbook of Pharmaceutical Excipient)(第4版,Royal Pharmaceutical Society of Great Britain,Science & Practice Publishers)或雷氏:藥理科學與操作(Remingtons:The Science and Practice of Pharmacy)(第19版,Mack Publishing Company)。
本文所採用術語「約」係指所提供單位數值+/- 10%。本文所採用術語「實質上」係指所需特徵或性質所呈現總計或約略程度之定性條件。熟悉相關生物技術者咸了解,生物與化學現象即使有也很少達成或避免絕對結果。因此本文所採用術語「實質上」係指許多生物與化學現象可能缺乏固有之完整性。本文所採用術語「等滲性」及「等張性」可與術語「實質上等滲性」及「實質上等張性」交換使用,且係指該調配物之特徵在於其滲透壓與另一種溶液中由調配物所達成之滲透壓相同或至少實質上相同,其中該調配物中溶質(包括可通透性及不可通透性溶質)總濃度係與另一種溶液中溶質總量相同或至少實質上相同。因此,熟悉此相關技術者咸了解,用於活體內投藥之「等滲性」及「等張性」調配物之滲透壓範圍通常為約270mmol/kg至約310mmol/kg,在本發明揭示之高濃度、低黏度調配物中,術語「等滲性」、「等張性」、「實質上等滲性」及「實質上等張性」可交換使用,係指滲透壓範圍為約240mmol/kg至約380mmol/kg,或約270mmol/kg至約370mmol/kg,或約300mmol/kg至約330mmol/kg之調配物。
本發明所揭示之高濃度、低黏度、實質上等滲性抗體及其他蛋白質調配物包含約0mM至約30mM組胺酸;約50ppm至約200ppm之非離子性表面活性劑,如,例如:聚山梨酸酯(Tween®)80或聚山梨酸酯(Tween®)20;約88mM至約292mM之糖或糖醇,如,例如:甘露糖醇、右旋糖、葡萄糖、海藻糖、與/或蔗糖;約0mM至約50mM精胺酸;約0mM至約50mM離胺酸;約0mM至約133mM甘胺酸或丙胺酸;約0mM至約10mM甲硫胺酸;及約20mg/ml至約150mg/ml之蛋白質,其pH為約pH 4至約pH 6。本文所揭示調配物之黏度範圍為22℃下之約1mPa-S至約20mPa-S,或22℃下之約1mPa-S至約15mPa-S,或22℃下之約1mPa-S至約10mPa-S,或22℃下之約1mPa-S至約8mPa-S,或22℃下之約1mPa-S至約6mPa-S,及滲透壓範圍為約240至約380mmol/kg。
此等調配物中,組胺酸為緩衝劑,可用於維持調配物pH在約pH 4至約pH 6.0,或約pH 5至約pH 6,如:約pH 5、約pH 5.5、或約pH 6。糖或糖醇,如:甘露糖醇、右旋糖、葡萄糖、海藻糖、與/或蔗糖係分開使用或組合使用,均可在液態調配物中及在冷凍乾燥期間及之後作為抗體之低溫保護劑及安定劑。非離子性表面活性劑(如:聚山梨酸酯,包括聚山梨酸酯20及聚山梨酸酯80;泊洛沙姆(polyoxamer),包括泊洛沙姆184及188;pluronic®多元醇;及其他乙烯/聚丙烯嵌段聚合物)可藉由降低界面交互作用而在加工處理及儲存期間穩定抗體,並防止蛋白質吸附。精胺酸為一種蛋白質溶解劑,亦作為降低抗體及其他蛋白質凝集(如:aTFPI mAb凝集)及糖基化之安定劑。甲硫胺酸為一種在加工處理及儲存期間防止抗體氧化之抗氧化劑。
糖類與無機鹽類為常用之蛋白質安定劑;然而,糖類與無機鹽類亦為有效之張力劑。若調配物需要高濃度之一或多種糖類來安定蛋白質時,該無機鹽濃度應為零或保持低濃度,以維持調配物之滲透壓,以降低投藥時之注射疼痛。相當意外地發現,氯化鈉會增加抗體調配物之混濁度。因此本文所說明調配物實質上不添加無機鹽。此等無機鹽調配物維持抗體及其他蛋白質調配物之滲透壓,並提高安定性及降低層相變化,如:沉澱或凝集。
本文所採用術語「鹽」係指無機鹽類,其包括(但不限於):氯化鈉(NaCl)、硫酸鈉(Na2SO4)、硫代氰酸鈉(NaSCN)、氯化鎂(MgCl)、硫酸鎂(MgSO4)、硫代氰酸銨(NH4SCN)、硫酸銨((NH4)2SO4)、氯化銨(NH4Cl)、氯化鈣(CaCl2)、硫酸鈣(CaSO4)、氯化鋅(ZnCl2),等等,或其組合。本文所揭示抗體及其他蛋白質調配物之特徵在於實質上不添加鹽,因此本文稱為無鹽抗體與/或蛋白質調配物。熟悉此相關技術者咸了解,本發明所揭示調配物中為了調整pH而添加之無機鹽類並不視為外加之鹽類,且此等無機鹽類若存在於根據本發明所揭示調配物中時,其濃度不應超過約2mM。
本文所採用術語「表面活性劑」包括非離子性表面活性劑,其包括(但不限於):聚山梨酸酯類,如:聚山梨酸酯20或80,及泊洛沙姆類(polyoxamers),如:泊洛沙姆184或188,Pluronic®多元醇,及其他乙烯/聚丙烯嵌段聚合物。可有效提供安定高濃度抗體及其他蛋白質調配物之表面活性劑用量通常在50ppm至200ppm之範圍內。使用非離子性表面活性劑可以讓調配物接受到剪切與表面應力,不會造成抗體或其他蛋白質變性,亦可在加工處理及儲存期間減少吸附在表面上。本文所揭示之調配物包括(但不限於):包含一或多種非離子性表面活性劑之調配物,其包括例如:一或多種聚山梨酸酯類,如:聚山梨酸酯20或80;一或多種泊洛沙姆類(polyoxamers),如:泊洛沙姆184或188;一或多種Pluronic®多元醇類;與/或一或多種乙烯/聚丙烯嵌段聚合物。本文之實例為包含聚山梨酸酯類(如:聚山梨酸酯20(Tween® 20)或聚山梨酸酯80(Tween® 80))之調配物。
本文所採用術語「蛋白質」係指胺基酸聚合物,其包含至少5個利用肽鍵共價連接之組成性胺基酸。該組成性胺基酸可來自由遺傳密碼編碼之胺基酸群組中,包括:丙胺酸、纈胺酸、白胺酸、異白胺酸、甲硫胺酸、苯基丙胺酸、酪胺酸、色胺酸、絲胺酸、蘇胺酸、天冬醯胺、麩醯胺、半胱胺酸、甘胺酸、脯胺酸、精胺酸、組胺酸、離胺酸、天冬胺酸、及麩胺酸。本文所採用術語「蛋白質」與其相關術語「肽」與「多肽」為同義字。
本文所採用術語「抗體」係指一種習知作為免疫球蛋白之蛋白質。抗體包括全長單株抗體(mAb),如:IgG2單株抗體,其包括免疫球蛋白Fc區。術
語抗體亦包括雙重特異性抗體、雙功能抗體、單鏈分子、及抗體片段,如:Fab、F(ab')2、及Fv。
本文所採用術語「抗TFPI抗體」係指對人類TFPI蛋白質與人類TFPI蛋白質之片段及變異體具有特異結合性之抗體。本文提出之抗TFPI抗體可為IgG2抗體,且包括抗TFPI IgG2單株抗體,如:嵌合性、擬人化、及全人類抗TFPI IgG2單株抗體。本發明揭示內容中例舉之抗TFPI抗體為具有包含如本文所提出SEQ ID NO:1之序列之輕鏈與/或如本文所提出SEQ ID NO:2之重鏈之人類抗TFPI IgG2單株抗體。其他亦適合用於本文所揭示調配物之抗TFPI單株抗體,包括全長抗體及其抗原結合性片段及變異體已由PCT專利公告案案號WO 2011/109452及WO 2010/017196提出,其揭示內容均已以引用之方式併入本文中。
「單株抗體」之特徵在於對單一抗原性決定子具有特異性。單株抗體可例如:由Kohler及Milstein,Nature 256:495(1975)說明之雜化瘤方法或採用重組DNA方法(如:美國專利案案號4,816,567說明之彼等方法)製造。單株抗體亦可採用如:Clackson等人之Nature 352:624-628(1991)及Marks等人之J.Mol.Biol.222:581-597(1991)說明之彼等技術,從噬菌體表現集合庫中單離。
單株抗體包括「嵌合性單株抗體」,其中一部份重鏈與/或輕鏈包括來自一種物種之抗體之序列,而其餘抗體(包括Fc區)則包括來自第二種物種之抗體之序列,通常該第二種物種為人類。參見例如:美國專利案案號4,816,567及Morrison等人之Proc.Natl.Acad.Sci.USA 81:6851-6855(1984)。
單株抗體亦包括「擬人化單株抗體」,其中來自一種物種之抗體之重鏈與/或輕鏈序列中之一個或多個互補決定區(CDR)被來自第二種物種之抗體之重鏈與/或輕鏈序列中之一個或多個CDR置換,通常該第二種物種為人類。"擬人化"過程通常用於開發用於投與人類之單株抗體上。參見例如:Riechmann等人之Nature 332(6162):323-27(1988)及Queen等人之Proc.Natl.Acad.Sci.USA 86(24):10029-33(1989)。
單株抗體亦包括「全人類單株抗體」,其中整個重鏈與輕鏈序列均來自人類抗體序列。全人類單株抗體可採用噬菌體表現技術產生,且可自已經過
基因改造以表現人類抗體庫之小鼠中單離。參見例如:McCafferty等人之Nature 348(6301):552-554(1990)、Marks等人之J.Mol.Biol.222(3):581-597(1991)、及Carmen及Jermutus,Brief Funct.Genomic Proteomic 1(2):189-203(2002)。
本文所採用術語抗體或其他蛋白質調配物之「醫藥上有效量」係指在投藥療程中提供醫療效力之調配物用量。本文所揭示高濃度抗體及蛋白質調配物通常包括之抗體或其他蛋白質濃度範圍為約20mg/ml至約150mg/ml,或約50mg/ml至約150mg/ml,或約60mg/ml至約150mg/ml,或約70mg/ml至約150mg/ml,或約80mg/ml至約150mg/ml,或約90mg/ml至約150mg/ml,或約100mg/ml至約150mg/ml,或約120mg/ml至約150mg/ml,或約140mg/ml至約150mg/ml。有些態樣中,此等調配物中之蛋白質或抗體濃度為約150mg/ml。此等調配物在每個注射部位之投藥體積通常小於約2.0ml,或約1.5ml,或約1ml,或約0.5ml。
某些態樣中,該抗體或其他蛋白質調配物包含約30mM組胺酸、約100ppm Tween 80、約292mM蔗糖、約20mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約234mM蔗糖、約50mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約234mM蔗糖、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約88mM蔗糖、約133mM甘胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 20、約88mM蔗糖、約133mM甘胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約200ppm Tween 20、約88mM蔗糖、約133mM甘胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約30mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約88mM蔗糖、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約10mM至約50mM精胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約88mM蔗糖、約133mM甘胺酸、約10mM精胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約0mM至約10mM甲硫胺酸。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約88mM蔗糖、約133mM甘胺酸、約30mM離胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。
其他態樣中,該抗體或其他蛋白質調配物包含約10mM組胺酸、約75ppm Tween 80、約234mM蔗糖、約30mM精胺酸、約100mg/ml抗體或其他蛋白質,其pH範圍在約pH 5.0至約pH 6.0。相關態樣中,該抗體及其他蛋白質調配物亦包含約0mM至10mM甲硫胺酸。
本文所例舉之抗體調配物為其中抗體包括IgG2抗體,如:抗組織因子途徑抑制劑抗體(aTFPI Ab),包括其輕鏈包含SEQ ID NO:1序列及重鏈包含SEQ ID NO:2序列之人類IgG2單株抗體。
因此,本發明揭示內容提供一種抗TFPI mAb調配物,包括抗TFPI IgG2 mAb調配物,其中該抗-TFPI mAb可在高蛋白質濃度下溶解。通常,本所
揭示調配物中之抗TFPI mAb可在約20至約150mg/ml之濃度間保持溶解,及在等滲性儲存條件下保持安定,並具有低於目前可利用之抗體調配物之黏度。
該具有包含SEQ ID NO:1序列之輕鏈及包含SEQ ID NO:2序列之重鏈之抗TFPI抗體為一種阻斷組織因子途徑抑制劑(TFPI)之IgG2抗體。由於TFPI向下調控外因性凝血作用,因此抗TFPI抗體會藉由阻斷TFPI來促進外因性途徑所驅動之凝血作用,藉以繞過內因性途徑之FVIII或FIX缺陷來治療血友病。本文所提出高濃度且無鹽之抗TFPI抗體調配物可經由靜脈內注射或皮下注射或其他注射途徑投與患者。
在一部份本發明揭示內容中,吾等發現抗TFPI抗體之溶解性與安定性會受到賦形劑影響。抗TFPI抗體之溶解度會隨著NaCl濃度下降而提高。當不含NaCl時,抗TFPI抗體之溶解度高於包含NaCl之調配物。此外,已發現帶正電價之胺基酸(如:精胺酸及離胺酸)可改善抗TFPI抗體之安定性,且pH會大幅影響抗TFPI抗體溶解度。抗體溶液之混濁度會隨pH上升而提高;然而,當pH下降時,可逆轉沉澱現象。最適合安定本文所提出抗TFPI抗體之pH範圍為約pH 4至約pH 6,或約pH 5至約pH 6,如:約pH 5、約pH 5.5,或約pH 6。
本文例舉之調配物係如上述,其中抗體為抗TFPI抗體(aTFPI Ab)。在至少一項態樣中,該抗TFPI抗體為人類IgG2單株抗體。例如:該人類抗TFP1 IgG2單株抗體包括之抗體包含具有如SEQ ID NO:1所示胺基酸序列之輕鏈及具有如SEQ ID NO:2所示胺基酸序列之重鏈。
本發明揭示內容亦提供治療患者之病變之方法,其包括對該患者投與醫療有效量之一或多種本文說明之調配物。例如:提供治療患者之病變之方法,其包括對該患者投與醫療有效量之抗體或其他蛋白質調配物,其包含約0mM至約30mM組胺酸,及約50ppm至約200ppm聚山梨酸酯(Tween®)80或聚山梨酸酯(Tween®)20、約88mM至約292mM蔗糖、約0mM至約50mM精胺酸、約0mM至約50mM離胺酸、約0mM至約133mM甘胺酸或丙胺酸、約0mM至約10mM甲硫胺酸、及約20mg/ml至約150mg/ml之蛋白質,其pH範圍在約pH 4.0至約pH 6.0。此等方法之至少一項態樣中,該抗體或其他蛋白質調配物可經靜脈內投藥。此等方法之其他項態樣中,該抗體或其他蛋白質調配物可經皮下投藥。此等方法之其他態樣中,該抗體或其他蛋白質調配物可經肌內投藥。
相關態樣中,本發明揭示內容提供治療患者之血友病A或血友病B之方法,其包括對該患者投與醫療有效量之抗TFPI抗體調配物,其包含約0mM至約30mM組胺酸,及約50ppm至約200ppm聚山梨酸酯(Tween®)80或聚山梨酸酯(Tween®)20、約88mM至約292mM蔗糖、約0mM至約50mM精胺酸、約0mM至約50mM離胺酸、約0%(0mM)至約1%(133mM)甘胺酸、約0mM至約10mM甲硫胺酸、及約20mg/ml至約150mg/ml之蛋白質,其pH範圍在約pH 4.0至約pH 6.0。此等方法之至少一項態樣中,該抗TFPI抗體調配物可經靜
脈內投藥。此等方法之其他態樣中,該抗TFPI抗體調配物可經皮下投藥。此等方法之其他態樣中,該抗體或其他蛋白質調配物可經肌內投藥。
根據此等治療患者之血友病A或血友病B之方法之某些態樣中,該抗TFPI抗體為人類抗TFP1 IgG2單株抗體,如,例如:人類抗TFPI IgG2單株抗體,其包含具有如SEQ ID NO:1所示胺基酸序列之輕鏈及具有如SEQ ID NO:2所示胺基酸序列之重鏈。
為了闡明本說明書,將採用下列定義,且若適當時,以單數表示之術語將亦包括複數,反之亦然。若下文所示任何定義與該術語於任何其他文獻(包括本文引用之參考文獻)中之用法相抵觸時,為了闡明本說明書及其相關之申請專利範圍,仍以下文所示之定義為準,除非另有明確說明(例如:採用該術語之原始文獻中之說明)。"或"之用法係指"與/或",除非另有說明。本文中「一個(種)」之用法係指「一或多個(種)」,除非另有說明或不適合採用「一或多個(種)」之用法時。「含有」、「包含」、「涵括」、及「包括」可交換使用,並無意限制。此外,若一或多項具體實施例之說明中採用術語「包括」時,熟悉此相關技術者咸了解,在某些特例中,該(等)具體實施例可改用「基本上包括」與/或「其組成為」之語法。
本發明揭示內容之態樣可從下列實例中進一步了解,其未以任何方式構成本發明之限制範圍。
實例
實例1
NaCl濃度及pH對該抗體溶液之影響
本實例揭示鹽(NaCl)濃度及pH對包含抗TFPI人類單株抗體(其具有如SEQ ID NO:1所示胺基酸序列之輕鏈及如SEQ ID NO:2所示胺基酸序列之重鏈)之溶液之混濁度之影響。
溶液之混濁度係採用比濁法(Nephelometry)測定,以快速分析鹽濃度與pH對aTFPI Ab溶液之影響。本實例中所採用該抗TFPI抗體調配物包含10mM乙酸鹽緩衝液、88mM蔗糖、及200ppm Tween 80。NaCl濃度在0mM至
300mM之間變化。抗TFPI調配物於pH 5.5下之混濁度隨NaCl變化之測定結果示於圖1。此等數據證實,該抗TFPI mAb調配物之混濁度隨NaCl濃度上升而顯著提高。鹽濃度從0上升至300mM時,使比濁法所測定混濁度提高72 FNU,其可能歸因於aTFPI Ab於溶液中沉澱、凝集或不溶解。由此結果可見,本發明所揭示之抗TFPI抗體調配物建議不包含氯化鈉。
在不受理論限制下,咸信抗TFPI mAb調配物隨NaCl濃度上升而提高之混濁度歸因於抗TFPI mAb精胺酸側鏈上之正電價被中和所致。aTFPI mAb在不同pH下受到單價鹽(NaCl)影響之層相現象即可解釋可達成安定、可溶、無鹽且實質上等滲性之aTFPI mAb調配物之原因。
本發明所揭示之aTFPI mAb分子具有116個胺基酸(42個精胺酸與74個離胺酸),其所具有之側鏈會在低於PI之pH下帶正電價。該抗TFPI抗體之PI為~7.9。在低於PI之pH下,如:pH 4-6,此抗TFPI抗體具有淨正電價。此抗TFPI抗體表面上正電價之排斥作用很可能防止個別分子之間蛋白質-蛋白質結合作用,藉以顯著提高溶解度。據推斷,鹽之陰離子(Cl-)結合在抗TFPI抗體表面上精胺酸側鏈之胍鎓基,以中和正電價,結果加強蛋白質-蛋白質交互作用,因此降低溶解度及形成混濁溶液。將pH調至4-6時,本文所說明該無鹽調配物即可提高抗體溶解度及安定性(參見圖1)。當不含鹽時,其他安定劑(如:蔗糖)之濃度可提高至>150mM及<300mM,不會破壞滲透壓。
亦探討pH對該抗TFPI抗體之混濁度之影響。如圖2所示,pH亦可能大幅影響aTFPI Ab溶液之混濁度。當pH從4上升至6.5時,aTFPI Ab溶液之混濁度提高81 FNU。當pH進一步上升至7時,該溶液之混濁度則超出可以準確測定之範圍。然而,當pH下降時,即可逆轉溶液中所形成之沉澱物。此結果可歸因於當pH上升至接近aTFPI Ab之PI值時之表面電價之中和作用,因為aTFPI Ab之PI值為約7.9。依據此研究,aTFPI Ab調配物以較低之pH較佳。然而,低pH可能在注射期間刺激組織。因此,從患者適應性觀點而言,中性pH較佳。在這兩種因素之間取其平衡,aTFPI Ab調配物之最佳pH應介於pH 5至pH 6之間。
實例2
抗TFPI抗體調配物
依據實例1所提出之意外發現,在不使用NaCl下,製備實質上等滲性之高濃度抗TFPI Ab調配物。此等調配物通常利用高蔗糖濃度來協助安定抗TFPI Ab。
取冷凍之抗TFPI抗體解凍,依據表1所示調配物,經由透析法重新調配。製備該調配物,使用0.22μm濾器過濾,填入玻璃管瓶中,使用橡皮塞密封。
亦發現,當不含NaCl,但包含蔗糖(88mM至292mM)及聚山梨酸酯80或聚山梨酸酯20(50-200ppm)時,帶正電價胺基酸(如:精胺酸(10-50mM))可以有效抑制aTFPI Ab之糖化。
採用HPLC-SEC分別分析此等抗TFPI mAb調配物之蛋白質凝集及降解,採用LC-MS分析aTFPI結構變化(糖化及氧化),及採用比濁法分析混濁度,採用黏度計測定黏度,及採用滲透壓儀器測定滲透壓。此等分析結果示於表2。
實例3
精胺酸對該抗TFPI Ab之糖化作用之影響
本實例證實該包含精胺酸之抗TFPI Ab調配物之抗體糖化作用低於不添加精胺酸之抗TFPI Ab調配物。
取添加或不添加精胺酸之抗TFPI Ab調配物於pH 6下,於40℃下存放14天,並利用LC-MS測試。示於表3之結果證實,帶正電價之胺基酸精胺酸降低抗TFPI Ab之糖化作用,其可能歸因於aTFPI Ab之獨特結構,使其降至相當於參考標準物之程度。
依據本研究結果得到之結論為aTFPI Ab之安定性高度受到調配物pH之影響,且當考慮進行IV、IM及皮下注射時,調配物安定性之最佳pH在pH 5至pH 6之間。精胺酸似乎可以防止aTFPI Ab之糖化作用。實例4及實例5所示之調配物發展及安定性研究即依據此等結果設計。
實例4
抗TFPI Ab調配物之安定性
抗TFPI Ab調配物之HPLC-SEC結果與LC-MS結果綜合示於表4至7。
Claims (26)
- 一種無鹽蛋白質或抗體調配物,其包含:a. 10mM至30mM組胺酸;b. 50ppM至200ppm非離子性表面活性劑;c. 88mM至292mM糖或糖醇,其係選自:甘露糖醇、右旋糖、葡萄糖、海藻糖、及蔗糖;d. 0mM至50mM精胺酸;e. 0mM至50mM離胺酸;f. 0mM至133mM甘胺酸或丙胺酸;g. 0mM至10mM甲硫胺酸;及h. 20mg/ml至150mg/ml蛋白質或抗體;其中該抗體為包含具有SEQ ID NO:1所示之胺基酸序列之輕鏈及具有SEQ ID NO:2所示之胺基酸序列之重鏈的人類IgG2單株抗體或其抗原結合片段或變異體;其中該蛋白質或抗體調配物之pH範圍為pH 4.0至pH 6.0,且其中該蛋白質調配物實質上不含無機鹽。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其中該調配物於22℃下之黏度範圍為1至8mPa-S。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其中該調配物之滲透壓範圍為240至380mmol/kg。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其中該非離子性表面活性劑為聚山梨酸酯,其係選自:聚山梨酸酯20及聚山梨酸酯80。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其中該糖為蔗糖。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含10mM至50mM之精胺酸。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 30mM組胺酸,b. 100ppm聚山梨酸酯80, c. 292mM蔗糖,及d. 20mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 234mM蔗糖,d. 50mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 234mM蔗糖,及d. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 88mM蔗糖,d 133mM甘胺酸,及e. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯20,c. 88mM蔗糖,d. 133mM甘胺酸,及e. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 200ppm聚山梨酸酯20,c. 88mM蔗糖,d. 133mM甘胺酸,及e. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至PH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 88mM蔗糖,及d. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 88mM蔗糖,d. 10mM精胺酸,及e. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之PH範圍為PH 5.0至pH 6.0。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含5mM至10mM甲硫胺酸。
- 根據申請專利範圍第1項之無鹽蛋白質或抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm聚山梨酸酯80,c. 88mM蔗糖,d. 30mM離胺酸,及e. 100mg/ml蛋白質或抗體;其中該蛋白質或抗體調配物之pH範圍為pH5.0至pH 6.0。
- 一種無鹽抗TFPI抗體調配物,其包含: a. 10mM至30mM組胺酸,b. 50ppm至200ppm非離子性表面活性劑,c. 88mM至292mM糖或糖醇,其係選自甘露糖醇、右旋糖、葡萄糖、海藻糖、及蔗糖,d. 0mM至50mM精胺酸,e. 0mM至50mM離胺酸,f. 0mM至133mM甘胺酸或丙胺酸,g. 0mM至10mM甲硫胺酸,及h. 20mg/ml至150mg/ml之抗TFPI抗體;其中該抗TFPI抗體為包含具有SEQ ID NO:1所示之胺基酸序列之輕鏈及具有SEQ ID NO:2所示之胺基酸序列之重鏈的人類IgG2單株抗體或其抗原結合片段或變異體;其中該抗TFPI抗體調配物之pH為pH 4.0至pH 6.0,且其中該抗TFPI抗體調配物實質上不含無機鹽。
- 根據申請專利範圍第17項之無鹽抗TFPI抗體調配物,其中該調配物於22℃下之黏度範圍為1至8mPa-S。
- 根據申請專利範圍第17項之無鹽抗TFPI抗體調配物,其中該調配物之滲透壓範圍為240至380mmol/kg。
- 根據申請專利範圍第17項之無鹽抗TFPI抗體調配物,其中該非離子性表面活性劑為聚山梨酸酯,其係選自:聚山梨酸酯20及聚山梨酸酯80。
- 根據申請專利範圍第17項之無鹽抗TFPI抗體調配物,其中該糖為蔗糖。
- 根據申請專利範圍第17項之無鹽抗TFPI抗體調配物,其包含:a. 10mM組胺酸,b. 75ppm Tween 80,c. 234mM蔗糖,d. 30mM精胺酸,及e. 10mM甲硫胺酸,及f. 100mg/ml抗TFPI抗體;其中該抗TFPI抗體調配物之pH為5.5。
- 一種蛋白質或抗體調配物於製備治療患者之病變的醫藥品之用途,其中該蛋白質或抗體調配物包含10mM至30mM之間之組胺酸、50ppm至200ppm之間之聚山梨酸酯80或聚山梨酸酯20、88mM至292mM之間之蔗糖、0mM至50mM之間之精胺酸、0mM至50mM之間之離胺酸、0mM至133mM之間之甘胺酸、0mM至10mM之間之甲硫胺酸、及20mg/ml至150mg/ml之間之蛋白質或抗體,其pH為pH 4.0至pH 6.0之間,其中該抗體為包含具有SEQ ID NO:1所示之胺基酸序列之輕鏈及具有SEQ ID NO:2所示之胺基酸序列之重鏈的人類IgG2單株抗體或其抗原結合片段或變異體;且其中該蛋白質或抗體調配物實質上不含無機鹽。
- 根據申請專利範圍第23項之用途,其中該蛋白質或抗體調配物係經靜脈內、皮下或肌內投藥。
- 一種抗TFPI抗體調配物於製備治療患者之血友病A或血友病B的醫藥品之用途,其中該抗TFPI抗體調配物包含10mM至30mM之間之組胺酸、50ppm至200ppm之間之聚山梨酸酯80或聚山梨酸酯20、88mM至292mM之間之蔗糖、0mM至50mM之間之精胺酸、0mM至50mM之間之離胺酸、0mM至133mM之間之甘胺酸、0mM至10mM之間之甲硫胺酸、及20mg/ml至150mg/ml之間之蛋白質,其pH為pH 4.0至pH 6.0之間,其中該抗TFPI抗體為包含具有SEQ ID NO:1所示之胺基酸序列之輕鏈及具有SEQ ID NO:2所示之胺基酸序列之重鏈的人類IgG2單株抗體或其抗原結合片段或變異體;且其中該抗TFPI調配物實質上不含無機鹽。
- 根據申請專利範圍第25項之用途,其中該抗TFPI抗體調配物係經靜脈內、肌內或皮下投藥。
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