TW202302138A - 包含IgE Fc受體次單元α之胞外區域的融合蛋白的調配物 - Google Patents
包含IgE Fc受體次單元α之胞外區域的融合蛋白的調配物 Download PDFInfo
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Abstract
本發明係關於一種針對融合蛋白二聚體最佳化之調配物,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域。特定言之,本發明係關於一種包含融合蛋白二聚體之水性醫藥調配物,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域、組胺酸、脯胺酸、甲硫胺酸及泊洛沙姆188,其中該調配物之pH為6.0至7.0。與包含抗IgE抗體之習知治療劑相比,存在於根據本發明之調配物中之融合蛋白以高濃度包括在內,具有改良之穩定性,可藉由皮下注射方便地投予,且具有極佳IgE結合能力。因此,其可有效地用作治療由IgE介導之過敏性疾病之注射劑。
Description
發明領域
本發明係關於針對融合蛋白二聚體最佳化之調配物,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域。
發明背景
在工業化及西化的現代社會,過敏性疾病,諸如過敏性鼻炎、異位性皮膚炎及食物過敏,包括哮喘正在迅速增加,且全身性過敏反應,一種重度過敏性疾病之發生率亦在增加。此等慢性免疫疾病嚴重損害個體之生活品質,且社會經濟成本亦相應飆升。因此,迫切需要採取措施來克服此類疾病。
大部分過敏性疾病係由免疫球蛋白E (IgE)之過度免疫反應引起。IgE係一種在正常狀況下以極低濃度存在於血清中的抗體。IgE亦通常由無害抗原產生。存在IgE之數目在無任何特定刺激下增加的情況。此類情況可導致過敏性疾病。異常增加數目之IgE可結合至在肥大細胞、嗜鹼性球及類似細胞之表面上表現之高親和力IgE Fc受體(FcεRI)。此類結合導致肥大細胞或嗜鹼性球釋放化學介體,諸如組織胺、白三烯、前列腺素、緩激肽及血小板活化因子。此等化學介體之釋放導致過敏性症狀。特定言之,過敏性疾病可由於IgE與FcεRI之間的結合而展現惡化的症狀。
目前,已提出各種方法來治療過敏性疾病,諸如避免過敏原、投予抗過敏藥物、調節體內IgE合成及開發抗IgE抗體。然而,迄今為止已知的治療方法具有許多缺點,諸如無法解決過敏之根本原因、藥物功效不足以及出現嚴重的副作用。
另外,正在研究能夠以高親和力結合IgE及FcγRIIb且抑制表現IgE之細胞的免疫球蛋白組成物(KR 10-1783272 B1)。已報導此類組成物可用於治療IgE介導之疾病,包括過敏及哮喘。
同時,已開發靶向IgE抗體之Fc部分的奧馬珠單抗(Omalizumab) (商品名:Xolair),且將其用作難治性重度哮喘及難治性蕁麻疹之治療劑。然而,為了維持治療效果而以高劑量投予奧馬珠單抗會導致高成本負擔,以及諸如血管性水腫及全身性過敏反應等副作用。另外,根據上市後的結果,已報導過敏性肉芽腫性血管炎及特發性重度血小板減少症。因此,愈來愈需要開發能夠有效治療過敏性疾病而無副作用之治療劑。
為了開發可有效治療過敏性疾病而無副作用之治療劑,開發了包含IgE Fc受體之α次單元之胞外區域的融合蛋白,且證實該融合蛋白可治療過敏性疾病(KR 10-2038675 B1)。為了有效地將此蛋白質應用於過敏性疾病的治療,有必要開發一種提供劑量及投予優勢之穩定的高濃度蛋白質調配物。
發明概要
技術問題
本發明之一個目標為提供一種最佳化調配物,以商業化用於治療由IgE介導之過敏性疾病的融合蛋白二聚體。特定言之,本發明人開發一種針對皮下注射最佳化之高濃度水性醫藥調配物,以商業化融合蛋白二聚體,從而完成本發明。
問題之解決方案
為了解決上述問題,本發明提供了包含融合蛋白二聚體之水性醫藥調配物,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)且具有6.0至7.0之pH。
發明效果
根據本發明之水性醫藥調配物具有極佳穩定性,該醫藥調配物包含融合蛋白二聚體,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)且pH為6.0至7.0。此外,根據本發明的包含高濃度融合蛋白二聚體之調配物可藉由皮下注射快速且方便地投予。另外,該調配物具有極佳穩定性,且可藉由減少聚集體形成來增加儲存期。因此,含有包含IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)的融合蛋白二聚體之調配物可有效地用作治療過敏性疾病之注射劑。
較佳實施例之詳細說明
針對融合蛋白二聚體最佳化之調配物
在本發明之一態樣中,提供一種水性醫藥調配物,其包含融合蛋白二聚體,該融合蛋白二聚體包含IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)。此處,水性醫藥調配物之pH可在6.0至7.0、6.1至7.0、6.2至6.9、6.3至6.8、6.4至6.8或6.4至6.6範圍內。
如本文所用,術語「醫藥調配物」係指以允許活性成分之生物活性明確有效的形式存在,且不包括在調配物所投予之個體中引起副作用之成分的製劑。
術語「個體」可為哺乳動物,諸如人類、犬、牛、馬、豬、綿羊、山羊、貓、小鼠、兔及大鼠,且較佳可為人類、犬或貓。
如本文所用,術語「水性醫藥調配物」係指使用適合之水溶劑,諸如水或水性/油性混合物(例如水及醇之混合物)的醫藥調配物。調配物可維持穩定性,諸如化學或物理穩定性,或生物活性。
術語「穩定性」係指一種維持恆定狀態的特性,且大體上關於使生物活性物質(諸如蛋白質、肽或生物活性巨分子)的降解、變性、聚集或解摺疊最小化。
同時,調配物可為液體調配物。液體調配物為水性溶液或懸浮液,且可在室溫下穩定地維持,在儲存期間冷藏(例如2℃至8℃)或冷凍(例如-20℃或-70℃)。
本發明之水性醫藥調配物可非經腸投予。在此情況下,非經腸投予可藉由諸如皮下投予、靜脈內投予、黏膜投予及肌肉內投予等方法執行。在本發明之一實施例中,調配物可較佳藉由皮下注射投予。
在本發明之一實施例中,水性醫藥調配物中可含有高濃度,特定言之50 mg/mL或更高、60 mg/mL或更高或70 mg/mL或更高的融合蛋白二聚體。在本發明之一實施例中,融合蛋白二聚體之濃度可為50 mg/mL至150 mg/mL、50 mg/mL至130 mg/mL、50 mg/mL至120 mg/mL、50 mg/mL至110 mg/mL、50 mg/mL至100 mg/mL、50 mg/mL至90 mg/mL、50 mg/mL至80 mg/mL、60 mg/mL至150 mg/mL、60 mg/mL至130 mg/mL、60 mg/mL至120 mg/mL、60 mg/mL至110 mg/mL、60 mg/mL至100 mg/mL、60 mg/mL至90 mg/mL、60 mg/mL至80 mg/mL、70 mg/mL至150 mg/mL、70 mg/mL至130 mg/mL、70 mg/mL至120 mg/mL、70 mg/mL至110 mg/mL、70 mg/mL至100 mg/mL、70 mg/mL至90 mg/mL或70 mg/mL至80 mg/mL,且較佳為75 mg/mL,但不限於此。
另外,水性醫藥調配物可進一步包含緩衝劑及穩定劑。此處,緩衝劑可為組胺酸。組胺酸可以10 mM至100 mM之濃度存在於調配物中。在本發明之一實施例中,作為緩衝劑之組胺酸可以如下濃度存在於調配物中:10 mM至90 mM、10 mM至80 mM、10 mM至70 mM、10 mM至60 mM、20 mM至90 mM、20 mM至80 mM、20 mM至70 mM、20 mM至60 mM、30 mM至90 mM、30 mM至80 mM、30 mM至70 mM、30 mM至60 mM、40 mM至90 mM、40 mM至80 mM、40 mM至70 mM、40 mM至60 mM、50 mM至90 mM、50 mM至80 mM、50 mM至70 mM或50 mM至60 mM。較佳地,其可以55 mM之濃度存在。
組胺酸緩衝劑可包含組胺酸氯化物、組胺酸乙酸鹽、組胺酸磷酸鹽、組胺酸硫酸鹽之溶液,但不限於此。組胺酸緩衝劑或組胺酸-HCl緩衝劑之pH可在5.5至7.5、6.0至7.0、6.1至7.0、6.2至6.9、6.3至6.8、6.4至6.8或6.4至6.6範圍內,且較佳可為pH 6.5。
穩定劑可為脯胺酸。脯胺酸可以200 mM至300 mM之濃度存在於調配物中。在本發明之一實施例中,脯胺酸可以如下濃度存在於調配物中:200 mM至290 mM、200 mM至280 mM、200 mM至270 mM、200 mM至260 mM、210 mM至290 mM、210 mM至280 mM、210 mM至270 mM、210 mM至260 mM、220 mM至290 mM、220 mM至280 mM、220 mM至270 mM、220 mM至260 mM、230 mM至290 mM、230 mM至280 mM、230 mM至270 mM、230 mM至260 mM、240 mM至290 mM、240 mM至280 mM、240 mM至270 mM或240 mM至260 mM。較佳地,其可以250 mM之濃度存在。
本發明之水性醫藥調配物可進一步包含抗氧化劑。此處,抗氧化劑可為甲硫胺酸。甲硫胺酸可以10 mg/mL至30 mg/mL之濃度存在於調配物中。在本發明之一實施例中,甲硫胺酸可以如下濃度存在於調配物中:10 mg/mL至28 mg/mL、10 mg/mL至26 mg/mL、10 mg/mL至24 mg/mL、10 mg/mL至22 mg/mL、12 mg/mL至28 mg/mL、12 mg/mL至26 mg/mL、12 mg/mL至24 mg/mL、12 mg/mL至22 mg/mL、14 mg/mL至28 mg/mL、14 mg/mL至26 mg/mL、14 mg/mL至24 mg/mL、14 mg/mL至22 mg/mL、16 mg/mL至28 mg/mL、16 mg/mL至26 mg/mL、16 mg/mL至24 mg/mL、16 mg/mL至22 mg/mL、18 mg/mL至28 mg/mL、18 mg/mL至26 mg/mL、18 mg/mL至24 mg/mL或18 mg/mL至22 mg/mL。較佳地,其可以20 mg/mL之濃度存在。
抗氧化劑係一種抑制其他分子之氧化的試劑,且可藉由移除氧氣來減少調配物中聚集體的形成。
另外,水性醫藥調配物可進一步包含界面活性劑。界面活性劑係一種降低液體表面張力之試劑,且可控制可溶性及不溶性聚集體的形成。界面活性劑可為非離子界面活性劑,且可為聚山梨醇酯,諸如聚山梨醇酯20、聚山梨醇酯28、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65、聚山梨醇酯80、聚山梨醇酯81及聚山梨醇酯85;泊洛沙姆(poloxamers),諸如泊洛沙姆181、泊洛沙姆188及泊洛沙姆407;或聚乙二醇(PEG),但不限於此。較佳地,界面活性劑可為泊洛沙姆。
特定言之,泊洛沙姆可為泊洛沙姆188。泊洛沙姆188可以0.01 w/v%至1 w/v%之濃度存在於調配物中。在本發明之一實施例中,泊洛沙姆188可以如下濃度存在於調配物中:0.02 w/v%至0.8 w/v%、0.02 w/v%至0.6 w/v%、0.02 w/v%至0.4 w/v%、0.02 w/v%至0.2 w/v%、0.02 w/v%至0.15 w/v%、0.04 w/v%至0.8 w/v%、0.04 w/v%至0.6 w/v%、0.04 w/v%至0.4 w/v%、0.04 w/v%至0.2 w/v%、0.04 w/v%至0.15 w/v%、0.06 w/v%至0.8 w/v%、0.06 w/v%至0.6 w/v%、0.06 w/v%至0.4 w/v%、0.06 w/v%至0.2 w/v%、0.06 w/v%至0.15 w/v%、0.08 w/v%至0.8 w/v%、0.08 w/v%至0.6 w/v%、0.08 w/v%至0.4 w/v%、0.08 w/v%至0.2 w/v%、0.08 w/v%至0.15 w/v%、0.09 w/v%至0.8 w/v%、0.09 w/v%至0.6 w/v%、0.09 w/v%至0.4 w/v%、0.09 w/v%至0.2 w/v%或0.09 w/v%至0.15 w/v%。較佳地,其可以0.1 w/v%之濃度存在。
在本發明之另一態樣中,提供一種水性醫藥調配物,其包含i)包含濃度為50 mg/mL至150 mg/mL之FcεRIα ECD的融合蛋白二聚體;ii)濃度為10 mM至100 mM之組胺酸;iii)濃度為200 mM至300 mM之脯胺酸;iv)濃度為10 mg/mL至30 mg/mL之甲硫胺酸;及v)濃度為0.01 w/v%至1 w/v%之泊洛沙姆188。此處,水性醫藥調配物之pH可在6.0至7.0、6.1至7.0、6.2至6.9、6.3至6.8、6.4至6.8或6.4至6.6範圍內。較佳地,其可為pH 6.5。
在本發明之一實施例中,水性醫藥調配物可包含i)包含濃度為75 mg/mL之FcεRIα ECD的融合蛋白二聚體;ii)濃度為55 mM之組胺酸;iii)濃度為250 mM之脯胺酸;iv)濃度為20 mg/mL之甲硫胺酸;及v)濃度為0.1 w/v%之泊洛沙姆188。
水性醫藥調配物可儲存於選自由以下組成之群的容器中:小瓶、藥筒、注射器及自動注射器。
另外,儲存調配物之容器可在室溫下、在2℃至8℃下或在25℃至40℃下儲存,直至向需要治療之個體投予。
調配物可如下地投予:藉由非經腸投藥,諸如皮下投藥、靜脈內投藥、黏膜投藥、肌肉內投藥或腹膜內投藥,但不限於此,使用18G至32G針頭以5 mL或更小、3 mL或更小或2 mL或更小之體積。較佳地,其可使用27G針頭以1 mL或更小之體積皮下投予。
包含 IgE Fc 受體之 α 次單元之胞外區域的融合蛋白
上文所述之融合蛋白二聚體如下。特定言之,該二聚體包含二個單體,其中之每一者包含IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)。
單體可包含經修飾之Fc區,且經修飾之Fc區及FcεRIα ECD可經由IgD抗體之鉸鏈連接。
如本文所用,術語「IgE」意謂稱為免疫球蛋白E之抗體蛋白質。IgE對肥大細胞、血液中之嗜鹼性球或其類似物具有親和力。另外,IgE抗體與對應於其之抗原(過敏原)之間的反應引起發炎反應。另外,已知IgE係一種引起全身性過敏反應之抗體,該全身性過敏反應由於肥大細胞或嗜鹼性球之急劇分泌而發生。
如本文所用,術語「IgE Fc受體」亦稱為Fcε受體,且結合至IgE之Fc部分。受體有二種類型。對IgE Fc具有高親和力之受體被稱為Fcε受體I (FcεRI)。對IgE Fc具有低親和力之受體被稱為Fcε受體II (FcεRII)。FcεRI表現於肥大細胞及嗜鹼性球中。在結合至FcεRI之IgE抗體藉由多價抗原交聯之情況下,肥大細胞或嗜鹼性球中發生脫粒,從而釋放出包括組胺在內的各種化學遞質物質。此釋放導致立即的過敏反應。
FcεRI係由一條α鏈、一條β鏈及二條γ鏈藉由二硫鍵連接構成的膜蛋白。在此等鏈中,與IgE結合之部分為α鏈(FcεRIα),且FcεRIα之大小為約60 kDa,由存在於細胞膜內之疏水性區域及存在於細胞膜外之親水性區域構成。特定言之,IgE結合至α鏈之胞外區域。
特定言之,IgE Fc受體之α次單元可具有NP_001992.1中所闡述之胺基酸序列。另外,IgE Fc受體之α次單元之胞外區域(FcεRIα ECD)可具有SEQ ID NO: 1之胺基酸序列。在本說明書中,IgE Fc受體之α次單元之胞外區域可為IgE Fc受體之α次單元之胞外區域的片段或變異體,只要該片段或變異體能夠結合至IgE。
變異體可經由在野生型FcεRIα ECD (胞外區域)中取代、缺失或添加一或多種蛋白質之方法製備,只要該方法不改變FcεRI之α鏈的功能即可。此類各種蛋白質或肽可與SEQ ID NO: 1之胺基酸序列具有90%、91%、92%、93%、94%、95%、96%、97%、98%或99%或更高一致性。另外,SEQ ID NO: 1之FcεRIα ECD可由具有SEQ ID NO: 5之序列的多核苷酸編碼。
另外,如本文所用,術語「經修飾之Fc區」意謂其中抗體之Fc部分的一部分已經修飾之區域。此處,術語「Fc區」係指含有免疫球蛋白之重鏈恆定區2 (CH2)及重鏈恆定區3 (CH3)且不含免疫球蛋白之重鏈及輕鏈可變區及輕鏈恆定區1 (CH1)的蛋白質。特定言之,經修飾之Fc區意謂藉由取代Fc區中之一些胺基酸或藉由組合不同類型之Fc區而獲得的區域。特定言之,經修飾之Fc區可具有SEQ ID NO: 2之胺基酸序列。另外,SEQ ID NO: 2之經修飾之Fc區可由具有SEQ ID NO: 6之序列的多核苷酸編碼。
另外,本發明之「經修飾之Fc區」可呈具有呈天然形式之糖鏈、相對於天然形式增加之糖鏈或相對於天然形式減少之糖鏈形式,或可呈糖鏈經移除之形式。免疫球蛋白Fc糖鏈可藉由習知方法,諸如化學方法、酶方法及使用微生物之基因工程化方法進行修飾。
此處,本發明之「經修飾之Fc區」可為由於不具有FcγR或C1q結合位點而缺乏抗體依賴性細胞毒性(ADCC)及補體依賴性細胞毒性(CDC)功能的區域。另外,經修飾之Fc區及FcεRIα ECD可經由IgD抗體之鉸鏈連接。IgD抗體之鉸鏈由64個胺基酸構成且可選擇性地包括20至60個連續胺基酸,或25至50個連續胺基酸,或30至40個胺基酸。在一個實施例中,IgD抗體之鉸鏈可由30或49個胺基酸構成,如下文所示。另外,IgD抗體之鉸鏈可為藉由修飾鉸鏈區獲得之鉸鏈變異體,其中鉸鏈可包括至少一個半胱胺酸。此處,鉸鏈變異體可藉由修飾IgD抗體之鉸鏈序列中之一些來獲得,以便使蛋白質生產過程中截短形式的產生最小化。
在一個實施例中,鉸鏈可包括以下序列:
Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa1 Xaa2 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (SEQ ID NO: 17),其中Xaa1可為Lys或Gly,且Xaa2可為Glu、Gly或Ser。特定言之,鉸鏈可具有SEQ ID NO: 3或SEQ ID NO: 19之胺基酸序列,從而使蛋白質生產過程中截短形式的產生最小化。
在另一實施例中,鉸鏈可包括以下序列:
Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa3 Xaa4 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro (SEQ ID NO: 18),其中Xaa3可為Lys或Gly,且Xaa4可為Glu、Gly或Ser。特定言之,鉸鏈可具有SEQ ID NO: 4之胺基酸序列,從而使蛋白質生產過程中截短形式的產生最小化。
特定言之,具有SEQ ID NO: 4之序列之鉸鏈中之至少一個Thr可經醣基化。特定言之,SEQ ID NO: 18之胺基酸中之第13、第14、第18及第19個Thr可經醣基化。較佳地,所有四個胺基酸均可經醣基化。此處,醣基化可為O-醣基化。
另外,如上文所述,本發明提供之融合蛋白二聚體可呈以下形式:其中二個單體彼此結合,且各單體係藉由IgE Fc受體之α次單元之胞外區域與經修飾之Fc區之間的結合獲得。融合蛋白二聚體可呈其中相同的二個單體藉由位於鉸鏈位點處之半胱胺酸彼此結合之形式。另外,融合蛋白二聚體可呈其中二個不同的單體彼此結合之形式。舉例而言,在其中二個單體呈彼此不同之形式的情況下,多肽二聚體可呈以下形式:其中一個單體包括IgE Fc受體之α次單元之胞外區域,且另一單體包括IgE Fc受體之α次單元之胞外區域的片段。此處,單體之實施例可具有SEQ ID NO: 20、SEQ ID NO: 21或SEQ ID NO: 22之胺基酸序列。
另外,本發明提供之融合蛋白二聚體展現比奧馬珠單抗(一種抗IgE抗體)高10至100倍、20至90倍、20至70倍、30至70倍或40至70倍的與IgE之結合親和力,且可較佳展現比奧馬珠單抗高70倍的與IgE之結合親和力。
針對融合蛋白二聚體最佳化之調配物的治療用途
在本發明之另一態樣中,提供包含融合蛋白二聚體之水性醫藥調配物用於預防或治療過敏性疾病之用途。
在本說明書中,術語「過敏性疾病」意謂由肥大細胞活化,諸如肥大細胞脫粒介導之過敏反應引起的病理症狀。此類過敏性疾病包括食物過敏、異位性皮膚炎、哮喘、過敏性鼻炎、過敏性結膜炎、過敏性皮膚炎、過敏性接觸性皮膚炎、全身性過敏反應、蕁麻疹、搔癢症、昆蟲過敏、慢性特發性蕁麻疹、慢性自發性蕁麻疹、藥物過敏及類似疾病。特定言之,過敏性疾病可為IgE介導的。
本發明之水性醫藥調配物可根據對治療過敏性疾病有效之給藥方案及劑量向個體投予。本發明調配物中可含有任何量(有效量)之融合蛋白二聚體,只要活性成分可展現抗過敏活性即可。基於組成物之總重量,活性成分之典型有效量將被確定處於0.001重量%至20.0重量%範圍內。此處,「有效量」係指能夠誘導抗過敏作用之量。此類有效量可在熟習此項技術者之正常技能內以實驗方式確定。
取決於患者之狀況、體重、性別、年齡、疾病嚴重程度或投予途徑,調配物之較佳日劑量範圍為0.01 μg/kg至10 g/kg,且較佳為0.01 mg/kg至1 g/kg。投予可一天一次或若干次地進行。此類劑量決不應解釋為限制本發明之範疇。
另一方面,本發明提供一種治療或預防過敏性疾病之方法,其包含向個體投予包含融合蛋白二聚體之水性醫藥調配物。
個體可為哺乳動物,較佳人類。在此情況下,投予可經由非經腸途徑進行。在此情況下,非經腸投予可藉由皮下投予、靜脈內投予、黏膜投予、肌肉內投予或其類似者進行。
實施本發明之方式
在下文中,將參考以下實例更詳細描述本發明。然而,以下實例僅意欲說明本發明,且本發明之範疇不限於此。
製備實例 1. 製備包含 FcεRIα ECD 及經修飾之 Fc 區的 融合蛋白二聚體 : GI-301
IgE Fc受體之α次單元之胞外區域(FcεRIα-ECD)之C末端經修飾多肽係根據美國專利第7,867,491號中所揭示之方法製備。
首先,為了表現蛋白質(FcεRIαECD-Fc1)、蛋白質(FcεRIαECD-Fc2)及蛋白質(FcεR1αECD-Fc3),其中具有SEQ ID NO: 1之胺基酸序列的FcεRI之α鏈之胞外區域及SEQ ID NO: 2之經修飾之免疫球蛋白Fc分別經由SEQ ID NO: 19之鉸鏈、SEQ ID NO: 3之鉸鏈及SEQ ID NO: 4之鉸鏈連接,將藉由連接編碼各蛋白質之基因獲得的卡匣選殖至載體中以構築FcεRIα ECD-Fc蛋白質表現載體。接著,將表現載體中之每一者轉染至CHO細胞中。
此處,在轉導至細胞株中時,藉由將α-2,6-唾液酸轉移酶基因選殖至載體中獲得之表現載體經同時轉染,以分別製備能夠表現被添加唾液酸之FcεRIα ECD-Fc2ST及FcεRIα ECD-Fc3ST蛋白質的細胞株。由細胞株產生之融合蛋白二聚體被命名為「GI-301」。
實例 1. 生產高度濃縮 GI-301 之 緩衝液及 pH 條件的 最佳化
進行測試以開發包括約100 mg/mL GI-301物質之皮下注射用液體調配物。調配物應在2℃至8℃下穩定儲存,且調配物之黏度應低至足以用於注射。首先,使緩衝液及pH條件最佳化。
為確定適當調配緩衝液,藉由實驗設計(DOE)選擇總計25種具有不同pH、緩衝液組分、離子強度及穩定劑之不同緩衝液,且進行預篩選(步驟1及步驟2)及最終篩選(步驟3)。
i)預篩選(步驟1及步驟2):
- 在DLS盤讀取器中量測動態雷射光散射以確認樣品之膠體及熱力學穩定性的增加。
- 對於各條件,使樣品針對調配物緩衝液進行透析。
- 藉由量測各調配物緩衝液中各濃度之樣品的流體動力半徑而藉由確認蛋白質-蛋白質相互作用來確定膠體穩定性。此等結果用於預測在處理及儲存期間具有低蛋白質聚集風險之調配物候選物。
- 變性溫度(熱力學穩定性)係藉由量測各調配物緩衝液中各溫度之樣品的流體動力半徑來確定。此等結果用於預測在處理及儲存期間具有低蛋白質變性風險之調配物候選物。當蛋白質區域開始變性時,蛋白質之流體動力半徑顯著增加。解摺疊之起始溫度可被視為蛋白質二級結構穩定性的一個指標。
ii)最終篩選(步驟3):
- 膠體穩定性(分子間相互作用,A2)係藉由CG-MALS (成分梯度多角度光散射)量測。
- 熱力學穩定性係藉由Nano DSC (奈米差示掃描熱量測定)量測。
- 蛋白質之聚集狀態係藉由SE-HPLC確認。
- 相對效能係藉由ELISA量測。
- 根據以上結果,選擇四種最適合調配物。
特定言之,在表1中之前14個樣品中,評估了GI-301關於pH、緩衝液組分及離子強度之一般物理特性。藉由針對各調配物緩衝液透析GI-301來製備樣品。
將pH自6.0調節至7.4,其為皮下注射可接受的pH範圍。對於各pH值,選擇適合之緩衝液組分以實現足夠的緩衝容量。緩衝液組分係選自醫藥學上可接受之賦形劑。添加氯化鈉以調節調配物之離子強度(最大離子強度設定為等張)。第一預篩選之結果概述於下表1中。
[表1]
1)樣品#1之實例:kd = -0.1 mL/mg × 10
-2= -0.001 mL/mg
# | pH | 緩衝液組分 | 鹽 / 穩定劑 | T onset [℃ ] | kd[mL/mg×10 -2] 1) | 實際 pH |
1 | 7.4 | 10 mM磷酸鈉 | 150 NaCl | 65 | -0.1 | 7.36 |
2 | 7.4 | 10 mM磷酸鈉 | 無 | 68 | 3.1 | 7.36 |
3 | 7.4 | 10 mM Tris/HCl | 150 NaCl | 65 | -0.1 | 7.40 |
4 | 7.4 | 10 mM Tris/HCl | 無 | 64 | 5.7 | 7.38 |
5 | 6.7 | 10 mM磷酸鈉 | 150 NaCl | 66 | -1.2 | 6.72 |
6 | 6.7 | 10 mM磷酸鈉 | 無 | 60 | 3.3 | 6.68 |
7 | 6.7 | 10 mM His/HCl | 150 NaCl | 63 | -1.1 | 6.71 |
8 | 6.7 | 10 mM His/HCl | 無 | 69 | 14.2 | 6.53 |
9 | 6.0 | 10 mM His/HCl | 150 NaCl | 54 | -1.4 | 6.03 |
10 | 6.0 | 10 mM His/HCl | 無 | 59 | 5.8 | 6.01 |
11 | 6.7 | 10 mM檸檬酸鈉 | 150 NaCl | 65 | -1.2 | 6.62 |
12 | 6.7 | 10 mM檸檬酸鈉 | 無 | 66 | 0.6 | 6.66 |
13 | 6.0 | 10 mM檸檬酸鈉 | 150 NaCl | 64 | -1.4 | 6.00 |
14 | 6.0 | 10 mM檸檬酸鈉 | 無 | 63 | 0.1 | 6.00 |
一般而言,GI-301之膠體穩定性在高離子強度下較低且與所使用之緩衝系統及調配物之pH無關。在低離子強度下,緩衝組分對GI-301之膠體穩定性展示最大影響。pH之影響不顯著。在His/HCl緩衝系統中觀測到最佳膠體穩定性,接著為Tris/HCl、磷酸鈉及檸檬酸鈉。一般而言,調配物之酸性pH值愈高,一個緩衝組中之膠體穩定性愈低。在調配物樣品#8 (10 mM His/HCl,pH 6.7)、樣品#10 (10 mM His/HCl,pH 6.0)及樣品#4 (10 mM Tris/HCl,pH 7.4)中觀測到極佳膠體穩定性。
GI-301之熱力學穩定性在除樣品#9及#10之外的所有調配物樣品中類似。GI-301在通常使用之藥物儲存溫度下展現高熱力學穩定性。
透析樣品之實際pH值符合所需pH值,但調配物樣品#8除外,其中觀測到輕微的唐南效應(Donnan-effect)。
考慮到此等結果,選擇pH 6.7下之His/HCl及pH 7.4下之Tris/HCl作為GI-301之最適當緩衝液。在樣品#15至#20中測試了適於液體及/或凍乾之穩定劑及非離子等張劑。測試中使用之賦形劑為海藻糖(凍乾中使用之低溫保護劑)、甘露醇(凍乾中使用之增積劑及非離子等張劑)及脯胺酸(液體調配物中使用之胺基酸穩定劑,非離子)。賦形劑之二步篩選的結果概述於下表2中。
[表2]
# | pH | 緩衝液組分 | 鹽 / 穩定劑 | T onset [℃ ] | kd[mL/mg×10 -2] | 實際 pH |
15 | 6.7 | 10 mM His/HCl | 250 mM海藻糖 | 67 | 6.3 | 6.44 |
16 | 6.7 | 10 mM His/HCl | 250 mM 甘露醇 | 66 | 13.5 | 6.52 |
17 | 6.7 | 10 mM His/HCl | 250 mM 脯胺酸 | 64 | 20.4 | 6.55 |
18 | 7.4 | 10 mM Tris/HCl | 250 mM海藻糖 | 65 | 5.2 | 7.34 |
19 | 7.4 | 10 mM Tris/HCl | 250 mM 甘露醇 | 68 | 6.1 | 7.40 |
20 | 7.4 | 10 mM Tris/HCl | 250 mM 脯胺酸 | 68 | 7.3 | 7.39 |
在緩衝液系統His/HCl及Tris/HCl二者中添加甘露醇及脯胺酸時均觀測到膠體穩定性增加。添加海藻糖後,觀測到膠體穩定性略微降低。賦形劑對GI-301之熱力學穩定性或對實際pH均不展現顯著影響。
在最終篩選實驗中,使用CG-MALS (A
2)、Nano DSC (T
onset) SE-HPLC (相對單體含量)及ELISA (相對效能)研究液體及凍乾物之最具前景的調配物樣品。最終篩選之結果概述於下表3中。
[表3]
# | pH | 緩衝液組分 | 穩定劑 | T onset Nano DSC [℃ ] | A 2 [10 -4mol*ml*g -2] | 根據 SE-HPLC 之相對單體含量 [%] | ELISA 效能 [%] |
21 | 6.7 | 10 mM His/HCl | 250 mM海藻糖 | 51 | 4.8 | 96.2 | 103 |
22 | 6.7 | 10 mM His/HCl | 250 mM甘露醇 | 52 | 7.8 | 96.1 | 98 |
23 | 6.7 | 10 mM His/HCl | 250 mM脯胺酸 | 52 | 8.7 | 96.1 | 101 |
24 | 7.4 | 10 mM Tris/HCl | 250 mM甘露醇 | 51 | 4.4 | 96.1 | 92 |
25 | 7.4 | 10 mM Tris/HCl | 250 mM脯胺酸 | 49 | 4.8 | 96.1 | 106 |
五種樣品之膠體穩定性及T
onset的相對排名與先前使用DLS獲得之結果類似。CG-MALS結果展示在所有調配物樣品中之強排斥蛋白質-蛋白質相互作用。相比於DLS量測,nanoDSC量測中之熱解摺疊的T
onset較低。DLS量測蛋白質之流體動力學半徑增加,其為由於熱解摺疊所致之聚集的結果。相比之下,nanoDSC量測摺疊蛋白質至未摺疊蛋白質之熱力學轉變且因此展示較低T
onset值。如藉由ELISA所量測之相對效能在所有調配物樣品中均幾乎為100%。
基於以上結果,考慮到以下表4中所述之項目,進行了「濃度挑戰測試」。
[表4]
實例 2. 關於高濃度 GI-301 之可能性的測試
# | pH | 緩衝液組分 | 穩定劑 | 描述 |
21 | 6.7 | 10 mM His/HCl | 250 mM海藻糖 | 實際pH為6.5之液體調配物;備份用於冷凍乾燥呈現 |
22 | 6.7 | 10 mM His/HCl | 250 mM甘露醇 | pH為6.5之液體調配物;常用賦形劑 |
23 | 6.7 | 10 mM His/HCl | 250 mM脯胺酸 | pH為6.5之液體調配物;可具有較低聚集傾向 |
25 | 7.4 | 10 mM Tris/HCl | 250 mM脯胺酸 | pH為7.4之液體調配物;完美等張條件,但可具有較低化學穩定性 |
在實例1中測試之25種樣品中,選擇四種最適當樣品用於濃度挑戰測試。基於實例1之結果選擇之四種候選調配物樣品概述於下表5中。
[表5]
如下測試以上四種調配物候選物:
# | pH | 緩衝液組分 | 穩定劑 |
1 | 6.7 | 10 mM His/HCl | 250 mM海藻糖 |
2 | 6.7 | 10 mM His/HCl | 250 mM甘露醇 |
3 | 6.7 | 10 mM His/HCl | 250 mM脯胺酸 |
4 | 7.4 | 10 mM Tris/HCl | 250 mM脯胺酸 |
- 確認在各調配物樣品中是否達成約100 mg/mL之目標濃度(使用超濾及製程相關的時間間隔)。
- 量測濃縮及混合樣品之pH值以監測由唐南效應所致之pH偏移。
- 使用0.22 μm膜過濾器過濾樣品,且將其使用帶有無菌柱塞頭之多通道移液器無菌填充至2R小瓶中(100 mg/mL之目標填充體積為1.2 mL)。
- 藉由在4℃及35℃下儲存72小時對所有高度濃縮樣品進行挑戰測試。
- 72小時之後,以肉眼分析樣品之濁度及沈澱。
- 黏度及可注射性:藉由量測推出力來評估各調配物樣品之可注射性。使用力/位移量測裝置經由連接的針頭以規定的橫向速度分配注射器之內容物。分析樣品之以下項目:視覺外觀、根據UV 280之濃度、pH、使用毛細管黏度計之黏度、根據比濁法量測之濁度、重量莫耳滲透濃度、根據ELISA之相對效能及根據SE-HPLC之聚集狀態。
結果,上表5中之四種調配物樣品可成功濃縮至100 mg/mL之濃度。在35℃下儲存72小時後,小瓶中之高度黏滯(100 mg/mL)溶液不顯示沈澱或明顯濁度。
根據可注射性測試,確認使用30G套管導致所有100 mg/mL樣品之推出力超過20 N限制。當使用27G套管時,推出力係可接受的。當其被稀釋至50 mg/mL之濃度時,30G套管係可接受的。
作為濃縮之結果,pH降低約0.4至0.8 (唐南效應)。為補償唐南效應,使用高度濃縮之L-組胺酸及TRIS鹼將pH值調節至原始濃度。
最終蛋白質濃度為約65 mg/mL。將裝有1 mL樣品之1 mL注射器推過拉伸機,且分析剪切應力材料(自注射器中推出之內容物)。
所有結果展示於下表6中。
[表6]
可接受的結果: √ 不可接受的結果: X
樣品 | ||||||
GI-301 之濃度 | 初級包裝材料 | 方法 | #1 | #2 | #3 | #4 |
100 mg/mL | 2R小瓶 | 視覺外觀/沈澱 在5℃下72小時之後 | √ | √ | √ | √ |
100 mg/mL | 2R小瓶 | 視覺外觀/沈澱 在35℃下72小時之後 | √ | √ | √ | √ |
100 mg/mL | 1 mL注射器30G套管 | 推出力 | X | X | X | X |
視覺外觀/沈澱 | √ | √ | √ | √ | ||
100 mg/mL | 1 mL注射器27G套管 | 推出力 | √ | √ | √ | √ |
視覺外觀/沈澱 | √ | √ | √ | √ | ||
50 mg/mL | 1 mL注射器30G套管 | 推出力 | √ | √ | √ | √ |
視覺外觀/沈澱 | √ | √ | √ | √ | ||
pH -推出之影響 | √ | √ | √ | √ | ||
65 mg/mL (唐南效應;補償樣品#2-#4) | 1 mL注射器27G套管 | 推出力 | √ | √ | √ | |
視覺外觀/沈澱 | √ | √ | √ | |||
pH -推出之影響 | √ | √ | √ | |||
SEC | √ | √ | √ | |||
ELISA | √ | √ | √ | |||
黏度 | √ | √ | √ | |||
濁度 | √ | √ | √ | |||
重量莫耳滲透濃度 | √ | √ | √ |
在使用濃度為65 mg/mL或更低之蛋白質的情況下,即使使用30G套管,亦確認所有四種調配物樣品之可注射性。
在所有四種調配物樣品中,GI-301蛋白質在濃度為100 mg/mL或更低之短期儲存期間極穩定。
由於無法根據短期資料預測長期穩定性,因此另外進行了加速穩定性測試。
四種調配物候選物展示類似結果,如上表6中所示。
實例 3. 加速穩定性測試 ( 強制降解測試 I)
在實例2中,蛋白質可在四種調配物緩衝液中以高濃度濃縮,且亦驗證了可注射性。作為對四個樣品之分析的結果,確認在其之間不存在顯著差異。因此,另外使用2R小瓶對實例2之四個樣品(參見表5)進行強制降解測試。
製備目標蛋白質濃度為50 mg/mL之四種調配物候選物,且進行以下步驟:
- 每個樣品無菌裝填十個2R小瓶
- 強制熱應力及攪拌:在200 rpm下在35℃下持續2週或5天
- 光照:在750 W/m
2條件下持續7.5小時
- 分析樣品之以下項目:視覺外觀、根據UV 280之濃度、pH、根據比濁法量測之濁度、重量莫耳滲透濃度、根據ELISA之相對效能及根據SE-HPLC之聚集狀態。
四個調配物樣品成功濃縮至約50 mg/mL之濃度,且具有適當的pH偏移補償。此後,使用2R小瓶進行加速應力穩定性測試。
最佳(√)及最差(X)結果展示於下表7中。
[表7]
實驗方法 | 樣品 | ||||||||||||||||
#1 | #2 | #3 | #4 | ||||||||||||||
目視檢查 | 5天, 35℃,200 rpm | 14天,35℃,200 rpm | 光 | 5天, 35℃,200 rpm | 14天, 35℃,200 rpm | 光 | 5天, 35℃, 200 rpm | 14天, 35℃, 200 rpm | 光 | 5天, 35℃,200 rpm | 14天,35℃,200 rpm | 光 | |||||
X | X | √ | √ | X | √ | √ | X | √ | √ | X | √ | ||||||
SE-HPLC | 14天, 35℃, 200 rpm | 光 | 14天, 35℃, 200 rpm | 光 | 14天, 35℃, 200 rpm | 光 | 14天, 35℃, 200 rpm | 光 | |||||||||
SE- HPLC | 主峰(一般) | √ | √ | X | X | ||||||||||||
聚集體 | √ | √ | X | X | |||||||||||||
片段 | √ | X | X | √ | |||||||||||||
根據結果,樣品#3 (脯胺酸、組胺酸/HCl,pH 6.7)係最適用於下一顯影步驟之緩衝液。另外,此樣品用於經由交錯流過濾進行150 mg/mL濃度測試。
同時,作為SE-HPLC分析之結果,所有調配物樣品均可冷凍/解凍三次,而無顯著負面影響。
實例 4. 經由交錯流過濾之高濃度可行性分析
基於實例3之結果,選擇包含250 mM脯胺酸、10 mM組胺酸/HCl,pH 6.7之調配物作為經由交錯流過濾之高濃度(150 mg/mL)可行性分析的調配物。目標為獲得濃縮蛋白質溶液(150 mg/mL)。
實例 4.1. 交錯流過濾及 pH 調節
在第一步中,將1,400 g 7.5 mg/mL物質濃縮至約200 mL之體積。在1.0巴之跨膜壓力(TMP)下進行濃縮。
在此步驟之後,緩衝液交換(各透濾)以等容方式開始。
用目標緩衝液替代滲透物排出液,將該緩衝液饋入交錯流裝置之攪拌容器中。目標緩衝液之總饋入量為950 g。原始DS緩衝液之濃度在透濾步驟結束時低於1%。
接著,進行第二濃縮步驟直至達到約110 g之體積。用150 mM組胺酸/250 mM脯胺酸緩衝液調節6.70之pH目標。此後,繼續濃縮步驟。
經確認,當滲透物體積減小且交錯流過濾裝置發出峰值壓力警報時,達到最大濃度。精細調節pH,且收集濃縮物。將所得溶液用1 μm過濾器預過濾,在無菌條件下用0.2 μm過濾器過濾,且在2℃至8℃下儲存直至進一步處理。
實例 4.2. 目視檢查
在透濾及濃縮之後,溶液呈微黃色且展示濁度。
在用1.0 μm及0.2 μm過濾器過濾之後獲得的溶液為透明的且呈微黃色。
實例 4.3. UV 280
過濾後,所得溶液之濃度為106.3 mg/mL±2.6 mg/mL (n=3)。
實例 4.4. 可注射性
表8展示量測期間之最大推出力。27G套管適合於濃度為約100 mg/mL之GI-301。30G套管展現濃度為約100 mg/mL之過高推出力。以上實驗中之每一者重複二次(n=2)。
[表8]
套管 | F max[N] |
27G (0.4 mm OD) 12 mm | 10.6±0.5 |
30G (0.3 mm OD) 12 mm | 23.5±1.1 |
確認GI-301之交錯流濃度係可行的。由於溶液在高濃度下之高黏度,無法達成目標濃度(150 mg/mL)。透濾之後的濃度為約106 mg/mL。可注射性被證明為使用27G套管之約11 N的中等推出力。
實例 5. 加速穩定性測試 ( 強制降解測試 II)
在實例4中,經由交錯流過濾將緩衝液組成物(250 mM脯胺酸、組胺酸/HCl,pH 6.7)濃縮至約106 mg/mL之最大濃度。因此,以100 mg/mL之GI-301目標濃度進行強制降解測試II。將界面活性劑及/或抗氧化劑甲硫胺酸添加至實例2中獲得之樣品#3中,以確認此等添加劑之優點(表9)。用1.5 mL之對應溶液填充2R小瓶,且在熱/機械應力及光應力暴露後分析樣品。
[表9]
1)在獲得#1至#4結果之後製備樣品。
基本組成 | 250 mM脯胺酸、組胺酸/HCl,pH 6.7 | |||||
添加劑 | #1(無添加劑) | #2 | #3 | #4 | #5 1) | #6 1) |
甲硫胺酸 | 20 mg/mL | 20 mg/mL | 20 mg/mL | 20 mg/mL | ||
Tween 80 | 0.1 w/v% | 0.1 w/v% | ||||
泊洛沙姆 | 0.1 w/v% | |||||
Tween 20 | 0.1 w/v% |
用界面活性劑及甲硫胺酸進行強制降解測試之調配物樣品如下:
#1:不含添加劑之調配物(無PS80,無甲硫胺酸)
#2:包含甲硫胺酸(20 mg/mL)之調配物
#3:包含Tween 80 (0.1 w/v%)之調配物
#4:包含Tween 80 (0.1 w/v%)及甲硫胺酸(20 mg/mL)之調配物
#5:包含泊洛沙姆188 (0.1 w/v%)及甲硫胺酸(20 mg/mL)之調配物
#6:包含Tween 20 (0.1 w/v%)及甲硫胺酸(20 mg/mL)之調配物
實例 5.1. 目視檢查
作為目視檢查之結果,溶液由於光應力而更黃。在35℃及200 rpm下儲存14天後,樣品#1、#3及#4之濁度增加,樣品#6展示略微混濁,且樣品#2及#5展示澄清溶液狀態(圖1至3)。表10展示各樣品之目視檢查的結果。
[表10]
實例 5.2. UV 280
樣品 | ||||||
#1 | #2 | #3 | #4 | #5 | #6 | |
光應力 7.5小時,750 W/m 2 | 澄清溶液,淡黃色 | 澄清溶液,淡黃色 | 澄清溶液,淡黃色 | 澄清溶液,淡黃色 | 不適用 | 不適用 |
35℃, 200 rpm,5天 | 可見濁度,淺淡黃色 | 澄清溶液,淺淡黃色 | 可見濁度,淺淡黃色 | 可見濁度,淺淡黃色 | 澄清溶液,淺淡黃色 | 澄清溶液,淺淡黃色 |
35℃, 200 rpm, 14天 | 強濁度,淺淡黃色 | 澄清溶液,淺淡黃色 | 強濁度,淺淡黃色 | 強濁度,淺淡黃色 | 澄清溶液,淺淡黃色 | 略微濁度,淺淡黃色 |
表11展示在強制降解測試之後樣品之濃度。根據應力暴露不存在顯著差異。
[表11]
實例 5.3. pH 量測
樣品(n=2) | ||||||
#1 | #2 | #3 | #4 | #5 | #6 | |
c [mg/mL] | c [mg/mL] | c [mg/mL] | c [mg/mL] | c [mg/mL] | c [mg/mL] | |
35℃, 200 rpm,5天 | 96.8±0.7 | 98.9±2.1 | 96.2±0.3 | 95.5±0.3 | 93.9±1.5 | 95.3±2.8 |
35℃, 200 rpm,14天 | 102.1±1.6 | 94.3±1.7 | 96.5±2.5 | 94.5±1.5 | 95.6±1.0 | 96.0±2.5 |
光應力 7.5小時750 W/m 2 | 97.6±1.6 | 96.1±1.1 | 95.2±0.8 | 95.8±2.4 | - | - |
表12展示在強制降解測試之後樣品之pH。pH不存在顯著變化。
[表12]
實例 5.4. 尺寸排阻層析法 ( SE-HPLC )
樣品(n=2) | ||||||
#1 | #2 | #3 | #4 | #5 | #6 | |
pH | pH | pH | pH | pH | pH | |
35℃, 200 rpm,5天 | 6.82±0.01 | 6.74±0.00 | 6.74±0.00 | 6.72±0.00 | 不適用 | 不適用 |
35℃, 200 rpm,14天 | 6.76±0.00 | 6.71±0.00 | 6.73±0.01 | 6.70±0.00 | 不適用 | 不適用 |
光應力 7.5小時750 W/m 2 | 6.72±0.01 | 6.72±0.00 | 6.71±0.01 | 6.70±0.01 | 不適用 | 不適用 |
SE-HPLC為偵測聚集及片段化蛋白質之標準方法。SEC量測結果展示於表13及圖5至7中。
[表13]
樣品(n=2) | ||||||
應力類型 | #1 | #2 | #3 | #4 | #5 | #6 |
主峰面積/百分比(%) | ||||||
35℃, 200 rpm, 5天 | 53.15±1.14 | 90.07±0.29 | 89.84±0.00 | 90.27±0.02 | 90.15±0.17 | 89.20±0.08 |
35℃, 200 rpm, 14天 | 36.83±0.08 | 88.07±0.05 | 87.52±0.04 | 87.89±0.05 | 87.78±0.03 | 86.19±0.01 |
光應力 | 92.97±0.07 | 94.08±0.45 | 93.12±0.43 | 93.74±0.52 | 不適用 | 不適用 |
聚集體面積/百分比(%) | ||||||
35℃, 200 rpm, 5天 | 5.78±0.23 | 8.20±0.08 | 8.72±0.04 | 8.24±0.06 | 8.26±0.11 | 9.23±0.05 |
35℃, 200 rpm, 14天 | 4.90±0.07 | 9.38±0.06 | 9.85±0.05 | 9.42±0.01 | 9.46±0.05 | 10.97±0.01 |
光應力 | 6.06±0.03 | 5.28±0.00 | 6.26±0.02 | 5.63±0.06 | 不適用 | 不適用 |
片段面積/百分比(%) | ||||||
35℃, 200 rpm, 5天 | 41.07±1.37 | 1.73±0.21 | 1.44±0.03 | 1.50±0.04 | 1.59±0.05 | 1.58±0.13 |
35℃, 200 rpm, 14天 | 58.27±0.01 | 2.55±0.01 | 2.63±0.01 | 2.69±0.05 | 2.77±0.02 | 2.84±0.01 |
光應力 | 0.98±0.04 | 0.64±0.45 | 0.62±0.45 | 0.63±0.46 | 不適用 | 不適用 |
回收率/百分比(%) | ||||||
35℃, 200 rpm, 14天 | 97.17±0.26 | 100.25±0.07 | 98.61±0.14 | 98.56±0.04 | 100.17±0.14 | 100.43±0.12 |
如表13中所展示,在35℃及200 rpm之應力條件下持續14天之回收率與目視檢查相當:樣品#2、#5及#6展示高回收率(圖4)。
另外,如圖5中所示,作為量測主峰之結果,在施加熱/機械應力之樣品#2、#4及#5中獲得更好的結果,且樣品#1及#6展示較差的結果。同時,如圖6中所示,樣品#6中展示蛋白質聚集。在光應力條件下,樣品#2展示最小量之蛋白質聚集。如圖7中所示,樣品#2展示關於蛋白質片段之最佳結果。
實例 5.5. GI-301 之基於 ELISA 之效能分析
GI-301之相對效能係根據基於ELISA之效能分析之結果確定。此分析之原理為定量能夠結合至人類IgE之GI-301分子。
藉由ELISA分析之相對效能展示於表14中。所有樣品均維持高結合親和力。
[表14]
實例 5.6. 根據比濁法量測之濁度
樣品(n=2) | ||||
#1 | #2 | #3 | #4 | |
35℃,200 rpm,5天 | 79.7%±3.8% | 112.7%±1.6% | 92.1%±5.2% | 94.3%±30.4 |
35℃,200 rpm,14天 | 104.9%±0.0% | 74.2%±6.5% | 80.4%±7.5% | 110.9%±12.6% |
光應力 | 110.2%±6.6% | 112.2%±5.1% | 110.1%±6.8% | 111.2%±3.3% |
表15展示濁度量測之結果。視覺外觀與濁度量測之間無明顯相關性(比較在35℃下儲存5天後之樣品#3及#4)。此差異之一個潛在原因可為濃縮蛋白質溶液中之乳白光增加,其增加了基礎濁度。結果,由於蛋白質聚集,可見濁度可能高於基礎濁度。因此,將樣品在35℃下儲存14天且接著藉由DLS分析。
[表15]
實例 5.7. 重量莫耳滲透濃度
樣品(n=2) | ||||
#1 | #2 | #3 | #4 | |
NTU | NTU | NTU | NTU | |
35℃,200 rpm,5天 | 35.05±0.07 | 11.52±3.80 | 11.50±0.14 | 10.70±0.14 |
光應力 | 11.65±1.48 | 9.38±1.59 | 7.37±0.20 | 6.84±0.06 |
重量莫耳滲透濃度結果展示於表16中。如所預期,甲硫胺酸增加了重量莫耳滲透濃度。
[表16]
實例 5.8. 對量測結果之分析
樣品(n=2) | ||||
#1 | #2 | #3 | #4 | |
mOSMOL/kg | mOSMOL/kg | mOSMOL/kg | mOSMOL/kg | |
35℃,200 rpm,5天 | 351±1 | 500±2 | 338±0 | 498±1 |
35℃,200 rpm, 14天 | 363±1 | 488±3 | 333±1 | 492±0 |
光應力 | 338±2 | 496±1 | 338±1 | 495±0 |
結果概括於下表17中。
[表17]
×:不良結果,△:中等結果,○:良好結果
樣品 | #1 | #2 | #3 | #4 | #5 | #6 |
在35℃/200 rpm下14天之後的視覺外觀 | △ | ○ | × | × | ○ | △ |
在35℃/200 rpm下14天之後的SEC回收率 | × | ○ | △ | △ | ○ | ○ |
在35℃/200 rpm下14天之後的SEC主峰 | × | ○ | △ | ○ | ○ | × |
在35℃/200 rpm下14天之後的DLS | △ | △ | × | × | △ | △ |
基於該等結果,最適合調配物樣品如下:
樣品#2:His/脯胺酸pH 6.7;20 mg/mL甲硫胺酸
樣品#5:His/脯胺酸pH 6.7;20 mg/mL甲硫胺酸;0.1 w/v%泊洛沙姆188
作為測試之結果,樣品#2及樣品#5在上表17中之調配物樣品中係合適的。
實例 6. 使用注射器之強制降解測試
根據實例5使用2R小瓶選擇二種調配物:250 mM脯胺酸、組胺酸/HCl,pH 6.7、0.1 w/v%泊洛沙姆188,含/不含20 mg/mL甲硫胺酸(抗氧化劑)。基於此等結果,將抗氧化劑及界面活性劑添加至樣品中(表18)。樣品之目標濃度為100 mg/mL。用1.75 mL對應溶液填充2.25 mL注射器,且在熱/機械應力暴露14天後對樣品進行分析。
用於強制降解研究之樣品如下:
#1:包含甲硫胺酸(20 mg/mL)之調配物
#2:包含泊洛沙姆188 (0.1 w/v%)及甲硫胺酸(20 mg/mL)之調配物
[表18]
實例 6.1. 目視檢查
基本成分 | 250 mM脯胺酸、組胺酸/HCl,pH 6.7 | |
添加劑 | #1 | #2 |
甲硫胺酸 | 20 mg/mL | 20 mg/mL |
泊洛沙姆188 | - | 0.1 w/v% |
目視檢查之結果展示於表19中。如圖8中所示,在35℃下儲存14天後不存在明顯差異。
[表19]
實例 6.2. 推出力之量測
樣品 | ||
#1 | #2 | |
初始狀態 | 澄清溶液,淡黃色 | 澄清溶液,淡黃色 |
35℃,200 rpm,14天 | 澄清溶液,淡黃色 | 澄清溶液,淡黃色 |
表20展示拉伸機之結果。當使用27G套管時,二個樣品中均出現超過20 N之推出力(圖9)。因此,應選擇內徑較大或針頭尺寸較大(例如25G)之注射器,以耐受100 mg/mL濃度之蛋白質。
[表20]
實例 6.3. UV 280
27G (0.4 mm OD) 18 mm | 樣品 | |
27G (0.4 mm OD) 18 mm | #1 | #2 |
27G (0.4 mm OD) 18 mm | F max[N] | F max[N] |
n1 | 43.7 | 43.3 |
n2 | 42.6 | 41.0 |
表21展示在強制降解測試之後樣品之濃度。在應力暴露之後不存在顯著差異。
[表21]
實例 6.4. pH 量測
樣品(n=2) | |||||
初始狀態 | 在35℃、200 rpm下14天之後 | ||||
#1 | #2 | #1 注射器1 | #1 注射器2 | #2 注射器1 | #2 注射器2 |
c[mg/mL] | c[mg/mL] | c[mg/mL] | c[mg/mL] | c[mg/mL] | c[mg/mL] |
98.9±2.9 | 99.6±1.6 | 100.2±1.2 | 101.3±0.8 | 98.2±1.0 | 98.9±0.7 |
表22展示在強制降解測試之後樣品之pH。pH不存在顯著變化。
[表22]
實例 6.5. 尺寸排阻層析法 (SE-HPLC)
樣品(n=2) | |||||
初始狀態 | 在35℃、200 rpm下14天之後 | ||||
#1 | #2 | #1 注射器1 | #1 注射器2 | #2 注射器1 | #2 注射器2 |
pH | pH | pH | pH | pH | pH |
6.74±0.00 | 6.77±0.01 | 6.75±0.01 | 6.73±0.03 | 6.75±0.00 | 6.75±0.00 |
SEC量測結果展示於表23及圖10中。
[表23]
樣品(n=2) | |||||
初始狀態(t0) | 在35℃、200 rpm下14天之後 | ||||
#1 | #2 | #1 注射器1 | #1 注射器2 | #2 注射器1 | #2 注射器2 |
主峰面積/百分比(%) | |||||
93.87±0.14 | 93.73±0.03 | 83.83±0.04 | 83.74±0.16 | 84.44±0.41 | 84.10±0.11 |
聚集體面積/百分比(%) | |||||
4.36±0.04 | 4.49±0.01 | 9.60±0.04 | 9.61±0.08 | 9.40±0.16 | 9.48±0.05 |
片段面積/百分比(%) | |||||
1.76±0.18 | 1.79±0.02 | 6.57±0.00 | 6.66±0.08 | 6.16±0.26 | 6.41±0.06 |
回收率/百分比(%) | |||||
98.19±0.02 | 98.79±0.03 | 101.56±0.28 | 102.99±0.34 | 101.44±0.72 | 102.72±0.14 |
在35℃及200 rpm下儲存14天之後,二個樣品之間的差異不顯著。然而,與樣品#1 (不含泊洛沙姆)相比,在樣品#2 (含泊洛沙姆)中展示之主峰面積結果更好。與小瓶之結果相比,片段面積增加了約4%。此與主峰結果一致(圖10)。
實例 6.6. 重量莫耳滲透濃度
重量莫耳滲透濃度結果展示於表24中。即使在應力暴露之後,重量莫耳滲透濃度亦維持在相同位準下。
[表24]
實例 6.7. 亞可見粒子
樣品(n=2) | |||||
初始狀態 | 在35℃、200 rpm下14天之後 | ||||
#1 | #2 | #1 注射器1 | #1 注射器2 | #2 注射器1 | #2 注射器2 |
mOSMOL/kg | mOSMOL/kg | mOSMOL/kg | mOSMOL/kg | mOSMOL/kg | mOSMOL/kg |
504±1 | 507±2 | 515±8 | 514±6 | 514±2 | 516±1 |
使用流體成像顯微鏡評估亞可見粒子之量。用水填充之壓力注射器具有低粒子負荷。此表明矽化注射器對粒子負荷之影響係有限的。
樣品#1及樣品#2顯示相當的粒子負荷。觀測到的大部分粒子為聚矽氧粒子,且無粒子表明蛋白質聚集/沈澱。
實例 6.8. 對量測結果之分析
結果概述於表25中。
[表25]
×:不良結果,△:中等結果,○:良好結果
樣品 | #1 | #2 |
在35℃/200 rpm下14天之後的視覺外觀 | ○ | ○ |
在35℃/200 rpm下14天之後的SEC回收率 | ○ | ○ |
在35℃/200 rpm下14天之後的SEC主峰 | ○ | ○ |
在35℃/200 rpm下14天之後的DLS | △ | △ |
流動成像顯微鏡(定性) | ○ | ○ |
二種樣品展示幾乎類似的結果。唯一的區別為樣品#2在SEC分析(相對主峰面積)中展示略好的結果。
根據以上結果,包含濃度為100 mg/mL之GI-301、20 mg/mL作為抗氧化劑之甲硫胺酸及0.1 w/v%作為界面活性劑之泊洛沙姆188的250 mM脯胺酸、10 mM組胺酸/HCl,pH 6.7之緩衝液調配物係最適於GI 301之調配物。
然而,在以上條件之情況下,由於超濾過程中發生的唐南效應,將pH降至低於目標pH 6.7,以滿足100 mg/mL之最終濃度。為補償pH之降低,增加了在超濾後藉由高濃度組胺酸稀釋來調節pH之過程。最後,將75 mg/mL GI-301、20 mg/mL甲硫胺酸、250 mM脯胺酸、55 mM組胺酸/HCl、0.1 w/v%泊洛沙姆188,pH 6.5確立為GI-301之調配條件。
(無)
圖1為在750 W/m
2之條件下經受光應力(light stress) 7.5小時之樣品(#1至#4)的照片。
圖2為在35℃及200 rpm之條件下經受應力5天之樣品(#1至#6)的照片。
圖3為在35℃及200 rpm之條件下經受應力14天之樣品(#1至#6)的照片。
圖4為展示在35℃及200 rpm之條件下經受應力14天之樣品(#1至#6)之回收率(%)的圖。
圖5為展示根據各應力條件之樣品之主峰面積的圖。
圖6為展示根據各應力條件之樣品之聚集體面積的圖式。
圖7為展示根據各應力條件之樣品之片段面積的圖式。
圖8為填充有初始狀態樣品(#1或#2)之注射器及在35℃及200 rpm下應力暴露14天之後的注射器之照片。
圖9為展示力/長度圖之圖式。在此情況下,其以190 mm/min之推出速度進行。
圖10為展示根據各應力條件之樣品(#1及#2)之主峰面積的圖式。
<![CDATA[<110> 南韓商GI醫諾微新股份有限公司 (GI INNOVATION, INC.)]]> <![CDATA[<120> 包含IgE Fc受體次單元α之胞外區域的融合蛋白的調配物]]> <![CDATA[<140> TW 111108408]]> <![CDATA[<141> 2022-03-08]]> <![CDATA[<150> KR 10-2021-0030501]]> <![CDATA[<151> 2021-03-09]]> <![CDATA[<160> 22]]> <![CDATA[<170> KopatentIn 2.0]]> <![CDATA[<210> 1]]> <![CDATA[<211> 180]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRI1 ECD]]> <![CDATA[<400> 1]]> Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln 180 <![CDATA[<210> 2]]> <![CDATA[<211> 215]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 經修飾之Fc]]> <![CDATA[<400>]]> 2 Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys 1 5 10 15 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 20 25 30 Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp 35 40 45 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe 50 55 60 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 65 70 75 80 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu 85 90 95 Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 100 105 110 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys 115 120 125 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 130 135 140 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 145 150 155 160 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 165 170 175 Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser 180 185 190 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 195 200 205 Leu Ser Leu Ser Leu Gly Lys 210 215 <![CDATA[<210> 3]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體]]> <![CDATA[<400> 3]]> Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <![CDATA[<210> 4]]> <![CDATA[<211> 49]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體]]> <![CDATA[<400> 4]]> Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser 20 25 30 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <![CDATA[<210> 5]]> <![CDATA[<211> 540]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRI1 ECD之核苷酸序列]]> <![CDATA[<400> 5]]> gtgccccaga agcccaaggt gagcctgaac cctccctgga acagaatctt caagggcgag 60 aacgtgaccc tgacctgcaa cggcaacaac ttcttcgagg tgagcagcac caagtggttc 120 cacaatggca gcctgagcga ggagaccaac agctccctga acatcgtgaa cgccaagttc 180 gaggacagcg gcgagtacaa gtgccagcac cagcaggtga acgagagcga gcccgtgtac 240 ctggaggtgt tcagcgactg gctgctgctg caggccagcg ccgaggtggt gatggagggc 300 cagcccctgt tcctgagatg ccacggctgg agaaactggg acgtgtacaa ggtgatctac 360 tacaaggatg gcgaggccct gaagtactgg tacgagaacc acaacatctc catcaccaac 420 gccaccgtgg aggacagcgg cacctactac tgcacaggca aggtgtggca gctggactac 480 gagagcgagc ccctgaacat caccgtgatc aaggctccca gagagaagta ctggctgcag 540 540 <![CDATA[<210> 6]]> <![CDATA[<211> 561]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 經修飾之Fc之核苷酸序列]]> <![CDATA[<400> 6]]> tgcgtggtcg tggatgtgag ccaggaagat cccgaagtgc agttcaactg gtacgtggat 60 ggcgtggaag tgcacaacgc caagaccaag cccagagaag agcagttcaa ctccacctac 120 agagtggtga gcgtgctgac cgtgctgcac caggactggc tgaacggcaa ggagtacaag 180 tgcaaggtgt ccaacaaagg cctgcccagc tccatcgaga agaccatcag caaagccaaa 240 ggccagccca gagaacccca ggtgtacacc ctgcctccca gccaggaaga gatgaccaag 300 aaccaggtgt ccctgacctg cctggtgaaa ggcttctacc ccagcgacat cgccgtggag 360 tgggaaagca acggccagcc cgagaacaat tacaagacaa cccctcccgt gctggatagc 420 gatggcagct tctttctgta cagcagactg accgtggaca agagcagatg gcaggaaggc 480 aacgtgttca gctgcagcgt gatgcacgaa gccctgcaca accactacac ccagaagagc 540 ctgtccctga gcctgggcaa g 561 <![CDATA[<210> 7]]> <![CDATA[<211> 174]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體之核苷酸序列]]> <![CDATA[<400> 7]]> aggaacaccg gcagaggagg cgaggaaaag aaaggaagca aggagaagga ggagcaggag 60 gaaagagaaa ccaagacccc cgagtgcccc agccacaccc agcccctggg cgtgttcctg 120 ttccccccca agcccaagga caccctgatg atcagcagaa cccccgaggt gacc 174 <![CDATA[<210> 8]]> <![CDATA[<211> 231]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體之核苷]]>酸序列 <![CDATA[<400> 8]]> gcccagcccc aggccgaggg cagcctggct aaggccacca cagctcccgc caccaccagg 60 aacaccggca gaggaggcga ggaaaagaaa ggaagcaagg agaaggagga gcaggaggaa 120 agagaaacca agacccccga gtgccccagc cacacccagc ccctgggcgt gttcctgttc 180 ccccccaagc ccaaggacac cctgatgatc agcagaaccc ccgaggtgac c 231 <![CDATA[<210> 9]]> <![CDATA[<211> 25]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 信號肽]]> <![CDATA[<400> 9]]> Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala 20 25 <![CDATA[<210> 10]]> <![CDATA[<211> 75]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 信號肽之核苷酸序列]]> <![CDATA[<400> 10]]> atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgcc 75 <![CDATA[<210> 11]]> <![CDATA[<211> 450]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc2]]> <![CDATA[<400> 11]]> Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Arg Asn Thr 195 200 205 Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys Glu Glu Gln 210 215 220 Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His Thr Gln Pro 225 230 235 240 Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu 260 265 270 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu 435 440 445 Gly Lys 450 <![CDATA[<210> 12]]> <![CDATA[<211> 1350]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc2之核苷酸序列]]> <![CDATA[<400> 12]]> atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcagaggaa caccggcaga ggaggcgagg aaaagaaagg aagcaaggag 660 aaggaggagc aggaggaaag agaaaccaag acccccgagt gccccagcca cacccagccc 720 ctgggcgtgt tcctgttccc ccccaagccc aaggacaccc tgatgatcag cagaaccccc 780 gaggtgacct gcgtggtcgt ggatgtgagc caggaagatc ccgaagtgca gttcaactgg 840 tacgtggatg gcgtggaagt gcacaacgcc aagaccaagc ccagagaaga gcagttcaac 900 tccacctaca gagtggtgag cgtgctgacc gtgctgcacc aggactggct gaacggcaag 960 gagtacaagt gcaaggtgtc caacaaaggc ctgcccagct ccatcgagaa gaccatcagc 1020 aaagccaaag gccagcccag agaaccccag gtgtacaccc tgcctcccag ccaggaagag 1080 atgaccaaga accaggtgtc cctgacctgc ctggtgaaag gcttctaccc cagcgacatc 1140 gccgtggagt gggaaagcaa cggccagccc gagaacaatt acaagacaac ccctcccgtg 1200 ctggatagcg atggcagctt ctttctgtac agcagactga ccgtggacaa gagcagatgg 1260 caggaaggca acgtgttcag ctgcagcgtg atgcacgaag ccctgcacaa ccactacacc 1320 cagaagagcc tgtccctgag cctgggcaag 1350 <![CDATA[<210> 13]]> <![CDATA[<211> 469]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc3]]> <![CDATA[<400> 13]]> Met Asp Ala Met Leu Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly 1 5 10 15 Ala Val Phe Val Ser Pro Ser His Ala Val Pro Gln Lys Pro Lys Val 20 25 30 Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr 35 40 45 Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp 50 55 60 Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile 65 70 75 80 Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln 85 90 95 Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp 100 105 110 Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu 115 120 125 Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile 130 135 140 Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn 145 150 155 160 Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys 165 170 175 Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile 180 185 190 Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Ala Gln Pro 195 200 205 Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro Ala Thr Thr 210 215 220 Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly Ser Lys Glu Lys 225 230 235 240 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro Ser His 245 250 255 Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr 260 265 270 Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val 275 280 285 Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val 290 295 300 Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser 305 310 315 320 Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu 325 330 335 Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser 340 345 350 Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro 355 360 365 Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln 370 375 380 Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala 385 390 395 400 Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr 405 410 415 Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu 420 425 430 Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser 435 440 445 Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser 450 455 460 Leu Ser Leu Gly Lys 465 <![CDATA[<210> 14]]> <![CDATA[<211> 1407]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc3之核苷酸序列]]> <![CDATA[<400> 14]]> atggacgcca tgctgagagg cctgtgctgt gtgctgctgc tgtgcggcgc cgtgttcgtg 60 tcccctagcc acgccgtgcc ccagaagccc aaggtgagcc tgaaccctcc ctggaacaga 120 atcttcaagg gcgagaacgt gaccctgacc tgcaacggca acaacttctt cgaggtgagc 180 agcaccaagt ggttccacaa tggcagcctg agcgaggaga ccaacagctc cctgaacatc 240 gtgaacgcca agttcgagga cagcggcgag tacaagtgcc agcaccagca ggtgaacgag 300 agcgagcccg tgtacctgga ggtgttcagc gactggctgc tgctgcaggc cagcgccgag 360 gtggtgatgg agggccagcc cctgttcctg agatgccacg gctggagaaa ctgggacgtg 420 tacaaggtga tctactacaa ggatggcgag gccctgaagt actggtacga gaaccacaac 480 atctccatca ccaacgccac cgtggaggac agcggcacct actactgcac aggcaaggtg 540 tggcagctgg actacgagag cgagcccctg aacatcaccg tgatcaaggc tcccagagag 600 aagtactggc tgcaggccca gccccaggcc gagggcagcc tggctaaggc caccacagct 660 cccgccacca ccaggaacac cggcagagga ggcgaggaaa agaaaggaag caaggagaag 720 gaggagcagg aggaaagaga aaccaagacc cccgagtgcc ccagccacac ccagcccctg 780 ggcgtgttcc tgttcccccc caagcccaag gacaccctga tgatcagcag aacccccgag 840 gtgacctgcg tggtcgtgga tgtgagccag gaagatcccg aagtgcagtt caactggtac 900 gtggatggcg tggaagtgca caacgccaag accaagccca gagaagagca gttcaactcc 960 acctacagag tggtgagcgt gctgaccgtg ctgcaccagg actggctgaa cggcaaggag 1020 tacaagtgca aggtgtccaa caaaggcctg cccagctcca tcgagaagac catcagcaaa 1080 gccaaaggcc agcccagaga accccaggtg tacaccctgc ctcccagcca ggaagagatg 1140 accaagaacc aggtgtccct gacctgcctg gtgaaaggct tctaccccag cgacatcgcc 1200 gtggagtggg aaagcaacgg ccagcccgag aacaattaca agacaacccc tcccgtgctg 1260 gatagcgatg gcagcttctt tctgtacagc agactgaccg tggacaagag cagatggcag 1320 gaaggcaacg tgttcagctg cagcgtgatg cacgaagccc tgcacaacca ctacacccag 1380 aagagcctgt ccctgagcct gggcaag 1407 <![CDATA[<210> 15]]> <![CDATA[<211> 406]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類α-2,6唾液酸轉移酶]]> <![CDATA[<400> 15]]> Met Ile His Thr Asn Leu Lys Lys Lys Phe Ser Cys Cys Val Leu Val 1 5 10 15 Phe Leu Leu Phe Ala Val Ile Cys Val Trp Lys Glu Lys Lys Lys Gly 20 25 30 Ser Tyr Tyr Asp Ser Phe Lys Leu Gln Thr Lys Glu Phe Gln Val Leu 35 40 45 Lys Ser Leu Gly Lys Leu Ala Met Gly Ser Asp Ser Gln Ser Val Ser 50 55 60 Ser Ser Ser Thr Gln Asp Pro His Arg Gly Arg Gln Thr Leu Gly Ser 65 70 75 80 Leu Arg Gly Leu Ala Lys Ala Lys Pro Glu Ala Ser Phe Gln Val Trp 85 90 95 Asn Lys Asp Ser Ser Ser Lys Asn Leu Ile Pro Arg Leu Gln Lys Ile 100 105 110 Trp Lys Asn Tyr Leu Ser Met Asn Lys Tyr Lys Val Ser Tyr Lys Gly 115 120 125 Pro Gly Pro Gly Ile Lys Phe Ser Ala Glu Ala Leu Arg Cys His Leu 130 135 140 Arg Asp His Val Asn Val Ser Met Val Glu Val Thr Asp Phe Pro Phe 145 150 155 160 Asn Thr Ser Glu Trp Glu Gly Tyr Leu Pro Lys Glu Ser Ile Arg Thr 165 170 175 Lys Ala Gly Pro Trp Gly Arg Cys Ala Val Val Ser Ser Ala Gly Ser 180 185 190 Leu Lys Ser Ser Gln Leu Gly Arg Glu Ile Asp Asp His Asp Ala Val 195 200 205 Leu Arg Phe Asn Gly Ala Pro Thr Ala Asn Phe Gln Gln Asp Val Gly 210 215 220 Thr Lys Thr Thr Ile Arg Leu Met Asn Ser Gln Leu Val Thr Thr Glu 225 230 235 240 Lys Arg Phe Leu Lys Asp Ser Leu Tyr Asn Glu Gly Ile Leu Ile Val 245 250 255 Trp Asp Pro Ser Val Tyr His Ser Asp Ile Pro Lys Trp Tyr Gln Asn 260 265 270 Pro Asp Tyr Asn Phe Phe Asn Asn Tyr Lys Thr Tyr Arg Lys Leu His 275 280 285 Pro Asn Gln Pro Phe Tyr Ile Leu Lys Pro Gln Met Pro Trp Glu Leu 290 295 300 Trp Asp Ile Leu Gln Glu Ile Ser Pro Glu Glu Ile Gln Pro Asn Pro 305 310 315 320 Pro Ser Ser Gly Met Leu Gly Ile Ile Ile Met Met Thr Leu Cys Asp 325 330 335 Gln Val Asp Ile Tyr Glu Phe Leu Pro Ser Lys Arg Lys Thr Asp Val 340 345 350 Cys Tyr Tyr Tyr Gln Lys Phe Phe Asp Ser Ala Cys Thr Met Gly Ala 355 360 365 Tyr His Pro Leu Leu Tyr Glu Lys Asn Leu Val Lys His Leu Asn Gln 370 375 380 Gly Thr Asp Glu Asp Ile Tyr Leu Leu Gly Lys Ala Thr Leu Pro Gly 385 390 395 400 Phe Arg Thr Ile His Cys 405 <![CDATA[<210> 16]]> <![CDATA[<211> 1218]]> <![CDATA[<212> DNA]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 人類α-2,6唾液酸轉移酶之核苷酸序列]]> <![CDATA[<400> 16]]> atgatccaca ccaacctgaa gaagaagttc agctgctgcg tgctggtgtt cctgctgttc 60 gccgtgatct gcgtgtggaa ggagaagaag aaaggcagct actacgacag cttcaagctg 120 cagaccaagg agttccaggt gctgaagagc ctgggcaagc tggccatggg cagcgacagc 180 cagagcgtgt ccagctcctc cacccaggat ccccacagag gcagacagac cctgggcagc 240 ctgagaggcc tggccaaggc caagcccgag gccagcttcc aggtgtggaa caaggacagc 300 agcagcaaga acctgatccc cagactgcag aagatctgga agaactacct gagcatgaac 360 aagtacaagg tgagctacaa aggacccgga cccggcatca agttcagcgc cgaggccctg 420 aggtgccacc tgagagacca cgtgaacgtg agcatggtgg aagtgaccga cttccccttc 480 aacaccagcg agtgggaagg ctacctgccc aaggagagca tcaggaccaa ggctggcccc 540 tggggcagat gcgccgtggt gagcagcgct ggcagcctga agagctccca gctgggcaga 600 gagatcgacg accacgatgc cgtgctgagg ttcaatggcg ctcccaccgc caacttccag 660 caggacgtgg gcaccaagac cacaatccgg ctgatgaaca gccagctggt gacaaccgag 720 aagcggttcc tgaaggacag cctgtacaac gagggcatcc tgatcgtgtg ggatcccagc 780 gtgtaccaca gcgacatccc caagtggtac cagaatcccg actacaactt cttcaacaac 840 tacaagacct atagaaagct gcaccccaac cagcccttct acatcctgaa gccccagatg 900 ccctgggagc tgtgggacat cctgcaggag atcagccctg aagagatcca gcccaaccct 960 ccctccagcg gcatgctggg cattatcatc atgatgaccc tgtgcgacca ggtggacatc 1020 tacgagttcc tgcccagcaa gagaaagacc gacgtgtgct actactatca gaagttcttc 1080 gacagcgcct gcaccatggg cgcctaccac cccctgctgt acgagaagaa cctggtgaag 1140 cacctgaacc agggcaccga cgaggacatc tacctgctgg gcaaagccac cctgcccggc 1200 ttcagaacca tccactgc 1218 <![CDATA[<210> 17]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體]]> <![CDATA[<220>]]> <![CDATA[<221> VARIANT]]> <![CDATA[<222> (12)]]> <![CDATA[<223> X]]>aa選自由Lys及Gly組成之群。 <![CDATA[<220>]]> <![CDATA[<221> VARIANT]]> <![CDATA[<222> (13)]]> <![CDATA[<223> Xaa選自由Glu、Gly及Ser組成之群。]]> <![CDATA[<400> 17]]> Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <![CDATA[<210> 18]]> <![CDATA[<211> 49]]> <![CDATA[<212> PR]]>T <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈變異體]]> <![CDATA[<220>]]> <![CDATA[<221> VARIANT]]> <![CDATA[<222> (31)]]> <![CDATA[<223> Xaa選自由Lys及Gly組成之群。]]> <![CDATA[<220>]]> <![CDATA[<221> VARIANT]]> <![CDATA[<222> (32)]]> <![CDATA[<223> Xaa選自由Glu、Gly或Ser組成之群。]]> <![CDATA[<400> 18]]> Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala Thr Thr Ala Pro 1 5 10 15 Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Xaa Xaa 20 25 30 Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys 35 40 45 Pro <![CDATA[<210> 19]]> <![CDATA[<211> 30]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> IgD鉸鏈]]> <![CDATA[<400> 19]]> Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys Glu Lys Glu Lys 1 5 10 15 Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu Cys Pro 20 25 30 <![CDATA[<210> 20]]> <![CDATA[<211> 425]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc1]]> <![CDATA[<400> 20]]> Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Lys 180 185 190 Glu Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <![CDATA[<210> 21]]> <![CDATA[<211> 425]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc2]]> <![CDATA[<400> 21]]> Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Arg Asn Thr Gly Arg Gly Gly Glu Glu Lys Lys Gly 180 185 190 Ser Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys Thr Pro Glu 195 200 205 Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe Pro Pro Lys 210 215 220 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 225 230 235 240 Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr 245 250 255 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 260 265 270 Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 275 280 285 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 290 295 300 Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 305 310 315 320 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met 325 330 335 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 340 345 350 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 355 360 365 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 370 375 380 Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val 385 390 395 400 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 405 410 415 Lys Ser Leu Ser Leu Ser Leu Gly Lys 420 425 <![CDATA[<210> 22]]> <![CDATA[<211> 444]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> FceRIa ECD-鉸鏈-Fc3]]> <![CDATA[<400> 22]]> Val Pro Gln Lys Pro Lys Val Ser Leu Asn Pro Pro Trp Asn Arg Ile 1 5 10 15 Phe Lys Gly Glu Asn Val Thr Leu Thr Cys Asn Gly Asn Asn Phe Phe 20 25 30 Glu Val Ser Ser Thr Lys Trp Phe His Asn Gly Ser Leu Ser Glu Glu 35 40 45 Thr Asn Ser Ser Leu Asn Ile Val Asn Ala Lys Phe Glu Asp Ser Gly 50 55 60 Glu Tyr Lys Cys Gln His Gln Gln Val Asn Glu Ser Glu Pro Val Tyr 65 70 75 80 Leu Glu Val Phe Ser Asp Trp Leu Leu Leu Gln Ala Ser Ala Glu Val 85 90 95 Val Met Glu Gly Gln Pro Leu Phe Leu Arg Cys His Gly Trp Arg Asn 100 105 110 Trp Asp Val Tyr Lys Val Ile Tyr Tyr Lys Asp Gly Glu Ala Leu Lys 115 120 125 Tyr Trp Tyr Glu Asn His Asn Ile Ser Ile Thr Asn Ala Thr Val Glu 130 135 140 Asp Ser Gly Thr Tyr Tyr Cys Thr Gly Lys Val Trp Gln Leu Asp Tyr 145 150 155 160 Glu Ser Glu Pro Leu Asn Ile Thr Val Ile Lys Ala Pro Arg Glu Lys 165 170 175 Tyr Trp Leu Gln Ala Gln Pro Gln Ala Glu Gly Ser Leu Ala Lys Ala 180 185 190 Thr Thr Ala Pro Ala Thr Thr Arg Asn Thr Gly Arg Gly Gly Glu Glu 195 200 205 Lys Lys Gly Ser Lys Glu Lys Glu Glu Gln Glu Glu Arg Glu Thr Lys 210 215 220 Thr Pro Glu Cys Pro Ser His Thr Gln Pro Leu Gly Val Phe Leu Phe 225 230 235 240 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 245 250 255 Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe 260 265 270 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 275 280 285 Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 290 295 300 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 305 310 315 320 Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala 325 330 335 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln 340 345 350 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 355 360 365 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 370 375 380 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 385 390 395 400 Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu 405 410 415 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 420 425 430 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440
(無)
Claims (24)
- 一種水性醫藥調配物,其包含: 包含一IgE Fc受體之一α次單元之一胞外區域(FcεRIα ECD)的一融合蛋白二聚體, 其中該調配物之pH為6.0至7.0。
- 如請求項1之水性醫藥調配物,其中該調配物用於皮下注射。
- 如請求項1之水性醫藥調配物,其中該融合蛋白二聚體包含二種單體,其各自包含該IgE Fc受體之該α次單元之該胞外區域。
- 如請求項3之水性醫藥調配物, 其中該單體包含一經修飾之Fc區,且 該經修飾之Fc區及該IgE Fc受體之該α次單元之該胞外區域經由一鉸鏈連接。
- 如請求項4之水性醫藥調配物,其中該經修飾之Fc區由SEQ ID NO: 2組成。
- 如請求項4之水性醫藥調配物,其中該鉸鏈為衍生自免疫球蛋白IgD或其一變異體之一鉸鏈區。
- 如請求項1之水性醫藥調配物,其中該IgE Fc受體之該α次單元之該胞外區域由SEQ ID NO: 1之胺基酸序列或其一片段組成。
- 如請求項1之水性醫藥調配物,其中該融合蛋白二聚體之一濃度為50 mg/mL至150 mg/mL。
- 如請求項1之水性醫藥調配物,其中該調配物進一步包含一緩衝劑及一穩定劑。
- 如請求項9之水性醫藥調配物,其中該緩衝劑為組胺酸。
- 如請求項10之水性醫藥調配物,其中該組胺酸之一濃度為10 mM至100 mM。
- 如請求項9之水性醫藥調配物,其中該穩定劑為脯胺酸。
- 如請求項12之水性醫藥調配物,其中該脯胺酸之一濃度為200 mM至300 mM。
- 如請求項1之水性醫藥調配物,其中該調配物進一步包含一抗氧化劑。
- 如請求項14之水性醫藥調配物,其中該抗氧化劑為甲硫胺酸。
- 如請求項15之水性醫藥調配物,其中該甲硫胺酸之一濃度為10 mg/mL至30 mg/mL。
- 如請求項1之水性醫藥調配物,其中該調配物進一步包含一界面活性劑。
- 如請求項17之水性醫藥調配物,其中該界面活性劑為泊洛沙姆188 (poloxamer 188)。
- 如請求項18之水性醫藥調配物,其中該泊洛沙姆188之一濃度為0.01 w/v%至1 w/v%。
- 一種水性醫藥調配物,其包含: i)一融合蛋白二聚體,其包含一濃度為50 mg/mL至150 mg/mL之一IgE Fc受體之一α次單元之一胞外區域; ii)一濃度為10 mM至100 mM之組胺酸; iii)一濃度為200 mM至300 mM之脯胺酸; iv)一濃度為10 mg/mL至30 mg/mL之甲硫胺酸;及 v)一濃度為0.01 w/v%至1 w/v%之泊洛沙姆188, 其中該調配物之pH為6.0至7.0。
- 如請求項20之水性醫藥調配物,其中該調配物存在於選自由以下組成之群的一容器中:一小瓶、一藥筒、一注射器及一自動注射器。
- 如請求項20之水性醫藥調配物,其中該調配物用於皮下投予。
- 如請求項20之水性醫藥調配物,其中該調配物用於預防或治療一過敏性疾病。
- 如請求項23之水性醫藥調配物,其中該過敏性疾病為選自由以下組成之群的疾病:食物過敏、異位性皮膚炎、哮喘、過敏性鼻炎、過敏性結膜炎、過敏性皮膚炎、慢性特發性蕁麻疹、慢性自發性蕁麻疹及過敏性接觸性皮膚炎。
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ES2415604T3 (es) | 2007-05-30 | 2013-07-26 | Postech Academy-Industry- Foundation | Proteínas de fusión de inmunoglobulina |
EP2331578B1 (en) | 2008-09-17 | 2014-06-04 | Xencor, Inc. | Novel compositions and methods for treating ige-mediated disorders |
US20120294866A1 (en) * | 2010-01-19 | 2012-11-22 | F. Hoffmann-La Roche Ag | Pharmaceutical formulation for proteins |
WO2019135666A1 (ko) * | 2018-01-08 | 2019-07-11 | 주식회사 프로젠 | Ige fc 수용체의 알파 서브유닛의 세포외 도메인을 포함하는 약학적 조성물 |
SG11202005858WA (en) | 2018-01-08 | 2020-07-29 | Gi Innovation Inc | Extracellular domain of alpha subunit of ige fc receptor, pharmaceutical composition comprising same and method for producing same |
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EP3876978A4 (en) * | 2018-11-07 | 2022-09-28 | Merck Sharp & Dohme Corp. | STABLE FORMULATIONS OF PROGRAMMED DEATH RECEPTOR 1 (MP-1) ANTIBODIES AND THEIR METHODS OF USE |
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AU2022232566A1 (en) | 2023-08-03 |
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EP4306103A1 (en) | 2024-01-17 |
US20240148829A1 (en) | 2024-05-09 |
CA3211978A1 (en) | 2022-09-15 |
CN116963721A (zh) | 2023-10-27 |
MX2023010457A (es) | 2023-09-14 |
CL2023001670A1 (es) | 2023-11-24 |
PE20240120A1 (es) | 2024-01-22 |
AU2022232566A9 (en) | 2024-05-16 |
KR20220126654A (ko) | 2022-09-16 |
WO2022191550A1 (ko) | 2022-09-15 |
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