專利名稱：Il－1拮抗劑制劑的制作方法
背景技術(shù)：
發(fā)明領(lǐng)域本發(fā)明旨在包含能夠抑制白介素-1(IL-1)的試劑的藥物制劑，以及制造和使用此類制劑的方法。
相關(guān)領(lǐng)域的陳述能夠阻斷或抑制IL-1的生物學(xué)作用的白介素-1(IL-1)拮抗劑已得到描述。2003年7月31日公開的美國(guó)專利公開號(hào)2003/0143697中描述了IL-1拮抗劑的實(shí)例——IL-1捕獲劑。IL-1捕獲劑是包括兩種IL-1受體組分和多聚化組分的IL-1特異性融合蛋白。
凍干法(在受控的條件下冷凍干燥)通常用于蛋白質(zhì)的長(zhǎng)期儲(chǔ)存。凍干的蛋白質(zhì)基本上耐降解、聚集、氧化以及冷凍干燥狀態(tài)時(shí)的其他變性過程(參見，例如U.S.6,436,897)。
發(fā)明簡(jiǎn)述本文提供了白介素-1(IL-1)拮抗劑的穩(wěn)定制劑。本發(fā)明的藥物學(xué)上可接受的制劑包含IL-1捕獲劑以及藥物學(xué)上可接受的載體。在具體實(shí)施方案中，提供了液體和冷凍干燥的、或凍干的制劑。
在第一個(gè)實(shí)例方面，本發(fā)明的特征在于白介素-1(IL-1)拮抗劑的預(yù)凍干制劑，其包含能夠結(jié)合并抑制IL-1的生物學(xué)作用的IL-1蛋白拮抗劑、緩沖劑、有機(jī)共溶劑或填充劑、和一種或多種凍干保護(hù)劑(lyoprotectant)。在一個(gè)具體實(shí)施方案中，IL-1拮抗劑是能夠結(jié)合IL-1的融合蛋白，緩沖劑是組氨酸，有機(jī)共溶劑或填充劑是PEG，和凍干保護(hù)劑是甘氨酸、精氨酸和蔗糖中的至少一種。在一個(gè)實(shí)施方案中，本發(fā)明的預(yù)凍干制劑不包含防腐劑。
在本發(fā)明預(yù)凍干制劑的一個(gè)實(shí)施方案中，該制劑包含5-100mM組氨酸、0.5-3.0％PEG、0.25-3.0％甘氨酸、5-50mM精氨酸、0.5-30.0％蔗糖和5-50mg/ml IL-1拮抗劑，pH為約6.5。在一個(gè)實(shí)施方案中，所述預(yù)凍干制劑可以進(jìn)一步包含高達(dá)5mM的檸檬酸鹽和/或0.003-0.005％聚山梨醇酯。在此，聚山梨醇酯可以是例如聚山醇酯20或80。
在一個(gè)更具體的實(shí)施方案中，IL-1拮抗劑的預(yù)凍干制劑包含約20mM組氨酸、約1.5％PEG3350、約0.5％甘氨酸、約25mM精氨酸、約1.0％蔗糖和約40mg/ml IL-1捕獲劑，pH為約6.5。在一個(gè)具體實(shí)施方案中，IL-1拮抗劑是如SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26中所示的IL-1捕獲劑融合蛋白。更優(yōu)選地，IL-1捕獲劑是SEQ ID NO10中所示的捕獲劑。
在一個(gè)優(yōu)選實(shí)施方案中，預(yù)凍干IL-1拮抗劑制劑基本上由約20mM組氨酸、約1.5％PEG3350、約0.5％甘氨酸、約25mM精氨酸、約1.0％蔗糖和約40mg/ml具有SEQ ID NO10的序列的IL-1融合蛋白組成，pH為約6.5?？梢源嬖跈幟仕猁}(小于或等于約0.15mM)和聚山梨醇酯(小于或等于約0.005％)。
在第二個(gè)方面，本發(fā)明的特征在于預(yù)凍干IL-1拮抗劑制劑，所述制劑基本上由約20mM組氨酸、約1.5％PEG3350、約0.5％甘氨酸、約25mM精氨酸、約1.0％蔗糖和約40mg/ml具有SEQ ID NO10的序列的IL-1融合蛋白組成，pH為約6.5，其中預(yù)凍干制劑不包含防腐劑、磷酸鹽緩沖液、超過痕量的NaCl、和/或超過1.5％的蔗糖?？梢源嬖谛∮诩s0.15mM的量的檸檬酸鹽，和還可以存在高達(dá)約0.005-0.01％的聚山梨醇酯20。
在第三個(gè)方面，本發(fā)明的特征在于生產(chǎn)IL-1拮抗劑的凍干制劑的方法，所述方法包括對(duì)本發(fā)明的預(yù)凍干IL-1拮抗劑制劑實(shí)施凍干以產(chǎn)生凍干的IL-1拮抗劑制劑。凍干的制劑可以通過本領(lǐng)域已知用于凍干液體的任何方法來凍干。
在第四個(gè)相關(guān)方面，本發(fā)明的特征在于生產(chǎn)IL-1拮抗劑的復(fù)原的(reconstituted)凍干制劑的方法，其包括將本發(fā)明的凍干制劑復(fù)原為復(fù)原制劑。在一個(gè)實(shí)施方案中，復(fù)原制劑是預(yù)凍干制劑濃度的兩倍，例如，本發(fā)明方法包括(a)產(chǎn)生IL-1拮抗劑的預(yù)凍干制劑，所述制劑由約20mM組氨酸、約1.5％PEG3350、約0.5％甘氨酸、約25mM精氨酸、約1.0％蔗糖和約40mg/ml IL-1蛋白拮抗劑組成，pH為約6.5；(b)對(duì)步驟(a)的預(yù)凍干制劑實(shí)施凍干；以及(c)將步驟(b)的凍干制劑復(fù)原為由約40mM組氨酸、約3％PEG3350、約1％甘氨酸、約50mM精氨酸、約2.0％蔗糖和約80mg/ml IL-1蛋白拮抗劑組成的組合物，其中復(fù)原制劑可以進(jìn)一步包含約0.2mM檸檬酸鹽和/或約0.008％聚山梨醇酯20。在一個(gè)具體實(shí)施方案中，IL-1拮抗劑是如SEQ INO2、4、6、8、10、12、14、16、18、20、22、24、26中所示的IL-1捕獲劑融合蛋白。更優(yōu)選地，IL-1捕獲劑是SEQ ID NO10中所示的捕獲劑。在另外實(shí)施方案中，復(fù)原制劑是預(yù)凍干制劑濃度的3倍，例如，將20mg IL-1拮抗劑蛋白質(zhì)/ml預(yù)凍干制劑復(fù)原為60mg IL-1拮抗劑蛋白質(zhì)/ml的最終制劑。一般地，凍干制劑用適合于注射的無菌水復(fù)原。在一個(gè)實(shí)施方案中，復(fù)原液可以是抑菌水。
在生產(chǎn)復(fù)原的凍干制劑的方法的具體實(shí)施方案中，預(yù)凍干溶液以40mg IL-1拮抗劑蛋白質(zhì)/ml預(yù)凍干制劑溶液存在于管形瓶中，它被凍干并復(fù)原為80mg/ml溶液。在另一實(shí)施方案中，20mg/ml預(yù)凍干溶液被凍干并復(fù)原為40mg/ml溶液。在另一實(shí)施方案中，25mg/ml預(yù)凍干溶液被凍干并復(fù)原為50mg/ml溶液。在另一實(shí)施方案中，12.5mg/ml預(yù)凍干溶液被凍干并復(fù)原為25mg/ml溶液。在另一實(shí)施方案中，12.5mg/ml預(yù)凍干溶液被凍干并復(fù)原為50mg/ml溶液。在另一實(shí)施方案中，25mg/ml預(yù)凍干溶液被凍干并復(fù)原為75mg/ml溶液。在另一實(shí)施方案中，40mg/ml預(yù)凍干溶液被凍干并復(fù)原為120mg/ml溶液。在另一實(shí)施方案中，40mg/ml預(yù)凍干溶液被凍干并復(fù)原為20mg/ml溶液。優(yōu)選地，復(fù)原的凍干制劑不包含防腐劑。在另一實(shí)施方案中，復(fù)原制劑包括高達(dá)30％的蔗糖以及一種或多種防腐劑。
在第五個(gè)方面，本發(fā)明的特征在于IL-1拮抗劑的穩(wěn)定液體制劑，所述液體制劑包含能夠結(jié)合并抑制IL-1的生物學(xué)作用的IL-1拮抗劑蛋白質(zhì)、緩沖劑、有機(jī)共溶劑以及一種或多種熱穩(wěn)定劑。在一個(gè)具體實(shí)施方案中，IL-1拮抗劑是如SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26中所示的IL-1捕獲劑融合蛋白。更優(yōu)選地，IL-1捕獲劑是SEQ ID NO10中所示的捕獲劑。在一個(gè)實(shí)施方案中，緩沖劑是磷酸鹽緩沖液。在一個(gè)實(shí)施方案中，有機(jī)共溶劑是PEG，優(yōu)選PEG3350。在一個(gè)實(shí)施方案中，熱穩(wěn)定劑是NaCl和/或蔗糖。更優(yōu)選地，熱穩(wěn)定劑是NaCl和蔗糖。
在一個(gè)具體實(shí)施方案中，IL-1拮抗劑的穩(wěn)定液體制劑包含5-100mM磷酸鹽緩沖液、0.5-3.0％PEG、25-150mM NaCl、5-30％蔗糖、10-500mg/ml IL-1捕獲劑蛋白質(zhì)，pH為約6-6.5。在一個(gè)更具體的實(shí)施方案中，IL-1拮抗劑的穩(wěn)定液體制劑包含10mM磷酸鹽緩沖液、3％PEG3350、50mM NaCl、5-20％蔗糖、12.5-50mg/ml IL-1捕獲劑蛋白質(zhì)，pH為約6-6.5。另外，可以存在低或痕量的檸檬酸鹽緩沖液或聚山梨醇酯。在50mg/ml IL-1捕獲劑制劑于5℃儲(chǔ)存高達(dá)約29個(gè)月后，根據(jù)目檢確定本發(fā)明的IL-1拮抗劑穩(wěn)定液體制劑顯示很少或沒有沉淀。進(jìn)一步地，在50mg/ml IL-1捕獲劑制劑于5℃儲(chǔ)存高達(dá)約2 4個(gè)月后，根據(jù)大小排阻層析例如HPLC的測(cè)定，觀察到很少或沒有聚集。
其他目的和優(yōu)點(diǎn)經(jīng)參閱隨后的詳細(xì)描述將是顯而易見的。
發(fā)明詳述本發(fā)明不限于所描述的具體方法和實(shí)驗(yàn)條件，因?yàn)榇祟惙椒ê蜅l件可以改變。還應(yīng)當(dāng)理解本文所使用的術(shù)語僅用于描述具體實(shí)施方案，并不希望用于限制，除非另有說明，因?yàn)楸景l(fā)明的范圍將僅由所附的權(quán)利要求來限定。
如本說明書和所附權(quán)利要求中所使用的，除非上下文明確說明，否則單數(shù)形式“a”、“an”和“the”包括復(fù)數(shù)。因此，例如提及“一種方法”包括本文所描述的和/或閱讀本公開內(nèi)容后對(duì)于本領(lǐng)域技術(shù)人員將是顯而易見的類型的一種或多種方法和/或步驟。
除非另外定義，本文所使用的所有技術(shù)和科學(xué)術(shù)語具有與本發(fā)明所屬領(lǐng)域普通技術(shù)人員通常理解相同的含義。盡管與本文所述那些類似或等同的任何方法和材料均可用于本發(fā)明的實(shí)踐或測(cè)試中，但現(xiàn)在還是描述優(yōu)選的方法和材料。
一般描述包含蛋白質(zhì)的制劑的安全操作和施用代表了對(duì)于藥物配方設(shè)計(jì)師來說的重大挑戰(zhàn)。蛋白質(zhì)具有存在穩(wěn)定性問題的獨(dú)特化學(xué)和物理特性存在蛋白質(zhì)的各種降解途徑，牽涉到化學(xué)和物理不穩(wěn)定性?；瘜W(xué)不穩(wěn)定性包括脫氨作用、聚集、肽主鏈的剪斷以及甲硫氨酸殘基的氧化。物理不穩(wěn)定性包括許多現(xiàn)象，包括例如聚集。
通過從蛋白質(zhì)中去除水可以促進(jìn)化學(xué)和物理穩(wěn)定性。凍干法(在受控條件下的冷凍干燥)通常用于蛋白質(zhì)的長(zhǎng)期儲(chǔ)存。凍干的蛋白質(zhì)基本上耐降解、聚集、氧化以及冷凍干燥狀態(tài)時(shí)的其他變性過程。凍干的蛋白質(zhì)通常在施用前用任選包含抑菌性防腐劑(例如苯甲醇)的水來復(fù)原。
定義術(shù)語“治療上或藥物學(xué)上有效劑量”指產(chǎn)生施用其所期望的效果的劑量。確切的劑量將取決于治療的目的，并且將可由本領(lǐng)域技術(shù)人員利用已知技術(shù)來確定(參見，例如Lloyd(1999)The Art，Scienceand Technology of Pharmaceutical Compounding)。
術(shù)語“阻滯劑”、“抑制劑”或“拮抗劑”是指延緩或阻止化學(xué)或生理反應(yīng)或應(yīng)答的物質(zhì)。通常的阻滯劑或抑制劑包括但不限于反義分子、抗體、拮抗劑及其衍生物。
術(shù)語“藥物學(xué)上可接受的”包括指經(jīng)聯(lián)邦或州政府管理機(jī)構(gòu)批準(zhǔn)的或者在美國(guó)藥典或其他普遍公認(rèn)的藥典中列出的用于動(dòng)物并且更具體而言用于人的。
術(shù)語“載體(carrier)”指稀釋劑、佐劑、賦形劑或用于與組合物一起施用的媒介物。載體可以包括無菌的液體，例如水和油，包括石油，動(dòng)物、植物或合成來源的油，例如花生油、大豆油、礦物油、芝麻油等。
術(shù)語“賦形劑”包括加入到藥物組合物中以提供所需稠度或穩(wěn)定效果的非治療試劑。合適的藥物賦形劑包括，例如淀粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、米、面粉、白堊、硅膠、硬脂酸鈉、單硬脂酸甘油酯、滑石、氯化鈉、脫脂奶粉、甘油、丙二醇、水、乙醇等。
術(shù)語“凍干的”或“冷凍干燥的”包括已經(jīng)歷干燥操作例如凍干的物質(zhì)的狀態(tài)，其中至少50％的水分已被去除。
術(shù)語“填充劑”包括藥物學(xué)上可接受且增加凍干團(tuán)塊(lyo cake)體積的化合物。一般地，本領(lǐng)域已知的可接受的填充劑包括，例如碳水化合物，包括單糖例如右旋糖、核糖、果糖等，醇糖例如甘露醇、肌醇和山梨糖醇，二糖包括海藻糖、蔗糖和乳糖，天然發(fā)生的聚合物例如淀粉、葡聚糖、殼聚糖、透明質(zhì)酸鹽、蛋白質(zhì)(例如明膠和血清白蛋白)、糖原，以及合成的單體和聚合物。在本發(fā)明的制劑中，PEG3350是一種有機(jī)共溶劑，其用于在攪動(dòng)、混合或處理時(shí)穩(wěn)定IL-1蛋白拮抗劑，并且作為填充劑以幫助產(chǎn)生可接受的體積。
術(shù)語“凍干保護(hù)劑”包括可以加入冷凍干燥或凍干的制劑中以幫助在冷凍干燥或凍干時(shí)維持蛋白質(zhì)結(jié)構(gòu)的物質(zhì)。
“防腐劑”包括抑菌、殺菌、抑真菌或殺真菌的化合物，它們一般加入制劑以延緩或消除制劑中細(xì)菌或其他污染微生物的生長(zhǎng)。防腐劑包括，例如苯甲醇、苯酚、苯扎氯銨、間甲酚、硫柳汞(thimerosol)、三氯叔丁醇、羥基苯甲酸甲酯、羥基苯甲酸丙酯等。藥物學(xué)上可接受的防腐劑的其他實(shí)例可以在USP中找到。
IL-1拮抗劑IL-1拮抗劑是能夠阻斷或抑制IL-1的生物學(xué)作用的化合物，包括能夠捕獲IL-1的融合蛋白，例如IL-1捕獲劑。在一個(gè)優(yōu)選實(shí)施方案中，IL-1捕獲劑是包括兩種IL-1受體組分和多聚化組分的IL-1特異性融合蛋白，例如2003年7月31日公開的美國(guó)專利公開號(hào)2003/0143697中描述的IL-1捕獲劑。在一個(gè)具體實(shí)施方案中，IL-1捕獲劑是SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26中所示的融合蛋白。優(yōu)選的IL-1捕獲劑顯示于SEQ ID NO10中。本發(fā)明包括基本上等同于SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26的蛋白質(zhì)的IL-1捕獲劑的用途，即與SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26的蛋白質(zhì)具有至少95％同一性、優(yōu)選至少97％同一性、和更優(yōu)選至少98％同一性，并且能夠結(jié)合并抑制IL-1的蛋白質(zhì)。進(jìn)一步地，在具體實(shí)施方案中，IL-1拮抗劑是經(jīng)修飾的IL-1捕獲劑，其包括一種或多種受體組分以及一種或多種對(duì)于IL-1和/或IL-1受體來說特異的免疫球蛋白質(zhì)來源組分。在另一實(shí)施方案中，IL-1拮抗劑是經(jīng)修飾的IL-1捕獲劑，其包括一種或多種對(duì)于IL-1和/或IL-1受體來說特異的免疫球蛋白質(zhì)來源組分。
本發(fā)明方法和制劑的IL-1捕獲劑可以通過本領(lǐng)域已知或?qū)?huì)已知的、可用于制備IL-1捕獲劑的任何合適方法進(jìn)行制備。IL-1捕獲劑在用于制備藥物學(xué)上可接受的制劑時(shí)優(yōu)選基本上不含蛋白質(zhì)污染物。“基本上不含蛋白質(zhì)污染物”優(yōu)選地指，用于制造包含IL-1捕獲劑的制劑的IL-1捕獲劑制備物中至少90重量％蛋白質(zhì)是IL-1捕獲劑蛋白質(zhì)，更優(yōu)選至少95％，最優(yōu)選至少99％。IL-1捕獲劑優(yōu)選基本上不含聚集物?！盎旧喜缓奂铩敝?，在IL-1捕獲劑用于制備藥物學(xué)上有效的制劑時(shí)至少90重量％的IL-1捕獲劑蛋白質(zhì)不以聚集物的形式存在。本發(fā)明方法和制劑的IL-1捕獲劑可以包含由于純化過程而引起的低或痕量化合物，例如低或痕量的檸檬酸鹽和/或聚山梨醇酯。在包含約40mg IL-1捕獲劑/ml的本發(fā)明預(yù)凍干制劑的一個(gè)實(shí)施方案中，檸檬酸鹽可以以約0.1mM的濃度存在，和/或聚山梨醇酯可以以約0.004％的濃度存在。如果預(yù)凍干制劑在凍干后復(fù)原為原始體積的一半(例如80mg/ml的IL-1捕獲劑)，則所得到的濃度可以是0.2mM檸檬酸鹽和/或0.008％聚山梨醇酯。如果預(yù)凍干制劑在凍干后復(fù)原為原始體積的三分之一(例如120mg/ml的IL-1捕獲劑)，則所得到的濃度可以是0.6mM檸檬酸鹽和/或0.012％聚山梨醇酯。凍干過程和凍干制劑在本發(fā)明的一個(gè)方面，提供了包含IL-1捕獲劑的藥物學(xué)上可接受的制劑，其中該制劑是冷凍干燥或凍干的制劑。優(yōu)選地，冷凍干燥或凍干的制劑包含藥物學(xué)上有效量的IL-1捕獲劑。凍干制劑可以復(fù)原為溶液、懸浮液、乳狀液或適合于施用或使用的任何其他適當(dāng)形式。凍干制劑一般首先制備為液體，然后冷凍并凍干。凍干前的總液體體積可以少于、等于或多于凍干制劑的最終復(fù)原體積。凍干方法是本領(lǐng)域普通技術(shù)人員眾所周知的，并且一般包括在受控條件下水從冷凍制劑中的升華。
凍干制劑可以儲(chǔ)存在寬的溫度范圍內(nèi)。凍干制劑可以在等于或低于30℃的溫度下儲(chǔ)存，例如于4℃冷藏，或于室溫(例如大約25℃)儲(chǔ)存。優(yōu)選地，凍干制劑儲(chǔ)存在低于約25℃，更優(yōu)選地，在約4-20℃；低于約4℃；低于約-20℃；約-40℃；或約-70℃。
凍干制劑一般通過添加水溶液以溶解凍干制劑，從而復(fù)原以供使用?？梢允褂枚喾N多樣的水溶液來復(fù)原凍干制劑。優(yōu)選地，凍干制劑可以用水復(fù)原。凍干制劑優(yōu)選用基本上由水(例如USP WFI或注射用水)或抑菌水(例如含0.9％苯甲醇的USP WFI)組成的溶液復(fù)原。然而，還可使用包含緩沖劑和/或賦形劑和/或一種或多種藥物學(xué)上可接受的載體的溶液。
冷凍干燥或凍干的制劑一般從液體，即從溶液、懸浮液、乳狀液等制備。因此，待經(jīng)歷冷凍干燥或凍干的液體優(yōu)選包含最終復(fù)原液體制劑中所需的所有組分。因此，在復(fù)原時(shí)，冷凍干燥或凍干的制劑在復(fù)原后將提供所需的液體制劑。用于產(chǎn)生冷凍干燥或凍干的制劑的優(yōu)選液體制劑包含藥物學(xué)上有效量的IL-1捕獲劑、緩沖劑、穩(wěn)定劑和填充劑。冷凍干燥或凍干的制劑優(yōu)選包含組氨酸，因?yàn)楫?dāng)IL-1捕獲劑被凍干時(shí)，與磷酸鹽相比，組氨酸在穩(wěn)定IL-1捕獲劑方面更有效。有機(jī)共溶劑，例如PEG3350用于在攪動(dòng)、混合或處理時(shí)穩(wěn)定IL-1捕獲劑。凍干保護(hù)劑優(yōu)選用于冷凍干燥或凍干的制劑中。在冷凍干燥或凍干時(shí)，凍干保護(hù)劑幫助維持蛋白質(zhì)的二級(jí)結(jié)構(gòu)。凍干保護(hù)劑的三個(gè)優(yōu)選實(shí)例是甘氨酸、精氨酸和蔗糖，它們優(yōu)選一起使用。
穩(wěn)定的液體制劑在一個(gè)方面，本發(fā)明提供了包含IL-1捕獲劑的穩(wěn)定的藥物學(xué)上可接受的制劑，其中該制劑是液體制劑。優(yōu)選地，所述液體制劑包含藥物學(xué)上有效量的IL-1捕獲劑。該制劑還可包含一種或多種藥物學(xué)上可接受的載體、緩沖劑、填充劑、穩(wěn)定劑、防腐劑和/或賦形劑。包含IL-1捕獲劑的藥物學(xué)上可接受的液體制劑的實(shí)例包含藥物學(xué)上有效量的IL-1捕獲劑、緩沖劑、共溶劑以及一種或多種穩(wěn)定劑。
優(yōu)選的液體制劑包含磷酸鹽緩沖液、有機(jī)共溶劑、和一種或多種熱穩(wěn)定劑、以及約12.5mg/ml-約50mg/ml IL-1捕獲劑，所述熱穩(wěn)定劑用于在儲(chǔ)存時(shí)將聚集物以及低分子量產(chǎn)物的形成降至最低，其中該制劑的pH為約6.0-約6.75。更優(yōu)選的液體制劑包含10mM磷酸鹽緩沖液、3％PEG、50mM NaCl、5-20％蔗糖、10-100mg/ml IL-1捕獲劑，其中該制劑的pH為約6.0-約6.5。盡管NaCl或蔗糖均可用作穩(wěn)定劑，但已確定NaCl和蔗糖的組合比單獨(dú)的任何單個(gè)穩(wěn)定劑更有效地穩(wěn)定IL-1捕獲劑。優(yōu)選地，PEG是PEG3350，已確定它增強(qiáng)IL-1捕獲劑穩(wěn)定性。
表1顯示了如當(dāng)在5℃孵育時(shí)于長(zhǎng)達(dá)24個(gè)月的時(shí)間內(nèi)所測(cè)定的，在包含5或20％蔗糖的樣品中天然IL-1捕獲劑的百分比或聚集的IL-1捕獲劑的百分比。在20％蔗糖存在下，天然(非聚集)形式的IL-1捕獲劑從第0天的92.6％降至24個(gè)月時(shí)的88.9％，并且聚集物的百分比在相同時(shí)間內(nèi)從2.3％增至3.4％。5％蔗糖制劑的天然(非聚集)形式的IL-1捕獲劑從第0天的92.4％降至24個(gè)月時(shí)的86.9％，并且聚集物的百分比在相同時(shí)間內(nèi)從2.6％增至3.6％。
表1
表2顯示了如當(dāng)在5℃孵育時(shí)于長(zhǎng)達(dá)2.9個(gè)月的時(shí)間內(nèi)所測(cè)定的，在包含0、5或20％蔗糖的樣品中天然IL-1捕獲劑的百分比(50mg/mlIL-1捕獲劑、10mM磷酸鹽、0.2％聚山梨醇酯-20、50或135(含0％蔗糖)mM NaCl，pH6.5。在0％蔗糖存在下，天然(非聚集)形式的IL-1捕獲劑從第0天的96.4％降至2.9個(gè)月時(shí)的0.5％。5％蔗糖制劑的天然(非聚集)形式的IL-1捕獲劑從第0天的96.5％降至2.9個(gè)月時(shí)的39.2％。20％蔗糖制劑的天然(非聚集)形式的IL-1捕獲劑從第0天的96.4％降至2.9個(gè)月時(shí)的95.3％。
表2
液體或冷凍干燥的和凍干的制劑可以儲(chǔ)存在去除氧的環(huán)境中。去除氧的環(huán)境可以通過將制劑儲(chǔ)存在惰性氣體下而產(chǎn)生，所述惰性氣體例如為氬、氮或氦。
測(cè)定預(yù)凍干和凍干的制劑的穩(wěn)定性。包含40mg/ml IL-1捕獲劑(SEQ ID NO10)、20mM組氨酸、1.5％PEG-3350、1％蔗糖、0.5％甘氨酸、25mM精氨酸-HCl，pH6.5的預(yù)凍干制劑在5℃孵育0-52周。如表3中所示，天然(非聚集)形式的IL-1從94.9(0周)降至92.3(52周)，并且聚集物的百分比在相同時(shí)間內(nèi)從1％增至1.8％。
表3
包含40mg/ml IL-1捕獲劑(SEQ ID NO10)、20mM組氨酸、1.5％PEG-3350、1％蔗糖、0.5％甘氨酸、25mM精氨酸-HCl，pH6.5(預(yù)凍干濃度)的預(yù)凍干制劑的穩(wěn)定性在25℃孵育0-56周。如表4中所示，天然(非聚集)形式的IL-1從97.0(0周)降至94.0(56周)，并且聚集物的百分比在相同時(shí)間內(nèi)從0.8％增至3.6％。
表4
盡管前述發(fā)明已通過圖表和實(shí)施例得到相當(dāng)詳細(xì)的描述，但對(duì)于本領(lǐng)域普通技術(shù)人員將會(huì)顯而易見的是，可對(duì)本發(fā)明的教導(dǎo)進(jìn)行某些改變和修改，而不離開所附權(quán)利要求的精神或范圍。
序列表<110>Regeneron Pharmaceuticals，Inc.
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ggcgcgccta tgctgagcga ggctgataaa tgcaaggaac gtgaagaaaa aataatttta 1140gtgtcatctg caaatgaaat tgatgttcgt ccctgtcctc ttaacccaaa tgaacacaaa 1200ggcactataa cttggtataa ggatgacagc aagacacctg tatctacaga acaagcctcc 1260aggattcatc aacacaaaga gaaactttgg tttgttcctg ctaaggtgga ggattcagga 1320cattactatt gcgtggtaag aaattcatct tactgcctca gaattaaaat aagtgcaaaa 1380tttgtggaga atgagcctaa cttatgttat aatgcacaag ccatatttaa gcagaaacta 1440cccgttgcag gagacggagg acttgtgtgc ccttatatgg agttttttaa aaatgaaaat 1500aatgagttac ctaaattaca gtggtataag gattgcaaac ctctacttct tgacaatata 1560cactttagtg gagtcaaaga taggctcatc gtgatgaatg tggctgaaaa gcatagaggg 1620aactatactt gtcatgcatc ctacacatac ttgggcaagc aatatcctat tacccgggta 1680atagaattta ttactctaga ggaaaacaaa cccacaaggc ctgtgattgt gagcccagct 1740aatgagacaa tggaagtaga cttgggatcc cagatacaat tgatctgtaa tgtcaccggc 1800cagttgagtg acattgctta ctggaagtgg aatgggtcag taattgatga agatgaccca 1860gtgctagggg aagactatta cagtgtggaa aatcctgcaa acaaaagaag gagtaccctc 1920atcacagtgc ttaatatatc ggaaattgag agtagatttt ataaacatcc atttacctgt 1980tttgccaaga atacacatgg tatagatgca gcatatatcc agttaatata tccagtcact 2040aattccggag acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 2100ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 2160gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 2220tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 2280agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 2340gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 2400aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 2460atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 2520gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 2580ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 2640cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 2700cagaagagcc tctccctgtc tccgggtaaa tga 2733<210>2<211>910<212>PRT<213>智人<400>2Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Ser Gly Gly Ala Pro Met Leu Ser Glu Ala355 360 365Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val Ser Ser Ala370 375 380Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn Glu His Lys385 390 395 400Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro Val Ser Thr405 410 415Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu Trp Phe Val
420 425 430Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val Val Arg Asn435 440 445Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe Val Glu Asn450 455 460Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys Gln Lys Leu465 470 475 480Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met Glu Phe Phe485 490 495Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr Lys Asp Cys500 505 510Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val Lys Asp Arg515 520 525Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn Tyr Thr Cys530 535 540His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile Thr Arg Val545 550 555 560Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg Pro Val Ile565 570 575Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly Ser Gln Ile580 585 590Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile Ala Tyr Trp595 600 605Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val Leu Gly Glu610 615 620Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg Ser Thr Leu625 630 635 640Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe Tyr Lys His645 650 655Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp Ala Ala Tyr660 665 670Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Gly Asp Lys Thr His Thr675 680 685Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe690 695 700Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro705 710 715 720Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val725 730 735Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr740 745 750Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val755 760 765Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
770 775 780Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser785 790 795 800Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro805 810 815Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val820 825 830Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly835 840 845Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp850 855 860Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp865 870 875 880Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His885 890 895Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys900 905 910<210>3<211>2703<212>DNA<213>智人<400>3atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca 2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700tga 2703<210>4<211>900<212>PRT<213>智人<400>4Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>5<211>2709<212>DNA<213>智人<400>5atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 2709<210>6<211>902<212>PRT<213>智人<400>6Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235 240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265 270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310 315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu ValVal Gln Lys Asp Ser
435 440 445Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys GIu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785790 795 800Pro Gln ValTyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>7<211>2709<212>DNA<213>智人<400>7atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 2709<210>8<211>902<212>PRT<213>智人<400>8Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser1 5 10 15Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val20 25 30Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn35 40 45Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro50 55 60Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu65 70 75 80Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe100 105 110Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys115 120 125Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met130 135 140Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr145 150 155 160Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val165 170 175Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn180 185 190Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile195 200 205Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg210 215 220Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly225 230 235240Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile245 250 255Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val260 265270Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg275 280 285Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe290 295 300Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp305 310315 320Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys325 330 335Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp340 345 350Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe355 360 365Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp370 375 380Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro385 390 395 400Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr405 410 415Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr420 425 430Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu450 455 460Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro465 470 475 480Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile485 490 495Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu500 505 510Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr515 520 525Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys530 535 540Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro545 550 555 560Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile565 570 575Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val580 585 590Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val595 600 605Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg610 615 620Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg625 630 635 640Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala645 650 655Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>9<211>2703<212>DNA<213>智人<400>9atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700tga 2703<210>10<211>900<212>PRT<213>智人<400>10Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu675 680 685Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu690 695 700Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser705 710 715 720His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu725 730 735Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr740 745 750Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn755 760 765Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro770 775 780Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln785 790 795 800Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
805 810 815Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val820 825 830Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro835 840 845Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr850 855 860Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val865 870 875 880Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu885 890 895Ser Pro Gly Lys900<210>11<211>2709<212>DNA<213>智人<400>11atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 2709<210>12<211>902<212>PRT<213>智人<400>12Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>13<211>2709<212>DNA<213>智人<400>13atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700ggtaaatga 2709<210>14<211>902<212>PRT<213>智人<400>14Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile355 360 365Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu370 375 380Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser385 390 395 400Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys405 410 415Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr420 425 430Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser435 440 445Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala450 455 460Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu485 490 495Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe500 505 510Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His515 520 525Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln530 535 540Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys545 550 555 560Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val565 570 575Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu580 585 590Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp595 600 605Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn610 615 620Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu625 630 635 640Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His645 650 655Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser660 665 670Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu675 680 685Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp690 695 700Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp705 710 715 720Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly725 730 735Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn740 745 750Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp755 760 765Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro770 775 780Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu785 790 795 800Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn805 810 815Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr835 840 845Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg850 855 860Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys865 870 875 880Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu885 890 895Ser Leu Ser Leu Gly Lys900<210>15<211>2748<212>DNA<213>智人<400>15atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748<210>16<211>915<212>PRT<213>智人<400>16Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>17<211>2754<212>DNA<213>智人<400>17atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>18<211>917<212>PRT<213>智人<400>18Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580 585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>19<211>2754<212>DNA<213>智人<400>19atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>20<211>917<212>PRT<213>智人<400>20Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu1 5 10 15Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly20 25 30Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu35 40 45Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg50 55 60Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly65 70 75 80Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu85 90 95Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn115 120 125Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu130 135 140Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg145 150 155 160Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu165 170 175Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu180 185 190Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val195 200 205Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile210 215 220Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile225 230 235 240Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile245 250 255Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu260 265 270Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly275 280 285Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn290 295 300Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu305 310 315 320His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr325 330 335Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys340 345 350Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp355 360 365Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe370 375 380Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp385 390 395 400Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro405 410 415Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr420 425 430Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr435 440 445Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu465 470 475 480Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro485 490 495Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile500 505 510Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu515 520 525Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr530 535 540Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys545 550 555 560Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro565 570 575Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile580585 590Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val595 600 605Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val610 615 620Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg625 630 635 640Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg645 650 655Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala660 665 670Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>21<211>2748<212>DNA<213>智人<400>21atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748<210>22<211>915<212>PRT<213>智人<400>22Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly690 695 700Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met705 710 715 720Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His725 730 735Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val740 745 750His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr755 760 765Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly770 775 780Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile785 790 795 800Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
805 810 815Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser820 825 830Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu835 840 845Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro850 855 860Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val865 870 875 880Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met885 890 895His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser900 905 910Pro Gly Lys915<210>23<211>2754<212>DNA<213>智人<400>23atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>24<211>917<212>PRT<213>智人<400>24Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys915<210>25<211>2754<212>DNA<213>智人<400>25atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754<210>26<211>917<212>PRT<213>智人<400>26Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu1 5 10 15Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met20 25 30Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro35 40 45Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala50 55 60Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu65 70 75 80Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr100 105 110Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro115 120 125Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu130 135 140Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys145 150 155 160Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr165 170 175Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro180 185 190Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly195 200 205Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His210 215 220Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala225 230 235 240Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys245 250 255Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe260 265 270Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys275 280 285Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His290 295 300Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys305 310 315 320Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser325 330 335Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro340 345 350Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe355 360 365Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val370 375 380Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser385 390 395 400Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val405 410 415Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp420 425 430Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe450 455 460Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu465 470 475 480Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe485 490 495Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu500 505 510Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr515 520 525His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg530 535 540Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg545 550 555 560Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val565 570 575Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu580 585 590Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr595 600 605Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro610 615 620Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn625 630 635 640Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu645 650 655Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe660 665 670Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly675 680 685Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe690 695 700Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr705 710 715 720Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val725 730 735Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val740 745 750Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser755 760 765Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu770 775 780Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro805 810 815Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln820 825 830Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala835 840 845Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr850 855 860Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu865 870 875 880Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser885 890 895Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser900 905 910Leu Ser Leu Gly Lys91權(quán)利要求
1.一種適合于凍干的制劑，其包含5-100mM組氨酸、0.5-3.0％PEG、0.25-3％甘氨酸、5-50mM精氨酸、0.5-30％蔗糖和5-50mg/ml IL-1蛋白拮抗劑。
2.權(quán)利要求1的制劑，其中所述IL-1拮抗劑是融合蛋白的二聚體，所述融合蛋白選自SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24和26，優(yōu)選SEQ ID NO10。
3.權(quán)利要求1或2的制劑，其包含約20mM組氨酸、約1.5％PEG3350、約0.5％甘氨酸、約25mM精氨酸、約1.0％蔗糖和約40mg/mlIL-1拮抗劑。
4.前述權(quán)利要求中任何一項(xiàng)的制劑，其不包含磷酸鹽緩沖液、超過約1.5％的蔗糖、超過約0.15mM的檸檬酸鹽和超過約0.005％的聚山梨醇酯20。
5.前述權(quán)利要求中任何一項(xiàng)的制劑，其中pH可以是6-6.75，優(yōu)選6-6.5，更優(yōu)選6.5。
6.一種生產(chǎn)IL-1拮抗劑的凍干制劑的方法，其包括復(fù)原前述權(quán)利要求中任何一項(xiàng)的制劑以產(chǎn)生凍干的I L-1拮抗劑制劑。
7.權(quán)利要求6的方法，其中復(fù)原的制劑包含約20-120mg/ml IL-1拮抗劑。
8.一種穩(wěn)定的液體制劑，其包含能夠結(jié)合并抑制IL-1的生物學(xué)作用的IL-1蛋白拮抗劑、緩沖劑、有機(jī)共溶劑或填充劑、和一種或多種熱穩(wěn)定劑，其中所述IL-1拮抗劑是包含2種融合蛋白的二聚體，所述融合蛋白顯示于SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24、26中。
9.權(quán)利要求8的液體制劑，其中所述融合蛋白包含SEQ ID NO10。
10.權(quán)利要求8或9的液體制劑，其包含5-100mM磷酸鹽緩沖液，優(yōu)選10mM磷酸鹽緩沖液；0.5-3％PEG 3350，優(yōu)選3％PEG 3350；25-150mM NaCl，優(yōu)選50mM NaCl；5-30％蔗糖，優(yōu)選5-20％蔗糖；以及10-100mg/ml IL-1拮抗劑。
11.權(quán)利要求8-10中任何一項(xiàng)的液體制劑，其中在將50mg/mlIL-1捕獲劑制劑于5℃儲(chǔ)存29個(gè)月后，依據(jù)目檢所述IL-1拮抗劑顯示少于4％的聚集。
全文摘要
提供了白介素－1(IL－1)拮抗劑制劑，包括預(yù)凍干制劑、復(fù)原凍干制劑和穩(wěn)定的液體制劑。優(yōu)選地，所述IL－1拮抗劑是由2種融合蛋白的二聚體組成的IL－1捕獲劑，所述融合蛋白具有選自SEQ ID NO2、4、6、8、10、12、14、16、18、20、22、24和26的氨基酸序列。最優(yōu)選地，融合蛋白具有SEQ ID NO10的序列。
文檔編號(hào)C07K14/545GK101014617SQ200580028189
公開日2007年8月8日 申請(qǐng)日期2005年8月17日 優(yōu)先權(quán)日2004年8月17日
發(fā)明者D·迪克斯, K·鮑爾斯, G·齊曼拉爾 申請(qǐng)人:瑞澤恩制藥公司