TW202308683A - 聚乙二醇化精胺酸脫亞胺酶之調配物 - Google Patents
聚乙二醇化精胺酸脫亞胺酶之調配物 Download PDFInfo
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Abstract
提供包含聚乙二醇化精胺酸脫亞胺酶(ADI-PEG)及相關經復原液體組成物之凍乾調配物,及使用該組成物以進行精胺酸耗盡療法(包括治療各種癌症)之方法。
Description
本揭示之實施例尤其係關於包含聚乙二醇化精胺酸脫亞胺酶(ADI-PEG)及相關經復原液體組成物之凍乾調配物,及使用該組成物以進行精胺酸耗盡療法(包括治療各種癌症)之方法。
精胺酸耗盡療法可為某些形式的癌症以及其他疾病之有效治療。例如,聚乙二醇化精胺酸脫亞胺酶(ADI-PEG)可藉由將精胺酸轉化為瓜胺酸及氨而耗盡精胺酸之血流供應。ADI-PEG 20為正在臨床上經研究用於缺乏關鍵酶精胺基琥珀酸合成酶-1 (ASS1)之腫瘤的示範性ADI-PEG,該精胺基琥珀酸合成酶-1牽涉於將瓜胺酸轉化為精胺酸。ADI-PEG 20已經良好耐受且在臨床研究中顯示出希望(參見,例如,Qiu等人, Cancer Lett. 2015 Aug 1;364(1):1-7;Phillips等人, Cancer Res Treat. 2013 Dec;45(4):251-62;Feun等人, Curr Pharm Des. 2008;14(11):1049-57;Feun及Savaraj, Expert Opin Investig Drugs. 2006 Jul;15(7):815-22;Feun等人, Curr Opin Clin Nutr Metab Care. 2015 Jan;18(1):78-82)。
凍乾或冷凍乾燥為一種自液體藥劑中除去水以產生固體粉末或餅之製程。凍乾固態或調配物之製備代表一種優化生物醫藥藥劑之穩定性的方法。使用凍乾調配物可減少降解反應、運輸過程中之攪動及儲存過程中之溫度波動之影響以及其他益處。
某些實施例係關於凍乾調配物,其包含聚乙二醇化精胺酸脫亞胺酶(ADI-PEG),其中該凍乾調配物為無菌的,實質上不含內毒素,且處於醫藥學上可接受之pH下。
一些實施例包含醫藥學上可接受之緩衝劑,例如選自以下中之一或多者之緩衝劑:組胺酸、檸檬酸鈉、甘胺醯-甘胺酸、磷酸鈉、Tris及離胺酸。在某些實施例中,緩衝劑之濃度為約0.10 mM至約200 mM,或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM,包括其間所有整數及範圍。在特定實施例中,緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM或約10 mM。
一些實施例包含醫藥學上可接受之賦形劑,例如選自以下中之一或多者的賦形劑:冷凍保護劑、凍乾保護劑、穩定劑、增積劑、張力調節劑、界面活性劑、醫藥塑化劑、螯合劑及前述者之任何組合。
在一些實施例中,冷凍保護劑以以下量存在:約0.001%至約20% (wt%),包括其間所有整數及範圍。在一些實施例中,防凍劑係選自以下中之一或多者:蔗糖、海藻糖、乙二醇、丙二醇、甘油及前述者之任何組合。
在一些實施例中,凍乾保護劑以以下量存在:約0.001%至約20% (wt%),包括其間所有整數及範圍。在一些實施例中,凍乾保護劑係選自以下中之一或多者:蔗糖、海藻糖、甘露醇、山梨醇、甘油及前述者之任何組合。
在一些實施例中,穩定劑以以下量存在:約0.001%至約20% (wt%),包括其間所有整數及範圍。在某些實施例中,穩定劑係選自以下中之一或多者:蔗糖、甘露醇、乳糖、海藻糖、麥芽糖、山梨醇、明膠、白蛋白及前述者之任何組合。
在某些實施例中,增積劑以以下量存在:約0.001%至約20% (wt%),包括其間所有整數及範圍。在某些實施例中,增積劑係選自以下中之一或多者:甘露醇、山梨醇、乳糖、葡萄糖、蔗糖、甘胺酸、白蛋白、葡聚糖40。
在某些實施例中,張力調節劑以以下量存在:約0.001%至約20% (wt%),包括其間所有整數及範圍。在特定實施例中,張力調節劑係選自以下中之一或多者:氯化鈉、蔗糖、甘露醇及前述者之任何組合。
特定凍乾調配物包含選自以下中之一或多者的醫藥學上可接受之賦形劑:蔗糖、海藻糖、葡聚糖、甘露醇、脯胺酸、甘胺酸、界面活性劑、醫藥塑化劑、螯合劑及前述者之任何組合。
某些凍乾調配物包含之蔗糖為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
一些凍乾調配物包含之海藻糖為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
某些凍乾調配物包含之葡聚糖即視情況葡聚糖40為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
特定凍乾調配物包含之甘露醇為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
一些凍乾調配物包含之脯胺酸為約0.10 mM至約200 mM、或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM、或約0.001%至約20%、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
某些凍乾調配物包含之甘胺酸為約0.10 mM至約200 mM、或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM、或約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。
某些凍乾調配物包含之界面活性劑為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在一些實施例中,界面活性劑係選自以下中之一或多者:Tween-80、聚山梨醇酯20 (P20)、聚山梨醇酯80 (P80)、泊洛沙姆188及前述者之任何組合。
一些凍乾調配物包含之醫藥塑化劑為約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在某些實施例中,醫藥塑化劑為甘油。
某些凍乾調配物包含螯合劑,例如乙二胺四乙酸(EDTA)。在一些實施例中,螯合劑以以下量存在:約0.001%至約1% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95或1.0%,包括其間所有整數及範圍。
在某些實施例中,醫藥學上可接受之pH為約5.0至約8.0 (±0.01至±0.1)、或約5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0 (±0.01至±0.1),包括其間所有整數及範圍。
在具體實施例中,緩衝劑為組胺酸,其濃度約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。
此等及相關實施例中的某些包含之蔗糖為約1%至約10%、或約4%至約6%、或約5%。一些實施例包含之甘露醇為約1%至約10%、或約4%至約6%、或約5%。一些實施例包含之葡聚糖例如葡聚糖40為約0.1%至約5%、或約0.5%至約2%、或約1%。一些實施例包含之葡聚糖例如葡聚糖40為約0.1%至約5%、或約0.5%至約2%、或約1%,且包含之蔗糖為約1%至約10%、或約4%至約6%、或約5%。一些實施例包含之海藻糖為約1%至約10%、或約4%至約6%、或約5%。一些實施例包含之甘露醇為約1%至約10%、或約3%至約5%、或約4%,且包含之蔗糖為約0.1%至約5%、或約0.5%至約2%、或約1%。一些實施例包含之蔗糖為約1%至約10%、或約4%至約6%、或約4.8%或5%,且包含之Tween-80為約0.001%至約0.1%、或約0.005%至約0.05%、或約0.01%。一些實施例包含之蔗糖為約1%至約10%、或約4%至約6%、或約4.8%或5%,包含之Tween-80為約0.001%至約0.1%、或約0.005%至約0.05%、或約0.01%,且包含之甘油為約0.01%至約1.0%、或約0.1%至約0.5%、或約0.25%。在此等及相關實施例中之一些中,pH為約6.0至約6.5至約7.2 (±0.1)、或約6.6至約7.0 (±0.1)、或約6.8 (±0.1)。
一些實施例包含之海藻糖為約1%至約15%、或約5%至約12%、或約10%或9.5%。一些實施例包含之海藻糖為約1%至約15%、或約5%至約12%、或約10%或9.5%,且包含之脯胺酸為約10 mM至約40 mM、或約15至約30 mM、或約20 mM。一些實施例包含之海藻糖為約5%至約15%、或約8%至約12%、或約10%或9.5%,且包含之甘胺酸為約10 mM至約40 mM、或約15至約30 mM、或約20 mM。一些實施例包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或9.5%。一些實施例包含之蔗糖為約1%至約10%、約4%至約6%、或約5%或4.5%,且包含之海藻糖為約1%至約10%、約4%至約6%、或約5%或4.5%。一些實施例包含之海藻糖為約5%至約15%、或約8%至約12%、或約10%或9.5%,且包含之EDTA為約0.01%至約0.1%、或約0.02%至約0.08%、或約0.05%。在此等及相關實施例中之一些中,pH為約6.0至約7.2 (±0.1)、或約6.4至約6.8 (±0.1)、或約6.5 (±0.1)。
在某些實施例中,緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM的組胺酸,包含之甘胺酸為約1%至約5%、或約2%或1.9%,包含之海藻糖為約0.1%至約2%、或約0.5%至約1.5%、或約1%,且包含之界面活性劑例如P20為約0.001%至約0.1%、或約0.005%至約0.02%、或約0.01%。在某些實施例中,緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM的組胺酸,包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或8.5%,且包含之海藻糖為約0.1%至約2%、或約0.5%至約1.5%、或約1%。在某些實施例中,緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM的組胺酸,包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或9%。在某些實施例中,緩衝劑為約1至約50 mM、或約10至約40 mM、或約20、25、30或35 mM的組胺酸,包含之氯化鈉為約100至約150 mM、或約120、130或140 mM。在一些實施例中,緩衝劑為約100至約200 mM、或約150 mM的磷酸鈉,包含之蔗糖及/或海藻糖為約1%至約10%、約4%至約6%、或約5%或4.5%,包含之甘胺酸為約0.1至約1%、或約0.5%,包含之甘油為約0.1至約1.0%、或約0.25%,包含之Tween 80為約0.001至約0.1%、或約0.01%,且包含之EDTA為約0.01至約0.1%、或約0.05%。在某些實施例中,pH為約6.0至約6.5至約7.2 (±0.1)、或約6.6至約7.0 (±0.1)、或約6.8 (±0.1)。
在一些實施例中,ADI-PEG之乾重為約50 mg/g至約150 mg/g。在一些實施例中,ADI-PEG包含與
表 A1中序列至少80、95、90、95、96、97、98、99或100%一致的胺基酸序列。在一些實施例中,ADI-PEG共價鍵結至約1至約21個PEG分子。在一些實施例中,ADI-PEG包含一或多個共價附接ADI及PEG之水不穩定連接子。在一些實施例中,ADI-PEG為ADI-PEG 20,其中精胺酸脫亞胺酶共價鍵結至約5±1.0之質量平均數的PEG分子。
在一些實施例中,相對於非凍乾液體對照組成物中之相應ADI-PEG,ADI-PEG保留其精胺酸脫亞胺酶(ADI)活性之至少80、85、90或95%。在一些實施例中,例如相對於非凍乾液體對照組成物中之相應ADI-PEG,ADI-PEG保留(原始) PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。
亦包括復原本文所述之凍乾調配物的方法,該方法包括將醫藥學上可接受之溶劑添加至凍乾調配物以形成經復原液體組成物。
在一些實施例中,凍乾調配物在小於約五分鐘之時間內復原成約5-20 mg/ml ADI-PEG之實質上不含聚集體的溶液。在一些實施例中,凍乾調配物在小於約一或二分鐘之時間內復原成約5-20 mg/ml ADI-PEG之實質上不含聚集體的溶液。
在一些實施例中,相對於非凍乾液體對照組成物中之相應ADI-PEG,經復原液體組成物中之ADI-PEG保留其精胺酸脫亞胺酶活性之至少75、80、85、90或95%,且/或保留PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。在一些實施例中,在作為凍乾調配物儲存約或至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、60或72個月後,例如在約2-8℃之溫度及/或約室溫下儲存後,ADI-PEG在復原時保留其精胺酸脫亞胺酶活性之至少75、80、85、90或95%。在一些實施例中,在作為凍乾調配物儲存約或至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、60或72個月後,例如在約2-8℃之溫度及/或約室溫下儲存後,ADI-PEG保留(原始) PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。在一些實施例中,ADI-PEG在復原後之酶比活性為約5.0至約120 IU/mg、或約5.5、6、6.5、7、7.5、8、8.5、9.0、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5、20、20.5、21、21.5、22、22.5、23、23.5、24、24.5、25、25.5、26、26.5、27、27.5、28、28.5、29、29.5、30、30.5、35、40、45、50、55、55、60、65、70、75、80、85、90、95、100、105、110、115或120 IU/mg。
在一些實施例中,ADI-PEG之重量莫耳滲透濃度為約50 mOsm/kg至約500 mOsm/kg、或約50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295、300、305、310、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495或約500 mOsm/kg。
在具體實施例中,溶劑為水。
某些實施例係關於藉由本文所述之任何方法製備之經復原液體組成物。
一些實施例包括經復原液體組成物,其包含本文所述之凍乾調配物及醫藥學上可接受之溶劑。在一些實施例中,ADI-PEG之濃度為約5-20 mg/ml、或約5、6、7、8、9、10、10.5、11、11.5、12、12.5、13、13.5、14、15、16、17、18、19或20 mg/ml,包括其間所有整數及範圍。在一些實施例中,相對於非凍乾液體對照組成物中之相應ADI-PEG,經復原液體組成物中之ADI-PEG保留其精胺酸脫亞胺酶活性之至少75、80、85、90或95%。
在一些實施例中,ADI-PEG之酶比活性為約5.0至約120 IU/mg、或約5.5、6、6.5、7、7.5、8、8.5、9.0、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5、20、20.5、21、21.5、22、22.5、23、23.5、24、24.5、25、25.5、26、26.5、27、27.5、28、28.5、29、29.5、30、30.5、35、40、45、50、55、55、60、65、70、75、80、85、90、95、100、105、110、115或120 IU/mg。
在一些實施例中,ADI-PEG之重量莫耳滲透濃度為約50 mOsm/kg至約500 mOsm/kg、或約50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295、300、305、310、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495或約500 mOsm/kg。
在一些實施例中,溶劑為水。某些經復原溶液適於注射至受試者中。
亦包括治療、改善有需要之受試者的癌症之症狀或抑制該癌症之進展的方法,其包含向該受試者投與本文所述之經復原液體調配物。
在某些實施例中,該癌症係選自以下一或多者:肝細胞癌(HCC)、黑色素瘤、轉移性黑色素瘤、胰腺癌、前列腺癌、小細胞肺癌、間皮瘤、淋巴球性白血病、慢性骨髓性白血病、淋巴瘤、肝癌、肉瘤、白血病、急性骨髓性白血病、復發性急性骨髓性白血病、B細胞惡性腫瘤、乳癌、卵巢癌、結腸直腸癌、胃癌、神經膠質瘤(例如星形細胞瘤、寡樹突神經膠細胞瘤、室管膜瘤或脈絡叢乳頭狀瘤)、多形性神經膠質母細胞瘤(例如,巨細胞神經膠母細胞瘤或神經膠肉瘤)、腦膜瘤、垂體腺瘤、前庭神經鞘瘤、原發性CNS淋巴瘤、原始神經外胚層腫瘤(神經管胚細胞瘤)、非小細胞肺癌(NSCLC)、腎癌、膀胱癌、子宮癌、食道癌、腦癌、頭頸癌、子宮頸癌、睪丸癌及胃癌。
在一些實施例中,癌症展現減少的精胺基琥珀酸合成酶-1表現。
某些實施例包括一或多種患者護理套組,其包含本文所述之凍乾調配物及視情況醫藥學上可接受之溶劑。在具體實施例中,溶劑為水。
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除非另外定義,否則本文所使用的所有技術及科學術語皆具有與本揭示所屬技術之一般技藝人士通常所理解相同之含義。儘管與本文所述之彼等類似或等效的任何方法、材料、組成物、試劑、細胞可用於本揭示主題之實踐或測試,但描述的為較佳方法及材料。本說明書中所引用的所有出版物及參考文獻(包括但不限於專利及專利申請案)以全文引用之方式併入本文中,如同具體地及單獨地指示各單獨出版物或參考文獻如所完全闡述以引用之方式併入本文中一樣。為本申請案所主張優先權之任何專利申請案亦以以上對於出版物及參考文獻所述之方式以全文引用之方式併入本文中。
除非具體相反地指示,否則本揭示之實踐將此項技術內採用病毒學、免疫學、微生物學、分子生物學之習知方法及重組DNA技術,其中許多在以下出於說明之目的來描述。此類技術在文獻中得到充分說明。參見,例如,
Current Protocols in Protein Science, Current Protocols in Molecular Biology or Current Protocols in Immunology, John Wiley & Sons, New York, N.Y. (2009);Ausubel
等人,
Short Protocols in Molecular Biology,第3版, Wiley & Sons, 1995;Sambrook及Russell,
Molecular Cloning: A Laboratory Manual(第3版, 2001);Maniatis
等人 Molecular Cloning: A Laboratory Manual (1982) ; DNA Cloning: A Practical Approach,第I及II卷 (D. Glover,編);
Oligonucleotide Synthesis(N. Gait,編, 1984);
Nucleic Acid Hybridization(B. Hames及S. Higgins,編, 1985);
Transcription and Translation(B. Hames及S. Higgins,編, 1984);
Animal Cell Culture(R. Freshney,編, 1986);Perbal,
A Practical Guide to Molecular Cloning(1984)以及其他類似參考文獻。
標準技術可用於重組DNA、寡核苷酸合成及組織培養與轉化(例如,電穿孔、脂轉染)。可根據製造商說明書或如此項技術中通常所達成或如本文所述來執行酶促反應及純化技術。此等技術及相關技術及程序可通常根據此項技術中熟知及如本說明書整篇引用及論述之各種一般及更具體參考文獻中所述之習用方法來執行。除非提供具體定義,否則結合本文所述之分子生物學、分析化學、合成有機化學以及醫療及醫藥化學使用的命名法以及該等領域之實驗室程序及技術為此項技術中所熟知及常用者。標準技術可用於重組技術、分子生物學、微生物學、化學合成、化學分析、醫藥製備、調配及遞送以及患者治療。
出於本揭示之目的,下列術語定義如下。
冠詞「一(個/種)」在本文中用於指代一個(種)或一個(種)以上(亦即,至少一個(種))的該冠詞之語法客體。舉例而言,「一要素」意指一個要素或多於一個要素。
「約」意指數量、位準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度變化多達參考數量、位準、值、數目、頻率、百分比、尺寸、大小、量、重量或長度之30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%。
如本文所使用,術語「胺基酸」意欲指代天然產生之胺基酸及非天然產生之胺基酸以及胺基酸類似物及模擬物。天然產生之胺基酸包括在蛋白質生物合成期間利用的20種(L)-胺基酸以及其他胺基酸,諸如,例如4-羥基脯胺酸、羥基離胺酸、鎖鏈素、異鎖鏈素、高半胱胺酸、瓜胺酸及鳥胺酸。非天然產生之胺基酸包括例如(D)-胺基酸、正白胺酸、正纈胺酸、對氟苯基丙胺酸、乙硫胺酸及類似物,其為熟習此項技術者所知。胺基酸類似物包括天然產生之胺基酸及非天然產生之胺基酸之經修飾形式。此等修飾可包括例如胺基酸上化學基團及部分之取代或置換,或胺基酸之衍生作用。胺基酸模擬物包括例如有機結構,該等有機結構在功能上展現類似性質,諸如參考胺基酸之電荷及電荷間距特性。例如,模擬精胺酸(Arg或R)之有機結構將具有正電荷部分,該正電荷部分位於類似分子空間中且具有與天然產生之Arg胺基酸之側鏈之e-胺基相同的遷移率程度。模擬物亦包括限制結構以便維持胺基酸或胺基酸官能基之最佳間距及電荷相互作用。熟習此項技術者知曉或可判定何種結構構成功能上等效的胺基酸類似物及胺基酸模擬物。
「生物相容性」係指通常不會損害生物功能且不會導致任何程度的不可接受之毒性(包括過敏及疾病狀態)之材料或化合物。
「編碼序列」意指有助於編碼基因之多肽產物的任何核酸序列。相比之下,術語「非編碼序列」係指並不直接有助於編碼基因之多肽產物的任何核酸序列。
在本揭示整篇中,除非上下文另外需要,否則「包含(comprise)」、「包含(comprises)」及「包含(comprising)」等詞將理解為暗示包括所述步驟或要素或步驟或要素之群組,而不排除任何其他步驟或要素或步驟或要素之群組。
「由以下組成」意指包括且限於片語「由以下組成」後接之內容。因此,片語「由...組成」指示所列要素為必需或必備的,且不可存在其他要素。「基本上由以下組成」意指包括該片語之後所列的任何要素,且限於不干擾或貢獻於本揭示內容中對所列要素所規定的活性或作用之其他要素。因此,片語「基本上由以下組成」指示:所列要素為必需或必備的,但其他要素為可選的且可存在或可不存在,此取決於該等其他要素是否實質上影響所列要素之活性或作用。
術語「不含內毒素」或「實質上不含內毒素」通常係關於含有至多痕量(例如,對受試者沒有臨床不良生理效應之量)內毒素且較佳不可偵測量之內毒素的組成物、溶劑及/或器皿。內毒素為與某些微生物(諸如細菌,典型地為革蘭氏陰性細菌)相關聯的毒素,儘管內毒素亦可見於革蘭氏陽性細菌諸如單核球增多性李斯特菌(
Listeria monocytogenes)中。最盛行的內毒素為脂多醣(LPS)或脂寡糖(LOS),其見於各種革蘭氏陰性細菌之外膜中,且代表此等細菌引起疾病之能力的中心致病特徵。人類中之少量內毒素可能產生發熱、血壓降低及炎症與凝血之激活,以及其他不良生理效應。
因此,在醫藥生產中,通常期望自藥物產品及/或藥物容器中除去大部分或全部痕量之內毒素,因為即使少量亦可能在人類中引起不良影響。去熱原烘箱可用於此目的,因為典型地需要超過300℃之溫度來分解大部分內毒素。例如,基於主要包裝材料諸如注射器或小瓶,250℃之玻璃溫度與30分鐘之保持時間之組合通常足以達成內毒素位準之3 log降低。涵蓋除去內毒素之其他方法,包括例如如本文所述及此項技術已知的層析及過濾方法。
可使用此項技術已知的常規技術來偵測內毒素。例如,利用來自鱟之血液的鱟變形細胞溶胞產物測定為用於偵測內毒素存在之非常靈敏的測定。在此測試中,極低位準之LPS可由於強大的酶促級聯而引起可偵測的鱟溶胞產物之凝結,該強大的酶促級聯放大此反應。內毒素亦可藉由酶聯免疫吸附測定(ELISA)來定量。為了實質上不含內毒素,內毒素位準可小於約0.001、0.005、0.01、0.02、0.03、0.04、0.05、0.06、0.08、0.09、0.1、0.5、1.0、1.5、2、2.5、3、4、5、6、7、8、9或10 EU/mg的活性化合物。典型地,1 ng脂多醣(LPS)對應於約1至10 EU。
多肽之「半衰期」可指代多肽相對於投與至生物體之血清或組織中時的活性或相對於任何其他定義的時間點而損失其一半藥理學、生理學或其他活性所花費的時間。「半衰期」亦可指代多肽之量或濃度相對於投與至生物體之血清或組織中時的量或濃度或相對於任何其他定義的時間點而減少了投與至生物體之血清或組織中之起始量的一半所花費的時間。半衰期可在血清及/或任何一或多個所選組織中量測。
術語「調節」及「改變」包括典型地以相對於對照之統計學上顯著或生理學上顯著的量或程度「增加」、「增強」或「刺激」,以及「減少」或「降低」。「增加的」、「刺激的」或「增強的」量典型地為「統計學上顯著的」量,且可包括作為並未由組成物(例如,在不存在藥劑之情況下)或由對照組成物所產生的量之1.1、1.2、2、3、4、5、6、7、8、9、10、15、20、30或更多倍(例如,500、1000倍)(包括其間所有整數及範圍,例如1.5、1.6、1.7、1.8等等)之增加。「減少的」量或「降低的」量典型地為「統計顯著」量,且可包括例如並未由組成物(例如,在不存在藥劑之情況下)或由對照組成物所產生的量之1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%減少(包括其間所有整數及範圍)。本文描述比較及「統計顯著」量之實例。
術語「多肽」、「蛋白質」與「肽」可互換使用,且意指不限於任何特定長度之胺基酸聚合物。術語「酶」包括多肽或蛋白質催化劑,且關於ADI,與蛋白質、多肽或肽可互換使用。此等術語包括諸如肉豆蔻醯化、硫酸化、糖基化、磷酸化以及信號序列之添加或缺失的修飾。術語「多肽」或「蛋白質」意指一或多個胺基酸鏈,其中各鏈包含藉由肽鍵共價鍵聯之胺基酸,且其中該多肽或蛋白質可包含非共價及/或藉由肽鍵共價鍵聯在一起的複數個鏈,該複數個鏈具有天然蛋白質(即由天然產生且具體而言非重組細胞或遺傳工程化或重組細胞所產生的蛋白質)之序列,且包含具有天然蛋白質之胺基酸序列的分子,或具有天然序列之一或多個胺基酸的缺失、添加及/或取代的分子。術語「多肽」及「蛋白質」具體涵蓋本文所述之ADI酶/蛋白質,或具有ADI蛋白質之一或多個胺基酸的缺失、添加及/或取代之序列。在某些實施例中,多肽為由包含一或多個重組DNA分子的重組細胞所產生之「重組」多肽,該一或多個重組DNA分子典型地由異源多核苷酸序列或否則將不會見於細胞中的多核苷酸序列之組合製成。
術語「分離的」多肽或蛋白質在本文中係指受試蛋白(1)不含通常與其一起見於自然界中的至少一些其他蛋白質,(2)基本上不含來自相同來源,例如來自相同物種之其他蛋白質,(3)由來自不同物種之細胞表現,(4)已經與至少約50%在自然界中與其締合的多核苷酸、脂質、碳水化合物或其他材料分離,(5)未與在自然界中與「分離的蛋白質」締合的蛋白質之部分締合(藉由共價或非共價相互作用),(6)與在自然界中未與其締合的多肽可操作地締合(藉由共價或非共價相互作用),或(7)未存在於自然界中。該種分離的蛋白質可由可能具有合成來源的基因組DNA、cDNA、mRNA或其他RNA或其任何組合編碼。在某些實施例中,分離的蛋白質實質上不含見於其天然環境中且將干擾其使用(治療、診斷、預防、研究或其他方面)的蛋白質或多肽或其他污染物。
在某些實施例中,組成物中任何給定藥劑(例如,ADI-PEG)之「純度」可經具體定義。例如,某些組成物可包含至少70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%純(例如,基於蛋白質) (包括其間所有小數及範圍)的藥劑,如例如藉由高效液相層析(HPLC)所測定,該高效液相層析為常用於生物化學及分析化學中以分離、鑒定及量化化合物之管柱層析法之熟知形式。
術語「參考序列」通常係指另一序列正在與之比較的核酸編碼序列或胺基酸序列。本文所述之所有多肽及多核苷酸序列係作為參考序列而包括,包括由名稱描述的彼等序列以及表中及序列表中描述的彼等序列。
如本文所使用的術語「序列一致性」或例如包含「與...50%一致之序列」係指在比較窗上基於核苷酸對核苷酸或胺基酸對胺基酸而言序列為一致之程度。因此,「序列一致性之百分比」可藉由以下方式來計算:在比較窗口上比較兩個最佳比對序列,判定兩個序列中出現一致核酸鹼基(例如,A、T、C、G、I)或一致胺基酸殘基(例如,Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys及Met)所處位置之數目以得出匹配位置之數目,將匹配位置之數目除以比較窗口中位置之總數(亦即,窗口大小),且將結果乘以100得出序列一致性之百分比。用於比對比較窗口的序列之最佳比對可藉由演算法之電腦化實行方案(Wisconsin Genetics軟體套件7.0發佈版中之GAP、BESTFIT、FASTA及TFASTA, Genetics Computer Group, 575 Science Drive Madison, Wis., USA)或藉由檢查及由所選各種方法中之任一種所產生的最佳比對(亦即,在比較窗口上產生更高百分比同源性)來進行。亦可對如例如藉由Altschul等人, Nucl. Acids Res. 25:3389, 1997所揭示的BLAST家族程式進行參考。
術語「溶解度」係指本文所提供之藥劑(例如,ADI-PEG)溶解在液體溶劑中且形成均質溶液之性質。溶解度通常表示為濃度,藉由每單位體積溶劑之溶質質量(每公斤溶劑之溶質公克數、g/dL (100 mL)、mg/ml等等)、莫耳濃度、重量莫耳濃度、莫耳分數或其他類似濃度描述來表示。每單位溶劑量可溶解的溶質之最大平衡量為在規定條件下,彼溶質於彼溶劑中之溶解度,該等規定條件包括溫度、壓力、pH及溶劑之性質。在某些實施例中,溶解度係於生理pH下或其他pH下量測,例如在pH 5.0、pH 6.0、pH 7.0、pH 7.4、pH 7.6、pH 7.8或pH 8.0 (例如,約pH 5至pH 8)下量測。在某些實施例中,溶解度係於水或諸如PBS或NaCl (有或沒有NaP)之生理緩衝液中量測。在具體實施例中,溶解度係於相對較低pH (例如,pH 6.0)及相對較高鹽(例如,500 mM NaCl及10 mM NaP)下量測。在某些實施例中,溶解度係於諸如血液或血清之生物流體(溶劑)中量測。在某些實施例中,溫度可為約室溫(例如,約20、21、22、23、24、25℃)或約體溫(約37℃)。在某些實施例中,藥劑在室溫下或在37℃下具有至少約0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、40、50、60、70、80、90或100 mg/ml之溶解度。
「受試者」或「有需要的受試者」或「患者」或「有需要的患者」包括哺乳動物受試者,諸如人類受試者。
「實質上」或「基本上」意指幾乎全部地或完全地,例如,某一給定數量之95%、96%、97%、98%、99%或更大。
「統計顯著的」意指結果不可能偶然發生。統計顯著性可藉由此項技術中已知的任何方法來判定。顯著性之常用量度包括p值,其為在虛無假設為真的情況下,將發生所觀察事件的頻率或機率。若所獲得p值小於顯著性位準,則拒絕虛無假設。在簡單狀況下,顯著性位準係定義在0.05或更小之p值。
「治療反應」係指基於投與一或多種治療劑之症狀改善(無論是否持續)。
如本文所使用,受試者(例如哺乳動物,諸如人類)或細胞之「治療」為用於試圖改變個體或細胞之自然過程的任何類型的干預。治療包括但不限於醫藥組成物之投與,且可預防性地抑或在病理事件起始或與病原因子接觸之後執行。亦包括「預防性」治療,其可旨在降低所治療疾病或病狀之進展速率、延遲該疾病或病狀之發作或降低其發作之嚴重性。「治療」或「預防」未必指示疾病或病狀或其相關聯症狀之完全根除、治癒或預防。
術語「野生型」係指基因或基因產物(例如,多肽),其在群體中最常觀察到,且因此經任意設計而呈現基因之「正常」或「野生型」形式。
除非另有明確說明,否則本說明書中之每個實施例將在加以必要修正的情況下應用於每個其他實施例。
在本揭示整篇中,可使用以下縮寫:PEG,聚乙二醇;ADI,精胺酸脫亞胺酶;SS,琥珀醯亞胺基琥珀酸酯;SSA,琥珀醯亞胺基琥珀醯亞胺;SPA,琥珀醯亞胺基丙酸酯;NHS,N-羥基-琥珀醯亞胺;ASS-1,精胺基琥珀酸合成酶-1。
凍乾調配物某些實施例係關於凍乾調配物,其包含聚乙二醇化精胺酸脫亞胺酶(ADI-PEG),其中該凍乾調配物為無菌的,實質上不含內毒素,且處於醫藥學上可接受之pH下。在一些實施例中,調配物包含醫藥學上可接受之緩衝劑。在某些實施例中,調配物包含一或多種醫藥學上可接受之賦形劑,包括例如一或多種冷凍保護劑、凍乾保護劑、穩定劑、增積劑、張力調節劑、界面活性劑、醫藥塑化劑或螯合劑,包括前述者之任何組合。
一些調配物包含一或多種醫藥學上可接受之緩衝劑。在某些實施例中,緩衝劑之濃度為約0.10 mM至約200 mM,或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM,包括其間所有整數及範圍。在某些實施例中,緩衝劑之濃度為約1 mM至約50 mM、或約10 mM至約30 mM、或約15 mM至約25 mM、或約10 mM至約20 mM、或約20 mM或約10 mM。在特定實施例中,緩衝劑係選自以下中之一或多者:組胺酸、檸檬酸鈉、甘胺醯-甘胺酸、磷酸鈉、Tris、離胺酸及前述者之任何組合。
在具體實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。在一些實施例中,調配物包含之檸檬酸鈉為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。在特定實施例中,調配物包含之甘胺醯-甘胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。在具體實施例中,調配物包含之磷酸鈉緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。在一些實施例中,調配物包含之Tris緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。在某些實施例中,調配物包含之甘胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。
一些調配物包含一或多種冷凍保護劑。「冷凍保護劑」係指在凍乾之一個(或多個)冷凍階段保護一種(或多種)活性劑之醫藥學上可接受之物質或賦形劑。在一些實施例中,冷凍保護劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在具體實施例中,防凍劑係選自以下中之一或多者:蔗糖、海藻糖、乙二醇、丙二醇、甘油及前述者之任何組合。
某些調配物包含一或多種凍乾保護劑。「凍乾保護劑」係指在凍乾之一個(或多個)乾燥階段保護一種(或多種)活性劑之醫藥學上可接受之物質或賦形劑。在一些實施例中,凍乾保護劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在具體實施例中,凍乾保護劑係選自以下中之一或多者:蔗糖、海藻糖、甘露醇、山梨醇、甘油及前述者之任何組合。
某些調配物包含一或多種醫藥學上可接受之穩定劑。在一些實施例中,穩定劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在一些實施例中,穩定劑係選自以下中之一或多者:蔗糖、甘露醇、乳糖、海藻糖、麥芽糖、山梨醇、明膠、白蛋白及前述者之任何組合。
一些調配物包含一或多種醫藥學上可接受之增積劑。在一些實施例中,增積劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在具體實施例中,增積劑係選自以下中之一或多者:甘露醇、山梨醇、乳糖、葡萄糖、蔗糖、甘胺酸、白蛋白、葡聚糖40及前述者之任何組合。
一些調配物包含一或多種醫藥學上可接受之張力調節劑。在一些實施例中,張力調節劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,或濃度為約0.10 mM至約200 mM、或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM,包括其間所有整數及範圍。在特定實施例中,張力調節劑係選自以下中之一或多者:氯化鈉、蔗糖、甘露醇及前述者之任何組合。
在某些實施例中,調配物包含一或多種界面活性劑。在一些實施例中,界面活性劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%。示範性界面活性劑包括Tween-80、聚山梨醇酯20 (P20)、聚山梨醇酯80 (P80)、泊洛沙姆188及其組合。
某些調配物包含一或多種醫藥塑化劑。在一些實施例中,醫藥塑化劑以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,包括其間所有整數及範圍。在一些實施例中,醫藥塑化劑為甘油。
一些調配物包含一或多種螯合劑。在一些實施例中,螯合劑以以下量存在:約0.001%至約1% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95或1.0%,包括其間所有整數及範圍。在具體實施例中,螯合劑為乙二胺四乙酸(EDTA)。
特定調配物包含選自以下中之一或多者的醫藥學上可接受之賦形劑:蔗糖、海藻糖、葡聚糖、甘露醇、脯胺酸、甘胺酸、界面活性劑、醫藥塑化劑、螯合劑及前述者之任何組合。例如,在一些實施例中,蔗糖、海藻糖、葡聚糖(例如葡聚糖40)、甘露醇、脯胺酸及/或甘胺酸以以下量存在:約0.001%至約20% (wt%)、或約0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.010、0.015、0.020、0.025、0.030、0.035、0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080、0.085、0.090、0.095、0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.1、1.2、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5、8.6、8.7、8.8、8.9、9.0、9.1、9.2、9.3、9.4、9.5、9.6、9.7、9.8、9.9、10、11、12、13、14、15、16、17、18、19或20%,或濃度為約0.10 mM至約200 mM、或約0.10、0.15、0.20、0.25、0.30、0.35、0.40、0.45、0.50、0.55、0.60、0.65、0.70、0.75、0.80、0.85、0.90、0.95、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195或200 mM,包括其間所有整數及範圍。
在具體實施例中,如上所述,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之蔗糖為約1%至約10%、或約4%至約6%、或約5%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之甘露醇為約1%至約10%、或約4%至約6%、或約5%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之葡聚糖例如葡聚糖40為約0.1%至約5%、或約0.5%至約2%、或約1%。
在特定實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之葡聚糖例如葡聚糖40為約0.1%至約5%、或約0.5%至約2%、或約1%,且包含之蔗糖為約1%至約10%、或約4%至約6%、或約5%。
在某些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之海藻糖為約1%至約10%、或約4%至約6%、或約5%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之甘露醇為約1%至約10%、或約3%至約5%、或約4%,且包含之蔗糖為約0.1%至約5%、或約0.5%至約2%、或約1%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之蔗糖為約1%至約10%、或約4%至約6%、或約4.8%或5%,且包含之Tween-80為約0.001%至約0.1%、或約0.005%至約0.05%、或約0.01%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之蔗糖為約1%至約10%、或約4%至約6%、或約4.8%或5%,包含之Tween-80為約0.001%至約0.1%、或約0.005%至約0.05%、或約0.01%,且包含之甘油為約0.01%至約1.0%、或約0.1%至約0.5%、或約0.25%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之海藻糖為約1%至約15%、或約5%至約12%、或約10%或9.5%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之海藻糖為約1%至約15%、或約5%至約12%、或約10%或9.5%,且包含之脯胺酸為約10 mM至約40 mM、或約15至約30 mM、或約20 mM。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之海藻糖為約5%至約15%、或約8%至約12%、或約10%或9.5%,且包含之甘胺酸為約10 mM至約40 mM、或約15至約30 mM、或約20 mM。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或9.5%。
在一些實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之蔗糖為約1%至約10%、約4%至約6%、或約5%或4.5%,且包含之海藻糖為約1%至約10%、約4%至約6%、或約5%或4.5%。
在特定實施例中,調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約30 mM、或約15至約25 mM、或約20 mM,且包含之海藻糖為約5%至約15%、或約8%至約12%、或約10%或9.5%,且包含之EDTA為約0.01%至約0.1%、或約0.02%至約0.08%、或約0.05%。
某些調配物包含之組胺酸緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM,且包含之甘胺酸為約1%至約5%、或約2%或1.9%,包含之海藻糖為約0.1%至約2%、或約0.5%至約1.5%、或約1%,且包含之界面活性劑例如P20為約0.001%至約0.1%、或約0.005%至約0.02%、或約0.01%。一些調配物包含之組胺酸緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM,且包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或8.5%,且包含之海藻糖為約0.1%至約2%、或約0.5%至約1.5%、或約1%。特定調配物包含之組胺酸緩衝劑為約1至約30 mM、或約5至約20 mM、或約10 mM,且包含之蔗糖為約1%至約15%、或約5%至約12%、或約10%或9%。一些調配物包含之組胺酸緩衝劑為約1至約50 mM、或約10至約40 mM、或約20、25、30或35 mM,且包含之氯化鈉為約100至約150 mM、或約120、130或140 mM。某些調配物包含之磷酸鈉緩衝劑為約100至約200 mM、或約150 mM,且包含之蔗糖及/或海藻糖為約1%至約10%、約4%至約6%、或約5%或4.5%,且包含之甘胺酸為約0.1至約1%、或約0.5%,且包含之甘油為約0.1至約1.0%、或約0.25%,且包含之Tween 80為約0.001至約0.1%、或約0.01%,且包含之EDTA為約0.01至約0.1%、或約0.05%。
在一些實施例中,調配物之醫藥學上可接受之pH為約5.0至約8.0 (±0.01至±0.1或至±1.0)、或約5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0 (±0.01至±0.1),包括其間所有整數及範圍。在具體實施例中,包含ADI-PEG之調配物之pH為約6.8 (± 1.0)。在特定實施例中,pH為約6.5至約7.2 (±0.1)、或約6.6至約7.0 (±0.1)、或約6.8 (±0.1)。在一些實施例中,pH為約6.0至約7.2 (±0.1)、或約6.4至約6.8 (±0.1)、或約6.5 (±0.1)。
如上所述,本文所述之調配物包含一或多個藉由共價附接至一或多個聚乙二醇(PEG)分子而修飾之聚乙二醇化精胺酸脫亞胺酶(ADI-PEG)分子或精胺酸脫亞胺酶(ADI)多肽。當與未經修飾ADI相比時,ADI-PEG保持其大部分酶活性,免疫原性或抗原性較低,具有極大延長的循環半衰期,且在腫瘤治療中更為有效。
在某些實施例中,凍乾調配物中ADI-PEG之乾重為約50 mg/g至約150 mg/g、或約50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145或150 mg/g,包括其間所有整數及範圍。
在某些實施例中,ADI多肽或ADI-PEG分子具有「ADI活性」或將精胺酸轉化或代謝成瓜胺酸及氨之能力。ADI活性可根據此項技術中之常規技術來量測。例如,L-瓜胺酸之量可藉由比色終點測定來偵測(參見,例如Knipp及Vasak, Analytical Biochem. 286:257-264, 2000),且與已知量的L-瓜胺酸之標準曲線進行比較,以便計算ADI之比活性,該比活性可表示為IU/mg蛋白質。在一些實施例中,將一個IU的ADI酶活性定義為在所測試pH及溫度下每分鐘產生1 µmol瓜胺酸之酶之量。
一種(或多種)ADI-PEG分子之ADI部分可來源於多種來源。例如,在一些實施例中,ADI多肽來自人型黴漿菌(
M. hominis)、精胺酸黴漿菌(
M. arginini)、關節炎黴漿菌(
M. arthritidis)、海豹腦黴漿菌(
M. phocicerebrale)、貓黴漿菌(
M. gateae)、海豹黴漿菌(
M. phocidae)、鴿黴漿菌(
M. columbinum)、衣阿華黴漿菌(
M. iowae)、鱷魚黴漿菌(
M. crocodyli)、短吻鱷黴漿菌(
M. alligatoris)、奧氏嗜熱鹽絲菌(
H. orenii)或牛黴漿菌(
M. bovis)。在一些實施例中,ADI多肽來自唾液黴漿菌(
Mycoplasma salivarium)、泡沫黴漿菌(
Mycoplasma spumans)、加拿大黴漿菌(
Mycoplasma canadense)、耳黴漿菌(
Mycoplasma auris)、豬滑液黴漿菌(
Mycoplasma hyosynoviae)、泄殖腔黴漿菌(
Mycoplasma cloacale)、鵝黴漿菌(
Mycoplasma anseris)、產鹼黴漿菌(
Mycoplasma alkalescens)、口腔黴漿菌(
Mycoplasma orale)、惰性黴漿菌(
Mycoplasma iners)、火雞黴漿菌(
Mycoplasma meleagridis)、蜂房黴漿菌(
Mycoplasma alvi)、滲透黴漿菌(
Mycoplasma penetrans)、家禽黴漿菌(
Mycoplasma gallinarum)、梨黴漿菌(
Mycoplasma pirum)、靈長類黴漿菌(
Mycoplasma primatum)、發酵黴漿菌(
Mycoplasma fermentans)、
Mycoplasma lipofaciens、小貓黴漿菌(
Mycoplasma felifaucium)、模仿黴漿菌(
Mycoplasma imitans)、乳白色黴漿菌(
Mycoplasma opalescens)、毛氏黴漿菌(
Mycoplasma moatsii)、象黴漿菌(
Mycoplasma elephantis)、肺炎黴漿菌(
Mycoplasma pneumoniae)、龜黴漿菌(
Mycoplasma testudinis)、黴漿菌屬
CAG:877(
Mycoplasma sp. CAG:877)或黴漿菌屬
CAG:472(
Mycoplasma sp. CAG:472)。
說明性ADI多肽提供於下
表 A1中。
因此,在一些實施例中,ADI-PEG中之ADI多肽包含以下、由以下組成或基本上由以下組成:來自
表 A1(SEQ ID NO:1至56)之說明性序列或其具有ADI活性之變異體或片段。
某些實施例包括本文所述之參考ADI多肽序列之變異體,無論是由名稱抑或藉由參考表或序列標識符(例如,表A1,SEQ ID NO:1至56)來描述。「變異體」序列係指與參考序列相差一或多個取代、缺失(例如,截短)、添加及/或插入之多肽或多核苷酸序列。某些變異體因此包括本文所述之參考序列之片段。多肽變異體為生物活性的,亦即,其持續擁有參考多肽之酶活性或結合活性。此等變異體可由例如遺傳多型性及/或人類操縱而產生。
在許多情況下,生物活性變異體將含有一或多個保守取代。「保守取代」為其中一個胺基酸由具有類似性質之另一胺基酸取代以使得熟習肽化學技術者可預測多肽之二級結構及親水性質實質上不會改變的取代。如上所述,可在本揭示之多核苷酸及多肽之結構中進行修飾,且仍獲得編碼具有合乎需要特性之變異或衍生多肽之功能分子。當意欲改變多肽之胺基酸序列以產生本文所述之多肽之等效或甚至改良變異體或部分時,熟習此項技術者通常將改變編碼DNA序列之密碼子中之一或多者。
例如,蛋白質結構中之某些胺基酸可由其他胺基酸取代,而沒有與諸如抗體之抗原結合區或受質分子上之結合位點的結構之相互作用結合能力的可觀損失。因為正是蛋白質之相互作用能力及性質界定蛋白質之生物功能活性,所以可在蛋白質序列中且當然可在其基本DNA編碼序列中進行某些胺基酸序列取代,且雖然如此仍獲得具有類似性質之蛋白質。因此涵蓋的是,可在所揭示組成物之肽序列或編碼該等肽之相應DNA序列中進行各種改變,而沒有其效用之可觀損失。
在進行此等改變時,可考慮胺基酸之親水指數。此項技術中通常理解親水胺基酸指數在對蛋白質賦予相互作用生物功能中之重要性(Kyte & Doolittle, 1982,以引用方式併入本文)。所接受的是,胺基酸之相對親水特性促成所得蛋白質之二級結構,其繼而界定蛋白質與其他分子之相互作用,該等其他分子為例如酶、受質、受體、DNA、抗體、抗原及類似物。已基於各胺基酸之疏水性及電荷特性來指定該等胺基酸之親水指數(Kyte & Doolittle, 1982)。此等值為:異白胺酸(+4.5);纈胺酸(+4.2);白胺酸(+3.8);苯丙胺酸(+2.8);半胱胺酸(+2.5);甲硫胺酸(+1.9);丙胺酸(+1.8);甘胺酸(-0.4);蘇胺酸(-0.7);絲胺酸(-0.8);色胺酸(-0.9);酪胺酸(-1.3);脯胺酸(-1.6);組胺酸(-3.2);麩胺酸(-3.5);麩醯胺酸(-3.5);天冬胺酸(-3.5);天冬醯胺酸(-3.5);離胺酸(-3.9);及精胺酸(-4.5)。此項技術中已知的是,某些胺基酸可由具有類似疏水或記分之其他胺基酸取代,且產生具有類似生物活性之蛋白質,亦即,仍獲得生物學上功能等效之蛋白質。在進行此等改變時,親水指數在±2內之胺基酸之取代較佳,親水指數在±1內之胺基酸之取代尤其較佳,且親水指數在±0.5內之胺基酸之取代甚至尤其更佳。
此項技術中亦理解,可基於親水性來有效地進行類似胺基酸之取代。美國專利4,554,101 (特別地以全文引用方式併入本文中)闡述:如受蛋白質之相鄰胺基酸之親水性所支配,蛋白質之最大局部平均親水性與該蛋白質之生物性質有關。如美國專利4,554,101中所詳述,已對胺基酸殘基指定以下親水性值:精胺酸(+3.0);離胺酸(+3.0);天冬胺酸(+3.0 ± 1);麩胺酸(+3.0 ± 1);絲胺酸(+0.3);天冬醯胺酸(+0.2);麩醯胺酸(+0.2);甘胺酸(0);蘇胺酸(-0.4);脯胺酸(–0.5 ± 1);丙胺酸(-0.5);組胺酸(-0.5);半胱胺酸(-1.0);甲硫胺酸(-1.3);纈胺酸(-1.5);白胺酸(-1.8);異白胺酸(-1.8);酪胺酸(-2.3);苯丙胺酸(-2.5);色胺酸(-3.4)。應理解,胺基酸可由具有類似親水性值之另一胺基酸取代,並且仍獲得生物上等效且尤其免疫上等效之蛋白質。在此等改變中,親水性值在±2內之胺基酸之取代較佳,親水性值在±1內之胺基酸之取代尤其較佳,且親水性值在±0.5內之胺基酸之取代甚至尤其更佳。
如以上所概述,胺基酸取代因此通常係基於胺基酸側鏈取代基之相對相似性,例如基於其疏水性、親水性、電荷、大小及類似者。將各種前述特性考慮在內的示範性取代為熟習此項技術者所熟知,且包括:精胺酸及離胺酸;麩胺酸及天冬胺酸;絲胺酸及蘇胺酸;麩醯胺酸及天冬醯胺酸;以及纈胺酸、白胺酸及異白胺酸。
胺基酸取代可進一步基於殘基之極性、電荷、溶解度、疏水性、親水性及/或兩親性質之相似性來進行。例如,帶負電的胺基酸包括天冬胺酸及麩胺酸;帶正電的胺基酸包括離胺酸及精胺酸;且具有未帶電極性頭部基團的具有類似親水性值之胺基酸包括白胺酸、異白胺酸及纈胺酸;甘胺酸及丙胺酸;天冬醯胺酸及麩醯胺酸;以及絲胺酸、蘇胺酸、苯丙胺酸及酪胺酸。可表示保守改變之其他胺基酸群組包括:(1) ala、pro、gly、glu、asp、gln、asn、ser、thr;(2) cys、ser、tyr、thr;(3) val、ile、leu、met、ala、phe;(4) lys、arg、his;以及(5) phe、tyr、trp、his。
變異體亦可或替代地含有非保守改變。在一較佳實施例中,多肽變異體與天然或參考序列相差少於約10、9、8、7、6、5、4、3、2個胺基酸或甚至1個胺基酸之取代、缺失或添加。變異體亦可(或替代地)藉由例如對多肽之免疫原性、二級結構、酶促活性及/或疏親性質具有最小影響的胺基酸之缺失或添加來修飾。
在某些實施例中,多肽序列之長度係約、至少約或多達約5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、660、670、680、690、700、710、720、730、740、750、760、770、780、790、800、800、810、820、830、840、850、860、870、880、890、900、900、910、920、930、940、950、960、970、980、990、1000或更多個鄰接胺基酸,包括其間所有整數,且該多肽序列可包含參考序列(
參見,例如,序列表)之全部或一部分。
在一些實施例中,多肽序列由以下組成:約或不大於約5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、55、60、65、70、75、80、85、90、95、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、660、670、680、690、700、710、720、730、740、750、760、770、780、790、800、800、810、820、830、840、850、860、870、880、890、900、900、910、920、930、940、950、960、970、980、990、1000或更多個鄰接胺基酸,包括其間所有整數,且該多肽序列可包含參考序列(
參見,例如,序列表)之全部或一部分。
在某些實施例中,多肽序列為約10至1000個、10至900個、10至800個、10至700個、10至600個、10至500個、10至400個、10至300個、10至200個、10至100個、10至50個、10至40個、10至30個、10至20個、20至1000個、20至900個、20至800個、20至700個、20至600個、20至500個、20至400個、20至300個、20至200個、20至100個、20至50個、20至40個、20至30個、50至1000個、50至900個、50至800個、50至700個、50至600個、50至500個、50至400個、50至300個、50至200個、50至100個、100至1000個、100至900個、100至800個、100至700個、100至600個、100至500個、100至400個、100至300個、100至200個、200至1000個、200至900個、200至800個、200至700個、200至600個、200至500個、200至400個或200至300個鄰接胺基酸,包括其間所有範圍,且包含參考序列之全部或一部分。在某些實施例中,任何參考多肽之C端或N端區可截短了約1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、250、300、350、400、450、500、550、600、650、700、750或800或更多個胺基酸,或截短了約10至50個、20至50個、50至100個、100至150個、150至200個、200至250個、250至300個、300至350個、350至400個、400至450個、450至500個、500至550個、550至600個、600至650個、650至700個、700至750個、750至800個或更多個胺基酸,包括其間所有整數及範圍(例如,101、102、103、104、105),只要經截短之多肽保持參考多肽之結合性質及/或活性即可。典型地,生物活性片段具有不小於其所來源於之生物活性參考多肽的活性之約1%、約5%、約10%、約25%或約50%。
一般而言,變異體將與參考多肽序列顯示至少約30%、40%、50%、55%、60%、65%、70%、75%、80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%相似性或序列一致性或序列同源性。此外,涵蓋與天然或親本序列之區別在於約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、55、60、65、70、75、80、85、90、95或100個胺基酸(包括其間所有整數及範圍)之添加(例如,C端添加、N端添加、兩者兼有)、缺失、截短、插入或取代(例如,保守取代),但保持親本或參考多肽序列之性質或活性的序列。
在一些實施例中,多肽變異體與參考序列相差至少一個但小於50、40、30、20、15、10、8、6、5、4、3或2個胺基酸殘基。在某些實施例中,多肽變異體與參考序列相差至少1%但小於20%、15%、10%或5%之殘基。(若此比較需要比對,則序列應針對最大相似性來比對。因缺失或插入或錯配而處於「環」外的序列被視為差異。
序列之間的序列相似性或序列一致性(該等術語在本文中可互換使用)之計算如下執行。為判定兩個胺基酸序列或兩個核酸序列之一致性百分比,針對最佳比較目的來比對序列(例如,可將空隙引入第一胺基酸或核酸序列及第二胺基酸或核酸序列之一或兩者中以達最佳比對,且出於比較目的可忽視非同源序列)。在某些實施例中,出於比較目的而比對的參考序列之長度為參考序列長度之至少30%、較佳至少40%、更佳至少50%、60%且甚至更佳至少70%、80%、90%、100%。隨後比較相應胺基酸位置或核苷酸位置處之胺基酸殘基或核苷酸。當第一序列中之位置由與第二序列中相應位置相同的胺基酸殘基或核苷酸佔據時,則分子在彼位置處為一致的。
兩個序列之間的一致性百分比隨序列共有的一致位置之數目而變化,考慮到了空隙之數目及各空隙之長度,需要引入該等空隙以達成兩個序列之最佳比對。
序列之比較及兩個序列之間的一致性百分比之判定可使用數學演算法來完成。在一較佳實施例中,使用已併入GCG軟體套件之GAP程式中的Needleman及Wunsch (
J.
Mol.
Biol. 48: 444-453, 1970)演算法,使用Blossum 62矩陣或PAM250矩陣以及16、14、12、10、8、6或4之空隙加權值及1、2、3、4、5或6之長度加權值來測定兩個胺基酸序列之間的一致性百分比。在又一較佳實施例中,使用GCG軟體套件中之GAP程式,使用NWSgapdna.CMP矩陣以及40、50、60、70或80之空隙加權值及1、2、3、4、5或6之長度加權值來測定兩個核苷酸序列之間的一致性百分比。一組尤其較佳之參數(且為除非另有規定否則應使用之參數)包括Blossum 62記分矩陣,其中空隙罰分為12、空隙延伸罰分為4且框架移位空隙罰分為5。
兩個胺基酸或核苷酸序列之間的一致性百分比可使用E. Meyers及W. Miller (
Cabios. 4:11-17, 1989)之演算法來判定,該演算法已經併入ALIGN程式(2.0版)中,使用PAM120加權殘基表,空隙長度罰分為12,空隙罰分為4。
本文所述之核酸及蛋白質序列可用作「查詢序列」以執行針對公眾資料庫之搜索,以便例如鑒定其他家族成員或相關序列。此等搜索可使用Altschul
等人, (1990,
J.
Mol.
Biol, 215: 403-10)之NBLAST及XBLAST程式(2.0版)執行。BLAST核苷酸搜索可利用NBLAST程式、記分= 100、字長= 12來執行,以獲得與本文所述之核酸分子同源的核苷酸序列。BLAST蛋白質搜索可利用XBLAST程式、記分= 50、字長= 3來執行,以獲得與本文所述之蛋白質分子同源的胺基酸序列。為了獲得用於比較目的之空隙化比對,可利用如Altschul
等人, (
Nucleic Acids Res. 25: 3389-3402, 1997)中所述的空隙化BLAST。當利用BLAST及空隙化BLAST程式時,可使用各個程式(例如,XBLAST及NBLAST)之預設參數。
在一些實施例中,如上所述,可使用BLAST比對工具評估多核苷酸及/或多肽。局部比對僅由一對序列節段組成,各序列節段來自每個受比較序列。Smith-Waterman或Sellers演算法之修改形式將找出其記分無法藉由延伸或修整而改良的所有節段對,此稱為高記分節段對(HSP)。BLAST比對之結果包括統計學量度,以指示可有機會單獨預期BLAST記分之可能性。
原始記分S係由與各比對序列相關聯的空隙及取代之數目計算,其中較高相似性記分指示更顯著比對。取代記分係藉由檢查表(參見PAM, BLOSUM)給出。
空隙記分係典型地計算為空隙開放罰分G及空隙延伸罰分L之總和。對於長度n之空隙而言,空隙耗值將為G+Ln。空隙耗值、G及L之選擇為經驗性的,但習慣對G選擇高值(10-15),例如11,而對L選擇低值(1-2),例如1。
位元記分S’係衍生自原始比對記分S,其中已考慮到所使用記分系統之統計學性質。位元記分相對於記分系統加以正規化,因此該等位元記分可用於比較來自不同搜索之比對記分。術語「位元記分」及「相似性記分」可互換使用。位元記分給出對該比對良好程度如何之指示;分數愈高,比對愈好。
E-值或預期值描述具有類似分數之序列將偶然出現在資料庫中之可能性。其為具有相當於或優於S之記分的不同比對數目之預測值,預期S有機會出現在資料庫搜索中。E-值愈小,比對愈顯著。例如,具有e
-117之E值的比對意指:具有類似記分之序列極不可能有機會簡單地出現。另外,用於比對一對隨機胺基酸之預期記分需要為負值,否則長比對將趨向於具有高記分,此不依賴於所比對之節段是否相關。另外,BLAST演算法使用適當取代矩陣、核苷酸或胺基酸,且針對空隙化比對而言,使用空隙創建及延伸罰分。例如,多肽序列之BLAST比對及比較典型地使用BLOSUM62矩陣、11之空隙存在罰分及1之空隙延伸罰分來進行。
在一些實施例中,序列相似性記分係由使用BLOSUM62矩陣、11之空隙存在罰分及1之空隙延伸罰分進行的BLAST分析來報導。
在特定實施例中,本文所提供之序列一致性/相似性記分係指使用10版GAP (GCG, Accelrys, San Diego, Calif.)使用以下參數所獲得之值:核苷酸序列之一致性%及相似性%使用50之GAP加權值、及3之長度加權值及nwsgapdna.cmp記分矩陣;胺基酸序列之一致性%及相似性%使用8之GAP加權值、及2之GAP長度加權值及BLOSUM62記分矩陣(Henikoff及Henikoff,
PNAS USA. 89:10915-10919, 1992)。GAP使用Needleman及Wunsch (
J Mol Biol.48:443-453, 1970)之演算法來找出最大化匹配數目並最小化空隙數目之兩個完全序列之比對。
在特定實施例中,多肽變異體包含可與參考多肽序列最佳比對以產生以下BLAST位元記分或序列相似性記分的胺基酸序列(參見,例如,序列表),:至少約50、60、70、80、90、100、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290、300、310、320、330、340、350、360、370、380、390、400、410、420、430、440、450、460、470、480、490、500、510、520、530、540、550、560、570、580、590、600、610、620、630、640、650、660、670、680、690、700、710、720、730、740、750、760、770、780、790、800、810、820、830、840、850、860、870、880、890、900、910、920、930、940、950、960、970、980、990、1000或1000以上,包括其間所有整數及範圍,其中BLAST比對使用BLOSUM62矩陣、11之空隙存在罰分及1之空隙延伸罰分。
如上所述,參考多肽可以包括胺基酸取代、缺失、截短、添加及插入之各種方式改變。用於此類操縱之方法為此項技術中通常已知的。例如,參考多肽之胺基酸序列變異體可藉由DNA中之突變來製備。此項技術中熟知用於突變誘發及核苷酸序列改變之方法。參見,例如,Kunkel (
PNAS USA. 82: 488-492, 1985);Kunkel
等人, (
Methods in Enzymol. 154: 367-382, 1987)、美國專利第4,873,192號、Watson, J. D.
等人, (「Molecular Biology of the Gene,」第4版, Benjamin/Cummings, Menlo Park, Calif., 1987)及其中所引用之參考文獻。關於不影響所關注蛋白質之生物活性的適當胺基酸取代之指導可見於Dayhoff等人, (1978) Atlas of Protein Sequence and Structure (Natl. Biomed. Res. Found., Washington, D.C.)之模型中。
用於篩選藉由此類修飾製成的組合文庫之基因產物以及用於篩選cDNA文庫之具有所選性質之基因產物的方法在此項技術中已知。此類方法亦適於快速篩選藉由參考多肽之組合突變誘發所產生的基因文庫。作為一個實例,遞迴系集突變誘發(REM)可與篩選測定組合使用來鑒定多肽變異體,該遞迴系集突變誘發為一種提高文庫中功能突變體之出現頻率的技術(Arkin及Yourvan,
PNAS USA89: 7811-7815, 1992;Delgrave等人,
Protein Engineering.6: 327-331, 1993)。
「聚乙二醇」或「PEG」係指環氧乙烷與水之縮合聚合物之混合物,呈支鏈或直鏈,由通式H(OCH
2CH
2)
nOH表示,其中n為至少4。「聚乙二醇」或「PEG」與數字後綴組合使用以指示其近似重量平均分子量。例如,PEG5,000係指總重量平均分子量為約5,000之PEG;PEG12,000係指總重量平均分子量為約12,000之PEG;PEG20,000係指總重量平均分子量為約20,000之PEG。
在一些實施例中,PEG之總重量平均分子量為約1,000至約50,000;約3,000至約40,000;約5,000至約30,000;約8,000至約30,000;約11,000至約30,000;約12,000至約28,000;約16,000至約24,000;約18,000至約22,000;或約19,000至約21,000。在一些實施例中,PEG之總重量平均分子量為約1,000至約50,000;約3,000至約30,000;約3,000至約20,000;約4,000至約12,000;約4,000至約10,000;約4,000至約8,000;約4,000至約6,000;或約5,000。在具體實施例中,PEG之總重量平均分子量為約20,000。通常,分子量為30,000或更高之PEG難以溶解,且可能降低調配產物之產率。PEG可為支鏈或直鏈。通常,增加PEG之分子量會降低ADI之免疫原性。PEG可為支鏈或直鏈,且在某些實施例中為直鏈。具有本文所述之分子量的PEG可聯合ADI及視情況生物相容性連接子一起使用。
某些實施例採用一種(或多種)硫醇、巰基或半胱胺酸反應性PEG。在一些實施例中,一種(或多種)硫醇、巰基或半胱胺酸反應性PEG附接至一或多個天然產生之半胱胺酸殘基、一或多個引入的半胱胺酸殘基(例如,用一個(或多個)半胱胺酸殘基取代一或多個野生型殘基、插入一或多個半胱胺酸殘基)或其任何組合(參見,例如,Doherty等人, Bioconjug Chem. 16:1291-98, 2005)。在某些實施例中,某些野生型ADI半胱胺酸殘基可首先經另一個胺基酸取代,以防止PEG聚合物附接至野生型半胱胺酸,例如以防止一種(或多種)PEG在其他方面所需的生物活性受到破壞。一些實施例採用一或多種非天然半胱胺酸衍生物(例如同型半胱胺酸)代替半胱胺酸。
硫醇、巰基或半胱胺酸反應性PEG之非限制性實例包括甲氧基PEG順丁烯二醯亞胺 (M-PEG-MAL) (例如,MW 2000、MW 5000、MW 10000、MW 20000、MW 30000、MW 40000)。M-PEG-MAL與蛋白質及肽中之半胱胺酸側鏈上的硫醇基反應以產生穩定的3-硫代琥珀醯亞胺基醚鍵聯。此反應為高度選擇性的,且可以在其他官能基存在下在約pH 5.0至pH 6.5的溫和條件下進行。市售之硫醇、巰基(sulfyhdryl)或半胱胺酸反應性PEG分子之具體實例示於圖1A至圖1D中。因此,在某些實施例中,ADI酶係共軛至本文所述之硫醇、巰基或半胱胺酸反應性PEG分子中之任一或多者。
儘管較佳實施例利用連接子,但ADI可用或不用連接子來共價鍵結至修飾劑,諸如PEG。ADI可經由此項技術已知的方法經由生物相容性連接子來共價鍵結至PEG,該等方法如由例如以下所述:Park
等人, Anticancer Res., 1:373-376 (1981);以及Zaplipsky及Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris,編, Plenum Press, NY,第21章(1992),該等文獻之揭示特此以全文引用之方式併入本文中。在一些情況下,ADI可例如經由胺基、巰基、羥基、羧基或其他基團直接(亦即,不用連接子)偶聯至修飾劑,諸如PEG。
用於將ADI共價附接至修飾劑(例如PEG)之連接子可為任何生物相容性連接子。如上所述,「生物相容性」指示化合物或基團係無毒的且可在體外或體內利用,而不引起損傷、病患、疾病或死亡。修飾劑諸如PEG可例如經由醚鍵、硫醇鍵、醯胺鍵或其他鍵來鍵結至連接子。
在一些實施例中,合適之連接子之總鏈長為約1至100個原子、1至80個原子、1至60個原子、1至40個原子、1至30個原子、1至20個原子或例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20個原子,其中鏈中之原子包含C、S、N、P及/或O。在某些實施例中,連接子係可選的,例如PEG共軛的ADI酶不包含連接子。在一些情況下,連接子基團包括例如琥珀醯基、醯胺基、醯亞胺基、氨基甲酸酯基、酯基、環氧基、羧基、羥基、碳水化合物、酪胺酸基、半胱胺酸基、組胺酸基、亞甲基及其任何組合。穩定連接子之具體實例包括琥珀醯亞胺、丙酸、羧甲基化鍵、醚、胺基甲酸酯、醯胺、胺、胺甲醯胺、醯亞胺、脂族C-C鍵及硫醚。在某些實施例中,生物相容性連接子為琥珀醯亞胺基琥珀酸酯(SS)基。
其他合適之連接子包括氧羰基咪唑基(包括例如羰基咪唑(CDI))、硝基苯基(包括例如碳酸硝基苯酯(NCP)或碳酸三氯苯酯(TCP))、trysylate基、醛基、異氰酸酯基、乙烯基碸基或一級胺。在某些實施例中,連接子來源於SS、SPA、SCM或NHS;在某些實施例中,使用SS、SPA或NHS,且在一些實施例中,使用SS或SPA。因此,在某些實施例中,潛在連接子可由以下形成:甲氧基PEG琥珀醯亞胺基琥珀酸酯(SS)、甲氧基PEG琥珀醯亞胺基戊二酸酯(SG)、甲氧基PEG琥珀醯亞胺基碳酸酯(SC)、甲氧基PEG琥珀醯亞胺基羧甲基酯(SCM)、甲氧基PEG2 N-羥基琥珀醯亞胺基(NHS)、甲氧基PEG琥珀醯亞胺基丁酸甲酯(SBA)、甲氧基PEG琥珀醯亞胺基丙酸酯(SPA)、甲氧基PEG琥珀醯亞胺基戊二醯胺及/或甲氧基PEG琥珀醯亞胺基琥珀醯亞胺。
連接子之另外實例包括但不限於以下中之一或多者:—O—、—NH—、—S—、—C(O)—、C(O)—NH、NH—C(O)—NH、O—C(O)—NH、—C(S)—、—CH2—、—CH2—CH2—、—CH2—CH2—CH2—、—CH2—CH2—CH2—CH2—、—O—CH2—、—CH2—O—、—O—CH2—CH2—、—CH2—O—CH2—、—CH2—CH2—O—、—O—CH2—CH2—CH2—、—CH2—O—CH2—CH2—、—CH2—CH2—O—CH2—、—CH2—CH2—CH2—O—、—O—CH2—CH2—CH2—CH2—、—CH2—O—CH2—CH2—CH2—、—CH2—CH2—O—CH2—CH2—、—CH2—CH2—CH2—O—CH2—、—CH2—CH2—CH2—CH2—O—、—C(O)—NH—CH2—、—C(O)—NH—CH2—CH2—、—CH2—C(O)—NH—CH2—、—CH2—CH2—C(O)—NH—、—C(O)—NH—CH2—CH2—CH2—、—CH2—C(O)—NH—CH2—CH2—、—CH2—CH2—C(O)—NH—CH2—、—CH2—CH2—CH2—C(O)—NH—、—C(O)—NH—CH2—CH2—CH2—CH2—、—CH2—C(O)—NH—CH2—CH2—CH2—、—CH2—CH2—C(O)—NH—CH2—CH2—、—CH2—CH2—CH2—C(O)—NH—CH2—、—CH2—CH2—CH2—C(O)—NH—CH2—CH2—、—CH2—CH2—CH2—CH2—C(O)—NH —、—NH—C(O)—CH2—、—CH2—NH—C(O)—CH2—、—CH2—CH2—NH—C(O)—CH2—、—NH—C(O)—CH2—CH2—、—CH2—NH—C(O)—CH2—CH2、—CH2—CH2—NH—C(O)—CH2—CH2、—C(O)—NH—CH2—、—C(O)—NH—CH2—CH2—、—O—C(O)—NH—CH2—、—O—C(O)—NH—CH2—CH2—、—NH—CH2—、—NH—CH2—CH2—、—CH2—NH—CH2—、—CH2—CH2—NH—CH2—、—C(O)—CH2—、—C(O)—CH2—CH2—、—CH2—C(O)—CH2—、—CH2—CH2—C(O)—CH2—、—CH2—CH2—C(O)—CH2—CH2—、—CH2—CH2—C(O)—、—CH2—CH2—CH2—C(O)—NH—CH2—CH2—NH—、—CH2—CH2—CH2—C(O)—NH—CH2—CH2—NH—C(O)—、—CH2—CH2—CH2—C(O)—NH—CH2—CH2—NH—C(O)—CH2—、二價環烷基、—N(R6)—,R6係H或選自由以下組成之群組之有機基:烷基、經取代之烷基、烯基、經取代之烯基、炔基、經取代之炔基、芳基及經取代之芳基。另外,本文所述之任何連接子部分可進一步包括包含1至20個環氧乙烷單體單元[亦即,-(CH
2CH
2O)
1-20-]之環氧乙烷寡聚物鏈。亦即,環氧乙烷寡聚物鏈可出現在連接子之前或之後,且視情況出現在包含二或更多個原子的連接子部分之任何兩個原子之間。此外,若寡聚物相鄰於聚合物鏈段且僅代表聚合物鏈段之延伸,則寡聚物鏈將不被視為連接子部分之一部分。
在某些實施例中,ADI酶包含如本文所述之一或多個PEG分子及/或連接子。在某些實施例中,連接子為水不穩定連接子。
PEG附接至ADI增加了ADI之循環半衰期。通常,PEG附接至ADI之一級胺上。如熟習此項技術者所知,PEG或其他修飾劑在ADI上之附接位點的選擇係藉由蛋白質之活性域內的每個位點之作用來判定。PEG可附接至ADI之一級胺,而不會實質上損失酶活性。例如,存在於ADI中之離胺酸殘基皆為可能的點,在該等可能的點處,如本文所述之ADI可經由生物相容性連接子諸如SS、SPA、SCM、SSA及/或NHS附接至PEG。鑒於本揭示,熟習此項技術者將顯而易知,PEG亦可附接至ADI上之其他位點。
1至約30個PEG分子可共價鍵結至ADI。在某些實施例中,ADI經修飾有(亦即包含)一個PEG分子。在一些實施例中,ADI係以一個以上PEG分子來修飾。在特定實施例中,ADI係以約1至約10個或約7至約15個PEG分子、或約2至約8個或約9至約12個PEG分子來修飾。在一些實施例中,ADI係以約2、3、4、5、6、7、8、9、10、11、12、13、14或15個PEG分子來修飾。在具體實施例中,ADI係以4.5至5.5個PEG分子/ADI來修飾。在一些實施例中,ADI以5 ± 1.5個PEG分子來修飾。
在某些實施例中,ADI中約15%至約70%的一級胺基係以PEG來修飾,在一些實施例中,約20%至約65%、約25%至約60%,或在某些實施例中,約30%至約55%、或45%至約50%,或在一些實施例中,在精胺酸脫亞胺酶中約50%的一級胺基係以PEG來修飾。當PEG共價鍵結至ADI之末端時,可能僅需要使用1個PEG分子。增加ADI上的PEG單元之數目延長了酶之循環半衰期。然而,增加ADI上的PEG單元之數目降低了酶之比活性。因此,鑒於本揭示,熟習此項技術者將顯而易知,需要在兩者之間達成平衡。
在一些實施例中,生物相容性連接子之共同特徵在於它們經由琥珀醯亞胺基附接至精胺酸脫亞胺酶之一級胺。一旦與ADI偶聯,SS-PEG便具有緊挨著PEG之酯鍵,由此可能使得此位點對血清酯酶敏感,該血清酯酶可在體內將PEG自ADI中釋放。SPA-PEG及PEG2-NHS不具有酯鍵,因此它們對血清酯酶不敏感。
與SS-PEG、SPA-PEG及SC-PEG一樣,附接至蛋白質之PEG可為直鏈,或者與PEG2-NHS一樣,可使用PEG之支鏈。
在一些實施例中,例如,胺基酸取代採用非天然胺基酸以共軛至PEG或其他修飾劑(參見,例如,de Graaf等人, Bioconjug Chem. 20:1281-95, 2009)。因此,某些實施例包括經由一或多個非天然胺基酸共軛至一或多個PEG之ADI酶。在一些實施例中,非天然胺基酸包含具有選自由以下組成之群組之官能基的側鏈:烷基、芳基、芳基鹵化物、乙烯基鹵化物、烷基鹵化物、乙醯基、酮、吖丙啶、腈、硝基、鹵化物、醯基、酮基、疊氮基、羥基、肼、氰基、鹵基、醯肼、烯基、炔基、醚、硫醚、環氧化合物、碸、硼酸、硼酸酯、硼烷、苯基硼酸、硫醇、硒基、磺醯基、硼酸鹽、酸鹽、二氧磷基、膦醯基、膦、雜環-、吡啶基、萘基、二苯甲酮、受限的環諸如環辛烯、硫酯、烯酮、亞胺、醛、酯、硫代酸、羥胺、胺基、羧酸、α-酮羧酸、α或β不飽和酸及醯胺、乙醛醯胺及有機矽烷基。在一些實施例中,非天然胺基酸係選自由以下組成之群組:對乙醯基-L-苯丙胺酸、O-甲基-L-酪胺酸、L-3-(2-萘基)丙胺酸、3-甲基-苯丙胺酸、O-4-烯丙基-L-酪胺酸、升半胱胺酸、4-丙基-L-酪胺酸、三-O-乙醯基-GlcNAcβ-絲胺酸、β-O-GlcNAc-L-絲胺酸、三-O-乙醯基-GalNAc-α-蘇胺酸、α-GalNAc-L-蘇胺酸、L-多巴、氟化苯丙胺酸、異丙基-L-苯丙胺酸、對疊氮基-L-苯丙胺酸、對醯基-L-苯丙胺酸、對苯甲醯基-L-苯丙胺酸、L-二氧磷基絲胺酸、膦醯絲胺酸、膦醯酪胺酸、對碘苯丙胺酸、對溴苯丙胺酸、對胺基-L-苯丙胺酸及異丙基-L-苯丙胺酸。
雖然ADI-PEG為本文所述之說明性經修飾ADI,但熟習此項技術者將認識到,ADI可用其他聚合物或適當的分子來修飾以達到所需效果,尤其是降低抗原性及增加血清半衰期。
應當理解,一些實施例係基於以下認識,當經由重組技術產生時,精胺酸脫亞胺酶之某些結構特性可阻止或干擾適當及快速的複性。詳言之,此等結構特性阻礙或阻止酶在重組生產期間呈現活性構形。在一些實施例中,術語「活性構形」係定義為允許未經修飾或經修飾之精胺酸脫亞胺酶的酶活性之三維結構。具體而言,活性構形對於催化精胺酸轉化成瓜胺酸為必需的。術語「結構特性」可定義為由特定胺基酸或胺基酸組合產生的多肽鏈之任何性狀、品質或性質。例如,精胺酸脫亞胺酶可含有導致正常肽鏈彎曲或扭結之胺基酸,且由此阻礙酶在酶複性期間呈現活性構形。特別地,來自人型黴漿菌之精胺酸脫亞胺酶在210位處具有脯胺酸,該脯胺酸可在肽鏈中導致彎曲或扭結,使得難以使酶在重組生產期間複性。應當理解,來源於其他生物體之精胺酸脫亞胺酶亦可具有對應於來自人型黴漿菌的精胺酸脫亞胺酶之210位的位點。
一些實施例提供野生型精胺酸脫亞胺酶之多肽鏈中的具體胺基酸取代。例如,在一些實施例中,位置210處脯胺酸(或等效殘基)係經絲胺酸取代。其他取代之非限制性實例包括Pro210至Thr210、Pro210至Arg210、Pro210至Asn210、Pro210至Gln210或Pro210至Met210。
在具體實施例中,經修飾之ADI為ADI-PEG 20。ADI-PEG 20係指例如以下中所述之ADI分子:美國專利第6,183,738號;美國專利第6,635,462號;Ascierto PA,等人 (2005) Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J Clin Oncol 23(30): 7660– 7668;Izzo F,等人 (2004) Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 22(10): 1815–1822;Holtsberg FW,等人 (2002), Poly(ethylene glycol) (PEG) conjugated arginine deiminase: effects of PEG formulations on its pharmacological properties. J Control Release 80(1– 3): 259–271;及Kelly等人, (2012) British Journal of Cancer 106, 324-332。熟習此項技術者將認識到,ADI-PEG 20係來源於人型黴漿菌之聚乙二醇化ADI酶(約5.5 ± 1.0之質量平均數的鍵結的PEG 20,000分子),其相對於野生型人型黴漿菌ADI序列具有兩個取代(K112E;P210S)。
在某些實施例中,例如相對於非凍乾液體對照組成物中之相應ADI-PEG,調配物中之ADI-PEG保留其ADI活性之至少50、55、60、65、70、75、80、85、90或95%。在一些實施例中,在作為凍乾調配物儲存約或至少約1、2、3或4週、或約或至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、60或72個月後,ADI-PEG保留其(原始)ADI活性之至少50、55、60、65、70、75、80、85、90或95%。在一些實施例中,ADI活性在約2-8℃之溫度下、或在約室溫下、或在應力溫度(例如,約或至少約50-60℃之溫度)下儲存後保留。在某些實施例中,例如相對於非凍乾液體對照組成物中之相應ADI-PEG,ADI-PEG保留(原始) PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。
熟習此項技術者將理解,本文所述之ADI-PEG多肽可與本文所述之各種調配物組分中之任一或多者組合,且根據本文所述之方法及組成物中之任一或多者來使用。
經復原液體組成物及相關方法某些實施例包括經復原液體組成物、復原液體組成物之方法及使用該經復原液體組成物以進行精胺酸耗盡療法(包括治療各種癌症)之方法。
例如,某些實施例包括復原本文所述之凍乾調配物的方法,該方法包括將醫藥學上可接受之溶劑或稀釋劑添加至凍乾調配物以形成經復原液體組成物。亦包括藉由本文所述之任何方法製備的經復原液體組成物。某些示範性實施例係關於經復原液體組成物,其包含本文所述之凍乾調配物及醫藥學上可接受之稀釋劑或溶劑,即其中將凍乾調配物溶解或以其他方式增溶於溶劑中以形成液體組成物。
在特定實施例中,溶劑或稀釋劑為水或無菌水。在一些情況下,凍乾調配物在約或小於約五、四、三、二或一分鐘之時間內復原成約5-20 mg/ml ADI-PEG (例如,約5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20 mg/ml ADI-PEG)之實質上不含聚集體的溶液。
在一些實施例中,例如相對於非凍乾液體對照組成物中之相應ADI-PEG,經復原液體組成物中之ADI-PEG保留其精胺酸脫亞胺酶(ADI)活性之至少50、55、60、65、70、75、80、85、90或95%。在一些實施例中,在作為凍乾調配物儲存約或至少約1、2、3或4週、或約或至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、60或72個月後,經復原液體組成物中之ADI-PEG保留其ADI活性之至少50、55、60、65、70、75、80、85、90或95%。在一些實施例中,ADI活性在約2-8℃之溫度下、或在約室溫下、或在應力溫度(例如,約或至少約50-60℃之溫度)下儲存後保留。在一些實施例中,經復原液體調配物中之ADI-PEG之ADI酶比活性為約5.0至約120 IU/mg、或約5.5、6、6.5、7、7.5、8、8.5、9.0、9.5、10、10.5、11、11.5、12、12.5、13、13.5、14、14.5、15、15.5、16、16.5、17、17.5、18、18.5、19、19.5、20、20.5、21、21.5、22、22.5、23、23.5、24、24.5、25、25.5、26、26.5、27、27.5、28、28.5、29、29.5、30、30.5、35、40、45、50、55、55、60、65、70、75、80、85、90、95、100、105、110、115或120 IU/mg,包括其間所有整數及範圍。
在某些實施例中,例如相對於非凍乾液體對照組成物中之相應ADI-PEG,經復原液體組成物中之ADI-PEG在復原時保留(原始) PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。在一些實施例中,例如在作為凍乾調配物儲存約或至少約1、2、3或4週、或約或至少約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、36、48、60或72個月後,視情況在約2-8℃之溫度及/或約室溫下儲存後,經復原液體組成物中之ADI-PEG在復原時保留(原始) PEG分子(每ADI單體/單元體)之至少50、55、60、65、70、75、80、85、90、95或100%。
在一些實施例中,液體組成物中之ADI-PEG之重量莫耳滲透濃度為約50 mOsm/kg至約500 mOsm/kg、或約50、55、60、65、70、75、80、85、90、95、100、105、110、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295、300、305、310、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490、495或約500 mOsm/kg,包括其間所有整數及範圍。在一些實施例中,經復原液體組成物適於注射至受試者(例如,人類受試者)中。
亦包括使用經復原液體組成物以進行精胺酸耗盡療法之方法。例如某些實施例包括治療、改善有需要之受試者的癌症之症狀或抑制該癌症之進展的方法,其包含向該受試者投與本文所述之經復原液體調配物。
本文所述之方法及組成物可用於治療各種癌症。在一些實施例中,該癌症係選自以下一或多者:肝細胞癌(HCC)、黑色素瘤、轉移性黑色素瘤、胰腺癌、前列腺癌、小細胞肺癌、間皮瘤、淋巴球性白血病、慢性骨髓性白血病、淋巴瘤、肝癌、肉瘤、白血病、急性骨髓性白血病、復發性急性骨髓性白血病、B細胞惡性腫瘤、乳癌、卵巢癌、結腸直腸癌、胃癌、神經膠質瘤(例如星形細胞瘤、寡樹突神經膠細胞瘤、室管膜瘤或脈絡叢乳頭狀瘤)、多形性神經膠質母細胞瘤(例如,巨細胞神經膠母細胞瘤或神經膠肉瘤)、腦膜瘤、垂體腺瘤、前庭神經鞘瘤、原發性CNS淋巴瘤、原始神經外胚層腫瘤(神經管胚細胞瘤)、非小細胞肺癌(NSCLC)、腎癌、膀胱癌、子宮癌、食道癌、腦癌、頭頸癌、子宮頸癌、睪丸癌及胃癌。
在一些實施例中,癌症展現減少的精胺基琥珀酸合成酶-1(ASS-1)表現及/或活性,或在其他方面為精胺基琥珀酸合成酶-1缺陷的。在一些情況下,相對於適當對照樣品(例如,正常細胞或組織)之表現及/或活性,減少的ASS-1表現或活性為約5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%或更多之表現及/或活性減少。在某些實施例中,相對於對照樣品之表現或活性,ASS或ASL表現或活性減少至少兩倍。ASS-1表現或活性減少可根據此項技術中常規技術來量測,該常規技術包括例如定量PCR、免疫組織化學、酶活性測定(例如,量測瓜胺酸至精胺基琥珀酸之轉化或精胺基琥珀酸至精胺酸及富馬酸鹽之轉化ADI活性測定)及類似者。
在一些實施例中,本文所述之方法或組成物將患者之中值存活時間增加了4週、5週、6週、7週、8週、9週、10週、15週、20週、25週、30週、40週或更長時間。在某些實施例中,本文所述之方法或組成物將患者之中值存活時間增加了1年、2年、3年或更長時間。在一些實施例中,本文所述之方法或組成物將無進展存活增加了2週、3週、4週、5週、6週、7週、8週、9週、10週或更長時間。在某些實施例中,本文所述之方法或組成物將無進展存活增加了1年、2年、3年或更長時間。
在某些實施例中,如藉由存活腫瘤量之統計學上顯著減少(例如,腫瘤質量之至少10%、20%、30%、40%、50%或更大的減少)或藉由改變的(例如,在統計學上顯著減少)掃描尺寸所指示,所投與之組成物足以導致腫瘤消退。在某些實施例中,所投與之組成物足以導致疾病穩定。在某些實施例中,所投與之組成物足以導致熟練臨床醫師已知的具體疾病適應症症狀之穩定或臨床上相關的減少。
用於治療癌症之方法或組成物可與其他治療模式組合。例如,本文所述之組成物可在其他治療干預(包括症狀護理、放射療法、手術、移植、激素療法、光動力療法、抗生素療法或其任何組合)之前、期間或之後向受試者投與。症狀護理包括投與皮質類固醇,以減輕腦水腫、頭痛、認知功能不全及嘔吐,且投與抗痙攣劑,以減少癲癇型發作。放射療法包括全腦照射、分級放射療法及放射手術,諸如立體定向放射手術,該放射療法可進一步與傳統手術組合。
用於鑒定患有本文所述之一或多種疾病或病狀之受試者的方法係此項技術中已知的。
投藥可藉由各種不同途徑達成,包括口服、腸胃外、鼻內、靜脈內、皮內、肌肉內、囊內、皮下、舌下、口腔、直腸、陰道及局部。較佳投與方式取決於待治療或預防之病狀的性質。特定實施例包括藉由IV輸注進行之投與。
精確劑量及持續時間隨所治療之疾病而變,且可使用已知測試方案或藉由在此項技術已知的模型系統中測試組成物且由此外推而憑經驗判定。亦可執行對照臨床試驗。劑量亦可隨待緩解之病狀之嚴重性而變化。醫藥組成物通常經調配及投與以發揮治療上有用的作用,同時使不期望有的副作用最小化。組成物可投與一次,或可分成許多較小劑量,以便以一定時間間隔投與。對於任何具體受試者,特定劑量方案可隨時間推移根據個體需要來調整。
在一些實施例中,本文所述之組成物之治療有效量或治療劑量為有效使腫瘤生長降低或穩定的量。在某些情況下,治療以小劑量起始,該小劑量可以小的增量增加直至達成該等情況下之最佳效果。
在一些實施例中,自約一天一次至約每二或三週一次投與劑量。例如,在某些實施例中,約每1、2、3、4、5、6或7天一次、或約一週一次、或約一週兩次、或約一週三次、或約每二或三週一次投與劑量。
在一些實施例中,劑量為約0.1 mg/kg至約20 mg/kg、或至約10 mg/kg、或至約5 mg/kg、或至約3 mg/kg。在一些實施例中,劑量為約0.10 mg/kg、0.15 mg/kg、0.20 mg/kg、0.25 mg/kg、0.30 mg/kg、0.35 mg/kg、0.40 mg/kg、0.45 mg/kg、0.50 mg/kg、0.55 mg/kg、0.60 mg/kg、0.65 mg/kg、0.70 mg/kg、0.75 mg/kg、0.80 mg/kg、0.85 mg/kg、0.90 mg/kg、0.95 mg/kg、1.0 mg/kg、1.5 mg/kg、2.0 mg/kg、2.5 mg/kg、3.0 mg/kg、3.5 mg/kg、4.0 mg/kg、4.5 mg/kg、5.0 mg/kg、5.5 mg/kg、6.0 mg/kg、6.5 mg/kg、7.0 mg/kg、7.5 mg/kg、8.0 mg/kg、8.5 mg/kg、9.0 mg/kg、9.5 mg/kg、10 mg/kg、11 mg/kg、12 mg/kg、13 mg/kg、14 mg/kg、15 mg/kg、16 mg/kg、17 mg/kg、18 mg/kg、19 mg/kg或20 mg/kg,包括其間所有整數及範圍。在具體實施例中,劑量作為2 ml靜脈內注射為每週一次約1 mg/kg至每3天一次約20 mg/kg。
在一些實施例中,劑量為約50 IU/m
2至約1000 IU/m
2。在特定實施例中,劑量為約50 IU/m
2、60 IU/m
2、70 IU/m
2、80 IU/m
2、90 IU/m
2、100 IU/m
2、110 IU/m
2、120 IU/m
2、130 IU/m
2、140 IU/m
2、150 IU/m
2、160 IU/m
2、170 IU/m
2、180 IU/m
2、190 IU/m
2、200 IU/m
2、210 IU/m
2、220 IU/m
2、230 IU/m
2、240 IU/m
2、250 IU/m
2、260 IU/m
2、270 IU/m
2、280 IU/m
2、290 IU/m
2、300 IU/m
2、310 IU/m
2、約320 IU/m
2、約330 IU/m
2、340 IU/m
2約350 IU/m
2、360 IU/m
2、370 IU/m
2、380 IU/m
2、390 IU/m
2、400 IU/m
2、410 IU/m
2、420 IU/m
2、430 IU/m
2、440 IU/m
2、450 IU/m
2、500 IU/m
2、550 IU/m
2、600 IU/m
2、620 IU/ m
2、630 IU/m
2、640 IU/m
2、650 IU/m
2、660 IU/m
2、670 IU/m
2、680 IU/m
2、690 IU/m
2、700 IU/m
2、710 IU/m
2、720 IU/m
2、730 IU/m
2、740 IU/m
2、750 IU/m
2、760 IU/m
2、770 IU/m
2、780 IU/m
2、790 IU/m
2、800 IU/m
2、810 IU/m
2、820 IU/m
2、830 IU/m
2、840 IU/m
2、850 IU/m
2、860 IU/m
2、870 IU/m
2、880 IU/m
2、890 IU/m
2、900 IU/m
2、910 IU/m
2、920 IU/m
2、930 IU/m
2、940 IU/m
2、950 IU/m
2、960 IU/m
2、970 IU/m
2、980 IU/m
2、990 IU/m
2或約1000 IU/m
2,包括其間所有整數及範圍。
亦包括患者護理套組,其包含本文所述之一或多種凍乾調配物。某些套組亦包含一或多種醫藥學上可接受之稀釋劑或溶劑,諸如水(例如,無菌水)。在一些實施例中,凍乾調配物儲存在小瓶、藥筒、雙室注射器及/或預填充混合系統中。
本文中之套組亦可包括適合於或意欲用於所治療適應症或所欲診斷應用的一或多種另外的治療劑或其他組分。本文中之套組亦可包括一或多種注射器或促進意欲的遞送方式所必需或所需的其他組分(例如,支架、可植入式貯庫等等)。
本說明書中所引用之所有公開案、專利申請案及發佈的專利均以引用之方式併入本文中,如同明確及單獨地指示將各單獨公開案、專利申請案或發佈的專利以引用之方式併入一樣。
儘管已以說明及舉例方式出於清晰理解之目的而在一定程度上詳細地描述前述發明,但此項技術之一般技藝人士根據本發明之教示將顯而易知,可在不偏離所附申請專利範圍之精神或範疇的情況下對本發明進行某些改變及修改。以下實例僅經由說明方式且不經由限制方式來提供。熟習此項技術者將容易地認識到可進行改變或修改以產生基本上類似結果之多種非關鍵參數。
實例 實例 1在本研究中,對各種賦形劑類型提供具有雅觀餅外觀的凍乾ADI-PEG 20調配物之能力進行評估,且各種賦形劑類型在凍乾過程及復原之後維持穩定。下
表 E1提供本研究中測試之調配物之概述。
使用VirTis Genesis 25XL凍乾器在小瓶中凍乾
表 E1之調配物。將擱架預冷至5℃,之後加載小瓶。凍乾循環如下:
• 將擱架在5℃下維持30分鐘;
• 將擱架以1℃/min冷卻至-40℃,且在-40℃下保持1小時;
• 在初級乾燥在50 mtorr下進行72小時之情況下,將擱架以1℃/分鐘加熱至-35℃;
• 在次級乾燥在50 mtorr下進行8小時之情況下,將擱架以0.1℃/分鐘加熱至20℃。
在60℃之應力儲存條件下一週之前及之後,藉由視覺外觀評估凍乾調配物。所有凍乾調配物在凍乾後顯示白色著色,且在應力儲存條件下顯示灰白色至黃色著色。
相對於凍乾前調配物(無陰影結果)以及在應力儲存條件(陰影結果)之前及之後,亦藉由粒徑篩析層析評估凍乾調配物之酶活性。結果示於下
表 E2 及表 E3中。
亦評估總PEG水準及游離PEG水準(mg/ml) (資料未顯示),且根據分配的+值之總數來對調配物進行分級及分組)。自最高(第1組)至最低(第5組)之分級示於下
表 E4中。
總而言之,本研究中製備之所有ADI-PEG 20調配物(F1至F10)產生雅觀、均勻凍乾餅,且全部似乎基於來自酶活性及粒徑篩析層析之評估保持穩定。來自應力儲存條件(60℃,一週)之結果指示,最佳凍乾ADI-PEG 20調配物含有冷凍保護劑及凍乾保護劑。添加增積劑(諸如葡聚糖40或結晶甘露醇)或高玻璃轉移溫度賦形劑(諸如海藻糖)似乎減弱活性損失且改善復原後PEG分子之形成。
實例 2在本研究中,調配物開發包括(a)緩衝劑評估(組胺酸、檸檬酸鹽及甘胺醯-甘胺酸緩衝劑、pH 6-7)及(b)組合評估(增積劑,海藻糖及蔗糖;穩定劑,脯胺酸、甘胺酸;EDTA,以增強酶活性)。調配物之評估使用快速凍乾循環(FAST LYO循環;冷凍,隨後進行次級乾燥)。
下
表 E5提供經測試用於緩衝劑評估之調配物之概述。亦提供某些凍乾前特徵。在透析之後評估凍乾前液體樣品之RALS (直角光散射)及濃度,且亦評估與激烈溫度緩變組合之RALS。
回收百分比之結果相對較高,且所有調配物在透析後保持透明,指示沒有緩衝劑不相容性問題。含檸檬酸鹽之調配物之RALS值較高,這可能指示可溶性聚集體。
隨後在SP Durastop凍乾器中使用Formatch’s FAST LYO循環進行透析後執行凍乾。在沒有初級乾燥循環之情況下執行FAST LYO循環;代替地,僅使用次級乾燥循環來乾燥樣品。用於評估緩衝劑選擇之凍乾循環為:在-50℃下冷凍2小時(2℃/min);在60 mtorr下在22℃下乾燥4小時(所有緩變為2℃/min)。
使用RALS及IF (內在螢光)評估來自
表 E5之所有凍乾緩衝劑調配物。使用兩種技術來評估不同調配物之熱穩定性。將樣品自20℃加熱至90℃。此溫度掃描顯露Tm,即發生急劇變化之溫度,反映蛋白質之熱誘導之變性或去折疊。若偵測到較高的Tm值,則認為蛋白質更穩定。
在T(0)時,觀察到所有液體對照調配物之RALS及IF之轉變溫度為約60℃。在凍乾之前,將透析後的液體調配物分別透過0.2 µm過濾器過濾。另外,緩衝劑調配物之間沒有顯著差異。含有組胺酸pH 6.5及7.0之調配物顯示略好,藉由RALS分析來執行,且含有pH值為6.5之組胺酸緩衝劑的調配物顯示總體最低的初始RALS讀數,指示可溶性聚集體之量最少。
為了組合評估,採用pH 6.5的20 mM組胺酸之鹼緩衝劑。將海藻糖、蔗糖及其組合評估為增積劑,其評估其等向調配物提供等滲性之能力。將胺基酸脯胺酸及甘胺酸評估為穩定劑。另外,將EDTA評估為螯合劑。下
表 E6提供經測試用於組合評估之調配物之概述。
在SP Durastop凍乾器中使用Formatch’s FAST LYO循環進行透析後執行凍乾。用於評估組合研究之凍乾循環如下:在-50℃下冷凍2小時;在75 mtorr下在22℃下乾燥隔夜(所有緩變為1℃/min)。將ADI-PEG 20樣品以11.1 mg/mL凍乾(1 mL填充於10 mL小瓶中)。
RALS溫度緩變資料即RALS初始值及酶活性結果表明,含有蔗糖之調配物為ADI-PEG 20提供最佳的穩定化可凍乾調配物。含有海藻糖或海藻糖及蔗糖二者之調配物亦提供穩定化調配物。另外的賦形劑(例如甘胺酸、脯胺酸、EDTA)未顯著增強凍乾調配物之活性。
含有9%蔗糖或9%海藻糖之調配物亦藉由調製微差掃描熱量法(MDSC)來評估以判定玻璃轉移。此分析之結果(約-16℃至-18℃之共熔點)表明-20℃或更低之初級乾燥溫度應導致非坍塌的凍乾餅。隨後評估
表 E7中之凍乾循環,且其顯示可接受之餅外觀。
總而言之,緩衝劑評估(組胺酸、檸檬酸鹽及甘胺醯-甘胺酸緩衝劑顯示,所有緩衝劑為可接受的,但將組胺酸緩衝劑(pH 6.5)鑒定為最佳凍乾緩衝劑。組合評估(增積劑,海藻糖及蔗糖;穩定劑,脯胺酸、甘胺酸;EDTA,以增強酶活性)指示含有蔗糖之調配物顯示最佳總體結果。然而,含有海藻糖及經組合蔗糖/海藻糖之調配物亦表現良好。與相應液體對照相比,所有緩衝劑之酶活性結果顯示,凍乾後之回收大於90%,且加速穩定性(50℃下培育5天)後之回收大於80%。所有緩衝劑之復原時間小於1分鐘,且所有餅藉由粒徑篩析層析顯示100%純度。
實例 3在本研究中,用填充體積為3.5 mL/瓶的11 mg/mL ADI-PEG 20之三種不同調配物中之各者評估兩種不同的凍乾循環。評估之凍乾參數為乾燥期間的擱架溫度、室壓力及冷凍條件。下
表 E8提供本研究中測試之調配物之概述。
如上所述,測試兩種不同的凍乾循環:侵襲性循環(凍乾循環1)及中間循環(凍乾循環2)。
凍乾循環1之參數概述於下
表 E9中。
在完成循環1時,分析所得親液物(lyophile)。在用3.5 mL水複溶後,調配物ID 1明顯混濁,而調配物ID 2及3透明且沒有微粒。
對來自循環1之凍乾產物及經復原產物執行傅立葉轉換紅外光譜(FTIR)、微差掃描熱量法(DSC)及SDS-PAGE分析。在乾燥時在調配物ID 2及3中觀察到β褶板(1630 cm-1)之一些結構變化,但是在復原之後,這兩種調配物之ADI-PEG 20之結構返回至其原始狀態。在乾燥時偵測到調配物ID 1之主要結構變化。復原後,此調配物中之ADI-PEG 20之結構似乎與凍乾前樣品相似,但不一致。SDS-PAGE分析顯示在任何調配物中沒有降解峰。
為了調節保守性及侵襲性循環之間之昇華速率,設計0℃之擱架溫度以在凍乾循環2中進行初級乾燥。中間凍乾循環2之參數概述於下
表 E10中。
在完成循環2時,分析所得親液物。在用3.5 mL水複溶後,調配物ID 1明顯渾濁,而調配物ID 2及3澄清且無色。
對來自凍乾循環2之凍乾產物及經復原產物執行FTIR、DSC及SDS-PAGE分析。在乾燥時在調配物ID 2及3中觀察到β褶板(1630 cm-1)之一些結構變化,但是在復原之後,這兩種調配物之ADI-PEG 20之結構返回至其原始狀態。亦在乾燥時偵測到調配物ID 1之顯著結構變化。複溶後,此調配物中之ADI-PEG 20之結構與凍乾前的結構類似。SDS-PAGE分析顯示在任何調配物中沒有降解峰。
再次執行凍乾循環2以確認其作為經優化乾燥循環之穩健性。在此後續凍乾循環中僅乾燥調配物2及3。藉由SDS-PAGE檢查調配物ID 2及3之經復原樣品之物理降解。當將結果與液體藥物物質及凍乾前樣品比較時,未觀察到經復原樣品之降解產物。
總而言之,本研究用三種不同的ADI-PEG 20調配物評估侵襲性及中間凍乾循環。在各循環之後,經由DSC分析樣品之餅外觀、水分含量、濁度、二級結構之變化及物理穩定性。調配物ID 1 (w/甘胺酸)在循環1及2後在復原時顯示沉澱跡象,且自確認性凍乾循環中排除。相反,在各測試之凍乾循環之後,含有蔗糖之調配物ID 2及3之完整性維持良好。乾燥後結構之任何變化在復原時為可逆的。
實例 4在本研究中,在兩種不同的儲存溫度下評估兩種具有不同PEG數目之ADI-PEG 20製劑。評估之穩定性參數包括復原之前及之後的外觀、酶活性及PEG數目。下
表 E11提供PEG數目及本研究中測試之調配物之概述。
凍乾過程如下。將樣品冷凍以確保整個調配物呈固相。隨後,使用Virtis Freeze Mobile 25 EL在-78℃至-85℃及50-120 mTorr下將各小瓶之樣品冷凍乾燥約24小時,以使盡可能多的水昇華。
如先前所提及,此等凍乾產物中之各者的儲存溫度為2-8℃或室溫。兩種儲存溫度及儲存持續時間列出於下
表 E12中。
在各個溫度下凍乾且儲存後,分析親液物。在凍乾後,產物之外觀為白色且蓬鬆的鬆散的餅。在用水復原後,調配物ID P204及C204皆透明且無微粒。P204及C204中之各者之復原時間少於1分鐘。
對凍乾產物及經復原產物執行酶活性、逆相(RP)層析及SDS-PAGE分析。如下
表 E13中所示,在2-8℃下儲存親液物相對於室溫儲存時的儲存導致ADI酶活性之較大保留。例如,P204在2-8℃下儲存3個月後保留其ADI酶活性之約92%,且在室溫下儲存3個月後保留其活性之約86% (相對於0個月時間點)。C204在2-8℃下儲存3個月後保留其ADI酶活性之約96%,且在室溫下儲存3個月後保留其酶活性之約74% (相對於0個月時間點)。
使用RP層析來分析PEG數目。如下
表 E14中所示,凍乾及復原之前及之後每單元體一種(或多種) PEG之數目未顯著改變。凍乾過程及儲存未導致PEG之任何解偶聯。SDS-PAGE分析亦顯示每ADI單元體一種(或多種) PEG之數目未顯著改變。
在用溶劑復原後,P204及C204中之各者皆透明且無微粒,且在小於1分鐘內發生復原。此外,對於P204及C204中之各者,在室溫下儲存後發生的ADI酶活性之損失大於在2-8℃儲存後所觀察到者。此外,對於兩種儲存溫度,每ADI單元體PEG之數目保持不變。
實例 5執行研究以評估由藉由水不穩定連接子與PEG共價鍵結之ADI組成的ADI-PEG 20調配物之儲存條件。儲存條件為2-8℃多達28個月。評估之穩定性參數包括外觀、PEG數目、游離PEG及ADI酶活性。下
表 E12提供本研究中測試之調配物之概述。
在評估之條件下凍乾且儲存時,分析調配物ID HS。在2-8℃下凍乾且儲存28個月後,調配物之外觀為均勻的緻密的白色餅,而無肉眼可見的回熔。在儲存28個月之凍乾產物用水復原後,調配物ID HS透明且無微粒。復原時間為約40秒。
對在2-8℃儲存之凍乾產物進行酶活性評估,且與在-70℃下冷凍儲存之產物之活性進行比較。在2-8℃儲存親液物28個月時,酶活性完全保留。結果顯示於下
表 E13中。
分別使用RP層析及SEC層析分析PEG數目及游離PEG濃度(mg/mL)。下
表 E14中顯示,凍乾之前及之後以及在2-8℃下儲存28個月後每單元體一種(或多種) PEG之數目及游離PEG未顯著改變。顯然,凍乾過程及多達28個月之儲存未導致PEG與酶解偶聯。
總之,在用溶劑復原後,調配物HS透明且無微粒,且在小於1分鐘內發生復原。另外,本研究亦顯示,共價附接之PEG之解偶聯未在儲存期間發生,且酶在復原時為完全活性的。與水不穩定PEG共價鍵聯之ADI在凍乾及復原之前及之後在2-8℃之儲存條件下穩定至少28個月。
表 A1. ADI 多肽序列 | ||
來源 | 序列 | SEQ ID NO: |
人型黴漿菌 | MSVFDSKFNGIHVYSEIGELETVLVHEPGREIDYITPARLDELLFSAILESHDARKEHQSFVKIMKDRGINVVELTDLVAETYDLASKAAKEEFIETFLEETVPVLTEANKKAVRAFLLSKPTHEMVEFMMSGITKYELGVESENELIVDPMPNLYFTRDPFASVGNGVTIHFMRYIVRRRETLFARFVFRNHPKLVKTPWYYDPAMKMPIEGGDVFIYNNETLVVGVSERTDLDTITLLAKNIKANKEVEFKRIVAINVPKWTNLMHLDTWLTMLDKNKFLYSPIANDVFKFWDYDLVNGGAEPQPQLNGLPLDKLLASIINKEPVLIPIGGAGATEMEIARETNFDGTNYLAIKPGLVIGYDRNEKTNAALKAAGITVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 1 |
PHX8 | MSVFDSKFNGIHVYSEIGELETVLVHEPGREIDYITPARLDELLFSAILESHDARKEHQSFVKIMKDRGINVVELTDLVAETYDLASKAAKEEFIETFLEETVPVLTEANKEAVRAFLLSKPTHEMVEFMMSGITKYELGVESENELIVDPMPNLYFTRDPFASVGNGVTIHFMRYIVRRRETLFARFVFRNHPKLVKTPWYYDPAMKMSIEGGDVFIYNNETLVVGVSERTDLDTITLLAKNIKANKEVEFKRIVAINVPKWTNLMHLDTWLTMLDKNKFLYSPIANDVFKFWDYDLVNGGAEPQPQLNGLPLDKLLASIINKEPVLIPIGGAGATEMEIARETNFDGTNYLAIKPGLVIGYDRNEKTNAALKAAGITVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 2 |
海豹腦黴漿菌 | IHVYSEIGELETVLVHEPGREIDYITPARLDELLFSAILESHDARKEHQSFVKQLKDNGINVVELTDLVAETFDLASKEEQEKLIEEFLEDSEPVLSEAHKTAVRKFLTSRKSTREMVEFMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVKTPWYYDPAMKMSIEGGDVFIYNNDTLVVGVSERTDLETITLLAKNIKANKEVEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGAEPQPKENGLPLEGLLQSIINKKPVLIPIAGNNASHIDIERETHFDGTNYLAIKPGVVIGYARNEKTNAALAAAGIKVLPFHGNQLSLGMGNARCMSMP | 3 |
精胺酸黴漿菌 | MSVFDSKFKGIHVYSEIGELESVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKQFVAELKANDINVVELIDLVAETYDLASQEAKDKLIEEFLEDSEPVLSEEHKVVVRNFLKAKKTSRELVEIMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLINTPWYYDPSLKLSIEGGDVFIYNNDTLVVGVSERTDLQTVTLLAKNIVANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGAEPQPVENGLPLEGLLQSIINKKPVLIPIAGEGASQMEIERETHFDGTNYLAIRPGVVIGYSRNEKTNAALEAAGIKVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 4 |
關節炎黴漿菌 | MSVFDSKFKGIHVYSEIGELETVLVHEPGKEIDYITPARLDELLFSAILESHDARKEHKEFVAELKKRGINVVELVDLIVETYDLASKEAKEKLLEEFLDDSVPVLSDEHRAAVKKFLQSQKSTRSLVEYMIAGITKHDLKIESDLELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVNTPWYYDPAEGLSIEGGDVFIYNNDTLVVGVSERTDLQTITLLAKNIKANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGDAPQPVDNGLPLEDLLKSIIGKKPTLIPIAGAGASQIDIERETHFDGTNYLAVAPGIVIGYARNEKTNAALEAAGITVLPFRGNQLSLGMGNARCMSMPLSRKDVK | 5 |
口腔黴漿菌 | SVFSDKFNGIHVYSEIGDLESVLVHEPGKEIDYITPARLDELLFSAILESTDARKEHKEFVEILKKQGINVVELVDLVVETYNLVDKKTQEKLLKDFLDDSEPVLSPEHRKAVEKFLKSLKSTKELIQYMMAGITKYDLGIKADKELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSKFIFTNHPKLVKTPXYYDPAMKLSIEGGDVFIYNNDTLVVGVSERTDLETITLLAKNIKANKECEFKRIVAINVPKXTNLMHLDTXLTMLDKDKFLYSPIANDVFKFXDYDLVNGGSNPEPVVNGLPLDKLLESIINKKPVLIPIAGKGATEIETAVETHFDGTNYLAIKPGVVVGYSRNVKTNAALEANGIKVLPFKGNQLSLGMGNARCMSMPLSRKDVK | 6 |
貓黴漿菌 | IHVYSEIGELESVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKLFVSELKANDINVVELTDLVTETYDLASQEAKDNLIEEFLEDSEPVLTEELKSVVRTYLKSIKSTRELIQMMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVNTPWYYDPSLKLSIEGGDVFIYNNNTLVVGVSERTDLETVTLLAKNIVANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGEEPQPVENGLPLEGLLESIINKKPILIPIAGEGASQIDIERETHFDGTNYLAIRPGVVIGYSRNEKTNAALEAAGIKVLPFHGNQLSLGMGNARCMSM | 7 |
海豹黴漿菌 | IHVYSEIGELQTVLVHEPGREIEYITPARLDELLFSAILESHDARKEHQEFVAELKKNNINVVELTDLVSETYDMVSKEKQEKLIEEFLEDSEPVLSEEHKGLVRKFLKSLKSSKELIQYMMAGITKHDLNIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFANHPKLMNTPLYYNPDMKLSIEGGDVFVYNNETLVVGVSERTDLDTITLLAKNIKANKEREFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGDEPQPKVNGLPLEKLLESIINKKPILIPIAGTSASNIDVERETHFDGTNYLAIAPGVVIGYSRNVKTNEALEAAGIKVLPFKGNQLSLGMGNARCMSMP | 8 |
鴿黴漿菌 | MSKINVYSEIGELKEVLVHTPGDEIRRISPSRLDELLFSAILEPNEAIKEHKGFLKILQDKGIKVIQLSDLVAETYTYHATQKEREAFIEKWLDEAEPALTKDLRAKVKSYVLSKEGTPVAMVRTMMAGVSKQELNVESETELVVDPMPNLYFTRDPFASAGNGISLNNMKYVTRKRETIFAEFIFATHPDYKTTPHWFDRLDEGNIEGGDVFIYNKDTLVIGVSERTNKEAILTIAKKIKNNKEAKFKKIVAINVPPMPNLMHLDTWLTMVDKDKFLYSPNMLSVLKVWEIDLSKEIEMVETNKPLADVLESIIGVKPVLIPIAGKGATQLDIDIETHFDGTNYLTIAPGVVVGYSRNIKTEAALRAAGVTVLSFEGNQLSLGMGSARCMSMPLVREDVK | 9 |
衣阿華黴漿菌 | MGNNIPKKINVFSEIGNLKRVLVHTPGKEIEYVTPQRLDELLFSAILDPVRAREEHKEFIKILESQGVEVVQLVDLTAETYDVAESQAKENFIQKWLDESLPKLTDENRNKVYSLLKSLEKDPKEMIRKMMSGVLASEIGVKSDVELIVDPMPNLYFTRDPFASVGNGITLHRMFRPTRRRETIFADFIFSNHPEYKSTQKYYEREDKFSLEGGDVFIYNNKTLVVGVSERTEKGAIKALAKAVQNNSNMSFEKIYAINVPKMSNLMHLDTWLTMLDTDKFLYSPNMMGVLKIWEIDLSDKSLKWKEIRDSLDHFLSTIIGKKAITVPVAGKDAMQFEIDIETHFDATNFIAVAPGVVIGYDRNKKTNEALKEAGIKVLSWNGDQLSLGMGSARCMTMPLYREELKK | 10 |
鱷魚黴漿菌 | MNKINVYSEVGKLKEVLVHTPGDEIRRISPSRLEELLFSAILEPDSAIEEHKRFLKILEDNNIKVIQLDQLVADTYELVNPSVRDAFIEKWLNESEPKLDKKLREKVKEYLLHTQKTVGTKRMVRIMMAGVDRVELGVELDRQLVVDPMPNLYFTRDPFASAGNGISLNNMKYVTRKRETIFSEFIFENHPDYKTTPHWFDRLDKGNIEGGDVFIYNRTTLVIGISERTNKDALLTIANNIKSNKESKFERIVAVNVPPMPNLMHLDTWLTMVDHDKFLYSPNMMKTLKFWTIDLTKPIKMVELEESLSDMIETIIGKKPVLIPIAGHDASPLDVDIETHFDGTNYLTIAPGVVVGYSRNKLTEKALTKAGVKVLSFEGNQLSLGMGSARCMSMPLVREDIK | 11 |
發酵黴漿菌 | MQIIAKIDLLTNMLIFMKIYFIGRLIMKKINVYSEYGKLKEVLVHTPGDEIRRIAPSRLDELLFSAILEPDSAIAEHKRFVQLLKDNGIKVIQLDELFAKTFDLVSESVKQSLIERWLDECEPKLDATLRAKVKEYILELKAKSSKKMVRVMMAGIDKKELGIELDRDLVVDPMPNLYFTRDPFASVGNGISLHHMKYVTRQRETIFSEFIFDNNLDYNTVPRWFDRKDEGRIEGGDVFIYSADTLVVGVSERTNKEAINVMARKIAADKEVKFKRIYAINVPPMPNLMHLDTWLTMLDKNKFLYSPNMLSVLKVWRIDLNDPDFVWHEIEGSLEEILEQIIGMKPILIPIAGKGASQLDIDIETHFDGTNYLTIAPSVVVGYSRNEKTEKALKAAKVKVLSFEGNQLSLGMGSARCMSMPLIREDIKKK | 12 |
滲透黴漿菌 | MVITIALNILNKIYFKPQNRSILKLYRLPSLCTQISIFIGGKMSSIDKNSLGNGINVYSEIGELKEVLVHTPGDEIRYTAPSRLEELLFSAVLKADTAIEEHKGFVKILQNNGIKVIQLCDLVAETYELCSKEVRNSFIEQYLDEALPVLKKEIRPVVKDYLLSFPTVQMVRKMMSGILANELNIKQDNPLIIDGMPNLYFTRDPFASMGNGVSINCMKYPTRKREVIFSRFVFTNNPKYKNTPRYFDIVGNNGTIEGGDIFIYNSKTLVIGNSERTNFAAIESVAKNIQANKDCTFERIVVINVPPMPNLMHLDTWLTMLDYDKFLYSPNMMNVLKIWEIDLNVKPVKFVEKKGTLEEVLYSIIDKKPILIPIAGKGANQLDIDIETHFDGTNYLTIAPGVVVGYERNEKTQKALVEAGIKVLSFNGSQLSLGMGSARCMSMPLIRENLKK | 13 |
雞毒黴漿菌(Mycoplasma gallisepticum) | MFNKIRVYSEIGKLRKVLVHTPGKELDYVTPQRLDELLFSSLLNPIKARQEHETFIKLLEDHDVECVQLSTLTAQTFQAVNSKIQEEFINRWLDECLPVLSEINRLKVYDYLKSLATNPQVMIRKMMSGILAKEVGIQSEVELVADPMPNLYFTRDPFASIGKGITLHSMFHPTRKRETIFADFIFSHHPEYKNAPKYYSREDKYSIEGGDLFVYDDKTLVIGVSERTEKKAIQSLAEKLRQNDETSFEKIYAINVPKMSNLMHLDTWLTMLDYDKFLYSPNMMGVLKIWEIDLIHPTLIWRELNESLEGFLSMVIGKKATLIPVAGEDSTQIEIDVETNFDATNFLVIQPGVVVGYDRNYKTNQALRDAGVKVISWNGDQLSLGMGSARCMSMPLYRDPIKK | 14 |
鱷黴漿菌 | MSKINVYSEVGRLKEVLVHTPGDEIRRISPTRLEELLFSAILEPDTAIEEHKRFLNVLEKNGIKAIQLDELVAQTYDQVDQKIKDEFIDQWLQEAKPVLNDQLKKLVKNYLLKSQKEFSTKKMVRIMMAGIDKKEINIDLDRDLVVDPMPNLYFTRDPFASVGNGISLHNMKYQTRKRETIFAQFIFKYNKDYKTTPHWFDRFDHGSIEGGDVFVYTKDTLVIGISERTTKEAVLNIAKKIKANTDSKFKKIVAINVPPMPNLMHLDTWITMVDHDKFLYSPNMMKSLKFWLIDLSKEIKMVELEESLSNMLEAIIGKKPILIPIAGKNASQLDIDIETHFDGTNYLTIAPGVVVGYSRNKLTQKALEDAGVKVLSFDGNQLSLGMGSARCMSMPLVREDIK | 15 |
肺炎黴漿菌 | MSKKQLVKTDGHNQLDQPNTKALQLKKKQFNSGVRVTSEISFLREVIAHHPGIETERVIDNQTFGSAMYLERAQKEHQLFIKILRQHGTKVHYLQDLLLEALSAADPNVRQDFIKNFLLESGIKSVSTFEACLNFFRSLDSLVDVIKVMFGGIKVSDVPPITPQRFADIHVSNSPFLIKPLSFSLYPHKFFNTLGTGVALFVTNDSELKRHSLVYEYIMRFHPRFDGVKLYTNRDFKNCLINSSDIIQISNEILLIGISHDTDVLGIESLARNLLSDHTNPIKQIIAINIHKFGAKTNLNKLIAMVDVDKFIIARKVLQATEIFELTATAQRDVDGLAQIKFKPLKFNFGEIIEAIIDKQPRFVIIGGGDEVAERKELLDCGMGVLNLSPGEIVVFDRNHYTNNLLNELGLIIHKIPASELSRGPSGPLEMVCSLWRE | 16 |
運動黴漿菌(Mycoplasma mobile) | MKDTKDIINVFSEIGELKKVLIHTPGNELKYVSPYRLDELLFSNVLEWREAKKEHNEFIQKLKSEGVEPVELTDLVAESFEESSIKVKNDFIRQYLDEATPILDGLTKQKLLPFFLDIKHSTRKTIELMMSGITQKDISISHIERELIIDPMPNLYFSRDNFISIGNSVIISNMKYKTRKRETIFTDFIFKNHPLYKKVNMAFERKDLNNQISIIEGGDVLVYSKEILIIGISERTTMSAILELAENFKKTKRSFKKIYGVEVPKMKNLMHLDTWLTMIDYDKFIYSPNVLTDLKFWEINLDYEKISSKELHASLSEFLKLIIGKDPILIPIGGKGASQITIDIETNFVAANYLVIRPGVVIGYSRNYETQKALEGHGVKVIAFEGNQLSLGMGSSRCMSMPLIRSNLK | 17 |
化膿性鏈球菌(Streptococcus pyogenes) | MTAQTPIHVYSEIGKLKKVLLHRPGKEIENLMPDYLERLLFDDIPFLEDAQKEHDAFAQALRDEGIEVLYLETLAAESLVTPEIREAFIDEYLSEANIRGRATKKAIRELLMAIEDNQELIEKTMAGVQKSELPEIPASEKGLTDLVESNYPFAIDPMPNLYFTRDPFATIGTGVSLNHMFSETRNRETLYGKYIFTHHPIYGGGKVPMVYDRNETTRIEGGDELVLSKDVLAVGISQRTDAASIEKLLVNIFKQNLGFKKVLAFEFANNRKFMHLDTVFTMVDYDKFTIHPEIEGDLRVYSVTYDNEELHIVEEKGDLAELLAANLGVEKVDLIRCGGDNLVAAGREQWNDGSNTLTIAPGVVVVYNRNTITNAILESKGLKLIKIHGSELVRGRGGPRCMSMPFEREDI | 18 |
糞腸球菌(Enterococcus faecalis) | MSHPINVFSEIGKLKTVMLHRPGKELENLMPDYLERLLFDDIPFLEKAQAEHDAFAELLRSKDIEVVYLEDLAAEALINEEVRRQFIDQFLEEANIRSESAKEKVRELMLEIDDNEELIQKAIAGIQKQELPKYEQEFLTDMVEADYPFIIDPMPNLYFTRDNFATMGHGISLNHMYSVTRQRETIFGQYIFDYHPRFAGKEVPRVYDRSESTRIEGGDELILSKEVVAIGISQRTDAASIEKIARNIFEQKLGFKNILAFDIGEHRKFMHLDTVFTMIDYDKFTIHPEIEGGLVVYSITEKADGDIQITKEKDTLDNILCKYLHLDNVQLIRCGAGNLTAAAREQWNDGSNTLAIAPGEVVVYDRNTITNKALEEAGVKLNYIPGSELVRGRGGPRCMSMPLYREDL | 19 |
山羊黴漿菌(Mycoplasma capricolum) | MEKKINVFSEIGTLKTVLVHRPGDEIENLTPELLERLLFDDVPFKDVAVKEHDAFTKIMRDNGVEVLYIEKLAAETLDQHPDLREKFIDQFISEANIEDKYKEKYRDFISSLDNYRMIKKMIAGTKKLELGIDEGYKAYPFIADPLPNVLFQRDPFSSVGFGITMNRMWSVTRNRETIFPDLVFKHHNRFANQVPYYYERDWKEETIEGGDILVLNKETLIIGVTQRTTLKAIEKFSERLFNDPESSYSKVIALDLPKSRAFMHLDTVFTNIDYDKFIAHPLIFDCIDEFKIYEVSKQGTKEVKKTLIELLSDAAGREVQIIRCGGNDVVGASREQWNDGTNVVALRPGKVIAYERNWITIDLLRKAGVEVLTIASSELSRGRGGPRCMTMPLWREDLQEIKR | 20 |
奧氏嗜熱鹽絲菌 | MFKKSPLNVTSEIGKLKKVLLHRPGHEIENLTPDLLERLLFDDIPYLKVAQEEHDAFAQTLRDNGVEVLYLHELAAEAIQEDEIRKKFIEQFLDEAGVIGKGARQVLKEYFADMDNETLIRKMMAGVRKKEIPAIEKVASLNDMVEEDYPFVLDPMPNLYFTRDPFATIGTGITLNHMRTETRNREVIFAEYIFSYHPDFKDTEIPFWFDRNETTSIEGGDELILSDKVLAMGISERTDAASIEKVARNIFTDGQPFETILAFKIPEKRAFMHLDTVFTMVDYDKFTIHAEIEGPLKVYSITKGDNDELKIDEEKATLEDTLKKYLGLDEVTLIRCAGGDYIDAGREQWNDGSNTLAIAPGEVVVYNRNHTTNRLLEEHGIKLHVIPSSELSRGRGGPRCMSMPLVREDI | 21 |
金黃色葡萄球菌 | MTDGPIKVNSEIGALKTVLLKRPGKELENLVPDYLDGLLFDDIPYLEVAQKEHDHFAQVLREEGVEVLYLEKLAAESIENPQVRSEFIDDVLAESKKTILGHEEEIKALFATLSNQELVDKIMSGVRKEEINPKCTHLVEYMDDKYPFYLDPMPNLYFTRDPQASIGHGITINRMFWRARRRESIFIQYIVKHHPRFKDANIPIWLDRDCPFNIEGGDELVLSKDVLAIGVSERTSAQAIEKLARRIFENPQATFKKVVAIEIPTSRTFMHLDTVFTMIDYDKFTMHSAILKAEGNMNIFIIEYDDVNKDIAIKQSSHLKDTLEDVLGIDDIQFIPTGNGDVIDGAREQWNDGSNTLCIRPGVVVTYDRNYVSNDLLRQKGIKVIEISGSELVRGRGGPRCMSQPLFREDI | 22 |
香魚假單胞菌(Pseudomonas plecoglossicida) | MSAEKQKYGVHSEAGKLRKVMVCAPGLAHKRLTPSNCDELLFDDVIWVDQAKRDHFDFVTKMRERGVDVLEMHNLLTDIVQNPEALKWILDRKITPDTVGVGLTNEVRSWLEGQEPRHLAEFLIGGVAGQDLPESEGASVVKMYNDYLGHSSFILPPLPNTQFTRDTTCWIYGGVTLNPMYWPARRQETLLTTAIYKFHPEFTKADFQVWYGDPDQEHGQATLEGGDVMPIGKGIVLIGMGERTSRQAIGQLAQNLFAKGAVEQVIVAGLPKSRAAMHLDTVFSFCDRDLVTVFPEVVREIVPFIIRPDESKPYGMDVRRENKSFIEVVGEQLGVKLRVVETGGNSFAAEREQWDDGNNVVALEPGVVIGYDRNTYTNTLLRKAGIEVITISAGELGRGRGGGHCMTCPIVRDPINY | 23 |
戀臭假單胞菌(Pseudomonas putida) | MSAEKQKYGVHSEAGKLRKVMVCAPGLAHKRLTPSNCDELLFDDVIWVDQAKRDHFDFVTKMRERGVDVLEMHNLLTDIVQNKDALKWILDRKITPDTVGVGLTNEVRSWLEGLEPRHLAEFLIGGVAGQDLPQSEGADVVKMYNDYLGHSSFILPPLPNTQFTRDTTCWIYGGVTLNPMYWPARRQETLLTTAIYKFHPQFTGADFQVWYGDPDKDHGNATLEGGDVMPIGKGIVLIGMGERTSRQAIGQLAQNLFAKGAVEKVIVAGLPKSRAAMHLDTVFSFCDRDLVTIFPEVVKEIVPFIIRPDESKPYGMDVRRENKSFIEVVGEQLGVKLRVVETGGNSFAAEREQWDDGNNVVAVEPGVVIGYDRNTYTNTLLRKAGIEVITISAGELGRGRGGGHCMTCPIVRDPIDY | 24 |
綠膿桿菌(Pseudomonas aeruginosa) | MSTEKTKLGVHSEAGKLRKVMVCSPGLAHQRLTPSNCDELLFDDVIWVNQAKRDHFDFVTKMRERGIDVLEMHNLLTETIQNPEALKWILDRKITADSVGLGLTSELRSWLESLEPRKLAEYLIGGVAADDLPASEGANILKMYREYLGHSSFLLPPLPNTQFTRDTTCWIYGGVTLNPMYWPARRQETLLTTAIYKFHPEFANAEFEIWYGDPDKDHGSSTLEGGDVMPIGNGVVLIGMGERSSRQAIGQVAQSLFAKGAAERVIVAGLPKSRAAMHLDTVFSFCDRDLVTVFPEVVKEIVPFSLRPDASSPYGMSIRREEKTFLEVVAESLGLKKLRVVETGGNSFAAEREQWDDGNNVVCLEPGVVVGYDRNTYTNTLLRKAGVEVITISASELGRGRGGGHCMTCPIIRDPIDY | 25 |
結核分枝桿菌群(Mycobacterium tuberculosis complex) | MGVELGSNSEVGALRVVILHRPGAELRRLTPRNTDQLLFDGLPWVSRAQDEHDEFAELLASRGAEVLLLSDLLTEALHHSGAARMQGIAAAVDAPRLGLPLAQELSAYLRSLDPGRLAHVLTAGMTFNELPSDTRTDVSLVLRMHHGGDFVIEPLPNLVFTRDSSIWIGPRVVIPSLALRARVREASLTDLIYAHHPRFTGVRRAYESRTAPVEGGDVLLLAPGVVAVGVGERTTPAGAEALARSLFDDDLAHTVLAVPIAQQRAQMHLDTVCTMVDTDTMVMYANVVDTLEAFTIQRTPDGVTIGDAAPFAEAAAKAMGIDKLRVIHTGMDPVVAEREQWDDGNNTLALAPGVVVAYERNVQTNARLQDAGIEVLTIAGSELGTGRGGPRCMSCPAARDPL | 26 |
關節炎黴漿菌 | MSVFDSKFKGIHVYSEIGELETVLVHEPGKEIDYITPARLDELLFSAILESHDARKEHKEFVAELKKRGINVVELVDLIVETYDLASKEAKEKLLEEFLDDSVPVLSDEHRAAVKKFLQSQKSTRSLVEYMIAGITKHDLKIESDLELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVNTPWYYDPAEGLSIEGGDVFIYNNDTLVVGVSERTDLQTITLLAKNIKANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGDAPQPVDNGLPLEDLLKSIIGKKPTLIPIAGAGASQIDIERETHFDGTNYLAVAPGIVIGYARNEKTNAALEAAGITVLPFRGNQLSLGMGNARCMSMPLSRKDVK | 27 |
海豹腦黴漿菌 來自新物種專利之人工全長。 | MSVFDSKFNGIHVYSEIGELETVLVHEPGREIDYITPARLDELLFSAILESHDARKEHQSFVKQLKDNGINVVELTDLVAETFDLASKEEQEKLIEEFLEDSEPVLSEAHKTAVRKFLTSRKSTREMVEFMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVKTPWYYDPAMKMSIEGGDVFIYNNDTLVVGVSERTDLETITLLAKNIKANKEVEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGAEPQPKENGLPLEGLLQSIINKKPVLIPIAGNNASHIDIERETHFDGTNYLAIKPGVVIGYARNEKTNAALAAAGIKVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 28 |
貓黴漿菌 來自新物種專利之人工全長。 | MSVFDSKFNGIHVYSEIGELESVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKLFVSELKANDINVVELTDLVTETYDLASQEAKDNLIEEFLEDSEPVLTEELKSVVRTYLKSIKSTRELIQMMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVNTPWYYDPSLKLSIEGGDVFIYNNNTLVVGVSERTDLETVTLLAKNIVANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGEEPQPVENGLPLEGLLESIINKKPILIPIAGEGASQIDIERETHFDGTNYLAIRPGVVIGYSRNEKTNAALEAAGIKVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 29 |
海豹黴漿菌 來自新物種專利之人工全長。 | MSVFDSKFNGIHVYSEIGELQTVLVHEPGREIEYITPARLDELLFSAILESHDARKEHQEFVAELKKNNINVVELTDLVSETYDMVSKEKQEKLIEEFLEDSEPVLSEEHKGLVRKFLKSLKSSKELIQYMMAGITKHDLNIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFANHPKLMNTPLYYNPDMKLSIEGGDVFVYNNETLVVGVSERTDLDTITLLAKNIKANKEREFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGDEPQPKVNGLPLEKLLESIINKKPILIPIAGTSASNIDVERETHFDGTNYLAIAPGVVIGYSRNVKTNEALEAAGIKVLPFKGNQLSLGMGNARCMSMPLSRKDVKW | 30 |
唾液黴漿菌 | MSVFSSKFNGIHVYSEIGELETVLVHEPGKEIDYITPSRLDELLFSAILESHDARKEHQEFVATLKKEKINVVELTDLVTETYDLVDQKTKDKLIDEFLEDSEPVLTAELKATVKKFLKSFKETRKLIEVMMAGITKYDLGIKADRELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFNNHPKLVKTPWYYDPAMKMSIEGGDVFIYNNDTLVVGVSERTDLDTITLLAKNIKANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDIFKFWDYDLVNGGANPQPKDNGLPLDKLLKSIIGKEPVLIPIAGHHATEIEVARETHFDGTNYLAIRPGVVIGYARNEKTNEALKDAGITVLPFKGNQLSLGMGNARCMSMPLSRKDVKW | 31 |
泡沫黴漿菌 | MSVFDSKFKGIHVYSEIGELESVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKGFVAELKKQNVNVIELTDLVAETYELASKEAQAKLIEDFIEDSEPVLNAEEAQAVRKFLSERKSTREMVEYMMSGLTKYELGLESADRELIVDPMPNLYFTRDPFASVGNGVTIHYMKYKVRQRETLFAKFVFSNHPKLVNTPRYYDPSMKLPIEGGDVFIYNNETLVVGCSERTELETITLLAKNIKANKEVEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGEEPQPVENGLPLEELLASIINKKPTLIPIAGEGATHIDVERETHFDGTNYLAIAPALIIGYSRNEKTNAALEKAGITVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 32 |
耳黴漿菌 | MSVFDSKFKGIHVYSEIGELETVLVHEPGREIDYITPKRLDELLFSAILESHEARKEHKQFVAELKANDINVVELTDLVAETYDLVSQELKDKLIEEFLDDSYPVLTEEHKKAVRSFLKSRSSTRELIEYMMAGITKYDLGIEAEGDLIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFDNHPKLVNTPRYYDPSLKLSIEGGDVFIYNNDTLVMGVSERTDLETVTLLAKNIVANKECEFKRIVAINVPHWTNLMHLDTWLTMLDKDKFLYSPIANDYFKFWDYDLVNGGAEPQPVVNELPLDKLLESIIHKKPILIPIAGEGASQIDLERETHFDGTNYLVLRPGVVVGYARNEKTNAALEAVGIKVLPFYGNQLSLGMGNSRCMSMPLSRKDVKW | 33 |
豬滑液黴漿菌 | MSVFNSKFKGIHVYSEIGDLESVLVHEPGKEIDYITPSRLDELLFSAILESNDARKEHKEFVEILKKEGVNVVELVDLIAETIDLVDAKKKEALIDEYIEDSEPVVDAKVKPLVKKLLLGIKDTKELVKLMMAGITKYDLEIESEKELIIDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFRNHPKLTSTPWYYDPAMKLSIEGGDVFIYNNDTLVVGVSERTDLDTITLLAKNIKANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDIFKFWDYDLVNGGSEPQPKDNGLPLEKLLESIIGKKPVLIPIAGCCASDIEIARETHFDGTNYLAIKPGVVIGYARNEKTNKALEKAGIKVLPFKGNQLSLGMGNARCMSMPLSRKDVKW | 34 |
泄殖腔黴漿菌 | MSVFDKRFKGIHVYSEIGELQTVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKEFVKILESQGINVVELTDLIAETYELASEEAKDNLIEEFLDESEPVLSEEHRILVRNFLKGITKTKELVKMMMAGITKYDLGIEADRELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFENHPKLVSTPIYYHPSQGLSIEGGDVFIYNNDTLVVGVSERTDLQTITLLAKNIKANEECEFKRIVAINVPKWTNLMHLDTWLTMLDKNKFLYSPIANDVFKFWDYDLVNGGDEPQPVDNGLPLNELLASIIGEEPVLVPIAGEGASKMDIERETHFDGTNYLAIAPGVVVGYSRNEKTNAALEKAGIKVLPFKGHQLSLGMGNARCMSMPLYRKDVK | 35 |
產鹼黴漿菌 | MSVFDSKFKGIHVYSEIGELESVLVHEPGHEIDYITPSRLDELLFSAMLESHDARKEHKQFVAELKANNVNVIELTDLVAETYDLASQEAKDKLIEEFLEDSEPVLSEENKIAVRDFLKSRKTTRELIEVMMAGITKYDLGIKNCKCQDLVVDPMPNLYFTRDPFASVGNGITIHYMRYKVRQRETLFSRFIFANHPKLVNTPIYYHPSLKLSIEGGDVFIYNNDTLVVGVSERTDLETITLLAKNIVANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGAEPKPVENGSSLEAILESIIHKKPILIPIGGDSASQIEVERETHFDGTNYLAIRPGVVIGYSRNVKTNAALEAAGIKVIPFHGNQLSLGMGNARCMSMPLSRKDVKW | 36 |
惰性黴漿菌 | MSKINVYSEIGVLKEVLVHTPGDEIRRIAPSRLDELLFSAILEPSAAIQEHKSFLKILQDRGIKTIQLSDLVAETYKHYASEAEKEAFIEKYLDEATPVLSKDMRAKVKNYILSMQGEPVKMVRTMMAGVSKQELNVESEVELIVDPMPNLYFTRDPFASAGNGISLNNMKYVVRKRETIFAEFIFSIHPEYKKTPHWFDRLDNGSIEGGDVFIYNKDTLVIGVSERTNKEAIITIAKHIQDNKEAQFKKIVAINVPPMPNLMHLDTWLTMVDKNKFLYSPNMLSVLKVWEIDLSKPIEMVETNKPLAEVLESIIGEKPILIPIAGKDATQLDIDIETHFDGTNYLTIAPGVVVGYSRNVKTEAALRAAGVTVLSFEGNQLSLGMGSARCMSMPLVREDVK | 37 |
家禽黴漿菌 | MSKIRVYSEIGNLKKVLVHTPGDEIRRISPSRLEELLFSAVLEPNAAIEEHKRFVKLLEDRGIQAIQLSDLVAETYVKYATAEQKAAFIEKYLDEATPALSAENRERAKKYILSLEMQPVKMIRTMMAGLSKYELNVESNIELIIDPMPNLYFTRDPFASAGNGISLNNMKYVVRKRETIFAEFIFAIHPEYKETPHWFDRLDHGSIEGGDVFVYNKDTLVIGVSERTNKEAIITIAKHIQDNKEAEFKKIVAINVPPMPNLMHLDTWLTMVDKNKFIYSPNMLSVLKIWEIDLAKPIEMVESNKSLTEVLESIIGEKPILIPIAGEGASQLDIDIETHFDGTNYLTIAPGVVVGYSRNEKTEKALKAAGITVLSFEGNQLSLGMGSARCMSMPLVREDVK | 38 |
梨黴漿菌 | MNSNQKGIHVYSEIGKLKEVLVHRPGRELDFLDPTRLDELLFAATLEAETARLEHDNFTNALKNQGVTVIELADLVAQTYSSSTPTIKAAFINKYLDEATPALTTKLRTLVKDFLTKQKSVRKMVDYMIGGILSTDLNIKGKPELIVEPMPNAYFTHDPFASVGNGVTLHYMKHNVRRREVLFSEFIFNNNERFQNTPRYIVPTKGLDIEGGDVFVYNKNTLVVGVSERTKMVTIKELAKNILKNKECLFKKIYAINVPKMPNLMHLDTWLTMLDHNKFLYSPNMLSVLKIWEIDISSGKSISSPKELNMDLSKALSIIIGKKPILIPVAGENASQIDINIETNFDATNYLVTQPGVVVGYSRNKKTEAALIKAGIEVIPFQGNQLSLGMGSARCMSMPLIREDV | 39 |
靈長類黴漿菌 | MSKSKINVYSEYGNLKEVLVHTPGDEIRRITPSRLDELLFSAILEPKSAIAEHKSFCQILKDNKVKAIQLDELVAATYKGVSESVQNSFVERWLDECEPKLENNVRPIVKEYLLKAAEQSVKKMIRIMMAGIDKREIGVESEVDFIVDPMPNLYFTRDPFASVGNGITLHHMKYVVRQRETLFSEFIFDNHPDYKFVPRYFDRDDEGKIEGGDVFIYNSKTLVVGISERTNKDAIRIVAKKIQANADAKFEKIFAINVPPMPNLMHLDTWLTMLDSNKFLYSPNMLSVLKVWEINLDDPALEWKEISGSLEEILTYIIGKKPILIPIAGKGASQFEIDIETHFDGTNYLAIAPSVVIGYSRNELTEKALKKAGVKVLSLDGNQLSLGMGSARCMSMPLIREDVK | 40 |
Mycoplasma lipofaciens | MSKINVYSEVGVLKEVLVHTPGDEIRRVAPSRLDELLFSAILEPQDAIAEHKRFIKILEDNNIKVIQLDELVSETWEKATAEQRDAFIEKWLDEAEPVLDAKLRETVKKYLLSLNPVKKMVRTMMAGIDKKELKIELDRDLVVDPMPNLYFTRDPFASAGNGISLNNMKYVTRKRETIFAEFIFNIHPDYKTTPHWFDRLDKGNIEGGDVFIYNKDTLVLGVSERTNKDAVMTIAKHIQSNEQAKFKKLVAINVPPMPNLMHLDTWLTMVDHDKFLYSPNMLSVLKIWEIDLTPGKEIEMVESTKSLSDMLESIIGKKPVLIPIAGKDASQLDIDIETHFDGTNYLTIRPGVVVGYSRNCLTEQALKDAGVTVLSFDGNQLSLGMGSARCMSMPLVREDIK | 41 |
小貓黴漿菌 | MNKINVYSEIGKLKEVLVHTPGNEIRRISPSRLDELLFSALLEPNFAAKEHTAFCEILKENGIKAIQLVDLVSDTWRIASEKAKTEFIERWLDECEPKLDSNLREIVRKHIYAIEKRSVKRMVKTMMAGIERRELPVTSKEVARELVVDPMPNLYFTRDPFASVGNGISLHHMKYVTRQRETIFAEFVFGNHPDYIDTPRWFDRSDDGRIEGGDVFIYGSKTLVIGVSERTNKEAIKVMAKKIQANKEATFEKIYAINVPPMPNLMHLDTWLTMLDKNKFLYSPNMLAVLQVWEIDLKDPELTWHELSGSLEEILHKIIGRKPILIPIAGHGAQQIDIDIETHFDGTNYLAIAPGVVVGYNRNVLTERALKKAGIKVLSFEGNQLSLGMGSARCMSMPLIRENLK | 42 |
模仿黴漿菌 | MFNKIKVYSEIGRLRKVLVHTPGKELEYVTPQRLDELLFSSLLNPVKARQEHEAFIKILQDQGVECVQLTTLTAQTFQSATSEVKEKFINRWLDECLPKLSDDNRIKVYAYLKDLSSDPEVMIRKMMSGILAKEVNVQSDVELIADPMPNLYFTRDPFASIGKGVTLHSMFHPTRKRETIFADFVFSHHPEYKQTPKYYSRLNEYSIEGGDLFVYDDKTLVIGVSERTEKKAIQFLAEKLRENYETTFEKIYAINVPKMSNLMHLDTWLTMLDYDKFLYSPNMMGVLKIWEIDLTHEQLSWRELNESLEEFLSMVIGKKATTIPVAGEDSTQIEIDVETNFDATNFLVIQPGVVVGYDRNYKTNQALVNAGIKVLSWNGDQLSLGMGSARCMSMPLYRDPIKKG | 43 |
乳白色黴漿菌 | MSKINVYSEIGTLKEVLVHTPGDEIRRVAPARLDELLFSAILEPNHAIAEHKAFIKILEDNGIKVIQLDELVVQTWNQVDEATRKAFVTKWLDECEPKLESNVRVEVEKYIYSLAKEPKKMVRTMMAGISKEELPLNVNRPLVVDPMPNLYFTRDPFASVGTGISLHHMKYVTRQRETIFAQFVFDNHKDYNTVPRWFDNKDQGRIEGGDVFIYNTKTLVIGVSERTDKDAIKIMAKKIQADKNCKFEKIFAINVPPMPNLMHLDTWLTMVDRNKFLYSPNMLSVLKVWEIDLKDASLAWKEIEGSLSQILEKIIGEKPILIPIAGENASQLDIDIETHFDGTNYLTIAPGVVVGYSRNVKTEQALKAAGVKVLSFEGNQLSLGMGSARCMSMPLIREDLK | 44 |
毛氏黴漿菌 | MKKNAINVYSEIGKLKKVLVHRPGDELKYVTPQRMDELLMSAIIELEQAKEEHDAFTKILRDNGVEVIELADLTAEMYDSLTPSEKDAFLNQWVKEASWGKKSSIDALKIKKNLSKKVFDYVKSIKPTRKMIDKLMAGVLLSEIGEKSIILNKDKKNEMVIDLVVDPMPNLYFTRDPFASVGNGITLHNMKYPTRKRETIFAQWIFNKHPEYKDVPQFISKRDGKETIEGGDVFIYTKDVLAIGVSERTNMEAILRIATNIKKDKNCEFKKIVAINVPPMGNLMHLDTWLTMLDKDLFLYSGNIKSALKVWEIDLTKPITPKSPKLSTAKLADILAKIVGKKVRMIPIGGKDGNQMDIDIETHFDGTNYLAIAPGVVVGYHRNRKTQKALEEAGVKVLAFQGNQLSLGMGSARCMSMPLVREEVK | 45 |
象黴漿菌 | MSQINVFSEIGQLKEVLVHTPGDEIRRISPKRYNELLFSAILEADVAIKEHKSFVKILEENNVKVIQLKDILLETWNICSKEAKNIFINKWIEEAQPVIHSSSLKEKIKLFLKSKTPLEIIDIMMKGILKQELGIEYKHELIIDPMPNLYFTRDPFTSMGSGITINNMKYQTRKRETIFSEFIFNNHPKYKNTPRWFDRFDSGNIEGGDLFVYTKETIVVGVSERTKKKAILKIAKNIQENNNSFKKIVVIKVPIMQNLMHLDTWIVMVDFDKFIYSPNVTKSLKFWEIDLTKKPKFIQLKNETLEDVLYRVIGKKPILIPVAGENANQIDIDVETHFDATNYLTIRPGVVVGYSRNKKTEEALINAGVKVYAFEGNQLSLGMGSARCMSMPLIREDII | 46 |
龜黴漿菌 | MKNINVYSEVGKLKEVVVHTPGEELHNVAPSRLQELLTSAVLEPEVARKEHLKFIKILNDYGVKVIQIVDLITETYEAVDSNKKEAFINNWLDNSVPKLTDKNRMILRNYLTQFSTKAMIRKMISGIRAKELNLKTPSALLVDPMPNLCFARDTFACVGSAISLSTMKHPTRRREALLTEFIFQNHPKYKDVIKYFDSKNSKATIEGGDIFVYNPKTLVVGNSERTNMQACLLLAKKIQSNPNNKFEKIVIVNVPPLPHLMHLDTWLTMVDYDKFIYSPNILHTLKFWVIDLKKRKLEAVEKHNTLKAMLRMIIKKEPILIPVGDVGADQLDIDLETHFDATNYLALAPGVVVGYDRNIKTQRALEKAGVKVLSFSGNQLSLAMGSARCLSMPLIREEN | 47 |
加拿大黴漿菌 | MSVFDSKFKGIHVYSEIGELESVLVHEPGREIDYITPARLDELLFSAILESHDARKEHKQFVSELKANDINVVELTDLVAETYDLASQEAKDKLIEEFLEDSEPVLSEEHKAIVRKYLKGIQPTRKLIEMMMAGITKYDLGIEADHELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFVFSNHPKLVNTPWYYDPSLKLSIEGGDVFVYNNDTLVVGVSERTDLQTVTLLAKNIVANKECEFKRIVAINVPKWTNLMHLDTWLTMLDKDKFLYSPIANDVFKFWDYDLVNGGSEPQPVENGLPLEGLLESIINKKPILIPIAGEGASQMEIERETHFDGTNYLAIRPGVVIGYSRNEKTNAALEAAGIKVLPFHGNQLSLGMGNARCMSMPLSRKDVKW | 48 |
鵝黴漿菌 | MSVFDKRFKGIHVYSEIGELQTVLVHEPGREIDYITPARLDELLFSAILESHDARAEHKKFVATLKEQGINTVELTDLVAETYDLASQEARDNLLEEFLDDSAPVLSEEHKEIVRTYLKGIKGTRKLIETMMAGITKYDLGIEAEQELIVDPMPNLYFTRDPFASVGNGVTIHYMRYKVRQRETLFSRFIFSNHPQLVNTPWYYNPAEGLSIEGGDVFIYNNDTLVVGVSERTDLQTITLLAKNIKANEECEFKRIVAINVPKWTNLMHLDTWLTMLDTNKFLYSPIANDVFKFWDYDLVNGGDEPQPVDNGLPLNELLKSIIGEEPILIPIAGDGATQIEIERETHFDGTNYLAIAPGVVIGYSRNEKTNAALEAAGIKVLPFKGHQLSLGMGNARCMSMPLYRKDVK | 49 |
火雞黴漿菌 | MSKINVYSEIGVLKEVLVHTPGDEIRRISPSRLDELLFSAILQPEQAIKEHQSFVKILQDRGIKVIQLSDLVAETYVKYATSKEKESFIEKWLDEATPALNSENRARVKNYITAMQGQPVKMVRAMMAGVSKQELNIESDVELIVDPMPNLYFTRDPFASAGNGISLNNMKYVVRKRETIFAEFIFSIHPEYKQTPHWFDRLDKGNIEGGDVFIYNKDTLVIGVSERTNKEAILTIAEHIKNNKEAKFKKIVAINVPPMPNLMHLDTWLTMVDKNKFLYSPNMLSVLKIWEIDLSKEIKMVETSKPLADVLESIIGEKPILIPIAGENASQLDIDIETHFDGTNYLTIAPGVVVGYSRNVKTEAALKAAGVTVYSFDGNQLSLGMGSGRCMSMPLVREDVK | 50 |
蜂房黴漿菌 | MSIKENGIHVYSEIGKLRDVLVHRPGRELNFLDPSRLDELLFAATLEPETARLEHDNFTTVLKNQGVNVIELADLVSQTYSKVDSKVKKEFIDQYLNEATPKLTSELSKKVYDFLTKQKSNREMVDFMMGGILSSDLNIKGQPYLIVEPMPNLYFTRDPFASVGNGATIHWMKHNVRRREVLFANFIFKYNERFQNTPKYITPTKGLDIEGGDVFVYNKKTLVVGVSERTKMETIKELAKNISKNKECTFTKIYAINVPKMPNLMHLDTWLTMLDYNKFLYSPNMLSVLKVWEINISNNKVSAPKELNVNLEKALSMIIGKKPILIPVAGANASQIDINIETNFDATNYLVIEPGVVVGYSRNKKTEEALVKAGIKVLPFHGNQLSLGMGSARCMSMPLYREDV | 51 |
滲透黴漿菌 | MSSIDKNSLGNGINVYSEIGELKEVLVHTPGDEIRYTAPSRLEELLFSAVLKADTAIEEHKGFVKILQNNGIKVIQLCDLVAETYELCSKEVRNSFIEQYLDEALPVLKKEIRPVVKDYLLSFPTVQMVRKMMSGILANELNIKQDNPLIIDGMPNLYFTRDPFASMGNGVSINCMKYPTRKREVIFSRFVFTNNPKYKNTPRYFDIVGNNGTIEGGDIFIYNSKTLVIGNSERTNFAAIESVAKNIQANKDCTFERIVVINVPPMPNLMHLDTWLTMLDYDKFLYSPNMMNVLKIWEIDLNVKPVKFVEKKGTLEEVLYSIIDKKPILIPIAGKGANQLDIDIETHFDGTNYLTIAPGVVVGYERNEKTQKALVEAGIKVLSFNGSQLSLGMGSARCMSMPLIRENLKK | 52 |
發酵黴漿菌 | MKKINVYSEYGKLKEVLVHTPGDEIRRIAPSRLDELLFSAILEPDSAIAEHKRFVQLLKDNGIKVIQLDELFAKTFDLVSESVKQSFIERWLDECEPKLDATLRAKVKEYILELKAKSSKKMVRVMMAGIDKKELGIELDRDLVVDPMPNLYFTRDPFASVGNGISLHHMKYVTRQRETIFSEFIFDNNLDYNTVPRWFDRKDEGRIEGGDVFIYSADTLVVGVSERTNKEAINVMARKIAADKEVKFKRIYAINVPPMPNLMHLDTWLTMLDKNKFLYSPNMLSVLKVWRIDLNDPDFVWHEIEGSLEEILEQIIGMKPILIPIAGKGASQLDIDIETHFDGTNYLTIAPSVVVGYSRNEKTEKALKAAKVKVLSFEGNQLSLGMGSARCMSMPLIREDIKKK | 53 |
肺炎黴漿菌 | MKYNINVHSEIGQLQTVLVHTPGNEIRRISPRRLDDLLFSAVIEPDTAIQEHQTFCQLLQEQNIEVVQLTDLTATTFDKANATAQNQFIETWLDQAEPKLTPEHRKVAKQYLLEQKAKSTLSMVRSMMGGIDKRKVAAANTINGDFLVDPMPNLYFTRDPFASIGHGISINRMKYLTRRRETLFASFIFANHPIIAARKFYFKPIDMGTIEGGDIFVYDQQTVVMGLSERTTEAAINVLAKKIQQDSSTSFKRIFVINVPQLPNLMHLDTWLTMLDRNKFLYSPNMLAVLKAWRIDFTDPALKWNEIAGDLSTILHTIIGQKPMLIPIAGADANQTEIDIETHFDGTNYLTIAPSVVVGYARNKLTHQTLEAAGVKVIAFKGNQLSLGMGSARCMSMPLVRKPL | 54 |
黴漿菌屬CAG:877 | MEKIHVTSEIGPLKKVLLHRPGNELLNLTPDTLSRLLFDDIPYLPDAIKEHDEFADALRANGVEVVYLENLMADVLDLSDEIRDKFIKQFIYEAGIRTPKYKYLVFDYLDQITNSKKLVLKTMEGIQISDIPRRKREIEKSLVDLIETEDEFIADPMPNLYFTRDPFASVGEGISLNKMYSVTRNRETIYAEYIFKYHPDYKDQARLYYDRYNPYHIEGGDVLNINDHVLAIGISQRTTAEAIDQIAKNLFKDPECKIDTILAFNIPESRAFMHLDTVFTQVDYDKFTYHPGIMGTLQVFEITEGDDPNSDEDLTVTEINAPLEEILTKYVGRKVTLIPCAGGDKVSAEREQWNDGSNTLCIAPGVVVVYDRNNLTNAVLRSYGLKVIEIHGAELSRGRGGPRCMSMPLVREDI | 55 |
黴漿菌屬CAG:472 | MHVTSEIKKLKKVLVHRPGKELLNLTPDTLGRLLFDDIPYLKDAILEHDEFCQILRDNDVEVVYLEDLMAETLDENPQVKPSFIRQFIYEAGVRTPKYKDLLFDYLMSYTNNKELVLKTMEGIKVSEVHRNKQDSEYSLVDQISEETKFLAEPMPNLYFTRDPFASVGDGIILNKMHSVTRSRETIYAYYIFNYHPDYMDKVPKYYDRENPFSIEGGDVLNLNEHTLAIGISQRTSAEAIDLVAKNMFNDEKCNIDTILAFKIPECRAFMHLDTVFTQIDIDKFTYHPGIMDTLEVFEITKNEDDLDEVRVIKKEGSLENILEEYLGIDITLIPCAGGDKIASEREQWNDGTNTLCIAPGVVVVYNRNNITNEVLREKGIKVIEMNSAELSRGRGGPRCMSMPLERED | 56 |
表 E1. | ||||
調配物ID | 組成 | 冷凍保護劑 | 凍乾保護劑 | 增積劑 |
F1 | 20 mM磷酸鈉 130 mM氯化鈉 | 否 | 否 | 否 |
F2 | 20 mM組胺酸 | 否 | 否 | 否 |
F3 | 20 mM組胺酸 5%蔗糖 | 是 | 是 | 否 |
F4 | 20 mM組胺酸 5%甘露醇 | 否 | 否 | 是 |
F5 | 20 mM組胺酸 1%葡聚糖40 | 是 | 否 | 是 |
F6 | 20 mM組胺酸 1%葡聚糖40 5%蔗糖 | 是 | 是 | 是 |
F7 | 20 mM組胺酸 5%海藻糖 | 是 | 是 | 是 |
F8 | 20 mM組胺酸 4%甘露醇 1%蔗糖 | 是 | 是 | 是 |
F9 | 20 mM組胺酸 4.8%蔗糖 0.01% Tween-80* | 是 | 是 | 否 |
F10 | 20 mM組胺酸 4.8%蔗糖 0.01% Tween-80* 0.25%甘油** | 是 | 是 | 否 |
pH 6.8 ±0.1之調配物 *界面活性劑 **塑化劑 |
表 E2. 酶活性評估 ADI-PEG 20 活性,以 IU/mL 計。 | |||||||
調配物 | 凍乾前 | 凍乾後 | 保留之活性% | 分級 | 60℃下1 wk | 保留之活性% | 分級 |
F1 | 163 | 107 | 66 | + | 6 | 6 | ++ |
F2 | 161 | 132 | 82 | +++ | 1 | 1 | + |
F3 | 169 | 137 | 81 | +++ | 13 | 9 | ++ |
F4 | 155 | 128 | 83 | +++ | 0 | 0 | + |
F5 | 154 | 126 | 82 | +++ | 10 | 8 | ++ |
F6 | 132 | 131 | 99 | ++++ | 14 | 11 | +++ |
F7 | 147 | 152 | 103 | ++++ | 30 | 20 | +++ |
F8 | 132 | 138 | 105 | ++++ | 34 | 25 | ++++ |
F9 | 135 | 118 | 87 | +++ | 9 | 8 | ++ |
F10 | 150 | 137 | 91 | ++++ | 8 | 6 | ++ |
表 E3. 藉由 SEC 進行之 ADI-PEG 20 表觀濃度 (mg/mL) 評估。 | |||||||
調配物 | 凍乾前 | 凍乾後 | 保留之活性% | 分級 | 60℃下1 wk | 保留之活性% | 分級 |
F1 | 11.0 | 10.3 | 94 | ++ | 0.5 | 5 | + |
F2 | 13.9 | 12.7 | 91 | ++ | 7.9 | 62 | ++ |
F3 | 14.1 | 12.4 | 88 | + | 13 | 105 | +++ |
F4 | 14.2 | 12.6 | 89 | + | 3.4 | 27 | + |
F5 | 14.3 | 13 | 91 | ++ | 14.1 | 108 | +++ |
F6 | 14.3 | 12.9 | 90 | ++ | 13.7 | 106 | +++ |
F7 | 14.4 | 12.9 | 90 | ++ | 13.8 | 107 | +++ |
F8 | 13.7 | 12.2 | 89 | + | 13.3 | 109 | +++ |
F9 | 13.4 | 12.2 | 91 | ++ | 13.2 | 108 | +++ |
F10 | 13.7 | 12.6 | 92 | ++ | 10.2 | 81 | ++ |
表 E4. | |||||||
分級 | ID | 組成 | 冷凍保護劑 | 凍乾保護劑 | 增積劑 | 界面活性劑 | 塑化劑 |
第1組 | F6、F7及F8 | F6:H+葡聚糖40+蔗糖 F7:H+海藻糖 F8:H+甘露醇+蔗糖 | 是 | 是 | 是 | 否 | 否 |
第2組 | F5 | H+葡聚糖40 | 是 | 否 | 是 | 否 | 否 |
第3組 | F3、F9及F10 | F3:H+蔗糖 F9:H+蔗糖+ Tween 80 F10:H+蔗糖+Tween 80+甘油 | 是 | 是 | 是 | 否:F3 是:F9 是:F10 | 否:F3 否:F9 是:F10 |
第4組 | F2 | 組胺酸(H) | 否 | 否 | 否 | 否 | 否 |
第5組 | F1及F4 | F1:磷酸鹽 F4:H+甘露醇 | 否 | 否 | 否:F1 是:F4 | 否 | 否 |
表 E5. | ||||
緩衝劑 | pH | 基於A280之回收% 濃度 | 外觀 | RALS |
20 mM磷酸鹽、130 mM NaCl | 6.75 | N/A | 透明 | 1.451 |
20mM組胺酸 | 5.99 | 93 | 透明 | 2.519 |
20mM組胺酸 | 6.42 | 93 | 透明 | 2.555 |
20mM組胺酸 | 6.92 | 100 | 透明 | 2.823 |
20mM檸檬酸鈉 | 6.15 | 89 | 透明 | 4.534 |
20mM檸檬酸鈉 | 6.68 | 97 | 透明 | 3.662 |
20mM甘胺醯-甘胺酸 | 6.71 | 88 | 透明 | 1.859 |
20mM甘胺醯-甘胺酸 | 7.05 | 93 | 透明 | 2.025 |
表 E6. | ||||
調配物ID | 組成 | 增積劑 | 穩定劑 | 重量莫耳滲透濃度 (mOsmol/kg) |
F1 | 20 mM磷酸鈉 130 mM NaCl pH 6.8 | 否 | 否 | 300 |
F2 | 20 mM組胺酸 pH 6.5 | 否 | 否 | 39 |
F3 | 20 mM組胺酸 pH 6.5 | 9.5%海藻糖 | 否 | 325 |
F4 | 20 mM組胺酸 pH 6.5 | 9.5%海藻糖 | 20 mM脯胺酸 | 332 |
F5 | 20 mM組胺酸 pH 6.5 | 9.5%海藻糖 | 20 mM甘胺酸 | 465 |
F6 | 20 mM組胺酸 pH 6.5 | 9.5%蔗糖 | 否 | 436 |
F7 | 20 mM組胺酸 pH 6.5 | 4.5%蔗糖 + 4.5 %海藻糖 | 否 | 328 |
F8 | 20 mM組胺酸 pH 6.5 | 9.5%海藻糖 | 0.05% EDTA | 313 |
表 E7. | ||||
步驟 | 溫度 | 壓力 | 緩變率 | 乾燥之持續時間 |
冷凍 | -50℃ | 大氣壓 | 1.0℃/min | 2小時 |
初級乾燥 | -20℃ | 75 mtorr | 1.0℃/min | 22小時+緩變時間 |
次級乾燥 | +20℃ | 200 mtorr | 1.0℃/min | 7小時+緩變時間 |
表 E8. | |||||
調配物ID | 緩衝劑 | 增積劑 | 穩定劑 | pH | 界面活性劑 |
1 | 10 mM組胺酸 | 1.9%甘胺酸 | 1%海藻糖 | 6.8 | 0.01% P20 |
2 | 10 mM組胺酸 | 8.5%蔗糖 | 1%海藻糖 | 6.8 | 否 |
3 | 10 mM組胺酸 | 9.0%蔗糖 | 否 | 6.8 | 否 |
表 E9. 凍乾循環 1 。 | ||||
步驟 | 溫度 | 時間 | 緩變率 | 室壓力 |
加載 | 5℃ | N/A | N/A | N/A |
冷凍 | 5℃至-50℃ | N/A | 1℃/min | N/A |
-50℃ | 2小時 | N/A | N/A | |
退火 | -50℃至-20℃ | N/A | 1℃/min | N/A |
-20℃ | 2小時 | N/A | N/A | |
初級乾燥 | -20℃ | 1小時 | N/A | 100 mTorr |
-20℃至20℃ | N/A | 1℃/min | 100 mTorr | |
20℃ | 22.5小時 | N/A | 100 mTorr | |
次級乾燥 | 20℃至30℃ | N/A | 1℃/min | 100 mTorr |
30℃ | 10小時 | N/A | 100 mTorr |
表 E10. 凍乾循環 2 。 | ||||
步驟 | 溫度 | 時間 | 緩變率 | 室壓力 |
加載 | 5℃ | N/A | N/A | N/A |
冷凍 | 5℃至-50℃ | N/A | 1℃/min | N/A |
-50℃ | 2小時 | N/A | N/A | |
退火 | -50℃至-20℃ | N/A | 1℃/min | N/A |
-20℃ | 2小時 | N/A | N/A | |
初級乾燥 | -20℃ | 0.5小時 | N/A | 100 mTorr |
-20℃至0℃ | N/A | 1℃/min | 100 mTorr | |
0℃ | 17.5小時 | N/A | 100 mTorr | |
次級乾燥 | 0℃至25℃ | N/A | 1℃/min | 50 mTorr |
25℃ | 10小時 | N/A | 50 mTorr |
表 E11. | |||||||
形式 ID | PEG數目 | 組成/ 緩衝劑 | 增積劑 | 穩定劑 | 塑化劑 | 界面活性劑 | 螯合劑 |
P204 | 高(5) | 150 mM磷酸鈉 pH 6.8 | 4.5%蔗糖 4.5%海藻糖 | 0.5%甘胺酸 | 0.25%甘油 | 0.01% Tween 80 | 0.05% EDTA |
C204 | 低(2) | 150 mM磷酸鈉 pH 6.8 | 4.5%蔗糖 4.5%海藻糖 | 0.5%甘胺酸 | 0.25%甘油 | 0.01% Tween 80 | 0.05% EDTA |
表 E12. 儲存條件。 | |||
溫度\持續時間 | 0個月 | 1個月 | 3個月 |
2-8℃ | N/A | N/A | X |
室溫 | X | X | X |
表E13. 凍乾/ 經復原產物酶活性(IU/mg) | ||||||
P204 | C204 | |||||
溫度\時間 | 0個月 | 1個月 | 3個月 | 0個月 | 1個月 | 3個月 |
2-8℃ | N/A | N/A | 22.4 (92%) | N/A | N/A | 68.3 (96%) |
室溫 | 24.3 (100%) | 21.2 (87%) | 20.8 (86%) | 70.9 (100%) | 61.3 (86%) | 52.2 (74%) |
表E14. 每單元體一種( 或多種) 凍乾/ 經復原PEG 數目 | ||||||
P204 | C204 | |||||
溫度\時間 | 0個月 | 1個月 | 3個月 | 0個月 | 1個月 | 3個月 |
2-8℃ | N/A | N/A | 4.64 (100.2%) | N/A | N/A | 1.32 (86%) |
室溫 | 4.63 (100%) | 4.62 (99.8%) | 4.57 (98.7%) | 1.53 (100%) | 1.49 (97.4%) | 1.53 (100%) |
表 E12. | ||
調配物ID | 組成/緩衝劑 | pH |
HS | 130 mM氯化鈉、 35 mM組胺酸緩衝劑 | 6.8 |
表 E13. 凍乾產物酶活性 (IU/mg) | ||
儲存條件 | 控制冷凍產物在-70℃下儲存 | 將調配物ID HS在2-8℃下儲存 28個月 |
6.0 | 6.3 | 105 %剩餘 |
表E14. 凍乾產物每單元體一種( 或多種) PEG 數目及游離PEG | ||
測試之樣品 | PEG/單元體 | 游離PEG (mg/mL) |
對照 | 5.33 | 0.2 |
調配物ID HS | 5.51 | 0.1 |
圖 1A-1D繪示可共軛至本文所述之ADI多肽的多種半胱胺酸反應性PEG分子。
<![CDATA[<110> 開曼群島商北極星藥業集團股份有限公司(Polaris Group)]]> <![CDATA[<120> 聚乙二醇化精胺酸脫亞胺酶之調配物]]> <![CDATA[<130> POLA-007/00US 314479-2045]]> <![CDATA[<150> 62/416,607]]> <![CDATA[<151> 2016-11-02]]> <![CDATA[<160> 56 ]]> <![CDATA[<170> Pa]]>tentIn 3.5版 <![CDATA[<210> 1]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人型黴漿菌]]> <![CDATA[<400> 1]]> Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Ser Phe Val Lys Ile 50 55 60 Met Lys Asp Arg Gly Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Lys Ala Ala Lys Glu Glu Phe Ile Glu 85 90 95 Thr Phe Leu Glu Glu Thr Val Pro Val Leu Thr Glu Ala Asn Lys Lys 100 105 110 Ala Val Arg Ala Phe Leu Leu Ser Lys Pro Thr His Glu Met Val Glu 115 120 125 Phe Met Met Ser Gly Ile Thr Lys Tyr Glu Leu Gly Val Glu Ser Glu 130 135 140 Asn Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp 145 150 155 160 Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Phe Met Arg Tyr 165 170 175 Ile Val Arg Arg Arg Glu Thr Leu Phe Ala Arg Phe Val Phe Arg Asn 180 185 190 His Pro Lys Leu Val Lys Thr Pro Trp Tyr Tyr Asp Pro Ala Met Lys 195 200 205 Met Pro Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Glu Thr Leu 210 215 220 Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu Leu 225 230 235 240 Ala Lys Asn Ile Lys Ala Asn Lys Glu Val Glu Phe Lys Arg Ile Val 245 250 255 Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr Trp 260 265 270 Leu Thr Met Leu Asp Lys Asn Lys Phe Leu Tyr Ser Pro Ile Ala Asn 275 280 285 Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala Glu 290 295 300 Pro Gln Pro Gln Leu Asn Gly Leu Pro Leu Asp Lys Leu Leu Ala Ser 305 310 315 320 Ile Ile Asn Lys Glu Pro Val Leu Ile Pro Ile Gly Gly Ala Gly Ala 325 330 335 Thr Glu Met Glu Ile Ala Arg Glu Thr Asn Phe Asp Gly Thr Asn Tyr 340 345 350 Leu Ala Ile Lys Pro Gly Leu Val Ile Gly Tyr Asp Arg Asn Glu Lys 355 360 365 Thr Asn Ala Ala Leu Lys Ala Ala Gly Ile Thr Val Leu Pro Phe His 370 375 380 Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser Met 385 390 395 400 Pro Leu Ser Arg Lys Asp Val Lys Trp 405 <![CDATA[<210> 2]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> PHX8]]> <![CDATA[<400> 2]]> Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Ser Phe Val Lys Ile 50 55 60 Met Lys Asp Arg Gly Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Lys Ala Ala Lys Glu Glu Phe Ile Glu 85 90 95 Thr Phe Leu Glu Glu Thr Val Pro Val Leu Thr Glu Ala Asn Lys Glu 100 105 110 Ala Val Arg Ala Phe Leu Leu Ser Lys Pro Thr His Glu Met Val Glu 115 120 125 Phe Met Met Ser Gly Ile Thr Lys Tyr Glu Leu Gly Val Glu Ser Glu 130 135 140 Asn Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp 145 150 155 160 Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Phe Met Arg Tyr 165 170 175 Ile Val Arg Arg Arg Glu Thr Leu Phe Ala Arg Phe Val Phe Arg Asn 180 185 190 His Pro Lys Leu Val Lys Thr Pro Trp Tyr Tyr Asp Pro Ala Met Lys 195 200 205 Met Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Glu Thr Leu 210 215 220 Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu Leu 225 230 235 240 Ala Lys Asn Ile Lys Ala Asn Lys Glu Val Glu Phe Lys Arg Ile Val 245 250 255 Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr Trp 260 265 270 Leu Thr Met Leu Asp Lys Asn Lys Phe Leu Tyr Ser Pro Ile Ala Asn 275 280 285 Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala Glu 290 295 300 Pro Gln Pro Gln Leu Asn Gly Leu Pro Leu Asp Lys Leu Leu Ala Ser 305 310 315 320 Ile Ile Asn Lys Glu Pro Val Leu Ile Pro Ile Gly Gly Ala Gly Ala 325 330 335 Thr Glu Met Glu Ile Ala Arg Glu Thr Asn Phe Asp Gly Thr Asn Tyr 340 345 350 Leu Ala Ile Lys Pro Gly Leu Val Ile Gly Tyr Asp Arg Asn Glu Lys 355 360 365 Thr Asn Ala Ala Leu Lys Ala Ala Gly Ile Thr Val Leu Pro Phe His 370 375 380 Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser Met 385 390 395 400 Pro Leu Ser Arg Lys Asp Val Lys Trp 405 <![CDATA[<210> 3]]> <![CDATA[<211> 392]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 海豹腦黴漿菌]]> <![CDATA[<400> 3]]> Ile His Val Tyr Ser Glu Ile Gly Glu Leu Glu Thr Val Leu Val His 1 5 10 15 Glu Pro Gly Arg Glu Ile Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu 20 25 30 Leu Leu Phe Ser Ala Ile Leu Glu Ser His Asp Ala Arg Lys Glu His 35 40 45 Gln Ser Phe Val Lys Gln Leu Lys Asp Asn Gly Ile Asn Val Val Glu 50 55 60 Leu Thr Asp Leu Val Ala Glu Thr Phe Asp Leu Ala Ser Lys Glu Glu 65 70 75 80 Gln Glu Lys Leu Ile Glu Glu Phe Leu Glu Asp Ser Glu Pro Val Leu 85 90 95 Ser Glu Ala His Lys Thr Ala Val Arg Lys Phe Leu Thr Ser Arg Lys 100 105 110 Ser Thr Arg Glu Met Val Glu Phe Met Met Ala Gly Ile Thr Lys Tyr 115 120 125 Asp Leu Gly Ile Glu Ala Asp His Glu Leu Ile Val Asp Pro Met Pro 130 135 140 Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Val 145 150 155 160 Thr Ile His Tyr Met Arg Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe 165 170 175 Ser Arg Phe Val Phe Ser Asn His Pro Lys Leu Val Lys Thr Pro Trp 180 185 190 Tyr Tyr Asp Pro Ala Met Lys Met Ser Ile Glu Gly Gly Asp Val Phe 195 200 205 Ile Tyr Asn Asn Asp Thr Leu Val Val Gly Val Ser Glu Arg Thr Asp 210 215 220 Leu Glu Thr Ile Thr Leu Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu 225 230 235 240 Val Glu Phe Lys Arg Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn 245 250 255 Leu Met His Leu Asp Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe 260 265 270 Leu Tyr Ser Pro Ile Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp 275 280 285 Leu Val Asn Gly Gly Ala Glu Pro Gln Pro Lys Glu Asn Gly Leu Pro 290 295 300 Leu Glu Gly Leu Leu Gln Ser Ile Ile Asn Lys Lys Pro Val Leu Ile 305 310 315 320 Pro Ile Ala Gly Asn Asn Ala Ser His Ile Asp Ile Glu Arg Glu Thr 325 330 335 His Phe Asp Gly Thr Asn Tyr Leu Ala Ile Lys Pro Gly Val Val Ile 340 345 350 Gly Tyr Ala Arg Asn Glu Lys Thr Asn Ala Ala Leu Ala Ala Ala Gly 355 360 365 Ile Lys Val Leu Pro Phe His Gly Asn Gln Leu Ser Leu Gly Met Gly 370 375 380 Asn Ala Arg Cys Met Ser Met Pro 385 390 <![CDATA[<210> 4]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 精胺酸黴漿菌]]> <![CDATA[<400> 4]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu 50 55 60 Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Ile Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Val 100 105 110 Val Val Arg Asn Phe Leu Lys Ala Lys Lys Thr Ser Arg Glu Leu Val 115 120 125 Glu Ile Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser 180 185 190 Asn His Pro Lys Leu Ile Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala 290 295 300 Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln 305 310 315 320 Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Glu Gly 325 330 335 Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 5]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 關節炎黴漿菌]]> <![CDATA[<400> 5]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Lys Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Glu Phe Val Ala Glu 50 55 60 Leu Lys Lys Arg Gly Ile Asn Val Val Glu Leu Val Asp Leu Ile Val 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Lys Glu Ala Lys Glu Lys Leu Leu Glu 85 90 95 Glu Phe Leu Asp Asp Ser Val Pro Val Leu Ser Asp Glu His Arg Ala 100 105 110 Ala Val Lys Lys Phe Leu Gln Ser Gln Lys Ser Thr Arg Ser Leu Val 115 120 125 Glu Tyr Met Ile Ala Gly Ile Thr Lys His Asp Leu Lys Ile Glu Ser 130 135 140 Asp Leu Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser 180 185 190 Asn His Pro Lys Leu Val Asn Thr Pro Trp Tyr Tyr Asp Pro Ala Glu 195 200 205 Gly Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Ala Pro Gln Pro Val Asp Asn Gly Leu Pro Leu Glu Asp Leu Leu Lys 305 310 315 320 Ser Ile Ile Gly Lys Lys Pro Thr Leu Ile Pro Ile Ala Gly Ala Gly 325 330 335 Ala Ser Gln Ile Asp Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Val Ala Pro Gly Ile Val Ile Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Thr Val Leu Pro Phe 370 375 380 Arg Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys 405 <![CDATA[<210> 6]]> <![CDATA[<211> 408]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 口腔黴漿菌]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (201)..(201)]]> <![CDATA[<223> > Xaa可為任何天然存在之胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (263)..(263)]]> <![CDATA[<223> Xaa可為任何天然存在之胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (272)..(272)]]> <![CDATA[<223> Xaa可為任何天然存在之胺基酸]]> <![CDATA[<220>]]> <![CDATA[<221> misc_feature]]> <![CDATA[<222> (294)..(294)]]> <![CDATA[<223> Xaa可為任何天然存在之胺基酸]]> <![CDATA[<400> 6]]> Ser Val Phe Ser Asp Lys Phe Asn Gly Ile His Val Tyr Ser Glu Ile 1 5 10 15 Gly Asp Leu Glu Ser Val Leu Val His Glu Pro Gly Lys Glu Ile Asp 20 25 30 Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu 35 40 45 Glu Ser Thr Asp Ala Arg Lys Glu His Lys Glu Phe Val Glu Ile Leu 50 55 60 Lys Lys Gln Gly Ile Asn Val Val Glu Leu Val Asp Leu Val Val Glu 65 70 75 80 Thr Tyr Asn Leu Val Asp Lys Lys Thr Gln Glu Lys Leu Leu Lys Asp 85 90 95 Phe Leu Asp Asp Ser Glu Pro Val Leu Ser Pro Glu His Arg Lys Ala 100 105 110 Val Glu Lys Phe Leu Lys Ser Leu Lys Ser Thr Lys Glu Leu Ile Gln 115 120 125 Tyr Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Lys Ala Asp 130 135 140 Lys Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp 145 150 155 160 Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg Tyr 165 170 175 Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Lys Phe Ile Phe Thr Asn 180 185 190 His Pro Lys Leu Val Lys Thr Pro Xaa Tyr Tyr Asp Pro Ala Met Lys 195 200 205 Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr Leu 210 215 220 Val Val Gly Val Ser Glu Arg Thr Asp Leu Glu Thr Ile Thr Leu Leu 225 230 235 240 Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile Val 245 250 255 Ala Ile Asn Val Pro Lys Xaa Thr Asn Leu Met His Leu Asp Thr Xaa 260 265 270 Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala Asn 275 280 285 Asp Val Phe Lys Phe Xaa Asp Tyr Asp Leu Val Asn Gly Gly Ser Asn 290 295 300 Pro Glu Pro Val Val Asn Gly Leu Pro Leu Asp Lys Leu Leu Glu Ser 305 310 315 320 Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Lys Gly Ala 325 330 335 Thr Glu Ile Glu Thr Ala Val Glu Thr His Phe Asp Gly Thr Asn Tyr 340 345 350 Leu Ala Ile Lys Pro Gly Val Val Val Gly Tyr Ser Arg Asn Val Lys 355 360 365 Thr Asn Ala Ala Leu Glu Ala Asn Gly Ile Lys Val Leu Pro Phe Lys 370 375 380 Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser Met 385 390 395 400 Pro Leu Ser Arg Lys Asp Val Lys 405 <![CDATA[<210> 7]]> <![CDATA[<211> 391]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 貓黴漿菌]]> <![CDATA[<400> 7]]> Ile His Val Tyr Ser Glu Ile Gly Glu Leu Glu Ser Val Leu Val His 1 5 10 15 Glu Pro Gly Arg Glu Ile Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu 20 25 30 Leu Leu Phe Ser Ala Ile Leu Glu Ser His Asp Ala Arg Lys Glu His 35 40 45 Lys Leu Phe Val Ser Glu Leu Lys Ala Asn Asp Ile Asn Val Val Glu 50 55 60 Leu Thr Asp Leu Val Thr Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala 65 70 75 80 Lys Asp Asn Leu Ile Glu Glu Phe Leu Glu Asp Ser Glu Pro Val Leu 85 90 95 Thr Glu Glu Leu Lys Ser Val Val Arg Thr Tyr Leu Lys Ser Ile Lys 100 105 110 Ser Thr Arg Glu Leu Ile Gln Met Met Met Ala Gly Ile Thr Lys Tyr 115 120 125 Asp Leu Gly Ile Glu Ala Asp His Glu Leu Ile Val Asp Pro Met Pro 130 135 140 Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Val 145 150 155 160 Thr Ile His Tyr Met Arg Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe 165 170 175 Ser Arg Phe Val Phe Ser Asn His Pro Lys Leu Val Asn Thr Pro Trp 180 185 190 Tyr Tyr Asp Pro Ser Leu Lys Leu Ser Ile Glu Gly Gly Asp Val Phe 195 200 205 Ile Tyr Asn Asn Asn Thr Leu Val Val Gly Val Ser Glu Arg Thr Asp 210 215 220 Leu Glu Thr Val Thr Leu Leu Ala Lys Asn Ile Val Ala Asn Lys Glu 225 230 235 240 Cys Glu Phe Lys Arg Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn 245 250 255 Leu Met His Leu Asp Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe 260 265 270 Leu Tyr Ser Pro Ile Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp 275 280 285 Leu Val Asn Gly Gly Glu Glu Pro Gln Pro Val Glu Asn Gly Leu Pro 290 295 300 Leu Glu Gly Leu Leu Glu Ser Ile Ile Asn Lys Lys Pro Ile Leu Ile 305 310 315 320 Pro Ile Ala Gly Glu Gly Ala Ser Gln Ile Asp Ile Glu Arg Glu Thr 325 330 335 His Phe Asp Gly Thr Asn Tyr Leu Ala Ile Arg Pro Gly Val Val Ile 340 345 350 Gly Tyr Ser Arg Asn Glu Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly 355 360 365 Ile Lys Val Leu Pro Phe His Gly Asn Gln Leu Ser Leu Gly Met Gly 370 375 380 Asn Ala Arg Cys Met Ser Met 385 390 <![CDATA[<210> 8]]> <![CDATA[<211> 392]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 海豹黴漿菌]]> <![CDATA[<400> 8]]> Ile His Val Tyr Ser Glu Ile Gly Glu Leu Gln Thr Val Leu Val His 1 5 10 15 Glu Pro Gly Arg Glu Ile Glu Tyr Ile Thr Pro Ala Arg Leu Asp Glu 20 25 30 Leu Leu Phe Ser Ala Ile Leu Glu Ser His Asp Ala Arg Lys Glu His 35 40 45 Gln Glu Phe Val Ala Glu Leu Lys Lys Asn Asn Ile Asn Val Val Glu 50 55 60 Leu Thr Asp Leu Val Ser Glu Thr Tyr Asp Met Val Ser Lys Glu Lys 65 70 75 80 Gln Glu Lys Leu Ile Glu Glu Phe Leu Glu Asp Ser Glu Pro Val Leu 85 90 95 Ser Glu Glu His Lys Gly Leu Val Arg Lys Phe Leu Lys Ser Leu Lys 100 105 110 Ser Ser Lys Glu Leu Ile Gln Tyr Met Met Ala Gly Ile Thr Lys His 115 120 125 Asp Leu Asn Ile Glu Ala Asp His Glu Leu Ile Val Asp Pro Met Pro 130 135 140 Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Val 145 150 155 160 Thr Ile His Tyr Met Arg Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe 165 170 175 Ser Arg Phe Ile Phe Ala Asn His Pro Lys Leu Met Asn Thr Pro Leu 180 185 190 Tyr Tyr Asn Pro Asp Met Lys Leu Ser Ile Glu Gly Gly Asp Val Phe 195 200 205 Val Tyr Asn Asn Glu Thr Leu Val Val Gly Val Ser Glu Arg Thr Asp 210 215 220 Leu Asp Thr Ile Thr Leu Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu 225 230 235 240 Arg Glu Phe Lys Arg Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn 245 250 255 Leu Met His Leu Asp Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe 260 265 270 Leu Tyr Ser Pro Ile Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp 275 280 285 Leu Val Asn Gly Gly Asp Glu Pro Gln Pro Lys Val Asn Gly Leu Pro 290 295 300 Leu Glu Lys Leu Leu Glu Ser Ile Ile Asn Lys Lys Pro Ile Leu Ile 305 310 315 320 Pro Ile Ala Gly Thr Ser Ala Ser Asn Ile Asp Val Glu Arg Glu Thr 325 330 335 His Phe Asp Gly Thr Asn Tyr Leu Ala Ile Ala Pro Gly Val Val Ile 340 345 350 Gly Tyr Ser Arg Asn Val Lys Thr Asn Glu Ala Leu Glu Ala Ala Gly 355 360 365 Ile Lys Val Leu Pro Phe Lys Gly Asn Gln Leu Ser Leu Gly Met Gly 370 375 380 Asn Ala Arg Cys Met Ser Met Pro 385 390 <![CDATA[<210> 9]]> <![CDATA[<211> 401]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 鴿黴漿菌 ]]> <![CDATA[<400> 9]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Ile Gly Glu Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ser Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Asn Glu Ala Ile 35 40 45 Lys Glu His Lys Gly Phe Leu Lys Ile Leu Gln Asp Lys Gly Ile Lys 50 55 60 Val Ile Gln Leu Ser Asp Leu Val Ala Glu Thr Tyr Thr Tyr His Ala 65 70 75 80 Thr Gln Lys Glu Arg Glu Ala Phe Ile Glu Lys Trp Leu Asp Glu Ala 85 90 95 Glu Pro Ala Leu Thr Lys Asp Leu Arg Ala Lys Val Lys Ser Tyr Val 100 105 110 Leu Ser Lys Glu Gly Thr Pro Val Ala Met Val Arg Thr Met Met Ala 115 120 125 Gly Val Ser Lys Gln Glu Leu Asn Val Glu Ser Glu Thr Glu Leu Val 130 135 140 Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Ala Gly Asn Gly Ile Ser Leu Asn Asn Met Lys Tyr Val Thr Arg Lys 165 170 175 Arg Glu Thr Ile Phe Ala Glu Phe Ile Phe Ala Thr His Pro Asp Tyr 180 185 190 Lys Thr Thr Pro His Trp Phe Asp Arg Leu Asp Glu Gly Asn Ile Glu 195 200 205 Gly Gly Asp Val Phe Ile Tyr Asn Lys Asp Thr Leu Val Ile Gly Val 210 215 220 Ser Glu Arg Thr Asn Lys Glu Ala Ile Leu Thr Ile Ala Lys Lys Ile 225 230 235 240 Lys Asn Asn Lys Glu Ala Lys Phe Lys Lys Ile Val Ala Ile Asn Val 245 250 255 Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Val 260 265 270 Asp Lys Asp Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys 275 280 285 Val Trp Glu Ile Asp Leu Ser Lys Glu Ile Glu Met Val Glu Thr Asn 290 295 300 Lys Pro Leu Ala Asp Val Leu Glu Ser Ile Ile Gly Val Lys Pro Val 305 310 315 320 Leu Ile Pro Ile Ala Gly Lys Gly Ala Thr Gln Leu Asp Ile Asp Ile 325 330 335 Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly Val 340 345 350 Val Val Gly Tyr Ser Arg Asn Ile Lys Thr Glu Ala Ala Leu Arg Ala 355 360 365 Ala Gly Val Thr Val Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu Gly 370 375 380 Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp Val 385 390 395 400 Lys <![CDATA[<210> 10]]> <![CDATA[<211> 407]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 衣阿華黴漿菌]]> <![CDATA[<400> 10]]> Met Gly Asn Asn Ile Pro Lys Lys Ile Asn Val Phe Ser Glu Ile Gly 1 5 10 15 Asn Leu Lys Arg Val Leu Val His Thr Pro Gly Lys Glu Ile Glu Tyr 20 25 30 Val Thr Pro Gln Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Asp 35 40 45 Pro Val Arg Ala Arg Glu Glu His Lys Glu Phe Ile Lys Ile Leu Glu 50 55 60 Ser Gln Gly Val Glu Val Val Gln Leu Val Asp Leu Thr Ala Glu Thr 65 70 75 80 Tyr Asp Val Ala Glu Ser Gln Ala Lys Glu Asn Phe Ile Gln Lys Trp 85 90 95 Leu Asp Glu Ser Leu Pro Lys Leu Thr Asp Glu Asn Arg Asn Lys Val 100 105 110 Tyr Ser Leu Leu Lys Ser Leu Glu Lys Asp Pro Lys Glu Met Ile Arg 115 120 125 Lys Met Met Ser Gly Val Leu Ala Ser Glu Ile Gly Val Lys Ser Asp 130 135 140 Val Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp 145 150 155 160 Pro Phe Ala Ser Val Gly Asn Gly Ile Thr Leu His Arg Met Phe Arg 165 170 175 Pro Thr Arg Arg Arg Glu Thr Ile Phe Ala Asp Phe Ile Phe Ser Asn 180 185 190 His Pro Glu Tyr Lys Ser Thr Gln Lys Tyr Tyr Glu Arg Glu Asp Lys 195 200 205 Phe Ser Leu Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Lys Thr Leu 210 215 220 Val Val Gly Val Ser Glu Arg Thr Glu Lys Gly Ala Ile Lys Ala Leu 225 230 235 240 Ala Lys Ala Val Gln Asn Asn Ser Asn Met Ser Phe Glu Lys Ile Tyr 245 250 255 Ala Ile Asn Val Pro Lys Met Ser Asn Leu Met His Leu Asp Thr Trp 260 265 270 Leu Thr Met Leu Asp Thr Asp Lys Phe Leu Tyr Ser Pro Asn Met Met 275 280 285 Gly Val Leu Lys Ile Trp Glu Ile Asp Leu Ser Asp Lys Ser Leu Lys 290 295 300 Trp Lys Glu Ile Arg Asp Ser Leu Asp His Phe Leu Ser Thr Ile Ile 305 310 315 320 Gly Lys Lys Ala Ile Thr Val Pro Val Ala Gly Lys Asp Ala Met Gln 325 330 335 Phe Glu Ile Asp Ile Glu Thr His Phe Asp Ala Thr Asn Phe Ile Ala 340 345 350 Val Ala Pro Gly Val Val Ile Gly Tyr Asp Arg Asn Lys Lys Thr Asn 355 360 365 Glu Ala Leu Lys Glu Ala Gly Ile Lys Val Leu Ser Trp Asn Gly Asp 370 375 380 Gln Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Thr Met Pro Leu 385 390 395 400 Tyr Arg Glu Glu Leu Lys Lys 405 <![CDATA[<210> 11]]> <![CDATA[<211> 402]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 鱷魚黴漿菌]]> <![CDATA[<400> 11]]> Met Asn Lys Ile Asn Val Tyr Ser Glu Val Gly Lys Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ser Pro Ser Arg 20 25 30 Leu Glu Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Asp Ser Ala Ile 35 40 45 Glu Glu His Lys Arg Phe Leu Lys Ile Leu Glu Asp Asn Asn Ile Lys 50 55 60 Val Ile Gln Leu Asp Gln Leu Val Ala Asp Thr Tyr Glu Leu Val Asn 65 70 75 80 Pro Ser Val Arg Asp Ala Phe Ile Glu Lys Trp Leu Asn Glu Ser Glu 85 90 95 Pro Lys Leu Asp Lys Lys Leu Arg Glu Lys Val Lys Glu Tyr Leu Leu 100 105 110 His Thr Gln Lys Thr Val Gly Thr Lys Arg Met Val Arg Ile Met Met 115 120 125 Ala Gly Val Asp Arg Val Glu Leu Gly Val Glu Leu Asp Arg Gln Leu 130 135 140 Val Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala 145 150 155 160 Ser Ala Gly Asn Gly Ile Ser Leu Asn Asn Met Lys Tyr Val Thr Arg 165 170 175 Lys Arg Glu Thr Ile Phe Ser Glu Phe Ile Phe Glu Asn His Pro Asp 180 185 190 Tyr Lys Thr Thr Pro His Trp Phe Asp Arg Leu Asp Lys Gly Asn Ile 195 200 205 Glu Gly Gly Asp Val Phe Ile Tyr Asn Arg Thr Thr Leu Val Ile Gly 210 215 220 Ile Ser Glu Arg Thr Asn Lys Asp Ala Leu Leu Thr Ile Ala Asn Asn 225 230 235 240 Ile Lys Ser Asn Lys Glu Ser Lys Phe Glu Arg Ile Val Ala Val Asn 245 250 255 Val Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met 260 265 270 Val Asp His Asp Lys Phe Leu Tyr Ser Pro Asn Met Met Lys Thr Leu 275 280 285 Lys Phe Trp Thr Ile Asp Leu Thr Lys Pro Ile Lys Met Val Glu Leu 290 295 300 Glu Glu Ser Leu Ser Asp Met Ile Glu Thr Ile Ile Gly Lys Lys Pro 305 310 315 320 Val Leu Ile Pro Ile Ala Gly His Asp Ala Ser Pro Leu Asp Val Asp 325 330 335 Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly 340 345 350 Val Val Val Gly Tyr Ser Arg Asn Lys Leu Thr Glu Lys Ala Leu Thr 355 360 365 Lys Ala Gly Val Lys Val Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu 370 375 380 Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp 385 390 395 400 Ile Lys <![CDATA[<210> 12]]> <![CDATA[<211> 430]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 發酵黴漿菌]]> <![CDATA[<400> 12]]> Met Gln Ile Ile Ala Lys Ile Asp Leu Leu Thr Asn Met Leu Ile Phe 1 5 10 15 Met Lys Ile Tyr Phe Ile Gly Arg Leu Ile Met Lys Lys Ile Asn Val 20 25 30 Tyr Ser Glu Tyr Gly Lys Leu Lys Glu Val Leu Val His Thr Pro Gly 35 40 45 Asp Glu Ile Arg Arg Ile Ala Pro Ser Arg Leu Asp Glu Leu Leu Phe 50 55 60 Ser Ala Ile Leu Glu Pro Asp Ser Ala Ile Ala Glu His Lys Arg Phe 65 70 75 80 Val Gln Leu Leu Lys Asp Asn Gly Ile Lys Val Ile Gln Leu Asp Glu 85 90 95 Leu Phe Ala Lys Thr Phe Asp Leu Val Ser Glu Ser Val Lys Gln Ser 100 105 110 Leu Ile Glu Arg Trp Leu Asp Glu Cys Glu Pro Lys Leu Asp Ala Thr 115 120 125 Leu Arg Ala Lys Val Lys Glu Tyr Ile Leu Glu Leu Lys Ala Lys Ser 130 135 140 Ser Lys Lys Met Val Arg Val Met Met Ala Gly Ile Asp Lys Lys Glu 145 150 155 160 Leu Gly Ile Glu Leu Asp Arg Asp Leu Val Val Asp Pro Met Pro Asn 165 170 175 Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Ile Ser 180 185 190 Leu His His Met Lys Tyr Val Thr Arg Gln Arg Glu Thr Ile Phe Ser 195 200 205 Glu Phe Ile Phe Asp Asn Asn Leu Asp Tyr Asn Thr Val Pro Arg Trp 210 215 220 Phe Asp Arg Lys Asp Glu Gly Arg Ile Glu Gly Gly Asp Val Phe Ile 225 230 235 240 Tyr Ser Ala Asp Thr Leu Val Val Gly Val Ser Glu Arg Thr Asn Lys 245 250 255 Glu Ala Ile Asn Val Met Ala Arg Lys Ile Ala Ala Asp Lys Glu Val 260 265 270 Lys Phe Lys Arg Ile Tyr Ala Ile Asn Val Pro Pro Met Pro Asn Leu 275 280 285 Met His Leu Asp Thr Trp Leu Thr Met Leu Asp Lys Asn Lys Phe Leu 290 295 300 Tyr Ser Pro Asn Met Leu Ser Val Leu Lys Val Trp Arg Ile Asp Leu 305 310 315 320 Asn Asp Pro Asp Phe Val Trp His Glu Ile Glu Gly Ser Leu Glu Glu 325 330 335 Ile Leu Glu Gln Ile Ile Gly Met Lys Pro Ile Leu Ile Pro Ile Ala 340 345 350 Gly Lys Gly Ala Ser Gln Leu Asp Ile Asp Ile Glu Thr His Phe Asp 355 360 365 Gly Thr Asn Tyr Leu Thr Ile Ala Pro Ser Val Val Val Gly Tyr Ser 370 375 380 Arg Asn Glu Lys Thr Glu Lys Ala Leu Lys Ala Ala Lys Val Lys Val 385 390 395 400 Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu Gly Met Gly Ser Ala Arg 405 410 415 Cys Met Ser Met Pro Leu Ile Arg Glu Asp Ile Lys Lys Lys 420 425 430 <![CDATA[<210> 13]]> <![CDATA[<211> 452]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 滲透黴漿菌]]> <![CDATA[<400> 13]]> Met Val Ile Thr Ile Ala Leu Asn Ile Leu Asn Lys Ile Tyr Phe Lys 1 5 10 15 Pro Gln Asn Arg Ser Ile Leu Lys Leu Tyr Arg Leu Pro Ser Leu Cys 20 25 30 Thr Gln Ile Ser Ile Phe Ile Gly Gly Lys Met Ser Ser Ile Asp Lys 35 40 45 Asn Ser Leu Gly Asn Gly Ile Asn Val Tyr Ser Glu Ile Gly Glu Leu 50 55 60 Lys Glu Val Leu Val His Thr Pro Gly Asp Glu Ile Arg Tyr Thr Ala 65 70 75 80 Pro Ser Arg Leu Glu Glu Leu Leu Phe Ser Ala Val Leu Lys Ala Asp 85 90 95 Thr Ala Ile Glu Glu His Lys Gly Phe Val Lys Ile Leu Gln Asn Asn 100 105 110 Gly Ile Lys Val Ile Gln Leu Cys Asp Leu Val Ala Glu Thr Tyr Glu 115 120 125 Leu Cys Ser Lys Glu Val Arg Asn Ser Phe Ile Glu Gln Tyr Leu Asp 130 135 140 Glu Ala Leu Pro Val Leu Lys Lys Glu Ile Arg Pro Val Val Lys Asp 145 150 155 160 Tyr Leu Leu Ser Phe Pro Thr Val Gln Met Val Arg Lys Met Met Ser 165 170 175 Gly Ile Leu Ala Asn Glu Leu Asn Ile Lys Gln Asp Asn Pro Leu Ile 180 185 190 Ile Asp Gly Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 195 200 205 Met Gly Asn Gly Val Ser Ile Asn Cys Met Lys Tyr Pro Thr Arg Lys 210 215 220 Arg Glu Val Ile Phe Ser Arg Phe Val Phe Thr Asn Asn Pro Lys Tyr 225 230 235 240 Lys Asn Thr Pro Arg Tyr Phe Asp Ile Val Gly Asn Asn Gly Thr Ile 245 250 255 Glu Gly Gly Asp Ile Phe Ile Tyr Asn Ser Lys Thr Leu Val Ile Gly 260 265 270 Asn Ser Glu Arg Thr Asn Phe Ala Ala Ile Glu Ser Val Ala Lys Asn 275 280 285 Ile Gln Ala Asn Lys Asp Cys Thr Phe Glu Arg Ile Val Val Ile Asn 290 295 300 Val Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met 305 310 315 320 Leu Asp Tyr Asp Lys Phe Leu Tyr Ser Pro Asn Met Met Asn Val Leu 325 330 335 Lys Ile Trp Glu Ile Asp Leu Asn Val Lys Pro Val Lys Phe Val Glu 340 345 350 Lys Lys Gly Thr Leu Glu Glu Val Leu Tyr Ser Ile Ile Asp Lys Lys 355 360 365 Pro Ile Leu Ile Pro Ile Ala Gly Lys Gly Ala Asn Gln Leu Asp Ile 370 375 380 Asp Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro 385 390 395 400 Gly Val Val Val Gly Tyr Glu Arg Asn Glu Lys Thr Gln Lys Ala Leu 405 410 415 Val Glu Ala Gly Ile Lys Val Leu Ser Phe Asn Gly Ser Gln Leu Ser 420 425 430 Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Ile Arg Glu 435 440 445 Asn Leu Lys Lys 450 <![CDATA[<210> 14]]> <![CDATA[<211> 403]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 雞毒黴漿菌]]> <![CDATA[<400> 14]]> Met Phe Asn Lys Ile Arg Val Tyr Ser Glu Ile Gly Lys Leu Arg Lys 1 5 10 15 Val Leu Val His Thr Pro Gly Lys Glu Leu Asp Tyr Val Thr Pro Gln 20 25 30 Arg Leu Asp Glu Leu Leu Phe Ser Ser Leu Leu Asn Pro Ile Lys Ala 35 40 45 Arg Gln Glu His Glu Thr Phe Ile Lys Leu Leu Glu Asp His Asp Val 50 55 60 Glu Cys Val Gln Leu Ser Thr Leu Thr Ala Gln Thr Phe Gln Ala Val 65 70 75 80 Asn Ser Lys Ile Gln Glu Glu Phe Ile Asn Arg Trp Leu Asp Glu Cys 85 90 95 Leu Pro Val Leu Ser Glu Ile Asn Arg Leu Lys Val Tyr Asp Tyr Leu 100 105 110 Lys Ser Leu Ala Thr Asn Pro Gln Val Met Ile Arg Lys Met Met Ser 115 120 125 Gly Ile Leu Ala Lys Glu Val Gly Ile Gln Ser Glu Val Glu Leu Val 130 135 140 Ala Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Ile Gly Lys Gly Ile Thr Leu His Ser Met Phe His Pro Thr Arg Lys 165 170 175 Arg Glu Thr Ile Phe Ala Asp Phe Ile Phe Ser His His Pro Glu Tyr 180 185 190 Lys Asn Ala Pro Lys Tyr Tyr Ser Arg Glu Asp Lys Tyr Ser Ile Glu 195 200 205 Gly Gly Asp Leu Phe Val Tyr Asp Asp Lys Thr Leu Val Ile Gly Val 210 215 220 Ser Glu Arg Thr Glu Lys Lys Ala Ile Gln Ser Leu Ala Glu Lys Leu 225 230 235 240 Arg Gln Asn Asp Glu Thr Ser Phe Glu Lys Ile Tyr Ala Ile Asn Val 245 250 255 Pro Lys Met Ser Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Leu 260 265 270 Asp Tyr Asp Lys Phe Leu Tyr Ser Pro Asn Met Met Gly Val Leu Lys 275 280 285 Ile Trp Glu Ile Asp Leu Ile His Pro Thr Leu Ile Trp Arg Glu Leu 290 295 300 Asn Glu Ser Leu Glu Gly Phe Leu Ser Met Val Ile Gly Lys Lys Ala 305 310 315 320 Thr Leu Ile Pro Val Ala Gly Glu Asp Ser Thr Gln Ile Glu Ile Asp 325 330 335 Val Glu Thr Asn Phe Asp Ala Thr Asn Phe Leu Val Ile Gln Pro Gly 340 345 350 Val Val Val Gly Tyr Asp Arg Asn Tyr Lys Thr Asn Gln Ala Leu Arg 355 360 365 Asp Ala Gly Val Lys Val Ile Ser Trp Asn Gly Asp Gln Leu Ser Leu 370 375 380 Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Tyr Arg Asp Pro 385 390 395 400 Ile Lys Lys <![CDATA[<210> 15]]> <![CDATA[<211> 402]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 短吻鱷黴漿菌]]> <![CDATA[<400> 15]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Val Gly Arg Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ser Pro Thr Arg 20 25 30 Leu Glu Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Asp Thr Ala Ile 35 40 45 Glu Glu His Lys Arg Phe Leu Asn Val Leu Glu Lys Asn Gly Ile Lys 50 55 60 Ala Ile Gln Leu Asp Glu Leu Val Ala Gln Thr Tyr Asp Gln Val Asp 65 70 75 80 Gln Lys Ile Lys Asp Glu Phe Ile Asp Gln Trp Leu Gln Glu Ala Lys 85 90 95 Pro Val Leu Asn Asp Gln Leu Lys Lys Leu Val Lys Asn Tyr Leu Leu 100 105 110 Lys Ser Gln Lys Glu Phe Ser Thr Lys Lys Met Val Arg Ile Met Met 115 120 125 Ala Gly Ile Asp Lys Lys Glu Ile Asn Ile Asp Leu Asp Arg Asp Leu 130 135 140 Val Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala 145 150 155 160 Ser Val Gly Asn Gly Ile Ser Leu His Asn Met Lys Tyr Gln Thr Arg 165 170 175 Lys Arg Glu Thr Ile Phe Ala Gln Phe Ile Phe Lys Tyr Asn Lys Asp 180 185 190 Tyr Lys Thr Thr Pro His Trp Phe Asp Arg Phe Asp His Gly Ser Ile 195 200 205 Glu Gly Gly Asp Val Phe Val Tyr Thr Lys Asp Thr Leu Val Ile Gly 210 215 220 Ile Ser Glu Arg Thr Thr Lys Glu Ala Val Leu Asn Ile Ala Lys Lys 225 230 235 240 Ile Lys Ala Asn Thr Asp Ser Lys Phe Lys Lys Ile Val Ala Ile Asn 245 250 255 Val Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Ile Thr Met 260 265 270 Val Asp His Asp Lys Phe Leu Tyr Ser Pro Asn Met Met Lys Ser Leu 275 280 285 Lys Phe Trp Leu Ile Asp Leu Ser Lys Glu Ile Lys Met Val Glu Leu 290 295 300 Glu Glu Ser Leu Ser Asn Met Leu Glu Ala Ile Ile Gly Lys Lys Pro 305 310 315 320 Ile Leu Ile Pro Ile Ala Gly Lys Asn Ala Ser Gln Leu Asp Ile Asp 325 330 335 Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly 340 345 350 Val Val Val Gly Tyr Ser Arg Asn Lys Leu Thr Gln Lys Ala Leu Glu 355 360 365 Asp Ala Gly Val Lys Val Leu Ser Phe Asp Gly Asn Gln Leu Ser Leu 370 375 380 Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp 385 390 395 400 Ile Lys <![CDATA[<210> 16]]> <![CDATA[<211> 438]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 肺炎黴漿菌]]> <![CDATA[<400> 16]]> Met Ser Lys Lys Gln Leu Val Lys Thr Asp Gly His Asn Gln Leu Asp 1 5 10 15 Gln Pro Asn Thr Lys Ala Leu Gln Leu Lys Lys Lys Gln Phe Asn Ser 20 25 30 Gly Val Arg Val Thr Ser Glu Ile Ser Phe Leu Arg Glu Val Ile Ala 35 40 45 His His Pro Gly Ile Glu Thr Glu Arg Val Ile Asp Asn Gln Thr Phe 50 55 60 Gly Ser Ala Met Tyr Leu Glu Arg Ala Gln Lys Glu His Gln Leu Phe 65 70 75 80 Ile Lys Ile Leu Arg Gln His Gly Thr Lys Val His Tyr Leu Gln Asp 85 90 95 Leu Leu Leu Glu Ala Leu Ser Ala Ala Asp Pro Asn Val Arg Gln Asp 100 105 110 Phe Ile Lys Asn Phe Leu Leu Glu Ser Gly Ile Lys Ser Val Ser Thr 115 120 125 Phe Glu Ala Cys Leu Asn Phe Phe Arg Ser Leu Asp Ser Leu Val Asp 130 135 140 Val Ile Lys Val Met Phe Gly Gly Ile Lys Val Ser Asp Val Pro Pro 145 150 155 160 Ile Thr Pro Gln Arg Phe Ala Asp Ile His Val Ser Asn Ser Pro Phe 165 170 175 Leu Ile Lys Pro Leu Ser Phe Ser Leu Tyr Pro His Lys Phe Phe Asn 180 185 190 Thr Leu Gly Thr Gly Val Ala Leu Phe Val Thr Asn Asp Ser Glu Leu 195 200 205 Lys Arg His Ser Leu Val Tyr Glu Tyr Ile Met Arg Phe His Pro Arg 210 215 220 Phe Asp Gly Val Lys Leu Tyr Thr Asn Arg Asp Phe Lys Asn Cys Leu 225 230 235 240 Ile Asn Ser Ser Asp Ile Ile Gln Ile Ser Asn Glu Ile Leu Leu Ile 245 250 255 Gly Ile Ser His Asp Thr Asp Val Leu Gly Ile Glu Ser Leu Ala Arg 260 265 270 Asn Leu Leu Ser Asp His Thr Asn Pro Ile Lys Gln Ile Ile Ala Ile 275 280 285 Asn Ile His Lys Phe Gly Ala Lys Thr Asn Leu Asn Lys Leu Ile Ala 290 295 300 Met Val Asp Val Asp Lys Phe Ile Ile Ala Arg Lys Val Leu Gln Ala 305 310 315 320 Thr Glu Ile Phe Glu Leu Thr Ala Thr Ala Gln Arg Asp Val Asp Gly 325 330 335 Leu Ala Gln Ile Lys Phe Lys Pro Leu Lys Phe Asn Phe Gly Glu Ile 340 345 350 Ile Glu Ala Ile Ile Asp Lys Gln Pro Arg Phe Val Ile Ile Gly Gly 355 360 365 Gly Asp Glu Val Ala Glu Arg Lys Glu Leu Leu Asp Cys Gly Met Gly 370 375 380 Val Leu Asn Leu Ser Pro Gly Glu Ile Val Val Phe Asp Arg Asn His 385 390 395 400 Tyr Thr Asn Asn Leu Leu Asn Glu Leu Gly Leu Ile Ile His Lys Ile 405 410 415 Pro Ala Ser Glu Leu Ser Arg Gly Pro Ser Gly Pro Leu Glu Met Val 420 425 430 Cys Ser Leu Trp Arg Glu 435 <![CDATA[<210> 17]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 運動黴漿菌]]> <![CDATA[<400> 17]]> Met Lys Asp Thr Lys Asp Ile Ile Asn Val Phe Ser Glu Ile Gly Glu 1 5 10 15 Leu Lys Lys Val Leu Ile His Thr Pro Gly Asn Glu Leu Lys Tyr Val 20 25 30 Ser Pro Tyr Arg Leu Asp Glu Leu Leu Phe Ser Asn Val Leu Glu Trp 35 40 45 Arg Glu Ala Lys Lys Glu His Asn Glu Phe Ile Gln Lys Leu Lys Ser 50 55 60 Glu Gly Val Glu Pro Val Glu Leu Thr Asp Leu Val Ala Glu Ser Phe 65 70 75 80 Glu Glu Ser Ser Ile Lys Val Lys Asn Asp Phe Ile Arg Gln Tyr Leu 85 90 95 Asp Glu Ala Thr Pro Ile Leu Asp Gly Leu Thr Lys Gln Lys Leu Leu 100 105 110 Pro Phe Phe Leu Asp Ile Lys His Ser Thr Arg Lys Thr Ile Glu Leu 115 120 125 Met Met Ser Gly Ile Thr Gln Lys Asp Ile Ser Ile Ser His Ile Glu 130 135 140 Arg Glu Leu Ile Ile Asp Pro Met Pro Asn Leu Tyr Phe Ser Arg Asp 145 150 155 160 Asn Phe Ile Ser Ile Gly Asn Ser Val Ile Ile Ser Asn Met Lys Tyr 165 170 175 Lys Thr Arg Lys Arg Glu Thr Ile Phe Thr Asp Phe Ile Phe Lys Asn 180 185 190 His Pro Leu Tyr Lys Lys Val Asn Met Ala Phe Glu Arg Lys Asp Leu 195 200 205 Asn Asn Gln Ile Ser Ile Ile Glu Gly Gly Asp Val Leu Val Tyr Ser 210 215 220 Lys Glu Ile Leu Ile Ile Gly Ile Ser Glu Arg Thr Thr Met Ser Ala 225 230 235 240 Ile Leu Glu Leu Ala Glu Asn Phe Lys Lys Thr Lys Arg Ser Phe Lys 245 250 255 Lys Ile Tyr Gly Val Glu Val Pro Lys Met Lys Asn Leu Met His Leu 260 265 270 Asp Thr Trp Leu Thr Met Ile Asp Tyr Asp Lys Phe Ile Tyr Ser Pro 275 280 285 Asn Val Leu Thr Asp Leu Lys Phe Trp Glu Ile Asn Leu Asp Tyr Glu 290 295 300 Lys Ile Ser Ser Lys Glu Leu His Ala Ser Leu Ser Glu Phe Leu Lys 305 310 315 320 Leu Ile Ile Gly Lys Asp Pro Ile Leu Ile Pro Ile Gly Gly Lys Gly 325 330 335 Ala Ser Gln Ile Thr Ile Asp Ile Glu Thr Asn Phe Val Ala Ala Asn 340 345 350 Tyr Leu Val Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Tyr 355 360 365 Glu Thr Gln Lys Ala Leu Glu Gly His Gly Val Lys Val Ile Ala Phe 370 375 380 Glu Gly Asn Gln Leu Ser Leu Gly Met Gly Ser Ser Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ile Arg Ser Asn Leu Lys 405 <![CDATA[<210> 18]]> <![CDATA[<211> 411]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 化膿性鏈球菌]]> <![CDATA[<400> 18]]> Met Thr Ala Gln Thr Pro Ile His Val Tyr Ser Glu Ile Gly Lys Leu 1 5 10 15 Lys Lys Val Leu Leu His Arg Pro Gly Lys Glu Ile Glu Asn Leu Met 20 25 30 Pro Asp Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Glu 35 40 45 Asp Ala Gln Lys Glu His Asp Ala Phe Ala Gln Ala Leu Arg Asp Glu 50 55 60 Gly Ile Glu Val Leu Tyr Leu Glu Thr Leu Ala Ala Glu Ser Leu Val 65 70 75 80 Thr Pro Glu Ile Arg Glu Ala Phe Ile Asp Glu Tyr Leu Ser Glu Ala 85 90 95 Asn Ile Arg Gly Arg Ala Thr Lys Lys Ala Ile Arg Glu Leu Leu Met 100 105 110 Ala Ile Glu Asp Asn Gln Glu Leu Ile Glu Lys Thr Met Ala Gly Val 115 120 125 Gln Lys Ser Glu Leu Pro Glu Ile Pro Ala Ser Glu Lys Gly Leu Thr 130 135 140 Asp Leu Val Glu Ser Asn Tyr Pro Phe Ala Ile Asp Pro Met Pro Asn 145 150 155 160 Leu Tyr Phe Thr Arg Asp Pro Phe Ala Thr Ile Gly Thr Gly Val Ser 165 170 175 Leu Asn His Met Phe Ser Glu Thr Arg Asn Arg Glu Thr Leu Tyr Gly 180 185 190 Lys Tyr Ile Phe Thr His His Pro Ile Tyr Gly Gly Gly Lys Val Pro 195 200 205 Met Val Tyr Asp Arg Asn Glu Thr Thr Arg Ile Glu Gly Gly Asp Glu 210 215 220 Leu Val Leu Ser Lys Asp Val Leu Ala Val Gly Ile Ser Gln Arg Thr 225 230 235 240 Asp Ala Ala Ser Ile Glu Lys Leu Leu Val Asn Ile Phe Lys Gln Asn 245 250 255 Leu Gly Phe Lys Lys Val Leu Ala Phe Glu Phe Ala Asn Asn Arg Lys 260 265 270 Phe Met His Leu Asp Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe 275 280 285 Thr Ile His Pro Glu Ile Glu Gly Asp Leu Arg Val Tyr Ser Val Thr 290 295 300 Tyr Asp Asn Glu Glu Leu His Ile Val Glu Glu Lys Gly Asp Leu Ala 305 310 315 320 Glu Leu Leu Ala Ala Asn Leu Gly Val Glu Lys Val Asp Leu Ile Arg 325 330 335 Cys Gly Gly Asp Asn Leu Val Ala Ala Gly Arg Glu Gln Trp Asn Asp 340 345 350 Gly Ser Asn Thr Leu Thr Ile Ala Pro Gly Val Val Val Val Tyr Asn 355 360 365 Arg Asn Thr Ile Thr Asn Ala Ile Leu Glu Ser Lys Gly Leu Lys Leu 370 375 380 Ile Lys Ile His Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg 385 390 395 400 Cys Met Ser Met Pro Phe Glu Arg Glu Asp Ile 405 410 <![CDATA[<210> 19]]> <![CDATA[<211> 408]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 糞腸球菌]]> <![CDATA[<400> 19]]> Met Ser His Pro Ile Asn Val Phe Ser Glu Ile Gly Lys Leu Lys Thr 1 5 10 15 Val Met Leu His Arg Pro Gly Lys Glu Leu Glu Asn Leu Met Pro Asp 20 25 30 Tyr Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Phe Leu Glu Lys Ala 35 40 45 Gln Ala Glu His Asp Ala Phe Ala Glu Leu Leu Arg Ser Lys Asp Ile 50 55 60 Glu Val Val Tyr Leu Glu Asp Leu Ala Ala Glu Ala Leu Ile Asn Glu 65 70 75 80 Glu Val Arg Arg Gln Phe Ile Asp Gln Phe Leu Glu Glu Ala Asn Ile 85 90 95 Arg Ser Glu Ser Ala Lys Glu Lys Val Arg Glu Leu Met Leu Glu Ile 100 105 110 Asp Asp Asn Glu Glu Leu Ile Gln Lys Ala Ile Ala Gly Ile Gln Lys 115 120 125 Gln Glu Leu Pro Lys Tyr Glu Gln Glu Phe Leu Thr Asp Met Val Glu 130 135 140 Ala Asp Tyr Pro Phe Ile Ile Asp Pro Met Pro Asn Leu Tyr Phe Thr 145 150 155 160 Arg Asp Asn Phe Ala Thr Met Gly His Gly Ile Ser Leu Asn His Met 165 170 175 Tyr Ser Val Thr Arg Gln Arg Glu Thr Ile Phe Gly Gln Tyr Ile Phe 180 185 190 Asp Tyr His Pro Arg Phe Ala Gly Lys Glu Val Pro Arg Val Tyr Asp 195 200 205 Arg Ser Glu Ser Thr Arg Ile Glu Gly Gly Asp Glu Leu Ile Leu Ser 210 215 220 Lys Glu Val Val Ala Ile Gly Ile Ser Gln Arg Thr Asp Ala Ala Ser 225 230 235 240 Ile Glu Lys Ile Ala Arg Asn Ile Phe Glu Gln Lys Leu Gly Phe Lys 245 250 255 Asn Ile Leu Ala Phe Asp Ile Gly Glu His Arg Lys Phe Met His Leu 260 265 270 Asp Thr Val Phe Thr Met Ile Asp Tyr Asp Lys Phe Thr Ile His Pro 275 280 285 Glu Ile Glu Gly Gly Leu Val Val Tyr Ser Ile Thr Glu Lys Ala Asp 290 295 300 Gly Asp Ile Gln Ile Thr Lys Glu Lys Asp Thr Leu Asp Asn Ile Leu 305 310 315 320 Cys Lys Tyr Leu His Leu Asp Asn Val Gln Leu Ile Arg Cys Gly Ala 325 330 335 Gly Asn Leu Thr Ala Ala Ala Arg Glu Gln Trp Asn Asp Gly Ser Asn 340 345 350 Thr Leu Ala Ile Ala Pro Gly Glu Val Val Val Tyr Asp Arg Asn Thr 355 360 365 Ile Thr Asn Lys Ala Leu Glu Glu Ala Gly Val Lys Leu Asn Tyr Ile 370 375 380 Pro Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg Cys Met Ser 385 390 395 400 Met Pro Leu Tyr Arg Glu Asp Leu 405 <![CDATA[<210> 20]]> <![CDATA[<211> 403]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 山羊黴漿菌]]> <![CDATA[<400> 20]]> Met Glu Lys Lys Ile Asn Val Phe Ser Glu Ile Gly Thr Leu Lys Thr 1 5 10 15 Val Leu Val His Arg Pro Gly Asp Glu Ile Glu Asn Leu Thr Pro Glu 20 25 30 Leu Leu Glu Arg Leu Leu Phe Asp Asp Val Pro Phe Lys Asp Val Ala 35 40 45 Val Lys Glu His Asp Ala Phe Thr Lys Ile Met Arg Asp Asn Gly Val 50 55 60 Glu Val Leu Tyr Ile Glu Lys Leu Ala Ala Glu Thr Leu Asp Gln His 65 70 75 80 Pro Asp Leu Arg Glu Lys Phe Ile Asp Gln Phe Ile Ser Glu Ala Asn 85 90 95 Ile Glu Asp Lys Tyr Lys Glu Lys Tyr Arg Asp Phe Ile Ser Ser Leu 100 105 110 Asp Asn Tyr Arg Met Ile Lys Lys Met Ile Ala Gly Thr Lys Lys Leu 115 120 125 Glu Leu Gly Ile Asp Glu Gly Tyr Lys Ala Tyr Pro Phe Ile Ala Asp 130 135 140 Pro Leu Pro Asn Val Leu Phe Gln Arg Asp Pro Phe Ser Ser Val Gly 145 150 155 160 Phe Gly Ile Thr Met Asn Arg Met Trp Ser Val Thr Arg Asn Arg Glu 165 170 175 Thr Ile Phe Pro Asp Leu Val Phe Lys His His Asn Arg Phe Ala Asn 180 185 190 Gln Val Pro Tyr Tyr Tyr Glu Arg Asp Trp Lys Glu Glu Thr Ile Glu 195 200 205 Gly Gly Asp Ile Leu Val Leu Asn Lys Glu Thr Leu Ile Ile Gly Val 210 215 220 Thr Gln Arg Thr Thr Leu Lys Ala Ile Glu Lys Phe Ser Glu Arg Leu 225 230 235 240 Phe Asn Asp Pro Glu Ser Ser Tyr Ser Lys Val Ile Ala Leu Asp Leu 245 250 255 Pro Lys Ser Arg Ala Phe Met His Leu Asp Thr Val Phe Thr Asn Ile 260 265 270 Asp Tyr Asp Lys Phe Ile Ala His Pro Leu Ile Phe Asp Cys Ile Asp 275 280 285 Glu Phe Lys Ile Tyr Glu Val Ser Lys Gln Gly Thr Lys Glu Val Lys 290 295 300 Lys Thr Leu Ile Glu Leu Leu Ser Asp Ala Ala Gly Arg Glu Val Gln 305 310 315 320 Ile Ile Arg Cys Gly Gly Asn Asp Val Val Gly Ala Ser Arg Glu Gln 325 330 335 Trp Asn Asp Gly Thr Asn Val Val Ala Leu Arg Pro Gly Lys Val Ile 340 345 350 Ala Tyr Glu Arg Asn Trp Ile Thr Ile Asp Leu Leu Arg Lys Ala Gly 355 360 365 Val Glu Val Leu Thr Ile Ala Ser Ser Glu Leu Ser Arg Gly Arg Gly 370 375 380 Gly Pro Arg Cys Met Thr Met Pro Leu Trp Arg Glu Asp Leu Gln Glu 385 390 395 400 Ile Lys Arg <![CDATA[<210> 21]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 奧氏嗜熱鹽絲菌]]> <![CDATA[<400> 21]]> Met Phe Lys Lys Ser Pro Leu Asn Val Thr Ser Glu Ile Gly Lys Leu 1 5 10 15 Lys Lys Val Leu Leu His Arg Pro Gly His Glu Ile Glu Asn Leu Thr 20 25 30 Pro Asp Leu Leu Glu Arg Leu Leu Phe Asp Asp Ile Pro Tyr Leu Lys 35 40 45 Val Ala Gln Glu Glu His Asp Ala Phe Ala Gln Thr Leu Arg Asp Asn 50 55 60 Gly Val Glu Val Leu Tyr Leu His Glu Leu Ala Ala Glu Ala Ile Gln 65 70 75 80 Glu Asp Glu Ile Arg Lys Lys Phe Ile Glu Gln Phe Leu Asp Glu Ala 85 90 95 Gly Val Ile Gly Lys Gly Ala Arg Gln Val Leu Lys Glu Tyr Phe Ala 100 105 110 Asp Met Asp Asn Glu Thr Leu Ile Arg Lys Met Met Ala Gly Val Arg 115 120 125 Lys Lys Glu Ile Pro Ala Ile Glu Lys Val Ala Ser Leu Asn Asp Met 130 135 140 Val Glu Glu Asp Tyr Pro Phe Val Leu Asp Pro Met Pro Asn Leu Tyr 145 150 155 160 Phe Thr Arg Asp Pro Phe Ala Thr Ile Gly Thr Gly Ile Thr Leu Asn 165 170 175 His Met Arg Thr Glu Thr Arg Asn Arg Glu Val Ile Phe Ala Glu Tyr 180 185 190 Ile Phe Ser Tyr His Pro Asp Phe Lys Asp Thr Glu Ile Pro Phe Trp 195 200 205 Phe Asp Arg Asn Glu Thr Thr Ser Ile Glu Gly Gly Asp Glu Leu Ile 210 215 220 Leu Ser Asp Lys Val Leu Ala Met Gly Ile Ser Glu Arg Thr Asp Ala 225 230 235 240 Ala Ser Ile Glu Lys Val Ala Arg Asn Ile Phe Thr Asp Gly Gln Pro 245 250 255 Phe Glu Thr Ile Leu Ala Phe Lys Ile Pro Glu Lys Arg Ala Phe Met 260 265 270 His Leu Asp Thr Val Phe Thr Met Val Asp Tyr Asp Lys Phe Thr Ile 275 280 285 His Ala Glu Ile Glu Gly Pro Leu Lys Val Tyr Ser Ile Thr Lys Gly 290 295 300 Asp Asn Asp Glu Leu Lys Ile Asp Glu Glu Lys Ala Thr Leu Glu Asp 305 310 315 320 Thr Leu Lys Lys Tyr Leu Gly Leu Asp Glu Val Thr Leu Ile Arg Cys 325 330 335 Ala Gly Gly Asp Tyr Ile Asp Ala Gly Arg Glu Gln Trp Asn Asp Gly 340 345 350 Ser Asn Thr Leu Ala Ile Ala Pro Gly Glu Val Val Val Tyr Asn Arg 355 360 365 Asn His Thr Thr Asn Arg Leu Leu Glu Glu His Gly Ile Lys Leu His 370 375 380 Val Ile Pro Ser Ser Glu Leu Ser Arg Gly Arg Gly Gly Pro Arg Cys 385 390 395 400 Met Ser Met Pro Leu Val Arg Glu Asp Ile 405 410 <![CDATA[<210> 22]]> <![CDATA[<211> 411]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 金黃色葡萄球菌]]> <![CDATA[<400> 22]]> Met Thr Asp Gly Pro Ile Lys Val Asn Ser Glu Ile Gly Ala Leu Lys 1 5 10 15 Thr Val Leu Leu Lys Arg Pro Gly Lys Glu Leu Glu Asn Leu Val Pro 20 25 30 Asp Tyr Leu Asp Gly Leu Leu Phe Asp Asp Ile Pro Tyr Leu Glu Val 35 40 45 Ala Gln Lys Glu His Asp His Phe Ala Gln Val Leu Arg Glu Glu Gly 50 55 60 Val Glu Val Leu Tyr Leu Glu Lys Leu Ala Ala Glu Ser Ile Glu Asn 65 70 75 80 Pro Gln Val Arg Ser Glu Phe Ile Asp Asp Val Leu Ala Glu Ser Lys 85 90 95 Lys Thr Ile Leu Gly His Glu Glu Glu Ile Lys Ala Leu Phe Ala Thr 100 105 110 Leu Ser Asn Gln Glu Leu Val Asp Lys Ile Met Ser Gly Val Arg Lys 115 120 125 Glu Glu Ile Asn Pro Lys Cys Thr His Leu Val Glu Tyr Met Asp Asp 130 135 140 Lys Tyr Pro Phe Tyr Leu Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Gln Ala Ser Ile Gly His Gly Ile Thr Ile Asn Arg Met Phe 165 170 175 Trp Arg Ala Arg Arg Arg Glu Ser Ile Phe Ile Gln Tyr Ile Val Lys 180 185 190 His His Pro Arg Phe Lys Asp Ala Asn Ile Pro Ile Trp Leu Asp Arg 195 200 205 Asp Cys Pro Phe Asn Ile Glu Gly Gly Asp Glu Leu Val Leu Ser Lys 210 215 220 Asp Val Leu Ala Ile Gly Val Ser Glu Arg Thr Ser Ala Gln Ala Ile 225 230 235 240 Glu Lys Leu Ala Arg Arg Ile Phe Glu Asn Pro Gln Ala Thr Phe Lys 245 250 255 Lys Val Val Ala Ile Glu Ile Pro Thr Ser Arg Thr Phe Met His Leu 260 265 270 Asp Thr Val Phe Thr Met Ile Asp Tyr Asp Lys Phe Thr Met His Ser 275 280 285 Ala Ile Leu Lys Ala Glu Gly Asn Met Asn Ile Phe Ile Ile Glu Tyr 290 295 300 Asp Asp Val Asn Lys Asp Ile Ala Ile Lys Gln Ser Ser His Leu Lys 305 310 315 320 Asp Thr Leu Glu Asp Val Leu Gly Ile Asp Asp Ile Gln Phe Ile Pro 325 330 335 Thr Gly Asn Gly Asp Val Ile Asp Gly Ala Arg Glu Gln Trp Asn Asp 340 345 350 Gly Ser Asn Thr Leu Cys Ile Arg Pro Gly Val Val Val Thr Tyr Asp 355 360 365 Arg Asn Tyr Val Ser Asn Asp Leu Leu Arg Gln Lys Gly Ile Lys Val 370 375 380 Ile Glu Ile Ser Gly Ser Glu Leu Val Arg Gly Arg Gly Gly Pro Arg 385 390 395 400 Cys Met Ser Gln Pro Leu Phe Arg Glu Asp Ile 405 410 <![CDATA[<210> 23]]> <![CDATA[<211> 417]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 香魚假單胞菌a]]> <![CDATA[<400> 23]]> Met Ser Ala Glu Lys Gln Lys Tyr Gly Val His Ser Glu Ala Gly Lys 1 5 10 15 Leu Arg Lys Val Met Val Cys Ala Pro Gly Leu Ala His Lys Arg Leu 20 25 30 Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val 35 40 45 Asp Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu 50 55 60 Arg Gly Val Asp Val Leu Glu Met His Asn Leu Leu Thr Asp Ile Val 65 70 75 80 Gln Asn Pro Glu Ala Leu Lys Trp Ile Leu Asp Arg Lys Ile Thr Pro 85 90 95 Asp Thr Val Gly Val Gly Leu Thr Asn Glu Val Arg Ser Trp Leu Glu 100 105 110 Gly Gln Glu Pro Arg His Leu Ala Glu Phe Leu Ile Gly Gly Val Ala 115 120 125 Gly Gln Asp Leu Pro Glu Ser Glu Gly Ala Ser Val Val Lys Met Tyr 130 135 140 Asn Asp Tyr Leu Gly His Ser Ser Phe Ile Leu Pro Pro Leu Pro Asn 145 150 155 160 Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr 165 170 175 Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr 180 185 190 Thr Ala Ile Tyr Lys Phe His Pro Glu Phe Thr Lys Ala Asp Phe Gln 195 200 205 Val Trp Tyr Gly Asp Pro Asp Gln Glu His Gly Gln Ala Thr Leu Glu 210 215 220 Gly Gly Asp Val Met Pro Ile Gly Lys Gly Ile Val Leu Ile Gly Met 225 230 235 240 Gly Glu Arg Thr Ser Arg Gln Ala Ile Gly Gln Leu Ala Gln Asn Leu 245 250 255 Phe Ala Lys Gly Ala Val Glu Gln Val Ile Val Ala Gly Leu Pro Lys 260 265 270 Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg 275 280 285 Asp Leu Val Thr Val Phe Pro Glu Val Val Arg Glu Ile Val Pro Phe 290 295 300 Ile Ile Arg Pro Asp Glu Ser Lys Pro Tyr Gly Met Asp Val Arg Arg 305 310 315 320 Glu Asn Lys Ser Phe Ile Glu Val Val Gly Glu Gln Leu Gly Val Lys 325 330 335 Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala Glu Arg Glu 340 345 350 Gln Trp Asp Asp Gly Asn Asn Val Val Ala Leu Glu Pro Gly Val Val 355 360 365 Ile Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu Arg Lys Ala 370 375 380 Gly Ile Glu Val Ile Thr Ile Ser Ala Gly Glu Leu Gly Arg Gly Arg 385 390 395 400 Gly Gly Gly His Cys Met Thr Cys Pro Ile Val Arg Asp Pro Ile Asn 405 410 415 Tyr <![CDATA[<210> 24]]> <![CDATA[<211> 417]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 戀臭假單胞菌]]> <![CDATA[<400> 24]]> Met Ser Ala Glu Lys Gln Lys Tyr Gly Val His Ser Glu Ala Gly Lys 1 5 10 15 Leu Arg Lys Val Met Val Cys Ala Pro Gly Leu Ala His Lys Arg Leu 20 25 30 Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val 35 40 45 Asp Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu 50 55 60 Arg Gly Val Asp Val Leu Glu Met His Asn Leu Leu Thr Asp Ile Val 65 70 75 80 Gln Asn Lys Asp Ala Leu Lys Trp Ile Leu Asp Arg Lys Ile Thr Pro 85 90 95 Asp Thr Val Gly Val Gly Leu Thr Asn Glu Val Arg Ser Trp Leu Glu 100 105 110 Gly Leu Glu Pro Arg His Leu Ala Glu Phe Leu Ile Gly Gly Val Ala 115 120 125 Gly Gln Asp Leu Pro Gln Ser Glu Gly Ala Asp Val Val Lys Met Tyr 130 135 140 Asn Asp Tyr Leu Gly His Ser Ser Phe Ile Leu Pro Pro Leu Pro Asn 145 150 155 160 Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr 165 170 175 Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr 180 185 190 Thr Ala Ile Tyr Lys Phe His Pro Gln Phe Thr Gly Ala Asp Phe Gln 195 200 205 Val Trp Tyr Gly Asp Pro Asp Lys Asp His Gly Asn Ala Thr Leu Glu 210 215 220 Gly Gly Asp Val Met Pro Ile Gly Lys Gly Ile Val Leu Ile Gly Met 225 230 235 240 Gly Glu Arg Thr Ser Arg Gln Ala Ile Gly Gln Leu Ala Gln Asn Leu 245 250 255 Phe Ala Lys Gly Ala Val Glu Lys Val Ile Val Ala Gly Leu Pro Lys 260 265 270 Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg 275 280 285 Asp Leu Val Thr Ile Phe Pro Glu Val Val Lys Glu Ile Val Pro Phe 290 295 300 Ile Ile Arg Pro Asp Glu Ser Lys Pro Tyr Gly Met Asp Val Arg Arg 305 310 315 320 Glu Asn Lys Ser Phe Ile Glu Val Val Gly Glu Gln Leu Gly Val Lys 325 330 335 Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala Glu Arg Glu 340 345 350 Gln Trp Asp Asp Gly Asn Asn Val Val Ala Val Glu Pro Gly Val Val 355 360 365 Ile Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu Arg Lys Ala 370 375 380 Gly Ile Glu Val Ile Thr Ile Ser Ala Gly Glu Leu Gly Arg Gly Arg 385 390 395 400 Gly Gly Gly His Cys Met Thr Cys Pro Ile Val Arg Asp Pro Ile Asp 405 410 415 Tyr <![CDATA[<210> 25]]> <![CDATA[<211> 418]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 綠膿桿菌]]> <![CDATA[<400> 25]]> Met Ser Thr Glu Lys Thr Lys Leu Gly Val His Ser Glu Ala Gly Lys 1 5 10 15 Leu Arg Lys Val Met Val Cys Ser Pro Gly Leu Ala His Gln Arg Leu 20 25 30 Thr Pro Ser Asn Cys Asp Glu Leu Leu Phe Asp Asp Val Ile Trp Val 35 40 45 Asn Gln Ala Lys Arg Asp His Phe Asp Phe Val Thr Lys Met Arg Glu 50 55 60 Arg Gly Ile Asp Val Leu Glu Met His Asn Leu Leu Thr Glu Thr Ile 65 70 75 80 Gln Asn Pro Glu Ala Leu Lys Trp Ile Leu Asp Arg Lys Ile Thr Ala 85 90 95 Asp Ser Val Gly Leu Gly Leu Thr Ser Glu Leu Arg Ser Trp Leu Glu 100 105 110 Ser Leu Glu Pro Arg Lys Leu Ala Glu Tyr Leu Ile Gly Gly Val Ala 115 120 125 Ala Asp Asp Leu Pro Ala Ser Glu Gly Ala Asn Ile Leu Lys Met Tyr 130 135 140 Arg Glu Tyr Leu Gly His Ser Ser Phe Leu Leu Pro Pro Leu Pro Asn 145 150 155 160 Thr Gln Phe Thr Arg Asp Thr Thr Cys Trp Ile Tyr Gly Gly Val Thr 165 170 175 Leu Asn Pro Met Tyr Trp Pro Ala Arg Arg Gln Glu Thr Leu Leu Thr 180 185 190 Thr Ala Ile Tyr Lys Phe His Pro Glu Phe Ala Asn Ala Glu Phe Glu 195 200 205 Ile Trp Tyr Gly Asp Pro Asp Lys Asp His Gly Ser Ser Thr Leu Glu 210 215 220 Gly Gly Asp Val Met Pro Ile Gly Asn Gly Val Val Leu Ile Gly Met 225 230 235 240 Gly Glu Arg Ser Ser Arg Gln Ala Ile Gly Gln Val Ala Gln Ser Leu 245 250 255 Phe Ala Lys Gly Ala Ala Glu Arg Val Ile Val Ala Gly Leu Pro Lys 260 265 270 Ser Arg Ala Ala Met His Leu Asp Thr Val Phe Ser Phe Cys Asp Arg 275 280 285 Asp Leu Val Thr Val Phe Pro Glu Val Val Lys Glu Ile Val Pro Phe 290 295 300 Ser Leu Arg Pro Asp Ala Ser Ser Pro Tyr Gly Met Ser Ile Arg Arg 305 310 315 320 Glu Glu Lys Thr Phe Leu Glu Val Val Ala Glu Ser Leu Gly Leu Lys 325 330 335 Lys Leu Arg Val Val Glu Thr Gly Gly Asn Ser Phe Ala Ala Glu Arg 340 345 350 Glu Gln Trp Asp Asp Gly Asn Asn Val Val Cys Leu Glu Pro Gly Val 355 360 365 Val Val Gly Tyr Asp Arg Asn Thr Tyr Thr Asn Thr Leu Leu Arg Lys 370 375 380 Ala Gly Val Glu Val Ile Thr Ile Ser Ala Ser Glu Leu Gly Arg Gly 385 390 395 400 Arg Gly Gly Gly His Cys Met Thr Cys Pro Ile Ile Arg Asp Pro Ile 405 410 415 Asp Tyr <![CDATA[<210> 26]]> <![CDATA[<211> 402]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 結核分枝桿菌群]]> <![CDATA[<400> 26]]> Met Gly Val Glu Leu Gly Ser Asn Ser Glu Val Gly Ala Leu Arg Val 1 5 10 15 Val Ile Leu His Arg Pro Gly Ala Glu Leu Arg Arg Leu Thr Pro Arg 20 25 30 Asn Thr Asp Gln Leu Leu Phe Asp Gly Leu Pro Trp Val Ser Arg Ala 35 40 45 Gln Asp Glu His Asp Glu Phe Ala Glu Leu Leu Ala Ser Arg Gly Ala 50 55 60 Glu Val Leu Leu Leu Ser Asp Leu Leu Thr Glu Ala Leu His His Ser 65 70 75 80 Gly Ala Ala Arg Met Gln Gly Ile Ala Ala Ala Val Asp Ala Pro Arg 85 90 95 Leu Gly Leu Pro Leu Ala Gln Glu Leu Ser Ala Tyr Leu Arg Ser Leu 100 105 110 Asp Pro Gly Arg Leu Ala His Val Leu Thr Ala Gly Met Thr Phe Asn 115 120 125 Glu Leu Pro Ser Asp Thr Arg Thr Asp Val Ser Leu Val Leu Arg Met 130 135 140 His His Gly Gly Asp Phe Val Ile Glu Pro Leu Pro Asn Leu Val Phe 145 150 155 160 Thr Arg Asp Ser Ser Ile Trp Ile Gly Pro Arg Val Val Ile Pro Ser 165 170 175 Leu Ala Leu Arg Ala Arg Val Arg Glu Ala Ser Leu Thr Asp Leu Ile 180 185 190 Tyr Ala His His Pro Arg Phe Thr Gly Val Arg Arg Ala Tyr Glu Ser 195 200 205 Arg Thr Ala Pro Val Glu Gly Gly Asp Val Leu Leu Leu Ala Pro Gly 210 215 220 Val Val Ala Val Gly Val Gly Glu Arg Thr Thr Pro Ala Gly Ala Glu 225 230 235 240 Ala Leu Ala Arg Ser Leu Phe Asp Asp Asp Leu Ala His Thr Val Leu 245 250 255 Ala Val Pro Ile Ala Gln Gln Arg Ala Gln Met His Leu Asp Thr Val 260 265 270 Cys Thr Met Val Asp Thr Asp Thr Met Val Met Tyr Ala Asn Val Val 275 280 285 Asp Thr Leu Glu Ala Phe Thr Ile Gln Arg Thr Pro Asp Gly Val Thr 290 295 300 Ile Gly Asp Ala Ala Pro Phe Ala Glu Ala Ala Ala Lys Ala Met Gly 305 310 315 320 Ile Asp Lys Leu Arg Val Ile His Thr Gly Met Asp Pro Val Val Ala 325 330 335 Glu Arg Glu Gln Trp Asp Asp Gly Asn Asn Thr Leu Ala Leu Ala Pro 340 345 350 Gly Val Val Val Ala Tyr Glu Arg Asn Val Gln Thr Asn Ala Arg Leu 355 360 365 Gln Asp Ala Gly Ile Glu Val Leu Thr Ile Ala Gly Ser Glu Leu Gly 370 375 380 Thr Gly Arg Gly Gly Pro Arg Cys Met Ser Cys Pro Ala Ala Arg Asp 385 390 395 400 Pro Leu <![CDATA[<210> 27]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 關節炎黴漿菌]]> <![CDATA[<400> 27]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Lys Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Glu Phe Val Ala Glu 50 55 60 Leu Lys Lys Arg Gly Ile Asn Val Val Glu Leu Val Asp Leu Ile Val 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Lys Glu Ala Lys Glu Lys Leu Leu Glu 85 90 95 Glu Phe Leu Asp Asp Ser Val Pro Val Leu Ser Asp Glu His Arg Ala 100 105 110 Ala Val Lys Lys Phe Leu Gln Ser Gln Lys Ser Thr Arg Ser Leu Val 115 120 125 Glu Tyr Met Ile Ala Gly Ile Thr Lys His Asp Leu Lys Ile Glu Ser 130 135 140 Asp Leu Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser 180 185 190 Asn His Pro Lys Leu Val Asn Thr Pro Trp Tyr Tyr Asp Pro Ala Glu 195 200 205 Gly Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Ala Pro Gln Pro Val Asp Asn Gly Leu Pro Leu Glu Asp Leu Leu Lys 305 310 315 320 Ser Ile Ile Gly Lys Lys Pro Thr Leu Ile Pro Ile Ala Gly Ala Gly 325 330 335 Ala Ser Gln Ile Asp Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Val Ala Pro Gly Ile Val Ile Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Thr Val Leu Pro Phe 370 375 380 Arg Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys 405 <![CDATA[<210> 28]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 來自新物種患者之海豹腦黴漿菌-全長]]> <![CDATA[<400> 28]]> Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Ser Phe Val Lys Gln 50 55 60 Leu Lys Asp Asn Gly Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Phe Asp Leu Ala Ser Lys Glu Glu Gln Glu Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Ala His Lys Thr 100 105 110 Ala Val Arg Lys Phe Leu Thr Ser Arg Lys Ser Thr Arg Glu Met Val 115 120 125 Glu Phe Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser 180 185 190 Asn His Pro Lys Leu Val Lys Thr Pro Trp Tyr Tyr Asp Pro Ala Met 195 200 205 Lys Met Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Glu Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Val Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala 290 295 300 Glu Pro Gln Pro Lys Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Gln 305 310 315 320 Ser Ile Ile Asn Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Asn Asn 325 330 335 Ala Ser His Ile Asp Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Lys Pro Gly Val Val Ile Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Ala Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 29]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 來自新物種專利之貓黴漿菌-人工全長]]> <![CDATA[<400> 29]]> Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Gln Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Glu Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Glu Phe Val Ala Glu 50 55 60 Leu Lys Lys Asn Asn Ile Asn Val Val Glu Leu Thr Asp Leu Val Ser 65 70 75 80 Glu Thr Tyr Asp Met Val Ser Lys Glu Lys Gln Glu Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Gly 100 105 110 Leu Val Arg Lys Phe Leu Lys Ser Leu Lys Ser Ser Lys Glu Leu Ile 115 120 125 Gln Tyr Met Met Ala Gly Ile Thr Lys His Asp Leu Asn Ile Glu Ala 130 135 140 Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Ala 180 185 190 Asn His Pro Lys Leu Met Asn Thr Pro Leu Tyr Tyr Asn Pro Asp Met 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Val Tyr Asn Asn Glu Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Arg Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Glu Pro Gln Pro Lys Val Asn Gly Leu Pro Leu Glu Lys Leu Leu Glu 305 310 315 320 Ser Ile Ile Asn Lys Lys Pro Ile Leu Ile Pro Ile Ala Gly Thr Ser 325 330 335 Ala Ser Asn Ile Asp Val Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Ala Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Val 355 360 365 Lys Thr Asn Glu Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 Lys Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 30]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 人工序列]]> <![CDATA[<220>]]> <![CDATA[<223> 來自新物種專利之海豹黴漿菌-人工全長。]]> <![CDATA[<400> 30]]> Met Ser Val Phe Asp Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Gln Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Glu Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Glu Phe Val Ala Glu 50 55 60 Leu Lys Lys Asn Asn Ile Asn Val Val Glu Leu Thr Asp Leu Val Ser 65 70 75 80 Glu Thr Tyr Asp Met Val Ser Lys Glu Lys Gln Glu Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Gly 100 105 110 Leu Val Arg Lys Phe Leu Lys Ser Leu Lys Ser Ser Lys Glu Leu Ile 115 120 125 Gln Tyr Met Met Ala Gly Ile Thr Lys His Asp Leu Asn Ile Glu Ala 130 135 140 Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Ala 180 185 190 Asn His Pro Lys Leu Met Asn Thr Pro Leu Tyr Tyr Asn Pro Asp Met 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Val Tyr Asn Asn Glu Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Arg Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Glu Pro Gln Pro Lys Val Asn Gly Leu Pro Leu Glu Lys Leu Leu Glu 305 310 315 320 Ser Ile Ile Asn Lys Lys Pro Ile Leu Ile Pro Ile Ala Gly Thr Ser 325 330 335 Ala Ser Asn Ile Asp Val Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Ala Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Val 355 360 365 Lys Thr Asn Glu Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 Lys Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 31]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 唾液黴漿菌]]> <![CDATA[<400> 31]]> Met Ser Val Phe Ser Ser Lys Phe Asn Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Lys Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ser Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Gln Glu Phe Val Ala Thr 50 55 60 Leu Lys Lys Glu Lys Ile Asn Val Val Glu Leu Thr Asp Leu Val Thr 65 70 75 80 Glu Thr Tyr Asp Leu Val Asp Gln Lys Thr Lys Asp Lys Leu Ile Asp 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Thr Ala Glu Leu Lys Ala 100 105 110 Thr Val Lys Lys Phe Leu Lys Ser Phe Lys Glu Thr Arg Lys Leu Ile 115 120 125 Glu Val Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Lys Ala 130 135 140 Asp Arg Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Asn 180 185 190 Asn His Pro Lys Leu Val Lys Thr Pro Trp Tyr Tyr Asp Pro Ala Met 195 200 205 Lys Met Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Ile Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala 290 295 300 Asn Pro Gln Pro Lys Asp Asn Gly Leu Pro Leu Asp Lys Leu Leu Lys 305 310 315 320 Ser Ile Ile Gly Lys Glu Pro Val Leu Ile Pro Ile Ala Gly His His 325 330 335 Ala Thr Glu Ile Glu Val Ala Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Glu Ala Leu Lys Asp Ala Gly Ile Thr Val Leu Pro Phe 370 375 380 Lys Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 32]]> <![CDATA[<211> 411]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 泡沫黴漿菌]]> <![CDATA[<400> 32]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gly Phe Val Ala Glu 50 55 60 Leu Lys Lys Gln Asn Val Asn Val Ile Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Glu Leu Ala Ser Lys Glu Ala Gln Ala Lys Leu Ile Glu 85 90 95 Asp Phe Ile Glu Asp Ser Glu Pro Val Leu Asn Ala Glu Glu Ala Gln 100 105 110 Ala Val Arg Lys Phe Leu Ser Glu Arg Lys Ser Thr Arg Glu Met Val 115 120 125 Glu Tyr Met Met Ser Gly Leu Thr Lys Tyr Glu Leu Gly Leu Glu Ser 130 135 140 Ala Asp Arg Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr 145 150 155 160 Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met 165 170 175 Lys Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ala Lys Phe Val Phe 180 185 190 Ser Asn His Pro Lys Leu Val Asn Thr Pro Arg Tyr Tyr Asp Pro Ser 195 200 205 Met Lys Leu Pro Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Glu 210 215 220 Thr Leu Val Val Gly Cys Ser Glu Arg Thr Glu Leu Glu Thr Ile Thr 225 230 235 240 Leu Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Val Glu Phe Lys Arg 245 250 255 Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp 260 265 270 Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile 275 280 285 Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly 290 295 300 Glu Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Glu Leu Leu 305 310 315 320 Ala Ser Ile Ile Asn Lys Lys Pro Thr Leu Ile Pro Ile Ala Gly Glu 325 330 335 Gly Ala Thr His Ile Asp Val Glu Arg Glu Thr His Phe Asp Gly Thr 340 345 350 Asn Tyr Leu Ala Ile Ala Pro Ala Leu Ile Ile Gly Tyr Ser Arg Asn 355 360 365 Glu Lys Thr Asn Ala Ala Leu Glu Lys Ala Gly Ile Thr Val Leu Pro 370 375 380 Phe His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met 385 390 395 400 Ser Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 33]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 耳黴漿菌]]> <![CDATA[<400> 33]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Lys Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Glu Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu 50 55 60 Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Val Ser Gln Glu Leu Lys Asp Lys Leu Ile Glu 85 90 95 Glu Phe Leu Asp Asp Ser Tyr Pro Val Leu Thr Glu Glu His Lys Lys 100 105 110 Ala Val Arg Ser Phe Leu Lys Ser Arg Ser Ser Thr Arg Glu Leu Ile 115 120 125 Glu Tyr Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Glu Gly Asp Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Asp 180 185 190 Asn His Pro Lys Leu Val Asn Thr Pro Arg Tyr Tyr Asp Pro Ser Leu 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Met Gly Val Ser Glu Arg Thr Asp Leu Glu Thr Val Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro His Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Tyr Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ala 290 295 300 Glu Pro Gln Pro Val Val Asn Glu Leu Pro Leu Asp Lys Leu Leu Glu 305 310 315 320 Ser Ile Ile His Lys Lys Pro Ile Leu Ile Pro Ile Ala Gly Glu Gly 325 330 335 Ala Ser Gln Ile Asp Leu Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Val Leu Arg Pro Gly Val Val Val Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Val Gly Ile Lys Val Leu Pro Phe 370 375 380 Tyr Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ser Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 34]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 豬滑液黴漿菌]]> <![CDATA[<400> 34]]> Met Ser Val Phe Asn Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Asp Leu Glu Ser Val Leu Val His Glu Pro Gly Lys Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ser Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser Asn Asp Ala Arg Lys Glu His Lys Glu Phe Val Glu Ile 50 55 60 Leu Lys Lys Glu Gly Val Asn Val Val Glu Leu Val Asp Leu Ile Ala 65 70 75 80 Glu Thr Ile Asp Leu Val Asp Ala Lys Lys Lys Glu Ala Leu Ile Asp 85 90 95 Glu Tyr Ile Glu Asp Ser Glu Pro Val Val Asp Ala Lys Val Lys Pro 100 105 110 Leu Val Lys Lys Leu Leu Leu Gly Ile Lys Asp Thr Lys Glu Leu Val 115 120 125 Lys Leu Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Glu Ile Glu Ser 130 135 140 Glu Lys Glu Leu Ile Ile Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Arg 180 185 190 Asn His Pro Lys Leu Thr Ser Thr Pro Trp Tyr Tyr Asp Pro Ala Met 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Asp Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Ile Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ser 290 295 300 Glu Pro Gln Pro Lys Asp Asn Gly Leu Pro Leu Glu Lys Leu Leu Glu 305 310 315 320 Ser Ile Ile Gly Lys Lys Pro Val Leu Ile Pro Ile Ala Gly Cys Cys 325 330 335 Ala Ser Asp Ile Glu Ile Ala Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Lys Pro Gly Val Val Ile Gly Tyr Ala Arg Asn Glu 355 360 365 Lys Thr Asn Lys Ala Leu Glu Lys Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 Lys Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 35]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 泄殖腔黴漿菌]]> <![CDATA[<400> 35]]> Met Ser Val Phe Asp Lys Arg Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Gln Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Glu Phe Val Lys Ile 50 55 60 Leu Glu Ser Gln Gly Ile Asn Val Val Glu Leu Thr Asp Leu Ile Ala 65 70 75 80 Glu Thr Tyr Glu Leu Ala Ser Glu Glu Ala Lys Asp Asn Leu Ile Glu 85 90 95 Glu Phe Leu Asp Glu Ser Glu Pro Val Leu Ser Glu Glu His Arg Ile 100 105 110 Leu Val Arg Asn Phe Leu Lys Gly Ile Thr Lys Thr Lys Glu Leu Val 115 120 125 Lys Met Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Asp Arg Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Glu 180 185 190 Asn His Pro Lys Leu Val Ser Thr Pro Ile Tyr Tyr His Pro Ser Gln 195 200 205 Gly Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Glu Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asn Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Glu Pro Gln Pro Val Asp Asn Gly Leu Pro Leu Asn Glu Leu Leu Ala 305 310 315 320 Ser Ile Ile Gly Glu Glu Pro Val Leu Val Pro Ile Ala Gly Glu Gly 325 330 335 Ala Ser Lys Met Asp Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Ala Pro Gly Val Val Val Gly Tyr Ser Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Lys Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 Lys Gly His Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Tyr Arg Lys Asp Val Lys 405 <![CDATA[<210> 36]]> <![CDATA[<211> 412]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 產鹼黴漿菌]]> <![CDATA[<400> 36]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly His Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ser Arg Leu Asp Glu Leu Leu Phe Ser Ala Met 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ala Glu 50 55 60 Leu Lys Ala Asn Asn Val Asn Val Ile Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu Asn Lys Ile 100 105 110 Ala Val Arg Asp Phe Leu Lys Ser Arg Lys Thr Thr Arg Glu Leu Ile 115 120 125 Glu Val Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Lys Asn 130 135 140 Cys Lys Cys Gln Asp Leu Val Val Asp Pro Met Pro Asn Leu Tyr Phe 145 150 155 160 Thr Arg Asp Pro Phe Ala Ser Val Gly Asn Gly Ile Thr Ile His Tyr 165 170 175 Met Arg Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile 180 185 190 Phe Ala Asn His Pro Lys Leu Val Asn Thr Pro Ile Tyr Tyr His Pro 195 200 205 Ser Leu Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn 210 215 220 Asp Thr Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Glu Thr Ile 225 230 235 240 Thr Leu Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys 245 250 255 Arg Ile Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu 260 265 270 Asp Thr Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro 275 280 285 Ile Ala Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly 290 295 300 Gly Ala Glu Pro Lys Pro Val Glu Asn Gly Ser Ser Leu Glu Ala Ile 305 310 315 320 Leu Glu Ser Ile Ile His Lys Lys Pro Ile Leu Ile Pro Ile Gly Gly 325 330 335 Asp Ser Ala Ser Gln Ile Glu Val Glu Arg Glu Thr His Phe Asp Gly 340 345 350 Thr Asn Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg 355 360 365 Asn Val Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Ile 370 375 380 Pro Phe His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys 385 390 395 400 Met Ser Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 37]]> <![CDATA[<211> 401]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 惰性黴漿菌]]> <![CDATA[<400> 37]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Ile Gly Val Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ala Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Ser Ala Ala Ile 35 40 45 Gln Glu His Lys Ser Phe Leu Lys Ile Leu Gln Asp Arg Gly Ile Lys 50 55 60 Thr Ile Gln Leu Ser Asp Leu Val Ala Glu Thr Tyr Lys His Tyr Ala 65 70 75 80 Ser Glu Ala Glu Lys Glu Ala Phe Ile Glu Lys Tyr Leu Asp Glu Ala 85 90 95 Thr Pro Val Leu Ser Lys Asp Met Arg Ala Lys Val Lys Asn Tyr Ile 100 105 110 Leu Ser Met Gln Gly Glu Pro Val Lys Met Val Arg Thr Met Met Ala 115 120 125 Gly Val Ser Lys Gln Glu Leu Asn Val Glu Ser Glu Val Glu Leu Ile 130 135 140 Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Ala Gly Asn Gly Ile Ser Leu Asn Asn Met Lys Tyr Val Val Arg Lys 165 170 175 Arg Glu Thr Ile Phe Ala Glu Phe Ile Phe Ser Ile His Pro Glu Tyr 180 185 190 Lys Lys Thr Pro His Trp Phe Asp Arg Leu Asp Asn Gly Ser Ile Glu 195 200 205 Gly Gly Asp Val Phe Ile Tyr Asn Lys Asp Thr Leu Val Ile Gly Val 210 215 220 Ser Glu Arg Thr Asn Lys Glu Ala Ile Ile Thr Ile Ala Lys His Ile 225 230 235 240 Gln Asp Asn Lys Glu Ala Gln Phe Lys Lys Ile Val Ala Ile Asn Val 245 250 255 Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Val 260 265 270 Asp Lys Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys 275 280 285 Val Trp Glu Ile Asp Leu Ser Lys Pro Ile Glu Met Val Glu Thr Asn 290 295 300 Lys Pro Leu Ala Glu Val Leu Glu Ser Ile Ile Gly Glu Lys Pro Ile 305 310 315 320 Leu Ile Pro Ile Ala Gly Lys Asp Ala Thr Gln Leu Asp Ile Asp Ile 325 330 335 Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly Val 340 345 350 Val Val Gly Tyr Ser Arg Asn Val Lys Thr Glu Ala Ala Leu Arg Ala 355 360 365 Ala Gly Val Thr Val Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu Gly 370 375 380 Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp Val 385 390 395 400 Lys <![CDATA[<210> 38]]> <![CDATA[<211> 348]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 家禽黴漿菌]]> <![CDATA[<400> 38]]> Phe Val Lys Leu Leu Glu Asp Arg Gly Ile Gln Ala Ile Gln Leu Ser 1 5 10 15 Asp Leu Val Ala Glu Thr Tyr Val Lys Tyr Ala Thr Ala Glu Gln Lys 20 25 30 Ala Ala Phe Ile Glu Lys Tyr Leu Asp Glu Ala Thr Pro Ala Leu Ser 35 40 45 Ala Glu Asn Arg Glu Arg Ala Lys Lys Tyr Ile Leu Ser Leu Glu Met 50 55 60 Gln Pro Val Lys Met Ile Arg Thr Met Met Ala Gly Leu Ser Lys Tyr 65 70 75 80 Glu Leu Asn Val Glu Ser Asn Ile Glu Leu Ile Ile Asp Pro Met Pro 85 90 95 Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Ala Gly Asn Gly Ile 100 105 110 Ser Leu Asn Asn Met Lys Tyr Val Val Arg Lys Arg Glu Thr Ile Phe 115 120 125 Ala Glu Phe Ile Phe Ala Ile His Pro Glu Tyr Lys Glu Thr Pro His 130 135 140 Trp Phe Asp Arg Leu Asp His Gly Ser Ile Glu Gly Gly Asp Val Phe 145 150 155 160 Val Tyr Asn Lys Asp Thr Leu Val Ile Gly Val Ser Glu Arg Thr Asn 165 170 175 Lys Glu Ala Ile Ile Thr Ile Ala Lys His Ile Gln Asp Asn Lys Glu 180 185 190 Ala Glu Phe Lys Lys Ile Val Ala Ile Asn Val Pro Pro Met Pro Asn 195 200 205 Leu Met His Leu Asp Thr Trp Leu Thr Met Val Asp Lys Asn Lys Phe 210 215 220 Ile Tyr Ser Pro Asn Met Leu Ser Val Leu Lys Ile Trp Glu Ile Asp 225 230 235 240 Leu Ala Lys Pro Ile Glu Met Val Glu Ser Asn Lys Ser Leu Thr Glu 245 250 255 Val Leu Glu Ser Ile Ile Gly Glu Lys Pro Ile Leu Ile Pro Ile Ala 260 265 270 Gly Glu Gly Ala Ser Gln Leu Asp Ile Asp Ile Glu Thr His Phe Asp 275 280 285 Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly Val Val Val Gly Tyr Ser 290 295 300 Arg Asn Glu Lys Thr Glu Lys Ala Leu Lys Ala Ala Gly Ile Thr Val 305 310 315 320 Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu Gly Met Gly Ser Ala Arg 325 330 335 Cys Met Ser Met Pro Leu Val Arg Glu Asp Val Lys 340 345 <![CDATA[<210> 39]]> <![CDATA[<211> 405]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 梨黴漿菌]]> <![CDATA[<400> 39]]> Met Asn Ser Asn Gln Lys Gly Ile His Val Tyr Ser Glu Ile Gly Lys 1 5 10 15 Leu Lys Glu Val Leu Val His Arg Pro Gly Arg Glu Leu Asp Phe Leu 20 25 30 Asp Pro Thr Arg Leu Asp Glu Leu Leu Phe Ala Ala Thr Leu Glu Ala 35 40 45 Glu Thr Ala Arg Leu Glu His Asp Asn Phe Thr Asn Ala Leu Lys Asn 50 55 60 Gln Gly Val Thr Val Ile Glu Leu Ala Asp Leu Val Ala Gln Thr Tyr 65 70 75 80 Ser Ser Ser Thr Pro Thr Ile Lys Ala Ala Phe Ile Asn Lys Tyr Leu 85 90 95 Asp Glu Ala Thr Pro Ala Leu Thr Thr Lys Leu Arg Thr Leu Val Lys 100 105 110 Asp Phe Leu Thr Lys Gln Lys Ser Val Arg Lys Met Val Asp Tyr Met 115 120 125 Ile Gly Gly Ile Leu Ser Thr Asp Leu Asn Ile Lys Gly Lys Pro Glu 130 135 140 Leu Ile Val Glu Pro Met Pro Asn Ala Tyr Phe Thr His Asp Pro Phe 145 150 155 160 Ala Ser Val Gly Asn Gly Val Thr Leu His Tyr Met Lys His Asn Val 165 170 175 Arg Arg Arg Glu Val Leu Phe Ser Glu Phe Ile Phe Asn Asn Asn Glu 180 185 190 Arg Phe Gln Asn Thr Pro Arg Tyr Ile Val Pro Thr Lys Gly Leu Asp 195 200 205 Ile Glu Gly Gly Asp Val Phe Val Tyr Asn Lys Asn Thr Leu Val Val 210 215 220 Gly Val Ser Glu Arg Thr Lys Met Val Thr Ile Lys Glu Leu Ala Lys 225 230 235 240 Asn Ile Leu Lys Asn Lys Glu Cys Leu Phe Lys Lys Ile Tyr Ala Ile 245 250 255 Asn Val Pro Lys Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr 260 265 270 Met Leu Asp His Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val 275 280 285 Leu Lys Ile Trp Glu Ile Asp Ile Ser Ser Gly Lys Ser Ile Ser Ser 290 295 300 Pro Lys Glu Leu Asn Met Asp Leu Ser Lys Ala Leu Ser Ile Ile Ile 305 310 315 320 Gly Lys Lys Pro Ile Leu Ile Pro Val Ala Gly Glu Asn Ala Ser Gln 325 330 335 Ile Asp Ile Asn Ile Glu Thr Asn Phe Asp Ala Thr Asn Tyr Leu Val 340 345 350 Thr Gln Pro Gly Val Val Val Gly Tyr Ser Arg Asn Lys Lys Thr Glu 355 360 365 Ala Ala Leu Ile Lys Ala Gly Ile Glu Val Ile Pro Phe Gln Gly Asn 370 375 380 Gln Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu 385 390 395 400 Ile Arg Glu Asp Val 405 <![CDATA[<210> 40]]> <![CDATA[<211> 404]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 靈長類黴漿菌]]> <![CDATA[<400> 40]]> Met Ser Lys Ser Lys Ile Asn Val Tyr Ser Glu Tyr Gly Asn Leu Lys 1 5 10 15 Glu Val Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Thr Pro 20 25 30 Ser Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Lys Ser 35 40 45 Ala Ile Ala Glu His Lys Ser Phe Cys Gln Ile Leu Lys Asp Asn Lys 50 55 60 Val Lys Ala Ile Gln Leu Asp Glu Leu Val Ala Ala Thr Tyr Lys Gly 65 70 75 80 Val Ser Glu Ser Val Gln Asn Ser Phe Val Glu Arg Trp Leu Asp Glu 85 90 95 Cys Glu Pro Lys Leu Glu Asn Asn Val Arg Pro Ile Val Lys Glu Tyr 100 105 110 Leu Leu Lys Ala Ala Glu Gln Ser Val Lys Lys Met Ile Arg Ile Met 115 120 125 Met Ala Gly Ile Asp Lys Arg Glu Ile Gly Val Glu Ser Glu Val Asp 130 135 140 Phe Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe 145 150 155 160 Ala Ser Val Gly Asn Gly Ile Thr Leu His His Met Lys Tyr Val Val 165 170 175 Arg Gln Arg Glu Thr Leu Phe Ser Glu Phe Ile Phe Asp Asn His Pro 180 185 190 Asp Tyr Lys Phe Val Pro Arg Tyr Phe Asp Arg Asp Asp Glu Gly Lys 195 200 205 Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Ser Lys Thr Leu Val Val 210 215 220 Gly Ile Ser Glu Arg Thr Asn Lys Asp Ala Ile Arg Ile Val Ala Lys 225 230 235 240 Lys Ile Gln Ala Asn Ala Asp Ala Lys Phe Glu Lys Ile Phe Ala Ile 245 250 255 Asn Val Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr 260 265 270 Met Leu Asp Ser Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val 275 280 285 Leu Lys Val Trp Glu Ile Asn Leu Asp Asp Pro Ala Leu Glu Trp Lys 290 295 300 Glu Ile Ser Gly Ser Leu Glu Glu Ile Leu Thr Tyr Ile Ile Gly Lys 305 310 315 320 Lys Pro Ile Leu Ile Pro Ile Ala Gly Lys Gly Ala Ser Gln Phe Glu 325 330 335 Ile Asp Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Ala Ile Ala 340 345 350 Pro Ser Val Val Ile Gly Tyr Ser Arg Asn Glu Leu Thr Glu Lys Ala 355 360 365 Leu Lys Lys Ala Gly Val Lys Val Leu Ser Leu Asp Gly Asn Gln Leu 370 375 380 Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Ile Arg 385 390 395 400 Glu Asp Val Lys <![CDATA[<210> 41]]> <![CDATA[<211> 401]]> <![CDATA[<212> PRT]]> <![CDATA[<213> Mycoplasma lipofaciens]]> <![CDATA[<400> 41]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Val Gly Val Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Val Ala Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Gln Asp Ala Ile 35 40 45 Ala Glu His Lys Arg Phe Ile Lys Ile Leu Glu Asp Asn Asn Ile Lys 50 55 60 Val Ile Gln Leu Asp Glu Leu Val Ser Glu Thr Trp Glu Lys Ala Thr 65 70 75 80 Ala Glu Gln Arg Asp Ala Phe Ile Glu Lys Trp Leu Asp Glu Ala Glu 85 90 95 Pro Val Leu Asp Ala Lys Leu Arg Glu Thr Val Lys Lys Tyr Leu Leu 100 105 110 Ser Leu Asn Pro Val Lys Lys Met Val Arg Thr Met Met Ala Gly Ile 115 120 125 Asp Lys Lys Glu Leu Lys Ile Glu Leu Asp Arg Asp Leu Val Val Asp 130 135 140 Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Ala Gly 145 150 155 160 Asn Gly Ile Ser Leu Asn Asn Met Lys Tyr Val Thr Arg Lys Arg Glu 165 170 175 Thr Ile Phe Ala Glu Phe Ile Phe Asn Ile His Pro Asp Tyr Lys Thr 180 185 190 Thr Pro His Trp Phe Asp Arg Leu Asp Lys Gly Asn Ile Glu Gly Gly 195 200 205 Asp Val Phe Ile Tyr Asn Lys Asp Thr Leu Val Leu Gly Val Ser Glu 210 215 220 Arg Thr Asn Lys Asp Ala Val Met Thr Ile Ala Lys His Ile Gln Ser 225 230 235 240 Asn Glu Gln Ala Lys Phe Lys Lys Leu Val Ala Ile Asn Val Pro Pro 245 250 255 Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Val Asp His 260 265 270 Asp Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys Ile Trp 275 280 285 Glu Ile Asp Leu Thr Pro Gly Lys Glu Ile Glu Met Val Glu Ser Thr 290 295 300 Lys Ser Leu Ser Asp Met Leu Glu Ser Ile Ile Gly Lys Lys Pro Val 305 310 315 320 Leu Ile Pro Ile Ala Gly Lys Asp Ala Ser Gln Leu Asp Ile Asp Ile 325 330 335 Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Arg Pro Gly Val 340 345 350 Val Val Gly Tyr Ser Arg Asn Cys Leu Thr Glu Gln Ala Leu Lys Asp 355 360 365 Ala Gly Val Thr Val Leu Ser Phe Asp Gly Asn Gln Leu Ser Leu Gly 370 375 380 Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp Ile 385 390 395 400 Lys <![CDATA[<210> 42]]> <![CDATA[<211> 405]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 小貓黴漿菌]]> <![CDATA[<400> 42]]> Met Asn Lys Ile Asn Val Tyr Ser Glu Ile Gly Lys Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asn Glu Ile Arg Arg Ile Ser Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Leu Leu Glu Pro Asn Phe Ala Ala 35 40 45 Lys Glu His Thr Ala Phe Cys Glu Ile Leu Lys Glu Asn Gly Ile Lys 50 55 60 Ala Ile Gln Leu Val Asp Leu Val Ser Asp Thr Trp Arg Ile Ala Ser 65 70 75 80 Glu Lys Ala Lys Thr Glu Phe Ile Glu Arg Trp Leu Asp Glu Cys Glu 85 90 95 Pro Lys Leu Asp Ser Asn Leu Arg Glu Ile Val Arg Lys His Ile Tyr 100 105 110 Ala Ile Glu Lys Arg Ser Val Lys Arg Met Val Lys Thr Met Met Ala 115 120 125 Gly Ile Glu Arg Arg Glu Leu Pro Val Thr Ser Lys Glu Val Ala Arg 130 135 140 Glu Leu Val Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro 145 150 155 160 Phe Ala Ser Val Gly Asn Gly Ile Ser Leu His His Met Lys Tyr Val 165 170 175 Thr Arg Gln Arg Glu Thr Ile Phe Ala Glu Phe Val Phe Gly Asn His 180 185 190 Pro Asp Tyr Ile Asp Thr Pro Arg Trp Phe Asp Arg Ser Asp Asp Gly 195 200 205 Arg Ile Glu Gly Gly Asp Val Phe Ile Tyr Gly Ser Lys Thr Leu Val 210 215 220 Ile Gly Val Ser Glu Arg Thr Asn Lys Glu Ala Ile Lys Val Met Ala 225 230 235 240 Lys Lys Ile Gln Ala Asn Lys Glu Ala Thr Phe Glu Lys Ile Tyr Ala 245 250 255 Ile Asn Val Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu 260 265 270 Thr Met Leu Asp Lys Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ala 275 280 285 Val Leu Gln Val Trp Glu Ile Asp Leu Lys Asp Pro Glu Leu Thr Trp 290 295 300 His Glu Leu Ser Gly Ser Leu Glu Glu Ile Leu His Lys Ile Ile Gly 305 310 315 320 Arg Lys Pro Ile Leu Ile Pro Ile Ala Gly His Gly Ala Gln Gln Ile 325 330 335 Asp Ile Asp Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Ala Ile 340 345 350 Ala Pro Gly Val Val Val Gly Tyr Asn Arg Asn Val Leu Thr Glu Arg 355 360 365 Ala Leu Lys Lys Ala Gly Ile Lys Val Leu Ser Phe Glu Gly Asn Gln 370 375 380 Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Ile 385 390 395 400 Arg Glu Asn Leu Lys 405 <![CDATA[<210> 43]]> <![CDATA[<211> 404]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 模仿黴漿菌]]> <![CDATA[<400> 43]]> Met Phe Asn Lys Ile Lys Val Tyr Ser Glu Ile Gly Arg Leu Arg Lys 1 5 10 15 Val Leu Val His Thr Pro Gly Lys Glu Leu Glu Tyr Val Thr Pro Gln 20 25 30 Arg Leu Asp Glu Leu Leu Phe Ser Ser Leu Leu Asn Pro Val Lys Ala 35 40 45 Arg Gln Glu His Glu Ala Phe Ile Lys Ile Leu Gln Asp Gln Gly Val 50 55 60 Glu Cys Val Gln Leu Thr Thr Leu Thr Ala Gln Thr Phe Gln Ser Ala 65 70 75 80 Thr Ser Glu Val Lys Glu Lys Phe Ile Asn Arg Trp Leu Asp Glu Cys 85 90 95 Leu Pro Lys Leu Ser Asp Asp Asn Arg Ile Lys Val Tyr Ala Tyr Leu 100 105 110 Lys Asp Leu Ser Ser Asp Pro Glu Val Met Ile Arg Lys Met Met Ser 115 120 125 Gly Ile Leu Ala Lys Glu Val Asn Val Gln Ser Asp Val Glu Leu Ile 130 135 140 Ala Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Ile Gly Lys Gly Val Thr Leu His Ser Met Phe His Pro Thr Arg Lys 165 170 175 Arg Glu Thr Ile Phe Ala Asp Phe Val Phe Ser His His Pro Glu Tyr 180 185 190 Lys Gln Thr Pro Lys Tyr Tyr Ser Arg Leu Asn Glu Tyr Ser Ile Glu 195 200 205 Gly Gly Asp Leu Phe Val Tyr Asp Asp Lys Thr Leu Val Ile Gly Val 210 215 220 Ser Glu Arg Thr Glu Lys Lys Ala Ile Gln Phe Leu Ala Glu Lys Leu 225 230 235 240 Arg Glu Asn Tyr Glu Thr Thr Phe Glu Lys Ile Tyr Ala Ile Asn Val 245 250 255 Pro Lys Met Ser Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Leu 260 265 270 Asp Tyr Asp Lys Phe Leu Tyr Ser Pro Asn Met Met Gly Val Leu Lys 275 280 285 Ile Trp Glu Ile Asp Leu Thr His Glu Gln Leu Ser Trp Arg Glu Leu 290 295 300 Asn Glu Ser Leu Glu Glu Phe Leu Ser Met Val Ile Gly Lys Lys Ala 305 310 315 320 Thr Thr Ile Pro Val Ala Gly Glu Asp Ser Thr Gln Ile Glu Ile Asp 325 330 335 Val Glu Thr Asn Phe Asp Ala Thr Asn Phe Leu Val Ile Gln Pro Gly 340 345 350 Val Val Val Gly Tyr Asp Arg Asn Tyr Lys Thr Asn Gln Ala Leu Val 355 360 365 Asn Ala Gly Ile Lys Val Leu Ser Trp Asn Gly Asp Gln Leu Ser Leu 370 375 380 Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Tyr Arg Asp Pro 385 390 395 400 Ile Lys Lys Gly <![CDATA[<210> 44]]> <![CDATA[<211> 401]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 乳白色黴漿菌]]> <![CDATA[<400> 44]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Ile Gly Thr Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Val Ala Pro Ala Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Asn His Ala Ile 35 40 45 Ala Glu His Lys Ala Phe Ile Lys Ile Leu Glu Asp Asn Gly Ile Lys 50 55 60 Val Ile Gln Leu Asp Glu Leu Val Val Gln Thr Trp Asn Gln Val Asp 65 70 75 80 Glu Ala Thr Arg Lys Ala Phe Val Thr Lys Trp Leu Asp Glu Cys Glu 85 90 95 Pro Lys Leu Glu Ser Asn Val Arg Val Glu Val Glu Lys Tyr Ile Tyr 100 105 110 Ser Leu Ala Lys Glu Pro Lys Lys Met Val Arg Thr Met Met Ala Gly 115 120 125 Ile Ser Lys Glu Glu Leu Pro Leu Asn Val Asn Arg Pro Leu Val Val 130 135 140 Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val 145 150 155 160 Gly Thr Gly Ile Ser Leu His His Met Lys Tyr Val Thr Arg Gln Arg 165 170 175 Glu Thr Ile Phe Ala Gln Phe Val Phe Asp Asn His Lys Asp Tyr Asn 180 185 190 Thr Val Pro Arg Trp Phe Asp Asn Lys Asp Gln Gly Arg Ile Glu Gly 195 200 205 Gly Asp Val Phe Ile Tyr Asn Thr Lys Thr Leu Val Ile Gly Val Ser 210 215 220 Glu Arg Thr Asp Lys Asp Ala Ile Lys Ile Met Ala Lys Lys Ile Gln 225 230 235 240 Ala Asp Lys Asn Cys Lys Phe Glu Lys Ile Phe Ala Ile Asn Val Pro 245 250 255 Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Val Asp 260 265 270 Arg Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys Val 275 280 285 Trp Glu Ile Asp Leu Lys Asp Ala Ser Leu Ala Trp Lys Glu Ile Glu 290 295 300 Gly Ser Leu Ser Gln Ile Leu Glu Lys Ile Ile Gly Glu Lys Pro Ile 305 310 315 320 Leu Ile Pro Ile Ala Gly Glu Asn Ala Ser Gln Leu Asp Ile Asp Ile 325 330 335 Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly Val 340 345 350 Val Val Gly Tyr Ser Arg Asn Val Lys Thr Glu Gln Ala Leu Lys Ala 355 360 365 Ala Gly Val Lys Val Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu Gly 370 375 380 Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Ile Arg Glu Asp Leu 385 390 395 400 Lys <![CDATA[<210> 45]]> <![CDATA[<211> 425]]> <![CDATA[<212> ]]> PRT <![CDATA[<213> 毛氏黴漿菌]]> <![CDATA[<400> 45]]> Met Lys Lys Asn Ala Ile Asn Val Tyr Ser Glu Ile Gly Lys Leu Lys 1 5 10 15 Lys Val Leu Val His Arg Pro Gly Asp Glu Leu Lys Tyr Val Thr Pro 20 25 30 Gln Arg Met Asp Glu Leu Leu Met Ser Ala Ile Ile Glu Leu Glu Gln 35 40 45 Ala Lys Glu Glu His Asp Ala Phe Thr Lys Ile Leu Arg Asp Asn Gly 50 55 60 Val Glu Val Ile Glu Leu Ala Asp Leu Thr Ala Glu Met Tyr Asp Ser 65 70 75 80 Leu Thr Pro Ser Glu Lys Asp Ala Phe Leu Asn Gln Trp Val Lys Glu 85 90 95 Ala Ser Trp Gly Lys Lys Ser Ser Ile Asp Ala Leu Lys Ile Lys Lys 100 105 110 Asn Leu Ser Lys Lys Val Phe Asp Tyr Val Lys Ser Ile Lys Pro Thr 115 120 125 Arg Lys Met Ile Asp Lys Leu Met Ala Gly Val Leu Leu Ser Glu Ile 130 135 140 Gly Glu Lys Ser Ile Ile Leu Asn Lys Asp Lys Lys Asn Glu Met Val 145 150 155 160 Ile Asp Leu Val Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp 165 170 175 Pro Phe Ala Ser Val Gly Asn Gly Ile Thr Leu His Asn Met Lys Tyr 180 185 190 Pro Thr Arg Lys Arg Glu Thr Ile Phe Ala Gln Trp Ile Phe Asn Lys 195 200 205 His Pro Glu Tyr Lys Asp Val Pro Gln Phe Ile Ser Lys Arg Asp Gly 210 215 220 Lys Glu Thr Ile Glu Gly Gly Asp Val Phe Ile Tyr Thr Lys Asp Val 225 230 235 240 Leu Ala Ile Gly Val Ser Glu Arg Thr Asn Met Glu Ala Ile Leu Arg 245 250 255 Ile Ala Thr Asn Ile Lys Lys Asp Lys Asn Cys Glu Phe Lys Lys Ile 260 265 270 Val Ala Ile Asn Val Pro Pro Met Gly Asn Leu Met His Leu Asp Thr 275 280 285 Trp Leu Thr Met Leu Asp Lys Asp Leu Phe Leu Tyr Ser Gly Asn Ile 290 295 300 Lys Ser Ala Leu Lys Val Trp Glu Ile Asp Leu Thr Lys Pro Ile Thr 305 310 315 320 Pro Lys Ser Pro Lys Leu Ser Thr Ala Lys Leu Ala Asp Ile Leu Ala 325 330 335 Lys Ile Val Gly Lys Lys Val Arg Met Ile Pro Ile Gly Gly Lys Asp 340 345 350 Gly Asn Gln Met Asp Ile Asp Ile Glu Thr His Phe Asp Gly Thr Asn 355 360 365 Tyr Leu Ala Ile Ala Pro Gly Val Val Val Gly Tyr His Arg Asn Arg 370 375 380 Lys Thr Gln Lys Ala Leu Glu Glu Ala Gly Val Lys Val Leu Ala Phe 385 390 395 400 Gln Gly Asn Gln Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser 405 410 415 Met Pro Leu Val Arg Glu Glu Val Lys 420 425 <![CDATA[<210> 46]]> <![CDATA[<211> 399]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 象黴漿菌]]> <![CDATA[<400> 46]]> Met Ser Gln Ile Asn Val Phe Ser Glu Ile Gly Gln Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ser Pro Lys Arg 20 25 30 Tyr Asn Glu Leu Leu Phe Ser Ala Ile Leu Glu Ala Asp Val Ala Ile 35 40 45 Lys Glu His Lys Ser Phe Val Lys Ile Leu Glu Glu Asn Asn Val Lys 50 55 60 Val Ile Gln Leu Lys Asp Ile Leu Leu Glu Thr Trp Asn Ile Cys Ser 65 70 75 80 Lys Glu Ala Lys Asn Ile Phe Ile Asn Lys Trp Ile Glu Glu Ala Gln 85 90 95 Pro Val Ile His Ser Ser Ser Leu Lys Glu Lys Ile Lys Leu Phe Leu 100 105 110 Lys Ser Lys Thr Pro Leu Glu Ile Ile Asp Ile Met Met Lys Gly Ile 115 120 125 Leu Lys Gln Glu Leu Gly Ile Glu Tyr Lys His Glu Leu Ile Ile Asp 130 135 140 Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Thr Ser Met Gly 145 150 155 160 Ser Gly Ile Thr Ile Asn Asn Met Lys Tyr Gln Thr Arg Lys Arg Glu 165 170 175 Thr Ile Phe Ser Glu Phe Ile Phe Asn Asn His Pro Lys Tyr Lys Asn 180 185 190 Thr Pro Arg Trp Phe Asp Arg Phe Asp Ser Gly Asn Ile Glu Gly Gly 195 200 205 Asp Leu Phe Val Tyr Thr Lys Glu Thr Ile Val Val Gly Val Ser Glu 210 215 220 Arg Thr Lys Lys Lys Ala Ile Leu Lys Ile Ala Lys Asn Ile Gln Glu 225 230 235 240 Asn Asn Asn Ser Phe Lys Lys Ile Val Val Ile Lys Val Pro Ile Met 245 250 255 Gln Asn Leu Met His Leu Asp Thr Trp Ile Val Met Val Asp Phe Asp 260 265 270 Lys Phe Ile Tyr Ser Pro Asn Val Thr Lys Ser Leu Lys Phe Trp Glu 275 280 285 Ile Asp Leu Thr Lys Lys Pro Lys Phe Ile Gln Leu Lys Asn Glu Thr 290 295 300 Leu Glu Asp Val Leu Tyr Arg Val Ile Gly Lys Lys Pro Ile Leu Ile 305 310 315 320 Pro Val Ala Gly Glu Asn Ala Asn Gln Ile Asp Ile Asp Val Glu Thr 325 330 335 His Phe Asp Ala Thr Asn Tyr Leu Thr Ile Arg Pro Gly Val Val Val 340 345 350 Gly Tyr Ser Arg Asn Lys Lys Thr Glu Glu Ala Leu Ile Asn Ala Gly 355 360 365 Val Lys Val Tyr Ala Phe Glu Gly Asn Gln Leu Ser Leu Gly Met Gly 370 375 380 Ser Ala Arg Cys Met Ser Met Pro Leu Ile Arg Glu Asp Ile Ile 385 390 395 <![CDATA[<210> 47]]> <![CDATA[<211> 399]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 龜黴漿菌]]> <![CDATA[<400> 47]]> Met Lys Asn Ile Asn Val Tyr Ser Glu Val Gly Lys Leu Lys Glu Val 1 5 10 15 Val Val His Thr Pro Gly Glu Glu Leu His Asn Val Ala Pro Ser Arg 20 25 30 Leu Gln Glu Leu Leu Thr Ser Ala Val Leu Glu Pro Glu Val Ala Arg 35 40 45 Lys Glu His Leu Lys Phe Ile Lys Ile Leu Asn Asp Tyr Gly Val Lys 50 55 60 Val Ile Gln Ile Val Asp Leu Ile Thr Glu Thr Tyr Glu Ala Val Asp 65 70 75 80 Ser Asn Lys Lys Glu Ala Phe Ile Asn Asn Trp Leu Asp Asn Ser Val 85 90 95 Pro Lys Leu Thr Asp Lys Asn Arg Met Ile Leu Arg Asn Tyr Leu Thr 100 105 110 Gln Phe Ser Thr Lys Ala Met Ile Arg Lys Met Ile Ser Gly Ile Arg 115 120 125 Ala Lys Glu Leu Asn Leu Lys Thr Pro Ser Ala Leu Leu Val Asp Pro 130 135 140 Met Pro Asn Leu Cys Phe Ala Arg Asp Thr Phe Ala Cys Val Gly Ser 145 150 155 160 Ala Ile Ser Leu Ser Thr Met Lys His Pro Thr Arg Arg Arg Glu Ala 165 170 175 Leu Leu Thr Glu Phe Ile Phe Gln Asn His Pro Lys Tyr Lys Asp Val 180 185 190 Ile Lys Tyr Phe Asp Ser Lys Asn Ser Lys Ala Thr Ile Glu Gly Gly 195 200 205 Asp Ile Phe Val Tyr Asn Pro Lys Thr Leu Val Val Gly Asn Ser Glu 210 215 220 Arg Thr Asn Met Gln Ala Cys Leu Leu Leu Ala Lys Lys Ile Gln Ser 225 230 235 240 Asn Pro Asn Asn Lys Phe Glu Lys Ile Val Ile Val Asn Val Pro Pro 245 250 255 Leu Pro His Leu Met His Leu Asp Thr Trp Leu Thr Met Val Asp Tyr 260 265 270 Asp Lys Phe Ile Tyr Ser Pro Asn Ile Leu His Thr Leu Lys Phe Trp 275 280 285 Val Ile Asp Leu Lys Lys Arg Lys Leu Glu Ala Val Glu Lys His Asn 290 295 300 Thr Leu Lys Ala Met Leu Arg Met Ile Ile Lys Lys Glu Pro Ile Leu 305 310 315 320 Ile Pro Val Gly Asp Val Gly Ala Asp Gln Leu Asp Ile Asp Leu Glu 325 330 335 Thr His Phe Asp Ala Thr Asn Tyr Leu Ala Leu Ala Pro Gly Val Val 340 345 350 Val Gly Tyr Asp Arg Asn Ile Lys Thr Gln Arg Ala Leu Glu Lys Ala 355 360 365 Gly Val Lys Val Leu Ser Phe Ser Gly Asn Gln Leu Ser Leu Ala Met 370 375 380 Gly Ser Ala Arg Cys Leu Ser Met Pro Leu Ile Arg Glu Glu Asn 385 390 395 <![CDATA[<210> 48]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 加拿大黴漿菌]]> <![CDATA[<400> 48]]> Met Ser Val Phe Asp Ser Lys Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Glu Ser Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Lys Glu His Lys Gln Phe Val Ser Glu 50 55 60 Leu Lys Ala Asn Asp Ile Asn Val Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Lys Asp Lys Leu Ile Glu 85 90 95 Glu Phe Leu Glu Asp Ser Glu Pro Val Leu Ser Glu Glu His Lys Ala 100 105 110 Ile Val Arg Lys Tyr Leu Lys Gly Ile Gln Pro Thr Arg Lys Leu Ile 115 120 125 Glu Met Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Asp His Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Val Phe Ser 180 185 190 Asn His Pro Lys Leu Val Asn Thr Pro Trp Tyr Tyr Asp Pro Ser Leu 195 200 205 Lys Leu Ser Ile Glu Gly Gly Asp Val Phe Val Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Val Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Val Ala Asn Lys Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Lys Asp Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Ser 290 295 300 Glu Pro Gln Pro Val Glu Asn Gly Leu Pro Leu Glu Gly Leu Leu Glu 305 310 315 320 Ser Ile Ile Asn Lys Lys Pro Ile Leu Ile Pro Ile Ala Gly Glu Gly 325 330 335 Ala Ser Gln Met Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Arg Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 His Gly Asn Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ser Arg Lys Asp Val Lys Trp 405 410 <![CDATA[<210> 49]]> <![CDATA[<211> 409]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 鵝黴漿菌]]> <![CDATA[<400> 49]]> Met Ser Val Phe Asp Lys Arg Phe Lys Gly Ile His Val Tyr Ser Glu 1 5 10 15 Ile Gly Glu Leu Gln Thr Val Leu Val His Glu Pro Gly Arg Glu Ile 20 25 30 Asp Tyr Ile Thr Pro Ala Arg Leu Asp Glu Leu Leu Phe Ser Ala Ile 35 40 45 Leu Glu Ser His Asp Ala Arg Ala Glu His Lys Lys Phe Val Ala Thr 50 55 60 Leu Lys Glu Gln Gly Ile Asn Thr Val Glu Leu Thr Asp Leu Val Ala 65 70 75 80 Glu Thr Tyr Asp Leu Ala Ser Gln Glu Ala Arg Asp Asn Leu Leu Glu 85 90 95 Glu Phe Leu Asp Asp Ser Ala Pro Val Leu Ser Glu Glu His Lys Glu 100 105 110 Ile Val Arg Thr Tyr Leu Lys Gly Ile Lys Gly Thr Arg Lys Leu Ile 115 120 125 Glu Thr Met Met Ala Gly Ile Thr Lys Tyr Asp Leu Gly Ile Glu Ala 130 135 140 Glu Gln Glu Leu Ile Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg 145 150 155 160 Asp Pro Phe Ala Ser Val Gly Asn Gly Val Thr Ile His Tyr Met Arg 165 170 175 Tyr Lys Val Arg Gln Arg Glu Thr Leu Phe Ser Arg Phe Ile Phe Ser 180 185 190 Asn His Pro Gln Leu Val Asn Thr Pro Trp Tyr Tyr Asn Pro Ala Glu 195 200 205 Gly Leu Ser Ile Glu Gly Gly Asp Val Phe Ile Tyr Asn Asn Asp Thr 210 215 220 Leu Val Val Gly Val Ser Glu Arg Thr Asp Leu Gln Thr Ile Thr Leu 225 230 235 240 Leu Ala Lys Asn Ile Lys Ala Asn Glu Glu Cys Glu Phe Lys Arg Ile 245 250 255 Val Ala Ile Asn Val Pro Lys Trp Thr Asn Leu Met His Leu Asp Thr 260 265 270 Trp Leu Thr Met Leu Asp Thr Asn Lys Phe Leu Tyr Ser Pro Ile Ala 275 280 285 Asn Asp Val Phe Lys Phe Trp Asp Tyr Asp Leu Val Asn Gly Gly Asp 290 295 300 Glu Pro Gln Pro Val Asp Asn Gly Leu Pro Leu Asn Glu Leu Leu Lys 305 310 315 320 Ser Ile Ile Gly Glu Glu Pro Ile Leu Ile Pro Ile Ala Gly Asp Gly 325 330 335 Ala Thr Gln Ile Glu Ile Glu Arg Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Ala Ile Ala Pro Gly Val Val Ile Gly Tyr Ser Arg Asn Glu 355 360 365 Lys Thr Asn Ala Ala Leu Glu Ala Ala Gly Ile Lys Val Leu Pro Phe 370 375 380 Lys Gly His Gln Leu Ser Leu Gly Met Gly Asn Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Tyr Arg Lys Asp Val Lys 405 <![CDATA[<210> 50]]> <![CDATA[<211> 401]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 火雞黴漿菌]]> <![CDATA[<400> 50]]> Met Ser Lys Ile Asn Val Tyr Ser Glu Ile Gly Val Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ser Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Gln Pro Glu Gln Ala Ile 35 40 45 Lys Glu His Gln Ser Phe Val Lys Ile Leu Gln Asp Arg Gly Ile Lys 50 55 60 Val Ile Gln Leu Ser Asp Leu Val Ala Glu Thr Tyr Val Lys Tyr Ala 65 70 75 80 Thr Ser Lys Glu Lys Glu Ser Phe Ile Glu Lys Trp Leu Asp Glu Ala 85 90 95 Thr Pro Ala Leu Asn Ser Glu Asn Arg Ala Arg Val Lys Asn Tyr Ile 100 105 110 Thr Ala Met Gln Gly Gln Pro Val Lys Met Val Arg Ala Met Met Ala 115 120 125 Gly Val Ser Lys Gln Glu Leu Asn Ile Glu Ser Asp Val Glu Leu Ile 130 135 140 Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Ala Gly Asn Gly Ile Ser Leu Asn Asn Met Lys Tyr Val Val Arg Lys 165 170 175 Arg Glu Thr Ile Phe Ala Glu Phe Ile Phe Ser Ile His Pro Glu Tyr 180 185 190 Lys Gln Thr Pro His Trp Phe Asp Arg Leu Asp Lys Gly Asn Ile Glu 195 200 205 Gly Gly Asp Val Phe Ile Tyr Asn Lys Asp Thr Leu Val Ile Gly Val 210 215 220 Ser Glu Arg Thr Asn Lys Glu Ala Ile Leu Thr Ile Ala Glu His Ile 225 230 235 240 Lys Asn Asn Lys Glu Ala Lys Phe Lys Lys Ile Val Ala Ile Asn Val 245 250 255 Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Val 260 265 270 Asp Lys Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys 275 280 285 Ile Trp Glu Ile Asp Leu Ser Lys Glu Ile Lys Met Val Glu Thr Ser 290 295 300 Lys Pro Leu Ala Asp Val Leu Glu Ser Ile Ile Gly Glu Lys Pro Ile 305 310 315 320 Leu Ile Pro Ile Ala Gly Glu Asn Ala Ser Gln Leu Asp Ile Asp Ile 325 330 335 Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Gly Val 340 345 350 Val Val Gly Tyr Ser Arg Asn Val Lys Thr Glu Ala Ala Leu Lys Ala 355 360 365 Ala Gly Val Thr Val Tyr Ser Phe Asp Gly Asn Gln Leu Ser Leu Gly 370 375 380 Met Gly Ser Gly Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp Val 385 390 395 400 Lys <![CDATA[<210> 51]]> <![CDATA[<211> 404]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 蜂房黴漿菌]]> <![CDATA[<400> 51]]> Met Ser Ile Lys Glu Asn Gly Ile His Val Tyr Ser Glu Ile Gly Lys 1 5 10 15 Leu Arg Asp Val Leu Val His Arg Pro Gly Arg Glu Leu Asn Phe Leu 20 25 30 Asp Pro Ser Arg Leu Asp Glu Leu Leu Phe Ala Ala Thr Leu Glu Pro 35 40 45 Glu Thr Ala Arg Leu Glu His Asp Asn Phe Thr Thr Val Leu Lys Asn 50 55 60 Gln Gly Val Asn Val Ile Glu Leu Ala Asp Leu Val Ser Gln Thr Tyr 65 70 75 80 Ser Lys Val Asp Ser Lys Val Lys Lys Glu Phe Ile Asp Gln Tyr Leu 85 90 95 Asn Glu Ala Thr Pro Lys Leu Thr Ser Glu Leu Ser Lys Lys Val Tyr 100 105 110 Asp Phe Leu Thr Lys Gln Lys Ser Asn Arg Glu Met Val Asp Phe Met 115 120 125 Met Gly Gly Ile Leu Ser Ser Asp Leu Asn Ile Lys Gly Gln Pro Tyr 130 135 140 Leu Ile Val Glu Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe 145 150 155 160 Ala Ser Val Gly Asn Gly Ala Thr Ile His Trp Met Lys His Asn Val 165 170 175 Arg Arg Arg Glu Val Leu Phe Ala Asn Phe Ile Phe Lys Tyr Asn Glu 180 185 190 Arg Phe Gln Asn Thr Pro Lys Tyr Ile Thr Pro Thr Lys Gly Leu Asp 195 200 205 Ile Glu Gly Gly Asp Val Phe Val Tyr Asn Lys Lys Thr Leu Val Val 210 215 220 Gly Val Ser Glu Arg Thr Lys Met Glu Thr Ile Lys Glu Leu Ala Lys 225 230 235 240 Asn Ile Ser Lys Asn Lys Glu Cys Thr Phe Thr Lys Ile Tyr Ala Ile 245 250 255 Asn Val Pro Lys Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr 260 265 270 Met Leu Asp Tyr Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val 275 280 285 Leu Lys Val Trp Glu Ile Asn Ile Ser Asn Asn Lys Val Ser Ala Pro 290 295 300 Lys Glu Leu Asn Val Asn Leu Glu Lys Ala Leu Ser Met Ile Ile Gly 305 310 315 320 Lys Lys Pro Ile Leu Ile Pro Val Ala Gly Ala Asn Ala Ser Gln Ile 325 330 335 Asp Ile Asn Ile Glu Thr Asn Phe Asp Ala Thr Asn Tyr Leu Val Ile 340 345 350 Glu Pro Gly Val Val Val Gly Tyr Ser Arg Asn Lys Lys Thr Glu Glu 355 360 365 Ala Leu Val Lys Ala Gly Ile Lys Val Leu Pro Phe His Gly Asn Gln 370 375 380 Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Tyr 385 390 395 400 Arg Glu Asp Val <![CDATA[<210> 52]]> <![CDATA[<211> 410]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 滲透黴漿菌]]> <![CDATA[<400> 52]]> Met Ser Ser Ile Asp Lys Asn Ser Leu Gly Asn Gly Ile Asn Val Tyr 1 5 10 15 Ser Glu Ile Gly Glu Leu Lys Glu Val Leu Val His Thr Pro Gly Asp 20 25 30 Glu Ile Arg Tyr Thr Ala Pro Ser Arg Leu Glu Glu Leu Leu Phe Ser 35 40 45 Ala Val Leu Lys Ala Asp Thr Ala Ile Glu Glu His Lys Gly Phe Val 50 55 60 Lys Ile Leu Gln Asn Asn Gly Ile Lys Val Ile Gln Leu Cys Asp Leu 65 70 75 80 Val Ala Glu Thr Tyr Glu Leu Cys Ser Lys Glu Val Arg Asn Ser Phe 85 90 95 Ile Glu Gln Tyr Leu Asp Glu Ala Leu Pro Val Leu Lys Lys Glu Ile 100 105 110 Arg Pro Val Val Lys Asp Tyr Leu Leu Ser Phe Pro Thr Val Gln Met 115 120 125 Val Arg Lys Met Met Ser Gly Ile Leu Ala Asn Glu Leu Asn Ile Lys 130 135 140 Gln Asp Asn Pro Leu Ile Ile Asp Gly Met Pro Asn Leu Tyr Phe Thr 145 150 155 160 Arg Asp Pro Phe Ala Ser Met Gly Asn Gly Val Ser Ile Asn Cys Met 165 170 175 Lys Tyr Pro Thr Arg Lys Arg Glu Val Ile Phe Ser Arg Phe Val Phe 180 185 190 Thr Asn Asn Pro Lys Tyr Lys Asn Thr Pro Arg Tyr Phe Asp Ile Val 195 200 205 Gly Asn Asn Gly Thr Ile Glu Gly Gly Asp Ile Phe Ile Tyr Asn Ser 210 215 220 Lys Thr Leu Val Ile Gly Asn Ser Glu Arg Thr Asn Phe Ala Ala Ile 225 230 235 240 Glu Ser Val Ala Lys Asn Ile Gln Ala Asn Lys Asp Cys Thr Phe Glu 245 250 255 Arg Ile Val Val Ile Asn Val Pro Pro Met Pro Asn Leu Met His Leu 260 265 270 Asp Thr Trp Leu Thr Met Leu Asp Tyr Asp Lys Phe Leu Tyr Ser Pro 275 280 285 Asn Met Met Asn Val Leu Lys Ile Trp Glu Ile Asp Leu Asn Val Lys 290 295 300 Pro Val Lys Phe Val Glu Lys Lys Gly Thr Leu Glu Glu Val Leu Tyr 305 310 315 320 Ser Ile Ile Asp Lys Lys Pro Ile Leu Ile Pro Ile Ala Gly Lys Gly 325 330 335 Ala Asn Gln Leu Asp Ile Asp Ile Glu Thr His Phe Asp Gly Thr Asn 340 345 350 Tyr Leu Thr Ile Ala Pro Gly Val Val Val Gly Tyr Glu Arg Asn Glu 355 360 365 Lys Thr Gln Lys Ala Leu Val Glu Ala Gly Ile Lys Val Leu Ser Phe 370 375 380 Asn Gly Ser Gln Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser 385 390 395 400 Met Pro Leu Ile Arg Glu Asn Leu Lys Lys 405 410 <![CDATA[<210> 53]]> <![CDATA[<211> 4]]>04 <![CDATA[<212> PRT]]> <![CDATA[<213> 發酵黴漿菌]]> <![CDATA[<400> 53]]> Met Lys Lys Ile Asn Val Tyr Ser Glu Tyr Gly Lys Leu Lys Glu Val 1 5 10 15 Leu Val His Thr Pro Gly Asp Glu Ile Arg Arg Ile Ala Pro Ser Arg 20 25 30 Leu Asp Glu Leu Leu Phe Ser Ala Ile Leu Glu Pro Asp Ser Ala Ile 35 40 45 Ala Glu His Lys Arg Phe Val Gln Leu Leu Lys Asp Asn Gly Ile Lys 50 55 60 Val Ile Gln Leu Asp Glu Leu Phe Ala Lys Thr Phe Asp Leu Val Ser 65 70 75 80 Glu Ser Val Lys Gln Ser Phe Ile Glu Arg Trp Leu Asp Glu Cys Glu 85 90 95 Pro Lys Leu Asp Ala Thr Leu Arg Ala Lys Val Lys Glu Tyr Ile Leu 100 105 110 Glu Leu Lys Ala Lys Ser Ser Lys Lys Met Val Arg Val Met Met Ala 115 120 125 Gly Ile Asp Lys Lys Glu Leu Gly Ile Glu Leu Asp Arg Asp Leu Val 130 135 140 Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro Phe Ala Ser 145 150 155 160 Val Gly Asn Gly Ile Ser Leu His His Met Lys Tyr Val Thr Arg Gln 165 170 175 Arg Glu Thr Ile Phe Ser Glu Phe Ile Phe Asp Asn Asn Leu Asp Tyr 180 185 190 Asn Thr Val Pro Arg Trp Phe Asp Arg Lys Asp Glu Gly Arg Ile Glu 195 200 205 Gly Gly Asp Val Phe Ile Tyr Ser Ala Asp Thr Leu Val Val Gly Val 210 215 220 Ser Glu Arg Thr Asn Lys Glu Ala Ile Asn Val Met Ala Arg Lys Ile 225 230 235 240 Ala Ala Asp Lys Glu Val Lys Phe Lys Arg Ile Tyr Ala Ile Asn Val 245 250 255 Pro Pro Met Pro Asn Leu Met His Leu Asp Thr Trp Leu Thr Met Leu 260 265 270 Asp Lys Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ser Val Leu Lys 275 280 285 Val Trp Arg Ile Asp Leu Asn Asp Pro Asp Phe Val Trp His Glu Ile 290 295 300 Glu Gly Ser Leu Glu Glu Ile Leu Glu Gln Ile Ile Gly Met Lys Pro 305 310 315 320 Ile Leu Ile Pro Ile Ala Gly Lys Gly Ala Ser Gln Leu Asp Ile Asp 325 330 335 Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile Ala Pro Ser 340 345 350 Val Val Val Gly Tyr Ser Arg Asn Glu Lys Thr Glu Lys Ala Leu Lys 355 360 365 Ala Ala Lys Val Lys Val Leu Ser Phe Glu Gly Asn Gln Leu Ser Leu 370 375 380 Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Ile Arg Glu Asp 385 390 395 400 Ile Lys Lys Lys <![CDATA[<210> 54]]> <![CDATA[<211> 404]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 肺炎黴漿菌]]> <![CDATA[<400> 54]]> Met Lys Tyr Asn Ile Asn Val His Ser Glu Ile Gly Gln Leu Gln Thr 1 5 10 15 Val Leu Val His Thr Pro Gly Asn Glu Ile Arg Arg Ile Ser Pro Arg 20 25 30 Arg Leu Asp Asp Leu Leu Phe Ser Ala Val Ile Glu Pro Asp Thr Ala 35 40 45 Ile Gln Glu His Gln Thr Phe Cys Gln Leu Leu Gln Glu Gln Asn Ile 50 55 60 Glu Val Val Gln Leu Thr Asp Leu Thr Ala Thr Thr Phe Asp Lys Ala 65 70 75 80 Asn Ala Thr Ala Gln Asn Gln Phe Ile Glu Thr Trp Leu Asp Gln Ala 85 90 95 Glu Pro Lys Leu Thr Pro Glu His Arg Lys Val Ala Lys Gln Tyr Leu 100 105 110 Leu Glu Gln Lys Ala Lys Ser Thr Leu Ser Met Val Arg Ser Met Met 115 120 125 Gly Gly Ile Asp Lys Arg Lys Val Ala Ala Ala Asn Thr Ile Asn Gly 130 135 140 Asp Phe Leu Val Asp Pro Met Pro Asn Leu Tyr Phe Thr Arg Asp Pro 145 150 155 160 Phe Ala Ser Ile Gly His Gly Ile Ser Ile Asn Arg Met Lys Tyr Leu 165 170 175 Thr Arg Arg Arg Glu Thr Leu Phe Ala Ser Phe Ile Phe Ala Asn His 180 185 190 Pro Ile Ile Ala Ala Arg Lys Phe Tyr Phe Lys Pro Ile Asp Met Gly 195 200 205 Thr Ile Glu Gly Gly Asp Ile Phe Val Tyr Asp Gln Gln Thr Val Val 210 215 220 Met Gly Leu Ser Glu Arg Thr Thr Glu Ala Ala Ile Asn Val Leu Ala 225 230 235 240 Lys Lys Ile Gln Gln Asp Ser Ser Thr Ser Phe Lys Arg Ile Phe Val 245 250 255 Ile Asn Val Pro Gln Leu Pro Asn Leu Met His Leu Asp Thr Trp Leu 260 265 270 Thr Met Leu Asp Arg Asn Lys Phe Leu Tyr Ser Pro Asn Met Leu Ala 275 280 285 Val Leu Lys Ala Trp Arg Ile Asp Phe Thr Asp Pro Ala Leu Lys Trp 290 295 300 Asn Glu Ile Ala Gly Asp Leu Ser Thr Ile Leu His Thr Ile Ile Gly 305 310 315 320 Gln Lys Pro Met Leu Ile Pro Ile Ala Gly Ala Asp Ala Asn Gln Thr 325 330 335 Glu Ile Asp Ile Glu Thr His Phe Asp Gly Thr Asn Tyr Leu Thr Ile 340 345 350 Ala Pro Ser Val Val Val Gly Tyr Ala Arg Asn Lys Leu Thr His Gln 355 360 365 Thr Leu Glu Ala Ala Gly Val Lys Val Ile Ala Phe Lys Gly Asn Gln 370 375 380 Leu Ser Leu Gly Met Gly Ser Ala Arg Cys Met Ser Met Pro Leu Val 385 390 395 400 Arg Lys Pro Leu <![CDATA[<210> 55]]> <![CDATA[<211> 414]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 黴漿菌屬CAG:877]]> <![CDATA[<400> 55]]> Met Glu Lys Ile His Val Thr Ser Glu Ile Gly Pro Leu Lys Lys Val 1 5 10 15 Leu Leu His Arg Pro Gly Asn Glu Leu Leu Asn Leu Thr Pro Asp Thr 20 25 30 Leu Ser Arg Leu Leu Phe Asp Asp Ile Pro Tyr Leu Pro Asp Ala Ile 35 40 45 Lys Glu His Asp Glu Phe Ala Asp Ala Leu Arg Ala Asn Gly Val Glu 50 55 60 Val Val Tyr Leu Glu Asn Leu Met Ala Asp Val Leu Asp Leu Ser Asp 65 70 75 80 Glu Ile Arg Asp Lys Phe Ile Lys Gln Phe Ile Tyr Glu Ala Gly Ile 85 90 95 Arg Thr Pro Lys Tyr Lys Tyr Leu Val Phe Asp Tyr Leu Asp Gln Ile 100 105 110 Thr Asn Ser Lys Lys Leu Val Leu Lys Thr Met Glu Gly Ile Gln Ile 115 120 125 Ser Asp Ile Pro Arg Arg Lys Arg Glu Ile Glu Lys Ser Leu Val Asp 130 135 140 Leu Ile Glu Thr Glu Asp Glu Phe Ile Ala Asp Pro Met Pro Asn Leu 145 150 155 160 Tyr Phe Thr Arg Asp Pro Phe Ala Ser Val Gly Glu Gly Ile Ser Leu 165 170 175 Asn Lys Met Tyr Ser Val Thr Arg Asn Arg Glu Thr Ile Tyr Ala Glu 180 185 190 Tyr Ile Phe Lys Tyr His Pro Asp Tyr Lys Asp Gln Ala Arg Leu Tyr 195 200 205 Tyr Asp Arg Tyr Asn Pro Tyr His Ile Glu Gly Gly Asp Val Leu Asn 210 215 220 Ile Asn Asp His Val Leu Ala Ile Gly Ile Ser Gln Arg Thr Thr Ala 225 230 235 240 Glu Ala Ile Asp Gln Ile Ala Lys Asn Leu Phe Lys Asp Pro Glu Cys 245 250 255 Lys Ile Asp Thr Ile Leu Ala Phe Asn Ile Pro Glu Ser Arg Ala Phe 260 265 270 Met His Leu Asp Thr Val Phe Thr Gln Val Asp Tyr Asp Lys Phe Thr 275 280 285 Tyr His Pro Gly Ile Met Gly Thr Leu Gln Val Phe Glu Ile Thr Glu 290 295 300 Gly Asp Asp Pro Asn Ser Asp Glu Asp Leu Thr Val Thr Glu Ile Asn 305 310 315 320 Ala Pro Leu Glu Glu Ile Leu Thr Lys Tyr Val Gly Arg Lys Val Thr 325 330 335 Leu Ile Pro Cys Ala Gly Gly Asp Lys Val Ser Ala Glu Arg Glu Gln 340 345 350 Trp Asn Asp Gly Ser Asn Thr Leu Cys Ile Ala Pro Gly Val Val Val 355 360 365 Val Tyr Asp Arg Asn Asn Leu Thr Asn Ala Val Leu Arg Ser Tyr Gly 370 375 380 Leu Lys Val Ile Glu Ile His Gly Ala Glu Leu Ser Arg Gly Arg Gly 385 390 395 400 Gly Pro Arg Cys Met Ser Met Pro Leu Val Arg Glu Asp Ile 405 410 <![CDATA[<210> 56]]> <![CDATA[<211> 408]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 黴漿菌屬CAG:472]]> <![CDATA[<400> 56]]> Met His Val Thr Ser Glu Ile Lys Lys Leu Lys Lys Val Leu Val His 1 5 10 15 Arg Pro Gly Lys Glu Leu Leu Asn Leu Thr Pro Asp Thr Leu Gly Arg 20 25 30 Leu Leu Phe Asp Asp Ile Pro Tyr Leu Lys Asp Ala Ile Leu Glu His 35 40 45 Asp Glu Phe Cys Gln Ile Leu Arg Asp Asn Asp Val Glu Val Val Tyr 50 55 60 Leu Glu Asp Leu Met Ala Glu Thr Leu Asp Glu Asn Pro Gln Val Lys 65 70 75 80 Pro Ser Phe Ile Arg Gln Phe Ile Tyr Glu Ala Gly Val Arg Thr Pro 85 90 95 Lys Tyr Lys Asp Leu Leu Phe Asp Tyr Leu Met Ser Tyr Thr Asn Asn 100 105 110 Lys Glu Leu Val Leu Lys Thr Met Glu Gly Ile Lys Val Ser Glu Val 115 120 125 His Arg Asn Lys Gln Asp Ser Glu Tyr Ser Leu Val Asp Gln Ile Ser 130 135 140 Glu Glu Thr Lys Phe Leu Ala Glu Pro Met Pro Asn Leu Tyr Phe Thr 145 150 155 160 Arg Asp Pro Phe Ala Ser Val Gly Asp Gly Ile Ile Leu Asn Lys Met 165 170 175 His Ser Val Thr Arg Ser Arg Glu Thr Ile Tyr Ala Tyr Tyr Ile Phe 180 185 190 Asn Tyr His Pro Asp Tyr Met Asp Lys Val Pro Lys Tyr Tyr Asp Arg 195 200 205 Glu Asn Pro Phe Ser Ile Glu Gly Gly Asp Val Leu Asn Leu Asn Glu 210 215 220 His Thr Leu Ala Ile Gly Ile Ser Gln Arg Thr Ser Ala Glu Ala Ile 225 230 235 240 Asp Leu Val Ala Lys Asn Met Phe Asn Asp Glu Lys Cys Asn Ile Asp 245 250 255 Thr Ile Leu Ala Phe Lys Ile Pro Glu Cys Arg Ala Phe Met His Leu 260 265 270 Asp Thr Val Phe Thr Gln Ile Asp Ile Asp Lys Phe Thr Tyr His Pro 275 280 285 Gly Ile Met Asp Thr Leu Glu Val Phe Glu Ile Thr Lys Asn Glu Asp 290 295 300 Asp Leu Asp Glu Val Arg Val Ile Lys Lys Glu Gly Ser Leu Glu Asn 305 310 315 320 Ile Leu Glu Glu Tyr Leu Gly Ile Asp Ile Thr Leu Ile Pro Cys Ala 325 330 335 Gly Gly Asp Lys Ile Ala Ser Glu Arg Glu Gln Trp Asn Asp Gly Thr 340 345 350 Asn Thr Leu Cys Ile Ala Pro Gly Val Val Val Val Tyr Asn Arg Asn 355 360 365 Asn Ile Thr Asn Glu Val Leu Arg Glu Lys Gly Ile Lys Val Ile Glu 370 375 380 Met Asn Ser Ala Glu Leu Ser Arg Gly Arg Gly Gly Pro Arg Cys Met 385 390 395 400 Ser Met Pro Leu Glu Arg Glu Asp 405
Claims (10)
- 一種凍乾調配物,其包含聚乙二醇化精胺酸脫亞胺酶(ADI-PEG),其中該凍乾調配物為無菌的,實質上不含內毒素,且處於醫藥學上可接受之pH下。
- 如請求項1之凍乾調配物,其包含視情況選自組胺酸、檸檬酸鈉、甘胺醯-甘胺酸、磷酸鈉、Tris及離胺酸的醫藥學上可接受之緩衝劑。
- 如請求項1之凍乾調配物,其包含選自以下中之一或多者的醫藥學上可接受之賦形劑:冷凍保護劑、凍乾保護劑、穩定劑、增積劑、張力調節劑、界面活性劑、醫藥塑化劑、螯合劑及前述者之任何組合。
- 如請求項1之凍乾調配物,其中該ADI-PEG包含與 表 A1中序列至少80、95、90、95、96、97、98、99或100%一致的胺基酸序列。
- 如請求項1之凍乾調配物,其中該ADI-PEG共價鍵結至約1至約21個PEG分子。
- 如請求項1之凍乾調配物,其中該ADI-PEG包含共價附接至該ADI及PEG之一或多個水不穩定連接子。
- 一種復原如請求項1之凍乾調配物的方法,其包含向該凍乾調配物中添加醫藥學上可接受之溶劑以形成經復原液體組成物。
- 一種藉由如請求項7之方法製備之經復原液體組成物。
- 一種如請求項8之經復原液體組成物之用途,其係用於製備用以治療、改善有需要之受試者的癌症之症狀或抑制該癌症之進展的醫藥品。
- 一種患者護理套組,其包含如請求項1之凍乾調配物及視情況醫藥學上可接受之溶劑。
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EP (1) | EP3534963B1 (zh) |
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US4554101A (en) | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
US6183738B1 (en) * | 1997-05-12 | 2001-02-06 | Phoenix Pharamacologics, Inc. | Modified arginine deiminase |
AU2001275810A1 (en) * | 2000-07-27 | 2002-02-13 | Angiolab, Inc. | The pharmaceutical composition comprising arginine deiminase for inhibiting angiogenesis |
CA2430077A1 (en) * | 2000-11-28 | 2002-06-06 | Phoenix Pharmacologics, Inc. | Modified arginine deiminase |
CA2454587C (en) * | 2001-07-25 | 2012-11-13 | Protein Design Labs, Inc. | Stable lyophilized pharmaceutical formulation of igg antibodies |
JP4733393B2 (ja) * | 2002-11-18 | 2011-07-27 | ポラリス・グループ | インビボでウイルス複製を阻害する方法 |
CN1536079A (zh) * | 2003-04-09 | 2004-10-13 | 上海复旦张江生物医药股份有限公司 | 修饰的精氨酸脱亚氨酶 |
WO2006015512A1 (fr) * | 2004-08-11 | 2006-02-16 | Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd. | Arginine déiminase modifiée |
ES2828656T3 (es) * | 2012-04-04 | 2021-05-27 | Polaris Group | Composición que comprende arginina desiminasa pegilada |
CN103571814A (zh) * | 2012-08-02 | 2014-02-12 | 北京双鹭药业股份有限公司 | 一种巯基修饰的重组人精氨酸酶ⅰ、其制备方法及应用 |
EP2968482B1 (en) * | 2013-03-15 | 2020-05-06 | TDW Group | Arginine deiminase with reduced cross-reactivity toward adi - peg 20 antibodies for cancer treatment |
NL1040254C2 (en) * | 2013-05-17 | 2014-11-24 | Ablynx Nv | Stable formulations of immunoglobulin single variable domains and uses thereof. |
CA2923859C (en) * | 2013-09-11 | 2021-11-23 | Arsia Therapeutics, Inc. | Liquid protein formulations containing viscosity-lowering agents |
SG11201607736UA (en) * | 2014-03-18 | 2016-10-28 | Tdw Group | Engineered chimeric pegylated adi and methods of use |
ES2915382T3 (es) * | 2014-09-16 | 2022-06-22 | Polaris Group | Arginina desiminasa con reactividad cruzada reducida hacia anticuerpos ADI - PEG 20 para el tratamiento del cáncer |
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US20180296652A1 (en) | 2018-10-18 |
EP3534963B1 (en) | 2024-04-17 |
EP3534963C0 (en) | 2024-04-17 |
CN110121340B (zh) | 2023-03-31 |
WO2018085551A3 (en) | 2018-06-14 |
EP3534963A2 (en) | 2019-09-11 |
CA3039796A1 (en) | 2018-05-11 |
WO2018085551A2 (en) | 2018-05-11 |
CN116407644A (zh) | 2023-07-11 |
EP3534963A4 (en) | 2020-06-24 |
TWI784982B (zh) | 2022-12-01 |
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