CN117677394A - 用于治疗眼部疾病的生长因子的组合物 - Google Patents
用于治疗眼部疾病的生长因子的组合物 Download PDFInfo
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- CN117677394A CN117677394A CN202280047869.4A CN202280047869A CN117677394A CN 117677394 A CN117677394 A CN 117677394A CN 202280047869 A CN202280047869 A CN 202280047869A CN 117677394 A CN117677394 A CN 117677394A
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Abstract
本公开涉及包含生长因子的药物组合物以及使用所述生长因子及其组合物治疗或预防眼部疾病的方法。
Description
优先权要求
本申请要求2021年5月14日提交的序列号为63/188,816的美国临时申请的权益。上述全部内容以引用方式并入本文。
序列表
本申请包含已作为名称为“Sequence_Listing.txt”的ASCII文本文件以电子方式提交的序列表。该ASCII文本文件创建于2022年5月10日,大小为171千字节。该ASCII文本文件中的材料据此全文以引用方式并入。
技术领域
本公开涉及包含生长因子的药物组合物以及使用所述生长因子及其组合物治疗或预防眼部疾病的方法。
背景技术
已经研究了肝细胞生长因子(HGF)用于治疗角膜混浊或瘢痕形成。参见美国专利号10,449,234。已经确定了其他眼部损伤和疾病可以受益于新的治疗方法。例如,神经营养性角膜炎(也称为神经营养性角膜病(NK)或神经麻痹性角膜炎)是一种角膜疾病,由三叉神经或其到角膜的途径损伤或眼表面受损引起,其导致随之发生的角膜感觉减少或丧失。NK在1824年被Magendie首次认为是一种角膜病症(Okada等人,2010,Histol Histopathol,25:771-780),其分子基础随后在1954年由Sigelman和Friedenwald在动物模型中建立(Sigelman和Friedenwald,1954,Arch Ophthalmol,53:46-57)。角膜是眼睛的透明“窗口”,并且与巩膜一起形成眼球的外壳。由于角膜缺乏血管供应,营养物质和氧气主要通过前面的泪液和角膜缘血管以及后面的房水供应到该组织。角膜组织分为五层:上皮、鲍曼氏膜、基质、德斯密氏膜和内皮,其中上皮用作保护下面的角膜基质的主要屏障。角膜是身体中最敏感的组织,由跨越各层的广泛神经纤维网络和密集神经末梢支配。角膜的感觉神经支配源自三叉神经的眼支,其分泌对上皮存活至关重要的生长因子。三叉神经维持泪膜的稳定性,并且与上皮分泌的各种生理活性物质(例如细胞因子、蛋白酶和神经肽)一起进一步确保角膜上皮和基质的活力。三叉神经或上皮的损伤最常见的是由感染(例如单纯疱疹或带状疱疹感染)、眼科手术(例如白内障手术、角膜移植、屈光手术)、其他全身性疾病(诸如糖尿病、麻风病、眼眶肿瘤和炎症)或物理创伤(包括化学灼伤和热灼伤)以及使用隐形眼镜引起的。
因此,持续需要针对眼部疾病诸如NK的新治疗方法以及可施用于眼睛的新药物制剂。本文描述的方法是为此目的而开发的。
发明内容
本发明提供了治疗或预防有需要的受试者的神经营养性角膜炎的方法,该方法包括向受试者施用生长因子,诸如肝细胞生长因子(HGF)或成纤维细胞生长因子(FGF)。
本发明还提供了用于治疗眼部疾病的包含HGF或FGF的药物组合物。
本文提供了治疗或预防有需要的受试者的神经营养性角膜炎的方法,该方法包括向受试者施用治疗有效量的肝细胞生长因子(HGF)或成纤维细胞生长因子(FGF),例如,如本文所述。
在一些实施方案中,HGF或FGF是纯化的。
在一些实施方案中,HGF或FGF与角膜基质渗透赋形剂组合施用。
在一些实施方案中,FGF的HGF被配制在液体药物组合物中。
在一些实施方案中,HGF或FGF施用于眼睛。在一些实施方案中,HGF或FGF局部施用于眼睛。在一些实施方案中,HGF或FGF通过注射施用于眼睛。在一些实施方案中,HGF或FGF经结膜下施用。在一些实施方案中,HGF或FGF经前房内施用。
在一些实施方案中,液体药物组合物包含浓度为约0.01%(w/v)至约1.0%(w/v)的HGF或FGF。在一些实施方案中,液体药物组合物包含浓度为约0.08%(w/v)至约0.25%(w/v)的HGF或FGF。在一些实施方案中,液体药物组合物包含浓度为约0.1%(w/v)的HGF或FGF。在一些实施方案中,液体药物组合物包含浓度为约0.2%(w/v)的HGF或FGF。
在一些实施方案中,HGF或FGF与另一种治疗剂组合施用。在一些实施方案中,另一种治疗剂是另一种生长因子。
在一些实施方案中,HGF包含具有SEQ ID NO:1-27中任一个的多肽序列。在一些实施方案中,HGF包含与SEQ ID NO:1具有95%序列同一性的多肽序列。在一些实施方案中,HGF包括具有SEQ ID NO:1的多肽序列。
本文还提供了药物组合物,其包含:约0.01%至约1.0%(w/v)HGF;能够将组合物的pH维持在约5.8至约6.2的缓冲剂;约100至约300mM的稳定剂,该稳定剂选自海藻糖、脯氨酸、山梨糖醇以及它们的混合物;任选的张力调节剂,其能够提供组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及任选的表面活性剂。
在一些实施方案中,药物组合物包含约0.05%至约0.5%(w/v)HGF。在一些实施方案中,药物组合物包含约0.08%至约0.25%(w/v)HGF。在一些实施方案中,药物组合物包含约0.1%(w/v)HGF。在一些实施方案中,药物组合物包含约0.2%(w/v)HGF。
在一些实施方案中,组合物的pH为约6.0。
在一些实施方案中,药物组合物包含约150至约250mM的稳定剂。在一些实施方案中,药物组合物包含约200mM的稳定剂。在一些实施方案中,稳定剂是海藻糖或脯氨酸。在一些实施方案中,稳定剂是海藻糖。在一些实施方案中,稳定剂是脯氨酸。在一些实施方案中,稳定剂是山梨糖醇。
在一些实施方案中,缓冲剂是柠檬酸盐缓冲剂。在一些实施方案中,缓冲剂是柠檬酸钠。在一些实施方案中,药物组合物包含约10至约50mM的缓冲剂。
在一些实施方案中,组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,药物组合物不包含张力调节剂。在一些实施方案中,药物组合物包含张力调节剂,其为碱金属盐。在一些实施方案中,药物组合物包含张力调节剂,其为氯化钠。
在一些实施方案中,药物组合物包含表面活性剂。在一些实施方案中,表面活性剂选自聚山梨醇酯80(PS80)、泊洛沙姆188和泊洛沙姆407。在一些实施方案中,表面活性剂是聚山梨醇酯80(PS80)。在一些实施方案中,表面活性剂以约0.01%至约0.1%(w/v)的量存在。在一些实施方案中,表面活性剂以约0.02%至约0.8%(w/v)的量存在。在一些实施方案中,表面活性剂以约0.05%(w/v)的量存在。
本文还提供了水性药物组合物,其包含:约0.1%(w/v)HGF;约20mM柠檬酸钠;约200mM的海藻糖、脯氨酸或山梨糖醇;约0.05%(w/v)表面活性剂;其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.1%(w/v)HGF;约20mM柠檬酸钠;约200mM的海藻糖;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.1%(w/v)HGF;约20mM柠檬酸钠;约200mM的脯氨酸;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.1%(w/v)HGF;约20mM柠檬酸钠;约200mM的山梨糖醇;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.2%(w/v)HGF;约20mM柠檬酸钠;约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.2%(w/v)HGF;约20mM柠檬酸钠;约200mM的海藻糖;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.2%(w/v)HGF;约20mM柠檬酸钠;约200mM的脯氨酸;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,水性药物组合物包含:约0.2%(w/v)HGF;约20mM柠檬酸钠;约200mM的山梨糖醇;约0.05%(w/v)的聚山梨醇酯80(PS80);其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,HGF包含SEQ ID NO:1-27中任一个的多肽序列。在一些实施方案中,HGF包含与SEQ ID NO:1具有95%序列同一性的多肽序列。在一些实施方案中,HGF包含具有SEQ ID NO:1的多肽序列。
本文还提供了治疗或预防有需要的受试者的眼部疾病的方法,该方法包括向受试者施用治疗有效量的本文所述的药物组合物。
在一些实施方案中,眼部疾病是选自以下的角膜疾病:神经营养性角膜炎、持续性角膜缺损、角膜溃疡、干眼病、微生物性角膜炎、细菌性角膜炎、病毒性角膜炎、真菌性角膜炎、化学灼伤、热灼伤、机械性创伤、角膜擦伤、内皮受损、大泡性角膜病、富克氏角膜营养不良、角膜瘢痕、干燥综合征或术后并发症。在一些实施方案中,眼部疾病是角膜混浊或瘢痕形成。在一些实施方案中,眼部疾病是神经营养性角膜炎。在一些实施方案中,组合物与角膜基质渗透赋形剂组合施用。
在一些实施方案中,组合物施用于眼睛。在一些实施方案中,组合物局部施用于眼睛。在一些实施方案中,组合物通过注射施用于眼睛。在一些实施方案中,组合物经结膜下施用。在一些实施方案中,组合物经前房内施用。
在本文所述的方法或组合物的一些实施方案中,HGF是活化HGF。在一些实施方案中,活化HGF是活化dHGF。
在本文所述的方法或组合物的一些实施方案中,HGF包含:
(a)第一多肽,其包含与SEQ ID NO:2的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:2的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:2的氨基酸161-165的氨基酸的缺失;或者
(b)第一多肽,其包含与SEQ ID NO:7的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:7的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:7的氨基酸161-165的氨基酸的缺失;或者
(c)第一多肽,其包含与SEQ ID NO:8的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:8的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:8的氨基酸161-165的氨基酸的缺失;或者
(d)第一多肽,其包含与SEQ ID NO:9的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:9的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:9的氨基酸161-165的氨基酸的缺失;或者
(e)第一多肽,其包含与SEQ ID NO:10的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:10的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:10的氨基酸161-165的氨基酸的缺失;或者
(g)第一多肽,其包含与SEQ ID NO:11的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:11的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:11的氨基酸161-165的氨基酸的缺失;或者
(h)第一多肽,其包含与SEQ ID NO:12的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:12的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:12的氨基酸161-165的氨基酸的缺失;或者
(i)第一多肽,其包含与SEQ ID NO:13的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:13的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:13的氨基酸161-165的氨基酸的缺失;或者
(j)第一多肽,其包含与SEQ ID NO:14的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:14的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:14的氨基酸161-165的氨基酸的缺失;或者
(k)第一多肽,其包含与SEQ ID NO:15的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:15的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:15的氨基酸161-165的氨基酸的缺失;或者
(l)第一多肽,其包含与SEQ ID NO:16的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:16的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:16的氨基酸161-165的氨基酸的缺失;或者
(m)第一多肽,其包含与SEQ ID NO:17的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:17的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:17的氨基酸161-165的氨基酸的缺失;或者
(n)第一多肽,其包含与SEQ ID NO:18的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:18的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:18的氨基酸161-165的氨基酸的缺失;或者
(o)第一多肽,其包含与SEQ ID NO:19的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:19的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:19的氨基酸161-165的氨基酸的缺失;或者
(p)第一多肽,其包含与SEQ ID NO:20的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:20的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:20的氨基酸161-165的氨基酸的缺失;或者
(q)第一多肽,其包含与SEQ ID NO:21的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:21的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:21的氨基酸161-165的氨基酸的缺失;或者
(r)第一多肽,其包含与SEQ ID NO:22的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:22的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:22的氨基酸161-165的氨基酸的缺失;或者
(s)第一多肽,其包含与SEQ ID NO:23的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:23的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:23的氨基酸161-165的氨基酸的缺失;或者
(t)第一多肽,其包含与SEQ ID NO:24的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:24的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:24的氨基酸161-165的氨基酸的缺失;或者
(u)第一多肽,其包含与SEQ ID NO:25的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:25的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:25的氨基酸161-165的氨基酸的缺失;或者
(v)第一多肽,其包含与SEQ ID NO:26的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:26的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:26的氨基酸161-165的氨基酸的缺失;或者
(w)第一多肽,其包含与SEQ ID NO:27的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:27的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:27的氨基酸161-165的氨基酸的缺失。
在本文所述的方法或组合物的一些实施方案中,HGF包含:
(a)第一多肽,其包含对应于SEQ ID NO:2的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:2的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:2的氨基酸161-165的氨基酸的缺失;或者
(b)第一多肽,其包含对应于SEQ ID NO:7的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:7的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:7的氨基酸161-165的氨基酸的缺失;或者
(c)第一多肽,其包含对应于SEQ ID NO:8的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:8的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:8的氨基酸161-165的氨基酸的缺失;或者
(d)第一多肽,其包含对应于SEQ ID NO:9的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:9的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:9的氨基酸161-165的氨基酸的缺失;或者
(e)第一多肽,其包含对应于SEQ ID NO:10的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:10的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:10的氨基酸161-165的氨基酸的缺失;或者
(g)第一多肽,其包含对应于SEQ ID NO:11的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:11的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:11的氨基酸161-165的氨基酸的缺失;或者
(h)第一多肽,其包含对应于SEQ ID NO:12的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:12的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:12的氨基酸161-165的氨基酸的缺失;或者
(i)第一多肽,其包含对应于SEQ ID NO:13的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:13的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:13的氨基酸161-165的氨基酸的缺失;或者
(j)第一多肽,其包含对应于SEQ ID NO:14的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:14的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:14的氨基酸161-165的氨基酸的缺失;或者
(k)第一多肽,其包含对应于SEQ ID NO:15的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:15的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:15的氨基酸161-165的氨基酸的缺失;或者
(l)第一多肽,其包含对应于SEQ ID NO:16的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:16的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:16的氨基酸161-165的氨基酸的缺失;或者
(m)第一多肽,其包含对应于SEQ ID NO:17的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:17的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:17的氨基酸161-165的氨基酸的缺失;或者
(n)第一多肽,其包含对应于SEQ ID NO:18的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:18的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:18的氨基酸161-165的氨基酸的缺失;或者
(o)第一多肽,其包含对应于SEQ ID NO:19的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:19的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:19的氨基酸161-165的氨基酸的缺失;或者
(p)第一多肽,其包含对应于SEQ ID NO:20的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:20的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:20的氨基酸161-165的氨基酸的缺失;或者
(q)第一多肽,其包含对应于SEQ ID NO:21的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:21的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:21的氨基酸161-165的氨基酸的缺失;或者
(r)第一多肽,其包含对应于SEQ ID NO:22的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:22的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:22的氨基酸161-165的氨基酸的缺失;或者
(s)第一多肽,其包含对应于SEQ ID NO:23的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:23的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:23的氨基酸161-165的氨基酸的缺失;或者
(t)第一多肽,其包含对应于SEQ ID NO:24的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:24的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:24的氨基酸161-165的氨基酸的缺失;或者
(u)第一多肽,其包含对应于SEQ ID NO:25的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:25的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:25的氨基酸161-165的氨基酸的缺失;或者
(v)第一多肽,其包含对应于SEQ ID NO:26的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:26的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:26的氨基酸161-165的氨基酸的缺失;或者
(w)第一多肽,其包含对应于SEQ ID NO:27的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:27的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:27的氨基酸161-165的氨基酸的缺失。
在本文所述的方法或组合物的一些实施方案中,第一多肽包含SEQ ID NO:36的氨基酸序列或由其组成,并且第二多肽包含SEQ ID NO:37的氨基酸序列或由其组成。
在本文所述的方法或组合物的一些实施方案中,第一多肽的N-末端氨基酸是吡咯烷酮羧酸。
在本文所述的方法或组合物的一些实施方案中,第一多肽和第二多肽通过一个或多个二硫键连接。
在本文所述的方法或组合物的一些实施方案中,HGF能够结合c-MET和/或活化上皮细胞中的MAPK途径。
附图说明
图1.含有小鼠视神经连续切片的载玻片的荧光显微镜图像,用于评估术后第3天的角膜神经支配。对组织样品进行TUJ-1(也称为βIII微管蛋白,圆圈区域)染色,用于评估角膜神经支配。与接受0.1%dHGF(SEQ ID.NO.1)的眼睛相比,用对照(PBS)治疗的动物在第3天显示出潜在较低的TUJ-1染色(圆圈区域);DAPI用作复染剂以突出显示所有细胞核。
图2.在小鼠角膜机械损伤模型的第1期研究中,对手术后并且每日用PBS(媒介物对照)、0.1%或0.2%dHGF、0.1%mNGF或0.1%mHGF治疗的动物的荧光素染色角膜表面进行闭合时间分析。
图3A.在小鼠角膜机械损伤模型中,在手术后第7天对用PBS(对照)、0.1%dHGF或0.2%dHGF治疗的动物的角膜表面中测量的平均瘢痕面积(以像素为单位)进行明场图像分析。
图3B.在小鼠角膜机械损伤模型中,在手术后第7天对用PBS(对照)、0.1%mNGF或0.1%mHGF治疗的动物的角膜表面中测量的瘢痕面积(以像素为单位)的平均减少进行明场图像分析。
图4.在小鼠角膜机械损伤模型中,用PBS(对照)、dHGF(0.1%和0.2%)、mHGF和mNGF治疗的动物从第8天到第21天的瘢痕减少的平均百分比、测量标准误差(SEM)和统计比较。
图5.在小鼠角膜大肠杆菌LPS诱导的角膜炎模型中,用PBS(对照)、dHGF(0.1%和0.2%)或mNGF治疗的动物在第9天的瘢痕大小的百分比变化。
具体实施方式
在一些实施方案中,本发明尤其提供了治疗或预防有需要的受试者的神经营养性角膜炎(NK)的方法,该方法包括向受试者施用肝细胞生长因子(HGF)或成纤维细胞生长因子(FGF)。
神经营养性角膜炎或神经营养性角膜病(NK)是由三叉神经或其分支损伤或眼表面受损引起的角膜退行性病况,其导致随之发生的角膜敏感性降低或角膜感觉完全丧失。如本文所用,可互换使用的术语“疾病”,“病况”或“病症”是指受影响组织或器官的多种病理学病况中的任一种。三叉神经或其分支的损伤最常见的是由感染(例如病毒感染,包括单纯疱疹或带状疱疹感染、细菌性溃疡、晚期棘阿米巴溃疡)、眼科手术(例如白内障手术、角膜移植、屈光手术和视网膜手术)、其他全身性疾病(诸如糖尿病、麻风病、眼眶肿瘤和炎症、由后颅窝中的三叉神经引起的第五神经麻痹、动脉瘤、听神经瘤、脑膜瘤)或由化学灼伤和热灼伤引起的对角膜层的其他物理损伤引起的。NK的其他原因包括遗传性疾病(例如常见的角膜感觉减退、Goldenhar-Gorlin综合征、遗传性感觉和自主神经病III、IV或V型、角膜营养不良和多发性内分泌肿瘤IIb)、使用某些药物(例如局部β-阻滞剂、局部非甾体抗炎药(NSAID)、局部麻醉药)和使用隐形眼镜(关于综述,参见Okada等人,同上)。
NK可以根据本文所述的方法通过施用肝细胞生长因子(HGF)和/或成纤维细胞生长因子(FGF)来治疗或预防。
HGF(例如,UniProt ID No.P14210)是一种cMet激酶激动剂,其尤其通过酪氨酸激酶信号传导途径刺激各种器官中的上皮细胞增殖、运动、形态发生和血管生成,并且在胚胎器官发育和成人器官再生和伤口愈合中发挥重要作用。HGF是大约84kDa的蛋白质,由两个亚基组成:表观分子量为69kDa的α亚基和表观分子量为34kDa的β亚基,通过单个二硫键连接。
HGF由间充质基质细胞(例如成纤维细胞和巨噬细胞)产生为728个氨基酸的pro-HGF分子,其中前1-31个氨基酸残基对应于分泌信号传导序列(Matsumoto和Nakamura,Encyclopedia of Endocrine Diseases,Elsevier,2004,436-442)。pro-HGF的一级氨基酸序列被组织成四个Kringle(K)结构域的结构域结构(Sigurdardottir等人,2015,Chem.Sci.,6:6147-6157)。如本文所用,“Kringle”结构域是指折叠成三环、二硫键交联结构域的多肽线性序列(Simonneau等人,2015,Chem.Sci.,6:2110-2121)。Kringle结构域存在于多种多肽中,包括载脂蛋白A、凝血因子XII、纤溶酶原和HGF。名称“Kringle”来源于这些结构类似的斯堪的纳维亚糕点。Kringle结构域被认为介导蛋白、膜和磷脂之间的结合相互作用。在一些实施方案中,本发明的多肽含有至少一个Kringle结构域。
在分泌信号传导序列切割后,在pro-HGF的第四个Kringle结构域与C-末端丝氨酸-蛋白酶同源(SPH)结构域之间的胰蛋白酶样位点(R494-V495)处的蛋白水解切割产生成熟的活化HGF。胰蛋白酶样切割位点是在带正电荷的氨基酸(例如赖氨酸或精氨酸)之后的肽键。在活化后,HGF结合并活化其受体cMet(也称为MET酪氨酸激酶),其导致酪氨酸磷酸化,进一步影响多种下游接头分子的募集和各种细胞内途径和生物活性的调节,统称为侵入性生长程序(Nakamura,T.,1991,Prog.Growth Factor Res.,3:67-85;Bottaro等人,1991,Science251:802-804)。HGF及其受体cMet均在角膜上皮、基质细胞、内皮和泪腺中表达,但水平极低,人泪液中HGF的量估计为约500pg/mL(Wilson等人,1993,Invest.Ophthalmol.Vis.Sci.,34:2544-2561;Li等人,1996,Invest.Ophthalmol.Vis.Sci.,37:727-739)。
文献中已知由HGF mRNA基因转录物的选择性剪接产生的HGF的六种天然存在的异型体,其中主要异型体是异型体1(例如,SEQ ID NO:2)和2(例如,SEQ ID NO:3)(Bottaro等人,1991,Science,251:802-804;Chan等人,1991,Science,254:1382-1385;Lokker和Godowski,1992,EMBO J.,11:2503-2510;Cioce等人,1996,J.Biol.Chem.,271:13110-13115)。如本文所用,术语“异型体”是指由编码HGF的前mRNA的选择性剪接产生的蛋白质。异型体1mRNA转录物编码最长的HGF基因序列,其包含728个氨基酸残基。第二主要HGF异型体由异型体2的mRNA转录物编码,其相对于异型体1转录物缺乏多个3'外显子但包含替代的3'外显子。由异型体2mRNA转录物编码的HGF蛋白包含290个氨基酸残基,并且与异型体1HGF蛋白相比在第二Kringle结构域后被截短(Miyazawa等人,1991,Eur.J.Biochem.,197:15-22)。异型体3mRNA转录物缺乏异型体1中存在的框内编码区段,并且编码包含723个氨基酸残基(例如,SEQ ID NO:1)的HGF蛋白,该HGF蛋白在异型体1的第一Kringle结构域内的位置161-165处缺乏序列“SFLPS”(Rubin等人,1991,Proc.Natl.Acad.Sci.,88:415-419)。异型体4HGF蛋白(例如,SEQ ID NO:4)是包含残基1-296的较小分子,其中氨基酸序列仅延伸穿过第二Kringle结构域(Chan等人,1991,Science,254:1382-1385)。异型体5HGF蛋白(例如,SEQ ID NO:5)与异型体2HGF蛋白相似,具有如异型体3HGF中残基161-165(SFLPS)的额外缺失(Rubin等人,1991,Proc.Natl.Acad.Sci.,88:415-419)。异型体6HGF蛋白(也称为NK1)(例如,SEQ ID NO:6)是所有HGF异型体中最小的,仅包含210个氨基酸(Cioce等人,1996,J.Bio.Chem.,271:13110-13115)。
HGF的全长和截短的异型体均已显示结合cMet,尽管具有不同的效力和与细胞外基质的硫酸肝素蛋白聚糖的相互作用,这有助于延长HGF在体内的循环半衰期(Masumoto和Yamamoto,1991,Biochem.Biophys.Res.Commun.,174:90-95;Montesano等人,1998,CellGrowth Differ.,9:355-365;Sakata等人,1997,J.Biol.Chem.,272:9457-9463;Stahl等人,1997,Biochem.J.,326:763-772)。虽然异型体1和3需要在R494-V495处的蛋白水解切割才能具有生物活性,但截短的异型体2、4、5和6不具有R494-V495切割位点,因此,该活化步骤对于它们的生物活性不是必需的。然而,已知截短的异型体2、4、5和6通常不如全长异型体1和3对应物有效(Stahl等人,1997;Montesano等人,1998;同上)。
成纤维细胞生长因子(FGF)是细胞信号传导蛋白家族,其涉及包括发育的多种生物过程。人FGF家族包括22个成员:FGF1、FGF2、FGF3(INT2)、FGF4、FGF5、FGF6、FGF7(KGF)、FGF8(AIGF)、FGF9、FGF10、FGF11、FGF12、FGF13、FGF14、FGF16、FGF17、FGF18、FGF19、FGF20、FGF21、FGF22和FGF23。
FGF通过结合和活化成纤维细胞生长因子受体(FGFR)发挥其生物学作用。活化FGFR通过募集在受体的细胞溶质部分处结合磷酸化酪氨酸的特定分子来介导信号传导,从而触发导致特定细胞反应的许多信号传导路径。人FGFR家族包括4个成员:FGFR1、FGFR2、FGFR3和FGFR4。
在一些实施方案中,HGF是包含SEQ ID NO:1-27中任一个的氨基酸序列的多肽,具有或不具有信号序列(即,对应于SEQ ID NO:1的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的多肽,具有或不具有信号序列(即,对应于SEQ ID NO:1或SEQ ID NO:2的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含SEQ ID NO:1的氨基酸序列的多肽,具有或不具有信号序列(即,对应于SEQ ID NO:1的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含SEQ ID NO:2的氨基酸序列的多肽,具有或不具有信号序列(即,对应于SEQ ID NO:2的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含SEQ ID NO.1或SEQ ID NO.2的氨基酸序列的活化形式的多肽。术语“活化形式”尤其是指HGF多肽,信号序列(例如SEQ ID NO:1或SEQ ID NO:2的氨基酸1-31)已从该HGF多肽切割,并且该HGF多肽已在SEQ ID NO:1的R489与V490之间或在SEQ ID NO:2的R494与V495之间切割以形成HGF的二硫键连接的α和β链。在一些实施方案中,N-末端氨基酸(例如,SEQ ID NO:1或SEQ ID NO:2的氨基酸32)是吡咯烷酮羧酸,例如由信号序列的切割产生。在一些实施方案中,本发明的多肽以HGF前体(pro-HGF)形式存在,其中SEQ ID NO:1的R489与V490或SEQ ID NO:2的R494与V495之间的肽键是完整的。在一些实施方案中,本发明的多肽可以通过在体内对SEQ ID NO:1的R489与V490氨基酸残基之间或SEQ ID NO:2pro-HGF蛋白的R494与V495氨基酸残基之间的胰蛋白酶样切割位点进行蛋白水解切割而转化为活性形式。在一些实施方案中,本发明的多肽可以通过在体外对SEQ ID NO:1的R489与V490氨基酸残基之间或SEQ ID NO:2pro-HGF蛋白的R494与V495氨基酸残基之间的胰蛋白酶样切割位点进行蛋白水解切割而转化为活性形式。在一些实施方案中,HGF是包含SEQID NO:1pro-HGF蛋白的氨基酸32-723的氨基酸序列的多肽。在一些实施方案中,HGF是包含SEQ ID NO:1活化蛋白的氨基酸32-723的氨基酸序列的多肽。在一些实施方案中,HGF是包含SEQ ID NO:2pro-HGF蛋白的氨基酸32-728的氨基酸序列的多肽。在一些实施方案中,HGF是包含SEQ ID NO:2活化蛋白的氨基酸32-728的氨基酸序列的多肽。
在一些实施方案中,HGF是包含SEQ ID NO:3、4、5或6的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:3、4、5或6的氨基酸1-31的氨基酸)。
在一些实施方案中,HGF是SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6的多肽变体,具有或不具有信号序列(例如,对应于SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5或SEQ ID NO:6的氨基酸1-31的氨基酸)。如本文所用,术语“变体”意指这样的多肽,由于由编码该多肽的核酸中的突变导致的一个或多个氨基酸取代、缺失或插入而与另一多肽不同。在一些实施方案中,HGF是包含与SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:6具有至少90%序列同一性的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:6的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含与SEQ ID NO:1、SEQ ID NO:2或SEQID NO:6具有至少95%序列同一性的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:6的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含与SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:6具有至少98%序列同一性的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:1、SEQ ID NO:2或SEQID NO:6的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是包含与SEQ ID NO:1、SEQ IDNO:2或SEQ ID NO:6具有至少99%序列同一性的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:1、SEQ ID NO:2或SEQ ID NO:6的氨基酸1-31的氨基酸)。在一些实施方案中,HGF变体可以(1)结合c-MET和/或(2)活化上皮细胞(例如,人角膜上皮细胞)中的MAPK途径。
在一些实施方案中,HGF是包含野生型HGF异型体1的氨基酸序列(例如,SEQ IDNO:2)中的突变的多肽,在位置62、64、77、95、125、127、130、132、137、142、148、154、170、173和193中的一个或多个处具有或不具有信号序列(例如,对应于SEQ ID NO:2的氨基酸1-31的氨基酸)。在一些实施方案中,野生型HGF异型体3(例如,SEQ ID NO 1)中的类似位置发生突变。在一些实施方案中,HGF是包含如下表1和表2中所示的氨基酸序列中的突变的多肽。表1和
表2中所示的突变的任何组合可以包括在本文公开的HGF多肽中。
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在一些实施方案中,HGF是包含选自由SEQ ID NO:7-27组成的组的氨基酸序列的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:7-27的氨基酸1-31的氨基酸)。在一些实施方案中,HGF是由选自由SEQ ID NO:7-27组成的组的氨基酸序列组成的多肽,具有或不具有信号序列(例如,对应于SEQ ID NO:7-27的氨基酸1-31的氨基酸)。
在一些实施方案中,FGF是包含SEQ ID NO:28的氨基酸序列的多肽。在一些实施方案中,FGF是SEQ ID NO:28的多肽变体。在一些实施方案中,FGF是包含与SEQ ID NO:28具有至少90%、至少95%、至少98%或至少99%序列同一性的氨基酸序列的多肽。在一些实施方案中,FGF变体与野生型FGF1相比表现出增加的蛋白水解稳定性。
在一些实施方案中,FGF是包含野生型FGF异型体1的氨基酸序列(例如,SEQ IDNO:28)中的位置28、40、47、93或131中的一个或多个处的突变的多肽。本文公开的FGF多肽中可以包括位置28、40、47、93和131处的突变的任何组合。
在一些实施方案中,FGF1变体包含至少一个选自由D28N、Q40P、S47I、H93G、L131R和L131K组成的组的氨基酸取代。在一些实施方案中,FGF1变体包含氨基酸取代L131R。在一些实施方案中,FGF1变体包含氨基酸取代L131K。在一些实施方案中,变体包含氨基酸取代D28N和L131R(例如,SEQ ID NO:29)。在一些实施方案中,变体包含氨基酸取代D28N和L131K。在一些实施方案中,变体包含氨基酸取代Q40P、S47I和H93G(例如,SEQ ID NO:30)。在一些实施方案中,变体包含氨基酸取代Q40P、S47I、H93G和L131R。在一些实施方案中,变体包含氨基酸取代Q40P、S47I、H93G和L131K。在一些实施方案中,变体包含氨基酸取代D28N、Q40P、S47I、H93G和L131R(例如,SEQ ID NO:31)。在一些实施方案中,变体包含氨基酸取代D28N、Q40P、S47I、H93G和L131K。在一些实施方案中,FGF1变体不包含氨基酸取代L131A。
在一些实施方案中,FGF是包含选自由SEQ ID NO:29-33组成的组的氨基酸序列的多肽。在一些实施方案中,FGF是具有选自由SEQ ID NO:29-33组成的组的氨基酸序列的多肽。
本文公开的多肽(例如,HGF多肽、FGF多肽)可以是单体或二聚体。在一些实施方案中,HGF是SEQ ID NO:1-27中任一个的多肽或其多肽变体的共价二聚体,具有或不具有信号序列(例如,对应于SEQ ID NO:1-27的氨基酸1-31的氨基酸)。在一些实施方案中,FGF是SEQID NO:29-33中任一个的多肽或其多肽变体的共价二聚体。HGF或FGF多肽的共价二聚体可以通过在合适的表达系统(例如,酵母或大肠杆菌)中表达SEQ ID NO:1-27的HGF多肽序列中的任一个或其变体来获得,而单个氨基酸残基(特别是N-末端氨基酸残基)被半胱氨酸残基替代。表达的和(例如信号序列切割的)HGF多肽单体或表达的FGF多肽单体可以通过在引入的半胱氨酸残基之间形成二硫键而被诱导二聚化(参见例如Liu等人,2014,FEBSLetters,588:4831-4837;Jones II等人,2011,Proc.Natl.Acad.Sci.,108:13035-13040;以及USSN 15/365,514)。
在一些情况下,本文所述的HGF多肽包含一种或多种翻译后修饰,包括例如以下的一种或多种:
本文公开的多肽(例如,HGF多肽、FGF多肽)可以包括用天然存在的氨基酸或非天然存在的氨基酸的取代,所述氨基酸包括但不限于羟脯氨酸(Hyp)、β-丙氨酸、瓜氨酸(Cit)、鸟氨酸(Orn)、正亮氨酸(Nle)、3-硝基酪氨酸、硝基精氨酸和焦谷氨酸(Pyr)。在一些情况下,HGF多肽被翻译后修饰,例如,如上表中所示。
如本文所用,术语“序列同一性”是指两个多肽或核酸序列之间相同残基的百分比。本领域技术人员可以容易地确定与HGF或FGF的氨基酸的序列同一性,例如,通过使用可在https://blast.ncbi.nlm.nih.gov/Blast.cgi在线获得的基本局部比对搜索工具(BLAST),通过输入HGF或FGF的氨基酸(或核酸)序列和所讨论的多肽(或核酸)。例如,程序BLAST可用于比对两个序列(使用默认参数),如通过Tatiana A.Tatusova和ThomasL.Madden(1999),"Blast 2sequences-a new tool for comparing protein andnucleotide sequences",FEMS Microbiol Lett.174:247-250所述。可用于获得氨基酸或核苷酸序列的比对的各种其他算法和软件是本领域熟知的。这些包括但不限于ALIGN、Megalign、BestFit、GCG Wisconsin Package以及它们的变形。在一些实施方案中,本发明的多肽与HGF具有至少约50%、至少约60%、至少约70%、至少约80%、至少约85%、至少约90%、至少约95%、至少约97%、至少约98%或至少约99%的同源性,例如通过使用程序BLAST比对两个序列(默认参数)来确定。在一些情况下,序列在所比较的序列的全长上基本上相同,例如,(i)核苷酸序列的编码区或(ii)氨基酸序列。
在一些实施方案中,HGF和/或FGF分离自生物来源,诸如羊膜或羊水、产生HGF和/或FGF的细胞或组织(例如,间充质基质细胞或肝细胞)或泪液。在一些实施方案中,HGF是在合适的宿主蛋白表达系统例如大肠杆菌、酿酒酵母、中国仓鼠卵巢(CHO)细胞、人胚肾(HEK293)细胞或昆虫细胞系(例如Sf9、Sf21或S2)中表达的重组蛋白。在一些实施方案中,HGF是纯化的。如本文所用,“纯化的”HGF是指已被加工以除去其他不需要的组分或污染物的多肽。在一些实施方案中,FGF是在合适的宿主蛋白表达系统例如大肠杆菌、酿酒酵母、中国仓鼠卵巢(CHO)细胞、人胚肾(HEK293)细胞或昆虫细胞系(例如Sf9、Sf21或S2)中表达的重组蛋白。在一些实施方案中,FGF是纯化的。如本文所用,“纯化的”FGF是指已被加工以除去其他不需要的组分或污染物的多肽。
在纯化过程中除去的不需要的组分或污染物的实例包括与HGF和/或FGF不相关的细胞、组织、核酸、多肽(例如来自所用表达系统的宿主细胞蛋白,或来自从例如白蛋白和免疫球蛋白分离的生物来源的丰富蛋白)、具有小于50%序列同源性的HGF和/或FGF的小片段、金属和其他无机盐。本领域技术人员使用的纯化方法的实例包括:沉淀、絮凝、切向流过滤(TFF)、超滤(UF)、渗滤(DF)、透析、凝胶过滤色谱法(GFC)、液相色谱法(LC)、离子交换色谱法(IEX)、疏水相互作用色谱法(HIC)和电泳。在一些实施方案中,纯化的HGF的纯度为至少约50%。在一些实施方案中,纯化的HGF的纯度为至少约60%。在一些实施方案中,纯化的HGF的纯度为约75%。在一些实施方案中,纯化的HGF的纯度为约80%。在一些实施方案中,纯化的HGF的纯度为约85%。在一些实施方案中,纯化的HGF的纯度为约90%。在一些实施方案中,纯化的HGF的纯度为约95%。在一个优选的实施方案中,纯化的HGF的纯度为约97%。在一些实施方案中,纯化的FGF的纯度为至少约50%。在一些实施方案中,纯化的FGF的纯度为至少约60%。在一些实施方案中,纯化的FGF的纯度为约75%。在一些实施方案中,纯化的FGF的纯度为约80%。在一些实施方案中,纯化的FGF的纯度为约85%。在一些实施方案中,纯化的FGF的纯度为约90%。在一些实施方案中,纯化的FGF的纯度为约95%。在一个优选的实施方案中,纯化的FGF的纯度为约97%。
HGF和/或FGF的纯度和含量的测定可由本领域技术人员使用常规分析测定和方法容易地实现,例如通过反相高效液相色谱法(RP-HPLC)、尺寸排阻色谱法(SEC)、离子交换色谱法(IEX)、聚丙烯酰胺凝胶电泳(PAGE)、毛细管凝胶电泳(CGE)和蛋白质印迹。
如本文所用,“多肽”或“蛋白质”是具有例如2至约1000个或更多个氨基酸残基的氨基酸的聚合物。在一些实施方案中,“多肽”具有10至约130个氨基酸、10至约220个氨基酸、10至约500个氨基酸或10至约730个氨基酸。任何天然存在的或合成的氨基酸都可以形成多肽。多肽还可以包括修饰诸如糖基化和其他部分。在一些实施方案中,本发明的多肽具有基于例如靶标的氨基酸序列(诸如N-末端或C-末端的氨基酸序列)选择性结合靶标多肽的能力。
如本文所用,术语“约”用于意指大约、在...的区域中、大致或周围。当术语“约”与数值范围结合使用时,其通过延伸所示数值的上下边界修饰该范围。通常,术语“约”在本文中用于修饰数值,使其高于和低于所述值10%的方差。
治疗和预防方法
本公开的特征在于治疗或预防受试者的眼部疾病或病症的方法。在一些实施方案中,眼部疾病或病症是角膜疾病。角膜疾病的非限制性实例包括神经营养性角膜炎、持续性角膜缺损、角膜溃疡、干眼病、微生物性角膜炎、细菌性角膜炎、病毒性角膜炎、真菌性角膜炎、化学灼伤、热灼伤、机械性创伤、角膜擦伤、内皮受损、大泡性角膜病、富克氏角膜营养不良、角膜瘢痕、干燥综合征和术后并发症。在一些实施方案中,疾病或病症是角膜损伤,包括角膜混浊或瘢痕形成。在一些实施方案中,疾病是神经性角膜炎。该方法包括向受试者施用治疗有效量的如本文所述的HGF和/或FGF多肽。如本文所用,“受试者”或“患者”可互换使用,包括哺乳动物,诸如人、牛、马、犬、猫、猪和绵羊动物。受试者优选为人。
在一些实施方案中,受试者患有NK,其中存在三叉神经或其分支的损伤。在某些情况下,三叉神经或其分支的损伤是由感染(例如细菌或病毒感染,诸如单纯疱疹或带状疱疹感染)引起的。在某些情况下,三叉神经或其分支的损伤是由眼科手术(例如白内障手术、角膜移植、屈光手术)引起的。在某些情况下,三叉神经或其分支的损伤是由全身性疾病诸如糖尿病、麻风病、眼眶肿瘤和炎症引起的。在一些情况下,三叉神经或其分支的损伤是由物理创伤(包括化学灼伤和热灼伤)引起的。在其他情况下,三叉神经或其分支的损伤是由使用隐形眼镜引起的。在一些实施方案中,受试者患有NK,其中上皮损伤与三叉神经途径的任何扰动无关。
在一些实施方案中,HGF和/或FGF施用于受试者的眼睛。HGF和/或FGF施用途径可以根据已知方法进行,例如局部通过滴眼剂或绷带隐形眼镜、局部眼部注射(例如,结膜下、玻璃体内、眼球后和前房内)或通过如下所述的缓释系统。在一些实施方案中,HGF和/或FGF局部施用于眼睛。术语“局部”是指将HGF和/或FGF直接施用于眼睛的表面(即角膜)。在一些实施方案中,HGF和/或FGF通过注射施用于眼睛。在一些实施方案中,HGF和/或FGF经结膜下施用。术语“结膜下”是指在眼球结膜下(眼球上)或眼睑结膜内层下(眼睑下)进行的注射(Stanley,R.,2008“Ocular Clinical Pharmacology”,Small Animal ClinicalPharmacology(第2版))。在一些实施方案中,HGF和/或FGF经玻璃体内施用。术语“玻璃体内”是指直接注射到眼睛的玻璃体腔中。在一些实施方案中,HGF和/或FGF经前房内施用。术语“前房内”是指直接注射到眼睛的前房中。预期用于注射的治疗性多肽组合物通常置于具有合适入口的无菌容器中,例如具有可被皮下注射针刺穿的塞子的小瓶。对于局部施用,可以将包含HGF和/或FGF的药物组合物置于可挤压滴眼剂容器中。在一些实施方案中,包含HGF和/或FGF的药物组合物使用眼科挤压分配器(例如,得自Aptar Pharma的分配器)局部施用。
缓释制剂的合适实例包括成形制品形式的半透性聚合物基质,例如膜、植入物或微胶囊。缓释基质包括聚酯、水凝胶、聚交酯(美国专利号3,773,919和EP 58,481)、L-谷氨酸和γ-乙基-L-谷氨酸的共聚物(Sidman等人,1983,Biopolymers,22:547-556)、聚(2-羟基乙-甲基丙烯酸酯)(Langer等人,1981,J.Biomed.Mater.Res.,15:267-277以及Langer,1982,Chem.Tech.,12:98-105)、乙烯乙酸乙烯酯(Langer等人,同上)或聚-D-(-)-3-羟基丁酸(EP 133,988)。缓释组合物还包括脂质体包裹的HGF、FGF或HGF和FGF两者。含有HGF、FGF或HGF和FGF两者的脂质体可以通过本身已知的方法制备:DE 3,218,121;Eppstein等人,1985,Proc.Natl.Acad.Sci.U.S.A.,82:3688-3692;Hwang等人,1980,Proc.Natl.Acad.Sci.U.S.A.,77:4030-4034;EP 52,322;EP 36,676;EP 88,046;EP 143,949;EP 142,641;美国专利号4,485,045和4,544,545;以及EP 102,324。通常,脂质体是小的(约200-800埃)单层类型,其中脂质含量大于约30摩尔%胆固醇,调整选择的比例以获得最有效的治疗。
治疗上使用的HGF或含HGF的组合物和/或FGF或含FGF的组合物的“有效量”将取决于例如治疗目的、施用途径和受试者的病况。因此,治疗师可能有必要根据需要调整剂量并改变施用途径以获得最佳治疗效果。通常,临床医生将施用HGF和/或FGF直至达到实现期望效果的剂量。这种疗法的进展很容易通过常规测定和方法来监测。
在治疗和预防眼部疾病和病症诸如角膜混浊或瘢痕形成以及NK时,包含HGF和/或FGF的药物组合物可以以符合良好医学实践的方式配制、给药和施用。在本文中需要考虑的因素包括所治疗的具体哺乳动物、个体受试者的临床病况、病症的原因、施用方法、施用时间安排以及执业医师已知的其他因素。待施用的HGF和/或FGF的“治疗有效量”可以由此类考虑来控制,并且是预防、改善或治疗眼部疾病症状所需的最小量。这样的量优选低于对宿主有毒或产生显著副作用的量。
作为一般建议,局部施用于受试者眼睛的药物组合物包含基于重量-体积(w/v)的初始浓度为约0.01%至约1.0%、约0.05%至约0.5%、约0.05%至约0.4%、约0.05%至约0.3%或约0.08%至约0.25%的HGF和/或FGF。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含浓度为约0.1%(w/v)的HGF。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含浓度为约0.2%(w/v)的HGF。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含浓度为约0.1%(w/v)的FGF。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含浓度为约0.2%(w/v)的FGF。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含HGF和FGF,各自的浓度为约0.1%(w/v)。在一些实施方案中,局部施用于受试者眼睛的药物组合物包含HGF和FGF,各自的浓度为约0.2%(w/v)。在一些实施方案中,药物组合物包含HGF并且基本上不含FGF。在一些实施方案中,药物组合物包含FGF并且基本上不含HGF。
本公开的特征还在于组合疗法。例如,向受试者(例如,人)施用本文所述的HGF与第二治疗剂的组合。在一些实施方案中,向受试者同时施用HGF多肽与第二治疗剂。如本文所用,术语“同时”是指“在同一时间段内发生”。在一些实施方案中,HGF多肽和第二治疗剂配制在同一制剂中。在一些实施方案中,HGF多肽和第二治疗剂配制在分开的制剂中。在一些实施方案中,HGF多肽和第二治疗剂同时施用。在一些实施方案中,HGF多肽和第二治疗剂顺序施用。在一些实施方案中,HGF多肽在施用第二治疗剂之前施用。在一些实施方案中,HGF多肽在施用第二治疗剂之后施用。在一些实施方案中,HGF多肽和第二治疗剂间隔1至60分钟、间隔5至30分钟或间隔10至20分钟施用。在一些实施方案中,HGF多肽和第二治疗剂间隔5分钟施用。在一些实施方案中,HGF多肽和第二治疗剂间隔10分钟施用。在一些实施方案中,HGF多肽和第二治疗剂间隔15分钟施用。在一些实施方案中,HGF多肽和第二治疗剂间隔30分钟施用。在一些实施方案中,HGF多肽和第二治疗剂间隔1小时施用。在一些实施方案中,FGF多肽是第二治疗剂。
在一些实施方案中,第二治疗剂可以引发与HGF相同的生物学和生理学作用,例如,相似的细胞内途径的活化。在一些实施方案中,第二治疗剂可引发与HGF不同的生物学和生理学作用。在一些实施方案中,第二治疗剂增强由HGF引起的生物学和生理学作用。在一些实施方案中,第二治疗剂是与HGF相同类别的分子(即两者都是多肽)。在一些实施方案中,第二治疗剂是不同类别的分子(例如小分子或核酸)。第二治疗剂的非限制性实例包括小分子、肽、蛋白质、抗体和抗原结合片段、核酸、细胞和组织提取物以及羊水和其他体液。第二治疗剂可以通过从天然来源分离、合成产生或通过细胞培养获得。如本文所用,术语“小分子”是指小于900道尔顿的低分子量有机化合物。如本文所用,术语“肽”是指2至约50个亚基氨基酸、氨基酸类似物或肽模拟物的化合物。亚基可以通过肽键连接。如本文所用,术语“氨基酸”是指天然和/或非天然或合成的氨基酸,包括甘氨酸和D或L光学异构体,以及氨基酸类似物和肽模拟物。如本文所用,术语“抗体”包括多克隆抗体和单克隆抗体及其片段。抗体包括但不限于小鼠、大鼠、兔、人或嵌合抗体等。术语“抗体”还包括所有异型体的抗体。如本文所用,“核酸”或“多核苷酸”是指任何长度的核苷酸或其类似物的聚合形式。多核苷酸可以含有脱氧核糖核苷酸、核糖核苷酸和/或它们的类似物。核苷酸可以具有任何三维结构,并且可以执行任何已知或未知的功能。核酸分子还包括寡核苷酸,诸如反义分子、探针、引物等。寡核苷酸通常具有约2至约100、8至约30或10至约28个核苷酸或其类似物。
在一些实施方案中,第二治疗剂是抗生素。抗生素的非限制性实例包括甲氧苄啶、多粘菌素B、阿奇霉素、庆大霉素、贝西沙星、加替沙星、莫西沙星、左氧氟沙星、环丙沙星、氧氟沙星和妥布霉素。在一些实施方案中,第二治疗剂是非甾体抗炎药(NSAID)。NSAID的非限制性实例包括阿司匹林、双水杨酯、塞来昔布、双氯芬酸、依托度酸、布洛芬、吲哚美辛、酮洛芬、酮咯酸、萘丁美酮、萘普生、奥沙普秦、吡罗昔康、舒林酸和托美汀。在一些实施方案中,第二治疗剂是眼用类固醇。眼用类固醇的非限制性实例包括眼用地塞米松()、眼用二氟泼尼酯(/>)、眼用氟米龙(/> FML/>FML)、眼用依碳酸氯替泼诺(/> )、眼用醋酸泼尼松龙(Pred/>Pred/>)、眼用泼尼松龙磷酸钠和眼用利美索龙()。在一些实施方案中,第二治疗剂是局部麻醉剂。局部麻醉剂的非限制性实例包括丙胺卡因、肾上腺素、利多卡因、布比卡因、隆托卡因、奴佛卡因、罗哌卡因、普鲁卡因、阿美卡因、辛可卡因、甲哌卡因和依替卡因。在一些实施方案中,第二治疗剂是另一种生长因子。生长因子的非限制性实例包括上皮生长因子(EGF)、成纤维细胞生长因子(FGF)、胰岛素样生长因子(IGF-1)、血小板衍生生长因子(PDGF)、角质形成细胞生长因子(KGF)、转化生长因子(TGF)、血管内皮生长因子和粒细胞-巨噬细胞集落刺激因子(GM-CSF)、神经营养素和神经生长因子(NGF)、肿瘤坏死因子-α(TNF-α)和白介素。
药物组合物和制剂
在包含多肽的药物组合物、特别是基本上包含需要长期储存的水溶液的药物组合物的开发中,维持多肽对抗热应力的稳定性和最小化可见颗粒和可溶性聚集体的形成是重要的焦点。参见以下参考文献,其中HGF和相关蛋白质与各种稳定剂一起配制:WO90/10651WO00/72873(欧洲专利号1180368)、JP-A 9-25241(美国专利号7,173,008)、WO 2008/102849(美国专利号8461112)和US 10213485。尽管使用现有技术中描述的此类冻干的HGF制剂可以在一定程度上避免蛋白质聚集和热稳定性的问题,但是这需要在包含HGF的药物组合物的生产中进行冷冻干燥单元操作,这会产生额外的制造成本和过程的复杂性。此外,冻干的HGF制剂需要在给药和施用前重新配制。因此,稳定的解决方案是有利的。
在本发明的一些实施方案中,HGF(和/或FGF)被配制在液体药物组合物中。在一些实施方案中,药物组合物是水性药物组合物。如本文所用,“水性药物制剂”是指水基液体。在一些实施方案中,水性药物组合物包含蒸馏水。在一些实施方案中,水性药物组合物包含去离子水。在一些实施方案中,水性药物组合物包含无菌水。在一些实施方案中,水性药物组合物包含注射用水(WFI)。在一些实施方案中,液体药物组合物被配制为滴眼剂。在一些实施方案中,液体药物组合物被配制为溶液。在一些实施方案中,液体药物组合物被配制为悬浮液。在一些实施方案中,HGF与另一种治疗剂一起配制在液体药物组合物中。在一些实施方案中,HGF与另一种治疗剂一起配制为滴眼剂。在一些实施方案中,HGF与另一种治疗剂一起配制为溶液。
本发明的多肽或其衍生物的药物制剂可以通过将具有所需纯度的多肽或其衍生物与任选的药学上可接受的载体、赋形剂、张力调节剂或稳定剂混合来制备用于储存(参见例如Remington's Pharmaceutical Sciences,第43章,第14版,Mack Publishing Co,Easton Pa.18042,USA),以冻干饼或水溶液的形式。可接受的载体、赋形剂、张力调节剂或稳定剂在使用的剂量和浓度下对接受者是无毒的,并且包括缓冲剂,诸如磷酸盐、柠檬酸盐、琥珀酸盐和其他有机酸,其中术语“缓冲剂”是指弱酸及其共轭碱的混合物,或反之亦然,其用于将溶液的pH维持在几乎恒定的值;抗氧化剂,包括抗坏血酸;低分子量(小于约10个残基)多肽;蛋白质,诸如血清白蛋白、明胶或免疫球蛋白;亲水性聚合物,诸如聚乙烯吡咯烷酮(PVP)和聚乙二醇(PEG);氨基酸,诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸、组氨酸、脯氨酸或赖氨酸;单糖、二糖和其他碳水化合物,包括葡萄糖、甘露糖、蔗糖、海藻糖或糊精;螯合剂,诸如EDTA;糖醇,诸如甘露醇或山梨醇;成盐抗衡离子,诸如钠或钾;和/或非离子表面活性剂或共溶剂,诸如聚山梨醇酯和泊洛沙姆;张力调节剂,诸如氯化钠、氯化钾、甘露醇、葡萄糖、甘油和氯化镁。
在一些实施方案中,本发明的制剂基本上不含张力调节剂。在一些实施方案中,本发明的制剂基本上不含氯化物盐,诸如氯化钠、氯化钾和氯化镁。
在一些实施方案中,包含HGF(和/或FGF)的药物制剂的pH为约5.5至约7.5。在一些实施方案中,药物制剂的pH为约5.5至约6.0。在一些实施方案中,药物制剂的pH为约5.8至约6.2。在一些实施方案中,药物制剂的pH为约6.0至约6.5。在一些实施方案中,药物制剂的pH为约6.5至约7.0。在一些实施方案中,药物制剂的pH为约7.0至约7.5。在一些实施方案中,药物制剂的pH为约6.0。在一些实施方案中,药物制剂的pH为约6.5。在一些实施方案中,药物制剂的pH为约7.0。
在一些实施方案中,本发明的药物制剂还包含缓冲剂。在一些实施方案中,缓冲剂选自乙酸盐、柠檬酸盐、谷氨酸盐、组氨酸、琥珀酸盐、酒石酸盐和三(羟甲基)氨基甲烷(Tris)。在一些实施方案中,缓冲剂是柠檬酸盐缓冲剂,诸如柠檬酸钠(例如,柠檬酸钠二水合物)。在一些实施方案中,缓冲剂是乙酸盐缓冲剂。在一些实施方案中,缓冲剂是琥珀酸盐缓冲剂。在一些实施方案中,缓冲剂是酒石酸盐缓冲剂。在一些实施方案中,缓冲剂是谷氨酸盐缓冲剂。在一些实施方案中,缓冲液是Tris。在一些实施方案中,缓冲剂以约10mM至约100mM存在。在一些实施方案中,缓冲剂以约20mM至约50mM存在。在一些实施方案中,缓冲液以约20mM存在。
在一些实施方案中,本发明的药物制剂还任选地包含张力调节剂。在一些实施方案中,药物制剂基本上不含张力调节剂。在一些实施方案中,张力调节剂是碱金属盐,诸如氯化钠(NaCl)或氯化钾(KCl)。在一些实施方案中,张力调节剂是氯化钙(CaCl2)。在一些实施方案中,张力调节剂是甘露醇。在一些实施方案中,张力调节剂是海藻糖(例如,海藻糖二水合物)。在一些实施方案中,张力调节剂以约0.1至约1.0M、约0.2至约0.8M、约0.3M、约0.4M、约0.5M、约0.6M、约0.7M或约0.75M存在。在一些实施方案中,制剂的渗透压为约200至约500mOsm/kg H2O、约200至约300mOsm/kg H2O、约250至约350mOsm/kg H2O、约350至约400mOsm/kg H2O、约400至约450mOsm/kg H2O或约450mOsm/kg H2O至约500mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约300mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约350mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约400mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约425mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约450mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约475mOsm/kg H2O。在一些实施方案中,制剂的渗透压为约500mOsm/kg H2O。
在一些实施方案中,本发明的药物制剂还包含一种或多种稳定剂。在一些实施方案中,一种或多种稳定剂选自山梨糖醇、海藻糖、蔗糖、丙氨酸、甘氨酸、脯氨酸、谷氨酸和精氨酸。在一些实施方案中,一种或多种稳定剂选自山梨糖醇、脯氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂选自脯氨酸、精氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂选自谷氨酸、脯氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂选自精氨酸、谷氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂选自精氨酸、脯氨酸和山梨糖醇。在一些实施方案中,一种或多种稳定剂选自谷氨酸、脯氨酸和山梨糖醇。在一些实施方案中,一种或多种稳定剂选自精氨酸、谷氨酸和山梨糖醇。在一些实施方案中,一种或多种稳定剂是精氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂是山梨糖醇和海藻糖。在一些实施方案中,一种或多种稳定剂是脯氨酸和海藻糖。在一些实施方案中,一种或多种稳定剂是精氨酸和山梨糖醇。在一些实施方案中,一种或多种稳定剂是谷氨酸和山梨糖醇。在一些实施方案中,一种或多种稳定剂是脯氨酸和山梨糖醇。在一些实施方案中,稳定剂是海藻糖。在一些实施方案中,稳定剂是脯氨酸。在一些实施方案中,稳定剂是精氨酸。在一些实施方案中,稳定剂是山梨糖醇。
在一些实施方案中,本发明的药物制剂基本上不含蔗糖、丙氨酸和甘氨酸。在一些实施方案中,药物制剂基本上不含蔗糖。在一些实施方案中,药物制剂基本上不含丙氨酸。在一些实施方案中,药物制剂基本上不含甘氨酸。
在一些实施方案中,稳定剂以约100mM至约500mM的浓度存在于制剂中。在一些实施方案中,稳定剂以约150mM至约250mM的浓度存在。在一些实施方案中,稳定剂以约200mM的浓度存在。
在一些实施方案中,本发明的药物制剂还任选地包含表面活性剂。在一些实施方案中,表面活性剂选自聚山梨醇酯80(PS80)、聚山梨醇酯20(PS20)、泊洛沙姆188(P188)和泊洛沙姆407(P407)。在一些实施方案中,表面活性剂是聚山梨醇酯80。在一些实施方案中,表面活性剂以约0.02%至约0.07%(w/v)存在。在一些实施方案中,表面活性剂以约0.04%至约0.06%(w/v)存在。在一些实施方案中,表面活性剂以约0.05%(w/v)存在。
在一些实施方案中,本发明的药物组合物包含:
(i)约0.1%(w/v)至约1.0%(w/v)HGF;
(ii)能够将组合物的pH维持在约5.8至约6.2的缓冲剂;
(iii)约100至约300mM的海藻糖、脯氨酸、山梨糖醇或它们的混合物;
(iv)任选的张力调节剂,其能够提供所述组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及
(v)任选的表面活性剂。
在一些实施方案中,本发明的药物组合物包含:
(i)约0.1%至约0.5%(w/v)HGF;
(ii)能够将组合物的pH维持在约5.8至约6.2的缓冲剂;
(iii)约100至约300mM的海藻糖、脯氨酸、山梨糖醇或它们的混合物;
(iv)任选的张力调节剂,其能够提供所述组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及
(v)任选的表面活性剂。
在一些实施方案中,本发明的药物组合物包含:
(i)约0.1%(w/v)HGF;
(ii)能够将组合物的pH维持在约5.8至约6.2的缓冲剂;
(iii)约100至约300mM的海藻糖、脯氨酸、山梨糖醇或它们的混合物;
(iv)任选的张力调节剂,其能够提供所述组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及
(v)任选的表面活性剂。
在一些实施方案中,本发明的药物组合物包含:
(i)约0.2%(w/v)HGF;
(ii)能够将组合物的pH维持在约5.8至约6.2的缓冲剂;
(iii)约100至约300mM的海藻糖、脯氨酸、山梨糖醇或它们的混合物;
(iv)任选的张力调节剂,其能够提供所述组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及
(v)任选的表面活性剂。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;约0.05%(w/v)表面活性剂;
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中组合物的pH为约6.0。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;
其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约350mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;
其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,本发明的药物组合物包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中该组合物的pH为约6.0并且该组合物的渗透压为约450mOsm/kg H2O。
在一些实施方案中,HGF与角膜基质渗透赋形剂组合施用。基质渗透赋形剂是可以增强治疗剂穿过角膜层(主要是上皮)的递送的化合物(Moiseev等人,2019,Pharmaceutics,11:321-354)。这些化合物(当包含在药物组合物中并局部施用于眼睛时)能够改变泪膜、粘液层或眼膜,从而增加治疗剂的角膜渗透性。基质渗透赋形剂的非限制性实例包括环糊精(CD),包括α-、β-和γ-CD;螯合剂,诸如乙二胺-N,N,N',N'-四乙酸(EDTA)、乙二醇-双(β-氨基乙基)-N,N,N',N'-四乙酸(EGTA)、1,2-双(邻氨基苯氧基)乙烷-N,N,N',N'-四乙酸(BAPTA)和乙二胺-N,N,N',N'-二琥珀酸(EDDS);冠醚、表面活性剂、胆汁酸和胆汁盐以及细胞穿透肽。用于体内施用的HGF优选是无菌的。这可以通过经无菌滤膜过滤HGF水溶液而容易地实现。HGF或其变体通常以冻干形式或溶液形式储存。
应当理解,为了清楚起见,在单独的实施方案的上下文中描述的本发明的某些特征也可以在单个实施方案中组合提供。相反,为了简洁起见,在单个实施方案的上下文中描述的本发明的各种特征也可以单独地或以任何合适的子组合来提供。
实施例
实施例1:在UniProtKB上可获得的人HGF异型体的氨基酸序列(uniprot.org/uniprot/P14210)
SEQ ID NO:1.智人HGF异型体3(标识符:P14210-3,登录号NP_001010932.1)(dHGF)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYA KWIHKIILTYKVPQS
SEQ ID NO:2.智人HGF异型体1(标识符:P14210-1,登录号:NP_000592.3)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:3.智人HGF异型体2(标识符:P14210-2,登录号:NP_001010931.1)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGL MDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCET
SEQ ID NO:4.智人HGF异型体4(标识符:P14210-4)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKNMRDITWALN
SEQ ID NO:5.智人HGF异型体5(标识符:P14210-5,NP_001010933.1)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCET
SEQ ID NO:6.智人HGF异型体6(标识符:P14210-6,NP_001010934.1)的氨基酸序列:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCR NPRGEEGGPWCFTSNPEVRYEVCDIPQCSEGK
SEQ ID NO:7.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALEIKTKKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGKGRSYRGTVSITKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:8.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCIRNKGLPFTCKAFVFDKARKRCLWFPVNSMSSGVKKEFGHEFDLYENKDYTRNCIVGNGRSYRGTVSTTKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQ GEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:9.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSITKSGIECQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:10.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAKGQGKRRNTIHEFKKSAKTTLIKIDPALKIKTEKADTADQCANRCTRSKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSVTKSGIKCQPWSSMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:11.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNAIHEFKKSAKATLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSITKSGIECQPWSSMIPHEHSFLPSSYRGEDLQENYCRNPWGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGK NYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:12.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYTRNCIVGNGRSYRGTVSITKSGIECQPWSAMIPHEHSFLPSSYQGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:13.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:14.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRDAIHECKRSAKTTLIKIDPALKIKTEKANTADQCANRCTRNKGLPSTCKAFVFDKARKRRLRFPFNSMSSGVKKEFGHEFDLYENKDYTRNCIVGKGRSYRGTVSTTKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVI SCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:15.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQGKRRNTIHEFKKSAKTTLIKIDPALKIKTEKVNTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGRGRSYRGTVSITKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:16.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPHAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFV FDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYTRNCIVGNGRSYRGTVSTTKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:17.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSRGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGNGRSYRGTVSVTKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGP EGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:18.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRNKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:19.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSVKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPVNSMSSGVKKESGHEFDLYENKDYIRDCIVGNGRSYRGTVSTTKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYC RNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:20.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGEDLRENYCRNPWGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKI GSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:21.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALRIKTEKANTADQCANRCTRSRGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGNGRSYRGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:22.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSRRLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGKGRSYRGTVSVTKSGIECQPWSAMIPHEHSFLPSNYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDG QPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:23.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIVGNGRSYRGTVSITKSGIECQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:24.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVDTADQCANRCTRNKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGNGRSYRGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:25.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQGKRRNTIHEFKKSAKTTLIKIDPALRIKTEKANTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKAYIRDCIIGRGRNYRGTVSITKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNY MGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:26.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAKGQRKRRNTIHEFKKSAKTTLIKIDPALEIKTEKVNTADQCANRCIRNKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKAYIRDCIIGRGRNYRGTVSITKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:27.HGF变体:
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQGKRRNTIHEFKKSAKTTLIKIDPALKIKTEKVNTADQCANRCTRSKGLPFTCKAFVFDKARKRCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRDCIIGNGRSYRGTVSITKSGIKCQPWSAMIPHEHSFLPSSYRGEDLRENYCRNPRGEEGGPWCYTSDPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:28.FGF1野生型:
FNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD
SEQ ID NO:29.FGF1变体:
FNLPPGNYKKPKLLYCSNGGHFLRILPNGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAIRFLPLPVSSD
SEQ ID NO:30.FGF1变体:
FNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDPHIQLQLIAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENGYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAILFLPLPVSSD
SEQ ID NO:31.FGF1变体:
FNLPPGNYKKPKLLYCSNGGHFLRILPNGTVDGTRDRSDPHIQLQLIAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENGYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAIRFLPLPVSSD
SEQ ID NO:32.FGF1变体:
FNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAIRFLPLPVSSD
SEQ ID NO:33.FGF1变体:
FNLPPGNYKKPKLLYCSNGGHFLRILPDGTVDGTRDRSDQHIQLQLSAESVGEVYIKSTETGQYLAMDTDGLLYGSQTPNEECLFLERLEENHYNTYISKKHAEKNWFVGLKKNGSCKRGPRTHYGQKAIKFLPLPVSSD
SEQ ID NO:34.SEQ ID NO:1的信号肽
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEG
SEQ ID NO:35.SEQ ID NO:1的未切割的α和β链肽
QRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
SEQ ID NO:36.SEQ ID NO:1的α链肽
QRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLR
SEQ ID NO:37.SEQ ID NO:1的β链肽
VVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
实施例2:制剂
进行了实验设计(DoE)研究以确定可防止溶液制剂中HGF聚集并维持最佳物理化学稳定性的最佳pH、缓冲液和稳定剂。HGF蛋白(来自SEQ.ID NO.1的活化dHGF)在10mM柠檬酸盐、1M NaCl、0.075% PS80、pH 6.0中配制为34.67mg/mL,并使用Amicon-15浓缩器单元(10kDa MWCO)将缓冲液交换为表3中列出的制剂至1mg/mL的浓度。将340μL体积的34.67mg/mL溶液添加到预冲洗的浓缩器(含有适当的缓冲液)中,并在适当的配制缓冲溶液(不含表面活性剂)中稀释至15mL。将样品以3200rcf离心直至达到约5mL的体积,然后用适当的配制缓冲液再次稀释至约15mL总体积。重复该缓冲液交换过程五个循环,总稀释度为~3610倍。在最后的离心循环中将样品体积减少至约7mL。假设最差情况下的回收率为~60%,则每个样品的最终蛋白质浓度为~1mg/mL,PS80的估计残留浓度为~0.004%。
使用消光系数1.890mL mg-1cm-1通过UV-可见光谱分析缓冲液交换的样品的蛋白质含量。根据需要使用适当的制剂缓冲液将样品标准化至目标1mg/mL,并在HGF制剂中加标10% PS80(w/v,由USP级PS80、目录号4117-04J.T.Baker或等同物制备)至目标浓度为0.05% PS80。没有考虑缓冲液交换过程结束时的理论残留PS80水平(~0.004%),因为PS80的残留水平相对于加标PS80的量是最小的。
将蛋白质含量和表面活性剂浓度标准化后,使用0.22μm无菌浓缩器(MilliporeUltrafree-CL GV,P/N UFC40GV0S)对制剂进行无菌过滤。将每种制剂无菌过滤到六个灭菌的1型硼硅酸盐玻璃小瓶(2mL,13mm,目录号RTF8418,Afton)中,每个小瓶1.0mL。将剩余样品体积转移到1mL LDPE管(目录号03-439-61W Fisher)并用作分析测试的初始时间点对照(T0)。对于中心点制剂,将来自T0测试小瓶的200μL转移至1mL LDPE管(目录号03-439-61WFisher)并用于如下所述的吸附研究。使用无菌技术在无菌生物安全柜中进行样品转移和无菌过滤程序。将小瓶用灭菌的Fluorotec塞子塞住,并用带按钮的13FO铝盖盖上。每种制剂类型的两个小瓶在以下储存条件下储存:2-8℃4周和40℃4周。通过目视检查评估样品外观的颜色、透明度和颗粒。通过DSF/SLS评估蛋白质的热稳定性。此外,使用UV-可见光谱通过测量340nm波长处的吸收进行浊度测量。分别通过DLS和SEC-HPLC测定蛋白质的构象稳定性和聚集稳定性。使用还原和非还原毛细管凝胶电泳(CE-SDS)和等电聚焦(icIEF)凝胶电泳进一步分析样品。使用HIAC颗粒计数器评估颗粒物质的存在,其中报告了样品中>2μm、≥5μm、≥10μm和≥25μm的平均颗粒计数。所有DoE分析均以随机顺序进行。使用DesignExpert Stat软件评估所有DoE制剂的T0和稳定性时间点的数据,以获得统计上显著的趋势。
评估LDPE容器表面非特异性HGF蛋白吸附的吸附研究
LDPE管中的样品在2-8℃下储存至少五天。储存五天后,测量这些样品的蛋白质含量,如通过280nm处的UV吸光度(A280)所测定的,并将这些值与T0时的相应结果进行比较,以确定LDPE容器材料是否有任何蛋白质吸附。当储存在LDPE容器中时,观察到最小的蛋白质吸附,其中对于大多数测试的制剂,5天后测量的HGF浓度的%差异小于4%,但包含蔗糖和丙氨酸的制剂除外,其中观察到HGF蛋白质浓度下降8%(表3)。本研究的结果支持使用LDPE管作为HGF制剂的可行容器。
表3.LDPE吸附研究
结果
通常,在40℃或5℃下储存1个月后,在6.0-6.5的较高pH范围内的制剂中观察到较低浊度(表4)。包含200mM海藻糖的制剂在5.0-6.5的pH范围内显示出低浊度(低于0.01),其中包含200mM海藻糖的制剂在pH 6.0下在40℃储存1个月后显示出最低浊度。
表4.各种HGF溶液制剂在40℃或5℃下储存1个月的浊度。
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*所有A340值均报告为两种独立制剂的测量平均值,但用**表示的制剂除外,其表示单一制剂。
如使用HIAC检测的,观察到几种制剂在5℃或40℃下储存1个月后存在颗粒物质(表5)。包含200mM山梨糖醇、200mM脯氨酸或200mM海藻糖(pH 5.0)或200mM海藻糖或0.08%甘氨酸(pH 6.0)的制剂显示出最低的颗粒计数。然而,其他分析数据,包括表4中所示的浊度数据,表明HGF蛋白质在pH 6.0下具有更好的总体稳定性,其中仅200mM海藻糖和0.08%甘氨酸制剂在储存时显示出低颗粒计数。
表5.如通过HIAC所测量的HGF制剂在40℃或5℃下储存1个月的颗粒计数。
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*所有HIAC值均报告为两种独立制剂的测量平均值,但用**表示的制剂除外,其表示单一制剂
使用还原毛细管凝胶电泳(R-CE-SDS)进一步评估不同制剂中HGF蛋白的化学稳定性。HGF是包含通过二硫键连接的α链和β链的异二聚体。在还原条件下,电泳图谱中存在两个峰(表6中的%主峰1和%主峰2);标有“%其他”的列表示HGF蛋白质的潜在降解产物。如表6中所示,pH 6.0的HGF制剂通常在40℃和5℃的长期储存过程中表现出更好的化学稳定性,其中在pH 6.0包含200mM海藻糖或200mM脯氨酸的制剂中观察到最高%总主峰。包含0.08%甘氨酸的HGF制剂在颗粒计数和浊度方面表现出良好的稳定性,但R-CE-SDS显示其化学稳定性较差。
表6.HGF制剂在40℃或5℃下储存1个月的还原毛细管凝胶电泳(R-CE-SDS)。
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*所有%峰值均是两种独立制剂的测量平均值,但用**表示的制剂除外,其表示单一制剂。
实施例3:确定相对效力的生物测定
在存在转化生长因子β(TGF-β)的情况下,使用Mv.1.Lu细胞(美国貂肺细胞系)的细胞增殖促进活性效力测定,进一步评估显示如实施例2中描述的制剂开发实验中所鉴别的最佳总体属性的制剂的相对效力。TGF-β抑制Mv.1.Lu细胞中的细胞生长,并且本文所述的HGF制剂可以逆转这种生长抑制。将Mv.1.Lu细胞解冻,并通过台盼蓝染色评估细胞储液的活力。确定活细胞密度后,将适当数量的细胞转移到烧瓶中进行初始培养。细胞在组织培养瓶中连续生长和扩增,然后铺板用于样品分析。
用测定培养基稀释每个参考标准品和每个测试样品以生成八点稀释曲线。通过将由测试样品生成的稀释曲线与参考标准品进行比较来确定每个测试样品的效力。
将组织培养瓶中的培养细胞用胰蛋白酶消化并重悬于测定培养基(含有250pg/mLTGF-β)中至约0.1×106个细胞/mL。将五十微升细胞悬浮液接种在96孔板的每个孔中。将含有培养细胞的96孔板在37℃/5% CO2下孵育1至4小时,然后添加参考标准品和测试样品。将测试样品和参考标准品一式三份添加到单独的孔中,并将细胞孵育72小时。
孵育后,将MTS增殖试剂(Promega,目录号G3582)或等同物添加到每个孔中,并将96孔板在37℃/5% CO2下孵育4小时。孵育后,将板置于UV-vis读板器中,并在490nm处测量吸光度。每个参考标准品和测试样品一式三份进行分析,并通过平行线评估确定效力。通过四参数约束拟合将每个样品与参考标准品进行比较以确定相对效力。
测试样品(TS)验收标准:
1.当绘制平均反应与对数蛋白质浓度的关系时,TS独立四参数曲线拟合必须表现出剂量依赖性关系。
2.TS独立4参数拟合的R2值必须≥0.97。
3.TS的所有%CV值必须≤20%。
4.系统适用性样品的效力将使用全局拟合模型确定,并且每个TS的F概率必须≥0.01
5.未通过上述所有标准的测试样品将在相同条件下重新测试。
6.未通过上述任何标准的测定板必须在相同条件下重新测试一次。
7.标准样品(SS)的%RP必须在50%-200%内。
表7总结了所选制剂的体外相对效力生物测定的结果。包含200mM海藻糖、pH 6.0的HGF溶液制剂被证实也保持了HGF蛋白的优异效力(99%)。
表7.不同制剂中HGF的相对效力
**与参考标准相比的相对效力。
实施例4:局部制剂在小鼠角膜机械损伤模型中的功效
在小鼠角膜损伤模型中测试了HGF局部制剂用于治疗NK的有效性。使用雄性C57BL/6小鼠分两个阶段进行功效测试。在第I阶段,使用3.5μL体积的测试物品通过移液管每天4次(QID)对75只动物中的每只一只眼睛给药,其中第0天(损伤)的剂给药间隔为2小时,并且研究的剩余时间(第8天)的给药间隔为3小时。将对损伤没有反应(即,在第3天没有角膜混浊/不透明)的动物(~10%-20%)从研究中排除。下表8总结了第1阶段研究实验设计。
表8:小鼠角膜机械损伤模型中HGF在NK治疗中的第1阶段功效测试的实验设计
缩写:
mNGF:鼠神经生长因子
mHGF:鼠肝细胞生长因子
*在第3天排除以下动物:
1.发起人在第3天排除对损伤没有反应(即,第3天无角膜混浊/不透明)的动物(n=1-2只/组),并且发起人被掩蔽。
2.收集动物(n=3只/组)作为每组的代表进行组织学检查(H&E染色)。
**T1:0.1%(w/v)人dHGF(SEQ ID NO:1)的PBS溶液。
T2:0.2%(w/v)人dHGF(SEQ ID NO:1)的PBS溶液。
表9:进行试验以确定上皮刮擦的频率(将来自第1阶段的PBS组的动物(n=9-10)用于该试验),并且基于第1阶段的结果选择0.1%与0.2%dHGF剂量。
在效力研究的第2阶段,以3.5μL体积的测试物品每天4次(QID)对85只动物在损伤的角膜处给药,其中第11天(损伤)的剂给药间隔为2小时,并且研究的剩余时间(第20天)的给药间隔为3小时。在第一次治疗应用时(第11天),通过将Algerbrush的尖端轻轻涂抹角膜的不透明区域(用1mm环钻标记)来除去角膜上皮。在第16天第二次除去角膜上皮。下表10总结了第2阶段的研究设计。
表10:小鼠角膜机械损伤模型中HGF在NK治疗中的第2阶段功效测试的实验设计
*具有正确表型的动物入组治疗。
缩写:
mNGF:鼠神经生长因子
mHGF:鼠肝细胞生长因子
dHGF:人肝细胞生长因子(SEQ.ID NO.1)
**媒介物=PBS;将mNGF、mHGF和dHGF以指定浓度配制在媒介物中。
角膜损伤(第1阶段和第2阶段):
在模型诱导之前,向测试受试者皮下给予0.01-0.05mg/kg丁丙诺啡。还给动物局部给予托吡卡胺(1.0%)和去氧肾上腺素(2.5%)的混合物以扩张和突出眼睛。然后用氯胺酮/甲苯噻嗪混合物和一滴0.5%盐酸丙美卡因使动物镇静以进行外科手术。使用镊子(例如Dumont#4)将动物的眼睛突出,并用轻微的压力将2mm环钻放置在中央角膜上。轻轻按压环钻,旋转3个小时,以限定缺损区域。使用带有0.5mm磨头的Algerbrush II(AlgerCompany Inc.,Lago Vista,TX)除去环钻区域内的角膜上皮和前基质。通过基质碎片的外观来标记损伤的基质。通过用平衡盐水(BSS)洗涤除去基质碎片。在对损伤的眼睛进行第一剂量的治疗之前,通过光学相干断层扫描术(OCT)扫描动物并进行荧光素染色。15分钟后使用局部抗生素(氧氟沙星),使动物从手术中恢复正常。动物在术后约6-8小时皮下接受第二剂量的0.01-0.05mg/kg丁丙诺啡,并且在术后两天内每天两次,每6-8小时一次。
角膜损伤(上皮去除,仅第2阶段):
在第2阶段开始之前,进行了初步研究以确定如上述第1阶段的初始损伤后上皮刮擦的最佳数量。两次刮擦足以实现所需的模型诱导。在第2阶段开始后,皮下给予动物0.01-0.05mg/kg丁丙诺啡。还给动物局部给予托吡卡胺(1.0%)和去氧肾上腺素(2.5%)的混合物以扩张和突出眼睛。然后用氯胺酮/甲苯噻嗪混合物使动物镇静以进行外科手术,并施用一滴0.5%盐酸丙美卡因。在第0天,如上述第1阶段对动物进行外科手术。在初始损伤和瘢痕形成后的第11天和第16天,使用镊子(例如Dumont#4)将动物的眼睛突出,并用轻微的压力将1mm环钻放置在角膜上的瘢痕区域上。轻轻按压环钻,旋转3个小时,以限定缺损区域。使用带有0.5mm磨头的Algerbrush II(Alger Company Inc.,Lago Vista,TX)除去环钻区域内的角膜上皮。然后用BSS清洗眼表面。在对损伤的眼睛进行第一剂量的治疗之前,通过光学相干断层扫描术(OCT)扫描动物、荧光素染色并拍照。15分钟后使用局部抗生素(氧氟沙星),使动物从手术中恢复正常。动物在术后约6-8小时皮下接受第二剂量的0.01-0.05mg/kg丁丙诺啡,并且在术后两天内每天两次(BID),每6-8小时一次。
监测参数:
(i)检查和体重:
每天观察两次死亡率和发病率以及笼边观察结果,特别注意双眼情况。由于在本研究的第1阶段期间给药和成像的处理量很大,n=18只动物在研究结束前死亡(第1组:4只小鼠;第2组:3只小鼠;第3组:3只小鼠;第4组:3只小鼠;第5组:5只小鼠)或被安乐死。在2阶段试点期间,没有死亡。在第2阶段,减少了成像阶段的数量,并且仅n=3只小鼠死亡(第1组:1只小鼠;第2组:1只小鼠;第4组:1只小鼠)。在模型诱导前和尸检时称重。
(ii)眼部检查和明场图像:
在入组前,由兽医眼科医师在裂隙灯生物显微镜下评估基线眼表面形态。使用Image J软件在基线和研究设计中指定的日期捕获明场图像以分析角膜混浊。
(iii)荧光素染色:
在实验设计表中所示的时间点,对动物进行荧光素眼表面染色。将约1.5μl的2.5%荧光素钠应用于角膜表面30秒,随后使用1ml注射器用1X PBS冲洗。使用安装在三脚架上的Nikon数字SLR相机在钴蓝光下拍摄角膜染色。将相机镜头置于手动模式,镜头设置在1英尺外。将动物的眼睛聚焦在观察窗的中心,收集图像以保持相机镜头与动物眼睛之间的距离一致。使用Image J软件(NIH)测定每个时间点每只眼睛的荧光素染色面积(以像素为单位)。
(iv)光学相干断层扫描术(OCT):
在实验设计表所示的日子里,所有动物都进行了眼前节的OCT成像程序。在OCT检查前将动物麻醉并用PBS清洗角膜。
(v)组织学(仅第1阶段):
在第3天,在最终活体测量之后,通过二氧化碳窒息随后胸廓切开术对一部分动物进行人道安乐死。将动物的手术眼收集到10%中性缓冲福尔马林中。第二天,将眼睛置于70%乙醇中,包埋在石蜡中并矢状切割。用苏木精和曙红(H&E)对三张含有包括视神经的连续切片的载玻片进行染色以用于形态学分析。此外,将H&E后剩余的块进一步切片并进行TUJ-1染色(也称为βIII微管蛋白)的免疫组织化学以评估角膜神经支配。DAPI(蓝色)用作复染剂以突出显示所有细胞核。兽医眼科医生对载玻片进行了分析。
(vii)结果:
1)加速愈合(荧光素染色)
与接受PBS媒介物的动物相比,在用0.1%dHGF治疗的动物的术后第3天组织样品中观察到更多的TUJ01染色(图1),表明用0.1%dHGF治疗的动物中的角膜神经支配。与PBS对照和0.1%mNGF相比,0.1%dHGF(p=0.041)和0.2%dHGF的上皮愈合时间更快(图2)。0.1%dHGF组中50%的眼睛完全愈合所需时间为三天,是PBS组所需时间的一半(六天;p=0.41)。0.2%dHGF和0.1%mHGF组的愈合速度是PBS组的三分之二(四天与六天)。此外,0.1%mHGF显著快于mNGF(p=0.053)和PBS(p=0.0018)。接受0.1%dHGF的动物较早开始闭合,并且>75%在治疗后第4天已达到闭合;对于0.1%mHGF观察到相同的效果(图2)。相比之下,只有50%的PBS治疗的动物达到完全伤口闭合,而且直到第6天才达到。
2)瘢痕预防(明场图像分析)
在手术后并且每日用PBS(对照)、0.1%或0.2%dHGF、0.1%mNGF或0.1%mHGF治疗,除PBS对照外,所有测试物品到第7天均有效减小了平均瘢痕大小(图3)。测试物品对瘢痕形成作用的定量显示,0.1%mHGF的作用最大,其次是0.1%dHGF。在dHGF组中,瘢痕显著小于PBS对照组(0.1%组和0.2%组分别为p=0.0439和p=0.0126),但彼此没有显著差异(p=0.7406)。0.1%mHGF组的瘢痕平均面积在第7天显著小于对照组(p=0.0001)和0.1%mNGF(p=0.0029)。对照组和0.1%mNGF组的瘢痕平均大小彼此没有显著差异(p=0.2481)。
由HGF驱动的作用大小反映在闭合时间分析中(参见第vii.1节)。0.1%mHGF所减少的瘢痕形成是对照组中观察到的减少的约9倍,而0.1%和0.2%dHGF所减少的百分比则是对照组的5倍以上。0.1%mNGF的百分比减小是dHGF组的大约一半,在数值上,但不是统计学上显著的,瘢痕大小的减小比PBS对照组大。
3)瘢痕逆转(明场图像分析)
在去除角膜上皮和前基质的手术和仅去除上皮的两次重复刮擦后,PBS治疗的动物的瘢痕大小几乎没有变化,而接受0.1%dHGF、0.2%dHGF或0.1%mHGF的动物的角膜瘢痕大小减小。在PBS对照组中,平均瘢痕大小从基线(第8天)到第21天持续增加20%以上。相比之下,三个HGF组中的瘢痕大小从基线到第21天减小了35%以上,与PBS组相比平均大小的总体差异为55%。与PBS对照相比,0.1%dHGF与0.2%dHGF之间的差异具有统计学显著性(分别为p=0.0054和p=0.0015),如图4所示。0.1%mNGF组的平均瘢痕大小从第8天到第21天减小,但与PBS对照没有显著差异(p=0.0859)。使用0.1%或0.2%dHGF治疗的结果没有显著差异(p=0.7558)。
基于本研究的结果,在第一次外科手术日期(第1阶段)或第11天(第2阶段)开始每天给药四次时,单次上皮和前基质去除(第1阶段)或多次上皮刮除(第2阶段)后的0.1%dHGF治疗导致伤口闭合更快(第1阶段)和瘢痕大小更大减小(第2阶段)
在第1阶段,所有动物均接受一次外科手术以去除2mm区域内的角膜上皮和前基质。所有动物在手术后每天接受四次给药。尽管约50%的PBS治疗的动物(媒介物对照)在术后第7天愈合,但>75%的接受0.1%dHGF或0.1%mHGF的动物在第7天愈合(图2和图3)。此外,与PBS治疗相比,这些动物的角膜在术后第3天完全愈合的百分比更大(分别为>60%与30%)。在第3天通过免疫荧光对角膜神经支配的分析揭示在0.1%dHGF治疗的动物中TUJ-1染色增加(图1)。
在第2阶段,动物经历了与第1阶段相同的外科手术,但随后接受了另外两次手术以仅去除上皮。在该实验中,动物在第一次上皮刮擦后开始接受治疗。在这些条件下,接受HGF(0.1%dHGF、0.2%dHGF或0.1%mHGF)的动物与PBS治疗的眼睛相比显示出瘢痕大小显著减小,所有HGF治疗的眼睛的瘢痕大小减小了>35%(图4)。
该研究的结果表明,在单个或多个损伤模型中,角膜上皮损伤后局部施用HGF导致愈合速率更快和瘢痕大小减小。
实施例5:局部制剂在小鼠角膜细菌LPS诱导的角膜炎模型中的功效
在小鼠角膜细菌LPS诱导的角膜炎模型中测试了HGF局部制剂用于治疗NK的有效性。在雄性C57BL/6小鼠中进行了功效测试。在损伤后第4-9天,使用3.5μL体积的测试物品通过移液管每天4次(QID)对40只动物中的每只一只眼睛给药,其中给药间隔为3小时。按照实验设计(表11)所示,损伤的眼睛接受了测试物品或对照。用1mL无菌水稀释来自大肠杆菌O111:B4(Invivogen)的脂多糖(LPS)储备液,将其等分并根据制造商的方案储存。在给药当天,将稀释的LPS溶液用PBS进一步稀释为1:1(v/v),以在2.0μL注射液中递送约5μg LPS材料。
表11.HGF在治疗小鼠角膜细菌LPS诱导的角膜炎损伤模型的NK中的功效测试的实验设计
*对n=5只小鼠进行基线眼部检查;在随后的几天中对所有入组的动物进行评估。
缩写:
mNGF:鼠神经生长因子
dHGF:人肝细胞生长因子(SEQ.ID NO.1)
**以指定浓度配制在PBS中。
使用来自大肠杆菌O111:B4的LPS治疗角膜损伤
在模型诱导之前,向测试受试者皮下给予0.01-0.05mg/kg丁丙诺啡。还给动物局部给予托吡卡胺(1.0%)和去氧肾上腺素(2.5%)的混合物以扩张和突出眼睛。然后用氯胺酮/甲苯噻嗪混合物和一滴0.5%盐酸丙美卡因使动物镇静以进行外科手术。使用镊子(例如Dumont#4)将动物的眼睛突出,并使用与2.5μL注射器连接的34G针,以2.0μL体积注射约5μg LPS(大肠杆菌O111:B4)。在第0天和第4天进行LPS注射。在第4天注射LPS后对损伤的眼睛进行第一剂量的治疗。15分钟后使用局部抗生素(氧氟沙星),使动物从手术中恢复正常。动物在术后约6-8小时皮下接受第二剂量的0.01-0.05mg/kg丁丙诺啡,并且在术后两天内每天两次,每6-8小时一次。
监测参数
(i)检查和体重:
每天观察两次死亡率和发病率以及笼边观察结果。在模型诱导前和尸检时称重。
(ii)眼部检查和明场图像:
在入组前,由兽医眼科医师在裂隙灯生物显微镜下评估眼表面形态。使用Image J软件在基线和研究设计中指定的日期捕获明场图像以分析角膜混浊。
(iii)荧光素染色:
在实验设计表中所示的时间点,对动物进行荧光素眼表面染色。将约1.5μl的2.5%荧光素钠应用于角膜表面30秒,随后使用1ml注射器用1X PBS冲洗。使用安装在三脚架上的Nikon数字SLR相机在钴蓝光下拍摄角膜染色。将相机镜头置于手动模式,镜头设置在1英尺外。将动物的眼睛聚焦在观察窗的中心,收集图像以保持相机镜头与动物眼睛之间的距离一致。使用Image J软件(NIH)测定每个时间点每只眼睛的荧光素染色面积(以像素为单位)。
(iv)光学相干断层扫描术(OCT):
在实验设计表所示的日子里,所有动物都进行了眼前节的OCT成像程序。在OCT检查前将动物麻醉并用PBS清洗角膜。
(v)结果:
在诱导模型并每天用PBS(对照)、0.1%或0.2%dHGF或0.1%mNGF治疗四次后,第2组和第3组(分别为0.1%和0.2%dHGF)到第9天显示出最大的瘢痕大小减小。当相对于第1组归一化时,第2组和第3组将瘢痕大小减小了近60%,而第4组中的测试物品将瘢痕大小减小了约25%(图5)。与PBS对照相比,0.1%dHGF(p=0.0110)和0.2%dHGF(p=0.0028)的平均瘢痕面积显著更小。与0.1%和0.2%HGF组相比,使用PBS对照组的瘢痕约为5倍,而与0.1%mNGF组相比,使用PBS的瘢痕约为2.5倍(p=0.0417)。两个dHGF组中所得的平均瘢痕大小彼此没有显著差异(p=0.6176)(图5)。
总之,本研究的结果表明,在基质施用大肠杆菌LPS诱导角膜上皮损伤后,用HGF治疗损伤的眼睛可提高治愈率。
根据上文的描述,除本文所述的那些之外的对本发明的各种修改对于本领域的技术人员而言将是显而易见的。此类修改也意图落在所附权利要求书的范围之内。本申请中引用的每篇参考文献,包括所有专利、专利申请和出版物,均以引用方式全文并入本文。
序列表
<110> 克拉里斯生物医疗股份有限公司
<120> 用于治疗眼部疾病的生长因子的组合物
<130> 49082-0004WO1
<150> US 63/188,816
<151> 2021-05-14
<160> 37
<170> PatentIn version 3.5
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Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser
180 185 190
Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Asn Met
275 280 285
Arg Asp Ile Thr Trp Ala Leu Asn
290 295
<210> 5
<211> 285
<212> PRT
<213> 智人(Homo sapiens)
<400> 5
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg
165 170 175
Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser Asn Pro Glu Val Arg
180 185 190
Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu Val Glu Cys Met Thr
195 200 205
Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp His Thr Glu Ser Gly
210 215 220
Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro His Arg His Lys Phe
225 230 235 240
Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp Asp Asn Tyr Cys Arg
245 250 255
Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr Thr Leu Asp Pro His
260 265 270
Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys Glu Thr
275 280 285
<210> 6
<211> 210
<212> PRT
<213> 智人(Homo sapiens)
<400> 6
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser
180 185 190
Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Gly Lys
210
<210> 7
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 7
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Glu Ile Lys Thr Lys Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 8
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 8
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Ile Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Val Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Thr Arg Asn Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Thr Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 9
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 9
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Glu Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 10
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 10
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Lys Gly Gln
20 25 30
Gly Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asp Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Val Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 11
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 11
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Ala Ile His Glu Phe Lys Lys Ser Ala Lys Ala
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Glu Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Gln Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Trp Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 12
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 12
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Thr Arg Asn Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Glu Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Gln Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 13
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 13
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser
180 185 190
Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 14
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 14
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asp Ala Ile His Glu Cys Lys Arg Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Ser Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Arg
85 90 95
Leu Arg Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Thr Arg Asn Cys
115 120 125
Ile Val Gly Lys Gly Arg Ser Tyr Arg Gly Thr Val Ser Thr Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 15
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 15
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Gly Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Arg Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 16
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 16
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro His Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Thr Arg Asn Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Thr Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 17
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 17
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Arg Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Val Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 18
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 18
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 19
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 19
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Val Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Val Asn Ser Met Ser Ser Gly Val Lys Lys Glu Ser
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Thr Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 20
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 20
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Trp Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 21
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 21
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Arg Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Arg Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 22
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 22
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Arg Arg Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Lys Gly Arg Ser Tyr Arg Gly Thr Val Ser Val Thr Lys
130 135 140
Ser Gly Ile Glu Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Asn Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 23
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 23
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Val Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Glu Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 24
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 24
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys Val
50 55 60
Asp Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 25
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 25
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Gly Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Arg Ile Lys Thr Glu Lys Ala
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Arg Gly Arg Asn Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 26
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 26
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Lys Gly Gln
20 25 30
Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Glu Ile Lys Thr Glu Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Ile Arg Asn Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Arg Gly Arg Asn Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 27
<211> 728
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HGF变体
<400> 27
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly Gln
20 25 30
Gly Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys Thr
35 40 45
Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Glu Lys Val
50 55 60
Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Ser Lys Gly Leu
65 70 75 80
Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Arg Cys
85 90 95
Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu Phe
100 105 110
Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asp Cys
115 120 125
Ile Ile Gly Asn Gly Arg Ser Tyr Arg Gly Thr Val Ser Ile Thr Lys
130 135 140
Ser Gly Ile Lys Cys Gln Pro Trp Ser Ala Met Ile Pro His Glu His
145 150 155 160
Ser Phe Leu Pro Ser Ser Tyr Arg Gly Glu Asp Leu Arg Glu Asn Tyr
165 170 175
Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro Trp Cys Tyr Thr Ser
180 185 190
Asp Pro Glu Val Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu
195 200 205
Val Glu Cys Met Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp
210 215 220
His Thr Glu Ser Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro
225 230 235 240
His Arg His Lys Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp
245 250 255
Asp Asn Tyr Cys Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr
260 265 270
Thr Leu Asp Pro His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys
275 280 285
Ala Asp Asn Thr Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu
290 295 300
Cys Ile Gln Gly Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile
305 310 315 320
Trp Asn Gly Ile Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu
325 330 335
His Asp Met Thr Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn
340 345 350
Tyr Cys Arg Asn Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr
355 360 365
Asp Pro Asn Ile Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp
370 375 380
Met Ser His Gly Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met
385 390 395 400
Gly Asn Leu Ser Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp
405 410 415
Lys Asn Met Glu Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala
420 425 430
Ser Lys Leu Asn Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His
435 440 445
Gly Pro Trp Cys Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys
450 455 460
Pro Ile Ser Arg Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu
465 470 475 480
Asp His Pro Val Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val
485 490 495
Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg
500 505 510
Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp
515 520 525
Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr
530 535 540
Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys
545 550 555 560
Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly
565 570 575
Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp
580 585 590
Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu
595 600 605
Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn
610 615 620
Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu
625 630 635 640
Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu
645 650 655
Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp
660 665 670
Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu
675 680 685
Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly
690 695 700
Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile
705 710 715 720
Leu Thr Tyr Lys Val Pro Gln Ser
725
<210> 28
<211> 140
<212> PRT
<213> 智人(Homo sapiens)
<400> 28
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 29
<211> 140
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGF1变体
<400> 29
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asn Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Arg Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 30
<211> 140
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGF1变体
<400> 30
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Pro His Ile Gln Leu Gln Leu Ile Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn Gly Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 31
<211> 140
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGF1变体
<400> 31
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asn Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Pro His Ile Gln Leu Gln Leu Ile Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn Gly Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Arg Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 32
<211> 140
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGF1变体
<400> 32
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Arg Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 33
<211> 140
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> FGF1变体
<400> 33
Phe Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys
1 5 10 15
Ser Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp
20 25 30
Gly Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala
35 40 45
Glu Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr
50 55 60
Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn
65 70 75 80
Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr
85 90 95
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
100 105 110
Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys
115 120 125
Ala Ile Lys Phe Leu Pro Leu Pro Val Ser Ser Asp
130 135 140
<210> 34
<211> 31
<212> PRT
<213> 智人(Homo sapiens)
<400> 34
Met Trp Val Thr Lys Leu Leu Pro Ala Leu Leu Leu Gln His Val Leu
1 5 10 15
Leu His Leu Leu Leu Leu Pro Ile Ala Ile Pro Tyr Ala Glu Gly
20 25 30
<210> 35
<211> 692
<212> PRT
<213> 智人(Homo sapiens)
<400> 35
Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys
1 5 10 15
Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys
20 25 30
Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly
35 40 45
Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln
50 55 60
Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu
65 70 75 80
Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn
85 90 95
Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr
100 105 110
Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu
115 120 125
His Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr Cys Arg Asn Pro
130 135 140
Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser Asn Pro Glu Val
145 150 155 160
Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu Val Glu Cys Met
165 170 175
Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp His Thr Glu Ser
180 185 190
Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro His Arg His Lys
195 200 205
Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp Asp Asn Tyr Cys
210 215 220
Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr Thr Leu Asp Pro
225 230 235 240
His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys Ala Asp Asn Thr
245 250 255
Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu Cys Ile Gln Gly
260 265 270
Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile Trp Asn Gly Ile
275 280 285
Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu His Asp Met Thr
290 295 300
Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn Tyr Cys Arg Asn
305 310 315 320
Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr Asp Pro Asn Ile
325 330 335
Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp Met Ser His Gly
340 345 350
Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met Gly Asn Leu Ser
355 360 365
Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp Lys Asn Met Glu
370 375 380
Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala Ser Lys Leu Asn
385 390 395 400
Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His Gly Pro Trp Cys
405 410 415
Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys Pro Ile Ser Arg
420 425 430
Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu Asp His Pro Val
435 440 445
Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg Val Val Asn Gly Ile Pro
450 455 460
Thr Arg Thr Asn Ile Gly Trp Met Val Ser Leu Arg Tyr Arg Asn Lys
465 470 475 480
His Ile Cys Gly Gly Ser Leu Ile Lys Glu Ser Trp Val Leu Thr Ala
485 490 495
Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys Asp Tyr Glu Ala Trp Leu
500 505 510
Gly Ile His Asp Val His Gly Arg Gly Asp Glu Lys Cys Lys Gln Val
515 520 525
Leu Asn Val Ser Gln Leu Val Tyr Gly Pro Glu Gly Ser Asp Leu Val
530 535 540
Leu Met Lys Leu Ala Arg Pro Ala Val Leu Asp Asp Phe Val Ser Thr
545 550 555 560
Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile Pro Glu Lys Thr Ser Cys
565 570 575
Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu Ile Asn Tyr Asp Gly Leu
580 585 590
Leu Arg Val Ala His Leu Tyr Ile Met Gly Asn Glu Lys Cys Ser Gln
595 600 605
His His Arg Gly Lys Val Thr Leu Asn Glu Ser Glu Ile Cys Ala Gly
610 615 620
Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu Gly Asp Tyr Gly Gly Pro
625 630 635 640
Leu Val Cys Glu Gln His Lys Met Arg Met Val Leu Gly Val Ile Val
645 650 655
Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg Pro Gly Ile Phe Val Arg
660 665 670
Val Ala Tyr Tyr Ala Lys Trp Ile His Lys Ile Ile Leu Thr Tyr Lys
675 680 685
Val Pro Gln Ser
690
<210> 36
<211> 458
<212> PRT
<213> 智人(Homo sapiens)
<400> 36
Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys Lys Ser Ala Lys
1 5 10 15
Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile Lys Thr Lys Lys
20 25 30
Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr Arg Asn Lys Gly
35 40 45
Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys Ala Arg Lys Gln
50 55 60
Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly Val Lys Lys Glu
65 70 75 80
Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp Tyr Ile Arg Asn
85 90 95
Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr Val Ser Ile Thr
100 105 110
Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met Ile Pro His Glu
115 120 125
His Ser Tyr Arg Gly Lys Asp Leu Gln Glu Asn Tyr Cys Arg Asn Pro
130 135 140
Arg Gly Glu Glu Gly Gly Pro Trp Cys Phe Thr Ser Asn Pro Glu Val
145 150 155 160
Arg Tyr Glu Val Cys Asp Ile Pro Gln Cys Ser Glu Val Glu Cys Met
165 170 175
Thr Cys Asn Gly Glu Ser Tyr Arg Gly Leu Met Asp His Thr Glu Ser
180 185 190
Gly Lys Ile Cys Gln Arg Trp Asp His Gln Thr Pro His Arg His Lys
195 200 205
Phe Leu Pro Glu Arg Tyr Pro Asp Lys Gly Phe Asp Asp Asn Tyr Cys
210 215 220
Arg Asn Pro Asp Gly Gln Pro Arg Pro Trp Cys Tyr Thr Leu Asp Pro
225 230 235 240
His Thr Arg Trp Glu Tyr Cys Ala Ile Lys Thr Cys Ala Asp Asn Thr
245 250 255
Met Asn Asp Thr Asp Val Pro Leu Glu Thr Thr Glu Cys Ile Gln Gly
260 265 270
Gln Gly Glu Gly Tyr Arg Gly Thr Val Asn Thr Ile Trp Asn Gly Ile
275 280 285
Pro Cys Gln Arg Trp Asp Ser Gln Tyr Pro His Glu His Asp Met Thr
290 295 300
Pro Glu Asn Phe Lys Cys Lys Asp Leu Arg Glu Asn Tyr Cys Arg Asn
305 310 315 320
Pro Asp Gly Ser Glu Ser Pro Trp Cys Phe Thr Thr Asp Pro Asn Ile
325 330 335
Arg Val Gly Tyr Cys Ser Gln Ile Pro Asn Cys Asp Met Ser His Gly
340 345 350
Gln Asp Cys Tyr Arg Gly Asn Gly Lys Asn Tyr Met Gly Asn Leu Ser
355 360 365
Gln Thr Arg Ser Gly Leu Thr Cys Ser Met Trp Asp Lys Asn Met Glu
370 375 380
Asp Leu His Arg His Ile Phe Trp Glu Pro Asp Ala Ser Lys Leu Asn
385 390 395 400
Glu Asn Tyr Cys Arg Asn Pro Asp Asp Asp Ala His Gly Pro Trp Cys
405 410 415
Tyr Thr Gly Asn Pro Leu Ile Pro Trp Asp Tyr Cys Pro Ile Ser Arg
420 425 430
Cys Glu Gly Asp Thr Thr Pro Thr Ile Val Asn Leu Asp His Pro Val
435 440 445
Ile Ser Cys Ala Lys Thr Lys Gln Leu Arg
450 455
<210> 37
<211> 234
<212> PRT
<213> 智人(Homo sapiens)
<400> 37
Val Val Asn Gly Ile Pro Thr Arg Thr Asn Ile Gly Trp Met Val Ser
1 5 10 15
Leu Arg Tyr Arg Asn Lys His Ile Cys Gly Gly Ser Leu Ile Lys Glu
20 25 30
Ser Trp Val Leu Thr Ala Arg Gln Cys Phe Pro Ser Arg Asp Leu Lys
35 40 45
Asp Tyr Glu Ala Trp Leu Gly Ile His Asp Val His Gly Arg Gly Asp
50 55 60
Glu Lys Cys Lys Gln Val Leu Asn Val Ser Gln Leu Val Tyr Gly Pro
65 70 75 80
Glu Gly Ser Asp Leu Val Leu Met Lys Leu Ala Arg Pro Ala Val Leu
85 90 95
Asp Asp Phe Val Ser Thr Ile Asp Leu Pro Asn Tyr Gly Cys Thr Ile
100 105 110
Pro Glu Lys Thr Ser Cys Ser Val Tyr Gly Trp Gly Tyr Thr Gly Leu
115 120 125
Ile Asn Tyr Asp Gly Leu Leu Arg Val Ala His Leu Tyr Ile Met Gly
130 135 140
Asn Glu Lys Cys Ser Gln His His Arg Gly Lys Val Thr Leu Asn Glu
145 150 155 160
Ser Glu Ile Cys Ala Gly Ala Glu Lys Ile Gly Ser Gly Pro Cys Glu
165 170 175
Gly Asp Tyr Gly Gly Pro Leu Val Cys Glu Gln His Lys Met Arg Met
180 185 190
Val Leu Gly Val Ile Val Pro Gly Arg Gly Cys Ala Ile Pro Asn Arg
195 200 205
Pro Gly Ile Phe Val Arg Val Ala Tyr Tyr Ala Lys Trp Ile His Lys
210 215 220
Ile Ile Leu Thr Tyr Lys Val Pro Gln Ser
225 230
Claims (72)
1.一种治疗或预防有需要的受试者的神经营养性角膜炎的方法,所述方法包括向所述受试者施用治疗有效量的肝细胞生长因子(HGF)或成纤维细胞生长因子(FGF)。
2.如权利要求1所述的方法,其中所述HGF或FGF是纯化的。
3.如权利要求1或2所述的方法,其中所述HGF或FGF与角膜基质渗透赋形剂组合施用。
4.如权利要求1至3中任一项所述的方法,其中所述HGF或FGF被配制在液体药物组合物中。
5.如权利要求1至4中任一项所述的方法,其中所述HGF或FGF施用于眼睛。
6.如权利要求5所述的方法,其中所述HGF或FGF局部施用于眼睛。
7.如权利要求5所述的方法,其中所述HGF或FGF通过注射施用于眼睛。
8.如权利要求7所述的方法,其中所述HGF或FGF经结膜下施用。
9.如权利要求7所述的方法,其中所述HGF或FGF经前房内施用。
10.如权利要求1至9中任一项所述的方法,其中所述液体药物组合物包含浓度为约0.01%(w/v)至约1.0%(w/v)的HGF或FGF。
11.如权利要求10所述的方法,其中所述液体药物组合物包含浓度为约0.08%(w/v)至约0.25%(w/v)的HGF或FGF。
12.如权利要求10所述的方法,其中所述液体药物组合物包含浓度为约0.1%(w/v)的HGF或FGF。
13.如权利要求10所述的方法,其中所述液体药物组合物包含浓度为约0.2%(w/v)的HGF或FGF。
14.如权利要求1至13中任一项所述的方法,其中所述HGF或FGF与另一种治疗剂组合施用。
15.如权利要求14所述的方法,其中所述另一种治疗剂是另一种生长因子。
16.如权利要求1至15中任一项所述的方法,其中所述HGF包含具有SEQ ID NO:1-27中任一个的多肽序列。
17.如权利要求1至15中任一项所述的方法,其中所述HGF包含与SEQ ID NO:1具有95%序列同一性的多肽序列。
18.如权利要求1至15中任一项所述的方法,其中所述HGF包括具有SEQ ID NO:1的多肽序列。
19.一种药物组合物,包含:
约0.01%至约1.0%(w/v)HGF;
能够将所述组合物的pH维持在约5.8至约6.2的缓冲剂;
约100至约300mM的稳定剂,所述稳定剂选自海藻糖、脯氨酸、山梨糖醇以及它们的混合物;
任选的张力调节剂,其能够提供所述组合物约250mOsm/kg H2O至约500mOsm/kg H2O的渗透压;以及
任选的表面活性剂。
20.如权利要求19所述的组合物,包含约0.05%至约0.5%(w/v)HGF。
21.如权利要求19所述的组合物,包含约0.08%至约0.25%(w/v)HGF。
22.如权利要求19所述的组合物,包含约0.1%(w/v)HGF。
23.如权利要求19所述的组合物,包含约0.2%(w/v)HGF。
24.如权利要求19至23中任一项所述的组合物,其中所述组合物具有约6.0的pH。
25.如权利要求19至24中任一项所述的组合物,包含约150至约250mM的稳定剂。
26.如权利要求25所述的组合物,包含约200mM的稳定剂。
27.如权利要求19至26中任一项所述的组合物,其中所述稳定剂是海藻糖或脯氨酸。
28.如权利要求19至26中任一项所述的组合物,其中所述稳定剂是海藻糖。
29.如权利要求19至26中任一项所述的组合物,其中所述稳定剂是脯氨酸。
30.如权利要求19至26中任一项所述的组合物,其中所述稳定剂是山梨糖醇。
31.如权利要求19至30中任一项所述的组合物,其中所述缓冲剂是柠檬酸盐缓冲剂。
32.如权利要求19至30中任一项所述的组合物,其中所述缓冲剂是柠檬酸钠。
33.如权利要求19至30中任一项所述的组合物,包含约10至约50mM的缓冲剂。
34.如权利要求19至33中任一项所述的组合物,其中所述组合物的渗透压为约450mOsm/kg H2O。
35.如权利要求19至33中任一项所述的组合物,其不包含张力调节剂。
36.如权利要求19至33中任一项所述的组合物,包含张力调节剂,所述张力调节剂为碱金属盐。
37.如权利要求19至33中任一项所述的组合物,包含张力调节剂,所述张力调节剂为氯化钠。
38.如权利要求19至37中任一项所述的组合物,其包含表面活性剂。
39.如权利要求38所述的组合物,其中所述表面活性剂选自聚山梨醇酯80(PS80)、泊洛沙姆188和泊洛沙姆407。
40.如权利要求38所述的组合物,其中所述表面活性剂是聚山梨醇酯80(PS80)。
41.如权利要求19至40中任一项所述的组合物,其中所述表面活性剂以约0.01%至约0.1%(w/v)的量存在。
42.如权利要求19至40中任一项所述的组合物,其中所述表面活性剂以约0.02%至约0.8%(w/v)的量存在。
43.如权利要求19至40中任一项所述的组合物,其中所述表面活性剂以约0.05%(w/v)的量存在。
44.一种水性药物组合物,包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约350mOsm/kg H2O。
45.如权利要求44所述的水性药物组合物,包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约350mOsm/kg H2O。
46.如权利要求44所述的水性药物组合物,包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约350mOsm/kg H2O。
47.如权利要求44所述的水性药物组合物,包含:
约0.1%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约350mOsm/kg H2O。
48.一种水性药物组合物,包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖、脯氨酸或山梨糖醇;
约0.05%(w/v)表面活性剂;
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约450mOsm/kg H2O。
49.如权利要求48所述的水性药物组合物,包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的海藻糖;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约450mOsm/kg H2O。
50.如权利要求48所述的水性药物组合物,包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的脯氨酸;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约450mOsm/kg H2O。
51.如权利要求49所述的水性药物组合物,包含:
约0.2%(w/v)HGF;
约20mM柠檬酸钠;
约200mM的山梨糖醇;
约0.05%(w/v)的聚山梨醇酯80(PS80);
其中所述组合物的pH为约6.0并且所述组合物的渗透压为约450mOsm/kg H2O。
52.如权利要求19至51中任一项所述的药物组合物,其中所述HGF包含SEQ ID NO:1-27中任一个的多肽序列。
53.如权利要求19至51中任一项所述的药物组合物,其中所述HGF包含与SEQ ID NO:1具有95%序列同一性的多肽序列。
54.如权利要求19至51中任一项所述的药物组合物,其中所述HGF包含具有SEQ ID NO:1的多肽序列。
55.一种治疗或预防有需要的受试者的眼部疾病的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求19至55中任一项所述的药物组合物。
56.如权利要求55所述的方法,其中所述眼部疾病是选自以下的角膜疾病:神经营养性角膜炎、持续性角膜缺损、角膜溃疡、干眼病、微生物性角膜炎、细菌性角膜炎、病毒性角膜炎、真菌性角膜炎、化学灼伤、热灼伤、机械性创伤、角膜擦伤、内皮受损、大泡性角膜病、富克氏角膜营养不良、角膜瘢痕、干燥综合征或术后并发症。
57.如权利要求55所述的方法,其中所述眼部疾病是角膜混浊或瘢痕形成。
58.如权利要求55所述的方法,其中所述眼部疾病是神经营养性角膜炎。
59.如权利要求55至58中任一项所述的方法,其中所述组合物与角膜基质渗透赋形剂组合施用。
60.如权利要求55至58中任一项所述的方法,其中所述组合物施用于眼睛。
61.如权利要求60所述的方法,其中所述组合物局部施用于眼睛。
62.如权利要求60所述的方法,其中所述组合物通过注射施用于眼睛。
63.如权利要求62所述的方法,其中所述组合物经结膜下施用。
64.如权利要求62所述的方法,其中所述组合物经前房内施用。
65.如前述权利要求中任一项所述的组合物或方法,其中所述HGF是活化HGF。
66.如权利要求65所述的组合物或方法,其中所述活化HGF是活化dHGF。
67.如前述权利要求中任一项所述的组合物或方法,其中所述HGF包含:
(a)第一多肽,其包含与SEQ ID NO:2的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:2的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:2的氨基酸161-165的氨基酸的缺失;或者
(b)第一多肽,其包含与SEQ ID NO:7的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:7的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:7的氨基酸161-165的氨基酸的缺失;或者
(c)第一多肽,其包含与SEQ ID NO:8的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:8的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:8的氨基酸161-165的氨基酸的缺失;或者
(d)第一多肽,其包含与SEQ ID NO:9的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:9的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:9的氨基酸161-165的氨基酸的缺失;或者
(e)第一多肽,其包含与SEQ ID NO:10的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:10的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:10的氨基酸161-165的氨基酸的缺失;或者
(g)第一多肽,其包含与SEQ ID NO:11的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:11的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:11的氨基酸161-165的氨基酸的缺失;或者
(h)第一多肽,其包含与SEQ ID NO:12的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:12的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:12的氨基酸161-165的氨基酸的缺失;或者
(i)第一多肽,其包含与SEQ ID NO:13的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:13的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:13的氨基酸161-165的氨基酸的缺失;或者
(j)第一多肽,其包含与SEQ ID NO:14的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:14的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:14的氨基酸161-165的氨基酸的缺失;或者
(k)第一多肽,其包含与SEQ ID NO:15的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:15的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:15的氨基酸161-165的氨基酸的缺失;或者
(l)第一多肽,其包含与SEQ ID NO:16的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:16的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:16的氨基酸161-165的氨基酸的缺失;或者
(m)第一多肽,其包含与SEQ ID NO:17的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:17的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:17的氨基酸161-165的氨基酸的缺失;或者
(n)第一多肽,其包含与SEQ ID NO:18的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:18的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:18的氨基酸161-165的氨基酸的缺失;或者
(o)第一多肽,其包含与SEQ ID NO:19的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:19的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:19的氨基酸161-165的氨基酸的缺失;或者
(p)第一多肽,其包含与SEQ ID NO:20的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:20的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:20的氨基酸161-165的氨基酸的缺失;或者
(q)第一多肽,其包含与SEQ ID NO:21的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:21的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:21的氨基酸161-165的氨基酸的缺失;或者
(r)第一多肽,其包含与SEQ ID NO:22的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:22的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:22的氨基酸161-165的氨基酸的缺失;或者
(s)第一多肽,其包含与SEQ ID NO:23的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:23的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:23的氨基酸161-165的氨基酸的缺失;或者
(t)第一多肽,其包含与SEQ ID NO:24的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:24的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:24的氨基酸161-165的氨基酸的缺失;或者
(u)第一多肽,其包含与SEQ ID NO:25的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:25的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:25的氨基酸161-165的氨基酸的缺失;或者
(v)第一多肽,其包含与SEQ ID NO:26的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:26的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:26的氨基酸161-165的氨基酸的缺失;或者
(w)第一多肽,其包含与SEQ ID NO:27的氨基酸32-494具有至少80%、优选90%同一性的氨基酸序列;以及第二多肽,其包含与SEQ ID NO:27的氨基酸495-728具有至少80%、优选90%同一性的氨基酸序列,任选地其中所述第一多肽包含对应于SEQ ID NO:27的氨基酸161-165的氨基酸的缺失。
68.如前述权利要求中任一项所述的组合物或方法,其中所述HGF包含:
(a)第一多肽,其包含对应于SEQ ID NO:2的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:2的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:2的氨基酸161-165的氨基酸的缺失;或者
(b)第一多肽,其包含对应于SEQ ID NO:7的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:7的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:7的氨基酸161-165的氨基酸的缺失;或者
(c)第一多肽,其包含对应于SEQ ID NO:8的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:8的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:8的氨基酸161-165的氨基酸的缺失;或者
(d)第一多肽,其包含对应于SEQ ID NO:9的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:9的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:9的氨基酸161-165的氨基酸的缺失;或者
(e)第一多肽,其包含对应于SEQ ID NO:10的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:10的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:10的氨基酸161-165的氨基酸的缺失;或者
(g)第一多肽,其包含对应于SEQ ID NO:11的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:11的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:11的氨基酸161-165的氨基酸的缺失;或者
(h)第一多肽,其包含对应于SEQ ID NO:12的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:12的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:12的氨基酸161-165的氨基酸的缺失;或者
(i)第一多肽,其包含对应于SEQ ID NO:13的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:13的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:13的氨基酸161-165的氨基酸的缺失;或者
(j)第一多肽,其包含对应于SEQ ID NO:14的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:14的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:14的氨基酸161-165的氨基酸的缺失;或者
(k)第一多肽,其包含对应于SEQ ID NO:15的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:15的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:15的氨基酸161-165的氨基酸的缺失;或者
(l)第一多肽,其包含对应于SEQ ID NO:16的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:16的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:16的氨基酸161-165的氨基酸的缺失;或者
(m)第一多肽,其包含对应于SEQ ID NO:17的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:17的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:17的氨基酸161-165的氨基酸的缺失;或者
(n)第一多肽,其包含对应于SEQ ID NO:18的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:18的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:18的氨基酸161-165的氨基酸的缺失;或者
(o)第一多肽,其包含对应于SEQ ID NO:19的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:19的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:19的氨基酸161-165的氨基酸的缺失;或者
(p)第一多肽,其包含对应于SEQ ID NO:20的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:20的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:20的氨基酸161-165的氨基酸的缺失;或者
(q)第一多肽,其包含对应于SEQ ID NO:21的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:21的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:21的氨基酸161-165的氨基酸的缺失;或者
(r)第一多肽,其包含对应于SEQ ID NO:22的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:22的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:22的氨基酸161-165的氨基酸的缺失;或者
(s)第一多肽,其包含对应于SEQ ID NO:23的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:23的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:23的氨基酸161-165的氨基酸的缺失;或者
(t)第一多肽,其包含对应于SEQ ID NO:24的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:24的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:24的氨基酸161-165的氨基酸的缺失;或者
(u)第一多肽,其包含对应于SEQ ID NO:25的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:25的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:25的氨基酸161-165的氨基酸的缺失;或者
(v)第一多肽,其包含对应于SEQ ID NO:26的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:26的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:26的氨基酸161-165的氨基酸的缺失;或者
(w)第一多肽,其包含对应于SEQ ID NO:27的氨基酸32-494的氨基酸序列或由其组成;以及第二多肽,其包含对应于SEQ ID NO:27的氨基酸495-728的氨基酸序列或由其组成,任选地其中所述第一多肽包含对应于SEQ ID NO:27的氨基酸161-165的氨基酸的缺失。
69.如权利要求66所述的组合物或方法,其中所述第一多肽包含SEQ ID NO:36的氨基酸序列或由其组成,并且所述第二多肽包含SEQ ID NO:37的氨基酸序列或由其组成。
70.如权利要求66或权利要求67所述的组合物或方法,其中所述第一多肽的N-末端氨基酸是吡咯烷酮羧酸。
71.如权利要求65至68中任一项所述的组合物或方法,其中所述第一多肽和所述第二多肽通过一个或多个二硫键连接。
72.如权利要求65至69中任一项所述的组合物或方法,其中所述HGF能够结合c-MET和/或活化上皮细胞中的MAPK途径。
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DE3169595D1 (en) | 1980-11-10 | 1985-05-02 | Gersonde Klaus | Method of preparing lipid vesicles by ultrasonic treatment, the use of this method and apparatus for its application |
IE52535B1 (en) | 1981-02-16 | 1987-12-09 | Ici Plc | Continuous release pharmaceutical compositions |
US4485045A (en) | 1981-07-06 | 1984-11-27 | Research Corporation | Synthetic phosphatidyl cholines useful in forming liposomes |
DE3374837D1 (en) | 1982-02-17 | 1988-01-21 | Ciba Geigy Ag | Lipids in the aqueous phase |
DE3218121A1 (de) | 1982-05-14 | 1983-11-17 | Leskovar, Peter, Dr.-Ing., 8000 München | Arzneimittel zur tumorbehandlung |
EP0102324A3 (de) | 1982-07-29 | 1984-11-07 | Ciba-Geigy Ag | Lipide und Tenside in wässriger Phase |
US4544545A (en) | 1983-06-20 | 1985-10-01 | Trustees University Of Massachusetts | Liposomes containing modified cholesterol for organ targeting |
HUT35524A (en) | 1983-08-02 | 1985-07-29 | Hoechst Ag | Process for preparing pharmaceutical compositions containing regulatory /regulative/ peptides providing for the retarded release of the active substance |
EP0142641B1 (de) | 1983-09-26 | 1991-01-16 | Udo Dr. Ehrenfeld | Mittel und Erzeugnis für die Diagnose und Therapie von Tumoren sowie zur Behandlung von Schwächen der zelligen und humoralen Immunabwehr |
EP0143949B1 (en) | 1983-11-01 | 1988-10-12 | TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION | Pharmaceutical composition containing urokinase |
US5510329A (en) * | 1988-04-26 | 1996-04-23 | Ramot University For Applied Research And Industrial Development Ltd. | Preparations for the treatment of eyes |
NZ232813A (en) | 1989-03-10 | 1992-08-26 | Snow Brand Milk Products Co Ltd | Human fibroblast glycoprotein, cell differentiation, blood vessel endothelial cell growth factor, cellular immunology inforcing factor of 78 or 74 thousand daltons plus or minus two thousand daltons |
JP3927248B2 (ja) * | 1995-07-11 | 2007-06-06 | 第一製薬株式会社 | Hgf凍結乾燥製剤 |
JP2000344680A (ja) * | 1999-05-31 | 2000-12-12 | Mitsubishi Chemicals Corp | Hgf含有医薬組成物 |
JP4635340B2 (ja) | 1999-05-31 | 2011-02-23 | 三菱化学株式会社 | Hgf凍結乾燥製剤 |
WO2004026244A2 (en) * | 2002-09-18 | 2004-04-01 | Emiliano Ghinelli | Use of a human amniotic membrane composition for prophylaxis and treatment of diseases and conditions of the eye and skin |
WO2008102452A1 (ja) | 2007-02-22 | 2008-08-28 | Kringle Pharma Inc. | Hgf製剤 |
WO2011010399A1 (ja) * | 2009-07-24 | 2011-01-27 | 千寿製薬株式会社 | 角膜内皮細胞増殖促進剤 |
US11547743B2 (en) * | 2014-04-28 | 2023-01-10 | Eisai R&D Management Co., Ltd. | Lyophilized formulation of HGF |
WO2016039163A1 (ja) * | 2014-09-10 | 2016-03-17 | クリングルファーマ株式会社 | 神経疾患の治療に適したhgf製剤 |
US10449234B2 (en) * | 2015-09-11 | 2019-10-22 | The Schepens Eye Research Institute, Inc. | Compositions and methods for prevention and treatment of corneal haze and scarring |
BR112019023260A2 (pt) * | 2017-05-05 | 2022-02-22 | Trefoil Therapeutics, Inc. | Fatores de crescimento de fibroblastos recombinantes modificados e seus usos terapêuticos |
EP4172351A1 (en) * | 2020-06-26 | 2023-05-03 | Trefoil Therapeutics, Inc. | Recombinant modified fibroblast growth factors and therapeutic uses thereof |
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