CN111936171A - Aav介导的治疗性抗体到内耳的递送 - Google Patents
Aav介导的治疗性抗体到内耳的递送 Download PDFInfo
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Abstract
本文提供了包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中的方法,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;(b)包括可操作地连接到信号肽的抗原结合抗体片段的多肽;或(c)可操作地连接到信号肽的可溶性血管内皮生长因子受体。
Description
相关申请的交叉引用
本申请要求2017年12月19日提交的美国临时专利申请序列号62/607,665的优先权,所述申请的全部内容以引用方式并入本文。
技术领域
本公开总体上涉及使用核酸治疗人受试者中的听力损失。
发明背景
感音神经性听力损失是由哺乳动物内耳中的细胞(例如,毛细胞)功能失调引起的听力损失。感音神经性听力损失的非限制性原因包括暴露于大的噪音、头部创伤、病毒感染、自身免疫性内耳疾病、遗传性听力损失、衰老、内耳畸形、梅尼埃病、耳硬化症和肿瘤。
发明内容
本发明涉及包括将治疗有效量的任何腺相关病毒(AAV)载体引入哺乳动物(例如,人)的内耳中的方法,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
本文提供了用于提高对其有需要的哺乳动物的内耳中的抗体或抗原结合抗体片段的水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括连接到信号肽的抗原结合抗体片段的多肽;其中引入使得哺乳动物的内耳中抗体或抗原结合抗体片段的水平升高。
在一些实施方案中,抗体或抗原结合抗体片段特异性结合血管内皮生长因子(VEGF)。在一些实施方案中,抗体或抗原结合抗体片段降低VEGF活性。在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
在一些实施方案中,AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定为患有内耳病症。在本文所述的任何方法的一些实施方案中,哺乳动物已被诊断为患有内耳病症。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号的抗原结合抗体片段的多肽。
本文还提供了用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括连接到信号肽的抗原结合抗体片段的多肽;其中引入使得哺乳动物中的内耳病症得到治疗。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
在一些实施方案中,AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定为患有内耳病症。在本文所述的任何方法的一些实施方案中,哺乳动物已被诊断为患有内耳病症。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号的抗原结合抗体片段的多肽。
本文还提供了降低对其有需要的哺乳动物的内耳中VEGF活性的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括连接到信号肽的抗原结合抗体片段的多肽;其中(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;其中引入使得哺乳动物的内耳中VEGF活性降低。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
在一些实施方案中,AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。在本文所述的任何方法的一些实施方案中,哺乳动物为人。
在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有听神经瘤。在一些实施方案中,哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
本文还提供了治疗哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或2型神经纤维瘤病的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括连接到信号肽的抗原结合抗体片段的多肽;其中(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;其中引入使得哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病分别得到治疗。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
在本文所述的任何方法的一些实施方案中,AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有听神经瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
在本文所述的任何方法的一些实施方案中,AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
在本文所述的任何方法的一些实施方案中,抗体包括有包括一个或多个氨基酸置换的Fc区,与对照抗体相比,所述氨基酸置换缩短了哺乳动物中抗体的半衰期;或
与对照抗原结合抗体片段相比,所述抗体的抗原结合抗体片段的体内半衰期缩短。
本文还提供了包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中的方法,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列。
本文还提供了用于提高对其有需要的哺乳动物的内耳中可溶性血管内皮生长因子(VEGF)受体水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性VEGF受体的核苷酸序列;其中引入使得哺乳动物的内耳中可溶性VEGF受体水平升高。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-1(VEGFR-1)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括与来自野生型人VEGFR-1的连续序列有至少90%同一性的序列。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-2(VEGFR-2)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括与来自野生型人VEGFR-2的连续序列有至少90%同一性的序列。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分和VEGFR-2的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域;并且VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,可溶性VEGF受体为阿柏西普(aflibercept)。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-3(VEGFR-3)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括与来自野生型人VEGFR-3的连续序列有至少90%同一性的序列。在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括Fc结构域。在本文所述的任何方法的一些实施方案中,Fc结构域为IgG1 Fc结构域。在本文所述的任何方法的一些实施方案中,IgG1 Fc结构域为人野生型IgG1 Fc结构域。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体降低了VEGF结合到VEGFR-1、VEGFR-2和VEGFR-3中的一者或多者的能力。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。在本文所述的任何方法的一些实施方案中,AAV载体包括选自以下的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定为患有内耳病症。在本文所述的任何方法的一些实施方案中,哺乳动物已被诊断为患有内耳病症。
本文还提供了用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物中的内耳病症得到治疗。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。在本文所述的任何方法的一些实施方案中,AAV载体包括选自以下的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定为患有内耳病症。在本文所述的任何方法的一些实施方案中,哺乳动物已被诊断为患有内耳病症。
本文还提供了降低对其有需要的哺乳动物的内耳中VEGF活性的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物的内耳中VEGF活性降低。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。在本文所述的任何方法的一些实施方案中,AAV载体包括选自以下的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有听神经瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
本文还提供了治疗哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或2型神经纤维瘤病的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病分别得到治疗。
在本文所述的任何方法的一些实施方案中,AAV载体还包括可操作地连接到编码可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。在本文所述的任何方法的一些实施方案中,AAV载体包括选自以下的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在本文所述的任何方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。
在本文所述的任何方法的一些实施方案中,哺乳动物为人。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有听神经瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。在本文所述的任何方法的一些实施方案中,哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-1(VEGFR-1)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括与来自野生型人VEGFR-1的连续序列有至少90%同一性的序列。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-2(VEGFR-2)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-2的胞外区的一部分包括与来自野生型人VEGFR-2的连续序列有至少90%同一性的序列。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分和VEGFR-2的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域;并且VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,可溶性VEGF受体为阿柏西普。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括VEGF受体-3(VEGFR-3)的胞外区的一部分。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的连续序列。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的胞外区中的一个或多个免疫球蛋白样结构域。在本文所述的任何方法的一些实施方案中,VEGFR-3的胞外区的一部分包括与来自野生型人VEGFR-3的连续序列有至少90%同一性的序列。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体包括Fc结构域。在本文所述的任何方法的一些实施方案中,Fc结构域为IgG1 Fc结构域。在本文所述的任何方法的一些实施方案中,IgG1Fc结构域为人野生型IgG1 Fc结构域。
在本文所述的任何方法的一些实施方案中,可溶性VEGF受体降低了VEGF结合到VEGFR-1、VEGFR-2和VEGFR-3中的一者或多者的能力。在本文所述的任何方法的一些实施方案中,AAV载体还包括分泌序列。
除非另外规定,否则“编码氨基酸序列的核苷酸序列”包括是彼此的简并形式并因此编码相同的氨基酸序列的所有核苷酸序列。
术语“分离的”意指从天然状态改变或去除。例如,天然存在于活体动物中的核酸或肽不是“分离的”,但是相同的与其天然状态的共存物质部分或完全分离的核酸或肽是“分离的”。分离的核酸或蛋白质可以基本上纯化的形式存在,或可存在于非天然环境中,例如像,宿主细胞中。
术语“转染的”、“转化的”或“转导的”是指将外源性核酸转移或引入细胞的过程。“转染的”、“转化的”或“转导的”哺乳动物细胞是已用外源性核酸转染、转化或转导的细胞。
术语“表达”是指编码蛋白质的特定核苷酸序列的转录和/或翻译。
术语“瞬时表达”是指短时间(例如,数小时或数天)内非整合编码序列的表达。在细胞(例如,哺乳动物细胞)中瞬时表达的编码序列在多轮细胞分裂后丢失。
术语“受试者”旨在包括任何哺乳动物。在一些实施方案中,受试者为啮齿动物(例如,大鼠或小鼠)、兔子、绵羊、山羊、猪、狗、猫、非人灵长类动物或人。在一些实施方案中,受试者患有非综合征性耳聋或有发展为非综合征性耳聋的风险。在一些实施方案中,受试者先前已被鉴定为患有内耳病症。在一些实施方案中,受试者先前已被诊断为患有内耳病症。在一些实施方案中,受试者已被鉴定为患有药物性听力损失。在一些实施方案中,受试者为婴儿(例如,人类婴儿)。
当治疗使得受试者(例如,人)中疾病的一种或多种症状(例如,无症状感音神经性听力损失)的数量、严重程度和频率中的一种或多种减少时,所述治疗为“治疗有效的”。
术语“核酸”或“多核苷酸”是指单链或双链形式的脱氧核糖核酸(DNA)或核糖核酸(RNA)或其组合。除非明确限制,否则术语包括含有天然核苷酸的已知类似物的核酸,所述类似物具有与参考核苷酸类似的结合特性。除非另外指出,否则特定的核酸序列还隐含地包括互补序列以及明确指出的序列。在本文所述的任何核酸的一些实施方案中,核酸为DNA。在本文所述的任何核酸的一些实施方案中,核酸为RNA。
术语“信号肽”是指存在于新生分泌蛋白的N端但不存在于天然存在的成熟蛋白中的序列。在信号肽被翻译后,“信号肽”被蛋白酶(例如,信号肽酶)裂解。信号肽在本领域中是已知的。信号肽的非限制性实例包括:MEFFKKTALAALVMGFSGAALA(SEQ ID NO:9)和MKYLLPTAAAGLLLLAAQPAMA(SEQ ID NO:10)。
术语“内耳病症”是指由哺乳动物的内耳中或周围的细胞(例如,毛细胞、支持细胞、螺旋神经节神经元、巨噬细胞或雪旺式细胞)的功能障碍引起的病症。内耳病症的非限制性实例包括,例如,感音神经性听力损失(SNHL)、噪声性听力损失、药物性听力损失、年龄相关性听力损失、听神经瘤、2型神经纤维瘤病、听觉神经病、噪声性耳蜗突触病而无毛细胞缺失、年龄相关性耳蜗突触病、获得性感音神经性听力损失和前庭神经鞘瘤。参见,例如,Kujawa等人,Hear Res330(0 0):191-199,2015;和Suzuki等人,Scientific Reports 6:24907。本文描述了内耳病症的非限制性实例,并且内耳病症的其他实例在本领域中是已知的。
术语“抗体”意指相互作用以形成至少一个抗原结合结构域的两个或更多个单多肽链的复合物。抗体的非限制性实例包括单克隆抗体(例如,全长或完整单克隆抗体)、多克隆抗体、多价抗体、多特异性抗体(例如,双特异性、三特异性等抗体,只要其表现出所需的生物学活性即可)。抗体可以是人、人源化的和/或亲和力成熟的。
术语“抗原结合抗体片段”是单一多肽,其包括构成至少一个抗原结合结构域(例如,scFv)的所有氨基酸。
如本文所用,术语“单克隆抗体”是指从基本上同质抗体的群体获得的抗体,即,包含该群体的各个抗体是相同的,不同的是可以微量存在的可能的天然存在的突变。单克隆抗体具有高度特异性(针对单一抗原)。另外,与通常包括针对不同决定簇(表位)的不同抗体的多克隆抗体制品相反,每种单克隆抗体针对抗原上的单一决定簇。
本文中的单克隆抗体具体包括“嵌合”抗体,以及此类抗体的片段,其中重链和/或轻链的一部分与源于特定物种或属于特定抗体类或亚类的抗体中的对应序列相同或同源,而链的其余部分与源于其他物种或属于其他抗体类或亚类的抗体中的对应序列相同或同源,只要其表现出所需的生物学活性即可(参见,例如,美国专利号4,816,567;和Morrison等人,Proc.Natl.Acad.Sci.USA 81:6851-6855(1984))。
“抗原结合结构域”是一个或多个能够特异性结合到一种或多种不同抗原的蛋白质结构域(例如,由单一多肽的氨基酸形成或由两个或更多个多肽(例如,相同或不同的多肽)的氨基酸形成。在一些实例中,抗原结合结构域可以与天然存在的抗体类似的特异性和亲和力结合到抗原或表位。在一些实施方案中,抗原结合结构域可包括替代支架。本文描述了抗原结合结构域的非限制性实例。抗原结合结构域的其他实例在本领域中是已知的。在一些实例中,抗原结合结构域可结合到单一抗原。
“亲和力”是指抗原结合位点与其结合伴侣(例如,抗原或表位)之间的非共价相互作用的总和的强度。除非另外说明,否则如本文所用,“亲和力”是指反映抗原结合结构域的成员与抗原或表位之间的1∶1相互作用的内在结合亲和力。分子X对其伴侣Y的亲和力可用解离平衡常数(KD)来表示。亲和力可通过本领域已知的常用方法(包括本文中描述的那些方法)进行测量。亲和力可例如使用表面等离子体共振(SPR)技术(例如,)或生物层干涉法(例如,)来测定。用于测定抗原结合结构域与其对应的抗原或表位之间的亲和力的其他方法在本领域中是已知的。
短语“半衰期”是指在哺乳动物(例如,本文所述的任何哺乳动物)的循环(例如,血液)中的抗体、其抗原结合抗体片段或可溶性VEGF受体的半衰期,并且由从循环中清除50%的抗体、其抗原结合抗体片段或可溶性VEGF受体所需的时间表示。在一些实施方案中,通过比较受试者中抗体、抗原结合抗体片段或可溶性VEGF受体的半衰期与类似哺乳动物中对照抗体、对照抗原结合抗体片段或对照可溶性VEGF受体的半衰期来测定半衰期的改变(例如,抗体、其抗原结合抗体片段或可溶性VEGF受体的半衰期的减少)。
在一些实施方案中,通过在全身性施用(例如,静脉内施用)本文所述的任何AAV载体后的不同时间点,测量从受试者获得的样品(例如,血液样品)中抗体、其抗原结合抗体片段或可溶性VEGF受体的水平来测定哺乳动物中抗体、其抗原结合抗体片段或可溶性VEGF受体的半衰期。在一些实施方案中,使用酶联免疫吸附测定(ELISA)或本领域已知的另一种测定来测定从哺乳动物获得的样品中存在的抗体、其抗原结合抗体片段或可溶性VEGF受体的水平,并且使用软件程序(例如,GraphPad Prism)将样品中存在的抗体、其抗原结合抗体片段或可溶性VEGF受体的测定水平作为时间函数作图。
术语“VEGF活性”是指VEGF蛋白的一种或多种已知活性。例如,VEGF蛋白的一种活性是结合到一种或多种VEGF受体的能力。在另一个实例中,VEGF蛋白的一种活性是VEGF在表达VEGF受体的哺乳动物细胞中触发下游信号转导途径的能力。用于检测VEGF的一种或多种活性的方法在本领域中是已知的。
术语“可溶性VEGF受体”是指包括可操作地连接到信号肽的一种或多种哺乳动物VEGF受体(例如,VEGFR-1、VEGFR-2和VEGFR-3)的胞外区的一部分的多肽,其中可溶性VEGF受体能够特异性结合到一种或多种哺乳动物VEGF蛋白(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一个或多个)。在一些实例中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分(例如,来自野生型人VEGFR-1的连续序列(例如,来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域)或与来自野生型人VEGFR-1的连续序列有至少90%同一性的序列)。在一些实例中,可溶性VEGF受体包括VEGFR-2的胞外区的一部分(例如,来自野生型人VEGFR-2的连续序列(例如,来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域)或与来自野生型人VEGFR-2的连续序列有至少90%同一性的序列)。在一些实例中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分和VEGFR-2的胞外区的一部分(例如,来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域以及来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域)(例如,阿柏西普)。在一些实例中,可溶性VEGF受体包括VEGFR-3的胞外区的一部分(例如,来自野生型人VEGFR-3的连续序列(例如,来自野生型人VEGFR-3的胞外区中的一个或多个免疫球蛋白样结构域)或与来自野生型人VEGFR-3的连续序列有至少90%同一性的序列)。
在一些实例中,可溶性VEGF受体还可包括稳定结构域(例如,Fc结构域,诸如IgG1Fc结构域(例如,人野生型IgG1 Fc结构域)。在一些实例中,可溶性VEGF受体降低VEGF结合到VEGFR-1、VEGFR-2和VEGFR-3中的一个或多个(例如,两个或三个)的能力。除非另有限定,否则本文中所使用的所有技术和科学术语具有与本发明领域内的普通技术人员对于该发明所属的通常理解的意义相同的意义。本文描述了用于本发明的方法和材料;还可使用本领域已知的其他合适的方法和材料。材料、方法和实例仅是说明性的而不是旨在限制。本文提及的所有出版物、专利申请、专利、序列、数据库条目和其他参考文献以引用方式整体并入。在有冲突的情况下,将以本说明书(包括定义)为准。
附图简述
图1C是4573 bp的示例性AAV载体,其包括编码兰尼单抗和绿色荧光蛋白(GFP)的序列。
图2是示出使用本文所述的示例性AAV载体的不同抗VEGF抗体或抗原结合抗体片段或可溶性VEGF受体的HEK细胞表达的蛋白质印迹。泳道1:预染色的PageRulerTM蛋白梯。泳道2:未转染/阴性对照。泳道3:用图1A中示出的AAV载体转染。泳道4:用图1C中示出的AAV载体转染。泳道5:用图1B中示出的AAV载体转染。泳道6:用图1A中示出的AAV载体转染,其中感染复数(MOI)为7.5x 104。泳道7:用图1A中示出的AAV载体转染,其中MOI为2.2x105。泳道8:用图1A中示出的AAV载体转染,其中MOI为5.5x 105。泳道9:预染色的PageRulerTM蛋白梯。泳道10:未转染/阴性对照。泳道11:用图1A中示出的AAV载体转染。泳道12:用图1C中示出的AAV载体转染。泳道13:用图1B中示出的AAV载体转染。泳道14:用图1A中示出的AAV载体转染,其中感染复数(MOI)为7.5x 104。泳道15:用图1A中示出的AAV载体转染,其中MOI为2.2x105。泳道16:用图1A中示出的AAV载体转染,其中MOI为5.5x 105。泳道2-8含有还原蛋白。泳道10-16含有非还原蛋白。
图3A是示出通过使用分析软件Data Analysis HT10.0的HTX生物传感器仪器测量的,对照小鼠抗人VEGF单克隆抗体(抗hVEGF MmAb)在使用重组人VEGF作为结合剂的缓冲液中的亲和力的图。
图3B是示出通过使用分析软件Data Analysis HT10.0的HTX生物传感器仪器测量的,对照抗hVEGF MmAb在使用重组人VEGF作为结合剂的条件培养基(CM)样品中的亲和力的图。*:在CM中以100μg/mL制备抗hVEGF MmAb,然后在1x动力学缓冲液中稀释至最终浓度10μg/mL。
图4C是示出由图3A、图3B、图4A和图4B中示出的数据确定的平衡解离常数(KD)的表(表从上到下)。
具体实施方式
本文提供了包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中的方法,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括可操作地连接到信号肽的抗原结合抗体片段(例如,Fab或scFv)的多肽。
本文还提供了用于提高对其有需要的哺乳动物的内耳中的抗体或抗原结合抗体片段的水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括可操作地连接到信号肽的抗原结合抗体片段(例如,Fab或scFv)的多肽;其中引入使得哺乳动物的内耳中抗体或抗原结合抗体片段的水平升高。
还提供了用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括连接到信号肽的抗原结合抗体片段的多肽;其中引入使得哺乳动物中的内耳病症得到治疗。
本文还提供了降低对其有需要的哺乳动物的内耳中VEGF活性的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括可操作地连接到信号肽的抗原结合抗体片段(例如,Fab或scFv)的多肽;其中(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;并且其中引入使得哺乳动物的内耳中VEGF活性降低。
本文还提供了治疗哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或(b)包括可操作地连接到信号肽的抗原结合抗体片段(例如,Fab或scFv)的多肽;其中(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;并且其中引入使得哺乳动物的内耳中听神经瘤或前庭神经鞘瘤得到治疗。
本文还提供了包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中的方法,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列。
本文还提供了用于提高对其有需要的哺乳动物的内耳中可溶性血管内皮生长因子(VEGF)受体水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性VEGF受体的核苷酸序列;其中引入使得哺乳动物的内耳中可溶性VEGF受体水平升高。
本文还提供了用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物中的内耳病症得到治疗。
本文还提供了降低对其有需要的哺乳动物的内耳中VEGF活性的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物的内耳中VEGF活性降低。
本文还提供了治疗哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或2型神经纤维瘤病的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;其中引入使得哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病分别得到治疗。
还提供了包括本文所述的任何AAV载体的试剂盒。
组合物、试剂盒和方法的其他非限制性方面在本文中描述,并且可以任何组合使用而不受限制。
抗体和抗原结合抗体片段
在一些实施方案中,抗体可以是人源化抗体、嵌合抗体或多价抗体。在一些实施方案中,抗体或抗原结合抗体片段可以是scFv-Fc、VHH结构域、VNAR结构域、(scFv)2、微抗体或BiTE。在一些实施方案中,抗体或抗原结合抗体片段可以是DVD-Ig和双亲和重新定位抗体(DART)、三功能抗体(triomab)、kih IgG共有LC、crossmab、正交Fab IgG、二合一IgG、IgG-ScFv、scFv2-Fc、双特异性纳米抗体、串联抗体、DART-Fc、scFv-HAS-scFv、DNL-Fab3、DAF(二合一或四合一)、DutaMab、DT-IgG、杵臼结构共有LC(knobs-in-holes common LC)、杵臼结构组件(knobs-in-holes assembly)、电荷对抗体、Fab臂交换抗体、SEEDbody、三功能抗体、LUZ-Y、Fcab、kλ体、正交Fab、DVD-IgG、IgG(H)-scFv、scFv-(H)IgG、IgG(L)-scFv、scFv-(L)-IgG、IgG(L,H)-Fc、IgG(H)-V、V(H)-IgG、IgG(L)-V、V(L)-IgG、KIH IgG-scFab、2scFv-IgG、IgG-2scFv、scFv4-Ig、Zybody、DVI-IgG、纳米抗体、纳米抗体HSA、双抗体(diabody)、TandAb、scDiabody、scDiabody-CH3、双抗体CH3、三联体(Triple Body)、微型抗体(miniantibody)、微抗体(minibody)、TriBi微抗体、scFv-CH3 KIH、Fab-scFv、scFv-CH-CL-scFv、F(ab’)2-scFV2、scFv-KIH、Fab-scFv-Fc、四价HCAb、scDiabody-Fc、双抗体Fc、串联scFv-Fc、细胞内抗体、对接和锁定(dock and lock)双特异性抗体、ImmTAC、HSAbody、scDiabody-HAS、串联scFv、IgG-IgG、Cov-X-Body和scFv1-PEG-scFv2。
抗体或抗原结合抗体片段的其他实例包括Fv片段、Fab片段、F(ab’)2片段和Fab’片段。抗体或抗原结合抗体片段的其他实例包括:IgG的抗原结合片段(例如,IgG1、IgG2、IgG3或IgG4的抗原结合片段)(例如,人或人源化IgG(例如,人或人源化IgG1、IgG2、IgG3或IgG4)的抗原结合片段);IgA的抗原结合片段(例如,IgA1或IgA2的抗原结合片段)(例如,人或人源化IgA(例如,人或人源化IgA1或IgA2)的抗原结合片段);IgD的抗原结合片段(例如,人或人源化IgD的抗原结合片段);IgE的抗原结合片段(例如,人或人源化IgE的抗原结合片段);或IgM的抗原结合片段(例如,人或人源化IgM的抗原结合片段)。
本文所述的任何抗体或抗原结合抗体片段可特异性结合到VEGF。
VHH结构域是可在骆驼中发现的单一单体可变抗体结构域。VNAR结构域是可在软骨鱼中发现的单一单体可变抗体结构域。VHH结构域和VNAR结构域的非限制性方面描述于例如,Cromie等人,Curr.Top.Med.Chem.15:2543-2557,2016;De Genst等人,Dev.Comp.Immunol.30:187-198,2006;De Meyer等人,Trends Biotechnol.32:263-270,2014;Kijanka等人,Nanomedicine 10:161-174,2015;Kovaleva等人,Expert.Opin.Biol.Ther.14:1527-1539,2014;Krah等人,Immunopharmacol.Immunotoxicol.38:21-28,2016;Mujic-Delic等人,Trends Pharmacol.Sci.35:247-255,2014;Muyldermans,J.Biotechnol.74:277-302,2001;Muyldermans等人,TrendsBiochem.Sci.26:230-235,2001;Muyldermans,Ann.Rev.Biochem.82:775-797,2013;Rahbarizadeh等人,Immunol.Invest.40:299-338,2011;Van Audenhove等人,EBioMedicine 8:40-48,2016;Van Bockstaele等人,Curr.Opin.Investig.Drugs 10:1212-1224,2009;Vincke等人,Methods Mol.Biol.911:15-26,2012;以及Wesolowski等人,Med.Microbiol.Immunol.198:157-174,2009。
“Fv”片段包括一个重链可变结构域和一个轻链可变结构域的非共价连接的二聚体。
除Fv片段的重链可变结构域和轻链可变结构域外,“Fab”片段还包括轻链的恒定结构域和重链的第一恒定结构域(CH1)。
“F(ab’)2”片段包括在铰链区附近通过二硫键连接的两个Fab片段。
“双重可变结构域免疫球蛋白”或“DVD-Ig”是指多价和多特异性结合蛋白,如描述于例如,DiGiammarino等人,Methods Mol.Biol.899:145-156,2012;Jakob等人,MABs 5:358-363,2013;以及美国专利号7,612,181;8,258,268;8,586,714;8,716,450;8,722,855;8,735,546和8,822,645中的,其各自以引用方式整体并入。
DART描述于例如Garber,NatureReviewsDrugDiscovery13:799-801.2014中。
抗体和抗原结合抗体片段的其他方面在本领域中是已知的。
在一些实施方案中,本文所述的任何抗体或抗原结合抗体片段具有的解离常数(KD)小于1x 10-5M(例如,小于0.5x 10-5M、小于1x10-6M、小于0.5x 10-6M、小于1x 10-7M、小于0.5x 10-7M、小于1x 10-8M、小于0.5x 10-8M、小于1x 10-9M、小于0.5x 10-9M、小于1x10-10M、小于0.5x 10-10M、小于1x 10-11M、小于0.5x 10-11M或小于1x 10-12M),例如,如在磷酸盐缓冲盐水中使用表面等离子体共振(SPR)针对VEGF蛋白(例如,本文所述的任何VEGF蛋白,例如,成熟人VEGF-A、成熟人VEGF-B、成熟人VEGF-C和成熟人VEGF-D中的一个或多个)所测量的。
在一些实施方案中,本文所述的任何抗体或抗原结合抗体片段具有的KD为约1x10-12M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x 10-7M、约1x 10-8M、约0.5x10-8M、约1x 10-9M、约0.5x 10-9M、约1x 10-10M、约0.5x 10-10M、约1x 10-11M或约0.5x 10-11M(包括端值);约0.5x 10-11M至约1x10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x10-6M、约1x 10-7M、约0.5x 10-7M、约1x 10-8M、约0.5x 10-8M、约1x 10-9M、约0.5x10-9M、约1x10-10M、约0.5x 10-10M或约1x 10-11M(包括端值);约1x 10-11M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x10-6M、约1x 10-7M、约0.5x 10-7M、约1x 10-8M、约0.5x 10-8M、约1x 10-9M、约0.5x 10-9M、约1x 10-10M或约0.5x 10-10M(包括端值);约0.5x 10-10M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x 10-7M、约1x 10-8M、约0.5x10-8M、约1x 10-9M、约0.5x 10-9M或约1x 10-10M(包括端值);约1x 10-10M至约1x 10-5M、约0.5x 10- 5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x 10-7M、约1x 10-8M、约0.5x 10-8M、约1x10-9M或约0.5x 10-9M(包括端值);约0.5x 10-9M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x10-7M、约1x 10-8M、约0.5x 10-8M或约1x 10-9M(包括端值);约1x 10-9M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x 10- 7M、约1x 10-8M或约0.5x 10-8M(包括端值);约0.5x 10-8M至约1x 10-5M、约0.5x 10-5M、约1x10-6M、约0.5x 10-6M、约1x 10-7M、约0.5x 10-7M或约1x 10-8M(包括端值);约1x 10-8M至约1x10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M、约1x 10-7M或约0.5x 10-7M(包括端值);约0.5x 10-7M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M、约0.5x 10-6M或约1x 10-7M(包括端值);约1x 10-7M至约1x 10-5M、约0.5x 10-5M、约1x 10-6M或约0.5x 10-6M(包括端值);约0.5x 10-6M至约1x 10-5M、约0.5x 10-5M或约1x 10-6M(包括端值);约1x 10-6M至约1x10-5M或约0.5x 10-5M(包括端值);或约0.5x 10-5M至约1x 10-5M(包括端值),例如,如在磷酸盐缓冲盐水中使用表面等离子体共振(SPR)针对VEGF蛋白(例如,本文所述的任何VEGF蛋白,例如,成熟人VEGF-A、成熟人VEGF-B、成熟人VEGF-C和成熟人VEGF-D中的一个或多个)所测量的。
可使用本领域已知的多种不同方法来测定本文所述的任何抗体或抗原结合抗体片段的KD值(例如,电泳迁移率变动测定、滤膜结合测定、表面等离子体共振和生物分子结合动力学测定等)。
在本文所述的任何抗体和/或抗原结合抗体片段的一些实施方案中,与类似受试者中的对照抗体和/或对照抗原结合抗体片段(例如,本文所述的任何对照抗体和/或对照抗原结合抗体片段)的半衰期相比,受试者(例如,人)中的抗体和/或抗原结合抗体片段的半衰期缩短约0.5倍至约4倍(例如,约0.5倍至约3.5倍、约0.5倍至约3倍、约0.5倍至约2.5倍、约0.5倍至约2倍、约0.5倍至约1.5倍、约0.5倍至约1倍、约1倍至约4倍、约1倍至约3.5倍、约1倍至约3倍、约1倍至约2.5倍、约1倍至约2倍、约1.5倍至约4倍、约1.5倍至约3.5倍、约1.5倍至约3倍、约1.5倍至约2.5倍、约1.5倍至约2倍、约2倍至约4倍、约2倍至约3.5倍、约2倍至约3倍、约2倍至约2.5倍、约2.5倍至约4倍、约2.5倍至约3.5倍、约2.5倍至约3倍、约3倍至约4倍、约3倍至约3.5倍或约3.5倍至约4倍)。参见,例如,Leabman等人,MAbs.5(6):896-903,2013。在一些实施方案中,本文所述的抗体或抗原结合抗体片段在Fc区中具有缩短其在哺乳动物中的半衰期的一个或多个氨基酸置换,并且对照抗体缺少Fc区中的这些一个或多个氨基酸置换中的至少一个(例如,缺少全部)。
VEGF
VEGF基因编码血管内皮生长因子(VEGF),以前称为fms样酪氨酸激酶(Flt-1)。VEGF蛋白是诱导血管内皮细胞迁移和增殖的肝素抑制蛋白。
下面示出编码野生型VEGF蛋白的蛋白质和核苷酸序列的非限制性实例。
人VEGF转录变体1蛋白质序列(SEQ ID NO:1)
人VEGF转录变体1cDNA(SEQ ID NO:2)
人VEGF转录变体3蛋白质序列(SEQ ID NO:3)
人VEGF转录变体3cDNA(SEQ ID NO:4)
成熟人VEGF-A(SEQ ID NO:13)
成熟人VEGF-B(SEQ ID NO:14)
成熟人VEGF-C(SEQ ID NO:15)
成熟人VEGF-D(SEQ ID NO:16)
在本文所述的任何抗体及其抗原结合片段的一些实例中,抗体和抗原结合片段可结合到VEGF抗原(例如,本文所述的任何示例性VEGF蛋白,例如,成熟人VEGF-A、成熟人VEGF-B、成熟人VEGF-C和成熟人VEGF-D中的一个或多个)(例如,本文所述的任何结合亲和力)。
在本文所述的一些实施方案中,抗体或抗原结合抗体片段可降低VEGF的活性(例如,本文所述的任何示例性VEGF蛋白中的一个或多个,例如,成熟人VEGF-A、成熟人VEGF-B、成熟人VEGF-C和成熟人VEGF-D中的一个或多个)。在一些实施方案中,抗体或抗原结合抗体片段可阻断VEGF(例如,本文所述的任何示例性VEGF蛋白中的一个或多个,例如,成熟人VEGF-A、成熟人VEGF-B、成熟人VEGF-C和成熟人VEGF-D中的一个或多个)与其受体中的一个或多个(例如,一个或多个VEGF受体)的结合。参见,例如,WO1998/045331,US 9,079,953,US2015/0147317,US 2016/0289314,Plotkin等人,Otology&Neurotology 33:1046-1052(2012);和Ferrara等人,(2005)Biochem Biophys Res Commun 333(2):328-335。在一些实施方案中,抗体或抗原结合抗体可减少下游信号传导(例如,VEGF受体(例如,本文所述的任何示例性VEGF受体中的一个或多个,例如,人VEGFR-1、人VEGFR-2和人VEGFR-3中的一个或多个)的下游信号传导)。在一些实施方案中,可间接地检测VEGF活性的降低,例如,通过分别与在施用本文所述的任何AAV载体之前的哺乳动物的听力水平或听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病的大小相比,哺乳动物听力的增加(例如,听力增加1%至约400%(或本文所述的此范围的任何子范围))或听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病的的大小或一种或多种症状的严重程度的减少(例如,减少1%至99%、1%至95%、1%至90%、1%至85%、1%至80%、1%至75%、1%至70%、1%至65%、1%至60%、1%至55%、1%至50%、1%至45%、1%至40%、1%至35%、1%至30%、1%至25%、1%至20%、1%至15%、1%至10%、1%至5%、5%至99%、5%至95%、5%至90%、5%至85%、5%至80%、5%至75%、5%至70%、5%至65%、5%至60%、5%至55%、5%至50%、5%至45%、5%至40%、5%至35%、5%至30%、5%至25%、5%至20%、5%至15%、5%至10%、10%至99%、10%至95%、10%至90%、10%至85%、10%至80%、10%至75%、10%至70%、10%至65%、10%至60%、10%至55%、10%至50%、10%至45%、10%至40%、10%至35%、10%至30%、10%至25%、10%至20%、10%至15%、15%至99%、15%至95%、15%至90%、15%至85%、15%至80%、15%至75%、15%至70%、15%至65%、15%至60%、15%至55%、15%至50%、15%至45%、15%至40%、15%至35%、15%至30%、15%至25%、15%至20%、20%至99%、20%至95%、20%至90%、20%至85%、20%至80%、20%至75%、20%至70%、20%至65%、20%至60%、20%至55%、20%至50%、20%至45%、20%至40%、20%至35%、20%至30%、20%至25%、25%至99%、25%至95%、25%至90%、25%至85%、25%至80%、25%至75%、25%至70%、25%至65%、25%至60%、25%至55%、25%至50%、25%至45%、25%至40%、25%至35%、25%至30%、30%至99%、30%至95%、30%至90%、30%至85%、30%至80%、30%至75%、30%至70%、30%至65%、30%至60%、30%至55%、30%至50%、30%至45%、30%至40%、30%至35%、35%至99%、35%至95%、35%至90%、35%至85%、35%至80%、35%至75%、35%至70%、35%至65%、35%至60%、35%至55%、35%至50%、35%至45%、35%至40%、40%至99%、40%至95%、40%至90%、40%至85%、40%至80%、40%至75%、40%至70%、40%至65%、40%至60%、40%至55%、40%至50%、40%至45%、45%至99%、45%至95%、45%至90%、45%至85%、45%至80%、45%至75%、45%至70%、45%至65%、45%至60%、45%至55%、45%至50%、50%至99%、50%至95%、50%至90%、50%至85%、50%至80%、50%至75%、50%至70%、50%至65%、50%至60%、50%至55%、55%至99%、55%至95%、55%至90%、55%至85%、55%至80%、55%至75%、55%至70%、55%至65%、55%至60%、60%至99%、60%至95%、60%至90%、60%至85%、60%至80%、60%至75%、60%至70%、60%至65%、65%至99%、65%至95%、65%至90%、65%至85%、65%至80%、65%至75%、65%至70%、70%至99%、70%至95%、70%至90%、70%至85%、70%至80%、70%至75%、75%至99%、75%至95%、75%至90%、75%至85%、75%至80%、80%至99%、80%至95%、80%至90%、80%至85%、85%至99%、85%至95%、85%至90%、90%至99%、90%至95%或95%至99%)。在一些实施方案中,可在体外测定中检测到VEGF活性的降低。
在一些实施方案中,特异性结合到VEGF的抗体是贝伐单抗或其抗原结合片段。贝伐单抗(全长抗体约150kDa)抑制VEGF-A的所有同工型。贝伐单抗于2004年获得食品和药物管理局(FDA)批准用于结肠癌,对于静脉内(IV)剂量为4.0-7.5mg/kg,2-3周(血浆半衰期为21天),对于玻璃体内(IVT)剂量为1.25mg/0.05mL(半衰期为5.6天)。贝伐单抗对于VEGF 165(VEGF-A)的KD为58pM。参见,例如,WO 2017/050825。在一些实施方案中,特异性结合到VEGF的抗体是兰尼单抗或其抗原结合片段。兰尼单抗(约50kDa)抑制VEGF-A的所有同工型。贝伐单抗于2006年获得FDA批准用于眼部用途,对于静脉内(IV)剂量为4.0-7.5mg/kg,2-3周(血浆半衰期为0.5天),对于玻璃体内(IVT)剂量为0.5mg/0.05mL(半衰期为3.2天)。兰尼单抗对于VEGF 165(VEGF-A)的KD为46pM。参见,例如,WO 2014/178078。在一些实施方案中,特异性结合到VEGF的抗体是sevacizumab(APX003/SIM-BD0801)或其抗原结合片段。
编码贝伐单抗的轻链的氨基酸(SEQ ID NO:5)
编码贝伐单抗的重链的氨基酸(SEQ ID NO:6)
在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括与贝伐单抗的可变轻链结构域有至少80%同一性(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%同一性)的序列;并且/或者包括可变重链结构域,所述可变重链结构域为或包括与贝伐单抗的可变重链结构域有至少80%同一性(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%同一性)的序列。
在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括贝伐单抗的可变轻链结构域;和/或可变重链结构域,所述可变重链结构域为或包括贝伐单抗的可变重链结构域。在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括贝伐单抗的可变轻链结构域的序列,不同之处在于它包括一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个或十五个氨基酸置换;并且/或者包括可变重链结构域,所述可变重链结构域为或包括贝伐单抗的可变重链的序列,不同之处在于它包括一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个或十五个氨基酸置换。在一些实施方案中,第一抗原结合结构域包括贝伐单抗的轻链可变结构域中的三个CDR和/或贝伐单抗的重链可变结构域中的三个CDR。
编码兰尼单抗的轻链的氨基酸(SEQ ID NO:7)
编码兰尼单抗的重链的氨基酸(SEQ ID NO:8)
在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括与兰尼单抗的可变轻链结构域有至少80%同一性(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%同一性)的序列;并且/或者包括可变重链结构域,所述可变重链结构域为或包括与兰尼单抗的可变重链结构域有至少80%同一性(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%同一性)的序列。
在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括兰尼单抗的可变轻链结构域;和/或可变重链结构域,所述可变重链结构域为或包括兰尼单抗的可变重链结构域。在本文所述的特异性结合到VEGF的抗体及其抗原结合片段的一些实施方案中,抗体或其抗原结合片段包括可变轻链结构域,所述可变轻链结构域为或包括兰尼单抗的可变轻链结构域的序列,不同之处在于它包括一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个或十五个氨基酸置换;并且/或者包括可变重链结构域,所述可变重链结构域为或包括兰尼单抗的可变重链的序列,不同之处在于它包括一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个或十五个氨基酸置换。在一些实施方案中,第一抗原结合结构域包括兰尼单抗的轻链可变结构域中的三个CDR和/或兰尼单抗的重链可变结构域中的三个CDR。
可溶性VEGF受体
可溶性VEGF受体是包括可操作地连接到信号肽(例如,本文所述的任何示例性信号肽)的一种或多种(例如,两种或三种)哺乳动物VEGF受体(例如,VEGFR-1、VEGFR-2和VEGFR-3中的一种或多种)的胞外区的一部分的多肽,其中可溶性VEGF受体能够特异性结合到一种或多种哺乳动物VEGF蛋白(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种(例如,两种、三种或四种),例如,人野生型VEGF-A、人野生型VEGF-B、人野生型VEGF-C和人野生型VEGF-D中的一种或多种(例如,两种、三种或四种))。
在一些实例中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分(例如,约10个氨基酸至约732个氨基酸、约10个氨基酸至约700个氨基酸、约10个氨基酸至约650个氨基酸、约10个氨基酸至约600个氨基酸、约10个氨基酸至约550个氨基酸、约10个氨基酸至约500个氨基酸、约10个氨基酸至约450个氨基酸、约10个氨基酸至约400个氨基酸、约10个氨基酸至约350个氨基酸、约10个氨基酸至约300个氨基酸、约10个氨基酸至约250个氨基酸、约10个氨基酸至约200个氨基酸、约10个氨基酸至约150个氨基酸、约10个氨基酸至约100个氨基酸、约10个氨基酸至约50个氨基酸、约50个氨基酸至约732个氨基酸、约50个氨基酸至约700个氨基酸、约50个氨基酸至约650个氨基酸、约50个氨基酸至约600个氨基酸、约50个氨基酸至约550个氨基酸、约50个氨基酸至约500个氨基酸、约50个氨基酸至约450个氨基酸、约50个氨基酸至约400个氨基酸、约50个氨基酸至约350个氨基酸、约50个氨基酸至约300个氨基酸、约50个氨基酸至约250个氨基酸、约50个氨基酸至约200个氨基酸、约50个氨基酸至约150个氨基酸、约50个氨基酸至约100个氨基酸、约100个氨基酸至约732个氨基酸、约100个氨基酸至约700个氨基酸、约100个氨基酸至约650个氨基酸、约100个氨基酸至约600个氨基酸、约100个氨基酸至约550个氨基酸、约100个氨基酸至约500个氨基酸、约100个氨基酸至约450个氨基酸、约100个氨基酸至约400个氨基酸、约100个氨基酸至约350个氨基酸、约100个氨基酸至约300个氨基酸、约100个氨基酸至约250个氨基酸、约100个氨基酸至约200个氨基酸、约100个氨基酸至约150个氨基酸、约150个氨基酸至约732个氨基酸、约150个氨基酸至约700个氨基酸、约150个氨基酸至约650个氨基酸、约150个氨基酸至约600个氨基酸、约150个氨基酸至约550个氨基酸、约150个氨基酸至约500个氨基酸、约150个氨基酸至约450个氨基酸、约150个氨基酸至约400个氨基酸、约150个氨基酸至约350个氨基酸、约150个氨基酸至约300个氨基酸、约150个氨基酸至约250个氨基酸、约150个氨基酸至约200个氨基酸、约200个氨基酸至约732个氨基酸、约200个氨基酸至约700个氨基酸、约200个氨基酸至约650个氨基酸、约200个氨基酸至约600个氨基酸、约200个氨基酸至约550个氨基酸、约200个氨基酸至约500个氨基酸、约200个氨基酸至约450个氨基酸、约200个氨基酸至约400个氨基酸、约200个氨基酸至约350个氨基酸、约200个氨基酸至约300个氨基酸、约200个氨基酸至约250个氨基酸、约250个氨基酸至约732个氨基酸、约250个氨基酸至约700个氨基酸、约250个氨基酸至约650个氨基酸、约250个氨基酸至约600个氨基酸、约250个氨基酸至约550个氨基酸、约250个氨基酸至约500个氨基酸、约250个氨基酸至约450个氨基酸、约250个氨基酸至约400个氨基酸、约250个氨基酸至约350个氨基酸、约250个氨基酸至约300个氨基酸、约300个氨基酸至约732个氨基酸、约300个氨基酸至约700个氨基酸、约300个氨基酸至约650个氨基酸、约300个氨基酸至约600个氨基酸、约300个氨基酸至约550个氨基酸、约300个氨基酸至约500个氨基酸、约300个氨基酸至约450个氨基酸、约300个氨基酸至约400个氨基酸、约300个氨基酸至约350个氨基酸、约350个氨基酸至约732个氨基酸、约350个氨基酸至约700个氨基酸、约350个氨基酸至约650个氨基酸、约350个氨基酸至约600个氨基酸、约350个氨基酸至约550个氨基酸、约350个氨基酸至约500个氨基酸、约350个氨基酸至约450个氨基酸、约350个氨基酸至约400个氨基酸、约400个氨基酸至约732个氨基酸、约400个氨基酸至约700个氨基酸、约400个氨基酸至约650个氨基酸、约400个氨基酸至约600个氨基酸、约400个氨基酸至约550个氨基酸、约400个氨基酸至约500个氨基酸、约400个氨基酸至约450个氨基酸、约450个氨基酸至约732个氨基酸、约450个氨基酸至约700个氨基酸、约450个氨基酸至约650个氨基酸、约450个氨基酸至约600个氨基酸、约450个氨基酸至约550个氨基酸、约450个氨基酸至约500个氨基酸、约500个氨基酸至约732个氨基酸、约500个氨基酸至约700个氨基酸、约500个氨基酸至约650个氨基酸、约500个氨基酸至约600个氨基酸、约500个氨基酸至约550个氨基酸、约550个氨基酸至约732个氨基酸、约550个氨基酸至约700个氨基酸、约550个氨基酸至约650个氨基酸、约550个氨基酸至约600个氨基酸、约600个氨基酸至约732个氨基酸、约600个氨基酸至约700个氨基酸、约600个氨基酸至约650个氨基酸、约650个氨基酸至约732个氨基酸、约650个氨基酸至约700个氨基酸或约700个氨基酸至约732个氨基酸)(例如,野生型人VEGFR-1的连续序列(例如,包括野生型人VEGFR-1(例如,SEQ ID NO:23)的胞外区中的一个或多个(例如,一个、两个、三个、四个、五个、六个或七个)免疫球蛋白样结构域的连续序列,或与野生型人VEGFR-1的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列,例如,与SEQ ID NO:23中的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列)。
在一些实例中,可溶性VEGF受体包括VEGFR-2的胞外区的一部分(例如,约20个氨基酸至约745个氨基酸,或本文所述的此范围的任何子范围)(例如,野生型人VEGFR-2的连续序列(例如,包括野生型人VEGFR-2(例如,SEQ ID NO:26)的胞外区中的一个或多个(例如,一个、两个、三个、四个、五个、六个或七个)免疫球蛋白样结构域的连续序列,或与野生型人VEGFR-2的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列,例如,与SEQ IDNO:26中的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列)。
在一些实例中,可溶性VEGF受体包括VEGFR-1的胞外区的一部分(例如本文所述的VEGFR-1的胞外区的任何部分)和VEGFR-2的胞外区的一部分(例如,(本文所述的VEGFR-2胞外区的任何部分)。例如,可溶性VEGF受体可包括野生型人VEGFR-1的胞外区中的一个或多个(例如,两个、三个、四个、五个、六个或七个)免疫球蛋白样结构域以及野生型人VEGFR-2的胞外区中的一个或多个(例如,两个、三个、四个、五个、六个或七个)免疫球蛋白样结构域(例如,阿柏西普)。
在一些实例中,可溶性VEGF受体包括VEGFR-3的胞外区的一部分(例如,约20个氨基酸至约751个氨基酸,或本文所述的此范围的任何子范围)(例如,野生型人VEGFR-3的连续序列(例如,包括野生型人VEGFR-3(例如,SEQ ID NO:29)的胞外区中的一个或多个(例如,一个、两个、三个、四个、五个、六个或七个)免疫球蛋白样结构域的连续序列,或与野生型人VEGFR-3的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列,例如,与SEQ IDNO:29中的连续序列有至少80%(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%)同一性的序列)。
本文描述了不同哺乳动物VEGFR-1、不同哺乳动物VEGFR-2和不同哺乳动物VEGFR-3的胞外区的非限制性实例。下面示出编码野生型VEGF受体蛋白的蛋白质和核苷酸序列的非限制性实例。如本领域技术人员可理解的,在物种之间保守的氨基酸置换更可能导致蛋白质功能的改变,而在物种之间不保守的氨基酸位置的置换不太可能对蛋白质功能产生影响。
人VEGF受体1同工型2蛋白质序列(SEQ ID NO:17)
人VEGF受体1同工型2cDNA(SEQ ID NO:18)
人VEGF受体1同工型3蛋白质序列(SEQ ID NO:19)(sFlt1-14)
人VEGF受体1同工型3cDNA(SEQ ID NO:20)
人VEGF受体1同工型4蛋白质序列(SEQ ID NO:21)
人VEGF受体1同工型4cDNA(SEQ ID NO:22)
野生型人VEGFR-1的胞外区(SEQ ID NO:23)(七个Ig样结构域以粗体和下划线显示)
野生型小鼠VEGFR-1的胞外区(SEQ ID NO:24)
野生型大鼠VEGFR-1的胞外区(SEQ ID NO:25)
野生型人VEGFR-2的胞外区(sEQ ID NO:26)(七个Ig样结构域以粗体和下划线显示)
野生型小鼠VEGFR-2的胞外区(SEQ ID NO:27)
野生型大鼠VEGFR-2的胞外区(SEQ ID NO:28)
野生型人VEGFR-3的胞外区(SEQ ID NO:29)(七个Ig样结构域以粗体显示)
野生型小鼠VEGFR-3的胞外区(SEQ ID NO:30)
野生型大鼠VEGFR-3的胞外区(SEQ ID NO:31)
在一些实例中,可溶性VEGF受体还可包括稳定结构域(例如,Fc结构域或Fc结构域的一部分)。例如,稳定结构域可以是IgG1 Fc结构域(例如,人野生型IgG1 Fc结构域或其一部分)。例如,稳定结构域可以是IgG2 Fc结构域(例如,人野生型IgG2 Fc结构域或其一部分)。例如,稳定结构域可以是IgG3 Fc结构域(例如,人野生型IgG3结构域或其一部分)。
下面示出了人野生型IgG1 Fc结构域、人野生型IgG2 Fc结构域和人野生型IgG3Fc结构域的非限制性实例。
人野生型IgG1 Fc结构域(SEQ ID NO:32)
人野生型IgG2 Fc区(SEQ ID NO:33)
人野生型IgG3 Fc区(SEQ ID NO:34)
在一些实施方案中,可溶性VEGF受体为阿柏西普阿柏西普包括与人IgG1的Fc部分融合的人VEGF受体1和2的胞外结构域的部分(大小为约115kDa)。阿柏西普抑制VEGF-A、VEGF-B和PIGF的活性。阿柏西普针对VEGF-A的KD为0.49pM。参见,例如,WO 2017/218974。
编码阿柏西普的氨基(SEQ ID NO:12)
在可溶性VEGF受体的一些实施方案中,所述可溶性VEGF受体包括与SEQ ID NO:12有至少80%同一性(例如,至少82%、至少84%、至少86%、至少88%、至少90%、至少92%、至少94%、至少96%、至少98%或至少99%同一性)的序列。
在可溶性VEGF受体的一些实施方案中,所述可溶性VEGF受体包括胞外结构域,所述胞外结构域为或包括SEQ ID NO:12的序列,不同之处在于它包括SEQ ID NO:12的序列中的一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个或十五个氨基酸置换。
可溶性VEGF受体的其他实例描述于例如,Kendall等人,PNAS90:10705-10709,1993;Kendall等人,Biochem Biophys Res Commun226:324-328,1996;Failla等人,Int JMol Sci 19(5):pii.E1306,2018;以及Jung等人,PLoS One 7(9):e44572。
载体
重组AAV载体或“rAAV”通常至少由转基因或其一部分和调控序列、以及任选地5’和3’AAV反向末端重复序列(ITR)组成。将这种重组AAV载体包装到衣壳中并递送至选定的靶细胞(例如,耳蜗毛细胞)。
载体的AAV序列通常包括顺式作用的5’和3’ITR序列(参见,例如,B.J.Carter,“Handbook of Parvoviruses”,P.Tijsser编,CRC Press,第155168页,1990)。典型的AAVITR序列的长度为约145个核苷酸。在一些实施方案中,将典型的ITR序列的至少75%(例如,至少80%、至少85%、至少90%或至少95%)并入AAV载体。修饰这些ITR序列的能力在本领域技术范围内。(参见,例如,文本诸如Sambrook等人,“Molecular Cloning.A LaboratoryManual”,第2版,Cold SpringHarbor Laboratory,New York,1989;和K.Fisher等人,JVirol.70:520532,1996)。在一些实施方案中,本文所述的任何编码序列由AAV载体中的5’和3’AAV ITR序列侧接。AAV ITR序列可从任何已知的AAV获得,包括目前鉴定的AAV类型。
如本文所述的AAV载体可包括本文所述的任何调控元件(例如,启动子、多聚腺苷酸化(poly(A))信号序列和IRES中的一个或多个)。
在一些实施方案中,载体为腺病毒(参见,例如,Dmitriev等人,(1998)J.Viral.72:9706-9713;和Poulin等人,J.Virol 8:10074-10086,2010)。在一些实施方案中,载体为逆转录病毒(参见,例如,Maier等人,(2010)Future Microbiol5:1507-23)。
本文提供的载体可具有不同的大小。在本文所述的任何组合物、试剂盒和方法中使用的载体的选择可取决于载体的大小。
在一些实施方案中,载体可具有多至10kb的核苷酸总数。在一些实施方案中,病毒载体可具有的核苷酸总数在以下范围内:约1kb至约2kb、1kb至约3kb、约1kb至约4kb、约1kb至约5kb、约1kb至约6kb、约1kb至约7kb、约1kb至约8kb、约1kb至约9kb、约1kb至约10kb、约2kb至约3kb、约2kb至约4kb、约2kb至约5kb、约2kb至约6kb、约2kb至约7kb、约2kb至约8kb、约2kb至约9kb、约2kb至约10kb、约3kb至约4kb、约3kb至约5kb、约3kb至约6kb、约3kb至约7kb、约3kb至约8kb、约3kb至约9kb、约3kb至约10kb、约4kb至约5kb、约4kb至约6kb、约4kb至约7kb、约4kb至约8kb、约4kb至约9kb、约4kb至约10kb、约5kb至约6kb、约5kb至约7kb、约5kb至约8kb、约5kb至约9kb、约5kb至约10kb、约6kb至约7kb、约6kb至约8kb、约6kb至约9kb、约6kb至约10kb、约7kb至约8kb、约7kb至约9kb、约7kb至约10kb、约8kb至约9kb、约8kb至约10kb或约9kb至约10kb。
在一些实施方案中,载体为慢病毒并且可具有多至8kb的核苷酸总数。在一些实例中,慢病毒可具有的核苷酸总数为约1kb至约2kb、约1kb至约3kb、约1kb至约4kb、约1kb至约5kb、约1kb至约6kb、约1kb至约7kb、约1kb至约8kb、约2kb至约3kb、约2kb至约4kb、约2kb至约5kb、约2kb至约6kb、约2kb至约7kb、约2kb至约8kb、约3kb至约4kb、约3kb至约5kb、约3kb至约6kb、约3kb至约7kb、约3kb至约8kb、约4kb至约5kb、约4kb至约6kb、约4kb至约7kb、约4kb至约8kb、约5kb至约6kb、约5kb至约7kb、约5kb至约8kb、约6kb至约8kb、约6kb至约7kb或约7kb至约8kb。
在一些实施方案中,载体为腺病毒并且可具有多至8kb的核苷酸总数。在一些实施方案中,腺病毒可具有的核苷酸总数在以下范围内:约1kb至约2kb、约1kb至约3kb、约1kb至约4kb、约1kb至约5kb、约1kb至约6kb、约1kb至约7kb、约1kb至约8kb、约2kb至约3kb、约2kb至约4kb、约2kb至约5kb、约2kb至约6kb、约2kb至约7kb、约2kb至约8kb、约3kb至约4kb、约3kb至约5kb、约3kb至约6kb、约3kb至约7kb、约3kb至约8kb、约4kb至约5kb、约4kb至约6kb、约4kb至约7kb、约4kb至约8kb、约5kb至约6kb、约5kb至约7kb、约5kb至约8kb、约6kb至约7kb、约6kb至约8kb或约7kb至约8kb。
在一些实施方案中,载体为腺相关病毒(AAV载体)并且可包括多至5kb的核苷酸总数。在一些实施方案中,AAV载体可包括的核苷酸总数在以下范围内:约1kb至约2kb、约1kb至约3kb、约1kb至约4kb、约1kb至约5kb、约2kb至约3kb、约2kb至约4kb、约2kb至约5kb、约3kb至约4kb、约3kb至约5kb或约4kb至约5kb。
可使用本领域中已知的多种不同方法将本文公开的任何载体引入哺乳动物细胞(例如,内耳细胞、耳蜗内毛细胞)。用于将核酸引入哺乳动物细胞的方法的非限制性实例包括:脂质转染、转染(例如,磷酸钙转染、使用高度支化的有机化合物的转染、使用阳离子聚合物的转染、基于树状聚合物的转染、光学转染、基于颗粒的转染(例如,纳米颗粒转染)或使用脂质体(例如,阳离子脂质体)的转染)、显微注射、电穿孔、细胞挤压、声致穿孔、原生质体融合、穿刺转染、流体动力学递送、基因枪、磁转染、病毒转染和核转染。
本文所述的任何载体还可包括控制序列,例如,选自转录起始序列、转录终止序列、启动子序列、增强子序列、RNA剪接序列、多聚腺苷酸化(polyA)信号和Kozak共识序列的组的控制序列。本文描述了这些控制序列的非限制性实例。在一些实施方案中,启动子可以是天然启动子、组成型启动子、诱导型启动子和/或组织特异性启动子。
启动子
术语“启动子”意指启动特定基因的转录所需的由哺乳动物细胞中的酶/蛋白质识别的DNA序列。启动子通常是指例如,与RNA聚合酶和/或任何相关因子结合并在此处启动转录的核苷酸序列。本文描述了启动子的非限制性实例。启动子的其他实例在本领域中是已知的。
在一些实施方案中,编码抗体(例如,特异性结合到VEGF的抗体或其抗原结合抗体片段)的载体(例如,腺相关病毒(AAV)载体)可包括启动子和/或增强子。编码抗体或抗原结合抗体片段的载体可包括本文所述或本领域已知的任何启动子和/或增强子。
在一些实施方案中,启动子是诱导型启动子、组成型启动子、哺乳动物细胞启动子、病毒启动子、嵌合启动子、工程启动子、组织特异性启动子或本领域已知的任何其他类型的启动子。在一些实施方案中,启动子为RNA聚合酶II启动子,诸如哺乳动物RNA聚合酶II启动子。在一些实施方案中,启动子为RNA聚合酶III启动子,包括但不限于H1启动子、人U6启动子、小鼠U6启动子或猪U6启动子。启动子通常将是能够在内毛细胞中促进转录的启动子。在一些实例中,启动子为耳蜗特异性启动子或耳蜗定向启动子。
可在本文中使用的各种启动子在本领域中是已知的。可在本文中使用的启动子的非限制性实例包括:人EF1a、人巨细胞病毒(CMV)(美国专利号5,168,062)、人泛素C(UBC)、小鼠磷酸甘油酸激酶1、多瘤腺病毒、猿猴病毒40(SV40)、β-球蛋白、β-肌动蛋白、α-甲胎蛋白、γ-球蛋白、β-干扰素、γ-谷氨酰转移酶、小鼠乳腺肿瘤病毒(MMTV)、劳斯肉瘤病毒、大鼠胰岛素、甘油醛-3-磷酸脱氢酶、金属硫蛋白II(MT II)、淀粉酶、组织蛋白酶、MI毒蕈碱受体、逆转录病毒LTR(例如,人T细胞白血病病毒HTLV)、AAV ITR、白介素-2、胶原酶、血小板衍生的生长因子、腺病毒5E2、基质溶解素、鼠MX基因、葡萄糖调节蛋白(GRP78和GRP94)、α-2-巨球蛋白、波形蛋白、I类MHC基因H-2r b、HSP70、增殖蛋白、肿瘤坏死因子、甲状腺刺激激素α基因、免疫球蛋白轻链、T细胞受体、HLA DQα和DQβ、白介素-2受体、II类MHC、II类MHC HLA-DRα、肌肉肌酸激酶、前白蛋白(甲状腺素运载蛋白)、弹性蛋白酶I、白蛋白基因、c-fos、c-HA-ras、神经细胞粘附分子(NCAM)、H2B(TH2B)组蛋白、大鼠生长激素、人血清淀粉样蛋白(SAA)、肌钙蛋白I(TN I)、杜氏肌营养不良症、人类免疫缺陷病毒和长臂猿白血病病毒(GALV)启动子。启动子的其他实例在本领域中是已知的。参见,例如,Lodish,MolecularCell Biology,Freeman and Company,New York 2007。在一些实施方案中,启动子为CMV立即早期启动子。在一些实施方案中,启动子为CAG启动子或CAG/CBA启动子。
术语“组成型”启动子是指当与编码蛋白质的核酸(例如,抗体或抗原结合抗体片段)可操作地连接时,在大多数或所有生理条件下致使RNA从哺乳动物细胞中的核酸中转录的核苷酸序列。
组成型启动子的实例包括但不限于逆转录病毒劳斯肉瘤病毒(RSV)LTR启动子、巨细胞病毒(CMV)启动子(参见,例如,Boshart等人,Cell 41:521-530,1985)、SV40启动子、二氢叶酸还原酶启动子、β-肌动蛋白启动子、磷酸甘油激酶(PGK)启动子和EF1-α启动子(Invitrogen)。
诱导型启动子允许调节基因表达,并且可通过外源化合物、环境因素(诸如温度)或特定生理状态(例如,急性期、细胞的特定分化状态或仅在复制细胞中)的存在来调节。诱导型启动子和诱导型体系可商购自各种商业来源,包括但不限于Invitrogen、Clontech和Ariad。诱导型启动子的其他实例在本领域中是已知的。
由外源化合物调节的诱导型启动子的实例包括锌诱导型绵羊金属硫蛋白(MT)启动子、地塞米松(Dex)诱导型小鼠乳腺肿瘤病毒(MMTV)启动子、T7聚合酶启动子体系(WO98/10088)、蜕皮激素昆虫启动子(No等人,Proc.Natl.Acad.Sci.U.S.A.93:3346-3351,1996),四环素抑制型体系(Gossen等人,Proc.Natl.Acad.Sci.U.S.A.89:5547-5551,1992)、四环素诱导型体系(Gossen等人,Science268:1766-1769,1995,也参见Harvey等人,Curr.Opin.Chem.Biol.2:512-518,1998)、RU486诱导型体系(Wang等人,Nat.Biotech.15:239-243,1997)和Wang等人,Gene Ther.4:432-441,1997)以及雷帕霉素诱导型体系(Magari等人,J.Clin.Invest.100:2865-2872,1997)。
术语“组织特异性”启动子是指仅在某些特定细胞类型和/或组织中具有活性的启动子(例如,特定基因的转录仅在表达结合到组织特异性启动子的转录调节蛋白的细胞内发生)。
在一些实施方案中,调节序列赋予组织特异性基因表达能力。在一些情况下,组织特异性调节序列结合以组织特异性方式诱导转录的组织特异性转录因子。
示例性组织特异性启动子包括但不限于以下:肝特异性甲状腺素结合球蛋白(TBG)启动子、胰岛素启动子、胰高血糖素启动子、生长抑素启动子、胰腺多肽(PPY)启动子、突触蛋白-1(Syn)启动子、肌酸激酶(MCK)启动子、哺乳动物结蛋白(DES)启动子、α-肌球蛋白重链(a-MHC)启动子和心肌肌钙蛋白T(cTnT)启动子。其他示例性启动子包括β-肌动蛋白启动子、乙型肝炎病毒核心启动子(Sandig等人,GeneTher.3:1002-1009,1996)、甲胎蛋白(AFP)启动子(Arbuthnot等人,Hum.Gene Ther.7:1503-1514,1996)、骨钙素启动子(Stein等人,Mol.Biol.Rep.24:185-196,1997)、骨唾液蛋白启动子(Chen等人,J.BoneMiner.Res.11:654-664,1996)、CD2启动子(Hansal等人,J.Immunol.161:1063-1068,1998)、免疫球蛋白重链启动子、T细胞受体α链启动子、神经元诸如神经元特异性烯醇化酶(NSE)启动子(Andersen等人,Cell.Mol.Neurobiol.13:503-515,1993)、神经丝轻链基因启动子(Piccioli等人,Proc.Natl.Acad.Sci.U.S.A.88:5611-5615,1991)和神经元特异性vgf基因启动子(Piccioli等人,Neuron 15:373-384,1995)。
在一些实施方案中,组织特异性启动子为耳蜗特异性启动子。在一些实施方案中,组织特异性启动子为耳蜗毛细胞特异性启动子。耳蜗毛细胞特异性启动子的非限制性实例包括但不限于:ATOH1启动子、POU4F3启动子、LHX3启动子、MYO7A启动子、MYO6启动子、α9ACHR启动子和α10ACHR启动子。在一些实施方案中,启动子为耳蜗毛细胞特异性启动子,诸如PRESTIN启动子或ONCOMOD启动子。参见,例如,Zheng等人,Nature 405:149-155,2000;Tian等人,Dev.Dyn.231:199-203,2004;和Ryan等人,Adv.Otorhinolaryngol.66:99-115,2009。
增强子
在一些情况下,载体(例如,AAV载体)可包括增强子序列。术语“增强子”是指可增加编码感兴趣的蛋白(例如,特异性结合到VEGF的抗体或其抗原结合抗体片段或可溶性VEGF受体)的核酸的转录水平的核苷酸序列。增强子序列(长度为50-1500个碱基对)通常通过为转录相关蛋白(例如,转录因子)提供额外的结合位点来增加转录水平。在一些实施方案中,在内含子序列内发现增强子序列。与启动子序列不同,增强子序列可在离转录起始位点更大的距离处起作用(例如,与启动子相比)。增强子的非限制性实例包括RSV增强子、CMV增强子和SV40增强子。
Poly(A)信号序列
在一些实施方案中,本文提供的任何载体(例如,AAV载体)可包括多聚腺苷酸化(poly(A))信号序列。大多数新生的真核mRNA在其3’端具有在复杂的过程中添加的poly(A)尾巴,所述过程包括对初始转录物的裂解以及由poly(A)信号序列驱动的偶联多聚腺苷酸化反应(参见,例如,Proudfoot等人,Cell 108:501-512,2002)。Poly(A)尾巴赋予mRNA稳定性和转移性(Molecular Biology of the Cell,第三版B.Alberts等人,GarlandPublishing,1994)。在一些实施方案中,poly(A)信号序列位于编码抗体重链、抗体轻链、抗原结合抗体片段或可溶性VEGF受体的核酸序列的3’处。
如本文所用,“多聚腺苷酸化”是指多聚腺苷酸基部分或其修饰的变体与信使RNA分子的共价连接。在真核生物中,大多数信使RNA(mRNA)分子在3’端是多聚腺苷酸化的。3’poly(A)尾巴是通过酶、多聚腺苷酸聚合酶的作用添加到pre-mRNA的长序列的腺嘌呤核苷酸(例如,50、60、70、100、200、500、1000、2000、3000、4000或5000)。在高等真核生物中,poly(A)尾巴被添加到含有特定序列(多聚腺苷酸化(或poly(A))信号)的转录物上。Poly(A)尾巴及其结合的蛋白质有助于保护mRNA免受核酸外切酶的降解。多聚腺苷酸化对于转录终止、mRNA从细胞核中输出和翻译也很重要。DNA转录为RNA后,多聚腺苷酸化立即在细胞核中发生,但随后也可在细胞质中发生。转录终止后,通过与RNA聚合酶相关联的核酸内切酶复合物的作用使mRNA链裂解。裂解位点通常特征在于在裂解位点附近存在碱基序列AAUAAA。在mRNA已被裂解后,腺苷残基被添加到裂解位点处的游离3’端。
如本文所用,“poly(A)信号序列”或“多聚腺苷酸化信号序列”是触发mRNA的核酸内切酶裂解并且在裂解的mRNA的3’端添加一系列腺苷的序列。
存在可使用的若干种poly(A)信号序列,包括源自以下的那些序列:牛生长激素(bgh)(Woychik等人,Proc.Natl.Acad.Sci.U.S.A.81(13):3944-3948,1984;美国专利号5,122,458)、小鼠β-珠蛋白、小鼠α-珠蛋白(Orkin等人,EMBO J.4(2):453-456,1985;Thein等人,Blood 71(2):313-319,1988)、人胶原蛋白、多瘤病毒(Batt等人,Mol.Cell Biol.15(9):4783-4790,1995)、单纯疱疹病毒胸苷激酶基因(HSV TK)、IgG重链基因多聚腺苷酸化信号(US 2006/0040354)、人生长激素(hGH)(Szymanski等人,Mol.Therapy 15(7):1340-1347,2007)、由SV40 poly(A)位点组成的组,诸如SV40晚期和早期的poly(A)位点(Schek等人,Mol.Cell Biol.12(12):5386-5393,1992)。
Poly(A)信号序列可以是AATAAA。AATAAA序列可由与AATAAA同源并且能够信号传导多聚腺苷酸化的其他六核苷酸序列置换,包括ATTAAA、AGTAAA、CATAAA、TATAAA、GATAAA、ACTAAA、AATATA、AAGAAA、AATAAT、AAAAAA、AATGAA、AATCAA、AACAAA、AATCAA、AATAAC、AATAGA、AATTAA或AATAAG(参见,例如,WO 06/12414)。
在一些实施方案中,poly(A)信号序列可以是合成的多聚腺苷酸化位点(参见,例如,Promega的pCl-neo表达载体,其基于Levitt等人,Genes Dev.3(7):1019-1025,1989)。在一些实施方案中,poly(A)信号序列为可溶性神经菌毛素-1(sNRP)(AAATAAAATACGAAATG;SEQ ID NO:11)的多聚腺苷酸化信号(参见,例如,WO 05/073384)。poly(A)信号序列的其他实例在本领域中是已知的。
内部核糖体进入位点(IRES)
在一些实施方案中,编码抗体(例如,抗体重链和抗体轻链)、抗原结合抗体片段或可溶性VEGF受体的载体(例如,腺相关病毒(AAV)载体)可包括多核苷酸内部核糖体进入位点(IRES)。使用IRES序列由单一基因转录物产生多于一种多肽。IRES形成复杂的二级结构,所述二级结构允许翻译起始在mRNA紧靠IRES所处位置的下游的任何位置发生(参见,例如,Pelletier和Sonenberg,Mol.Cell.Biol.8(3):1103-1112,1988)。
存在本领域技术人员已知的若干种IRES序列,包括来自例如口蹄疫病毒(FMDV)、脑心肌炎病毒(EMCV)、人鼻病毒(HRV)、蟋蟀麻痹病毒、人免疫缺陷病毒(HIV)、甲型肝炎病毒(HAV)、丙型肝炎病毒(HCV)和脊髓灰质炎病毒(PV)的那些序列。参见,例如,Alberts,Molecular Biology of the Cell,Garland Science,2002;和Hellen等人,Genes Dev.15(13):1593-612,2001。
在一些实施方案中,并入AAV载体中的IRES序列为口蹄疫病毒(FMDV)2A序列。口蹄疫病毒2A序列为小肽(长度为约18个氨基酸),已证明其介导多聚蛋白的裂解(Ryan,M D等人,EMBO 4:928-933,1994;Mattion等人,J.Virology 70:8124-8127,1996;Furler等人,Gene Therapy 8:864-873,2001;和Halpin等人,Plant Journal 4:453-459,1999)。先前已在包括质粒和基因治疗载体(AAV和逆转录病毒)的人工体系中证明了2A序列的裂解活性(Ryan等人,EMBO 4:928-933,1994;Mattion等人,J.Virology 70:8124-8127,1996;Furler等人,Gene Therapy 8:864-873,2001;和Halpin等人,Plant Journal 4:453-459,1999;deFelipe等人,Gene Therapy 6:198-208,1999;de Felipe等人,Human Gene Therapy 11:1921-1931,2000;以及Klump等人,Gene Therapy 8:811-817,2001)。
报告序列
本文提供的任何AAV可任选地包括编码报告蛋白的序列(“报告序列”)。报告序列的非限制性实例包括编码以下的DNA序列:β-内酰胺酶、β-半乳糖苷酶(LacZ)、碱性磷酸酶、胸苷激酶、绿色荧光蛋白(GFP)、红色荧光蛋白、mCherry荧光蛋白、黄色荧光蛋白、氯霉素乙酰转移酶(CAT)和荧光素酶。报告序列的其他实例在本领域中是已知的。当与驱动其表达的调控元件缔合时,报告序列可提供可通过常规手段检测的信号,所述常规手段包括酶促、射线检测、比色、荧光或其他光谱测定;荧光活化细胞分选(FACS)测定;免疫测定(例如,酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)和免疫组织化学)。
在一些实施方案中,报告序列为LacZ基因,并且通过测定β-半乳糖苷酶活性来检测哺乳动物细胞(例如,耳蜗毛细胞)中携带LacZ基因的载体的存在。当报告基因为荧光蛋白(例如,绿色荧光蛋白)或荧光素酶时,可通过荧光技术(例如,荧光显微镜检查术或FACS)或光度计(例如,分光光度计或IVIS成像仪器)中的光产生来测量哺乳动物细胞(例如,耳蜗毛细胞)中携带荧光蛋白或荧光素酶的载体的存在。在一些实施方案中,可使用报告序列验证本文所述的任何载体的组织特异性靶向能力和组织特异性启动子调节活性。
侧翼区非翻译区(UTR)
在一些实施方案中,任何腺相关病毒(AAV)载体可包括非翻译区,诸如5’UTR或3’UTR。
基因的非翻译区(UTR)被转录但未被翻译。5’UTR在转录起始位点开始,并且继续到起始密码子,但不包括起始密码子。3’UTR在终止密码子之后立即开始,并且继续直到转录终止信号。越来越多的证据表明,UTR在核酸分子的稳定性和翻译方面起调节作用。可将UTR的调节特征并入如本文所述的任何载体、组合物、试剂盒或方法中,以增强抗体(例如,特异性结合到VEGF的抗体)、抗原结合抗体片段((例如,特异性结合到VEGF的抗原结合片段)或可溶性VEGF受体的表达。
天然的5’UTR包括在翻译起始中起作用的序列。它们携带类似Kozak序列的签名,通常已知所述签名参与核糖体启动许多基因的翻译的过程。Kozak序列具有共有序列CCR(A/G)CCAUGG,其中R为嘌呤(A或G),起始密码子(AUG)上游的三个碱基,并且起始密码子后接另一个“G”。还已知5’UTR形成参与延伸因子结合的二级结构。
在一些实施方案中,5’UTR包括在本文所述的任何载体中。5’UTR的非限制性实例包括来自以下基因的那些:白蛋白、血清淀粉样蛋白A、载脂蛋白A/B/E、转铁蛋白、甲胎蛋白、促红细胞生成素和因子VIII,可用于增强诸如mRNA的核酸分子的表达。
在一些实施方案中,来自由耳蜗中的细胞转录的mRNA的5’UTR可包括在本文所述的任何载体、组合物、试剂盒和方法中。
已知3’UTR中嵌入了许多段腺苷和尿苷(呈RNA形式)或胸苷(呈DNA形式)。这些富含AU的签名在具有高周转率的基因中特别普遍。基于其序列特征和功能特性,富含AU的元件(ARE)可分为三类(Chen等人,Mol.Cell.Biol.15:5777-5788,1995;Chen等人,Mol.CellBiol.15:2010-2018,1995):I类ARE在富含U的区域内含有若干个分散的AUUUA基序的拷贝。例如,c-Myc和MyoD mRNA含有I类ARE。II类ARE具有两个或更多个重叠的UUAUUUA(U/A)(U/A)九聚物。GM-CSF和TNF-α mRNA是含有II类ARE的实例。III类ARE的定义不太明确。这些富含U的区域并不含有AUUUA基序。这些类别的两个经过充分研究的实例是c-Jun和肌细胞生成素mRNA。
已知大多数结合到ARE的蛋白质使信使不稳定,而ELAV家族的成员(最著名的是HuR)已被证明增加mRNA的稳定性。HuR结合到所有三个类别的ARE。将HuR特异性结合位点工程化到核酸分子的3’UTR内将导致HuR结合,并因此稳定体内信息。
在一些实施方案中,3’UTR ARE的引入、去除或修饰可用于调节编码感兴趣的蛋白质(例如,本文所述的任何抗体、本文所述的任何抗原结合抗体片段或本文所述的任何可溶性VEGF受体)的mRNA的稳定性。在其他实施方案中,ARE可被去除或突变以增加胞内稳定性,并因此增加感兴趣的蛋白质(例如,本文所述的任何抗体、本文所述的任何抗原结合抗体片段或本文所述的任何可溶性VEGF受体)的翻译和产生。
在其他实施方案中,非ARE序列可并入5’或3’UTR中。在一些实施方案中,内含子或内含子序列的一部分可并入本文提供的任何载体、组合物、试剂盒和方法中的多核苷酸的侧翼区中。内含子序列的并入可增加蛋白质产生以及mRNA水平。
缩短哺乳动物中抗体、抗原结合抗体片段或可溶性VEGF受体的半衰期的Fc突变
本文所述的任何抗体、抗原结合抗体片段或可溶性VEGF受体可包括Fc区中的一个或多个(例如,两个、三个、四个,五个,六个,七个,八个,九个或十个)氨基酸置换,例如,与在其他方面相同的抗体、抗原结合抗体片段或可溶性VEGF受体(不包括Fc区中的一个或多个氨基酸置换中的至少一个)的半衰期相比,所述氨基酸置换缩短哺乳动物中抗体、抗原结合抗体片段或可溶VEGF受体的半衰期。用于测定哺乳动物中抗体、抗原结合抗体片段或可溶性VEGF受体的半衰期的方法在本领域中是众所周知的。
Fc突变中可缩短抗体、抗原结合抗体片段或可溶性VEGF受体的半衰期的点突变的非限制性实例描述于Leabman等人,MAbs5(6):896-903,2013中。
方法
本文还提供了包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中的方法,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体重链可变结构域(例如,本文所述的任何示例性抗体重链可变结构域)的多肽和包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体轻链可变结构域(例如,本文所述的任何示例性抗体轻链可变结构域)的多肽;(b)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗原结合抗体片段(例如,scFv)(例如,本文所述的任何示例性抗原结合抗体片段)的多肽,或(c)可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体(例如,本文所述的任何可溶性VEGF受体)。本文还提供了用于提高对其有需要的哺乳动物的内耳中的抗体或抗原结合抗体片段的水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽的抗体重链可变结构域(例如,本文所述的任何抗体重链可变结构域)的多肽和包括可操作地连接到信号肽的抗体轻链可变结构域(例如,本文所述的任何抗体轻链可变结构域)的多肽;或(b)包括可操作地连接到信号肽(例如,本文所述的任何示例性信号肽)的抗原结合抗体片段(例如,scFv)(例如,本文所述的任何示例性抗原结合抗体片段)的多肽;其中引入使得例如,与施用之前哺乳动物的内耳中的抗体或抗原结合抗体片段的水平相比,哺乳动物的内耳中的抗体或抗原结合抗体片段的水平增加(例如,增加1%至400%(或本文所述的此范围的任何子范围)、或增加至少1%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少150%、至少200%、至少250%、至少300%、至少350%、至少400%、至少450%、至少500%、至少550%、至少600%、至少650%、至少700%、至少750%、至少800%、至少850%、至少900%、至少950%、至少1000%、至少1100%、至少1200%、至少1300%、至少1400%、至少1500%、至少1600%、至少1700%、至少1800%、至少1900%或至少2000%)。
本文还提供了用于提高可溶性VEGF受体的水平的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体的核苷酸序列;其中引入使得例如,与施用之前哺乳动物的内耳中的可溶性VEGF受体的水平相比,哺乳动物的内耳中的可溶性VEGF受体的水平增加(例如,增加1%至400%(或本文所述的此范围的任何子范围)、或增加至少1%、至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少150%、至少200%、至少250%、至少300%、至少350%、至少400%、至少450%、至少500%、至少550%、至少600%、至少650%、至少700%、至少750%、至少800%、至少850%、至少900%、至少950%、至少1000%、至少1100%、至少1200%、至少1300%、至少1400%、至少1500%、至少1600%、至少1700%、至少1800%、至少1900%或至少2000%)。
本文还提供了用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体重链可变结构域(例如,例如,本文所述的任何抗体重链可变结构域)的多肽和包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体轻链可变结构域(例如,本文所述的任何抗体轻链可变结构域)的多肽;(b)包括连接到信号肽(例如,本文所述的任何信号肽)的抗原结合抗体片段(例如,本文所述的任何示例性抗原结合抗体片段)的多肽;或(c)可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体(例如,本文所述的任何可溶性VEGR受体),其中引入使得哺乳动物中的内耳病症得到治疗。在一些实施方案中,对内耳病症的治疗使得与引入之前相比,引入后哺乳动物中内耳病症的症状的严重程度、频率或数量减少(例如,减少1%至100%,或本文所述的此范围的任何子范围)。在一些实施方案中,对任何内耳病症的治疗使得与引入之前相比,引入后哺乳动物的听力(例如,听力的一个或多个指标)增加(例如,增加1%至400%,或本文所述的此范围的任何子范围)。
在任何这些方法的一些实施方案中,抗体或抗原结合抗体片段或可溶性VEGF受体特异性结合到血管内皮生长因子(VEGF)(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种,例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种)。在任何这些方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。在一些实施方案中,其中AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。在任何这些方法的一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。在任何这些方法的一些实施方案中,哺乳动物为人。在任何这些方法的一些实施方案中,哺乳动物(例如,人)已被鉴定为患有内耳病症。在任何这些方法的一些实施方案中,哺乳动物(例如,人)先前已被诊断为患有内耳病症。在任何这些方法的一些实施方案中,载体包括编码包括抗体重链和抗体轻链的多肽的核酸序列。在任何这些方法的一些实施方案中,载体包括编码抗原结合抗体片段的核酸序列。在任何这些方法的一些实施方案中,载体包括编码可操作地连接到信号肽的可溶性VEGF受体的核酸序列。
本文还提供了用于降低对其有需要的哺乳动物的内耳中的VEGF活性(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种,例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种)的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体重链可变结构域(例如,本文所述的任何抗体重链可变结构域)的多肽和包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体轻链可变结构域(例如,本文所述的任何抗体轻链可变结构域)的多肽;(b)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗原结合抗体片段(例如,Fab或scFv)(例如,本文所述的任何抗原结合抗体片段)的多肽;或(c)可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体(例如,本文所述的任何可溶性VEGF受体),其中(a)的多肽包括特异性结合到VEGF并降低VEGF活性的抗体,(b)的多肽包括特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段,或(c)的可溶性VEGF受体特异性结合到一种或多种VEGF蛋白并降低一种或多种VEGF蛋白的活性;并且其中引入使得,与引入之前哺乳动物中的VEGF活性相比,哺乳动物的内耳中的VEGF活性(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种的活性,例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种的活性)降低(降低1%至100%,或本文所述的此范围的任何子范围)。可使用本文所述的任何示例性方法来检测哺乳动物中的VEGF活性的降低。
本文还提供了治疗哺乳动物的内耳中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病(NF2)的方法,所述方法包括:将治疗有效量的AAV载体引入哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:(a)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体重链可变结构域(例如,本文所述的任何抗体重链可变结构域)的多肽和包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗体轻链可变结构域(例如,本文所述的任何抗体轻链可变结构域)的多肽;(b)包括可操作地连接到信号肽(例如,本文所述的任何信号肽)的抗原结合抗体片段(例如,Fab或scFv)(例如,本文所述的任何抗原结合抗体片段)的多肽;或(c)可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体(例如,本文所述的任何可溶性VEGF受体);其中(a)的多肽编码特异性结合到VEGF(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种,例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种)并降低VEGF活性的抗体,(b)的多肽编码特异性结合到VEGF(例如,VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种,例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种)并降低VEGF活性的抗原结合抗体片段,或(c)的可溶性VEGF受体特异性结合到VEGF-A、VEGF-B、VEGF-C和VEGF-D中的一种或多种(例如,人VEGF-A、人VEGF-B、人VEGF-C和人VEGF-D中的一种或多种),并且其中引入使得哺乳动物的内耳中的听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病(NF2)得到治疗。如本文所述,可通过观察到,例如与引入步骤之前相比,哺乳动物中听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病的一种或多种症状的数量、严重程度或频率分别减少(例如,减少1%至100%,或本文所述的此范围的任何子范围)来检测听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病中的一种或多种的成功治疗。
在任何这些方法的一些实施方案中,载体包括编码以下多肽的核酸序列,所述多肽编码抗体重链可变结构域(例如,本文所述的任何抗体重链)和抗体轻链可变结构域(例如,本文所述的任何抗体轻链可变结构域)。在任何这些方法的一些实施方案中,载体包括编码以下多肽的核酸序列,所述多肽包括抗原结合抗体片段(例如,本文所述的任何抗原结合抗体片段)。在任何这些方法的一些实施方案中,载体包括编码可操作地连接到信号肽(例如,本文所述的任何信号肽)的可溶性VEGF受体(例如,本文所述的任何可溶性VEGF受体)的核酸序列。在任何这些方法的一些实施方案中,AAV载体还包括可操作地连接到编码抗体或抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。在一些实施方案中,AAV载体包括启动子,其中启动子选自由以下组成的组:诱导型启动子、组成型启动子或组织特异性启动子。在一些实施方案中,AAV载体还包括多聚腺苷酸化信号序列。在任何这些方法的一些实施方案中,哺乳动物为人。在任何这些方法的一些实施方案中,哺乳动物(例如,人)已被鉴定为患有内耳病症。在任何这些方法的一些实施方案中,哺乳动物(例如,人)先前已被诊断为患有内耳病症。在任何这些方法的一些实施方案中,哺乳动物(例如,人)已被鉴定或诊断为患有药物性听力损失。在任何这些方法的一些实施方案中,哺乳动物(例如,人)已被鉴定或诊断为患有年龄相关性听力损失。
在一些实施方案中,抗体或其抗原结合片段包括有包含一个或多个点突变的Fc区,所述点突变降低抗体或抗原结合抗体片段在体内的半衰期。
在任何这些方法的一些实施方案中,将两次或更多次剂量的本文所述的任何腺相关病毒(AAV)载体引入或施用到哺乳动物或受试者的内耳中。任何这些方法的一些实施方案可包括将第一剂量的腺相关病毒(AAV)载体引入或施用到哺乳动物或受试者的内耳中,在引入或施用第一剂量后评估哺乳动物或受试者的听力功能,并且向发现在正常范围内没有听力功能(例如,如使用本领域已知的任何听力测试所确定的)的哺乳动物或受试者的内耳中施用额外剂量的腺相关病毒(AAV)载体。
在本文所述的任何方法的一些实施方案中,可配制腺相关病毒(AAV)载体用于耳蜗内施用。在本文所述的任何方法的一些实施方案中,可通过耳蜗内施用或局部施用来施用本文所述的腺相关病毒(AAV)载体。在本文所述的任何方法的一些实施方案中,通过使用医疗装置(例如,本文所述的任何示例性医疗装置)来施用腺相关病毒(AAV)载体。
在一些实施方案中,可使用本文所述或本领域已知的任何方法来进行耳蜗内施用。例如,可使用以下外科手术技术将腺相关病毒(AAV)载体施用或引入到耳蜗中:首先使用0度、2.5mm的刚性内窥镜进行可视化,清理外耳道并使用圆刀清晰划定约5mm的鼓膜瓣。然后,将鼓膜瓣抬高,并向后进入中耳。识别并分离鼓索神经,并使用刮匙去除缝骨(scutalbone),从而暴露圆窗膜。为了增强所施用或引入的腺相关病毒(AAV)载体的顶端分布,可使用手术激光在椭圆窗口中做一个2mm的开窗,以允许腺相关病毒(AAV)载体的经圆窗膜输注过程中的外淋巴移位。然后,准备好微输注装置并带入手术区域。将装置移动到圆窗,并且将尖端放置在骨状圆窗悬垂物内,以允许微针穿透膜。接合踏板以允许平稳、稳定地输注腺相关病毒(AAV)载体。然后,取出装置并使用明胶泡沫贴片密封圆窗和镫骨足板。
在本文所述的任何方法的一些实施方案中,受试者或哺乳动物为啮齿动物、非人灵长类动物或人。在本文所述的任何方法的一些实施方案中,受试者或哺乳动物为成人、青少年、少年、儿童、学步儿童、婴儿或新生儿。在本文所述的任何方法的一些实施方案中,受试者或哺乳动物为1-5、1-10、1-20、1-30、1-40、1-50、1-60、1-70、1-80、1-90、1-100、1-110、2-5、2-10、10-20、20-30、30-40、40-50、50-60、60-70、70-80、80-90、90-100、100-110、10-30、10-40、10-50、10-60、10-70、10-80、10-90、10-100、10-110、20-40、20-50、20-60、20-70、20-80、20-90、20-100、20-110、30-50、30-60、30-70、30-80、30-90、30-100、40-60、40-70、40-80、40-90、40-100、50-70、50-80、50-90、50-100、60-80、60-90、60-100、70-90、70-100、70-110、80-100、80-110或90-110岁。在本文所述的任何方法的一些实施方案中,受试者或哺乳动物为1、2、3、4、5、6、7、8、9、10或11个月大。
在本文所述的任何方法的一些实施方案中,受试者或哺乳动物患有听力损失(例如,药物性听力损失)或有发展其的风险。
在本文所述的任何方法的一些实施方案中,受试者或哺乳动物先前已被鉴定为具有VEGF基因突变。
在一些实施方案中,可使用本领域已知的任何常规功能性听力测试确定受试者中的听力损失(例如,药物性听力损失)的成功治疗。功能性听力测试的非限制性实例是各种类型的听力测定(例如,纯音测试、语音测试、中耳测试、听觉脑干反应和耳声发射)。
用于将本文所述的任何腺相关病毒(AAV)载体引入哺乳动物细胞中的方法在本领域中是已知的(例如,通过脂质转染或通过使用病毒载体,例如,本文所述的任何病毒载体)。
药物组合物和试剂盒
在一些实施方案中,本文所述的任何组合物还可包括促进核酸或本文所述的任何载体进入哺乳动物细胞中的一种或多种剂(例如,脂质体或阳离子脂质)。在一些实施方案中,可使用天然和/或合成聚合物来配制本文所述的任何载体。可包括在本文所述的任何组合物中的聚合物的非限制性实例可包括但不限于DYNAMIC (Arrowhead Research Corp.,Pasadena,Calif.)、来自Mirus Bio(Madison,Wis.)和RocheMadison(Madison,Wis.)的制剂、PhaseRX聚合物制剂诸如但不限于SMARTT POLYMER(PhaseRX,Seattle,Wash.)、DMRI/DOPE、泊洛沙姆、来自Vical(SanDiego,Calif.)的佐剂、壳聚糖、来自Calando Pharmaceuticals(Pasadena,Calif.)的环糊精、树状聚合物和聚(乳酸-共-乙醇酸)(PLGA)聚合物、RONDELTM(RNAi/寡核苷酸纳米颗粒递送)聚合物(Arrowhead Research Corporation,Pasadena,Calif.)和pH响应性共嵌段聚合物诸如但不限于PhaseRX(Seattle,Wash.)生产的那些。这些聚合物中的许多已证明了在体内将寡核苷酸递送至哺乳动物细胞中的功效(参见,例如,deFougerolles,Human Gene Ther.19:125-132,2008;Rozema等人,Proc.Natl.Acad.Sci.U.S.A.104:12982-12887,2007;Rozema等人,Proc.Natl.Acad.Sci.U.S.A.104:12982-12887,2007;Hu-Lieskovan等人,Cancer Res.65:8984-8982,2005;Heidel等人,Proc.Natl.Acad.Sci.U.S.A.104:5715-5721,2007)。
本文所述的任何组合物可以是例如药物组合物。药物组合物可包括本文所述的任何组合物和一种或多种药学上或生理学上可接受的载剂、稀释剂或赋形剂。此类组合物可包含一种或多种缓冲剂,诸如中性缓冲盐水、磷酸盐缓冲盐水等;一种或多种碳水化合物,诸如葡萄糖、甘露糖、蔗糖和葡聚糖;甘露醇;一种或多种蛋白质、多肽或氨基酸,诸如甘氨酸;一种或多种抗氧化剂;一种或多种螯合剂,诸如EDTA或谷胱甘肽;和/或一种或多种防腐剂。
在一些实施方案中,组合物包括药学上可接受的载剂(例如,磷酸盐缓冲盐水、盐水或抑菌水)。当配制时,将以与剂量制剂相容的方式且以治疗有效量施用溶液。制剂以诸如可注射溶液、可注射凝胶、药物释放胶囊等多种剂型容易地施用。
如本文所用,术语“药学上可接受的载剂”包括与药物施用相容的溶剂、分散介质、包衣、抗细菌剂、抗真菌剂等。补充性有效化合物也可并入本文所述的任何组合物中。
在一些实施方案中,本文所述的任何组合物的单剂量可包括例如,缓冲溶液中的至少1ng、至少2ng、至少4ng、约6ng、约8ng、至少10ng、至少20ng、至少30ng、至少40ng、至少50ng、至少60ng、至少70ng、至少80ng、至少90ng、至少100ng、至少200ng、至少300ng、至少400ng、至少500ng、至少1μg、至少2μg、至少4μg、至少6μg、至少8μg、至少10μg、至少12μg、至少14μg、至少16μg、至少18μg、至少20μg、至少22μg、至少24μg、至少26μg、至少28μg、至少30μg、至少32μg、至少34μg、至少36μg、至少38μg、至少40μg、至少42μg、至少44μg、至少46μg、至少48μg、至少50μg、至少52μg、至少54μg、至少56μg、至少58μg、至少60μg、至少62μg、至少64μg、至少66μg、至少68μg、至少70μg、至少72μg、至少74μg、至少76μg、至少78μg、至少80μg、至少82μg、至少84μg、至少86μg、至少88μg、至少90μg、至少92μg、至少94μg、至少96μg、至少98μg、至少100μg、至少102μg、至少104μg、至少106μg、至少108μg、至少110μg、至少112μg、至少114μg、至少116μg、至少118μg、至少120μg、至少122μg、至少124μg、至少126μg、至少128μg、至少130μg、至少132μg、至少134μg、至少136μg、至少138μg、至少140μg、至少142μg、至少144μg、至少146μg、至少148μg、至少150μg、至少152μg、至少154μg、至少156μg、至少158μg、至少160μg、至少162μg、至少164μg、至少166μg、至少168μg、至少170μg、至少172μg、至少174μg、至少176μg、至少178μg、至少180μg、至少182μg、至少184μg、至少186μg、至少188μg、至少190μg、至少192μg、至少194μg、至少196μg、至少198μg或至少200μg的至少两种不同载体的总和量。
本文提供的组合物可例如被配制成与其预期的施用途径相容。预期施用途径的非限制性实例为局部施用(例如,耳蜗内施用)。
在一些实施方案中,治疗组合物被配制成包括脂质纳米颗粒。在一些实施方案中,治疗组合物被配制成包括聚合物纳米颗粒。在一些实施方案中,治疗组合物被配制成包含微环DNA。在一些实施方案中,治疗组合物被配制成包含CELiD DNA。在一些实施方案中,治疗组合物被配制成包含合成外淋巴液。示例性合成外淋巴液包括20-200mM NaCl;1-5mMKCl;0.1-10mM CaCl2;1-10mM葡萄糖;2-50mM HEPES,具有的pH在约6和约9之间。
还提供了包括本文所述的任何组合物的试剂盒。在一些实施方案中,试剂盒可包括固体组合物(例如,包括本文所述的至少两种不同载体的冻干组合物)和用于溶解冻干组合物的液体。在一些实施方案中,试剂盒可包括预装载的注射器,其包含本文所述的任何组合物。
在一些实施方案中,试剂盒包括包含本文所述的任何组合物(例如,配制成水性组合物,例如,水性药物组合物)的小瓶。
在一些实施方案中,试剂盒可包括用于进行本文所述的任何方法的说明书。
装置和手术方法
本文提供了用于治疗听力损失(例如,听神经瘤/前庭神经鞘瘤和相关的听力损失)的治疗性递送体系。在一方面,治疗性递送体系包括i)能够在对其有需要的人受试者的内耳的圆窗膜中产生一个或多个切口的医疗装置,以及ii)有效剂量的组合物(例如,本文所述的任何组合物)。在一些实施方案中,医疗装置包括多个微针。
本文还提供了用于治疗听力损失(例如,听神经瘤/前庭神经鞘瘤和相关的听力损失)的手术方法。在一些实施方案中,所述方法包括以下步骤:在第一切口点处将第一切口引入人受试者的耳蜗中;并且耳蜗内施用治疗有效量的本文提供的任何组合物。在一些实施方案中,在第一切口点处将组合物施用于受试者。在一些实施方案中,将组合物施用于受试者的第一切口内或通过第一切口。
在本文所述的任何方法的一些实施方案中,将本文所述的任何组合物施用于受试者的耳蜗椭圆形窗膜内或通过耳蜗椭圆形窗膜。在本文所述的任何方法的一些实施方案中,将本文所述的任何组合物施用于受试者的耳蜗圆窗膜内或通过耳蜗圆窗膜。在本文所述的任何方法的一些实施方案中,使用能够在圆窗膜中产生多个切口的医疗装置来施用组合物。在一些实施方案中,医疗装置包括多个微针。在一些实施方案中,医疗装置包括总体上圆形的第一方面的多个微针,其中每个微针具有至少约10微米的直径。在一些实施方案中,医疗装置包括基座和/或能够容纳组合物的储存器。在一些实施方案中,医疗装置包括多个空心微针,其分别包括能够转移组合物的腔。在一些实施方案中,医疗装置包括用于产生至少部分真空的装置。
通过参考以下实验实施例进一步详细描述本发明。除非另外指明,否则这些实施例仅出于说明的目的而提供并且不意图进行限制。因此,本发明决不应解释为限于以下实施例,而应解释为涵盖由于本文提供的教导而变得显而易见的任何和所有变型。
无需进一步描述,相信本领域普通技术人员可以使用前述的描述和以下说明性实施例,制备和利用本发明的组合物并实践所要求保护的方法。以下工作实施例特别指出本发明的各个方面,并且不应当被解释为以任何方式限制本公开的其余部分。
实施例
实施例1.病毒载体的构建
生成四种不同的重组AAV载体,并且在图1A-D中示出。
图1A中的载体为4474bp(SEQ ID NO:35)的示例性AAV载体,其包括以下5’至3’方向的子序列:
由SEQ ID NO:39和43中的每个编码的IL-2信号序列为MYRMQLLSCIALSLALVTNS(SEQ ID NO:49)。由SEQ ID NO:42编码的T2A序列为GSGEGRGSLLTCGDVEENPGP(SEQ ID NO:50)。SEQ ID NO:40编码贝伐单抗的重链(SEQ ID NO:6)。SEQ ID NO:44编码贝伐单抗的轻链(SEQ ID NO:5)。SEQ ID NO:44中的最后三个核苷酸为终止密码子。
图1B中的载体为3814bp(SEQ ID NO:51)的示例性AAV载体,其包括以下5’至3’方向的子序列:
由SEQ ID NO:39和43中的每个编码的IL-2信号序列为MYRMQLLSCIALSLALVTNS(SEQ ID NO:49)。由SEQ ID NO:42编,码的T2A序列为GSGEGRGSLLTCGDVEENPGP(SEQ ID NO:50)。SEQ ID NO:52编码兰尼单抗的重链(EVQLVESGGGLVQPGGSLRLSCAASGYDFTHYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPYYYGTSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTGK;SEQ ID NO:54)。SEQ ID NO:53编码贝伐单抗的轻链(SEQ ID NO:7)。SEQ ID NO:53中的最后三个核苷酸为终止密码子。
图1C为4573bp(SEQ ID NO:55)的示例性AAV载体,其包括以下5’至3’方向的子序列:
由SEQ ID NO:39和43中的每个编码的IL-2信号序列为MYR MQLLSCIALSLALVTNS(SEQ ID NO:49)。由SEQ ID NO:42编,码的T2A序列为GSGEGRGSLLTCGDVEENPGP(SEQ ID NO:50)。SEQ ID NO:52编码兰尼单抗的重链(SEQ ID NO:54)。SEQ ID NO:56编码贝伐单抗的轻链(SEQ ID NO:7)。SEQ ID NO:58编,码TurboGFP(MESDESGLPAMEIECRITGTLNGVEFELVGGGEGTPEQGRMTNKMKSTKGALTFSPYLLSHVMGYGFYHFGTYPSGYENPFLHAINNGGYTNTRIEKYEDGGVLHVSFSYRYEAGRVIGDFKVMGTGFPEDSVIFTDKIIRSNATVEHLHPMGDNDLDGSFTRTFSLRDGGYYSSVVDSHMHFKSAIHPSILQNGGPMFAFRRVEEDHSNTELGIVEYQHAFKTPDADAGEE;SEQ ID NO:59)。SEQ ID NO:58中的最后三个核苷酸为终止密码子。
图1D为3631bp(SEQ ID NO:60)的示例性AAV载体,其包括以下5’至3’方向的子序列:
由SEQ ID NO:39编码的IL-2信号序列为MYRMQLLSCIALSLALVTNS(SEQ ID NO:49)。SEQ ID NO:61编码阿柏西普(SEQ ID NO:12)。SEQ ID NO:61中的最后三个核苷酸为终止密码子。
为了测定由图1A-1C中示出的AAV载体驱动的蛋白质表达,将HEK293FT细胞在24孔板的孔中以7x 104个细胞/孔(每孔400μL)接种过夜。使用Jetprime Polypus试剂用图1A-1D中示出的AAV载体以约800ng转染HEK293FT细胞(用于生成图2的泳道2-5和10-13中的数据)。还在2μM依托泊苷的存在下将HEK293FT细胞在96孔板的孔中以4x 104个细胞/孔(每孔50μL)接种六小时(用于生成图2的泳道6-8和14-16中的数据)。将图1A中示出的AAV载体加入到培养基中,其中感染复数(MOI)为7.5x 104、2.2x 105或5.5x 105。在处理后72小时从孔中收获上清液,并且在还原(图2的泳道2-8)和非还原条件(图2的泳道10-16)下将其装载到4%-12%的Bolt蛋白凝胶上。将检测Fab区的抗兰尼单抗抗体被用作第一抗体,并且将抗人IgG用作第二抗体。
如图2所示,在泳道3和6-8中检测到重链和轻链兰尼单抗,并且在泳道11和14-16中检测到完整的兰尼单抗(异二聚体)。
实施例2.抗人VEGF单克隆抗体的结合活性
进行了一系列实验,以测定用图1A所示的AAV载体转染后在HEK293FT细胞中产生的贝伐单抗的结合活性。进行第一组对照实验,以使用重组人VEGF作为结合剂校准等离子体表面共振仪器(使用在缓冲液或在条件培养基中(分别为图3A和图3B)的小鼠抗人VEGF单克隆抗体(抗hVEGF MmAb;R&D,MAB293-100)。进行第二组实验,以测定对照条件培养基和用图1A所示的AAV载体转染后的HEK293TF细胞的条件培养基的人VEGF结合活性(分别为图4A和4B)。
通过在1x动力学缓冲液(Fortebio,18-1105)中稀释1∶10在384孔样品板中制备用图1A所示的AAV载体转染的HEK293TF细胞培养基或条件培养基中的样品贝伐单抗。以10μg/mL的浓度稀释抗Anti-hVEGF MmAb(R&D,MAB293-100)作为阳性对照。将捕获剂,重组人VEGF(R&D,293-VE-010)以1∶2系列稀释比从200nM稀释至3.125nM。
在HTX生物传感器仪器中的1x动力学缓冲液中测量条件培养基样品与小鼠抗人VEGF抗体(R&D)样品的结合亲和力。结合特征和KD值由分析软件DataAnalysis HT10.0生成。如图3A-B所示,缓冲液中抗hVEGF MmAb的KD为<1.0x 10-12M,并且条件培养基中的抗hVEGF MmAb为<1.0x 10-12M。条件培养基本身没有结合亲和力且强度非常低(仅背景信号)(图4A)。相比之下,包括由用图1A所示的AAV载体转染的HEK293TF细胞产生的贝伐单抗的条件培养基具有高结合亲和力,但强度较低(图4B;KD<1.0x 10-12M)。图4C示出了在装载样品和相应的KD、KD误差、平衡缔合常数(ka)以及解离(kdis)和kdis误差的表格。
总之,抗hVEGF小鼠抗体(R&D)示出了高结合亲和力(KD低于1.0x 10-12M的可测量范围)。贝伐单抗条件培养基样品示出高结合亲和力(KD低于可测量范围)。从对照条件培养基样品的结合数据中不能推断出KD值。
总之,这些数据示出本文提供的AAV载体可导致抗VEGF抗体的表达和分泌,并且可用于在哺乳动物的内耳中表达抗VEGF抗体。
其他实施方案
应当理解,尽管已结合本发明的详细描述对本发明进行了描述,但是前述描述旨在说明,并不限制由所附权利要求的范围限定的本发明的范围。其他方面、优点和修改在以下权利要求的范围内。
本文提及的所有出版物、专利申请、专利和其他参考文献以引用方式整体并入。在有冲突的情况下,将以本说明书(包括定义)为准。材料、方法和实施例的章节标题和任何描述仅是说明性的而不是旨在限制。
序列表
<110> 阿库斯股份有限公司(Akouos LLC)
McKenna, Michael
<120> AAV介导的治疗性抗体到内耳的递送
<130> 44628-0019WO1
<150> US 62/607,665
<151> 2017-12-19
<160> 61
<170> PatentIn version 3.5
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<223> 信号肽
<400> 10
Met Lys Tyr Leu Leu Pro Thr Ala Ala Ala Gly Leu Leu Leu Leu Ala
1 5 10 15
Ala Gln Pro Ala Met Ala
20
<210> 11
<211> 17
<212> DNA
<213> 人(Human)
<400> 11
aaataaaata cgaaatg 17
<210> 12
<211> 431
<212> PRT
<213> 人工(Artificial)
<220>
<223> 阿柏西普
<400> 12
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
420 425 430
<210> 13
<211> 206
<212> PRT
<213> 人(Human)
<400> 13
Ala Pro Met Ala Glu Gly Gly Gly Gln Asn His His Glu Val Val Lys
1 5 10 15
Phe Met Asp Val Tyr Gln Arg Ser Tyr Cys His Pro Ile Glu Thr Leu
20 25 30
Val Asp Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys
35 40 45
Pro Ser Cys Val Pro Leu Met Arg Cys Gly Gly Cys Cys Asn Asp Glu
50 55 60
Gly Leu Glu Cys Val Pro Thr Glu Glu Ser Asn Ile Thr Met Gln Ile
65 70 75 80
Met Arg Ile Lys Pro His Gln Gly Gln His Ile Gly Glu Met Ser Phe
85 90 95
Leu Gln His Asn Lys Cys Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg
100 105 110
Gln Glu Lys Lys Ser Val Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys
115 120 125
Arg Lys Lys Ser Arg Tyr Lys Ser Trp Ser Val Tyr Val Gly Ala Arg
130 135 140
Cys Cys Leu Met Pro Trp Ser Leu Pro Gly Pro His Pro Cys Gly Pro
145 150 155 160
Cys Ser Glu Arg Arg Lys His Leu Phe Val Gln Asp Pro Gln Thr Cys
165 170 175
Lys Cys Ser Cys Lys Asn Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu
180 185 190
Glu Leu Asn Glu Arg Thr Cys Arg Cys Asp Lys Pro Arg Arg
195 200 205
<210> 14
<211> 186
<212> PRT
<213> 人(Human)
<400> 14
Pro Val Ser Gln Pro Asp Ala Pro Gly His Gln Arg Lys Val Val Ser
1 5 10 15
Trp Ile Asp Val Tyr Thr Arg Ala Thr Cys Gln Pro Arg Glu Val Val
20 25 30
Val Pro Leu Thr Val Glu Leu Met Gly Thr Val Ala Lys Gln Leu Val
35 40 45
Pro Ser Cys Val Thr Val Gln Arg Cys Gly Gly Cys Cys Pro Asp Asp
50 55 60
Gly Leu Glu Cys Val Pro Thr Gly Gln His Gln Val Arg Met Gln Ile
65 70 75 80
Leu Met Ile Arg Tyr Pro Ser Ser Gln Leu Gly Glu Met Ser Leu Glu
85 90 95
Glu His Ser Gln Cys Glu Cys Arg Pro Lys Lys Lys Asp Ser Ala Val
100 105 110
Lys Pro Asp Arg Ala Ala Thr Pro His His Arg Pro Gln Pro Arg Ser
115 120 125
Val Pro Gly Trp Asp Ser Ala Pro Gly Ala Pro Ser Pro Ala Asp Ile
130 135 140
Thr His Pro Thr Pro Ala Pro Gly Pro Ser Ala His Ala Ala Pro Ser
145 150 155 160
Thr Thr Ser Ala Leu Thr Pro Gly Pro Ala Ala Ala Ala Ala Asp Ala
165 170 175
Ala Ala Ser Ser Val Ala Lys Gly Gly Ala
180 185
<210> 15
<211> 116
<212> PRT
<213> 人(Human)
<400> 15
Ala His Tyr Asn Thr Glu Ile Leu Lys Ser Ile Asp Asn Glu Trp Arg
1 5 10 15
Lys Thr Gln Cys Met Pro Arg Glu Val Cys Ile Asp Val Gly Lys Glu
20 25 30
Phe Gly Val Ala Thr Asn Thr Phe Phe Lys Pro Pro Cys Val Ser Val
35 40 45
Tyr Arg Cys Gly Gly Cys Cys Asn Ser Glu Gly Leu Gln Cys Met Asn
50 55 60
Thr Ser Thr Ser Tyr Leu Ser Lys Thr Leu Phe Glu Ile Thr Val Pro
65 70 75 80
Leu Ser Gln Gly Pro Lys Pro Val Thr Ile Ser Phe Ala Asn His Thr
85 90 95
Ser Cys Arg Cys Met Ser Lys Leu Asp Val Tyr Arg Gln Val His Ser
100 105 110
Ile Ile Arg Arg
115
<210> 16
<211> 117
<212> PRT
<213> 人(Human)
<400> 16
Phe Ala Ala Thr Phe Tyr Asp Ile Glu Thr Leu Lys Val Ile Asp Glu
1 5 10 15
Glu Trp Gln Arg Thr Gln Cys Ser Pro Arg Glu Thr Cys Val Glu Val
20 25 30
Ala Ser Glu Leu Gly Lys Ser Thr Asn Thr Phe Phe Lys Pro Pro Cys
35 40 45
Val Asn Val Phe Arg Cys Gly Gly Cys Cys Asn Glu Glu Ser Leu Ile
50 55 60
Cys Met Asn Thr Ser Thr Ser Tyr Ile Ser Lys Gln Leu Phe Glu Ile
65 70 75 80
Ser Val Pro Leu Thr Ser Val Pro Glu Leu Val Pro Val Lys Val Ala
85 90 95
Asn His Thr Gly Cys Lys Cys Leu Pro Thr Ala Pro Arg His Pro Tyr
100 105 110
Ser Ile Ile Arg Arg
115
<210> 17
<211> 687
<212> PRT
<213> 人(Human)
<400> 17
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Thr Val
325 330 335
Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala Gly Lys Arg Ser
340 345 350
Tyr Arg Leu Ser Met Lys Val Lys Ala Phe Pro Ser Pro Glu Val Val
355 360 365
Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu
370 375 380
Thr Arg Gly Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala
385 390 395 400
Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys
405 410 415
Asn Leu Thr Ala Thr Leu Ile Val Asn Val Lys Pro Gln Ile Tyr Glu
420 425 430
Lys Ala Val Ser Ser Phe Pro Asp Pro Ala Leu Tyr Pro Leu Gly Ser
435 440 445
Arg Gln Ile Leu Thr Cys Thr Ala Tyr Gly Ile Pro Gln Pro Thr Ile
450 455 460
Lys Trp Phe Trp His Pro Cys Asn His Asn His Ser Glu Ala Arg Cys
465 470 475 480
Asp Phe Cys Ser Asn Asn Glu Glu Ser Phe Ile Leu Asp Ala Asp Ser
485 490 495
Asn Met Gly Asn Arg Ile Glu Ser Ile Thr Gln Arg Met Ala Ile Ile
500 505 510
Glu Gly Lys Asn Lys Met Ala Ser Thr Leu Val Val Ala Asp Ser Arg
515 520 525
Ile Ser Gly Ile Tyr Ile Cys Ile Ala Ser Asn Lys Val Gly Thr Val
530 535 540
Gly Arg Asn Ile Ser Phe Tyr Ile Thr Asp Val Pro Asn Gly Phe His
545 550 555 560
Val Asn Leu Glu Lys Met Pro Thr Glu Gly Glu Asp Leu Lys Leu Ser
565 570 575
Cys Thr Val Asn Lys Phe Leu Tyr Arg Asp Val Thr Trp Ile Leu Leu
580 585 590
Arg Thr Val Asn Asn Arg Thr Met His Tyr Ser Ile Ser Lys Gln Lys
595 600 605
Met Ala Ile Thr Lys Glu His Ser Ile Thr Leu Asn Leu Thr Ile Met
610 615 620
Asn Val Ser Leu Gln Asp Ser Gly Thr Tyr Ala Cys Arg Ala Arg Asn
625 630 635 640
Val Tyr Thr Gly Glu Glu Ile Leu Gln Lys Lys Glu Ile Thr Ile Arg
645 650 655
Gly Glu His Cys Asn Lys Lys Ala Val Phe Ser Arg Ile Ser Lys Phe
660 665 670
Lys Ser Thr Arg Asn Asp Cys Thr Thr Gln Ser Asn Val Lys His
675 680 685
<210> 18
<211> 2064
<212> DNA
<213> 人(Human)
<400> 18
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggttc aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120
cacatcatgc aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa 180
tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac taaatctgcc 240
tgtggaagaa atggcaaaca attctgcagt actttaacct tgaacacagc tcaagcaaac 300
cacactggct tctacagctg caaatatcta gctgtaccta cttcaaagaa gaaggaaaca 360
gaatctgcaa tctatatatt tattagtgat acaggtagac ctttcgtaga gatgtacagt 420
gaaatccccg aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt 480
acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt gatccctgat 540
ggaaaacgca taatctggga cagtagaaag ggcttcatca tatcaaatgc aacgtacaaa 600
gaaatagggc ttctgacctg tgaagcaaca gtcaatgggc atttgtataa gacaaactat 660
ctcacacatc gacaaaccaa tacaatcata gatgtccaaa taagcacacc acgcccagtc 720
aaattactta gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg 780
agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc cgtaaggcga 840
cgaattgacc aaagcaattc ccatgccaac atattctaca gtgttcttac tattgacaaa 900
atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagcattca tcactgtgaa acatcgaaaa 1020
cagcaggtgc ttgaaaccgt agctggcaag cggtcttacc ggctctctat gaaagtgaag 1080
gcatttccct cgccggaagt tgtatggtta aaagatgggt tacctgcgac tgagaaatct 1140
gctcgctatt tgactcgtgg ctactcgtta attatcaagg acgtaactga agaggatgca 1200
gggaattata caatcttgct gagcataaaa cagtcaaatg tgtttaaaaa cctcactgcc 1260
actctaattg tcaatgtgaa accccagatt tacgaaaagg ccgtgtcatc gtttccagac 1320
ccggctctct acccactggg cagcagacaa atcctgactt gtaccgcata tggtatccct 1380
caacctacaa tcaagtggtt ctggcacccc tgtaaccata atcattccga agcaaggtgt 1440
gacttttgtt ccaataatga agagtccttt atcctggatg ctgacagcaa catgggaaac 1500
agaattgaga gcatcactca gcgcatggca ataatagaag gaaagaataa gatggctagc 1560
accttggttg tggctgactc tagaatttct ggaatctaca tttgcatagc ttccaataaa 1620
gttgggactg tgggaagaaa cataagcttt tatatcacag atgtgccaaa tgggtttcat 1680
gttaacttgg aaaaaatgcc gacggaagga gaggacctga aactgtcttg cacagttaac 1740
aagttcttat acagagacgt tacttggatt ttactgcgga cagttaataa cagaacaatg 1800
cactacagta ttagcaagca aaaaatggcc atcactaagg agcactccat cactcttaat 1860
cttaccatca tgaatgtttc cctgcaagat tcaggcacct atgcctgcag agccaggaat 1920
gtatacacag gggaagaaat cctccagaag aaagaaatta caatcagagg tgagcactgc 1980
aacaaaaagg ctgttttctc tcggatctcc aaatttaaaa gcacaaggaa tgattgtacc 2040
acacaaagta atgtaaaaca ttaa 2064
<210> 19
<211> 733
<212> PRT
<213> 人(Human)
<400> 19
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Thr Val
325 330 335
Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala Gly Lys Arg Ser
340 345 350
Tyr Arg Leu Ser Met Lys Val Lys Ala Phe Pro Ser Pro Glu Val Val
355 360 365
Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu
370 375 380
Thr Arg Gly Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala
385 390 395 400
Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys
405 410 415
Asn Leu Thr Ala Thr Leu Ile Val Asn Val Lys Pro Gln Ile Tyr Glu
420 425 430
Lys Ala Val Ser Ser Phe Pro Asp Pro Ala Leu Tyr Pro Leu Gly Ser
435 440 445
Arg Gln Ile Leu Thr Cys Thr Ala Tyr Gly Ile Pro Gln Pro Thr Ile
450 455 460
Lys Trp Phe Trp His Pro Cys Asn His Asn His Ser Glu Ala Arg Cys
465 470 475 480
Asp Phe Cys Ser Asn Asn Glu Glu Ser Phe Ile Leu Asp Ala Asp Ser
485 490 495
Asn Met Gly Asn Arg Ile Glu Ser Ile Thr Gln Arg Met Ala Ile Ile
500 505 510
Glu Gly Lys Asn Lys Met Ala Ser Thr Leu Val Val Ala Asp Ser Arg
515 520 525
Ile Ser Gly Ile Tyr Ile Cys Ile Ala Ser Asn Lys Val Gly Thr Val
530 535 540
Gly Arg Asn Ile Ser Phe Tyr Ile Thr Asp Val Pro Asn Gly Phe His
545 550 555 560
Val Asn Leu Glu Lys Met Pro Thr Glu Gly Glu Asp Leu Lys Leu Ser
565 570 575
Cys Thr Val Asn Lys Phe Leu Tyr Arg Asp Val Thr Trp Ile Leu Leu
580 585 590
Arg Thr Val Asn Asn Arg Thr Met His Tyr Ser Ile Ser Lys Gln Lys
595 600 605
Met Ala Ile Thr Lys Glu His Ser Ile Thr Leu Asn Leu Thr Ile Met
610 615 620
Asn Val Ser Leu Gln Asp Ser Gly Thr Tyr Ala Cys Arg Ala Arg Asn
625 630 635 640
Val Tyr Thr Gly Glu Glu Ile Leu Gln Lys Lys Glu Ile Thr Ile Arg
645 650 655
Asp Gln Glu Ala Pro Tyr Leu Leu Arg Asn Leu Ser Asp His Thr Val
660 665 670
Ala Ile Ser Ser Ser Thr Thr Leu Asp Cys His Ala Asn Gly Val Pro
675 680 685
Glu Pro Gln Ile Thr Trp Phe Lys Asn Asn His Lys Ile Gln Gln Glu
690 695 700
Pro Glu Leu Tyr Thr Ser Thr Ser Pro Ser Ser Ser Ser Ser Ser Pro
705 710 715 720
Leu Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser
725 730
<210> 20
<211> 2202
<212> DNA
<213> 人(Human)
<400> 20
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggttc aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120
cacatcatgc aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa 180
tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac taaatctgcc 240
tgtggaagaa atggcaaaca attctgcagt actttaacct tgaacacagc tcaagcaaac 300
cacactggct tctacagctg caaatatcta gctgtaccta cttcaaagaa gaaggaaaca 360
gaatctgcaa tctatatatt tattagtgat acaggtagac ctttcgtaga gatgtacagt 420
gaaatccccg aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt 480
acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt gatccctgat 540
ggaaaacgca taatctggga cagtagaaag ggcttcatca tatcaaatgc aacgtacaaa 600
gaaatagggc ttctgacctg tgaagcaaca gtcaatgggc atttgtataa gacaaactat 660
ctcacacatc gacaaaccaa tacaatcata gatgtccaaa taagcacacc acgcccagtc 720
aaattactta gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg 780
agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc cgtaaggcga 840
cgaattgacc aaagcaattc ccatgccaac atattctaca gtgttcttac tattgacaaa 900
atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagcattca tcactgtgaa acatcgaaaa 1020
cagcaggtgc ttgaaaccgt agctggcaag cggtcttacc ggctctctat gaaagtgaag 1080
gcatttccct cgccggaagt tgtatggtta aaagatgggt tacctgcgac tgagaaatct 1140
gctcgctatt tgactcgtgg ctactcgtta attatcaagg acgtaactga agaggatgca 1200
gggaattata caatcttgct gagcataaaa cagtcaaatg tgtttaaaaa cctcactgcc 1260
actctaattg tcaatgtgaa accccagatt tacgaaaagg ccgtgtcatc gtttccagac 1320
ccggctctct acccactggg cagcagacaa atcctgactt gtaccgcata tggtatccct 1380
caacctacaa tcaagtggtt ctggcacccc tgtaaccata atcattccga agcaaggtgt 1440
gacttttgtt ccaataatga agagtccttt atcctggatg ctgacagcaa catgggaaac 1500
agaattgaga gcatcactca gcgcatggca ataatagaag gaaagaataa gatggctagc 1560
accttggttg tggctgactc tagaatttct ggaatctaca tttgcatagc ttccaataaa 1620
gttgggactg tgggaagaaa cataagcttt tatatcacag atgtgccaaa tgggtttcat 1680
gttaacttgg aaaaaatgcc gacggaagga gaggacctga aactgtcttg cacagttaac 1740
aagttcttat acagagacgt tacttggatt ttactgcgga cagttaataa cagaacaatg 1800
cactacagta ttagcaagca aaaaatggcc atcactaagg agcactccat cactcttaat 1860
cttaccatca tgaatgtttc cctgcaagat tcaggcacct atgcctgcag agccaggaat 1920
gtatacacag gggaagaaat cctccagaag aaagaaatta caatcagaga tcaggaagca 1980
ccatacctcc tgcgaaacct cagtgatcac acagtggcca tcagcagttc caccacttta 2040
gactgtcatg ctaatggtgt ccccgagcct cagatcactt ggtttaaaaa caaccacaaa 2100
atacaacaag agcctgaact gtatacatca acgtcaccat cgtcatcgtc atcatcacca 2160
ttgtcatcat catcatcatc gtcatcatca tcatcatcat ag 2202
<210> 21
<211> 541
<212> PRT
<213> 人(Human)
<400> 21
Met Val Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser
1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro
20 25 30
Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln Thr
35 40 45
Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp Ser Leu Pro
50 55 60
Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser Ile Thr Lys Ser Ala
65 70 75 80
Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser Thr Leu Thr Leu Asn Thr
85 90 95
Ala Gln Ala Asn His Thr Gly Phe Tyr Ser Cys Lys Tyr Leu Ala Val
100 105 110
Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile
115 120 125
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
130 135 140
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
145 150 155 160
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
165 170 175
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
180 185 190
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
195 200 205
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
210 215 220
Gln Thr Asn Thr Ile Ile Asp Val Gln Ile Ser Thr Pro Arg Pro Val
225 230 235 240
Lys Leu Leu Arg Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr
245 250 255
Pro Leu Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys
260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His
275 280 285
Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn Lys
290 295 300
Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro Ser Phe Lys
305 310 315 320
Ser Val Asn Thr Ser Val His Ile Tyr Asp Lys Ala Phe Ile Thr Val
325 330 335
Lys His Arg Lys Gln Gln Val Leu Glu Thr Val Ala Gly Lys Arg Ser
340 345 350
Tyr Arg Leu Ser Met Lys Val Lys Ala Phe Pro Ser Pro Glu Val Val
355 360 365
Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu
370 375 380
Thr Arg Gly Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala
385 390 395 400
Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys
405 410 415
Asn Leu Thr Ala Thr Leu Ile Val Asn Val Lys Pro Gln Ile Tyr Glu
420 425 430
Lys Ala Val Ser Ser Phe Pro Asp Pro Ala Leu Tyr Pro Leu Gly Ser
435 440 445
Arg Gln Ile Leu Thr Cys Thr Ala Tyr Gly Ile Pro Gln Pro Thr Ile
450 455 460
Lys Trp Phe Trp His Pro Cys Asn His Asn His Ser Glu Ala Arg Cys
465 470 475 480
Asp Phe Cys Ser Asn Asn Glu Glu Ser Phe Ile Leu Asp Ala Asp Ser
485 490 495
Asn Met Gly Asn Arg Ile Glu Ser Ile Thr Gln Arg Met Ala Ile Ile
500 505 510
Glu Gly Lys Asn Lys Leu Pro Pro Ala Asn Ser Ser Phe Met Leu Pro
515 520 525
Pro Thr Ser Phe Ser Ser Asn Tyr Phe His Phe Leu Pro
530 535 540
<210> 22
<211> 1626
<212> DNA
<213> 人(Human)
<400> 22
atggtcagct actgggacac cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60
acaggatcta gttcaggttc aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120
cacatcatgc aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa 180
tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac taaatctgcc 240
tgtggaagaa atggcaaaca attctgcagt actttaacct tgaacacagc tcaagcaaac 300
cacactggct tctacagctg caaatatcta gctgtaccta cttcaaagaa gaaggaaaca 360
gaatctgcaa tctatatatt tattagtgat acaggtagac ctttcgtaga gatgtacagt 420
gaaatccccg aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt 480
acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt gatccctgat 540
ggaaaacgca taatctggga cagtagaaag ggcttcatca tatcaaatgc aacgtacaaa 600
gaaatagggc ttctgacctg tgaagcaaca gtcaatgggc atttgtataa gacaaactat 660
ctcacacatc gacaaaccaa tacaatcata gatgtccaaa taagcacacc acgcccagtc 720
aaattactta gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg 780
agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc cgtaaggcga 840
cgaattgacc aaagcaattc ccatgccaac atattctaca gtgttcttac tattgacaaa 900
atgcagaaca aagacaaagg actttatact tgtcgtgtaa ggagtggacc atcattcaaa 960
tctgttaaca cctcagtgca tatatatgat aaagcattca tcactgtgaa acatcgaaaa 1020
cagcaggtgc ttgaaaccgt agctggcaag cggtcttacc ggctctctat gaaagtgaag 1080
gcatttccct cgccggaagt tgtatggtta aaagatgggt tacctgcgac tgagaaatct 1140
gctcgctatt tgactcgtgg ctactcgtta attatcaagg acgtaactga agaggatgca 1200
gggaattata caatcttgct gagcataaaa cagtcaaatg tgtttaaaaa cctcactgcc 1260
actctaattg tcaatgtgaa accccagatt tacgaaaagg ccgtgtcatc gtttccagac 1320
ccggctctct acccactggg cagcagacaa atcctgactt gtaccgcata tggtatccct 1380
caacctacaa tcaagtggtt ctggcacccc tgtaaccata atcattccga agcaaggtgt 1440
gacttttgtt ccaataatga agagtccttt atcctggatg ctgacagcaa catgggaaac 1500
agaattgaga gcatcactca gcgcatggca ataatagaag gaaagaataa gcttccacca 1560
gctaacagtt ctttcatgtt gccacctaca agcttctctt ccaactactt ccatttcctt 1620
ccgtga 1626
<210> 23
<211> 732
<212> PRT
<213> 人(Human)
<400> 23
Ser Lys Leu Lys Asp Pro Glu Leu Ser Leu Lys Gly Thr Gln His Ile
1 5 10 15
Met Gln Ala Gly Gln Thr Leu His Leu Gln Cys Arg Gly Glu Ala Ala
20 25 30
His Lys Trp Ser Leu Pro Glu Met Val Ser Lys Glu Ser Glu Arg Leu
35 40 45
Ser Ile Thr Lys Ser Ala Cys Gly Arg Asn Gly Lys Gln Phe Cys Ser
50 55 60
Thr Leu Thr Leu Asn Thr Ala Gln Ala Asn His Thr Gly Phe Tyr Ser
65 70 75 80
Cys Lys Tyr Leu Ala Val Pro Thr Ser Lys Lys Lys Glu Thr Glu Ser
85 90 95
Ala Ile Tyr Ile Phe Ile Ser Asp Thr Gly Arg Pro Phe Val Glu Met
100 105 110
Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly Arg Glu Leu
115 120 125
Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu Lys
130 135 140
Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp
145 150 155 160
Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile
165 170 175
Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr Lys Thr
180 185 190
Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp Val Gln Ile
195 200 205
Ser Thr Pro Arg Pro Val Lys Leu Leu Arg Gly His Thr Leu Val Leu
210 215 220
Asn Cys Thr Ala Thr Thr Pro Leu Asn Thr Arg Val Gln Met Thr Trp
225 230 235 240
Ser Tyr Pro Asp Glu Lys Asn Lys Arg Ala Ser Val Arg Arg Arg Ile
245 250 255
Asp Gln Ser Asn Ser His Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile
260 265 270
Asp Lys Met Gln Asn Lys Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg
275 280 285
Ser Gly Pro Ser Phe Lys Ser Val Asn Thr Ser Val His Ile Tyr Asp
290 295 300
Lys Ala Phe Ile Thr Val Lys His Arg Lys Gln Gln Val Leu Glu Thr
305 310 315 320
Val Ala Gly Lys Arg Ser Tyr Arg Leu Ser Met Lys Val Lys Ala Phe
325 330 335
Pro Ser Pro Glu Val Val Trp Leu Lys Asp Gly Leu Pro Ala Thr Glu
340 345 350
Lys Ser Ala Arg Tyr Leu Thr Arg Gly Tyr Ser Leu Ile Ile Lys Asp
355 360 365
Val Thr Glu Glu Asp Ala Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys
370 375 380
Gln Ser Asn Val Phe Lys Asn Leu Thr Ala Thr Leu Ile Val Asn Val
385 390 395 400
Lys Pro Gln Ile Tyr Glu Lys Ala Val Ser Ser Phe Pro Asp Pro Ala
405 410 415
Leu Tyr Pro Leu Gly Ser Arg Gln Ile Leu Thr Cys Thr Ala Tyr Gly
420 425 430
Ile Pro Gln Pro Thr Ile Lys Trp Phe Trp His Pro Cys Asn His Asn
435 440 445
His Ser Glu Ala Arg Cys Asp Phe Cys Ser Asn Asn Glu Glu Ser Phe
450 455 460
Ile Leu Asp Ala Asp Ser Asn Met Gly Asn Arg Ile Glu Ser Ile Thr
465 470 475 480
Gln Arg Met Ala Ile Ile Glu Gly Lys Asn Lys Met Ala Ser Thr Leu
485 490 495
Val Val Ala Asp Ser Arg Ile Ser Gly Ile Tyr Ile Cys Ile Ala Ser
500 505 510
Asn Lys Val Gly Thr Val Gly Arg Asn Ile Ser Phe Tyr Ile Thr Asp
515 520 525
Val Pro Asn Gly Phe His Val Asn Leu Glu Lys Met Pro Thr Glu Gly
530 535 540
Glu Asp Leu Lys Leu Ser Cys Thr Val Asn Lys Phe Leu Tyr Arg Asp
545 550 555 560
Val Thr Trp Ile Leu Leu Arg Thr Val Asn Asn Arg Thr Met His Tyr
565 570 575
Ser Ile Ser Lys Gln Lys Met Ala Ile Thr Lys Glu His Ser Ile Thr
580 585 590
Leu Asn Leu Thr Ile Met Asn Val Ser Leu Gln Asp Ser Gly Thr Tyr
595 600 605
Ala Cys Arg Ala Arg Asn Val Tyr Thr Gly Glu Glu Ile Leu Gln Lys
610 615 620
Lys Glu Ile Thr Ile Arg Asp Gln Glu Ala Pro Tyr Leu Leu Arg Asn
625 630 635 640
Leu Ser Asp His Thr Val Ala Ile Ser Ser Ser Thr Thr Leu Asp Cys
645 650 655
His Ala Asn Gly Val Pro Glu Pro Gln Ile Thr Trp Phe Lys Asn Asn
660 665 670
His Lys Ile Gln Gln Glu Pro Gly Ile Ile Leu Gly Pro Gly Ser Ser
675 680 685
Thr Leu Phe Ile Glu Arg Val Thr Glu Glu Asp Glu Gly Val Tyr His
690 695 700
Cys Lys Ala Thr Asn Gln Lys Gly Ser Val Glu Ser Ser Ala Tyr Leu
705 710 715 720
Thr Val Gln Gly Thr Ser Asp Lys Ser Asn Leu Glu
725 730
<210> 24
<211> 737
<212> PRT
<213> 小鼠(Mouse)
<400> 24
Tyr Gly Ser Gly Ser Lys Leu Lys Val Pro Glu Leu Ser Leu Lys Gly
1 5 10 15
Thr Gln His Val Met Gln Ala Gly Gln Thr Leu Phe Leu Lys Cys Arg
20 25 30
Gly Glu Ala Ala His Ser Trp Ser Leu Pro Thr Thr Val Ser Gln Glu
35 40 45
Asp Lys Arg Leu Ser Ile Thr Pro Pro Ser Ala Cys Gly Arg Asp Asn
50 55 60
Arg Gln Phe Cys Ser Thr Leu Thr Leu Asp Thr Ala Gln Ala Asn His
65 70 75 80
Thr Gly Leu Tyr Thr Cys Arg Tyr Leu Pro Thr Ser Thr Ser Lys Lys
85 90 95
Lys Lys Ala Glu Ser Ser Ile Tyr Ile Phe Val Ser Asp Ala Gly Ser
100 105 110
Pro Phe Ile Glu Met His Thr Asp Ile Pro Lys Leu Val His Met Thr
115 120 125
Glu Gly Arg Gln Leu Ile Ile Pro Cys Arg Val Thr Ser Pro Asn Val
130 135 140
Thr Val Thr Leu Lys Lys Phe Pro Phe Asp Thr Leu Thr Pro Asp Gly
145 150 155 160
Gln Arg Ile Thr Trp Asp Ser Arg Arg Gly Phe Ile Ile Ala Asn Ala
165 170 175
Thr Tyr Lys Glu Ile Gly Leu Leu Asn Cys Glu Ala Thr Val Asn Gly
180 185 190
His Leu Tyr Gln Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile
195 200 205
Leu Asp Val Gln Ile Arg Pro Pro Ser Pro Val Arg Leu Leu His Gly
210 215 220
Gln Thr Leu Val Leu Asn Cys Thr Ala Thr Thr Glu Leu Asn Thr Arg
225 230 235 240
Val Gln Met Ser Trp Asn Tyr Pro Gly Lys Ala Thr Lys Arg Ala Ser
245 250 255
Ile Arg Gln Arg Ile Asp Arg Ser His Ser His Asn Asn Val Phe His
260 265 270
Ser Val Leu Lys Ile Asn Asn Val Glu Ser Arg Asp Lys Gly Leu Tyr
275 280 285
Thr Cys Arg Val Lys Ser Gly Ser Ser Phe Gln Ser Phe Asn Thr Ser
290 295 300
Val His Val Tyr Glu Lys Gly Phe Ile Ser Val Lys His Arg Lys Gln
305 310 315 320
Pro Val Gln Glu Thr Thr Ala Gly Arg Arg Ser Tyr Arg Leu Ser Met
325 330 335
Lys Val Lys Ala Phe Pro Ser Pro Glu Ile Val Trp Leu Lys Asp Gly
340 345 350
Ser Pro Ala Thr Leu Lys Ser Ala Arg Tyr Leu Val His Gly Tyr Ser
355 360 365
Leu Ile Ile Lys Asp Val Thr Thr Glu Asp Ala Gly Asp Tyr Thr Ile
370 375 380
Leu Leu Gly Ile Lys Gln Ser Arg Leu Phe Lys Asn Leu Thr Ala Thr
385 390 395 400
Leu Ile Val Asn Val Lys Pro Gln Ile Tyr Glu Lys Ser Val Ser Ser
405 410 415
Leu Pro Ser Pro Pro Leu Tyr Pro Leu Gly Ser Arg Gln Val Leu Thr
420 425 430
Cys Thr Val Tyr Gly Ile Pro Arg Pro Thr Ile Thr Trp Leu Trp His
435 440 445
Pro Cys His His Asn His Ser Lys Glu Arg Tyr Asp Phe Cys Thr Glu
450 455 460
Asn Glu Glu Ser Phe Ile Leu Asp Pro Ser Ser Asn Leu Gly Asn Arg
465 470 475 480
Ile Glu Ser Ile Ser Gln Arg Met Thr Val Ile Glu Gly Thr Asn Lys
485 490 495
Thr Val Ser Thr Leu Val Val Ala Asp Ser Gln Thr Pro Gly Ile Tyr
500 505 510
Ser Cys Arg Ala Phe Asn Lys Ile Gly Thr Val Glu Arg Asn Ile Lys
515 520 525
Phe Tyr Val Thr Asp Val Pro Asn Gly Phe His Val Ser Leu Glu Lys
530 535 540
Met Pro Ala Glu Gly Glu Asp Leu Lys Leu Ser Cys Val Val Asn Lys
545 550 555 560
Phe Leu Tyr Arg Asp Ile Thr Trp Ile Leu Leu Arg Thr Val Asn Asn
565 570 575
Arg Thr Met His His Ser Ile Ser Lys Gln Lys Met Ala Thr Thr Gln
580 585 590
Asp Tyr Ser Ile Thr Leu Asn Leu Val Ile Lys Asn Val Ser Leu Glu
595 600 605
Asp Ser Gly Thr Tyr Ala Cys Arg Ala Arg Asn Ile Tyr Thr Gly Glu
610 615 620
Asp Ile Leu Arg Lys Thr Glu Val Leu Val Arg Asp Ser Glu Ala Pro
625 630 635 640
His Leu Leu Gln Asn Leu Ser Asp Tyr Glu Val Ser Ile Ser Gly Ser
645 650 655
Thr Thr Leu Asp Cys Gln Ala Arg Gly Val Pro Ala Pro Gln Ile Thr
660 665 670
Trp Phe Lys Asn Asn His Lys Ile Gln Gln Glu Pro Gly Ile Ile Leu
675 680 685
Gly Pro Gly Asn Ser Thr Leu Phe Ile Glu Arg Val Thr Glu Glu Asp
690 695 700
Glu Gly Val Tyr Arg Cys Arg Ala Thr Asn Gln Lys Gly Ala Val Glu
705 710 715 720
Ser Ala Ala Tyr Leu Thr Val Gln Gly Thr Ser Asp Lys Ser Asn Leu
725 730 735
Glu
<210> 25
<211> 736
<212> PRT
<213> 大鼠(Rat)
<400> 25
Tyr Cys Ser Gly Ser Lys Leu Lys Gly Pro Glu Leu Ser Leu Lys Gly
1 5 10 15
Thr Gln His Val Met Gln Ala Gly Gln Thr Leu Phe Leu Lys Cys Arg
20 25 30
Gly Glu Ala Ala His Ser Trp Ser Leu Pro Thr Thr Val Ser Gln Glu
35 40 45
Asp Lys Lys Leu Ser Val Thr Arg Ser Ala Cys Gly Arg Asn Asn Arg
50 55 60
Gln Phe Cys Ser Thr Leu Thr Leu Asn Met Ala Gln Ala Asn His Thr
65 70 75 80
Gly Leu Tyr Ser Cys Arg Tyr Leu Pro Lys Ser Thr Ser Lys Glu Lys
85 90 95
Lys Met Glu Ser Ala Ile Tyr Ile Phe Val Ser Asp Ala Gly Ser Pro
100 105 110
Phe Ile Glu Met His Ser Asp Ile Pro Lys Leu Val His Met Thr Glu
115 120 125
Gly Arg Glu Leu Ile Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr
130 135 140
Val Thr Leu Lys Lys Phe Pro Phe Asp Ala Leu Thr Pro Asp Gly Gln
145 150 155 160
Arg Ile Ala Trp Asp Ser Arg Arg Gly Phe Ile Ile Ala Asn Ala Thr
165 170 175
Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His
180 185 190
Leu Tyr Gln Thr Ser Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Leu
195 200 205
Asp Val Gln Ile Ser Pro Pro Ser Pro Val Arg Phe Leu Arg Gly Gln
210 215 220
Thr Leu Val Leu Asn Cys Thr Val Thr Thr Asp Leu Asn Thr Arg Val
225 230 235 240
Gln Met Ser Trp Asn Tyr Pro Gly Lys Ala Thr Lys Arg Ala Ser Ile
245 250 255
Arg Gln Arg Ile Asp Gln Ser Asn Pro His Ser Asn Val Phe His Ser
260 265 270
Val Leu Lys Ile Asn Asn Val Glu Ser Arg Asp Lys Gly Leu Tyr Thr
275 280 285
Cys Arg Val Lys Ser Gly Ser Ser Phe Arg Thr Phe Asn Thr Ser Val
290 295 300
His Val Tyr Glu Lys Gly Phe Ile Ser Val Lys His Arg Lys Gln Gln
305 310 315 320
Val Gln Glu Thr Ile Ala Gly Lys Arg Ser His Arg Leu Ser Met Lys
325 330 335
Val Lys Ala Phe Pro Ser Pro Glu Val Val Trp Leu Lys Asp Gly Val
340 345 350
Pro Ala Thr Glu Lys Ser Ala Arg Tyr Ser Val His Gly Tyr Ser Leu
355 360 365
Ile Ile Lys Asp Val Thr Ala Glu Asp Ala Gly Asp Tyr Thr Ile Leu
370 375 380
Leu Gly Ile Lys Gln Ser Lys Leu Phe Arg Asn Leu Thr Ala Thr Leu
385 390 395 400
Ile Val Asn Val Lys Pro Gln Ile Tyr Glu Lys Ser Val Ser Ser Leu
405 410 415
Pro Ser Pro Pro Leu Tyr Pro Leu Gly Ser Arg Gln Val Leu Thr Cys
420 425 430
Thr Val Tyr Gly Ile Pro Gln Pro Thr Ile Lys Trp Leu Trp His Pro
435 440 445
Cys His Tyr Asn His Ser Lys Glu Arg Asn Asp Phe Cys Phe Gly Ser
450 455 460
Glu Glu Ser Phe Ile Leu Asp Ser Ser Ser Asn Ile Gly Asn Arg Ile
465 470 475 480
Glu Gly Ile Thr Gln Arg Met Met Val Ile Glu Gly Thr Asn Lys Thr
485 490 495
Val Ser Thr Leu Val Val Ala Asp Ser Arg Thr Pro Gly Ser Tyr Ser
500 505 510
Cys Lys Ala Phe Asn Lys Ile Gly Thr Val Glu Arg Asp Ile Arg Phe
515 520 525
Tyr Val Thr Asp Val Pro Asn Gly Phe His Val Ser Leu Glu Lys Ile
530 535 540
Pro Thr Glu Gly Glu Asp Leu Lys Leu Ser Cys Val Val Ser Lys Phe
545 550 555 560
Leu Tyr Arg Asp Ile Thr Trp Ile Leu Leu Arg Thr Val Asn Asn Arg
565 570 575
Thr Met His His Ser Ile Ser Lys Gln Lys Met Ala Thr Thr Gln Asp
580 585 590
Tyr Ser Ile Thr Leu Asn Leu Val Ile Lys Asn Val Ser Leu Glu Asp
595 600 605
Ser Gly Thr Tyr Ala Cys Arg Ala Arg Asn Ile Tyr Thr Gly Glu Glu
610 615 620
Ile Leu Arg Lys Thr Glu Val Leu Val Arg Asp Leu Glu Ala Pro Leu
625 630 635 640
Leu Leu Gln Asn Leu Ser Asp His Glu Val Ser Ile Ser Gly Ser Thr
645 650 655
Thr Leu Asp Cys Gln Ala Arg Gly Val Pro Ala Pro Gln Ile Thr Trp
660 665 670
Phe Lys Asn Asn His Lys Ile Gln Gln Glu Pro Gly Ile Ile Leu Gly
675 680 685
Pro Gly Asn Ser Thr Leu Phe Ile Glu Arg Val Thr Glu Glu Asp Glu
690 695 700
Gly Val Tyr Arg Cys Arg Ala Thr Asn Gln Lys Gly Val Val Glu Ser
705 710 715 720
Ser Ala Tyr Leu Thr Val Gln Gly Thr Ser Asp Lys Ser Asn Leu Glu
725 730 735
<210> 26
<211> 745
<212> PRT
<213> 人(Human)
<400> 26
Ala Ser Val Gly Leu Pro Ser Val Ser Leu Asp Leu Pro Arg Leu Ser
1 5 10 15
Ile Gln Lys Asp Ile Leu Thr Ile Lys Ala Asn Thr Thr Leu Gln Ile
20 25 30
Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro Asn Asn Gln
35 40 45
Ser Gly Ser Glu Gln Arg Val Glu Val Thr Glu Cys Ser Asp Gly Leu
50 55 60
Phe Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn Asp Thr Gly
65 70 75 80
Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser Val Ile Tyr
85 90 95
Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser Val Ser Asp
100 105 110
Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn Lys Thr Val Val
115 120 125
Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu Asn Val Ser Leu Cys Ala
130 135 140
Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg Ile Ser Trp
145 150 155 160
Asp Ser Lys Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile Ser Tyr Ala
165 170 175
Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser Tyr Gln Ser
180 185 190
Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr Asp Val Val
195 200 205
Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys Leu Val
210 215 220
Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp Phe Asn
225 230 235 240
Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val Asn Arg
245 250 255
Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr
260 265 270
Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys
275 280 285
Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg
290 295 300
Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met Glu Ser Leu
305 310 315 320
Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Ala Lys Tyr Leu
325 330 335
Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly Ile Pro Leu
340 345 350
Glu Ser Asn His Thr Ile Lys Ala Gly His Val Leu Thr Ile Met Glu
355 360 365
Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val Ile Leu Thr Asn Pro
370 375 380
Ile Ser Lys Glu Lys Gln Ser His Val Val Ser Leu Val Val Tyr Val
385 390 395 400
Pro Pro Gln Ile Gly Glu Lys Ser Leu Ile Ser Pro Val Asp Ser Tyr
405 410 415
Gln Tyr Gly Thr Thr Gln Thr Leu Thr Cys Thr Val Tyr Ala Ile Pro
420 425 430
Pro Pro His His Ile His Trp Tyr Trp Gln Leu Glu Glu Glu Cys Ala
435 440 445
Asn Glu Pro Ser Gln Ala Val Ser Val Thr Asn Pro Tyr Pro Cys Glu
450 455 460
Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys Ile Glu Val
465 470 475 480
Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn Lys Thr Val Ser
485 490 495
Thr Leu Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr Lys Cys Glu
500 505 510
Ala Val Asn Lys Val Gly Arg Gly Glu Arg Val Ile Ser Phe His Val
515 520 525
Thr Arg Gly Pro Glu Ile Thr Leu Gln Pro Asp Met Gln Pro Thr Glu
530 535 540
Gln Glu Ser Val Ser Leu Trp Cys Thr Ala Asp Arg Ser Thr Phe Glu
545 550 555 560
Asn Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro Ile His Val
565 570 575
Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr Leu Trp Lys
580 585 590
Leu Asn Ala Thr Met Phe Ser Asn Ser Thr Asn Asp Ile Leu Ile Met
595 600 605
Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr Val Cys Leu
610 615 620
Ala Gln Asp Arg Lys Thr Lys Lys Arg His Cys Val Val Arg Gln Leu
625 630 635 640
Thr Val Leu Glu Arg Val Ala Pro Thr Ile Thr Gly Asn Leu Glu Asn
645 650 655
Gln Thr Thr Ser Ile Gly Glu Ser Ile Glu Val Ser Cys Thr Ala Ser
660 665 670
Gly Asn Pro Pro Pro Gln Ile Met Trp Phe Lys Asp Asn Glu Thr Leu
675 680 685
Val Glu Asp Ser Gly Ile Val Leu Lys Asp Gly Asn Arg Asn Leu Thr
690 695 700
Ile Arg Arg Val Arg Lys Glu Asp Glu Gly Leu Tyr Thr Cys Gln Ala
705 710 715 720
Cys Ser Val Leu Gly Cys Ala Lys Val Glu Ala Phe Phe Ile Ile Glu
725 730 735
Gly Ala Gln Glu Lys Thr Asn Leu Glu
740 745
<210> 27
<211> 743
<212> PRT
<213> 小鼠(Mouse)
<400> 27
Ala Ser Val Gly Leu Pro Gly Asp Phe Leu His Pro Pro Lys Leu Ser
1 5 10 15
Thr Gln Lys Asp Ile Leu Thr Ile Leu Ala Asn Thr Thr Leu Gln Ile
20 25 30
Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro Asn Ala Gln
35 40 45
Arg Asp Ser Glu Glu Arg Val Leu Val Thr Glu Cys Gly Gly Gly Asp
50 55 60
Ser Ile Phe Cys Lys Thr Leu Thr Ile Pro Arg Val Val Gly Asn Asp
65 70 75 80
Thr Gly Ala Tyr Lys Cys Ser Tyr Arg Asp Val Asp Ile Ala Ser Thr
85 90 95
Val Tyr Val Tyr Val Arg Asp Tyr Arg Ser Pro Phe Ile Ala Ser Val
100 105 110
Ser Asp Gln His Gly Ile Val Tyr Ile Thr Glu Asn Lys Asn Lys Thr
115 120 125
Val Val Ile Pro Cys Arg Gly Ser Ile Ser Asn Leu Asn Val Ser Leu
130 135 140
Cys Ala Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg Ile
145 150 155 160
Ser Trp Asp Ser Glu Ile Gly Phe Thr Leu Pro Ser Tyr Met Ile Ser
165 170 175
Tyr Ala Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Thr Tyr
180 185 190
Gln Ser Ile Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr Asp
195 200 205
Val Ile Leu Ser Pro Pro His Glu Ile Glu Leu Ser Ala Gly Glu Lys
210 215 220
Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Leu Asp
225 230 235 240
Phe Thr Trp His Ser Pro Pro Ser Lys Ser His His Lys Lys Ile Val
245 250 255
Asn Arg Asp Val Lys Pro Phe Pro Gly Thr Val Ala Lys Met Phe Leu
260 265 270
Ser Thr Leu Thr Ile Glu Ser Val Thr Lys Ser Asp Gln Gly Glu Tyr
275 280 285
Thr Cys Val Ala Ser Ser Gly Arg Met Ile Lys Arg Asn Arg Thr Phe
290 295 300
Val Arg Val His Thr Lys Pro Phe Ile Ala Phe Gly Ser Gly Met Lys
305 310 315 320
Ser Leu Val Glu Ala Thr Val Gly Ser Gln Val Arg Ile Pro Val Lys
325 330 335
Tyr Leu Ser Tyr Pro Ala Pro Asp Ile Lys Trp Tyr Arg Asn Gly Arg
340 345 350
Pro Ile Glu Ser Asn Tyr Thr Met Ile Val Gly Asp Glu Leu Thr Ile
355 360 365
Met Glu Val Thr Glu Arg Asp Ala Gly Asn Tyr Thr Val Ile Leu Thr
370 375 380
Asn Pro Ile Ser Met Glu Lys Gln Ser His Met Val Ser Leu Val Val
385 390 395 400
Asn Val Pro Pro Gln Ile Gly Glu Lys Ala Leu Ile Ser Pro Met Asp
405 410 415
Ser Tyr Gln Tyr Gly Thr Met Gln Thr Leu Thr Cys Thr Val Tyr Ala
420 425 430
Asn Pro Pro Leu His His Ile Gln Trp Tyr Trp Gln Leu Glu Glu Ala
435 440 445
Cys Ser Tyr Arg Pro Gly Gln Thr Ser Pro Tyr Ala Cys Lys Glu Trp
450 455 460
Arg His Val Glu Asp Phe Gln Gly Gly Asn Lys Ile Glu Val Thr Lys
465 470 475 480
Asn Gln Tyr Ala Leu Ile Glu Gly Lys Asn Lys Thr Val Ser Thr Leu
485 490 495
Val Ile Gln Ala Ala Asn Val Ser Ala Leu Tyr Lys Cys Glu Ala Ile
500 505 510
Asn Lys Ala Gly Arg Gly Glu Arg Val Ile Ser Phe His Val Ile Arg
515 520 525
Gly Pro Glu Ile Thr Val Gln Pro Ala Ala Gln Pro Thr Glu Gln Glu
530 535 540
Ser Val Ser Leu Leu Cys Thr Ala Asp Arg Asn Thr Phe Glu Asn Leu
545 550 555 560
Thr Trp Tyr Lys Leu Gly Ser Gln Ala Thr Ser Val His Met Gly Glu
565 570 575
Ser Leu Thr Pro Val Cys Lys Asn Leu Asp Ala Leu Trp Lys Leu Asn
580 585 590
Gly Thr Met Phe Ser Asn Ser Thr Asn Asp Ile Leu Ile Val Ala Phe
595 600 605
Gln Asn Ala Ser Leu Gln Asp Gln Gly Asp Tyr Val Cys Ser Ala Gln
610 615 620
Asp Lys Lys Thr Lys Lys Arg His Cys Leu Val Lys Gln Leu Ile Ile
625 630 635 640
Leu Glu Arg Met Ala Pro Met Ile Thr Gly Asn Leu Glu Asn Gln Thr
645 650 655
Thr Thr Ile Gly Glu Thr Ile Glu Val Thr Cys Pro Ala Ser Gly Asn
660 665 670
Pro Thr Pro His Ile Thr Trp Phe Lys Asp Asn Glu Thr Leu Val Glu
675 680 685
Asp Ser Gly Ile Val Leu Arg Asp Gly Asn Arg Asn Leu Thr Ile Arg
690 695 700
Arg Val Arg Lys Glu Asp Gly Gly Leu Tyr Thr Cys Gln Ala Cys Asn
705 710 715 720
Val Leu Gly Cys Ala Arg Ala Glu Thr Leu Phe Ile Ile Glu Gly Ala
725 730 735
Gln Glu Lys Thr Asn Leu Glu
740
<210> 28
<211> 741
<212> PRT
<213> 大鼠(Rat)
<400> 28
Ala Ser Val Gly Leu Pro Gly Asp Ser Leu His Pro Pro Lys Leu Ser
1 5 10 15
Thr Gln Lys Asp Ile Leu Thr Ile Leu Ala Asn Thr Thr Leu Gln Ile
20 25 30
Thr Cys Arg Gly Gln Arg Asp Leu Asp Trp Leu Trp Pro Asn Thr Pro
35 40 45
Arg Asp Ser Glu Glu Arg Val Leu Val Thr Glu Cys Gly Asp Ser Ile
50 55 60
Phe Cys Lys Thr Leu Thr Val Pro Arg Val Val Gly Asn Asp Thr Gly
65 70 75 80
Ala Tyr Lys Cys Phe Tyr Arg Asp Thr Asp Val Ser Ser Ile Val Tyr
85 90 95
Val Tyr Val Gln Asp His Arg Ser Pro Phe Ile Ala Ser Val Ser Asp
100 105 110
Glu His Gly Ile Val Tyr Ile Thr Glu Asn Lys Asn Lys Thr Val Val
115 120 125
Ile Pro Cys Arg Gly Ser Ile Ser Asn Leu Asn Val Ser Leu Cys Ala
130 135 140
Arg Tyr Pro Glu Lys Arg Phe Val Pro Asp Gly Asn Arg Ile Ser Trp
145 150 155 160
Asp Ser Glu Lys Gly Phe Thr Ile Pro Ser Tyr Met Ile Ser Tyr Ala
165 170 175
Gly Met Val Phe Cys Glu Ala Lys Ile Asn Asp Glu Thr Tyr Gln Ser
180 185 190
Ile Met Tyr Ile Val Leu Val Val Gly Tyr Arg Ile Tyr Asp Val Val
195 200 205
Leu Ser Pro Pro His Glu Ile Glu Leu Ser Ala Gly Glu Lys Leu Val
210 215 220
Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Leu Asp Phe Ser
225 230 235 240
Trp Gln Phe Pro Ser Ser Lys His Gln His Lys Lys Ile Val Asn Arg
245 250 255
Asp Val Lys Ser Leu Pro Gly Thr Val Ala Lys Met Phe Leu Ser Thr
260 265 270
Leu Thr Ile Asp Ser Val Thr Lys Ser Asp Gln Gly Glu Tyr Thr Cys
275 280 285
Thr Ala Tyr Ser Gly Leu Met Thr Lys Lys Asn Lys Thr Phe Val Arg
290 295 300
Val His Thr Lys Pro Phe Ile Ala Phe Gly Ser Gly Met Lys Ser Leu
305 310 315 320
Val Glu Ala Thr Val Gly Ser Gln Val Arg Ile Pro Val Lys Tyr Leu
325 330 335
Ser Tyr Pro Ala Pro Asp Ile Lys Trp Tyr Arg Asn Gly Arg Pro Ile
340 345 350
Glu Ser Asn Tyr Thr Met Ile Val Gly Asp Glu Leu Thr Ile Met Glu
355 360 365
Val Ser Glu Arg Asp Ala Gly Asn Tyr Thr Val Ile Leu Thr Asn Pro
370 375 380
Ile Ser Met Glu Lys Gln Ser His Met Val Ser Leu Val Val Asn Val
385 390 395 400
Pro Pro Gln Ile Gly Glu Lys Ala Leu Ile Ser Pro Met Asp Ser Tyr
405 410 415
Gln Tyr Gly Thr Met Gln Thr Leu Thr Cys Thr Val Tyr Ala Asn Pro
420 425 430
Pro Leu His His Ile Gln Trp Tyr Trp Gln Leu Glu Glu Ala Cys Ser
435 440 445
Tyr Arg Pro Ser Gln Thr Asn Pro Tyr Thr Cys Lys Glu Trp Arg His
450 455 460
Val Lys Asp Phe Gln Gly Gly Asn Lys Ile Glu Val Thr Lys Asn Gln
465 470 475 480
Tyr Ala Leu Ile Glu Gly Lys Asn Lys Thr Val Ser Thr Leu Val Ile
485 490 495
Gln Ala Ala Tyr Val Ser Ala Leu Tyr Lys Cys Glu Ala Ile Asn Lys
500 505 510
Ala Gly Arg Gly Glu Arg Val Ile Ser Phe His Val Ile Arg Gly Pro
515 520 525
Glu Ile Thr Val Gln Pro Ala Thr Gln Pro Thr Glu Arg Glu Ser Met
530 535 540
Ser Leu Leu Cys Thr Ala Asp Arg Asn Thr Phe Glu Asn Leu Thr Trp
545 550 555 560
Tyr Lys Leu Gly Ser Gln Ala Thr Ser Val His Met Gly Glu Ser Leu
565 570 575
Thr Pro Val Cys Lys Asn Leu Asp Ala Leu Trp Lys Leu Asn Gly Thr
580 585 590
Val Phe Ser Asn Ser Thr Asn Asp Ile Leu Ile Val Ala Phe Gln Asn
595 600 605
Ala Ser Leu Gln Asp Gln Gly Asn Tyr Val Cys Ser Ala Gln Asp Lys
610 615 620
Lys Thr Lys Lys Arg His Cys Leu Val Lys Gln Leu Val Ile Leu Glu
625 630 635 640
Arg Met Ala Pro Met Ile Thr Gly Asn Leu Glu Asn Gln Thr Thr Thr
645 650 655
Ile Gly Glu Thr Ile Glu Val Val Cys Pro Thr Ser Gly Asn Pro Thr
660 665 670
Pro Leu Ile Thr Trp Phe Lys Asp Asn Glu Thr Leu Val Glu Asp Ser
675 680 685
Gly Ile Val Leu Lys Asp Gly Asn Arg Asn Leu Thr Ile Arg Arg Val
690 695 700
Arg Lys Glu Asp Gly Gly Leu Tyr Thr Cys Gln Ala Cys Asn Val Leu
705 710 715 720
Gly Cys Ala Arg Ala Glu Thr Leu Phe Ile Ile Glu Gly Val Gln Glu
725 730 735
Lys Thr Asn Leu Glu
740
<210> 29
<211> 756
<212> PRT
<213> 人(Human)
<400> 29
Tyr Ser Met Thr Pro Pro Thr Leu Asn Ile Thr Glu Glu Ser His Val
1 5 10 15
Ile Asp Thr Gly Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro
20 25 30
Leu Glu Trp Ala Trp Pro Gly Ala Gln Glu Ala Pro Ala Thr Gly Asp
35 40 45
Lys Asp Ser Glu Asp Thr Gly Val Val Arg Asp Cys Glu Gly Thr Asp
50 55 60
Ala Arg Pro Tyr Cys Lys Val Leu Leu Leu His Glu Val His Ala Asn
65 70 75 80
Asp Thr Gly Ser Tyr Val Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile
85 90 95
Glu Gly Thr Thr Ala Ala Ser Ser Tyr Val Phe Val Arg Asp Phe Glu
100 105 110
Gln Pro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp
115 120 125
Ala Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Val Thr
130 135 140
Leu Arg Ser Gln Ser Ser Val Leu Trp Pro Asp Gly Gln Glu Val Val
145 150 155 160
Trp Asp Asp Arg Arg Gly Met Leu Val Ser Thr Pro Leu Leu His Asp
165 170 175
Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu
180 185 190
Ser Asn Pro Phe Leu Val His Ile Thr Gly Asn Glu Leu Tyr Asp Ile
195 200 205
Gln Leu Leu Pro Arg Lys Ser Leu Glu Leu Leu Val Gly Glu Lys Leu
210 215 220
Val Leu Asn Cys Thr Val Trp Ala Glu Phe Asn Ser Gly Val Thr Phe
225 230 235 240
Asp Trp Asp Tyr Pro Gly Lys Gln Ala Glu Arg Gly Lys Trp Val Pro
245 250 255
Glu Arg Arg Ser Gln Gln Thr His Thr Glu Leu Ser Ser Ile Leu Thr
260 265 270
Ile His Asn Val Ser Gln His Asp Leu Gly Ser Tyr Val Cys Lys Ala
275 280 285
Asn Asn Gly Ile Gln Arg Phe Arg Glu Ser Thr Glu Val Ile Val His
290 295 300
Glu Asn Pro Phe Ile Ser Val Glu Trp Leu Lys Gly Pro Ile Leu Glu
305 310 315 320
Ala Thr Ala Gly Asp Glu Leu Val Lys Leu Pro Val Lys Leu Ala Ala
325 330 335
Tyr Pro Pro Pro Glu Phe Gln Trp Tyr Lys Asp Gly Lys Ala Leu Ser
340 345 350
Gly Arg His Ser Pro His Ala Leu Val Leu Lys Glu Val Thr Glu Ala
355 360 365
Ser Thr Gly Thr Tyr Thr Leu Ala Leu Trp Asn Ser Ala Ala Gly Leu
370 375 380
Arg Arg Asn Ile Ser Leu Glu Leu Val Val Asn Val Pro Pro Gln Ile
385 390 395 400
His Glu Lys Glu Ala Ser Ser Pro Ser Ile Tyr Ser Arg His Ser Arg
405 410 415
Gln Ala Leu Thr Cys Thr Ala Tyr Gly Val Pro Leu Pro Leu Ser Ile
420 425 430
Gln Trp His Trp Arg Pro Trp Thr Pro Cys Lys Met Phe Ala Gln Arg
435 440 445
Ser Leu Arg Arg Arg Gln Gln Gln Asp Leu Met Pro Gln Cys Arg Asp
450 455 460
Trp Arg Ala Val Thr Thr Gln Asp Ala Val Asn Pro Ile Glu Ser Leu
465 470 475 480
Asp Thr Trp Thr Glu Phe Val Glu Gly Lys Asn Lys Thr Val Ser Lys
485 490 495
Leu Val Ile Gln Asn Ala Asn Val Ser Ala Met Tyr Lys Cys Val Val
500 505 510
Ser Asn Lys Val Gly Gln Asp Glu Arg Leu Ile Tyr Phe Tyr Val Thr
515 520 525
Thr Ile Pro Asp Gly Phe Thr Ile Glu Ser Lys Pro Ser Glu Glu Leu
530 535 540
Leu Glu Gly Gln Pro Val Leu Leu Ser Cys Gln Ala Asp Ser Tyr Lys
545 550 555 560
Tyr Glu His Leu Arg Trp Tyr Arg Leu Asn Leu Ser Thr Leu His Asp
565 570 575
Ala His Gly Asn Pro Leu Leu Leu Asp Cys Lys Asn Val His Leu Phe
580 585 590
Ala Thr Pro Leu Ala Ala Ser Leu Glu Glu Val Ala Pro Gly Ala Arg
595 600 605
His Ala Thr Leu Ser Leu Ser Ile Pro Arg Val Ala Pro Glu His Glu
610 615 620
Gly His Tyr Val Cys Glu Val Gln Asp Arg Arg Ser His Asp Lys His
625 630 635 640
Cys His Lys Lys Tyr Leu Ser Val Gln Ala Leu Glu Ala Pro Arg Leu
645 650 655
Thr Gln Asn Leu Thr Asp Leu Leu Val Asn Val Ser Asp Ser Leu Glu
660 665 670
Met Gln Cys Leu Val Ala Gly Ala His Ala Pro Ser Ile Val Trp Tyr
675 680 685
Lys Asp Glu Arg Leu Leu Glu Glu Lys Ser Gly Val Asp Leu Ala Asp
690 695 700
Ser Asn Gln Lys Leu Ser Ile Gln Arg Val Arg Glu Glu Asp Ala Gly
705 710 715 720
Arg Tyr Leu Cys Ser Val Cys Asn Ala Lys Gly Cys Val Asn Ser Ser
725 730 735
Ala Ser Val Ala Val Glu Gly Ser Glu Asp Lys Gly Ser Met Glu Ile
740 745 750
Val Ile Leu Val
755
<210> 30
<211> 751
<212> PRT
<213> 小鼠(Mouse)
<400> 30
Tyr Ser Met Thr Pro Pro Thr Leu Asn Ile Thr Glu Asp Ser Tyr Val
1 5 10 15
Ile Asp Thr Gly Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro
20 25 30
Leu Glu Trp Thr Trp Pro Gly Ala Gln Glu Val Leu Thr Thr Gly Gly
35 40 45
Lys Asp Ser Glu Asp Thr Arg Val Val His Asp Cys Glu Gly Thr Glu
50 55 60
Ala Arg Pro Tyr Cys Lys Val Leu Leu Leu Ala Gln Thr His Ala Asn
65 70 75 80
Asn Thr Gly Ser Tyr His Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile
85 90 95
Glu Gly Thr Thr Ala Ala Ser Thr Tyr Val Phe Val Arg Asp Phe Lys
100 105 110
His Pro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp
115 120 125
Ser Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Ile Thr
130 135 140
Leu Arg Ser Gln Ser Ser Ala Leu His Pro Asp Gly Gln Glu Val Leu
145 150 155 160
Trp Asp Asp Arg Arg Gly Met Arg Val Pro Thr Gln Leu Leu Arg Asp
165 170 175
Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp Gly Asp Gln Asn Phe Leu
180 185 190
Ser Asn Leu Phe Val Val His Ile Thr Gly Asn Glu Leu Tyr Asp Ile
195 200 205
Gln Leu Tyr Pro Lys Lys Ser Met Glu Leu Leu Val Gly Glu Lys Leu
210 215 220
Val Leu Asn Cys Thr Val Trp Ala Glu Phe Asp Ser Gly Val Thr Phe
225 230 235 240
Asp Trp Asp Tyr Pro Gly Lys Gln Ala Glu Arg Ala Lys Trp Val Pro
245 250 255
Glu Arg Arg Ser Gln Gln Thr His Thr Glu Leu Ser Ser Ile Leu Thr
260 265 270
Ile His Asn Val Ser Gln Asn Asp Leu Gly Pro Tyr Val Cys Glu Ala
275 280 285
Asn Asn Gly Ile Gln Arg Phe Arg Glu Ser Thr Glu Val Ile Val His
290 295 300
Glu Lys Pro Phe Ile Ser Val Glu Trp Leu Lys Gly Pro Val Leu Glu
305 310 315 320
Ala Thr Ala Gly Asp Glu Leu Val Lys Leu Pro Val Lys Leu Ala Ala
325 330 335
Tyr Pro Pro Pro Glu Phe Gln Trp Tyr Lys Asp Arg Lys Ala Val Thr
340 345 350
Gly Arg His Asn Pro His Ala Leu Val Leu Lys Glu Val Thr Glu Ala
355 360 365
Ser Ala Gly Val Tyr Thr Leu Ala Leu Trp Asn Ser Ala Ala Gly Leu
370 375 380
Arg Gln Asn Ile Ser Leu Glu Leu Val Val Asn Val Pro Pro His Ile
385 390 395 400
His Glu Lys Glu Ala Ser Ser Pro Ser Ile Tyr Ser Arg His Ser Arg
405 410 415
Gln Thr Leu Thr Cys Thr Ala Tyr Gly Val Pro Gln Pro Leu Ser Val
420 425 430
Gln Trp His Trp Arg Pro Trp Thr Pro Cys Lys Thr Phe Ala Gln Arg
435 440 445
Ser Leu Arg Arg Arg Gln Gln Arg Asp Gly Met Pro Gln Cys Arg Asp
450 455 460
Trp Lys Glu Val Thr Thr Gln Asp Ala Val Asn Pro Ile Glu Ser Leu
465 470 475 480
Asp Ser Trp Thr Glu Phe Val Glu Gly Lys Asn Lys Thr Val Ser Lys
485 490 495
Leu Val Ile Gln Asp Ala Asn Val Ser Ala Met Tyr Lys Cys Val Val
500 505 510
Val Asn Lys Val Gly Gln Asp Glu Arg Leu Ile Tyr Phe Tyr Val Thr
515 520 525
Thr Ile Pro Asp Gly Phe Ser Ile Glu Ser Glu Pro Ser Glu Asp Pro
530 535 540
Leu Glu Gly Gln Ser Val Arg Leu Ser Cys Arg Ala Asp Asn Tyr Thr
545 550 555 560
Tyr Glu His Leu Arg Trp Tyr Arg Leu Asn Leu Ser Thr Leu His Asp
565 570 575
Ala Gln Gly Asn Pro Leu Leu Leu Asp Cys Lys Asn Val His Leu Phe
580 585 590
Ala Thr Pro Leu Glu Ala Asn Leu Glu Glu Ala Glu Pro Gly Ala Arg
595 600 605
His Ala Thr Leu Ser Leu Asn Ile Pro Arg Val Ala Pro Glu Asp Glu
610 615 620
Gly Asp Tyr Val Cys Glu Val Gln Asp Arg Arg Ser Gln Asp Lys His
625 630 635 640
Cys His Lys Lys Tyr Leu Ser Val Gln Ala Leu Glu Ala Pro Arg Leu
645 650 655
Thr Gln Asn Leu Thr Asp Leu Leu Val Asn Val Ser Asp Ser Leu Glu
660 665 670
Met Arg Cys Pro Val Ala Gly Ala His Val Pro Ser Ile Val Trp Tyr
675 680 685
Lys Asp Glu Arg Leu Leu Glu Lys Glu Ser Gly Ile Asp Leu Ala Asp
690 695 700
Ser Asn Gln Arg Leu Ser Ile Gln Arg Val Arg Glu Glu Asp Ala Gly
705 710 715 720
Arg Tyr Leu Cys Ser Val Cys Asn Ala Lys Gly Cys Val Asn Ser Ser
725 730 735
Ala Ser Val Ala Val Glu Gly Ser Glu Asp Lys Gly Ser Met Glu
740 745 750
<210> 31
<211> 751
<212> PRT
<213> 大鼠(Rat)
<400> 31
Tyr Ser Met Thr Pro Pro Thr Leu Asn Ile Thr Glu Asp Ser Tyr Val
1 5 10 15
Ile Asp Thr Gly Asp Ser Leu Ser Ile Ser Cys Arg Gly Gln His Pro
20 25 30
Leu Glu Trp Thr Trp Arg Gly Ala Gln Glu Val Leu Thr Thr Gly Gly
35 40 45
Lys Asp Ser Glu Asp Thr Gln Val Val Gln Asp Cys Glu Gly Thr Glu
50 55 60
Ala Arg Pro Tyr Cys Lys Val Leu Ser Leu Ala Gln Thr His Ala Asn
65 70 75 80
Asn Thr Gly Ser Tyr Tyr Cys Tyr Tyr Lys Tyr Ile Lys Ala Arg Ile
85 90 95
Glu Gly Thr Thr Ala Ala Ser Thr Tyr Val Phe Val Arg Asp Phe Glu
100 105 110
Gln Pro Phe Ile Asn Lys Pro Asp Thr Leu Leu Val Asn Arg Lys Asp
115 120 125
Ser Met Trp Val Pro Cys Leu Val Ser Ile Pro Gly Leu Asn Ile Thr
130 135 140
Leu Arg Ser Gln Ser Ser Val Leu His Pro Asp Gly Gln Glu Val Leu
145 150 155 160
Trp Asp Asp Arg Arg Gly Met Arg Val Pro Thr Leu Leu Leu Arg Asp
165 170 175
Ala Leu Tyr Leu Gln Cys Glu Thr Thr Trp Gly Asp Gln Asp Phe Leu
180 185 190
Ser Asn Pro Phe Leu Val His Ile Thr Gly Asn Glu Leu Tyr Asp Ile
195 200 205
Gln Leu Tyr Pro Lys Lys Ser Leu Glu Leu Leu Val Gly Glu Lys Leu
210 215 220
Val Leu Asn Cys Thr Val Trp Ala Glu Phe Asp Ser Gly Val Thr Phe
225 230 235 240
Asp Trp Asp Tyr Pro Gly Lys Gln Ala Glu Arg Ala Lys Trp Val Pro
245 250 255
Glu Arg Arg Ser Gln Gln Thr His Thr Glu Leu Ser Ser Ile Leu Thr
260 265 270
Ile His Asn Val Ser Gln His Asp Leu Gly Pro Tyr Val Cys Glu Ala
275 280 285
Asn Asn Gly Ile Gln Gln Phe Arg Glu Ser Thr Glu Val Ile Val His
290 295 300
Glu Lys Pro Phe Ile Ser Val Glu Trp Leu Lys Gly Pro Val Leu Glu
305 310 315 320
Ala Thr Ala Gly Asp Glu Met Val Lys Leu Pro Val Lys Leu Ala Ala
325 330 335
Tyr Pro Pro Pro Glu Phe Gln Trp Tyr Lys Asp Arg Lys Ala Val Thr
340 345 350
Gly Arg His Asn Pro His Ala Leu Val Leu Lys Glu Val Thr Glu Ala
355 360 365
Ser Ala Gly Val Tyr Thr Leu Ala Leu Trp Asn Ser Ala Ala Gly Leu
370 375 380
Arg Gln Asn Ile Ser Leu Glu Leu Val Val Asn Val Pro Pro His Ile
385 390 395 400
His Glu Lys Glu Ala Ser Ser Pro Ser Ile Tyr Ser Arg His Ser Arg
405 410 415
Gln Thr Leu Thr Cys Thr Thr Tyr Gly Val Pro Gln Pro Leu Ser Val
420 425 430
Gln Trp His Trp Arg Pro Trp Thr Pro Cys Lys Thr Phe Ala Gln Arg
435 440 445
Ser Leu Arg Arg Arg Gln Pro Arg Asp Gly Met Pro Gln Cys Arg Asp
450 455 460
Trp Lys Glu Val Thr Thr Gln Asp Ala Val Asn Pro Ile Glu Ser Leu
465 470 475 480
Asp Thr Trp Thr Glu Ser Val Glu Gly Lys Asn Lys Thr Val Ser Lys
485 490 495
Leu Val Ile Gln Asp Ala Asn Val Ser Ala Met Tyr Lys Cys Val Val
500 505 510
Phe Asn Lys Val Gly Gln Asp Glu Arg Leu Ile Tyr Phe Tyr Val Thr
515 520 525
Thr Ile Pro Asp Gly Phe Ser Ile Glu Ser Glu Pro Ser Glu Asp Pro
530 535 540
Leu Glu Gly Gln Ser Val Arg Leu Ser Cys Arg Ala Asp Asn Tyr Thr
545 550 555 560
Tyr Glu His Leu Arg Trp Tyr Arg Leu Asn Leu Ser Thr Leu His Asp
565 570 575
Ala Gln Gly Asn Pro Leu Leu Leu Asp Cys Lys Asn Val His Leu Phe
580 585 590
Ala Thr Pro Leu Glu Ala Asn Leu Glu Glu Ala Glu Pro Gly Ala Arg
595 600 605
His Ala Thr Leu Ser Leu Asn Ile Pro Arg Val Ala Pro Glu Asp Glu
610 615 620
Gly Asp Tyr Val Cys Glu Val Gln Asp Arg Arg Ser Gln Asp Lys His
625 630 635 640
Cys His Lys Lys Tyr Leu Ser Val Gln Ala Leu Glu Ala Pro Arg Leu
645 650 655
Thr Gln Asn Leu Thr Asp Leu Leu Val Asn Val Arg Thr Ser Leu Glu
660 665 670
Met Arg Cys Pro Val Ala Gly Ala His Val Pro Ser Ile Val Trp Tyr
675 680 685
Lys Asp Glu Arg Leu Leu Glu Lys Glu Ser Gly Ile Asp Leu Ala Asp
690 695 700
Ser Asn Gln Arg Leu Ser Ile Gln Arg Val Arg Glu Glu Asp Ala Gly
705 710 715 720
Arg Tyr Leu Cys Ser Val Cys Asn Ala Lys Gly Cys Val Asn Ser Ser
725 730 735
Ala Ser Val Ala Val Glu Gly Ser Glu Asp Lys Gly Ser Met Glu
740 745 750
<210> 32
<211> 220
<212> PRT
<213> 人(Human)
<400> 32
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
1 5 10 15
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
20 25 30
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
35 40 45
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
50 55 60
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
65 70 75 80
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
85 90 95
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
100 105 110
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
115 120 125
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
130 135 140
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
145 150 155 160
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
165 170 175
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
180 185 190
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
195 200 205
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215 220
<210> 33
<211> 223
<212> PRT
<213> 人(Human)
<400> 33
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
35 40 45
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
100 105 110
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215 220
<210> 34
<211> 223
<212> PRT
<213> 人(Human)
<400> 34
Thr Cys Pro Arg Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
35 40 45
Val Gln Phe Lys Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
100 105 110
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Ser
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Gln Gly Asn Ile Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn Arg Phe Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210 215 220
<210> 35
<211> 4474
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> pITR.CBA.贝伐单抗
<400> 35
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct gcggccgcac gcgtgacatt gattattgac tagttattaa tagtaatcaa 180
ttacggggtc attagttcat agcccatata tggagttccg cgttacataa cttacggtaa 240
atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 300
ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggac tatttacggt 360
aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 420
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 480
ctacttggca gtacatctac gtattagtca tcgctattac catgggtcga ggtgagcccc 540
acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtatttattt 600
attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg cgccaggcgg 660
ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg cagccaatca 720
gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc ggccctataa 780
aaagcgaagc gcgcggcggg cgggagtcgc tgcgttgcct tcgccccgtg ccccgctccg 840
cgccgcctcg cgccgcccgc cccggctctg actgaccgcg ttactcccac aggtgagcgg 900
gcgggacggc ccttctcctc cgggctgtaa ttagcgcttg gtttaatgac ggctcgtttc 960
ttttctgtgg ctgcgtgaaa gccttaaagg gctccgggag ggccctttgt gcggggggga 1020
gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggcccgcgct 1080
gcccggcggc tgtgagcgct gcgggcgcgg cgcggggctt tgtgcgctcc gcgtgtgcgc 1140
gaggggagcg cggccggggg cggtgccccg cggtgcgggg gggctgcgag gggaacaaag 1200
gctgcgtgcg gggtgtgtgc gtgggggggt gagcaggggg tgtgggcgcg gcggtcgggc 1260
tgtaaccccc ccctgcaccc ccctccccga gttgctgagc acggcccggc ttcgggtgcg 1320
gggctccgtg cggggcgtgg cgcggggctc gccgtgccgg gcggggggtg gcggcaggtg 1380
ggggtgccgg gcggggcggg gccgcctcgg gccggggagg gctcggggga ggggcgcggc 1440
ggcccccgga gcgccggcgg ctgtcgaggc gcggcgagcc gcagccattg ccttttatgg 1500
taatcgtgcg agagggcgca gggacttcct ttgtcccaaa tctgtgcgga gccgaaatct 1560
gggaggcgcc gccgcacccc ctctagcggg cgcggggcga agcggtgcgg cgccggcagg 1620
aaggaaatgg gcggggaggg ccttcgtgcg tcgccgcgcc gccgtcccct tctccctctc 1680
cagcctcggg gctgtccgcg gggggacggc tgccttcggg ggggacgggg cagggcgggg 1740
ttcggcttct ggcgtgtgac cggcggctct agagcctctg ctaaccatgt tcatgccttc 1800
ttctttttcc tacagctcct gggcaacgtg ctggttattg tgaccggtgc caccatgtac 1860
cggatgcagc tgctgagctg tatcgccctg tctctggccc tggtcaccaa ttctgaggtg 1920
cagctggtgg aatctggcgg cggacttgtt caacctggcg gctctctgag actgagctgt 1980
gccgcttctg gctacacctt caccaactac ggcatgaact gggtccgaca ggcccctggc 2040
aaaggccttg aatgggtcgg atggatcaac acctacaccg gcgagccaac atacgccgcc 2100
gacttcaagc ggagattcac cttcagcctg gacaccagca agagcaccgc ctacctgcag 2160
atgaacagcc tgagagccga ggacaccgcc gtgtactact gcgccaagta tccccactac 2220
tacggcagca gccactggta ctttgacgtg tggggacagg gcacactggt cacagtgtct 2280
agcgcctcta caaagggccc cagcgttttc ccactggctc ctagcagcaa gtctaccagc 2340
ggaggaacag ccgctctggg ctgtctggtc aaggactact ttcccgagcc tgtgaccgtg 2400
tcctggaatt ctggcgctct gacaagcggc gtgcacacct ttccagctgt gctgcaaagc 2460
agcggcctgt actctctgag cagcgtcgtg acagtgccaa gcagctctct gggcacccag 2520
acctacatct gcaatgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggaa 2580
cccaagagct gcgacaagac ccacacctgt cctccatgtc ctgctccaga actgctcggc 2640
ggaccttccg tgttcctgtt tcctccaaag cctaaggaca ccctgatgat cagcagaacc 2700
cctgaagtga cctgcgtggt ggtggatgtg tcccacgagg atcccgaagt gaagttcaat 2760
tggtacgtgg acggcgtgga agtgcacaac gccaagacca agcctagaga ggaacagtac 2820
aacagcacct acagagtggt gtccgtgctg accgtgctgc accaggattg gctgaacggc 2880
aaagagtaca agtgcaaggt gtccaacaag gccctgcctg ctcctatcga gaaaaccatc 2940
agcaaggcca agggccagcc tagggaaccc caggtttaca cactgcctcc aagccgggaa 3000
gagatgacca agaaccaggt gtccctgacc tgcctcgtga agggcttcta cccttccgat 3060
atcgccgtgg aatgggagag caatggccag ccagagaaca actacaagac aacccctcct 3120
gtgctggaca gcgacggctc attcttcctg tacagcaagc tgacagtgga caagtccaga 3180
tggcagcagg gcaacgtgtt cagctgcagc gtgatgcacg aggccctgca caaccactac 3240
acccagaagt ctctgagcct gtctcctggc aagcggaaga gaagaggctc tggcgaaggc 3300
agaggcagcc tgcttacatg tggcgacgtg gaagagaacc ccggacctat gtatagaatg 3360
cagctcctgt cctgcattgc cctgagcctg gctctcgtga ccaacagcga catccagatg 3420
acacagagcc ccagcagcct gtctgcctct gtgggagaca gagtgaccat cacctgtagc 3480
gccagccagg acatctccaa ctacctgaac tggtatcagc aaaagcccgg caaggcccct 3540
aaggtgctga tctacttcac aagcagcctg cactccggcg tgcccagcag attttctggc 3600
tctggcagcg gcaccgactt caccctgacc atatctagcc tgcagcctga ggacttcgcc 3660
acctactact gccagcagta cagcaccgtg ccttggacat ttggccaggg cacaaaggtg 3720
gaaatcaagc ggactgtggc cgctcctagc gtgttcatct ttccacctag cgacgagcag 3780
ctgaagtctg gcacagcctc tgtcgtgtgc ctgctgaaca acttctaccc cagagaagcc 3840
aaggtgcagt ggaaagtgga caatgccctg cagagcggca acagccaaga gagcgtgaca 3900
gagcaggact ccaaggatag cacctatagc ctgagcagca ccctgacact gagcaaggcc 3960
gactacgaga agcacaaagt gtacgcctgc gaagtgaccc accagggcct ttctagccct 4020
gtgaccaaga gcttcaaccg gggcgaatgt taagagctcg ctgatcagcc tcgactgtgc 4080
cttctagttg ccagccatct gttgtttgcc cctcccccgt gccttccttg accctggaag 4140
gtgccactcc cactgtcctt tcctaataaa atgaggaaat tgcatcgcat tgtctgagta 4200
ggtgtcattc tattctgggg ggtggggtgg ggcaggacag caagggggag gattgggaag 4260
acaatagcag gcatgctggg gatgcggtgg gctctatgga agcttgaatt cagctgacgt 4320
gcctcggacc gctaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc 4380
tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc 4440
tcagtgagcg agcgagcgcg cagctgcctg cagg 4474
<210> 36
<211> 144
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> ITR序列
<400> 36
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct gcggccgcac gcgt 144
<210> 37
<211> 1671
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> CBA序列
<400> 37
gacattgatt attgactagt tattaatagt aatcaattac ggggtcatta gttcatagcc 60
catatatgga gttccgcgtt acataactta cggtaaatgg cccgcctggc tgaccgccca 120
acgacccccg cccattgacg tcaataatga cgtatgttcc catagtaacg ccaataggga 180
ctttccattg acgtcaatgg gtggactatt tacggtaaac tgcccacttg gcagtacatc 240
aagtgtatca tatgccaagt acgcccccta ttgacgtcaa tgacggtaaa tggcccgcct 300
ggcattatgc ccagtacatg accttatggg actttcctac ttggcagtac atctacgtat 360
tagtcatcgc tattaccatg ggtcgaggtg agccccacgt tctgcttcac tctccccatc 420
tcccccccct ccccaccccc aattttgtat ttatttattt tttaattatt ttgtgcagcg 480
atgggggcgg gggggggggg ggcgcgcgcc aggcggggcg gggcggggcg aggggcgggg 540
cggggcgagg cggagaggtg cggcggcagc caatcagagc ggcgcgctcc gaaagtttcc 600
ttttatggcg aggcggcggc ggcggcggcc ctataaaaag cgaagcgcgc ggcgggcggg 660
agtcgctgcg ttgccttcgc cccgtgcccc gctccgcgcc gcctcgcgcc gcccgccccg 720
gctctgactg accgcgttac tcccacaggt gagcgggcgg gacggccctt ctcctccggg 780
ctgtaattag cgcttggttt aatgacggct cgtttctttt ctgtggctgc gtgaaagcct 840
taaagggctc cgggagggcc ctttgtgcgg gggggagcgg ctcggggggt gcgtgcgtgt 900
gtgtgtgcgt ggggagcgcc gcgtgcggcc cgcgctgccc ggcggctgtg agcgctgcgg 960
gcgcggcgcg gggctttgtg cgctccgcgt gtgcgcgagg ggagcgcggc cgggggcggt 1020
gccccgcggt gcgggggggc tgcgagggga acaaaggctg cgtgcggggt gtgtgcgtgg 1080
gggggtgagc agggggtgtg ggcgcggcgg tcgggctgta acccccccct gcacccccct 1140
ccccgagttg ctgagcacgg cccggcttcg ggtgcggggc tccgtgcggg gcgtggcgcg 1200
gggctcgccg tgccgggcgg ggggtggcgg caggtggggg tgccgggcgg ggcggggccg 1260
cctcgggccg gggagggctc gggggagggg cgcggcggcc cccggagcgc cggcggctgt 1320
cgaggcgcgg cgagccgcag ccattgcctt ttatggtaat cgtgcgagag ggcgcaggga 1380
cttcctttgt cccaaatctg tgcggagccg aaatctggga ggcgccgccg caccccctct 1440
agcgggcgcg gggcgaagcg gtgcggcgcc ggcaggaagg aaatgggcgg ggagggcctt 1500
cgtgcgtcgc cgcgccgccg tccccttctc cctctccagc ctcggggctg tccgcggggg 1560
gacggctgcc ttcggggggg acggggcagg gcggggttcg gcttctggcg tgtgaccggc 1620
ggctctagag cctctgctaa ccatgttcat gccttcttct ttttcctaca g 1671
<210> 38
<211> 39
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 间隔子
<400> 38
ctcctgggca acgtgctggt tattgtgacc ggtgccacc 39
<210> 39
<211> 60
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> IL-2分泌信号序列
<400> 39
atgtaccgga tgcagctgct gagctgtatc gccctgtctc tggccctggt caccaattct 60
<210> 40
<211> 1359
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码贝伐单抗的重链的序列
<400> 40
gaggtgcagc tggtggaatc tggcggcgga cttgttcaac ctggcggctc tctgagactg 60
agctgtgccg cttctggcta caccttcacc aactacggca tgaactgggt ccgacaggcc 120
cctggcaaag gccttgaatg ggtcggatgg atcaacacct acaccggcga gccaacatac 180
gccgccgact tcaagcggag attcaccttc agcctggaca ccagcaagag caccgcctac 240
ctgcagatga acagcctgag agccgaggac accgccgtgt actactgcgc caagtatccc 300
cactactacg gcagcagcca ctggtacttt gacgtgtggg gacagggcac actggtcaca 360
gtgtctagcg cctctacaaa gggccccagc gttttcccac tggctcctag cagcaagtct 420
accagcggag gaacagccgc tctgggctgt ctggtcaagg actactttcc cgagcctgtg 480
accgtgtcct ggaattctgg cgctctgaca agcggcgtgc acacctttcc agctgtgctg 540
caaagcagcg gcctgtactc tctgagcagc gtcgtgacag tgccaagcag ctctctgggc 600
acccagacct acatctgcaa tgtgaaccac aagcctagca acaccaaggt ggacaagaag 660
gtggaaccca agagctgcga caagacccac acctgtcctc catgtcctgc tccagaactg 720
ctcggcggac cttccgtgtt cctgtttcct ccaaagccta aggacaccct gatgatcagc 780
agaacccctg aagtgacctg cgtggtggtg gatgtgtccc acgaggatcc cgaagtgaag 840
ttcaattggt acgtggacgg cgtggaagtg cacaacgcca agaccaagcc tagagaggaa 900
cagtacaaca gcacctacag agtggtgtcc gtgctgaccg tgctgcacca ggattggctg 960
aacggcaaag agtacaagtg caaggtgtcc aacaaggccc tgcctgctcc tatcgagaaa 1020
accatcagca aggccaaggg ccagcctagg gaaccccagg tttacacact gcctccaagc 1080
cgggaagaga tgaccaagaa ccaggtgtcc ctgacctgcc tcgtgaaggg cttctaccct 1140
tccgatatcg ccgtggaatg ggagagcaat ggccagccag agaacaacta caagacaacc 1200
cctcctgtgc tggacagcga cggctcattc ttcctgtaca gcaagctgac agtggacaag 1260
tccagatggc agcagggcaa cgtgttcagc tgcagcgtga tgcacgaggc cctgcacaac 1320
cactacaccc agaagtctct gagcctgtct cctggcaag 1359
<210> 41
<211> 12
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 接头序列
<400> 41
cggaagagaa ga 12
<210> 42
<211> 63
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> T2A序列
<400> 42
ggctctggcg aaggcagagg cagcctgctt acatgtggcg acgtggaaga gaaccccgga 60
cct 63
<210> 43
<211> 60
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> IL-2分泌信号序列
<400> 43
atgtatagaa tgcagctcct gtcctgcatt gccctgagcc tggctctcgt gaccaacagc 60
<210> 44
<211> 645
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码贝伐单抗的轻链的序列
<400> 44
gacatccaga tgacacagag ccccagcagc ctgtctgcct ctgtgggaga cagagtgacc 60
atcacctgta gcgccagcca ggacatctcc aactacctga actggtatca gcaaaagccc 120
ggcaaggccc ctaaggtgct gatctacttc acaagcagcc tgcactccgg cgtgcccagc 180
agattttctg gctctggcag cggcaccgac ttcaccctga ccatatctag cctgcagcct 240
gaggacttcg ccacctacta ctgccagcag tacagcaccg tgccttggac atttggccag 300
ggcacaaagg tggaaatcaa gcggactgtg gccgctccta gcgtgttcat ctttccacct 360
agcgacgagc agctgaagtc tggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420
cccagagaag ccaaggtgca gtggaaagtg gacaatgccc tgcagagcgg caacagccaa 480
gagagcgtga cagagcagga ctccaaggat agcacctata gcctgagcag caccctgaca 540
ctgagcaagg ccgactacga gaagcacaaa gtgtacgcct gcgaagtgac ccaccagggc 600
ctttctagcc ctgtgaccaa gagcttcaac cggggcgaat gttaa 645
<210> 45
<211> 21
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 接头序列
<400> 45
gagctcgctg atcagcctcg a 21
<210> 46
<211> 225
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 牛生长激素polyA尾巴序列
<400> 46
ctgtgccttc tagttgccag ccatctgttg tttgcccctc ccccgtgcct tccttgaccc 60
tggaaggtgc cactcccact gtcctttcct aataaaatga ggaaattgca tcgcattgtc 120
tgagtaggtg tcattctatt ctggggggtg gggtggggca ggacagcaag ggggaggatt 180
gggaagacaa tagcaggcat gctggggatg cggtgggctc tatgg 225
<210> 47
<211> 34
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 接头序列
<400> 47
aagcttgaat tcagctgacg tgcctcggac cgct 34
<210> 48
<211> 141
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> ITR
<400> 48
aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg ctcactgagg 60
ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca gtgagcgagc 120
gagcgcgcag ctgcctgcag g 141
<210> 49
<211> 20
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> IL-2信号序列
<400> 49
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser
20
<210> 50
<211> 21
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> T2A序列
<400> 50
Gly Ser Gly Glu Gly Arg Gly Ser Leu Leu Thr Cys Gly Asp Val Glu
1 5 10 15
Glu Asn Pro Gly Pro
20
<210> 51
<211> 3814
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> pITR.CBA.lucentis
<400> 51
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct gcggccgcac gcgtgacatt gattattgac tagttattaa tagtaatcaa 180
ttacggggtc attagttcat agcccatata tggagttccg cgttacataa cttacggtaa 240
atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 300
ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggac tatttacggt 360
aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 420
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 480
ctacttggca gtacatctac gtattagtca tcgctattac catgggtcga ggtgagcccc 540
acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtatttattt 600
attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg cgccaggcgg 660
ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg cagccaatca 720
gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc ggccctataa 780
aaagcgaagc gcgcggcggg cgggagtcgc tgcgttgcct tcgccccgtg ccccgctccg 840
cgccgcctcg cgccgcccgc cccggctctg actgaccgcg ttactcccac aggtgagcgg 900
gcgggacggc ccttctcctc cgggctgtaa ttagcgcttg gtttaatgac ggctcgtttc 960
ttttctgtgg ctgcgtgaaa gccttaaagg gctccgggag ggccctttgt gcggggggga 1020
gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggcccgcgct 1080
gcccggcggc tgtgagcgct gcgggcgcgg cgcggggctt tgtgcgctcc gcgtgtgcgc 1140
gaggggagcg cggccggggg cggtgccccg cggtgcgggg gggctgcgag gggaacaaag 1200
gctgcgtgcg gggtgtgtgc gtgggggggt gagcaggggg tgtgggcgcg gcggtcgggc 1260
tgtaaccccc ccctgcaccc ccctccccga gttgctgagc acggcccggc ttcgggtgcg 1320
gggctccgtg cggggcgtgg cgcggggctc gccgtgccgg gcggggggtg gcggcaggtg 1380
ggggtgccgg gcggggcggg gccgcctcgg gccggggagg gctcggggga ggggcgcggc 1440
ggcccccgga gcgccggcgg ctgtcgaggc gcggcgagcc gcagccattg ccttttatgg 1500
taatcgtgcg agagggcgca gggacttcct ttgtcccaaa tctgtgcgga gccgaaatct 1560
gggaggcgcc gccgcacccc ctctagcggg cgcggggcga agcggtgcgg cgccggcagg 1620
aaggaaatgg gcggggaggg ccttcgtgcg tcgccgcgcc gccgtcccct tctccctctc 1680
cagcctcggg gctgtccgcg gggggacggc tgccttcggg ggggacgggg cagggcgggg 1740
ttcggcttct ggcgtgtgac cggcggctct agagcctctg ctaaccatgt tcatgccttc 1800
ttctttttcc tacagctcct gggcaacgtg ctggttattg tgaccggtgc caccatgtac 1860
cggatgcagc tgctgagctg tatcgccctg tctctggccc tggtcaccaa ttctgaggtg 1920
cagctggtgg aatctggcgg cggacttgtt caacctggcg gctctctgag actgagctgt 1980
gccgcttctg gctacgactt cacccactac ggcatgaact gggtccgaca ggcccctggc 2040
aaaggccttg aatgggtcgg atggatcaac acctacaccg gcgagccaac atacgccgcc 2100
gacttcaagc ggagattcac cttcagcctg gacaccagca agagcaccgc ctacctgcag 2160
atgaacagcc tgagagccga ggacaccgcc gtgtactact gcgccaagta tccctactac 2220
tacggcacca gccactggta ctttgacgtg tggggacagg gcacactggt cacagtgtct 2280
agcgcctcta caaagggccc cagcgttttc ccactggctc ctagcagcaa gtctaccagc 2340
ggaggaacag ccgctctggg ctgtctggtc aaggactact ttcccgagcc tgtgaccgtg 2400
tcctggaatt ctggcgctct gacaagcggc gtgcacacct ttccagctgt gctgcaaagc 2460
agcggcctgt actctctgag cagcgtcgtg acagtgccaa gcagctctct gggcacccag 2520
acctacatct gcaatgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggaa 2580
cccaagagct gcgacaagac ccacaccggc aagcggaaga gaagaggctc tggcgaaggc 2640
agaggcagcc tgcttacatg tggcgacgtg gaagagaacc ccggacctat gtatagaatg 2700
cagctcctgt cctgcattgc cctgagcctg gctctcgtga ccaacagcga catccagctg 2760
acacagagcc ccagcagcct gtctgcctct gtgggagaca gagtgaccat cacctgtagc 2820
gccagccagg acatctccaa ctacctgaac tggtatcagc aaaagcccgg caaggcccct 2880
aaggtgctga tctacttcac aagcagcctg cactccggcg tgcccagcag attttctggc 2940
tctggcagcg gcaccgactt caccctgacc atatctagcc tgcagcctga ggacttcgcc 3000
acctactact gccagcagta cagcaccgtg ccttggacat ttggccaggg cacaaaggtg 3060
gaaatcaagc ggactgtggc cgctcctagc gtgttcatct ttccacctag cgacgagcag 3120
ctgaagtctg gcacagcctc tgtcgtgtgc ctgctgaaca acttctaccc cagagaagcc 3180
aaggtgcagt ggaaagtgga caatgccctg cagagcggca acagccaaga gagcgtgaca 3240
gagcaggact ccaaggatag cacctatagc ctgagcagca ccctgacact gagcaaggcc 3300
gactacgaga agcacaaagt gtacgcctgc gaagtgaccc accagggcct ttctagccct 3360
gtgaccaaga gcttcaaccg gggcgaatgt taagagctcg ctgatcagcc tcgactgtgc 3420
cttctagttg ccagccatct gttgtttgcc cctcccccgt gccttccttg accctggaag 3480
gtgccactcc cactgtcctt tcctaataaa atgaggaaat tgcatcgcat tgtctgagta 3540
ggtgtcattc tattctgggg ggtggggtgg ggcaggacag caagggggag gattgggaag 3600
acaatagcag gcatgctggg gatgcggtgg gctctatgga agcttgaatt cagctgacgt 3660
gcctcggacc gctaggaacc cctagtgatg gagttggcca ctccctctct gcgcgctcgc 3720
tcgctcactg aggccgggcg accaaaggtc gcccgacgcc cgggctttgc ccgggcggcc 3780
tcagtgagcg agcgagcgcg cagctgcctg cagg 3814
<210> 52
<211> 699
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码兰尼单抗重链的序列
<400> 52
gaggtgcagc tggtggaatc tggcggcgga cttgttcaac ctggcggctc tctgagactg 60
agctgtgccg cttctggcta cgacttcacc cactacggca tgaactgggt ccgacaggcc 120
cctggcaaag gccttgaatg ggtcggatgg atcaacacct acaccggcga gccaacatac 180
gccgccgact tcaagcggag attcaccttc agcctggaca ccagcaagag caccgcctac 240
ctgcagatga acagcctgag agccgaggac accgccgtgt actactgcgc caagtatccc 300
tactactacg gcaccagcca ctggtacttt gacgtgtggg gacagggcac actggtcaca 360
gtgtctagcg cctctacaaa gggccccagc gttttcccac tggctcctag cagcaagtct 420
accagcggag gaacagccgc tctgggctgt ctggtcaagg actactttcc cgagcctgtg 480
accgtgtcct ggaattctgg cgctctgaca agcggcgtgc acacctttcc agctgtgctg 540
caaagcagcg gcctgtactc tctgagcagc gtcgtgacag tgccaagcag ctctctgggc 600
acccagacct acatctgcaa tgtgaaccac aagcctagca acaccaaggt ggacaagaag 660
gtggaaccca agagctgcga caagacccac accggcaag 699
<210> 53
<211> 645
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码兰尼单抗轻链的序列
<400> 53
gacatccagc tgacacagag ccccagcagc ctgtctgcct ctgtgggaga cagagtgacc 60
atcacctgta gcgccagcca ggacatctcc aactacctga actggtatca gcaaaagccc 120
ggcaaggccc ctaaggtgct gatctacttc acaagcagcc tgcactccgg cgtgcccagc 180
agattttctg gctctggcag cggcaccgac ttcaccctga ccatatctag cctgcagcct 240
gaggacttcg ccacctacta ctgccagcag tacagcaccg tgccttggac atttggccag 300
ggcacaaagg tggaaatcaa gcggactgtg gccgctccta gcgtgttcat ctttccacct 360
agcgacgagc agctgaagtc tggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420
cccagagaag ccaaggtgca gtggaaagtg gacaatgccc tgcagagcgg caacagccaa 480
gagagcgtga cagagcagga ctccaaggat agcacctata gcctgagcag caccctgaca 540
ctgagcaagg ccgactacga gaagcacaaa gtgtacgcct gcgaagtgac ccaccagggc 600
ctttctagcc ctgtgaccaa gagcttcaac cggggcgaat gttaa 645
<210> 54
<211> 233
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> 兰尼单抗重链
<400> 54
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Gly Lys
225 230
<210> 55
<211> 4573
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> pITR.CBA.Lucentis.tGFP
<400> 55
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct gcggccgcac gcgtgacatt gattattgac tagttattaa tagtaatcaa 180
ttacggggtc attagttcat agcccatata tggagttccg cgttacataa cttacggtaa 240
atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 300
ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggac tatttacggt 360
aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 420
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 480
ctacttggca gtacatctac gtattagtca tcgctattac catgggtcga ggtgagcccc 540
acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtatttattt 600
attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg cgccaggcgg 660
ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg cagccaatca 720
gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc ggccctataa 780
aaagcgaagc gcgcggcggg cgggagtcgc tgcgttgcct tcgccccgtg ccccgctccg 840
cgccgcctcg cgccgcccgc cccggctctg actgaccgcg ttactcccac aggtgagcgg 900
gcgggacggc ccttctcctc cgggctgtaa ttagcgcttg gtttaatgac ggctcgtttc 960
ttttctgtgg ctgcgtgaaa gccttaaagg gctccgggag ggccctttgt gcggggggga 1020
gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggcccgcgct 1080
gcccggcggc tgtgagcgct gcgggcgcgg cgcggggctt tgtgcgctcc gcgtgtgcgc 1140
gaggggagcg cggccggggg cggtgccccg cggtgcgggg gggctgcgag gggaacaaag 1200
gctgcgtgcg gggtgtgtgc gtgggggggt gagcaggggg tgtgggcgcg gcggtcgggc 1260
tgtaaccccc ccctgcaccc ccctccccga gttgctgagc acggcccggc ttcgggtgcg 1320
gggctccgtg cggggcgtgg cgcggggctc gccgtgccgg gcggggggtg gcggcaggtg 1380
ggggtgccgg gcggggcggg gccgcctcgg gccggggagg gctcggggga ggggcgcggc 1440
ggcccccgga gcgccggcgg ctgtcgaggc gcggcgagcc gcagccattg ccttttatgg 1500
taatcgtgcg agagggcgca gggacttcct ttgtcccaaa tctgtgcgga gccgaaatct 1560
gggaggcgcc gccgcacccc ctctagcggg cgcggggcga agcggtgcgg cgccggcagg 1620
aaggaaatgg gcggggaggg ccttcgtgcg tcgccgcgcc gccgtcccct tctccctctc 1680
cagcctcggg gctgtccgcg gggggacggc tgccttcggg ggggacgggg cagggcgggg 1740
ttcggcttct ggcgtgtgac cggcggctct agagcctctg ctaaccatgt tcatgccttc 1800
ttctttttcc tacagctcct gggcaacgtg ctggttattg tgaccggtgc caccatgtac 1860
cggatgcagc tgctgagctg tatcgccctg tctctggccc tggtcaccaa ttctgaggtg 1920
cagctggtgg aatctggcgg cggacttgtt caacctggcg gctctctgag actgagctgt 1980
gccgcttctg gctacgactt cacccactac ggcatgaact gggtccgaca ggcccctggc 2040
aaaggccttg aatgggtcgg atggatcaac acctacaccg gcgagccaac atacgccgcc 2100
gacttcaagc ggagattcac cttcagcctg gacaccagca agagcaccgc ctacctgcag 2160
atgaacagcc tgagagccga ggacaccgcc gtgtactact gcgccaagta tccctactac 2220
tacggcacca gccactggta ctttgacgtg tggggacagg gcacactggt cacagtgtct 2280
agcgcctcta caaagggccc cagcgttttc ccactggctc ctagcagcaa gtctaccagc 2340
ggaggaacag ccgctctggg ctgtctggtc aaggactact ttcccgagcc tgtgaccgtg 2400
tcctggaatt ctggcgctct gacaagcggc gtgcacacct ttccagctgt gctgcaaagc 2460
agcggcctgt actctctgag cagcgtcgtg acagtgccaa gcagctctct gggcacccag 2520
acctacatct gcaatgtgaa ccacaagcct agcaacacca aggtggacaa gaaggtggaa 2580
cccaagagct gcgacaagac ccacaccggc aagcggaaga gaagaggctc tggcgaaggc 2640
agaggcagcc tgcttacatg tggcgacgtg gaagagaacc ccggacctat gtatagaatg 2700
cagctcctgt cctgcattgc cctgagcctg gctctcgtga ccaacagcga catccagctg 2760
acacagagcc ccagcagcct gtctgcctct gtgggagaca gagtgaccat cacctgtagc 2820
gccagccagg acatctccaa ctacctgaac tggtatcagc aaaagcccgg caaggcccct 2880
aaggtgctga tctacttcac aagcagcctg cactccggcg tgcccagcag attttctggc 2940
tctggcagcg gcaccgactt caccctgacc atatctagcc tgcagcctga ggacttcgcc 3000
acctactact gccagcagta cagcaccgtg ccttggacat ttggccaggg cacaaaggtg 3060
gaaatcaagc ggactgtggc cgctcctagc gtgttcatct ttccacctag cgacgagcag 3120
ctgaagtctg gcacagcctc tgtcgtgtgc ctgctgaaca acttctaccc cagagaagcc 3180
aaggtgcagt ggaaagtgga caatgccctg cagagcggca acagccaaga gagcgtgaca 3240
gagcaggact ccaaggatag cacctatagc ctgagcagca ccctgacact gagcaaggcc 3300
gactacgaga agcacaaagt gtacgcctgc gaagtgaccc accagggcct ttctagccct 3360
gtgaccaaga gcttcaaccg gggcgaatgt ggctccggag agggcagagg aagtctgcta 3420
acatgcggtg acgtcgagga gaatcctggc ccaatggaga gcgacgagag cggcctgccc 3480
gccatggaga tcgagtgccg catcaccggc accctgaacg gcgtggagtt cgagctggtg 3540
ggcggcggag agggcacccc cgagcagggc cgcatgacca acaagatgaa gagcaccaaa 3600
ggcgccctga ccttcagccc ctacctgctg agccacgtga tgggctacgg cttctaccac 3660
ttcggcacct accccagcgg ctacgagaac cccttcctgc acgccatcaa caacggcggc 3720
tacaccaaca cccgcatcga gaagtacgag gacggcggcg tgctgcacgt gagcttcagc 3780
taccgctacg aggccggccg cgtgatcggc gacttcaagg tgatgggcac cggcttcccc 3840
gaggacagcg tgatcttcac cgacaagatc atccgcagca acgccaccgt ggagcacctg 3900
caccccatgg gcgataacga tctggatggc agcttcaccc gcaccttcag cctgcgcgac 3960
ggcggctact acagctccgt ggtggacagc cacatgcact tcaagagcgc catccacccc 4020
agcatcctgc agaacggggg ccccatgttc gccttccgcc gcgtggagga ggatcacagc 4080
aacaccgagc tgggcatcgt ggagtaccag cacgccttca agaccccgga tgcagatgcc 4140
ggtgaagaat aagagctcgc tgatcagcct cgactgtgcc ttctagttgc cagccatctg 4200
ttgtttgccc ctcccccgtg ccttccttga ccctggaagg tgccactccc actgtccttt 4260
cctaataaaa tgaggaaatt gcatcgcatt gtctgagtag gtgtcattct attctggggg 4320
gtggggtggg gcaggacagc aagggggagg attgggaaga caatagcagg catgctgggg 4380
atgcggtggg ctctatggaa gcttgaattc agctgacgtg cctcggaccg ctaggaaccc 4440
ctagtgatgg agttggccac tccctctctg cgcgctcgct cgctcactga ggccgggcga 4500
ccaaaggtcg cccgacgccc gggctttgcc cgggcggcct cagtgagcga gcgagcgcgc 4560
agctgcctgc agg 4573
<210> 56
<211> 642
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码兰尼单抗轻链的序列
<400> 56
gacatccagc tgacacagag ccccagcagc ctgtctgcct ctgtgggaga cagagtgacc 60
atcacctgta gcgccagcca ggacatctcc aactacctga actggtatca gcaaaagccc 120
ggcaaggccc ctaaggtgct gatctacttc acaagcagcc tgcactccgg cgtgcccagc 180
agattttctg gctctggcag cggcaccgac ttcaccctga ccatatctag cctgcagcct 240
gaggacttcg ccacctacta ctgccagcag tacagcaccg tgccttggac atttggccag 300
ggcacaaagg tggaaatcaa gcggactgtg gccgctccta gcgtgttcat ctttccacct 360
agcgacgagc agctgaagtc tggcacagcc tctgtcgtgt gcctgctgaa caacttctac 420
cccagagaag ccaaggtgca gtggaaagtg gacaatgccc tgcagagcgg caacagccaa 480
gagagcgtga cagagcagga ctccaaggat agcacctata gcctgagcag caccctgaca 540
ctgagcaagg ccgactacga gaagcacaaa gtgtacgcct gcgaagtgac ccaccagggc 600
ctttctagcc ctgtgaccaa gagcttcaac cggggcgaat gt 642
<210> 57
<211> 63
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 接头序列
<400> 57
ggctccggag agggcagagg aagtctgcta acatgcggtg acgtcgagga gaatcctggc 60
cca 63
<210> 58
<211> 699
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码Turbo GFP的序列
<400> 58
atggagagcg acgagagcgg cctgcccgcc atggagatcg agtgccgcat caccggcacc 60
ctgaacggcg tggagttcga gctggtgggc ggcggagagg gcacccccga gcagggccgc 120
atgaccaaca agatgaagag caccaaaggc gccctgacct tcagccccta cctgctgagc 180
cacgtgatgg gctacggctt ctaccacttc ggcacctacc ccagcggcta cgagaacccc 240
ttcctgcacg ccatcaacaa cggcggctac accaacaccc gcatcgagaa gtacgaggac 300
ggcggcgtgc tgcacgtgag cttcagctac cgctacgagg ccggccgcgt gatcggcgac 360
ttcaaggtga tgggcaccgg cttccccgag gacagcgtga tcttcaccga caagatcatc 420
cgcagcaacg ccaccgtgga gcacctgcac cccatgggcg ataacgatct ggatggcagc 480
ttcacccgca ccttcagcct gcgcgacggc ggctactaca gctccgtggt ggacagccac 540
atgcacttca agagcgccat ccaccccagc atcctgcaga acgggggccc catgttcgcc 600
ttccgccgcg tggaggagga tcacagcaac accgagctgg gcatcgtgga gtaccagcac 660
gccttcaaga ccccggatgc agatgccggt gaagaataa 699
<210> 59
<211> 232
<212> PRT
<213> 人工序列(Artificial sequence)
<220>
<223> Turbo GFP
<400> 59
Met Glu Ser Asp Glu Ser Gly Leu Pro Ala Met Glu Ile Glu Cys Arg
1 5 10 15
Ile Thr Gly Thr Leu Asn Gly Val Glu Phe Glu Leu Val Gly Gly Gly
20 25 30
Glu Gly Thr Pro Glu Gln Gly Arg Met Thr Asn Lys Met Lys Ser Thr
35 40 45
Lys Gly Ala Leu Thr Phe Ser Pro Tyr Leu Leu Ser His Val Met Gly
50 55 60
Tyr Gly Phe Tyr His Phe Gly Thr Tyr Pro Ser Gly Tyr Glu Asn Pro
65 70 75 80
Phe Leu His Ala Ile Asn Asn Gly Gly Tyr Thr Asn Thr Arg Ile Glu
85 90 95
Lys Tyr Glu Asp Gly Gly Val Leu His Val Ser Phe Ser Tyr Arg Tyr
100 105 110
Glu Ala Gly Arg Val Ile Gly Asp Phe Lys Val Met Gly Thr Gly Phe
115 120 125
Pro Glu Asp Ser Val Ile Phe Thr Asp Lys Ile Ile Arg Ser Asn Ala
130 135 140
Thr Val Glu His Leu His Pro Met Gly Asp Asn Asp Leu Asp Gly Ser
145 150 155 160
Phe Thr Arg Thr Phe Ser Leu Arg Asp Gly Gly Tyr Tyr Ser Ser Val
165 170 175
Val Asp Ser His Met His Phe Lys Ser Ala Ile His Pro Ser Ile Leu
180 185 190
Gln Asn Gly Gly Pro Met Phe Ala Phe Arg Arg Val Glu Glu Asp His
195 200 205
Ser Asn Thr Glu Leu Gly Ile Val Glu Tyr Gln His Ala Phe Lys Thr
210 215 220
Pro Asp Ala Asp Ala Gly Glu Glu
225 230
<210> 60
<211> 3631
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> pITR.CBA.Eylea
<400> 60
cctgcaggca gctgcgcgct cgctcgctca ctgaggccgc ccgggcgtcg ggcgaccttt 60
ggtcgcccgg cctcagtgag cgagcgagcg cgcagagagg gagtggccaa ctccatcact 120
aggggttcct gcggccgcac gcgtgacatt gattattgac tagttattaa tagtaatcaa 180
ttacggggtc attagttcat agcccatata tggagttccg cgttacataa cttacggtaa 240
atggcccgcc tggctgaccg cccaacgacc cccgcccatt gacgtcaata atgacgtatg 300
ttcccatagt aacgccaata gggactttcc attgacgtca atgggtggac tatttacggt 360
aaactgccca cttggcagta catcaagtgt atcatatgcc aagtacgccc cctattgacg 420
tcaatgacgg taaatggccc gcctggcatt atgcccagta catgacctta tgggactttc 480
ctacttggca gtacatctac gtattagtca tcgctattac catgggtcga ggtgagcccc 540
acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtatttattt 600
attttttaat tattttgtgc agcgatgggg gcgggggggg ggggggcgcg cgccaggcgg 660
ggcggggcgg ggcgaggggc ggggcggggc gaggcggaga ggtgcggcgg cagccaatca 720
gagcggcgcg ctccgaaagt ttccttttat ggcgaggcgg cggcggcggc ggccctataa 780
aaagcgaagc gcgcggcggg cgggagtcgc tgcgttgcct tcgccccgtg ccccgctccg 840
cgccgcctcg cgccgcccgc cccggctctg actgaccgcg ttactcccac aggtgagcgg 900
gcgggacggc ccttctcctc cgggctgtaa ttagcgcttg gtttaatgac ggctcgtttc 960
ttttctgtgg ctgcgtgaaa gccttaaagg gctccgggag ggccctttgt gcggggggga 1020
gcggctcggg gggtgcgtgc gtgtgtgtgt gcgtggggag cgccgcgtgc ggcccgcgct 1080
gcccggcggc tgtgagcgct gcgggcgcgg cgcggggctt tgtgcgctcc gcgtgtgcgc 1140
gaggggagcg cggccggggg cggtgccccg cggtgcgggg gggctgcgag gggaacaaag 1200
gctgcgtgcg gggtgtgtgc gtgggggggt gagcaggggg tgtgggcgcg gcggtcgggc 1260
tgtaaccccc ccctgcaccc ccctccccga gttgctgagc acggcccggc ttcgggtgcg 1320
gggctccgtg cggggcgtgg cgcggggctc gccgtgccgg gcggggggtg gcggcaggtg 1380
ggggtgccgg gcggggcggg gccgcctcgg gccggggagg gctcggggga ggggcgcggc 1440
ggcccccgga gcgccggcgg ctgtcgaggc gcggcgagcc gcagccattg ccttttatgg 1500
taatcgtgcg agagggcgca gggacttcct ttgtcccaaa tctgtgcgga gccgaaatct 1560
gggaggcgcc gccgcacccc ctctagcggg cgcggggcga agcggtgcgg cgccggcagg 1620
aaggaaatgg gcggggaggg ccttcgtgcg tcgccgcgcc gccgtcccct tctccctctc 1680
cagcctcggg gctgtccgcg gggggacggc tgccttcggg ggggacgggg cagggcgggg 1740
ttcggcttct ggcgtgtgac cggcggctct agagcctctg ctaaccatgt tcatgccttc 1800
ttctttttcc tacagctcct gggcaacgtg ctggttattg tgaccggtgc caccatgtac 1860
cggatgcagc tgctgagctg tatcgccctg tctctggccc tggtcaccaa ttctagcgat 1920
accggcagac ccttcgtgga aatgtacagc gagatccccg agatcatcca catgaccgag 1980
ggcagagagc tggtcatccc ctgcagagtg acaagcccca acatcaccgt gactctgaag 2040
aagttccctc tggacacact gatccccgac ggcaagagaa tcatctggga cagccggaag 2100
ggcttcatca tcagcaacgc cacctacaaa gagatcggcc tgctgacctg tgaagccacc 2160
gtgaatggcc acctgtacaa gaccaactac ctgacacaca gacagaccaa caccatcatc 2220
gacgtggtgc tgagccctag ccacggcatt gaactgtctg tgggcgagaa gctggtgctg 2280
aactgtaccg ccagaaccga gctgaacgtg ggcatcgact tcaactggga gtaccccagc 2340
agcaagcacc agcacaagaa actggtcaac cgggacctga aaacccagag cggcagcgag 2400
atgaagaaat tcctgagcac cctgaccatc gacggcgtga ccagatctga ccagggcctg 2460
tacacatgtg ccgccagctc tggcctgatg accaagaaaa acagcacctt cgtgcgggtg 2520
cacgagaagg acaagaccca cacctgtcct ccatgtcctg ctccagaact gctcggcgga 2580
ccttccgtgt tcctgtttcc tccaaagcct aaggacaccc tgatgatcag cagaacccct 2640
gaagtgacct gcgtggtggt ggatgtgtcc cacgaggatc ccgaagtgaa gttcaattgg 2700
tacgtggacg gcgtggaagt gcacaacgcc aagaccaagc ctagagagga acagtacaat 2760
agcacctaca gagtggtgtc cgtgctgacc gtgctgcacc aggattggct gaacggcaaa 2820
gagtacaagt gcaaggtgtc caacaaggcc ctgcctgctc ctatcgagaa aaccatctcc 2880
aaggccaagg gccagcctag ggaaccccag gtttacacac tgcctccaag cagggacgag 2940
ctgacaaaga accaggtgtc cctgacctgc ctggtcaagg gcttctaccc ttccgatatc 3000
gccgtggaat gggagagcaa tggccagcct gagaacaact acaagacaac ccctcctgtg 3060
ctggacagcg acggctcatt cttcctgtac agcaagctga cagtggacaa gagcagatgg 3120
cagcagggca acgtgttcag ctgcagcgtg atgcacgagg ccctgcacaa ccactacacc 3180
cagaagtccc tgagcctgtc tcctggataa gagctcgctg atcagcctcg actgtgcctt 3240
ctagttgcca gccatctgtt gtttgcccct cccccgtgcc ttccttgacc ctggaaggtg 3300
ccactcccac tgtcctttcc taataaaatg aggaaattgc atcgcattgt ctgagtaggt 3360
gtcattctat tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca 3420
atagcaggca tgctggggat gcggtgggct ctatggaagc ttgaattcag ctgacgtgcc 3480
tcggaccgct aggaacccct agtgatggag ttggccactc cctctctgcg cgctcgctcg 3540
ctcactgagg ccgggcgacc aaaggtcgcc cgacgcccgg gctttgcccg ggcggcctca 3600
gtgagcgagc gagcgcgcag ctgcctgcag g 3631
<210> 61
<211> 1296
<212> DNA
<213> 人工序列(Artificial sequence)
<220>
<223> 编码阿柏西普的序列
<400> 61
agcgataccg gcagaccctt cgtggaaatg tacagcgaga tccccgagat catccacatg 60
accgagggca gagagctggt catcccctgc agagtgacaa gccccaacat caccgtgact 120
ctgaagaagt tccctctgga cacactgatc cccgacggca agagaatcat ctgggacagc 180
cggaagggct tcatcatcag caacgccacc tacaaagaga tcggcctgct gacctgtgaa 240
gccaccgtga atggccacct gtacaagacc aactacctga cacacagaca gaccaacacc 300
atcatcgacg tggtgctgag ccctagccac ggcattgaac tgtctgtggg cgagaagctg 360
gtgctgaact gtaccgccag aaccgagctg aacgtgggca tcgacttcaa ctgggagtac 420
cccagcagca agcaccagca caagaaactg gtcaaccggg acctgaaaac ccagagcggc 480
agcgagatga agaaattcct gagcaccctg accatcgacg gcgtgaccag atctgaccag 540
ggcctgtaca catgtgccgc cagctctggc ctgatgacca agaaaaacag caccttcgtg 600
cgggtgcacg agaaggacaa gacccacacc tgtcctccat gtcctgctcc agaactgctc 660
ggcggacctt ccgtgttcct gtttcctcca aagcctaagg acaccctgat gatcagcaga 720
acccctgaag tgacctgcgt ggtggtggat gtgtcccacg aggatcccga agtgaagttc 780
aattggtacg tggacggcgt ggaagtgcac aacgccaaga ccaagcctag agaggaacag 840
tacaatagca cctacagagt ggtgtccgtg ctgaccgtgc tgcaccagga ttggctgaac 900
ggcaaagagt acaagtgcaa ggtgtccaac aaggccctgc ctgctcctat cgagaaaacc 960
atctccaagg ccaagggcca gcctagggaa ccccaggttt acacactgcc tccaagcagg 1020
gacgagctga caaagaacca ggtgtccctg acctgcctgg tcaagggctt ctacccttcc 1080
gatatcgccg tggaatggga gagcaatggc cagcctgaga acaactacaa gacaacccct 1140
cctgtgctgg acagcgacgg ctcattcttc ctgtacagca agctgacagt ggacaagagc 1200
agatggcagc agggcaacgt gttcagctgc agcgtgatgc acgaggccct gcacaaccac 1260
tacacccaga agtccctgag cctgtctcct ggataa 1296
Claims (112)
1.一种方法,所述方法包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中,所述腺相关病毒(AAV)载体包括编码以下多肽的核苷酸序列:
(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或
(b)包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
2.一种用于提高对其有需要的哺乳动物的内耳中的抗体或抗原结合抗体片段的水平的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:
(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或
(b)包括连接到信号肽的抗原结合抗体片段的多肽;
其中所述引入使得所述哺乳动物的内耳中的所述抗体或抗原结合抗体片段的水平升高。
3.如权利要求1或2所述的方法,其中所述抗体或所述抗原结合抗体片段特异性结合到血管内皮生长因子(VEGF)。
4.如权利要求3所述的方法,其中所述抗体或抗原结合抗体片段降低VEGF活性。
5.如权利要求1-4中任一项所述的方法,其中所述AAV载体还包括可操作地连接到编码所述抗体或所述抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
6.如权利要求5所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
7.如权利要求1-6中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
8.如权利要求1-7中任一项所述的方法,其中所述哺乳动物为人。
9.如权利要求1-8中任一项所述的方法,其中所述哺乳动物已被鉴定为患有内耳病症。
10.如权利要求1-8中任一项所述的方法,其中所述哺乳动物已被诊断为患有内耳病症。
11.如权利要求1-10中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
12.如权利要求1-10中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号的抗原结合抗体片段的多肽。
13.一种用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:
(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或
(b)包括连接到信号肽的抗原结合抗体片段的多肽;
其中所述引入使得所述哺乳动物中的所述内耳病症得到治疗。
14.如权利要求13所述的方法,其中所述AAV载体还包括可操作地连接到编码所述抗体或所述抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
15.如权利要求14所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
16.如权利要求13-15中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
17.如权利要求13-16中任一项所述的方法,其中所述哺乳动物为人。
18.如权利要求13-17中任一项所述的方法,其中所述哺乳动物已被鉴定为患有内耳病症。
19.如权利要求13-17中任一项所述的方法,其中所述哺乳动物已被诊断为患有内耳病症。
20.如权利要求13-19中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
21.如权利要求13-19中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号的抗原结合抗体片段的多肽。
22.一种降低对其有需要的哺乳动物的内耳中的VEGF活性的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:
(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或
(b)包括连接到信号肽的抗原结合抗体片段的多肽;
其中所述(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,所述(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;
其中所述引入使得所述哺乳动物的内耳中的VEGF活性降低。
23.如权利要求22所述的方法,其中所述AAV载体还包括可操作地连接到编码所述抗体或所述抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
24.如权利要求23所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
25.如权利要求22-24中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
26.如权利要求22-25中任一项所述的方法,其中所述哺乳动物为人。
27.如权利要求22-26中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有听神经瘤。
28.如权利要求22-26中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。
29.如权利要求22-26中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
30.如权利要求22-29中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
31.如权利要求22-29中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
32.一种治疗哺乳动物的内耳中的听神经瘤、前庭神经鞘瘤或2型神经纤维瘤病的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码以下多肽的核苷酸序列:
(a)包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽;或
(b)包括连接到信号肽的抗原结合抗体片段的多肽;
其中所述(a)的多肽编码特异性结合到VEGF并降低VEGF活性的抗体,所述(b)的多肽编码特异性结合到VEGF并降低VEGF活性的抗原结合抗体片段;
其中所述引入使得所述哺乳动物的内耳中的听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病分别得到治疗。
33.如权利要求32所述的方法,其中所述AAV载体还包括可操作地连接到编码所述抗体或所述抗原结合抗体片段的序列的启动子和Kozak序列中的一者或两者。
34.如权利要求33所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
35.如权利要求32-34中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
36.如权利要求32-35中任一项所述的方法,其中所述哺乳动物为人。
37.如权利要求32-36中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有听神经瘤。
38.如权利要求32-36中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。
39.如权利要求32-36中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
40.如权利要求32-39中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗体重链可变结构域的多肽以及包括可操作地连接到信号肽的抗体轻链可变结构域的多肽。
41.如权利要求32-40中任一项所述的方法,其中所述AAV载体包括编码以下多肽的核酸序列:包括可操作地连接到信号肽的抗原结合抗体片段的多肽。
42.如权利要求1-41中任一项所述的方法,其中所述抗体包括有包含一个或多个氨基酸置换的Fc区,与对照抗体相比,所述一个或多个氨基酸置换缩短哺乳动物中所述抗体的半衰期;或
与对照抗原结合抗体片段相比,所述抗体的抗原结合抗体片段的体内半衰期缩短。
43.一种方法,所述方法包括将治疗有效量的腺相关病毒(AAV)载体引入哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列。
44.一种用于提高对其有需要的哺乳动物的内耳中的可溶性血管内皮生长因子(VEGF)受体的水平的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性VEGF的核苷酸序列;
其中所述引入使得所述哺乳动物的内耳中的所述可溶性VEGF受体的水平升高。
45.如权利要求43或44所述的方法,其中所述可溶性VEGF受体包括VEGF受体-1(VEGFR-1)的胞外区的一部分。
46.如权利要求45所述的方法,其中所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的连续序列。
47.如权利要求46所述的方法,其中所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域。
48.如权利要求45所述的方法,其中所述VEGFR-1的胞外区的一部分包括与来自野生型人VEGFR-1的连续序列有至少90%同一性的序列。
49.如权利要求43或44所述的方法,其中所述可溶性VEGF受体包括VEGF受体-2(VEGFR-2)的胞外区的一部分。
50.如权利要求49所述的方法,其中所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的连续序列。
51.如权利要求50所述的方法,其中所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。
52.如权利要求49所述的方法,其中所述VEGFR-2的胞外区的一部分包括与来自野生型人VEGFR-2的连续序列有至少90%同一性的序列。
53.如权利要求43或44所述的方法,其中所述可溶性VEGF受体包括VEGFR-1的胞外区的一部分和VEGFR-2的胞外区的一部分。
54.如权利要求53所述的方法,其中:
所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域;并且
所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。
55.如权利要求54所述的方法,其中所述可溶性VEGF受体为阿柏西普。
56.如权利要求43或44所述的方法,其中所述可溶性VEGF受体包括VEGF受体-3(VEGFR-3)的胞外区的一部分。
57.如权利要求56所述的方法,其中所述VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的连续序列。
58.如权利要求57所述的方法,其中所述VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的胞外区中的一个或多个免疫球蛋白样结构域。
59.如权利要求56所述的方法,其中所述VEGFR-3的胞外区的一部分包括与来自野生型人VEGFR-3的连续序列有至少90%同一性的序列。
60.如权利要求43-59中任一项所述的方法,其中所述可溶性VEGF受体包括Fc结构域。
61.如权利要求60所述的方法,其中所述Fc结构域为IgG1 Fc结构域。
62.如权利要求61所述的方法,其中所述IgG1 Fc结构域为人野生型IgG1 Fc结构域。
63.如权利要求43-62中任一项所述的方法,其中所述可溶性VEGF受体降低VEGF结合到VEGFR-1、VEGFR-2和VEGFR-3中的一者或多者的能力。
64.如权利要求43-63中任一项所述的方法,其中所述AAV载体还包括可操作地连接到编码所述可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。
65.如权利要求64所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
66.如权利要求43-65中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
67.如权利要求43-66中任一项所述的方法,其中所述哺乳动物为人。
68.如权利要求43-67中任一项所述的方法,其中所述哺乳动物已被鉴定为患有内耳病症。
69.如权利要求43-67中任一项所述的方法,其中所述哺乳动物已被诊断为患有内耳病症。
70.一种用于治疗对其有需要的哺乳动物中的内耳病症的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;
其中所述引入使得所述哺乳动物中的所述内耳病症得到治疗。
71.如权利要求70所述的方法,其中所述AAV载体还包括可操作地连接到编码所述可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。
72.如权利要求71所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
73.如权利要求70-72中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
74.如权利要求70-73中任一项所述的方法,其中所述哺乳动物为人。
75.如权利要求70-74中任一项所述的方法,其中所述哺乳动物已被鉴定为患有内耳病症。
76.如权利要求70-74中任一项所述的方法,其中所述哺乳动物已被诊断为患有内耳病症。
77.一种降低对其有需要的哺乳动物的内耳中的VEGF活性的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;
其中所述引入使得所述哺乳动物的内耳中的所述VEGF活性降低。
78.如权利要求77所述的方法,其中所述AAV载体还包括可操作地连接到编码所述可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。
79.如权利要求78所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
80.如权利要求77-79中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
81.如权利要求77-80中任一项所述的方法,其中所述哺乳动物为人。
82.如权利要求77-81中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有听神经瘤。
83.如权利要求77-81中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。
84.如权利要求77-81中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
85.一种治疗哺乳动物的内耳中的听神经瘤、前庭神经鞘瘤或2型神经纤维瘤病的方法,所述方法包括:
将治疗有效量的AAV载体引入所述哺乳动物的内耳中,所述AAV载体包括编码可操作地连接到信号肽的可溶性血管内皮生长因子(VEGF)受体的核苷酸序列;
其中所述引入使得所述哺乳动物的内耳中的听神经瘤、前庭神经鞘瘤或II型神经纤维瘤病分别得到治疗。
86.如权利要求85所述的方法,其中所述AAV载体还包括可操作地连接到编码所述可溶性VEGF受体的序列的启动子和Kozak序列中的一者或两者。
87.如权利要求86所述的方法,其中所述AAV载体包括选自由以下组成的组的启动子:诱导型启动子、组成型启动子和组织特异性启动子。
88.如权利要求85-87中任一项所述的方法,其中所述AAV载体还包括多聚腺苷酸化信号序列。
89.如权利要求85-88中任一项所述的方法,其中所述哺乳动物为人。
90.如权利要求85-89中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有听神经瘤。
91.如权利要求85-89中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有前庭神经鞘瘤。
92.如权利要求85-89中任一项所述的方法,其中所述哺乳动物已被鉴定或诊断为患有2型神经纤维瘤病。
93.如权利要求70-92中任一项所述的方法,其中所述可溶性VEGF受体包括VEGF受体-1(VEGFR-1)的胞外区的一部分。
94.如权利要求93所述的方法,其中所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的连续序列。
95.如权利要求94所述的方法,其中所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域。
96.如权利要求93所述的方法,其中所述VEGFR-1的胞外区的一部分包括与来自野生型人VEGFR-1的连续序列有至少90%同一性的序列。
97.如权利要求70-92中任一项所述的方法,其中所述可溶性VEGF受体包括VEGF受体-2(VEGFR-2)的胞外区的一部分。
98.如权利要求97所述的方法,其中所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的连续序列。
99.如权利要求98所述的方法,其中所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。
100.如权利要求97所述的方法,其中所述VEGFR-2的胞外区的一部分包括与来自野生型人VEGFR-2的连续序列有至少90%同一性的序列。
101.如权利要求70-92中任一项所述的方法,其中所述可溶性VEGF受体包括VEGFR-1的胞外区的一部分和VEGFR-2的胞外区的一部分。
102.如权利要求101所述的方法,其中:
所述VEGFR-1的胞外区的一部分包括来自野生型人VEGFR-1的胞外区中的一个或多个免疫球蛋白样结构域;并且
所述VEGFR-2的胞外区的一部分包括来自野生型人VEGFR-2的胞外区中的一个或多个免疫球蛋白样结构域。
103.如权利要求102所述的方法,其中所述可溶性VEGF受体为阿柏西普。
104.如权利要求70-92中任一项所述的方法,其中所述可溶性VEGF受体包括VEGF受体-3(VEGFR-3)的胞外区的一部分。
105.如权利要求104所述的方法,其中所述VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的连续序列。
106.如权利要求105所述的方法,其中所述VEGFR-3的胞外区的一部分包括来自野生型人VEGFR-3的胞外区中的一个或多个免疫球蛋白样结构域。
107.如权利要求104所述的方法,其中所述VEGFR-3的胞外区的一部分包括与来自野生型人VEGFR-3的连续序列有至少90%同一性的序列。
108.如权利要求70-107中任一项所述的方法,其中所述可溶性VEGF受体包括Fc结构域。
109.如权利要求108所述的方法,其中所述Fc结构域为IgG1 Fc结构域。
110.如权利要求109所述的方法,其中所述IgG1 Fc结构域为人野生型IgG1 Fc结构域。
111.如权利要求70-110中任一项所述的方法,其中所述可溶性VEGF受体降低VEGF结合到VEGFR-1、VEGFR-2和VEGFR-3中的一者或多者的能力。
112.如权利要求43-111中任一项所述的方法,其中所述AAV载体还包括分泌序列。
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US20210363499A1 (en) | 2021-11-25 |
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US20220267739A1 (en) | 2022-08-25 |
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BR112020012336A2 (pt) | 2021-03-30 |
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WO2019126329A1 (en) | 2019-06-27 |
EP3727468A1 (en) | 2020-10-28 |
AU2018392480A1 (en) | 2020-07-02 |
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EP3727468A4 (en) | 2021-09-22 |
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