CN114933657A - 神经生长因子突变体重组蛋白及其应用 - Google Patents
神经生长因子突变体重组蛋白及其应用 Download PDFInfo
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Abstract
本申请涉及一种重组蛋白,其包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽。本申请还提供了包含编码所述重组蛋白的mRNA和递送载体的组合,以及该组合在治疗中毒性/遗传性/代谢性周围神经病变、神经再生修复和/或中枢神经系统退行性疾病中的应用。
Description
技术领域
本申请涉及生物医药领域,具体的涉及一种神经生长因子突变体重组蛋白,包含编码该重组蛋白的mRNA,以及它们在治疗神经系统疾病中的应用。
背景技术
神经生长因子(Nerve growth factor,NGF)是具有神经元营养功能的生长调节因子,在维持中枢基底前脑胆碱能神经元(basal forebrain cholinergic neurons,BFCNs)和外周伤害性感觉神经元的发育和功能分化中起重要作用,对成熟的中枢和周围神经元正常功能的维持、神经损伤的自我保护与修复也至关重要。NGF作为一种强有力的神经营养因子,在过去的20-30年成为多种中枢和周围神经系统疾病药物治疗的热点。
在临床研究过程中,NGF的应用却导致了剂量依赖型的疼痛副作用。阿尔茨海默症(Alzheimer's disease,AD)是一种以认知功能障碍和记忆力减退为主要临床表现的进行性和致命性的中枢神经系统退行性疾病。临床实验中大剂量NGF对AD患者进行治疗时发现,虽然AD患者的认知能力以及大脑皮质代谢均得到明显改善,但是痛楚与体重减少等不良反应的出现则抵消了其治疗效果,最终宣告临床试验失败。在使用NGF治疗糖尿病神经病和HIV周围神经病时也发现相同的现象。这是由于NGF是导致疼痛和痛觉过敏的重要中间介质之一。TrkA和p75NTR信号通路均介导了NGF的致痛功能,许多研究表明TrkA和p75NTR信号通路存在相互影响。因此,丢失任一信号通路(TrkA或p75NTR)或打破TrkA和p75NTR信号通路之间的平衡都将会对NGF的致痛作用产生影响。
“无痛性”神经生长因子的发现为NGF的临床应用带来了极大的希望。继发于NGFR100W的遗传性感觉和自主神经病V型(hereditary sensory and autonomousneuropathy type V,HSAN V),是在一北部瑞典家庭中发现的成熟NGF蛋白第100位精氨酸替换为色氨酸,患者痛觉和温度觉丧失,但智力正常,提示NGFR100W可能选择性的丢失介导痛觉的功能,而保留神经营养的功能。NGFR100W的发现为研究NGF神经营养和介导痛觉的功能提供了重要的依据,其生物学特性和相关作用机制的研究可能为解决NGF用于中毒性/遗传性/代谢性周围神经病变、神经再生修复和/或中枢神经系统退行性疾病等的治疗寻求新的突破点。
但是,HSAN V的敲入小鼠模型证明表达NGFR100W突变体的小鼠通常在大约2个月大时完全丧失了痛觉,并且经常无法存活到成年。并且全长的NGFR100W突变体蛋白会影响其成熟体的切割,从而使成熟NGFR100W无法正常外泌到胞外行使其神经滋养功能。因此,目前仍未有获得NGFR100W突变体蛋白的简便高效的方法,极大地限制了应用于NGFR100W突变体蛋白在治疗神经疾病的中的应用。
发明内容
本申请提供了一种重组蛋白,所述重组蛋白包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽,所述重组蛋白具有以下至少一种特点:(1)与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少;(2)且表达量和/或分泌量增加至少50%;(3)具有可观的表达量和/或分泌量,例如,可以达到野生型NGF蛋白的至少50%以上;(4)降低痛觉;(5)延长的半衰期,以及(6)促进损伤神经细胞的修复及再生。本申请还提供了包含编码所述NGF蛋白或NGF蛋白变体的mRNA和递送载体的组合物。本申请的重组蛋白和组合物能够用于治疗周围神经病变及神经变性病等神经系统病变,促进神经修复及再生。例如,本申请的重组蛋白和组合物能够用于治疗中毒性/遗传性/代谢性周围神经病变、神经再生修复和/或中枢神经系统退行性疾病(例如,糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症)。
一方面,本申请提供了一种重组蛋白,所述重组蛋白包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽,其中,与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少约50%,
与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少约50%。
在某些实施方式中,所述野生型NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中,所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
在某些实施方式中,所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
在某些实施方式中,所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
在某些实施方式中,所述重组蛋白还包括前导肽。
在某些实施方式中,自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体。
在某些实施方式中,所述重组蛋白还包括免疫球蛋白的Fc区。
在某些实施方式中,自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
另一方面,本申请提供了一种分离的核酸分子,所述分离的核酸分子编码所述的重组蛋白。
在某些实施方式中,所述分离的核酸分子包括DNA和/或RNA。在某些实施方式中,所述分离的核酸分子为DNA。在某些实施方式中,所述分离的核酸分子为RNA。
在某些实施方式中,所述分离的核酸分子在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
在某些实施方式中,所述分离的核酸分子包含至少一种经修饰的核苷酸。
在某些实施方式中,所述分离的核酸分子包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
在某些实施方式中,所述分离的核酸分子是密码子优化的。
另一方面,本申请提供一种组合物,所述组合物包含(a)mRNA,所述mRNA包含编码神经生长因子(NGF)蛋白或其变体的多核苷酸,和(b)递送载体。
在某些实施方式中,所述NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中,与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少约50%。
在某些实施方式中,所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
在某些实施方式中,所述mRNA包含编码异源信号肽的多核苷酸,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少约50%。
在某些实施方式中,所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上。
在某些实施方式中,所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
在某些实施方式中,所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
在某些实施方式中,所述mRNA还包括编码前导肽的多核苷酸。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸和所述编码NGF蛋白或其变体的多核苷酸。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括编码所述BDNF信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
在某些实施方式中,所述其中所述mRNA还包含编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸、所述编码NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸、编码所述NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,所述mRNA编码包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
在某些实施方式中,所述mRNA在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
在某些实施方式中,所述mRNA包含至少一种经修饰的核苷酸。
在某些实施方式中,所述mRNA包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
在某些实施方式中,所述mRNA是密码子优化的。
在某些实施方式中,所述mRNA包含如SEQ ID NO:22-28和50-51中任一项所示的核苷酸序列。在某些实施方式中,所述mRNA包含如SEQ ID NO:23和27中任一项所示的核苷酸序列。
在某些实施方式中,所述递送载体包括脂质体。
在某些实施方式中,所述递送载体包括脂质纳米颗粒(LNP)。
在某些实施方式中,所述递送载体包括阳离子脂质。
在某些实施方式中,所述阳离子脂质的摩尔比为约45%至约55%。
在某些实施方式中,所述阳离子脂质SM102和DLin-MC3-DMA。
在某些实施方式中,所述递送载体包括非阳离子脂质。
在某些实施方式中,所述非阳离子脂质包括磷脂和/或脂质缀合物。
在某些实施方式中,所述磷脂的摩尔比为约35%至约40%。
在某些实施方式中,所述磷脂包括二硬脂酰基磷脂酰胆碱(DSPC)。
在某些实施方式中,所述脂质缀合物包括聚乙二醇修饰的脂分子。
在某些实施方式中,在所述递送载体中,其中所述脂质缀合物的摩尔比为约1%至约2%。
在某些实施方式中,所述聚乙二醇修饰的脂分子包括PEG2000-DMG。
在某些实施方式中,所述递送载体包括胆固醇。
在某些实施方式中,在所述递送载体中,其中所述胆固醇的摩尔比为约8%至约12%。
在某些实施方式中,所述递送载体包含阳离子脂质、胆固醇、磷脂和脂质缀合物,且所述阳离子脂质、胆固醇、磷脂和脂质缀合物的质量比为50:10:38.5:1.5。
在某些实施方式中,所述递送载体包含DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE,且所述DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE的质量比为50:10:38.5:1.5。
在某些实施方式中,所述递送载体的直径为约60nm至约500nm。
在某些实施方式中,所述递送载体的直径为约80nm至约200nm。
在某些实施方式中,所述mRNA包载在所述递送载体中。
另一方面,本申请提供了一种载体,所述载体包含所述的核酸分子。
另一方面,本申请提供了一种细胞,所述细胞包含本申请所述的核酸分子,和/或所述的载体,或其表达本申请所述的重组蛋白。
另一方面,本申请提供了一种制备所述的重组蛋白的方法,所述方法包括在使得所述的重组蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供了一种药物组合物,所述药物组合物包含所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体和/或所述的细胞,以及任选地药学上可接受的载体。
另一方面,本申请提供了一种试剂盒或给药装置,所述试剂盒或给药装置包含所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。
另一方面,本申请提供了一种所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物在制备药物中的用途,所述药物用于缓解、预防和/或治疗中枢和/或周围神经系统疾病。
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的,本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地,本申请的附图和说明书中的描述仅仅是示例性的,而非为限制性的。
附图说明
本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明如下:
图1A显示的是NGFR100W重组蛋白的多种组成。
图1B显示的是不同NGFR100W重组蛋白在293T细胞中的表达情况。
图1C显示的是包含不同核苷酸修饰的IGK19-NGFmut mRNA的表达情况。
图1D显示的是NGF和NGFR100W重组蛋白mRNA在PC12细胞中表达,并促进PC12细胞分化的荧光显微镜观察结果。
图1E显示的是NGF和NGFR100W重组蛋白mRNA促进PC12细胞分化的电子显微镜观察结果。
图1F至图1G显示的是成熟NGF蛋白和成熟NGFR100W蛋白在细胞裂解液和细胞上清液中的含量检测结果。
图1H至图1I显示的是成熟NGF蛋白和成熟NGFR100W蛋白在细胞上清液中的含量检测结果。
图1J显示的是NGFR100W重组蛋白的多种组成。
图2显示的是mRNA-LNP的组装和体内递送。
图3A显示的是NGF和NGFR100W重组蛋白mRNA纳米粒径分布。
图3B显示的是NGF和NGFR100W重组蛋白mRNA在293T细胞的表达情况。
图3C显示的是IGK19-NGFmut mRNA LNP小鼠体内表达定位。
图4A显示的是表达NGF与IGK19-NGFmut对小鼠热痛痛阈的影响。
图4B显示的是表达NGF与IGK19-NGFmut对小鼠机械痛痛阈的影响。
图5A显示的是表达IGK19-NGFmut对小鼠周围神经损伤修复的实验流程。
图5B显示的是注射paclitaxel对小鼠热痛以及机械痛痛阈的影响。
图5C显示的是表达IGK19-NGFmut对小鼠受损外周神经的修复情况。
图5D显示的是表达IGK19-NGFmut对外周神经受损小鼠热痛以及机械痛痛阈的影响。
具体实施方式
以下由特定的具体实施例说明本申请发明的实施方式,本领域技术人员可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。
术语定义
在本申请中,术语“神经生长因子(NGF)”,通常是指在多种神经元的生长和存活中起作用的分泌蛋白。如本文所用的,术语NGF不限于人NGF,并且包含人NGF的所有物种直向同源物。术语“NGF”涵盖NGF的前体形式(pro-form)、NGF前体(proNGF)、全长NGF、以及由细胞内过程产生的任何形式的NGF。该术语还涵盖天然存在的NGF的变体,例如剪接变体、等位基因变体和同种型。
NGF存在于一个由3个蛋白α-NGF、β-NGF和γ-NGF组成的约为130-kDa的复合体中,这种NGF也被称为proNGF(NGF前体)。proNGF也而被称为未成熟的NGF。该复合物的γ亚基起丝氨酸蛋白酶的作用,能裂解β亚基的n端,从而激活该蛋白,生成具有功能的NGF,即β-NGF。NGF能结合两个受体:p75神经营养蛋白受体(p75NTR)和TrkA,其是一种跨膜酪氨酸激酶。NGF是经过充分验证的针对疼痛的靶标,已知其介导伤害性感受器的致敏作用。人的全长NGF的氨基酸序列可参见Genbank登录号NP_002497.2或UniProtKB登录号P01138。人的全长NGF通常包含241个氨基酸,其中第1-18位为NGF信号肽部分(氨基酸序列如SEQ ID NO:29所示),第19-121位为前导肽部分(氨基酸序列如SEQ ID NO:34所示),第122-241位为成熟NGF(mature NGF,氨基酸序列如SEQ ID NO:32所示)。全长NGF可通过剪切过程成为成熟NGF。
在本申请中,术语“变体”通常是指,与参比序列相比,有一个或多个氨基酸改变(例如,一个或多个氨基酸的取代、变化、修饰、替代、缺失或添加)的氨基酸序列,或者,有一个或多个核苷酸改变(例如,一个或多个核苷酸的取代、变化、修饰、替代、缺失或添加)的核酸序列。对于多肽,变体包括由于一个或多个氨基酸替代、删除、或插入而具有改变的氨基酸序列的多肽。变体可以天然存在或者是非天然存在的。变体可以保留参比序列的一种或多种活性,但是于参比序列相比,变体的该一种或多种活性可以增强、减弱或保持不变。
在本申请中,术语“NGF变体”通常是指,与全长NGF氨基酸序列相比(例如,Genbank登录号NP_002497.2或UniProtKB登录号P01138,或如SEQ ID NO:13所示的氨基酸序列),有一个或多个氨基酸改变(例如,一个或多个氨基酸的取代、变化、修饰、替代、缺失或添加)的氨基酸序列。例如,氨基酸改变可以在成熟NGF部分。与野生型NGF蛋白相比,所述氨基酸改变(例如,突变)使得NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少。例如,对于氨基酸序列如SEQ ID NO:13所示的全长NGF序列来说,氨基酸突变可以是第221位的精氨酸(R)突变为色氨酸(W),突变后的全长NGF蛋白可以称为NGFR221W(氨基酸序列如SEQ ID NO:14所示)。例如,对于氨基酸序列如SEQ ID NO:32所示的成熟NGF序列来说,氨基酸突变可以是第100位的精氨酸(R)突变为色氨酸(W),突变后的成熟NGF蛋白可以称为NGFR100W(氨基酸序列如SEQ ID NO:33所示)。
在本申请中,术语“连接”,可以和“融合(fused)”或“融合(fusion)”互换使用,通常是指通过包括化学轭合或重组手段的任何手段将两个更多个元件或组分连接在一起。在多肽情况下氨基酸残基的两个聚合物直接彼此偶联,或在多核苷酸情况下核苷酸的两个聚合物直接彼此偶联,或在相同的多肽或多核苷酸内但通过插入氨基酸残基或核苷酸而分离。
在本申请中,术语“异源”通常是指多肽或核酸包含两种或更多种序列或子序列,这些序列或子序列在自然界中未以彼此相同的关系发现。例如,通常重组产生表达盒,其具有来自不相关基因的两个或更多个序列,以排列成新的功能性核酸。术语“异源信号肽”通常是指,在天然情况下,该信号肽与信号肽连接的氨基酸序列不属于一个相同的起源,可以是源自不同物种,不同个体,可以源自同一物种但不同的个体,可以是源自同一个体但源自不同的蛋白,可以是源自同一物种但源自不同的蛋白。例如,异源信号肽和与该异源信号肽连接的氨基酸序列由天然情况下来自不相关基因编码,以排列成新的多肽。例如,对于一个信号肽和与该信号肽连接的NGF蛋白或NGF蛋白变体连接时,当该信号肽与该NGF蛋白或NGF蛋白变体由天然情况下来自不相关基因编码,即编码该信号肽的基因与编码该NGF蛋白或NGF蛋白变体的基因不相关时,或者,天然情况下,与该信号肽连接的蛋白不是NGF蛋白或NGF蛋白变体时,可以说该信号肽时异源的。
在本申请中,术语“信号肽”通常是指引导新合成的蛋白质向分泌通路转移的短肽链。信号肽的一般长度为5~30个氨基酸。信号肽可以位于蛋白前体形式的N端或C端,但是大多数情况下以N-端肽存在于蛋白前体形式上。信号肽的功能可以是促进连接至内质网的表达多肽的易位。信号肽通常在该过程中被切除。蛋白前体被切除信号肽对于用于产生多肽的生物体可以是异源的或同源的。例如,本申请的信号肽可以包含野生型信号肽的功能活性片段、截短体和/或突变体。例如,本申请的信号肽可以具有引导包含信号肽的物质结合于细胞膜的功能。
在本申请中,术语“野生型”通常是指在某一物种或群体(例如人、小鼠、大鼠、细胞等)内天然存在的氨基酸或核酸的序列。
在本申请中,术语“神经营养因子受体p75”通常是指一种低亲和力神经生长因子受体(LNGFR),可以与神经营养因子结合,是肿瘤坏死因子受体超家族的一员,也可称为p75NTR。示例性的人p75NTR的氨基酸序列及其他信息可参见UniProtKB数据库登录号P08138下。如本文所用的,p75NTR不限于人p75NTR,并且包含人p75NTR的所有物种直向同源物。术语“p75NTR”涵盖p75NTR的前体形式、p75NTR前体、全长p75NTR、以及由细胞内过程产生的任何形式的p75NTR。该术语还涵盖天然存在的p75NTR的变体,例如剪接变体、等位基因变体和同种型。
在本申请中,术语“神经营养因子”通常是指一种为神经元的生存、发展以及实现正常功能提供支持的蛋白质。它是生长因子的一种。示例性的神经营养因子可包括神经生长因子(NGF)、脑源性神经营养因子(BDNF)、神经营养因子-3(NT-3)、神经营养因子-4(NT-4)、神经营养因子-6(NT-6)、神经营养因子-7(NT-7)、脱氢表雄酮(DHEA)、DHEA硫酸盐(DHEA-S)、GDNF配体家族和睫状神经营养因子(CNTF)以及其他生物分子。
在本申请中,术语“脑源性神经营养因子(BDNF)”通常是指神经营养因子中的一种,也可称为“abrineurin”。BDNF是神经营养因子生长因子家族的成员,与经典神经生长因子有关。BDNF通常存在于大脑和外周。如本文所用的,BDNF不限于人BDNF,并且包含人BDNF的所有物种直向同源物。术语“BDNF”涵盖BDNF的前体形式、BDNF前体、全长BDNF、以及由细胞内过程产生的任何形式的BDNF。该术语还涵盖天然存在的BDNF的变体,例如剪接变体、等位基因变体、和同种型。人BDNF蛋白的氨基酸序列可参见UniProtKB数据库的登录号P23560下。全长人BDNF蛋白通常具有247个氨基酸,可包含信号肽、前体部分、前导肽和成熟BDNF。BDNF信号肽可以为全长人BDNF蛋白的第1-18位氨基酸,例如,BDNF信号肽可包含SEQ IDNO:31所示的氨基酸序列。
在本申请中,术语“神经营养因子-3(NT-3)”通常是指神经营养因子NGF(神经生长因子)家族中的一种神经营养因子。NT-3是一种蛋白质生长因子,对周围和中枢神经系统的某些神经元有活性。示例性的人NT-3的氨基酸序列可参见UniProtKB数据库登录号P20783下。
在本申请中,术语“神经营养因子-4(NT-4)”通常是指神经营养因子NGF(神经生长因子)家族中的一种神经营养因子。NT-4主要通过TrkB受体酪氨酸激酶发出信号。NT4也可称为NT-5。示例性的人NT-4的氨基酸序列可参见UniProtKB数据库登录号P34130下。
在本申请中,术语“前导肽”通常是指在蛋白质成熟或激活过程中被切割的一部分。一旦被切割,前导肽通常没有独立的生物学功能。前导肽可以协助蛋白质的折叠和正确的表达。有些情况下,前导肽可包含信号肽或信号肽的一部分。有些情况下,前导肽不包含信号肽。
在本申请中,术语“递送载体”通常是指能够将试剂(例如,mRNA)递送至靶细胞的转移媒介物。递送载体可以将试剂(例如,mRNA)递送到特定的细胞亚类。例如,借助递送载体的固有特征或者通过与载体相偶联的部分、包含在其内的部分(或者与载体结合的部分,从而使得该部分和该递送载体维持在一起,进而使得该部分足以靶向递送载体)使递送载体靶向某些类型的细胞。递送载体还可提高要递送的试剂(例如,mRNA)的体内半衰期和/或要递送的试剂的生物利用度。递送载体可包括病毒载体、病毒样颗粒、聚阳离子载体、肽载体、脂质体和/或杂交载体。例如,如果靶细胞是肝细胞,所述递送载体的性质(例如,尺寸、电荷和/或pH)可以有效地将所述递送载体和/或其中包载的分子(例如,mRNA)递送至靶细胞、降低免疫清除和/或促进在该靶细胞中停留。
在本申请中,术语“脂质纳米颗粒(LNP)”通常是指包含通过分子间力彼此物理结合(例如,共价或非共价)的多个(即多于一个)脂质分子的颗粒。脂质纳米颗粒可以是例如微球(包括单层和多层囊泡,例如脂质体)、乳液中的分散相、胶团或悬浮液中的内相。脂质纳米颗粒可以包含一种或多种脂质(例如,阳离子脂质、非阳离子脂质和PEG-修饰的脂质)。
在本申请中,术语“脂质体”通常是指通过一个或多个双层的膜与外部介质隔离的具有内部空间的囊泡。例如,所述双层的膜可以通过两性分子形成,如包含空间隔离的亲水性和疏水性结构域的合成或天然来源的脂质;又例如,所述双层的膜可以通过两亲性聚合物和表面活性剂形成。
在本申请中,术语“修饰”用于核酸(例如RNA或DNA)时通常是指,与相应的野生型相比,所述核酸具有不同的核苷酸分子,不同的核苷酸序列,由不同的键组成和/或在其结构中掺入非天然部分。例如,所述修饰可包括核苷酸的修饰,例如,所述核苷酸可包含经修饰的碱基、糖或磷酸基团。例如,所述修饰可包括不同的核苷酸序列但是编码相同氨基酸序列的多肽或蛋白质,或相同功能的多肽或蛋白质。所述修饰可以是化学修饰和/或生物修饰。“化学修饰”可包括引入不同于野生型或天然存在的核酸中所见到的那些化学物质的修饰,例如,共价修饰,例如,引入经修饰的核苷酸(例如,核苷酸类似物,或者引入在这些核酸分子中未天然发现的侧基)。术语“经修饰的核苷酸”通常是指核酸聚合物中的单元,其含有经修饰的碱基、糖或磷酸基团,或在其结构中掺入非天然部分。
在本申请中,术语“密码子优化”用于核酸时,通常表示通过用在细胞中具有不同的相对使用频率的编码相同氨基酸残基的密码子,替换亲代多肽编码核酸中的一个、至少一个、或一个以上密码子,已经改良而在细胞中具有改善的表达的编码多肽的核酸,例如哺乳动物细胞或细菌细胞。
在本申请中,术语“多核苷酸”通常包括DNA分子(例如cDNA或基因组DNA)、RNA分子(例如mRNA)、使用核苷酸类似物(例如肽核酸和非天然存在的核苷酸类似物)产生的DNA或RNA的类似物,及其杂合体。核酸分子可以是单链或双链的。
在本申请中,术语“分离的核酸分子”通常是指从5’至3’末端阅读的脱氧核糖核苷酸或核糖核苷酸碱基的单链或双链聚合物或其类似物,其已与至少约50%的当从来源细胞分离总核酸时与核酸分子一起被天然发现的多肽、肽、脂质、糖类、多核苷酸或其它材料分离。例如,分离的核酸分子大体上不含任何其它污染性核酸分子或在核酸的天然环境中发现的可干扰其的用途或其治疗性、诊断性、预防性或研究用途的其它分子。
在本申请中,术语“mRNA”通常是指经过处理去除了内含子,且能够被翻译成多肽的RNA转录本。
在本申请中,术语“载体”通常是指能够在合适的宿主中自我复制的核酸分子,其将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体,以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常,通过培养包含所述载体的合适的宿主细胞,所述载体可以产生期望的表达产物。
在本申请中,术语“细胞”通常是指可以或已经含有包括本申请所述的核酸分子的质粒或载体,或者能够表达本申请所述的抗体或其抗原结合片段的个体细胞、细胞系或细胞培养物。所述细胞可以包括单个宿主细胞的子代。由于天然的、意外的或故意的突变,子代细胞与原始亲本细胞在形态上或在基因组上可能不一定完全相同,但能够表达本申请所述的抗体或其抗原结合片段即可。所述细胞可以通过使用本申请所述的载体体外转染细胞而得到。所述细胞可以是原核细胞,也可以是真核细胞。
在本申请中,术语“药学上可接受的载体”通常包括药剂学可接受的载体、赋形剂或稳定剂,它们在所采用的剂量和浓度对暴露于其的细胞或哺乳动物是无毒的。通常,生理学可接受的载体是pH缓冲水溶液。生理学可接受载体的例子可包括缓冲剂,抗氧化剂,低分子量(少于约10个残基)多肽,蛋白质,亲水性聚合物,氨基酸,单糖,二糖和其它碳水化合物,螯合剂,糖醇,成盐反荷离子,诸如钠;和/或非离子表面活性剂。
在本申请中,术语“药物组合物”通常是指以允许活性成分(例如,本申请的S蛋白变体、核酸分子)的生物学活性有效的形式的制剂,并且其不含有对所述制剂待施用的受试者有不可接受的毒性的另外成分。这些制剂可为无菌的。
在本申请中,术语“试剂盒”通常是指包含用于给予本申请的抗原结合蛋白治疗PD-1介导的相关病症的组分的包装产品。试剂盒的组分可包含在分开的小瓶中(即具有分开部分的试剂盒),或在单个小瓶内提供。试剂盒可包含试剂,诸如缓冲剂、蛋白稳定试剂、信号产生体系(例如,荧光信号生成体系)、抗体、对照蛋白、以及测试容器。试剂盒还可以包含实施所述方法的说明书。
在本申请中,术语“给药装置”包括:(i)输注模块,所述输注模块用于对受试者施用包括具有一活性成分的药物组合物;(ii)用于输注的药物组合物,所述药物组合物中含有一活性成分,所述活性成分选自下组:重组蛋白、核酸分子、mRNA、载体、细胞、组合物、药物组合物或其组合;以及(iii)任选的药效监控模块。
在本申请中,术语“中枢和/或周围神经系统疾病”通常是指中枢神经系统(脑或脊髓)和周围神经系统(脑或脊髓外的神经)病变相关的疾病。例如:中枢和/或周围神经系统疾病可以表现由以下一种或多种引起:神经细胞退化、少突胶质细胞发炎或丢失、脑部血液供应梗塞、损伤或肿瘤和细菌或病毒感染。中枢和/或周围神经系统疾病可以包括阿尔茨海默症、亨廷顿氏舞蹈症、帕金森病、多发性硬化、脑炎或脑膜炎、脑或脊髓结构损伤和/或中风。
在本申请中,术语“神经退行性疾病”通常是指神经元功能和结构的逐渐丧失以导致认知障碍。神经退行性疾病可包括阿尔茨海默症、帕金森病、亨廷顿氏舞蹈症、早发性阿尔茨海默症或早发性帕金森病,和/或肌萎缩性侧索硬化症。
在本申请中,术语“周围神经病变”通常是指周围神经系统异常引起的疾病或病症。周围神经系统包括除中枢神经系统(脑和脊髓)以外的所有神经,例如:连接头部、面部、眼睛、鼻子、肌肉和耳朵与脑的神经(脑神经),连接脊髓与身体其它部位的神经,和分布于全身各个部位的神经细胞。
在本申请中,术语“受试者”通常是指需要诊断、预后、改善、预防和/或治疗疾病的人或非人动物(包括哺乳动物),诸如人、非人灵长类动物(猿、长臂猿、大猩猩、黑猩猩、猩猩、猕猴)、家畜(狗和猫)、农场动物(家禽如鸡和鸭、马、牛、山羊、绵羊、猪)和实验动物(小鼠、大鼠、兔、豚鼠)。人受试者包括胎儿、新生儿、婴儿、青少年和成人受试者。受试者可以包括动物疾病模型。
在本申请中,术语“包括”、“包含”、“具有”、“可以”、“含有”及其变体通常旨在是开放式过渡性短语、术语或词语,其不排除额外行为或结构的可能性。术语“由……组成”通常表示不能存在别的组分(或同样地,特征、整数、步骤、等)。除非上下文另有明确规定,单数形式如英文的“a”,“an”,“the”,中文的“一个”、“一种”和“所述/该”一般包括所指代事物的复数形式。
在本申请中,术语“约”通常意指大约(approximately)、在......的附近(intheregionof)、粗略地(roughly)、或左右(around)。当术语“约”当用于指涉数值范围时,截值或特定数值用于指示所载明的数值可与该列举数值有多达10%的差异。因此,术语“约”可用于涵盖自特定值±10%或更少的变异、±5%或更少的变异、±1%或更少的变异、±0.5%或更少的变异、或±0.1%或更少的变异。
发明详述
重组蛋白
一方面,本申请提供了一种重组蛋白,所述重组蛋白包含神经生长因子(NGF)蛋白变体,其中,与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少约50%(例如,减少至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%或更多),例如,所述野生型NGF蛋白可包含SEQ ID NO:32所示的氨基酸序列。
在本申请中,与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体可包含一个或多个氨基酸突变。例如,与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体可在R100处(即,第100位精氨酸处)包含氨基酸突变。例如,与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体第100位的精氨酸突变为色氨酸(即R100W)。例如,所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
本领域已知,当成熟NGF蛋白发生R100W突变时,其被分泌到细胞外的能力降低。本身请提供了一种,与天然存在的NGFR100W变体蛋白相比,表达量和/或分泌量增加的NGFR100W变体的重组蛋白。本申请的重组蛋白能够增加成熟NGFR100W变体蛋白分泌到细胞外的量。例如,本申请的重组蛋白可包含异源信号肽,所述异源信号肽可以位于所述NGF蛋白变体的N端。例如,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少约50%(例如,增加至少约55%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约90%、至少约95%、至少约98%或更多)。
本申请所述的异源信号肽的长度可以为5~30个氨基酸。例如,本申请所述的异源信号肽的长度可以为5-25个氨基酸。例如,本申请所述的异源信号肽的长度可以为5-20个氨基酸。例如,本申请所述的异源信号肽的长度可以为10-25个氨基酸。例如,本申请所述的异源信号肽的长度可以为10-30个氨基酸。例如,本申请所述的异源信号肽的长度可以为15-30个氨基酸。例如,本申请所述的异源信号肽的长度可以为10-20个氨基酸。例如,本申请所述的异源信号肽的长度可以为15-20个氨基酸。例如,本申请所述的异源信号肽的长度可以为18个氨基酸。例如,本申请所述的异源信号肽的长度可以为19个氨基酸。例如,本申请所述的异源信号肽的长度可以为20个氨基酸。
本申请所述的异源信号肽可以来自原核生物,如细菌(大肠杆菌、金黄色葡萄球菌、枯草芽孢杆菌)。本申请所述的异源信号肽可以来自真核生物,例如,酵母或哺乳动物细胞(人类、小鼠、猴等)。
本申请所述的异源信号肽可以源自分泌型蛋白、周质蛋白和/或膜结合蛋白,例如,酶。例如,信号肽可以源自大肠杆菌外膜蛋白A OmpA、OmpF、λ噬菌体受体LamB、热稳定肠毒素ST、碱性磷酸酶PhoA、麦芽糖结合蛋白MBP、DsbA,金黄色葡萄球菌蛋白A,枯草芽孢杆菌蛋白酶、中性蛋白酶,崖边杆菌RNA酶、果聚糖酶。例如,信号肽还可以源自酵母表达系统中的外源蛋白的天然信号肽、α-因子信号肽、蔗糖酶基因SUC信号肽序列、酸性磷酸酶基因PHO1和/或间质金属蛋白酶,或者源自人血清蛋白和牛凝乳酶。
本申请所述的异源信号肽可以源自Gaussia、Homo sapiens、Oikopleura dioica或Musmusculus。本申请所述的异源信号肽可以包含源自Gaussia荧光素酶、人胰蛋白酶原-2、Oikosin1突变体、天青素前蛋白和/或Igκ的信号肽。在某些实施方式中,所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
本申请所述的异源信号肽可以包含源自神经营养因子的信号肽。例如,所述异源信号肽可以为脑源性神经营养因子(BDNF)、神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)的信号肽。例如,所述异源信号肽可以包含SEQ ID NO:30、31和35-43中任一项所示的氨基酸序列。例如,所述异源信号肽为IgK信号肽和/或BDNF信号肽。例如,所述异源信号肽包含SEQ ID NO:30-31中任一项所示的氨基酸序列。
例如,所述异源信号肽为IgK信号肽,又例如,所述异源信号肽包含SEQ ID NO:30所示的氨基酸序列。
例如,所述异源信号肽为BDNF信号肽,又例如,所述异源信号肽包含SEQ ID NO:31所示的氨基酸序列。
例如,所述异源信号肽为hIL-2信号肽,又例如,所述异源信号肽包含SEQ ID NO:35所示的氨基酸序列。
例如,所述异源信号肽为APP信号肽,又例如,所述异源信号肽包含SEQ ID NO:36所示的氨基酸序列。
例如,所述异源信号肽为HC信号肽,又例如,所述异源信号肽包含SEQ ID NO:37所示的氨基酸序列。
例如,所述异源信号肽为Cystatin信号肽,又例如,所述异源信号肽包含SEQ IDNO:38所示的氨基酸序列。
例如,所述异源信号肽为Gp67信号肽,又例如,所述异源信号肽包含SEQ ID NO:39所示的氨基酸序列。
例如,所述异源信号肽为HBM信号肽,又例如,所述异源信号肽包含SEQ ID NO:40所示的氨基酸序列。
例如,所述异源信号肽为Gp64信号肽,又例如,所述异源信号肽包含SEQ ID NO:41所示的氨基酸序列。
例如,所述异源信号肽为Alb信号肽,又例如,所述异源信号肽包含SEQ ID NO:42所示的氨基酸序列。
例如,所述异源信号肽为SP信号肽,又例如,所述异源信号肽包含SEQ ID NO:43所示的氨基酸序列。
在本申请中,所述重组蛋白还包括前导肽。所述前导肽可以是NGF蛋白的前导肽,也可以是源自非NGF蛋白的异源的前导肽。例如,所述前导肽可以包含SEQ ID NO:34所示的氨基酸序列。
在本申请中,所述重组蛋白还包括前导肽。在本申请中,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体。
在本申请中,所述重组蛋白还包括前导肽。在本申请中,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体,且所述异源信号肽包含SEQ ID NO:30-31和35-43中任一项所示的氨基酸序列,所述前导肽包含SEQ ID NO:34所示的氨基酸序列,且所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:15所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:16所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述BDNF信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:19所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述BDNF信号肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:20所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述SP信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:58所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述hIL-2信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:59所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述Cystatin信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:60所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述APP信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:61所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述HC信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:62所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述Gp67信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:63所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述HBM信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:64所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述Gp64信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:65所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述Alb信号肽、所述前导肽和所述NGF蛋白变体。例如,所述重组蛋白包含SEQ ID NO:66所示的氨基酸序列。
在某些实施方式中,所述重组蛋白还包括标签肽。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述前导肽,所述NGF蛋白变体和所述标签肽。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述NGF蛋白变体和所述标签肽。
例如,所述标签肽可以包含(YPYDVPDYA)n所示的氨基酸序列,其中n为1至5的任意整数。又例如,所述标签肽可以包含YPYDVPDYA(SEQ ID NO:68)或YPYDVPDYAYPYDVPDYA(SEQID NO:69)所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述前导肽,所述NGF蛋白变体和所述标签肽。例如,所述重组蛋白包含SEQ ID NO:70所示的氨基酸序列。
在某些实施方式中,所述重组蛋白还包括穿膜锚定区。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述前导肽,所述NGF蛋白变体和所述穿膜锚定区。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述NGF蛋白变体和所述穿膜锚定区。
例如,所述穿膜锚定区可以是血小板衍生生长因子受体的C端跨膜锚定域(C-terminaltransmembrane anchoring domain of platelet-derived growth factorreceptor,PDGFR)。又例如,所述穿膜锚定区可以包含SEQ ID NO:67所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述前导肽,所述NGF蛋白变体和所述穿膜锚定区。例如,所述重组蛋白包含SEQ ID NO:17所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述NGF蛋白变体和所述穿膜锚定区。例如,所述重组蛋白包含SEQ ID NO:18所示的氨基酸序列。
在某些实施方式中,所述重组蛋白还包括延长半衰期的结构域。
例如,所述重组蛋白还包括免疫球蛋白的Fc区。所述Fc区可以延长所述重组蛋白的半衰期。所述Fc区可以位于所述重组蛋白的C端。例如,与不包含Fc区的重组蛋白相比,所述包含Fc区的重组蛋白的半衰期可延长至少约10%、20%、30%、40%、50%、60%、70%、80%、90%或更高。
例如,所述Fc区可以源自人免疫球蛋白和/或小鼠免疫球蛋白。
例如,所述Fc区可以为人IgG1的Fc区。
例如,所述Fc区可以为小鼠IgG的Fc区
例如,所述Fc区可以包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
又例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
例如,所述重组蛋白可以包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
核酸分子
另一方面,本申请提供了一种分离的核酸分子,所述分离的核酸分子编码所述的重组蛋白。例如,所述分离的核酸分子可以编码包含SEQ ID NO:15-20、54-55和58-66中任一项所示的氨基酸序列的重组蛋白。
例如,所述分离的核酸分子可以编码包含SEQ ID NO:15所示的氨基酸序列的重组蛋白。例如,所述分离的核酸分子可以编码包含SEQ ID NO:19所示的氨基酸序列的重组蛋白。
例如,所述分离的核酸分子可以包括DNA和/或RNA。例如,所述分离的核酸分子可以为DNA,且可以编码包含SEQ ID NO:15或19所示的氨基酸序列的重组蛋白。例如,所述分离的核酸分子可以为RNA,且可以编码包含SEQ ID NO:15或19所示的氨基酸序列的重组蛋白。
例如,所述分离的核酸分子可以在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
例如,所述分离的核酸分子可以包含至少一种经修饰的核苷酸。
在本申请中,所述核酸分子可包含如SEQ ID NO:2-8,10-11,23-28,46-47和50-51中任一项所示的核苷酸序列。在本申请中,所述核酸分子可包含与SEQ ID NO:2-8,10-11,23-28,46-47和50-51中任一项所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述核酸分子可包含如SEQ ID NO:11-12中任一项所示的核苷酸序列。在本申请中,所述核酸分子可包含与SEQ ID NO:11-12中任一项所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述核酸分子可包含如SEQ ID NO:3、11和23中任一项所示的核苷酸序列。在本申请中,所述核酸分子可包含与SEQ ID NO:3、11和23中任一项所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述核酸分子可包含如SEQ ID NO:7、12和27中任一项所示的核苷酸序列。在本申请中,所述mRNA可包含与SEQ ID NO:7、12和27中任一项所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
一方面,本申请提供一种分离的RNA,特别是一种mRNA,所述mRNA包含能够编码神经生长因子(NGF)蛋白或其变体的核酸分子,或者,所述mRNA的至少一部分能够编码所述NGF蛋白变体。
在某些实施方式中,所述NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
在某些实施方式中,与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%(例如,减少至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%或更多)。
在某些实施方式中,所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
在某些实施方式中,所述mRNA包含编码异源信号肽的多核苷酸,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%(例如,增加至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%或更多)。
在某些实施方式中,所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上(例如,达到至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、至少98%或更多)。
在某些实施方式中,所述异源信号肽源自神经营养因子。
在某些实施方式中,所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
在某些实施方式中,所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
在某些实施方式中,所述异源信号肽为IgK信号肽和/或BDNF信号肽。
在某些实施方式中,所述异源信号肽包含SEQ ID NO:30-31和35-43中任一项所示的氨基酸序列。
在某些实施方式中,所述异源信号肽包含SEQ ID NO:30-31中任一项所示的氨基酸序列。
在某些实施方式中,所述mRNA还包括编码前导肽的多核苷酸。
在某些实施方式中,所述前导肽包含SEQ ID NO:34所示的氨基酸序列。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸和所述编码NGF蛋白或其变体的多核苷酸。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
在某些实施方式中,自5’端至3’端,所述mRNA依次包括编码所述BDNF信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
在某些实施方式中,所述mRNA编码包含如SEQ ID NO:15-20中任一项所示的氨基酸序列。在某些实施方式中,所述mRNA编码包含如SEQ ID NO:15和19任一项所示的氨基酸序列。
在某些实施方式中,所述重组蛋白还包括穿膜锚定区。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述前导肽,所述NGF蛋白变体和所述穿膜锚定区。
例如,自N端至C端,所述重组蛋白可以依次包括所述异源信号肽,所述NGF蛋白变体和所述穿膜锚定区。
例如,所述穿膜锚定区可以是PDGFR穿膜锚定区。又例如,所述穿膜锚定区可以包含SEQ ID NO:67所示的氨基酸序列。
例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述前导肽,所述NGF蛋白变体和所述穿膜锚定区。例如,自N端至C端,所述重组蛋白可以依次包括所述IgK信号肽、所述NGF蛋白变体和所述穿膜锚定区。
在某些实施方式中,所述mRNA编码包含SEQ ID NO:17-18中任一项所示的氨基酸序列。
在某些实施方式中,所述其中所述mRNA还包含编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,所述Fc区源自人免疫球蛋白和/或小鼠免疫球蛋白。
在某些实施方式中,所述Fc区为人IgG1的Fc区。
在某些实施方式中,所述Fc区为小鼠IgG的Fc区
在某些实施方式中,所述Fc区包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
在某些实施方式中,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸、所述编码NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸、编码所述NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
在某些实施方式中,所述mRNA编码包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
一方面,本申请提供一种分离的RNA,特别是一种mRNA,所述mRNA包含能够编码所述重组蛋白的核酸分子,或者,所述mRNA的至少一部分能够编码所述重组蛋白,例如,所述重组蛋白可包含SEQ ID NO:15所示的氨基酸序列。
在本申请中,所述RNA可以是天然或非天然存在的RNA,例如mRNA。所述mRNA可以包括一个或多个核碱基、核苷或核苷酸。在本申请中,术语“核苷”通常是指包含糖分子(例如戊糖或核糖)或其衍生物和有机碱(例如嘌呤或嘧啶)或其衍生物(本文也称为“核碱基”)的组合的化合物。在本申请中,“核苷酸”通常是指包括磷酸基团的核苷。
在本申请中,所述mRNA可以包括5’非翻译区(5’UTR)、3’非翻译区(3’UTR)和/或编码区(例如开放阅读框)。
在本申请中,所述mRNA可以是修饰的。所述修饰可以是化学修饰或生物修饰。在本申请中,所述mRNA可以包含一个或多个修饰的核碱基、核苷或核苷酸,此时,它可以被称为“化学修饰的mRNA”,在本文中也可被称为“修饰的mRNA”。与未经修饰的参考序列(例如,天然存在的或野生型的mRNA)相比,修饰的mRNA可具有有用的性质,例如,包括增强的稳定性、提高的细胞内保留、增强的翻译效果和/或降低的免疫原性。因此,使用修饰的mRNA可以提高蛋白质生产的效率、提高核酸在细胞内的保留以及降低免疫原性。
在某些实施方式中,所述mRNA在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
在本申请中,所述mRNA可以包括修饰的核碱基,所述修饰的核碱基可以是修饰的尿嘧啶。在本申请中,所述mRNA可以包括修饰的核碱基,所述修饰的核碱基可以是修饰的胞嘧啶。在本申请中,所述mRNA可以包括修饰的核碱基,所述修饰的核碱基可以是修饰的腺嘌呤。在本申请中,所述mRNA可以包括修饰的核碱基,所述修饰的核碱基可以是修饰的鸟嘌呤。在本申请中,所述mRNA可以包括一种或多种前述修饰的核碱基的组合(例如,前述修饰的核碱基的2、3或4种的组合)。
例如,所述分离的核酸分子可以选自下组的一种或多种核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。在某些实施方案中,本申请的修饰的RNA包括一种或多种前述修饰的核碱基的组合(例如,前述修饰的核碱基的2、3或4的组合)。
在本申请中,所述mRNA可以被密码子优化,改变密码子的一种或多种核苷酸,仍使得密码子编码相同氨基酸。
在本申请中,所述mRNA可包含如SEQ ID NO:23-28和50-51中任一项所示的核苷酸序列。在本申请中,所述mRNA可包含与SEQ ID NO:23-28和50-51中任一项所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述mRNA可包含如SEQ ID NO:23所示的核苷酸序列。在本申请中,所述mRNA可包含与SEQ ID NO:23所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述mRNA可包含如SEQ ID NO:23所示的核苷酸序列。在本申请中,所述mRNA可包含与SEQ ID NO:23所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
在本申请中,所述mRNA可包含如SEQ ID NO:27所示的核苷酸序列。在本申请中,所述mRNA可包含与SEQ ID NO:27所示的核苷酸序列具有至少80%(例如,82%、85%、88%、90%、95%、98%、99%或以上)的序列同一性的核苷酸序列。
本申请的mRNA可以通过本领域任何可行的方法产生,包括但不限于体外转录(IVT)和合成方法。可以利用酶促、固相、液相、组合合成方法、小区域合成和连接方法制备mRNA。在一个实施方案中,使用IVT酶促合成方法制备mRNA。因此,本申请还涉及还可用于体外转录本申请的mRNA的多核苷酸,例如DNA、构建体和载体。
组合物
在本申请中,所述的组合物还可包含递送载体。本申请的mRNA可以配制在纳米颗粒或其他递送载体中,例如,以避免它们在递送至受试者时被降解。在本申请中,所述mRNA可以被包封在纳米颗粒内。在特定的实施方案中,纳米颗粒是具有至少一个尺寸(例如直径)小于或等于约1000nM、小于或等于约500nM、小于或等于约400nM、小于或等于约300nM、小于或等于约200nM或小于或等于约100nM的颗粒。在特定的实施方案中,纳米颗粒可包括脂质。脂质纳米颗粒可以包括但不限于脂质体和胶束。在本申请中,所述脂质纳米颗粒可以包括阳离子和/或可电离的脂质、阴离子脂质、非阳离子脂质、中性脂质、两亲性脂质、聚乙二醇化的脂质和/或结构性脂质,或上述的组合在某些实施方案中,脂质纳米颗粒包含一种或多种本申请所述的RNA,例如mRNA,又例如,编码目的多肽(例如,所述重组蛋白或所述NGF蛋白变体)的mRNA。例如,脂质纳米颗粒中包含一种或多种本申请所述的编码所述重组蛋白或所述NGF蛋白变体的mRNA。
本申请所述组合物中的递送载体可以是脂质纳米颗粒。所述脂质纳米颗粒可包含一种或多种(例如1、2、3、4、5、6、7或8)阳离子和/或可离子化的脂质。“阳离子脂质”通常指在一定pH(例如,生理pH)下携带任意数目的净正电荷的脂质。所述阳离子脂质可包括但不限于3-(双十二烷基氨基)-N1,N1,4-三十二烷基-1-哌嗪乙胺(KL10)、N1-[2-(二十二烷基氨基)乙基]-N1,N4,N4-三十二烷基-1,4-哌嗪二乙胺(KL22)、14,25-二十三烷基-15,18,21,24-四氮杂八孔并烷(KL25)、DLin-DMA、DLin-K-DMA、DLin-KC2-DMA、Octyl-CLinDMA、辛基-CLinDMA(2S)、DODAC、DOTMA、DDAB、DOTAP、DOTAP.C1、DC-Choi、DOSPA、DOGS、DODAP、DODMA和DMRIE。另外,可以使用许多商业化的阳离子和/或可离子化脂质,例如,(包括DOTMA和DOPE)和(包括DOSPA和DOPE)。例如,阳离子脂质可以是DLin-MC3-DMA或DLin-KC2-DMA。
在某些实施方式中,所述阳离子脂质在脂质纳米颗粒中的摩尔比例为约40-70%,例如,约40-65%、约40-60%、约45-55%或约48-53%。在某些实施方式中,所述阳离子脂质(例如,DLin-MC3-DMA)在脂质纳米颗粒中的摩尔比例为约50%。
在本申请中,所述脂质纳米颗粒可包含一种或多种(例如1、2、3、4、5、6、7或8)非阳离子脂质。所述非阳离子脂质可以包括阴离子脂质。适用于本申请的脂质纳米颗粒的阴离子脂质可包括磷脂酰甘油、心磷脂、二酰基磷脂酰丝氨酸、二酰基磷脂酸、N-十二烷酰基磷脂酰乙醇胺、N-琥珀酰基磷脂酰乙醇胺、N-戊二酰基磷脂酰磷酸乙醇基,以及其他连接了阴离子基团的中性脂质。
所述非阳离子脂质可以包括中性脂质。适用于本申请的脂质纳米颗粒的中性脂质可包括磷脂,例如二硬脂酰基磷脂酰胆碱(DSPC)、二油酰基磷脂酰胆碱(DOPC)、二棕榈酰基磷脂酰胆碱(DPPC)、二油酰基磷脂酰甘油(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、二油酰基磷脂酰乙醇胺(DOPE)、棕榈酰基油酰基磷脂酰胆碱(POPC)、棕榈酰基油酰基-磷脂酰乙醇胺(POPE)、二油酰基-磷脂酰乙醇胺4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(DOPE-mal)、二棕榈酰基磷脂酰基乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、二硬脂酰基-磷脂酰基-乙醇胺(DSPE)、16-O-单甲基PE、16-O-二甲基PE、18-1-反式PE、1-硬脂酰基-2-油酰基-磷脂酰乙醇胺(SOPE),或其混合物。另外,可以使用具有饱和和不饱和脂肪酸链的混合物的脂质。例如,本申请所述的中性脂质可以选自DOPE、DSPC、DPPC、POPC或任何相关的磷脂酰胆碱。
在某些实施方式中,所述磷脂在脂质纳米颗粒中的摩尔比例为约30-45%,例如,约33-42%、约35-40%或约38-39%。在某些实施方式中,所述磷脂(例如,DSPC)在脂质纳米颗粒中的摩尔比例为约38.5%。
在本申请中,所述脂质纳米颗粒可包含脂质缀合物,例如,聚乙二醇(PEG)修饰的脂质和衍生的脂质。PEG修饰的脂质可包括但不限于与具有C6-C20长度的烷基链的脂质共价连接的长度至多为5kDa的聚乙二醇链。这些组分的加入可防止脂质聚集,也可增加循环持续时间,易于脂质-核酸组合物递送至靶细胞,或快速释放出核酸。例如,所述聚乙二醇(PEG)修饰的脂分子可以是具有较短的酰基链(例如,C14或C18)的PEG-神经酰胺。例如,所述脂质纳米颗粒可包含PEG2000-DMG。
在某些实施方式中,所述聚乙二醇(PEG)修饰的脂分子在脂质纳米颗粒中的摩尔比例为约0.5-2%,例如,约1-2%、约1.2-1.8%或约1.4-1.6%。在某些实施方式中,所述聚乙二醇(PEG)修饰的脂分子(例如,PEG2000-DMG)在脂质纳米颗粒中的摩尔比例为约1.5%。
在本申请中,所述脂质纳米颗粒还可包含胆固醇。在某些实施方式中,所述胆固醇在脂质纳米颗粒中的摩尔比例为约5-15%,例如,约6-14%、约7-13%、约8-12%或约9-11%。在某些实施方式中,所述胆固醇在脂质纳米颗粒中的摩尔比例为约10%。
在本申请中,所述脂质纳米颗粒可包括阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子。在某些实施方式中,所述阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子的摩尔比可以为45~55:5~15:35~45:0.5~2。在某些实施方式中,所述阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子的摩尔比可以为50:10:38.5:1.5。
例如,所述组合物可包含所述mRNA和所述脂质纳米颗粒,其中,所述mRNA可以编码SEQ ID NO:15所示的氨基酸序列,所述脂质纳米颗粒可包括阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子,且所述阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子的摩尔比可以为50:10:38.5:1.5。
例如,所述组合物可包含所述mRNA和所述脂质纳米颗粒,其中,所述mRNA可以编码SEQ ID NO:15所示的氨基酸序列,所述脂质纳米颗粒可包含DLin-MC3-DMA、胆固醇、DSPC以及PEG2000-DMG的摩尔,且所述DLin-MC3-DMA、胆固醇、DSPC以及PEG2000-DMG的摩尔比可以为50:10:38.5:1.5。
例如,所述组合物可包含所述mRNA和所述脂质纳米颗粒,其中,所述mRNA可以包含SEQ ID NO:23所示的核苷酸序列,所述脂质纳米颗粒可包含阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子,且所述阳离子脂质、胆固醇、磷脂以及聚乙二醇修饰的脂分子的摩尔比可以为50:10:38.5:1.5。
例如,所述组合物可包含所述mRNA和所述脂质纳米颗粒,其中,所述mRNA可以包含SEQ ID NO:23所示的氨基酸序列,所述脂质纳米颗粒可包含DLin-MC3-DMA、胆固醇、DSPC以及PEG2000-DMG的摩尔,且所述DLin-MC3-DMA、胆固醇、DSPC以及PEG2000-DMG的摩尔比可以为50:10:38.5:1.5。
制备方法
本申请提供了制备所述组合物中的递送载体的方法。例如,通过现有技术可制备多层囊泡(MLV),例如,通过沉积选择的脂质在合适容器或器皿的内壁上;通过溶解脂质在合适溶剂中,以及然后蒸发溶剂以在器皿的内侧保留薄膜或者通过喷雾干燥。可将水相加入旋转运动着的器皿,其导致形成MLV。然后通过均质化、超声处理或挤压多层囊泡能够形成单层囊泡(ULV)。此外,通过洗涤剂去除技术能够形成单层囊泡。
在申请中,所述组合物包含递送载体(例如,脂质纳米颗粒),其中mRNA可以与脂质的递送载体的表面缔合,并包封在其中。例如,在制备本申请的组合物时,所述阳离子脂质的递送载体可与mRNA通过静电作用缔合。
在某些实施方案中,所述组合物包含体内外可检测的诊断放射性核素、荧光物质或其他物质。
在本申请中,考虑靶细胞或者组织的尺寸以及待制备的脂质体应用程度选择所述脂质递送载体(例如,脂质纳米颗粒)的合适尺寸。在某些实施方案中,可以将mRNA递送至特定的细胞或者组织。例如,为了靶向肝细胞,可确定脂质递送载体(例如,脂质纳米颗粒)的尺寸,使得它的尺寸比在肝中内皮层衬里肝窦状隙的开窗缝要小,使得脂质递送载体(例如,脂质纳米颗粒)能够容易地渗透这些内皮开窗缝以到达靶肝细胞。脂质递送载体(例如,脂质纳米颗粒)可以具有足够大的直径以限制或者明显避免分布至某些细胞或组织内。在本申请中,所述脂质递送载体(例如,脂质纳米颗粒)的尺寸(例如,直径)可以在约25至250nm范围内,例如小于约250nm、175nm、150nm、125nm、100nm、75nm、50nm、25nm或10nm。例如,所述脂质递送载体(例如,脂质纳米颗粒)的尺寸(例如,直径)可以在约25至250nm范围内,例如,约50至200nm、约75至175nm、约75至150nm或约75至125nm内。
载体、细胞和药物组合物
另一方面,本申请提供了载体,所述载体包含所述核酸分子。例如,所述载体可以为病毒载体,例如,腺病毒载体、腺相关病毒载体和/或慢病毒载体。
另一方面,本申请提供了细胞,所述细胞包含所述核酸分子,和/或所述载体。在本申请中,所述细胞可以是原核细胞,例如,大肠杆菌。在本申请中,所述细胞可以是真核细胞例如酵母细胞,昆虫细胞,植物细胞和动物细胞。在本申请中,所述细胞可以为哺乳动物的细胞,例如小鼠细胞、人细胞等。在本申请中,所述细胞可以为293T细胞或P12细胞。
另一方面,本申请提供了一种制备所述的重组蛋白的方法,所述方法包括在使得所述的重组蛋白表达的条件下,培养所述的细胞。
另一方面,本申请提供了一种药物组合物,所述药物组合物包含所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体和/或所述的细胞,以及任选地药学上可接受的载体。
另一方面,本申请提供了一种试剂盒或给药装置,所述试剂盒或给药装置包含所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。其可在单一常用容器中包括本申请所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物,也可任选地与一种或多种治疗剂组合,任选地一起配制于试剂盒中。
治疗方法
另一方面,本申请提供了一种缓解、预防和/或治疗中枢和/或周围神经系统疾病的方法,所述方法包括向有需要的受试者施用所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。例如,所述中枢和/或周围神经系统疾病可以包括神经退行性疾病。例如,所述中枢和/或周围神经系统疾病可以包括周围神经病变。例如,所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。例如,所述中枢和/或周围神经系统疾病可以包括在某些实施方式中,所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
在某些实施方式中,所述中枢和/或周围神经系统疾病包括糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症。
另一方面,本申请提供了一种所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物在制备药物中的用途,所述药物可以用于缓解、预防和/或治疗中枢和/或周围神经系统疾病。例如,所述中枢和/或周围神经系统疾病可以包括神经退行性疾病。例如,所述中枢和/或周围神经系统疾病可以包括周围神经病变。例如,所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。例如,所述中枢和/或周围神经系统疾病可以包括在某些实施方式中,所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
另一方面,本申请提供了一种促进神经生长因子(NGF)蛋白分泌和/或表达的方法,其包括使用所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。例如,所述方法可以为非治疗目的的方法。例如,所述方法可以为体外的和/或离体的方法。
另一方面,本申请提供了一种促进神经细胞增殖和/或分化的方法,其包括使用所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。例如,所述方法可以为非治疗目的的方法。例如,所述方法可以为体外的和/或离体的方法。
另一方面,本申请提供了一种修复损伤的神经细胞的方法,其包括使用所述的重组蛋白、所述的核酸分子、所述的组合物、所述的载体、所述的细胞,和/或所述的药物组合物。例如,所述方法可以为非治疗目的的方法。例如,所述方法可以为体外的和/或离体的方法。
具体地,本申请公开了以下具体实施方式:
1.重组蛋白,其包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽,其中,
与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%,
与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%。
2.根据实施方式1所述的重组蛋白,其中所述野生型NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
3.根据实施方式1-2中任一项所述的重组蛋白,其中所述NGF蛋白变体包含SEQIDNO:33所示的氨基酸序列。
4.根据实施方式1-3中任一项所述的重组蛋白,其中所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上。
5.根据实施方式1-4中任一项所述的重组蛋白,其中所述异源信号肽源自神经营养因子。
6.根据实施方式1-5中任一项所述的重组蛋白,其中所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
7.根据实施方式1-6中任一项所述的重组蛋白,其中所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白(Albumin,Alb)、IL-2、天青素前蛋白(Azurocidinpreproprotein,APP)、小鼠IgK、免疫球蛋白重链(Immunoglobulin heavychain,HC)和/或胱抑素-S前体(Cystatin-S precursor,Cystatin)。
8.根据实施方式1-7中任一项所述的重组蛋白,其中所述异源信号肽为IgK信号肽和/或BDNF信号肽。
9.根据实施方式1-8中任一项所述的重组蛋白,其中所述异源信号肽包含SEQ IDNO:30-31中任一项所示的氨基酸序列。
10.根据实施方式1-9中任一项所述的重组蛋白,其还包括前导肽。
11.根据实施方式10所述的重组蛋白,其中所述前导肽包含SEQ ID NO:34所示的氨基酸序列。
12.根据实施方式10-11中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体。
13.根据实施方式10-12中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述IgK信号肽、所述前导肽和所述NGF蛋白变体。
14.根据实施方式1-13中任一项所述的重组蛋白,其包含SEQ ID NO:15-20中任一项所示的氨基酸序列。
15.根据实施方式1-13中任一项所述的重组蛋白,其包含SEQ ID NO:15和19中任一项所示的氨基酸序列。
16.根据实施方式1-15中任一项所述的重组蛋白,其还包括免疫球蛋白的Fc区。
17.根据实施方式16所述的重组蛋白,其中所述Fc区源自人免疫球蛋白和/或小鼠免疫球蛋白。
18.根据实施方式16-17中任一项中所述的重组蛋白,其中所述Fc区为人IgG1的Fc区。
19.根据实施方式16-18中任一项所述的重组蛋白,其中所述Fc区为小鼠IgG的Fc区。
20.根据实施方式16-19中任一项所述的重组蛋白,其中所述Fc区包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
21.根据实施方式16-20中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
22.根据实施方式16-21中任一项所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述IgK信号肽、所述前导肽、所述NGF蛋白变体和所述Fc区。
23.根据实施方式1-22中任一项所述的重组蛋白,其包含SEQ ID NO:54-55中任一项所示的氨基酸序列。
24.分离的核酸分子,其编码实施方式1-23中任一项所述的重组蛋白。
25.根据实施方式24所述的核酸分子,其包括DNA和/或RNA。
26.根据实施方式24-25中任一项所述的核酸分子,其在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
27.根据实施方式24-26中任一项所述的核酸分子,其包含至少一种经修饰的核苷酸。
28.根据实施方式24-27中任一项所述的核酸分子,其包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
29.根据实施方式24-28中任一项所述的核酸分子,其是密码子优化的。
30.根据实施方式24-29中任一项所述的核酸分子,其包含SEQ ID NO:3-8和46-47中任一项所示的核苷酸序列。
31.根据实施方式24-30中任一项所述的核酸分子,其包含SEQ ID NO:3和7中任一项所示的核苷酸序列。
32.根据实施方式24-31中任一项所述的核酸分子,其包含SEQ ID NO:11-12中任一项所示的核苷酸序列。
33.根据实施方式24-32中任一项所述的核酸分子,其包含SEQ ID NO:23-28和50-51中任一项所示的核苷酸序列。
34.根据实施方式16-21中任一项所述的核酸分子,其包含SEQ ID NO:23和27中任一项所示的核苷酸序列。
35.组合物,其包含(a)mRNA,所述mRNA包含编码神经生长因子(NGF)蛋白或其变体的多核苷酸,和(b)递送载体。
36.根据实施方式35所述的组合物,其中所述NGF蛋白包含SEQ ID NO:32所示的氨基酸序列。
37.根据实施方式35-36中任一项所述的组合物,其中与SEQ ID NO:32所示的氨基酸序列相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%。
38.根据实施方式35-37中任一项所述的组合物,其中所述NGF蛋白变体包含SEQIDNO:33所示的氨基酸序列。
39.根据实施方式35-38中任一项所述的组合物,其中所述mRNA包含编码异源信号肽的多核苷酸,与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%。
40.根据实施方式39所述的组合物,其中所述异源信号肽能够使得所述NGF蛋白变体的表达量和/或分泌量达到野生型NGF蛋白的50%以上。
41.根据实施方式39-40中任一项所述的组合物,其中所述异源信号肽源自神经营养因子。
42.根据实施方式39-41中任一项所述的组合物,其中所述异源信号肽源自脑源性神经营养因子(BDNF),神经营养因子-3(NT-3)和/或神经营养因子-4(NT-4)。
43.根据实施方式39-42中任一项所述的组合物,其中所述异源信号肽源自Gp67、Gp64、蜂毒素(HBM)、白蛋白、IL-2、天青素前蛋白、小鼠IgK、免疫球蛋白重链和/或胱抑素-S前体。
44.根据实施方式39-43中任一项所述的组合物,其中所述异源信号肽为IgK信号肽和/或BDNF信号肽。
45.根据实施方式39-44中任一项所述的组合物,其中所述异源信号肽包含SEQ IDNO:30-31中任一项所示的氨基酸序列。
46.根据实施方式35-45中任一项所述的组合物,其中所述mRNA还包括编码前导肽的多核苷酸。
47.根据实施方式46所述的组合物,其中所述前导肽包含SEQ ID NO:34所示的氨基酸序列。
48.根据实施方式46-47中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸和所述编码NGF蛋白或其变体的多核苷酸。
49.根据实施方式46-48中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
50.根据实施方式46-48中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述BDNF信号肽的多核苷酸、所述编码前导肽的多核苷酸和编码所述NGF蛋白变体的多核苷酸。
51.根据实施方式35-50中任一项所述的组合物,其中所述mRNA编码包含如SEQIDNO:14-20中任一项所示的氨基酸序列。
52.根据实施方式35-50中任一项所述的组合物,其中所述mRNA编码包含如SEQIDNO:15和19中任一项所示的氨基酸序列。
53.根据实施方式35-52中任一项所述的组合物,其中所述mRNA还包含编码免疫球蛋白的Fc区的多核苷酸。
54.根据实施方式53所述的组合物,其中所述Fc区源自人免疫球蛋白和/或小鼠免疫球蛋白。
55.根据实施方式53-54中任一项中所述的组合物,其中所述Fc区为人IgG1的Fc区。
56.根据实施方式53-55中任一项所述的组合物,其中所述Fc区为小鼠IgG的Fc区。
57.根据实施方式53-56中任一项所述的组合物,其中所述Fc区包含SEQ ID NO:56-57中任一项所示的氨基酸序列。
58.根据实施方式53-57中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括所述编码异源信号肽的多核苷酸、所述编码前导肽的多核苷酸、所述编码NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
59.根据实施方式53-58中任一项所述的组合物,其中自5’端至3’端,所述mRNA依次包括编码所述IgK信号肽的多核苷酸、所述编码前导肽的多核苷酸、编码所述NGF蛋白变体的多核苷酸和所述编码免疫球蛋白的Fc区的多核苷酸。
60.根据实施方式35-59中任一项所述的组合物,其中所述mRNA编码包含SEQ IDNO:54-55中任一项所示的氨基酸序列。
61.根据实施方式35-60中任一项所述的组合物,其中所述mRNA在选自下组的一个或多个位置处包含修饰:5’帽、5’非翻译区、开放阅读框、3’非翻译区和poly A尾。
62.根据实施方式35-61中任一项所述的组合物,其中所述mRNA包含至少一种经修饰的核苷酸。
63.根据实施方式35-62中任一项所述的组合物,其中所述mRNA包含的经修饰的核苷酸包含一种或多种选自下组的核苷酸:N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP)和5-甲基胞苷三磷酸(5-Methyl-CTP)。
64.根据实施方式35-63中任一项所述的组合物,其中所述mRNA是密码子优化的。
65.根据实施方式35-64中任一项所述的组合物,其中所述mRNA包含如SEQ ID NO:22-28和50-51中任一项所示的核苷酸序列。
66.根据实施方式35-65中任一项所述的组合物,其中所述mRNA包含如SEQ ID NO:23和27中任一项所示的核苷酸序列。
67.根据实施方式35-66中任一项所述的组合物,其中所述递送载体包括脂质体。
68.根据实施方式35-67中任一项所述的组合物,其中所述递送载体包括脂质纳米颗粒(LNP)。
69.根据实施方式35-68中任一项所述的组合物,其中所述递送载体包括阳离子脂质。
70.根据实施方式69所述的组合物,在所述递送载体中,其中所述阳离子脂质的摩尔比为约45%至约55%。
71.根据实施方式69-70中任一项所述的组合物,其中所述阳离子脂质为SM102和DLin-MC3-DMA。
72.根据实施方式35-71中任一项所述的组合物,其中所述递送载体包括非阳离子脂质。
73.根据实施方式72所述的组合物,其中所述非阳离子脂质包括磷脂和/或脂质缀合物。
74.根据实施方式73所述的组合物,在所述递送载体中,其中所述磷脂的摩尔比为约35%至约40%。
75.根据实施方式73-74中任一项所述的组合物,其中所述磷脂包括二硬脂酰基磷脂酰胆碱(DSPC)。
76.根据实施方式73-75中任一项所述的组合物,其中所述脂质缀合物包括聚乙二醇修饰的脂分子。
77.根据实施方式73-76中任一项所述的组合物,在所述递送载体中,其中所述脂质缀合物的摩尔比为约1%至约2%。
78.根据实施方式76-77中任一项所述的组合物,其中所述聚乙二醇修饰的脂分子包括PEG2000-DMG。
79.根据实施方式35-78中任一项所述的组合物,其中所述递送载体包括胆固醇。
80.根据实施方式79所述的组合物,在所述递送载体中,其中所述胆固醇的摩尔比为约8%至约12%。
81.根据实施方式35-80中任一项所述的组合物,其中所述递送载体包含阳离子脂质、胆固醇、磷脂和脂质缀合物,且所述阳离子脂质、胆固醇、磷脂和脂质缀合物的质量比为50:10:38.5:1.5。
82.根据实施方式35-81中任一项所述的组合物,其中所述递送载体包含DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE,且所述DLin-MC3-DMA、胆固醇、DSPC和PEG2000-DMPE的质量比为50:10:38.5:1.5。
83.根据实施方式35-82中任一项所述的组合物,其中所述递送载体的直径为约60nm至约500nm。
84.根据实施方式35-83中任一项所述的组合物,其中所述递送载体的直径为约80nm至约200nm。
85.根据实施方式35-84中任一项所述的组合物,其中所述mRNA包载在所述递送载体中。
86.载体,其包含实施方式24-34中任一项所述的核酸分子。
87.细胞,其包含实施方式24-34中任一项所述的核酸分子,和/或实施方式86所述的载体,或其表达实施方式1-23中任一项所述的重组蛋白。
88.制备实施方式1-23中任一项所述的重组蛋白的方法,所述方法包括在使得实施方式1-23中任一项所述的重组蛋白表达的条件下,培养根据实施方式87所述的细胞。
89.药物组合物,其包含实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体和/或实施方式87所述的细胞,以及任选地药学上可接受的载体。
90.试剂盒或给药装置,其包含实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物。
91.缓解、预防和/或治疗中枢和/或周围神经系统疾病的方法,其包括向有需要的受试者施用实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物。
92.根据实施方式91所述的方法,其中所述中枢和/或周围神经系统疾病包括神经退行性疾病。
93.根据实施方式91所述的方法,其中所述中枢和/或周围神经系统疾病包括周围神经病变。
94.根据实施方式93所述的方法,其中所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
95.根据实施方式91所述的方法,其中所述中枢和/或周围神经系统疾病包括糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症。
96.实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物在制备药物中的用途,所述药物用于缓解、预防和/或治疗中枢和/或周围神经系统疾病。
97.根据实施方式96所述的用途,其中所述中枢和/或周围神经系统疾病包括神经退行性疾病。
98.根据实施方式96所述的用途,其中所述中枢和/或周围神经系统疾病包括周围神经病变。
99.根据实施方式98所述的用途,其中所述周围神经病变包括中毒性周围神经病变、遗传性周围神经病变和/或代谢性周围神经病变。
100.根据实施方式96所述的用途,其中所述中枢和/或周围神经系统疾病包括糖尿病周围神经病变、药物相关性周围神经病变、遗传性运动感觉神经病、周围神经外伤后修复、外伤性视神经炎和/或阿尔茨海默症。
101.促进神经生长因子(NGF)蛋白分泌和/或表达的方法,其包括使用实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物。
102.根据实施方式101所述的方法,其为非治疗目的的方法。
103.根据实施方式101所述的方法,其为体外的和/或离体的方法。
104.促进神经细胞增殖和/或分化的方法,其包括使用实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物。
105.根据实施方式104所述的方法,其为非治疗目的的方法。
106.根据实施方式104所述的方法,其为体外的和/或离体的方法。
107.修复损伤的神经细胞的方法,其包括使用实施方式1-23中任一项所述的重组蛋白、实施方式24-34中任一项所述的核酸分子、实施方式35-85中任一项所述的组合物、实施方式86所述的载体、实施方式87所述的细胞,和/或实施方式89所述的药物组合物。
108.根据实施方式107所述的方法,其为非治疗目的的方法。
109.根据实施方式107所述的方法,其为体外的和/或离体的方法。
不欲被任何理论所限,下文中的实施例仅仅是为了阐释本申请发明的各个技术方案,而不用于限制本申请发明的范围。
实施例
实施例1 NGFR100W mRNA的设计优化及合成
通过将NGF内源信号肽替换位外源信号肽、截短前导肽、增加穿膜锚定区等方式构建包含NGF突变体的重组蛋白,如图1A或图1J所示。其中,NGFwt:全长的野生型NGF蛋白,自N端至C端,依次为NGF信号肽+前导肽+成熟NGF蛋白;NGFmut:全长的NGFR221W突变体蛋白,自N端至C端,依次为NGF信号肽+前导肽+成熟NGFR100W突变体蛋白;IGK19-NGFmut:自N端至C端,依次为IGK信号肽+前导肽+成熟NGFR100W突变体蛋白;IGK122-NGFmut:自N端至C端,依次为IGK信号肽+成熟NGFR100W突变体蛋白;IGK19-NGF-PDGFRmut:自N端至C端,依次为IGK信号肽+前导肽+成熟NGFR100W突变体蛋白+PDGFR穿膜锚定区;IGK122-NGF-PDGFRmut:自N端至C端,依次为IGK信号肽+成熟NGFR100W突变体蛋白+PDGFR穿膜锚定区;BDNF19NGFmut:自N端至C端,依次为BDNF信号肽+前导肽+成熟NGFR100W突变体蛋白;BDNF122-NGFmut:自N端至C端,依次为BDNF信号肽+成熟NGFR100W突变体蛋白;氨基酸序列和核苷酸序列如下表1所示。
表1 NGF或其变体重组蛋白的序列
使用T7聚合酶进行体外转录得到上述编码区的DNA序列,在3’端添加HAtag并克隆到pSG5L载体上T7启动子的下游,利用载体上获取体外转录线性DNA模板的通用引物,PCR获取体外转录的DNA模板。使用T7 RNA聚合酶进行体外转录,使用DNA酶消化模板后,使用大肠杆菌poly(A)聚合酶EPAP(E.coli Poly(A)Polymerase)进行poly(A)加尾,最后纯化回收获取mRNA。
将mRNA在293T工具细胞系中进行表达,使用western blot检测表达量,结果如图1B所示,IGK19-NGFmut和BDNF19-NGFmut均检测到上清中有蛋白表达。且图1F显示,与野生型NGF蛋白(WT)相比,不包含异源信号肽的NGFR100W蛋白(Mut)分泌至上清液的含量较低,大部分以proNGF的形式存在于细胞中。此外,采用其他几种常用的信号肽(图1J),APP(Azurocidin preproprotein)、HC(Immunoglobulin heavy chain)、SP(Signal peptide)、Cystatin(Cystatin-S precursor)HBM、Gp64、Alb(Albumin)等,如图1G至1I,结果显示均能一定程度促进NGFmut的外泌。
实施例2 mRNA修饰后的蛋白表达量检测
本实施例对IGK19-NGFmut mRNA进行修饰,即在转录时分别加入携带不同化学修饰的核苷酸,得到携带化学修饰的mRNA,化学修饰核苷酸的引入均为100%的替换。使用的化学修饰分别为N1-甲基假尿苷三磷酸(N1-Methylpseudo-UTP,即N1-UTP)、假尿苷三磷酸(pseudo-UTP)、5-甲氧基尿苷三磷酸(5-Methoxy-UDP,即5mO-UTP)和5-甲基胞苷三磷酸(5-Methyl-CTP,5mCTP)。结果如图1C所示,包含不同修饰的IGK19-NGFmut mRNA翻译得到的蛋白表达量相当,且包含N1-UTP修饰的蛋白表达量最高。后续的生化及功能研究的mRNA均为N1-UTP修饰。
实施例3 NGFR100W促进神经细胞分化的功能检测
PC12细胞株来源于一种可移植的鼠嗜铬细胞瘤,该细胞对NGF有可逆的神经元显形反应。当PC12细胞暴露在有NGF蛋白的环境中,细胞会在一周之内作出反应,主要是停止细胞分裂并延伸神经突。将PC12细胞培养在含5%胎牛血清和5%马血清的RPMI1640培养基中,当细胞到达对数生长期时,用NGFwt或IGK19-NGFmut mRNA进行转染,24小时后对细胞进行DAPI和HA染色,荧光显微镜和电子显微镜下观察细胞的形态。结果如图1D和1E显示,IGK19NGFmut和NGFwt一样,mRNA能够翻译表达为NGFR100W突变蛋白,并促进PC12细胞的分化。
实施例4使用脂质包裹NGF mRNA获得脂质纳米颗粒
运用NGF mRNA与脂类混合物包裹成脂质纳米颗粒(LNP)体系来递送mRNA,流程如图2所示。使用的脂质分子包括四种:阳离子脂质(DLin-MC3-DMA)、胆固醇、二硬脂酰基磷脂酰胆碱(DSPC)以及聚乙二醇修饰的脂分子(PEG2000-DMG)。四种脂质以50:10:38.5:1.5的摩尔比溶于乙醇,将溶于乙醇的脂质与体外转录的mRNA通过T管快速混匀,自包装得到直径约为100nm的脂质纳米颗粒。将体外转录的NGFwt及IGK19-NGFmut与脂质按照mRNA:阳离子脂质=1:3(摩尔比)的比例混合包装成纳米颗粒LNP,使用Malvern Zetasizer纳米粒径电位分析仪对LNP进行粒径检测,结果显示NGFwt及IGK19-NGFmut大小大约为100nm,如图3A。
取NGF LNP 2ug直接滴加到293T细胞中进行细胞转染,可以在细胞和上清中检测到外泌到上清中的成熟NGF蛋白表达,如图3B。我们利用荧光素酶(luciferase)氧化荧光素(D-luciferin)发出荧光的荧光报告系统,结合生物活体荧光成像技术,确定纳米颗粒在小鼠体内表达的定位及表达动力学。小鼠在给予尾静脉注射包载荧光素酶mRNA的纳米颗粒后,在不同时间点腹腔注射荧光素底物,利用小动物活体成像检测荧光素酶氧化底物产生的生物光的强度和定位。结果显示,通过循环途径给药时,纳米颗粒的表达效率较高,且主要集中在肝脏,如图3C。
实施例5在小鼠中验证IGK19-NGFmut LNP的低致痛效应
8周周龄的C57BL/6雄性小鼠8只,分为两组,每组4只,使用足底注射,每只小鼠分别将2μg IGK19-NGFmut LNP以及2μg NGFwt LNP注射进小鼠后爪足底足垫区。在注射后8h进行小鼠行为学实验,对小鼠足底的热痛痛阈进行检测。在足底注射8小时后将小鼠放置于透明架上,给予两组小鼠相同强度的红外热源刺激,记录小鼠抬爪的潜伏时间。
另将8周周龄的C57BL/6雄性小鼠10只分为两组,每组5只,以同样的方式分别注射2μg IGK19-NGFmut LNP以及2μg NGFwt LNP。在足底注射8小时,将小鼠置于网格架上,使用von frey细丝给予小鼠足底不同大小的机械应力,并记录能使小鼠发生抬爪动作的应力数值。
结果显示注射IGK19-NGFmut LNP的小鼠相较于注射了NGFwt LNP的对照组小鼠对于热痛的感应阈值明显升高,如图4A;同时图4B也显示IGK19-NGFmut mRNA的表达使得小鼠对机械痛觉的响应相比表达NGFwt更不敏感,说明IGK19-NGFmut LNP比NGFwt LNP在小鼠足底的表达,对小鼠有更低的致痛效应。
实施例6在外周神经损伤小鼠中验证IGK19-NGFmut LNP的神经修复作用
8周周龄的C57BL/6雄性小鼠15只,使用腹腔隔天注射paclitaxel的方法对小鼠外周神经损伤进行造模。造模完成的一周后分为三组,其中注射IGK19-NGFmut LNP以及NGFwtLNP的组每组6只,仅造模组3只。使用足底注射,每只小鼠分别将2μg IGK19-NGFmut LNP以及2μg NGFwt LNP注射进小鼠后爪足底足垫区,每隔两天注射一次。在注射5次后,对小鼠足底的热痛痛阈以及机械痛痛阈进行检测。将小鼠置于网格架上,使用von frey细丝给予小鼠足底不同大小的机械应力,并记录能使小鼠发生抬爪动作的应力数值。机械痛阈测试完毕后给予2h缓冲期,随后将两组小鼠放置于55℃的热盘上,记录小鼠抬爪的潜伏时间。实验流程如图5A所示。
图5B中热痛和机械痛的结果显示,12mg/kg的paclitaxel注射剂量所造成的小鼠周围神经损伤均能引起小鼠足底痛阈升高。随着注射次数的增加,注射IGK19-NGFmut LNP的小鼠相较于注射了NGFwt LNP的对照组的小鼠,能够明显增加周围神经的连续性以及密度,如图5C;同时图5D也显示IGK19-NGFmut mRNA的表达使得小鼠对机械痛觉以及热痛的响应相比表达NGFwt更敏感,说明IGK19-NGFmut LNP在小鼠足底的表达能够修复由paclitaxel引起的外周神经损伤。
前述详细说明是以解释和举例的方式提供的,并非要限制所附权利要求的范围。目前本申请所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的,且保留在所附的权利要求和其等同方式的范围内。
序列表
<110> 上海交通大学医学院;上海蓝鹊生物医药有限公司
<120> 神经生长因子突变体重组蛋白及其应用
<130> 0217-PA-009
<150> CN2021109817215
<151> 2021-08-25
<160> 70
<170> PatentIn version 3.5
<210> 1
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt优化后的编码区序列
<400> 1
atgtccatgt tgttctacac tctgatcaca gcttttctga tcggcataca ggcggaacca 60
cactcagaga gcaatgtccc tgcaggacac accatccccc aagcccactg gactaaactt 120
cagcattccc ttgacactgc ccttcgcaga gcccgcagcg ccccggcagc ggcgatagct 180
gcacgcgtgg cggggcagac ccgcaacatt actgtggacc ccaggctgtt taaaaagcgg 240
cgactccgtt caccccgtgt gctgtttagc acccagcctc cccgtgaagc tgcagacact 300
caggatctgg acttcgaggt cggtggtgct gcccccttca acaggactca caggagcaag 360
cggtcatcat cccatcccat cttccacagg ggcgaattct cggtgtgtga cagtgtcagc 420
gtgtgggttg gggataagac caccgccaca gacatcaagg gcaaggaggt gatggtgttg 480
ggagaggtga acattaacaa cagtgtattc aaacagtact tttttgagac caagtgccgg 540
gacccaaatc ccgttgacag cgggtgccgg ggcattgact caaagcactg gaactcatat 600
tgtaccacga ctcacacctt tgtcaaggcg ctgaccatgg atggcaagca ggctgcctgg 660
cggtttatcc ggatagatac ggcctgtgtg tgtgtgctca gcaggaaggc tgtgagaaga 720
gcc 723
<210> 2
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFmut优化后的编码区序列
<400> 2
atgtccatgt tgttctacac actgatcacc gccttcctga tcggcatcca ggccgagcct 60
cacagcgagt ccaatgtgcc cgccggccac accatccccc aggctcattg gaccaagctg 120
cagcactccc tggatacagc cctgagaaga gccagatccg cccctgccgc cgccatcgct 180
gctagagtgg ccggacagac aaggaacatc acagtggacc ctagactgtt taagaagaga 240
agactgagga gccccagagt gctgttctcc acacagcccc ccagagaggc cgccgacaca 300
caggacctgg atttcgaggt gggcggcgcc gcccctttta acagaacaca cagatccaag 360
aggtccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 420
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 480
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 540
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 600
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 660
tggttcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 720
gcc 723
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atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gacgagcctc acagcgagtc caatgtgccc gccggccaca ccatccccca ggctcattgg 120
accaagctgc agcactccct ggatacagcc ctgagaagag ccagatccgc ccctgccgcc 180
gccatcgctg ctagagtggc cggacagaca aggaacatca cagtggaccc tagactgttt 240
aagaagagaa gactgaggag ccccagagtg ctgttctcca cacagccccc cagagaggcc 300
gccgacacac aggacctgga tttcgaggtg ggcggcgccg ccccttttaa cagaacacac 360
agatccaaga ggtccagctc ccaccctatc ttccacagag gcgagttcag cgtgtgcgac 420
tccgtgagcg tgtgggtggg cgacaagacc accgccaccg acatcaaggg caaggaggtc 480
atggtgctgg gcgaggtgaa catcaataac agcgtgttta agcagtactt tttcgagacc 540
aagtgcagag accctaaccc tgtggactcc ggctgtagag gcatcgactc caagcactgg 600
aatagctact gcaccacaac ccacacattc gtgaaggccc tgacaatgga cggcaagcag 660
gccgcctgga gattcatcag aatcgacacc gcctgtgtgt gtgtgctgag cagaaaggcc 720
gtgagaaggg cctacccgta cgacgtgccg gactacgcct ga 762
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atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gactccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 120
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 180
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 240
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 300
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 360
tggttcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 420
gcc 423
<210> 5
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<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGF-PDGFRmut 优化后的编码区序列
<400> 5
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gacgagcctc acagcgagtc caatgtgccc gccggccaca ccatccccca ggctcattgg 120
accaagctgc agcactccct ggatacagcc ctgagaagag ccagatccgc ccctgccgcc 180
gccatcgctg ctagagtggc cggacagaca aggaacatca cagtggaccc tagactgttt 240
aagaagagaa gactgaggag ccccagagtg ctgttctcca cacagccccc cagagaggcc 300
gccgacacac aggacctgga tttcgaggtg ggcggcgccg ccccttttaa cagaacacac 360
agatccaaga ggtccagctc ccaccctatc ttccacagag gcgagttcag cgtgtgcgac 420
tccgtgagcg tgtgggtggg cgacaagacc accgccaccg acatcaaggg caaggaggtc 480
atggtgctgg gcgaggtgaa catcaataac agcgtgttta agcagtactt tttcgagacc 540
aagtgcagag accctaaccc tgtggactcc ggctgtagag gcatcgactc caagcactgg 600
aatagctact gcaccacaac ccacacattc gtgaaggccc tgacaatgga cggcaagcag 660
gccgcctgga gattcatcag aatcgacacc gcctgtgtgt gtgtgctgag cagaaaggcc 720
gtgagaaggg cctacccgta cgacgtgccg gactacgcct gatacccgta cgacgtgccg 780
gactacgcca atgctgtggg ccaggacacg caggaggtca tcgtggtgcc acactccttg 840
ccctttaagg tggtggtgat ctcagccatc ctggccctgg tggtgctcac catcatctcc 900
cttatcatcc tcatcatgct ttggcagaag aagccacgt 939
<210> 6
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<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK122-NGF-PDGFRmut 优化后的编码区序列
<400> 6
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gactccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 120
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 180
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 240
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 300
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 360
tggttcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 420
gcctacccgt acgacgtgcc ggactacgcc aatgctgtgg gccaggacac gcaggaggtc 480
atcgtggtgc cacactcctt gccctttaag gtggtggtga tctcagccat cctggccctg 540
gtggtgctca ccatcatctc ccttatcatc ctcatcatgc tttggcagaa gaagccacgt 600
<210> 7
<211> 723
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF19-NGFmut优化后的编码区序列
<400> 7
atgaccatcc tgttcctgac aatggtcatt agctacttcg gctgcatgaa ggccgagcct 60
cacagcgagt ccaatgtgcc cgccggccac accatccccc aggctcattg gaccaagctg 120
cagcactccc tggatacagc cctgagaaga gccagatccg cccctgccgc cgccatcgct 180
gctagagtgg ccggacagac aaggaacatc acagtggacc ctagactgtt taagaagaga 240
agactgagga gccccagagt gctgttctcc acacagcccc ccagagaggc cgccgacaca 300
caggacctgg atttcgaggt gggcggcgcc gcccctttta acagaacaca cagatccaag 360
aggtccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 420
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 480
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 540
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 600
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 660
tggttcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 720
gcc 723
<210> 8
<211> 744
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF122-NGFmut优化后的编码区序列
<400> 8
atgaccatcc tgttcctgac aatggtcatt agctacttcg gctgcatgaa ggccgccccc 60
atgaaggagg ccaacatcag aggccagggc ggcctggcct accccggagt gagaacacac 120
ggcacactgg agtccgtgaa cggccccaag gccggctcca ggggactgac aagcctggcc 180
gataccttcg agcacgtgat cgaggagctg ctggacgagg accagaaggt gaggcccaat 240
gaggagaata ataaggacgc cgacctgtac acctccaggg tcatgctgag cagccaggtg 300
cccctggagc ccccactgct gttcctgctg gaggagtaca agaattacct ggacgccgcc 360
aatatgtcca tgagagtgag aaggtccagc tcccacccta tcttccacag aggcgagttc 420
agcgtgtgcg actccgtgag cgtgtgggtg ggcgacaaga ccaccgccac cgacatcaag 480
ggcaaggagg tcatggtgct gggcgaggtg aacatcaata acagcgtgtt taagcagtac 540
tttttcgaga ccaagtgcag agaccctaac cctgtggact ccggctgtag aggcatcgac 600
tccaagcact ggaatagcta ctgcaccaca acccacacat tcgtgaaggc cctgacaatg 660
gacggcaagc aggccgcctg gtggttcatc agaatcgaca ccgcctgtgt gtgtgtgctg 720
agcagaaagg ctgtgagaag agcc 744
<210> 9
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt编码区序列
<400> 9
atgtccatgt tgttctacac tctgatcaca gcttttctga tcggcataca ggcggaacca 60
cactcagaga gcaatgtccc tgcaggacac accatccccc aagcccactg gactaaactt 120
cagcattccc ttgacactgc ccttcgcaga gcccgcagcg ccccggcagc ggcgatagct 180
gcacgcgtgg cggggcagac ccgcaacatt actgtggacc ccaggctgtt taaaaagcgg 240
cgactccgtt caccccgtgt gctgtttagc acccagcctc cccgtgaagc tgcagacact 300
caggatctgg acttcgaggt cggtggtgct gcccccttca acaggactca caggagcaag 360
cggtcatcat cccatcccat cttccacagg ggcgaattct cggtgtgtga cagtgtcagc 420
gtgtgggttg gggataagac caccgccaca gacatcaagg gcaaggaggt gatggtgttg 480
ggagaggtga acattaacaa cagtgtattc aaacagtact tttttgagac caagtgccgg 540
gacccaaatc ccgttgacag cgggtgccgg ggcattgact caaagcactg gaactcatat 600
tgtaccacga ctcacacctt tgtcaaggcg ctgaccatgg atggcaagca ggctgcctgg 660
cggtttatcc ggatagatac ggcctgtgtg tgtgtgctca gcaggaaggc tgtgagaaga 720
gcctga 726
<210> 10
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFmut编码区序列
<400> 10
atgtccatgt tgttctacac tctgatcaca gcttttctga tcggcataca ggcggaacca 60
cactcagaga gcaatgtccc tgcaggacac accatccccc aagcccactg gactaaactt 120
cagcattccc ttgacactgc ccttcgcaga gcccgcagcg ccccggcagc ggcgatagct 180
gcacgcgtgg cggggcagac ccgcaacatt actgtggacc ccaggctgtt taaaaagcgg 240
cgactccgtt caccccgtgt gctgtttagc acccagcctc cccgtgaagc tgcagacact 300
caggatctgg acttcgaggt cggtggtgct gcccccttca acaggactca caggagcaag 360
cggtcatcat cccatcccat cttccacagg ggcgaattct cggtgtgtga cagtgtcagc 420
gtgtgggttg gggataagac caccgccaca gacatcaagg gcaaggaggt gatggtgttg 480
ggagaggtga acattaacaa cagtgtattc aaacagtact tttttgagac caagtgccgg 540
gacccaaatc ccgttgacag cgggtgccgg ggcattgact caaagcactg gaactcatat 600
tgtaccacga ctcacacctt tgtcaaggcg ctgaccatgg atggcaagca ggctgcctgg 660
tggtttatcc ggatagatac ggcctgtgtg tgtgtgctca gcaggaaggc tgtgagaaga 720
gcctga 726
<210> 11
<211> 735
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut编码区序列
<400> 11
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccactggt 60
gacgaaccac actcagagag caatgtccct gcaggacaca ccatccccca agcccactgg 120
actaaacttc agcattccct tgacactgcc cttcgcagag cccgcagcgc cccggcagcg 180
gcgatagctg cacgcgtggc ggggcagacc cgcaacatta ctgtggaccc caggctgttt 240
aaaaagcggc gactccgttc accccgtgtg ctgtttagca cccagcctcc ccgtgaagct 300
gcagacactc aggatctgga cttcgaggtc ggtggtgctg cccccttcaa caggactcac 360
aggagcaagc ggtcatcatc ccatcccatc ttccacaggg gcgaattctc ggtgtgtgac 420
agtgtcagcg tgtgggttgg ggataagacc accgccacag acatcaaggg caaggaggtg 480
atggtgttgg gagaggtgaa cattaacaac agtgtattca aacagtactt ttttgagacc 540
aagtgccggg acccaaatcc cgttgacagc gggtgccggg gcattgactc aaagcactgg 600
aactcatatt gtaccacgac tcacaccttt gtcaaggcgc tgaccatgga tggcaagcag 660
gctgcctggt ggtttatccg gatagatacg gcctgtgtgt gtgtgctcag caggaaggct 720
gtgagaagag cctga 735
<210> 12
<211> 726
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF19-NGFmut编码区序列
<400> 12
atgaccatcc ttttccttac tatggttatt tcatactttg gttgcatgaa ggctgaacca 60
cactcagaga gcaatgtccc tgcaggacac accatccccc aagcccactg gactaaactt 120
cagcattccc ttgacactgc ccttcgcaga gcccgcagcg ccccggcagc ggcgatagct 180
gcacgcgtgg cggggcagac ccgcaacatt actgtggacc ccaggctgtt taaaaagcgg 240
cgactccgtt caccccgtgt gctgtttagc acccagcctc cccgtgaagc tgcagacact 300
caggatctgg acttcgaggt cggtggtgct gcccccttca acaggactca caggagcaag 360
cggtcatcat cccatcccat cttccacagg ggcgaattct cggtgtgtga cagtgtcagc 420
gtgtgggttg gggataagac caccgccaca gacatcaagg gcaaggaggt gatggtgttg 480
ggagaggtga acattaacaa cagtgtattc aaacagtact tttttgagac caagtgccgg 540
gacccaaatc ccgttgacag cgggtgccgg ggcattgact caaagcactg gaactcatat 600
tgtaccacga ctcacacctt tgtcaaggcg ctgaccatgg atggcaagca ggctgcctgg 660
tggtttatcc ggatagatac ggcctgtgtg tgtgtgctca gcaggaaggc tgtgagaaga 720
gcctga 726
<210> 13
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt氨基酸序列
<400> 13
Met Ser Met Leu Phe Tyr Thr Leu Ile Thr Ala Phe Leu Ile Gly Ile
1 5 10 15
Gln Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Arg Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala
<210> 14
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFmut氨基酸序列
<400> 14
Met Ser Met Leu Phe Tyr Thr Leu Ile Thr Ala Phe Leu Ile Gly Ile
1 5 10 15
Gln Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala
<210> 15
<211> 253
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut氨基酸序列
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
245 250
<210> 16
<211> 141
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK122-NGFmut氨基酸序列
<400> 16
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ser Ser Ser His Pro Ile Phe His Arg Gly Glu
20 25 30
Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr
35 40 45
Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu Gly Glu Val Asn
50 55 60
Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg
65 70 75 80
Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His
85 90 95
Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr
100 105 110
Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile Arg Ile Asp Thr Ala
115 120 125
Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg Ala
130 135 140
<210> 17
<211> 312
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGF-PDGFRmut氨基酸序列
<400> 17
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr
245 250 255
Asp Val Pro Asp Tyr Ala Asn Ala Val Gly Gln Asp Thr Gln Glu Val
260 265 270
Ile Val Val Pro His Ser Leu Pro Phe Lys Val Val Val Ile Ser Ala
275 280 285
Ile Leu Ala Leu Val Val Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile
290 295 300
Met Leu Trp Gln Lys Lys Pro Arg
305 310
<210> 18
<211> 200
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK122-NGF-PDGFRmut氨基酸序列
<400> 18
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ser Ser Ser His Pro Ile Phe His Arg Gly Glu
20 25 30
Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr
35 40 45
Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu Gly Glu Val Asn
50 55 60
Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg
65 70 75 80
Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His
85 90 95
Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr
100 105 110
Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile Arg Ile Asp Thr Ala
115 120 125
Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg Ala Tyr Pro Tyr
130 135 140
Asp Val Pro Asp Tyr Ala Asn Ala Val Gly Gln Asp Thr Gln Glu Val
145 150 155 160
Ile Val Val Pro His Ser Leu Pro Phe Lys Val Val Val Ile Ser Ala
165 170 175
Ile Leu Ala Leu Val Val Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile
180 185 190
Met Leu Trp Gln Lys Lys Pro Arg
195 200
<210> 19
<211> 241
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF19-NGFmut氨基酸序列
<400> 19
Met Thr Ile Leu Phe Leu Thr Met Val Ile Ser Tyr Phe Gly Cys Met
1 5 10 15
Lys Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala
<210> 20
<211> 248
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF122-NGFmut氨基酸序列
<400> 20
Met Thr Ile Leu Phe Leu Thr Met Val Ile Ser Tyr Phe Gly Cys Met
1 5 10 15
Lys Ala Ala Pro Met Lys Glu Ala Asn Ile Arg Gly Gln Gly Gly Leu
20 25 30
Ala Tyr Pro Gly Val Arg Thr His Gly Thr Leu Glu Ser Val Asn Gly
35 40 45
Pro Lys Ala Gly Ser Arg Gly Leu Thr Ser Leu Ala Asp Thr Phe Glu
50 55 60
His Val Ile Glu Glu Leu Leu Asp Glu Asp Gln Lys Val Arg Pro Asn
65 70 75 80
Glu Glu Asn Asn Lys Asp Ala Asp Leu Tyr Thr Ser Arg Val Met Leu
85 90 95
Ser Ser Gln Val Pro Leu Glu Pro Pro Leu Leu Phe Leu Leu Glu Glu
100 105 110
Tyr Lys Asn Tyr Leu Asp Ala Ala Asn Met Ser Met Arg Val Arg Arg
115 120 125
Ser Ser Ser His Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp
130 135 140
Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys
145 150 155 160
Gly Lys Glu Val Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val
165 170 175
Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val
180 185 190
Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys
195 200 205
Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln
210 215 220
Ala Ala Trp Trp Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu
225 230 235 240
Ser Arg Lys Ala Val Arg Arg Ala
245
<210> 21
<211> 723
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt mRNA序列
<400> 21
auguccaugu uguucuacac ucugaucaca gcuuuucuga ucggcauaca ggcggaacca 60
cacucagaga gcaauguccc ugcaggacac accauccccc aagcccacug gacuaaacuu 120
cagcauuccc uugacacugc ccuucgcaga gcccgcagcg ccccggcagc ggcgauagcu 180
gcacgcgugg cggggcagac ccgcaacauu acuguggacc ccaggcuguu uaaaaagcgg 240
cgacuccguu caccccgugu gcuguuuagc acccagccuc cccgugaagc ugcagacacu 300
caggaucugg acuucgaggu cgguggugcu gcccccuuca acaggacuca caggagcaag 360
cggucaucau cccaucccau cuuccacagg ggcgaauucu cgguguguga cagugucagc 420
guguggguug gggauaagac caccgccaca gacaucaagg gcaaggaggu gaugguguug 480
ggagagguga acauuaacaa caguguauuc aaacaguacu uuuuugagac caagugccgg 540
gacccaaauc ccguugacag cgggugccgg ggcauugacu caaagcacug gaacucauau 600
uguaccacga cucacaccuu ugucaaggcg cugaccaugg auggcaagca ggcugccugg 660
cgguuuaucc ggauagauac ggccugugug ugugugcuca gcaggaaggc ugugagaaga 720
gcc 723
<210> 22
<211> 723
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFmut mRNA序列
<400> 22
auguccaugu uguucuacac acugaucacc gccuuccuga ucggcaucca ggccgagccu 60
cacagcgagu ccaaugugcc cgccggccac accauccccc aggcucauug gaccaagcug 120
cagcacuccc uggauacagc ccugagaaga gccagauccg ccccugccgc cgccaucgcu 180
gcuagagugg ccggacagac aaggaacauc acaguggacc cuagacuguu uaagaagaga 240
agacugagga gccccagagu gcuguucucc acacagcccc ccagagaggc cgccgacaca 300
caggaccugg auuucgaggu gggcggcgcc gccccuuuua acagaacaca cagauccaag 360
agguccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 420
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 480
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 540
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 600
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 660
ugguucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 720
gcc 723
<210> 23
<211> 762
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut mRNA序列
<400> 23
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacgagccuc acagcgaguc caaugugccc gccggccaca ccauccccca ggcucauugg 120
accaagcugc agcacucccu ggauacagcc cugagaagag ccagauccgc cccugccgcc 180
gccaucgcug cuagaguggc cggacagaca aggaacauca caguggaccc uagacuguuu 240
aagaagagaa gacugaggag ccccagagug cuguucucca cacagccccc cagagaggcc 300
gccgacacac aggaccugga uuucgaggug ggcggcgccg ccccuuuuaa cagaacacac 360
agauccaaga gguccagcuc ccacccuauc uuccacagag gcgaguucag cgugugcgac 420
uccgugagcg uguggguggg cgacaagacc accgccaccg acaucaaggg caaggagguc 480
auggugcugg gcgaggugaa caucaauaac agcguguuua agcaguacuu uuucgagacc 540
aagugcagag acccuaaccc uguggacucc ggcuguagag gcaucgacuc caagcacugg 600
aauagcuacu gcaccacaac ccacacauuc gugaaggccc ugacaaugga cggcaagcag 660
gccgccugga gauucaucag aaucgacacc gccugugugu gugugcugag cagaaaggcc 720
gugagaaggg ccuacccgua cgacgugccg gacuacgccu ga 762
<210> 24
<211> 423
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK122-NGFmut mRNA序列
<400> 24
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacuccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 120
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 180
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 240
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 300
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 360
ugguucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 420
gcc 423
<210> 25
<211> 939
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGF-PDGFRmut mRNA序列
<400> 25
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacgagccuc acagcgaguc caaugugccc gccggccaca ccauccccca ggcucauugg 120
accaagcugc agcacucccu ggauacagcc cugagaagag ccagauccgc cccugccgcc 180
gccaucgcug cuagaguggc cggacagaca aggaacauca caguggaccc uagacuguuu 240
aagaagagaa gacugaggag ccccagagug cuguucucca cacagccccc cagagaggcc 300
gccgacacac aggaccugga uuucgaggug ggcggcgccg ccccuuuuaa cagaacacac 360
agauccaaga gguccagcuc ccacccuauc uuccacagag gcgaguucag cgugugcgac 420
uccgugagcg uguggguggg cgacaagacc accgccaccg acaucaaggg caaggagguc 480
auggugcugg gcgaggugaa caucaauaac agcguguuua agcaguacuu uuucgagacc 540
aagugcagag acccuaaccc uguggacucc ggcuguagag gcaucgacuc caagcacugg 600
aauagcuacu gcaccacaac ccacacauuc gugaaggccc ugacaaugga cggcaagcag 660
gccgccugga gauucaucag aaucgacacc gccugugugu gugugcugag cagaaaggcc 720
gugagaaggg ccuacccgua cgacgugccg gacuacgccu gauacccgua cgacgugccg 780
gacuacgcca augcuguggg ccaggacacg caggagguca ucguggugcc acacuccuug 840
cccuuuaagg ugguggugau cucagccauc cuggcccugg uggugcucac caucaucucc 900
cuuaucaucc ucaucaugcu uuggcagaag aagccacgu 939
<210> 26
<211> 600
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK122-NGF-PDGFRmut mRNA序列
<400> 26
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacuccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 120
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 180
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 240
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 300
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 360
ugguucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 420
gccuacccgu acgacgugcc ggacuacgcc aaugcugugg gccaggacac gcaggagguc 480
aucguggugc cacacuccuu gcccuuuaag guggugguga ucucagccau ccuggcccug 540
guggugcuca ccaucaucuc ccuuaucauc cucaucaugc uuuggcagaa gaagccacgu 600
<210> 27
<211> 723
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF19-NGFmut mRNA序列
<400> 27
augaccaucc uguuccugac aauggucauu agcuacuucg gcugcaugaa ggccgagccu 60
cacagcgagu ccaaugugcc cgccggccac accauccccc aggcucauug gaccaagcug 120
cagcacuccc uggauacagc ccugagaaga gccagauccg ccccugccgc cgccaucgcu 180
gcuagagugg ccggacagac aaggaacauc acaguggacc cuagacuguu uaagaagaga 240
agacugagga gccccagagu gcuguucucc acacagcccc ccagagaggc cgccgacaca 300
caggaccugg auuucgaggu gggcggcgcc gccccuuuua acagaacaca cagauccaag 360
agguccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 420
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 480
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 540
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 600
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 660
ugguucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 720
gcc 723
<210> 28
<211> 744
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF122-NGFmut mRNA序列
<400> 28
augaccaucc uguuccugac aauggucauu agcuacuucg gcugcaugaa ggccgccccc 60
augaaggagg ccaacaucag aggccagggc ggccuggccu accccggagu gagaacacac 120
ggcacacugg aguccgugaa cggccccaag gccggcucca ggggacugac aagccuggcc 180
gauaccuucg agcacgugau cgaggagcug cuggacgagg accagaaggu gaggcccaau 240
gaggagaaua auaaggacgc cgaccuguac accuccaggg ucaugcugag cagccaggug 300
ccccuggagc ccccacugcu guuccugcug gaggaguaca agaauuaccu ggacgccgcc 360
aauaugucca ugagagugag aagguccagc ucccacccua ucuuccacag aggcgaguuc 420
agcgugugcg acuccgugag cgugugggug ggcgacaaga ccaccgccac cgacaucaag 480
ggcaaggagg ucauggugcu gggcgaggug aacaucaaua acagcguguu uaagcaguac 540
uuuuucgaga ccaagugcag agacccuaac ccuguggacu ccggcuguag aggcaucgac 600
uccaagcacu ggaauagcua cugcaccaca acccacacau ucgugaaggc ccugacaaug 660
gacggcaagc aggccgccug gugguucauc agaaucgaca ccgccugugu gugugugcug 720
agcagaaagg cugugagaag agcc 744
<210> 29
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NGF信号肽
<400> 29
Met Ser Met Leu Phe Tyr Thr Leu Ile Thr Ala Phe Leu Ile Gly Ile
1 5 10 15
Gln Ala
<210> 30
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK信号肽
<400> 30
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20
<210> 31
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> BDNF信号肽
<400> 31
Met Thr Ile Leu Phe Leu Thr Met Val Ile Ser Tyr Phe Gly Cys Met
1 5 10 15
Lys Ala
<210> 32
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 成熟NGFwt
<400> 32
Ser Ser Ser His Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp
1 5 10 15
Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys
20 25 30
Gly Lys Glu Val Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val
35 40 45
Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val
50 55 60
Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys
65 70 75 80
Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln
85 90 95
Ala Ala Trp Arg Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu
100 105 110
Ser Arg Lys Ala Val Arg Arg Ala
115 120
<210> 33
<211> 120
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 成熟NGFmut
<400> 33
Ser Ser Ser His Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp
1 5 10 15
Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys
20 25 30
Gly Lys Glu Val Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val
35 40 45
Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val
50 55 60
Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys
65 70 75 80
Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln
85 90 95
Ala Ala Trp Trp Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu
100 105 110
Ser Arg Lys Ala Val Arg Arg Ala
115 120
<210> 34
<211> 103
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 前导肽
<400> 34
Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile Pro Gln
1 5 10 15
Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu Arg Arg
20 25 30
Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala Gly Gln
35 40 45
Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg Arg Leu
50 55 60
Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu Ala Ala
65 70 75 80
Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro Phe Asn
85 90 95
Arg Thr His Arg Ser Lys Arg
100
<210> 35
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人IL-2信号肽
<400> 35
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> 36
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 天青素前蛋白信号肽
<400> 36
Met Thr Arg Leu Thr Val Leu Ala Leu Leu Ala Gly Leu Leu Ala Ser
1 5 10 15
Ser Arg Ala
<210> 37
<211> 19
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 免疫球蛋白重链信号肽
<400> 37
Met Asp Trp Thr Trp Arg Val Phe Cys Leu Leu Ala Val Thr Pro Gly
1 5 10 15
Ala His Pro
<210> 38
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 胱抑素-S前体信号肽
<400> 38
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala
20
<210> 39
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Gp67信号肽
<400> 39
Met Leu Leu Val Asn Gln Ser His Gln Gly Phe Asn Lys Glu His Thr
1 5 10 15
Ser Lys Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala
20 25 30
Ala His Ser Ala Phe Ala
35
<210> 40
<211> 21
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> HBM信号肽
<400> 40
Met Lys Phe Leu Val Asn Val Ala Leu Val Phe Met Val Val Tyr Ile
1 5 10 15
Ser Tyr Ile Tyr Ala
20
<210> 41
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> Gp64信号肽
<400> 41
Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala Ala His
1 5 10 15
Ser Ala Phe Ala
20
<210> 42
<211> 18
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 白蛋白信号肽
<400> 42
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser
<210> 43
<211> 26
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> SP信号肽
<400> 43
Met Arg Val Thr Ala Pro Arg Thr Leu Ile Leu Leu Leu Ser Gly Ala
1 5 10 15
Leu Ala Leu Thr Glu Thr Trp Ala Gly Ser
20 25
<210> 44
<211> 1431
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc1优化后的编码区序列
<400> 44
atgtccatgt tgttctacac actgatcacc gccttcctga tcggcatcca ggccgagcct 60
cacagcgagt ccaatgtgcc cgccggccac accatccccc aggctcattg gaccaagctg 120
cagcactccc tggatacagc cctgagaaga gccagatccg cccctgccgc cgccatcgct 180
gctagagtgg ccggacagac aaggaacatc acagtggacc ctagactgtt taagaagaga 240
agactgagga gccccagagt gctgttctcc acacagcccc ccagagaggc cgccgacaca 300
caggacctgg atttcgaggt gggcggcgcc gcccctttta acagaacaca cagatccaag 360
aggtccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 420
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 480
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 540
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 600
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 660
agattcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 720
gccggaagcg gatctgagcc caagagccag gacaagaccc acacctgccc tccctgtcct 780
gcccccgagc tgctgggagg accttccgtg ttcctgttcc cccctaagcc taaggacacc 840
ctgatgatca gcaggacccc tgaggtgacc tgtgtggtgg tggatgtgtc ccacgaggac 900
cctgaggtga agttcaactg gtatgtggac ggcgtggagg tgcacaatgc taagaccaag 960
cccagggaag agcagtacaa cagcacctat agggtggtga gcgtgctgac cgtgctgcac 1020
caggattggc tgaatggcaa ggagtacaag tgtaaggtga gcaacaaggc tctgcccgct 1080
cctatcgaga agaccatctc caaggccaag ggccagccca gggagcctca ggtgtatacc 1140
ctgccccctt ccagggatga gctgaccaag aatcaggtgt ccctgacctg tctggtgaag 1200
ggcttttacc cctccgacat cgctgtggag tgggagagca atggccagcc tgagaacaac 1260
tacaagacca cccctcccgt gctggattcc gacggctcct ttttcctgta tagcaagctg 1320
accgtggaca agtcccggtg gcagcagggc aacgtgtttt cctgtagcgt gatgcacgag 1380
gccctgcaca accactacac ccagaagtcc ctgtccctgt cccctggcaa g 1431
<210> 45
<211> 1428
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc2 优化后的编码区序列
<400> 45
atgtccatgt tgttctacac actgatcacc gccttcctga tcggcatcca ggccgagcct 60
cacagcgagt ccaatgtgcc cgccggccac accatccccc aggctcattg gaccaagctg 120
cagcactccc tggatacagc cctgagaaga gccagatccg cccctgccgc cgccatcgct 180
gctagagtgg ccggacagac aaggaacatc acagtggacc ctagactgtt taagaagaga 240
agactgagga gccccagagt gctgttctcc acacagcccc ccagagaggc cgccgacaca 300
caggacctgg atttcgaggt gggcggcgcc gcccctttta acagaacaca cagatccaag 360
aggtccagct cccaccctat cttccacaga ggcgagttca gcgtgtgcga ctccgtgagc 420
gtgtgggtgg gcgacaagac caccgccacc gacatcaagg gcaaggaggt catggtgctg 480
ggcgaggtga acatcaataa cagcgtgttt aagcagtact ttttcgagac caagtgcaga 540
gaccctaacc ctgtggactc cggctgtaga ggcatcgact ccaagcactg gaatagctac 600
tgcaccacaa cccacacatt cgtgaaggcc ctgacaatgg acggcaagca ggccgcctgg 660
agattcatca gaatcgacac cgcctgtgtg tgtgtgctga gcagaaaggc tgtgagaaga 720
gccggatctg gcagcgataa gaagatcgtg cccagggatt gcggctgcaa gccttgcatc 780
tgcaccgtgc ccgaggtgtc cagcgtgttc atcttccccc ctaagcccaa ggatgtgctg 840
accatcaccc tgacccccaa ggtgacctgt gtggtggtgg ctatcagcaa ggatgacccc 900
gaggtgcagt ttagctggtt tgtggatgat gtggaggtgc acaccgccca gacccagccc 960
agagaggagc agtttaattc cacctttcgg tccgtgtccg agctgcctat catgcaccag 1020
gattggctga acggcaagga gttcaagtgc agggtgaaca gcgctgcttt ccccgccccc 1080
atcgagaaga ccatcagcaa gaccaagggc aggcccaagg cccctcaggt gtacaccatc 1140
ccccccccca aggagcagat ggccaaggat aaggtgagcc tgacctgcat gatcaccgat 1200
ttcttccctg aggatatcac cgtggagtgg cagtggaatg gccagcccgc cgagaattac 1260
aagaataccc agcccatcat ggacaccgac ggcagctatt tcgtgtattc caagctgaat 1320
gtgcagaagt ccaattggga ggccggcaac accttcacct gcagcgtgct gcacgagggc 1380
ctgcacaatc accacaccga gaagagcctg tcccactccc ccggcaag 1428
<210> 46
<211> 1440
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc1优化后的编码区序列
<400> 46
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gacgagcctc acagcgagtc caatgtgccc gccggccaca ccatccccca ggctcattgg 120
accaagctgc agcactccct ggatacagcc ctgagaagag ccagatccgc ccctgccgcc 180
gccatcgctg ctagagtggc cggacagaca aggaacatca cagtggaccc tagactgttt 240
aagaagagaa gactgaggag ccccagagtg ctgttctcca cacagccccc cagagaggcc 300
gccgacacac aggacctgga tttcgaggtg ggcggcgccg ccccttttaa cagaacacac 360
agatccaaga ggtccagctc ccaccctatc ttccacagag gcgagttcag cgtgtgcgac 420
tccgtgagcg tgtgggtggg cgacaagacc accgccaccg acatcaaggg caaggaggtc 480
atggtgctgg gcgaggtgaa catcaataac agcgtgttta agcagtactt tttcgagacc 540
aagtgcagag accctaaccc tgtggactcc ggctgtagag gcatcgactc caagcactgg 600
aatagctact gcaccacaac ccacacattc gtgaaggccc tgacaatgga cggcaagcag 660
gccgcctggt ggttcatcag aatcgacacc gcctgtgtgt gtgtgctgag cagaaaggct 720
gtgagaagag ccggaagcgg atctgagccc aagagccagg acaagaccca cacctgccct 780
ccctgtcctg cccccgagct gctgggagga ccttccgtgt tcctgttccc ccctaagcct 840
aaggacaccc tgatgatcag caggacccct gaggtgacct gtgtggtggt ggatgtgtcc 900
cacgaggacc ctgaggtgaa gttcaactgg tatgtggacg gcgtggaggt gcacaatgct 960
aagaccaagc ccagggaaga gcagtacaac agcacctata gggtggtgag cgtgctgacc 1020
gtgctgcacc aggattggct gaatggcaag gagtacaagt gtaaggtgag caacaaggct 1080
ctgcccgctc ctatcgagaa gaccatctcc aaggccaagg gccagcccag ggagcctcag 1140
gtgtataccc tgcccccttc cagggatgag ctgaccaaga atcaggtgtc cctgacctgt 1200
ctggtgaagg gcttttaccc ctccgacatc gctgtggagt gggagagcaa tggccagcct 1260
gagaacaact acaagaccac ccctcccgtg ctggattccg acggctcctt tttcctgtat 1320
agcaagctga ccgtggacaa gtcccggtgg cagcagggca acgtgttttc ctgtagcgtg 1380
atgcacgagg ccctgcacaa ccactacacc cagaagtccc tgtccctgtc ccctggcaag 1440
<210> 47
<211> 1437
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc2优化后的编码区序列
<400> 47
atggagacag acacactcct gctatgggta ctgctgctct gggttccagg ttccaccgga 60
gacgagcctc acagcgagtc caatgtgccc gccggccaca ccatccccca ggctcattgg 120
accaagctgc agcactccct ggatacagcc ctgagaagag ccagatccgc ccctgccgcc 180
gccatcgctg ctagagtggc cggacagaca aggaacatca cagtggaccc tagactgttt 240
aagaagagaa gactgaggag ccccagagtg ctgttctcca cacagccccc cagagaggcc 300
gccgacacac aggacctgga tttcgaggtg ggcggcgccg ccccttttaa cagaacacac 360
agatccaaga ggtccagctc ccaccctatc ttccacagag gcgagttcag cgtgtgcgac 420
tccgtgagcg tgtgggtggg cgacaagacc accgccaccg acatcaaggg caaggaggtc 480
atggtgctgg gcgaggtgaa catcaataac agcgtgttta agcagtactt tttcgagacc 540
aagtgcagag accctaaccc tgtggactcc ggctgtagag gcatcgactc caagcactgg 600
aatagctact gcaccacaac ccacacattc gtgaaggccc tgacaatgga cggcaagcag 660
gccgcctggt ggttcatcag aatcgacacc gcctgtgtgt gtgtgctgag cagaaaggct 720
gtgagaagag ccggatctgg cagcgataag aagatcgtgc ccagggattg cggctgcaag 780
ccttgcatct gcaccgtgcc cgaggtgtcc agcgtgttca tcttcccccc taagcccaag 840
gatgtgctga ccatcaccct gacccccaag gtgacctgtg tggtggtggc tatcagcaag 900
gatgaccccg aggtgcagtt tagctggttt gtggatgatg tggaggtgca caccgcccag 960
acccagccca gagaggagca gtttaattcc acctttcggt ccgtgtccga gctgcctatc 1020
atgcaccagg attggctgaa cggcaaggag ttcaagtgca gggtgaacag cgctgctttc 1080
cccgccccca tcgagaagac catcagcaag accaagggca ggcccaaggc ccctcaggtg 1140
tacaccatcc ccccccccaa ggagcagatg gccaaggata aggtgagcct gacctgcatg 1200
atcaccgatt tcttccctga ggatatcacc gtggagtggc agtggaatgg ccagcccgcc 1260
gagaattaca agaataccca gcccatcatg gacaccgacg gcagctattt cgtgtattcc 1320
aagctgaatg tgcagaagtc caattgggag gccggcaaca ccttcacctg cagcgtgctg 1380
cacgagggcc tgcacaatca ccacaccgag aagagcctgt cccactcccc cggcaag 1437
<210> 48
<211> 1431
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc1 mRNA 序列
<400> 48
auguccaugu uguucuacac acugaucacc gccuuccuga ucggcaucca ggccgagccu 60
cacagcgagu ccaaugugcc cgccggccac accauccccc aggcucauug gaccaagcug 120
cagcacuccc uggauacagc ccugagaaga gccagauccg ccccugccgc cgccaucgcu 180
gcuagagugg ccggacagac aaggaacauc acaguggacc cuagacuguu uaagaagaga 240
agacugagga gccccagagu gcuguucucc acacagcccc ccagagaggc cgccgacaca 300
caggaccugg auuucgaggu gggcggcgcc gccccuuuua acagaacaca cagauccaag 360
agguccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 420
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 480
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 540
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 600
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 660
agauucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 720
gccggaagcg gaucugagcc caagagccag gacaagaccc acaccugccc ucccuguccu 780
gcccccgagc ugcugggagg accuuccgug uuccuguucc ccccuaagcc uaaggacacc 840
cugaugauca gcaggacccc ugaggugacc uguguggugg uggauguguc ccacgaggac 900
ccugagguga aguucaacug guauguggac ggcguggagg ugcacaaugc uaagaccaag 960
cccagggaag agcaguacaa cagcaccuau agggugguga gcgugcugac cgugcugcac 1020
caggauuggc ugaauggcaa ggaguacaag uguaagguga gcaacaaggc ucugcccgcu 1080
ccuaucgaga agaccaucuc caaggccaag ggccagccca gggagccuca gguguauacc 1140
cugcccccuu ccagggauga gcugaccaag aaucaggugu cccugaccug ucuggugaag 1200
ggcuuuuacc ccuccgacau cgcuguggag ugggagagca auggccagcc ugagaacaac 1260
uacaagacca ccccucccgu gcuggauucc gacggcuccu uuuuccugua uagcaagcug 1320
accguggaca agucccggug gcagcagggc aacguguuuu ccuguagcgu gaugcacgag 1380
gcccugcaca accacuacac ccagaagucc cugucccugu ccccuggcaa g 1431
<210> 49
<211> 1428
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc2 mRNA 序列
<400> 49
auguccaugu uguucuacac acugaucacc gccuuccuga ucggcaucca ggccgagccu 60
cacagcgagu ccaaugugcc cgccggccac accauccccc aggcucauug gaccaagcug 120
cagcacuccc uggauacagc ccugagaaga gccagauccg ccccugccgc cgccaucgcu 180
gcuagagugg ccggacagac aaggaacauc acaguggacc cuagacuguu uaagaagaga 240
agacugagga gccccagagu gcuguucucc acacagcccc ccagagaggc cgccgacaca 300
caggaccugg auuucgaggu gggcggcgcc gccccuuuua acagaacaca cagauccaag 360
agguccagcu cccacccuau cuuccacaga ggcgaguuca gcgugugcga cuccgugagc 420
gugugggugg gcgacaagac caccgccacc gacaucaagg gcaaggaggu cauggugcug 480
ggcgagguga acaucaauaa cagcguguuu aagcaguacu uuuucgagac caagugcaga 540
gacccuaacc cuguggacuc cggcuguaga ggcaucgacu ccaagcacug gaauagcuac 600
ugcaccacaa cccacacauu cgugaaggcc cugacaaugg acggcaagca ggccgccugg 660
agauucauca gaaucgacac cgccugugug ugugugcuga gcagaaaggc ugugagaaga 720
gccggaucug gcagcgauaa gaagaucgug cccagggauu gcggcugcaa gccuugcauc 780
ugcaccgugc ccgagguguc cagcguguuc aucuuccccc cuaagcccaa ggaugugcug 840
accaucaccc ugacccccaa ggugaccugu gugguggugg cuaucagcaa ggaugacccc 900
gaggugcagu uuagcugguu uguggaugau guggaggugc acaccgccca gacccagccc 960
agagaggagc aguuuaauuc caccuuucgg uccguguccg agcugccuau caugcaccag 1020
gauuggcuga acggcaagga guucaagugc agggugaaca gcgcugcuuu ccccgccccc 1080
aucgagaaga ccaucagcaa gaccaagggc aggcccaagg ccccucaggu guacaccauc 1140
ccccccccca aggagcagau ggccaaggau aaggugagcc ugaccugcau gaucaccgau 1200
uucuucccug aggauaucac cguggagugg caguggaaug gccagcccgc cgagaauuac 1260
aagaauaccc agcccaucau ggacaccgac ggcagcuauu ucguguauuc caagcugaau 1320
gugcagaagu ccaauuggga ggccggcaac accuucaccu gcagcgugcu gcacgagggc 1380
cugcacaauc accacaccga gaagagccug ucccacuccc ccggcaag 1428
<210> 50
<211> 1440
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc1 mRNA 序列
<400> 50
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacgagccuc acagcgaguc caaugugccc gccggccaca ccauccccca ggcucauugg 120
accaagcugc agcacucccu ggauacagcc cugagaagag ccagauccgc cccugccgcc 180
gccaucgcug cuagaguggc cggacagaca aggaacauca caguggaccc uagacuguuu 240
aagaagagaa gacugaggag ccccagagug cuguucucca cacagccccc cagagaggcc 300
gccgacacac aggaccugga uuucgaggug ggcggcgccg ccccuuuuaa cagaacacac 360
agauccaaga gguccagcuc ccacccuauc uuccacagag gcgaguucag cgugugcgac 420
uccgugagcg uguggguggg cgacaagacc accgccaccg acaucaaggg caaggagguc 480
auggugcugg gcgaggugaa caucaauaac agcguguuua agcaguacuu uuucgagacc 540
aagugcagag acccuaaccc uguggacucc ggcuguagag gcaucgacuc caagcacugg 600
aauagcuacu gcaccacaac ccacacauuc gugaaggccc ugacaaugga cggcaagcag 660
gccgccuggu gguucaucag aaucgacacc gccugugugu gugugcugag cagaaaggcu 720
gugagaagag ccggaagcgg aucugagccc aagagccagg acaagaccca caccugcccu 780
cccuguccug cccccgagcu gcugggagga ccuuccgugu uccuguuccc cccuaagccu 840
aaggacaccc ugaugaucag caggaccccu gaggugaccu gugugguggu ggaugugucc 900
cacgaggacc cugaggugaa guucaacugg uauguggacg gcguggaggu gcacaaugcu 960
aagaccaagc ccagggaaga gcaguacaac agcaccuaua ggguggugag cgugcugacc 1020
gugcugcacc aggauuggcu gaauggcaag gaguacaagu guaaggugag caacaaggcu 1080
cugcccgcuc cuaucgagaa gaccaucucc aaggccaagg gccagcccag ggagccucag 1140
guguauaccc ugcccccuuc cagggaugag cugaccaaga aucagguguc ccugaccugu 1200
cuggugaagg gcuuuuaccc cuccgacauc gcuguggagu gggagagcaa uggccagccu 1260
gagaacaacu acaagaccac cccucccgug cuggauuccg acggcuccuu uuuccuguau 1320
agcaagcuga ccguggacaa gucccggugg cagcagggca acguguuuuc cuguagcgug 1380
augcacgagg cccugcacaa ccacuacacc cagaaguccc ugucccuguc cccuggcaag 1440
<210> 51
<211> 1437
<212> RNA
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc2 mRNA 序列
<400> 51
auggagacag acacacuccu gcuaugggua cugcugcucu ggguuccagg uuccaccgga 60
gacgagccuc acagcgaguc caaugugccc gccggccaca ccauccccca ggcucauugg 120
accaagcugc agcacucccu ggauacagcc cugagaagag ccagauccgc cccugccgcc 180
gccaucgcug cuagaguggc cggacagaca aggaacauca caguggaccc uagacuguuu 240
aagaagagaa gacugaggag ccccagagug cuguucucca cacagccccc cagagaggcc 300
gccgacacac aggaccugga uuucgaggug ggcggcgccg ccccuuuuaa cagaacacac 360
agauccaaga gguccagcuc ccacccuauc uuccacagag gcgaguucag cgugugcgac 420
uccgugagcg uguggguggg cgacaagacc accgccaccg acaucaaggg caaggagguc 480
auggugcugg gcgaggugaa caucaauaac agcguguuua agcaguacuu uuucgagacc 540
aagugcagag acccuaaccc uguggacucc ggcuguagag gcaucgacuc caagcacugg 600
aauagcuacu gcaccacaac ccacacauuc gugaaggccc ugacaaugga cggcaagcag 660
gccgccuggu gguucaucag aaucgacacc gccugugugu gugugcugag cagaaaggcu 720
gugagaagag ccggaucugg cagcgauaag aagaucgugc ccagggauug cggcugcaag 780
ccuugcaucu gcaccgugcc cgaggugucc agcguguuca ucuucccccc uaagcccaag 840
gaugugcuga ccaucacccu gacccccaag gugaccugug uggugguggc uaucagcaag 900
gaugaccccg aggugcaguu uagcugguuu guggaugaug uggaggugca caccgcccag 960
acccagccca gagaggagca guuuaauucc accuuucggu ccguguccga gcugccuauc 1020
augcaccagg auuggcugaa cggcaaggag uucaagugca gggugaacag cgcugcuuuc 1080
cccgccccca ucgagaagac caucagcaag accaagggca ggcccaaggc cccucaggug 1140
uacaccaucc ccccccccaa ggagcagaug gccaaggaua aggugagccu gaccugcaug 1200
aucaccgauu ucuucccuga ggauaucacc guggaguggc aguggaaugg ccagcccgcc 1260
gagaauuaca agaauaccca gcccaucaug gacaccgacg gcagcuauuu cguguauucc 1320
aagcugaaug ugcagaaguc caauugggag gccggcaaca ccuucaccug cagcgugcug 1380
cacgagggcc ugcacaauca ccacaccgag aagagccugu cccacucccc cggcaag 1437
<210> 52
<211> 477
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc1氨基酸序列
<400> 52
Met Ser Met Leu Phe Tyr Thr Leu Ile Thr Ala Phe Leu Ile Gly Ile
1 5 10 15
Gln Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Arg Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala Gly Ser Gly Ser Glu Pro Lys Ser Gln Asp Lys Thr His Thr Cys
245 250 255
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
260 265 270
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
275 280 285
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
290 295 300
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
305 310 315 320
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
325 330 335
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
340 345 350
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
355 360 365
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
370 375 380
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
385 390 395 400
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
405 410 415
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
420 425 430
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
435 440 445
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
450 455 460
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475
<210> 53
<211> 476
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> NGFwt-Fc2 氨基酸序列
<400> 53
Met Ser Met Leu Phe Tyr Thr Leu Ile Thr Ala Phe Leu Ile Gly Ile
1 5 10 15
Gln Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Arg Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala Gly Ser Gly Ser Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
245 250 255
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
260 265 270
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
275 280 285
Thr Cys Val Val Val Ala Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
290 295 300
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
305 310 315 320
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
325 330 335
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
340 345 350
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
355 360 365
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
370 375 380
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
385 390 395 400
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
405 410 415
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
420 425 430
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
435 440 445
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
450 455 460
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
465 470 475
<210> 54
<211> 480
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc1 氨基酸序列
<400> 54
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala Gly Ser Gly Ser Glu Pro Lys Ser Gln Asp Lys Thr
245 250 255
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
260 265 270
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
275 280 285
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
290 295 300
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
305 310 315 320
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
325 330 335
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
340 345 350
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
355 360 365
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
370 375 380
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
385 390 395 400
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
405 410 415
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
420 425 430
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
435 440 445
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
450 455 460
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470 475 480
<210> 55
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> IGK19-NGFmut-Fc2氨基酸序列
<400> 55
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala Gly Ser Gly Ser Asp Lys Lys Ile Val Pro Arg Asp
245 250 255
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
260 265 270
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
275 280 285
Pro Lys Val Thr Cys Val Val Val Ala Ile Ser Lys Asp Asp Pro Glu
290 295 300
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
305 310 315 320
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
325 330 335
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
340 345 350
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
355 360 365
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
370 375 380
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
385 390 395 400
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
405 410 415
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
420 425 430
Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
435 440 445
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
450 455 460
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
465 470 475
<210> 56
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人Fc-1氨基酸序列
<400> 56
Glu Pro Lys Ser Gln Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 57
<211> 231
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 小鼠Fc-2氨基酸序列
<400> 57
Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys
1 5 10 15
Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys
20 25 30
Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val
35 40 45
Ala Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp
50 55 60
Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe
65 70 75 80
Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp
85 90 95
Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe
100 105 110
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys
115 120 125
Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys
130 135 140
Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp
145 150 155 160
Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys
165 170 175
Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser
180 185 190
Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr
195 200 205
Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser
210 215 220
Leu Ser His Ser Pro Gly Lys
225 230
<210> 58
<211> 249
<212> PRT
<213> Artificial Sequence
<220>
<223> SP-19-NGFmut氨基酸序列
<400> 58
Met Arg Val Thr Ala Pro Arg Thr Leu Ile Leu Leu Leu Ser Gly Ala
1 5 10 15
Leu Ala Leu Thr Glu Thr Trp Ala Gly Ser Glu Pro His Ser Glu Ser
20 25 30
Asn Val Pro Ala Gly His Thr Ile Pro Gln Ala His Trp Thr Lys Leu
35 40 45
Gln His Ser Leu Asp Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala
50 55 60
Ala Ala Ile Ala Ala Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val
65 70 75 80
Asp Pro Arg Leu Phe Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu
85 90 95
Phe Ser Thr Gln Pro Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp
100 105 110
Phe Glu Val Gly Gly Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys
115 120 125
Arg Ser Ser Ser His Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys
130 135 140
Asp Ser Val Ser Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile
145 150 155 160
Lys Gly Lys Glu Val Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser
165 170 175
Val Phe Lys Gln Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro
180 185 190
Val Asp Ser Gly Cys Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr
195 200 205
Cys Thr Thr Thr His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys
210 215 220
Gln Ala Ala Trp Trp Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val
225 230 235 240
Leu Ser Arg Lys Ala Val Arg Arg Ala
245
<210> 59
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> hIL12-19-NGFmut氨基酸序列
<400> 59
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His
20 25 30
Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr
35 40 45
Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg
50 55 60
Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys
65 70 75 80
Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro
85 90 95
Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala
100 105 110
Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro
115 120 125
Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp
130 135 140
Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met
145 150 155 160
Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe
165 170 175
Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg
180 185 190
Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr
195 200 205
Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe
210 215 220
Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val
225 230 235 240
Arg Arg Ala
<210> 60
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Cystatin 19-NGFmut氨基酸序列
<400> 60
Met Ala Arg Pro Leu Cys Thr Leu Leu Leu Leu Met Ala Thr Leu Ala
1 5 10 15
Gly Ala Leu Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His
20 25 30
Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr
35 40 45
Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg
50 55 60
Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys
65 70 75 80
Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro
85 90 95
Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala
100 105 110
Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro
115 120 125
Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp
130 135 140
Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met
145 150 155 160
Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe
165 170 175
Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg
180 185 190
Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr
195 200 205
Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe
210 215 220
Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val
225 230 235 240
Arg Arg Ala
<210> 61
<211> 242
<212> PRT
<213> Artificial Sequence
<220>
<223> APP-19-NGFmut氨基酸序列
<400> 61
Met Thr Arg Leu Thr Val Leu Ala Leu Leu Ala Gly Leu Leu Ala Ser
1 5 10 15
Ser Arg Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr
20 25 30
Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala
35 40 45
Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val
50 55 60
Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys
65 70 75 80
Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg
85 90 95
Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala
100 105 110
Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile
115 120 125
Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val
130 135 140
Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val
145 150 155 160
Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe
165 170 175
Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly
180 185 190
Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe
195 200 205
Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile
210 215 220
Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg
225 230 235 240
Arg Ala
<210> 62
<211> 242
<212> PRT
<213> Artificial Sequence
<220>
<223> HC-19-NGFmut氨基酸序列
<400> 62
Met Asp Trp Thr Trp Arg Val Phe Cys Leu Leu Ala Val Thr Pro Gly
1 5 10 15
Ala His Pro Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr
20 25 30
Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala
35 40 45
Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val
50 55 60
Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys
65 70 75 80
Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg
85 90 95
Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala
100 105 110
Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile
115 120 125
Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val
130 135 140
Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val
145 150 155 160
Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe
165 170 175
Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly
180 185 190
Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe
195 200 205
Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile
210 215 220
Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg
225 230 235 240
Arg Ala
<210> 63
<211> 261
<212> PRT
<213> Artificial Sequence
<220>
<223> Gp67-19-NGFmut氨基酸序列
<400> 63
Met Leu Leu Val Asn Gln Ser His Gln Gly Phe Asn Lys Glu His Thr
1 5 10 15
Ser Lys Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala
20 25 30
Ala His Ser Ala Phe Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala
35 40 45
Gly His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu
50 55 60
Asp Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala
65 70 75 80
Ala Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu
85 90 95
Phe Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln
100 105 110
Pro Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly
115 120 125
Gly Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser
130 135 140
His Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser
145 150 155 160
Val Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu
165 170 175
Val Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln
180 185 190
Tyr Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly
195 200 205
Cys Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr
210 215 220
His Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp
225 230 235 240
Trp Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys
245 250 255
Ala Val Arg Arg Ala
260
<210> 64
<211> 244
<212> PRT
<213> Artificial Sequence
<220>
<223> HBM-19-NGFmut氨基酸序列
<400> 64
Met Lys Phe Leu Val Asn Val Ala Leu Val Phe Met Val Val Tyr Ile
1 5 10 15
Ser Tyr Ile Tyr Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala
<210> 65
<211> 243
<212> PRT
<213> Artificial Sequence
<220>
<223> Gp64-19-NGFmut氨基酸序列
<400> 65
Met Val Ser Ala Ile Val Leu Tyr Val Leu Leu Ala Ala Ala Ala His
1 5 10 15
Ser Ala Phe Ala Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His
20 25 30
Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr
35 40 45
Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg
50 55 60
Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys
65 70 75 80
Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro
85 90 95
Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala
100 105 110
Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro
115 120 125
Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp
130 135 140
Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met
145 150 155 160
Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe
165 170 175
Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg
180 185 190
Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr
195 200 205
Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe
210 215 220
Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val
225 230 235 240
Arg Arg Ala
<210> 66
<211> 241
<212> PRT
<213> Artificial Sequence
<220>
<223> Alb-19-NGFmut氨基酸序列
<400> 66
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly His Thr Ile
20 25 30
Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp Thr Ala Leu
35 40 45
Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala Arg Val Ala
50 55 60
Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe Lys Lys Arg
65 70 75 80
Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro Pro Arg Glu
85 90 95
Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly Ala Ala Pro
100 105 110
Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His Pro Ile Phe
115 120 125
His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val Trp Val Gly
130 135 140
Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val Met Val Leu
145 150 155 160
Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr Phe Phe Glu
165 170 175
Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys Arg Gly Ile
180 185 190
Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His Thr Phe Val
195 200 205
Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp Phe Ile Arg
210 215 220
Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala Val Arg Arg
225 230 235 240
Ala
<210> 67
<211> 50
<212> PRT
<213> Artificial Sequence
<220>
<223> PDGFR
<400> 67
Asn Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro His Ser
1 5 10 15
Leu Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu Ala Leu Val Val
20 25 30
Leu Thr Ile Ile Ser Leu Ile Ile Leu Ile Met Leu Trp Gln Lys Lys
35 40 45
Pro Arg
50
<210> 68
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> 标签肽1
<400> 68
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
1 5
<210> 69
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> 标签肽2
<400> 69
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Tyr Pro Tyr Asp Val Pro Asp
1 5 10 15
Tyr Ala
<210> 70
<211> 253
<212> PRT
<213> Artificial Sequence
<220>
<223> IGK19-NGFmut氨基酸序列(含标签)
<400> 70
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Glu Pro His Ser Glu Ser Asn Val Pro Ala Gly
20 25 30
His Thr Ile Pro Gln Ala His Trp Thr Lys Leu Gln His Ser Leu Asp
35 40 45
Thr Ala Leu Arg Arg Ala Arg Ser Ala Pro Ala Ala Ala Ile Ala Ala
50 55 60
Arg Val Ala Gly Gln Thr Arg Asn Ile Thr Val Asp Pro Arg Leu Phe
65 70 75 80
Lys Lys Arg Arg Leu Arg Ser Pro Arg Val Leu Phe Ser Thr Gln Pro
85 90 95
Pro Arg Glu Ala Ala Asp Thr Gln Asp Leu Asp Phe Glu Val Gly Gly
100 105 110
Ala Ala Pro Phe Asn Arg Thr His Arg Ser Lys Arg Ser Ser Ser His
115 120 125
Pro Ile Phe His Arg Gly Glu Phe Ser Val Cys Asp Ser Val Ser Val
130 135 140
Trp Val Gly Asp Lys Thr Thr Ala Thr Asp Ile Lys Gly Lys Glu Val
145 150 155 160
Met Val Leu Gly Glu Val Asn Ile Asn Asn Ser Val Phe Lys Gln Tyr
165 170 175
Phe Phe Glu Thr Lys Cys Arg Asp Pro Asn Pro Val Asp Ser Gly Cys
180 185 190
Arg Gly Ile Asp Ser Lys His Trp Asn Ser Tyr Cys Thr Thr Thr His
195 200 205
Thr Phe Val Lys Ala Leu Thr Met Asp Gly Lys Gln Ala Ala Trp Trp
210 215 220
Phe Ile Arg Ile Asp Thr Ala Cys Val Cys Val Leu Ser Arg Lys Ala
225 230 235 240
Val Arg Arg Ala Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
245 250
Claims (10)
1.重组蛋白,其包含神经生长因子(NGF)蛋白变体以及与所述NGF蛋白变体连接的异源信号肽,其中,
与野生型NGF蛋白相比,所述NGF蛋白变体与神经营养因子受体p75(p75NTR)的结合减少至少50%,
与SEQ ID NO:29所示的信号肽相比,所述异源信号肽使得所述NGF蛋白变体的表达量和/或分泌量增加至少50%。
2.根据权利要求1所述的重组蛋白,其中所述NGF蛋白变体包含SEQ ID NO:33所示的氨基酸序列。
3.根据权利要求1-2中任一项所述的重组蛋白,其中所述异源信号肽包含SEQ ID NO:30-31中任一项所示的氨基酸序列。
4.根据权利要求1-3中任一项所述的重组蛋白,其还包括前导肽。
5.根据权利要求4所述的重组蛋白,其中自N端至C端,所述重组蛋白依次包括所述异源信号肽、所述前导肽和所述NGF蛋白变体。
6.根据权利要求1-5中任一项所述的重组蛋白,其还包括免疫球蛋白的Fc区。
7.分离的核酸分子,其编码权利要求1-6中任一项所述的重组蛋白。
8.根据权利要求7所述的核酸分子,其包含至少一种经修饰的核苷酸。
9.根据权利要求7-8中任一项所述的核酸分子,其是密码子优化的。
10.组合物,其包含(a)mRNA,所述mRNA包含编码神经生长因子(NGF)蛋白或其变体的多核苷酸,和(b)递送载体。
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US20180236031A1 (en) * | 2017-02-10 | 2018-08-23 | Vivibaba, Inc | Compositions and methods for recombinant nerve growth factor |
GB201705484D0 (en) * | 2017-04-05 | 2017-05-17 | Quethera Ltd | Genetic construct |
CN114933657B (zh) * | 2021-08-25 | 2024-02-02 | 上海交通大学医学院 | 神经生长因子突变体重组蛋白及其应用 |
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