CN109415739A - 腺病毒外壳蛋白衍生递送载体 - Google Patents
腺病毒外壳蛋白衍生递送载体 Download PDFInfo
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Abstract
本发明涉及新的基于腺病毒外壳蛋白的递送载体。它们基于修饰的五邻体基原体,其组装成VLP。可以修饰五邻体基蛋白的暴露区域以允许VLP特异性结合任何靶标和/或包含任何所需的肽表位。额外的承载物,例如药物、蛋白、或者核酸,可通过工程化纤维蛋白片段可逆地或不可逆地连接到VLP上。本发明涉及这样的工程化五邻体基原体;包含特异性结合五邻体基原体的腺病毒纤维蛋白结合缝的腺病毒纤维蛋白N端片段的工程化蛋白;包含工程化五邻体基原体和任选包含特异性结合五邻体基原体的腺病毒纤维蛋白结合缝的腺病毒纤维蛋白N端片段的工程化蛋白的VLP;编码工程化蛋白的核酸;VLP以及生产蛋白和VLP的方法。
Description
技术领域
本发明涉及一种新的基于腺病毒外壳蛋白的递送载体。它们基于修饰的五邻体基原体(penton base protomer),其组装成VLP。可以修饰五邻体基蛋白的暴露区域以允许VLP特异性结合任何靶标和/或包含任何所需的肽表位。额外的承载物,例如药物、多肽、蛋白或核酸,可以通过工程化纤维蛋白片段可逆地或不可逆地连接到VLP上。本发明涉及这样的工程化五邻体基原体、包含能够结合五邻体基原体的纤维蛋白片段的工程化蛋白、包含工程化五邻体基原体和任选包含纤维蛋白片段的工程化蛋白的VLP、编码工程化蛋白的核酸、VLP以及生产蛋白和VLP的方法。
背景技术
感染性疾病继续困扰和摧毁世界范围内的人群。在我们应对这种威胁的手段中,疫苗接种已被证明是非常有用的。通过疫苗接种,天花已被根除,麻疹、脊髓灰质炎和破伤风在世界上受到限制。尽管如此,严重的威胁仍在继续挑战人类健康,特别是来自新兴病毒,其已经适应并出现为促进致病性的新疾病或致病株。
最近这样的例子是基孔肯雅病毒和兹卡病毒构成的严重威胁,其是昆虫传播的病毒通过蚊子叮咬传染给人。这两种病毒都通过它的蚊子宿主迅速传播到亚洲和欧洲,引起了相当大的惊恐。基孔肯雅和兹卡病可能会给受影响的社区和经济带来严重的成本,并且非常需要有效的疫苗接种策略来对抗这种新出现的威胁。然而,迄今为止完全缺乏强大的疫苗。
理想情况下,疫苗将是安全的、非复制性的、高效和可调节的。而且,它将容易在工业规模上生产。重组病毒样颗粒(VLP)可以是理想的疫苗,因此具有很大的前景。在这个提案中,我们将创建这样的VLP疫苗。我们将利用称为ADDomer(腺病毒十二面体衍生多聚体)的令人吃惊的多功能生物相似多蛋白平台。ADDomer将用于产生疫苗候选物以对抗由病毒引起的感染性疾病(包括但不限于基孔肯雅病毒、兹卡病毒等)。
ADDomer是衍生自病毒样颗粒(VLP)的合成支架,其在自然界中发生于人类腺病毒血清型3(HAd3)复制循环催化内化中(Fender,P等人(2012)J Virol86,5380-5385)。ADDomer被设计为衍生自这种天然VLP的生物相似物,保留了自发自组装成十二面体的能力。ADDomer通过完全柔性的溶剂暴露环,独特地适合展示多个肽和蛋白表位。这些环的工程化不会破坏ADDomer颗粒的全局架构。通过使用来自合成生物学的方法,这些环为插入多拷贝的高免疫原性肽表位(例如来自病毒病原体)提供了方便的选择。ADDomer不限于针对感染性疾病的疫苗开发。广泛的应用可能会受益于ADDomer技术,包括癌症治疗。此外,ADDomer不仅仅展示肽表位。ADDomer同样可以暴露蛋白或者蛋白结构域,显著扩大了其应用范围。
发明内容
本发明人已经确定五邻体基原体中的某些区域适合于引入异源肽序列,而不破坏五邻体基原体组装成五邻体亚基,亚基又能自组装成五邻体十二聚体,形成病毒样颗粒(VLP),也被称为ADDomer。设计是高度模块化的,可实现延伸环用于多肽展示的快速和灵活功能化。通过使用特异性结合五邻体基原体的腺病毒纤维蛋白片段,甚至进一步增强了模块化。本发明的VLP是安全的,因为它们不包含遗传物质。五邻体基原体可以接收和展示多达180个外源多肽基序,包括抗原、中和多肽、肿瘤表位(oncoepitope)多肽、单链抗体和纳米抗体。
因此,在第一方面,本发明涉及包含腺病毒五邻体基原体的工程化多肽,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环(V环)、腺病毒纤维蛋白结合缝和/或N端结构域,并包含以下一个或更多个:
(i)在所述第一、第二、或者第一和第二RGD环和/或所述V环中至少一个靶标特异性结合结构域;和/或
(ii)在所述第一、第二、或者第一和第二RGD环和/或所述V环中一个或更多个非腺病毒多肽;和/或
(iii)所述五邻体基原体的N和/或C端的非腺病毒多肽;和/或
(iv)在所述第一、第二、或者第一和第二RGD环、V环中和/或在所述五邻体基原体N端结构域中的至少一个异源偶联残基,其中所述五邻体基原体中N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,以及
X2选自D和E;和/或
(v)药物或者多肽,其共价或非共价偶联至所述第一、第二、或者第一和第二RGD环的一个或更多个氨基酸和/或所述五邻体基原体V环的一个或更多个氨基酸;和/或
(vi)在所述五邻体基原体的腺病毒纤维蛋白结合缝中的至少一个异源偶联残基,
以及其中,优选地,第一方面的所述工程化多肽能够组装成VLP。
在第二方面中,本发明涉及一种工程化多肽,其包含至少一个特异性结合五邻体基原体的腺病毒纤维蛋白结合缝的腺病毒纤维蛋白N端片段,以及:
(i)非腺病毒多肽,和/或
(ii)与药物或者标记(label)共价或非共价偶联。
在第三方面中,本发明涉及一种编码工程化多肽的核酸,所述工程化多肽包含本发明的腺病毒五邻体基原体,和/或本发明的所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段。
在第四方面中,本发明涉及一种表达载体,其包含本发明的核酸。
在第五方面中,本发明涉及一种克隆载体,其编码:
(i)包含腺病毒五邻体基原体的多肽,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环和/或腺病毒纤维蛋白的结合位点,适用于将编码非腺病毒多肽的核酸引入编码所述第一RGD环,第二RGD环和/或可变环的核酸;或者
(ii)多肽,其包含腺病毒五邻体基原体结合纤维蛋白片段,适用于在C和/或N端引入编码非腺病毒多肽的核酸。
在第六方面中,本发明涉及一种重组宿主细胞,其包含本申请的表达载体或本申请的克隆载体。
在第七方面中,本发明涉及一种包含五个工程化多肽的五聚体,所述工程化多肽包含本发明的腺病毒五邻体基原体。
在第八方面中,本发明涉及一种病毒样颗粒(VLP),其包含12个本发明的五聚体。
在第九方面中,本发明涉及一种包含12个五聚体的VLP,各五聚体包含五个腺病毒五邻体基原体以及至少一个本发明的工程化多肽,所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段。
在第十方面中,本发明涉及一种用于生产包含本发明的腺病毒五邻体基原体的工程化多肽和/或包含腺病毒五邻体基原体结合纤维蛋白片段的本发明的工程化多肽的方法,所述方法包括步骤:
(a)提供本发明的重组宿主细胞;
(b)表达所述工程化多肽;以及
(c)纯化所述工程化多肽。
在第十一方面中,本发明涉及一种用于生产本发明的VLP的方法,其包括本发明第十方面方法的步骤以及允许所述工程化多肽组装成VLP的进一步步骤。
在第十二方面中,本发明涉及一种用于生产本发明的VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒多肽,所述方法包括步骤:
(a)提供本发明的克隆载体;
(b)确定疾病或患者特异性非腺病毒多肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒多肽的核酸插入编码所述腺病毒五邻体基原体的第一RGD环、第二RGD环和/或可变环的核酸中,和/或插入编码所述工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段;
(d)在宿主细胞中,任选地与所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽一起,表达所述工程化的腺病毒五邻体基原体,以及
(e)纯化任选地包含腺病毒五邻体基原体结合纤维蛋白片段的所述VLP,或者包含腺病毒五邻体基原体结合纤维蛋白片段的所述工程化多肽。
在第十三方面中,本发明涉及一种用于生产本发明VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒多肽,所述方法包括步骤:
(a)提供本发明的克隆载体;
(b)确定疾病或患者特异性非腺病毒多肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒多肽的核酸插入编码所述工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段;
(d)在宿主细胞中,任选地与腺病毒五邻体基原体一起,表达包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽;以及
(e1)纯化所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽,并且与本发明的腺病毒五邻体基原体或者工程化腺病毒五邻体基原体混合;或者
(e2)在腺病毒五邻体基原体共表达的情况下,纯化所述VLP。
在第十四方面中,本发明涉及一种用于生产本发明VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒多肽,所述方法包括步骤:
(a)确定疾病或患者特异性非腺病毒多肽的氨基酸序列;
(b)合成本发明的工程化多肽,所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段以及至少一个所述非腺病毒多肽;以及
(c)将所述工程化多肽与腺病毒五邻体基原体或与本发明的工程化腺病毒五邻体基原体、与本发明的五聚体或与本发明的VLP混合。
在第十五方面中,本发明涉及一种VLP,其是通过本发明生产VLP的方法所生产的。
在第十六方面中,本发明涉及一种药物组合物,其包含包含本发明腺病毒五邻体基原体的工程化多肽和/或包含腺病毒五邻体基原体结合纤维蛋白片段的本发明的工程化多肽、编码一个或更多个本发明工程化蛋白的核酸、本发明的表达载体、或本发明的VLP,以及药学上可接受的载体和/或合适的赋形剂。
在第十七方面中,本发明涉及包含本发明腺病毒五邻体基原体的工程化多肽和/或包含腺病毒五邻体基原体结合纤维蛋白片段的本发明的工程化多肽、编码一个或更多个本发明工程化蛋白的核酸、本发明的表达载体、或本发明的VLP用于治疗和/或预防感染性疾病、免疫疾病或癌症中。
附图说明
图1:显示本发明的合成自组装多聚体支架,也称为VLP。5个原体形成一个五邻体亚基,12个五邻体自发地自组装成大的超结构,或者也称为VLP或者ADDomer。
图2:显示五邻体的侧视图。五聚体原体含有两个高度异形的RGD环和一个非保守性长度和序列可广泛变化的可变环(V环)。在这方面,本发明人确定它们与抗体CDR相似并且适合于引入允许所得VLP结合任何所需靶标的结合位点。它适用于展示多个表位,并且每个VLP可以展示多达180个表位。
图3:五邻体基原体包含区域-粘性片-与腺病毒纤维蛋白相互作用。这种粘性片可以与腺病毒纤维片段以亚纳摩尔的亲和力结合-也称为“STICKER”。优选将这些纤维片段多聚化以增加结合亲和力。STICKERn-标签(n优选是2至4)可以与蛋白的C和/或N端融合以连接至VLP,或者可以与任何其它承载物共价或非共价偶联。因此,STICKERn-标签能够表面上展示VLP肽、蛋白、核酸、脂质体和VLP递送的任何其它承载物。ADDomer具有12个用于结合STICKER标签承载物的位点。在一个实施方案中,将五邻体基原体上的粘性片修饰为包含偶联残基,优选Cys,STICKERn-标签也被修饰为包含Cys,按这种方式在非还原条件下粘性片中的Cys和STICKERn-标签可以形成共价键,其将在还原条件下被切断。
图4:示意性地显示了产生ADDomer的过程。高产量生产的ADDomers易于纯化且非常稳定。pACEBac-ADDOMER载体具有编码第一和第二RGD环以及V环的三个区域,可以容易地被任何所需肽链取代,例如赋予特异性结合活性和/或抗原表位的肽。
图5:在组装成十二面体时,五邻体基原体包含与相邻原体相互作用的区域,称为“链交换(swapping)”。相关氨基酸残基突变为半胱氨酸通过共价二硫键的形成可以稳定VLP超结构,使ADDomer具有热稳定性。示意性表示突变为半胱氨酸的链交换残基的示意图。
图6:所示序列在物种中高度保守。比对显示来自不同天然血清型的野生型五邻体基序列。显示的序列是:亚组C Ad2,登录号P03276;亚组B Ad3,S41389;亚组B Ad7,AAR89958;亚组B Adl l,AAP49205;亚组F Ad41,AAF14179;亚组A Adl2,P36716;亚组DAdl7,NP_049379;亚组E Ad25,NP_478405;和亚组D Ad37,CAC82544进行比对。V环用深灰色框突出显示;RGD环用浅灰色框突出显示。用中间灰色突出显示与纤维结合的五邻体基原体的那些氨基酸残基。它们在血清型中都是保守的。
图7和8:显示了本发明的两种优选克隆载体的结构。克隆载体的核酸序列分别在SEQ ID NO:61和62中提供。
图9:Plug&Play表达盒和杆状病毒转移质粒。设计编码ADDomer的基因,以便在三个不同的基因座(深灰色)中插入“感兴趣的表位”,其两侧是独特的限制性位点。将该盒插入pACEBac质粒的BamHI/HindIII中。可以在构建体pACEBac-ADDomer2.0中容易实现利用感兴趣表位的ECoRI/RsrII、BssHII/SalI或Sacl XbaI的BioBrick插入。
图10:ADDomer2.0热稳定性。将纯化的ADDomer储存在不同温度下,然后进行电子显微镜检查。在室温或37℃下储存导致颗粒的完全保存。仅在温度高于45℃时观察到结构单元(五聚体)的解离。热变换分析(TSA)证实稳定性高达37℃,在45℃以上发生轻微解离,并且仅在60℃孵育时完全变性。
图11:基孔肯雅表位插入和表位展示模式。(a)并入ADDomer2.0展示环中的氨基酸序列显示在顶部(SEQ ID NO:78)。插入了主要的基孔肯雅中和性表位(以深灰色突出显示)。肽的N端含有编码TEV切割位点的额外氨基酸(以浅灰色突出显示)。(b)示意性地解释了表位展示的可能性。表达产生ADDomer-TevCHIK,其中肽的两端与ADDomer支架连接(“受约束的表位”)。与TEV蛋白酶一起孵育以“天然样”构型而释放肽的N端(“自由(relaxed)表位”),同时完全维持(现在多重切口)ADDomer VLP的完整性。(c)通过SDS-PAGE分析监测随时间进行切割,如预期的那样,显示完整ADDomer(约60kDa)被有效切割为约43和17kDa的两条带(左)。尽管切割,电子显微镜检查证实ADDomer支架未被破坏(右)。
图12:小鼠血清识别的CHIK表位的ELISA。8只小鼠的三组在w2和w4仅注射10mgADDomer支架(表位呈递环中没有抗原表位)、ADDomer-TevCHIKexp(表位呈递环中暴露的“天然样”CHIK抗原表位,自由的N端如在活性基孔肯雅糖蛋白中一样,C末端共价连接到支架)或ADDomer-TevCHIKconstr(表位呈递环中的“受约束”CHIK抗原表位,N末端和末C端连接到ADDomer支架上)。每两周收集血清并测试CHIK抗原表位识别(稀释度1/100)。具有暴露的、天然样表位的ADDomer-TevCHIKexp有效地引发应答。
图13:具有显著延伸的表位呈递环的ADDomer。将包含200个氨基酸的线性表位插入ADDomer支架的表位呈递环中,并与单独的ADDomer支架比较(无插入)。SDS-PAGE凝胶证明插入反映了向更高分子量的迁移(左)。质谱分析证实了分子量(对于无插入的ADDomer支架为63573Da;对于“延伸的”ADDomer为81179Da,其在表位呈递环中包含额外200个氨基酸插入)。
图14:“STICKER”肽与含有靶向半胱氨酸突变的ADDomer的共价偶联。野生型ADDomer(wt)和具有一个半胱氨酸突变的ADDomer(分别为K363C、Q476C或A477C)与STICKER肽(分别为C20(SEQ ID NO:77)和C9(SEQ IDNO:75))一起孵育。在还原(+bMeSH)和非还原(-bMeSH)条件下进行SDS-PAGE分析并转移至PVDF膜。通过标记抗体的结合和抗生物素蛋白结合分别显示ADDomer(深灰色)和STICKER肽(浅灰色),证明STICKER通过特定的二硫键形成与半胱氨酸-突变体ADDomer结合(在下图中用白色圆圈标记)。
具体实施方式
在下面详细描述本发明之前,应理解本发明不限于本文所述的特定方法、方案和试剂,因为它们可以变化。还应理解,本文使用的术语仅用于描述特定实施方案的目的,并不意图限制本发明的范围,本发明的范围仅受所附权利要求的限制。除非另外定义,否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的含义相同的含义。
在下文中,将描述本发明的要素。这些要素与特定实施方案一起列出,然而应该理解,它们可以以任何方式以任何数量进行组合以产生另外的实施方案。不应将各种描述的示例和优选实施方案解释为将本发明仅限于明确描述的实施方案。该描述应被理解为支持和包含了将明确描述的实施方案与任何数量的公开的和/或优选的要素进行组合的实施方案。此外,除非上下文另有说明,否则本申请中所有描述的要素的任何排列和组合应该被认为是本申请说明书中公开的。
在本说明书的全文中引用了几个文献。本文引用的每篇文献(包括所有专利、专利申请、科学出版物、制造商的说明书、说明书等),无论是上文还是下文,均通过引用整体并入本文。本文中的任何内容均不应解释为承认本发明无权先于在先发明的此类公开内容。
定义
为了实施本发明,除非另有说明,否则采用化学、生物化学和重组DNA技术的常规方法,其在该领域的文献中有解释(参见,例如,Molecular Cloning:A LaboratoryManual,第二版,J.Sambrook等人编辑,Cold Spring Harbor LaboratoryPress,ColdSpring Harbor 1989)。
在本说明书和随后的权利要求中,除非上下文另有要求,否则“包括”一词以及诸如“包含”和“含有”的变体,将理解为暗示包含所述整数或步骤、或者一组整数或步骤,但不排除任何其它整数或步骤、或者一组整数或步骤。如本说明书和所附权利要求中所用,单数形式“一(a)”、“一个(an)”和“该(the)”包括复数指代,除非内容另有明确说明。
术语“多核苷酸”和“核酸”在本文中可互换使用并且被理解为由核苷酸单体构成的聚合物或低聚物大分子。核苷酸单体由核碱基、五碳糖(例如但不限于核糖或者2'-脱氧核糖)以及一至三个磷酸基团组成。通常,通过各核苷酸单体之间的磷酸二酯键形成多核苷酸。在本发明的上下文中,提及核酸分子包括但不限于核糖核酸(RNA)、脱氧核糖核酸(DNA)及其混合物例如RNA-DNA杂交体。核酸可以例如是化学合成的,例如根据磷酸三酯方法(参见,例如,Uhlmann,E&Peyman,A(1990)Chemical Reviews,90,543-584)。“适体”是以高亲和力结合多肽的核酸。可以通过选择方法从不同单链RNA分子的大型库(pool)分离适体,例如SELEmirl46-a(参见例如Jayasena(1999)Clin.Chem.,45,1628-50;Klug和Famulok(1994)M.Mol.Biol.Rep.,20,97-107;US 5,582,981)。也可以以其镜像形式合成和选择适体,例如作为L-核糖核苷酸(Nolte等人(1996)Nat.BiotechnoL,14,1116-9;Klussmann等人(1996)Nat.Biotechnol,14,1112-5)。以这种方式分离的形式具有以下优点:它们不会被天然存在的核糖核酸酶降解,因此具有更高的稳定性。
术语“蛋白”和“多肽”在本文中可互换使用并且指任何肽键连接的氨基酸链,无论长度或者翻译后修饰情况如何。可用于本发明的蛋白(包括蛋白衍生物、蛋白变体、蛋白片段、蛋白节段、蛋白表位和蛋白结构域)可以通过化学修饰进一步修饰。这意味着这种化学修饰的多肽包含除20种天然存在的氨基酸之外的其它化学基团。此类其它化学基团的实例包括但不限于糖基化氨基酸和磷酸化氨基酸。与亲本多肽相比,多肽的化学修饰可以提供有利的性质,如增强的稳定性、增加的生物半衰期或增加的水溶性中的一种或多种。
在本发明的上下文中使用的术语“五邻体基蛋白”或“五邻体基原体”是指组装成所谓的“五邻体蛋白”的腺病毒蛋白。每个五邻体蛋白包含五个五邻体基蛋白。五邻体蛋白是形成腺病毒外壳的三种蛋白之一。其它蛋白是六邻体和纤维。组装的腺病毒的结构如图1左上角所示。用于本发明的五邻体基蛋白来源于对任何哺乳动物物种特异的腺病毒。优选地,腺病毒是人或非人大猿腺病毒,优选地黑猩猩(Pan)、大猩猩(Gorilla)和猩猩(Pongo),更优选倭黑猩猩(Pan paniscus)和普通黑猩猩(Pan troglodytes)。本领域技术人员应当理解,不同腺病毒的五邻体基蛋白的氨基酸序列会有所不同,所有这些天然存在的变体都包括在术语“五邻体基蛋白”中。另外,该术语包括人工变体,其包含天然存在的五邻体基蛋白序列的插入、缺失和/或突变。这些突变是N端结构域、V环、第一RGD、第二RGD环和/或粘性片区域的修饰的补充,下面将更详细地描述。只要人工修饰的五邻体基蛋白组装成五邻体亚基并且12个亚基组装成VLP,任何这样的人工变体都包括在内。优选地,在如下定义的N端结构域、V环、第一RGD和第二RGD环之外,人工变体和天然存在的五邻体基原体具有至少75%,更优选地至少80%,更优选地至少85%,更优选地至少90%,更优选地至少92%,更优选地94%,更优选地96%,和更优选地98%的序列同一性。优选的五邻体基蛋白是SEQIDNO:1至14中所示的那些。如上定义的五邻体基蛋白是本发明工程化五邻体基蛋白的基础。因此,通过氨基酸插入、缺失和突变,工程化的五邻体基蛋白与天然存在的五邻体基蛋白在序列上不同,如下文更详细概述的。
在本发明的上下文中可互换使用的短语“工程化多肽能够组装成VLP”或“组装成VLP”是指5个五邻体基原体自组装成五邻体蛋白,随后12个五邻体蛋白自组装成小的球形颗粒(即病毒样颗粒(VLP))的能力。组装和维持五邻体蛋白或者优选地VLP结构的能力可以通过本领域已知的和本文描述的方法来确定,特别是通过电子显微镜(EM)。组装成VLP的能力的优选条件被评估为20℃和生理缓冲条件。在进一步优选的实施方案中,该术语包括工程化多肽,其不仅组装成VLP而且在高于20℃的温度,优选地在高于30℃的温度,优选地在高于40℃的温度,更优选地高于45℃,甚至更优选高于50℃时保持球形。球形的完整性可以通过EM,优选地在生理缓冲条件下评估。
在本发明上下文中使用的术语“第一RGD环”是指10至40个氨基酸的多肽序列,其位于五邻体原体中包含的“RGD基序”N端(参见图6)。这种多肽序列在不同的腺病毒之间高度不同。因此,不能通过同源性定义它,但可以通过位于其N末端的N端的序列来定义。五邻体原体内的C末端由RGD基序确定。
在本发明上下文中使用的术语“第二RGD环”是指10至35个氨基酸的多肽序列,其位于五邻体原体中包含的“RGD基序”C端(参见图6)。这种多肽序列在不同的腺病毒之间高度不同。因此,不能通过同源性定义它。五邻体原体内的N末端由RGD基序确定。原体内的C末端可以由位于其C末端的C端的序列来定义,其在不同的腺病毒中是保守的。
在本发明的上下文中使用的术语“RGD基序”是指由精氨酸、甘氨酸和天冬氨酸组成的三个氨基酸长的多肽。该基序最初在纤连蛋白中被鉴定为介导与整联蛋白的结合。RGD基序也存在于许多其它受体中,介导细胞-基质和细胞-细胞相互作用。本发明的工程化多肽的五邻体原体中的RGD基序可以是完整的,或者可以按照五邻体原体不再与整联蛋白结合的方式发生突变。
在本发明的上下文中使用的术语“可变环”对应于位于腺病毒五邻体基β片层b3和β片层b4之间的序列。该环的长度和氨基酸组成在血清型中都是非常不同的。对应于可变环的序列在图6中以绿色突出显示。
在本发明的上下文中使用的术语“N端结构域”是指在五邻体基原体的N端中高度保守的区域。这部分蛋白包含α1和α2螺旋、β1和β2片层以及B和C结构域(见图6)。它参与五邻体基原体之间的相互作用,因此适合于引入部分(moiety)例如,稳定五邻体基原体之间相互作用的偶联残基。
在本发明的上下文中使用的术语“腺病毒纤维蛋白结合缝(cleft)”是指与腺病毒纤维蛋白形成相互作用表面的五邻体基原体的折叠。从图6中可以看出,结合缝是由几个非连续的多肽序列延伸(stretch)形成的,这些序列延伸在不同的腺病毒中是保守的。
在整个说明书中使用的术语“靶标特异性结合结构域”是指有助于特异性结合靶标的多肽。如果对相应靶标以最高的亲和力进行结合,而对于其它靶标甚至对具有相关氨基酸序列的靶标仅具有较低的亲和力,例如至少低10倍,优选至少低100倍的亲和力,则这种靶标特异性结合结构域的结合被认为特异于给定靶标。
本发明中使用的术语“靶标”是指天然存在的细胞或分子结构,分子对其具有一定的结合亲和力或分子对其特异性结合。靶标可以包含一个或更多个表位。抗原是靶标的优选实例。
在本发明的上下文中使用的术语“抗原”是指免疫应答分子(例如,抗体、T细胞受体(TCR)等)识别的任何结构。抗原可以是外来的或者对身体有毒或者可以是与特定疾病相关的细胞蛋白。抗原被适应性免疫系统的高度可变的抗原受体(B细胞受体或T细胞受体)识别,并且可以引发体液或细胞免疫应答。引发这种应答的抗原也称为免疫原。细胞内蛋白的一部分,无论它们是外来的还是细胞的,都被加工成较小的肽并由主要组织相容性复合物(MHC)呈递。如果小肽片段被T细胞受体结合,则引发细胞免疫应答。细胞表面抗原可选自细胞因子受体、整联蛋白、细胞粘附分子、细胞类型特异性细胞表面抗原、组织特异性细胞表面抗原、细胞表面表达的肿瘤相关抗原、分化抗原簇,或碳水化合物。
在本发明的上下文中使用的术语“特异性结合”是指结合部分(如抗体)与靶标(例如表位)结合更强,与另一个靶标的结合相比,如果其与第一靶标结合的解离常数(Kd)低于对第二靶标的解离常数,则它是特异性的。靶标可以被它们的配体识别,所述配体以一定的亲和力结合其靶标,因此配体与其各自靶标的结合产生生物学效应。优选地,结合是特异性的并且以高亲和力发生,优选地,Kd小于10-7、10-8、10-9、10-10M或者更少。优选地,在37℃测量这种亲和力。合适的测定包括表面等离子体共振测量(例如,Biacore)、石英晶体微量天平测量(例如Attana)以及竞争测定。
在本发明的上下文中使用的术语“抗体”是属于免疫球蛋白超家族的糖蛋白;术语抗体和免疫球蛋白通常可互换使用。抗体是指由浆细胞产生的蛋白分子,并且被免疫系统用于鉴定和中和诸如细菌和病毒的外来物体。抗体识别外源靶标(即其抗原)的独特部分。
本文所用的术语“抗体片段”是指保留特异性结合抗原的能力的一种或多种抗体片段。包含在术语“抗体片段”内的结合片段的实例包括片段抗原结合(Fab)片段、Fab'片段、F(ab')2片段、重链抗体、单结构域抗体(sdAb)、单链可变片段(scFv)、可变片段(Fv)、VH结构域、VL结构域、单结构域抗体、纳米抗体、IgNAR(免疫球蛋白新抗原受体)、二-scFv、双特异性T细胞接合物(BITE)、双亲和重新靶向(DART)分子、三体、双抗体、单链双抗体、替代支架蛋白及其融合蛋白。
本说明书中使用的术语“双抗体”是指可以结合不同抗原的融合蛋白或二价抗体。双抗体由两条单一的蛋白链组成,它们包含抗体片段,即可变片段。双抗体包含与同一多肽链上的轻链可变结构域(VL)连接的重链可变结构域(VH)(VH-VL,或者VL-VH)。通过使用连接两个可变结构域的短肽,结构域被迫与另一条链的互补结构域配对,从而产生两个抗原结合位点。双抗体可以靶向相同的(单特异性)或不同的抗原(双特异性)。
在本发明的上下文中使用的术语“单结构域抗体”是由抗体的单个、单体可变结构域组成的抗体片段。简单地说,它们仅包含由骆驼科动物或软骨鱼类产生的重链抗体的单体重链可变区。由于它们的起源不同,它们也可称为VHH或者VNAR(可变新抗原受体)片段。或者,通过使用基因工程,单结构域抗体可通过常规小鼠或人抗体的可变结构域单体化获得。它们显示出大约12-15kDa的分子量,因此是能够识别抗原的最小抗体片段。其它实例包括纳米体或纳米抗体。
在本说明书的上下文中使用的术语“抗体模拟物”是指可以特异性结合抗原的化合物,类似于抗体,但在结构上与抗体无关。通常,抗体模拟物是摩尔质量约3至20kDa的人工肽或蛋白,其包含一个、两个或更多暴露的特异性结合抗原的结构域。实例尤其包括LACI-D1(脂蛋白相关凝固抑制剂);affilins例如人γB结晶或人泛素;半胱氨酸蛋白酶抑制剂;来自嗜酸热硫化叶菌(Sulfolobus acidocaldarius)的Sac7D;脂质运载蛋白和来自脂质运载蛋白的抗运载蛋白(anticalin);DARPin(设计的锚蛋白重复结构域);Fyn的SH3结构域;蛋白酶抑制剂的Kunits结构域;单体,例如纤连蛋白的第10类III结构域;adnectin:knottin(半胱氨酸结迷你蛋白);atrimer;evibody例如基于CTLA4的结合物、亲和体例如来自金黄色葡萄球菌(Staphylococcus aureus)蛋白A的Z结构域的三螺旋束;转运体(trans-body),例如人转铁蛋白;四连蛋白,例如单体或三聚体人C型凝集素结构域;微体,例如胰蛋白酶抑制剂II;affilin;犰狳重复蛋白。核酸和小分子有时也被认为是抗体模拟物(适体),但不是人工抗体、抗体片段和由它们组成的融合蛋白。与抗体相比的共同优点是更好的溶解性、组织渗透性、对热和酶的稳定性以及相对低的生产成本。
如本文所用,术语“Kd”(通常以“mol/L”测量,有时缩写为“M”)意指结合部分(例如抗体或其片段)与靶分子(例如抗原或其表位)之间的特定相互作用的解离平衡常数。用于确定Kd的方法包括但不限于ELISA和表面等离子共振测定。
在本发明的上下文中使用的术语“表位”,也称为抗原决定簇,是免疫系统(特别是抗体、B细胞或T细胞)识别的大分子的一部分。如本文所用,“表位”是能够结合如本文所述的抗体(例如抗体或其抗原结合片段)的大分子的一部分。表位通常由分子的化学活性表面基团组成,例如氨基酸或糖侧链,并且通常具有特定的三维结构特征以及特定的电荷特征。构象和非构象表位的区别在于,在变性溶剂的存在下,与前者而非后者的结合丧失。
如本文所用,“构象表位”是指由所述大分子的三维结构形成的线性大分子(例如,多肽)的表位。在本申请的上下文中,“构象表位”是“不连续表位”,即大分子(例如,多肽)上的构象表位由大分子一级序列中至少两个独立区域形成(例如,多肽的氨基酸序列)。换句话说,如果表位由一级序列中和本发明抗体(或其抗原结合片段)同时结合的至少两个独立区域组成,则表位在本发明的上下文中被认为是“构象表位”,其中这至少两个独立的区域被一级序列中本发明抗体(或其抗原结合片段)不结合的一个或更多个区域所中断。优选地,这种“构象表位”存在于多肽上,并且一级序列中的两个独立区域是本发明抗体(或其抗原结合片段)结合的两个独立的氨基酸序列,其中这至少两个独立的氨基酸序列被一级序列中本发明抗体(或其抗原结合片段)不结合的一个或更多个氨基酸序列所中断。优选地,中断氨基酸序列是连续氨基酸序列,其包含抗体(或其抗原结合片段)不结合的两个或更多个氨基酸。本发明抗体(或其抗原结合片段)结合的至少两个独立的氨基酸序列在长度上没有特别限制。这种独立的氨基酸序列可以仅由一个氨基酸组成,只要所述至少两个独立的氨基酸序列中的氨基酸总数足够大以实现抗体(或其抗原结合片段)和构象表位之间的特异性结合即可。
在本发明的上下文中使用的术语“腺病毒纤维蛋白”是指腺病毒蛋白,其与五邻体原体非共价结合并有助于腺病毒与宿主细胞的附着。
关于多肽和多核苷酸序列的比较,在整个说明书中使用的术语“序列同一性”。在比较两个序列并且比较中未指定参考序列(相对于参考序列进行序列同一性百分比的计算)的情况下,如果没有特别指出的话,参考待比较的两个序列中较长者来计算序列同一性。如果没有另外具体指出的话,如指明参考序列则基于SEQ ID指示的参考序列的全长确定序列同一性。例如,与300个氨基酸长的参考多肽序列相比,由200个氨基酸组成的多肽序列可以表现出66.6%(200/300)的最大序列同一性百分比,而具有150个氨基酸长度的序列可以表现出50%(150/300)的最大序列同一性百分比。如果这150个氨基酸中的15个与300个氨基酸长的参考序列的相应氨基酸不同,则序列同一性水平降低至45%。核苷酸和氨基酸序列的相似性,即序列同一性的百分比,可以通过序列比对来确定。这种比对可以用几种本领域已知的算法进行,优选地用Karlin和Altschul的数学算法(Karlin&Altschul(1993)Proc.Natl.Acad.Sci.USA 90:5873-5877)、用hmmalign(HMMER包,http://hmmer.wustl.edu/)或CLUSTAL算法(Thompson,J.D.,Higgins,D.G.&Gibson,T.J.(1994)Nucleic Acids Res.22,4673-80),在例如http://www.ebi.ac.uk/Tools/clustalw/、或http://www.ebi.ac.uk/Tools/clustalw2/index.html或http://npsa-pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=/NPSA/npsa_clustalw.html上可获得。使用的优选参数是默认参数,因为它们在http://www.ebi.ac.uk/Tools/clustalw/或者http://www.ebi.ac.uk/Tools/clustalw2/index.html上设置。序列同一性的等级(序列匹配)可以使用例如BLAST、BLAT或者BlastZ(或BlastX)计算。类似的算法被并入Altschul等人(1990)J.Mol.Biol.215:403-410的BLASTN和BLASTP程序中。使用BLASTN程序进行BLAST多核苷酸搜索,得分=100,字长=12。用BLASTP程序进行BLAST蛋白搜索,得分=50,字长=3。为了获得用于比较目的的空位比对,使用缺口BLAST,如Altschul等人(1997)Nucleic Acids Res25:3389-3402所述。当使用BLAST和缺口BLAST程序时,使用相应程序的默认参数。序列匹配分析可以通过已建立的同源映射技术得以补充,例如Shuffle-LAGAN(Brudno M.,Bioinformatics 2003b,19 Suppl 1:154-162)或Markov随机场。当在本申请中提及序列同一性的百分比时,如果没有另外具体指出,则相对于较长序列的全长计算这些百分比。“杂交”也可用作两个核酸序列之间的序列同一性或者同源性的量度。根据标准杂交技术,编码F、N或者M2-1或其任何部分的核酸序列可以用作杂交探针。杂交条件是本领域技术人员已知的,并且可以在例如Current Protocols in Molecular Biology,John Wiley&Sons,N.Y,6.3.1-6.3.6,1991中找到。“中等杂交条件”定义为相当于在30℃在2×氯化钠/柠檬酸钠(SSC)中杂交,然后于50℃在1×SSC、0.1%SDS中洗涤。“高度严格条件”定义为相当于在45℃下在6×氯化钠/柠檬酸钠(SSC)中杂交,然后在65℃下在0.2×SSC、0.1%SDS中洗涤。
本发明上下文中使用的术语“偶联残基”是指具有能够形成共价键的侧链的天然或非天然存在的氨基酸。偶联残基可以插入本发明的多肽中。如果偶联残基是由DNA编码的天然存在的氨基酸,则偶联残基的插入仅需要修饰指导本发明多肽表达的DNA,例如插入编码这种氨基酸的密码子或突变已存在的密码子。作为该术语含义内的偶联残基,天然存在的氨基酸的优选实例是Asp、Glu、Lys和Cys。特别优选Cys,因为它将与另一Cys形成二硫键,这取决于环境的氧化还原状态。特别地,后者允许在两个独立的多肽之间形成稳定的互连。
在本发明的上下文中使用的术语“标记”是指适用于诊断目的的任何种类的化合物。优选的化合物选自荧光染料、放射性同位素和造影剂。造影剂是有助于显示体内异常区域的染料或其它物质。在一个实施方案中,术语标记是指包含螯合剂的化合物,所述螯合剂与二价或三价金属阳离子形成络合物。优选的放射性同位素/荧光发射同位素选自:发射α辐射的同位素、发射γ辐射的同位素、俄歇电子发射同位素、发射X射线的同位素、荧光发射同位素,例如18F、51Cr、67Ga、68Ga、111In、99mTc、140La、175Yb、153Sm、166Ho、88Y、90Y、149Pm、177Lu、47Sc、142Pr、159Gd、212Bi、72As、72Se、97Ru、109Pd、105Rh、101ml5Rh、119Sb、128Ba、123I、124I、131I、197Hg、211At、169Eu、203Pb、212Pb、64Cu、67Cu、188Re、186Re、198Au和199Ag。优选的荧光染料选自以下类别的染料:Xanthen(例如,荧光素)、吖啶(例如吖啶黄)、噁嗪(例如噁嗪1)、Cynines(例如Cy7/Cy3)、苯乙烯基染料(例如染料-28)、香豆素(例如Alexa Fluor 350)、卟啉(例如叶绿素B)、金属-配体复合物(例如PtOEPK)、荧光蛋白(例如APC、R-藻红蛋白)、纳米晶体(例如QuantumDot 705)、二萘嵌苯(例如Lumogen Red F300)和酞菁染料(例如IRDYETM 700DX)以及这些类染料的缀合物和组合。优选的造影剂选自顺磁剂例如Gd、Eu、W和Mn,优选与螯合剂络合。其它选择是超磁性铁(Fe)络合物和颗粒、含有高原子序数的原子的化合物,即用于计算机断层扫描(CT)的碘、含有这些造影剂的微泡和载体,如脂质体。
在本发明的上下文中术语“药物”应从最广泛的意义上理解,是指在患者中引起预防、治疗或缓和效果的任何化合物。优选地,它是小分子,例如分子大小在500D以下。
本发明的上下文中,“接头”是指任何化学部分,其是柔性的并且在空间上将两个化学部分分开,例如,将本发明第一方面的工程化多肽从药物或标记分开。优选的接头是长宽比至少为10:1,优选至少为20:1,更优选至少为50:1的部分。优选,接头是线性分子。优选,通过接头连接的两个部分共价或非共价地,优选地共价连接到接头的各个末端。
在本发明的上下文中,“肽接头”是指氨基酸序列,即多肽,其中在空间上将本发明的工程化多肽内的两部分分开。通常,这种接头由1至100个,优选3至50个,更优选5至20个氨基酸组成。因此,这种接头的最小长度至少为1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或者30个氨基酸,最大长度至少为100、95、90、85、80、75、70、65、60、55、50、45、40、35、34、33、32、31、30、29、28、27、26、25、24、23、22、21、20、19、18、17、16或者15个氨基酸或更少。肽接头也可以在连接在一起的两个部分之间提供柔性。如果氨基酸很小,这种柔性通常会增加。因此,柔性肽接头包含含量增加的小氨基酸,特别是甘氨酸和/或丙氨酸,和/或亲水氨基酸如丝氨酸、苏氨酸、天冬酰胺和谷氨酰胺。优选地,肽接头超过20%、30%、40%、50%、60%或更多的氨基酸是小氨基酸。
术语“制备物”和“组合物”意指包括活性化合物的制剂,如含有载体和/或赋形剂的本发明VLP。
“药学上可接受的”意指由联邦或州政府的管理机构批准、或在美国药典或其它公认药典中列出的,用于动物,更特别是人类。
如本文所用,术语“载体”是指药理学上无活性的物质,例如但不限于与治疗活性成分一起施用的稀释剂、赋形剂、表面活性剂、稳定剂、生理缓冲溶液或载体。此类药物载体可以是液体或固体。液体载体包括但不限于无菌液体,例如水和油中的盐溶液,所述油包括但不限于石油、动物、植物或合成来源的那些,例如花生油、大豆油、矿物油、芝麻油等。盐溶液和葡萄糖水溶液和甘油溶液也可用作液体载体,特别是用于可注射溶液。当静脉内施用药物组合物时,盐溶液是优选的载体。合适的药物载体的实例描述于E.W.Martin的“Remington's Pharmaceutical Sciences”中。
合适的药物“赋形剂”包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石、氯化钠、干脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。
“表面活性剂”包括阴离子、阳离子和非离子表面活性剂,例如但不限于脱氧胆酸钠、十二烷基硫酸钠、Triton X-100和聚山梨醇酯,如聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯65和聚山梨醇酯80。
“稳定剂”包括但不限于甘露醇、蔗糖、海藻糖、白蛋白、以及蛋白酶和/或核酸酶拮抗剂。
可以在本发明的上下文中使用的“生理缓冲溶液”包括但不限于氯化钠溶液、软化水、以及合适的有机或无机缓冲溶液,例如但不限于磷酸盐缓冲液、柠檬酸盐缓冲液、tris缓冲液(三(羟甲基)氨基甲烷)、HEPES缓冲液([4(2羟乙基)哌嗪基]乙磺酸)或MOPS缓冲液(3吗啉代-1丙磺酸)。各缓冲液的选择一般取决于所需的缓冲液摩尔浓度。磷酸盐缓冲液适用于例如注射和输注溶液。
术语“佐剂”是指在细胞或体液水平上增加、刺激、激活、增强或调节对组合物活性成分的免疫应答的药剂,例如免疫佐剂刺激免疫系统对实际抗原的应答,但本身没有免疫学作用。这些佐剂的实例包括但不限于无机佐剂(例如,无机金属盐,如磷酸铝或氢氧化铝)、有机佐剂(如皂苷或角鲨烯)、油基佐剂(如弗氏完全佐剂和弗氏不完全佐剂)、细胞因子(如IL-1β、IL-2、IL-7、IL-12、IL-18、GM-CFS和INF-γ)颗粒佐剂(例如,免疫刺激复合物(ISCOMS)、脂质体或可生物降解的微球体、病毒体、细菌佐剂(如单磷酰脂质A、或胞壁酰肽)、合成佐剂(例如,非离子嵌段共聚物、胞壁酰肽类似物或合成脂质A)、或合成多核苷酸佐剂(例如聚精氨酸或聚赖氨酸)。
“有效量”或“治疗有效量”是足以实现预期目的的治疗剂的量。给定治疗剂的有效量将随诸如药剂的性质、施用途径、接受治疗剂的动物的大小和物种、以及施用目的等因素而变化。每个个案中的有效量可以由技术人员根据本领域已建立的方法凭经验确定。
实施方案
本发明尤其提供了优于现有技术的以下优点:(i)对于抗原和/或靶标特异性结合结构域的插入/呈递而言,易于修饰的支架,其可以根据患者的需要而定制或者容易适应于变化的病毒表面抗原,(ii)可用于例如接种疫苗甚至在不利条件下(例如高温)储存的稳定的组合物,(iii)用于呈递一种或多种抗原的极高密度载体,(iv)在运行中(on the fly)使用纤维(STICKER)蛋白添加其它抗原或其它活性物。
因此,在第一方面,本发明涉及一种工程化多肽,其包含腺病毒五邻体基原体、基本上由腺病毒五邻体基原体组成、或由腺病毒五邻体基原体组成,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环(V环)、腺病毒纤维蛋白结合缝和/或N端结构域,并包含以下的一个或更多个:
(i)在所述第一、第二、或者第一和第二RGD环和/或所述V环中至少一个靶标特异性结合结构域;和/或
(ii)在所述第一、第二、或者第一和第二RGD环和/或所述V环中一个或更多个非腺病毒多肽;和/或
(iii)所述五邻体基原体的N和/或C端的非腺病毒多肽;和/或
(iv)在所述第一、第二、或者第一和第二RGD环、V环中和/或在所述五邻体基原体N端结构域中的至少一个异源偶联残基,其中所述五邻体基原体中N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,优选E,以及
X2选自D和E,优选E;和/或
(v)药物、标记和/或多肽,其共价或非共价偶联至所述第一、第二、或者第一和第二RGD环的一个或更多个氨基酸和/或所述五邻体基原体V环的一个或更多个氨基酸;和/或
(vi)在所述五邻体基原体的腺病毒纤维蛋白结合缝中的至少一个异源偶联残基,
以及其中,优选地,所述工程化多肽能够组装成VLP。
在上述实施方案之一中,如果残基或一组残基(例如靶标特异性结合结构域、一个或更多个非腺病毒多肽、或至少一个异源偶联残基)被指定包含在五邻体基蛋白的某些区域中,则该残基或该一组残基可以插入五邻体基蛋白相应的指定区域内,即其可以是添加,或者可以将其插入,并且可以额外删除分别形成指定的第一RGD环、第二RGD环和/或V环的至少一个或所有氨基酸,而不影响组装成VLP的能力。
本发明第一方面的工程化多肽的优选实施方案包含腺病毒五邻体基原体、基本上由腺病毒五邻体基原体组成、或由腺病毒五邻体基原体组成,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环(V环)、腺病毒纤维蛋白结合缝和/或N端结构域,并包含在所述第一、第二、或者第一和第二RGD环和/或所述V环中的一个或更多个非腺病毒多肽;任选地还包含以下一个或更多个:
(i)包含在所述第一、第二、或者第一和第二RGD环和/或所述V环中的至少一个靶标特异性结合结构域;和/或
(ii)在五邻体基原体的N和/或C端的非腺病毒多肽;和/或
(iii)在所述第一、第二、或者第一和第二RGD环、V环中和/或在所述五邻体基原体N端结构域中的至少一个异源偶联残基,其中所述五邻体基原体中N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,优选E,以及
X2选自D和E,优选E;和/或
(iv)药物、标记和/或多肽,其共价或非共价偶联至所述第一、第二、或者第一和第二RGD环的一个或更多个氨基酸和/或所述五邻体基原体V环的一个或更多个氨基酸;和/或
(vi)在所述五邻体基原体的腺病毒纤维蛋白结合缝中的至少一个异源偶联残基,
以及其中,优选地,所述工程化多肽能够组装成VLP。
在第一、第二或第一和第二RGD环中和/或在V环中的至少一个靶标特异性结合结构域提供五邻体基原体,因此提供具有特异性结合靶标结构(例如细胞表面的细胞受体)的能力的组装VLP。本发明人惊奇地发现,五邻体基原体的这些部分可以包含相当长的靶标特异性结合结构域而不破坏五邻体或VLP的形成。另外,包含在这些区域中的靶标特异性结合结构域可以自由地与靶标相互作用并与靶标结合。一个或更多个靶标特异性结合结构域可以插入相应环中的任何位置,即不除去任何环氨基酸。或者,各个环氨基酸的全部或部分可以被靶标特异性结合结构域的氨基酸取代。靶标特异性结合结构域可以N和/或C端侧接肽接头。
如果五邻体基原体包含多于一个靶标特异性结合结构域,则优选它们包含在五邻体基原体不同的环中,例如在第一和第二RGD环中、在第一RGD环和V环中、或第二RGD环和V环中。如果五邻体基原体包含一个以上的靶标特异性结合结构域,则它们也优选与不同的靶标结合,例如,与第一类细胞上的靶标以及在第二类细胞上不同的靶标结合。这种双重或多重特异性可用于将不通常或不经常彼此充分相互作用的细胞聚集在一起。此类细胞的实例是肿瘤细胞和免疫系统的细胞,特别是细胞毒性T细胞。
在可以与上文概述的一种或多种其它替代实施方案组合的可选的实施方案(ii)中,第一、第二或第一和第二RGD环和/或V环包含非腺病毒多肽。该实施方案还基于令人惊讶的观察结果,即插入到五邻体基原体一个或更多个这些区域中的多肽被充分暴露以被免疫系统的细胞识别,从而引发免疫应答。术语“非腺病毒”多肽是指与腺病毒中存在的任何多肽没有序列同一性的多肽,尤其是与天然存在的腺病毒五邻体基原体中在至少5个氨基酸的长度上的多肽没有序列同一性。优选地,非腺病毒多肽在至少10个优选至少15个氨基酸的延伸上与腺病毒中存在的任何多肽没有序列同一性。一个或更多个非腺病毒多肽在每种情况下可以独立地插入相应环中的任何位置,即不除去任何环氨基酸。或者,各环氨基酸的全部或部分可以被靶标特异性结合结构域的氨基酸取代。包含在一个或更多个环中的非腺病毒多肽可以N和/或C端侧接肽接头。这可能优选增加非腺病毒多肽在VLP表面上的暴露。如果每个环中插入至少一个非腺病毒多肽,则每个五邻体基原体在其表面上包含至少三个相同或不同的非腺病毒多肽。一旦组装成VLP,至少180个非腺病毒多肽可以展示在本发明的VLP的表面。
本发明人惊奇地发现,可以将50或更多,100或更多,150或更多,200或更多,250或更多,或300或更多氨基酸的长氨基酸序列引入第一、第二或第一和第二RGD环中和/或V环中,而不破坏五邻体基原体组装成五邻体蛋白,随后组装成VLP的能力。因此,在(i)和/或(ii)所示的实施方案中,可以插入上述长度的氨基酸序列(相应的环中有或没有一些氨基酸的缺失)。
如果组合(i)和(ii)指出的替代实施方案,则进一步优选将非腺病毒蛋白插入与靶标特异性结合结构域不同的环中。
本发明人观察到位于五邻体基原体N和/或C端的多肽不会干扰五邻体和随后的VLP组装,并且在组装的VLP表面暴露。因此,在进一步替代的实施方案(iii)中,非腺病毒多肽可以通过插入肽接头或不通过插入肽接头与五邻体基原体的N和/或C端连接。因此,如果与第一和/或第二实施方案组合,五邻体基原体可以在一个或更多个环,优选所有三个环中并且在N端、C端或N和C端包含非腺病毒多肽。优选地,该替代实施方案与其它替代实施方案(i)、(iii)、(iv)、(v)和/或(vi)中的至少一个组合。
关于将异源肽序列插入V-环、第一RGD环和/或第二RGD环(伴随或不伴随全部或部分各自指定环的缺失)的可能性,本发明人的观察结果产生进一步的替代实施方案(iv),其可以与一个或更多个先前讨论的替代实施方案组合。在该实施方案中,在第一、第二或第一和第二RGD环和/或V环中引入至少一个异源偶联残基。通过插入一个或更多个偶联残基,可以将其它分子共价偶联到环上。例如,设想VLP首先从第一方面的工程化多肽进行组装,该方面的工程化多肽在一个或更多个环中包含一个或更多个偶联残基,并且随后将包含偶联残基的多肽共价偶联至VLP。使用该策略,可以用多肽“装饰”VLP的表面。这种VLP可以用于引发针对这些多肽的体液和/或细胞免疫应答。
此外,本发明人已经确定了五邻体基原体内的区域,被称为“五邻体基原体的N端结构域”。该结构域涉及五邻体内五邻体基原体之间的相互作用以及形成VLP的五邻体之间的相互作用。偶联残基插入该区域允许在相同或分开的五邻体内两个或更多个五邻体基原体之间形成共价键。这种共价键的形成使五邻体以及组装的VLP稳定。N端结构域在不同的腺病毒种中是高度保守的。因此,可以在五邻体基原体内进一步描绘该结构域的N端和C端。因此,优选一个或更多个偶联残基包含在N端结构域中。偶联残基可以替代存在的氨基酸或者除了形成N端结构域的氨基酸之外,可以插入偶联残基。优选的是,一个或更多个偶联残基取代N端结构域内的残基。优选,五邻体基原体内N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且,优选地,所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,优选E,以及
X2选自D和E。
因此,在该替代实施方案(iv)中,一个或更多个偶联残基包含在上述N和C端区域界定的本发明工程化多肽所含的五邻体基原体的氨基酸序列内。本领域技术人员将理解,在该实施方案中还可以替换SEQ ID NO:44或45中的一个或更多个氨基酸残基。偶联残基可以位于N端结构域内的任何位置,只要它不干扰五邻体或VLP的组装。
可根据第一实施方案的替代方案(i)至(vi)进行修饰的优选原体氨基酸序列为SEQ ID NO:64(编码核苷酸序列在SEQ ID NO:63中指示)。优选根据实施方案(i)插入至少一个靶标特异性结合结构域,和/或根据实施方案(ii)插入一个或更多个非腺病毒肽,和/或根据实施方案(iv)插入至少一个异源偶联残基,和/或根据实施方案(v)药物或多肽共价或非共价偶联至第一、第二或第一和第二RGD环的一个或更多个氨基酸和/或V环的一个或更多个氨基酸发生在SEQ ID NO:64的氨基酸312至339之间的第一RGD环中和/或SEQ IDNO:64的氨基酸343至367之间的第二RGD环中和/或SEQ ID NO:64的氨基酸150至178之间的V环中。这样的插入可以删除全部或部分属于第一和第二RGD环和V环的各自指定的氨基酸。
优选地,必须有一对偶联残基,优选地突变为半胱氨酸以形成二硫键。所得稳定的VLP包含多达120个二硫键,并且在37℃甚至42℃下至少持续数月超稳定。在特别优选的实施方案中,偶联残基位于参考SEQ ID NO:64的氨基酸位置51和54处,即基于人Ad B3优选的五邻体基原体氨基酸序列,或另一种腺病毒的邻体基原体的类似位置,或在参考SEQ IDNO:64的氨基酸位置54和114处或在另一种腺病毒的五邻体基原体的类似位置。
已进一步发现氨基酸位置53处的偶联残基(参考SEQ ID NO:1)可以和氨基酸位置543(参考SEQ ID NO:64)处或在另一种腺病毒五邻体基原体的类似位置的偶联残基形成共价键。后一残留在N端结构域之外。因此,如果在位置53插入偶联残基,则优选第二偶联残基位于参考SEQ ID NO:64的氨基酸541处,或在另一种腺病毒的五邻体基原体的类似位置。参考图6并且在比对中纳入其它五邻体基蛋白,技术人员可以容易地确定在相应的五邻体基原体中占据和SEQ ID NO:64的氨基酸51、53、54、114和541类似位置的那些残基。
在本发明的工程化多肽的该实施方案中,优选五邻体基原体包含以下序列:
P-T-X1-Xc-R-N-Xc-I-R(SEQ ID NO:50);
P-T-X1-G-R-Xc-S-I-R(SEQ ID NO:51)和T-Q-T-I-N-X60-Xc-X61(SEQ ID NO:52)
或者
P-T-X1-G-R-N-Xc-I-R(SEQ ID NO:53)以及
T-C-P-Xc-V-X62-K-A-L-G(SEQ ID NO:54)
其中
X1选自G和E,优选E,
Xc在每种情况下都是偶联残基,优选C、D、E和K,最优选C;
X60选自F、I和L,优选F和L,最优选F,
X61选自D和E,优选E;以及
X62选自H和Y,优选Y。
特别地,优选稳定的五邻体基原体包含SEQ ID NO:65至67的氨基酸序列或由其组成。进一步优选,这些氨基酸序列包含根据替代实施方案(i)、(ii)、(iii)、(iv)的一个或更多个修饰,只要该替代实施方案与N端结构域、上述本发明的第一方面(v)或(vi)无关。
优选根据实施方案(i)的至少一个靶标特异性结合结构域的插入、和/或根据实施方案(ii)的一个或更多个非腺病毒肽的插入,和/或根据实施方案(iv)的至少一个异源偶联残基的插入,和/或根据实施方案(v)将药物或多肽共价或非共价偶联至第一、第二或第一和第二RGD环的一个或更多个氨基酸和/或V环的一个或更多个氨基酸,发生在SEQ IDNO:65至67的氨基酸312至339之间的第一RGD环中和/或插入SEQ ID NO:65至67的氨基酸343至367之间的第二RGD环中和/或插入SEQ ID NO:65至67的氨基酸150至178之间的V环中。这样的插入可以删除全部或部分属于第一和第二RGD环和V环的各自指定的氨基酸。
在本发明的工程化蛋白的任何其它替代实施方案的背景下,由本发明的工程化蛋白形成的五邻体和VLP的热稳定化是期望的。因此,在以上(iv)中提及的关于N端结构域的替代实施方案优选地与一个或更多个替代实施方案(i)、(ii)、(iii)、(iv)组合,只要该替代方案与N端结构域、(v)或(vi)无关。还有优选的是,在(iv)和(vi)中提及的替代实施方案存在于工程化的五邻体基原体中,并且与一个或更多个(i)、(ii)、(iii)、(iv)组合,只要只要该替代方案与N端结构域或(v)无关。
在可与本发明第一方面的一种或多种其它替代方案组合的本发明第一方面的另一替代实施方案(v)中,药物、标记和/或多肽共价或非共价偶联至第一、第二或第一和第二RGD环的一个或更多个氨基酸和/或五邻体基原体V环的一个或更多个氨基酸。同样,该实施方案基于以下观察:与这些区域偶联的部分不会干扰五邻体和VLP组装,并导致用这些部分修饰VLP。在优选的实施方案中,药物或标记通过接头优选肽接头与五邻体基原体连接,所述接头在生理条件下(例如蛋白酶)可被切割,从而在作用部位从VLP释放药物。在该优选实施方案中,接头优选肽接头包含内肽酶切割位点。
在优选实施方案中,腺病毒纤维的片段用于非共价地将部分(例如多肽、药物、或标记等)连接至五邻体基原体、组装的五邻体和/或组装的VLP。这种相互作用是通过存在于本发明第一方面的工程化多肽中的五邻体基原体腺病毒纤维蛋白结合缝介导的。在下文描述的优选实施方案中,纤维片段包含异源偶联残基,用于纤维片段与五邻体基原体的共价连接。由于偶联残基需要对应部分,即可与其形成共价键的残基,因此进一步优选的是本发明第一方面的工程化蛋白的替代实施方案(vi),即至少一个异源偶联残基包含在五邻体基原体的腺病毒纤维蛋白结合缝中。偶联残基在结合缝和纤维蛋白片段中的定位,允许一旦纤维蛋白片段结合在五邻体基原体的缝中便形成共价键。
每个五邻体基原体通过高度保守的区域与一个腺病毒纤维蛋白相互作用,该高度保守的区域在本文中称为“五邻体基原体的腺病毒纤维蛋白结合缝”。这种相互作用用于间接地将另外的部分(优选多肽、药物或标记)连接到五邻体基原体上,并且当本发明的60个五邻体基原体组装时,在组装的VLP表面上呈现多达60个其它部分。因此,在第二方面,本发明涉及工程化多肽,其包含至少一个腺病毒纤维蛋白N端片段、基本上由至少一个腺病毒纤维蛋白N端片段组成或由至少一个腺病毒纤维蛋白N端片段组成,所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,以及:
(i)非腺病毒肽,和/或
(ii)与药物或标记共价或非共价偶联。
特异性结合五邻体基原体腺病毒纤维蛋白结合缝的至少一种腺病毒纤维蛋白N端片段包含在本发明第二方面的工程化多肽中,在整个说明书中也被称为STICKER。
令人惊讶的是,腺病毒纤维蛋白相对小的N端片段足以特异性地结合五邻体基原体。纤维片段越小,可以连接到五邻体基原体的部分越大。此外,腺病毒纤维片段长度的减少,降低了腺病毒纤维引发新的免疫应答的可能性和/或与VLP结合的纤维被预先存在的抗纤维抗体清除的可能性。因此,优选纤维片段具有50个连续氨基酸的长度或更少的N端纤维序列。更优选的是片段长度为40个氨基酸或更少,35个氨基酸或更少,30个氨基酸或更少,25个氨基酸或更少或20个氨基酸或更少。特异性结合五邻体基原体的结合缝所需的最小纤维氨基酸序列是F-N-P-V-Y-P-Y。该最小序列优选侧接其它腺病毒纤维,优选地两侧是Ad3氨基酸序列。该小片段可用于扩展VLP表面上的多功能性和/或数量或者暴露的表位。或者,向任何蛋白或表位序列添加STICKER标签使其能够与VLP表面结合。这通过含有STICKER的蛋白质与VLP的体外孵育或通过杆状病毒系统中两种组分的共表达来完成。
优选工程化多肽不包含与STICKER邻接的任何其它纤维氨基酸序列。更优选地,本发明第二方面的多肽不包含任何其它腺病毒蛋白或STICKER以外的多肽。
令人惊讶地发现,STICKER可以与N和/或C端连接,而不干扰其和五邻体基原体的结合。优选地,STICKER与非腺病毒多肽的N端连接。该多肽可以是希望将其连接到本发明VLP表面的任何多肽。与STICKER连接的多肽的大小没有特别限制。它可以是仍然允许特异性结合五邻体基原体纤维蛋白结合缝的任何尺寸。工程化多肽可进一步包含非腺病毒多肽和STICKER之间的肽接头。如果非腺病毒多肽的大小能够阻止60个这样的多肽通过STICKER与组装的VLP结合,则可能需要这样做。在连接至STICKER的N和/或C端被埋在多肽内的情况下,肽接头也可能是有利的。
大多数人群已经暴露于人Ad5,并且具有能够对人Ad5产生免疫应答的记忆B细胞。因此,如果基于人Ad5的原体和/或纤维包含在本发明第一和第二方面的工程化蛋白中,则所产生的VLP更可能被预先存在的免疫从循环中清除。因此,在优选的实施方案中,根据本发明的第一和/或第二方面的工程化多肽中包含的腺病毒蛋白分别基于来自人或非人大猿的腺病毒五邻体和纤维蛋白,优选地来自黑猩猩(Pan)腺病毒、大猩猩(Gorilla)腺病毒和猩猩(Pongo)腺病毒,更优选倭黑猩猩(Pan paniscus)和普通黑猩猩(Pan troglodytes)。
特别优选地,包含腺病毒五邻体基原体的工程化多肽和包含至少一个腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽分别基于腺病毒的五邻体和纤维蛋白,所述腺病毒选自WO 2005/071093和WO 2010/086189中描述的hAd3、hAd4、hAd5、hAd7、hAd11、hAd26、hAd35和hAd49、ChAd3、ChAd4、ChAd5、ChAd6、ChAd7、ChAd8、ChAd9、ChAd10、ChAd11、ChAd16、ChAd17、ChAd19、ChAd20、ChAd22、ChAd24、ChAd26、ChAd30、ChAd31、ChAd37、ChAd38、ChAd44、ChAd63和ChAd82、PanAd1、PanAd2、PanAd3、ChAd55、ChAd73、ChAd83、ChAd146和ChAd147。
本发明第一方面的工程化多肽优选基于SEQ ID NO:1至14的野生型五邻体基原体,即SEQ ID NO:1至14反映了根据上文概述的替代实施方案(i)至(vi)的修饰前的蛋白序列。本领域技术人员将理解,将靶标特异性结合结构域插入V-环、第一和/或第二RGD环将改变SEQ ID NO:1至14的该部分中的序列。同样,用偶联残基取代氨基酸也将改变氨基酸序列。
根据上述(i)和(ii)的修饰需要修饰RGD环和/或V环中的一个或两个。在本发明的工程化多肽的优选实施方案中,待修饰的区域由大多数腺病毒共有的一致序列来限定。因此,这些一致序列基于来自腺病毒物种的几个优选五邻体基原体氨基酸序列的比对,并且分别适合于确定五邻体基蛋白部分的N和C端,从而根据上述实施方案(i)或(ii)进行修饰。优选地,五邻体基原体内第一RGD环的N端限定如下:
X3-X4-X5-X6-X7-X8-X9-X10-X11(SEQ ID NO:15)
其中
X3选自D、E和N,并且优选是D;
X4选自V、L和I,并且优选是V;
X5是任何氨基酸,优选选自A、D、E、K、S和T,更优选T;
X6是任何氨基酸,优选选自A、D、E和K,更优选A;
X7选自F、Y和W,并且优选是Y;
X8选自A、D、E、N和Q,优选是E或者Q,并且更优选E;
X9是任何氨基酸,优选选自A、D、E、N和K,更优选E;
X10选自S或者T,并且优选是S;以及
X11是任何氨基酸,并构成所述第一RGD环的N端氨基酸;
和/或
以下序列限定所述五邻体基原体中的第一RGD环的C端以及第二RGD环的N端:
X12-X13-X14-X15-X16(SEQ ID NO:16)
其中
X12是任何氨基酸并构成所述第一RGD环的C端氨基酸;
X13是R;
X14是G;
X15是D;以及
X16是任何氨基酸和第二RGD环的N端氨基酸;
和/或
以下序列构成五邻体基原体中第二RGD环的C端:
X15-X16-X17-X18-X19-X20-X21-X22(SEQ ID NO:17);
其中
X17是任何氨基酸并构成第二RGD环的C端氨基酸;
X18选自I、L和V,并且优选是I;
X19选自D、E、K、N、Q和V,优选是Q或者K,并且更优选Q;
X20选自C、G和P,并且优选是P;
X21选自I、L和V,优选是L或者V,更优选L;
X22选自D、E、S和T,优选是E或者T,更优选E;
X23选自D、E、K、S和T,优选是E、K或者T,更优选K;以及
X24选自D和E,并且优选是D。
同样,以下序列限定五邻体基原体V环的N端:
X25-X26-X27-X28-X29-X30-X31-X32(SEQ ID NO:18),
其中
X25选自F、Y和W,并且优选是F;
X26选自H、K和R,并且优选是K;
X27选自A、V、I和L,并且优选是A;
X28选自H、K和R,并且优选是R;
X29选自A、V、I和L,并且优选是V;
X30选自A、V、I、L和M,并且优选是M;
X31选自A、V、I和L,并且优选是V;以及
X32是任何氨基酸,并构成所述V环的N端氨基酸;
和/或
以下序列限定V环的C端:
X33-X34-X35-X36-X37-X38-X39(SEQ ID NO:19)
其中
X33是任何氨基酸并构成所述V环的C端氨基酸;
X34选自F、Y和W,并且优选是Y;
X35选自D、E、S和T,优选是E或者T,更优选E;
X36选自F、Y和W,并且优选是W;
X37选自A、F、V、Y和W,优选是F或者V,更优选F;
X38选自D、E、S和T,优选D和E,更优选E;以及
X39选自F、Y和W,并且优选是F。
X32是N端氨基酸,X33是V环的C端氨基酸。V环的一个或更多个或所有氨基酸可以被插入的靶标特异性结合结构域和/或非腺病毒多肽取代。
上面已经阐述了与STICKER特异性结合的五邻体基原体的一部分是非连续的表位。因此,五邻体基原体中的一个或更多个以下非连续肽形成腺病毒纤维蛋白结合缝(粗体氨基酸直接与纤维相互作用)
M-T-I-D-L-M-N-N-A-I-X40-X41-X42-Y-L-X43-X44-G-R-Q-X45-G-V-L-E-S(SEQ IDNO:20);
W-D-P-X46-T-X47-X48-P-G(SEQ ID NO:46);
X49-V-X50-X51-Y-X52-X53(SEQ ID NO:47);
X54-X55-R-S-Y(SEQ II NO:48);和/或
L-T-X56-V-F-N-R-F-P-X57(SEQ ID NO:49)
其中
X40选自V、I和L;
X41选自E和D;
X42选自H、N和Q,优选地H和N;
X43选自K、E、R、Q和A;
X44选自V、L和I,优选地V和I;
X45选自H、N和Q,优选地H和N;
X46选自V、I、L、E或者D,优选地V和E;
X47选自V、L和I,优选地V和I;
X48选自M、T和S,优选地M和T;
X49选自D、E、N和Q,优选地D和N;
X50是任何氨基酸,优选选自A、D、P、K和T;
X51选自A、D、E、K和R,优选地A、E和K;
X52选自D、E、L、I、Q和N,优选地E、L和Q;
X53选自A、D、E、K、N、Q和R,优选地A、E、N和K;
X54选自K、R、S和T,优选地K、S和T;
X55选自A、D、E、G、K、N、Q、R、S和T,优选地D、G、K、N和S;
X56选自H、K和R,优选地H和R;以及
X57选自D和E。
在本发明的工程化多肽的优选实施方案中,X3至X10的氨基酸序列彼此独立地选自DVTAYEES(SEQ ID NO:21)、DVDAYENS(SEQ ID NO:22)、DVAEYEKS(SEQ ID NO:23)、DVEAYEKS(SEQ ID NO:24)、DVDAYEKS(SEQ ID NO:25)、DVSKYEAS(SEQ ID NO:26)、NVKAYEDS(SEQ IDNO:27)、DVKKYENS(SEQ ID NO:28)、DVDAYQAS(SEQ ID NO:29)和DVDAYQAS(SEQ ID NO:30),X18至X24的氨基酸序列选自IQPLEKD(SEQ ID NO:31)、IQPVEKD(SEQ ID NO:32)、IKPLEKD(SEQ ID NO:33)、IVPLTKD(SEQ ID NO:34)、IEPVETD(SEQ ID NO:35)和IKPLTED(SEQ IDNO:36),X25至X31的氨基酸序列选自FKARVMV(SEQ ID NO:37)、FRAKLMV(SEQ ID NO:38)和FRAKVMV(SEQ ID NO:39),X33至X39的氨基酸序列选自YEWFEF(SEQ ID NO:40)、YEWVEF(SEQID NO:41)和YEWAEF(SEQ ID NO:42)。
令人惊讶地发现,大的异源多肽可以插入和或取代第一和/或第二RGD环,而不破坏五邻体以及随后本发明VLP的组装。
在本发明的工程化多肽的优选实施方案中,第一RGD环的每个靶标特异性结合结构域彼此独立地具有5至300个氨基酸,优选地6至200个氨基酸之间的长度;第二RGD环的靶标特异性结合结构域具有5至300个氨基酸,优选地10至200个氨基酸之间的长度;和/或V环中的靶标特异性结合结构域具有5至300个氨基酸,优选地10至200个氨基酸之间的长度。
在一个替代方案中,靶标特异性结合结构域结合的靶标是存在于细胞表面上或细胞外基质中的部分。如果VLP靶向特定细胞类型以便递送其有效负载(如药物或标记),则选择靶标特异性结合结构域的特异性。在本发明的工程化多肽的替代优选实施方案中,至少一个靶标特异性结合结构域能够特异性结合免疫原性肽、病原体中和肽、病毒肽、细菌肽、免疫调节肽、癌症肽、结合细胞表面优选细胞受体、低分子量标签优选生物素或几丁质。这提供了将各种肽结合到VLP表面的替代和快速方式。
在本发明第一或第二方面的工程化多肽的优选实施方案中,非腺病毒多肽或插入或连接的多肽选自免疫原性肽、病原体中和肽、病毒肽、细菌肽、免疫调节肽和癌症肽。特别优选的是登革的病毒肽HAKKQDVVVLGSQEGAM(SEQ ID NO:55)、基孔肯雅的病毒肽STKDNFNVYKATRPYLAH(SEQ ID NO:56)和兹卡病毒的病毒肽STKDNFNVYKATRPLAH(SEQ IDNO:57)。包含STICKER和基孔肯雅肽的本发明第二方面的工程化多肽的实例是AKRARLSTSFNPVPYEDESSTKDNFNVYKATRPYLAH(SEQ ID NO:58)、AKRARLSTSFNPVPYEDECSSTKDNFNVYKATRPYLAH(SEQ ID NO:59)和AKRARLSTCFNPVPYEDESSTKDNFNVYKATRPYLAH(SEQ ID NO:60)。后两个实例包括偶联残基即Cys,与五邻体基原体纤维的结合缝中的相应偶联残基形成共价键。
靶标特异性结合结构域的优选实例是抗体、单链抗体、抗体片段、纳米抗体、轻链或重链、可变轻链或可变重链、双抗体或抗体模拟物。优选的抗体片段包含片段抗原结合(Fab)片段、Fab'片段、F(ab')2片段、重链抗体、单结构域抗体(sdAb)、单链可变片段(scFv)、可变片段(Fv)、VH结构域、VL结构域、单结构域抗体、纳米抗体、IgNAR(免疫球蛋白新抗原受体)、二-scFv、双特异性T细胞接合物(BITE)、双亲和重新靶向(DART)分子、三体、双抗体、单链双抗体、替代支架蛋白及其融合蛋白。
如果将非腺病毒肽或肽插入第一RGD环,它们优选地具有5至60个氨基酸的长度,优选6至45个氨基酸。如果将非腺病毒肽或肽插入第二RGD环中,它们可以具有5至50个氨基酸的长度,优选10至36个氨基酸。如果将非腺病毒肽或者肽插入第二V环中,它们具有5至30个氨基酸的长度,优选10至21个氨基酸。
在本发明第一或第二方面的工程化多肽的优选实施方案中,非腺病毒多肽或多肽包含蛋白酶切割位点,优选序列特异性内肽酶切割位点,更优选地TEV切割位点。这种TEV切割位点的优选实例是ENLYFQG(SEQ ID NO:60)。一旦组装成五邻体或VLP,这种切割位点允许切割本发明第一方面的多肽。一些抗原需要暴露自由的N和/或C端以引发免疫应答。因此,当五邻体蛋白或VLP已经组装,如果切割位点位于这种非腺病毒多肽的N端和/或C端,那么用蛋白酶对其进行处理将暴露这种抗原的N和/或C端序列。相当令人惊讶的是,本发明人发现这种切割不会破坏组装的五邻体或VLP。这在强抗原特异性免疫应答需要暴露抗原自由N和/或C端的情况下,是非常有用的。或者,切割位点可包含在本发明第一和/或第二方面的工程化多肽中,以促进工程化多肽的纯化,例如,切割位点可以放置在相应工程化多肽的N或C端,将包含部分工程化多肽的五邻体或纤维和亲和标签如生物素、几丁质结合蛋白、Myc-taq隔开。这种亲和标签允许工程化多肽固定在合适的亲和基质上,并从基质上释放纯化的工程化多肽。
在本发明第一或第二方面的工程化多肽的优选实施方案中,偶联残基选自Lys、Cys、Asp和Glu,优选地Cys。
在本发明第一或第二方面的工程化多肽的优选实施方案中,药物选自化学治疗药物、抗病原体药物、免疫调节药物和抗炎药物。
在本发明第二方面的工程化多肽的优选实施方案中,纤维蛋白片段包含、基本上由或由以下组成:
X58-F-N-P-V-Y-P-Y-X59(SEQ ID NO:43)
其中
X58选自S、D和T,优选S或者D,更优选S;以及
X59选自E、D和G,优选E或者D,更优选E。
优选地,纤维蛋白片段具有纤维的9至20个连续氨基酸的长度。
进一步优选,本发明第二方面的工程化多肽包含纤维蛋白片段的2、3、4、5、6、7或8个重复序列。多聚化增加了结合亲和力。本发明人已观察到,2个或3个优选连续的重复序列适合以亚纳摩尔的亲和力来介导与五邻体基原体上纤维结合缝的结合。优选地,多聚体以头对尾方向排列。
如上所述,根据替代实施方案(vi)优选五邻体基原体结合缝中包含一个或更多个偶联残基。为了促进五邻体基原体中这些一个或更多个偶联残基和本发明第二方面工程化多肽中所含的偶联残基之间形成共价键。在本发明第二方面的工程化多肽的优选实施方案中,将至少一个偶联残基插入和/或位于纤维蛋白片段的N和/或C端,优选地插入和/或位于SEQ ID NO:43的N和/或C端,或与纤维蛋白片段的氨基酸连接。如上所述,偶联残基必须与相应的偶联残基形成共价键。一旦两个多肽相互作用,优选一个多肽的偶联残基在空间上接近另一个多肽中的偶联残基。
在替代实施方案(vi)的优选实施方案中,偶联残基位于包含在本发明第一方面的工程化多肽中的五邻体基原体中,位于氨基酸位置476和/或477(参考SEQ IDNO:64的氨基酸序列)或另一种腺病毒五邻体基原体中类似的氨基酸位置。可以通过用标准比对工具(例如,CLUSTAL)将SEQ ID NO:64的序列与其它腺病毒五邻体基原体序列进行比对来确定另一种腺病毒五邻体基原体中类似的位置。技术人员可以容易地确定在另一种腺病毒五邻体蛋白中占据氨基酸476或477的类似位置的氨基酸。优选的是,根据本发明第一方面和根据替代实施方案(iv)的工程化蛋白包含序列:
KSFX64NXc1Xc2AVY(SEQ ID NO:68)
其中
X64选自Y和F,优选地Y;
Xc1选自D、E和偶联残基,优选地Cys;
Xc2选自L、Q和偶联残基,优选地Cys;
以及其中至少一个,优选Xc1和Xc2都是偶联残基,优选地Cys。
如果五邻体基原体中的偶联残基位于氨基酸位置476和/或477或另一种腺病毒五邻体基原体的类似氨基酸位置,则优选本发明第二方面的工程化多肽的相应偶联残基在多肽STICKER部分的C端包含偶联残基。偶联残基优选位于STICKER中,如下列序列所示:
X58-F-N-P-V-Y-P-Y-X59-(X63)n-Xc(SEQ ID NO:69)
其中
X58选自S、D和T,优选S或者D,更优选S;以及
X59选自E、D和G,优选E或者D,更优选E;
X63在每种情况下独立地是任何氨基酸,优选在这个或这些位置上天然存在于纤维蛋白中的那些;
Xc是偶联残基,优选C、D、E和K,最优选C;以及
n是0到10之间的整数,即0、1、2、3、4、5、6、7、8、9或10,优选1至5,更优选2。
因此,本发明第二方面的工程化蛋白在优选实施方案中包含根据SEQ ID NO:69的STICKER多肽中。可以包含在本发明第二方面工程化蛋白中特别优选的STICKER多肽是
A-K-R-A-R-L-S-T-X58-F-N-P-V-Y-P-Y-X59-D-E-Xc(SEQ ID NO:76)
其中
X58选自S、D和T,优选S或者D,更优选S;
X59选自E、D和G,优选E或者D,更优选E;以及
Xc是偶联残基,优选C、D、E和K,最优选C。
在特别优选的实施方案中,STICKER多肽在位置20处包含偶联残基Cys并且由以下氨基酸序列组成:
A-K-R-A-R-L-S-T-S-F-N-P-V-Y-P-Y-E-D-E-C(SEQ ID NO:77)。
在替代实施方案(vi)的另一个优选实施方案中,偶联残基位于本发明第一方面工程化多肽中包含的五邻体基原体中,位于根据SEQ ID NO:64的五邻体基原体的Lys376处或者另一种腺病毒的五邻体基原体的类似位置。优选地,第一方面的工程化蛋白包含以下序列:
Xc-X65-R-S-Y-N(SEQ ID NO:73)
其中
Xc是偶联残基,优选C、D、E和K,最优选C;以及
X65是任何氨基酸,优选选自D、E、G、K、N或S,更优选S或N。
如果偶联残基包含在该位置,优选本发明第二方面的工程化多肽包含以下氨基酸序列所示的相应偶联残基:
Xc-F-N-P-V-Y-P-Y-X59(SEQ ID NO:70)
其中
X59选自E、D和G,优选E或者D,更优选E;以及
Xc是偶联残基,优选C、D、E和K,最优选C。
因此,在优选实施方案中本发明第二方面的工程化蛋白包含根据SEQ ID NO:70的STICKER多肽。可以包含在本发明第二方面的工程化蛋白中特别优选的STICKER多肽是
A-K-R-A-R-L-S-T-Xc-F-N-P-V-Y-P-Y-X59-D-E-S(SEQ ID NO:74)
其中
Xc是偶联残基,优选C、D、E和K,最优选C;以及
X59选自E、D和G,优选E或者D,更优选E。
在特别优选的实施方案中,STICKER多肽在第9位包含偶联残基Cys并且由以下氨基酸序列组成:
A-K-R-A-R-L-S-T-C-F-N-P-V-Y-P-Y-E-D-E-S(SEQ ID NO:75)。
在本发明第一方面工程化多肽的一些实施方案中,期望定位在第一和第二RGD环之间的RGD基序是完整的,以有助于五邻体基原体、五邻体或VLP与患者中存在的某些细胞和细胞外结构的结合。或者,如果在本发明第一方面的工程化多肽的特定应用中不需要这种靶向,则可以突变RGD基序使得其丧失与整联蛋白结合的能力。
在第三方面中,本发明涉及编码本发明第一方面的工程化多肽和/或本发明第二方面的工程化多肽的核酸。
在第四方面中,本发明涉及包含本发明核酸的表达载体。表达载体包含质粒以及病毒载体,并且含有编码本发明第一和/或第二方面工程化蛋白的编码序列、以及在特定宿主生物体(例如细菌、酵母、植物、昆虫或哺乳动物)或体外表达系统中表达可操作连接的编码序列所需的适当DNA序列。克隆载体通常用于工程化和放大某些所需DNA片段,可能缺乏表达所需DNA片段时需要的功能序列。
本领域中注意到,针对快速改变抗原性表位的疾病(如流感)、或特征在于患者特异性表位混合的疾病进行免疫接种,需要疫苗的快速适应或个体化。本发明的VLP可以快速适于呈现各自所需的抗原。因此,在第五方面本发明涉及克隆载体,所述载体适于将核酸区段快速插入第一和/或第二RGD环或V环中,其编码一种或多种所需抗原。本发明的这个方面的克隆载体包含:
(i)多肽,其包含腺病毒五邻体基原体,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环和/或腺病毒纤维蛋白的结合位点,适用于将编码非腺病毒肽的核酸引入编码所述第一RGD环,第二RGD环和/或可变环的核酸;或者
(ii)多肽,其包含腺病毒五邻体基原体结合纤维蛋白片段,适用于在C和/或N端引入编码非腺病毒肽的核酸。
在本发明克隆载体的优选实施方案中,适合(adaptation)包括一个或更多个限制性酶位点,优选BamHI、KpnI、KasI、NarI、SfdI、EcoRI和RsrII、PfoI、BssHII、SalI、SacI、XbaI、BstEII和HindIII。这种克隆载体的优选实例的核酸序列提供在SEQ ID NO:61和62中。这些载体的结构称为pACEBac-ADDOmer1.0和pACEBac-ADDOmer2.0,在图7和8中提供。包含优选基孔肯雅病毒抗原表位的克隆载体pACEBac-ADDOmer2.0的序列在SEQ ID NO:71和72中提供。
在第六方面中,本发明涉及包含本发明的表达载体或本发明的克隆载体的重组宿主细胞。本发明的表达载体或本发明的克隆载体可以在宿主细胞内以(i)自由分散、或(ii)整合到宿主细胞基因组或线粒体DNA中的方式存在。重组宿主细胞用于表达本发明的工程化多肽。术语“重组宿主细胞”包括已经用本发明的多核苷酸或重组载体转化、转染或感染的原始细胞的后代。重组宿主细胞可以是细菌细胞,例如大肠杆菌细胞、酵母细胞如酿酒酵母(Saccharomyces cerevisiae)或毕赤酵母(Pichia pastoris)、植物细胞、昆虫细胞如SF9或Hi5细胞、或哺乳动物细胞。哺乳动物细胞的优选实例是中国仓鼠卵巢(CHO)细胞、非洲绿猴肾(COS)细胞、人胚肾(HEK293)细胞、HELA细胞等。
尽管与相应的野生型五邻体基原体相比,根据替代实施方案(i)至(vi)对本发明第一方面的工程化多肽进行修饰,但它们能够组装成五邻体亚基,即形成五聚体。可以通过本领域技术人员熟知的方法轻易地评价本发明第一方面的给定工程化蛋白是否组装成五聚体,所述方法包括非变性聚丙烯酰胺凝胶电泳、尺寸排阻色谱、质谱等。因此,在第七方面中,本发明涉及包含五个工程化多肽的五聚体,所述五个工程化多肽包含本发明的腺病毒五邻体基原体。该五聚体可另外包含1至个本发明第二方面的工程化多肽。
由本发明第一方面的工程化多肽组装的五聚体还能够组装成VLP。因此,在第八方面,本发明涉及包含12个本发明的五聚体的病毒样颗粒(VLP)。VLP是稳定的,并且是用于向患者施用的最合适的组合物。优选地,VLP在非还原条件下组装和/或储存,以允许在五邻体基原体中的偶联残基之间形成共价键。
在优选的实施方案中,本发明的VLP进一步包含至少一个本发明第二方面的工程化多肽,优选多达60个本发明第二方面的工程化多肽。在后一实施方案中,本发明第一方面的工程化多肽的五邻体基蛋白的所有纤维蛋白结合缝都被本发明第二方面的工程化蛋白占据。优选的是,本发明的VLP包含本发明第一方面的工程化蛋白和本发明第二方面的工程化蛋白,所述第一方面的工程化蛋白包含根据备选方案(vi)的修饰,优选与备选方案(i)、(ii)、(iii)、(iv)和/或(v)的修饰组合,所述第二方面的工程化蛋白包含至少一个偶联残基,优选至少一个插入和/或位于纤维蛋白片段N和/或C端的偶联残基,优选地插入和/或位于SEQID NO:43的N和/或C端,或与纤维蛋白片段的氨基酸连接。优选地,本发明第一方面的工程化蛋白包含KSFX64NXc1Xc2AVY(SEQ ID NO:68),其中X64、Xc1和Xc2具有上述含义,本发明第二方面的工程化蛋白包含X58-F-N-P-V-Y-P-Y-X59-(X63)n-Xc(SEQ ID NO:69),其中X58、X59、X63、Xc和n具有上述含义。在替代优选实施方案中,本发明第一方面的工程化蛋白包含以下序列Xc-X65-R-S-Y-N(SEQ ID NO:73),其中Xc和X65具有上述含义,本发明第二方面的工程化蛋白包含Xc-F-N-P-V-Y-P-Y-X59(SEQ ID NO:70),其中Xc和X59具有上述含义。
优选地,VLP包含将本发明第一方面的工程化多肽与本发明第二方面的工程化多肽共价偶联的偶联残基,所述VLP在非还原条件下组装和/或储存,以允许在五邻体基原体中的偶联残基与本发明第二方面的工程化多肽中包含的STICKER多肽之间形成共价键。
还设想,由野生型五邻体基原体组成或包含野生型五邻体基原体的VLP用于提供载体,并且通过使用本发明第二方面的工程化多肽,用不同的非腺病毒多肽进行修饰。在优选的实施方案中由于本发明第二方面的工程化多肽具有较短的长度,因此,例如在不到一天的时间内通过固相化学进行合成。因此,在第九方面中,本发明涉及包含12个五聚体的VLP,每个五聚体包含五个腺病毒五邻体基原体和至少一个本发明第二方面的工程化多肽。优选的是,五邻体基原体的所有纤维蛋白结合缝都被占据,因此这些VLP包含60个本发明第二方面的工程化多肽。
在第十方面中,本发明涉及生产本发明第一或第二方面工程化多肽的方法,包括步骤:
(a)提供本发明的重组宿主细胞;
(b)表达工程化多肽;和
(c)纯化工程化多肽。
在第十一方面中,用于生产本发明VLP的方法包括本发明第十方面的方法的步骤和允许工程化多肽组装成VLP的进一步步骤。
本发明第十方面的方法还包括VLP和蛋白酶(优选序列特异性内肽酶切割位点,更优选TEV)孵育的步骤。
在第十二方面中,本发明涉及一种用于生产本发明的VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供本发明的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码腺病毒五邻体基原体的第一RGD环、第二RGD环和/或可变环的核酸中,和/或在编码工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段;
(d)在宿主细胞中,任选地与所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽一起,表达工程化的腺病毒五邻体基原体;以及
(e)纯化所述VLP,其任选地包含腺病毒五邻体基原体结合纤维蛋白片段,或者所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽。
在第十三方面中,本发明涉及一种用于生产本发明VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供本发明的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段;
(d)在宿主细胞中,任选地与腺病毒五邻体基原体一起,表达包含腺病毒五邻体基原体结合纤维蛋白片段的工程化的多肽;以及
(e1)纯化所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽,并且与本发明的腺病毒五邻体基原体或者工程化的腺病毒五邻体基原体混合;或者
(e2)在所述腺病毒五邻体基原体共表达的情况下,纯化所述VLP。
在第十四方面中,本发明涉及一种用于生产本发明VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(b)合成本发明的工程化多肽,所述工程化多肽包含腺病毒五邻体基原体结合纤维蛋白片段以及至少一个所述非腺病毒肽;以及
(c)将所述工程化多肽与本发明的腺病毒五邻体基原体,或与工程化腺病毒五邻体基原体混合,与本发明的五聚体或与本发明的VLP混合。
在第十五方面中,本发明涉及一种VLP,其是通过本发明生产VLP的方法所生产的。
在第十六方面中,本发明涉及一种药物组合物,其包含:含有本发明腺病毒五邻体基原体的工程化多肽和/或含有本发明腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽、编码一个或更多个本发明工程化蛋白的核酸、本发明的表达载体、或本发明的VLP,以及药学上可接受的载体和/或合适的赋形剂。优选,这种组合物是药物组合物。在优选的实施方案中,药物组合物还包含药学上可接受的载体和/或赋形剂以及任选一种或更多种其它活性物质。优选地,第五方面的组合物含有治疗有效量的化合物,优选纯化形式的化合物,连同适量的载体和/或赋形剂一起,以便为患者提供适当的施用形式。制剂应该适合施用方式。
药物组合物可以采取溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉末、缓释制剂等形式。药物组合物可以配制成栓剂,使用传统的粘合剂和载体如甘油三酯。
为了制备本发明的药物组合物,药学上可接受的载体可以是固体或液体。固体形式的组合物包括粉末、片剂、丸剂、胶囊、锭剂、扁囊剂、栓剂和可分散的颗粒。固体赋形剂可以是一种或多种物质,其也可以作为稀释剂、调味剂、粘合剂、防腐剂、片剂崩解剂、或包封材料。在粉末中,赋形剂优选是细碎的固体,其与本发明细碎的抑制剂混合。在片剂中,将活性成分与具有必要粘合性能的载体以合适的比例混合,并压制成所需的形状和大小。合适的赋形剂是碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。为了制备栓剂,首先熔化低熔点蜡,例如脂肪酸甘油酯或可可脂的混合物,并通过搅拌将活性组分均匀地分散在其中。然后将熔融的均匀混合物倒入方便大小的模具中,使其冷却,从而使其固化。片剂、粉剂、胶囊剂、丸剂、扁囊剂和锭剂可用作适于口服施用的固体剂型。
液体形式的组合物包括溶液、悬浮液和乳液例如水、盐溶液、葡萄糖水溶液、甘油溶液或水/丙二醇溶液。用于肠胃外注射(例如静脉内、动脉内、骨内输注、肌肉内、皮下、腹膜内、皮内和鞘内注射),液体制剂可以在溶液中,例如聚乙二醇水溶液中配制。当药物组合物静脉内施用时,盐溶液是优选的载体。
优选地,药物组合物是单位剂型。在这种形式中,组合物可以细分为含有适量活性成分的单位剂量。单位剂型可以是包装的组合物,该包装含有离散量的组合物,例如包装的片剂、胶囊和小瓶或安瓿中的粉末。此外,单位剂型可以是胶囊、注射小瓶、片剂、扁囊剂或锭剂本身,或者它可以是适当数量的包装形式中任何这些。
如果需要,组合物还可以含有少量润湿剂或乳化剂、或pH缓冲剂。
此外,这种药物组合物还可以包含其它药理学活性物质,例如但不限于佐剂和/或其它活性成分。本发明上下文中的佐剂包括但不限于无机佐剂、有机佐剂、油基佐剂、细胞因子、微粒佐剂、病毒体、细菌佐剂、合成佐剂或合成多核苷酸佐剂。
在第十七方面中,本发明涉及包含本发明腺病毒五邻体基原体的工程化多肽和/或包含腺病毒五邻体基原体结合纤维蛋白片段的本发明的工程化多肽、编码一个或更多个本发明工程化蛋白的核酸、本发明的表达载体、或本发明的VLP用于治疗和/或预防感染性疾病、免疫疾病或癌症。
实施例
设计并以极高的产率(数十克/升表达培养物)生产ADDomer。建立了通用三步方案将ADDomer纯化至均质水平(homogeneity)(见下文)。在概念验证项目中,通过实验确定可以将高免疫原性基孔肯雅表位插入ADDomer的官能化环中,而不会扰乱颗粒形成或显着降低产率。将含有基孔肯雅表位的ADDomer纯化至均质,开始基于细胞和动物的研究以确定其作为候选疫苗的效力。通过一系列技术验证(包括电子显微镜),证明ADDomer为均匀结构的离散多聚体(十二面体)。进行半胱氨酸-二硫化物化学,以进一步增加ADDomer已经显著的热稳定性(消除冷链要求)。此外,制备ADDomer,其不仅包含肽表位,而且还包含含有高亲和力结合物(纳米抗体DARPin、抗体片段)的蛋白结构域和整个蛋白,并且正在大规模建立制造这些的有效方案。由最近出现的兹卡病毒引发,设计基于ADDomer的兹卡疫苗候选物,并且ADDomer也可能同时对抗不止一种疾病(组合疫苗)。进行基于细胞和动物的实验以验证这些。
在下文中,描述了实验和方案以产生和验证ADDomer VLP和ADDomer VLP疫苗。
1.ADDomer设计
通过X射线晶体学确定天然存在的十二聚体种类的原子结构(例如源于腺病毒Ad3血清型)(Szolajska E等,PLoS One.2012;7(9):e46075和Zubieta C等,Mol.Cell 2005:17(1):121-35)。仔细检查原子结构揭示了延伸环结构的存在。更确切地说,野生型十二面体中一个可变环(命名为V-环)和所谓RGD环中的两个区域被确定为功能化的潜在位点。十二面体原体数量的比较揭示,无论在长度还是序列组成方面,V-环和两个RGD-环区在整个物种之间的广泛可变性,强调了它们的潜力。利用这些信息,我们设计了从头DNA序列,其编码合成设计的十二面体启动子(promoter)。通过引入代表内切核酸酶切割位点的DNA序列来应用BioBrick设计(Shetty等人,J.Biol.End.2008),以促进代表V环和两个RGD环区域(RGD环2、RGD环2)氨基酸的设计变异(甚至随机化)。反复优化原体设计,直到鉴定出可以产生重组十二面体(ADDomer)的原体,其特征在于上述环区域完整的BioBrick设计,同时维持了野生型人Ad3血清型十二面体的高溶解度和结构完整性。
2.工程化超稳定的ADDomer
ADDomer已经具有显著的热稳定性,可以在37℃下长时间储存,这表明在基础设施较差的偏远地区不需要冷链。检查天然Ad3颗粒的晶体坐标揭示了所谓的“链交换”区域,其中原体的区段延伸到相邻原体的附近,导致位于允许共价键形成的距离内的氨基酸的并置。我们用半胱氨酸遗传取代ADDomer中的这些氨基酸,使得两个来自不同原体的半胱氨酸的每一个都在二硫键形成所需的距离内。
3.基于MultiBac的ADDomer表达
接下来,使用MultiBac系统表达ADDomer。编码ADDomer的基因从头开始(fromscratch)合成(SEQ ID NO:63以及编码的ADDomer在SEQ ID NO:64中提供),并通过经典克隆方法(限制/连接)插入到pACEBac(一种MultiBac系统的转移质粒)中。MultiBac由发明人之一(Berger)开发,专门用于生产复杂的生物制品,如ADDomer。制备含有ADDomer基因的复合MultiBac病毒(参见图7和8),并按照先前描述的方案感染昆虫细胞培养物(Berger I等人,J Vis Exp(2013)(77):e50159和Fitzgerald DJ等Nat Methods(2006)3(12):1021)。如所述通过离心制备含ADDomer蛋白的细胞沉淀。将细胞沉淀储存在-80度。表达插入肽或蛋白表位的ADDomer,以及表达高度稳定的ADDomer,其均产生相当的、非常高的产率和均匀结构的十二面体颗粒。
3.中和表位
构建了基于ADDomer-CHIKADDomer的VLP疫苗候选物的实例,其呈递主要中和基孔肯雅免疫表位HAKKQDVVVLGSQEGAM(SEQ ID NO:55)的多个拷贝。主要的中和免疫表位是基孔肯雅包膜蛋白的一部分,其是位于极N端的线性肽表位(Kam YW等,EMBO Mol Med(2012);4(4):330-4)。在绝大多数患者血清中,发现了与该线性肽表位发生反应的抗体。ADDomer提供了以受约束的方式(N和C端共价连接至ADDomer支架)、或以不受约束的方式(通过用特定蛋白酶切割释放N端)、或者受约束或不受约束表位的组合来呈递线性表位的方法,同时保持ADDomer支架的结构完整性。使用的优选排列如下:
AKRARLSTSFNPVPYEDESSTKDNFNVYKATRPYLAH(SEQ ID NO:58)、AKRARLSTSFNPVPYEDECSSTKDNFNVYKATRPYLAH(SEQ ID NO:59)以及AKRARLSTCFNPVPYEDESSTKDNFNVYKATRPYLAH(SEQ ID NO:60)。通过TEV蛋白酶介导的ADDomer切割实现基孔肯雅主要中和表位的天然样呈现,所述ADDomer呈现表位的多个拷贝,每个拷贝在中和表位序列之前含有特定TEV切割位点,保留了天然N端。类似的方法可用于ADDomer展示的任何表位或肽或蛋白结构域。
4.ADDomer和变体的纯化
通过冻融裂解草地贪夜蛾(Spodoptera frugiperda)Sf21昆虫细胞沉淀。按照昆虫细胞的标准方案通过离心澄清裂解物(Berger I等人,J Vis Exp(2013)(77):e50159和Fitzgerald DJ等Nat Methods 2006,3(12):1021)。将澄清的上清液加载到15-40%蔗糖梯度上,用Beckman SW41转子过夜离心,从梯度顶部收集1.1mL的级分,并加载到变性的SDS聚丙烯酰胺凝胶上(SDS-PAGE)用于分析蛋白含量并鉴定含有ADDomer的级分,以便用于合并。然后在透析掉蔗糖后进行尺寸排阻色谱(SEC)和/或离子交换(IEX)。
5.通过电子显微镜验证ADDomer
纯化的ADDomer和ADDomer变体通过负染色电子显微镜(EM)观察它们以评估它们的组装状态和它们的结构完整性。采用标准云母碳制剂与约为0.1mg/ml浓度的ADDomer,然后沉积在支撑材料上。样本用1%(wt/vol)硅钨酸钠(pH7.0)染色,并在JEOL电子显微镜上在100kV下可视化。记录图像,并使用Gatan提供的软件进行分析。
对于热稳定性实验,将ADDomer冷冻、在4℃、室温(RT)或37℃下储存一周。电子显微镜显示在室温或37℃下储存导致正确的自动组装的颗粒,证明其热稳定性。在45℃下ADDomer(SEQ ID NO:64)孵育2小时,导致可逆的颗粒解离,其在转回室温时重新组装。通过热移位测定也观察到这种可逆解离(图10,见箭头),但仅在温度高于50℃时才看到不可逆的解离。
6.设计动物(鼠)实验用于评估ADDomer免疫原性
对于ADDomer-CHIK基孔肯雅ADDomer VLP疫苗候选物的鼠免疫分析,使用6周龄BALB/c雌性小鼠。每次8只小鼠的四组被指定免疫接种ADDomer种类(例如,在基孔肯雅VLP疫苗候选物的情况下:i)ADDomer、ii)ADDomer CHIK不受约束的表位、iii)ADDomer CHIK受约束的表位、iv)交联至KLH的分离CHIK主要中和肽表位,作为阳性对照)。以2周的间隔给每只动物注射10μg ADDomer和ADDomer变体。通过ELISA从小鼠血清中滴定IgA、IgM、总IgG、IgG1IgG2a和抗CHIK抗体。以类似的方式设计其它ADDomer VLP疫苗候选物的免疫分析。测试ADDomer表面上的两种表位展示(受约束的和自由的,见下文:第7点)。观察到时间依赖性反应(第0周至第6周)。对于引发抗Chik表位应答而言,自由形式的表位表现出优于受约束形式的优越潜力(图12)。
7.ADDomer表面上暴露感兴趣的表位
在感兴趣的表位上游添加TEV切割位点使其能够以两种不同的构型展示:受约束或自由的。纯化后,表位自然地限制在ADDomer环中。通过在室温下加入TEV(烟草蚀纹病毒)蛋白酶(1/100w:w)持续2H,可以释放出表位,并在支架表面以线性形式展示。通过SDS-PAGE可以容易地监测切割效率。值得注意的是,整个ADDomer支架不受该切割的影响(图11)。
8.ADDomer中表位延伸的插入能力
评估了ADDomer携带大表位序列的能力。为此,将200个氨基酸长度的人工表位插入ADDomer(命名为延伸的ADDomer)中。这产生正确自动组装的ADDomer。通过SDS-PAGE分析和质谱确认插入,如图13所示。
9.ADDomer表面上表位的共价连接
为了拓宽ADDomer潜力,开发了能够在ADDomer上添加额外表位的系统。在ADDomer序列的特定位置(K363C或Q476C或A477C)插入单个半胱氨酸。设计K363C以便和20个氨基酸长度的纤维蛋白片段(源自SEQ ID NO:59的肽C20(SEQ ID NO:77))形成共价二硫键,而设计Q476C或A477C以便与另一个纤维蛋白片段(源自SEQ ID NO 60的肽C9(SEQ ID NO:75))进行相同的操作。通过在氧化条件(即不存在β-巯基乙醇)或还原条件(添加β-巯基乙醇)下,将颗粒与其相应的肽一起孵育,来检查肽与其相应的Cys修饰的ADDomer的共价相互作用。复合物在SDS-PAGE上运行,通过特异性抗体以及Cy3标记的第二抗体检测ADDomer,而用Alexa488标记的抗生物素蛋白检测生物素化肽。当使用正确的Cys-ADDomer/肽时,在ADDomer条带大小处检测到肽的存在(图14中的圈)。因为在还原条件下防止了相互作用,因此这种相互作用是Cys-ADDomer和肽之间产生的二硫键所特异的。
在本发明涉及以下方面:
1.一种工程化多肽,其包含腺病毒五邻体基原体,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环(V环)、腺病毒纤维蛋白结合缝和/或N端结构域,并且包含以下的一个或更多个:
(i)在所述第一、第二、或者第一和第二RGD环和/或所述V环中至少一个靶标特异性结合结构域;和/或
(ii)在所述第一、第二、或者第一和第二RGD环和/或所述V环中的一个或更多个非腺病毒肽;和/或
(iii)五邻体基原体N和/或C端的非腺病毒肽;和/或
(iv)在所述第一、第二、或者第一和第二RGD环、V环中和/或在五邻体基原体N端结构域中的至少一个异源偶联残基,其中所述五邻体基原体中N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,以及
X2选自D和E;和/或
(v)药物、标记或者多肽,其共价或非共价偶联至所述第一、第二、或者第一和第二RGD环的一个或更多个氨基酸和/或五邻体基原体V环的一个或更多个氨基酸;和/或
(vi)在所述五邻体基原体的腺病毒纤维蛋白结合缝中的至少一个异源偶联残基,
以及,优选地,其中所述工程化多肽能够组装成VLP。
2.一种工程化多肽,其包含至少一个腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,以及:
(i)非腺病毒肽,和/或
(ii)与药物或者标记共价或非共价偶联。
3.根据项目1或2所述的工程化多肽,其中所述腺病毒是人或非人大猿腺病毒,优选地黑猩猩(Pan)、大猩猩(Gorilla)和猩猩(Pongo),更优选倭黑猩猩(Pan paniscus)和普通黑猩猩(Pan troglodytes)。
4.根据项目3所述的工程化多肽,其中所述腺病毒选自:hAd3、hAd4、hAd5、hAd7、hAd11、hAd26、hAd35和hAd49、ChAd3、ChAd4、ChAd5、ChAd6、ChAd7、ChAd8、ChAd9、ChAd10、ChAd11、ChAd16、ChAd17、ChAd19、ChAd20、ChAd22、ChAd24、ChAd26、ChAd30、ChAd31、ChAd37、ChAd38、ChAd44、ChAd63和ChAd82、PanAd1、PanAd2、PanAd3、ChAd55、ChAd73、ChAd83、ChAd146和ChAd147。
5.根据项目1或3或4所述的工程化多肽,其中所述工程化多肽所基于的野生型五邻体基原体的序列选自SEQ ID NO:1至14。
6.根据项目1或3至5所述的工程化多肽,其中以下序列限定所述五邻体基原体中第一RGD环的N端:
X3-X4-X5-X6-X7-X8-X9-X10-X11(SEQ ID NO:15)
其中
X3选自D、E和N,并且优选是D;
X4选自V、L和I,并且优选是V;
X5是任何氨基酸,优选选自A、D、E、K、S和T,更优选T;
X6是任何氨基酸,优选选自A、D、E和K,更优选A;
X7选自F、Y和W,并且优选是Y;
X8选自A、D、E、N和Q,优选是E或者Q,并且更优选E;
X9是任何氨基酸,优选选自A、D、E、N和K,更优选E;
X10选自S或者T,并且优选是S;以及
X11是任何氨基酸,并构成所述第一RGD环的N端氨基酸;
和/或
以下序列限定所述五邻体基原体中的所述第一RGD环的C端和所述第二RGD环的N端:
X12-X13-X14-X15-X16(SEQ ID NO:16)
其中
X12是任何氨基酸并构成所述第一RGD环的C端氨基酸;
X13是R;
X14是G;
X15是D;以及
X16是任何氨基酸并构成所述第二RGD环的N端氨基酸;
和/或
以下序列限定五邻体基原体中第二RGD环的C端:
X17-X18-X19-X20-X21-X22-X23-X24(SEQ ID NO:17);
其中
X17是任何氨基酸并构成所述第二RGD环的C端氨基酸;
X18选自I、L和V,并且优选是I;
X19选自D、E、K、N、Q和V,优选是Q或者K,并且更优选Q;
X20选自C、G和P,并且优选是P;
X21选自I、L和V,优选是L或者V,更优选L;
X22选自D、E、S和T,优选是E或者T,更优选E;
X23选自D、E、K、S和T,优选是E、K或者T,更优选K;以及
X24选自D和E,并且优选是D;
和/或
以下序列限定V环的N端:
X25-X26-X27-X28-X29-X30-X31-X32(SEQ ID NO:18),
其中
X25选自F、Y和W,并且优选是F;
X26选自H、K和R,并且优选是K;
X27选自A、V、I和L,并且优选是A;
X28选自H、K和R,并且优选是R;
X29选自A、V、I和L,并且优选是V;
X30选自A、V、I、L和M,并且优选是M;
X31选自A、V、I和L,并且优选是V;以及
X32是任何氨基酸,并构成所述V环的N端氨基酸;
和/或
以下序列限定所述V环的C端:
X33-X34-X35-X36-X37-X38-X39(SEQ ID NO:19)
其中
X33是任何氨基酸并构成所述V环的C端氨基酸;
X34选自F、Y和W,并且优选是Y;
X35选自D、E、S和T,优选是E或者T,更优选E;
X36选自F、Y和W,并且优选是W;
X37选自A、F、V、Y和W,优选是F或者V,更优选F;
X38选自D、E、S和T,优选是D或者E,更优选E;以及
X39选自F、Y和W,并且优选是F;
和/或,五邻体基原体中的一个或更多个以下非连续肽形成腺病毒纤维蛋白结合缝(粗体氨基酸直接与纤维相互作用)
M-T-I-D-L-M-N-N-A-I-X40-X41-X42-Y-L-X43-X44-G-R-Q-X45-G-V-L-E-S(SEQ IDNO:20);
W-D-P-X46-T-X47-X48-P-G(SEQ ID NO:46);
X49-V-X50-X51-Y-X52-X53(SEQ ID NO:47);
X54-X55-R-S-Y(SEQ II NO:48);和/或
L-T-X56-V-F-N-R-F-P-X57(SEQ ID NO:49)
其中
X40选自V、I和L;
X41选自E和D;
X42选自H、N和Q,优选地H和N;
X43选自K、E、R、Q和A;
X44选自V、L和I,优选地V和I;
X45选自H、N和Q,优选地H和N;
X46选自V、I、L、E或者D,优选地V和E;
X47选自V、L和I,优选地V和I;
X48选自M、T和S,优选地M和T;
X49选自D、E、N和Q,优选地D和N;
X50是任何氨基酸,优选选自A、D、P、K和T;
X51选自A、D、E、K和R,优选地A、E和K;
X52选自D、E、L、I、Q和N,优选地E、L和Q;
X53选自A、D、E、K、N、Q和R,优选地A、E、N和K;
X54选自K、R、S和T,优选地K、S和T;
X55选自A、D、E、G、K、N、Q、R、S和T,优选地D、G、K、N和S;
X56选自H、K和R,优选地H和R;以及
X57选自D和E。
7.根据项目6所述的工程化多肽,其中X3至X10的氨基酸序列彼此独立地选自:DVTAYEES(SEQ ID NO:21)、DVDAYENS(SEQ ID NO:22)、DVAEYEKS(SEQ ID NO:23)、DVEAYEKS(SEQ ID NO:24)、DVDAYEKS(SEQ ID NO:25)、DVSKYEAS(SEQ ID NO:26)、NVKAYEDS(SEQ IDNO:27)、DVKKYENS(SEQ ID NO:28)、DVDAYQAS(SEQ ID NO:29)和DVDAYQAS(SEQ ID NO:30),X18至X24的氨基酸序列选自:IQPLEKD(SEQ ID NO:31)、IQPVEKD(SEQ ID NO:32)、IKPLEKD(SEQ ID NO:33)、IVPLTKD(SEQ ID NO:34)、IEPVETD(SEQ ID NO:35)和IKPLTED(SEQ IDNO:36),X25至X31的氨基酸序列选自:FKARVMV(SEQ ID NO:37)、FRAKLMV(SEQ ID NO:38)和FRAKVMV(SEQ ID NO:39),X33至X39的氨基酸序列选自YEWFEF(SEQ ID NO:40)、YEWVEF(SEQID NO:41)和YEWAEF(SEQ ID NO:42)。
8.根据项目1或3至7任一项所述的工程化多肽,其中所述第一RGD环的靶标特异性结合结构域彼此独立地具有5至300个氨基酸,优选地6至200个氨基酸之间的长度;第二RGD环的靶标特异性结合结构域具有5至300个氨基酸,优选地10至200个氨基酸之间的长度;和/或V环中的靶标特异性结合结构域具有5至300个氨基酸,优选地10至200个氨基酸之间的长度。
9.根据项目1或3至8任一项所述的工程化多肽,其中至少一个靶标特异性结合结构域能够特异性结合免疫原性肽、病原体中和肽、病毒肽、细菌肽、免疫调节肽、癌症肽、细胞表面优选细胞受体、低分子量标签优选生物素或几丁质。
10.根据项目1至9任一项所述的工程化多肽,其中所述非腺病毒多肽或多肽选自免疫原性肽、病原体中和肽、病毒肽、细菌肽、免疫调节肽和癌症肽。
11.根据项目10任一项所述的工程化多肽,其中所述非腺病毒肽或肽包含蛋白酶切割位点,优选序列特异性内肽酶切割位点,更优选烟草蚀纹病毒NIa蛋白酶(TEV)。
12.根据项目1至11任一项所述的工程化多肽,其中所述偶联残基选自Lys、Cys、Asp和Glu,优选地Cys。
13.根据项目1至12任一项所述的工程化多肽,其中所述药物选自化学治疗药物、抗病原体药物、免疫调节药物和抗炎药物。
14.根据项目2所述的工程化多肽,其中所述纤维蛋白片段包含:
X58-F-N-P-V-Y-P-Y-X59(SEQ ID NO:43)
其中
X58选自S、D和T,优选S或者D,更优选S;以及
X59选自E、D和G,优选E或者D,更优选E。
15.根据项目14所述的工程化多肽,其中所述纤维蛋白片段具有9至20个氨基酸的长度。
16.根据项目2和14或15所述的工程化多肽,其中至少一个偶联残基插入和/或位于所述纤维蛋白片段的N和/或C端,优选地插入和/或位于SEQ ID NO:43的N和/或C端,或与所述纤维蛋白片段的氨基酸连接。
17.一种核酸,其编码项目1至16中任一项所述的多肽。
18.一种表达载体,其包含项目17所述的核酸。
19.一种克隆载体,其编码:
(i)多肽,其包含腺病毒五邻体基原体,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环和/或腺病毒纤维蛋白的结合位点,适合用于将编码非腺病毒肽的核酸引入编码所述第一RGD环,第二RGD环和/或可变环的核酸;或者
(ii)多肽,其包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,适合用于在C和/或N端引入编码非腺病毒肽的核酸。
20.根据项目19所述的克隆载体,其中所述的适合包括一个或更多个限制性酶位点,优选BamHI、KpnI、KasI、NarI、SfdI、EcoRI和RsrII、PfoI、BssHII、SalI、SacI、XbaI、BstEII和HindIII。
21.一种重组宿主细胞,其包含项目18所述的表达载体或项目19或20所述的克隆载体。
22.一种五聚体,其包含五个工程化多肽,所述工程化多肽包含项目1、3至13所述的腺病毒五邻体基原体。
23.一种病毒样颗粒(VLP),其包含12个项目22所述的五聚体。
24.根据项目23所述的VLP,其还包含项目2至4和10至16所述的至少一个工程化多肽,所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝。
25.根据项目24所述的VLP,其在氨基酸残基中还包含至少一个Cys突变,如G51C、S555C、G53C、Y64C、S54C、D114C。
26.一种VLP,其包含12个五聚体,各五聚体包含五个腺病毒五邻体基原体以及至少一个项目2至4和10至16所述的工程化多肽,所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝。
27.一种用于生产项目1至16中任一项所述的工程化多肽的方法,其包括步骤:
(a)提供项目21所述的重组宿主细胞;
(b)表达所述工程化多肽;以及
(c)纯化所述工程化多肽。
28.一种用于生产项目23至26任一项所述VLP的方法,其包括项目27所述方法的步骤,以及允许所述工程化多肽组装成VLP的进一步步骤。
29.根据项目28所述的方法,还包括VLP和蛋白酶孵育的步骤,优选和序列特异性内肽酶切割位点孵育,更优选和TEV孵育。
30.一种用于生产项目23至26中任一项所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供项目19和/或20所述的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码所述腺病毒五邻体基原体的第一RGD环、第二RGD环和/或可变环的核酸中,和/或插入编码所述工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;
(d)在宿主细胞中,任选地与所述包含腺病毒纤维蛋白N端片段的工程化多肽一起,表达所述工程化的腺病毒五邻体基原体,其中所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(e)纯化所述VLP,其任选地包含腺病毒五邻体基原体结合纤维蛋白片段,或者包含腺病毒五邻体基原体结合纤维蛋白片段的所述工程化多肽。
31.一种用于生产项目23至26任一项所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供项目20所述的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;
(d)在宿主细胞中,任选地与腺病毒五邻体基原体一起,表达所述包含腺病毒纤维蛋白N端片段的工程化多肽,所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(e1)纯化所述包含腺病毒纤维蛋白N端片段的工程化多肽,腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,并且与项目1或3至13所述的腺病毒五邻体基原体或者工程化腺病毒五邻体基原体混合;或者
(e2)在所述腺病毒五邻体基原体共表达的情况下,纯化所述VLP。
32.一种用于生产项目23至26任一项所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(b)合成项目2至4和10至16任一项所述的工程化多肽,所述工程化多肽包含腺病毒纤维蛋白N端片段以及至少一个所述非腺病毒肽,其中所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(c)将所述工程化多肽与项目1或3至10任一项所述的腺病毒五邻体基原体,或与工程化腺病毒五邻体基原体混合,与项目18所述的五聚体或与项目19所述的VLP混合。
33.一种VLP,其是通过项目28至32中任一项所述的方法生产的。
34.一种药物组合物,其包含项目1至16中任一项所述的工程化多肽、项目17所述的核酸、项目18所述的表达载体、或项目23至26或33中任一项所述的VLP,以及药学上可接受的载体和/或合适的赋形剂。
35.项目1至16中任一项所述的工程化多肽、项目17所述的核酸、项目18所述的表达载体、或项目23至26或33中任一项所述的VLP用于治疗和/或预防感染性疾病、免疫疾病或癌症。
序列表
<110> 欧洲分子生物学实验室
<120> 腺病毒外壳蛋白衍生递送载体
<130> 492-56 PCT
<150> EP 16163372.2
<151> 2016-03-31
<160> 78
<170> PatentIn version 3.5
<210> 1
<211> 544
<212> PRT
<213> 腺病毒类型B 3
<400> 1
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Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr
405 410 415
Thr Ser Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro
420 425 430
Asp Met Met Lys Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Ser
435 440 445
Asn Tyr Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser
450 455 460
Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Ser Thr
465 470 475 480
Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Ile
485 490 495
Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala
500 505 510
Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val
515 520 525
Gln Arg Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val
530 535 540
Tyr Lys Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr
545 550 555 560
Phe
<210> 4
<211> 535
<212> PRT
<213> 腺病毒类型E 4
<400> 4
Met Met Arg Arg Ala Tyr Pro Glu Gly Pro Pro Pro Ser Tyr Glu Ser
1 5 10 15
Val Met Gln Gln Ala Met Ala Ala Ala Ala Ala Ile Gln Pro Pro Leu
20 25 30
Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Ala Pro Thr Glu Gly Arg
35 40 45
Asn Ser Ile Arg Tyr Ser Glu Leu Thr Pro Leu Tyr Asp Thr Thr Arg
50 55 60
Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu Asn Tyr
65 70 75 80
Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn Asn Asp
85 90 95
Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn Phe Asp Glu Arg
100 105 110
Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His Thr Asn Met Pro
115 120 125
Asn Val Asn Gln Phe Met Tyr Ser Asn Lys Phe Lys Ala Arg Val Met
130 135 140
Val Ser Arg Lys Thr Pro Asn Gly Val Thr Val Gly Asp Asn Tyr Asp
145 150 155 160
Gly Ser Gln Asp Glu Leu Lys Tyr Glu Trp Val Glu Phe Glu Leu Pro
165 170 175
Glu Gly Asn Phe Ser Val Thr Met Thr Ile Asp Leu Met Asn Asn Ala
180 185 190
Ile Ile Asp Asn Tyr Leu Ala Val Gly Arg Gln Asn Gly Val Leu Glu
195 200 205
Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp
210 215 220
Asp Pro Val Thr Glu Leu Val Met Pro Gly Val Tyr Thr Asn Glu Ala
225 230 235 240
Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr
245 250 255
Glu Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro Phe
260 265 270
Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu Asp Gly Gly Asn Ile
275 280 285
Pro Ala Leu Leu Asp Val Glu Ala Tyr Glu Lys Ser Lys Glu Glu Ser
290 295 300
Val Ala Ala Ala Thr Thr Ala Val Ala Thr Ala Ser Thr Glu Val Arg
305 310 315 320
Asp Asp Asn Phe Ala Ser Ala Ala Ala Val Ala Ala Val Lys Ala Asp
325 330 335
Glu Thr Lys Ser Lys Ile Val Ile Gln Pro Val Glu Lys Asp Ser Lys
340 345 350
Glu Arg Ser Tyr Asn Val Leu Ser Asp Lys Lys Asn Thr Ala Tyr Arg
355 360 365
Ser Trp Tyr Leu Ala Tyr Asn Tyr Gly Asp Arg Asp Lys Gly Val Arg
370 375 380
Ser Trp Thr Leu Leu Thr Thr Ser Asp Val Thr Cys Gly Val Glu Gln
385 390 395 400
Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr Phe Arg
405 410 415
Ser Thr His Gln Val Ser Asn Tyr Pro Val Val Gly Ala Glu Leu Leu
420 425 430
Pro Val Tyr Ser Lys Ser Phe Phe Asn Glu Gln Ala Val Tyr Ser Gln
435 440 445
Gln Leu Arg Ala Phe Thr Ser Leu Thr His Val Phe Asn Arg Phe Pro
450 455 460
Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val
465 470 475 480
Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg
485 490 495
Ser Ser Ile Arg Gly Val Gln Arg Val Thr Val Thr Asp Ala Arg Arg
500 505 510
Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Ile Val Ala Pro Arg
515 520 525
Val Leu Ser Ser Arg Thr Phe
530 535
<210> 5
<211> 571
<212> PRT
<213> 腺病毒类型C 5
<400> 5
Met Arg Arg Ala Ala Met Tyr Glu Glu Gly Pro Pro Pro Ser Tyr Glu
1 5 10 15
Ser Val Val Ser Ala Ala Pro Val Ala Ala Ala Leu Gly Ser Pro Phe
20 25 30
Asp Ala Pro Leu Asp Pro Pro Phe Val Pro Pro Arg Tyr Leu Arg Pro
35 40 45
Thr Gly Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Phe
50 55 60
Asp Thr Thr Arg Val Tyr Leu Val Asp Asn Lys Ser Thr Asp Val Ala
65 70 75 80
Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Ile
85 90 95
Gln Asn Asn Asp Tyr Ser Pro Gly Glu Ala Ser Thr Gln Thr Ile Asn
100 105 110
Leu Asp Asp Arg Ser His Trp Gly Gly Asp Leu Lys Thr Ile Leu His
115 120 125
Thr Asn Met Pro Asn Val Asn Glu Phe Met Phe Thr Asn Lys Phe Lys
130 135 140
Ala Arg Val Met Val Ser Arg Leu Pro Thr Lys Asp Asn Gln Val Glu
145 150 155 160
Leu Lys Tyr Glu Trp Val Glu Phe Thr Leu Pro Glu Gly Asn Tyr Ser
165 170 175
Glu Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Val Glu His Tyr
180 185 190
Leu Lys Val Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val
195 200 205
Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Phe Asp Pro Val Thr Gly
210 215 220
Leu Val Met Pro Gly Val Tyr Thr Asn Glu Ala Phe His Pro Asp Ile
225 230 235 240
Ile Leu Leu Pro Gly Cys Gly Val Asp Phe Thr His Ser Arg Leu Ser
245 250 255
Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro Phe Gln Glu Gly Phe Arg
260 265 270
Ile Thr Tyr Asp Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp
275 280 285
Val Asp Ala Tyr Gln Ala Ser Leu Lys Asp Asp Thr Glu Gln Gly Gly
290 295 300
Gly Gly Ala Gly Gly Ser Asn Ser Ser Gly Ser Gly Ala Glu Glu Asn
305 310 315 320
Ser Asn Ala Ala Ala Ala Ala Met Gln Pro Val Glu Asp Met Asn Asp
325 330 335
His Ala Ile Arg Gly Asp Thr Phe Ala Thr Arg Ala Glu Glu Lys Arg
340 345 350
Ala Glu Ala Glu Ala Ala Ala Glu Ala Ala Ala Pro Ala Ala Gln Pro
355 360 365
Glu Val Glu Lys Pro Gln Lys Lys Pro Val Ile Lys Pro Leu Thr Glu
370 375 380
Asp Ser Lys Lys Arg Ser Tyr Asn Leu Ile Ser Asn Asp Ser Thr Phe
385 390 395 400
Thr Gln Tyr Arg Ser Trp Tyr Leu Ala Tyr Asn Tyr Gly Asp Pro Gln
405 410 415
Thr Gly Ile Arg Ser Trp Thr Leu Leu Cys Thr Pro Asp Val Thr Cys
420 425 430
Gly Ser Glu Gln Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro
435 440 445
Val Thr Phe Arg Ser Thr Arg Gln Ile Ser Asn Phe Pro Val Val Gly
450 455 460
Ala Glu Leu Leu Pro Val His Ser Lys Ser Phe Tyr Asn Asp Gln Ala
465 470 475 480
Val Tyr Ser Gln Leu Ile Arg Gln Phe Thr Ser Leu Thr His Val Phe
485 490 495
Asn Arg Phe Pro Glu Asn Gln Ile Leu Ala Arg Pro Pro Ala Pro Thr
500 505 510
Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr
515 520 525
Leu Pro Leu Arg Asn Ser Ile Gly Gly Val Gln Arg Val Thr Ile Thr
530 535 540
Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Ile
545 550 555 560
Val Ser Pro Arg Val Leu Ser Ser Arg Thr Phe
565 570
<210> 6
<211> 532
<212> PRT
<213> 腺病毒类型Y25
<400> 6
Met Met Arg Arg Ala Tyr Pro Glu Gly Pro Pro Pro Ser Tyr Glu Ser
1 5 10 15
Val Met Gln Gln Ala Met Ala Ala Ala Ala Ala Met Gln Pro Pro Leu
20 25 30
Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Ala Pro Thr Glu Gly Arg
35 40 45
Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr Thr Arg
50 55 60
Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu Asn Tyr
65 70 75 80
Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn Asn Asp
85 90 95
Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn Phe Asp Glu Arg
100 105 110
Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His Thr Asn Met Pro
115 120 125
Asn Val Asn Glu Phe Met Tyr Ser Asn Lys Phe Lys Ala Arg Val Met
130 135 140
Val Ser Arg Lys Thr Pro Asn Gly Val Thr Val Thr Asp Gly Ser Gln
145 150 155 160
Asp Ile Leu Glu Tyr Glu Trp Val Glu Phe Glu Leu Pro Glu Gly Asn
165 170 175
Phe Ser Val Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp
180 185 190
Asn Tyr Leu Ala Val Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile
195 200 205
Gly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Val
210 215 220
Thr Glu Leu Val Met Pro Gly Val Tyr Thr Asn Glu Ala Phe His Pro
225 230 235 240
Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser Arg
245 250 255
Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro Phe Gln Glu Gly
260 265 270
Phe Gln Ile Met Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu
275 280 285
Leu Asp Val Asp Ala Tyr Glu Lys Ser Lys Glu Glu Ser Ala Ala Ala
290 295 300
Ala Thr Ala Ala Val Ala Thr Ala Ser Thr Glu Val Arg Gly Asp Asn
305 310 315 320
Phe Ala Ser Pro Ala Ala Val Ala Ala Ala Glu Ala Ala Glu Thr Glu
325 330 335
Ser Lys Ile Val Ile Gln Pro Val Glu Lys Asp Ser Lys Asp Arg Ser
340 345 350
Tyr Asn Val Leu Pro Asp Lys Ile Asn Thr Ala Tyr Arg Ser Trp Tyr
355 360 365
Leu Ala Tyr Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr
370 375 380
Leu Leu Thr Thr Ser Asp Val Thr Cys Gly Val Glu Gln Val Tyr Trp
385 390 395 400
Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg
405 410 415
Gln Val Ser Asn Tyr Pro Val Val Gly Ala Glu Leu Leu Pro Val Tyr
420 425 430
Ser Lys Ser Phe Phe Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg
435 440 445
Ala Phe Thr Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln
450 455 460
Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn
465 470 475 480
Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile
485 490 495
Arg Gly Val Gln Arg Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys
500 505 510
Pro Tyr Val Tyr Lys Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser
515 520 525
Ser Arg Thr Phe
530
<210> 7
<211> 575
<212> PRT
<213> 腺病毒类型B 7
<400> 7
Met Met Arg Arg Ala Val Leu Gly Gly Ala Val Val Tyr Pro Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Ser Val Met Gln Gln Gln Ala Ala Ala Val
20 25 30
Met Gln Pro Ser Leu Glu Ala Pro Phe Val Pro Pro Arg Tyr Leu Ala
35 40 45
Pro Thr Glu Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Gln
50 55 60
Tyr Asp Thr Thr Arg Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile
65 70 75 80
Ala Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val
85 90 95
Val Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile
100 105 110
Asn Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met
115 120 125
His Thr Asn Met Pro Asn Val Asn Glu Tyr Met Phe Ser Asn Lys Phe
130 135 140
Lys Ala Arg Val Met Val Ser Arg Glu Ala Ser Lys Ile Asp Ser Glu
145 150 155 160
Lys Asn Asp Arg Ser Lys Asp Thr Leu Lys Tyr Glu Trp Phe Glu Phe
165 170 175
Thr Leu Pro Glu Gly Asn Phe Ser Ala Thr Met Thr Ile Asp Leu Met
180 185 190
Asn Asn Ala Ile Ile Asp Asn Tyr Leu Ala Val Gly Arg Gln Asn Gly
195 200 205
Val Leu Gln Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg
210 215 220
Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val Tyr Thr
225 230 235 240
Tyr Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro Asp Cys Gly Val
245 250 255
Asp Phe Thr Glu Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg
260 265 270
His Pro Phe Gln Glu Gly Phe Lys Ile Met Tyr Glu Asp Leu Glu Gly
275 280 285
Gly Asn Ile Pro Ala Leu Leu Asp Val Ala Glu Tyr Glu Lys Ser Lys
290 295 300
Lys Glu Ile Ala Ser Ser Thr Thr Thr Thr Ala Val Thr Thr Val Ala
305 310 315 320
Arg Asn Val Ala Asp Thr Ser Val Glu Ala Val Ala Val Ala Val Val
325 330 335
Asp Thr Ile Lys Ala Glu Asn Asp Ser Ala Val Arg Gly Asp Asn Phe
340 345 350
Gln Ser Lys Asn Asp Met Lys Ala Ser Glu Glu Val Thr Val Val Pro
355 360 365
Val Ser Pro Pro Thr Val Thr Glu Thr Glu Thr Lys Glu Pro Thr Ile
370 375 380
Lys Pro Leu Glu Lys Asp Thr Lys Asp Arg Ser Tyr Asn Val Ile Ser
385 390 395 400
Gly Thr Asn Asp Thr Ala Tyr Arg Ser Trp Tyr Leu Ala Tyr Asn Tyr
405 410 415
Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr Thr Ser
420 425 430
Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro Asp Met
435 440 445
Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Ser Asn Tyr
450 455 460
Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser Phe Tyr
465 470 475 480
Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Thr Thr Ser Leu
485 490 495
Thr His Ile Phe Asp Arg Phe Pro Glu Asn Gln Ile Leu Ile Arg Pro
500 505 510
Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
515 520 525
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val Gln Arg
530 535 540
Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys
545 550 555 560
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
565 570 575
<210> 8
<211> 503
<212> PRT
<213> 腺病毒类型52
<400> 8
Met Arg Arg Ala Val Arg Val Thr Pro Ala Ala Tyr Glu Gly Pro Pro
1 5 10 15
Pro Ser Tyr Glu Ser Val Met Gly Ser Ala Asn Val Pro Ala Thr Leu
20 25 30
Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Gly Pro Thr Glu Gly Arg
35 40 45
Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr Thr Lys
50 55 60
Val Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu Asn Tyr
65 70 75 80
Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn Asn Asp
85 90 95
Phe Thr Pro Thr Glu Ala Gly Thr Gln Thr Ile Asn Phe Asp Glu Arg
100 105 110
Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Leu His Thr Asn Met Pro
115 120 125
Asn Ile Asn Glu Phe Met Ser Thr Asn Lys Phe Arg Ala Arg Leu Met
130 135 140
Val Lys Lys Val Glu Asn Gln Pro Pro Glu Tyr Glu Trp Phe Glu Phe
145 150 155 160
Thr Ile Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp Leu Met
165 170 175
Asn Asn Ala Ile Val Asp Asn Tyr Leu Gln Val Gly Arg Gln Asn Gly
180 185 190
Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg
195 200 205
Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val Tyr Thr
210 215 220
Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val
225 230 235 240
Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg
245 250 255
Arg Pro Phe Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu Glu Gly
260 265 270
Gly Asn Ile Pro Ala Leu Leu Asp Val Thr Lys Tyr Glu Gln Ser Val
275 280 285
Gln Arg Ala Lys Ala Glu Gly Arg Glu Ile Arg Gly Asp Thr Phe Ala
290 295 300
Val Ser Pro Gln Asp Leu Val Ile Glu Pro Leu Glu His Asp Ser Lys
305 310 315 320
Asn Arg Ser Tyr Asn Leu Leu Pro Asn Lys Thr Asp Thr Ala Tyr Arg
325 330 335
Ser Trp Phe Leu Ala Tyr Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg
340 345 350
Ser Trp Thr Ile Leu Thr Thr Thr Asp Val Thr Cys Gly Ser Gln Gln
355 360 365
Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr Phe Arg
370 375 380
Pro Ser Thr Gln Val Ser Asn Phe Pro Val Val Gly Thr Glu Leu Leu
385 390 395 400
Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln
405 410 415
Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val Phe Asn Arg Phe Pro
420 425 430
Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val
435 440 445
Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg
450 455 460
Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile Thr Asp Ala Arg Arg
465 470 475 480
Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Val Val Ala Pro Lys
485 490 495
Val Leu Ser Ser Arg Thr Phe
500
<210> 9
<211> 504
<212> PRT
<213> 腺病毒类型53
<400> 9
Met Arg Arg Ala Val Arg Val Thr Pro Ala Val Tyr Ala Glu Gly Pro
1 5 10 15
Pro Pro Ser Tyr Glu Ser Val Met Gly Ser Ala Asn Val Pro Ala Thr
20 25 30
Leu Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Gly Pro Thr Glu Gly
35 40 45
Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr Thr
50 55 60
Lys Val Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu Asn
65 70 75 80
Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn Asn
85 90 95
Asp Phe Thr Pro Thr Glu Ala Gly Thr Gln Thr Ile Asn Phe Asp Glu
100 105 110
Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Leu His Thr Asn Met
115 120 125
Pro Asn Ile Asn Glu Phe Met Ser Thr Asn Lys Phe Arg Ala Arg Leu
130 135 140
Met Val Glu Lys Thr Ser Gly Gln Pro Pro Lys Tyr Glu Trp Phe Glu
145 150 155 160
Phe Thr Ile Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp Leu
165 170 175
Met Asn Asn Ala Ile Val Asp Asn Tyr Leu Gln Val Gly Arg Gln Asn
180 185 190
Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe
195 200 205
Arg Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val Tyr
210 215 220
Thr Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly
225 230 235 240
Val Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys
245 250 255
Arg Arg Pro Phe Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu Glu
260 265 270
Gly Gly Asn Ile Pro Gly Leu Leu Asp Val Pro Ala Tyr Glu Gln Ser
275 280 285
Leu Gln Gln Ala Gln Glu Glu Gly Arg Val Thr Arg Gly Asp Thr Phe
290 295 300
Ala Thr Ala Pro Asn Glu Val Val Ile Lys Pro Leu Leu Lys Asp Ser
305 310 315 320
Lys Asp Arg Ser Tyr Asn Ile Ile Thr Asp Thr Thr Asp Thr Leu Tyr
325 330 335
Arg Ser Trp Phe Leu Ala Tyr Asn Tyr Gly Asp Pro Glu Asn Gly Val
340 345 350
Arg Ser Trp Thr Ile Leu Thr Thr Thr Asp Val Thr Cys Gly Ser Gln
355 360 365
Gln Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr Phe
370 375 380
Arg Pro Ser Thr Gln Val Ser Asn Phe Pro Val Val Gly Thr Glu Leu
385 390 395 400
Leu Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr Ser
405 410 415
Gln Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val Phe Asn Arg Phe
420 425 430
Pro Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr
435 440 445
Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu
450 455 460
Arg Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile Thr Asp Ala Arg
465 470 475 480
Arg Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Val Val Ala Pro
485 490 495
Lys Val Leu Ser Ser Arg Thr Phe
500
<210> 10
<211> 505
<212> PRT
<213> 腺病毒类型51
<400> 10
Met Arg Arg Ala Val Arg Val Thr Pro Ala Ala Tyr Glu Gly Pro Pro
1 5 10 15
Pro Ser Tyr Glu Ser Val Met Gly Ser Ala Asn Val Pro Ala Thr Leu
20 25 30
Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Gly Pro Thr Glu Gly Arg
35 40 45
Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr Thr Lys
50 55 60
Val Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu Asn Tyr
65 70 75 80
Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn Asn Asp
85 90 95
Phe Thr Pro Thr Glu Ala Gly Thr Gln Thr Ile Asn Phe Asp Glu Arg
100 105 110
Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Leu His Thr Asn Met Pro
115 120 125
Asn Ile Asn Glu Phe Met Ser Thr Asn Lys Phe Arg Ala Lys Leu Met
130 135 140
Val Glu Lys Ser Asn Ala Glu Thr Arg Gln Pro Arg Tyr Glu Trp Phe
145 150 155 160
Glu Phe Thr Ile Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp
165 170 175
Leu Met Asn Asn Ala Ile Val Asp Asn Tyr Leu Gln Val Gly Arg Gln
180 185 190
Asn Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn
195 200 205
Phe Arg Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val
210 215 220
Tyr Thr Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys
225 230 235 240
Gly Val Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg
245 250 255
Lys Arg Arg Pro Phe Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu
260 265 270
Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp Val Ser Lys Tyr Glu Ala
275 280 285
Ser Ile Gln Arg Ala Lys Ala Glu Gly Arg Glu Ile Arg Gly Asp Thr
290 295 300
Phe Ala Val Ala Pro Gln Asp Leu Glu Ile Val Pro Leu Thr Lys Asp
305 310 315 320
Ser Lys Asp Arg Ser Tyr Asn Ile Ile Asn Asn Thr Thr Asp Thr Leu
325 330 335
Tyr Arg Ser Trp Phe Leu Ala Tyr Asn Tyr Gly Asp Pro Glu Lys Gly
340 345 350
Val Arg Ser Trp Thr Ile Leu Thr Thr Thr Asp Val Thr Cys Gly Ser
355 360 365
Gln Gln Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr
370 375 380
Phe Arg Pro Ser Thr Gln Val Ser Asn Phe Pro Val Val Gly Thr Glu
385 390 395 400
Leu Leu Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr
405 410 415
Ser Gln Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val Phe Asn Arg
420 425 430
Phe Pro Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr
435 440 445
Thr Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro
450 455 460
Leu Arg Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile Thr Asp Ala
465 470 475 480
Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Val Val Ala
485 490 495
Pro Lys Val Leu Ser Ser Arg Thr Phe
500 505
<210> 11
<211> 508
<212> PRT
<213> 腺病毒类型18
<400> 11
Met Arg Arg Ala Val Gly Val Pro Pro Val Met Ala Tyr Ala Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Thr Val Met Gly Ala Ala Asp Ser Pro Ala
20 25 30
Thr Leu Glu Ala Leu Tyr Val Pro Pro Arg Tyr Leu Gly Pro Thr Glu
35 40 45
Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr
50 55 60
Thr Arg Val Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu
65 70 75 80
Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn
85 90 95
Asn Asp Phe Thr Pro Val Glu Ala Gly Thr Gln Thr Ile Asn Phe Asp
100 105 110
Glu Arg Ser Arg Trp Gly Gly Asp Leu Lys Thr Ile Leu Arg Thr Asn
115 120 125
Met Pro Asn Ile Asn Glu Phe Met Ser Thr Asn Lys Phe Arg Ala Arg
130 135 140
Leu Met Val Glu Lys Val Asn Lys Glu Thr Asn Ala Pro Arg Tyr Glu
145 150 155 160
Trp Phe Glu Phe Thr Leu Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr
165 170 175
Ile Asp Leu Met Asn Asn Ala Ile Val Asp Asn Tyr Leu Glu Val Gly
180 185 190
Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr
195 200 205
Arg Asn Phe Arg Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro
210 215 220
Gly Val Tyr Thr Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro
225 230 235 240
Gly Cys Gly Val Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu Leu Gly
245 250 255
Ile Arg Lys Arg Met Pro Phe Gln Ala Gly Phe Gln Ile Met Tyr Glu
260 265 270
Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp Val Ala Lys Tyr
275 280 285
Glu Ala Ser Ile Gln Lys Ala Arg Glu Gln Gly Gln Glu Ile Arg Gly
290 295 300
Asp Asn Phe Thr Val Ile Pro Arg Asp Val Glu Ile Val Pro Val Glu
305 310 315 320
Lys Asp Ser Lys Asp Arg Ser Tyr Asn Leu Leu Pro Gly Asp Gln Thr
325 330 335
Asn Thr Ala Tyr Arg Ser Trp Phe Leu Ala Tyr Asn Tyr Gly Asp Pro
340 345 350
Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr Thr Thr Asp Val Thr
355 360 365
Cys Gly Ser Gln Gln Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp
370 375 380
Pro Val Thr Phe Arg Pro Ser Ser Gln Val Ser Asn Tyr Pro Val Val
385 390 395 400
Gly Val Glu Leu Leu Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln
405 410 415
Ala Val Tyr Ser Gln Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val
420 425 430
Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro
435 440 445
Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly
450 455 460
Thr Leu Pro Leu Arg Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile
465 470 475 480
Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val His Lys Ala Leu Gly
485 490 495
Ile Val Ala Pro Lys Val Leu Ser Ser Arg Thr Phe
500 505
<210> 12
<211> 511
<212> PRT
<213> 腺病毒类型49
<400> 12
Met Arg Arg Ala Val Pro Ala Ala Ala Ile Pro Ala Thr Val Ala Tyr
1 5 10 15
Ala Asp Pro Pro Pro Ser Tyr Glu Ser Val Met Ala Gly Val Pro Ala
20 25 30
Thr Leu Glu Ala Pro Tyr Val Pro Pro Arg Tyr Leu Gly Pro Thr Glu
35 40 45
Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr
50 55 60
Thr Arg Val Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu
65 70 75 80
Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn
85 90 95
Asn Asp Phe Thr Pro Val Glu Ala Gly Thr Gln Thr Ile Asn Phe Asp
100 105 110
Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Leu His Thr Asn
115 120 125
Met Pro Asn Val Asn Glu Phe Met Phe Thr Asn Ser Phe Arg Ala Lys
130 135 140
Val Met Val Ser Arg Lys Gln Asn Glu Glu Gly Gln Thr Glu Leu Glu
145 150 155 160
Tyr Glu Trp Val Glu Phe Val Leu Pro Glu Gly Asn Tyr Ser Glu Thr
165 170 175
Met Thr Leu Asp Leu Met Asn Asn Ala Ile Val Asp His Tyr Leu Leu
180 185 190
Val Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe
195 200 205
Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Val Thr Lys Leu Val
210 215 220
Met Pro Gly Val Tyr Thr Asn Glu Ala Phe His Pro Asp Val Val Leu
225 230 235 240
Leu Pro Gly Cys Gly Val Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu
245 250 255
Leu Gly Ile Arg Lys Arg Gln Pro Phe Gln Glu Gly Phe Arg Ile Met
260 265 270
Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asn Val Lys
275 280 285
Ala Tyr Glu Asp Ser Ile Ala Ala Ala Met Arg Lys His Asn Leu Pro
290 295 300
Leu Arg Gly Asp Val Phe Ala Val Gln Pro Gln Glu Ile Val Ile Gln
305 310 315 320
Pro Val Glu Lys Asp Gly Lys Glu Arg Ser Tyr Asn Leu Leu Pro Asp
325 330 335
Asp Lys Asn Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ala Tyr Asn Tyr
340 345 350
Gly Asp Pro Leu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr Thr Pro
355 360 365
Asp Val Thr Cys Gly Ser Glu Gln Val Tyr Trp Ser Leu Pro Asp Leu
370 375 380
Met Gln Asp Pro Val Thr Phe Arg Pro Ser Ser Gln Val Ser Asn Tyr
385 390 395 400
Pro Val Val Gly Ala Glu Leu Leu Pro Leu Gln Ala Lys Ser Phe Tyr
405 410 415
Asn Glu Gln Ala Val Tyr Ser Gln Leu Ile Arg Gln Ser Thr Ala Leu
420 425 430
Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Val Arg Pro
435 440 445
Pro Ala Ala Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
450 455 460
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Ser Gly Val Gln Arg
465 470 475 480
Val Thr Ile Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys
485 490 495
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
500 505 510
<210> 13
<211> 512
<212> PRT
<213> 腺病毒类型20
<400> 13
Met Arg Arg Ala Val Ala Ile Pro Ser Ala Ala Val Ala Leu Gly Pro
1 5 10 15
Pro Pro Ser Tyr Glu Ser Val Met Ala Ser Ala Asn Leu Gln Ala Pro
20 25 30
Leu Glu Asn Pro Tyr Val Pro Pro Arg Tyr Leu Glu Pro Thr Gly Gly
35 40 45
Arg Asn Ser Ile Arg Tyr Ser Glu Leu Thr Pro Leu Tyr Asp Thr Thr
50 55 60
Arg Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala Thr Leu Asn
65 70 75 80
Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Ser Val Val Gln Asn Ser
85 90 95
Asp Tyr Thr Pro Ala Glu Ala Ser Thr Gln Thr Ile Asn Leu Asp Asp
100 105 110
Arg Ser Arg Trp Gly Gly Asp Leu Lys Thr Ile Leu His Thr Asn Met
115 120 125
Pro Asn Val Asn Glu Phe Met Phe Thr Asn Ser Phe Arg Ala Lys Leu
130 135 140
Met Val Ala His Glu Thr Asn Lys Asp Pro Val Tyr Lys Trp Val Glu
145 150 155 160
Leu Thr Leu Pro Glu Gly Asn Phe Ser Glu Thr Met Thr Ile Asp Leu
165 170 175
Met Asn Asn Ala Ile Val Asp His Tyr Leu Ala Val Gly Arg Gln Asn
180 185 190
Gly Val Lys Glu Ser Glu Ile Gly Val Lys Phe Asp Thr Arg Asn Phe
195 200 205
Arg Leu Gly Trp Asp Pro Gln Thr Glu Leu Val Met Pro Gly Val Tyr
210 215 220
Thr Asn Glu Ala Phe His Pro Asp Val Val Leu Leu Pro Gly Cys Gly
225 230 235 240
Val Asp Phe Thr Tyr Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys
245 250 255
Arg Met Pro Phe Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu Val
260 265 270
Gly Gly Asn Ile Pro Ala Leu Leu Asp Val Pro Ala Tyr Glu Ala Ser
275 280 285
Ile Thr Thr Val Ala Ala Lys Glu Val Arg Gly Asp Asn Phe Glu Ala
290 295 300
Ala Ala Ala Ala Ala Ala Thr Gly Ala Gln Pro Gln Ala Ala Pro Val
305 310 315 320
Val Arg Pro Val Thr Gln Asp Ser Lys Gly Arg Ser Tyr Asn Ile Ile
325 330 335
Thr Gly Thr Asn Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ala Tyr Asn
340 345 350
Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr Thr
355 360 365
Pro Asp Val Thr Cys Gly Ser Glu Gln Val Tyr Trp Ser Met Pro Asp
370 375 380
Met Tyr Val Asp Pro Val Thr Phe Arg Ser Ser Gln Gln Val Ser Ser
385 390 395 400
Tyr Pro Val Val Gly Ala Glu Leu Leu Pro Ile His Ser Lys Ser Phe
405 410 415
Tyr Asn Glu Gln Ala Val Tyr Ser Gln Leu Ile Arg Gln Gln Thr Ala
420 425 430
Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Val Arg
435 440 445
Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu
450 455 460
Thr Asp His Gly Thr Leu Pro Leu Gln Asn Ser Ile Arg Gly Val Gln
465 470 475 480
Arg Val Thr Ile Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr
485 490 495
Lys Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
500 505 510
<210> 14
<211> 497
<212> PRT
<213> 腺病毒类型12
<400> 14
Met Arg Arg Ala Val Glu Leu Gln Thr Val Ala Phe Pro Glu Thr Pro
1 5 10 15
Pro Pro Ser Tyr Glu Thr Val Met Ala Ala Ala Pro Pro Tyr Val Pro
20 25 30
Pro Arg Tyr Leu Gly Pro Thr Glu Gly Arg Asn Ser Ile Arg Tyr Ser
35 40 45
Glu Leu Ser Pro Leu Tyr Asp Thr Thr Arg Val Tyr Leu Val Asp Asn
50 55 60
Lys Ser Ser Asp Ile Ala Ser Leu Asn Tyr Gln Asn Asp His Ser Asn
65 70 75 80
Phe Leu Thr Thr Val Val Gln Asn Asn Asp Tyr Ser Pro Ile Glu Ala
85 90 95
Gly Thr Gln Thr Ile Asn Phe Asp Glu Arg Ser Arg Trp Gly Gly Asp
100 105 110
Leu Lys Thr Ile Leu His Thr Asn Met Pro Asn Val Asn Asp Phe Met
115 120 125
Phe Thr Thr Lys Phe Lys Ala Arg Val Met Val Ala Arg Lys Thr Asn
130 135 140
Asn Glu Gly Gln Thr Ile Leu Glu Tyr Glu Trp Ala Glu Phe Val Leu
145 150 155 160
Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp Leu Met Asn Asn
165 170 175
Ala Ile Ile Glu His Tyr Leu Arg Val Gly Arg Gln His Gly Val Leu
180 185 190
Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly
195 200 205
Trp Asp Pro Glu Thr Gln Leu Val Thr Pro Gly Val Tyr Thr Asn Glu
210 215 220
Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe
225 230 235 240
Thr Glu Ser Arg Leu Ser Asn Ile Leu Gly Ile Arg Lys Arg Gln Pro
245 250 255
Phe Gln Glu Gly Phe Val Ile Met Tyr Glu His Leu Glu Gly Gly Asn
260 265 270
Ile Pro Ala Leu Leu Asp Val Lys Lys Tyr Glu Asn Ser Leu Gln Asp
275 280 285
Gln Asn Thr Val Arg Gly Asp Asn Phe Ile Ala Leu Asn Lys Ala Ala
290 295 300
Arg Ile Glu Pro Val Glu Thr Asp Pro Lys Gly Arg Ser Tyr Asn Leu
305 310 315 320
Leu Pro Asp Lys Lys Asn Thr Lys Tyr Arg Ser Trp Tyr Leu Ala Tyr
325 330 335
Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr
340 345 350
Thr Pro Asp Val Thr Gly Gly Ser Glu Gln Val Tyr Trp Ser Leu Pro
355 360 365
Asp Met Met Gln Asp Pro Val Thr Phe Arg Ser Ser Arg Gln Val Ser
370 375 380
Asn Tyr Pro Val Val Ala Ala Glu Leu Leu Pro Val His Ala Lys Ser
385 390 395 400
Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln Leu Ile Arg Gln Ser Thr
405 410 415
Ala Leu Thr Arg Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Val
420 425 430
Arg Pro Pro Ala Ala Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala
435 440 445
Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Ser Gly Val
450 455 460
Gln Arg Val Thr Ile Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val
465 470 475 480
Tyr Lys Ala Leu Gly Ile Val Ser Pro Arg Val Leu Ser Ser Arg Thr
485 490 495
Phe
<210> 15
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自D, E和N, 优选D
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> 选自V, L和I,优选V
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 是任何氨基酸,选自A, D, E, K, S和T,更优选T
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 是任何氨基酸,优选选自A, D, E和K,更优选A
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> 选自F, Y和W, 优选Y
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> 选自A, D, E, N和Q, 优选E或Q,更优选E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> 是任何氨基酸,优选选自A, D, E, N和K,更优选E
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> 选自S或T,优选S
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> 是任何氨基酸
<400> 15
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 16
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> 是R
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 是G
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 是D
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> 是任何氨基酸
<400> 16
Xaa Xaa Xaa Xaa Xaa
1 5
<210> 17
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> 选自I, L和V,优选I
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 选自D, E, K, N, Q和V,优选Q或K,更优选Q
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 选自C, G和P,优选P
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> 选自I, L和V,优选L或V,更优选L
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> 选自D, E, S和T,优选E或T,更优选E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> 选自D, E, K, S和T,优选E, K或T,更优选K
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> 选自D和E,优选D
<400> 17
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 18
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 选自F, Y和W,优选F
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> 选自H, K和R,优选K
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 选自A, V, I和L,优选A
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 选自H, K和R,优选R
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> 选自A, V, I和L,优选V
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> 选自A, V, I, L和M,优选M
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> 选自A, V, I和L,优选V
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> 是任何氨基酸
<400> 18
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 19
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 是任何氨基酸
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> 选自F, Y和W,优选Y
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> 选自D, E, S和T,优选E或T,更优选E
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> 选自F, Y和W,优选 W
<220>
<221> MISC_FEATURE
<222> (5)..(5)
<223> 选自A, F, V, Y和W,优选F或V,更优选F
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> 选自D, E, S和T,优选D或E,更优选E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> 选自F, Y和W,优选F
<400> 19
Xaa Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 20
<211> 26
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基蛋白的一致序列
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa选自V, I和L
<220>
<221> MISC_FEATURE
<222> (12)..(12)
<223> Xaa选自E和D
<220>
<221> MISC_FEATURE
<222> (13)..(13)
<223> Xaa选自H, N和Q
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa选自K, E, R, Q和A
<220>
<221> MISC_FEATURE
<222> (17)..(17)
<223> Xaa选自V, L和I
<220>
<221> MISC_FEATURE
<222> (21)..(21)
<223> Xaa选自H, N和Q
<400> 20
Met Thr Ile Asp Leu Met Asn Asn Ala Ile Xaa Xaa Xaa Tyr Leu Xaa
1 5 10 15
Xaa Gly Arg Gln Xaa Gly Val Leu Glu Ser
20 25
<210> 21
<211> 8
<212> PRT
<213> 腺病毒
<400> 21
Asp Val Thr Ala Tyr Glu Glu Ser
1 5
<210> 22
<211> 8
<212> PRT
<213> 腺病毒
<400> 22
Asp Val Asp Ala Tyr Glu Asn Ser
1 5
<210> 23
<211> 8
<212> PRT
<213> 腺病毒
<400> 23
Asp Val Ala Glu Tyr Glu Lys Ser
1 5
<210> 24
<211> 8
<212> PRT
<213> 腺病毒
<400> 24
Asp Val Glu Ala Tyr Glu Lys Ser
1 5
<210> 25
<211> 8
<212> PRT
<213> 腺病毒
<400> 25
Asp Val Asp Ala Tyr Glu Lys Ser
1 5
<210> 26
<211> 8
<212> PRT
<213> 腺病毒
<400> 26
Asp Val Ser Lys Tyr Glu Ala Ser
1 5
<210> 27
<211> 8
<212> PRT
<213> 腺病毒
<400> 27
Asn Val Lys Ala Tyr Glu Asp Ser
1 5
<210> 28
<211> 8
<212> PRT
<213> 腺病毒
<400> 28
Asp Val Lys Lys Tyr Glu Asn Ser
1 5
<210> 29
<211> 8
<212> PRT
<213> 腺病毒
<400> 29
Asp Val Asp Ala Tyr Gln Ala Ser
1 5
<210> 30
<211> 8
<212> PRT
<213> 腺病毒
<400> 30
Asp Val Asp Ala Tyr Gln Ala Ser
1 5
<210> 31
<211> 7
<212> PRT
<213> 腺病毒
<400> 31
Ile Gln Pro Leu Glu Lys Asp
1 5
<210> 32
<211> 7
<212> PRT
<213> 腺病毒
<400> 32
Ile Gln Pro Val Glu Lys Asp
1 5
<210> 33
<211> 7
<212> PRT
<213> 腺病毒
<400> 33
Ile Lys Pro Leu Glu Lys Asp
1 5
<210> 34
<211> 7
<212> PRT
<213> 腺病毒
<400> 34
Ile Val Pro Leu Thr Lys Asp
1 5
<210> 35
<211> 7
<212> PRT
<213> 腺病毒
<400> 35
Ile Glu Pro Val Glu Thr Asp
1 5
<210> 36
<211> 7
<212> PRT
<213> 腺病毒
<400> 36
Ile Lys Pro Leu Thr Glu Asp
1 5
<210> 37
<211> 7
<212> PRT
<213> 腺病毒
<400> 37
Phe Lys Ala Arg Val Met Val
1 5
<210> 38
<211> 7
<212> PRT
<213> 腺病毒
<400> 38
Phe Arg Ala Lys Leu Met Val
1 5
<210> 39
<211> 7
<212> PRT
<213> 腺病毒
<400> 39
Phe Arg Ala Lys Val Met Val
1 5
<210> 40
<211> 6
<212> PRT
<213> 腺病毒
<400> 40
Tyr Glu Trp Phe Glu Phe
1 5
<210> 41
<211> 6
<212> PRT
<213> 腺病毒
<400> 41
Tyr Glu Trp Val Glu Phe
1 5
<210> 42
<211> 6
<212> PRT
<213> 腺病毒
<400> 42
Tyr Glu Trp Ala Glu Phe
1 5
<210> 43
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 腺病毒纤维蛋白一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> 选自S, D和T,优选S或D,更优选S
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> 选自E, D和G,优选E或D,更优选E
<400> 43
Xaa Phe Asn Pro Val Tyr Pro Tyr Xaa
1 5
<210> 44
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> N端结构域N端的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自G和E
<400> 44
Xaa Gly Arg Asn Ser Ile Arg
1 5
<210> 45
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> N端结构域的C端一致序列
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa选自D和E
<400> 45
Asp Xaa Arg Ser Arg Gly
1 5
<210> 46
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 形成五邻体基原体纤维结合缝的部分构象表位
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自V, I, L, E或D
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自V, L和I
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa 选自M, T和S
<400> 46
Trp Asp Pro Xaa Thr Xaa Xaa Pro Gly
1 5
<210> 47
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 形成五邻体基原体纤维结合缝的部分构象表位
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自D, E, N和Q
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa是任何氨基酸,优选选自A, D, P, K和T
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自A, D, E, K和R
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自D, E, L, I, Q和N
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自A, D, E, K, N, Q,
和R
<400> 47
Xaa Val Xaa Xaa Tyr Xaa Xaa
1 5
<210> 48
<211> 5
<212> PRT
<213> 人工序列
<220>
<223> 形成五邻体基原体纤维结合缝的部分构象表位
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自K, R, S和T
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa选自A, D, E, G, K, N, Q,
R, S和T
<400> 48
Xaa Xaa Arg Ser Tyr
1 5
<210> 49
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 形成五邻体基原体纤维结合缝的部分构象表位
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自H, K和R
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> Xaa选自D和E
<400> 49
Leu Thr Xaa Val Phe Asn Arg Phe Pro Xaa
1 5 10
<210> 50
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的N端结构域一致序列
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自G和E
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<400> 50
Pro Thr Xaa Xaa Arg Asn Xaa Ile Arg
1 5
<210> 51
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的N端结构域一致序列
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自G和E
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<400> 51
Pro Thr Xaa Gly Arg Xaa Ser Ile Arg
1 5
<210> 52
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的N端结构域一致序列
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自D和E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<220>
<221> MISC_FEATURE
<222> (8)..(8)
<223> Xaa选自I, L和V
<400> 52
Thr Gln Thr Ile Asn Xaa Xaa Xaa
1 5
<210> 53
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的N端结构域一致序列
<220>
<221> MISC_FEATURE
<222> (3)..(3)
<223> Xaa选自G和E
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<400> 53
Pro Thr Xaa Gly Arg Asn Xaa Ile Arg
1 5
<210> 54
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 五邻体基原体C末端中偶联残基位置的一致序列
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa是偶联残基,优选C; D, E和K,最优选C
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自H和Y
<400> 54
Thr Cys Pro Xaa Val Xaa Lys Ala Leu Gly
1 5 10
<210> 55
<211> 17
<212> PRT
<213> 登革病毒
<400> 55
His Ala Lys Lys Gln Asp Val Val Val Leu Gly Ser Gln Glu Gly Ala
1 5 10 15
Met
<210> 56
<211> 18
<212> PRT
<213> 基孔肯雅病毒
<400> 56
Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu
1 5 10 15
Ala His
<210> 57
<211> 17
<212> PRT
<213> 兹卡病毒
<400> 57
Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg Pro Leu Ala
1 5 10 15
His
<210> 58
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 基孔肯雅抗原肽和STICKER的融合蛋白
<400> 58
Ala Lys Arg Ala Arg Leu Ser Thr Ser Phe Asn Pro Val Pro Tyr Glu
1 5 10 15
Asp Glu Ser Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg
20 25 30
Pro Tyr Leu Ala His
35
<210> 59
<211> 38
<212> PRT
<213> 人工序列
<220>
<223> 带有偶联残基的STICKER与基孔肯雅病毒抗原肽的融合蛋白
<400> 59
Ala Lys Arg Ala Arg Leu Ser Thr Ser Phe Asn Pro Val Pro Tyr Glu
1 5 10 15
Asp Glu Cys Ser Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr
20 25 30
Arg Pro Tyr Leu Ala His
35
<210> 60
<211> 37
<212> PRT
<213> 人工序列
<220>
<223> 带有偶联残基的STICKER与基孔肯雅病毒抗原肽的融合蛋白
<400> 60
Ala Lys Arg Ala Arg Leu Ser Thr Cys Phe Asn Pro Val Pro Tyr Glu
1 5 10 15
Asp Glu Ser Ser Thr Lys Asp Asn Phe Asn Val Tyr Lys Ala Thr Arg
20 25 30
Pro Tyr Leu Ala His
35
<210> 61
<211> 4453
<212> DNA
<213> 人工序列
<220>
<223> 克隆载体pACEBac-ADDomer1.0质粒序列
<400> 61
accggttgac ttgggtcaac tgtcagacca agtttactca tatatacttt agattgattt 60
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 120
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 180
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 240
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 300
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 360
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 420
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 480
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 540
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 600
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 660
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 720
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 780
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 840
ctttcctgcg ttatcccctg attgacttgg gtcgctcttc ctgtggatgc gcagatgccc 900
tgcgtaagcg ggtgtgggcg gacaataaag tcttaaactg aacaaaatag atctaaacta 960
tgacaataaa gtcttaaact agacagaata gttgtaaact gaaatcagtc cagttatgct 1020
gtgaaaaagc atactggact tttgttatgg ctaaagcaaa ctcttcattt tctgaagtgc 1080
aaattgcccg tcgtattaaa gaggggcgtg gccaagggca tgtaaagact atattcgcgg 1140
cgttgtgaca atttaccgaa caactccgcg gccgggaagc cgatctcggc ttgaacgaat 1200
tgttaggtgg cggtacttgg gtcgatatca aagtgcatca cttcttcccg tatgcccaac 1260
tttgtataga gagccactgc gggatcgtca ccgtaatctg cttgcacgta gatcacataa 1320
gcaccaagcg cgttggcctc atgcttgagg agattgatga gcgcggtggc aatgccctgc 1380
ctccggtgct cgccggagac tgcgagatca tagatataga tctcactacg cggctgctca 1440
aacttgggca gaacgtaagc cgcgagagcg ccaacaaccg cttcttggtc gaaggcagca 1500
agcgcgatga atgtcttact acggagcaag ttcccgaggt aatcggagtc cggctgatgt 1560
tgggagtagg tggctacgtc tccgaactca cgaccgaaaa gatcaagagc agcccgcatg 1620
gatttgactt ggtcagggcc gagcctacat gtgcgaatga tgcccatact tgagccacct 1680
aactttgttt tagggcgact gccctgctgc gtaacatcgt tgctgctgcg taacatcgtt 1740
gctgctccat aacatcaaac atcgacccac ggcgtaacgc gcttgctgct tggatgcccg 1800
aggcatagac tgtacaaaaa aacagtcata acaagccatg aaaaccgcca ctgcgccgtt 1860
accaccgctg cgttcggtca aggttctgga ccagttgcgt gagcgcatac gctacttgca 1920
ttacagttta cgaaccgaac aggcttatgt caactgggtt cgtgccttca tccgtttcca 1980
cggtgtgcgt cacccggcaa ccttgggcag cagcgaagtc gccataactt cgtatagcat 2040
acattatacg aagttatctg taactataac ggtcctaagg tagcgagttt aaacactagt 2100
atcgattcgc gacctactcc ggaatattaa tagatcatgg agataattaa aatgataacc 2160
atctcgcaaa taaataagta ttttactgtt ttcgtaacag ttttgtaata aaaaaaccta 2220
taaatattcc ggattattca taccgtccca ccatcgggcg cggatccatg aggagacgag 2280
ccgtgctagg cggagcggtg gtgtatccgg agggtcctcc tccttcttac gagagcgtga 2340
tgcagcaaca ggcggcgatg atacagcccc cactggaggc tcccttcgta cccccacggt 2400
acctggcgcc tacggaaggg agaaacagca ttcgttactc ggagctgtcg cccctgtacg 2460
ataccaccaa gttgtatctg gtggacaaca agtcggcgga catcgcctcc ctgaactatc 2520
agaacgacca cagcaacttc ctgaccacgg tggtgcagaa caatgacttt acccccacgg 2580
aggctagcac ccagaccatc aactttgacg agcggtcgcg atggggcggt cagctgaaga 2640
ccatcatgca caccaacatg cccaacgtga acgagtacat gttcagcaac aagttcaagg 2700
cgagggtgat ggtgtccaga aaagctcctg aaggtgttac agtaaatgac acctatgatc 2760
ataaagagga tatcttgaag tatgagtggt ttgagttcat tttaccagaa ggcaactttt 2820
cagccaccat gacgatcgac ctgatgaaca atgccatcat tgacaactac ctggaaattg 2880
gcagacagaa tggagtgctg gaaagtgaca ttggtgttaa gtttgacact agaaatttca 2940
ggctcgggtg ggaccccgaa actaagttga ttatgccagg tgtctacact tatgaggcat 3000
tccatcctga cattgtattg ctgcctggtt gcggggtaga ctttactgaa agccgactta 3060
gcaacttgct tggcatcagg aagagacatc cattccagga gggtttcaaa atcatgtatg 3120
aagatcttga agggggtaat attcctgccc ttttggatgt cactgcctat gaggaaagca 3180
aaaaggatac cactactgaa acaaccacac tggctgttgc agaggaaact agtgaagatg 3240
atgatataac tagaggagat acctatataa ctgaaaaaca aaaacgtgaa gctgcagctg 3300
ctgaagttaa aaaagagtta aagatccaac ctctagaaaa agacagcaag agtagaagct 3360
acaatgtctt ggaagacaaa atcaacacag cctaccgcag ttggtacctg tcctacaatt 3420
acggtaaccc tgagaaagga ataaggtctt ggacactgct caccacttca gatgtcacct 3480
gtggggcaga gcaggtctac tggtcgctcc ctgacatgat gcaagaccca gtcaccttcc 3540
gctccacaag acaagtcaac aactacccag tggtgggtgc agagcttatg cccgtcttct 3600
caaagagttt ctacaatgag caagccgtgt actctcagca gctccgacag gccacttcgc 3660
tcacgcacgt cttcaaccgc ttccctgaga accagatcct catccgcccg ccggcgccca 3720
caattaccac cgtcagtgaa aacgttcctg ctctcacaga tcacgggacc ctgccgttac 3780
gcagcagtat ccggggagtc cagcgcgtga ccgttactga cgccagacgc cgcacctgtc 3840
cctacgttta caaggccctg ggcatagtcg cgccgcgcgt tctttcaagc cgcactttct 3900
gataagcttg tcgagaagta ctagaggatc ataatcagcc ataccacatt tgtagaggtt 3960
ttacttgctt taaaaaacct cccacacctc cccctgaacc tgaaacataa aatgaatgca 4020
attgttgttg ttaacttgtt tattgcagct tataatggtt acaaataaag caatagcatc 4080
acaaatttca caaataaagc atttttttca ctgcattcta gttgtggttt gtccaaactc 4140
atcaatgtat cttatcatgt ctggatctga tcactgcttg agcctagaag atccggctgc 4200
taacaaagcc cgaaaggaag ctgagttggc tgctgccacc gctgagcaat aactatcata 4260
acccctaggg tatacccatc taattggaac cagataagtg aaatctagtt ccaaactatt 4320
ttgtcatttt taattttcgt attagcttac gacgctacac ccagttccca tctattttgt 4380
cactcttccc taaataatcc ttaaaaactc catttccacc cctcccagtt cccaactatt 4440
ttgtccgccc aca 4453
<210> 62
<211> 4614
<212> DNA
<213> 人工序列
<220>
<223> 克隆载体pACEBac-ADDOMER2.0质粒序列
<400> 62
accggttgac ttgggtcaac tgtcagacca agtttactca tatatacttt agattgattt 60
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 120
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 180
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 240
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 300
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 360
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 420
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 480
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 540
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 600
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 660
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 720
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 780
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 840
ctttcctgcg ttatcccctg attgacttgg gtcgctcttc ctgtggatgc gcagatgccc 900
tgcgtaagcg ggtgtgggcg gacaataaag tcttaaactg aacaaaatag atctaaacta 960
tgacaataaa gtcttaaact agacagaata gttgtaaact gaaatcagtc cagttatgct 1020
gtgaaaaagc atactggact tttgttatgg ctaaagcaaa ctcttcattt tctgaagtgc 1080
aaattgcccg tcgtattaaa gaggggcgtg gccaagggca tgtaaagact atattcgcgg 1140
cgttgtgaca atttaccgaa caactccgcg gccgggaagc cgatctcggc ttgaacgaat 1200
tgttaggtgg cggtacttgg gtcgatatca aagtgcatca cttcttcccg tatgcccaac 1260
tttgtataga gagccactgc gggatcgtca ccgtaatctg cttgcacgta gatcacataa 1320
gcaccaagcg cgttggcctc atgcttgagg agattgatga gcgcggtggc aatgccctgc 1380
ctccggtgct cgccggagac tgcgagatca tagatataga tctcactacg cggctgctca 1440
aacttgggca gaacgtaagc cgcgagagcg ccaacaaccg cttcttggtc gaaggcagca 1500
agcgcgatga atgtcttact acggagcaag ttcccgaggt aatcggagtc cggctgatgt 1560
tgggagtagg tggctacgtc tccgaactca cgaccgaaaa gatcaagagc agcccgcatg 1620
gatttgactt ggtcagggcc gagcctacat gtgcgaatga tgcccatact tgagccacct 1680
aactttgttt tagggcgact gccctgctgc gtaacatcgt tgctgctgcg taacatcgtt 1740
gctgctccat aacatcaaac atcgacccac ggcgtaacgc gcttgctgct tggatgcccg 1800
aggcatagac tgtacaaaaa aacagtcata acaagccatg aaaaccgcca ctgcgccgtt 1860
accaccgctg cgttcggtca aggttctgga ccagttgcgt gagcgcatac gctacttgca 1920
ttacagttta cgaaccgaac aggcttatgt caactgggtt cgtgccttca tccgtttcca 1980
cggtgtgcgt cacccggcaa ccttgggcag cagcgaagtc gccataactt cgtatagcat 2040
acattatacg aagttatctg taactataac ggtcctaagg tagcgagttt aaacactagt 2100
atcgattcgc gacctactcc ggaatattaa tagatcatgg agataattaa aatgataacc 2160
atctcgcaaa taaataagta ttttactgtt ttcgtaacag ttttgtaata aaaaaaccta 2220
taaatattcc ggattattca taccgtccca ccatcgggcg cggatccatg aggagacgag 2280
ccgtgctagg cggagcggtg gtgtatccgg agggtcctcc tccttcttac gagagcgtga 2340
tgcagcaaca ggcggcgatg atacagcccc cactggaggc tcccttcgta cccccacggt 2400
acctggcgcc tacggaaggg agaaacagca ttcgttactc ggagctgtcg cccctgtacg 2460
ataccaccaa gttgtatctg gtggacaaca agtcggcgga catcgcctcc ctgaactatc 2520
agaacgacca cagcaacttc ctgaccacgg tggtgcagaa caatgacttt acccccacgg 2580
aggctagcac ccagaccatc aactttgacg agcggtcgcg atggggcggt cagctgaaga 2640
ccatcatgca caccaacatg cccaacgtga acgagtacat gttcagcaac aagttcaagg 2700
cgagggtgat ggtgtccaga aaagctcctg aaggtgaatt cgttacagtc aatgacggtc 2760
cggtcaatga cacctatgat cataaagagg atatcttgaa gtatgagtgg tttgagttca 2820
ttttaccaga aggcaacttt tcagccacca tgacgatcga cctgatgaac aatgccatca 2880
ttgacaacta cctggaaatt ggcagacaga atggagtgct ggaaagtgac attggtgtta 2940
agtttgacac tagaaatttc aggctcgggt gggaccccga aactaagttg attatgccag 3000
gtgtctacac ttatgaggca ttccatcctg acattgtatt gctgcctggt tgcggggtag 3060
actttactga aagccgactt agcaacttgc ttggcatcag gaagagacat ccattccagg 3120
agggtttcaa aatcatgtat gaagatcttg aagggggtaa tattcctgcc cttttggatg 3180
tcactgccta tgaggaaagc aaaaaggata ccactactgc gcgcgaaaca accacactgg 3240
ctgttgcaga ggaaactagt gaagatgtcg acgatgatat aactagagga gatacctata 3300
taactgagct cgaaaaacaa aaacgtgaag ctgctgctgc tgaagtttct agaaaaaaag 3360
agttaaagat ccaacctctg gaaaaagaca gcaagagtag aagctacaat gtcttggaag 3420
acaaaatcaa cacagcctac cgcagttggt atctgtccta caattacggt aaccctgaga 3480
aaggaataag gtcttggaca ctgctcacca cttcagatgt cacctgtggg gcagagcagg 3540
tctactggtc gctccctgac atgatgcaag acccagtcac cttccgctcc acaagacaag 3600
tcaacaacta cccagtggtg ggtgcagagc ttatgcccgt cttctcaaag agtttctaca 3660
atgagcaagc cgtgtactct cagcagctcc gacaggccac ttcgctcacg cacgtcttca 3720
accgcttccc tgagaaccag atcctcatcc gcccgccggc acccacaatt accaccgtca 3780
gtgaaaacgt tcctgctctc acagatcacg ggaccctgcc gttacgcagc agtatccggg 3840
gagtccagcg cgtgaccgtt actgacgcca gacgccgcac ctgtccctac gtttacaagg 3900
ccctgggcat agtcgcgccg cgcgttcttt caagccgcac tttctgataa gcttccatca 3960
actttgacga gcggtcgcga tggggcggtc agctgaagac catcatgcac accaacatgc 4020
ccaacgtgaa cgagtacatg ttcagcaaca agttcaaggc gagggagctt gtcgagaagt 4080
actagaggat cataatcagc cataccacat ttgtagaggt tttacttgct ttaaaaaacc 4140
tcccacacct ccccctgaac ctgaaacata aaatgaatgc aattgttgtt gttaacttgt 4200
ttattgcagc ttataatggt tacaaataaa gcaatagcat cacaaatttc acaaataaag 4260
catttttttc actgcattct agttgtggtt tgtccaaact catcaatgta tcttatcatg 4320
tctggatctg atcactgctt gagcctagaa gatccggctg ctaacaaagc ccgaaaggaa 4380
gctgagttgg ctgctgccac cgctgagcaa taactatcat aacccctagg gtatacccat 4440
ctaattggaa ccagataagt gaaatctagt tccaaactat tttgtcattt ttaattttcg 4500
tattagctta cgacgctaca cccagttccc atctattttg tcactcttcc ctaaataatc 4560
cttaaaaact ccatttccac ccctcccagt tcccaactat tttgtccgcc caca 4614
<210> 63
<211> 1683
<212> DNA
<213> 人工序列
<220>
<223> 适合插入异源多肽的ADDomere 1工程化五邻体基原体核酸序列
<400> 63
atgaggagac gagccgtgct aggcggagcg gtggtgtatc cggagggtcc tcctccttct 60
tacgagagcg tgatgcagca acaggcggcg atgatacagc ccccactgga ggctcccttc 120
gtacccccac ggtacctggc gcctacggaa gggagaaaca gcattcgtta ctcggagctg 180
tcgcccctgt acgataccac caagttgtat ctggtggaca acaagtcggc ggacatcgcc 240
tccctgaact atcagaacga ccacagcaac ttcctgacca cggtggtgca gaacaatgac 300
tttaccccca cggaggctag cacccagacc atcaactttg acgagcggtc gcgatggggc 360
ggtcagctga agaccatcat gcacaccaac atgcccaacg tgaacgagta catgttcagc 420
aacaagttca aggcgagggt gatggtgtcc agaaaagctc ctgaaggtga attcgttaca 480
gtcaatgacg gtccggtcaa tgacacctat gatcataaag aggatatctt gaagtatgag 540
tggtttgagt tcattttacc agaaggcaac ttttcagcca ccatgacgat cgacctgatg 600
aacaatgcca tcattgacaa ctacctggaa attggcagac agaatggagt gctggaaagt 660
gacattggtg ttaagtttga cactagaaat ttcaggctcg ggtgggaccc cgaaactaag 720
ttgattatgc caggtgtcta cacttatgag gcattccatc ctgacattgt attgctgcct 780
ggttgcgggg tagactttac tgaaagccga cttagcaact tgcttggcat caggaagaga 840
catccattcc aggagggttt caaaatcatg tatgaagatc ttgaaggggg taatattcct 900
gcccttttgg atgtcactgc ctatgaggaa agcaaaaagg ataccactac tgcgcgcgaa 960
acaaccacac tggctgttgc agaggaaact agtgaagatg tcgacgatga tataactaga 1020
ggagatacct atataactga gctcgaaaaa caaaaacgtg aagctgctgc tgctgaagtt 1080
tctagaaaaa aagagttaaa gatccaacct ctggaaaaag acagcaagag tagaagctac 1140
aatgtcttgg aagacaaaat caacacagcc taccgcagtt ggtatctgtc ctacaattac 1200
ggtaaccctg agaaaggaat aaggtcttgg acactgctca ccacttcaga tgtcacctgt 1260
ggggcagagc aggtctactg gtcgctccct gacatgatgc aagacccagt caccttccgc 1320
tccacaagac aagtcaacaa ctacccagtg gtgggtgcag agcttatgcc cgtcttctca 1380
aagagtttct acaatgagca agccgtgtac tctcagcagc tccgacaggc cacttcgctc 1440
acgcacgtct tcaaccgctt ccctgagaac cagatcctca tccgcccgcc ggcacccaca 1500
attaccaccg tcagtgaaaa cgttcctgct ctcacagatc acgggaccct gccgttacgc 1560
agcagtatcc ggggagtcca gcgcgtgacc gttactgacg ccagacgccg cacctgtccc 1620
tacgtttaca aggccctggg catagtcgcg ccgcgcgttc tttcaagccg cactttctga 1680
taa 1683
<210> 64
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 适合插入异源多肽的ADDomere 1.0蛋白序列
<400> 64
Met Arg Arg Arg Ala Val Leu Gly Gly Ala Val Val Tyr Pro Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Ser Val Met Gln Gln Gln Ala Ala Met Ile
20 25 30
Gln Pro Pro Leu Glu Ala Pro Phe Val Pro Pro Arg Tyr Leu Ala Pro
35 40 45
Thr Glu Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ser Pro Leu Tyr
50 55 60
Asp Thr Thr Lys Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala
65 70 75 80
Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val
85 90 95
Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn
100 105 110
Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His
115 120 125
Thr Asn Met Pro Asn Val Asn Glu Tyr Met Phe Ser Asn Lys Phe Lys
130 135 140
Ala Arg Val Met Val Ser Arg Lys Ala Pro Glu Gly Glu Phe Val Thr
145 150 155 160
Val Asn Asp Gly Pro Val Asn Asp Thr Tyr Asp His Lys Glu Asp Ile
165 170 175
Leu Lys Tyr Glu Trp Phe Glu Phe Ile Leu Pro Glu Gly Asn Phe Ser
180 185 190
Ala Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr
195 200 205
Leu Glu Ile Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val
210 215 220
Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Glu Thr Lys
225 230 235 240
Leu Ile Met Pro Gly Val Tyr Thr Tyr Glu Ala Phe His Pro Asp Ile
245 250 255
Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser Arg Leu Ser
260 265 270
Asn Leu Leu Gly Ile Arg Lys Arg His Pro Phe Gln Glu Gly Phe Lys
275 280 285
Ile Met Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp
290 295 300
Val Thr Ala Tyr Glu Glu Ser Lys Lys Asp Thr Thr Thr Ala Arg Glu
305 310 315 320
Thr Thr Thr Leu Ala Val Ala Glu Glu Thr Ser Glu Asp Val Asp Asp
325 330 335
Asp Ile Thr Arg Gly Asp Thr Tyr Ile Thr Glu Leu Glu Lys Gln Lys
340 345 350
Arg Glu Ala Ala Ala Ala Glu Val Ser Arg Lys Lys Glu Leu Lys Ile
355 360 365
Gln Pro Leu Glu Lys Asp Ser Lys Ser Arg Ser Tyr Asn Val Leu Glu
370 375 380
Asp Lys Ile Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ser Tyr Asn Tyr
385 390 395 400
Gly Asn Pro Glu Lys Gly Ile Arg Ser Trp Thr Leu Leu Thr Thr Ser
405 410 415
Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro Asp Met
420 425 430
Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Asn Asn Tyr
435 440 445
Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser Phe Tyr
450 455 460
Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Ala Thr Ser Leu
465 470 475 480
Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Ile Arg Pro
485 490 495
Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
500 505 510
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val Gln Arg
515 520 525
Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys
530 535 540
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
545 550 555
<210> 65
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 在位置51和54带有偶联残基的ADDomere 2.0蛋白序列
<400> 65
Met Arg Arg Arg Ala Val Leu Gly Gly Ala Val Val Tyr Pro Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Ser Val Met Gln Gln Gln Ala Ala Met Ile
20 25 30
Gln Pro Pro Leu Glu Ala Pro Phe Val Pro Pro Arg Tyr Leu Ala Pro
35 40 45
Thr Glu Cys Arg Asn Cys Ile Arg Tyr Ser Glu Leu Ser Pro Leu Tyr
50 55 60
Asp Thr Thr Lys Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala
65 70 75 80
Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val
85 90 95
Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn
100 105 110
Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His
115 120 125
Thr Asn Met Pro Asn Val Asn Glu Tyr Met Phe Ser Asn Lys Phe Lys
130 135 140
Ala Arg Val Met Val Ser Arg Lys Ala Pro Glu Gly Glu Phe Val Thr
145 150 155 160
Val Asn Asp Gly Pro Val Asn Asp Thr Tyr Asp His Lys Glu Asp Ile
165 170 175
Leu Lys Tyr Glu Trp Phe Glu Phe Ile Leu Pro Glu Gly Asn Phe Ser
180 185 190
Ala Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr
195 200 205
Leu Glu Ile Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val
210 215 220
Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Glu Thr Lys
225 230 235 240
Leu Ile Met Pro Gly Val Tyr Thr Tyr Glu Ala Phe His Pro Asp Ile
245 250 255
Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser Arg Leu Ser
260 265 270
Asn Leu Leu Gly Ile Arg Lys Arg His Pro Phe Gln Glu Gly Phe Lys
275 280 285
Ile Met Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp
290 295 300
Val Thr Ala Tyr Glu Glu Ser Lys Lys Asp Thr Thr Thr Ala Arg Glu
305 310 315 320
Thr Thr Thr Leu Ala Val Ala Glu Glu Thr Ser Glu Asp Val Asp Asp
325 330 335
Asp Ile Thr Arg Gly Asp Thr Tyr Ile Thr Glu Leu Glu Lys Gln Lys
340 345 350
Arg Glu Ala Ala Ala Ala Glu Val Ser Arg Lys Lys Glu Leu Lys Ile
355 360 365
Gln Pro Leu Glu Lys Asp Ser Lys Ser Arg Ser Tyr Asn Val Leu Glu
370 375 380
Asp Lys Ile Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ser Tyr Asn Tyr
385 390 395 400
Gly Asn Pro Glu Lys Gly Ile Arg Ser Trp Thr Leu Leu Thr Thr Ser
405 410 415
Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro Asp Met
420 425 430
Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Asn Asn Tyr
435 440 445
Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser Phe Tyr
450 455 460
Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Ala Thr Ser Leu
465 470 475 480
Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Ile Arg Pro
485 490 495
Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
500 505 510
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val Gln Arg
515 520 525
Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys
530 535 540
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
545 550 555
<210> 66
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 在位置51和114带有偶联残基的ADDomere 2.0蛋白序列
<400> 66
Met Arg Arg Arg Ala Val Leu Gly Gly Ala Val Val Tyr Pro Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Ser Val Met Gln Gln Gln Ala Ala Met Ile
20 25 30
Gln Pro Pro Leu Glu Ala Pro Phe Val Pro Pro Arg Tyr Leu Ala Pro
35 40 45
Thr Glu Gly Arg Asn Cys Ile Arg Tyr Ser Glu Leu Ser Pro Leu Tyr
50 55 60
Asp Thr Thr Lys Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala
65 70 75 80
Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val
85 90 95
Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn
100 105 110
Phe Cys Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His
115 120 125
Thr Asn Met Pro Asn Val Asn Glu Tyr Met Phe Ser Asn Lys Phe Lys
130 135 140
Ala Arg Val Met Val Ser Arg Lys Ala Pro Glu Gly Glu Phe Val Thr
145 150 155 160
Val Asn Asp Gly Pro Val Asn Asp Thr Tyr Asp His Lys Glu Asp Ile
165 170 175
Leu Lys Tyr Glu Trp Phe Glu Phe Ile Leu Pro Glu Gly Asn Phe Ser
180 185 190
Ala Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr
195 200 205
Leu Glu Ile Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val
210 215 220
Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Glu Thr Lys
225 230 235 240
Leu Ile Met Pro Gly Val Tyr Thr Tyr Glu Ala Phe His Pro Asp Ile
245 250 255
Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser Arg Leu Ser
260 265 270
Asn Leu Leu Gly Ile Arg Lys Arg His Pro Phe Gln Glu Gly Phe Lys
275 280 285
Ile Met Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp
290 295 300
Val Thr Ala Tyr Glu Glu Ser Lys Lys Asp Thr Thr Thr Ala Arg Glu
305 310 315 320
Thr Thr Thr Leu Ala Val Ala Glu Glu Thr Ser Glu Asp Val Asp Asp
325 330 335
Asp Ile Thr Arg Gly Asp Thr Tyr Ile Thr Glu Leu Glu Lys Gln Lys
340 345 350
Arg Glu Ala Ala Ala Ala Glu Val Ser Arg Lys Lys Glu Leu Lys Ile
355 360 365
Gln Pro Leu Glu Lys Asp Ser Lys Ser Arg Ser Tyr Asn Val Leu Glu
370 375 380
Asp Lys Ile Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ser Tyr Asn Tyr
385 390 395 400
Gly Asn Pro Glu Lys Gly Ile Arg Ser Trp Thr Leu Leu Thr Thr Ser
405 410 415
Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro Asp Met
420 425 430
Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Asn Asn Tyr
435 440 445
Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser Phe Tyr
450 455 460
Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Ala Thr Ser Leu
465 470 475 480
Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Ile Arg Pro
485 490 495
Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
500 505 510
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val Gln Arg
515 520 525
Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys
530 535 540
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
545 550 555
<210> 67
<211> 559
<212> PRT
<213> 人工序列
<220>
<223> 在位置51和541带有偶联残基的ADDomere 2.0蛋白序列
<400> 67
Met Arg Arg Arg Ala Val Leu Gly Gly Ala Val Val Tyr Pro Glu Gly
1 5 10 15
Pro Pro Pro Ser Tyr Glu Ser Val Met Gln Gln Gln Ala Ala Met Ile
20 25 30
Gln Pro Pro Leu Glu Ala Pro Phe Val Pro Pro Arg Tyr Leu Ala Pro
35 40 45
Thr Glu Gly Arg Cys Ser Ile Arg Tyr Ser Glu Leu Ser Pro Leu Tyr
50 55 60
Asp Thr Thr Lys Leu Tyr Leu Val Asp Asn Lys Ser Ala Asp Ile Ala
65 70 75 80
Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu Thr Thr Val Val
85 90 95
Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr Gln Thr Ile Asn
100 105 110
Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys Thr Ile Met His
115 120 125
Thr Asn Met Pro Asn Val Asn Glu Tyr Met Phe Ser Asn Lys Phe Lys
130 135 140
Ala Arg Val Met Val Ser Arg Lys Ala Pro Glu Gly Glu Phe Val Thr
145 150 155 160
Val Asn Asp Gly Pro Val Asn Asp Thr Tyr Asp His Lys Glu Asp Ile
165 170 175
Leu Lys Tyr Glu Trp Phe Glu Phe Ile Leu Pro Glu Gly Asn Phe Ser
180 185 190
Ala Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr
195 200 205
Leu Glu Ile Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val
210 215 220
Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Glu Thr Lys
225 230 235 240
Leu Ile Met Pro Gly Val Tyr Thr Tyr Glu Ala Phe His Pro Asp Ile
245 250 255
Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser Arg Leu Ser
260 265 270
Asn Leu Leu Gly Ile Arg Lys Arg His Pro Phe Gln Glu Gly Phe Lys
275 280 285
Ile Met Tyr Glu Asp Leu Glu Gly Gly Asn Ile Pro Ala Leu Leu Asp
290 295 300
Val Thr Ala Tyr Glu Glu Ser Lys Lys Asp Thr Thr Thr Ala Arg Glu
305 310 315 320
Thr Thr Thr Leu Ala Val Ala Glu Glu Thr Ser Glu Asp Val Asp Asp
325 330 335
Asp Ile Thr Arg Gly Asp Thr Tyr Ile Thr Glu Leu Glu Lys Gln Lys
340 345 350
Arg Glu Ala Ala Ala Ala Glu Val Ser Arg Lys Lys Glu Leu Lys Ile
355 360 365
Gln Pro Leu Glu Lys Asp Ser Lys Ser Arg Ser Tyr Asn Val Leu Glu
370 375 380
Asp Lys Ile Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ser Tyr Asn Tyr
385 390 395 400
Gly Asn Pro Glu Lys Gly Ile Arg Ser Trp Thr Leu Leu Thr Thr Ser
405 410 415
Asp Val Thr Cys Gly Ala Glu Gln Val Tyr Trp Ser Leu Pro Asp Met
420 425 430
Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val Asn Asn Tyr
435 440 445
Pro Val Val Gly Ala Glu Leu Met Pro Val Phe Ser Lys Ser Phe Tyr
450 455 460
Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Gln Ala Thr Ser Leu
465 470 475 480
Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Ile Arg Pro
485 490 495
Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val Pro Ala Leu Thr
500 505 510
Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg Gly Val Gln Arg
515 520 525
Val Thr Val Thr Asp Ala Arg Arg Arg Thr Cys Pro Cys Val Tyr Lys
530 535 540
Ala Leu Gly Ile Val Ala Pro Arg Val Leu Ser Ser Arg Thr Phe
545 550 555
<210> 68
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> STICKER结合缝中五邻体基原体的一致序列
<220>
<221> MISC_FEATURE
<222> (4)..(4)
<223> Xaa选自Y和F
<220>
<221> MISC_FEATURE
<222> (6)..(6)
<223> Xaa选自D, E和偶联残基,优选Cys
<220>
<221> MISC_FEATURE
<222> (7)..(7)
<223> Xaa选自L, Q和偶联残基,优选Cys
<400> 68
Lys Ser Phe Xaa Asn Xaa Xaa Ala Val Tyr
1 5 10
<210> 69
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维的STICKER N端片段
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa选自S, D和T
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa选自E, D和G
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> 各种情况时,Xaa独立地是任何氨基酸,优选在这个或这些位置上纤维蛋白中天然存在的那些
<220>
<221> MISC_FEATURE
<222> (11)..(11)
<223> Xaa是偶联残基,优选Cys
<220>
<221> misc_feature
<222> (12)..(12)
<223> Xaa可以是任何天然存在的氨基酸
<400> 69
Xaa Phe Asn Pro Val Tyr Pro Tyr Xaa Xaa Asn Xaa
1 5 10
<210> 70
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维的STICKER N端片段
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是偶联残基,优选Cys
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa选自E, D和G
<400> 70
Xaa Phe Asn Pro Val Tyr Pro Tyr Xaa
1 5
<210> 71
<211> 4692
<212> DNA
<213> 人工序列
<220>
<223> pACEBac-ADDomer2.0TevChik质粒序列
<400> 71
accggttgac ttgggtcaac tgtcagacca agtttactca tatatacttt agattgattt 60
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 120
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 180
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 240
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 300
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 360
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 420
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 480
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 540
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 600
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 660
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 720
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 780
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 840
ctttcctgcg ttatcccctg attgacttgg gtcgctcttc ctgtggatgc gcagatgccc 900
tgcgtaagcg ggtgtgggcg gacaataaag tcttaaactg aacaaaatag atctaaacta 960
tgacaataaa gtcttaaact agacagaata gttgtaaact gaaatcagtc cagttatgct 1020
gtgaaaaagc atactggact tttgttatgg ctaaagcaaa ctcttcattt tctgaagtgc 1080
aaattgcccg tcgtattaaa gaggggcgtg gccaagggca tgtaaagact atattcgcgg 1140
cgttgtgaca atttaccgaa caactccgcg gccgggaagc cgatctcggc ttgaacgaat 1200
tgttaggtgg cggtacttgg gtcgatatca aagtgcatca cttcttcccg tatgcccaac 1260
tttgtataga gagccactgc gggatcgtca ccgtaatctg cttgcacgta gatcacataa 1320
gcaccaagcg cgttggcctc atgcttgagg agattgatga gcgcggtggc aatgccctgc 1380
ctccggtgct cgccggagac tgcgagatca tagatataga tctcactacg cggctgctca 1440
aacttgggca gaacgtaagc cgcgagagcg ccaacaaccg cttcttggtc gaaggcagca 1500
agcgcgatga atgtcttact acggagcaag ttcccgaggt aatcggagtc cggctgatgt 1560
tgggagtagg tggctacgtc tccgaactca cgaccgaaaa gatcaagagc agcccgcatg 1620
gatttgactt ggtcagggcc gagcctacat gtgcgaatga tgcccatact tgagccacct 1680
aactttgttt tagggcgact gccctgctgc gtaacatcgt tgctgctgcg taacatcgtt 1740
gctgctccat aacatcaaac atcgacccac ggcgtaacgc gcttgctgct tggatgcccg 1800
aggcatagac tgtacaaaaa aacagtcata acaagccatg aaaaccgcca ctgcgccgtt 1860
accaccgctg cgttcggtca aggttctgga ccagttgcgt gagcgcatac gctacttgca 1920
ttacagttta cgaaccgaac aggcttatgt caactgggtt cgtgccttca tccgtttcca 1980
cggtgtgcgt cacccggcaa ccttgggcag cagcgaagtc gccataactt cgtatagcat 2040
acattatacg aagttatctg taactataac ggtcctaagg tagcgagttt aaacactagt 2100
atcgattcgc gacctactcc ggaatattaa tagatcatgg agataattaa aatgataacc 2160
atctcgcaaa taaataagta ttttactgtt ttcgtaacag ttttgtaata aaaaaaccta 2220
taaatattcc ggattattca taccgtccca ccatcgggcg cggatccatg aggagacgag 2280
ccgtgctagg cggagcggtg gtgtatccgg agggtcctcc tccttcttac gagagcgtga 2340
tgcagcaaca ggcggcgatg atacagcccc cactggaggc tcccttcgta cccccacggt 2400
acctggcgcc tacggaaggg agaaacagca ttcgttactc ggagctgtcg cccctgtacg 2460
ataccaccaa gttgtatctg gtggacaaca agtcggcgga catcgcctcc ctgaactatc 2520
agaacgacca cagcaacttc ctgaccacgg tggtgcagaa caatgacttt acccccacgg 2580
aggctagcac ccagaccatc aactttgacg agcggtcgcg atggggcggt cagctgaaga 2640
ccatcatgca caccaacatg cccaacgtga acgagtacat gttcagcaac aagttcaagg 2700
cgagggtgat ggtgtccaga aaagctcctg aaggtgaatt cggcagcggt ggcgaaaacc 2760
tgtattttca gagcaccaaa gataacttta acgtgtataa agcgacccgc ccgtatctgg 2820
cgcatggtgg cagcggtccg gtcaatgaca cctatgatca taaagaggat atcttgaagt 2880
atgagtggtt tgagttcatt ttaccagaag gcaacttttc agccaccatg acgatcgacc 2940
tgatgaacaa tgccatcatt gacaactacc tggaaattgg cagacagaat ggagtgctgg 3000
aaagtgacat tggtgttaag tttgacacta gaaatttcag gctcgggtgg gaccccgaaa 3060
ctaagttgat tatgccaggt gtctacactt atgaggcatt ccatcctgac attgtattgc 3120
tgcctggttg cggggtagac tttactgaaa gccgacttag caacttgctt ggcatcagga 3180
agagacatcc attccaggag ggtttcaaaa tcatgtatga agatcttgaa gggggtaata 3240
ttcctgccct tttggatgtc actgcctatg aggaaagcaa aaaggatacc actactgcgc 3300
gcgaaacaac cacactggct gttgcagagg aaactagtga agatgtcgac gatgatataa 3360
ctagaggaga tacctatata actgagctcg aaaaacaaaa acgtgaagct gctgctgctg 3420
aagtttctag aaaaaaagag ttaaagatcc aacctctgga aaaagacagc aagagtagaa 3480
gctacaatgt cttggaagac aaaatcaaca cagcctaccg cagttggtat ctgtcctaca 3540
attacggtaa ccctgagaaa ggaataaggt cttggacact gctcaccact tcagatgtca 3600
cctgtggggc agagcaggtc tactggtcgc tccctgacat gatgcaagac ccagtcacct 3660
tccgctccac aagacaagtc aacaactacc cagtggtggg tgcagagctt atgcccgtct 3720
tctcaaagag tttctacaat gagcaagccg tgtactctca gcagctccga caggccactt 3780
cgctcacgca cgtcttcaac cgcttccctg agaaccagat cctcatccgc ccgccggcac 3840
ccacaattac caccgtcagt gaaaacgttc ctgctctcac agatcacggg accctgccgt 3900
tacgcagcag tatccgggga gtccagcgcg tgaccgttac tgacgccaga cgccgcacct 3960
gtccctacgt ttacaaggcc ctgggcatag tcgcgccgcg cgttctttca agccgcactt 4020
tctgataagc ttccatcaac tttgacgagc ggtcgcgatg gggcggtcag ctgaagacca 4080
tcatgcacac caacatgccc aacgtgaacg agtacatgtt cagcaacaag ttcaaggcga 4140
gggagcttgt cgagaagtac tagaggatca taatcagcca taccacattt gtagaggttt 4200
tacttgcttt aaaaaacctc ccacacctcc ccctgaacct gaaacataaa atgaatgcaa 4260
ttgttgttgt taacttgttt attgcagctt ataatggtta caaataaagc aatagcatca 4320
caaatttcac aaataaagca tttttttcac tgcattctag ttgtggtttg tccaaactca 4380
tcaatgtatc ttatcatgtc tggatctgat cactgcttga gcctagaaga tccggctgct 4440
aacaaagccc gaaaggaagc tgagttggct gctgccaccg ctgagcaata actatcataa 4500
cccctagggt atacccatct aattggaacc agataagtga aatctagttc caaactattt 4560
tgtcattttt aattttcgta ttagcttacg acgctacacc cagttcccat ctattttgtc 4620
actcttccct aaataatcct taaaaactcc atttccaccc ctcccagttc ccaactattt 4680
tgtccgccca ca 4692
<210> 72
<211> 4788
<212> DNA
<213> 人工序列
<220>
<223> pACEBac-ADDOmer2.0-[TevCHIK]2质粒序列
<400> 72
accggttgac ttgggtcaac tgtcagacca agtttactca tatatacttt agattgattt 60
aaaacttcat ttttaattta aaaggatcta ggtgaagatc ctttttgata atctcatgac 120
caaaatccct taacgtgagt tttcgttcca ctgagcgtca gaccccgtag aaaagatcaa 180
aggatcttct tgagatcctt tttttctgcg cgtaatctgc tgcttgcaaa caaaaaaacc 240
accgctacca gcggtggttt gtttgccgga tcaagagcta ccaactcttt ttccgaaggt 300
aactggcttc agcagagcgc agataccaaa tactgttctt ctagtgtagc cgtagttagg 360
ccaccacttc aagaactctg tagcaccgcc tacatacctc gctctgctaa tcctgttacc 420
agtggctgct gccagtggcg ataagtcgtg tcttaccggg ttggactcaa gacgatagtt 480
accggataag gcgcagcggt cgggctgaac ggggggttcg tgcacacagc ccagcttgga 540
gcgaacgacc tacaccgaac tgagatacct acagcgtgag ctatgagaaa gcgccacgct 600
tcccgaaggg agaaaggcgg acaggtatcc ggtaagcggc agggtcggaa caggagagcg 660
cacgagggag cttccagggg gaaacgcctg gtatctttat agtcctgtcg ggtttcgcca 720
cctctgactt gagcgtcgat ttttgtgatg ctcgtcaggg gggcggagcc tatggaaaaa 780
cgccagcaac gcggcctttt tacggttcct ggccttttgc tggccttttg ctcacatgtt 840
ctttcctgcg ttatcccctg attgacttgg gtcgctcttc ctgtggatgc gcagatgccc 900
tgcgtaagcg ggtgtgggcg gacaataaag tcttaaactg aacaaaatag atctaaacta 960
tgacaataaa gtcttaaact agacagaata gttgtaaact gaaatcagtc cagttatgct 1020
gtgaaaaagc atactggact tttgttatgg ctaaagcaaa ctcttcattt tctgaagtgc 1080
aaattgcccg tcgtattaaa gaggggcgtg gccaagggca tgtaaagact atattcgcgg 1140
cgttgtgaca atttaccgaa caactccgcg gccgggaagc cgatctcggc ttgaacgaat 1200
tgttaggtgg cggtacttgg gtcgatatca aagtgcatca cttcttcccg tatgcccaac 1260
tttgtataga gagccactgc gggatcgtca ccgtaatctg cttgcacgta gatcacataa 1320
gcaccaagcg cgttggcctc atgcttgagg agattgatga gcgcggtggc aatgccctgc 1380
ctccggtgct cgccggagac tgcgagatca tagatataga tctcactacg cggctgctca 1440
aacttgggca gaacgtaagc cgcgagagcg ccaacaaccg cttcttggtc gaaggcagca 1500
agcgcgatga atgtcttact acggagcaag ttcccgaggt aatcggagtc cggctgatgt 1560
tgggagtagg tggctacgtc tccgaactca cgaccgaaaa gatcaagagc agcccgcatg 1620
gatttgactt ggtcagggcc gagcctacat gtgcgaatga tgcccatact tgagccacct 1680
aactttgttt tagggcgact gccctgctgc gtaacatcgt tgctgctgcg taacatcgtt 1740
gctgctccat aacatcaaac atcgacccac ggcgtaacgc gcttgctgct tggatgcccg 1800
aggcatagac tgtacaaaaa aacagtcata acaagccatg aaaaccgcca ctgcgccgtt 1860
accaccgctg cgttcggtca aggttctgga ccagttgcgt gagcgcatac gctacttgca 1920
ttacagttta cgaaccgaac aggcttatgt caactgggtt cgtgccttca tccgtttcca 1980
cggtgtgcgt cacccggcaa ccttgggcag cagcgaagtc gccataactt cgtatagcat 2040
acattatacg aagttatctg taactataac ggtcctaagg tagcgagttt aaacactagt 2100
atcgattcgc gacctactcc ggaatattaa tagatcatgg agataattaa aatgataacc 2160
atctcgcaaa taaataagta ttttactgtt ttcgtaacag ttttgtaata aaaaaaccta 2220
taaatattcc ggattattca taccgtccca ccatcgggcg cggatccatg aggagacgag 2280
ccgtgctagg cggagcggtg gtgtatccgg agggtcctcc tccttcttac gagagcgtga 2340
tgcagcaaca ggcggcgatg atacagcccc cactggaggc tcccttcgta cccccacggt 2400
acctggcgcc tacggaaggg agaaacagca ttcgttactc ggagctgtcg cccctgtacg 2460
ataccaccaa gttgtatctg gtggacaaca agtcggcgga catcgcctcc ctgaactatc 2520
agaacgacca cagcaacttc ctgaccacgg tggtgcagaa caatgacttt acccccacgg 2580
aggctagcac ccagaccatc aactttgacg agcggtcgcg atggggcggt cagctgaaga 2640
ccatcatgca caccaacatg cccaacgtga acgagtacat gttcagcaac aagttcaagg 2700
cgagggtgat ggtgtccaga aaagctcctg aaggtgaatt cggcagcggt ggcgaaaacc 2760
tgtattttca gagcaccaaa gataacttta acgtgtataa agcgacccgc ccgtatctgg 2820
cgcatggtgg cagcggtccg gtcaatgaca cctatgatca taaagaggat atcttgaagt 2880
atgagtggtt tgagttcatt ttaccagaag gcaacttttc agccaccatg acgatcgacc 2940
tgatgaacaa tgccatcatt gacaactacc tggaaattgg cagacagaat ggagtgctgg 3000
aaagtgacat tggtgttaag tttgacacta gaaatttcag gctcgggtgg gaccccgaaa 3060
ctaagttgat tatgccaggt gtctacactt atgaggcatt ccatcctgac attgtattgc 3120
tgcctggttg cggggtagac tttactgaaa gccgacttag caacttgctt ggcatcagga 3180
agagacatcc attccaggag ggtttcaaaa tcatgtatga agatcttgaa gggggtaata 3240
ttcctgccct tttggatgtc actgcctatg aggaaagcaa aaaggatacc actactgcgc 3300
gcgaaacaac cacactggct gttgcagagg aaactagtga agatgtcgac gatgatataa 3360
ctagaggaga tacctatata actgagctcg gcagcggtgg cgaaaacctg tattttcaga 3420
gcaccaaaga taactttaac gtgtataaag cgacccgccc gtatctggcg catggtggca 3480
gcggtgaaaa acaaaaacgt gaagctgctg ctgctgaagt ttctagaaaa aaagagttaa 3540
agatccaacc tctggaaaaa gacagcaaga gtagaagcta caatgtcttg gaagacaaaa 3600
tcaacacagc ctaccgcagt tggtatctgt cctacaatta cggtaaccct gagaaaggaa 3660
taaggtcttg gacactgctc accacttcag atgtcacctg tggggcagag caggtctact 3720
ggtcgctccc tgacatgatg caagacccag tcaccttccg ctccacaaga caagtcaaca 3780
actacccagt ggtgggtgca gagcttatgc ccgtcttctc aaagagtttc tacaatgagc 3840
aagccgtgta ctctcagcag ctccgacagg ccacttcgct cacgcacgtc ttcaaccgct 3900
tccctgagaa ccagatcctc atccgcccgc cggcacccac aattaccacc gtcagtgaaa 3960
acgttcctgc tctcacagat cacgggaccc tgccgttacg cagcagtatc cggggagtcc 4020
agcgcgtgac cgttactgac gccagacgcc gcacctgtcc ctacgtttac aaggccctgg 4080
gcatagtcgc gccgcgcgtt ctttcaagcc gcactttctg ataagcttcc atcaactttg 4140
acgagcggtc gcgatggggc ggtcagctga agaccatcat gcacaccaac atgcccaacg 4200
tgaacgagta catgttcagc aacaagttca aggcgaggga gcttgtcgag aagtactaga 4260
ggatcataat cagccatacc acatttgtag aggttttact tgctttaaaa aacctcccac 4320
acctccccct gaacctgaaa cataaaatga atgcaattgt tgttgttaac ttgtttattg 4380
cagcttataa tggttacaaa taaagcaata gcatcacaaa tttcacaaat aaagcatttt 4440
tttcactgca ttctagttgt ggtttgtcca aactcatcaa tgtatcttat catgtctgga 4500
tctgatcact gcttgagcct agaagatccg gctgctaaca aagcccgaaa ggaagctgag 4560
ttggctgctg ccaccgctga gcaataacta tcataacccc tagggtatac ccatctaatt 4620
ggaaccagat aagtgaaatc tagttccaaa ctattttgtc atttttaatt ttcgtattag 4680
cttacgacgc tacacccagt tcccatctat tttgtcactc ttccctaaat aatccttaaa 4740
aactccattt ccacccctcc cagttcccaa ctattttgtc cgcccaca 4788
<210> 73
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> STICKER 结合缝中五邻体基原体的一致序列
<220>
<221> MISC_FEATURE
<222> (1)..(1)
<223> Xaa是偶联残基,优选C, D, E和K, 最优选C
<220>
<221> MISC_FEATURE
<222> (2)..(2)
<223> Xaa 是任何氨基酸,优选选自D, E, G, K, N或S, 更优选S或N
<400> 73
Xaa Xaa Arg Ser Tyr Asn
1 5
<210> 74
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维的STICKER N端片段
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa是偶联残基,其选自K,C, D或E, 优选C
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa选自E, D和G,优选E或D,更优选E
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可以是任何天然存在的氨基酸
<400> 74
Ala Lys Arg Ala Arg Leu Ser Thr Xaa Phe Asn Pro Val Tyr Pro Tyr
1 5 10 15
Xaa Asp Glu Ser
20
<210> 75
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维的STICKER N端片段
<400> 75
Ala Lys Arg Ala Arg Leu Ser Thr Cys Phe Asn Pro Val Tyr Pro Tyr
1 5 10 15
Glu Asp Glu Ser
20
<210> 76
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维的STICKER N端片段
<220>
<221> MISC_FEATURE
<222> (9)..(9)
<223> Xaa选自S, D和T,优选S或D,更优选S
<220>
<221> MISC_FEATURE
<222> (16)..(16)
<223> Xaa选自E, D和G,优选E或D,更优选E
<220>
<221> misc_feature
<222> (17)..(17)
<223> Xaa可以是任何天然存在的氨基酸
<220>
<221> MISC_FEATURE
<222> (20)..(20)
<223> Xaa是偶联残基,优选C, D, E和K,最优选C
<400> 76
Ala Lys Arg Ala Arg Leu Ser Thr Xaa Phe Asn Pro Val Tyr Pro Tyr
1 5 10 15
Xaa Asp Glu Xaa
20
<210> 77
<211> 20
<212> PRT
<213> 人工序列
<220>
<223> 含有偶联残基的纤维STICKER N端片段
<400> 77
Ala Lys Arg Ala Arg Leu Ser Thr Ser Phe Asn Pro Val Tyr Pro Tyr
1 5 10 15
Glu Asp Glu Cys
20
<210> 78
<211> 32
<212> PRT
<213> 人工序列
<220>
<223> 插入五邻体基原体的基孔肯雅表位构建体
<400> 78
Gly Ser Gly Gly Glu Asn Leu Tyr Phe Gln Ser Thr Lys Asp Asn Phe
1 5 10 15
Asn Val Tyr Lys Ala Thr Arg Pro Tyr Leu Ala His Gly Gly Ser Gly
20 25 30
Claims (18)
1.一种工程化多肽,其包含腺病毒五邻体基原体,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环(V环)、腺病毒纤维蛋白结合缝和/或N端结构域,并在所述第一、第二、或者第一和第二RGD环和/或所述V环中包含一个或更多个非腺病毒肽;和可选地以下的一个或更多个:
(i)在所述第一、第二、或者第一和第二RGD环和/或所述V环中至少一个靶标特异性结合结构域;和/或
(ii)所述五邻体基原体的N和/或C端的非腺病毒肽;和/或
(iii)在所述第一、第二、或者第一和第二RGD环、所述V环中和/或在所述五邻体基原体N端结构域中的至少一个异源偶联残基,其中所述五邻体基原体中N端结构域的N端限定如下:
X1-G-R-N-S-I-R(SEQ ID NO:44),
并且所述五邻体基原体中N端结构域的C端限定如下:
D-X2-R-S-R-G(SEQ ID NO:45),
其中
X1选自G和E,以及
X2选自D和E;和/或
(iv)药物、标记或者多肽,其共价或非共价偶联至所述第一、第二、或者第一和第二RGD环的一个或更多个氨基酸和/或五邻体基原体V环的一个或更多个氨基酸;和/或
(v)在所述五邻体基原体的腺病毒纤维蛋白结合缝中的至少一个异源偶联残基,
以及其中所述工程化多肽能够组装成VLP。
2.一种工程化多肽,其包含至少一个腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,以及:
(i)非腺病毒肽,和/或
(ii)与药物或者标记共价或非共价偶联。
3.根据权利要求1所述的工程化多肽,其中以下序列限定所述五邻体基原体中第一RGD环的N端:
X3-X4-X5-X6-X7-X8-X9-X10-X11(SEQ ID NO:15)
其中
X3选自D、E和N,并且优选是D;
X4选自V、L和I,并且优选是V;
X5是任何氨基酸,优选选自A、D、E、K、S和T,更优选T;
X6是任何氨基酸,优选选自A、D、E和K,更优选A;
X7选自F、Y和W,并且优选是Y;
X8选自A、D、E、N和Q,优选是E或者Q,并且更优选E;
X9是任何氨基酸,优选选自A、D、E、N和K,更优选E;
X10选自S或者T,并且优选是S;以及
X11是任何氨基酸,并构成所述第一RGD环的N端氨基酸;
和/或
以下序列限定所述五邻体基原体中的所述第一RGD环的C端和所述第二RGD环的N端:
X12-X13-X14-X15-X16(SEQ ID NO:16)
其中
X12是任何氨基酸并构成所述第一RGD环的C端氨基酸;
X13是R;
X14是G;
X15是D;以及
X16是任何氨基酸并构成所述第二RGD环的N端氨基酸;
和/或
以下序列限定五邻体基原体中第二RGD环的C端:
X17-X18-X19-X20-X21-X22-X23-X24(SEQ ID NO:17);
其中
X17是任何氨基酸并构成所述第二RGD环的C端氨基酸;
X18选自I、L和V,并且优选是I;
X19选自D、E、K、N、Q和V,优选是Q或者K,并且更优选Q;
X20选自C、G和P,并且优选是P;
X21选自I、L和V,优选是L或者V,更优选L;
X22选自D、E、S和T,优选是E或者T,更优选E;
X23选自D、E、K、S和T,优选是E、K或者T,更优选K;以及
X24选自D和E,并且优选是D;
和/或
以下序列限定V环的N端:
X25-X26-X27-X28-X29-X30-X31-X32(SEQ ID NO:18),
其中
X25选自F、Y和W,并且优选是F;
X26选自H、K和R,并且优选是K;
X27选自A、V、I和L,并且优选是A;
X28选自H、K和R,并且优选是R;
X29选自A、V、I和L,并且优选是V;
X30选自A、V、I、L和M,并且优选是M;
X31选自A、V、I和L,并且优选是V;以及
X32是任何氨基酸,并构成所述V环的N端氨基酸;
和/或
以下序列限定所述V环的C端:
X33-X34-X35-X36-X37-X38-X39(SEQ ID NO:19)
其中
X33是任何氨基酸并构成所述V环的C端氨基酸;
X34选自F、Y和W,并且优选是Y;
X35选自D、E、S和T,优选是E或者T,更优选E;
X36选自F、Y和W,并且优选是W;
X37选自A、F、V、Y和W,优选是F或者V,更优选F;
X38选自D、E、S和T,优选是D或者E,更优选E;以及
X39选自F、Y和W,并且优选是F;
和/或,五邻体基原体中的一个或更多个以下非连续肽形成腺病毒纤维蛋白结合缝(粗体氨基酸直接与纤维相互作用)
M-T-I-D-L-M-N-N-A-I-X40-X41-X42-Y-L-X43-X44-G-R-Q-X45-G-V-L-E-S(SEQ ID NO:20);
W-D-P-X46-T-X47-X48-P-G(SEQ ID NO:46);
X49-V-X50-X51-Y-X52-X53(SEQ ID NO:47);
X54-X55-R-S-Y(SEO II NO:48);和/或
L-T-X56-V-F-N-R-F-P-X57(SEO ID NO :49)
其中
X40选自V、I和L;
X41选自E和D;
X42选自H、N和Q,优选地H和N;
X43选自K、E、R、Q和A;
X44选自V、L和I,优选地V和I;
X45选自H、N和Q,优选地H和N;
X46选自V、I、L、E或者D,优选地V和E;
X47选自V、L和I,优选地V和I;
X48选自M、T和S,优选地M和T;
X49选自D、E、N和Q,优选地D和N;
X50是任何氨基酸,优选选自A、D、P、K和T;
X51选自A、D、E、K和R,优选地A、E和K;
X52选自D、E、L、I、Q和N,优选地E、L和Q;
X53选自A、D、E、K、N、Q和R,优选地A、E、N和K;
X54选自K、R、S和T,优选地K、S和T;
X55选自A、D、E、G、K、N、Q、R、S和T,优选地D、G、K、N和S;
X56选自H、K和R,优选地H和R;以及
X57选自D和E。
4.根据权利要求2所述的工程化多肽,其中所述纤维蛋白片段包含:
X58-F-N-P-V-Y-P-Y-X59(SEQ ID NO:43)
其中
X58选自S、D和T,优选S或者D,更优选S;以及
X59选自E、D和G,优选E或者D,更优选E。
5.一种核酸,其编码权利要求1至4中任一项所述的多肽。
6.一种表达载体,其包含权利要求5所述的核酸或者编码以下的克隆载体:
(i)多肽,其包含腺病毒五邻体基原体,其中所述五邻体基原体包含第一RGD环、第二RGD环、可变环和/或腺病毒纤维蛋白的结合位点,适用于将编码非腺病毒肽的核酸引入编码所述第一RGD环,第二RGD环和/或可变环的核酸;或者
(ii)多肽,其包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,适用于在C和/或N端引入编码非腺病毒肽的核酸。
7.一种重组宿主细胞,其包含权利要求所述的表达载体或权利要求6所述的克隆载体。
8.一种五聚体,其包含五个工程化多肽,所述工程化多肽包含权利要求1或3所述的腺病毒五邻体基原体。
9.一种病毒样颗粒(VLP),其包含12个权利要求6所述的五聚体。
10.一种VLP,其包含12个五聚体,各五聚体包含五个腺病毒五邻体基原体以及至少一个权利要求2或4所述的工程化多肽,所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝。
11.一种用于生产权利要求1至4中任一项所述的工程化多肽的方法,其包括步骤:
(a)提供权利要求7所述的重组宿主细胞;
(b)表达所述工程化多肽;以及
(c)纯化所述工程化多肽。
12.一种用于生产权利要求9或10所述VLP的方法,其包括权利要求11所述方法的步骤,以及允许所述工程化多肽组装成VLP的进一步步骤。
13.一种用于生产权利要求9或10所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供权利要求6所述的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码腺病毒五邻体基原体的第一RGD环、第二RGD环和/或可变环的核酸中,和/或插入编码工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;
(d)在宿主细胞中,任选地与包含腺病毒纤维蛋白N端片段的工程化多肽一起,表达工程化的腺病毒五邻体基原体,其中所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(e)纯化所述VLP,其任选地包含腺病毒五邻体基原体结合纤维蛋白片段,或者所述包含腺病毒五邻体基原体结合纤维蛋白片段的工程化多肽。
14.一种用于生产权利要求9或10所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)提供权利要求6所述的克隆载体;
(b)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(c)将编码至少一种所述非腺病毒肽的核酸插入编码工程化多肽N或C端的核酸之前或之后的核酸位置上,其中所述工程化多肽包含腺病毒纤维蛋白N端片段,其特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;
(d)在宿主细胞中,任选地与腺病毒五邻体基原体一起,表达所述包含腺病毒纤维蛋白N端片段的工程化多肽,所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(e1)纯化所述包含腺病毒纤维蛋白N端片段的工程化多肽,所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝,并且与权利要求1或3所述的腺病毒五邻体基原体或者工程化腺病毒五邻体基原体混合;或者
(e2)在所述腺病毒五邻体基原体共表达的情况下,纯化所述VLP。
15.一种用于生产权利要求9或10所述VLP的方法,所述VLP包含疾病和/或患者特异性非腺病毒肽,所述方法包括步骤:
(a)确定疾病或患者特异性非腺病毒肽的氨基酸序列;
(b)合成权利要求2或4所述的工程化多肽,所述工程化多肽包含腺病毒纤维蛋白N端片段以及至少一个所述非腺病毒肽,其中所述腺病毒纤维蛋白N端片段特异性结合五邻体基原体的腺病毒纤维蛋白结合缝;以及
(c)将所述工程化多肽与权利要求1或3所述的腺病毒五邻体基原体或与工程化腺病毒五邻体基原体混合,与权利要求8所述的五聚体或与权利要求9或10所述的VLP混合。
16.一种VLP,其是通过权利要求28至32中任一项所述的方法生产的。
17.一种药物组合物,其包含权利要求1至4中任一项所述的工程化多肽、权利要求5所述的核酸、权利要求6所述的表达载体、或权利要求7、8或14中任一项所述的VLP,以及药学上可接受的载体和/或合适的赋形剂。
18.权利要求1至4中任一项所述的工程化多肽、权利要求5所述的核酸、权利要求6所述的表达载体、或权利要求7、8或14中任一项所述的VLP用于治疗和/或预防感染性疾病、免疫疾病或癌症。
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JP2021532836A (ja) * | 2018-07-31 | 2021-12-02 | イモフォロン リミテッド | アデノウイルス ペントンベースのゼリーロールフォールドドメイン由来である多量体化ポリペプチド |
JP2023513512A (ja) | 2020-02-05 | 2023-03-31 | イモフォロン リミテッド | アデノウイルス ペントンベースの可変ドメイン由来の操作されたポリペプチド |
WO2022218997A1 (en) | 2021-04-12 | 2022-10-20 | Centre National De La Recherche Scientifique (Cnrs) | Novel universal vaccine presenting system |
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