CN116509997A - Cd24疫苗 - Google Patents
Cd24疫苗 Download PDFInfo
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- CN116509997A CN116509997A CN202210066823.9A CN202210066823A CN116509997A CN 116509997 A CN116509997 A CN 116509997A CN 202210066823 A CN202210066823 A CN 202210066823A CN 116509997 A CN116509997 A CN 116509997A
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Abstract
本发明涉及CD24疫苗,具体提供一种免疫原性复合物,其包含:(a)CD24或其免疫原性片段以及(b)载体蛋白。本发明的CD24疫苗具有突出的免疫原性,可以有效预防和治疗CD24相关疾病。
Description
技术领域
本发明涉及生物医药领域,具体涉及CD24疫苗。
背景技术
20世纪70年代末,一种具有有机溶剂可溶性和热稳定的脂样结构的小鼠膜糖蛋白被发现,称为热稳定抗原(heat-stable antigen,HSA),即小鼠CD24,人CD24是热稳定抗原在人类的同源分子,位于染色体6q21。CD24分子是一种高度糖基化的唾液酸糖蛋白,通过C端的磷脂酰肌醇(glycosylphoshphatidylinositol,GPI)锚固在细胞膜表面,成熟的小鼠和人CD24分子的氨基酸数目分别为27aa和31aa,CD24分子具有许多潜在的糖基化位点,其表观分子量约为25-75KDa。小鼠CD24主要在造血细胞亚群中表达,特别是B淋巴细胞、红细胞、中性粒细胞和胸腺细胞,人的CD24仅表达于B淋巴细胞表面,并在浆细胞成熟过程中丢失。
CD24具有多种生物学活性,参与细胞增殖和细胞间的相互作用,其唾液酸糖结构可与固有免疫细胞上的类胰岛素样凝集素10(sialic-acid-binding Ig-like lectin 10,Siglecl-10)相互作用,可对机体的免疫反应进行负调控,能够抑制感染、败血症、肝损伤和慢性移植物抗宿主疾病等导致的破坏性炎症反应。此外,CD24在几乎所有的肿瘤细胞中表达,包括卵巢癌、乳腺癌、胰腺癌、肾癌、肺癌、鼻咽癌和肝癌等,CD24的表达水平和肿瘤的侵袭、转移和预后密切相关,一方面,CD24可通过加强肿瘤细胞与周围组织基质的黏附而促进肿瘤转移,另一方面,CD24与Siglecl-10结合,阻止巨噬细胞对肿瘤细胞的吞噬作用,介导肿瘤的免疫逃逸。
但是,本领域尚无以CD24为抗原的肿瘤疫苗或免疫治疗产品。疫苗通常由抗原(免疫原)和佐剂两部分组成,机体免疫系统能否对疫苗起反应取决于抗原(免疫原)本身的特性,有效的疫苗抗原(免疫原)通常具有以下几个特征:1、异物性;2、分子量大;3、组成和结构复杂。CD24分子为机体自身多肽,不具有异物性的特征,成熟的CD24分子仅约30个氨基酸,分子量小,因此单独的CD24分子无法做为疫苗抗原使用。
发明内容
发明人通过基因工程技术对CD24进行重组表达并将其连接到纳米颗粒蛋白表面,构建以CD24为抗原的纳米颗粒疫苗,用于肿瘤的免疫治疗。
本发明第一方面提供一种免疫原性复合物,其包含:(a)CD24或其免疫原性片段以及(b)载体蛋白。
在一个或多个实施方案中,所述载体蛋白是能形成纳米颗粒的载体蛋白。优选地,所述载体蛋白是Ferritin蛋白,或,乙肝核心抗原(HBcAg)或其变体。
在一个或多个实施方案中,(a)和(b)共价连接。优选地,所述共价连接是肽键或通过SpyCatcher-SpyTag共价连接形成的异肽键。
在一个或多个实施方案中,所述CD24是小鼠CD24或人CD24。
在一个或多个实施方案中,所述CD24具有SEQ ID NO:1或2所示的序列。
在第一方面的一些实施方案中,所述免疫原性复合物是融合多肽,包含:(a)CD24或其免疫原性片段以及(b)乙肝核心抗原(HBcAg)或其变体,其中,所述HBcAg变体是(1)HBcAg的C末端缺失34或更少个氨基酸的变体,或(2)HBcAg在第78位氨基酸之后具有插入序列的并在C末端缺失34或更少个氨基酸的变体。
在一个或多个实施方案中,所述插入序列是((G)oS(G)pT)q,其中o、p和q各自独立是选自0、1、2、3、4、5和6的整数。优选地,q是1,o和p各自独立是选自0、1、2、3的整数。更优选地,q是1,o和p是4。
优选地,所述HBcAg变体具有SEQ ID NO:6或7所示序列。
在一个或多个实施方案中,所述CD24或其免疫原性片段位于HBcAg或其变体的第78位氨基酸之后或所述插入序列之后,将HBcAg或其变体分成位于N端的A和位于C端的B两个部分。优选地,所述CD24或其免疫原性片段位于SEQ ID NO:6的第78位氨基酸之后或SEQID NO:7的第88位氨基酸之后。
在一个或多个实施方案中,所述CD24或其免疫原性片段的C端与所述B部分通过接头连接。在一些实施方案中,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数;接头优选是GGGGGSGGGGS。
在一个或多个实施方案中,所述免疫原性复合物的序列如SEQ ID NO:9所示。
在第一方面的另一些实施方案中,所述免疫原性复合物包含通过SpyCatcher-SpyTag共价连接的:
(a)与SpyCatcher连接的CD24或其免疫原性片段,和(b)与SpyTag连接的Ferritin蛋白,或者
(a’)与SpyTag连接的CD24或其免疫原性片段,和(b’)与SpyCatcher连接的Ferritin蛋白。
在一个或多个实施方案中,(b)或(b’)自组装形成纳米颗粒载体。
在一个或多个实施方案中,所述各连接各自独立是直接连接或通过接头连接。在一些实施方案中,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数;接头优选是GGGGGSGGGGSGGGGS。
在一个或多个实施方案中,所述Ferritin蛋白来自人、马、牛蛙或细菌。优选地,所述Ferritin蛋白具有SEQ ID NO:3所示的序列。
在一个或多个实施方案中,所述SpyTag如SEQ ID NO:4所示。
在一个或多个实施方案中,所述SpyCatcher如SEQ ID NO:5所示。
在一个或多个实施方案中,所述CD24是小鼠CD24或人CD24。优选地,所述CD24具有SEQ ID NO:1或2所示的序列。
在一个或多个实施方案中,(a)如SEQ ID NO:13所示;(b)如SEQ ID NO:11所示。
本发明另一方面还提供一种组合物,包含(1)与SpyCatcher连接的CD24或其免疫原性片段,和与SpyTag连接的Ferritin蛋白,和/或(2)与SpyTag连接的CD24或其免疫原性片段,和与SpyCatcher连接的Ferritin蛋白。所述各连接各自独立是直接连接或通过接头连接。
在一些实施方案中,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数;接头优选是GGGGGSGGGGSGGGGS。
在一个或多个实施方案中,所述Ferritin蛋白来自人、马、牛蛙或细菌。优选地,所述Ferritin蛋白具有SEQ ID NO:3所示的序列。
在一个或多个实施方案中,所述SpyTag如SEQ ID NO:4所示。
在一个或多个实施方案中,所述SpyCatcher如SEQ ID NO:5所示。
在一个或多个实施方案中,所述CD24是小鼠CD24或人CD24。优选地,所述CD24具有SEQ ID NO:1或2所示的序列。
在一个或多个实施方案中,所述组合物包含具有SEQ ID NO:11和13所示序列的多肽。
本发明另一方面还提供核酸分子,其具有编码选自以下任一项的多肽的序列:
(1)本文第一方面中所述的包含由肽键连接的(a)CD24或其免疫原性片段以及(b)载体蛋白,所述载体蛋白优选乙肝核心抗原(HBcAg)或其变体的融合多肽,
(2)本文第一方面中所述的与SpyCatcher连接的CD24或其免疫原性片段,和/或与SpyTag连接的载体蛋白,优选本文第一方面中所述的与SpyTag连接的Ferritin蛋白,
(3)本文第一方面中所述的与SpyTag连接的CD24或其免疫原性片段,和/或与SpyCatcher连接的载体蛋白,优选本文第一方面中所述的与SpyCatcher连接的Ferritin蛋白,
(4)(1)-(3)的互补序列。
本发明还提供核酸构建物,其具有本文任一实施方案所述的核酸分子。所述核酸构建物是克隆载体或表达载体。
本发明还提供宿主细胞,其包含本文所述的核酸构建物。
在一个或多个实施方案中,所述宿主细胞包括但不限于大肠杆菌、毕赤酵母、汉逊酵母、酿酒酵母、昆虫细胞及哺乳动物细胞,例如大肠杆菌BL21(DE3)、Rosseta或JM109菌株。
本发明第二方面还提供一种免疫原性组合物,其包含本文任一实施方案所述的免疫原性复合物和佐剂。
在一个或多个实施方案中,所述免疫原性组合物是纳米颗粒疫苗。
在一个或多个实施方案中,所述佐剂为氢氧化铝。
本发明还提供一种药物组合物,其包含:本文任一实施方案所述的免疫原性复合物或免疫原性组合物,和药学上可接受的辅料。
本发明还提供一种试剂盒,其包含本文任一实施方案所述的免疫原性组合物或药物组合物,以及用于施用它们的容器。
本发明还提供本文任一实施方案所述的免疫原性复合物或免疫原性组合物在制备药物中的用途。
在一个或多个实施方案中,其中所述药物用于预防、减轻或者治疗CD24相关疾病或病症。
在一个或多个实施方案中,所述CD24相关疾病或病症是受益于CD24被抑制的疾病或病症。
在一个或多个实施方案中,所述CD24相关疾病是癌症,优选卵巢癌、乳腺癌、胰腺癌、肾癌、肺癌、鼻咽癌或肝癌。
在一个或多个实施方案中,所述CD24相关病症是肿瘤侵袭、转移或免疫逃逸。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1:SpyTag-Ferritin纯化SDS-page。M:预染蛋白maker;lane1:破菌全菌;lane2:破菌上清;lane3:加热后上清;lane4:Q-FF洗脱。
图2:Spycatcher-mCD24纯化SDS-page。M:预染蛋白maker;lane1:破菌上清;lane2:Q-FF洗脱;lane3:phenyl-Hisub流穿;lane4:Q-HP洗脱。
图3:mCD24-Ferritin纯化SDS-page。M:预染蛋白maker;lane1:破菌上清;lane2:DEAE FF流穿;lane3:Poros-50HQ流穿。
图4:HBcAg-mCD24纯化SDS-page。M:预染蛋白maker;lane1:破菌全菌;lane2:破菌上清;lane3:Poros-50HQ洗脱;lane4:Chromdex-200排阻峰。
图5:SpyTag-Ferritin和Spycatcher-mCD24的组装SDS-page。M:预染蛋白maker;lane1:SpyTag-Ferritin;lane2:Spycatcher-mCD24;lane3:0.5:1;lane4:1:1;lane5:1:0.5;lane6:1:0.25。
图6:SpyTag-Ferritin和Spycatcher-mCD24的组装后的纯化SDS-page。M:预染蛋白maker;lane1:连接产物超滤浓缩;lane2:Chromdex-200排阻峰。
图7:mCD24-Ferritin电镜观察
图8:SpyTag-Ferritin电镜观察
图9:SpymCD24-Ferritin电镜观察
图10:HBcAg-mCD24电镜观察
图11:小鼠肿瘤大小
具体实施方式
除非另有定义,否则与本发明关联使用的科学及技术术语应具有本领域普通技术人员通常所了解的含义。通常,本文所述的与细胞及组织培养、分子生物学、免疫学、微生物学、遗传学、蛋白质与核酸化学、杂交、医学及药物化学关联使用的命名及其技术是本领域公知和常用的。本文中所引用的所有出版物、专利及专利申请(无论上文或下文)均以全文引用的方式并入本文中。
本领域的共识是,CD24无法作为免疫原用于肿瘤疫苗,这是因为:CD24分子为机体自身多肽,不具有异物性的特征;成熟的CD24分子仅约30个氨基酸,分子量小,因此单独的CD24分子无法做为疫苗抗原使用。本发明实施例中也验证了单独的CD24分子无法诱导抗体生成。
发明人经过长期深入的研究,发现在与载体蛋白偶联(例如共价连接)后,CD24具有突出的免疫原性,可以制备得到肿瘤疫苗,该疫苗可以有效预防和治疗以乳腺癌为代表的CD24相关疾病。
本文所述的CD24可以来自任何物种,优选小鼠或人来源的CD24(SEQ ID NO:1或2)。本文的CD24还包括功能变体。多肽的变体与其野生型相应物(例如SEQ ID NO:1或2)相比在氨基酸水平具有例如至少80%、85%、90%、95%、97%或者99%相同性。
本文中,CD24的功能活性变体包含天然发生的功能活性变体,如等位基因变体和物种变体以及可通过例如诱变技术或者通过直接合成方法产生的非天然发生的功能活性变体。优选CD24功能变体与SEQ ID NO:1或2所示肽具有大约如1、2、3、4或5个氨基酸残基不同,且仍保留抗原性CD24生物学活性。变异的位点可以发生在所述肽中的任何位置,只要所述生物学活性与SEQ ID NO:1或2所示肽基本上相似即可。
可以在本发明的肽之一中进行的氨基酸取代的类型是保守氨基酸取代。“保守氨基酸取代”是其中氨基酸残基由具有相似化学性质(如电荷或疏水性)的侧链R基团的另一氨基酸残基取代。通常,保守氨基酸取代基本上不改变蛋白质的功能性质。具有相似化学性质侧链的氨基酸组的实例包括:1)脂肪族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂肪族-羟基侧链:丝氨酸和苏氨酸;3)含有酰胺的侧链:天冬酰胺和谷氨酰胺;4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸;及7)含硫侧链:半胱氨酸和甲硫氨酸。优选的保守氨基酸取代组是:缬氨酸-亮氨酸-异亮氨酸,苯丙氨酸-酪氨酸,赖氨酸-精氨酸,丙氨酸-缬氨酸,谷氨酸-天冬氨酸,以及天冬酰胺-谷氨酰胺。
本文的CD24还包含其免疫原性片段。在知晓了本文所发现的CD24可以作为免疫原制备肿瘤疫苗的基础上,本领域技术人员可以根据CD24的序列容易地确定具有免疫原性的CD24的片段。
本发明第一方面提供一种免疫原性复合物,其包含:(a)CD24或其免疫原性片段以及(b)载体蛋白。a组分和b组分之间优选共价连接,可以是肽键或通过SpyCatcher-SpyTag共价连接形成的异肽键。因此,免疫原性复合物可以是能融合表达的多肽或者是通过SpyCatcher-SpyTag共价连接的复合物。
本发明还涉及所述免疫原性复合物的制备方法,包括:融合表达所述包含CD24或其免疫原性片段以及载体蛋白的融合多肽,或者,分别提供(例如分别表达)(a)和(b)组分后通过组分间的化学交联或共价连接(例如异肽键)形成免疫原性复合物。
作为示例性的实施方案,发明人选用能形成纳米颗粒的载体蛋白。如本发明实施例中,载体蛋白是Ferritin蛋白,或乙肝核心抗原(HBcAg)或其变体。
因此,在一些实施方案中,本发明提供一种融合多肽形式的免疫原性复合物,包含:(a)CD24或其免疫原性片段以及(b)乙肝核心抗原(HBcAg)或其变体。乙型肝炎核心抗原(HBcAg)是183个氨基酸的多肽。HBcAg及其截短变体均可作为CD24纳米颗粒疫苗的载体蛋白。
可用于本发明中的特别感兴趣的HBcAg变体是其中一或多个天然存在的半胱氨酸残基已经被缺失或取代的那些变体。此外,本发明也可以使用加工形式的HBcAg,其缺少乙型肝炎核心抗原前体蛋白的N末端前导序列,特别是当HBcAg是在未发生加工的条件下产生的情况中(例如在细菌系统中表达)。
本发明的其它HBcAg变体包括:i)与野生型HBcAg氨基酸序列之一或者其亚部分具有至少80%、85%、90%、95%、97%或99%相同性的多肽序列,使用常规的已知计算机程序确定;ii)C-末端截短突变体,包括其中在C末端缺失34或更少(例如1、5、10、15、20、25、30)个氨基酸的突变体;ii)N-末端截短突变体,包括其中从N末端已经除去1、2、5、7、9、10、12、14、15或17个氨基酸的突变体;iii)在第78位氨基酸之后具有插入序列的并在C末端缺失34或更少(例如1、5、10、15、20、25、30)个氨基酸的HBcAg变体。适用于本发明中的HBsAg可衍生自任何生物体。适用于本发明中的HBsAg可衍生自任何生物体,只要其能形成病毒样颗粒并用作免疫原性载体即可。
本发明还涉及所述免疫原性复合物的制备方法,包括:表达所述包含CD24或其免疫原性片段以及HBcAg或其变体的融合多肽。
在一些实施方案中,所述HBcAg变体具有SEQ ID NO:6或7所示序列或与其具有至少80%序列相同性的功能变体;所述CD24或其免疫原性片段位于SEQ ID NO:6或其功能变体的第78位氨基酸之后或SEQ ID NO:7或其功能变体的第88位氨基酸之后。在优选实施方案中,所述免疫原性复合物的序列如SEQ ID NO:9所示或与其具有至少80%序列相同性的功能变体。
本文的融合多肽可以发生序列变化,得到的突变体与该融合多肽(例如SEQ IDNO:9)具有至少80%,优选至少85%,优选至少90%,优选至少95%,优选至少97%的序列相同性并保留该融合多肽的生物学活性(如免疫原性)。可采用例如NCBI的BLASTp计算两条比对的序列之间的序列相同性。
在另一些实施方案中,本发明提供载体蛋白为Ferritin蛋白的免疫原性复合物。所述免疫原性复合物包含通过SpyCatcher-SpyTag共价连接的:(a)与SpyCatcher连接的CD24或其免疫原性片段,和(b)与SpyTag连接的Ferritin蛋白,或者(a’)与SpyTag连接的CD24或其免疫原性片段,和(b’)与SpyCatcher连接的Ferritin蛋白。Ferritin蛋白来自嗜热古细菌(Pyrococcus furiosus)的铁蛋白,其是由24个亚基组成的八面体,优选具有SEQID NO:3所示的序列或与其具有至少80%序列相同性的功能变体。Ferritin蛋白可以自组装形成纳米颗粒载体。此外,包含未发生SpyCatcher-SpyTag共价连接的上述(a)和(b)或(a’)和(b’)的组合物也在本发明的范围内。本发明还涉及所述免疫原性复合物的制备方法,包括:表达(a)和(b)或(a’)和(b’)中的多肽,纯化后共孵育,自组装得到所述免疫原性复合物。
在一些实施方案中,所述SpyCatcher位于CD24或Ferritin蛋白的N端,所述SpyTag位于CD24或Ferritin蛋白的的N端。示例性地,所述SpyTag含有SEQ ID NO:4所示的氨基酸序列或与其具有至少80%序列相同性的功能变体,所述SpyCatcher含有SEQ ID NO:5所示的氨基酸序列或与其具有至少80%序列相同性的功能变体。
本文中,一条多肽中各组分(例如CD24和载体蛋白、SpyTag和CD24、SpyCatcher和CD24、SpyTag和载体蛋白、SpyCatcher和载体蛋白)之间的连接可以是直接连接或通过接头连接。所述接头的氨基酸是不具有除连接以外的额外功能(例如蛋白定位、酶切位点等)的无意义多肽。是否使用接头以及接头序列可由本领域技术人员根据需要选择。在优选实施方案中,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数。
在一些实施方式中,(a)组分为SpyCatcher-mCD24,其含有SEQ ID NO:13所示的氨基酸序列或与其具有至少80%序列相同性的功能变体;(b)组分为SpyTag-Ferritin,其含有SEQ ID NO:11所示的氨基酸序列或与其具有至少80%序列相同性的功能变体。
本文的连接有SpyCatcher或SpyTag的各多肽(例如SpyCatcher-CD24、SpyCatcher-载体蛋白、SpyTag-CD24、SpyTag-载体蛋白)可以发生序列变化,得到的突变体与相应多肽具有至少80%,优选至少85%,优选至少90%,优选至少95%,优选至少97%的序列相同性并保留该多肽的生物学活性(如与对应的SpyCatcher或SpyTag共价连接的活性、载体蛋白的自组装活性、发生SpyCatcher和SpyTag共价连接后的免疫原性等)。可采用例如NCBI的BLASTp计算两条比对的序列之间的序列相同性。
如上所述,所述免疫原性复合物的制备方法包括表达相应多肽的步骤。本文中,“表达”可通过孵育宿主细胞实现,该宿主细胞包含具有待表达多肽的编码序列的表达载体。因此,本发明还涉及本文所述多肽的编码序列和含有该编码序列的核酸构建物,所述核酸构建物可以是克隆载体、整合载体或表达载体。所述表达载体还含有多肽表达所需的其他组件,例如启动子、终止子等。宿主细胞、表达载体和组件均是本领域所熟知。示例性的表达载体包括pet24a。
本文所述宿主细胞可以是动物、植物或微生物细胞,包括但不限于大肠杆菌、毕赤酵母、汉逊酵母、酿酒酵母、昆虫细胞及哺乳动物细胞,例如大肠杆菌BL21(DE3)、Rosseta或JM109菌株。
本发明还涉及免疫原性组合物,其是包含如上所述的免疫原性复合物和佐剂的纳米颗粒疫苗。此外,本发明还提供药物组合物,其包含:本文所述的免疫原性复合物或免疫原性组合物,以及药学上可接受的辅料。
适用于本发明疫苗的佐剂包括可增强针对CD24或其免疫原性片段的抗体反应的佐剂,以及可增强细胞介导的针对CD24或其免疫原性片段的反应的佐剂。这些佐剂均是本领域所熟知并可通过商业渠道获得的。在一些实施方式中,所述佐剂选自Sigma AdjuvantSysterm、AddaVax、角鲨烯、胞壁酰二肽、MF59、AS03、单磷脂酰脂质A,鞭毛蛋白、CPG、以及铝或钙盐的小分子中的一种或多种。其中,优选的佐剂为氢氧化铝。
药学上可接受的辅料成分的示例包括结合剂(糖浆、阿拉伯树胶、明胶、山梨醇、黄芪胶(tragacanth)、聚乙烯吡咯烷酮等)、填充剂(乳糖、蔗糖、淀粉、磷酸钙、山梨糖醇、甘氨酸等)、润滑剂(硬脂酸镁、滑石、聚乙二醇等)、崩解剂(淀粉、微晶纤维素(microcrystalline cellulose)等)、湿润剂(十二烷基硫酸钠(sodium lauryl sulphate)等)、悬浮剂(山梨糖醇、糖浆、甲基纤维素、葡萄糖浆(glucose syrup)、明胶、氢化食用脂肪等)、乳化剂(卵磷脂、山梨醇单油酸酯、阿拉伯树胶等)、非水性载体(杏仁油、分馏椰子油或甘油、丙二醇、乙醇等疏水酯等)、防腐剂(对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、山梨酸等)、芳香剂(合成香料、天然香料等)、甜味剂(蔗糖、甜叶菊、木糖醇等)、pH调节剂(碳酸氢钠、碳酸钾等)、粉剂(色素、染料、树脂等)、增稠剂(阿拉伯树胶、甲基纤维素等)、抗氧化剂(维生素C、维生素E等)等等。
本发明的免疫原性组合物、药物组合物和制备其的方法为本领域技术人员显而易见。这种组合物和制备其的方法可见于例如Remington’s Pharmaceutical Sciences,19thEdition(Mack Publishing Company,1995)。药物组合物优选在GMP条件下生产。
本发明的药物组合物可以作为单一单位剂量或者多个单一单位剂量形式大批量制备、包装或者销售。如本文所用,“单位剂量”是指包含预定量活性成分的药物组合物的个别量。所述活性成分的量通常等于施用给对象的活性成分的剂量或者这种剂量的方便分数,例如这种剂量的一半。
本发明的疫苗和药物组合物典型地被配制用于肠胃外施用。如本文所用,肠胃外施用包括但不限于通过注射所述组合物施用药物组合物、通过手术切口应用所述组合物、通过组织穿透非手术创口应用所述组合物等。特别地,肠胃外施用包括但不限于皮下、腹膜内、肌内、胸骨内、静脉内、动脉内、鞘内、心室内、尿道内、颅内、滑膜内注射或者输注;以及肾透析灌注技术。典型的免疫接种是通过肌内途径的疫苗接种,但本发明还考虑了口腔、皮下(SC)、鼻腔(IN)、静脉内(IV)、腹膜内(IP)或真皮内(ID)施用实现。
适于肠胃外施用的药物组合物的配制典型通常包含活性成分可接受的载体,如无菌水或无菌等渗盐水。这种配制物可以适于推注施用或者连续施用的形式制备、包装或者销售。注射用配制物可以单位剂量形式如在含有防腐剂的安瓿或在多剂量容器中制备、包装或销售。肠胃外施用的配制物包括但不限于悬浮液、溶液、在油或水性载体中的乳状液、糊剂等。这种配制物可进一步包含一或多种其它成分,包括但不限于悬浮剂、稳定剂或者分散剂。在肠胃外施用的配制物的一个实施方案中,活性成分以干燥形式提供(即粉末或颗粒),在肠胃外施用之前用合适的载体(如无菌无热原水)重建之后肠胃外施用所述重建的组合物。肠胃外施用的配制物可以配制成立即、缓释、持续、脉冲、控制、靶向以及程序化释放的释放形式。示例性的本发明药物组合物是无菌水溶液,pH范围在大约5.0-6.5,包含约0.1mg/mL至大约20mg/mL本发明的免疫原性组合物、约1mmol至约100mmol的组氨酸缓冲液,约0.01mg/mL至约10mg/mL聚山梨酯80、约100mmol至约400mmol海藻糖,以及约0.01mmol至约1.0mmol的EDTA二钠二水合物。
上述免疫原性组合物或药物组合物是以与剂量配方相容的方式,以及诸如治疗有效量和免疫原性有效量的用量被施用的。“药物有效剂量”或者“治疗有效剂量”是治疗或预防或减轻对象的一或多种CD24相关疾病或症状需要的剂量。所述药物有效剂量依赖于施用的特定化合物、症状的严重性、对象对于副作用的易感性、疾病的类型、使用的组合物、施用途径、治疗的哺乳动物类型、特定哺乳动物的生理特性如健康和生理状况、同时服药情况、个体免疫系统合成抗体的能力、希望的保护作用程度以及本领域技术人员已知的其它因素。出于预防目的,选择的每个剂量中肽的量是在典型的疫苗接种个体中诱导免疫保护性应答且无明显不利副作用的量。在最初的免疫接种之后,所述对象可以接受一或多次足够间隔时间的加强免疫。所述有效量优选经皮下或口鼻或肌内施用(一次或多次)。
应理解对于任何特定患者的特定剂量水平根据各种因素确定,包括应用的特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、施用时间、施用途径及排泄率,药物组合及进行治疗的特定疾病的严重性。例如,本发明的CD24免疫原性组合物或者药物组合物可以以如下剂量施用给对象:约0.1μg至约5mg,如约0.1μg至约5μg,约5μg至约10μg,约10μg至约25μg,约25μg至约50μg,约50μg至约100μg,约100μg至约500μg,约500μg至约1mg,约1mg至约2mg,任选地加强剂量在例如1周、2周、3周、4周、2个月、3个月、6个月和/或1年之后。
本发明还涉及试剂盒,其包含本文所述的免疫原性组合物或药物组合物,以及用于施用所述免疫原性组合物或药物组合物的容器。容器优选为医用注射器。
本发明再一方面还涉及如上所述的免疫原性复合物或免疫原性组合物在制备用于预防、减轻或者治疗CD24相关疾病或病症的药物中的用途。
本发明进一步提供了降低或消除受试者患CD24相关疾病或病症的可能性或治疗受试者的CD24相关疾病或病症的方法,包括给所述受试者施用有效量的根据本发明的免疫原性复合物、免疫原性组合物或药物组合物。
另一方面,本发明提供了在对象体内诱导针对自身CD24免疫应答的方法,包括给所述对象施用治疗或免疫学有效量的本发明的免疫原性复合物、免疫原性组合物或药物组合物。
在本发明的用途或方法的一些方面中,CD24相关疾病或病症是例如其中CD24活性被抑制或者CD24与受体相互作用被抑制是有益的疾病或病症。CD24相关疾病包括但不限于癌症,例如卵巢癌、乳腺癌、胰腺癌、肾癌、肺癌、鼻咽癌或肝癌;CD24相关病症包括但不限于肿瘤侵袭、转移或免疫逃逸。
在一些实施方案中,本文的CD24免疫原性复合物、免疫原性组合物或者药物组合物可以与另一药物一起施用,两者可以以一定顺序相继施用或者同时施用。
在本发明的应用或方法中,受试者特别是哺乳动物,优选为灵长类动物,更优选为人。受试者包括健康对象、CD24相关疾病或病症患者、康复对象等。
除非另有指示,否则本发明的方法及技术一般根据本领域公知的和常规的方法来进行且如本说明书中所引用及论述的各种一般及更特定的参考文献中所述来进行。例如参见Sambrook J.及Russell D.Molecular Cloning:A Laboratory Manual,第3版(2000)。根据制造商的说明书进行酶促反应及纯化技术,通常如本领域或如本文所述完成。
实施例
1、序列及表达载体构建
1.1、小鼠CD24序列(mCD24)
蛋白质序列:NQTSVAPFPGNQNISASPNPTNATTRG(SEQ ID NO:1)
1.2、人CD24序列(hCD24)
蛋白质序列:SETTTGTSSNSSQSTSNSGLAPNPTNATTKV(SEQ ID NO:2)
1.3、Ferritin序列
蛋白质序列:
RMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE(SEQ ID NO:3)
1.4、SpyTag序列
蛋白质序列:AHIVMVDAYKPTK(SEQ ID NO:4)
1.5、Spycatcher序列
蛋白质序列:
MSYYHHHHHHDYDIPTTENLYFQGAMVDTLSGLSSEQGQSGDMTIEEDSATHIKFSKRDEDGKELAGATMELRDSSGKTISTWISDGQVKDFYLYPGKYTFVETAAPDGYEVATAITFTVNEQGQVTVNGKATKGDAHI(SEQID NO:5)
1.6、HBcAg序列
HBcAg 1-149aa蛋白序列:
MDIDPYKEFGATVELLSFLPSDFFPSVRDLLDTASALYREALESPEHCSPHHTALRQAILCWGELMTLATWVGVNLEDPASRDLVVSYVNTNMGLKFRQLLWFHISCLTFGRETVIEYLVSFGVWIRTPPAYRPPNAPILSTLPETTVV(SEQ ID NO:6)
HBcAg 1-149aa改造蛋白序列:
MDIDPYKEFGATVELLSFLPSDFFPSVRDLLDTASALYREALESPEHCSPHHTALRQAILCWGELMTLATWVGVNLEDGGGGSGGGGTPASRDLVVSYVNTNMGLKFRQLLWFHISCLTFGRETVIEYLVSFGVWIRTPPAYRPPNAPILSTLPETTVV(SEQ ID NO:7)
HBcAg 1-149aa改造核苷酸序列:
ATGGACATTGACCCGTACAAGGAGTTTGGTGCGACCGTTGAACTGCTGAGCTTTCTGCCGAGCGACTTTTTCCCGAGCGTGCGTGATCTGCTGGACACCGCGAGCGCGCTGTACCGTGAAGCGCTGGAAAGCCCGGAGCACTGCAGCCCGCACCACACCGCGCTGCGTCAGGCGATCCTGTGCTGGGGTGAACTGATGACCCTGGCGACCTGGGTGGGCGTTAACCTGGAGGATGGTGGCGGTGGCAGCGGTGGCGGTGGTACCCCGGCGTCTAGAGATCTGGTGGTTAGCTACGTGAACACCAACATGGGTCTGAAGTTCCGTCAACTGCTGTGGTTTCACATTAGCTGCCTGACCTTCGGTCGTGAAACCGTTATCGAGTATCTGGTGAGCTTTGGCGTTTGGATTCGTACCCCGCCGGCGTACCGCCCGCCGAATGCGCCGATCCTGAGCACCCTGCCGGAGACCACCGTTGTG(SEQ ID NO:8)
1.7、HBcAg-mCD24序列
蛋白质序列:
MDIDPYKEFGATVELLSFLPSDFFPSVRDLLDTASALYREALESPEHCSPHHTALRQAILCWGELMTLATWVGVNLEDGGGGSGGGGTNQTSVAPFPGNQNISASPNPTNATTRGGGGGSGGGGSRDLVVSYVNTNMGLKFRQLLWFHISCLTFGRETVIEYLVSFGVWIRTPPAYRPPNAPILSTLPETTVV(SEQ ID NO:9)
核苷酸序列:
ATGGACATTGACCCGTACAAGGAGTTTGGTGCGACCGTTGAACTGCTGAGCTTTCTGCCGAGCGACTTTTTCCCGAGCGTGCGTGATCTGCTGGACACCGCGAGCGCGCTGTACCGTGAAGCGCTGGAAAGCCCGGAGCACTGCAGCCCGCACCACACCGCGCTGCGTCAGGCGATCCTGTGCTGGGGTGAACTGATGACCCTGGCGACCTGGGTGGGCGTTAACCTGGAGGATGGTGGCGGTGGCAGCGGTGGCGGTGGTACCAATCAAACATCAGTAGCTCCATTTCCCGGAAACCAGAACATCAGCGCTTCCCCGAATCCGACGAACGCGACCACCCGTGGTGGTGGCGGTGGCAGCGGTGGCGGCGGTTCTAGAGATCTGGTGGTTAGCTACGTGAACACCAACATGGGTCTGAAGTTCCGTCAACTGCTGTGGTTTCACATTAGCTGCCTGACCTTCGGTCGTGAAACCGTTATCGAGTATCTGGTGAGCTTTGGCGTTTGGATTCGTACCCCGCCGGCGTACCGCCCGCCGAATGCGCCGATCCTGAGCACCCTGCCGGAGACCACCGTTGTG(SEQ ID NO:10)
1.8、SpyTag-Ferritin序列
蛋白质序列:
AHIVMVDAYKPTKGGGGSGGGGSGGGGSRMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE(SEQ ID NO:11)
核苷酸序列:
ATGGCTCACATAGTAATGGTTGATGCATATAAACCAACGAAAGGTGGCGGCGGCTCCGGCGGTGGCGGCTCTGGTGGCGGAGGCTCTCGTATGTTGAAGGCGTTGAACGATCAGCTGAACCGCGAACTCTACAGCGCATACCTGTACTTCGCCATGGCAGCGTATTTCGAAGATCTGGGTCTGGAAGGTTTTGCTAATTGGATGAAAGCGCAAGCTGAAGAGGAGATCGGTCATGCTTTACGCTTTTATAACTATATTTATGATCGTAATGGTCGTGTCGAGCTGGATGAGATTCCGAAGCCGCCTAAAGAATGGGAAAGCCCGTTGAAGGCCTTCGAGGCTGCGTACGAGCACGAAAAATTCATCAGCAAAAGCATTTACGAGTTGGCGGCGCTGGCAGAAGAGGAGAAGGACTACTCGACCCGTGCGTTTCTGGAATGGTTTATCAACGAACAGGTTGAGGAGGAGGCGTCCGTGAAGAAAATCCTTGACAAGCTGAAGTTCGCCAAAGACAGCCCGCAGATCTTGTTTATGCTGGACAAAGAGCTGAGCGCGAGAGCACCGAAGCTGCCGGGTCTGCTGATGCAAGGTGGTGAA(SEQID NO:12)
1.9、Spycatcher-mCD24序列
蛋白质序列:
SYYHHHHHHDYDIPTTENLYFQGAMVDTLSGLSSEQGQSGDMTIEEDSATHIKFSKRDEDGKELAGATMELRDSSGKTISTWISDGQVKDFYLYPGKYTFVETAAPDGYEVATAITFTVNEQGQVTVNGKATKGDAHIGGGGSGGGGSGGGGSNQTSVAPFPGNQNISASPNPTNATTRG(SEQ ID NO:13)
核苷酸序列:
ATGTCATATTACCATCACCACCATCACCACGACTACGACATCCCGACGACGGAAAATTTATACTTTCAGGGTGCTATGGTTGATACTCTGTCTGGGCTGAGTAGCGAACAGGGTCAAAGCGGCGACATGACCATCGAGGAAGATAGCGCTACGCACATCAAATTCAGCAAACGCGACGAAGACGGCAAAGAACTGGCGGGTGCGACCATGGAACTCCGCGATTCTTCCGGTAAGACCATCTCCACCTGGATTAGCGATGGCCAGGTGAAAGACTTCTATTTATACCCGGGTAAGTATACCTTTGTTGAGACAGCGGCACCGGACGGCTATGAGGTCGCGACTGCGATCACCTTCACCGTTAATGAGCAGGGTCAAGTCACCGTCAACGGCAAAGCAACGAAAGGTGACGCTCACATTGGTGGCGGAGGCAGCGGTGGCGGAGGCAGCGGTGGCGGAGGCAGCAACCAGACCTCTGTTGCTCCGTTCCCGGGTAACCAGAACATCTCTGCTTCTCCGAACCCGACCAACGCTACCACCCGTGGT(SEQ ID NO:14)
1.10、mCD24-Ferritin序列
蛋白质序列:
NQTSVAPFPGNQNISASPNPTNATTRGGGGGSGGGGSGGGGSRMLKALNDQLNRELYSAYLYFAMAAYFEDLGLEGFANWMKAQAEEEIGHALRFYNYIYDRNGRVELDEIPKPPKEWESPLKAFEAAYEHEKFISKSIYELAALAEEEKDYSTRAFLEWFINEQVEEEASVKKILDKLKFAKDSPQILFMLDKELSARAPKLPGLLMQGGE(SEQ IDNO:15)
核苷酸序列:
ATGAATCAAACATCAGTAGCTCCATTTCCCGGAAACCAGAACATCAGCGCTTCCCCGAATCCGACGAACGCGACCACCCGTGGTGGTGGCGGCGGCTCCGGCGGTGGCGGCTCTGGTGGCGGAGGCTCTCGTATGTTGAAGGCGTTGAACGATCAGCTGAACCGCGAACTCTACAGCGCATACCTGTACTTCGCCATGGCAGCGTATTTCGAAGATCTGGGTCTGGAAGGTTTTGCTAATTGGATGAAAGCGCAAGCTGAAGAGGAGATCGGTCATGCTTTACGCTTTTATAACTATATTTATGATCGTAATGGTCGTGTCGAGCTGGATGAGATTCCGAAGCCGCCTAAAGAATGGGAAAGCCCGTTGAAGGCCTTCGAGGCTGCGTACGAGCACGAAAAATTCATCAGCAAAAGCATTTACGAGTTGGCGGCGCTGGCAGAAGAGGAGAAGGACTACTCGACCCGTGCGTTTCTGGAATGGTTTATCAACGAACAGGTTGAGGAGGAGGCGTCCGTGAAGAAAATCCTTGACAAGCTGAAGTTCGCCAAAGACAGCCCGCAGATCTTGTTTATGCTGGACAAAGAGCTGAGCGCGAGAGCACCGAAGCTGCCGGGTCTGCTGATGCAAGGTGGTGAA(SEQ ID NO:16)
SpyTag-Ferritin、Spycatcher-mCD24a、mCD24-Ferritin和HBcAg-mCD24和DNA序列均通过Nde1和EcoR1酶切位点克隆至pet24a(+)表达载体上。
2、纳米颗粒抗原的表达和纯化
2.1、诱导表达
取SpyTag-Ferritin--pet24a、Spycatcher-mCD24-pet24a、mCD24-Ferritin-pet24a和HBcAg-mCD24-pet24a质粒各1μL,分别转化大肠杆菌BL21(DE3)感受态细胞,吸取200μL菌液涂布在含卡那霉素的LB平板上,置37℃培养箱中培养过夜。于平板上挑取单克隆菌落,接种于含5mL LK培养基的试管中培养至菌体OD600=0.6-0.8,取1mL菌液接种到含1.5L LK培养基的三角瓶中,37℃培养至菌体OD600=1.0左右,加入终浓度为1mM IPTG 37℃诱导表达6h。
2.2、分离纯化
2.2.1、SpyTag-Ferritin分离纯化
诱导后的菌液5000rpm离心30分钟收菌体,破菌缓冲液(20mM Tris,50mM Nacl,PH7.0-8.0)重悬菌体,高压均质匀浆机800bar破碎菌体,12000rpm离心20分钟,收集破菌上清;将破菌上清于75℃加热15分钟,12000rpm离心20分钟,收集上清液;加热后离心上清液进行Q-FF阴离子交换层析纯化,上样、平衡洗柱后,以洗脱缓冲液(20mM Tris,500mM Nacl,PH7.0-8.0)进行梯度洗脱,目的蛋白存在于洗脱液中(图1)。
2.2.2、Spycatcher-mCD24分离纯化
诱导后的菌液5000rpm离心30分钟收菌体,破菌缓冲液(20mM Tris,50mM Nacl,PH7.0-8.0)重悬菌体,高压均质匀浆机800bar破碎菌体,12000rpm离心20分钟,收集破菌上清;破菌上清进行Q-FF阴离子交换层析,以20mM Tris,500mM Nacl,PH7.0-8.0溶液梯度洗脱,目的蛋白可结合到Q-FF层析柱,并在0.1-0.3M Nacl之间被洗脱;将Q-FF柱层析含有目的蛋白的洗脱液,加硫酸铵至终浓度为0.5M,进行Phenyl-Hisub疏水层析,以20mM Tris,50mM Nacl,PH7.0-8.0缓冲液洗脱,目的蛋白未挂柱,存在于流穿液中,大部分杂蛋白挂柱,低盐洗脱后可去除;取Phenyl-Hisub流穿液进行Q-HP阴离子交换层析,20mM Tris,500mMNacl,PH7.0-8.0溶液梯度洗脱,目的蛋白存在于洗脱液中(图2)。
2.2.3、mCD24-Ferritin分离纯化
诱导后的菌液5000rpm离心30分钟收集菌体,破菌缓冲液(50mM Tris,50mM Nacl,PH7.0-8.0)重悬菌体,高压均质匀浆机800bar破碎菌体,12000rpm离心20分钟,收集破菌上清;破菌上清采用DEAE FF阴离子交换层析(上样缓冲液50mmTris,50mmNacl,PH7.0-8.0),洗脱缓冲液(洗脱缓冲液50mmTris,1000mmNacl,0.03%Tween80,PH7.0-8.0)采用0%-50%线性洗脱,目的蛋白基本不挂柱,主要存在于流穿中;第二步采用Poros-50HQ阴离子交换层析,DEAE FF阴离子交换层析的流穿上样,洗脱缓冲液(洗脱缓冲液50mmTris,1000mmNacl,0.03%Tween80,PH7.0-8.0)阶段洗脱,目的蛋白基本不挂柱,主要存在于流穿中(图3)。
2.2.4、HBcAg-mCD24分离纯化
诱导后的菌液5000rpm离心30分钟收集菌体,破菌缓冲液(50mM Tris,50mM Nacl,PH7.0-8.0)重悬菌体,高压均质匀浆机800bar 3遍破碎菌体,12000rpm离心20分钟,收集破菌上清;破菌上清采用Poros-50HQ阴离子交换层析(上样缓冲液50mmTris,50mmNacl,PH7.0-8.0),洗脱缓冲液(洗脱缓冲液50mmTris,1500mmNacl,0.03%Tween80,PH7.0-8.0)采用15%和30%两阶段洗脱,15%和30%洗脱峰中均有目的蛋白,其中30%的洗脱峰中目的蛋白的纯度较高;第二步采用Chromdex-200体积排阻层析,上样缓冲液为PBS,以Poros-50HQ阴离子交换层析30%的洗脱组分上样,收集排阻峰(图4)。
2.2.5、SpyTag-Ferritin和Spycatcher-mCD24的组装
2.2.5.1、SpyTag-Ferritin和Spycatcher-mCD24组装条件优化
将SpyTag-Ferritin和Spycatcher-mCD24的蛋白浓度分别调整至0.5mg/ml左右。按照下表中所示比例将样品混合均匀,4℃连接过夜,SDS-PAGE电泳分析可见SpyTag-Ferritin和Spycatcher-mCD24比例在1:0.25-0.5之间的连接效率较高,SpyTag-Ferritin和Spycatcher-mCD24连接后的蛋白命名为SpymCD24-Ferritin(表1和图5)。
表1 SpyTag-Ferritin和Spycatcher-mCD24的组装
SpyTag-Ferritin:Spycatcher-mCD24(v:v) | |
1# | 0.5:1 |
2# | 1:1 |
3# | 1:0.5 |
4# | 1:0.25 |
2.2.5.2、SpyTag-Ferritin和Spycatcher-mCD24的组装后的纯化
按照SpyTag-Ferritin和Spycatcher-mCD24的蛋白浓度分别调整至0.5mg/ml左右。按照1:0.25的体积比4℃连接过夜,连接产物经超滤浓缩后,采用Chromdex-200体积排阻层析纯化,收集排阻峰(图6)。
3、电镜观察
将mCD24-Ferritin、SpyTag-Ferritin、SpymCD24-Ferritin和HBcAg-mCD24纯化后的样品取100μL进行透射电镜观察。mCD24-Ferritin、SpyTag-Ferritin、SpymCD24-Ferritin和HBcAg-mCD24均呈纳米颗粒形态(图7-图10)。
4、动物实验
4.1、小鼠免疫
纯化后的SpymCD24-Ferritin、mCD24-Ferritin、HBcAg-mCD24和mCD24多肽(免疫剂量相当于1.4×1015个mCD24分子)分别与200μg/mL氢氧化铝佐剂等体积混合均匀,4℃吸附过夜,每组8只小鼠,每只小鼠腹腔免疫0.5mL,共免疫三次,两次免疫间隔4周,每次免疫后4周尾静脉取血,用ELISA方法检测抗体滴度(表2)。
表2,ELISA抗体滴度
4.2、小鼠肿瘤模型
经SpymCD24-Ferritin、mCD24-Ferritin、HBcAg-mCD24和mCD24免疫三次后,每只小鼠皮下接种1.0×106个4T1小鼠乳腺癌细胞,接种后第7天处死小鼠,摘取肿瘤组织并称重。结果显示,与mCD24对照组相比,SpymCD24-Ferritin和HBcAg-mCD24组的小鼠肿瘤重量明显小于mCD24对照组,表明小鼠免疫后产生的针对mCD24的抗体可抑制肿瘤细胞的生长(表3和图11)。
表3,肿瘤重量
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SEQUENCE LISTING
<110> 上海至成生物科技有限公司
<120> CD24疫苗
<130> 220401
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 27
<212> PRT
<213> Mus musculus
<400> 1
Asn Gln Thr Ser Val Ala Pro Phe Pro Gly Asn Gln Asn Ile Ser Ala
1 5 10 15
Ser Pro Asn Pro Thr Asn Ala Thr Thr Arg Gly
20 25
<210> 2
<211> 31
<212> PRT
<213> Homo sapiens
<400> 2
Ser Glu Thr Thr Thr Gly Thr Ser Ser Asn Ser Ser Gln Ser Thr Ser
1 5 10 15
Asn Ser Gly Leu Ala Pro Asn Pro Thr Asn Ala Thr Thr Lys Val
20 25 30
<210> 3
<211> 170
<212> PRT
<213> Pyrococcus furiosus
<400> 3
Arg Met Leu Lys Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser
1 5 10 15
Ala Tyr Leu Tyr Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu
20 25 30
Glu Gly Phe Ala Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly
35 40 45
His Ala Leu Arg Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val
50 55 60
Glu Leu Asp Glu Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu
65 70 75 80
Lys Ala Phe Glu Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser
85 90 95
Ile Tyr Glu Leu Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr
100 105 110
Arg Ala Phe Leu Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala
115 120 125
Ser Val Lys Lys Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro
130 135 140
Gln Ile Leu Phe Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys
145 150 155 160
Leu Pro Gly Leu Leu Met Gln Gly Gly Glu
165 170
<210> 4
<211> 13
<212> PRT
<213> Artificial Sequence
<220>
<223> SpyTag
<400> 4
Ala His Ile Val Met Val Asp Ala Tyr Lys Pro Thr Lys
1 5 10
<210> 5
<211> 139
<212> PRT
<213> Artificial Sequence
<220>
<223> Spycatcher
<400> 5
Met Ser Tyr Tyr His His His His His His Asp Tyr Asp Ile Pro Thr
1 5 10 15
Thr Glu Asn Leu Tyr Phe Gln Gly Ala Met Val Asp Thr Leu Ser Gly
20 25 30
Leu Ser Ser Glu Gln Gly Gln Ser Gly Asp Met Thr Ile Glu Glu Asp
35 40 45
Ser Ala Thr His Ile Lys Phe Ser Lys Arg Asp Glu Asp Gly Lys Glu
50 55 60
Leu Ala Gly Ala Thr Met Glu Leu Arg Asp Ser Ser Gly Lys Thr Ile
65 70 75 80
Ser Thr Trp Ile Ser Asp Gly Gln Val Lys Asp Phe Tyr Leu Tyr Pro
85 90 95
Gly Lys Tyr Thr Phe Val Glu Thr Ala Ala Pro Asp Gly Tyr Glu Val
100 105 110
Ala Thr Ala Ile Thr Phe Thr Val Asn Glu Gln Gly Gln Val Thr Val
115 120 125
Asn Gly Lys Ala Thr Lys Gly Asp Ala His Ile
130 135
<210> 6
<211> 149
<212> PRT
<213> Artificial Sequence
<220>
<223> HBcAg 149aa
<400> 6
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Val Asn Leu Glu Asp Pro Ala
65 70 75 80
Ser Arg Asp Leu Val Val Ser Tyr Val Asn Thr Asn Met Gly Leu Lys
85 90 95
Phe Arg Gln Leu Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg
100 105 110
Glu Thr Val Ile Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr
115 120 125
Pro Pro Ala Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro
130 135 140
Glu Thr Thr Val Val
145
<210> 7
<211> 159
<212> PRT
<213> Artificial Sequence
<220>
<223> HBcAg variant
<400> 7
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Val Asn Leu Glu Asp Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Gly Gly Thr Pro Ala Ser Arg Asp Leu Val Val
85 90 95
Ser Tyr Val Asn Thr Asn Met Gly Leu Lys Phe Arg Gln Leu Leu Trp
100 105 110
Phe His Ile Ser Cys Leu Thr Phe Gly Arg Glu Thr Val Ile Glu Tyr
115 120 125
Leu Val Ser Phe Gly Val Trp Ile Arg Thr Pro Pro Ala Tyr Arg Pro
130 135 140
Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro Glu Thr Thr Val Val
145 150 155
<210> 8
<211> 477
<212> DNA
<213> Artificial Sequence
<220>
<223> HBcAg variant
<400> 8
atggacattg acccgtacaa ggagtttggt gcgaccgttg aactgctgag ctttctgccg 60
agcgactttt tcccgagcgt gcgtgatctg ctggacaccg cgagcgcgct gtaccgtgaa 120
gcgctggaaa gcccggagca ctgcagcccg caccacaccg cgctgcgtca ggcgatcctg 180
tgctggggtg aactgatgac cctggcgacc tgggtgggcg ttaacctgga ggatggtggc 240
ggtggcagcg gtggcggtgg taccccggcg tctagagatc tggtggttag ctacgtgaac 300
accaacatgg gtctgaagtt ccgtcaactg ctgtggtttc acattagctg cctgaccttc 360
ggtcgtgaaa ccgttatcga gtatctggtg agctttggcg tttggattcg taccccgccg 420
gcgtaccgcc cgccgaatgc gccgatcctg agcaccctgc cggagaccac cgttgtg 477
<210> 9
<211> 193
<212> PRT
<213> Artificial Sequence
<220>
<223> HBcAg-mCD24
<400> 9
Met Asp Ile Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Glu Leu Leu
1 5 10 15
Ser Phe Leu Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp
20 25 30
Thr Ala Ser Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Glu His Cys
35 40 45
Ser Pro His His Thr Ala Leu Arg Gln Ala Ile Leu Cys Trp Gly Glu
50 55 60
Leu Met Thr Leu Ala Thr Trp Val Gly Val Asn Leu Glu Asp Gly Gly
65 70 75 80
Gly Gly Ser Gly Gly Gly Gly Thr Asn Gln Thr Ser Val Ala Pro Phe
85 90 95
Pro Gly Asn Gln Asn Ile Ser Ala Ser Pro Asn Pro Thr Asn Ala Thr
100 105 110
Thr Arg Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Asp Leu
115 120 125
Val Val Ser Tyr Val Asn Thr Asn Met Gly Leu Lys Phe Arg Gln Leu
130 135 140
Leu Trp Phe His Ile Ser Cys Leu Thr Phe Gly Arg Glu Thr Val Ile
145 150 155 160
Glu Tyr Leu Val Ser Phe Gly Val Trp Ile Arg Thr Pro Pro Ala Tyr
165 170 175
Arg Pro Pro Asn Ala Pro Ile Leu Ser Thr Leu Pro Glu Thr Thr Val
180 185 190
Val
<210> 10
<211> 579
<212> DNA
<213> Artificial Sequence
<220>
<223> HBcAg-mCD24
<400> 10
atggacattg acccgtacaa ggagtttggt gcgaccgttg aactgctgag ctttctgccg 60
agcgactttt tcccgagcgt gcgtgatctg ctggacaccg cgagcgcgct gtaccgtgaa 120
gcgctggaaa gcccggagca ctgcagcccg caccacaccg cgctgcgtca ggcgatcctg 180
tgctggggtg aactgatgac cctggcgacc tgggtgggcg ttaacctgga ggatggtggc 240
ggtggcagcg gtggcggtgg taccaatcaa acatcagtag ctccatttcc cggaaaccag 300
aacatcagcg cttccccgaa tccgacgaac gcgaccaccc gtggtggtgg cggtggcagc 360
ggtggcggcg gttctagaga tctggtggtt agctacgtga acaccaacat gggtctgaag 420
ttccgtcaac tgctgtggtt tcacattagc tgcctgacct tcggtcgtga aaccgttatc 480
gagtatctgg tgagctttgg cgtttggatt cgtaccccgc cggcgtaccg cccgccgaat 540
gcgccgatcc tgagcaccct gccggagacc accgttgtg 579
<210> 11
<211> 198
<212> PRT
<213> Artificial Sequence
<220>
<223> SpyTag-Ferritin
<400> 11
Ala His Ile Val Met Val Asp Ala Tyr Lys Pro Thr Lys Gly Gly Gly
1 5 10 15
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Met Leu Lys
20 25 30
Ala Leu Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser Ala Tyr Leu Tyr
35 40 45
Phe Ala Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu Glu Gly Phe Ala
50 55 60
Asn Trp Met Lys Ala Gln Ala Glu Glu Glu Ile Gly His Ala Leu Arg
65 70 75 80
Phe Tyr Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val Glu Leu Asp Glu
85 90 95
Ile Pro Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu Lys Ala Phe Glu
100 105 110
Ala Ala Tyr Glu His Glu Lys Phe Ile Ser Lys Ser Ile Tyr Glu Leu
115 120 125
Ala Ala Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr Arg Ala Phe Leu
130 135 140
Glu Trp Phe Ile Asn Glu Gln Val Glu Glu Glu Ala Ser Val Lys Lys
145 150 155 160
Ile Leu Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro Gln Ile Leu Phe
165 170 175
Met Leu Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys Leu Pro Gly Leu
180 185 190
Leu Met Gln Gly Gly Glu
195
<210> 12
<211> 597
<212> DNA
<213> Artificial Sequence
<220>
<223> SpyTag-Ferritin
<400> 12
atggctcaca tagtaatggt tgatgcatat aaaccaacga aaggtggcgg cggctccggc 60
ggtggcggct ctggtggcgg aggctctcgt atgttgaagg cgttgaacga tcagctgaac 120
cgcgaactct acagcgcata cctgtacttc gccatggcag cgtatttcga agatctgggt 180
ctggaaggtt ttgctaattg gatgaaagcg caagctgaag aggagatcgg tcatgcttta 240
cgcttttata actatattta tgatcgtaat ggtcgtgtcg agctggatga gattccgaag 300
ccgcctaaag aatgggaaag cccgttgaag gccttcgagg ctgcgtacga gcacgaaaaa 360
ttcatcagca aaagcattta cgagttggcg gcgctggcag aagaggagaa ggactactcg 420
acccgtgcgt ttctggaatg gtttatcaac gaacaggttg aggaggaggc gtccgtgaag 480
aaaatccttg acaagctgaa gttcgccaaa gacagcccgc agatcttgtt tatgctggac 540
aaagagctga gcgcgagagc accgaagctg ccgggtctgc tgatgcaagg tggtgaa 597
<210> 13
<211> 180
<212> PRT
<213> Artificial Sequence
<220>
<223> Spycatcher-mCD24
<400> 13
Ser Tyr Tyr His His His His His His Asp Tyr Asp Ile Pro Thr Thr
1 5 10 15
Glu Asn Leu Tyr Phe Gln Gly Ala Met Val Asp Thr Leu Ser Gly Leu
20 25 30
Ser Ser Glu Gln Gly Gln Ser Gly Asp Met Thr Ile Glu Glu Asp Ser
35 40 45
Ala Thr His Ile Lys Phe Ser Lys Arg Asp Glu Asp Gly Lys Glu Leu
50 55 60
Ala Gly Ala Thr Met Glu Leu Arg Asp Ser Ser Gly Lys Thr Ile Ser
65 70 75 80
Thr Trp Ile Ser Asp Gly Gln Val Lys Asp Phe Tyr Leu Tyr Pro Gly
85 90 95
Lys Tyr Thr Phe Val Glu Thr Ala Ala Pro Asp Gly Tyr Glu Val Ala
100 105 110
Thr Ala Ile Thr Phe Thr Val Asn Glu Gln Gly Gln Val Thr Val Asn
115 120 125
Gly Lys Ala Thr Lys Gly Asp Ala His Ile Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asn Gln Thr Ser Val Ala Pro
145 150 155 160
Phe Pro Gly Asn Gln Asn Ile Ser Ala Ser Pro Asn Pro Thr Asn Ala
165 170 175
Thr Thr Arg Gly
180
<210> 14
<211> 543
<212> DNA
<213> Artificial Sequence
<220>
<223> Spycatcher-mCD24
<400> 14
atgtcatatt accatcacca ccatcaccac gactacgaca tcccgacgac ggaaaattta 60
tactttcagg gtgctatggt tgatactctg tctgggctga gtagcgaaca gggtcaaagc 120
ggcgacatga ccatcgagga agatagcgct acgcacatca aattcagcaa acgcgacgaa 180
gacggcaaag aactggcggg tgcgaccatg gaactccgcg attcttccgg taagaccatc 240
tccacctgga ttagcgatgg ccaggtgaaa gacttctatt tatacccggg taagtatacc 300
tttgttgaga cagcggcacc ggacggctat gaggtcgcga ctgcgatcac cttcaccgtt 360
aatgagcagg gtcaagtcac cgtcaacggc aaagcaacga aaggtgacgc tcacattggt 420
ggcggaggca gcggtggcgg aggcagcggt ggcggaggca gcaaccagac ctctgttgct 480
ccgttcccgg gtaaccagaa catctctgct tctccgaacc cgaccaacgc taccacccgt 540
ggt 543
<210> 15
<211> 212
<212> PRT
<213> Artificial Sequence
<220>
<223> mCD24-Ferritin
<400> 15
Asn Gln Thr Ser Val Ala Pro Phe Pro Gly Asn Gln Asn Ile Ser Ala
1 5 10 15
Ser Pro Asn Pro Thr Asn Ala Thr Thr Arg Gly Gly Gly Gly Gly Ser
20 25 30
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg Met Leu Lys Ala Leu
35 40 45
Asn Asp Gln Leu Asn Arg Glu Leu Tyr Ser Ala Tyr Leu Tyr Phe Ala
50 55 60
Met Ala Ala Tyr Phe Glu Asp Leu Gly Leu Glu Gly Phe Ala Asn Trp
65 70 75 80
Met Lys Ala Gln Ala Glu Glu Glu Ile Gly His Ala Leu Arg Phe Tyr
85 90 95
Asn Tyr Ile Tyr Asp Arg Asn Gly Arg Val Glu Leu Asp Glu Ile Pro
100 105 110
Lys Pro Pro Lys Glu Trp Glu Ser Pro Leu Lys Ala Phe Glu Ala Ala
115 120 125
Tyr Glu His Glu Lys Phe Ile Ser Lys Ser Ile Tyr Glu Leu Ala Ala
130 135 140
Leu Ala Glu Glu Glu Lys Asp Tyr Ser Thr Arg Ala Phe Leu Glu Trp
145 150 155 160
Phe Ile Asn Glu Gln Val Glu Glu Glu Ala Ser Val Lys Lys Ile Leu
165 170 175
Asp Lys Leu Lys Phe Ala Lys Asp Ser Pro Gln Ile Leu Phe Met Leu
180 185 190
Asp Lys Glu Leu Ser Ala Arg Ala Pro Lys Leu Pro Gly Leu Leu Met
195 200 205
Gln Gly Gly Glu
210
<210> 16
<211> 639
<212> DNA
<213> Artificial Sequence
<220>
<223> mCD24-Ferritin
<400> 16
atgaatcaaa catcagtagc tccatttccc ggaaaccaga acatcagcgc ttccccgaat 60
ccgacgaacg cgaccacccg tggtggtggc ggcggctccg gcggtggcgg ctctggtggc 120
ggaggctctc gtatgttgaa ggcgttgaac gatcagctga accgcgaact ctacagcgca 180
tacctgtact tcgccatggc agcgtatttc gaagatctgg gtctggaagg ttttgctaat 240
tggatgaaag cgcaagctga agaggagatc ggtcatgctt tacgctttta taactatatt 300
tatgatcgta atggtcgtgt cgagctggat gagattccga agccgcctaa agaatgggaa 360
agcccgttga aggccttcga ggctgcgtac gagcacgaaa aattcatcag caaaagcatt 420
tacgagttgg cggcgctggc agaagaggag aaggactact cgacccgtgc gtttctggaa 480
tggtttatca acgaacaggt tgaggaggag gcgtccgtga agaaaatcct tgacaagctg 540
aagttcgcca aagacagccc gcagatcttg tttatgctgg acaaagagct gagcgcgaga 600
gcaccgaagc tgccgggtct gctgatgcaa ggtggtgaa 639
Claims (10)
1.一种免疫原性复合物,其包含:(a)CD24或其免疫原性片段以及(b)载体蛋白,
优选地,所述载体蛋白是能形成纳米颗粒的载体蛋白,和/或
优选地,(a)和(b)共价连接;更优选地,所述共价连接是肽键或通过SpyCatcher-SpyTag共价连接形成的异肽键,和/或
优选地,所述CD24是小鼠CD24或人CD24。
2.如权利要求1所述的免疫原性复合物,其特征在于,所述免疫原性复合物是融合多肽,包含:(a)CD24或其免疫原性片段以及(b)乙肝核心抗原(HBcAg)或其变体,其中,所述HBcAg变体是(1)HBcAg的C末端缺失34或更少个氨基酸的变体,或(2)HBcAg在第78位氨基酸之后具有插入序列的并在C末端缺失34或更少个氨基酸的变体,
优选地,所述插入序列是((G)oS(G)pT)q,其中o、p和q各自独立是选自0、1、2、3、4、5和6的整数;更优选地,q是1,o和p各自独立是选自0、1、2、3的整数,
优选地,所述CD24或其免疫原性片段位于HBcAg或其变体的第78位氨基酸之后或所述插入序列之后,将HBcAg或其变体分成位于N端的A和位于C端的B两个部分,
优选地,所述CD24或其免疫原性片段的C端与所述B部分通过接头连接;更优选地,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数。
3.如权利要求2所述的免疫原性复合物,其特征在于,
所述HBcAg变体具有SEQ ID NO:6或7所示序列,所述CD24或其免疫原性片段位于SEQID NO:6的第78位氨基酸之后或SEQ ID NO:7的第88位氨基酸之后,
优选地,所述免疫原性复合物的序列如SEQ ID NO:9所示。
4.如权利要求1所述的免疫原性复合物,其特征在于,所述免疫原性复合物包含通过SpyCatcher-SpyTag共价连接的:
(a)与SpyCatcher连接的CD24或其免疫原性片段,和(b)与SpyTag连接的Ferritin蛋白,或者
(a’)与SpyTag连接的CD24或其免疫原性片段,和(b’)与SpyCatcher连接的Ferritin蛋白,
优选地,所述各连接各自独立是直接连接或通过接头连接;更优选地,接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数,
所述Ferritin蛋白来自人、马、牛蛙或细菌。
5.如权利要求4所述的免疫原性复合物,其特征在于,
所述Ferritin蛋白具有SEQ ID NO:3所示的序列,
所述SpyTag具有SEQ ID NO:4所示的序列,
所述SpyCatcher具有SEQ ID NO:5所示的序列,
(a)组分如SEQ ID NO:13所示;(b)组分如SEQ ID NO:11所示。
6.一种组合物,包含(1)与SpyCatcher连接的CD24或其免疫原性片段,和与SpyTag连接的Ferritin蛋白,和/或(2)与SpyTag连接的CD24或其免疫原性片段,和与SpyCatcher连接的Ferritin蛋白,
优选地,所述各连接各自独立是直接连接或通过接头连接;更优选地,所述接头是((G)mS)n,其中m和n各自独立是选自0、1、2、3、4、5、6、7、8、9和10的整数,
优选地,所述Ferritin蛋白来自人、马、牛蛙或细菌;更优选地,所述Ferritin蛋白具有SEQ ID NO:3所示的序列,
优选地,所述SpyTag具有SEQ ID NO:4所示的序列,
优选地,所述SpyCatcher具有SEQ ID NO:5所示的序列,
优选地,所述CD24是小鼠CD24或人CD24;更优选地,所述CD24具有SEQ ID NO:1或2所示的序列,
更优选地,所述组合物包含具有SEQ ID NO:11和13所示序列的多肽。
7.一种免疫原性组合物,其包含权利要求1-5中任一项所述的免疫原性复合物和佐剂,
优选地,所述佐剂是氢氧化铝。
8.一种药物组合物,其包含:权利要求1-5中任一项所述的免疫原性复合物或权利要求7所述的免疫原性组合物,和药学上可接受的辅料。
9.一种试剂盒,其包含:权利要求7所述的免疫原性组合物或权利要求8所述的药物组合物,以及用于施用它们的容器。
10.权利要求1-5中任一项所述的免疫原性复合物或权利要求7所述的免疫原性组合物在制备药物中的用途,
优选地,所述药物用于预防、减轻或者治疗CD24相关疾病或病症,
更优选地,所述CD24相关疾病或病症是受益于CD24被抑制的疾病或病症。
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CN202210066823.9A CN116509997A (zh) | 2022-01-20 | 2022-01-20 | Cd24疫苗 |
PCT/CN2023/073026 WO2023138636A1 (zh) | 2022-01-20 | 2023-01-19 | Cd24疫苗 |
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CA3064556A1 (en) * | 2017-05-22 | 2018-11-29 | Oncoimmune, Inc. | Methods of use of soluble cd24 for treating immune related adverse events in cancer therapies |
CN108434450B (zh) * | 2018-02-06 | 2020-09-29 | 中国科学院生物物理研究所 | 基于铁蛋白纳米颗粒的疫苗及其制备方法 |
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