CN117264065A - 一种her2抗原结合分子及其应用 - Google Patents
一种her2抗原结合分子及其应用 Download PDFInfo
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Abstract
本发明公开了一种HER2抗原结合分子及其应用。所述HER2抗原结合分子至少包含一条VHH链,所述VHH链包含CDR1、CDR2和CDR3,其中,所述CDR1包含如SEQ ID NO:13所示的氨基酸序列,CDR2包含如SEQ ID NO:14所示的氨基酸序列,CDR3包含如SEQ ID NO:15所示的氨基酸序列。本发明提供的HER2抗原结合分子显示了与曲妥珠单抗相当的结合HER2的活性且具有与曲妥珠单抗竞争性结合HER2的活性;本发明提供的HER2抗原结合分子经ADCC和内吞活性检测,显示具有较好的杀伤肿瘤细胞的效果。
Description
技术领域
本发明属于生物技术领域,具体涉及一种HER2抗原结合分子及其应用。
背景技术
HER2基因是一种原癌基因,其编码p185跨膜蛋白,具有酪氨酸激酶活性,属于人类表皮生长因子受体(HER)家族,该家族成员包括HER1、HER2、HER3和HER4。HER家族调节正常乳腺的生长和发育,但HER2的过度表达与乳腺癌有关。HER2的过表达导致HER2同源及异源二聚体形成增多,从而通过激活PI3K及MAPK通路引起细胞增殖、抗凋亡、侵袭及血管生成等效应。大约15%-30%的乳腺癌和10%-30%的胃/食管癌会发生HER2基因扩增或过度表达。HER2过表达也可见于其他肿瘤如卵巢癌、肺癌、结肠癌等。针对HER2靶点相关的抗体药物包括单抗、双特异性抗体和ADC等形式。
其中,曲妥珠单抗(Trastuzumab)是首个针对HER2靶点的人源化单克隆抗体药物,与HER2受体胞外结构域IV结合,由此,在高HER2过表达的细胞内阻断配体非依赖性HER2同二聚化,并在一定程度上还阻断HER2与其他家族成员的异二聚化。围绕HER2靶点开发的双特异性抗体、ADC等药物大多数基于曲妥珠单抗或其相似表位抗体进行的药物开发。因此,开发与曲妥珠单抗具有相似表位的有效针对HER2的特异性单结构域抗体应具有重要价值。
发明内容
为解决现有技术中缺少与曲妥珠单抗具有相似表位的有效针对HER2的特异性单结构域抗体的问题,本发明提供了一种HER2抗原结合分子及其应用。本发明以HER2作为靶标,通过抗原免疫羊驼、构建纳米抗体噬菌体展示文库以及筛选文库,获得具有结合HER2抗原活性和与曲妥珠单抗竞争的纳米抗体分子,经细胞水平FACS亲和、内吞、ADCC等检测,显示具有较好的结合及杀伤肿瘤细胞的效果。
为解决上述技术问题,本发明提供的技术方案之一为:一种HER2抗原结合分子,所述抗原结合分子至少包含一条VHH链,所述VHH链包含选自以下的CDR1、CDR2和CDR3:CDR1包含如SEQ ID NO:13所示的氨基酸序列GFTLSTYX1MT,其中,X1为T或S;CDR2包含如SEQ ID NO:14所示的氨基酸序列TIAPGX2VTG,其中,X2为D或G;以及CDR3包含如SEQ ID NO:15所示的氨基酸序列PHRX3X4,其中,X3为R或V,X4为F或Y。
在一些实施方案中,所述CDR1包含如SEQ ID NO:6或SEQ ID NO:7所示的氨基酸序列,所述CDR2包含如SEQ ID NO:8或SEQ ID NO:9所示的氨基酸序列,以及所述CDR3包含如SEQ ID NO:10、SEQ ID NO:11或SEQ ID NO:12所示的氨基酸序列。
在一些实施方案中,所述CDR1的氨基酸序列如SEQ ID NO:6所示,CDR2的氨基酸序列如SEQ ID NO:8所示,CDR3的氨基酸序列如SEQ ID NO:10所示;或,所述CDR1的氨基酸序列如SEQ ID NO:6所示,CDR2的氨基酸序列如SEQ ID NO:9所示,CDR3的氨基酸序列如SEQID NO:11所示;或,所述CDR1的氨基酸序列如SEQ ID NO:7所示,CDR2的氨基酸序列如SEQID NO:9所示,CDR3的氨基酸序列如SEQ ID NO:11所示;或,所述CDR1的氨基酸序列如SEQID NO:7所示,CDR2的氨基酸序列如SEQ ID NO:8所示,CDR3的氨基酸序列如SEQ ID NO:12所示。
在一些实施方案中,所述VHH链包含如SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5任一所示的氨基酸序列或其变体;
其中,所述变体与其所源自的序列相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列相同性。
在一些实施方案中,所述HER2抗原结合分子还包含免疫球蛋白的Fc区;
在本发明优选的实施方案中,所述Fc区为人IgG1的Fc区;
在本发明更优选的实施方案中,所述Fc区的氨基酸序列如SEQ ID NO:16所示。
本发明提供的技术方案之二为:一种分离的核酸,所述核酸编码如技术方案之一所述的HER2抗原结合分子。
本发明提供的技术方案之三为:一种重组表达载体,所述重组表达载体包含如技术方案之二所述的分离的核酸;
在本发明优选的实施方案中,所述重组表达载体为质粒、粘粒、噬菌体或病毒载体;所述质粒的骨架例如为pcDNA3.4。
本发明提供的技术方案之四为:一种宿主细胞,所述宿主细胞包含如技术方案之三所述的重组表达载体;
在本发明优选的实施方案中,所述宿主细胞为原核细胞或真核细胞;
在本发明更优选的实施方案中,所述真核细胞为酵母细胞或哺乳动物细胞;其中,所述哺乳动物细胞例如为HEK293细胞。
本发明提供的技术方案之五为:一种HER2抗原结合分子的制备方法,所述方法包含以下步骤:
在适宜如技术方案之四所述的宿主细胞生长和发酵的条件下培养所述宿主细胞,从培养物中获得HER2抗原结合分子。
本发明提供的技术方案之六为:一种多特异性抗体,其包括如技术方案之一所述的HER2抗原结合分子,以及与所述HER2抗原结合分子可操作地连接的具有另一种抗原结合特性的抗原结合分子。
本发明提供的技术方案之七为:一种药物组合物,所述药物组合物包含如技术方案之一所述的HER2抗原结合分子,以及药学上可接受的载体;
在本发明优选的实施方案中,所述药物组合物还含有由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的组中的一种或多种。
本发明提供的技术方案之八为:如技术方案之一所述的HER2抗原结合分子、技术方案之二所述的核酸、技术方案之三所述的重组表达载体、技术方案之四所述的宿主细胞、技术方案之六所述的多特异性抗体或技术方案之七所述的药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
本发明提供的技术方案之九为:一种试剂盒,所述试剂盒包括如技术方案之一所述的HER2抗原结合分子、技术方案之二所述的核酸、技术方案之三所述的重组表达载体、技术方案之四所述的宿主细胞、技术方案之六所述的多特异性抗体或技术方案之七所述的药物组合物;
在本发明优选的实施方案中,所述试剂盒还包括(i)施用抗体或药物组合物的装置;和/或(ii)使用说明。
本发明提供的技术方案之十为:一种套装药盒,所述套装药盒包含药盒A和药盒B,其中,
所述药盒A含有如技术方案之一所述的HER2抗原结合分子,技术方案之六所述的多特异性抗体或技术方案之七所述的药物组合物;
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的组中的一种或多种。
本发明提供的技术方案之十一为:一种免疫检测或者测定HER2的方法,所述的方法包括使用如技术方案之一所述的HER2抗原结合分子、技术方案之六所述的多特异性抗体或技术方案之七所述的药物组合物与待检测样本混合;
在本发明优选的实施方案中,所述检测为非诊断目的的检测。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明的积极进步效果在于:本发明提供的HER2抗原结合分子显示了与曲妥珠单抗相当的结合HER2的活性且具有与曲妥珠单抗竞争性结合HER2的活性;本发明提供的HER2抗原结合分子经ADCC和内吞活性检测,显示具有较好的杀伤肿瘤细胞的效果。
附图说明
图1显示了用ELISA方法测定候选抗体结合HER2的亲和活性。
图2显示了用ELISA方法测定候选抗体与曲妥珠单抗(Trmab)竞争性结合HER2的竞争活性。
图3A-图3C显示了基于FACS方法测定候选抗体结合肿瘤细胞表面HER2的亲和活性,其中,图3A、图3B、图3C分别为在SK-BR-3细胞、BT-474细胞和SK-OV-3细胞上的FACS检测结果。
图4A和图4B显示候选抗体在SK-BR-3细胞上的ADCC活性。
图5A和图5B显示候选抗体在SK-BR-3细胞上的内吞活性。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。本发明所用试剂和原料均市售可得。
本发明中所用的术语的解释具体如下:
如本文所用,术语“抗体”以最广义使用,其涵盖单克隆抗体、多克隆抗体,涵盖单特异性抗体、多特异性抗体(例如双特异性抗体、diabody、triabody和tetrabody、串联二-scFv、串联三-scFv),也涵盖传统抗体(由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构抗体),以及具有抗原结合活性的Fab、Fab’、F(ab’)2、Fv、线性抗体、单链抗体、scFv、sdAb、sdFv、纳米抗体、肽抗体peptibody、结构域抗体(重链(VH)抗体、轻链(VL)抗体)。
术语“Fc”区是包含抗体的CH2和CH3结构域的两个重链片段,两个重链片段由两个或多个二硫键并通过CH3结构域的疏水作用保持在一起。现有技术中已公开多种Fc恒定区变体,例如抗体的重链恒定区的Fc具有238、265、269、270、297、327和329(采用EU编号系统)中的一个或更多个氨基酸的替代(美国专利No.6,737,056),或者抗体的重链恒定区的Fc具有234、235、265、329(采用EU编号系统)处的一个或更多个氨基酸的替代,或者抗体的重链恒定区的Fc具有238、252、254、256、265、272、286、303、305、307、311、312、317、340、356、360、362、376、378、380、382、413、424或434(采用EU编号系统)处的一个或更多个氨基酸的替代(参见美国专利No.7,371,826)等。这些突变已被证实使得抗体具有新的性能,但不改变抗体可变区的功能。
如本文所用,术语“HER2”(也被称为ErbB-2,HER-2和CD340)是指人表皮生长因子受体2(SwissProt P04626),包括细胞(包括肿瘤细胞)天然表达的或用HER2基因转染的细胞上表达的HER2的任何变体、同种型和物种同源物。物种同源物包括猕猴HER2(猕猴;GenBank登录号GI:109114897)。
如本文所用,术语“VHH”和“纳米抗体”具有相同的含义并可互换使用,是由单一重链可变结构域形成的小型稳定及高效的抗原识别单元,从C端到N端仅包含一条链FR4-CDR3-FR3-CDR2-FR2-CDR1-FR1的抗体。VHH特异性结合表位无需其他抗原结合结构域一起识别(此与常规四肽链结构抗体不同,常规四肽链结构抗体的表位由VL与VH形成的结构对一起识别)。纳米抗体具有优良的生物学特性,分子量12-15kDa,是完整抗体的十分之一,具有很好的组织穿透性,特异性高,水溶性好。因其特殊的结构性质,兼具了传统抗体与小分子药物的优势,几乎克服了传统抗体的开发周期长,稳定性较低,保存条件苛刻等缺陷,逐渐成为新一代抗体治疗中的新兴力量,在免疫诊断和治疗中显示出广阔的应用前景。VHH包括但不限于经骆驼科动物产生的天然抗体,也可以是骆驼科动物产生的抗体后再经人源化的,也可以是经噬菌体展示技术筛选获得的。获得结合特定抗原或表位的VHH的方法,先前已公开于例如以下文献中:R.van der Linden等人,Journal of Immunological Methods,240(2000)185-195;Li等人,J Biol Chem.,287(2012)13713-13721;Deffar等人,AfricanJournal of Biotechnology Vol.8(12),pp.2645-2652,6月17日,2009和WO94/04678。
术语“互补决定区”或“CDR区”或“CDR”是抗体可变结构域中在序列上高变并且形成在结构上确定的环(“超变环”)和/或含有抗原接触残基(“抗原接触点”)的区域。CDR主要负责与抗原表位结合,从N-端开始顺序编号依次包括CDR1、CDR2和CDR3。在一个给定的重链可变区氨基酸序列中,各CDR的精确氨基酸序列边界可以使用许多公知的抗体CDR指派系统的任一种或其组合确定,所述指派系统包括例如:基于抗体的三维结构和CDR环的拓扑学的Chothia(Chothia等人(1989)Nature 342:877-883,Al-Lazikani等人,“Standardconformations for the canonical structures of immunoglobulins”,Journal ofMolecular Biology,273,927-948(1997)),基于抗体序列可变性的Kabat(Kabat等人,Sequences of Proteins of Immunological Interest,第4版,U.S.Department ofHealth and Human Services,National Institutes of Health(1987)),AbM(Universityof Bath),Contact(University College London),国际ImMunoGeneTics database(IMGT)(http://imgt.cines.fr/),以及基于利用大量晶体结构的近邻传播聚类(affinitypropagation clustering)的North CDR定义。
除非另有说明,否则在本发明中,术语“CDR”或“CDR序列”涵盖以上述任一种方式确定的CDR序列。
CDR也可以基于与参考CDR序列(例如本发明示例的CDR之任一序列)具有相同的AbM编号位置而确定。在一个实施方案中,本发明的单结构域抗体的CDR根据AbM编号方案确定位置。
除非另有说明,否则在本发明中,当提及抗体可变区和CDR中的残基位置(包括重链可变区残基)时,是指根据AbM编号系统的编号位置。
具有不同特异性(即,针对不同抗原的不同结合位点)的抗体具有不同的CDR。然而,尽管CDR在抗体与抗体之间是不同的,但是CDR内只有有限数量的氨基酸位置直接参与抗原结合。使用Kabat、Chothia、AbM、IMGT和Contact方法中的至少两种,可以确定最小重叠区域,从而提供用于抗原结合的“最小结合单位”。最小结合单位可以是CDR的一个子部分。正如本领域技术人员明了,通过抗体的结构和蛋白折叠,可以确定CDR序列其余部分的残基。因此,本发明也考虑本文所给出的任何CDR的变体。例如,在一个CDR的变体中,最小结合单位的氨基酸残基可以保持不变,而根据Kabat或Chothia或AbM或IMGT或Contact定义的其余CDR残基可以被保守氨基酸残基替代。
如本文所用,氨基酸序列的“百分比(%)序列相同性”、“序列相同性”具有本领域公认的定义,其指通过序列比对(例如通过人工检视或可公知的算法)确定的两个多肽序列之间相同的百分比。可以使用本领域技术人员已知的方法确定,例如使用可公开获得的计算机软件如BLAST、BLAST-2、Clustal Omega和FASTA软件。
在本文中,“源自”或“衍生自”参考氨基酸序列的氨基酸序列与参考氨基酸序列的部分或者全部相同或同源。
如本文所用,术语“核酸”是指任何长度的核苷酸链,并且包括DNA和RNA。核苷酸可以是脱氧核糖核苷酸、核糖核苷酸、修饰的核苷酸或碱基、和/或它们的类似物、或者能够通过DNA或RNA聚合酶掺入链的任何底物。
如本文所用,术语“重组表达载体”意指基因修饰的寡核苷酸或聚核苷酸构筑体,当构筑体包含编码mRNA、蛋白质、多肽或肽的核苷酸序列,并且载体在足以使mRNA、蛋白质、多肽、或肽在细胞内表达的条件下与细胞接触时,所述构筑体准许由宿主细胞表达mRNA、蛋白质、多肽或肽。本发明的载体总体上不是天然存在的。然而,载体的部分可以是天然存在的。本发明的重组表达载体可以包含任何类型的核苷酸,包括但不限于如下DNA和RNA:其可以是单链或双链的,合成的或部分地从天然来源中获得,并且其可以含有天然、非天然或改变的核苷酸。重组表达载体可以包含天然存在或非天然存在的核苷酸间连接,或这两种类型的连接。在示范性方面中,改变的核苷酸或非天然存在的核苷酸间连接不阻碍载体的转录或复制。
本发明的重组表达载体可以是任何合适的重组表达载体,其能够用于转化或转染将一种或多种所关注的基因或序列递送入任何合适的宿主细胞并且优选在宿主细胞中表达所述基因或序列。合适的载体包括经过设计用于扩展和扩增或用于表达或以上两项的那些载体,载体的实例包括但不限于病毒载体、裸DNA或RNA表达载体、质粒、粘粒或噬菌体载体、与阳离子凝聚剂相关的DNA或RNA表达载体、包囊化于脂质体中的DNA或RNA表达载体以及某些真核细胞,例如生产细胞。
如本文所用,术语“宿主细胞”是指可以含有本文所描述的核酸或载体的任何类型的细胞。宿主细胞可以是真核细胞,例如植物、动物、真菌或海藻;或宿主细胞可以是原核细胞,例如细菌或原生动物。如本文所描述,宿主细胞可以是起源于或获自个体的细胞。宿主细胞可以是来源于或获自哺乳动物。如本文所使用,术语“哺乳动物”是指任何哺乳动物,包括但不限于啮齿目(order Rodentia)哺乳动物,如小鼠和仓鼠;和兔形目(orderLagomorpha)哺乳动物,如兔。优选地,哺乳动物来自食肉目(order Carnivora),包括猫科动物(猫)和犬科动物(犬)。更优选地,哺乳动物来自偶蹄目(order Artiodactyla),包括牛科动物(牛)和猪科动物(猪),或属于奇蹄目(order Perssodactyla),包括马科动物(马)。最优选地,哺乳动物属于灵长目(order Primate)、新世界猴类(Ceboids)或狐猴类(Simoids)(猴)或属于类人猿亚目(order Anthropoids)(人类和猿)。特别优选的哺乳动物是人类。
可以将表达载体转染或引入适宜的宿主细胞中。多种技术可以实现这个目的,例如,原生质体融合、磷酸钙沉淀、电穿孔、逆转录病毒的转导、病毒转染、基因编辑(CRISPR-Cas系统、ZFN系统或TALEN系统)、转座子(Sleeping Beauty或PiggyBAC)、基因枪、基于脂质的转染或其他常规技术。在原生质体融合的情况下,将细胞在培养基中培育并且筛选适宜的活性。用于培养所产生的转染细胞和用于回收产生的抗体分子的方法和条件是本领域技术人员已知的并且可以基于本说明书和现有技术已知的方法,根据使用的特定表达载体和哺乳动物宿主细胞变动或优化。另外,可以通过引入允许选择已转染的宿主细胞的一个或多个标记物,选出已经稳定将DNA掺入至其染色体中的细胞。标记物可以例如向营养缺陷型宿主提供原养型、杀生物抗性(例如,抗生素)或重金属(如铜)抗性等。可选择标记基因可以与待表达的DNA序列直接连接或通过共转化引入相同的细胞中。也可能需要额外元件以便最佳合成mRNA。这些元件可以包括剪接信号,以及转录启动子、增强子和终止信号。
如本文所用,术语“多特异性抗体”指具有至少两个抗原结合位点的抗体,所述至少两个抗原结合位点中的每一个抗原结合位点与相同抗原的不同表位或与不同抗原的不同表位结合。多特异性抗体是对至少两个不同抗原表位具有结合特异性的抗体。在一个实施方案中,本文提供了这样的多特异性抗体,其具有针对第一抗原和第二抗原的结合特异性,也称为“双特异性抗体”。
如本文所用,术语“药学上可接受的载体”是常规使用的那些载体中的任一种,并且仅受到物理-化学考虑因素(如溶解性和与靶向HER2的抗原结合分子的反应性的缺乏)限制,并且受给药途径限制。本文所描述的药学上可接受的载体,例如媒剂、佐剂、赋形剂和稀释剂为所属领域的技术人员所熟知并且公众可容易获得。在一个方面中,药学上可接受的载体是对药物组合物的活性成分具有化学惰性的载体,并且是在使用条件下不具有不利的副作用或毒性的载体。在一些实施例中,当向动物或人类给予时,载体不产生不良、过敏或其他不适当的反应。在一些方面中,药物组合物不含热原质以及会对人类或动物有害的其他杂质。药学上可接受的载体包括任何和所有溶剂、分散介质、涂料、抗细菌剂和抗真菌剂、等张剂和吸收延迟剂等;其用途在所属领域中是众所周知。
适用于实施本文所公开的方法的组合物的治疗配制物,如多肽、聚核苷酸或抗体,可以通过以冻干饼或水溶液的形式将具有所期望纯度的所选择组合物与任选的生理学上药学上可接受的载体、赋形剂或稳定剂混合(《雷明顿的药物科学(Remington′sPharmaceutical Sciences)》,第18版,A.R.Gennaro编,马克出版公司(MackPublishingCompany)(1990))来制备用于储存。药物组合物可以通过与一种或多种合适的载体或佐剂掺合来制造,所述载体或佐剂如水、矿物油、聚乙二醇、淀粉、滑石、乳糖、增稠剂、稳定剂、悬浮剂等。这类组合物可以呈溶液、悬浮液、片剂、胶囊、乳膏、油膏、软膏的形式或呈其他常规形式。
体内给药所用的组合物应为无菌的。这通过在冻干和复原之前或之后经由无菌过滤膜过滤容易地实现。治疗性组合物一般置于具有无菌接入端口的容器中,例如具有可被皮下注射针刺穿的塞子的静脉内溶液袋或小瓶。适用于可注射用途的医药形式包括无菌水溶液或分散液和用于临时制备无菌可注射溶液或分散液的无菌粉末。在一些情况下,所述形式应为无菌的,并且应是流体,以达到能够易于注射的程度。其应在制造和储存的条件下稳定并且应被保存以免遭微生物如细菌和真菌的污染作用。用于肠胃外给药的组合物通常将以冻干形式或以溶液形式储存。
载体可以是含有例如水或其合适的混合物和植物油的溶剂或分散介质。适当的流动性可以例如通过使用涂层如卵磷脂、在分散液情况下通过维持所需粒径和通过使用表面活性剂来维持。
载体的选择可通过靶向HER2的抗原结合分子的药物组合物的特定类型以及药物组合物的施用途径来确定。相应地,存在各种合适的药物组合物的配制物。
本发明的药物组合物可以包含任何药学上可接受的成份,包括例如酸化剂、添加剂、吸附剂、气雾剂推进剂(aerosol propellant)、空气置换剂、碱化剂、防结块剂、抗凝剂、抗微生物防腐剂、抗氧化剂、抗菌剂(antiseptic)、基质、粘合剂、缓冲剂、螯合剂、涂布剂、着色剂、干燥剂、清洁剂、稀释剂、消毒剂(disinfectant)、崩解剂、分散剂、溶解增强剂、染料、润肤剂、乳化剂、乳液稳定剂、填充剂、成膜剂、香味增强剂、调味剂、流动增强剂、胶凝剂、粒化剂、保温剂、润滑剂、粘膜粘着剂、软膏基质、软膏、油性媒剂、有机碱、锭剂基质、颜料、增塑剂、抛光剂、防腐剂、多价螯合剂、皮肤渗透剂、增溶剂、溶剂、稳定剂、栓剂基质、表面活性剂(surface active agent)、表面活性剂(surfactant)、悬浮剂、甜味剂、治疗剂、增稠剂、张力剂、毒性剂、增粘剂、吸水剂、水可混溶性共溶剂、水软化剂或湿润剂。
本文所描述的靶向HER2的抗原结合分子的药物组合物经过配制用于肠胃外给药、皮下给药、静脉内给药、肌内给药、动脉内给药、鞘内给药或腹膜内给药。药物组合物可通过经鼻、喷雾、口服、气雾剂、直肠或阴道给药来给予。组合物还可通过输注、快速注射或通过植入装置来给予。
所属领域的技术人员应了解,除上述药物组合物以外,本发明的组合物可以被配制成包合物,如环糊精包合物,或脂质体。
如本文所用,术语“单克隆抗体”,指由单一的克隆细胞株得到的抗体,所述的细胞株不限于真核的,原核的或噬菌体的克隆细胞株。
如本文所用,术语“表位”指能够与抗体特异性结合的抗原上的区域(area或region)。表位可以由连续氨基酸串(线性表位)形成或包含非连续氨基酸(构象表位),例如因抗原的折叠(即通过蛋白质性质的抗原的三级折叠)而变成空间接近。构象表位和线性表位的差别在于:在变性溶剂的存在下,抗体对构象表位的结合丧失。表位包含处于独特空间构象的至少3,至少4,至少5,至少6,至少7,或8-10个氨基酸。筛选结合特定表位的抗体(即那些结合相同表位的)可以使用本领域例行方法来进行,例如但不限于丙氨酸扫描、肽印迹(见Meth.Mol.Biol.248(2004)443-463)。
如本文所用,术语“特异性结合”是指抗体以比针对其他抗原或表位更高的亲和力结合至某个抗原或该抗原内的表位。通常,抗体以约1×10-7M或更小(例如约1×10-8M或更小、约1×10-9M或更小、约1×10-10M或更小、约1×10-11M或更小,或者约1×10-12M或更小)的平衡解离常数(KD)结合抗原或抗原内的表位。在一些实施方式中,抗体与抗原结合的KD为该抗体结合至非特异性抗原(例如BSA、酪蛋白)的KD的10%,或1%。可使用标准程序来测量KD,例如通过表面等离子体共振测定法所测量的。然而,特异性结合至抗原或抗原内的表位的抗体可能对其他相关的抗原具有交叉反应性,例如,对来自其他物种(同源)(诸如人或猴,例如食蟹猕猴(Macaca fascicularis)(cynomolgus,cyno)、黑猩猩(Pantroglodytes)(chimpanzee,chimp))或狨猴(Callithrix jacchus)(commonmarmoset,marmoset)的相同抗原具有交叉反应性。
如本文所用,术语“HER2抗原结合分子”(包括抗体),其于抗原HER2特异性结合。
实施例1:原材料制备
1.1抗原制备
本实施例分别制备了带His标签和Fc标签的人类表皮生长因子受体2(HER2)抗原蛋白,以下简称HER2-His、HER2-Fc。HER2(UniProt NO:P04626)基因(购自北京义翘神州生物技术有限公司,货号:HG10004-ACG),PCR扩增目的片段HER2胞外结构域(ECD,23-652AA,SEQ ID NO:1),将HER2基因的ECD区序列C端连接His标签或人Fc标签(Uniprot No:P0DOX5,218-449AA)序列后,将得到的含标签序列的融合基因通过同源重组的方法构建至真核表达载体pcDNA3.4(Invitrogen)。将构建好的各重组蛋白表达载体质粒分别转化到大肠杆菌DH5α中,37℃过夜培养,然后利用无内毒素质粒提取试剂盒(OMEGA,D6950-01)进行质粒提取,得到无内毒素的各质粒以供真核表达使用。
HER2-His、HER2-Fc均通过Expi293瞬转表达系统(ThermoFisher,A14635)表达,瞬转方法参见Expi293TM Expression System USER GUIDE。在转染7天后,将细胞表达上清于15000g高速离心10min,所得Fc标签蛋白表达上清用MabSelectSuRe LX(GE,17547403)进行亲和纯化,然后用100mM乙酸钠(pH 3.0)洗脱目的蛋白,接着用1M Tris-HCl中和;所得His标签蛋白表达上清用NiSmart Beads 6FF(常州天地人和生物科技有限公司,SA036050)进行亲和纯化,然后用梯度浓度的咪唑缓冲液洗脱目的蛋白。洗脱下来的各蛋白分别通过超滤浓缩管(Millipore,UFC901096)置换至PBS缓冲液中。经SDS-PAGE鉴定和活性鉴定合格后于-80℃冻存待用。
1.2对照抗体制备
在本实施例中,使用的对照抗体为抗HER2的曲妥珠单抗(Trastuzumab,以下也简称Trmab)和帕妥珠单抗(Pertuzumab,以下也简称Pemab),序列分别来自专利申请WO1992022653A1和WO2001000245A2。
抗体重链和轻链的DNA序列委托金唯智生物科技有限公司合成。PCR扩增各目的片段,然后通过同源重组的方法构建至真核表达载体pcDNA3.4(Invitrogen)。将构建好的重组蛋白表达载体转化到大肠杆菌DH5α中,37℃过夜培养,然后利用无内毒素质粒提取试剂盒(OMEGA,D6950-01)进行质粒提取,得到无内毒素的质粒以供真核表达使用。采用ExpiCHO瞬转表达系统(Thermo Fisher,A29133)表达(方法参见WO2020238730A1)。将细胞混悬液进行高速离心并收集上清,所得上清经0.22μm滤膜过滤后,采用MabSelect SuRe LX(GE,17547403)进行亲和层析纯化。目的蛋白使用100mM甘氨酸盐酸(pH 3.0)进行洗脱,经浓缩,缓冲液置换,分装,SDS-PAGE鉴定和活性检测后入库冻存。
实施例2:HER2抗原蛋白羊驼免疫与血清效价检测
2.1动物免疫
通过皮下注射的方式进行免疫,免疫1只羊驼NSY011(南昌大佳科技有限公司),所使用的免疫抗原为HER2-Fc。单次免疫剂量为500μg,并辅以CFA/IFA(弗氏完全佐剂和弗式不完全佐剂),每间隔2周免疫1次,共免疫4次。
2.2血清效价检测
在第2次、第3次和第4次免疫结束后,分别采血检测血清中靶向HER2的效价,以免疫前血清作为阴性对照。具体检测方法如下:将HER2-His重组蛋白用PBS稀释至终浓度2μg/mL,取30μL稀释液加入到ELISA板中,4℃包被过夜。在免疫效价测定当日用PBST润洗三遍,后用含有5%脱脂牛奶的PBST室温封闭2h,再用PBST润洗三遍。在另外一块稀释板上将未经免疫接种的阴性血清和免疫后血清用PBS进行稀释,首孔2000倍稀释,然后后续7个孔采用2倍梯度稀释。将稀释好的血清加到第一块ELISA板中,室温下孵育1h,PBST洗板三次后,以1:10000加入二抗Anti IgG-HRP(Millipore,MAC129),室温下孵育0.5h。孵育完成后,PBST洗板六次,加TMB(SurModics,TMBS-1000-01)显色,根据显色结果,加入2M HCl终止反应,通过酶标仪(Molecular Devices,SpecterMax 190)在OD450下读板。
结果如表1所示,第4次免结束时,羊驼血清中靶向HER2-His抗体的效价达到1:256K以上(当检测值高于背景值1.65倍,则判定为阳性)。
表1:HER2免疫羊驼血清IgG效价检测(OD450)
样品/稀释倍比 | 阴性血清 | 2次免疫血清 | 3次免疫血清 | 4次免疫血清 |
1:2K | 0.1284 | 2.3438 | 2.8244 | 2.8412 |
1:4K | 0.1262 | 1.8275 | 2.6672 | 2.7957 |
1:8K | 0.0722 | 1.2533 | 2.1639 | 2.6516 |
1:16K | 0.0984 | 0.8655 | 1.4027 | 2.1032 |
1:32K | 0.1031 | 0.4809 | 0.8567 | 1.3408 |
1:64K | 0.0702 | 0.2862 | 0.4695 | 0.774 |
1:128K | 0.0693 | 0.1814 | 0.3042 | 0.4697 |
1:256K | 0.0938 | 0.1507 | 0.1731 | 0.2701 |
实施例3:噬菌体展示文库构建和靶向HER2纳米抗体筛选
在本实施例中,克隆经HER2-Fc免疫的羊驼外周血B细胞纳米抗体基因,构建了纳米抗体基因噬菌体展示文库,并用HER2-Fc和HER2-His(实施例1自制)作为筛选抗原对该文库进行筛选,获得了多个具有特异性结合HER2的纳米抗体。
3.1构建驼源纳米抗体的噬菌体展示文库
取Ficoll-Paque密度梯度分离液(购自GE公司,货号:17144003S)分离外周单核细胞(Peripheral Blood Mononuclear Cell,PBMC),从分离的PBMC细胞中提取总RNA。使用反转录试剂盒(购自TaKaRa公司,货号:6210A)将提取的总RNA反转录成cDNA。基于VHH抗体种系(germline)的情况,在VHH抗体V区前端和第二个恒定区(CH2)中间设计简并引物,PCR扩增后得到抗体的VHH-CH2片段和VH-CH1-CH2片段,通过两个片段的长度差异,将PCR产物用琼脂糖凝胶电泳鉴定,并回收VHH-CH2片段。回收的VHH-CH2片段,通过二次PCR的方法,采用VHH的扩增的正向和反向引物、以VHH-CH2为模板扩增VHH抗体片段(Sabir JS,El-DomyatiFM等人。C R Biol.2014年3月20日;337(4):244-249)。接着,对该PCR产物和噬菌体展示用载体进行酶切、回收和连接,连接产物通过回收试剂盒(Omega,目录号:D6492-02)回收。最后,通过电转仪(Bio-Rad,MicroPulser)转化至感受态大肠杆菌SS320(Lucigen,MC1061 F)中,并将经转化的大肠杆菌SS320菌液涂布于具有氨苄青霉素抗性的2-YT固体平板。通过梯度稀释铺板,经测定文库库容大小为108级。将纳米抗体基因库的菌液加入到新鲜的2-YT液体培养基中,置于37℃、220rpm的摇床中培养至对数生长期,再以50倍于细菌数的数量(即感染复数(MOI)大约50)加入VSCM13辅助噬菌体(购自Stratagene),最终获得驼源纳米抗体的噬菌体展示文库。
3.2抗体基因噬菌体展示文库的筛选
3.2.1磁珠法筛选抗体基因噬菌体展示文库
磁珠法筛选是基于将抗原蛋白(HER2-Fc和HER2-His)进行生物素标记后,再与偶联有链霉亲和素的磁珠结合,通过将结合抗原的磁珠和抗体基因噬菌体展示文库进行孵育、洗涤和洗脱的淘选过程,由此针对抗原的特异性单克隆抗体可以大量富集。
具体方法如下:首先用生物素标记HER2-Fc蛋白与链霉亲和素偶联的磁珠孵育,使得生物素标记的HER2-Fc蛋白结合到磁珠上。将结合HER2-Fc蛋白的磁珠和构建的噬菌体库室温下孵育2h。经PBST洗涤6-8次后,去除非特异性吸附的噬菌体,加入Trypsin(Gibco,25200072)轻轻混匀并反应20min,以洗脱特异性结合的抗体展示噬菌体。随后,用洗脱下来的噬菌体侵染对数期的SS320菌体并静置30min,然后在220rpm条件下培养1h,再加入VSCM13辅助噬菌体并静置30min,继续在220rpm条件下培养1h,离心并置换至C+/K+2-YT培养基中,最终得到的噬菌体继续用于下一轮的淘选。第二轮和第三轮淘选分别用生物素标记的HER2-His和HER2-Fc筛选,以实现交叉筛选,尽可能去除结合抗原Fc段的抗体。
3.2.2免疫管法筛选抗体基因噬菌体展示文库
免疫管法和磁珠法的目的均为富集针对抗原的特异性抗体,为两个相互补充和验证的实验方法。
免疫管法筛选的原理是将HER2蛋白包被在具有高吸附力的免疫管表面,通过将噬菌体展示抗体文库加入免疫管中并和吸附于免疫管表面的抗原蛋白进行孵育、洗涤和洗脱的淘选过程,最终将针对抗原的特异性单克隆抗体富集下来。
具体方法如下:第一轮筛选时,在免疫管中加入1mL 30μg/mL的HER2-Fc,4℃包被过夜,第二天弃去包被液,加入5%牛奶的PBS封闭2h,PBS润洗两次后加入含有抗HER2-Fc纳米抗体展示的噬菌体库,孵育2h,润洗以去除非特异性结合的噬菌体,然后向免疫管中加入0.8mL 0.05%EDTA胰酶消化液,用于洗脱特异性结合目标抗原的噬菌体,接着将其侵染对数期的SS320菌体,37℃静置30min,然后220rpm条件下培养1h,再加入VSCM13辅助噬菌体,静置30min,继续在220rpm条件下培养1h,离心并置换至C+/K+2-YT培养基中,并于30℃、220rpm环境下继续培养过夜。第二天沉淀噬菌体,用于后续下一轮轮的筛选。第二轮和第三轮淘选分别用生物素标记的HER2-His和HER-Fc筛选,以实现交叉筛选,尽可能去除结合抗原Fc段的抗体。
3.3单克隆的挑选
对每轮洗脱下来的噬菌体池进行ELISA检测来评价富集的效果,针对富集较好的第三轮,挑取大量单克隆进行ELISA初筛,经测序分析和ELISA结合初筛获得多个序列多样性且和HER2抗原结合的纳米抗体。
以克隆号对候选纳米抗体进行命名,采用AbM定义CDR的方式,确定了重链单域抗体的互补决定区序列。本发明的4个示例性抗HER2纳米抗体的CDR和可变区(VHH)的序列见表2和表3。
表2:本发明的示例性抗HER2纳米抗体的CDR序列
表3:本发明的示例性抗HER2纳米抗体的VHH序列
注:表内加粗并斜体标记的为CDR序列;加粗并加下划线标记的为与NB46-1相比有区别的氨基酸。
实施例4:候选抗体的构建、表达和纯化
将实施例3中获得的4个纳米抗体构建为人IgG1亚型,形成VHH-Fc形式的抗体,其中,Fc区的氨基酸序列如下所示。
从筛选获得的含有候选单克隆菌株中,PCR扩增获取抗体重链可变区片段,即VHH。通过同源重组方法,构建至经过改造的含有人IgG1 Fc片段的真核表达载体质粒pcDNA3.4-TOPO(Invitrogen)上,组成完整的VHH-Fc全长基因。表达纯化方法与实施例1.2一致。
Fc区序列:
实施例5:候选抗体的理化性质鉴定
5.1候选抗体(VHH-Fc)SDS-PAGE鉴定
非还原溶液制备:候选抗体以及质控品IPI(所述IPI是伊匹木单抗(Ipilimumab)的缩写,通过实施例4的方法制备获得)1μg加入5×SDS上样缓冲液和40mM碘代乙酰胺,75℃干浴加热10min,冷却到室温后,12000rpm离心5min,取上清。还原溶液制备:候选抗体以及质控品IPI 2μg加入5×SDS上样缓冲液和5mM DTT,100℃干浴加热10min,冷却到室温后,12000rpm离心5min,取上清。将上清加入Bis-tris 4-15%梯度胶(购于金斯瑞),恒压110V电泳,当考马斯亮蓝迁移到凝胶底部,停止运行,取出凝胶片置考马斯亮蓝染色液中1-2h,弃去染色液,加入脱色液,根据需要更换2-3次脱色液,脱色至凝胶背景透明后保存在去离子水中。脱色后用EPSON V550彩色扫描仪扫描,通过Image J按照峰面积归一法计算还原和非还原条带纯度。
结果显示:候选抗体和质控品IPI非还原胶的条带分别在80kD和150kD左右,候选抗体还原胶的条带在40kD左右,质控品IPI分别是55kD左右和25kD左右,符合预期大小,且纯度均大于90%。
5.2候选抗体(VHH-Fc)的SEC-HPLC单体纯度鉴定
材料准备:(1)流动相:150mmol/L磷酸缓冲液,pH 7.4;(2)样品制备:候选抗体以及质控品IPI均用流动相溶液稀释到0.5mg/mL。Agilent HPLC 1100色谱柱(XBridge BEHSEC 3.5μm,7.8mm I.D.×30cm,Waters)流速设为0.8mL/min,进样体积20μL,VWD检测器波长为280nm和214nm。依次进样空白溶液、IPI质控品溶液和样品溶液。
候选抗体(VHH-Fc)的SEC-HPLC结果显示在表4:按照面积归一法计算样品中高分子聚合物、抗体单体和低分子物质百分比,候选抗体单体纯度均为100%。
表4:候选抗体理化数据
实施例6:基于ELISA方法测定候选抗体的亲和与竞争活性
6.1基于ELISA方法测定候选抗体的亲和活性
在96孔ELISA板上,包被HER2-His(2μg/mL、30μL/孔),4℃过夜。次日,将孔板用PBST洗3次后用5%脱脂牛奶封闭2h,用PBST洗板3次后,加入梯度稀释的候选抗体并孵育1h。之后,用PBST清洗3次后加入抗Fc二抗(Jackson Immuno Research,109-035-008)并孵育1h。孵育完成后,PBST洗板六次,加TMB(SurModics,TMBS-1000-01)显色。根据显色结果,加入2M HCl终止反应,通过酶标仪(Molecular Devices,SpecterMax 190)在OD450下读板。
结果显示在图1和表5中,结果表明,除了NB46-73亲和活性略弱于曲妥珠单抗(简称Trmab),其余3个抗体NB46-P-165、NB46-88和NB46-1都显示了略优于Trmab的基于ELISA的亲和活性。
表5:ELISA方法测定候选抗体的亲和活性
抗体名称 | EC50(μg/mL) |
NB46-1 | 0.1240 |
NB46-73 | 0.2211 |
NB46-88 | 0.08929 |
NB46-P-165 | 0.1183 |
Trmab | 0.1816 |
6.2基于ELISA方法测定候选抗体与Trmab竞争性结合HER2活性
包板人HER2-His(4μg/mL,30μL/孔),4℃过夜。次日,将孔板用PBST洗3次后用5%脱脂牛奶封闭2h。然后分别将梯度稀释的候选抗体或Trmab与1μg/mL生物标记后Trmab混合,在封闭完成并洗板结束后加至96孔ELISA板中,孵育1h。之后,用PBST清洗3次后加入二抗NeutrAvidin-HRP(Therofisher,31001)并孵育1h。孵育完成后,PBST洗板六次,加TMB(SurModics,TMBS-1000-01)显色,根据显色结果,加入2M HCl终止反应,通过酶标仪(Molecular Devices,SpecterMax190)在OD450下读板。
结果显示在图2和表6中,结果表明,NB46-P-165、NB46-88、NB46-73和NB46-1与对照抗体Trmab竞争性结合HER2抗原,具有相似结合表位。其中,NB46-1和NB46-P-165显示了较好的与Trmab竞争性结合HER2的活性。
表6:ELISA方法测定候选抗体与Trmab竞争性结合HER2活性
抗体名称 | IC50(μg/mL) |
NB46-1 | 1.417 |
NB46-73 | 4.494 |
NB46-88 | 2.127 |
NB46-P-165 | 1.687 |
Trmab | 2.111 |
实施例7:基于FACS方法测定抗体与肿瘤细胞表面HER2抗原结合
在本实施例中,基于FACS方法检测候选抗体和Trmab对照与肿瘤细胞SK-OV-3、BT-474和SK-BR-3表面HER2抗原结合活性。
收集指数生长期的人SK-OV-3、BT-474和SK-BR-3肿瘤细胞,300g离心去上清,将细胞用配制好的FACS缓冲液重悬,计数并将细胞悬液密度调整为2×106个/mL。随后,将细胞以每孔100μL加入96孔圆底板中,300g离心去上清。向对应孔中加入梯度稀释的候选纳米抗体和阳性对照Trmab稀释液,将细胞吹匀并放置于4℃下孵育30min。将孵育后的细胞混合液300g离心去上清,向对应孔中加入200μL的FACS缓冲液并重悬细胞;重复两次,300g离心去上清;加入FITC标记的anti-human-IgG-Fc流式抗体(Jackson,109-095-008),将细胞吹匀并放置于4℃下孵育30min,300g离心去上清。随后,加入FACS缓冲液并重悬细胞,重复上述离心重悬过程两次后向孔中加入200μLFACS缓冲液,重悬细胞。最后,通过流式细胞仪(Beckman,CytoFLEX AOO-1-1102)上机检测。
结果显示在图3A-图3C和表7中,结果表明在同等实验条件及抗体浓度条件下,候选抗体NB46-P-165、NB46-88、NB46-73和NB46-1与肿瘤细胞表面HER2结合活性与对照抗体Trmab相当。
表7:FACS方法测定候选抗体与Trmab竞争性结合HER2活性
实施例8:抗体依赖的细胞介导的细胞毒作用(ADCC)
利用乳酸脱氢酶(LDH)释放法检测ADCC效应。其原理是:抗体的可变区结合靶细胞上的目标抗原,当抗体的Fc段与PBMC中的NK效应细胞上的FcRIIIa(又名CD16a)结合后,NK细胞会释放穿孔素、颗粒酶等裂解靶细胞,然后通过LDH乳酸脱氢酶试剂盒(Takara,MK401)可以检测细胞上清中乳酸脱氢酶的释放,以此来测定NK细胞对靶细胞的杀伤程度。具体操作如下:
在96孔细胞培养板中每孔加入50μL密度为1×105个/mL的SK-BR-3细胞,置于37℃培养箱中培养过夜(16-20h)。加入梯度稀释的候选抗体NB46-1和NB46-P-165及对照抗体Trmab,50μL/孔,混匀后于37℃培养箱孵育30min,再加入复苏好的4×105个/孔的人PBMC细胞(效应细胞/靶细胞比例为40:1),37℃培养箱孵育16h后,通过300g离心得到上清,然后加入LDH检测试剂,反应60min,最后通过酶标仪(Molecular Devices,SpectraMax190)测定在492nm波长下的OD值并进行检测结果的分析。其中以10%Triton X-100加靶细胞作为全裂解的对照,以只加靶细胞作为空白阴性对照,以PBMC加靶细胞作为背景阴性对照。细胞杀伤率按如下公式计算:杀伤率(%)=(候选抗体孔OD值-背景孔OD值)/(全裂解孔OD值-空白孔OD值)×100%。
与阳性对照单抗比较的ADCC结果如图4A和图4B所示,候选抗体NB46-1和NB46-P-165与Trmab具有相当的细胞杀伤活性。其中,图4A中显示NB46-1和Trmab的ADCC细胞杀伤EC50分别为0.023μg/mL和0.011μg/mL;图4B中显示NB46-P-165和Trmab的ADCC细胞杀伤EC50分别为0.024μg/mL和0.013μg/mL。
实施例9:抗体内吞效率检测
本实验通过抗体介导Fab-ZAP内吞的细胞毒性来检测抗体的内吞活性。Fab-ZAP是连接了saporin(皂素)的Fab片段,saporin是一种核糖体抑制剂,能够抑制蛋白质的合成而使细胞死亡。本实验用的Fab-ZAP是一种能够和人源的抗体Fc结合的Fab片段,Fab-ZAP和带人源Fc的抗体孵育后使抗体带上毒素,当抗体被内吞时,毒素随着抗体进入到细胞内,使细胞死亡,然后通过MTS(Promega,G3580)检测细胞的活性来检测人源抗体是否内吞。本实施例的对照抗体为帕妥珠单抗,因其具有优于Trmab的内吞活性。
具体实验方法如下:首先将Fab-ZAP用DMEM完全培养基稀释成4.5nM,然后用4.5nMFab-ZAP梯度稀释候选抗体NB46-1、NB46-88及对照抗体帕妥珠单抗。将对数生长期SK-BR-3细胞制成单细胞悬液,调整密度为1×105个细胞/mL,以每孔50μL接种到96孔板中,然后取前述抗体稀释液,以每孔50μL加入细胞培养板中,充分吹打混匀。将细胞培养板放入37℃细胞培养箱孵育72h。孵育结束后,向每孔中加入7.5μL TritonX-100溶液,轻轻拍打混匀,将细胞培养板放入37℃细胞培养箱孵育0.5h。接着向每孔中继续加入20μL MTS,37℃孵育1-4h。最后以1000rpm离心细胞培养板5min,酶标仪读取数据,检测波长OD492。
结果如图5A和图5B所示,表明在本实施例限定的抗体浓度条件下,候选抗体在肿瘤细胞SK-BR-3比对照抗体帕妥珠单抗具有更优的内吞活性,EC50分别为Pemab vs.NB46-1=0.0145μg/mL vs.0.0006μg/mL,Pemab vs.NB46-88=0.0152μg/mL vs.0.0043μg/mL。
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Claims (15)
1.一种HER2抗原结合分子,其特征在于,所述抗原结合分子至少包含一条VHH链,所述VHH链包含CDR1、CDR2和CDR3,其中,
所述CDR1包含如SEQ ID NO:13所示的氨基酸序列,CDR2包含如SEQ ID NO:14所示的氨基酸序列,CDR3包含如SEQ ID NO:15所示的氨基酸序列。
2.权利要求1所述的HER2抗原结合分子,其特征在于,
所述CDR1包含如SEQ ID NO:6或SEQ ID NO:7所示的氨基酸序列,所述CDR2包含如SEQID NO:8或SEQ ID NO:9所示的氨基酸序列,以及所述CDR3包含如SEQ ID NO:10、SEQ IDNO:11或SEQ ID NO:12所示的氨基酸序列。
3.权利要求2所述的HER2抗原结合分子,其特征在于,所述CDR1的氨基酸序列如SEQ IDNO:6所示,CDR2的氨基酸序列如SEQ ID NO:8所示,CDR3的氨基酸序列如SEQ ID NO:10所示;或,所述CDR1的氨基酸序列如SEQ ID NO:6所示,CDR2的氨基酸序列如SEQ ID NO:9所示,CDR3的氨基酸序列如SEQ ID NO:11所示;或,所述CDR1的氨基酸序列如SEQ ID NO:7所示,CDR2的氨基酸序列如SEQ ID NO:9所示,CDR3的氨基酸序列如SEQ ID NO:11所示;或,所述CDR1的氨基酸序列如SEQ ID NO:7所示,CDR2的氨基酸序列如SEQ ID NO:8所示,CDR3的氨基酸序列如SEQ ID NO:12所示。
4.权利要求1~3任一项所述的HER2抗原结合分子,其特征在于,所述VHH链包含如SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5任一所示的氨基酸序列或其变体;
其中,所述变体与其所源自的序列相比具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%的序列相同性。
5.权利要求4所述的HER2抗原结合分子,其特征在于,所述HER2抗原结合分子还包含免疫球蛋白的Fc区;优选地,所述Fc区为人IgG1的Fc区;更优选地,所述Fc区的氨基酸序列如SEQ ID NO:16所示。
6.一种分离的核酸,其特征在于,所述核酸编码如权利要求1~5任一项所述的HER2抗原结合分子。
7.一种重组表达载体,其特征在于,所述重组表达载体包含如权利要求6所述的分离的核酸;
优选地,所述重组表达载体为质粒、粘粒、噬菌体或病毒载体;所述质粒的骨架例如为pcDNA3.4。
8.一种宿主细胞,其特征在于,所述宿主细胞包含权利要求6的核酸或权利要求7所述的重组表达载体;优选地,所述宿主细胞为原核细胞或真核细胞;更优选地,所述真核细胞为酵母细胞或哺乳动物细胞;其中,所述哺乳动物细胞例如为HEK293细胞。
9.一种HER2抗原结合分子的制备方法,其特征在于,所述方法包含以下步骤:
在适宜如权利要求8所述的宿主细胞生长和发酵的条件下培养所述宿主细胞,从培养物中获得HER2抗原结合分子。
10.一种多特异性抗体,其特征在于,其包括权利要求1~5任一项所述的HER2抗原结合分子,以及与所述HER2抗原结合分子可操作地连接的具有另一种抗原结合特性的抗原结合分子。
11.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~5任一项所述的HER2抗原结合分子,以及药学上可接受的载体;
优选地,所述药物组合物还含有由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的组中的一种或多种。
12.权利要求1~5任一项所述的HER2抗原结合分子、权利要求6所述的核酸、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的多特异性抗体或权利要求11所述的药物组合物在制备预防和/或治疗肿瘤的药物中的应用。
13.一种试剂盒,其特征在于,所述试剂盒包括权利要求1~5任一项所述的HER2抗原结合分子、权利要求6所述的核酸、权利要求7所述的重组表达载体、权利要求8所述的宿主细胞、权利要求10所述的多特异性抗体或权利要求11所述的药物组合物;
优选地,所述试剂盒还包括(i)施用抗体或药物组合物的装置;和/或(ii)使用说明。
14.一种套装药盒,其特征在于,所述套装药盒包含药盒A和药盒B,其中,
所述药盒A含有权利要求1~5任一项所述的HER2抗原结合分子,权利要求10所述的多特异性抗体或权利要求11所述的药物组合物;
所述药盒B含有其他抗肿瘤抗体或者包含所述其他抗肿瘤抗体的药物组合物,和/或由激素制剂、靶向小分子制剂、蛋白酶体抑制剂、成像剂、诊断剂、化疗剂、溶瘤药物、细胞毒性剂、细胞因子、共刺激分子的激活剂、抑制性分子的抑制剂以及疫苗组成的组中的一种或多种。
15.一种免疫检测或者测定HER2的方法,其特征在于,所述的方法包括使用权利要求1~5任一项所述的HER2抗原结合分子、权利要求10所述的多特异性抗体或权利要求11所述的药物组合物与待检测样本混合;优选地,所述检测为非诊断目的的检测。
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