CN103998468A - 抗原结合蛋白及其用作治疗癌症的定位产品的用途 - Google Patents
抗原结合蛋白及其用作治疗癌症的定位产品的用途 Download PDFInfo
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
- G01N33/5035—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on sub-cellular localization
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Abstract
本发明涉及一种能特异性地结合蛋白Axl的抗原结合蛋白(尤其是单克隆抗体)以及编码所述蛋白的氨基酸和核酸序列。根据一个方面,本发明涉及一种能特异性地结合Axl并通过诱导Axl的内在化而被内在化到细胞中的抗原结合蛋白或抗原结合片段。本发明还包括所述抗原结合蛋白连同其它抗癌化合物(如毒素、放射性元素或药物)作为定位产品的用途,及其用于治疗某些癌症的用途。
Description
技术领域
本发明涉及一种能特异性地结合蛋白Axl的新型抗原结合蛋白(尤其是单克隆抗体)以及编码所述蛋白的氨基酸和核酸序列。根据一个方面,本发明涉及一种能特异性地结合Axl并通过诱导Axl的内在化而被内在化到细胞中的抗原结合蛋白或抗原结合片段。本发明还包括所述抗原结合蛋白连同其它抗癌化合物(如毒素、放射性元素或药物)作为定位(addressing)产品的用途,及其用于治疗某些癌症的用途。
背景技术
“Axl”(也称为“Ufo”、“Ark”或“Tyro7”)克隆自患有慢性粒细胞白血病的患者,当由鼠NIH3T3过度表达时,作为致癌基因而触发转化。其属于受体酪氨酸激酶(RTK)家族,称为TAM(Tyro3、Axl、Mer)家族,其包括Tyro3(Rse、Sky、Dtk、Etk、Brt、Tif)、Axl以及Mer(Eyk、Nyk、Tyro-12)(Lemke G.Nat.Rev.Immunol.(2008).8,327-336)。
人蛋白Axl是894个氨基酸的蛋白质,其序列呈现于SEQ ID NO.29所列的序列中。氨基酸1-25对应着信号肽,不含所述信号肽的人蛋白Axl呈现于SEQ IDNO.30所列的序列中。
Gas6最初作为生长停滞特异性基因而被分离,是TAM家族成员的常见配体(Varnum B.C.等人Nature(1995).373,623-626)。Gas6呈现出对Axl最高的亲和性,其次是Tyro3,最后是Mer(Nagata K等人J.Biol.Chem.(1996).271,30022-30027)。Gas6由如下组成:介导对磷脂膜结合的富含γ-羧基谷氨酸(Gla)的结构域、4个表皮生长因子样结构域以及2个层粘连蛋白G样(LG)结构域(Manfioletti G.,Brancolini,C,Avanzi,G.&Schneider,C.Mol.Cell Biol.(1993).13,4976-4985)。对于许多其它RTK,配体的结合导致受体二聚化和酪氨酸残基的自身磷酸化(对于受体Axl而言,酪氨酸残基779、821和866),酪氨酸残基作为各种细胞内信号传导分子的停靠位点(Linger R.M.Adv.Cancer Res.(2008).100,35-83)。此外,Axl受体可通过配体非依赖性过程被激活。当Axl受体过度表达时,可发生这种激活。
Gas6/Axl信号传导已被证明调节各种细胞过程,包括大量各种细胞的体外细胞增殖、黏附、迁移和存活(Hafizi S.&Dahlback,B.FEBS J.(2006).273,5231-5244)。此外,TAM受体参与先天免疫的控制;它们抑制树突状细胞(DC)和巨噬细胞中对病原体的炎症反应。它们还驱动凋亡细胞被这些免疫细胞的吞噬作用,且其是自然杀伤(NK)细胞的成熟和杀伤活性所需要的(Lemke G.Nat.Rev.Immunol.(2008).8,327-336)。
于正常细胞中弱表达,其主要见于成纤维细胞、髓系祖细胞、巨噬细胞、神经组织、心肌和骨骼肌中,在其中主要支持细胞的存活。Gas6/Axl系统通过调节血管平滑肌细胞的动态平衡在血管生物学中发挥重要作用(Korshunov V.A.,Mohan,A.M.,Georger,M.A.&Berk,B.C.Circ.Res.(2006).98,1446-1452;Korshunov V.A.,Daul,M.,Massett,M.P.&Berk,B.C.Hypertension(2007).50,1057-1062)。
在肿瘤细胞中,Axl在调节细胞的侵袭和迁移中起重要作用。Axl的过度表达不仅与预后不良相关,也与乳房、结肠、食管癌、肝细胞、胃、神经胶质瘤、肺、黑色素瘤、骨肉瘤、卵巢、前列腺、横纹肌肉瘤、肾、甲状腺和子宫内膜癌中所报告的各种人癌症的侵袭增加相关(Linger R.M.Adv.Cancer Res.(2008).100,35-83以及Verma A.Mol.Cancer Ther.(2011).10,1763-1773,综述)。在乳癌中,Axl似乎是上皮至间质转化(EMT)强大的效应因子;EMT过程积极促进生物中癌症细胞的迁移和传播(Thiery J.P.Curr.Opin.Cell Biol.(2003).15,740-746)。
也已表明Axl调节血管生成。在内皮细胞中敲除Axl确实损伤管的形成和迁移(Holland S.J.等人Cancer Res.(2005).65,9294-9303)以及干扰特定的血管生成信号通路(Li Y.等人Oncogene(2009).28,3442-3455)。
最近对一系列细胞模型的一些研究描述了Axl过度表达在耐药现象中的参与。下表1总结了这些研究。
表1
上表1中引用的完整文献如下:
-Macleod,K等人Cancer Res.(2005).65,6789-6800
-Mahadevan D等人Oncogene(2007).26,3909-3919
-Lay J.D等人Cancer Res.(2007).67,3878-3887
-Hong C.C等人Cancer Lett.(2008).268,314-324
-Liu L等人Cancer Res.(2009).69,6871-6878
-Keating A.K.等人Mol.Cancer Ther.(2010).9,1298-1307
-Ye X.等人Oncogene(2010).29,5254-5264
在这些内容中,Axl RTK被视为肿瘤学中的兴趣靶标。一些小组已经开发了使用裸单克隆抗体或靶标小分子的靶向gas6/Axl轴的抗肿瘤策略(Verma A.Mol.Cancer Ther.(2011).10,1763-1773)。
发明内容
在第一实施方式中,本发明涉及抗原结合蛋白、或其抗原结合片段,其i)特异性结合人蛋白Axl、以及ii)结合所述人蛋白Axl之后被内在化。
更一般地,本发明涉及蛋白Axl用于选择抗原结合蛋白、或其抗原结合片段的用途,其中抗原结合蛋白、或其抗原结合片段能够在结合所述靶标Axl之后被内在化。更具体地,所述靶标是Axl的细胞外结构域。
在这个具体方面,本发明因此涉及一种用于筛选化合物、或其结合片段的体外方法,所述化合物、或其结合片段能够将兴趣分子递送或内在化至哺乳动物细胞,所述兴趣分子被共价连接到所述化合物,其中所述方法包括以下步骤:
a)选择能够特异性结合Axl蛋白、或其细胞外结构域(ECD)、或其表位的化合物;
b)任选地,将所述兴趣分子或对照分子共价连接至步骤a)中选择的所述化合物以形成复合物;
c)使步骤a)中选择的所述化合物或步骤b)中获得的所述复合物接触在其表面上表达Axl蛋白或其功能片段的哺乳动物细胞,优选活细胞;
d)确定是否所述化合物或所述兴趣分子或所述复合物已被细胞内递送或内在化至所述哺乳动物细胞中;以及
e)选择所述化合物作为能够将兴趣分子递送或内在化至活哺乳动物细胞的化合物。
在一个优选的实施方式中,能够将兴趣分子递送或内在化至活哺乳动物细胞的所述化合物是蛋白(此处也指多肽或肽)或含有肽结构的蛋白样化合物,特别是至少5、10、15或更多氨基酸残基的氨基酸序列,所述氨基酸残基可以被糖基化。
当能够将兴趣分子递送或内在化至活哺乳动物细胞的所述化合物是蛋白或蛋白样化合物时,所述化合物此处也被称为“抗原结合蛋白”,所述抗原结合蛋白或其结合片段可以:
-i)特异性结合蛋白Axl,优选人Axl蛋白,以及
-ii)当所述Axl蛋白表达在所述哺乳动物细胞表面时,结合所述蛋白Axl之后被内在化至哺乳动物细胞中。
在一个优选的实施方式中,所述哺乳动物活细胞是人细胞,优选天然表达Axl蛋白受体的细胞。
在一个具体实施方式中,步骤c)中的哺乳动物活细胞是在其表面表达重组Axl蛋白的哺乳动物细胞。
在又一个优选的实施方式中,所述兴趣分子是细胞毒性分子(在此处也称为细胞毒性剂或细胞抑制剂)。
在又一个优选的实施方式中,使用接头,更优选肽接头,更优选可切割的肽接头,更优选可被哺乳动物细胞中(特别是所述哺乳动物细胞的细胞质中)所包含的天然细胞内化合物切割的接头,将所述兴趣分子共价连接到能够结合Axl蛋白的所述化合物。
在又一个优选的实施方式中,所述能够结合Axl蛋白的化合物是特异性针对Axl蛋白、或针对其位于Axl EDC结构域中的表位的抗体、或其功能结合片段。
可通过本领域技术人员已知的用于评价细胞内递送或内在化的任何方法实现e)的选择步骤。能够证明或评价能够特异性结合Axl蛋白的所述化合物、或所述化合物和所述兴趣分子形成的所述复合物、或共价连接至所述化合物的所述兴趣分子的存在、不存在、或活性的分析或测试,是技术人员熟知的(参见,此后公开的这种测试或分析的一些实例,这些测试不限于下面这些测试的实例)。
更具体地,可以通过FACS、免疫荧光、流式细胞仪、Western印迹、细胞毒性/细胞抑制评价等实现这些测试或分析。
在这方面,本发明还涉及一种用于制备细胞毒性或细胞抑制性复合物的体外方法,所述细胞毒性或细胞抑制性复合物能够将细胞毒性化合物递送至哺乳动物细胞中,优选活细胞,所述方法包括步骤:
-将细胞毒性剂共价连接至如下的化合物:
-i)特异性结合蛋白Axl,优选人Axl蛋白的化合物,以及
-ii)当所述Axl蛋白表达在所述哺乳动物细胞表面时,所述化合物结合所述蛋白Axl之后被内在化至哺乳动物细胞中。
优选地,所述化合物是蛋白样蛋白,更优选是特异性针对Axl蛋白、或针对其位于Axl EDC结构域中的表位的抗体、或所述抗体的功能结合片段。
在优选的实施方式中,使用接头,更优选肽接头,更优选可切割的肽接头,更优选可被作为非限制性实例的天然细胞内化合物切割的接头,将所述细胞毒性剂共价连接到所述抗Ax1抗体或其功能片段。
像TAM家族的其它成员,Axl细胞外结构域(ECD)具有接近细胞粘附分子那些的结构。Axl ECD特征是两个免疫球蛋白样结构域的组合,紧接着是两个相邻III型纤连蛋白-样结构域(O'Bryan J.P.等人,Mol.Cell Biol.(1991).11,5016-5031)。两个N端免疫球蛋白样结构域足以结合Gas6配体(Sasaki T等人,EMBO J.(2006).25,80-87)。
人蛋白Axl的ECD是451个氨基酸的片段,对应着序列SEQ ID No.29的氨基酸1-451,其序列作为SEQ ID NO.31表示在序列表中。氨基酸1-25对应着信号肽,不含信号肽的人蛋白Axl的ECD对应着序列SEQ ID No.29的氨基酸26-451,由序列SEQ ID NO.32表示。
迄今为止已经确定了不同的内在化模式。它们定向成为细胞中的内在化的蛋白或蛋白复合物。内吞后,大部分膜蛋白或脂质返回到细胞表面(再循环),但有些膜成分递送至晚期胞内体(late endosome)或高尔基体(Maxfield F.R.&McGraw,T.E.Nat.Rev.Mol.Cell Biol.(2004).5,121-132)。
在一个优选的实施方式中,本发明涉及抗原结合蛋白或其抗原结合片段,其i)特异性结合人蛋白Axl、以及ii)结合所述人蛋白Axl之后被内在化,所述抗原结合蛋白包含至少选自SEQ ID NO.1至14的氨基酸序列,或与SEQ ID NO.1至14表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
在一个最优选的实施方式中,本发明涉及一种抗原结合蛋白或其抗原结合片段,其
i)特异性结合人蛋白Axl,优选具有序列SEQ ID NO.29或30或其天然变体序列,以及
ii)结合所述人蛋白Axl之后被内在化,
所述抗原结合蛋白包含至少选自SEQ ID NO.1至14的氨基酸序列。
“结合蛋白”或“抗原结合蛋白”是指与另一蛋白或分子(通常称为抗原)具有特异的或一般亲和性的肽链。当可能结合时,让蛋白接触并形成复合物。本发明的抗原结合蛋白可优选但不限于抗体;抗体、蛋白或肽的片段或衍生物。
根据本发明的抗原结合蛋白的“抗原结合片段”,意在表示保留了抗原结合蛋白特异性结合靶标(通常也称为抗原)的能力,以及包含抗原结合蛋白氨基酸序列的至少5个连续氨基酸残基、至少10个连续氨基酸残基、至少15个连续氨基酸残基、至少20个连续氨基酸残基、至少25个连续氨基酸残基、至少40个连续氨基酸残基、至少50个连续氨基酸残基、至少60个连续氨基酸残基、至少70个连续氨基酸残基、至少连续的80个氨基酸残基、至少连续的90个氨基酸残基、至少连续的100个氨基酸残基、至少连续的125个氨基酸残基、至少150个连续氨基酸残基、至少连续的175个氨基酸残基、至少连续的200个氨基酸残基、或至少连续的250个氨基酸残基的氨基酸序列的任何肽、多肽或蛋白。
在一个优选的实施方式中,其中抗原结合蛋白是抗体,这样的“抗原结合片段”选自Fv、scFv(sc表示单链)、Fab、(Fab’)2、Fab’、scFv-Fc片段或双特异抗体、或通过化学修饰,如添加聚(亚烷基)二醇如聚乙二醇(“聚乙二醇化”)(聚乙二醇化片段被称为Fv-PEG、scFv-PEG、Fab-PEG、F(ab’)2-PEG或Fab’-PEG)(“PEG”表示聚乙二醇)、或通过并入脂质体中来提高其半衰期的任意片段,所述片段具有至少一个根据本发明抗体的特征CDR。优选地,所述“抗原结合片段”将由如下构成或包括其所源自的抗体的可变重链或轻链的部分序列,所述部分序列足以保留与其所来自的抗体相同的结合特异性以及足够的亲和性,优选所述足够的亲和性优选至少等于其所来自的抗体对靶标亲和性的1/100、更优选至少1/10。这种功能片段含有其所来自的抗体序列的至少5个氨基酸,优选10、15、25、50或100个连续的氨基酸。
术语“表位”是指被抗原结合蛋白(包括抗体)所结合的抗原区域。表位可被定义为结构的或功能的。功能表位通常是结构表位的子集,并具有对相互作用的亲和性有直接贡献的那些残基。表位也可以是构象的,即由非线性氨基酸组成。在某些实施方式中,表位可以包括决定簇,决定簇是化学活性的分子表面基团,如氨基酸、糖侧链、磷酰基或磺酰基,以及在某些实施方式中,可以具有特定的三维结构特征,和/或特定的电荷特征。
在本申请中,所述表位定位于人蛋白Axl的细胞外结构域中。
根据本发明优选的实施方式,抗原结合蛋白、或其抗原结合片段特异性结合至定位于人蛋白Axl的细胞外结构域中的表位,优选具有序列SEQ ID NO.31或32或其天然变体序列。
“特异性结合”、“特异结合”等,意图表示抗原结合蛋白或其抗原结合片段与抗原形成生理条件下相对稳定的复合物。特异性结合可特征在于至少约1.10-6M或更小的平衡解离常数。确定两个分子是否特异性结合的方法是本领域中是众所周知的,并包括例如平衡透析、表面等离子体共振等。为避免疑问,这并不意味着所述抗原结合片段不能以低水平结合或干扰另一个抗原。无论如何,作为一个优选的实施方式,所述抗原结合片段仅结合所述抗原。
在这个意义上,“EC50”是指50%的有效浓度。更精确地,术语半数最大有效浓度(EC50)对应着一段特定暴露时间之后,诱导基线和最大值之间一半反应的药物、抗体或毒物浓度。其通常用作药物效力的量度。因此,分级剂量反应曲线的EC50代表观察到其最大作用的50%时的化合物浓度。量子剂量反应曲线的EC50表示暴露特定时间段之后,50%的群体表现出反应的化合物浓度。浓度测量通常遵循S形曲线,在相对小的浓度变化中迅速增加。这可以通过最佳拟合线的推导而数学上进行确定。
作为优选的实施方式,本发明中确定的EC50表征抗体结合暴露在人肿瘤细胞上的Axl ECD的效力。使用FACS分析确定EC50参数。EC50参数反映获得对人肿瘤细胞上表达的人Axl的50%最大结合的抗体浓度。使用四参数回归曲线拟合程序(Prism软件),各EC50值计算为剂量反应曲线的中点。该参数已被选定为生理/病理状况的代表。
在本发明的一个实施方式中,抗原结合蛋白、或其抗原结合片段,以至少10-9M,优选10-9和10-12M之间的EC50结合其表位。
本发明的另一实施方式,是一种选择能够被细胞内内在化到哺乳动物细胞中,优选人细胞中,优选活细胞中的抗原结合蛋白或其抗原结合片段的过程或方法,其包括步骤:
-i)选择特异性结合Axl蛋白,优选特异性结合其ECD结构域或其表位的抗原结合蛋白;以及
-ii)从之前的步骤i)中选择所述抗原结合蛋白,其中所述抗原结合蛋白结合哺乳动物细胞表面上表达的Axl蛋白之后被内在化至所述哺乳动物细胞中。
在一个具体的实施方式中,所述哺乳动物细胞在其表面上天然表达Axl蛋白受体,或者是在其表面上表达重组Axl蛋白的哺乳动物细胞,优选人细胞。
这样的方法或过程可以包括以下步骤:i)选择以至少10-9M的EC50特异性结合Axl的抗原结合蛋白,以及ii)从之前的步骤中选择结合Axl之后被内在化的抗原结合蛋白。可以由本领域技术人员已知的用于评价内在化的任何方法来实现ii)的选择步骤。更具体地说,可以通过FACS、免疫荧光、流式细胞仪、western印迹、细胞毒性评价等实现测试。
根据本发明的抗原结合蛋白的另一个特征是,它对肿瘤细胞的增殖不具有任何显著活性。更具体地,如下面实例所示,根据本发明的抗原结合蛋白对增殖SN12C模型不具有任何显著的体外活性。
在肿瘤学中,存在多种机制,通过所述机制mAb可以发挥治疗效果,但通常其活性不足以产生持久的益处。因此,一些策略已被用来增强其活性,特别是通过将其与药物组合作为化疗剂。作为一种对组合规程的有效替代方法,免疫毒素成为一种用于治疗癌症的新治疗选择(Beck A.等人Discov.Med.(2010).10,329-339;Alley S.C.等人J.Pharmacol.Exp.Ther.(2009).330,932-938)。抗体药物缀合物(ADC)代表一种这样的方法,其中利用mAb特异性以及将细胞毒性剂靶向递送至肿瘤的能力可显著增强mAb和药物的活性。理想情况下,mAb将特异性结合大量表达在肿瘤细胞上但在正常细胞上却表达有限的抗原。
本发明关注特异性的抗Ax1结合蛋白,以及更具体地特异性抗Axl抗体,其呈现出Axl结合之后被内在化的高度能力。作为免疫药物缀合物的组成之一,这样的抗原结合蛋白是令人感兴趣的,所以它将连接的细胞毒素带到靶向的癌症细胞中。一旦被内在化,细胞毒素触发肿瘤细胞死亡。
免疫缀合物疗法成功的重要关键之处被认为是靶标抗原的特异性和抗原结合蛋白复合物内在化至癌症细胞中。显然,相较于内在化的抗原,非内在化的抗原不能有效递送细胞毒性剂。随着抗原的不同以及取决于受结合蛋白影响的多种参数,内在化的过程是可变的。细胞表面的RTK构成一个对于研究这种过程有趣的抗原家族。
生物分子中,细胞毒素带来细胞毒性活性,所用的抗原结合蛋白带来其对癌症细胞的特异性,以及载体用于进入细胞内来正确定位细胞毒素。
因此,为了改善免疫缀合分子,载体结合蛋白必须表现出高的内在化至靶标癌症细胞中的能力。结合蛋白介导的内在化的效率根据所靶标的表位而显著不同。选择强效的内在化抗Axl结合蛋白,需要不仅研究Axl下调还研究抗Axl结合蛋白进入细胞之后的各种实验数据。
在一个优选的实施方式中,可以优选通过免疫荧光(如在本申请中下文举例说明的)或通过本领域技术人员已知的内在化机制特异的任何方法或过程,评价根据本发明的抗原结合蛋白的内在化。
在另一个优选实施方式中,由于根据本发明的复合物Axl-抗原结合蛋白,在本发明的结合蛋白结合所述Axl的ECD之后被内在化,所以诱导了Axl在细胞表面的量减少。可以通过本领域技术人员已知的任何方法(western印迹、FACS、免疫荧光等)定量这种减少。
在本发明的实施方式中,因此体现内在化的这种减少,优选可以通过FACS进行测量,并表示为在未处理细胞上测量的平均荧光强度(MFI)与根据本发明抗原结合蛋白处理过的细胞的MFI之间的差或Δ。
作为本发明的非限制性实例,基于未处理的细胞和用本发明抗原结合蛋白处理过的细胞所获得的MFI确定这种△,如实施例9中所描述的,使用i)用本发明抗原结合蛋白24小时孵育期后的人肾肿瘤SN12C细胞,以及ii)标记有Alexa488的第二抗体。该参数被定义为用下面的公式计算:
由于MFI与细胞表面上表达的Axl成正比,MFI之间的这种差异反映出Axl的下调。
在一个更优选和有利的方面,本发明的抗原结合蛋白或其抗原结合片段由单克隆抗体优选分离的Mab组成,其触发至少200、优选至少300的Δ(MFI24h未处理的细胞-MFI24h处理的细胞)。
根据本发明的抗原结合蛋白、或其抗原结合片段诱导至少200的MFI降低。
更详细地,可以按照下面的方法测量上述Δ,其必须被视为说明性和非限制性的实例:
a)用本发明的抗原结合蛋白处理和孵育兴趣肿瘤细胞;
b)用本发明的抗原结合蛋白平行处理步骤a)处理的细胞以及未处理的细胞,
c)用能结合抗原结合蛋白的第二标记抗体测量处理和未处理的细胞的MFI(代表存在于表面的Axl量),以及
d)将Δ计算为未处理的细胞所获得的MFI减去处理的细胞所获得的MFI的差。
以最广泛的意义,术语“抗体”或“免疫球蛋白”可以互换使用,并且包括单克隆抗体,优选分离的Mab(例如,全长或完整单克隆抗体)、多克隆抗体、多价抗体或多特异性抗体(例如,双特异性抗体,只要它们展现出期望的生物学活性)。
更具体地,这样的分子由糖蛋白组成,糖蛋白包含通过二硫键相互连接的至少两条重链(H)和两条轻链(L)。每条重链包含重链可变区(或结构域)(此处缩写为HCVR或VH)和重链恒定区。重链恒定区包含三个结构域,CH1、CH2和CH3。每条轻链包含轻链可变区(此处缩写为LCVR或VL)和轻链恒定区。轻链恒定区包含一个结构域CL。VH和VL区可以进一步细分成高变区,称为互补决定区(CDR),其中散布有更保守的区域,称为框架区(FR)。每个VH和VL包含三个CDR和四个FR,按以下顺序从氨基端到羧基端排列:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可以介导免疫球蛋白结合至宿主组织或因子,包括免疫系统的各种细胞(例如,效应细胞)和经典补体系统的第一补体(Clq)。
在本发明的意义上的抗体还包括其某些抗体片段。所述抗体片段展现出期望的结合特异性和亲和性,而不论其来源或免疫球蛋白类型如何(即IgG、IgE、IgM、IgA等),也就是说它们能够以和本发明全长抗体相媲美的亲和性来特异性结合Axl蛋白。
通常,为了制备单克隆抗体或其功能片段,尤其是鼠科来源的,可能涉及尤其是手册《抗体》中描述的技术(Harlow和Lane,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor NY,pp.726,1988)或涉及Kohler和Milstein描述的制备杂交瘤的技术(Nature,256:495-497,1975)。
如此处所用的术语“单克隆抗体”或“Mab”指的是针对特定抗原的并且由B细胞或杂交瘤的单克隆产生的抗体分子。单克隆抗体也可以是重组的,即通过蛋白工程生产。另外,不同于通常包括针对不同决定簇或表位的各种抗体的多克隆抗体制备,每个单克隆抗体针对抗原的单一表位。本发明涉及一种抗体,其通过纯化分离自或获自天然来源、或通过遗传重组或化学合成获得。
本发明的一个优选的实施方式,是一种抗原结合蛋白或其抗原结合片段,其包含或由抗体组成,所述抗体包含三个轻链CDR和三个重链CDR;三个轻链CDR包含序列SEQ ID NO.1、2和3,或与SEQ ID NO.1、2和3表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;三个重链CDR包含序列SEQ ID NO.4、5和6,或与SEQ ID NO.4、5和6表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
在本发明更优选的一个实施方式中,抗原结合蛋白、或其抗原结合片段由抗体组成,所述抗体包含含有序列SEQ ID NO.1、2和3的三个轻链CDR;以及含有序列SEQ ID NO.4、5和6的三个重链CDR。
在一个优选的方面,CDR区或CDR意图表示IMGT所定义的免疫球蛋白重链和轻链的高变区。没有任何矛盾的记载,在本说明书中根据IMGT编号系统定义CDR。
无论抗原受体、链类型或物种如何,都将IMGT独特的编号定义为比较可变结构域(Lefranc M.-P.,Immunology Today18,509(1997)/Lefranc M.-P.,TheImmunologist,7,132-136(1999)/Lefranc,M.-P.,Pommié,C.,Ruiz,M.,Giudicelli,V.,Foulquier,E.,Truong,L.,Thouvenin-Contet,V.和Lefranc,Dev.Comp.Immunol.,27,55-77(2003))。在IMGT独特编号中,保守性氨基酸总是具有相同位置,例如半胱氨酸23(第1个CYS)、色氨酸41(保守性TRP)、疏水性氨基酸89、半胱氨酸104(第2个CYS)、苯丙氨酸或色氨酸118(J-PHE或J-TRP)。IMGT独特编号提供了框架区(FR1-IMGT:位置1至26,FR2-IMGT:39至55,FR3-IMGT:66至104和FR4-IMGT:118至128)和互补决定区CDR1-IMGT:27至38,CDR2-IMGT:56至65和CDR3-IMGT:105至117的标准化定界。由于空位代表未占用的位置,CDR-IMGT长度(在括号之间显示,并用点分开,例如[8.8.13])成为关键信息。在2D图解中使用IMGT独特编号,命名为IMGT Colliers de Perles(Ruiz,M.和Lefranc,M.-P.,Immunogenetics,53,857-883(2002)/Kaas,Q.和Lefranc,M.-P.,CurrentBioinformatics,2,21-30(2007)),并在IMGT/3D结构DB中的3D结构中使用(Kaas,Q.,Ruiz,M.和Lefranc,M.-P.,T cell receptor and MHC structural data.Nucl.Acids.Res.,32,D208-D210(2004))。
但必须理解的是,在本说明书中没有矛盾的说明,互补决定区或CDR意思是根据IMGT编号系统定义的免疫球蛋白重链和轻链的高变区。
无论如何,也可根据Kabat编号系统定义CDR(Kabat等人,Sequences ofproteins of immunological interest,第5版,U.S.Department of Health and HumanServices,NIH,1991和之后的版本)。有三个重链CDR和三个轻链CDR。此处,取决于情况,术语“CDR”用于指代一个或多个、或甚至全部包含大多数氨基酸残基的区域,所述氨基酸残基负责其所识别的抗原或表位的抗体结合亲和性。
根据Kabat编号系统,本发明涉及一种抗原结合蛋白或其抗原结合片段,其由抗体组成,所述抗体包含根据Kabat编号系统定义的三个轻链CDR和根据Kabat编号系统定义的三个重链CDR;三个轻链CDR包含序列SEQ ID NO.9、10和11,或与SEQ ID NO.9、10和11表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;三个重链CDR包含序列SEQ ID NO.12、13和14,或与SEQ ID NO.12、13和14表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
在本发明的含义中,两个核酸或氨基酸序列之间的“百分比同一性”意指待比较的两条序列间相同核苷酸或氨基酸残基的百分比,其在最佳比对后获得,此百分比是纯粹统计上的,两条序列间的差异沿其长度随机分布。两条核酸或氨基酸序列的比较传统上通过在对其最佳比对后比较序列来进行,所述比较能通过节段(segment)或通过使用“比对窗口”来执行。除了手动比较之外,通过Smith和Waterman的局部同源性算法(1981)(Ad.App.Math.2:482)、通过Neddleman和Wunsch的局部同源性算法(1970)(J.Mol.Biol.48:443)、通过Pearson和Lipman的相似性搜索法(1988)(Proc.Natl.Acad.Sci.USA85:2444)或通过使用这些算法的计算机软件(Wisconsin遗传学软件包中的GAP、BESTFIT、FASTA和TFASTA,遗传学计算组,575Science Dr.,Madison,WI,或通过比较软件BLASTNR或BLAST P)可以进行待比较的序列的最佳比对。
通过比较两个最佳比对的序列确定两个核酸或氨基酸序列之间的百分比同一性,其中待比较的核酸或氨基酸序列,相较于用于两条序列间最佳比对的参考序列,可以有添加或删除。通过确定两条序列间(优选两条完整序列间)相同氨基酸核苷酸或残基的位点的数目计算百分比同一性,将相同位点数除以比对窗口的总位点数并将结果乘以100以获得两条序列间的百分比同一性。
例如,可以使用在网页http://www.ncbi.nlm.nih.gov/gorf/bl2.html上可用的BLAST程序,“BLAST2序列”(Tatusova等人,“Blast2sequences-a new tool forcomparing protein and nucleotide sequences”,FEMS Microbiol.,1999,Lett.174:247–250),使用用缺省参数(特别是参数“开放空位罚分”:5,和“延伸空位罚分”:2;所选矩阵是例如程序提出的“BLOSUM62”矩阵);直接用程序计算待比较的两条序列之间的百分比同一性。
对于显示出与参考氨基酸序列有至少80%、优选85%、90%、95%和98%同一性的氨基酸序列,优选的实例包括包含参考序列、某些修饰(特别是删除、插入或取代至少一个氨基酸、截短或延长)的那些。在一个或多个连续或不连续的氨基酸被取代的情况下,优选在取代中所取代的氨基酸被“等价”氨基酸所代替。在此,表述“等价氨基酸”意指可能取代一个结构氨基酸、而不改变相应抗体生物学活性的任意氨基酸,以及下面定义的那些具体实施例的任意氨基酸。
可以根据其与它们所取代的氨基酸的结构同源性、或者根据可能生成的各种抗原结合蛋白间生物活性比较测试的结果来确定等价氨基酸。
作为非限制性实例,下面表2总结了可以进行而不导致相应修饰的抗原结合蛋白生物活性显著变化的可能取代;在同一条件下自然可以做相反的取代。
表2
原始残基 | 取代 |
Ala(A) | Val,Gly,Pro |
Arg(R) | Lys,His |
Asn(N) | Gln |
Asp(D) | Glu |
Cys(C) | Ser |
Gln(Q) | Asn |
Glu(G) | Asp |
Gly(G) | Ala |
His(H) | Arg |
Ile(I) | Leu |
Leu(L) | Ile,Val,Met |
Lys(K) | Arg |
Met(M) | Leu |
Phe(F) | Tyr |
Pro(P) | Ala |
Ser(S) | Thr,Cys |
Thr(T) | Ser |
Trp(W) | Tyr |
Tyr(Y) | Phe,Trp |
Val(V) | Leu,Ala |
本发明的一个实施方式涉及抗原结合蛋白或其抗原结合片段,其包含序列SEQ ID NO.7的轻链可变结构域,或与SEQ ID NO.7表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及包含序列SEQ ID NO.4、5和6的三个重链CDR,或与SEQ ID NO.4、5和6表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
根据本发明一个优选的实施方式,抗原结合蛋白或其抗原结合片段包含序列SEQ ID NO.7的轻链可变结构域,或与SEQ ID NO.7表现出至少80%同一性的任何序列;以及包含序列SEQ ID NO.4、5和6的三个重链CDR。
根据本发明另一个优选的实施方式,抗原结合蛋白或其抗原结合片段包含序列SEQ ID NO.7的轻链可变结构域,或与SEQ ID NO.7表现出至少80%同一性的任何序列。
本发明的另一个实施方式涉及抗原结合蛋白或其抗原结合片段,其包含三个轻链CDR,三个轻链CDR含有序列SEQ ID NO.1、2和3,或与SEQ ID NO.1、2和3表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及序列SEQ ID NO.8的重链可变结构域,或与SEQ ID NO.8表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
根据本发明一个优选的实施方式,抗原结合蛋白或其抗原结合片段包含三个轻链CDR,三个轻链CDR含有序列SEQ ID NO.1、2和3;以及序列SEQ ID NO.8的重链可变结构域,或与SEQ ID NO.8表现出至少80%同一性的任何序列。
根据本发明另一个优选的实施方式,抗原结合蛋白或其抗原结合片段包含序列SEQ ID NO.8的重链可变结构域,或与SEQ ID NO.8表现出至少80%同一性的任何序列。
本发明的另一个实施方式涉及抗原结合蛋白或其抗原结合片段,其包含序列SEQ ID NO.7的轻链可变结构域、或与SEQ ID NO.7表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及序列SEQ ID NO.8的重链可变结构域,或与SEQ ID NO.8表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
根据本发明一个优选的实施方式,抗原结合蛋白或其抗原结合片段包含序列SEQ ID NO.7的轻链可变结构域、或与SEQ ID NO.7表现出至少80%同一性的任何序列,以及序列SEQ ID NO.8的重链可变结构域,或与SEQ ID NO.8表现出至少80%同一性的任何序列。
为了更清晰,下面表3a总结了对应于本发明的抗原结合蛋白的各种氨基酸序列(其中Mu.=鼠)。
表3a
本发明的一个具体方面涉及鼠抗体、或其衍生化合物或抗原结合片段,特征在于所述抗体还包含源自与鼠异源的物种(尤其是人)的抗体的轻链和重链恒定区。
本发明的另一具体方面涉及嵌合抗体、或其衍生化合物或抗原结合片段,特征在于所述抗体还包含源自与鼠异源的物种(尤其是人)的抗体的轻链和重链恒定区。
然而本发明另一具体方面涉及人源化抗体、或其衍生化合物或抗原结合片段,特征在于源自人抗体的轻链和重链的恒定区分别为λ或κ区及γ1、γ2或γ4区。
本发明的另一方面是由单克隆抗体1613F12组成的抗原结合蛋白,所述单克隆抗体1613F12源自2011年7月28日保藏在法国巴斯德研究所CNCM的杂交瘤I-4505。
根据另一方面,本发明涉及能够分泌根据本发明的抗原结合蛋白的鼠杂交瘤,尤其是2011年7月28日以编号I-4505提交于法国国家培养物和微生物保藏中心(法国巴黎巴斯德研究所CNCM)的鼠源杂交瘤。通过融合Balb/C免疫的鼠脾细胞/淋巴细胞和骨髓瘤Sp2/O-Ag14细胞系的细胞获得所述杂交瘤。
根据另一方面,本发明涉及能够分泌抗体的鼠杂交瘤,所述抗体包含含有序列SEQ ID NO.1、2和3的三个轻链CDR;以及含有序列SEQ ID NO.4、5和6的三个重链CDR,所述杂交瘤在2011年7月28日以编号I-4505提交于法国巴黎巴斯德研究所CNCM。通过融合Balb/C免疫的鼠脾细胞/淋巴细胞和骨髓瘤Sp2/O-Ag14细胞系的细胞获得所述杂交瘤。
本发明的一个主题是鼠杂交瘤I-4505,其在2011年7月28日保藏在法国巴斯德研究所CNCM。
本发明的抗原结合蛋白还包括嵌合或人源化抗体。
嵌合抗体是一种抗体,其包含来自于给定物种的抗体的天然可变区(轻链和重链)与异源于所述给定物种的物种的抗体轻链和重链的恒定区的组合。
可以通过使用重组遗传学技术制备抗体或其嵌合片段。例如,可以通过克隆含有启动子和编码本发明的非人(特别是鼠)单克隆抗体可变区的序列、及编码人抗体恒定区的序列的重组DNA来生产嵌合抗体。根据本发明的由一个此类重组基因编码的嵌合抗体可以是例如鼠-人嵌合体,来自鼠DNA的可变区决定这种抗体的特异性,而来自人DNA的恒定区决定其同种型。参考Verhoeyn等人(BioEssays,8:74,1988)用于制备嵌合抗体的方法。
另一方面,本发明描述了由嵌合抗体组成的结合蛋白。
在一个具体的优选实施方式中,本发明的嵌合抗体或其抗原结合片段包含含有氨基酸序列SEQ ID NO.7的轻链可变结构域序列,以及包含含有氨基酸序列SEQ ID NO.8的重链可变结构域序列。
另一方面,本发明描述了由人源化抗体组成的结合蛋白。
“人源化抗体”意指含有来自于非人来源的抗体的CDR区的抗体,所述抗体分子的其它部分来源于一个(或几个)人抗体。此外,某些骨架区段残基(称作FR)可被修饰以保持结合亲和性(Jones等人,Nature,321:522-525,1986;Verhoeyen等人,Science,239:1534-1536,1988;Riechmann等人,Nature,332:323-327,1988)。
本发明的人源化抗体或其片段能够通过本领域技术人员已知的技术(如,例如在文献Singer等人,J.Immun.,150:2844-2857,1992;Mountain等人,Biotechnol.Genet.Eng.Rev.,10:1-142,1992;和Bebbington等人,Bio/Technology,10:169-175,1992中所述的那些)制备。优选此类人源化抗体用于涉及体外诊断或体内预防和/或治疗性治疗的方法。本领域技术人员还知道的其它人源化技术如,例如,PDL在专利EP0451216、EP0682040、EP0939127、EP0566647或US5,530,101、US6,180,370、US5,585,089和US5,693,761中所述的“CDR接枝”技术。还能引用美国专利5,639,641或6,054,297、5,886,152和5,877,293。
此外,发明还涉及由上述鼠抗体产生的人源化抗体。
以优选的方式,来自人抗体的轻链和重链恒定区分别是λ或κ及γ1、γ2或γ4区。
在一个优选的实施方式中,本发明涉及由人源化抗体组成的抗原结合蛋白,或其抗原结合片段,其包含含有序列SEQ ID NO.36的轻链可变结构域、或与SEQID NO.36表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及含有序列SEQ ID NO.4、5和6的三个重链CDR。
本发明另一个实施方式涉及抗原结合蛋白,或其抗原结合片段,其包含选自SEQ ID NO.37-47的序列的轻链可变结构域、或与SEQ ID NO.37-47表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及含有序列SEQ ID NO.4、5和6的三个重链CDR。
“与SEQ ID NO.36或37-47表现出至少80%,优选85%、90%、95%和98%同一性的任何序列”意图是指呈现三个轻链CDR SEQ ID NO.1、2和3,并且此外,与对应着CDR序列(即SEQ ID NO.1、2和3)之外的全序列SEQ ID NO.36或37-47表现出至少80%,优选85%、90%、95%和98%同一性的序列。
为了更清晰,下面表3b总结了对应于本发明的人源化抗原结合蛋白轻链(VL)的各种氨基酸序列(其中Hz.=人源化)。
表3b
在本发明的一个实施方式中,抗原结合蛋白或其抗原结合片段,包含选自如下的轻链可变结构域:
i)序列SEQ ID NO.7的轻链可变结构域、或与SEQ ID NO.7表现出至少80%同一性的任何序列,
ii)序列SEQ ID NO.36的轻链可变结构域、或与SEQ ID NO.36表现出至少80%同一性的任何序列;以及
iii)序列SEQ ID NO.37-47的轻链可变结构域、或与SEQ ID NO.37-47表现出至少80%同一性的任何序列。
在一个优选的实施方式中,本发明涉及由人源化抗体组成的抗原结合蛋白,或其抗原结合片段,其包含含有序列SEQ ID NO.48的重链可变结构域、或与SEQID NO.48表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及含有序列SEQ ID NO.1、2和3的三个轻链CDR。
本发明另一个实施方式涉及抗原结合蛋白,或其抗原结合片段,其包含选自SEQ ID NO.49-68的序列的重链可变结构域、或与SEQ ID NO.49-68表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及含有序列SEQ ID NO.1、2和3的三个轻链CDR。
“与SEQ ID NO.48和49-68表现出至少80%,优选85%、90%、95%和98%同一性的任何序列”意图是指呈现三个重链CDR SEQ ID NO.4、5和6,并且此外,与对应着CDR序列(即SEQ ID NO.4、5和6)之外的全序列SEQ ID NO.48和49-68表现出至少80%,优选85%、90%、95%和98%同一性的序列。
为了更清晰,下面表3c总结了对应于本发明的人源化抗原结合蛋白重链(VH)的各种氨基酸序列(其中Hz.=人源化)。
表3c
在本发明的一个实施方式中,抗原结合蛋白或其抗原结合片段,包含选自如下的重链可变结构域:
i)序列SEQ ID NO.8的重链可变结构域、或与SEQ ID NO.8表现出至少80%同一性的任何序列;
ii)序列SEQ ID NO.48的重链可变结构域、或与SEQ ID NO.48表现出至少80%同一性的任何序列;以及
iii)序列SEQ ID NO.49-68的重链可变结构域、或与SEQ ID NO.49-68表现出至少80%同一性的任何序列。
在本发明一个实施方式中,抗原结合蛋白或其抗原结合片段,包含序列SEQ IDNO.36的轻链可变结构域、或与SEQ ID NO.36表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及序列SEQ ID NO.48的重链可变结构域、或与SEQ ID NO.48表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
在本发明另一个实施方式中,抗原结合蛋白或其抗原结合片段,包含选自SEQID NO.37-47的序列的轻链可变结构域、或与SEQ ID NO.37-47表现出至少80%,优选85%、90%、95%和98%同一性的任何序列;以及选自SEQ ID NO.49-68的序列的重链可变结构域、或与SEQ ID NO.49-68表现出至少80%,优选85%、90%、95%和98%同一性的任何序列。
在本发明的一个实施方式中,抗原结合蛋白或其抗原结合片段,包含:
i)序列SEQ ID NO.7、36或37-47的轻链可变结构域、或与SEQ ID NO.7、36或37-47表现出至少80%同一性的任何序列;以及
ii)序列SEQ ID NO.8、48或49-68的重链可变结构域、或与SEQ ID NO.8、48或49-68表现出至少80%同一性的任何序列。
本发明的一个新的方面涉及分离的核酸,特征在于其选自如下核酸(包括任何简并遗传密码):
a)核酸,其编码根据本发明的抗原结合蛋白或其抗原结合片段;
b)核酸,其包括:
-选自SEQ ID No.15至28及69至99的核酸序列,或
-包含六个核酸序列SEQ ID No.15至20的核酸序列,或
-核酸序列,其包含两个核酸序列SEQ ID No.21、22、或者其中一部分选自SEQ ID No.69至79且另一部分选自SEQ ID No.80至99的两个核酸序列;
c)如a)或b)中定义的核酸的互补核酸;以及
d)核酸,优选其具有至少18个核苷酸的核酸,其能够在高度严谨条件下与部分a)或b)中定义的核酸序列杂交,或者与部分a)或b)中定义的核酸序列在最佳比对之后具有至少80%,优选85%、90%、95%和98%同一性的序列杂交。
下面表4a总结了关于本发明结合蛋白的各种核苷酸序列(其中Mu.=鼠)。
表4a
为了更清晰,下面表4b总结了对应于本发明的人源化抗原结合蛋白轻链(VL)的各种核苷酸序列(其中Hz.=人源化)。
表4b
为了更清晰,下面表4c总结了对应于本发明的人源化抗原结合蛋白重链(VH)的各种核苷酸序列(其中Hz.=人源化)。
表4c
术语“核酸”、“核序列”、“核酸序列”、“多核苷酸”,“寡核苷酸”、“多核苷酸序列”和“核苷酸序列”在本说明书中可互换使用,表示无论有无修饰的限定核酸片段或区域的精确核苷酸序列,其含有或不含非天然核苷酸,是双链DNA、单链DNA或所述DNA的转录产物。
本发明的序列已经分离和/或纯化,即它们(例如以一个拷贝)直接或间接取样,其环境已经至少部分被改变。在此还应提及通过重组遗传学(例如以宿主细胞的方式)获得、或通过化学合成获得的分离核酸。
“在与优选序列最佳比对后显示至少80%、优选85%、90%、95%和98%百分比同一性的核序列”意指核序列相对于参考核序列显示某些修饰(尤其是定点的修饰),例如特别是删除、截短、延长、嵌合融合和/或取代。优选的是,这些序列编码与参考序列相同的氨基酸序列(这涉及遗传密码的简并)、或是优选在高度严谨条件下有可能与参考序列特异杂交的互补序列,特别是下面定义的那些。
在高度严谨条件下杂交意指,在此方式下选择涉及温度和离子强度的条件以允许两条互补DNA片段间维持杂交。在单纯说明性基础上,上述出于限定多核苷酸片段目的的杂交步骤的高度严谨条件是有利地如下。
在两个步骤中进行DNA-DNA或DNA-RNA杂交:(1)在42℃、在磷酸盐缓冲液(20mM,pH7.5,包含5×SSC(1×SSC对应于0.15M NaCl+0.015M柠檬酸钠的溶液)、50%甲酰胺、7%十二烷基硫酸钠(SDS)、10×Denhardt’s、5%硫酸葡聚糖和1%的鲑精DNA)中预杂交三个小时;(2)在取决于探针长度的温度(即,对于大于100核苷酸长的探针是42℃)下进行20小时初始杂交,然后在20℃、在2×SSC+2%SDS中进行两次20分钟洗涤,在20℃、在0.1×SSC+0.1%SDS中进行一次20分钟洗涤。对于大于100核苷酸长的探针,在60℃、在0.1×SSC+0.1%SDS中进行30分钟最后的洗涤。对于长些或短些的寡核苷酸,本领域技术人员能依据Sambrook等人所述的程序(Molecular cloning:a laboratory manual,Cold Spring Harbor Laboratory;第三版,2001)针对特定尺寸的多核苷酸调整上述高度严谨杂交条件。
本发明还涉及包括本发明所述的核酸的载体。
本发明尤其靶向包含此类核苷酸序列的克隆和/或表达载体。
本发明的载体优选包含在给定宿主细胞中允许核苷酸序列表达和/或分泌的元件。因而载体必须包含启动子、翻译起始和终止信号、还有适当的转录调控区。它必须能够在宿主细胞中以稳定的方式维持,并且任选地具有指导翻译蛋白质分泌的特异信号。根据所用的宿主细胞,本领域技术人员能选择和优化这些不同元件。为此目的,核苷酸序列能被插入至所选宿主内的自主复制载体,或者是所选宿主的整合载体。
此类载体以本领域技术人员通常使用的方法制备,而且产生的克隆能以如脂质转染、电穿孔、热激或化学方法的标准方法引入至适当的宿主。
载体是(例如)质粒或病毒来源的载体。它们被用于转化宿主细胞以克隆或表达本发明的核苷酸序列。
本发明还包括转化有或包含本发明所述载体的分离的宿主细胞。
宿主细胞能选自原核或真核系统,如细菌细胞例如,还有酵母细胞或动物细胞,特别是哺乳动物细胞(除了人)。还能使用昆虫或植物细胞。
本发明还涉及具有根据本发明所述转化细胞的动物(除了人)。
本发明的另一方面涉及用于生产根据本发明的抗原结合蛋白、或其抗原结合片段的方法,其特征在于所述方法包括下列步骤:
a)在培养基中及在适当培养条件下培养根据本发明所述的宿主细胞;及
b)从培养基或从所述培养细胞中回收因而产生的抗原结合蛋白、或其抗原结合片段之一。
根据本发明所述的转化细胞可用于制备根据本发明所述的重组抗原结合蛋白的方法。用于制备根据本发明的重组形式的抗原结合蛋白的方法也包括在本发明中,其特征在于所述方法使用根据本发明所述的载体和/或转化有根据发明所述的载体的细胞。优选地,转化有根据发明所述的载体的细胞在允许前述抗原结合蛋白得以表达和所述重组蛋白得以回收的条件下培养。
如已提及的,宿主细胞能选自原核或真核系统。特别是,可能鉴定有利于在此原核或真核系统中分泌的本发明的核苷酸序列。携带这样序列的根据本发明的载体因此能有利地用于生产待分泌的重组蛋白。事实上,蛋白在细胞培养物上清中而非在宿主细胞内存在的事实将有利于这些兴趣重组蛋白的纯化。
本发明的抗原结合蛋白还能通过化学合成制备。一种此类制备方法也是本发明的主题。本领域技术人员知道用于化学合成的方法,如通过浓缩片段或通过溶液中传统合成的固相技术(特别参见Steward等人,1984,Solid phase peptidessynthesis,Pierce Chem.Company,Rockford,111,第二版pp71-95)或部分固相技术。发明也包括通过化学合成获得并能够包含相应非天然氨基酸的多肽。
本发明还包括通过本发明的方法可能获得的抗原结合蛋白或其抗原结合片段。
根据一个具体的方面,本发明涉及上述的抗原结合蛋白或其抗原结合片段,用作、将细胞毒性剂递送至宿主靶标位点的定位产品,所述宿主靶标位点由定位于蛋白Axl细胞外结构域中的表位组成,优选人蛋白Axl细胞外结构域,更优选具有序列SEQ ID NO.31或21的人蛋白Axl细胞外结构域、或其天然变体序列。
在优选的实施方式中,所述宿主靶标位点是哺乳动物细胞的靶标位点,更优选人细胞,更优选天然或通过遗传重组的方式表达Axl蛋白的细胞。
本发明涉及免疫缀合物,其包含缀合至细胞毒性剂的本说明书中所述的抗原结合蛋白。
在本发明意义上,表述“免疫缀合物”或“免疫-缀合物”通常指包括至少一个定位产品的化合物,其中定位产品与一种或多种治疗剂物理连接,从而产生高度靶向的化合物。
在一个优选实施方式,这样的治疗剂由细胞毒性剂组成。
“细胞毒性剂”或“细胞毒素”,是指这样的试剂,当施用受试者时,其通过抑制或防止细胞功能和/或引起细胞死亡,来治疗或预防细胞增殖的发展,优选受试者身体中的癌症发展。
许多细胞毒性剂已被分离或合成,并使其能够抑制细胞的增殖,或(如未明确)至少显著破坏或减少肿瘤细胞。然而,这些试剂的毒性活性并不仅限于肿瘤细胞,非肿瘤细胞也受影响并且可以被破坏。更具体地,在快速更新的细胞中,如造血细胞或上皮细胞,尤其是粘膜中观察到副作用。通过举例说明的方式,通过使用这样的细胞毒性剂,胃肠道的细胞很受影响。
本发明的目的之一还能够提供一种细胞毒性剂,这使得可以限制对正常细胞的副作用,而同时保留对肿瘤细胞的高细胞毒性。
更具体地,细胞毒性剂可优选包括,但不限于药物(即“抗体药物缀合物”)、毒素(即“免疫毒素”或“抗体毒素缀合物”)、放射性同位素(例如“放射免疫缀合物”或“抗体放射性同位素缀合物”)等。
在本发明的第一优选实施方式中,免疫缀合物由连接于至少一种药物或药品的结合蛋白组成。当结合蛋白是抗体、或其抗原结合片段时,这样的免疫缀合物被称为抗体药物缀合物(或“ADC”)。
在第一实施方式中,可以根据其作用模式描述这样的药物。作为非限制性实例,可以提及烷化剂(如氮芥、烃基磺酸盐、亚硝基脲、oxazophorin(无对应中译文)、氮丙啶或乙撑亚胺)、抗代谢药、抗肿瘤抗生素、有丝分裂抑制剂、染色质功能抑制剂、抗血管生成剂、抗雌激素、抗雄激素、螯合剂、铁吸收刺激剂、环氧合酶抑制剂、磷酸二酯酶抑制剂、DNA抑制剂、DNA合成抑制剂、凋亡刺激剂、胸苷酸抑制剂、T细胞抑制剂、干扰素激动剂、核糖核苷三磷酸还原酶抑制剂、芳香酶抑制剂、雌激素受体拮抗剂、酪氨酸激酶抑制剂、细胞周期抑制剂、紫杉烷、微管蛋白抑制剂、血管生成抑制剂、巨噬细胞刺激剂、神经激肽受体拮抗剂、大麻素受体激动剂、多巴胺受体激动剂、粒细胞刺激因子激动剂、促红细胞生成素受体激动剂、促生长素抑制素受体激动剂、LHRH激动剂、钙增敏剂、VEGF受体拮抗剂、白细胞介素受体拮抗剂、破骨细胞抑制剂、自由基形成刺激剂、内皮素受体拮抗剂、长春花生物碱、抗激素或免疫调节剂或任何其它满足细胞毒素或毒素活性标准的新药物。
例如VIDAL2010在关于附着至癌症学和血液学栏“细胞毒素”的化合物的页中引用了这种药物,参考这一文件引用的这些细胞毒性化合物在此处引作优选细胞毒性剂。
更具体地,但不限于,根据本发明优选以下药物:二氯甲基二乙胺、苯丁酸氮芥(chlorambucol)、美法仑、氢氯化物(chlorydrate)、哌泊溴烷(pipobromen)、泼尼莫司汀(prednimustin)、焦亚(disodic)-磷酸盐、雌氮芥、环磷酰胺、六甲蜜胺(altretamine)、曲洛磷胺、硫代异环磷酰胺(sulfofosfamide)、异环磷酰胺、塞替派、三乙胺、altetramine(无对应中译文)、卡莫司汀、链脲霉素、佛替姆丁、洛莫司汀、白消安、曲奥舒凡(treosulfan)、英丙舒凡(improsulfan)、达卡巴嗪、顺铂、奥沙利铂、洛铂、庚铂(heptaplatin)、米铂(miriplatin)水合物、卡铂、甲氨蝶呤、培美曲塞、5-氟尿嘧啶、氟尿苷、5-氟脱氧尿苷、卡培他滨、阿糖胞苷、氟达拉滨、胞嘧啶阿拉伯糖苷、6-巯基嘌呤(6-MP)、奈拉滨、6-巯鸟嘌呤(6-TG)、氯脱氧腺苷、5-氮胞苷、吉西他滨(gemcitabine)、克拉屈滨(cladribine)、脱氧柯福霉素、替加氟、喷司他汀、阿霉素、道诺霉素、伊达比星、戊柔比星、米托蒽醌、更生霉素、光辉霉素、普卡霉素、丝裂霉素C、博来霉素、丙卡巴肼、紫杉醇、多烯紫杉醇、长春碱、长春新碱、长春地辛、长春瑞滨、托泊替康、伊立替康、依托泊苷、戊柔比星、盐酸氨柔比星、吡柔比星、依利醋铵、佐柔比星、表柔比星、伊达比星和替尼泊苷、雷佐生、马立马司他、巴马司他、普啉司他、坦诺司他、伊洛马司他、CGS-27023A、卤夫酮、COL-3、新伐司他、沙立度胺、CDC501、DMXAA、L-651582、角鲨胺、内皮他丁、SU5416、SU6668、干扰素-α、EMD121974、白介素-12、IM862、血管生成抑制因子、他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、iodoxyfene(无对应中译文)、阿那曲唑、来曲唑、依西美坦、氟他胺、尼鲁米特、安体舒通、醋酸环丙孕酮、非那雄胺、西米替丁、硼替佐米、万珂、比卡鲁胺、环丙孕酮、氟他胺、氟维司群(fulvestran)、依西美坦、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、尼洛替尼、索拉非尼、舒尼替尼、类视黄醇、rexinoid(无对应中译文)、methoxsalene(无对应中译文)、氨基酮戊酸甲酯、aldesleukine(无对应中译文)、OCT-43、地尼白介素(denileukin diflitox)、白介素-2、他索纳明(tasonermine)、香菇多糖、西佐喃、罗喹美克、匹多莫德、培加酶、刹莫潘汀(thymopentine)、聚I:C、procodazol(无对应中译文)、TicBCG、短棒状杆菌制剂(corynebacterium parvum)、NOV-002、ukrain(无对应中译文)、左旋咪唑、1311-chTNT、H-101、西莫白介素、干扰素α2a、干扰素α2b、干扰素γ1a、白介素-2、莫贝白介素、Rexin-G、替西白介素、阿克拉霉素、放线菌素、arglabin(无对应中译文)、门冬酰胺酶、carzinophilin(无对应中译文)、色霉素、道诺霉素、亚叶酸、马索罗酚、新制癌菌素、培洛霉素、肉瘤霉素、茄边碱、曲贝替定、链佐星、睾酮、库内儿茶素、sinecatechins(无对应中译文)、阿利维A酸、belotecan hydrocholoride(无对应中译文)、卡普睾酮、屈他雄酮、依利醋铵、乙炔雌二醇、依托泊苷、氟甲睾酮、福美坦、fosfetrol(无对应中译文)、醋酸戈舍瑞林、己基氨基乙酰丙酸、组氨瑞林、羟孕酮、伊沙匹隆、亮丙瑞林、甲羟孕酮醋酸酯、甲地孕酮醋酸酯、甲泼尼龙、甲基睾酮、米替福新、二溴甘露醇、苯丙酸诺龙、醋酸炔诺酮、泼尼松龙、泼尼松、替西罗莫司、睾内酯、氟羟氢化泼尼松、曲普瑞林、醋酸伐普肽、净司他丁斯酯、安吖啶、三氧化二砷、盐酸比生群、苯丁酸氮芥、三对甲氧苯乙烯(chlortrianisene)、顺二氨二氯铂、环磷酰胺、己烯雌酚、六甲蜜胺、羟基脲、来那度胺、氯尼达明、mechlorethanamine(无对应中译文)、米托坦、奈达铂、盐酸尼莫司汀、帕米膦酸、哌泊溴烷、卟吩姆钠、雷莫司汀、雷佐生、司莫司汀、索布佐生、甲磺酸盐、三乙撑蜜胺、唑来膦酸、甲磺酸卡莫司他、法倔唑HCl、萘福昔定、氨鲁米特、卡莫氟、氯法拉滨、胞嘧啶阿拉伯糖苷、地西他滨、去氧氟尿苷、依诺他滨、fludarabne phosphate(无对应中译文)、氟尿嘧啶、替加氟、尿嘧啶氮芥、阿巴瑞克、贝沙罗汀、raltiterxed(无对应中译文)、他米巴罗汀、替莫唑胺、伏立诺他、甲地孕酮、氯膦酸盐二钠、左旋咪唑、纳米氧化铁、iron isomaltoside(无对应中译文)、塞来昔布、异丁司特、苯达莫司汀、六甲蜜胺、二溴卫矛醇、西罗莫司、普拉曲沙、TS-1、地西他滨、比卡鲁胺、氟他胺、来曲唑、氯膦酸二钠、地加瑞克、枸橼酸托瑞米芬、组胺二盐酸盐、DW-166HC、二胺硝吖啶、地西他滨、irinoteacn hydrochloride(无对应中译文)、安吖啶、罗米地辛、维甲酸、卡巴他赛、凡德他尼、来那度胺、伊班膦酸、米替福新、vitespen(无对应中译文)、米伐木肽、那屈肝素、格拉司琼、昂丹司琼、托烷司琼、阿立必利、雷莫司琼、甲磺酸多拉司琼、福沙吡坦酸葡胺、大麻隆、阿瑞吡坦、屈大麻酚、TY-10721、马来酸氢麦角乙脲、epiceram(无对应中译文)、去纤苷、达比加群酯、非格司亭、培非司亭、reditux(无对应中译文)、促红细胞生成素、莫拉司亭、奥普瑞白介素、sipuleucel-T(无对应中译文)、M-VAX、乙酰左旋肉碱、盐酸多奈哌齐、5-氨基乙酰丙酸、氨基乙酰丙酸甲酯、醋酸西曲瑞克、艾考糊精、亮丙瑞林、metbylphenidate(无对应中译文)、奥曲肽、氨来占诺、普乐沙福、四烯甲萘醌、anethole dithiolethione(无对应中译文)、度骨化醇、盐酸西那卡塞、阿法赛特、咯咪珀咯、甲状腺球蛋白、胸腺法新、乌苯美司、咪喹莫特、依维莫司、西罗莫司、H-101、拉索昔芬、曲洛司坦、英卡膦酸、神经节苷脂、哌加他尼钠、vertoporfin(无对应中译文)、米诺膦酸、唑来膦酸、硝酸镓、阿仑磷酸钠、依替膦酸二钠、帕米膦酸二钠、度他雄胺、葡萄糖酸锑钠、阿莫达非尼、右雷佐生、氨磷汀、WF-10、替莫卟吩、达贝泊汀α、安西司亭、沙格司亭、帕利夫明、R-744、奈匹德明、奥普瑞白介素、denileukin diftitox(无对应中译文)、克立他酶(crisantaspase)、布舍瑞林、德舍瑞林、兰瑞肽、奥曲肽、毛果芸香碱、波生坦、卡奇霉素、美登素和环烟酯。
对于更多的细节,本领域的技术人员可以参照由“AssociationdesEnseignants de Chimie Thérapeutique”编辑并且题目为“traitéde chimie thérapeutique,卷6,Médicaments antitumoraux et perspectives dans le traitement des cancers,TEC&DOC版,2003”的手册。
在本发明的第二优选实施方式中,免疫缀合物由连接至至少放射性同位素的结合蛋白组成。当结合蛋白是抗体或其抗原结合片段时,这种免疫缀合物称为抗体放射性同位素缀合物(或“ARC”)。
为了选择性破坏肿瘤,抗体可以包括高度放射活性的原子。各种放射活性同位素可用于生产ARC,比如但不限于At211、C13、N15、O17、Fl19、I123、I131、I125、In111、Y90、Re186、Re188、Sm153、tc99m、Bi212、P32、Pb212、Lu、钆、锰或铁的放射活性同位素。
本领域技术人员已知的任何方法或过程可用于将这种放射性同位素并入ARC(参见例如“Monoclonal Antibodies in Immunoscintigraphy”Chatal,CRC Press1989)。作为非限制性实例,tc99m或I123、Re186、Re188和In111可通过半胱氨酸残基附着。Y90可通过赖氨酸残基附着。I123可使用IODOGEN方法附着(Fraker等人(1978)Biochem.Biophys.Res.Commun.80:49-57)。
可以提到多种实例来说明ARC领域技术人员的常识,ARC例如其是一种由抗CD20单克隆抗体和通过硫脲接头螯合剂结合的In111或Y90放射性同位素组成的ARC(Wiseman等人(2000)Eur.Jour.Nucl.Med.27(7):766-77;Wiseman等人(2002)Blood99(12):4336-42;Witzig等人(2002)J.Clin.Oncol.20(10):2453-63;Witzig等人(2002)J.Clin.Oncol.20(15):3262-69);或其由连接至卡里奇霉素的抗CD33抗体组成(US4,970,198;5,079,233;5,585,089;5,606,040;5,693,762;5,739,116;5,767,285;5,773,001)。最近,还可以提及称为Adcetris的ADC(对应着Brentuximab vedotin(无对应中译文)),其近期已被FDA接受用于治疗霍奇金氏淋巴瘤(Nature,卷476,pp380-381,2011年8月25日)。
在本发明的第三优选实施方案中,免疫缀合物由连接至毒素的结合蛋白组成。当结合蛋白是抗体或其抗原结合片段时,这种免疫缀合物称为抗体毒素缀合物(或“ATC”)。
毒素是由活的生物产生的有效和特定的毒物。它们通常由氨基酸链组成,所述氨基酸链在分子量方面可以变化,在几百(肽)和十万(蛋白质)之间。它们也可以是低分子量的有机化合物。毒素由许多生物产生,如细菌、真菌、藻和植物。它们中许多是非常有毒的,具有比神经剂强几个数量级的毒性。
用于ATC的毒素可以包括但不限于所有种类的毒素,其可以通过包括微管蛋白结合、DNA结合或拓扑异构酶抑制的机制表现其细胞毒作用。
可用的酶活性毒素及其片段包括白喉毒素A链、白喉毒素的非结合活性片段、外毒素A链(来自铜绿假单胞菌)、蓖麻毒素A链、相思豆毒蛋白A链、蒴莲根毒素A链、α-帚曲毒蛋白(sarcin)、油桐蛋白、石竹蛋白、Phytolaca americana蛋白(无对应中译文)(PAPI,PAPII和PAP-S)、苦瓜抑制剂、麻疯树毒蛋白、巴豆毒素、sapaonaria officinalis(无对应中译文)抑制剂、白树毒素、mitogellin(无对应中译文)、局限曲霉素、酚霉素、依诺霉素和tricothecene(无对应中译文)。
此处也可考虑小分子毒素,如多拉司他汀、auristatin(无对应中译文)、单端孢霉烯和CC1065,和具有毒素活性的这些毒素的衍生物。已显示多拉司他汀和auristatin干扰微管动力、GTP水解、以及核和细胞分裂并具有抗癌和抗真菌活性。
“接头”、“接头单元”或“链接”指包含共价键或原子链的化学部分,共价键或原子链将结合蛋白共价附着至至少一种细胞毒性剂。
使用多种双功能蛋白偶联剂可以制备接头,双功能蛋白偶联剂如N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(SMCC)、亚氨基硫烷(IT)、亚氨酸酯的双功能衍生物(如己二亚氨二甲酯HC1)、活性酯(如二琥珀酰亚胺辛二酸酯)、醛(如戊二醛)、双叠氮化合物(如双(对-叠氮苯甲酰基)己二胺)、双-重氮衍生物(如双-(对-重氮苯甲酰基)-乙二胺)、二异氰酸酯(如甲苯2,6-二异氰酸酯)和双活性氟化合物(如1,5-二氟-2,4-二硝基苯)。碳-14标记的1-异硫氰酸苯甲基-3-甲基乙基三胺五乙酸(MX-DTPA)是一种将细胞毒性剂缀合至定位系统的示例性螯合剂。其它交联接头试剂可以是BMPS、EMCS、GMBS、HBVS、LC-SMCC、MBS、MPBH、SBAP、SIA、SIAB、SMCC、SMPB、磺基-EMCS、磺基-GMBS、磺基-KMUS、磺基-MBS、磺基-SIAB、磺基-SMCC和磺基-SMPB和SVSB(琥珀酰亚胺基-(4-乙烯基砜)苯甲酸酯),其可以市售获得(例如,来自美国Rockford,111的PierceBiotechnology,Inc.)。
接头可以是“非可切割的”或“可切割的”。
在优选的实施方式中,它包括“可切割的接头”以利于细胞毒性剂在细胞内释放。例如,可使用酸不稳定的接头、肽酶敏感接头、光不稳定接头、二甲基接头或含二硫化物的接头。在优选的实施方式中,在细胞内条件下接头是可切割的,从而在细胞内环境中切割接头从结合蛋白释放细胞毒性剂。
例如,在一些实施方式中,通过存在于细胞内环境中的切割剂(例如,溶酶体或胞内体或细胞膜穴样内陷(caveolea)),接头是可切割的。接头可以是例如肽基接头,其被细胞内肽酶或蛋白酶(包括但不局限于溶酶体或胞内体蛋白酶)切割。典型地,肽基接头是至少2个氨基酸长,或至少3个氨基酸长。切割剂可包括组织蛋白酶B和D以及纤溶酶,所有这些都已知水解二肽药物衍生物,导致活性药物在靶细胞内释放。例如,可以使用可被癌组织中高度表达的硫醇依赖性蛋白酶组织蛋白酶B切割的肽基接头(如Phe-Leu或Gly-Phe-Leu-Gly接头)。在具体实施方式中,可被细胞内蛋白酶切割的肽基接头是Val-Cit接头或Phe-Lys接头。使用细胞内蛋白水解释放细胞毒性剂的一个优点是,当经过缀合时所述试剂通常是减毒,而且缀合物的血清稳定性通常较高。
在其它实施方式中,可切割接头是pH敏感的,即对一定pH值下的水解敏感。通常,在酸性条件下pH敏感的接头是可水解的。例如,可使用在溶酶体中可被水解的酸不稳定接头(如腙、缩氨基脲、缩氨基硫脲、顺式乌头酰胺、原酸酯、缩醛、缩酮等)。在中性pH条件下这样的接头相对稳定,如在血液中的那些,但在pH5.5或5.0以下(近似溶酶体的pH)不稳定。在某些实施方式中,可水解的接头是硫醚接头(如,例如通过酰腙键连接到治疗剂的硫醚)。
在又一些其它实施方式中,接头在还原条件下可切割(如,二硫键接头)。各种二硫化物接头是本领域已知的,包括例如可使用SATA(N-琥珀酰亚胺基-S-乙酰硫代乙酸酯)、SPDP(N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯)、SPDB(N-琥珀酰亚胺基-3-(2-吡啶二硫代)丁酸酯)和SMPT(N-琥珀酰亚胺基-氧羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯)、SPDB和SMPT形成的那些。
作为非可切割的或“不可还原的”接头的非限制性实例,可以提及免疫缀合物曲妥珠单抗-DM1(TDM1),其将曲妥珠单抗与化疗剂、美登素组合(CancerResearch2008;68:(22).November15,2008)。
在一个优选的实施方式中,本发明的免疫缀合物可以通过本领域技术人员已知的任何方法来制备,例如但不限于i)抗原结合蛋白的亲核基团与二价接头试剂反应,然后与细胞毒性剂反应或ii)细胞毒性剂的亲核基团与二价接头试剂反应,然后与抗原结合蛋白的亲核基团反应。
当抗原结合蛋白被糖基化时,抗原结合蛋白上的亲核基团包括但不限于N-端氨基、侧链氨基例如赖氨酸、侧链硫醇基团以及糖的羟基或氨基。胺、硫醇和羟基是亲核的,并且能够与接头部分上的亲电基团反应形成共价键,接头试剂包括但不限于活性酯如NHS酯、HOBt酯、卤代甲酸酯和酸性卤化物;烷基和苄基卤化物如卤代乙酰胺;醛、酮、羧基和马来酰亚胺基团。抗原结合蛋白可具有可还原的链间二硫键,即半胱氨酸桥。通过用还原剂如DTT(二硫苏糖醇)处理,可以使抗原结合蛋白具有反应性,而与接头试剂缀合。因此,每个半胱氨酸桥理论上将形成两个反应性硫醇亲核体。通过本领域技术人员已知的任何反应,附加的亲核基团可被引入到抗原结合蛋白。作为非限制性的实例,可通过引入一个或多个半胱氨酸残基,将反应性硫醇基团引入抗原结合蛋白。
也可以通过修饰抗原结合蛋白引入亲电部分从而产生免疫缀合物,亲电部分可以与接头试剂或细胞毒性剂的亲核取代基反应。糖基化的抗原结合蛋白的糖可以被氧化而形成醛或酮基团,其可以与接头试剂或细胞毒性剂的氨基反应。所得亚胺Schiff碱基团可形成稳定的键合,或者可以被还原而形成稳定的胺键合。在一个实施方式中,糖基化抗原结合蛋白的碳水化合物部分与半乳糖氧化酶或高碘酸钠反应可产生蛋白中的羰基(醛和酮),其中羰基可以与药物上的适当基团反应。在另一个实施方式中,含N-端丝氨酸或苏氨酸残基的蛋白质可与高碘酸钠反应,导致产生代替第一个氨基酸的醛。
在某些优选的实施方式中,接头单元可具有以下通式:
--Ta--Ww--Yy--
其中:
-T-是延伸(stretcher)单元;
a为0或1;
-W-是氨基酸单元;
w独立地是从1到12的整数;
-Y-是间隔单元;
y为0、1或2。
延伸单元(-T-)存在时,将抗原结合蛋白连接至氨基酸单元(-W-)。可存在于抗原结合蛋白的有用官能团,无论是天然的还是经化学处理,包括巯基、氨基、羟基、碳水化合物的异头羟基、和羧基。合适的官能团是巯基和氨基。如果存在的话,可通过还原抗原结合蛋白的分子间二硫键来生成巯基。或者,可通过抗原结合蛋白的赖氨酸部分的氨基与2-亚氨基硫烷或其它巯基生成试剂反应来产生巯基。在具体实施方式中,抗原结合蛋白是重组抗体,并且经工程化改造以携带一个或多个赖氨酸。更优选地,抗原结合蛋白可经工程化改造以携带一个或多个半胱氨酸(参见ThioMabs)。
在某些具体实施方式中,延伸单元与抗原结合蛋白的硫原子形成键。硫原子可以源自还原的抗原结合蛋白的巯基(-SH)基团。
在某些其它具体实施方式中,延伸单元经由抗原结合蛋白的硫原子与延伸单元的硫原子之间的二硫键连接至抗原结合蛋白。
在其它具体实施方式中,延伸物的反应基团包含可以和抗原结合蛋白的氨基进行反应的反应位点。氨基可以是精氨酸或赖氨酸。合适的胺反应性位点,包括但不限于活性酯,例如琥珀酰亚胺酯、4-硝基苯基酯、五氟苯酯、酐、酰氯、磺酰氯、异氰酸酯和异硫氰酸酯。
在又一个方面中,延伸物的反应基团包含可以和存在于抗原结合蛋白上的修饰碳水化合物基团进行反应的反应位点。在一个具体实施方式中,抗原结合蛋白经酶促糖基化以提供碳水化合物部分(要注意的是,当抗原结合蛋白是抗体时,所述抗体通常是天然糖基化)。可用试剂如高碘酸钠轻度氧化碳水化合物,得到的氧化碳水化合物的羰基单元可以和含有官能团(比如肼、肟、反应性胺、肼、氨基硫脲、肼羧酸酯,或芳基酰肼)的延伸物缩合。
如果间隔单元存在的话,氨基酸单元(-W-)将延伸单元(-T-)连接到间隔单元(-Y-),如果间隔单元不存在的话,氨基酸单元(-W-)将延伸单元连接到细胞毒性剂。
如前所述,-Ww-可以是二肽、三肽、四肽、五肽、六肽、七肽、八肽、九肽、十肽、十一肽或十二肽单元。
在一些实施方式中,氨基酸单元可包含氨基酸残基,例如但不限于被乙酰基或甲酰基保护的丙氨酸、缬氨酸、亮氨酸、异亮氨酸、蛋氨酸、苯丙氨酸、色氨酸、脯氨酸、赖氨酸,精氨酸,被甲苯磺酰基或硝基保护的精氨酸,组氨酸,鸟氨酸,被乙酰基或甲酰基保护的鸟氨酸,以及瓜氨酸。示例性氨基酸接头成分优选包括二肽、三肽、四肽或五肽。
示例性二肽包括:Val-Cit、Ala-Val、Lys-Lys、Cit-Cit、Val-Lys、Ala-Phe、Phe-Lys、Ala-Lys、Phe-Cit、Leu-Cit、Ile-Cit、Trp-Cit、Phe-Ala、Phe-N9-甲苯磺酰基-Arg、Phe-N9-硝基-Arg。
示例性三肽包括:Val-Ala-Val、Ala-Asn-Val、Val-Leu-Lys、Ala-Ala-Asn、Phe-Phe-Lys、Gly-Gly-Gly、D-Phe-Phe-Lys、Gly-Phe-Lys。
示例性四肽包括:Gly-Phe-Leu-Gly(SEQ ID NO.33)、Ala-Leu-Ala-Leu(SEQ IDNO.34)。
示例性五肽包括:Pro-Val-Gly-Val-Val(SEQ ID NO.35)。
包含氨基酸接头成分的氨基酸残基包括那些天然存在的、以及次要氨基酸和非天然存在的氨基酸类似物,如瓜氨酸。可设计并优化氨基酸接头成分对特定酶的酶切割选择性,例如肿瘤相关蛋白酶、组织蛋白酶B、C和D、或纤溶酶蛋白酶。
接头的氨基酸单元可以被酶(包括但不限于肿瘤相关蛋白酶)酶促切割以释放细胞毒性剂。
可以设计并优化氨基酸单元对特定肿瘤相关蛋白酶的酶切割选择性。合适的单元是其切割被蛋白酶、组织蛋白酶B、C和D、或纤溶酶所催化的那些。
当存在间隔单元(-Y-)时,其将氨基酸单元连接至细胞毒性剂。间隔单元一般有两种类型:自身去除型(self-immolative)和非自身去除型(non self-immolative)。非自身去除型间隔单元是这样的间隔单元,其中氨基酸单元从免疫缀合物经酶切割之后,部分或所有间隔单元保持与细胞毒性剂的结合。非自身去除型间隔单元的实例包括但不限于(甘氨酸-甘氨酸)间隔单元和甘氨酸间隔单元。为了释放细胞毒性剂,在靶细胞内应采取独立的水解反应,以切割甘氨酸-药物单元的键。
在另一个实施方式中,非自身去除型间隔单元(-Y-)是-Gly-。
在一个实施方式中,免疫缀合物缺少间隔单元(y=0)。或者,含有自身去除型间隔单元的免疫缀合物可以释放细胞毒性剂,而不需要单独的水解步骤。在这些实施方式中,-Y-是通过PAB基团的氮原子连接至-Ww-的对-氨基苄醇(PAB)单元,且通过碳酸酯、氨基甲酸酯或醚基团直接连接至-D。
自身去除型间隔的其它实例包括但不限于芳香化合物,其电子上相当于PAB基团,例如2-氨基咪唑-5-甲醇衍生物和邻位或对位-氨基苄基乙缩醛。酰胺键水解时,可以使用容易发生环化的间隔,如取代和未取代的4-氨基丁酸酰胺、适当取代的双环[2.2.1]和双环[2.2.2]环系统和2-氨基苯基丙酸酰胺。
在一个替代实施方式中,间隔单元是分支的双(羟甲基)苯乙烯(BHMS)单元,其可用于掺入附加的细胞毒性剂。
最后,本发明涉及如上所述用于治疗癌症的免疫缀合物。
癌症可以优选选自Axl相关的癌症,所述Axl相关的癌症包含在其表面表达或过表达整个或部分蛋白Axl的肿瘤细胞。
更具体地,所述癌症是乳癌、结肠癌、食管癌、肝细胞癌、胃癌、神经胶质瘤、肺癌、黑色素瘤、骨肉瘤、卵巢癌、前列腺癌、横纹肌肉瘤、肾癌、甲状腺癌、子宫内膜癌和任何耐药现象。本发明的另一个目的是药物组合物,其包含说明书中描述的免疫缀合物。
更具体地说,本发明涉及一种药物组合物,其包含本发明的免疫缀合物以及至少一种赋形剂和/或药学上可接受的载体。
在本说明书中,表述“药学上可接受的载体”或“赋形剂”是意图表示进入药物组合物中但不引起次级反应,并且允许例如促进活性化合物的施用、提高其在体内的寿命和/或功效、增加其在溶液中的溶解度或者改善其保存的化合物或化合物的组合。这些药学上可接受的载体和赋形剂是众所周知的,并且由本领域的技术人员按照所选活性化合物的性质以及施用模式的函数进行调整。
优选地,通过全身途径施用这些免疫缀合物,特别是通过静脉内途径、通过肌内、皮内、腹膜内或皮下途径、或通过口服途径施用。在一个更优选的方式中,包含根据本发明的免疫缀合物的组合物,将以顺序的方式被施用数次。
其施用模式、剂量规划和最佳药物形式可以根据建立适合于患者的治疗时通常要考虑的标准(如,例如患者的年龄或体重、他/她的一般状况的严重性、治疗耐受性和所注意到的副作用)来确定。
本发明的其它特征和优点在随后说明书中用实施例和图进一步呈现,图注显示如下。
附图说明
图1:采用Mab-zap缀合的第二抗体在SN12C细胞上进行的体外细胞毒性分析。
图2A、2B和2C:通过ELISA进行的1613F12对固定化rhAxl-Fc蛋白(图2A)、rhDtk-Fc(2B)或rhMer-Fc(图2C)蛋白质的结合特异性。
图3:在人肿瘤细胞上1613F12结合的FACS分析。
图4:固定化rmAxl-Fc蛋白上的ELISA(“rm”为鼠重组)。
图5:通过间接标记程序使用流式细胞仪方法确定COS7细胞上的1613F12结合。
图6:使用1613F12进行Gas6结合的竞争ELISA。
图7:通过western印迹使用SN12C细胞裂解物进行的表位结合分析。NH(无热);NR(没有还原);H(热);R(还原)。GAPDH检测证明凝胶上正确的上样。
图8A和8B:通过Western印迹进行SN12C细胞上1613F12结合之后Axl下调的研究,其中图8A-Western印迹图像代表3个独立进行的实验(SN12C细胞上1613F12孵育4小时和24小时之后进行的western印迹分析);以及图8B-使用“QuantityOne”软件呈现的膜的光密度定量。
图9A、9B和9C:用1613F12孵育之后SN12C细胞的免疫荧光显微术,图9A-针对膜和细胞内染色,mIgGl同种型对照条件的照片。图9B-膜染色。图9C-用1613F12和早期胞内体标记物EEA1进行的Axl受体的细胞内双染色。下方表示图像叠加,箭头表示可视化的共同定位。
图10:相较于mIgGl同种型对照抗体的作用,1613F12对体外SN12C细胞增殖的作用。
图11A-11K:使用各种人肿瘤细胞系进行的1613F12-皂素免疫缀合物的直接细胞毒性分析。A-SN12C、B-Calu-1、C-A172、D-A431、E-DU145、F-MDA-MB435S、G-MDA-MB231、H-PC3、I-NCI-H226、J-NCI-H125、K-Panc1。
图12:研究m1613F12和hz1613F12抗体二者对rhAxl-Fc蛋白结合的ELISA实验。
图13:在SN12C细胞上进行的鼠、嵌合和人源化抗体1613F12的结合比较。
图14:使用SN12C人肾肿瘤细胞系,在鼠和人源化1613F12-皂素免疫缀合物二者存在下以及在同种型对照存在下进行的直接细胞毒性分析。
图15:使用Calu-1人肺癌细胞系,在鼠和人源化1613F12-皂素免疫缀合物二者存在下以及在同种型对照存在下进行的直接细胞毒性分析。
具体实施方式
实施例
在如下实施例中,表述1613F12或m1613F12抗体是指1613F12抗体的鼠形式。1613F12抗体的人源化形式命名为hz1613F12。
以相同的方式,所用的同种型对照抗体由称为9G4的鼠IgG1组成。这意味着,在如下实施例中,表述mIgG1对照和9G4相似。
实施例1:Axl受体内在化
当靶标抗原是内在化蛋白时,由于免疫缀合物过程更有效,使用Mab-Zap细胞毒素分析在人肿瘤细胞系上研究Axl受体内在化。更准确的说,Mab-Zap试剂是包括亲和性纯化的羊抗鼠IgG和核糖体失活蛋白、皂素的化学缀合物。如果发生免疫复合物的内在化,皂素脱离靶标试剂并使核糖体失活,从而导致蛋白质合成的抑制,最终细胞死亡。在Axl-阳性细胞上用1613F12或mIgGl同种型对照抗体孵育72小时后确定细胞活力,允许实现1613F12诱导的Axl受体内在化。
对于这个实施例,如使用Qifikit试剂(Dako)确定的,使用高度Axl阳性的细胞。数据列于下表5中。
表5
在下面的例子中,SN12C细胞用作非限制性实例。可以使用任何其它在其细胞表面上表达适当水平Axl受体的细胞系。
浓度范围的1613F12或mIgGl同种型对照抗体与100ng Mab-Zap(高级靶向系统)二抗在细胞培养基中室温预孵育30分钟。将这些混合物加载至涂布于白色96孔板微孔板上亚汇合的SN12C细胞上。于37℃在5%CO2存在下,板孵育72小时。根据制造商的说明书(Promega)使用Cell Titer Glo细胞增殖方法确定细胞活力。进行若干对照:i)没有任何第二免疫缀合物和ii)没有第一抗体。平行地,用mIgGl同种型对照进行分析。
得到的结果表示在图1中。
1613F12显示对SN12C细胞约36%的最大细胞毒性作用。当9G4抗体(认为是实验中的mIgGl同种型对照)存在时,没有观察到细胞毒性作用。在仅含有第一抗体的孔中没有观察到细胞毒性(数据未示出)。因此,Axl受体似乎是一个方便用来靶向免疫缀合物过程的抗原,因为包含Axl-1613F12-MabZap的免疫复合物触发有效的靶标细胞的细胞毒性。
实施例2:针对rhAxl ECD的抗体的生成
为了产生针对人的Axl受体细胞外结构域(ECD)的鼠单克隆抗体(MAb),用15-20.106CHO-Axl细胞给5只BALB/c鼠进行5次s.c.免疫,两次有20μg的rhAxl ECD。在完全弗氏佐剂(Sigma,圣路易斯,MD,USA)存在下进行第一次免疫。在随后的免疫中加入不完全弗氏佐剂(Sigma)。
融合之前三天,用20.106CHO-Axl细胞和20μg的rhAxl ECD二者以及IFA加强免疫的鼠。
为了生成杂交瘤,通过脾灌注和切碎近端淋巴结,从5只免疫鼠中的1只(血清滴定后选择的)中收获,并融合至SP2/0-Ag14骨髓瘤细胞(ATCC,洛克维尔,MD,USA)分别制备脾细胞和淋巴细胞。融合规程由Kohler和Milstein(Nature,256:495-497,1975)描述。然后融合的细胞进行HAT选择。一般情况下,为了制备单克隆抗体或其功能片段,特别是鼠源的,有可能涉及特别在手册《抗体》中描述的那些技术(Harlow和Lane,Antibodies:A Laboratory Manual,Cold SpringHarbor Laboratory,Cold Spring Harbor NY,pp.726,1988)。
融合后约10天,筛选杂交细胞的集落。对于一级筛选,使用ELISA对杂交瘤上清评价所产生的针对Axl ECD蛋白的Mab分泌。平行地,使用wt CHO和表达Axl(ATCC)的CHO细胞,进行FACS分析以选择能够结合存在于细胞表面上细胞形式的Axl的Mab。
尽快通过有限稀释克隆选择的杂交瘤,随后筛选其对Axl ECD蛋白的反应性。然后用Isotyping试剂盒(cat#5300.05,Southern Biotech,伯明翰,AL,USA)为克隆的Mab划分同种型。选择并扩增获自每个杂交瘤的克隆。
使用纯杂交瘤上清按照如下进行ELISA分析,或者当在上清中确定IgG含量时,从5μg/ml开始进行滴定。然后在如下11行中进行1/2系列稀释。简言之,用50μl/孔rh Axl-Fc蛋白(R and D Systems,cat N°154-AL)或PBS中2μg/ml的rhAxlECD在4℃过夜包被96孔ELISA板(Costar3690,Corning,NY,USA)。然后用含有0.5%明胶的PBS(#22151,Serva Electrophoresis GmbH,海德堡,德国)在37℃封闭板2小时。敲板弃掉饱和缓冲液后,向ELISA板加入50μl纯杂交瘤细胞上清或50μl5μg/ml溶液,并在37℃孵育1小时。洗三次后,加入50μl辣根过氧化物酶缀合的单克隆羊抗鼠IgG(#115-035-164,Jackson Immuno-Research Laboratories,Inc.,West Grove,PA,USA)(所述单克隆羊抗鼠IgG以1/5000稀释度稀释在含有0.1%明胶和0.05%吐温20(w:w)的PBS中),37℃1小时。然后,ELISA板洗三次,加入TMB(#UP664782,Uptima,Interchim,法国)底物。在室温下,孵育10分钟后,使用1M硫酸终止反应,在450nm下测量光密度。
为通过流式细胞仪进行选择,105细胞(CHO wt或CHO-Axl)于4℃下涂布于96孔板的含有1%BSA和0.01%叠氮化钠(FACS缓冲液)的PBS的各孔中。2000rmp下离心2分钟后,除去缓冲液,加入待测杂交瘤上清或纯化的Mab(1μg/ml)。在4℃下孵育20分钟后,将细胞洗涤两次,加入FACS缓冲液中以1/500°稀释的Alexa488缀合的羊抗鼠抗体(#A11017,Molecular Probes Inc.,尤金,USA),在4℃下孵育20分钟。用FACS缓冲液最终洗涤后,以40μg/ml的终浓度向各管加入碘化丙啶后通过FACS(Facscalibur,Becton-Dickinson)分析细胞。仅含细胞以及用第二Alexa488缀合抗体孵育的细胞的孔包括在内作为阴性对照。在各实验中使用同种型对照(Sigma,ref M90351MG)。评价至少5000个细胞以计算荧光强度(MFI)的平均值。
更准确地,用300.106收获的脾细胞和300.106骨髓瘤细胞(1:1的比)进行融合。然后以2.106个细胞/ml在30个96孔板中涂布得到的200个细胞的细胞悬浮液。
通过ELISA在rhAxl ECD蛋白上以及通过FACS分析使用Wt CHO和表达Axl的CHO细胞进行第一筛选(融合后约14天),允许选择在rhAxl ECD蛋白包被上表现出大于1的光密度(OD)、并且在wt CHO细胞上的MFI低于50以及在CHO-Axl细胞上大于200的10个杂交瘤。
通过有限稀释扩增和克隆这10个杂交瘤。针对每个代码制备一个96孔板。涂布后9天,来自克隆板的上清首先通过ELISA筛选对rhAxlECD蛋白细胞外结构域的结合特异性。针对每个代码的三个克隆进行扩增并划分同种型。一旦产生抗Ax1抗体,就进一步研究它们在细胞表面结合Axl后被内在化的能力。
实施例3:Axl的结合特异性
在这个实施例中,首先在rhAxl-Fc蛋白上研究1613F12的结合。然后,研究其在TAM家族两个其它成员(rhDtk-Fc和rhMer-FC)上的结合。
简单地说,在4℃将重组人Axl-Fc(R and D systems,cat N°154AL/CF)、rhDtk(R and D Systems,cat N°859-DK)或rhMer-Fc(R and D Systems,cat N°891-MR)蛋白过夜包被至Immulon II96-孔板,用0.5%明胶溶液进行1h封闭步骤后,以5μg/ml(3.3310-8M)的起始浓度加入1613F12纯化抗体在37℃再持续1h。然后,在12列中进行1/2系列稀释。然后洗涤板,加入羊抗鼠(Jackson)特异性IgG HRP在37℃持续1h。使用TMB底物溶液进行反应显色。也平行使用同种型对照抗体mIgGl和市售抗Axl Mab154抗体。在标记有HRP的羊抗人IgG Fc多克隆血清(Jackson,ref109-035-098)存在下和/或HRP偶联的抗组氨酸抗体(R and DSystems,ref:MAB050H)存在下进行包被对照。结果分别显示在图2A、2B和2C中。
这种实施例显示1613F12抗体只结合rhAxl-Fc蛋白,不结合TAM家族的两名其它成员rhDtk或rhMer。TAM成员之间,没有观察到1613F12抗体结合的交叉特异性。在缺乏第一抗体时没有观察到非特异性结合(稀释液)。在同种型对照抗体的存在下没有观察到结合。
实施例4:1613F12识别肿瘤细胞上表达的细胞形式Axl
先使用市售Axl抗体(R and D Systems,ref:MAB154)确立人肿瘤细胞上细胞表面的Axl表达水平,与校准珠平行进行以允许定量Axl的表达水平。第二,用1613F12研究细胞表面Axl的结合。
对于细胞表面结合的研究,制备10μg/ml(6.6610-8M)第一抗体溶液(1613F12、MAB154抗体或mIgGl同种型对照9G4Mab)的2倍系列稀释,并施加到2.105细胞上在4℃持续20分钟。在补充有1%BSA和0.01%NaN3的磷酸盐缓冲盐水(PBS)中洗涤3次后,在4℃下将细胞和第二抗体羊抗鼠Alexa488(1/500°稀释)孵育20分钟。在含有1%BSA和0.1%NaN3的PBS中额外洗涤三次,通过FACS(Facscalibur,Becton-Dickinson)分析细胞。评价至少5000个细胞以计算荧光强度的平均值。
为了使用MAB154抗体确定定量ABC,使用校准珠。然后,平行用珠、多克隆羊抗鼠免疫球蛋白/FITC、羊F(ab')2在饱和浓度孵育细胞。然后通过校准曲线内插法确定标本细胞上的抗原位点数目(各珠群的荧光强度相对于珠上Mab分子的数目)。
4.1.定量细胞表面Axl表达水平
通过流式细胞仪使用间接免疫荧光分析(方法(Dako,Denmark)确定人肿瘤细胞表面上的Axl表达水平,定量流式细胞仪试剂盒用于评估细胞表面抗原。通过校准图比较珠的已知抗原水平的平均荧光强度(MFI),允许确定细胞系的抗体结合能力(ABC)。
表6表示各种人肿瘤细胞系(SN12C、Calu-1、A172、A431、DU145、MDA-MB435S、MDA-MB231、PC3、NCI-H226、NCI-H125、MCF7、Pancl)(ATCC,NCI)表面上检测到的Axl表达水平,如使用使用市售抗体MAB154(Rand D Systems)所确定。以抗原结合复合物(ABC)给出值。
表6
用市售Axl单克隆抗体(MAB154)获得的结果显示,取决于所考虑的人肿瘤细胞,Axl受体以各种水平表达。
4.2.在人肿瘤细胞上通过1613F12的Axl检测
更具体地,用1613F12研究Axl结合。
制备1613F12剂量反应曲线。然后用Prism软件分析用各种人肿瘤细胞获得的MFI。数据示于图3。
数据表明,如通过饱和曲线谱所证明的,1613F12特异性结合膜Axl受体。然而,观察到不同的标记强度,这揭示了人肿瘤细胞上细胞表面Axl受体的不同水平。用MCF7人乳腺肿瘤细胞系没有观察到Axl受体的结合。
实施例5:物种间1613F12的交叉特异性
为了解1613F12的物种交叉特异性,考虑两个物种:鼠和猴。首先,通过ELISA研究重组鼠(rm)Axl受体的结合(图4)。然后,用猴子COS7细胞进行流式细胞仪实验,因为这些细胞在其表面上表达Axl受体(图5)。通过用SV40版本基因组(可产生大T抗原、但在基因组复制中存在缺陷)将源自非洲绿猴肾细胞的CV-1细胞系永生化,得到COS7细胞系。
rmAxl-Fc ELISA
简言之,在4℃将重组鼠Axl-Fc(R and D systems,cat N°854-AX/CF)蛋白过夜包被至Immulon II96-孔板,用0.5%明胶溶液进行1h封闭步骤后,以5μg/ml(3.3310-8M)的起始浓度加入1613F12纯化抗体在37℃再持续1h。然后,在12列中进行1/2系列稀释。然后洗涤板,加入羊抗鼠(Jackson)特异性IgG HRP在37℃持续1h。使用TMB底物溶液进行反应显色。也平行使用mIgGl同种型对照和市售抗体Mab154。在偶联有HRP的羊抗人IgG Fc多克隆血清(Jackson,ref109-035-098)存在下和/或HRP偶联的抗组氨酸抗体(R and D Systems,ref:MAB050H)存在下进行包被对照。
结果显示在图4中。此图表明1613F12不结合鼠Axl ECD结构域。在缺乏第一抗体时没有观察到特异性结合(稀释液)。
FACS COS7
对于使用COS7细胞进行的1613F12细胞结合研究,用通过1/2系列稀释10μg/ml(6.6610-8M)1613F12或mIgGl同种型对照Mab的抗体溶液所制备的浓度范围的抗体(12个点)在4℃孵育2.105细胞20分钟。在补充有1%BSA和0.01%NaN3的磷酸盐缓冲盐水(PBS)中洗涤3次后,在4℃下将细胞和第二抗体羊抗鼠Alexa488(1/500°稀释)孵育20分钟。在含有1%BSA和0.1%NaN3的PBS中额外洗涤三次后,通过FACS(Facscalibur,Becton-Dickinson)分析细胞。评价至少5000个细胞以计算荧光强度的平均值。使用Prism软件分析数据。
结果示于图5。使用1613F12在COS7细胞中建立的滴定曲线证实1613F12能够识别COS7细胞表面上所表达的Axl受体的猴细胞形式。对于高于0.625μg/ml(4.210-10M)的1613F12浓度,达到平台。mIgGl同种型对照存在时没有观察到结合。
这个实施例说明一个事实,即1613F12不与鼠Axl受体交叉反应。相反,它强烈地结合COS7细胞表面上表达的猴Axl受体。
实施例6:1613F12存在下进行的Gas6竞争实验
为了进一步表征1613F12,进行Gas6竞争分析。在该分析中,游离rhAxl-Fc蛋白和1613F12孵育形成抗原-抗体复合物,然后将复合体加载至分析板中Gas6包被的表面上。加入抗rhAxl-Fc蛋白人Fc部分的酶联第二抗体之前,洗掉未结合的抗体-抗原复合物。然后加入底物,通过酶-底物反应所引起的信号强度确定抗原浓度。
简要地,在独立饱和的(PBS1X中0.5%明胶)板上,在存在或不存在待测抗Ax1Mab时,制备包含rhAxl-Fc蛋白的反应混合物。进行鼠抗Axl抗体的系列1:2稀释(在12列中,从80μg/ml开始)。然后加入0.5μg/ml rhAxl-Fc蛋白(R andD Systems,ref.154AL/CF),除了阴性对照系,其仅含有ELISA稀释液(PBS1X中0.1%明胶、0.05%吐温20)。匀浆后,竞争样本加载至含有PBS中6μg/ml rhGas6溶液的Gas6包被的板(R and D Systems cat N°885-GS-CS/CF)。孵育和几次洗涤后,用羊抗人IgG-HRP(Jackson,ref.109-035-098)检测结合的rhAxl-Fc蛋白。一旦结合,将TMB底物加到板上。通过加入1M H2SO4酸溶液终止反应,用微孔板阅读设备在450nm处得到光密度读取。
该实验(图6)显示1613F12能够与rhAxl-Fc竞争结合固定的配体。在大于2.5μg/ml(1.6710-8M)的1613F12抗体浓度存在时,发生Gas6结合的竞争。在大于10μg/ml(6.6710-8M)的1613F12浓度存在时,不再观察到rhAxl-Fc对固定化Gas6的结合。1613F12阻断Gas6对rhAxl-Fc的结合。
实施例7:通过Western印迹进行的表位识别
为确定1613F12是识别线性还是构象表位,用SN12C细胞裂解物进行western印迹分析。在还原或非还原条件下对样本进行不同的处理。如果在还原的样本中见到条带,则测试的抗体靶向ECD结构域的线性表位;如果不是,那么它针对Axl ECD的构象表位。
在RPMI+10%热失活的FBS+2mM L谷氨酰胺中,在T162cm2烧瓶中在5%CO2气氛中在37℃下,以5.104细胞/cm2接种SN12C细胞72小时。然后将细胞用磷酸盐缓冲盐水(PBS)洗涤两次,并用1.5ml冰冷的裂解缓冲液(50mM Tris-HCl(pH7.5);150mM NaCl;1%Nonidet P40;0.5%脱氧胆酸钠;和1片完全蛋白酶抑制剂混合物片,加1%抗磷酸酶)裂解。在4℃振摇细胞裂解物90分钟,并在15000rpm离心10分钟进行澄清。使用BCA定量蛋白浓度。加载各种样本。在还原条件下(1×样本缓冲液(BIORAD)+1×还原剂(BIORAD))制备第一10μg全细胞裂解物(20μl中10μg),并在96℃孵育2分钟后加载到SDS-PAGE上。其次,在非还原条件下(仅1×样本缓冲液(BIORAD))制备两个其它10μg的全细胞裂解物样本。加载到SDS-PAGE凝胶前,这后两个样本中的一个在96℃孵育中加热2分钟;另一个保持在冰上。迁移之后,将蛋白转移至硝酸纤维素膜上。在室温用TBS-吐温200.1%(TBST)、5%脱脂乳,将膜饱和1小时,并用10μg/ml1613F12在4℃下过夜探针杂交。抗体稀释在含有5%脱脂干乳的Tris缓冲盐水-0.1%吐温20(v/v)(TBST)中。然后用TBST洗涤膜,并在RT下用过氧化物酶缀合的第二抗体(稀释1/1000)孵育1小时。用ECL(Pierce#32209)使免疫反应性蛋白可视化。Axl可视化后,再次用TBST洗涤一次膜,并在RT下用鼠抗GAPDH抗体(稀释1/200000)孵育1小时。然后膜在TBST中洗涤,并在RT下用过氧化物酶缀合的第二抗体孵育1小时。洗涤膜并用ECL显示GAPDH。
结果示于图7。
1613F12主要识别构象表位,因为特异性条带主要在非还原条件下观察到。然而,在SN12C细胞裂解物的变性迁移条件下,检测到微弱信号,表明1613F12能够微弱地结合线性表位。
实施例8:通过Western印迹测量1613F12触发的Axl下调
在下面的实施例中,选择人肾细胞癌细胞系SN12C(ATCC)用于了解Axl抗体对Axl受体表达的活性。SN12C细胞系过表达Axl受体。图8A-8B中,通过Western印迹在全细胞提取物研究Axl的下调。
在RPMI+10%热失活的FBS+2mM L谷氨酰胺中,在六孔板中在5%CO2气氛中在37℃下,以6.104细胞/cm2接种SN12C细胞48小时。用磷酸盐缓冲盐水(PBS)洗涤两次后,在含有800ng/ml重组鼠gas6配体(R and D Systems,ref:986-GS/CF)或10μg/ml mIgGl同种型对照抗体(9G4)或10μg/ml本发明Ax1抗体的培养基中使细胞进行血清饥饿,并孵育额外的4小时或24小时。然后将培养基轻轻地取出,用冷PBS洗涤两次细胞。用200μl冰冷的裂解缓冲液(50mMTris-HCl(pH7.5);150mM NaCl;1%Nonidet P40;0.5%脱氧胆酸钠;和1片完全蛋白酶抑制剂混合物片加1%抗磷酸酶)裂解细胞。在4℃振摇细胞裂解物90分钟,并在15000rpm离心10分钟进行澄清。使用BCA方法定量蛋白浓度。通过SDS-PAGE分离全细胞裂解物(20μl中10μg),并转移至硝酸纤维素膜上。在室温用TBS-吐温200.1%(TBST)、5%脱脂乳,将膜饱和1小时,并用0.5μg/ml市售M02Ax1抗体(AbNova H00000558-M02)在4℃下过夜探针杂交。抗体稀释在含有5%脱脂干乳的Tris缓冲盐水-0.1%吐温20(v/v)(TBST)中。然后用TBST洗涤膜,并在RT下用过氧化物酶缀合的第二抗体(稀释1/1000)孵育1小时。用ECL(Pierce#32209)使免疫反应性蛋白可视化。Axl可视化后,再次用TBST洗涤一次膜,并在RT下用鼠抗GAPDH抗体(稀释1/200000)孵育1小时。然后膜在TBST中洗涤,并在RT下用过氧化物酶缀合的第二抗体孵育1小时。洗涤膜并用ECL显示GAPDH。通过光密度计量定量条带强度。
展示在图8A和8B中的结果代表3个独立的实验并证明1613F12能够下调过表达Axl的人肿瘤细胞系中的Axl。在4小时,1613F12触发66%的Axl下调,并在1613F12孵育24小时后高达87%。
实施例9:流式细胞仪研究1613F12对细胞表面Axl表达的作用
流式细胞仪技术允许标记细胞表面的Axl受体。使用这种技术可以突出显示抗体对膜Axl表达的作用。在本实施例中使用表达高水平Axl的人肾肿瘤SN12C细胞。
实验前的3天,SN12C肿瘤细胞系培养于含有1%L谷氨酰胺和10%FCS的RMPI1640中。然后用胰蛋白酶将细胞脱离,并涂布在6-多孔板中含有1%L谷氨酰胺和5%FBS的RMPI1640中。第二天,以10μg/ml加入兴趣抗体。也包括未经处理的孔。在37℃、5%CO2中孵育细胞。二十四小时后,用PBS洗涤细胞、脱离并在FACS缓冲液(PBS、1%BSA、0.01%叠氮化钠)中用相同的兴趣抗体孵育。也用相同的抗体染未处理的孔,以比较用相同Mab在处理过和未处理的细胞上获得的信号强度。在4℃下细胞孵育20分钟,用FACS缓冲液洗涤三次。Alexa488标记的羊抗鼠IgG抗体孵育20分钟,在碘化丙啶阴性细胞群上进行FACS分析前,洗三次细胞。
确定两个参数:(i)在T24h时,相较于Ab处理的细胞,在未处理(无Ab)细胞表面上检测到的荧光信号的差异,以及(ii)在细胞表面上剩余的Axl百分比。如下计算剩余的Axl百分比:
%剩余Axl=(MFIAb24h/MFI没有Ab24h)×100
来自代表性实验的数据列于表7中。在三个独立实验中结果可再现。
在未经处理的细胞和用相同抗体的处理条件下,Mab染色之间的MFI差异反映了由于所考虑的Mab的结合导致的细胞表面上Axl蛋白的下调。没有抗体的条件给出了与存在同种型对照抗体(m9G4)的条件类似的结果。
表7
数据表明,相较于用1613F12标记的未处理细胞所获得的MFI,在1613F12处理24小时的细胞表面上检测到的平均荧光强度降低(-514)。用1613F12抗体孵育24小时后,45.2%的细胞表面Axl受体仍保留在SN12C细胞表面。
实施例10:用荧光免疫细胞化学标记研究1613F12的内在化
用间接荧光标记方法通过共聚焦显微镜得到互补内在化结果。
简言之,实验前3天SN12C肿瘤细胞系培养于含有用1%L谷氨酰胺和10%FCS的RMPI1640中。然后用胰蛋白酶将细胞脱离,并涂布在含有盖玻片的6-多孔板的含有1%L谷氨酰胺和5%FCS的RMPI1640中。第二天,以10μg/ml加入1613F12。也包括用无关抗体处理的细胞。在37℃、5%CO2中孵育细胞1h和2h。对于T0h时,在4℃细胞孵育30分钟以确定细胞表面的抗体结合。用PBS洗涤细胞并用多聚甲醛固定15分钟。漂洗细胞并在4℃下用羊抗鼠IgG Alexa488抗体孵育60分钟,以确定细胞表面上的剩余抗体。为了跟踪抗体进入细胞,固定细胞并用皂素进行透化。用羊抗鼠IgG Alexa488(Invitrogen)染膜和细胞内抗体。使用抗EEA1的兔多克隆抗体,并用羊抗兔IgG-Alexa555抗体(Invitrogen)显色,鉴定早期胞内体。洗涤细胞三次,用Draq5染核。染色后,细胞装在Prolong Gold加载基质(Invitrogen)上,并使用Zeiss LSM510共聚焦显微镜分析。
照片示于图9A-9C。
通过共聚焦显微镜获得图像。在mIgG1同种型对照(9G4)存在下,既没有观察到膜染色,也没有观察到细胞内标记(图9A)。SN12C细胞与1613F12孵育1h后,便观察到膜抗Axl标记的逐渐消失(图9B)。在1h和2h时,清楚地观察到1613F12抗体的细胞内积累(图9C)。细胞内抗体与EEA1(早期胞内体标志物)共同定位。这些照片证实1613F12进入SN12C细胞的内在化。
实施例11:体外抗Ax1介导的抗肿瘤活性
SN12C增殖分析
在不含FCS的培养基中在96孔板上接种每孔1万个SN12C细胞,在37℃在5%CO2气氛中过夜孵育。第二天,在37℃下细胞用10μg/ml每种抗体预孵育1h。通过向孔中直接添加配体,用或不用rmGas6(R and D Systems,cat N°986-GS/CF)处理细胞,然后让细胞生长72小时。3H胸苷掺入后测量增殖。
数据示于图10。当1613F12加入到SN12C细胞时,其保持沉默,用1613F12没有观察到作用。
实施例12:1613F12-皂素免疫缀合物在各种人肿瘤细胞系中的细胞毒性效力
在本实施例中,记录了皂素偶联的1613F12的细胞毒性效力。为此目的,进行了用一大组(large panel)人肿瘤细胞系进行的直接体外细胞毒性分析(图11A-11K)。该肿瘤细胞系的组提供各种细胞表面的Axl表达。
简言之,5000个细胞接种于96孔培养板上的100μl的5%FBS完全培养基中(D0)。在37℃在5%CO2氛围中孵育24小时后,一系列的免疫缀合物浓度范围(1613F12-皂素或9G4-皂素或裸1613F12或9G4)被施加到细胞上。然后在37℃下在湿润的5%CO2培养箱中孵育培养板72小时。
在D4时,使用发光细胞活力试剂盒(Promega Corp.,麦迪逊,Wis.)评价细胞活力,该试剂盒允许基于定量存在的ATP(代谢活性细胞的指示)确定培养物中活细胞数目。通过光度计装置记录发光发射。
使用下式,根据发光输出计算细胞毒性的百分比:
细胞毒性%=100-[(RLUAb-sap×100)/RLU无Ab]
在图11A-l1K上,将显示细胞毒性百分比相对于免疫缀合物浓度的函数的图放在一起,该函数获自用一系列1613F12-皂素免疫缀合物浓度处理的不同体外细胞毒性分析,(A)SN12C、(B)Calu-1、(C)A172、(D)A431、(E)DU145、(F)MDA-MB-435S、(G)MDA-MB-231、(H)PC3、(I)NCI-H226、(J)NCI-H125或(K)Pancl肿瘤细胞。
图11A-11K表明1613F12-皂素免疫缀合物触发这些不同人肿瘤细胞系中的细胞毒性作用。得到的细胞毒性作用的效力依赖于人肿瘤细胞系。
实施例13:1613F12抗体可变结构域的人源化
使用鼠抗体(Mab)用于人的治疗应用通常会导致严重的副作用,患者产生人抗鼠抗体(HAMA)反应,从而降低了治疗的功效,并防止继续施用。克服这个问题的一个方法是通过用其人的对应部分替换鼠序列将鼠Mab人源化,但不改变抗原结合活性。这可以通过两种主要方式来实现:(i)通过构建鼠/人嵌合抗体,其中鼠可变区被连接到人恒定区(Boulianne等人1984)以及(ii)通过将来自鼠可变区的互补决定区(CDR)接枝到谨慎挑选的人可变区中,然后将这些“重塑的人”可变区连接至人恒定区(Riechmann等人,1988)。
13.1.1613F12抗体的人源化版本的设计
13.1.1轻链可变结构域VL的人源化
作为预备步骤,1613F12VL的核苷酸序列与IMGT数据库的鼠种系基因序列部分比较(http://www.imgt.org)。鉴定鼠IGKV16-104*01和IGKJ5*01种系基因。为了鉴定CDR接枝的最佳的人候选,搜索表现出与1613F12VL鼠序列最佳同一性的人种系基因。借助IMGT数据库的分析工具,鉴定出一种用于鼠1613F12VLCDR的可能受体人V区:IGKV1-27*01和IGKJ4*02。为了进行轻链可变结构域的人源化,给每个人和鼠序列之间不同的残基赋予一个优先排序次序。这些优先(1-4)被用于产生具有多达14个回复突变的11种不同的轻链可变区人源化变体。
13.1.2重链可变结构域VH的人源化
为了鉴定CDR接枝的最佳的人候选,搜索表现出与1613F12VH最佳同一性的鼠和人种系基因。使用序列比对软件“IMGT/V-QUEST”(这是IMGT数据库的一部分)将1613F12VH的核苷酸序列与鼠和人的种系基因序列比对。使用VectorNTI软件包的“Align X”软件还进行了氨基酸序列的比对,以验证核苷酸序列比对的结果。与鼠种系基因的比对表明鼠种系V基因IGHV14-3*02和J-基因IGHJ2*01是最同源的鼠种系基因。使用IMGT数据库,鼠D-基因种系IGHD1-1*01被鉴定为同源序列。为了选择适当的人种系用于CDR接枝,鉴定出与1613F12VH鼠序列具有最高同源性的人种系基因。借助IMGT数据库的分析工具,选择人IGHVl-2*02种系基因和人IGHJ5*01J种系基因作为用于鼠1613F12VH CDR的人受体序列。为了进行重链可变结构域的人源化,给每个人和鼠序列之间不同的残基赋予一个优先排序次序(1-4)。这些优先被用于产生具有多达18个回复突变的20种不同的重链可变区人源化变体,
13.2.hz1613F12与m1613F12的验证
为了确立人源化1613F12是否和它的鼠1613F12形式可比较,通过ELISA使用rhAxl-Fc蛋白分析和通过FACS使用SN12C细胞进行结合实验。作为补充,用SN12C人肾肿瘤细胞和Calu-1人肺癌细胞系进行直接体外细胞毒性分析。
首先实现ELISA实验。在分析中,用5μg/ml1×PBS中的1613F12溶液在4℃过夜包被96孔板(Immulon II,Thermo Fisher)。饱和步骤之后,一系列rh Axl-Fc蛋白(R and D Systems,ref:154-AL)浓度(从5μg/ml至0.02μg/ml)在包被板上在37℃孵育1小时。对于显色步骤,加入0.85μg/ml的生物素化Axl抗体(公司内产品)在37℃下持续1小时。这种Axl抗体属于不同的表位组。然后,稀释缓冲液中1/2000°的抗生物素蛋白-辣根过氧化物酶溶液加入到各孔中。然后,加入TMB底物溶液持续5分钟。加入过氧化物酶终止溶液后,用微孔板阅读器测量405nm处的吸光度。
图12显示鼠和人源化1613F12抗体相似地结合rhAxl-Fc蛋白。
对于FACS分析,SN12C细胞培养在RPMI1640+2mM L谷氨酰胺+10%血清中。用胰蛋白酶脱离细胞,细胞浓度调整至FACS缓冲液中1×106细胞/ml。用递增浓度的同种型对照或抗Axl抗体在4℃下孵育100μl体积的细胞悬浮液20分钟。然后用FACS缓冲液将细胞洗涤三次,并使用抗鼠IgG Alexa488第二抗体或抗人IgG Alexa488第二抗体于4℃在黑暗中孵育20分钟以上。加入碘化丙啶前,用FACS缓冲液将细胞洗涤3次,并用100μl FACS缓冲液重悬。
用递增浓度的同种型对照或抗Axl抗体孵育细胞。m1613F12对应鼠1613F12,c1613F12对应嵌合1613F12以及hz1613F12对应人源化抗体。用Prism软件确定EC50。
如图13所示,1613F12的人源化形式,以与1613F12嵌合和鼠形式相同的EC50结合SN12C细胞。这些结果表明hz1613F12按照与鼠1613F12相似的结合特性来识别Axl抗原。
直接体外细胞毒性分析的实验程序先前描述在实施例12中。在本实施例中,制备四种皂素-免疫缀合物,并在两种细胞模型(人SN12C肾肿瘤细胞和人Calu-1肺癌细胞)中测试:m9G4-皂素、ch9G4-皂素、1613F12-皂素和hz1613F12-皂素。
图14显示m9G4-皂素和ch9G4-皂素同种型对照是沉默的,而人源化Axl1613F12-皂素抗体在SN12C细胞上触发和鼠1613F12-皂素免疫缀合物相似的细胞毒性作用。
图15显示人源化1613F12-皂素免疫缀合物在Calu-1细胞上触发和鼠1613F12-皂素免疫缀合物相似的细胞毒性作用。与此相反,对高于10-9M的抗体浓度,m9G4-皂素和ch9G4-皂素同种型对照显示出弱的活性(最大细胞毒性的约10%)。
实施例14:1613F12对人Axl ECD的结合动力学
然后使用Biacore确定1613F12的亲和性测量。Biacore X被用来测量人AxlECD上的1613F12结合动力学。
根据Biacore系统所用的表面等离子体共振(SPR)光学现象的仪器,使得可以实时检测和测量蛋白-蛋白相互作用,而无需使用标记。
简言之,使用传感器芯片CM5作为生物传感器实现实验。以9300-10000响应单位(RU)的水平,将兔IgG固定在CM5传感器芯片的流动池1和2上(FC1和FC2),使用胺偶联化学捕获抗体。
使用多个循环评价结合。使用30μ1/min的流速在HBS-EP缓冲液中进行每个测量循环。然后,在FC2上在芯片上捕获1分钟待测Axl抗体,只为达到对1613F12的311.8RU(SD=5.1RU)平均捕获值。以200nM开始,注射分析物(Axl ECD抗原),使用2倍系列稀释来实时测量粗ka和kd。
在每个循环结束时,通过注射10mM盐酸甘氨酸pH1.5溶液来再生表面,以消除抗体抗原复合物以及捕获的抗体。所考虑的信号对应着FC1和FC2之间观察到的信号差异(FC2-FC1)。用一对一Langmuir结合模型计算结合速率(ka)和解离速率(kd)。平衡解离常数(KD)确定为ka/kd的比。在Biaevaluation软件版本3.0中分析实验值。将进行χ2分析来评价数据的准确性。
数据总结于下表8。
表8
抗体 | ka(1/Ms) | kd(1/s) | KD(M) | Chi2 |
1613F12 | 1.06 105 | 2.42 10-4 | 2.29 10-9 | 0.71(0.6%) |
为了产生Axl的人细胞外结构域(ECD),通过PCR首先将编码人可溶性AXL受体的人cDNA克隆到pCEP4表达载体中。然后用限制性酶HindIII和BamHI消化纯化的产物,并连接到pCEP4表达载体,pCEP4表达载体已经用相同的酶预先切割。最后,通过DNA测序进一步证实鉴定的重组质粒pCEP[Axl]His6。
然后将具有细胞HEK293E的悬浮液培养在含有4mM谷氨酰胺的Ex-Cell293(SAFC Biosciences)基质中。用线性25kDa的聚乙烯亚胺(PEI)进行所有转染。转染的细胞保持在37℃下在含有5%CO2的摇床上,并在120rpm下搅拌6天。通过离心收集细胞,以及处理含有重组His-标签的蛋白的上清用于在Ni-NTA琼脂糖柱上进行纯化。
Claims (14)
1.一种抗原结合蛋白、或其抗原结合片段,其:
i)特异性结合人蛋白Axl,优选具有序列SEQ ID NO.29或30或其天然变体序列,以及
ii)其结合所述人蛋白Axl之后被内在化,
所述抗原结合蛋白特征在于其包含至少选自SEQ ID NO.1至14或36至68的氨基酸序列。
2.根据权利要求1所述的抗原结合蛋白、或其抗原结合片段,特征在于其特异性结合至定位于人蛋白Axl细胞外结构域中的表位,优选具有序列SEQ ID NO.31或32或其天然变体序列。
3.根据权利要求1所述的抗原结合蛋白、或其抗原结合片段,特征在于其诱导至少200的MFI降低。
4.根据前述权利要求任一项所述的抗原结合蛋白、或其抗原结合片段,特征在于其由单克隆抗体组成。
5.一种抗原结合蛋白、或其抗原结合片段,特征在于其由抗体组成,所述抗体包含三个轻链CDR和三个重链CDR,其中三个轻链CDR包含序列SEQ IDNO.1、2和3,以及三个重链CDR包含序列SEQ ID NO.4、5和6。
6.根据权利要求5所述的抗原结合蛋白、或其抗原结合片段,特征在于其包含选自如下的轻链可变结构域:
i)序列SEQ ID NO.7的轻链可变结构域、或与SEQ ID NO.7表现出至少80%同一性的任何序列,
ii)序列SEQ ID NO.36的轻链可变结构域、或与SEQ ID NO.36表现出至少80%同一性的任何序列;以及
iii)序列SEQ ID NO.37至47的轻链可变结构域、或与SEQ ID NO.37至47表现出至少80%同一性的任何序列。
7.根据权利要求5所述的抗原结合蛋白、或其抗原结合片段,特征在于其包含选自如下的重链可变结构域:
i)序列SEQ ID NO.8的重链可变结构域、或与SEQ ID NO.8表现出至少80%同一性的任何序列;
ii)序列SEQ ID NO.48的重链可变结构域、或与SEQ ID NO.48表现出至少80%同一性的任何序列;以及
iii)序列SEQ ID NO.49至68的重链可变结构域、或与SEQ ID NO.49至68表现出至少80%同一性的任何序列。
8.根据权利要求5、6或7所述的抗原结合蛋白、或其抗原结合片段,特征在于其包含:
i)序列SEQ ID NO.7、36或37至47的轻链可变结构域、或与SEQ ID NO.7、36或37至47表现出至少80%同一性的任何序列;以及
ii)序列SEQ ID NO.8、48、或49至68的重链可变结构域、或与SEQ ID NO.8、48、或49至68表现出至少80%同一性的任何序列。
9.根据权利要求5所述的抗原结合蛋白,特征在于其由单克隆抗体1613F12或其抗原结合片段组成,所述单克隆抗体1613F12源自2011年7月28日保藏在法国巴斯德研究所CNCM的杂交瘤I-4505。
10.于2011年7月28日保藏在法国巴斯德研究所CNCM的鼠杂交瘤I-4505。
11.根据权利要求1至9任一项所述的抗原结合蛋白、或其抗原结合片段,其用作定位产品将细胞毒性剂递送至宿主靶标位点,所述宿主靶标位点由定位于蛋白Axl细胞外结构域中的表位组成,优选人蛋白Axl细胞外结构域,更优选具有序列SEQ ID NO.31或21的人蛋白Axl细胞外结构域或其天然变体序列。
12.一种免疫缀合物,其包含缀合至细胞毒性剂的根据权利要求1至9和11任一项所述的抗原结合蛋白、或其抗原结合片段。
13.根据权利要求12所述的免疫缀合物,其用于治疗癌症。
14.药物组合物,其包含根据权利要求13所述的免疫缀合物以及至少一种赋形剂和/或药学上可接受的载体。
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WO2019228345A1 (zh) * | 2018-05-29 | 2019-12-05 | 杭州尚健生物技术有限公司 | 结合axl蛋白的抗体及其应用 |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109476757A (zh) * | 2016-05-20 | 2019-03-15 | 新加坡科技研究局 | 抗-axl受体酪氨酸激酶抗体及其用途 |
US11306153B2 (en) | 2016-05-20 | 2022-04-19 | Agency For Science, Technology And Research | Anti-AXL tyrosine kinase receptor antibodies and uses thereof |
CN109476757B (zh) * | 2016-05-20 | 2022-06-07 | 新加坡科技研究局 | 抗-axl受体酪氨酸激酶抗体及其用途 |
WO2019228345A1 (zh) * | 2018-05-29 | 2019-12-05 | 杭州尚健生物技术有限公司 | 结合axl蛋白的抗体及其应用 |
CN110448557A (zh) * | 2019-09-05 | 2019-11-15 | 黄筱茜 | 抗凝血药达比加群酯的新药用途 |
CN110982791A (zh) * | 2019-12-26 | 2020-04-10 | 百泰生物药业有限公司 | 一种分泌axl抗体的杂交瘤细胞的制备筛选方法 |
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