CN112424227A - 与folr1特异性结合的抗体及其用途 - Google Patents
与folr1特异性结合的抗体及其用途 Download PDFInfo
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- CN112424227A CN112424227A CN201980027952.3A CN201980027952A CN112424227A CN 112424227 A CN112424227 A CN 112424227A CN 201980027952 A CN201980027952 A CN 201980027952A CN 112424227 A CN112424227 A CN 112424227A
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Abstract
本发明涉及一种与叶酸受体α(FOLR1)特异性结合并且由此阻断FOLR1的活性的抗体,并且涉及一种通过增强常规抗体的结合能力来显著增强与抗原的结合能力的经修饰的抗体。根据本发明的经修饰的抗体提供了如下序列,其中亲本抗体最初具有的抗原结合位点被如下氨基酸替代,所述氨基酸在保留所述亲本抗体的基础结构的同时更好地与抗原结合,由此增强与所述抗原的结合能力。另外,根据本发明的抗体或其抗原结合片段可以用于癌症的预防性或治疗性应用,并且可以用于诊断疾病。根据本发明的经修饰的抗体提供了氨基酸取代的序列,其在保留亲本抗体的基础结构的同时使所述亲本抗体最初具有的抗原结合位点更好地与抗原结合,由此增强与所述抗原的结合能力。另外,根据本发明的抗体或其抗原结合片段可以用于癌症的预防性或治疗性应用,并且可以用于诊断疾病。
Description
技术领域
本发明涉及与叶酸受体α(FOLR1)特异性结合并阻断FOLR1的活性的抗体,所述抗体是具有与亲本抗体相比显著增加的对抗原的结合亲和力的经修饰的抗体。更具体地,本发明涉及与FOLR1特异性结合的抗体或其抗原结合片段、包含所述抗体或其抗原结合片段的抗体-药物缀合物、包含所述抗体或其抗原结合片段的用于预防或治疗癌症的药物组合物以及包含所述抗体或其抗原结合片段的用于诊断疾病的组合物。
背景技术
叶酸受体α(FOLR1)是在正常上皮细胞中以低至中等水平表达并且在某些源自上皮的癌症(如卵巢癌、乳腺癌、肺癌、肾癌、结直肠癌和子宫内膜癌)中过表达的蛋白质。特别地,FOLR1在超过90%的卵巢癌中过表达,因此靶向FOLR1的抗体可用于治疗癌症(Sudimack和Lee,Adv.Drug Deliv.Rev.2000,41,147-162)。作为治疗性抗体的代表性例子,美国专利申请公开号2009/274697(PCT国际公开号2005/080431)中披露的法勒珠单抗(farletuzumab,MORAb-003)是人源化单克隆抗体。法勒珠单抗由Morphotek Inc.开发,并且已经作为卵巢癌的潜在治疗剂被报道。已知法勒珠单抗以对应于约2nM的KD值的结合亲和力与FOLR1结合(Grasso等人,Cancer Immun.2007,7,6)。
通常,此类治疗性抗体进行了广泛的工程化以具有所需的生物学和物理化学特性,如低免疫原性、高亲和力和特异性、最佳效应子功能以及良好的溶解性和稳定性。特别地,抗体人源化和亲和力成熟是在开发治疗性抗体候选物期间最常应用的工程化过程。抗体人源化方法是用人抗体的互补决定区(CDR)替代非人动物抗体的CDR的方法。人源化抗体解决了非人动物抗体(如小鼠抗体)的问题,如高免疫原性、低效应子功能和短血液半衰期。通过解决这些问题,已经开发出单克隆抗体作为药物,并且已经批准多种人源化抗体作为治疗性抗体来销售。尽管这些人源化抗体确实在临床实践中显示出一定作用,但是它们对抗原的结合亲和力低于原始人抗体对抗原的结合亲和力也是真的,并且需要具有较高作用的治疗性抗体。因为这些问题可能是由于因为将鼠CDR直接移植到人框架受体序列上引起的亲和力丧失而造成的,因此通常需要CDR或支持CDR环的结构的框架区(FR)残基的突变。
就此而言,需要应用抗体工程化技术以改进抗体功效。这些技术包括增加抗体对抗原的亲和力的亲和力成熟技术。亲和力成熟是指通过将随机突变引入抗体基因中来增加抗体对抗原的结合亲和力的技术,并且对于开发新的用于治疗和诊断目的的有效抗体药物可能极为有用。对于体外亲和力成熟,通常使用三种方法。这些方法包括易错PCR、使用简并寡核苷酸将所靶向残基随机化和链改组。可以选作靶残基的CDR是随机化的合理靶标,因为CDR-H3和CDR-L3往往支配抗体-抗原相互作用。通过改变靶抗体基因的CDR区中的氨基酸来增加抗体的结合亲和力。已经报道通过这种方法,AKA(与肿瘤相关糖蛋白72结合的人源化抗体)的结合亲和力通过改变AKA的CDR-H3中的氨基酸而增加22倍(Hong等人,J.Biol.Chem.2006,281,6985-6992),并且所开发的抗体对乙型肝炎病毒抗原的结合亲和力也增加6倍(Hong等人,J.Microbiol.2007,45,528-533)。
一组在CDR区中具有随机排列的氨基酸的序列可以被称为文库。由于抗体在文库中共存,需要进行从文库选择抗体的操作。从文库选择抗体的最有效技术之一是噬菌体展示技术。这种技术是基于噬菌体表型与其所包封的基因型之间的直接联系,这导致分子文库呈现在噬菌体表面上。噬菌体展示用于研究蛋白质-配体相互作用和受体结合位点,以及用于改进或修改蛋白质对其结合配偶体的亲和力。
噬菌体展示涉及通过与含有将表型与基因型选择相联系的遗传序列的噬菌体外壳蛋白融合,使所选蛋白质在丝状噬菌体表面上表达。在与抗体文库组合时,噬菌体展示允许快速体外选择抗原特异性抗体以及回收与其对应的编码序列。已经构建了大型非免疫和合成人文库以及基于捕获单一个体的免疫组库的较小免疫文库。这种完全体外的过程允许分离针对免疫原性较低的靶标的抗体以及无法通过动物免疫获得的那些抗体,从而进一步扩展了所述方法的实用性。噬菌体抗体展示代表最早开发的用于人治疗性抗体候选物的高通量筛选的方法。最近,已经开发出用于产生全人治疗性抗体的其他方法,如单B细胞筛选、下一代基因组测序和具有含有乙型肝炎基因的人胚胎干细胞的转基因小鼠。尽管这些方法各自具有特别的优点,但是在筛选方法的便捷性和通用性方面,噬菌体展示仍然是用于人抗体发现的重要方法,因为它是在体外进行的过程。另外,淘选(一种使用噬菌体展示选择抗体的方法)是指如下过程,其包括将抗原固定在免疫管上,然后将在噬菌体表面上展示的抗体文库添加至所述免疫管中,并且通过洗涤和洗脱过程仅选择结合的抗体。通过反复洗涤分离携带结合或未结合至抗原的Fab的噬菌体。将抗原结合的噬菌体通过pH改变或蛋白酶消化进行洗脱,并且再感染至大肠杆菌(E.coli)中,可以从其制备富集抗原结合克隆的新文库。在将这个过程重复数次后,可以充分富集文库,使得可以从大肠杆菌原液分离单独的克隆(表示为单克隆噬菌体),对其进行测试和测序,并且可以表达特异性抗体。
在这种技术背景下,诸位发明人已经认识到,对于开发具有优异的对FOLR1的结合能力的抗体以改进针对FOLR1的抗体的功效存在迫切的需求,并且已经通过将突变引入互补决定区发明了具有改进的对FOLR1的结合亲和力的抗体。另外,诸位发明人已经构建了具有通过亲和力成熟在亲本抗体的重链和轻链可变区的CDR中诱导的氨基酸突变的抗体文库,并且已经通过噬菌体展示技术选择了具有增加的对FOLR1的结合亲和力的单独抗体,由此完成了本发明。
上文在此背景技术部分中公开的信息仅用于增强对本发明的背景的理解。因此,它可能不含形成本发明所属领域中已知的常规技术的信息。
发明内容
本发明的目标是提供与FOLR1特异性结合的抗体或其抗原结合片段以及与上文抗体相比具有进一步改进的对抗原的结合亲和力的抗体。
本发明的另一个目标是提供抗体-药物缀合物,其中药物与抗体或其抗原结合片段缀合。
本发明的仍另一个目标是提供用于预防或治疗癌症的药物组合物,其包含抗体或其抗原结合片段或抗体-药物缀合物。
本发明的又另一个目标是提供用于治疗癌症的方法,其包括给予抗体或其抗原结合片段或抗体-药物缀合物。
本发明的仍又另一个目标是提供抗体或其抗原结合片段或抗体-药物缀合物用于治疗癌症的用途以及抗体或其抗原结合片段或抗体-药物缀合物在制造用于治疗癌症的药剂中的用途。
本发明的进一步的目标是提供包含抗体或其抗原结合片段或抗体-药物缀合物的用于诊断疾病的组合物以及用于使用抗体或其抗原结合片段或抗体-药物缀合物诊断疾病的方法。
为了实现所述目标,本发明提供了一种与叶酸受体-α(FOLR1)特异性结合的抗体或其抗原结合片段。
优选地,所述抗体或其抗原结合片段可以包含六个互补决定区(CDR),并且所述抗体或其抗原结合片段可以包含:SEQ ID NO:3的重链CDR1、SEQ ID NO:4的重链CDR2和SEQID NO:5或SEQ ID NO:28的重链CDR3;以及SEQ ID NO:6或SEQ ID NO:29的轻链CDR1、SEQID NO:7或SEQ ID NO:30的轻链CDR2和SEQ ID NO:8的轻链CDR3。
本发明还提供了一种包含所述抗体或其抗原结合片段的抗体-药物缀合物。
本发明还提供了一种用于预防或治疗癌症的药物组合物,所述药物组合物包含所述抗体或其抗原结合片段或所述抗体-药物缀合物。
本发明还提供了一种用于治疗癌症的方法,所述方法包括给予所述抗体或其抗原结合片段或所述抗体-药物缀合物。
本发明还提供了所述抗体或其抗原结合片段或所述抗体-药物缀合物用于治疗癌症的用途以及所述抗体或其抗原结合片段或所述抗体-药物缀合物在制造用于治疗癌症的药剂中的用途。
本发明还提供了一种包含所述抗体或其抗原结合片段或所述抗体-药物缀合物的用于诊断疾病的组合物以及一种用于使用所述抗体或其抗原结合片段或所述抗体-药物缀合物诊断疾病的方法。
附图说明
图1显示了对亲本抗体的重链可变区序列与经修饰的抗体的重链可变区序列的比较。在图1中,序列之间的匹配用星号标记,并且CDR-H3区的序列中的一个氨基酸在两种抗体之间是不同的。
图2显示了对亲本抗体的轻链可变区序列与经修饰的抗体的轻链可变区序列的比较。在图2中,序列之间的匹配用星号标记,并且CDR-L1和CDR-L2区的氨基酸序列在两种抗体之间是不同的。
图3显示了通过柱纯化使用亲和树脂色谱法将经修饰的抗体分级分离的结果,并且显示了色谱图和每种级分的SDS-PAGE分析的结果(M:标记,LS:加载样品,H:重链,L:轻链,R:还原性条件)。
图4显示了ELISA的结果,其指示随浓度而变的亲本抗体和经修饰的抗体各自对FOLR1的结合亲和力。
图5显示了SPR分析的结果,进行所述SPR分析以比较亲本抗体对FOLR1的结合亲和力与经修饰的抗体对FOLR1的结合亲和力。
具体实施方式
除非另有定义,否则本说明书中所用的所有技术和科学术语具有与本公开文本所属领域的技术人员通常理解相同的含义。通常,本说明书中所用的命名法是本领域熟知且常用的。
术语“抗体的抗原结合片段”或“抗体片段”是指具有抗原结合功能的片段,并且包括Fab、F(ab')、F(ab')2和Fv。在抗体片段中,Fab是具有轻链和重链可变区、轻链恒定区和第一重链恒定区(CH1)的结构,并且具有一个抗原结合位点。Fab'与Fab的不同之处在于,它在重链CH1区的C末端具有含有至少一个半胱氨酸残基的铰链区。F(ab')2抗体具有由Fab'的铰链区中的半胱氨酸残基形成的二硫键。Fv是仅具有重链可变区和轻链可变区的最小抗体片段,并且产生Fv片段的重组技术披露于PCT国际专利公开号WO 88/10649、WO 88/106630、WO 88/07085、WO 88/07086和WO 88/09344中。
本发明中所用抗体的可变区在抗体的重链部分中包括三个CDR(CDR-H1、CDR-H2和CDR-H3),并且在抗体的轻链部分中包括三个CDR(CDR-L1、CDR-L2和CDR-L3)。这些区域都形成环并且是与抗原特异性结合的区域。
在一方面,本发明涉及与叶酸受体-α(FOLR1)特异性结合的抗体或其抗原结合片段。
在本发明中,抗体或其抗原结合片段可以抑制叶酸受体-α的生物活性。此外,抗体或其抗原结合片段可以诱导针对表达叶酸受体-α的细胞的抗体依赖性细胞毒性。另外,抗体或其抗原结合片段可以具有1x10-7M或更小的对叶酸受体-α的解离常数。
如本文所用,术语“亲本抗体”是指与FOLR1特异性结合的抗FOLR1抗体。在本发明中,使用在先前专利申请(US 2005/0232919A1)中应用的抗体作为亲本抗体。在本说明书中,“亲本抗体”是所述先前专利申请中指定的一种抗体,并且具有对应于下文SEQ ID NO:1的重链序列和对应于下文SEQ ID NO:2的轻链序列:
重链(SEQ ID NO:1)
EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARHGDDPAWFAYWGQGTPVTVSS
轻链(SEQ ID NO:2)
DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGTKVEIK
本发明的范围不仅包括与FOLR1特异性结合的全长抗体(全长IgG),还包括抗体分子的抗原结合片段(片段化的IgG)。本发明中所用的亲本抗体包含由SEQ ID NO:3至8的序列表示的CDR。
因此,在本发明中,抗体或其抗原结合片段可以包含:SEQ ID NO:3的重链CDR1;SEQ ID NO:4的重链CDR2;SEQ ID NO:5的重链CDR3;SEQ ID NO:6的轻链CDR1;SEQ ID NO:7的轻链CDR2;和SEQ ID NO:8的轻链CDR3。
在本发明中,如PCT国际专利公开号WO2016/114567DP中所提及的来构建基于亲本抗体的CDR文库,并且其中引入所构建的文库基因的pComb3X载体是噬菌粒载体,其是具有噬菌体复制起点的质粒DNA并且包括噬菌体表面蛋白pIII。将文库基因与pIII基因的5'端连接,并且在大肠杆菌中表达为融合蛋白。VCSM13辅助噬菌体是如下噬菌体,其提供必要的遗传信息,使得将噬菌粒组装为噬菌体颗粒。VCSM13辅助噬菌体含有卡那霉素抗生素抗性基因,使得可以选择被辅助噬菌体感染的大肠杆菌。
另外,淘选是指从在噬菌体表面上展示的蛋白质(如抗体)的文库中仅选择性扩增与特定分子结合的克隆的过程。所述程序包括:将噬菌体文库添加至固定在表面上的靶分子中以诱导结合;通过洗涤去除未结合的噬菌体克隆;仅洗脱结合的噬菌体克隆;用洗脱的噬菌体克隆再感染大肠杆菌;以及使用辅助噬菌体扩增靶标结合的噬菌体克隆。通过重复这个程序,选择性扩增对固定在表面上的靶分子具有高结合亲和力的靶标结合的噬菌体克隆。
如本文所用,术语“经修饰的抗体”是指通过修饰亲本抗体制备的抗体。本发明还提供了用于分离和纯化经修饰的抗体的方法。可以将通过在产生抗体蛋白的条件下培养而获得的培养物离心以去除杂质,并且可以使用亲和色谱法纯化所得材料。
另外,本发明的经修饰的抗体具有对FOLR1的结合亲和力。对FOLR1的结合亲和力可以使用ELISA测定、SPR(表面等离子体共振)测定等来测量。具体而言,结合亲和力可以通过以下方式来测量:使抗体组合物与固定在板上的FOLR1以各种浓度反应,另外使识别所述抗体的经标记的抗体反应,并且计算结合至FOLR1的抗体组合物的浓度。由此,可以证实,从多CDR文库获得的抗体的结合能力比从单CDR文库获得的抗体的结合能力改进更多。
在本发明的实施方案中,经修饰的抗体可以包含SEQ ID NO:28的重链CDR3、SEQID NO:29的轻链CDR1或SEQ ID NO:30的轻链CDR2,其为从亲本抗体修饰的序列。
因此,在本发明中,抗体或其抗原结合片段可以包含:SEQ ID NO:3的重链CDR1;SEQ ID NO:4的重链CDR2;SEQ ID NO:5或SEQ ID NO:28的重链CDR3;SEQ ID NO:6或SEQ IDNO:29的轻链CDR1;SEQ ID NO:7或SEQ ID NO:30的轻链CDR2;和SEQ ID NO:8的轻链CDR3。
在本发明中,抗体或其抗原结合片段可以包含:SEQ ID NO:1或SEQ ID NO:31的重链可变区;以及选自SEQ ID NO:2和SEQ ID NO:32至34的轻链可变区。优选地,抗体或其抗原结合片段可以包含:SEQ ID NO:1的重链可变区和SEQ ID NO:32的轻链可变区;SEQ IDNO:1的重链可变区和SEQ ID NO:33的轻链可变区;SEQ ID NO:1的重链可变区和SEQ IDNO:34的轻链可变区;SEQ ID NO:31的重链可变区和SEQ ID NO:2的轻链可变区;或SEQ IDNO:31的重链可变区和SEQ ID NO:32的轻链可变区。
在另一方面,本发明涉及抗体-药物缀合物(ADC),其中药物与抗体或其抗原结合片段缀合。
关于抗体-药物缀合物(ADC),抗癌药物应当保持与抗体稳定结合,直至所述抗癌药物被递送至靶癌细胞为止。被递送至靶标的药物应当从抗体释放并诱导靶细胞的细胞凋亡。为此,药物应当与抗体稳定结合,并且同时,应当在靶细胞中释放时展现足够的细胞毒性以诱导靶细胞的细胞凋亡。
在本发明中,抗体或其抗原结合片段与包含药物(如抗癌剂)的细胞毒性物质彼此结合(例如,经由共价键、肽键等),因此可以作为缀合物或融合蛋白(在细胞毒性物质和/或标记物质(标记)是蛋白质时)使用。细胞毒性物质可以是对癌细胞、特别是实体癌细胞有毒的任何物质,并且可以是选自以下的至少一种:放射性同位素、细胞毒性化合物(小分子)、细胞毒性蛋白和抗癌药物,但不限于此。细胞毒性蛋白可以是选自以下的至少一种:蓖麻毒蛋白、皂草素、白树毒素、苦瓜毒蛋白、deBouganin、白喉毒素、假单胞菌毒素等,但不限于此。放射性同位素可以是选自以下的至少一种:131I、188Rh和90Y,但不限于此。细胞毒性化合物可以是选自以下的至少一种:多卡米星(duocarmycin)、一甲基瑞奥西汀E(MMAE)、一甲基瑞奥西汀F(MMAF)、N2'-二乙酰基-N2'-(3-巯基-1-氧代丙基)美登素(DM1)、PBD(吡咯并苯二氮卓)二聚体等,但不限于此。
在本发明中,抗体-药物缀合物可以根据本领域熟知的方法获得。
在本发明中,抗体-药物缀合物的特征可以在于,抗体或其抗原结合片段经由接头与药物缀合。
在本发明中,接头可以是可切割接头或不可切割接头。
接头是将抗体连接至药物的位点。例如,接头允许在细胞内条件下以可切割形式释放药物,即通过在细胞内环境中从抗体切割接头来释放。
接头可以是肽接头,其可以通过在细胞内环境中(例如,在溶酶体或内体中)存在的切割剂来切割,并且可以通过细胞内肽酶或蛋白酶(如溶酶体或内体蛋白酶)来切割。通常,肽接头的长度为至少两个氨基酸。切割剂可以包括组织蛋白酶B、组织蛋白酶D和纤溶酶,其水解肽以将药物释放至靶细胞中。肽接头可以通过在癌症组织中高度表达的硫醇依赖性蛋白酶组织蛋白酶-B来切割。例如,肽接头可以是Phe-Leu或Gly-Phe-Leu-Gly接头。另外,肽接头可以是例如Val-Cit接头或Phe-Lys接头,其可以通过细胞内蛋白酶来切割。
在本发明中,可切割接头对pH敏感并且可能对在某一pH值下的水解敏感。通常,pH敏感性接头是可以在酸性条件下水解的接头。可以在溶酶体中水解的酸不稳定接头的例子包括腙、缩氨基脲、缩氨基硫脲、顺式乌头酰胺、原酸酯、乙缩醛、缩酮等。
接头也可以在还原性条件下切割,并且可以例如是二硫化物接头。可以使用以下形成多种二硫键:N-琥珀酰亚胺基-S-乙酰基硫代乙酸酯(SATA)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丙酸酯(SPDP)、N-琥珀酰亚胺基-3-(2-吡啶基二硫代)丁酸酯(SPDB)和N-琥珀酰亚胺基-氧基羰基-α-甲基-α-(2-吡啶基-二硫代)甲苯(SMPT)。
在本发明中,药物和/或药物-接头可以通过抗体的赖氨酸随机缀合,或者可以通过在二硫键链被还原时暴露的半胱氨酸缀合。在一些情况下,接头-药物可以通过基因工程化标签(例如,肽或蛋白质)中存在的半胱氨酸来缀合。基因工程化标签(例如,肽或蛋白质)可以包括可以由例如类异戊二烯转移酶识别的氨基酸基序。肽或蛋白质具有在肽或蛋白质的羧基末端的缺失或在肽或蛋白质的羧基(C)末端通过间隔子单元的共价键的添加。肽或蛋白质可以与氨基酸基序直接共价键合,或者可以通过与间隔子单元的共价键与氨基酸基序连接。氨基酸间隔子单元由1至20个氨基酸组成,并且特别优选地是甘氨酸单元。
接头可以包含由β-葡糖醛酸糖苷酶识别和水解的β-葡糖苷酸接头,所述β-葡糖醛酸糖苷酶以多个拷贝存在于溶酶体中或者在一些肿瘤细胞中过表达。与肽接头不同,这种接头由于其高亲水性而具有在与具有高疏水性的药物结合时增加抗体-药物缀合物的溶解度的优点。
就此而言,在本发明中,可以使用在韩国专利申请公开号2015-0137015中披露的β-葡糖苷酸接头,例如包括自杀式基团的β-葡糖苷酸接头。
另外,接头可以是例如不可切割接头,并且药物可以仅通过水解抗体的单一步骤来释放,从而产生例如氨基酸/接头/药物复合物。这种类型的接头可以是硫醚基团或马来酰亚胺基己酰基,并且在血液中稳定。
在本发明中,药物可以是化学治疗剂、毒素、微小RNA(miRNA)、siRNA、shRNA或放射性同位素。作为具有药理学作用的药剂的药物可以与抗体缀合。
化学治疗剂可以是细胞毒性剂或免疫抑制剂。具体而言,化学治疗剂可以包含微管蛋白抑制剂、有丝分裂抑制剂、拓扑异构酶抑制剂或能够起DNA嵌入剂作用的化学治疗剂。化学治疗剂还可以包含免疫调节化合物、抗癌剂、抗病毒剂、抗细菌剂、抗真菌剂、驱肠虫药或其组合。
例如,药物可以包含选自以下的至少一种:美登木素生物碱(maytansinoid)、瑞奥西汀、氨基蝶呤、放线菌素、博来霉素、沙利度胺、喜树碱、N8-乙酰基亚精胺、1-(2氯乙基)-1,2-二甲基磺酰肼、埃斯培拉霉素(esperamycin)、依托泊苷、6-巯嘌呤、尾海兔素、单端孢霉烯、加利车霉素(calicheamicin)、紫杉醇(taxol)、紫杉烷、紫杉醇(paclitaxel)、多西他赛、甲氨蝶呤、长春新碱、长春碱、多柔比星、美法仑、苯丁酸氮芥、多卡米星、L-天冬酰胺酶、巯嘌呤、硫鸟嘌呤、羟基脲、阿糖胞苷、环磷酰胺(cyclophosphamide)、异环磷酰胺、亚硝基脲、顺铂、卡铂、丝裂霉素(丝裂霉素A和丝裂霉素C)、达卡巴嗪、丙卡巴肼、拓扑替康、氮芥、环磷酰胺(cytoxan)、依托泊苷、5-氟尿嘧啶、CNU(双氯乙基亚硝基脲)、伊立替康、喜树碱、博来霉素、伊达比星、柔红霉素、更生霉素、普卡霉素、天冬酰胺酶、长春瑞滨、苯丁酸氮芥、美法仑、卡莫司汀、洛莫司汀、白消安、曲奥舒凡、达卡巴嗪、依托泊苷、替尼泊苷、拓扑替康、9-氨基喜树碱、克立那托(crisnatol)、三甲曲沙、霉酚酸、噻唑羧胺核苷(tiazofurin)、利巴韦林、EICAR(5-乙炔基-1-β-呋喃核糖基咪唑-4-甲酰胺)、羟基脲、去铁胺、氟尿苷、去氧氟尿苷、雷替曲塞、阿糖胞苷(ara C)、胞嘧啶阿拉伯糖苷、氟达拉滨、他莫昔芬、雷洛昔芬、甲地孕酮、戈舍瑞林、醋酸亮丙瑞林、氟他胺、比卡鲁胺、EB1089、CB1093、KH1060、维替泊芬、酞菁、光敏剂Pe4、脱甲氧基竹红菌素A、干扰素-α、干扰素-γ、肿瘤坏死因子、吉西他滨、万珂(Velcade)、雷利米得(Revlimid)、撒利多迈(Thalomid)、洛伐他汀、1-甲基-4-苯基吡啶鎓离子、星状孢菌素、放线菌素D、更生霉素、博来霉素A2、博来霉素B2、培洛霉素、表柔比星、吡柔比星、佐柔比星、米托蒽醌、维拉帕米和毒胡萝卜内酯、核酸酶以及源自细菌或植物和动物的毒素,但是本发明不限于此。
在本发明中,药物可以具有选自以下的亲核基团:胺、硫醇、羟基、酰肼、肟、肼、缩氨基硫脲、肼羧酸酯和芳基酰肼基团,其可以与接头和接头试剂上的亲电子基团反应以形成共价键。
在仍另一方面,本发明涉及用于预防和/或治疗癌症的药物组合物,所述药物组合物包含抗体或其抗原结合片段或抗体-药物缀合物。
在又另一方面,本发明涉及用于治疗癌症的方法,所述方法包括将抗体或其抗原结合片段或抗体-药物缀合物给予需要预防或治疗的患者。
在仍又另一方面,本发明涉及抗体或其抗原结合片段或抗体-药物缀合物用于治疗癌症的用途。
在进一步的另一方面,本发明涉及抗体或其抗原结合片段或抗体-药物缀合物在制造用于治疗癌症的药剂中的用途。
在本发明中,癌症可以是卵巢癌、乳腺癌、肺癌、肾癌、结肠癌、脑癌、直肠癌、宫颈癌或子宫内膜癌,但不限于此。
尽管根据本发明的包含抗体或其抗原结合片段或抗体-药物缀合物的药物组合物也可以仅包含抗体或其抗原结合片段或抗体-药物缀合物作为活性成分,但是通常将其与一种或多种药理学上可接受的载体混合,并且优选地作为通过制药技术领域中已知的任何方法制备的药物配制品来提供。
本发明的药物组合物可以单独使用或与选自上述放射性同位素、低分子量药物、聚合物药物或抗体药物的至少一种治疗药物组合使用。另外,本发明的药物组合物可以与常规治疗剂组合使用。也就是说,根据本发明的包含抗体或其抗原结合片段或抗体-药物缀合物的药物组合物可以与常规治疗剂(如抗癌剂)同时或顺序给予。
作为给予途径,在治疗时优选地使用最有效的给予途径。给予途径的例子包括口服给予或肠胃外给予,如口腔内、气道内、直肠内、皮下、肌内或静脉内给予。静脉内给予是优选的。
剂型包括喷雾剂、胶囊剂、片剂、散剂、颗粒剂、糖浆剂、乳液剂、栓剂、注射剂、软膏剂或胶带剂。
给予的剂量或频率根据所需治疗效果、给予方式、治疗期和患者的年龄与体重而变,但是对于成人通常为10μg/kg/天至10mg/kg/天。
由于根据本发明的抗体或其抗原结合片段与叶酸受体-α(FOLR1)特异性结合,可以使用所述抗体或其抗原结合片段来检测或诊断FOLR1。FOLR1的表达与数种疾病(例如,癌症)相关。
因此,在另一方面,本公开文本涉及用于诊断疾病的组合物,所述组合物包含抗体或其抗原结合片段。
在本发明中,疾病可以是FOLR1相关疾病,例如癌症,但不限于此。
在仍另一方面,本发明涉及用于诊断疾病的方法或用于提供诊断疾病用的信息的方法,所述方法包括用抗体或其抗原结合片段处理(给予)从受试者分离的生物样品的步骤。
在本发明中,用于诊断疾病的方法在治疗步骤后还可以包括鉴定是否发生抗原-抗体反应的步骤。在检测方法中,在检测到抗原-抗体反应时,可以确定在生物样品或已经从其获得生物样品的患者中存在FOLR1相关疾病(例如,癌症)。因此,所述方法在鉴定步骤后还可以包括在检测到抗原-抗体反应时,确定生物样品或患者是FOLR1相关疾病患者(例如,癌症患者)的步骤。生物样品可以选自从哺乳动物如人(例如,癌症患者)获得(分离)的细胞、组织、体液、其培养物等。
鉴定是否发生抗原-抗体反应的步骤可以通过本领域已知的多种方法来进行。例如,所述步骤可以通过常规酶促反应、荧光、发光和/或辐射检测来进行。具体而言,所述步骤可以通过选自以下的方法来进行:免疫色谱法、免疫组织化学、酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、酶免疫测定(EIA)、荧光免疫测定(FIA)、发光免疫测定(LIA)、蛋白质印迹法、微阵列和免疫沉淀测定,但不限于此。
在这种情况下,抗体或其抗原结合片段还可以包含标记。标记可以是选自以下的至少一种:放射性同位素、荧光物质、色原和染色物质。标记可以通过常规方法(例如,化学键如共价键、配位键或离子键)与抗体或抗原结合片段结合(连接)。抗体(或抗原结合片段)与标记的结合可以根据本领域已知的技术来进行。
在下文中,将参考实施例更详细地描述本发明。对于本领域技术人员而言将明显的是,这些实施例仅用于说明本发明,并且本发明的范围不受限于这些实施例。
实施例1:文库克隆的选择
为了获得具有改进的对FOLR1结合亲和力的最佳序列,使用Fab片段构建CDR文库。
实施例1-1:亲本抗体Fab模板的制备
可变区分别从亲本抗体的轻链和重链合成,并且恒定区是从pComb3X-TT合成。在以下条件下进行PCR反应:在94℃下预变性2min,然后进行25个循环,每个循环由在94℃下30sec、在56℃下30sec和在72℃下30sec组成,之后在72℃下延伸7min。在PCR反应中,使用100ng的一种模板,或者使用通过将两种模板以每种模板3μL的量混合获得的混合物。以20pM的浓度使用3μL的每种引物,使用0.05mM dNTP和0.5μL(2.6个单位)Taq聚合酶,并且反应体积为100μL。在反应完成后,使用1%琼脂糖凝胶电泳检查是否发生扩增,并且使用Qiagen凝胶提取试剂盒纯化扩增产物。对于第二和第三PCR,使用经扩增的片段作为模板来进行重叠PCR。在琼脂糖凝胶上使用Qiagen凝胶提取试剂盒纯化PCR反应产物DNA,用SfiI限制酶进行切割,然后进行凝胶提取。将153ng的SfiI切割的抗体基因与136ng的SfiI切割的pComb3X载体彼此混合,添加至10X T4 DNA连接缓冲液和10个单位的连接酶中,在室温下反应3小时,然后在42℃下在大肠杆菌DH5α细胞中热休克45秒,之后在37℃下孵育1.5小时。根据通过上述转化方法获得的菌落,获得由50kDa Fab片段构成的用于抗体文库构建的模板。
实施例1-2:抗体文库构建
通过将多样性人工引入互补决定区中来构建文库,并且给定抗体的CDR和FR可以根据(http://www.bioinf.org.uk/abs/)中所述的内容来鉴定。
通过基于在实施例1-1中制备的模板将亲本抗体的CDR序列随机化来构建文库。在亲本抗体的六个CDR中,将CDR-H2从实验中排除,因为它过长而在实验中难以操作。亲本抗体的CDR序列示于下表1中。
[表1]亲本抗体的CDR序列
为了使区域中与抗原结合的特定位置随机化,使用混合碱基代码制备引物(表2)。混合碱基代码是简并引物,并且是指如下寡核苷酸,其中在一个位置中存在两个或更多个碱基,使得考虑到核苷酸序列相似性,它们可以与相似的核苷酸序列结合。在制备引物之前,为了确定要随机化的特定位置,通过对亲本抗体的CDR序列分析来鉴定保守残基。对于不包括这些残基的部分的密码子多样化,使用混合碱基代码来制备引物。
[表2]引物序列
对于亲本抗体CDR-L1、L2、L3、H1和H2区的密码子随机化,将每个区域通过PCR扩增并通过重叠延伸PCR附接至PCR扩增的CDR DNA,由此构建仅在一个CDR中具有多样性的单CDR文库和在两个CDR中具有多样性的多CDR文库。在以下条件下进行PCR反应:在94℃下预变性2min,然后进行25个循环,每个循环由在94℃下30sec、在56℃下30sec和在72℃下30sec组成,之后在72℃下延伸7min。然而,根据预测的DNA片段产物的长度,将在72℃下的延伸时间调整至1min 30sec或2min。具体而言,对于500至1,500bp的预测长度,延伸时间为1min 30sec,并且对于1,500至2,000bp的预测长度,延伸时间为2min。在这些过程中使用的模板、引物和产物的名称总结于下表3中。通过1%琼脂糖凝胶电泳分离和纯化所构建的单CDR或多CDR文库,并且通过用SfiI限制酶在50℃下处理12小时或更长时间来切割纯化产物。还用SfiI限制酶以相同方式切割pComb3X噬菌粒载体。
[表3]用于文库构建的PCR模板和引物
对于连接,将SfiI切割的载体和SfiI切割的插入物以等量混合在一起,并且使其在室温下反应过夜。如果连接产物的体积对于转化而言过大,则可以使用EtOH沉淀来缩小连接产物的体积,并且用于缩小体积的方法如下。向50μL连接产物中添加5μL(1/10)的3M乙酸钠(pH 5.2)和110μL(2倍)的100%EtOH,并且允许DNA在-20℃下沉淀2小时或更长时间。将经沉淀的DNA以12,000rpm离心15分钟,然后用1ml的70%EtOH洗涤,并且在相同条件下离心。将沉淀干燥,然后溶解于10μL去离子水中。通过电穿孔进行转化。具体而言,将10μL连接产物与50μL大肠杆菌TG1感受态细胞混合在一起,然后将其置于0.2cm冷却的比色皿中,将所述比色杯置于电穿孔仪中。随后,将细胞在2.5kV下脉冲处理4至5msec。在脉冲处理后立即将2mL加热至37℃的回收培养基添加至细胞中,然后在37℃下进行孵育1小时。随后,将1μL经孵育的细胞用SB培养基稀释1,000倍,并且将10μL和100μL的细胞稀释液分配于LB琼脂板上以制备用于测量文库大小的样品,并且将剩余稀释液铺板于一个板上并在37℃下孵育过夜。第二天,通过计数将经稀释的细胞分配至其中的板上的菌落数来测量文库大小。另外,将5mL的SB培养基添加至将未经稀释的细胞分配至其中的板中,使用涂布器收集细胞,然后将0.5倍体积的50%甘油添加至细胞中,然后将所述细胞储存在深度冷冻器(-75℃)中。
[表4]
CDR文库 | 文库大小 |
CDR-L1 | 4.56x10<sup>6</sup> |
CDR-L2 | 2.94x10<sup>7</sup> |
CDR-L3 | 6.22x10<sup>7</sup> |
CDR-H1 | 4.78x10<sup>6</sup> |
CDR-H3 | 1.30x10<sup>8</sup> |
CDR-L3H3 | 8.82x10<sup>7</sup> |
所获得的文库的大小指示转化效率,特别是单独克隆的数量。因此,可以认为抗原结合多样性对应于文库大小。也就是说,制备以下文库:多样性为106的CDR-L1文库、多样性为107的CDR-L2文库、多样性为107的CDR-L3文库、多样性为106的CDR-H1文库、多样性为108的CDR-H3文库和多样性为107的CDR-L3H3文库(表4)。
实施例1-3:在噬菌体展示淘选后通过ELISA进行选择
进行淘选以选择与人FOLR1结合的文库克隆,并且随着淘选重复进行,可以获得具有进一步增加的对FOLR1的结合亲和力的克隆。
对于文库扩增和表达Fab的噬菌体的回收,将100μL用所述文库转化的TG1原液接种至20mL的SB/Amp+2%葡萄糖培养基中,并且将所述文库在大肠杆菌TG1细胞中在37℃和220rpm下表达1.5至2小时。将细胞培养物以3500rpm离心15分钟。去除上清液,并且将沉淀重悬于20ml的SB/Amp培养基中。将0.5mL的辅助噬菌体VCSM13(约1011pfu)添加至悬浮液中,然后通过在37℃和120rpm下培养1小时用辅助噬菌体进行感染。随后,将卡那霉素(50mg/mL)添加至悬浮液中以达到70μg/mL,之后在30℃和200rpm下培养16小时。将培养物离心,并且将5mL的5X PEG浓缩溶液添加至含有噬菌体的上清液中,然后将其在冰上浓缩30分钟。将浓缩物以12,000rpm离心15分钟,并且去除上清液。将噬菌体沉淀重悬于0.3mL的PBS中以获得文库噬菌体(对于储存,将0.5倍体积的50%甘油添加至文库噬菌体中,然后将其储存在-75℃下)。
为了扩增所获得的文库噬菌体,将大肠杆菌TG1细胞原液接种至10mL的SB培养基中,并且在孵育器中在37℃和220rpm下培养约4至5小时直至对数中期(OD600=0.5至1.0),从而制备感受态细胞,然后将其储存在4℃下直至使用为止。按以下方式进行淘选。将1μg/mL的FOLR1涂布于免疫管上,然后用封闭溶液(3%脱脂乳)在37℃下封闭1小时。将0.5mL文库噬菌体通过以1:1的比率向其中添加0.5mL封闭溶液进行封闭,然后允许其与固定的抗原进行反应。在反应已经进行一小时或更长时间后,通过用PBS-Tween20缓冲液洗涤的步骤去除未反应的或弱结合的噬菌体,并且将强结合的噬菌体用1mL的TEA(100mM)洗脱10分钟,然后用0.5mL的Tris-HCl(1M,pH7.4)中和。将1.5mL经洗脱的噬菌体添加至8.5mL的感受态细胞中并感染至细胞中,在孵育器中在37℃和120rpm下持续1小时。随后,为了测量文库大小,将2mL反应溶液中的1μL稀释1,000倍和10,000倍并铺板,并且将剩余反应溶液铺板于一个板上并在37℃下孵育过夜。
将经转化的大肠杆菌文库用VCSM13辅助噬菌体培养和感染,以获得具有在其表面上展示的Fab克隆的抗体噬菌体文库。通过针对在免疫管表面上吸附的FOLR1将文库淘选3至5轮,仅选择与FOLR1强结合的噬菌体克隆。通过这个过程,去除由于合成的CDR序列中的缺陷而与FOLR1弱结合或未与FOLR1结合的克隆,因此,可以选择没有缺陷并且比现有序列更好地优化的CDR序列。将CDR-L1和CDR-L2文库淘选5轮,将CDR-L3、CDR-H3和CDR-L3H3文库淘选4轮,并且将CDR-H1文库淘选3轮。对于每轮淘选,计算经洗脱的噬菌体(输出噬菌体)与用于淘选的噬菌体(输入噬菌体)的比率(O/I比),并且将结果在下表5中表示为结合%。即使在重复进行淘选时也出现相似结合%值的事实指示,对FOLR1的结合亲和力达到饱和(表5)。在出现这种结果时,不再进行淘选,并且使用经洗脱的噬菌体进行下一个步骤。为了验证从淘选得到的抗体噬菌体文库的功能,通过ELISA从每个CDR文库筛选94个克隆。显示比背景信号强至少3倍的结合信号的ELISA阳性克隆的数量被鉴定为:对于CDR-L1为92,对于CDR-L2为66,对于CDR-L3为19,对于CDR-H1为94,对于CDR-H3为48,并且对于CDR-L3H3为63。在每个文库的显示更强结合信号的克隆中,对八个克隆进行测序(表6)。
[表5]淘选条件和结果
[表6]测序结果
实施例1-4:使用表达蛋白质的菌株TOP10F'的Fab产生和纯化
为了比较所选克隆对FOLR1的结合亲和力,对每个克隆进行纯化。在纯化前,将宿主菌株从TG1变为TOP10F'细胞,以仅表达Fab区。
将对应于每个所选克隆的菌落接种至4mL SB/氨苄西林培养基中并在37℃下培养过夜。第二天,将4ml的过夜培养物接种至400mL SB/氨苄西林培养基中并在孵育器中在37℃下培养约3至4小时,直至OD600达到0.5至1.0为止。随后,对于克隆的表达,将培养物用IPTG处理至终浓度为1mM,然后在30℃下培养过夜。然而,在仅证实表达时,在20mL的SB/氨苄西林培养基中进行培养。
为了从400mL培养物回收周质,将培养物离心以去除上清液,然后通过用16mL的1XTES溶液在4℃下处理并在4℃下孵育1小时来裂解细胞。另外,将细胞用24mL的0.2X TES溶液处理并孵育1小时。随后,通过离心收集上清液,并且向其中添加5mM MgCl2以去除EDTA。在加载样品前,将填充有0.5mL的Ni-NTA His-树脂的柱用20CV的洗脱缓冲液(PBS中的300mM咪唑,pH 7.4)洗涤,然后用20CV的PBS冲洗。将样品加载至柱上并收集流过物(flow-through)。在加载完成后,将柱用20CV的洗涤缓冲液(PBS中的20mM咪唑,pH 7.4)冲洗,并且收集洗出物(washing-through)。然后,将柱用10CV的洗脱缓冲液冲洗,并且收集洗脱液。将在纯化过程期间的每个步骤中收集的15μL样品加载于每个孔中的12%SDS-PAGE中并进行电泳(在150V下持续1小时)。通过考马斯蓝染色对条带进行可视化。
实施例1-5:在不同浓度下对所选克隆与FOLR1的直接结合模式的检查
出于比较最初选择的克隆与彼此的结合亲和力的目的,按以下方式在不同的克隆浓度下进行ELISA。将25μL的FOLR1以1μg/mL的浓度添加至96孔板的每个孔中,在室温下在板上涂布1小时,然后用180μL的3%脱脂乳在室温下封闭1小时。在封闭期间,制备要用作一抗的样品。作为一抗,使用通过筛选选择的样品。将样品稀释到0.1至100nM(0、0.1、0.3、1、3、10、30和100nM)的浓度并冷藏直至使用为止。在封闭后,去除3%脱脂乳,并且将25μL一抗添加至每个孔中,并且允许其在室温下反应1小时或更长时间。在反应完成后,用PBS-Tween20(0.1%)缓冲液将每个孔洗涤三次。作为二抗,用3%脱脂乳将HA-HRP稀释3,000倍,并且将25μL稀释液添加至每个孔中,并且允许其在室温下反应1小时或更长时间。在反应完成后,用PBS-Tween20(0.1%)将每个孔洗涤三次,并且将25μL的底物TMB添加至每个孔中以证实显色。在约5分钟后,将25μL的1M H2SO4添加至每个孔中以停止反应,并且在450nm的波长下测量吸光度。根据测量结果,使用GraphPad Prism 7程序计算EC(效应子浓度)值。
为了测量所选克隆对FOLR1的结合亲和力,使用Biacore3000进行SPR测量。在加载每个样品之前,用0.1M NHS/0.4M EDC激活CM5传感器芯片,然后将FOLR1(20μg/mL,在10mM乙酸盐中,pH 5.0)固定在所述芯片上。然后,用1M乙醇胺使未反应的NHS失活。以1、2、5、10、20和40nM的浓度制备250μL的每个样品,并且在以30μl/min冲洗每个样品的同时获得缔合和解离传感图。用10mM甘氨酸(pH 2.1)使传感器芯片再生。使用BIAevaluation软件分析所获得的传感图,并且计算KD值。
实施例1-6:抗体文库的测序
分析通过噬菌体文库的ELISA选择的克隆的随机化的互补决定区的序列。使用从在96孔板中培养的克隆选择的每个克隆的1μL培养物作为模板,使用pC3X-f和pC3X-b引物在以下条件下进行PCR反应:在94℃下预变性2分钟,然后进行25个循环,每个循环由在94℃下30sec、在56℃下30sec和在72℃下2min组成,之后在72℃下延伸7min。通过1%琼脂糖凝胶电泳检查是否发生扩增,并且使用QIAvac 96以DW纯化经扩增的PCR产物并进行测序。使用前导序列分析互补决定区的序列。
实施例2:经修饰的抗体(vAb)的构建
以与抗体文库构建方法相同的方式构建最终克隆pvAb。所用模板和引物示于下表7中,并且关于vAb抗体序列的信息总结于下表8至10中。
[表7]用于最终克隆构建的PCR模板和引物
[表8]亲本抗体与经修饰的抗体(vAb)之间的互补决定区的序列比较
通过如上所述鉴定的CDR序列的组合,构建经修饰的抗体vAb1、vAb2、vAb3、vAb4和vAb5。vAb1是反映CDR-H3、CDR-L1和CDR-L2的全部的经修饰的抗体,vAb2是反映CDR-L1和CDR-L2的经修饰的抗体,vAb3是反映CDR-L1的经修饰的抗体,vAb4是反映CDR-L2的经修饰的抗体,并且vAb5是反映CDR-H3的经修饰的抗体。
[表9]亲本抗体和经修饰的抗体(vAb)的氨基酸序列
[表10]经修饰的抗体(vAb)的序列
经修饰的抗体 | HC | LC |
vAb1 | SEQ ID NO:31 | SEQ ID NO:32 |
vAb2 | SEQ ID NO:1 | SEQ ID NO:32 |
vAb3 | SEQ ID NO:1 | SEQ ID NO:33 |
vAb4 | SEQ ID NO:1 | SEQ ID NO:34 |
vAb5 | SEQ ID NO:31 | SEQ ID NO:2 |
实施例3:经修饰的抗体(vAb)的表达和纯化
为了产生经修饰的抗体(vAb),将expiCHO细胞用含有编码经修饰的抗体(vAb)蛋白的基因的载体(pc 3.4-vAbL、pc 3.4-vAbH)转染并培养,并且使用亲和色谱法纯化经修饰的抗体。将填充有亲和树脂MabSelect SuReTM(GE Healthcare)的XK16柱通过用缓冲液A(25mM Tris(pH 7.0),25mM NaCl)冲洗来平衡,然后冲洗培养物并使其与亲和树脂结合,并且用缓冲液B(25mM柠檬酸,pH 3.5)洗脱经修饰的抗体(vAb)蛋白。在纯化完成后,将柱用0.5M NaOH洗涤,然后用20%乙醇填充并冷藏。通过向其中添加适当量的1M Tris(pH 9.0)将经洗脱的样品的pH调整至6.0。通过10%SDS-PAGE检查样品的状态。通过相对于含有10mM琥珀酸钠和30mM蔗糖的缓冲液(pH 6.0)进行透析使获得的经修饰的抗体(vAb)蛋白经历缓冲液交换。
实施例4:通过ELISA测定对经修饰的抗体(vAb)的结合亲和力的分析
出于比较在实施例2中产生的经修饰的抗体(vAb)的结合亲和力与亲本抗体的结合亲和力的目的,以与实施例1-5中所述相同的方式以0.006至6.250ng/mL的抗体浓度进行ELISA。作为测量结果,证实了经修饰的抗体vAb1至vAb5以比亲本抗体高4.48倍至1.42倍的结合亲和力与FOLR1结合(表11)。所测量的值是在用于与亲本抗体进行比较的不同实验中获得的。
[表11]ELISA测定的结果
实施例5:通过SPR测定对经修饰的抗体(vAb)的结合亲和力的检查
为了测量在实施例2中产生的经修饰的抗体vAb1对FOLR1的结合亲和力,以与实施例1-5中所述相同的方式使用Biacore3000进行SPR测定。使用BIAevaluation软件分析传感图,并且计算KD值。经修饰的抗体vAb1显示出0.24nM的KD值,其对应于比亲本抗体的结合亲和力高4倍的结合亲和力(表12)。这个值与使用ELISA获得的值的相对比率类似。
[表12]通过SPR测量的亲本抗体和经修饰的抗体vAb1的解离常数
工业实用性
根据本发明的经修饰的抗体具有如下序列,其中亲本抗体最初具有的抗原结合位点被如下氨基酸取代,所述氨基酸在保留亲本抗体的基础结构的同时更好地与抗原结合。因此,经修饰的抗体具有增加的对抗原的结合亲和力。另外,根据本发明的抗体或其抗原结合片段可以用于预防或治疗癌症,并且还可以用于诊断疾病。
尽管已经参考具体特征详细地描述了本发明,但是对于本领域技术人员而言将清楚的是,此描述仅是本发明的优选实施方案的描述,并不限制本发明的范围。因此,本发明的实质范围将由所附权利要求及其等同物限定。
序列表自由文本
附有电子文件。
<110> 阿特根公司
<120> 与FOLR1特异性结合的抗体及其用途
<130> PP-B2178
<150> KR 10-2018-0029762
<151> 2018-03-14
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<210> 28
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> CDR-H3
<400> 28
His Gly Asp Asp Val Ala Trp Phe Ala Tyr
1 5 10
<210> 29
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> CDR-L1
<400> 29
Ser Ala Ser Ser Gly Leu Ser Ser Ser Tyr Leu His
1 5 10
<210> 30
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> CDR-L2
<400> 30
Gly Thr Ser Ser Arg Ala Ser
1 5
<210> 31
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> HC
<400> 31
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Thr Phe Ser Gly Tyr
20 25 30
Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Met Ile Ser Ser Gly Gly Ser Tyr Thr Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Arg His Gly Asp Asp Val Ala Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser
115
<210> 32
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC
<400> 32
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Gly Leu Ser Ser Ser
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Tyr Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 33
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC
<400> 33
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Ser Gly Leu Ser Ser Ser
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Tyr Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 34
<211> 110
<212> PRT
<213> 人工序列
<220>
<223> LC
<400> 34
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Val Ser Ser Ser Ile Ser Ser Asn
20 25 30
Asn Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Ser Arg Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Tyr Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Claims (13)
1.一种与叶酸受体-α(FOLR1)特异性结合的抗体或其抗原结合片段。
2.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段抑制叶酸受体-α的生物活性。
3.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段在表达叶酸受体-α的细胞中诱导抗体依赖性细胞毒性。
4.根据权利要求1所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段具有1x10-7M或更小的对叶酸受体-α的解离常数。
5.根据权利要求1所述的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
SEQ ID NO:3的重链CDR1、SEQ ID NO:4的重链CDR2和SEQ ID NO:5或SEQ ID NO:28的重链CDR3;以及
SEQ ID NO:6或SEQ ID NO:29的轻链CDR1、SEQ ID NO:7或SEQ ID NO:30的轻链CDR2和SEQ ID NO:8的轻链CDR3。
6.根据权利要求1所述的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:SEQ ID NO:1或SEQ ID NO:31的重链可变区;以及选自SEQ ID NO:2和SEQ ID NO:32至34的轻链可变区。
7.根据权利要求6所述的抗体或其抗原结合片段,所述抗体或其抗原结合片段包含:
SEQ ID NO:1的重链可变区和SEQ ID NO:32的轻链可变区;或
SEQ ID NO:1的重链可变区和SEQ ID NO:33的轻链可变区;或
SEQ ID NO:1的重链可变区和SEQ ID NO:34的轻链可变区;或
SEQ ID NO:31的重链可变区和SEQ ID NO:2的轻链可变区;或
SEQ ID NO:31的重链可变区和SEQ ID NO:32的轻链可变区。
8.一种抗体-药物缀合物,其中药物与根据权利要求1所述的抗体或其抗原结合片段缀合。
9.根据权利要求8所述的抗体-药物缀合物,其中所述抗体或其抗原结合片段经由接头与所述药物缀合。
10.根据权利要求8所述的抗体-药物缀合物,其中所述药物是化学治疗剂、毒素、微小RNA(miRNA)、siRNA、shRNA或放射性同位素。
11.一种用于预防或治疗癌症的药物组合物,所述药物组合物包含根据权利要求1至7中任一项所述的抗体或其抗原结合片段或根据权利要求8至10中任一项所述的抗体-药物缀合物。
12.根据权利要求11所述的药物组合物,其中所述癌症是卵巢癌、乳腺癌、肺癌、肾癌、结肠癌、脑癌、直肠癌、宫颈癌或子宫内膜癌。
13.一种用于诊断疾病的组合物,所述组合物包含根据权利要求1至7中任一项所述的抗体或其抗原结合片段。
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KR10-2018-0029762 | 2018-03-14 | ||
KR1020180029762A KR102275930B1 (ko) | 2018-03-14 | 2018-03-14 | Folr1에 특이적으로 결합하는 항체 및 그의 용도 |
PCT/KR2019/002911 WO2019177372A1 (ko) | 2018-03-14 | 2019-03-13 | Folr1에 특이적으로 결합하는 항체 및 그의 용도 |
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US (1) | US11866492B2 (zh) |
EP (1) | EP3766900A4 (zh) |
JP (1) | JP6998470B2 (zh) |
KR (1) | KR102275930B1 (zh) |
CN (1) | CN112424227A (zh) |
CA (1) | CA3096982C (zh) |
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CN116462768A (zh) * | 2023-06-13 | 2023-07-21 | 浙江时迈药业有限公司 | 针对folr1的双特异性抗体及其用途 |
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GB202210407D0 (en) * | 2022-07-15 | 2022-08-31 | Iksuda Therapeutics Ltd | Folate receptor targeting antibody-drug conjugates |
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EP3766900A4 (en) | 2021-12-15 |
JP6998470B2 (ja) | 2022-02-04 |
CA3096982C (en) | 2023-10-03 |
KR20190108351A (ko) | 2019-09-24 |
KR102275930B1 (ko) | 2021-07-12 |
EP3766900A1 (en) | 2021-01-20 |
JP2021515571A (ja) | 2021-06-24 |
WO2019177372A1 (ko) | 2019-09-19 |
US11866492B2 (en) | 2024-01-09 |
CA3096982A1 (en) | 2019-09-19 |
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