CN102065868A - 诱发对于Globo H及SSEA3的特异免疫反应的组合物以及其在癌症治疗中的用途 - Google Patents
诱发对于Globo H及SSEA3的特异免疫反应的组合物以及其在癌症治疗中的用途 Download PDFInfo
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Abstract
本发明提供一种含有Globo H或其片段(如,SSEA3)以及一佐剂(如,α-GalCer)的免疫组合物,用以诱发对抗Globo H或其片段的免疫反应,以及其在癌症治疗中的用途。也公开了一种通过抑制FUT1及FUT2(两者皆参与Globo H的生物合成)其一的活性以治疗癌症的方法。
Description
相关申请
本案已向美国临时申请案第61/061,968号作过申请的优先权(2008年6月16日申请),其内容在此以其全文并入作为参考资料。
背景技术
Globo H是一种在各种上皮癌中过表达的癌症抗原。已建议此种抗原可作为癌症免疫治疗的靶标。尽管已研发出可诱发对抗Globo H的抗体反应的疫苗,但因Globo H的低抗原性,其抗癌功效并不令人满意。因此仍需要可诱发靶向Globo H的高量免疫反应的新疫苗。
发明内容
本发明是根据无法预见的发现:(1)Globo H的立即前驱物SSEA3在乳癌干细胞中有高量的表达,并因此可作为乳癌治疗的适当靶标,以及(2)α-半乳糖苷基-神经酰胺(α-GalCer)是一种有效的佐剂,其可促进抗-Globo H及抗-SSEA3抗体的生成。
因此,本发明一方面提出一种免疫组合物,其含有Globo H或其片段(如,SSEA3)以及一佐剂(如,α-GalCer)。Globo H或其片段可与匙孔戚血蓝蛋白(KLH)复合。在给予至对象(如,人类)体内时,此种免疫组合物可诱发靶向GloboH或其片段的免疫反应(如,抗体生成),并因此可有效治疗癌症(如,乳癌、前列腺癌、卵巢癌、及肺癌)。
另一方面,本发明涉及一种制备对于Globo H或其片段具有特异性的抗体的方法,其是对一非人类哺乳动物(如,小鼠、兔、山羊、绵羊、或马)给予上述的免疫组合物,并自该哺乳动物分离可结合Globo H或其片段的抗体。
又另一方面,本发明提出一种以可抑制2-岩藻糖基转移酶1(FUT1)或2-岩藻糖基转移酶2(FUT2)活性的第一剂来治疗癌症的方法。FUT1及FUT2两者皆参与Globo H的生物合成。此剂可以是阻碍FUT1/FUT2与其底物间交互作用的抗体或抑制FUT1或FUT2表达的干扰RNA(如,siFUT1或siFUT2)。选择性地,靶向FUT1的第一剂可与能抑制FUT2活性的第二剂合并。在一实例中,第一剂为siFUT1而第二剂为siFUT2。
该免疫组合物或该第一及第二剂对于治疗癌症以及生产治疗癌症的药剂的用途也在本发明范围的内。
本发明的各种具体实例于下文详述。本发明的其它特征或优势将可由下文图表及各种具体实例的详细叙述以及权利要求范围而清楚呈现。
在不须进一步说明的情形下,相信所属技术领域的技术人员根据本文的叙述可将本发明应用至其最广范围。因此,下文的叙述应仅被视为说明而不以任何方式限制本发明的范围。
附图简要说明
附图首次被描述。
图1描述Globo H(GH)中的六糖抗原表位及其片段的结构的图表。栏A:六糖抗原表位的结构。栏B:六糖抗原表位及七种其片段的结构。
图2显示单以KLH-复合的Globo H以及同时以KLH-复合的Globo H及α-GalCer免疫的小鼠中抗-Globo H及抗-SSEA3抗体的量的图表。
图3显示siFUT1及siFUT2对FUT1及FUT2在乳癌细胞中的表达的作用的图表。栏A:在MB157细胞中,藉由siFUT1抑制FUT1的表达。栏B:在T-47D细胞中,通过siFUT1及siFUT2分别抑制FUT1及FUT2的表达。
图4显示siFUT1及siFUT2对抑制异种移植乳癌的作用的图表。栏a:显示siFUT1及siFUT2抑制乳癌增长的图表。栏b:显示siFUT1及siFUT2降低肿瘤块重量的图表。
具体实施方式
除非此处另有说明,否则与本发明有关的科学和技术名词与所属技术领域的技术人员通常所了解的意义相同。如此处所述,除非另有说明,否则下列名词具有其所属的意义。
除非内文需要,否则单数名词应包括复数的涵意以及复数名词应包括单数的涵意。此处所使用的冠词″a″和″an″指该冠词的一或多于一个(即,至少一个)的语法受词。例如,“一组件”意指一个组件或多于一个的组件。
已发现Globo H以及其立即前驱物SSEA3两者皆可作为癌症治疗中的靶标。
因此,本发明的实施例之一是一种治疗癌症的方法,其是对需要其的对象给予一有效量的免疫组合物,该组合物包含Globo H或其片段(如SSEA-3,也称为Gb5)以及一佐剂。目标癌症的类型包括,但不限于,乳癌(包括1-4期)、肺癌(如,小细胞肺癌)、肝癌(如,肝细胞癌及胆管癌)、口腔癌、胃癌(包括T1-T4)、结肠癌、鼻咽癌、皮肤癌、肾癌、脑瘤(如,星形细胞瘤、多形性胶质母细胞瘤、及脑脊髓膜瘤)、前列腺癌、卵巢癌、子宫颈癌、膀胱癌、以及子宫内膜瘤、横纹肌肉瘤、骨肉瘤、平滑肌肉瘤、及胃肠道基质瘤。本文所用的术语“治疗”是指对一对象施用或给予包括一或多种活性剂的组合物,该对象具有癌症、癌症的症状、或是倾向癌症的素因,该施用及给予的目的为治愈、治疗、缓和、减轻、改变、补救、改善、改进、或影响该癌症、癌症的症状、或是倾向癌症的素因。本文所用的“有效量”是指在单独使用或是结合一或多种其它活性剂的情形下,欲对该对象产生治疗作用所需的各活性剂的量。如本领域技术人员所知,有效量会根据给予的途径、赋形剂的使用、以及其它活性剂的共使用而各有不同。
用于上述方法中的免疫组合物可含有一聚糖(即,含有糖分子部分的分子),其是Globo H或其片段,以及一佐剂。Globo H是含有六糖抗原表位(示于图1,栏A),并视情形含有一非糖分子部分的聚糖。其片段是含有该六糖抗原表位以及,如适用,该非糖分子部分的片段的聚糖。该些寡糖可由常规方法制备(参见,Huang et al.,Proc.Natl.Acad.Sci.USA 103:15-20(2006))。如需要,其可与非糖分子部分连结。
任何上述的聚糖可与一蛋白载体(诸如,KLH)复合。其可接着与佐剂及视情形的医药可接受性载体(如,磷酸缓冲盐水,或碳酸氢盐溶液)混合,以经由公知的方法而形成免疫组合物(如,疫苗)。参见,如,美国专利No.4,601,903;4,599,231;4,599,230;及4,596,792。该组合物可被制备为可注射物、液态溶液、或乳液,且该载体是根据给予的方式及途径并根据标准医药实务而选择。适当的医药载体及稀释剂,以及为其使用的医药辅料,述于Remington′s Pharmaceutical Sciences。该免疫组合物较佳地含有α-GalCer作为佐剂。佐剂的其它实例包括,但不限于,霍乱毒素、大肠杆菌忌热性肠毒素(LT)、脂质体、免疫刺激性复合物(ISCOM)、或免疫刺激性序列寡脱氧核苷酸(ISS-ODN)。该组合物也可包括可协助体内输送的聚合物。参见,Audran R.et al.Vaccine21:1250-5,2003;以及Denis-Mize et al.Cell Immunol.,225:12-20,2003。在需要时,其尚可含有少量的辅助物质,诸如,湿润及乳化剂,或pH缓冲剂,以增进该组合物诱发对抗Globo H或其片段中的糖分子部分的免疫反应的能力。
本文所述的免疫组合物可由肠外给予(如,静脉注射、皮下注射、或肌内注射)。或者,可能需要其它给予模式,包括栓剂及口服调配物。就栓剂而言,黏合剂及载体可包括,例如,聚烯烃基二醇或三酸甘油脂。口服调配物可包括正常使用的赋形剂,诸如,举例而言,医药级的糖精、纤维素、碳酸镁、及其类似者。该些组合物可为溶液、悬浮液、锭剂、丸剂、胶囊、持续释放调配物、或粉末的形式,且其含有10-95%的本文所述免疫组合物。
该免疫组合物是以可与该投剂调配物兼容的方式进行给予,且其给予量为具有治疗有效性、保护性、及免疫原性的量。给予的量取决于该待治疗的对象,包括,例如,该个体的免疫是统合成抗体及(如需要)产生细胞中介性免疫反应的能力。给予所需活性成分的精确量是由执业医师的判断决定。然而,适当的剂量范围可由本领域技术人员轻易决定。起始给予及强化剂的适当方案也是可变的,但可包括一起始的给予再接续后续的给予。该疫苗的剂量也可能取决于给予途径,并根据该宿主的尺寸而变化。
本发明的免疫组合物也可用于在动物体内产生抗体以进行抗体的制备,该些抗体可用于癌症的治疗及诊断。在动物(如,小鼠、兔、山羊、绵羊、或马)体内制备单克隆及多克隆抗体及其片段的方法为本领域技术人员公知的。参见,例如,Harlow and Lane,(1988)Antibodies:ALaboratory Manual,Cold SpringHarbor Laboratory,New York。术语“抗体”包括完整的免疫球蛋白分子以及其片段,如,Fab、F(ab′)2、Fv、scFv(单链抗体)、及dAb(域抗体;Ward,et.al.(1989)Nature,341,544)。
本发明的另一实施例是一种通过抑制FUT1及/或FUT2(两者皆负责GloboH的生物合成)活性治疗癌症的方法。FUT1及FUT2为熟知的2-岩藻糖基转移酶,其经由一α-1,2键结将海藻糖单元转移至寡糖底物的还原端。参见,如,NCBI Gene ID:2523及NCBI Gene ID:2524。
在一实例中,通过对需要其的对象给予一有效量可阻碍FUT1/FUT2及其底物间交互作用的抗体(意即,对FUT1/FUT2或其底物具有特异性的抗体)以实行前面描述的方法。
一般而言,为生产这样的抗体,FUT1/FUT2、其片段、或其底物可与载体蛋白(如,KLH)复合,如需要,与佐剂混合,然后注射至宿主动物。在动物体内产生的抗体可接着以公知的方法纯化,如,亲和色谱分析法。通常使用的动物包括,兔、小鼠、天竺鼠、及大鼠。根据宿主物种,可使用各种佐剂来增强免疫反应,并且包括,佛朗氏佐剂(Freund’s adjuvant(完全及非完全))、矿物胶诸如氢氧化铝、CpG、表面活性物质诸如脱脂酸卵磷脂、多聚醇(pluronicpolyols)、聚阴离子、肽、油乳化液、钥孔戚血蓝蛋白、及二硝基酚。有效的人类佐剂包括BCG(bacille Calmette-Guerin,卡介苗)及短棒状杆菌(Corynebacterium parvum)。
多克隆抗体,抗体分子的异质群体,存在于被免疫对象的血清中。单克隆抗体,(针对FUT 1/FUT2或其底物的)抗体的同质群体,可使用标准杂交瘤细胞技术制备(参见,例如,Kohler et al.(1976)Eur J Immunol 6,292;及Hammerling et al.(1981)Monoclonal Antibodies and T Cell Hybridomas,Elsevier,N.Y.)。具体而言,单克隆抗体可通过任何可提供由培养的连续细胞系产生抗体分子的技术获得,诸如描述于Kohler et al.(1975)Nature 256,495及美国专利No.4,376,110;the human B-cell hybridoma technique(Kosbor et al.(1983)Immunol Today 4,72);Cole et al.(1983)Proc.Natl.Acad.Sci.USA 80,2026,及EBV-hybridoma technique(Cole et al.(1983)Monoclonal Antibodies and CancerTherapy,Alan R.Liss,Inc.,pp.77-96)。该些抗体可为任何免疫球蛋白族,包括IgG、IgM、IgE、IgA、IgD、及任何其亚族。本发明中生产单克隆抗体的杂交瘤细胞可培养于体外或体内。在体内产生高效价单克隆抗体的能力为特别有用的生产方法。另外,可使用为生产“嵌合抗体”发展的技术。参见,如,Morrisonet al.(1984)Proc.Natl.Acad.Sci.USA 81,6851;Neuberger et al.(1984)Nature312,604;及Takeda et al.(1984)Nature 314,452。嵌合抗体是一分子,其不同部分来自不同动物物种,诸如具有来自小鼠单株抗体的可变区以及来自人类免疫球蛋白的固定区的那些。或者,可修改生产单链抗体的技术(美国专利No.4,946,778及4,704,692)以产生单链Fv抗体的噬菌体基因库。单链抗体是通过以氨基酸键连结重链及轻链的Fv区而形成。此外,抗体片段可通过已知的技术生产。例如,该些片段包括,但不限于,可通过以胃蛋白酶切割抗体分子而产生的F(ab’)2片段,以及可通过还原F(ab’)2的双硫键而产生的Fab片段。抗体通过本领域中已知的方法可被人源化。例如,具有所需结合特异性的单株抗体透过商业可被人源化(Scotgen,Scotland;以及Oxford Molecular,Palo Alto,Calif)。完全的人类抗体,诸如该些在转基因动物中被表达的,也为本发明的特征。参见,如,Green et al.(1994)Nature Genetics 7,13;及美国专利No.5,545,806及5,569,825。
在另一实例中,上述方法可被实行,其通过给予需癌症治疗的对象有效量的一或多种双链RNA(dsRNAs),经由RNA干扰来抑制FUT1和/或FUT2的表达,从而降低Globo H的量。RNA干扰(RNAi)是dsRNA将同源的特定序列的信使RNA导向降解的程序。在哺乳类细胞中,RNAi可通过双21-核苷酸的小干扰RNA(siRNA)被引发而不活化宿主的干扰素反应。
dsRNA可通过本领域中已知的方法合成。参见,如,Caruthers et al.,1992,Methods in Enzymology 211,3-19;Wincott et al.,1995,Nucleic Acids Res.23,2677-2684;Wincott et al.,1997,Methods Mol.Bio.74,59;Brennan et al.,1998,Biotechnol.Bioeng.,61,33-45;以及Brennan,美国专利No.6,001,311。其也可由表达载体被转录并且使用标准技术分离出来。
如上所述的dsRNA或载体通过诸如Akhtar et al.,1992,Trends Cell Bio.2,139所描述的方法可被递送至癌症细胞。例如,使用微脂体、水凝胶、环糊精、生物可降解的纳米胶囊、或具生物黏附性的微球可将其引入细胞。或者,通过直接注射或输液泵的使用,可局部地递送dsRNA或载体。其它的途径包括使用各种运输及载送系统,例如,透过偶合物及生物可降解的聚合物的使用。
作为一实例,上述dsRNA含有与CGCGGACTTGAGAGATCCTTT互补的第一链,或其互补链(如,描述于下,实施例2中的siFUT1)。在另一实例中,该dsRNA含有与CTATGTCCATGTCATGCCAAA互补的第一链,或其互补链(如,描述于下,实施例2中的siFUT2)。
为促进递送,上述dsRNA或可表达该dsRNA的DNA质体可与一陪伴剂(chaperone agent)复合。在此处使用的“复合”意谓两个体被联结,较佳地具有足够的亲和力,其使因两个体联结而来的治疗效益得以实现。“复合”包括共价或非共价键结以及其它形式的联结,诸如一个体在另一个体表面或内部的陷入(entrapment),或其一或两者在第三个个体(如,微胞)表面或内部的陷入。
陪伴剂可为自然界存在的物质,诸如蛋白质(如,人类血清白蛋白、低密度脂蛋白、或球蛋白)、碳水化合物(如,葡聚糖、普鲁兰多糖、几丁质、几丁聚糖、菊糖、环糊精、或糖醛酸)、或脂质。其也可为重组或合成分子,诸如合成的多氨基酸聚合物(如,聚赖氨酸、聚L-天冬氨酸、聚L-谷氨酸、苯乙烯-马来酸酐共聚物、聚乳酸-甘醇酸共聚物、二乙烯基醚-马来酸酐共聚物、N-(2-羟丙基)甲基丙烯酰胺共聚物、聚乙二醇、聚乙烯醇、聚氨酯、聚乙基丙烯酸、N-异丙基丙烯酰胺聚合物、及聚磷腈。或者,陪伴剂可为微胞、微脂体、纳米微粒、或微球,而dsRNA或DNA质体被封装其中。
在一实例中,陪伴剂作为一或多种膜融合剂、凝聚剂、或靶向剂的附着基质。
膜融合剂对局部pH具有易响应性。例如,当遇到内体内部的pH时,其可引起其立即周围中的物理变化(如,渗透性质的改变,其中断或增进内体膜的通透性),因而促进释放dsRNA或DNA质体至宿主细胞的细胞质中。较佳的膜融合剂可改变带电量,例如,在pH低于生理范围(如,在pH 4.5-6.5)时变为质子化。膜融合剂可为含有当曝露于特定pH范围时可改变带电量(如,质子化)的氨基的分子。该些膜融合剂包括具有多氨基链的聚合物(如,聚乙烯亚胺)以及膜破坏剂(如,蜂毒素)。其它实例包括聚组氨酸、聚咪唑、聚乙烯亚胺、蜂毒素、及聚甲醛物质(如,阳离子聚甲醛)。
凝聚剂与dsRNA或DNA质体相互作用(如,攻击、容纳、或结合)并且引起其凝聚(如,缩小dsRNA/质体的尺寸),因而保护dsRNA/质体对抗降解作用。较佳地,凝聚剂包含一部分(如,一带电部分),其经由,如,离子相互作用力,与dsRNA或DNA质体相互作用。凝聚剂的实例包括聚赖氨酸、精胺、亚精胺、多胺或其四级盐、伪肽-多胺、精氨酸、脒、精蛋白、阳离子脂质、阳离子卟啉、及α螺旋肽。
在无进一步阐述之下,相信本领域技术人员可根据以上说明将本发明运用至其最完全的程度。以下特定实例应被理解为仅是例示说明,而无论如何不以任何方式限制本说明书中的其它部分。所有本文中引用的文献并入本文作为参考资料。
实施例1以KLH-复合的Globo H以及α-GalCer诱发对于Globo H及SSEA3具有特异性的抗体
Globo H-KLH购自于Optimer Pharmaceuticals。三组(一组两只)的6周龄雌BALB/b小鼠(BioLASCO)分别被注射(s.c.)以PBS(“对照小鼠”)、0.6μgKLH-Globo H(“Globo H小鼠”)、以及0.6μg KLH-Globo H与2μg α-GalCer的组合(“Globo H-GalCer小鼠”),每周一次共三周。最后一次注射后10天收集各组小鼠的血清,并依据Huang et al.,Proc.Natl.Acad.Sci.USA 103:15-20(2006)所描述的方法侦测对于Globo H及SSEA3具有特异性的抗体。简言之,血清以3%BSA/PBS缓冲液1∶25稀释,然后50ml的各稀释血清在加湿室中与上黏附有Globo H及SSEA3的玻片共同培养1小时。玻片以0.05%PBS/Tween 20(PBST)清洗三次然后接着在同一室中与100μl的Cy5-复合山羊抗-小鼠IgG抗体(1∶200)共同培养。空气干燥后,玻片以PBST及水各清洗三次,然后以微阵列扫描仪(GenePix 4000B;Molecular Devices)测量从而释放的荧光强度。以GenePix Pro软件分析如此获得的结果。
于Globo H小鼠,仅少量的抗-Globo H IgG抗体被侦测到而抗-SSEA IgG抗体的量则侦测不到。参见图2。不同的是,于Globo H-GalCer小鼠,抗-GloboH IgG及抗-SSEA IgG两种抗体皆大量显现。也参见图2。该些发现指出GloboH-KLH与α-GalCer的组合是一有效诱发抗-Globo H IgG及抗-SSEA IgG此两种抗体的疫苗。
实施例2经由RNA干扰对FUT1及FUT2的抑制可降低Globo H的量
FUT1及FUT2在MCF-7、MB157、及T-47D三种乳癌细胞中的mRNA的量通过定量RT-PCR测定,如下。全RNA从该些癌细胞被提取出来,然后使用该RNA为模板而oligo(dT)为引物经由逆转录产生cDNA。五十纳克的cDNA进行RT-PCR,其使用下列引物:L-futl:CCTGCCAGACTCTGAGTTCC及AGGCTTAGCCAATGTCCAGA以及L-fut2:GGGAGTTACCGGTGCAGATA及R-fut2:GTCCCAGTGCCT TTGATGTT。RT-PCR在以下条件下实行:使用ABI Prism 7000序列侦测系统,50℃经2min,95℃经10min,接着进行40循环的95℃经10sec及60℃经1min,然后使用ABI Prism 7000SDS软件(Applied Biosystems)分析如此获得的结果进而得到FUT1及FUT2在各细胞是中mRNA量的循环数阈值(Ct值)。以同细胞中的HPRT1的mRNA量正常化Ct值以得到ΔCt值。使用FUT1在MCF-7中的ΔCt值来正常化FUT1或FUT2在各细胞是中的ΔCt值。mRNA量的变化倍数根据以下公式计算:2-[Δct(目标基因)-ΔCt(在MCF-7中的FUT1)]。使用HRPT1及GAPDH作为内部对照。
未发现FUT1的mRNA量在三种乳癌细胞之间有显著差异。另一方面,在MCF-7及MB157细胞中,几乎侦测不到FUT2的mRNA,然而在T47D细胞中的FUT2的mRNA量较其它两种细胞高6000倍。
经由RNA干扰降低FUT1及FUT2的量如下。可转译为siFUT1的核苷酸序列(含有与CGCGGACTTGAGAGATCCTTT互补的序列)及可转译为siFUT2的核苷酸序列(含有与CTATGTCCATGTCATGCCAAA互补的序列)被克隆进到VSV-G-伪型慢病毒载体中然后与套装质体pMD.G及PCMVΔR8.91一同引入293T细胞中。在转染48及72小时后收获如此产生的慢病毒微粒并且以超高速离心法(25,000rpm,90分钟)密集的。该些能够表达siFUT1及siFUT2的病毒微粒在8μg/mL凝聚胺(Sigma-Aldrich Corp.)存在下与ThT-47D或MB157(于6孔培养盘植入2x105细胞/孔)共同培养。在96小时后收获细胞然后通过定量RT-PCR测定FUT1及FUT2的mRNA量如上述。
如图3所示,siFUT1成功地降低了在MB157细胞中FUT1的mRNA量(见栏A)。相似地,siFUT1及siFUT2分别降低了FUT1及FUT2在T-47D细胞中的mRNA量。参见图3,栏B。
使用AlexaFluor488-VK-9抗体经由流式细胞计数分析测定在MB 157及T-47D细胞中的Globo H的量,如下。细胞的等分试样(各含1x105细胞)首先与anti-GloboH-Alexa488(Vk9;参见Chang et al.,Proc.Natl.Acad.Sci.USA105:11667-11672(2008))在冰上共同培养1小时,然后与生物素化-UEA1(Vector Laboratories)在冰上共同培养1小时,最后与FITC-复合的链亲和素(Jackson ImmunoResearch)在冰上共同培养1小时。细胞接着使用FACSCanto流式细胞计数器进行流式细胞计数分析,然后通过CellQuest程序(BD Biosciences)分析如此获得的数据。由此研究获得的结果显示,在MB157细胞中经由RNA干扰以抑制FUT1表达造成Globo H的量减少,而经由RNA干扰以抑制FUT2表达造成在T-47D细胞中的Globo H的量减少。
实施例3SiFUT1及SiFUT2的抗癌作用
抑制癌细胞的增长
乳癌细胞MB157及T-47D被植入96孔培养盘(Corning)中,每孔1x104细胞。该些细胞接着与如上实施例2所述可表达siFUT1或siFUT2的病毒微粒混合,或不与其混合,接着以300g离心5min进行旋转感染(spin infection)。24小时后,加入最终浓度为1:10稀释的阿尔玛蓝(alamar blue,AbD Serotec)至细胞,然后细胞在37℃、5%CO2中培养3hr。接着,以SpectraMax M2视读器测量于544nm及590nm的吸收。细胞在同条件下以新鲜培养液培养,在起初植入过程后48、72、及96小时后再次测量于544nm及590nm的吸收。由此研究获得的结果显示,相较于未受感染者,以病毒细胞感染的MB157及T-47D细胞两者的增长率皆降低。以上数据说明通过siRNA抑制FUT1及FUT2的表达造成癌细胞增长的抑制。
抑制乳腺球群细胞的形成
以可表达siFUT1或siFUT2的病毒微粒感染的MB157及T-47D细胞被以1,000细胞/ml的密度悬浮于辅加以0.4%BSA、20ng/ml EGF、20ng/ml bFGF、5ug/ml胰岛素、1M氢化皮质酮(hydrocortisone)、4μg/ml肝素、1x B27辅加物、以及1%甲基纤维素(Sigma-Aldrich)的DMEM/F12培养液中。悬浮的细胞接着植入超低吸附培养盘(Costar)中并且在适合条件下培养以容许乳腺球群细胞的形成。如此形成的初级乳腺球群细胞每周馈料培养。为进行次级乳腺球群细胞培养,收获初级乳腺球群细胞,以胰蛋白酶(Gibco)分散,离心成团粒,以1,000细胞/ml悬浮于上述培养液中。悬浮的细胞接着依据上述方法培养以容许次级乳腺球群细胞的形成。表达siFUT1的MB157及T-47D细胞所形成的乳腺球群细胞数目皆仅为未受感染者的50%,其指出siFUT1显著地降低癌细胞形成乳腺球群细胞的能力。相似地,表达siFUT2的T-47D细胞所形成的乳腺球群细胞数目仅为未受感染者的17%。此结果显示,如同siFUT1,siFUT2也显著地降低癌细胞形成乳腺球群细胞的能力。
降低致癌性
使用六周龄的balb/c裸鼠及NOD/SCID小鼠,于各小鼠的侧边以17-β-estradiol(1.7mg/ml)行皮下注射。于八周龄的雌balb/c裸鼠其乳腺脂肪垫注射(i)稳定表达siFUT的MB157细胞(1x107),(ii)对照载体MB157细胞(1x107),(iii)稳定表达siFUT1的T-47D细胞(5x106),(iv)稳定表达siFUT2的T-47D细胞(5x106),以及(v)对照载体T-47D细胞(5x106),以上皆悬浮于0.1ml的50%Matrigel(BD Biosciences)及50%具辅加的RPMI-1640培养液中。在该些经处理小鼠中形成的肿瘤尺寸于各个时间点通过测量其长(l)及宽(w)定期追踪。肿瘤体积计算如下:V=π/6×l×w×[l+w]/2。动物最终被牺牲后切下肿瘤并秤重。
如图4栏a所示,以对照载体处理的小鼠其肿瘤随时间持续增长,然而在以可表达siFUT1或siFUT2的细胞处理的小鼠中,肿瘤增长率被显著地降低。该些小鼠的肿瘤块重量也显著地低于以对照载体处理。参见图4栏b。
改变细胞形态及黏着能力
虽然一般的T-47D细胞为似正方形,表达siFUT1及siFUT2的T-47D细胞为小的圆形细胞并形成密集群集。在表达siFUT1的MB-157细胞观察到类似的形态变化。
使用RT-CES仪测定细胞黏着。简言之,ACEA’s 96微量盘以纤维连接蛋白(25μg/ml,Sigma),IV型胶原蛋白(2μg/ml,BD Biosciences),或层粘连蛋白(5μg/ml,Sigma)(以上皆以PBS稀释适当倍数)于37℃涂布1hr然后于37℃以1%BSA阻断1hr。MB157及T-47D细胞以2.5x 104每100μl培养液植入经涂布的ACEA’s 96微量盘。使用RT-CES在1小时内每10min追踪细胞黏着。加入Globo H神经酰胺(50μg/ml于无血清培养液中)至某些细胞以检验其是否抵消siFUT1及siFUT2的作用。结果指出,相较于不表达任一siRNA的细胞以及以Globo H神经酰胺挽回siRNA造成的黏着抑制,siFUT1及siFUT2降低癌细胞对于聚苯乙烯的细胞黏着0.63倍。
抑制细胞迁移
表达siFUT1及siFUT2的细胞的迁移能力在伤口愈合分析中被首次检验,如下。MB157及T-47D细胞以含血清培养液培养于12孔培养盘直到其生长达到60%满。细胞接着以述于上实施例1中的病毒微粒感染或引入一对照质体。该些细胞在2天的培养期间内达到100%满。接着细胞进行一夜的饥饿处理,然后以20μl塑料吸头锐利地创伤汇合的单层细胞。以辅加以血清的RPMI培养液清洗后,细胞被培养于RPMI培养液中然后使用可控制温度及CO2的时差显微镜检验的。每4h共3天或每2h共1天获取细胞的相差(phase-contrast)影像。细胞迁移的速率使用Metamorph软件决定,其测量细胞在一欲知时间内移动的距离。结果指出,相较于以对照质体转染的细胞,siFUT1抑制T47-D及MB158细胞的迁移各为2.81及2.13倍。外源性加入的Globo H神经酰胺可挽回表达siFUT1及siFUT2的细胞其降低的迁移能力。此资料指出所观察的迁移降低是因经由RNA干扰抑制FUT1及FUT2表达而使Globo H的量降低而造成。
综而言之,以上结果说明,通过抑制FUT1及FUT2表达并且因此降低Globo H的量,siFUT1及siFUT2在癌症治疗中是有效的。
其它实施例
可依任何的组合结合此专利说明书中所公开的全部特性。此专利说明书中所公开的每一特性可被用于相同、等效或类似目的的另类特性所取代。因此,除非另有说明,否则公开的每一种特性仅为一系列普通等效或类似特性的实施例。
从上述的描述,所属技术领域的技术人员可容易地确认本发明的必要特征,并可对本发明作出各种的改变和修饰以适应各种的用途和状况而不偏离其精神和范围。因此,其它实施例也在权利要求范围的中。
Claims (23)
1.一种免疫组合物,其包括聚糖及α-半乳糖苷基-神经酰胺,其中该聚糖为Globo H或其片段。
2.根据权利要求1所述的免疫组合物,其特征在于,该聚糖为Globo H。
3.根据权利要求1所述的免疫组合物,其特征在于,该聚糖为SSEA3。
4.根据权利要求1所述的免疫组合物,其特征在于,该聚糖或其片段与匙孔戚血蓝蛋白复合。
5.一种免疫组合物,其包括SSEA3及佐剂。
6.一种治疗癌症的方法,其包括对需要其的对象给予一有效量的根据权利要求1所述的免疫组合物。
7.根据权利要求6所述的方法,其特征在于,该癌症选自由乳癌、前列腺癌、卵巢癌、以及肺癌所组成的组。
8.根据权利要求7所述的方法,其特征在于,该癌症为乳癌。
9.根据权利要求6所述的方法,其特征在于,该聚糖为Globo H且该免疫组合物诱发对抗Globo H的免疫反应。
10.根据权利要求6所述的方法,其特征在于,该聚糖为SSEA3且该免疫组合物诱发对抗SSEA3的免疫反应。
11.一种治疗癌症的方法,其包括对需要其的对象给予一有效量的根据权利要求5所述的免疫组合物。
12.根据权利要求11所述的方法,其特征在于,该癌症选自由乳癌、肺癌、肝癌、口腔癌、胃癌、结肠癌、鼻咽癌、皮肤癌、肾癌、脑瘤、前列腺癌、卵巢癌、子宫颈癌、以及膀胱癌所组成的组。
13.根据权利要求12所述的方法,其特征在于,该癌症为乳癌。
14.一种生产对于Globo H或其片段具有特异的抗体的方法,其包括对一非人类哺乳动物给予有效量的包含Globo H或其片段的组合物及α-半乳糖苷基-神经酰胺以诱发可结合Globo H或其片段的抗体的产生,并分离出该抗体。
15.根据权利要求14所述的方法,其特征在于,该组合物包含Globo H。
16.根据权利要求14所述的方法,其特征在于,该组合物包含SSEA3。
17.一种治疗癌症的方法,其包括对需要其的对象给予一有效量的可抑制2-岩藻糖基转移酶1(FUT1)或2-岩藻糖基转移酶2(FUT2)活性的第一剂,其中该剂为可阻碍FUT1或FUT2与其底物间交互作用的抗体或抑制FUT1或FUT2表达的干扰RNA。
18.根据权利要求17所述的方法,其特征在于,该第一剂为小干扰RNA(siRNA)。
19.根据权利要求18所述的方法,其特征在于,该siRNA为siFUT1或siFUT2。
20.根据权利要求17所述的方法,其特征在于,该第一剂可抑制FUT1活性并且进一步给予该对象有效量的可抑制FUT2活性的第二剂,该第二剂为可阻碍FUT2与其底物间交互作用的抗体或抑制FUT2表达的干扰RNA。
21.根据权利要求20所述的方法,其特征在于,该第一及第二剂为siRNA。
22.根据权利要求21所述的方法,其特征在于,该第一及第二剂分别为siFUT1及siFUT2。
23.根据权利要求17所述的方法,其特征在于,该癌症为乳癌。
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US20090317411A1 (en) | 2009-12-24 |
CA2728344A1 (en) | 2010-01-14 |
JP2014144958A (ja) | 2014-08-14 |
AU2009269127B2 (en) | 2013-12-05 |
WO2010005598A1 (en) | 2010-01-14 |
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AU2009268937A1 (en) | 2010-01-14 |
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JP6151319B2 (ja) | 2017-06-21 |
US9603913B2 (en) | 2017-03-28 |
JP2016020363A (ja) | 2016-02-04 |
CA2728341C (en) | 2019-07-02 |
JP5795655B2 (ja) | 2015-10-14 |
WO2010005735A3 (en) | 2010-03-18 |
EP2303286A4 (en) | 2011-12-28 |
US8268969B2 (en) | 2012-09-18 |
US20150273034A1 (en) | 2015-10-01 |
US20100136042A1 (en) | 2010-06-03 |
CA2728341A1 (en) | 2010-01-14 |
JP2011524375A (ja) | 2011-09-01 |
MX2010013932A (es) | 2013-03-01 |
US9028836B2 (en) | 2015-05-12 |
KR20110031949A (ko) | 2011-03-29 |
AU2009269127A1 (en) | 2010-01-14 |
EP2303286A2 (en) | 2011-04-06 |
EP2310047A1 (en) | 2011-04-20 |
NZ590140A (en) | 2012-07-27 |
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