CN110041403B - 针对多种肿瘤例如包括nsclc在内的肺癌的新型免疫疗法 - Google Patents
针对多种肿瘤例如包括nsclc在内的肺癌的新型免疫疗法 Download PDFInfo
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Abstract
本发明涉及用于免疫治疗方法的肽、核酸和细胞。特别是,本发明涉及癌症的免疫疗法。本发明还涉及单独使用或与其他肿瘤相关肽(能够例如作为刺激抗肿瘤免疫反应或体外刺激T细胞并转入患者的疫苗组合物的活性药物成分)联合使用的肿瘤相关T细胞(CTL)肽表位。
Description
本申请是2014年8月4日提交的申请号为CN201480035925.8、发明名称为“用于治疗多种肿瘤(例如包括NSCLC在内的肺癌)的新型免疫疗法”的中国申请的分案。
技术领域
本发明涉及用于免疫治疗方法的肽、核酸和细胞。特别是,本发明涉及癌症的免疫疗法。本发明还涉及单独使用或与其他肿瘤相关肽(作为刺激抗肿瘤免疫反应的疫苗复合物的活性药物成分)联合使用的肿瘤相关T细胞(CTL)肽表位。本发明涉及67种新型肽序列及其变体,它们得自人肿瘤细胞的HLA-I和HLA-II类分子,可用在引发抗肿瘤免疫反应的疫苗组合物中。
背景技术
无论男女,肺癌均为癌症相关死亡的第一诱因。无论就发病率还是死亡率而言,肺癌均是全球最常见的癌症。2008年新增161万肺癌病例以及138万肺癌死亡病例,其中欧洲与北美的比率最高。
自1987年以来,每年死于肺癌的女性人数均高于死于乳腺癌的人数。1991年至2003年,男性死亡率持续显著下降,每年下降约1.9%。女性肺癌死亡率在连续增长数十年后正趋于平稳。以上肺癌死亡率的趋势反映了过去30年中吸烟率的降低。
据美国国立癌症研究所(NCI)数据,预计美国2013年将有约23万新增肺癌病例以及16万肺癌死亡病例。
为便于治疗,肺癌可临床分类为小细胞癌(13%,SCLC)或非小细胞癌(87%,NSCLC),其预后通常不良。在所有肺癌患者中,15%可在确诊后存活5年。确诊时通常已为晚期。出现病情时30-40%的NSCLC病例为IV期,60%的SCLC病例为IV期。
根据肿瘤的类型(小细胞或非小细胞)和期别选择治疗方案,包括手术、放疗、化疗以及靶向生物疗法,例如贝伐单抗和厄洛替尼对于局限性癌灶,通常选择外科手术治疗。最近的研究表明,手术后化疗改善了早期非小细胞肺癌的生存。由于该肿瘤发现时通常已扩散,因此常使用放疗与化疗,有时与手术联合使用。单一化疗或与放疗联合使用是小细胞肺癌的首选疗法;采用此治疗方案的患者有很大一部分出现缓解,某些患者甚至达到长期缓解。
肺癌的1年生存率略有升高,从1975-1979年的37%升至2002年的42%,这主要归因于手术技术与联合疗法的进步。但所有期别的肺癌一起5年生存率仅为16%。发现时为局限性肿瘤的患者,其生存率为49%;但仅有16%的肺癌可在此早期得到确诊。
尽管如此,仍亟需安全有效的新疗法治疗肺癌,特别是不同表型的非小细胞肺癌(NSCLC)、胃癌和脑癌,以在改善患者的健康状况的同时不过度使用化疗药物或其它可导致严重副作用的药物。
本发明使用可刺激患者免疫系统且以非侵入性方式作为抗肿瘤药物的肽。
发明内容
首先,本发明涉及一种肽或其药用盐,包含选自SEQ ID NO:1至SEQ ID NO:65、SEQID NO:76至SEQ ID NO:84、以及SEQ ID NO:92的氨基酸序列,或与SEQ ID NO:1至SEQ IDNO:65、SEQ ID NO:76至SEQ ID NO:84、以及SEQ ID NO:92具有至少80%、优选至少90%同源(优选至少80%或至少90%相同)的变体序列,其中变体诱导T细胞与所述肽发生交叉反应,其中所述肽不是全长多肽。
本发明进一步涉及本发明的肽,包含选自SEQ ID NO:1至SEQ ID NO:65、SEQ IDNO:76至SEQ ID NO:84、以及SEQ ID NO:92的序列,或与SEQ ID NO:1至SEQ ID NO:65、SEQID NO:76至SEQ ID NO:84、以及SEQ ID NO:92具有至少80%、优选至少90%同源(优选至少80%或至少90%相同)的变体序列,其中对于SEQ ID No:1至SEQ ID No:65、SEQ ID No:78至SEQ ID No:84和SEQ ID No:92而言,所述肽或其变体的总长度为8至100个、优选为8至30个、最优选为8至14个氨基酸;对于SEQ ID No:76和77,所述肽或其变体的总长度为12至100个、优选为12至30个、最优选为12至18个氨基酸。
下表为本发明所涉肽及其相应SEQ ID NO,以及此类肽的预期源蛋白。表1a、1b和1c中的所有肽均可与HLA A*02等位基因结合,表1d中的肽可与HLA-DR等位基因结合。表1c中的肽还可用于胃癌和/或成胶质细胞瘤的诊断和/或治疗。
表1d中的II类肽还可用于胃癌和其它过量表达或过量呈递MMP12或POSTN的癌症的诊断和/或治疗。
因此,本发明特别地涉及含有SEQ ID No.76的本发明的肽或其变体,该变体与SEQID No:76至少80%同源、优选为90%同源(优选为至少80%相同或至少90%相同),其中上述肽或其变体的总长度为12至100个氨基酸,优选为12至30个,最优选为12至18个氨基酸。本发明特别涉及由SEQ ID No:76序列组成的本发明肽。
同时,本发明特别地涉及含有SEQ ID No.77的本发明的肽或其变体,该变体与SEQID No:77至少80%同源、优选为90%同源(优选为至少80%相同或至少90%相同),其中上述肽或其变体的总长度为12至100个氨基酸,优选为12至30个,最优选为12至18个氨基酸。本发明特别涉及由SEQ ID No:77序列组成的本发明肽。
表1a:本发明的肽
表1b:本发明的其他肽
SEQ ID NO: | 肽代码 | 序列 | 源蛋白 |
49 | SAMSN1-001 | RLLJAAENFL | SAMSN1 |
50 | STAT2-001 | SLLPVDIRQYL | STAT2 |
51 | CNOT1-001 | YLAPFLRNV | CNOT1 |
52 | SHMT2-001 | ALLERGYSL | SHMT2 |
53 | JUNB-001 | YLPHAPPFA | JUNB |
54 | TACC3-001 | KLVEFDFLGA | TACC3 |
55 | CNOT1-002 | SLADFMQEV | CNOT1 |
56 | RAD54B-001 | SLYKGLLSV | RAD54B |
57 | EEF2-002 | GLAEDIDKGEV | EEF2 |
58 | CCNA2-001 | SLIDADPYL | CCNA2 |
59 | NET1-001 | ILVSWLPRL | NET1 |
60 | C11orf24-001 | VVDKTLLLV | C11orf24 |
61 | RCC1-001 | TLISRLPAV | RCC1 |
62 | MAGEF1-001 | ILFPDIIARA | MAGEF1 |
63 | NCAPD2-001 | SLAGDVALQQL | NCAPD2 |
64 | C12orf44-001 | AMLAVLHTV | C12orf44 |
65 | HERC4-001 | KVLEILHRV | HERC4 |
表1c:成胶质细胞瘤和/或胃癌中亦有过量表达的其他肽
SEQ ID NO: | 肽代码 | 序列 | 源蛋白 |
66 | IGF2BP3-001 | KIQEILTQV | IGF2BP3 |
67 | CDC6-001 | ILQDRLNQV | CDC6 |
68 | FAP-003 | YVYQNNIYL | FAP |
69 | WNT5A-001 | AMSSKFFLV | WNT5A |
70 | TPX2-001 | KILEDVVGV | TPX2 |
71 | HMMR-001 | KLLEYIEEI | HMMR |
72 | ADAM8-001 | KLLTEVHAA | ADAM8 |
73 | COL6A3-002 | FLLDGSANV | COL6A3 |
74 | THY1-001 | SLLAQNTSWLL | THY1 |
75 | DIO2-001 | ALYDSVILL | DIO2 |
表1d:本发明的MHC II类肽
SEQ ID NO: | 肽代码 | 序列 | 源蛋白 |
76 | MMP12-002 | INNYTPDMNREDVDYAIR | MMP12 |
77 | POSTN-002 | TNGVIHVVDKLLYPADT | POSTN |
表1e:在其他肿瘤中过度表达的其他本发明优选肽
SEQ ID NO: | 肽代码 | 序列 | 源蛋白 |
78 | SLI-001 | SLYDNQITTV | SLIT1,SLIT2 |
79 | TLX3-001 | SLAPAGVIRV | TLX3 |
80 | CEP192-001 | SLFGNSGILENV | CEP192 |
81 | ANKS1A-001 | ALYGRLEVV | ANKS1A |
82 | CEP250-002 | ALWEKNTHL | CEP250 |
83 | MDN1-001 | ALANQKLYSV | MDN1 |
84 | OLFM1-001 | ILMGTELTQV | OLFM1 |
92 | NEFH-001 | HLLEDIAHV | NEFH |
表1f:在其他肿瘤中过度表达的其他本发明的肽
SEQ ID NO: | 肽代码 | 序列 | 源蛋白 |
85 | BUB1B-001 | KIVDFSYSV | BUB1B |
86 | PI4KA-001 | AMATESILHFA | PI4KA |
87 | AURKB-001 | RVLPPSALQSV | AURKB |
88 | SLC3A2-001 | SLLESNKDLLL | SLC3A2 |
89 | IFT81-001 | ALASVIKEL | IFT81 |
90 | COG4-001 | SLVAVELEKV | COG4 |
91 | NCBP1-001 | AMFENFVSV | NCBP1 |
本发明还涉及本发明的肽,其具有与人主要组织兼容性复合体(MHC)I或II类分子结合的能力。
本发明还涉及本发明中的肽,其中所述肽由或基本由根据SEQ ID NO:1至SEQ IDNO:65、SEQ ID NO:76至SEQ ID NO:84、以及SEQ ID NO:92的氨基酸序列组成。
本发明还涉及本发明的肽,其中所述肽被修饰和/或包含非肽键。
本发明还涉及本发明的肽,其中所述肽为融合蛋白的一部分,特别是与HLA-DR抗原相关不变链(Ii)的N-端氨基酸融合,或与抗体(例如,树突状细胞特定抗体)融合,或融合到抗体的序列中。
本发明还涉及编码本发明肽的核酸。
本发明还涉及本发明的核酸,其为DNA、cDNA、PNA、RNA或其组合。
本发明还涉及一种能表达本发明核酸的表达载体。
本发明还涉及本发明的肽、本发明的核酸或本发明的表达载体在药物中的用途。
本发明还涉及本发明中的抗体、以及制备这些抗体的方法。
本发明还涉及本发明的T细胞受体(TCR),特别是可溶性TCR(sTCR),以及制造这些TCR的方法。
本发明还涉及含本发明核酸或前述表达载体的宿主细胞。
本发明还涉及本发明的宿主细胞,其为抗原提呈细胞。
本发明还涉及本发明的宿主细胞,其中抗体提呈细胞为树突细胞。
本发明还涉及制备本发明肽的方法,所述方法包括培养本发明的宿主细胞,以及从所述宿主细胞或其培养基中分离肽。
本发明还涉及体外制备激活的细胞毒性T细胞(CTL)的方法,该方法包括使CTL与表达在合适的抗原提呈细胞表面且加载有抗原的人MHC-I或II类分子在体外接触一段时间,该时间足以以抗原特异性方式激活该CTL,其中该抗原是本发明的任一肽。
本发明还涉及本发明中的方法,其中通过使足量的抗原与抗原提呈细胞接触,使抗原加载在表达于合适抗原提呈细胞表面的I或II类MHC分子上。
本发明还涉及本发明的方法,其中抗原提呈细胞包含能表达含SEQ ID NO:1至SEQID NO:92,优选为含SEQ ID NO:1至SEQ ID No:65和SEQ ID NO:76至SEQ ID No:84以及SEQID NO:92或其变体氨基酸序列的肽的表达载体。
本发明还涉及以本发明方法制造的激活的细胞毒性T细胞(CTL),其有选择性地识别一种细胞,该细胞异常地表达含本发明氨基酸序列的多肽。
本发明还涉及一种杀伤患者靶细胞的方法,其中靶细胞异常地表达含本发明任意氨基酸序列的多肽,该方法包括对患者施用本发明的有效量的细胞毒性T细胞(CTL)。
本发明还涉及任何所述肽、本发明的核酸、本发明的表达载体、本发明的细胞、本发明的激活的细胞毒性T淋巴细胞作为药物或在药物制备中的用途。
本发明还涉及本发明的用途,其中所述药物为疫苗。
本发明还涉及本发明的用途,其中所述药物有效抗癌。
本发明还还涉及本发明中的用途,其中所述癌细胞为肺癌、胃癌、胃肠癌、结直肠癌、胰腺癌或肾癌细胞,优选胶质细胞瘤细胞。
本发明进一步涉及一种基于本发明肽的特定标记物蛋白和生物标志物,其可用于肺癌、胃癌、胃肠癌、结直肠癌、胰腺癌或肾癌、以及胶质细胞瘤的诊断和/或预后。
此外,本发明涉及这些新靶点在癌症治疗中的用途。
具体实施方式
是否能刺激免疫反应取决于是否存在被宿主免疫系统视为异物的抗原。发现肿瘤相关抗原的存在增加了运用宿主免疫系统干预肿瘤生长的可能性。目前,针对癌症免疫治疗,正在探索利用免疫系统的体液和细胞进行免疫的各种机制。
细胞免疫反应的特定元素能特异性地识别和破坏肿瘤细胞。从肿瘤浸润细胞群或外周血中分离出的细胞毒性T细胞表明,这些细胞在癌症的天然免疫防御中发挥了重要作用。特别是CD8阳性T细胞在这种反应中发挥重要作用,CD8+T细胞识别携带有通常为8至10个氨基酸残基的源自蛋白或缺陷核糖体产物(DRIP)的肽的主要组织兼容性复合体(MHC)-I类分子。人MHC分子也称为人白细胞-抗原(HLA)。
MHC分子分为两类:MHC I类分子存在于多数带核细胞中。MHC分子包含一条α重链和一个β-2微球蛋白(MHC I类受体)或α和β重链各一条(MHC II类受体)。其三维构象形成一个结合槽,供与肽进行非共价相互作用。I类MHC所呈递的肽多源于主要内源蛋白、DRIP和较大肽的溶蛋白性裂解。MHC II类分子多见于专业性抗原呈递细胞(APC),其所呈递的肽多源于由APC在细胞内吞中所摄取的外源性或跨膜蛋白。肽与MHC I类分子的复合物可由负载适当的TCR(T细胞受体)的CD8阳性细胞毒性T细胞所识别,而肽与MHC II类分子的复合物可由负载适当的TCR的CD4阳性辅助T细胞所识别。本领域已熟知,TCR、肽与MHC由此按1:1:1的化学计算量比存在。
CD4阳性辅助T细胞对于引发和维持CD8阳性细胞毒性T细胞的有效应答起到重要作用。鉴别源于肿瘤相关性抗原(TAA)的CD4阳性T细胞表型对激发抗肿瘤免疫应答的药品之开发有重要意义(Kobayashi et al.,2002;Qin et al.,2003;Gnjatic et al.,2003)。在肿瘤部位,辅助T细胞可提供亲CTL的细胞因子环境(Mortara et al.,2006)并吸引效应细胞,例如CTL、自然杀伤细胞、巨噬细胞、粒细胞(Hwang et al.,2007)。
在炎症环境中,MHC II类分子的表达主要限于免疫系统细胞,特别是专业性抗原呈递细胞(APC),例如单核细胞、单核细胞衍生的细胞、巨噬细胞和树突细胞。在癌症患者中,意外发现肿瘤细胞可表达MHC II类分子(Dengjel et al.,2006)。
哺乳动物模型(如小鼠)试验显示,即使不存在CTL效应细胞(例如CD8阳性T淋巴细胞),CD4阳性T细胞仍足以通过抑制干扰素γ(IFNγ)分泌所导致的血管生成来抑制肿瘤表现。
此外,研究显示,可识别源自肿瘤相关性抗原(由HLA II类分子呈递)的肽的CD4阳性T细胞可通过引发抗体(Ab)应答来阻止肿瘤进展。
不同于与HLA I类分子相结合的肿瘤相关性肽,迄今仅报告了少数肿瘤相关性抗原(TAA)的II类配体。
由于HLA II类分子的组成型表达通常限于免疫系统细胞,因此认为无法直接从原发肿瘤中分离II类肽。但Dengjel等人成功地从肿瘤中直接识别出若干MHC II类表型(WO2007/028574,EP 1760088B1;(Dengjel et al.,2006))。
由肿瘤特异性细胞毒性T淋巴细胞所识别的抗原(即其表型)可以是源自各类蛋白(例如酶、受体、转录因子等)的分子,此类分子在相应的肿瘤细胞中存在表达和上调(相比于同源的未变化细胞)。
由于两种类型的应答(分别为CD8和CD4依赖型)可共同产生协同抗肿瘤作用,因此肿瘤相关性抗原(通过CD8+CTL(配体:MHC I类分子+多肽表型)或CD4阳性辅助T细胞(配体MHC II类分子+多肽表型)来识别)的鉴别和表征对于抗肿瘤疫苗的开发有重要意义。
本发明另涉及两种非常有用的新型MHC II类肽(对应于SEQ ID NO 76和77)。这两种肽对于胃癌、NSCLC和其它分别过量表达和/或过量呈递MMP12和POSTN的癌症之诊断和/治疗尤为有用。
本发明另涉及新型MHC II类肽的所谓长度变异体(对应于SEQ ID NO 76或77)。如上文所述,对应于SEQ ID NO 76的肽含有氨基酸序列INNYTPDMNREDVDYAIR(MMP12-肽),对应于SEQ ID NO 77的肽含有氨基酸序列TNGVIHVVDKLLYPADT(POSTN-002-肽)。变异体的长度通常为N和/或C末端延伸(1至5个氨基酸,优选为1至10个氨基酸)或N和/或C末端缩短(1至5个氨基酸),这些变异体仍可与MHC相结合并引发本文所述的细胞性免疫应答。目前已知肽与II类蛋白的结合不受限于大小,长度为11至30个氨基酸不等。MHC II类分子中的肽结合槽在两端均敞开,由此可结合相对较长的肽。虽然“核心”的9个残基长的一段对识别肽最重要,而侧翼区对肽的II类等位基因的特异性有重要作用(参见Meydan C,et al.,Prediction of peptides binding to MHC class I and II alleles by temporalmotifmining.BMC Bioinformatics.2013;14Suppl 2:S13.Epub 2013Jan 21)。使用现有的诸多软件工具(如上文所述工具),具备当前技术水平的人员可确定结合基序,并由此确定MHC II类肽是否能够出现相对于SEQ ID NO 76或77的延伸和/或缺失,以此产生长度变异体。
肽须与一种MHC分子相结合方可触发(引发)细胞系免疫应答。该过程取决于该MHC分子的等位基因以及该肽氨基酸序列的特定多态性。MHC I类结合肽的长度通常为8-12个氨基酸残基,其序列中通常包含2个保守残基(“锚位点”),可与相应MHC分子的结合槽相反应。由此每个MHC等位基因均包含一个“结合基序”,此基序可决定何种肽可与结合槽特异性结合。
在MHC I类依赖型免疫反应中,肽不仅须与特定的由肿瘤细胞表达的MHC I类分子相结合,而且须被负载特异性T细胞受体(TCR)的T细胞所识别。
由肿瘤特异性细胞毒性T淋巴细胞所识别的抗原(即其表型)可以是源自各类蛋白(例如酶、受体、转录因子等)的分子,此类分子在相应的肿瘤细胞中存在表达,并且与同源未变的细胞相比,其表达上调。
目前的肿瘤相关性抗原主要分为以下几组:
a)肿瘤-睪丸抗原:第一个发现可被T细胞识别的TAA即属于此类别。最初称其为肿瘤-睪丸(CT)抗原是因为该组成员在具有组织学差异的人体肿瘤中存在表达,而在正常组织中的表达仅限于睪丸精母细胞/精原细胞以及(少数情况下)胎盘。由于睪丸细胞不表达I类和II类HLA分子,此类抗原无法在正常组织中被T细胞识别,因此可认为具有免疫学肿瘤特异性。较为知名的CT抗体包括MAGE家族成员和NY-ESO-1。
b)分化抗原:此类抗原在肿瘤以及产生肿瘤的正常组织中均存在,最常见于黑素瘤和正常黑素细胞。有许多此类黑素细胞谱系相关性蛋白参与黑色素的生物合成,因此不具肿瘤特异性,但广泛用于肿瘤免疫治疗。实例包括但不限于络氨酸酶、Melan-A/MART-1(针对黑素瘤)和PSA(针对前列腺癌)。
c)过量表达的TAA:已在具有组织学差异的多种肿瘤以及许多正常组织中发现了编码广泛表达的TAA之基因,通常为低表达水平。有可能许多由正常组织加工并可能由正常组织呈递的表型低于T细胞识别阈水平,但这些表型在肿瘤细胞中的过量表达可通过打破之前建立的耐受性而触发抗肿瘤应答。该TAA类别中的知名抗原包括Her-2/neu、生存素、端区酶和WT1。
d)肿瘤特异性抗原:此类独特的TAA产生于正常基因(例如β-连环蛋白、CDK4等)的突变。此类分子变化中有一部分与瘤性转化和/进展相关。肿瘤特异性抗原通常可引发较强的免疫应答,且没有对正常组织的自免疫反应这一风险。从另一方面讲,此类TAA在多数情况下仅与发现此类TAA的特定肿瘤有关,且不同时存在于多种肿瘤。
e)异常翻译后修饰所产生的TAA:此类TAA可产生于在肿瘤中非特异性亦非过量表达的蛋白,但可通过主要活跃于肿瘤的翻译后加工过程而成为肿瘤相关性抗原。实例有:该类抗原产生于糖基化方式的改变,由此引发肿瘤中的新表型(例如MUCI)或降解过程中的蛋白质剪接等事件,可能具有肿瘤特异性,也可能不具有。
f)肿瘤病毒蛋白:此类TAA为病毒蛋白,可在肿瘤发生过程中起到关键作用,且由于其为外源性(非人源)蛋白,因此可引起T细胞应答。此类蛋白包括人乳头瘤16型病毒蛋白、E6和E7(表达于宫颈癌中)。
蛋白被细胞毒性T淋巴细胞识别为肿瘤特异性或相关性抗原并用于治疗需满足特定的前提条件。该抗原需主要由肿瘤细胞表达,且在正常健康组织中无表达或表达量相当小,或该肽在另一优选的实施方案中需由肿瘤细胞过量呈递(相比于正常健康组织)。若相关抗原不仅存在于某一肿瘤类型,而且含量较高,则更为理想。肿瘤特异性和肿瘤相关性抗原通常源自直接参与正常细胞转化为肿瘤细胞这一过程(通过细胞周期控制、雕亡抑制等功能)的蛋白。此外,直接引发转化的蛋白之下游目标可能因上调而间接具有肿瘤相关性。此类间接肿瘤相关性抗原也可作为接种免疫的目标(Singh-Jasuja et al.,2004)。两种情况下均须有表型存在于抗原的氨基酸序列,原因是此类源自肿瘤相关性抗原的肽(“免疫原性肽”)应能引发体外或体内T细胞应答。
基本上所有可与MHC分子结合的肽均可作为T细胞表型。引发体外或体内T细胞应答的前提条件是具有相应TCR的T细胞以及不存在对这一特定表型的免疫耐受。
综上所述,TAA是肿瘤疫苗开发的起始点。TAA的鉴别与表征方法基于(从患者或健康受试者分离的)CTL的使用,或基于肿瘤与正常组织间的分化转录谱或分化肽表达谱。
然而仅鉴别在肿瘤组织或人肿瘤细胞系中过量表达(或在此组织或细胞系中选择性表达)的基因不能为从此类基因转录的抗原用作免疫疗法提供准确的信息。其原因是:须存在具有相应TCR的T细胞,且对于此特定表型的免疫耐受须不存在或极小,导致此类基因仅有个别表型亚群适用于此用途。因此,在本发明的实施方案中,所选用的过量呈递或选择性呈递的肽须存在相应的功能性和/或增生性T细胞。该功能性T细胞定义为经特异性抗原刺激,可克隆性地扩张并产生效应功能的T细胞(“效应T细胞”)。
若为根据本发明所述的TCR和抗体,则基本肽的免疫原性为继发性。就根据本发明所述的TCR和抗体而言,其呈递为决定因素。
辅助T细胞对于CTL在抗肿瘤免疫中发挥效应功能有重要作用。可触发TH1型辅助T细胞应答的辅助T细胞表型可支持CD8阳性杀伤T细胞的效应功能。CD8阳性杀伤T细胞的细胞毒性功能直接作用于呈现肿瘤相关性肽/MHC复合物的肿瘤细胞。由此,肿瘤相关性辅助T细胞肽表型(单用或与其它肿瘤相关性肽联合使用)可作为疫苗组合物中的活性药物成分刺激抗肿瘤免疫应答。
下文披露了根据本发明所述的肽的蛋白在其它癌症中的应用。
NEFH(神经丝重链多肽)
编码神经丝重链的NEFH是神经元细胞骨架神经丝的主要组分之一。神经丝重链多肽(NEFH,200kD)基因位于染色体带22q12.2,被认为是2型多发性神经纤维瘤(NF2)家族症状发生前的DNA标记物之一。NEFH的缺失或下调多报告于人自主神经瘤或中枢神经细胞瘤中(Mena et al.,2001;Segal et al.,1994)。此外,在人前列腺癌(Schleicher et al.,1997)、透明细胞上皮样瘤(Tanaka et al.,2000)和小细胞肺癌(Bobos et al.,2006)中观察到NEFH表达的缺失或减少。值得注意的是,NEFH的过量表达可破坏正常细胞结
除非另有说明外,本文所使用的所有术语定义如下:
本文所用的“肽”这一术语系指一系列的氨基酸残基,彼此之间通常通过邻近氨基酸的α氨基酸与羰基间的肽键相连接。肽的长度优选为9个氨基酸,但也可以短至8个氨基酸,长至10、11、12、13或14个氨基酸,而MHC II类肽可长至15、16、17、18、19或20个氨基酸。
此外,“肽”这一术语应包括一系列氨基酸残基的盐类,彼此之间通常通过邻近氨基酸的α氨基酸与羰基间的肽键相连接。此盐类优选为药用盐。
“肽”这一术语应包括“寡肽”。本文所用的“寡肽”这一术语系指一系列的氨基酸残基,彼此之间通常通过邻近氨基酸的α氨基酸与羰基间的肽键相连接。只要寡肽能维持正确的表型,其长度对于本发明并非关键。寡肽通常少于约30个氨基酸残基,多余约15个氨基酸。
“本发明的肽”这一术语包括由SEQ ID No.1至SEQ ID No.92组成的肽或包含SEQID No.1至SEQ ID No.92的肽。
“多肽”这一术语系指一系列的氨基酸残基,彼此之间通常通过邻近氨基酸的α氨基酸与羰基间的肽键相连接。只要多肽能维持正确的表型,其长度对于本发明并非关键。与“肽”或“寡肽”相对,多肽这一术语系指包含多余约30个氨基酸残基的分子。
若一种肽、寡肽、蛋白或多聚核苷酸所编码的分子可引发免疫应答,则此肽、寡肽、蛋白或多聚核苷酸具有“免疫原性”(由此是本发明范围内的“免疫原”)。在本发明的情况下,免疫原性更具体定义为可诱导T细胞应答。因此“免疫原”是可诱导免疫应答的分子(具体到本发明则为可诱导T细胞应答的分子)。另一方面,免疫原可为一种肽、肽与MHC的复合物、寡肽和/或蛋白,用于产生其特异性抗体或TCR。
I类T细胞“表型”系指与I类MHC受体相结合的短肽,由此形成一个三元络合物(MHCI类α链、β-2-微球蛋白和肽),可由T细胞(携带与具有适当亲合力的MHC/肽复合物结合的相应T细胞受体)所识别。与MHC I类分子相结合的肽长度通常为8-14个氨基酸,以9个氨基酸最为常见。
人体中有3个不同的基因位点可编码MHC I类分子(人MHC-分子亦称人真核细胞抗原(HLA):HLA-A、HLA-B和HLA-C。HLA-A*01、HLA-A*02和HLA-B*07代表可从此位点表达的不同MHC I类等位基因。
表2:HLA*A02和最常见HLA-DR血清型的表达频率(F)。
依据Mori等人的方法,频率的推算基于美国人群中的单倍体频率Gf(Mori etal.,1997),该方法使用Hardy-Weinberg公式F=1-(1-Gf)2。由于连锁不平衡,A*02与某些HLA-DR等位基因组合后可能引起其各自单独频率的升高或降低。详情请参见Chanock等人的文献(Chanock et al.,2004)。
因此,出于治疗和诊断目的,能以适当的亲合力与多种不同的HLA II类受体相结合的肽是非常理想的。与数种不同的HLA II类分子结合的肽被称为混杂结合剂。
本文中对DNA序列的引用同时包括单链和多链DNA。因此除文中特别说明外,特定的序列均指该序列的单链DNA、此序列与其互补序列的双链体(双链DNA)以及此序列的互补序列。“编码区”这一术语系指可在自然基因组环境中自然或正常编码某基因表达产物的该基因组分,例如可在体外编码该基因天然表达产物的区域。
编码区域可来自非突变(“正常”)、突变或改变的基因,甚至可来自使用当前DNA合成方法在实验室全合成的DNA序列或基因。
“核苷酸序列”这一术语系指脱氧核糖核酸的异源多聚体。
编码特定肽、寡肽或多肽的核苷酸序列可为天然存在,也可为人工合成。通常而言,编码本发明的肽、多肽和蛋白的DNA片段组装自cDNA片段和短寡核苷酸连接器,或组装自一系列的寡肽,由此产生一个合成基因,该基因可在重组转录单元(由源自微生物或病毒操纵子的调控元素所组成)中表达。
本文所用的“编码肽的核苷酸”这一术语系指可编码肽的核苷酸序列(该肽含有适用于表达该序列的生物系统的人工起始和终止密码子)。
“表达产物”这一术语系指作为基因自然翻译产物的多肽或蛋白,或由遗传密码的简并性所产生的(因此可编码同种氨基酸的)任何氨基酸序列的同等编码产物。
“片段”这一术语用于编码序列时系指小于完整编码区的DNA的一部分,其表达产物所携带的生物功能或活性与完整编码区的表达产物本质上相同。
“DNA片段”这一术语系指作为单独片段或较大DNA构造组分的DNA聚合物。该片段源自至少分裂过一次、基本为初凝形式(即不含污染性内源物质,且其含量或浓度允许通过克隆用载体等标准生物化学方法对该片段或其氨基酸序列组分进行识别、操作和恢复)的DNA。此类片段表现为不被内部非翻译序列或内含子(通常存在于真核基因中)所打断的连续开放阅读框。非翻译DNA序列可能存在于该开放阅读框的下游,且该非翻译DNA序列不干扰编码区的操作或表达。
“引物”这一术语系指一种短核苷酸序列,可与一条DNA链配对形成一个游离3'-OH端,DNA聚合酶在此游离端开始合成脱氧核糖核酸链。
“启动子”这一术语系指一个参与RNA聚合酶结合(以此启动转录)的DNA区域。
“分离的”这一术语系指从原始环境(例如其天然环境(若为天然存在物质))中转移的物质。举例来说,天然存在的多聚核苷酸或存在于活体动物中的多肽为非分离物质,而从天然系统中某些或全部共存物质中分离的同种多聚核苷酸或多肽则为分离物质。此类多聚核苷酸可为载体的一部分,且/或此类多聚核苷酸或多肽可为某组分的一部分,但若此载体或组分不是其天然环境的一部分,此多聚核苷酸或多肽仍为分离物质。
根据本发明公开的多聚核苷酸以及重组或免疫原性多肽也可为“纯化”型。“纯化”这一术语并不要求绝对纯净,而是一个相对定义,可包含高度纯化的制剂或仅部分纯化的制剂。此类术语由具备相应的当前技术水平的人员所各自理解。例如,从cDNA库中分离的个体克隆物通常纯化至电泳匀质性即可。明确规定起始物料和自然物料应纯化至至少一个数量级(优选为2或3个数量级,更优选为4或5个数量级)。此外,明确规定多肽的纯度优选为99.999%,或至少99.99%或99.9%;甚至适宜以重量计为99%以上。
根据本发明公开的核苷酸和多肽表达产物以及含有此氨基酸和/或多肽的表达载体可能为“浓缩型”。本文所用“浓缩”这一术语系指物质的浓度至少为其(例如)天然浓度的2、5、10、100或1000倍,宜为0.01%(按重量),优选为至少0.1%(按重量)。也可考虑约0.5%、1%、5%、10%和20%(按重量)的浓缩制剂。本发明所涉序列、构造、载体、克隆物和其它物质宜为浓缩或分离型。
“活性片段”这一术语系指可单独使用或与适当辅剂联合使用,在动物(例如家兔或小鼠也包括人等哺乳动物)中产生免疫应答(即具有免疫原活性)的片段,此免疫应答的形式为在受体动物(例如人)中激发T细胞应答。“活性片段”也可用于引发体外T细胞应答。
本文中“部分”(portion)、“片段”(segment)和“片段”(fragment)等术语用于多肽时系指残基(例如氨基酸残基)的连续序列,该序列组成较大序列的一个亚组。例如,用常见的内肽酶(例如胰蛋白酶或糜蛋白酶)处理多肽后,由此处理所产生的寡肽即为起始多肽的部分、片段或片段。当用于多聚核苷酸时,以上术语系指用任何核酸内切酶处理相关多聚核苷酸后的产物。
本发明所涉“百分同一性”这一术语,用于序列时系指将需要比较的某一序列(“比较序列”)进行排列后与已明确的或已报告的序列(“参考序列”)相比较,然后用以下公式计算百分同一性:
百分同一性=100[1-(C/R)]
其中C为参考序列与比较序列在参考序列与比较序列之间排列长度中的差异数,其中(i)在比较序列中不存在相应排列碱基或氨基酸的参考序列中的各碱基或氨基酸、(ii)参考序列中的各空隙以及(iii)与比较序列中的排列碱基或氨基酸不同的参考序列中的各碱基或氨基酸均构成差异,并且(iiii)该排列必须起始于所排列序列的位置1;R为位于比较序列排列长度中的参考序列的碱基或氨基酸数量(将参考序列中的空隙也记为碱基或氨基酸)。
若比较序列与参考序列间存在排列,且二者按上述方法计算的百分同一性等于或大于特定的最低百分同一性限度,则可认为该比较序列与参考序列具有特定的最低百分同一性,即使也有可能存在按上述方法计算的排列百分同一性低于特定的百分同一性的情况。
如非另作说明,本文所涉的原始(非修饰)肽可均通过取代肽链中不同位点(有可能是选择性位点)上的一个或多个残基来进行修饰。
上述取代宜发生于氨基酸链的末端。此类取代可为保守性的,例如用一个结构或特性相似的氨基酸取代另一氨基酸(例如用一个疏水性氨基酸取代另一疏水性氨基酸)。相同或近似大小和化学性质的氨基酸间的取代则更为保守,例如用异亮氨酸取代白氨酸。在对天然存在的同源蛋白家族的序列变异体的研究中,某些氨基酸取代较之其它取代更易耐受,此类取代通常与相似大小、电荷、极性以及原氨基酸和其取代氨基酸间的疏水性相关。此类性质是定义“保守性取代”的基础。
本文定义保守性取代为以下任意五组残基间的交换:第1组-脂肪族、非极性或微极性小残基(Ala,Ser,Thr,Pro,Gly);第2组-极性、带负电荷残基及其酰胺(Asp,Asn,Glu,Gln);第3组-极性、带正电荷残基(His,Arg,Lys);第4组-脂肪族、非极性大残基(Met,Leu,Ile,Val,Cys);第5组-芳香族大残基(Phe,Tyr,Trp)。
较不保守的取代方式可能涉及用特性相近但大小有所不同的氨基酸取代另一氨基酸,例如用异亮氨酸残基取代丙氨酸。高度非保守取代可能涉及用酸性氨基酸取代具有极性或甚至碱性性质的氨基酸。但上述“激进”的取代不能因为有可能无效而被忽略,原因是化学作用并不是完全可预测的,激进的取代也有可能产生单一化学原则所无法预测的偶然效应。
当然,上述取代可能涉及与常见L-氨基酸不同的结构。因此,即使D-氨基酸有可能被本发明中的常见抗原性肽的L-氨基酸所替代,但是本发明仍然涵盖D-氨基酸。此外,可加工非标准R基团(即,除了天然蛋白的20个常见氨基酸之外的R基团)的氨基酸也有可能用于取代,以此产生根据本发明所述的免疫原和免疫原性多肽。
若发现存在多个位置的取代,产生了具有本质上同等或更强的抗原活性(定义见下文)的肽,则应检测此类取代组合以明确此组合取代是否对肽的抗原性产生了迭加或协同效应。同一个肽中最多可有不超过4个位置被同时取代。
本发明的肽可延长最多4个氨基酸,即:1、2、3或4个氨基酸可以4:0至0:4的任何组合形式加入任一末端。
表3列出了本发明所允许的肽延长组合类型:
C末端 | N末端 |
4 | 0 |
3 | 0或1 |
2 | 0或1或2 |
1 | 0或1或2或3 |
0 | 0或1或2或3或4 |
N末端 | C末端 |
4 | 0 |
3 | 0或1 |
2 | 0或1或2 |
1 | 0或1或2或3 |
0 | 0或1或2或3或4 |
用于延长的氨基酸可为蛋白原始序列的肽或任何其它氨基酸。延长的目的是提高肽的稳定性或溶解性。
“T细胞应答”这一术语系指肽在体外或体内引起的效应功能的特异性增殖和活化。对于MHC I类限制性CLT,其效应子功能可为肽冲击的、肽前体冲击的或天然肽呈递的靶细胞的溶解、细胞因子(优选为肽诱导的干扰素γ、TNFα或IL-2)分泌、效应分子(优选为肽诱导的粒酶或穿孔蛋白)分泌或脱粒。
理想情况下,当检测对SEQ ID No.1至SEQ ID No.92肽(相比于取代肽)特异性的CTL时,取代肽达到相对于背景值的最大溶解增值时的肽浓度不应超过约1mM,最好不超过约1μM,更优选为不超过约1nM,再更优选为不超过约100pM,最优选为不超过约10pM。取代肽宜在至少一个个体(最少为2个,更优选为3个)中被CTL识别。
因此本发明的表型可能与天然存在的肿瘤相关或肿瘤特异性表型一致,也可能包含与参考肽差异不超过4个残基的表型,只要该表型的抗原活性基本一致。
免疫应答的激发取决于被宿主免疫系统识别为外源性的抗原。肿瘤相关性抗原的发现提高了用宿主免疫系统阻碍肿瘤生长的可能性。对于癌症免疫疗法,目前正在探索各种利用免疫系统的体液和细胞免疫作用的机制。
细胞性免疫应答的特异性元素可特异性地识别和破坏肿瘤细胞。将细胞毒性T淋巴细胞(CTL)与肿瘤浸润细胞群或外周血相分离后发现,该细胞对于癌症的天然免疫防御起到重要作用。CD8阳性T细胞在该应答中的作用尤为重要,原因是其可识别携带主要组织相容性复复合物(MCH)I类分子(通常由8至10个由蛋白或细胞溶质中的缺陷核糖体产物(DRIPS)所衍生的氨基酸残基所组成)。人体中的MHC分子亦称为人白细胞抗原(HLA)。
MHC I类分子存在于多数带核细胞中,其所呈递的肽多源于内源蛋白、DRIPs和较大肽的溶蛋白性裂解。但也经常在MHC I类分子上发现源于内涵体腔室的或外源性肽。文献中将该非经典I类呈递称为交叉呈递。
由于两种类型的应答(分别为CD8和CD4依赖型)可共同产生协同抗肿瘤作用,因此肿瘤相关性抗原(通过CD8+CTL(配体:MHC I类分子+多肽表型)或CD4阳性辅助T细胞(配体MHC II类分子+多肽表型)来识别)的鉴别和表征对于抗肿瘤疫苗的开发有重要意义。因此本发明的目的之一是提出可与各类型MHC复合物相结合的肽组分。
考虑到癌症治疗的严重副作用和高昂费用,亟需更好的预后和诊断方法。因此有必要发现其它可作为癌症生物标记物的因子,特别是肺癌。此外,有必要发现肿瘤治疗所使用的因子,特别是肺癌。
本发明提出可用于治疗癌症/肿瘤(优选为肺癌,最优选为可过量表达或独特表达本发明的肽的非小细胞肺癌(NSCLC))的肽。质谱分析表明,此类肽可在原发性人肺癌样本中由HLA分子天然呈递(参见示例1和图1)。
肽的源基因/蛋白(亦称“全长蛋白”或“基本蛋白”)在非小细胞肺癌以及SEQ IDsNo.66至75的胃癌和成胶质细胞瘤中相比于正常组织存在高度过量表达(参见示例2,NSCLC参见图2),表明源基因与肿瘤的高度关联。此外,肽自身在肿瘤组织中也大量过量呈递,在正常组织中则没有(参见示例3和图3)。
HLA结合肽可被免疫系统特别是T淋巴细胞所识别。T细胞可破坏呈递所识别的HLA/肽复合物的细胞,例如呈递衍生肽的肺癌细胞。
研究显示本发明的肽可激发T细胞应答并/或存在过量呈递,因此可用于产生本发明所涉的抗体和/或TCR,特别是TCR(参见示例4和图4)。此外,与相应MHC络合的肽可用于产生本发明所涉的抗体和/或TCR,特别是TCR。相应的方法为技术熟练的人员所熟知,也可在相应的文献中找到。因此本发明的肽有助于产生免疫应答,该应答可在患者中破坏肿瘤细胞。可通过直接给予患者文中所述的肽或合适的前体物质(例如延长肽、蛋白或编码此类肽的核苷酸)可在患者中引发免疫应答,最好与促免疫原性药物(例如辅剂)联合使用。通过此治疗性接种免疫产生的免疫应答预计可对肿瘤细胞具有高度特异性,其原因是本发明的目的肽在正常组织中不存在一定的拷贝数,由此可防范对正常细胞的不良自免疫反应这一风险。
药品组合物包括游离形式或以一种药用盐形式存在的肽。本文中“药用盐”系指本发明所公开的肽的一种衍生物,其中的肽通过形成相应药物的酸或碱盐来进行修饰。例如酸盐可由游离碱(特别是含中性-NH2基团的药物的中性形式)与合适的酸反应而制得。用于制备酸盐的合适的酸包括有机酸(例如乙酸、丙酸、羟基乙酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、枸橼酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、p-甲苯磺酸、乙酰水杨酸等)和无机酸(例如盐酸、氢溴酸、硫酸、磷酸等)。相反地,可能存在于肽中的酸基团的碱盐的制备需使用药用碱,例如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙、三甲胺等。
在优选的实施方案中,药学组分可包括乙酸盐、三氟乙酸盐或盐酸盐形式的肽。
除可用于癌症治疗外,本发明的肽还可能用于诊断。由于此类肽产生于肺癌细胞而在正常细胞中不存在或水平较低,此类肽可用于癌症的诊断。
存在于活检组织中的相关肽类可协助病理医师诊断癌症。通过抗体、质谱或其它目前所用方法检测特定的肽可提示病理医师该组织为恶性、炎性还是一般疾病。特定组别的肽可用于病变组织的分类或次级分类。
检测病变组织标本中的肽可预测从免疫系统疗法的获益情况,特别是在已知或预期T淋巴细胞参与其作用机制的情况下。MHC表达缺失这一机制已得以充分报告,恶性细胞可通过该机制逃脱免疫监视。因此肽的存在显示所分析的细胞并未利用该机制。
本发明的肽有望用于分析淋巴细胞对此类肽的应答,例如对肽或肽-MHC分子复合物的T细胞应答或抗体应答。上述淋巴细胞应答可用作决定后续治疗步骤的预后标记物。此类应答亦可在旨在用多种方法(例如蛋白、核苷酸、自体物质的免疫接种和淋巴细胞的过继性转移)引发淋巴细胞应答的免疫疗法中用作替代标记物。在基因治疗中,副作用评估可考虑淋巴细胞对肽的应答。对淋巴细胞应答的监测有可能作为移植治疗中随访检查(例如发现移植物抗宿主或宿主抗移植物疾病)的有效工具。
本发明的肽可用于产生MHC/肽复合物的特异性抗体。此类抗体可用于治疗,使毒素或放射性物质靶向作用于病变组织。此类抗体的另一用途是使放射性核素靶向作用于病变组织,以便进行PET等影像疗法。这一用途有助于发现小转移或确定病变组织的大小和准确位置。
因此本发明的另一方面是提出产生一种可与人重要组织相容性复合物(MHC)I或II(与HLA限制性抗原相络合)特异性结合的重组抗体的方法,该方法包括:用络合了上述HLA限制性抗原的MHC I类或II类分子的可溶型对基因工程制备的非人哺乳动物细胞(可表达上述人MHC I类或II类)进行免疫;将mRNA分子从上述产生抗体的非人哺乳动物细胞中分离;产生一个噬菌体呈现文库以呈现由上述mRNA分子编码的蛋白分子;并从上述噬菌体呈现文库中分离至少一种噬菌体,该噬菌体可呈现上述可与MHC I类或I类(与上述HLA限制性抗原相络合)特异性结合的抗体。
本发明的另一方面是提出一种可与人重要组织相容性复合物(MHC)I或II(与HLA限制性抗原相络合)特异性结合的抗体,该抗体优选为多克隆抗体、单克隆抗体、双特异性抗体和/或嵌合抗体。
此外,本发明的另一方面涉及产生一种可与人重要组织相容性复合物(MHC)I或II(与HLA限制性抗原相络合)特异性结合的上述抗体的方法,该方法包括:用络合了上述HLA限制性抗原的MHC I类或II类分子可溶型对基因工程制备的非人哺乳动物细胞(可表达上述人MHC I类或II类)进行免疫;将mRNA分子从上述产生抗体的非人哺乳动物细胞中分离;产生一个噬菌体呈现文库以呈现由上述mRNA分子编码的蛋白分子;并从上述噬菌体呈现文库中分离至少一种噬菌体,该噬菌体可呈现上述可与MHC I类或I类(与上述HLA限制性抗原相络合)特异性结合的抗体。产生上述抗体、单链I类MHC以及产生上述抗体所用的其它工具的相应方法参见WO 03/068201、WO 2004/084798、WO 01/72768、WO 03/070752以及CohenCJ,Denkberg G,Lev A,Epel M,Reiter Y.Recombinant antibodies with MHC-restricted,peptide-specific,T-cell receptor-like specificity:new tools tostudy antigen presentation and TCR-peptide-MHC interactions.J MolRecognit.2003Sep-Oct;16(5):324-32.;Denkberg G,Lev A,Eisenbach L,Benhar I,Reiter Y.Selective targeting of melanoma and APCs using a recombinantantibody with TCR-like specificity directed toward a melanoma differentiationantigen.J Immunol.2003Sep 1;171(5):2197-207;以及Cohen CJ,Sarig O,Yamano Y,Tomaru U,Jacobson S,Reiter Y.Direct phenotypic analysis of human MHC class Iantigen presentation:visualization,quantitation,and in situ detection ofhuman viral epitopes using peptide-specific,MHC-restricted human recombinantantibodies.J Immunol.2003Apr15;170(8):4349-61,上述文献用于本发明时均通过完整引用而明确成为本文的一部分。
抗体对复合物的结合亲合力宜低于20纳摩尔,最好低于10纳摩尔,由此在本发明中即可认为具有“特异性”。
本发明的另一方面是提出可识别特异性肽-MHC复合物的一种可溶性T细胞受体的产生方法。此类T细胞受体可由特异性T细胞克隆产生,其亲合力可因作用于互补性决定区域的突变发生而增强。T细胞受体的选择可使用噬菌体呈现(US2010/0113300,Liddy N,Bossi G,Adams KJ,Lissina A,Mahon TM,Hassan NJ,et al.Monoclonal TCR-redirectedtumor cell killing.NatMed2012Jun;18(6):980-987)。出于使噬菌体呈现中的T细胞受体稳定的目的,以及在药物的实际应用中,α和β链可由非天然二硫键、其它共价键(单链T细胞受体)或二聚作用域等所连接(参见Boulter JM,Glick M,Todorov PT,Baston E,Sami M,Rizkallah P,et al.Stable,soluble T-cell receptor molecules forcrystallization and therapeutics.Protein Eng 2003Sep;16(9):707-711.;Card KF,Price-Schiavi SA,Liu B,Thomson E,Nieves E,Belmont H,et al.A soluble single-chain T-cell receptor IL-2fusion protein retains MHC-restricted peptidespecificity and IL-2bioactivity.Cancer Immunol Immunother 2004Apr;53(4):345-357;and Willcox BE,Gao GF,Wyer JR,O'Callaghan CA,Boulter JM,Jones EY,etal.Production of soluble alphabeta T-cell receptor heterodimers suitable forbiophysical analysis of ligand binding.Protein Sci1999Nov;8(11):2418-2423)。T细胞受体可与毒素、药物、细胞因子(参见US2013/0115191)、抗CD3域等效应细胞募集域等相连接,以对靶细胞产生特定功能。此外,T细胞受体可表达于过继性转移所用的T细胞中。
更详细信息参见WO 2004/033685A1和WO 2004/074322A1。sTCR的组合物使用报告于WO 2012/056407A1。受体产生的更详细信息包含于WO 2013/057586A1。
此外,此类受体可用于病理医师对活检标本所作的癌症诊断。
对呈递谱进行了测算以选择过量呈递肽,表明存在中度样本呈递和复制变异性。该图谱将相关肿瘤样本与正常组织样本(基线)相并列。由此可通过计算线性混合效应模型的p值将上述各谱用于过量呈递评分中(J.Pinheiro,D.Bates,S.DebRoy,Sarkar D.,RCore team.Nlme:Linear and Nonlinear Mixed Effects Models.2008)从而通过假发现率调整多项检验(Y.Benjamini and Y.Hochberg.Controlling the False DiscoveryRate:A Practical and Powerful Approach to Multiple Testing.Journal of theRoyal Statistical Society.Series B(Methodological),Vol.57(No.1):289-300,1995)。
使用质谱法进行HLA配体的鉴别和相对定量分析,对来自急速冷冻组织样本的HLA分子进行纯化,且分离HLA相关性肽。所分离的肽互相分开,用在线纳米电喷射离子化(nanoESI)液相色谱-质谱(LC-MS)试验对其序列进行鉴别。通过将NSCLC样本所记录的天然TUMAP的断裂谱与相应的合成参考肽同一序列的断裂谱相比较,对所产生的肽序列进行了验证。由于将肽直接鉴别为原发肿瘤HLA分子的配体,因此上述结果为所鉴别的肽在NSCLC患者原发肿瘤组织中的自然加工和呈递提供了直接证据。
专利发现平台v2.1(参见US 2013-0096016等,以完整引用形式并入本文))可实现相关过量呈递肽候选疫苗的鉴别和选择(通过将癌症组织中的HLA限制性肽水平进行直接相对定量,与数种不同的肺癌组织器官相比较)。这一功能依赖于无标记型鉴别定量分析(使用经专利数据分析平台处理的LC-MS数据)的开发,结合了序列鉴别算法、谱聚类、离子计数、保留时间校正、电荷状态去卷积(deconvolution)和正态化。
确立了各个肽和样本的呈递水平(包括误差预估)。发现了仅呈递于肿瘤组织和在肿瘤组织(相比如非癌组织器官)中过量呈递的肽。
对从50份急速冷冻NSCLC肿瘤组织样本中获取的HLA-肽复合物进行了纯化,并用LC-MS对HLA相关性肽进行了分离和分析。
本项申请所含的所有TUMAPs均使用上述方法在原发NSCLC肿瘤样本中发现,证实其在原发NSCLC中的呈递。
通过对无标记LC-MS数据进行离子计数对多种NSCLC肿瘤和正常组织中的TUMAPs进行了定量分析。该方法假定肽的LC-MS信号面积与其在样本中的含量相关。多种LC-MS试验中的所有肽定量信号均按集中趋势和每个样本的平均值进行正态化,并绘制为条形图,该图即为呈递谱。呈递谱结合了多种不同的分析方法,例如蛋白质数据库搜索、谱聚类、电荷状态去卷积(去电荷)、保留时间校正和正态化。
因此本发明涉及包含选自SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92或其(与SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92至少90%同源(优选为同一))的变异序列的序列的肽,且上述变异序列可引发T细胞与上述肽的交叉反应,其中上述肽为非全长多肽。
本发明还涉及包含选自SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92或其(与SEQ ID No.1至SEQ ID No.65和SEQ ID No.76至SEQ IDNo.84至少90%同源(优选为同一))的变体序列的序列的肽。其中,上述肽或其变异体的总长度为8至100个氨基酸(优选为8至30个,最优选为8至14个)。
T本发明还涉及根据本发明所述的、可与人主要组织相容性复合物(MHC)I类或II类相结合的肽。
本发明还涉及根据本发明所述的肽,此类肽由、或基本由SEQ ID No.1至SEQ IDNo.65、SEQ ID No.76至SEQ ID No.84和SEQ ID No.92的氨基酸序列所组成。
本发明还涉及根据本发明所述的肽,此类肽经过修饰且/或包含非肽键。
本发明还涉及根据本发明所述的肽,此类肽为融合蛋白的一部分,特别是与HLA-DR抗原相关性不变链(Ii)的N末端氨基酸相融合的蛋白,或与某种抗体(或其序列)(例如树突细胞特异性抗体)相融合的蛋白。
本发明还涉及一种核酸,该核酸可编码根据本发明所述的肽(条件是该肽并非完整人体蛋白)。
本发明还涉及根据本发明所述的核酸,该核酸为DNA、cDNA、PNA、RNA或DNA、cDNA、PNA、RNA的组合形式。
本发明还涉及一种表达载体,该载体可表达根据本发明所述的核酸。
本发明还涉及一种根据本发明所述的肽、根据本发明所述的核酸或根据本发明所述的表达载体在医学中的用途。
本发明还涉及包含本发明核酸或本发明表达载体的宿主细胞。
本发明还涉及根据本发明所述的一种宿主细胞,其为抗原呈递细胞。
本发明还涉及根据本发明所述的一种宿主细胞,其中的抗原呈递细胞为树突细胞。
本发明还涉及根据本发明所述的一种肽的制备方法,该方法包括培养本发明所述的宿主细胞,以及将肽从宿主细胞或其培养基中分离。
本发明还涉及活化的细胞毒性T淋巴细胞(CTL)的体外制备方法,该方法包括将体外CTL与在适当抗原呈递细胞表面表达且负载抗原的人I类或MHC II类分子相接触一段时间,该时间足以以抗原特异性方式活化上述CTL,其中所述抗原可为根据本发明所述的任何肽。
本发明还涉及一种根据本发明所述的方法,其中通过将足量的抗原与抗原呈递细胞相接触,使抗原载入表达于适当的抗原呈递细胞表面的I类或MHC II类分子。
本发明还涉及一种根据本发明所述的方法,其中的抗原呈递细胞包含能够表达含SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84,以及SEQ ID No.92或其上述变体氨基酸序列的肽的表达载体。
本发明还涉及根据本发明所述的方法所制备的活化细胞毒性T淋巴细胞(CTL),可选择性地识别异常表达含有根据本发明所述的氨基酸序列的多肽的细胞。
本发明还涉及在患者中杀伤异常表达含有任何根据本发明所述的氨基酸序列的多肽的靶细胞的方法,包括根据本发明所述的方法给予患者有效数量的细胞毒性T淋巴细胞(CTL)。
本发明还涉及本发明的任何上述肽、根据本发明所述的核酸、根据本发明所述的表达载体、根据本发明所述的细胞或根据本发明所述的活化细胞毒性T淋巴细胞作为药物或在药物制备中的用途。
本发明还涉及根据本发明所述的用途,其中所述药剂为疫苗。
本发明还涉及根据本发明所述的用途,其中所述药剂具有抗肿瘤活性。
发明还涉及根据本发明所述的用途,其中癌细胞为肺癌、胃癌、胃肠癌、结直肠癌、胰腺癌或肾癌细胞,以及成胶质细胞瘤细胞。
本发明还涉及基于根据本发明所述的肽的特定标记蛋白和生物标记物,可用于肺癌的预后。
此外,本发明还涉及上述新型靶标用于癌症治疗的用途。
本文所用的“抗体”是一个广义术语,包括多克隆与单克隆抗体。除了完整的或“全”免疫球蛋白分子外,“抗体”这一术语也包括此类免疫球蛋白的片段或多聚体,或免疫球蛋白分子的人源化形式,只要其能产生本发明所期望的特性(例如肺癌标记物多肽的特异性结合、将毒素传递至肺癌标记物基因表达水平升高的肺癌细胞以及/或抑制肺癌标记物多肽的活性)。
本发明的抗体应尽可能购自市售途径。本发明的抗体也可通过常用的方法来制备。本领域技术人员会知晓全长肺癌标记物多肽或其片段皆可用于生成本发明的肽。生成本发明的抗体所用的多肽可通过自然途径部分或完全纯化,也可通过重组DNA技术制得。
例如,编码ABCA13、MMP12、DST、MXRA5、CDK4、HNRNPH、TANC2、1RNF213、SMYD3和SLC34A2或SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84或SEQ ID No.92的任何相关多肽的cDNA(或其片段)可在原核细胞(例如细菌)或真核细胞(例如酵母、昆虫或哺乳动物细胞)中表达,其后可对重组蛋白进行纯化,用于产生单克隆或多克隆抗体制品,该抗体可与本发明中用于产生抗体的肺癌标记物多肽特异性地结合。
具备当前技术水平的人员知晓,产生至少2组单克隆或多克隆抗体可最大程度的确保所得抗体具备其预定用途所(例如ELISA免疫组织化学、体内影像分析、免疫毒素治疗)要求的特异性和亲合力。可依据抗体的预定用途采用已知方法(例如ELISA、免疫组织化学、免疫治疗等;有关抗体生成和检测的更为具体的指导请参见Harlow and Lane,Antibodies:A Laboratory Manual,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,N.Y.,1988,new 2nd edition 2013等)对抗体的期望活性进行检测。例如,可使用ELISA分析、Western印迹或免疫组织化学染色对福尔马林固定的肺癌或冷冻组织切片进行抗体检测。在初次体外表征完成后,对计划用于治疗或体内诊断的抗体,应使用已知的临床检测方法进行检测。
本文所用“单克隆抗体”这一术语系指从本质上同源的抗体群中获取的抗体,即:该抗体群中的各抗体除了可能的少量天然突变外是完全相同的。本文中单克隆抗体具体还包括“嵌合”抗体,该抗体中的一部分重链和/或轻链与从特定物种获取的或属于特定的抗体类别或子类别的抗体的相应序列同一或同源,而剩余的链与从另一物种获取的或属于另一的抗体类别或子类别的抗体(以及此抗体的片段)的相应序列同一或同源,只要该抗体可表现期望的抗肿瘤活性(美国专利编号4816567,以完整引用形式并入本文)。
本发明的单克隆抗体可使用杂交瘤方法制备。采用杂交瘤方法时,通常用免疫剂对小鼠或其它适当的宿主细胞进行免疫,以使淋巴细胞生成或可以生成可与该免疫剂特异性结合的抗体。或者可以对淋巴细胞进行体外免疫。
单克隆抗体也可通过重组DNA方法(例如美国专利编号4816567所描述的方法)制得。编码本发明的单克隆抗体的DNA可用传统的操作进行分离和测序(例如使用可与编码鼠抗体重链和轻链的基因相结合的寡核苷酸探针)。
体外方法也适用于制备单价抗体。可使用本领域已知的常规方法将抗体分解为其片段(特别是Fab片段)。例如可用番木瓜蛋白酶进行分解。1994年12月22日发表的WO 94/29348以及美国专利编号4342566均描述了番木瓜蛋白酶分解的示例。番木瓜蛋白酶分解抗体通常产生两个完全相同的抗原结合片段(称为Fab片段,各含一个单抗原结合位点)以及一个残留Fe片段。胃蛋白酶处理可产生一个包含2个抗原结合位点且可与抗原进行交联的片段。
抗体片段(无论是否加入其它序列)也可包含特定区域或特定氨基酸残基的插入、缺失、取代或其它选定的修饰,只要与未修饰的抗体或抗体片段相比该片段的活性未被显著改变或损伤即可。这些修饰可产生某些附加特性,例如移除/加入可成二硫键的氨基酸以延长其生物寿命或改变其分泌特征等。任何情况下该抗体片段均应具备生物活性特性,例如结合活性以及对结合域结合的调控等。可通过蛋白特定区域中的突变发生然后通过量表达以及所表达多肽的检测来识别抗体的功能或活性区域。此类方法为本领域技术人员所熟知,可包含编码抗体片段的核苷酸的特定位点的突变。
本发明的抗体还可包含人源化抗体或人体抗体。非人(例如鼠类)抗体的人源化形式可为嵌合免疫球蛋白、免疫球蛋白链或其片段(例如Fv、Fab、Fab'或抗体的其它抗原结合序列),包含源自非人免疫球蛋白的最小序列。人源化抗体包括人免疫球蛋白(受体抗体),其中受体的互补决定区(CDR)残基被非人物种(供体抗体)(例如小鼠、大鼠、兔)的CDR中具有期望的特异性、亲合力和能力的残基所取代。某些情况下人免疫球蛋白的Fv框架(FR)残基可被相应的非人残基所取代。人源化抗体还可包含受体抗体、输入的CDR或框架序列中均不存在的残基。一般而言,人源化抗体包含至少1个(通常为2个)可变域,其中所有或几乎所有的CDR区域均与一种非人免疫球蛋白的CDR区域相对应,且所有或几乎所有FR区域均为人免疫球蛋白共有序列的FR区域。人源化抗体最好还包含免疫球蛋白(通常是人免疫球蛋白)恒定区(Fc)的至少一个片段。
非人抗体的人源化方法为本领域所熟知。一般而言,一种人源化抗体含有一个或多个氨基酸残基,该残基来源于非人途径。此类非人氨基酸残基常被称为“输入”残基,通常来源于“输入”可变域。本质上人源化通常可通过用相应的人体抗体序列取代啃齿类CDR或CDR序列来实现,由此产生的“人源化”抗体为嵌合抗体(美国专利编号4816567),其中一个小于完整的人可变域的序列被来自非人物种的相应序列所取代。实际操作中,人源化抗体通常为人抗体,其中某些CDR残基(也有可能是某些FR残基)被源于啃齿类抗体中同类位点的残基所取代。
可使用即使不存在在内源性免疫球蛋白也可经免疫产生全部人抗体的转基因动物(例如小鼠)。例如,嵌合与种系突变小鼠的抗体重链链接区基因的纯合缺失可引发内源性抗体生成的完全抑制。而将人种系免疫球蛋白基因阵列转移至上述种系突变小鼠中可在抗原激发下产生人抗体。人抗体也可在噬菌体呈现文库中产生。
本发明的抗体优选为通过药用载体给予受试者。通常在制剂中使用适当剂量的药用盐,以使该制剂呈等渗性。药用载体包括生理盐水、Ringer溶液和葡萄糖溶液。溶液的pH优选为约5至约8,更优选为约7至约7.5。其它载体包括缓释制剂(例如含抗体的固体疏水多聚物的半渗透性基质溶液),其基质为有形物,例如膜、脂质体或微粒。本领域的技术人员熟知,某些载体可为更优选(依据给药途径和所给予的抗体浓度等)。
抗体可注射(例如静脉注射、腹膜内注射、皮下注射、肌肉注射)给予受试者、患者或细胞,也可通过其它途径(例如输注),只要能保证抗体可以有效形式进入血流。抗体也可通过瘤内或瘤周途径给药,以产生局部和全身疗效反应。局部或静脉注射给药为优选。
抗体给药剂量和日程可在当前技术范围内按经验确定。本领域的技术人员知晓抗体的给药剂量会依据接受抗体的受试者类型、给药途径、所使用的抗体和其它药物的特定类型等而有所不同。依据上述因素,常见的抗体单用每日剂量从约每日1μg/kg至最高100mg/kg体重不等,也可能更高。肺癌治疗抗体给药后可通过技术熟练的相关人员所熟知的多种方式评估治疗用抗体的疗效。例如可通过标准肿瘤影像技术对接受治疗的受试者的肿瘤大小、数量和/或分布情况进行监测。若某一治疗性抗体可停止肿瘤生长、引发肿瘤缩小并/或防止肿瘤新生的治疗性抗体(相比于不进行抗体治疗的正常病程),则可认为该抗体可有效治疗肺癌。
由于本发明的非肿瘤标记物ABCA13和MMP12在肺癌细胞中高度表达且在正常细胞中表达水平极低,因此抑制ABCA13和MMP12表达或多肽活性可作为NSCLC治疗或预防策略的一部分。
反义治疗原则基于下列假设:基因表达的序列特异性抑制(通过转录或翻译)可通过基因组DNA或mRNA与互补反义序列的细胞内杂交而实现。此杂交核酸双链体的形成可干扰编码目标肿瘤抗原的DNA的转录,或干扰目标肿瘤抗原mRNA的加工/转运/翻译和/或稳定性。
反义核酸可通过多种途径来传递。例如反义寡核苷酸或反义RNA可以肿瘤细胞可摄取的形式直接给予(例如通过静脉注射)受试者。或者可在体外将编码反义RNA(或RNA片段)的病毒或质粒载体导入细胞中。也可通过有义序列引发反义效应;但表型变化的大小具有高度差异性。有效的反义治疗所引发的表型变化可根据变化来评估,例如通过靶mRNA水平、靶蛋白水平和/或靶蛋白活性水平。
具体举例而言,反义基因治疗抑制肺部肿瘤标记物功能可通过直接给予受试者反义肺部肿瘤标记物RNA而实现。反义肿瘤标记物RNA可通过标准技术产生和分离,但也可在高效启动子(例如T7启动子)的调控下通过反义肿瘤标记物cDNA在体外即刻制备。反义肿瘤标记物RNA的细胞内给药可通过以下任一直接核酸给药方法来进行。
抑制ABCA13和MMP12功能的另一种基因治疗策略涉及抗ABCA13、MMP12抗体或抗ABCA13、MMP12抗体片段的细胞内表达。例如可使编码某一可与ABCA13、MMP12多肽特异性结合并抑制其生物活性的单克隆抗体的基因在核酸表达载体中受到特异性(例如组织或肿瘤特异性)基因调控序列的转录调控。随后将该载体给予受试者以便肺癌细胞或其它细胞摄取,该细胞随后分泌抗ABCA13、MMP12抗体,以此抑制ABCA13、MMP12多肽的活性。ABCA13、MMP12多肽宜位于胃癌细胞的细胞外表面中。
在上述将外源DNA给予或摄入受试者细胞(例如通过基因转导或转染)的方法中,本发明的核苷酸可为裸DNA形式,或者核苷酸可通过载体传递至细胞中,以抑制胃部肿瘤标记物蛋白的表达。该载体可为市售制剂,例如腺病毒载体(Quantum Biotechnologies,Inc.(Laval,Quebec,Canada)。可通过多种机制将核苷酸或载体传递至细胞中。例如可使用LIPOFECTIN、LIPOFECTAMINE(GIBCO-25BRL,Inc.,Gaithersburg,Md.)、SUPERFECT(Qiagen,Inc.Hilden,Germany)和TRANSFECTAM(Promega Biotec,Inc.,Madison,Wis.)等市售脂质体制剂以及其它按照当前标准操作制备的脂质体进行脂质体传递。此外,本发明的核苷酸或载体可通过电穿孔法在体内传递,这一技术可购自Genetronics,Inc.(San Diego,Calif.),也可通过SONOPORATION仪器(ImaRx Pharmaceutical Corp.,Tucson,Arizona)来开展。
举例而言,可通过病毒系统(例如可包装一个重组逆转录病毒基因组的逆转录病毒载体系统)进行载体传递。重组逆转录病毒随后可感染细胞,由此将可抑制ABCA13、MMP12表达的反义核苷酸传递至受染细胞中。当然,将改变的核苷酸导入哺乳动物细胞的具体方法不限于使用逆转录病毒载体。这一步骤所普遍采用的其它技术包括使用腺病毒载体、腺病毒伴随病毒(AAV)载体、慢病毒载体和假型病毒载体。也可使用物理传导技术,例如脂质体传递以及受体介导的和其它细胞内吞机制。本发明可与上述或任何其它常用的基因转移方法联合使用。
抗体也可用于体内诊断检测。一般而言,可用放射性核苷酸(例如111In、99Tc、14C、131I、3H、32P或35S)标记抗体,以使用免疫闪烁照相术进行肿瘤定位。在一实施方案中,抗体或其片段可与至少2个ABCA13、MMP12靶标的细胞外域相结合,其亲合力值(Kd)低于1x 10μM。
诊断抗体可用适于通过多种影像方法检测的探针来标记。探针检测方法包括但不限于荧光、自然光、共聚焦和电子显微镜;磁共振成像和磁共振波谱;荧光镜透视检查、计算机断层摄影和正电子发射断层摄影。适用的探针包括但不限于荧光素、罗丹明、曙红和其它荧光基团、放射性同位素、金、钆或其它镧系元素、顺磁离子、氟-18和其它正电子发射放射性核素。此外,上述探针可为双功能或多功能探针,且可用上述多种方法来检测。探针与抗体的结合方法包括探针共价结合、探针掺合入抗体、螯合物共价结合引发的探针结合以及其它常用的技术。用于免疫组织化学检测的病变组织样本可为新鲜或冷冻样本,也可为石蜡包埋样本或防腐剂(例如福尔马林)固定样本。固定或包埋切片样本与标记的初级抗体或次级抗体相接触,其中的抗体用于检测ABCA13、MMP12蛋白的原位表达。
因此本发明提出一种包含选自SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQID No.84和SEQ ID No.92或其(与SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92为90%同源)的变体序列的序列的肽,且上述序列或其变体序列可引发T细胞与上述肽的交叉反应。
本发明的肽具有与人主要组织相容性复合物(MHC)I类和/或II类分子相结合的能力。
在本发明中,“同源的”这一术语系指两个氨基酸序列(即肽或多肽序列)之间的同一度(参见上文中的百分同一度)。上文所述“同源性”通过将两个序列在最优条件下排列在需比较的序列之上来评定。此序列同源性可通过使用ClustalW等算法来建立序列对比来计算。公共数据库中提供了常用的序列分析软件(体为Vector NTI,GENETYX)或其它分析工具。
技术熟练的人员有能力评估由特定的肽变异序列引发的T细胞是否可与肽本身交叉反应(Fong et al.,2001);(Zaremba et al.,1997;Colombetti et al.,2006;Appay etal.,2006)。
发明者所使用的特定氨基酸序列的“变异序列”是指一或两个氨基酸残基的侧链发生改变(例如通过用另一天然氨基酸残基的侧链或其它的侧链来取代该侧链),但该肽仍可以与SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84以及SEQ ID No.92中特定氨基酸序列所组成的的肽基本相同的方式与HLA分子相结合。例如,某肽经修饰后至少可以维持(即使不能提高)与适当的MHC分子(例如HLA-A*02或-DR)的结合槽相反应和结合的能力,且至少可以维持(即使不能提高)与活化CTL的TCR相结合的能力。
上述CTL可与细胞进一步交叉反应,并可杀伤表达包含本发明所定义的关联肽的天然氨基酸序列的多肽。可从科学文献(Rammensee et al.,1997)以及数据库(Rammenseeet al.,1999)推断,HLA结合肽中的某些位置是典型的锚定残基,可形成一个核心序列,该序列可装配至HLA受体的结合基序。这一过程由组成结合槽的多肽链的极性、电子物理学特性、疏水性和空间特性所决定。由此本领域技术人员可通过维持已知的锚定残基来修饰SEQID No.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84和SEQ ID No.92所对应的氨基酸序列,并可确定此类变异序列是否可保持与MHC I或II类分子相结合的能力。本发明的变异序列可保留与活化CTL的TCR相结合的能力,后者可进一步与表达包含本发明所定义的关联肽的天然氨基酸序列的多肽的细胞交叉反应并杀死该细胞。
基本不参与与T细胞受体相互反应的氨基酸残可通过由另一氨基酸(其掺合基本不影响T细胞反应性且不消除与相关MHC的结合)取代来修饰。因此,除了上述条件外,本发明的肽可能是任何肽(发明者使用该术语时同时包含寡肽和多肽),包含给定的氨基酸序列或其片段或变异序列。
表4:与SEQ ID NO:1、2、4、5和7相对应的肽的变异序列和基序
较长的肽也可能适用。虽然MHC I类表型通常长度为8-11个氨基酸,但也有可能产生于包含实际表型的更长的肽或蛋白的加工。实际表型的侧面残基优选为基本不影响实际表型暴露所需的蛋白水解裂解的残基。
相应地,本发明也提出MHC I类表型的肽与变异序列,其中的肽或变异序列总长度为8至100个氨基酸(优选为8至30个氨基酸,最优选为8至14个,即8、9、10、11、12、13或14个氨基酸,而II类结合肽的长度也可为15、16、17、18、19、20,21或33个氨基酸)。
当然,本发明的肽或变异序列有能力与人主要组织相容性复合物(MHC)I类分子相结合。肽或变异序列与MHC的结合可由已知的方法来检测。
在本发明的一优选实施方案中,此类肽由、或基本由SEQ ID No.1至SEQ IDNo.65、SEQ ID No.76至SEQ ID No.84和SEQ ID No.92氨基酸序列所组成。
“基本由。。。组成”意指除SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92或其变体序列外,本发明的肽还包含额外的N或C末端氨基酸延伸,而该延伸对形成MHC分子表型所需的肽表型并非必需。
尽管如此,此类延伸有可能对根据本发明所述的肽有效导入细胞起到重要作用。在本发明的一优选实施方案中,肽可以是一种融合蛋白,例如含80个N末端氨基酸的HLA-DR抗原相关性不变链(p33,后面简称“Ii”)(衍生自NCBI,GenBank登记号X00497)。在其它融合中,本发明的肽可与本文所述的抗体(或其功能基团)(具体为抗体的序列)相融合,以此特异性的针对上述抗体,例如树突细胞特异性抗体。
此外,肽或变异序列可被进一步修饰以提高稳定性和/或与MHC分子的结合强度,以此激发更强的免疫应答。肽序列的此种优化方法为该技术领域所常用,例如导入反向肽键或非肽键。
在反向肽键中,氨基酸残基不通过肽的(-CO-NH-)键合而连接,而是通过反向的肽键。此类逆向拟肽可由本领域已知的方法所制得,例如Meziere et al(1997)J.Immunol.159,3230-3237(通过引用并入本文)中所描述的方法。这一方法包括制备含有骨架(而不是侧链方向)变化的假肽。Meziere等人(1997)表明,上述假肽有助于MHC结合与辅助T细胞应答。包含NH-CO键而不是CO-NH肽键的逆向肽对于蛋白水解更为耐抗。
非肽键包括-CH2-NH、-CH2S-、-CH2CH2-、-CH=CH-、-COCH2-、-CH(OH)CH2-、-CH2SO-等。美国专利4897445提出了一种多肽链中非肽键(-CH2-NH)固相合成的方法,其中涉及通过标准操作合成多肽,以及在NaCNBH3的参与下通过氨基醛与氨基酸反应来合成非肽键。
组成上述序列的肽可通过在其氨基和/或羧基端加入化学基团来合成,以此提高肽的稳定性、生物利用度和/或对肽的亲合力。例如可在肽的氨基末端加入芐氧羰基、丹酰基或t-叔丁氧羟基等疏水基团。类似地,可在肽的氨基末端加入乙酰基或9-芴甲氧羰基。此外,可在肽的羧基末端加入疏水基团、t-叔丁氧羟基或氨基。
本发明的肽也可通过改变其空间构型来合成。例如可使用肽的一种或多种氨基酸残基的D-异构体(而不是常见的L-异构体)。此外,本发明的肽的至少一个氨基酸残基可被一种常见的非天然氨基酸残基所取代。此类改变可提高本发明的肽的稳定性、生物利用度和/或结合活性。
类似地,本发明的肽或变异序列可通过与特定的氨基酸进行化学反应(在该肽的合成前后均可)来修饰。此类修饰的实施例为本领域所熟知,例如,在R.Lundblad所著的《Chemical Reagents for Protein Modification》(3rd ed.CRC Press,2005)(通过引用并入本文)对其进行了汇总。氨基酸的化学修饰包括但不限于酰化、胍基化、赖氨酸吡哆酸化、还原烷基化、用2,4,6-三硝基苯磺酸(TNBS)进行氨基的三硝基苯基化、羧基的酰胺修饰、通过半胱氨酸氧化为磺丙氨酸进行巯烃基修饰、汞衍生物的形成、与其它巯基化合物形成混合二硫化物、与马来酰亚胺反应、碘乙酸或碘乙酸胺引起的羧甲基化以及碱性环境下氰酸盐所引起的氨基甲酰化。有关蛋白化学修饰的更多方法,技术人员参考了《蛋白质科学最新技术方案》第15章,Eds.Coligan et al.(John Wiley and Sons NY 1995-2000)。
简而言之,蛋白中精氨酰残基等的修饰一般基于邻近的二碳化合物(例如苯乙二醛、2,3-丁二酮和1,2-环己二酮)以形成加成物。另例如甲基乙二醛与精氨酸残基的反应。半胱氨酸不经其它亲核位点(例如赖氨酸和组氨酸)的伴随修饰也可进行修饰,因此可用于半胱氨酸修饰的试剂数量众多。Sigma-Aldrich等公司的网站(http://www.sigma-aldrich.com)提供了特定试剂的信息。
蛋白二硫键的选择性还原也较常见。二硫键可在生物药物的热处理过程中形成和氧化。
Woodward试剂K可用于修饰特定的谷氨酸残基。N-(3-(二甲氨)丙基)-N’-碳酰二亚胺可用于形成赖氨酸残基和谷氨酸残基间的分子内交联。
例如,焦碳酸二乙酯试剂可用于修饰蛋白中的组氨酸残基。组氨酸也可用4-羟基-2-壬烯醛来修饰。
赖氨酸残基和其它α-氨基的反应有助于肽结合至蛋白/肽表面或与蛋白/肽的交联等。赖氨酸是聚(乙烯)乙二醇的附着位点,且是蛋白糖基化的主要修饰位点。
蛋白中的甲硫氨酸残基可用碘乙酰胺、溴乙胺和氯胺-T来修饰。
四硝基甲烷和N-乙酰基咪唑可用于酪氨酸残基的修饰。二酪氨酸形成所产生的交联可通过过氧化氢/铜离子来实现。
近期的色氨酸修饰研究使用了N-溴代琥珀酰亚胺、2-羟基-5-硝基溴化苄或3-溴基-3-甲基-2-(2-硝苯巯基)-3H-吲哚(BPNS-甲基吲哚)。
治疗用蛋白和肽成功的PEG修饰常涉及循环半衰期的延长。蛋白与戊二醛、丙烯酸聚乙二醇以及甲醛的交联用于水凝胶的制备。常通过氰酸钾氨的甲酰化来实现变应原化学修饰用于免疫治疗。
本发明实施方案中优选采用经过肽修饰的或包含非肽键的肽或变异体。一般而言,肽或变异体(至少为氨基酸残基间存在肽链合的肽或变异体)可通过Fmoc-聚酰胺固相肽合成法(如Lu等人(1981年)和本文的参考文献所述)来合成。9-芴甲氧羰基(Fmoc)可为时序N氨基提供保护。使用N,N-二甲基酰胺的20%哌啶溶液来进行这一高度碱基不稳定的保护基团的重复裂解。侧链功能的保护形式可为其丁基醚(丝氨酸、苏氨酸和酪氨酸的情况)、丁基酯(谷氨酸和天冬氨酸的情况)、叔丁氧羟基衍生物(赖氨酸和组氨酸的情况)、三苯甲基衍生物(半胱氨酸的情况)以及4-甲氧基-2,3,6-三甲基苯磺基衍生物(精氨酸的情况)。若谷氨酸或天冬氨酸为C末端残基,则使用4,4'-二甲基联苄来保护其侧链氨功能。固相支持的基础是由三种单体构成的聚二甲基-丙基酰胺聚合物:二甲基丙基酰胺(骨架单体)、二丙烯酰乙烯二胺(交联剂)和丙烯酰肌氨酸甲基酯(功能化剂)。所使用的肽-树脂可裂解连接剂为酸敏感性4-羟甲基-苯氧乙酸衍生物。加入的所有氨基酸衍生物皆为其预形成的对称酐衍生物,天冬氨酸和谷氨酸除外(其加成使用反向N,N-二环己基-碳化二亚胺/羟基苯并三唑介导的耦合程序)。所有耦合和脱保护反应均通过茚三酮、三硝基苯磺酸或异荷素检测程序来检测。合成完成后,肽被从树脂支承中裂解开,同时使用含50%清除剂混合物的95%三氟乙酸处理来移除侧链保护基团。常用的清除剂包括乙二硫醇、苯酚、苯甲醚和水,具体的选择取决于所合成肽的组成氨基酸。也有可能将固相和溶液相方法联合用于肽合成(参见(Bruckdorfer et al.,2004)及其所引用的参考文献等)。
三氟乙酸通过真空蒸发来去除,随后用二乙醚来碾制粗肽。留存的清除剂采用单一萃取程序来去除,随后将液相冻干制成不含清除剂的粗肽。肽合成所需的制剂基本可购自Calbiochem-Novabiochem(UK)Ltd,Nottingham NG72QJ,UK等。
可采用以下一种或多种技术组合进行纯化:再结晶、分子筛析色谱、离子交换色谱、疏水作用色谱和(通常为)反相高效液相色谱(采用乙腈/水梯度分离)。
可使用薄层色谱、电泳(特别是毛细管电泳)、固体萃取(CSPE)、反相高效液相色谱、酸水解后的氨基酸分析、快原子轰击(FAB)质谱分析,以及MALDI和ESI-Q-TOF质谱分析。
本发明的另一方面提出一种可编码本发明肽或肽变异体的核苷酸(例如多聚核苷酸)。此多聚核苷酸可为DNA、cDNA、PNA、RNA或其组合等,单链或双链皆可,或为多聚核苷酸的天然或稳定化形式,例如包含一个磷硫酰骨架的多聚肽。只要能编码所对应的肽,该多聚核苷酸包不包含内含子皆可。当然,多聚核苷酸仅可编码含由天然肽键结合的天然氨基酸残基的肽。本发明的另一方面提出一种可表达根据本发明所述的多肽表达载体。
已开发了多种方法以使多聚核苷酸(特别是DNA)与载体相连接,例如通过互补性粘性末端。举例而言,可在插入载体DNA的DNA片段中加入互补性同聚体区。该载体和DNA片段随后通过互补性同聚体尾之间的氢键来连接,以形成重组DNA分子。
包含一个或多个限制位点的合成连接子是DNA片段与载体相连接的另一种方法。包含多个限制位点的合成连接子可从多个渠道购得,例如InternationalBiotechnologies Inc.New Haven,CN,USA。
编码本发明的多肽的DNA的理想修饰方法之一使用聚合酶链式反应,如(Saiki etal.,1988)所述。该方法可用于将DNA导入合适的载体(例如合适限制位点的操作),也可用于在常见的技术中进行DNA修饰。若使用病毒载体,则宜使用痘病毒或腺病毒载体。
DNA(逆转录病毒载体则为RNA)可在合适的宿主中表达以产生含有本发明的肽或变异序列的多肽。因此可使用编码本发明的肽或变异序列的DNA,按已知的技术(根据本文作适当改进)来构建表达载体,该载体随后用于转化合适的宿主细胞使其表达和产生本发明的多肽。上述技术包括美国专利号4440859、4530901、4582800、4677063、4678751、4704362、4710463、4757006、4766075和4810648所述的技术。
编码本发明化合物的组成多肽的DNA(逆转录病毒载体则为RNA)可与许多其它DNA序列相结合以导入合适的宿主。伴侣DNA的选择取决于宿主的性质、将DNA导入宿主的方式以及是否需要附加型维持或整合。
一般而言,DNA以适当的方向和按正确的表达阅读框插入表达载体(例如质粒)。如有必要,可将DNA与适当的转录或翻译调控核苷酸序列(由期望的宿主所识别)相连接,虽然此类调控通常在表达载体中已存在。随后使用标准技术将载体导入宿主中。一般而言,并非所有宿主都会被载体所转化。因此有必要选择被成功转化的宿主细胞。有一种选择技术涉及使用任何必要的控制元素将一个DNA序列掺入表达载体中,该DNA序列可编码转化细胞的可选择特征(例如抗生素耐抗)。
此类可选择特征的基因也可位于用于共转化期望的宿主细胞的另一载体中。
经本发明的重组DNA转化的宿主细胞随后按本文的指导在适当的条件下(该条件为技术熟练人员所熟知)培养足够长时间以实现多肽的表达,随后可回收此多肽。
已知有多种表达系统,包括细菌(例如大肠杆菌、枯草杆菌)、酵母(例如啤酒酵母)、丝状真菌(例如曲霉属)、植物细胞、动物细胞和昆虫细胞。该系统优选为哺乳动物细胞,例如ATCC细胞生物学收集库中的CHO细胞。
用于组成型表达的典型哺乳动物细胞载体质粒包含带有一个适当的poly A尾和抗性标记的CMV或SV40启动子,例如新霉素。例如可购自Pharmacia,Piscataway,NJ,USA的pSVL。诱导性哺乳动物表达载体包括pMSG(也可购自Pharmacia)。有用的酵母质粒载体包括pRS403-406和pRS413-416,通常可购自Stratagene Cloning Systems,La Jolla,CA92037,USA。pRS403、pRS404、pRS405和pRS406质粒属于酵母整合型质粒(YIP),掺入了酵母可选择标记HIS3、TRP1、LEU2和URA3。pRS413-416质粒属于酵母中心粒质粒(Ycp)。含CMV启动子的载体(例如Sigma-Aldrich供应的载体)可产生顺势或稳定表达、细胞质表达或分泌,以及多种FLAG、3xFLAG、c-myc或MAT组合形式的N末端或C末端标记。此类融合蛋白可实现重组蛋白的检测、纯化和分析。双标记融合可使检测具有灵活性。
强效人巨细胞病毒(CMV)启动子调控区可使COS细胞中组成蛋白的表达水平高达1mg/L。而较弱细胞系的蛋白水平通常为约0.1mg/L。存在SV40复制起点可在SV40复制受纳COS细胞中引发高水平的DNA复制。CMV载体可含有细菌细胞中的pMB1(pBR322衍生物)复制起点、细菌中氨苄西林耐抗选择的b-内酰胺酶基因、hGH polyA以及f1起点。胰蛋白酶原前前导(PPT)序列的载体可将FLAG融合蛋白的分泌导入培养基中,以使用抗-FLAG抗体、树脂和板进行纯化。其它载体和表达系统使用该技术领域常用的多种宿主细胞。
在另一实施方案中,本发明的两种或两种以上的肽或肽变异体被编码并相继表达(类似于“线珠”(beads on a string)结构)。由此可将肽或肽变异体与连接氨基酸的延伸基团(例如LLLLLL)相连接或融合,其间没有任何其它肽时,也可相连接。
本发明还涉及一种由本发明的一种多聚核苷酸载体结构所转化的宿主细胞。该宿主细胞可为原核或真核细胞。某些情况下,细菌细胞是优先使用的原核宿主细胞,通常是大肠杆菌株,例如大肠杆菌DH5菌种,可购自BethesdaResearch Laboratories Inc.,Bethesda,MD,USA以及RR1菌种,可供自美国典型培养物保藏中心(ATCC)(Rockville,MD,USA(No ATCC 31343)。优先选用的真核宿主细胞包括酵母、昆虫和哺乳动物细胞,优选为脊椎动物细胞,例如小鼠、大鼠、猴或人成纤维细胞或结肠细胞系。酵母宿主细胞包括YPH499、YPH500和YPH501,通常可购自Stratagene Cloning Systems,La Jolla,CA 92037,USA。优先选用的哺乳动物宿主细胞包括中国仓鼠卵巢(CHO)细胞(ATCC CCL61细胞系)、NIH瑞士小鼠胚胎细胞NIH/3T3(ATCC CRL 1658)、猴肾源COS-1细胞(ATCC CRL 1650细胞系)以及293细胞(人真核肾脏细胞)。优先使用的昆虫细胞包括Sf9细胞(可通过杆状病毒表达载体转染)。合适的表达用宿主细胞的选择的综述可参见Paulina Balbás和Argelia Lorence的教科书《分子生物技术重组基因表达的方法:综述与方案》第2版第1部分,ISBN978-1-58829-262-9,以及为熟练人员所知的其它文献。
通过本发明的DNA结构对宿主细胞进行适当的转化可通过常见的方法来实现,该方法通常依赖于所使用的载体类型。原核宿主细胞转化方面的信息可参见Cohen et al(1972)Proc.Natl.Acad.Sci.USA 69,2110以及Sambrook et al(1989)MolecularCloning,A Laboratory Manual,Cold Spring Harbor Laboratory,Cold Spring Harbor,NY等。酵母细胞的转化方法参见Sherman et al(1986)Methods In Yeast Genetics,ALaboratory Manual,Cold Spring Harbor,NY。Beggs(1978)Nature 275,104-109所提供的方法同样有用。脊椎动物细胞方面,可用于转染该类细胞的试剂(例如磷酸钙和DEAE-乙基葡聚糖或脂质体制剂)可购自Stratagene Cloning Systems或Life Technologies Inc.,Gaithersburg,MD 20877,USA。电穿孔也可用于细胞的转化和/或转染,该方法常用于酵母细胞、细菌细胞、昆虫细胞和脊椎动物细胞转化技术中。
成功转化的细胞(即包含本发明的DNA结构的细胞)可通过常见的PCR等技术来识别,或者可使用抗体来检测上清液中的蛋白质。
有价值的是,本发明的某些宿主细胞(例如细菌、酵母和昆虫细胞)可用于本发明的肽的制备。但其它宿主细胞也可能用于某些治疗方法。例如,抗原呈递细胞(例如树突细胞)有可能用于表达本发明的肽,此肽可能被载入适当的MHC分子中。因此本发明提出根据本发明所述的包含氨基酸的宿主细胞或表达载体。
在一个优选的实施方案中,宿主细胞是抗原呈递细胞,特别是树突细胞或抗原呈递细胞。载入了含前列腺酸性磷酸酶(PAP)的重组融合蛋白的APC(Sipuleucel–T)目前正研究用于治疗前列腺癌(Small et al.,2006;Rini et al.,2006)。
本发明的另一方面还包括一种肽或其变异体的制备方法,该方法包括培养宿主细胞以及将肽从宿主细胞或其培养基中分离。
在另一实施方案中,本发明的肽、核酸或表达载体被用于药物中。例如,可将肽或其变异体制成静脉(i.v.)注射剂、皮下(s.c.)注射剂、皮内(i.d.)注射剂、腹膜内(i.p.)注射剂和肌肉(i.m.)注射剂。优先选用的肽注射方法包括皮下、皮内、腹膜内和静脉注射。优先选用的DNA注射方法包括皮内、肌肉、皮下、腹膜内和静脉注射。所给予的肽或DNA剂量可为50μg至1.5mg之间(优选为125μg至500μg之间),具体取决于肽或DNA类型。该剂量范围在既往试验中曾被成功使用(Walter et al Nature Medicine 18,1254–1261(2012))。
本发明的另一方面包括一种体外制备活化T细胞的方法,该方法涉及将体外T细胞与负载抗原的人MHC分子相接触,该分子在合适的抗原呈递细胞表面表达足够长的时间以抗原特异性地激活T细胞,其中所述抗原为根据本发明所述的肽。宜采用抗原呈递细胞使用足量的抗原。
理想情况下哺乳动物应缺少或具备降低的TAP肽转运体水平或功能。缺少TAP肽转运体的合适细胞包括T2、RMA-S和果蝇细胞。TAP是与抗原加工相关的转运体。
可携带缺失T2细胞系的人体肽参见美国典型培养物保藏中心(ATCC)(12301Parklawn Drive,Rockville,Maryland 20852,USA)目录号CRL 1992;Drosophila细胞系Schneider细胞系2可参见ATCC目录号CRL 19863;小鼠RMA-S细胞系详情参见Karre etal 1985。
理想情况下,转染前的宿主细胞应基本不表达MHC I类分子。优先使用一种刺激细胞,该细胞可表达对于T细胞共刺激信号(例如B7.1、B7.2、ICAM-1和LFA 3)具有重要作用的分子。许多MHC I类分子和共刺激分子的核酸序列可参见公共的GenBank和EMBL数据库。
若将MHC I类表型用作抗原,则T细胞为CD8阳性CTL。
若将抗原呈递细胞转染用于表达上述表型,则该细胞宜包含可表达含SEQ IDNo.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84和SEQ ID No.92序列的肽(或其变异氨基酸序列)的表达载体。
另有数种方法可用于体外制备CTL。例如Peoples等人(1995)和Kawakami等人(1992)所描述的方法使用自体肿瘤浸润淋巴细胞来制备CTL。Plebanski等人(1995)使用自体外周血淋巴细胞(PLB)制备CTL。Jochmus等人(1997)描述了通过用肽或多肽冲击树突细胞(或通过重组病毒感染)来制备自体CTL。Hill等人(1995)和Jerome等人(1993)使用B细胞制备自体CTL。此外,经肽或多肽冲击或经重组病毒感染的巨噬细胞也可用于制备自体CTL。S.Walter等人(2003)描述了使用人工抗原呈递细胞(aAPC)来体外激发T细胞,这种方法也适用于制备抗首选肽的T细胞。该研究中通过将预成MHC/肽复合物耦合至聚苯乙烯粒子(微珠)表面(通过生物素/抗生蛋白链霉素生物化学机制)来产生aAPC。该系统可实现aAPC中MHC密度的精准控制,由此可从血液样本中选择性地高效激发高亲合力或低亲合力的抗原特异性T细胞应答。除MHC/肽复合物外,aAPC还应携带其它具有共刺激活性的蛋白(耦合至aAPC表面),例如抗CD28抗体。此外,此类aAPC系统常需要加入适当的可溶性因子,例如白介素-12等细胞因子。
也可使用同种异体细胞来制备T细胞,其中一种方法详述于WO 97/26328(通过引用而成为本文的一部分)。举例而言,除Drosophila细胞和T2细胞外,其它细胞也可用于抗原呈递,例如CHO细胞、感染杆状病毒的昆虫细胞、细菌、酵母、感染牛痘的靶细胞等。此外还可使用植物病毒(参见Porta et al(1994)等),该文献描述了将豇豆花叶病毒开发为外源性肽呈递的高产系统。
靶标为本发明的肽的活化T细胞可用于治疗。因此本发明的另一方面提出可通过本发明上述方法获得的活化T细胞。
通过上述方法制得的活化T细胞可选择性地识别异常表达一种含有SEQ ID No.1至SEQ ID No.92(优选为SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ ID No.84和SEQ ID No.92)氨基酸序列的多肽的细胞。
优选情况是,T细胞通过其TCR与HLA/肽复合物相互反应(例如结合)来识别细胞。T细胞可用于一种靶细胞杀伤方法,其中患者的靶细胞异常表达含本发明氨基酸序列的多肽,且患者接受有效数量的活化T细胞。患者接受的T细胞可来源于患者自身并通过上述方法活化(即为自体T细胞)。该T细胞也可并非来自患者自身而是来自另一个体。当然,该个体优选为健康个体。发明者所用“健康个体”系指个体的总体健康状况良好,优选为具有完备的免疫系统,更优选为未患有易于检测或发现的疾病。
在体内,根据本发明所述的CD8阳性T细胞的靶细胞可为肿瘤细胞(某些情况下表达MHC II类)和/或肿瘤(肿瘤细胞)周围的间质细胞(某些情况下也可表达MHC II类;(Dengjel et al.,2006))。
本发明的T细胞可用作治疗组分中的活性成分。因此本发明还提出一种靶细胞杀伤方法,其中患者的靶细胞异常表达含本发明氨基酸序列的多肽,且患者接受有效数量的活化T细胞(如上文所定义)。
发明者使用“异常表达”系指多肽相比于正常表达水平过量表达,或在肿瘤中表达的基因在肿瘤组织标本中沉默。发明者使用“过量表达”系指多肽的表达水平至少为正常组织中的1.2倍,优选为正常组织中的至少2倍,更优选为至少5倍或10倍。
T细胞可通过本领已知的技术方法制得,例如上文所述方法。
T细胞的所谓过继性转移方法为常见的技术方法。其综述可参见(Gattinoni etal.,2006)和(Morgan et al.,2006)。
本发明的任何分子(即肽、核苷酸、抗体、表达载体、细胞、活化CTL、T细胞受体或其编码核苷酸)均可用于治疗特征为细胞逃脱免疫应答的疾病。因此本发明的任何分子均可能用作药剂或用于药剂生产。上述分子可单独使用或与本发明的其它分子或已知的分子结合使用。
优选情况是,本发明的药剂是一种疫苗。该疫苗可直接给予患者的病变器官或通过皮内、肌肉、皮下、腹膜内和静脉全身给药;或离体作用于源自患者的细胞或人细胞系中,随后将该细胞或细胞系给予患者;或在体外作用于源自患者的免疫细胞亚群,随后将该免疫细胞再次给予患者。若在体外给予细胞核苷酸,则将细胞转染以共表达免疫刺激细胞因子(例如白介素2)可能有所帮助。所用的肽可为基本纯净或与免疫刺激辅剂(见下文)联合使用,或通过合适的传递系统(例如脂质体)来给药。肽也可与合适的载体(例如钥孔戚血蓝素或甘露聚糖)相结合(参见WO 95/18145和Longenecker,1993)。肽也可进行标记,可为融合蛋白,也可为杂交分子。根据本发明所述的序列所编码的肽预期可刺激CD4或CD8T细胞,但刺激CD8CTL在CD4辅助T细胞的协助下更为高效。因此,对于刺激CD8CTL的MHC I类表型而言,使用融合伴侣或杂交分子剖面可适当产生刺激CD4阳性T细胞的表型。CD4和CD8刺激表型在相关技术领域常见,包括本发明所提出的表型。
一方面,疫苗包含具有SEQ ID No.1至SEQ ID No.92氨基酸序列的至少一种肽,以及至少一种其他肽,优选为2至50种其他肽,更优选为2至25种,再更优选为2至20种,最优选为2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18种其他肽。肽可源自一种或多种特异性TAA,且可与MHC I类分子相结合。
另一方面,疫苗包含具有SEQ ID No.1至SEQ ID No.65、SEQ ID No.76至SEQ IDNo.84和SEQ ID No.92氨基酸序列的至少一种肽,以及至少一种其他肽,优选为2至50种其他肽,更优选为2至25种其他,再更优选为2至20种其他肽,最优选为2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18种肽。肽可源自一种或多种特异性TAA,且可与MHC I类分子相结合。
多肽可为基本纯净,或包含在合适的载体或传递系统中。核苷酸可为DNA、cDNA、PNA、RNA或DNA、cDNA、PNA、RNA的组合(Pascolo et al.,2005)。多聚核苷酸疫苗易于制备,但此类载体诱导免疫应答的作用方式尚不完全清楚。合适的载体和传递系统包括病毒DNA和/或RNA,例如腺病毒、牛痘病毒、逆转录病毒、疱疹病毒、腺相关病毒系统,或含有多种病毒原件的杂交体。非病毒传递系统包括阳离子脂质和阳离子多聚体,此类系统为DNA传递技术所常见。也可使用物理传递方法,例如“基因枪”。由核酸编码的肽可为融合蛋白,例如含有刺激T细胞相应CDR的T细胞的表型的融合蛋白。
本发明的药剂也可含有一种或多种辅剂。辅剂是指可非特异性地提高或增强对抗原的免疫应答(例如CTL和辅助T(TH)细胞所介导的免疫应答)的物质,因此可认为对本发明的药剂有用。合适的辅剂包括但不限于1018ISS、铝盐、AS15、BCG、CP-870,893、CpG7909、CyaA,dSLIM、鞭毛蛋白或鞭毛蛋白的TLR5配体、FLT3配体、GM-CSF、IC30、IC31、咪喹莫特瑞奎莫特、ImuFact IMP321、IL-2、IL-13、IL-21等白介素、干扰素-α或干扰素-β或其PEG化衍生物、IS贴剂、ISS、ISCOMATRIX、ISCOMs、LipoVac、MALP2、MF59、单磷酸类脂A、山小星蒜碱IMS 1312、山小星蒜碱ISA 206、山小星蒜碱ISA50V、山小星蒜碱ISA-51、油包水和水包油乳剂、OK-432、OM-174、OM-197-MP-EC、ONTAK、OspA、载体系统、聚羟基乙酸共聚物[PLG]和葡聚糖微利、乳铁传递蛋白SRL172、病毒小体或其它病毒样颗粒、YF-17D、VEGF陷阱、R848、β-葡聚糖、Pam3Cys、AquilaQS21促病毒素(衍生自皂角苷)、分支杆菌提取物和合成细菌细胞壁模拟物,以及其它专利辅剂例如Ribi's Detox、Quil或Superfos。优选佐剂如:Freund或GM-CSF。针对树突细胞的数种免疫辅剂(例如MF59)及其制剂曾有报告(Allison and Krummel,1995;Allison andKrummel,1995)。此外可使用细胞因子。已发现数种细胞因子可直接影响树突细胞迁移至淋巴组织(例如TNF-),由此加速树突细胞成熟为T淋巴细胞高效抗原呈递细胞(例如GM-CSF、IL-1和IL-4)(美国专利编号5849589,特别以完整引用形式并入本文)并起到免疫辅剂的作用(例如IL-12、IL-15、IL-23、IL-7、IFN-α、IFN-β)(Gabrilovich,1996)。
也有报告称CpG免疫刺激性寡核苷酸可增强疫苗中辅剂的作用。不受理论约束,CpG寡核苷酸可通过Toll样受体(TLR)(主要是TLR9)产生激活先天(非适应性)免疫系统。CpG触发的TLR9活化可增强对一系列抗原的抗原特异性体液性或细胞性应答,包括肽或蛋白抗原、活病毒或死病毒、树突细胞疫苗、自体细胞疫苗以及预防性和治疗性疫苗中的多糖结合物。更重要的是,该活化可促进树突细胞成熟和分化,引发TH1细胞活化和强细胞毒性T淋巴细胞(CTL)生成的增多(即使不存在CD4T细胞的协助)。即使存在通常促进TH2偏倚的不完全弗氏佐剂(IFA),TLR9刺激所引发的TH1偏倚仍可以维持。CpG寡核苷酸与其它辅剂联合给药时或在微粒、毫微粒、脂质乳剂或类似制剂中可产生更高的辅助活性,这对于效力相对较弱的抗原引发较强的应答尤为必要。CpG寡核苷酸还可加速免疫应答并确保抗原剂量降低约2个数量级,其所产生的抗体应答与不使用CpG的某些试验中的全剂量疫苗相当(Krieg,2006)。美国6406705B1号专利描述了CpG寡核苷酸、非核苷酸辅剂和抗原联合使用以引发抗原特异性免疫应答。一种CpG TLR9拮抗剂为Mologen公司(德国柏林)的dSLIM(双干环免疫调节剂),这是本发明药物组合物的优选成分。也可使用其它TLR结合分子,例如RNA结合性TLR 7、TLR8和/或TLR9。
其他有用的辅剂还包括但不限于化学修饰的CpGs(例如CpR,Idera)、dsRNA类似物(例如聚(I:C))及其衍生物(例如聚(ICLC)、聚(IC-R)、聚(I:C12U))、非CpG细菌DNA或RNA,以及免疫活性小分子和抗体,例如环磷酰胺、舒尼替尼、西乐葆、NCX-4016、昔多芬、他达拉非、伐地那非、索拉非尼、替莫唑胺、驮瑞塞尔、XL-999、CP-547632、帕唑帕尼、VEGF陷阱、ZD2171、AZD2171、抗-CTLA4、其它针对免疫系统关键结构的抗体(例如抗-CD40、抗-TGFβ、抗-TNFα受体)以及SC58175(可起到治疗作用并/或用作辅剂)。本领域技术人员无需过度进行不当实验就很容易确定本发明中有用的佐剂和添加剂的数量和浓度。
优先选用的辅剂包括咪喹莫特、瑞奎莫特、GM-CSF、环磷酰胺、舒尼替尼、贝伐单抗、干扰素-α、CpG寡核苷酸及衍生物、聚(I:C)和衍生物、RNA、昔多芬以及含有PLG或病毒小体的颗粒剂型。
在一个优选的实施方案中,本发明的药物组成中的辅料选自一组集落刺激因子,例如粒细胞-巨噬细胞集落刺激因子(GM-CSF,沙漠司亭)、环磷酰胺、咪喹莫特、瑞奎莫特和干扰素-α。
在一个优选的实施方案中,本发明的药物组成中的辅料选自一组集落刺激因子,例如粒细胞-巨噬细胞集落刺激因子(GM-CSF,沙漠司亭)、环磷酰胺、咪喹莫特和瑞奎莫特。
在根据本发明的药物组合物的一个优选实施方案中,辅剂为环磷酰胺、咪喹莫特或瑞奎莫特。.
这一组成用于经肠给药,例如皮下、皮内、肌肉或口服给药。为方便给药,肽或其它分子溶解或混悬于药用、优选为液体的载体中。此外,药物组合物可包含辅料(例如缓冲剂、结合剂、爆炸剂、稀释剂、增味剂、润滑剂等)。肽也可与免疫刺激物质(例如细胞因子)联合给药。此药物组合物可用辅料的更广泛的列表可参见A.Kibbe,Handbook ofPharmaceutical Excipients,3rd Ed.,2000,American Pharmaceutical Association andpharmaceutical press等。此组合物可用于腺瘤样或癌性疾病的预防和/或治疗。典型的制剂可参见EP2113253等。
尽管如此,根据本发明的肽的数量和物理化学性质,需进行进一步研究以产生肽的特定组合制剂,特别是含超过20个肽、稳定期超过12至18个月的组合制剂。
本发明提出一种可用于治疗癌症的药剂,特别是非小细胞肺癌、胃癌、肾细胞癌、结肠癌、腺癌、前列腺癌、良性肿瘤和恶性黑素瘤。
本发明还涉及下列试剂盒:
(a)包含上述药物组合物的包装,可为溶液或冻干剂型;
(b)(非必需)包含冻干制剂的稀释剂或复溶溶液的次级包装;
(c)(非必需)(i)溶液使用或(ii)冻干制剂复溶和/或使用说明书。
该试剂盒还可包含(iii)缓冲剂、(iv)稀释剂、(v)过滤器、(vi)针头或(v)注射器中的一种或多种。包装优选为药瓶、西林瓶、注射器或是试管,可为多用途包装。药物组合物优选为冻干制剂。
本发明的药物包装宜包含本发明的冻干制剂(带有合适的包装及其复溶和/使用说明书)。合适的包装包括药瓶、西林瓶(例如双腔西林瓶)、注射器(例如双腔注射器)和试管。理想情况下试剂盒和/或包装应在包装上或包装中加入复溶和/或使用说明。例如,可在标签中注明应将冻干制剂复溶至上述肽浓度。可在标签中进一步注明该制剂可用于或预定用于皮下给药。
存放制剂的包装可为多用途西林瓶,以便进行复溶制剂的重复给药(例如2-6次给药)。试剂盒中可包含另一装有适当稀释剂(例如碳酸氢钠溶液)的包装。
将稀释剂和复溶制剂混合后所得的最终复溶制剂中的肽浓度优选为至少0.15mg/mL/肽(=75μg)且不超过3mg/mL/肽(=1500μg)。试剂盒中还可包含其它销售和使用者方面的材料,包括其它缓冲剂、稀释剂、过滤器、针头、注射器和包含使用说明的说明书。
本发明的试剂盒可为根据本发明所述药物组合物制剂的单一包装,含有或不含有其它成分(例如其它化合物或这些化合物的药物组合物)皆可,也可为每一成分提供独立的包装。
理想情况下,本发明的试剂盒包含本发明的一种制剂,用于与另一化合物(例如辅剂(GM-CSF等)、化疗药物、天然制品、激素或拮抗剂、抗血管生成剂或血管生成抑制剂、雕亡诱导剂或螯合剂)或其药物组合物联合给药。在患者给药前,试剂盒的成分可为预混合,也可为每一成分提供独立包装。试剂盒的成分可为一种或多种液体溶液,优选为水性溶液,更优选为无菌水性溶液。试剂盒成分也可为固体,可通过加入适当的溶剂来转换为液体,该溶剂宜保存在另一独立包装中。
治疗试剂盒的包装可为西林瓶、试管、细颈瓶、药瓶、注射器或包封固体或液体的任何其它装置。通常情况下,若存在不止一种成分,则试剂盒会包含另一西林瓶或其它包装,以便于分开给药。试剂盒也可包含另一包装用于存放药用液体。理想情况下,治疗试剂盒应包含一种装置(例如一个或多个针头、注射器、滴眼管、移液管等),用于该试剂盒组分中本发明药物的给药。
本制剂允许用任何可接受的途径(例如口服(肠内)、鼻内、眼内、皮下、皮内、肌肉、静脉或经皮给药)进行肽的给药。优先使用皮下给药,皮内给药最宜使用输注泵。
由于本发明的肽分离自NSCLC,因此本发明的药剂优选用于治疗NSCLC。在一个优选实施方案中,由于源自ABCA13和MMP12的本发明的肽分离自NSCLC,因此本发明的药剂宜用于治疗NSCLC。
序列为SEQ ID Nos.78至92的肽分离自Merkel细胞癌,因此可用于治疗Merkel细胞癌。
现将在以下示例(描述其优先使用的实施方案)中介绍本发明,但不限于这些示例。出于本发明的目的,所有参考文献均以完整引用形式并入本文。
附图说明
图1示出ABC13-001的示例性质谱图,表明其在原发肿瘤样本NSCLC898中的呈递。对从NSCLC样本898洗脱的肽池进行NanoESI-LCMS。A)m/z 543.8318±0.001Da,z=2的质谱图呈现保留时间为86.36min的肽峰。B)质谱图中86.36min处的检测峰代表MS谱中的m/z543.8318信号。C)nanoESI-LCMS试验中特定保留时间处所记录的m/z 543.8318选定前体的碰撞衰变质谱证实NSCLC898肿瘤样本中存在ABCA13-001。D)记录了合成型ABCA13-001参考肽的裂解谱并与C中所生成的天然TUMP裂解谱相比较,以进行序列验证。
图2a和2b示出选定蛋白在正常组织和21份肺癌样本中的表达谱,其中图2a示出ABCA13(Probeset ID:1553605_a_at),图2b示出MMP12(Probeset ID:204580_at)的表达谱。
图3a-3c示出选定HLA I类分子的呈递谱。测算了每种肽的表达谱,给出样本平均表达量以及重复检测方差。谱中将相关的肿瘤样本与正常组织样本(基线)相并列。其中图3a示出ABCA13-001,图3b示出DST-001,图3c示出MXRA5-001的HLA I类分子呈递谱。
图4示出I类TUMAPs肽特异性体外免疫原性的示例性结果。特异性CD8+T细胞用连接两种不同荧光色素的HLA多聚体来染色。点状图代表刺激肽的MHC多聚体双阳性肽群(左图)以及相应的阴性对照刺激(右图)。
图5示出POSTN-002和MMP12-002对所研究的HLA单倍型的结合特性。图示为POSTN-002和MMP12-002对7种接受分析的HLA-DR单倍型中的5种的结合评分。
图6示出HLA-POSTN-002和MMP12-002复合物在37℃下放置24h的稳定性:图示出带有相应HLA分子的完整HLA-POSTN-002和HLA-MMP12-002复合物在37℃下放置24h后的结合评分百分比。
图7示出II类ICS分析中疫苗诱导的对CEA-006的典型CD4T细胞应答。体外致敏后,对36-031号患者的PBMCs进行分析以检测时间点池V8/EOS处CD4T细胞对CEA-006(上图)与模拟对照(下图)的应答。细胞用相应的肽刺激,并分别用细胞活力、抗CD3、抗CD-8、抗CD4和效应标记物(从右至左:CD154,TNF-α,IFN-γ,IL-2,IL-10)来染色。
图8示出多种II类肽的免疫原性。图示为使用ICS检测的对5种II类肽的免疫应答率(16名患者为IMA950肽,71名患者为IMA910肽)。
实施例
实施例1:细胞表面呈递的肿瘤相关性肽的鉴定与定量
组织样本
患者肿瘤样本由University of Heidelberg,Heidelberg,Germany提供。术前所有患者均给予了书面知情同意。手术结束后立即将组织在液氮中急速冷冻并保存于-80℃下,直至TUMAPs的分离。
从组织样本中分离HLA肽
按照一种略有改动的方案(Falk,K.,1991;Seeger,F.H.T.,1999),通过固态组织的免疫沉淀从急速冷冻样本获取HLA肽池,该方案使用HLA-A*02特异性抗体BB7.2、HLA-A、-B、C-特异性抗体W6/32、CNBr活化的琼脂糖、酸处理以及超滤。
方法
采用反相色谱(Acquity UPLC system,Waters)依据其疏水性对获取的HLA肽池进行分离,并用LTQ-轨道阱杂交质谱仪(ThermoElectron)(带有ESI源)对洗脱肽进行分析。肽池直接载入烧结二氧化硅微毛细管分析柱(75μm i.d.x 250mm),填充剂为1.7μm C18反相材料(Waters),流速为400nL/min。随后以300nL/min的流速进行从10%至33%B的二步二元梯度洗脱180min以分离肽。该梯度包括溶剂A(0.1%甲酸水溶液)和溶剂B(0.1%甲酸乙腈溶液)。采用包金玻璃柱(PicoTip,New Objective)来导入nanoESi源。LTQ-轨道阱质谱仪的操作采用数据依赖模式中的TOP5策略。简言之,在轨道阱中进行高质量准确度的全扫描以启动扫描周期(R=30000),随后依然在轨道阱中对含量最高的5种前体离子进行MS/MS扫描(R=7500)。采用SEQUEST和其它人工对照物进行串联质谱解析。通过将所生成的天然肽断裂谱与合成型同一序列参考肽的断裂谱相对比来确认所识别的肽序列。图1为肿瘤组织中MHC I类相关肽ABCA13-001在UPLC系统中的典型图谱及其洗脱图谱。
使用离子计数进行了无标记相对LC-MS定量分析(即LC-MS特征的提取和分析)(Mueller et al.2007a)。该方法假定肽的LC-MS信号面积与其在样本中的含量相关。随后通过电荷状态去卷积和保留时间校正对所提取的特征进行了进一步处理(Mueller etal.2007b;Sturm et al.2008)。最后将所有LC-MS特征与序列鉴定结果交叉参考,以将不同样本和组织的定量数据与肽呈递谱相结合。考虑到重复检测中的技术和生物变异性,根据中心趋势对定量数据作双层正态化。因此识别的每种肽均可与定量数据相关联,以实现样本和组织间的相对定量分析。此外,从候选肽获取的所有定量数据均作人工检查以确保数据一致性,并核实自动分析的准确性。测算了每种肽的表达谱,给出了样本平均表达量以及重复检测方差。该图谱将相关肿瘤样本与正常组织样本(基线)相并列。
示例性的过呈递肽的呈递谱示于图3。
实施例2:编码本发明肽的基因的表达谱测定
不是所有被鉴定为通过MHC分子呈递在肿瘤细胞表面的肽都适用于免疫治疗,因为这些肽中的大多数来自由众多细胞类型所表达的正常细胞蛋白。此类肽中仅有极少数与肿瘤相关并极有可能诱发对其源肿瘤具有高度识别特异性的T细胞。为明确此类的肽并尽量降低疫苗引起的自体免疫风险,发明者重点关注源自在肿瘤细胞中过量表达(相比于多数正常组织)的蛋白的肽。
理想的肽应源自相关肿瘤中所独有的且不存在于其它任何组织中的蛋白。为明确表达谱与理想表达谱相近的基因所衍生的肽,将所识别的肽分别与其来源蛋白和基因相并列,并生成此类基因的表达谱。
RNA来源和制备
手术切除组织标本由University of Heidelberg,Heidelberg,Germany(参见实施例1)提供。术前所有患者均给予了书面知情同意。手术结束后立即将肿瘤组织标本在液氮中急速冷冻,随后使用研钵和研棒在液氮环境中进行匀化。使用TRI试剂(Ambion,Darmstadt,Germany)从上述样本中制备总RNA,随后用RNeasy(QIAGEN,Hilden,Germany)进行RNA纯化;上述方法均按照制造商的说明来进行。
健康人体组织总RNA购自Ambion,Huntingdon,UK;Clontech,Heidelberg,Germany;Stratagene,Amsterdam,Netherlands;BioChain,Hayward,CA,USA。将来自多个个体(2到123个个体)的RNA进行混合以使来自各个体的RNA比重相同。
采用RNA 6000Pico LabChip试剂盒(Agilent),用Agilent 2100生物分析仪(Agilent,Waldbronn,Germany)对所有RNA样本进行定性和定量分析。
微阵列试验
所有肿瘤和正常组织RNA样本的基因表达分析均使用Affymetrix人基因组(HG)U133A或HG-U133Plus 2.0寡核苷酸微阵列(Affymetrix,Santa Clara,CA,USA)。所有步骤均按照Affymetrix的说明书开展。简言之,按照说明书所述,使用SuperScript RTII(Invitrogen)和寡-dT-T7引物(MWG Biotech,Ebersberg,Germany)从5-8μg总RNA合成双链cDNA。使用生物阵列高产RNA转录标记试剂盒(ENZO Diagnostics,Inc.,Farmingdale,NY,USA)(针对U133A阵列)或GeneChip IVT标记试剂盒(Affymetrix)(针对U133Plus 2.0阵列)进行体外转录,随后使用抗生蛋白链霉素-藻红蛋白以及生物素化抗-抗生蛋白链霉素抗体(Molecular Probes,Leiden,Netherlands)进行cRNA链断裂、杂交和染色。随后用Agilent2500A基因阵列扫描仪(U133A)或Affymetrix基因芯片扫描仪3000(U133Plus 2.0)进行图像扫描,并用GCOS软件(Affymetrix)(所有参数均为默认设定)进行资料分析。使用了Affymetrix提供的100个管家基因。使用软件所提供的信号对数比计算相对表达值,并将正常肾脏样本值任意设定为1.0。
在非小细胞肺癌中高度过量表达或独特表达的本发明的源基因的示例性表达谱见图2。
实施例4:MHC I类呈递肽对NSCLC的体外免疫原性
为获得本发明TUMAP的免疫原性信息,我们使用体外T细胞启动分析进行研究,采用负载肽/MHC复合物的人工抗原呈递细胞(aAPCs)对CD8+T细胞进行反复刺激。通过此方法我们明确了本发明迄今为止对9种HLA-A*0201限制性TUMAPs的免疫原性,表明此类肽为T细胞表型,且在人体中存在其CD8+前体T细胞(表4)。
CD8+T细胞的体外启动
为使用负载肽-MHC复合物(pMHC)和抗-CD28抗体的人工抗原呈递细胞进行体外刺激,我们首先使用CD8微珠(Miltenyi Biotec,Bergisch-Gladbach,Germany)进行正向选择以从新鲜HLA-A*02白细胞分离产物(来自Transfusion Medicine Tuebingen,Germany的给予知情同意的健康供者)中分离CD8+T细胞。
分离的CD8+淋巴细胞或PBMCs持续培养直至用于含RPMI-GutaMax的T细胞培养基(TCM)(Invitrogen,Karlsruhe,Germany)中,该培养基加入了10%热失活人AB血清(PAN-Biotech,Aidenbach,Germany)、100U/ml青霉素/100μg/ml链霉素(Cambrex,Cologne,Germany)、1mM丙酮酸钠(CC Pro,Oberdorla,Germany)、20μg/ml庆大霉素(Cambrex)。另在此步骤中向TCM中加入2.5ng/ml IL-7(PromoCell,Heidelberg,Germany)和10U/ml IL-2(Novartis Pharma,Nürnberg,Germany)。
采用明确定义的体外系统(每种刺激条件使用4种不同的pMHC分子,每种读出条件使用8种pMHC分子)进行pMHC/抗-CD28涂珠的生成、T细胞刺激和读出。
aAPC载入和细胞读数所用的所有pMHC复合物均由UV诱导的MHC配体交换来产生(Rodenko et al.,2006,有微小的改动)。为测定通过交换所得的pMHC单体数量,我们依据(Rodenko et al.,2006)的方法进行了抗生蛋白链霉素夹心ELISA。
纯化共刺激鼠IgG2a抗人CD28抗体9.3(Jung et al.,1987)使用生产商(Perbio,Bonn,Germany)推荐的硫代-N-羟基琥珀酰亚胺基生物素进行化学生物素化。所使用的微珠为5.6μm直径抗生蛋白链霉素,涂有聚苯乙烯颗粒(Bangs Laboratories,Illinois,USA)。
阳性和阴性对照刺激所使用的pMHC分别为A*0201/MLA-001(从修饰的Melan-A/MART得到的肽ELAGIGILTV)和A*0201/DDX5-001(从DDX5得到的DDX5YLLPAIVHI)。
将800.000微珠/200μl涂布于96孔板中(加入了4x 12.5ng不同的生物素-pMHC),洗板后加入200μl的600ng生物素抗-CD28。在96孔板中,将1x106CD8+T细胞与2x105冲洗所得涂布微珠在37℃下共孵育于200μl TCM(加入了5ng/ml IL-12(PromoCell))中3-4天,以此启动刺激。随后用加入了80U/ml IL-2的新鲜TCM取代一半的上述培养基,继续在37℃下孵育3-4天。这一刺激循环共重复三次。对于pMHC多聚体读数(每种条件使用8种不同的pMHC)采用二维组合编码法(如既往文献所述,仅作微小改动)(Andersen et al.,2012)使与5种不同的荧光色素相耦合。最后使用活/死近红外染料(Invitrogen,Karlsruhe,Germany)、CD8-FITC单抗体克隆SK1(BD,Heidelberg,Germany)以及荧光pMHC多聚体进行多聚体分析。分析中使用带有合适的激光与滤器的BD LSRII SORP细胞仪。肽特异性细胞数记为在总CD8+细胞中的百分比。使用FlowJo软件(Tree Star,Oregon,USA)进行多聚体分析的评估。通过与阴性对照刺激相比较来检测特异性多聚体+CD8+淋巴细胞的体外启动。若体外刺激后至少一名健康供着的可评估体外刺激孔中存在特异性CD8+T细胞系(即该孔CD8+T细胞中至少1%为特异性多聚体+且特异性多聚体+细胞是阴性对照刺激中位值的至少10倍)。
NSCLC肽的体外免疫原性
受试HLA I类肽的体外免疫原性可通过肽特异性T细胞系的产生来表现。图4为本发明的2种肽经TUMAP特异性多聚体染色后典型的流式细胞计量结果(另附相应的阴性对照结果)。本发明的25个肽的结果汇总于表5。
表5:本发明HLA I类肽的体外免疫原性
本发明的肽的申请者开展的体外免疫原性试验的典型结果。<20%=+;20%-49%=++;50%-70%=+++;以及>70%=++++
实施例5:肽的合成
所有肽的合成均使用标准、公认的固相肽合成方法(使用Fmoc-策略)。通过预备的RP-HPLC进行纯化后,通过离子交换程序结合生理相容性抗衡离子(例如三氟乙酸酯、乙酸酯、铵或氯化物)。
通过质谱法和RP-HPLC分析对各肽进行了鉴别和纯度测定。离子交换程序后所得的肽为白色或类白色冻干产物,纯度为90%至99.7%。
所有TUMAPs的给药形式均优选为三氟乙酸盐或乙酸盐,也可能是其它盐类。示例4中的测定使用肽的三氟乙酸盐形式。
实施例6:UV-配体交换
采用体外启动(priming)分析进一步检测根据本发明所述疫苗的候选肽的免疫原性。该分析所需的各种肽-MHC复合物通过UV-配体交换产生,其中UV敏感肽通过UV辐射来解离,并与所分析的候选肽相交换。只有能有效结合并稳定肽-感受MHC分子的候选肽方可防止MHC复合物的解离。通过ELISA检测稳定后的MHC复合物的轻链(β2m)来测定交换反应的产率。该分析方法基本依据Rodenko等人所述(Rodenko B,Toebes M,Hadrup SR,van EschWJ,Molenaar AM,Schumacher TN,Ovaa H.Generation of peptide-MHC class Icomplexes through UV-mediated ligand exchange.Nat Protoc.2006;1(3):1120-32.)。
96孔MAXISorp板(NUNC)用2ug/ml抗生蛋白链霉素的PBS溶液在室温下涂布整夜,在37℃下冲洗30min,重复4次,并用含封闭液的2%BSA封闭30min。以复性HLA-A*0201/MLA-001单体为标准品(涵盖8-500ng/ml)。UV交换反应中的肽-MHC单体用封闭液稀释100倍。样本在37℃下孵育1h,冲洗4次,用结合了抗-β2m的2ug/ml HRP在37℃下孵育1h,再次冲洗,最后用TMB溶液进行检测(用NH2SO4停流)。测定了450nm处的吸光度。
表6:UV-配体交换
表现出高交换产率(即高于40%,优选为高于50%,更优选为高于70%,最优选为高于80%)的候选肽通常优先用于抗体或其片段以及/或T细胞受体或其片段的生成和生产,原因是其对MHC分子具有足够的亲合力并可防止MHC复合物的解离。
实施例7:选定的MHC II类肽的结合与免疫活性
HLA II类蛋白可分为3个主要同种型,即HLA-DR、-DP和DQ,可由多种单倍型所编码。多种α-和β-链的组合增加了任意人群中HLA II类蛋白的多样性。因此选定的HLA II类TUMAP须可与多种不同的HLA-DR分子相结合(即表现出广泛的结合能力),从而在相当大百分比的患者中引发有效的T细胞应答。
通过外部服务提供商的体外结合试验评估了POSTN-002和MMP12-002与多种HLA-DR单倍型的广泛结合以及所形成的的复合物的稳定性,如下文所述。
材料和方法
肽列表
序列号 | 肽编号 | 序列 | 来源 | 大小 |
76 | MMP12-002 | INNYTPDMNREDVDYAIR | IMA-942 | 18 |
77 | POSTN-002 | TNGVIHVVDKLLYPADT | IMA-942 | 17 |
受试HLA-DR单倍型列表
根据在HLA-A*02和HLA-A*24阳性北美人群中的发生频率选择受试的7种HLA-DR单倍型(表7.1和7.2)
资料来源于对国家骨髓供着计划中登记的135万名经HLA分型的志愿者的分析(Mori et al.,1997)。分析人群进一步分为以下人种组:白种美国人(N=997,193)、非裔美国人(N=110,057)、亚裔美国人(N=81,139)、拉丁裔美国人(N=100,128)和美洲印第安人(N=19,203)。
表7.1 HLA-A*02阳性北美人群中各单倍型的频率:经分析的单倍型标灰突出。
表7.2 HLA-A*24阳性北美人群中各单倍型的发生频率:经分析的单倍型标灰突出。
检测原理
ProImmuneMHC-肽结合分析可测定各候选肽与选定的HLA II类单倍型相结合并稳定HLA-肽复合物的能力。通过此方法将候选肽与特定的HLA II类蛋白在体外装配。肽并入HLA分子的程度通过(复性程序完成后的)时间0点时装配后的HLA-肽复合物中天然构象的存在或缺失来评定(所谓“装配率”)。
除肽对特定HLA分子的亲合力外,所形成的的HLA-肽复合物的长期稳定性也对产生免疫应答至关重要。为此将所形成的HLA-肽复合物在37℃下孵育24h以检测其存在。随后计算所形成的MHC-肽复合物在24h时的结合评分与复性后(即时间0点)的即刻结合评分的百分比,以此评估所形成的的MHC-肽复合物的稳定性。
结果
对POSTN-002和MMP12-002所作的MHC-肽结合分析表明,两种肽均可与多种HLA单倍型相结合。在所研究的7种HLA单倍型中,POSTN-002可与其中的5种形成复合物,MMP12-002可与其中的4种形成复合物(图5)。两种肽均不与HLA-DR3和HLA-DR6结合。所测得的结合评分为阳性对照的0.02%至2.5%不等,且明显高于非结合肽的评分。
对所形成的HLA-POSTN-002和HLA-MMP12-002复合物的稳定性分析表明,在所研究的7种HLA-肽复合物中,分别有3种和2种可在37℃下稳定24h(图6)。
通过将肽的结合评分与已知具有免疫原性的肽的结合评分相比较,可推断该肽的免疫原性(依据与HLA分子的结合能力)。因此本项比较选用了5种经充分研究确认具有免疫原性的肽。离体测定了免疫接种患者(使用胞内细胞因子染色(ICS)CD4体细胞)血液样本中上述肽的免疫原性。
ICS检测原则上通过效应功能来评估特异性T细胞的质量。因此体外培养外周血单核细胞(PBMC),随后用待测肽、参考肽和阴性对照(此例为MOCK)进行再刺激。随后将再刺激细胞染色产生FN-γ、TNF-α、IL-2和IL-10,并表达共刺激分子CD154。用流式细胞仪对相关细胞进行计数(图7)。
免疫原性分析表明,16名患者通过IMA950肽(BIR-002和MET-005)免疫接种后产生了100%的免疫应答,而71名患者通过IMA910肽(CEA-006、TGFBI-004、MMP-001)免疫接种后产生了44%至86%的免疫应答。
为了将POSTN-002和MMP12-002结合评分与IMA910和IMA950肽的结合评分相比较,将所有肽按对所研究的各HLA-DR单倍型的结合评分结果列于表格中(表8.1、表8.2、表8.3、表8.4和表8.5)。
表8.1 POSTN-002和MMP12-002对HLA-DR1的结合评分(相比于已知免疫原性的II类肽的结合评分):POSTN-002和MMP12-002的结果标灰突出。
表8.2 POSTN-002和MMP12-002对HLA-DR2的结合评分(相比于已知免疫原性的II类肽的结合评分):POSTN-002和MMP12-002的结果标灰突出。
表8.3 POSTN-002和MMP12-002对HLA-DR4的结合评分(相比于已知免疫原性的II类肽的结合评分):POSTN-002和MMP12-002的结果标灰突出。
表8.4 POSTN-002和MMP12-002对HLA-DR5的结合评分(相比于已知免疫原性的II类肽的结合评分):POSTN-002和MMP12-002的结果标灰突出。
表8.5 POSTN-002和MMP12-002对HLA-DR7的结合评分(相比于已知免疫原性的II类肽的结合评分):POSTN-002和MMP12-002的结果标灰突出。
POSTN-002和MMP12-002相比于其它已知具有免疫原性的II类肽的结合评分表明,两种肽的结合能力多位于表的中下部(HLA-DR2除外)。两种肽对HLA-DR2的结合能力位于表的上半部分,其中MMP12-002为结合能力最强的候选肽。基于此分析,预期POSTN-002和MMP12-002这两种肽定可诱导免疫应答。
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序列表
<110> 伊玛提克斯生物技术有限公司
<120> 针对多种肿瘤例如包括NSCLC的肺癌的新型免疫疗法
<130> I32387WO
<150> GB1313987.8
<151> 2013-08-05
<150> US61/862,213
<151> 2013-08-05
<150> GB1403297.3
<151> 2014-02-25
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Lys Ile Tyr Asn Glu Phe Ile Ser Val
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Gly Leu Thr Asp Asn Ile His Leu Val
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Ser Ile Leu Thr Ile Glu Asp Gly Ile Phe Glu Val
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Ser Leu Trp Gly Gly Asp Val Val Leu
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Ala Leu Phe Pro His Leu Leu Gln Pro Val
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Asn Leu Leu Ala Glu Ile His Gly Val
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Ala Ile Met Gly Phe Ile Gly Phe Phe Val
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Gly Val Leu Glu Asn Ile Phe Gly Val
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Arg Leu Leu Ala Ala Glu Asn Phe Leu
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Ser Leu Leu Pro Val Asp Ile Arg Gln Tyr Leu
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Tyr Leu Ala Pro Phe Leu Arg Asn Val
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Ala Leu Leu Glu Arg Gly Tyr Ser Leu
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Tyr Leu Pro His Ala Pro Pro Phe Ala
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Lys Leu Val Glu Phe Asp Phe Leu Gly Ala
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Ser Leu Ala Asp Phe Met Gln Glu Val
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Ser Leu Tyr Lys Gly Leu Leu Ser Val
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Gly Leu Ala Glu Asp Ile Asp Lys Gly Glu Val
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Ser Leu Ile Asp Ala Asp Pro Tyr Leu
1 5
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Ile Leu Val Ser Trp Leu Pro Arg Leu
1 5
<210> 60
<211> 9
<212> PRT
<213> 智人
<400> 60
Val Val Asp Lys Thr Leu Leu Leu Val
1 5
<210> 61
<211> 9
<212> PRT
<213> 智人
<400> 61
Thr Leu Ile Ser Arg Leu Pro Ala Val
1 5
<210> 62
<211> 10
<212> PRT
<213> 智人
<400> 62
Ile Leu Phe Pro Asp Ile Ile Ala Arg Ala
1 5 10
<210> 63
<211> 11
<212> PRT
<213> 智人
<400> 63
Ser Leu Ala Gly Asp Val Ala Leu Gln Gln Leu
1 5 10
<210> 64
<211> 9
<212> PRT
<213> 智人
<400> 64
Ala Met Leu Ala Val Leu His Thr Val
1 5
<210> 65
<211> 9
<212> PRT
<213> 智人
<400> 65
Lys Val Leu Glu Ile Leu His Arg Val
1 5
<210> 66
<211> 9
<212> PRT
<213> 智人
<400> 66
Lys Ile Gln Glu Ile Leu Thr Gln Val
1 5
<210> 67
<211> 9
<212> PRT
<213> 智人
<400> 67
Ile Leu Gln Asp Arg Leu Asn Gln Val
1 5
<210> 68
<211> 9
<212> PRT
<213> 智人
<400> 68
Tyr Val Tyr Gln Asn Asn Ile Tyr Leu
1 5
<210> 69
<211> 9
<212> PRT
<213> 智人
<400> 69
Ala Met Ser Ser Lys Phe Phe Leu Val
1 5
<210> 70
<211> 9
<212> PRT
<213> 智人
<400> 70
Lys Ile Leu Glu Asp Val Val Gly Val
1 5
<210> 71
<211> 9
<212> PRT
<213> 智人
<400> 71
Lys Leu Leu Glu Tyr Ile Glu Glu Ile
1 5
<210> 72
<211> 9
<212> PRT
<213> 智人
<400> 72
Lys Leu Leu Thr Glu Val His Ala Ala
1 5
<210> 73
<211> 9
<212> PRT
<213> 智人
<400> 73
Phe Leu Leu Asp Gly Ser Ala Asn Val
1 5
<210> 74
<211> 11
<212> PRT
<213> 智人
<400> 74
Ser Leu Leu Ala Gln Asn Thr Ser Trp Leu Leu
1 5 10
<210> 75
<211> 9
<212> PRT
<213> 智人
<400> 75
Ala Leu Tyr Asp Ser Val Ile Leu Leu
1 5
<210> 76
<211> 18
<212> PRT
<213> 智人
<400> 76
Ile Asn Asn Tyr Thr Pro Asp Met Asn Arg Glu Asp Val Asp Tyr Ala
1 5 10 15
Ile Arg
<210> 77
<211> 17
<212> PRT
<213> 智人
<400> 77
Thr Asn Gly Val Ile His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp
1 5 10 15
Thr
<210> 78
<211> 10
<212> PRT
<213> 智人
<400> 78
Ser Leu Tyr Asp Asn Gln Ile Thr Thr Val
1 5 10
<210> 79
<211> 10
<212> PRT
<213> 智人
<400> 79
Ser Leu Ala Pro Ala Gly Val Ile Arg Val
1 5 10
<210> 80
<211> 12
<212> PRT
<213> 智人
<400> 80
Ser Leu Phe Gly Asn Ser Gly Ile Leu Glu Asn Val
1 5 10
<210> 81
<211> 9
<212> PRT
<213> 智人
<400> 81
Ala Leu Tyr Gly Arg Leu Glu Val Val
1 5
<210> 82
<211> 9
<212> PRT
<213> 智人
<400> 82
Ala Leu Trp Glu Lys Asn Thr His Leu
1 5
<210> 83
<211> 10
<212> PRT
<213> 智人
<400> 83
Ala Leu Ala Asn Gln Lys Leu Tyr Ser Val
1 5 10
<210> 84
<211> 10
<212> PRT
<213> 智人
<400> 84
Ile Leu Met Gly Thr Glu Leu Thr Gln Val
1 5 10
<210> 85
<211> 9
<212> PRT
<213> 智人
<400> 85
Lys Ile Val Asp Phe Ser Tyr Ser Val
1 5
<210> 86
<211> 11
<212> PRT
<213> 智人
<400> 86
Ala Met Ala Thr Glu Ser Ile Leu His Phe Ala
1 5 10
<210> 87
<211> 11
<212> PRT
<213> 智人
<400> 87
Arg Val Leu Pro Pro Ser Ala Leu Gln Ser Val
1 5 10
<210> 88
<211> 11
<212> PRT
<213> 智人
<400> 88
Ser Leu Leu Glu Ser Asn Lys Asp Leu Leu Leu
1 5 10
<210> 89
<211> 9
<212> PRT
<213> 智人
<400> 89
Ala Leu Ala Ser Val Ile Lys Glu Leu
1 5
<210> 90
<211> 10
<212> PRT
<213> 智人
<400> 90
Ser Leu Val Ala Val Glu Leu Glu Lys Val
1 5 10
<210> 91
<211> 9
<212> PRT
<213> 智人
<400> 91
Ala Met Phe Glu Asn Phe Val Ser Val
1 5
<210> 92
<211> 9
<212> PRT
<213> 智人
<400> 92
His Leu Leu Glu Asp Ile Ala His Val
1 5
Claims (29)
1.一种肽或其药学上可接受的盐,所述肽由SEQ ID No.:92的氨基酸序列组成。
2.根据权利要求1所述的肽或其药学上可接受的盐,其具有与主要组织相容性复合体(MHC)I类分子结合的能力。
3.根据权利要求1所述的肽或其药学上可接受的盐,其中所述肽包含非肽键。
4.根据权利要求1所述的肽或其药学上可接受的盐,其中所述肽是融合蛋白的一部分,所述肽与HLA-DR抗原相关不变链(Ii)的N-端氨基酸融合。
5.一种核酸,其编码权利要求1所述的肽。
6.根据权利要求5所述的核酸,所述核酸为DNA、PNA、RNA或其组合。
7.一种表达载体,其包含权利要求5所述的核酸。
8.一种宿主细胞,其包含权利要求5所述的核酸或权利要求7所述的表达载体。
9.根据权利要求8所述的宿主细胞,其为抗原提呈细胞。
10.根据权利要求9所述的宿主细胞,其中所述抗原提呈细胞为树突状细胞。
11.一种制备权利要求1所述的肽的方法,该方法包括培养权利要求8至10中任一项所述的宿主细胞,以及将上述肽从该宿主细胞或其培养基中分离出。
12.一种体外制备活化的细胞毒性T淋巴细胞(CTL)或辅助T细胞(Th细胞)的方法,该方法包括将CTL或Th细胞与在合适的抗原提呈细胞表面表达的负载有抗原的人MHC I类分子在体外接触足够的一段时间,从而以抗原特异性方式激活CTL或Th细胞,其中所述抗原为权利要求1所述的肽。
13.根据权利要求12所述的方法,其中通过将足量的所述抗原与抗原提呈细胞相接触,从而将上述抗原载入MHC I类分子,所述MHC I类分子在合适的抗原提呈细胞表面表达。
14.根据权利要求12或13所述的方法,其中该抗原提呈细胞含有表达载体,该表达载体能够表达权利要求1所述的肽。
15.一种活化的细胞毒性T淋巴细胞(CTL)或辅助T细胞(Th细胞),由权利要求12至14中任一项所述的方法所制备,其中该CTL或Th细胞选择性地识别一种细胞,该细胞异常表达含有SEQ ID No.:92所示氨基酸序列的多肽。
16.一种体外制备对权利要求1所述的肽特异的TCR或sTCR或其片段的方法,该方法包括克隆权利要求15所述的活化的细胞毒性T淋巴细胞(CTL)或辅助T细胞(Th细胞)的可变域,以及在合适的宿主和/或表达系统中表达上述TCR或sTCR或其片段。
17.一种分离的结合剂,其选自抗体或其片段、蛋白、核酸、肽、TCR或sTCR或其片段,其与权利要求1所述的肽、或与权利要求1所述的肽与MHC分子的复合物特异性地结合。
18.一种分离的T细胞受体,其与HLA配体反应,所述HLA配体与SEQ ID No.92所示的氨基酸序列相同。
19.一种自体或同种异体的人细胞毒性T细胞(CTL)或辅助T细胞(Th细胞),其转染有权利要求18所述的T细胞受体。
20.权利要求1至4中任一项所述的肽或其药学上可接受的盐、权利要求5或6所述的核酸、权利要求7所述的表达载体、权利要求8至10中任一项所述的宿主细胞、权利要求15所述的活化的细胞毒性T淋巴细胞(CTL)或辅助T细胞(Th细胞)、权利要求17所述的分离的结合剂、权利要求18所述的T细胞受体、或权利要求19所述的自体或同种异体的人细胞毒性T细胞(CTL)或辅助T细胞(Th细胞)在制备用于治疗癌症的药物中的用途。
21.根据权利要求20所述的用途,其中所述药物为疫苗。
22.根据权利要求20所述的用途,其中癌症为肺癌、胃癌和/或成胶质细胞瘤。
23.根据权利要求22所述的用途,其中所述肺癌是非小细胞肺癌。
24.根据权利要求20所述的用途,其中所述药物用于人的输入细胞疗法。
25.一种药物组合物,其包含:
(a)选自以下的实体:
(a1)权利要求1至4中任一项所述的肽或其药学上可接受的盐,
(a2)权利要求18所述的T细胞受体,
(a3)权利要求5或6所述的核酸,
(a4)权利要求7所述的表达载体,
(a5)权利要求8至10中任一项所述的宿主细胞,
(a6)权利要求15所述的活化的细胞毒性T淋巴细胞(CTL)或辅助T细胞(Th细胞);和
(b)药学上可接受的载体。
26.根据权利要求25所述的药物组合物,其中所述药物组合物还包含选自药学上可接受的赋形剂、缓冲剂、结合剂、爆炸剂、稀释剂、增味剂、润滑剂、和免疫刺激物质或免疫调节物质中的至少一种其他成分。
27.根据权利要求26所述的药物组合物,其中所述免疫刺激物质是佐剂。
28.根据权利要求27所述的药物组合物,其中所述佐剂是白细胞介素。
29.根据权利要求28所述的药物组合物,其中所述白细胞介素是IL-2、IL-15或其组合。
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