CN110022890A - 包含肿瘤相关抗原l6的b细胞抗原决定位的免疫原胜肽 - Google Patents
包含肿瘤相关抗原l6的b细胞抗原决定位的免疫原胜肽 Download PDFInfo
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Abstract
本公开关于一种包含序列CLDSLGQWN(SEQ ID NO:2)的免疫原胜肽,以及使用此胜肽治疗癌症的方法。
Description
技术领域
本公开关于一种免疫原胜肽,尤指一种包含肿瘤相关抗原L6的B细胞抗原决定位的免疫原胜肽。
背景技术
肿瘤相关抗原L6(tumor-associated antigen L6,TAL6)是四穿膜超家族(transmembrane-4 superfamily,TM4SF)的细胞表面蛋白,也称为TM4SF1。TM4SF蛋白在不同类型的人类癌症中过度表现,包括肺癌、乳癌、结肠癌、前列腺癌和肝癌。TM4SF1-、TM4SF4-和TM4SF5专一性单株抗体可抑制结肠癌生长,表示TM4SF蛋白是癌症治疗的关键标的。TAL6在人类肺、乳、结肠和卵巢肿瘤中有超过80%的过度表现,但在正常组织中并无此现象。最近研究发现TAL6在癌细胞移动、侵犯、转移和血管生成中具关键角色。先前研究已证实TAL6的HLA-A2限制性毒杀性T淋巴细胞(cytotoxic T lymphocytes,CTL)抗原决定位A2-5胜肽,能够诱发CTL反应,以抑制表现TAL6的癌细胞生长。此外,被诱发的CTL被转入免疫功能受损小鼠中,可以抑制人类肺癌细胞在免疫功能受损小鼠的生长。
发明内容
于本公开的一形态中,提供一免疫原胜肽,其包含序列CLDSLGQWN(SEQ ID NO:2),其中,胜肽具有100个或更少的胺基。在一实施例中,胜肽具有序列X1X2X3X4X5X6X7CLDSLGQWNX8X9X10X11(SEQ ID NO:3),其中,X1至X11各自为胺基酸(例如,20个标准胺基酸之一)。举例而言,胜肽可包括序列GLAEGPLCLDSLGQWNYTFA(SEQ ID NO:4)。在一实施例中,胜肽更包括TAL6的细胞毒性T淋巴球(cytotoxic T lymphocyte,CTL)抗原决定位或辅助T细胞(helper T cell,Th)抗原决定位。在另一实施例中,胜肽包含序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA(SEQ ID NO:9)。
于本公开的另一形态中,提供一核酸分子,其包含一序列,其编码出本文所述免疫原胜肽。
于本公开的另一形态中,提供一含有免疫原胜肽的免疫原组合物。免疫原组合物可更包括一佐剂。佐剂可选自由不完全弗氏佐剂(incomplete Freund's adjuvant,IFA)、DOTAP、PELC、及含有非甲基化CpG的去氧寡核苷酸(CpG)所组成的群组。在一实施例中,CpG为类铎受体9(Toll-like receptor 9,TLR9)的促效剂。在一实施例中,免疫原组合物包括PELC和CpG。
于本公开的一形态中,提供一治疗所需主体的癌症的方法。此方法包含向主体施用本公开所述的免疫原组合物。
本公开的一或多个实施例将以附图及下文加以说明。实施例的其他特征、目的及优点,将由下文及图示、及权利要求更加明了。
附图说明
图1(A)为涵盖TAL6细胞外结构域的EL1(SEQ ID NO:1的残基31至46)、EL2(SEQ IDNO:1的残基114至164)、EP1(SEQ ID NO:4)、EP2(SEQ ID NO:17、EP3(SEQ ID NO:18)、以及EP4(SEQ ID NO:19)的重迭胜肽示意图;以及(B)为胜肽与抗TAL6抗体结合的图表。在96孔盘中,将指定的胜肽(10μg/ml)涂覆于每孔中。利用三种抗TAL6抗体(1:500)检测这些胜肽。CP:对照组胜肽。
图2为利用EP1胜肽诱发野生型小鼠抗肿瘤免疫反应的系列图。对小鼠施用以不完全弗氏佐剂(IFA)配制的EP1或正控制组MCF-7/TAL6细胞两次,每次间隔两周。(A)为利用细胞ELISA(cell based ELISA)检测抗TAL6抗体力价。抗原专一性抗体计算方式为:EL4-L6(O.D.)-EL4(O.D.)。(B)为在Cr51释放试验中测定TAL6专一性ADCC。裂解百分比计算方式为:免疫接种的血清(裂解%)-初始血清(裂解%)。***P<0.001。
图3为利用EP1胜肽诱发野生型小鼠抗肿瘤免疫反应的系列图。向小鼠施用以不完全弗氏佐剂(IFA)配制的EP1或正控制组MCF-7/TAL6细胞两次,每次间隔两周。(A)最终免疫接种后第7天,皮下注射B16-L6(2×104个)细胞。每周监测肿瘤生长2-3次。(B)测定小鼠的存活率。
图4为以PELC/CpG配制的EP1诱发抗肿瘤作用系列图。间隔14天,用指定佐剂配制的EP1(50mg)免疫接种小鼠两次。(A)第二次免疫接种后第7天,皮下注射2×104个B16/TAL6细胞。每周监测肿瘤生长2-3次。获得的结果以平均值标准差表示(n=6)。(B)监测小鼠存活率。结果以平均值±标准差表示(*P<0.05,**P<0.01)。
图5为T和B细胞抗原决定位的组合,在HLA-A2小鼠中诱发抗肿瘤活性的系列图。用以不完全弗氏佐剂(IFA)配制的胜肽(50μg/小鼠)免疫接种HLA-A2小鼠两次,每次间隔两周。在最终免疫接种后第7天,皮下注射B16/L6/A2细胞(2×104个)。每周监测肿瘤大小2-3次。肿瘤体积=长x宽x宽/2。每张图中的每一条线对应一只动物(n=5-6)。
图6为用PELC/CpG/Th-A2-5-EP1在HLA-A2小鼠中诱发大量的体液和细胞免疫的系列图。Th-A2-5-EP1胜肽以不同的佐剂配制。用不同的制剂免疫接种HLA-A2基因转殖小鼠两次,每次间隔两周。(A)使用IFN-γELISpot测定法测定IFN-γ分泌细胞。结果以平均值标准差表示。***P<0.001。(B)在抗CD107a和抗CD8抗体存在下,使用照射的EL4-TAL6-A2或EL4-TAL6细胞(2×104个)刺激脾细胞(splenocyte)2小时。***P<0.001。(C)将10mg/ml的EP1胜肽涂覆在96孔ELISA盘上,加入免疫接种的小鼠的抗血清(1:500)。*P<0.05。***P<0.001。(D)以Cr51释放测定法测定TAL6专一性ADCC。裂解百分比计算方式为:免疫接种的血清(裂解%)-初始血清(裂解%)***P<0.001。
图7为用Th-A2-5-EP1诱发HLA-A2基因转殖小鼠的抗肿瘤活性免疫反应结果图。用以不同佐剂配制的Th-A2-5-EP1胜肽免疫接种HLA-A2基因转殖小鼠两次,每次间隔两周。在最终免疫接种后第7天,皮下注射2×104个B16/TAL6/HLA-A2细胞。每组有6只小鼠。每周监测肿瘤生长2-3次。结果以平均值标准差表示。
图8为免疫接种的小鼠血清抑制癌细胞迁移的结果图。将B16-L6细胞种在24孔盘中,每孔中含有一个培养小室(Culture-Insert)(500μm)。24小时后,除去Culture-Insert,加入100ml具有或不具有免疫接种小鼠的抗血清(1:100,v/v)的培养基。在体外0、24和48小时照相。使用L6mAb(10mg/ml)作为正控制组。在显微镜下,于指定时间观察迁移到限定的无细胞间隙的细胞迁移。数据以平均值±SD表示(n=5)。迁移率(%)=48小时的细胞间隙面积/0小时的细胞间隙面积×100%。***P<0.001。
图9为以不同佐剂配制的胜肽,诱发抗人类癌细胞的抗体依赖性细胞毒性(ADCC)的系列图。用以多种佐剂配制的Th-EP1-A2-5胜肽免疫接种小鼠两次,每次间隔两周。6周时收集血清,并进行ADCC测定。(A)使用肺癌细胞株H2981作为目标。(B)使用人类乳癌细胞株MCF7和MCF7-TAL6作为目标。以Cr51释放测定法,测定TAL6专一性ADCC。裂解百分比计算方式为:免疫接种的血清(裂解%)-初始血清(裂解%)***P<0.001。
图10为使用丙胺酸扫描法检测对抗体结合重要的EP1残基的检测结果图。EP1中的胺基酸残基分别被丙胺酸取代,而产生EP1-1至EP1-20胜肽。使用单株抗体L6检测这些胜肽。EP1是正控制组,EP-3是负控制组。
具体实施方式
TAL6意外被发现含有可在体内诱发抗体依赖性细胞毒性(antibody-dependentcellular cytotoxicity,ADCC)和抗肿瘤作用的B细胞抗原决定位。
以下为TAL6(SEQ ID NO:1)的胺基酸序列:
MCYGKCARCIGHSLVGLALL CIAANILLYF PNGETKYASE NHLSRFVWFF
SGIVGGGLLM LLPAFVFIGL EQDDCCGCCG HENCGKRCAM LSSVLAALIG
IAGSGYCVIV AALGLAEGPLCLDSLGQWNY TFASTEGQYL LDTSTWSECT
EPKHIVEWNV SLFSILLALG GIEFILCLIQ VINGVLGGIC GFCCSHQQQY DC
TAL6包含两个细胞外环,例如EL1(SEQ ID NO:1的a.a.31至a.a.46)以及EL2(SEQID NO:1的a.a.114至a.a.164)。B细胞抗原决定位位于EL2中。
因此,本公开提供一种包含抗原决定位的免疫原胜肽,此抗原决定位包含序列CLDSLGQWN(SEQ ID NO:2)。此免疫原胜肽可具有100个或更少的胺基酸(例如,9、10、11、12、13、14、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100个胺基酸)。
此胜肽可具有序列X1X2X3X4X5X6X7CLDSLGQWNX8X9X10X11(SEQ ID NO:3),其中,X1至X11各自为一胺基酸。「胺基酸」一词是指20个标准胺基酸(即丙胺酸(alanine)、精胺酸(arginine)、天冬酰胺(asparagine)、天冬胺酸(aspartic acid)、半胱胺酸(cysteine)、谷胺酰胺(glutamine)、谷胺酸(glutamic acid)、甘胺酸(glycine)、组胺酸(histidine)、异亮胺酸(isoleucine)、亮胺酸(leucine)、赖胺酸(lysine)、甲硫胺酸(methionine)、苯丙胺酸(phenylanaline)、脯胺酸(praline)、丝胺酸(serine)、苏胺酸(threonine)、色胺酸(tryptophan)、酪胺酸(tyrosine)和缬胺酸(valine))的任何一个。「胺基酸」一词还可以指非标准的,非蛋白质的或化学修饰的胺基酸,或胺基酸类似物。
在一实施例中,免疫原胜肽具有序列GLAEGPLCLDSLGQWNYTFA(SEQ ID NO:4)。
免疫原胜肽可为包含前述TAL6的B细胞抗原决定位以及一或多个其他胜肽片段的嵌合肽。例如,嵌合肽可更包含非TAL6抗原抗原决定位或辅助T细胞刺激抗原决定位其中之一或两者皆有。嵌合肽还可包含TAL6的另一抗原决定位(例如另一B细胞抗原决定位或T细胞抗原决定位)。美国专利第8465756号中描述了TAL6的抗原决定位的例子。
其他可存在于嵌合肽中的胜肽片段,包含一或多个亲和标签(affinity tag,例如FLAG、poly-His、Myc、HA、CBP、HBH、或V5)、一讯息序列(signal sequence,例如,前导序列或定位讯息)、一标靶胜肽(targeting peptide,用于将嵌合肽标靶至特定细胞、细胞位置或组织)、一配体(例如受体配体)以及治疗性胜肽。
在一实施例中,嵌合肽含有SEQ ID NO:2、3或4的序列,以及TAL6的细胞毒性T淋巴球(cytotoxic T lymphocyte,CTL)抗原决定位和辅助T细胞(Th)抗原决定位其中之一或两者皆有。
CTL抗原决定位可为LLMLLPAFV(SEQ ID NO:5)或RFVWFFSGI(SEQ ID NO:6)。
Th抗原决定位可为PADRE胜肽,例如AKFVAAWTLKAAA(SEQ ID NO:7)、或来自破伤风类毒素的胜肽,例如AQYIKANSKFIGITEL(SEQ ID NO:8)。嵌合肽的例子,可具有序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA(SEQ ID NO:9)。嵌合肽中的抗原决定位可以以任何顺序排列。
连接子,例如包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15个胺基酸的柔性连接子,为可连接嵌合肽中两相邻的胜肽片段。本领域中具有通常知识者可设计合适的连接子。
可使用已知方法来制备免疫原胜肽,例如化学合成或重组技术。
免疫原胜肽还可与一或多个非胜肽片段共轭连结,以形成免疫原胜肽复合物。非胜肽片段包括核酸分子、抗体、蛋白质、碳水化合物、可检测的标记(例如萤光、放射性或酶标记)、小分子药物、聚合物(例如聚乙二醇)、固体支持物(例如珠或奈米颗粒)、植物萃取物成分和微生物成分。于胜肽合成时还可以进行其他修饰,例如修饰侧链、胺基酸取代、非天然胺基酸及/或其衍生物的并入,以增加如免疫原胜肽的稳定性及/或在生物体内功效。
由于上述免疫原胜肽包括TAL6的B细胞抗原决定位(一种癌抗原),因此可用于增强对TAL6阳性癌症(例如肺癌、结肠癌、乳癌、卵巢癌、胃癌、卡波西氏肉瘤、肝癌、胰脏癌、子宫颈癌、子宫内膜癌、头颈癌、卵巢癌或前列腺癌)的免疫反应(例如抗体依赖性细胞毒性反应)。
免疫原胜肽或能够表现免疫原胜肽的表现载体可与药学上可接受的载体混合以形成一免疫原组合物。此组合物可施用于有需要的主体以治疗癌症或增强免疫反应。
组合物可以药学上可接受的载体,如磷酸盐缓冲液、碳酸氢盐溶液及/或佐剂配制。合适的药物载体和稀释剂以及其使用的药剂辅料为本领域已知的。组合物可制备成可注射的液体溶液、乳液或其他合适的剂型。
佐剂的例子包括但不限于,明矾沉淀物、弗氏完全佐剂、不完全弗氏佐剂、单磷酰脂质A/海藻糖二霉菌酸酯佐剂(monophosphoryl-lipid A/trehalose dicorynomycolateadjuvant)、含有短棒菌(Corynebacterium parvum)和tRNA的油包水乳剂、以及其他物质,其可藉由模拟特定演化保留分子,包括脂质体、脂多醣(LPS)、抗原分子笼、细菌细胞壁成分和内噬核酸(如双股RNA、单股DNA和含未甲基化的CpG二核苷酸的DNA)以增加免疫反应的物质。其他例子包括霍乱毒素、大肠杆菌不耐热肠毒素、脂质体、免疫刺激复合物(immune-stimulating complex、ISCOM)、免疫刺激序列寡脱氧核苷酸(immunostimulatorysequences oligodeoxynucleotide)和氢氧化铝。组合物还可包括促进体内释放的聚合物。
在一实施例中,佐剂为不完全弗氏佐剂(IFA)、DOTAP或DOTAP盐、PELC(为含有生物可再吸收聚合物、85和角鲨烯的乳剂型佐剂)、或含未甲基化的CpG的寡脱氧核苷酸(unmethylated CpG-containing oligodeoxynucleotide,CpG),例如,类铎受体9(TLR9)促效剂。在免疫原组合物中可包括一或多种佐剂的组合。
TLR9CpG促效剂包括但不限于5’-tcgtcgttttgtcgttttgtcgtt-3’(SEQ ID NO:10)、5’-ggGGGACGATCGTCgggggg-3’(SEQ ID NO:11)、5’-gggGACGACGTCGTGgggggg-3’(SEQID NO:12)、5’-tcgcgacgttcgcccgacgttcggta-3’(SEQ ID NO:13)、5’-tcgtcgttttcggcgcgcgccg-3’(SEQ ID NO:14)、5’-tcgtcgtcgttcgaacgacgttgat-3’(SEQID NO:15)、以及5’-tcgcgaacgttcgccgcgttcgaacgcgg-3’(SEQ ID NO:16)。大写字母的碱基是磷酸二酯。小写字母的碱基是硫代磷酸酯。
有效剂量的免疫原组合物可经肠胃外施用,例如皮下注射或肌内注射。或者,包括栓剂和口服制剂等其他施用方式也是可能的施用方式。对于栓剂、黏合剂和载体可包括,例如聚亚烷基二醇或三酸甘油酯。口服制剂可包括通常使用的初剂(incipient),例如药物级糖精、纤维素、碳酸镁及其相似物。这些组合物为溶液、悬浮液、片剂、丸剂、胶囊、缓释制剂或粉剂的形式。
下述特定实施例仅为了说明,而不以任何形式限制本公开的其他部分。虽未进一步说明,本技术领域者仍可依照本文所述,将本公开做最大的应用。本文所引用的所有文献均全部并入本公开以供参酌。
实施例:[用于治疗癌症的抗原胜肽]
肿瘤相关抗原L6(tumor-associated antigen L6,TAL6)的B细胞抗原决定位被认为可在生物体内诱发抗体依赖性细胞毒性(antibody-dependent cellularcytotoxicity,ADCC)。将B细胞抗原决定位与细胞毒性T淋巴细胞(CTL)及辅助T细胞(Th)抗原决定位结合以形成嵌合肽。嵌合肽与不同的佐剂配制以免疫HLA-A2基因转殖小鼠,并评估其免疫性。与乳剂型奈米颗粒(PELC)佐剂和类铎受体9促效剂(即,含未甲基化的CpG的寡脱氧核苷酸,CpG)配制的嵌合肽,可诱发最大程度的ADCC和CTL反应。被诱发的抗肿瘤免疫反应可抑制TAL6阳性癌细胞的生长。此外,嵌合肽的免疫作用能够抑制体外癌细胞迁移和体内转移。这些数据指出,以PELC/CpG佐剂配制的包含TAL6的B和T细胞抗原决定位的嵌合肽可用于癌症免疫治疗。
[鉴定TAL6的B细胞抗原决定位]
使用三种纯化的抗TAL6单株抗体(1F4、9C7、L6)检测TAL6在EL-4(EL-4/L6)细胞表面上的表现。请参考Chang等人,Int J Cancer,116(2005)243-252。连续稀释的单株抗体可结合EL-4/L6细胞,但无法与负控制组EL-4细胞(数据未显示)结合,证实这三种单株抗体识别TAL6的细胞外结构域。为了进一步定位抗体结合抗原决定位,使用涵盖EL1和EL2细胞外环的五种胜肽(EL1和EP1至4),并以ELISA来确定线性B细胞抗原决定位。请参考图1A。单株抗体1F4和9C7无法识别这些胜肽。相比之下,EP1胜肽可被L6mAb测得。请参考图1B。
为了测试EP1胜肽是否能产生可结合天然TAL6的抗体,对C57BL/6小鼠施用以IFA/Th配制的EP1胜肽或MCF-7/L6细胞(作为正控制组)。收集来自免疫接种的小鼠的血清,并使用细胞ELISA分析抗TAL6抗体力价。以EP1或MCF-7/L6细胞免疫接种的小鼠血清(1:500)比以载体(PBS)免疫接种的小鼠血清明显具有更高的抗体量。请参考图2A。另外,还研究了EP1免疫作用是否能诱发抗体依赖性细胞毒性(antibody-dependent cellularcytotoxicity,ADCC)。以EP1或MCF-7/L6细胞免疫接种的小鼠血清(1:100)可杀死表现TAL6的EL4(EL4/L6)细胞,但不能杀死EL4母细胞(61.82%±6.12%v.s.0.36%±0.96%和65.54%±1.77%v.s.11.41%±3.094%)。请参考图2B。为了研究EP1胜肽是否能诱发抗肿瘤活性,以EP1胜肽免疫接种小鼠,而后,在最终免疫接种后第7天用B16-L6细胞(2×10 4个/小鼠)进行攻击。以EP1或MCF-7/L6细胞免疫接种的小鼠明显抑制肿瘤生长。请参考图3A。小鼠的存活率如图3B所示。数据显示,EP1胜肽是TAL6的线性B细胞抗原决定位,其对表现TAL6癌症细胞具有抗肿瘤活性。
[EP1胜肽在小鼠模型中诱发抗肿瘤作用]
EP1胜肽以不同的佐剂配制成制剂。间隔14天,用50mg制剂对小鼠进行两次免疫接种。在第二次免疫接种后第7天,皮下注射小鼠2×10 4个B16/TAL6细胞。每周监测肿瘤生长2-3次。EP1显示出抗肿瘤作用。请参考图4A。生存率如图4B所示。
[包含B和T细胞抗原决定位的嵌合肽比单独只有B或T细胞抗原决定位诱发更大的抗肿瘤活性]
为了研究细胞毒性T细胞(Tc)抗原决定位的并入是否能增强基于B细胞抗原决定位方法的抗肿瘤效果,制备合成肽Th-A2-5、Th-EP1和Th-A2-5-EP1。请参考表1。以不完全弗氏佐剂(IFA)配制胜肽,并用于免疫接种HLA-A2转殖基因(transgenic,Tg)小鼠。在最终免疫接种后第7天,皮下注射小鼠2×104个B16-L6-A2细胞。每周监测肿瘤生长2-3次。用嵌合Th-A2-5-EP1胜肽诱发的免疫作用可强烈抑制肿瘤生长。请参考图5。使用嵌合肽诱发体液和细胞免疫可协同抗肿瘤活性。
表1.合成肽
[以PELC/CpG配制的嵌合肽诱发强烈的体液和细胞抗肿瘤免疫反应]
为了研究Th-A2-5-EP1嵌合肽是否能诱发A2-5专一性T细胞反应,进行IFN-γELISPOT和CTL活性测定。施用以不同佐剂配制的Th-A2-5-EP1于HLA-A2基因转殖小鼠两次,每次间隔两周。
使用IFN-γELISPOT测定法测定小鼠的IFN-γ分泌细胞。以PELC/CpG配制的Th-A2-5-EP1比在其他佐剂制剂中的胜肽诱发更多的斑点(368.5±40.42)。请参考图6A。与控制组小鼠相比,以DOTAP(60.5±7.85)、CpG(107.2±23.89)或DOTAP/CpG(112.5±33.18)配制Th-A2-5-EP1胜肽,可检测到的斑点数显著增加,但以PELC(16.7±4.74)或IFA(18±9.75)配制的Th-A2-5-EP1胜肽,检测到的班点数并没有显著增加。我们得出结论,以PELC/CpG配制的Th-A2-5-EP能够诱发强烈的A2-5专一性T细胞反应。
为了进一步确定PELC/CpG制剂是否能诱发细胞毒活性,故分析CD107a+CD8+T细胞的数量。在抗CD107a和抗CD8抗体存在下,用照射的EL4-L6-A2或EL4-L6细胞刺激来自小鼠的脾细胞2小时。以PELC/CpG配制的Th-A2-5-EP1比其他佐剂制剂诱发更多的CD107a+CD8+T细胞(6.69±0.49%)。请参考图6B。这些结果显示,以PELC/CpG配制的Th-A2-5-EP1可诱发强烈且特定的CTL反应。
用EP1涂覆的96孔ELISA盘测试来自小鼠的抗血清。以含有CpG的PELC配制的Th-A2-5-EP1胜肽,可诱发最多的抗EP1的IgG抗体量(O.D.1.41±0.04)。请参考图6C。PELC佐剂比IFA佐剂诱发更多的抗体(O.D.1.01±0.24v.s.0.622±0.183)。请参考图6C,以DOTAP脂质体配制的C.Th-A2-5-EP1胜肽、DOTAP/CpG、或单独的CpG产生相似的抗体量(分别为O.D.0.454±0.025、0.46±0.02和0.54±0.02)。请参考图6C。与抗体力价数据相反,仅用PELC配制的Th-A2-5-EP1胜肽并未显著诱发IFN-γ分泌细胞数量。参见图6B。
用免疫接种的小鼠的血清评估ADCC活性。以PELC/CpG配制的Th-A2-5-EP1胜肽诱发最高程度的ADCC。请参考图6D。以PELC佐剂配制的Th-A2-5-EP1胜肽诱发第二高的ADCC活性。这些结果与抗体力价数据相符。
为了评估Th-A2-5-EP在不同佐剂制剂中的抗肿瘤效果,用制剂免疫接种HLA-A2转基因小鼠两次,每次间隔两周。在第二次免疫接种后第7天,用B16/L6/A2细胞(2x 104)攻击小鼠。每周监测肿瘤生长2-3次。与其他制剂相比,以PELC/CpG配制的Th-A2-5-EP胜肽显著抑制肿瘤生长。请参考图7。以IFA、DOTAP、PELC、CpG、或DOTAP/CpG配制的Th-A2-5-EP胜肽显示出普通的抗肿瘤活性。请参考图7。数据显示,以PELC/CpG配制的含有Th、Tc和B细胞抗原决定位的嵌合肽可强烈诱发对抗癌症的体液和细胞免疫。
[以PELC/CpG配制的嵌合肽Th-A2-5-EP1抑制肿瘤迁移及转移]
测试Th-A2-5-EP1免疫接种的小鼠的血清是否可以抑制癌细胞迁移。进行腔室伤口测定(chambers wound assay)以评估细胞迁移的抑制。将B16-L6细胞种在具有Culture-Insert(500μm)的24孔盘中培养24小时。然后取出Culture-Insert,加入100μl培养基、血清(1:100,v/v)、或正控制组(L6mAb)。在0、24、和48小时获得的图像显示,经过L6或用Th-A2-5-EP1和PELC/CpG免疫接种小鼠的血清处理后,癌细胞迁移作用受到抑制(数据未显示)。
在三个独立的实验中,无细胞间隙的定量显示,单独以CpG(72.97%±5.97)或PELC/CpG(43.04%±15.47)配制的Th-A2-5-EP1所免疫接种的小鼠血清显著抑制B16-L6细胞迁移。请参考图8。而迁移的抑制并不是因为细胞增殖的差异所导致(数据未显示)。
癌细胞迁移的抑制表示癌细胞转移也可透过嵌合肽免疫作用来抑制。在B16-L6转移小鼠模型中检验了胜肽的抗转移活性。以PELC、CpG、或PELC/CpG配制的Th-A2-5-EP1胜肽免疫接种HLA-A2基因转殖小鼠两次,每次间隔两周。第二次免疫接种后第7天,静脉注射5×105个B16-L6细胞。细胞接种后22天,牺牲小鼠,收集肺组织进行分析。以PELC、CpG、或PELC/CpG配制的Th-A2-5-EP1显著降低了肺中的肿瘤结节的形成(数据未显示)。有趣的是,以PELC/CpG配制的Th-A2-5-EP1胜肽免疫接种的小鼠中几乎没有观察到肿瘤结节。数据显示,以PELC/CpG配制的Th-A2-5-EP1可抑制癌细胞肺转移。
[以PELC/CpG配制的嵌合肽Th-A2-5-EP1诱发抗人类癌细胞的抗体介导的细胞毒性]
以不同佐剂配制的Th-A2-5-EP1免疫接种小鼠两次,每次间隔两周。6周后收集血清,并以ADCC测定。人类肺癌细胞株H2981、乳癌细胞株MCF7、和MCF7-TAL6为目标细胞。以Cr51释放试验测定TAL6专一性ADCC(TAL6-specific ADCC)。将初始血清中的溶解百分比减去免疫接种血清的溶解百分比来计算溶解百分比。如图9所示,以PELC/CpG配制的Th-A2-5-EP1对癌细胞具有最强的细胞毒性。
[以丙胺酸扫描法辨识EP1的抗体结合区]
EP1中的胺基酸残基1至20分别以丙胺酸取代以产生EP1-1至EP1-20胜肽。用单株抗体L6检测这些胜肽。当用丙胺酸取代时,某些残基会造成抗体结合减少。请参考图10。数据显示,这些残基对于抗体结合是重要的。
[动物和细胞株]
6周龄的C57BL/6雌性小鼠来自中国台湾实验动物中心。HLA-A2基因转殖小鼠引进后,在中国台湾卫生研究院实验动物中心进行繁殖。所有动物实验均在中国台湾卫生研究院(NHRI)动物委员会批准的方案下,在无特定病原体(specific pathogen-free,SPF)条件进行。
B16F1细胞稳定表现TAL6(B16-L6),然后用HLA-A2基因转染,得到稳定的细胞株B16-L6-A2。将B16-L6-A2和MCF-7-TAL6细胞培养在添加有胎牛血清(FBS,10%)、青霉素/链霉素(penicillin/streptomycin,50units/mL)、0.5mM丙酮酸钠、以及20mM HEPES(购自Biological industries,Beit Haemek,Israel)的DMEM培养基中,在37℃、5%CO2的环境下培养。请参考Tu等人,Journal ofimmunotherapy,35(2012)235-244。将EL4-L6-A2和EL4-L6细胞培养在添加有10%FBS的RPMI-1640培养基中。
[单株抗体的制备]
从美国菌种中心(American Type Culture Collection)取得可产生抗TAL6抗体的融合瘤(L6)。如前所述,用人类TAL6质体DNA免疫接种的BALB/c小鼠可产生1F4和9C7抗TAL6单株抗体。藉由使用如前所述的高盐条件的蛋白质A亲和层析法以纯化单株抗体。请参考Chang等人,Int J Cancer,116(2005)243-252。
利用微量BCA蛋白定量分析套组(Micro BCA protein Assay Kit,购自PIERCE)检测抗体浓度。
[ELISA]
对于抗体抗原决定位定位,利用ELISA测定L6、9C7和1F4单株抗体。为了要测定专一性抗体的EP1力价,收集用EP1胜肽免疫接种小鼠的抗血清,并藉由ELISA测定专一性抗体的力价。用胜肽(1μg/ml)或细胞(2×106)涂覆96孔盘。在使用5%BSA-PBS中止后,用5%BSA-PBS稀释抗血清(1:1000v/v),并将其加入至孔盘中1小时。使用HRP复合的山羊抗小鼠IgG(1:4000v/v)检测EP1抗体力价。然后加入TMB过氧化物酶EIA受质,其可用1当量浓度(N)的H2SO4终止反应。于450nm测量其吸光度。
[动物实验]
将以IFA、明矾、DOTAP脂质体、PELC奈米颗粒或TLR9促效剂CpG配制的胜肽皮下注射HLA-A2TG小鼠两次,每次间隔两周。第二次免疫接种后第7天,在注射胜肽的另一侧位置皮下注射2×104个B16-L6-A2或B16-L6细胞。每周测量肿瘤大小2-3次。肿瘤体积计算公式为:肿瘤体积=长×宽×宽/2。
[抗体依赖性细胞毒性(ADCC)]
在ADCC试验中,小鼠脾细胞为作用细胞(effector cell)。在LCM培养基中将脾细胞的细胞浓度调整为8x106cells/ml。将细胞加入试管中,然后分成等分(在96孔盘中每孔为100μl)。在37℃下,用100μCi的51C(Na251CrO4,购自PerkinElmer,MA)标记EL4-L6或EL-4目标细胞(2x107/ml)一小时。将51Cr标记的EL4-L6或EL4细胞的浓度调整成2×10 5cells/ml(在LCM培养基中),然后加入TAL6抗血清或空白小鼠血清(1:10)。6小时后收集上清液,使用γ计数器测量放射性。在单独含有目标细胞的孔中测量自发性释放。使用Triton X-100(2%)裂解目标细胞以估计最大的释放量。根据下列公式计算细胞毒性百分比:裂解百分比=100×(实验的51Cr释放-自发性51Cr释放)/(最大51Cr释放-自发性51Cr释放)。
[ELISPOT试验]
将脾细胞(5×105)与10μg/ml的指定胜肽混合,并且加至用抗-IFN-γ抗体(anti-IFN-γantibody)涂覆的96孔PVDF膜盘(96-well PVDF-membrane plate)中。然后将孔盘放置在37℃、含有5%CO2的湿润空气中培养48小时。培养后,用含有tween 20(0.05%(w/v))的PBS冲洗孔盘6次以移除细胞。在每孔中加入50μl等量的生物素化的二次抗-IFN-γ抗体(R46A2株;购自eBioscience,San Diego,CA)。2小时后,冲洗孔盘,并且加入链霉亲和素-HRP(streptavidin-HRP,购自eBioscience)。使用3-胺-9-乙基咔唑(3-amine-9-ethylcarbazole;购自AEC,Sigma)溶液使斑点呈色。4-6分钟后,以自来水清洗孔盘以终止反应。然后使用ELISPOT读取器(Cellular Technology Ltd.,Shaker Heights,OH)计算斑点。
[CD107a细胞毒试验]
在有或没有CpG ODN(10μg/mouse)的状况下,皮下注射在IFA、DOTAP或PELC中乳化的指定胜肽(50μg/ml)至HLA-A2基因转殖小鼠两次。
在第二次免疫接种后第7天,收集脾细胞,然后在96孔圆底盘中将含有10μg/ml的指定胜肽(50μg/ml)或细胞(2×106cell/ml)、及PE-复合的抗小鼠CD107a抗体(1:100)的培养基中,再悬浮脾细胞至浓度2×107cell/ml。在37℃下2小时后,加入布雷非德菌素A(brefeldin A,10μg/ml)和莫能菌素(monensin,0.66μg/ml)放置2-6小时。用含有0.1%FBS的PBS冲洗孔盘,加入抗小鼠Fc抗体(1:100)放置5分钟,然后加入FITC-复合的抗小鼠CD8抗体(1:100)放置30分钟。用萤光流式细胞分选仪(FACS calibur,BD Bioscience)分析细胞毒性CD107a+CD8+细胞。
[伤口愈合试验]
使用Culture-Insert(500μm;购自Ibidi)研究伤口愈合。将100μl在DMEM-10%FBS中的B16-L6细胞悬浮液(5×106cells/ml)种入Culture-Insert的每一孔中。细胞附着24小时后,取出Culture-Insert,并将细胞与抗血清(1:100v/v)在DMEM-10%FBS中培养。如倒置显微镜下所示,于48小时的观察中,可观察到细胞迁移到限定的细胞间隙中。对于试验分析,使用ImageJ programmer的手动追踪软体组件,追踪细胞。
[数据分析]
使用student t test和ANOVA得到实验组平均值间的统计学显著差异。如果P值<0.05,则差异被认为是统计学显著性差异。
[其他实施例]
本说明书中公开的所有技术特征可以任何组合。本说明书中公开的每个特征可由可达成相同、等同或相似目的的替代特征来代替。因此,除非另有明确说明,所公开的每个特征仅是等效或相似特征的通用示范例。
由上述实施例,本技术领域者可轻易了解所述实施例的必要特征,且在不偏离其精神及范围下,对实施例可作各种的改变及修饰,以适用于各种使用及状况。因此,其他实施例亦落在权利要求中。
Claims (21)
1.一种免疫原胜肽,包含序列CLDSLGQWN,其特征在于,该胜肽具有100个或更少的胺基。
2.如权利要求1所述的胜肽,其特征在于,该胜肽具有一序列
X1X2X3X4X5X6X7CLDSLGQWNX8X9X10X11,其中,X1至X11各自为胺基酸。
3.如权利要求2所述的胜肽,其特征在于,X6为脯胺酸。
4.如权利要求2或3所述的胜肽,其特征在于,X8为苏胺酸。
5.如权利要求3或4所述的胜肽,其特征在于,该胜肽包含一序列GLAEGPLCLDSLGQWNYTFA。
6.如权利要求1至5中任一项所述的胜肽,其特征在于,更包含(i)一TAL6的细胞毒性T淋巴球(CTL)抗原决定位,及/或(ii)一辅助T细胞(Th)抗原决定位。
7.如权利要求6所述的胜肽,其特征在于,该CTL抗原决定位为LLMLLPAFV或RFVWFFSGI。
8.如权利要求6或7所述的胜肽,其特征在于,该Th抗原决定位为AKFVAAWTLKAAA或QYIKANSKFIGITEL。
9.如权利要求6至8中任一项所述的胜肽,其特征在于,更包含一连接序列(linkersequence),位于两个抗原决定位之间。
10.如权利要求9所述的胜肽,其特征在于,该胜肽包含一序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA。
11.一种核酸分子,包含一序列,该序列编码出如权利要求1至10中任一项所述的免疫原胜肽。
12.如权利要求11所述的核酸分子,其特征在于,该核酸分子为一种可表现该胜肽的表现载体。
13.一种免疫原组合物,其特征在于,包含如权利要求1至10中任一项所述的该胜肽。
14.如权利要求13所述的免疫原组合物,其特征在于,更包含一佐剂。
15.如权利要求14所述的免疫原组合物,其特征在于,该佐剂是选自由不完全弗氏佐剂IFA)、DOTAP、PELC、及含有非甲基化CpG的去氧寡核苷酸(CpG)所组成的群组。
16.如权利要求15所述的免疫原组合物,其特征在于,该组合物包含PELC以及CpG,且该胜肽具有一序列AKFVAAWTLKAAAAAALLMLLPAFVAAAGLAEGPLCLDSLGQWNYTFA。
17.一种免疫原组合物,其特征在于,包含如权利要求11或12所述的该核酸分子。
18.如权利要求17所述的免疫原组合物,其特征在于,更包含一佐剂。
19.一种免疫原组合物的用途,用于制备治疗一主体的癌症的医药组成物,其特征在于,免疫原组合物包括如权利要求13至18中任一项所述的免疫原组合物。
20.如权利要求19所述的用途,其特征在于,该癌症具有表现TAL6的细胞。
21.如权利要求20所述的用途,其特征在于,该癌症为肺癌、结肠癌、乳癌、卵巢癌、胃癌、卡波西氏肉瘤、肝癌、胰脏癌、子宫颈癌、子宫内膜癌、头颈癌、卵巢癌或前列腺癌。
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US20070032413A1 (en) * | 1999-03-12 | 2007-02-08 | Rosen Craig A | Human secreted proteins |
US20110038894A1 (en) * | 2009-08-12 | 2011-02-17 | National Health Research Institutes | Immunogenic Peptides of Tumor Associated Antigen L6 and Uses Thereof in Cancer Therapy |
CN102590531A (zh) * | 2012-03-24 | 2012-07-18 | 广西壮族自治区肿瘤防治研究所 | 卵巢癌相关抗原自身抗体谱液相芯片检测试剂盒及其制备方法 |
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US5200508A (en) | 1989-05-04 | 1993-04-06 | The State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon Health Sciences University | Cell surface antigen that binds with L6 monoclonal antibody |
US5314995A (en) | 1990-01-22 | 1994-05-24 | Oncogen | Therapeutic interleukin-2-antibody based fusion proteins |
US5597707A (en) | 1993-04-15 | 1997-01-28 | Bristol-Myers Squibb Company | Tumor associated antigen recognized by the murine monoclonal antibody L6, its oligonucleotide sequence and methods for their use |
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