CN1319991C - 用于治疗过度表达神经节苷脂的肿瘤的免疫治疗组合物 - Google Patents
用于治疗过度表达神经节苷脂的肿瘤的免疫治疗组合物 Download PDFInfo
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- CN1319991C CN1319991C CNB028084330A CN02808433A CN1319991C CN 1319991 C CN1319991 C CN 1319991C CN B028084330 A CNB028084330 A CN B028084330A CN 02808433 A CN02808433 A CN 02808433A CN 1319991 C CN1319991 C CN 1319991C
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Abstract
本发明涉及免疫学领域，更确切地说是涉及应用于控制肿瘤生长和/或细胞增殖的免疫治疗组合物。借助于本发明，通过将含有以抗神经节苷脂抗体(Ab1)为有效成分的独特型疫苗和以针对抗神经节苷脂抗体获得的抗独特型抗体(Ab2)为有效成分的独特型疫苗，或者有效成分是一种或多种神经节苷脂的疫苗混合，观察到了对肿瘤的治疗作用。叙述了这些疫苗组合物导致的对肿瘤的协同治疗作用。涉及的组合物可以应用于处于不同临床情况下的表达神经节苷脂的肿瘤患者。
Description
技术领域
本发明涉及人用药品，特别是治疗疫苗，其可引起对过度表达神经节苷脂的肿瘤的免疫反应。
现有技术
神经节苷脂是大部分哺乳动物细胞中细胞质膜的组分。由于在细胞恶变期间的表达形式，即使当这些鞘糖脂在正常组织中表达时，它们也是免疫疗法非常有吸引力的目标。(Hakomori，S.Ann.Rev.Biochem.50；1981：733-764；Hakomori，Cancer Res.45；1985：2405-2414；Irie，R.F.，等人：治疗用单克隆抗体(Therapeuticmonoclonal antibodies).Borrebaeck，C.A.K.，和Larrick，J.W.(Eds.).M Stockton Press，1990，pp.75-94)
神经节苷脂的糖类特性，与其是自身抗原的事实一起，使其成为极低免疫原性的分子。某些策略已经应用于提高该抗原的免疫原性。它们是基于将神经节苷脂在不同分子环境中暴露于免疫系统。策略之一是共轭疫苗的应用，其中糖类抗原与载体蛋白共价相连，该载体对于T细胞的免疫原性是很强的。这使得获得强烈而持久的抗体免疫反应成为可能。采用此方法有提高抗神经节苷脂的IgG抗体的可能，尽管在再免疫接种之后获得的滴度比与抗胸腺非依赖抗原的经典免疫反应中所获得的滴度要小。(Helling，F等人Cancer Res.54；1994：197-203；Helling，F等人Cancer Res.55；1995：2783-2788；Livingston PO等人Cancer Immunol Immunother 45；1997：10-19)
新的疫苗组合物已见报道，其可诱导抗N-乙酰化和N-乙醇酰基化(N-glycolylated)的神经节苷脂的免疫反应。该疫苗是基于神经节苷脂和极小尺寸的蛋白脂质体(VSSP)之间的疏水共轭物(神经节苷脂/VSSP)，VSSP由从脑膜炎奈瑟球菌(Neisseria meningitidis)、革兰氏阴性菌中获得的外膜蛋白复合体(OMPC)与神经节苷脂进行的结合而获得。(Estévez F.等人Vaccine 18；1999：190-197；美国专利US5,788,985和US 6,149,921)由GM3神经节苷脂/VSSP或(NeuGcGM3)神经节苷脂/VSSP组成的疫苗，可以提高抗GM3和NeuGcGM3的特异性IgM和IgG抗体滴度。
另外，接种GM3/VSSP提高了带有黑素瘤B16的小鼠的生存，也减小肿瘤体积并且提高了对肿瘤的皮下移植的排斥率。(Alonso等人Int.J Oncology 15；1999：59-66；Car，A.等人Melanoma Research，出版中)
Jerne 1974年提出了独特型(idiotype)网络学说(Jerne，N.K.Ann.Immunol.125C；1974：373-389)，指出免疫系统是有着它们和若干自然抗原之间的复杂相互作用模式构成的一种抗体网络，其相互作用通过可变区或独特型(Id)而发生，并且免疫系统通过独特型-抗独特型的相互反应而被调节。Jerne的学说支持基于应用抗独特型疫苗的肿瘤主动免疫疗法(AI)的新策略。用一种识别肿瘤相关抗原的抗体(Ab1)进行接种，以诱导抗独特型抗体(Ab2)。该抗独特型抗体模拟名义上的抗原并且反过来产生抗抗独特型抗体(Ab3)来对抗肿瘤相关抗原(Schmolling J，等人Hybridoma14；1995：183-186).另一方面，在用抗独特型抗体(Ab2)接种之后，抗肿瘤相关抗原的免疫反应的诱导已经有报道。(Raychauhuri，s.等人J.Immmnol.137；1986：1743-1749；Raychauhuri，s.等人J.Immunol.139；1987：3902-3910；Bhattacharya-Chatterjee，M.等人J.Immunol.139；1987：1354-1360；Bhattacharya-Chatterjee，M.等人J.Immunol.141；1988：1398-1403；Herlyn，D.等人Intern.Rev.Immunol.4；1989：347-357；Chen，Z-J.等人Cell.Imm.Immunother.Cancer；1990：351-359；Herlyn，D.等人In Vivo 5；1991：615-624；Furuya，A.等人Anticancer Res.12；1992：27-32；Mittelman，A.等人Proc.Natl.Acad.Sci.USA 89；1992：466-470；Durrant，LG.等人Cancer Res.54；1994：4837-4840；Mittelman，A.等人Cancer Res.54；1994：415-421；Schmitt，H.等人Hybridoma13；1994：389-396；Chakrobarty，M.等人J.Immunother.18；1995：95-103；Chakrobarty，M.等人Cancer Res.55；1995：1525-1530；Foon，KA.等人Clin.Cancer Res.1；1995：1285-1294；Herlyn，D.等人Hybridoma 14；1995：159-166；Sclebusch，H.等人Hybridoma 14；1995：167-174；Herlyn，D.等人Cancer Inmunol.Immunother.；43；1996：65-76
关于Ab2抗体的应用和为了提高糖类残基的免疫原性，其他选择涉及在抗体分子上的蛋白表位可以代表糖类表位的可能性。实际上，许多这样的抗独特型抗体已经被获得，它们模拟在癌细胞中大量表达的神经节苷脂，如GM3、GD3和GD2。(Yamamoto，S.等人J.Natl.Cancer Inst.82；1990：1757-1760；Chapman，P.B.等人J.Clin.Invest 88；1991：186-192；Cheung N-K V，等人Int J Cancer 54；1993：499-505；Saleh MN.等人J.Immunol.151；1993：3390-3398；SenG.等人J.Immunotherapy 21；1998：75-83)
在癌症患者中用BCG或QS21作为佐剂与Ab2抗体同时应用的临床实验已经获得初步成果。(McCaffery M.等人Clin.Cancer Res.2；1996：679-686.；Foon，KA.等人Clin.Cancer Res.4；1998：1117-1124)
从现有技术已知的单克隆抗体P3(保藏号ECACC 94113026)，其特异性识别在含有N-乙醇酰基(glycolyl)的单唾液酸和二唾液酸神经节苷脂中的唾液酸。此Mab Ab1识别在人乳腺肿瘤和黑素瘤上的抗原。(美国专利US 5,788,985；Vázquez AM.等人Hybridoma 14；1995：551-556；Moreno E.等人Glycobiology 8；1998：695-705；Marquina G.等人Cancer Res.56；1996：5165-5171；Carr，A.等人Hybridoma 19(3)；2000：241-247)
用MAb P3免疫接种获得的抗独特型抗体1E10(Ab2MAb 1E10)(保藏号ECACC 97 112901)是一种γ型抗体(非内部映像)。Ab2MAb 1E10显示出了对生长的乳腺肿瘤和黑素瘤的抗肿瘤作用。(美国专利US 6,063,379；Vázquez等人Hybridoma 14；1995：183-186；Vázquez等人Oncology Reports 7；2000：751-756)
在现有技术中不存在关于含有神经节苷脂的疫苗和含有抗神经节苷脂抗体(Ab1)或抗独特型抗体(Ab2)的药物组合物(其被称为独特型疫苗)的组合应用的证据；也没有独特型疫苗Ab1与独特型疫苗Ab2一起组合应用的证据。
本发明涉及所述全部可能的疫苗的组合应用，以加强其每一个分别产生的作用。
发明详述
本发明涉及一种药物组合物或药物组合物的组合物，其可应用于癌的免疫疗法，特别是应用于过度表达神经节苷脂的肿瘤，其含有至少两种下述化合物：
(A)一种独特型疫苗，其含有抗神经节苷脂抗体(Ab1)；
(B)一种独特型疫苗，其含有针对抗神经节苷脂抗体的抗独特型抗体(Ab2)；和
(C)一种含有神经节苷脂的疫苗。
药物组合物，或药物组合物的组合物可以含有A加B，或A加C，或B加C。
优选的药物组合物，或药物组合物的组合物，其中A可以是含有保藏号ECACC 94113026的鼠MAb P3的独特型疫苗；B可以是含有保藏号ECACC 97112901的鼠抗独特型抗体1E10的独特型疫苗；C可以是含有N-乙醇酰基化GM3(NeuGcGM3)或N-乙酰化GM3(NeuAcGM3)神经节苷脂的疫苗。
在本发明中的A加B，或A加C，或B加C可以以同时的或交替的方式给药。
本发明的组合物可以在癌的治疗中应用，尤其是那些过度表达神经节苷脂的癌，以及肺、乳腺、消化系统、泌尿生殖系统、黑素瘤、肉瘤以及从神经外胚层组织来源的那些肿瘤。
本发明也叙述了其药物组合物，或药物组合物的组合物治疗哺乳动物的给药方案。
在本发明中还叙述了一种方法，其包括将前述的药物组合物，或药物组合物的组合物对哺乳动物给药，以预防或治疗乳腺肿瘤、肺肿瘤、消化系统肿瘤、泌尿生殖系统的肿瘤、黑素瘤、肉瘤和从神经外胚层起源的肿瘤。
1.含有神经节苷脂的疫苗的制备：
含有神经节苷脂的疫苗是根据Estevez和Col在《疫苗》(Vaccines)18，1999：190-197和美国专利US 5,788,985和US 6,149,921中的详述来获得。极小尺寸的蛋白脂质体(VSSP)VSSP由从革兰氏阴性菌脑膜炎奈瑟球菌中获得的外膜蛋白复合体(OMPC)与已整合入其中的合成的或天然的神经节苷脂进行的结合而获得(VSSP-G)。神经节苷脂可以是(NeuGcGM3)、GD3或(NeuAcGM3)。
2.独特型疫苗的制备：
药物组合物根据美国专利US 5,817,513和US 6,063,379的详述来获得。该疫苗含有鼠抗神经节苷脂单克隆抗体，这种抗神经节苷脂抗体如MAb P3，或含有鼠抗独特型单克隆抗体，如Mab 1E10，它能识别抗神经节苷脂单克隆抗体。
3.免疫疗法组合物，其加强神经节苷脂疫苗和独特型疫苗在动物模型中的免疫反应和抗肿瘤作用：
所涉及的方法可应用于小鼠或任何其他种类的哺乳动物。组合物的组分是神经节苷脂疫苗和独特型疫苗；它们可用不同的方法组合。
在一种组合中，可给动物用25μg～1mg鼠抗神经节苷脂单克隆抗体接种3～10次；给药的时间间隔可以是7和14天。在这期间让动物接受3～10次60～1000μg的神经节苷脂疫苗，给药的时间间隔可以是7～14天。
在另一种组合中，可给动物用25μg～1mg针对抗神经节苷脂抗体的特异性的鼠抗独特型抗体接种3～10次；给药的时间间隔可以是7～14天。在这期间让动物接受3～10次60～1000μg的神经节苷脂疫苗，给药的时间间隔可以是7～14。
两种类型疫苗的给药都可以是同时或交替进行。当以同时的方式给药时，疫苗可以作为单独的产品或作为一种疫苗组合物来配制。当以交替的方式给药时，每一类型的疫苗之间的间隔可为3～7天。疫苗在一种佐剂中被给药时，其佐剂可以是氢氧化铝(62.5μg～2.5mg)、Montanide ISA 51(0.1～1.2ml/剂)或任何其它合适的佐剂。每一剂量的总体积可为10μl～2ml。含有神经节苷脂的疫苗可以用皮内、皮下、肌内、腹膜内、粘膜内的方法或它们的组合来给药。相同的给药方法可以应用于含有抗体的疫苗。
免疫治疗组合物在治疗动物时提高抗体免疫反应，以及细胞的免疫反应。
用接受治疗的被试者的局部肿瘤出现的时间、肿瘤的体积和生存期与对照组的相同参数比较，以评价免疫治疗组合物的效力。在进行治疗组和对照组之间这些参数的比较时，可以看到，使用本发明治疗组合物的治疗组的局部肿瘤出现的时间较短、肿瘤体积减小并且存活增加。对照组不仅是那些用佐剂治疗的动物，而且还有仅用一种疫苗而不是其组合物治疗的那些组。
4.免疫治疗组合物，其增强神经节苷脂疫苗和独特型疫苗在人类患者中的免疫反应和抗肿瘤作用：
前面涉及的方法亦可以应用于不同临床阶段的癌症患者。尤其是那些过度表达神经节苷脂的肿瘤，以及肺、乳房、消化系统、泌尿生殖系统、黑素瘤、肉瘤以及从神经外胚层组织产生的那些肿瘤。
在一种组合中，可给患者用0.1～5mg鼠抗神经节苷脂单克隆抗体的剂量接种3～10次；用药的时间间隔可以是7和14天。在这期间让患者接受60～1000μg的神经节苷脂疫苗3～10次，给药的时间间隔可以是7～14天。
在第二种组合中，可给患者用0.1～5mg针对抗神经节苷脂抗体的特异性的鼠抗独特型抗体接种3～10次；给药的时间间隔可以是7～14天。在这期间让患者接受60～1000μg的神经节苷脂疫苗4～6次，给药的时间间隔可以是7～14天。
在第三种组合中，可给患者用鼠抗神经节苷脂单克隆抗体免疫接种；剂量、频率和时间间隔可以如前面所述。在这期间让患者接受3～10次0.1～2mg针对抗神经节苷脂抗体的特异性的鼠抗独特型抗体。
两种类型疫苗的给药都可以同时或交替进行。当以同时的方式给药时，疫苗可以作为单独的产品或作为一种疫苗组合物来配制。当以交替的方式给药时，每一类型的疫苗之间的间隔可为3～7天。疫苗在一种佐剂中被给药时，其佐剂可以是氢氧化铝(1mg～5mg/剂)、Montanide ISA 51(0.6～1.2ml/剂)或任何其它合适的佐剂。每一剂量的总体积可为10μl～2ml。
含有神经节苷脂的疫苗可以用皮内、皮下、肌内、腹膜内、粘膜内的方法或它们的组合来给药。相同的给药方法可以应用于含有抗体的疫苗。
在接种期间，通过血液中的测量监控某些生物化学参数和抗体的滴度。其频率可为1星期至3个月。细胞免疫是通过从患者中采集的淋巴细胞来研究的。采集是以一星期到三个月的波动的频率进行。
最后，患者用两种疫苗以前述浓度再次免疫接种，给药的时间间隔可以是1～6个月。他们可以用同时的或不同时的方式在1～2年的时间内用药。
本接种方案诱导患者抗体和细胞免疫反应增强，并因此减小肿瘤负荷。
实施例
实施例1：通过用鼠MAB P3免疫接种诱导在同基因模型中的抗独特型T2和抗抗独特型T3细胞的激活。
雌性6-8周大的相同遗传背景的Balb/c裸鼠，给其皮下免疫接种100μg鼠MAb P3(抗-N-乙醇酰基化神经节苷脂，保藏号ECACC94113026；Vázquez等人Hybridoma 14；1995：551-558；Moreno等人Glycobiology 8；1998：695-705)和完全弗氏佐剂(CFA)。七天后给鼠再次接种不完全弗氏佐剂(IFA)中的抗体50μg。在第10天，采集引流淋巴结并通过按压注射器得到淋巴细胞。在细胞增殖的实验中使用细胞悬液，该实验用掺入3H-胸腺嘧啶脱氧核苷来测定。体外淋巴细胞增殖的测定是通过在提高浓度(25到150μg/ml)的鼠MAb P3和它的Ab2MAb 1E10(保藏号ECACC 97112901)存在的情况下培养淋巴细胞悬液进行的。对照组使用相匹配的同种型(isotype)的鼠MAb。刺激指数等于或高于3被认为是阳性。用P3MAb给Balb/c鼠免疫接种之后获得的淋巴细胞，在此MAb存在的情况下特异性地增殖，并且在鼠对照MAB A3(IgM)存在的情况下进行细胞培养时未观察到这种增殖。(Alfonso M.和col.Hybridoma 14；1995：209-216)这种增殖依赖于T细胞的存在，因为用从P3免疫接种的无胸腺nu/nH鼠的淋巴结细胞没有获得此增殖。用鼠MAb P3免疫接种，不仅诱导针对Ab1 Mab(T2)的独特型的T细胞的增殖，而且也诱导特异性抗鼠Ab2MAb 1E10(IgG1)而不对抗Mab C5的同种型(IgG1)的抗抗独特型T细胞(T3)的增殖(图1)。
实施例2：用嵌合抗体P3免疫接种，诱导抗独特型(T2)和抗抗独特型(T3)的激活。
将嵌合抗体P3(其重链(VH)和轻链(VL)可变区的氨基酸序列分别见图8和图9)用于6-8周大的雌性Balb/c小鼠的免疫接种。对于第一次皮下用药，使用100μg用ACF乳化的抗体。七天后给动物再免疫接种50μg用AIF乳化的抗体。在第10天，采集引流淋巴结(LN)，并且通过在抗体P3和Ab21E10的鼠嵌合变体存在的情况下培养分析LN细胞的淋巴增殖能力，其可变区的序列见图13(重链)和图14(轻链)。用C5鼠MAb及其嵌合变体作为相匹配的同种型对照(专利申请WO 97/33916A1)。在该抗体或嵌合1E10 MAb存在的情况下进行培养时，从用嵌合抗体P3免疫接种的鼠中得到的淋巴细胞特异性地增殖，在这些鼠抗体变体存在的情况下培养时，其亦特异性地增殖。用相匹配的同种型对照MAbs证明了增殖的特异性。因此，嵌合P3 MAb保留了鼠变体诱导抗独特型(T2)和抗抗独特型(T3)T细胞的特异性增殖的能力(图2)。
实施例3：GM3-VSSP/Montanide ISA 51疫苗通过与吸附在氢氧化铝上的鼠MAb 1E10组成的疫苗结合，增强抗肿瘤效果。
给一组6-8周大的C57BL/6雌性小鼠在第0、14、28和42天用50μg吸附在氢氧化铝上的鼠1E10MAb进行皮下免疫接种。在第7、21、35和49天，小鼠接受120μg GM3-VSSP/Montanide ISA 51的肌内给药。另一组小鼠以类似方法被免疫接种，但开始时用含有GM3神经节苷脂的疫苗制剂免疫接种。在这些实验中，使用了分别在相同时间间隔并且与每种疫苗给药次数相同的或仅用磷酸缓冲的盐溶液接种的对照组。在第63天，用10 000个鼠肿瘤B16细胞对所有组的小鼠进行皮下接种。评价所有组的肿瘤生长情况。
应用混合直线模型(Mixed Lineal Pattern)统计数据分析比较所有组和仅接受PBS的对照组的肿瘤生长情况。单独使用1E10 MAb疫苗接种不能保护小鼠使其免受10,000黑素瘤B16细胞的挑战。VSSP-GM3疫苗使肿瘤生长放慢(p＜0.05)。GM3-VSSP和1E10 MAb疫苗的组合物导致在单独使用GM3-VSSP疫苗时观察到的保护效果有所提高(p＜0.05)(图3)。
实施例4：用Montanide ISA 51作为佐剂的NeuGc-GM3/VSSP神经节苷脂疫苗对癌症患者的免疫接种方案。
临床试验在20名患晚期恶性黑素瘤(不符合其他任何肿瘤特异性治疗的条件)的患者中进行，给其接种该疫苗，目的在于证明以用Montanide ISA 51为佐剂(美国专利US 5,788,985和US 6,149,921)的NeuGc-GM3/VSSP的免疫接种的安全性和免疫源性。
患者接受9次含有200μg GM3神经节苷脂的疫苗制剂。在第0、14、28、42、56、84、112、140及168天给药。根据医师的标准，在第六个月之后患者每28天接受额外的剂量，直到他们完成一年的治疗。
在第0、14、28、56、112、168、224、280及332天，采血样做常规生物化学测定和测定抗NeuGcGM3神经节苷脂抗体的血清滴度。
抗体滴定度用ELISA测定。当抗神经节苷脂的OD值等于或高于0,1时血清稀释液被认为是阳性(参照抗甲醇OD)。
疫苗NeuGcGM3-VSSP/Montanide ISA 51的毒性在于在注射部位的红斑、局部疼痛、硬化和发热，根据OMS规范这属允许的轻微毒性级别，为I/II级。
患者提高了抗NeuGcGM3的特异性抗体的滴度(1∶80～1∶2560)。检测出的同种型抗体包括IgG和IgM(全部患者)和IgG(75％患者；表I)。
就患者01而论，其以晚期恶性黑素瘤(进展的转移疾病(Evolutionary Metastatic Disease)，EMD)的诊断参加本试验，在治疗两个月后观察到，某些皮肤的病灶的消退和稳定，这些病灶周围有无色晕轮，在其活检组织中用病理解剖学研究证明有炎性浸润和坏死存在(图4)。
就患者02而论，诊断为晚期恶性黑素瘤，在至少4个月期间，观察到在右肺尖18-20mm的肺部转移病灶的稳定(图5)。
表I：
在晚期恶性黑素瘤患者中用NeuGcGM3/VSSP/Montanide ISA 51疫苗免疫接种后，抗NeuGcGM3抗体的滴度。
| 患者 | 天 | IgM | IgG | IgA |
| 01 | 0 | 0 | 0 | 0 |
| 14 | 640 | 80 | 320 | |
| 28 | 320 | 160 | 320 | |
| 56 | 1280 | 160 | 320 | |
| 02 | 0 | 160 | 160 | 160 |
| 14 | 160 | 160 | 320 | |
| 28 | 160 | 160 | 320 | |
| 56 | 1280 | 320 | 320 | |
| 03 | 0 | 80 | 320 | 0 |
| 14 | 320 | 320 | 0 | |
| 28 | 640 | 320 | 0 | |
| 56 | 640 | 640 | 0 | |
| 04 | 0 | 0 | 0 | 0 |
| 14 | 160 | 80 | 160 | |
| 28 | 1280 | 80 | 160 | |
| 56 | 2560 | 640 | 2560 |
实施例5：用含有1E10 Ab2 Mab氢氧化铝沉淀的独特型疫苗在癌症患者中进行免疫接种的方案。
临床试验在20名患晚期恶性黑素瘤(不符合其他任何肿瘤特异性治疗的条件)的患者中进行，目的在于证明含有鼠抗独特型MAb 1E10(美国专利US 5,817,513和US 6,063,379)和作为佐剂的氢氧化铝的独特型疫苗的安全性和免疫源性。
患者接受4次含有2mg 1E10 MAb的疫苗。在治疗前和每次接种后14天采血样，做常规生物化学测定和测定抗1E10 MAb独特型和NeuGc-GM3神经节苷脂的抗体的血清滴度。抗体滴度用ELISA试验测定，等于或高于0,15时被认为是阳性。
疫苗的使用给患者带来轻微毒性，根据OMS分类为I和II级。
在接受2或3次疫苗后，在有价值的17名患者中有16名可检测到被诱导出的强烈的IgG Ab3抗体反应。对该Ab3特异性的分析显示，在与其他相匹配的同种型的对照MAb比较时，它被患者1E10 MAb血清优先识别，表明在对1E10 MAb的抗体反应中诱导出独特型特异的成分。这被抗该MAb的F(ab′)2片段的强血清反应所证实，其滴度的中位数为1∶15000(滴度为从1∶10000到大于1∶100000)，作为对照的对照MAbs的F(ab′)2片段很少或没有识别。(图6)
在大多数情况，对抗NeuGcGM3产生的抗体是IgM和IgG两种，其滴度分别为1∶4000和1∶800(图7)。
临床试验包括一名诊断为恶性黑素瘤和肝转移的患者，在治疗后显示病情稳定8个月并且患者生存期为15个月。
实施例6：用含有Ab2 MAb 1E10的抗独特型疫苗和NeuGcGM3-VSSP神经节苷脂疫苗组合免疫接种。
一名转移的黑素瘤患者，诊断后已经接受了每月一次的外科治疗，在第0、14、28、42、56天接受6次含有Ab2 MAb1E10和氢氧化铝凝胶的独特型疫苗(每剂2mgMAb)。在这期间，在第7、21、35、49、63天也给患者施用含有200ug NeuGcGM3-VSSP神经节苷脂和作为佐剂的Montanide ISA 51的神经节苷脂疫苗。在患者接受此免疫接种方案后，对其在两个月内同时用两种疫苗每月再免疫接种一次。疫苗接种期间，没有新的病灶出现并且患者状况良好。
实施例7：用MAb 14F7识别肿瘤组织。
用MAb 14F7来识别NeuGcGM3神经节苷脂(专利申请WO99/40119)。显示了用抗体识别肿瘤组织。
将以福尔马林固定的组织包埋在石蜡中。对苏木素-伊红(hematoxillin-eosin)染色的切片进行组织学检查。
这些切片用生物素-链霉亲和素(estreptavidin)-过氧化物酶复合物进行免疫染色。(Hsu，S.M.和Raine，L.1981，J.HistochemCytochem.，29：1349-1353)简单地说，去除石蜡并将湿切片用3％H2O2(在甲醇溶液中)处理30分钟，以降低其内源性过氧化物酶的活性。在室温下与MAb 14F7(纯的)温育1小时后，在室温下加入(Dakopatts)生物素化抗小鼠免疫球蛋白和链霉亲和素-过氧化物酶复合物；在各次温育之间，用Tris-HCl缓冲液洗涤切片。反应(POD)由5ml Tris-HCl、0,005ml含有30％H2O2的缓冲液和3-3二氨基联苯胺3mg引发。
用苏木素-对照(hematoxillin-contrasted)水(Mayer)洗涤之后，切片用树胶(balm)覆盖并封片。酶反应使其呈现褐色。
病理组织的新鲜活检标本是在手术后一小时获得。全部组织用盐溶液洗涤，并且立刻在液氮中冷冻，并在-80℃冷冻保藏。
在-25℃用Leica低温保持器将冰冻的片段切片。得到5um系列切片，之后用空气干燥并立刻使用，或者用铝箔包装保藏在-20℃；之后，将切片用4％的低聚甲醛固定20分钟。
在表II中显示了若干人的肿瘤用MAb 14F7免疫染色的情况。在50％以上的肿瘤细胞中，观察到很强的细胞膜和胞质染色。在结肠癌、子宫癌、卵巢癌、肉瘤、乳腺癌的淋巴结和脑转移瘤中，以及在黑色素转移瘤中，染色非常强。
表II：
用MAb 14F7进行肿瘤免疫染色。
| 肿瘤 | 免疫染色(阳性/总数) |
| 结肠癌 | 9/9* |
| 子宫癌 | 2/2* |
| 卵巢癌 | 2/2* |
| 肉瘤 | 2/2* |
| 乳腺癌及其淋巴结转移 | 6/6* |
| 黑色素转移瘤 | 2/2* |
*大于50％的细胞显示出细胞膜和胞质被很强地免疫染色。
附图简述：
图1：给胸腺机能正常的Balb/c小鼠和无胸腺的小鼠，皮下免疫接种100μg在CFA中的鼠MAb P3，接着用50μg在IFA中的乳化MAb再免疫接种。三天后，采集淋巴结细胞并且对其用不同浓度的MAb P3、A3、1E10和C5进行增殖试验。
图2：给Balb/c小鼠皮下免疫接种100μg在CFA中的嵌合抗体P3，接着用50μg在IFA中乳化的抗体再免疫接种。三天后，采集淋巴结细胞，并且对其用不同浓度的抗体进行增殖试验，鼠嵌合抗体作为对照。
图3：如实施例3中叙述的，在用免疫治疗组合物，特别是含有Ab2MAb 1E10的独特型疫苗和GM3-VSSP神经节苷脂疫苗，免疫接种小鼠时，鼠B16肿瘤的生长动力学。
图4：黑素瘤患者中皮肤转移的进展。用疫苗NeuGcGM3/VSSP/ISA 51免疫接种前、在治疗后2和4个月时拍下照片。可观察到某些病灶周围有无色晕轮，病灶稳定，在一个病灶中观察到其尺寸减小，而在一个病灶看到增大。
图5：黑素瘤患者中肺转移瘤的进展。用计算机辅助轴向断层照相观察右肺尖，用疫苗NeuGcGM3/VSSP/ISA 51免疫接种前，病灶尺寸为18×20mm，而免疫接种后4个月观察到病灶稳定。
图6：用从接种了含有Ab2 MAb 1E10和作为佐剂的氢氧化铝凝胶独特型疫苗的患者中获得的血清，从Ab2 MAb1E10和含有相同同种型的其他MAb中识别F(ab′)2片段。
图7：用从接种了含有Ab2 MAb1E10和作为佐剂的氢氧化铝凝胶独特型疫苗的患者中获得的血清，识别GM3(NeuGc)和GM3(NeuAc)神经节苷脂。
Claims (11)
1.一种免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的免疫疗法，该组合物含有下述组分中的至少两种：
(A)一种独特型疫苗，其含有鼠抗神经节苷脂单克隆抗体(Ab1)；
(B)一种独特型疫苗，其含有针对抗神经节苷脂单克隆抗体的特异性鼠抗独特型单克隆抗体(Ab2)；
(C)一种神经节苷脂疫苗。
2.根据权利要求1所述的免疫治疗组合物，其中所述组合物含有A加B或A加C或B加C。
3.根据权利要求2所述的免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的癌症治疗，其中所述疫苗A含有鼠抗神经节苷脂MAb(保藏号ECACC 94113026)。
4.根据权利要求2所述的免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的癌症治疗，其中所述疫苗B含有Ab2 MAb 1E10(保藏号ECACC 97112901)。
5.根据权利要求2所述的免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的癌症治疗，其中所述疫苗C含有NeuGcGM3神经节苷脂。
6.根据权利要求2所述的免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的癌症治疗，其中所述疫苗C含有NeuAcGM3神经节苷脂。
7.根据权利要求1-6任一项所述的免疫治疗组合物，其用于过度表达神经节苷脂的肿瘤的癌症治疗，其中将A和B或A和C或B和C同时或交替用药。
8.根据权利要求1-7任一项所述的免疫治疗组合物在制备用于治疗过度表达神经节苷脂的肿瘤的药物中的应用。
9.根据权利要求8所述的应用，其中所述药物用于治疗在乳腺肿瘤、肺肿瘤、消化系统肿瘤、泌尿生殖系统肿瘤、黑素瘤、肉瘤以及从神经外胚层组织产生的那些肿瘤。
10.权利要求1-7中任一项的免疫治疗组合物在制备药物中的应用，所述药物用于控制哺乳动物中过度表达神经节苷脂的肿瘤生长和/或细胞增殖。
11.根据权利要求10所述的应用，其中所述哺乳动物是人。
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| CU2001008420010084A CU23007A1 (es) | 2001-04-06 | 2001-04-06 | Combinaciones inmunoterapéuticas para el tratamiencombinaciones inmunoterapéuticas para el tratamiento de tumores que sobre-expresan gangliósidos to de tumores que sobre-expresan gangliósidos |
| CU84/2001 | 2001-04-06 |
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| CNB028086309A Expired - Fee Related CN100349920C (zh) | 2001-04-06 | 2002-04-08 | 神经节苷脂相关的重组抗体及其在制备肿瘤的诊断和治疗的药物中的应用 |
| CN2007101021039A Expired - Fee Related CN101054417B (zh) | 2001-04-06 | 2002-04-08 | 神经节苷脂相关的重组抗体及其在肿瘤的诊断和治疗中的应用 |
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| CN2007101021039A Expired - Fee Related CN101054417B (zh) | 2001-04-06 | 2002-04-08 | 神经节苷脂相关的重组抗体及其在肿瘤的诊断和治疗中的应用 |
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| JP5415071B2 (ja) * | 2005-08-19 | 2014-02-12 | ワイス・エルエルシー | Ｇｄｆ−８に対するアンタゴニスト抗体ならびにａｌｓおよびその他のｇｄｆ−８関連障害の処置における使用 |
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| EP0657471A1 (en) * | 1993-12-09 | 1995-06-14 | Centro de Inmunologia Molecular | Anti ganglioside monoclonal antibodies and their use in the specific active immunotherapy of malignant tumours |
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