CN102971003A - 基于细胞周期素d1衍生的肿瘤相关抗原的癌症改进疗法 - Google Patents
基于细胞周期素d1衍生的肿瘤相关抗原的癌症改进疗法 Download PDFInfo
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Abstract
本发明是关于用于患者癌症改进型治疗的细胞周期素D1衍生肽，尤其是以使用疫苗联合治疗的形式。另外方面是关于将肽或其组合作为一种诊断工具的用途。
Description
本专利是关于用于患者癌症改进型治疗的细胞周期素(Cyclin)衍生肽，尤其是以使用疫苗的联合治疗形式。另外方面是关于将该肽或其组合用作一种诊断工具的用途。
发明背景
免疫反应的刺激依赖于被宿主免疫系统视为异物的抗原的存在。肿瘤相关抗原存在的发现现在已经提高了利用宿主免疫系统干预肿瘤生长的可能性。对于癌症免疫疗法，目前正在探索各种增强免疫系统的体液和细胞作用的机制。
细胞免疫反应的某些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淋巴细胞(CTL)表明，这些细胞在对癌症的天然免疫防御中发挥重要作用(Cheever et al.，Annals N.Y.Acad.Sci.1993 690：101-112；ZehHJ，Perry-Lalley D，Dudley ME，Rosenberg SA，Yang JC；J Immunol.1999，162(2)：989-94；High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivoantitumor efficacy.)。特别是CD8阳性T细胞(TCD8+)在这种反应中发挥重要作用，TCD8+能识别细胞浆中载有源自蛋白或缺陷核糖体产物(DRiPS)(Schubert U，Antón LC，Gibbs J，Norbury CC，Yewdell JW，Bennink JR.；Rapid degradation of a largefraction of newly synthesized proteins by proteasomes；Nature 2000；404(6779)：770-774)的通常为8至10个氨基酸残基的I类主要组织相容性复合体(MHC)分子。人类MHC分子也称为人类白细胞抗原(HLA)。
MHC分子有两类：MHC-I类分子，大部分提呈酶切内源性蛋白、DRiPS、以及较大肽而生成的肽的有核细胞上都能发现此类分子。MHC-II类分子，主要见于在内吞作用过程中摄取并且随后进行加工外源性蛋白提呈肽的专职抗原提呈细胞(APCs)上(Cresswell P.Annu.Rev.Immunol.1994；12：259-93)。肽和MHC-I类分子的复合物由携带相应T细胞受体(TCR)的CD8阳性细胞毒性T淋巴细胞识别，肽和MHC-II类分子的复合物由携带相应TCR的CD4阳性辅助T细胞的识别。众所周知，TCR、肽和MHC由此按1∶1∶1的化学计算量大量存在。
CD4阳性辅助T细胞在协调抗肿瘤T细胞反应的效应子功能中发挥重要作用，因此，识别肿瘤相关抗原(TAA)衍生的CD4阳性T细胞表位对於开发能引发抗肿瘤免疫反应的药物可能非常重要(Kobayashi，H.，R.Omiya，M.Ruiz，E.Huarte，P.Sarobe，J.J.Lasarte，M.Herraiz，B.Sangro，J.Prieto，F.Borras-Cuesta，and E.Celis.Identification of an antigenic epitope for helper T lymphocytes from carcinoembryonicantigen.Clin.Cancer Res.8：3219-3225.，Gnjatic，S.，D.Atanackovic，E.
M.Matsuo，A.Selvakumar，N.K.Altorki，R.G.Maki，B.Dupont，G.Ritter，Y.T.Chen，A.Knuth，andL.J.Old.2003.Survey of naturally occurring CD4+T-cell responses against NY-ESO-1 incancer patients：Correlation with antibody responses.Proc.Natl.Acad.Sci.U.S.A.100(15)：8862-7)。CD4+T细胞可能导致局部-干扰素水平的增加(Qin Z，Schwartzkopff J，Pradera F，Kammertoens T，Seliger B，Pircher H，Blankenstein T；Acritical requirement of interferon gamma-mediated angiostasis for tumor rejection byCD8+T cells；Cancer Res.2003 J；63(14)：4095-4100)。
在没有炎症的情况下，MHC II类分子的表达主要局限于免疫系统细胞，尤其是专职抗原提呈细胞(APC)，例如，单核细胞、单核细胞衍生细胞、巨噬细胞和树突状细胞。令人惊异的是，在肿瘤患者的肿瘤细胞中发现有MHC-II类分子的表达(Dengjel J，Nastke MD，Gouttefangeas C，Gitsioudis G，Schoor O，Altenberend F，MüllerM，
B，Missiou A，Sauter M，Hennenlotter J，Wernet D，Stenzl A，Rammensee HG，Klingel K，
S.；Unexpected abundance of HLA class II presented peptides inprimary renal cell carcinomas；Clin Cancer Res.2006；12：4163-4170)。
由于HLA-II类分子的组成型表达通常仅限于免疫系统的细胞(Mach，B.，V.Steimle，E.Martinez-Soria，and W.Reith.1996.Regulation of MHC class II genes：lessonsfrom a disease.Annu.Rev.Immunol.14：301-331)，因此，直接从原发肿瘤中分离II类肽被认为是不可能的。然而，Dengjel等人最近成功地直接在肿瘤中识别了数个MHC-II类抗原的表位(EP 04023546.7，EP 05019254.1；Dengjel J，Nastke MD，Gouttefangeas C，Gitsioudis G，Schoor O，Altenberend F，Müller M，
B，Missiou A，Sauter M，Hennenlotter J，Wernet D，Stenzl A，Rammensee HG，Klingel K，
S.；Unexpected abundance of HLA class II presented peptides in primary renal cellcarcinomas；Clin Cancer Res.2006；12：4163-4170)。
对于触发(引发)细胞免疫反应的肽，它必须与MHC分子结合。这一过程依赖于MHC分子的等位基因以及肽氨基酸序列。MHC-I类-结合肽的长度通常为8-10个氨基酸残基，并且在其与MHC分子相应结合沟槽相互作用的序列中通常包含两个保守残基(“锚”)。这样，每个MHC的等位基因都有“结合基序”，从而确定哪些肽能与结合沟槽特异性结合(Rammensee H.G.，Bachmann J.and Stevanovic，S；MHC Ligands and Peptide Motifs，Chapman&Hall 1998)。在MHC-I类依赖性免疫反应中，肽不仅能与肿瘤细胞表达的某些MHC-I类分子结合，而且它们还必须能被负载特异性T细胞受体(TCR)的T细胞识别。
肿瘤特异性的细胞毒性T淋巴细胞所识别的抗原，即它们的表位，可以是源自所有蛋白质种类的分子，例如，酶、受体、转录因子等，这些分子在各种肿瘤的细胞中表达上调。此外，肿瘤相关抗原也可以是肿瘤细胞特异的，例如，突变基因或替代开放阅读框架(ORF)产物或蛋白质剪接产物(Vigneron N，Stroobant V，Chapiro J，Ooms A，Degiovanni G，Morel S，van der Bruggen P，Boon T，Van den Eynde BJ.Anantigenic peptide produced by peptide splicing in the proteasome，Science 2004 Apr 23；304(5670)：587-90)。另一种重要的肿瘤相关抗原是组织特异性抗原，例如，表达于不同类型肿瘤和健康睾丸组织中的癌睾丸(CT)抗原。基本上，任何能与MHC分子结合的肽都可能充当一个T细胞表位。诱导体外或体内T细胞反应的前提是存在有着相应TCR的T细胞，并且没有对这个特定表位的免疫耐受性。
因此，TAA是开发肿瘤疫苗的起点。识别和标记TAA的方法基于对可以从患者或健康受试者分离出来的细胞毒性T淋巴细胞的使用情况，或基于肿瘤与正常组织之间的差别转录谱或差别肽表达模式的产生(Lemmel C.，Weik S.，Eberle U.，Dengjel J.，Kratt T.，Becker H.D.，Rammensee H.G.，Stevanovic S.Nat.Biotechnol.2004Apr.；22(4)：450-4，T.Weinschenk，C.Gouttefangeas，M.Schirle，F.Obermayr，S.Walter，O.Schoor，R.Kurek，W.Loeser，K.H.Bichler，D.Wernet，S.Stevanovic，and H.G.Rammensee.Integrated functional genomics approach for the design of patient-individualantitumor vaccines.Cancer Res.62(20)：5818-5827，2002)。
然而，识别肿瘤组织或人肿瘤细胞株中过量或选择性表达的基因，不能提供免疫疗法中使用这些基因所转录抗原的准确信息。这是因为这些抗原表位只有一部分适用于这个应用，必须要有具有相应T细胞受体的T细胞的存在，以及对这个特定表位的免疫耐受性的缺失或达到最低水平。因此，非常重要的一点是只选择那些由过量或选择性表达的蛋白质的肽，并且这些肽能与相关的MHC分子一起提呈给功能性的T细胞。这种功能性T细胞被定义为“效应T细胞”，其在特异性抗原刺激后，可复制扩增并可执行效应功能。
辅助T细胞在协调抗肿瘤免疫的细胞毒性T淋巴细胞效应子功能中发挥着重要作用。触发TH1细胞反应的辅助T细胞表位支持CD8阳性杀伤T细胞的效应子功能，其中包括直接作用于肿瘤细胞的细胞毒性功能(该类肿瘤细胞表面显示有肿瘤相关的肽/MHC复合物)。这样，以单独形式或与其他肿瘤相关肽形成组合物的肿瘤相关T辅助细胞表位可作为刺激抗肿瘤免疫反应的疫苗组合物的活性药物成分。
由于CD8依赖型和CD4依赖型这两种类型反应共同并协同增强地促进抗肿瘤作用，因此，确定和表征由CD8+细胞毒性T淋巴细胞(配体：MHC-I类分子+肽表位)或CD4阳性细胞毒性T淋巴细胞(配体：MHC-II类分子+肽表位)识别的肿瘤相关抗原对开发肿瘤疫苗非常重要。
细胞周期素D1属高度保守的细胞周期蛋白家族，更具体而言属细胞周期素D亚族(Lew DJ，Dulic V，Reed SI(1991).Isolation of three novel human cyclins by rescueof G1 cyclin(Cln)function in yeast.Cell 66，1197-1206；Xiong Y，Connolly T，Futcher B，Beach D(1991).Human D-type cyclin.Cell 65，691-699)。细胞周期素的功能是作为细胞周期素依赖性激酶(CDK)的调节器。不同的细胞周期素表现出不同的表达和降解模式，以进行细胞周期中每个活动的时序协调(Deshpande A，Sicinski P，Hinds PW(2005).Cyclins and cdks in development and cancer：a perspective.Oncogene 24，2909-2915.)。细胞周期素D1与CDK4或CDK6形成一个复合物，并作为其的一种调节亚基，其活性是细胞周期G1/S期转换所需的。细胞周期素D1(CCND1)与CDK4和CDK6形成丝氨酸/苏氨酸激酶全酶复合物，赋予该复合物的底物特异性(Bates S，Bonetta L，MacAllan D，Parry D，Holder A，Dickson C，Peters G(1994).CDK6(PLSTIRE)and CDK4(PSK-J3)are a distinct subset of the cyclin-dependent kinases that associatewith cyclin D1.Oncogene 9，71-79)。改变细胞周期进程的这个基因之突变、扩增和过量表达经常可在各种肿瘤中观察到，并可能有助于肿瘤形成(Hedberg Y，DavoodiE，Roos G，Ljungberg B，Landberg G(1999).Cyclin-D1 expression in human renal-cellcarcinoma.Int.J.Cancer 84，268-272；Vasef MA，Brynes RK，Sturm M，Bromley C，Robinson RA(1999).Expression of cyclin D 1in parathyroid carcinomas，adenomas，andhyperplasias：a paraffin immunohistochemical study.Mod.Pathol.12，412-416；TroussardX，vet-Loiseau H，Macro M，Mellerin MP，Malet M，Roussel M，Sola B(2000).Cyclin D1expression in patients with multiple myeloma.Hematol.J.1，181-185)。细胞周期素D1在结直肠、胃、食管、肺、肾和乳腺癌，以及白血病和淋巴瘤中过量表达，在正常组织中很少表达。它通常也在套细胞淋巴瘤中过量表达，其特征为t(11；14)(q13；q32)迁移，使11q13染色体上的CCND1原癌基因与14q32染色体的Ig重链基因并列(Wang et al.，2009；Kondo et al.，2008)。
常见的A/G单核苷酸多态性(A870G)导致细胞周期素D1的a、b两种不同的mRNA异构体。交替拼接异构体b可编码一种截短蛋白，该截短蛋白与较高的肿瘤发病率有关(包括散发性肾细胞癌、肺癌、结肠癌和其它种类的癌)(Fu M，Wang C，LI Z，Sakamaki T，Pestell RG(2004).Minireview：Cyclin D1：normal and abnormalfunctions.Endocrinology 145，5439-5447；Yu J，Habuchi T，Tsuchiya N，Nakamura E，Kakinuma H，Horikawa Y，Inoue T，Ogawa O，Kato T(2004).Association of the cyclinD1 gene G870A polymorphism with susceptibility to sporadic renal cell carcinoma.J Urol.172，2410-2413)。CCND1增强表达预示着肿瘤分级高、有转移以及生存期下降(Maeda K，Chung Y，Kang S，Ogawa M，Onoda N，Nishiguchi Y，Ikehara T，Nakata B，Okuno M，Sowa M(1998).Cyclin D1 overexpression and prognosis in colorectaladenocarcinoma.Oncology 55，145-151；McKay JA，Douglas JJ，Ross VG，Curran S，Murray GI，Cassidy J，McLeod HL(2000).Cyclin D1 protein expression and genepolymorphism in colorectal cancer.Aberdeen Colorectal Initiative.Int.J Cancer 88，77-81；Bahnassy AA，Zekri AR，El-Houssini S，El-Shehaby AM，Mahmoud MR，Abdallah S，El-Serafi M(2004).Cyclin A and cyclin D1 as significant prognostic markers in colorectalcancer patients.BMC.Gastroenterol.4，22；Balcerczak E，Pasz-Walczak G，Kumor P，Panczyk M，Kordek R，Wierzbicki R，Mirowski M(2005).Cyclin D 1protein and CCND1gene expression in colorectal cancer.Eur.J Surg.Oncol.31，721-726)。
对于结直肠癌，也经常报道有CCND1在mRNA和蛋白质水平上过量表达。CCND1是结直肠癌中经常上调的β-Catenin-TCF/LEF途径的靶向基因这一既定事实可以解释上述现象(Shtutman M，Zhurinsky J，Simcha I，Albanese C，D′Amico M，Pestell R，Ben-Ze'ev A(1999).The cyclin D1 gene is a target of the beta-catenin/LEF-1pathway.Proc.Natl.Acad.Sci.U.S.A.96，5522-5527；Tetsu O，McCormick F(1999).Beta-catenin regulates expression of cyclin D 1in colon carcinoma cells.Nature 398，422-426)。
CCN-001细胞周期素肽(LLGATCMFV)是由Sadovnikova及其同事发现的(Sadovnikova E，Jopling LA，Soo KS，Stauss HJ(1998).Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules.Eur.J.Immunol.28，193-200)。研究表明，在诱导针对数个细胞周期素D1衍生的HLA-A*02结合肽的同种限制T细胞(即HLA-A2阴性供体)后，识别CCN-001的T细胞克隆体可以裂解内源性表达细胞周期素D1的HLA-A*02阳性肿瘤细胞，但是对细胞周期素D1阴性的HLA-A*02阳性细胞无作用。因此，只有间接证据表明CCN-001是天然加工和提呈的。
在过去一段时间内的研究认为，由于细胞周期素D1的胸腺表达，整个T细胞群中不存在识别细胞周期素D1衍生表位的T细胞。如果真是这样，产生针对细胞周期素D1的自体细胞毒性T淋巴细胞将是不可能的。
但是，Kondo等人(Kondo E，Maecker B，Weihrauch MR，Wickenhauser C，ZengW，Nadler LM，Schultze JL，von Bergwelt-Baildon MS(2008).Cyclin D 1-specificcytotoxic T lymphocytes are present in the repertoire of cancer patients：implications forcancer immunotherapy.Clin Cancer Res 14，6574-6579)发现对CCN-001表位(LLGATCMFV)有特异性细胞毒性T淋巴细胞也可由HLA-A2+供体生成。他们在健康供体及结肠癌患者和套细胞淋巴瘤患者中证实了这一点。他们使用自体CD40激活的B细胞作为抗原提呈细胞(APC)。
Wang等人(Wang M，Sun L，Qian J，Han X，Zhang L，Lin P，Cai Z，Yi Q(2009).Cyclin D1 as a universally expressed mantle cell lymphoma-associated tumor antigen forimmunotherapy.Leukemia 23，1320-1328)以来自套细胞淋巴瘤患者的T细胞和成熟的自体单核细胞衍生的树突状细胞作为抗原提呈细胞，生成了作用于CCN-001的细胞周期素D1特异性细胞毒性T淋巴细胞。他们没有使用原始肽，而是使用了一种不规则肽，其第一个氨基酸亮氨酸(L)被酪氨酸(Y)取代，因而增强了MHC结合作用。所产生的细胞毒性T淋巴细胞可以杀伤表达细胞周期素D1+的细胞，包括来自HLA-A2+套细胞淋巴瘤患者的原发性淋巴瘤细胞。其它研究也采用了这种肽(Kondo E，Gryschok L，Klein-Gonzalez N，Rademacher S，Weihrauch MR，Liebig T，Shimabukuro-Vornhagen A，Kochanek M，Draube A，von Bergwelt-Baildon MS(2009a).CD40-activated B cells can be generated in high number and purity in cancerpatients：analysis of immunogenicity and homing potential.Clin Exp.Immunol.155，249-256；Kondo E，Gryschok L，Schultze JL，von Bergwelt-Baildon MS(2009b).Using CD40-activated B cells to efficiently identify epitopes of tumor antigens.J Immunother.32，157-160)来证明CD40激活的B细胞作为抗原提呈细胞的有效性。Buchner等人(Buchner et al.Phase 1 Trial of Allogeneic Gene-Modified Tumor Cell Vaccine RCC-26/CD80/IL-2 in Patients with Metastatic Renal Cell Carcinoma.Human Gene Therapy.March 2010，21(3)：285-297)在一项临床研究中也提到了CCN-001肽。
WO 2005/035714描述了用于治疗或预防癌症的疫苗，包括肿瘤相关HLA限制性抗原，特别是HLA-A2限制性抗原。在具体的方面，该专利提供了细胞周期素D肽。此类肽可用于诱导出优先进攻肿瘤细胞的特异性细胞毒性T淋巴细胞。细胞周期素D肽可能包括LLGATCMFV序列或其片段。该专利进一步描述了一种治疗或预防患者癌症的方法，包括给予患者有效治疗量的由肽组成的疫苗。该方法可能进一步包括以第二种抗癌药物治疗患者，其中第二种抗癌药物选自一个很长的药剂列表，例如化疗药物，如环磷酰胺。第二种抗癌药物可与疫苗同时使用，或与疫苗在不同时间使用。不过，WO 2005/035714没有描述采用细胞周期素D1肽的组合治疗的任何优点。
鉴于以上情况，关于在癌症免疫疗法中有效使用细胞周期素D1衍生肽的有效用途知之甚少。因此，本发明的一个目标是提出基于细胞周期素D1衍生肽的、更有效的癌症免疫治疗的新方法。
本发明的第一方面，本发明的目标是通过以下多肽达到：由或基本由选自SEQ识别序列号1至SEQ识别序列号18的氨基酸序列组成、用于治疗患者癌症的肽，或包括至少一种由或基本由选自SEQ识别序列号1至SEQ识别序列号18的氨基酸序列组成的肽、用于治疗患者癌症的组合物。
根据本发明，癌症可选自肺癌、头颈部癌、乳腺癌、胰腺癌、前列腺癌、肾癌、食管癌、骨癌、睾丸癌、宫颈癌、胃肠癌、胶质母细胞瘤、白血病、淋巴瘤、套细胞淋巴瘤、肺部瘤前病变、结肠癌、黑色素瘤、膀胱癌和任何其他肿瘤性疾病组成的群组。优选为肾癌、结肠癌和胶质母细胞瘤。
在本发明的内容中，优选肽为由根据SEQ识别序列号1至SEQ识别序列号18的任一氨基酸序列组成的肽。“基本由...组成”系指本发明的肽，除了根据SEQ识别序列号1至SEQ识别序列号18的任一序列组成外，还含有位于其它在N和/或C端延伸处的氨基酸，而它们不一定能形成作为含结合基序肽的核心序列并作为免疫原T辅助表位的肽。但这些延伸区域对于有效将肽引进细胞具有重要作用。
下表列出了本发明中所用的细胞周期素D1衍生肽。
表1：本发明内容中所用的肽
在本发明包含的一项方案中，本发明中所用的肽为融合蛋白，含来自NCBI、GenBank登录号X00497的HLA-DR抗原相关恒定链(p33，以下称为“Ii”)的80个N-端氨基酸等(Strubin，M.，Mach，B.and Long，E.O.The complete sequence of themRNA for the HLA-DR-associated invariant chain reveals a polypeptide with an unusualtransmembrane polarity EMBO J.3(4)，869-872(1984))。
如果本发明中所用长度大于12个氨基酸残基左右的肽直接与MHC分子结合，在HLA结合核心区两侧的氨基酸残基应该是对该肽与MHC分子的结合槽特异性结合能力或该肽提呈至细胞毒性T细胞的能力不产生重大影响的为优选。然而，如上所述，应尽量使用较大的肽(特别是多聚核苷酸进行编码时)，因为这些较大的肽有可能被适当的抗原提呈细胞分成片段。
MHC配体、基序、变异肽的实例，以及N和/或C-端延伸区的某些实例可来自，例如SYFPEITHI数据库(Rammensee H，Bachmann J，Emmerich NP，Bachor OA，Stevanovic S.SYFPEITHI：database for MHC ligands and peptide motifs.Immunogenetics.1999 Nov；50(3-4)：213-9)自http://syfpeithi.bmi-heidelberg.com/以及本文引用的参考文献。本专利中所用的优选MHC-I类特异性肽总体长度为9至16个氨基酸，其中以9至12个氨基酸为优选。应该认识到，这些肽可能(例如在疫苗中)被用作较长的肽，类似于MHC-II类肽。具有HLA-I类分子的某种HLA特异性氨基酸基序的MHC-I类特异性“核心序列”的识别方法为熟练技术人员所知，而且这些序列可以通过计算机程序如PAProC(http://www.uni-tuebingen.de/uni/kxi/)和SYFPEITHI(http://www.syfpeithi.de)预测。
发明者所指的“肽”不仅包括通过肽键(-CO-NH-)连接氨基酸残基的分子，也包括反向肽键的分子。这种逆反异构模拟肽(retro-inverso peptidomimetics)可通过本领域已知的方法制备，例如：Meziere等人(1997)在《免疫学杂志》(J.Immunol.159，3230-3237)中所述的方法，以引用的方式并入本文。这种方法涉及制备包含主链(而并非侧链)改变的假肽。Meziere等人(1997年)的研究显示，这些假肽至少有利于MHC-II类和辅助性T细胞的反应。以NH-CO键替代CO-NH肽键的逆反异构肽大大地提高了抗水解性能。
在一个特定的优选实施方案中，本发明中所用的肽包括上述氨基酸序列，和至少另外一个T细胞表位，其中另外的T细胞表位能够促进产生针对异常表达肿瘤相关抗原的肿瘤类型的T细胞反应。因此，本发明中的肽包括也可用作疫苗的所谓“串珠式”多肽。
从以下内容应了解，在一些应用中本发明中所用的肽可直接使用(即它们不是通过多聚核苷酸在患者的细胞中或注入患者的细胞中表达进行生产)；在此类应用中少于100或50个残基的多肽为优选。本发明中优选肽的总体长度为9至30个氨基酸残基。
在本发明的内容中，一个“组合”系指2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个不同的肽或甚至更多本发明中所用的肽。合适的疫苗将最好包含4、5、6或7个不同的肽，最优选为6个不同的肽。组合物可能会依赖于待治疗患者的具体癌症类型、以及疾病状态、早期治疗方案、患者免疫状态，以及(当然)还有患者的HLA基因型。优选的组合物选自至少一种选自SEQ识别序列号1至SEQ识别序列号18的肽以及非细胞周期素衍生的第二种肿瘤相关肽，如SEQ识别序列号19至SEQ识别序列号26的肽。组合物应包括单独或结合容器或剂型中、可同时给予或单独用药的肽，只要肽在本文中所述的治疗中体现出协同作用，特别是治疗作用。
本发明中所用的肽或组合物在免疫疗法中特别有用，用以有效靶向和杀死表达或异常表达细胞周期素D1的癌细胞。
本发明的另一个重要方面涉及根据本发明而使用的肽或组合物，其中所述肽或组合物以抗癌疫苗的形式给予。优选为包括如上所述的一种或多种(合成)肽或其组合物的疫苗。组合物疫苗可能会依赖于待治疗患者具体的癌症类型、以及疾病状态、早期治疗方案、患者免疫状态，当然，还有患者的HLA基因型。
优选为根据本发明而使用的组合物，其进一步包括给予至少一种非细胞周期素D1衍生的附加肿瘤相关肽，例如，根据下表2选自SEQ识别序列号19至SEQ识别序列号26的任何一种肽。
表2：本发明的组合物所用的肽
| 肽名称 | 肽序列 | 结合对象 | 序列ID号 |
| Met-001 | YVDPVITSI | HLA-A*02 | 19 |
| Muc-001 | STAPPVHNV | HLA-A*02 | 20 |
| Muc-002 | LLLLTVLTV | HLA-A*02 | 21 |
| CEA-004 | YLSGANLNL | HLA-A*02 | 22 |
| CEA-005 | YLSGADLNL | HLA-A*02 | 23 |
| CEA-006 | SPQYSWRINGIPQQHT | HLA-DR | 24 |
| TGFBI-001 | ALFVRLLALA | HLA-A*02 | 25 |
| BIR-002 | TLGEFLKLDRERAKN | HLA-DR | 26 |
优选为根据本发明而使用的一种组合物，其中所述至少一种附加肿瘤相关肽是根据其与所述组合物中存在的其它肽相比结合不同HLA分子的能力进行选择。
鉴于以上情况，本发明中所用的优选组合物选自以下组合物中的一种：
包括SEQ识别序列号1和SEQ识别序列号19；或SEQ识别序列号1和SEQ识别序列号20；或SEQ识别序列号1、SEQ识别序列号19和SEQ识别序列号20的组合物；
包括SEQ识别序列号1和一个肽选自SEQ识别序列号22、SEQ识别序列号23和SEQ识别序列号24的肽组合物；
包括SEQ识别序列号1和一个肽选自SEQ识别序列号22、SEQ识别序列号23、SEQ识别序列号24和SEQ识别序列号25的肽组合物；
包括SEQ识别序列号1和一个肽选自SEQ识别序列号22、SEQ识别序列号23、SEQ识别序列号24和SEQ识别序列号19的肽组合物；
包括SEQ ID No.1和至少一个肽选自SEQ识别序列号2至SEQ识别序列号14的肽组合物；以及
包括SEQ识别序列号1和SEQ识别序列号26的组合物。
本专利还提出一种包括SEQ识别序列号6和至少一个肽选自SEQ识别序列号1至5和7至14的肽组合物；以及一个包括SEQ识别序列号5和至少一个肽选自SEQ识别序列号1至4和SEQ识别序列号6至14的肽组合物。
本专利还提供一种由上述肽组成的组合物。
根据本发明而使用的肽或组合物优选地构成一种肿瘤疫苗或癌症疫苗。该疫苗可直接给予患者，注入受影响的器官或全身给药，或间接体内应用到来自患者的细胞或人类细胞株的细胞，然后再将这些细胞注入患者体内，或体外用于来自患者的免疫细胞的一个细胞亚群，然后再将细胞重新给予患者。该肽可能为纯肽，也可能是与免疫刺激佐剂的组合物，例如Detox，或与免疫刺激细胞因子联合使用，或以适当的给药系统给药，例如脂质体。该肽也可与一种合适的载体偶联(如钥孔帽贝血蓝蛋白(KLH)或甘露聚糖)(参阅WO 95/18145及Longenecker等人(1993)Ann.NY Acad.Sci.690-291)。该肽也可进行标记，或作为融合蛋白，或作为杂合分子。
本发明中给出肽序列中的一些肽预期会刺激CD8细胞毒性T淋巴细胞。但是，在有CD 4阳性T细胞提供帮助时，刺激更为有效。因此，融合伙伴或杂合分子片段适合提供刺激CD4阳性T细胞的表位。CD4阳性T细胞刺激表位为本领域所熟知、并包括破伤风类毒素中确定的表位。
用于癌症疫苗的肽可为任何合适的肽。特别是，它可能是一种合适的9肽或一种合适的7肽或8肽或10肽或11肽或12肽。更长的肽也可能合适，但是本文中表1所述的9肽或10肽为优选的HLA-I类肽。
该肽可肌肉注射、皮内注射、腹腔注射、静脉注射或皮下注射。首选是将疫苗注入肌肉。另一优选方法是将疫苗注入皮肤，即皮内注射。另一方面，本发明提供了一个肽在本发明中使用于静脉(i.v)注射、皮下(s.c.)注射、皮内(i.d.)注射、腹腔(i.p.)注射、肌肉(i.m.)注射。肽的优选注射方式为皮下、皮内、腹腔和静脉。用药剂量为100μg至100mg的肽或DNA，优选范围为200μg至800μg，更优选范围为200μg至600μg，更加优选的范围为400μg至500μg，最佳优选为大约413μg。
肽疫苗可不配合佐剂给药。优选地，肽作为活性药物成分与佐剂联合使用，例如IL-2、IL-12、GM-CSF或弗氏完全佐剂。最优选佐剂可在文献中找到，比如，Brinkman JA，Fausch SC，Weber JS，Kast WM.Peptide-based vaccines for cancerimmunotherapy.Expert Opin Biol Ther.2004 Feb；4(2)：181-98。肽疫苗也可与BCG或铝盐佐剂一起给予。其它适合的佐剂包括源自皂角苷的Aquila公司的QS21刺激子(Aquila Biotech，Worcester，MA，USA)、分支杆菌提取物、人工合成的细菌细胞壁模拟物以及专有佐剂，如Ribi公司的Detox。还可使用另一种源自皂角苷的佐剂QuilA(Superfos，Denmark)。还可使用其它佐剂，例如CpG寡核苷酸、稳定化RNA、咪喹莫特(市售商品名
美国3M Pharma公司)、弗氏不完全佐剂(市售商品名Montanide ISA-51，法国巴黎的Seppic S.A.公司)或脂质体制剂。给予与钥孔帽贝血蓝蛋白偶联的肽也可能有益，优选为与佐剂一起给予。
疫苗可多次给予。有效治疗量可以是0.20mg至5.0mg范围内，或0.025mg至1.0mg范围内，或2.0mg至5.0mg范围内的肽或组合物。优选地，所述肽或组合物为重复给予，例如，每月一次、每周一次、或每两周一次。
疫苗接种导致专职抗原提呈细胞激发的细胞毒性T淋巴细胞(CTL)反应；一旦激活细胞毒性T淋巴细胞，在改善肿瘤细胞中MHC的表达方面可能有优势。这也可能有益于疫苗靶向作用于特别的细胞群(例如抗原提呈细胞)，可通过局部注射(使用靶向性载体和输送系统)或对患者该类细胞群的选择性纯化并间接体内(exvivo)给予肽(例如树突状细胞可按照Zhou等人(1995)Blood 86，3295-3301；Roth等人(1996)Scand.J.Immunology 43，646-651所述的方法进行分类)。
在本发明的另一重要方面，本发明中所用肽或组合物(例如疫苗)给予宿主为单独或与另一种癌症疗法联合(优选)使用，以抑制或阻止肿瘤的形成。
本发明中所用肽和组合物可用于癌症，其可包括肺癌、头颈部癌、乳腺癌、胰腺癌、前列腺癌、肾癌、食管癌、骨癌、睾丸癌、宫颈癌、胃肠癌、胶质母细胞瘤、白血病、淋巴瘤、套细胞淋巴瘤、肺部瘤前病变、结肠癌、黑色素瘤、膀胱癌和任何其他肿瘤疾病。优选为肾癌、结肠癌或胶质母细胞瘤。
为了增加本发明中所用肽和组合物的治疗效果，理想的是将这些组合物与有效治疗那些疾病和状况的其它药物联合使用。例如，可采用本发明中所用肽和组合物和其它抗癌疗法(如抗癌药物)实施癌症治疗。
因此，本发明用途因此进一步包括以第二种抗癌药物治疗患者，其中第二种抗癌药物为一治疗性多肽、一编码治疗性多肽的核苷酸、一化疗药物、一免疫疗法药物，或一放疗药物。第二种抗癌药物可与疫苗同时使用，或与疫苗在不同时间使用，优选情况是在疫苗接种前使用一个剂量的药。
特别优选的用途是根据本发明的肽或组合物的使用，其进一步包括以至少一种化疗药物进行治疗，如钝化和/或消除所述患者CD4+CD25+T细胞的药物，优选为钝化和/或消除CD4+CD25hi FOXP3+CD127lo T细胞的药物，如(举例)环磷酰胺。
更优选的用途是根据本发明的肽或组合物的使用，其中以所述至少一种化疗药物进行的所述治疗在给予所述肽或组合物之前进行，优选为单次剂量给药。
特别优选的用途是根据本发明的肽或组合物的使用，其中以所述至少一种化疗药物进行的所述治疗在给予所述肽或组合物之前进行，优选为单次剂量给药，如(举例)单次剂量300mg/m2的环磷酰胺，优选为单次输注。
另一优选用途是根据本发明的肽或组合物的使用，其中所述治疗为辅助治疗，在此之前的TKI疗法，如(举例)舒尼替单抗或索拉非尼，和/或在此之前的细胞因子疗法，如(举例)干扰素或白细胞介素，之后进行。
最优选的用途是根据本发明的肽或组合物的使用，其中所述治疗包括细胞因子疗法，然后是单剂环磷酰胺疗法，之后在第1、2、3、7天给予疫苗进行第一周的激活，然后每两星期进行一次，至少持续6个月。
“抗癌”药物能够对受试者的癌症造成负面影响，例如通过杀死癌细胞，诱导癌细胞的凋亡，减缓癌细胞的生长速度，减少转移瘤的发生率或数目，减小肿瘤尺寸，抑制肿瘤生长，减少流向肿瘤或癌细胞的血液供应，促进针对癌细胞或肿瘤的免疫反应，防止或抑制癌症的进展，或延长罹患癌症的受试者的寿命。优选抗癌药物包括化疗药物。在本发明的内容中，考虑到了基于所用肽或组合物的肿瘤相关HLA限制性肽疗法，同样可与化疗干预一起使用。
免疫疗法药物可为GM-CSF、CD40配体、抗CD28单克隆抗体、抗CTL-4单克隆抗体、抗4-1BB(CD137)单克隆抗体和寡核苷酸。化疗药物可为多柔比星、柔红霉素、更生霉素、米托葱醌、顺铂、甲基苄肼、丝裂霉素、卡铂、博来霉素、依托泊甙、替尼泊苷、氮芥、环磷酰胺、异环磷酰胺、美法仑、苯丁酸氮芥、六甲密胺、硫喷妥、白消安、卡莫司汀、洛莫司汀、司莫司汀、链脲霉素、氮烯唑胺、阿霉素、5-氟尿嘧啶(5FU)、喜树碱、放线菌素D、过氧化氢、亚硝基脲、普卡霉素、他莫昔芬、紫杉醇、反铂、长春新碱、长春碱、TRAIL R1和R2受体抗体或激动剂、海兔毒素10、苔藓抑素、脂质体蒽环霉素、
苯乙酸钠、丁酸钠、甲氨蝶呤、地西他滨、甲磺酸伊马替尼
干扰素-α、贝伐单抗、西妥昔单抗、沙利度胺、硼替佐米、吉非替尼、埃罗替尼、氮杂胞苷、5-氮杂-2-脱氧胞苷、雷利米得、2C4、抗血管增生因子、信号转导靶向药物、干扰素-y、白细胞介素-2和白细胞介素-12。
可能使用不同的组合物；例如，肽或组合物或各自的疫苗为“A”和次级疗法为“B”：A/B/A、B/A/B、B/B/A、A/A/B、A/B/B、B/A/A、A/B/B/B、B/A/B/B、B/B/B/A、B/B/A/B、A/A/B/B、A/B/A/B、A/B/B/A、B/B/A/A、B/A/B/A、B/A/A/B、A/A/A/B、B/A/A/A、A/B/A/A、A/A/B/A。将遵照特定次级疗法的一般操作规程对患者给予本发明中所用的肽或组合物，考虑肿瘤相关HLA限制性肽治疗的毒性(如有)。预计必要时将重复治疗周期。也考虑了可能针对所述癌细胞应用各种标准疗法以及外科干预联合治疗。不过，优选为以下进一步详述的单剂治疗。
优选地，进一步采用人单克隆抗体进行被动免疫疗法，因为它们在患者中很少或不产生副作用。
肽(至少含氨基酸残基之间的肽联接)可使用Lu等人(1981)J.Org.Chem.46，3433以及其中参考文献所披露的固相肽合成Fmoc-聚酰胺模式进行合成。9-芴甲氧羰基(Fmoc)团对N-氨基提供临时保护。使用N，N-二甲基甲酰胺中的20％哌啶对这种高度碱敏感的保护基团进行重复分裂。由于它们的丁基醚(在丝氨酸、苏氨酸和酪氨酸的情况下)、丁基酯(在谷氨酸和天门冬氨酸的情况下)、丁氧羰基衍生物(在赖氨酸和组氨酸的情况下)、三苯甲基衍生物(在半胱氨酸的情况下)及4-甲氧基-2,3,6-三甲基苯磺酰基衍生物(在精氨酸的情况下)，侧链功能可能会受到保护。当谷氨酰胺或天冬酰胺为C-末端残基时，侧链氨基功能保护使用的是由4，4′-二甲氧基二苯甲基团。固相支撑基于聚二甲基丙烯酰胺聚合物，其由三个单体二甲基丙烯酰胺(主链单体)、双丙烯酰乙烯二胺(交联剂)和N-丙烯酰肌胺酸甲酯(功能剂)构成。使用的肽-树脂可裂解联剂为酸敏感的4-羟甲基苯氧乙酸衍生物。所有的氨基酸衍生物均作为其预制对称酸酐衍生物加入，但是天冬酰胺和谷氨酰胺除外，它们使用被逆转的N，N-二环己基碳二亚胺/羟基苯并三唑介导的耦合程序而加入。所有的耦合和脱保护反应用茚三酮、硝基苯磺酸或靛红测试程序监测。合成完成后，用浓度为95％三氟醋酸含50％清道夫混合物将肽从树脂支承物上裂解，伴随去除侧链保护基团。常用的清道夫混合物为乙二硫醇、苯酚、苯甲醚和水，具体的选择依据合成肽的氨基酸组成。此外，固相和液相方法结合使用对肽进行合成是可能的(例如，请参阅Bruckdorfer T，Marder O，Albericio F.From production ofpeptides in milligram amounts for research to multi-ton quantities for drugs of the future.Curr Pharm Biotechnol.2004 Feb；5(1)：29-43以及其中引用的参考文献)。
三氟乙酸用真空蒸发去除、随后用二乙醚滴定承载粗肽。用简单萃取程序(液相冻干)清除任何存留的清道夫混合物，制得不含清道夫混合物的肽。肽合成试剂一般可从Calbiochem-Novabiochem(英国)公司(英国诺丁汉NG7 2QJ)获得。
纯化可通过以下技术的任何一种或组合方法实现，如：体积排阻色谱法、离子交换色谱法、疏水作用色谱法以及(通常)反相高效液相色谱法(使用乙腈/水梯度分离)。
肽分析可使用以下方法进行：薄层色谱法、反相高效液相色谱法、酸水解后的氨基酸分析、快原子轰击(FAB)质谱分析法，以及基体辅助激光解吸电离(MALDI)和电喷雾电离(ESI)质谱分析法。
应了解，某些宿主细胞对于制备用于本发明中所用的肽很有用，例如细菌细胞、酵母细胞和昆虫细胞。然而，其它宿主细胞可能对某些治疗方法有用。例如，抗原提呈细胞(如树突状细胞)可用于表达本发明中所用的肽，使它们可以加载入相应的MHC分子中。
另一方面，本发明提出了使用根据本发明的肽或组合物体外生产激活的细胞毒性T淋巴细胞(CTL)的用途，包括将CTL与载有肽或组合物的人I或II类MHC分子进行体外连接，这些分子在合适的抗原提呈细胞表面表达一段时间足够以抗原特异性方式激活所述CTL。
进一方面，本发明提供了一种杀伤患者体内靶细胞的方法，其中患者的靶细胞异常表达含本发明中的氨基酸序列的多肽，该方法包括给予患者有效量的根据本发明的肽，或有效量的编码所述肽的多聚核苷酸或表达载体，其中所述肽的量或所述多聚核苷酸或表达载体的量可有效激发所述患者的抗靶细胞免疫反应。靶细胞通常为肿瘤或癌细胞。
应理解，关于杀伤患者靶细胞的方法，靶细胞特别优选为上述的癌细胞，更优选为肾或结肠癌细胞。
进一方面，本发明特别包括使用本发明的肽进行活性体内疫苗接种；进行自体树突状细胞的体外操纵，然后将受操纵的树突状细胞导入体内以激活CTL反应；体外激活自体CTL，然后进行过继疗法(即将受操纵的CTL导入患者)；以及体外激活来自健康供体的CTL(MHC匹配或不匹配)，随后进行过继疗法。
进一方面，本发明涉及将根据本发明的肽或组合物用作一种诊断工具，用以检测和/或监控患者免疫系统的激活或调节。在这方面，肽可用于检测针对抗癌治疗的反应，尤其是针对非肽治疗的反应，或导致免疫系统激活或调节的任何其它合适治疗的反应。为了诊断，可对肽进行标记。此外，还可以使用针对肽(或组合物)的抗体。诊断可在体内或体外进行。
进一方面，本发明涉及将根据本发明的肽或组合物用作一种癌症诊断工具。基本上，患者体内存在肽或其组合物表示有癌症。例如，在某些患者中发现了针对CCN-001和CEA-004的疫苗接种前反应。再次，为了诊断，同样可对肽进行标记。此外，也可以使用针对肽(或组合物)的抗体。诊断可在体内或体外进行。
短语“分离的”系指物质基本上或本质上没有天然状态下发现的一般伴随该物质的组分。因此，依照本发明分离的肽优选地不含在自然环境中一般与该肽相关的物质。
进一方面，本发明涉及一种肽包含选自SEQ识别序列号5或SEQ识别序列号6的组群的一个序列，或该序列的与SEQ识别序列号5或SEQ识别序列号6具有85％以上的同源性的一种变体，或该序列的诱导与所述变异肽发生T细胞交叉反应的一种变体；其中所述肽不是各自的(基础)全长多肽。优选地，所述肽选自具有特异性HLA亚型的肽，如HLA-A*02。
进一方面，本发明涉及一种核酸，其编码根据SEQ识别序列号5或SEQ识别序列号6的肽或根据本专利的该肽的变异，或能够表达所述核酸的表达载体。在本发明的另一方面，本发明涉及一种宿主细胞，包括根据本发明的核酸或表达载体，其中所述宿主细胞优选为抗原提呈细胞，特别是树突状细胞或抗原提呈细胞。
在本发明的另一方面，本发明涉及一种体外产生激活的细胞毒性T淋巴细胞(CTL)的方法，包括将CTL与载有抗原的人I或II类MHC分子进行体外接触，该等分子在合适的抗原提呈细胞表面或人工构造的模拟抗原提呈细胞表面上表达一段时间足够可以按抗原特异性方式激活CTL，其中所述抗原为根据本发明的SEQ识别序列号5或SEQ识别序列号6的肽。
在本发明的又一方面，本发明涉及一种试剂盒套件，包括：(a)一个容器，其含有一种根据本发明的SEQ识别序列号5或SEQ识别序列号6的一种肽、根据本发明的核酸或表达载体、根据本发明的一种细胞或根据本发明的一种激活的细胞毒性T淋巴细胞的溶液或冻干形式的药物组合物；(b)可选的第二个容器，其含有冻干粉剂型的稀释剂或重组溶液；(c)可选的至少一种选自根据SEQ识别序列号1至4和7至26的肽构成的组群的肽，以及(d)可选的使用溶液和/或重组和/或使用冻干粉剂型的说明书。
在本发明的又一方面，本发明涉及一种抗体，其根据本发明特异性结合至与根据SEQ识别序列号5或SEQ识别序列号6的HLA限制性抗原络合的I或II类人主要组织相容性复合体(MHC)，其中抗体优选为多克隆抗体、单克隆抗体和/或嵌合抗体。
本发明的进一方面涉及一种基于上述肽或组合物用于治疗癌性疾病的方法。
通过以下实施例的描述，本发明的其它目标、特点和优点将是显而易见的。然而，应当了解，具体实施例尽管体现了本发明的优选实施方案，但是仅以阐述的方式给出，因为通过以下详细说明，本发明的精神和范围内的各种变化和修改对于本领域技术人员来说是显而易见的。为了本发明之目的，所有参考文献均以完整引用的形式并入本文。
附图
图1显示根据SEQ识别序列号27的细胞周期素D1的氨基酸序列，本发明中所用肿瘤相关肽的位置以粗体字表示。
图2显示与正常组织中的平均表达量(图2A)相比，CCND1在肾癌细胞中(ccRCC)的平均过量表达量为3.0倍(表达数据来自数据集1)，在单独分析的原发肿瘤中为5.7倍，在转移瘤中为5.4倍(图2B，表达数据来自独立的数据集2)。与正常肾脏相比，60％的原发肿瘤显示出过量表达(图2A，带“I”的黑条上方“增加”部分)。
图3显示接受先期细胞因子疗法的患者(虚线)接种IMA901疫苗后有较好的无进展生存期(A)和总生存期(OS)，对比接受先期TKI疗法的患者(实线)。
图4显示了含CCN-001的IMA901疫苗(例如，如通过引用并入本文的EP1760089所述)对比细胞因子治疗后二线治疗药(A)以及
(B)的总体生存期(OS)。
图5显示以环磷酰胺(+CY)预先治疗的患者组中调节性T细胞的减少。(A)图显示绝对数目，(B)图显示自基线变化的百分比。
图6显示对CCN-001有反应的患者生存期显著长于对CCN-001没有反应的患者(A)。这种针对CCN-001的T细胞反应的有益作用在以环磷酰胺预先治疗的患者组中甚至更明显(B)。
图7显示疫苗诱发的针对CCN-001的反应。在给予GM-CSF(同期组1)或GM-CSF+Imiquimod(同期组2)的情况下，患者在不同时间点接种IMA910肽混合剂(例如，如通过引用并入本文的WO2009/015841所述)。以多聚体进行的免疫检测分析研究了针对HLA-A*0201结合肽的免疫反应。随后，将患者的PBMCs体外致敏并以流式细胞仪和多聚体染色进行分析。A)所有(黑色)患者或以咪喹莫特治疗患者(深灰色)及未以咪喹莫特治疗患者(浅灰色)的CCN-001免疫应答率。条带显示患者出现疫苗诱发的CCN-01肽反应的频率。B)一名代表性患者在疫苗接种前(左)后(右)针对CCN-001的免疫反应。
SEQ识别序列号1至26显示本发明内容中所用的肽。SEQ识别序列号5和SEQ识别序列号6显示根据本发明的细胞周期素肽。
SEQ识别序列号27显示细胞周期素D1的氨基酸序列。
实施例
根据本发明使用的肽的鉴定和表征
通常，根据本发明使用的肽采用技术(参见例如Weinschenk etal.Integrated Functional Genomics Approach for the Design of Patient-individualAntitumor Vaccines，CANCER RESEARCH 62，5818-5827，October 15，2002)基于肾癌细胞进行鉴定。与正常组织中的平均表达量相比，细胞周期素D1(CCND1)在ccRCC中的平均过量表达量为3.0倍，在原发肿瘤中为5.7倍，在转移瘤中为5.4倍。与正常肾脏相比，55％的原发肿瘤显示过量表达。
所鉴定的肽的HLA限制性
对于CCN-001和CCN-002，采用SYFPEITHI常规程序预算出与HLA A*02的稳定结合(Rammensee et al.，1997；Rammensee et al.，1999)。CCN-001与HLA A*0201的稳定结合得到基于ELISA方法的确认(Sylvester-Hvid et al.，2002)。对于CCN-004，观察到其与HLA-A*26的高结合率和与HLA-A*02实际上不结合。
对于CCN-006肽，预算仅能与HLA-A*02弱结合。确实，CCN-006似乎是HLA-A*68的结合子。新的CCN-007肽是中等强度的HLA A*02结合子。CCN-003与HLA-II类结合，因此似乎是DRB1*0401限制性的。
以下临床研究选择了CCN-001肽。然而，技术人员将会意识到也可使用本文所述的所有其它肽或其组合物，且必要时可根据本文所述的这些肽或其组合物轻易地对实施例进行调整。
采用本发明肽和组合物的临床研究
一些患者接受了舒尼替单抗或索拉非尼的先期TKI疗法，其他患者接受了干扰素或白细胞介素的先期细胞因子疗法。然后，将患者分为两组，一组接受环磷酰胺(300mg/m2)单次输注，再接种含一种细胞周期素D1肽的疫苗，(在这种情况下，Immatics Biotechnologies公司的含CCN-001的IMA901疫苗，9个月内接种17次)，另一组不接受环磷酰胺，就接种含一种细胞周期素D1肽的疫苗(仍为IMA901，9个月内接种17次)。
随访调查两组患者的无进展生存期(PFS)和总体生存期(OS)。
研究结果
研究发现疫苗总体上是安全的，患者对其耐受良好。唯一的常见副作用是注射位点的局部反应。
第6个月的疾病控制率(DCR)达到预期(即研究方案规定第6个月细胞因子治疗后患者的临床相关效果为DCR大于30％)。
含细胞周期素肽的疫苗显示了比细胞因子治疗后其它二线治疗(或
)更好的总体生存期。
与接受先期TKI疗法患者相比，接受先期细胞因子疗法的患者PFS和OS更好。无进展生存期(PFS)分析显示，与其它临床试验的安慰剂组相比其积极作用延迟。与TKI数据(即二线mRCC治疗中的索拉非尼和舒尼替单抗)相比，总体生存期(OS)似乎更长。
在患者总体中，多重肽免疫反应和OS之间有显著的相关性。
更令人惊讶的是，一个低剂量的先期环磷酰胺治疗进一步显著改善疫苗治疗的结果。和预期的一样，低剂量的环磷酰胺减少了调节性T细胞的数目。
对CCN-001有反应与对CCN-001没有反应的患者的比较表明，可能由疫苗接种所诱发的CCN-001反应的患者生存期明显更长。这种针对CCN-001的T细胞反应的有益作用在以环磷酰胺预先治疗的患者组中甚至更明显。
Claims (15)
1.一种由或基本由选自SEQ识别序列号1至SEQ识别序列号18的氨基酸序列组成、用于治疗患者癌症的肽，或一种包括至少一种由或基本由选自SEQ识别序列号1至SEQ识别序列号18的氨基酸序列组成的肽、用于治疗患者癌症的组合物。
2.根据权利要求1的肽或组合物，其中所述肽选自SEQ识别序列号1、SEQ识别序列号4和/或SEQ识别序列号18。
3.根据权利要求1或2的肽或组合物，其中所述癌症选自肺癌、头颈部癌、乳腺癌、胰腺癌、前列腺癌、肾癌、食管癌、骨癌、睾丸癌、宫颈癌、胃肠癌、胶质母细胞瘤、白血病、淋巴瘤、套细胞淋巴瘤、肺部瘤前病变、结肠癌、黑色素瘤、膀胱癌和任何其他肿瘤病组成的组群。
4.根据权利要求1至3中任意一项的肽或组合物，其中所述肽或组合物以抗癌疫苗的形式给予，可选择地进一步包括至少一种佐剂，如(举例)GM-CSF。
5.根据权利要求1至4中任意一项的肽或组合物，进一步包括给予至少一种非细胞周期素D1衍生的附加肿瘤相关肽，如(举例)选自SEQ识别序列号19至SEQ识别序列号26中的任意一种肽。
6.根据权利要求5的组合物，其中所述至少一种附加肿瘤相关肽是根据其与所述组合物中存在的其它肽相比结合不同HLA分子的能力进行选择。
7.根据权利要求1至6中任意一项的肽或组合物，其中所述肽或组合物为重复给予，如(举例)每月一次，每周一次或每周两次。
8.根据权利要求1至7中任意一项的肽或组合物，进一步包括以至少一种化疗药物进行治疗，如(举例)钝化和/或消除所述患者中免疫调节细胞(如CD4+CD25+调节性T细胞)数目的药物，如(举例)环磷酰胺。
9.根据权利要求8的肽或组合物，其中以所述至少一种化疗药物进行的所述治疗在给予所述肽或组合物之前进行，优选为单次剂量给予，如(举例)剂量300mg/m2的环磷酰胺，优选为单次输注。
10.根据权利要求1至9中任意一项的肽或组合物，其中所述治疗为辅助治疗，在先期TKI疗法(如[举例]舒尼替单抗或索拉非尼)和/或先期细胞因子疗法(如[举例]干扰素或白细胞介素)后进行。
11.根据权利要求1至10中任意一项的肽或组合物，其中所述治疗包括细胞因子疗法，然后是单剂环磷酰胺疗法，随后每天给予疫苗进行激活，持续一周，然后每两周给予疫苗，持续6个月。
12.使用根据权利要求1至6中任意一项的肽或组合物体外产生激活的细胞毒性T淋巴细胞(CTL)的用途，包括将CTL与载有肽或组合物的人I或II类MHC分子进行体外连接，这些分子在合适的抗原提呈细胞表面表达一段时间足够以抗原特异性方式激活所述CTL。
13.将根据权利要求1至6中任意一项的肽或组合物用作一种诊断工具的用途，旨在检测和/或监控患者免疫系统的激活或调节。
14.将根据权利要求1至6中任意一项的肽或组合物用作一种癌症诊断工具的用途。
15.一种由或基本由选自SEQ识别序列号5或SEQ识别序列号6的氨基酸序列组成的肿瘤相关肽。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35073110P | 2010-06-02 | 2010-06-02 | |
| US61/350,731 | 2010-06-02 | ||
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| CN104017051A (zh) * | 2014-06-23 | 2014-09-03 | 苏州普罗达生物科技有限公司 | 一种CyclinD蛋白抑制剂多肽及其应用 |
| CN107912043A (zh) * | 2015-07-06 | 2018-04-13 | 伊玛提克斯生物技术有限公司 | 用于食管癌和其他癌症免疫治疗的新型肽和肽组合物 |
| CN112553336A (zh) * | 2020-12-17 | 2021-03-26 | 兰州大学 | Snp在乳腺癌化疗耐药性检测领域的应用及其检测试剂盒 |
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| GB201009222D0 (en) * | 2010-06-02 | 2010-07-21 | Immatics Biotechnologies Gmbh | Improved cancer therapy based on tumour associated antigens derived from cyclin D1 |
| CN103848891B (zh) * | 2012-11-30 | 2015-09-09 | 北京市结核病胸部肿瘤研究所 | Ccnd1自身抗体识别的抗原多肽 |
| CN103961702B (zh) * | 2013-02-05 | 2019-04-09 | 日东电工株式会社 | 粘膜给予用wt1肽癌症疫苗组合物 |
| CA2841016A1 (en) * | 2013-02-05 | 2014-08-05 | Nitto Denko Corporation | Wt1 peptide cancer vaccine composition for transdermal administration |
| ES2900004T3 (es) | 2013-08-05 | 2022-03-15 | Immatics Biotechnologies Gmbh | Nueva inmunoterapia contra diversos tumores como el cáncer de pulmón, incluido el carcinoma de pulmón amicrocítico (NSCLC) |
| TWI777198B (zh) * | 2013-08-05 | 2022-09-11 | 德商伊瑪提克斯生物科技有限公司 | 新穎肽類，細胞及其用於治療多種腫瘤的用途，其製造方法及包含其等之醫藥組成物（七） |
| GB201510771D0 (en) | 2015-06-19 | 2015-08-05 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer |
| PE20180253A1 (es) | 2015-06-19 | 2018-02-02 | Immatics Biotechnologies Gmbh | Nuevos peptidos y nuevas combinaciones de peptidos para el uso en la inmunoterapia y metodos para crear soportes para el uso contra el cancer de pancreas y otros tipos de cancer |
| GB201511191D0 (en) | 2015-06-25 | 2015-08-12 | Immatics Biotechnologies Gmbh | T-cell epitopes for the immunotherapy of myeloma |
| ZA201707555B (en) | 2015-06-25 | 2018-11-28 | Immatics Biotechnologies Gmbh | Novel cell epitopes and combination of cell epitopes for use in the immuno-therapy of myeloma and other cancers |
| CN108026154B (zh) | 2015-07-01 | 2022-03-08 | 伊玛提克斯生物技术有限公司 | 用于卵巢癌和其他癌症免疫治疗的新型肽和肽组合物 |
| GB201511546D0 (en) | 2015-07-01 | 2015-08-12 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers |
| GB201511792D0 (en) | 2015-07-06 | 2015-08-19 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against esopageal cancer and other cancers |
| MY198087A (en) | 2015-10-05 | 2023-07-31 | Immatics Biotechnologies Gmbh | Peptides and combination of peptides for use in immunotherapy against small cell lung cancer and other cancers |
| GB201517538D0 (en) | 2015-10-05 | 2015-11-18 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against small cell lung cancer and other cancers |
| MA55153A (fr) | 2016-02-19 | 2021-09-29 | Immatics Biotechnologies Gmbh | Nouveaux peptides et combinaison de peptides pour une utilisation dans l'immunothérapie contre le lymphome non hodgkinien et d'autres cancers |
| GB201602918D0 (en) | 2016-02-19 | 2016-04-06 | Immatics Biotechnologies Gmbh | Novel peptides and combination of peptides for use in immunotherapy against NHL and other cancers |
| GB201603568D0 (en) | 2016-03-01 | 2016-04-13 | Immatics Biotechnologies Gmbh | Efficient treatment options including peptides and combination of peptide and cell based medicaments for use in immunotherapy against urinary bladder cancer |
| MA54832A (fr) | 2016-03-01 | 2021-12-01 | Immatics Biotechnologies Gmbh | Peptides, combinaison de peptides et médicaments à base de cellules destinés à être utilisés en immunothérapie contre le cancer de la vessie et d'autres cancers |
| GB201603987D0 (en) | 2016-03-08 | 2016-04-20 | Immatics Biotechnologies Gmbh | Uterine cancer treatments |
| KR102639592B1 (ko) | 2016-12-08 | 2024-02-21 | 이매틱스 바이오테크놀로지스 게엠베하 | 짝짓기가 향상된 t 세포 수용체 |
| DE102016123893A1 (de) | 2016-12-08 | 2018-06-14 | Immatics Biotechnologies Gmbh | T-Zellrezeptoren mit verbesserter Bindung |
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- 2011-06-01 UA UAA201210089A patent/UA110473C2/uk unknown
- 2011-06-01 EA EA201291195A patent/EA201291195A1/ru unknown
- 2011-06-01 WO PCT/EP2011/059121 patent/WO2011151403A1/en active Application Filing
- 2011-06-01 CN CN2011800266565A patent/CN102971003A/zh active Pending
- 2011-06-01 SG SG2012065918A patent/SG185353A1/en unknown
- 2011-06-01 JP JP2013512926A patent/JP2013536157A/ja active Pending
- 2011-06-01 KR KR1020127034291A patent/KR20130089175A/ko not_active Application Discontinuation
- 2011-06-01 EP EP11722825.4A patent/EP2575850A1/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| NZ601677A (en) | 2015-01-30 |
| EA201291195A1 (ru) | 2014-06-30 |
| UA110473C2 (uk) | 2016-01-12 |
| SG185353A1 (en) | 2012-12-28 |
| EP2575850A1 (en) | 2013-04-10 |
| AU2011260277B2 (en) | 2015-01-15 |
| US9023803B2 (en) | 2015-05-05 |
| CA2793601A1 (en) | 2011-12-08 |
| AU2011260277A1 (en) | 2012-08-30 |
| WO2011151403A1 (en) | 2011-12-08 |
| MX2012013998A (es) | 2013-01-28 |
| GB201009222D0 (en) | 2010-07-21 |
| US20120027684A1 (en) | 2012-02-02 |
| JP2013536157A (ja) | 2013-09-19 |
| MY162741A (en) | 2017-07-15 |
| KR20130089175A (ko) | 2013-08-09 |
| US9056069B2 (en) | 2015-06-16 |
| US20130177525A1 (en) | 2013-07-11 |
| BR112012030479A2 (pt) | 2017-01-24 |
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