CN103889440A - 用于癌症治疗和预防的涉及p62的方法和组合物 - Google Patents
用于癌症治疗和预防的涉及p62的方法和组合物 Download PDFInfo
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Abstract
本发明提供了预防和治疗癌症的新的p62组合物和相关方法。本发明还提供了提高p62抗癌活性的修饰的p62组合物。
Description
相关专利申请交叉参考
本申请要求题目是“P62作为抗癌药物”的2012年3月11日提交的俄罗斯专利申请系列号No.2012108927,2011年8月8日提交的美国临时申请系列号No.61/521,280的利益。这两份文献在此全文引入并为了所有目的作为参考。
技术领域
本发明一般性涉及癌症预防和治疗领域。更具体地,本发明涉及利用使用p62组合物激活抗癌响应的癌症预防和治疗。
背景技术
癌症在美国和欧盟是死亡第二最普遍原因(全国人口统计报告,Vol.60,No.4,2012),以及在欧盟,年龄45-64人群,男性和女性两者,癌症是死亡第一最普遍原因。据2008年1月1日估计,美国癌症患者已发生肿瘤病例男性是5,506,000例,女性是6,452,000例。
癌症疫苗正在研究中,一些进入III期功效研究(Rosenberg等,Nat Med.,10:909(2004),Johnson等,Expert Rev Anticancer Ther.,9:67(2009)3,4)。一些癌症疫苗指向抗实体瘤,前列腺癌,肺癌,乳腺癌和结肠直肠癌。两类高风险人群从预防性抗癌疫苗特别受益:手术去除属于已知具有高转移潜在性的癌类型肿瘤(例如,卵巢癌或一些类型的乳腺癌)的患者,还有与较高癌症风险相关的已知突变(例如,乳腺癌和卵巢癌BRCA1和BRCA2基因中的突变,卵巢癌的RAD51基因,等)的携带者。女性高风险人群选择性预防性免疫接种是重要的公共健康任务。
p62是一种多功能蛋白质,其结合泛蛋白并且调节核因子κ-B(NF-kB)信号途径的激活。这种蛋白质作为与TNF受体-相关因子6合作以介导响应于上游信号的NF-kB的激活的支架蛋白/衔接蛋白而发挥功能。或者,对这种基因已经鉴定了编码相同或不同同种型的剪接转录变体。
p62被鉴定是62-kDa蛋白质,其以不依赖磷酸酪氨酸方式结合酪氨酸激酶Lckp56的src同源物2(SH2)结构域(Park等,Proc Natl Acad Sci U S A.,92:12338(1995))。p62的一级序列是已知的(Joung等,Proc Natl Acad Sci U S A.,93:5991,(1996)),并且证实结合泛蛋白(Vadlamudi等,J.Biol.Chem.,271:20235(1996))。人p62的DNA序列,人死骨片1(SQSTM1),转录变体1,mRNA,能在NCBI参考序列:NM_003900.4入口获得。人p62的氨基酸序列,死骨片-1同种型1[人类],能在NCBI参考序列:NP_003891.1入口获得。p62即不与泛蛋白C-末端水解酶同源也不与26S蛋白酶体复合体的S5a亚基同源,是已知与泛蛋白非共价结合的唯一蛋白质。这些结果提示p62属于新的一类泛蛋白-结合蛋白质。
p62是脑和肝蛋白质聚集疾病中发现的内含体成份:p62螯合到胞质内含体中,称作死骨片(sequestosomes)。这些包含p62的蛋白质聚集体通过细胞自我吞噬作用而降解。提示p62的这种功能可以具有对亨廷顿蛋白-诱导的细胞死亡的保护作用(等,J CellBiol.,171:603(2005))。p62基因的诱变与散发的或家族的佩吉特病(Paget disease)(JennyChung等,Semin Arthritis Rheum.,41:619(2012)),一种代谢骨疾病。
发明内容
这里提供的是通过对受试者施用下面的药物而对受试者癌症的一个或几个症状治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率的方法,所述药物具有(a)p62多肽或(b)p62编码核酸。所述药物能具有(a)一个或多个结构域缺失,(b)与SEQ ID NO.1至少95%同一性的p62编码核酸,或者(c)与SEQ ID NO:2至少98%同一性的p62多肽。该方法结构域缺失能是下面的一种或多种:PB1,ZZ,NLS2,TB,NLS1,NES,LIR,KIR,和UBA。该方法能分别使用融合蛋白或编码融合蛋白的核酸。该方法能使用翻译后修饰的p62多肽。
所述药物能通过下面任何途径给药:肠胃外,口服,鼻,直肠,皮肤,叶鞘内或通过气雾剂吸入。肠胃外途径能是下面任何一种:血管内,静脉内,动脉内,肌内,眼内,腹膜内,皮内和皮下,或者能对器官或对肿瘤施用。该方法能进一步包括下面任何和所有的:对受试者佐剂的给与,共刺激成份的给与,给与阻断抑制或负调节免疫机理的一种或多种分子,或者给与一种或多种抗癌治疗。
该方法能被用来治疗受试者的任何癌症,包括:乳腺癌,肺癌,前列腺癌,胃癌,大肠癌,皮肤癌,头颈癌,支气管癌,胰腺癌,膀胱癌,脑癌,中枢神经系统癌,周围神经系统癌,食道癌,口腔或咽癌,肝癌,肾癌,睾丸癌,胆汁管癌,小肠或阑尾癌,卵巢癌,子宫癌,唾液腺癌,甲状腺癌,肾上腺癌,骨肉瘤,软骨肉瘤,肉瘤和血液组织癌。受试者可以是:诊断有癌症的受试者,以前治疗过癌症的受试者,有癌症家族史的受试者,或者预诊癌症的受试者。
该方法包括一种药物,该药物是p62编码核酸并且该核酸能包含在质粒或病毒载体中。该方法还能包括提高以核酸为基础的免疫作用效力的策略。
这里还提供对受试者癌症的一个或几个症状治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率的药物,所述药物是p62多肽或p62编码核酸,其具有至少一个或多个结构域缺失,或者由p62多肽的一个或多个结构域组成或者由编码p62的一个或多个结构域的核酸组成。所述一个或多个结构域可以是下面的:PB1,ZZ,NLS2,TB,NLS1,NES,LIR,KIR,和UBA。
该药物能分别包含融合蛋白或编码核酸。p62多肽能是翻译后修饰的。
该药物能进一步含有一种或几种佐剂,一种或几种共同刺激成份,或者阻断抑制或负调节免疫机理的一种或多种分子,或者一种或多种化学治疗分子或抗血管生成分子。
该药物能是p62编码核酸,进一步地,是质粒或病毒载体的成份。
这里还提供了包含适合对受试者给药的药物的组合物。
附图说明
图1显示人p62野生型核酸序列(SEQ ID NO:1)。
图2显示核酸序列编码的人p62野生型氨基酸序列(SEQ ID NO:2)。
图3显示人p62结构域结构的示意图。
图4显示用p62或HER2(阳性对照)的DNA疫苗,或单独载体(阴性对照)注射的小鼠乳腺癌模型小鼠肿瘤生成时间进程之比较。
图5显示来自p62-免疫动物的肿瘤的苏木精-伊红染色(HE)。上图:箭头指向坏死的多个病灶。下图:箭头指向炎性细胞网眼。
图6显示来自HER2-和p62-免疫动物的免疫组织化学染色。左侧一组图显示HE染色,中间一组图显示抗-CD3染色,右侧一组图显示抗-CD11b染色。
图7显示T5大鼠乳腺癌模型中给与p62DNA疫苗的图解时间线。
图8显示携带T5可移植乳腺癌p62-接种大鼠和对照大鼠肿瘤体积的时间进程。
图9显示携带T5可移植乳腺癌p62-接种大鼠和对照大鼠肿瘤生长抑制的时间进程。
图10显示携带T5可移植乳腺癌p62-接种大鼠和对照大鼠大鼠存活的时间进程。
图11显示携带T5可移植乳腺癌p62-接种大鼠和对照载体接种大鼠的肿瘤切片。
图12显示携带T5可移植乳腺癌p62-接种大鼠和对照载体接种大鼠的肿瘤切片的苏木精-伊红染色(HE)。
图13显示p62-接种小鼠和对照载体接种小鼠之间Lewis肺癌转移数之比较。
具体实施方式
本发明提供了用于治疗癌症的p62组合物和方法。虽然没有寄希望于理论支持,本发明人发现通过对受试者施用p62编码核酸,宿主免疫防御机理被刺激来攻击赘生性细胞。因此,对受试者施用编码p62多肽的DNA疫苗或者p62多肽能刺激抗癌免疫应答。
如这里所使用的,“多肽”意思是相应于全长p62/SQSTM1蛋白质的多肽。该术语包括p62/SQSTM1蛋白质的所有的同系物、类似物、片段或衍生物。在一个实施方案中,分离的p62多肽具有图2(SEQ ID NO:2)所示氨基酸序列。“p62编码核酸”意思是编码p62多肽的DNA或RNA。
在一些实施方案中,受试者是人。在另一些实施方案中,受试者是非人的动物,例如马、牛、羊、猪、鹿、狗、猫、大鼠、或小鼠。
除了全长氨基酸序列之外,本发明的多肽还可以包括p62多肽的片段或截短物,类似物,和同系物,以及如这里所述的截短物。片段能包括全长多肽的至少5、至少10、至少15、至少20、至少25、或至少30个氨基酸残基的肽。
还包括p62/SQSTM1蛋白质的氨基酸序列中一个或多个氨基酸的缺失,或者不连续部分。缺失的氨基酸可以是或者可以不是连续性的。缺失突变得到的类似物的下限长度是大约10、大约20、大约50、或大约100个氨基酸。
在一些实施方案中,p62多肽具有一个或多个缺失的结构域。没有寄希望于理论支持,本发明人发现p62多肽的一个或多个结构域的缺失提供指向免疫应答的更紧凑而可操作的多肽。例如,通过截断或除去p62多肽的一个或多个结构域,能在更简洁的分子中保留免疫原性(或者改善,如果缺失或截断的结构域对免疫原性没有贡献)并且有潜力地增加每重量基数所呈递给宿主的表位数。另外,负责涉及其它细胞过程或者其自身在胞内蛋白质降解的结构域的去除或重新排序能改善其抗癌作用。p62多肽具有下面表1提供的和图3所示的结构域结构:
表1.p62多肽结构域结构
序列编号:NP_003891(死骨片-1同种型1[人源])。
在一些实施方案中,上述结构域的一个或多个在p62核酸的核酸区的相应密码子处从p62多肽缺失(读框内缺失),如下表2所示。
表2.p62中的缺失
缺失的结构域 | 缺失起始,之间的nts | 缺失起始,之间的nts |
PB1 | 1和20 | 102和122 |
ZZ | 102和122 | 167和183 |
NLS2 | 167和183 | 194和228 |
TB | 194和228 | 233和261 |
NLS1 | 233和261 | 273和303 |
NES-LIR-KIR | 273和303 | 357和389 |
UBA | 357和389之间的终止密码子 | 没有应用 |
参照p62NCBI参考序列NP_003891的核苷酸编号(死骨片-1同种型1[人源])。
例如,在核苷酸102至多至核苷酸122开始在167至多至183终止的编码核酸序列的任何缺失都被认为是ZZ缺失。因此,例如110-175是一种ZZ缺失。产生读框内缺失的技术是本领域技术人员公知的。
在一些实施方案中,p62多肽(或者核酸编码的p62多肽)由上述结构域的一个或多个组成。在一些实施方案中,p62多肽(或者核酸编码的p62多肽)由上述结构域的两个或多个组成,在其它实施方案中,组成多肽的结构域是与野生型p62多肽中存在的不同的N-末端至C-末端顺序。
如这里所使用的,"生物活性或免疫活性"指根据本发明的多肽具有和各个野生型多肽相似的结构功能(但不必须到相同程度),和/或相似调节功能(但不必须到相同程度),和/或相似生物化学功能(但不必须到相同程度)和/或免疫活性(但不必须到相同程度)。
如这里所使用的,"缺失"被定义为与野生型蛋白质相比其中一个或多个氨基酸残基不存在的氨基酸序列中的变化。
如这里所使用的,"插入"或"添加"是与野生型蛋白质相比导致加入一个或多个氨基酸残基的氨基酸序列中的变化。
如这里所使用的,"取代"是与野生型蛋白质相比由不同的氨基酸分别置换一个或多个氨基酸的结果。在一些实施方案中,取代突变是C145R或Q418R。
如这里所使用的,术语"变体"意思是与野生型蛋白质相比对序列由取代、缺失、或添加一个(或多个)氨基酸(或者这些的任何组合)的任何多肽,包括等位基因变体,只要得到的蛋白质与本发明使用的野生型蛋白质相比保持至少75%、至少80%、至少85%、至少90%、至少95%、或至少99%的免疫原性。典型地,本发明所包括的多肽的变体与SEQ.ID.NO.2具有至少80%、至少85%、至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%、或至少99%序列同一性。
序列同一性或同源性能利用本领域公知的标准技术来测定,例如Devereux等,Nucl.AcidRes.12;387-395(1984)所描述的Best Fit序列程序或者(Altschul等,J Mol.Biol.215,403-410)所描述的BLASTX。序列排比可以包括在要排比的序列中引入缺口。另外,对于包含比这里所公开的蛋白质多几个或少几个氨基酸的序列,要明白将以与氨基酸总数相关的同源氨基酸的数目为基础确定同源百分比。
在一些实施方案中,本发明多肽的变体或衍生物保持氨基酸序列的疏水性/亲水性。可以进行保守性氨基酸取代,例如1、2或3至10、20或30取代,前提是被修饰的序列保持作为根据本发明的免疫原起作用的能力。氨基酸取代可以包括使用非天然存在的类似物,例如以延长血浆半衰期。保守取代是本领域公知的。
这里所使用的与氨基酸序列相关的术语"衍生物"意思是本发明多肽的化学修饰。
这样的修饰的非限制性例子包括但不限于:羧基末端的或包含羧基侧链的残基的脂肪酸酯或酰胺,含羟基残基的O-酰基衍生物,和氨基末端氨基酸的或含氨基末端残基,例如赖氨酸或精氨酸,的N-酰基衍生物。
另外的修饰作用能包括,例如,与聚乙二醇(PEG)偶联的多肽的制备,或者本发明多肽的化学合成期间PEG的加入。
多肽或者其部分的修饰作用还可以包括还原作用/烷基化作用;与合适载体的化学偶联或者适度甲醛水溶液处理。
如这里所使用的术语"修饰的"指多肽上存在翻译后修饰作用。术语"(修饰的)"意思是所讨论的多肽任选地被修饰,即所讨论的多肽可以是修饰的或者未被修饰的。
术语"翻译后修饰的"和"修饰的"指在其已经被插入到多肽链之后对这样的氨基酸发生的天然的或非天然氨基酸的任何修饰作用。该术语包括,仅为了举例,体内共同翻译修饰,体内翻译后修饰,和体外翻译后修饰。
本发明多肽的其它衍生物包括非天然氨基酸的插入,或者磷酸化氨基酸残基的插入,例如磷酸酪氨酸,磷酸丝氨酸或磷酸苏氨酸残基。其它可能的修饰作用包括磺化,生物素化,或者其它部分的加入,特别是具有类似于磷酸根基团分子形状的那些部分的加入。
衍生物还包括通过糖基化作用修饰的多肽。在各种可选择真核宿主表达系统中的合成和过程中,或者在进一步处理步骤中,通过修饰糖基化方式能制备这些。制备糖基化修饰的方法包括将p62多肽暴露给从通常携带这样的过程的细胞产生的糖基化酶,例如哺乳动物糖基化酶。或者能使用去糖基化酶来去除在真核表达系统中制备期间连接的碳水化合物。另外,人们也能修饰编码序列,使得加入糖基化位点或缺失糖基化位点或者使其丧失功能。此外,如果没有期望的糖基化作用,则能在原核宿主表达系统中制备蛋白质。
通过化学合成或者通过利用定点诱变(Gillman等,Gene8:81(1979);Roberts等,Nature328:731(1987)或者Innis(编著),1990,PCR Protocols:方法和应用指南(A Guide toMethods and Applications),科学出版社,纽约,N.Y.)或者聚合酶链式反应方法(PCR;Saiki等,Science239:487(1988)),如Daugherty等举例说明的(Nucleic Acids Res.19:2471(1991)),来修饰编码本发明p62多肽的核酸,能制备本发明的多肽的变体和/或衍生物。
在另一个实施方案中,本发明的多肽可以在其N-末端包含一个异源信号序列。在一些宿主细胞(例如哺乳动物宿主细胞)中,通过使用异源信号序列能增加融合蛋白的表达和/或分泌。信号序列典型地特征在于疏水性氨基酸核,其一般在一个或多个裂解事件的分泌期间从成熟蛋白质裂解。这样的信号肽包含处理位点,该位点使得信号序列在它们通过分泌途径时从成熟蛋白质裂解。这样,本发明适合上述多肽具有信号序列,以及适合从中蛋白水解裂解信号序列的多肽。
为了增强稳定性和/或反应性,也能修饰本发明的多肽以在天然等位基因变种氨基酸序列中插入一个或多个多态性。另外,D-氨基酸,非天然氨基酸或非氨基酸类似物能被取代或加入,以制备本发明范围内的修饰的p62多肽。
可以通过在合适的表达载体中编码多肽的核苷酸序列的表达可以制备本发明的多肽。
另外,或者可选择的,利用合成期望的氨基酸序列的化学方法能全长或部分制备多肽。例如,多肽能通过固相技术合成,从树脂上裂解,并且通过制备高效液相色谱纯化(例如,Creighton(1983)《蛋白质结构和分子原理》(Proteins Structures And MolecularPrinciples),WH Freeman和Co,纽约,N.Y.)。通过氨基酸分析和测序(例如,Edman降解程序)可以证实合成多肽的成份。另外,p62多肽的氨基酸序列,或者其部分,可以在定向合成中被改变和/或利用化学方法与来自其它亚基或者其部分的序列化合,制备变体多肽。
测定本发明任何多肽的任何同系物、衍生物或变体的免疫原活性的试验是本领域公知的。
如这里所使用的,术语"融合蛋白"指包含两个或多个不同蛋白质的氨基酸序列的嵌合蛋白。典型地,融合蛋白从本领域公知的体外重组技术而获得。
在另外的实施方案中,本发明的融合蛋白可以进一步包括加入的一个或多个另外的多肽结构域来促进蛋白质纯化,增加重组蛋白的表达,或者增加重组蛋白的溶解性。这样的纯化/表达/溶解性促进结构域包括但不限于,使在固定化金属上纯化的金属螯合肽,例如组氨酸-色氨酸模块(Porath J(1992)Protein Expr Purif3-.263281),使在固定化免疫球蛋白上纯化的蛋白质A结构域,和FLAGS延伸/亲和性纯化系统中使用的结构域(ImmunexCorp,西雅图,华盛顿)。纯化结构域和p62多肽之间的可裂解接头序列例如因子Xa或肠激酶(Invitrogen,圣地亚哥,加利福尼亚)的包含物对于促进纯化是有用的。
另外的融合表达载体包括pGEX(Pharmaci,a Piscataway,N.J.),pMAL(New EnglandBiolabs,Beverly,Mass.)和pRITS(Pharmacia,Piscataway,N.J.),其分别将谷胱甘肽S转移酶(GST),麦芽糖B结合蛋白,或蛋白质A与靶重组蛋白融合。也能使用EBV,BKV,和其它附加型表达载体(Invitrogen)。
在一些实施方案中,使用编码p62多肽的核酸。核酸分子可以包括或者由下面的物质构成:编码一个或多个p62多肽的核苷酸序列,或者其片段(包括其中一个或多个结构域缺失或截断的任何顺序或多肽中结构域的编码片段)或者其衍生物,例如ATCC保藏物中DNA插入物中包含的。术语"核酸序列"或"核酸分子"指DNA或RNA序列。该术语包括从DNA和RNA的任何已知碱基类似物形成的分子,例如,但不限于:其中包括4-乙酰基胞嘧啶、8-羟基-N6-甲基腺苷、氮丙啶基-胞嘧啶、假异胞嘧啶、5-(羧羟基甲基)尿嘧啶、5-氟代尿嘧啶、5-溴代尿嘧啶、5-羧基甲基氨基甲基-2-硫尿嘧啶、5-羧基-甲基氨基甲基尿嘧啶、二氢尿嘧啶、肌苷、N6-异-戊烯基腺苷、1-甲基腺苷、1-甲基假尿嘧啶、1-甲基鸟嘌呤、1-甲基肌苷、2,2-二甲基-鸟嘌呤、2-甲基腺苷、2-甲基鸟嘌呤、3-甲基胞嘧啶、5-甲基胞嘧啶、N6-甲基腺苷、7-甲基鸟嘌呤、5-甲基氨基甲基尿嘧啶、5-甲氧基氨基-甲基-2-硫尿嘧啶、β-D-甘露糖基queosine、5'-甲氧基羰基-甲基尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-异戊烯基腺苷、尿嘧啶-5-氧乙酸甲酯、尿嘧啶-5-氧乙酸、oxybutoxosine、假尿嘧啶、queosine、2-硫胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、N-尿嘧啶-5-氧乙酸甲酯、尿嘧啶-5-氧乙酸、假尿嘧啶、queosine、2-硫胞嘧啶、和2,6-二氨基嘌呤。
在本发明的一些实施方案中,使用载体来将核酸序列转移到宿主细胞。载体是被用来将核酸序列转移到宿主细胞的任何分子。在某些情况下,使用表达载体。表达载体是适合导入宿主细胞和/或在宿主细胞中增殖并且包含指引和/或调控被转移核酸序列的表达的核酸序列的核酸分子。表达包括但不限于,象转录、翻译和剪接这样的过程,如果存在内含子。表达质载体典型地包括与编码多肽的异源核酸序列操作连接的一个或多个旁侧序列。旁侧序列可以是,例如同源的(即来自和宿主细胞相同的种和/或菌株),异源的(即来自除宿主细胞种或菌株之外的种),杂种的(即来自多于一个来源的旁侧序列的组合),或合成的。
旁侧序列优选能影响编码序列的复制、转录和/或翻译,并且与编码序列操作连接。如这里所使用的,术语操作连接指功能关系中多核苷酸元件的键合。例如,如果它影响编码序列的转录,则启动子或增强子与编码序列操作连接。但是,旁侧序列不必需与编码序列相邻,只要它正确发挥功能。因此,例如,介入未翻译但是转录的序列能在启动子序列和编码序列之间存在,并且启动子仍然可以被认为与编码序列操作连接。类似地,增强子序列可以位于编码序列的上游或下游并且影响序列的转录。
在一些实施方案中,优选旁侧序列是驱动在靶细胞中高水平基因表达的转录调控区。转录调控区可以包括,例如,启动子、增强子、沉默基因、阻抑元件,或者其组合。转录调控区可以是构成的、组织特异性的、细胞类型特异性的(即,与另外的相比,该区驱动更高水平的在一种类型的组织或细胞中的转录),或者可调节的(即,响应与分子的相互作用)。转录调节区的来源可以是任何原核生物或真核生物,任何脊椎动物或无脊椎生物,或者任何植物,前提是旁侧序列通过在那个细胞中引起核酸的转录而在细胞中发挥功能。在实施本发明中可以利用很多种转录调节区。
合适的转录调节区包括,例如,CMV启动子(即,CMV-即时早期启动子);来自真核生物基因的启动子(即,雌激素可诱导鸡卵清蛋白基因,干扰素基因,糖皮质激素-可诱导酪蛋白氨基转移酶基因,和胸苷激酶基因);和主要早期和晚期腺病毒基因启动子;SV40早期启动子区(Bernoist和Chambon,1981,Nature290:304-10);劳斯肉瘤病毒(RSV)的3'长末端重复结构(LTR)中包含的启动子(Yamamoto等,1980,Cell22:787-97);单纯疱疹病毒胸苷激酶(HSV-TK)启动子(Wagner等,1981,Proc.Natl.Acad.Sci.U.S.A.78:1444-45);金属硫蛋白基因的调控序列(Brinster等,1982,Nature296:39-42);原核表达载体,例如β-内酰胺酶启动子(VIIIa-Kamaroff等,1978,Proc.Natl.Acad.Sci.U.S.A.,75:3727-31);或者tac启动子(DeBoer等,1983,Proc.Natl.Acad.Sci.U.S.A.,80:21-25)。组织-和/或细胞-型特异性转录调控区包括,例如,其中包括,在胰腺腺细胞中是活性的弹性蛋白酶I基因调控区(Swift等,1984,Cell38:639-46;Ornitz等,1986,Cold Spring HarborSymp.Quant.Biol.50:399-409(1986);MacDonald,1987,Hepalology7:425-515);在胰腺β细胞中是活性的胰岛素基因调控区(Hanahan,1985,Nature315:115-22);在淋巴样细胞中是活性的免疫球蛋白基因调控区(Grosschedl等,1984,Cell38:647-58;Adames等,1985,Nature318:533-38;Alexander等,1987,Mol.Cell.Biol.,7:1436-44);睾丸细胞、乳房细胞、淋巴细胞和肥大细胞中的小鼠乳腺肿瘤病毒调控区(Leder等,1986,Cell45:485-95);肝脏中的白蛋白基因调控区(Pinkert等,1987,Genes and Devel.1:268-76);肝脏中α-胎儿-蛋白基因调控区(Krumlauf等,1985,Mol.Cell.Biol.,5:1639-48;Hammer等,1987,Science235:53-58);肝脏中α1-抗胰岛素基因调控区(Kelsey等,1987,Genes和Devel.1:161-71);骨髓细胞中β-球蛋白基因调控区(Mogram等,1985,Nature315:338-40;Kollias等,1986,Cell46:89-94);脑中少突细胞中髓磷脂碱性蛋白基因调控区(Readhead等,1987,Cell48:703-12);骨骼肌中肌球蛋白轻链-2基因调控区(Sani,1985,Nature314:283-86);下丘脑中促性腺释放激素基因调控区(Mason等,1986,Science234:1372-78),和黑素瘤细胞中酪氨酸酶启动子(Hart,I.Semin Oncol1996年2月;23(1):154-8;Siders,等,Cancer Gene Ther1998年9-10月;5(5):281-91)。可以利用在某些分子存在下或者象例如光、热、放射、四环素、或热激蛋白这样的条件下是活性的之可诱导启动子(参见,例如,WO00/10612)。其它合适的启动子是本领域公知的。
如上所述,增强子也可以是合适的旁侧序列。增强子是DNA的顺式-作用元件,通常长度大约10-300bp,其作用于启动子以增强转录。增强子典型地是定位-和位置-独立性的,鉴定5'和3'两者来调控编码序列。可从哺乳动物基因获得的几种增强子序列是公知的(即,球蛋白、弹性蛋白酶、白蛋白、α-胎儿-蛋白和胰岛素)。类似地,SV40增强子,细胞巨化病毒早期启动子增强子,多瘤增强子,和腺病毒增强子与真核启动子序列使用。增强子可以在核酸编码序列位置5'或3'被剪接到载体中,其一般位于启动子5'位。其它合适的增强子是本领域公知的,并且适用本发明。
在一些实施方案中,将p62多肽或编码p62多肽的核酸或者其衍生物与一种或多种共同刺激成份,例如细胞表面蛋白、细胞因子、或信号分子组合在本发明组合物中是有益的。组合物中可以含有的共同刺激成份例如是多肽或编码多肽的核酸。合适的共同刺激分子包括,例如,结合CD28家族成员的多肽(即,CD28,ICOS;Hutloff等,Nature1999,397:263-265;Peach等,J Exp Med1994,180:2049-2058),例如CD28结合多肽B7.1(CD80;Schwartz,1992;Chen等,1992;Ellis等,J.Immunol.,156(8):2700-9)和B7.2(CD86;Ellis等,J.Immunol.,156(8):2700-9);结合整合蛋白家族成员的多肽(即,LFA-1(CD11a/CD18);Sedwick等,J Immunol1999,162:1367-1375;Wulfing等,Science1998,282:2266-2269;Lub等,Immunol Today1995,16:479-483),包括ICAM家族成员(即,ICAM-1,-2或-3);结合CD2家族成员的多肽(即,CD2,信号淋巴细胞激活分子(CDw150或"SLAM";Aversa等,J Immunol1997,158:4036-4044)),例如CD58(LFA-3;CD2配体;Davis等,Immunol Today1996,17:177-187)或SLAM配体(Sayos等,Nature1998,395:462-469);结合热稳定抗原的多肽(HAS或CD24;Zhou等,Eur J Immunol1997,27:2524-2528);与TNF受体(TNFR)家族成员结合的多肽(即,4-1BB(CD137;Vinay等,Semin Immunol1998,10:481-489),OX40(CD134;Weinberg等,Semin Immunol1998,10:471-480;Higgins等,J Immunol1999,162:486-493),和CD27(Lens等,Semin Immunol1998,10:491-499)),例如4-1BBL(4-1BB配体;Vinay等,Semin Immunol1998,10:481-48;DeBenedette等,J Immunol1997,158:551-559),TNFR相关因子-1(TRAF-1;4-1BB配体;Saoulli等,J Exp Med1998,187:1849-1862,Arch等,Mol Cell Biol1998,18:558-565),TRAF-2(4-1BB和OX40配体;Saoulli等,J Exp Med1998,187:1849-1862;Oshima等,Int Immunol1998,10:517-526,Kawamata等,J Biol Chem1998,273:5808-5814),TRAF-3(4-1BB和OX40配体;Arch等,Mol CellBiol1998,18:558-565;Jang等,Biochem Biophys Res Commun1998,242:613-620;KawamataS等,J Biol Chem1998,273:5808-5814),OX40L(OX40配体;Gramaglia等,J Immunol1998,161:6510-6517),TRAF-5(OX40配体;Arch等,Mol Cell Biol1998,18:558-565;Kawamata等,J Biol Chem1998,273:5808-5814),和CD70(CD27配体;Couderc等,CancerGene Ther.,5(3):163-75)。CD154(CD40配体或"CD40L";Gurunathan等,J.Immunol.,1998,161:4563-4571;Sine等,Hum.Gene Ther.,2001,12:1091-1102)也可以是合适的。
一种或多种细胞因子也可以是合适的共刺激成份或"佐剂",或者作为本发明组合物包含的多肽或者是核酸编码的(Parmiani等,Immunol Lett2000Sep.15;74(1):41-4;Berzofsky等,Nature Immunol.1:209-219)。合适的细胞因子包括,例如,白细胞介素-2(IL-2)(Rosenberg等,Nature Med.4:321-327(1998)),IL-4,IL-7,IL-12(Pardoll的综述,1992;Harries等,J.Gene Med.2000年7-8月;2(4):243-9;Rao等,J.Immunol.156:3357-3365(1996)),IL-15(Xin等,Vaccine,17:858-866,1999),IL-16(Cruikshank等,J.Leuk Biol.67(6):757-66,2000),IL-18(J.Cancer Res.Clin.Oncol.2001.127(12):718-726),GM-CSF(CSF(Disis等,Blood,88:202-210(1996)),肿瘤坏死因子-α(TNF-α),或者干扰素,例如IFN-α或INF-γ。其它细胞因子也适合实施本发明,这是本领域公知的。
也可以使用趋化因子。例如,已经证明包含与肿瘤自身抗原融合的CXCL10(IP-10)和CCL7(MCP-3)的融合蛋白诱导抗肿瘤免疫性(Biragyn等,Nature Biotech.1999,17:253-258)。趋化因子CCL3(MIP-1α)和CCL5(RANTES)(Boyer等,Vaccine,1999,17(增刊2):S53-S64)也可以在实施本发明中使用。其它合适的趋化因子是本领域公知的。
“信号分子”是细胞之间引导形成中涉及的化学生物化合物。这样的分子从发送信号的细胞释放,通过扩散跨越细胞之间的间隙,并且与另一个细胞中的特异性受体相互作用,通过激活控制导致细胞内变化的反应的一系列酶而触发那个细胞中的响应。例如,人体一些细胞少量产生氢化硫并且具有数个生物学信号功能。只有实施例包括氧化氮和一氧化碳。
本领域还公知抑制或负调节免疫机理可以被阻断,导致增强的免疫应答。例如,已经证明使用抗-CTLA-4抗体(Shrikant等,Immunity,1996,14:145-155;Sutmuller等,J.Exp.Med.,2001,194:823-832),抗-CD25抗体(Sutmuller,上文),抗-CD4抗体(Matsui等,J.Immunol.,1999,163:184-193),融合蛋白IL13Ra2-Fc(Terabe等,Nature Immunol.,2000,1:515-520),和其组合(即,抗-CTLA-4和抗-CD25抗体,Sutmuller,上文)处理会增量调节抗癌免疫应答并且适合实施本发明。
这些成份中的任一个可以单独使用或者与另一种联合使用。例如,已经证明CD80,ICAM-1和LFA-3("TRICOM")的联合可以加强抗癌免疫应答(Hodge等,Cancer Res.59:5800-5807(1999)。其它有效联合包括,例如,IL-12+GM-CSF(Ahlers等,J.Immunol.,158:3947-3958(1997);Iwasaki等,J.Immunol.158:4591-4601(1997)),IL-12+GM-CSF+TNF-α.(Ahlers等,Int.Immunol.13:897-908(2001)),CD80+IL-12(Fruend等,Int.J.Cancer,85:508-517(2000);Rao等,上文),和CD86+GM-CSF+IL-12(Iwasaki,上文)。本领域技术人员知道实施本发明有用的另外的联合。另外,本领域技术人员知道可以用来调节这样的机理的另外的药物或方法。这些药物和方法,以及本领域技术人员已知的那些,可以在实施本发明中被利用。
改善以核酸为基础的免疫效率的其它策略也可以被利用,包括,例如,使用自我复制病毒复制子(Caley等,1999.Vaccine,17:3124-2135;Dubensky等,2000.Mol.Med.6:723-732;Leitner等,2000.Cancer Res.60:51-55),密码子优化(Liu等,2000.Mol.Ther.,1:497-500;Dubensky,上文;Huang等,2001.J.Virol.75:4947-4951),体内电穿孔(Widera等,2000.J.Immunol.164:4635-3640),CpG刺激基序的插入(Gurunathan等,Ann.Rev.Immunol.,2000,18:927-974;Leitner,上文;Cho等,J.Immunol.168(10):4907-13),靶向内吞作用或泛蛋白过程途径的序列(Thomson等,1998.J.Virol.72:2246-2252;Velders等,2001.J.Immunol.166:5366-5373),Marek's疾病病毒1型VP22序列(J.Virol.76(6):2676-82,2002),已接触抗原-加强法(Gurunathan,上文;Sullivan等,2000.Nature,408:605-609;Hanke等,1998.Vaccine,16:439-445;Amara等,2001.Science,292:69-74),和使用粘膜送递载体例如沙门氏菌(Darji等,1997.Cell,91:765-775;Woo等,2001.Vaccine,19:2945-2954)。其它方法是本领域公知的,其中一些在下文中描述。
在使用p62多肽或p62-编码核酸治疗和/或预防癌症中也可以使用化学治疗药物,放射治疗,抗-血管生成分子(Sebti等,Oncogene2000Dec.27;19(56):6566-73)。例如,在治疗转移乳腺癌中,有用的化学治疗药物其中包括环磷酰胺,阿霉素,紫杉醇,多烯紫杉醇,失碳长春碱,希罗达,和丝裂霉素C。联合的化学治疗方案已被证明有效,例如,包括环磷酰胺+甲氨喋呤+5-氟尿嘧啶;环磷酰胺+环磷酰胺+5-环磷酰胺;或者,环磷酰胺+阿霉素。其它化合物,例如强的松,紫杉烷,失碳长春碱,丝裂霉素C,或长春碱也已经被用于各种原因。大多数乳腺癌患者有雌激素受体阳性(ER+)肿瘤,并且在这些患者中,内分泌治疗(即,
它莫西芬)比化学治疗优选。对于这样的患者,它莫西芬,或者,作为二线治疗,黄体酮(醋酸甲孕酮或醋酸甲地孕酮)是优选的。芳化酶抑制剂(即,氨基乙哌啶酮及其类似物,例如来曲唑)降低保持肿瘤生长所需要的雌激素的可用性,并且对某些患者可以被用作第二或第三线内分泌治疗。
其它癌症可能需要不同的化学疗法方案。例如,转移大肠癌典型地用伊立替康(伊立替康或CPT-11),5-氟尿嘧啶或亚叶酸单独或者与另一种联合治疗。蛋白酶和氧基哌吲哚抑制剂,例如MMP抑制剂马马司他(British Biotech),COL-3(Collagenex),尼华斯他(Aeterna),AG3340(Agouron),BMS-275291(Bristol Myers Squibb),CGS27023A(Novartis)或者氧基哌吲哚抑制剂Vitaxin(Medimmune),或MED1522(Merck KgaA)也适合使用。因此,与使用那些化疗药的治疗联合能实现与大肠癌相关的免疫原靶物的免疫靶向。类似地,用来治疗其它类型癌症的化学治疗药物是本领域公知的并且可以与这里描述的免疫原性靶物联合。
很多抗血管生成药物是本领域公知的,并且适合与p62核酸或多肽疫苗共同给药(参见,例如,Timar等,2001.Pathology Oncol.Res.,7(2):85-94)。这样的药物包括,例如,生理学制剂,例如生长因子(即,ANG-2,NK1,2,4(HGF),转化生长因子β(TGF-β)),细胞因子(即,干扰素,例如IFN-α,-β,-γ,血小板因子4(PF-4),PR-39),蛋白酶(即,裂解的AT-III,胶原质XVIII片段(内皮抑制素)),HmwKallikrein-d5血浆酶片段(制管张素),凝血素-F1-2,TSP-1),蛋白酶抑制剂(即,金属蛋白酶的组织抑制剂,例如TIMP-1,-2,或-3;乳腺丝抑蛋白;纤溶酶原激活物抑制剂,例如PAI-1;色素上皮衍生因子(PEDF)),肿瘤抑素(从ILEX,Inc.可获得),抗体产物(即,胶原结合抗体HUIV26,HUI77,XL313;抗-VEGF;抗-整合蛋白(即,Vitaxin,(Lxsys))),和糖苷酶(即,肝素酶-I,-III)。是血管生成相关抗原的拮抗物(包括蛋白质和多肽)也是合适的,并且包括但不限于,定向抗下列物质的分子:VEGF,VEGF受体,EGFR,bFGF,PDGF-B,PD-ECGF,TGFs包括TGF-α,内皮糖蛋白,Id蛋白质,各种蛋白酶,氧化氮合酶,氨基肽酶,血小板反应蛋白,k-ras,Wnt,细胞周期蛋白依赖性激酶,微管,热激蛋白,肝素结合因子,合酶,胶原受体,整合蛋白,和表面蛋白多糖NG2。已知或据信具有抗血管生成潜力的"化学的"或修饰的生理物质包括,例如,长春碱,紫杉醇,酮康唑,肽胺哌啶酮,dolestatin,combrestatin A,瑞帕霉素(Guba等,2002,Nature Med.,8:128-135),CEP-7055(从Cephalon,Inc.可获得),黄酮醋酸,Bay12-9566(Bayer Corp.),AG3340(Agouron,Inc.),CGS.27023A(Novartis),四环素衍生物(即,COL-3(Collagenix,Inc.)),尼华斯他(Aeterna),BMS-275291(Bristol-MyersSquibb),低剂量5-FU,低剂量甲氨喋呤(MTX),irsofladine,根赤壳菌素,环孢霉素,卡托普利,塞来昔布,D45152-硫酸多糖,阳离子蛋白质(精蛋白),阳离子肽-VEGF,苏拉明(多磺酸化萘脲),干扰VEGF的功能或产生的化合物(即,SU5416或SU6668(Sugen),PTK787/ZK22584(Novartis)),司他霉素,Angiozyme(核酶),isoflavinoids,星形孢菌素衍生物,金雀黄素,EMD121974(Merck KcgaA),酪氨酸磷酸化抑制剂,视黄酸,羧基酰胺三唑,TNP-470,抑生长肽,2-甲氧基雌二醇,氨基甾酮(即,角鲨烷胺),谷胱甘肽类似物(即,N-乙酰基-L-半胱氨酸),combretastatin A-4(Oxigene),Eph受体阻断剂(Nature,414:933-938,2001),Rh-制管张素,Rh-内皮抑制素(WO01/93897),环-RGD肽,accutin-解联蛋白,benzodiazepenes,人源化抗-avb3Ab,Rh-PAI-2,阿米洛利,p-酰胺基苯甲脒,抗-uPA ab,抗-uPAR Ab,L-苯丙氨酸-N-甲酰胺(即,巴马司他,马马司他),AG3340,和米诺环素。很多其它合适的药物是本领域公知的并且满足实施本发明。
本发明也可以与治疗癌症的"非传统"方法联合使用。例如,已经证明施用一些厌氧性细菌有助于减缓肿瘤生长。在一项研究中,诺维氏梭状芽孢杆菌(Clostridium novyi)被修饰除去噬菌体附加体所携带的毒素基因,并且对有大肠癌的小鼠施用(Dang等,P.N.A.S.USA,98(26):15155-15160,2001)。与化学疗法联合,显示治疗引起动物肿瘤坏死。本申请描述的制剂和方法可以与这样的治疗方法联合。
通过几种可行的技术的任一个可以对患者施用编码p62多肽的核酸。成功用于向宿主导入核酸的各种病毒载体其中包括逆转录病毒,腺病毒,腺相关病毒(AAV),疱疹病毒,和痘病毒。本领域明白很多这样的病毒载体是本领域可获得的。利用本领域熟练人员广泛可获得的标准重组技术可以构建本发明的载体。这样的技术可以在普通分子生物学参考文献中找到,例如《分子克隆:实验手册》(Molecular Cloning:A Laboratory Manual)(Sambrook等,1989,冷泉港实验出版社),《基因表达技术》(Gene Expression Technology)(《酶学方法》(Methods in Enzymology),Vol.185,D.Goeddel编著,1991,科学出版社,圣地亚哥,加利福尼亚),和《PCR规程:方法和应用指南》(PCR Protocols:A Guide to Methodsand Applications)(Innis等,1990,科学出版社,圣地亚哥,加利福尼亚)。
合适的逆转录病毒载体包括lentivirus的衍生物以及鼠或鸟逆转录病毒的衍生物。合适的逆转录病毒载体包括,例如,鼠莫洛尼氏白血病病毒(MoMuLV),鼠Harvey肉瘤病毒(HaMuSV),鼠乳腺肿瘤病毒(MuMTV),SIV,BIV,HIV和Rous肉瘤病毒(RSV)。很多逆转录病毒载体能参入多个外源核酸序列。重组逆转录病毒是缺陷型的,为了产生感染载体颗粒,它们需要辅助。例如编码逆转录病毒结构基因的辅助细胞系能提供这种辅助。合适的辅助细胞系其中包括PSI.2,PA317和PA12。使用这样的细胞系产生的载体病毒体然后可以被用来感染组织细胞系,例如NIH3T3细胞,产生大量嵌合逆转录病毒病毒体。逆转录病毒载体可以通过传统方法(即,注射)或者通过植入亲近靶细胞种群的"生产者细胞系"来施用(Culver,K.等,1994,Hum.Gene Ther.,5(3):343-79;Culver,K.等,Cold Spring Harb.Symp;Quant.Biol.,59:685-90);Oldfield,E.,1993,Hum.Gene Ther.,4(1):39-69)。对生产者细胞系基因工程处理以生产病毒载体并邻近靶细胞释放病毒粒。释放的病毒粒的一部分接触靶细胞并且感染那些细胞,这样将本发明的核酸送递给靶细胞。靶细胞感染之后,发生载体核酸的表达。
已经证明腺病毒载体特别用于基因转移到真核细胞中(Rosenfeld,M.等,1991,Science,252(5004):431-4;Crystal,R.等,1994,Nat.Genet.,8(1):42-51),研究真核细胞基因表达(Levrero,M.等,1991,Gene,101(2):195-202),疫苗开发(Graham,F.和Prevec,L.,1992,Biotechnology,20:363-90),和转移到动物模型中(Stratford-Perricaudet,L.等,1992,Bone Marrow Transplant.,9(增刊1):151-2;Rich,D.等,1993,Hum.GeneTher.,4(4):461-76)。对不同组织体内施用重组腺病毒的实验途径其中包括气管内灌输(Rosenfeld,M.等,1992,Cell,68(1):143-55),给肌肉注射(Quantin,B.等,1992,Proc.Natl.Acad.Sci.U.S.A.,89(7):2581-4),外周静脉注射(Herz,J.,和Gerard,R.,1993,Proc.Natl.Acad.Sci.U.S.A.,90(7):2812-6)和对脑立体顺序接种(Le GalLa Salle,G.等,1993,Science,259(5097):988-90)。
腺相关病毒(AAV)证明高水平易感性,广谱宿主范围和整合到宿主细胞基因组中的特异性(Hermonat,P.等,1984,Proc.Natl.Acad.Sci.U.S.A.,81(20):6466-70)。单纯疱疹病毒型-1(HSV-1)是另一个有吸引力的载体系统,特别是在神经系统中使用,因为它的亲神经性质(Geller,A.等,1991,Trends Neurosci.,14(10):428-32;Glorioso等,1995,Mol.Biotechnol.,4(1):87-99;Glorioso等,1995,Annu.Rev.Microbiol.,49:675-710)。
痘病毒是另一种有用的表达载体(Smith等,1983,Gene,25(1):21-8;Moss等,1992,Biotechnology,20:345-62;Moss等,1992,Curr.Top.Microbiol.Immunol.,158:25-38;Moss等,1991.Science,252:1662-1667)。证明有用的痘病毒其中包括牛痘,NYVAC,禽痘,鸟痘,金丝雀痘,ALVAC,和ALVAC(2)。
NYVAC(vP866)通过从编码已知的或潜在的毒力因子的基因组缺失六个非基本区而从牛痘病毒的Copenhagen疫苗株得到(参见,例如,美国专利U.S.Pat.Nos.5,364,773和5,494,807)。将缺失基因座基因工程处理为用于插入外来基因的接受者基因座。缺失的区是:胸苷激酶基因(TK;J2R);出血区(u;B13R+B14R);典型内含体区(ATI;A26L);血凝素基因(HA;A56R);宿主范围基因区(C7L-K1L);和大亚基,核苷酸还原酶(I4L)。NYVAC是遗传工程牛痘病毒株,其通过特异性缺失编码与毒力和宿主范围相关的基因产物的18个可读框而产生。NYVAC已经证明对于表达TAs是有用的(参见,例如,美国专利U.S.Pat.No.6,265,189)。NYVAC(vP866),vP994,vCP205,vCP1433,placZH6H4Lreverse,pMPC6H6K3E3和pC3H6FHVB也都根据布达佩斯条约在ATCC保藏,保藏号分别是VR-2559,VR-2558,VR-2557,VR-2556,ATCC-97913,ATCC-97912,和ATCC-97914。
以ALVAC为基础的重组病毒(即,ALVAC-1和ALVAC-2)也适合用于实施本发明(参见,例如,美国专利U.S.Pat.No.5,756,103)。ALVAC(2)与ALVAC(1)相同,除了ALVAC(2)基因组包括在牛痘启动子调控下的牛痘E3L和K3L基因(美国专利U.S.Pat.No.6,130,066;Beattie等,1995a,1995b,1991;Chang等,1992;Davies等,1993)。ALVAC(1)和ALVAC(2)两者已被证明在表达外来DNA序列例如TAs是有用的(Tartaglia等,1993a,b;美国专利U.S.Pat.No.5,833,975)。ALVAC根据布达佩斯条约在美国典型培养物保藏中心(AmericanType Culture Collection)(ATCC)保藏,10801University Boulevard,Manassas,Va.20110-2209,USA,ATCC保藏号是VR-2547。
另一个有用的痘病毒载体是是TROVAC。TROVAC指削弱的鸟痘,是从接种一天的老鸡的鸟痘病毒的FP-1疫苗株产生的噬斑克隆分离物。TROVAC同样根据布达佩斯条约保藏在ATCC,保藏号2553。
"非病毒"质粒载体也适合实施本发明。合适的质粒载体适合细菌、昆虫、和/或哺乳动物宿主细胞。这样的载体包括,例如,PCR-II,pCR3,和pcDNA3.1(Invitrogen,圣地亚哥,加利福尼亚),pBSII(Stratagene,La Jolla,Calif.),pET15(Novagen,Madison,Wis.),pGEX(Pharmacia Biotech,Piscataway,N.J.),pEGFP-N2(Clontech,Palo Alto,Calif.),pETL(BlueBacII,Invitrogen),pDSR-α(PCT公开No.WO90/14363)和pFastBacDual(Gibco-BRL,Grand Island,N.Y.)以及Bluescript.RTM。质粒衍生物(高拷贝数以COLE1-为基础的噬菌粒,Stratagene Cloning Systems,La Jolla,Calif.),PCR为克隆Taq-扩增PCR产物设计的克隆质粒(例如,TOPO.TM.TA Cloning.RTM.药物盒,PCR2.1.RTM..RTM.质粒衍生物,Invitrogen,Carlsbad,Calif.)。本发明也可以使用细菌载体。这些载体包括,例如,志贺氏菌(Shigella),沙门氏菌(Salmonella),霍乱弧菌(Vibrio cholerae),Laclobacillus,Bacille calmette guerin(BCG),和链球菌(Streptococcus)(参见,例如,WO88/6626;WO90/0594;WO91/13157;WO92/1796;和WO92/21376)。很多其它非病毒质粒表达载体和系统是本领域公知的并且能用于本发明。
合适的核酸送递技术其中包括DNA-配体复合体,腺病毒-配体-DNA复合体,直接注射DNA,CaPO.sub.4沉淀,基因枪技术,电穿孔,和胶体分散系统。胶体分散系统包括大分子复合体,纳米胶囊,微球体,小球,和脂质为基础的系统,包括水包油乳剂,胶囊,混合胶囊,和脂质体。本发明优选的胶体系统是脂质体,其是作为体外和体内送递载体有用的人工膜载体。RNA,DNA和完整病毒体能在含水内部制成胶囊并且以生物活性形式送递给细胞(Fraley,R.等,1981,Trends Biochem.Sci.,6:77)。脂质体的成分通常是磷脂,特别是高相转移温度磷脂的组合,通常与类固醇类特别是胆固醇联合。其它磷脂或其它脂质也可以被使用。脂质体的物理特征取决于pH,离子强度,和二价阳离子的存在。在脂质体生产中有用的脂质的例子包括磷脂酰化合物,例如磷脂酰甘油,磷脂酰胆碱,磷脂酰丝氨酸,磷脂酰乙醇胺,鞘脂类,脑苷脂,和神经节苷脂。特别有用的是二酰基磷脂酰甘油,其中脂质部分包含14-18个碳原子,特别是16-18个碳原子,并且是饱和的。详细说明的磷脂包括鸡蛋磷脂酰胆碱,二棕榈酰磷脂酰胆碱和二硬脂酰磷脂酰胆碱。
免疫原靶物也可以与加强免疫应答的一种或多种佐剂联合给药。例示的佐剂如下面表3所示:
表3.免疫佐剂类型
在一些实施方案中,根据本发明的p62多肽或p62 编码核酸可以被用来对疾病,紊乱和/或症状的一个或多个征兆或特征进行治疗,减轻,改善,缓解,延迟发生(预防),抑制进程,减轻严重程度,和/或减少发生。在一些实施方案中,p62多肽或p62 编码核酸可以被用来治疗实体瘤,例如癌症和/或癌细胞。术语"癌症"包括恶性前以及恶性毒瘤。癌症包括但不限于,前列腺癌,胃癌,大肠癌,皮肤癌,例如,黑素瘤或基底细胞癌,肺癌,乳腺癌,卵巢癌,子宫癌,头颈癌,支气管癌,胰腺癌,膀胱癌,脑或中枢神经系统癌,周围神经系统癌,食道癌,口腔或咽癌,肝癌,肾癌,睾丸癌,胆汁管癌,小肠或阑尾癌,唾液腺癌,甲状腺癌,肾上腺癌,骨肉瘤,软骨肉瘤,肉瘤和血液组织癌等等。"癌细胞"可以是肿瘤形式,单独在患者身上存在(例如,白血病细胞或腹水),或者是从癌产生的细胞系。
癌症与各种各样的身体症状相关。癌症症状一般取决于肿瘤的类型和位置。例如,肺癌能引起,呼吸短促和胸痛,而结肠癌经常引起腹泻,便秘,和便血。但是为了给出几个例子,下面的症状一般经常与很多癌症相关:发烧,寒冷,夜间出汗,咳嗽,呼吸困难,体重减轻,食欲减退,厌食,恶心,呕吐,痢疾,贫血,黄疸,肝肿大,咳血,疲劳,不舒服,认知功能障碍,沮丧,激素紊乱,嗜中性白血球减少,疼痛,不愈疼痛,淋巴结肿大,外周神经病,和性功能紊乱。
在本发明的一个方面,提供了癌症的治疗方法(例如前列腺癌或乳腺癌)。在一些实施方案中,癌症的治疗包括对需要的受试者施用治疗有效量的p62多肽或p62编码核酸,以这样的量和 这样的时间是实现期望结果所必需的。在本发明的一些实施方案中,发明的靶向颗粒的 "治疗有效量" 是癌症的一个或几个症状或特征的治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率有效的量。
在本发明的一个方面,提供了对患有癌症(例如乳腺癌)或复发癌症的受试者施用p62多肽或p62编码核酸方法。在一些实施方案中,以实现期望结果(即治疗癌症)所必需的这样的量和这样的时间对受试者施用p62多肽或p62编码核酸。在本发明的一些实施方案中,p62多肽和p62编码核酸发明的"治疗有效量"是癌症的一个或几个症状或特征的治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率有效的量。在一些实施方案中,在治疗癌症之前对受试者施用本发明的p62多肽或p62编码核酸。在一些实施方案中,对有癌症家族史的受试者施用本发明的p62多肽或p62编码核酸。在一些实施方案中,对易患癌症体质的受试者施用本发明的p62多肽或p62编码核酸。例如,BRCA-阳性的受试者一般易患某些形式的乳腺癌。
本发明治疗方案包括对健康个体(即,没有表现任何癌症症状和/或还没有诊断出癌症的受试者)施用治疗有效量的p62多肽或p62编码核酸。例如,可以在癌症发生和/或发生癌症症状之前对健康个体用p62多肽或p62编码核酸"免疫";有风险个体(例如,有癌症家族史的患者;携带与发生癌症相关一个或多个基因突变的患者;具有与癌症发生相关的基因多态性的患者;感染与癌症发生相关的病毒的患者;有与癌症发生相关的习惯和/或生活方式的患者等)能在癌症症状发作基本上同期(例如48小时内,24小时内,或12小时内)得到治疗。当然,已知患有癌症的个体可以在任何时间接受本发明治疗。
在另外的实施方案中,本发明的p62多肽或p62编码核酸能被用来抑制癌细胞的生长,例如乳腺癌细胞。如这里所使用的,术语"抑制癌细胞的生长"或"约束癌细胞的生长"指减缓癌细胞增殖和/或转移的速度,截留癌细胞增殖和/或转移,或杀死癌细胞,使得与观察到的或预计的未处理对照癌细胞生长速度相比,细胞生长速度减缓。术语"抑制生长"也指癌细胞或肿瘤大小的减小或消失,以及其转移可能性的减小。优选地,这样的细胞水平的抑制作用可以减小患者癌症的大小,阻止生长,减小入侵性,或防止或抑制癌症转移。本领技术人员通过各种各样的合适的指征容易确定癌细胞生长是否被抑制。
例如通过捕获细胞周期特定阶段的癌细胞,例如在细胞周期的G2/M期捕获癌细胞,可以证据证明癌细胞生长的抑制。癌细胞生长的抑制也能通过癌细胞或肿瘤大小的直接或间接测定来证明。在人癌症患者中,这样的测定一般利用公知的成像方法例如核磁共振成像,计算机化轴向分层造影和X-光来进行。癌细胞生长也能间接测定,例如通过测定与癌细胞生长相关的循环癌胚抗原,前列腺特异性抗原或其它癌特异性抗原水平。通常也将受试者延长的存活和/或增加的死亡和康宁与癌症生长的抑制相联系。
这里所描述的化合物和组合物能作为与药学可接受载体配制的药物或药剂来给药。因此,在药剂或药物组合物的制备中可以使用化合物和组合物。本发明的制药组合物可以配制成肠胃外给药的溶液或冻干粉末剂。粉末剂可以通过在使用之前加入合适的稀释剂或其它药学可接受载体来再组成。液体制剂可以是缓冲的,等张的,含水溶液。粉末剂也可以以干燥形式喷雾。合适的稀释剂的例子是常规等张盐水溶液,标准5%葡萄糖水溶液,或者钠或铵乙酸盐缓冲液。这样的制剂特别适合肠胃外给药,但是也可以用于口服或包含在计量剂量吸入器或用于吹入法的喷雾器中。可以期望加入赋形剂,例如聚乙烯吡咯烷酮,明胶,羟基纤维素,阿拉伯树胶,聚乙二醇,甘露醇,氯化钠,柠檬酸钠等等。
因此,化合物和组合物也可以制成用于口服的胶囊,片剂,或者在乳状液或糖浆中制备。可以加入药学可接受固体或液体载体来增强或稳定组合物,或者有利于组合物的制备。固体载体包括淀粉,乳糖,硫酸钙二水合物,石膏粉,硬脂酸镁,滑石,胶质,阿拉伯树胶,琼脂或明胶。液体载体包括糖浆,花生油,橄榄油,盐水和水。载体还可以包括缓释材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯,单独或者与蜡混合。固体载体的量是变化的,但是优选在每剂量单位大约20毫克至大约1克。根据制药业常规技术制备药物制剂,包括研磨、混合、制粒、和片剂形式需要时,压片;或者对于硬明胶胶囊形式,研磨、混合和装填。当使用液体载体时,制剂可以是糖浆、酏剂、乳状液、含水悬浮液或不含水悬浮液形式。对于直肠投药,本发明化合物可以与赋形剂混合,例如可可油、甘油、明胶或聚乙二醇,并且模压成栓剂。
可以配制化合物和组合物使包括其它医疗有用的药物或生物制剂。化合物和组合物也可以用于本发明化合物和组合物所针对的疾病或症状的其它药物或生物制剂联合给药。
如这里所使用的,短语“有效量”指足以提供足够高以对其接受者给予有益效果的浓度。任何特定受试者的具体治疗有效剂量水平取决于多种因素,包括治疗的病症,病症的严重度,具体化合物或组合物的活性,给药途径,化合物或组合物的清除率,治疗期,与化合物或组合物联合或一同使用的药物,年龄,体重,性别,饮食,和受试者一般健康状态,以及医药领域和科学上公知的类似因素。在确定“治疗有效量”时考虑的各种通常性考虑事项是本领域技术人员公知的并且描述于,例如,Gilman等,编著,Goodman和Gilman's:《治疗方法的药理学基础》(The Pharmacological Bases of Therapeutics),第八版,Pergamon Press,1990;和《雷明顿制药科学》(Remington's Pharmaceutical Sciences),第十七版,MackPublishing Co.,Easton,Pa.,1990。剂量水平一般在大约0.001至多至100mg/kg/天范围;大约0.05至多至10mg/kg/天范围内的水平一般可应用。化合物或组合物能肠胃外给药,例如血管内、静脉内、动脉内、肌肉内、眼内、皮内、皮下给药等。也能口服、鼻内、直肠、经皮、叶鞘内、或通过气溶胶吸入给药。化合物或组合物能对有肿瘤(或肿瘤潜在靶物)器官或肿瘤本身给药。化合物或组合物可以作为大丸药、或缓慢输液给药,或者作为皮内、皮下、肌内、或腹膜内注射给药。
治疗有效量能通过测定导入编码p62多肽核酸的p62表达水平从细胞培养分析初步估计。然后在动物模型上能配置剂量来实现肿瘤生长的合适的免疫应答和/或保护作用。这样的信息能被用来更精确地测定有用的人的初始剂量。各医师考虑患者状况能选择精确的药剂、给药途径和剂量。
实施例
实施例1:细胞系和载体构建
从FVB/neu NT转基因小鼠产生的小鼠乳癌得到转基因小鼠A233-VSGA1乳腺癌细胞系,超表达激活的大鼠HER/2neu致癌基因。这个细胞系根据(Nanni P,Pupa SM,Nicoletti G等,Int J Cancer2000;87:186)所述保持。HeLa细胞(ATCC#CCL-2.2TM)在ATCC完全生长培养基(ATCC MD-6108)中繁殖。
大鼠HER2/neu的细胞外结构域通过PCR扩增并且克隆到pcDNA3.1载体(Invitrogen),如(FM Venanzi,A Barucca,K Havas,M Capitani,M Provinciali S Scotti,A Concetti.Vaccine2010(22);3841-7)所述。
作为编码p62的cDNA的来源,从HeLa细胞提取总RNA。使用下面的引物通过PCR(HotStar HiFidelity Polymerase Kit Qiagen)扩增编码p62较长同种型全长cDNA(转录变体变体1,GenBank参考号No.NP_003891):FW:5-CCCGCTAGCATGGCGTCGCTCACCGTG-3和REV:5’-CCCAAGCTTTCACAACGGCGGGGGATGCTTTG-3’。纯化PCR产物并且将Nhe I-Hind III消化片段克隆到pcDNA3.1中。
通过测序证明插入的p62DNA序列(MGWBiotech/M-medical,Martinsried,德国)。发现编码的多肽不同于野生型氨基酸序列在于两个取代突变:C145R和Q418R。
实施例2:p62免疫在小鼠乳腺癌模型中的预防性抗肿瘤作用
FVB/N小组分成三组(每组15只小鼠)并且用下面之一免疫:
1.pcDNA.3.1(空质粒载体,阴性对照);
2.携带pHER2的pcDNA.3.1(阳性对照);或
3.携带p62的pcDNA.3.1(试验)。
将雌性FVB/N麻醉,暴露大腿四头肌后,使用胰岛素注射器用盐水中100μg DNA(1mg/mL)注射。对小鼠免疫两次(在肿瘤攻击之前4星期和2星期)。用3x105233-VSGA1肿瘤细胞/100μl PBS缓冲液在侧翼皮内攻击小鼠。在所有情况下,通过每周三次用卡尺测定两个正交直径来测量肿瘤。当肿瘤溃烂或者任何直径达到1cm时杀死小鼠。
在攻击后第13天用空白质粒载体接种的小鼠(阴性对照)100%发生肿瘤。用HER2-编码质粒接种给出40%保护作用(图4)。同时,p62-编码质粒证明第13天时100%保护作用,其逐渐减小至70%。结果,证明p62-编码质粒在移植乳腺癌小鼠模型中的保护作用。因此,对小鼠模型乳腺癌证明p62疫苗的保护作用。发明人猜测如果继续接种疫苗就能保持100%保护作用。
对用编码HER2或p62的质粒载体免疫并且在第一次癌细胞攻击后没有发生肿瘤的动物在第50天施与同量的癌细胞。用HER2-编码质粒接种的所有的动物发生肿瘤,而用p62接种没有动物出现肿瘤。结论是p62免疫保持免疫记忆,而HER2则没有。
实施例3:p62疫苗刺激自然免疫性
接受p62疫苗的小鼠中的肿瘤包含大面积坏死(图5)。坏死面积中大量存在与炎症相关的免疫细胞。
HER2疫苗引起抗原特异性适应性免疫应答和淋巴细胞(CD3+细胞,肿瘤渗透淋巴细胞)大量移往肿瘤中(图6)。同时,用p62质粒接种不明显增加肿瘤渗透淋巴细胞水平。相反,注射p62质粒,而不是HER2疫苗,增加肿瘤中CD11B+细胞水平(图6)。结果,p62疫苗通过自然免疫性刺激而其作用,与HER2疫苗不一样。
实施例4:T5大鼠乳腺癌模型中p62DNA疫苗的抗肿瘤活性的证明
T5可移植大鼠乳腺癌得自乌克兰肿瘤学和放射生物学国家科学院实验病理学R.E.Kavetsky研究所(R.E.Kavetsky Institute of Experimental Pathology,Oncology andRadiobiology of National Academy of Sciences of Ukraine)Wistar大鼠自发乳腺腺癌。通过皮下注射2,5х106肿瘤细胞/大鼠的0.4mL PBS用T5大鼠乳腺癌对两月龄雌性Wistar大鼠(体重–130-150毫克,每组10只动物)进行攻击。肿瘤移植后的第二天开始,每周一次对大鼠接种三次(图7)。Eac注射含有78μg的pcDNA.3.1(空白质粒载体,阴性对照)或者携带p62的pcDNA.3.1(试验)。
通过用p62免疫抑制肿瘤生长(图8),与载体注射对照大鼠相比,p62-接种大鼠70%肿瘤生长抑制(p<0.004)(图9)。
对肿瘤移植大鼠(8载体-和8p62-免疫)的存活监测超过75天。对照组的50%动物死亡,而p62-接种组没有动物死亡(图10)。
肿瘤的组织学分析显示坏死区(图11)。接受p62DNA疫苗的大鼠的瘤内坏死与接受p62DNA疫苗的小鼠肿瘤中发现的类似(图12)。
因此,在第二动物(大鼠)模型中证明p62DNA疫苗的抗肿瘤作用,表明p62DNA疫苗能被用来治疗乳腺癌。
实施例5:p62DNA疫苗的抗转移效力
路易斯肺癌是俄罗斯联邦制药委员会(Pharmacological Committee of RussianFederation)“俄罗斯FDA”官方接受的模型,用于试验药物的抗转移作用。在用肿瘤移植攻击之前4星期和2星期以及攻击后1,8和15天将100μg质粒肌内注射给每只小鼠。使用每组15只动物。图13显示p62接种对对照相比将肺中转移的数量减少50%。
除非另有定义,这里使用的技术和科学术语和本领域所属领域技术人员通常理解的相同的意义。
这里详细描述的本发明适合在一个或多个要素、一个或多个限制不存在下实施本发明,这里没有具体公开。因此,例如,术语“包含”、“包括”、“含有”等应该广义理解而不是限制。另外,这里所使用的术语和表达是用作描述术语而不是限制,使用这样的术语和表达不是意图排除其所示、描述特征的任何等同物或者其部分,但是要认识到各种修饰在本发明范围内是可能的。
因此,应该明白尽管通过所具体表达的本发明优选实施方案和任选特征、修饰、改进和变化来具体公开本发明,但是本领域技术人员可以采用这里所公开的,并且这样的修饰、改进和变化被认为是在本发明的范围内。这里提供的材料、方法和实施例是优选实施方案的代表,是例示的,不是要限制本发明的范围。
这里广泛性和一般性地描述了本发明。落在一般性公开内的较窄物种和亚属组的每一个也是本发明的部分。这包括本发明的分类描述,从属中限制性或否定限制性去除某些主题,不考虑其中是否具体叙述离体材料。
另外,以马库什通式形式描述本发明的特征或方面时,本领域技术人员认识到本发明也从而以马库什通式中各成员或成员亚组的形式描述。
这里提到的所有公开物、专利申请、专利、和其它参考文献表达上全文引作参考,其引用程度就好像各自引作参考。在有冲突情况下,以本发明说明书,包括定义,为准。
上面公开内容只为了向本领域技术人员传达本发明的理解,而不是为了限制。要明白对公开的实施方案的各种修饰不离开本发明的范围是可能的。因此,本发明的范围只有参照后面的权利要求书而解释。
Claims (38)
1.一种对受试者癌症的一个或几个症状治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率的方法,包括对所述受试者施用一种药物,所述药物包含:
a.p62多肽;或,
b.p62编码核酸。
2.如权利要求1所述的方法,其中所述药物包括
a.一个或多个结构域缺失;
b.其中所述p62编码核酸与SEQ ID NO.1至少95%同一性;或者
c.其中所述p62多肽与SEQ ID NO.2至少98%同一性。
3.如权利要求2所述的方法,其中所述一个或多个结构域缺失选自PB1、ZZ、NLS2、TB、NLS1、NES、LIR、KIR、和UBA所构成的群组。
4.如权利要求1-3任一项所述的方法,其中所述p62多肽或p62编码核酸分别进一步包括融合多肽或编码融合多肽的核酸。
5.如权利要求1-4任一项所述的方法,其中所述p62多肽被翻译后修饰。
6.如权利要求5所述的方法,其中所述p62多肽被翻译后体外修饰。
7.如权利要求1-6任一项所述的方法,其中所述药物通过选自下面所构成的群组的任何途径给药:肠胃外,口服、鼻内、直肠、经皮、叶鞘内、或通过气溶胶吸入。
8.如权利要求7所述的方法,其中所述药物通过选自下面所构成的群组的任何途径给药:血管内、静脉内、动脉内、肌肉内、眼内、皮内和皮下。
9.如权利要求7所述的方法,其中所述药物对器官或对肿瘤施用。
10.如权利要求1-9任一项所述的方法,进一步包括对所述受试者施用佐剂。
11.如权利要求10所述的方法,其中所述佐剂选自凝胶型,微生物,颗粒,油乳状液,表面活性剂为基础的,和合成的佐剂所构成的群组。
12.如权利要求1-11任一项所述的方法,进一步包括施用一种或多种共同刺激成份。
13.如权利要求12所述的方法,其中所述一种或多种共同刺激成份选自细胞表面蛋白质、细胞因子、趋化因子、和信号分子所构成的群组。
14.如权利要求1-13任一项所述的方法,进一步包括施用阻断抑制或负调节免疫机理的一种或多种分子。
15.如权利要求14所述的方法,其中所述阻断抑制或负调节免疫机理的一种或多种分子选自抗-CTLA-4抗体、抗-CD25抗体、抗-CD4抗体、和融合蛋白IL13Ra2-Fc所构成的群组。
16.如权利要求1-15任一项所述的方法,进一步包括对所述受试者施用一种或多种抗癌治疗。
17.如权利要求16所述的方法,其中所述一种或多种抗癌治疗选自化学治疗分子、放射治疗、和抗血管生成分子所构成的群组。
18.如权利要求17所述的方法,其中所述化学治疗分子选自下面所构成的群组:环磷酰胺、阿霉素、紫杉醇、多烯紫杉醇、失碳长春碱、希罗达、和丝裂霉素。
19.如权利要求1-18任一项所述的方法,其中所述癌症选自下面所构成的群组:乳腺癌、肺癌、前列腺癌、胃癌、大肠癌、皮肤癌、头颈癌、支气管癌、胰腺癌、膀胱癌、脑癌、中枢神经系统癌、周围神经系统癌、食道癌、口腔或咽癌、肝癌、肾癌、睾丸癌、胆汁管癌、小肠或阑尾癌、卵巢癌、子宫癌、唾液腺癌、甲状腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、肉瘤和血液组织癌。
20.如权利要求1-19所述的方法,其中所述受试者选自下面所构成的群组:以前治疗过癌症的受试者、有癌症家族史的受试者、和预诊癌症的受试者。
21.如权利要求1-20任一项所述的方法,其中所述药物包含p62编码核酸,其中所述p62编码核酸与SEQ ID NO.1至少95%同一性,并且其中所述p62编码核酸进一步包括质粒或病毒载体。
22.根据如权利要求21所述的方法,进一步包括改进以核酸为基础免疫效力的策略。
23.根据如权利要求22所述的方法,其中所述策略选自下面所构成的群组:自我复制病毒复制子、密码子优化、体内电穿孔、CpG刺激基序的插入、靶向内吞作用或泛蛋白过程途径的序列、Marek's疾病病毒1型VP22序列、已接触抗原-加强法、和使用粘膜送递载体。
24.一种对受试者癌症的一个或几个症状治疗、减轻、改善、缓解、延迟发生、抑制发展、减小严重性和/或减小发生率的药物,包含:
a.p62多肽或p62编码核酸,包括至少一个或多个结构域缺失,或
b.p62多肽的一个或多个结构域或编码p62的一个或多个结构域的核酸。
25.如权利要求24所述的药物,其中所述一个或多个结构域缺失或者结构域分别选自
PB1、ZZ、NLS2、TB、NLS1、NES、LIR、KIR、和UBA所构成的群组。
26.如权利要求24或25所述的药物,其中所述p62多肽或p62编码核酸分别进一步包括融合多肽或编码核酸。
27.如权利要求24-26任一项所述的药物,其中所述p62多肽被翻译后修饰。
28.如权利要求27所述的药物,其中所述p62多肽被翻译后体外修饰。
29.如权利要求24-28任一项所述的药物,进一步含有佐剂。
30.如权利要求29所述的药物,其中所述佐剂选自下面所构成的群组:凝胶型,微生物,颗粒,油乳状液,表面活性剂为基础的,和合成的佐剂。
31.如权利要求24-30任一项所述的药物,进一步包括施用一种或多种共同刺激成份。
32.如权利要求31所述的药物,其中所述一种或多种共同刺激成份选自细胞表面蛋白质,细胞因子,趋化因子和信号分子所构成的群组。
33.如权利要求24-32所述的药物,进一步包括施用阻断抑制或负调节免疫机理的一种或多种分子。
34.如权利要求33所述的药物,其中所述阻断抑制或负调节免疫机理的一种或多种分子选自下面所构成的群组:抗-CTLA-4抗体,抗-CD25抗体,抗-CD4抗体,和融合蛋白IL13Ra2-Fc。
35.如权利要求24-34任一项所述的药物,进一步含有化学治疗分子,或抗血管生成分子。
36.如权利要求35所述的药物,其中所述化学治疗分子选自下面所构成的群组:环磷酰胺,阿霉素,紫杉醇,多烯紫杉醇,失碳长春碱,希罗达,和丝裂霉素。
37.如权利要求24-36任一项所述的药物,其中所述p62编码核酸进一步包括质粒或病毒载体。
38.一种组合物,含有适合对受试者给药的权利要求24-37任一项药物。
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN106061501A (zh) * | 2013-12-29 | 2016-10-26 | Cl昂科莱吉有限公司 | 用于治疗和预防炎症相关疾病的涉及p62/sqstm1的方法和组合物 |
US11098098B2 (en) | 2013-12-29 | 2021-08-24 | Curelab Oncology, Inc. | Methods and compositions relating to p62/SQSTM1 for the treatment and prevention of inflammation-associated diseases |
CN106153922A (zh) * | 2016-09-14 | 2016-11-23 | 深圳大学 | 一种结肠癌预后预测标志物及其检测方法 |
CN106153922B (zh) * | 2016-09-14 | 2018-03-06 | 深圳大学 | 一种结肠癌预后预测标志物及其检测方法 |
CN114106207A (zh) * | 2022-01-24 | 2022-03-01 | 诺未科技(北京)有限公司 | Ccl5的用途 |
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EP2750694A2 (en) | 2014-07-09 |
CL2014000291A1 (es) | 2014-08-08 |
CA2844283C (en) | 2024-06-04 |
AU2012294454A1 (en) | 2014-02-13 |
KR102001582B1 (ko) | 2019-07-18 |
MX2014001418A (es) | 2014-09-15 |
CA2844283A1 (en) | 2013-02-14 |
AU2012294454B2 (en) | 2017-02-02 |
US10716837B2 (en) | 2020-07-21 |
EP2750694B8 (en) | 2018-11-14 |
EP2750694B1 (en) | 2018-09-19 |
EA026228B1 (ru) | 2017-03-31 |
WO2013022991A3 (en) | 2013-04-18 |
KR20140083976A (ko) | 2014-07-04 |
US9717781B2 (en) | 2017-08-01 |
JP2014527053A (ja) | 2014-10-09 |
HK1200086A1 (zh) | 2015-07-31 |
MX353299B (es) | 2018-01-08 |
SG2014008411A (en) | 2014-03-28 |
EA201490423A1 (ru) | 2014-07-30 |
WO2013022991A2 (en) | 2013-02-14 |
EP2750694A4 (en) | 2015-04-15 |
US20170043002A1 (en) | 2017-02-16 |
JP6193231B2 (ja) | 2017-09-06 |
IL230770A0 (en) | 2014-03-31 |
US20140161824A1 (en) | 2014-06-12 |
BR112014002817A2 (pt) | 2021-09-08 |
US20200338176A1 (en) | 2020-10-29 |
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