CN1951398A - 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 - Google Patents
用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 Download PDFInfo
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Abstract
本发明公开了用于引发和提高对HER-2/neu蛋白的免疫反应性的化合物和组合物。这些化合物包括多肽和编码该多肽的核酸分子。这些化合物可被用于预防或治疗与HER-2/neu癌基因相关的恶性肿瘤。
Description
本申请是1996年3月28日的提交的中国专利申请96193629.0,发明名称为“用于预防和治疗恶性肿瘤的HER-2/neu蛋白胞内区”的申请的分案申请。
技术领域
本发明主要针对用于诱导或增强对HER-2/neu蛋白免疫反应的多肽及编码该多肽的核酸分子,包括其在与HER-2/neu癌基因相关的恶性肿瘤治疗中的应用。
发明的背景
尽管在经济和人力资源方面做了大量的投资,癌症仍是一个主要的死亡原因。例如,癌症是35到74岁妇女的主要死亡原因。乳腺癌是妇女最常见的恶性肿瘤并且发病率在继续上升。有1/9的妇女将被诊断患有此病。治疗乳腺癌的标准方法以联合应用外科手术、放疗和化疗为主。这些方法在某些恶性肿瘤的治疗上取得了巨大的成功。然而,这些方法并不能成功地治疗所有的恶性肿瘤,当试图治疗超过某个阶段的乳腺癌时,通常是不能治愈的。用于预防和治疗的其它方法是必需的。
恶性肿瘤的一个共同特点是不受控制的细胞生长。癌细胞经过了由正常细胞向能自主生长的恶性细胞的转化。体细胞基因的扩增和过度表达被认为是导致正常细胞向恶性细胞转化的一个共同的首要事件。在细胞分裂时,由癌基因编码的恶性表型特征被传递给已转化的子代细胞。
正在进行的涉及瘤基因的研究工作已经发现了至少40个在恶性细胞中起作用及引起或与转化相关的癌基因。癌基因基于其推定的功能或其基因产物(如:由癌基因表达的蛋白)的定位而被分成不同的类。
癌基因被认为对正常细胞生理学的某些方面是至关重要的。在这点上,HER-2/neu癌基因是酪氨酸蛋白激酶癌基因家族的一个成员,并与表皮生长因子受体有着高度的同源性。HER-2/neu可能在细胞的生长和/或分化中起作用。HER-2/neu可能通过由增加或下调一种必要的正常基因产物的表达而导致的数量上的机理诱导了恶性肿瘤。
HER-2/neu(p185)是HER-2/neu癌基因的蛋白产物。在包括乳腺癌、卵巢癌、结肠癌、肺癌及前列腺癌在内的许多癌症中HER-2/neu基因被扩增并有HER-2/neu蛋白的过度表达。HER-2/neu与恶性转化相关。在50%-60%的管状原发性肉瘤、20%-40%的乳腺癌及相当部分出现在卵巢、前列腺、结肠及肺的腺癌都发现了HER-2/neu。HER-2/neu不仅与恶性表型紧密相关,而且与肿瘤的浸润也紧密相关,在1/4的浸润性乳腺癌中发现了这一点。在乳腺癌和卵巢癌中,HER-2/neu的过度表达与预后较差相关。HER-2/neu是一个相对分子量为185kd,长度是大约1255个氨基酸(aa)的跨膜蛋白。它含有一个与表皮生长因子(EGFR)有40%同源性的大约645氨基酸的细胞膜外结合区(ECD)、一个高度疏水的穿膜锚定区(TMD)以及一个与EGFR有80%同源性的约有580个氨基酸的羧基端胞质区(CD)。
由于目前在治疗与HER-2/neu相关肿瘤中的困难,因而本领域需要改进的化合物和组合物。本发明满足了这种需要并进一步提供了其它相关的优点。
发明小结
简言之,本发明提供了用于免疫温血动物抗与HER-2/neu相关的恶性肿瘤或用于生产进行免疫的药物的多肽、核酸分子(指导该多肽的表达)以及病毒载体(指导该多肽的表达)。根据本发明的多肽或核酸分子可存在于一种包括药物学上可用的载体或稀释剂的组合物中。可将这样一种多肽、核酸分子、病毒载体或药物组合物用于一次性免疫(如:当疑有恶性肿瘤时)或周期性免疫(如:发生恶性肿瘤或恶性肿瘤复发的危险增加的个体)。用于免疫的药物可能在治疗已存在的肿瘤或防止肿瘤的发生或复发中发挥作用。
在一个实施方案中,本发明提供了一种由一段选自于:(a)序列号1的2026位到3765位核苷酸;和(b)在中度严格的条件下,能同互补于序列号1的2026位到3765位核苷酸的序列杂交的DNA序列的DNA序列编码的多肽,这段DNA序列编码一种能刺激产生对HER-2/neu蛋白免疫反应的多肽。在一优选的实施方案中,一种多肽具有序列号2中从676号赖氨酸到1255号缬氨酸的氨基酸序列或其产生至少一种等价的免疫反应的变体。所提供的组合物包括本发明的一种多肽并联合一种药学上可用的载体或稀释剂。
在另一实施方案中,本发明的多肽或组合物被用于免疫一种温血动物以对抗与HER-2/neu癌基因相关的恶性肿瘤。在另一实施方案中,这种多肽或组成物被用于生产一种用来免疫温血动物以对抗与HER-2/neu癌基因相关恶性肿瘤的药物。
在另一实施方案中,一种指导本发明的多肽表达的核酸分子被用于通过用核酸分子转染温血动物的细胞进行免疫。在另一实施方案中,这种核酸分子被用于生产一种用来免疫温血动物以对抗与HER-2/neu癌基因相关恶性肿瘤的药物。
在另一实施方案中,一种指导本发明的多肽表达的病毒载体被用于通过用载体感染温血动物的细胞进行免疫。在另一实施方案中,这种病毒载体被用于生产一种用来免疫温血动物以对抗与HER-2/neu癌基因相关恶性肿瘤的药物。
参考下面的详细描述和附图,本发明的这些和其它方面将变得清楚。
图的简要描述
图1显示幼稚T细胞通过树突状细胞由HER-2/neu多肽的致敏结果。骨髓来源的DC是由CD34+干细胞通过GM-CSF和IL-6刺激产生。由HER-2/neu刺激的DC在和T细胞培养7天后诱导自体CD4+/CD45RA+T淋巴细胞的蛋白质特异性增殖。将在含有GM-CSF和IL-6的无血清培养基中培养一周的骨髓来源的CD34+干细胞用作APC。将APC以各种浓度接种于圆底96孔板中(Corning,Corning,NY,USA)并和20-25ug/ml重组HER-2/neu多肽孵育16-18小时。利于免疫亲和柱(CellPro,Inc.,Bothell,WA,USA)通过阳性筛选从自体外周血单核细胞中分离CD4+T淋巴细胞。对抗原刺激的APC进行照射(10Gy),并以每孔105加入CD4+T淋巴细胞。通过对在第7天加入(3H)胸苷(1μCi/孔)的16-18小时的摄取量来评价T细胞的增殖反应。在无血清和无细胞因子的培养基中5孔平行进行增殖检测。符号代表:-●-DC+HER-2/neu多肽+CD4+/CD45RA+T细胞;-○-DC+CD4+/CD45RA+T细胞;及-□-DC+HER-2/neu多肽。
图2显示CD4+细胞对HER-2/neu多肽的反应。利用对图1所描述的引发检测来测试正常供者的CD4+T细胞对重组人HER-2/neu多肽的反应。符号代表:-■-SC+CD4及…◆…SC+CD4+HER-2/neu多肽。“SC”为干细胞。
图3显示用大鼠HER-2/neu多肽免疫的大鼠产生大鼠neu特异性抗体。用25ug在MPL或vacell佐剂中的重组大鼠HER-2/neu多肽免疫大鼠。每隔20天进行一次,共给予三次免疫。最后一次免疫后20天评价大鼠对大鼠neu的抗体反应。用大鼠HER-2/neu多肽和vaccel佐剂免疫的动物显示高滴度大鼠neu特异反性。以用人HER-2/neu多肽(外源蛋白)免疫的动物作为对照。在独立的试验中,用100ug和300ug纯化的全长大鼠neu免疫的大鼠未产生可检测到的neu特异性抗体(数据未示)。数据代表3个动物的均值和标准差。符号代表:-■-大鼠HER-2/neu多肽/MPL;…●…大鼠HER-2/neu多肽/vacell;…□…单独MPL;…○…单独vacell;及…
…对照。“MPL”和“vaccel”为佐剂(Ribi,Bozcman,MT,USA)。“Neu”为HER-2/neu蛋白。
图4显示乳腺癌患者对HER-2/neu多肽有预存在的免疫性。通过氘化胸苷的掺入在平行的24孔中评价患者PBMC。反应孔计高于对照孔的均值和3倍标准差(372cpm)。这种HER-2/neu阳性II期乳腺癌患者对重组人HER-2/neu多肽有显著的反应。符号“p”代表HER-2/neu蛋白的肽,“tt”代表破伤风毒素,而“hHNP”代表重组人HER-2/neu多肽。
本发明的详细描述
在阐明本发明前,阐明此后所用的某些术语的定义可能对其理解有帮助。
HER-2/neu多肽-此中所用的该术语指具有序列号2中从676位赖氨酸到1255位缬氨酸的氨基酸序列的HER-2/neu蛋白(此蛋白也被称为p185或c-erbB2)的一部分,并且可天然获得、合成产生、基因工程生产,或如一个或多个氨基酸被其它氨基酸或非氨基酸取代而并不严重影响对HER-2/neu蛋白免疫反应的引发或增强的功能等价变体(例如,变体通过辅助T细胞或细胞毒性T细胞刺激一种反应)。
T细胞的增殖-此中所用的该术语包括T细胞的扩增和导致扩增的对T细胞刺激,即引起有丝分裂的启始事件和有丝分裂本身。下面对检测T细胞增殖的方法进行讨论。
如上面提到的,本发明针对用于引发或增强对HER-2/neu癌基因表达蛋白产物、包括对温血动物中与扩增的HER-2/neu基因相关的恶性肿瘤的免疫性的化合物和组合物。扩增的HER-2/neu基因与恶性肿瘤的联系并不需要基因的蛋白表达产物存在于肿瘤上。例如,蛋白表达产物的过度表达可能涉及一种肿瘤的发生,但随后蛋白的表达可能消失。本发明的一个用途是引发或增强局部的免疫反应来将HER-2/neu阳性的肿瘤转变为HER-2/neu阴性。
更具体地,本发明的公开一方面表明基于HER-2/neu基因蛋白表达产物的一特定部分的多肽(HER-2/neu多肽)可被胸腺依赖淋巴细胞(此后为“T细胞”)识别,因而局部的免疫T细胞反应可被预防性利用或用来治疗这种蛋白正被或已经被过度表达的恶性肿瘤。另一方面,本发明的公开也表明指导这种肽表达的核酸分子可被单独或在一病毒载体中用以进行免疫。
大体上认为CD4+T细胞群在被一特定抗原刺激时通过释放淋巴因子而发挥辅助细胞/诱导细胞的功能;然而,CD4+细胞的一个亚群可作为细胞毒性T细胞(CTL)。类似地,认为CD8+T细胞通过直接裂解抗原性靶子发挥作用;然而,在多种情况下它们可以分泌淋巴因子来提供辅助细胞或DTH功能。尽管有潜在重叠的功能,CD4和CD8的表型标志与识别结合于I类或II类MHC抗原的肽有关。在II类或I类MHC情况下递呈对抗原的识别使得CD4+和CD8+T细胞对不同抗原或在不同情况下递呈的相同抗原发生反应。免疫原性肽与II类MHC抗原的结合最常发生于被抗原提呈细胞摄取的抗原。因此,CD4+T细胞通常识别在肿瘤细胞外的抗原。相反,在正常情况下,肽对I类MHC的结合只发生于存在于胞浆中的和由靶细胞自己合成的蛋白,而不包括在外环境中的蛋白。对此的一个例外是外源肽与以高浓度存在于细胞外的一种精确的I类结合区的结合。因此,CD4+和CD8+T细胞具有广泛不同的功能并趋于识别不同的抗原作为一种对抗原的正常停留位点的反映。
如在本发明中公开的,由HER-2/neu癌基因表达的蛋白产物的一个多肽部分被T细胞识别。循环HER-2/neu多肽降解为肽片段。来自多肽的肽片段结合于主要组织相容性复合体(MHC)抗原。通过展示在细胞表面结合于MHC抗原的肽和宿主T细胞对肽与自身MHC抗原的结合体的识别,HER-2/neu多肽(包括表达于恶性细胞表面的)对T细胞具有免疫原性。T细胞受体的精确特异性使得单个T细胞能够区别仅有一个氨基酸残基不同的肽。
在对来自多肽的一个肽片段的免疫反应过程中,表达一种以高亲和力结合于肽-MHC复合体的T细胞受体的T细胞结合于肽-MHC复合体,由此被活化并被诱导增殖。在与肽的首次相遇中,少量的免疫T细胞将分泌淋巴因子、增殖并分化成为效应细胞和记忆T细胞。初次免疫反应发生在体内但难以在体外检测。由记忆T细胞随后再次遇到同一抗原将导致一种更快更强烈的免疫反应。再次应答将发生在体内或体外。体外应答通过衡量增殖的程度、细胞因子产生的程度或再次暴露于抗原的T细胞群的裂解细胞活性的产生而易于计量。T细胞群对一特异抗原反应而大量增殖被认为指示着对抗原的首次暴露或致敏。
本发明的化合物大体上包括HER-2/neu多肽或指导这种肽表达的DNA分子,其中DNA分子可存在于一病毒载体之中。如上面提到的,本发明的多肽包括序列号2中从676位氨基酸到1255位氨基酸的多肽的变体,它们保持有刺激免疫反应的能力。这些变体包括原始多肽的各种结构形式。由于存在可离子化的氨基和羧基基团,例如,一种HER-2/neu多肽可能是以一种酸性或碱生盐的形式或者可能以中性的形式存在。单个氨基酸残基也可被氧化或还原修饰。
在本发明范围中的变体还包括原始的HER-2/neu多肽的一级氨基酸结构通过与其它肽、多肽或者如糖基、脂质、磷酸、乙酰基等化学成分形成共价的或凝集的偶联物而被修饰的多肽。可通过例如在氨基酸侧链或者在N-末端或C-末端上连接特定功能的基团来制备共价衍生物。
本发明还包括糖基化和未糖基化的HER-2/neu多肽。根据表达系统,在酵母或哺乳动物表达系统中表达的多肽在分子量和糖基化模式上可能与原始的分子类似或稍有不同。例如,在细菌如大肠杆菌中编码多肽的DNA的表达典型地产生非糖基化的分子。真核蛋白的N-糖基化位点以氨基酸三联体Asn-A1-Z为特征,其中A1为除Pro外的任何氨基酸,而Z为Ser或Thr。可通过本领域普通技术人员所了解的技术如寡核苷酸合成和连接或位点特异性突变技术制备具有失活的N-糖基化位点的HER-2/neu多肽的变体,它们也属于本发明的范围。另外,N-连接糖基化位点可被加到HER-2/neu多肽中。
本发明的多肽还包括序列号2多肽的变体(即具有序列号2中676号氨基酸到1255号氨基酸的氨基酸序列的多肽的变体),它具有因一个或多个缺失、插入、置换或其它修饰而具有与该序列不同的氨基酸序列。在一个实施方案中,这种变体与天然HER-2/neu多肽具有高度的同源性并保持刺激免疫反应的能力。这里所用的“高度的同源性”指可由在中度严格的条件下能够与同此中编码序列号2的特定多肽部分的天然DNA序列(即序列号1中的2026到3765位核苷酸)互补的核苷酸序列杂交的DNA序列编码的氨基酸序列。合适的中度严格的条件包括在5×SSC、0.5%SDS、1.0mM EDTA(pH8.0)组成的溶液中预冲洗;在50℃-65℃、5×SSC条件下杂交过夜;随后分别用2×、0.5×和0.2×SSC(含有0.1%SDS)在65℃冲洗两次每次20分钟。这种杂交的DNA序列也属于本发明的范围。任何这种修饰对HER-2/neu多肽引起免疫反应的能力的影响可很容易地测定(例如,用如此中所描述的方法通过分析突变的HER-2/neu多肽诱导T细胞反应的能力)。
一般,可通过多种方法达到氨基酸置换以提供本发明的其它变体。例如,首先,可保守地进行氨基酸置换;即一个置换氨基酸取代具有相似性质的氨基酸以便肽化学领域的技术人员能够预期多肽的二级结构和亲水性不被严重地改变。大体上,下组的氨基酸代表保守改变:(1)ala、pro、gly、glu、asp、gln、asn、ser、thr;(2)cys、ser、tyr、thr;(3)val、ile、leu、met、ala、phe;(4)lys、arg、his;和(5)phe、tyr、trp、his。一个非保守改变的例子是将一组中的一个氨基酸用另一组中的氨基酸取代。
制备氨基酸置换以产生本发明的变体的另一方法是在有潜能结合II类MHC分子(对于CD4+T细胞反应)或I类MHC分子(对于CD8+T细胞反应)的T细胞基元中鉴定和取代氨基酸。可通过计算机分析来鉴定带有理论上有潜能结合于II类MHC分子基元的肽片段(HER-2/neu肽的)。例如,可用一种包括几种设计用来区别T细胞识别的潜在位点的计算机参数蛋白质序列分析软件包,T Sites(Feller和de la Cruz,《自然》(Nature)349:720-721,1991)。利用两个搜索参数:(1)由Margalit等描述的AMPHI参数(Feller和de la Cruz,《自然》349:720-721;Margalit等《免疫学杂志》(J.Immunol.)138:2213-2229,1987)根据α-螺旋周期性和双亲性鉴别表位基元;(2)Rothbard和Taylor参数根据电荷和极性模型鉴别表位基元(Rothbard和Taylor,《欧洲分子生物学组织杂志》(EMBO)7:93-100,1988)。具有两种基元的片段最适于结合II类MHC分子。CD8+T细胞识别结合于I类MHC分子的肽。Falk等已经证明结合于特异的MHC分子的肽具有可辨的序列基元(Falk等,《自然》351:290-296,1991)。通过Edman降解从一种培养细胞系的HLA-A2.1分子剥离的肽已经确定了用于在HLA-A2.1的沟中结合的一种肽基元(表2,摘自Falk等,supra)。该方法将典型的或普通的HLA-A2.1结合肽鉴定为带有在位点2(L)和9(V)上的主要锚定残基的9个氨基酸。通常的强结合残基被鉴定在位点2(M)、4(E、K)、6(V)和8(K)。所鉴定的基元代表许多结合肽的平均。
HLA-A2.1限制性基元
氨基酸位点1 2 3 4 5 6 7 8 9 | 点排布 | |
主要结合锚定残基 | L V | +3 |
强结合残基 | M E V KK | +2 |
弱结合残基 | I A G I I A E LL Y P K L Y SF F D Y T HK P T NM M G | +1 |
续表
Y S VH |
按这里定义的所衍生的肽基元并不特别严格。一些HLA-A2.1结合肽不合有这两种主要锚定残基而且在主要锚定残基两侧的氨基酸在允许或不允许结合方面发挥主导作用。并非每个带有这里所描述的结合基元的肽都会结合,而一些没有这种基元的肽也会结合。值得注意的是,这里的HLA-A2.1基元在位于2号和9号残基上的主要锚定氨基酸之间置有6个氨基酸。
在HER-2/neu多肽中的肽基元鉴定后,可制备保守的或非保守的氨基酸置换。后一类型的置换意在产生一种改进的更有效和/或可更广泛交叉反应(MHC多态性)的多肽。更有效多肽的一个例子是一种象天然多肽一样以更高的亲和力结合于相同的MHC分子,而不影响T细胞对天然多肽的特异性识别的多肽。可更广泛交叉反应的多肽的一个例子是一种比天然多肽诱导更广泛交叉反应免疫应答(即结合更大范围的MHC分子)的多肽。类似地,定位在肽基元之间和具有间隔区功能(即不与一种MHC分子或T细胞受体相互作用)的一个或多个氨基酸可被保守地或非保守地置换。对本领域普通技术人员来说显然可通过多种检测包括此中所描述的用于检测刺激T细胞识别的能力的那些方法来对含有一个或多个氨基酸置换的多肽测试其有利或不利的免疫学相互作用。
在本发明范围内的变体也可以含有或者替代地含有对多肽预期的免疫学特性具有最小影响的其它修饰,包括氨基酸的缺失或加入。那些本领域普通技术人员会认识到可使用HER-2/neu多肽的截短形式或非天然伸展形式,只要其预期的免疫学特性至少粗略地与全长的天然HER-2/neu多肽相当。半胱氨酸可被删除或用其它氨基酸取代以阻止在复性时不正确分子内二硫桥连的形成。引起突变的其它方法包括对邻近的二元氨基酸残基的修饰以提高在有KEX2蛋白酶活性存在的酵母系统中的表达。
一般可利用一个编码HER-2/neu蛋白的基因组或cDNA克隆来获得HER-2/neu多肽。在序列号1中列出编码全长HER-2/neu的基因组序列,并且在序列号2中列出推导的氨基酸序列。这些克隆可通过筛选一合适的表达文库以寻找表达HER-2/neu蛋白的克隆而被分离出来。文库的制备和筛选大体上可利用被本领域的普通技术人员了解的方法进行,如在Sambrook等《分子克隆:实验室指南》(Molecular Cloning:A Laboratory Manual),冷泉港实验室,冷泉港,N.Y.,1989中所描述的方法,这里并入本文作为参考。简言之,可将一噬菌体表达文库铺板并转移至滤膜上。然后用一种检测剂孵育滤膜。在本发明的情况中,“检测剂”是任何能够结合于HER-2/neu蛋白的化合物,然后可以通过那些本领域普通技术人员所了解的许多方法中的任何方法将其检测出来。典型的检测剂含有一种偶联有一个报道基团的“结合剂”,如蛋白A、蛋白G、IgG或一种凝集素。优选的报道基团包括酶、底物、辅助因子、抑制剂、染料、放射性核素、发光基团、荧光基团和生物素。报道基团更优选为可通过与如四甲基联苯胺或2,2′-连氮-双-3-乙基苯并噻唑啉磺酸的一种底物孵育而进行检测的辣根过氧化物酶。利用那些本领域的普通技术人员所了解的技术将含有表达HER-2/neu蛋白的基因组或cDNA序列的菌斑分离和纯化。例如,在Sambrook等《分子克隆:实验室指南》(Molecular Cloning:A Laboratory Manual),冷泉港实验室,冷泉港,N.Y.,1989中可以找到合适的方法。
大体上可通过在上面所描述的一个或多个方面对序列进行修饰并对所得多肽检测刺激免疫反应如T细胞反应的能力来鉴定保持有刺激免疫反应能力的多肽的变体。例如,大体上可通过用修饰的多肽接触T细胞并检测其反应来进行这些检测。例如也可通过筛选带有一编码多肽或其变体的DNA序列的cDNA或基因组文库分离多肽的天然变体。
可用标准的重组技术或通过被修饰多肽的自动合成引入上面所描述的序列修饰。例如,可通过合成带有一突变序列的由能够连接到天然序列片段上的限制性位点作为侧翼序列的寡核苷酸在特异的位点引入突变。在连接后,所得的重建序列编码一种带有预期的氨基酸插入、置换或缺失的类似物。
另外,定向寡核苷酸位点特异性突变方法可被用于提供一根据所要求的置换、缺失或插入而改变特定密码子的基因。上面提出的进行改变的典型方法由Walder等,《基因》(Gene)42:133,1986;Bauer等,《基因》37:73,1985;Craik,《生物技术》(BioTechniques)1985年一月,12-19;Smith等,《遗传工程:原理和方法》(GeneticEngineering:Principles and Methods),Plenum出版社,1981;和U.S.专利4,518,584和4,737,462号公开。
当然,在构建的用于这种HER-2/neu多肽表达的核苷酸序列中的突变必须保留编码序列的阅读框,并且优选不产生能够杂交以形成二级mRNA结构的互补区,如环或发夹,这些可能不利地影响mRNA的翻译。虽然可以预先确定一个突变位点,但不必预先确定突变本身的性质。例如,为了寻找在一给定位点的突变体的最佳特点,可在靶密码子上进行随机突变并对所表达的HER-2/neu多肽突变体筛选预期的活性。
并非在编码HER-2/neu多肽的核苷酸序列中的所有突变在终产物中都将被表达。例如,可制备核苷酸置换来提高表达,首要地在被转录的mRNA中来避免二级结构环(例如见欧洲专利申请75,444A),或来提供更易被所选宿主翻译的密码子,如已知大肠杆菌优先密码子用于大肠杆菌表达。
本发明的多肽不论天然的和修饰的都优选通过重组DNA方法制备。这些方法包括在一重组表达载体中插入一个编码HER-2/neu多肽的DNA序列,和在一种重组微生物、哺乳动物或昆虫细胞表达系统中在促进表达的条件下表达该DNA序列。编码本发明所提供多肽的DNA序列可由cDNA片段和短的寡核苷酸接头或由一系列寡核苷酸组装以提供一个能够被插入一个重组表达载体并在一个重组的转录单位中表达的合成基因。
重组表达载体含有一个被可操作地连接到源自哺乳动物、微生物、病毒或昆虫基因的适宜转录或翻译调节元件上的编码HER-2/neu多肽的DNA序列。这种调节元件包括一个转录启动子、一个可有可无的的控制转录的操纵子序列、一个编码适宜的mRNA核糖体结合位点的序列以及控制转录和翻译终止的序列。另外应加入一个复制起点和一个便于识别转化体的可筛选标志。
当DNA区彼此功能上相关时它们被可操作地连接。例如,如果一种信号肽(分泌性前导序列)的DNA被表达为一种参与多肽分泌的前体,则将其可操作地连于一种多肽的DNA;如果一个启动子控制序列的转录,则将其可操作地连于一编码序列;或如果一个核糖体结合位点被定位以便允许翻译,则将其可操作地连于一编码序列。大体上,可操作地连接意味着毗邻和在分泌性前导序列情况下意味着在阅读框中。编码要在一微生物中表达的HER-2/neu多肽的DNA序列将优选不含有能够提前终止DNA转录为mRNA的内含子。
用于细菌的表达载体可含有一个可筛选标志和由含有所熟知的克隆载体pBR322(ATCC 37017)的遗传学元件的商品化质粒衍生来的细菌复制起点。例如,这些商业的载体包括pKK223-3(Pharmacia FineChemicals,Uppsala,Sweden)和pGEM1(Promega Biotec,Madison,WI,USA)。将这些pBR322“骨架”部分与一种合适的启动子和所要表达的结构序列连接起来。利用pBR322(一种源自大肠杆菌的质粒(Bolivar等,《基因》2:95,1977))的衍生物典型地转化大肠杆菌。pBR322含有氨苄青霉素和四环素抗性的基因,因此提供了用于鉴别被转化细胞的简便工具。
在重组微生物表达载体中通常所用的启动子包括β-内酰胺酶(青霉素酶)和乳糖启动子系统(Chang等,《自然》275:615,1978;和Goeddel等,《自然》281:544,1979)、色氨酸(trp)启动子系统(Goeddel等,《核酸研究》(Nucl.Acids Res.)8:4057,1980;和欧洲专利申请36,776)和tac启动子(Maniatis,《分子克隆:实验室指南》(Molecular Cloning:A Laboratory Manual),冷泉港实验室,冷泉港,412页,1982)。一种特别有用的细菌表达系统利用噬菌体λPL启动子和cI857ts热不稳定阻遏物。从美国典型培养物保藏中心(ATCC)获得的连有λPL启动子衍生物的质粒载体包括存在于大肠杆菌JMB9(ATCC 37092)中的质粒pHUB2和存在于大肠杆菌RR1(ATCC 53082)中的质粒pPLc28。
在酵母载体中合适的启动子序列包括金属硫蛋白的、3-磷酸甘油酸激酶的(Hitzeman等,《生物和化学杂志》(J.Biol.Chem.)255:2073,1980)或其它糖酵解的酶(Hess等,《高级酶注册杂志》(J.Adv.Enzyme Reg.)7:149,1968;和Holland等,《生物化学》(Biochem)17:4900,1978)如烯醇化酶、甘油醛-3-磷酸脱氢酶、己糖激酶、丙酮酸脱羧酶、果糖磷酸激酶、葡萄糖-6-磷酸异构酶、3-磷酸甘油酸变位酶、丙酮酸激酶、丙糖磷酸异构酶、磷酸葡糖异构酶和葡糖激酶的启动子。用在酵母表达中的适宜的载体和启动子在R.Hitzeman等的欧洲专利申请73,657中有进一步描述。
可以利用来自pBR322的用于在大肠杆菌中筛选和复制的DNA序列(Ampr基因和复制起点)和包括一个葡萄糖可抑制ADH2启动子和α-因子分泌前导序列的酵母DNA序列来组装优选的酵母载体。ADH2启动子已经由Russell等(《生物学和化学杂志》258:2674,1982)和Beier等(《自然》300:724,1982)描述。可将指导异源性蛋白分泌的酵母α-因子前导序列插到启动子和所要表达的结构基因之间(例如见Kurjan等,《细胞》(Cell)30:933,1982;和Bitter等,《美国国家科学院进展》(Proc.Natl.Acad.Sci.USA)81:5330,1984)。前导序列可被修饰使之在靠近其3′末端处含有一个或多个有用的限制性酶切位点以利于前导序列与外源基因的融合。用于转化脊椎动物细胞的表达载体中的转录和翻译控制序列可由病毒来源的提供。例如,常用的启动子和增强子源自多瘤病毒、腺病毒2、猴病毒40(SV40)和人巨细胞病毒。源自SV40病毒基因组的DNA序列,如SV40起点、早期和晚期启动子、增强子、剪接和聚腺苷酸化位点可被用于提供表达一种外源DNA序列所需的其它遗传学元件。早期和晚期启动子因为都易于以一个还含有SV40病毒复制起点的片段从病毒获得而特别有用(Fiers等,《自然》273:113,1978)。只要包括从Hind III位点向位于病毒复制起点的Bgl II位点延伸的大约250bp的序列,则较小或较大的SV40片段也可使用。此外,只要这些控制序列与所选的宿主细胞相容,则可利用病毒基因组的启动子、控制和/或信号序列。可按照Okayama和Berg,《分子细胞生物学》(Mol.Cell.Biol.)3:280,1983所公布的构建典型的载体。
可基本按照Cosman等所描述的(《分子免疫学》(Mol.mmunol.)23:935,1986)构建一种用于在C127小鼠乳腺上皮细胞中哺乳动物受体cDNA稳定高水平表达的有效系统。用于表达LbeIF4A蛋白DNA的一种优选的真核载体为pDC406(McMahan等,《欧洲分子生物学组织杂志》(EMBOJ.)10:2821,1991),而且包括源自SV40、人免疫缺陷病毒(HIV)和Epstein-Barr病毒(EBV)的调节序列。其它优选的载体包括pDC409和pDC410,它们都源自pDC406。pDC410是通过用编码SV40大T抗原的序列置换EBV复制起点而从pDC406衍生来。pDC409与pDC406的不同之处在于缺失了一个位于多克隆位点外的Bgl II限制性酶切位点,使得在多克隆位点内的Bgl II位点成为单一位点。
一种允许含有EBV复制起点的表达载体,如pDC406和pDC409,游离型复制的有用的细胞系为CV-1/EBNA(ATCC CRL 10478)。CV-1/EBNA细胞系是通过用一编码Epstein-Barr病毒核抗原-I(EBNA-1)的基因转染CV-1细胞系而获得,并且组成性地表达由人CMV立即早期增强子/启动子驱动的EBNA-1
转化的宿主细胞是已经用通过重组DNA技术构建的含有编码一种本发明的HER-2/neu多肽的表达载体转化或转染的细胞。转化的宿主细胞可以表达预期的HER-2/neu多肽,但为了克隆或扩增HER-2/neu DNA的目的而转化的宿主细胞不需要表达HER-2/neu多肽。根据所选的DNA,表达的多肽优选被分泌到培养上清中,而且也可沉积在细胞膜上。
用于表达重组蛋白的合适的宿主细胞包括在适宜启动子控制下的原核细胞、酵母或高等真核细胞。原核细胞包括革兰氏阴性或革兰氏阳性生物体,例如大肠杆菌或芽胞杆菌。高等真核细胞包括按照下面的描述建立的昆虫或哺乳动物起源的细胞系。利用由DNA结构得来的RNA也可用无细胞翻译系统来制备HER-2/neu多肽。例如,用于细菌、真菌、酵母和哺乳动物细胞宿主的适宜的克隆和表达载体由Pouwels等,《克隆载体:实验室指南》(Cloning Vectors:A Laboratory Manual),Elsevier,NewYork,1985描述。
原核表达宿主可被用于不需要广泛蛋白酶解和二硫键加工的HER-2/neu多肽的表达。原核表达载体一般包括一个或多个可筛选的表型标志例如编码传递抗生素抗性或提供自养需要的蛋白的基因和一个被宿主识别以保证在宿主内扩增的复制起点。虽然也可用其它宿主,但用于转化的合适的原核宿主包括大肠杆菌、枯草芽胞杆菌、鼠伤寒沙门氏菌以及假单胞杆菌属、链霉菌属和葡萄球菌属的各种菌。
重组的HER-2/neu多肽也可在酵母宿主中表达,优选来自酵母菌属如酿酒酵母。还可以用其它属的酵母如毕赤酵母或克罗维氏酵母属。酵母载体一般含有一个来自2μ酵母质粒的复制起点或一个自主复制序列(ARS)、一个启动子、编码HER-2/neu多肽的DNA、用于聚腺苷酸化和转录终止的序列以及一筛选基因。酵母载体优选包括一个复制起点和允许转化酵母和大肠杆菌的可筛选标志,例如大肠杆菌的氨苄青霉素抗性基因和为在色氨酸中不能生长的酵母突变菌株提供了一个筛选标志的酿酒酵母的trp1基因,以及源自一高度表达酵母基因来诱导下游的结构基因转录的启动子。在酵母宿主细胞基因组中trp1缺损的存在为在缺少色氨酸时通过生长检测转化提供了有效的环境。
本领域的技术人员了解合适的酵母转化方法。由Hind等(《美国国家科学院进展》75:1929,1978)描述的一个典型的技术涉及在一由0.67%酵母氮碱、0.5%酪蛋白氨基酸、2%葡萄糖、10mg/ml腺嘌呤和20mg/ml尿嘧啶组成的选择性培养基中筛选Trp+转化体。由含有ADH2启动子的载体转化的宿主菌株可以在一由1%酵母提取物、2%胨和1%葡萄糖组成的补加80mg/ml腺嘌呤和80mg/ml尿嘧啶的丰富培养基中生长进行表达。在培养基中的葡萄糖耗尽时,ADH2启动子受到抑制。通过过滤收获粗制酵母上清并在进一步纯化前保持在4℃。
也可以利用各种哺乳动物或昆虫细胞(如草地夜蛾或粉纹夜蛾)培养系统来表达重组多肽。例如用于在昆虫细胞中制备外源性多肽的杆状病毒系统由Luckow和Summers,《生物技术》(Bio/Technology)6:47,1988综述。合适的哺乳动物宿主细胞系的例子包括由Gluzman(《细胞》(Ce11)23:175,1981)描述的猴肾细胞COS-7细胞系和能够表达一种适宜载体的包括如CV-1/EBNA(ATCC CRL 10478)、L细胞、C127、3T3、中国仓鼠卵巢细胞(CHO)、COS、NS-1、HeLa和BHK细胞系的其它细胞系。哺乳动物表达载体可含有非转录元件如一个复制起点、一个连接到要表达基因上的合适的启动子和增强子、和其它5′或3′侧翼非转录序列以及5′或3′非翻译序列,如必要的核糖体结合位点、聚腺苷酸化位点、剪接供者和受者位点以及转录终止序列。
可通过培养合适的宿主/载体系统以表达本发明的DNA的重组翻译产物,然后从培养基或细胞提取物中将之纯化来制备纯化的HER-2/neu多肽。例如,取自将重组的多肽分泌入培养基中的系统的上清首先可以用一种商品化的蛋白质浓缩滤膜如一种Amicon或Millipore Pellicon超滤单位来浓缩。在浓缩步骤后,浓缩物可被注入一种合适的纯化基质。例如,一种合适的亲和基质可能含有一个对应的结构蛋白(即基于结构,HER-2/neu多肽以一种特异性的相互作用与之结合的蛋白质)或凝集素或结合于一合适载体的抗体分子。另外,可利用一种阴离子交换树脂,例如具有侧基二乙氨乙基(DEAE)基团的基质。基质可以为丙烯酰胺、琼脂糖、葡聚糖、纤维素或在蛋白质纯化中常用的其它类型。另外,可以利用一个阳离子交换步骤。合适的阳离子交换剂包括各种含有磺丙基或羧甲基基团的不可溶基质。优选磺丙基基团。凝胶过滤层析也提供了一种纯化HER-2/neu的方法。
亲和层析是一种优选的纯化HHER-2/neu多肽的方法。例如,通过利用本领域所熟知的方法,抗HER-2/neu多肽的单克隆抗体在亲和层析纯化中可能也有用。
最后,利用疏水RP-HPLC介质(如,具有侧基甲基或其它脂肪族基团的硅胶)的一次或多次反相高效液相色谱(RP-HPLC)步骤可被用来进一步纯化HER-2/neu多肽。一些或所有的前述纯化步骤以各种组合也可被用来提供一均质的重组多肽。
在细菌培养中产生的重组HER-2/neu多肽优选从细胞沉淀中通过初次提取来分离,随后进行一个或多个浓缩、脱盐、水性离子交换或大小排阻层析步骤。高效液相色谱(HPLC)可以用于最后纯化步骤。可以通过任何方便的方法,包括冻溶循环、超声处理、机械破坏或用细胞裂解剂来破坏在重组LbeIF4A蛋白表达中所用的微生物细胞。
以分泌蛋白形式表达HER-2/neu多肽的酵母的发酵大大地简化了纯化。由大规模发酵所获的分泌的重组蛋白可通过与Urdal等(《层析杂志》(J.Chromatog.)296:171,1984)公布的那些方法类似的方法来纯化。这个参考文献描述了在一制备性HPLC柱上进行重组人GM-CSF纯化的两个顺序的反相HPLC步骤。
在重组培养中合成的HER-2/neu多肽制备物可能含有依所采取的用来从培养中回收HER-2/neu的纯化步骤所定的数量和特点的非HER-2/neu的细胞成分,包括蛋白质。这些成分通常是酵母、原核细胞或非人真核细胞来源的。这些制备典型地不含有在HER-2/neu蛋白来源的物种中天然发现它时可能与它正常相连的其它蛋白质。
自动合成为制备本发明的多肽提供了另一种方法。例如,可以利用任何商品化的固相技术如Merrifield固相合成方法,其中氨基酸被顺序地加至一延伸的氨基酸链(见Merrifield,《美国化学会杂志》(J.Am.Chem.Soc.)85:2149-2146,1963)。用于多肽自动合成的设备由供应商如Applied Biosystem,Inc.of Foster City,CA商业性提供,并且大体上可按制造商的指令来操作。
在本发明的一个方面中,可以检测到用一种HER-2/neu多肽(或指导该多肽表达的DNA分子)来产生对HER-2/neu蛋白(包括表达在与HER-2/neu癌基因相关的恶性肿瘤表面的HER-2/neu蛋白)的免疫反应。这些恶性肿瘤的代表性例子包括乳腺癌、卵巢癌、直肠癌、肺癌和前列腺癌。一旦通过HER-2/neu多肽产生了一种对HER-2/neu蛋白的免疫反应,这种免疫反应变能够长期存在,并且在免疫后的很长时间仍能检测到,而不论在检测时体内是否存在或缺乏该蛋白。一种经与HER-2/neu多肽反应而产生的对HER-2/neu蛋白的免疫反应可以通过测试CD4+或CD8+T细胞的特异性活化的存在或不存在或增强来检测。更特别的是,将利用常规技术(如通过外周血淋巴细胞的Ficoll/Hypaque密度梯度离心)从一被免疫的个体分离的T细胞与HER-2/neu蛋白孵育。例如,可在体外37℃用HER-2/neu蛋白(典型地是5ug/ml的全蛋白或分级数量的合成HER-2/neu蛋白的细胞)孵育T细胞2-9天(典型地4天)。最好在缺少HER-2/neu蛋白的情况下孵育另一份T细胞样品作为对照。
可以多种方式检测CD4+或CD8+T细胞的特异性活化。用于检测特异性T细胞活化的方法包括T细胞增殖检测、细胞因子(例如淋巴因子)的产生或溶细胞活性的产生(即特异性针对HER-2/neu蛋白的细胞毒性T细胞的产生)。对于CD4+T细胞,用于检测特异性T细胞活化的一种优选的方法是检测T细胞的增殖。对于CD8+T细胞,用于检测特异性T细胞活化的一种优选的方法是检测溶细胞活性的产生。
T细胞增殖的检测可以通过许多已知的技术来完成。例如,可以通过测定DNA合成率检测T细胞的增殖。已被刺激增殖的细胞表现出增加的DNA合成率。例如测定DNA合成率的一个典型的方法是通过用氚化胸苷(一种掺入新合成DNA的核苷酸前体)脉冲标记培养T细胞。掺入的氚化胸苷的量可用一个液体闪烁分光光度计测定。检测T细胞增殖的其它方法包括测定白细胞介素-2(IL-2)产生的增长、Ca2+流或染料摄取,如3-(4,5-二甲基噻唑-2-y1)-2,5-二苯基-四唑。另外,可测定淋巴因子(如γ干扰素)的合成或者可以定量能对完整p185HER-2/neu蛋白发生反应的T细胞的相对数。
通过利用或表达HER-2/neu多肽,识别HER-2/neu蛋白的T细胞能够在体内增殖。例如,一种用HER-2/neu肽来进行免疫的药物(即如一种疫苗)可以诱导用于治疗性攻击抗HER-2/neu癌基因相关肿瘤所必需的T细胞在数量上的持续扩增。典型地,通过皮内、皮下或静脉内途径给予大约0.01ug/kg到大约100mg/kg体重。一个优选的剂量是大约1ug/kg到1mg/kg,特别优选大约5ug/kg到200ug/kg。对于本领域的技术人员来说显然给药的数量和频率应依患者的反应而定。理想的是反复地给予HER-2/neu多肽。对于本领域的技术人员来说显然可以同时或顺序地给予一种以上的HER-2/neu多肽。优选的用在进行免疫的药物中的肽是那些包括序列号2中从大约在676号氨基酸位点上的赖氨酸残基开始并延伸到大约在1255号氨基酸位点上的缬氨酸残基的氨基酸序列的肽。本领域的技术人员将认识到,本发明考虑使用一种完整的HER-2/neu多肽和将该多肽分裂而成的多种肽。完整的p185HER-2/neu蛋白和具有其完整细胞外区的氨基酸序列的肽(即一种具有序列号2中从氨基酸位点1到氨基酸位点650的氨基酸序列的,加上或减去大约1到5个位点,并带有或没有前面21个氨基酸位点的肽)都未单独用于免疫。
优选将HER-2/neu多肽(或核酸)配制成用于上述方法中的一种药物组合物(如疫苗)。药物组合物大体上含有联合一种药学可用的载体、赋形剂或稀释剂的一种或多种多肽。这些载体在所用的剂量和浓度下应对受者无毒。也考虑与化疗药联合应用一种EER-2/neu多肽。
除了HER-2/neu多肽外(发挥抗原的功能),理想的是在疫苗中包括其它成分如抗原传递载体和设计用于提高蛋白质免疫原性的免疫刺激物。用于抗原传递的载体的例子包括铝盐、油包水乳剂、生物可降解油载体、水包油乳剂、生物可降解微囊和脂质体。免疫刺激物(佐剂)的例子包括N-乙酰胞壁酰-L-丙氨酸-D-异谷氨酰胺(MDP)、脂多糖(LPS)、葡聚糖、IL-12、GM-CSF、γ-干扰素和IL-15。对本领域普通技术人员来说,显然可合成制备或天然获得用于疫苗的HER-2/neu多肽。
尽管在本发明的药物组合物中可以使用本领域的普通技术人员所了解的任何合适的载体,但载体的类型根据给药的方式和是否需要持续的释放而变化。对于非肠道给药,如皮下注射,载体优选包括水、盐水、酒精、脂肪、蜡或缓冲液。对于口服给药,可以使用上述的任何载体或一种固体载体,如甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖和碳酸镁。生物可降解微球(例如聚乳糖半乳糖苷)也可用作本发明药物组合物的载体。例如,合适的生物可降解微球在美国专利号4,897,268和5,075,109中被公开。HER-2/neu多肽可被包在生物可降解微球中或连接在微球的表面。例如,在一优选的实施方案中,将具有序列号2中从676号氨基酸到l255号氨基酸的氨基酸序列的多肽包在一种生物可降解微球中。在这点上,微球优选大于大约25微米。
药物组合物(包括疫苗)还可含有稀释剂如缓冲液、抗氧化剂如抗坏血酸、低分子量(少于大约10个残基)多肽、蛋白质、氨基酸、碳水化合物包括葡萄糖、蔗糖或糊精、螯合剂如EDTA、谷胱甘肽以及其它稳定剂和赋形剂。中性缓冲盐水或与非特异的血清白蛋白混合的盐水是典型适宜的稀释剂。优选利用适宜的赋形剂溶液(如蔗糖)作为稀释剂将产物制成一种冻干物。
作为HER-2/neu多肽提呈的一种替换物,本发明包括能够传递编码一种HER-2/neu多肽的核酸分子的组合物。这些组合物包括重组病毒载体(例如,逆转录病毒(见WO 90/07936,WO 91/02805,WO 93/25234,WO93/25698和WO 94/03622)、腺病毒(见Berkner,《生物技术》(Biotechniques)6:616-627,1988;Li等,《人基因治疗》(Hum.Gene Ther.)4:403-409,1993;Vincent等,《自然遗传学》(Nat.Genet.)5:130-134,1993;和Kolls等,《美国国家科学院进展》91:215-219,1994)、痘病毒(见美国专利4,769,330号;美国专利5,017,487号;和WO 89/01973))、裸DNA(见WO 90/11092)、复合到一种聚阳离子分子上的核酸分子(见WO 93/03709)和结合于脂质体的核酸(见Wang等,《美国国家科学院进展》84:7851,1987)。在某些实施方案中,可将DNA连接至被杀死或灭活的腺病毒(见Curiel等,《人基因治疗》3:147-154,1992;Cotton等《美国国家科学院进展》89:6094,1992)。其它合适的组合物包括DNA-配体结合体(见Wu等,《生物学和化学杂志》264:16985-16987,1989)和脂质-DNA结合体(见Felgner等,《美国国家科学院进展》84:7413-7417,1989)。另外,通过将DNA包被在生物可降解珠表面可提高裸DNA被摄入细胞的效率。
除了直接体内方法,可以利用离体方法,在这个方法中细胞从一个动物体内取出、修饰并植入同一个或另一个动物。显然,在离体方法中可以利用任何上面提到的组合物来将HER-2/neu核酸分子引入组织细胞。病毒的、物理的和化学的摄取方法是本领域众所周知的。
相应地,本发明在患者或细胞培养中用于提高或引发一种细胞免疫反应(如,抗原特异性溶细胞T细胞的产生)是有效的。本文所用术语“患者”指任何温血动物,优选为人。患者可以患有癌症,如乳腺癌,或者可以正常(即,没有可检测的疾病或感染)。“细胞培养”是任何T细胞或被分离的成分细胞(包括但不限于巨噬细胞、单核细胞、B细胞和树突状细胞)的制备物。这些细胞可通过被本领域普通技术人员所熟知的许多技术中的任何技术来(如Ficoll-hypaque密度梯度离心)分离。细胞可以(但不需要)从患有HER-2/neu相关恶性肿瘤的患者分离,并在处理后可被重新引入患者。
本发明还揭示HER-2/neu多肽除了对T细胞有免疫原性外,似乎刺激B细胞产生能够识别HER-2/neu多肽的抗体。在包括血清和腹水的多种体液中可发现对HER-2/neu蛋白的特异性抗体(即表现一种大约107升/摩尔或更好的结合亲和力)。简言之,一种体液标本是从一温血动物如人分离的,意在确定HER-2/neu多肽的特异性抗体是否存在。将体液和HER-2/neu多肽在一些条件下孵育并持续一段足以允许在多肽和针对蛋白的特异性抗体之间形成免疫复合物的时间。例如,可以将一种体液和HER-2/neu多肽在4℃孵育24-48小时。孵育后,检测反应混合物中免疫复合物的存在。通过多种已知的技术如放射免疫分析(RIA)和酶联免疫吸附测定(ELISA)进行在HER-2/neu多肽和针对HER-2/neu多肽的特异性抗体之间所形成的一种或多种免疫复合物的检测。
合适的免疫检测法包括David等的双单克隆抗体夹心免疫测定技术(美国专利4,376,110);单克隆-多克隆抗体夹心测定法(Wide等,Kirkham和Hunter编,《放射免疫分析方法》(RadioimmunoassayMethods),E.and S.Livingstone,Edinburgh,1970);Gordon等的“蛋白质印迹”方法(美国专利4,452,901);标记配体的免疫沉淀(Brown等,《生物学和化学杂志》255:4980-4983,1980);由例如Raines和Ross所描述的酶联免疫吸附测定(《生物学和化学杂志》257:5154-5160,1982);包括使用荧光染料的免疫细胞化学技术(Brooks等,《临床试验免疫学》(Clin.Exp.Immunol.)39:477,1980);和活性的中和作用〔Bowen-Pope等,《美国国家科学院进展》81:2396-2400(1984)〕,所有这些全部并入本文作为参考。除了上面描述的免疫检测法,许多其它的免疫检测法也可用,包括那些在美国专利号:3,817,827;3,850,752;3,901,654;3,935,074;3,984,533;3,996,345;4,034,074;和4,098,876中所描述的方法,所有这些全部并入本文作为参考。
为了测定的目的,HER-2/neu多肽(“抗原”)可以是标记的或非标记的。当为非标记的时,抗原用在凝集检测法中。另外,非标记的抗原可以和与免疫复合物有反应的标记的分子联合使用,或者和与针对HER-2/neu多肽的抗体有反应的标记的抗体(二抗)如特异性针对免疫球蛋白的抗体联合使用。或者,可以直接标记抗原。在所标记的之处,报道基团可以包括放射性同位素、荧光团、酶、发光物或染料颗粒。这些和其它的标记在本领域中是众所周知的并且被描述,例如在下列的美国专利:3,766,162;3,791,932;3,817,837;3,966,345;和4,233,402中。
典型地在一个ELISA检测中,抗原被吸附于微量滴定孔的表面。然后用一种合适的试剂如牛血清白蛋白(BSA)、热灭活正常山羊血清(NGS)或BLOTTO(也含有一种防腐剂、盐和一种消泡剂的脱脂奶粉的缓冲溶液)来阻断在表面残留的蛋白质结合位点。然后用一可疑含有特异性抗体的标本对加样孔进行孵育。标本可以利用纯净的,或者,更常用的是,它通常可被稀释于一种含有少量(0.1%-5.0%重量)蛋白质如BSA、NGS或BLOTTO的缓冲溶液中。在孵育一段允许发生特异性结合的足够长的时间后,冲洗加样孔移走未结合的蛋白质,然后用由一报道基团标记的抗种特异性免疫球蛋白抗体孵育。报道基团可以选自多种酶,包括辣根过氧化物酶、β-半乳糖苷酶、碱性磷酸酶和葡萄糖氧化酶。允许孵育足够长的时间以便产生特异性结合,然后再一次冲洗加样孔来移走未结合的偶联物,并加入酶的底物。进行成色反应,并目测或用仪器测定加样孔中内容物的光密度。
在本发明该方面的一个优选的实施方案中,将一种报道基团结合于HER-2/neu蛋白。检测免疫复合物的步骤包括基本除去任何未结合的HER-2/neu蛋白,然后检测报道基团的存在或不存在。
在另一优选的实施方案中,将一种报道基团结合于一种能够与特异性针对HER-2/neu蛋白的抗体结合的二抗。检测免疫复合物的步骤包括(a)基本除去任何未结合的抗体,(b)加入二抗,(c)基本除去任何未结合的二抗,然后(d)检测报道基团的存在或不存在。特异性针对HER-2/neu蛋白的抗体源自人,二抗是抗人抗体的抗体。
在用于检测免疫复合物的第三个优选的实施方案中,将一种报道基团结合于一种能够与免疫复合物结合的分子。检测的步骤包括(a)加入该分子,(b)基本除去任何未结合的分子,然后(c)检测报道基团的存在或不存在。一个能够结合于免疫复合物的分子的例子是蛋白A。
对于本领域的技术人员,在本发明中显然可以使用多种检测免疫复合物的方法。适于在任何方法中使用的报道基团包括放射性同位素、荧光团、酶、发光物和染料颗粒。
在本发明的一个相关方面,对于在HER-2/neu多肽和体液中特异性针对HER-2/neu多肽的抗体之间所形成的免疫复合物的检测可以用于对与HER-2/neu癌基因相关的恶性肿瘤监测,包括HER-2/neu多肽的癌症治疗的效果。可以通过上面所描述的方法对在治疗前和治疗开始后从个体所取的体液标本进行免疫复合物的分析。简言之,将在两种标本中所检测的免疫复合物的量进行比较。第二个标本(治疗开始后)中在免疫复合物数量上相对于第一个标本(治疗前)的巨大变化反映成功的治疗。
提供下面的实施例以求说明而不是为了限定。
实施例
实施例1
重组人HER-2/neu多肽的表达和纯化
通过PCR方法利用额外地在5′端引入一个BssH II限制性酶切位点和一个肠激酶蛋白酶位点以及在3′端引入一个EcoR I位点的寡核苷酸引物从按照Di Fiore等(King等,《科学》(Science)229:974-976,1985;Di Fiore等,《科学》237:178-182,1987)制备的质粒中回收人HER-2/neu多肽(如,美国专利4,683,195;4,683,202;4,800,159号)。5′端引物为
5′-TCTGGCGCGCTGGATGACGATGACAAGAAACGACGGCAGCAGAAGATC-3′
(序列号3),而3′端引物为
5′-TGAATTCTCGAGTCATTACACTGGCACGTCCAGACCCAG-3′
(序列号4)。将所获的1.8kb PCR片段亚克隆到来自Novagen(Madison,WI,USA)的T-载体中,并用重叠测序引物在ABI 373自动DNA测序仪(Applied Biosystem Inc.,Foster City,CA,USA)上测定所筛选的克隆的序列。然后将具有与公布的人HER-2/neu cDNA的DNA序列(序列号1;Coussens等,《科学》230:1132,1985;Yamamoto等,《自然》319:230,1986)一致的序列的PCR片段经BssH II位点以正确的阅读框架连接至一个修饰过的大肠杆菌硫氧还蛋白还原酶上。将一个在所表达融合蛋白的Ni-NTA亲和纯化中所用的6X组氨酸亲和标志物掺入硫氧还蛋白还原酶融合伙伴中。为了在大肠杆菌中表达,将这种trxA-人HER-2/neu多肽融合蛋白的cDNA亚克隆至一个修饰过的pET表达载体中。
虽然硫氧还蛋白还原酶被报道可以使其它在大肠杆菌中表达的异源蛋白稳定和可溶,但它对人HER-2/neu多肽在大肠杆菌中的表达似乎没有提供任何显著的好处。虽然有显著比例的trxA-HER-2/neu多肽融合蛋白是可溶的,但大部分都表达在包涵体中。在大肠杆菌中表达的过程中,融合蛋白也遭到降解。然而,硫氧还蛋白还原酶融合伙伴的存在可以在纯化过程中使蛋白稳定。针对硫氧还蛋白还原酶的单克隆抗体的可用性在纯化过程中为追踪提供了一种方便的标志物。
为纯化人HER-2/neu多肽和含有6XHis亲和标志物的硫氧还蛋白还原酶融合伙伴,用蛋白酶抑制剂和溶菌酶重悬大肠杆菌沉淀并用超声波处理。通过离心分离包涵体,并用脱氧胆酸盐洗涤3次,最后一次洗涤过夜以除去LPS。为进行Ni纯化将洗涤过的包涵体溶于GuHCl。在尿素中用咪唑洗脱Ni柱并以pH8的10mM Tris透析。利用这种方法回收的HER-2/neu多肽是以被降解的蛋白为主要污染物的80%-95%纯的全长蛋白。从500ml发酵液中回收20mg。它含有大于98%的HER-2/neu多肽。这里所用的技术为本领域的人员所熟知,并在例如J.Sambrook等,《分子克隆:实验室指南》(第二版,冷泉港实验室出版,1989,冷泉港,美国纽约)中被描述。
实施例2
树突状细胞可以递呈人HER-2/neu多肽
A.来自骨髓的DC培养物的产生
DC培养物由CD34+造血祖细胞(HPC)产生。用细胞分离系统CeprateLC试剂盒(CellPro,Bothell,WA,USA)从正常供者的骨髓中分离CD34+细胞。通过流式细胞术分析确定回收的CD34+细胞的纯度为80%到95%。将CD34+细胞培养于补充有L-谷氨酰胺(584ug/l)、青霉素(10IU/ml)、链霉素(100ug/ml)、100ng/ml人rGM-CSF和50ng/ml人rIL-6的无血清培养基(X-VIVO 10,Biowhittaker,Inc.,Walkersville,MD,USA)中。在培养0到17天后,收获细胞并用于表型检测和T细胞刺激测试。已经报道单独GM-CSF和与IL-4或TNFα联合使用诱导DC的体外生长。在用KLH和OVA作为抗原来致敏幼稚T细胞的试验中,与GM-CSF加IL-4或TNFα相比GM-CSF加IL-6持续产生一种类似的总刺激但却具有较低的本底因而具有较高的刺激指数。
B.T细胞致敏测试
将在含有GM-CSF和IL-6的无血清培养基中培养的骨髓来源的CD34+HPC经0-17天培养后用作APC。DC的致敏能力是通过将它们与自体的幼稚T淋巴细胞在蛋白抗原重组人HER-2/neu多肽(hHNP)(10ug/ml)存在或不存在的条件下培养来检测的。利用免疫亲和柱(CellPro,Inc.,Bothell,WA,USA)通过阳性选择法从外周血单核细胞中分离CD4+T淋巴细胞。用一种直接偶联至FITC(Immunotech,Westbrook,ME,USA)的抗CD45RA mAb通过流式细胞术分选法从CD4+T淋巴细胞中筛选CD4+CD45RA+(幼稚)T淋巴细胞。所获CD4+CD45RA+T细胞的纯度为99%。将DC培养物以各种浓度接种于圆底96孔板(Corning,Corning,NY,USA)中并与10ug/ml终浓度的hHNP孵育16-18小时。将抗原刺激的DC照射(10Gy),并加入自体CD4+CD45RA+T淋巴细胞(5×104/孔)。通过对在第6天加入的(3H)胸苷(1uCi/孔)的16-18小时摄取量来测定T细胞的增殖反应。在无血清和无细胞因子培养液中进行增殖检测。结果显示在图1中。图2显示来自一个正常供者的CD4+T细胞对hHNP的反应的测试结果。用取自10个正常个体中的9个的T细胞获得类似的数据。
实施例3
检测低频数淋巴细胞前体的测试法
3种测试法可用于检测CD4+反应:一种标准的增殖测试法、一种低频数事件筛选方法和一种有限稀释测试法(LDA)。传统的增殖测试法能够很容易地检测致敏反应。增殖反应刺激指数提供了一种与抗原反应性T细胞的前体频数的粗略的相关性。由PBL检测到的任何特异性增殖反应被认为是一种致敏反应。
为了提供一种对CD4+T细胞反应的更定量化的解释,使用一种用于检测低淋巴细胞前体频数反应而发展的测试系统(下面描述的)。这种测试简单而且经济有效。在需要更精确的条件下,通过有限稀释测试法证实前体的频数(Bishop和Orosz,《移植》(Transplantation)47:671-677,1989)。
比在正常个体中所检测到的反应更强烈的反应被定义为一种致敏反应,并且它表明存在的免疫力。只有通过LDA条件才可检测到的低的反应被认为是未致敏的反应。通过LDA而无反应或一种比通过正常群体分析所定义的反应低的反应被认为是耐受/无反应。
大体上,可以通过传统的增殖测试法来检测致敏的CD4+T细胞反应,而用同样的方法则无法检测未致敏的反应。包括对自身MHC抗原的自身混合淋巴细胞反应(AMLR)加上对加工过的自身血清蛋白和外源加入的血清蛋白的反应在内的复杂的本底胸苷摄取量限制了对少量未致敏T细胞的检测。
为了引发和检测未致敏T细胞,利用了一种基于Poisson取样统计的低频数反应测试系统(于:Pinnacles,Chiron Corporation,1:1-2,1991)。这种类型的分析特异性地用于低频事件,其中如果前体频数低于在一个重复培养中的细胞数,则需要许多重复来检测一种统计学上显著的阳性数量。理论上,该测试法可通过设立一个已知的阳性对照(如PHA或破伤风类毒素)和已知的阴性对照(无抗原)并不考虑它们属于哪个实验组评价从最低到最高的所有数据点来纠正自身反应。基于等式截断值=M+(F+SD)计算截断值,其中M=算术均数,F=3.29,一种来自所选标准化的正态分布表中的参数使在截断值以上不超过0.1%的正态分布本底的“真阴性”,而SD=标准差。在这种筛选测试法中,在截断值以上的加样孔被认为是可能含有一个对抗原的刺激发生特异性增殖的淋巴细胞的真阳性。虽然用这种方法对淋巴细胞前体频数进行估计是可能的,但精确的测定需要正规的LDA分析。
实施例4
HER-2/neu多肽为基础的疫苗引起对HER-2/neu蛋白的免疫
A.动物
在本研究中所用的大鼠为Fischer系344(CDF(F-344)/CrlBR)(Charles River实验室,Portage MI)。将动物在华盛顿大学的动物实验室于无特异性病原体条件下饲养,并在3和4个月月龄之间常规进行实验研究。
B.免疫
用在多种佐剂(MPL,Vaccel;Ribi,Bozeman,MT,USA)中的重组大鼠HER-2/neu多肽(rHNP)免疫Fischer大鼠。在皮下给动物注射50ug与佐剂混合的rHNP。20天后将50ug rHNP以同样的方式给药,对动物用第二次免疫来加强。20天后测试加强免疫的动物中针对大鼠HER-2/neu蛋白(neu)的抗体的存在。
C.细胞系
利用2个细胞系作为neu蛋白的来源。将SKBR3,一种显著过度表达HER-2/neu的乳腺癌细胞系(美国典型培养物保藏中心,Rockville,MD)维持在10%胎牛血清(FBS)(Gemini Bioproducts,Inc.,Calabasas,CA)和RPMI的培养物中。DHFR-G8,一种用cneu-p和pSV2-DHFR共转染的NIH/3T3细胞系(美国典型培养物保藏中心,Rockville,MD)被用作非转化大鼠neu蛋白的来源(Bernards等,《美国国家科学院进展》84:6854-6858,1987)。将该细胞系维持在10%FBS和含有4.5g/L葡萄糖的Dulbecco′s改良的Eagle′s培养基中。DHFR-G8细胞在每3次传代时用加有0.3μM氨甲蝶呤的相同的培养基传代来维持neu转染子。
D.细胞裂解液的制备
制备SKBR3和DHFR-G8的裂解液,并将之用作neu蛋白的来源。简言之,制备一种由tris碱、氯化钠和Triton-X(1%)pH7.5组成的裂解缓冲液。加入蛋白酶抑制剂:抑蛋白酶(1ug/ml)、苯甲脒(1mM)和PMSF(1mM)。用1ml裂解缓冲液悬浮107细胞。将细胞每10分钟旋振15秒持续1小时直至被裂解。所有的步骤均在一个4℃房间中于冰上进行。裂解后4℃微离心细胞20分钟。从细胞碎片中移走上清,并以小份储存于-70℃备用。通过蛋白质印迹分析确定在裂解液中人和大鼠neu的存在。E.ELISA检测大鼠neu抗体反应
将96孔Immulon 4板(Baxter SP,Redmond,WA:DynatechLaboratorie)于4℃用在碳酸盐盐缓冲液(等摩尔浓度的Na2CO3和NaHCO3,pH9.6)中稀释的浓度为10ug/ml的大鼠neu特异性单克隆抗体孵育过夜。孵育后,在室温用PBS-1%BSA(Sigma Chemical,St.Louis,MO,USA)100ul/孔将所有加样孔封闭3小时,用PBS-0.5%Tween冲洗培养板并在交替的行中加入一种大鼠neu蛋白的来源DHFR-G8,一种用大鼠neu DNA转染的小鼠细胞系(美国典型培养物保藏中心,Rockville,MD,USA),的裂解液。将培养板于4℃孵育过夜。然后用PBS-0.5%Tween冲洗培养板并以下列的稀释度:1∶25到1∶200加入实验血清。将血清稀释于PBS-1%BSA-1%FBS-25ug/ml小鼠IgG-0.01%NaN3中然后序列地稀释于PBS-1%BSA。在每孔加入50ul稀释的血清并于室温孵育1小时。将每种实验血清加入含有和不含有大鼠neu的加样孔中。将羊抗大鼠IgF(ab′)2辣根过氧化物酶(HRP)在PBS-1%BSA中以1∶5000稀释度加入加样孔并于室温孵育45分钟(Amersham Co,Arlington Heights,1L,USA)。经最后冲洗后,加入TMB(Kirkegaard and Perry Laboratories,Gaithersburg,MD)显色试剂。在450nm的光密度下读取成色反应。以大鼠neu包被的加样孔的OD减去PBS-1%BSA包被的加样孔的OD计算每种血清稀释度的OD。也以类似的方式评价来源于单独用佐剂免疫的动物和用hHNP(外源蛋白)免疫的动物的血清。结果显示在图3中。
F.T细胞增殖测试
为测试HER-2/neu多肽特异性反应:通过机械破碎和线网过滤以及洗涤来收获新鲜的脾和淋巴结细胞。将2×105脾细胞/孔和1×105淋巴结细胞/孔以每个实验组重复6次接种于96孔圆底微量滴定板中(Corning,Corning,NY)。培养基由含L-谷氨酰胺的EHAA 120(Biofluids)、青霉素/链霉素、2-巯基乙醇和5%FBS组成。将细胞与多肽孵育。4天后,用1μCi的[3H]胸苷将加样孔脉冲6-8小时并计数。数据由一种被定义为实验孔的均值除以对照孔(无抗原)的均值的刺激指数(SI)来表示。为测试HER-2/neu蛋白特异性反应:培养脾或淋巴结细胞进行3次体外刺激。在测试时,如上所述将1×105培养的脾或淋巴结T细胞接种于96孔微量滴定板中。用1ug/ml免疫亲和柱纯化的大鼠neu(来自作为大鼠neu来源的DHFR-G8细胞)孵育细胞。4天后,用1uCi的[3H]胸苷将加样孔脉冲6-8小时并计数。数据由一种被定义为实验孔的均值除以对照孔(无抗原)的均值的刺激指数来表示。
实施例5
在乳腺癌患者中可以检测到对人HER-2/neu多肽的致敏反应
从患有II期HER-2/neu过度表达乳腺癌的患者获得肝素化的血。通过Ficoll Hypaque密度离心分离外周血单核细胞(PBMC)。将PBMC以2×105/孔的浓度接种于96孔圆底板(Corning,Corning,NY,USA)中。每个实验组进行24孔的重复。在每个24重复孔中加入由HER-2/neu衍生的肽(带有在所列的序列中第一个氨基酸号的长度为15-20个氨基酸)组成的抗原25ug/ml、人HER-2/neu多肽(hHNP)1ug/ml、破伤风类毒素1ug/ml和一种来自破伤风的肽p30 25ug/ml。在含有10%人血清的培养基中进行测试。通过在第4天加入的(3H)胸苷(1μCi/孔)的10小时摄取量来测定T细胞的增殖反应。如果cpm大于无抗原孔的均值和3倍标准差,则阳性孔,抗原反应孔,被计数为阳性。结果显示于图4中。该II期乳腺癌患者对重组hHNP具有显著的反应。
从前面的描述中,显然虽然为了说明此中已经描述了本发明的特定实施方案,但是可以进行各种修饰而不偏离本发明的精神和范围。
序列表
(1)一般信息:
(i)申请人:华盛顿大学
(ii)发明题目:用于引发或提高对HER-2/neu蛋白的免疫活性以预防或治疗与HER-2/neu癌基因相关的恶性肿瘤的化合物
(iii)序列数:4
(iv)联系地址:
(A)收信人:Seed和Berry LLP
(B)街:6300哥伦比亚中心,第五大街701
(C)城市:西雅图
(D)州:华盛顿
(E)国家:美国
(F)由编:98104-7092
(V)计算机可读形式:
(A)媒体类型:软盘
(B)计算机:IBM PC兼容
(C)操作系统:PC-DOS/MS-DOS
(D)软件:Patent In Release#1.0,版本#1.30
(vi)本申请资料:
(A)申请号:
(B)申请日期:1996年3月28日
(C)分类:
(viii)律师/代理人信息:
(A)姓名:Sharky,Richard G.
(B)注册号:32,629
(C)参考/案卷号:920010.448PC
(ix)通讯信息:
(A)电话:(206)622-4900
(B)传真:(206)682-6031
(2)序列号1的资料:
(i)序列特征:
(A)长度:3768个碱基
(B)类型:核酸
(C)成链类型:单链
(D)拓扑结构:线性
(ix)特征:
(A)名字/解释(KEY):CDS
(B)位置:1..3765
(xi)序列描述:序列号1:
ATG GAG CTG GCG GCC TTG TGC CGC TGG GGG CTC CTC CTC GCC CTC TTG 48
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
CCC CCC GGA GCC GCG AGC ACC CAA GTG TGC ACC GGC ACA GAC ATG AAG 96
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
CTG CGG CTC CCT GCC AGT CCC GAG ACC CAC CTG GAC ATG CTC CGC CAC 144
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
CTC TAC CAG GGC TGC CAG GTG GTG CAG GGA AAC CTG GAA CTC ACC TAC 192
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
CTG CCC ACC AAT GCC AGC CTG TCC TTC CTG CAG GAT ATC CAG GAG GTG 240
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
CAG GGC TAC GTG CTC ATC GCT CAC AAC CAA GTG AGG CAG GTC CCA CTG 288
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
CAG AGG CTG CGG ATT GTG CGA GGC ACC CAG CTC TTT GAG GAC AAC TAT 336
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
GCC CTG GCC GTG CTA GAC AAT GGA GAC CCG CTG AAC AAT ACC ACC CCT 384
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
GTC ACA GGG GCC TCC CCA GGA GGC CTG CGG GAG CTG CAG CTT CGA AGC 432
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
CTC ACA GAG ATC TTG AAA GGA GGG GTC TTG ATC CAG CGG AAC CCC CAG 480
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
CTC TGC TAC CAG GAC ACG ATT TTG TGG AAG GAC ATC TTC CAC AAG AAC 528
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
AAC CAG CTG GCT CTC ACA CTG ATA GAC ACC AAC CGC TCT CGG GCC TGC 576
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
CAC CCC TGT TCT CCG ATG TGT AAG GGC TCC CGC TGC TGG GGA GAG AGT 624
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
TCT GAG GAT TGT CAG AGC CTG ACG CGC ACT GTC TGT GCC GGT GGC TGT 672
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
GCC CGC TGC AAG GGG CCA CTG CCC ACT GAC TGC TGC CAT GAG CAG TGT 720
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
GCT GCC GGC TGC ACG GGC CCC AAG CAC TCT GAC TGC CTG GCC TGC CTC 768
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
CAC TTC AAC CAC AGT GGC ATC TGT GAG CTG CAC TGC CCA GCC CTG GTC 816
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Alā Leu Val
260 265 270
ACC TAC AAC ACA GAC ACG TTT GAG TCC ATG CCC AAT CCC GAG GGC CGG 864
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
TAT ACA TTC GGC GCC AGC TGT GTG ACT GCC TGT CCC TAC AAC TAC CTT 912
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
TCT ACG GAC GTG GGA TCC TGC ACC CTC GTC TGC CCC CTG CAC AAC CAA 960
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
GAG GTG ACA GCA GAG GAT GGA ACA CAG CGG TGT GAG AAG TGC AGC AAG 1008
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
CCC TGT GCC CGA GTG TGC TAT GGT CTG GGC ATG GAG CAC TTG CGA GAG 1056
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
GTG AGG GCA GTT ACC AGT GCC AAT ATC CAG GAG TTT GCT GGC TGC AAG 1104
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
AAG ATC TTT GGG AGC CTG GCA TTT CTG CCG GAG AGC TTT GAT GGG GAC 1152
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
CCA GCC TCC AAC ACT GCC CCG CTC CAG CCA GAG CAG CTC CAA GTG TTT 1200
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
GAG ACT CTG GAA GAG ATC ACA GGT TAC CTA TAC ATC TCA GCA TGG CCG 1248
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
GAC AGC CTG CCT GAC CTC AGC GTC TTC CAG AAC CTG CAA GTA ATC CGG 1296
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
GGA CGA ATT CTG CAC AAT GGC GCC TAC TCG CTG ACC CTG CAA GGG CTG 1344
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
GGC ATC AGC TGG CTG GGG CTG CGC TCA CTG AGG GAA CTG GGC AGT GGA 1392
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
CTG GCC CTC ATC CAC CAT AAC ACC CAC CTC TGC TTC GTG CAC ACG GTG 1440
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
CCC TGG GAC CAG CTC TTT CGG AAC CCG CAC CAA GCT CTG CTC CAC ACT 1488
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
GCC AAC CGG CCA GAG GAC GAG TGT GTG GGC GAG GGC CTG GCC TGC CAC 1536
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
CAG CTG TGC GCC CGA GGG CAC TGC TGG GGT CCA GGG CCC ACC CAG TGT 1584
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
GTC AAC TGC AGC CAG TTC CTT CGG GGC CAG GAG TGC GTG GAG GAA TGC 1632
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
CGA GTA CTG CAG GGG CTC CCC AGG GAG TAT GTG AAT GCC AGG CAC TGT 1680
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Gys
545 550 555 560
TTG CCG TGC CAC CCT GAG TGT CAG CCC CAG AAT GGC TCA GTG ACC TGT 1728
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
TTT GGA CCG GAG GCT GAC CAG TGT GTG GCC TGT GCC CAC TAT AAG GAC 1776
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
CCT CCC TTC TGC GTG GCC CGC TGC CCC AGC GGT GTG AAA CCT GAC CTC 1824
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
TCC TAC ATG CCC ATC TGG AAG TTT CCA GAT GAG GAG GGC GCA TGC CAG 1872
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
CCT TGC CCC ATC AAC TGC ACC CAC TCC TGT GTG GAC CTG GAT GAC AAG 1920
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
GGC TGC CCC GCC GAG CAG AGA GCC AGC CCT CTG ACG TCC ATC ATC TCT 1968
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
GCG GTG GTT GGC ATT CTG CTG GTC GTG GTC TTG GGG GTG GTC TTT GGG 2016
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
ATC CTC ATC AAG CGA CGG CAG CAG AAG ATC CGG AAG TAC ACG ATG CGG 2064
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
AGA CTG CTG CAG GAA ACG GAG CTG GTG GAG CCG CTG ACA CCT AGC GGA 2112
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
GCG ATG CCC AAC CAG GCG CAG ATG CGG ATC CTG AAA GAG ACG GAG CTG 2160
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
AGG AAG GTG AAG GTG CTT GGA TCT GGC GCT TTT GGC ACA GTC TAC AAG 2208
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
GGC ATC TGG ATC CCT GAT GGG GAG AAT GTG AAA ATT CCA GTG GCC ATC 2256
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
AAA GTG TTG AGG GAA AAC ACA TCC CCC AAA GCC AAC AAA GAA ATC TTA 2304
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
GAC GAA GCA TAC GTG ATG GCT GGT GTG GGC TCC CCA TAT GTC TCC CGC 2352
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
CTT CTG GGC ATC TGC CTG ACA TCC ACG GTG CAG CTG GTG ACA CAG CTT 2400
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
ATG CCC TAT GGC TGC CTC TTA GAC CAT GTC CGG GAA AAC CGC GGA CGC 2448
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
CTG GGC TCC CAG GAC CTG CTG AAC TGG TGT ATG CAG ATT GCC AAG GGG 2496
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
ATG AGC TAC CTG GAG GAT GTG CGG CTC GTA CAC AGG GAC TTG GCC GCT 2544
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
CGG AAC GTG CTG GTC AAG AGT CCC AAC CAT GTC AAA ATT ACA GAC TTC 2592
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
GGG CTG GCT CGG CTG CTG GAC ATT GAC GAG ACA GAG TAC CAT GCA GAT 2640
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
GGG GGC AAG GTG CCC ATC AAG TGG ATG GCG CTG GAG TCC ATT CTC CGC 2688
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
CGG CGG TTC ACC CAC CAG AGT GAT GTG TGG AGT TAT GGT GTG ACT GTG 2736
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
TGG GAG CTG ATG ACT TTT GGG GCC AAA CCT TAC GAT GGG ATC CCA GCC 2784
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
CGG GAG ATC CCT GAC CTG CTG GAA AAG GGG GAG CGG CTG CCC CAG CCC 2832
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
CCC ATC TGC ACC ATT GAT GTC TAC ATG ATC ATG GTC AAA TGT TGG ATG 2880
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
ATT GAC TCT GAA TGT CGG CCA AGA TTC CGG GAG TTG GTG TCT GAA TTC 2928
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
TCC CGC ATG GCC AGG GAC CCC CAG CGC TTT GTG GTC ATC CAG AAT GAG 2976
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
GAC TTG GGC CCA GCC AGT CCC TTG GAC AGC ACC TTC TAC CGC TCA CTG 3024
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
CTG GAG GAC GAT GAC ATG GGG GAC CTG GTG GAT GCT GAG GAG TAT CTG 3072
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu
1010 1015 1020
GTA CCC CAG CAG GGC TTC TTC TGT CCA GAC CCT GCC CCG GGC GCT GGG 3120
Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala Gly
1025 1030 1035 1040
GGC ATG GTC CAC CAC AGG CAC CGC AGC TCA TCT ACC AGG AGT GGC GGT 3168
Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg Ser Gly Gly
1045 1050 1055
GGG GAC CTG ACA CTA GGG CTG GAG CCC TCT GAA GAG GAG GCC CCC AGG 3216
Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu Ala Pro Arg
1060 1065 1070
TCT CCA CTG GCA CCC TCC GAA GGG GCT GGC TCC GAT GTA TTT GAT GGT 3264
Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp Val Phe Asp Gly
1075 1080 1085
GAC CTG GGA ATG GGG GCA GCC AAG GGG CTG CAA AGC CTC CCC
Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln Ser Leu Pro Thr His
1090 1095 1100
GAC CCC AGC CCT CTA CAG CGG TAC AGT GAG GAC CCC ACA GTA CCC CTG 3360
Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu Asp Pro Thr Val Pro Leu
1105 1110 1115 1120
CCC TCT GAG ACT GAT GGC TAC GTT GCC CCC CTG ACC TGC AGC CCC CAG 3408
Pro Ser Glu Thr Asp Gly Tyr Val Ala Pro Leu Thr Cys Ser Pro Gln
1125 1130 1135
CCT GAA TAT GTG AAC CAG CCA GAT GTT CGG CCC CAG CCC CCT TCG CCC 3456
Pro Glu Tyr Val Asn Gln Pro Asp Val Arg Pro Gln Pro Pro Ser Pro
1140 1145 1150
CGA GAG GGC CCT CTG CCT GCT GCC CGA CCT GCT GGT GCC ACT CTG GAA 3504
Arg Glu Gly Pro Leu Pro Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu
1155 1160 1165
AGG CCC AAG ACT CTC TCC CCA GGG AAG AAT GGG GTC GTC AAA GAC GTT 3552
Arg Pro Lys Thr Leu Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val
1170 1175 1180
TTT GCC TTT GGG GGT GCC GTG GAG AAC CCC GAG TAC TTG ACA CCC CAG 3600
Phe Ala Phe Gly Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln
1185 1190 1195 1200
GGA GGA GCT GCC CCT CAG CCC CAC CCT CCT CCT GCC TTC AGC CCA GCC 3648
Gly Gly Ala Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala
1205 1210 1215
TTC GAC AAC CTC TAT TAC TGG GAC CAG GAC CCA CCA GAG CGG GGG GCT 3696
Phe Asp Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala
1220 1225 1230
CCA CCC AGC ACC TTC AAA GGG ACA CCT ACG GCA GAG AAC CCA GAG TAC 3744
Pro Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
CTG GGT CTG GAC GTG CCA GTG TGA 3768
Leu Gly Leu Asp Val Pro Val
1250 1255
(2)序列号2的资料:
(i)序列特征:
(A)长度:1255个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(xi)序列描述:序列号2:
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Vel Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe AsP Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr Leu
1010 1015 1020
Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly Ala Gly
1025 1030 1035 1040
Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg Ser Gly Gly
1045 1050 1055
Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu Glu Ala Pro Arg
1060 1065 1070
Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser Asp Val Phe Asp Gly
1075 1080 1085
Asp Leu Gly Met Gly Ala Ala Lys Gly Leu Gln Ser Leu Pro Thr His
1090 1095 1100
Asp Pro Ser Pro Leu Gln Arg Tyr Ser Glu Asp Pro Thr Val Pro Leu
1105 1110 1115 1120
Pro Ser Glu Thr Asp Gly Tyr Val Ala Pro Leu Thr Cys Ser Pro Gln
1125 1130 1135
Pro Glu Tyr Val Asn Gln Pro Asp Val Arg Pro Gln Pro Pro Ser Pro
1140 1145 1150
Arg Glu Gly Pro Leu Pro Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu
1155 1160 1165
Arg Pro Lys Thr Leu Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val
1170 1175 1180
Phe Ala Phe Gly Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln
1185 1190 1195 1200
Gly Gly Ala Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala
1205 1210 1215
Phe Asp Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala
1220 1225 1230
Pro Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
(2)序列号3的资料:
(i)序列特征:
(A)长度:48个碱基
(B)类型:核酸
(C)成链类型:单链
(D)拓扑结构:线性
(xi)序列描述:序列号3:
TCTGGCGCGC TGGATGACGA TGACAAGAAA CGACGGCAGC AGAAGATC 48
(2)序列号4的资料:
(i)序列特征:
(A)长度:39个碱基
(B)类型:核酸
(C)成链类型:单链
(D)拓扑结构:线性
(xi)序列描述:序列号4:
TGAATTCTCG AGTCATTACA CTGGCACGTC CAGACCCAG 39
Claims (31)
1.用于产生T细胞应答的组合物,其中包含佐剂以及由选自下组的DNA序列编码的多肽:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
2.权利要求1的组合物,其中所述多肽具有SEQ ID NO:2的从第676位氨基酸至第1255位氨基酸的氨基酸序列。
3.权利要求2的组合物,其中所述多肽是截短的。
4.权利要求3的组合物,其中所述多肽与肽或多肽相连接。
5.权利要求1的组合物,其中所述多肽与肽或多肽相连接。
6.权利要求1-5中任一项的组合物在制备用于免疫温血动物以抗与HER-2/neu癌基因相关的恶性肿瘤的药物中的用途。
7.通过用核酸分子与佐剂联合转染温血动物细胞用于免疫的核酸分子组合物,所述核酸分子指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
8.核酸分子与佐剂联合在制备通过转染温血动物细胞用于免疫温血动物以抗与HER-2/neu癌基因相关的恶性肿瘤的药物中的用途,其中所述核酸分子指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQIDNO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
9.核酸分子与佐剂联合在制备用于免疫温血动物以抗与HER-2/neu癌基因相关的恶性肿瘤的药物中的用途,其中所述核酸分子指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
10.通过病毒载体与佐剂联合感染温血动物细胞用于免疫的病毒载体,所述病毒载体指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
11.病毒载体与佐剂联合在制备通过转染温血动物细胞用于免疫温血动物以抗与HER-2/neu癌基因相关的恶性肿瘤的药物中的用途,其中所述病毒载体指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
12.病毒载体与佐剂联合在制备用于免疫温血动物以抗与HER-2/neu癌基因相关的恶性肿瘤的药物中的用途,其中所述病毒载体指导由选自下组的DNA序列编码的多肽的表达:
(a)SEQ ID NO:1的第2026-3765位核苷酸;和
(b)在中等严谨条件下与和SEQ ID NO:1的第2026-3765位核苷酸互补的核苷酸序列可杂交的DNA序列,该DNA序列编码可产生针对HER-2/neu蛋白的免疫应答的多肽,前提条件是该多肽不是完整HER-2/neu蛋白。
13.权利要求1-5中任一项的组合物在制备可用于激发或增强针对HER-2/neu蛋白的免疫应答的药物中的用途。
14.权利要求7的核酸分子在制备可用于激发或增强针对HER-2/neu蛋白的免疫应答的药物中的用途。
15.权利要求7的核酸分子,其中所述多肽具有SEQ ID NO:2的从第676位氨基酸-赖氨酸至第1255位氨基酸-缬氨酸的氨基酸序列。
16.权利要求13的核酸分子,其中所述多肽是截短的。
17.权利要求16的核酸分子,其中所述多肽与肽或多肽相连接。
18.权利要求7的核酸分子,其中所述多肽与肽或多肽相连接。
19.权利要求8或9的核酸分子的用途,其中所述多肽具有SEQ ID NO:2的从第676位氨基酸-赖氨酸至第1255位氨基酸-缬氨酸的氨基酸序列。
20.权利要求19的核酸分子的用途,其中所述多肽是截短的。
21.权利要求20的核酸分子的用途,其中所述多肽与肽或多肽相连接。
22.权利要求8或9的核酸分子的用途,其中所述多肽与肽或多肽相连接。
23.权利要求10的病毒载体在制备可用于激发或增强针对HER-2/neu蛋白的免疫应答的药物中的用途。
24.权利要求10的病毒载体,其中所述多肽具有SEQ ID NO:2的从第676位氨基酸-赖氨酸至第1255位氨基酸-缬氨酸的氨基酸序列。
25.权利要求24的病毒载体,其中所述多肽是截短的。
26.权利要求25的病毒载体,其中所述多肽与肽或多肽相连接。
27.权利要求10的病毒载体,其中所述多肽与肽或多肽相连接。
28.权利要求11或12的病毒载体的用途,其中所述多肽具有SEQ ID NO:2的从第676位氨基酸-赖氨酸至第1255位氨基酸-缬氨酸的氨基酸序列。
29.权利要求28的病毒载体的用途,其中所述多肽是截短的。
30.权利要求29的病毒载体的用途,其中所述多肽与肽或多肽相连接。
31.权利要求11或12的病毒载体的用途,其中所述多肽与肽或多肽相连接。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/414,417 US5801005A (en) | 1993-03-17 | 1995-03-31 | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US08/414,417 | 1995-03-31 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2004100319155A Division CN1597953A (zh) | 1995-03-31 | 1996-03-28 | 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1951398A true CN1951398A (zh) | 2007-04-25 |
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CNA200610099911XA Pending CN1951398A (zh) | 1995-03-31 | 1996-03-28 | 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 |
CNB961936290A Expired - Fee Related CN1150318C (zh) | 1995-03-31 | 1996-03-28 | 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 |
CNA2004100319155A Pending CN1597953A (zh) | 1995-03-31 | 1996-03-28 | 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 |
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CNA2004100319155A Pending CN1597953A (zh) | 1995-03-31 | 1996-03-28 | 用于预防或治疗恶性肿瘤的HER-2/neu蛋白胞内区 |
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