CN1251134A - 神经营养因子nnt-1 - Google Patents
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- CN1251134A CN1251134A CN98803642A CN98803642A CN1251134A CN 1251134 A CN1251134 A CN 1251134A CN 98803642 A CN98803642 A CN 98803642A CN 98803642 A CN98803642 A CN 98803642A CN 1251134 A CN1251134 A CN 1251134A
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Abstract
本发明公开了编码命名为NNT-1的新型神经营养因子的核酸。本发明还公开了针对NNT-1多肽的氨基酸序列、用于制备NNT-1多肽的方法以及其它相关的方面。这类多肽对刺激B-细胞和/或T细胞的产生以及减轻炎症的反应具有活性。
Description
本申请是1997年2月3日递交的申请顺序号为08/792,019号申请的部分继续申请,将08/792,019号申请引入本文作为参考。
背景技术
发明领域
本发明涉及一种命名为NNT-1的新型多肽和具有神经营养活性的相关多肽、涉及编码这类多肽的新型核酸分子并涉及其它相关的方面。
相关领域描述
许多神经性障碍和疾病至少部分是由特殊种类的神经元的变性或死亡所导致的。例如,帕金森病的特征在于迟缓的随意肌运动、肌肉强直和震颤。这类症状至少部分归因于位于称作黑质的大脑特殊区域的产生多巴胺的神经元的进行性变性。这些神经元(“多巴胺能神经元”)的变性导致称作纹状体的大脑邻接区域中的多巴胺水平下降。这种纹状体含有表达多巴胺受体的神经元;这些神经元涉及控制运动活性。目前对多巴胺能神经元变性的原因还不了解,但是已经将它归因于自由基、过量的铁含量、环境毒素、兴奋性氨基酸神经毒性、以及可能的某些神经营养因子的缺乏(Jenner,《神经病学》(Neurology)增刊3:S6-S12[1995];Adams和Victor编辑《神经病学机理》(Principles of Neurology)第42章:“神经系统的变性疾病”,McGraw Hill,NY[1993])。
诸如肌萎缩性侧索硬化(ALS;也称作Lou Gehrig’s病)、进行性肌肉萎缩、以及遗传运动和感觉神经病(进行性神经病性疾病)这样的所有疾病至少部分是由于位于脊髓腹侧角中的运动神经元蜕变所造成的。
海马(一种定义清楚的结构、它是大脑皮层的部分)在形成长期记忆的过程中起重要作用。例如由局部缺血造成的海马的破坏可以导致无法形成新的记忆。位于海马CA1区域中的锥体CA1神经元的变性是阿尔茨海默病的一个特征。对于发生在诸如中风和大脑损伤这样的疾病中的局部缺血和缺氧性损害来说,这些相同的神经元是选择性易受损的。此外,在癫痫病中,CA1锥体海马神经元以及位于海马CA3区域中的锥体神经元选择性地受到损伤。
纹状体是来自黑质的含多巴胺能神经元的神经末梢的神经支配区。大多数纹状体神经元利用GABA(4-氨基丁酸)作为其神经递质。纹状体是发生在亨廷顿舞蹈病中的进行性神经变性的主要靶向物,其中主要神经元的缺失是使用GABA的纹状体神经元的缺失。
含血清素的神经元位于群集在菱脑中线周围的群体神经元中。这些神经元涉及控制体温、情绪和睡眠。含血清素的神经元系统的障碍包括、例如抑郁症、其它情绪疾病和失眠。
感光细胞是视网膜神经元的特殊亚群并且是产生视觉的原因。感光细胞的损伤和/或死亡可导致失明。诸如因色素性视网膜炎、老年斑变性和静止性夜盲导致的视网膜变性的特征均在于感光细胞外侧部分的进行性萎缩和功能的丧失,其中所述的感光细胞外侧部分是含有将光刺激物转化成电活性的视觉色素的特殊结构。
尽管有一些可获得的用于治疗所述症状和减轻这类疾病严重性的疗法(例如用于治疗帕金森病的L-多巴胺),但是目前没有预防或减少多数上述种类受影响神经元的变性、或促进其修复的有效疗法。
近来,已经根据其对各种神经元的营养活性而鉴定了几种天然存在的蛋白质分子。将这些分子命名为“神经营养因子”。神经营养因子是内源性可溶性蛋白质,它们可以刺激或调节神经元的存活、生长、和/或形态成形性(参见Fallon和Laughlin,《神经营养因子》(Neurotrophic Factors),Academic Press,San Diego,CA[1993])。
根据氨基酸序列的同源性和/或三维结构,公知的神经营养因子属于多肽生长因子的几种不同蛋白质的超家族(MacDonald和Hendrikson,《细胞》(Cell),73:421-424[1993])。神经营养因子的一个族是神经营养蛋白族。通常该族由NGF(神经生长因子)、BDNF(大脑衍生的神经营养因子)、NT-3(神经营养蛋白-3)、NT-4(神经营养蛋白-4)和NT-6(神经营养蛋白-6)组成。
CNTF(睫状神经营养因子)和LIF(白血病抑制因子)是具有神经营养活性的细胞因子多肽。根据它们的结构特征和受体组成,这些多肽与一族造血细胞因子有关,该族造血细胞因子包括IL-6(白细胞介素-6)、IL-11(白细胞介素-11)、G-CSF(粒细胞集落刺激因子)和制癌蛋白-M。本发明的NNT-1具有显著类似于各种该族神经营养因子的特征。参见附图6。
GDNF(神经胶质衍生的神经营养因子)是一种属于TGF-β(转化生长因子β)超家族的神经营养因子。GDNF表现出对多巴胺能和运动神经元的有效促进存活和分化的作用(Lin等,《科学》(Science)260:1130-1132[1993];Yan等,《自然》(Nature)373:341-344[1995])。
尽管公知这些神经营养因子可以促进神经元的生长和/或存活,但是几乎很少有人了解有关与这些因子一起起作用的分子的情况。在一种可以鉴定其它神经蛋白和相关分子的方式中,给予动物一种或多种公知对神经系统有作用的化合物,然后对组织分析涉及对该化合物产生神经反应的基因的诱导情况。例如,可以筛选在某些神经系统的组织、诸如大脑的海马区中诱导的基因。该技术由Nedivi等(《自然》(Nature),363:718-722[1993];Nedivi等,《美国国家科学院学报》(Proc.Natl.Acad Sci.USA),93:2048-2053[1996])用于鉴定海马齿状回中诱导的新型基因对给予称作红藻氨酸(海人草酸)的谷氨酸的神经递质类似物的反应。
通过传入神经元的活性和/或通过神经元损伤来调节许多神经营养因子的表达,所述神经营养因子诸如NGF、BDNF、NT3、GDNF、bFGF、IGF-1和TGF-β。在海马的齿状回中可以观察到这些基因中的一些对谷氨酸类似物红藻氨酸的强诱导反应(Isackson,《神经生物学中的最新观点》5:50-357[1995])。看起来红藻氨酸的处理可以增加新型化合物从警觉大鼠的海马中的释放,且看起来这种活性不同于公知的神经营养因子的作用(Humpel等,《科学》(Science),269:552-554[1995])。
鉴于许多神经系统疾病和障碍还没有公知的疗法这一事实,本领域中存在一种对确定用于治疗神经疾患和疾病的新型化合物的需求,所述疾病诸如帕金森病、肌萎缩性侧索硬化(ALS)、阿尔茨海默病、中风、以及影响视觉的各种变性疾病。
本文中另有证据证明NNT-1化合物可以具有调节免疫系统的生物活性、特别是通过使得B-细胞和T-细胞的生产增加的方式。
因此,本发明的一个目的是提供可用于促进神经元再生并恢复神经功能的新型化合物。
本发明的另一个目的是提供治疗神经性疾病、诸如那些本文所列疾病的方法。
本发明的另一个目的是提供治疗免疫性疾病、诸如那些本文所列疾病的方法。
对于本领域普通技术人员来说,从本发明公开的技术内容中,这些和其它的目的是显而易见的。
发明概述
在一种实施方案中,本发明提供了编码多肽的一种核酸分子,它选自如下核酸分子组成的组:
(a)SEQ ID NO:1的核酸分子;
(b)SEQ ID NO:3的核酸分子;
(c)编码SEQ ID NO:2的多肽或其生物活性片段的核酸分子;
(d)编码一种与SEQ ID NO:2多肽至少有70%同一性的多肽的核酸分子;
(e)在严格条件下与上述(a)-(d)中任意一种核酸分子杂交的核酸分子;以及
(f)作为上述(a)-(e)中任意一种核酸分子的互补序列的核酸分子。
在另一种实施方案中,本发明提供了编码多肽的一种核酸分子,它选自如下核酸分子组成的组:
(a’)SEQ ID NO:4的核酸分子;
(b’)编码SEQ ID NO:5的多肽或其生物活性片段的核酸分子;
(c’)编码一种与SEQ ID NO:5多肽有至少70%同一性的多肽的核酸分子;
(d’)在严格条件下与上述(a’)-(c’)中任意一种核酸分子杂交的核酸分子;以及
(e’)作为上述(a’)-(d’)中任意一种核酸分子的互补序列的核酸分子。
在另一种实施方案中,本发明提供了含有这些核酸分子的载体和含有该载体的宿主细胞(原核或真核细胞)。
本发明进一步提供了一种NNT-1多肽,它选自下列多肽组成的组:
(a)SEQ ID NO:2的多肽;
(b)SEQID NO:2的1-198位氨基酸的多肽;
(c)与(a)或(b)的多肽至少有70%同一性的多肽;以及
(d)(a)-(c)中的任意一种多肽的生物活性片段。
本发明进一步提供了一种NNT-1多肽,它选自下列多肽组成的组:
(a’)SEQ ID NQ:5的多肽;
(b’)SEQ ID NO:5的1-198位氨基酸的多肽;
(c’)与(a’)或(b’)的多肽至少70%同一性的多肽;以及
(d)(a’)-(c’)中的任意一种多肽的生物活性片段。
可选择的情况是,NNT-1多肽可以或可以不含有氨基末端甲硫氨酸。
在另一种实施方案中,本发明提供了一种用于生产NNT-1多肽的方法,其中多肽可以是SEQ ID NO:2或SEQ ID NO:5、SEQ ID NO:2的1-198位氨基酸、SEQ ID NO:5的1-198位氨基酸、或它们的生物活性片段,且其中该方法包括下列步骤:
(a)在一种合适的宿主中表达由NNT-1核酸分子编码的一种多肽;并且
(b)分离该多肽。
本发明进一步提供了抗NNT-1抗体。
附图的简要说明
附图1描绘了编码人NNT-1的cDNA的核酸序列(SEQ ID NO:1)。
附图2描绘了针对NNT-1的人体基因组DNA的核酸序列(SEQ IDNO:3)。
附图3描绘了当翻译自cDNA(SEQ ID NO:2)时针对的人NNT-1的氨基酸序列(SEQ ID NO:1)。前27个氨基酸可以代表一个信号肽序列,使得NNT-1的成熟形式起始于如号码1表示的亮氨酸。*表示终止密码子。
附图4描绘了编码鼠NNT-1的cDNA的核酸序列(SEQ ID NO:4)。
附图5描绘了当翻译自cDNA(SEQ ID NO:4)时针对的鼠NNT-1的氨基酸序列(SEQ ID NO:5)。前27个氨基酸可以代表一个信号肽序列,使得鼠NNT-1的成熟形式起始于如号码1表示的亮氨酸。*表示终止密码子。
附图6描绘了NNT-1、IL-11(SEQ ID NO:8)、IL-6(SEQ IDNO:9)、G-CSF(SEQ ID NO:10)、心营养蛋白(cardiotrophin)(SEQ ID NO:11)、CNTF(SEQ ID NO:12)、制癌蛋白(SEQ IDNO:13)和LIF(SEQ ID NO:14)的氨基酸的比较情况。在每一种情况中,均比较人体分子。
附图7描绘了针对与人CNTF相比的人NNT-1的鸡运动神经元活性检测结果的示意图。
附图8描绘了针对与人CNTF相比的人NNT-1的鸡交感神经元活性检测结果的示意图。
附图9描绘了来自阴性对照小鼠(#22)的正常脾,20x物镜,H&E染色。
附图10描绘了来自患有淋巴增生的NNT-1转基因小鼠(#62)的脾(箭头)。
附图11描绘了来自对照小鼠的正常肝,10x物镜,H&E染色。
附图12描绘了来自患有窦状隙中(箭头)和周围血管淋巴聚集的NNT-1转基因小鼠(#60)的肝,H&E染色。
附图13描绘了表明NNT-1诱导血清SAA的数据(p<0.001)。每组有5只小鼠。
附图14描绘了表明NNT-1增强由血清中皮质酮的IL-1的诱导作用的数据(p<0.01)和增加与IL-1无关的皮质酮血清水平的数据(p<0.001)。每组有5只小鼠。
附图15描绘了表明NNT-1增强由血清中IL-6中的IL-1的诱导作用的数据(p<0.001)。每组有5只小鼠。
附图16描绘了表明NNT-1阻断LPS诱导的血清TNF水平增加的数据(p<0.001)。在LPS治疗组中有10只小鼠,其它组中有5只小鼠。
附图17描绘了表明NNT-1增加小鼠体内外周淋巴节中总数(p<0.04)的数据和CD45-阳性细胞的数据(p<0.001)。
发明详述
本发明范围中所包括的技术内容是NNT-1多肽、诸如SEQ ID NO:2或SEQ ID NO:5的多肽,及其相关生物活性多肽片段和衍生物。本发明范围内还包括的技术内容是编码这些多肽的核酸分子以及用于制备该多肽的方法。
I.NNT-1蛋白质/多肽、片段及其衍生物
本文所用的术语“NNT-1蛋白质”或“NNT-1多肽”指的是具有本文针对NNT-1所述特性的任意蛋白质或多肽。NNT-1多肽可以或可以不含有氨基末端甲硫氨酸,这取决于、例如它的制备方式。通过举例说明,NNT-1蛋白质或NNT-1多肽指的是:
(1)由下列任意一项所定义的NNT-1核酸分子编码的氨基酸序列:
(a)SEQ ID NO:1的核酸分子;
(b)SEQ ID NO:3的核酸分子;
(c)编码SEQ ID NO:2的多肽或其生物活性片段的核酸分子;
(d)编码一种与SEQ ID NO:2多肽至少70%同一性的多肽的核酸分子;
(e)在严格条件下与上述(a)-(d)中任意一种核酸分子杂交的核酸分子;和
(f)作为上述(a)-(e)中任意一种核酸分子的互补序列的核酸分子;以及
(a’)SEQ ID NO:4的核酸分子;
(b’)编码SEQ ID NO:5的多肽或其生物活性片段的核酸分子;
(c’)编码一种与SEQ ID NO:5多肽至少70%同一性的多肽的核酸分子;
(d’)在严格条件下与上述(a’)-(c’)中任意一种核酸分子杂交的核酸分子;和
(e’)作为上述(a’)-(d’)中任意一种核酸分子的互补序列的核酸分子;以及
(2)与SEQ ID NO:2或SEQ ID NO:5的NNT-1多肽比较,导致一个或多个氨基酸取代、缺失和/或插入的NNT-1基因的天然存在的等位变体,和/或
(3)如本文所提供的化学修饰的衍生物及其核酸或氨基酸序列变体。
已经用于实施本发明的NNT-1多肽可以是天然存在的全长多肽、或者是截短的多肽或肽(即“片段”)。
多肽可以是成熟形式或者它们可以与天然或异质的信号肽结合。例如,人和小鼠NNT-1分别含有SEQ ID NO:2和5的-27位至-1位氨基酸的信号肽。
如下所述,可以将多肽或片段进行化学修饰,即将其糖基化、磷酸化和/或与一种聚合物连接;且它们可以含有一个氨基末端甲硫氨酸,这取决于如何制备它们。此外,该多肽或片段可以是天然存在的NNT-1多肽的变体(即与天然存在的NNT-1比较,它们可以含有一个或多个氨基酸的缺失、插入和/或取代)。
本文所用的术语“NNT-1片段”指的是小于天然存在的NNT-1蛋白质的全长氨基酸序列、而定性地具有与上述NNT-1多肽或NNT-1蛋白质基本相似的生物活性的肽或多肽。可以将这类片段在氨基末端、羧基末端或两个末端进行截短;且可以将这类片段进行化学修饰。这类NNT-1片段可以用或可以不用氨基末端甲硫氨酸来制备。该片段的活性可以大于、或小于全长(成熟)NNT-1多肽的活性、或与之相同。正如标准活性检测法、诸如本文实施例部分所列的那些方法所测定的,优选该片段的活性≥50%、更优选≥65%、最优选≥80%的全长多肽的活性。本发明的某些典型片段包括从NNT-1多肽的C末端、N-末端或两个末端去除了1-20个氨基酸的多肽。
本文所用的术语“NNT-1衍生物”或“NNT-1变体”指的是NNT-1多肽、蛋白质或片段,它们1)例如通过添加一个或多个聚乙二醇分子、糖类、磷酸酯类或其它不与野生型NNT-1多肽天然结合的这类分子已经被化学修饰;和/或它们2)与附图3(人)或附图5(小鼠)中所列NNT-1氨基酸序列相比,含有一个或多个核酸或氨基酸序列的取代、缺失和/或插入。
本文所用的术语“生物活性多肽”和“生物活性片段”指的是按照以上针对NNT-1描述的肽或多肽,其中NNT-1对于(a)神经元(例如运动神经元和/或交感神经元)或(b)诸如B细胞和T细胞这样的免疫细胞起到了生长因子的作用。
可以将在活性测定中本身不具备活性的NNT-1片段和/或衍生物用作体外或体内NNT-1受体的调节剂(例如抑制剂或刺激剂)或用于制备抗NNT-1多肽的抗体。
本发明NNT-1的氨基酸变体优选与SEQ ID NO:2或SEQ ID NO:5至少有70%同一性、更优选与SEQ ID NO:2或SEQ ID NO:5至少有约80%同一性、甚至更优选90%与SEQ ID NO:2或SEQ IDNO:5至少有约同一性。
通过通常用于比较两种多肽在氨基酸位置上的相似性的标准方法可以测定序列同一性的百分比。举例来说、使用诸如BLAST或FASTA这样的计算机程序,将待测序列同一性百分比的两种多肽的相应氨基酸排列成最佳配对(“配对广度”,它可以包括全长的一个或两个序列或预测定的一个或两个序列的部分)。每一计算机程序提供一种“默认”开口补偿(penalty)和一种“默认”缺口补偿,并提供一种得分矩阵、诸如PAM250。可以将一种标准得分矩阵(参见Dayhoff等:《蛋白质序列和结构图谱集》(Atlas of Protein Sequence andStructure)第5卷增刊3[1978])与该计算机程序联用。然后使用在如下的诸如FASTA这样的程序中包含的公式,可以来计算同一性百分比:
与野生型NNT-1相比,至少70%相同的多肽一般含有一个或多个氨基酸的取代、缺失和/或插入。取代通常是保守的以便对蛋白质的总净电荷、极性、或疏水性有较小或没有影响,而取代可以任意增加NNT-1的活性。保守取代的情况如下表I中所列。
表I
保守的氨基酸的取代
碱性: 精氨酸
赖氨酸
组氨酸
酸性: 谷氨酸
天冬氨酸
极性: 谷氨酰胺
天冬酰胺
疏水性: 亮氨酸
异亮氨酸
缬氨酸
芳族的: 苯丙氨酸
色氨酸
酪氨酸
小: 甘氨酸
丙氨酸
丝氨酸
苏氨酸
甲硫氨酸
本发明还包括NNT-1的种的同系物;例如除人以外,来自诸如狗、猫、小鼠、大鼠、猴、马、猪、山羊、家兔、绵羊等这样的哺乳动物物种的NNT-1同系物也是所预计的。将小鼠cDNA和蛋白质的序列定为SEQ ID NOS:4和5。
本发明进一步包括嵌合多肽,诸如与另一种多肽的全部或部分结合的NNT-1。优选该嵌合多肽含有与另一种神经营养因子的全部或部分结合的NNT-1,所述的神经营养因子诸如BDNF、GDNF、NT-3、NT-4、NT-5、NT-6等。可以将所述多肽的N与C末端、C与C末端或N与N末端结合。
II.核酸
当本文所用的术语“NNT-1”用于描述核酸分子时,该术语指的是如上所述的核酸分子或其片段。
术语“严格条件”指的是在仅允许将诸如寡核苷酸或cDNA分子探针这样的核酸分子与高度同源序列结合的条件下进行的杂交和洗涤。一种严格的洗涤溶液是在55℃-65℃的温度下使用的0.015MNaCl、0.005M柠檬酸钠和0.1%SDS。另一种严格的洗涤溶液是在50℃-65℃的温度下使用的0.2×SSC和0.1%SDS。在将寡核苷酸探针用于筛选cDNA或基因组文库的情况下,可以使用下列严格的洗涤条件。一种方案是在35℃-62℃的温度下使用含有0.05%焦磷酸钠的6×SSC,这取决于寡核苷酸探针的长度。例如,在35-40℃下洗涤14个碱基对的探针、在45-50℃下洗涤17个碱基对的探针、在52-57℃下洗涤20个碱基对的探针、且在57-63℃下洗涤23个碱基对的探针。可以将温度升高2-3℃,其中背景非特异性结合看起来很高。第二种方案是使用氯化四甲铵(TMAC)洗涤寡核苷酸探针。一种严格的洗涤溶液是3M TMAC、50mM Tris-HCl(pH8.0)和0.2%的SDS。使用该溶液的洗涤温度是探针长度的函数。例如,在约45-50℃下洗涤17个碱基对的探针。
对于在哺乳动物组织或体液样品中NNT-1DNA或RNA的存在来说,可以将自身不编码在活性测定中有活性的多肽的NNT-1核酸分子、片段、和/或衍生物定性地或定量地用作在用于测试的诊断测定中的杂交探针。
本发明范围内还包括编码与上述文本所述天然或异源信号肽和/或嵌合多肽结合的NNT-1多肽的NNT-1核酸分子。
III.用于制备NNT-1多肽的方法A.重组方法
使用诸如Sambrook等(《分子克隆:实验室手册》冷泉港实验室出版社,冷泉港,NY[1989])和/或Ausubel等编辑(《分子生物学最新技术方案》,Green Publishers Inc.以及Wiley和Sons,NY[1994])所列的那些众所周知的重组DNA技术方法可以制备全长NNT-1多肽或其片段。例如通过筛选基因组或cDNA文库或通过PCR扩增可以获得编码NNT-1蛋白质或其片段的一种基因或cDNA。另一方面,使用诸如由Engels等所述的那些本领域技术人员众所周知的方法通过化学合成可以制备编码NNT-1多肽或片段的一种基因(Angew.Chem.Intl.Ed.,28:716-734[1989])。这些方法尤其包括用于核酸合成的磷酸三酯、亚磷酰胺和H-磷酸酯法。用于这类化学合成的优选方法是使用标准亚磷酰胺化学法的聚合物支持的合成法。一般来说,编码NNT-1多肽的DNA长度为几百个核苷酸。使用这些方法可以将大于约100个核苷酸的核酸合成为几个片段。然后可以将所述片段相互连接成全长NNT-1多肽。通常,编码多肽氨基末端的DNA片段含有ATG,它编码甲硫氨酸残基。该甲硫氨酸可以或可以不存在于NNT-1多肽的成熟形式之上,这取决于宿主细胞中产生的多肽是否是从该细胞中分泌的。
在某些情况中,制备天然存在的NNT-1的核酸和/或氨基酸变体可能是所希望的。使用位点定向突变或PCR扩增可以生产核酸变体(其中将一个或多个核苷酸设计成不同于野生型或天然存在的NNT-1的形式),其中引物具有所需的点突变(参见Sambrook等,见上文;和Ausubel等,见上文,对于突变技术的描述)。也可以将使用上文由Engels等所述方法的化学合成用于制备这类变体。也可以使用本领域技术人员公知的其它方法。优选的核酸变体是那些含有核苷酸取代的物质,其中核苷酸的取代导致在用于产生NNT-1的宿主细胞中出现优选的密码子。其它优选的变体是那些编码如上所述与野生型相比为保守的氨基酸变体的物质(例如,其中天然存在的氨基酸侧链的电荷或极性基本上没有因用不同氨基酸的取代而改变)、和/或那些设计成在NNT-1上产生新型糖基化和/或磷酸化位点的物质、或那些设计成使NNT-1上缺失存在的糖基化和/或磷酸化位点的物质。
可以将NNT-1基因或cDNA插入用于在宿主细胞中表达的合适的表达载体。所选择的该载体在所用特定的宿主细胞中起作用(即该载体与宿主细胞机器相容,使得可以发生NNT-1基因的扩增和/或该基因的表达)。可以在原核、酵母、昆虫(杆状病毒系)和/或真核宿主细胞中扩增/表达该NNT-1多肽或其片段。宿主细胞的选择至少部分取决于NNT-1多肽或其片段是否被糖基化。如果如此,那么酵母、昆虫或哺乳动物宿主细胞是优选的;酵母细胞将使多肽糖基化,且昆虫和哺乳动物细胞可以使多肽糖基化和/或磷酸化,此时,这种情况自然发生在NNT-1多肽上(即“天然”糖基化和/或磷酸化)。
一般来说,在任何宿主细胞中所用的载体含有5’侧翼序列(也称作“启动子”),和其它调节元件,诸如增强子、复制元件起点、转录终止元件、含有供体和受体剪接位点的完全内含子序列、信号肽序列、核糖体结合位点元件、聚腺苷酸化序列、用于插入编码待表达多肽的核酸的多接头区以及选择标记元件。下面将讨论这些元件中的每一种。可选择的是,载体可以含有一种“标记”序列,即位于编码聚-His(诸如六-His)的NNT-1编码序列的5’或3’末端的寡核苷酸序列或另一种小的免疫原性序列。这种标记物将与蛋白质一起被表达,并且这种标记物可用作用于纯化来自宿主细胞的NNT-1多肽的亲和标记物。可选择的是,随后可以通过各种方式、诸如使用一种选择的肽酶,将该标记物从纯化的NNT-1多肽中去除。
5’侧翼序列可以是同源的(即来自与宿主细胞相同的种和/或株)、异源的(即来自不是宿主细胞的种或株的一个种)、杂交的(即来自一种以上来源的5’侧翼序列的结合)、合成的、或者它可以是天然NNT-1的5’侧翼序列。就此而论,5’侧翼序列的来源可以是任意单细胞的原核或真核生物体、任意的脊椎动物或无脊椎动物生物体、或任意的植物,条件是5’侧翼序列在宿主细胞机器中起作用并且可以被宿主细胞机器激活。
通过本领域众所周知的几种方法的任意一种方法可以获得用于本发明载体的5’侧翼序列。一般来说,通过做图谱和/或通过限制酶切消化已经预先鉴定了本文所用的5’侧翼序列而不是NNT-15’侧翼序列且因此可以使用合适的限制酶从适当的组织来源中分离本文所用的5’侧翼序列。在某些情况中,5’侧翼序列的全部核苷酸序列可以是公知的。此处,使用上述用于核酸合成或克隆的方法可以合成5’侧翼序列。
如果已知全部或仅部分的5’侧翼序列,那么它可以使用PCR和/或通过用来自相同或另一物种的合适的寡核苷酸和/或5’侧翼序列片段筛选基因组文库来获得。
如果5’侧翼序列不是已知的,那么可以从可含有例如编码序列或者甚至另一种基因或多种基因的更长一段DNA中分离含有5’侧翼序列的DNA片段。使用一种或多种仔细选择的酶、通过限制酶切消化来完成分离过程,从而分离出合适的DNA片段。消化后,通过琼脂糖凝胶纯化、Qiagen柱或其它本领域技术人员公知的方法可以分离所需的片段。达到这一目的的合适酶的选择对于本领域普通技术人员来说是显而易见的。
复制元件的起点一般是商购原核表达载体的一部分并且在宿主细胞中辅助该载体的扩增。在某些情况中,将该载体扩增至某一拷贝数这一过程对于NNT-1多肽的最佳表达来说是重要的。如果选择的载体不含有复制位点的起点,那么可以以公知的序列为基础、通过化学方式来合成它并且将它连入载体。
转录终止元件一般位于NNT-1多肽编码序列的3’末端且用于终止NNT-1多肽的转录。原核细胞中转录终止元件通常是一个G-C富含片段,后面是一个poly T序列。当从一种文库中简易克隆该元件或者甚至商购该元件作为载体的部分时,它也可以使用用于核酸合成的方法、诸如那些上述的方法方便地来合成。
选择标记基因元件编码对在选择性培养基中培养的宿主细胞的存活和生长而言所必需的蛋白质。典型的选择标记基因编码具有下列特征的蛋白质:(a)对于原核宿主细胞来说,对抗菌素或其它毒素赋予了抗性,例如氨苄青霉素、四环素或卡那霉素;(b)补充细胞的营养缺陷型缺失;或(c)提供不会从复合培养基中得到的关键营养物。优选的选择标记是卡那霉素抗性基因、氨苄青霉素抗性基因和四环素抗性基因。
通常称作SD序列(原核细胞)或Kozak序列(真核细胞)的核糖体结合元件是mRNA翻译起始所必需的。该元件一般位于待合成的NNT-1多肽的3’端至启动子和5’端至编码序列。SD序列是可变的,但一般是一种聚嘌呤(即含有高含量的A-G)。已经鉴定了许多SD序列,使用上述所列的方法可以方便地合成它们中的每一种并将它们用于原核载体。
在希望从宿主细胞中分泌NNT-1的那些情况中,可以将信号序列用于指导NNT-1多肽由其被合成的宿主细胞中出来,且可以使蛋白质羧基末端部分缺失以便防止膜的锚着。一般来说,将信号序列定位在NNT-1核酸序列的编码区中、或直接定位在NNT-1编码区的5’末端。已经鉴定了许多信号序列,且可以将在所选宿主细胞中起作用的它们中的任意一种与NNT-1基因一起使用。因此,该信号序列可以是与NNT-1多肽同源的或异源的。此外,使用上述所列的方法可以以化学方式合成该信号序列。在大多数情况中,通过存在的信号肽从宿主细胞中分泌多肽这一过程将导致氨基末端甲硫氨酸从该多肽中被除去。用于进行NNT-1多肽的表达和分泌的分泌序列的实例选自tPA前导序列(参见,例如Rickles等《生物化学杂志》(J.Biol.Chem.)263:1563-1560[1988]和Feng等《生物化学杂志》(J.Biol.Chem.)265:2022-2027[1990])、BPO前导序列和心营养蛋白(cardiotrophin)前导序列。
在许多情况中,通过载体上存在的一种或多种内含子来增加NNT-1多肽的转录;在真核宿主细胞、特别是哺乳动物宿主细胞中产生NNT-1这一事实是非常确定的。所用内含子可以是NNT-1核酸序列内天然存在的,特别是其中所用的NNT-1序列是一种全长基因组序列或其片段。如果在NNT-1 DNA序列(到目前为止最多的是cDNAs)中内含子不是天然存在的,那么该内含子可以从另一种来源获得。当将内含子必须转录成有效的时,相对于5’侧翼序列和NNT-1编码序列的内含子的位置是重要的。就此而言,如果NNT-1核酸序列是cDNA序列,那么内含子的优选位置是3’端至转录起始位点和5’端至polyA转录终止序列。对于NNT-1 cDNAs来说,优选内含子位于NNT-1编码序列的一侧或另一侧(即5’或3’)上,使得它不切断该编码序列。可以将来自任意来源的任意内含子、包括任何病毒、原核和真核(植物或动物)生物体用于实施本发明,条件是它与插入的宿主细胞相容。本文还包括的是合成的内含子。可选择的是,在载体中可以使用一种以上的内含子。
如果上述所列的一种或多种元件已经不存在于待用的载体中,那么可以分别获得它们并将它们连入该载体。用于获得所述元件中的每一种的方法是本领域技术人员众所周知的并且可与上述所列方法(即DNA的合成、文库筛选等)相比拟。
一般由诸如市售可得的载体这样的起始载体来构建用于实施本发明的最终载体。这类载体可以含有或可以不含有完整载体中所包括的某些元件。如果没有任何一种所需元件存在于起始载体中,那么通过用合适的限制酶切割该载体可以分别将每一种元件连入载体,使得所连入元件的末端和载体的末端适于连接。在某些情况中,必须使相互连接的末端“钝化”,以便获得一种令人满意的连接方式。在有所有四种核苷酸存在的情况下,使用Klenow DNA聚合酶或T4 DNA聚合酶通过首先补平“粘端”来实现钝化。该过程是本领域众所周知的且例如上文Sambrook等所述。
另一方面,可以首先将待插入载体的两种或多种元件相互连接(如果它们以相互邻接的方式定位),然后将它们连入该载体。
用于构建该载体的一种其它方法是在一种反应混合物中同时进行各种元件的全部连接。此处,将产生许多无义或非功能性载体,原因是不适当地连接或插入了这些元件,然而,通过限制酶切消化可以鉴定并选择功能性载体。
用于实施本发明的优选载体是那些与细菌、昆虫和/或哺乳动物宿主细胞相容的载体。这类载体尤其包括pCRII(Invitrogen Company,San Diego,CA)、pBSII(Stratagene Company,LaJolla,CA)和pETL(BlueBacII;Invitrogen)。
在已经构建载体并已经将NNT-1核酸插入该载体的合适位点后,可以将该完整的载体插入用于扩增和/或NNT-1多肽表达的合适的宿主细胞中。
宿主细胞可以是原核宿主细胞(诸如大肠杆菌)或真核宿主细胞(诸如一种酵母细胞、一种昆虫细胞或一种脊椎动物细胞)。当在合适的条件下培养时,该宿主细胞可以合成NNT-1蛋白质,随后可以从培养基中收集这种蛋白质(如果宿主细胞将其分泌入培养基)或直接从产生该蛋白质的宿主细胞中收集它(如果它不是分泌的)。收集后,可以使用诸如分子筛层析、亲和层析等方法来纯化这种NNT-1蛋白质。
宿主细胞的选择部分取决于NNT-1蛋白质是否被糖基化或磷酸化(其中真核宿主细胞的情况是优选的),且宿主细胞能够将蛋白质“折叠”成其天然三级结构(例如合适的二硫键取向等)的方式使得通过该细胞来制备生物活性蛋白质。然而,如果该宿主细胞不合成生物活性NNT-1,那么使用如下讨论的合适的化学条件在合成后可以将NNT-1“折叠”。
合适的细胞或细胞系可以是哺乳动物细胞,诸如中国仓鼠卵巢细胞(CHO)或3T3细胞。合适的哺乳动物宿主细胞的选择和用于转化、培养、扩增、筛选和产物的产生和纯化的方法是本领域公知的。其它合适的哺乳动物细胞系是猴COS-1和COS-7细胞系以及CV-1细胞系。另外典型的哺乳动物宿主细胞包括灵长类动物细胞系和啮齿类动物细胞系、其中包括转化的细胞系。正常的二倍体细胞、来源于初生组织体外培养物的细胞株以及初生外植块也是合适的。候选的细胞在选择基因中可以是基因型缺损的或者可以含有显著作用的选择基因。其它合适的哺乳动物细胞系包括但不限于HeLa、小鼠L-929细胞、来源于Swiss、Balb-c或NIH小鼠的3T3系、BHK或HaK仓鼠细胞系。
类似用作适于本发明的宿主细胞是细菌细胞。例如大肠杆菌的各种菌株(例如HB101、DH5α、DH10和MC1061)作为生物技术领域中的宿主细胞是众所周知的。还可以将枯草芽孢杆菌、假单胞菌属的种、其它芽孢杆菌属的种、链霉菌属的种等的各种菌株用于本方法。
为本领域技术人员公知的许多酵母细胞菌株也可以用作用于表达本发明多肽的宿主细胞。另外,如果需要,可以将昆虫细胞用作本发明方法中的宿主细胞(Miller等,《遗传工程》(GeneticEngineering)8:277-298[1986])。
使用诸如氯化钙法、电穿孔法、微注射法、脂转染法或DEAE葡聚糖法这类的方法可以完成将载体插入所选宿主细胞中的过程(也称作“转化”或“转染”)。所选方法部分上是所用宿主细胞类型的函数。这些方法和其它合适的方法对于本领域技术人员来说是众所周知的并且例如上文中Sambrook等所列。
使用本领域技术人员众所周知的标准培养基可以培养含有该载体的宿主细胞(即“转化”或“转染”的)。通常该培养基含有细胞生长和存活所必需的全部营养物。用于培养大肠杆菌细胞的合适培养基是、例如Luria肉汤(LB)和/或Terrific肉汤(TB)。用于培养真核细胞的合适培养基是RPMI 1640、MEM、DMEM,可以用作为所培养的具体细胞系所需的血清和/或生长因子补充上述所有培养基。用于昆虫培养的合适培养基是Grace’s培养基,将该培养基用所需的yeasto1ate、水解乳白蛋白和/或胎牛血清进行了补充。
一般来说,用于转化细胞选择性生长的抗菌素或其它化合物仅作为补充物加入培养基。所用化合物由存在于质粒上的选择标记元件来确定,其中用所述质粒来转化宿主细胞。例如,如果选择标记元件是卡那霉素抗性元件,那么加入培养基的化合物将是卡那霉素。
使用本领域公知的标准方法可以估计宿主细胞中产生的NNT-1多肽的量。这类方法包括但不限于蛋白质印迹分析法、SDS-聚丙烯酰胺凝胶电泳法、非变性凝胶电泳法、HPLC分离法、免疫沉淀法和/或诸如DNA结合凝胶位移测定这样的活性测定法。
如果已经将NNT-1多肽设计成从宿主细胞中分泌的话,那么在细胞培养基中可以发现大部分的多肽。以这种方式制备的多肽一般不含有氨基末端甲硫氨酸,因为在从细胞分泌的过程中它被去除。但是如果NNT-1多肽不从宿主细胞中分泌的话,它将存在于胞质中(对于真核、革兰氏阳性细菌和昆虫宿主细胞来说)或周质中(对于革兰氏阴性细菌宿主细胞来说)并且可以含有氨基末端甲硫氨酸。
对于胞内NNT-1蛋白质来说,一般首先将宿主细胞用机械或渗透方式破碎以便将胞质内容物释放入缓冲溶液。然后可以从这种溶液中分离NNT-1多肽。
使用各种技术可以完成从溶液中纯化NNT-1多肽。如果已经合成的该多肽使得它含有诸如六组氨酸(NNT-1/hexaHis)或在其羧基或氨基末端的其它小肽这样的标记物,那么它可以通过使该溶液经过亲和柱以一步法而基本上得到纯化,其中柱基质直接对该标记物或对该多肽具有高度的亲和性(即特异性识别NNT-1的单克隆抗体)。例如,聚组氨酸以巨大的亲和性和特并性与镍结合,由此可以将镍亲和柱(诸如Qiagen镍柱)用于纯化NNT-1/聚-His。(参见,例如,Ausubel等编辑《最新分子生物学技术方案》(Current Protocols inMolecular Biology)第10.11.8节,John Wiley & Sons,New York[1993])。
如果NNT-1多肽不含有标记物且没有得到抗体,那么可以使用用于纯化的其它众所周知的方法。这类方法包括但不限于离子交换层析法、分子筛层析法、HPLC、与凝胶洗脱联用的天然凝胶电泳法和制备等电聚焦法(“异原”机/技术,Hoefer Scientific)。在某些情况中,可以将这些技术中的两种或多种联用以便达到增加纯度的目的。用于纯化的优选方法包括与制备等电聚焦法联用的聚组氨酸标记法和离子交换层析法。
如果预计主要在细菌周质空间内或在真核细胞胞质内发现NNT-1多肽,那么如果所加工的多肽已经形成了这类复合物,则使用本领域技术人员公知的任意标准技术可以从宿主细胞中提取包括内含体(例如革兰氏阴性细菌)在内的周质或胞质的内含物。例如,用弗氏压碎器、匀浆和/或超声处理可以将宿主细胞裂解以便释放周质的内含物。然后可以将匀浆进行离心。
如果NNT-1多肽已经在周质中形成了内含体,那么内含体通常可以与细胞内和/或外膜结合并由此主要在离心后的沉淀物中得以发现。然后可以将沉淀物用离液剂、诸如胍或脲处理以便使内含体释放、分裂并溶解。然后使用凝胶电泳法、免疫沉淀法等可以分析目前是可溶形式的NNT-1多肽。如果需要分离NNT-1多肽,那么使用诸如如下所列和由Marston等(《酶法》(Meth.Enz.)182:264-275[1990])所述的标准方法可以完成分离过程。
如果NNT-1多肽内含体没有在宿主细胞的周质中形成到一种显著的程度,那么主要在离心细胞匀浆后的上清液中发现NNT-1多肽,且使用如下所列的方法可以从该上清液中分离NNT-1多肽。
在优选部分或全部分离NNT-1多肽的那些情况中,使用本领域技术人员众所周知的标准方法可以实现纯化过程。这类方法包括但不限于:通过电泳、随后进行电洗脱的分离法;各种类型的层析法(免疫亲和法、分子筛法和/或离子交换法);和/或高压液相层析法。在某些情况中,可以优选使用用于完全纯化的一种以上的这些方法。B.化学合成法
除使用重组DNA技术制备并纯化NNT-1多肽以外,还可以通过使用诸如由Merrifield等(《美国化学协会杂志》(J.Am.Chem.Soc.),85:2149[1964])、Houghten等(《美国国家科学院学报》(Proc.Natl.Acad. Sci.USA),82:5132[1985])以及Stewart和Young(《固相肽的合成》(Solid Phase Peptide Synthesis),PierceChem Co.,Rockford,IL[1984])所列本领域公知方法的化学合成法(诸如固相肽合成法)来制备NNT-1多肽、其片段和/或其衍生物。这类多肽可以用或可以不用氨基末端上的甲硫氨酸来合成。使用这些参考文献中所列的方法可以将化学合成的NNT-1多肽或片段氧化以便形成二硫键。可以将NNT-1多肽或片段用作治疗和免疫过程中天然纯化的NNT-1多肽的生物活性或免疫替代物。IV.化学修饰的NNT-1衍生物
在本发明的范围内包括化学修饰的NNT-1组合物(即“衍生物”),其中NNT-1多肽与一种聚合物连接(“NNT-1-聚合物”)。所选聚合物一般是水溶性的,使得与之结合的蛋白质不会在水环境、诸如生理环境中沉淀。通常将所选聚合物修饰成带有一种单一反应基团、诸如用于酰化的活性酯或用于烷基化的醛,使得聚合度可以得到控制而用于本发明的方法中。该聚合物可以是任意的分子量且可以是支链的或非支链的。NNT-1-聚合物的范围中包括聚合物的混合物。对于所制备终产物的治疗用途来说,优选该聚合物是药物上可接受的。
水溶性聚合物或其混合物可以选自下列物质组成的组:例如聚乙二醇(PEG)、一甲氧基聚乙二醇、葡聚糖、纤维素或其它以碳水化合物为骨架的聚合物、聚-(N-乙烯基吡咯烷酮)聚乙二醇、丙二醇均聚物、聚环氧丙烷/环氧乙烷共聚物、聚氧乙基化的多元醇(例如甘油)和聚乙烯醇。
对于酰化反应来说,所选聚合物应含有一个单一的反应的酯基。对于还原性烷基化来说,所选聚合物应含有一个单一反应的醛基。优选的具有反应性的醛是水稳定性的聚乙二醇丙醛或其单C1-C10的烷氧基或芳氧基衍生物(参见美国专利5,252,714)。
NNT-1的聚乙二醇化(Pegylation)可以通过本领域公知的任何聚乙二醇化反应来进行,正如下列参考文献中所述:《生长因子上的转化灶》(Focus on Growth Factors)3:4-10(1992);EP 0 154316和EP 0 401 384。优选的情况是,如下所述通过与一种反应性聚乙二醇分子(或一种类似的反应性水溶性聚合物)的酰化反应或烷基化反应来进行该聚乙二醇化过程。
经酰化的聚乙二醇化一般包括使聚乙二醇(PEG)的活性酯衍生物与NNT-1蛋白质反应。可以将任意公知的或随后发现的反应性PEG分子用于进行NNT-1的聚乙二醇化。优选的活化PEG酯是酯化成N-羟基琥珀酰亚胺(“NHS”)的PEG。正如《生物缀合物化学》5:133-140(1994)中所述,预计本文所用的“酰化”包括但不限于下列NNT-1与一种诸如PEG这样的水溶性聚合物的键合类型:酰胺、氨基甲酸酯、尿烷等。反应条件可以选自聚乙二醇化领域或随后开发的任意公知的那些条件,但条件是应当避免使待修饰的NNT-1种类失活的诸如温度、溶剂和pH这样的条件。
经酰化的聚乙二醇化通常产生聚-Pegylated的NNT-1产物,其中赖氨酸ε-氨基经酰基连接基团而被Pegylated。优选的连接键是酰胺。另外优选所得的产物至少有约95%的单、二或三Pegylated的。然而,通常将形成具有高度聚乙二醇化的某些种类(NNT-1的赖氨酸ε-氨基酸基团与NNT-1氨基末端上的一个α-氨基之和达到最大值),其量取决于所用的具体的反应条件。如果需要,通过标准的纯化技术可以从混合物、特别是未反应的种类中分离更加纯化的Pegylated的种类,所述的标准技术包括渗析、盐析、超滤、离子交换层析、凝胶过滤层析和电泳。
经烷基化的聚乙二醇化通常包括在有还原剂存在的情况下使PEG的末端醛衍生物与一种诸如NNT-1这样的蛋白质进行反应。无论聚乙二醇化的程度如何,优选将PEG基团通过一种-CH2-NH-基团与该蛋白质结合。特别对于-CH2-基团来说,本文将这类键称作“烷基”键。
经还原性烷基化产生单Pegylated产物的衍生作用利用了NNT-1中衍生可得的不同类伯氨基(赖氨酸-N-末端)的不同反应性。一般来说,该反应在可以利用赖氨酸残基的ε-氨基与所述蛋白质N-末端残基的α-氨基之间的pKa差值的pH(见下文)下来进行。通过这类选择性衍生作用,含有诸如醛这样的反应基团的水溶性聚合物与蛋白质的结合得到控制:与该聚合物的缀合主要发生在蛋白质的N-末端而没有显著修饰其它的反应基团、诸如赖氨酸侧链氨基。本发明提供了NNT-1-单聚合蛋白缀合分子的基本上均匀的制剂(即聚合物分子在NNT-1蛋白质上的单一位置中基本上仅(即至少约95%)与NNT-1蛋白质结合)。更具体地说,如果使用聚乙二醇,那么本发明还提供了缺乏可能的抗原连接基团并具有与NNT-1蛋白质直接偶联的聚乙二醇分子的Pegylated的NNT-1蛋白质。
本文所用的一种特别优选的水溶性聚合物是聚乙二醇、缩写为PEG。本文所用的聚乙二醇指的是包括已经用于衍生其它蛋白质的任意形式的PEG,诸如单一(C1-C10)烷氧基或芳氧基聚乙二醇。
一般来说,在用于使生物活性物质与活化的聚合物分子反应的任何合适的条件下可以进行化学衍生。用于制备Pegylated的NNT-1的方法一般包括下列步骤:(a)在使得NNT-1与一个或多个PEG基团结合的条件下,使NNT-1多肽与聚乙二醇(诸如PEG的反应性酯或醛的衍生物)反应;和(b)得到反应产物。一般来说,酰化反应的最佳反应条件将根据公知的参数和所需结果来确定。例如,PEG与蛋白质的比例越大,则聚Pegylated产物的百分比越高。
产生基本上均匀数量的单聚合物/NNT-1蛋白质缀合分子的还原性烷基化一般包括下列步骤:(a)在还原性烷基化条件和在适于允许对所述NNT-1蛋白质氨基末端上的α-氨基进行选择性修饰的pH下使NNT-1蛋白质与一种反应性PEG分子反应;和(b)得到反应产物。
对于总体基本上均匀的单聚合物/NNT-1蛋白质缀合分子来说,还原性烷基化反应条件是使得水溶性聚合物部分与NNT-1的N-末端选择性结合的那些条件。这类反应条件一般在赖氨酸的氨基与N-末端的α-氨基之间产生pKa差(pKa是在使50%的氨基质子化且50%的氨基非质子化时的pH)。该pH还影响所用聚合物与蛋白质之比。一般来说,如果pH越低,那么需要的聚合物与蛋白质之比过量越多(即N-末端α-氨基的反应性越低,则实现最佳条件所需的聚合物的量越大)。如果pH越高,那么聚合物:蛋白质之比不需如此之大(即可用的反应性基团越多,则需要的聚合物分子越少)。对于本发明的目的来说,pH一般在3-5的范围内,优选4-5。
另一重要的需考虑的内容是聚合物的分子量。一般来说,聚合物的分子量越大,则可以与蛋白质结合的聚合物分子的数量越少。类似地,当使这些参数达到最佳值时,应考虑聚合物的分支。一般地,分子量越高(或分支越多),则聚合物:蛋白质之比越高。一般来说,对于本文所预计的聚乙二醇化反应,优选的平均分子量是约2kDa-约100kDa(术语“约”表示±1kDa)。优选的平均分子量为约5kDa-约50kDa,特别优选约12kDa-约25kDa。水溶性聚合物与NNT-1蛋白质之比一般在1∶1-100∶1的范围内,优选(对于聚聚乙二醇化)1∶1-20∶1和(对于单聚乙二醇化)1∶1-5∶1。
使用上述条件,还原性烷基化将使得聚合物与在氨基末端带有α-氨基的任何NNT-1蛋白质选择性结合并提供单聚合物/NNT-1蛋白质缀合物的基本上均匀的制剂。此处所用的术语“单聚合物/NNT-1蛋白质缀合物”指的是由与NNT-1蛋白质分子结合的单一聚合物分子组成的一种组合物。单聚合物/NNT-1蛋白质缀合物优选在位于N-末端而不是在赖氨酸氨基侧基上带有一种聚合物分子。该制剂优选是大于90%的单聚合物/NNT-1蛋白质缀合物、且更优选是大于95%的单聚合物/NNT-1蛋白质缀合物,剩余的是可观测到的未反应分子(即缺乏聚合物部分的蛋白质)。下列实例提供了一种至少约90%是单聚合物/蛋白质缀合物且约10%是未反应蛋白质的制剂。这种单聚合物/蛋白质缀合物具有生物活性。
对于本还原性烷基化来说,还原剂在水溶液中应是稳定的且优选仅能够还原在还原性烷基化的初始过程中形成的席夫碱。优选的还原剂可以选自由下列物质组成的组:硼氢化钠、氰基硼氢化钠、二甲胺甲硼烷、三甲胺甲硼烷和吡啶甲硼烷。特别优选的还原剂是氰基硼氢化钠。
其它反应参数诸如溶剂、反应时间、温度等以及产物纯化的方式可以根据涉及用水溶性聚合物衍生蛋白质的公开的信息来确定。
如上所述,通过酰化和/或烷基化方法可以制备聚合物-NNT-1蛋白质缀合物分子的一种混合物,且可以对包括在该混合物中的单聚合物/蛋白质缀合物的比例进行选择。因此,如果需要,可以制备与不同数量聚合物分子连接的各种蛋白质的混合物(即二、三、四等)并将它们与使用本发明方法制备的单聚合物/NNT-1蛋白质缀合物合并。
通常通过将本聚合物/NNT-1给药可缓解或调节的疾病包括一般针对NNT-1分子的那些本文所述的疾病。然而,与非衍生的分子相比,本文公开的聚合物/NNT-1分子可以具有另外的活性、即增强或降低的活性或其它特征。V.组合物
在治疗神经或免疫系统疾病的过程中,可以将NNT-1多肽及其片段(不管是否是被化学修饰的)单独使用或与其它药物组分一起使用,所述的药物组分例如神经营养因子、细胞因子、干扰素、白细胞介素、生长因子、抗菌素、抗炎药、神经递质受体兴奋剂或拮抗剂和/或抗体。VI.抗体
可以将NNT-1多肽、片段和/或其衍生物用于制备由标准方法产生的抗体。因此,还认为与NNT-1多肽反应的抗体以及这类抗体的反应性片段在本发明的范围内。该抗体可以是多克隆、单克隆、重组、嵌合、单链和/或双特异性抗体。一般来说,抗体或其片段将被“人源化”,即制备抗体或其片段以便当对病人给药时防止对抗体产生免疫反应或将这种反应减小到最低限度。抗体片段可以是可与本发明NNT-1反应的任意片段,诸如Fab、Fab,等。本发明还提供了下列技术内容:通过将NNT-1或其片段作为抗原给予所选哺乳动物、随后将哺乳动物细胞(例如脾细胞)与某些癌细胞融合而产生杂交瘤,从而由公知技术生成无限增殖化细胞系。本发明还包括用于产生这类细胞系的方法和抗本发明全部或部分人NNT-1多肽的抗体。
可以以治疗的方式使用该抗体,诸如抑制NNT-1与其受体的结合。可以将该抗体进一步用于体内和体外诊断的目的,诸如以标记的形式用于检测体液中存在的NNT-1。VII.治疗组合物及其给药
本文所用的术语“有效量”和“治疗有效量”指的是保持上文所列NNT-1的一种或多种生物活性所必需的NNT-1的用量。
用于治疗各种神经障碍或疾病的治疗组合物在本发明的范围内。这类组合物可以含有治疗有效量的NNT-1多肽或其片段(两者均可以被化学修饰)并混有一种药物上可接受的载体。载体物质可以是注射用水,优选用对哺乳动物给药的溶液中常用的其它物质补充的注射用水。一般来说,以一种组合物的形式将NNT-1治疗化合物进行给药,所述组合物含有纯化的NNT-1多肽或片段(可以被化学修饰)并结合一种或多种生理上可接受的载体、赋形剂或稀释剂。中性缓冲盐水或混有血清白蛋白的盐水是典型的合适载体。优选使用合适的赋形剂(例如蔗糖)将产物配制成冻干物。根据需要可以包含其它标准的载体、稀释剂和赋形剂。一种典型的组合物含有pH约为4.0-4.5的柠檬酸盐缓冲液,它可以进一步包括NaCl。
可以通过非肠道系统地给予NNT-1组合物。另一方面,可以通过静脉或皮下给予该组合物。当进行系统性给药时,用于本发明的治疗组合物可以是无热原的非肠道可接受的水溶液形式。适当考虑到pH、等渗性、稳定性等,这类药物上可接受的蛋白质溶液的制剂属于本领域的技术范围。
对于储存来说,用于实施本发明的NNT-1组合物的治疗制剂可以通过将所选具有所需纯度的组分与任意生理上可接受的载体、赋形剂或稳定剂进行混合来制备、剂型为冻干块或水溶液(Remington’s《药物科学》(Pharmaceutical Science)第18版,A.R.Gennaro编辑,Mack Publishing Company[1990])。可接受的载体、赋形剂或稳定剂对于接受者来说是无毒性的且优选在所用剂量和浓度上是惰性的,且它们包括:诸如磷酸、柠檬酸或其它有机酸这样的缓冲液;诸如抗坏血酸这样的抗氧化剂;低分子量多肽;诸如血清白蛋白、明胶或免疫球蛋白这样的蛋白质;诸如聚乙烯吡咯烷酮这样的亲水聚合物;诸如甘氨酸、谷氨酰胺、天冬酰胺、精氨酸或赖氨酸这样的氨基酸;包括葡萄糖、甘露糖或糊精在内的单糖、二糖和其它碳水化合物;诸如EDTA这样的螯合剂;诸如甘露醇或山梨醇这样的糖醇;诸如钠这样的形成盐的平衡离子;和/或诸如吐温、泊洛沙姆或聚乙二醇(PEG)这样的非离子表面活性剂。
用于体内给药的NNT-1组合物必须是无菌的。通过无菌滤膜的过滤会方便地完成这一过程。如果NNT-1组合物是冻干的,那么在冻干和再溶解之前或之后可以进行使用这些方法的灭菌。通常将用于非肠道给药的该组合物以冻干的形式或以体溶液的形式储存。
一般将治疗组合物放入带有无菌入口的一种容器中、例如带有皮下注射针头刺入塞的静脉溶液袋或小瓶中。
该组合物的给药途径与公知的方法一致,例如:口服、通过静脉、腹膜内、大脑内(实质内)、脑室、肌内、眼内、动脉内或损害内的途径注射或输注;或者通过可任意包括使用导管的持续释放系统或植入装置。如果需要,可以通过输注、造影剂团注射或通过植入装置连续给予该组合物。可选择地或另外,通过植入其上已经吸附了NNT-1多肽的膜、海绵或其它合适材料的受侵染区可以局部给予NNT-1。
如果使用植入装置,那么可以将该装置植入任何合适的组织或器官,诸如植入脑室或脑实质,且通过经由造影剂团或连续给药的装置或通过使用连续输注的导管可以直接运送NNT-1。
可以以持续释放的配制品或制剂的形式给予NNT-1多肽。持续释放制剂的合适实例包括成型制品的形状为半透性聚合物基质的形式,例如薄膜或微囊。持续释放的基质包括聚酯、水凝胶、polyactide(U.S.3,773,919,EP 58,481)、L-谷氨酸和γ乙基-L-谷氨酰胺的共聚物(Sidman等《生物聚合物》(Biopolymer)22:547-556[1983])、聚(2-羟乙基-甲基丙烯酸酯)(Langer等《生物医学材料研究杂志》(J.Biomed.Mater.Res.)15:167-277[1981]和Langer等《化学技术》(Chem.Tech.)12:98-105[1982])、乙烯基乙酸乙烯酯(Langer等,上文)或聚-D(-)-3-羟基丁酸(EP 133,988)。持续释放的组合物还可以包含脂质体、它可以由本领域公知的几种方法的任一种来制备(例如DE 3,218,121;Epstein等《美国国家科学院学报》(Proc.Natl.Acad Sci.USA)82:3688-3692[1985];Hwang等《美国国家科学院学报》(Proc.Natl.Acad.Sci.USA)77:4030-4034[1985];EP 52,322;EP 36,676;EP 88,046;EP143,949)。
在某些情况中,以来自体内的方式使用NNT-1组合物可能是所希望的,即处理已经从病人体内取出的细胞或组织、然后将它们植回病人体内。
在其它情况中,通过向病人体内植入某些细胞可以传递NNT-1,所述细胞已经进行了遗传工程改造以便表达并分泌NNT-1多肽。这类细胞可以是动物或人体细胞且可以来源于病人自身的组织或来自另一种来源、即人体的或非人体的。可选择的,细胞可以是无限增殖化的。可以将这些细胞植入大脑、肾上腺或植入其它合适的病人的身体组织或器官。
在某些情况中,使用基因疗法来对患有某种神经性或免疫性障碍的病人给予NNT-1可能是所希望的。在这些情况中,可以将编码NNT-1或其片段或其变体的基因组DNA、cDNA、和/或合成DNA可操作地与在将注入组合物的组织中起作用的组成型或诱导型启动子进行连接。可以将这种可插入载体或单独使用而不需载体的NNT-1 DNA构建体直接注入大脑或其它神经或非神经组织。
另一方面,可以将NNT-1 DNA构建体直接注入肌肉组织,其中它可以被吸收进入细胞并在该细胞中被表达,条件是将该NNT-1 DNA可操作地与在肌肉组织中起作用的启动子、诸如巨细胞病毒(CMV)启动子、劳斯肉瘤病毒(RSV)启动子或肌酸激酶启动子进行连接。一般来说,该DNA构建体可以包括(除NNT-1 DNA和启动子外)从诸如腺病毒载体、腺伴随病毒载体、逆转录病毒载体、和/或疱疹病毒载体这样的载体中获得的载体序列。该载体/DNA构建体中可以混有注射用药物上可接受的载体。
在治疗上所用的NNT-1组合物的有效量取决于、例如治疗目的,诸如所用NNT-1的适应症、给药途径和病人的具体情况。因此,对于治疗学家来说必须根据需要确定剂量并改变给药途径根据以获得最佳的疗效。一般每日剂量可以在约0.1μg/kg-10mg/kg或更高的范围,这取决于上述因素。一般来说,临床医生将NNT-1组合物给药至达到获得所需疗效的剂量为止。因此可以在一段时间内将NNT-1组合物作为单一剂量给药或作为两倍或更高的剂量(可以含有或可以不含有相同量的NNT-1)给药、或通过植入装置或导管的连续输注进行给药。
当进行进一步的研究时,将出现有关用于治疗各种病人中不同情况的合适剂量水平的研究资料,且考虑到治疗的前后关系、治疗过程中的疾病类型、年龄和接受治疗者的一般身体状况,本领域普通技术人员能够确定合适的用药剂量。VIII.用NNT-1治疗的疾病
可以将NNT-1蛋白质、其片段和/或衍生物用于治疗中枢或外周神经系统疾病和障碍,这些疾病和障碍与NNT-1表达模式中的改变有关或得益于与NNT-1或抗NNT-1抗体的接触。
可以将NNT-1蛋白质、其片段和/或衍生物用于治疗中枢、自主或外周神经系统的各种细胞已经变性和/或已经被下列情况损害的病人:先天性疾病、创伤、机械性损伤、外伤、中风、局部出血、感染、代谢性疾病、营养缺乏、恶性肿瘤、和/或毒性剂。更具体地说,可以调节NNT-1蛋白质的水平(向上或向下调节)以便适于下列疾病的适应症:阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性神经病性综合征、亨廷顿舞蹈病、因糖尿病或其它代谢性障碍诱发的外周神经病和/或营养不良或中枢视网膜变性,诸如色素性视网膜炎、药物诱发的视网膜病、夜盲的静止形式、进行性锥柱变性等。由于在免疫系统细胞中也表达NNT-1(参见下面的实施例V),所以也可以将NNT-1用于治疗因免疫障碍导致的疾病。此外,由于还在造血细胞中表达NNT-1(参见下面的实施例V),所以还可以将NNT-1用于治疗因造血系统障碍导致的疾病。
此外,可以将NNT-1蛋白质、其片段和/或衍生物用于治疗涉及B-细胞和/或T细胞、优选B-细胞在内的免疫系统的疾病和障碍。正如本文实施例IX-XI中所示的,NNT-1具有刺激B-细胞和T细胞(程度较低)产生的活性。
存在作为针对这一因素的潜在靶向物的几种主要的体液免疫缺陷。尽管比较少见,但是这些疾病都是慢性的且需要长期治疗。首先是通常可变的免疫缺陷或CVID,其特征在于有些正常水平的循环的B-细胞但缺乏正确地分化为免疫球蛋白产生细胞的能力。患CVID的个体对复发的细菌感染敏感。
另一种NNT-1靶疾病是还导致感染复发的选择性IgA缺失,所述感染通常限于肺、胃肠和尿道。选择性IgA缺失是在0.03%-0.97%人群中流行的多种常见疾病中的一种。
其它的NNT-1靶疾病包括各种形式的丙球蛋白缺乏血症、X连锁丙球蛋白缺乏血症和/或与这些疾病之一相关的病症、诸如感染复发、肾脏缺损或贾第鞭毛虫病。参见《临床免疫学和免疫病理学》(Clin.Immunol.and Immunopath.)40(1):13-24(1986)。
提高对某些疫苗的体液免疫反应是NNT-1多肽的另一种用途。例如,在给予口服疫苗后产生的抗体的量往往很低且由此产生的保护期很有限。预计NNT-1的用途是作为接种时增加抗体产生量的佐剂。
由于NNT-1在抑制LPS诱导的TNF-α产生的能力,所以它可以在治疗脓毒病中找到用途。尽管还没有证实对这一非常重要的临床难题的以修饰基因为主的解决方案产生的许多生物反应具有任何令人信服的可靠性,但是这种可能性还有待于NNT-1在此处的成功,而其它治疗选择方案均已失败。Jarish-Schwarzmann反应是一种具有与脓毒病相似症状的临床疾病且严格来说是TNF毒性作用的结果。已经证实抗TNF抗体的应用是对治疗这一疾病的临床上成功的方法。这是一种NNT-1可以根据其抗TNF和抗炎特性显示出临床价值的情况。IX.筛选NNT-1抑制剂的试验
在某些情况中,抑制或显著降低NNT-1活性的水平可能是所希望。可以以下列方式给予抑制NNT-1活性的化合物:来自体内的方式、或以通过局部或静脉注射的体内方式、或通过口服转运的方式、植入装置等。下述试验提供了用于鉴定可抑制NNT-1活性的化合物的方法实例。
为了便于理解,本文所用的下列定义用于描述这些试验:
“检测分子”指的是评估中作为NNT-1抑制剂的分子、一般根据的是其阻断NNT-1与其受体相互作用的潜在能力。
例如,通过使用标记的(例如碘化的)NNT-1的表达克隆法可以分离NNT-1受体。
可以进行几种类型的使用纯化蛋白质的体外试验以便鉴定那些破坏NNT-1活性的化合物。通过一种通常抑制NNT-1与其受体相互作用的化合物可以实现这类破坏过程。
在一种试验中,纯化的NNT-1蛋白质或其片段(例如使用上述方法制备的)可以通过与微量滴定板的孔的底部结合而被固定化。然后可以将放射性标记的NNT-1受体以及检测分子按一次一种或同时添加到孔中。培养后,可以将孔洗涤并使用闪烁计数器对放射性进行计数,以便测定在有检测分子存在的情况下NNT-1/受体的结合程度。一般来说,在一定的浓度范围内检测该分子,可以将一系列缺乏检测试验的一个或多个元素的对照“孔”用于评估结果中的精确度。这种试验的误差包括使受体与孔结合并将放射性标记的NNT-1与检测分子一起添加到孔中。培养并洗涤后,可以对孔进行放射性的计数。
包括放射性标记法在内的几种方法可以用来“标记”NNT-1。例如,可以使用125-I或35-S对NNT-1蛋白质进行放射性标记。另一方面,在一种NNT-1的融合蛋白质中,编码NNT-1的DNA与诸如c-myc表位这样的一种肽的编码序列融合。用市售可得的抗myc的抗体可以方便地检测NNT-1-myc融合蛋白质。
一种替换微量滴定平板类结合试验的方法包括使NNT-1或其受体固定化在琼脂糖珠、丙烯酸珠或其它类的这类惰性基质上的步骤。可以将含有NNT-1或其受体的这种惰性基质放入含有检测分子与互补组分(受体或NNT-1蛋白质)的溶液中,所述互补组分已经被放射性标记或以荧光方式标记;培养后,通过离心可以使惰性基质沉淀并可以使用上述方法估计NNT-1与受体之间结合的量。另一方面,可以将该惰性基质复合物固定在一种柱上并使检测分子和互补组分通过该柱。然后可以使用上文所列的任何技术、即放射性标记法、抗体结合法等来评价形成的NNT-1/受体复合物。
另一类用于鉴定抑制NNT-1活性的分子的体外试验是使用表面胞质基因共振检测器系统并遵循制造商的说明的Biacore检测系统(Pharmacia,Piscataway,NJ)。这种试验主要包括使NNT-1或其受体与位于检测器中的葡聚糖包被的传感器芯片共价结合的步骤。然后可以将检测分子和互补组分同时或依次注入含有传感器芯片的室中并可以根据分子量的变化来估计NNT-1/受体结合的量,其中所述的分子量变化实际上与传感器芯片的葡聚糖包被一侧有关;通过检测器系统可以测定分子量的改变。
在某些情况中,一起评价用于降低或抑制NNT-1活性的两种或多种检测分子可能是所希望的。在这些情况中,通过同时或依次与第一种检测分子一起添加这类附加的检测分子,可以方便地改进上文所列的试验。本试验中其余的步骤可以如上文所列。X.转基因哺乳动物
本发明的范围还包括的技术内容是非人类的哺乳动物,诸如小鼠、大鼠、家兔、山羊或绵羊,其中编码相当于人NNT-1的基因(或多种基因)已被破坏(“剔除”),使得这种基因的表达水平显著降低或完全消除。使用诸如美国专利5,557,032中所述的技术和方法可以准备这样的哺乳动物。本发明进一步包括非人类的哺乳动物,诸如小鼠、大鼠、家兔、山羊或绵羊,其中编码NNT-1(哺乳动物NNT-1的天然形式或异源NNT-1基因)的基因(或多种基因)由所述哺乳动物超表达、由此创造了“转基因”哺乳动物。使用如美国专利5,489,743和PCT专利申请WO94/28122(公开于1994年12月8日)中所述的那些众所周知的方法可以准备这样的转基因哺乳动物。
下列实施例仅用来解释的目的且不应以任何方式构成对本发明范围的限制。
实施例
Sambrook等(《分子克隆:实验室手册》,冷泉港实验室出版社,冷泉港NY[1989]和Ausubel等编辑《最新分子生物学技术方案》(Current Protocols in Molecular Biology),Wiley,New York,NY[1995])列出了用于文库制备、DNA克隆和蛋白质表达的标准方法。
实施例I:cDNA的克隆和针对NNT-1的基因组克隆A.cDNA文库的构建
在37℃下、5%CO2环境中,使人T-细胞淋巴瘤细胞(Jurkat细胞)在含有10%胎牛血清的RPMI 400培养基中生长。将该培养基用10mM HEPES缓冲(pH7.5)。8次传代后将细胞分成两组。使一组生长至汇合(2×107细胞/瓶),从这些细胞中收获的RNA用作“驱动子(driver)”RNA。另一组是“试验物”组并用下列处理方法将其激活。
通过添加超抗原链球菌肠毒素B和F(TSST)80ng/ml、PKC激活剂PMA 50ng/ml、钙离子载体A21832 125ng/ml而将细胞激活8小时。还以1mg/ml的浓度添加蛋白质翻译抑制剂环己酰亚胺。在不同的时间点上从不同组的细胞中收获RNA。
1.总RNA的制备:
通过以300×g离心5分钟使细胞沉淀并用PBS(磷酸缓冲盐溶液)洗涤,将其重新悬浮于Ultraspec II(Biotex,Inc.,TX)、浓度为5×106细胞/ml的Ultraspec II。然后通过4次穿过21号注射器使细胞溶解,将匀浆在冰上培养15分钟,接着加入0.2体积的氯仿,充分混合,并在冰上进一步再培养10分钟,在30ml科雷克斯离心管中以12000×g离心30分钟。离心后保留上清液并弃去残余物。在加入0.5体积的异丙醇后,添加作为分离试剂盒组成部分的由Biotex销售的0.05体积的RNA结合树脂。通过离心沉淀树脂后(300×g,5分钟),用75%不含核糖核酸酶的乙醇将该树脂洗涤两次并在50℃下使其在空气中干燥10分钟。然后通过下列步骤从该树脂中洗脱总RNA:将树脂重新悬浮于1体积的不含核糖核酸酶的水中、剧烈搅动1分钟、接着以13000×g离心1分钟。然后将总RNA转入新的Eppendoff管中并弃去树脂沉淀。
2.poly(A)+RNA的分离
根据制造商所述使用Qiagen’s Oligotex mRNA分离系统;将该过程重复两次以获得纯poly(A)+RNA。这一过程对于随机引发的文库以便将cDNA中的核糖体RNA的拷贝数降至最低来说是特别重要的。然后通过光谱法和甲酰胺变性凝胶电泳法来测定mRNA的整合度。
通过遵照BRL cDNA合成方案来合成第一链cDNA。为了从靶cDNA中除去残余的mRNA,用苯酚/氯仿提取第一链cDNA反应物并用2M乙酸铵和3体积的乙醇沉淀。然后在有2mM EDTA存在的情况下将cDNA/mRNA杂交体重新悬浮于0.3M NaOH中并在68℃下培养15分钟。用过量约1.5M的纯Tris-HCl中和水解反应。接着用苯酚/氯仿提取cDNA并将其用2M乙酸铵和3体积的乙醇重新沉淀、用75%乙醇冲洗并重新悬浮于7ml无菌水中。通过按照Boehringer Mannheim加尾试剂盒的方案来使单链cDNA加尾。
3.驱动子mRNA的制备和光生物素化:
如上所述分离poly(A)RNA。然后用20mg光生物素乙酸酯(Sigma)使约20mg poly(A)RNA光生物素化两次,并使其在不含核糖核酸酶的水中以1mg/ml的浓度再溶解。用水饱和的异丁醇萃取过量的光生物素、将其用乙醇沉淀并重新悬浮于30ml DEPC处理的水中。
4.扣除杂交反应:
使光生物素化的驱动子mRNA与检测物cDNA共沉淀并重新悬浮于2ml不含核糖核酸酶的水中。为了使核酸进入溶液,在室温下通过间歇缓慢的搅拌将制备液保持几小时、随后在68℃下再温育20小时。将光生物素化的驱动子溶解成最终浓度为2mg/ml。一般来说,应使用浓度至少为1mg/ml的驱动子RNA。
5.杂交后杂交体的去除:
杂交后,将链霉抗生物素加至最终浓度为0.2mg/ml并在室温下培养10分钟。然后用苯酚/氯仿提取法除去链霉抗生物素。提取后,用乙醇沉淀cDNA。
在PCR中使用一对引物:AGCGCTACGGTCGACCCG GCG TTT TTT TTTTTT TTT TTT TTT(ACG)X(SEQ ID NO:15)(Sal I T21锚式引物)和GGA AGG AAA AAA GCG GCC GCT ACA(SEQ ID NO:16)(NotI-N9引物)、用来扩增cDNA。使用消耗(expend)PCR试剂盒。将15个循环用于生成足量用于凝胶分级分离法的物质,使得在文库中出现的大小相同。为了使第一种引物退火,将PCR初始的5个循环的退火温度在35℃下持续1分钟。在凝胶上分级分离具有不同大小的级分的cDNA。将SalI衔接头添加到双螺旋cDNA中,然后用NotI消化并克隆入pSport载体中。B.cDNA克隆的分离
通过表达的序列标记(最有特征的)分析来筛选文库。随机从该文库中挑选单个克隆并使用载体引物和Taq染料终止子反应(应用生物系统公司)在一种应用生物系统373A自动DNA测序仪上将它们进行测序。将从随机挑取的克隆NNT-1中获得的所得核苷酸序列进行翻译,然后使用改版的FASTA程序与公知蛋白质序列的现有数据库进行比较。
在所翻译的氨基酸序列水平上,一种克隆(khjl-00008-f2)与CNTF具有约21%的同源性。将cDNA克隆的整个插入片段进行测序并发现它编码全长克隆,即它含有在5’末端的Met和Met上游的一种终止密码予以及在3’末端的另一种终止密码子。
这种全长cDNA的序列如附图1中所示。所预测的蛋白质的氨基酸序列如附图3中所示。推定的信号肽为从第-27位氨基酸(Met)至第-1位氨基酸(Ala)的范围。C.基因组克隆的分离
从人基因组P1文库(Genome Systems Inc.,St.Louis,MO;目录号P1-2535)中获得NNT-1的基因组DNA。使用NNT-1 cDNA作为探针来筛选该文库。使用Amersham Rediprime试剂盒(Amersham,Arlington Heights,IL;目录号RPN-1633)对cDNA进行放射性标记,且杂交和预杂交溶液是:50%的甲酰胺、5×SSC、5×Denhardt’s、0.05%焦磷酸钠、0.1%SDS和100mg/ml鲑精DNA。预杂交进行约1小时且杂交在42℃下进行约16小时。
杂交后,在42℃下于0.2×SSC和0.1%SDS中洗涤滤器约30分钟,然后使之与膜接触。鉴定两种阳性克隆并根据Genome SystemsInc.的方案纯化含有这些克隆的质粒。接着直接对质粒DNA进行测序。
编码NNT-1的基因组序列如附图2中所示(SEQ ID NO:3)。该基因由3个外显子和2个内含子组成。用大写字母表示的是编码区,而用小写字母表示包括5’未翻译区、内含子和3’未翻译区在内的非编码区。
实施例II:重组哺乳动物NNT-1蛋白质的制备
通过融合基因的PCR扩增来构建含有人NNT-1 cDNA和旗-标记肽的表达载体。在5’末端带有Hind III位点的有义引物:(5’-AGCAAGCTTCACCATGGACCTCCGAGCAGGGGACTC-3’)(SEQ ID NO:6)它编码第-27位氨基酸(Met)至第-21位氨基酸(Asp),且在5’末端带有NotI位点的反义引物编码旗-标记肽和3’末端的最后8个氨基酸(5’AGCGGGGCCGCACTACTTGRCATCGTCGRCGTCCTTGTACTCGAAGCCATGAGCCCCCAGGTGCAG-3’)(SEQ ID NO:7),在PCR中使用它们以扩增融合基因。将该融合基因与P CEP4载体(Invitrogen Inc.,San Diego,CA)连接。使用制造商建议的方法用脂转染试剂(BRL,Gaithersburg,MD)将表达载体转染入EBNA-1-293细胞。转染48小时后,收集293细胞和条件培养基并通过使用抗旗(anti-flag)-标记抗体(Eastman Kodak Co.,New Haven CT)以蛋白质印迹法来对它们进行分析。在293细胞溶胞产物中发现了大部分的重组蛋白质。因此,将抗旗抗体凝胶(Eastman Kodak Co.,New Haven CT)用于纯化来自293细胞溶胞产物的蛋白质。根据制造商的方案纯化28-30kd的蛋白质。在生物功能分析中使用这种重组蛋白质(用于运动神经元和交感神经元的存活试验)。测定该蛋白质的N-末端氨基酸为Leu(氨基酸1),这表明潜在的信号肽被切割了(氨基酸-27至氨基酸-1)。
实施例III:重组大肠杆菌NNT-1蛋白质的制备
将编码SEQ ID NO:2氨基酸Leu(1)至Phe(198)的NNT-1的cDNA克隆插入载体pAMG21,该载体是pCFM 1656(ATCC登记号69576)的衍生物并含有用于插入来自lux PR启动子的下游基因的合适的限制位点(参见美国专利5,169,318对lux表达系统的描述)。所用的宿主细胞是大肠杆菌K12、菌株CGSC6159(耶鲁大学的遗传原种,New Haven,CT)。使用标准转化法用载体转化该宿主细胞,然后将它们在30℃下在含有约50μl/ml卡那霉素的2XYT培养基中培养。通过向该培养基中添加自体诱导物N-(3-氧己酰)-DL-高丝氨酸内酯至终浓度约为30ng/ml而开始进行NNT-1基因产物的诱导,并将培养物在30℃或37℃下培养约6小时,此后,通过显微术检测细胞的内含体。
发现大部分的NNT-1蛋白质位于这种内含体中。因此,通过沉淀细胞来制备细胞膏状物。在低pH下溶解内含体并通过顺序沉淀法来纯化蛋白质。在上样至SDS-PAGE以评价纯度之前透析蛋白质。凝胶的考马斯染色显示该蛋白质的纯度至少为95%。
实施例IV:NNT-1的神经生物功能A.鸡运动神经元试验
由胚胎期为E5.5的鸡制备来自腰椎脊髓的富集运动神经元(MN)的培养物。通过使用6.8%三碘苯甲酰氨基葡萄糖梯度来富集MN神经元。简单地说,解剖腰椎脊髓、不包括(freed of)脑膜和DRG。在37℃下,在含有L15培养基(Gibco/BRL,Grand Island,NY)的木瓜蛋白酶中将脊髓培养20分钟(Worthington Biochemical Corp,Freehold,NJ)。通过用吸管移取将经酶软化的脊髓片段分离成单细胞。然后将细胞悬浮液在6.8%三碘苯甲酰氨基葡萄糖(Serva,Feinbiochemicala,Germany)垫层上铺层,并在500g将试管离心20分钟。收集三碘苯甲酰氨基葡萄糖垫层与细胞悬浮液之间的界面物并将其稀释入培养基。接着轻轻地将该级分在4%BSA垫层上铺层并在280g离心10分钟。将沉淀重新悬浮于含有L15培养基的培养基中,所述L15培养基含有用3.6mg/ml葡萄糖、5ng/ml亚硒酸钠、6.25ng/ml孕酮、0.1mg/ml伴清蛋白、16mg/ml腐胺和5mg/ml胰岛素进行了补充的10%胎牛血清。将10,000细胞/孔接种入96孔组织培养平板。向该培养物中添加连续稀释的神经营养因子(NNT-1或CNTF)并培养3天。在第3天时,将MTT加入培养物4.5小时。溶解甲产物并通过650nm处减去570nm波长处的值来对平板读取以便消除可见干扰。光密度(OD)的读数与培养物中存活的神经元数量成正比。将一式三份的孔中570nm处的吸光值(增加神经元的存活)作为NNT-1或CNTF最终浓度的函数来作图。
将分析结果列在附图7中。将570nm处的吸光值表示为实际读数的1000倍。结果证明NNT-1可以支持鸡运动神经元的生长。其最高活性达到CNTF活性的约90%。B.鸡交感神经元试验
制备初生鸡胚胎交感链神经节的培养物。简单地说,从已经在37.6℃下、湿润空气中孵育9天的能育的无病原体的鸡卵中取出交感神经节。通过下列步骤以化学方式分离神经节:首先在37℃下与不含二价阳离子而含有10mM HEPES缓冲液(pH7.2)的Hanks’平衡盐溶液接触10分钟;然后在37℃下与溶于如上所述修饰的Hanks’平衡盐溶液的0.125%细菌胰蛋白酶1∶250溶液(Difco,Detroit,Michigan)接触12分钟。通过添加胎牛血清至10%的终浓度而终止胰蛋白酶消化。
这种处理完成后,将神经节转入由含有碳酸氢盐的Dulbecco氏高葡萄糖改进的Eagle培养基组成的一种溶液中,该培养基含有10%胎牛血清和10mM HEPES(pH7.2),并通过经20号1”双头式不锈钢针头约14次研磨而将神经节以机械方式分离。
然后将分离的神经节平铺在直径为100mm的组织培养皿中的培养基(用10%胎牛血清、4mM谷氨酰胺、60mg/L青霉素G、25mMHEPES,pH7.2进行了补充的Dulbecco氏改进的Eagle培养基)中(约40个分离的神经节/培养皿)2-3小时。进行这种预铺板以便分离出与培养皿粘附的非神经元细胞和不粘附的神经细胞。预铺板后,通过离心收集非粘附性神经细胞、将它们重新悬浮于培养基中并以2500个神经细胞/孔的密度平铺在96孔微量滴定组织培养平板上半数区域的每一孔中、每孔50ml。在4℃下,使微量滴定孔预先与溶于10mM硼酸钠(pH8.4)的1mg/ml聚-L-鸟氨酸的溶液接触过夜,在无菌纯水中洗涤并在空气中干燥。
与细胞接触的神经营养因子的终浓度如下:1)对于CNTF标准来说,9点连续稀释曲线在100ng/ml-6pg/ml的范围;2)对于NNT-1蛋白质来说,9点连续稀释曲线在100ng/ml-0.12pg/ml的范围。将25ml用于检测神经营养活性的连续稀释的样品添加到每个孔中并在37℃下、含7.5%CO2的湿润空气中将培养皿培养38-46小时。然后每孔添加18ml的溶于含有碳酸氢盐的Dulbecco氏高葡萄糖改进的Eagle培养基的四氮唑染料MTT的1.5mg/ml溶液,所述Dulbecco氏高葡萄糖改进的Eagle培养基含有(contain)10mM HEPES(pH7.2),将该培养物放入37℃的培养箱内4.5小时。接着添加含有20%十二烷基硫酸钠(pH4.7)的50%N,N-二甲基甲酰胺的75ml溶液以便溶解结晶的甲产物,并将平板在37℃的培养箱内培养最少12小时。对于每一孔来说,使用自动微量滴定平板读数器以650nm为参考来测定579nm处的吸光值。所得吸光值与每一孔中的活细胞数成正比,将所述细胞定义为能够还原染料的那些神经细胞。
将分析结果列在附图8中。该结果证明NNT-1支持鸡交感神经元的生长。
实施例V:组织分布的Northern印迹分析
人体组织的RNA印迹购自Clontech(Palo Alto,CA)。用一种人NNT-1 cDNA探针探测该RNA印迹。标记NNT-15’至3’编码区的两种cDNA片段并将它们用作分析NNT-1基因组织表达的探针。结果证明在脾、淋巴节的组织和外周血液淋巴细胞、骨髓以及胎儿的肝、肾、肺、结肠腺癌细胞SW480、海拉细胞S3、肺癌A549、慢性髓细胞性白血病K-562细胞、伯基特淋巴Raji细胞中NNT-1被表达为2.2kb转录物。该基因的组织分布提示该基因可能还与免疫系统或造血细胞的发育有关。
实施例VI:NNT-1基因的染色体定位
通过FISH进行基因的染色体定位。使用BRL BioNick标记试剂盒通过dATP使14kb的基因组片段生物素化(15C 1小时)。按照Heng等在《美国国家科学院学报》(Proc.Nat.Acad.Sci.USA)89:9509-9513,1992中所述来进行FISH的程序。结果证明该基因位于接近于人CNTF基因座(染色体11 q12)的染色体11 q13上。
实施例VII:小鼠cDNA克隆的分离
使用人特异性引物、通过从小鼠11天龄胚胎的cDNA(Clontech,Palo Alto,CA)的PCR扩增来分离小鼠部分的cDNA克隆。进一步通过5’RACE和3’RACE来获得全长cDNA克隆。小鼠cDNA核苷酸序列和氨基酸序列分别如附图4和5中所示。小鼠蛋白质与人体蛋白质之间具有96%的同一性,这证明在整个进化过程中该蛋白质是高度保守的。类似于人体蛋白质,小鼠蛋白质也在第2位氨基酸(Asn)上含有潜在的N-联接的糖基化位点。
实施例VIII:NNT-1与该族其它成员的比较
NNT-1的氨基酸序列提示该蛋白质属于CNTF族(SEQ ID NO:12),该族包括IL-11(SEQ ID NO:8)、IL-6(SEQ ID NO:9)、心营养蛋白(cardiotrophin)(SEQ ID NO:11)、制癌蛋白(SEQ ID NO:13)和粒细胞集落刺激因子(G-CSF)(SEQ ID NO:10)。我们通过计算机程序PILEUP将NNT-1的氨基酸序列与本族的所有成员进行了比较且结果如附图6中所示。当与该族的所有其它成员相比,预计NNT-1蛋白质的二级结构含有4个不平行α-螺旋结构。
实施例IX:NNT-1转基因小鼠的表型A.NNT-1转基因小鼠的表型
在骨髓和神经细胞试验中由NNT-1基因编码的蛋白质具有与CNTF一定的同源性和体外活性。对用NNT-1转染的骨髓移植的小鼠的研究证实了与胃肠道相关的淋巴组织中的轻度淋巴增生、而没有其它显著的表型改变。材料与方法
物种:小鼠 菌株:BDF1 年龄:17周(120天)
试验品:NNT-1(WX240) 性别:雄性/雌性治疗组
组 | 小鼠号 |
阴性 | 22 23 45 63 65 |
阳性 | 35 36 46 60 62 |
在两组中没有检测到显著的异常情况。
进行横向尸体解剖、所选择的组织固定在福尔马林锌缓冲液中而用于组织病理学检查[脑、心、肾、肾上腺、十二指肠、胰、膀胱、肝、肺、脾、任何大的损害]。在常规组织学检查过程前将这些组织固定过夜。使用JMP(SAS Institute,Cary,NC)软件程序分析数据。
检测范围:器官重、体重、组织病理学、免疫组织学、RNA印迹。
在NNT-1转基因小鼠中存在下列与治疗相关的变化:
在转基因小鼠体内,脾具有轻度至明显的反应性淋巴增生(附图10)、包括滤泡(B细胞)和动脉周(T细胞)区在内。在高度表达的小鼠#62中这种淋巴增生最为显著(附图10),而在尸检处发现这种淋巴增生明显与脾肿大相关。其它高度表达的小鼠#60仅具有淋巴区的轻度增生、伴随所有三种谱系的大量弥漫性髓外血细胞生成。尽管根据这两种高度表达的小鼠作出有关NNT-1的脾效应的任何一般性结论都是困难的,但是在小鼠#62中观察到的淋巴增生与我们使用注射蛋白质的发现(参见如下的实施例X A)相一致,而在小鼠#60中发现的EMH可以反映出以前在体外骨髓培养物中发现的情况与体内情况的相互关系。
小鼠#60的肝具有淋巴细胞和浆细胞的多灶聚集物,所述细胞渗入血管周围的空间并以特有的模式膨胀入邻近类似于肝内“淋巴组织生成岛”的窦状隙中(附图12)。通过免疫组织化学发现,淋巴聚集物由B220+细胞和CD3+细胞组成。在小鼠#62中还发现了类似而轻度的且一般是在血管周围的淋巴渗入物。在对照组和/或转基因组中的各个小鼠体内偶尔发生了肝中发现的其它改变。
胃肠道具有最低限度至中度反应性的派依尔结(与肠相关的淋巴组织)的淋巴增生。类似地,在转基因小鼠中颈和肠系膜淋巴节比对照组中更具有反应性,尽管比起我们用注射NNT-1蛋白质进行的研究来这种改变不是最为本研究特征的重点(参见如下的实施例X A)。
转基因小鼠的骨髓、中枢和外周神经系统看起来是正常的。一般地,在阴性对照组和/或转基因组中的一种或多种动物体内偶尔发现了其它组织中的改变并不将它们解释为与转基因有关。
从本研究中获得的数据证明NNT-1转基因小鼠具有令人感兴趣的表型,其特征在于包括脾、淋巴节、与肠相关的淋巴组织、肾和肝在内的多数外周组织中的T和B淋巴细胞和浆细胞的增殖。在外周血液或骨髓中没有显著改变的情况下,NNT-1还可以诱导某些外周组织、诸如脾和胰中的髓外血细胞生成。因此,从NNT-1转基因小鼠中获得的数据一般支持从我们对7天龄小鼠使用注射用NNT-1蛋白质的研究中的发现(如下实施例X A),即诱发淋巴组织增生而没有检测到对骨髓或中枢神经系统的作用。
令人感兴趣的是,在两种高度表达的NNT-1转基因雌性小鼠中检测到的肾小球性肾炎接近类似于在MRL/lpr(Fas缺乏)小鼠中观察到的自发肾小球性肾炎,这显示出早期发病的SLE类自身免疫综合征与下列情况有关:多克隆B细胞激活、多种自身抗体、循环免疫复合物和双阴性(CD4-CD8-TCRab+CD3+)T细胞的非正常群体的蓄积,它们还表达称作B220+(一般是B细胞的标记物)的CD45R同种型(Singer等《最新免疫学观点》(Curr.Opin.Immunol.)6:913-920,1994)。此外,某些NNT-1的生物效应还模拟白细胞介素-6的那些效应,白细胞介素-6(类似于CNTF、LIF和IL-11)可利用gp130信号转导物并具有对肝、肾、脑、皮肤、免疫和造血系统的多效作用(Ryffel等,《国际病理学实验研究》(Int.Rev.Exp.Pathol.)34A:79-89,1993)。因此,重要的是通过流式细胞分析法测定在外周血液或组织中发现的淋巴细胞是否具有带有二重表达的T和B细胞标记物的非常规的表型。B.NNT-1转基因生成物的FACS免疫分型组织分析
通过使眼眶后出血获得外周血液样品。得到了来自每组原始同窝出生小鼠的对照组和NNT-1阳性(通过PCR)小鼠的9份样品;没有凝结现象。首先用各种细胞表面抗原的Fc阻断抗体、随后用它们的荧光抗体培养约20-40μl血/样品。
选择抗体的标记物以便在循环的外周血液中区分多数造血细胞群体。此外,某些B和T细胞激活/分化标记物根据用于这种表达的序列标记(最有特征的)的原始文库来选择。该文库由用毒性休克综合征毒素(TSST)激活的Jurkat细胞(一种T细胞系)来生成。抗体
Fc阻断(CD32/16)-作为阻断非特异性结合的预培养的一部分,使用的是全部21种抗体。根据单色柱形图分析数据。大鼠IgG异硫氰酸荧光素(FITC)+大鼠IgG藻红蛋白(phycoerythren)(PE)Ham IgG FITC+Ham IgG PECD45 FITC+GR-1(CD97)PE-----灵长属白细胞与有粒白细胞比较CD4 FITC+CD8 PE-----T-细胞亚群辅助细胞与杀伤者比较Th1.2 FITC+B220 PE-----T细胞与灵长属B细胞标记物比较CD69 FITC+CD28 PE-----用于T和B或仅为T细胞的激活标记物CD3 FITC+CTLA4 PE-----灵长属T细胞与T细胞激活的比较ckit FITC+Sca-1 PE-----髓样和先祖细胞与先祖细胞和外周淋巴细胞比较CD40 FITC+CD40L PE-----B细胞Ag差(diff.)与T细胞的相同配体比较CD62L FITC+CD54 PE-----B和T细胞上的活化粘着分子CD34 FITC(未经分析的数据)结果
对于B220+、CD40+、CD62L+、和CD54+细胞来说,在NNT-1阳性动物中的4种中观察到了绝对细胞数的显著增加。
稍后通过RNA印迹证实这4种动物(#24、35、60、62)为表达体。B220+和CD40+细胞比上述对照组增加的范围在2-4倍。CD62L+(LECAM)和CD54+(ICAM)比上述对照组增加的范围在1.5-3倍。证明4种表达体中3种增加的标记物包括Sca-1(对照组的2-6倍)和ckit(对照组的2-3倍)。尽管不是一致的形式(尽管这些都是T细胞标记物,但是它们在相同的表达体中不全是阳性的),但是包括CD3、CD4、CD8、Thy1.2在内的其它标记物在4种表达体中的2种中表现出最适度的增加。GR1在表达体之一中表现出增加,而在对照组动物之一中甚至有更高数量的GR1+细胞,所以这可能不值得注意。其余抗体不是阳性的、不具备显著性差异,或在CD34的情况下不可能分析。总结
在这些小鼠中观察到了循环淋巴细胞绝对数量的非常确定的增加。尽管也观察到了某些T细胞数量上的增加,但是在淋巴群体上的这种增加看起来主要由B细胞组成。看起来淋巴群体不会表现出活化细胞种类的增加。在循环髓样细胞群体上几乎没有观察到作用或没有作用。ckit和Sca-1的增加不一定与先祖细胞的增加有关,因为在成熟的循环细胞上也发现了这些标记物。
数据提示了B细胞的定向增殖,因为这些细胞数量均与表达充分相关。某些动物的T细胞增加可能是由增加的B细胞产生的某些其它因子的次级效应。关于B细胞的一个令人感兴趣的观察结果是在B220+细胞与CD40+细胞数目之间存在很小而却非常一致的差异。尽管两者均是B细胞的标记物,但是在树突细胞上也发现了CD40。
实施例X:注射有NNT-1的小鼠体内的淋巴增生A.在用NNT-1治疗的BDF1雌性小鼠中的7天静脉/皮下研究
在骨髓和神经细胞检测中,由NNT-1编码的蛋白质与CNTF具有某些同源性和体外活性。本研究的目的是确定当持续7天每日对小鼠给药时NNT-1蛋白质的系统作用和潜在毒性。材料和方法
将20只6周龄的雌性BDF1小鼠用于本研究。将这些小鼠随机分成下列治疗组(n=5/组):
1.PBS缓冲液对照组(每日一次静脉给药,持续7天)
2.NNT-1 1.5mg/kg(静脉给药)
3.NNT-1 0.15mg/kg(静脉给药)
4.NNT-1 1.5mg/kg(皮下给药)
在横向尸体解剖前不给小鼠禁食。尸体解剖前1小时(最后一次给药后24小时),给小鼠腹膜内注射BrdU(对于细胞增殖研究来说为50mg/ml)。通过心脏穿刺获得血液以便进行血液学测定(血红蛋白、血细胞比容、血红细胞计数、血小板计数、平均血小板容积、总体和分化的白细胞计数)和临床化学参数测定(丙氨酸氨基转移酶、天冬氨酸氨基转移酶、碱性磷酸酶、乳酸脱氢酶、葡萄糖、尿素、氮、肌酸酐、总蛋白、白蛋白、球蛋白、钙、磷、总胆红素、尿酸、胆固醇和甘油三酯)。
进行横向尸体解剖、所选择的组织固定在福尔马林锌缓冲液中而用于组织病理学检查[肾上腺、骨髓、骨(股骨)、脑、盲肠、近端和远端结肠、十二指肠、食管、心脏、回肠、空肠、肾、肝、肺、乳腺、卵巢、胰、骨骼肌、皮肤、脾、胃、胸腺、甲状腺、气管、膀胱、子宫、阴道、白色和棕色脂肪组织、任何大的损害]。在常规组织学检查过程前将这些组织固定过夜。获得脾、肝、胃、肾和胸腺的器官重量。结果
脾在NNT-1治疗组中具有动脉周(periarteriolar)淋巴鞘(T细胞区)和滤泡(B细胞区)肥大的脾的白髓中存在显著的淋巴增生。然而,在这些组中髓外造血的程度没有显著增加,这提示这种蛋白质可对体内淋巴细胞而不是对体内造血细胞具有刺激或生长因子这样的作用。
淋巴节NNT-1治疗的小鼠在淋巴节皮质的滤泡(B细胞)和副皮质(T细胞)区具有轻度至明显的反应性淋巴增生。尽管这种改变可以反映出对重组蛋白质的早期免疫反应,但是在脾、淋巴节、派依尔结和骨髓中存在的全身化反应性淋巴增生的程度提示这可能是NNT-1特异性治疗相关的作用。总结和结论
来源于本研究的最明显的发现是用NNT-1治疗7天的小鼠看起来可诱发淋巴组织、特别是在脾和淋巴节中的增生。然而,看起来在本研究条件下这种蛋白质对造血或中枢神经系统不具有任何可检测到的作用。B.NNT-1注射的小鼠的FACS分析
试剂和小鼠重组人NNT-1和rhIL-1来自Amgen Inc.,ThousandOaks,CA.。LPS(大肠杆菌0111:B4)购自LIST BiologicLaboratories,Campbell,CA。约20g的雌性Balb/c小鼠购自Charles River Laboratories,Wilmington,MA。将小鼠放在维持恒定温度和湿度的室中并进行12小时的光/暗周期。小鼠接受标准的实验室饮食并随意饮水。按照与国家和国际法与政策一致的规定原则进行涉及动物及其护理的程序(美国国家研究委员会《实验室动物护理及使用指南》,1996)。
淋巴节重和细胞计数
连续7天,小鼠每日接受腹膜内注射5mg/Kg的NNT-1或缓冲液。第7次注射后24小时,处死小鼠以收集外周(颈和axyllary)淋巴节。收集淋巴节、称重并匀浆化以便制备一种细胞悬浮液。然后用Sismex细胞计数器(Toa Medical Corporation,Kobe,Japan)来对细胞计数、使用大鼠抗小鼠抗CD45R(抗B220)MAb(Pharmingen,San Diego,CA)通过直接IF对其染色并以应用细胞探测软件(Becton和Dickinson,San Jose,CA)的FACSCAN来对其进行分析。
统计学分析将结果表示为平均值±SD。将TNF值进行对数转化以减小其斜率分布并使之达到正常值。将Shapiro-Wilks试验用于分析在转化之前和之后分布的正常值。通过“Student’s”t检验来分析组间的差异。由于对每一个体重复测定BW,所以通过对重复测定的误差(ANOVA)的分析来检测组间和组内BW的差异。
淋巴节重和细胞计数NNT-1的治疗增加了总体和CD45阳性细胞在外周淋巴节中的计数(附图17)。实施例XI:NNT-1表现出以IL-6族细胞因子为特征的体内活性
试剂、小鼠和统计学分析如上述实施例XB中所列。
通过IL-1的血清类淀粉蛋白A(SAA)的诱导、皮质酮的强化和IL-6的诱导以及LPS诱导的TNF的抑制作用。以5mg/Kg的剂量单独、或与IL-1(100ng/小鼠)或LPS(100ng/小鼠)联合腹膜内给予NNT-1。对照组小鼠接受NNT-1的溶剂(10mM溶于盐水的乙酸盐)。在给予NNT-1或盐水8小时后从眼眶后丛中取血而用于SAA测定,给药2小时后测定皮质酮和IL-6且在1.5小时后测定TNF。在5-10只小鼠的组中进行实验。
使用商购的试剂盒(Biogen,Camarillo,CA)、通过ELISA来测定血清中的SAA、IL-6和TNF;结果分别用μg、ng和Pg/ml表示。使用商购的试剂盒(ICB Biomedical,Costa Mesa,CA)、通过RIA来测定皮质酮;结果用ng/ml表示。
通过IL-1的SAA的诱导、皮质酮的强化和IL-6的诱导以及LPS诱导的TNF的抑制作用。NNT-1诱导循环的SAA(附图13)。
NNT-1强化了低剂量的IL-1对血清皮质酮或IL-6的诱导(附图14和15)。当进行单独注射时,NNT-1还表现出增加皮质酮循环水平的能力。
NNT-1通过血清TNF的LPS抑制了诱导作用(附图16)。结果总结
发炎过程伴随TNF的产生,细胞因子主要导致区别与炎症有关的病理情况的组织损害和功能性损害。通常IL-1与TNF一起产生且它还被认为在发炎过程中是致病介体。皮质类固醇是广谱和非常强的抗炎剂,它们可由IL-1通过一种有效的阴性反馈路线来诱导。皮质类固醇抑制TNF和IL-1的产生。也由TNF和IL-1诱导的IL-6还能够通过另一种阴性反馈路线来抑制TNF和IL-1的产生。
至少在有IL-1存在的情况下,NNT-1诱导皮质类固醇和IL-6的能力提示这种分子具有强化两种生理抗炎症路线的能力。这可能导致加速抑制TNF和IL-1的产生且由此加速消退炎症过程。除与皮质类固醇和IL-6的产生的诱导作用无关外,NNT-1还表现出直接阻断TNF产生的特性。令人感兴趣的是这提高了上述概括的抗炎特征。DNA的保藏
在1997年1月21日已经将含有编码NNT-1人基因组DNA的载体P1(NNT-g-PI)的大肠杆菌细胞DH10B和含有编码NNT-1人cDNA的载体PSPORT的大肠杆菌细胞DH10B保藏在ATCC(美国典型培养物保藏中心,12301 Parklawn Drive,Rockville,MD,USA)并分别给予它们登记号98294和98295。
序列表(1)一般信息:(i)申请人:CHANG,MING-SHI
ELLIOTT,GARY S.
SARMIENTO,ULLA
SENALDI,GIORGIO(ii)发明名称:神经营养因子NNT-1(iii)序列数:16(iv)通信地址:
(A)地址:AMGEN INC.
(B)街道:ONE AMGEN CENTER
(C)城市:THOUSAND OAKS
(D)州:CA
(E)国家:USA
(F)邮政编码:91320(v)计算机可读形式:
(A)媒体类型:软盘
(B)计算机:IBM PC兼容机
(C)操作系统:PC-DOS/MS-DOS
(D)软件:PatentIn Release#1.0,版本#1.30(vi)当前申请数据:
(A)申请号:US
(B)申请日:
(C)分类: (vii)在先申请数据:
(A)申请号:US 08/792,019
(B)申请日:1997年2月3日(viii)律师/代理人信息:
(A)姓名:COOK,ROBERT R.
(B)注册号:31,602
(C)参考/记录号:A-442B(2)SEQ ID NO:1的信息:(i)序列特征:
(A)长度:797个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:cDNA(ix)特征:
(A)名称/关键词:CDS
(B)位置:90..764(ix)特征:
(A)名称/关键词:mat_peptide
(B)位置:171..764(ix)特征:
(A)名称/关键词:sig_peptide
(B)位置:90..170(xi)序列描述:SEQ ID NO:1:ATTAAAGCTT CGCCGGAGCC GCGGCTCGCC CTCCCACTCC GCCAGCCTCC GGGAGAGGAG 60CCGCACCCGG CCGGCCCAGC CCCAGCCCC ATG GAC CTC CGA GCA GGG GAC TCG 113
Met Asp Leu Arg Ala Gly Asp Ser
-27 -25 -20TGG GGG ATG TTA GCG TGC CTG TGC ACG GTG CTC TGG CAC CTC CCT GCA 161Trp Gly Met Leu Ala Cys Leu Cys Thr Val Leu Trp His Leu Pro Ala
-15 -10 -5GTG CCA GCT CTC AAT CGC ACA GGG GAC CCA GGG CCT GGC CCC TCC ATC 209Val Pro Ala Leu Asn Arg Thr Gly Asp Pro Gly Pro Gly Pro Ser Ile
1 5 10CAG AAA ACC TAT GAC CTC ACC CGC TAC CTG GAG CAC CAA CTC CGC AGC 257Gln Lys Thr Tyr Asp Leu Thr Arg Tyr Leu Glu His Gln Leu Arg Ser
15 20 25TTG GCT GGG ACC TAT CTG AAC TAC CTG GGC CCC CCT TTC AAC GAG CCA 305Leu Ala Gly Thr Tyr Leu Asn Tyr Leu Gly Pro Pro Phe Asn Glu Pro30 35 40 45GAC TTC AAC CCT CCC CGC CTG GGG GCA GAG ACT CTG CCC AGG GCC ACT 353Asp Phe Asn Pro Pro Arg Leu Gly Ala Glu Thr Leu Pro Arg Ala Thr
50 55 60GTT GAC TTG GAG GTG TGG CGA AGC CTC AAT GAC AAA CTG CGG CTG ACC 401Val Asp Leu Glu Val Trp Arg Ser Leu Asn Asp Lys Leu Arg Leu Thr
65 70 75CAG AAC TAC GAG GCC TAC AGC CAC CTT CTG TGT TAC TTG CGT GGC CTC 449Gln Asn Tyr Glu Ala Tyr Ser His Leu Leu Cys Tyr Leu Arg Gly Leu
80 85 90AAC CGT CAG GCT GCC ACT GCT GAG CTG CGC CGC AGC CTG GCC CAC TTC 497Asn Arg Gln Ala Ala Thr Ala Glu Leu Arg Arg Ser Leu Ala His Phe
95 100 105TGC ACC AGC CTC CAG GGC CTG CTG GGC AGC ATT GCG GGC GTC ATG GCA 545Cys Thr Ser Leu Gln Gly Leu Leu Gly Ser Ile Ala Gly Val Met Ala110 115 120 125GCT CTG GGC TAC CCA CTG CCC CAG CCG CTG CCT GGG ACT GAA CCC ACT 593Ala Leu Gly Tyr Pro Leu Pro Gln Pro Leu Pro Gly Thr Glu Pro Thr
130 135 140TGG ACT CCT GGC CCT GCC CAC AGT GAC TTC CTC CAG AAG ATG GAC GAC 641Trp Thr Pro Gly Pro Ala His Ser Asp Phe Leu Gln Lys Met Asp Asp
145 150 155TTC TGG CTG CTG AAG GAG CTG CAG ACC TGG CTG TGG CGC TCG GCC AAG 689Phe Trp Leu Leu Lys Glu Leu Gln Thr Trp Leu Trp Arg Ser Ala Lys
160 165 170GAC TTC AAC CGG CTC AAG AAG AAG ATG CAG CCT CCA GCA GCT GCA GTC 737Asp Phe Asn Arg Leu Lys Lys Lys Met Gln Pro Pro Ala Ala Ala Val
175 180 185ACC CTG CAC CTG GGG GCT CAT GGC TTC TGACTTCTGA CCTTCTCCTC 784Thr Leu His Leu Gly Ala His Gly Phe190 195TTCGCTCCCC CCC 797(2)SEQ ID NO:2的信息: (i)序列特征:
(A)长度:225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:SEQ ID NO:2:Met Asp Leu Arg Ala Gly Asp Ser Trp Gly Met Leu Ala Cys Leu Cys-27 -25 -20 -15Thr Val Leu Trp His Leu Pro Ala Val Pro Ala Leu Asn Arg Thr Gly
-10 -5 1 5Asp Pro Gly Pro Gly Pro Ser Ile Gln Lys Thr Tyr Asp Leu Thr Arg
10 15 20Tyr Leu Glu His Gln Leu Arg Ser Leu Ala Gly Thr Tyr Leu Asn Tyr
25 30 35Leu Gly Pro Pro Phe Asn Glu Pro Asp Phe Asn Pro Pro Arg Leu Gly
40 45 50Ala Glu Thr Leu Pro Arg Ala Thr Val Asp Leu Glu Val Trp Arg Ser
55 60 65Leu Asn Asp Lys Leu Arg Leu Thr Gln Asn Tyr Glu Ala Tyr Ser His70 75 80 85Leu Leu Cys Tyr Leu Arg Gly Leu Asn Arg Gln Ala Ala Thr Ala Glu
90 95 100Leu Arg Arg Ser Leu Ala His Phe Cys Thr Ser Leu Gln Gly Leu Leu
105 110 115Gly Ser Ile Ala Gly Val Met Ala Ala Leu Gly Tyr Pro Leu Pro Gln
120 125 130Pro Leu Pro Gly Thr Glu Pro Thr Trp Thr Pro Gly Pro Ala His Ser
135 140 145Asp Phe Leu Gln Lys Met Asp Asp Phe Trp Leu Leu Lys Glu Leu Gln150 155 160 165Thr Trp Leu Trp Arg Ser Ala Lys Asp Phe Asn Arg Leu Lys Lys Lys
170 175 180Met Gln Pro Pro Ala Ala Ala Val Thr Leu His Leu Gly Ala His Gly
185 190 195Phe(2)SEQ ID NO:3的信息:(i)序列特征:
(A)长度:5087个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:DNA(基因组)(ix)特征:
(A)名称/关键词:misc_feature
(B)位置:137..138
(D)其它信息:/产物=“>1 KB的间插非测序区”(xi)序列描述:SEQ ID NO:3:AACCTGCGAG TGGGCCTGGC GGATGGGATT ATTAAAGCTT CGCCGGAGCC GCGGCTCGCC 60CTCCCACTCC GCCAGCCTCC GGGAGAGGAG CCGCACCCGG CCGGCCCAGC CCCAGCCCCA 120TGGACCTCCG AGCAGGTTGA AAACCCAAAC TAGCCCTGCT CTTCATAACA TGACAAGCAG 180CGCCCCATCT GATACCTAAA CCGACCAAGT CACAGCCCTC CAACTCACCC TCTGCCTGCC 240CAGACCTCAC CACATCCTTG TGGACTCAAA CCTCAACCGC ACTAAATCAA CCAAATCCCA 300AGTCTAAACT AATCTGAAAC TTTTAAAGTA ACCCAGTCCT TAAACCTAAC CTAGCCCAAT 360GCCAATTATA TCTACCCTAG CCAAACCCTA ACTGCCTTTG CCAGTCCAAA GTGTCCACTG 420AATCCTCACC TTGGTCCTCA CTGAAAATCC CAGAAAAGCA TATTTCCCCA CTGCCCACAT 480CCCTCCTTAC AGCACCCAAC CCTGGCCTCT GGACTCCTGG TATCCTGGGA TGTCCAAACT 540CTGCAGTGCC ATCAGCCAAC AAGCCCGACT CGTCAAATGC ACCTCTCTCC CTTCCTGTCC 600CCACCCTTGC AGGCTGATGG AAAGGCCTCA TTGAAGTCCA ACTTTTCCCC ACCTAACACC 660AAGAACGGGG TGAACCTCCA CACTGCCACC GTTCCCTGAG AGTGAGCACT AAATCTCCTT 720CAATCTAACC CCACCCTACA CTTCCCACAC TCAGGAATCA CATCCTAGAA TATACCCAAA 780ACTAAGCCCC ATAAGGCAGC CCGACCCTAG TGGTCTAACC CTATACCTTG CTTCCTATGG 840GTGAGTCTGT TCTTGGCGGC CGCCTCTCTC CTGCTTCCTC CCTTAGAGCT GACTGTGCTC 900AGCCTGCCAG CTCTGACATG TGCTGTCTCC CACCCTCTGA CTCCCCTCAA GCTGCAGTGG 960GACTGGAAGA CTGGCAGGAA GCTAGGGTAC AACTGGAACA CAGGCAGGTC GACCTGCAGT 1020CCCTAGGCCT GGCCCCGTCC CTCCATGTAC ACACATATAC ATGTTGGCAC ACACACAGTG 1080GCACACATGC CAAAGACTCT CTCAGCTGAC ACACAGATCC ATTCTCAAGT ATCTACTGAT 1140AGACACTCAT GCGTGCCAAG TCCTCATCCT CAAACATACA CATGCCTCTC TTTCTCTCCC 1200GTCTTGCCAG GAGTGTTTCC CCTCCTCCAT CCCCTCTGCC TCCCATCTGG TGTCCCACCC 1260TCACCCCCCA CCCAGCCCAA GGTGGGGACA GACACCTGAG GGGCTGCCAG CTGCTTCCCC 1320GTGTGGGCCC GGGCCGCGCT CATGCTTCTC GTCCATCCTG CCCACAGGGG ACTCGTGGGG 1380GATGTTAGCG TGCCTGTGCA CGGTGCTCTG GCACCTCCCT GCAGTGCCAG CTCTCAATCG 1440CACAGGGGAC CCAGGGCCTG GCCCCTCCAT CCAGAAAACC TATGACCTCA CCCGCTACCT 1500GGAGCACCAA CTCCGCAGCT TGGCTGGGAC CTATGTGAGT ATCCAGCGTA GGAATCTGGG 1560AGTTGGGGAG GAGTGAGGAG TTGGGGAAAG ACAGTCCTAA CCGTGGAGGG TTCTGGTAAA 1620TGATGGGGTG AGGAGGGGCT CTTTGGCTCC CACCAGTCCC CCTGTCTGGT CTATCTCCTG 1680CCCTTCCCTC TTAGGTGGCC CCCCCACTTC CCCATCCCTG GCCCCAGGAC TAGGCATGTG 1740GGCAGGCCTC GCACCCGCCT TGGCCCATTG CCCCACTGGC TGCCAGCCCA GCCGCCCGCC 1800TCCCCCTGGG GGCCGGGGAA GTCTCCTCTG TTTACACCGT GTTGTGGTGT CTCTTGCGCG 1860GGCGGGGTTG GGTGGGGACA GAGGGGCCCC ACCTCCCATG CCTGCGTTCC AGCTCGCCTC 1920TGCCCCCAGA CCTGGGGCCC TGCTGCTCTG GACCCAGGGG CCTCCCTTCC GTCTGCCTCT 1980CCCATCCTAG CTGGGCCTCC TAGGGGGGTC ATGGGGGAAG GGGACTGTAG GGAACCCAGG 2040CAGTAGTGGC AGGGGGTTTA GGGTGTGGAT GGAGGTTATG CTGTAAGGAT TTGGGGGTGG 2100TCCAGAGGTG TTCAGAGAGC CCAGGAGAGA AGGAAGGAGG GTTGGAGGAG CCGAGGCACC 2160ATGGGGAACC GGCCCCCTCT TCCCGTGTTC CTCTTCCACA TCCCAGACCC TACTCTGGAG 2220CCAGGGAAAG AAAAGGGAAG AAGGTGGCGG GGGAGCTGGC TCCAGCCCCA GGATACACCG 2280AGGAAATTAG TTTGTCTCTG TGCTTGTCAG CGTGTGAACC TCCCCCTGGG CCCTTGCCTA 2340TCCCAGGCCT CTCCCCTTGC TTCTCCCTTC TTTCCCAGTT ATACATCTCC CTCATCCCTT 2400TCCCTGGGCC CCAGCCGCTC CCCCGAGGGT TGGAAAGGGC TCTGCCCTCT TCCCTATACC 2460ATGCTGTCTT CCATAGCCTT CCTCCTGTCC TACTCATGAG ACTGCCTCCA TTTCTTCCTT 2520CTGCAACCCT GCTCCTATCA GCTGAACCCT TCTTTCGGAG TGTTAGTGAG TACCCGTCTC 2580TCCCCAGCCC CTCAGCTGGT GGGCCTGGGT GTGTCAGCGG CAAATGGGGC TCTGGTTCCA 2640ATGGGCCACT CTCATCTCTC TCTTGTTCCT TGTGCAGAAA ACCTTTGCTT CACTCCACTG 2700CCCTCTCTAG TTCCCGACCC TTTTTCTCTC CTGGCTTTCC CTGCCAAATT TCTCCAAGGA 2760GTGGTCTACA CCCTCTGCCT CCACTTCCTC TCCACCCACT CACTTCTTAA CCCCCTGCAA 2820TCTGGCTTCC AGGCCCCAGC AATGGTTCTC TCCAAGGTCG TCAGGCACCT CCTTGCCAAG 2880CCCGACAGTG TTTTGAAGGC TCATTCTCCT TGCTGTCTGT TTTGCAGCCA CACTGCTGAG 2940CGCTGCTGCC TTCTCGAACT CCTCTTCCTT GGTCTCTGCA CTCTCCTGGG CCACCTTCTA 3000CCTCTCCAGC TCCTCCAGGC TCCTCTTCCT CTCTGTCCTG CCCCCACAGC GGGCACTCTC 3060CCAAGGTTTG CCCACCCAGC CAATCAGCAC GTCCTTCCTG AGCGTCTTGT GCGTCTCCTC 3120CTCCTCCTTT TTCTACGCCT CTCCATTGGA GAGCTCACCA CCGCCACTGC TTCAACTGTC 3180ACCTGCATAC AAATGATATC CTTATTGGAA AAACTCAGGG AGGCCATGAA CAAAGAAGCC 3240TAGCATGGAG ACAGGGCCAG TGTCAGGGGA CACAAAAAAT AGAAACTTTG GGAGCAGGTA 3300TCTCCTTGGT GGTGAGCCAG CGGCTCTGCC CTCCTCCTTC CCCATCACCC TCTCCTTTTC 3360ACAGCTGAAC TACCTGGGCC CCCCTTTCAA CGAGCCAGAC TTCAACCCTC CCCGCCTGGG 3420GGCAGAGACT CTGCCCAGGG CCACTGTTGA CTTGGAGGTG TGGCGAAGCC TCAATGACAA 3480ACTGCGGCTG ACCCAGAACT ACGAGGCCTA CAGCCACCTT CTGTGTTACT TGCGTGGCCT 3540CAACCGTCAG GCTGCCACTG CTGAGCTGCG CCGCAGCCTG GCCCACTTCT GCACCAGCCT 3600CCAGGGCCTG CTGGGCAGCA TTGCGGGCGT CATGGCAGCT CTGGGCTACC CACTGCCCCA 3660GCCGCTGCCT GGGACTGAAC CCACTTGGAC TCCTGGCCCT GCCCACAGTG ACTTCCTCCA 3720GAAGATGGAC GACTTCTGGC TGCTGAAGGA GCTGCAGACC TGGCTGTGGC GCTCGGCCAA 3780GGACTTCAAC CGGCTCAAGA AGAAGATGCA GCCTCCAGCA GCTGCAGTCA CCCTGCACCT 3840GGGGGCTCAT GGCTTCTGAC TTCTGACCTT CTCCTCTTCG CTCCCCCTTC AAACCCTGCT 3900CCCACTTTGT GAGAGCCAGC CCTGTATGCC AACACCTGTT GAGCCAGGAG ACAGAAGCTG 3960TGAGCCTCTG GCCCTTTCCT GGACCGGCTG GGCGTGTGAT GCGATCAGCC CTGTCTCCTC 4020CCCACCTCCC AAAGGTCTAC CGAGCTGGGG AGGAGGTACA GTAGGCCCTG TCCTGTCCTG 4080TTTCTACAGG AAGTCATGCT CGAGGGAGTG TGAAGTGGTT CAGGTTGGTG CAGAGGCGCT 4140CATGGCCTCC TGCTTCTTGC CTACCACTTG GCCAGTGCCC ACCCAGCCCC TCAGGTGGCA 4200CATCTGGAGG GCAGGGGTTG AGGGGCCACC ACCACACATG CCTTTCTGGG GTGAAGCCCT 4260TTGGCTGCCC CACTCTCCTT GGATGGGTGT TGCTCCCTTA TCCCCAAATC ACTCTATACA 4320TCCAATTCAG GAAACAAACA TGGTGGCAAT TCTACACAAA AAGAGATGAG ATTAACAGTG 4380CAGGGTTGGG GTCTGCATTG GAGGTGCCCT ATAAACCAGA AGAGAAAATA CTGAAAGCAC 4440AGGGGCAGGG ACAGACCAGA CCAGACCCAG GAGTCTCCAA AGCACAGAGT GGCAAACAAA 4500ACCCGAGCTG AGCATCAGGA CCTTGCCTCG AATTGTCTTC CAGTATTACG GTGCCTCTTC 4560TCTGCCCCCT TTCCCAGGGT ATCTGTGGGT TGCCAGGCTG GGGAGGGCAA CCATAGCCAC 4620ACCACAGGAT TTCCTGAAAG TTTACAATGC AGTAGCATTT TGGGGTGTAG GGTGGCAGCT 4680CCCCAAGGCC CTGCCCCCCA GCCCCACCCA CTCATGACTC TAAGTGTGTT GTATTAATAT 4740TTATTTATTT GGAGATGTTA TTTATTAGAT GATATTTATT GCAGAATTTC TATTCTTGTA 4800TTAACAAATA AAATGCTTGC CCCAGAACTT AGTCTCTTTG CCCAGCCTCA CCCCTCCTGG 4860TGCTCATCAG ACTCTTGCCA CCCCTGGCTC CCACTCCCTG CTTGCCTCTG GTGGAGCTGC 4920ACAGAGCTCT GGGAAGAGGC CCTCTTCCTC CCCGCACTGG GGCGATGGGC GCACCTCAGA 4980CTTACCCACT GCTGCTGCCA CCACCAACCC CTTGATCCCT CAGTCCTCCC ACACAGCTTC 5040TGTCCACCCC AGGTTTCCCT CACCCCACCT TTGCTAAGTC TTCCTCA 5087(2)SEQ ID NO:4的信息:(i)序列特征:
(A)长度:819个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:cDNA(ix)特征:
(A)名称/关键词:CDS
(B)位置:95..769(ix)特征:
(A)名称/关键词:mat_peptide
(B)位置:176..769(ix)特征:
(A)名称/关键词:sig_peptide
(B)位置:95..175(xi)序列描述:SEQ ID NO:4:TATTATTAAA GCTTCGCCGG AGCCGCGGCT CGCCCTCCCA CTCCGCCAGC CTCTGGGAGA 60GGAGCCGCGC CCGGCCGGCC CGGCCCCCAG CCCC ATG GAC CTC CGA GCA GGG 112
Met Asp Leu Arg Ala Gly
-27 -25GAC TCG TGG GGG ATG TTA GCT TGC CTA TGC ACG GTG CTG TGG CAC CTC 160Asp Ser Trp Gly Met Leu Ala Cys Leu Cys Thr Val Leu Trp His Leu
-20 -15 -10CCT GCA GTG CCA GCT CTT AAT CGC ACA GGA GAT CCA GGC CCT GGC CCC 208Pro Ala Val Pro Ala Leu Asn Arg Thr Gly Asp Pro Gly Pro Gly Pro-5 1 5 10TCC ATC CAG AAA ACC TAT GAC CTC ACC CGC TAC CTG GAG CAT CAA CTC 256Ser Ile Gln Lys Thr Tyr Asp Leu Thr Arg Tyr Leu Glu His Gln Leu
15 20 25CGC AGC TTA GCT GGG ACC TAC CTG AAC TAC CTG GGG CCC CCT TTC AAC 304Arg Ser Leu Ala Gly Thr Tyr Leu Asn Tyr Leu Gly Pro Pro Phe Asn
30 35 40GAG CCT GAC TTC AAT CCT CCT CGA CTG GGG GCA GAA ACT CTG CCC AGG 352Glu Pro Asp Phe Asn Pro Pro Arg Leu Gly Ala Glu Thr Leu Pro Arg
45 50 55GCC ACG GTC AAC TTG GAA GTG TGG CGA AGC CTC AAT GAC AGG CTG CGG 400Ala Thr Val Asn Leu Glu Val Trp Arg Ser Leu Asn Asp Arg Leu Arg60 65 70 75CTG ACC CAG AAC TAT GAG GCG TAC AGT CAC CTC CTG TGT TAC TTG CGT 448Leu Thr Gln Asn Tyr Glu Ala Tyr Ser His Leu Leu Cys Tyr Leu Arg
80 85 90GGC CTC AAC CGT CAG GCT GCC ACA GCT GAA CTC CGA CGT AGC CTG GCC 496Gly Leu Asn Arg Gln Ala Ala Thr Ala Glu Leu Arg Arg Ser Leu Ala
95 100 105CAC TTC TGT ACC AGC CTC CAG GGC CTG CTG GGC AGC ATT GCA GGT GTC 544His Phe Cys Thr Ser Leu Gln Gly Leu Leu Gly Ser Ile Ala Gly Val
110 115 120ATG GCG ACG CTT GGC TAC CCA CTG CCC CAG CCT CTG CCA GGG ACT GAG 592Met Ala Thr Leu Gly Tyr Pro Leu Pro Gln Pro Leu Pro Gly Thr Glu
125 130 135CCA GCC TGG GCC CCT GGC CCT GCC CAC AGT GAC TTC CTC CAG AAG ATG 640Pro Ala Trp Ala Pro Gly Pro Ala His Ser Asp Phe Leu Gln Lys Met140 145 150 155GAT GAC TTC TGG CTG CTG AAG GAG CTG CAG ACC TGG CTA TGG CGT TCA 688Asp Asp Phe Trp Leu Leu Lys Glu Leu Gln Thr Trp Leu Trp Arg Ser
160 165 170GCC AAG GAC TTC AAC CGG CTT AAG AAG AAG ATG CAG CCT CCA GCA GCT 736Ala Lys Asp Phe Asn Arg Leu Lys Lys Lys Met Gln Pro Pro Ala Ala
175 180 185TCA GTC ACC CTG CAC TTG GAG GCA CAT GGT TTC TGACCTCTGA CCCTTAACCC 789Ser Val Thr Leu His Leu Glu Ala His Gly Phe
190 195CCACACCTCC AGGCCCAGTC AGCTGTGCTT 819(2)SEQ ID NO:5的信息:(i)序列特征:
(A)长度:225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:SEQ ID NO:5:Met Asp Leu Arg Ala Gly Asp Ser Trp Gly Met Leu Ala Cys Leu Cys-27 -25 -20 -15Thr Val Leu Trp His Leu Pro Ala Val Pro Ala Leu Asn Arg Thr Gly
-10 -5 1 5Asp Pro Gly Pro Gly Pro Ser Ile Gln Lys Thr Tyr Asp Leu Thr Arg
10 15 20Tyr Leu Glu His Gln Leu Arg Ser Leu Ala Gly Thr Tyr Leu Asn Tyr
25 30 35Leu Gly Pro Pro Phe Asn Glu Pro Asp Phe Asn Pro Pro Arg Leu Gly
40 45 50Ala Glu Thr Leu Pro Arg Ala Thr Val Asn Leu Glu Val Trp Arg Ser
55 60 65Leu Asn Asp Arg Leu Arg Leu Thr Gln Asn Tyr Glu Ala Tyr Ser His70 75 80 85Leu Leu Cys Tyr Leu Arg Gly Leu Asn Arg Gln Ala Ala Thr Ala Glu
90 95 100Leu Arg Arg Ser Leu Ala His Phe Cys Thr Ser Leu Gln Gly Leu Leu
105 110 115Gly Ser Ile Ala Gly Val Met Ala Thr Leu Gly Tyr Pro Leu Pro Gln
120 125 130Pro Leu Pro Gly Thr Glu Pro Ala Trp Ala Pro Gly Pro Ala His Ser
135 140 145Asp Phe Leu Gln Lys Met Asp Asp Phe Trp Leu Leu Lys Glu Leu Gln150 155 160 165Thr Trp Leu Trp Arg Ser Ala Lys Asp Phe Asn Arg Leu Lys Lys Lys
170 175 180Met Gln Pro Pro Ala Ala Ser Val Thr Leu His Leu Glu Ala His Gly
185 190 195Phe(2)SEQ ID NO:6的信息:(i)序列特征:
(A)长度:36个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:其它核酸(xi)序列描述:SEQ ID NO:6:AGCAAGCTTC ACCATGGACC TCCGAGCAGG GGACTC 36(2)SEQ ID NO:7的信息:(i)序列特征:
(A)长度:64个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:其它核酸(xi)序列描述:SEQ ID NO:7:AGCGGGGCCG CACTACTTGC ATCGTCGCGT CCTTGTACTC GAAGCCATGA GCCCCCAGGT 60GCAG 64(2)SEQ ID NO:8的信息:(i)序列特征:
(A)长度:199个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(ix)特征:
(A)名称/关键词:Protein
(B)位置:1..178(ix)特征:
(A)名称/关键词:Region
(B)位置:-21..0(xi)序列描述:SEQ ID NO:8:Met Asn Cys Val Cys Arg Leu Val Leu Val Val Leu Ser Leu Trp Pro
-20 -15 -10Asp Thr Ala Val Ala Pro Gly Pro Pro Pro Gly Pro Pro Arg Val Ser-5 1 5 10Pro Asp Pro Arg Ala Glu Leu Asp Ser Thr Val Leu Leu Thr Arg Ser
15 20 25Leu Leu Ala Asp Thr Arg Gln Leu Ala Ala Gln Leu Arg Asp Lys Phe
30 35 40Pro Ala Asp Gly Asp His Asn Leu Asp Ser Leu Pro Thr Leu Ala Met
45 50 55Ser Ala Gly Ala Leu Gly Ala Leu Gln Leu Pro Gly Val Leu Thr Arg60 65 70 75Leu Arg Ala Asp Leu Leu Ser Tyr Leu Arg His Val Gln Trp Leu Arg
80 85 90Arg Ala Gly Gly Ser Ser Leu Lys Thr Leu Glu Pro Glu Leu Gly Thr
95 100 105Leu Gln Ala Arg Leu Asp Arg Leu Leu Arg Arg Leu Gln Leu Leu Met
110 115 120Ser Arg Leu Ala Leu Pro Gln Pro Pro Pro Asp Pro Pro Ala Pro Pro
125 130 135Leu Ala Pro Pro Ser Ser Ala Trp G1y Gly Ile Arg Ala Ala His Ala140 145 150 155Ile Leu Gly Gly Leu His Leu Thr Leu Asp Trp Ala Val Arg Gly Leu
160 165 170Leu Leu Leu Lys Thr Arg Leu
175(2)SEQ ID NO:9的信息:(i)序列特征:
(A)长度:212个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(ix)特征:
(A)名称/关键词:Protein
(B)位置:1..182(ix)特征:
(A)名称/关键词:Region
(B)位置:-30..0(xi)序列描述:SEQ ID NO:9:Met Asn Ser Phe Ser Thr Ser Ala Phe Gly Pro Val Ala Phe Ser Leu-30 -25 -20 -15Gly Leu Leu Leu Val Leu Pro Ala Ala Phe Pro Ala Pro Val Pro Pro
-10 -5 1Gly Glu Asp Ser Lys Asp Val Ala Ala Pro His Arg Gln Pro Leu Thr
5 10 15Ser Ser Glu Arg Ile Asp Lys Gln Ile Arg Tyr Ile Leu Asp Gly Ile
20 25 30Ser Ala Leu Arg Lys Glu Thr Cys Asn Lys Ser Asn Met Cys Glu Ser35 40 45 50Ser Lys Glu Ala Leu Ala Glu Asn Asn Leu Asn Leu Pro Lys Met Ala
55 60 65Glu Lys Asp Gly Cys Phe Gln Ser Gly Phe Asn Glu Glu Thr Cys Leu
70 75 80Val Lys Ile Ile Thr Gly Leu Leu Glu Phe Glu Val Tyr Leu Glu Tyr
85 90 95Leu Gln Asn Arg Phe Glu Ser Ser Glu Glu Gln Ala Arg Ala Val Gln
100 105 110Met Ser Thr Lys Val Leu Ile Gln Phe Leu Gln Lys Lys Ala Lys Asn115 120 125 130Leu Asp Ala Ile Thr Thr Pro Asp Pro Thr Thr Asn Ala Ser Leu Leu
135 140 145Thr Lys Leu Gln Ala Gln Asn Gln Trp Leu Gln Asp Met Thr Thr His
150 155 160Leu Ile Leu Arg Ser Phe Lys Glu Phe Leu Gln Ser Ser Leu Arg Ala
165 170 175Leu Arg Gln Met
180(2)SEQ ID NO:10的信息:(i)序列特征:
(A)长度:204个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(ix)特征:
(A)名称/关键词:Protein
(B)位置:1..174(ix)特征:
(A)名称/关键词:Region
(B)位置:-30..0(xi)序列描述:SEQ ID NO:10:Met Ala Gly Pro Ala Thr Gln Ser Pro Met Lys Leu Met Ala Leu Gln-30 -25 -20 -15Leu Leu Leu Trp His Ser Ala Leu Trp Thr Val Gln Glu Ala Thr Pro
-10 -5 1Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu
5 10 15Glu Gln Val Arg Lys Ile Gin Gly Asp Gly Ala Ala Leu Gln Glu Lys
20 25 30Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu35 40 45 50Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser
55 60 65Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu
70 75 80Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu
85 90 95Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala
100 105 110Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu115 120 125 130Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg
135 140 145Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu
150 155 160Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro
165 170(2)SEQ ID NO:11的信息:(i)序列特征:
(A)长度:201个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(xi)序列描述:SEQ ID NO:11:Met Ser Arg Arg Glu Gly Ser Leu Glu Asp Pro Gln Thr Asp Ser Ser1 5 10 15Val Ser Leu Leu Pro His Leu Glu Ala Lys Ile Arg Gln Thr His Ser
20 25 30Leu Ala His Leu Leu Thr Lys Tyr Ala Glu Gln Leu Leu Gln Glu Tyr
35 40 45Val Gln Leu Gln Gly Asp Pro Phe Gly Leu Pro Ser Phe Ser Pro Pro
50 55 60Arg Leu Pro Val Ala Gly Leu Ser Ala Pro Ala Pro Ser His Ala Gly65 70 75 80Leu Pro Val His Glu Arg Leu Arg Leu Asp Ala Ala Ala Leu Ala Ala
85 90 95Leu Pro Pro Leu Leu Asp Ala Val Cys Arg Arg Gln Ala Glu Leu Asn
100 105 110Pro Arg Ala Pro Arg Leu Leu Arg Arg Leu Glu Asp Ala Ala Arg Gln
115 120 125Ala Arg Ala Leu Gly Ala Ala Val Glu Ala Leu Leu Ala Ala Leu Gly
130 135 140Ala Ala Asn Arg Gly Pro Arg Ala Glu Pro Pro Ala Ala Thr Ala Ser145 150 155 160Ala Ala Ser Ala Thr Gly Val Phe Pro Ala Lys Val Leu Gly Leu Arg
165 170 175Val Cys Gly Leu Tyr Arg Glu Trp Leu Ser Arg Thr Glu Gly Asp Leu
180 185 190Gly Gln Leu Leu Pro Gly Gly Ser Ala
195 200(2)SEQ ID NO:12的信息:(i)序列特征:
(A)长度:199个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(xi)序列描述:SEQ ID NO:12:Met Ala Phe Thr Glu His Pro Leu Thr Pro His Arg Arg Asp Leu Cys1 5 10 15Ser Arg Ser Ile Trp Leu Ala Arg Lys Ile Arg Ser Asp Leu Thr Ala
20 25 30Leu Thr Glu Ser Tyr Val Lys His Gln Gly Leu Asn Lys Asn Ile Asn
35 40 45Leu Asp Ser Ala Asp Gly Met Pro Val Ala Ser Thr Asp Gln Trp Ser
50 55 60Glu Leu Thr Glu Ala Glu Arg Leu Gln Glu Asn Leu Gln Ala Tyr Arg65 70 75 80Thr Phe His Val Leu Leu Ala Arg Leu Leu Glu Asp Gln Gln Val His
85 90 95Phe Thr Pro Thr Glu Gly Asp Phe His Gln Ala Ile His Thr Leu Leu
100 105 110Leu Gln Val Ala Ala Phe Ala Tyr Gln Ile Glu Glu Leu Met Ile Leu
115 120 125Leu Glu Tyr Lys Ile Pro Arg Asn Glu Ala Asp Gly Met Pro Ile Asn
130 135 140Val Gly Asp Gly Gly Leu Phe Glu Lys Lys Leu Trp Gly Leu Lys Val145 150 155 160Leu Gln Glu Leu Ser Gln Trp Thr Val Arg Ser Ile His Asp Leu Arg
165 170 175Phe Ile Ser Ser His Gln Thr Gly Ile Pro Ala Arg Gly Ser His Tyr
180 185 190Ile Ala Asn Asn Lys Lys Met
195(2)SEQ ID NO:13的信息:(i)序列特征:
(A)长度:252个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(ix)特征:
(A)名称/关键词:Protein
(B)位置:1..227(ix)特征:
(A)名称/关键词:Region
(B)位置:-25..0(xi)序列描述:SEQ ID NO:13:Met Gly Val Leu Leu Thr Gln Arg Thr Leu Leu Ser Leu Val Leu Ala-25 -20 -15 -10Leu Leu Phe Pro Ser Met Ala Ser Met Ala Ala Ile Gly Ser Cys Ser
-5 1 5Lys Glu Tyr Arg Val Leu Leu Gly Gln Leu Gln Lys Gln Thr Asp Leu
10 15 20Met Gln Asp Thr Ser Arg Leu Leu Asp Pro Tyr Ile Arg Ile Gln Gly
25 30 35Leu Asp Val Pro Lys Leu Arg Glu His Cys Arg Glu Arg Pro Gly Ala40 45 50 55Phe Pro Ser Glu Glu Thr Leu Arg Gly Leu Gly Arg Arg Gly Phe Leu
60 65 70Gln Thr Leu Asn Ala Thr Leu Gly Cys Val Leu His Arg Leu Ala Asp
75 80 85Leu Glu Gln Arg Leu Pro Lys Ala Gln Asp Leu Glu Arg Ser Gly Leu
90 95 100Asn Ile Glu Asp Leu Glu Lys Leu Gln Met Ala Arg Pro Asn Ile Leu
105 110 115Gly Leu Arg Asn Asn Ile Tyr Cys Met Ala Gln Leu Leu Asp Asn Ser120 125 130 135Asp Thr Ala Glu Pro Thr Lys Ala Gly Arg Gly Ala Ser Gln Pro Pro
140 145 150Thr Pro Thr Pro Ala Ser Asp Ala Phe Gln Arg Lys Leu Glu Gly Cys
155 160 165Arg Phe Leu His Gly Tyr His Arg Phe Met His Ser Val Gly Arg Val
170 175 180Phe Ser Lys Trp Gly Glu Ser Pro Asn Arg Ser Arg Arg His Ser Pro
185 190 195His Gln Ala Leu Arg Lys Gly Val Arg Arg Thr Arg Pro Ser Arg Lys200 205 210 215Gly Lys Arg Leu Met Thr Arg Gly Gln Leu Pro Arg
220 225(2)SEQ ID NO:14的信息:(i)序列特征:
(A)长度:202个氨基酸
(B)类型:氨基酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:蛋白质(ix)特征:
(A)名称/关键词:Protein
(B)位置:1..180(ix)特征:
(A)名称/关键词:Region
(B)位置:-22..0(xi)序列描述:SEQ ID NO:14:Met Lys Val Leu Ala Ala Gly Val Val Pro Leu Leu Leu Val Leu His
-20 -15 -10Trp Lys His Gly Ala Gly Ser Pro Leu Pro Ile Thr Pro Val Asn Ala
-5 1 5 10Thr Cys Ala Ile Arg His Pro Cys His Asn Asn Leu Met Asn Gln Ile
15 20 25Arg Ser Gln Leu Ala Gln Leu Asn Gly Ser Ala Asn Ala Leu Phe Ile
30 35 40Leu Tyr Tyr Thr Ala Gln Gly Glu Pro Phe Pro Asn Asn Leu Asp Lys
45 50 55Leu Cys Gly Pro Asn Val Thr Asp Phe Pro Pro Phe His Ala Asn Gly
60 65 70Thr Glu Lys Ala Lys Leu Val Glu Leu Tyr Arg Ile Val Val Tyr Leu75 80 85 90Gly Thr Ser Leu Gly Asn Ile Thr Arg Asp Gln Lys Ile Leu Asn Pro
95 100 105Ser Ala Leu Ser Leu His Ser Lys Leu Asn Ala Thr Ala Asp Ile Leu
110 115 120Arg Gly Leu Leu Ser Asn Val Leu Cys Arg Leu Cys Ser Lys Tyr His
125 130 135Val Gly His Val Asp Val Thr Tyr Gly Pro Asp Thr Ser Gly Lys Asp
140 145 150Val Phe Gln Lys Lys Lys Leu Gly Cys Gln Leu Leu Gly Lys Tyr Lys155 160 165 170Gln Ile Ile Ala Val Leu Ala Gln Ala Phe
175 180(2)SEQ ID NO:15的信息:(i)序列特征:
(A)长度:45个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:其它核酸(xi)序列描述:SEQ ID NO:15:AGCGCTACGG TCGACCCGGC GTTTTTTTTT TTTTTTTTTT TTACG 45(2)SEQ ID NO:16的信息:(i)序列特征:
(A)长度:24个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构;线性(ii)分子类型:其它核酸(xi)序列描述:SEQ ID NO:16:GGAAGGAAAA AAGCGGCCGC TACA 24
Claims (23)
1.一种编码多肽的核酸分子,选自如下核酸分子组成的组:
(a)SEQ ID NO:1的核酸分子;
(b)SEQ ID NO:3的核酸分子;
(c)编码SEQ ID NO:2的多肽或其生物活性片段的核酸分子;
(d)编码一种与SEQ ID NO:2多肽至少有70%同一性的多肽的核酸分子;
(e)在严格条件下与上述(a)-(d)中任意一种核酸分子杂交的核酸分子;以及
(f)作为上述(a)-(e)中任意一种核酸分子的互补序列的核酸分子。
2.一种编码多肽的核酸分子,选自如下核酸分子组成的组:
(a’)SEQ ID NO:4的核酸分子;
(b’)编码SEQ ID NO:5的多肽或其生物活性片段的核酸分子;
(c’)编码一种与SEQ ID NO:5多肽至少有70%同一性的多肽的核酸分子;
(d’)在严格条件下与上述(a’)-(c’)中任意一种核酸分子杂交的核酸分子;以及
(e’)作为上述(a’)-(d’)中任意一种核酸分子的互补序列的核酸分子。
3.SEQ ID NO:1的核酸分子。
4.SEQ ID NO:3的核酸分子。
5.一种编码SEQ ID NO:2的多肽的核酸分子。
6.一种编码SEQ ID NO:2的1-198位氨基酸的核酸分子。
7.一种含有权利要求1-6中任意一项的核酸分子的载体。
8.一种含有权利要求7的载体的宿主细胞。
9.一种用于生产NNT-1多肽的方法,包括下列步骤:
(a)在一种合适的宿主中表达由权利要求1-6中任意一项的核酸编码的多肽;
(b)分离该多肽。
10.一种NNT-1多肽,选自下列多肽组成的组:
(a)SEQ ID NO:2的多肽;
(b)SEQ ID NO:2的1-198位氨基酸的多肽;
(c)与(a)或(b)的多肽至少有70%同一性的多肽;以及
(d)(a)-(c)中的任意一种多肽的生物活性片段。
11.一种NNT-1多肽,选自下列多肽组成的组:
(a’)SEQ ID NO:5的多肽;
(b’)SEQ ID NO:5的1-198位氨基酸的多肽;
(c’)与(a’)或(b’)的多肽至少有70%同一性的多肽;以及
(d)(a’)-(c’)中的任意一种多肽的生物活性片段。
12.一种是SEQ ID NO:2多肽的NNT-1多肽或其生物活性片段。
13.一种是SEQ ID NO:5多肽的NNT-1多肽或其生物活性片段。
14.权利要求12或13的NNT-1多肽,它不含有氨基末端甲硫氨酸。
15.权利要求12或13的NNT-1多肽,它另外含有氨基末端甲硫氨酸。
16.一种特异性结合人NNT-1的抗体或其片段。
17.权利要求16的抗体,它是一种单克隆抗体。
18.一种治疗患有神经或免疫疾病或障碍的病人的方法,包括对所述病人给予有效量的权利要求12-15中任意一项的NNT-1多肽。
19.一种根据权利要求18的方法,其中所述的疾病或障碍选自阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性神经病性综合征、亨廷顿舞蹈病、外周神经病、营养不良、或神经视网膜变性。
20.一种根据权利要求18的方法,其中所述疾病或障碍的特征在于缺乏B-细胞或T细胞。
21.一种根据权利要求20的方法,其中所述的疾病或障碍是常见的可变性免疫缺陷(CVID)、选择性IgA缺失、血丙球蛋白过少、和X连锁丙球蛋白缺乏血症(aggammaglobulinemia)。
22.一种在接种时提高免疫反应性以及产生抗体的方法,包括对需要的病人给予有效量的权利要求12-15中任意一项的NNT-1多肽。
23.一种治疗需要的病人中的炎症疾病的方法,包括对所述病人给予有效量的权利要求12-15中任意一项的NNT-1多肽。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/792,019 | 1997-02-03 | ||
US08/792,019 US5741772A (en) | 1997-02-03 | 1997-02-03 | Neurotrophic factor NNT-1 |
US08/792019 | 1997-02-03 | ||
US09/016,534 US6143874A (en) | 1997-02-03 | 1998-01-30 | Antibodies to the neurotrophic factor NNT-1 |
US09/016534 | 1998-01-30 | ||
US09/016,534 | 1998-01-30 |
Publications (2)
Publication Number | Publication Date |
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CN1251134A true CN1251134A (zh) | 2000-04-19 |
CN1195853C CN1195853C (zh) | 2005-04-06 |
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB988036428A Expired - Fee Related CN1195853C (zh) | 1997-02-03 | 1998-02-02 | 神经营养因子nnt-1 |
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Country | Link |
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EP (1) | EP0977859B1 (zh) |
JP (1) | JP2002514067A (zh) |
CN (1) | CN1195853C (zh) |
AT (1) | ATE273391T1 (zh) |
AU (1) | AU718882B2 (zh) |
CA (1) | CA2279999C (zh) |
DE (1) | DE69825580T2 (zh) |
DK (1) | DK0977859T3 (zh) |
ES (1) | ES2226097T3 (zh) |
HK (1) | HK1025125A1 (zh) |
HU (1) | HU225307B1 (zh) |
IL (2) | IL131103A0 (zh) |
PT (1) | PT977859E (zh) |
WO (1) | WO1998033922A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999000415A1 (en) * | 1997-06-30 | 1999-01-07 | Human Genome Sciences, Inc. | Cardiotrophin-like cytokine |
AU3873200A (en) * | 1999-03-11 | 2000-09-28 | Schering Corporation | Mammalian cytokines; related reagents and methods |
US6800460B1 (en) | 1999-03-11 | 2004-10-05 | Schering Corporation | Mammalian cytokine complexes |
FR2804436B1 (fr) * | 2000-01-27 | 2002-08-02 | Pf Medicament | PROTEINE DE FUSION scsCNTFR/NNT-1 |
FR2804434A1 (fr) * | 2000-01-27 | 2001-08-03 | Pf Medicament | Heterocomplexe nnt-1/clf-1 et son utilisation en tant qu'activateur du recepteur complexe cntrfalpha/gp130/lifrbet a |
FR2804435A1 (fr) * | 2000-01-27 | 2001-08-03 | Pf Medicament | COMPLEXE ISOLE COMPRENANT UNE PROTEINE NNT-1 ET EN OUTRE AU MOINS UNE PROTEINE CLF-1 ET/OU UNE PROTEINE sCNTFRalpha |
US6849260B2 (en) * | 2000-08-18 | 2005-02-01 | Amgen Inc. | Methods and compositions for treating IgE-related disease using NNT-1 inhibitors |
-
1998
- 1998-02-02 IL IL13110398A patent/IL131103A0/xx not_active IP Right Cessation
- 1998-02-02 ES ES98906215T patent/ES2226097T3/es not_active Expired - Lifetime
- 1998-02-02 JP JP53325898A patent/JP2002514067A/ja active Pending
- 1998-02-02 HU HU0001969A patent/HU225307B1/hu not_active IP Right Cessation
- 1998-02-02 IL IL15454398A patent/IL154543A0/xx active IP Right Grant
- 1998-02-02 CA CA002279999A patent/CA2279999C/en not_active Expired - Fee Related
- 1998-02-02 CN CNB988036428A patent/CN1195853C/zh not_active Expired - Fee Related
- 1998-02-02 EP EP98906215A patent/EP0977859B1/en not_active Expired - Lifetime
- 1998-02-02 DK DK98906215T patent/DK0977859T3/da active
- 1998-02-02 AT AT98906215T patent/ATE273391T1/de not_active IP Right Cessation
- 1998-02-02 AU AU61495/98A patent/AU718882B2/en not_active Ceased
- 1998-02-02 WO PCT/US1998/002363 patent/WO1998033922A1/en active IP Right Grant
- 1998-02-02 PT PT98906215T patent/PT977859E/pt unknown
- 1998-02-02 DE DE69825580T patent/DE69825580T2/de not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
---|---|
EP0977859B1 (en) | 2004-08-11 |
WO1998033922A1 (en) | 1998-08-06 |
PT977859E (pt) | 2004-12-31 |
CN1195853C (zh) | 2005-04-06 |
IL131103A0 (en) | 2001-01-28 |
AU6149598A (en) | 1998-08-25 |
AU718882B2 (en) | 2000-04-20 |
HUP0001969A3 (en) | 2002-01-28 |
DE69825580D1 (de) | 2004-09-16 |
CA2279999C (en) | 2004-07-27 |
HK1025125A1 (en) | 2000-11-03 |
HUP0001969A2 (hu) | 2000-10-28 |
DK0977859T3 (da) | 2004-12-06 |
HU225307B1 (en) | 2006-09-28 |
DE69825580T2 (de) | 2005-09-29 |
EP0977859A1 (en) | 2000-02-09 |
IL154543A0 (en) | 2003-09-17 |
ATE273391T1 (de) | 2004-08-15 |
ES2226097T3 (es) | 2005-03-16 |
JP2002514067A (ja) | 2002-05-14 |
CA2279999A1 (en) | 1998-08-06 |
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