CN103703021A - 用于治疗肝癌的Robo1-Fc融合蛋白 - Google Patents

用于治疗肝癌的Robo1-Fc融合蛋白 Download PDF

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CN103703021A
CN103703021A CN201180068378.XA CN201180068378A CN103703021A CN 103703021 A CN103703021 A CN 103703021A CN 201180068378 A CN201180068378 A CN 201180068378A CN 103703021 A CN103703021 A CN 103703021A
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F.多尔-格莱兹
G.盖盖恩多布斯
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Abstract

本发明涉及Robo1-Fc重组蛋白治疗癌症具体是肝癌的用途。

Description

用于治疗肝癌的Robo1-Fc融合蛋白
本发明涉及重组蛋白Robo1-Fc和其治疗其中Slit蛋白过量表达的疾病的用途。具体而言，本发明涉及Robo-Fc蛋白治疗癌症尤其是肝癌的用途。它还涉及包含此类重组蛋白的组合物。本发明的另一方面由Robo1-Fc分子作为诊断工具检测患者中Slit家族分子的过量表达的用途组成。
最初描述Slit配体为它们在神经发育中抵制轴突生长的作用。从那时起，Robo/Slit调控途径也已经被描述于肿瘤血管发生中。具体地，已经描述了Robo4/Slit2途径抑制内皮细胞对VEGF的应答(Jones C.A.等 Nat. Med 14, 448–453 (2008))。由Robo/Slit途径的调控使引导内皮未成熟新血管或芽的过度增殖（非生产性血管发生）以及使这些血管成熟成为可能。已经在几种人类癌症系中证明了Slit2在转录水平上的表达，所述人类癌症系具体为源自结肠癌的HCT116、源自卵巢癌的Skov-3、源自子宫颈癌的HeLa、源自黑素瘤的MDA-MB-435、源自子宫癌的Hec-1A和最后源自肾癌的769-P (Stella MC 等, Mol Biol Cell. 2009 Vol. 20, Issue 2, 642-657)。也已经证明Slit2蛋白在源自以下癌症的人组织中的过量表达：口腔癌 (Wang 等 2008, Cancer Sci. 2008 Mar; 99(3): 510-7)、前列腺癌 (Latil 等 2003 Int J Cancer. 2003 Jan 20; 103(3): 306-15)、结肠癌 (Wang 等 2003, Cancer Cell, Volume 4, Issue 1, July 2003, Pages 19-29)和肝癌(Avci 等 2008, BMC cancer, 8: 392)。更近些时候，Slit2蛋白的过量表达已经显示在子宫内膜异位的样品中(Shen等, 2009, AJP 175 (2): 479)。
Robo1蛋白以两个同种型a和b存在。Robo1蛋白同种型b (NP_598334)的胞外结构域包含5个免疫球蛋白结构域：Ig1、Ig2、Ig3、Ig4和Ig5。Robo蛋白与Slit配体在Ig1和Ig2结构域的水平上相互作用。Liu 等 (2004, Mol. Cell Neurosci, 26: 232-240)已经证明了Ig2结构域在与Slit的相互作用中以及在Robo活性（化学排斥）中的重要性。
对Robo1和Slit2蛋白特异性的抗体的用途已描述于申请WO2003/075860中。这些抗体使得抑制肿瘤血管发生成为可能。
然而，提出治疗癌症的替代方法具体是能够抑制Slit2信号转导途径的分子将是有利的。
本发明人已经开发了能够结合Slit配体并且因此抑制Robo/Slit途径的胞内信号转导的可溶性嵌合Robo1受体的策略。令人惊讶的是，本发明的Robo1-Fc分子通过阻止成熟血管的形成，而不是通过抑制内皮细胞的增殖，以具有抗血管发生的作用。
本发明人已显示Robo1-Fc分子还在肺癌和肝癌中具有抗肿瘤作用。
发明详述
本发明的主题是Robo-Fc重组蛋白，其包含Robo1蛋白同种型b的胞外结构域或该结构域的部分、连接区（接头）和免疫球蛋白Fc结构域。
在一个具体的实施方式中，Robo1蛋白同种型b的胞外结构域由Ig1和Ig2结构域组成。这些结构域对应由核苷酸序列SEQ ID NO.1编码的SEQ ID NO.2的肽、或与序列SEQ ID NO.2具有至少80%、85%、90%、95%或99%同一性的序列。
融合蛋白还包含连接区，也称为“接头”。在本发明的上下文中，接头使得给予重组蛋白稳定性，其具体通过限制体内切割，成为可能。可以用于Robo1-Fc分子中的接头例如是GluArgProSerPheVal和GlyGlyGlyGlySer。本领域技术人员具有足够的知识来选择适合于此用途的接头。
根据本发明的Robo1-Fc重组分子的Fc结构域对应免疫球蛋白的可结晶片段。该Fc片段可以来自多种免疫球蛋白IgG1、IgG2、IgG3或IgG4。它负责免疫应答的效应子功能 (WO2008/065543)。
在本发明的一个实施方式中，Fc结构域来自IgG4免疫球蛋白。在一个具体实施方式中，至少一点突变或缺失已经被引入到IgG4 Fc结构域中，从而提高了分子的稳定性，具体是通过稳定由两个Fc结构域构成的铰链区 (Angla 等, 1993, Mol. Immunol., 30: 105-108)来降低或消除IgG4-Fc的残留活性，具体为效应子活性 (WO 97/09351)，并且提高重组蛋白生产过程中的同质性。具体而言，至少两点突变优选三点突变已经被引入IgG4 Fc结构域中。在本发明的Robo1-Fc L1、Robo1-Fc L2和Robo1-Fc L3分子中，优选的突变如下：
- S241P (Kabat编号)，以稳定Fc铰链区中的二硫键；
- L248E (Kabat编号)，以消除IgG4-Fc结构域的残留效应子活性；
- C末端赖氨酸缺失，以降低蛋白的异质性。
如上所述的包含Robo1同种型b的Ig1和Ig2结构域、接头和突变的IgG4结构域的本发明的Robo1-Fc分子是Robo1-Fc L1、Robo1-Fc L2和Robo1-Fc L3。
Robo1-Fc L1对应序列SEQ ID NO.4的蛋白，由核苷酸序列SEQ ID NO.3编码。
Robo1-Fc L2对应序列SEQ ID NO.6的蛋白，由核苷酸序列SEQ ID NO.5编码。
Robo1-Fc L1和Robo1-Fc L2区别在于接头的性质。
Robo1-Fc L3对应序列SEQ ID NO.24的蛋白，由核苷酸序列SEQ ID NO.23编码。
在本发明的一个具体实施方式中，已经引入一个或多个点突变或缺失来提高生产过程中的同质性。具体而言，已经在N末端位置上截短了一个氨基酸优选两个氨基酸。本发明这样的Robo-1-Fc分子是Robo1-Fc L3分子，其中两个氨基酸(Ser20和Arg21)已被截短，并且其中氨基酸Leu22已经与白细胞介素2的信号肽融合。
如之前描述，本发明的Robo1-Fc分子的同质性还通过缺失C末端Lys来提高。
本发明的主题还是这样的蛋白，所述蛋白的蛋白序列对应于序列SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6或SEQ ID NO.24，或者与序列SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6或SEQ ID NO.24具有至少80%、85%、90%、95%或99%同一性。这些蛋白变体具有与具有序列SEQ ID NO.2、SEQ ID NO.4、SEQ ID NO.6或SEQ ID NO.24的蛋白相同的生物学活性，具体为它们与Slit家族的蛋白相互作用的能力。
本发明的Robo1-Fc蛋白可以通过将编码这些蛋白的表达质粒转染入任何适合于真核重组蛋白表达的细胞类型：HEK293、CHO等中来生产，并且随后根据常规方法在培养上清液中回收并且纯化。
本发明的Robo1-Fc L1、Robo1-Fc L2和Robo1-Fc L3蛋白的定性已经使确认它们具有作为生物治疗剂对于其施用所必需的性质成为可能。
本发明的Robo1-Fc蛋白具有与Slit家族的蛋白相互作用的能力。
本发明的Robo1-Fc蛋白具体通过与它们的D2结构域相互作用来特定地识别人Slit1、Slit2和Slit3蛋白以及鼠Slit2蛋白。它们对于Slit家族的3个成员的亲和力是相似的。
本发明的另一主题对应编码本发明的蛋白的核酸分子。
因此，对应于序列SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5或SEQ ID NO.23或者与具有序列SEQ ID NO.1、SEQ ID NO.3、SEQ ID NO.5或SEQ ID NO.23的分子具有至少80%、85%、90%、95%或99% 同一性的核酸分子是本发明的一部分。
本发明的另一主题由本发明的Robo1-Fc蛋白治疗其中Slit家族的蛋白过量表达的疾病的用途组成。
可以被本发明的Robo1-Fc靶向的Slit家族的蛋白是Slit1、Slit2或Slit3。
已显示Robo1能够与Slit家族的多个成员相互作用。因此，有利地注意到本发明的Robo1-Fc蛋白能够同时抑制由Slit1、Slit2和Slit3介导的信号转导途径，其使得与仅对这些途径之一是特异性的抗体相比拓宽治疗范围成为可能。
在另一个实施方式中，Robo1-Fc蛋白用于治疗其中Slit家族的蛋白过量表达的疾病，其通过抑制血管发生而不抑制内皮细胞增殖来进行。将这种与血管成熟缺陷相关的抗血管发生活性称为“非生产性血管发生”。
具体而言，实验研究已经显示本发明的Robo1-Fc分子能够抑制小管的形成，而不抑制内皮细胞增殖。它们使得在肺癌的小鼠模型中非常显著地降低肿瘤体积成为可能。
在一个优选的实施方式中，可以用于治疗其中Slit蛋白过量表达的疾病的Robo1-Fc蛋白是Robo1-Fc L1、Robo1-Fc L2和Robo1-Fc L3，并且源自其中的分子具体包括旨在提高生产过程中的同质性而不会显著改变这些分子的生物学特性的点突变或缺失。
通常，可以用本发明的Robo-1-Fc蛋白治疗的疾病是所有其中Slit途径的抑制可以具有治疗作用的疾病，具体是其中Slit家族的蛋白过量表达的疾病，并且具体是其中Slit2过量表达的疾病。
由于本发明的Robo1-Fc分子具体结合Slit2分子，有趣的是注意到所述分子能够同时抑制其中Slit2参与的两条途径，即Robo1/Slit2和Robo4/Slit2途径。
在本发明的一个具体实施方式中，本发明的Robo1-Fc蛋白用于治疗癌症，具体为胰癌、结肠癌、具有或不具有淋巴转移的结肠直肠癌、乳腺癌、肺癌和肺转移、卵巢癌、子宫颈癌、黑素瘤、肾癌、口腔癌、前列腺癌、肝癌等。在一个具体实施方式中，所述癌症是其中Slit2过量表达的癌症。
在一个具体实施方式中，Robo-Fc蛋白用于治疗肺癌。
在另一个具体实施方式中，Robo-Fc蛋白用于治疗肝癌，如例如肝癌、肝细胞癌 (HCC)、纤维板层癌（肝细胞癌的病理学变体）、胆管癌、肝母细胞瘤或肝的血管肉瘤。
本发明的Robo1-Fc分子还可以用作抗癌药物作为目前治疗的替代物或补充物。
具体而言，这些分子可以与抗癌化合物组合（任选同时）施用。
本发明的另一主题涉及包含如上文定义的Robo1-Fc蛋白和一种或多种药学上可接受的赋形剂的组合物。
本发明的Robo1-Fc蛋白可以配制于药物组合物中以进行局部、口部、肠胃外、鼻内、静脉内、肌内、皮下、眼内等施用。优选地，药物组合物包含用于可注射制剂的药学上可接受的载体。它们具体可以是等渗的无菌盐溶液（磷酸二氢钠或磷酸氢二钠、氯化钠、氯化钾、氯化钙或氯化镁等，或这些盐的混合物），或干燥的具体是冷冻干燥的组合物，其适当地通过加入无菌水或生理盐水来允许可注射溶质的形成。
本发明的另一方面由Robo1-Fc分子作为诊断工具检测患者中Slit家族分子的过量表达的用途组成。这是由于已经显示Slit途径涉及许多癌。提供用于评价Slit信号转导途径的紊乱的检测对于选择患者的目的是非常有帮助的，所述患者能够响应基于施用Robo1-Fc分子的治疗。
诊断工具可以是即开即用试剂盒形式，包含以适合于将其与来自患者的生物样品（血液、尿、肿瘤活组织检查）接触的形式的Robo1-Fc分子，所述患者易于表现为Slit分子的过量表达。可以任选预先标记Robo-Fc分子，并且检测Robo-Fc和Slit的结合，以评价与对照样品相比生物样品中Slit蛋白表达的升高。该试剂盒例如可以为ELISA试剂盒的形式。
附图说明
图1：Robo1-Fc L1、Robo1-Fc L2和Robo1-Fc L3蛋白的表达质粒。
图2：通过ELISA的Robo1-Fc融合蛋白变体与Slit2蛋白相互作用的评价。
图3：通过FACS测定的Robo1-Fc对不表达Slit2的HEK293细胞的亲和力。
图4：通过FACS测定的Robo1-Fc对表达Slit2的HEK293细胞的亲和力。
图5：在小鼠中静脉注射后Robo1-Fc蛋白的药代动力学概况A。施用Robo1-Fc L1，B. 施用Robo1-Fc L2。
图6：用内皮细胞和间充质细胞的共培养试验中Robo1-Fc L1分子的作用。A. Robo1-Fc L1抑制培养中小管形成。B. Robo1-Fc L1显著抑制VEGF诱导的假小管形成。
图7：Robo1-Fc L1分子在小鼠中的离体主动脉环模型中的作用的评价。A: 制备主动脉环和测量小管的方案描述。B: a.对照; b. Robo1-Fc Slit2-minus 500 µg/mL + VEGF 10 ng/mL; c. Robo1-Fc L1 500 µg/mL + VEGF 10 ng/mL。
图8：对照组中和已接受以25 mg/kg的4次Robo1-Fc注射的组中细胞注射后28天的平均肿瘤重（SCID小鼠的肝的左叶中的HepG2细胞）。
图9：对照组中和已接受一周两次5 mg/kg的Robo1-Fc注射的组中细胞注射后28天的平均肿瘤重（SCID小鼠的肝的一叶的Hep3B细胞）。
图10：对照组中和已接受一周两次5 mg/kg的Robo1-Fc的组中血浆AFP浓度。
实施例
实施例1：Robo1-Fc蛋白的制备
a. 用作生物治疗剂的允许Robo1-Fc重组蛋白的表达的构建体
Robo1-Fc重组蛋白由人Robo1蛋白同种型b (NP_598334)的前两个免疫球蛋白结构域(Ig1-Ig2)和人免疫球蛋白G4的Fc结构域(hIgG4-Fc, SwissProt IGHG4_HUMAN)之间的融合组成。
为了获得Robo1-Fc L1构建体，使用人胎心cDNA文库(参考号HL5042T, Clontech)通过PCR扩增cDNA (SEQ ID NO.1)的片段，所述片段对应该蛋白(SEQ ID NO.2)的免疫球蛋白(Ig)结构域Ig1和Ig2，其后为GluArgProSerPheVal接头。将该扩增片段随后克隆至真核表达载体pXL4904（描述于图1中）中，使Robo1的两个Ig结构域在C末端位置与人IgG4的Fc结构域融合表达。将三点突变引入IgG4-Fc结构域中以获得以下特征：S241P (Kabat编号)，以稳定Fc铰链区中的二硫键；L248E，以消除IgG4-Fc结构域的残留效应子活性；C末端赖氨酸缺失，以降低蛋白的异质性。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.3。将所获的重组蛋白称为Robo1-Fc L1，并且对应蛋白序列SEQ ID NO.4。
为了获得Robo1-Fc L2构建体，将对应于Ig1-Ig2结构域但无提及的接头的相同cDNA克隆至真核表达载体pXL4909（描述于图1中）中，其允许这些Ig结构域与包含在Robo1-Fc L1的构建中描述的3个点突变的IgG4的相同Fc结构域融合表达，但这次在Fc结构域的上游引入了GlyGlyGlyGlySer接头。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.5。将所获的重组蛋白称为Robo1-Fc L2，并且对应蛋白序列SEQ ID NO.6。
b. 用作对照的Robo1-Fc蛋白的构建
为了获得Robo1-Fc Slit2-minus构建体，通过PCR修饰之前克隆入pXL4904质粒的cDNA，以引入允许位置38的亮氨酸置换为谷氨酰胺和位置89的苯丙氨酸置换为酪氨酸的点突变。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.7。将所获的重组蛋白称为Robo1-Fc Slit2-minus，并且对应蛋白序列SEQ ID NO.8。
为了获得Robo1-Fc 肝素-minus构建体，通过PCR修饰克隆入pXL4904质粒的cDNA，以引入允许位置97的精氨酸置换为苯胺和位置98的赖氨酸置换为丙氨酸的点突变。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.9。将所获的重组蛋白称为Robo1-Fc 肝素-minus，并且对应蛋白序列SEQ ID NO.10。
c. 多种Robo1-Fc蛋白的生产
分别使用pXL4904和pXL4909质粒以及如在申请WO2008/065543中已描述的允许两个N-聚糖糖基化酶即α-2,3-唾液酸转移酶和β-1,4-半乳糖转移酶表达的辅助质粒pXL4544和pXL4551通过在HEK293系（FreeStyle 293-F细胞，参考号51-0029, Invitrogen，根据供应商推荐）中瞬时转染来生产两个蛋白Robo1-Fc L1和Robo1-Fc L2。还分别使用pXL4904和pXL4909质粒通过在CHO系（CHO-S细胞，参考号11619-012, Invitrogen，根据供应商推荐）中转染来生产这些蛋白。
通过在蛋白A亲和柱(MabSelect参考号17-5199-02, Amersham Biosciences)上层析和在20 mM NaCl / 100 mM乙酸缓冲液中洗脱，并且随后在PBS缓冲液（参考号14190-094, Invitrogen）中配制来纯化HEK293细胞的培养上清液中表达的Robo1-Fc L1和Robo1-Fc L2蛋白。
Robo1-Fc Slit2-minus和Robo1-Fc 肝素-minus重组蛋白以相同方式生产并纯化。
d. Robo1-Fc重组蛋白的物理化学特征
SDS-PAGE和凝胶渗透分析可以显示蛋白是二聚化的并且多于96％纯。质谱分析可以证明这些蛋白的同一性，去糖基化的蛋白的测定重量与计算机计算的重量完全一致。如Saddic等 2002. (Methods Mol. Biol. 194: 23-36和Anumula 等 1998. Glycobiology 8: 685-694)描述的单糖组合物分析和N-聚糖唾液酸的定量可以证明蛋白在非常大程度上被唾液酸化。结果显示于表1中。将要注意Robo1-Fc L1和Robo1-Fc L2分子的N末端分析显示这些纯化的蛋白包含可变比例（0至40％）的具有前2个残基(丝氨酸20和Arg20)截短的形式。
表 1 ：Robo1-Fc蛋白同一性
Figure DEST_PATH_IMAGE002
实施例2：用作配体的Slit蛋白的制备
编码人Slit2蛋白的cDNA对应参考蛋白NP_004778。使用人脑cDNA文库(参考号639300, Clontech)通过PCR扩增该cDNA的片段。
将对应D2结构域的cDNA克隆入真核表达载体pXL4911中，以表达在C末端位置上包含His标签的该结构域。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.11。将所获的重组蛋白称为Slit2-D2，并且对应蛋白序列SEQ ID NO.12。
将对应D1-D2结构域的cDNA克隆入真核表达载体pXL4912中，以表达在C末端位置上包含His标签的这两个结构域。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.13。将所获的重组蛋白称为Slit2-D1D2，并且对应蛋白序列SEQ ID NO.14。
将对应Slit2蛋白的胞外部分（Nt）的cDNA克隆入真核表达载体pXL5033中，以表达在C末端位置上具有His标签的该蛋白。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.15。将所获的重组蛋白称为Slit2-N，并且对应蛋白序列SEQ ID NO.16。
编码鼠Slit2蛋白的D2结构域并对应所描述的参考蛋白NP_848919的D2结构域的cDNA获自克隆入pXL4911质粒中的cDNA。用pXL4911作为模板通过PCR产生可以产生五个点突变的四条片段，并且随后将这些片段用作模板通过连续PCR来扩增编码完整D2结构域的cDNA。蛋白携带允许其与鼠Slit2蛋白的D2结构域一致的Thr311Ser、Lys313Arg、Ile329Leu、Ile411Val和Pro418Ala突变。该质粒可以表达在C末端位置上具有His标签的鼠Slit2蛋白的D2结构域。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.17。将所获的重组蛋白称为mSlit2-D2，并且对应蛋白序列SEQ ID NO.18。
编码人Slit1蛋白的cDNA对应所描述的参考蛋白NP_003052。使用人脑cDNA文库(参考号639300, Clontech)通过PCR扩增该cDNA的片段。将对应D2结构域的cDNA克隆入真核表达载体pXL5020中，以表达在C末端位置上包含His标签的该结构域。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.19。将所获的重组蛋白称为Slit1-D2，并且对应蛋白序列SEQ ID NO.20。
编码人Slit3蛋白的cDNA对应所描述的参考蛋白NP_003053。使用人脑cDNA文库(参考号639300, Clontech)通过PCR扩增该cDNA的片段。将对应D2结构域的cDNA克隆入真核表达载体pXL5021中，以表达在C末端位置上包含His标签的该结构域。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.21。将所获的重组蛋白称为Slit3-D2，并且对应蛋白序列SEQ ID NO.22。
使用pXL4911质粒(分别为pXL4912或pXL5033)在HEK293系（FreeStyle 293-F细胞，根据供应商的推荐，Invitrogen）中通过瞬时转染来生产称为Slit2-D2、Slit2-D1D2和Slit2-N的三个蛋白。
通过在Ni螯合琼脂糖柱(参考号17-0409-03, Amersham Biosciences)上层析和在咪唑缓冲液中洗脱并且随后在调节至1M NaCl的PBS缓冲液（参考号14190-094, Invitrogen）中配制来纯化HEK293细胞的培养上清液中表达的Slit2-D2和Slit2-D1D2蛋白。质谱分析(LC/MS)可以证明这些蛋白的同一性。
以类似的方式生产、纯化并表征称为mSlit2-D2、Slit1-D2和Slit3-D2的三个蛋白。
实施例3：通过三种方法：ELISA、SPR和FACS研究Robo1-Fc重组蛋白对Slit蛋白和对肝素的亲和力
a. Robo1-Fc蛋白对肝素的亲和力
为了测定Robo1-Fc构建体对肝素的亲和力，将2 mg纯化的并在10 mM磷酸盐pH 7.0中配制的Robo1-Fc蛋白在肝素柱(1 mL HiTrap Heparin-Sepharose HP, GE Heathcare)上通过用从0至1.5 M的线性梯度NaCl洗脱进行层析。
表2显示了如文献(Fukuhara, N.等 2008 J. Biol. Chem. 283 p16226-16234)中描述的对于洗脱Robo1-Fc L1蛋白必需的448 mM的NaCl浓度。
表 2 ：Robo1-Fc对肝素的亲和力
Robo1-Fc构建体 从肝素柱上脱附[NaCl], mM
Robo1-Fc L1 448
Robo1-Fc 肝素-minus 无结合
这些结果显示Robo1-Fc 肝素-minus蛋白没有保留在该柱上，并且因此它不再具有对肝素的亲和力。因此该蛋白是肝素-阴性突变体。
b. Robo1-Fc蛋白变体与人Slit2蛋白D2结构域的相互作用的评价
本实施例描述了通过ELISA测定的称为Robo1-Fc L1和Robo1-Fc L2的两个变体与它们的天然配体（在这些实验中，为人Slit2的D2结构域）的相互作用。
将人Slit2-D2蛋白结合至Immulon-4酶联板(VWR Scientific Inc. Swedesboro, NJ)上。加入一定浓度范围（从20 µg/mL至0.02 µg/mL）的Robo1-Fc L1和Robo1-Fc L2变体并且随后通过过氧化物酶缀合的山羊抗人IgG抗体(Sigma; 参考号A0170, 稀释至1:50 000)来检测。用TMB-H2O2底物(Interchim; 参考号UP664780)进行显色，并且用平板读数器在450 nm处进行测定。结果报告于图2中。它们显示两个变体Robo1-Fc L1和L2特定地与人Slit2蛋白（具体与D2结构域）相互作用。
c. Robo1-Fc蛋白与Slit家族的人变体即Slit1和Slit3的相互作用的评价
本实施例描述了通过ELISA测定的Robo1-Fc L1融合蛋白与Slit1-D2、Slit2-D2和Slit3-D2的相互作用。
将人Slit变体的D2结构域结合至Immulon-4酶联板(VWR Scientific Inc. Swedesboro, NJ)上。加入一定浓度范围（从1 µg/mL至0.001 µg/mL）的Robo1-Fc L1融合蛋白并且随后使用过氧化物酶缀合的山羊抗人IgG抗体(Sigma; 参考号A0170, 稀释至1:50 000)来检测。用TMB-H2O2底物(Interchim; 参考号UP664780)进行显色，并且用平板读数器在450 nm处进行测定。类似地，通过ELISA测定在上文描述的相同条件下根据浓度范围（从20 µg/mL至0.02 µg/mL）评价在Slit2结合位点的水平上突变的Robo1-Fc Slit2-minus变体。结果报告于下文表3中。
表 3 ：Robo1-Fc对Slit蛋白的人变体的亲和力
Slit蛋白（配体） Robo1-Fc蛋白 EC50 (µg/mL) CV (%)
Slit2-D2 Robo1-Fc L1 1.32 E-01 3.3
Slit1-D2 Robo1-Fc L1 7.88 E-02 3.9
Slit3-D2 Robo1-Fc L1 2.60 E-01 12
Slit2-D2 Robo1-Fc Slit2-minus 1.78 E+01 18
这些结果显示Robo1-Fc蛋白特定地与该家族的三个蛋白Slit1、Slit2和Slit3（具体与它们的D2结构域）相互作用。
此外，Robo1-Fc Slit2-minus蛋白不再具有对肝素的亲和力，并且因此它是肝素-阴性突变体。
d. Robo1-Fc蛋白与鼠Slit2蛋白的相互作用的评价
本实施例描述了通过ELISA测定的Robo1-Fc L1融合蛋白与鼠蛋白mSlit2-D2的相互作用。
将鼠蛋白mSlit2-D2结合至Immulon-4酶联板(VWR Scientific Inc. Swedesboro, NJ)上。加入一定浓度范围（从2 µg/mL至0.002 µg/mL）的Robo1-Fc L1融合蛋白并且随后使用过氧化物酶缀合的山羊抗人IgG抗体(Sigma; 参考号A0170, 稀释至1:50 000)来检测。用TMB-H2O2底物(Interchim; 参考号UP664780)进行显色，并且用平板读数器在450 nm处进行测定。结果报告于下文表4中。
表 4 ：Robo1-Fc L1对鼠Slit2蛋白的亲和力
研究的蛋白 EC50 (µg/mL) CV (%)
mSlit2-D2 2.21 E-01 18
这些结果显示Robo1-Fc蛋白特定地与鼠Slit2蛋白相互作用。
e. 通过SPR测定的Robo1-Fc对Slit蛋白的亲和力
本实施例描述了通过SPR（表面等离子共振(Surface Plasmon Resonance); BIAcore 2000）测定Robo1-Fc L1融合蛋白与人Slit2蛋白(在本实验中，为Slit2-D2)的亲和常数。在已经将Robo1-Fc蛋白结合到CM5芯片上之后，分析Robo1-Fc蛋白和人Slit2蛋白间的相互作用。根据Canziani等的方案(2004. Anal. Biochem. 325: 301-307)进行动力学测定。
表 5 ：通过SPR（稳态分析）的Robo-Fc L1与人Slit2-D2的亲和常数
蛋白 KD (nM)
Robo1-Fc L1 32
在已经将Slit2-D2蛋白结合到CM5芯片上之后分析第二种方法，其由测定Robo1-Fc L1融合蛋白和人Slit2蛋白间的亲和常数组成。根据Canziani等的方案(2004. Anal. Biochem. 325: 301-307)使用根据具有两个非相同的结合位点的模型的Scatchard方法来进行动力学测定。
表 6 ：通过SPR根据二相Scatchard模型的Robo1-Fc与人Slit2-D2的亲和常数
Robo1-Fc L1 KD (nM)
高亲和力位点 KD1:1.5
低亲和力位点 KD2:160
f. 通过FACS测定的Robo1-Fc对Slit的亲和力
本实施例描述了Robo1-Fc蛋白在表达Slit2的HEK293哺乳动物细胞上的亲和力。
用不具有在哺乳动物细胞中编码的cDNA的压载（ballast）质粒、或实施例2中描述的编码Slit2-D2蛋白的pXL4911质粒、或编码Slit2-D1D2蛋白的pXL4912质粒、或编码Slit2-N蛋白的pXL5033转染在实施例1中描述并使用的HEK293细胞。转染后48小时将细胞分配到96孔板中，并且4℃下将Robo1-Fc蛋白以0.01至3□mg/L的浓度范围加入30分钟。Robo1-Fc蛋白是Robo1-Fc L1生物治疗剂、或Robo1-Fc Slit2-minus突变体、或Robo1-Fc 肝素-minus突变体。洗涤细胞并且将标记有Alexa 488的抗人Fc抗体(参考号: A-11013, Invitrogen)在4℃下孵育30分钟。随后通过FACS (Geomean)对标记的HEK293细胞定量。
图3描述了在不存在Slit2表达的情况下通过FACS经荧光测定的HEK293细胞与Robo1-Fc蛋白的结合。Robo1-Fc蛋白以及Robo1-Fc Slit2-minus突变体结合HEK293细胞，而Robo1-Fc 肝素-minus突变体不结合HEK293细胞。因此在0.3至0.03 mg/L的低Robo1-Fc浓度下，Robo1-Fc经肝素结合部分结合到HEK293细胞上。
图4描述了当通过瞬时转染表达Slit2-N时，通过FACS经荧光测定的HEK293细胞与Robo1-Fc蛋白的结合。只有Robo1-Fc蛋白结合表达Slit2-N的HEK293细胞。相比于生物治疗的Robo1-Fc L1蛋白，在3.0至0.3 mg/L的Robo1-Fc浓度范围内Robo1-Fc Slit2-minus和Robo1-Fc 肝素-minus突变体不（或实际上不）结合。
表7描述了当Slit2-N、Slit2-D1D2或Slit2-D2蛋白在HEK293系中表达时，通过FACS测定的Robo1-Fc蛋白的亲和常数。
表 7 ：通过FACS的Robo1-Fc对Slit2蛋白的亲和力
Figure DEST_PATH_IMAGE003
如上文实施例中，证明Robo1-Fc Slit2-minus突变体是Slit2-阴性的并且Robo1-Fc 肝素-minus突变体比生物治疗蛋白具有对Slit2更弱的亲和力。
Robo1-Fc以可比较的亲和力结合由HEK293细胞表达的Slit2-N和Slit2-D1D2，所述亲和力高于对Slit2-D2的亲和力。
实施例4：Robo1-Fc L1和Robo1-Fc L2蛋白的药代动力学特性
本实施例描述了在小鼠中静脉内(iv)注射一次的Robo1-Fc蛋白的药代动力学概况和血浆浓度。
用2.5 mg/mL的每一种Robo1-Fc蛋白以100 µL/10 g (≈ 25 mg/kg)的比例经尾静脉对三只Balb/C小鼠（对于每一次）注射。在预定的时间（施用后0.5、1、6、24、48和72小时）时，麻醉小鼠，并且取血并将其收集在包含10 µL的柠檬酸盐(CPD-A, C-4431 Sigma)和2 µL的蛋白酶抑制剂(Complete Protease Inhibitor Mix, Roche Molecular Biochemical)的管中。将管离心，并且收集血浆样品并冷冻于-20℃。
用Slit2蛋白(Slit2-D2)包被96孔板的孔，并且加入稀释至1/5000和1/20 000的血浆样品在37℃下接触一小时。随后孵育过氧化物酶缀合的抗人Fc抗体(参考号31413, Pierce)并且然后用TMB-H2O2 (参考号UP664780, Interchim)显影，并且在450 nm处读取吸光度。用每一种纯化的Robo1-Fc蛋白制备校准范围。
Robo1-Fc L1和Robo1-Fc L2蛋白的血浆浓度表示于图5中。药代动力学参数描述于下文表8中并且所述蛋白在小鼠中注射后是稳定的。
表 8 ：在小鼠中静脉注射后Robo1-Fc蛋白的药代动力学参数
Figure 782726DEST_PATH_IMAGE004
实施例5：改善了N末端位置上的同质性的Robo1-Fc生物治疗蛋白的描述
本实施例描述了称为Robo1-Fc L3的另一个Robo1-Fc蛋白的表达质粒、生产和物理化学特征，其由于缺乏前两个残基Ser20和Arg20而与Robo1-Fc L1蛋白不同。
通过PCR修饰克隆入pXL4904质粒中的cDNA以消除Ser20和Arg20密码子，并且将下一个密码子（亮氨酸22）融合到白细胞介素2的肽信号的编码序列上。随后产生pXL5004表达质粒，见图1。用于表达该重组蛋白的cDNA序列对应序列SEQ ID NO.23。
如实施例1中描述生产、纯化并表征Robo1-Fc L3蛋白。N末端分析显示该纯化的蛋白是完全同质的。将所获的重组蛋白称为Robo1-Fc L3，并且对应蛋白序列SEQ ID NO.24。
实施例6：Robo1-Fc L3蛋白与人Slit2蛋白的相互作用的评价
本实施例描述了通过ELISA测定的Robo1-Fc L3融合蛋白与人Slit2蛋白（Slit2-D2）的相互作用。
将人Slit2-D2蛋白结合至Immulon-4酶联板(VWR Scientific Inc. Swedesboro, NJ)上。加入一定浓度范围（从1 µg/mL至0.001 µg/mL）的Robo1-Fc L3融合蛋白并且随后通过过氧化物酶缀合的山羊抗人IgG抗体(Sigma; 参考号A0170, 稀释至1:50 000)来检测。用TMB-H2O2底物(Interchim; 参考号UP664780)进行显色，并且用平板读数器在450 nm处进行测定。获得的结果报告于下文表9中。
表 9 ：Robo1-Fc L3蛋白对Slit2蛋白的亲和力－与Robo1-Fc L1蛋白比较
研究的蛋白 EC50 (µg/mL) CV (%)
Robo1-Fc L1 0.13 3.3
Robo1-Fc L3 0.17 4.4
这些结果显示两个变体Robo1-Fc L1和Robo1-Fc L3对Slit2-D2蛋白的亲和力是可比较的。
实施例7：Robo-Fc蛋白在新血管形成中活性的评价
a. 体外内皮细胞和成纤维细胞共培养模型：Robo1-Fc L1分子的特定活性
体外血管发生模型符合人静脉内皮细胞在人皮成纤维细胞的单细胞层上的重排。简述之，将1 ml培养基中的成纤维细胞(Lonza)以40 000细胞/孔接种至24孔板(Becton Dickinson)中。增殖3天（D3）后，将500 µl的EGM®培养基(内皮基础培养基, Lonza) + 2% FCS (胎腓肠血清– Lonza) + 10 µg/ml hEGF (重组人上皮生长因子 – Lonza)中的人静脉内皮细胞(HUVEC-Lonza)以10 000细胞/孔接种至成纤维细胞单细胞层中。用30 ng/mL的VEGF (R&D Systems)、Robo1-Fc L1分子或Robo1-Fc Slit2-minus阴性对照以500 µg/ml的浓度(D3至D9)刺激细胞。3天后，更换培养基并且根据实验条件刺激孔。
2天后，将细胞用乙醇固定并且用对HUVECs特异性的抗CD31抗体标记，随后用抗碱性磷酸酶抗体标记，并且随后用碱性磷酸酶底物显影（D11）。通过在显微镜(×4物镜)下产生的图像采集进行用抗CD31抗体标记的小管的定量，并且使用图像分析软件(Biocom Visiolab 2000软件)分析假小管的长度（图6）。
在该体外血管发生测定中，Robo1-Fc L1 (500 µg/ml)显示出对由HUVECs形成的小管形成的抑制活性。该抑制总计82％并且它与用Robo1-Fc Slit2-minus分子（阴性对照）所获的作用相比在统计学上是显著的。
b. 离体小鼠主动脉环模型：Robo1-Fc L1分子的特定活性
在小鼠主动脉环模型中评价Robo1-Fc L1分子。简述之，将小鼠主动脉去除并清理，并且切为1 mm的部分(D0)。在存在10 ng/ml的VEGF、浓度为500 µg/ml的Robo1-Fc L1分子或浓度为500 µg/ml的Robo1-Fc Slit2-minus阴性对照的情况下，将这些环植入大鼠胶原中。小管将从环上形成，因而体外模拟了新血管的形成。6天后，通过在显微镜(×3物镜)下产生的图像采集进行标记的小管的定量（图7A），并且使用图像分析软件(Biocom Visiolab 2000软件)分析假小管的长度（图7）。
在这些实验条件下，相比于用作阴性对照的Robo1-Fc Slit2-minus分子，Robo1-Fc L1 (500 µg/ml)显示出对形成的小管的形成的强烈抑制活性。
这些结果暗示Robo1-Fc L1能够抑制新血管的形成而不抑制内皮细胞的增殖。将与血管成熟缺陷相关的抗血管发生活性称为“非生产性血管发生”。
实施例8：Robo1-Fc L1蛋白在小鼠中的肺肿瘤模型中的评价
在C57/Bl6小鼠中的肺癌肿瘤模型中评价Robo1-Fc L1分子。
a. 鼠肺肿瘤模型
为了建立鼠肺肿瘤模型，将8周龄雌性C57/Bl6小鼠麻醉。将小鼠左肩胛骨位置的区域剃毛并消毒。在肩胛骨上方切开1 cm的切口。
待注射的细胞源自Lewis肺癌肿瘤系(ATCC, CRL-1642)。将细胞以1体积的Matrigel比4体积的细胞的比例与Matrigel®混合。细胞浓度为62 500细胞/ml。将细胞以每只小鼠20 µl的比例注射如肺中，并且随后缝合伤口。
23天后，将小鼠安乐死。打开胸腔，并且去除左肺和纵隔淋巴结。使用电子卡尺测量左肺上存在的肿瘤，以根据公式：l2×L×0.52确定肿瘤体积。将纵隔淋巴结称重。将结果表示为平均值 ± 标准平均偏差。通过parametric Student’s检验进行统计学分析。
b. 用Robo1-Fc重组蛋白治疗患有肺肿瘤的小鼠
使用Robo1-Fc蛋白的治疗如下进行：在肿瘤细胞注射后的D10、D14、D17和D21，将包含Robo1-Fc蛋白的制剂以25 mg/kg/天的剂量静脉内注射。用PBS缓冲液(10 ml/kg)注射对照组。
c. 结果
在D23，用Robo1-Fc重组蛋白治疗的组中所获肿瘤的平均体积为21.45 ± 2.16 mm3；在对照组中所获的肿瘤的平均体积为39.93 ± 8.41 mm3。用Robo1-Fc蛋白治疗的动物中肿瘤体积的降低为46％。该差异是统计学上显著的(p<0.05)。用Robo1-Fc蛋白治疗的组中所获的纵隔淋巴结（转移淋巴结）的平均重量是12.50 ± 1.26 mg。对照组中所获的纵隔淋巴结的平均重量是30.67 ± 7.69 mg。用Robo1-Fc蛋白治疗的组的纵隔淋巴结的重量的降低为59％，处于显著性界限(p=0.07)上。
实施例9：Robo1-Fc L1蛋白在两个人肝癌模型中的评价
在SCID小鼠中的两种人肝癌模型中评价Robo1-Fc L1分子。
A. 在SCID小鼠中使用HepG2细胞系的人肝癌原位模型
a. 模型描述
将雌性SCID小鼠麻醉（用氯胺酮/甲苯噻嗪的混合物）并且将切口处区域剃毛。在皮肤内和在肌肉壁内切开1 cm的肋下切口之前，将皮肤清洁并消毒。将一部分肝叶小心地从腹膜中取出以进行细胞注射。将50 µl体积的细胞悬液（HepG2源自ATCC，以40 × 106细胞/ml的混合有Matrigel ®的人肝母细胞瘤细胞）注射入左叶中。将该叶放回入腹腔中。用外科胶封闭腹膜并且随后用钉缝合皮肤。用溶于PBS中的Robo1-Fc以25 mg/kg一周两次腹膜内注射来治疗小鼠。治疗开始于细胞植入后两周。用细胞接种后四周，将动物处死进行尸体解剖。
b. 用Robo1-Fc重组蛋白治疗患有人肝癌的小鼠
在该模型中以25 mg/kg的剂量一周治疗两次来评价Robo1-Fc。在方案的第一天和最后一天测量小鼠的体重。在注射细胞后28天，在处死动物后测量肿瘤重量。
c. 结果
在方案过程中，肿瘤生长导致对照动物相当大的体重降低，而用Robo1-Fc治疗的动物在实验结束时具有相同的体重（表10）。在实验结束时，4次腹膜内注射Robo1-Fc后，相比于已接受了溶剂注射的对照组，Robo-1-Fc治疗组的平均肿瘤重量显著降低30% (p < 0.05)（图8）。
表 10：在方案开始和结束时的动物体重
Figure DEST_PATH_IMAGE005
B. 在SCID小鼠中使用Hep3B细胞系的人肝癌原位模型
a. 模型描述
在该HCC模型中，使用Hep3B细胞系。该肿瘤细胞系是来自年轻患者的肝母细胞瘤的商品化细胞系（来自ATCC）。如上文实施例9 A a)中描述使用相同的细胞注射方案。细胞的初始浓度为在50µl的注射体积中2.106。
b. 用Robo1-Fc治疗患有Hep3B肿瘤的小鼠
在该模型中以5 mg/kg一周治疗两次来评价Robo1-Fc。在治疗前和每一次下次治疗之前称重小鼠，以调整注射体积的剂量。在方案的最后一天处死前也称重小鼠。在方案的最后一天处死后测量具有肿瘤的叶。此外，处死前，取小鼠血液，并且将血清取出，进行α胎蛋白（AFP）测定；AFP由癌肝细胞分泌并且目前将它认为是人中HCC发育的生物标记(Fimus 等, 2004, Mol Diagn8(4):207-12. Review)。
c.结果
在肿瘤发育35天过程中，小鼠没有增加体重。用Robo1-Fc以5 mg/kg的治疗对小鼠体重没有显示出作用（表11）。在实验结束时，对照组的平均肿瘤重量为895 ±156 mg。Robo1-Fc治疗组的平均肿瘤重量为483±55 mg（图9）。用Robo1-Fc治疗诱导46％的肿瘤负担的显著降低。
此外，血浆AFP浓度在对照肿瘤携带小鼠中为316 ± 73 µg/ml并且在Robo1-Fc治疗小鼠中为139 ± 28 µg/ml，显示出在治疗的动物中血浆AFP 56 %的抑制（图10）。血浆AFP的这种抑制与Robo1-Fc的抗肿瘤活性良好相关。
表 11：在方案开始和结束时的小鼠体重
Figure 637550DEST_PATH_IMAGE006
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Leu Ser Leu Ser Leu Gly
450
<210> 5
<211> 1362
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(1362)
<400> 5
atg att gcg gag ccc gct cac ttt tac ctg ttt gga tta ata tgt ctc 48
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
tgt tca ggc tcc cgt ctt cgt cag gaa gat ttt cca cct cgc att gtt 96
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
gaa cac cct tca gac ctg att gtc tca aaa gga gaa cct gca act ttg 144
Glu His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
aac tgc aaa gct gaa ggc cgc ccc aca ccc act att gaa tgg tac aaa 192
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
ggg gga gag aga gtg gag aca gac aaa gat gac cct cgc tca cac cga 240
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
atg ttg ctg ccg agt gga tct tta ttt ttc tta cgt ata gta cat gga 288
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly
85 90 95
cgg aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat 336
Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
tac ctt gga gag gct gtg agc cac aat gca tcg ctg gaa gta gcc ata 384
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
ctt cgg gat gac ttc aga caa aac cct tcg gat gtc atg gtt gca gta 432
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
gga gag cct gca gta atg gaa tgc caa cct cca cga ggc cat cct gag 480
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
ccc acc att tca tgg aag aaa gat ggc tct cca ctg gat gat aaa gat 528
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
gaa aga ata act ata cga gga gga aag ctc atg atc act tac acc cgt 576
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
aaa agt gac gct ggc aaa tat gtt tgt gtt ggt acc aat atg gtt ggg 624
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
gaa cgt gag agt gaa gta gcc gag ctg act gtc tta gga ggc gga gga 672
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Gly Gly Gly Gly
210 215 220
tcc gag tcc aag tac ggc cct cct tgc cct ccc tgc cct gcc cct gag 720
Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
ttc gag ggc gga cct agc gtg ttc ctg ttc cct cct aag cct aag gac 768
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
acc ctg atg atc tcc cgg acc cct gag gtg acc tgt gtg gtg gtg gac 816
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
gtg tcc cag gag gac cct gag gtc cag ttc aac tgg tac gtg gac ggc 864
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
275 280 285
gtg gag gtg cac aac gcc aag acc aag cct cgg gag gag cag ttc aat 912
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
290 295 300
tcc acc tac cgg gtg gtg tct gtg ctg acc gtg ctg cac cag gac tgg 960
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
ctg aac ggc aaa gaa tac aag tgt aag gtc tcc aac aag ggc ctg ccc 1008
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
325 330 335
tcc tcc atc gag aaa acc atc tcc aag gcc aag ggc cag cct agg gag 1056
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
cct cag gtg tac acc ctg cct cct agc cag gaa gag atg acc aag aac 1104
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
355 360 365
cag gtg tcc ctg acc tgt ctg gtg aag ggc ttc tac cct tcc gac atc 1152
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
gcc gtg gag tgg gag tcc aac ggc cag cct gag aac aac tac aag acc 1200
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
acc cct cct gtg ctg gac tcc gac ggc tcc ttc ttc ctg tac tcc agg 1248
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
405 410 415
ctg acc gtg gac aag tcc cgg tgg cag gag ggc aac gtc ttt tcc tgc 1296
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
420 425 430
tcc gtg atg cac gag gcc ctg cac aac cac tac acc cag aag tcc ctg 1344
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
tcc ctg tct ctg ggc tga 1362
Ser Leu Ser Leu Gly
450
<210> 6
<211> 453
<212> PRT
<213> 人
<400> 6
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
Glu His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly
85 90 95
Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Gly Gly Gly Gly
210 215 220
Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
325 330 335
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Leu Gly
450
<210> 7
<211> 1365
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(1365)
<400> 7
atg att gcg gag ccc gct cac ttt tac ctg ttt gga tta ata tgt ctc 48
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
tgt tca ggc tcc cgt ctt cgt cag gaa gat ttt cca cct cgc att gtt 96
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
gaa cac cct tca gac cag att gtc tca aaa gga gaa cct gca act ttg 144
Glu His Pro Ser Asp Gln Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
aac tgc aaa gct gaa ggc cgc ccc aca ccc act att gaa tgg tac aaa 192
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
ggg gga gag aga gtg gag aca gac aaa gat gac cct cgc tca cac cga 240
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
atg ttg ctg ccg agt gga tct tta tat ttc tta cgt ata gta cat gga 288
Met Leu Leu Pro Ser Gly Ser Leu Tyr Phe Leu Arg Ile Val His Gly
85 90 95
cgg aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat 336
Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
tac ctt gga gag gct gtg agc cac aat gca tcg ctg gaa gta gcc ata 384
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
ctt cgg gat gac ttc aga caa aac cct tcg gat gtc atg gtt gca gta 432
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
gga gag cct gca gta atg gaa tgc caa cct cca cga ggc cat cct gag 480
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
ccc acc att tca tgg aag aaa gat ggc tct cca ctg gat gat aaa gat 528
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
gaa aga ata act ata cga gga gga aag ctc atg atc act tac acc cgt 576
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
aaa agt gac gct ggc aaa tat gtt tgt gtt ggt acc aat atg gtt ggg 624
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
gaa cgt gag agt gaa gta gcc gag ctg act gtc tta gag aga cca tca 672
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser
210 215 220
ttt gtg gag tcc aag tac ggc cct cct tgc cct ccc tgc cct gcc cct 720
Phe Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
gag ttc gag ggc gga cct agc gtg ttc ctg ttc cct cct aag cct aag 768
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
gac acc ctg atg atc tcc cgg acc cct gag gtg acc tgt gtg gtg gtg 816
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
gac gtg tcc cag gag gac cct gag gtc cag ttc aac tgg tac gtg gac 864
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
ggc gtg gag gtg cac aac gcc aag acc aag cct cgg gag gag cag ttc 912
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
aat tcc acc tac cgg gtg gtg tct gtg ctg acc gtg ctg cac cag gac 960
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
tgg ctg aac ggc aaa gaa tac aag tgt aag gtc tcc aac aag ggc ctg 1008
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
ccc tcc tcc atc gag aaa acc atc tcc aag gcc aag ggc cag cct agg 1056
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
gag cct cag gtg tac acc ctg cct cct agc cag gaa gag atg acc aag 1104
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
aac cag gtg tcc ctg acc tgt ctg gtg aag ggc ttc tac cct tcc gac 1152
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
atc gcc gtg gag tgg gag tcc aac ggc cag cct gag aac aac tac aag 1200
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
acc acc cct cct gtg ctg gac tcc gac ggc tcc ttc ttc ctg tac tcc 1248
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
agg ctg acc gtg gac aag tcc cgg tgg cag gag ggc aac gtc ttt tcc 1296
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
tgc tcc gtg atg cac gag gcc ctg cac aac cac tac acc cag aag tcc 1344
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
ctg tcc ctg tct ctg ggc tga 1365
Leu Ser Leu Ser Leu Gly
450
<210> 8
<211> 454
<212> PRT
<213> 人
<400> 8
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
Glu His Pro Ser Asp Gln Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
Met Leu Leu Pro Ser Gly Ser Leu Tyr Phe Leu Arg Ile Val His Gly
85 90 95
Arg Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser
210 215 220
Phe Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly
450
<210> 9
<211> 1365
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(1365)
<400> 9
atg att gcg gag ccc gct cac ttt tac ctg ttt gga tta ata tgt ctc 48
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
tgt tca ggc tcc cgt ctt cgt cag gaa gat ttt cca cct cgc att gtt 96
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
gaa cac cct tca gac ctg att gtc tca aaa gga gaa cct gca act ttg 144
Glu His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
aac tgc aaa gct gaa ggc cgc ccc aca ccc act att gaa tgg tac aaa 192
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
ggg gga gag aga gtg gag aca gac aaa gat gac cct cgc tca cac cga 240
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
atg ttg ctg ccg agt gga tct tta ttt ttc tta cgt ata gta cat gga 288
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly
85 90 95
gcc gcc agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat 336
Ala Ala Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
tac ctt gga gag gct gtg agc cac aat gca tcg ctg gaa gta gcc ata 384
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
ctt cgg gat gac ttc aga caa aac cct tcg gat gtc atg gtt gca gta 432
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
gga gag cct gca gta atg gaa tgc caa cct cca cga ggc cat cct gag 480
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
ccc acc att tca tgg aag aaa gat ggc tct cca ctg gat gat aaa gat 528
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
gaa aga ata act ata cga gga gga aag ctc atg atc act tac acc cgt 576
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
aaa agt gac gct ggc aaa tat gtt tgt gtt ggt acc aat atg gtt ggg 624
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
gaa cgt gag agt gaa gta gcc gag ctg act gtc tta gag aga cca tca 672
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser
210 215 220
ttt gtg gag tcc aag tac ggc cct cct tgc cct ccc tgc cct gcc cct 720
Phe Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
gag ttc gag ggc gga cct agc gtg ttc ctg ttc cct cct aag cct aag 768
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
gac acc ctg atg atc tcc cgg acc cct gag gtg acc tgt gtg gtg gtg 816
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
gac gtg tcc cag gag gac cct gag gtc cag ttc aac tgg tac gtg gac 864
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
ggc gtg gag gtg cac aac gcc aag acc aag cct cgg gag gag cag ttc 912
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
aat tcc acc tac cgg gtg gtg tct gtg ctg acc gtg ctg cac cag gac 960
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
tgg ctg aac ggc aaa gaa tac aag tgt aag gtc tcc aac aag ggc ctg 1008
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
ccc tcc tcc atc gag aaa acc atc tcc aag gcc aag ggc cag cct agg 1056
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
gag cct cag gtg tac acc ctg cct cct agc cag gaa gag atg acc aag 1104
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
aac cag gtg tcc ctg acc tgt ctg gtg aag ggc ttc tac cct tcc gac 1152
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
atc gcc gtg gag tgg gag tcc aac ggc cag cct gag aac aac tac aag 1200
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
acc acc cct cct gtg ctg gac tcc gac ggc tcc ttc ttc ctg tac tcc 1248
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
agg ctg acc gtg gac aag tcc cgg tgg cag gag ggc aac gtc ttt tcc 1296
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
tgc tcc gtg atg cac gag gcc ctg cac aac cac tac acc cag aag tcc 1344
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
ctg tcc ctg tct ctg ggc tga 1365
Leu Ser Leu Ser Leu Gly
450
<210> 10
<211> 454
<212> PRT
<213> 人
<400> 10
Met Ile Ala Glu Pro Ala His Phe Tyr Leu Phe Gly Leu Ile Cys Leu
1 5 10 15
Cys Ser Gly Ser Arg Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val
20 25 30
Glu His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu
35 40 45
Asn Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys
50 55 60
Gly Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg
65 70 75 80
Met Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly
85 90 95
Ala Ala Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn
100 105 110
Tyr Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile
115 120 125
Leu Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val
130 135 140
Gly Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu
145 150 155 160
Pro Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp
165 170 175
Glu Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg
180 185 190
Lys Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly
195 200 205
Glu Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser
210 215 220
Phe Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
225 230 235 240
Glu Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
245 250 255
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
260 265 270
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
275 280 285
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
290 295 300
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
305 310 315 320
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
325 330 335
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
340 345 350
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
355 360 365
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
370 375 380
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
385 390 395 400
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
405 410 415
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
420 425 430
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
435 440 445
Leu Ser Leu Ser Leu Gly
450
<210> 11
<211> 717
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(717)
<400> 11
atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
gtc acg aat tca ttg cac tgc cct gcc gcc tgt acc tgt agc aac aat 96
Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn
20 25 30
atc gta gac tgt cgt ggg aaa ggt ctc act gag atc ccc aca aat ctt 144
Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu
35 40 45
cca gag acc atc aca gaa ata cgt ttg gaa cag aac aca atc aaa gtc 192
Pro Glu Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Thr Ile Lys Val
50 55 60
atc cct cct gga gct ttc tca cca tat aaa aag ctt aga cga att gac 240
Ile Pro Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp
65 70 75 80
ctg agc aat aat cag atc tct gaa ctt gca cca gat gct ttc caa gga 288
Leu Ser Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly
85 90 95
cta cgc tct ctg aat tca ctt gtc ctc tat gga aat aaa atc aca gaa 336
Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
ctc ccc aaa agt tta ttt gaa gga ctg ttt tcc tta cag ctc cta tta 384
Leu Pro Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu
115 120 125
ttg aat gcc aac aag ata aac tgc ctt cgg gta gat gct ttt cag gat 432
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp
130 135 140
ctc cac aac ttg aac ctt ctc tcc cta tat gac aac aag ctt cag acc 480
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
atc gcc aag ggg acc ttt tca cct ctt cgg gcc att caa act atg cat 528
Ile Ala Lys Gly Thr Phe Ser Pro Leu Arg Ala Ile Gln Thr Met His
165 170 175
ttg gcc cag aac ccc ttt att tgt gac tgc cat ctc aag tgg cta gcg 576
Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
gat tat ctc cat acc aac ccg att gag acc agt ggt gcc cgt tgc acc 624
Asp Tyr Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr
195 200 205
agc ccc cgc cgc ctg gca aac aaa aga att gga cag atc aaa agc aag 672
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys
210 215 220
aaa ttc cgt tgt tca ggt agc gct cat cac cat cat cat cac tga 717
Lys Phe Arg Cys Ser Gly Ser Ala His His His His His His
225 230 235
<210> 12
<211> 238
<212> PRT
<213> 人
<400> 12
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn
20 25 30
Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu
35 40 45
Pro Glu Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Thr Ile Lys Val
50 55 60
Ile Pro Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp
65 70 75 80
Leu Ser Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly
85 90 95
Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
Leu Pro Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu
115 120 125
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp
130 135 140
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
Ile Ala Lys Gly Thr Phe Ser Pro Leu Arg Ala Ile Gln Thr Met His
165 170 175
Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
Asp Tyr Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr
195 200 205
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys
210 215 220
Lys Phe Arg Cys Ser Gly Ser Ala His His His His His His
225 230 235
<210> 13
<211> 1467
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(1467)
<400> 13
atg cgc ggc gtt ggc tgg cag atg ctg tcc ctg tcg ctg ggg tta gtg 48
Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val
1 5 10 15
ctg gcg atc ctg aac aag gtg gca ccg cag gcg tgc ccg gcg cag tgc 96
Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys
20 25 30
tct tgc tcg ggc agc aca gtg gac tgt cac ggg ctg gcg ctg cgc agc 144
Ser Cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser
35 40 45
gtg ccc agg aat atc ccc cgc aac acc gag aga ctg gat tta aat gga 192
Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly
50 55 60
aat aac atc aca aga att acg aag aca gat ttt gct ggt ctt aga cat 240
Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His
65 70 75 80
cta aga gtt ctt cag ctt atg gag aat aag att agc acc att gaa aga 288
Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg
85 90 95
gga gca ttc cag gat ctt aaa gaa cta gag aga ctg cgt tta aac aga 336
Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg
100 105 110
aat cac ctt cag ctg ttt cct gag ttg ctg ttt ctt ggg act gcg aag 384
Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys
115 120 125
cta tac agg ctt gat ctc agt gaa aac caa att cag gca atc cca agg 432
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg
130 135 140
aaa gct ttc cgt ggg gca gtt gac ata aaa aat ttg caa ctg gat tac 480
Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr
145 150 155 160
aac cag atc agc tgt att gaa gat ggg gca ttc agg gct ctc cgg gac 528
Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp
165 170 175
ctg gaa gtg ctc act ctc aac aat aac aac att act aga ctt tct gtg 576
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val
180 185 190
gca agt ttc aac cat atg cct aaa ctt agg act ttt cga ctg cat tca 624
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser
195 200 205
aac aac ctg tat tgt gac tgc cac ctg gcc tgg ctc tcc gac tgg ctt 672
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu
210 215 220
cgc caa agg cct cgg gtt ggt ctg tac act cag tgt atg ggc ccc tcc 720
Arg Gln Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser
225 230 235 240
cac ctg aga ggc cat aat gta gcc gag gtt caa aaa cga gaa ttt gtc 768
His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val
245 250 255
tgc agt ggt cac cag tca ttt atg gct cct tct tgt agt gtt ttg cac 816
Cys Ser Gly His Gln Ser Phe Met Ala Pro Ser Cys Ser Val Leu His
260 265 270
tgc cct gcc gcc tgt acc tgt agc aac aat atc gta gac tgt cgt ggg 864
Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly
275 280 285
aaa ggt ctc act gag atc ccc aca aat ctt cca gag acc atc aca gaa 912
Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu Thr Ile Thr Glu
290 295 300
ata cgt ttg gaa cag aac aca atc aaa gtc atc cct cct gga gct ttc 960
Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro Pro Gly Ala Phe
305 310 315 320
tca cca tat aaa aag ctt aga cga att gac ctg agc aat aat cag atc 1008
Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser Asn Asn Gln Ile
325 330 335
tct gaa ctt gca cca gat gct ttc caa gga cta cgc tct ctg aat tca 1056
Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg Ser Leu Asn Ser
340 345 350
ctt gtc ctc tat gga aat aaa atc aca gaa ctc ccc aaa agt tta ttt 1104
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro Lys Ser Leu Phe
355 360 365
gaa gga ctg ttt tcc tta cag ctc cta tta ttg aat gcc aac aag ata 1152
Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
370 375 380
aac tgc ctt cgg gta gat gct ttt cag gat ctc cac aac ttg aac ctt 1200
Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His Asn Leu Asn Leu
385 390 395 400
ctc tcc cta tat gac aac aag ctt cag acc atc gcc aag ggg acc ttt 1248
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala Lys Gly Thr Phe
405 410 415
tca cct ctt cgg gcc att caa act atg cat ttg gcc cag aac ccc ttt 1296
Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala Gln Asn Pro Phe
420 425 430
att tgt gac tgc cat ctc aag tgg cta gcg gat tat ctc cat acc aac 1344
Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn
435 440 445
ccg att gag acc agt ggt gcc cgt tgc acc agc ccc cgc cgc ctg gca 1392
Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro Arg Arg Leu Ala
450 455 460
aac aaa aga att gga cag atc aaa agc aag aaa ttc cgt tgt tca ggt 1440
Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Gly
465 470 475 480
agc gct cat cac cat cat cat cac tga 1467
Ser Ala His His His His His His
485
<210> 14
<211> 488
<212> PRT
<213> 人
<400> 14
Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val
1 5 10 15
Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys
20 25 30
Ser Cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser
35 40 45
Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly
50 55 60
Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His
65 70 75 80
Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg
85 90 95
Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg
100 105 110
Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys
115 120 125
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg
130 135 140
Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr
145 150 155 160
Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp
165 170 175
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val
180 185 190
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser
195 200 205
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu
210 215 220
Arg Gln Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser
225 230 235 240
His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val
245 250 255
Cys Ser Gly His Gln Ser Phe Met Ala Pro Ser Cys Ser Val Leu His
260 265 270
Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly
275 280 285
Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu Thr Ile Thr Glu
290 295 300
Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro Pro Gly Ala Phe
305 310 315 320
Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser Asn Asn Gln Ile
325 330 335
Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg Ser Leu Asn Ser
340 345 350
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro Lys Ser Leu Phe
355 360 365
Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
370 375 380
Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His Asn Leu Asn Leu
385 390 395 400
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala Lys Gly Thr Phe
405 410 415
Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala Gln Asn Pro Phe
420 425 430
Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn
435 440 445
Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro Arg Arg Leu Ala
450 455 460
Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Gly
465 470 475 480
Ser Ala His His His His His His
485
<210> 15
<211> 3390
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(3390)
<400> 15
atg cgc ggc gtt ggc tgg cag atg ctg tcc ctg tcg ctg ggg tta gtg 48
Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val
1 5 10 15
ctg gcg atc ctg aac aag gtg gca ccg cag gcg tgc ccg gcg cag tgc 96
Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys
20 25 30
tct tgc tcg ggc agc aca gtg gac tgt cac ggg ctg gcg ctg cgc agc 144
Ser Cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser
35 40 45
gtg ccc agg aat atc ccc cgc aac acc gag aga ctg gat tta aat gga 192
Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly
50 55 60
aat aac atc aca aga att acg aag aca gat ttt gct ggt ctt aga cat 240
Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His
65 70 75 80
cta aga gtt ctt cag ctt atg gag aat aag att agc acc att gaa aga 288
Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg
85 90 95
gga gca ttc cag gat ctt aaa gaa cta gag aga ctg cgt tta aac aga 336
Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg
100 105 110
aat cac ctt cag ctg ttt cct gag ttg ctg ttt ctt ggg act gcg aag 384
Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys
115 120 125
cta tac agg ctt gat ctc agt gaa aac caa att cag gca atc cca agg 432
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg
130 135 140
aaa gct ttc cgt ggg gca gtt gac ata aaa aat ttg caa ctg gat tac 480
Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr
145 150 155 160
aac cag atc agc tgt att gaa gat ggg gca ttc agg gct ctc cgg gac 528
Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp
165 170 175
ctg gaa gtg ctc act ctc aac aat aac aac att act aga ctt tct gtg 576
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val
180 185 190
gca agt ttc aac cat atg cct aaa ctt agg act ttt cga ctg cat tca 624
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser
195 200 205
aac aac ctg tat tgt gac tgc cac ctg gcc tgg ctc tcc gac tgg ctt 672
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu
210 215 220
cgc caa agg cct cgg gtt ggt ctg tac act cag tgt atg ggc ccc tcc 720
Arg Gln Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser
225 230 235 240
cac ctg aga ggc cat aat gta gcc gag gtt caa aaa cga gaa ttt gtc 768
His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val
245 250 255
tgc agt ggt cac cag tca ttt atg gct cct tct tgt agt gtt ttg cac 816
Cys Ser Gly His Gln Ser Phe Met Ala Pro Ser Cys Ser Val Leu His
260 265 270
tgc cct gcc gcc tgt acc tgt agc aac aat atc gta gac tgt cgt ggg 864
Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly
275 280 285
aaa ggt ctc act gag atc ccc aca aat ctt cca gag acc atc aca gaa 912
Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu Thr Ile Thr Glu
290 295 300
ata cgt ttg gaa cag aac aca atc aaa gtc atc cct cct gga gct ttc 960
Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro Pro Gly Ala Phe
305 310 315 320
tca cca tat aaa aag ctt aga cga att gac ctg agc aat aat cag atc 1008
Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser Asn Asn Gln Ile
325 330 335
tct gaa ctt gca cca gat gct ttc caa gga cta cgc tct ctg aat tca 1056
Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg Ser Leu Asn Ser
340 345 350
ctt gtc ctc tat gga aat aaa atc aca gaa ctc ccc aaa agt tta ttt 1104
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro Lys Ser Leu Phe
355 360 365
gaa gga ctg ttt tcc tta cag ctc cta tta ttg aat gcc aac aag ata 1152
Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
370 375 380
aac tgc ctt cgg gta gat gct ttt cag gat ctc cac aac ttg aac ctt 1200
Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His Asn Leu Asn Leu
385 390 395 400
ctc tcc cta tat gac aac aag ctt cag acc atc gcc aag ggg acc ttt 1248
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala Lys Gly Thr Phe
405 410 415
tca cct ctt cgg gcc att caa act atg cat ttg gcc cag aac ccc ttt 1296
Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala Gln Asn Pro Phe
420 425 430
att tgt gac tgc cat ctc aag tgg cta gcg gat tat ctc cat acc aac 1344
Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn
435 440 445
ccg att gag acc agt ggt gcc cgt tgc acc agc ccc cgc cgc ctg gca 1392
Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro Arg Arg Leu Ala
450 455 460
aac aaa aga att gga cag atc aaa agc aag aaa ttc cgt tgt tca gct 1440
Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Ala
465 470 475 480
aaa gaa cag tat ttc att cca ggt aca gaa gat tat cga tca aaa tta 1488
Lys Glu Gln Tyr Phe Ile Pro Gly Thr Glu Asp Tyr Arg Ser Lys Leu
485 490 495
agt gga gac tgc ttt gcg gat ctg gct tgc cct gaa aag tgt cgc tgt 1536
Ser Gly Asp Cys Phe Ala Asp Leu Ala Cys Pro Glu Lys Cys Arg Cys
500 505 510
gaa gga acc aca gta gat tgc tct aat caa aag ctc aac aaa atc ccg 1584
Glu Gly Thr Thr Val Asp Cys Ser Asn Gln Lys Leu Asn Lys Ile Pro
515 520 525
gag cac att ccc cag tac act gca gag ttg cgt ctc aat aat aat gaa 1632
Glu His Ile Pro Gln Tyr Thr Ala Glu Leu Arg Leu Asn Asn Asn Glu
530 535 540
ttt acc gtg ttg gaa gcc aca gga atc ttt aag aaa ctt cct caa tta 1680
Phe Thr Val Leu Glu Ala Thr Gly Ile Phe Lys Lys Leu Pro Gln Leu
545 550 555 560
cgt aaa ata aac ttt agc aac aat aag atc aca gat att gag gag gga 1728
Arg Lys Ile Asn Phe Ser Asn Asn Lys Ile Thr Asp Ile Glu Glu Gly
565 570 575
gca ttt gaa gga gca tct ggt gta aat gaa ata ctt ctt acg agt aat 1776
Ala Phe Glu Gly Ala Ser Gly Val Asn Glu Ile Leu Leu Thr Ser Asn
580 585 590
cgt ttg gaa aat gtg cag cat aag atg ttc aag gga ttg gaa agc ctc 1824
Arg Leu Glu Asn Val Gln His Lys Met Phe Lys Gly Leu Glu Ser Leu
595 600 605
aaa act ttg atg ttg aga agc aat cga ata acc tgt gtg ggg aat gac 1872
Lys Thr Leu Met Leu Arg Ser Asn Arg Ile Thr Cys Val Gly Asn Asp
610 615 620
agt ttc ata gga ctc agt tct gtg cgt ttg ctt tct ttg tat gat aat 1920
Ser Phe Ile Gly Leu Ser Ser Val Arg Leu Leu Ser Leu Tyr Asp Asn
625 630 635 640
caa att act aca gtt gca cca ggg gca ttt gat act ctc cat tct tta 1968
Gln Ile Thr Thr Val Ala Pro Gly Ala Phe Asp Thr Leu His Ser Leu
645 650 655
tct act cta aac ctc ttg gcc aat cct ttt aac tgt aac tgc tac ctg 2016
Ser Thr Leu Asn Leu Leu Ala Asn Pro Phe Asn Cys Asn Cys Tyr Leu
660 665 670
gct tgg ttg gga gag tgg ctg aga aag aag aga att gtc acg gga aat 2064
Ala Trp Leu Gly Glu Trp Leu Arg Lys Lys Arg Ile Val Thr Gly Asn
675 680 685
cct aga tgt caa aaa cca tac ttc ctg aaa gaa ata ccc atc cag gat 2112
Pro Arg Cys Gln Lys Pro Tyr Phe Leu Lys Glu Ile Pro Ile Gln Asp
690 695 700
gtg gcc att cag gac ttc act tgt gat gac gga aat gat gac aat agt 2160
Val Ala Ile Gln Asp Phe Thr Cys Asp Asp Gly Asn Asp Asp Asn Ser
705 710 715 720
tgc tcc cca ctt tct cgc tgt cct act gaa tgt act tgc ttg gat aca 2208
Cys Ser Pro Leu Ser Arg Cys Pro Thr Glu Cys Thr Cys Leu Asp Thr
725 730 735
gtc gtc cga tgt agc aac aag ggt ttg aag gtc ttg ccg aaa ggt att 2256
Val Val Arg Cys Ser Asn Lys Gly Leu Lys Val Leu Pro Lys Gly Ile
740 745 750
cca aga gat gtc aca gag ttg tat ctg gat gga aac caa ttt aca ctg 2304
Pro Arg Asp Val Thr Glu Leu Tyr Leu Asp Gly Asn Gln Phe Thr Leu
755 760 765
gtt ccc aag gaa ctc tcc aac tac aaa cat tta aca ctt ata gac tta 2352
Val Pro Lys Glu Leu Ser Asn Tyr Lys His Leu Thr Leu Ile Asp Leu
770 775 780
agt aac aac aga ata agc acg ctt tct aat cag agc ttc agc aac atg 2400
Ser Asn Asn Arg Ile Ser Thr Leu Ser Asn Gln Ser Phe Ser Asn Met
785 790 795 800
acc cag ctc ctc acc tta att ctt agt tac aac cgt ctg aga tgt att 2448
Thr Gln Leu Leu Thr Leu Ile Leu Ser Tyr Asn Arg Leu Arg Cys Ile
805 810 815
cct cct cgc acc ttt gat gga tta aag tct ctt cga tta ctt tct cta 2496
Pro Pro Arg Thr Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu
820 825 830
cat gga aat gac att tct gtt gtg cct gaa ggt gct ttc aat gat ctt 2544
His Gly Asn Asp Ile Ser Val Val Pro Glu Gly Ala Phe Asn Asp Leu
835 840 845
tct gca tta tca cat cta gca att gga gcc aac cct ctt tac tgt gat 2592
Ser Ala Leu Ser His Leu Ala Ile Gly Ala Asn Pro Leu Tyr Cys Asp
850 855 860
tgt aac atg cag tgg tta tcc gac tgg gtg aag tcg gaa tat aag gag 2640
Cys Asn Met Gln Trp Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu
865 870 875 880
cct gga att gct cgt tgt gct ggt cct gga gaa atg gca gat aaa ctt 2688
Pro Gly Ile Ala Arg Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu
885 890 895
tta ctc aca act ccc tcc aaa aaa ttt acc tgt caa ggt cct gtg gat 2736
Leu Leu Thr Thr Pro Ser Lys Lys Phe Thr Cys Gln Gly Pro Val Asp
900 905 910
gtc aat att cta gct aag tgt aac ccc tgc cta tca aat ccg tgt aaa 2784
Val Asn Ile Leu Ala Lys Cys Asn Pro Cys Leu Ser Asn Pro Cys Lys
915 920 925
aat gat ggc aca tgt aat agt gat cca gtt gac ttt tac cga tgc acc 2832
Asn Asp Gly Thr Cys Asn Ser Asp Pro Val Asp Phe Tyr Arg Cys Thr
930 935 940
tgt cca tat ggt ttc aag ggg cag gac tgt gat gtc cca att cat gcc 2880
Cys Pro Tyr Gly Phe Lys Gly Gln Asp Cys Asp Val Pro Ile His Ala
945 950 955 960
tgc atc agt aac cca tgt aaa cat gga gga act tgc cac tta aag gaa 2928
Cys Ile Ser Asn Pro Cys Lys His Gly Gly Thr Cys His Leu Lys Glu
965 970 975
gga gaa gaa gat gga ttc tgg tgt att tgt gct gat gga ttt gaa gga 2976
Gly Glu Glu Asp Gly Phe Trp Cys Ile Cys Ala Asp Gly Phe Glu Gly
980 985 990
gaa aat tgt gaa gtc aac gtt gat gat tgt gaa gat aat gac tgt gaa 3024
Glu Asn Cys Glu Val Asn Val Asp Asp Cys Glu Asp Asn Asp Cys Glu
995 1000 1005
aat aat tct aca tgt gtc gat ggc att aat aac tac aca tgc ctt 3069
Asn Asn Ser Thr Cys Val Asp Gly Ile Asn Asn Tyr Thr Cys Leu
1010 1015 1020
tgc cca cct gag tat aca ggt gag ttg tgt gag gag aag ctg gac 3114
Cys Pro Pro Glu Tyr Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp
1025 1030 1035
ttc tgt gcc cag gac ctg aac ccc tgc cag cac gat tca aag tgc 3159
Phe Cys Ala Gln Asp Leu Asn Pro Cys Gln His Asp Ser Lys Cys
1040 1045 1050
atc cta act cca aag gga ttc aaa tgt gac tgc aca cca ggg tac 3204
Ile Leu Thr Pro Lys Gly Phe Lys Cys Asp Cys Thr Pro Gly Tyr
1055 1060 1065
gta ggt gaa cac tgc gac atc gat ttt gac gac tgc caa gac aac 3249
Val Gly Glu His Cys Asp Ile Asp Phe Asp Asp Cys Gln Asp Asn
1070 1075 1080
aag tgt aaa aac gga gcc cac tgc aca gat gca gtg aac ggc tat 3294
Lys Cys Lys Asn Gly Ala His Cys Thr Asp Ala Val Asn Gly Tyr
1085 1090 1095
acg tgc ata tgc ccc gaa ggt tac agt ggc ttg ttc tgt gag ttt 3339
Thr Cys Ile Cys Pro Glu Gly Tyr Ser Gly Leu Phe Cys Glu Phe
1100 1105 1110
tct cca ccc atg gtc ctc cct cgt agc gct cat cac cat cat cat 3384
Ser Pro Pro Met Val Leu Pro Arg Ser Ala His His His His His
1115 1120 1125
cac tga 3390
His
<210> 16
<211> 1129
<212> PRT
<213> 人
<400> 16
Met Arg Gly Val Gly Trp Gln Met Leu Ser Leu Ser Leu Gly Leu Val
1 5 10 15
Leu Ala Ile Leu Asn Lys Val Ala Pro Gln Ala Cys Pro Ala Gln Cys
20 25 30
Ser Cys Ser Gly Ser Thr Val Asp Cys His Gly Leu Ala Leu Arg Ser
35 40 45
Val Pro Arg Asn Ile Pro Arg Asn Thr Glu Arg Leu Asp Leu Asn Gly
50 55 60
Asn Asn Ile Thr Arg Ile Thr Lys Thr Asp Phe Ala Gly Leu Arg His
65 70 75 80
Leu Arg Val Leu Gln Leu Met Glu Asn Lys Ile Ser Thr Ile Glu Arg
85 90 95
Gly Ala Phe Gln Asp Leu Lys Glu Leu Glu Arg Leu Arg Leu Asn Arg
100 105 110
Asn His Leu Gln Leu Phe Pro Glu Leu Leu Phe Leu Gly Thr Ala Lys
115 120 125
Leu Tyr Arg Leu Asp Leu Ser Glu Asn Gln Ile Gln Ala Ile Pro Arg
130 135 140
Lys Ala Phe Arg Gly Ala Val Asp Ile Lys Asn Leu Gln Leu Asp Tyr
145 150 155 160
Asn Gln Ile Ser Cys Ile Glu Asp Gly Ala Phe Arg Ala Leu Arg Asp
165 170 175
Leu Glu Val Leu Thr Leu Asn Asn Asn Asn Ile Thr Arg Leu Ser Val
180 185 190
Ala Ser Phe Asn His Met Pro Lys Leu Arg Thr Phe Arg Leu His Ser
195 200 205
Asn Asn Leu Tyr Cys Asp Cys His Leu Ala Trp Leu Ser Asp Trp Leu
210 215 220
Arg Gln Arg Pro Arg Val Gly Leu Tyr Thr Gln Cys Met Gly Pro Ser
225 230 235 240
His Leu Arg Gly His Asn Val Ala Glu Val Gln Lys Arg Glu Phe Val
245 250 255
Cys Ser Gly His Gln Ser Phe Met Ala Pro Ser Cys Ser Val Leu His
260 265 270
Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn Ile Val Asp Cys Arg Gly
275 280 285
Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu Pro Glu Thr Ile Thr Glu
290 295 300
Ile Arg Leu Glu Gln Asn Thr Ile Lys Val Ile Pro Pro Gly Ala Phe
305 310 315 320
Ser Pro Tyr Lys Lys Leu Arg Arg Ile Asp Leu Ser Asn Asn Gln Ile
325 330 335
Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly Leu Arg Ser Leu Asn Ser
340 345 350
Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu Leu Pro Lys Ser Leu Phe
355 360 365
Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu Leu Asn Ala Asn Lys Ile
370 375 380
Asn Cys Leu Arg Val Asp Ala Phe Gln Asp Leu His Asn Leu Asn Leu
385 390 395 400
Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr Ile Ala Lys Gly Thr Phe
405 410 415
Ser Pro Leu Arg Ala Ile Gln Thr Met His Leu Ala Gln Asn Pro Phe
420 425 430
Ile Cys Asp Cys His Leu Lys Trp Leu Ala Asp Tyr Leu His Thr Asn
435 440 445
Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr Ser Pro Arg Arg Leu Ala
450 455 460
Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys Lys Phe Arg Cys Ser Ala
465 470 475 480
Lys Glu Gln Tyr Phe Ile Pro Gly Thr Glu Asp Tyr Arg Ser Lys Leu
485 490 495
Ser Gly Asp Cys Phe Ala Asp Leu Ala Cys Pro Glu Lys Cys Arg Cys
500 505 510
Glu Gly Thr Thr Val Asp Cys Ser Asn Gln Lys Leu Asn Lys Ile Pro
515 520 525
Glu His Ile Pro Gln Tyr Thr Ala Glu Leu Arg Leu Asn Asn Asn Glu
530 535 540
Phe Thr Val Leu Glu Ala Thr Gly Ile Phe Lys Lys Leu Pro Gln Leu
545 550 555 560
Arg Lys Ile Asn Phe Ser Asn Asn Lys Ile Thr Asp Ile Glu Glu Gly
565 570 575
Ala Phe Glu Gly Ala Ser Gly Val Asn Glu Ile Leu Leu Thr Ser Asn
580 585 590
Arg Leu Glu Asn Val Gln His Lys Met Phe Lys Gly Leu Glu Ser Leu
595 600 605
Lys Thr Leu Met Leu Arg Ser Asn Arg Ile Thr Cys Val Gly Asn Asp
610 615 620
Ser Phe Ile Gly Leu Ser Ser Val Arg Leu Leu Ser Leu Tyr Asp Asn
625 630 635 640
Gln Ile Thr Thr Val Ala Pro Gly Ala Phe Asp Thr Leu His Ser Leu
645 650 655
Ser Thr Leu Asn Leu Leu Ala Asn Pro Phe Asn Cys Asn Cys Tyr Leu
660 665 670
Ala Trp Leu Gly Glu Trp Leu Arg Lys Lys Arg Ile Val Thr Gly Asn
675 680 685
Pro Arg Cys Gln Lys Pro Tyr Phe Leu Lys Glu Ile Pro Ile Gln Asp
690 695 700
Val Ala Ile Gln Asp Phe Thr Cys Asp Asp Gly Asn Asp Asp Asn Ser
705 710 715 720
Cys Ser Pro Leu Ser Arg Cys Pro Thr Glu Cys Thr Cys Leu Asp Thr
725 730 735
Val Val Arg Cys Ser Asn Lys Gly Leu Lys Val Leu Pro Lys Gly Ile
740 745 750
Pro Arg Asp Val Thr Glu Leu Tyr Leu Asp Gly Asn Gln Phe Thr Leu
755 760 765
Val Pro Lys Glu Leu Ser Asn Tyr Lys His Leu Thr Leu Ile Asp Leu
770 775 780
Ser Asn Asn Arg Ile Ser Thr Leu Ser Asn Gln Ser Phe Ser Asn Met
785 790 795 800
Thr Gln Leu Leu Thr Leu Ile Leu Ser Tyr Asn Arg Leu Arg Cys Ile
805 810 815
Pro Pro Arg Thr Phe Asp Gly Leu Lys Ser Leu Arg Leu Leu Ser Leu
820 825 830
His Gly Asn Asp Ile Ser Val Val Pro Glu Gly Ala Phe Asn Asp Leu
835 840 845
Ser Ala Leu Ser His Leu Ala Ile Gly Ala Asn Pro Leu Tyr Cys Asp
850 855 860
Cys Asn Met Gln Trp Leu Ser Asp Trp Val Lys Ser Glu Tyr Lys Glu
865 870 875 880
Pro Gly Ile Ala Arg Cys Ala Gly Pro Gly Glu Met Ala Asp Lys Leu
885 890 895
Leu Leu Thr Thr Pro Ser Lys Lys Phe Thr Cys Gln Gly Pro Val Asp
900 905 910
Val Asn Ile Leu Ala Lys Cys Asn Pro Cys Leu Ser Asn Pro Cys Lys
915 920 925
Asn Asp Gly Thr Cys Asn Ser Asp Pro Val Asp Phe Tyr Arg Cys Thr
930 935 940
Cys Pro Tyr Gly Phe Lys Gly Gln Asp Cys Asp Val Pro Ile His Ala
945 950 955 960
Cys Ile Ser Asn Pro Cys Lys His Gly Gly Thr Cys His Leu Lys Glu
965 970 975
Gly Glu Glu Asp Gly Phe Trp Cys Ile Cys Ala Asp Gly Phe Glu Gly
980 985 990
Glu Asn Cys Glu Val Asn Val Asp Asp Cys Glu Asp Asn Asp Cys Glu
995 1000 1005
Asn Asn Ser Thr Cys Val Asp Gly Ile Asn Asn Tyr Thr Cys Leu
1010 1015 1020
Cys Pro Pro Glu Tyr Thr Gly Glu Leu Cys Glu Glu Lys Leu Asp
1025 1030 1035
Phe Cys Ala Gln Asp Leu Asn Pro Cys Gln His Asp Ser Lys Cys
1040 1045 1050
Ile Leu Thr Pro Lys Gly Phe Lys Cys Asp Cys Thr Pro Gly Tyr
1055 1060 1065
Val Gly Glu His Cys Asp Ile Asp Phe Asp Asp Cys Gln Asp Asn
1070 1075 1080
Lys Cys Lys Asn Gly Ala His Cys Thr Asp Ala Val Asn Gly Tyr
1085 1090 1095
Thr Cys Ile Cys Pro Glu Gly Tyr Ser Gly Leu Phe Cys Glu Phe
1100 1105 1110
Ser Pro Pro Met Val Leu Pro Arg Ser Ala His His His His His
1115 1120 1125
His
<210> 17
<211> 717
<212> DNA
<213> 小鼠（Mus musculus）
<220>
<221> CDS
<222> (1)..(717)
<400> 17
atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
gtc acg aat tca ttg cac tgc cct gcc gcc tgt acc tgt agc aac aat 96
Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn
20 25 30
atc gta gac tgt cgt ggg aaa ggt ctc act gag atc ccc aca aat ctt 144
Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu
35 40 45
cca gag acc atc aca gaa ata cgt ttg gaa cag aac agc atc aga gtc 192
Pro Glu Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Ser Ile Arg Val
50 55 60
atc cct cct gga gct ttc tca cca tat aaa aag ctt aga cga ctg gac 240
Ile Pro Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Leu Asp
65 70 75 80
ctg agc aat aat cag atc tct gaa ctt gca cca gat gct ttc caa gga 288
Leu Ser Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly
85 90 95
cta cgc tct ctg aat tca ctt gtc ctc tat gga aat aaa atc aca gaa 336
Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
ctc ccc aaa agt tta ttt gaa gga ctg ttt tcc tta cag ctc cta tta 384
Leu Pro Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu
115 120 125
ttg aat gcc aac aag ata aac tgc ctt cgg gta gat gct ttt cag gat 432
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp
130 135 140
ctc cac aac ttg aac ctt ctc tcc cta tat gac aac aag ctt cag acc 480
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
gtc gcc aag ggg acc ttt tca gct ctt cgg gcc att caa act atg cat 528
Val Ala Lys Gly Thr Phe Ser Ala Leu Arg Ala Ile Gln Thr Met His
165 170 175
ttg gcc cag aac ccc ttt att tgt gac tgc cat ctc aag tgg cta gcg 576
Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
gat tat ctc cat acc aac ccg att gag acc agt ggt gcc cgt tgc acc 624
Asp Tyr Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr
195 200 205
agc ccc cgc cgc ctg gca aac aaa aga att gga cag atc aaa agc aag 672
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys
210 215 220
aaa ttc cgt tgt tca ggt agc gct cat cac cat cat cat cac tga 717
Lys Phe Arg Cys Ser Gly Ser Ala His His His His His His
225 230 235
<210> 18
<211> 238
<212> PRT
<213> 小鼠
<400> 18
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Leu His Cys Pro Ala Ala Cys Thr Cys Ser Asn Asn
20 25 30
Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Glu Ile Pro Thr Asn Leu
35 40 45
Pro Glu Thr Ile Thr Glu Ile Arg Leu Glu Gln Asn Ser Ile Arg Val
50 55 60
Ile Pro Pro Gly Ala Phe Ser Pro Tyr Lys Lys Leu Arg Arg Leu Asp
65 70 75 80
Leu Ser Asn Asn Gln Ile Ser Glu Leu Ala Pro Asp Ala Phe Gln Gly
85 90 95
Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys Ile Thr Glu
100 105 110
Leu Pro Lys Ser Leu Phe Glu Gly Leu Phe Ser Leu Gln Leu Leu Leu
115 120 125
Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asp Ala Phe Gln Asp
130 135 140
Leu His Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys Leu Gln Thr
145 150 155 160
Val Ala Lys Gly Thr Phe Ser Ala Leu Arg Ala Ile Gln Thr Met His
165 170 175
Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys His Leu Lys Trp Leu Ala
180 185 190
Asp Tyr Leu His Thr Asn Pro Ile Glu Thr Ser Gly Ala Arg Cys Thr
195 200 205
Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile Lys Ser Lys
210 215 220
Lys Phe Arg Cys Ser Gly Ser Ala His His His His His His
225 230 235
<210> 19
<211> 726
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(726)
<400> 19
atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
gtc acg aat tca ctg tcc tcc ggc tcc tgc ccg gcc atg tgc acc tgc 96
Val Thr Asn Ser Leu Ser Ser Gly Ser Cys Pro Ala Met Cys Thr Cys
20 25 30
agc aat ggc atc gtg gac tgt cgt gga aaa ggc ctc act gcc atc ccg 144
Ser Asn Gly Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Ala Ile Pro
35 40 45
gcc aac ctg ccc gag acc atg acg gag ata cgc ctg gag ctg aac ggc 192
Ala Asn Leu Pro Glu Thr Met Thr Glu Ile Arg Leu Glu Leu Asn Gly
50 55 60
atc aag tcc atc cct cct gga gcc ttc tca ccc tac aga aag cta cgg 240
Ile Lys Ser Ile Pro Pro Gly Ala Phe Ser Pro Tyr Arg Lys Leu Arg
65 70 75 80
agg ata gac ctg agc aac aat cag atc gct gag att gca ccc gac gcc 288
Arg Ile Asp Leu Ser Asn Asn Gln Ile Ala Glu Ile Ala Pro Asp Ala
85 90 95
ttc cag ggc ctc cgc tcc ctg aac tcg ctg gtc ctc tat gga aac aag 336
Phe Gln Gly Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys
100 105 110
atc aca gac ctc ccc cgt ggt gtg ttt gga ggc cta tac acc cta cag 384
Ile Thr Asp Leu Pro Arg Gly Val Phe Gly Gly Leu Tyr Thr Leu Gln
115 120 125
ctc ctg ctc ctg aat gcc aac aag atc aac tgc atc cgg ccc gat gcc 432
Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn Cys Ile Arg Pro Asp Ala
130 135 140
ttc cag gac ctg cag aac ctc tca ctg ctc tcc ctg tat gac aac aag 480
Phe Gln Asp Leu Gln Asn Leu Ser Leu Leu Ser Leu Tyr Asp Asn Lys
145 150 155 160
atc cag agc ctc gcc aag ggc act ttc acc tcc ctg cgg gcc atc cag 528
Ile Gln Ser Leu Ala Lys Gly Thr Phe Thr Ser Leu Arg Ala Ile Gln
165 170 175
act ctg cac ctg gcc cag aac cct ttc att tgc gac tgt aac ctc aag 576
Thr Leu His Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys Asn Leu Lys
180 185 190
tgg ctg gca gac ttc ctg cgc acc aat ccc atc gag acg agt ggt gcc 624
Trp Leu Ala Asp Phe Leu Arg Thr Asn Pro Ile Glu Thr Ser Gly Ala
195 200 205
cgc tgt gcc agt ccc cgg cgc ctc gcc aac aag cgc atc ggg cag atc 672
Arg Cys Ala Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile
210 215 220
aag agc aag aag ttc cgg tgc tca ggt agc gct cat cac cat cat cat 720
Lys Ser Lys Lys Phe Arg Cys Ser Gly Ser Ala His His His His His
225 230 235 240
cac tga 726
His
<210> 20
<211> 241
<212> PRT
<213> 人
<400> 20
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Leu Ser Ser Gly Ser Cys Pro Ala Met Cys Thr Cys
20 25 30
Ser Asn Gly Ile Val Asp Cys Arg Gly Lys Gly Leu Thr Ala Ile Pro
35 40 45
Ala Asn Leu Pro Glu Thr Met Thr Glu Ile Arg Leu Glu Leu Asn Gly
50 55 60
Ile Lys Ser Ile Pro Pro Gly Ala Phe Ser Pro Tyr Arg Lys Leu Arg
65 70 75 80
Arg Ile Asp Leu Ser Asn Asn Gln Ile Ala Glu Ile Ala Pro Asp Ala
85 90 95
Phe Gln Gly Leu Arg Ser Leu Asn Ser Leu Val Leu Tyr Gly Asn Lys
100 105 110
Ile Thr Asp Leu Pro Arg Gly Val Phe Gly Gly Leu Tyr Thr Leu Gln
115 120 125
Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn Cys Ile Arg Pro Asp Ala
130 135 140
Phe Gln Asp Leu Gln Asn Leu Ser Leu Leu Ser Leu Tyr Asp Asn Lys
145 150 155 160
Ile Gln Ser Leu Ala Lys Gly Thr Phe Thr Ser Leu Arg Ala Ile Gln
165 170 175
Thr Leu His Leu Ala Gln Asn Pro Phe Ile Cys Asp Cys Asn Leu Lys
180 185 190
Trp Leu Ala Asp Phe Leu Arg Thr Asn Pro Ile Glu Thr Ser Gly Ala
195 200 205
Arg Cys Ala Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Gly Gln Ile
210 215 220
Lys Ser Lys Lys Phe Arg Cys Ser Gly Ser Ala His His His His His
225 230 235 240
His
<210> 21
<211> 726
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(726)
<400> 21
atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
gtc acg aat tca gcc aac tcc atc tcc tgc cct tcg ccc tgc acg tgc 96
Val Thr Asn Ser Ala Asn Ser Ile Ser Cys Pro Ser Pro Cys Thr Cys
20 25 30
agc aat aac atc gtg gac tgt cga gga aag ggc ttg atg gag att cct 144
Ser Asn Asn Ile Val Asp Cys Arg Gly Lys Gly Leu Met Glu Ile Pro
35 40 45
gcc aac ttg ccg gag ggc atc gtc gaa ata cgc cta gaa cag aac tcc 192
Ala Asn Leu Pro Glu Gly Ile Val Glu Ile Arg Leu Glu Gln Asn Ser
50 55 60
atc aaa gcc atc cct gca gga gcc ttc acc cag tac aag aaa ctg aag 240
Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys
65 70 75 80
cga ata gac atc agc aag aat cag ata tcg gat att gct cca gat gcc 288
Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala
85 90 95
ttc cag ggc ctg aaa tca ctc aca tcg ctg gtc ctg tat ggg aac aag 336
Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys
100 105 110
atc acc gag att gcc aag gga ctg ttt gat ggg ctg gtg tcc cta cag 384
Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln
115 120 125
ctg ctc ctc ctc aat gcc aac aag atc aac tgc ctg cgg gtg aac acg 432
Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr
130 135 140
ttt cag gac ctg cag aac ctc aac ttg ctc tcc ctg tat gac aac aag 480
Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys
145 150 155 160
ctg cag acc atc agc aag ggg ctc ttc gcc cct ctg cag tcc atc cag 528
Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln
165 170 175
aca ctc cac tta gcc caa aac cca ttt gtg tgc gac tgc cac ttg aag 576
Thr Leu His Leu Ala Gln Asn Pro Phe Val Cys Asp Cys His Leu Lys
180 185 190
tgg ctg gcc gac tac ctc cag gac aac ccc atc gag aca agc ggg gcc 624
Trp Leu Ala Asp Tyr Leu Gln Asp Asn Pro Ile Glu Thr Ser Gly Ala
195 200 205
cgc tgc agc agc ccg cgc cga ctc gcc aac aag cgc atc agc cag atc 672
Arg Cys Ser Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Ser Gln Ile
210 215 220
aag agc aag aag ttc cgg tgc tca ggt agc gct cat cac cat cat cat 720
Lys Ser Lys Lys Phe Arg Cys Ser Gly Ser Ala His His His His His
225 230 235 240
cac tga 726
His
<210> 22
<211> 241
<212> PRT
<213> 人
<400> 22
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Ala Asn Ser Ile Ser Cys Pro Ser Pro Cys Thr Cys
20 25 30
Ser Asn Asn Ile Val Asp Cys Arg Gly Lys Gly Leu Met Glu Ile Pro
35 40 45
Ala Asn Leu Pro Glu Gly Ile Val Glu Ile Arg Leu Glu Gln Asn Ser
50 55 60
Ile Lys Ala Ile Pro Ala Gly Ala Phe Thr Gln Tyr Lys Lys Leu Lys
65 70 75 80
Arg Ile Asp Ile Ser Lys Asn Gln Ile Ser Asp Ile Ala Pro Asp Ala
85 90 95
Phe Gln Gly Leu Lys Ser Leu Thr Ser Leu Val Leu Tyr Gly Asn Lys
100 105 110
Ile Thr Glu Ile Ala Lys Gly Leu Phe Asp Gly Leu Val Ser Leu Gln
115 120 125
Leu Leu Leu Leu Asn Ala Asn Lys Ile Asn Cys Leu Arg Val Asn Thr
130 135 140
Phe Gln Asp Leu Gln Asn Leu Asn Leu Leu Ser Leu Tyr Asp Asn Lys
145 150 155 160
Leu Gln Thr Ile Ser Lys Gly Leu Phe Ala Pro Leu Gln Ser Ile Gln
165 170 175
Thr Leu His Leu Ala Gln Asn Pro Phe Val Cys Asp Cys His Leu Lys
180 185 190
Trp Leu Ala Asp Tyr Leu Gln Asp Asn Pro Ile Glu Thr Ser Gly Ala
195 200 205
Arg Cys Ser Ser Pro Arg Arg Leu Ala Asn Lys Arg Ile Ser Gln Ile
210 215 220
Lys Ser Lys Lys Phe Arg Cys Ser Gly Ser Ala His His His His His
225 230 235 240
His
<210> 23
<211> 1362
<212> DNA
<213> 人
<220>
<221> CDS
<222> (1)..(1362)
<400> 23
atg tac agg atg caa ctc ctg tct tgc att gca cta agt ctt gca ctt 48
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
gtc acg aat tca ctt cgt cag gaa gat ttt cca cct cgc att gtt gaa 96
Val Thr Asn Ser Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val Glu
20 25 30
cac cct tca gac ctg att gtc tca aaa gga gaa cct gca act ttg aac 144
His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu Asn
35 40 45
tgc aaa gct gaa ggc cgc ccc aca ccc act att gaa tgg tac aaa ggg 192
Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys Gly
50 55 60
gga gag aga gtg gag aca gac aaa gat gac cct cgc tca cac cga atg 240
Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg Met
65 70 75 80
ttg ctg ccg agt gga tct tta ttt ttc tta cgt ata gta cat gga cgg 288
Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly Arg
85 90 95
aaa agt aga cct gat gaa gga gtc tat gtc tgt gta gca agg aat tac 336
Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn Tyr
100 105 110
ctt gga gag gct gtg agc cac aat gca tcg ctg gaa gta gcc ata ctt 384
Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile Leu
115 120 125
cgg gat gac ttc aga caa aac cct tcg gat gtc atg gtt gca gta gga 432
Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val Gly
130 135 140
gag cct gca gta atg gaa tgc caa cct cca cga ggc cat cct gag ccc 480
Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu Pro
145 150 155 160
acc att tca tgg aag aaa gat ggc tct cca ctg gat gat aaa gat gaa 528
Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp Glu
165 170 175
aga ata act ata cga gga gga aag ctc atg atc act tac acc cgt aaa 576
Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg Lys
180 185 190
agt gac gct ggc aaa tat gtt tgt gtt ggt acc aat atg gtt ggg gaa 624
Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly Glu
195 200 205
cgt gag agt gaa gta gcc gag ctg act gtc tta gag aga cca tca ttt 672
Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser Phe
210 215 220
gtg gag tcc aag tac ggc cct cct tgc cct ccc tgc cct gcc cct gag 720
Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
ttc gag ggc gga cct agc gtg ttc ctg ttc cct cct aag cct aag gac 768
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
acc ctg atg atc tcc cgg acc cct gag gtg acc tgt gtg gtg gtg gac 816
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
gtg tcc cag gag gac cct gag gtc cag ttc aac tgg tac gtg gac ggc 864
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
275 280 285
gtg gag gtg cac aac gcc aag acc aag cct cgg gag gag cag ttc aat 912
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
290 295 300
tcc acc tac cgg gtg gtg tct gtg ctg acc gtg ctg cac cag gac tgg 960
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
ctg aac ggc aaa gaa tac aag tgt aag gtc tcc aac aag ggc ctg ccc 1008
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
325 330 335
tcc tcc atc gag aaa acc atc tcc aag gcc aag ggc cag cct agg gag 1056
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
cct cag gtg tac acc ctg cct cct agc cag gaa gag atg acc aag aac 1104
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
355 360 365
cag gtg tcc ctg acc tgt ctg gtg aag ggc ttc tac cct tcc gac atc 1152
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
gcc gtg gag tgg gag tcc aac ggc cag cct gag aac aac tac aag acc 1200
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
acc cct cct gtg ctg gac tcc gac ggc tcc ttc ttc ctg tac tcc agg 1248
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
405 410 415
ctg acc gtg gac aag tcc cgg tgg cag gag ggc aac gtc ttt tcc tgc 1296
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
420 425 430
tcc gtg atg cac gag gcc ctg cac aac cac tac acc cag aag tcc ctg 1344
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
tcc ctg tct ctg ggc tga 1362
Ser Leu Ser Leu Gly
450
<210> 24
<211> 453
<212> PRT
<213> 人
<400> 24
Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Leu Arg Gln Glu Asp Phe Pro Pro Arg Ile Val Glu
20 25 30
His Pro Ser Asp Leu Ile Val Ser Lys Gly Glu Pro Ala Thr Leu Asn
35 40 45
Cys Lys Ala Glu Gly Arg Pro Thr Pro Thr Ile Glu Trp Tyr Lys Gly
50 55 60
Gly Glu Arg Val Glu Thr Asp Lys Asp Asp Pro Arg Ser His Arg Met
65 70 75 80
Leu Leu Pro Ser Gly Ser Leu Phe Phe Leu Arg Ile Val His Gly Arg
85 90 95
Lys Ser Arg Pro Asp Glu Gly Val Tyr Val Cys Val Ala Arg Asn Tyr
100 105 110
Leu Gly Glu Ala Val Ser His Asn Ala Ser Leu Glu Val Ala Ile Leu
115 120 125
Arg Asp Asp Phe Arg Gln Asn Pro Ser Asp Val Met Val Ala Val Gly
130 135 140
Glu Pro Ala Val Met Glu Cys Gln Pro Pro Arg Gly His Pro Glu Pro
145 150 155 160
Thr Ile Ser Trp Lys Lys Asp Gly Ser Pro Leu Asp Asp Lys Asp Glu
165 170 175
Arg Ile Thr Ile Arg Gly Gly Lys Leu Met Ile Thr Tyr Thr Arg Lys
180 185 190
Ser Asp Ala Gly Lys Tyr Val Cys Val Gly Thr Asn Met Val Gly Glu
195 200 205
Arg Glu Ser Glu Val Ala Glu Leu Thr Val Leu Glu Arg Pro Ser Phe
210 215 220
Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
225 230 235 240
Phe Glu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
245 250 255
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
260 265 270
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
275 280 285
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
290 295 300
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
305 310 315 320
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
325 330 335
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
340 345 350
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
355 360 365
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
370 375 380
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
385 390 395 400
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
405 410 415
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
420 425 430
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
435 440 445
Ser Leu Ser Leu Gly
450

Claims (11)

1. 重组蛋白，其包含源自Robo1蛋白的胞外结构域或该结构域的部分，用于治疗癌症。
2. 根据权利要求1的重组蛋白，其中所述癌症是肝癌。
3. 根据权利要求1或2任一项的重组蛋白，其不抑制内皮细胞增殖。
4. 根据权利要求1-3任一项的重组蛋白，其中所述胞外结构域是源自Robo1蛋白的同种型b的胞外结构域。
5. 根据权利要求4的重组蛋白，其中所述Robo1的胞外结构域或其部分由所述胞外结构域的Ig1和Ig2免疫球蛋白结构域组成。
6. 根据权利要求5的重组蛋白，其中所述Robo1的胞外结构域具有与序列SEQ ID NO.2至少80％的同一性。
7. 根据前述权利要求任一项的重组蛋白，其中所述蛋白进一步包含接头和免疫球蛋白Fc结构域。
8. 根据权利要求7的重组蛋白，其中所述Fc结构域来自人免疫球蛋白G4。
9. 根据权利要求8的重组蛋白，其中所述Fc结构域包含S241P和L248E突变，并且其中位于C末端位置的赖氨酸缺失。
10. 根据前述权利要求任一项的重组蛋白，其序列具有与序列SEQ ID NO. 4、SEQ ID NO.6或SEQ ID NO. 24至少80％的同一性。
11. 根据前述权利要求任一项的重组蛋白，其序列是序列SEQ ID NO. 4、SEQ ID NO.6或SEQ ID NO. 24。
CN201180068378.XA 2010-12-23 2011-12-22 用于治疗肝癌的Robo1-Fc融合蛋白 Pending CN103703021A (zh)

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FR1061163A FR2969617A1 (fr) 2010-12-23 2010-12-23 Proteine de fusion robo1-fc et son utilisation dans le traitement des tumeurs.
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PCT/EP2011/073739 WO2012085178A1 (en) 2010-12-23 2011-12-22 Robo1-fc fusion protein for use in the treatment of hepatocarcinoma

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CN107298715A (zh) * 2016-04-15 2017-10-27 李华顺 Slit2D2-嵌合抗原受体及其应用
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