CN114292331A - 抗人bdca-2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物 - Google Patents
抗人bdca-2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物 Download PDFInfo
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Abstract
本发明的目的在于提供一种抗人BDCA‑2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物。所述抗人BDCA‑2抗体包含:由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区或者由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区。抗人BDCA‑2抗体与人BDCA‑2结合,经由人BDCA‑2而调节浆细胞样树突状细胞的功能,由此预防或治疗自身免疫疾病。
Description
本申请是申请日为2014年12月22日,发明名称为“抗人BDCA-2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物”的中国专利申请No.2018113760788的分案申请。
技术领域
本发明涉及新型的抗人BDCA-2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物。
背景技术
BDCA-2(Blood Dendritic Cell Antigen 2,血树突状细胞抗原2)为单次跨膜型的膜蛋白质。已知BDCA-2在人浆细胞样树突状细胞(plasmacytoid dendritic cells;pDCs)中限制性表达。BDCA-2通过向pDCs的细胞内传递信号而起到调节pDCs的功能的作用(Int.Immunol.,Vol.25,p.271-277,2013)。
已知BDCA-2对于活化了的免疫反应而抑制性地起作用(非专利文献1)。关于该机制的详细内容,不清楚的部分仍然较多,但如后所述,据报道通过使用针对BDCA-2的抗体将BDCA-2分子交联,可以抑制处于活化状态的pDCs(专利文献1、非专利文献1~4)。
已知作为BDCA-2的特异性表达细胞的pDCs在系统性红斑狼疮、硬皮病、多发性肌炎·皮肌炎、牛皮癣、Sjoegren综合征、类风湿性关节炎、Graves病、桥本氏病等自身免疫疾病中,在末梢血中或紊乱部位异常地活化,大量地产生干扰素(interferon;IFN)α,显然pDCs与这些自身免疫疾病的病态密切相关。(Arthritis Rheum.,Vol.65,p.853-863,2013)。
据报道在作为自身免疫疾病的一种的系统性红斑狼疮中,有时候患者的重症度与血中IFNα浓度存在正的相关性(Lupus,Vol.9,p.664-671,2000)。另外,当对于系统性红斑狼疮病态模型小鼠以不产生pDCs的方式实施基因改变时,抑制了系统性红斑狼疮的发病,由此直接证明了pDCs与系统性红斑狼疮病态有关(Proc.Natl.Acad.Sci.USA,Vol.110,p.2940-2945,2013)。
作为针对人BDCA-2的抗体,已知有作为小鼠单克隆抗体的AC144(专利文献1、非专利文献1~4),据报道AC144通过将BDCA-2分子交联,可以抑制处于活化状态的pDCs。具体而言,据报道pDCs所诱导的IFNα的产生等可以使用AC144而得到抑制,其中pDCs被针对Toll样受体(Toll-like receptor;TLR)9的配体所刺激(非专利文献1~4)。另外,据报道当将系统性红斑狼疮患者的血清用于刺激剂时,由pDCs诱导了IFNα产生,但是该IFNα的产生同样也可以使用AC144而得到抑制(非专利文献4)。
现有技术文献
专利文献
专利文献1:国际公开第2001/036487号
非专利文献
非专利文献1:“PLoS生物学(PLoS Biology)”,(美国),Sep.11 2007,Vol.5,10,p.2190-2200
非专利文献2:“欧洲免疫学杂志(European Journal ofImmunology)”,(德国)、Nov.16 2007,Vol.37,p.3564-3575
非专利文献3:“细胞免疫学(Cellular Immunology)”,(荷兰),Jul.6 2010,Vol.265,p.15-22
非专利文献4:“实验医学杂志(The Journal of ExperimentalMedicine)”,(美国),Dec.17 2001,Vol.194,12,p.1823-1834
发明内容
发明要解决的课题
本发明的课题在于提供一种抗人BDCA-2抗体,其通过与人BDCA-2结合、经由人BDCA-2来调节pDCs的功能从而预防或治疗自身免疫疾病。
解决课题的手段
本发明人在抗人BDCA-2抗体的制作中反复进行了大量的深入研究,结果发现:制作这样的抗体,其各自含有:由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区、由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区、以及由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区(实施例5),将这些抗体与人BDCA-2的胞外区结合(实施例7),经由人BDCA-2来调节pDCs的功能,从而抑制由pDCs产生IFNα(实施例8)。因此,提供了上述抗人BDCA-2抗体,从而完成了本发明。
本发明包含以下的发明作为医学上或工业上有用的物质或方法。
(1)一种抗人BDCA-2抗体或其抗原结合片段,其选自以下的1)~4)中的任一个。
1)包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段;
2)包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段;
3)包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段;以及
4)作为通过上述1)~3)中的任一个抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段的抗人BDCA-2抗体或其抗原结合片段。
(2)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区。
(3)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
(4)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
(5)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其为通过以下的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段,所述抗人BDCA-2抗体或其抗原结合片段包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区。
(6)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其为通过下述的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段,所述抗人BDCA-2抗体或其抗原结合片段包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
(7)如上述(1)所述的抗人BDCA-2抗体或其抗原结合片段,其为通过下述的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段,所述抗人BDCA-2抗体或其抗原结合片段包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
(8)如上述(1)及(5)~(7)中任一项所述的抗人BDCA-2抗体或其抗原结合片段,其中,翻译后修饰为重链可变区N末端的焦谷氨酰化(ピログルタミル化)和/或重链C末端的赖氨酸缺失。
(9)如上述(1)~(8)中任一项所述的抗人BDCA-2抗体或其抗原结合片段,其包含作为人Igγ1恒定区的重链恒定区。
(10)如上述(1)~(8)中任一项所述的抗人BDCA-2抗体或其抗原结合片段,其包含作为人Igκ恒定区的轻链恒定区。
(11)如上述(1)~(8)中任一项所述的抗人BDCA-2抗体或其抗原结合片段,其包含作为人Igγ1恒定区的重链恒定区及作为人Igκ恒定区的轻链恒定区。
(12)如上述(2)所述的抗人BDCA-2抗体,其包含由序列号2所示的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链。
(13)如上述(3)所述的抗人BDCA-2抗体,其包含由序列号6所示的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链。
(14)如上述(4)所述的抗人BDCA-2抗体,其包含由序列号10所示的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
(15)如上述(1)~(11)中任一项所述的抗原结合片段,其为单链可变区片段、Fab、Fab’、或F(ab’)2。
(16)一种抗人BDCA-2抗体,其为通过上述(12)~(14)中任一项所述的抗人BDCA-2抗体的翻译后修饰而生成的抗体。
(17)如上述(16)所述的抗人BDCA-2抗体,其中,翻译后修饰为重链可变区N末端的焦谷氨酰化和/或重链C末端的赖氨酸缺失。
(18)如上述(16)所述的抗人BDCA-2抗体,其包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号2的氨基酸序号1至449的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链。
(19)如上述(16)所述的抗人BDCA-2抗体,其包含由序列号6的氨基酸序号1至449的氨基酸序号构成的重链以及由序列号8所示的氨基酸序列构成的轻链。
(20)如上述(16)所述的抗人BDCA-2抗体,其包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序号1至451的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
(21)一种多核苷酸,其含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列。
(22)一种多核苷酸,其含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列。
(23)一种表达载体,其包含上述(21)和/或(22)所述的多核苷酸。
(24)一种用上述(23)所述的表达载体进行了转化的宿主细胞,其选自由以下(a)~(d)构成的组:
(a)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸;
(b)用包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(c)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸;以及
(d)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸。
(25)一种用上述(23)所述的表达载体进行了转化的宿主细胞,其选自由以下(a)~(d)构成的组。
(a)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸;
(b)用包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体和包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(c)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸;以及
(d)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的轻链的碱基序列的多核苷酸。
(26)一种生产抗人BDCA-2抗体或其抗原结合片段的方法,包括:对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,以使抗人BDCA-2抗体或其抗原结合片段表达的工序。
(a)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸;
(b)用包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码上述(1)~(4)中任一项所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞,以及用包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
(27)一种生产抗人BDCA-2抗体的方法,包括:对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,以使抗人BDCA-2抗体表达的工序。
(a)用以下的表达载体进行了转化的宿主细胞,所述表达载体包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸;
(b)用包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体和包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码上述(12)~(14)中任一项所述的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞,以及用包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
(28)一种抗人BDCA-2抗体或其抗原结合片段,其是通过上述(26)所述的方法生产的。
(29)一种抗人BDCA-2抗体,其是通过上述(27)所述的方法生产的。
(30)一种医药组合物,包含上述(1)~(20)、(28)及(29)中任一项所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
(31)一种医药组合物,包含上述(2)所述的抗人BDCA-2抗体或其抗原结合片段、上述(5)所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
(32)一种医药组合物,包含上述(3)所述的抗人BDCA-2抗体或其抗原结合片段、上述(6)所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
(33)一种医药组合物,包含上述(4)所述的抗人BDCA-2抗体或其抗原结合片段、上述(7)所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
(34)一种医药组合物,包含上述(12)所述的抗人BDCA-2抗体、上述(18)所述的抗人BDCA-2抗体、以及药学上可接受的赋形剂。
(35)一种医药组合物,包含上述(13)所述的抗人BDCA-2抗体、上述(19)所述的抗人BDCA-2抗体、以及药学上可接受的赋形剂。
(36)一种医药组合物,包含上述(14)所述的抗人BDCA-2抗体、上述(20)所述的抗人BDCA-2抗体、以及药学上可接受的赋形剂。
(37)如上述(30)~(36)中任一项所述的医药组合物,其为系统性红斑狼疮的预防或治疗用医药组合物。
(38)一种预防或治疗系统性红斑狼疮的方法,包括施用治疗有效量的上述(1)~(20)、(28)及(29)中任一项所述的抗人BDCA-2抗体的工序。
(39)如上述(1)~(20)、(28)及(29)中任一项所述的抗人BDCA-2抗体或其抗原结合片段,其用于系统性红斑狼疮的预防或治疗。
(40)上述(1)~(20)、(28)及(29)中任一项所述的抗人BDCA-2抗体或其抗原结合片段在制造预防或治疗系统性红斑狼疮用医药组合物中的应用。
所述抗人BDCA-2抗体或其抗原结合片段也包含其与其它肽及蛋白质的融合体、或使其结合修饰剂而成的修饰体。
发明效果
本发明的抗人BDCA-2抗体与在pDCs的表面上特异性表达的人BDCA-2的胞外区结合,经由人BDCA-2来调节pDCs的功能,可以作为系统性红斑狼疮的预防或治疗剂使用。
具体实施方式
以下,对本发明进行详述。
在抗体中存在IgG、IgM、IgA、IgD及IgE这5类。抗体分子的基本结构在各类中是共通的,由分子量5万~7万的重链和2~3万的轻链构成。重链通常由含有约440个氨基酸的多肽链构成,每类均具有特征性结构,对应于IgG、IgM、IgA、IgD、IgE被称为Igγ、Igμ、Igα、Igδ、Igε。此外,在IgG中存在IgG1、IgG2、IgG3、IgG4的亚类,分别与之对应的重链被称为Igγ1、Igγ2、Igγ3、Igγ4。轻链通常由含有约220个氨基酸的多肽链构成,已知有L型和K型2种,分别被称为Igλ、Igκ。就抗体分子的基本结构的肽构成而言,各自同源的2条重链及2条轻链由二硫键(S-S键)及非共价键结合,分子量为15万~19万。2种轻链可以与任一个重链构成对。各个抗体分子通常可由2条相同的轻链和2条相同的重链形成。
链内S-S键在重链上存在四个(在Igμ、Igε上存在五个),在轻链上存在两个,每100~110个氨基酸残基形成一个环,该立体结构在各环间类似,被称为结构单元或结构域。即使为来自同种动物的相同类(亚类)的标准品,重链、轻链中位于N末端的结构域的氨基酸序列也不恒定,被称为可变区,各结构域分别被称为重链可变区(VH)及轻链可变区(VL)。来自可变区的C末端侧的氨基酸序列在各类或亚类中大致恒定,被称为恒定区(各结构域分别表示为CH1、CH2、CH3或CL)。
抗体的抗原决定部位由VH及VL构成,结合的特异性取决于该部位的氨基酸序列。另一方面,与补体或各种细胞的结合这样的生物学活性反映各类Ig的恒定区的结构差别。已知轻链和重链的可变区的可变性大致限于在任一个链上均存在的3个小的超可变区,将这些区域称为互补性决定区域(CDR;从N末端侧起分别为CDR1、CDR2、CDR3)。可变区的其余部分被称为骨架区(FR),相对恒定。
含有抗体的VH及VL的各种抗原结合片段也具有抗原结合活性,作为这种代表性的抗原结合片段,可列举单链可变区片段(scFv)、Fab、Fab’、F(ab’)2。Fab为由轻链和含有VH、CH1结构域和铰链区的一部分的重链片段构成的一价的抗体片段。Fab’为由轻链和含有VH、CH1结构域和铰链区的一部分的重链片段构成的一价的抗体片段,在该铰链区的部分中含有构成了重链间S-S键的半胱氨酸残基。F(ab’)2片段为2个Fab’片段通过铰链区中的重链间S-S键结合的二价的抗体片段。scFv为由用连接子连结的VH和VL构成的一价的抗体片段。
<本发明的抗人BDCA-2抗体>
本发明的抗人BDCA-2抗体或其抗原结合片段包含具有以下任一个特征的抗人BDCA-2抗体或其抗原结合片段。
1)包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
2)包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
3)包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
关于本发明的抗人BDCA-2抗体或其抗原结合片段,优选具有上述1)~3)中任一个特征、且进一步含有重链恒定区及轻链恒定区的抗体。作为恒定区,任何亚类的恒定区(例如,作为重链的Igγ1、Igγ2、Igγ3或Igγ4的恒定区,作为轻链的Igλ或Igκ的恒定区)均可以选择,但作为重链恒定区,优选人Igγ1恒定区,作为轻链恒定区,优选人Igκ恒定区。
作为人Igγ1恒定区,例如,可列举由序列号2的氨基酸序号121至450的氨基酸序列构成的人Igγ1恒定区。
作为人Igκ恒定区,例如,可列举由序列号4的氨基酸序号110至215的氨基酸序列构成的人Igκ恒定区。
作为本发明的抗人BDCA-2抗体或其抗原结合片段,更优选具有上述1)~3)中任一个特征、重链恒定区为人Igγ1恒定区、且轻链恒定区为人Igκ恒定区的抗人BDCA-2抗体或其抗原结合片段。
在1个实施方式中,本发明的抗原结合片段为scFv、Fab、Fab’、或F(ab’)2。
如果是本领域技术人员,也可以使用该领域中公知的方法将抗体或其抗原结合片段制作成融合有其它肽或蛋白质的融合体,或制作成使之与修饰剂结合而成的修饰体。本发明的抗人BDCA-2抗体或其抗原结合片段也包含这种融合体或修饰体形态的抗体或抗原结合片段。例如,包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段,包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段,或者包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段,也包含与其它肽或蛋白质融合的抗人BDCA-2抗体或其抗原结合片段、或者使之与修饰剂结合而成的抗人BDCA-2抗体或其抗原结合片段。只要本发明的抗人BDCA-2抗体或其抗原结合片段作为融合体具有对人BDCA-2的胞外区的结合活性,对用于融合的其它肽或蛋白质就没有特别限定,例如,可列举:人血清白蛋白、各种标记肽、人工螺旋基序肽、麦芽糖结合蛋白质、谷胱甘肽S转移酶、各种毒素、能够促进多聚化的其它肽或蛋白质等。只要本发明的抗人BDCA-2抗体或其抗原结合片段作为修饰体具有对人BDCA-2的胞外区的结合活性,对用于修饰的修饰剂就没有特别限定,例如可列举聚乙二醇、糖链、磷脂、脂质体、低分子化合物等。
在1个实施方式中,本发明的抗人BDCA-2抗体为具有以下i)~iii)中任一个特征的抗人BDCA-2抗体。
i)包含由序列号2所示的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
ii)包含由序列号6所示的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
iii)包含由序列号10所示的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
已知在使抗体在细胞中表达的情况下,翻译后抗体受到修饰。作为翻译后修饰的实例,可列举:重链C末端的赖氨酸利用羧基肽酶的切断;重链及轻链N末端的谷氨酰胺或谷氨酸通过焦谷氨酰化修饰为焦谷氨酸;糖基化、氧化、脱酰胺化、糖化等,在各种抗体中,已知产生这种翻译后修饰(Journal of Pharmaceutical Sciences,2008,Vol.97,p.2426-2447)。
本发明的抗人BDCA-2抗体或其抗原结合片段也包含通过翻译后修饰而生成的抗人BDCA-2抗体或其抗原结合片段。作为通过翻译后修饰而生成的本发明的抗人BDCA-2抗体或其抗原结合片段的实例,可列举经受了重链可变区N末端的焦谷氨酰化和/或重链C末端的赖氨酸缺失的抗人BDCA-2抗体或其抗原结合片段。在该领域中已知这种N末端的焦谷氨酰化或C末端赖氨酸缺失引起的翻译后修饰对抗体的活性并不产生影响(AnalyticalBiochemistry,2006,Vol.348,p.24-39)。
本发明的抗人BDCA-2抗体包含具有下述(1)~(3)中任一个特征的抗人BDCA-2抗体或其抗原结合片段。
(1)通过包含由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗人BDCA-2抗体或其抗原结合片段。
(2)通过包含由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗人BDCA-2抗体或其抗原结合片段。
(3)通过包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的抗人BDCA-2抗体或其抗原结合片段的翻译后修饰而生成的抗人BDCA-2抗体或其抗原结合片段。
在1个实施方式中,本发明的抗人BDCA-2抗体为具有下述(1)~(3)中任一个特征的抗人BDCA-2抗体。
(1)包含由其中序列号2的氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸和/或氨基酸序号450的赖氨酸缺失的序列号2的氨基酸序列构成的重链、以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(2)包含由其中序列号6的氨基酸序号1的谷氨酸被修饰为焦谷氨酸和/或氨基酸序号450的赖氨酸缺失的序列号6的氨基酸序列构成的重链、以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(3)包含由其中序列号10的氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸和/或氨基酸序号452的赖氨酸缺失的序列号10的氨基酸序列构成的重链、以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
在本发明中,也包含具有以下任一个特征的抗人BDCA-2抗体或其抗原结合片段。
1)包含含有由序列号2的氨基酸序号31至35的氨基酸序列构成的CDR1、由序列号2的氨基酸序号50至66的氨基酸序列构成的CDR2及由序列号2的氨基酸序号99至109的氨基酸序列构成的CDR3的重链可变区、以及含有由序列号4的氨基酸序号24至34的氨基酸序列构成的CDR1、由序列号4的氨基酸序号50至56的氨基酸序列构成的CDR2及由序列号4的氨基酸序号89至98的氨基酸序列构成的CDR3的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
2)包含含有由序列号6的氨基酸序号31至35的氨基酸序列构成的CDR1、由序列号6的氨基酸序号50至66的氨基酸序列构成的CDR2及由序列号6的氨基酸序号99至109的氨基酸序列构成的CDR3的重链可变区、以及含有由序列号8的氨基酸序号24至34的氨基酸序列构成的CDR1、由序列号8的氨基酸序号50至56的氨基酸序列构成的CDR2及由序列号8的氨基酸序号89至97的氨基酸序列构成的CDR3的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
3)包含含有由序列号10的氨基酸序号31至37的氨基酸序列构成的CDR1、由序列号10的氨基酸序号52至67的氨基酸序列构成的CDR2及由序列号10的氨基酸序号100至111的氨基酸序列构成的CDR3的重链可变区、以及含有由序列号12的氨基酸序号24至34的氨基酸序列构成的CDR1、由序列号12的氨基酸序号50至56的氨基酸序列构成的CDR2及由序列号12的氨基酸序号89至97的氨基酸序列构成的CDR3的轻链可变区的抗人BDCA-2抗体或其抗原结合片段。
本发明的抗人BDCA-2抗体或其抗原结合片段与人BDCA-2的胞外区(由序列号13的氨基酸序号42至213的氨基酸序列构成)结合。抗人BDCA-2抗体或其抗原结合片段是否与人BDCA-2的胞外区结合可以使用公知的结合活性测定方法来确认。作为测定结合活性的方法,例如可列举酶联免疫吸附测定(Enzyme-Linked Immuno Sorbent Assay,ELISA)等方法。使用ELISA的情况下,在示例性的方法中,将其中使人BDCA-2(序列号13)或如后述实施例3中所述那样使人BDCA-2突变体(序列号15)表达了的细胞(例如CHO-K1细胞)接种于ELISA板上,向其中添加被验抗体而使其反应。反应后,使利用辣根过氧化物酶(HRP)等酶标记了的抗IgG抗体等二次抗体反应并清洗之后,使用检测其活性的试剂(例如,在HRP标记的情况下,BM-Chemiluminescence ELISA Substrate(POD)(ロシュ·ダイアグノスティックス公司))等进行活性测定,由此确认被验抗体是否与人BDCA-2的胞外区结合。
另外,关于本发明的抗人BDCA-2抗体或其抗原结合片段,如果为与人BDCA-2的胞外区结合的抗体或其抗原结合片段,也包含除了对人BDCA-2的胞外区的结合之外,还与来自其它动物的BDCA-2(例如猴BDCA-2)的胞外区结合的抗体或其抗原结合片段。
此外,本发明的抗人BDCA-2抗体或其抗原结合片段与人BDCA-2的胞外区结合,具有抑制IFNα的产生的活性。作为抑制IFNα的产生的活性的具体评价方法,可以使用后述实施例4中所记载的方法。
本发明的抗人BDCA-2抗体或其抗原结合片段可以基于本说明书中所公开的本发明抗体的重链可变区及轻链可变区的序列信息,使用该领域中公知的方法,由本领域技术人员容易地制作。本发明的抗人BDCA-2抗体或其抗原结合片段没有特别限定,例如,可以按照后述的<生产本发明的抗人BDCA-2抗体的方法及利用该方法生产的抗人BDCA-2抗体>中记载的方法来制造。
将本发明的抗人BDCA-2抗体或其抗原结合片段根据需要进一步精制之后,按照常规方法进行制剂,可以用于系统性红斑狼疮、硬皮病、多发性肌炎·皮肌炎、牛皮癣、Sjogren综合征、类风湿性关节炎、Graves病、桥本氏病等自身免疫疾病等pDCs参与病态形成的疾病的预防或治疗。
<本发明的多核苷酸>
本发明的多核苷酸包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸、以及含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸。
在1个实施方式中,含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸为含有编码由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区的碱基序列的多核苷酸、含有编码由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区的碱基序列的多核苷酸、或者含有编码由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区的碱基序列的多核苷酸。
作为含有编码序列号2的氨基酸序号1至120的氨基酸序列所示的重链可变区的碱基序列的多核苷酸,例如可列举含有序列号1的碱基序号1至360的碱基序列的多核苷酸。作为含有编码由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区的碱基序列的多核苷酸,例如可列举含有序列号5的碱基序号1至360的碱基序列的多核苷酸。作为含有编码由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区的碱基序列的多核苷酸,例如可列举含有序列号9的碱基序号1至366的碱基序列的多核苷酸。
在优选的实施方式中,含有编码本发明的抗人BDCA-2抗体的重链可变区的碱基序列的多核苷酸为含有编码由序列号2所示的氨基酸序列构成的重链的碱基序列的多核苷酸、含有编码由序列号6所示的氨基酸序列构成的重链的碱基序列的多核苷酸、或者含有编码由序列号10所示的氨基酸序列构成的重链的碱基序列的多核苷酸。
作为含有编码由序列号2所示的氨基酸序列构成的重链的碱基序列的多核苷酸,例如可列举含有序列号1所示的碱基序列的多核苷酸。作为含有编码由序列号6所示的氨基酸序列构成的重链的碱基序列的多核苷酸,例如可列举含有序列号5所示的碱基序列的多核苷酸。作为含有编码由序列号10所示的氨基酸序列构成的重链的碱基序列的多核苷酸,例如可列举含有序列号9所示的碱基序列的多核苷酸。
在1个实施方式中,含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸为含有编码由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸、含有编码由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸、或者含有编码由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸。
作为含有编码由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸,例如可列举含有序列号3的碱基序号1至327的碱基序列的多核苷酸。作为含有编码由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸,例如可列举含有序列号7的碱基序号1至324的碱基序列的多核苷酸。作为含有编码由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区的碱基序列的多核苷酸,例如可列举含有序列号11的碱基序号1至324的碱基序列的多核苷酸。
在优选的实施方式中,含有编码本发明的抗人BDCA-2抗体的轻链可变区的碱基序列的多核苷酸为含有编码由序列号4所示的氨基酸序列构成的轻链的碱基序列的多核苷酸、含有编码由序列号8所示的氨基酸序列构成的轻链的碱基序列的多核苷酸、或者含有编码由序列号12所示的氨基酸序列构成的轻链的碱基序列的多核苷酸。
作为含有编码由序列号4所示的氨基酸序列构成的轻链的碱基序列的多核苷酸,例如可列举含有序列号3所示的碱基序列的多核苷酸。作为含有编码由序列号8所示的氨基酸序列构成的轻链的碱基序列的多核苷酸,例如可列举含有序列号7所示的碱基序列的多核苷酸。作为含有编码由序列号12所示的氨基酸序列构成的轻链的碱基序列的多核苷酸,例如可列举含有序列号11所示的碱基序列的多核苷酸。
本发明的多核苷酸可以基于其碱基序列,使用该领域中公知的方法由本领域技术人员容易地制作。例如,本发明的多核苷酸可以利用该领域中公知的基因合成方法来合成。作为这种基因合成方法,可以使用WO 90/07861中记载的抗体基因合成方法等本领域技术人员公知的各种方法。
<本发明的表达载体>
本发明的表达载体包含如下表达载体:其包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和/或含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸。
作为优选的本发明的表达载体,可列举:包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体,包含含有编码本发明的抗人BDCA-2抗体的轻链的碱基序列的多核苷酸的表达载体,或者包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体。
作为用于使本发明的多核苷酸表达的表达载体,只要在真核细胞(例如,动物细胞、昆虫细胞、植物细胞、酵母)和/或原核细胞(例如大肠杆菌)的各种宿主细胞中表达含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和/或含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸并可以产生由它们编码的多肽,就没有特别限制。作为这种表达载体,例如可列举质粒载体、病毒载体(例如腺病毒、逆转录病毒)等,优选可以使用pEE6.4或pEE12.4(ロンザ公司)。另外,也可以通过在AG-γ1或AG-κ(例如参照WO94/20632)等预先具有人Ig恒定区基因的表达载体中导入可变区基因片段而表达抗体基因。
本发明的表达载体可以含有能够与本发明的多核苷酸可操作地连接的启动子。作为用于用动物细胞使本发明的多核苷酸表达的启动子,例如可列举:CMV、RSV、SV40等来自病毒的启动子、肌动蛋白启动子、EF(elongation factor)1α启动子、热激启动子等。作为用于用细菌(例如大肠埃希氏杆菌属菌)进行表达的启动子,例如可列举:trp启动子、lac启动子、λPL启动子、tac启动子等。另外,作为用于用酵母进行表达的启动子,例如可列举:GAL1启动子、GAL10启动子、PH05启动子、PGK启动子、GAP启动子、ADH启动子等。
使用动物细胞、昆虫细胞或酵母作为宿主细胞的情况下,本发明的表达载体可以含有起始密码子及终止密码子。该情况下,本发明的表达载体可以含有增强子序列、编码本发明的抗体或其重链可变区或轻链可变区的基因的5’侧及3’侧的非翻译区域、分泌信号序列、剪接接合部、聚腺苷酸化位点、或者可复制单元等。使用大肠杆菌作为宿主细胞的情况下,本发明的表达载体可以含有起始密码子、终止密码子、终止子区域、及可复制单元。该情况下,本发明的表达载体可以根据目的含有通常所使用的选择标记(例如四环素抗性基因、氨苄青霉素抗性基因、卡那霉素抗性基因、新霉素抗性基因、二氢叶酸还原酶基因)。
<本发明的进行了转化的宿主细胞>
本发明的进行了转化的宿主细胞包含选自由以下(a)~(d)构成的组中的、用本发明的表达载体进行了转化的宿主细胞。
(a)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(c)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(d)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
在1个实施方式中,本发明的进行了转化的宿主细胞为选自由以下(a)~(d)构成的组中的、用本发明的表达载体进行了转化的宿主细胞。
(a)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体和包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(c)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(d)用包含含有编码本发明的抗人BDCA-2抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
作为优选的本发明的进行了转化的宿主细胞,可列举:用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞、以及用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体和包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
作为进行转化的宿主细胞,只要适合于所使用的表达载体、用该表达载体进行转化从而能够表达抗体,就没有特别限定。作为进行转化的宿主细胞,例如可列举在本发明的技术领域中通常使用的天然细胞或人工建立的细胞等各种细胞(例如,动物细胞(例如CHOK1SV细胞)、昆虫细胞(例如Sf9)、细菌(大肠埃希氏杆菌属菌等)、酵母(酵母属、毕赤酵母属等)等),优选可以使用CHOK1SV细胞、CHO-DG44细胞、293细胞、NS0细胞等培养细胞。
对转化宿主细胞的方法没有特别限定,例如可以使用磷酸钙法、电穿孔法等。
<生产本发明的抗人BDCA-2抗体的方法及利用该方法生产的抗人BDCA-2抗体>
生产本发明的抗人BDCA-2抗体或其抗原结合片段的方法包括这样的生产抗人BDCA-2抗体或其抗原结合片段的方法:该方法包括对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,并使抗人BDCA-2抗体或其抗原结合片段表达的工序。
(a)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码本发明的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞、以及用包含含有编码该抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
在1个实施方式中,生产本发明的抗人BDCA-2抗体的方法包括这样的生产抗人BDCA-2抗体的方法:该方法包括对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,并使抗人BDCA-2抗体表达的工序。
(a)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸和含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体和包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码本发明的抗人BDCA-2抗体的重链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞、以及用包含含有编码该抗体的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
生产本发明的抗人BDCA-2抗体或其抗原结合片段的方法只要包括了对本发明的进行了转化的宿主细胞进行培养、并使抗人BDCA-2抗体或其抗原结合片段表达的工序,就没有特别限定。作为该方法中所使用的优选的宿主细胞,可列举上述优选的本发明的进行了转化的宿主细胞。
进行了转化的宿主细胞的培养可以利用公知方法来进行。培养条件例如温度、培养基的pH及培养时间可适当选择。宿主细胞为动物细胞的情况下,作为培养基,例如可以使用含有约5~20%的胎牛血清的MEM培养基(Science,1959,Vol.130,No.3373,p.432-7)、DMEM培养基(Virology,1959,Vol.8,p.396)、RPMI1640培养基(J.Am.Med.Assoc.,1967,Vol.199,p.519)、199培养基(Exp.Biol.Med.,1950,Vol.73,p.1-8)等。培养基的pH优选为约6~8,培养时,根据需要一边进行通气或搅拌,一边在通常约30~40℃下进行约15~72小时。宿主细胞为昆虫细胞的情况下,作为培养基,例如可以使用含有胎牛血清的Grace’s培养基(Proc.Natl.Acad.Sci.USA,1985,Vol.82,p.8404)等。培养基的pH优选为约5~8,培养时,根据需要一边进行通气或搅拌,一边在通常约20~40℃下进行约15~100小时。宿主细胞为大肠杆菌或酵母的情况下,作为培养基,例如含有营养源的液体培养基是适当的。营养培养基优选含有进行了转化的宿主细胞的生长所必需的碳源、无机氮源或有机氮源。作为碳源,例如可列举葡萄糖、葡聚糖、可溶性淀粉、蔗糖等,作为无机氮源或有机氮源,例如可列举铵盐类、硝酸盐类、氨基酸、玉米浆、胨、酪蛋白、肉类提取物、大豆粕、马铃薯提取液等。根据期望可以含有其它营养素(例如,无机盐(例如氯化钙、磷酸二氢钠、氯化镁)、维生素类等)、抗生素(例如四环素、新霉素、氨苄青霉素、卡那霉素等)。培养基的pH优选为约5~8。宿主细胞为大肠杆菌的情况下,作为优选的培养基,例如可以使用LB培养基、M9培养基(Mol.Clo.,Cold Spring Harbor Laboratory,Vol.3,A2.2)等。培养时,根据需要一边进行通气或搅拌,一边在通常约14~39℃下进行约3~24小时。宿主细胞为酵母的情况下,作为培养基,例如可以使用Burkholder基本培养基(Proc.Natl.Acad.Sci.USA,1980,Vol.77,p.4505)等。培养时,根据需要一边进行通气或搅拌,一边在通常约20~35℃下进行约14~144小时。通过如上所述的培养,可以使本发明的抗人BDCA-2抗体或其抗原结合片段表达。
生产本发明的抗人BDCA-2抗体或其抗原结合片段的方法除了包括对本发明的进行了转化的宿主细胞进行培养、并使抗人BDCA-2抗体或其抗原结合片段表达的工序之外,还可以进一步包括从该进行了转化的宿主细胞中回收(优选分离或精制)抗人BDCA-2抗体或其抗原结合片段的工序。作为分离或精制方法,例如可列举:盐析、溶剂沉淀法等利用溶解度的方法,透析、超滤、凝胶过滤等利用分子量差的方法,离子交换色谱、羟基磷灰石色谱等利用电荷的方法,亲和色谱法等利用特异亲和性的方法,反相高效液相色谱等利用疏水性差的方法,等电点电泳等利用等电点差的方法等。优选的是,蓄积于培养上清液中的抗体可以利用各种色谱法(例如使用了Protein A柱或Protein G柱的柱色谱法)进行精制。
本发明的抗人BDCA-2抗体或其抗原结合片段也包含用生产本发明的抗人BDCA-2抗体或其抗原结合片段的方法生产的抗人BDCA-2抗体或其抗原结合片段。
<本发明的医药组合物>
本发明的医药组合物包含含有本发明的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂的医药组合物。本发明的医药组合物可以使用该领域中通常所用的赋形剂(即,药剂用赋形剂或药剂用载体等)并通过通常所使用的方法来制备。作为这些医药组合物的剂型的实例,例如可列举注射剂、点滴用剂等非经口剂,可以通过静脉内给药、皮下给药等进行给药。在制剂时,可以在药学上所允许的范围内使用与这些剂型相应的赋形剂、载体、添加剂等。
本发明的医药组合物可以含有多种本发明的抗人BDCA-2抗体或其抗原结合片段。例如,含有没有经受翻译后修饰的抗体或其抗原结合片段、以及通过该抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段的医药组合物也包含在本发明中。
在1个实施方式中,含有抗人BDCA-2抗体或其抗原结合片段的本发明的医药组合物也包含下述(1)~(3)中任一个记载的医药组合物。
(1)包含下述抗人BDCA-2抗体或其抗原结合片段、以及通过该抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段的医药组合物,所述抗人BDCA-2抗体或其抗原结合片段含有由序列号2的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号4的氨基酸序号1至109的氨基酸序列构成的轻链可变区;
(2)包含下述抗人BDCA-2抗体或其抗原结合片段、以及通过该抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段的医药组合物,所述抗人BDCA-2抗体或其抗原结合片段含有由序列号6的氨基酸序号1至120的氨基酸序列构成的重链可变区及由序列号8的氨基酸序号1至108的氨基酸序列构成的轻链可变区;以及
(3)包含下述抗人BDCA-2抗体或其抗原结合片段、以及通过该抗体或其抗原结合片段的翻译后修饰而生成的抗体或其抗原结合片段的医药组合物,所述抗人BDCA-2抗体或其抗原结合片段含有由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
本发明的医药组合物也包含这样的医药组合物,其含有:重链C末端的赖氨酸缺失的抗体、经受了N末端翻译后修饰的抗体或其抗原结合片段、重链C末端赖氨酸缺失且经受了N末端翻译后修饰的抗体、和/或具有重链C末端赖氨酸且没有经受N末端翻译后修饰的抗体。
在1个实施方式中,含有抗人BDCA-2抗体的本发明的医药组合物也包含含有下述(1)~(4)中2种以上的抗人BDCA-2抗体的医药组合物。
(1)包含由序列号2的氨基酸序号1至449的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(2)包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号2的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(3)包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号2的氨基酸序号1至449的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(4)包含由序列号2所示的氨基酸序列构成的重链以及由序列号4所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
在1个实施方式中,含有抗人BDCA-2抗体的本发明的医药组合物也包含含有下述(1)~(4)中2种以上的抗人BDCA-2抗体的医药组合物。
(1)包含由序列号6的氨基酸序号1至449的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(2)包含由其中氨基酸序号1的谷氨酸被修饰为焦谷氨酸的序列号6的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(3)包含由其中氨基酸序号1的谷氨酸被修饰为焦谷氨酸的序列号6的氨基酸序号1至449的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(4)包含由序列号6所示的氨基酸序列构成的重链以及由序列号8所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
在1个实施方式中,含有抗人BDCA-2抗体的本发明的医药组合物也包含含有下述(1)~(4)中2种以上的抗人BDCA-2抗体的医药组合物。
(1)包含由序列号10的氨基酸序号1至451的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(2)包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(3)包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序号1至451的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
(4)包含由序列号10所示的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链的抗人BDCA-2抗体。
制剂时本发明的抗人BDCA-2抗体或其抗原结合片段的添加量根据患者的症状程度或年龄、所使用的制剂的剂型、或抗体的结合效价等而不同,例如可以使用0.001mg/kg~100mg/kg左右。
本发明的医药组合物可以用作pDCs参与病态形成的疾病(例如系统性红斑狼疮)的预防或治疗用医药组合物。
本发明包含系统性红斑狼疮的预防或治疗用医药组合物,其含有本发明的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。另外,本发明包含预防或治疗系统性红斑狼疮的方法,包括施用治疗有效量的本发明的抗人BDCA-2抗体或其抗原结合片段的工序。另外,本发明包含用于预防或治疗系统性红斑狼疮的本发明的抗人BDCA-2抗体或其抗原结合片段。另外,本发明包含本发明的抗人BDCA-2抗体或其抗原结合片段在制造系统性红斑狼疮的预防或治疗用医药组合物中的应用。
为了对本发明进一步进行理解在此提供参考的特定实施例,但是它们作为例示性目的,而并不限定本发明。
实施例
关于使用了市售试剂盒或试剂等的部分,如果没有特殊说明,则按照随附的实验方案进行实验。
(实施例1:人BDCA-2突变体表达CHO-K1细胞的获得)
为了在抗人BDCA-2抗体的结合性试验中使用,获得了人BDCA-2突变体表达CHO-K1细胞。具体而言,将利用PCR法扩增了的编码人BDCA-2突变体(序列号15:由将野生型人BDCA-2(序列号13)的氨基酸序号33的丝氨酸置换为半胱氨酸后的氨基酸序列构成。由于该突变部位存在于跨膜区域中,因此,胞外区的氨基酸序列与野生型相同。)的基因(序列号14)与编码人FcεRIγ全长序列的基因(序列号16)一起插入到作为哺乳细胞表达用载体的pIRES载体(クロンテック公司)中,制作同时表达人BDCA-2突变体和人FcεRIγ的载体。接着,使用基因导入试剂Lipofectamine2000(ライフテクノロジーズ公司)将该载体基因导入到CHO-K1细胞中。将该细胞在含Geneticin(ライフテクノロジーズ公司)RPMI1640培养基中进行选择培养之后,进一步利用Cellsorter FACSAriaTM(ベクトン·ディッキンソンアンドカンパニー)筛选高表达人BDCA-2突变体蛋白质的细胞群(以下称为人BDCA-2突变体/CHO细胞)。
(实施例2:产生抗人BDCA-2抗体的杂种瘤的制作)
使用人单克隆抗体开发技术“ベロシミューン”(VelocImmune antibodytechnology:Regeneron公司(美国专利6596541号))小鼠来制作抗体。具体而言,与引起免疫反应的佐剂一起,将人BDCA-2胞外区和小鼠Fc的融合蛋白质以及人BDCA-2表达CHO-K1细胞、或人BDCA-2胞外区和小鼠Fc的融合蛋白质、猴BDCA-2胞外区和小鼠Fc的融合蛋白质以及人BDCA-2表达CHO-K1细胞注射于VelocImmune小鼠,实施免疫。
其后,按照常规方法摘出免疫后的小鼠的脾脏或淋巴节并收集淋巴细胞,将其与小鼠骨髓瘤细胞SP2/0-Ag14进行细胞融合,由此制作杂种瘤。进行杂种瘤的单克隆化,对于各克隆,在无血清培养基中进行培养。由得到的培养上清液精制抗体。使用VelocImmune技术得到的抗体为具有人抗体的可变区和小鼠抗体的恒定区的抗体(也称为嵌合抗体)。
(实施例3:细胞ELISA结合测定)
为了测定抗体的抗原特异性结合活性,评价了抗体对实施例1中所制作的人BDCA-2突变体/CHO细胞的结合。具体而言,首先,将人BDCA-2突变体/CHO细胞以2×105个/mL的方式悬浮于RPMI1640培养基(ライフテクノロジーズ公司)中,以每1孔50μL将其接种在多聚D赖氨酸包被的384孔板(グライナー公司)上,并在设定为37℃的CO2培养箱中培养一夜。其后,除去培养基,分别添加用稀释液(装有1%牛血清白蛋白的汉克斯平衡盐溶液)以从10000ng/mL到4.6ng/mL的浓度梯度稀释(3倍稀释系列中为8级)了的来自杂种瘤的抗体(实施例2中所精制的抗体)及比较抗体各20μL,在室温下反应1小时。接着,用清洗液(装有0.1%牛血清白蛋白的汉克斯平衡盐溶液)清洗,添加用稀释液稀释为5000倍的HRP标记兔抗小鼠IgG抗体(HRP-rabbit anti-human IgG antibody:ダコ公司)20μL,在室温下反应30分钟。其后,用清洗液清洗,加入作为化学发光检测试剂的BM-Chemiluminescence ELISASubstrate(POD)(ロシュ·ダイアグノスティックス公司)30μL,用EnVision计数器(パーキンエルマー公司)测定其化学发光量。就测定结果而言,通过4参数逻辑曲线拟合来分析EC50值。本试验中,作为比较抗体,使用了作为针对人BDCA-2的小鼠抗体的AC144(非专利文献1~4,ミルテニーバイオテク公司)。
结果,命名为BDC3-12A2、BDC3-12F5及BDC13-32E3的抗体(嵌合抗体)具有对人BDCA-2的胞外区的高结合活性(表1)。
表1:抗人BDCA-2抗体对人BDCA-2的胞外区的结合活性
[表1]
(实施例4:对人IFNα产生的抑制活性评价)
向人末梢血单核细胞中添加ODN2216等TLR9的配体并进行培养时,存在于人末梢血单核细胞中的pDCs被激活,从pDCs中诱导产生IFNα(非专利文献1)。因此,以抗人BDCA-2抗体对从pDCs产生的IFNα的产生抑制为指标,评价抗体对pDCs的功能调节活性。具体而言,首先,在96孔U底板(グライナー公司)中,添加25μL的用RPMI1640培养基制备成1.6μM的ODN2216(インヴィヴォジェン公司),接着,添加用RPMI1640培养基在4000ng/mL至0.02ng/mL范围内稀释了11级的来自杂种瘤的抗体及比较抗体各25μL。在此,添加以2×106个/mL的方式悬浮于含有人IL-3(ぺプロテック公司)20ng/mL的RPMI1640培养基中的人末梢血单核细胞(ロンザ公司)50μL。作为对照,分别准备取代抗体而添加有RPMI1640培养基的孔、取代ODN2216而添加有RPMI1640培养基的孔。在设定为37℃的CO2培养箱中培养20小时之后,使用AlphaLISA IFNα检测试剂盒(パーキンエルマー公司)定量上清液中的IFNα蛋白量。进而以定量的值为基础,算出IFNα产生抑制率。更具体而言,将取代抗体而添加有RPMI1640培养基的组作为0%抑制对照组,另外,将取代ODN2216而添加有RPMI1640培养基的组作为100%抑制对照组设定。分析所算出的IFNα产生抑制率,通过4参数逻辑曲线拟合来算出抗体的IC50值和IC90值。IC90值为可以期待各自的抗体的最大作用的最小值,即,近似于完全抑制从人末梢血单核细胞产生IFNα所需要的抗体浓度的最小值的值。据报道在系统性红斑狼疮病态模型小鼠中,极其微量的IFNα引起病态恶化(The Journal of Immunology,Vol.174,p.2499,2005),暗示了在系统性红斑狼疮的预防及治疗中完全抑制IFNα的重要性。需要说明的是,本实施例中,作为比较抗体,使用了AC144。
结果可知:BDC3-12A2、BDC3-12F5及BDC13-32E3在IC50值和IC90值的任一个中,都具有高于比较抗体AC144的IFNα产生抑制活性(表2)。另外,由IC90值的结果可知:与AC144相比,BDC3-12A2、BDC3-12F5及BDC13-32E3完全抑制IFNα产生所需要的浓度小。
表2:抗人BDCA-2抗体对于人IFNα产生的抑制活性
[表2]
IC50(ng/mL) | IC90(ng/mL) | |
BDC3-12A2(嵌合) | 0.27 | 1.03 |
BDC3-12F5(嵌合) | 0.23 | 0.93 |
BDC13-32E3(嵌合) | 0.43 | 1.03 |
AC144 | 2.57 | 56.5 |
(实施例5:完全人型抗人BDCA-2抗体的序列决定和制作)
由分别产生BDC3-12A2、BDC3-12F5及BDC13-32E3的杂种瘤克隆编码抗体的重链及轻链的基因,并确定序列。
上述的抗体为可变区来自人、恒定区来自小鼠的抗体。因此,使用GS GeneExpression System(ロンザ公司)构建包含重链及轻链的两基因的表达载体,制作了可变区及恒定区来自人的完全人型抗体。具体而言,在BDC3-12A2、BDC3-12F5及BDC13-32E3的各抗体的重链可变区基因的5’侧连接编码信号序列(N.Whittle等,Protein Eng.,Vol.1,p.499,1987)的基因,而且在3’侧连接人Igγ1的恒定区基因(由序列号1的碱基序号361至1353的碱基序列构成),将该重链基因插入pEE6.4中。另外,在抗体的轻链可变区基因的5’侧连接编码信号序列(N.Whittle等,前面提到的)的基因,而且在3’侧连接人Igκ的恒定区基因(由序列号3的碱基序号328至648的碱基序列构成),将该轻链基因插入pEE12.4中。
用测序仪分析插入pEE6.4中的各抗体的重链基因序列、插入pEE12.4中的各抗体的轻链基因序列,由结果得到的氨基酸序列,参照Kabat等的数据库(“Sequences ofProteins of Immunological Interest”,US Department of Health and HumanServices,US Government Printing Office)来确定CDR序列。
将制作的BDC3-12A2的完全人型抗体(完全人型BDC3-12A2)的重链的碱基序列示于序列号1,将由此所编码的氨基酸序列示于序列号2,将该抗体的轻链的碱基序列示于序列号3,将由此所编码的氨基酸序列示于序列号4。由序列号2表示的重链的可变区由序列号2的氨基酸序号1至120的氨基酸序列构成,重链的CDR1、CDR2、CDR3分别由序列号2的氨基酸序号31至35、50至66、99至109的氨基酸序列构成。由序列号4表示的轻链的可变区由序列号4的氨基酸序号1至109的氨基酸序列构成,轻链的CDR1、CDR2、CDR3分别由序列号4的氨基酸序号24至34、50至56、89至98的氨基酸序列构成。
将制作的BDC3-12F5的完全人型抗体(完全人型BDC3-12F5)的重链的碱基序列示于序列号5,将由此所编码的氨基酸序列示于序列号6,将该抗体的轻链的碱基序列示于序列号7,将由此所编码的氨基酸序列示于序列号8。由序列号6表示的重链的可变区由序列号6的氨基酸序号1至120的氨基酸序列构成,重链的CDR1、CDR2、CDR3分别由序列号6的氨基酸序号31至35、50至66、99至109的氨基酸序列构成。由序列号8表示的轻链的可变区由序列号8的氨基酸序号1至108的氨基酸序列构成,轻链的CDR1、CDR2、CDR3分别由序列号8的氨基酸序号24至34、50至56、89至97的氨基酸序列构成。
将制作的BDC13-32E3的完全人型抗体(完全人型BDC13-32E3)的重链的碱基序列示于序列号9,将由此所编码的氨基酸序列示于序列号10,将该抗体的轻链的碱基序列示于序列号11,将由此所编码的氨基酸序列示于序列号12。由序列号10表示的重链的可变区由序列号10的氨基酸序号1至122的氨基酸序列构成,重链的CDR1、CDR2、CDR3分别由序列号10的氨基酸序号31至37、52至67、100至111的氨基酸序列构成。由序列号12表示的轻链的可变区由序列号12的氨基酸序号1至108的氨基酸序列构成,轻链的CDR1、CDR2、CDR3分别由序列号12的氨基酸序号24至34、50至56、89至97的氨基酸序列构成。
为了制作各完全人型抗体,以GS Gene Expression System(ロンザ公司)的实验方案中记载的方法为参考,将分别插入有各抗体的重链和轻链的基因的上述GS载体用NotI和PvuI进行限制酶切断,并使用Ligation-Convenience Kit(ニッポンジーン公司)连接,从而构建了插入有重链和轻链的两基因的Double-Gene载体。接着,对于CHOK1SV细胞(ロンザ公司),利用电穿孔法基因导入上述的Double-Gene载体,并在以最终浓度成为50μM的方式添加有蛋氨酸亚砜亚胺(シグマ公司)的CD-CHO Medium(ライフテクノロジーズ公司)中培养5天~6天。使用Protein A柱或Protein G柱(GEヘルスケア·ジャパン公司)由得到的培养上清液精制各完全人型抗体。
(实施例6:完全人型抗人BDCA-2抗体的氨基酸修饰分析)
作为实施例5中精制的各完全人型抗人BDCA-2抗体的氨基酸修饰的分析结果,在大部分精制抗体中,在完全人型BDC3-12A2中产生重链N末端的焦谷氨变换及重链C末端的赖氨酸缺失,在完全人型BDC3-12F5中产生重链C末端的赖氨酸缺失,在完全人型BDC13-32E3中产生重链N末端的焦谷氨变换及重链C末端的赖氨酸缺失。
(实施例7:完全人型抗体对于人BDCA-2的胞外区的结合活性评价)
按照实施例3的方法,对于各完全人型抗体,评价其对人BDCA-2的胞外区的结合活性。但是,作为来自杂种瘤的抗体的替代,分别添加了实施例5中制作的各完全人型抗体(完全人型BDC3-12A2、完全人型BDC3-12F5或完全人型BDC13-32E3)。另外,作为HRP标记兔抗小鼠IgG抗体的替代,使用了HRP标记兔抗人IgG抗体(DAKO公司)。本活性评价试验独立实施3次。
结果确认:本发明的完全人型抗体中的任一个均具有对人BDCA-2的胞外区的高结合活性(表3)。表3所示的EC50值为由3次独立的活性评价得到的EC50值的平均。
表3:完全人型抗人BDCA-2抗体对于人BDCA-2的胞外区的结合活性
[表3]
EC50(ng/mL) | |
完全人型BDC3-12A2 | 80 |
完全人型BDC3-12F5 | 88 |
完全人型BDC13-32E3 | 203 |
(实施例8:完全人型抗体对于人IFNα产生的抑制活性评价)
按照实施例4的方法,对于实施例5中制作的各完全人型抗体,以抗人BDCA-2抗体对由pDCs产生的IFNα的产生抑制为指标,评价抗体对pDCs的功能调节活性。但是,在本实施例中,为了得到更稳定的评价结果,使用了在多个人末梢血单核细胞的批次中对于ODN2216刺激而言IFNα产生比较高的批次,在含有人IL-3的RPMI1640培养基中使细胞以5×106个/mL的方式悬浮而用于评价。另外,作为来自杂种瘤的抗体的替代,分别添加在1200ng/mL至0.06ng/mL范围内稀释9级的各完全人型抗体(完全人型BDC3-12A2、完全人型BDC3-12F5或完全人型BDC13-32E3)。本实施例使用AC144作为比较抗体。另外,本活性评价试验独立实施2次。
结果可知:与比较抗体AC144相比,本发明的完全人型抗体中的任意一个在IC50值和IC90值的任一者中,都具有对于pDCs的高抑制活性(表4)。另外,由IC90值的结果可知:与AC144相比,BDC3-12A2、BDC3-12F5及BDC13-32E3完全抑制IFNα产生所需要的浓度小。
表4:完全人型抗人BDCA-2抗体对于人IFNα产生的抑制活性
[表4]
工业应用性
本发明的抗人BDCA-2抗体对特异性地表达人BDCA-2的pDCs参与病态形成的自身免疫疾病的预防或治疗是有用的。另外,本发明的多核苷酸、表达载体、进行了转化的宿主细胞以及生产抗体的方法对产生所述抗人BDCA-2抗体是有用的。
序列表自由文本
在以下序列表的数字标题<223>中,记载了“人工序列”的说明。具体而言,由序列表的序列号1和3表示的碱基序列分别为完全人型BDC3-12A2的重链及轻链的碱基序列,由序列号2和4表示的氨基酸序列分别为由序列号1和3所编码的重链及轻链的氨基酸序列。由序列表的序列号5和7表示的碱基序列分别为完全人型BDC3-12F5的重链及轻链的碱基序列,由序列号6和8表示的氨基酸序列分别为由序列号5和7所编码的重链及轻链的氨基酸序列。由序列表的序列号9和11表示的碱基序列分别为完全人型BDC13-32E3的重链及轻链的碱基序列,由序列号10和12表示的氨基酸序列分别为由序列号9和11所编码的重链及轻链的氨基酸序列。由序列表的序列号14表示的碱基序列为人BDCA-2突变体的碱基序列,由序列号15表示的氨基酸序列为人BDCA-2突变体的氨基酸序列。
序列表
<110> 安斯泰来制药株式会社
<120> 抗人BDCA-2抗体、其生产方法、多核苷酸、表达载体、宿主细胞及医药组合物
<130> A14019A00
<150> JP2013-265304
<151> 2013-12-24
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 1353
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的H-链
<220>
<221> CDS
<222> (1)..(1353)
<400> 1
cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct ggg agg 48
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcg tct gga ttc acc ttg agt agc tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr
20 25 30
ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctg gag tgg gtg 144
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
gca gtt ata tgg tat gat gga aat gat aaa tac tat gca gac tcc gtg 192
Ala Val Ile Trp Tyr Asp Gly Asn Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aat tcc aag aac acg ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
ctg caa gtg aac agc ctg aga gcc gag gac acg gct gtg tat tac tgt 288
Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
gcg aga gga act gga act cct tac tgg tac ttc gat ctc tgg ggc cgt 336
Ala Arg Gly Thr Gly Thr Pro Tyr Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
ggc acc ctg gtc act gtc tcc tca gcc tcc acc aag ggc cca tcg gtc 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gca ccc tcc tcc aag agc acc tct ggg ggc aca gcg gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtc aag gac tac ttc ccc gaa ccg gtg acg gtg tcg 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac tca ggc gcc ctg acc agc ggc gtg cac acc ttc ccg gct gtc 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
cta cag tcc tca gga ctc tac tcc ctt agt agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
tcc agc agc ttg ggc acc cag acc tac atc tgc aac gtg aat cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aag aaa gtt gag ccc aaa tct tgt gac 672
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg tac cgt 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc agc ctg 1104
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct ccc gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat 1296
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg tct ccg 1344
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
ggt aaa tga 1353
Gly Lys
450
<210> 2
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 2
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Val Ile Trp Tyr Asp Gly Asn Asp Lys Tyr Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Val Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Gly Thr Pro Tyr Trp Tyr Phe Asp Leu Trp Gly Arg
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 3
<211> 648
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的L-链
<220>
<221> CDS
<222> (1)..(648)
<400> 3
gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct cca ggg 48
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt aac aac tac 96
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Asn Asn Tyr
20 25 30
tta gcc tgg tac caa cag aaa cct ggc cag gct ccc agg ctc ctc atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
tat gat gca tcc aac agg gcc act ggc atc cca gcc agg ttc agt ggc 192
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
agt ggg tct ggg aca gac ttc act ctc acc atc agc agc cta gag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
gaa gat ttt gca gtt tat tac tgt cag cag cgt agc acc tgg cct ccg 288
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Trp Pro Pro
85 90 95
tac act ttt ggc cag ggg acc aag ctg gag atc aaa cgg act gtg gct 336
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
gca cca tct gtc ttc atc ttc ccg cca tct gat gag cag ttg aaa tct 384
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
gga act gcc tct gtt gtg tgc ctg ctg aat aac ttc tat ccc aga gag 432
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
gcc aaa gta cag tgg aag gtg gat aac gcc ctc caa tcg ggt aac tcc 480
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
cag gag agt gtc aca gag cag gac agc aag gac agc acc tac agc ctc 528
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
agc agc acc ctg acg ctg agc aaa gca gac tac gag aaa cac aaa gtc 576
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
tac gcc tgc gaa gtc acc cat cag ggc ctg agc tcg ccc gtc aca aag 624
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
agc ttc aac agg gga gag tgt tag 648
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 4
<211> 215
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 4
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Asn Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Thr Trp Pro Pro
85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 5
<211> 1353
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的H-链
<220>
<221> CDS
<222> (1)..(1353)
<400> 5
gag gtg cag ctg gtg gag tct ggg gga ggc ttg gtc cag ccg ggg ggg 48
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt agt aat tat 96
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
ttg atg aac tgg gtc cgc cag gct cca ggg aag ggg ctg gag tgg gtg 144
Leu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
gcc aac ata gaa caa gat gga agt gag aaa tac tat gtg gac tct gtg 192
Ala Asn Ile Glu Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat 240
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
cta caa atg aac agc ctg aga gcc gag gac acg gct gtg tat ttc tgt 288
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
gcg aga gat gga gat aca gct atg att act ttt gac ttc tgg ggc cag 336
Ala Arg Asp Gly Asp Thr Ala Met Ile Thr Phe Asp Phe Trp Gly Gln
100 105 110
gga act ctg gtc acc gtc tcc tca gcc tcc acc aag ggc cca tcg gtc 384
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
ttc ccc ctg gca ccc tcc tcc aag agc acc tct ggg ggc aca gcg gcc 432
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
ctg ggc tgc ctg gtc aag gac tac ttc ccc gaa ccg gtg acg gtg tcg 480
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
tgg aac tca ggc gcc ctg acc agc ggc gtg cac acc ttc ccg gct gtc 528
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
cta cag tcc tca gga ctc tac tcc ctt agt agc gtg gtg acc gtg ccc 576
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
tcc agc agc ttg ggc acc cag acc tac atc tgc aac gtg aat cac aag 624
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
ccc agc aac acc aag gtg gac aag aaa gtt gag ccc aaa tct tgt gac 672
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga 720
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc 768
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa 816
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat 864
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg tac cgt 912
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag 960
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag 1008
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac 1056
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc agc ctg 1104
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg 1152
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct ccc gtg 1200
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc gtg gac 1248
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat 1296
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg tct ccg 1344
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
ggt aaa tga 1353
Gly Lys
450
<210> 6
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 6
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Leu Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Asn Ile Glu Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Asp Gly Asp Thr Ala Met Ile Thr Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 7
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的L-链
<220>
<221> CDS
<222> (1)..(645)
<400> 7
gac atc cag atg acc cag tct cca tct tcc gtg tct gca tct gta gga 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgt cgg gcg agt cag ggc att agg aga tgg 96
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Arg Trp
20 25 30
tta gcc tgg tat cag cag aaa cca ggg aaa gcc cct aag ctc ctg atc 144
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
tat gct gca tcc agt ttg caa agg ggg gtc cca tca agg ttc agc ggc 192
Tyr Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttc act ctc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat ttt gca act tac tat tgt caa cag gct aac agt ttc ccg tgg 288
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp
85 90 95
acg ttc ggc caa ggg acc aag gtg gaa atc aaa cgg act gtg gct gca 336
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
cca tct gtc ttc atc ttc ccg cca tct gat gag cag ttg aaa tct gga 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
act gcc tct gtt gtg tgc ctg ctg aat aac ttc tat ccc aga gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
aaa gta cag tgg aag gtg gat aac gcc ctc caa tcg ggt aac tcc cag 480
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
gag agt gtc aca gag cag gac agc aag gac agc acc tac agc ctc agc 528
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
agc acc ctg acg ctg agc aaa gca gac tac gag aaa cac aaa gtc tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gaa gtc acc cat cag ggc ctg agc tcg ccc gtc aca aag agc 624
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
ttc aac agg gga gag tgt tag 645
Phe Asn Arg Gly Glu Cys
210
<210> 8
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 8
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Arg Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 9
<211> 1359
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的H-链
<220>
<221> CDS
<222> (1)..(1359)
<400> 9
cag gtg cag ctg cag gag tcg ggc cca gga ctg gtg aag cct tca cag 48
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
acc ctg tcc ctc acc tgc act gtc tct ggt ggc tcc atc agc agt ggt 96
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
ggt tac tac tgg aac tgg atc cgc cag cac cca ggg aag ggc ctg gag 144
Gly Tyr Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
tgg att ggg tac atc tat tat agt ggg aac acc tac tac aac ccg tcc 192
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser
50 55 60
ctc aag agt cga gtt acc att tca gtg gac acg tct aag aac cag ttc 240
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
tcc ctg aag ctg agc tct gtg act gcc gcg gac gcg gcc gtg tat cat 288
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Ala Ala Val Tyr His
85 90 95
tgt gcg aga ggc tac ggt gac tac ggg ggg gga tat ttt gac tac tgg 336
Cys Ala Arg Gly Tyr Gly Asp Tyr Gly Gly Gly Tyr Phe Asp Tyr Trp
100 105 110
ggc cag gga acc ctg gtc acc gtc tcc tca gcc tcc acc aag ggc cca 384
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
tcg gtc ttc ccc ctg gca ccc tcc tcc aag agc acc tct ggg ggc aca 432
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
gcg gcc ctg ggc tgc ctg gtc aag gac tac ttc ccc gaa ccg gtg acg 480
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
gtg tcg tgg aac tca ggc gcc ctg acc agc ggc gtg cac acc ttc ccg 528
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
gct gtc cta cag tcc tca gga ctc tac tcc ctt agt agc gtg gtg acc 576
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
gtg ccc tcc agc agc ttg ggc acc cag acc tac atc tgc aac gtg aat 624
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
cac aag ccc agc aac acc aag gtg gac aag aaa gtt gag ccc aaa tct 672
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
tgt gac aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg 720
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
ggg gga ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc 768
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
atg atc tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc 816
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
cac gaa gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag 864
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
gtg cat aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg 912
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
tac cgt gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat 960
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
ggc aag gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc 1008
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
atc gag aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag 1056
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
gtg tac acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc 1104
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
agc ctg acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg 1152
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
gag tgg gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct 1200
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
ccc gtg ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc 1248
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
gtg gac aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg 1296
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
atg cat gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg 1344
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
tct ccg ggt aaa tga 1359
Ser Pro Gly Lys
450
<210> 10
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 10
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly
20 25 30
Gly Tyr Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Ala Ala Val Tyr His
85 90 95
Cys Ala Arg Gly Tyr Gly Asp Tyr Gly Gly Gly Tyr Phe Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
115 120 125
Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
130 135 140
Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
145 150 155 160
Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro
165 170 175
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
180 185 190
Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn
195 200 205
His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
210 215 220
Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 11
<211> 645
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗人BDCA-2抗体的L-链
<220>
<221> CDS
<222> (1)..(645)
<400> 11
gac atc cag atg acc cag tct cca tcc tcc ctg tct gca tct gta gga 48
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
gac aga gtc acc atc act tgc cag gcg agt cag gac att agc aac tat 96
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
tta aat tgg tat cag cag aaa cca ggg aaa gcc cct aag ttc ctg atc 144
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile
35 40 45
tac gat gta tcc aat ttg gaa aca ggg gtc cca tca agg ttc agt gga 192
Tyr Asp Val Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
agt gga tct ggg aca gat ttt act ttc acc atc agc agc ctg cag cct 240
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
gaa gat att gca aca tat tac tgt caa cag tat gat aat ctc ccg tac 288
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Tyr
85 90 95
act ttt ggc cag ggg acc aag ctg gag atc aaa cgg act gtg gct gca 336
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
cca tct gtc ttc atc ttc ccg cca tct gat gag cag ttg aaa tct gga 384
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
act gcc tct gtt gtg tgc ctg ctg aat aac ttc tat ccc aga gag gcc 432
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
aaa gta cag tgg aag gtg gat aac gcc ctc caa tcg ggt aac tcc cag 480
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
gag agt gtc aca gag cag gac agc aag gac agc acc tac agc ctc agc 528
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
agc acc ctg acg ctg agc aaa gca gac tac gag aaa cac aaa gtc tac 576
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
gcc tgc gaa gtc acc cat cag ggc ctg agc tcg ccc gtc aca aag agc 624
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
ttc aac agg gga gag tgt tag 645
Phe Asn Arg Gly Glu Cys
210
<210> 12
<211> 214
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Phe Leu Ile
35 40 45
Tyr Asp Val Ser Asn Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Pro Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 13
<211> 213
<212> PRT
<213> 智人(Homo sapiens)
<400> 13
Met Val Pro Glu Glu Glu Pro Gln Asp Arg Glu Lys Gly Leu Trp Trp
1 5 10 15
Phe Gln Leu Lys Val Trp Ser Met Ala Val Val Ser Ile Leu Leu Leu
20 25 30
Ser Val Cys Phe Thr Val Ser Ser Val Val Pro His Asn Phe Met Tyr
35 40 45
Ser Lys Thr Val Lys Arg Leu Ser Lys Leu Arg Glu Tyr Gln Gln Tyr
50 55 60
His Pro Ser Leu Thr Cys Val Met Glu Gly Lys Asp Ile Glu Asp Trp
65 70 75 80
Ser Cys Cys Pro Thr Pro Trp Thr Ser Phe Gln Ser Ser Cys Tyr Phe
85 90 95
Ile Ser Thr Gly Met Gln Ser Trp Thr Lys Ser Gln Lys Asn Cys Ser
100 105 110
Val Met Gly Ala Asp Leu Val Val Ile Asn Thr Arg Glu Glu Gln Asp
115 120 125
Phe Ile Ile Gln Asn Leu Lys Arg Asn Ser Ser Tyr Phe Leu Gly Leu
130 135 140
Ser Asp Pro Gly Gly Arg Arg His Trp Gln Trp Val Asp Gln Thr Pro
145 150 155 160
Tyr Asn Glu Asn Val Thr Phe Trp His Ser Gly Glu Pro Asn Asn Leu
165 170 175
Asp Glu Arg Cys Ala Ile Ile Asn Phe Arg Ser Ser Glu Glu Trp Gly
180 185 190
Trp Asn Asp Ile His Cys His Val Pro Gln Lys Ser Ile Cys Lys Met
195 200 205
Lys Lys Ile Tyr Ile
210
<210> 14
<211> 642
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 人BDCA-2突变体
<220>
<221> CDS
<222> (1)..(642)
<400> 14
atg gtg cct gaa gaa gag cct caa gac cga gag aaa gga ctc tgg tgg 48
Met Val Pro Glu Glu Glu Pro Gln Asp Arg Glu Lys Gly Leu Trp Trp
1 5 10 15
ttc cag ttg aag gtc tgg tcc atg gca gtc gta tcc atc ttg ctc ctc 96
Phe Gln Leu Lys Val Trp Ser Met Ala Val Val Ser Ile Leu Leu Leu
20 25 30
tgt gtc tgt ttc act gtg agt tct gtg gtg cct cac aat ttt atg tat 144
Cys Val Cys Phe Thr Val Ser Ser Val Val Pro His Asn Phe Met Tyr
35 40 45
agc aaa act gtc aag agg ctg tcc aag tta cga gag tat caa cag tat 192
Ser Lys Thr Val Lys Arg Leu Ser Lys Leu Arg Glu Tyr Gln Gln Tyr
50 55 60
cat cca agc ctg acc tgc gtc atg gaa gga aag gac ata gaa gat tgg 240
His Pro Ser Leu Thr Cys Val Met Glu Gly Lys Asp Ile Glu Asp Trp
65 70 75 80
agc tgc tgc cca acc cct tgg act tca ttt cag tct agt tgc tac ttt 288
Ser Cys Cys Pro Thr Pro Trp Thr Ser Phe Gln Ser Ser Cys Tyr Phe
85 90 95
att tct act ggg atg caa tct tgg act aag agt caa aag aac tgt tct 336
Ile Ser Thr Gly Met Gln Ser Trp Thr Lys Ser Gln Lys Asn Cys Ser
100 105 110
gtg atg ggg gct gat ctg gtg gtg atc aac acc agg gaa gaa cag gat 384
Val Met Gly Ala Asp Leu Val Val Ile Asn Thr Arg Glu Glu Gln Asp
115 120 125
ttc atc att cag aat ctg aaa aga aat tct tct tat ttt ctg ggg ctg 432
Phe Ile Ile Gln Asn Leu Lys Arg Asn Ser Ser Tyr Phe Leu Gly Leu
130 135 140
tca gat cca ggg ggt cgg cga cat tgg caa tgg gtt gac cag aca cca 480
Ser Asp Pro Gly Gly Arg Arg His Trp Gln Trp Val Asp Gln Thr Pro
145 150 155 160
tac aat gaa aat gtc aca ttc tgg cac tca ggt gaa ccc aat aac ctt 528
Tyr Asn Glu Asn Val Thr Phe Trp His Ser Gly Glu Pro Asn Asn Leu
165 170 175
gat gag cgt tgt gcg ata ata aat ttc cgt tct tca gaa gaa tgg ggc 576
Asp Glu Arg Cys Ala Ile Ile Asn Phe Arg Ser Ser Glu Glu Trp Gly
180 185 190
tgg aat gac att cac tgt cat gta cct cag aag tca att tgc aag atg 624
Trp Asn Asp Ile His Cys His Val Pro Gln Lys Ser Ile Cys Lys Met
195 200 205
aag aag atc tac ata taa 642
Lys Lys Ile Tyr Ile
210
<210> 15
<211> 213
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 合成构建体
<400> 15
Met Val Pro Glu Glu Glu Pro Gln Asp Arg Glu Lys Gly Leu Trp Trp
1 5 10 15
Phe Gln Leu Lys Val Trp Ser Met Ala Val Val Ser Ile Leu Leu Leu
20 25 30
Cys Val Cys Phe Thr Val Ser Ser Val Val Pro His Asn Phe Met Tyr
35 40 45
Ser Lys Thr Val Lys Arg Leu Ser Lys Leu Arg Glu Tyr Gln Gln Tyr
50 55 60
His Pro Ser Leu Thr Cys Val Met Glu Gly Lys Asp Ile Glu Asp Trp
65 70 75 80
Ser Cys Cys Pro Thr Pro Trp Thr Ser Phe Gln Ser Ser Cys Tyr Phe
85 90 95
Ile Ser Thr Gly Met Gln Ser Trp Thr Lys Ser Gln Lys Asn Cys Ser
100 105 110
Val Met Gly Ala Asp Leu Val Val Ile Asn Thr Arg Glu Glu Gln Asp
115 120 125
Phe Ile Ile Gln Asn Leu Lys Arg Asn Ser Ser Tyr Phe Leu Gly Leu
130 135 140
Ser Asp Pro Gly Gly Arg Arg His Trp Gln Trp Val Asp Gln Thr Pro
145 150 155 160
Tyr Asn Glu Asn Val Thr Phe Trp His Ser Gly Glu Pro Asn Asn Leu
165 170 175
Asp Glu Arg Cys Ala Ile Ile Asn Phe Arg Ser Ser Glu Glu Trp Gly
180 185 190
Trp Asn Asp Ile His Cys His Val Pro Gln Lys Ser Ile Cys Lys Met
195 200 205
Lys Lys Ile Tyr Ile
210
<210> 16
<211> 261
<212> DNA
<213> 智人(Homo sapiens)
<400> 16
atgattccag cagtggtctt gctcttactc cttttggttg aacaagcagc ggccctggga 60
gagcctcagc tctgctatat cctggatgcc atcctgtttc tgtatggaat tgtcctcacc 120
ctcctctact gtcgactgaa gatccaagtg cgaaaggcag ctataaccag ctatgagaaa 180
tcagatggtg tttacacggg cctgagcacc aggaaccagg agacttacga gactctgaag 240
catgagaaac caccacagta g 261
Claims (15)
1.一种抗人BDCA-2抗体或其抗原结合片段,其选自以下(1)~(2)中的任一个:
(1)一种抗人BDCA-2抗体或其抗原结合片段,包含由序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区;以及
(2)一种抗人BDCA-2抗体或其抗原结合片段,包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序号1至122的氨基酸序列构成的重链可变区及由序列号12的氨基酸序号1至108的氨基酸序列构成的轻链可变区。
2.根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段,包含由序列号10所示的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
3.根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段,包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
4.根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段,包含由其中氨基酸序号452的赖氨酸缺失的序列号10的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
5.根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段,包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸和氨基酸序号452的赖氨酸缺失的序列号10的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。。
6.根据权利要求5所述的抗人BDCA-2抗体或其抗原结合片段,包含由其中氨基酸序号1的谷氨酰胺被修饰为焦谷氨酸的序列号10的氨基酸序号1至451的氨基酸序列构成的重链以及由序列号12所示的氨基酸序列构成的轻链。
7.一种多核苷酸,其包含以下(1)和(2):
(1)含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸;以及
(2)含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸。
8.一种表达载体,包含以下(1)和(2):
(1)含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸;和
(2)含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸。
9.一种宿主细胞,其选自由以下(a)~(b)构成的组:
(a)用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(b)用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
10.一种宿主细胞,其选自由以下(a)~(b)构成的组:
(a)用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的重链的碱基序列的多核苷酸和含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(b)用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的重链的碱基序列的多核苷酸的表达载体和包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
11.一种生产抗人BDCA-2抗体或其抗原结合片段的方法,包括:对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,从而使所述抗人BDCA-2抗体或其抗原结合片段表达:
(a)用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸和含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体和包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的重链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞、以及用包含含有编码根据权利要求1所述的抗人BDCA-2抗体或其抗原结合片段的轻链可变区的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
12.一种生产抗人BDCA-2抗体的方法,包括:对选自由以下(a)~(c)构成的组中的宿主细胞进行培养,从而使所述抗人BDCA-2抗体或其抗原结合片段表达:
(a)用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的重链的碱基序列的多核苷酸和含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;
(b)用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的重链的碱基序列的多核苷酸的表达载体和包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞;以及
(c)用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的重链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞、以及用包含含有编码根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段的轻链的碱基序列的多核苷酸的表达载体进行了转化的宿主细胞。
13.一种医药组合物,包含根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
14.一种医药组合物,包含根据权利要求3到5中任意一项所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
15.一种医药组合物,包含根据权利要求2所述的抗人BDCA-2抗体或其抗原结合片段、根据权利要求3到5中任意一项所述的抗人BDCA-2抗体或其抗原结合片段、以及药学上可接受的赋形剂。
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PCT/JP2014/083862 WO2015098813A1 (ja) | 2013-12-24 | 2014-12-22 | 新規抗ヒトbdca-2抗体 |
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MX2020010204A (es) * | 2018-04-02 | 2021-01-29 | Bristol Myers Squibb Co | Anticuerpos anti-trem-1 y usos de los mismos. |
AU2020324542A1 (en) * | 2019-08-05 | 2022-03-24 | Capella Bioscience Ltd | Anti BDCA-2 antibodies |
KR20230119664A (ko) * | 2020-12-03 | 2023-08-16 | 바이오젠 엠에이 인코포레이티드 | 피부 홍반성 루푸스 및 전신성 홍반성 루푸스를 치료하는방법 |
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CN105829534A (zh) | 2016-08-03 |
TW201609806A (zh) | 2016-03-16 |
RU2016129744A (ru) | 2018-01-30 |
US11046770B2 (en) | 2021-06-29 |
BR112016014920A2 (pt) | 2017-12-12 |
JPWO2015098813A1 (ja) | 2017-03-23 |
US20160319025A1 (en) | 2016-11-03 |
JP6604204B2 (ja) | 2019-11-13 |
MX2016008520A (es) | 2016-11-30 |
CA2934604A1 (en) | 2015-07-02 |
CN109535254B (zh) | 2022-06-24 |
KR20160099083A (ko) | 2016-08-19 |
CN105829534B (zh) | 2021-08-03 |
EP3088519A4 (en) | 2017-09-13 |
CN109535254A (zh) | 2019-03-29 |
WO2015098813A1 (ja) | 2015-07-02 |
EP3088519A1 (en) | 2016-11-02 |
AR098950A1 (es) | 2016-06-22 |
US20190248904A1 (en) | 2019-08-15 |
US10294301B2 (en) | 2019-05-21 |
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