CN107556382A - 一种能够特异性地结合il‑17a的抗体及其功能片段 - Google Patents
一种能够特异性地结合il‑17a的抗体及其功能片段 Download PDFInfo
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Abstract
本发明涉及医学生物技术和人源化抗体改造研究领域,具体而言,涉及一种能够特异性地结合IL‑17A的抗体及其功能片段,所述抗体或其功能片段包括IL‑17A嵌合抗体及其功能片段及IL‑17A人源化抗体及其功能片段。
Description
技术领域
本发明涉及医学生物技术和人源化抗体改造研究领域,具体而言,涉及一种能够特异性地结合IL-17A的抗体及其功能片段。
背景技术
白细胞介素17A(IL-17或IL-17A)是一种促炎性细胞因子,主要产生自Th17细胞,是IL-17家族中最具代表性的成员(Miossec P,Kolls JK.Nat.Rev.Drug.Discov.,2012,11:763-776)。IL-17A与其受体(IL-17RA)结合后,可诱导多种细胞(如成纤维细胞、上皮细胞和内皮细胞)表达炎症性细胞因子以及趋化因子,在机体免疫防御中发挥重要作用(LinY,Ritchea S,Logar A.Immunity,2009,31:799-810)。
然而,过高表达的IL-17A可引起诸多炎症疾病。如IL-17A作用于巨噬细胞,DC细胞,诱发IL-1,IL-6,TNF,CRP的高表达,导致炎症反应,参与银屑病和移植排斥的病理过程;IL-17A作用于内皮细胞,诱发IL-6,MMP,凝血因子的高表达,导致血管活化,参与再灌注损伤、血栓和动脉粥样硬化的病理过程;IL-17A作用于成纤维细胞,诱发IL-6,趋化因子,生长因子,MMP的高表达,导致基质破坏,参与多发性硬化症、克隆恩病的病理过程;IL-17A作用于成骨细胞和软骨细胞,诱导RANKL、MMP、破骨细胞生成、导致骨侵蚀、软骨损伤,参与风湿性关节炎、牙周病的病理过程(N Engl J Med.2009Aug 27;361(9):888-98.Nat Rev DrugDiscov.2012Oct;11(10):763-76.Semin Arthritis Rheum.2013Oct;43(2):158-70.Trends Mol Med.2016Mar;22(3):230-41.)。
IL-17A中和抗体可以抑制类风湿关节炎患者的滑膜组织高表达IL-17A,并降低重要炎症因子IL-6的产生(Chabaud M,Durand JM,Buchs N,et al.Arthritis Rheum.1999,42:963-70)。很多自身免疫疾病的动物模型实验证明,使用抗体中和IL-17A,可有效抑制炎症的病理发展(Lubberts E,Koenders MI,Oppers-Walgreen B,et al.Arthritis Rheum.,2004,50:650-659)。
目前,IL-17A相关抗体药物已经被批准上市,分别是Secukinumab(IL-17A靶向抗体)、Ixekizumab(IL-17A靶向抗体),均用于治疗银屑病。然而,药物临床研究结果表明,对于某些慢性炎症疾病如类风湿性关节炎,这些药物并未表现出预期的治疗效果(KellnerH,Ther Adv Musculoskelet Dis.,2013,5:141-152)。
有鉴于此,特提出本发明。
发明内容
本发明是基于所获得的一株具有与人IL-17A蛋白特异性结合的亲本抗人IL-17A鼠单克隆抗体,通过克隆、鉴定与基因结构的分析,确定了其CDR区序列,构建了相应的嵌合抗体及人源化抗体,并建立了相应的真核细胞表达***,生产纯化出了该嵌合抗体及人源化抗体。
为了实现本发明的上述目的,特采用以下技术方案:
一种能够特异性地结合IL-17A的抗体及其功能片段,所述抗体及其功能片段包含轻链和重链;
所述轻链具有由CDR-L1、CDR-L2、CDR-L3组成的轻链CDR;所述重链具有由CDR-H1、CDR-H2、CDR-H3组成的重链CDR;
所述CDR-L1、CDR-L2、CDR-L3的氨基酸序列分别如SEQ ID NO:1、2和3所示;所述CDR-H1、CDR-H2、CDR-H3的氨基酸序列分别如SEQ ID NO:4、5和6所示;
优选的,所述抗体及其功能片段包括IL-17A嵌合抗体及其功能片段及IL-17A人源化抗体及其功能片段。
本领域公知,抗体的结合特异性及亲合力均主要由CDR序列决定,根据成熟、公知的现有各项技术可轻易地将非CDR区域的氨基酸序列改变而获得具有相类似的生物活性的变体。本发明涉及的具有与上述CDR序列完全相同的CDR序列的单克隆抗体变体,因其具有与本发明所述的人源化抗体完全相同的CDR序列,因此具有相类似的生物活性。
优选的,如上所述的抗体及其功能片段,所述抗体包含人抗体IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
优选的,如上所述的抗体及其功能片段,所述功能片段包括F(ab’)2、Fab’、Fab、Fv、scFv、双特异抗体和抗体最小识别单位中的一种或多种。
本发明所述的“功能片段”特别地指对于IL-17A具有与母体抗体相同特异性的抗体片段。除上述功能片段外,还包括半衰期已增加的任何片段。
scFv(sc=单链),双特异抗体(diabodies)。
这些功能片段通常具有与其来源抗体相同的结合特异性。本领域技术人员根据本发明说明中记载的内容推断,本发明的抗体片段可以通过比如酶消化的方法(包括胃蛋白酶或木瓜蛋白酶)和/或通过化学还原***二硫键的方法获得上述的功能片段。
抗体片段还可以通过也是本领域技术人员所知的重组遗传学技术或通过例如自动肽合成仪,比如Applied BioSystems等销售的自动肽合成仪,通过肽合成获得。
优选的,如上所述的抗体及其功能片段,所述IL-17A嵌合抗体及其功能片段的轻链可变区序列和重链可变区序列的氨基酸序列分别如SEQ ID NO:7和SEQ ID NO:8所示。
进一步优选的,如上所述的抗体及其功能片段,所述IL-17A嵌合抗体及其功能片段的轻链恒定区序列和重链恒定区序列的氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10所示。
优选的,如上所述的抗体及其功能片段,所述IL-17A人源化抗体及其功能片段的轻链骨架区包括FR-L1、FR-L2、FR-L3及FR-L4,重链骨架区包括FR-H1、FR-H2、FR-H3及FR-H4;
所述FR-L1选自SEQ ID NO:11所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第1个氨基酸替换为I;
第2个氨基酸替换为I;
所述FR-L2选自SEQ ID NO:12所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第4个氨基酸替换为Y;
第14个氨基酸替换为L;
所述FR-L3选自SEQ ID NO:13所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第35个氨基酸替换为F;
所述FR-L4选自SEQ ID NO:14所示的氨基酸序列;
所述FR-H1选自SEQ ID NO:15所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第4个氨基酸替换为V;
所述FR-H2选自SEQ ID NO:16所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第15个氨基酸替换为M;
所述FR-H3选自SEQ ID NO:17所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第2个氨基酸替换为I;
第6个氨基酸替换为R;
所述FR-H4选自SEQ ID NO:18所示的氨基酸序列;
通常从鼠抗移植CDR到人源框架上,选择序列同源性高的人源框架会有一定的成功率。但是研究表明,许多CDR移植需要做回复突变,才能恢复一定的抗体活性。如何选择合适的人源框架是主要的瓶颈。
CDR是抗原结合的主要相关位点,但多数情况下FR(Framework region)对结合位点构象的影响明显,为获得高亲和力的人源化抗体,本发明选择了合适的FR区,并将相关FR残基需回复为原鼠源氨基酸或其他作用相同的人中可见的氨基酸。
优选的,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:19-26任一项所示;
优选的,所述IL-17A人源化抗体及其功能片段的重链可变区序列如SEQ ID NO:27-34任一项所示;
更优选的,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:19所示;其对应的重链可变区序列如SEQ ID NO:27所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:20所示;其对应的重链可变区序列如SEQ ID NO:28所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:21所示;其对应的重链可变区序列如SEQ ID NO:29所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:22所示;其对应的重链可变区序列如SEQ ID NO:30所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:22所示;其对应的重链可变区序列如SEQ ID NO:31所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:23所示;其对应的重链可变区序列如SEQ ID NO:32所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:24所示;其对应的重链可变区序列如SEQ ID NO:33所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:25所示;其对应的重链可变区序列如SEQ ID NO:32所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:26所示;其对应的重链可变区序列如SEQ ID NO:34所示;
最优选的,所述IL-17A人源化抗体及其功能片段的轻链恒定区序列和重链恒定区序列的氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10所示。
所述IL-17A人源化抗体及其功能片段的轻链恒定区选自人抗体Kappa轻链恒定区,其氨基酸序列如SEQ ID NO:9所示;
所述IL-17A人源化抗体及其功能片段的重链恒定区选自人抗体IgG1重链恒定区,其氨基酸序列如SEQ ID NO:10所示。
需要说明的是,除本申请上述公开的氨基酸序列外,嵌合抗体和人源化抗体的产生可以由本领域技术人员通过任何已知的方法来实现,比如通过根据鼠抗体经测序的CDR而设计的重组人源化抗体,所述鼠抗体由来自免疫的小鼠或与骨髓瘤细胞相融合的其它物种的脾细胞的骨髓瘤细胞所分泌。所述免疫的动物可以包括转基因小鼠,其具有人类免疫球蛋白基因座,然后直接产生人类抗体。另外一个可能的实施方式可以包括使用噬菌体展示技术筛选文库。
一种分离的核酸分子,所述核酸分子选自如下核酸:
A)、DNA或RNA,其编码如上所述的抗体及其功能片段;
B)、与A)中定义的核酸互补的核酸。
一种载体,其包括如上所述的核酸。
本发明进一步包含至少一种编码如上所述的核酸分子的核构建体,优选载体,进一步优选为表达载体,比如质粒,在本申请的一个实施例中会介绍该载体的构建方法
一种宿主细胞,其被如上所述的载体转化。
所述宿主细胞是真核细胞,比如哺乳动物细胞。
一种生产能够特异性地结合IL-17A的抗体及其功能片段的方法,包括如下步骤:
在培养基中和合适的培养条件下培养如上所述的宿主细胞;
从培养基中或从所培养的宿主细胞中回收如此产生的抗体及其功能片段。
一种组合物,所述组合物以如上所述的抗体及其功能片段、或它们与其他成分组成的化合物作为活性成分。
优选的,如上所述的组合物,所述抗体及其功能片段与至少一种诊断剂和/或治疗剂偶联以形成免疫偶联物。
优选的,如上所述的组合物,所述诊断剂选自:
放射性核素、放射性造影剂、顺磁离子、金属、荧光标记、化学发光标记物、超声造影剂、光敏剂中的一种或多种;
优选的,所述所述放射性核素包括110In、111In、177Lu、18F、52Fe、62Cu、64Cu、67Cu、67Ga、68Ga、86Y、90Y、89Zr、94mTc、94Tc、99mTc、120I、123I、124I、125I、131I、154-158Gd、32P、11C、13N、15O、186Re、188Re、51Mn、52mMn、55Co、72As、75Br、76Br、82mRb和83Sr中的一种或多种;
优选的,所述顺磁离子包括铬(III)、锰(II)、铁(III)、铁(II)、钴(II)、镍(II)、铜(II)、钕(III)、钐(III)、镱(III)、钆(III)、钒(II)、铽(III)、镝(III)、钬(III)和铒(III)中的一种或多种;
优选的,所述荧光标记包括Alexa 350、Alexa 405、Alexa 430、Alexa 488、Alexa555、Alexa 647、AMCA、氨基吖啶、BODIPY 630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、5-羧基-4′,5′-二氯-2′,7′-二甲氧基荧光素、5-羧基-2′,4′,5′,7′-四氯荧光素、5-羧基荧光素、5-羧基罗丹明、6-羧基罗丹明、6-羧基四甲基罗丹明、Cascade Blue、Cy2、Cy3、Cy5、Cy7、6-FAM、丹磺酰氯、荧光素、HEX、6-JOE、NBD(7-硝基苯并-2-氧杂-1,3-二唑)、Oregon Green 488、Oregon Green500、Oregon Green514、PacificBlue、邻苯二甲酸、对苯二甲酸、间苯二甲酸、甲酚固紫、甲酚蓝紫、亮甲酚蓝、对氨基苯甲酸、赤藓红、酞菁、偶氮甲碱、花青、黄嘌呤、琥珀酰荧光素、稀土金属穴状化合物、三双吡啶基二胺铕、铕穴状化合物或螯合物、二胺、双花青苷、La Jolla蓝染料、别藻蓝蛋白、allococyanin B、藻蓝蛋白C、藻蓝蛋白R、硫胺、藻红青蛋白、藻红蛋白R、REG、罗丹明绿、罗丹明异硫氰酸酯、罗丹明红、ROX、TAMRA、TET、TRIT(四甲基罗丹明异硫醇)、四甲基罗丹明和德克萨斯红中的一种或多种。
优选的,如上所述的组合物,所述治疗剂选自:裸抗体、细胞毒素剂、药物、放射性核素、硼原子、免疫调节剂、抗凋亡试剂、光敏性治疗剂、免疫偶联物、寡核苷酸中的一种或多种;
优选的,所述药物选自***、双氯芬酸、萘丁美酮、美洛昔康、塞来昔布、甲氨蝶呤、环磷酰胺、硫唑嘌呤、环孢素A、长春新碱中的一种或多种;
优选的,所述寡核苷酸选自shRNA、miRNA和siRNA中的一种或多种;
优选的,所述免疫调节剂选自:细胞因子、趋化因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素、***、促血小板生成素、肿瘤坏死因子(TNF)、白介素(IL)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)和干细胞生长因子中的一种或多种;
其中,所述细胞因子优选选自:人生长激素、N-甲硫氨酰基人生长激素、牛生长激素、甲状旁腺激素、甲状腺素、胰岛素、胰岛素原、松弛素、松弛素原、促卵胞激素(FSH)、促甲状腺激素(TSH)、***(LH)、肝生长因子、***素、成纤维细胞生长因子、催乳素、胎盘催乳素、OB蛋白、肿瘤坏死因子-α、肿瘤坏死因子-β、苗勒氏管抑制物质、小鼠***相关肽、抑制素、激活素、血管内皮生长因子、整联蛋白、促血小板生成素(TPO)、NGF-β、血小板-生长因子、TGF-α、TGF-β、***-I、***-II、***(EPO)、骨诱导因子、干扰素-α、干扰素-β、干扰素-γ、巨噬细胞-CSF(M-CSF)、IL-1、IL-1α、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-12、IL-13、IL-14、IL-15、IL-16、IL-17、IL-18、IL-21、IL-25、LIF、FLT-3、血管抑素、血小板反应素、内皮抑素、肿瘤坏死因子和LT中的一种或多种。
所述趋化因子优选选自RANTES、MCAF、MIP1-α、MIP1-β和IP-10中的一种或多种。
优选的,所述放射性核素选自111In、111At、177Lu、211Bi、212Bi、213Bi、211At、62Cu、67Cu、90Y、125I、131I、133I、32P、33P、47Sc、111Ag、67Ga、153Sm、161Tb、152Dy、166Dy、161Ho、166Ho、186Re、188Re、189Re、211Pb、212Pb、223Ra、225Ac、77As、89Sr、99Mo、105Rh、149Pm、169Er、194Ir、58Co、80mBr、99mTc、103mRh、109Pt、119Sb、189mOs、192Ir、219Rn、215Po、221Fr、255Fm、11C、13N、15O、75Br、198Au、199Au、224Ac、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、165Tm、167Tm、168Tm、197Pt、109Pd、142Pr、143Pr、161Tb、57Co、58Co、51Cr、59Fe、75Se、201Tl、76Br和169Yb中的一种或多种。
如上所述的组合物在制备用于预防和/或治疗与IL-17A过量表达和/或释放相关的疾病的药物中的应用;
优选的,所述疾病包括:
气道炎症、哮喘、支气管哮喘、过敏性哮喘、慢性阻塞性肺病、特发性肺纤维化、类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、银屑病、多发性硬化症、***性硬化症、***性红斑狼疮、狼疮肾炎、硬皮病、溃疡性结肠炎、炎性肠病、葡萄膜炎、幽门螺杆菌相关性胃炎、骨质疏松、骨质侵蚀、腹膜内脓肿和粘连、艾迪生氏病、丙种球蛋白缺乏症、斑秃、乳糜泻、查加斯病,克隆氏病、同种异体移植排斥、***、败血症、脓毒性或内毒素性休克、缺血。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本发明实施例1中88号克隆分泌的单抗与人IL-17A的结合活性;
图2为本发明实施例1中88号克隆分泌的单抗对人IL-17A刺激HFF-1细胞分泌人IL-6的中和活性;
图3为本发明实施例4中抗人IL-17A嵌合单抗的种属特异性;
图4为本发明实施例4中抗人IL-17A嵌合单抗的结合特异性;
图5为本发明实施例5中抗人IL-17A嵌合单抗的体外中和活性;
图6为本发明实施例6中抗人IL-17A嵌合单抗的体内中和活性;
图7为本发明实施例7中单次静脉注射后的药时曲线;
图8为本发明实施例9中抗人IL-17A人源化单抗的抗原结合活性;
图9为本发明实施例10中抗人IL-17A人源化单抗的体外中和活性;
图10为本发明实施例15中单次皮下注射后的药时曲线。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限制本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1鼠源的抗人IL-17A单抗的制备
1.1、动物免疫
实验动物选用雌性BALB/c小鼠,6至8周龄,购自北京华阜康生物科技股份有限公司。小鼠适应环境一周后,开始免疫。重组人IL-17A蛋白使用大肠杆菌E.coli表达,收集包涵体后对包涵体进行变复性处理,获得可溶性IL-17A蛋白。首次免疫使用重组人IL-17A蛋白100μg与弗氏完全佐剂(Sigma-Aldrich,货号F5881),充分混合形成乳液,于小鼠腹腔注射。两周之后,进行加强免疫。加强免疫使用重组人IL-17A蛋白50μg与弗氏不完全佐剂(Sigma-Aldrich,货号F5806),充分混合形成乳液,于小鼠腹腔注射。每隔2周以同样的方法加强免疫,共加强免疫3次。末次免疫后第7天,从小鼠眼眶后静脉丛采血并离心分离血清,ELISA测定抗体效价。选择效价高的小鼠用来融合做杂交瘤。融合前三天,腹腔注射重组人IL-17A蛋白50μg,不含佐剂。融合当天,无菌取脾,制成单脾细胞悬液,以待融合。
1.2、杂交瘤细胞的制备
取对数生长的骨髓瘤细胞SP2/0,1000rpm离心5分钟,弃上清,用不完全DMEM培养液(Gibco,cat No.11965)混悬细胞后计数,取所需的细胞数,用不完全培养液洗涤2次。同时制备免疫脾细胞悬液,用不完全培养液洗涤2次。将骨髓瘤细胞与脾细胞按1∶10或1∶5的比例混合在一起,在50ml塑料离心管内用不完全培养液洗1次,1200rpm,8分钟。弃上清,用滴管吸净残留液体。在手掌上轻击离心管底,使沉淀细胞松散均匀;置40℃水浴中预热。用1ml吸管在1分钟左右(最佳时间为45秒)加预热至40℃的45%PEG-4000(PH 8.0,Sigma,catNo.P7181)1ml,边加边轻轻搅拌(用吸管搅拌),肉眼观察应有可见颗粒出现。用10ml吸管在90s内加20~30ml预热至37℃的不完全培养基以终止PEG作用;20~37℃静置10分钟。1000r/min离心5分钟,弃去上清。加入5ml HAT培养基(DMEM+HAT,Sigma,cat No.1H0262-10VL),轻轻吹吸沉淀细胞(切记不能用力吹打,以免使融合在一起的细胞散开),使其悬浮并混匀,然后补加HAT培养基至80-100ml(使脾细胞浓度为1~2×106/ml)。分装96孔细胞培养板,每孔0.1ml;分装24孔板,每孔1.0~1.5ml;然后将培养板置37℃,6%CO2培养箱内培养。一般铺6块96孔板。5天后用HAT培养基换出1/2培养基。再7~10天后用HT培养基(DMEM+HT,Sigma cat No.H0137-10VL)换出HAT培养基。经常观察杂交瘤细胞生长情况,待其长至孔底面积1/10以上时吸出上清供抗体检测。将阳性克隆的细胞扩大培养并冻存。
1.3、克隆筛选与鉴定
ELISA用于筛选杂交瘤培养上清液的抗人IL-17A抗体。用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板上包被重组人IL-17A,包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入培养上清液样品以及阳性对照,每孔加入100μL,25℃孵育1小时。PBST洗涤5次。然后加入1:10000稀释在含1%BSA的PBST里的辣根过氧化物酶标记的抗小鼠IgG抗体(Abcam,货号Ab7068),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H2SO4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。根据OD450nm的强弱选取能够分泌抗人IL-17A结合抗体的阳性克隆。
细胞实验测定阳性克隆分泌的抗人IL-17A抗体是否是中和抗体。将抗人IL-17A抗体样品稀释于含10%FBS(Hyclone,货号SH30084.03)的DMEM(GIBCO,货号11995-073)完全培养基中,样品起始浓度为160nM(终浓度40nM),5倍序列稀释,每孔50μL,加入细胞培养板中。再向细胞培养板中加入稀释于相同完全培养基的浓度为20ng/mL(终浓度5ng/mL)的人IL-17A,每孔50μL。在37℃,5%CO2培养箱中孵育1小时。然后将HFF-1细胞重悬在完全培养基中,接种到96孔细胞培养板内,100μL每孔,每孔5000个细胞。细胞在37℃,5%CO2培养箱中孵育培养24小时。孵育结束后,将细胞培养板250g离心5分钟,取出培养上清,用人IL-6ELISA试剂盒(R&D systems,货号S6050),按说明书测定人IL-6的水平。能够抑制人IL-17A刺激HFF-1细胞分泌人IL-6的抗体,即是抗人IL-17A中和抗体。根据中和能力强弱选取能够分泌抗人IL-17A中和抗体的阳性克隆。
结果如图1所示,88号克隆具有强的人IL-17A结合活性,根据图2所示,88号克隆同时具有很强的人IL-17A中和活性。
1.4、单克隆抗体序列的测定
将筛选得到的同时具有抗原结合活性以及抗原中和活性的克隆,进行抗体DNA序列的测定。首先提取细胞mRNA,使用RNAprep Pure试剂盒(Tiangen,DP430)。步骤如下:悬浮细胞的收集1×107,300×g离心5min,将细胞收集到离心管中,仔细吸除所有培养基上清。立即进行裂解步骤。轻弹离心管底部,使细胞沉淀松散,加入适量裂解液RL600uL,旋涡震荡。将所有溶液转移至过滤柱CS上(过滤柱CS放在收集管中),12,000rpm(~13,400×g)离心2min,收集滤液。向滤液中加入1倍体积70%乙醇(通常为350μl或600μl),混匀,得到的溶液和沉淀一起转入吸附柱CR3中(吸附柱CR3放入收集管中),12,000rpm(~13,400×g)离心30-60sec,倒掉收集管中的废液,将吸附柱CR3放回收集管中。向吸附柱CR3中加入350μl去蛋白液RW1,12,000rpm(~13,400×g)离心30~60sec,倒掉收集管中的废液,将吸附柱CR3放回收集管中。向吸附柱CR3中央加入80μl的DNase I工作液,室温放置15min。向吸附柱CR3中加入350μl去蛋白液RW1,12,000rpm(~13,400×g)离心30~60sec,倒掉收集管中的废液,将吸附柱CR3放回收集管中。向吸附柱CR3中加入500μl漂洗液RW(使用前请先检查是否已加入乙醇),室温静置2min,12,000rpm(~13,400×g)离心30~60sec,倒掉收集管中的废液,将吸附柱CR3放回收集管中。12,000rpm(~13,400×g)离心2min,倒掉废液。将吸附柱CR3置于室温放置数分钟,以彻底晾干吸附材料中残余的漂洗液。将吸附柱CR3转入一个新的RNase-Free离心管中,加入30~100μl RNase-Free ddH2O室温放置2min,12,000rpm(~13,400×g)离心2min,得到RNA溶液。
使用QuantScript RT试剂盒(Tiangen,KR103)合成cDNA第一链。步骤如下,将模板RNA在冰上解冻;引物、10×RT mix(其中包含RNasin和DTT)、Super pure dNTP混合液、RNase-Free ddH2O在室温(15~25℃)解冻,解冻后迅速置于冰上。使用前将每种溶液涡旋振荡混匀,简短离心以收集残留在管壁的液体。按照表1的逆转录体系配制混合液,彻底混匀,涡旋振荡时间不超过5min。简短离心,并置于冰上,最后将模板RNA(50ng~2μg)加入到混合液中,彻底混匀,涡旋振荡时间不超过5sec,简短离心以收集管壁残留的液体。37℃孵育60min。将逆转录的产生的cDNA第一链用于后续PCR反应。
PCR反应使用的引物如表1所示。
表1 PCR引物
使用引物时,VH primer中的任一上游引物可与任一下游引物配合使用;同理在VLprimer中的任一上游引物也可与任一下游引物配合使用。将PCR扩增得到的目的条带克隆到pGEM-T载体中。挑取单克隆进行DNA测序。
实施例2嵌合的抗人IL-17A单抗的制备
经过PCR扩增得到抗体轻链可变区序列如SEQ ID NO:7所示,抗体重链可变区序列如SEQ ID NO:8所示。根据小鼠可变区序列排除骨架区序列后即可得到其互补决定区序列;其中轻链的三个互补决定区CDR-L1、CDR-L2、CDR-L3的氨基酸序列分别如SEQ ID NO:1、2和3所示;重链的三个互补决定区CDR-H1、CDR-H2、CDR-H3的氨基酸序列分别如SEQ ID NO:4、5和6所示。将上述可变区序列克隆到真核细胞表达载体X0GC中,抗体轻链恒定区序列如SEQID NO:9所示,抗体重链恒定区序列如SEQ ID NO:10所示。将抗体轻链(轻链全长序列为将SEQ ID NO:7和SEQ ID NO:9连接即得)及重链(重链全长序列为将SEQ ID NO:8和SEQ IDNO:10连接即得)表达载体转染293F细胞系(FreeStyleTM293-F Cells,货号R79007,invitrogen)。转染前一天接种细胞,转染当天将细胞离心收集细胞,将细胞重悬于新鲜的FreeStyleTM293表达培养基(FreeStyleTM293Expression Medium,货号12338001,Gibco)中,细胞密度为200×105细胞/mL。按照转染体积加入质粒,终浓度为36.67ug/mL,轻轻混匀;然后加入线性PEI(聚乙烯亚胺,线形,M.W.25000,货号43896,Alfa Aesar),终浓度为55ug/mL,轻轻混匀。之后放入细胞培养箱,120rpm摇床37℃培养1小时。之后加入19倍转染体积的新鲜培养基。继续120rpm摇床37℃培养。离心收集转染5~6天的细胞培养上清。
实施例3嵌合的抗人IL-17A单抗与人IL-17A结合的动力学常数
用Biacore3000仪器来检测抗人IL-17A嵌合单抗与其抗原人IL-17A结合的动力学常数。该仪器利用光学的表面等离子体共振技术来检测偶联包被在生物芯片上的分子与待测分子之间的结合和解离。所用的主要试剂为氨基偶联试剂盒(GE Healthcare,BR-1000-14)和CM5芯片(GE Healthcare,BR-1000-50)。实验过程简要的说,将人IL-17A溶于pH=5.0的醋酸钠缓冲溶液中,10μL/min的速度注入偶联到CM芯片上,并用1M乙醇胺以10μL/min的速度注入来进行封闭。在结合阶段,将不同浓度的抗人IL-17A嵌合单抗以及对照分别以30μL/min的速度注入180秒,在解离阶段,用PBS缓冲溶液以30μL/min的速度注入600秒。再生条件为10mM甘氨酸盐溶液,pH 2.0。结合动力学常数和解离动力学常数通过Biacore3000control software来进行分析计算。
抗人IL-17A嵌合抗体的结合动力学常数、解离动力学常数和解离平衡常数见表2。
表2.抗人IL-17A嵌合抗体与人IL-17A结合的动力学常数
实施例4嵌合的抗人IL-17A单抗的种属特异性和结合特异性
用ELISA测定抗人IL-17A嵌合单抗的种属特异性。用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板上包被重组人IL-17A,猴IL-17A,大鼠IL-17A和小鼠IL-17A,均购自义翘神州,包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入序列稀释在含1%BSA的PBST里的抗人IL-17A嵌合单抗样品以及对照,每孔加入100μL,25℃孵育1小时。PBST洗涤5次。然后加入1:2000稀释在含1%BSA的PBST里的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H2SO4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
用ELISA测定抗人IL-17A嵌合单抗的结合特异性。用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板上包被重组人IL-17A,IL-17B,IL-17C,IL-17D,IL-17E,IL-17F,IL-1,IL-2,IL-6,IL-8,IL-21,IL-22,IL-23,IFN-g和TNFa,购自北京义翘神州或者R&D systems,包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入稀释在含1%BSA的PBST里的抗人IL-17A嵌合单抗样品以及对照,每孔加入100μL,25℃孵育1小时。PBST洗涤5次。然后加入1:2000稀释在含1%BSA的PBST里的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1M H2SO4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图3所示,抗人IL-17A嵌合单抗可以结合人,猴子IL-17A,但不与大鼠,小鼠IL-17A结合,具有种属特异性。同时,如图4所示,抗人IL-17A嵌合单抗还具有很强的结合特异性,仅与IL-17A结合,不与IL-17家族的其他细胞因子,以及不相关细胞因子结合。
实施例5嵌合的抗人IL-17A单抗的体外中和活性
将抗人IL-17A抗体样品稀释于含10%FBS(Hyclone,货号SH30084.03)的DMEM(GIBCO,货号11995-073)完全培养基中,样品起始浓度为160nM(终浓度40nM),5倍序列稀释,每孔50μL,加入细胞培养板中。再向细胞培养板中加入稀释于相同完全培养基的浓度为20ng/mL(终浓度5ng/mL)的人IL-17A,每孔50μL。在37℃,5%CO2培养箱中孵育1小时。然后将HFF-1细胞重悬在完全培养基中,接种到96孔细胞培养板内,100μL每孔,每孔5000个细胞。细胞在37℃,5%CO2培养箱中孵育培养24小时。孵育结束后,将细胞培养板250g离心5分钟,取出培养上清,用人IL-6ELISA试剂盒(R&D systems,货号S6050),按说明书测定人IL-6的水平。
结果如图5所示,抗人IL-17A嵌合单抗具有比secukinumab更强的体外IL-17A中和活性,更强的抑制人IL-17A刺激HFF-1细胞分泌的人IL-6。
实施例6嵌合的抗人IL-17A单抗的体内中和活性
实验材料选用雌性BALB/c小鼠,6-8周龄,购自北京华阜康生物科技股份有限公司。小鼠适应环境一周后,随机分组,每组6只。各组分别给予抗人IL-17A嵌合单抗,对照单抗secukinumab,三个剂量水平0.7nmol/kg,7nmol/kg,70nmol/kg,静脉注射,单次给药。在给药1小时候,皮下注射人IL-17A,每只小鼠10μg。再2小时之后,眼眶采血,不予抗凝,室温放置血样30分钟至1个小时,待凝血后,3000rpm离心10分钟,得到血清样品。采用小鼠CXCL1ELISA试剂盒(RayBiotech,货号ELM-KC),按说明书测定血清中小鼠CXCL1(C-X-CMotif Chemokine Ligand,又名KC)的浓度。
结果如图6所示,抗人IL-17A嵌合单抗能够抑制人IL-17A刺激小鼠分泌的CXCL1的水平,比对照单抗secukinumab显示出了更强的活性。
实施例7嵌合的抗人IL-17A单抗的在大鼠体内的药代动力学研究
实验材料选用雌性SD大鼠,6-8周龄,购自北京华阜康生物科技股份有限公司。大鼠适应环境一周后,随机分组,每组3只。各组分别给予抗人IL-17A嵌合单抗,对照单抗secukinumab,剂量均为20nmol/kg,静脉注射,单次给药。在0点,给药后5分钟,30分钟,1小时、3小时、6小时、10小时、24小时、48小时、72小时、96小时、120小时、168小时、216小时、264小时、312小时眼眶采血,不予抗凝,室温放置血样30分钟至1个小时,待凝血后,3000rpm离心10分钟,得到的血清样品冷冻于-80℃保存,待测。
ELISA测定血清中抗人IL-17A嵌合单抗,对照单抗secukinumab的浓度。简要的说,用pH=9.6的碳酸盐缓冲溶液4℃过夜包被人重组IL-17A蛋白于高吸附酶标板上。PBST洗涤。为了防止非特异性结合,用含5%脱脂奶粉的PBST封闭该板,PBST洗涤。然后加入用含10%混合大鼠血清、1%BSA的PBST稀释的待测血清样品孵育,25℃,1小时,PBST洗涤该板。加入稀释于含5%脱脂奶粉的PBST中的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),25℃,1小时,PBST洗涤该板。最后使用比色底物TMB进行显色,室温显色10分钟。加入1M H2SO4,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图7所示,单次静脉注射的剂量为20nmol/kg的抗人IL-17A嵌合单抗,对照单抗secukinumab,在大鼠体内显示出了相似的药时曲线和药代动力学特征。抗人IL-17A嵌合单抗的药代参数如下:半衰期t1/2为458小时;药时曲线下面积AUClast为44286nM.hr;估算零浓度C0为413nM;表观分布容积Vd为115mL/Kg;清除率CL为0.17mL/hr/kg;平均驻留时间MRTlast为140小时。
实施例8人源化的抗人IL-17A单抗的制备
人源化形式的抗IL-17抗体是根据Leung等人(1995,Molecule Immunol 32:1413-27)产生的,在Germline数据库中选取与其非CDR区匹配最好的人源化模板。其中重链可变区的模板为IGVH4-59*01,序列如SEQ ID NO:35所示。轻链可变区的模板为IGKV2-30*02,序列如SEQ ID NO:36所示。将鼠源抗体CDR区移植到选择的人源化模板上,替换人模板的CDR区。得到移植的人源化抗体重链可变区,序列如SEQ ID NO:37所示,移植的人源化抗体轻链可变区,序列如SEQ ID NO:38所示。通过序列比对选择9个位点进行回复突变,其中重链4个,L4V,I49M,V68I,V72R,轻链5个,D1I,V2I,F41Y,R51L,Y92F。减少回复突变位点数量,构建不同的人源化序列,重链序列及轻链可变区序列如表3所示。将人源化的抗人IL-17A单抗的重链可变区(SEQ ID NO:27-34)与人抗体IgG1重链恒定区(SEQ ID NO:10)连接,分别得到对应的重链全长序列。将人源化的抗人IL-17A单抗的轻链可变区(SEQ ID NO:19-26)与人抗体Kappa轻链的恒定区(SEQ ID NO:9)连接,分别得到对应的轻链全长序列。将重链全长序列与轻链全长序列组合得到人源化抗体全长序列,将全长序列通过EcoRI和HindIII酶切,连接入X0GC载体中。
表3.抗人IL-17A人源化抗体的可变区序列
实施例9人源化的抗人IL-17A单抗的抗原结合活性
用ELISA测定抗人IL-17A人源化单抗的抗原结合活性。用pH=9.6的碳酸盐缓冲溶液在96孔高吸附酶标板上包被重组人IL-17A,购自义翘神州,包被浓度为1μg/mL,包被量为100μL每孔,包被在4℃过夜进行。PBST洗涤5次。用含1%BSA的PBST按300μL/孔封闭,25℃孵育1小时。PBST洗涤5次。加入序列稀释在含1%BSA的PBST里的抗人IL-17A人源化单抗样品以及对照,每孔加入100μL,25℃孵育1小时。PBST洗涤5次。然后加入1:2000稀释在含1%BSA的PBST里的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),每孔加入100μL,25℃孵育1小时。PBST洗涤5次。加入比色底物TMB,100μL/孔,室温显色10分钟。加入1MH2SO4,100μL/孔,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图8所示,抗人IL-17A人源化单抗AS15799,AS15802,AS15803,AS15805,AS15810,AS15815,AS15820均可以结合人IL-17A,具有很高的亲和活性。
实施例10.人源化的抗人IL-17A单抗的体外中和活性
将抗人IL-17A抗体样品稀释于含10%FBS(Hyclone,货号SH30084.03)的DMEM(GIBCO,货号11995-073)完全培养基中,样品起始浓度为160nM(终浓度40nM),5倍序列稀释,每孔50μL,加入细胞培养板中。再向细胞培养板中加入稀释于相同完全培养基的浓度为20ng/mL(终浓度5ng/mL)的人IL-17A,每孔50μL。在37℃,5%CO2培养箱中孵育1小时。然后将HFF-1细胞重悬在完全培养基中,接种到96孔细胞培养板内,100μL每孔,每孔5000个细胞。细胞在37℃,5%CO2培养箱中孵育培养24小时。孵育结束后,将细胞培养板250g离心5分钟,取出培养上清,用人IL-6ELISA试剂盒(R&D systems,货号S6050),按说明书测定人IL-6的水平。
结果如图9所示,抗人IL-17A人源化单抗AS15799,AS15802,AS15803,AS15805,AS15810,AS15815,AS15820具有比secukinumab更强的体外IL-17A中和活性,更强的抑制人IL-17A刺激HFF-1细胞分泌的人IL-6。
实施例11.分子筛高效液相色谱法(SE-HPLC)检测人源化的抗人IL-17A单抗的纯度及其热稳定性
选用的TSKgel SuperSW3000色谱柱(货号:0018675);流动相为0.1mol/L磷酸盐缓冲液
(NaH2PO4-Na2HPO4),0.1mol/L硫酸钠缓冲液,pH 6.7;流速为0.35mL/min;柱温为25℃;样品池温度:4℃;检测波长280nm;用样品缓冲液稀释样品至1mg/mL,上样量为5μg。用Agilent高效液相分析仪1260***工作站对实验结果进行数据处理,用面积归一化法计算主峰比例即为纯度。对上述制备的人源化的抗人IL-17A单抗进行了SE-HPLC纯度检测。为了确定这些单抗的热稳定性,将上述样品置于40℃高温条件下,
在第2周和第4周分别取样进行SE-HPLC检测以观察热稳定性,结果如下表所示。
表4.SE-HPLC检测人源化的抗人IL-17A单抗在40℃条件下的热稳定性
实施例12.人源化的抗人IL-17A单抗Tm值的测定
采用差示扫描荧光法(Differential scanning fluorimetry,DSF)测定人源化的抗人IL-17A单抗的变性温度(Tm)。DSF是一种利用荧光指示剂的荧光强度改变来检测样品中蛋白热变性过程的方法,实现蛋白变性温度的测定。选用的试剂为SYPRO Orange蛋白质荧光染料(货号:S5692,5000倍浓度,溶剂为DMSO)购自美国Sigma-Aldrich公司。仪器为AB7500Real Time PCR仪购自美国Applied Biosystems公司。将蛋白质荧光染料按1:50用样品缓冲液进行稀释,取1μl稀释后染料分别与19μl蛋白溶液混合,荧光染料终稀释度为1:1000,加入96孔板中,每个样品设三个平行孔。用光学封板膜封板,1000rpm离心2min,去除气泡。RT-PCR仪器设置如下:熔解曲线,采用连续模式,扫描温度范围为25~99℃,升温速率为1%(约1℃/min),25℃平衡2min,在升温过程中采集数据,报告基团选择ROX,淬灭基团选择None,反应体积20μl。样品测定浓度为1mg/ml,参比溶液为样品缓冲液。采用ProteinThermal ShiftTMSoftware v1.3软件绘制荧光曲线及其一阶导数图。DSF试验中,通常以蛋白第1个转变中点温度作为蛋白制剂热稳定性的变性温度。如下表所示,对上述制备的人源化的抗人IL-17A单抗进行了Tm值测定。
表5.人源化的抗人IL-17A单抗的Tm值
人源化的抗人IL-17A单抗 | Tm值 |
AS15802 | 67.2℃ |
AS15803 | 68.3℃ |
AS15810 | 67.9℃ |
AS15815 | 69.3℃ |
AS15820 | 67.7℃ |
实施例13.离子交换色谱法(CEX)检测人源化的抗人IL-17A单抗的电荷异构体
采用阳离子交换色谱柱MabPac SCX-10,4mm×250mm(货号:78655),以20mmol/L吗啉乙磺酸【2-(N-Morpholino)ethanesulfonic acid,MES】(pH5.6)和60mmol/L氯化钠为流动相A;以20mmol/L MES(pH5.6)和300mmol/L氯化钠为流动相B;流速为0.5mL/min;柱温为25℃;样品池温度:4℃;检测波长为280nm;样品上样量为50μl(1mg/mL);洗脱为5~50%线性梯度运行60分钟。用Agilent高效液相分析仪1260***工作站对实验结果进行数据处理,用面积归一化法计算峰面积百分比。对上述制备的人源化的抗人IL-17A单抗进行了CEX检测。为了确定这些单抗的化学稳定性,将上述样品置于40℃高温条件下,在第2周和第4周分别取样进行CEX检测,观察电荷变异体比例的变化,结果如表6所示。
表6.CEX检测人源化的抗人IL-17A单抗在40℃条件下电荷变异体的变化
实施例14.人源化的抗人IL-17A单抗在低pH病毒灭活条件下的稳定性
取测试样品200μg分别用1mol/L柠檬酸母液将pH调整到3.4±0.05,样品最终浓度为1mg/mL。室温下放置,分别在0,1,2,4及6小时取样,用2mol/LTris-HCl pH 9.5母液将pH调至7.5。样品用上述SEC方法进行分析,结果如表7所示。
表7.SE-HPLC检测人源化的抗人IL-17A单抗在低pH条件下的稳定性
实施例15.人源化的抗人IL-17A单抗的在大鼠体内的药代动力学研究
实验材料选用雌性SD大鼠,6-8周龄,购自北京华阜康生物科技股份有限公司。大鼠适应环境一周后,随机分组,每组3只。各组分别给予不同的抗人IL-17A人源化单抗、对照抗体,剂量均为15nmol/kg,皮下注射,单次给药。在0点,给药后1小时、4小时、8小时、24小时、48小时、72小时、96小时、120小时、168小时、216小时、264小时、312小时,360小时、408小时、480小时眼眶采血,不予抗凝,室温放置血样30分钟至1个小时,待凝血后,3000rpm离心10分钟,得到的血清样品冷冻于-80℃保存,待测。
ELISA测定血清中抗人IL-17A人源化单抗、对照抗体的浓度。简要的说,用pH=9.6的碳酸盐缓冲溶液4℃过夜包被人重组IL-17A蛋白于高吸附酶标板上。PBST洗涤。为了防止非特异性结合,用含5%脱脂奶粉的PBST封闭该板,PBST洗涤。然后加入用含10%混合大鼠血清、1%BSA的PBST稀释的待测血清样品孵育,25℃,1小时,PBST洗涤该板。加入稀释于含5%脱脂奶粉的PBST中的辣根过氧化物酶标记的抗人IgG抗体(Chemicon,货号AP309P),25℃,1小时,PBST洗涤该板。最后使用比色底物TMB进行显色,室温显色10分钟。加入1M H2SO4,终止显色。在酶标仪上读取450nm处的吸光度。
结果如图10所示,单次皮下注射的剂量为15nmol/kg的不同的抗人IL-17A人源化单抗,对照单抗secukinumab,对照单抗ixekizumab,在大鼠体内显示出了相似的药时曲线和药代动力学特征。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,但本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
SEQUENCE LISTING
<110> 北京韩美药品有限公司
<120> 一种能够特异性地结合IL-17A的抗体及其功能片段
<150> CN2016108270972
<151> 2016-09-14
<160> 38
<170> PatentIn version 3.3
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Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 21
<211> 111
<212> PRT
<213> 人工序列
<400> 21
Ile Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 22
<211> 111
<212> PRT
<213> 人工序列
<400> 22
Ile Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 23
<211> 111
<212> PRT
<213> 人工序列
<400> 23
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 24
<211> 111
<212> PRT
<213> 人工序列
<400> 24
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 25
<211> 111
<212> PRT
<213> 人工序列
<400> 25
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 26
<211> 111
<212> PRT
<213> 人工序列
<400> 26
Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Tyr Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Phe Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
<210> 27
<211> 120
<212> PRT
<213> 人工序列
<400> 27
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 28
<211> 120
<212> PRT
<213> 人工序列
<400> 28
Asp Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Ser Leu Ser Leu Thr Cys Thr Val Thr Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe
65 70 75 80
Leu Gln Leu Asn Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 29
<211> 120
<212> PRT
<213> 人工序列
<400> 29
Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 30
<211> 120
<212> PRT
<213> 人工序列
<400> 30
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 31
<211> 120
<212> PRT
<213> 人工序列
<400> 31
Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 32
<211> 120
<212> PRT
<213> 人工序列
<400> 32
Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Ile Thr Ile Ser Arg Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 33
<211> 120
<212> PRT
<213> 人工序列
<400> 33
Gln Val Gln Val Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 34
<211> 120
<212> PRT
<213> 人工序列
<400> 34
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Met Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 35
<211> 98
<212> PRT
<213> 人工序列
<220>
<221> misc_feature
<222> (98)..(98)
<223> Xaa can be any naturally occurring amino acid
<400> 35
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr
20 25 30
Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Xaa
<210> 36
<211> 101
<212> PRT
<213> 人工序列
<400> 36
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asp Gly Asn Thr Tyr Leu Asn Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Ser Asn Arg Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Gly
85 90 95
Thr His Trp Pro Pro
100
<210> 37
<211> 120
<212> PRT
<213> 人工序列
<400> 37
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asn Ser Ile Thr Ser Tyr
20 25 30
Tyr Ala Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
35 40 45
Ile Gly Tyr Ile Thr Tyr Ser Gly Thr Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser
65 70 75 80
Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Glu Tyr Asp Asp Ile Tyr Ala Val Asp Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 38
<211> 111
<212> PRT
<213> 人工序列
<400> 38
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser
20 25 30
Asn Gly Asn Thr Tyr Leu His Trp Phe Gln Gln Arg Pro Gly Gln Ser
35 40 45
Pro Arg Arg Leu Ile Tyr Lys Val Tyr Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Phe Pro Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 110
Claims (14)
1.一种能够特异性地结合IL-17A的抗体及其功能片段,其特征在于,所述抗体及其功能片段包含轻链和重链;
所述轻链具有由CDR-L1、CDR-L2、CDR-L3组成的轻链CDR;所述重链具有由CDR-H1、CDR-H2、CDR-H3组成的重链CDR;
所述CDR-L1、CDR-L2、CDR-L3的氨基酸序列分别如SEQ ID NO:1、2和3所示;所述CDR-H1、CDR-H2、CDR-H3的氨基酸序列分别如SEQ ID NO:4、5和6所示;
优选的,所述抗体及其功能片段包括IL-17A嵌合抗体及其功能片段及IL-17A人源化抗体及其功能片段。
2.根据权利要求1所述的抗体及其功能片段,其特征在于,所述抗体包含人抗体IgG1、IgG2、IgG3、IgG4、IgA、IgM、IgE、IgD任何其中之一恒定区的序列。
3.根据权利要求1所述的抗体及其功能片段,其特征在于,所述功能片段包括F(ab’)2、Fab’、Fab、Fv、scFv、双特异抗体和抗体最小识别单位中的一种或多种。
4.根据权利要求1所述的抗体及其功能片段,其特征在于,所述IL-17A嵌合抗体及其功能片段的轻链可变区序列和重链可变区序列的氨基酸序列分别如SEQ ID NO:7和SEQ IDNO:8所示;
优选的,所述IL-17A嵌合抗体及其功能片段的轻链恒定区序列和重链恒定区序列的氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10所示。
5.根据权利要求1所述的抗体及其功能片段,其特征在于,所述IL-17A人源化抗体及其功能片段的轻链骨架区包括FR-L1、FR-L2、FR-L3及FR-L4,重链骨架区包括FR-H1、FR-H2、FR-H3及FR-H4;
所述FR-L1选自SEQ ID NO:11所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第1个氨基酸替换为I;
第2个氨基酸替换为I;
所述FR-L2选自SEQ ID NO:12所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第4个氨基酸替换为Y;
第14个氨基酸替换为L;
所述FR-L3选自SEQ ID NO:13所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第35个氨基酸替换为F;
所述FR-L4选自SEQ ID NO:14所示的氨基酸序列;
所述FR-H1选自SEQ ID NO:15所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第4个氨基酸替换为V;
所述FR-H2选自SEQ ID NO:16所示的氨基酸序列,或经过以下取代所得到的氨基酸序列:
第15个氨基酸替换为M;
所述FR-H3选自SEQ ID NO:17所示的氨基酸序列,或经过以下取代及其组合所得到的氨基酸序列:
第2个氨基酸替换为I;
第6个氨基酸替换为R;
所述FR-H4选自SEQ ID NO:18所示的氨基酸序列;
优选的,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:19-26任一项所示;
优选的,所述IL-17A人源化抗体及其功能片段的重链可变区序列如SEQ ID NO:27-34任一项所示;
更优选的,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:19所示;其对应的重链可变区序列如SEQ ID NO:27所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:20所示;其对应的重链可变区序列如SEQ ID NO:28所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:21所示;其对应的重链可变区序列如SEQ ID NO:29所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:22所示;其对应的重链可变区序列如SEQ ID NO:30所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:22所示;其对应的重链可变区序列如SEQ ID NO:31所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:23所示;其对应的重链可变区序列如SEQ ID NO:32所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:24所示;其对应的重链可变区序列如SEQ ID NO:33所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:25所示;其对应的重链可变区序列如SEQ ID NO:32所示;
或,所述IL-17A人源化抗体及其功能片段的轻链可变区序列如SEQ ID NO:26所示;其对应的重链可变区序列如SEQ ID NO:34所示;
更优选的,所述IL-17A人源化抗体及其功能片段的轻链恒定区序列和重链恒定区序列的氨基酸序列分别如SEQ ID NO:9和SEQ ID NO:10所示。
6.一种分离的核酸分子,其特征在于,所述核酸分子选自如下核酸:
A)、DNA或RNA,其编码权利要求1~5任一项所述的抗体及其功能片段;
B)、与A)中定义的核酸互补的核酸。
7.一种载体,其包括权利要求6所述的核酸。
8.一种宿主细胞,其被权利要求7所述的载体转化。
9.一种生产能够特异性地结合IL-17A的抗体及其功能片段的方法,其特征在于,包括如下步骤:
在培养基中和合适的培养条件下培养权利要求8所述的宿主细胞;
从培养基中或从所培养的宿主细胞中回收如此产生的抗体及其功能片段。
10.一种组合物,其特征在于,所述组合物以权利要求1~5任一项所述的抗体及其功能片段、或它们与其他成分组成的化合物作为活性成分。
11.根据权利要求10所述的组合物,其特征在于,所述抗体及其功能片段与至少一种诊断剂和/或治疗剂偶联以形成免疫偶联物。
12.根据权利要求11所述的组合物,其特征在于,所述诊断剂选自:
放射性核素、放射性造影剂、顺磁离子、金属、荧光标记、化学发光标记物、超声造影剂、光敏剂中的一种或多种;
优选的,所述所述放射性核素包括110In、111In、177Lu、18F、52Fe、62Cu、64Cu、67Cu、67Ga、68Ga、86Y、90Y、89Zr、94mTc、94Tc、99mTc、120I、123I、124I、125I、131I、154-158Gd、32P、11C、13N、15O、186Re、188Re、51Mn、52mMn、55Co、72As、75Br、76Br、82mRb和83Sr中的一种或多种;
优选的,所述顺磁离子包括铬(III)、锰(II)、铁(III)、铁(II)、钴(II)、镍(II)、铜(II)、钕(III)、钐(III)、镱(III)、钆(III)、钒(II)、铽(III)、镝(III)、钬(III)和铒(III)中的一种或多种;
优选的,所述荧光标记包括Alexa 350、Alexa 405、Alexa 430、Alexa 488、Alexa 555、Alexa 647、AMCA、氨基吖啶、BODIPY630/650、BODIPY 650/665、BODIPY-FL、BODIPY-R6G、BODIPY-TMR、BODIPY-TRX、5-羧基-4′,5′-二氯-2′,7′-二甲氧基荧光素、5-羧基-2′,4′,5′,7′-四氯荧光素、5-羧基荧光素、5-羧基罗丹明、6-羧基罗丹明、6-羧基四甲基罗丹明、Cascade Blue、Cy2、Cy3、Cy5、Cy7、6-FAM、丹磺酰氯、荧光素、HEX、6-JOE、NBD(7-硝基苯并-2-氧杂-1,3-二唑)、Oregon Green 488、Oregon Green 500、Oregon Green514、PacificBlue、邻苯二甲酸、对苯二甲酸、间苯二甲酸、甲酚固紫、甲酚蓝紫、亮甲酚蓝、对氨基苯甲酸、赤藓红、酞菁、偶氮甲碱、花青、黄嘌呤、琥珀酰荧光素、稀土金属穴状化合物、三双吡啶基二胺铕、铕穴状化合物或螯合物、二胺、双花青苷、La Jolla蓝染料、别藻蓝蛋白、allococyanin B、藻蓝蛋白C、藻蓝蛋白R、硫胺、藻红青蛋白、藻红蛋白R、REG、罗丹明绿、罗丹明异硫氰酸酯、罗丹明红、ROX、TAMRA、TET、TRIT(四甲基罗丹明异硫醇)、四甲基罗丹明和德克萨斯红中的一种或多种。
13.根据权利要求11所述的组合物,其特征在于,所述治疗剂选自:裸抗体、细胞毒素剂、药物、放射性核素、硼原子、免疫调节剂、抗凋亡试剂、光敏性治疗剂、免疫偶联物、寡核苷酸中的一种或多种;
优选的,所述药物选自***、双氯芬酸、萘丁美酮、美洛昔康、塞来昔布、甲氨蝶呤、环磷酰胺、硫唑嘌呤、环孢素A、长春新碱中的一种或多种;
优选的,所述寡核苷酸选自shRNA、miRNA和siRNA中的一种或多种;
优选的,所述免疫调节剂选自:细胞因子、趋化因子、干细胞生长因子、淋巴毒素、造血因子、集落刺激因子(CSF)、干扰素、***、促血小板生成素、肿瘤坏死因子(TNF)、白介素(IL)、粒细胞-集落刺激因子(G-CSF)、粒细胞巨噬细胞-集落刺激因子(GM-CSF)和干细胞生长因子中的一种或多种;
优选的,所述放射性核素选自111In、111At、177Lu、211Bi、212Bi、213Bi、211At、62Cu、67Cu、90Y、125I、131I、133I、32P、33P、47Sc、111Ag、67Ga、153Sm、161Tb、152Dy、166Dy、161Ho、166Ho、186Re、188Re、189Re、211Pb、212Pb、223Ra、225Ac、77As、89Sr、99Mo、105Rh、149Pm、169Er、194Ir、58Co、80mBr、99mTc、103mRh、109Pt、119Sb、189mOs、192Ir、219Rn、215Po、221Fr、255Fm、11C、13N、15O、75Br、198Au、199Au、224Ac、77Br、113mIn、95Ru、97Ru、103Ru、105Ru、107Hg、203Hg、121mTe、122mTe、125mTe、165Tm、167Tm、168Tm、197Pt、109Pd、142Pr、143Pr、161Tb、57Co、58Co、51Cr、59Fe、75Se、201Tl、76Br和169Yb中的一种或多种。
14.权利要求10~13所述的组合物在制备用于预防和/或治疗与IL-17A过量表达和/或释放相关的疾病的药物中的应用;
优选的,所述疾病包括:气道炎症、哮喘、支气管哮喘、过敏性哮喘、慢性阻塞性肺病、特发性肺纤维化、类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、银屑病、多发性硬化症、***性硬化症、***性红斑狼疮、狼疮肾炎、硬皮病、溃疡性结肠炎、炎性肠病、葡萄膜炎、幽门螺杆菌相关性胃炎、骨质疏松、骨质侵蚀、腹膜内脓肿和粘连、艾迪生氏病、丙种球蛋白缺乏症、斑秃、乳糜泻、查加斯病,克隆氏病、同种异体移植排斥、***、败血症、脓毒性或内毒素性休克、缺血。
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