CN111662381B - 人IL-1β蛋白结合分子及其编码基因和应用 - Google Patents
人IL-1β蛋白结合分子及其编码基因和应用 Download PDFInfo
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Abstract
本发明公开了一种人IL‑1β蛋白结合分子及其编码基因和应用。该人IL‑1β蛋白结合分子具有与人IL‑1β蛋白特异结合的抗原结合位点,抗原结合位点含有至少一个重链可变区和至少一个轻链可变区,重链可变区具有三个重链互补决定区,三个重链互补决定区的氨基酸序列选自SEQ ID No.11‑17,轻链可变区具有三个轻链互补决定区,三个轻链互补决定区的氨基酸序列选自SEQ ID No.28‑33。本申请的人IL‑1β蛋白结合分子是新型的抗体分子序列,具有高亲和力和高阻断活性,具有很大的疾病治疗价值。
Description
技术领域
本发明属于生物制药技术领域,具体涉及一种人IL-1β蛋白结合分子及其编 码基因和应用。
背景技术
IL-1β是IL-1家族众多成员中研究的最为深入的成员。包括免疫细胞(如 单核细胞和巨噬细胞)在内的很多细胞都可以产生并分泌。IL-1β的释放大致分 为3个步骤:i)无活性前体的产生;ii)前体的成熟活化;iii)活化蛋白向胞外 的分泌。IL-1β初始产生时是一个31KD的前体,接着裂解活化产生17KD的 成熟形式,这样才可以与IL-1受体结合。Caspase-1是主要的裂解蛋白,其可 以在IL-1β上两个位点进行切割(D26位和D116位),从而得到26KD的前 蛋白和17KD的成熟形式蛋白。此外,其他的一些蛋白酶如PR-3,Neutrophil elastase等也能切割IL-1β(Andrei C,Margiocco P,Poggi A,etal.Phospholipases C and A2control lysosome-mediated IL-1βsecretion:Implications for inflammatory processes[J].Proceedings of the NationalAcademy of Sciences of the United States of America,2004,101(26):9745-9750;Van Damme J,De Ley M,Opdenakker G,et al.Homogeneous interferon-inducing 22Kfactor is related to endogenous pyrogen and interleukin-1.[J].Nature,1985,314(6008):266-268;Zsebo K M,Wypych J, Yuschenkoff V N,et al.Effects ofHematopoietin-1and Interleukin 1Activities on Early Hematopoietic Cells ofthe Bone Marrow[J].Blood,1988,71(4):962-968)。
IL-1β具有很强的生物学活性,包括:(1)介导炎症反应:IL-1β不仅本身能 够引起炎症反应,而且可以诱导环氧化酶2(cyclooxygenase-2,COX-2)、iNOS、 IL-6等其他炎症因子的表达,从而进一步激活基质细胞和免疫细胞产生更多的 IL-1β参与炎症反应;(2)免疫调节作用,协同刺激I细胞,诱导许多细胞产生其 他淋巴因子;(3)参与恶液质的形成,有致负氮平衡的效应,可以刺激骨骼肌分 解蛋白质;(4)诱导急性时相蛋白,参与急性期反应;(5)诱导成纤维细胞增殖等。
白介素IL-1β释放是早期炎症反应的关键因子,IL-1β与受体IL-1RI结合后 与辅助受体IL-1RAcP作用形成IL-1beta/IL-1RI/IL-1RAcP三元复合物,激活靶 细胞内的NF-κB和MAPKs信号通路,从而诱导一系列炎症相关分子的表达。 有大量的基础和临床数据显示IL-1分泌在急性痛风中起关键作用,通过与细胞 因子或其受体结合阻断IL-1的治疗是减少炎症风暴的策略。抑制IL-1分泌是可 行的,并且已经有许多IL-1抑制剂可用,因此它可以补充可用的方法来缓解急 性痛风发作(So A,Dumusc A,Nasi S,et al.The role ofIL-1in gout:from bench to bedside[J].Rheumatology,2018)。
慢阻肺患者气道中IL-1β和系统炎症与频繁急性加重相关,并可能通过恶性 循环来介导既往和未来的急性加重。(Fu J,Mcdonald V M,Baines K J,et al. Airway IL-1βand Systemic Inflammation as Predictors of Future Exacerbation Risk in Asthmaand COPD[J].Chest,2015,148(3):618-629)。此外,IL-1β通过促进癌 症干细胞和上皮细胞间质转化来支持转移。IL-1β还可以参与Th17分化,参与 Th17相关细胞因子的产生。(Tominaga K,Yoshimoto T,Torigoe K,et al.IL-12 synergizes with IL-18or IL-1βfor IFN-γproduction from human T cells[J]. International Immunology,2000,12(2):151-160)。
IL-1β在慢性局部炎症过度表达,也会促进肿瘤发生转化。IL-1β在癌症发 生的晚期具有重要作用,可以在肿瘤微环境中产生,并通过与血管生成因子(如VEGF)的细胞信号传导相互作用驱动血管生成,实现肿瘤转移扩散(Voronov E, Carmi Y,Apte R N,etal.The role IL-1in tumor-mediated angiogenesis[J].Frontiers in Physiology,2014:114-114)。此外,吸入肺部的硅石或石棉等异物可通过激活 白介素-1β等促炎症细胞因子引起肺癌,而且IL-1β可以可诱导肿瘤细胞分泌内 源性TNF-α促进肿瘤生长。因此,抑制IL-1β表达也可以达到预防和治疗肿瘤 的作用。
阻断炎症因子的释放可以比较有效的进行抗炎症治疗。针对IL-1β细胞因 子,抗IL-1β抗体可以阻断IL-1β与其受体的结合,阻断下游的信号传导。诺华 公司的卡纳单抗(Canakinumab,商品名Ilaris)是一种全人源高亲和力抗IL-1β 抗体,最初卡纳单抗被批准用于2岁及以上儿童幼年特发性关节炎治疗。基于 两项国际随机、安慰剂对照试验,显示了卡纳单抗对幼年特发性关节炎的疗效。 在试验1中,单次注射卡纳单抗后,33%患者在15天内出现无疾病活动。试验 2证实了这些结果,在治疗2年后,82%的患者具有持续疗效(Vanoni F,Minoia F,Malattia C,et al.Biologics in juvenile idiopathicarthritis:a narrative review.[J]. European Journal of Pediatrics,2017,176(9):1147-1153)。随着研究的深入,卡纳 单抗在痛风、动脉粥样硬化、冠心病、肺癌等疾病领域都取得了临床试验的成 功。
从新型的治疗性抗体分子、提高药物疗效、降低病人使用成本等方面考量, 开发新的抗IL-1β抗体仍然有其必要性。
发明内容
本申请的发明目的是提供一种新型的人IL-1β蛋白结合分子。
为实现上述发明目的,本申请的技术方案如下:
一种人IL-1β蛋白结合分子,所述的人IL-1β蛋白结合分子具有与人IL-1β 蛋白特异结合的抗原结合位点,该抗原结合位点含有至少一个重链可变区和至 少一个轻链可变区,所述的重链可变区具有三个重链互补决定区,三个重链互 补决定区的氨基酸序列选自SEQ ID No.11-17;所述的轻链可变区具有三个轻链 互补决定区,三个轻链互补决定区的氨基酸序列选自SEQ ID No.28-33。
本申请以市售的重组人IL-1β蛋白(novoprotein,CG93)作为抗原免疫小 鼠,取免疫小鼠的脾细胞与小鼠骨髓瘤细胞融合制备杂交瘤细胞以表达鼠源人 IL-1β多抗,从鼠源人IL-1β多抗中筛选具有优良阻断功能的鼠源人IL-1β单抗, 然后根据鼠源人IL-1β单抗的重链可变区和轻链可变区氨基酸序列,结合人抗体 恒定区序列设计人鼠嵌合抗体,经人源化改造后获得了本申请的人IL-1β蛋白结 合分子,该人IL-1β蛋白结合分子能够特异性结合人IL-1β蛋白,阻断IL-6的分 泌水平,具有与卡纳单抗(Canakinumab,商品名Ilaris)相当的功能抑制活性, 而与全人源化的卡纳单抗相比,本申请的人IL-1β蛋白结合分子是一个全新序列 的抗体分子,具有高亲和力和高阻断活性,具有很大的疾病治疗价值。
在上述的人IL-1β蛋白结合分子中,三个重链互补决定区的氨基酸序列依次 如SEQ ID No.15、SEQ ID No.16和SEQ ID No.17所示,三个轻链可变区的氨基 酸序列依次如SEQ ID No.31、SEQ ID No.32和SEQ ID No.33所示。
或者,三个重链互补决定区的氨基酸序列依次如SEQ ID No.11、SEQ ID No.12和SEQ ID No.13所示,三个轻链可变区的氨基酸序列依次如SEQ ID No.28、SEQ ID No.29和SEQ ID No.30所示。
在上述的人IL-1β蛋白结合分子中,重链可变区的重链框架区以及轻链可变 区的轻链框架区均来自于人的抗体胚系基因序列或与人的抗体胚系基因序列具 有至少90%同源性的基因序列。
作为优选,所述的重链可变区具有四个重链框架区,四个重链框架区的氨 基酸序列选自SEQ ID No.1-10。作为进一步优选,四个重链框架区的氨基酸序 列依次如SEQ IDNo.1、SEQ ID No.2、SEQ ID No.5和SEQ ID No.6所示。
作为优选,所述的轻链可变区具有四个轻链框架区,四个轻链框架区的氨 基酸序列选自SEQ ID No.18-27。作为进一步优选,四个轻链框架区的氨基酸序 列依次如SEQ IDNo.18、SEQ ID No.20、SEQ ID No.21和SEQ ID No.23所示。
本申请的人IL-1β蛋白结合分子可以是人源化的嵌合抗体,也可以是抗原结 合片段或单链抗体可变区片段。其中,嵌合抗体的抗体亚型优选为IgG1、IgG2 或IgG4。
嵌合抗体和抗原结合片段除了具有重链可变区和轻链可变区外,还具有重 链恒定区和轻链恒定区(氨基酸序列如SEQ ID No.35所示),区别在于:抗原结 合片段仅具有重链恒定区1,且重链恒定区1与轻链恒定区通过链间二硫键相连; 而嵌合抗体则具有完整的重链恒定区:重链恒定区1-铰链区-重链恒定区2-重链 恒定区3(氨基酸序列如SEQ IDNo.34所示);而在单链抗体可变区片段中,重 链可变区和轻链可变区直接通过-(GGGGS)3-短肽相连。
本申请还提供了编码所述的人IL-1β蛋白结合分子的核苷酸分子,以及含有 所述的核苷酸分子的表达载体和重组细胞,该重组细胞可以是原核细胞或真核 细胞,如CHO细胞、293细胞、大肠杆菌细胞和酵母细胞等,在构件不同的重 组细胞时,可以根据不同细胞的密码子偏好对所述的人IL-1β蛋白结合分子的密 码子进行优化,进而获得相应的核苷酸分子。
本申请还提供了所述的人IL-1β蛋白结合分子在制备IL-1介导型疾病治疗 药物中的应用,其中,所述的IL-1介导型疾病包括自身免疫相关疾病,如幼年 特发性关节炎、痛风、哮喘、免疫性脑脊髓炎、炎症性肠病、银屑病、白癜风、 糖尿病、动脉粥样硬化、系统性红斑狼疮、硬皮病、皮肌炎、胰腺炎、肾炎、 慢性阻碍性肺病、肺纤维化;以及癌症,如胃癌、肝癌、胰腺癌、结肠癌、直 肠癌、肺癌、膀胱癌,前列腺癌、宫颈癌、卵巢癌、输卵管癌、乳腺癌、白血 病、淋巴瘤、骨髓瘤、神经胶质瘤和骨肉瘤。
上述的IL-1介导型疾病治疗药物可以单独使用也可以与其他对症药物联 用,优选以注射制剂的形式使用。
本申请还提供了所述的人IL-1β蛋白结合分子在制备双特异性抗体中的应 用,在用于制备双特异性抗体时,所述的人IL-1β蛋白结合分子应以人源化的抗 原结合片段或单链抗体可变区片段的形式作为双特异性抗体的其中一个结合 臂。
与现有技术相比,本申请的有益效果体现在:
本申请以市售的重组人IL-1β蛋白(novoprotein,CG93)作为抗原免疫小 鼠,取免疫小鼠的脾细胞与小鼠骨髓瘤细胞融合制备杂交瘤细胞以表达鼠源人 IL-1β多抗,从鼠源人IL-1β多抗中筛选具有优良阻断功能的鼠源人IL-1β单抗, 然后根据鼠源人IL-1β单抗的重链可变区和轻链可变区氨基酸序列,结合人抗体 恒定区序列设计人鼠嵌合抗体,经人源化改造后获得了本申请的人IL-1β蛋白结 合分子,该人IL-1β蛋白结合分子能够特异性结合人IL-1β蛋白,阻断IL-6的分 泌水平,具有与卡纳单抗(Canakinumab,商品名Ilaris)相当的功能抑制活性; 本申请的抗人IL-1β蛋白抗体是新型的抗体分子序列,具有高亲和力和高阻断活 性,具有很大的疾病治疗价值。
附图说明
图1为各亚克隆杂交瘤细胞培养上清抑制IL6因子释放实验结果一;
图2为各亚克隆杂交瘤细胞培养上清抑制IL6因子释放实验结果二;
图1和图2中,“Sample”表示亚克隆杂交瘤细胞培养上清样本, “inhibition%”表示亚克隆杂交瘤细胞培养上清抑制IL6因子释放的抑制率 (%);
图3为抗IL-1β人鼠嵌合抗体抑制IL6因子释放的IC50测定结果;
图3中,“Ab conc.(nM)”表示抗体浓度(nM),“IL-6(pg/ml)”表示IL6的 分泌水平(pg/ml),A13-8、A13-60、B8-8、B27-4、C20-2表示不同抗IL-1β人 鼠嵌合抗体,CAN和IgG1分别为阳性对照抗体和阴性对照抗体。
具体实施方式
下面结合附图和具体实施方式对本发明的技术方案做进一步详细说明。
实施例1制备IL-1β鼠单抗
为了生成针对IL-1β的鼠抗,用市售的重组人IL-1β(novoprotein,CG93) 作为抗原,免疫BALB/c小鼠,然后通过ELISA筛选血浆效价,筛选出具有抗 重组人IL-1β免疫球蛋白最高滴度的小鼠进行杂交瘤融合。具体步骤如下:
(1)免疫小鼠
首先,每只小鼠使用50μg重组人IL-1β皮下免疫BALB/c小鼠(共5只), 然后,交替使用Gold Adjuvant liquid(Sigma,T2684)和Alum Adjuvant(Thermo,77161)皮下免疫BALB/c小鼠(共免疫5次)。
(2)血浆效价检测
将免疫小鼠剪尾取血,通过ELISA筛选血浆效价,以对各免疫小鼠的免疫 应答进行检测,筛选出具有抗重组人IL-1β免疫球蛋白最高滴度的小鼠。
用1μg/ml的重组人IL-1β包被ELISA板,每孔100μl于4℃过夜孵育;用 200μl/孔PBS/Tween(0.1%)洗板,随后用200μl/孔PBS/Tween(0.1%)中的3%牛 血清白蛋白进行封闭1小时;洗板后,每孔加入来自重组人IL-1β免疫小鼠血清 稀释液,37℃孵育2小时,洗板;然后用稀释后的带HRP山羊抗小鼠IgG(H+L) (北京博奥龙免疫技术有限公司,BF03001)抗体37℃孵育1小时;洗涤后,每 孔用100μl TMB显色液(Biopanda,TMB-S-002)显色;颜色变化后加入50μl 2M 硫酸终止反应,之后于酶标仪OD450nm-620nm通过酶标仪进行分析。效价检测 结果见表1。
表1各BALB/c小鼠免疫效价
(3)杂交瘤细胞的融合
根据表1的检测结果,选取具有抗重组人IL-1β免疫球蛋白较高滴度的小鼠 进行融合,融合前先对小鼠作抗原腹腔加强免疫,连续加强免疫3天后,处死 小鼠并取出脾脏,然后利用电融合法将分离自BALB/c小鼠的小鼠脾细胞与小鼠 骨髓瘤细胞系融合(共3次融合),获得能够分泌表达抗人IL-1β鼠多抗的杂交 瘤细胞。融合方法包括:
将来自小鼠脾脏的B细胞与sp2/0细胞按1:1-1:2的比例混匀,离心之后去 上清,用10ml Medium C(BTX,47-0001)重悬细胞清洗2次,之后用Medium C 调整细胞密度为1×107/ml进行电融合。
将融合后的细胞以2×104/孔铺在96孔板,之后在选择性培养基中温育4-7 天,该选择性培养基是在RPMI Medium 1640(Gibco,11875-093)加入终浓度为 1×Penicillin-Streptomycin(Gibco,15140122),终浓度为 1×GlutaMax-100×(Gibco,35050-061),终浓度为1×HAT(Gibco,21060-017),终 浓度为1×HyMax-20×(Gibco,113004),以及终浓度为20%的胎牛血清;4-7天后 用HT替换HAT进行培养。
(4)亚克隆筛选
杂交瘤细胞培养10-14天后,通过ELISA(方法步骤参考步骤(2))对96 孔板各个孔内的培养液进行IL-1β鼠多抗筛选;然后利用有限稀释法,将对应阳 性孔内的母克隆(OD>0.2)按照0.8/孔的细胞数目进行亚克隆铺板;10天后检 测杂交瘤细胞培养基上清,将对应阳性孔的亚克隆(OD>0.2)转移至24孔板中 生成小量抗体用于进一步表征。
(5)抗IL-1β杂交瘤上清的体外功能筛选
根据IL-1β可刺激MRC-5(人胚胎成纤维细胞)产生IL-6的原理,应用ELISA 方法检测IL-6的表达水平来间接反映抗体的阻断功能。
当MRC-5细胞达到60%的汇合度时,胰酶消化,之后用培养基重悬调整 MRC-5细胞密度为2×104;在96孔平底板中加入50μl的MRC-5细胞,之后加 入25μl的杂交瘤细胞上清(即步骤(4)中筛选出的亚克隆)以及对照抗体(所 有样本作1:1和1:10两个稀释倍数),加入25μl稀释过的hIL-1β,于37℃、5% CO2培养箱中孵育18-24小时;之后收集上清,用ELISA试剂盒检测IL-6的分 泌水平,在540nm处读取吸光度值。检测结果见图1和图2。
由图1和图2可见,各亚克隆杂交瘤细胞所分泌的抗体均表现出不同的阻 断功能,本实施例选取其中阻断功能较好的A13-8、A13-60、B8-8、B27-4和 C20-2亚克隆进行基因测序以及抗IL-1β人鼠嵌合抗体的构建。
实施例2抗IL-1β人鼠嵌合抗体的构建及表达纯化
收集扩大培养的亚克隆杂交瘤细胞,提取mRNA,逆转录成cDNA,经PCR 扩增、克隆和测序,分别获得A13-8、A13-60、B8-8、B27-4和C20-2亚克隆表 达的抗IL-1β鼠单抗的可变区序列如表2所示:
表2各抗IL-1β鼠单抗的可变区序列
在各可变区序列前添加信号肽序列(如SEQ ID No.48所示),并在重链可变 区序列后添加重链恒定区序列(如SEQ ID No.34所示),在轻链可变区序列后添 加轻链恒定区序列(如SEQ ID No.35所示),然后在重链恒定区序列和轻链恒定 区序列后添加TGA终止密码子;根据设计的重链和轻链氨基酸序列合成相应的 基因序列,并将合成的基因序列构建至真核细胞表达载体中。
阳性对照抗体CAN的重轻链氨基酸序列来自美国专利US20040063913,具 体的序列信息为SEQ ID No.36和SEQ ID No.37所示,同样地,在CAN氨基酸 序列前添加信号肽、氨基酸序列后添加TGA终止密码子后进行对应的基因序列 合成与真核细胞表达载体构建。基因合成与载体构建由苏州泓迅生物科技股份 有限公司完成。
将构架的载体质粒组合(即包含抗体重链的载体质粒和包含抗体轻链的载 体质粒)瞬时转染293细胞,培养7天后,利用亲和层析的方法纯化和富集细 胞上清中的抗体。
载体质粒扩大后采用从天根生化科技(北京)有限公司购买的质粒提取试 剂盒进行质粒抽提,获得的载体质粒用于如下的抗体组合表达。取轻链表达载 体和重链表达载体以1:1比例混合后,加入稀释过的3倍体积(DNA加入的体 积量)的PEI转染试剂。形成DNA-PEI复合物后滴加到293细胞中。转染24 小时后,添加10%体积的生长培养基。7天后收取细胞上清,4000rpm离心20 分钟后,取上清,再用0.22μm滤膜过滤,进行Protein A亲和层析纯化。纯化之 后用PBS透析,4℃透析过夜。
实施例3抗IL-1β人鼠嵌合抗体亲和力的测定及种属交叉反应测定
本实施例利用Biacore分析验证抗IL-1β人鼠嵌合抗体的结合亲和力和结合 动力学,以及其与猴IL-1β(Sino Biological Inc,90010-CNAE)的结合亲和力和 结合动力学。
将嵌合抗体连接到Protein A芯片,通过将hIL-1β、猴IL-1β以5nm、50nm 的浓度、30μl/min的流速在HBS-EP缓冲液中流动测量结合。使用BIAevaluation 软件将结合和解离曲线拟合至1:1朗格谬尔(Langmuir)结合模型。测定的KD、 Ka、Kd值显示于表3。
表3抗IL-1β人鼠嵌合抗体的Biacore结合数据
如上表所示,实施例2表达纯化的抗IL-1β人鼠嵌合抗体与人IL1β蛋白和 猴IL1β蛋白均具有很高的亲和力。
实施例4抗IL-1β人鼠嵌合抗体的体外IC50测定
根据IL-1β可刺激MRC-5(人胚胎成纤维细胞)产生IL-6的原理,本实施 例通过应用ELISA试剂盒检测IL-6的分泌水平来间接反映抗IL-1β人鼠嵌合抗 体结合hIL-1β的能力。
当MRC-5细胞达到60%的汇合度时,胰酶消化,之后用培养基重悬调整其 密度为2×104;在96孔平底板中加入50μl的MRC-5细胞,之后加入25μl 10倍 梯度稀释的嵌合抗体以及对照抗体,加入25μl稀释过的hIL-1β;于37℃、5% CO2培养箱中孵育18-24小时,之后收集上清,用ELISA试剂盒检测IL-6的分 泌水平,在540nm处读取吸光度值。检测结果如图3所示。
由图3可见,B27-4与C20-2表现出了和阳性对照抗体相当的功能抑制活性。
实施例5抗IL-1β抗体人源化改造
为了进一步提高B27-4抗体的空间构型稳定性,同时提高抗体的人源化程 度,降低免疫副作用,本实施例对B27-4抗体作进一步改造。
关于抗体人源化改造有很多报道的成功案例,可供参考(Kettleborough C A,Saldanha J W,Heath V J,et al.Humanization of a mouse monoclonal antibody byCDR–grafting:the importance of framework residues on loop conformation[J].Protein Engineering,1991,4(7):773-783;Acqua W F,Damschroder M,Zhang J,etal.Antibody humanization by framework shuffling[J].Methods,2005,36(1): 43-60),本实施例采用抗体CDR移植和蛋白质同源建模的方法对B27-4抗体可 变区进行抗体人源化改造,表达后使用Biacore分析改造后人源化抗体的亲和力, 同时比较人源化后的抗体hB27-4与对照抗体CAN的亲和力。
经过同源建模和生物信息学分析后,人源化后抗体Hb27-4的信息如下表所 示。
表4人源化抗IL-1β人鼠嵌合抗体的氨基酸序列信息
(注:SEQ ID No.1-48为氨基酸序列,其对应的核苷酸序列依次如SEQ ID No.49-96所示。)
参考实施例2和实施例3的方法,对人源化抗体进行基因合成、载体构建 和抗体表达,表达后的抗体上清进行Biacore仪器进行亲和力检测,使用 BIAevaluation软件将结合和解离曲线拟合至1:1朗格谬尔(Langmuir)结合模型。 测定的KD、Ka、Kd值显示于下表:
表5人源化抗体hB27-4与CAN抗体的Biacore结合数据
样品ID | 分析物 | ka(1/Ms) | kd(1/s) | KD(M) |
hB27-4 | rHuman IL-1β | 8.29E+05 | 4.51E-04 | 5.45E-10 |
CAN | rHuman IL-1β | 3.93E+06 | 6.01E-05 | 1.53E-11 |
由表5可见,改造后的抗体很好的保留了与人IL-1β蛋白的亲和力,并且 亲和力水平与对照抗体相当。经过人源化改造的抗体hB27-4在保持现有的生物 学功能情况下也会有更低的免疫原性、更低的副作用。
序列表
<110> 瑞阳(苏州)生物科技有限公司
<120> 人IL-1β蛋白结合分子及其编码基因和应用
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Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Ala Arg
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Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
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Asp Arg Val Thr Ile Thr Cys
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<213> 小鼠( Mus musculus)
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<213> 小鼠( Mus musculus)
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Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Lys
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<210> 21
<211> 32
<212> PRT
<213> 小鼠( Mus musculus)
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Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
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Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Pro Ala Thr Tyr Tyr Cys
20 25 30
<210> 22
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<212> PRT
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Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
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<213> 小鼠( Mus musculus)
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Asp Arg Val Thr Ile Asn Cys
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<213> 小鼠( Mus musculus)
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<213> 小鼠( Mus musculus)
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Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser
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Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys
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<213> 小鼠( Mus musculus)
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Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
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<213> 小鼠( Mus musculus)
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Arg Ala Ser Gln Asp Ile Thr Asn Tyr Leu Asn
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<213> 小鼠( Mus musculus)
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Tyr Thr Ser Arg Leu His Ser
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<213> 小鼠( Mus musculus)
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Gln Gln Gly Tyr Thr Leu Pro Arg Ala
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<213> 小鼠( Mus musculus)
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Arg Ala Ser Gln Ser Val Thr Ser Ser Ser Tyr Ser Phe Ile His
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Asp Ala Ser Asn Leu Glu Ser
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Gln His Ser Trp Glu Ile Pro Tyr Thr
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Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
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Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
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Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
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Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
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Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
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Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
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His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
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Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
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Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
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Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
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Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
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Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
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Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
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Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
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<210> 37
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<210> 38
<211> 112
<212> PRT
<213> 小鼠( Mus musculus)
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Asp Ile Leu Met Thr Gln Ser Pro Ala Ser Leu Ala Ala Ser Leu Gly
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Glu Ile Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
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<210> 39
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Gly Thr Ser Val Thr Val Ser Ala
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<210> 40
<211> 121
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<213> 小鼠( Mus musculus)
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ala Tyr Ile Ser Ser Gly Ser Tyr Thr Ile Tyr Tyr Ala Asp Thr Val
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Ala Arg Asp Asp Tyr Asp Val His Tyr Tyr Ala Met Asp Tyr Trp Gly
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Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 41
<211> 107
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<213> 小鼠( Mus musculus)
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Asp Ile Val Ile Thr Gln Ser Thr Ser Ser Leu Ser Ala Ser Leu Gly
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Asp Arg Val Thr Ile Asn Cys Arg Ala Ser Gln Asp Ile Thr Asn Tyr
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Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
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Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
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Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Tyr Thr Leu Pro Arg
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Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
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<210> 42
<211> 105
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<213> 小鼠( Mus musculus)
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Asp Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
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Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Thr Ser Ser Pro Ser Phe
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Gly Gly Gly Thr Lys Leu Glu Ile Lys
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<210> 43
<211> 118
<212> PRT
<213> 小鼠( Mus musculus)
<400> 43
Gln Val Thr Leu Lys Val Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Phe
85 90 95
Cys Ala Arg Tyr Asp Asn Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 44
<211> 105
<212> PRT
<213> 小鼠( Mus musculus)
<400> 44
Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ile Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Ser Asp Ala Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Tyr Thr Ser Asn Leu Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Ala Asp Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Thr Ser Ser Pro Ser Phe
85 90 95
Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 45
<211> 118
<212> PRT
<213> 小鼠( Mus musculus)
<400> 45
Gln Val Thr Leu Lys Val Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Thr Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu
35 40 45
Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Ser Ala Ser Arg Asn Gln Val
65 70 75 80
Phe Leu Lys Ile Thr Asn Val Asp Thr Ala Asp Ser Ala Thr Tyr Phe
85 90 95
Cys Ala Arg Tyr Asp Asn Gly Pro Leu Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser
115
<210> 46
<211> 107
<212> PRT
<213> 小鼠( Mus musculus)
<400> 46
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile His Asn Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Gln Gly Arg Ser Pro Gln Phe Leu Val
35 40 45
Tyr Asp Ala Lys Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Ser Ile Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 47
<211> 121
<212> PRT
<213> 小鼠( Mus musculus)
<400> 47
Glu Val Gln Gly Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Arg Lys Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Ser Ser Phe
20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Ser Ser Thr Phe Tyr Tyr Ala Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Pro Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Phe Ser Leu Arg Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Tyr Arg Tyr Gly Pro Ala Trp Phe Ala Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 48
<211> 20
<212> PRT
<213> 人(Homo sapiens)
<400> 48
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly
20
<210> 49
<211> 75
<212> DNA
<213> 未知(Unknown)
<400> 49
caggtgcagc tgcaggagtc aggaccagga ctggtgaagc ctagcgagac actgagcctg 60
acctgcacag tgtcc 75
<210> 50
<211> 42
<212> DNA
<213> 未知(Unknown)
<400> 50
tggatcaggc agcctccagg aaaaggcctc gagtggatcg ga 42
<210> 51
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 51
cgcgtgacca ttagcgtgga caccagcaag aaccagttct ccctgaagct gagcagcgtg 60
acagccgccg atacagccgt gtattattgc gcccgg 96
<210> 52
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 52
cgcgtgacca tctctaagga caacagcaag agccaggtgt ccctgaagct gtctagcgtg 60
acagccgccg ataccgccgt gtactattgc gccaga 96
<210> 53
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 53
cgcgtgacca tctctaagga caacagcaag agccaggtgt ccctgaagct gtctagcgtg 60
acagccgccg ataccgccgt gtattattgc gccacc 96
<210> 54
<211> 33
<212> DNA
<213> 未知(Unknown)
<400> 54
tggggccagg gaaccaccgt gacagtgtct tct 33
<210> 55
<211> 75
<212> DNA
<213> 未知(Unknown)
<400> 55
gaggtgcagc tggtggaatc aggaggagga ctggtgcagc caggaggatc tagagagctg 60
tcttgcgccg ccagc 75
<210> 56
<211> 39
<212> DNA
<213> 未知(Unknown)
<400> 56
tgggtccggc aggctccaga aaagggactc gagtgggtg 39
<210> 57
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 57
agattcacca tcagccggga caaccccaag aacaccctgt tcctgcagat gaccagcctg 60
agaagcgagg acaccgccat gtactattgc gccagg 96
<210> 58
<211> 33
<212> DNA
<213> 未知(Unknown)
<400> 58
tggggacagg gaacaagcgt gacagtgtcc agc 33
<210> 59
<211> 30
<212> DNA
<213> 未知(Unknown)
<400> 59
ggctttacat tcagcacctt cggaatgcat 30
<210> 60
<211> 51
<212> DNA
<213> 未知(Unknown)
<400> 60
tacatcagca gcggcagcta caccatctac tacgccgaca ccgtgaaggg c 51
<210> 61
<211> 36
<212> DNA
<213> 未知(Unknown)
<400> 61
gacgactacg acgtgcacta ctacgccatg gactat 36
<210> 62
<211> 30
<212> DNA
<213> 未知(Unknown)
<400> 62
ggctttagcc tgaccaccag cggagtgcat 30
<210> 63
<211> 30
<212> DNA
<213> 未知(Unknown)
<400> 63
ggattcagcc tgaccaccta cggcgtgcat 30
<210> 64
<211> 48
<212> DNA
<213> 未知(Unknown)
<400> 64
gtgatttgga gcggcggcag caccgactac aacgccgcct ttatcagc 48
<210> 65
<211> 48
<212> DNA
<213> 未知(Unknown)
<400> 65
gtgatttgga gcggcggcag caccgactac aacgccgcct ttatcagc 48
<210> 66
<211> 69
<212> DNA
<213> 未知(Unknown)
<400> 66
gacatccaga tgacccagag ccctagcagc ctgagcgcta gcgtgggaga tagagtgacc 60
atcacttgc 69
<210> 67
<211> 45
<212> DNA
<213> 未知(Unknown)
<400> 67
tggtaccagc agaagccagg caaggctcct aagctgctga tctac 45
<210> 68
<211> 45
<212> DNA
<213> 未知(Unknown)
<400> 68
tggtaccagc agaagccagg caaggctcct aagctgctga tcaag 45
<210> 69
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 69
ggagtgccta gcagattcag cggcagcgga agcggaaccg acttcaccct gaccatcagc 60
tctctgcagc cagaggatcc agccacctac tactgc 96
<210> 70
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 70
ggagtgccta gcagattcag cggcagcgga agcggaaccg acttcaccct gaccatcagc 60
tctctgcagc cagaggatcc agccacctac tactgc 96
<210> 71
<211> 30
<212> DNA
<213> 未知(Unknown)
<400> 71
ttcggcggag gcaccaaagt ggagatcaag 30
<210> 72
<211> 69
<212> DNA
<213> 未知(Unknown)
<400> 72
gacatcgtga tcacccagag cacaagcagc ctgagcgctt ctctgggcga tagagtgacc 60
atcaattgc 69
<210> 73
<211> 45
<212> DNA
<213> 未知(Unknown)
<400> 73
tggtaccagc agaagcccga cggcaccgtg aagctgctga tctac 45
<210> 74
<211> 96
<212> DNA
<213> 未知(Unknown)
<400> 74
ggagtgcctt ctagattcag cggcagcgga agcggcacag attacagcct gaccatcagc 60
aacctggagc aggaggacat cgccacctac ttctgc 96
<210> 75
<211> 30
<212> DNA
<213> 未知(Unknown)
<400> 75
tttggaggag gaaccaagct ggagatcaag 30
<210> 76
<211> 33
<212> DNA
<213> 未知(Unknown)
<400> 76
cgggccagcc aggacatcac caactacctg aat 33
<210> 77
<211> 21
<212> DNA
<213> 未知(Unknown)
<400> 77
tacaccagca gactgcacag c 21
<210> 78
<211> 27
<212> DNA
<213> 未知(Unknown)
<400> 78
cagcagggct acaccctgcc tagagcc 27
<210> 79
<211> 45
<212> DNA
<213> 未知(Unknown)
<400> 79
agagccagcc agagcgtgac cagcagcagc tacagcttca tccat 45
<210> 80
<211> 21
<212> DNA
<213> 未知(Unknown)
<400> 80
gacgccagca acctggagag c 21
<210> 81
<211> 27
<212> DNA
<213> 未知(Unknown)
<400> 81
cagcactctt gggagatccc ctacacc 27
<210> 82
<211> 990
<212> DNA
<213> 未知(Unknown)
<400> 82
gccagcacca agggacctag cgtgtttcct ctggcccctt ctagcaagag cacaagcgga 60
ggaacagccg ctctgggctg tctggtgaaa gactactttc ccgagcccgt gaccgtgtct 120
tggaattcag gagccctgac cagcggagtg cacacatttc cagccgtgct gcagagcagc 180
ggactgtata gcctgagcag cgtggtgacc gtgccttctt cttctctggg cacccagacc 240
tacatctgca acgtgaacca caagcccagc aacaccaagg tggacaagaa ggtggagccc 300
aagtcttgcg acaagaccca cacttgcccc ccttgtccag ctccagaact cctgggagga 360
cctagcgtgt tcctgttccc tcccaagcct aaggacaccc tgatgatcag ccggacccca 420
gaagtgactt gcgtggtggt ggacgtgtcc cacgaagacc ccgaggtcaa gttcaattgg 480
tacgtggacg gagtggaggt gcacaacgct aagaccaagc ccagggagga gcagtacaac 540
agcacctaca gggtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaag 600
gagtacaagt gcaaggtgtc caacaaggcc ctgccagccc ctatcgagaa gaccatcagc 660
aaggccaagg gccagcctag agaacctcag gtgtacaccc tgcccccttc tagagacgag 720
ctgaccaaga accaggtgtc cctgacttgc ctcgtgaagg gcttctaccc cagcgatatc 780
gccgtggagt gggaatctaa cggtcagcca gagaacaact acaagaccac ccccccagtg 840
ctggacagcg acggcagctt cttcctgtac agcaagctga ccgtggacaa aagccgctgg 900
cagcagggca acgtgttctc ttgcagcgtg atgcacgagg ccctgcacaa ccactacacc 960
cagaagagcc tgagcctgag cccaggaaag 990
<210> 83
<211> 321
<212> DNA
<213> 未知(Unknown)
<400> 83
agaaccgtgg ccgctcctag cgtgttcatc ttccctccca gcgacgagca gctgaaaagc 60
ggaacagcca gcgtcgtctg cctgctgaat aacttctacc cccgggaggc caaagtccag 120
tggaaagtgg acaacgccct gcagagcgga aactctcagg agagcgtgac cgagcaggac 180
agcaaggaca gcacctacag cctgagcagc acactgaccc tgagcaaggc cgactacgag 240
aagcacaagg tgtacgcttg cgaggtcaca caccagggac tgtctagccc agtgaccaag 300
agcttcaacc gcggcgagtg t 321
<210> 84
<211> 1344
<212> DNA
<213> 未知(Unknown)
<400> 84
caggtgcagc tggtggaatc aggaggagga gtggtgcagc caggcagatc tctgagactg 60
tcttgcgccg ccagcggctt tacattcagc gtgtacggca tgaattgggt ccggcaggct 120
ccaggaaaag gactcgagtg ggtggccatc atctggtacg acggcgacaa ccagtactac 180
gccgacagcg tgaagggcag attcaccatc agccgggaca acagcaagaa caccctgtac 240
ctgcagatga acggcctgag agccgaggat accgccgtgt actattgcgc tagggacctg 300
aggaccggcc ctttcgacta ttggggacag ggcacactgg tgacagtgtc tagcgccagc 360
accaagggac ctagcgtgtt tcctctggcc ccttctagca agagcacaag cggaggaaca 420
gccgctctgg gctgtctggt gaaagactac tttcccgagc ccgtgaccgt gtcttggaat 480
tcaggagccc tgaccagcgg agtgcacaca tttccagccg tgctgcagag cagcggactg 540
tatagcctga gcagcgtggt gaccgtgcct tcttcttctc tgggcaccca gacctacatc 600
tgcaacgtga accacaagcc cagcaacacc aaggtggaca agagggtgga gcccaagtct 660
tgcgacaaga cccacacttg ccccccttgt ccagctccag aactcctggg aggacctagc 720
gtgttcctgt tccctcccaa gcctaaggac accctgatga tcagccggac cccagaagtg 780
acttgcgtgg tggtggacgt gtcccacgaa gaccccgagg tcaagttcaa ttggtacgtg 840
gacggagtgg aggtgcacaa cgctaagacc aagcccaggg aggagcagta caacagcacc 900
tacagggtgg tgtccgtgct gacagtgctg caccaggatt ggctgaacgg caaggagtac 960
aagtgcaagg tgtccaacaa ggccctgcca gcccctatcg agaagaccat cagcaaggcc 1020
aagggccagc ctagagaacc tcaggtgtac accctgcccc ctagcagaga ggagatgacc 1080
aagaaccagg tgtccctgac ttgcctcgtg aagggcttct accccagcga tatcgccgtg 1140
gagtgggaat ctaacggtca gccagagaac aactacaaga ccaccccccc agtgctggac 1200
agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaaaagccg ctggcagcag 1260
ggcaacgtgt tctcttgcag cgtgatgcac gaggccctgc acaaccacta cacccagaag 1320
agcctgagcc tgagcccagg aaag 1344
<210> 85
<211> 642
<212> DNA
<213> 未知(Unknown)
<400> 85
gagatcgtgc tgacccagag cccagacttc cagtcagtga cccccaagga gaaggtcacc 60
atcacttgca gagccagcca gagcatcggc agcagcctgc attggtacca gcagaagccc 120
gaccagagcc ccaagctgct gatcaagtac gccagccaga gctttagcgg agtgcctagc 180
agattcagcg gcagcggaag cggcacagat ttcaccctga ccatcaacag cctggaggca 240
gaagacgccg cagcctacta ttgccaccag agcagcagcc tgcccttcac atttggccct 300
ggcaccaagg tggacatcaa gagaaccgtg gccgctccta gcgtgttcat cttccctccc 360
agcgacgagc agctgaaaag cggaacagcc agcgtcgtct gcctgctgaa taacttctac 420
ccccgggagg ccaaagtcca gtggaaagtg gacaacgccc tgcagagcgg aaactctcag 480
gagagcgtga ccgagcagga cagcaaggac agcacctaca gcctgagcag cacactgacc 540
ctgagcaagg ccgactacga gaagcacaag gtgtacgctt gcgaggtcac acaccaggga 600
ctgtctagcc cagtgaccaa gagcttcaac cgcggcgagt gt 642
<210> 86
<211> 336
<212> DNA
<213> 未知(Unknown)
<400> 86
gacatcctga tgacccagag cccagcctct ctggcagctt ctctgggaca gagagccaca 60
atctcttgca gagccagcca gagcgtgacc agcagcagct acagcttcat ccattggtac 120
cagcagaaac caggccagcc tcctaagctg ctgatcaagg acgccagcaa cctggagagc 180
ggagtgccag ccagattcag cggaagcgga agcggcaccg acttcaccct gaacatccac 240
ccagtggaag aggaggatcc agccacctac tactgccagc actcttggga gatcccctac 300
accttcggcg gaggcacaaa gctggagatc aagaga 336
<210> 87
<211> 360
<212> DNA
<213> 未知(Unknown)
<400> 87
caggtgcagc tgcagcagtc aggaccagga ctggtgcagc cttctcagag cctgagcatc 60
acctgtaccg tgtccggctt cagcctgaca acttgcggag tgcattgggt ccggcagtct 120
ccaggaaagg gactcgagtg gctgggagtg atttggagcg gcggcagcac cgactacaac 180
gccgccttta tcagcaggct gagcatcagc aaggacaaca gcaagagcca ggtgttcttc 240
aagatgaaca gcctgcaggc ctacgacacc gccatctact attgcgccac cttccggagg 300
gacttcttcc actaccccat ggactattgg ggccagggaa caagcgtgac agtgtcagct 360
<210> 88
<211> 363
<212> DNA
<213> 未知(Unknown)
<400> 88
gaggtgcagc tggtggaatc aggaggagga ctggtgcagc caggaggatc tagagagctg 60
tcttgcgccg ccagcggctt tacattcagc accttcggaa tgcattgggt ccggcaggct 120
ccagaaaagg gactcgagtg ggtggcctac atcagcagcg gcagctacac catctactac 180
gccgacaccg tgaagggcag attcaccatc agccgggaca accccaagaa caccctgttc 240
ctgcagatga ccagcctgag aagcgaggac accgccatgt actattgcgc cagggacgac 300
tacgacgtgc actactacgc catggactat tggggacagg gaacaagcgt gacagtgtcc 360
agc 363
<210> 89
<211> 321
<212> DNA
<213> 未知(Unknown)
<400> 89
gacatcgtga tcacccagag cacaagcagc ctgagcgctt ctctgggcga tagagtgacc 60
atcaattgcc gggccagcca ggacatcacc aactacctga attggtacca gcagaagccc 120
gacggcaccg tgaagctgct gatctactac accagcagac tgcacagcgg agtgccttct 180
agattcagcg gcagcggaag cggcacagat tacagcctga ccatcagcaa cctggagcag 240
gaggacatcg ccacctactt ctgccagcag ggctacaccc tgcctagagc ctttggagga 300
ggaaccaagc tggagatcaa g 321
<210> 90
<211> 315
<212> DNA
<213> 未知(Unknown)
<400> 90
gacatcgtgc tgacccagtc tccagccatc atgagcgcta gcctgggcga gaaagtgacc 60
atgacctgca gggccagcag cagcatcaac tacatgtatt ggtaccagca gaagagcgac 120
gccagcccca agctctggat ctactacacc agcaatctgg ccccaggagt gccagctaga 180
ttcagcggca gcggaagcgg caacagctac agcctgacca tcagcagcat ggccgacgaa 240
gacgccgcca cctactattg ccagcagttc accagctctc cttcttttgg cggcggcaca 300
aagctggaga tcaag 315
<210> 91
<211> 354
<212> DNA
<213> 未知(Unknown)
<400> 91
caggtcacac tgaaggtgtc cggaccagga atcctgcagc ctagccagac actgagcctg 60
acctgcagct tcagcggctt tagcctgagc accagcggaa tgggagtgtc ttggatccgg 120
cagcctagcg gaaaaggact ggagtggctc gcccacatct attgggacga cgacaagcgg 180
tacaacccta gcctgaagag ccggctgacc atcagcaagg acaccagcag caaccaggtg 240
ttcctgaaga tcaccagcgt ggacaccgcc gataccgcca cctacttttg cgcccgctac 300
gacaacggcg ctatggacta ttggggccag ggaacaagcg tgaccgtgtc tagc 354
<210> 92
<211> 315
<212> DNA
<213> 未知(Unknown)
<400> 92
gagatcgtgc tgacccagtc tccagccatc atgagcgcta gcctgggcga gaaagtgacc 60
atgtcttgcc gggccaacag cagcgtgaac tacatgtatt ggtaccagca gaagagcgac 120
gccagcccca agctctggat ctactacacc agcaatctgg ccccaggagt gccagctaga 180
ttcagcggca gcggaagcgg caacagctac agcctgacca tcagcagcat ggagggcgaa 240
gacgccgcca cctactattg ccagcagttc accagctctc cttcttttgg cggcggcaca 300
aagctggaag tgaag 315
<210> 93
<211> 354
<212> DNA
<213> 未知(Unknown)
<400> 93
caggtcacac tgaaggtgtc cggaccagga atcctgcagc ctagccagac actgaccctg 60
acctgcagct tcagcggctt tagcctgagc accagcggaa tgggagtgtc ttggatccgg 120
cagcctagcg gaaaaggact ggagtggctc gcccacatct attgggacga cgacaagcgg 180
tacaacccct ccctgaagag caggctgacc atctctaaga gcgccagccg gaaccaggtg 240
ttcctgaaga tcaccaacgt ggacaccgcc gatagcgcca cctacttttg cgcccgctac 300
gacaacggcc ctctggacta ttggggacag ggaaccagcg tgacagtgtc tagc 354
<210> 94
<211> 321
<212> DNA
<213> 未知(Unknown)
<400> 94
gacatccaga tgacccagag cccagcctct ctgagcgcta gcgtgggaga gacagtgaca 60
atcacttgcc gggccagcga gaacatccac aactacctgg cttggtacca gcagaagcag 120
ggcagaagcc ctcagttcct ggtgtacgac gccaaaacac tggcagacgg agtgcctagc 180
agattcagcg gcagcggaag cggaacccag tacagcctga agatcaacag cctgcagccc 240
gaggacttcg gcagctacta ttgccagcac ttttggagca tccccttcac cttcggcagc 300
ggcaccaagc tggagatcaa g 321
<210> 95
<211> 363
<212> DNA
<213> 未知(Unknown)
<400> 95
gaggtgcagg gagtggaatc aggaggagga ctggtgcagc caggaggctc tagaaagctg 60
tcttgcgccg ccagcggctt taacttcagc agcttcggaa tgcattgggt ccggcaggct 120
ccagaaaagg gactcgagtg ggtggcctac atcagcagcg gcagcagcac cttctactac 180
gccgacaccg tgaagggcag attcaccatc agccgggaca accccaagaa caccctgttc 240
ctgcagatgt tcagcctgcg gagcgaggat accgccatct actattgcgc ccgggaggat 300
taccgctacg gcccagcttg gttcgcctat tggggacagg gaacactggt gaccgtgtca 360
tct 363
<210> 96
<211> 60
<212> DNA
<213> 未知(Unknown)
<400> 96
atggagacag ataccctgct gctgtgggtg ctgctgctgt gggtccctgg cagcaccgga 60
Claims (8)
1.一种人IL-1β蛋白结合分子,其特征在于,所述的人IL-1β蛋白结合分子具有与人IL-1β蛋白特异结合的抗原结合位点,该人IL-1β蛋白结合分子含有至少一个重链可变区和至少一个轻链可变区,所述的重链可变区具有三个重链互补决定区CDR1、CDR2和CDR3,三个重链互补决定区CDR1、CDR2和CDR3的氨基酸序列依次如SEQ ID No.15、SEQ ID No.16和SEQID No.17所示;所述的轻链可变区具有三个轻链互补决定区CDR1、CDR2和CDR3,三个轻链可变区CDR1、CDR2和CDR3的氨基酸序列依次如SEQ ID No.31、SEQ ID No.32和SEQ ID No.33所示。
2.如权利要求1所述的人IL-1β蛋白结合分子,其特征在于,所述的重链可变区具有四个重链框架区FR1、FR2、FR3和FR4,四个重链框架区FR1、FR2、FR3和FR4的氨基酸序列依次如SEQ ID No.1、SEQ ID No.2、SEQ ID No.5和SEQ ID No.6所示。
3.如权利要求1所述的人IL-1β蛋白结合分子,其特征在于,所述的轻链可变区具有四个轻链框架区FR1、FR2、FR3和FR4,四个轻链框架区FR1、FR2、FR3和FR4的氨基酸序列依次如SEQ ID No.18、SEQ ID No.20、SEQ ID No.21和SEQ ID No.23所示。
4.如权利要求1-3中任意一项所述的人IL-1β蛋白结合分子,其特征在于,人IL-1β蛋白结合分子为人鼠嵌合抗体、抗原结合片段或单链抗体可变区片段。
5.编码如权利要求1-4中任意一项所述的人IL-1β蛋白结合分子的核酸分子。
6.含有如权利要求5所述的核酸分子的表达载体。
7.权利要求1-4中任意一项所述的人IL-1β蛋白结合分子在制备治疗IL-1介导的疾病的药物中的应用,其特征在于,所述的疾病为自身免疫病或癌症。
8.权利要求1-3中任意一项所述的人IL-1β蛋白结合分子在制备双特异性抗体中的应用,其特征在于,所述的人IL-1β蛋白结合分子为人源化的抗原结合片段或单链抗体可变区片段。
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