CN111875694B - 一种白细胞介素-1受体拮抗剂以及包含其的融合蛋白 - Google Patents
一种白细胞介素-1受体拮抗剂以及包含其的融合蛋白 Download PDFInfo
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Abstract
一种白细胞介素‑1受体拮抗剂(IL‑1RN)蛋白或其变体或类似物;一种包含白细胞介素‑1受体拮抗剂蛋白或其变体或类似物,延长半衰期的结构域,和可选择的肿瘤坏死因子受体2三部分的融合蛋白;以及他们的制备方法和用途,上述蛋白或其变体或类似物与以及融合蛋白具有延长半衰期,与白细胞介素‑1受体亲和力更高,生物活性更优的效果,可用于治疗和预防炎性相关疾病领域。
Description
【技术领域】
本发明属于生物医药领域,涉及IL-1RN变体及包含其的蛋白在医疗方面的应用。
【背景技术】
白细胞介素-1(IL-1)由机体对炎症刺激反应产生,主要由IL-1α和IL-1β两种蛋白质组成,参与了多种自身免疫性和自身炎症性疾病的发病机理,包括炎性肠病、类风湿性关节炎、冷吡啉相关周期性综合征等。IL-1α和IL-1β具有相似的生物学活性,能够在IL-1受体辅助蛋白(IL-1RAcP)的帮助下与IL-1受体(IL-1R1)结合,向细胞内部传递信号。IL-1α表达比较普遍,主要在上皮细胞、角化细胞和内皮细胞中表达,通常在局部起作用。IL-1β主要由单核细胞和巨噬细胞产生,可以全身分泌并循环作用。在正常情况下,IL-1α和IL-1β都以低水平表达,转录和翻译水平需要诱导,加工和分泌需要调节,该调节步骤的丧失会导致以发热、皮疹和关节炎为特征的综合征。
IL-1受体拮抗剂(Interleukin 1receptor antagonist,IL-1RN)是IL-1α和IL-β的高亲和力竞争者,在不同细胞中由不同的细胞因子诱导产生,是一种存在于人体的蛋白质类细胞因子受体拮抗剂。IL-1RN能够与IL-1R1紧密结合,从而阻断IL-1α和IL-1β与相应受体的结合,进而拮抗IL-1的各种生物学效应,因此在临床上能够用于治疗IL-1参与病理变化过程的相关炎性疾病,包括类风湿性关节炎、CAPS、特应性皮炎、化脓性汗腺炎等。
由于IL-1RN的分子量小,其在血浆中的半衰期很短(2-3小时),通常需要每天注射一次以维持体内有效的血药浓度。除此之外,为了达到显著的临床效果,IL-1RN的临床应用剂量很大,治疗类风湿关节炎每次需要注射75-150mg。过于频繁的高剂量注射会增加病人的痛苦,而且容易产生不良反应,本发明通过对IL-1RN进行改造,提高其生物学活性,延长半衰期,进而降低注射频率和给药剂量,并维持良好的临床效果。
【发明内容】
定义以及术语
除非另外说明,下述定义适用于本发明全文。未定义的术语可以根据行业内约定的定义理解。
在整个说明书中,除非上下文另有要求,字"包括",或变化,例如"包括"或"包括",将被理解为意味着包括所述元件的元素或基团或者是整数,但或整数不排除任何其它元件的元素或基团或者是整数或整数。
如本说明书和权利要求书中所用的,除非上下文另有明确说明,否则单数形式“一个”、“一种”和“所述”包括复数指代。例如,术语“细胞”包括多个细胞,包括其混合物。
术语“约”或“大约”意指在如本领域普通技术人员所确定的特定值的可接受误差范围内,其将部分取决于该值如何测量或确定,即,测量系统的局限性。例如,“约”可按照本领域中的实践意指在1或大于1的标准偏差内。或者,“约”可意指给定值的至多20%、至多10%、至多5%或至多1%的范围。或者,特别是对于生物系统或过程,该术语可意指在数值的数量级内,优选在5倍以内,并且更优选在2倍以内。在本申请和权利要求书中描述特定值的情况下,除非另有说明,否则应当假定术语“约”意指在该特定值的可接受误差范围内。
此处所使用的术语″多核苷酸″及″核酸分子″可交互地使用,其意指任何长度的核苷酸的聚合物。多核苷酸可含有脱氧核糖核苷酸、核糖核苷酸及/或其类似物。核苷酸可具有任何三维立体结构,且可执行任何已知或未知的功能。术语″多核苷酸″包含例如:单股、双股及三螺旋分子、基因或基因片段、外显子(exon)、内含子(intron)、mRNA、tRNA、rRNA、核糖酶(ribozyme)、反义分子(antisense molecule)、cDNA、重组多核苷酸、分支多核苷酸、适体(aptamer)、质粒、载体、经分离的任何序列DNA、经分离的任何序列RNA、核酸探针、及引物。核酸分子亦可包括经修饰的核酸分子(例如,包括经糖类修饰的碱基和/或核苷酸间接头)。
术语“氨基酸”应理解为包括20个天然存在的氨基酸;那些氨基酸通常在体内翻译后修饰,包括例如羟脯氨酸,磷酸丝氨酸和磷酸苏氨酸;和其它非天然的氨基酸,包括但不限于2-氨基己二酸,羟赖氨酸异十二烷,去甲缬氨酸,去甲亮氨酸和鸟氨酸。此外,术语“氨基酸”包括D-和L-氨基酸。下面给出了可根据本发明使用的可能氨基酸的进一步详细说明和非天然氨基酸的例子。
术语“变体”指与参照肽或多核苷酸不同但保留了主要性质的肽或多核苷酸。典型的肽变体在氨基酸序列方面与另一个参照肽不同。一般来讲,差异是有限的以使参照肽和变体的序列整体近似且在许多区域相同。可通过一种或多种修饰(例如,置换、添加和/或缺失)引起变体和参照肽的氨基酸序列不同。肽变体包括保守修饰的变体(例如,具有约75、约80、约85、约90、约95、约98、约99%的参照序列的保守变体)。置换或插入的氨基酸残基可以是或可以不是由遗传密码编码的氨基酸残基。肽变体可以是天然形成的,例如等位基因变体,或其可以是未知天然形成的变体。
术语“类似物”是指:蛋白修饰,所述修饰包括但不限于甲基化、乙酰化、磷酸化、腺苷酸化、泛素化、ADP核糖基化等;偶联物,包括但不限于抗体偶联、多肽偶联等;缀合物,包括但不限于药物缀合、聚合物缀合等。以上仅为列举,所有与蛋白总体功能相近的类似物均在保护范围内。
术语″多肽″意指无论其大小,优选地实质上由任意的20个天然氨基酸所组成的任何聚合物。尽管术语″蛋白质″常用来指相对较大的蛋白质,″肽″常用来指小的多肽,在此领域中术语″多肽″,″蛋白质″和″肽″常部分重叠使用。除非另行注明,否则术语″多肽″一般是指蛋白质、多肽、及肽。
术语″载体″为能够在宿主细胞中自行复制且可接受外来DNA的核酸分子。载体带有其本身的复制起始点、可用于插入外来DNA的一种或多种限制性内切酶的独特识别位置、以及通常带有筛选标志(selectable marker)(例如,编码抗生素抗性的基因)、且常带有用于表达所插入的DNA的识别序列(例如,启动子)。常见的载体包含质粒载体及噬菌体载体。
术语″细胞″意图包含任何原核细胞、真核细胞、初级细胞或永生化细胞系(immortalized cell line)、组织或器官中的细胞的任何群集。优选地,细胞得自哺乳动物(尤其是人类)来源,且可经一种或多种病原体感染。依据本发明的″宿主细胞″可为任何来源的经转染(transfected)、经转化(transformed)、经转导(transduced)或经感染(infected)的细胞,包含原核细胞、真核细胞、哺乳动物细胞、鸟类细胞、昆虫细胞、植物细胞或细菌细胞,或者其可为可用于增殖此处所述核酸的任何来源的细胞。
本发明的蛋白质或其变体和类似物可以对不同种细胞类型具有改变的生物学效果,包括但不限于人原代细胞,淋巴细胞,红细胞,视网膜细胞,肝细胞,神经元,角质形成细胞,内皮细胞,内胚层细胞,外胚层细胞,中胚层细胞,上皮细胞,肾细胞,肝细胞,骨细胞,骨髓细胞,淋巴结细胞,真皮细胞,成纤维细胞,T细胞,B细胞,血浆细胞,自然杀伤细胞,巨噬细胞,粒细胞,嗜中性粒细胞,朗格罕氏细胞,树突状细胞,嗜酸性粒细胞,嗜碱性粒细胞,乳腺细胞,小叶细胞,前列腺细胞,肺部细胞,食管细胞,胰腺细胞,β细胞的胰岛素分泌细胞,成血管细胞,肌肉细胞,卵形细胞(肝细胞),间充质细胞,脑微血管内皮细胞,星形神经胶质细胞,各种细胞群包括成人干细胞和胚胎干细胞,各种祖细胞;和永生的转化细胞系或癌细胞系。
同一性百分比由本领域已知的软件进行分析,示例性的,如GAP(Needleman和Wunsh,1970)分析(GCG程序)确定,其中参数gap creation penalty=5,gap extensionpenalty=0.3。被分析的序列长度至少为15个氨基酸时,GAP分析就在参与测试的两个序列的至少为15个氨基酸的区域进行测试。更优选地,被分析的序列长度至少为50个氨基酸时,GAP分析就在参与测试的两个序列的至少为50个氨基酸的区域进行测试。更优选地,被分析的序列长度至少为100个氨基酸时,GAP分析就在参与测试的两个序列的至少为100个氨基酸的区域进行测试。更优选地,被分析的序列长度至少为250个氨基酸时,GAP分析就在参与测试的两个序列的至少为250个氨基酸的区域进行测试。甚至更优选地,被分析的序列长度至少为500个氨基酸时,GAP分析就在参与测试的两个序列的至少为500个氨基酸的区域进行测试。
本文所用的IL-1RN的“变体”是指一个或多个氨基酸改变的氨基酸序列。该变体可以具有“保守的”改变,其中取代的氨基酸具有类似的结构或化学性质,例如用异亮氨酸取代亮氨酸。或者,变体可能具有“非保守性”改变,例如甘氨酸被色氨酸取代。类似的微小变化也可包括氨基酸缺失或插入,或两者兼有。使用本领域公知的计算机程序,例如DNAstar软件,可以确定哪些氨基酸残基可以被取代,插入或删除而不破坏生物学或免疫学活性。
用于本发明的载体可以是如噬菌体、质粒、粘粒、微型染色体、病毒或逆转录病毒载体。可用于克隆和/或表达本发明的多核苷酸的载体是能在需复制和/或表达多核苷酸的宿主细胞中复制和/或表达多核苷酸的载体。一般说来,多核苷酸和/或载体可用于任何真核或原核细胞,包括哺乳动物细胞(如人(如HeLa)、猴(如Cos)、兔(如兔网织红细胞)、大鼠、仓鼠(如CHO、NSO和幼仓鼠肾细胞)或小鼠细胞(如L细胞))、植物细胞、酵母细胞、昆虫细胞或细菌细胞(如大肠杆菌)。有关适用于多种类型宿主细胞的适当载体的例子可参见例如F.Ausubel et al.Current Protocols in Molecular Biology.Greene PublishingAssociates and Wiley-Int erscience(1992)和Sambrook et al.(1989)。可以使用含有这些多核苷酸的宿主细胞来大量表达可用于例如药物、诊断试剂、疫苗和治疗剂的蛋白质。已开发出多种方法用于经由互补的粘性末端使多核苷酸与载体可操作相连。例如,可在欲插入载体DNA内的DNA区段添加互补的同聚体序列片段。然后通过互补同聚体尾之间的氢键连接载体和DNA区段以形成重组DNA分子。
发明概述
本发明涉及一种白细胞介素-1受体拮抗剂(IL-1RN)蛋白或其变体或类似物,其与SEQID NO:1所示的氨基酸序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性。本发明进一步提供了编码上述蛋白或其变体或类似物的核苷酸序列,其与SEQ ID NO:2所示的核苷酸序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性,或在严格杂交条件下,与所述核苷酸序列的互补序列杂交的序列,其中SEQ ID NO:2所示的核苷酸序列为野生型白细胞介素-1受体拮抗剂的核苷酸序列。
进一步的,本发明还提供了白细胞介素-1受体拮抗剂(IL-1RN)蛋白或其变体或类似物,其与SEQ ID NO:3、5、7、9、11、13、15所示的氨基酸序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性,所述蛋白或其变体或类似物包括选自R5T,R14T和D74N中的至少一个突变位点。
本发明还提供了编码白细胞介素-1受体拮抗剂(IL-1RN)蛋白或其变体或类似物的核苷酸序列,其与SEQ ID NO:4、6、8、10、12、14、16所示的核苷酸序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性,或在严格杂交条件下,与所述核苷酸序列的互补序列杂交的核苷酸序列,并且所述核苷酸序列的编码蛋白中具有选自R5T,R14T和D74N中的至少一个突变位点。
进一步的,本发明还提供了一种融合蛋白,其包括用于延长IL-1RN蛋白半衰期的结构域,所述结构域与可抑制IL-1活性的上述IL-1RN蛋白或其变体或类似物连接;进一步的,所述融合蛋白或其变体或类似物可以包括或不包括肿瘤坏死因子受体2(TNFR2)的一部分,作为双靶点设计。优选地,所述肿瘤坏死因子受体2(TNFR2)的一部分包含肿瘤坏死因子受体2(TNFR2)的胞外结构域,更优选地,所述肿瘤坏死因子受体2(TNFR2)的一部分为肿瘤坏死因子受体2(TNFR2)的胞外结构域。
其中用于延长IL-1RN蛋白半衰期的结构域,包括但不限于选自IgG1Fc,IgG2Fc,IgG3Fc,IgG4Fc,IgMFc,IgAFc和IgDFc中的一种或多种Fc结构域;或血清白蛋白;或转铁蛋白(transferrin,Tf)。其中,哺乳动物的免疫球蛋白的Fc或骨架区、血清白蛋白衍生自哺乳动物,所述哺乳动物选自包括人,猩猩和大猩猩和灵长类动物,家畜(例如牛,羊,猪,马,驴),室内试验动物(例如小鼠,大鼠,豚鼠,仓鼠,兔),伴侣动物(如猫,狗)和野生动物(例如啮齿动物,狐,鹿,长颈鹿)。
其中,TNFR2片段的序列与SEQ ID NO:17所示序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性,并且可以包含不影响其总体功能的突变。
其中,Fc结构域可以具有突变位点,其包括但不限于与SEQ ID NO:18-21任一项所示的序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性的序列。
其中,血清白蛋白的序列包括但不限于与SEQ ID NO:22具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性的序列。
其中,用于延长IL-1RN蛋白半衰期的结构域与可抑制IL-1活性的IL-1RN蛋白之间,通过柔软连接肽连接,所述连接肽的通式为(GnS)m,其中n为0-6的整数,优选n为0、1、2、3、4、5或6,m为1-4的整数,优选m为1、2、3或4;优选地,通式为(GlyGlyGlyGlySer)m,其中m为1-3的整数,优选m为1、2或3。该通式仅为示例,所有可以连接上述两部分的连接肽均在本发明的保护范围内。
进一步的,本发明还提供了一种融合蛋白或其变体或类似物,包括但不限于与SEQID NO:23-(IL-1RN D74N-hIgG4 Fc S228P)或SEQ ID NO:24(hIgG4 Fc S228P-IL-1RND74N)所示的序列具有至少70%、75%、80%、85%、90%、95%、96%、97%、98%、99%、99.5%或100%的序列同一性。其中由SEQ ID NO:23或SEQ ID NO:24所示序列表征的蛋白仅为融合蛋白的示例,如上所述,任何具备或不具备连接肽、以及延长半衰期的结构域的选择、双靶点设计的选择,从而获得的融合蛋白序列,均在本发明的保护范围内。本发明还进一步提供了编码上述融合蛋白的核苷酸序列。
进一步的,上述蛋白或其变体或类似物、融合蛋白或其变体或类似物,作为一个蛋白亚基,可选择的组合成为多肽复合物,每个亚基之间可相同或不同,所述蛋白亚基至少具有两个,每个蛋白亚基之间可/不采用连接肽进行连接。
上述蛋白或其变体或类似物、融合蛋白或其变体或类似物、多肽复合物,可选择的包括本领域已知的N端信号肽,可在本领域已知的载体中进行克隆、表达,并可选择的植入宿主细胞。
并且进一步的,本发明的蛋白或其变体或类似物、融合蛋白或其变体或类似物、多肽复合物可制备成药物组合物,所述药物组合物可选择的与一种或多种药学上可接受的载体或赋形剂混合制成不同给药途径的药物剂型,包括但不限于片剂、胶囊、散剂、颗粒剂、糖浆剂、溶液剂、口服液、醑剂、酊剂、气雾剂、粉雾剂、注射剂、注射用无菌粉末、栓剂等。本发明的蛋白或其变体或类似物、融合蛋白或其变体或类似物、多肽复合物可通过口服、静脉、肌肉、皮下等途径给药。“药学上可接受的”成分是适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。“药学上可接受的载体”是用于将本发明的蛋白或其变体或类似物、融合蛋白或其变体或类似物、多肽复合物递送给动物或人的药学上或食品上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体。
本发明进一步提供了白细胞介素-1受体拮抗剂突变体以及包含其的融合蛋白的制备方法。所述方法包括用编码融合蛋白的核苷酸序列转化宿主细胞,在适于表达和从细胞培养物中回收蛋白质的条件下进行培养,由转化细胞产生的蛋白质可以根据所用的序列和/或载体分泌或包含在细胞内。通过三步纯化工艺,纯化由CHO细胞表达的重组融合蛋白,蛋白质的总产率大于50%,并且通过HPLC测定目标蛋白质的纯度大于98.5%。
进一步的,本发明提供了对所设计、构建并纯化得到的目的蛋白经活性试验进行检测,结果表明,突变体融合蛋白,相对于野生型具有3倍的活性提高,增加连接肽,活性可进一步提高3倍。且突变体在小鼠CIA疾病模型中显示出了对炎症反应的完全抑制效应。
本发明公开的IL-1RN突变体以及融合蛋白可用来制备治疗炎症性疾病的药物,所述炎症性疾病包括关节炎、肠炎、哮喘、肺纤维化、肾小球肾炎、移植物抗宿主反应、急性肺损伤、严重角膜烧伤、类风湿性关节炎、Cryopyrin相关周期热综合征(CAPS)、特应性皮炎、化脓性汗腺炎、心血管疾病、非小细胞肺癌等中的一种或多种。
【附图说明】
图1为本发明实施例中的Mabselect SuRe层析图谱。
图2为本发明实施例中通过SEC-HPLC测定的Mabselect SuRe层析洗脱蛋白的纯度图。
图3为本发明实施例中的Capto Phenyl(HS)疏水层析图谱。
图4为本发明实施例中通过SEC-HPLC测定的Capto Phenyl(HS)疏水层析洗脱蛋白的纯度图。
图5为本发明实施例中的Capto adhere复合型离子交换层析图谱。
图6为本发明实施例中通过SEC-HPLC测定的Capto adhere复合型离子交换层析流穿蛋白的纯度图。
图7为本发明实施例中各纯化步骤样品的电泳(SDS-PAGE)图。
其中各泳道样品如下:
1.Marker
2.细胞培养上清液
3.亲和层析洗脱蛋白液
4.疏水层析洗脱蛋白液
5.复合层析流穿蛋白液
图8为IL-1RN-Fc融合蛋白细胞生物学活性检测结果图。
图9为双靶点融合蛋白细胞生物学活性检测结果图。
图10为DBA/1小鼠CIA功效结果图。
【具体实施方式】
·TNFR2-Fc融合蛋白的制备
根据CN1829739(A)中公开的Etanercept(TNFR2-Fc)的氨基酸序列设计其核苷酸序列并进行密码子优化。将人工合成的TNFR2-Fc基因克隆到载体pEE12.4中。对构建好的重组质粒进行测序,确认插入序列与设计序列完全一致。用限制性内切酶Pvu I对重组质粒进行线性化,然后转染CHO-K1细胞,采用MSX(L-Methionine Sulfoximine)筛选稳定表达目的蛋白的CHO细胞株。将筛选到的细胞株在摇瓶中进行发酵培养,发酵完成后通过离心去除发酵液中的细胞和细胞碎片,然后用0.22μm滤膜过滤,获得澄清的发酵液。发酵液首先用Protein A亲和层析进行粗提,填料为MabSelect SuReTM(GE Healthcare),用结合缓冲液(20mM PB,0.15M NaCl,pH 7.2)平衡填料,上样完成后再冲洗至基线,最后用洗脱缓冲液(50mM柠檬酸钠,pH 3.3)洗脱目的蛋白。将亲和层析洗脱物浓缩后进一步用凝胶过滤层析纯化,填料为Superdex 200(GE Healthcare),缓冲液为PBS,收集凝胶过滤层析的各个洗脱峰进行非还原SDS-PAGE分析,选择电泳纯度高且分子量与TNFR2-Fc一致的洗脱峰用于生物学活性分析,从而制备出TNFR2-Fc融合蛋白。
·蛋白的构建
首先根据目的蛋白的氨基酸序列进行密码子优化,并送基因合成公司进行DNA合成,然后将合成好并测序正确的目的基因插入到pEE12.4载体。该载体含有强启动子hCMV-MIE,复制子pEE6 ori,终止子SV40 poly(A)signal,复制起始位点SV40(ori),HindIII/EcoRI酶切位点以及谷氨酰胺合成酶基因。对构建好的重组质粒进行测序,确认插入序列与设计序列完全一致。用限制性内切酶Pvu I对重组质粒进行线性化,然后转染CHO-K1细胞,采用MSX(L-Methionine Sulfoximine)筛选稳定表达目的蛋白的CHO细胞株。
·细胞株的构建
提前准备CHO-K1细胞,转染前一天,调整细胞密度至0.5×106cells/mL。取1.43×107个细胞,经洗涤、离心,去除培养基中的GlutaMAX。用0.7mL CD CHO medium悬浮细胞,并加入40μg酶切线性质粒,混合均匀,转移至0.4cm电转杯中。调整电转仪以电容1000μF,电压300V电击。将电击后细胞迅速转移到37℃预热的150mL培养基中,50μL/孔,接种于96孔板中,5%CO2,37℃静置培养。转染24小时后,每孔补加150μL CD CHO medium(含66.6μMMSX),MSX终浓度为50μM,5%CO2,37℃继续培养。转染后培养21-28天,挑取长出的单克隆,扩增培养后,收获上清进行SDS-PAGE还原电泳检测,蛋白条带染色的深浅与蛋白浓度正相关。
·纯化目的蛋白
本实施例中的白细胞介素-1受体拮抗剂融合蛋白的纯化方法,包括以下步骤。
1.深层过滤后,将得到CHO细胞培养物,首先用Mabselect SuRe亲和层析纯化,捕
获融合蛋白液。
1.1四倍柱体积平衡溶液(20mmol/L PB,0.15mol/L NaCl pH7.2)平衡,并且pH和电导率监测值与平衡缓冲液一致。
1.2在加载样品之前,将紫外线吸收值设置为零。将经过深层过滤的培养上清液直接上样,样品保留时间为9分钟,上样量为15mg/ml。
1.3上样后,用三倍柱体积亲和色谱平衡溶液洗涤,然后用洗涤液1(20mmol/L PB,1.5mol/L NaCl,2.0mol/L尿素pH 7.2)。
1.4用洗涤溶液2(100mmol/L柠檬酸,0.3mol/L甘氨酸,10%山梨糖醇pH 5.5)洗涤柱,pH和电导率监测的显示值与冲洗缓冲液2一致。
1.5洗脱液(100mmol/L柠檬酸盐,0.3mol/L甘氨酸,15%海藻糖,30%山梨糖醇pH3.7)用于洗脱样品,并在280nm UV下收集蛋白质的主峰。UV的初始收集为120mAU,UV的最终收集为120mAU。
1.6用氢氧化钠洗涤三倍柱的体积,然后使用平衡溶液将柱的pH平衡至中性稳定性,然后使用三个柱体积的乙醇保存柱。
1.7。如图1所示,黑框标记是目标蛋白的Mabselect SuRe层析成像图;如图2所示,黑框标记是通过HPLC测定目标蛋白的纯度。
2.步骤1中捕获的融合蛋白通过Capto Phenyl(HS)疏水色谱法纯化以去除大部分
杂质:
2.1样品预处理:将亲和洗脱蛋白溶液用样品稀释液(20mmol/L PB,3.0mol/LNaCl pH7.1)以1:5的体积比稀释以调节pH7.1,电导率为165至175mS/厘米。
2.2使用平衡缓冲液(20mmol/L PB,2.2mol/L NaCl pH7.1)平衡色谱柱中四个色谱柱体积,pH和电导率监测值与平衡缓冲液一致。
2.3在加载样品之前,将uv吸收值设置为零。样品为步骤1中的Mabselect SuRe亲和层析洗脱的蛋白溶液,样品保留时间为9分钟,上样量为15mg/ml。
2.4样品加载完成后,用三倍柱体积平衡溶液冲洗色谱柱,以完全冲洗掉未结合的组分。
2.5用洗涤缓冲液(20mmol/L PB,1.8mol/L NaCl pH7.1)进一步洗涤两倍色谱柱体积,以除去一些弱结合的杂质。
2.6用洗脱缓冲液(20mmol/L PB,0.1mol/L NaCl pH7.1)洗脱样品,在280nm的紫外线下收集蛋白质的主峰,在100mAU处开始收集UV,然后停止收集UV在100mAU。
2.7用3倍柱体积再生缓冲液(0.1mol/L NaOH)洗涤,然后用水洗至中性,色谱柱中用3倍柱体积的20%乙醇存储。
2.8如图3所示,目标蛋白的Capto Phenyl(HS)色谱图用黑色方框标出;如图4所示,黑框的标记是通过HPLC测定目标蛋白的纯度图。
3.步骤2层析后的融合蛋白通过Capto adhere复合离子交换层析进行精制和纯
化,以去除少量杂质:
3.1使用平衡溶液(20mmol/L PB,0.5mol/L NaCl pH5.9)平衡5CV色谱柱,pH和电导率监测值与平衡溶液一致。
3.2样品加样,样品为步骤2的洗脱蛋白溶液,调节至与平衡溶液一致的条件后开始加样,样品上样时间为4.5分钟,样品上样量为115mg/ml,加载后使用平衡缓冲液平衡样品,直到收集样品为止。
3.3收集的蛋白质的主峰在280nm的紫外线吸收处。最初的UV收集为80mAU,最终的UV收集为100mAU。
3.4再生,用500mmol/L NaOH和2.0mol/L NaC洗涤5倍柱体积,然后用水洗涤至中性,色谱柱用3倍柱体积20%的乙醇柱保存。
3.5。如图5所示,黑块标记是目标蛋白的Capto粘附色谱图;如图6所示,黑框的标记是通过HPLC测定目标蛋白的纯度图。
4.0讨论
根据通过上述发明确定的Mabselect SuRe/Capto Phenyl(HS)/Capto adhere的三步纯化工艺条件,纯化由CHO细胞表达的重组形式的包含IL-1RN的融合蛋白。蛋白质的总产率大于50%,并且通过SEC-HPLC测定的目标蛋白质的纯度大于98.5%。
·结合亲和力测定
所有SPR测量均在BIAcore 3000仪器(GE Biosciences,Piscataway,N.J.)上进行。使用BIAcore软件-BIAcore 3000控制软件V3.2来操作和控制BIAcore 3000仪器。使用评估软件V4.1分析来自BIAcore 3000仪器的SPR数据,并使用Graph Pad Prism软件版本5绘制数据。使用HBS-EP缓冲液(10mM HEPES,15Mm NaCl,在25℃下使用3.4nM EDTA,0.005%P20)。亲和力研究的流速为30μL/分钟。所示的融合蛋白用作构建芯片参考通道的配体。测量与固定受体结合的分析物IL-1RN-Fc,浓度为1.2至100nM(3倍稀释度)。每个样品以30μL/min的流速注入3分钟,以便与芯片结合的融合蛋白结合。接下来,将不含分析物的结合缓冲液以相同的流速通过芯片,以使结合的分析物解离。500s之后,通过注入再生溶液(1M甲酸)去除残留的结合分析物。使用动力学向导和BiaEvaluation软件V4.1随附的手动拟合程序对数据进行了分析。
表1抗体结合活性
样品# | 受体 | <u>K<sub>a</sub></u>(1/<u>Ms</u>) | <u>K<sub>d</sub></u>(1s) | K<sub>D</sub>(M) | 相对亲和力 |
IL-1RN-Fc | IL-1R1 | 1.55E+05 | 1.82E-04 | 1.17E-9 | 1 |
IL-1RN R5T-Fc | IL-1R1 | 1.72E+05 | 5.75E-05 | 3.34E-10 | 3.5 |
IL-1RN R14T-Fc | IL-1R1 | 1.69E+05 | 8.05E-05 | 4.76E-10 | 2.5 |
IL-1RN D74N-Fc | IL-1R1 | 1.88E+05 | 2.06E-05 | 1.10E-10 | 10.7 |
IL-1RN R5TR14T-Fc | IL-1R1 | 1.79E+05 | 4.65E-05 | 2.60E-10 | 4.5 |
IL-1RN R5TD74N-Fc | IL-1R1 | 1.89E+05 | 1.83E-05 | 0.97E-10 | 12.1 |
IL-1RN R14TD74N-Fc | IL-1R1 | 1.85E+05 | 1.98E-05 | 1.07E-10 | 11.0 |
IL-1RN R5TR14TD74N-Fc | IL-1R1 | 1.92E+05 | 1.75E-05 | 0.91E-10 | 12.9 |
(示例性的,选用hIg64 Fc S228P作为延长半衰期结构域的选择,以及示例性的,选择GGGGSGGGGSGGGGS作为连接肽。)
·重组人IL-1RN-Fc融合蛋白生物学活性测定
根据IL-1β可诱导A375.s2凋亡,IL-1RN蛋白可抑制此过程的原理来检测其生物学活性。A375.s2细胞使用MEM加10%FBS培养基培养。将A375.s2细胞以1.5×105个/ml,80μl/孔铺于96孔板。将IL-1β(R&D systems)浓度调节至10μg/ml,每孔加入10μl。再将IL-1RN-Fc融合蛋白浓度调节至100μg/ml,以此为最高浓度,4倍梯度稀释成8个浓度,每孔加入10μl。37℃培养96小时后,每孔加入20μl MTS检测试剂(Promega),37℃孵育0.5小时后,酶标仪490nm波长读数。检测结果如下所示:
表2重组人IL-1RN-Fc融合蛋白生物学活性检测结果
结果显示:无linker(连接肽)情况下,突变体D74N(w/o linker)是野生型生物活性的3倍。突变体D74N(w/linker)是没有linker的突变体D74N(w/o linker)的生物学活性的3倍,结果参见图8。(示例性的,选择IL-1RN(D74N)作为突变的IL-1RN,示例性的,选用hIgG4 Fc S228P作为延长半衰期结构域的选择,以及示例性的,选择GGGGSGGGGSGGGGS作为连接肽。)
表3重组人IL-1RN突变体-Fc融合蛋白生物学活性检测结果
结果显示:单位点突变体的生物学活性为D74N>R14T>R5T;三位点突变体的生物学活性高于双位点和单位点突变体。(示例性的,选用hIgG4 Fc S228P作为延长半衰期结构域的选择,以及示例性的,选择GGGGSGGGGSGGGGS作为连接肽。)
表4重组双靶点融合蛋白生物学活性检测结果
结果显示:双靶点融合蛋白的生物学活性与单靶点融合蛋白相当,结果参见图9。(示例性的,选择IL1-RN(D74N)和TNFR2作为双靶点蛋白,示例性的,选用hIgG4 Fc S228P作为延长半衰期结构域的选择,以及示例性的,选择GGGGSGGGGSGGGGS作为连接肽。)
·免疫模型与治疗实验
一、小鼠CIA模型制备
1.初次免疫
3.3ml完全弗氏佐剂分三次加入到胶原中进行乳化,每只小鼠腹腔注射0.4ml麻醉剂,待小鼠麻醉后用电动剃刀剔去尾根部被毛,在尾根部皮内注射100μl乳化胶原。
2.加强免疫
在初次免疫21天后进行第二次加强免疫,免疫前一天准备小鼠第二次免疫的麻醉剂和胶原。乳化抗原的过程中,3.3ml不完全弗氏佐剂佐剂分三次加入到胶原中进行乳化,每只小鼠腹腔注射0.4ml麻醉剂,待小鼠麻醉后用电动剃刀剔去尾根部被毛,尾根部皮内注射50μl乳化胶原。
二、药物治疗
1.小鼠二次免疫后4~10天开始发病。造模小鼠在发病24小时内进行随机分组,进行腹腔注射给药,连续观察21天。在用药治疗期间每隔一天进行一次关节评分及体重称量。
2.实验分组
除空白对照组小鼠外,所有小鼠均进行CIA造模,待小鼠发病出模24小时内评分并随机分组进行治疗,药物治疗周期21天。
表5小鼠CIA模型动物实验
分组 | 是否造模 | 给药频率 | 给药剂量 | 给药方式 | 每组数量 | |
1 | 空白对照组 | 否 | ---- | ---- | ---- | 3只 |
2 | PBS对照组 | 是 | 一次/周 | PBS(400ul) | 腹腔注射 | 5只 |
3 | TNFR2-Fc阳性对照组 | 是 | 一次/周 | 10mg/kg(400ul) | 腹腔注射 | 8只 |
4 | IL-1RN-Fc组 | 是 | 一次/周 | 10mg/kg(400ul) | 腹腔注射 | 8只 |
5 | IL-1RN D74N-Fc组 | 是 | 一次/周 | 10mg/kg(400ul) | 腹腔注射 | 8只 |
结果显示:在小鼠CIA动物模型中,同等注射剂量的野生型IL-1RN-Fc与TNFR2-Fc融合蛋白的药效相当,而突变型IL-1RN D74N-Fc显示出了对炎症反应的完全抑制效应,结果参见图10。(示例性的,选择IL-RN(D74N)突变体,连接肽选择GGGGSGGGGSGGGGS,Fc为hIgG4 Fc S228P。)
虽然本发明是通过具体实施例进行说明的,本领域技术人员应当明白,在不脱离本发明范围的情况下,还可以对本发明进行各种变换及等同替代。另外,针对特定情形或材料,可以对本发明做各种修改,而不脱离本发明的范围。因此,本发明不局限于所公开的具体实施例,而应当包括落入本发明权利要求范围内的全部实施方式。
序列表
<110> 北京伟德杰生物科技有限公司
<120> 一种白细胞介素-1受体拮抗剂以及包含其的融合蛋白
<130> RYP2010695.3
<160> 24
<170> SIPOSequenceListing 1.0
<210> 1
<211> 152
<212> PRT
<213> 野生型IL-1RN蛋白序列()
<400> 1
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 2
<211> 456
<212> DNA
<213> 野生型IL-1RN核苷酸序列()
<400> 2
cgaccctctg ggagaaaatc cagcaagatg caagccttca gaatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggtg atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 3
<211> 152
<212> PRT
<213> IL-1RN D74N蛋白序列()
<400> 3
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 4
<211> 456
<212> DNA
<213> IL-1RN D74N核苷酸序列()
<400> 4
cgaccctctg ggagaaaatc cagcaagatg caagccttca gaatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggta atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 5
<211> 152
<212> PRT
<213> IL-1RN R5T蛋白序列()
<400> 5
Arg Pro Ser Gly Thr Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 6
<211> 456
<212> DNA
<213> IL-1RN R5T核苷酸序列()
<400> 6
cgaccctctg ggacaaaatc cagcaagatg caagccttca gaatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggtg atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 7
<211> 152
<212> PRT
<213> IL-1RN R14T蛋白序列()
<400> 7
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Thr Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 8
<211> 456
<212> DNA
<213> IL-1RN R14T核苷酸序列()
<400> 8
cgaccctctg ggagaaaatc cagcaagatg caagccttca caatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggtg atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 9
<211> 152
<212> PRT
<213> IL-1RN R5T+R14T蛋白序列()
<400> 9
Arg Pro Ser Gly Thr Lys Ser Ser Lys Met Gln Ala Phe Thr Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 10
<211> 456
<212> DNA
<213> IL-1RN R5T+R14T核苷酸序列()
<400> 10
cgaccctctg ggacaaaatc cagcaagatg caagccttca caatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggtg atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 11
<211> 152
<212> PRT
<213> IL-1RN R5T+D74N蛋白序列()
<400> 11
Arg Pro Ser Gly Thr Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 12
<211> 456
<212> DNA
<213> IL-1RN R5T+D74N核苷酸序列()
<400> 12
cgaccctctg ggacaaaatc cagcaagatg caagccttca gaatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggta atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 13
<211> 152
<212> PRT
<213> IL-1RN R14T+D74N蛋白序列()
<400> 13
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Thr Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 14
<211> 456
<212> DNA
<213> IL-1RN R14T+D74N核苷酸序列()
<400> 14
cgaccctctg ggagaaaatc cagcaagatg caagccttca caatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggta atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 15
<211> 152
<212> PRT
<213> IL-1RN R5T,R14T,D74N蛋白序列()
<400> 15
Arg Pro Ser Gly Thr Lys Ser Ser Lys Met Gln Ala Phe Thr Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu
145 150
<210> 16
<211> 456
<212> DNA
<213> IL-1RN R5T,R14T,D74N核苷酸序列()
<400> 16
cgaccctctg ggacaaaatc cagcaagatg caagccttca caatctggga tgttaaccag 60
aagaccttct atctgaggaa caaccaacta gttgctggat acttgcaagg accaaatgtc 120
aatttagaag aaaagataga tgtggtaccc attgagcctc atgctctgtt cttgggaatc 180
catggaggga agatgtgcct gtcctgtgtc aagtctggta atgagaccag actccagctg 240
gaggcagtta acatcactga cctgagcgag aacagaaagc aggacaagcg cttcgccttc 300
atccgctcag acagcggccc caccaccagt tttgagtctg ccgcctgccc cggttggttc 360
ctctgcacag cgatggaagc tgaccagccc gtcagcctca ccaatatgcc tgacgaaggc 420
gtcatggtca ccaaattcta cttccaggag gacgag 456
<210> 17
<211> 235
<212> PRT
<213> TNFR2蛋白序列()
<400> 17
Leu Pro Ala Gln Val Ala Phe Thr Pro Tyr Ala Pro Glu Pro Gly Ser
1 5 10 15
Thr Cys Arg Leu Arg Glu Tyr Tyr Asp Gln Thr Ala Gln Met Cys Cys
20 25 30
Ser Lys Cys Ser Pro Gly Gln His Ala Lys Val Phe Cys Thr Lys Thr
35 40 45
Ser Asp Thr Val Cys Asp Ser Cys Glu Asp Ser Thr Tyr Thr Gln Leu
50 55 60
Trp Asn Trp Val Pro Glu Cys Leu Ser Cys Gly Ser Arg Cys Ser Ser
65 70 75 80
Asp Gln Val Glu Thr Gln Ala Cys Thr Arg Glu Gln Asn Arg Ile Cys
85 90 95
Thr Cys Arg Pro Gly Trp Tyr Cys Ala Leu Ser Lys Gln Glu Gly Cys
100 105 110
Arg Leu Cys Ala Pro Leu Arg Lys Cys Arg Pro Gly Phe Gly Val Ala
115 120 125
Arg Pro Gly Thr Glu Thr Ser Asp Val Val Cys Lys Pro Cys Ala Pro
130 135 140
Gly Thr Phe Ser Asn Thr Thr Ser Ser Thr Asp Ile Cys Arg Pro His
145 150 155 160
Gln Ile Cys Asn Val Val Ala Ile Pro Gly Asn Ala Ser Met Asp Ala
165 170 175
Val Cys Thr Ser Thr Ser Pro Thr Arg Ser Met Ala Pro Gly Ala Val
180 185 190
His Leu Pro Gln Pro Val Ser Thr Arg Ser Gln His Thr Gln Pro Thr
195 200 205
Pro Glu Pro Ser Thr Ala Pro Ser Thr Ser Phe Leu Leu Pro Met Gly
210 215 220
Pro Ser Pro Pro Ala Glu Gly Ser Thr Gly Asp
225 230 235
<210> 18
<211> 232
<212> PRT
<213> IgG1Fc蛋白序列()
<400> 18
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 19
<211> 232
<212> PRT
<213> IgG1Fc突变体蛋白序列()
<400> 19
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Ala Glu Gly Ala Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 20
<211> 228
<212> PRT
<213> IgG2Fc蛋白序列()
<400> 20
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Met Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
100 105 110
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Pro Gly Lys
225
<210> 21
<211> 229
<212> PRT
<213> IgG4Fc突变体蛋白序列()
<400> 21
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 22
<211> 585
<212> PRT
<213> HSA蛋白序列()
<400> 22
Asp Ala His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu
1 5 10 15
Glu Asn Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln
20 25 30
Gln Cys Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu
65 70 75 80
Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu
100 105 110
Pro Arg Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His
115 120 125
Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg
145 150 155 160
Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala
165 170 175
Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser
180 185 190
Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro
210 215 220
Lys Ala Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys
225 230 235 240
Val His Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser
260 265 270
Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His
275 280 285
Cys Ile Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser
290 295 300
Leu Ala Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr
340 345 350
Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu
355 360 365
Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro
370 375 380
Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu
385 390 395 400
Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys
420 425 430
Val Gly Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys
435 440 445
Ala Glu Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His
450 455 460
Glu Lys Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser
465 470 475 480
Leu Val Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp
500 505 510
Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Val Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu
530 535 540
Lys Ala Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys
545 550 555 560
Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val
565 570 575
Ala Ala Ser Gln Ala Ala Leu Gly Leu
580 585
<210> 23
<211> 396
<212> PRT
<213> IL-1RN D74N-hIgG4 Fc S228P 蛋白序列()
<400> 23
Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala Phe Arg Ile Trp
1 5 10 15
Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn Gln Leu Val Ala
20 25 30
Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu Lys Ile Asp Val
35 40 45
Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly Lys
50 55 60
Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr Arg Leu Gln Leu
65 70 75 80
Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp Lys
85 90 95
Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe Glu
100 105 110
Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala Asp
115 120 125
Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val Thr
130 135 140
Lys Phe Tyr Phe Gln Glu Asp Glu Gly Gly Gly Gly Ser Gly Gly Gly
145 150 155 160
Gly Ser Gly Gly Gly Gly Ser Glu Ser Lys Tyr Gly Pro Pro Cys Pro
165 170 175
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
180 185 190
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
195 200 205
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
210 215 220
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
225 230 235 240
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
245 250 255
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
260 265 270
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
275 280 285
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
290 295 300
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
305 310 315 320
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
325 330 335
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
340 345 350
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
355 360 365
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
370 375 380
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
385 390 395
<210> 24
<211> 396
<212> PRT
<213> hIgG4 Fc S228P-IL-1RN D74N 蛋白序列()
<400> 24
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
225 230 235 240
Gly Gly Gly Ser Arg Pro Ser Gly Arg Lys Ser Ser Lys Met Gln Ala
245 250 255
Phe Arg Ile Trp Asp Val Asn Gln Lys Thr Phe Tyr Leu Arg Asn Asn
260 265 270
Gln Leu Val Ala Gly Tyr Leu Gln Gly Pro Asn Val Asn Leu Glu Glu
275 280 285
Lys Ile Asp Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile
290 295 300
His Gly Gly Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asn Glu Thr
305 310 315 320
Arg Leu Gln Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg
325 330 335
Lys Gln Asp Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr
340 345 350
Thr Ser Phe Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala
355 360 365
Met Glu Ala Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly
370 375 380
Val Met Val Thr Lys Phe Tyr Phe Gln Glu Asp Glu
385 390 395
Claims (16)
1.IL-1RN蛋白或其变体,其特征在于:所述蛋白或其变体的氨基酸序列选自SEQ IDNO:3、5、7、9、11、13、15所示的序列,并且突变位点为在N末端第5、14、74位的至少一个;
所述突变位点选自R5T、R14T、D74N中的至少一个。
2.编码权利要求1所述的蛋白或其变体的核酸。
3.融合蛋白或其变体,所述融合蛋白或其变体通过用于延长IL-1RN蛋白半衰期的结构域与权利要求1所述的IL-1RN蛋白或其变体连接构成;其中所述结构域为Fc结构域。
4.如权利要求3所述的融合蛋白或其变体,进一步包括肿瘤坏死因子受体2或其变体。
5.如权利要求4所述的融合蛋白或其变体,其中所述变体为肿瘤坏死因子受体2胞外结构域。
6.如权利要求3所述的融合蛋白或其变体,所述Fc结构域为选自IgG1Fc、IgG2Fc、IgG3Fc、IgG4Fc、IgMFc、IgAFc、IgDFc及其变体中的一种或多种。
7.如权利要求3或4所述的融合蛋白或其变体,其中用于延长IL-1RN蛋白半衰期的结构域,IL-1RN蛋白和TNFR2之间通过连接肽连接,所述连接肽为通式(GlyGlyGlyGlySer)m所示的连接肽,其中m为1-3的整数。
8.如权利要求7所述的融合蛋白或其变体,其中通式(GlyGlyGlyGlySer)m中,m为1。
9.如权利要求7所述的融合蛋白或其变体,其中通式(GlyGlyGlyGlySer)m中,m为2。
10.如权利要求7所述的融合蛋白或其变体,其中通式(GlyGlyGlyGlySer)m中,m为3。
11.载体,其能够表达权利要求1所述的IL-1RN蛋白或其变体或权利要求3-10任一项所述的融合蛋白或其变体。
12.宿主细胞,其包含权利要求11所述的载体。
13.多肽复合物,其中包含权利要求1所述的蛋白或其变体或权利要求3-10任一项所述的融合蛋白或其变体中的至少两种。
14.一种药物组合物,包括权利要求1所述的蛋白或其变体、权利要求3-10任一项所述的融合蛋白或其变体、权利要求11所述的载体、权利要求12所述的细胞或权利要求13所述的多肽复合物和制药学上可接受的载体或添加剂。
15.权利要求1所述的蛋白或其变体、权利要求3-10任一项所述的融合蛋白或其变体、权利要求11所述的载体、权利要求12所述的细胞或权利要求13所述的多肽复合物、权利要求14所述的药物组合物在制备用于治疗和预防炎症性相关疾病的药物中的用途,其中,所述炎症性相关疾病选自关节炎、Cryopyrin相关周期热综合征和非小细胞肺癌中的一种或多种。
16.如权利要求15所述的用途,其中所述关节炎为类风湿性关节炎。
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