CN114907477A - 抗人il-36r抗体及其应用 - Google Patents
抗人il-36r抗体及其应用 Download PDFInfo
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- CN114907477A CN114907477A CN202210117681.4A CN202210117681A CN114907477A CN 114907477 A CN114907477 A CN 114907477A CN 202210117681 A CN202210117681 A CN 202210117681A CN 114907477 A CN114907477 A CN 114907477A
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Abstract
本发明公开了抗人IL‑36R单克隆抗体及其应用。通过杂交瘤技术制备鼠源抗人IL‑36R单克隆抗体,对鼠源抗人IL‑36R抗体进行筛选获得能特异性结合人IL‑36R并与食蟹猴IL‑36R具有交叉反应的抗体,构建人‑鼠嵌合抗人IL‑36R单克隆抗体,检测其与细胞表面IL‑36R结合实验。在鼠源抗体、嵌合抗体性能分析的基础上,采用CDRs移植技术、CDR区突变设计构建人源化抗人IL‑36R单克隆抗体,分析结合活性、亲和力、种间IL‑36R交叉反应,所述人源化抗人IL‑36R单克隆抗体能抑制IL36诱导的炎性细胞因子分泌。
Description
优先权信息
本申请请求2021年2月8日向中国国家知识产权局提交的、专利申请号为202110183575.1的专利申请的优先权和权益,并且通过参照将其全文并入此处。
技术领域
本发明涉及抗体工程领域,具体涉及一种抗人IL-36R单克隆抗体及其应用,特别是涉及一种针对人IL-36R具有高亲和力、与猴IL-36R具有交叉反应的鼠源单克隆抗体、嵌合抗体、人源化抗体及其应用。
背景技术
白介素36,即IL-36,包括IL-36α,IL-36β和IL-36γ(也叫IL-1F6,IL-1F8和IL-1F9),是白介素1(IL-1)的家族成员,其受体是IL-36R(也叫做IL-1RL2或IL-1Rrp2)。白介素1(IL-1)家族是由11个不同配体组成,即IL-1α(也叫做IL-1F11)、IL-1β(IL-1F2)、IL-1受体拮抗剂(IL-1F3或IL-1Ra)、IL-18(IL-1F4)、IL-1F5至IL-1F10和IL-1F11(即IL-33)IL-36Ra(也叫做IL-1F5)是IL-36R天然的拮抗剂。IL-36作为一种新发现的促炎因子,在银屑病、炎性肠病、关节炎、系统性红斑狼疮、肺部疾病等多种炎性疾病中发挥着重要作用。
IL36受体拮抗剂(IL36 receptor antagonist,IL36Ra)是其天然拮抗剂。细胞外的IL-36与跨膜蛋白IL-36R结合后,招募IL-1受体辅助蛋白(IL-1 receptor accessoryprotein,IL-1RAcP),形成异源三聚体复合物,通过胞内区功能域与接头蛋白髓样分化蛋白88(MyD88)结合,活化MAPKs/JNK/ERK信号级联途径,通过核转录因子NFKB启动靶基因的表达,从而发挥促炎症作用。而IL-36Ra与IL-36a、IL-36b和IL-36y竞争性结合IL-36R。IL-36Ra与IL-36R结合后的复合物不能招募IL-1RAcP结合,从而不能激活信号转导通路而起到抗炎症作用。
随着IL-36R对炎性疾病发生发展的作用机理日渐清晰,治疗性抗人IL-36R抗体吸引了越来越多的关注。我们经过研究发现现有技术存在以下不足:首先,抗人IL-36R抗体在抗炎、减少炎症细胞因子释放等方面的能力与其对人IL-36R的结合能力的相关性并不稳定,前期试验结果表明并非亲和力越高抗炎效果越好,抗人IL-36R抗体对炎症的治疗效果受到除亲和力以外其它因素的影响。其次,抗人IL-36R对细胞膜表面IL-36R的结合易激发效应子活性加重局部炎症和损伤,一定程度上影响甚至抵消了抗人IL-36R抗体对炎症的治疗效果。另外,小鼠IL-36不与人IL-36受体相互作用,动物造模困难、动物试验难以有效模拟对人类患者的治疗情况。由此,抗IL-36R抗体有待进一步研究。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。本发明提供一种抗人IL-36R单克隆抗体及其应用。通过杂交瘤技术制备鼠源抗人IL-36R单克隆抗体,对鼠源抗人IL-36R抗体进行筛选获得能特异性结合人IL-36R并与食蟹猴IL-36R具有交叉反应的抗体,构建人-鼠嵌合抗人IL-36R单克隆抗体,检测其与细胞表面IL-36R结合实验。在鼠源抗体、嵌合抗体性能分析的基础上,采用CDRs移植技术、CDR区突变设计构建人源化抗人IL-36R单克隆抗体,分析结合活性、亲和力、种间IL-36R交叉反应,所述人源化抗人IL-36R单克隆抗体能抑制IL36诱导的炎性细胞因子分泌。
具体而言:
一方面,本发明提供一种抗人IL-36R抗体或其片段。根据本发明的实施例,该人IL-36R抗体或其片段能够特异性结合人IL-36R和猴IL-36R,并且对人IL-36R的结合能力高于对猴IL-36R的结合能力。
本发明实施例的抗人IL-36R抗体或其片段,在杂交瘤筛选过程中即选择了对人IL-36R、猴IL-36R均具有特异性结合能力的候选抗体,在人源化改造过程中也兼顾了对猴IL-36R的特异性,人源化抗人IL-36R抗体可以直接施用于猴皮肤炎症动物模型用于临床期评估治疗效果。
进一步,根据本发明的实施例,该抗人IL-36R抗体或其片段与鼠IL-36R无特异性结合,与IL-1家族其它成员的细胞受体无特异性结合。
进一步,该抗人IL-36R抗体或其片段与人IL-36R结合的KD值<5×109。由此,该抗体或其片段与人IL-36R的亲和力强。
通过分析抗体的氨基酸序列来鉴定抗体的CDR区的方法是公知的,并且CDR的许多定义是常用的。Kabat定义基于序列变异性,Chothia定义基于结构环区域的位置。除非在本公开内容中特别指出,否则在本公开内容中默认使用Kabat编号。
根据本发明的实施例,该抗人IL-36R抗体包括:重链可变区,所述重链可变区(VH)包括抗原决定区(CDRs)1、2和3,其中,VH CDR1包含与所选VH CDR1氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR2包含与所选VH CDR2氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR3与所选VH CDR3氨基酸序列具有至少75%同一性的氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性;轻链可变区,所述轻链可变区(VL)包括CDRs 1、2和3,其中,VL CDR1包含与所选VL CDR1氨基酸序列具有至少75%同一性的氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性;VLCDR2包含与所选VL CDR2氨基酸序列具有至少75%同一性的氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性;VL CDR3与所选VL CDR3氨基酸序列具有至少75%同一性的氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性。
根据本发明的一些实施例,所述所选VH CDRs 1、2和3的氨基酸序列以及所述所选VL CDRs 1、2和3的氨基酸序列选自下列之一:
所述所选VH CDRs 1和3的氨基酸序列分别如SEQ ID NO:27和30所示,VH CDR2具有GEIFPNX1GR所示的氨基酸序列,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:31、32和33所示;
所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:34、35和36所示,且所述所选VL CDRs 1和2的氨基酸序列如SEQ ID NO:37和38所示,VL CDR3具有QQYX2X3YPLT所示的氨基酸序列,
其中,
X1为S或T;
X2为N或T;
X3为S或T。
根据本发明实施例的抗人IL-36R抗体或其片段能结合到靶细胞膜表面IL-36R激发效应子活性,通过ADCC或CDC效应杀伤靶细胞,从而释放炎症细胞因子、加重局部炎症和损伤。根据本发明的实施例,由于IgG4亚型抗体效应子活性低但稳定性较差,本发明实施例的抗人IL-36R抗体采用IgG1亚型的重链恒定区并对其进行突变改造,即保持了IgG1亚型抗体的稳定性又消除或降低了效应子活性。
根据本发明的实施例,所述VH包括与SEQ ID NO:5具有至少75%同一性氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性,且所述VL包括与SEQID NO:11具有至少75%同一性氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性。
根据本发明的实施例,所述VH包括与SEQ ID NO:15具有至少75%同一性氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性且所述VL包括与SEQID NO:18具有至少75%同一性氨基酸序列,具体地,可以是至少80、83、85、88、90、93、95、98和99%以上同一性。
根据本发明的实施例,所述VH包括SEQ ID NO:1、5、6、7、8、9或10所示的氨基酸序列,所述VL包括SEQ ID NO:2、11、12、13或14所示的氨基酸序列。
根据本发明的实施例,所述VH包括SEQ ID NO:3、15、16或17所示的氨基酸序列,所述VL包括SEQ ID NO:4、18、19、20、21、22、23、24、25或26所示的氨基酸序列。
其中,具有至少75%同一性氨基酸序列,可以是与原序列具有0、1、2或多个氨基酸插入、缺失或替换的氨基酸序列。
进一步,根据本发明的实施例,所述VH包括SEQ ID NO:1、5、6、7、8、9或10所示的氨基酸序列,所述VL包括SEQ ID NO:2、11、12、13或14所示的氨基酸序列。
根据本发明的实施例,所述VH包括SEQ ID NO:3、15、16或17所示的氨基酸序列,所述VL包括SEQ ID NO:4、18、19、20、21、22、23、24、25或26所示的氨基酸序列。
更进一步,根据本发明的实施例,具有SEQ ID NO:27所示氨基酸序列的HCDR1、SEQID NO:28-29任一所示氨基酸序列的HCDR2、SEQ ID NO:30所示氨基酸序列的HCDR3,且具有SEQ ID NO:31所示氨基酸序列的LCDR1、SEQ ID NO:32所示氨基酸序列的LCDR2、SEQ IDNO:33所示氨基酸序列的LCDR3;或
具有SEQ ID NO:34所示氨基酸序列的HCDR1、SEQ ID NO:35所示氨基酸序列的HCDR2、SEQ ID NO:36所示氨基酸序列的HCDR3;且具有SEQ ID NO:37所示氨基酸序列的LCDR1、SEQ ID NO:38所示氨基酸序列的LCDR2、SEQ ID NO:39-40和74中任一所示氨基酸序列的LCDR3。
进一步,根据本发明的实施例,具有选自SEQ ID NO:1、5-10中任一氨基酸序列所示重链可变区,选自SEQ ID NO:2、11-14中任一氨基酸序列所示轻链可变区;或
具有选自SEQ ID NO:3、15-17中任一氨基酸序列所示重链可变区,选自SEQ IDNO:4、18-26中任一氨基酸序列所示轻链可变区。
进一步,根据本发明的实施例,该抗人IL-36R抗体或其片段能够阻断IL36α、IL36β、和/或IL36γ诱导的IL36R+细胞炎性细胞因子释放,不具有效应子活性或效应子活性显著降低,其中,所述炎性细胞因子包括IL-8,所述效应子活性包括ADCC和CDC。
更进一步,根据本发明的实施例,所述抗体包括鼠源抗体、兔源抗体、人源抗体、嵌合抗体等;所述抗体部分包括Fab、Fab’、F(ab’)2、Fv、scFv、dAb等。
第二方面,本发明提供一种人源化抗人IL-36R抗体或其片段。根据本发明的实施例,该人源化抗人IL-36R抗体或其片段是在本发明前述抗人IL-36R抗体或其片段的基础上进行CDRs移植获得。
进一步,根据本发明的实施例,该人源化抗人IL-36R抗体或其片段具有IgG1亚类的重链恒定区,且在所述IgG1亚类重链恒定区的234和235位的亮氨酸(L)均突变为丙氨酸(A)。
第三方面,本发明提供一种多核苷酸。根据本发明的实施例,该多核苷酸编码本发明前述任一项所述抗人IL-36R抗体或其片段、或本发明前述任一项所述人源化抗人IL-36R抗体或其片段。
第四方面,本发明提供一种构建体,根据本发明的实施例,该构建体包含前述多核苷酸。
第五方面,本发明提供一种宿主细胞,根据本发明的实施例,该宿主细胞包含前文所述的多核苷酸或前文所述的核酸构建体。
第六方面,本发明提供一种组合物,根据本发明的实施例,该组合物包含本发明前述任一项所述抗人IL-36R抗体或其片段、前述任一项所述人源化抗人IL-36R抗体或其片段、前述多核苷酸和/或前述核酸构建体,以及可选的药学上可接受的辅料。
第七方面,本发明提供一种组合物。根据本发明的实施例,该组合物包含两种或两种以上抗人IL-36R单克隆抗体,所述两种或两种以上抗人IL-36R单克隆抗体选自前述任一项所述抗人IL-36R抗体或其片段、前述任一项所述人源化抗人IL-36R抗体或其片段;并且所述两种或两种以上抗人IL-36R单克隆抗体相互之间对人IL-36R无竞争结合关系。
第八方面,本发明提供一种制备抗人IL-36R抗体或其片段的方法。根据本发明的实施例,该方法包括:
(1)在合适的条件下,培养本发明前述的宿主细胞;
(2)分离回收抗人IL-36R抗体或其片段、人源化抗人IL-36R抗体或其片段。
第九方面,本发明提供前述任一项所述抗人IL-36R抗体或其片段、前述任一项所述人源化抗人IL-36R抗体或其片段、前述多核苷酸、前述构建体、前述宿主细胞和前述任一项所述组合物在制备治疗炎性疾病的药物中的应用。
进一步,根据本发明的实施例,所述炎性疾病是IL36相关的炎性疾病,所述药物通过阻断IL36α、IL36β、和/或IL36γ诱导与细胞受体IL36R的结合发挥治疗炎性疾病的作用。
更进一步,根据本发明的实施例,所述炎性疾病包括皮炎、银屑病、炎性肠病、关节炎、系统性红斑狼疮、炎性肺病、慢性肾病;其中银屑病包括脓疱型银屑病、泛发性银屑病和掌跖脓疱病。
进一步,根据本发明的实施例,所述炎性疾病具有皮肤损伤症状,所述药物通过阻断IL36α、IL36β、和/或IL36γ诱导与细胞受体IL36R的结合改善皮肤损伤。
第十方面,本发明提供了治疗患有癌症或炎性疾病的对象的方法。根据本发明的实施例,所述方法包括向所述对象施用治疗有效量的组合物,所述组合物为前述的组合物。
根据本发明的实施例,所述炎性疾病包括皮炎、银屑病、炎性肠病、关节炎、系统性红斑狼疮、炎性肺病和慢性肾病。
根据本发明的实施例,所述银屑病包括脓疱型银屑病、泛发性银屑病和掌跖脓疱病。
根据本发明的实施例,所述癌症为乳腺癌。
第十一方面,本发明提供了一种用于治疗或预防有需要的个体的IL-36R介导的疾病的方法。根据本发明的实施例,该方法包含任选地与另一种治疗剂结合施用治疗有效量的前述的组合物。
为更好理解本发明,首先定义一些术语。其他定义则贯穿具体实施方式部分而列出。
术语“IL-36R”,是细胞表面能与IL-36相互作用的膜蛋白,能够与IL-36α、IL-36β、IL-36γ、以及IL-36Ra结合。其中IL-36α、IL-36β、IL-36γ为IL-36R受体激动剂,IL-36Ra为IL-36R受体拮抗剂。在人体内,编码IL-36Ra的基因失活突变会导致IL-36R信号失调,主要表现为弥漫型脓疱银屑病,这表明IL-36在银屑病的皮肤炎症中有重要作用。研究表明IL-36在其他器官的炎症性疾病中也有重要作用。
术语“特异性结合”是指,两分子间的非随机的结合反应,如抗体和其所针对的抗原之间的反应。术语“免疫结合”是指发生在抗体分子和抗原(对于该抗原而言抗体为特异性的)之间的特异性结合反应。免疫结合相互作用的强度或亲和力可以相互作用的平衡解离常数(KD)表示,其中KD值越小,表示亲和力越高。两分子间的的免疫结合性质可使用本领域中公知的方法定量。一种方法涉及测量抗原结合位点/抗原复合物形成和解离的速度。指特定抗体-抗原相互作用的“结合速率常数”(Ka或Kon)和“解离速率常数”(Kd或Koff)两者都可通过浓度及缔合和解离的实际速率而计算得出,参见Malmqvist M,1993,Nature,361:186-187。Kd/Ka的比率等于解离常数KD,参见Davies DR等,1990,Annual Rev Biochem.,59:439-473。可用任何有效的方法测量KD、Ka和Kd值。在优选的实施方案中,用生物发光干涉测量法来测量解离常数。在其它优选的实施方案中,可用表面等离子共振技术(例如Biacore)或KinExa来测量解离常数。
本文中的术语“抗体”意在包括全长抗体及其任何抗原结合片段(即,抗原结合部分)或单链。全长抗体是包含至少两条重(H)链和两条轻(L)链的糖蛋白,重链和轻链由二硫键连接。各重链由重链可变区(简称VH)和重链恒定区构成。重链恒定区由三个结构域构成,即CH1、CH2和CH3。各轻链由轻链可变区(简称VL)和轻链恒定区构成。轻链恒定区由一个结构域CL构成。VH和VL区还可以划分为称作互补决定区(CDR)的高变区,其由较为保守的框架区(FR)区分隔开。各VH和VL由三个CDR以及四个FR构成,从氨基端到羧基端以FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4的顺序排布。重链和轻链的可变区包含与抗原相互作用的结合域。抗体的恒定区可以介导免疫球蛋白与宿主组织或因子的结合,包括多种免疫系统细胞(例如,效应细胞)和传统补体系统的第一组分(C1q)。
术语“单克隆抗体”或“单抗”或“单克隆抗体组成”是指单一分子组成的抗体分子制品。单克隆抗体组成呈现出对于特定表位的单一结合特异性和亲和力。
本文中的术语,抗体的“抗原结合片段”(或简称为抗体片段),是指抗体的保持有特异结合抗原能力的一个或多个片段。已证实,抗体的抗原结合功能可以通过全长抗体的片段来实施。包含在抗体的“抗原结合部分”中的结合片段的例子包括(i)Fab片段,由VL、VH、CL和CH1构成的单价片段;(ii)F(ab′)2片段,包含铰链区二硫桥连接的两个Fab片段的二价片段;(iii)由VH和CH1构成的Fd片段;(iv)由抗体单臂VL和VH构成的Fv片段;(v)由VH构成的dAb片段(Ward et al.,(1989)Nature 341:544-546);(vi)分离的互补决定区(CDR);以及(vii)纳米抗体,一种包含单可变结构域和两个恒定结构域的重链可变区。此外,尽管Fv片段的两个结构域VL和VH由不同的基因编码,它们可以通过重组法经由使两者成为单蛋白链的合成接头而连接,其中VL和VH区配对形成单价分子(称为单链Fc(scFv);参见例如Bird et al.,(1988)Science 242:423-426;and Huston et al.,(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。这些单链抗体也意在包括在术语涵义中。这些抗体片段可以通过本领域技术人员已知的常用技术而得到,且片段可以通过与完整抗体相同的方式进行功能筛选。
本发明的抗原结合片段包括能够特异性结合抗原分子的那些。抗体结合片段的实例包括例如但不限于Fab、Fab'、F(ab')2、Fv片段、单链Fv(scFv)片段和单结构域片段。
Fab片段含有轻链的恒定结构域和重链的第一恒定结构域(CH1)。Fab'片段与Fab片段的不同之处在于在重链CH1结构域的羧基末端处的少数残基的添加,包括来自抗体铰链区的一个或多个半胱氨酸。通过切割在F(ab')2胃蛋白酶消化产物的铰链半胱氨酸处的二硫键产生Fab'片段。抗体片段的另外化学偶联是本领域普通技术人员已知的。Fab和F(ab')2片段缺乏完整抗体的片段可结晶(Fc)区,从动物的循环中更快速地清除,并且可能具有比完整抗体更少的非特异性组织结合(参见例如,Wahl等人,1983,J.Nucl.Med.24:316)。
如本领域通常理解的,“Fc”区是不包含抗原特异性结合区的抗体的片段可结晶恒定区。在IgG、IgA和IgD抗体同种型中,Fc区由两个相同的蛋白质片段组成,衍生自抗体的两条重链的第二和第三恒定结构域(分别为CH2和CH3结构域)。IgM和IgE Fc区在每条多肽链中含有三个重链恒定结构域(CH2、CH3和CH4结构域)。
术语“人源化抗体”,人源化抗体主要指鼠源单克隆抗体以基因克隆及DNA重组技术改造,重新表达的抗体,其大部分氨基酸序列为人源序列取代,基本保留亲本鼠单克隆抗体的亲和力和特异性,又降低了其异源性。
术语“嵌合抗体”是指重链和/或轻链的一部分与衍生自特定物种或属于特定抗体类别或亚类的抗体中的相应序列相同或同源,而链的剩余部分与衍生自另一物种或属于另一抗体类别或亚类的抗体中的相应序列相同或同源,以及此类抗体的片段,只要它们展现出期望的生物学活性(美国专利No.4,816,567;Morrison SL等,Proc.Natl.Acad.Sci.USA,81:6851-6855,1984)。例如,术语“嵌合抗体”可包括这样的抗体(例如人鼠嵌合抗体),其中抗体的重链和轻链可变区来自第一抗体(例如鼠源抗体),而抗体的重链和轻链恒定区来自第二抗体(例如人抗体)。
术语“重链”,重链(heavy chain,H链)大小约为轻链的2倍,含450~550个氨基酸残基,分子量约为55或75kD。每条H链含有4~5个链内二硫键所组成的环肽。不同的H链由于氨基酸组成的排列顺序、二硫键的数目和位置、含的种类和数量不同,其抗原性也不相同,根据H链抗原性的差异可将其分为5类:μ链、γ链、α链、δ链和ε链,不同H链与L链(κ或λ链)组成完整免疫球蛋白的分子分别称之为IgM、IgG、IgA、IgD和IgE。γ、α和δ链上含有4个肽,μ和ε链含有5个环肽。
术语“轻链”,轻链(light chain,L)指在免疫球蛋白单体分子中相对于重链而论,在分子量上较小的多肽链。每条轻链近氨基末端(N端)1/2区域内的氨基酸组成序列多变处为轻链可变区(VL),是Ig分子与抗原结合部位的一个组成部分。其余1/2区域内的氨基酸组成及排列顺序相对稳定处为轻链恒定区(CL)。由于轻链恒定区内氨基酸序列存在某些差异,故轻链有k和λ两型。
术语“种系”,又称胚系(germline),抗体形成细胞具有编码Ig分子的全部基因(即有限数量的C基因和未知数量的V基因,它是通过长期进化形成并通过生殖细胞从亲代传给子代,人免疫球蛋白的重链基因由V-D-J-C基因片段编码而成;轻链基因由V-J-C基因片段编码而成,基因片段的个数不等。人重链基因定位于第14号染色体长臂,跨度约1,100kb,由V、D、J和C四种基因片段组成,包含约95个Va基因片段(分VHl~VH7七个家族,其中功能性基因片段65个、27个D基因片段、6个JH基因片段和9个CH基因片段。Va基因片段位于上游,D基因片段位于VH和JH基因簇之间,JH基因位于DH下游,与下游C基因区相隔7Kb左右,CH基因成簇(cluster)排列,跨度约200kb,P和S基因紧位于JH基因片段下游,C8下游依次是Cγ、Cα和Cε。人轻链基因分为λ和x基因,分别定位于第22号染色体长臂和第2号染色体短臂。功能性VK基因片段约40个,Vc基因片段后是5个功能性J和1个Cκ;Vλ基因片段约30个,4个Jλ基因片段和4个Cλ基因片段。
术语“载体”、“核酸构建体”是指能够运输与其连接的另一种核酸的核酸分子。一种类型的载体是“质粒”,其是指其中可以连接另外的DNA区段的环状双链DNA环。另一种类型的载体是病毒载体,其中额外的DNA区段可以连接到病毒基因组中。某些载体能够在它们被导入的宿主细胞中自主复制(例如,具有细菌复制起点和游离型哺乳动物载体的细菌载体)。其他载体(例如非附加型哺乳动物载体)可以在导入宿主细胞后整合到宿主细胞的基因组中,并由此与宿主基因组一起复制。此外,某些载体能够指导它们有效连接的基因的表达。这种载体在本文中被称为“重组表达载体”(或简称为“表达载体”)。通常,在重组DNA技术中有用的表达载体通常以质粒的形式存在。然而,也包括其他形式的表达载体,如病毒载体(例如,复制缺陷型逆转录病毒,腺病毒和腺伴随病毒),其起到等同的功能。
术语“多核苷酸”旨在包括DNA分子和RNA分子。多核苷酸可以是单链或双链的,并且可以是cDNA或其片段。
术语“多肽”是指包含至少两个连续连接的氨基酸残基的链,对链的长度没有上限。蛋白质中的一个或多个氨基酸残基可含有修饰,例如但不限于糖基化,磷酸化或二硫键。“蛋白质”可以包含一种或多种多肽。
术语“宿主细胞”在其中载体可以增殖并且其DNA可以表达的细胞,所述细胞可以是原核细胞或者真核细胞。该术语还包括受试宿主细胞的任何后代。应理解,并不是所有的后代都与亲本细胞相同,因为在复制过程中可能会发生突变,这类后代被包括在内。
本发明实施例的抗人IL-36R抗体或其片段至少具有以下有益的技术效果之一:
1、本发明实施例的抗人IL-36R抗体不仅对人IL36R具有较高的亲和力,而且在Jurkat-hIL36R-IL1Racp-NF-κB报告基因细胞模型、表皮鳞癌A431细胞中均能够抑制IL-36诱导的炎性细胞因子分泌,因此在治疗炎性疾病特别是银屑病等炎性相关的皮肤疾病时预期具有较好的治疗效果。
2、本发明实施例的抗人IL-36R抗体或其片段对癌症和炎症疾病具有良好的治疗效果,并且,该抗体或其片段兼顾了动物模型的适应性和动物试验的有效性,在杂交瘤筛选过程中即选择了对人IL-36R、猴IL-36R均具有特异性结合能力的候选抗体,在人源化改造过程中也兼顾了对猴IL-36R的特异性,因此本发明的人源化抗人IL-36R抗体可以直接施用于猴皮肤炎症动物模型用于临床期评估治疗效果。
3、发明人研究发现抗人IL-36R抗体能结合到靶细胞膜表面IL-36R激发效应因子活性,通过ADCC或CDC效应杀伤靶细胞,从而释放炎症细胞因子、加重局部炎症和损伤。IgG4亚型抗体效应子活性低但稳定性较差,本发明的抗人IL-36R抗体采用IgG1亚型的重链恒定区并对其进行突变改造,即保持了IgG1亚型抗体的稳定性又消除或降低了效应子活性。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1:本发明实施例的鼠源单克隆抗体与hu-IL36R蛋白的结合活性的结果示意图;
图2:本发明实施例的人-鼠嵌合抗体与重组HEK293细胞表面hu-IL36R和cyno-IL36R的结合活性的结果示意图,其中,A为人-鼠嵌合抗体与重组HEK293细胞表面hu-IL36R的结合曲线,B为人-鼠嵌合抗体与重组HEK293细胞表面cyno-IL36R的结合曲线;
图3:本发明实施例的Jurkat-hIL36R-IL1Racp-NF-κB细胞模型中人-鼠嵌合抗体对IL-36诱导的炎性细胞因子分泌的抑制活性的结果示意图;
图4:本发明实施例的表皮鳞癌A431细胞中人-鼠嵌合抗体对IL-36诱导的炎性细胞因子分泌的抑制活性的结果示意图,其中,A为在A431细胞中嵌合抗体对IL-36α诱导的IL-8分泌的抑制活性的结果示意图,B为在A431细胞中嵌合抗体对IL-36β诱导的IL-8分泌的抑制活性的结果示意图,C为在A431细胞中嵌合抗体对IL-36γ诱导的IL-8分泌的抑制活性的结果示意图;
图5:本发明实施例的人源化抗体与人IL36R和食蟹猴IL36R的结合的结果示意图,其中,A为人源化抗体与人IL36R的结合的结果示意图,B为人源化抗体与食蟹猴IL36R的结合的结果示意图;
图6:本发明实施例的表皮鳞癌A431细胞中人源化抗体对IL-36诱导的炎性细胞因子分泌的抑制活性的结果示意图,其中,A为在A431细胞中人源化抗体对IL-36α诱导的IL-8分泌的抑制活性的结果示意图,B为在A431细胞中人源化抗体对IL-36β诱导的IL-8分泌的抑制活性的结果示意图,C为在A431细胞中人源化抗体对IL-36γ诱导的IL-8分泌的抑制活性的结果示意图。
具体实施方式
下面详细描述本发明的实施例,所述实施例的示例在附图中示出,其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的,仅用于解释本发明,而不能理解为对本发明的限制。
需要说明的是,术语“第一”、“第二”仅用于描述目的,而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地,在本发明的描述中,除非另有说明,“多个”的含义是两个或两个以上。
下面参考具体实施例,对本发明进行说明,需要说明的是,这些实施例仅仅是说明性的,而不能理解为对本发明的限制。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解,下面的实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体技术或条件的,按照本领域内的文献所描述的技术或条件(例如参考J.萨姆布鲁克等著,黄培堂等译的《分子克隆实验指南》,第三版,科学出版社)或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品,例如可以采购自Sigma公司。
实施例1:抗人IL-36R单克隆抗体杂交瘤细胞制备与筛选
1.1杂交瘤制备和筛选
将得到的人白介素36受体蛋白(带His标签,货号CI17,近岸蛋白质科技有限公司)按常规方法(Lonberg,N.,et al.,nature 368(1994)856-859;Fishwild,D.M.,et al.,Nat.Biotechnol.14(1996)845-851and WO 98/24884)免疫10只Balb/c小鼠。每只小鼠初次免疫蛋白用量为50ug,此后进行3次加强免疫,蛋白用量为25ug/小鼠。
利用抗原特异性酶联免疫吸附法(ELISA)来测定小鼠血清中的IL-36R效价:将浓度为1ug/ml的白介素36受体蛋白(IL-36R,带Fc标签,货号CJ62,近岸蛋白质科技公司)包被于96孔板中,每孔100μl,4℃孵育过夜,然后洗去包被液,每孔添加200ul封闭液(protein-free blocking buffer),室温静置2小时。将小鼠血清在PBSA(含1%BSA的PBS溶液)中预先稀释200倍,并以1:2连续稀释12个梯度至409600倍。洗去封闭液后,将稀释的小鼠血清加入96孔板,室温孵育1小时,用PBST洗涤96孔,然后每孔加入100ul以1:3000稀释的二抗(HRP标记的羊抗鼠IgG),室温静置45分钟,PBST洗涤5遍,每孔加入50ul室温平衡的TMB,室温孵育10分钟,在450nm测量吸光度。
取血清效价较高的小鼠,取脾脏,分离得到小鼠B细胞,与预先制好备的小鼠骨髓瘤细胞P3X63Ag8.653以1:2的比例混合,进行电击融合;将融合后的杂交瘤细胞接种于384孔板中,加入适当培养基进行培养,经过7-10天,取杂交瘤细胞培养上清,用上述酶联免疫吸附法(ELISA)筛选阳性克隆。筛选得到若干强反应阳性克隆,通过有限稀释法将筛到的这些强反应阳性克隆单细胞华,最终得到的每个杂交瘤细胞只分泌同一种小鼠抗体,获得23株分泌鼠源抗人IL-36R的单克隆抗体,其对hu-IL36R蛋白的结合活性如图1所示。
1.2鼠源抗人IL-36R单克隆抗体序列的确定
将上述得到的分泌抗人IL-36R抗体杂交瘤细胞扩大培养后,按照RNAfast200试剂盒(上海飞捷生物技术有限公司)说明书步骤提取细胞总RNA;利用5×PrimeScript RTMaster Mix(Takara)将杂交瘤细胞总RNA反转录成cDNA;使用简并引物(AnkeKrebber.1997)和Extaq PCR试剂(Takara)扩增抗体轻链可变区IgVL(κ)和重链可变区VH序列;利用PCR clean-up Gel extraction试剂盒(Macherey-Nagel公司)纯化PCR扩增产物;按照pClone007 Simple Vector Kit试剂盒(擎科生物科技有限公司)说明书将扩增PCR产物连接至T载体并转化大肠杆菌感受态细胞,菌株扩增、抽提质粒后进行DNA测序获得单克隆抗体可变区序列。测序结果如表1所示,表1a为重链可变区测序结果,表1b为轻链可变区测序结果。
表1a鼠源抗人IL-36R单克隆抗体重链可变区氨基酸序列
表1b.鼠源抗人IL-36R单克隆抗体轻链可变区氨基酸序列
实施例2:抗人IL-36R嵌合抗体的制备与纯化
将上述鼠源抗人IL-36R单克隆抗体的重链可变区和公开发表的人单克隆抗体IgG1亚类的重链恒定区(具有两个替代突变Leu234Ala以及Leu235Ala,借此降低效应子功能如FcRn及补体结合而消除ADCC和CDC活性)拼接在一起,形成嵌合抗体的重链(hIgG1-LALA),将该重链构建到哺乳动物细胞表达载体中;将鼠源抗人IL-36R单克隆抗体的轻链可变区和公开发表的人单克隆抗体Kappa亚类轻链恒定区拼接在一起,形成嵌合抗体的轻链,将该轻链构建到哺乳动物细胞表达载体中。
将构建好的抗人IL-36R嵌合抗体的重链质粒和轻链质粒配对混合,使用聚乙烯亚胺(PEI)转染HEK293细胞,约7天后收集细胞上清,使用Protein A纯化得到抗人IL-36R嵌合抗体蛋白,检测嵌合抗体蛋白的浓度、体积和蛋白总量,结果如表2所示。
表2纯化获得的重组嵌合抗体
实施例3:抗人IL-36R嵌合抗体的活性和理化特征
3.1抗人IL-36R嵌合抗体对不同种属IL-36R的特异性和交叉反应性
分别将编码人IL-36R(huIL-36R,NCBI accession:NM_001351446)、小鼠IL-36R(muIL-36R,NCBI accession:NM_001356478)和食蟹猴IL-36R(cyno-IL36R,NCBIaccession:XP_014968513)全长基因的质粒用聚乙烯亚胺(PEI)转染HEK293细胞,并挑选稳定高表达的单细胞备用。
将上述得到的表达人IL-36R的HEK293细胞以30,000/孔铺于96孔板中,随后每孔添加50ul上述得到的嵌合抗体,添加的嵌合抗体从100nM起始,并以1:3连续稀释8个梯度,随后在室温下静置1小时。用PBSA(含有1%BSA的PBS溶液)洗涤,加入50ul 1:400稀释的二抗(FITC-羊抗人IgG),4℃静置30分钟,随后用PBSA洗涤,最后用50ul PBSA重悬细胞,用流式细胞仪分析目标细胞群的平均荧光强度。
同样将上述表达小鼠IL-36R和食蟹猴IL-36R的HEK293细胞铺于96孔板中,随后按照上述流程检测嵌合抗体与这两个细胞的结合。结果如图2、表3(表3a.与HEK293细胞表面人IL-36R结合的嵌合抗体EC50值,表3b.与HEK293细胞表面猴IL-36R结合的嵌合抗体EC50值)所示,上述结果表明,15株嵌合抗体能以高亲和力结合重组HEK293细胞表面的huIL-36R,只有4株嵌合抗体能以高亲和力结合重组HEK293细胞表面的cyno-IL36R,所有的嵌合抗体都不能特异性结合重组HEK293细胞表面的muIL-36R。
表3a.与HEK293细胞表面人IL-36R结合的嵌合抗体EC50值
表3b.与HEK293细胞表面猴IL-36R结合的嵌合抗体EC50值
3.2抗人IL-36R嵌合抗体与人IL-36R结合的动力学检测
利用Fortebio(BLITZ pro1.1.0.28)仪器分析嵌合抗与抗原huIL-36R的结合动力学参数。测定前先将AHC生物探针浸泡于PBS中10分钟;然后将该探针置于含100nM的抗体的PBS中300秒,捕获带hIgG1-Fc标签的抗体;进一步将探针与100nM抗原进行结合反应,结合时间400秒;之后将探针转移至PBS中,进行解离反应,时间为600秒。实验完毕,扣除空白亲本响应值,用软件进行1:1 Langmuir结合模式拟合,计算抗原抗体结合的动力学常数,结果如表4所示。同样利用Fortebio(BLITZ pro1.1.0.28)仪器分析嵌合抗体与人IL-1R1的结合动力学参数,结合信号显示为0(结果未显示)。这表明所有的嵌合抗体特异性的结合人IL-36R。因此,表4的结果表明纯化得到的嵌合抗体在体外能以高亲和力特异性结合人IL-36R。
表4:嵌合抗体与huIL-36R结合的动力学检测
3.3抗人IL-36R嵌合抗体的表位竞争分析
使用Fortebio(BLITZ pro1.1.0.28)仪器测定嵌合抗体与人IL-36R的交叉竞争性结合。在每个测试中,利用NTA芯片捕获人IL-36R(带有His标签),然后用PBSA(含有1%BSA的PBS溶液)来阻断未被利用的捕获位点,随后加入饱和量的嵌合抗体1,然后再加入嵌合抗体2以确定嵌合抗体2是否竞争性结合人IL-36R。如果这两个嵌合抗体结合人IL-36R的同一或近似表位,则不会观察到二级结合,如果嵌合抗体2结合了人IL-36R的不同结合位点,嵌合抗体2将与嵌合抗体1/人IL-36R复合物结合。
随后变换嵌合抗体1和2的上样顺序(之前先使用嵌合抗体1,此次则先使用嵌合抗体2),再次测定这两个嵌合抗体的交叉竞争性结合。结果如表5所示,表5的结果表明纯化得到的不同嵌合抗体能结合人IL36R的不同表位。
表5:嵌合抗体与人IL-36R的交叉竞争反应
3.4抗人IL-36R嵌合抗体的理化性质检测
分别对上述获得的嵌合抗体进行理化性质检测,包括单体率(SEC)、疏水性(HIC)、热稳定性(TM)及分子量测定(MALS)。
抗体单体率分析:将50ul浓度为1mg/ml的抗体进样至预平衡好的层析柱(TSKgelG3000SWXL 7.8*300(TOSHI)内,室温,0.7ml/min的流速流动35min,并同时检测机器(WATERS UPLC CLASS ACQUITYH)A280的吸收值,进入根据出峰时间和出峰体积来判断抗体的单体含量和比例。
抗体疏水性质分析:使用WATERS ARC仪器和疏水层析柱(TSKgel Butyl-NPR(4.6mmX3.5cm,Cat No 14947)使用说明,来分析抗体的疏水性质。
抗体热稳定性分析:使用Bio-rad的荧光定量PCR仪和ProteoSTAT Thermal shiftassay kit(Cat No.ENZ-51027-K400)分析抗体的热稳定性(TM)。
嵌合抗体单体率(SEC)、疏水性(HIC)、热稳定性(TM)及分子量测定(MALS)的检测结果如表6所示,表明选定的6株嵌合抗体理化性质(包括不同pH条件下的热稳定性、单体率和疏水性)比较稳定可靠。
表6.嵌合抗体的初步理化性质分析
3.5抗人IL-36R嵌合抗体对重组报告基因细胞株的作用
将编码人IL-36R(huIL-36R,NCBI accession:NM_001351446)、编码人IL-1RAcP以及编码Luc2P-NFkB基因的3个质粒依次稳定转染至Jurkat细胞(上海细胞库,Cat.No.TCHU123),挑选稳定高表达的单细胞备用,建立Jurkat-hIL36R-IL1Racp-NF-κB报告基因细胞株。
将上述所得的嵌合抗体配制成167nM、10nM和0.7nM三个浓度,分别与近似EC50浓度的IL-36R配体混合(之前已预先测定了IL36α、IL36β和IL36γ这三个配体各自刺激报告基因细胞产生荧光信号的EC50浓度);混合后的溶液按照50ul/孔加入到白色底透96孔板中。将上述所得的报告基因细胞离心换液,然后按1x105个细胞/孔加入到上述白色底透96孔板中,过夜培养后每孔加入100ul Bio-Lite显色剂,读取化学发光值。结果如图3所示,该结果表明嵌合抗体能以剂量依赖的方式抑制经IL-36R配体(IL36α、IL36β和IL36γ)刺激Jurkat细胞分泌炎性细胞因子,而同型抗体对照则不能。
3.6抗人IL-36R嵌合抗体在表皮鳞癌A431细胞中抑制IL-36诱导的IL-8分泌
A431细胞在IL36R配体(IL36α、IL36β和IL36γ)的刺激下会产生细胞因子IL-8,而抗IL-36R抗体则会抑制A431细胞产生IL-8.
将上述所得的嵌合抗体从30ug/ml起始按照3倍倍比稀释10个梯度,分别与近似EC50浓度的IL-36R配体混合(之前已预先测定了IL36α、IL36β和IL36γ这三个配体各自的EC50浓度);混合后的溶液按照50ul/孔加入到白色底透96孔板中。将A431细胞离心换液,然后按1x105个细胞/孔加入到上述白色底透96孔板中,培养48小时,然后使用R&D SystemsDUO-SET ELISA试剂盒,根据制造商提供的标准方案,通过ELISA评估细胞上清液中IL-8的水平。结果如图4所示,上述结果证实嵌合抗体能以剂量依赖的方式抑制经IL-36R配体(IL36α、IL36β和IL36γ)刺激的A431细胞分泌炎性细胞因子IL-8。
实施例4:抗人IL-36R人源化抗体的设计与制备
4.1抗人IL-36R人源化抗体的设计和工程化改造
为降低小鼠抗体潜在的免疫原性,需将先前得到的小鼠抗人IL-36R抗体人类化,即将小鼠抗体中的鼠源序列尽可能多的变更为人源序列,同时在此过程中,鼠源抗体的结合特异性、动力学参数、理化性质、稳定性等特性应予以保留。为达此目的,基于框架同源性、CDR结构、保守标准残基、保守接口封装残基和其他参数选择小鼠前导序列的人类框架序列。所形成的人源化抗体,包括结合特异性、结合动力学参数、理化性质等,选择与亲代鼠源抗体相比显示较好或相等结合的人源化抗体进行后续进一步验证。在此,选择鼠源抗体A10-6B12和A19-35D19进行人源化(克隆至人类IgG1-LALA/κ骨架中,可变区序列见表7)。
表7A.A10-6B12人源化抗体的可变区及其CDR氨基酸序列
注:CDRs区以下划线标出。
表7B.A10-6B12人源化抗体的轻重链配对设计
表7C.A19-35D19人源化抗体的可变区及其CDR氨基酸序列
注:CDRs区以下划线标出。
表7D.A19-35D19人源化抗体的轻重链配对设计
4.2抗人IL-36R人源化抗体的制备和纯化
将上述人源化抗人IL-36R单克隆抗体的重链可变区和公开发表的人单克隆抗体IgG1亚类的重链恒定区(具有两个替代突变Leu234Ala以及Leu235Ala,借此降低效应子功能如FcRn及补体结合而消除ADCC和CDC活性)拼接在一起,形成人源化抗体的重链(hIgG1-LALA),将该重链构建到哺乳动物细胞表达载体中;同时也将上述人源化抗IL-36R单克隆抗体的重链可变区和公开发表的人单克隆抗体IgG1亚类的重链恒定区1(hIgG1-VH1)拼接在一起,形成人源化抗体的重链Fd(VH-CH1),将该重链Fd同样构建到哺乳动物细胞表达载体中。
将人源化抗人IL-36R单克隆抗体的轻链可变区和公开发表的人单克隆抗体Kappa亚类轻链恒定区拼接在一起,形成人源化抗体的轻链,将该轻链构建到哺乳动物细胞表达载体中。
将构建好的抗人IL-36R嵌合抗体的重链质粒(包括重链Fd质粒)和轻链质粒配对混合,使用聚乙烯亚胺(PEI)转染HEK293细胞,约7天后收集细胞上清,使用Protein A纯化得到抗人IL-36R嵌合抗体蛋白(该人源化抗体为hIgG1-LALA亚型,同时也得到部分人源化抗体hIgG1-LALA亚型的Fab形式,见表8)。
表8:纯化得到的抗人IL-36R人源化抗体
实施例5:抗人IL-36R人源化抗体的活性和功能
5.1人源化抗体的亲和力参数测定
利用Fortebio(BLITZ pro1.1.0.28)仪器分析人源化抗与抗原huIL-36R的结合动力学参数。测定前先将AHC生物探针浸泡于PBS中10分钟;然后将该探针置于含100nM的抗体的PBS中300秒,捕获带hIgG1-Fc标签的抗体;进一步将探针与100nM抗原进行结合反应,结合时间400秒;之后将探针转移至PBS中,进行解离反应,时间为600秒。实验完毕,扣除空白亲本响应值,用软件进行1:1 Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。
同样使用Fortebio(BLITZ pro1.1.0.28)仪器测定抗体(Fabric形式)与人IL-36R的结合活性。在每个测试中,利用NTA芯片捕获人IL-36R(带有His标签),然后用PBSA(含有1%BSA的PBS溶液)来阻断未被利用的捕获位点,进一步将探针与100nM抗体Fab进行结合反应,结合时间400秒;之后将探针转移至PBS中,进行解离反应,时间为600秒。实验完毕,扣除空白亲本响应值,用软件进行1:1 Langmuir结合模式拟合,计算抗原抗体结合的动力学常数。上述人源化抗体和Fab抗体的亲和力检测结果如表9所示。
同样利用Fortebio(BLITZ pro1.1.0.28)仪器分析嵌合抗体与人IL-1R1的结合动力学参数,结合信号显示为0(结果未显示),这表明所有的人源化抗体特异性的结合人IL-36R。
表9:人源化抗体与人IL-36R结合的动力学参数
表9的结果表明,A10-6B12和A19-35D19经过人源化改造之后,大多数人源化抗体都保持了与人IL36R的高亲和力结合。
5.2抗人IL-36R人源化抗体对不同种属IL-36R的交叉反应性
将上述得到的表达人IL-36R的HEK293细胞以30,000/孔铺于96孔板中,随后每孔添加50ul上述得到的人源化抗体,添加的人源化抗体从100nM起始,并以1:3连续稀释8个梯度,随后在室温下静置1小时。用PBSA(含有1%BSA的PBS溶液)洗涤,加入50ul 1:400稀释的二抗(FITC-羊抗人IgG),4℃静置30分钟,随后用PBSA洗涤,最后用50ul PBSA重悬细胞,用流式细胞仪分析目标细胞群的平均荧光强度。同样将上述表达小鼠IL-36R和食蟹猴IL-36R的HEK293细胞铺于96孔板中,随后按照上述流程检测人源化抗体与这两个细胞的结合。
结果如图5、表10所示,上述结果表明大多人源化抗体都能以高亲和力结合细胞表面表达的huIL-36R和cyno-IL36R。所有的人源化抗体都不能结合细胞表面的muIL-36R。
表10.人源化抗体与人IL36R和食蟹猴IL36R的结合活性
5.3抗人IL-36R人源化抗体在A431细胞中抑制IL-36诱导的IL-8分泌
A431细胞在IL36R配体(IL36α、IL36β和IL36γ)的刺激下会产生炎症细胞因子IL-8而IL-36R抗体则会抑制A431细胞产生IL-8.
将上述所得的人源化抗体从30ug/ml起始按照3倍倍比稀释10个梯度,分别与近似EC50浓度的IL-36R配体混合(之前已预先测定了IL36α、IL36β和IL36γ这三个配体各自的EC50浓度);混合后的溶液按照50ul/孔加入到白色底透96孔板中。将A431细胞离心换液,然后按1x105个细胞/孔加入到上述白色底透96孔板中,培养48小时,然后使用R&D SystemsDUO-SET ELISA试剂盒,根据制造商提供的标准方案,通过ELISA评估细胞上清液中IL-8的水平。该结果(表11和图6)证实人源化抗体能以剂量依赖的方式高效抑制经IL-36R配体(IL36α、IL36β和IL36γ)刺激的A431细胞分泌炎性细胞因子IL-8。
表11.人源化抗体在体外阻断A431细胞经IL36刺激释放炎性细胞因子IL8
综上所述,本发明实施例的人IL-36R抗体对人IL36R具有较高的亲和力,并且能抑制IL-36诱导的炎性细胞因子分泌,并且,该抗体对人和猴IL-36R均具有特异性结合能力。此外,本发明实施例的人IL-36R抗体采用IgG1亚型的重链恒定区并对其进行突变改造,即保持了IgG1亚型抗体的稳定性又消除或降低了效应子活性,避免了抗人IL-36R抗体结合到靶细胞膜表面IL-36R激发效应子活性,释放炎症细胞因子、加重局部炎症和损伤,使本发明实施例的人IL-36R抗体抗炎和抗肿瘤效果更好,安全性更高。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例,本领域的普通技术人员可以理解:在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由权利要求及其等同物限定。
序列表
<110> 上海普铭生物科技有限公司
<120> 抗人IL-36R抗体及其应用
<150> 202110183575.1
<151> 2021-02-08
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<213> 小鼠(Mus musculus)
<400> 3
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ile Asp His
20 25 30
Ala Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Ile Asn Ser Leu Gln Val Asp Asp Thr Ala Ile Tyr Ser Cys Ala
85 90 95
Lys Lys Gly Asp Tyr Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ala
115
<210> 4
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 4
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 5
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Ser Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Asp
115
<210> 6
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Ser Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Pro Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Asp
115
<210> 7
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Arg Val Thr Met Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Pro Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Asp
115
<210> 8
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Ser Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Val Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 9
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Ser Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Lys Val Thr Met Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Pro Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 10
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 10
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Asn Gln
20 25 30
Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Phe Pro Asn Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe
50 55 60
Lys Ser Lys Val Thr Met Thr Val Asp Lys Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Pro Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 11
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ser Ser Ile Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 12
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Ile Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu
65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Gly Ser Ser Ile Pro
85 90 95
Val Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 13
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Ile Pro
85 90 95
Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 14
<211> 108
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Met Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn
20 25 30
Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp
35 40 45
Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Arg Leu Glu
65 70 75 80
Pro Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Ile Pro
85 90 95
Val Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 15
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Glu 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 Phe Ser Leu Ile Asp His
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
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 Lys Gly Asp Tyr Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 16
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Glu 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 Phe Ser Leu Ile Asp His
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val 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
Lys Lys Gly Asp Tyr Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 17
<211> 118
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Glu 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 Phe Ser Leu Ile Asp His
20 25 30
Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Trp Arg Gly Gly Ser Thr Asp Tyr Asn Ala Ala Phe Met
50 55 60
Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe
65 70 75 80
Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Ser Cys Ala
85 90 95
Lys Lys Gly Asp Tyr Gly Tyr Trp Phe Ala Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 18
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 19
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 20
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Asn Thr Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 21
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 22
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 23
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Thr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 24
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Asp Ile Gln Met Thr Gln Ser Gln Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 25
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Asp Ile Gln Met Thr Gln Ser Gln Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Thr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 26
<211> 107
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Asp Ile Gln Met Thr Gln Ser Gln Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
20 25 30
Val Val Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
35 40 45
Tyr Ser Ala Ser Asn Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Thr Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 27
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gly Asp Thr Phe Thr Asn Gln
1 5
<210> 28
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gly Glu Ile Phe Pro Asn Ser Gly Arg
1 5
<210> 29
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gly Glu Ile Phe Pro Asn Thr Gly Arg
1 5
<210> 30
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Val Phe Tyr Gly Ala Pro Trp Phe Ala Tyr
1 5 10
<210> 31
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Ser Ala Ser Ser Ser Ile Ser Ser Asn Tyr Leu His
1 5 10
<210> 32
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Arg Thr Ser Asn Leu Ala Ser
1 5
<210> 33
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Gln Gln Gly Ser Ser Ile Pro Val Thr
1 5
<210> 34
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Gly Phe Ser Leu Ile Asp His Ala Val His
1 5 10
<210> 35
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Trp Arg Gly Gly Ser
1 5
<210> 36
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Lys Gly Asp Tyr Gly Tyr Trp Phe Ala Tyr
1 5 10
<210> 37
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Val
1 5 10
<210> 38
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Ser Ala Ser Asn Arg Tyr Ser
1 5
<210> 39
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Gln Gln Tyr Asn Ser Tyr Pro Leu Thr
1 5
<210> 40
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Gln Gln Tyr Thr Ser Tyr Pro Leu Thr
1 5
<210> 41
<211> 127
<212> PRT
<213> 小鼠(Mus musculus)
<400> 41
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Gly Asn Lys Ala Asn Gly Tyr Lys Thr Asp Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Leu Asn Ser Gln Asn Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Val Ser Leu Leu Tyr Asp Gly Tyr Gly Asn Tyr
100 105 110
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 42
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 42
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Asp Ala Arg Leu Asn Arg Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Gln Gly Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 43
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 43
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Lys Leu Ser Cys Thr Thr Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Asn Gly Gly Val Asn Ile His Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Ser Arg Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys
85 90 95
Ala Arg His Gly Gly Glu Gly Tyr Pro Tyr Tyr Phe Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Leu Thr Val Ser Ser
115 120
<210> 44
<211> 122
<212> PRT
<213> 小鼠(Mus musculus)
<400> 44
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ile Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile Asp Pro Ser Asp Ser Glu Val His Tyr Ser Gln Met Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Thr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Gly Ile Thr Thr Val Val Pro Tyr Asp Met Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 45
<211> 117
<212> PRT
<213> 小鼠(Mus musculus)
<400> 45
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr
20 25 30
Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Val Ile Asp Pro Ser Asp Ser Tyr Ile Ser Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Thr Ser Ser Ser Thr Val Tyr
65 70 75 80
Met Gln Leu Ser Arg Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Thr Ser Asp Tyr Tyr Gly Ser Leu Ala Phe Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 46
<211> 124
<212> PRT
<213> 小鼠(Mus musculus)
<400> 46
Glu Val Leu Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Arg Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Leu
35 40 45
Gly Arg Ile Asp Pro Ala Asn Ala Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Val Thr Ala Val Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Thr Ser Glu Glu Ser Ala Tyr Tyr Lys Tyr Asp Asp Ala Met Ala
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 47
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 47
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Leu Asn Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala His Gly Gly Thr Trp Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 48
<211> 127
<212> PRT
<213> 小鼠(Mus musculus)
<400> 48
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Val Gly Asn Lys Ala Asn Gly Tyr Thr Thr Asp Tyr Ile Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Pro Asp Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Ile Ser Leu Leu Phe Asp Gly Tyr Gly Asn Tyr
100 105 110
Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120 125
<210> 49
<211> 121
<212> PRT
<213> 小鼠(Mus musculus)
<400> 49
Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ser
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Asp Tyr Ala Phe Ser Asn Tyr
20 25 30
Tyr Met Asn Trp Val Lys Glu Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Gln Ile Tyr Pro Gly Asp Gly Asp Thr Lys Tyr Asn Gly Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys
85 90 95
Ala Arg Trp Thr Thr Val Val Gly Gly Asn Val Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 50
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 50
Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu
35 40 45
Gly Phe Ile Gly Asn Lys Ala Asn Gly Tyr Lys Thr Asp Tyr Ser Ala
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Val Asn Ser Gln Asn Ile
65 70 75 80
Leu Tyr Leu Gln Met Asn Thr Leu Arg Ala Glu Asp Ser Ala Thr Tyr
85 90 95
Tyr Cys Ala Arg Asp Val Ser Leu Leu Tyr Asp Gly Tyr Gly Asn Tyr
100 105 110
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Ser Val
115 120
<210> 51
<211> 124
<212> PRT
<213> 小鼠(Mus musculus)
<400> 51
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met Tyr Trp Val Ile Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Gly Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Ile Ala Tyr
65 70 75 80
Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Gly Arg Ser Glu Gly Ser Ala Tyr Tyr Ser Tyr Asp Asp Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
115 120
<210> 52
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 52
Glu Val Arg Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Thr Asp Pro Ala Arg Gly Asn Asn Lys Tyr Asp Pro Asn Phe
50 55 60
Tyr Asp Lys Ala Thr Ile Thr Glu Asp Thr Ser Ser Asn Thr Val Tyr
65 70 75 80
Leu Gln Leu Ser Gly Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys
85 90 95
Ala Arg Ser Lys Ile Ser Ala Ser Tyr Trp Tyr Asp Asp Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Asn Ser Val Thr Val Ser
115 120
<210> 53
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 53
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln His Asn Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Ala Ser His Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ile Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Asp Ile Lys
100 105
<210> 54
<211> 117
<212> PRT
<213> 小鼠(Mus musculus)
<400> 54
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr
20 25 30
Gly Val Tyr Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Pro Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Asn Ser Leu Gln Thr Glu Asp Ser Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Phe Asp Asp Tyr Phe Asp Phe Trp Gly Gln Gly Thr Thr
100 105 110
Leu Thr Val Ser Ser
115
<210> 55
<211> 123
<212> PRT
<213> 小鼠(Mus musculus)
<400> 55
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Val Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Thr
20 25 30
Tyr Met Tyr Trp Val Arg Gln Arg Pro Glu Leu Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Ala Asn Asp Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Ser Ala Asp Thr Ser Ser Asn Thr Ala Asn
65 70 75 80
Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Gly Arg Ser Glu Gly Ser Ala Asp Tyr Lys Tyr Asp Asp Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser
115 120
<210> 56
<211> 117
<212> PRT
<213> 小鼠(Mus musculus)
<400> 56
Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr
20 25 30
Gly Val Tyr Trp Val Arg Gln Pro Pro Gly Lys Val Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Pro Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Met Lys Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala
85 90 95
Arg Gly Gly Tyr Asp Asp Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Phe Thr Val Ser Ser
115
<210> 57
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 57
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Leu Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala His Gly Gly Thr Trp Leu Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 58
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 58
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Asp Thr Arg Leu Asn Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Gln Gly Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 59
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 59
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Asp Ala Arg Leu Asn Arg Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Thr Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Gln Gly Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 60
<211> 117
<212> PRT
<213> 小鼠(Mus musculus)
<400> 60
Gln Val His Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Thr Tyr
20 25 30
Gly Val Tyr Trp Phe Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Ile Ile Trp Ala Gly Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met
50 55 60
Ser Gly Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu
65 70 75 80
Lys Leu Ser Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr His Cys Ala
85 90 95
Arg Gly Gly Tyr Asp Asp Trp Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ala
115
<210> 61
<211> 116
<212> PRT
<213> 小鼠(Mus musculus)
<400> 61
Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Ile Ser Phe Thr Ser Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Asp Ser Asp Ala Arg Leu Asn Arg Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ser Gln Gly Gly Thr Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ala
115
<210> 62
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 62
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Pro Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Tyr Phe Cys Gln Gln Leu Tyr Leu Ala Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 63
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 63
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Asn Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Arg Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Val Gln Tyr Ala Ser Ser Pro Asn
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 64
<211> 106
<212> PRT
<213> 小鼠(Mus musculus)
<400> 64
Gln Ile Val Leu Ser Gln Ser Pro Thr Ile Leu Ser Ala Ser Pro Gly
1 5 10 15
Glu Met Val Thr Met Thr Cys Arg Ala Ser Ser Arg Val Thr Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Asn Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Phe Cys Gln Gln Trp Ser Ser Asn Pro Phe Thr
85 90 95
Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 65
<211> 112
<212> PRT
<213> 小鼠(Mus musculus)
<400> 65
Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly
1 5 10 15
Gln Pro Val Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val Asn Ser
20 25 30
Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser
35 40 45
Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro
50 55 60
Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Leu Val Val Tyr Tyr Cys Trp Gln Ser
85 90 95
Thr His Phe Pro Gln Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105 110
<210> 66
<211> 106
<212> PRT
<213> 小鼠(Mus musculus)
<400> 66
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Asn Ile Ser Tyr Met
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Thr Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Tyr Pro Tyr Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 67
<211> 104
<212> PRT
<213> 小鼠(Mus musculus)
<400> 67
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro Phe Gly
85 90 95
Gly Gly Thr Lys Leu Glu Ile Lys
100
<210> 68
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 68
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Ser Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Val Gln Tyr Ala Ser Ser Pro Asn
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 69
<211> 108
<212> PRT
<213> 小鼠(Mus musculus)
<400> 69
Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr
20 25 30
Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile
35 40 45
Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Tyr
65 70 75 80
Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
100 105
<210> 70
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 70
Asp Ile Val Met Thr Gln Ser Gln Asp Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Asp Thr Asn
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ile Leu Leu
35 40 45
Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser
65 70 75 80
Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 71
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 71
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Pro Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Phe Phe Cys Gln Gln Leu Tyr Leu Ala Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 72
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 72
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Asn Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Val Gln Tyr Ala Ser Ser Pro Asn
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 73
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 73
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Thr Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Ser Phe Thr Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Tyr Tyr Cys Gln Gln Leu Tyr Ile Thr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Asn
100 105
<210> 74
<211> 9
<212> PRT
<213> 小鼠(Mus musculus)
<400> 74
Gln Gln Tyr Asn Thr Tyr Pro Leu Thr
1 5
<210> 75
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 75
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Val Gly
1 5 10 15
Asp Arg Val Ser Ile Ala Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ile Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Thr Gly Thr Met Leu Glu Leu Arg
100 105
<210> 76
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 76
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly
1 5 10 15
Glu Ser Val Thr Ile Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile
35 40 45
Tyr Ala Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Lys Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala
65 70 75 80
Glu Asp Phe Val Ser Tyr Tyr Cys Gln Gln Leu Tyr Ile Pro Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 77
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 77
Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Leu Glu
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Gln Ser
65 70 75 80
Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ile Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Arg
100 105
<210> 78
<211> 107
<212> PRT
<213> 小鼠(Mus musculus)
<400> 78
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Glu Arg Val Ser Leu Thr Cys Arg Ala Ser Gln Asp Ile Gly Asn Ser
20 25 30
Leu Asn Trp Leu Gln Gln Glu Pro Asp Gly Thr Ile Lys Arg Leu Ile
35 40 45
Tyr Ala Thr Ser Ser Leu Asp Ser Gly Val Pro Lys Arg Phe Ser Gly
50 55 60
Ser Arg Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser
65 70 75 80
Glu Asp Phe Val Asp Tyr Tyr Cys Val Gln Tyr Ala Thr Ser Pro Asn
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
Claims (23)
1.一种抗人IL-36R抗体或其片段,其特征在于,能够特异性结合人IL-36R和猴IL-36R,并且对人IL-36R的结合能力高于对猴IL-36R的结合能力。
2.根据权利要求1所述抗人IL-36R抗体或其片段,其特征在于,与人IL-36R结合的KD值<5×109。
3.根据权利要求1所述抗人IL-36R抗体或其片段,其特征在于,包括:
重链可变区,所述重链可变区(VH)包括抗原决定区(CDRs)1、2和3,其中,VH CDR1包含与所选VH CDR1氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR2包含与所选VHCDR2氨基酸序列具有至少75%同一性的氨基酸序列;VH CDR3与所选VH CDR3氨基酸序列具有至少75%同一性的氨基酸序列;
轻链可变区,所述轻链可变区(VL)包括CDRs 1、2和3,其中,VL CDR1包含与所选VLCDR1氨基酸序列具有至少75%同一性的氨基酸序列;VL CDR2包含与所选VL CDR2氨基酸序列具有至少75%同一性的氨基酸序列;VL CDR3与所选VL CDR3氨基酸序列具有至少75%同一性的氨基酸序列;
其中,所述所选VH CDRs 1、2和3的氨基酸序列以及所述所选VL CDRs 1、2和3的氨基酸序列选自下列之一:
所述所选VH CDRs 1和3的氨基酸序列分别如SEQ ID NO:27和30所示,VH CDR2具有GEIFPNX1GR所示的氨基酸序列,且所述所选VL CDRs 1、2和3的氨基酸序列如SEQ ID NO:31、32和33所示;
所述所选VH CDRs 1、2和3的氨基酸序列分别如SEQ ID NO:34、35和36所示,且所述所选VL CDRs 1和2的氨基酸序列如SEQ ID NO:37和38所示,VL CDR3具有QQYX2X3YPLT所示的氨基酸序列,
其中,
X1为S或T;
X2为N或T;
X3为S或T。
4.根据权利要求3所述抗人IL-36R抗体或其片段,其特征在于,所述VH包括与SEQ IDNO:5具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:11具有至少75%同一性氨基酸序列。
5.根据权利要求3所述抗人IL-36R抗体或其片段,其特征在于,所述VH包括与SEQ IDNO:15具有至少75%同一性氨基酸序列,且所述VL包括与SEQ ID NO:18具有至少75%同一性氨基酸序列。
6.根据权利要求4所述抗人IL-36R抗体或其片段,其特征在于,所述VH包括SEQ ID NO:1、5、6、7、8、9或10所示的氨基酸序列,所述VL包括SEQ ID NO:2、11、12、13或14所示的氨基酸序列。
7.根据权利要求5所述抗人IL-36R抗体或其片段,其特征在于,所述VH包括SEQ ID NO:3、15、16或17所示的氨基酸序列,所述VL包括SEQ ID NO:4、18、19、20、21、22、23、24、25或26所示的氨基酸序列。
8.根据权利要求1所述抗人IL-36R抗体或其片段,其特征在于,所述抗体或其片段能够阻断IL36α、IL36β、和/或IL36γ诱导的IL36R+细胞炎性细胞因子释放,不具有效应子活性或效应子活性显著降低,
其中,所述炎性细胞因子包括IL-8,所述效应子活性包括ADCC和CDC。
9.根据权利要求1所述抗人IL-36R抗体或其片段,其特征在于,所述抗体或其片段为鼠源抗体或其抗原结合片段、兔源抗体或其抗原结合片段、人源抗体或其抗原结合片段,或嵌合抗体或其抗原结合片段。
10.根据权利要求1所述抗人IL-36R抗体或其片段,其特征在于,所述抗体或其片段为Fab、Fab’、F(ab’)2、Fv、scFv或dAb。
11.一种人源化抗人IL-36R抗体或其片段,其特征在于,是在权利要求1-10任一所述抗人IL-36R抗体或其片段的基础上进行CDRs移植获得的。
12.根据权利要求11所述的人源化抗人IL-36R抗体或其片段,其特征在于,所述人源化抗人IL-36R抗体或其片段具有IgG1亚类的重链恒定区,且在所述IgG1亚类重链恒定区的234和235位的亮氨酸(L)均突变为丙氨酸(A)。
13.一种多核苷酸,其编码权利要求1-10中任一项所述抗人IL-36R抗体或其片段、或权利要求11-12中任一项所述人源化抗人IL-36R抗体或其片段。
14.构建体,其特征在于,包含权利要求13所述的多核苷酸。
15.宿主细胞,其特征在于,包含权利要求11所述的多核苷酸或权利要求12所述的核酸构建体。
16.一种组合物,其特征在于,包含权利要求1-10中任一项所述抗人IL-36R抗体或其片段、权利要求11-12中任一项所述人源化抗人IL-36R抗体或其片段、权利要求13所述多核苷酸和/或权利要求14所述核酸构建体,以及可选的药学上可接受的辅料。
17.一种组合物,其特征在于,包含两种或两种以上抗人IL-36R单克隆抗体,所述两种或两种以上抗人IL-36R单克隆抗体选自权利要求1-10中任一项所述抗人IL-36R抗体或其片段或权利要求11-12中任一项所述人源化抗人IL-36R抗体或其片段;
并且所述两种或两种以上抗人IL-36R单克隆抗体相互之间对人IL-36R无竞争结合关系。
18.一种制备抗人IL-36R抗体或其片段的方法,包括:
(1)在合适的条件下,培养权利要求15所述的宿主细胞;
(2)分离回收抗人IL-36R抗体或其片段、人源化抗人IL-36R抗体或其片段。
19.权利要求1-10中任一项所述抗人IL-36R抗体或其片段、权利要求11-12中任一项所述人源化抗人IL-36R抗体或其片段、权利要求13所述多核苷酸、权利要求14所述构建体、权利要求15所述宿主细胞、权利要求16所述组合物和权利要求17所述组合物在制备治疗炎性疾病的药物中的应用。
20.根据权利要求19所述的应用,其特征在于,所述炎性疾病是IL36相关的炎性疾病,所述药物通过阻断IL36α、IL36β、和/或IL36γ诱导与细胞受体IL36R的结合发挥治疗炎性疾病的作用。
21.根据权利要求19所述的应用,其特征在于,所述炎性疾病包括皮炎、银屑病、炎性肠病、关节炎、系统性红斑狼疮、炎性肺病和慢性肾病。
22.根据权利要求21所述的应用,其特征在于,所述银屑病包括脓疱型银屑病、泛发性银屑病和掌跖脓疱病。
23.根据权利要求19所述的应用,其特征在于,所述炎性疾病具有皮肤损伤症状,所述药物通过阻断IL36α、IL36β、和/或IL36γ诱导与细胞受体IL36R的结合改善皮肤损伤。
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