CN111574626A - 一种ildr2抗体、其药物组合物及其用途 - Google Patents
一种ildr2抗体、其药物组合物及其用途 Download PDFInfo
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- CN111574626A CN111574626A CN202010463330.XA CN202010463330A CN111574626A CN 111574626 A CN111574626 A CN 111574626A CN 202010463330 A CN202010463330 A CN 202010463330A CN 111574626 A CN111574626 A CN 111574626A
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Abstract
提供了一种针对Ig样结构域受体2(ILDR2)的单克隆抗体或其抗原结合片段，该单克隆抗体能够特异性与ILDR2结合，并且能够十分有效地抑制其ILDR2免疫作用，本发明还提供了包含该单克隆抗体的药物组合物及用途，所述药物组合物具有用于制备辅助治疗类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、系统性硬化症、系统性红斑狼疮、克隆氏病、过敏性哮喘的药物的潜力。
Description
技术领域
本发明涉及药物组合物领域，特别地涉及一种ILDR2抗体、其药物组合物及其用途。
背景技术
类风湿关节炎(Rheumatoid arthritis，RA)是一种病因未明的慢性、以炎性滑膜炎为主的系统性疾病。其特征是手、足小关节的多关节、对称性、侵袭性关节炎症，经常伴有关节外器官受累及血清类风湿因子阳性，可以导致关节畸形及功能丧失。
类风湿关节炎的发病可能与遗传、感染、性激素等有关，类风湿关节炎的病理主要有滑膜衬里细胞增生、间质大量炎性细胞浸润，以及微血管的新生、血管翳的形成及软骨和骨组织的破坏等。
药物治疗主要包括非甾类抗炎药、慢作用抗风湿药、免疫抑制剂、免疫和生物制剂及植物药等。非甾类抗炎药有抗炎、止痛、解热作用，是类风湿关节炎治疗中最为常用的药物，适用于活动期等各个时期的患者。常用的药物包括双氯芬酸、萘丁美酮、美洛昔康、塞来昔布等。
抗风湿药(DMARDs)又被称为二线药物或慢作用抗风湿药物。常用的有甲氨蝶呤，口服或静注；柳氮磺吡啶，从小剂量开始，逐渐递增，以及羟氯喹、来氟米特、环孢素等。目前已有多种用于类风湿关节炎的植物药，如雷公藤、白芍总甙、青藤碱等。上述药物对治疗类风湿关节炎具有一定的疗效，但总体上没有有效药物可控制类风湿性关节炎的发病进程。
为解决上述技术问题，本发明提供一种辅助治疗类风湿性关节炎的药物，可以高效、无副作用的辅助治疗类风湿关节炎，已达到缓解疼痛、减缓病程和/或治愈的目的。
发明内容
为了解决上述技术问题，本发明提供一种ILDR2抗体、其药物组合物及其用途
本发明是以如下技术方案实现的：
一种ILDR2抗体，所述抗体包含轻链和重链；所述轻链包含CDR-L1、CDR-L2、CDR-L3区，所述重链包含CDR-H1、CDR-H2、CDR-H3区。
进一步地，所述轻链CDR-L1氨基酸序列如SEQ ID NO:1；CDR-L2氨基酸序列如SEQID NO:2、CDR-L3的氨基酸序列如SEQ ID NO:3所示；所述重链CDR-H1氨基酸序列如SEQ IDNO:4、CDR-H2氨基酸序列如SEQ ID NO:5、CDR-H3氨基酸序列如SEQ ID NO:6所示。
进一步地，所述抗体重链可变区氨基酸序列如SEQ ID NO:12所示，所述抗体轻链可变区氨基酸序列如SEQ ID NO:16所示。
进一步地，所述抗体为抗人ILDR2人源化抗体和/或其多肽功能片段。
进一步地，所述抗体重链可变区氨基酸序列如SEQ ID NO:7所示，所述抗体轻链可变区氨基酸序列如SEQ ID NO:8所示。
进一步地，所述抗体包含选自人抗体IgG1、IgG2、IgG3、IgG4的任一Fc端的氨基酸序列。
进一步地，所述抗体的生产步骤包括：在培养基中和合适的培养条件下培养含有权利要求1-6所述抗体的宿主细胞；从培养基中或从所培养的宿主细胞中回收产生的抗体及其多肽功能片段并与药学上可接受的载体制成药物。
一种药物组合物，包括上述抗体，所述药物可用于辅助治疗类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、系统性硬化症、系统性红斑狼疮、克隆氏病、过敏性哮喘。
本领域公知，抗原结合功能区是指可以与目标分子如抗原发生特异性相互作用的区域，其作用具有高度选择性，识别一种目标分子的序列通常不能识别其他分子序列。
代表性的抗原结合功能区包括：抗体的可变区、抗体可变区的结构变构体、受体的结合域、配体结合域或酶结合域。
IgG是免疫球蛋白G(Immunoglobulin G，IgG)的缩写，是血清主要的抗体成分，根据IgG分子中的r链抗原性差异，人IgG有四个亚型：IgG1、IgG2、IgG3、IgG4。
抗体的结合特异性及亲合力均主要由CDR序列决定，根据成熟、公知的现有各项技术可轻易地将非CDR区域的氨基酸序列改变而获得具有相类似的生物活性的变体。
本发明的宿主细胞包括但不限于大肠杆菌、噬菌体展示系统、酵母、植物细胞、动物细胞。
药学上可接受的载体是指是指药学领域常规的药物载体，包括但不限于稀释剂、赋形剂和水等；包括但不限于粘合剂如明胶和聚乙烯吡咯烷酮；润湿剂如甘油；包括但不限于促吸收剂如季铵化合物；包括但不限于表面活性剂如十六烷醇、十二烷基硫酸钠等。
本发明的单克隆抗体特别是RCA-2933能够很好地特异性与ILDR2结合，并且能够十分有效地抑制其ILDR2免疫作用，具有用于制备辅助治疗类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、系统性硬化症、系统性红斑狼疮、克隆氏病、过敏性哮喘的药物的潜力。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明作进一步地详细描述。
实施例1：获得新型ILDR2嵌合抗体
小鼠免疫使用6至8周龄雌性BALB/c小鼠作为实验动物(购自上海加科生物科技股份有限公司)，首次免疫使用50μg人ILDR2蛋白(购自北京义翘神州生物技术有限公司)与完全福氏佐剂充分混合形成乳液，按0.5ml/只注射量注射小鼠腹腔，每隔2周进行加强免疫，加强免疫使用25μg人ILDR2蛋白与不完全福氏佐剂充分混合形成乳液，按0.5ml/只注射量注射小鼠腹腔，加强免疫3次，末次免疫一周后，取小鼠静脉血并分离血清，用ELISA法测定获得抗体的效价，选择效价高的小鼠细胞制备杂交瘤制备单脾细胞悬液。
取对数生长的骨髓瘤细胞(SP2/0)，不完全培养液洗涤2次。同时制备免疫脾细胞悬液，将骨髓瘤细胞与脾细胞按1∶10的比例混合在一起，在离心管内用不完全培养液洗1次，1200rpm离心8分钟后弃上清，将细胞沉淀均匀后置于40℃水浴中预热，向细胞沉淀中加入预热至40℃的PEG-4000 1ml，出现颗粒后，一分钟内加25ml预热至40℃的不完全培养基以终止PEG-4000作用。室温静置，加入2ml HAT培养基，轻吹沉淀细胞使其悬浮，混匀后补充HAT培养基至离心管内的脾细胞浓度达到2×106/ml，将上述脾细胞悬浮液分装至96孔板上，培养并观察杂交瘤细胞生长情况，待细胞面积长至孔底面积1/2以上时，吸出上清液样品供抗体检测。
筛选杂交瘤培养上清液的抗人ILDR2抗体。具体地，步骤一、用碳酸盐缓冲溶液在96孔高吸附酶标板上包被人ILDR2(购自北京索莱宝科技有限公司，BIOSS)，包被量100μL每孔，之后用缓冲液洗涤3次后。步骤二、用含1％BSA的缓冲液阻断并于25℃孵育1小时，阻断量300μL/孔，孵育完成后缓冲液洗涤3次，分别向1-90号孔中加入100μL上清液样品(S1-S85)以及阳性血清(对照，CK1-5)，25℃孵育1小时，缓冲液洗涤5次。步骤三、每孔加入100μL以比例1/10000稀释在含1％BSA缓冲液里的抗小鼠IgG抗体，所述抗小鼠IgG抗体被辣根过氧化物酶标记，25℃孵育1小时，缓冲液洗涤5次。步骤四、每孔加入100μL比色底物3,3',5,5'-四甲基联苯胺(TMB)，30℃显色10min后终止显色反应，在酶标仪上读取450nm处的吸光度，根据OD450nm的强弱选取能够分泌人ILDR2结合抗体的阳性克隆。
将筛选得到的同时具有抗原结合活性以及抗原中和活性的克隆，进行抗体DNA序列的测定。首先按照说明书使用RNAprep Pure试剂盒(Tiangen)提取细胞mRNA。之后使用QuantScript RT试剂盒(Tiangen)合成cDNA第一链。将逆转录产生的cDNA第一链用于后续PCR反应，将PCR扩增得到的目的条带克隆到pGEM-T载体中，挑取单克隆进行DNA测序，测序由南京金斯瑞生物科技有限公司完成。
经过PCR扩增得到抗体轻链可变区和抗体重链可变区，排除骨架区序列后即可得到其互补决定区序列；其中轻链的三个互补决定区CDR-L1氨基酸序列如SEQ ID NO:1；CDR-L2氨基酸序列如SEQ ID NO:2、CDR-L3的氨基酸序列如SEQ ID NO:3所示；重链的三个互补决定区CDR-H1氨基酸序列如SEQ ID NO:4、CDR-H2氨基酸序列如SEQ ID NO:5、CDR-H3氨基酸序列如SEQ ID NO:6所示；抗体轻链恒定区氨基酸序列来源自鼠源IgVH4-21*07、抗体重链恒定区序列序列鼠源IgVH2-09*01，轻链全长序列为将抗体轻链可变区和轻链恒定区连接即得；重链全长序列为将抗体重链可变区和重链恒定区连接即得，将上述可变区序列及恒定区序列分别克隆到真核细胞表达载体LRET-713(载体骨架pEGFP-N1)中。将抗体轻链及抗体重链表达载体转染293F细胞系(购自上海复祥生物科技)。转染前一天接种细胞，转染当天将细胞离心收集细胞，将细胞重悬于新鲜的表达培养基中，细胞密度为150×105细胞/mL。按照转染体积加入质粒，终浓度为42.13μg/mL，加入线性聚乙烯亚胺至终浓度为60μg/mL。将上述混合物放入细胞培养箱120rpm，37℃培养1小时，之后向培养液中加入新鲜培养基至终体积为20倍转染体积，继续培养5～6天后收集上清。
实施例2：检测抗人ILDR2嵌合单抗
检测实施例1获得的抗人ILDR2嵌合单抗(以下简称Anti-ILDR2-M)与其抗原结合的动力学常数，利用仪器光学表面等离子体共振技术来检测偶联包被在生物芯片上的分子与待测分子之间的结合和解离。具体地，将Anti-ILDR2-M溶于的醋酸钠缓冲溶液(pH 5.0)中并偶联到CM芯片上，之后用1M乙醇胺封闭。在结合阶段，将不同浓度的Anti-ILDR2-M以30μL/min的速度注入3min，在解离阶段，用PBS缓冲溶液以30μL/min的速度注入10min，结合动力学常数和解离动力学常数通过Biacore3000软件进行分析计算。Anti-ILDR2-M的结合动力学常数、解离动力学常数和解离平衡常数如表1所示。
表1.Anti-ILDR2-M与其抗原结合的动力学常数
测定Anti-ILDR2-M的体内中和活性。具体地，选用6-8周龄雌性BALB/c小鼠(购自广东省医学实验动物中心)。随机分成三组，每组10只，按3三个剂量水平0.5nmol/kg,5nmol/kg，50nmol/kg分别给予各组Anti-ILDR2-M(静脉注射，单次给药)。给药一小时后，给每只小鼠皮下注射人10μg ILDR2，注射2小时后，对各小鼠进行眼眶采血并不予抗凝，室温放置血样约45分钟左右至凝血，离心获取血清样品，采用ELISA试剂盒(CCK)按说明书测定血清中小鼠CCK的浓度，结果显示，Anti-ILDR2-M能够抑制人ILDR2刺激小鼠分泌的CCK的水平，基本能将小鼠CCK水平降低至未刺激状态。
测定Anti-ILDR2-M的在大鼠体内的药代动力学研究，具体地，选用6-8周龄雌性SD大鼠(购自广东省医学实验动物中心)。随机分成三组，每组5只，各组分别给予10nmol/kgAnti-ILDR2-M(静脉注射，单次给药)。分别在0点，给药后5分钟，30分钟，1小时、2小时、3小时、6小时、9小时、12小时、24小时、48小时、72小时、96小时、120小时、168小时、216小时、264小时眼眶采血并不予抗凝，室温放置血样45分钟至凝血后，离心获得血清样品，血清样品冷冻于-80℃待测。ELISA测定血清中Anti-ILDR2-M，测试结果表明，单次静脉注射的剂量为10nmol/kg的Anti-ILDR2-M的药代参数如下：半衰期为512小时；药时曲线下面积为52139nM.hr；估算零浓度为496nM；表观分布容积为121mL/Kg；清除率为0.193mL/hr/kg；平均驻留时间为168小时。
实施例3：制备新型人源化ILDR2抗体
人源化形式的抗人ILDR2抗体参考Molecule Immunol的制备方法制备，在Germline数据库中选取与Anti-ILDR2-M非CDR区匹配最好的人源化模板，其中重链可变区的模板为人源IgVH4-28*03，轻链可变区的模板为人源IGKV1-16*02，将鼠源抗体CDR区移植到选择的人源化模板上，替换人模板的CDR区得到人源化抗体重链可变区，氨基酸序列如SEQ ID NO:7所示，得到人源化抗体轻链可变区，氨基酸序列如SEQ ID NO:8所示。通过序列比对选择适合位点进行回复突变，获得的重链可变区氨基酸序列(VH)及轻链可变区氨基酸序列(VL)如表2所示。
表2.重链可变区氨基酸序列及轻链可变区氨基酸序列
| VH | SEQ ID NO |
| ORI | SEQ ID NO:7 |
| RCA-2931 | SEQ ID NO:9 |
| RCA-2932 | SEQ ID NO:10 |
| RCA-2933 | SEQ ID NO:11 |
| RCA-2934 | SEQ ID NO:12 |
| VL | SEQ ID NO |
| ORI | SEQ ID NO:8 |
| RCA-2931 | SEQ ID NO:13 |
| RCA-2932 | SEQ ID NO:14 |
| RCA-2933 | SEQ ID NO:15 |
| RCA-2934 | SEQ ID NO:16 |
将人源化的抗人ILDR2单抗的重链可变区(SEQ ID NO：9-12)与人抗体IgG1重链恒定区(SEQ ID NO:17)连接，分别得到对应的重链全长序列。将人源化的抗人ILDR2单抗的轻链可变区(SEQ ID NO：13-16)与人抗体Kappa轻链的恒定区(SEQ ID NO:18)连接，分别得到对应的轻链全长序列，将上述所有重链全长序列与轻链全长序列组合得到人源化抗体全长序列，经酶切连接入LRET-713(载体骨架pEGFP-N1)载体中。
实施例4：检测人源化ILDR2单抗
检测实施例3获得人源化ILDR2单抗(测试组编号：ORI、RCA-2931、RCA-2932、RCA-2933、RCA-2934)与其ILDR2抗原结合的动力学常数，利用仪器光学表面等离子体共振技术来检测偶联包被在生物芯片上的分子与待测分子之间的结合和解离。具体地，将待检测人源化ILDR2单抗分别溶于的醋酸钠缓冲溶液(pH 5.0)中并注入偶联到CM芯片上，之后用1M乙醇胺封闭。在结合阶段，将不同测试组的人源化ILDR2单抗以30μL/min的速度注入3min，在解离阶段，用PBS缓冲溶液以30μL/min的速度注入10min，结合动力学常数和解离动力学常数通过Biacore3000软件来进行分析计算。人源化ILDR2单抗的结合动力学常数、解离动力学常数和解离平衡常数如表3所示。
表3.人源化ILDR2单抗与其抗原结合的动力学常数
测定人源化ILDR2单抗在大鼠体内的药代动力学研究，具体地，选用6-8周龄雌性SD大鼠(购自广东省医学实验动物中心)。随机分成五组(编号测试组1、测试组2、测试组3、测试组4、测试组5，每组10只)，测试组1给予10nmol/kg RCA-2931(静脉注射，单次给药)；测试组2给予10nmol/kg RCA-2932(静脉注射，单次给药)；测试组3给予10nmol/kgRCA-2933(静脉注射，单次给药)；测试组4给予10nmol/kg RCA-2934(静脉注射，单次给药)；测试组5给予10nmol/kg Anti-ILDR2-M(静脉注射，单次给药)。分别在0点，给药后5分钟，30分钟，1小时、2小时、3小时、6小时、9小时、12小时、24小时、48小时、72小时、96小时、120小时、168小时、216小时、264小时眼眶采血并不予抗凝，室温放置血样45分钟至凝血后，离心获得血清样品，血清样品冷冻于-80℃待测。
单次静脉注射的剂量为10nmol/kg的Anti-ILDR2-M的药代参数如下：半衰期t1/2为512小时，药时曲线下面积AUClast为52139nM.hr，估算零浓度C0为496nM，表观分布容积Vd为121mL/Kg，清除率CL为0.193mL/hr/kg，平均驻留时间MRTlast为168小时。
单次静脉注射的剂量为10nmol/kg的RCA-2931的药代参数如下：半衰期t1/2为487小时，药时曲线下面积AUClast为46139nM.hr，估算零浓度C0为486nM，表观分布容积Vd为119mL/Kg，清除率CL为0.181mL/hr/kg，平均驻留时间MRTlast为176小时。
单次静脉注射的剂量为10nmol/kg的RCA-2932的药代参数如下：半衰期t1/2为502小时，药时曲线下面积AUClast为51132nM.hr，估算零浓度C0为523nM，表观分布容积Vd为124mL/Kg，清除率CL为0.197mL/hr/kg，平均驻留时间MRTlast为201小时。
单次静脉注射的剂量为10nmol/kg的RCA-2933的药代参数如下：半衰期t1/2为462小时，药时曲线下面积AUClast为47141nM.hr，估算零浓度C0为456nM，表观分布容积Vd为101mL/Kg，清除率CL为0.173mL/hr/kg，平均驻留时间MRTlast为179小时。
单次静脉注射的剂量为10nmol/kg的RCA-2934的药代参数如下：半衰期t1/2为490小时，药时曲线下面积AUClast为48593nM.hr，估算零浓度C0为398nM，表观分布容积Vd为116mL/Kg，清除率CL为0.177mL/hr/kg，平均驻留时间MRTlast为181小时。
由结果可见，人源化ILDR2单抗与其抗原结合能力强，其中以测试组RCA-2933、RCA-2934与抗原结合能力更为突出，RCA-2931、RCA-2932结合能力弱于RCA-2933、RCA-2934但是优于ORI租，人源化ILDR2单抗在大鼠体内的药代动力学接近嵌合抗体。
实施例5人源化ILDR2单抗的药效研究
针对所述人源化ILDR2单抗，在小鼠胶原诱导关节炎模型(CIA模型)中进行药效研究。实验动物为18只8周龄雄性DBA1/J小鼠(购自广东省医学实验动物中心)，其中3只作为对照(CK)，另外15只建立CIA模型。CIA小鼠模型的建立参考文章“C57BL-6小鼠CIA模型建立方法的改进及CIA小鼠脾淋巴”。模型建立后，在观察到小鼠四肢足爪红肿等临床性关节炎症状之初，对CIA小鼠随机进行分组，每组3只，分5组(A、B、C、D、E)，对分组的CIA模型小鼠分别给药，给药剂量为：A组PBS、B组RCA-2931(10mg/kg,25nmol/kg)、C组RCA-2932(10mg/kg,25nmol/kg)、D组(10mg/kg,25nmol/kg)和E组RCA-2934(10mg/kg,50nmol/kg)，给药规则为：每两天腹腔注射给药一次，共给药8次。
每两天称量一次体重并记录前后四肢足爪病变状态，进行关节炎指数评分，评分标准如表4所示：
表4.评分标准
每两天测量一次后两肢足掌厚度，关节炎指数评分测定结果如表5所示。
表5.关节炎指数评分测定结果
| 测试组 | 1 | 2 | 3 | 平均分 |
| A | 4 | 4 | 3 | 3.7 |
| B | 1 | 1 | 1 | 1 |
| C | 0 | 1 | 0 | 0.3 |
| D | 0 | 0 | 0 | 0 |
| E | 1 | 1 | 0 | 0.7 |
| CK | 0 | 0 | 0 | 0 |
表5结果显示，经治疗后CIA诱导的小鼠的关节炎指数评分显著下降，显示了良好的炎症缓解效果，其中测试组D的发病小鼠经治疗后，评分基本接近于健康小鼠，显示出了在关节炎初期良好的治疗效果，测试组B、C、E也显示出明显有效的治疗效果，但其中以测试组C的治疗效果最为显著。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。
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<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VH RCA-2933
<400> 11
Gln Val Ala Trp Val Gln Trp Gln Leu Pro Lys Trp Ser Ile Arg Ser
1 5 10 15
Asp Lys Phe Tyr Ser Cys Thr Asp Tyr Cys Asn Ser Asp Arg Tyr Met
20 25 30
Glu Met Trp Glu Trp Val Phe Ala Leu Glu Leu Gly Gln Ala Asn His
35 40 45
Phe Cys Asp His Phe Val Trp Gln Arg Leu Glu Trp Ile Gly Thr Ile
50 55 60
Thr Met Arg Asp Gly Arg Asn Asn Ser Asp Ala Arg Ser Arg Val Gly
65 70 75 80
Thr Lys Ala Ala Ile Ile Gly Trp Pro Val Gly Trp Cys Glu Ala Trp
85 90 95
Gly Ala Gly Ser Ser Leu Arg Ser Asp Arg Asn Asp Pro Met Trp Ala
100 105 110
Cys Ala Arg Val Thr Val Ser Ser Phe Ser
115 120
<210> 12
<211> 122
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VH RCA-2934
<400> 12
Gln Val Ala Trp Ser Gln Trp Gln Leu Pro Lys Trp Ser Ile Val Ser
1 5 10 15
Asp Lys Phe Tyr Ser Cys Thr Asp Tyr Cys Asn Ser Asp Arg Leu Met
20 25 30
Glu Met Trp Glu Trp Val Phe Ala Leu Glu His Gly Gln Ala Asn His
35 40 45
Phe Cys Asp Glu Phe Val Trp Gln Arg Leu Glu Trp Ile Gly Thr Ile
50 55 60
Thr Met Arg Asp Gly Arg Asn Asn Ser Met Ala Arg Ser Arg Val Gly
65 70 75 80
Thr Lys Ala Ala Ile Ile Gly Trp Pro Val Gly Trp Cys Trp Ala Trp
85 90 95
Gly Ala Gly Ser Tyr Leu Arg Ser Asp Arg Asn Asp Pro Met Trp Ala
100 105 110
Cys Ala Arg Val Thr Val Ser Ser Phe Ser
115 120
<210> 13
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VL RCA-2931
<400> 13
Glu Ile Val Leu Thr Trp Ser Pro Arg Ile Thr Ala Cys Arg Asp Leu
1 5 10 15
Ile Tyr Leu Ala Ser Tyr Leu Glu Cys Gln Ala Gln Arg Val Lys His
20 25 30
Gly Arg Cys His Ala Gln Trp Ala Tyr Ala Arg Lys Thr Gln Asn Leu
35 40 45
Leu His Arg Glu Ile Trp Gln Trp Glu His Thr Ala Arg Ser Glu Ile
50 55 60
Ile His Phe Ala Asn Met Pro Lys Val Glu Ile Lys Arg Thr Ala Thr
65 70 75 80
Asn Ala Val Cys Tyr Asn Glu Val Ser Cys Gln Gly Val Cys Ala Arg
85 90 95
Phe Ser Gly Asn Glu Leu Trp Asp Gln Ala Cys Asp Gly Ser Tyr His
100 105 110
Arg
<210> 14
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VL RCA-2932
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Arg Ile Thr Ala Cys Arg Asp Leu
1 5 10 15
Ile Tyr Leu Ala Ser Tyr Leu Glu Cys Gln Ala Gln Arg Val Lys His
20 25 30
Gly Arg Cys His Ala Gln Gln Tyr Gln Ala Arg Lys Thr Gln Asn Leu
35 40 45
Leu His Arg Glu Ile Trp Gln Trp Glu His Thr Ala Arg Ile Glu Ile
50 55 60
Ile His Phe Ala Asn Met Pro Lys Val Glu Ile Lys Arg Thr Tyr Thr
65 70 75 80
Asn Glu Val Cys Tyr Asn Glu Val Ser Cys Gln Gly Val Cys Ala Arg
85 90 95
Phe Ser Gly Asn Glu Leu Trp Asp Gln Ala Cys Asp Gly Cys Tyr His
100 105 110
Arg
<210> 15
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VL RCA-2933
<400> 15
Glu Ile Val Leu Thr Gln Ser Pro Glu Ile Thr Ala Cys Arg Asp Leu
1 5 10 15
Ile Tyr Leu Ala Ser Tyr Leu Glu Cys Gln Ala Gln Arg Val Lys His
20 25 30
Gly Arg Cys His Ala Gln Trp Tyr Leu Ala Arg Gln Thr Gln Asn Leu
35 40 45
Leu His Arg Glu Ile Trp Gln Trp Glu His Thr Ala Arg Ser Glu Ile
50 55 60
Ile His Phe Ala Asn Met Pro Lys Val Glu Ile Lys Arg Thr Tyr Thr
65 70 75 80
Asn Ala Ile Cys Tyr Asn Glu Val Ser Cys Gln Gly Val Cys Ala Arg
85 90 95
Phe Ser Gly Asn Glu Leu Trp Asp Gln Ala Cys Asp Gly Ser Tyr His
100 105 110
Arg
<210> 16
<211> 113
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<221> UNSURE
<223> VL RCA-2934
<400> 16
Glu Ile Val Leu Thr Gln Ser Ala Arg Ile Thr Ala Cys Arg Asp Leu
1 5 10 15
Ile Tyr Leu Ala Ser Tyr Leu Glu Cys Gln Ala Gln Arg Val Lys His
20 25 30
Gly Arg Cys His Ala Gln Trp Tyr Gln Ala Arg Lys Thr Gln Asn Leu
35 40 45
Leu His Arg Glu Ile Trp Gln Trp Glu Thr Thr Ala Arg Ser Glu Ile
50 55 60
Ile His Phe Ala Asn Met Pro Lys Val Glu Ile Lys Arg Thr Tyr Thr
65 70 75 80
Asn Ala Val Leu Tyr Asn Glu Val Ser Cys Gln Gly Val Cys Ala Arg
85 90 95
Phe Ser Gly Asn Glu Leu Trp Asp Gln Ala Cys Asp Gly Tyr Tyr His
100 105 110
Arg
Claims (8)
1.一种ILDR2抗体，其特征在于，所述抗体包含轻链和重链；所述轻链包含CDR-L1、CDR-L2、CDR-L3区，所述重链包含CDR-H1、CDR-H2、CDR-H3区。
2.根据权利要求1所述的抗体，其特征在于，所述轻链CDR-L1氨基酸序列如SEQ ID NO:1；CDR-L2氨基酸序列如SEQ ID NO:2、CDR-L3的氨基酸序列如SEQ ID NO:3所示；所述重链CDR-H1氨基酸序列如SEQ ID NO:4、CDR-H2氨基酸序列如SEQ ID NO:5、CDR-H3氨基酸序列如SEQ ID NO:6所示。
3.根据权利要求1所述的抗体，其特征在于，所述抗体重链可变区氨基酸序列如SEQ IDNO:12所示，所述抗体轻链可变区氨基酸序列如SEQ ID NO:16所示。
4.根据权利要求1所述的抗体，其特征在于，所述抗体为抗人ILDR2人源化抗体和/或其多肽功能片段。
5.根据权利要求1所述的抗体，其特征在于，所述抗体重链可变区氨基酸序列如SEQ IDNO:7所示，所述抗体轻链可变区氨基酸序列如SEQ ID NO:8所示。
6.根据权利要求1所述的抗体，其特征在于，所述抗体包含选自人抗体IgG1、IgG2、IgG3、IgG4的任一Fc端的氨基酸序列。
7.根据权利要求1所述的抗体，其特征在于，所述抗体的生产步骤包括：在培养基中和合适的培养条件下培养含有权利要求1-6所述抗体的宿主细胞；从培养基中或从所培养的宿主细胞中回收产生的抗体及其多肽功能片段并与药学上可接受的载体制成药物。
8.一种药物组合物，其特征在于，包括权利要求1-7所述抗体，所述药物可用于辅助治疗类风湿性关节炎、骨关节炎、强直性脊柱炎、银屑病关节炎、系统性硬化症、系统性红斑狼疮、克隆氏病、过敏性哮喘。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104185681A (zh) * | 2012-02-01 | 2014-12-03 | 卡姆普根有限公司 | C1orf32抗体及其用于治疗癌症的用途 |
| CN107441480A (zh) * | 2010-06-30 | 2017-12-08 | 卡姆普根有限公司 | 多肽及其作为用于治疗多发性硬化、类风湿性关节炎以及其他自身免疫病症的药物的用途 |
| WO2019105972A1 (en) * | 2017-11-30 | 2019-06-06 | Bayer Aktiengesellschaft | Ildr2 antagonists and combinations thereof |
| CN111171150A (zh) * | 2020-02-05 | 2020-05-19 | 北京智仁美博生物科技有限公司 | 抗人tslp抗体及其用途 |
| CN111558038A (zh) * | 2020-05-27 | 2020-08-21 | 杭州伽南企业管理有限公司 | 一种用于癌症治疗的免疫检查点抑制剂 |
-
2020
- 2020-05-27 CN CN202010463330.XA patent/CN111574626B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107441480A (zh) * | 2010-06-30 | 2017-12-08 | 卡姆普根有限公司 | 多肽及其作为用于治疗多发性硬化、类风湿性关节炎以及其他自身免疫病症的药物的用途 |
| CN104185681A (zh) * | 2012-02-01 | 2014-12-03 | 卡姆普根有限公司 | C1orf32抗体及其用于治疗癌症的用途 |
| WO2019105972A1 (en) * | 2017-11-30 | 2019-06-06 | Bayer Aktiengesellschaft | Ildr2 antagonists and combinations thereof |
| CN111171150A (zh) * | 2020-02-05 | 2020-05-19 | 北京智仁美博生物科技有限公司 | 抗人tslp抗体及其用途 |
| CN111558038A (zh) * | 2020-05-27 | 2020-08-21 | 杭州伽南企业管理有限公司 | 一种用于癌症治疗的免疫检查点抑制剂 |
Non-Patent Citations (3)
| Title |
|---|
| JOSEPH R. PODOJIL等: "ILDR2-Fc Is a Novel Regulator of Immune Homeostasis and Inducer of Antigen-Specific Immune Tolerance", 《IMMUNOL.》 * |
| JULIA HUETTER等: "Characterization of BAY1905254, an Immune Checkpoint Inhibitor Targeting the Immunoglobulin-Like Domain Containing Receptor 2 (ILDR2)", 《CANCER IMMUNOLOGY RESEARCH》 * |
| 赵婷: "C57BL/6小鼠CIA模型建立方法的改进及CIA小鼠脾淋巴细胞Th1与Th2的动态观察", 《万方学位论文数据库》 * |
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