CN114621345B - 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 - Google Patents
一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域,具体提供了一种抗LAG‑3的单克隆抗体、其抗原结合片段及其应用,其包括重链可变区和轻链可变区,单克隆抗体或其抗原结合片段选自A‑1、A‑2、A‑3、A‑4中任意一种。本发明提供的单克隆抗体能够特异性结合LAG‑3,亲和力较高,且具有很好的生物学活性,能够用于治疗多种癌症或者免疫疾病,癌症包括但不限于白血病、肺癌、胃癌、食道癌、卵巢癌、头颈癌、黑色素瘤、肾癌、乳腺癌、结直肠癌、肝癌、胰腺癌或膀胱癌,免疫疾病包括但不限于银屑病、克罗恩病、类风湿性关节炎、原发性胆汁性肝硬化、系统性红斑狼疮、多发性硬化症、溃疡性结肠炎和自身免疫性肝炎。
Description
技术领域
本发明涉及生物医药技术领域,特别涉及一种抗LAG-3的单克隆抗体、其抗原结合片段及其应用。
背景技术
免疫疗法是当今最火热的癌症治疗方式,被誉为癌症治疗的第三次革命。所谓的“癌症免疫治疗”是借助人体自身的免疫系统,去攻击癌细胞的治疗方法。免疫系统和癌细胞之间的抗衡是一个长期博弈的动态过程,既正面交锋也相互交织。健康机体的免疫细胞能发现和杀灭癌细胞,但在各种先天和后天因素的诱导下,免疫系统会失去绝对优势,甚至被癌细胞“策反”,助长癌症的发生和发展。靶向药物曾以其精准性被寄予厚望,但由于癌细胞的善变和复杂,癌细胞很容易产生耐药性,精准性也很容易没有了用武之地。为此,自CTLA-4和PD-1被发现后,免疫检查点抑制治疗癌症逐渐成为研究热点。
随着免疫抗癌疗法的兴起,LAG-3逐渐被认为是一个颇有潜力的免疫检查点受体,据报道,LAG-3在促进调节性T细胞活性和下调T细胞活化和增殖中起重要作用(Workman CJ等人,J.Immunol.2005;174:688-695)。LAG-3(Lymphocyte-activation gene 3)又称为CD223,该基因包括8个外显子,位于人的12号染色体(小鼠的6号染色体),属于免疫球蛋白超家族,其由胞外区、跨膜区和胞质区3个部分组成,编码由498个氨基酸构成的I型跨膜蛋白。LAG-3在激活的NK细胞、T细胞等免疫细胞表面广泛表达,可负向调控淋巴细胞功能,并且已有部分研究证实其在肿瘤以及自身免疫性疾病方面均发挥着重要作用。
临床前研究显示,抑制LAG-3能够让T细胞重新恢复细胞毒性,从而限制肿瘤的生长,进而增强对肿瘤的杀伤效果,同时抑制LAG-3还能够降低调节T细胞抑制免疫反应的功能,所以LAG-3是能够调节T细胞功能的免疫检查点受体,抑制LAG-3有助于使患者受益更多,特别是那些肿瘤中含有表达LAG-3的免疫细胞的患者,为此,LAG-3被认为是一个比其它免疫检查点蛋白更吸引人的靶点。目前免疫检查点二代靶点中,LAG-3是临床数据较多、成药性相对确定的靶点。鉴于LAG-3存在的上述重要性,为了满足国内外肿瘤或其他免疫疾病患者的需求,急需开发具有较高生物学活性的抗LAG-3的单克隆抗体。
发明内容
为了满足国内市场的需求,本发明通过对免疫文库的筛选,得到了可以与LAG-3特异性结合且具有较高生物学活性的抗LAG-3的单克隆抗体或抗原结合片段。
本发明具体技术方案如下:
本发明提供了一种抗LAG-3的单克隆抗体或其抗原结合片段,包括重链可变区和轻链可变区,所述重链可变区包括3个重链互补决定区,3个所述重链互补决定区分别用HCDR1、HCDR2和HCDR3表示,所述轻链可变区包括3个轻链互补决定区,3个所述轻链互补决定区分别用LCDR1、LCDR2和LCDR3表示,所述单克隆抗体或其抗原结合片段选自以下任意一种:
A-1:所述重链互补决定区HCDR1包含如SEQ ID No:1所示的氨基酸序列,所述重链互补决定区HCDR2包含如SEQ ID No:2所示的氨基酸序列,所述重链互补决定区HCDR3包含如SEQ ID No:3所示的氨基酸序列,所述轻链互补决定区LCDR1包含如SEQ ID No:4所示的氨基酸序列,所述轻链互补决定区LCDR2包含如SEQ ID No:5所示的氨基酸序列,所述轻链互补决定区LCDR3包含如SEQ ID No:6所示的氨基酸序列;
A-2:所述重链互补决定区HCDR1包含如SEQ ID No:1所示的氨基酸序列,所述重链互补决定区HCDR2包含如SEQ ID No:2所示的氨基酸序列,所述重链互补决定区HCDR3包含如SEQ ID No:3所示的氨基酸序列,所述轻链互补决定区LCDR1包含如SEQ ID No:4所示的氨基酸序列,所述轻链互补决定区LCDR2包含如SEQ ID No:7所示的氨基酸序列,所述轻链互补决定区LCDR3包含如SEQ ID No:8所示的氨基酸序列;
A-3:所述重链互补决定区HCDR1包含如SEQ ID No:9所示的氨基酸序列,所述重链互补决定区HCDR2包含如SEQ ID No:10所示的氨基酸序列,所述重链互补决定区HCDR3包含如SEQ ID No:11所示的氨基酸序列,所述轻链互补决定区LCDR1包含如SEQ ID No:12所示的氨基酸序列,所述轻链互补决定区LCDR2包含如SEQ ID No:13所示的氨基酸序列,所述轻链互补决定区LCDR3包含如SEQ ID No:14所示的氨基酸序列;
A-4:所述重链互补决定区HCDR1包含如SEQ ID No:15所示的氨基酸序列,所述重链互补决定区HCDR2包含如SEQ ID No:16所示的氨基酸序列,所述重链互补决定区HCDR3包含如SEQ ID No:17所示的氨基酸序列,所述轻链互补决定区LCDR1包含如SEQ ID No:18所示的氨基酸序列,所述轻链互补决定区LCDR2包含如SEQ ID No:19所示的氨基酸序列,所述轻链互补决定区LCDR3包含如SEQ ID No:20所示的氨基酸序列。
本发明提供的上述抗LAG-3的单克隆抗体或其抗原结合片段能够与LAG-3特异性结合,结合活性更好,阻断LAG-3则可以逆转LAG-3对T细胞的抑制作用,增强T细胞活性,并减少调节性T细胞数量,还可以提高T细胞免疫应答的敏感度,从而用于治疗免疫或癌症疾病。
进一步的,所述单克隆抗体或其抗原结合片段为鼠源抗体分子,所述鼠源抗体分子选自以下任意一种:
MA-1:所述重链可变区包含如SEQ ID No:21所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:22所示的氨基酸序列;
MA-2:所述重链可变区包含如SEQ ID No:21所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:23所示的氨基酸序列;
MA-3:所述重链可变区包含如SEQ ID No:24所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:25所示的氨基酸序列;
MA-4:所述重链可变区包含如SEQ ID No:26所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:27所示的氨基酸序列;
优选的,所述鼠源抗体分子为MA-1。
本发明通过小鼠免疫用LAG-3抗原免疫小鼠,优化免疫方法,创建噬菌体展示库,并筛选出上述亲和力较高,活性较好且较为稳定的鼠源抗体分子,通过大量的细胞水平实验验证,发现相对其他3个鼠源抗体分子,MA-1具有更高的生物学活性,为此,本发明优选的选择MA-1。
进一步的,所述鼠源抗体分子还包括重链恒定区和轻链恒定区,所述重链恒定区为鼠的IgG1型、IgG2a型、IgG2b型、IgG3型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQ ID No:29所示,所述IgG2a型的重链恒定区氨基酸序列如SEQ ID No:30所示,所述IgG2b型的重链恒定区氨基酸序列如SEQ ID No:31所示,所述IgG3型的重链恒定区氨基酸序列如SEQ ID No:32所示;所述轻链恒定区为氨基酸序列如SEQ ID No:28所示的鼠源Ck链;
优选的,所述重链恒定区为鼠的IgG1型。
进一步的,所述单克隆抗体或其抗原结合片段为嵌合抗体分子,所述嵌合抗体分子包括所述鼠源抗体分子的重链可变区、所述鼠源抗体分子的轻链可变区和人源抗体恒定区;所述人源抗体恒定区包括人源抗体重链恒定区和人源抗体轻链恒定区,所述人源抗体重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQ ID No:39所示,所述IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,所述IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示;所述人源抗体轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链;
优选的,所述人源抗体重链恒定区为人的IgG4型。
嵌合抗体分子包括鼠源抗体分子的可变区序列和人源抗体恒定区,嵌合抗体分子的设计用于验证本发明恒定区人源化后没有改变CDR的功能,为人源化抗体分子的研究提供了进一步的研发基础。
进一步的,所述单克隆抗体或其抗原结合片段为人源化抗体分子,所述人源化抗体分子选自以下任意一种:
HA-1:所述重链可变区包含如SEQ ID No:33所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:34所示的氨基酸序列;
HA-2:所述重链可变区包含如SEQ ID No:33所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:35所示的氨基酸序列;
HA-3:所述重链可变区包含如SEQ ID No:36所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:35所示的氨基酸序列;
HA-4:所述重链可变区包含如SEQ ID No:36所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:34所示的氨基酸序列;
HA-5:所述重链可变区包含如SEQ ID No:37所示的氨基酸序列,所述轻链可变区包含如SEQ ID No:38所示的氨基酸序列;
优选的,所述人源化抗体分子为HA-1。
本发明通过人源化筛选后得到了人源化抗体分子,通过体内外的实验验证发现本发明中提供的5种人源化抗体分子中,HA-1的活性较高,药效最为显著,为此本发明优选HA-1。
进一步的,所述人源化抗体分子还包括重链恒定区和轻链恒定区,所述重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQID No:39所示,所述IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,所述IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示,所述轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链;
优选的,所述重链恒定区为人的IgG4型。
进一步的,所述人源化抗体分子为全长抗体或抗体片段,所述人源化抗体分子包括Fab、F(ab)2、Fv或ScFv中的一种或几种组合。
本发明还提供了一种多肽或蛋白,所述多肽或所述蛋白包含所述的抗LAG-3的单克隆抗体或其抗原结合片段。
本发明还提供了一种多核苷酸序列或组合,所述多核苷酸序列或组合编码所述的抗LAG-3的单克隆抗体或其抗原结合片段的氨基酸序列。
本发明还提供了一种重组DNA表达载体,所述重组DNA表达载体包含所述的多核苷酸序列或组合。
本发明还提供了一种转染所述的重组DNA表达载体的宿主细胞,所述宿主细胞包括原核细胞、酵母细胞、昆虫细胞或哺乳动物细胞;
优选的,所述宿主细胞为哺乳动物细胞,所述哺乳动物细胞为HEK293E细胞、CHO细胞或NS0细胞。
本发明还提供了一种药物或药物组合物,所述药物或所述药物组合物包含所述的抗LAG-3的单克隆抗体或其抗原结合片段。
本发明还提供了所述的抗LAG-3的单克隆抗体或其抗原结合片段在制备治疗癌症或免疫疾病药物中的应用;
优选的,所述癌症包括白血病、肺癌、胃癌、食道癌、卵巢癌、头颈癌、黑色素瘤、肾癌、乳腺癌、结直肠癌、肝癌、胰腺癌或膀胱癌;
所述免疫疾病包括银屑病、克罗恩病、类风湿性关节炎、原发性胆汁性肝硬化、系统性红斑狼疮、多发性硬化症、溃疡性结肠炎和自身免疫性肝炎。
本发明的有益效果如下:本发明提供的抗LAG-3的单克隆抗体或其抗原结合片段能够特异性结合LAG-3,亲和力较高,且具有很好的生物学活性,能够用于治疗多种癌症或者免疫疾病,癌症包括但不限于白血病、肺癌、胃癌、食道癌、卵巢癌、头颈癌、黑色素瘤、肾癌、乳腺癌、结直肠癌、肝癌、胰腺癌或膀胱癌,免疫疾病包括但不限于银屑病、克罗恩病、类风湿性关节炎、原发性胆汁性肝硬化、系统性红斑狼疮、多发性硬化症、溃疡性结肠炎和自身免疫性肝炎。
附图说明
图1为本发明实施例2中pScFv-Disb-HS载体的质粒图谱;
图2为本发明实施例3中梯度稀释ELISA抗LAG-3噬菌体单克隆抗体相对亲和力的比较图;
图3为本发明实施例5中载体pTSE的图谱;
图4为本发明实施例5中鼠源抗体分子的变性聚丙烯酰胺凝胶电泳图;
图5为本发明实施例6中鼠源抗体与LAG-3的结合能力比较图;
图6为本发明实施例7中鼠源抗体在混合淋巴细胞反应中对细胞因子IL-2分泌情况图;
图7为本发明实施例12中人源化抗体分子的变性聚丙烯酰胺凝胶电泳图;
图8为本发明实施例15中人源化抗体分子与LAG-3的结合能力比较图;
图9为本发明实施例16中混合淋巴细胞反应(MLR)测试抗LAG-3人源化抗体分子活性。
图10为本发明实施例17中抗LAG-3单克隆抗体对小鼠体内MC38结直肠癌的抑制试验效果图;
图11为本发明实施例18中抗LAG-3单克隆抗体HA-1蛋白分子热稳定性评价图。
具体实施方式
为了更加容易理解本发明,描述实施例之前,先对本发明某些技术和科学术语作以下说明:
本文所使用的术语“LAG-3”是指淋巴细胞活化因子3,这里的LAG-3包括但不限于活化的T细胞、NK细胞和B细胞表面上的二聚物表达的LAG-3(例如本领域公知的CD223)和人血清中发现的LAG-3的可溶形式,在本文中均称为LAG-3。
本文所使用的术语“抗体”,包含全抗体及其任一抗原结合片段,抗体包括鼠源抗体、人源化抗体、双特异抗体或嵌合抗体,抗体也可以是Fab、F(ab)2、Fv或ScFv(单链抗体),抗体可以是天然存在的抗体也可以是通过改变(例如突变、缺失、置换等)的抗体。
本文所使用的术语“可变区”和“恒定区”,即为抗体重链和轻链靠近N段的序列区为可变区(V区),靠近C段的其余氨基酸序列相对稳定,为恒定区(C区),可变区包括3个互补性决定区(CDR)和4个框架区(FR),每条轻链可变区和重链可变区均有3个CDR区和4个FR区组成,重链的3个CDR区分别通过HCDR1、HCDR2和HCDR3表示,轻链的3个CDR区分别通过LCDR1、LCDR2和LCDR3表示。
本文所使用的术语“鼠源抗体分子”,其来源是用LAG-3抗原免疫注射小鼠后得到的抗体。
本文所使用的术语“嵌合抗体分子”,是将鼠源抗体的可变区与人源抗体的恒定区融合而成的抗体,可以减轻鼠源抗体在人体内诱发的免疫应答反应。嵌合抗体是利用DNA重组技术,将鼠源单抗的轻、重链可变区基因插入含有人抗体恒定区的表达载体中,这样表达的抗体分子中轻重链的可变区是鼠源的,而恒定区是人源的,整个抗体分子的近2/3部分都是人源的。这样产生的抗体,减少了鼠源抗体的免疫原性,同时保留了亲本抗体特异性结合抗原的能力。
本文所使用的术语“人源化抗体分子”,其是将鼠源单抗的CDR移植至人源抗体可变区,替代人源抗体CDR,使人源抗体获得鼠源单抗的抗原结合特异性,同时减少其异源性。
术语“CHO细胞”为中国仓鼠卵巢细胞(chinese hamster ovary cell);术语“HEK293E细胞”为人胚肾293E细胞(human embryonic kidney 293E cell),术语“NS0细胞”为小鼠NS0胸腺瘤细胞。
下面结合以下实施例对本发明作进一步详细说明。
实施例1
本发明实施例1提供了一种抗LAG-3的单克隆抗体或其抗原结合片段,具体包括重链可变区和轻链可变区,重链可变区包括3个重链互补决定区,3个重链互补决定区分别用HCDR1、HCDR2和HCDR3表示,轻链可变区包括3个轻链互补决定区,3个轻链互补决定区分别用LCDR1、LCDR2和LCDR3表示,单克隆抗体或其抗原结合片段选自以下任意一种。
实施例2鼠源抗体分子筛选
本发明通过用LAG-3抗原免疫小鼠,优化免疫方法,创建噬菌体展示库,具体噬菌体展示库的构建与筛选鉴定如下:
步骤一:LAG-3抗原免疫小鼠
1、实验动物:
种属品系:BALB/c,雌性,小鼠;
体重:18-20g;
实验动物提供商:北京华阜康生物科技股份有限公司。
2、免疫:对小鼠进行免疫,免疫抗原为人LAG-3(南京金斯瑞生物科技有限公司合成基因,本公司构建载体并表达纯化)。
步骤二:噬菌体抗体库的构建
取效价较高的小鼠脾细胞,利用Trizol试剂(购买自Ambion,货号:15596026),提取小鼠脾细胞中的总RNA,RT-PCR获得cDNA,以cDNA为模板,采用简并引物(所用简并引物参考文献:Journal of Immunological Methods233(2000)167-177)进行PCR扩增,从而获得免疫小鼠抗体重链可变区基因库(VH)及轻链可变区基因库(VL),轻重链分别双酶切,连接至同样分步骤酶切处理过的载体上,构建pScFv-Disb-HS-VH-VL基因库,PscFv-DisB-HS载体是采用一系列基因克隆的方法对载体pComb3载体(购自中国质粒载体菌株细胞株基因保藏中心)进行改造,使之用于噬菌体单链抗体库的构建和表达。改造后的载体命名pScFv-Disb-HS载体,获得其质粒图谱如图1所示,并以此载体为基础,构建小鼠免疫噬菌体抗体库。
步骤三:以LAG-3为抗原包被免疫管,抗原包被量为5μg/500μl/管,4℃包被过夜,再用4%脱脂奶粉/PBST分别封闭免疫管和免疫噬菌体抗体库,室温封闭1h。封闭后的免疫噬菌体抗体库加入免疫管中进行抗原抗体结合,噬菌体投入量约为109~1012个,室温反应1h后,使用PBST-PBS洗去未结合的噬菌体,通过0.1MpH2.2的Glycine-HCl洗脱,最后使用1.5M pH 8.8的Tris-HCl中和洗脱下来的噬菌体抗体溶液至pH7.0左右。
步骤四:将上述中和后的噬菌体感染10ml生长至对数期的TG1菌液,37℃培养箱中静置30min,取出部分菌液进行梯度稀释,涂布于2YTAG平板上,用于计算噬菌体产出量。剩余的菌液离心弃上清,将菌体沉淀重悬于少量培养基,吸出后涂布于2YTAG大平板,为下一轮筛选做准备。
步骤五:将上述感染后涂板的菌体从大平板上刮下,接菌至2YTAG液体培养基,摇至对数期后加入M13KO7辅助噬菌体超感染,在28℃条件下,220rpm培养过夜制备噬菌体,PEG/NaCl沉降纯化噬菌体用于下一轮筛选,共进行一轮噬菌体库富集筛选。
步骤六:LAG-3噬菌体单链抗体阳性克隆的筛选:经过一轮筛选后,挑取分隔良好的单克隆菌落,接种于加有2YTAG液体培养基的96孔深孔板,在37℃条件下,220rpm的条件下培养至其对数生长期,每孔加入约1010的辅助噬菌体M13KO7,在37℃的温度条件下静止感染30min。4000rpm,离心15min,弃去上清,菌体用2YTAK重悬沉淀,在28℃且220rpm的条件下培养过夜。4000rpm,4℃的条件下离心15min后,吸取扩增后的噬菌体上清进行ELISA鉴定,最终筛选得到四个亲和力较高的抗LAG-3的鼠源抗体分子,分别命名为MA-1,MA-2,MA-3和MA-4,将上述得到的单克隆抗体进行基因测序确定为正确的抗体序列,经过测序,上述筛选到的4个单克隆抗体序列如下:
鼠源抗体分子 | 重链可变区序列 | 轻链可变区序列 |
MA-1 | SEQ ID No:21 | SEQ ID No:22 |
MA-2 | SEQ ID No:21 | SEQ ID No:23 |
MA-3 | SEQ ID No:24 | SEQ ID No:25 |
MA-4 | SEQ ID No:26 | SEQ ID No:27 |
具体的,SEQ ID No:21(MA-1和MA-2的重链可变区的氨基酸序列):
EVQLQQSGAELVKPGASVKLSCTASGFNIKDTYMHWVKQRPEQGLEWIGKIDPANGNTKYDPKFQGKATITADTSSNTAYLQLSRLTSEDTAVYYCARDTTVGLDYWGQGTTLTVSS;
SEQ ID No:22(MA-1的轻链可变区的氨基酸序列):
DIVITQSTAIMSASLGEKVTMSCRASSSVNYMYWYQQKSDASPKLWIYYTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSSNPHTFGGGTKLEIK;
SEQ ID No:23(MA-2的轻链可变区的氨基酸序列):
DIVLTQTPAIMSASLGEKVTMSCRASSSVNYMYWYQQKSDASPKLWIYYTSNLAPGVPARFSGSGSGNSYSLTISSMEGEDAATYYCQQFTSSPSMTFGGGTKLEIK;
SEQ ID No:24(MA-3的重链可变区的氨基酸序列):
EVKLEESGPELVKPGASVKISCKASGYSFTSYYIHWVKQRPGQGLEWIGWIFPGTGNTRYNEKFKGKATLTADTSSSTVYMQLSGLTSEDSAVYFCARIGGRLTGDAMDYWGQGTSVTVSS;
SEQ ID No:25(MA-3的轻链可变区的氨基酸序列):
DIVLTQSTASLAVSLGQRATISCRASESVDSYGNSFMHWYQQKPGQPPKLLIYLASNLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPWTFGGGTKLEIK;
SEQ ID No:26(MA-4的重链可变区的氨基酸序列):
QVKLEESGPGLVQPSQSLSITCTVSAFSLTTYAVHWVRQSPGKGLEWLGVIWSGGSTDYNTAFISRLNITKDNSKSQVFFKMNSLQANDTAIYYCARLDGTFFDYWGQGTTLTVSS;
SEQ ID No:27(MA-4的轻链可变区的氨基酸序列):
DIVLTQTPAIMSASLGERVTMTCTASSSVSSSYLHWYQQKPGSSPKLWIYSTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPPTFGGGTKLEIK。
实施例3梯度稀释ELISA比较抗LAG-3噬菌体单克隆抗体的亲和力
将实施例2中获得的4个鼠源抗体分子(MA-1,MA-2,MA-3和MA-4)进行单克隆噬菌体的展示和纯化,然后进行噬菌体梯度稀释ELISA实验鉴定亲和力,对照抗体选择专利CN105992595A中的中提供的抗LAG-3的单克隆抗体,具体方法如下:
用pH9.6的碳酸盐缓冲液包被LAG-3,100ng/孔/100μl,在4℃温度条件下包被过夜,使用PBST洗涤三次,将实施例2中筛选得到的4个噬菌体单克隆抗体分别用PBST三倍梯度稀释,每孔加入100μl稀释后的样品,在室温下静置1小时。用PBST洗涤ELISA板,将PBST稀释后的HRP-anti-M13单克隆抗体加入ELISA板中,在室温放置1h。TMB显色试剂盒显色,室温显色10分钟,用2M H2SO4终止后,在450nm/630nm下读数,并计算对应的EC50值,具体数据如下:
克隆 | MA-1 | MA-2 | MA-3 | MA-4 | 对照抗体 |
EC50 | 0.010 | 0.058 | 0.024 | 0.117 | 0.115 |
通过上述数据及如图2所示,实施例2筛选出的4个不同的鼠源抗体分子均能够与LAG-3进行结合,本发明提供的单克隆抗体与LAG-3均具有较高的亲和力。
实施例4
本发明实施例4在实施例2基础上进一步限定了鼠源抗体分子还包括重链恒定区和轻链恒定区,重链恒定区为鼠的IgG1型、IgG2a型、IgG2b型、IgG3型中的一种,IgG1型的重链恒定区氨基酸序列如SEQ ID No:29所示,IgG2a型的重链恒定区氨基酸序列如SEQ IDNo:30所示,IgG2b型的重链恒定区氨基酸序列如SEQ ID No:31所示,IgG3型的重链恒定区氨基酸序列如SEQ ID No:32所示;轻链恒定区为氨基酸序列如SEQ ID No:28所示的鼠源Ck链;具体序列如下:
SEQ ID No:28(鼠源Ck链的轻链恒定区序列):
ADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC;
SEQ ID No:29(鼠的IgG1型的重链恒定区序列):
AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG;
SEQ ID No:30(鼠的IgG2a型的重链恒定区序列):
AKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK;
SEQ ID No:31(鼠的IgG2b型的重链恒定区序列):
AKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECHKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAPQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK;
SEQ ID No:32(鼠的IgG3型的重链恒定区序列):
ATTTAPSVYPLVPGCSDTSGSSVTLGCLVKGYFPEPVTVKWNYGALSSGVRTVSSVLQSGFYSLSSLVTVPSSTWPSQTVICNVAHPASKTELIKRIEPRIPKPSTPPGSSCPPGNILGGPSVFIFPPKPKDALMISLTPKVTCVVVDVSEDDPDVHVSWFVDNKEVHTAWTQPREAQYNSTFRVVSALPIQHQDWMRGKEFKCKVNNKALPAPIERTISKPKGRAQTPQVYTIPPPREQMSKKKVSLTCLVTNFFSEAISVEWERNGELEQDYKNTPPILDSDGTYFLYSKLTVDTDSWLQGEIFTCSVVHEALHNHHTQKNLSRSPELELNETCAEAQDGELDGLWTTITIFISLFLLSVCYSASVTLFKVKWIFSSVVQVKQTAIPDYRNMIGQGA。
实施例5抗LAG-3鼠源抗体分子制备
本发明实施例5在实施例4的基础上优选的限定了鼠源抗体分子的重链恒定区为鼠的IgG1型,IgG1型包含如SEQ ID No:29所示的氨基酸序列;轻链恒定区为鼠源Ck链,鼠源Ck链包含如SEQ ID No:28所示的氨基酸序列。抗体制备方法具体如下:
1、在将实施例2筛选出来的4个单克隆抗体的重链VH和轻链VL的编码基因分别克隆至装有重链和轻链恒定区基因的载体pTSE(如图3所示),优选的重链恒定区为鼠的IgG1型恒定区(氨基酸序列如SEQ ID No:29所示),轻链恒定区为鼠源Ck链(氨基酸序列如SEQID No:28所示),pTSE载体结构如图3所示(pTSE载体制备过程参见CN103525868A说明书第3页第[0019]段)。
2、瞬时转染HEK293E细胞(购自中国医学科学院基础医学研究所,货号为GNHu43),进行抗体表达,使用AKTA仪器通过protein A亲和柱纯化获得4个单克隆抗体,同时使用BCA试剂盒(购买自:北京汇天东方科技有限公司,货号:BCA0020)进行蛋白浓度测定,之后通过SDS-PAGE鉴定蛋白大小,结果如图4所示,从左侧到右侧依次为非还原MA-1,MA-2,MA-3和MA-4和蛋白质分子量Marker1、Marker2及还原MA-1,MA-2,MA-3和MA-4鼠源抗LAG-3单克隆抗体,每条带的分子量大小与理论一致。
实施例6鼠源抗体与LAG-3的结合实验
用pH9.6的碳酸盐缓冲液包被LAG-3,100ng/孔/100μl,在4℃的温度条件下过夜包被。用300μl/孔PBST洗涤五次,再加入1%BSA-PBST在37℃温度条件下封闭1h,加入不同稀释浓度的MA-1,MA-2,MA-3和MA-4鼠源抗体,4种全抗体的起始最高浓度均是5μg/ml,分别经过3倍稀释后每个抗体均做12个梯度,在37℃温度条件下孵育1h。用300μl/孔PBST洗涤五次,再加入用1%BSA-PBST1:10000稀释的Anti-Mouse Fc-HRP,在37℃温度条件下孵育1h。TMB显色试剂盒显色,100μl/孔,室温显色8min,然后用2MH2SO4终止显色。在450nm/630nm下读数,并计算对应的EC50值,具体数据如下:
克隆 | MA-1 | MA-2 | MA-3 | MA-4 |
EC50(ng/ml) | 10.08 | 25.99 | 255.9 | 22.12 |
通过上述数据及如图5所示,筛选出的4个不同的鼠源抗体均能与LAG-3进行结合,此外,这4个鼠源抗体分子中MA-1的EC50值最低,说明其与LAG-3结合能力最好,亲和力最高。
实施例7鼠源抗体在混合淋巴细胞反应中对细胞因子IL-2分泌量的影响
按密度梯度离心法分离新鲜外周血PBMC,磁珠分选CD14+T细胞;用20ng/mL GM-CSF与10ng/mL IL-4的培养基培养CD14+T细胞,每2天换液,7-10天诱导成为树突状DC细胞。在DC使用前两天,加入25ng/mL的TNF-α诱导DC为成熟的DC细胞,收集成熟的DC细胞,配制成细胞密度为1x105个/mL细胞悬液。从新鲜外周血PBMC中磁珠分选出CD4+T细胞,计数,制成细胞密度为1x106个/mL细胞悬液。将CD4+T细胞与DC细胞各取100ul,按比例10:1加入96孔板。
将实施例5中制备的MA-1,MA-2,MA-3和MA-4鼠源抗体分别进行4倍梯度稀释,每个抗体均设置6个梯度,各取50ul加入到96孔板中,培养5天后检测IL-2的浓度,在450nm下读数,并计算对应的EC50值,具体数据如下:
克隆 | MA-1 | MA-2 | MA-3 | MA-4 |
EC50(ug/ml) | 0.024 | 0.030 | 0.076 | 0.121 |
通过上述数据及如图6所示,本发明筛选出来的4个鼠源抗体分子,均具有较好的活性,此外,通过上述数据还可以得出,本发明筛选出的4个单克隆抗体中MA-1的EC50值最低,所以其活性最好,为此,本发明可以针对鼠源抗体分子MA-1进行人源化处理。
实施例8
本发明实施例8进一步的限定了单克隆抗体或其抗原结合片段为嵌合抗体分子,嵌合抗体分子包括实施例2中鼠源抗体分子的重链可变区、鼠源抗体分子的轻链可变区和人源抗体恒定区;人源抗体恒定区包括人源抗体重链恒定区和人源抗体轻链恒定区,人源抗体重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,IgG1型的重链恒定区氨基酸序列如SEQ ID No:39所示,IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示;人源抗体轻链恒定区为氨基酸序列如SEQ IDNo:42所示的人的Ck链。
SEQ ID No:39(人的IgG1型的重链恒定区氨基酸序列):
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;
SEQ ID No:40(人的IgG2型的重链恒定区氨基酸序列):
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK;
SEQ ID No:41(人的IgG4型的重链恒定区氨基酸序列):
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK;
SEQ ID No:42(人的Ck链的轻链恒定区氨基酸序列):
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
实施例9嵌合抗体分子抗体的制备
本发明实施例9在实施例8的基础上进一步限定了嵌合抗体分子的重链恒定区为人的IgG4型,IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示;嵌合抗体轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链。
具体的制备方法:
将实施例2中免疫噬菌体抗体库筛选得到的抗体分子MA-1的重链可变区VH(SEQID No:21)和轻链可变区VL基因(SEQ ID No:22)保持鼠源序列不变,分别克隆至装有重链恒定区和轻链恒定区基因的载体pTSE(如图3所示),重链恒定区为人的IgG4型(氨基酸序列如SEQ ID NO:41所示),轻链恒定区为人的Ck链(氨基酸序列如SEQ ID NO:42所示)。瞬时转染HEK293E细胞(购买自:中国医学科学院基础医学研究所,货号为:GNHu43),进行抗体表达,得到嵌合抗体CA-1。
实施例10鼠源抗体分子MA-1进行人源化
首先使用实施例2中鼠源抗体分子MA-1的序列和人抗体种系数据库(v-base)比较,寻找同源性较高的人抗体轻、重链种系作为候选序列,然后将鼠源抗体分子MA-1的CDR的序列移植到人源候选序列上进行同源建模。然后通过三维结构模拟计算可能对于维持CDR环状结构起重要作用的关键框架氨基酸残基,从而设计人源化抗体的回复突变。将设计好的包含回复突变的人源化抗体的轻、重链可变区分别由南京金斯瑞生物科技有限公司优化合成,然后再连接到瞬时表达载体上,对人源化得到的轻重链组合分析,得到如下人源化抗体分子:HA-1,HA-2,HA-3,HA-4,HA-5,上述筛选到的5个单克隆抗体序列如下:
单克隆抗体 | 重链可变区 | 轻链可变区 |
HA-1 | SEQ ID No:33 | SEQ ID No:34 |
HA-2 | SEQ ID No:33 | SEQ ID No:35 |
HA-3 | SEQ ID No:36 | SEQ ID No:35 |
HA-4 | SEQ ID No:36 | SEQ ID No:34 |
HA-5 | SEQ ID No:37 | SEQ ID No:38 |
具体的,SEQ ID No:33(HA-1和HA-2的重链可变区的氨基酸序列):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDTYMHWVRQAPGQGLEWIGKIDPANGNTKYDPKFQGRATITADTSISTAYMELSRLRSDDTAVYYCARDTTVGLDYWGQGTLVTVSS;
SEQ ID No:34(HA-1和HA-4的轻链可变区的氨基酸序列):
DIVITQSPAFLSVTPGEKVTITCRASSSVNYMYWYQQKPDASPKLWIYYTSKLASGVPSRFSGSGSGTDYTFTISSLEAEDAATYYCQQWSSNPHTFGGGTKVEIK;
SEQ ID No:35(HA-2和HA-3的轻链可变区的氨基酸序列):
DIVITQSPAFLSVTPGEKVTITCRASSSVNYMYWYQQKPDQAPKLLIYYTSKLASGVPSRFSGSGSGTDYTFTISSLEAEDAATYYCQQWSSNPHTFGGGTKVEIK;
SEQ ID No:36(HA-3和HA-4的重链可变区的氨基酸序列):
QVQLVQSGAEVKKPGASVKVSCKASGYNITDTYMHWVRQAPGQGLEWIGKIDPANGNTKYDPKFQGRATITADTSISTAYMELSRLRSDDTAVYYCARDTTVGLDYWGQGTLVTVSS;
SEQ ID No:37(HA-5的重链可变区的氨基酸序列):
QVQLVQSGAEVKKPGASVKVSCKASGYNIKDTYMHWVKQAPGQGLEWIGKIDPANGNTKYDPKFQGKATITADTSISTAYMELSRLRSDDTAVYYCARDTTVGLDYWGQGTLVTVSS;
SEQ ID No:38(HA-5的轻链可变区的氨基酸序列):
DIVITQSPAFLSVTPGEKVTITCRASSSVNYMYWYQQKPDASPKLWIYYTSKLASGVPARFSGSGSGTSYTFTISSLEAEDAATYYCQQWSSNPHTFGGGTKVEIK。
实施例11
本发明实施例11在实施例10的基础上进一步的限定了人源化抗体分子还包括重链恒定区和轻链恒定区,重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,IgG1型的重链恒定区氨基酸序列如SEQ ID No:39所示,IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示,轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链。
实施例12人源化抗体分子的制备
本发明实施例12在实施例11的基础上进一步的限定了人源化抗体分子的重链恒定区为人的IgG4型,IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示;轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链。
将上述实施例10人源化得到的5个人源化抗体分子的重链VH和轻链VL的编码基因分别克隆至装有重链恒定区和轻链恒定区基因的载体pTSE(如图3所示),重链恒定区为人的IgG4型(氨基酸序列如SEQ ID NO:41所示),轻链恒定区为Ck链(氨基酸序列如SEQ IDNO:42所示)。
将嵌合抗体CA-1和人源化抗体瞬时转染HEK293E细胞(购自中国医学科学院基础医学研究所,货号为GNHu43),进行抗体表达,使用AKTA仪器通过protein A亲和柱纯化获得单克隆抗体,同时使用BCA试剂盒(购买自:北京汇天东方科技有限公司,货号:BCA0020)进行蛋白浓度测定,之后通过SDS-PAGE鉴定蛋白大小,结果如图7所示,从左侧到右侧依次为非还原蛋白质分子量Marker1、HA-1、HA-2、HA-3、HA-4、HA-5、实施例9中制备的嵌合抗体CA-1及核心专利CN105992595A提供的抗LAG-3单克隆抗体和还原蛋白质分子量Marker2、HA-1、HA-2、HA-3、HA-4、HA-5、嵌合抗体CA-1及核心专利CN105992595A提供的抗LAG-3单克隆抗体,每条带的分子量大小与理论一致。
实施例13
本发明实施例13在上述实施例的基础上进一步的限定了人源化抗体分子为全长抗体或抗体片段,人源化抗体分子包括Fab、F(ab)2、Fv或ScFv中的一种或几种组合。
实施例14
本发明实施例14在上述实施例的基础上进一步的限定了如下方案:
进一步限定了一种多肽或蛋白,多肽或所述蛋白包含上述任意一个实施例限定的抗LAG-3的单克隆抗体或其抗原结合片段。
进一步的限定了一种多核苷酸序列或组合,多核苷酸序列或组合编码上述任意一个实施例限定的抗LAG-3的单克隆抗体或其抗原结合片段的氨基酸序列。
进一步的限定了一种重组DNA表达载体,重组DNA表达载体包含上述的多核苷酸序列或组合。
进一步的限定了一种转染上述限定的重组DNA表达载体的宿主细胞,宿主细胞包括原核细胞、酵母细胞、昆虫细胞或哺乳动物细胞;
优选的,宿主细胞为哺乳动物细胞,哺乳动物细胞为HEK293E细胞、CHO细胞或NS0细胞。
进一步的限定了一种药物或药物组合物,药物或药物组合物包含上述任意一个实施例限定的抗LAG-3的单克隆抗体或其抗原结合片段。
本发明进一步的提供了抗LAG-3的单克隆抗体或其抗原结合片段在制备治疗癌症或免疫疾病药物中的应用;
优选的,癌症包括但不限于白血病、肺癌、胃癌、食道癌、卵巢癌、头颈癌、黑色素瘤、肾癌、乳腺癌、结直肠癌、肝癌、胰腺癌或膀胱癌;免疫疾病包括但不限于银屑病、克罗恩病、类风湿性关节炎、原发性胆汁性肝硬化、系统性红斑狼疮、多发性硬化症、溃疡性结肠炎和自身免疫性肝炎。
实施例15人源化抗体分子与LAG-3结合实验
用pH9.6的碳酸盐缓冲液包被LAG-3,100ng/孔/100μl,在4℃的温度条件下过夜包被。用300μl/孔PBST洗涤五次,再加入1%BSA-PBS在37℃温度条件下封闭2h,加入不同稀释浓度的人源化抗体HA-1,HA-2,HA-3,HA-4,HA-5和实施例9中制备的嵌合抗体CA-1及专利CN105992595A中的抗LAG-3抗体,7个抗体的起始最高浓度均是5μg/ml,分别经过5倍稀释后每个抗体均做8个梯度,在37℃温度条件下孵育1h。用300μl/孔PBST洗涤五次,再加入用1%BSA-PBS1:10000稀释的Anti-Human Fc-HRP,在37℃温度条件下孵育1h。TMB显色试剂盒显色,100μl/孔,室温显色8min,然后用2M H2SO4终止显色。在450nm/630nm下读数,并计算对应的EC50值,具体数据如下:
克隆 | HA-1 | HA-2 | HA-3 | HA-4 | HA-5 | 嵌合抗体CA-1 | CN105992595A |
EC50(ng/ml) | 46.25 | 150.7 | 102.5 | 538.8 | 380.3 | 52.16 | 747.2 |
通过上述数据及实验结果如图8所示,5个不同的人源化抗体分子均能与LAG-3进行结合,本发明提供的5个不同的单克隆抗体的EC50值均明显低于专利CN105992595A中的抗LAG-3抗体,说明本发明提供的单克隆抗体与LAG-3的结合能力强,亲和力高,此外,从图8及上述数据中还可以得出,5个不同的单克隆抗体中HA-1的EC50值最低,说明其与LAG-3结合能力最好,亲和力最高;同时HA-1的EC50值与嵌合抗体CA-1相似,说明人源化后的HA-1保留了鼠源亲本抗体MA-1与LAG-3的高亲和力,亲和力没有下降。
实施例16混合淋巴细胞反应(MLR)测试抗LAG-3人源化抗体分子活性
按密度梯度离心法分离新鲜外周血PBMC,磁珠分选CD14+T细胞;用20ng/ml GM-CSF与10ng/ml IL-4的培养基培养CD14+T细胞,每两天换液,7-10天诱导成为树突状DC细胞。在DC使用前两天,加入25ng/ml的TNF-α诱导DC为成熟的DC细胞,收集成熟的DC细胞,配制成细胞密度为1×105个/ml细胞悬液。从新鲜PMBC中磁珠分选出CD14+T细胞,计数,制成细胞密度为1×106个/ml细胞悬液。将CD14+T细胞与DC细胞各取100μl,按比例10:1加入96孔板。
将实施例12制备的5个抗LAG-3人源化抗体分子、实施例9制备的嵌合抗体CA-1及专利CN105992595A提供的抗LAG-3抗体作为阳性对照,分别进行4倍梯度稀释,每个抗体均设置8个梯度,各取50μl加入到96孔板中,5天后,CCK8测试CD14+T细胞增殖,在450nm/630nm下读数,并计算对应的EC50值,具体数据如下:
克隆 | HA-1 | HA-2 | HA-3 | HA-4 | HA-5 | 嵌合抗体CA-1 | CN105992595A |
EC5O(ng/m) | 6.875 | 27.09 | 15.01 | 33.8 | 31.84 | 7.226 | 39.59 |
通过上述数据及如图9所示,本发明筛选出的5个不同的抗LAG-3抗体的EC50值均明显低于专利CN105992595A中提供的抗LAG-3的抗体,说明本发明提供的抗LAG-3抗体的活性均比较高,同时本发明筛选出的5个单克隆抗体中,抗LAG-3全抗体HA-1的EC50值最低,说明其活性最高,此外,从图9还可以看出,嵌合抗体CA-1的亲和力与抗LAG-3抗体HA-1的EC50值比较接近,说明人源化抗体HA-1保留了鼠源亲本抗体MA-1的生物活性,其生物活性没有下降。
实施例17抗LAG-3单克隆抗体HA-1对小鼠体内MC38结直肠癌的抑制试验
1、实验动物:
种属品系:Mus Musculus,NCG,小鼠;
周龄:6-8周;
实验动物提供商:江苏集萃药康生物科技有限公司。
2、细胞培养,MC38肿瘤细胞(YK-CL-256-02)(购自:普如汀生物技术(北京)有限公司(Biovector NTCC Inc.),货号:NTCC-MC38)。用含有灭活的10%胎牛血清(ExCell Bio,货号:FND500),100U/ml的青霉素和100μg/ml的链霉素以及2mM谷氨酰胺的DMEM培养基(购自:赛默飞世尔科技(中国)有限公司(Gibco),货号:10566-016)在37℃、5%CO2的培养箱中培养肿瘤细胞,每隔3至4天待细胞长满后分瓶传代,将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
3、肿瘤细胞的接种与分组:PBS重悬的MC38肿瘤细胞,浓度为1.0×107/ml,接种于实验动物的右侧胁肋部皮下,100μl/只,在肿瘤生长至61mm3左右时分组给药,共3组,每组8只,分别为溶媒对照组、HA-1(10mg/kg,i.p.,biw×3w)、HA-1(30mg/kg,i.p.,biw×3w)。
4、检测指标:每周使用游标卡尺对肿瘤体积进行2次的测量,测量肿瘤的长径和短径,其体积计算公式为:体积=0.5×长径×短径2;记录肿瘤体积的变化与给药时间的关系,实验结果如图10所示。
通过图10数据显示,抗LAG-3单克隆抗体HA-1能够抑制肿瘤的生长,且呈现剂量依赖性反应。
实施例18抗LAG-3单克隆抗体HA-1蛋白分子热稳定性评估
将抗LAG-3单克隆抗体HA-1蛋白分子超滤换液到PBS缓冲体系中,12000rpm,在4℃条件下,离心5min,使用多功能蛋白热稳定性分析系统(购买自Unchained Labs)对抗LAG-3单克隆抗体HA-1蛋白分子的热稳定性进行评估。通过监测蛋白内源性荧光随温度变化(从25℃开始,以0.3℃/min的升温速度升温至95℃)检测蛋白构象的变化,从而确定蛋白熔解温度Tm,评估蛋白构象稳定性。样品发生聚集时,会导致散射光波发生干涉,散射光信号增加,通过静态光散射测定蛋白的胶体稳定性(以Tagg进行表征),结果参加如下表和附图11所示。
如上表和图11显示,抗LAG-3单克隆抗体HA-1蛋白分子的温度为66.6℃,平均Tagg为68.0℃,显示出较好的构象稳定性和胶体稳定性。
本发明不局限于上述最佳实施方式,任何人在本发明的启示下都可得出其他各种形式的产品,但不论在其形状或结构上作任何变化,凡是具有与本申请相同或相近似的技术方案,均落在本发明的保护范围之内。
序列表
<110> 北京东方百泰生物科技股份有限公司
北京精益泰翔技术发展有限公司
<120> 一种抗LAG-3的单克隆抗体、其抗原结合片段及其应用
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<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 32
Ala Thr Thr Thr Ala Pro Ser Val Tyr Pro Leu Val Pro Gly Cys Ser
1 5 10 15
Asp Thr Ser Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Lys Trp Asn Tyr Gly Ala Leu Ser Ser
35 40 45
Gly Val Arg Thr Val Ser Ser Val Leu Gln Ser Gly Phe Tyr Ser Leu
50 55 60
Ser Ser Leu Val Thr Val Pro Ser Ser Thr Trp Pro Ser Gln Thr Val
65 70 75 80
Ile Cys Asn Val Ala His Pro Ala Ser Lys Thr Glu Leu Ile Lys Arg
85 90 95
Ile Glu Pro Arg Ile Pro Lys Pro Ser Thr Pro Pro Gly Ser Ser Cys
100 105 110
Pro Pro Gly Asn Ile Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro
115 120 125
Lys Pro Lys Asp Ala Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys
130 135 140
Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val His Val Ser Trp
145 150 155 160
Phe Val Asp Asn Lys Glu Val His Thr Ala Trp Thr Gln Pro Arg Glu
165 170 175
Ala Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Ala Leu Pro Ile Gln
180 185 190
His Gln Asp Trp Met Arg Gly Lys Glu Phe Lys Cys Lys Val Asn Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly
210 215 220
Arg Ala Gln Thr Pro Gln Val Tyr Thr Ile Pro Pro Pro Arg Glu Gln
225 230 235 240
Met Ser Lys Lys Lys Val Ser Leu Thr Cys Leu Val Thr Asn Phe Phe
245 250 255
Ser Glu Ala Ile Ser Val Glu Trp Glu Arg Asn Gly Glu Leu Glu Gln
260 265 270
Asp Tyr Lys Asn Thr Pro Pro Ile Leu Asp Ser Asp Gly Thr Tyr Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Thr Asp Ser Trp Leu Gln Gly Glu
290 295 300
Ile Phe Thr Cys Ser Val Val His Glu Ala Leu His Asn His His Thr
305 310 315 320
Gln Lys Asn Leu Ser Arg Ser Pro Glu Leu Glu Leu Asn Glu Thr Cys
325 330 335
Ala Glu Ala Gln Asp Gly Glu Leu Asp Gly Leu Trp Thr Thr Ile Thr
340 345 350
Ile Phe Ile Ser Leu Phe Leu Leu Ser Val Cys Tyr Ser Ala Ser Val
355 360 365
Thr Leu Phe Lys Val Lys Trp Ile Phe Ser Ser Val Val Gln Val Lys
370 375 380
Gln Thr Ala Ile Pro Asp Tyr Arg Asn Met Ile Gly Gln Gly Ala
385 390 395
<210> 33
<211> 117
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 33
Gln 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 Tyr Thr Phe Thr Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala 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 Asp Thr Thr Val Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 34
<211> 106
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 34
Asp Ile Val Ile Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Asp Ala Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Tyr Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro His Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 35
<211> 106
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 35
Asp Ile Val Ile Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Tyr Thr Ser Lys Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Asp Tyr Thr Phe Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro His Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 36
<211> 117
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 36
Gln 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 Tyr Asn Ile Thr Asp Thr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Ala Thr Ile Thr Ala 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 Asp Thr Thr Val Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 37
<211> 117
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 37
Gln 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 Tyr Asn Ile Lys Asp Thr
20 25 30
Tyr Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Lys Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Lys Ala Thr Ile Thr Ala 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 Asp Thr Thr Val Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 38
<211> 106
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 38
Asp Ile Val Ile Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Asn Tyr Met
20 25 30
Tyr Trp Tyr Gln Gln Lys Pro Asp Ala Ser Pro Lys Leu Trp Ile Tyr
35 40 45
Tyr Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Thr Phe Thr Ile Ser Ser Leu Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asn Pro His Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 39
<211> 330
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 39
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115 120 125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130 135 140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145 150 155 160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165 170 175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180 185 190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195 200 205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210 215 220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu
225 230 235 240
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245 250 255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260 265 270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290 295 300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305 310 315 320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325 330
<210> 40
<211> 326
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 40
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100 105 110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115 120 125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130 135 140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145 150 155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165 170 175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180 185 190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195 200 205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210 215 220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225 230 235 240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245 250 255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260 265 270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275 280 285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290 295 300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305 310 315 320
Ser Leu Ser Pro Gly Lys
325
<210> 41
<211> 327
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 41
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 42
<211> 107
<212> PRT
<213> 2 Ambystoma laterale x Ambystoma jeffersonianum
<400> 42
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
Claims (19)
1.一种抗LAG-3的单克隆抗体,其特征在于,包括重链可变区和轻链可变区,所述重链可变区包括3个重链互补决定区,3个所述重链互补决定区分别用HCDR1、HCDR2和HCDR3表示,所述轻链可变区包括3个轻链互补决定区,3个所述轻链互补决定区分别用LCDR1、LCDR2和LCDR3表示,所述重链互补决定区HCDR1的氨基酸序列如SEQ ID No:1所示,所述重链互补决定区HCDR2的氨基酸序列如SEQ ID No:2所示,所述重链互补决定区HCDR3的氨基酸序列如SEQ ID No:3所示,所述轻链互补决定区LCDR1的氨基酸序列如SEQ ID No:4所示,所述轻链互补决定区LCDR2的氨基酸序列如SEQ ID No:5所示,所述轻链互补决定区LCDR3的氨基酸序列如SEQ ID No:6所示。
2.如权利要求1所述的抗LAG-3的单克隆抗体,其特征在于,所述单克隆抗体为鼠源抗体分子,所述重链可变区的氨基酸序列如SEQ ID No:21所示,所述轻链可变区的氨基酸序列如SEQ ID No:22所示。
3.如权利要求2所述的抗LAG-3的单克隆抗体,其特征在于,所述鼠源抗体分子还包括重链恒定区和轻链恒定区,所述重链恒定区为鼠的IgG1型、IgG2a型、IgG2b型、IgG3型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQ ID No:29所示,所述IgG2a型的重链恒定区氨基酸序列如SEQ ID No:30所示,所述IgG2b型的重链恒定区氨基酸序列如SEQ ID No:31所示,所述IgG3型的重链恒定区氨基酸序列如SEQ ID No:32所示;所述轻链恒定区为氨基酸序列如SEQ ID No:28所示的鼠源Ck链。
4.如权利要求3所述的抗LAG-3的单克隆抗体,其特征在于,所述重链恒定区为鼠的IgG1型。
5.如权利要求2所述的抗LAG-3的单克隆抗体,其特征在于,所述单克隆抗体为嵌合抗体分子,所述嵌合抗体分子包括所述鼠源抗体分子的重链可变区、所述鼠源抗体分子的轻链可变区和人源抗体恒定区;所述人源抗体恒定区包括人源抗体重链恒定区和人源抗体轻链恒定区,所述人源抗体重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQ ID No:39所示,所述IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,所述IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示;所述人源抗体轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链。
6.如权利要求5所述的抗LAG-3的单克隆抗体,其特征在于,所述人源抗体重链恒定区为人的IgG4型。
7.如权利要求1所述的抗LAG-3的单克隆抗体,其特征在于,所述单克隆抗体为人源化抗体分子,所述人源化抗体分子选自以下任意一种:HA-1:所述重链可变区的氨基酸序列如SEQ ID No:33所示,所述轻链可变区的氨基酸序列如SEQ ID No:34所示;
HA-2:所述重链可变区的氨基酸序列如SEQ ID No:33所示,所述轻链可变区的氨基酸序列如SEQ ID No:35所示;
HA-3:所述重链可变区的氨基酸序列如SEQ ID No:36所示,所述轻链可变区的氨基酸序列如SEQ ID No:35所示;
HA-4:所述重链可变区的氨基酸序列如SEQ ID No:36所示,所述轻链可变区的氨基酸序列如SEQ ID No:34所示;
HA-5:所述重链可变区的氨基酸序列如SEQ ID No:37所示,所述轻链可变区的氨基酸序列如SEQ ID No:38所示。
8.如权利要求7所述的抗LAG-3的单克隆抗体,其特征在于,所述人源化抗体分子为HA-1。
9.如权利要求7所述的抗LAG-3的单克隆抗体,其特征在于,所述人源化抗体分子还包括重链恒定区和轻链恒定区,所述重链恒定区为人的IgG1型、IgG2型或IgG4型中的一种,所述IgG1型的重链恒定区氨基酸序列如SEQ ID No:39所示,所述IgG2型的重链恒定区氨基酸序列如SEQ ID No:40所示,所述IgG4型的重链恒定区氨基酸序列如SEQ ID No:41所示,所述轻链恒定区为氨基酸序列如SEQ ID No:42所示的人的Ck链。
10.如权利要求9所述的抗LAG-3的单克隆抗体,其特征在于,所述重链恒定区为人的IgG4型。
11.如权利要求7所述的抗LAG-3的单克隆抗体,其特征在于,所述单克隆抗体为全长抗体。
12.一种权利要求7所述的抗LAG-3的单克隆抗体的抗体片段,其特征在于,所述抗体片段选自Fab、F(ab)2、Fv或ScFv。
13.一种多核苷酸序列或组合,其特征在于,所述多核苷酸序列或组合编码权利要求1-11任一项所述的抗LAG-3的单克隆抗体的氨基酸序列。
14.一种重组DNA表达载体,其特征在于,所述重组DNA表达载体包含权利要求13所述的多核苷酸序列或组合。
15.一种转染如权利要求14所述的重组DNA表达载体的宿主细胞,其特征在于,所述宿主细胞包括原核细胞、酵母细胞、昆虫细胞或哺乳动物细胞。
16.如权利要求15所述的宿主细胞,其特征在于,所述宿主细胞为哺乳动物细胞,所述哺乳动物细胞为HEK293E细胞、CHO细胞或NS0细胞。
17.一种药物或药物组合物,其特征在于,所述药物或所述药物组合物包含权利要求1-11任一项所述的抗LAG-3的单克隆抗体。
18.权利要求1-11任一项所述的抗LAG-3的单克隆抗体在制备治疗癌症或免疫疾病药物中的应用。
19.如权利要求18所述的应用,其特征在于,所述癌症包括白血病、肺癌、胃癌、食道癌、卵巢癌、头颈癌、黑色素瘤、肾癌、乳腺癌、结直肠癌、肝癌、胰腺癌或膀胱癌;
所述免疫疾病包括银屑病、克罗恩病、类风湿性关节炎、原发性胆汁性肝硬化、系统性红斑狼疮、多发性硬化症、溃疡性结肠炎和自身免疫性肝炎。
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CN202211155535.7A CN116514971B (zh) | 2020-12-10 | 2020-12-10 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
CN202011436581.5A CN114621345B (zh) | 2020-12-10 | 2020-12-10 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
CN202211155576.6A CN115819585B (zh) | 2020-12-10 | 2020-12-10 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
CN202211155539.5A CN116514972B (zh) | 2020-12-10 | 2020-12-10 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
IL303443A IL303443A (en) | 2020-12-10 | 2021-11-29 | A monoclonal antibody against LAG-3 and its antigen-binding fragment, and their use |
CN202180007833.9A CN114901697B (zh) | 2020-12-10 | 2021-11-29 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
AU2021398061A AU2021398061A1 (en) | 2020-12-10 | 2021-11-29 | Anti-lag-3 monoclonal antibody, and antigen-binding fragment and application thereof |
US18/039,720 US20240025994A1 (en) | 2020-12-10 | 2021-11-29 | Anti-lag-3 monoclonal antibody and antigen binding fragment thereof, and use thereof |
EP21902427.0A EP4242234A1 (en) | 2020-12-10 | 2021-11-29 | Anti-lag-3 monoclonal antibody, and antigen-binding fragment and application thereof |
KR1020237023286A KR20230118922A (ko) | 2020-12-10 | 2021-11-29 | 항lag-3의 단일 클론 항체, 이의 항원 결합 단편 및이의 응용 |
PCT/CN2021/133941 WO2022121720A1 (zh) | 2020-12-10 | 2021-11-29 | 一种抗lag-3的单克隆抗体、其抗原结合片段及其应用 |
CA3204858A CA3204858A1 (en) | 2020-12-10 | 2021-11-29 | Anti-lag-3 monoclonal antibody and antigen binding fragment thereof, and use thereof |
JP2023535502A JP2023552621A (ja) | 2020-12-10 | 2021-11-29 | 抗lag-3のモノクローナル抗体、その抗原結合性断片及びその使用 |
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CN116199779B (zh) * | 2022-12-08 | 2023-08-11 | 北京东方百泰生物科技股份有限公司 | 一种抗lilrb4单克隆抗体、其抗原结合片段及其应用 |
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DK3556775T3 (da) * | 2014-01-28 | 2022-01-03 | Bristol Myers Squibb Co | Anti-lag-3 antistoffer til behandling af hæmatologiske maligniteter |
JO3663B1 (ar) * | 2014-08-19 | 2020-08-27 | Merck Sharp & Dohme | الأجسام المضادة لمضاد lag3 وأجزاء ربط الأنتيجين |
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CN114617961B (zh) * | 2020-12-10 | 2022-12-02 | 北京东方百泰生物科技股份有限公司 | 一种抗lag-3单克隆抗体的注射制剂 |
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