CN112521509A - 一种抗ceacam5人源化抗体、其缀合物及其用途 - Google Patents
一种抗ceacam5人源化抗体、其缀合物及其用途 Download PDFInfo
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- CN112521509A CN112521509A CN202011532666.3A CN202011532666A CN112521509A CN 112521509 A CN112521509 A CN 112521509A CN 202011532666 A CN202011532666 A CN 202011532666A CN 112521509 A CN112521509 A CN 112521509A
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Abstract
本发明公开了一种抗CEACAM5人源化抗体、其缀合物及其用途，属于生物医药领域。本发明抗体包括重链和轻链，重链包含三个CDR区，重链的三个CDR区分别具有如SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的氨基酸序列；轻链包含三个CDR区，轻链的三个CDR区分别具有如SEQ ID NO.4、SEQ ID NO.5和SEQ ID NO.6所示的氨基酸序列。抗体与CEACAM5亲和力强；裸抗体通过连接子与治疗剂偶联后的三种ADC与CEACAM5的亲和力与裸抗体相似。本发明可用于靶向抑制CEACAM5表达阳性的肿瘤细胞的增殖，进而用于制备治疗或预防结直肠癌、胰腺癌的药物。
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CEACAM5人源化抗体、其缀合物及其用途。
背景技术
CEACAM5（Carcinoembryonic Antigen，简写为CEA，又叫CD66e）是一种分子量约180 kDa的酸性糖蛋白，是免疫球蛋白超家族的一名成员，含有经由糖基磷脂酰肌醇锚与细胞膜连接的7个结构域。CEACAM5主要存在于成人癌组织以及胎儿的胃肠管组织中，参与癌细胞侵袭和转移的细胞间粘附，是一种较广谱的肿瘤标志物。
单克隆抗体治疗因具有靶点特异性高、副作用低等特点，受到越来越多的关注，但是单独使用，其疗效比较有限。抗体药物缀合物属于一类新型抗癌生物导弹药物，是由三部分组成的：抗体，连接子，细胞毒素。通过化学偶联将单克隆抗体与细胞毒素偶联后，抗体药物缀合物利用单克隆抗体的靶向性，特异性地识别癌细胞表面的受体，并与受体结合，然后进入到细胞内部，利用细胞内的蛋白酶释放细胞毒物，阻止癌细胞增殖与杀灭癌细胞。抗体药物偶联技术使小分子药物与生物蛋白融为一体，兼具二者之长，极大增强了药效，并减少毒副作用，成为新一代治疗药物。
目前，已经有10个抗体药物缀合物获得FDA批准上市，分别为靶向CD33的吉妥珠单抗偶联物（gemtuzumab ozogamicin）、靶向CD30的本妥昔单抗偶联物（brentuximabvedotin）、靶向HER2的恩美曲妥珠单抗（trastuzumab emtansine）、靶向HER2的曲妥珠单抗偶联物（trastuzumab deruxtecan）、靶向CD22的moxetumomab pasudotox和奥英妥珠单抗（inotuzumab ozogamicin）、靶向CD79b的泊洛妥珠单抗偶联物（polatuzumab vedotin）、靶向Nectin-4的enfortumab vedotin、靶向TROP-2的sacituzumab govitecan和靶向BCMA的belantamab mafodotin。
IMMU-130是一款靶向CEACAM5的抗体缀合物，又名为labetuzumab govitecan，由Immunomedics公司研发，它是由一种抗CEACAM5的单克隆抗体，通过可裂解的连接子CL2与拓扑异构酶I的抑制剂SN-38 （7-ethyl-10-hydroxycamptothecin）偶联获得。目前，IMMU-130正在进行临床研究。在一项完成的结直肠癌I/II期临床试验中，IMMU-130显示了可控的安全性和一定的有效性。86名患者被分成四组：8 mg/kg组，每周用药一次； 10 mg/kg组，每周用药一次；4 mg/kg组，每周用药二次；6 mg/kg组，每周用药二次。药物治疗后，38%的患者肿瘤和血浆癌胚抗原降低；1名患者获得部分缓解，持续时间为2年；42名患者总体上病情稳定；中位无进展生存期和总生存期分别为3.6个月和6.9个月。药物的主要毒性（3级）分别为中性粒细胞减少症（16%）、白细胞减少症（11%）、贫血（9%）和腹泻（7%）。药物的平均半衰期为16.5小时，并且未检测到抗药物抗体。
本领域中仍然需要开发具有更加优越性质的抗CEACAM5抗体以及包含该抗体的抗体药物缀合物。
发明内容
为了弥补现有技术的不足，本发明提供了一种抗CEACAM5人源化抗体、其缀合物及其用途。本发明提供的抗体为一种新型的靶向CEACAM5的抗体，所述抗体通过连接子连接治疗剂得到的缀合物可用于抑制CEACAM5表达阳性的肿瘤细胞的增殖。
本发明的技术方案为：
本发明的第一方面，
一种抗CEACAM5人源化抗体，包括重链和轻链，所述重链包含三个CDR区，重链的三个CDR区分别具有如SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的氨基酸序列或者与其具有至少80％序列同一性的序列；
所述轻链包含三个CDR区，轻链的三个CDR区分别具有如SEQ ID NO.4、SEQ IDNO.5和SEQ ID NO.6所示的氨基酸序列或者与其具有至少80％序列同一性的序列。
在一些实施方案中，所述重链包含重链可变区，所述轻链包含轻链可变区；
所述重链可变区具有如SEQ ID NO.7所示的氨基酸序列或者与其具有至少80％序列同一性的序列；
所述轻链可变区具有如SEQ ID NO.8所示的氨基酸序列或者与其具有至少80％序列同一性的序列。
在一些实施方案中，所述重链具有如SEQ ID NO.9所示的氨基酸序列；所述轻链具有如SEQ ID NO.10所示氨基酸序列。
在一些实施方案中，所述抗CEACAM5抗体是分离的功能性片段。
在一些实施方案中，所述抗CEACAM5抗体是单克隆抗体。
在一些实施方案中，所述抗CEACAM5抗体是人源化抗体。
在一些实施方案中，所述抗CEACAM5抗体是IgG1抗体。
本发明的第二方面，
包含所述抗CEACAM5抗体的缀合物，所述缀合物的表达式为：mAb-(X-Y)n；
其中，
mAb为所述抗CEACAM5抗体；
X为连接子；
Y为治疗剂；
n为≤8的正整数；
所述治疗剂与抗CEACAM5抗体通过连接子偶联。
该缀合物为所述抗CEACAM5抗体偶联一个或更多个治疗剂。
在一些实施方案中，所述连接子选自马来酰亚氨基己酰基-缬氨酸-瓜氨酸-p-氨基苯甲氧羰基（mc-vc-pAB）或马来酰亚氨基己酰基（mc）。
在一些实施方案中，所述连接子与抗CEACAM5抗体通过巯基连接。
在一些实施方案中，所述治疗剂为细胞毒性药物（如，抗代谢药、抗肿瘤抗生素、生物碱）、免疫增强剂或放射性同位素。
优选地，所述治疗剂选自美登素类抗体药或海兔毒素肽及其衍生物。
更优选地，所述治疗剂选自单甲基耳抑素肽E（MMAE）或单甲基耳抑素肽F（MMAF）。
本发明的第三方面，
包含所述缀合物的药物组合物，由所述缀合物以及药用载体组成。
本发明的第四方面，
所述抗体、所述缀合物或所述药物组合物在制备治疗或预防CEACAM5阳性恶性肿瘤的药物中的用途。
作为优选，所述恶性肿瘤为结直肠癌或胰腺癌。
本发明的有益效果为：
本发明的抗CEACAM5抗体与CEACAM5亲和力强；而且本发明抗体通过连接子与治疗剂偶联后得到的三种ADC与CEACAM5 的亲和力与裸抗体相似。本发明的ADC可用于抑制CEACAM5表达阳性的肿瘤细胞的增殖。
通过实验验证，本发明的ADC对人结直肠癌LS174T细胞、人胰腺癌CaPan 1细胞的增殖抑制效果显著，可用于制备治疗或预防结直肠癌、胰腺癌的药物，具有非常好的应用前景。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为裸抗体mAb的疏水作用（HIC）分析图谱；
图2为mAb-MC-VC-PAB-MMAE的HIC分析图谱；
图3为mAb-MC-VC-PAB-MMAF的HIC分析图谱；
图4为mAb-MC-MMAF的HIC分析图谱；
图5为裸抗体mAb与CEACAM5的亲和力图谱；
图6为mAb-MC-VC-PAB-MMAE与CEACAM5的亲和力图谱；
图7为mAb-MC-VC-PAB-MMAF与CEACAM5的亲和力图谱；
图8为mAb-MC-MMAF与CEACAM5的亲和力图谱；
图9为裸抗体及三种ADC对人结直肠癌LS174T细胞的增殖抑制效果；
图10为裸抗体及三种ADC对人胰腺癌CaPan 1细胞的增殖抑制效果。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1 鼠源抗CEACAM5单克隆抗体的制备
使用CEACAM5蛋白（ACRO）作为抗原免疫小鼠，制备单克隆抗体。共免疫6只小鼠，包括3只Balb/c小鼠和3只C57小鼠。0.15 ml CEACAM5蛋白（75 μg蛋白溶解于PBS缓冲液中）和0.15 ml弗氏完全佐剂（Sigma）等体积混合均匀后，取小鼠，背部皮下注射，每只小鼠注射0.3 ml。间隔2周后进行第2次注射，每只小鼠注射抗原量同第1次，间隔4周后进行第3次注射，每只小鼠注射抗原量同第1次，第3次注射后7天取血。
用酶联免疫吸附试验（ELISA）检测小鼠的血清，将血清中抗CEACAM5抗体滴度最大的1只小鼠的脾脏取出（6只小鼠中，其中一只Balb/c小鼠的血清抗CEACAM5抗体滴度最大），然后与骨髓瘤细胞SP2/0 （ATCC）融合。
将融合细胞稀释到50块96孔板上，用ELISA方法进行初筛，588个孔中杂交瘤细胞株的上清液与CEACAM5结合呈阳性。将588个孔中杂交瘤细胞株的上清液用培养基置换后，继续培养，然后用ELISA方法复筛，其中196个孔中杂交瘤细胞株的上清液表现出与CEACAM5较好的结合力。用流式细胞仪（BD FACS Calibur）来进一步测试他们对CEACAM5的结合能力，筛选出20个与CEACAM5结合能力最强的母克隆，通过有限稀释方法进行亚克隆，用ELISA和流式细胞仪筛选，最后得到7个单克隆细胞与CEACAM5结合能力最强。通过悬浮培养7个亚克隆杂交瘤细胞株，纯化上清液中的蛋白，用Biacore T200（GE）测定蛋白与CEACAM5的亲和力，筛选到一株单克隆杂交瘤细胞株，所产生的单克隆鼠抗体与CEACAM5有较强的亲和力，对该单克隆鼠抗体进行DNA测序，单克隆抗体CDR的氨基酸序列如表1所示。
表1 抗CEACAM5单克隆抗体CDR的氨基酸序列
实施例2 抗CEACAM5单克隆抗体的人源化
通过移植鼠抗CEACAM5单克隆抗体的轻链和重链CDR到人的IgG1可变区来人源化。
设计了人源化抗CEACAM5单克隆抗体的重链可变区（VH），将人种系重链框架区2（FWR2）中的氨基酸残基Arg和Met转换为鼠源的等位置残基Ser和Ile，将人种系重链框架区3（FWR3）中的氨基酸残基Val、Ile和Arg转换为鼠源的等位置残基Ala、Met和Val，在重构CEACAM5结合抗体中保留CDR的构象。
同时设计了人源化抗CEACAM5单克隆抗体的轻链可变区（VL），将人种系轻链FWR3中的一个氨基酸残基Phe转换为鼠源的等位置残基Tyr，在重构CEACAM5结合抗体中保留CDR的构象。
最终获得的人源化抗CEACAM5抗体的VH和VL氨基酸序列如表2所示。最终获得的人源化抗CEACAM5抗体的重链和轻链氨基酸序列见表3所示。
表2 人源化抗CEACAM5抗体的VH和VL氨基酸序列
表3 人源化抗CEACAM5抗体的重链和轻链氨基酸序列
将含有人源化抗CEACAM5抗体的重链和轻链基因克隆到表达载体pcDNA3.4上，然后转染HEK-293细胞（ATCC），进行表达，收集细胞培养的上清液，经Protein A（GE）进行纯化，得到人源化抗CEACAM5抗体。
实施例3 抗体缀合物的制备
配制还原缓冲液：用PBS溶解TCEP（Tris-2-carboxyethyl-phosphine，三(2-羧乙基)膦）和DTPA （diethylenetriaminepentaacetic acid，二乙烯三胺五乙酸），两种物质在还原缓冲液中的浓度分别为0.26 mM和2 mM。
抗体还原：将20 mg/mL mAb（在PBS缓冲液中）与还原缓冲液按照1：1的体积比混合，25 ℃搅拌反应2 h。
配制小分子药物溶液：将小分子毒素MC-VC-PAB-MMAE、MC-VC-PAB-MMAF或MC-MMAF分别溶于DMSO（dimethyl sulfoxide，二甲亚砜）中，至终浓度10 mM。
偶联：在还原蛋白里加入25%的DMSO，然后按照小分子药物与抗体的摩尔比4.4，缓慢加入小分子药物溶液，进行偶联， 25 ℃搅拌反应1 h。最后，将偶联后的蛋白透析于PBS中，去除未偶联的小分子药物，获得三种ADC（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF），待用。
三种ADC（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF）的最终结构式如下：
实施例4 疏水作用色谱（HIC-HPLC）分析ADC的药物偶联率（DAR）
使用1260 bio 高效液相色谱仪（购自Agilent）和TSK-GEL Butyl-NPR色谱柱（4.6mm×35mm，购自TOSOH）分析抗CEACAM5抗体（mAb）及三种ADC（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF）。流动相A：75% (v/v) 20 mM磷酸盐缓冲液（pH=7.0），25% (v/v)异丙醇；流动相B：20 mM磷酸盐缓冲液（pH=7.0），1.5 M硫酸铵；实验过程中流动相梯度见表4。检测波长：280 nm；柱温：25 ℃；流速：1.0 ml/min；进样量：约10 μg。抗CEACAM5抗体（mAb）及三种ADC（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF）的HIC图谱如图1-图4所示。图1为裸抗体的mAb的疏水作用（HIC）分析图谱，图2、图3、图4为抗体偶联治疗剂后的缀合物（mAb-(X-Y)n）的疏水作用（HIC）分析图谱，分别对应mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF；图2、图3、图4中的2drugs、4drugs、6drugs、8drugs，表示mAb-(X-Y)n中的n分别为2、4、6、8。通过计算峰面积的积分比例，可以得出三种ADC的平均DAR值都在3.5-4.5之间（即每个抗体分子平均偶联3.5-4.5个小分子药物）。
表4 疏水作用色谱检测（HIC）方法
实施例5 人源化抗体及ADC与CEACAM5的结合亲和力分析
利用Biacore T200 （购自 GE）来检测抗CEACAM5抗体（mAb）及三种ADC（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF）与抗原的亲和力。
HBS-EP+（10×）缓冲液购自GE，Gly pH1.5购自GE，Protein A芯片购自GE，重组的人CEACAM5购自 ACRO。
选用Protein A芯片，2-1通道进行实验，HBS-EP+(1×) 作为缓冲液，捕获 0.5 μg/ml mAb或ADC，捕获15 s，流速30 μl/min。进样样品为不同浓度的CEACAM5，浓度分别为140 nM、70 nM、35 nM、17.5 nM、8.75 nM、4.38 nM，进样时间60 s，流速30 ul/min，解离时间600 s。再生液为Gly pH1.5，进样时间30 s，流速30 μl/min。使用Kinetics法进行数据分析及图谱拟合。
mAb及三种ADC的亲和力图谱如图5~8所示，亲和力检测结果见表5。
表5 裸抗体mAb及三种ADC的亲和力
由图5~8和表5可知：
裸抗体（mAb）与CEACAM5之间的亲和力非常好，可用于靶向结合CEACAM5表达阳性的肿瘤细胞。mAb-MC-VC-PAB-MMAE, mAb-MC-VC-PAB-MMAF, mAb-MC-MMAF 与CEACAM5之间的亲和力与裸抗体相似，裸抗体偶联毒素后，并没有降低裸抗体与CEACAM5之间的亲和力。mAb-MC-VC-PAB-MMAE, mAb-MC-VC-PAB-MMAF, mAb-MC-MMAF可用于靶向结合CEACAM5表达阳性的肿瘤细胞。
实施例6 药物缀合物对人结直肠癌细胞、人胰腺癌细胞的抑制作用
将生长状态良好的人结直肠癌LS174T细胞（购自CLS公司）、人胰腺癌CaPan 1细胞（购自ATCC）用胰酶（购自Sigma）消化后，分别重悬于含10%胎牛血清的EMEM培养基（购自ATCC）中和20%胎牛血清的IMDM培养基（购自ATCC）中，按照每孔5000个细胞（100μl）接种于96孔板。将抗CEACAM5的人源化抗体（mAb）及偶联后抗体（mAb-MC-VC-PAB-MMAE、mAb-MC-VC-PAB-MMAF、mAb-MC-MMAF）用含10%胎牛血清的培养基进行梯度稀释后加入96孔板，置于37℃、5% CO2培养箱中培养72小时后，用CCK-8试剂盒（购自DojingDo）及ABS plus 酶标仪（购自 MD）检测，所得数据使用Prism软件进行统计分析。
药物缀合物对肿瘤细胞的抑制曲线见图9~10，EC50值见表6。
表6 三种ADC对不同肿瘤细胞的增殖抑制作用EC50（ng/ml）
由图9~10和表6可知，裸抗体对各细胞基本无抑制作用，本发明偶联了MC-VC-PAB-MMAE或MC-VC-PAB-MMAF的ADC药物对两种肿瘤细胞的抑制作用明显。
SEQUENCE LISTING
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Claims (10)
1.一种抗CEACAM5人源化抗体，包括重链和轻链，其特征在于：所述重链包含三个CDR区，重链的三个CDR区分别具有如SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示的氨基酸序列或者与其具有至少80％序列同一性的序列；
所述轻链包含三个CDR区，轻链的三个CDR区分别具有如SEQ ID NO.4、SEQ ID NO.5和SEQ ID NO.6所示的氨基酸序列或者与其具有至少80％序列同一性的序列。
2.如权利要求1所述抗CEACAM5人源化抗体，其特征在于：所述重链包含重链可变区，所述轻链包含轻链可变区；
所述重链可变区具有如SEQ ID NO.7所示的氨基酸序列或者与其具有至少80％序列同一性的序列；
所述轻链可变区具有如SEQ ID NO.8所示的氨基酸序列或者与其具有至少80％序列同一性的序列。
3.如权利要求1或2所述抗CEACAM5人源化抗体，其特征在于：所述重链具有如SEQ IDNO.9所示的氨基酸序列；所述轻链具有如SEQ ID NO.10所示氨基酸序列。
4.包含如权利要求1所述抗CEACAM5抗体的缀合物，其特征在于，所述缀合物的表达式为：mAb-(X-Y)n；
其中，
mAb为所述抗CEACAM5抗体；
X为连接子；
Y为治疗剂；
n为≤8的正整数；
所述治疗剂与抗CEACAM5抗体通过连接子偶联。
5.如权利要求4所述缀合物，其特征在于：所述连接子选自马来酰亚氨基己酰基-缬氨酸-瓜氨酸-p-氨基苯甲氧羰基或马来酰亚氨基己酰基。
6.如权利要求5所述缀合物，其特征在于：所述连接子与抗CEACAM5抗体通过巯基连接。
7.如权利要求4所述缀合物，其特征在于：所述治疗剂为细胞毒性药物、免疫增强剂或放射性同位素。
8.包含如权利要求4所述缀合物的药物组合物，其特征在于：由所述缀合物以及药用载体组成。
9.权利要求1所述抗体、权利要求4所述缀合物或权利要求8所述药物组合物在制备治疗或预防CEACAM5阳性恶性肿瘤的药物中的用途。
10.权利要求9所述用途，其特征在于：所述恶性肿瘤为结直肠癌或胰腺癌。
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