CN112175082B - 抗叶酸受体α抗体、其缀合物及其用途 - Google Patents
抗叶酸受体α抗体、其缀合物及其用途 Download PDFInfo
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- CN112175082B CN112175082B CN202011044721.4A CN202011044721A CN112175082B CN 112175082 B CN112175082 B CN 112175082B CN 202011044721 A CN202011044721 A CN 202011044721A CN 112175082 B CN112175082 B CN 112175082B
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Abstract
本发明公开了一种抗叶酸受体α抗体、其缀合物及其用途，属于生物医药技术领域。所述抗体，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。所述抗体与FRα亲和力强；裸抗体通过连接子与治疗剂偶联后的三种ADC与FRα的亲和力与裸抗体相似。本发明的裸抗体以及三种ADC可用于靶向抑制FRα表达阳性的肿瘤细胞的增殖，进而用于制备治疗或预防绒毛膜癌、卵巢癌、肺癌的药物。
Description
技术领域
本发明涉及生物医药技术领域，特别涉及一种抗叶酸受体α抗体、其缀合物及其用途。
背景技术
叶酸受体α(Folate receptorα,FRα)是一个糖基磷脂酰基醇偶联的糖蛋白，对叶酸及其衍生物具有高度亲和力，并通过内吞作用转运叶酸进入细胞。FRα由FOLR1基因编码,由7个外显子和6个内含子组成，长度为6 800kb。FRα在正常组织中不表达或者表达量很低，但在特定上皮来源的卵巢癌、输卵管癌、子宫内膜癌、绒毛膜癌、原发性腹膜癌、肺癌、乳腺癌等恶性肿瘤中呈高表达。
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8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enfortumabvedotin和靶向TROP-2的sacituzumab govitecan。
IMGN853是一款靶向FRα的抗体缀合物，又名为Mirvetuximab soravtansine，由ImmunoGen公司研发，它是由一种抗FRα的单克隆抗体，通过可裂解的连接子sSPDB(N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate)与细胞毒素DM4(N2’-deacetyl-N2’-(4-mercapto-4-methyl-1-oxopentyl)-maytansi ne)偶联获得。目前，IMGN853正在进行卵巢癌、原发性腹膜癌和输卵管癌的三期临床试验。在一项完成的一期临床试验中，IMGN853显示了可控的安全性和良好的有效性。该试验一共入组了46名卵巢癌、原发性腹膜癌或输卵管癌患者，不良反应一般较轻(2级)，腹泻、视力模糊、恶心和疲劳是最常见的治疗相关毒性。对于所有可评价的患者，确定的客观缓解率为26％，包括一次完全缓解和11次部分缓解，平均PFS为4.8个月，中位缓解时间为19.1周。值得注意的是，在先前接受过三种或三种以下治疗方案的患者中(n＝23)，观察到39％的客观缓解率、6.7个月的PFS和19.6周的缓解时间。
本领域中仍然需要开发具有更加优越性质的抗FRα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叶酸受体α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FRα的抗体，并且使用该抗体通过mc-vc-pAB(马来酰亚氨基己酰基-缬氨酸-瓜氨酸-p-氨基苯甲氧羰基)或mc(马来酰亚氨基己酰基)偶联MMAE(Monomethyl auristatin E，单甲基耳抑素肽E)、MMAF(Monomethyl auristatin F，单甲基耳抑素肽F)等。
本发明的技术方案为：
第一方面，一种抗叶酸受体α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 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。
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，所述抗叶酸受体α抗体是分离的功能性片段。
在一些实施方案中，所述抗叶酸受体α抗体是单克隆抗体。
在一些实施方案中，所述抗叶酸受体α抗体是人源化抗体。
在一些实施方案中，所述抗叶酸受体α抗体是IgG1抗体
第二方面，包含所述抗叶酸受体α抗体的缀合物，所述缀合物的表达式为：mAb-(X-Y)n；
其中，
mAb为所述抗叶酸受体α抗体；
X为连接子；
Y为治疗剂；
n为≤8的正整数；
所述治疗剂与抗叶酸受体α抗体通过连接子偶联。
该缀合物为所述抗叶酸受体α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，所述连接子与抗叶酸受体α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)。
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。
第四方面，所述抗体、所述缀合物、所述药物组合物在制备治疗或预防叶酸受体α阳性恶性肿瘤的药物中的用途。
在一些实施方案中，所述用途，所述恶性肿瘤为绒毛膜癌、卵巢癌、输卵管癌、子宫内膜癌、原发性腹膜癌或肺癌。
本发明的有益效果为：
本发明的抗叶酸受体α抗体与叶酸受体α(FRα)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FRα的亲和力与裸抗体相似。本发明的三种ADC可用于抑制FRα表达阳性的肿瘤细胞的增殖。
通过实验验证本发明的三种ADC对绒毛膜癌JEG-3细胞、卵巢癌SK-OV-3细胞、卵巢癌OVCAR-3细胞、肺癌HCC827细胞的增殖抑制效果显著，可用于制备治疗或预防绒毛膜癌、卵巢癌、肺癌的药物，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FLOR1的亲和力图谱；
图6为mAb-MC-VC-PAB-MMAE与FLOR1的亲和力图谱；
图7为mAb-MC-VC-PAB-MMAF与FLOR1的亲和力图谱；
图8为mAb-MC-MMAF与FLOR1的亲和力图谱；
图9为裸抗体及三种ADC对绒毛膜癌细胞JEG-3的增殖抑制效果；
图10为裸抗体及三种ADC对卵巢癌细胞SK-OV-3的增殖抑制效果；
图11为裸抗体及三种ADC对卵巢癌细胞OVCAR-3的增殖抑制效果；
图12为裸抗体及三种ADC对肺癌细胞HC8827的增殖抑制效果。
具体实施方式
本发明提供了以下实施例以证明并进一步解释本发明的一些优选的实施方式和方面，不应被解释为限制其范围。
实施例1鼠源抗FRα单克隆抗体的制备
使用FRα的胞外区蛋白FOLR1(abcam)作为抗原免疫小鼠，制备单克隆抗体。0.15mlFOLR1蛋白(75μg蛋白溶解于PBS缓冲液中)和0.15ml弗氏完全佐剂(Sigma)等体积混合均匀后，取Balb/c小鼠，背部皮下注射。
共免疫5只小鼠，每只小鼠注射0.3ml。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FOLR1抗体滴度最大的1只小鼠的脾脏取出，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，455个孔中杂交瘤细胞株的上清液与FOLR1结合呈阳性。将455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161个孔中杂交瘤细胞株的上清液表现出与FOLR1较好的结合力。用流式细胞仪(BD FACS Calibur)来进一步测试他们对FOLR1的结合能力，筛选出25个与FOLR1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20个单克隆细胞与FOLR1结合能力最强。通过悬浮培养20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FOLR1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FOLR1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FRα单克隆抗体CDR的氨基酸序列
| 重链(VH) | 轻链(VL) | |
| CDR1 | GFSLSTSGMGVS(SEQ ID NO.1) | KASQDVGTALA(SEQ ID NO.4) |
| CDR2 | HIDWDEGKRYKSSLKS(SEQ ID NO.2) | WASTRHT(SEQ ID NO.5) |
| CDR3 | NAGYYPAWFTY(SEQ ID NO.3) | QQYSSSPYT(SEQ ID NO.6) |
实施例2抗FRα单克隆抗体的人源化
通过移植鼠抗FRα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FRα单克隆抗体的重链可变区(VH)，将人种系重链框架区3(FWR3)中的一个氨基酸残基His转换为鼠源的等位置残基Arg，在重构FOLR1结合抗体中保留CDR的构象。
同时设计了人源化抗FRα单克隆抗体的轻链可变区(VL)，将人种系轻链FWR2中的氨基酸残基Val和Tyr转换为鼠源的等位置残基Ser和Ser，将人种系轻链FWR3中的氨基酸残基Ala和Tyr转换为鼠源的等位置残基Thr和Phe，在重构FOLR1结合抗体中保留CDR的构象。
最终获得的人源化抗FRα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FRα抗体的重链和轻链氨基酸序列见表3所示。
表2人源化抗FRα抗体的VH和VL氨基酸序列
表3人源化抗FRα抗体的重链和轻链氨基酸序列
将含有人源化抗FRα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FRα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0.26mM和2mM。
抗体还原：将20mg/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2h。
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10mM。
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1h。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)的结构式如下：
实施例4疏水作用色谱(HIC-HPLC)分析ADC的偶联率(DAR)
使用1260bio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FRα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)20mM磷酸盐缓冲液(pH＝7.0)，25％(v/v)异丙醇；流动相B：20mM磷酸盐缓冲液(pH＝7.0)，1.5M硫酸铵；实验过程中流动相梯度见表4。检测波长：280nm；柱温：25℃；流速：1.0ml/min；进样量：约10μg。通过峰面积的积分比例，计算偶联不同数目小分子的抗体药物分布比例以及平均DAR值，结果见表5。抗FRα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。
表4疏水作用色谱检测(HIC)方法
表5三种ADC的平均偶联率及药物分布比例
由表5可知，三种ADC的平均DAR值在3.5-4.5之间。
实施例5人源化抗体及ADC与FRα的结合亲和力分析
利用Biacore T200(购自GE)来检测抗FRα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FOLR1(FRα的胞外区片段)购自abcam。
选用Protein A芯片，2-1通道进行实验，HBS-EP+(1×)作为缓冲液，捕获0.5μg/mlmAb或ADC，捕获30s，流速30μl/min。进样样品为不同浓度的FOLR1，浓度分别为200nM、100nM、50nM、25nM、12.5nM、6.25nM，进样时间40s，流速30ul/min，解离时间600s。再生液为Gly pH1.5，进样时间30s，流速30μl/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6。
表6裸抗体mAb及三种ADC的亲和力
由图5～8和表6可知：
裸抗体(mAb)与FOLR1之间的亲和力非常好，可用于靶向结合FRα表达阳性的肿瘤细胞。mAb-MC-VC-PAB-MMAE,mAb-MC-VC-PAB-MMAF,mAb-MC-MMAF与FOLR1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FOLR1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FRα表达阳性的肿瘤细胞。
实施例6药物缀合物对绒毛膜癌细胞、卵巢癌细胞、肺癌细胞的抑制作用
将生长状态良好的绒毛膜癌JEG-3细胞、卵巢癌SK-OV-3细胞、卵巢癌OVCAR-3细胞、肺癌HCC827细胞(细胞均购自ATCC)用胰酶(购自Sigma)消化后，重悬于含10％胎牛血清的EMEM培养基(购自ATCC)中或1640培养基(购自Gibco)中，按照每孔5000个细胞(100μl)接种于96孔板。将抗FRα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9～12，EC50值见表7。
表7三种ADC对不同肿瘤细胞的增殖抑制作用EC50(ng/ml)
由图9～12和表7可知，裸抗体对各细胞基本无抑制作用，本发明的ADC药物对各细胞的抑制作用明显。根据本发明偶联了MC-VC-PAB-MMAE或MC-VC-PAB-MMAF的ADC药物对几种肿瘤细胞的抑制作用强于根据本发明偶联了MC-MMAF的ADC药物。
序列表
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Claims (9)
1.一种抗叶酸受体α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CDR1-3的氨基酸序列分别如SEQ ID NO:1、SEQ ID NO:2和SEQ ID NO:3所示；
所述轻链包含三个CDR区，轻链CDR1-3的氨基酸序列分别如SEQ ID NO:4、SEQ ID NO:5和SEQ ID NO:6所示。
2.如权利要求1所述抗叶酸受体α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；
所述重链可变区的氨基酸序列如SEQ ID NO:7所示；
所述轻链可变区的氨基酸序列如SEQ ID NO:8所示。
3.如权利要求1或2所述抗叶酸受体α抗体，其特征在于：所述重链的氨基酸序列如SEQID NO:9所示；所述轻链的氨基酸序列如SEQ ID NO:10所示。
4.包含如权利要求1所述抗叶酸受体α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为所述抗叶酸受体α抗体；
X为连接子；
Y为治疗剂；
n为≤8的正整数；
所述治疗剂与抗叶酸受体α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：所述连接子与抗叶酸受体α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4所述缀合物、权利要求8所述药物组合物在制备治疗叶酸受体α阳性恶性肿瘤的靶向药物中的用途。
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