CN105085681B - 靶向人前列腺特异性膜抗原的j591微抗体和双抗体 - Google Patents
靶向人前列腺特异性膜抗原的j591微抗体和双抗体 Download PDFInfo
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Abstract
在一个实施方式中,提供了结合PSMA的微抗体单体。微抗体单体由核苷酸序列编码,该核苷酸序列自N端至C端包含可结合PSMA的scFv序列、人工铰链序列和人IgG CH3序列。在另一实施方式中,提供了结合PSMA的CysDB单体。CysDB单体可由核苷酸序列编码,该核苷酸序列自N端至C端包含可结合PSMA的scFv序列和半胱氨酸尾部。在其他实施方式中,提供了诊断或治疗个体中与PSMA表达有关的癌症的方法。
Description
本申请是申请日为2010年12月2日、申请号为201080062988.4、题为“靶向人前列腺特异性膜抗原的J591微抗体和双抗体”的专利申请的分案申请。
关于联邦政府资助的研究的声明
本发明是以政府资助在由国家癌症研究所(NCI)给予的合约编号HHSN261200900051C下进行的。政府拥有本发明的一定权利。
优先权要求
本申请要求享有2009年12月2日提交的美国临时申请号61/266,134的权益,在此将其主题引入作为参考,如其在本文中被完整描述。
背景
抗体工程的进展已能开发具有不同药物动力学和结合性质的特征的多种抗体片段(Wu et al 2005、Wu et al 2008、Wu et al 2009)。微抗体是特征在于分子量(~80kD)比全长抗体小同时保持对抗原的二价结合特性的抗体形式(Hu et al1996)。由于其较小的尺寸,微抗体的特征在于从系统的更快清除和靶向肿瘤组织时的增强渗透。在强靶向结合迅速清除的能力下,微抗体是可用于诊断成像的优化抗体形式(Wu et al 2005)。自从发现了抗肿瘤相关靶标(tumor associated target)CEA的第一个微抗体,已开发了许多用于临床前诊断成像的抗不同癌靶标的微抗体,包括乳腺癌中的人表皮生长因子受体-2(HER2)、非何杰金氏淋巴瘤中的B-淋巴细胞抗原CD20和前列腺癌中的前列腺干细胞抗原(PSCA)(Huet al 1996、Leyton et al 2008、Olafsen et al 2004、Olafsen et al 2009)。例如,已在临床中评价123I标记的CEA微抗体以用于通过SPECT使结直肠癌患者成像,并且已用111In-DOTA标记的微抗体进行了类似的研究(Wong et al 2004)。新成像剂的开发对于用现有技术成像不佳的特定癌症如前列腺癌的诊断、控制和治疗是尤为至关重要的。
需要开发全部癌症类型的成像剂从而能够靶向、分期和监测疾病。现有的前列腺癌诊断成像的方法仍相对不准确。对于2006年评估的234,460例新病例和27,350例死亡,需要能够准确诊断、分期和监测前列腺癌症的成像剂(Olson et al2007)。
前列腺特异性膜抗原(PSMA)——与前列腺癌有关的细胞表面生物标记(Slovin2005),是具有谷氨酸羧肽酶活性的单通道II型跨膜蛋白,虽然对PSMA的功能性作用并不十分了解(Olson et al 2007)。PSMA的表达在前列腺之外的正常组织,包括脑、小肠、肝、近端肾小管和唾液腺中相对有限(Olson et al 2007)。
前列腺癌中的PSMA表达随肿瘤的侵占性而增加,并在高级肿瘤、转移性损伤和不依赖于雄激素的疾病中最高(Olson et al 2007)。因此,PSMA是癌症生物标记——成像剂靶向的良好侯选物。PSMA表达也在多种非前列腺实体肿瘤的新血管系统中上调,该非前列腺实体肿瘤包括肺癌、结肠癌、乳腺癌、肾癌、肝癌和胰腺癌以及肉瘤和黑素瘤(Olson etal 2007)。
已开发了靶向PSMA的全长抗体,其中一些处于临床前和临床发展的不同阶段(Olson et al 2007)。PSMA最初由鼠抗体(mAb)7E11限定,该鼠抗体(mAb)7E11识别PSMA的胞内表位(Olson et al 2007)。后来7E11mAb发展为FDA批准的SPECT成像剂,称为Prostascint,用于在软组织中检测和成像前列腺癌(Olson et al 2007)。但是,由于7E11识别胞内表位,Prostascint是相对弱的成像剂,其被限于检测坏死的肿瘤组织(Olson etal 2007)。Prostascint具有全长抗体的药物动力学性质,在注射与成像之间也需要长的时间(Olson et al 2007)。此外,Prostascint是引起强免疫应答的鼠抗体,阻挠多次给药(Olson et al 2007)。
另一种靶向PSMA的全长抗体——J591,被发现,并随后去免疫(deimmunize),去免疫的形式称为huJ591(Liu et al 1997,Bander et al 2003)。去免疫的huJ591是抗人PSMA抗体,其识别和结合PSMA的胞外表位(Bander et al 2003)。huJ591抗体正被开发为针对前列腺癌的潜在放射免疫治疗剂。在I期试验中,用发射γ的同位素铟111和镥177标记的DOTA结合的huJ591抗体证实了优良地靶向转移部位、无免疫原性,并且良好地耐受多次给药(Bander et al 2003、Milowsky et al 2004、Bander et al 2005、Olson et al 2007)。除前列腺癌外,111In-DOTA huJ591的I期研究证实了特异性靶向晚期实体肿瘤的肿瘤新血管系统(Milowsky et al 2007)。
概述
在一个实施方式中,提供了结合PSMA的微抗体(minibody)。根据该实施方式,微抗体由核苷酸序列编码,该核苷酸序列自N端至C端包含能够结合前列腺特异性膜抗原(PSMA)的scFv序列、人工铰合(铰链)序列和人IgG1 CH3序列。微抗体单体还可包含N端信号序列,从而在细胞中表达时能分泌微抗体。
本文所述微抗体scFv包含通过连接序列连接至轻链可变区(VL)的重链可变区(VH)。一方面,scFv为VHVL方向,以使VH在VL的上游。具有这种scFv的微抗体单体可具有包含SEQIDNO:1或SEQIDNO:2的核苷酸序列。另一方面,scFv为VLVH方向,以使VL在VH的上游。
微抗体单体可由细胞表达。在这种实施方式中,由细胞表达的CysDB单体可包含氨基酸序列SEQIDNO:10或SEQIDNO:11。
在另一实施方式中,提供了结合PSMA的cys-双抗体(diabody)(CysDB)。根据该实施方式,CysDB单体由核苷酸序列编码,该核苷酸序列自N端至C端包含能够结合PSMA的scFv序列和半胱氨酸尾。CysDB还可包括N端信号序列,从而在细胞中表达时能分泌微抗体。
本文所述的CysDB scFv包含通过连接序列连接至轻链可变区(VL)的重链可变区(VH)。一方面,scFv为VHVL方向,以使VH在VL的上游。具有这种scFv的CysDB单体可具有包含SEQIDNO:6或SEQIDNO:7的核苷酸序列。另一方面,scFv为VLVH方向,以使VL在VH的上游。具有这种scFv的CysDB单体可具有包含SEQIDNO:8或SEQIDNO:9的核苷酸序列。
CysDB可由细胞表达。在一些实施方式中,由细胞表达的CysDB可包含氨基酸序列SEQIDNO:12、SEQIDNO:13、SEQIDNO:14或SEQIDNO:15。
在另一实施方式中,提供了诊断个体中与PSMA表达有关的癌症的方法。该方法包括向患有或疑患与PSMA表达有关的癌症的个体给予结合于(缀合于)诊断剂的抗PSMA微抗体或cys-双抗体;使个体暴露于成像方法以在体内显现被标记的微抗体或cys-双抗体;和当标记的微抗体或cys-双抗体定位于肿瘤部位时,确定个体患有与PSMA表达有关的癌症。
在另一实施方式中,提供了治疗个体中与PSMA表达有关的癌症的方法。该方法包括向个体给予治疗有效量的药物组合物,该组合物包含抗PSMA微抗体或抗PSMA cys-双抗体。一方面,抗PSMA微抗体或抗PSMA cys-双抗体结合至治疗剂。
个体中与PSMA表达有关的癌症可以是肺癌、结直肠癌、乳腺癌、肾癌、肝癌、膀胱癌、胰腺癌或黑素瘤。
可用于上述方法的微抗体可以是本文所述任何适当的微抗体,或可包含SEQIDNO:10或SEQIDNO:11。可用于上述方法的cys-双抗体可以是本文所述任何适当的微抗体,或可包含SEQIDNO:12、SEQIDNO:13、SEQIDNO:14或SEQIDNO:15。
附图简述
图1A是J591微抗体的示意图。该图显示了以VHVL方向结合目标PSMA的微抗体。
图1B是VHVL方向J591微抗体的表达构建物的示意图。SP=信号肽,VH–重链可变区,VL–轻链可变区,L–18氨基酸连接体,H./E–人工铰链/延伸,CH3来自人IgG1。
图2是去免疫(第3行;SEQ ID NO:5;SEQ ID NO:19)、鼠(第2行;SEQ ID NO:4;SEQID NO:18)和人复合(第1行;SEQ ID NO:3;SEQ ID NO:17)J591V区氨基酸序列之间的比较。沿HC行(第1行)突出的残基表示HC与鼠V区之间的差异。沿去免疫行(第3行)突出的残基表示最初去免疫过程导致的去免疫V区与鼠V区之间的差异。两个星表示通过去免疫被引入的两个脯氨酸。
图3是J591人复合VHVL微抗体核苷酸序列(SEQ ID NO:1)和经翻译的相应氨基酸序列(SEQ ID NO:10)。
图4是J591 2P VHVL微抗体核苷酸序列(SEQ ID NO:2)和经翻译的相应氨基酸序列(SEQ ID NO:11)。
图5是cys-双抗体(CysDB)的示意图(A)、VLVH方向CysDB的表达构建物的示意图(B)和VHVL方向CysDB的表达构建物的示意图(C)。SS=信号序列,VH=重链可变区,VL=轻链可变区,L连接体(可以是5或8个氨基酸),GGS=半胱氨酸尾部(Gly-Gly-Cys)。
图6是J591 cys-双抗体(CysDB)VH-5-VL核苷酸序列(SEQ ID NO:6)和经翻译的相应氨基酸序列(SEQ ID NO:12)。
图7是J591 cys-双抗体(CysDB)VH-8-VL核苷酸序列(SEQ ID NO:7)和经翻译的相应氨基酸序列(SEQ ID NO:13)。
图8是J591 cys-双抗体(CysDB)VL-5-VH核苷酸序列(SEQ ID NO:8)和经翻译的相应氨基酸序列(SEQ ID NO:14)。
图9是J591 cys-双抗体(CysDB)VL-8-VH核苷酸序列(SEQ ID NO:9)和经翻译的相应氨基酸序列(SEQ ID NO:15)。
图10是A、B、C形式的pcDNA 3.1/myc-His(-)的载体图谱。来自Invitrogen Corp.的这种表达载体的特征在于用于哺乳动物表达的CMV启动子和用于选择的新霉素抗性。
图11是确定CHO-K1细胞表达J591微抗体的代表性免疫印迹分析。第1泳道相应于分子量标记样本,第2泳道相应于空白载体样本,第3泳道相应于阳性对照微抗体样本,第4泳道相应于J591 HC VLVH样本,第5泳道相应于J591 HC VHVL样本,第6泳道相应于J591 2PVLVH样本,第7泳道相应于J591 2P VHVL样本。
图12A-D是表示J591微抗体的流式细胞计量分析的图。柱状图将细胞计数相对于PE信号(FL2-H)作图。图12A显示了表示J591 HC VLVH微抗体的流式细胞计量分析的图,图12B显示了表示J591 HC VHVL微抗体的流式细胞计量分析的图,图12C显示了表示J591 2PVLVH微抗体的流式细胞计量分析的图,图12D显示了表示J591 2P VHVL微抗体的流式细胞计量分析的图。
图13是纯化的J591微抗体的SDS-PAGE分析。纯化的J591微抗体蛋白在非还原条件(第1列)和还原条件(第2列)下被装载于SDS-PAGE凝胶上。凝胶用GelCode Blue(Pierce,Thermo Scientific)染色。微抗体以1/5稀释,以装载于凝胶上。
图14是纯化的J591微抗体的尺寸排阻层析(SEC)分析。该图将220nm UV吸光度(mAU)相对于时间(min)作图。4μg J591微抗体被装载于TSK-GEL Super SW3000柱上。使蛋白质分子量标准品也在柱上单独运行以提供参照。聚集体相对于微抗体蛋白(在此被标记为单体)的百分比通过计算曲线下的面积确定。
图15通过ELISA示例了J591微抗体蛋白结合PSMA。以1μg/ml的纯化重组PSMA蛋白包被96孔ELISA板。将纯化的J591微抗体蛋白(1,●)以2μg/ml的初始浓度引入,并由第三稀释液连续稀释10倍。对阴性对照微抗体(2,■)进行同样的稀释。样本各稀释重复三次进行,误差条表示标准偏差。最初温育后,用结合碱性磷酸酶的山羊抗人IgG(Fc特异的)抗体检测结合的微抗体,并将其用pNPP溶液显像。在405nm下检测吸光度。
图16A-D是表示流式细胞计量分析的图,示例了J591微抗体结合PSMA+细胞系。所有柱状图将细胞计数相对于PE信号(FL2-H)作图。对J591微抗体蛋白和阴性对照微抗体(1)均以20μg/ml测试其结合PSMA+细胞系LNCaP(A和B)和CWR22rv1(C和D)。细胞随后用二级抗人IgG(Fc特异的)-PE结合的抗体染色。1×105个细胞/点和以5,000事件/点进行分析。(A)J591微抗体(2)结合LNCaP细胞(B)J591-DOTA微抗体(2)结合LNCaP细胞(C)J591微抗体(2)结合CWR细胞(D)J591-DOTA微抗体(2)结合CWR细胞。
图17是显示J591微抗体在LNCaP细胞中内化的代表性图像。将LNCaP细胞在12孔板中聚-d-赖氨酸包被的盖玻片上铺平。生长2天后,将细胞在4℃下预冷30分钟,然后用一级抗体或微抗体在4℃下温育30分钟。在最初温育后的所示时间点,将细胞固定,透化,并用二级抗人IgG-Alexa 488染色。同时将盖玻片置于载玻片上,并在封固介质中用DAPI复染。用63×油浸没透镜在Leica SP2-1P-FCS共焦显微镜上观察载玻片。
图18是显示J591微抗体在CWR22rv1细胞中内化的代表性图像。将CWR22rv1细胞在12孔板中聚-d-赖氨酸包被的盖玻片上铺平。生长2天后,将细胞在4℃下预冷30分钟,然后用一级抗体或微抗体在4℃下温育30分钟。在最初温育后的所示时间点,将细胞固定,透化,并用二级抗人IgG-Alexa 488染色。同时将盖玻片置于载玻片上,并在封固介质中用DAPI复染。用63×油浸没透镜在Leica SP2-1P-FCS共焦显微镜上观察载玻片。
图19是示例131I标记的J591微抗体和111In-DOTA标记的J591微抗体的细胞相关放射活性的获取和保留的图。细胞相关放射活性在结合CWR22rv1细胞时随时间的获取和保留。细胞膜、细胞溶胞产物(内化)和所有(膜+内化)部分的放射活性表示为每分钟的计数(cpm)。在实验前一天将CWR22rv1细胞接种于24孔板中,5×105个细胞/孔。将细胞在4℃下预冷,然后用过量(A)131I标记的J591微抗体或(B)111In-DOTA标记的J591微抗体温育。在每个时间点,去除含有放射标记微抗体的上清液,用酸性甘氨酸缓冲液清除细胞以得到膜部分,并溶解细胞。各时间点进行三次。Y-条表示标准偏差。
图20是比较131I标记的J591微抗体与111In-DOTA标记的J591微抗体的细胞相关放射活性的图。总细胞相关放射活性(膜+内化)表示为初始细胞相关放射活性在结合CWR22rv1细胞时随时间的百分比。该图显示了131I标记的J591微抗体(下线)和111In-DOTA标记的J591微抗体(上线)。
图21示例了具有CWR22rv1和PC3异种移植体、注射64Cu-DOTA-J591微抗体的小鼠的代表性连续微PET/CT图像。在注射后连续多次扫描代表性小鼠。CWR22rv1肿瘤表示为(+)肿瘤,PC3肿瘤表示为(-)肿瘤。(A)注射后4小时的CT扫描。显示了冠状平面和横断面。(B)注射后4小时的PET/CT覆盖图像。显示了冠状平面和横断面。(C)注射后4小时的代表性小鼠冠状PET/CT覆盖3D投影(D)注射后43小时代表性小鼠冠状PET/CT覆盖3D投影。
图22是示例64Cu-DOTA-J591微抗体在注射后19小时和43小时的生物分布的条形图。图中绘制了64Cu-DOTA-J591微抗体在异种移植肿瘤和所选目标正常组织中的生物分布。生物分布被图示为注射剂量除以重量(克数)的%(%ID/g)。各数据点表示一组小鼠在注射后19hrs(n=8)和43hrs(n=4)的平均%ID/g。误差条表示标准偏差。
图23示例了具有CWR22rv1和PC3异种移植体、注射124I-J591微抗体的小鼠的代表性连续微PET图像。在注射后连续多次扫描代表性小鼠。CWR22rv1肿瘤表示为(+)肿瘤,PC3肿瘤表示为(-)肿瘤。(A)注射后4小时的CT扫描。显示了冠状平面和横断面。(B)注射后4小时的PET/CT覆盖图像。显示了冠状平面和横断面。(C)注射后4、20和44小时的冠状PET/CT覆盖图像。
图24是示例124I-J591微抗体在注射后19小时和44小时的生物分布的条形图。图中绘制了124I-J591微抗体在异种移植肿瘤和所选目标正常组织中的生物分布。生物分布表示为注射剂量除以重量(克数)的%(%ID/g)。各数据点表示一组小鼠(在第19小时n=4,在第44小时n=2)在注射后19hrs和44hrs的平均%ID/g。误差条表示标准偏差。
图25是示例下列微抗体变体在瞬时转染的CHO-K1细胞中的表达水平的条形图:(1)J591 HC VLVH微抗体(J591 VLVH Mb)、(2)J591 HC VHVL微抗体(J591 VHVL Mb)、(3)J591 2P VLVH微抗体(J591 VLVH**Mb)和(4)J591 2P VHVL微抗体(J591 VHVL**Mb)。huJ591 HC VHVL呈现瞬时转染的最高表达(6.7μg/mL)。
图26是显示在注射64Cu-DOTA-J591微抗体后4小时、20小时和43小时的生物分布比(即,阳性肿瘤与组织的比)的条形图。生物分布比包括阳性肿瘤(Pos)相对于肝(Liv)、肾(Kid)和软组织(Soft)的比。误差条表示平均标准误差(SEM)。
图27是显示在注射124I-J591微抗体后4小时、20小时和43小时的生物分布比(即,阳性肿瘤与组织的比)的条形图。生物分布比包括阳性肿瘤(Pos)相对于肝(Liv)、肾(Kid)和软组织(Soft)的比。误差条表示平均标准误差(SEM)。
详细描述
本公开涉及靶向前列腺特异性膜抗原(PSMA)的抗体或功能性抗体片段。PSMA抗体或其功能性抗体片段可结合至物质如诊断剂、治疗剂或纳米颗粒,形成抗PSMA结合体。还公开了包括PSMA抗体、功能性PSMA抗体片段或抗PSMA偶联物用于诊断、显现、监测或治疗与PSMA过表达有关的癌症或其他状况的方法。
PSMA抗体及其功能性片段
根据本文所述实施方式,本文提供了PSMA抗体或功能性PSMA抗体片段。PSMA抗体或功能性抗体片段是包含免疫球蛋白或免疫球蛋白相关分子的一个或多个部分的分子,其特异性结合PSMA或与PSMA具有免疫反应性。术语修饰抗体包括但不限于遗传改造形式或其他修饰形式的免疫球蛋白,如胞内抗体(intrabody)、嵌合抗体、全人抗体、人源化抗体和杂合抗体(例如,双特异性抗体、双抗体、三抗体和四抗体)。术语功能性抗体片段包含抗体的一个或多个单独或与其他分子组合的抗原结合片段,包括但不限于Fab'、F(ab’)2、Fab、Fv、rIgG、scFv片段、单区(single domain)片段、肽抗体(peptibodies)、微抗体和cys-双抗体。术语scFv指单链Fv抗体,其中传统二链抗体的重链和轻链的可变区已结合形成一条链。
在一个实施方式中,修饰抗体或功能性抗体片段是抗PSMA微抗体。在一个实施方式中,抗PSMA抗体是J591微抗体。抗PSMA微抗体具有抗PSMA抗体片段,该抗PSMA抗体片段具有优化的如下文所述体内成像和生物分布药效学性质。“微抗体”是同型二聚体,其中各单体是单链可变片段(scFv),其通过连接体如ana铰链序列连接于人IgG1 CH3结构域。在一个实施方式中,铰链序列是人IgG1铰链序列(EPKSCDKTHTCPPCPAPELLGGP;SEQ ID NO:16)。在另一实施方式中,铰链序列是人工铰链序列。人工铰链序列可包含人IgG1铰链部分和GlySer连接序列。在一个实施方式中,人工铰链序列包含人IgG1铰链的大约前14或15个残基,然后是长度为8、9或10个氨基酸的GlySer连接序列。在另一实施方式中,人工铰链序列包含IgG1铰链的大约前15个残基,然后是长度为10个氨基酸的GlySer连接序列。
scFv可具有VHVL或VLVH方向,其中VHVL方向意为scFv的重链可变区(VH)在轻链可变区(VL)的上游,VLVH方向意为scFv的VL在VH的上游。如本文所用,“上游”意为朝向氨基酸的N端或核苷酸序列的5’端。VH和VL通过氨基酸连接序列彼此连接。氨基酸连接体可以是任意适当的长度。在一个实施方式中,连接体富含Gly-Ser,且长度为大约15-20个氨基酸。在另一实施方式中,连接体富含Cly-Ser,且长度为18个氨基酸。
根据本文所述实施方式,抗PSMA微抗体各单体可由自N端至C端包含下列组分的核苷酸序列编码:(a)能够结合PSMA的scFv序列,(b)人工铰链序列,和(c)人IgG CH3序列。微抗体可由本文所述细胞、细胞系或其他适当的表达系统表达。因此,信号序列可被融合至scFv的N端,从而能够在细胞或细胞系中表达时分泌微抗体。在一些实施方式中,核苷酸序列是SEQ ID NO:1或SEQ ID NO:2。当由细胞或细胞系表达时,核苷酸被转录和翻译为氨基酸序列。在一些实施方式中,表达的氨基酸序列是SEQ ID NO:10或SEQ ID NO:11。
在另一实施方式中,提供的修饰抗体或功能性抗体片段是抗PSMA cys-双抗体(CysDB)。“双抗体”包含第一多肽链和与第二多肽链,所述第一多肽链包含重链可变区(VH),该重链可变区通过肽连接体连接而连接于第一多肽链上的轻链可变区(VL)(VH-VL),该肽连接体太短而不能使第一多肽链上的两个结构域之间配对;所述第二多肽链包含轻链可变区(VL),该轻链可变区通过肽连接体连接而连接于第二多肽链上的重链可变区VH(VL-VH),该肽连接体太短而不能使第二多肽链的两个结构域之间配对。短连接体促使第一与第二多肽链的互补结构域之间进行链配对,并促进具有两个功能性抗原结合位点的二聚分子组装。因此,肽连接体可以是促进这种组装的任意适合长度,例如,长度为5至10个氨基酸。如下进一步描述,一些cys-双抗体可包含长度为5或8个氨基酸的肽连接体。抗PSMA CysDB是同型二聚体抗体形式,其由两个相同的单体形成,该单体包含分子量大约为55kDa的单链Fv(scFv)片段。在一个实施方式中,抗PSMA是J591 CysDB。如上述抗PSMA微抗体,本文所述抗PSMA CysDBs具有药效学性质优化的抗PSMA抗体片段,其可用于体内成像和生物分布。
根据本文所述实施方式,CysDB各单体可由自N端至C端包含下列组分的核苷酸序列编码:(a)能够结合PSMA的scFv序列和(b)半胱氨酸尾部。CysDBs可由本文所述细胞或细胞系表达。因此,信号序列可被融合至scFv的N端,从而在细胞或细胞系中表达时能分泌微抗体。在一些实施方式中,核苷酸序列是SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8或SEQ IDNO:9。当由细胞或细胞系表达时,核苷酸被转录和翻译为氨基酸序列。在一些实施方式中,表达的氨基酸序列是SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14或SEQ ID NO:15。
根据一些实施方式,CysDB scFv序列类似于微抗体scFv序列,上述scFv。因此,scFv可具有VHVL或VLVH方向,其中VHVL方向意为scFv的重链可变区(VH)在轻链可变区(VL)的上游,VLVH方向意为scFv的VL在VH的上游。抗体可变区如上所述通过GlySer连接体被连接在一起。半胱氨酸尾部(Gly-Gly-Cys)被添加在C端。该半胱氨酸尾部使双抗体复合形成共价半胱氨酸键,并为功能性部分如放射标记的位点特异性结合的可用硫残基提供选择。
多种CysDBs已被成功地从抗不同目标的不同亲本抗体改造,包括CEA、Her2(曲妥珠单抗(trastuzumab)/赫赛汀)、PSCA和CD20(利妥昔单抗(rituximab)/美罗华)。CysDB形式的不同变化已经用四种特定形式评价,证明关于结合和表达水平的最大前景。对于各个单独的抗体,重链可变区和轻链可变区以不同方式结合。因此,不同连接体长度的应用允许确保二硫键形成的构象灵活性和运动范围。在一些实施方式中,两种连接体长度变体具有5氨基酸连接体或8氨基酸连接体。可利用两个方向(VL-连接体-VH-Cys尾部和VH-连接体-VL-Cys尾部)开发各连接体长度的变体,以确保实现适当的折叠和稳定性。根据一些实施方式,可用于本文所述方法的四种CysDB变体已被构建:VH5VL、VH8VL、VL5VH和VL8VH(参见图6-9)。虽然各CysDB变体已被成功表达,但结果可能取决于所用亲本抗体而变化。生成全部四种变体和测试全部四种变体的表达和结合确保鉴定到各新型CysDB蛋白质生成的最佳形式。评价变体组对于确保生成二硫桥可用的高品质稳定蛋白质是重要的。因此,改造CysDB试剂实际上涉及利用两种不同的连接体长度,而非一种——如在微抗体中;和两种可变区方向,VH/VL和VL/VH。
在一些实施方式中,哺乳动物细胞系(例如,CHO-K1细胞系)可被用作表达系统以生成本文所述微抗体、cys-双抗体或其他抗体片段。但是,由于本文所述微抗体、cys-双抗体和其他抗体片段是非糖基化的,不需要细胞系或表达——哺乳动物表达系统,因此无需翻译后修饰。因此,多种哺乳动物和非哺乳动物表达系统可根据本公开实施方式用于生成PSMA抗体片段(例如,抗PSMA微抗体和cys-双抗体),包括但不限于哺乳动物表达系统(例如,CHO-K1细胞)、细菌表达系统(例如,大肠杆菌(E.Coli)、枯草芽孢杆菌(B.subtilis))酵母菌表达系统(例如,毕赤酵母(Pichia),酿酒酵母(S.cerevisiae))或任何其他已知表达系统。
如下文实施例详细描述,在CHO-K1细胞中制成和表达了区别在于svFv区的四种微抗体变体。通过ELISA和流式细胞术证明了特异性结合PSMA。其中一种高表达和PSMA结合的变体(J591 HC VHVL)被选择用于蛋白质生成、纯化和进一步评价。J591 HC VHVL微抗体的蛋白质生成成功按比例增加,以生成足以用于下文所述内化和微PET成像实验的量。
J591微抗体的共焦显微镜研究显示在CWR22rv1和LNCaP细胞中的胞内染色随时间增加,类似于完整huJ591mAb,这表明J591微抗体进行了迅速内化。为进一步评价J591微抗体的内化,利用两种放射标记策略:用I-131放射性碘标记和DOTA结合以用于In-111放射性金属标记。111In-DOTA J591微抗体显示细胞相关放射活性经过3小时时间增加260%。相反,131I-J591微抗体的初始细胞结合随后为达到初始活性80%的显著丧失。
J591微抗体在结合PSMA+细胞系CWR22rv1和LNCaP后迅速内化。对于131I标记的J591微抗体,总细胞相关放射活性随时间减少,表明标记的损失有可能归因于131I-J591微抗体的脱卤和/或迅速代谢和从细胞释放。相反,111In-DOTA-J591微抗体的总细胞相关放射活性随时间显著增加(~2.5倍),这与俘获在溶酶体中的残留标记一致。基于总细胞相关放射活性随时间的维持,残留111In-DOTA放射标记策略呈现为内化PSMA抗原的适当体内成像方法。
抗PSMA衍生物和偶联物
在一些实施方式中,PSMA抗体或功能性抗体片段可包括经修饰的抗体衍生物。例如,抗体衍生物包括但不限于,通过糖基化、乙酰化、聚乙二醇化、磷酸化、酰胺化、已知保护/封闭基团衍生化、蛋白质水解切割和连接细胞配体或其他蛋白质修饰的抗体。多种化学修饰中任一种可通过已知技术进行,包括但不限于,特异性化学切割、乙酰化、甲酰化和衣霉素代谢合成。此外,衍生物可含有一个或多个非天然氨基酸。
在其他实施方式中,PSMA抗体或功能性抗体片段可结合(偶联)至另一种物质,形式抗PSMA偶联物。本文所述抗PSMA偶联物可通过已知的连接抗体与脂质、碳水化合物、蛋白质或其他原子和分子的方法制备。一方面,抗PSMA偶联物利用适当的连接体或键通过位点特异性结合形成。位点特异性结合更可能保持抗体或功能性抗体片段的结合活性。物质可通过二硫键形成结合或连接在还原性抗体组分或抗体片段的铰链区。例如,在scFv片段C端引入半胱氨酸残基,如在上述双抗体中引入的半胱氨酸残基,允许与多种试剂在远离抗原结合位点的位点进行位点特异性巯基反应性偶联。或者,用于形成抗PSMA偶联物的其他连接体或键可包括但不限于,共价键、非共价键、硫连接体、腙连接体、肼连接体、酯连接体、酰胺基连接体和氨基连接体、亚氨基连接体、缩氨硫脲连接体、缩氨基脲连接体、肟连接体以及碳-碳连接体。
在一个实施方式中,抗PSMA偶联物可包含结合于诊断剂的PSMA抗体或功能性PSMA抗体片段。“诊断剂”是可用于诊断、检测或显现疾病的原子、分子或化合物。根据本文所述实施方式,诊断剂可包括但不限于,放射性物质(例如,放射性同位素、放射性核素、放射标记或放射性示踪剂)、染料、造影剂、荧光化合物或分子、生物发光化合物或分子、酶和增强剂(例如,顺磁离子)。此外,应当注意的是,一些纳米颗粒,例如量子点和金属纳米颗粒(下文所述)也可适用作检测剂。
根据本公开的实施方式,可被用作诊断剂的放射性物质包括但不限于18F、32P、33P、45Ti、47Sc、52Fe、59Fe、62Cu、64Cu、67Cu、67Ga、68Ga、75Sc、77As、86Y、90Y。89Sr、89Zr、94Tc、94Tc、99mTc、99Mo、105Pd、105Rh、111Ag、111In、123I、124I、125I、131I、142Pr、143Pr、149Pm、153Sm、154-1581Gd、161Tb、166Dy、166Ho、169Er、175Lu、177Lu、186Re、188Re、189Re、194Ir、198Au、199Au、211At、211Pb、212Bi、212Pb、213Bi、223Ra和225Ac。根据本公开的实施方式可被用作诊断剂的顺磁离子包括但不限于,过渡金属离子和镧系金属离子(例如具有原子数6至9、21-29、42、43、44或57-71的金属)。这些金属包括Cr、V、Mn、Fe、Co、Ni、Cu、La、Ce、Pr、Nd、Pm、Sm、Eu、Gd、Tb、Dy、Ho、Er、Tm、Yb和Lu离子。
当诊断剂是放射性金属或顺磁离子时,该剂可与具有长尾部的试剂发生反应,该试剂的一个或多个螯合基团连接于长尾部以结合这些离子。长尾部可以是聚合物,如聚赖氨酸、多糖或具有可结合螯合基团以结合离子的侧基的其他衍生链或可衍生链。可根据本公开应用的螯合基团的实例包括但不限于乙二胺四乙酸(EDTA)、二乙烯三胺五乙酸(DTPA)、DOTA、NOTA、NETA、卟啉、多胺、冠醚、二硫缩氨基脲、多肟及类似基团。通常使螯合物通过能与分子形成键并且免疫反应性损失最小和聚集和/或内部交联最少的基团连接于PSMA抗体或功能性抗体片段。同样的螯合物当与非放射性金属如锰、铁和钆络合时,在与本文所述抗体和载体一起使用时可用于MRI。大环螯合物如NOTA、DOTA和TETA可分别与多种金属和放射性金属一起应用,该放射性金属包括但不限于镓、钇和铜的放射性核素。可应用其他环形螯合物如大环聚醚,其令人感兴趣的在于稳定结合核素如用于RAIT的223Ra。在某些实施方式中,螯合部分可用于使PET成像剂如Al-18F复合物连接到目标分子以用于PET分析。
根据本公开的实施方式可被用作诊断剂的造影剂包括但不限于泛影酸钡、乙碘油、柠檬酸镓、碘卡酸、碘西他酸、碘达胺、胆影酸、碘沙酸、碘古酰胺(iogulamide)、异己基、碘帕醇、碘番酸、碘普西酸(ioprocemic acid)、碘西法酸、碘丝酸、碘砜葡胺、碘琥酸(iosemetic acid)、碘酞硫(iotasul)、碘得酸、碘拉酸、碘出酸、碘克沙酸(ioxaglicacid)、羟泛影酸(ioxotrizoic acid)、胺碘苯丙酸、甲基葡胺、甲泛葡胺、甲泛影盐(metrizoate)、丙碘酮、氯化铊或其组合。
根据本公开的实施方式可被用作诊断剂的生物发光和荧光化合物或分子和染料包括但不限于荧光素、异硫氰酸荧光素(FITC)、Oregon Green.TM.、若丹明、德克萨斯红、异硫氰酸四若丹明(TRITC)、Cy3、Cy5等)、荧光标记物(例如、绿色荧光蛋白(GFP)、藻红蛋白等)、由肿瘤相关蛋白酶激活的自动猝灭的荧光化合物、酶(例如、荧光素酶、辣根过氧化物酶、碱性磷酸酶等)、纳米颗粒、生物素、地高辛或其组合。
根据本公开的实施方式可被用作诊断剂的酶包括但不限于辣根过氧化物酶、碱性磷酸酶、酸性磷酸酶、葡萄糖氧化酶、β-半乳糖苷酶、β-葡萄糖醛酸酶或β-内酰胺酶。这种酶可与色原、荧光化合物或发光化合物联合用于生成可检测信号。
在另一实施方式中,抗PSMA偶联物可包含结合(偶联)于治疗剂的PSMA抗体或功能性PSMA抗体片段。本文所用“治疗剂”是可用于治疗与PSMA相关的癌症或其他状况的原子、分子或化合物。治疗剂的实例包括但不限于药物、化疗剂、治疗性抗体和抗体片段、毒素、放射性同位素、酶(例如,在肿瘤部位将前体药物分解为细胞毒性剂的酶)、核酸酶、激素、免疫调节剂、反义寡核苷酸、螯合剂、硼化合物、光活性剂和染料。
化疗剂本质上通常具有细胞毒性或细胞抑制性,并可包括烷化剂、抗代谢物、抗肿瘤抗生素、拓扑异构酶抑制剂、有丝分裂抑制剂激素治疗、靶向治疗剂和免疫治疗剂。在一些实施方式中,根据本公开的实施方式可被用作诊断剂的化疗剂包括但不限于13-顺式-维甲酸、2-氯脱氧腺苷、5-阿扎胞苷、5-氟尿嘧啶、6-巯基嘌呤、6-硫鸟嘌呤、放线菌素-D、阿霉素、阿德斯白细胞、阿仑珠单抗(alemtuzumab)、阿利维甲酸(alitretinoin)、全反式维甲酸、α干扰素、六甲蜜胺、氨甲蝶呤(amethopterin)、阿米福汀(amifostine)、阿那格雷(anagrelide)、阿那曲唑(anastrozole)、阿糖胞苷(arabinosylcytosine)、三氧化二砷、苯胺吖啶、氨基喜树碱、氨基格鲁米特、天冬酰胺酶、氮杂胞苷、卡介苗(BCG)、苯达莫司汀(bendamustine)、贝伐单抗(bevacizumab)、蓓萨罗丁(bexarotene)、比卡鲁胺(bicalutamide)、硼替佐米(bortezomib)、博莱霉素、白消安、四氢叶酸钙、嗜橙菌因子、卡培他滨(capecitabine)、卡奈替尼(canertinib)、卡波铂(carboplatin)、卡莫司汀(carmustine)、西妥昔单抗(cetuximab)、苯丁酸氮芥(chlorambucil)、顺铂、克拉屈滨(cladribine)、可的松、环磷酰胺、阿糖胞苷、达贝泊汀α(darbepoetin alfa)、达沙替尼(dasatinib)、道诺霉素、地西他滨(decitabine)、地尼白介素(denileukin diftitox)、地塞米松、dexasone、右雷佐生(dexrazoxane)、放线菌素D、柔红霉素(daunorubicin)、氨烯咪胺、多西他奇(docetaxel)、亚德里亚霉素、脱氧氟尿苷、恩尿嘧啶(eniluracil)、表柔比星(epirubicin)、依泊汀α(epoetin alfa)、厄洛替尼(erlotinib)、依维莫司(everolimus)、依西美坦(exemestane)、雌氮芥、依托泊甙、非格司亭(filgrastim)、氟甲睾酮(fluoxymesterone)、氟维司群(fulvestrant)、黄酮吡醇(flavopiridol)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、氟尿嘧啶、氟他胺(flutamide)、吉非替尼(gefitinib)、吉西他滨(gemcitabine)、奥吉妥珠单抗(gemtuzumab ozogamicin)、戈舍瑞林(goserelin)、粒细胞集落刺激因子、粒细胞巨噬细胞集落刺激因子、六甲基三聚氰胺、氢化可的松羟基脲、替伊莫单抗(ibritumomab)、干扰素α、白细胞介素–2、白细胞介素-11、异维甲酸、伊沙匹隆(ixabepilone)、伊达比星(idarubicin)、甲磺酸伊马替尼(imatinibmesylate)、异环磷酰胺(ifosfamide)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸、亮脯利特(leuprolide)、脂质体Ara-C、洛莫司汀(lomustine)、氮芥、甲地孕酮(megestrol)、美法仑(melphalan)、巯基嘌呤、美司钠(mesna)、氨甲喋呤(methotrexate)、甲基泼尼松龙(methylprednisolone)、丝裂霉素C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、奈拉滨(nelarabine)、尼鲁米特、奥曲肽(octreotide)、奥普瑞白介素(oprelvekin)、奥沙利铂(oxaliplatin)、紫杉醇、帕米膦酸钠(pamidronate)、培美曲塞(pemetrexed)、帕尼单抗(panitumumab)、PEG干扰素、培加帕酶(pegaspargase)、聚乙二醇非格司亭(pegfilgrastim)、PEG-L-天冬酰胺酶、喷司他丁(pentostatin)、光辉霉素、泼尼松龙、泼尼松、甲基苄肼(procarbazine)、雷洛昔芬(raloxifene)、利妥昔单抗、罗米司亭(romiplostim)、雷替曲塞(ralitrexed)、沙帕他滨(sapacitabine)、沙莫司亭(sargramostim)、沙铂(satraplatin)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、司莫司汀(semustine)、链脲霉素(streptozocin)、它莫西芬(tamoxifen)、替加氟(tegafur)、替加氟-尿嘧啶、坦西莫司(temsirolimus)、替莫唑胺(temozolamide)、替尼泊甙(teniposide)、萨立多胺(thalidomide)、硫鸟嘌呤、噻替派(thiotepa)、托泊替康(topotecan)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗、维甲酸(tretinoin)、三甲曲沙(trimitrexate)、alrubicin、长春新碱、长春碱、长春碱酰胺、长春瑞滨、伏立诺他(vorinostat)或唑来膦酸(zoledronic acid)。
根据本公开的实施方式可被用作诊断剂的治疗性抗体及其功能性片段包括但不限于,阿仑珠单抗、贝伐单抗、西妥昔单抗、依决可单抗(edrecolomab)、吉姆珠单抗(gemtuzumab)、替伊莫单抗(ibritumomab tiuxetan)、帕尼单抗、利妥昔单抗、托西莫单抗和曲妥珠单抗。
根据本公开的实施方式可被用作诊断剂的毒素包括但不限于篦麻毒素、相思子毒素、核糖核酸酶(RNase)、脱氧核糖核酸酶(DNase)I、葡萄球菌肠毒素-A(Staphylococcalenterotoxin-A)、美洲商陆抗病毒蛋白、白树毒素、白喉毒素、假单胞菌外毒素(Pseudomonas exotoxin)和假单胞菌内毒素(Pseudomonas endotoxin)。
根据本公开的实施方式可被用作诊断剂的放射性同位素包括但不限于32P、89Sr、90Y、99mTc、99Mo、131I、153Sm、177Lu、186Re、213Bi、223Ra和225Ac。
在另一实施方式中,抗PSMA偶联物可包含结合于纳米颗粒的PSMA抗体或功能性PSMA抗体片段。术语“纳米颗粒”指尺寸以纳米测量的微观粒子,例如,至少一个维度小于约100nm的粒子。纳米颗粒尤其可用作可检测物质,因为其小到足以散射可见光,而非吸收可见光。例如,金纳米颗粒具有显著的可见光消光性质,并在溶液中呈现深红色至黑色。由此,包含结合于纳米颗粒的PSCA-特异性抗体或片段的组合物可用于个体肿瘤或癌细胞的体内成像。在尺寸范围的小值端,纳米颗粒通常被称为团簇(cluster)。已形成金属、电介质和半导体纳米颗粒以及混合结构(例如核壳型纳米颗粒)。纳米球、纳米棒和纳米杯(nanocups)只是其中几种已生成的形状。半导体量子点和纳米晶体是另外的纳米颗粒类型的实例。这种纳米级粒子在结合于PSMA抗体或功能性抗体片段时可被用作上述肿瘤细胞体内检测的成像剂。或者,纳米颗粒可在治疗应用中用作药物载体,其在结合于本发明的PSCA-特异性抗体或片段时,向在细胞表面过表达PSCA的癌细胞输送化疗剂、激素治疗剂、放射治疗剂、毒素或本领域已知的任何其他细胞毒性剂或抗癌剂。
上述任何抗PSMA偶联物可进一步结合一个或多个另外的治疗剂、诊断剂、纳米颗粒、载体或其组合。例如,PSMA抗体或功能性PSMA抗体片段可用131I放射标记并结合于脂质载体,以使抗PSMA-脂质偶联物形成微团。该微团可掺入一种或多种治疗剂或诊断剂。或者,除载体外,PSMA抗体或功能性PSMA抗体片段可结合于131I(例如,在酪氨酸残基处)和药物(例如,在赖氨酸残基的ε氨基处),并且载体可掺入另外的治疗剂或诊断剂。
诊断、分期和监测癌症的方法
PSMA抗体、功能性PSMA抗体片段或抗PSMA偶联物可用于靶向PSMA阳性细胞,如过表达PSMA的癌细胞。因此,诊断、检测、显现、监测或治疗与PSMA表达有关的癌症或其他状况的方法可包括向患有或疑患与PSMA表达有关的癌症或其他状况的个体给予PSMA抗体、功能性PSMA抗体片段或抗PSMA偶联物。如本文所用,术语“个体”指任何动物(例如,哺乳动物),包括但不限于人、非人灵长类、啮齿类、狗、猪及类似动物。
与PSMA表达有关的的癌症可包括具有过表达PSMA的癌症肿瘤组织的癌症(例如,前列腺癌)或具有过表达PSMA的实体肿瘤新血管系统的癌症(例如,前列腺癌、肺癌、结肠(或结直肠)癌、乳腺癌、肾癌、肝癌、膀胱癌和胰腺癌以及肉瘤和黑素瘤)。多数实体肿瘤新血管系统表达PSMA,使PSMA成为新血管系统生物标记。因此,除表达PSMA的癌细胞外,与PSMA表达有关的癌症可包括任何具有新血管系统的癌组织,包括但不限于,癌如前列腺癌、肺癌、结肠(或结直肠)癌、乳腺癌、肾癌、肝癌、膀胱癌和胰腺癌以及肉瘤和黑素瘤。
在一个实施方式中,诊断、检测、显现或监测与PSMA表达有关的癌症的方法包括向患有或疑患癌症的个体给予诊断性抗PSMA偶联物。诊断性抗PSMA偶联物包含结合至一种或多种上述诊断剂的PSMA抗体或功能性PSMA抗体片段。在一个实施方式中,PSMA抗体或功能性PSMA抗体片段是微抗体或CysDB,衍生自J591抗体,如本文所述的那些J591微抗体和J591CysDBs。诊断性抗PSMA偶联物可结合或连接于一种或多种本文所述的其他物质,如治疗性抗PSMA偶联物(如下文所述)、未结合的治疗剂、造影液、载体脂质或纳米颗粒。
用于上述方法的诊断性抗PSMA偶联物适于体内或体外检测或显现方法。在一个实施方式中,将进行体外诊断或预后分析,以确定PSMA在从患有或疑患与PSMA有关的癌症的个体提取的组织样本中相对于正常(即,非癌症)或对照组织样本(即,已知癌性或良性组织样本)的表达水平。考虑多种确定这种表达水平的分析,包括免疫组织化学、荧光原位杂交(FISH)和脱落抗原(shed antigen)分析、DNA印迹或PCR技术。
在另一实施方式中,诊断性抗PSMA偶联物可用于体内成像模式以显现个体体内X射线断层术(tomography)中的目标细胞。根据本文所述方法,确定个体患有与PSMA表达有关的癌症是通过显现被标记的微抗体或CysDB实现的,其中显现的标记微抗体或CysDB定位于肿瘤部位。除诊断与PSMA表达有关的癌症外,PSMA微抗体还可根据上述类似方法用于分期和监测癌症进程。
根据本文所述方法可应用的适当的体内成像方法包括但不限于,磁共振成像(MRI)、正电子发射断层扫描(PET)或微PET、电脑断层扫描(CT)、PET/CT联合成像仪、冷却充电偶联设备(CCD)、相机光学成像、光学成像(例如,生物发光光学成像、荧光光学成像或反射吸收)和单光子发射电脑断层扫描(SPECT)。
如下文实施例所述,用适当的放射性同位素(例如,残留124I、64Cu-DOTA或89Zr-DOTA)标记的本文所述的微抗体或CysDB可被用作临床成像剂,从而根据本文所述方法体内靶向PSMA。根据本文所述实施方式,这些J591微抗体和CysDBs还可被开发为潜在的单光子发射电脑断层扫描(SPECT)成像剂。通过改变放射标记,例如111In-DOTA-J591,J591微抗体可被用作SPECT成像剂。
通过如下评价本文所述J591微抗体的肿瘤靶向:用正电子发射体I-124(t1/2=4.2d)和Cu-64(t1/2=12.7h)进行放射性标记,然后进行小动物PET(微PET)和生物分布实验,以比较体内细胞相关放射活性的保留。
124I和64Cu-DOTA标记的J591微抗体均以高摄取和高特异性迅速靶向CWR22rv1肿瘤。携带PSMA阳性CWR22rv1和阴性PC-3异种移植体的小鼠的连续成像生成高对比度图像和两种标记很好的肿瘤摄取。在注射后19小时,分别以64Cu-DOTA-和124I-J591微抗体实现8.2(±1.2)%ID/g和8.8(±2.0)%ID/g。在注射后43小时(p.i.),64Cu-DOTA-J591微抗体的肿瘤摄取增加至13.3(±8.3)%ID/g,而124I-J591微抗体的肿瘤摄取减少至3.25(±0.9)%ID/g。64Cu-DOTA-和124I-J591微抗体的阳性与阴性肿瘤比在第19小时分别为3.1和4.9,在第43小时分别为5.4和7.3。64Cu-DOTA-J591微抗体可见持续的高肝摄取[在第19hr为21.4(±3.1)%ID/g,且在第43hr为14.4(±2.1)%ID/g],但124I-J591微抗体呈现迅速的背景清除,导致较高的对比度图像。两种放射性标记的微抗体在第19小时类似的肿瘤摄取是预料之外的,并且暗示了较慢的体内内化。因此,I-124放射性标记的J591微抗体是有效检测PSMA阳性细胞的示踪剂。
治疗癌症的方法
在一些实施方式中,提供了治疗与PSMA过表达有关的癌症或其他病症的方法。这种方法包括向个体给予治疗有效量的包含上述PSMA抗体或功能性PSMA抗体片段的药物组合物。在一个实施方式中,PSMA抗体或功能性PSMA抗体片段是微抗体或CysDB,衍生自J591抗体,如本文所述那些J591微抗体和J591CysDBs。
病症的“治疗”或“医疗”可指预防病症,减缓发病或病症发展速度,减少发生病症的危险,预防或延缓与癌症有关的症状发生,减少或终止与癌症有关的症状,产生病症的完全或部分消退或其一些组合。
“治疗有效量”或“治疗性有效剂量”是化合物在个体中产生期望治疗效果如预防或治疗目标病症或减轻与病症有关的症状的量。精确的治疗有效量是组合物在给定个体中在治疗效力方面产生最大有效效果的量。该量将取决于多种因素而改变,包括但不限于治疗性化合物的特性(包括活性、药物动力学、药效学和生物利用度)、个体生理条件(包括年龄、性别、疾病类型和阶段、总体身体状况、对给定剂量的应答和药物类型)、制剂中药学可接受的载体或多种载体的性质和给药途径。临床和药理学领域的技术人员将能够通过常规实验法——即通过监测个体对化合物给予的应答和由此调整剂量——确定治疗有效量。对于另外的指导,参见Remington:The Science and Practice of Pharmacy第21版,Univ.ofSciences in Philadelphia(USIP),Lippincott Williams&Wilkins,Philadelphia,PA,2005。
在一个实施方式中,药物组合物可包含治疗性抗PSMA偶联物,其中该偶联物包含结合至一种或多种上述治疗剂的PSMA抗体或功能性PSMA抗体片段。在一个实施方式中,PSMA抗体或功能性PSMA抗体片段是微抗体或CysDB,衍生自J591抗体,如本文所述那些J591微抗体和J591CysDBs。例如,本文所述J591微抗体或cys-双抗体可用于放射免疫治疗法,其中一个或多个3B J591微抗体用适当的β发射放射标记如钇-90进行放射标记。放射标记的3B J591微抗体或多个微抗体可用于向表达PSMA的局部癌组织输送细胞损伤和死亡。进一步,对放射标记的J591微抗体和双抗体的应用有可能呈现相对于放射标记的全长亲本huJ591抗体改善的肿瘤渗透。
治疗性抗PSMA偶联物可与本文所述一种或多种另外的物质结合或缔合,如诊断性抗PSMA偶联物(上文所述)、未结合的诊断剂、造影液、载体脂质或纳米颗粒。
在一些实施方式中,药物组合物还可包含药学可接受的载体。药学可接受的载体可以是涉及从一个组织、器官或身体部分向另一个组织、器官或身体部分携带或运输目标化合物的药学可接受的物质、组合物或介质。例如,载体可以是液体或固体填充剂、稀释剂、赋形剂、溶剂或封装材料或其一些组合。载体各组分必须是“药学可接受的“,因为其必须与制剂中的其他成分相容。其还必须适于接触其可能碰到的任何组织、器官或身体部分,意思是其必须不携带过度超过其治疗效益的毒性、刺激、过敏反应、免疫原性或任何其他并发症的危险。
本文所述药物组合物可通过任何适当的给药途径给予。给药途径可指本领域中已知的任何给药途径,包括但不限于气溶胶、肠内、鼻腔、眼部、口腔、胃肠外、直肠、经皮(例如、局部霜剂或膏剂、贴剂)或阴道。“经皮”给予可用局部霜剂或膏剂或借助于经皮贴剂实现。“胃肠外”指一般与注射相关的给药途径,包括眶下、输注、动脉内、囊内、心脏内、皮内、肌内、腹膜内、肺内、脊柱内、胸骨内、鞘内、子宫内、静脉内、蛛网膜下、囊下、皮下、经粘膜或经气管途径。
下列实施例意欲为示例本发明的多个实施方式。因此,所述具体实施方式不被解释为限制本发明的范围。对于本领域技术人员显而易见的是,可进行多种等同形式、改变和修正而没有脱离本发明的范围,并且要理解的是,这种等同实施方式将在此被包含在内。进一步,在本公开引用的所有参考文献的全部内容并入本文作为参考,如同本文对其进行了完整叙述。
实施例1:生成J591微抗体
J591微抗体构建物。第三代J591微抗体是整合全长亲本huJ591抗体的修饰可变区的改造抗体片段。该微抗体形式是同型二聚体,其中各单体是连接人IgG1CH3区的单链可变片段(scFv)(图1A)。scFv可具有VHVL或VLVH方向。如图1B所示,具有VHVL方向的scFv的J591微抗体表达构建物具有重链可变(VH)区,其通过18氨基酸连接体(L)序列连接轻链可变(VL)区。在VLVH方向,在图1B中VL和VH将转换,以使VL区在VH区的上游。
合成四种J591微抗体序列,用于下文所述表达研究:如下构建的微抗体序列:
1)VHVL方向的J591人复合体(HC)(J591 HC VHVL;SEQ ID NO:1);
2)VLVH方向的J591人复合体(HC)(J591 HC VLVH);
3)VHLV方向、2个脯氨酸置换(2P)的J591(J591 2P VHVL;SEQ ID NO:2);和
4)VLVH方向、2个脯氨酸置换(2P)的J591(J591 2P VLVH)。
图3显示J591 HC VHVL微抗体的序列(SEQ ID NO:1),图4显示J591 2P VHVL微抗体的序列(SEQ ID NO:2)。18个氨基酸的连接体(L)具有特定的序列——富含GlySer残基(参见图1,序列参见图3和4)。scFv通过人工铰链序列连接于人IgG1 CH3区,该人工铰链序列其中前15个残基是人IgG1铰链部的残基,然后是10个氨基酸GlySer连接序列(参见图1,序列参见图3和4)。该特定铰链序列也已被成功整合到之前的微抗体中。微抗体(VH-VL-CH3或VL-VH-CH3方向)由于CH3区之间的缔合和铰合区中二硫键的形成而以稳定的二聚体存在。为能分泌微抗体,κ轻链信号序列引导表达构建体,并使其融合在重链可变区N端(参见图1B,序列参见图3和4)。
通过在亲本huJ591重链可变区和轻链可变区中进行氨基酸置换改造J591微抗体组。全长亲本huJ591可变区的序列分析确定了异常多的构象限制性脯氨酸残基,其被确认为减少蛋白质结构的灵活性。去免疫J591(SEQ ID NO:5;SEQ ID NO:19)与原鼠J591(SEQID NO:4;SEQ ID NO:18)之间的序列比对比较表明,去免疫过程引入另外的脯氨酸残基(参见图2)。经序列和蛋白建模分析后,对蛋白质进行两种改变,以提高灵活性和折叠能力。第一,将轻链可变区的两个脯氨酸残基(P42Q和P100A)变为鼠序列中发现的残基(参见图2,下文被称为2P)。第二,利用人复合(HC)抗体技术(Antitope)计算两可变区的置换,该人复合(HC)抗体技术通过避免潜在表位而非破坏表位使序列去免疫(参见图2,下文被称为HC)。
J591微抗体的表达。生成上述四种微抗体序列中每一种的表达载体。将四种微抗体序列的每一种克隆到用于哺乳动物表达的pcDNA3.1/myc-His(-)A版载体(Invitrogen,Inc.)中相应的XbaI/HindIII位点。pcDNA3.1表达载体的特征在于哺乳动物表达的CMV启动子和哺乳动物(新霉素)和细菌(氨苄青霉素)的选择标记物(参见图10)。
将四种J591微抗体表达载体暂时转染到CHO-K1细胞中,以确认J591微抗体的表达。转染利用Lipofectamine试剂以6孔板形式进行。72小时转染后,收集和过滤上清液,以去除任何细胞。
为确定J591微抗体由CHO-K1细胞表达,用取自瞬时转染的上清液样本进行蛋白质印迹分析。空载体转染的上清液被包含作为阴性对照,不同微抗体转染的上清液被用作阳性对照。将转染上清液进行SDS-PAGE,并转移至PVDF膜。用结合碱性磷酸酶(AP)的抗人IgG(Fc-特异性)抗体探测该膜,并通过用AP底物BCIP/NBT温育而使其显影。图11是确定J591微抗体表达的多个实验的代表性印迹。在非还原条件下,J591微抗体以大约90kD的预期分子量运行(图11)。表示单体形式的较小带也在大约40kD被检测到。
进行定量ELISA以分析瞬时转染的J591微抗体表达。ELISA是夹心分析,其将山羊抗人IgG(Fc特异性)用作捕捉抗体和将AP结合的山羊抗人IgG(Fc特异性)用作检测抗体。之前生成的微抗体的纯化蛋白质被用作标准品。连续稀释J591微抗体上清液,找到适于标准曲线线性范围的稀释点。利用程序SoftMax Pro插入根据标准曲线未知的浓度。
分析多个转染的上清液,并且平均值展示在图25中。J591 HC VHVL微抗体呈现第三代微抗体中的最高表达(6.7ug/ml)。
J591微抗体的结合能力。为确定J591微抗体结合细胞PSMA的能力,通过流式细胞计量术分析上述瞬时转染的上清液。如图12A-12D所示,测试各J591微抗体瞬时转染的上清液的结合PSMA阳性(PSMA+)的LNCaP细胞(2),并与PSMA阴性的阴性对照细胞进行比较。所有上清液被标准化至2.1ug/ml的J591微抗体浓度。随后细胞用二级抗人IgG(Fc特异性)-PE结合的抗体染色。阴性对照细胞仅用二级抗人IgG(Fc特异性)抗体染色(1)。1×105个细胞/点,且以10,000事件/点进行分析。
用J591微抗体染色的各细胞群证实了信号相对于阴性对照细胞显著增加(参见图12)。J591微抗体上清液没有显著染色阴性对照PC3细胞(PSMA阴性)(数据未显示)。全部四种微抗体显示对LNCaP细胞的相当结合亲和力(参见图12)。
实施例2:稳定的细胞系群
基于上述表达和结合数据,将J591人复合VHVL(HC VHVL)微抗体选作主要候选以推进至较大规模(~低毫克量)蛋白质生产,用于下文所述的后续体内成像研究。虽然下文所述实施例对J591 HC VHVL微抗体特异,但要注意的是,本文所述任何J591微抗体或cys-双抗体均可被纯化和用于类似研究。
用新霉素作为选择标记物将J591 HC VHVL微抗体稳定转染到CHO-K1细胞中。选择高表达克隆后,以大约36mg/L(经过4天培养)选择表达J591微抗体的克隆用于大规模生产。
蛋白质生产运行。为生成至少10mg最终纯化的蛋白质,将稳定的细胞系扩大至400ml生产运行(在2%FBS介质)。将细胞接种到8个T175烧瓶中,并持续生产运行7天。
蛋白质纯化。在生产运行结束时,收集上清液,将其旋转以去除任何细胞,并用0.2um过滤装置过滤。用蛋白L亲和层析从上清液纯化J591微抗体。装载后,将柱用PBS(pH=7.2)洗涤,并用IgG洗脱缓冲液(Pierce,Thermo Scientific)将微抗体从柱洗脱。立即用1MTris缓冲液(pH=8)中和洗脱部分。将最终的洗过部分浓缩,并缓冲交换到最终的PBS制剂(pH=7.2)中。
纯化的蛋白质分析。纯化后,利用280A下的UV吸光度计算J591微抗体蛋白的最终浓度。吸光系数为1.76(吸光单位为A280下每mg/ml)。最终的蛋白质浓度为1.06mg/ml。
为分析J591微抗体的纯度,蛋白质通过SDS-PAGE在非还原和还原条件下运行。在非还原的条件下,微抗体被检测到在大约85kDa(图13)。相对小的拖尾(smear)存在于85kDa带,其可表示少量降解。大约40kDa小带表示微抗体单体。在还原条件下,微抗体被检测到为约40kDa的单体形式(图13)。
为检测装配微抗体复合物的纯度,通过尺寸排阻层析分析蛋白质。通过SEC分析4微克纯化蛋白(图14)。主峰相应于微抗体同型二聚体。在早期时间点洗脱的两个小峰表示较大的聚集蛋白。峰下面积的分析显示85%的蛋白质产物相对于15%的聚集体以适当的微抗体同型二聚体存在。
实施例3:J591微抗体结合PSMA+细胞并被PSMA+细胞内化
通过Catalent专有GPEx技术利用无血清CHO-S细胞的慢病毒转导生成高表达稳定细胞库。利用离子交换层析,以足够高纯度从细胞上清液纯化J591微抗体,用于下游实验。通过SDS-PAGE和SEC分析确定产物高纯度(>85%纯度)。纯化的蛋白质不具有任何显著的生物负载(0cfu/ml),和具有相对低的内毒素水平(8至16EU/mg)。此生产运行批次的总产量为65mg J591微抗体蛋白。
功能性ELISA。为确定J591微抗体蛋白结合纯化的PSMA的能力,利用纯化的重组PSMA进行间接ELISA。实验中包括阴性对照微抗体。在2μg/ml的初始浓度下,J591微抗体以饱和状态结合重组PSMA(参见图15)。随后连续稀释J591微抗体显示出浓度依赖性结合(参见图15)。如预期,阴性对照微抗体不结合PSMA(参见图15)。
流式细胞计量术。在ELISA中成功结合重组PSMA后,通过流式细胞计量术测试J591微抗体蛋白结合PSMA+细胞的能力。全长hJ591抗体被包含在实验中作为阳性对照(数据未显示),并且阴性对照微抗体也被包含在内。在本实验中,PSMA+细胞是LNCaP和CWR22rv1细胞,PSMA-细胞系是PC3。J591微抗体相比起同等浓度的阴性对照微抗体明显结合LNCaP(参见图16A)和CWR22rv1(参见图16C)。已知LNCaP细胞具有高于CWRs的PSMA表达,其可解释细胞群的较高PE信号(参见图16,上排相对于下排)。如预期,J591微抗体不显著结合PC3细胞(数据未显示)。
在此流式细胞计量分析前,使J591微抗体蛋白结合双功能性螯合剂1,4,7,10-四氮杂环十二烷-N,N',N”,N”'-四乙酸(DOTA),准备用于下游放射性金属标记。利用水溶性N-羟基琥珀酰亚胺方法(Lewis et al 2001)实施结合。DOTA结合后,透析蛋白质偶联物以改变缓冲液和去除过量的DOTA。
为在结合后检验结合能力,通过流式细胞计量术测试J591-DOTA微抗体与PSMA的结合。相比起未结合的J591微抗体,J591-DOTA微抗体呈现免疫反应性略微降低,如细胞群的PE信号的略微改变所示(参见图16B和16D)。已知双功能螯合剂与抗体的过度结合是免疫反应性降低的原因(Kukis et al 1995)。结合条件可被优化以防止过度结合和造成的结合损失。但是,J591-DOTA微抗体结合的略微改变被认为是可接受的,并且蛋白推进至放射标记。
未标记微抗体的内化。利用免疫荧光共焦显微镜来检测J591微抗体至PSMA+细胞的内化。用于本实验的两种PSMA+细胞系,LNCaP和CWR22rv1细胞系,之前已被用于细胞结合研究,并且还用于随后的放射标记内化研究。PC3细胞被用作PSMA-阴性对照细胞系。全长亲本J591抗体被包含在实验中作为阳性对照。阴性对照微抗体也被包含在内以进一步证明PSMA+细胞中摄取J591微抗体的特异性。
由于原始全长J591抗体在LNCaP细胞上的之前的内化研究显示到180分钟时的强内化(Liu et al 1998),在一级抗体温育后t=0和t=180分钟将细胞染色以测定内化。通过结合Alexa 488荧光团的二级抗人IgG抗体检测抗体和微抗体的定位。细胞用DAPI复染,以使核染色。
J591全长抗体显示在t=0时对质膜非常鲜明和清楚的染色(参见图17)。在37℃下温育180分钟后,J591全长抗体内化到LNCaP细胞中,如Alexa 488染色在整个细胞的分散所示。J591微抗体还显示t=0时清楚的质膜染色和到t=180分钟时的强内化(图17)。J591微抗体在t=0时的染色明显不如J591全长清楚,可能表明较小尺寸的微抗体在LNCaP细胞中更迅速的内化。阴性对照微抗体在t=0时不能结合LNCaP细胞。J591全长抗体和微抗体不能结合PSMA-PC3细胞(数据未显示)。
全长J591抗体至CWR22rv1细胞的内化显示与LNCaP细胞所见非常类似的染色图谱。染色在t=0时对质膜非常鲜明和清楚,并且到t=180分钟时变得非常分散(参见图18)。J591微抗体也被内化到CWR22rv1中。染色在t=0时在质膜中清楚,到t=180分钟时变得更加分散(图18)。如预期,阴性对照微抗体不结合CWR22rv1细胞(图18)。
实施例4:放射标记的PSMA特异性微抗体
用碘-131放射标记J591微抗体。利用Pierce Thermo Scientific的Iodogen法(如Olafsen et al 2006所述)用大约50μCi的131I放射性标记纯化的J591微抗体蛋白(50μg)。该试剂能发生化学氧化反应,以使131I连接于J591微抗体的可用的酪氨酸残基。表2是J591微抗体放射标记结果的概括,包括放射标记效力、纯化后结合放射活性百分比和比活性。利用瞬时薄层色谱法(ITLC)测定结合蛋白质的放射活性相对于未结合的百分比,确定放射标记效力为约51%。(参见下表2)。通过利用剂量校准器测量放射标记蛋白质的总活性和基于标记效力计算比活性,确定比活性为0.46μCi/μg(表2)。为去除多余的未结合131I,利用旋转柱(spin column)进一步纯化放射标记的蛋白质。纯化后结合J591微抗体的放射活性百分比在纯化后显著增加至大约96%(表2)。
DOTA结合和用铟-111放射性金属标记J591。用111In放射标记之前结合有双功能性金属螯合剂DOTA的J591微抗体。将100μg DOTA-J591微抗体用200μCi111In-氯化物在0.1M无金属乙酸铵(pH 6.0)中于43℃下温育50分钟。通过添加10mM DTPA至1mM的最终浓度来终止反应。测定放射标记效力为大约60%,比活性为1.1μCi/μg(参见表2)。利用旋转柱进一步纯化放射标记的蛋白质以去除过量的未结合111In。类似于131I-J591微抗体,纯化后结合J591微抗体的放射活性百分比显著增加至大约94%(表2)。
表2.用131I和111In放射标记J591微抗体。
经放射标记的J591微抗体的内化和保留。测试131I标记和111In-DOTA标记的J591微抗体在PSMA+CWR22rv1细胞中细胞相关放射活性的摄取和保留。将CWR22rv1细胞选作这些体外实验的唯一PSMA+细胞系,因为其将被用于微PET成像实验。鉴于文献和同事的实验知识,CWR22rv1异种移植模型具有比LNCaP模型高的肿瘤发生率(take rate)和比LNCaP模型快的体外和肿瘤生长速率。
对于131I标记的J591微抗体的摄取和保留,与膜有关的放射活性量在前30分钟内迅速减少,而内化放射活性在此时间框内迅速增加(参见图19A)。这些数据一起表明131I-J591微抗体的内化。虽然内化131I J591的量随时间增加,但总细胞相关放射活性到180分钟时相对于~2900cpm的最初起始点显著降低(参见图19A)。
与之形成鲜明对比的是,111In-DOTA标记的J591微抗体的摄取和保留显示总细胞相关放射活性随时间相对大的增加(参见图19B)。类似于131I标记的J591微抗体,膜相关的放射活性随内化放射活性增加而显著减少,表明具有活性的内化(参见图19B)。很大程度上归功于内化放射活性随时间的增加,总细胞相关放射活性到180分钟时从~7,500cpm的起始点增至大约20,000cpm(图19B)。
为比较两种放射标记J591微抗体,通过以各个放射标记分别在t=0时的初始细胞相关放射活性的百分比的形式表示数据而标准化总细胞相关放射活性(参见图20)。到t=180分钟时,111In-DOTA标记的J591微抗体增至初始细胞相关放射活性的~250%,而131I标记的J591微抗体降至初始的~80%(图20)。如文献(Vaidyanathan et al 2009)中的其他组所示,非残留131I标记策略导致细胞相关放射活性随时间总体减少。这些数据明确表明,残留111In-DOTA放射标记的细胞相关放射活性随时间保留和积累。
纯化的J591 HC VHVL微抗体(或上述任何微抗体)可用于在微PET成像和生物分布研究中证明在体内靶向人PSMA的能力。在一个实施方式中,纯化的J591 HC VHVL微抗体蛋白可首先在成像研究的准备中被再次检验以确定其体外结合PSMA的能力。在确定结合后,然后可将J591 HC VHVL微抗体结合于双功能性螯合剂DOTA,并用适于微PET的发射正电子的放射性金属如铜64进行放射标记。在进行微PET成像前,可分析放射标记的微抗体以确保高放射标记效力和免疫反应性。
在一些实施方式中,放射标记的微抗体可静脉内注入移植有PSMA阳性或PSMA阴性肿瘤的异种移植小鼠。在注射后的特定时间点,可通过PET连续扫描各动物。在最后一次扫描后,可通过CT扫描动物,用于解剖参考。然后可分析各动物的PET和CT图像,从而评价肿瘤靶向和特异性。
实施例5:124I-J591和64Cu-DOTA结合的J591微抗体的体内结合和生物分布
用碘-124放射标记J591微抗体。利用Pierce Thermo Scientific的Iodogen法(如Olafsen et al 2006所述)用大约1.3mCi 124I放射标记纯化的J591微抗体蛋白(总量为300μg)。该方法涉及化学氧化反应以将124I放射性同位素连接于J591微抗体可用的酪氨酸残基。下文表3是J591微抗体放射标记结果的概括,包括放射标记效力、纯化后结合的放射活性百分比、比活性和免疫反应性。标记反应后,利用瞬时薄层色谱(ITLC)确定放射标记效力为大约62%(结合蛋白质的放射活性相对于未结合的百分比)(参见表3)。利用Sephadex G-25旋转柱部分地纯化放射标记的J591微抗体,并通过ITLC对其进行重新评价,从而确定结合放射活性的百分比。放射标记蛋白质的比活性为2.6μCi/μg(表3),如通过用剂量校准器测量蛋白质总放射活性所确定。为从反应去除多余的未结合124I,用旋转柱进一步纯化放射标记的蛋白质。纯化后结合J591微抗体的放射活性百分比显著增加至大约98%(表3)。通过测试与CWR22rv1相对于PC3细胞的结合来确定124I-J591微抗体的免疫反应性为48%(表3)。虽然该免疫反应性低于预期,但基于之前的微抗体结合性能,做出推进124I J591微抗体至成像和生物分布实验的决定。进一步的放射标记条件(pH、时间、温度等)的优化和得到较高蛋白质纯度可潜在地提高免疫反应性。
表3.用124I和64Cu对J591微抗体进行放射标记。
铜-64放射性金属标记DOTA-J591微抗体。用64Cu放射标记J591微抗体,其之前结合双功能性金属螯合剂DOTA。对于初始放射标记条件,在43℃下于25mM无金属柠檬酸铵[pH5.2]中将PBS中的400μg DOTA-J591微抗体与大约745μCi64CuCl2温育60分钟。通过添加10mMEDTA至最终浓度1mM而终止反应。利用这些标记条件,确定放射标记效力低于预期约40%(参见表3)。
在提高标记效力的努力中,在开始放射标记反应前首先将DOTA-J591微抗体透析到0.25乙酸铵缓冲液[pH 7.2]中。用大约730uCi 64CuCl2标记乙酸铵缓冲液中的另外的560μg DOTA-J591微抗体。改善放射标记的另一种调整涉及增加反应所用的柠檬酸铵缓冲液百分比。随着这些调整,放射标记效力显著增加至大约92%(表3)。
将两种标记条件的所有64Cu-DOTA J591微抗体组分混合在一起,并用旋转柱进一步纯化以去除过量的未结合64Cu。纯化后结合J591微抗体的放射活性的百分比为大约85%,并且比活性为1μCi/μg(表3)。利用之前关于124I J591微抗体所述的基于细胞的方法确定放射标记的微抗体免疫反应性为大约29%(表3)。虽然免疫反应性低于预期,但做出推进至微PET和生物分布实验的决定。除蛋白质纯度和标记条件外,未来优化免疫反应性的努力可包括优化DOTA结合反应(即,DOTA-分子比等)。
实施例6:放射标记的J591微抗体的连续微PET成像和生物分布
64Cu-DOTA J591微抗体。为了评价64Cu-DOTA-J591微抗体的肿瘤靶向和结合特异性,利用植入CWR22rv1(PSMA+)和PC3(PSMA-)异种移植体的小鼠进行微PET成像和生物分布分析。在开始成像实验前,使两种异种移植肿瘤均生长至39-223mg的尺寸。在注射后4小时CT和PET/CT图像显示,CWR22rv1肿瘤相比起PC3肿瘤迅速肿瘤定位(图21A和21B显示代表性小鼠)。如对放射性金属标记的微抗体的预期,在胸部中检测到显著活性,并具体定位于肝脏。放射性金属如64Cu的定位已在文献(Yazaki et al 2001)中得到充分研究。除肝脏外,背景活性甚至在注射后4小时仍相对较低,这允许具有显著对比的PET/CT图像(图21B和21C)。强肿瘤定位在注射后19小时甚至43小时仍持续(图21D)。总背景活性随时间略微减少,但肝脏仍保持强活性源(图21D)。
最后一次扫描后,安乐死所有动物(在注射后19小时n=8,在注射后43小时n=4),并将选定的目标组织(包括阳性和阴性肿瘤、血液、肝、脾、肺和肾)切除、称重和通过γ计数器测量放射活性。图22中在注射后19小时的生物分布表明,CWR22rv1肿瘤(肿瘤+)达到8.23%ID/g的平均摄取,与之相比PC3肿瘤(肿瘤-)为2.69%ID/g。在CWR22rv1的定位明显高于PC3肿瘤(p<0.05)。如微PET/CT成像所示,注射后19小时肝脏的摄取相对较高(21.43%ID/g),而其他目标组织的定位非常较不显著(参见图22)。
在注射后43小时,生物分布表明CWR22rv1肿瘤的平均摄取(肿瘤+;13.25%ID/g)相比注射后19小时增加(图22)。背景活性相比注射后19小时减少,特别是肝活性显著减少至14.37%ID/g(图22)。
随着背景活性总体减少结合CWR22rv1肿瘤的积累增加,肿瘤与背景的比在注射后19小时至注射后43小时之间显著增加(图26)。
124I J591微抗体。如同64Cu-DOTA J591微抗体,对124I J591微抗体进行微PET和生物分布实验,以评价肿瘤靶向。在开始成像实验前使两种异种移植肿瘤均生长至36-192mg的尺寸范围。注射后(p.i.)4小时的微PET图像显示在CWR22rv1肿瘤迅速定位,但在胸部、腹部和膀胱中具有高循环活性(图23A和23B)。到注射后20小时,背景活性从系统明显清除,并且到44小时几乎完全消失,而在阳性肿瘤处活性保持(图23C)。
对于生物分布分析,在最后一次扫描后安乐死组中的所有动物(注射后20小时n=6,注射后44小时n=2.),并将选定的目标组织切除、称重和通过γ计数器测量放射活性。图24中小鼠注射后20小时的生物分布显示,CWR22rv1肿瘤(肿瘤+)摄取达到8.75%ID/g,与之相比PC3肿瘤(肿瘤-)为1.8%ID/g。在CWR22rv1的定位明显高于PC3肿瘤(p<0.05)。背景活性到注射后20小时相对较低(图24)。
到注射后44小时,CWR22rv1肿瘤(肿瘤+)摄取显著减少至3.25%ID/g(图24)。细胞相关放射活性由于124I-J591微抗体脱卤和/或代谢随时间减少,支持之前上述体外内化和保留实验的结果。到注射后44小时,背景活性几乎完全从系统清除(图24)。
虽然CWR22rv1肿瘤的活性摄取随时间减少(图24),但背景活性迅速减少造成图像的强烈对比。生物分布比反映出肿瘤比背景随时间的巨大增加(图27)。
在通过J591微抗体使PSMA阳性肿瘤成功成像后,根据本公开的实施方式可考察微抗体的生物分布。这些生物分布研究可考察注射后微抗体在肿瘤位点相对于其他选定组织随时间的定位。这些研究可用于证明高肿瘤/背景比。J591微抗体的应用将可能在使过量表达PSMA的肿瘤——如前列腺癌中——成像时,产生高肿瘤/背景比。这些成像和生物分布实验的阳性结果可引起毒理学实验,为临床研究做准备。
进一步,通过PET成像研究,J591微抗体体内靶向人PSMA的能力可通过癌症患者的临床试验得到证明。在一个实施方式中,临床试验可在前列腺癌症患者中进行。癌症患者的这些临床试验可利用上述类似方法进行。简而言之,放射标记的微抗体可被静脉内注入患有已知过量表达PSMA的癌症形式的癌症患者。在注射后特定时间点,可通过PET连续扫描各患者。在最后一次扫描后,可通过CT扫描患者用于解剖学参考。然后可分析各患者的PET和CT图像,从而评价肿瘤靶向和特异性。
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Claims (40)
1.微抗体,包含:
scFv序列,所述scFv序列能够结合前列腺特异性膜抗原(PSMA),所述scFv包含通过氨基酸连接序列连接到轻链可变区(VL)的重链可变区(VH);
铰链序列;和
人IgG CH3序列,
其中下列的至少一个:
a)所述VH包括SEQ ID NO:3并且所述VL包括SEQ ID NO:17;或
b)所述VH包括SEQ ID NO:5并且所述VL包括SEQ ID NO:19。
2.权利要求1所述的微抗体,其中所述VH包括SEQ ID NO:3并且所述VL包括SEQ ID NO:17。
3.权利要求1所述的微抗体,其中所述VH包括SEQ ID NO:5并且所述VL包括SEQ ID NO:19。
4.权利要求1所述的微抗体,其中所述微抗体包含包括SEQ ID NO:10的氨基酸序列。
5.权利要求1所述的微抗体,其中所述微抗体由包含SEQ ID NO:1的核酸序列编码。
6.权利要求1所述的微抗体,其中所述微抗体包含包括SEQ ID NO:11的氨基酸序列。
7.权利要求5所述的微抗体,其中所述微抗体由包含SEQ ID NO:2的核酸序列编码.
8.权利要求1所述的微抗体,其中所述铰链包括人工铰链。
9.权利要求8所述的微抗体,其中所述人工铰链包括人IgG1铰链部分和GlySer连接体。
10.权利要求1所述的微抗体,其中所述氨基酸连接序列的长度为15-20个氨基酸。
11.权利要求1所述的微抗体,进一步包含N端信号序列,从而在细胞中表达时能分泌所述微抗体。
12.权利要求1-11任一项所述的微抗体,其中所述scFv为VHVL方向,以使所述VH在所述VL的上游,或所述scFv为VLVH方向,以使所述VL在所述VH的上游。
13.权利要求1-11任一项所述的微抗体,其中所述微抗体缀合于诊断剂并且可以结合PSMA,用于体内诊断与PSMA表达有关的状况的应用,所述应用包括:
向患有或疑患与PSMA表达有关的状况的个体给予所述微抗体;
使所述个体暴露于成像方法以显现缀合于所述诊断剂的所述微抗体;和
当缀合于所述诊断剂的所述微抗体定位于肿瘤部位时,确定所述样品具有与PSMA表达有关的状况。
14.根据权利要求13的用于所述应用的微抗体,其中所述抗PSMA微抗体靶向实体肿瘤的新血管系统;或者
其中所述与PSMA表达有关的状况是癌症并且其中所述癌症是前列腺癌、肺癌、结肠癌、乳腺癌、肾癌、肝癌、膀胱癌、胰腺癌或黑素瘤。
15.根据权利要求13的用于所述应用的微抗体,其中所述诊断剂选自:放射性物质、染料、造影剂、荧光分子、生物发光分子、酶、增强剂、量子点和金属纳米颗粒。
16.根据权利要求13的用于所述应用的微抗体,其中所述诊断剂是生物发光化合物。
17.根据权利要求1-11任一项所述的微抗体,其用于与PSMA表达有关的癌症治疗的应用。
18.根据权利要求17的用于所述应用的微抗体,所述微抗体缀合于治疗剂。
19.根据权利要求18的用于所述应用的微抗体,其中所述治疗剂选自化疗剂、治疗性抗体或抗体片段、毒素、放射性同位素、酶、激素、免疫调节剂、反义寡核苷酸、螯合剂、硼化合物、光活性剂和染料。
20.根据权利要求18的用于所述应用的微抗体,其中所述治疗剂是核酸酶。
21.根据权利要求19的用于所述应用的微抗体,其中所述微抗体靶向实体肿瘤的新血管系统。
22.根据权利要求17的用于所述应用的微抗体,其中所述与PSMA表达有关的癌症是前列腺癌、肺癌、结肠癌、乳腺癌、肾癌、肝癌、膀胱癌、胰腺癌或黑素瘤。
23.权利要求1-4或8-11任一项所述的微抗体,其中所述微抗体包含包括SEQ ID NO:10的氨基酸序列,并且其中如果与PSMA+、CWR22rv1或LNCaP细胞接触,则所述微抗体被所述细胞内化。
24.权利要求1-11任一项所述的微抗体在制备用于与PSMA表达相关的癌症的药物中的应用。
25.根据权利要求24的用于所述应用的微抗体,其中所述微抗体缀合于治疗剂。
26.根据权利要求25的用于所述应用的微抗体,其中所述治疗剂选自化疗剂、治疗性抗体或抗体片段、毒素、放射性同位素、酶、激素、免疫调节剂、反义寡核苷酸、螯合剂、硼化合物、光活性剂和染料。
27.根据权利要求25的用于所述应用的微抗体,其中所述治疗剂是核酸酶。
28.cys-双抗体,包含:
通过氨基酸连接序列连接到轻链可变区(VL)的重链可变区(VH),其中所述VH包括SEQID NO:3并且所述VL包括SEQ ID NO:17;和
半胱氨酸尾部。
29.权利要求28所述的cys-双抗体,其中所述cys-双抗体包括scFv,所述scFv包括以VHVL方向的VH和VL,以使所述VH在所述VL的上游。
30.权利要求28所述的cys-双抗体,其中所述cys-双抗体包括scFv,所述scFv包括以VLVH方向的VH和VL,以使所述VL在所述VH的上游。
31.权利要求28所述的cys-双抗体,进一步包含N端信号序列,从而在细胞中表达时能分泌所述cys-双抗体。
32.权利要求28所述的cys-双抗体,其中所述氨基酸连接序列的长度为5或8个氨基酸。
33.权利要求28-32任一项所述的cys-双抗体,其中所述cys-双抗体缀合于诊断剂并且能够结合PSMA,用于体内诊断与PSMA表达有关的状况的应用,所述应用包括:
将所述cys-双抗体给予患有或疑患与PSMA表达有关的状况的个体;
使所述个体暴露于成像方法以显现缀合于所述诊断剂的所述cys-双抗体;和
当缀合于所述诊断剂的所述cys-双抗体定位到肿瘤部位时,确定所述样品具有与PSMA表达有关的状况。
34.根据权利要求33的用于所述应用的cys-双抗体,其中所述抗PSMA cys-双抗体靶向实体肿瘤的新血管系统;或者
其中所述与PSMA表达有关的状况是癌症并且其中所述癌症是前列腺癌、肺癌、结肠癌、乳腺癌、肾癌、肝癌、膀胱癌、胰腺癌或黑素瘤。
35.根据权利要求28-32任一项所述的cys-双抗体,其用于癌症治疗的应用。
36.根据权利要求35的用于所述应用的cys-双抗体,其中所述cys-双抗体缀合于治疗剂。
37.根据权利要求36的用于所述应用的cys-双抗体,其中所述治疗剂选自化疗剂、治疗性抗体或抗体片段、毒素、放射性同位素、酶、激素、免疫调节剂、反义寡核苷酸、螯合剂、硼化合物、光活性剂和染料。
38.根据权利要求36的用于所述应用的cys-双抗体,其中所述治疗剂是核酸酶。
39.根据权利要求34的用于所述应用的cys-双抗体,其中所述cys-双抗体靶向实体肿瘤的新血管系统。
40.根据权利要求34的用于所述应用的cys-双抗体,其中所述与PSMA表达有关的癌症是前列腺癌、肺癌、结肠癌、乳腺癌、肾癌、肝癌、膀胱癌、胰腺癌或黑素瘤。
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