CN108883197A - 靶向uPARAP的抗体-药物缀合物 - Google Patents
靶向uPARAP的抗体-药物缀合物 Download PDFInfo
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- CN108883197A CN108883197A CN201780010196.4A CN201780010196A CN108883197A CN 108883197 A CN108883197 A CN 108883197A CN 201780010196 A CN201780010196 A CN 201780010196A CN 108883197 A CN108883197 A CN 108883197A
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Abstract
本发明涉及靶向uPARAP的缀合物,特别是包含针对uPARAP的N端区域的单克隆抗体的抗体‑药物缀合物(ADC)及其在将活性剂递送至表达uPARAP的细胞和组织中的用途。本发明进一步涉及所述ADC在治疗涉及表达uPARAP的细胞的疾病如癌症中的用途。
Description
发明领域
本发明涉及靶向受体uPARAP的分子缀合物,特别是针对uPARAP的抗体-药物缀合物(ADC),及其在将活性剂递送至表达uPARAP的细胞和组织中的用途。本发明进一步涉及所述ADC在治疗涉及表达uPARAP的细胞的疾病如某些癌症中的用途。
背景
尿激酶型纤溶酶原激活物受体相关蛋白(uPARAP),也称为CD280、Endo180和2型甘露糖受体C,是内吞跨膜糖蛋白的巨噬细胞甘露糖受体家族的成员。uPARAP是一种在组织重塑过程中(特别是胶原的摄取和细胞内降解)参与基质转换的膜蛋白。
受体uPARAP在包括肉瘤和晚期胶质母细胞瘤的特定癌症的肿瘤细胞中上调。此外,该受体最常在实体瘤周围的基质细胞中上调,并且一些文献表明uPARAP在前列腺癌骨转移中高表达(Caley et al.,2012,J.Pathol 5:775-783)。在健康的成年个体中,该受体表现出受限的表达模式(Melander et al.,2015,Int J Oncol 47:1177-1188)。
抗体-药物缀合物(ADC)是一类新的被设计为靶向治疗、特别是用于治疗癌症的高效生物药物。ADC是由抗体(完整mAb或抗体片段)通过可能具有不稳定键的稳定的化学接头连接至生物活性药物或细胞毒性化合物而组成的复杂分子。通过将抗体的独特靶向能力与细胞毒性药物的细胞杀伤能力相结合,基于抗体抗原的表达,抗体-药物缀合物可以在健康组织和患病组织之间的实现灵敏区分。这意味着,与传统的化学治疗剂相比,抗体-药物缀合物主动靶向并攻击癌细胞,使得具有很少或没有抗原表达的健康细胞受影响较小。迄今为止,三种ADC已获得市场认可,若干ADC正在进行临床试验。
WO 2010/111198公开了包含抗uPARAP抗体的缀合物并且提出了这样的缀合物在将治疗剂递送至表达uPARAP的细胞中的用途。
目前大多数癌症类型都有治疗方法。但是,在大多数情况下,由于治疗缺乏特异性,效率不理想或具有有害的副作用。因此,需要具有特异性增加的更高效的治疗。
概述
本发明提供了基于能够与uPARAP受体的N端区域结合的抗uPARAP抗体的抗体-药物缀合物(ADC)。如本文所述的ADC能够特异性靶向表达uPARAP的细胞和组织,并且具有优异的体外和体内功效而没有记录的副作用。
具体而言,本公开涉及抗体-药物缀合物,其包含:
a.抗体或其抗原结合片段,其能够结合:
i.SEQ ID NO:36或37的氨基酸序列(uPARAP的CysR-FN-II-CTLD-1结构域),
ii.SEQ ID NO:38或39的氨基酸序列(uPARAP的CysR-FN-II结构域),
iii.SEQ ID NO:40或41的氨基酸序列(uPARAP的FN-II-CTLD-1结构域),
iv.SEQ ID NO:30或31的氨基酸序列(uPARAP的富含半胱氨酸(CysR)结构域),
v.SEQ ID NO:32或33的氨基酸序列(uPARAP的II型纤连蛋白(FN-II)结构域),和/或
vi.SEQ ID NO:34或35的氨基酸序列(uPARAP的C型凝集素样结构域1(CTLD 1)),
b.活性剂,和任选地
c.接头,其连接a)至b)。
此外,本公开涉及如上所定义的ADC用于治疗涉及uPARAP受体的表达的疾病和/或病症的用途。
附图说明
图1.包含uPARAP的甘露糖受体家族的四种蛋白质家族成员的示意图。所有蛋白质具有相同的总体结构域组成,其中具有N端信号肽,接着是富含半胱氨酸的结构域,纤连蛋白II型结构域(FN-II结构域),8-10个C型凝集素样结构域(CTLD),跨膜跨越区域和小细胞质尾部(改编自Melander et al.,2015 Int J Oncology 47:1177-1188)。
图2.与马来酰亚胺己酰基-缬氨酸-瓜氨酸-对氨基苯甲酰氧基羰基-单甲基奥瑞他汀E(MC-VC-PAB-MMAE)接头-毒素构建体缀合的靶向抗体形式的uPARAP引导的ADC的示意图。靶向抗体是特异性针对受体uPARAP,发现它在某些癌症类型中高表达。接头-毒素构建体通过马来酰亚胺化学连接至游离半胱氨酸的巯基或还原链间二硫桥(每个抗体N=1-10个毒素)。具有与间隔子实体结合的肽/酰胺键的缬氨酸-瓜氨酸接头区域是溶酶体蛋白酶如组织蛋白酶B的底物,但在细胞外环境中足够稳定以确保仅当被表达该靶抗原的细胞摄取时释放该缀合的药物。该缀合的药物是单甲基奥瑞他汀E(MMAE)形式的高效微管蛋白抑制剂。作为一个单元(mAb-vc-MMAE),这种ADC构建体确保了药物组分仅向表达uPARAP抗原的细胞特异性递送以及该缀合的药物在这些细胞中的细胞内释放。
图3:使用与图2的图例中描述的缀合操作步骤相似的方法(部分还原后与马来酰亚胺衍生的AlexaFluor 647试剂反应),通过流式细胞术测量在uPARAP阳性细胞系中标记有荧光团(AlexaFluor 647,AF647)的mAb 2h9的细胞摄取。MFI:平均荧光强度。特异性比:2h9-AF647/aTNP-AF647信号的比率,其中aTNP是非靶向对照mAb。这些数字证明了2h9-AF647的特异性摄取,并且证实了按照这种缀合方法mAb 2h9被uPARAP阳性细胞摄取。
图4:A.靶向抗体(2h9)、具有~4-5的中等药物与抗体之比(DAR)的mAb-vc-MMAEADC和具有~8-10的DAR的mAb-vc-MMAE ADC的还原SDS-PAGE。可以看出,缀合的mAb在凝胶中显示出降低的迁移率,并且中等缀合的ADC物质优选经由mAb重链缀合,而具有较高DAR的ADC经由重链和轻链两者缀合。B.还原SDS-PAGE显示ADC与活化的重组组织蛋白酶B(+rh组织蛋白酶B)的孵育使ADC凝胶迁移率回复到未修饰的靶向抗体的凝胶迁移率,并且因此接头区确实可被溶酶体蛋白酶如组织蛋白酶B切割。C.ELISA分析显示在缀合过程的还原步骤之后保留的mAb 2h9以及以ADC形式的mAb 2h9针对uPARAP的亲和力。总之,这些数据显示缀合后ADC 2h9-vc-MMAE表现出与凝胶迁移率和对靶受体的亲和力相关的预期行为。
图5:基于暴露于系列稀释中的ADC的体外细胞生存力测定。系列稀释开始于10μg/mL ADC(mAb组分),接着4倍系列稀释的ADC。将细胞培养72小时,然后通过比色生存力测定进行分析。此处,与非靶向ADC(aTNP-vc-MMAE)相比,在表达靶受体的四种细胞系(U937、THP-1、HT1080和KNS42细胞)中,与uPARAP引导的ADC 2h9-vc-MMAE孵育后,该测定显示总体生存力的特异性降低,而受体阴性细胞系(CHO-K1)则不受影响。这证明了在与ADC 2h9-vc-MMAE孵育后,uPARAP阳性细胞系的生存力的受体特异性降低。
图6:在1μg/mL的uPARAP引导的ADC 2h9-vc-MMAE或对照ADC aTNP-vc-MMAE或50nM游离MMAE毒素的存在下孵育3天后四种uPARAP阳性细胞系(U937、THP-1、HT1080或KNS42)的细胞周期分布分析。由于MMAE是微管蛋白抑制剂,药物作用可能导致Sub-G1期(最终导致凋亡)或G2-M期(DNA复制后抑制基因组分离)的细胞部分(fraction)增加。由于大量细胞死亡和崩解,破折号表示细胞数量太低而无法记录。可以看出,所有四种细胞系都显示出针对uPARAP引导的ADC 2h9-vc-MMAE(和游离MMAE)的特异性敏感性,这从这些样品中的细胞周期分布朝着Sub-G1期和G2/M期的转变可以得到证实。
图7:竞争性测定显示在存在1μg/mL的uPARAP引导的ADC 2h9-vc-MMAE同时存在不同浓度的未缀合靶向抗体(2h9)、另一靶向uPARAP的抗体(5f4)或非靶向对照抗体(aTNP)的情况下,孵育U937细胞3天。可以看出,只有非偶联靶向抗体2h9的摩尔过剩(1+μg/mL竞争mAb)能够竞争ADC的作用,从而挽救细胞免于ADC介导的细胞死亡。因此,显示uPARAP与靶向抗体2h9之间的相互作用对观察到的细胞毒性效应是至关重要的。
图8:结果表明,在溶酶体蛋白酶(E64D)的广谱抑制剂存在下预孵育U937细胞导致uPARAP引导的ADC 2h9-vc-MMAE的细胞毒性作用完全消除。因此,显示该缀合的药物的溶酶体释放对于获得细胞毒性效应是至关重要的。
图9:体内测试uPARAP引导的ADC 2h9-vc-MMAE在对抗CB17 SCID小鼠中通过注射细胞系U937建立的uPARAP阳性的皮下异种移植肿瘤中的功效。通过用uPARAP引导的ADC2h9-vc-MMAE(N=10)、对照ADC aTNP-vc-MMAE(N=9)、未缀合的mAb 2h9(N=5)或盐水溶液(PBS,N=5)在肿瘤附近皮下(s.c.)注射,对小鼠进行治疗。所有治疗均以3mg/kg/注射mAb组分的剂量完成,总共4剂,每4天给药一次。第0天标记为第一次注射的日子,一旦肿瘤达到50-100mm3的可触及大小则开始,图显示每个治疗组的平均肿瘤大小。可以看出,用ADC2h9-vc-MMAE治疗导致肿瘤生长急剧下降,而所有其他治疗组在开始治疗后10-12天内达到了处死点。这证明了uPARAP引导的ADC 2h9-vc-MMAE有效抑制体内预先建立的uPARAP阳性肿瘤的生长。此外,2h9-vc-MMAE治疗组的数据代表了50%的永久治愈率(另见图10)。
图10:对图9中描述的2h9-vc-MMAE处理组的肿瘤生长的更详细的研究显示,该组包括患有未完全治疗和肿瘤复发的小鼠,以及完全丧失肿瘤负荷并显示出没有肿瘤复发的小鼠。在10只用2h9-vc-MMAE治疗的小鼠中,5只显示出治疗后肿瘤生长几乎立即复发,迅速达到处死点,而剩下的5只失去了肿瘤的所有病征,并且在90天内保持无肿瘤生长,给出了2h9-vc-MMAE治疗的小鼠在s.c.施用后总体永久治愈率为50%。
图11:体内测试uPARAP引导的ADC 2h9-vc-MMAE在对抗CB17 SCID小鼠中通过注射细胞系U937建立的uPARAP阳性的皮下异种移植肿瘤中的功效。通过用uPARAP引导的ADC2h9-vc-MMAE(N=10)、对照ADC aTNP-vc-MMAE(N=10)、未缀合的mAb 2h9(N=5)或盐水溶液(PBS,N=5)经尾静脉静脉内(i.v.)注射,对小鼠进行治疗。所有治疗均以5mg/kg/注射mAb组分的剂量完成,总共3剂,每4天给药一次。第0天标记为第一次注射的日子,一旦肿瘤达到50-100mm3的可触及的大小,且图显示每个治疗组的平均肿瘤大小。在这些条件下,用uPARAP引导的ADC 2h9-vc-MMAE治疗导致全部10只小鼠中的肿瘤负荷完全消除,静脉内施用该ADC后给出了小鼠100%的总体永久治愈率,进一步证明了ADC2h9-vc-MMAE在对抗uPARAP阳性瘤中的功效。
图12:与非靶向ADC(aTNP-vc-MMAE)相比,在U937细胞系中,在用uPARAP引导的ADC2h9-vc-MMAE或uPARAP引导的ADC 5f4-vc-MMAE孵育后,体外细胞生存力测定显示整体生存力的特异性降低。数据表明,基于5f4的ADC具有与基于2h9抗体的ADC相媲美的功效。
图13:不同肉瘤(脂肪肉瘤、粘液纤维肉瘤、隆凸性皮肤纤维肉瘤(DFSP)和平滑肌肉瘤(LMS))的免疫组化染色。染色方法显示uPARAP的组织表达为深红棕色。uPARAP的表达在恶性癌(肿瘤)组织的切片中是明显的,而非癌组织的切片不含uPARAP,表明在肉瘤中发现uPARAP的表达水平增加。比例尺:20μm。
图14:针对uPARAP的N端部分的不同抗体可用于ADC形式的有效药物递送。使用针对uPARAP的三个N端结构域内的表位的三种不同抗体(mAb 2h9、mAb 5f4和mAb 9b7),如图2的说明中所述制备组成为mAb-vc-MMAE的ADC。为了比较,以相同的方式制备ADC,但使用针对N端三个结构域外的表位的抗uPARAP抗体(mAb 11c9)。然后使用所有这些ADC,如图5的图例中所述,用U937细胞进行体外细胞生存力测定。所有ADC导致总体细胞生存力特异性下降,但其中对2h9-vc-MMAE、5f4-vc-MMAE和9b7-vc-MMAE的细胞敏感性高于11c9-vc-MMAE的敏感性。
图15:不同的毒素能够以靶向uPARAP的N端部分的ADC形式进行使用。如图2的图例中所述制备具有作为抗体组分的mAb 2h9的ADC,但使用以下接头-细胞毒素单元代替VC-PAB-MMAE:VC-PAB-MMAF(其中MMAF为单甲基奥瑞他汀F,MMAE的羧基变体)和PEG4-va-PBD(其中PEG4是指聚乙二醇间隔子,va是缬氨酸-丙氨酸,PBD是指二聚吡咯并苯并二氮)。所得ADC(分别称为2h9-vc-MMAF和2h9-va-PBD)用于U937细胞的体外细胞生存力测定,如图5的图例中所述进行。U937细胞对2h9-vc-MMAF表现出非常强的敏感性,对2h9-va-PBD表现出更适度的敏感性。
图16:如图2的图例中所述制备具有作为抗体组分的mAb 2h9的ADC,但使用下列接头-细胞毒素单元代替VC-PAB-MMAE:PEG4-vc-多卡霉素SA(其中PEG4指聚乙二醇间隔子并且vc是缬氨酸-瓜氨酸)。所得ADC(称为2h9-vc-DuocSA)用于U937细胞的体外细胞生存力测定,如图5的图例中所述进行。U937细胞表现出对2h9-vc-DuocSA低但可测量的敏感性。
图17:使用以下接头-细胞毒素单元:VC-PAB-MMAE或VC-PAB-MMAF,如图2的图例中所述制备具有作为抗体组分的mAb 2h9或aTNP的ADC。使用人胶质母细胞瘤外植体细胞,如图5的图例中所述,使用所得ADC(称为2h9-vc-MMAE、2h9-vc-MMAF、aTNP-vc-MMAE和aTNP-vc-MMAF)进行体外细胞生存力测定。基于MMAE和MMAF毒素二者,这些胶质母细胞瘤外植体细胞显示出对uPARAP引导的ADC的高度特异性敏感性。
图18:在用包含编码mAb 2h9的轻链和重链的DNA序列(分别为[SEQ ID NO:1]和[SEQ ID NO:5])的表达载体转染的CHO细胞中,产生称为“克隆2h9”的重组mAb 2h9产物。在蛋白质印迹中分析该产物的反应性,并与杂交瘤细胞培养物产生的mAb 2h9(“原始2h9”)进行比较。对于蛋白质印迹,使用相同浓度的“克隆2h9”和“原始2h9”作为一抗,分析由uPARAP阳性MG63人骨肉瘤细胞制备的去污剂细胞裂解物。两种抗体产物显示相同的反应并且都与uPARAP蛋白特异性反应。在没有一抗的情况下没有反应(阴性对照)。
序列
使用由Dunbar和Deane(2016)发表的计算机化的Kabat编号程序,根据如参考文献Kabat等人(1983)、Kabat等人(1991)以及Wu和Kabat(2008)指出的Kabat等人的定义方案,预测互补决定区(CDR)。根据Paratome算法的抗原结合区域(ABR)也如参考文献Kunik等人(2012a和b)所指出的进行预测。ABR代表本文所公开的抗体的替代性CDR。
涉及抗原识别和结合的完整区域可能略微偏离特定的CDR和ABR,并且包含在此处指出的可变区或Fab片段中的所有序列数据作为可能有助于抗原结合而被涵盖。与这里使用的方法或算法不同的方法或算法可以用于鉴定潜在的结合/识别区域。因此,除了如本文所呈现的预测的CDR,本发明涵盖使用这样的方法或算法基于各自Fab区和可变区被预测为代表mAb 2h9、5f4和9b7的CDR或ABR的任意氨基酸序列(分别为SEQ ID NO:9、10、11、15、20和25)。用于预测CDR的另外的方法和算法的实例包括但不限于IMGT系统(LeFranc et al.,(2003))。
由于Fab 9B7轻链和重链测序期间引物区的位置,预计这些序列的N端区存在一些模糊性。因此,SEQ ID NO:19的前7个氨基酸可能不确切。SEQ ID NO:24的氨基酸1-8同样如此。SEQ ID NO:20和25分别对应于SEQ ID NO:19和24而不含有模糊的N端氨基酸。
详述
本公开内容的靶向uPARAP的抗体-药物缀合物包含
a)抗体,其能够结合uPARAP的富含半胱氨酸的结构域(CysR)、II型纤连蛋白(FN-II)结构域和/或C型凝集素样结构域1(CTLD1),
b)活性剂,和
c)任选地接头,其连接a)至b)。
在具体方面,本公开内容的靶向uPARAP的抗体-药物缀合物包含
a.抗体或其抗原结合片段,其能够结合:
i.SEQ ID NO:36或37的氨基酸序列(uPARAP的CysR-FN-II-CTLD-1结构域),
ii.SEQ ID NO:38或39的氨基酸序列(uPARAP的CysR-FN-II结构域),
iii.SEQ ID NO:40或41的氨基酸序列(uPARAP的FN-II-CTLD-1结构域),
iv.SEQ ID NO:30或31的氨基酸序列(uPARAP的富含半胱氨酸结构域(CysR)),
v.SEQ ID NO:32或33的氨基酸序列(uPARAP的II型纤连蛋白(FN-II)结构域),和/或
vi.SEQ ID NO:34或35的氨基酸序列(uPARAP的C型凝集素样结构域1(CTLD 1)),
b.活性剂,和任选地
c.接头,其连接a)至b)。
针对uPARAP的抗体
本公开的抗uPARAP抗体在与细胞表面的uPARAP结合后内化,从而允许ADC复合物的活性剂的细胞内作用。从例如WO 2010/111198已知,不是所有的能够结合的uPARAP抗体以相同的速率或以相同的量被内化。实际上,一些抗uPARAP抗体根本不被内化并因此不适用于ADC。
uPARAP受体由N端富含半胱氨酸的结构域(CysR)、II型纤连蛋白(FN-II)结构域和八个C型凝集素样结构域(CTLD 1-8)组成,参见图1。短的氨基酸序列连接各结构域。本文呈现的数据表明,靶向uPARAP的三个最N端结构域的抗uPARAP抗体在用于ADC时非常有效。
因此,本公开内容的抗uPARAP抗体优选结合uPARAP的N端区域,更优选地结合位于uPARAP的三个最N端结构域中的表位,所述结构域是富含半胱氨酸的结构域、II型纤连蛋白结构域和/或C型凝集素样结构域1,包括连接uPARPA的这些结构域的接头序列。
因此,本公开内容的抗uPARAP抗体能够结合包含uPARAP的富含半胱氨酸的结构域(CysR)(SEQ ID NO:30或31)、II型纤连蛋白(FN-II)结构域(SEQ ID NO:32或33)和/或C型凝集素样结构域1(CTLD 1)(SEQ ID NO:34或35)的肽或由其组成的肽。
如由NCBI列出的包括连接这些结构域的接头序列的富含半胱氨酸的结构域、II型纤连蛋白结构域和C型凝集素样结构域1对应于全长人uPARAP的aa 46-361。因此,在一个实施方案中,针对抗uPARAP抗体的表位位于SEQ ID NO:29(全长人uPARAP)的aa 46-361。在一个实施方案中,本公开内容的抗uPARAP抗体结合位于SEQ ID NO:29的aa 31-365中、更优选位于SEQ ID NO:29的aa 46-361(对应于本文的SEQ ID NO:36)的表位。SMART预测包括连接这些结构域的接头序列的CYSR-FN-II-CTLD1为SEQ ID NO:29的aa 41-360。因此,在一个实施方案中,针对抗uPARAP抗体的表位位于SEQ ID NO:29的aa 41-360,对应于本文的SEQ IDNO:37。
在一个实施方案中,本公开内容的抗uPARAP抗体结合CysR结构域和/或CTLD-1结构域。
在一个实施方案中,本公开内容的抗uPARAP抗体结合CysR结构域,其被NCBI预测为由全长人uPARAP的aa 46-161组成,对应于本文的SEQ ID NO:30,并且被SMART预测为由全长人uPARAP的aa 41-161组成,对应于本文的SEQ ID NO:31。即在一个实施方案中,它结合位于SEQ ID NO:29的aa 46-161或41-161的表位。
在一个实施方案中,本公开内容的抗uPARAP抗体结合FN-II结构域,其被NCBI预测为由全长人uPARAP的aa 181-228组成,对应于本文的SEQ ID NO:32,并且被SMART预测为由全长人uPARAP的aa 180-228组成,对应于本文的SEQ ID NO:33。即在一个实施方案中,它结合位于SEQ ID NO:29的aa 181-228或180-228的表位。
在一个实施方案中,本公开内容的抗uPARAP抗体结合CTLD-1结构域,其被NCBI预测为由全长人uPARAP的aa 247-361组成,对应于本文的SEQ ID NO:34,并且被SMART预测为由全长人uPARAP的aa 235-360组成,对应于本文的SEQ ID NO:35。即在一个实施方案中,它结合位于SEQ ID NO:29的aa 247-361或235-360的表位。
在一个实施方案中,本公开内容的抗uPARAP抗体能够结合包含包括连接这些结构域的接头序列的CvsR和FN-II结构域的肽或由其组成的肽,其被NCBI预测为由全长人uPARAP的aa 46-228组成,对应于SEQ ID NO:38,并且被SMART预测为由全长人uPARAP的aa41-228组成,对应于本文的SEQ ID NO:39。即在一个实施方案中,它结合位于SEQ ID NO:29的aa 46-228或41-228的表位。
在一个实施方案中,本公开内容的抗uPARAP抗体能够结合包含包括连接这些结构域的接头序列的FN-II和CTLD-1结构域的肽或由其组成的肽,其被NCBI预测为由全长人uPARAP的aa 181-361组成,对应于SEQ ID NO:40,并且被SMART预测为由全长人uPARAP的aa180-360组成,对应于本文的SEQ ID NO:41。即在一个实施方案中,它结合位于SEQ ID NO:29的aa 180-361或181-360的表位。
在一个实施方案中,本公开内容的抗uPARAP抗体是小鼠单克隆IgG1κ抗体的克隆2.h.9:F12,可从Merck Millipore市售获得(http://www.merckmillipore.com/DK/en/product/Anti-UPAR-Associated-Protein-Antibody%2C-clone-2.h.9%3AF12,MM_NF-MAB2613?cid=BI-XX-BRC-P-GOOG-ANTI-B302-1075)或其功能片段或变体,例如其嵌合或人源化形式。小鼠单克隆IgG1κ抗体克隆2.h.9:F12在本文中被称为“2h9”抗体或“mAb2h9”。2h9抗体与人和小鼠uPARAP均反应,因此非常适合临床前和临床研究。
先前的研究表明2h9抗体的表位位于uPARAP的三个最N端结构域中,特别是在CysR结构域或CTLD-1结构域中。由uPARAP的三个n端结构域(CysR、FN-II和CTLD-1)组成的可溶性重组蛋白在BIAcore设置中与固定的2h9结合,限制mAb 2h9与这三个n端结构域的结合位置(Jürgensen et al.,2011,JBC 286(37):32736-48)。此外,将uPARAP的FN-II结构域与相同受体家族的其他成员的FN-II结构域交换对mAb 2h9的结合没有影响,这表明FN-II结构域不太可能含有针对mAb 2h9的表位(Jürgensen et al.,2014,JBC 289(11):7935-47)。这有效限制了mAb 2h9与CysR结构域或CTLD-1结构域的结合。
预测的mAb 2h9的免疫球蛋白轻链可变区的CDR对应于SEQ ID NO:2-4,预测的mAb2h9的免疫球蛋白重链可变区的CDR对应于SEQ ID NO:6-8。
在一个实施方案中,本公开内容的抗uPARAP抗体是对应于2h9抗体或其功能片段或变体的抗体,其选自:
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:1或9的氨基酸序列或与SEQ ID NO:1或9的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:5或10的氨基酸序列或与SEQ IDNO:5或10的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:2、3、4、6、7和8的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:2、3和4的氨基酸序列,和/或SEQ ID NO:6、7和8的氨基酸序列,
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:42、43、44、45、46和47的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:42、43和44的氨基酸序列,和/或SEQ ID NO:45、46和47的氨基酸序列。
为了保持本文公开的抗体的抗原识别,序列变异通常不在CDR或ABR中。因此,在优选的实施方案中,任何序列变异位于CDR或ABR之外。本文公开的所有变异的抗体和抗原结合片段保留结合uPARAP的能力。
例如,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:1或9的氨基酸序列或与SEQ ID NO:1或9的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:2的aa序列,
ii.CDR2,其具有SEQ ID NO:3的aa序列,
iii.CDR3,其具有SEQ ID NO:4的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:5或10的氨基酸序列或与SEQ IDNO:5或10的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:6的aa序列,
ii.CDR2,其具有SEQ ID NO:7的aa序列,
iii.CDR3,其具有SEQ ID NO:8的aa序列,
其中任何序列变异均在CDR之外。
或者,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:1或9的氨基酸序列或与SEQ ID NO:1或9的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:42的aa序列,
ii.ABR2,其具有SEQ ID NO:43的aa序列,
iii.ABR3,其具有SEQ ID NO:44的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:5或10的氨基酸序列或与SEQ IDNO:5或10的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:45的aa序列,
ii.ABR2,其具有SEQ ID NO:46的aa序列,
iii.ABR3,其具有SEQ ID NO:47的aa序列,
其中任何序列变异均在ABR之外。
在一个实施方案中,本公开内容的抗uPARAP抗体是小鼠单克隆抗体5f4或其功能片段或变体。5f4抗体是IgG1κ。
研究表明,5f4的表位位于uPARAP的FN-II结构域中。在Jürgensen et al.,2014中显示,5f4抗体能够结合野生型uPARAP和甘露糖受体家族的人工成员,在所述成员中野生型FN-II结构域已经用uPARAP的FN-II结构域交换。5f4不能结合野生型形式的甘露糖受体家族蛋白的其他成员,或与uPARAP结合,其中野生型FN-II结构域已经用来自甘露糖受体家族的其他成员的等价结构域交换(Jürgensen et al.,2014,JBC 289(11):7935-47)。
在一个实施方案中,本公开内容的抗uPARAP抗体是对应于5f4抗体或其功能片段或变体的抗体,其选自
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:11的氨基酸序列或与SEQ ID NO:11的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:15的氨基酸序列或与SEQ ID NO:15的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:12、13、14、16、17和18的氨基酸序列中的一种或多种,或
ii.SEQ ID NO:12、13和14的氨基酸序列,和/或SEQ ID NO:16、17和18的氨基酸序列,
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:48、49、50、51、52和53的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:48、49和50的氨基酸序列,和/或SEQ ID NO:51、52和53的氨基酸序列。
为了允许CDR之外的一些序列变异,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:11的氨基酸序列或与SEQ ID NO:11的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:12的aa序列,
ii.CDR2,其具有SEQ ID NO:13的aa序列,
iii.CDR3,其具有SEQ ID NO:14的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:15的氨基酸序列或与SEQ ID NO:15的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:16的aa序列,
ii.CDR2,其具有SEQ ID NO:17的aa序列,
iii.CDR3,其具有SEQ ID NO:18的aa序列,
其中任何序列变异均在CDR之外。
或者,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:11的氨基酸序列或与SEQ ID NO:11的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:48的aa序列,
ii.ABR2,其具有SEQ ID NO:49的aa序列,
iii.ABR3,其具有SEQ ID NO:49的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:15的氨基酸序列或与SEQ ID NO:15的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:51的aa序列,
ii.ABR2,其具有SEQ ID NO:52的aa序列,
iii.ABR3,其具有SEQ ID NO:53的aa序列,
其中任何序列变异均在ABR之外。
在一个实施方案中,本公开内容的抗uPARAP抗体是小鼠单克隆抗体9b7(mAb 9b7)或其功能片段或变体。先前的研究表明,9b7抗体的表位位于uPARAP的三个最N端结构域中。当将由uPARAP的三个N端结构域(CysR、FN-II和CTLD-1)组成的可溶性重组蛋白固定在BIAcore设置中时,mAb 9b7与该构建体结合。
在一个实施方案中,抗uPARAP抗体选自
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:19或20的氨基酸序列或与SEQ IDNO:19或20的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:24或25的氨基酸序列或与SEQ IDNO:24或25的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,或由其组成,
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:21、22、23、26、27和28的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:21、22和23的氨基酸序列,和/或SEQ ID NO:26、27和28的氨基酸序列,
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:54、55、56、57、58和59的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:54、55和56的氨基酸序列,和/或SEQ ID NO:57、58和59的氨基酸序列。
在一个实施方案中,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:19或20的氨基酸序列或与SEQ IDNO:19或20的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:21的aa序列,
ii.CDR2,其具有SEQ ID NO:22的aa序列,
iii.CDR3,其具有SEQ ID NO:23的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:24或25的氨基酸序列或与SEQ IDNO:24或25的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.CDR1,其具有SEQ ID NO:26的aa序列,
ii.CDR2,其具有SEQ ID NO:27的aa序列,
iii.CDR3,其具有SEQ ID NO:28的aa序列,
其中任何序列变异均在CDR之外。
或者,本公开内容的抗体可以包含
a.免疫球蛋白轻链可变区,其包含SEQ ID NO:19或20的氨基酸序列或与SEQ IDNO:19或20的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:54的aa序列,
ii.ABR2,其具有SEQ ID NO:55的aa序列,
iii.ABR3,其具有SEQ ID NO:56的aa序列,和
b.免疫球蛋白重链可变区,其包含SEQ ID NO:24或25的氨基酸序列或与SEQ IDNO:24或25的氨基酸序列具有至少70%序列同一性、例如至少80%序列同一性、例如至少90%序列同一性的序列,并进一步包含
i.ABR1,其具有SEQ ID NO:57的aa序列,
ii.ABR2,其具有SEQ ID NO:58的aa序列,
iii.ABR3,其具有SEQ ID NO:59的aa序列,
其中任何序列变异均在ABR之外。
“抗体”包括基本上完整的抗体分子、嵌合抗体、人源化抗体、人抗体、单链抗体、双特异性抗体、抗体重链、抗体轻链,抗体重链和/或轻链的同二聚体和异二聚体及其抗原结合片段和衍生物。
“抗原结合片段”是指能够结合uPARAP的抗体的功能片段。
在一个实施方案中,根据本公开内容的抗uPARAP抗体选自小鼠抗体、嵌合抗体、人抗体、人源化抗体、人源化抗原结合片段、Fab片段、Fab′片段、F(ab’)2片段、Fv片段、单链抗体(SCA)如scFv、其重链和/或轻链的可变部分或Fab微型抗体,其中这些片段或修饰的抗体可以衍生自小鼠、嵌合、人或人源化抗体。
在一个实施方案中,抗uPARAP抗体是人源化或全人单克隆抗体或其抗原结合片段。
在一个实施方案中,本公开内容的抗uPARAP抗体是重组抗体。
本公开内容的抗uPARAP抗体可以具有任何免疫球蛋白类别,包括IgG、IgM、IgD、IgE、IgA及其任意亚类。IgG亚类也是本领域众所周知的并且包括但不限于人IgG1、IgG2、IgG3和IgG4。在一个实施方案中,抗体是IgG单克隆抗体。在一个实施方案中,抗体是IgG1κ。
在一个实施方案中,抗uPARAP抗体是抗原结合片段。
使用抗体片段而不是完整抗体的优点是数倍。较小尺寸的片段可以导致改善的药理学性质,例如更好的组织穿透性。而且,抗原结合片段可以在大肠杆菌或其他非哺乳动物宿主细胞中表达和分泌,因此可以容易地产生大量的所述片段。
Fab是含有抗体分子的单价抗原结合片段的片段,其能够通过用木瓜蛋白酶消化完整抗体或其他特定的蛋白水解方法产生轻链和部分重链来产生。
F(ab′)2是可以通过用胃蛋白酶或其他特异性蛋白水解手段处理完整抗体以获得二价抗原结合片段而无需随后还原而获得的抗体片段;F(ab′)2是由两个二硫键结合在一起的两个Fab片段的二聚体。
Fv是遗传工程化的片段,其含有轻链的可变区和重链的可变区,表达为两条链。
单链抗体(SCA)是含有轻链可变区和重链可变区的遗传工程分子,通过合适的多肽接头连接为遗传融合的单链分子(包括scFv)。
产生抗体和抗体片段的方法是本领域众所周知的。例如,可以通过几种方法中的任何一种来产生抗体,这些方法采用诱导体内产生抗体分子,筛选免疫球蛋白文库或通过培养中的细胞系产生单克隆抗体分子。这些包括但不限于杂交瘤技术、人B细胞杂交瘤技术和EB病毒(EBV)杂交瘤技术。
同样地,可以使用本领域众所周知的方法获得抗体片段。例如,根据本发明的抗体片段可通过用各种酶对抗体进行蛋白水解或通过在编码该片段的DNA的大肠杆菌或哺乳动物细胞(例如中国仓鼠卵巢细胞培养物或其他蛋白质表达系统)中表达来制备。或者,可以通过常规方法通过胃蛋白酶或木瓜蛋白酶消化完整抗体来获得抗体片段。
本领域技术人员将会理解,对于人的治疗或诊断,优选使用人或人源化抗体。非人(例如鼠)抗体的人源化形式是遗传工程嵌合抗体或抗体片段,其优选具有衍生自非人抗体的最小部分。人源化抗体包括其中人抗体(受体抗体)的互补决定区(CDR)被来自非人物种(供体抗体)(例如具有所需功能性的小鼠、兔或大鼠)的互补决定区的残基所替换。在一些情况下,人抗体的Fv框架残基被相应的非人残基所替换。人源化抗体还可包含在受体抗体中或引入的CDR或框架序列中均未发现的残基。一般而言,人源化抗体将包含以下基本上所有:至少一种(和典型地两种)可变结构域,其中所有或基本上所有的互补决定区对应于非人抗体的互补决定区并且所有(或基本上所有)的框架区对应于相关人共有序列的框架区。人源化抗体最佳地还包括通常来源于人抗体的抗体恒定区的至少一部分,例如Fc区。
人源化非人抗体的方法是本领域众所周知的。一般地,人源化抗体具有从非人源引入的一个或多个氨基酸残基。这些非人氨基酸残基(通常称为引入残基)通常取自引入的可变区。基本上可以如通过用相应的非人CDR取代人CDR所描述的那样进行人源化。因此,这样的人源化抗体是嵌合抗体,其中基本上少于完整的人可变区已经被来自非人物种的相应序列取代。在实践中,人源化抗体通常可以是人抗体,其中一些CDR残基和可能的一些框架残基被非人抗体中类似位点的残基取代。
还可以使用本领域已知的各种技术来鉴定人抗体,包括噬菌体展示文库。
一旦获得合适的抗体,就可以测试它们的抗原特异性,例如通过ELISA。
活性剂
本公开内容的抗uPARAP ADC包含活性剂即药物,其能够被细胞内递送至在其表面上表达uPARAP的细胞。活性剂可以例如是治疗剂、细胞毒性剂、放射性同位素或可检测标记。在优选的实施方案中,活性剂是治疗剂。
在一个实施方案中,活性剂是化疗剂。化疗剂的类别包括烷化剂、蒽环类抗生素、抗代谢物、抗微管/抗有丝分裂剂、组蛋白脱乙酰酶抑制剂、激酶抑制剂、肽抗生素、基于铂的抗肿瘤药、拓扑异构酶抑制剂和细胞毒性抗生素。
在优选的实施方案中,活性剂是细胞毒性剂,其允许有效杀死表达uPARAP的细胞。
在一个实施方案中,活性剂是抗有丝分裂剂,例如单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、紫杉烷(例如紫杉醇或多西他赛)、长春花生物碱(vinca alkaloid)(例如长春花碱(vinblastine)、长春新碱、长春地辛或长春瑞滨)、秋水仙碱或鬼臼毒素。
在一个实施方案中,细胞毒性剂是单甲基奥瑞他汀E(MMAE)。由于其高毒性,通过阻断微管蛋白聚合抑制细胞分裂的MMAE不能用作单药性化疗药物。然而,连接到抗CD30单克隆抗体(Brentuximab Vedotin,商品名AdcetrisTM)的MMAE的组合已被证明在细胞外液中稳定,可被组织蛋白酶切割并且安全用于治疗。
在一个实施方案中,细胞毒性剂是单甲基奥瑞他汀F(MMAF)。MMAF是抗微管/抗有丝分裂剂并且是MMAE的羧基变体。
在一个实施方案中,细胞毒性剂是DNA交联剂,如吡咯并苯并二氮杂或二聚的吡咯并苯并二氮杂衍生物。
在一个实施方案中,细胞毒性剂是DNA烷化剂,例如多卡霉素SA。
另外的烷化剂的例子包括噻替派(thiotepa)和环磷酰胺;烷基磺酸酯例如白消安,英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮杂环丙烷例如苯佐替哌(benzodopa),卡波醌,美妥替派(meturedopa)和乌瑞替派(uredopa);乙烯亚胺和甲基蜜胺(methylamelamine),包括六甲蜜胺(altretamine),三乙撑蜜胺(triethylenemelamine),三乙撑磷酰胺(trietylenephosphoramide),三乙撑硫代磷酰胺(triethiylenethiophosphoramide)和三羟甲基蜜胺(trimethylolomelamine);多聚乙酰(acetogenin)(特别是布拉它辛(bullatacin)和布拉他辛酮(bullatacinone));δ-9-四氢大麻酚(屈大麻酚(dronabinol),);β-拉帕醌(beta-lapachone);拉帕醇(lapachol);秋水仙碱(colchicines);桦木酸(betulinic acid);喜树碱(camptothecin)(包括合成类似物拓扑替康(topotecan),CPT-I l(伊立替康(irinotecan),乙酰喜树碱(acetylcamptothecin),东莨菪素(scopolectin)和9-氨基喜树碱(9-aminocamptothecin));苔藓虫素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin),卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);鬼臼毒素(podophyllotoxin);鬼臼酸(podophyllinic acid);替尼泊苷(teniposide);念珠藻素(cryptophycins)(特别是念珠藻素1和念珠藻素8);尾海兔素(dolastatin);多卡霉素(duocarmycin)(包括合成类似物KW-2189和CBl-TMl);五加素(eleutherobin);水鬼蕉碱(pancratistatin);sarcodictyin;海绵素(spongistatin);氮芥(nitrogen mustards)例如苯丁酸氮芥(chlorambucil),萘氮芥(chlornaphazine),环磷酰胺(cholophosphamide),雌莫司汀(estramustine),异环磷酰胺(ifosfamide),甲二氯二乙胺(mechlorethamine),盐酸甲氧氮芥(mechlorethamine oxide hydrochloride),美法仑(melphalan),新恩比兴(novembichin),phenesterine,泼尼氮芥(prednimustine),氯乙环磷酰胺(trofosfamide),乌拉莫司汀(uracil mustard);硝基脲(nitrosureas)例如卡莫司汀(carmustine),氯脲霉素(chlorozotocin),福莫司汀(fotemustine),洛莫司汀(lomustine),尼莫司汀(nimustine)和ranimnustine;抗生素例如烯二炔类抗生素(enediyne antibiotics)(例如卡里奇霉素(calicheamicin),特别是卡里奇霉素γll(calicheamicin gamma ll)和卡里奇霉素Ωll(calicheamicin omega ll);dynemicin,包括dynemicin A;埃斯波霉素(esperamicin);以及新制癌菌素发色团(neocarzinostatinchromophore)和相关发色蛋白烯二炔抗生素发色团(related chromoprotein enediyneantiobiotic chromophores)),阿克拉霉素(aclacinomycins),放线菌素(actinomycin),authramycin,偶氮丝氨酸(azaserine),博来霉素(bleomycins),cactinomycin,carabicin,洋红霉素(carminomycin),嗜癌菌素(carzinophilin),chromomycinis,更生霉素(dactinomycin),道诺霉素(daunorubicin),地托比星(detorubicin),6-重氮-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine),多柔比星(包括吗啉代多柔比星(morpholino-doxorubicin),氰基吗啉代多柔比星(cyanomorpholino-doxorubicin),2-吡咯啉多柔比星(2-pyrrolino-doxorubicin),盐酸多柔比星脂质体注射液和脱氧多柔比星(deoxy doxorubicin)),表柔比星(epirubicin),依索比星(esorubicin),伊达比星(idarubicin),麻西罗霉素(marcellomycin),丝裂霉素(mitomycins)例如丝裂霉素C,霉酚酸(mycophenolic acid),诺加霉素(nogalamycin),橄榄霉素(olivomycins),培洛霉素(peplomycin),potfiromycin,嘌呤霉素(puromycin),三铁阿霉素(quelamycin),罗多比星(rodorubicin),链黑菌素(streptonigrin),链脲佐菌素(streptozocin),结核菌素(tubercidin),乌苯美司(ubenimex),净司他丁(zinostatin),佐柔比星(zorubicin);抗代谢物例如氨甲喋呤,吉西他滨替加氟(tegafur,),卡培他滨埃坡霉素(epothilone)和5-氟尿嘧啶(5-FU);叶酸类似物例如二甲叶酸(denopterin),氨甲蝶呤(methotrexate),蝶罗呤(pteropterin),三甲曲沙(trimetrexate);嘌呤类似物例如氟达拉滨(fludarabine),6-巯基嘌呤(6-mercaptopurine),硫咪嘌呤(thiamiprine),硫鸟嘌呤(thioguanine);嘧啶类似物如安西他滨(ancitabine),阿扎胞苷(azacitidine),6-氮尿苷(6-azauridine),卡莫氟(carmofur),阿糖胞苷(cytarabine),二脱氧尿苷(dideoxyuridine),脱氧氟尿苷(doxifluridine),依诺他滨(enocitabine),氟尿苷(floxuridine);雄激素如卡鲁巴酮(calusterone),屈他雄酮丙酸酯(dromostanolone propionate),环硫雄醇(epitiostanol),美雄烷(mepitiostane),睾内脂(testolactone);抗肾上腺素例如氨鲁米特(aminoglutethimide),米托坦(mitotane),曲洛司坦(trilostane);叶酸补充剂例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamideglycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);edatraxate;defofamine;脱羰秋水仙碱(demecolcine);亚丝醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖(lentinan);lonidainine;美登木素生物碱(maytansinoids)例如美登素(maytansine)和安沙霉素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;nitraerine;喷司他丁(pentostatin);苯来美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);2-乙基酰肼(2-ethylhydrazide);甲基苄肼(procarbazine);多糖复合物;雷佐生(razoxane);利索新(rhizoxin);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2′,2″-三氯三乙胺;单端孢菌素(trichothecenes)(特别是T-2毒素,verracurin A,漆斑菌素A(roridin A)和anguidine);氨基甲酸乙酯(urethan);长春地辛达卡巴嗪(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿拉伯糖苷(″Ara-C″);噻替派(thiotepa);紫杉烷类(taxoids),例如紫杉醇紫杉醇的白蛋白工程纳米粒子制剂(ABRAXANE.TM.),和多西他赛苯丁酸氮芥(chloranbucil);6-硫鸟嘌呤(6-thioguanine);巯基嘌呤(mercaptopurine);甲氨喋呤(methotrexate);铂类似物例如顺铂和卡铂;长春花碱铂;依托泊苷(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春花新碱奥沙利铂(oxaliplatin);leucovovin;长春瑞滨能灭瘤(novantrone);依达曲沙(edatrexate);道诺霉素(daunomycin);氨基喋呤(aminopterin);伊班膦酸盐(ibandronate);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类维生素A(retinoid),如维甲酸(retinoic acid);上述任一种的药学上可接受的盐、酸或衍生物;以及上述两种或更多种的组合例如CHOP:环磷酰胺、阿霉素、长春花新碱和泼尼松龙联合治疗的缩写,FOLFOX:奥沙利铂联合5-FU和leucovovin的治疗方案的缩写。
抗激素药的作用是调节、减少、阻断或抑制可促进癌症生长的激素的作用,并且通常作为系统性或全身治疗施用。它们可以是激素本身。实例包括抗雌激素和选择性雌激素受体调节剂(SERM),包括例如他莫昔芬(包括他莫昔芬),雷洛昔芬屈洛昔芬(droloxifene),4-羟基他莫昔芬(4-hydroxytamoxifen),曲沃昔芬(trioxifene),keoxifene,LYl 17018,奥那司酮(onapristone)和托瑞米芬抗孕酮(anti-progesterones);雌激素受体下调剂(ERD);作用为用来抑制或关闭卵巢的药剂例如促黄体激素释放激素(LHRH)激动剂如醋酸亮丙瑞林(leuprolideacetate)(和),醋酸戈舍瑞林(goserelin acetate),醋酸布舍瑞林(buserelin acetate)和三苯羟瑞林(tripterelin);其他抗雄激素如氟他胺(flutamide),尼鲁米特(nilutamide)和比卡鲁胺(bicalutamide);和芳香酶抑制剂,例如4(5)-咪唑,氨鲁米特(aminoglutethimide),醋酸甲地孕酮(megestrol acetate)依西美坦(exemestane)formestanie,fadrozole,vorozole来曲唑和阿那曲唑此外,二膦酸盐如氯膦酸盐(例如或),依替膦酸钠NE-58095,唑来膦酸/唑来膦酸盐阿仑膦酸盐帕米膦酸盐替鲁膦酸盐或利塞膦酸盐以及曲沙他滨(1,3-二氧戊环胞嘧啶核苷类似物);siRNA,核酶和反义寡核苷酸,特别是抑制与异常细胞增殖有关的信号传导通路中基因表达的那些;疫苗例如疫苗和基因治疗疫苗例如疫苗,疫苗和疫苗;拓扑异构酶1抑制剂(例如,rmRH(例如拉帕替尼二甲苯磺酸盐(lapatinib ditosylate)(一种ErbB-2和EGFR双酪氨酸激酶小分子抑制剂也称为GW572016);COX-2抑制剂如塞来昔布4-(5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基)苯磺酰胺;和任何上述药学上可接受的盐、酸或衍生物。
在一个实施方案中,活性剂是核苷酸,例如寡核苷酸,例如siRNA或miRNA。
每个抗体分子可能有一个或多个药物单元。药物分子的每个抗体的数量之间的比率表示为药物与抗体的比率(DAR)。在一个实施方案中,DAR为1至10,即每个抗体分子将存在1至10个药物单元。在一个实施方案中,DAR为2至8,例如3至6,如4或5。
接头
抗体和活性剂之间的稳定连接是ADC技术的一个重要方面。接头可以例如基于包括二硫化物、腙或肽(可裂解的)或硫醚(不可裂解)的化学基序,并且控制细胞毒素剂向靶细胞的分布和递送。在临床前和临床试验中,已证明可切割和不可切割的接头类型是安全的。例如,Brentuximab Vedotin包含一种酶敏感性可切割接头,可将有效且高度毒性的抗微管剂单甲基奥瑞他汀E(MMAE)(一种合成的抗肿瘤药)递送至细胞。
Trastuzumab Emtansine是另一种经过批准的ADC,是由稳定的不可切割接头连接的美登素衍生物微管形成抑制剂mertansine(DM-1)和抗体曲妥珠单抗(HerceptinTM,Genentech/Roche)的组合。
接头的类型,可切割或不可切割,赋予递送药物特定的性质。例如,可切割的接头可以例如被靶细胞中的酶切割,导致活性剂(例如细胞毒性剂)的细胞内有效释放。相反,含有不可切割接头的ADC没有药物释放机制,并且必须依赖诸如靶向抗体降解的机制来释放药物。此外,如本领域技术人员所理解的,接头组成可以影响整个ADC的关键因素,例如溶解度和药代动力学性质。
对于这两种类型的接头,药物释放对于获得细胞效应是至关重要的。能够自由地扩散穿过细胞膜的药物可以从靶细胞中逃逸,并且在称为“旁观者杀死”的过程中,也攻击相邻细胞,例如表达uPARAP的靶细胞附近的癌细胞。
在优选的实施方案中,本文公开的靶向uPARAP的ADC包含连接抗uPARAP抗体和活性剂的接头。接头可以是可切割或不可切割的。在一个实施方案中,接头是可切割接头,其允许活性剂在表达uPARAP的细胞内的细胞内释放。
可切割基团包括二硫键,酰胺键,肽键形式的取代酰胺键,硫代酰胺,键,酯键,硫酯键,邻位二醇键或半缩醛。这些或其他可切割的键可包括酶促可切割的键,例如肽键(被肽酶切割),磷酸键(被磷酸酶切割),核酸键(被内切核酸酶切割)和糖键(被糖苷酶切割)。
接头可以例如是多肽接头,肽接头或核酸接头。
在具体实施方案中,接头是肽接头。肽序列的选择对于缀合物的成功至关重要。在一些实施方案中,接头对血清蛋白酶稳定,但被靶细胞中的溶酶体酶裂解。在非限制性实例中,接头是选自鱼精蛋白、鱼精蛋白片段、(Arg)9、生物素-抗生物素蛋白、生物素-链霉抗生物素蛋白和触角肽(antennapedia peptide)的肽。其他非核苷酸接头包括约5至约100个原子的烷基或芳基链。在一些实施方案中,接头是核苷酸接头。
在一个实施方案中,接头是酶可切割的含肽接头,例如组织蛋白酶可切割的含肽接头。组织蛋白酶可以是几种组织蛋白酶类型之一,是一组溶酶体蛋白酶之一。
在一个实施方案中,接头包含或由以下组成:二肽例如缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA),其可以通过酰胺键进一步连接至其他结构元件。基于缬氨酸-瓜氨酸的接头,其中瓜氨酸羧基功能被修饰为取代的酰胺,可被溶酶体组织蛋白酶切割,而基于缬氨酸-丙氨酸的接头,其中丙氨酸羧基功能被修饰为取代的酰胺,可以被其他溶酶体蛋白酶(包括其他组织蛋白酶)切割。
在一个实施方案中,本公开内容的ADC进一步包含间隔子。间隔子可以例如连接接头与活性剂。在一个实施方案中,间隔子是对氨基苯甲酸(PAB)。
在一个实施方案中,间隔子是或包括聚乙二醇间隔子,诸如PEG4间隔子。
在一个实施方案中,本公开内容的ADC进一步包含附接实体。附接实体可以例如连接抗体和可切割接头,其中附接实体是接头前体中抗体氨基酸侧链和反应性附接基团之间的反应产物。在一个实施方案中,该反应性连接基团包含马来酰亚胺和己酸(MC)或由马来酰亚胺和己酸(MC)组成,其中马来酰亚胺优选在偶联过程中与半胱氨酸硫醇反应。在其他实施方案中,附接基团包含N-羟基琥珀酰亚胺、叠氮化物或炔烃,或由其组成。
在一个实施方案中,本公开内容的ADC包含本文公开的抗uPARAP抗体和接头-药物复合物Vedotin。Vedotin是包含细胞毒性剂MMAE、间隔子(对氨基苯甲酸)、组织蛋白酶可切割接头(缬氨酸-瓜氨酸二肽)和由己酸和马来酰亚胺组成的附接基团的接头-药物复合物。Vedotin是MC-VC-PAB-MMAE。Brentuximab Vedotin(商品名AdcetrisTM)是FDA批准的包含Vedotin的ADC的一个例子。
在一个实施方案中,本公开内容的ADC包含本文公开的抗uPARAP抗体和接头-间隔子-毒素单元VC-PAB-MMAF。
在一个实施方案中,本公开内容的ADC包含本文公开的抗uPARAP抗体和接头-间隔子-毒素单元PEG4-VA-PBD。
在一个实施方案中,本公开内容的ADC包含本文公开的抗uPARAP抗体和接头-间隔子-毒素单元PEG4-VC-多卡霉素SA。
在一个实施方案中,本公开内容的ADC包含US 2006/074008中所述的接头-药物复合物,US 2006/074008通过引用整体并入本文。
接头-药物构建体可以例如通过马来酰亚胺化学至还原的链间或链内二硫桥的巯基而附接至抗uPARAP抗体。
治疗用途
如本文所述的针对uPARAP引导的ADC可用于将活性剂(例如治疗剂或细胞毒性剂)递送至表达uPARAP的细胞,并因此用于治疗一系列以uPARAP表达、特别是uPARAP过表达为特征的疾病和病症。
在一个实施方案中,本公开内容提供药物组合物,其包含有效量的如本文所述的抗uPARAP ADC,以及药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
药物组合物可以以本领域已知的方式制备,所述方式具有足够的储存稳定性并且适合施用于人和/或动物。例如,药物组合物可以被冻干,例如,通过冷冻干燥、喷雾干燥、喷雾冷却或通过使用超临界颗粒形成的颗粒形成。
“药学上可接受的”是指无毒物质,其不会降低抗uPARAP ADC的有效性。此类药学上可接受的缓冲剂、承载体或赋形剂是本领域众所周知的(参见Remington′sPharmaceutical Sciences,18th edition,A.R Gennaro,Ed.,Mack Publishing Company(1990)and handbook of Pharmaceutical Excipients,3rd edition,A.Kibbe,Ed.,Pharmaceutical Press(2000),其公开内容通过引用并入本文)。
术语“缓冲剂”旨在表示含有酸碱混合物的水溶液,目的是稳定pH。药学上可接受的缓冲剂是本领域众所周知的。
术语“稀释剂”旨在表示含水或非含水溶液,目的是稀释药物制剂中的药剂。
术语“佐剂”意指添加到制剂中以增加本发明药剂的生物学效应的任何化合物。佐剂可以是具有不同阴离子的锌盐、铜盐或银盐中的一种或多种,例如但不限于氟化物,氯化物,溴化物,碘化物,硫氰酸盐,亚硫酸盐,氢氧化物,磷酸盐,碳酸盐,乳酸盐,乙醇酸盐,柠檬酸盐,硼酸盐,酒石酸盐和乙酸盐,其具有不同酰基组成。佐剂也可以是阳离子聚合物如阳离子纤维素醚,阳离子纤维素酯,脱乙酰透明质酸,壳聚糖,阳离子树状聚合物,阳离子合成聚合物如聚乙烯咪唑,和阳离子多肽如聚组氨酸,聚赖氨酸,聚精氨酸和含有这些氨基酸的肽。
赋形剂可以是碳水化合物、聚合物、脂质和矿物质中的一种或多种。碳水化合物的例子包括乳糖、葡萄糖、蔗糖、甘露糖醇和环糊精,它们被加入到组合物中,例如用于促进冻干。聚合物的实例是淀粉,纤维素醚,纤维素羧甲基纤维素,羟丙基甲基纤维素,羟乙基纤维素,乙基羟乙基纤维素,藻酸盐,角叉菜胶,透明质酸及其衍生物,聚丙烯酸,聚磺酸盐,聚乙二醇/聚环氧乙烷,聚环氧乙烷/聚环氧丙烷共聚物,不同水解度的聚乙烯醇/聚乙酸乙烯酯和聚乙烯吡咯烷酮,所有均为不同分子量,被添加到组合物中,例如用于粘度控制,用于实现生物粘附或用于保护脂质免受化学和蛋白水解降解。脂质的例子是脂肪酸,磷脂,甘油单酯,甘油二酯和甘油三酯,神经酰胺,鞘脂和糖脂,所有不同的酰基链长度和饱和度,卵磷脂,大豆卵磷脂,氢化蛋和大豆卵磷脂,以与聚合物相似的原因将其添加到组合物。矿物质的实例是滑石,氧化镁,氧化锌和氧化钛,它们被添加到组合物中以获得益处,例如减少液体积聚或有利的颜料性质。
本公开内容的ADC可配制成本领域已知适合于其递送的任何类型的药物组合物。
本公开内容的ADC或包含ADC的药物组合物可以经由本领域技术人员已知的任何合适的途径施用。因此,可能的给药途径包括肠胃外(静脉内,皮下和肌肉内),局部(topical),眼,鼻,肺,口含(buccal),经口(oral),阴道和直肠。此外,从植入物施用也是可能的。
在一个优选的实施方案中,药物组合物胃肠外施用,例如静脉内,脑室内,关节内,动脉内,腹膜内,鞘内,心室内,胸骨内,颅内,肌肉内或皮下施用,或者可以通过输注技术施用。它们可方便地以无菌水溶液的形式使用,其可含有其它物质,例如足够的盐或葡萄糖以使溶液与血液等渗。如果需要,水溶液应适当缓冲。在无菌条件下制备合适的胃肠外制剂容易通过本领域技术人员众所周知的标准制药技术完成。
适用于肠胃外施用的制剂包括含水和非含水无菌注射溶液,其可含有抗氧化剂,缓冲剂,抑菌剂和溶质,使制剂与预期接受者的血液等渗;以及可包含悬浮剂和增稠剂的含水和非含水无菌悬浮液。制剂可以以单位剂量或多剂量容器(例如密封的安瓿和小瓶)存在,并且可以以冷冻干燥(冻干)条件存储,仅需要在使用之前立刻添加无菌液体承载体例如注射用水。即时注射溶液和混悬液可以由前述种类的无菌粉末、颗粒和片剂制备。
在一个实施方案中,静脉内施用本公开内容的ADC。
在一个实施方案中,皮下施用本公开内容的ADC。
在一个实施方案中,颅内或脑内施用本公开内容的ADC。
药物组合物将以药学上有效量施用于患者。本文使用的‘治疗有效量’或‘有效量’或‘治疗有效’是指针对给定病况和施用方案提供治疗效果的量。这是预定量的活性物质,经计算可与所需的添加剂和稀释剂(即承载体或给药媒介物)一起产生所需的治疗效果。此外,旨在表示足以减少并且最优选地预防宿主的活性、功能和应答的临床显著缺陷的量。或者,治疗有效量足以引起宿主临床显著病况的改善。如本领域技术人员所理解的,化合物的量可以根据其比活性而变化。合适的剂量可含有预定量的活性组合物,经计算可与所需的稀释剂结合产生所需的治疗效果。如本领域所众所周知的,治疗有效量可以由普通技术的医学或兽医工作者基于患者特征如年龄、体重、性别、病况、并发症、其他疾病等来确定。药物有效剂量的施用可以通过以单个剂量单位形式的单次施用,或者几个较小剂量单位,以及通过以特定间隔多次施用细分剂量来进行。或者,剂量可以作为长时间连续输注提供。
本领域技术人员将理解,本文所述的靶向uPARAP的ADC可以单独施用或与其他治疗剂组合施用。例如,本文所述的靶向uPARAP的ADC可以与一系列抗癌剂组合施用,所述抗癌剂例如抗代谢物、烷化剂、蒽环类和其他细胞毒性抗生素、长春花烷烃类(vincaalkyloids)、抗微管/抗有丝分裂剂、组蛋白脱乙酰酶抑制剂、激酶抑制剂、肽抗生素、基于铂的抗肿瘤药、依托泊苷、紫杉烷、拓扑异构酶抑制剂、抗增殖性免疫抑制剂、皮质类固醇、性激素和激素拮抗剂、细胞毒性抗生素和其他治疗剂。
在一个实施方案中,本公开内容的ADC与可以提高ADC的功能效率的其他试剂和/或治疗剂一起施用,例如增加溶酶体膜渗透性的已建立的或新的药物,从而促进溶酶体内部的分子进入细胞质或增加血脑屏障通透性的药物。
在一个实施方案中,本公开内容提供了包含如本文所述的靶向uPARAP的ADC或包含其的药物组合物的试剂盒。该试剂盒可任选地进一步包括用于向受试者施用ADC的工具(means)和使用说明书。
在一个实施方案中,本公开内容涉及用于将活性剂递送至受试者中表达uPARAP的细胞的方法,其包括向受试者施用uPARAP引导的ADC或包含如本文所述的uPARAP引导的ADC的组合物,使得活性剂被递送到所述细胞。
在一个实施方案中,本公开内容涉及uPARAP引导的ADC或包含如本文所述的uPARAP引导的ADC的组合物,用于将活性剂递送至受试者中表达uPARAP的细胞,其包括向受试者施用uPARAP引导的ADC或包含如本文所述的uPARAP引导的ADC的组合物,使得活性剂被递送到所述细胞。
在一个实施方案中,本公开内容涉及用于治疗以受试者中表达uPARAP的细胞为特征的疾病或病症的方法,包括向受试者施用uPARAP引导的ADC或包含本文所述的uPARAP引导的ADC的组合物。
在一个实施方案中,本公开内容涉及本文所述的uPARAP引导的ADC或包含所述uPARAP引导的ADC的组合物,用于治疗以表达uPARAP的细胞为特征的疾病或病症。
在一个实施方案中,本公开内容涉及在体内或体外抑制表达uPARAP的细胞生长的方法,包括施用uPARAP引导的ADC或包含本文所述的uPARAP引导的ADC的组合物。这种生长抑制可能包括细胞死亡或可能包括抑制生长而没有细胞死亡。
在特别优选的实施方案中,表达uPARAP的细胞是肿瘤细胞和/或肿瘤相关细胞,并且本公开内容涉及用于治疗受试者中的癌症的方法,包括向受试者施用uPARAP引导的ADC或包含本文所述的uPARAP引导的ADC的组合物给所述受试者。
肿瘤相关细胞包括但不限于活化的成纤维细胞,成肌纤维细胞,巨噬细胞-单核细胞谱系或其他白细胞细胞类型的新血管系统细胞和浸润细胞,以及肿瘤周围基质组织的细胞。
在一个实施方案中,本公开内容涉及用于抑制受试者中肿瘤进展的方法,包括向受试者施用uPARAP引导的ADC或包含本文所述的uPARAP引导的ADC的组合物给所述受试者。这种抑制肿瘤进展可以包括完全或不完全根除肿瘤,或可能包括无细胞死亡的生长停滞。
在一个实施方案中,本公开内容涉及用于抑制、降低或消除受试者中肿瘤转移能力的方法,包括向受试者施用uPARAP引导的ADC或包含本文所述的uPARAP引导的ADC的组合物给所述受试者。
在一个实施方案中,肿瘤细胞表达或过表达uPARAP。
在一个实施方案中,肿瘤相关细胞表达或过表达uPARAP。
在一个实施方案中,本公开内容提供了用于诱导细胞死亡和/或抑制表达uPARAP的细胞的生长和/或增殖的方法,所述方法包括向所述个体施用有效量的如本文所述的靶向uPARAP的ADC或者包含如本文所述的靶向uPARAP的ADC的药物组合物。
治疗优选诱导细胞死亡和/或抑制表达uPARAP的细胞如肿瘤细胞或肿瘤相关细胞的生长和/或增殖。
在一个实施方案中,治疗是改善型的。
在一个实施方案中,治疗是治愈型的。
在一个实施方案中,本公开内容提供了如本文所述的靶向uPARAP的ADC,其用于制备诱导细胞死亡和/或抑制表达uPARAP的细胞如肿瘤细胞或肿瘤相关细胞的生长和/或增殖的药物。
几个研究小组已经研究了uPARAP在癌症中的表达和作用;参见Melander等人的综述(Melander et al.,2015,Int J Oncol 47:1177-1188)和Engelholm等人的文章(Engelholm et al.,2016,J.Pathol.238,120-133)。
在一个实施方案中,癌症是实体瘤,其中肿瘤细胞和/或肿瘤相关细胞表达uPARAP。
在一个实施方案中,癌症是实体瘤,其中肿瘤细胞表达uPARAP。
以过表达uPARAP为特征的癌症的实例包括但不限于肉瘤,包括骨肉瘤(Engelholmet al.,2016,J Pathol 238(1):120-33)以及其他肉瘤,胶质母细胞瘤(Huijbers et al.,2010,PLoS One 5(3):e9808),前列腺癌和前列腺癌骨转移(Kogianni et al.,2009,Eur JCancer 45(4):685-93),乳腺癌,特别是“基底样”乳腺癌(Wienke et al.,2007,CancerRes 1;67(21):10230-40),和头颈癌(Sulek et al.,2007,J Histochem Cytochem 55(4):347-53)。
在一个实施方案中,癌症是肉瘤,例如骨肉瘤,脂肪肉瘤,粘液纤维肉瘤,皮肤纤维肉瘤突起(DFSP)和/或平滑肌肉瘤(LMS)。
在一个实施方案中,癌症是胶质母细胞瘤。
在一个实施方案中,癌症是实体瘤,其中肿瘤相关细胞表达uPARAP。当肿瘤相关细胞表达uPARAP时,认为治疗效果是通过所谓的“旁观者”效应和/或通过减少和/或消除基质细胞介导的肿瘤生长和传播的刺激来介导。
以肿瘤相关细胞中过表达uPARAP为特征的癌症的实例包括但不限于乳腺癌(Schnack et al.,2002,Int J Cancer 10;98(5):656-64),头颈癌(Sulek et al.,2007,JHistochem Cytochem 55(4):347-53)和多种其他实体恶性肿瘤。
在一个实施方案中,癌症不是实体瘤。例如,本公开内容的ADC可以例如是可用于治疗表达uPARAP的白血病,例如来自巨噬细胞-单核细胞谱系。
在其他实施方案中,以表达uPARAP的细胞为特征的疾病或病症不是癌症。
uPARAP参与骨生长和体内平衡(Madsen et al.,2013,PLoS One 5;8(8):e71261)。因此,在一个实施方案中,本公开内容的ADC可用于治疗以骨降解为特征的疾病,其中骨降解由非恶性细胞介导,例如骨质疏松症。
由于其在胶原积累中的作用,uPARAP的作用也已显示在纤维化中(Madsen etal.,2012,J Pathol 227(1):94-105)。因此,在一个实施方案中,本公开内容的ADC可以用于治疗例如肾、肺和肝的纤维化。
在一个实施方案中,本公开内容的ADC可以用于治疗与巨噬细胞相关的疾病和病症,包括动脉粥样硬化和慢性炎症。
参考文献
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Kabat,E.A.,Wu,T.T.,Perry,H.,Gottesman,K.and Foeller,C.(1991)Sequencesof proteins of immunological interest.Fifth Edition.NIH Publication No.91-3242.
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实施例1:针对uPARAP的N端区域的ADC的体外和体内功效
材料与方法
制备和评估mAb-vc-MMAE ADC
根据本领域已知的已知方法,在小鼠免疫后使用杂交瘤技术产生并生产针对uPARAP或针对三硝基苯酚(TNP)的单克隆抗体(mAb)。在针对uPARAP的mAbs的情况下,用于免疫的宿主小鼠在uPARAP方面具有基因缺陷,导致与人类和鼠类抗原都具有反应性的抗体。ADC是通过本领域先前描述的常用缀合方法制备的(Doronina et al.2003 Naturebiotechnology 21(7):778-84;Francisco et al.,2003.Blood 102(4):1458-65;Hamblett et al.,2004.Clinical cancer research 10(20):7063-70)。
在存在10mM DTT的50mM硼酸钠、50mM NaCl、pH8.0缓冲液中,在5mg/mL浓度下,通过在37℃孵育10分钟使抗体温和还原,接着使用30kDa NMWL离心过滤器通过缓冲液交换至新鲜的具有1mM EDTA的PBS pH7.4而除去DTT,然后调节至2mg/mL浓度。随后立即缀合至溶于无水DMSO中的5-10倍摩尔过量的马来酰亚胺己酰基-缬氨酸-瓜氨酸-对氨基苯甲酰氧基羰基-单甲基奥瑞他汀E(MC-VC-PAB-MMAE,即,Vedotin),至在37℃偶联2小时期间DMSO含量为10%v/v。所得mAb-vc-MMAE ADC通过在PD-10脱盐柱上进行凝胶过滤来纯化。基于在λ=248nm和λ=280nm处纯化的缀合物样品的吸光度比率确定所得ADC的平均药物与抗体的比率(DAR)。未修饰的mAb显示A248nm/A280nm比为0.43,并且MMAE在λ=248nm的AMAX得到mAb-vc-MMAE ADC的更高的A248nm/A280nm比,这已经证明反映了所得ADC的DAR(Hamblett et al.,2004.Clinical cancer research 10(20):7063-70;Sanderson et al.,2005.ClinicalCancer Research 11:843-852)。
细胞系
U937、THP-1和HT1080细胞均获得自ATCC。KNS42细胞由Lara Perryman,BiotechResearch and Innovation Centre(BRIC),University of Copenhagen友情提供。CHO-K1细胞获得自Invitrogen。在37℃、5%CO2的大气培养箱中将所有细胞维持在补充有10%胎牛血清和1%青霉素/链霉素的适当培养基中。
缀合物质的SDS-PAGE分析
通过运行4-12%NuPAGE Bis-Tris SDS-PAGE凝胶进行还原性SDS-PAGE,每个泳道加载5μg总蛋白,通过在40mM DTT存在下在样品缓冲液中煮沸3分钟而还原。凝胶使用标准的0.1%考马斯蓝染色剂进行染色。对于组织蛋白酶B接头切割测定,使用100ng活化的rh组织蛋白酶B相对20μgADC(mAb组分),根据制造商的说明书在25mM MES、pH 5.0缓冲液中用重组人(rh)组织蛋白酶B处理样品,并在37℃孵育过夜。
ELISA分析mAb的uPARAP结合
使用具有mAb 2h9的完整表位的含有人uPARAP前3个N端结构域的可溶性截短uPARAP蛋白质,以25ng/孔包被96孔ELISA板。然后将未处理的mAb(2h9或aTNP)、经受缀合物的还原处理的相同mAB或ADC 2h9-vc-MMAE或aTNP-vc-MMAE用作一抗,然后HRP缀合的兔抗鼠Ig二抗。最后加入含邻苯二胺二盐酸盐的底物溶液,通过加入1M H2SO4终止显色反应。使用酶标仪在492nm处读取板。
ADC的体外细胞毒性——细胞生存力测定
测试的细胞在含90μL培养基的96孔板中以低密度(20-25%汇合度,通常5-10x103个细胞/孔)接种,并过夜培养。第二天,在PBS中作为连续稀释液(1∶4)制备基于mAb 2h9、mAb 5f4或非靶向对照mAb aTNP的mAb-vc-MMAE缀合物,并以10μL体积加入到每个孔中,最终ADC最大浓度为10μg/mL mAb组分。将细胞孵育72小时,然后加入20μL的CellTiter 96AQueous One Solution Cell Proliferation Assay(MTS,Promega),并孵育适当的时间以形成颜色(通常1小时)。然后使用酶标仪在490nm(减去630nm的背景)读取板。
ADC的体外细胞毒性——细胞周期测定
基于每种细胞的DNA含量,使用制造商用于分析细胞群的细胞周期分布的标准方案,使用Nucleocounter NC-3000系统(ChemoMetec Denmark)进行细胞周期分析。使用NucleoView NC-3000软件从直方图分析确定细胞周期的Sub-G1、G1、S或G2/M期细胞的百分比。
受体竞争和溶酶体蛋白酶抑制
如细胞生存力测定(参见上文)接种U937细胞用于受体竞争测定、受体耗尽测定和抑制溶酶体蛋白酶的测定。对于受体竞争测定,在所有孔中保持1μg/mL mAb组分的恒定2h9-vc-MMAE浓度,并且同时添加以8μg/mL的浓度开始的系列(1∶2)稀释的未修饰的竞争mAb。然后对细胞进行72小时细胞毒性细胞生存力测定(参见上文)。对于抑制溶酶体蛋白酶的测定,将U937细胞与20μM E64D蛋白酶抑制剂一起预孵育2小时,然后开始72小时细胞毒性细胞生存力测定(参见上文)。
动物实验
所有动物实验都在丹麦兽医和食品管理局的合法批准下进行。用于动物实验的所有试剂和细胞系对于鼠病毒、细菌、支原体和真菌的存在检测都为阴性。动物接受标准护理,并且在出现以下任何迹象时被处死:体重减少超过10%、明显的痛苦或疾病、受损的食物或水的摄入或排便、肿瘤附近的严重炎症迹象或超过1000mm3体积的肿瘤生长或动物自由运动受损。使用电子卡尺测量肿瘤生长,使用式体积=(LxW2)/2计算肿瘤体积,其中L是肿瘤的最长尺寸,W是垂直方向的宽度。
通过s.c.注射治疗小鼠皮下uPARAP阳性U937异种移植肿瘤模型
为了建立肿瘤,将小鼠在侧面剃毛,并接受皮下注射1×106个U937细胞,然后密切监测以观察实体瘤的发展。在形成体积为50-100mm3的可触及肿瘤后,小鼠开始以下四个治疗组之一中的治疗:2h9-vc-MMAE(N=10)、aTNP-vc-MMAE(N=9)、未修饰的mAb 2h9(N=5)或PBS溶媒对照(N=5)。所有治疗均以4天的间隔在肿瘤区域中共4次皮下给予3mg/kg mAb组分。在短暂的异氟醚麻醉下进行注射以避免动物操作者的风险。在治疗过程中,每两天评估一次肿瘤,直到达到处死的点。在完成治疗后,完全失去任何肿瘤负荷的小鼠每周检查两次,持续3个月。
通过静脉内注射治疗小鼠皮下uPARAP阳性U937异种移植肿瘤模型
为了建立肿瘤,将小鼠在侧面剃毛,并接受皮下注射1×106个U937细胞,然后密切监测以观察实体瘤的发展。在形成体积为50-100mm3的可触及肿瘤后,小鼠开始以下四个治疗组之一中的治疗:2h9-vc-MMAE(N=10)、aTNP-vc-MMAE(N=10)、未修饰的mAb 2h9(N=5)或PBS溶媒对照(N=5)。所有治疗均以4天的间隔在小鼠尾静脉中共4次静脉内给予5mg/kgmAb组分。在治疗过程中,每两天评估一次肿瘤,直到达到处死的点。在完成治疗后,完全失去任何肿瘤负荷的小鼠每周检查两次,持续3个月。
统计
所有样品以一式三份完成。误差条:标准偏差。
结果和结论
胶原蛋白受体uPARAP在包括肉瘤和晚期胶质母细胞瘤的特定癌症的肿瘤细胞中上调。另外,受体最通常在实体瘤周围的基质细胞中上调。在健康成人个体中,受体表现出限制性表达,因此使其成为ADC治疗的潜在目标。
为此,我们选择了免疫uPARAP基因缺陷型小鼠后获得的单克隆抗体2h9,并使用公认的缀合方法制备了uPARAP引导的ADC(2h9-vc-MMAE)。靶向抗体2h9显示良好耐受缀合过程,亲和力损失可忽略不计。显示所得的ADC在体外杀死或诱导uPARAP阳性细胞中的生长停滞方面具有高度特异性,其中U937细胞是测试的最敏感的细胞系。
uPARAP是一种组成型再循环受体,其将货物引导至溶酶体室。我们发现,在高度敏感的细胞如U937细胞中的ADC效率完全依赖于接头切割,因为用E64D抑制溶酶体组织蛋白酶后uPARAP依赖性细胞毒性被消除。因此,我们提出,溶酶体切割接头的能力促成了不同细胞类型之间ADC敏感性的差异,这与对缀合的细胞毒素的敏感性的总体差异协作。
对于体内研究,我们利用了CB17 SCID小鼠中具有U937细胞的快速生长的皮下异种移植肿瘤模型。使用该模型,发现ADC 2h9-vc-MMAE在根除体内U937实体瘤方面非常有效。局部皮下施用治疗后,5只小鼠在完成治疗方案后90天仍保持无肿瘤,因此形成50%的治愈率。更重要的是,在静脉内施用治疗后,我们观察到产生100%的治愈率的有效效果。值得注意的是,这种肿瘤根除在对治疗小鼠的定期检查中获得,没有任何明显的不利影响。重要的是,2h9抗体对人和鼠uPARAP均具有反应性,这是通过在培养抗体时使用uPARAP缺陷型小鼠进行免疫而实现的交叉反应。因此,在这种异种移植模型中,除了有益的抗肿瘤作用之外,对宿主的任何潜在的有害副作用都将被显露,但没有观察到有害作用的迹象。
2h9抗体的表位位于uPARAP的前三个N端结构域内,更具体地位于CysR结构域或CTLD-1中。本文提供的体外研究表明,包含靶向uPARAP的前三个N端结构域的抗UPARAP抗体(即5f4)的另一个ADC与包含2h9抗体的ADC一样有效。5f4抗体的表位在uPARAP的FN-II结构域中。因此,我们假设包含针对uPARAP的前三个N端结构域内的表位的抗uPARAP抗体的ADC作为ADC特别有效。
总之,这里提供的数据非常强烈地支持胶原蛋白受体uPARAP作为基于表达模式和分子功能的ADC癌症治疗中的通用靶标的概念。此外,这些数据显示,包含针对uPARAP的前三个N端结构域的抗体的ADC,例如ADC 2h9-vc-MMAE,在体外和体内高效靶向表达uPARAP的细胞。
实施例2:基于MMAE的ADC的体外功效
除了实施例1的ADC之外,还生成了以下MMAE ADC:9b7-vc-MMAE和11c9-vc-MMAE。
mAb 2h9、mAb 5f4和mAb 9b7针对uPARAP的三个N端结构域内的表位,而mAb 11c9是针对uPARAP的N端三个结构域外表位的抗uPARAP抗体。
如实施例1中所述,使用所有这些ADC进行用U937细胞进行的体外细胞生存力测定。所有ADC导致总体细胞生存力的特异性下降,但其中对2h9-vc-MMAE、5f4-vc-MMAE和9b7-vc-MMAE的细胞敏感性显著高于11c9-vc-MMAE的敏感性(图14)。
因此,发明人得出结论,包含能够与uPARAP的三个最N端结构域内的表位结合的抗uPARAP抗体的ADC是非常有效的ADC。
实施例3:包含不同接头、间隔子和毒素的ADC的体外功效
不同的毒素能够以靶向uPARAP的N端部分的ADC形式进行使用。如上所述制备具有作为抗体组分的mAb 2h9的ADC,但使用以下接头-细胞毒素单元代替VC-PAB-MMAE:
-VC-PAB-MMAF(其中MMAF是单甲基奥瑞他汀F,MMAE的羧基变体)
-PEG4-va-PBD(其中PEG4是指聚乙二醇间隔子,va是缬氨酸-丙氨酸,PBD是指二聚吡咯并苯并二氮杂)
-PEG4-vc-多卡霉素SA(其中PEG4是指聚乙二醇间隔子,vc是缬氨酸-瓜氨酸)
如上所述所得ADC(分别称为2h9-vc-MMAF、2h9-va-PBD和2h9-vc-DuocSA)用于使用U937细胞的体外细胞生存力测定。U937细胞对2h9-vc-MMAF表现出非常强的敏感性,对2h9-va-PBD更中等的敏感性,对2h9-vc-DuocSA敏感性较低但可测量。结果示于图15和16中。
实施例4:ADC对人胶质母细胞瘤外植体细胞的体外功效
如实施例1所述,通过体外细胞生存力测定测试ADC 2h9-vc-MMAE和2h9-vc-MMAF特异性杀死人胶质母细胞瘤外植体细胞的能力。胶质母细胞瘤外植体细胞例如在Staberget al.,2017,Cell Oncol.40:21-32中所述。这些细胞对ADC 2h9-vc-MMAE以及ADC 2h9-vc-MMAF均显示出非常强的特异性敏感性,因此证明了这些ADC在对抗人胶质母细胞瘤细胞方面的高效率。结果示于图17中。
实施例5:重组抗体
在CHO细胞中表达由包含[SEQ ID NO:1](抗uPARAP的单克隆抗体2h9的轻链)和[SEQ ID NO:5](相同抗体的重链)的合成DNA编码的蛋白质产物。纯化得到的重组抗体产物并通过蛋白质印迹显示以与杂交瘤细胞培养产生的单克隆抗体2h9相同的方式特异性识别uPARAP(图18)。
Claims (53)
1.针对uPARAP的抗体-药物缀合物,其包含:
a.抗体,其能够结合:
i.SEQ ID NO:36或37的氨基酸序列(uPARAP的CysR-FN-II-CTLD-1结构域),
ii.SEQ ID NO:38或39的氨基酸序列(uPARAP的CysR-FN-II结构域),
iii.SEQ ID NO:40或41的氨基酸序列(uPARAP的FN-II-CTLD-1结构域),
iv.SEQ ID NO:30或31的氨基酸序列(uPARAP的富含半胱氨酸结构域(CysR)),
v.SEQ ID NO:32或33的氨基酸序列(uPARAP的II型纤连蛋白(FN-II)结构域),和/或
vi.SEQ ID NO:34或35的氨基酸序列(uPARAP的C型凝集素样结构域1(CTLD 1)),
b.活性剂,和任选地
c.接头,其连接a)至b)。
2.根据权利要求1所述的抗体-药物缀合物,其中,所述抗体能够结合:
a.SEQ ID NO:30或31的氨基酸序列,或
b.SEQ ID NO:34或35的氨基酸序列。
3.根据权利要求1所述的抗体-药物缀合物,其中,所述抗体能够结合SEQ ID NO:32或33的氨基酸序列。
4.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体选自:
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:1或9的氨基酸序列或与SEQ ID NO:1或9的氨基酸序列具有至少70%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:5或10的氨基酸序列或与SEQ ID NO:5或10的氨基酸序列具有至少70%序列同一性的序列.或由其组成。
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:2、3、4、6、7和8的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:2、3和4的氨基酸序列,和/或SEQ ID NO:6、7和8的氨基酸序列;
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:42、43、44、45、46和47的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:42、43和44的氨基酸序列,和/或SEQ ID NO:45、46和47的氨基酸序列。
5.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体选自:
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:11的氨基酸序列或与SEQ ID NO:11的氨基酸序列具有至少70%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:15的氨基酸序列或与SEQ ID NO:15的氨基酸序列具有至少70%序列同一性的序列,或由其组成,
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:12、13、14、16、17和18的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:12、13和14的氨基酸序列,和/或SEQ ID NO:16、17和18的氨基酸序列,
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:48、49、50、51、52和53的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:48、49和50的氨基酸序列,和/或SEQ ID NO:51、52和53的氨基酸序列。
6.根据前述任一项权利要求所述的抗体-药物缀合物,其中抗体选自:
a.抗体或其抗原结合片段,其包含
i.免疫球蛋白轻链可变区,其包含SEQ ID NO:19或20的氨基酸序列或与SEQ ID NO:19或20的氨基酸序列具有至少70%序列同一性的序列,或由其组成,和/或
ii.免疫球蛋白重链可变区,其包含SEQ ID NO:24或25的氨基酸序列或与SEQ ID NO:24或25的氨基酸序列具有至少70%序列同一性的序列,或由其组成。
b.抗体或其抗原结合片段,其结合与a)的抗体相同的表位,
c.a)的抗体或其抗原结合片段的人源化形式,或者b)的抗体或其抗原结合片段的人源化形式,
d.a)的抗体或其抗原结合片段的嵌合形式,或者b)的抗体或其抗原结合片段的嵌合形式,
e.抗体或其抗原结合片段,其包含
i.SEQ ID NO:21、22、23、26、27和28的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:21、22和23的氨基酸序列,和/或SEQ ID NO:26、27和28的氨基酸序列,
f.抗体或其抗原结合片段,其包含
i.SEQ ID NO:54、55、56、57、58和59的氨基酸序列中的一个或多个,或
ii.SEQ ID NO:54、55和56的氨基酸序列,和/或SEQ ID NO:57、58和59的氨基酸序列。
7.根据前述任一项权利要求所述的抗体-药物缀合物,其中任何序列变异都在互补决定区之外。
8.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体选自小鼠抗体、嵌合抗体、人抗体、人源化抗体、人源化抗原结合片段、Fab片段、Fab′片段、F(ab’)2片段、Fv、单链抗体(SCA)如scFv、其重链和/或轻链的可变部分以及Fab微型抗体。
9.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体是单克隆抗体。
10.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体是人源化或完全人单克隆抗体或其抗原结合片段。
11.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体是重组抗体。
12.根据前述任一项权利要求所述的抗体-药物缀合物,其中所述活性剂选自治疗剂、细胞毒性剂、放射性同位素和可检测标记。
13.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是细胞毒性剂。
14.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是化疗剂,例如选自烷化剂、蒽环类抗生素、抗代谢物、抗微管/抗有丝分裂剂、组蛋白脱乙酰酶抑制剂、激酶抑制剂、肽抗生素、基于铂的抗肿瘤药、拓扑异构酶抑制剂和细胞毒性抗生素的化疗剂。
15.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是抗有丝分裂剂,例如选自单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、紫杉烷(例如紫杉醇或多西他赛)、长春花生物碱(例如长春花碱、长春新碱、长春地辛或长春瑞滨)、秋水仙碱或鬼臼毒素。
16.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是单甲基奥瑞他汀E(MMAE)或单甲基奥瑞他汀F(MMAF)。
17.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是DNA交联剂,例如选自吡咯并苯并二氮杂或二聚吡咯并苯并二氮杂衍生物的DNA交联剂。
18.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述活性剂是烷化剂,例如多卡霉素SA。
19.根据前述任一项权利要求所述的抗体-药物缀合物,其具有1至10、例如2至8、例如3至6、例如4或5的药物与抗体的比率(DAR)。
20.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物包含选自可切割接头和不可切割接头的接头。
21.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述接头是肽接头。
22.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述接头是酶可切割肽接头,例如组织蛋白酶可切割接头。
23.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述接头包含二肽例如缬氨酸-瓜氨酸(VC)或缬氨酸-丙氨酸(VA),或由其组成。
24.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物进一步包含间隔子,例如包含对氨基苯甲酸(PABA)或聚乙二醇(PEG)的间隔子。
25.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物进一步包含为PEG4的间隔子或者进一步包含含PEG4的间隔子。
26.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物进一步包含连接基团,例如包含马来酰亚胺和己酸(MC)、N-羟基琥珀酰亚胺、叠氮化物或炔烃或通过与抗体反应而衍生自这些的衍生物的连接基团,或由其组成的连接基团。
27.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物包含Vedotin(MC-VC-PAB-MMAE)。
28.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物包含以下接头-间隔子-毒素单元:VC-PAB-MMAF。
29.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物包含以下接头-间隔子-毒素单元:PEG4-VA-PBD。
30.根据前述任一项权利要求所述的抗体-药物缀合物,其中,所述抗体-药物缀合物包含以下接头-间隔子-毒素单元:PEG4-VC-多卡霉素SA。
31.根据前述任一项权利要求所述的抗体-药物缀合物,其用作药物。
32.药物组合物,包含根据前述任一项权利要求所述的抗体-药物缀合物和药学上可接受的缓冲剂、稀释剂、载体、佐剂或赋形剂。
33.向表达uPARAP的细胞递送活性剂的方法,包括向所述细胞施用根据权利要求1至31中任一项所述的抗体-药物缀合物或根据权利要求32所述的药物组合物,使得将活性剂递送至所述细胞。
34.治疗特征在于受试者中表达uPARAP的细胞的疾病的方法,包括向所述受试者施用根据权利要求1至31中任一项所述的抗体-药物缀合物或根据权利要求32所述的药物组合物。
35.根据权利要求34所述的方法,其中,特征在于表达uPARAP的细胞的所述疾病选自癌症、骨退化疾病如骨质疏松症、纤维化和与巨噬细胞相关的疾病或病症如动脉粥样硬化或慢性炎症。
36.根据权利要求34至35中任一项所述的方法,其中,所述疾病是癌症。
37.根据权利要求36所述的方法,其中,所述癌症选自肉瘤、胶质母细胞瘤、前列腺癌、来自前列腺癌的骨转移瘤、乳腺癌、头颈癌和白血病。
38.根据权利要求36至37中任一项所述的方法,其中,所述癌症是实体瘤。
39.根据权利要求36至38中任一项所述的方法,其中,所述癌症是胶质母细胞瘤。
40.根据权利要求36至38中任一项所述的方法,其中,所述癌症是肉瘤,例如骨肉瘤。
41.根据权利要求33至40中任一项所述的方法,其中,所述抗体-药物缀合物通过肠胃外施用,例如静脉内、脑室内、关节内、动脉内、腹膜内、鞘内、心室内、胸骨内、颅内、肌内或皮下或通过输注技术。
42.根据权利要求33至41中任一项所述的方法,其中,所述抗体-药物缀合物静脉内施用。
43.根据权利要求33至41中任一项所述的方法,其中,所述抗体-药物缀合物颅内施用。
44.根据权利要求33至41中任一项所述的方法,其中,所述抗体-药物缀合物皮下施用。
45.根据权利要求33至43中任一项所述的方法,其中,所述抗体-药物缀合物与一种或多种其它药剂例如一种或多种其它治疗剂组合施用。
46.根据权利要求33至45中任一项所述的方法,其中表达uPARAP的所述细胞显示uPARAP过表达。
47.根据权利要求33至46中任一项所述的方法,其中表达uPARAP的所述细胞是肿瘤细胞。
48.根据权利要求33至47中任一项所述的方法,其中表达uPARAP的所述细胞是肿瘤相关细胞。
49.根据权利要求33至48中任一项所述的方法,其中,所述抗体-药物缀合物诱导细胞死亡和/或抑制表达uPARAP的细胞的生长和/或增殖。
50.根据权利要求34至49中任一项所述的方法,其中,所述治疗是改善或治愈的。
51.抑制受试者中肿瘤进展的方法,包括向所述受试者施用根据权利要求1至31中任一项所述的抗体-药物缀合物或根据权利要求32所述的药物组合物。
52.抑制、降低或消除受试者中肿瘤转移能力的方法,包括向所述受试者施用根据权利要求1至31中任一项所述的抗体-药物缀合物或根据权利要求32所述的药物组合物。
53.试剂盒,包含根据权利要求1至31中任一项所述的抗体-药物缀合物或根据权利要求32所述的药物组合物,任选进一步包含用于向受试者施用抗体-药物缀合物的工具和/或使用说明书。
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