CN117999101A - 靶向EGFR的Fc抗原结合片段-药物缀合物 - Google Patents
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Abstract
本发明涉及靶向EGFR的Fc抗原结合片段‑药物缀合物(EGFR Fcab‑药物缀合物)和本发明的EGFR Fcab‑药物缀合物用于治疗和/或预防哺乳动物(尤其是人类)中的过度增殖性疾病和病症的用途,以及含有这些EGFR Fcab‑药物缀合物的药物组合物。进一步地,本发明涉及EGFR Fcab‑标记缀合物和含有这些EGFR Fcab‑标记缀合物的诊断组合物。
Description
本发明涉及靶向EGFR的Fc抗原结合片段-药物缀合物(EGFR Fcab-药物缀合物)和本发明的EGFR Fcab-药物缀合物用于治疗和/或预防哺乳动物(尤其是人类)中的过度增殖性疾病和病症的用途,以及含有这些EGFR Fcab-药物缀合物的药物组合物。进一步地,本发明涉及EGFR Fcab-标记缀合物和含有这些EGFR Fcab-标记缀合物的诊断组合物。
背景技术
表皮生长因子受体(EGFR;也称为ErbB-1和HER1)是细胞外蛋白质配体的表皮生长因子家族(EGF家族)成员的细胞表面受体。EGFR是具有单个跨膜区域和两侧为非催化调节区域的细胞质酪氨酸激酶结构域的大单体糖蛋白。序列分析显示,胞外结构域含有四个亚结构域,分别称为L1、CR1、L2和CR2,其中L和CR分别是大和富含Cys的缩略语。L1结构域和L2结构域也分别称为结构域I和结构域III。CR结构域以前称为结构域II和结构域IV,或S1.1-S1.3和S2.1-S2.3,其中S是小的缩写。
已知表达EGFR的癌症包括肺癌(例如非小细胞肺癌[NSCLC])(Pao等,2010;Amman等,2005)、多形性胶质母细胞瘤(Taylor等,2002)、皮肤癌(例如皮肤鳞状细胞癌)(Uribe等,2011)、头颈癌(如头颈鳞状细胞癌[HNSCC])(Zimmermann等,2006;Smilek等,2012)、乳腺癌(Masuda等,2013)、胃部癌症(胃癌)(Terashima等,2012年)、结肠直肠癌(CRC)(Spano等,2005;Saletti等,2015)、卵巢癌(Hudson等,2009)、胰腺癌(Troiani等,2012),或子宫内膜癌(Scambia等,1994)。
已描述了针对EGFR细胞外结构域的单克隆抗体。这些抗体扰乱配体与EGFR的结合以及随后的信号转导。
mAbC225(ERBITUX/西妥昔单抗(cetuximab))是与EGFR细胞外结构域结合并与EGF竞争结合EGFR的嵌合IgG1抗体,从而抑制下游通路信号传导并且阻断肿瘤细胞增殖(Voigt等,2012)。西妥昔单抗经FDA批准用于治疗头颈癌,特别是与放射治疗组合治疗局部或区域的晚期头颈部鳞状细胞癌,与具有5-FU的基于铂的疗法组合治疗头颈部的复发性局部疾病或转移性鳞状细胞癌,以及在基于铂的疗法后又进展的复发性或转移性头颈部鳞状细胞癌。
FDA还批准将西妥昔单抗用于治疗通过FDA批准的测试测定的KRAS突变阴性(野生型)EGFR表达的转移性结肠直肠癌,特别是与FOLFIRI组合作为第一线治疗,或在用基于伊立替康的化疗难治的患者中与伊立替康组合,以及用于治疗用基于奥沙利铂和伊立替康的化疗失败的患者或对作为单一药剂的伊立替康不耐受的患者。
ABX-EGF(VECTIBIX/帕尼单抗(panitumumab))是类似于西妥昔单抗与EGFR细胞外结构域结合,并且与EGF竞争结合EGFR的人IgG2抗体,从而抑制下游通路信号传导并且阻断肿瘤细胞增殖(Voigt等,2012)。FDA批准帕尼单抗用于治疗通过FDA批准的测试测定的野生型KRAS(密码子12或密码子13中的外显子2)转移性结肠直肠癌(mCRC)患者,在用含有氟嘧啶、奥沙利铂和伊立替康的化疗先行治疗而疾病又进展之后,与FOLFOX组合作为第一线疗法或作为单一疗法。
耐昔妥珠单抗(Necitumumab,Portrazza)是另一种结合EGFR的抗体,并且FDA于2015年批准该抗体与吉西他滨和顺铂组合用于转移性鳞状非小细胞肺癌患者的第一线治疗。
尼妥珠单抗(Nimotuzumab)(以前称为h-R3)是一种与EGFR细胞外区域结合的人源化IgG1抗体,其已在几个国家中参与临床试验。在印度、古巴、阿根廷、哥伦比亚、科特迪瓦、加蓬、乌克兰、秘鲁和斯里兰卡,尼妥珠单抗已被批准用于治疗头颈部鳞状细胞癌;以及在古巴、阿根廷、菲律宾和乌克兰用于治疗神经胶质瘤(儿童和成人);以及在中国用于治疗鼻咽癌(Ramakrishnan等,2009)。
包括扎芦木单抗(zalutuzumab)(HuMax-EGFr)和马妥珠单抗(matuzumab)(以前称为EMD 72000)的靶向EGFR的其他抗体的临床测试已经启动,但这些抗体尚未获得监管批准且其开发自此停止。
抗体-药物缀合物(ADC)在过去几年中进展迅速,并且其被确立为肿瘤学领域的永久参与者,为患有各种癌症的患者提供治疗益处。因此,在2019年至2020年8月之间,FDA批准了五种新的ADC,证明这种治疗类别的临床成功。1-3ADC将单克隆抗体的优异选择性与高细胞毒性药物的细胞杀伤能力联系起来,并且通过引导这些毒素至肿瘤细胞来扩大治疗窗口。至今,批准的ADC以及绝大多数临床阶段和临床前阶段的ADC都拥有单克隆IgG支架。4由于常规全尺寸ADC的巨大成功,基于较小的抗体片段的替代药物缀合物正在不断发展。5这种缀合物由Fab片段6,7、单链可变片段(scFv)8,9、双链抗体(diabody)10或如abdurin、纳米抗体10或humabody13的基于单结构域抗体的结构组成。由于从血管到间质组织空间的外渗和通过组织在间质扩散增加,其小尺寸允许更好的实体瘤渗透。16,19然而,抗体片段经常没有显示出更好的功效7,13,这可能涉及不存在Fc结构域及其延长半衰期的功能。Fc结构域与其天然配体(新生儿Fc受体(FcRn))的相互作用,介导全长IgG抗体在血流中循环延长(例如小鼠肢端t1/2曲妥珠单抗比FcRn未结合曲妥珠单抗,212h比6.9h19)。因此,缺少Fc部分的片段经常受到快速全身清除率和有限暴露的阻碍(例如曲妥珠单抗Fab,小鼠肢端t1/24.4h19)。这些发现得到多种新的缀合物形式,其中小的结合片段PAS化,与PEG10、白蛋白结合结构域10、12、13或Fc部分融合以改善其体内半衰期,然而代价是增加限制肿瘤渗透的流体动力学半径。
因此,由于ADC的尺寸增加(150kDa),其显示实体瘤渗透降低。这导致癌症细胞对有效载荷细胞毒性剂量的不均匀暴露及较低的ADC疗效。
相反,已知较小的基于抗体片段的药物缀合物(≤50kDa)显示增加的实体瘤渗透,理论上会导致癌症细胞对治疗剂的更均匀暴露。然而,其较小的尺寸和缺少FcRn结合位点造成这些片段药物缀合物的半衰期较短,这抵消了持久的肿瘤渗透。
因此,仍需要开发新的通过ADC或基于抗体片段的缀合物治疗癌症的治疗选项,其显示肿瘤渗透增加而同时半衰期长,二者都介导疗效增加。
发明内容
令人惊讶地,已经发现,与已知ADC和已知较小的基于抗体片段的药物缀合物相反,由于更小的尺寸和Fc介导的半衰期延长,另一种基于抗体片段的形式的药物缀合物(Fc抗原结合片段(Fcab)),同时显示增加的肿瘤渗透和长半衰期两者,两者介导所述Fcab-药物缀合物的治疗功效增加。因此,观察到本发明EGFR Fcab-药物缀合物的有效溶酶体递送,导致在肿瘤细胞中强效的细胞毒性效应。因此,本发明EGFR Fcab-药物缀合物可用于治疗过度增殖性疾病和病症(如癌症)。
Fcab从未作为抗癌药物缀合物被描述或探索过。通过工程化CH3结构域的C端结构环以形成抗原结合位点,Fcab来源于人IgG1抗体的Fc片段(图3A,B)。因此,Fcab组合了Fc介导的效应器功能和新生儿Fc受体(FcRn)结合(具有抗原结合功能),但仅包含常规IgG三分之一的尺寸。[15]Fcab形式的较小尺寸有望通过增强从循环进入间质空间的外渗以及增加通过间质和肿瘤组织的扩散率来改善实体瘤渗透。[16]此外,延长半衰期的FcRn结合位点延迟Fcab的全身清除(小鼠肢端t1/2Fcab 60-85h[17,18])和从而保持高血浆浓度,其进一步驱动渗透进入组织。[16]与缺少FcRn结合位点并因此遭受体内半衰期短(小鼠肢端t1/2曲妥珠单抗衍生的Fab 4.4h[19])的其他报道的≤50kDa的基于Fab[6,7]、scFv[8,9]、双链抗体[10]或单结构域抗体的药物缀合物[11-13]相比,FcRn结合为Fcab提供显著的优点。在采用HER-Fcab药物缀合物的相似实验中,我们能表明Fcab形式适合生成结合HER2的药物缀合物。[14]运用工程化的微生物转谷氨酰胺酶,我们能将接头-有效载荷位点特异性地缀合至保守Fc Q295位置,导致具有2.0的药物比抗体比率(DAR)的稳定和功能性Fcab-药物缀合物。此外,在体外球体实验中,我们证明了与全长抗体对照相比,Fcab的球体积累更高,这确认了Fcab的有利渗透能力。[14]
在本实验中,我们将基于Fcab的ADC概念从结合HER2的Fcab-ADC扩展到结合EGFR的Fcab-ADC,并且证明了这种抗体形式用于生成位点特异、稳定和高效的药物缀合物的多功能性。首先我们使用携带pH依赖性染料的异质缀合物,基于选择性细胞摄取数据证明了所选的结合EGFR的Fcab适用于ADC方法。然后,我们采用位点特异性酶促缀合将微管蛋白抑制剂单甲基澳瑞他汀E(monomethyl auristatin E)(MMAE)附接至Q295位置,也附接至新的Q311位置和Q438位置以达到较高的DAR。药物缀合物显示保留的EGFR结合和FcRn结合特性,并且在小鼠和人血清中拥有出色稳定性。最终,我们显示了在不同癌症细胞系上我们的Fcab-药物缀合物由EGFR介导的亚纳摩尔细胞毒性。
如本文所示,Fcab的有利药代动力学特征与其小尺寸组合惊人地引起基于Fcab的药物缀合物的更好且持久的实体瘤渗透。这导致与其他相似大小的基于片段的药物缀合物或常规基于IgG的ADC相比,本发明缀合物的总体肿瘤暴露增加和功效更好(概念如图1所示)。
在本文中,我们首次提出靶向EGFR的Fcab-药物缀合物的生成和功能性。为了验证概念,我们选择了一组靶向实体瘤抗原EGFR的不同Fcab。由于细胞内释放弹头是ADC的前提,因此在癌症细胞上测定了所选Fcab分子的EGFR依赖性摄取率。随后,采用多种位点特异性缀合技术将Fcab与公认的微管蛋白抑制剂单甲基澳瑞他汀E(MMAE)偶联。此外,评估与亲代Fcab分子相比,所有Fcab-药物缀合物的靶标依赖性细胞毒性和血清稳定性以及FcRn结合和靶标结合特性。总之,公开的实验和结果强调将Fcab用于生成Fcab-药物-缀合物。
在本实验范围内产生的Fcab以纳摩尔亲和力结合EGFR,并且在表达EGFR的细胞中靶标依赖性积累。经由mTG与Q295和新的Q311和Q438位置的位点特异性缀合产生DAR 2.7–2.9的Val-Cit-PAB MMAE缀合物,而EGFR或FcRn结合亲和力未变化。生成的Fcab-药物缀合物在人和小鼠血清中展现高度稳定性,并在亚纳摩尔浓度下显示了EGFR介导的细胞毒性,与基于西妥昔单抗的参考缀合物相似。
基于大量的体外表征,我们的实验和结果提供了Fcab形式适用于生成稳定的和细胞毒性的药物缀合物的概念验证。此外,在先前采用HER2-Fcab药物缀合物的实验中,我们能够证明与150kDa参考构建体相比,50kDa Fcab形式显示了优异的渗透[14]。与ADC相比,Fcab-药物缀合物的有益渗透证明肿瘤渗透更好和总体肿瘤暴露增加以及最后功效改善。
因此,本发明涉及一种EGFR Fcab-药物缀合物或其药学上可接受的盐,其包含式Fcab-(L)m-(D)n,其中:
a)Fcab包含EGFR Fcab,
b)L包含接头,
c)D包括药物,
D)m是1-5的整数和n是1-10的整数。
在本发明的优选实施方案中,m为1至3和n为1至5。
本发明涉及一种根据本发明的EGFR Fcab-药物缀合物,其中EGFR Fcab选自Fcab-1、Fcab-2、Fcab-3、Fcab-4、Fcab-5和Fcab-6,其具有如SEQ ID No.1-6所示的氨基酸序列。
本发明的优选实施方案是根据本发明的EGFR Fcab-药物缀合物,其中EGFR Fcab选自Fcab-1、Fcab-2和Fcab-3,其具有如SEQ IDNo.1-3所示的氨基酸序列。
本发明还涵盖根据本发明的EGFR Fcab-药物缀合物,其中通过保守氨基酸取代修改或修饰Fcab的氨基酸序列。如本文所用,术语“保守取代”是指本领域技术人员已知的氨基酸取代,并且可以在大体上不改变所得分子的生物活性的情况下进行。本领域技术人员认识到,一般来说,在多肽的非必需区域中的单个氨基酸取代基本上不改变生物活性(参见例如Watson等,MOLECULAR BIOLOGY OF THE GENE,Benjamin/Cummings Pub.Co.,第224页(1987年第4版))。
一般来说,任何药物都可以缀合至根据本发明方法获得的EGFR Fcab-药物缀合物,优选地只要其足够稳定以防止在到达所需靶细胞之前过早释放,从而防止损伤非靶细胞并增加在靶位点的利用度。由于药物最常见在接头分子裂解后在溶酶体中释放,重要的是确保药物在低pH环境中保持稳定并有能力移动进入其起作用的细胞的细胞质区室或核区室。相似地,合乎需要的是,药物的分子结构允许其缀合至接头,同时避免免疫原性,保持EGFR Fcab-药物缀合物的内化率以及促进或至少不减弱其生物效应(如有)(即ADCC、CDCC和CDC)。不管药物的稳定性如何,典型地只有一小部分施用的EGFR Fcab-药物缀合物会到达靶细胞。因此,优选地缀合药物在低浓度下是强效的。
因此,本发明的一个实施方案是EGFR Fcab-药物缀合物,其中EGFR Fcab缀合至选自细胞毒性剂的药物,所述细胞毒性剂例如化疗剂、生长抑制剂、毒素(例如细菌、真菌、植物或动物来源的酶促活性毒素或其片段)或放射性同位素(即放射性缀合物)。将抗体-药物缀合物(ADC)和本发明的EGFR Fcab-药物缀合物用于局部递送细胞毒性剂或细胞抑制剂,即在癌症治疗中杀死或抑制肿瘤细胞的药物(Syrigos和Epenetos(1999)AnticancerResearch 19:605-614;Niculescu Duvaz和Springer(1997)Adv.Drg。Del.Rev.26:151-172;美国专利4,975,278)允许将药物部分靶向递送至肿瘤,并在其中的细胞内积累,其中这些未缀合药剂的全身给药可能导致对正常细胞以及寻求消除的肿瘤细胞的不可接受的毒性水平(Baldwin等,(1986)Lancet(1986年3月15日):603-05;Thorpe,(1985)“AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy:A Review,”载于MonoclonalAntibodies’84:Biological And Clinical Applications,A.Pinchera等(编辑),第475-506页)。从而寻求伴随最小毒性的最大功效。这些方法中使用的药物包括道诺霉素、多柔比星、甲氨蝶呤和长春地辛(Rowland等,(1986)同上)。抗体-毒素缀合物中使用的毒素包括细菌毒素例如白喉毒素、植物毒素例如蓖麻毒素、小分子毒素例如格尔德霉素(geldanamycin)(Mandler等(2000)Jour.of the Nat.Cancer Inst.92(19):1573-1581;Mandler等(2000)Bioorganic&Med.Chem.Letters 10:1025-1028;Mandler等(2002)Bioconjugate Chem.13:786-791)、美坦生类化合物(maytansinoids)(EP 1391213;Liu等,(1996)Proc.Natl.Acad.Sci.USA 93:8618-8623)和卡奇霉素(calicheamicin)(Lode等(1998)Cancer Res.58:2928;Hinman等(1993)Cancer Res.53:3336-3342)。毒素可能通过包括微管蛋白结合、DNA结合或拓扑异构酶抑制的机制发挥其细胞毒性效应和细胞抑制效应。当缀合至大的抗体或蛋白质受体配体时,一些细胞毒性药物倾向于无活性或较少活性。
设想用于制备本发明的EGFR Fcab-药物缀合物的合适药物包括至今ADC中通常利用的所有细胞毒素。大多数细胞毒素类别起抑制细胞分裂的作用并且基于其作用机制分类。可想到作为本发明EGFR Fcab-药物缀合物的一部分的示例性细胞毒素,包括但不限于蒽环霉素(anthracycline)、多柔比星、甲氨蝶呤、澳瑞他汀包括单甲基澳瑞他汀E(MMAE)和单甲基澳瑞他汀F(MMAF)、美登素及其美坦生类化合物衍生物(DM)、卡奇霉素、倍癌霉素(duocarymycin)和吡咯并苯二氮(pyrrolobenzodiazepine,PBD)二聚体。
在一个实施方案中,药物部分选自V-ATP酶抑制剂、促凋亡剂、Bcl2抑制剂、MCL1抑制剂、HSP90抑制剂、IAP抑制剂、mTor抑制剂、微管稳定剂、微管失稳剂、澳瑞他汀、鹅膏蕈碱、吡咯并苯二氮、RNA聚合酶抑制剂、多拉司他汀、美坦生类化合物、MetAP(甲硫氨酸氨基肽酶)、蛋白质CRM1的核输出抑制剂、DPPIV抑制剂、蛋白酶体抑制剂、线粒体中磷酰基转移反应抑制剂、蛋白质合成抑制剂、激酶抑制剂、CDK2抑制剂、CDK9抑制剂、驱动蛋白抑制剂、HDAC抑制剂、DNA损伤剂、DNA烷基化剂、DNA嵌入剂、DNA小沟结合剂和DHFR抑制剂。在一些实施方案中,细胞毒性剂为美坦生类化合物,其中美坦生类化合物为N(2')-脱乙酰基-N(2')-(3-巯基-l-氧代丙基)-美登素(DM1)、N(2')-脱乙酰基-N(2')-(4-巯基-l-氧代戊基)-美登素(DM3)或N(2')-脱乙酰基-N2-(4-巯基-4-甲基-1-氧代戊基)-美登素(DM4)。
因此,本发明的优选实施方案是本发明的EGFR Fcab-药物缀合物,其中药物选自蒽环霉素、多柔比星、甲氨蝶呤、澳瑞他汀包括单甲基澳瑞他汀E(MMAE)和单甲基澳瑞他汀F(MMAF)、美登素及其美坦生类化合物(DM)、卡奇霉素、倍癌霉素和吡咯并苯二氮(PBD)二聚体、V-ATP酶抑制剂、促凋亡剂、Bcl2抑制剂、MCL1抑制剂、HSP90抑制剂、IAP抑制剂、mTor抑制剂、微管稳定剂、微管失稳剂、鹅膏蕈碱、吡咯并苯二氮/>、RNA聚合酶抑制剂、多拉司他汀、美坦生类化合物、MetAP(甲硫氨酸氨基肽酶)、蛋白质CRM1的核输出抑制剂、DPPIV抑制剂、蛋白酶体抑制剂、线粒体中磷酰基转移反应的抑制剂、蛋白质合成抑制剂、激酶抑制剂、CDK2抑制剂、CDK9抑制剂、驱动蛋白抑制剂、HDAC抑制剂、DNA损伤剂、DNA烷基化剂、DNA嵌入剂、DNA小沟结合剂和DHFR抑制剂。
在特定的优选实施方案中,该药物是微管蛋白抑制剂单甲基澳瑞他汀E(MMAE)。
优选地,将接头设计为在血流中稳定(以符合抗体循环时间增加)而在靶位点不稳定以允许快速释放药物。当设计合适的接头时要考虑的参数典型地包括接头的可裂解性以及键合的位置和机制(即缀合化学)。传统上现有接头被分类为可裂解接头或不可裂解接头。
可裂解的接头利用EGFR Fcab-抗原复合物内化进入靶细胞中时环境的改变,导致接头裂解和药物释放进入靶细胞。预计与本文提供的EGFR Fcab-药物缀合物一起使用的示例性可裂解接头包括腙接头、二硫化物接头和肽接头。与依赖独特的细胞内条件来释放药物的可裂解接头相反,不可裂解接头例如硫醚接头仅依赖于EGFR Fcab-抗原内化后的蛋白质水解降解过程和溶酶体途径中的加工。用于抗体-药物设计的接头已为本领域熟知且有综述,即Peters和Brown,Biosci.Rep.2015年8月;35(4):e00225。为实现充足的疗效,可将一种或几种药物连接至每个EGFR Fcab。
本领域描述了制备ADC的手段和方法且有综述,即Peters和Brown(同上)。传统上,使用常规技术将药物化学缀合至抗体,由此使天然氨基酸的反应部分与接头分子的特定部分相互作用并结合。反应基团的实施例包括赖氨酸残基的ε-氨基端和存在于部分还原形式的半胱氨酸残基中的硫醇侧链。常规缀合技术的替代包括经由(i)使用定点诱变沿着抗体在特定、可控位点引入的新的未配对的半胱氨酸残基的缀合,(ii)识别谷氨酰胺“标签”序列的微生物转谷氨酰胺酶的缀合,该“标签”序列可经由质粒掺入抗体,将含胺药物添加至谷氨酰胺侧链,或(iii)非天然氨基酸的缀合,如在转录过程中引入抗体的硒代半胱氨酸或乙酰苯丙氨酸,其可用于与合适的细胞毒素缀合,例如在亲核硒代半胱氨酸(带正电荷的药物分子)的情况下。
药物部分D可以通过接头L连接至EGFR Fcab。L是任何能够通过共价键将药物部分连接至抗体的化学部分。交联试剂是可用于将药物部分和Fcab连接以形成EGFR Fcab-药物缀合物的双功能或多功能试剂。可以使用具有反应功能性的交联试剂制备EGFR Fcab-药物缀合物,所述交联试剂与药物部分和EGFR Fcab二者都能结合。例如,半胱氨酸、硫醇或胺(例如N-端或氨基酸侧链(例如EGFR Fcab的赖氨酸))可与交联试剂的官能团形成键。
在一个实施方案中,L是可裂解接头。在另一个实施方案中,L是不可裂解接头。在一些实施方案中,L是酸不稳定性接头、光不稳定性接头、肽酶可裂解接头、酯酶可裂解接头、二硫键可裂解接头、亲水性接头、带电荷的接头(procharged linker)或基于二羧酸的接头。
在药物部分(例如美坦生类化合物)与抗体之间形成不可裂解接头的合适的交联试剂是本领域熟知的,并且可以形成包含硫原子的不可裂解接头(例如SMCC)或不具有硫原子的不可裂解接头。在药物部分(例如美坦生类化合物)和EGFR Fcab之间形成不可裂解接头的优选交联试剂包含基于马来酰亚胺或基于卤代乙酰基的部分。根据本发明,这些不可裂解接头被认为来源于基于马来酰亚胺或基于卤代乙酰基的部分。
包含基于马来酰亚胺的部分的交联试剂包括但不限于N-琥珀酰亚胺基-4-(马来酰亚胺甲基)环己烷羧酸酯(SMCC)、磺基琥珀酰亚胺基-4-(N-马来酰亚胺甲基)环己烷-1-羧酸酯(磺基SMCC)、N-琥珀酰亚胺基-4-(马来酰亚胺甲基)环己烷-1-羧基-(6-氨基己酸酯)(其是SMCC的长链类似物)(LC-SMCC)、K-马来酰亚胺基十一烷酸N-琥珀酰亚胺酯(KMUA)、Y-马来酰亚胺基丁酸N-琥珀酰亚胺酯(GMBS)、e-马来酰亚胺基己酸N-琥珀酰亚胺酯(EMCS)、间马来酰亚胺基苯甲酰基-N-羟基琥珀酰亚胺酯(MBS)、N-O-马来酰亚胺基乙酰氧基)-琥珀酰亚胺酯(AMSA)、琥珀酰亚胺基-6-(B-马来酰亚胺基丙酰胺基)己酸酯(SMPH)、N-琥珀酰亚胺基-4-(对马来酰亚胺基苯基)-丁酸酯(SMPB)、N-(-对马来酰氨基苯基)-异氰酸酯(PMIP)和含有聚乙二醇间隔基的基于马来酰亚胺的交联试剂(例如MAL-PEG-NHS)。这些交联试剂形成了来源于基于马来酰亚胺部分的不可裂解接头。
因此,本发明的一个优选实施方案是本发明的EGFR Fcab-药物缀合物,其中接头选自本文所述的接头。
本发明的另一优选实施方案是本发明的EGFR Fcab-药物缀合物,其中接头选自酸不稳定性接头、光不稳定性接头、肽酶可裂解接头、酯酶可裂解接头、二硫键可裂解接头、亲水性接头、带电荷的接头和基于二羧酸的接头。
本发明的进一步优选实施方案是本发明的EGFR Fcab-药物缀合物,其中接头是二硫键可裂解接头。
本文描述的每个实施方案可以与本文描述的与要组合的实施方案无不一致的任何其他实施方案组合。此外,除非在给定的上下文中不兼容,无论何处规定化合物能够离子化(例如质子化或去质子化),则对所述化合物的定义都包括任何其药学上可接受的盐。因此,在本文所述的所有化合物的描述中都隐含了短语“或其药学上可接受的盐”。如下所述某一方面内的实施方案可与在相同方面或不同方面内无不一致的任何其他实施方案组合。例如,本发明的任何治疗方法的实施方案可与本发明的组合产品或本发明的药物组合物的任何实施方案组合,并且反之亦然。同样地,对本发明的治疗方法给出的任何细节或特征,也适用于(如无不一致)本发明的组合产品和本发明的药物组合物的细节或特征,并且反之亦然。
通过参考上文和下文对本发明的特定和优选实施方案以及本文所包括的实施例的详细描述,可以更容易理解本发明。要理解本文使用的术语仅用于描述特定实施方案的目的并且不旨在限定。进一步要理解,除非本文有明确定义,给予本文使用的术语在相关领域中已知的传统含义。下文明确定义某些技术术语和科学术语以使本发明可以更容易理解。除非在本文件另有明确定义,本文中使用的所有其他技术术语和科学术语具有本发明所属领域普通技术人员通常理解的含义。
除非上下文另有清楚规定,“一个”、“一种”和“所述”包括复数指称。因此,例如提及一种抗体是指一种或多种抗体或至少一种抗体。因此,术语“一个”(或“一种”)、“一个或多个”和“至少一个”在本文中可互换使用。
当用于修饰数字定义的参数时,术语“约”是指该参数中不改变总体效果(例如在疾病或病症的治疗中,药剂的功效)的任何最小变化。在一些实施方案中,术语“约”意为参数可以在小于或大于该参数的所述数值多达10%的程度变化。
向患者“给药”或“施用”药物(以及该短语的语法等价物)指的是直接给药,其可能是通过医疗专业人员给患者给药或可能是自行给药,和/或间接给药,其可能是给药物开处方的行为,例如医生指导患者自行施用药物或向患者提供药物处方是向患者施用该药物。
“氨基酸差异”是指氨基酸的取代、缺失或插入。
“抗体”是通过位于免疫球蛋白分子可变区的至少一个抗原识别位点,能够与靶标(例如碳水化合物、多核苷酸、脂质、多肽等)特异性结合的免疫球蛋白(Ig)分子。如本文所用,术语“抗体”不仅涵盖完整的多克隆或单克隆抗体,而且也涵盖(除非另有说明)与完整抗体竞争特异性结合的其任何抗原结合片段或抗体片段,以及包含所述其抗原结合片段或抗体片段的任何蛋白质,包括融合蛋白(例如抗体-药物缀合物、与细胞因子融合的抗体或与细胞因子受体融合的抗体)、具有多表位特异性的抗体组合物和多特异性抗体(例如双特异性抗体)。基本的4链抗体单元是由两条相同的轻(L)链和两条相同重(H)链组成的异源四聚体糖蛋白。IgM抗体由5个基本异源四聚体单元连同称为J链的额外多肽组成,并且含有10个抗原结合位点,而IgA抗体包含2-5个基本4链单元,这些单元与J链组合可聚合形成多价聚集体。在IgG的情况下,4链单元大体上约为150,000道尔顿。每个L链通过一个共价二硫键与H链连接,而两个H链通过一个或多个二硫键(取决于H链的同种型)彼此连接。每个H和L链也具有规律间隔的链内二硫桥。每个H链的N端都有可变结构域(VH),随后每条α链和γ链各有三个恒定结构域(CH)以及μ同种型和ε同种型有四个CH结构域。每个L链在N端都有可变结构域(VL)随后在其另一端有恒定结构域。VL与VH配对,并且CL与重链(CH1)的第一恒定结构域配对。特定氨基酸残基被认为在轻链和重链可变结构域之间形成交界面。VH和VL一起配对形成单个抗原结合位点。对于不同类别抗体的结构和特性,参见例如,Basic and ClinicalImmunology,第8版,Sties等(编辑),Appleton&Lange,Norwalk,CT,1994,第71页和第6章。基于其恒定结构域的氨基酸序列,可将来自任何脊椎动物物种的L链都分配为两种显然不同的类型之一,称为κ和λ。取决于其重链(CH)恒定结构域的氨基酸序列,免疫球蛋白可以分配到不同的类别或同种型。免疫球蛋白有五种类别:IgA、IgD、IgE、IgG和IgM,分别具有命名为α、δ、ε、γ和μ的重链。基于CH序列和功能的相对小的差异,γ类别和α类别被进一步划分为亚类别,例如人表达以下亚类别:IgG1、IgG2A、IgG2B、IgG3、IgG4、IgA1和IgK1。
抗体的“抗原结合片段”或“抗体片段”包含完整抗体的一部分,其仍然能与抗原结合。抗原结合片段包括,例如Fab、Fab'、F(ab')2、Fd、Fcab和Fv片段、结构域抗体(dAbs,例如鲨鱼和骆驼抗体)、包括CDR的片段、单链可变片段抗体(scFv)、单链抗体分子、由抗体片段形成的多特异性抗体、巨型抗体(maxibody)、纳米抗体、微型抗体、胞内抗体、双链抗体、三链抗体、四链抗体、v-NAR和bis-scFv、线性抗体(参见例如美国专利5,641,870,实施例2;Zapata等(1995)Protein Eng.8HO:1057),以及至少含有一部分免疫球蛋白的多肽,其足够赋予多肽特异性抗原结合。木瓜蛋白酶消化抗体产生两个相同的抗原结合片段,称为“Fab”片段和残留的“Fc”片段,该命名反映了其易于结晶的能力。Fab片段由整个L链以及H链的可变区结构域(VH)和一条重链的第一恒定结构域(CH1)一起组成。对于抗原结合,每个Fab片段都是单价的,即它具有单个抗原结合位点。胃蛋白酶处理抗体产生单个大的F(ab’)2片段,其粗略对应于具有不同抗原结合活性的两个二硫化物连接的Fab片段,并且仍然能够交联抗原。Fab’片段与Fab片段不同在于,其在CH1结构域的羧基端有一些额外残基,包括来自抗体铰链区的一个或多个半胱氨酸。本文中Fab’-SH是对恒定结构域的半胱氨酸残基带有游离巯基的Fab’的命名。最初产生的F(ab’)2抗体片段为其间具有铰链半胱氨酸的Fab’片段对。也已知抗体片段的其他化学偶联。
“生物标志物”大体上指生物分子及其定量和定性测量,其可指示疾病状态。“预后性生物标志物”与独立于疗法的疾病结局相关。例如,肿瘤缺氧是一个阴性的预后标志物—肿瘤缺氧程度越高,疾病结局呈阴性的可能性就越高。“预测性生物标志物”指示患者是否可能对特定疗法有积极反应,例如EGFR图谱分析通常用于乳腺癌患者以确定这些患者是否可能对赫塞汀(曲妥珠单抗,Genentech)有反应。“反应性生物标志物”提供了对疗法的反应的测量并且因此提供了疗法是否在起作用的指示。例如,前列腺特异性抗原水平的降低大体上指示对前列腺癌症患者的抗癌疗法在起作用。当标志物用作为本文所述治疗确定或选择患者的基础时,可以在治疗之前和/或治疗期间测量该标志物,并且临床医生使用所获得的值来评定以下任何一项:(a)个体初始接受治疗的大概或可能的适当性;(b)个体初始接受治疗的大概或可能的不适当性;(c)对治疗的反应性;(d)个体继续接受治疗的大概或可能的适当性;(e)个体继续接受治疗的大概或可能的不适当性;(f)调整剂量;(g)预测临床益处的可能性;或(h)毒性。本领域技术人员将会充分理解的是,在临床环境中对生物标志物的测量为清楚指示,即,该参数用作开始、继续、调整和/或停止本文所述治疗的施用的基础。
“癌症”意为以异常方式增殖的细胞集合。如本文所用,术语“癌症”是指在哺乳动物中发现的所有类型的癌症、肿瘤、恶性肿瘤或良性肿瘤,包括白血病、癌和肉瘤。示例性癌症包括急性和慢性淋巴细胞性白血病、急性粒细胞性白血病、肾上腺皮质癌、膀胱癌、脑癌、乳腺癌、宫颈癌、宫颈增生、绒毛膜癌、慢性粒细胞性白血病、慢性淋巴细胞性白血病、结肠癌、子宫内膜癌、肾癌、胆道癌、肝细胞瘤、肝癌、食管癌、原发性血小板增多症、泌尿生殖系统癌、神经胶质瘤、胶质母细胞瘤、毛细胞白血病、头颈癌、霍奇金病、卡波西肉瘤、肺癌、淋巴瘤、恶性类癌、恶性高钙血症、恶性黑色素瘤、恶性胰腺胰岛素瘤、甲状腺髓样癌、黑色素瘤、软骨肉瘤、多发性骨髓瘤、蕈样肉芽肿病、髓性和淋巴细胞性白血病、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、成骨肉瘤、卵巢癌、胰腺癌、真性红细胞增多症、原发性脑癌、原发性巨球蛋白血症、前列腺癌、肾细胞癌、横纹肌肉瘤、皮肤癌、小细胞肺癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌和威尔姆斯瘤。
“CDR”是抗体、抗体片段或抗原结合片段的互补性决定区氨基酸序列。这些是免疫球蛋白重链和轻链的高可变区。免疫球蛋白的可变部分有三个重链CDR和三个轻链CDR(或CDR区)。
“临床结局”、“临床参数”、“临床反应”或“临床终点”是指涉及患者对疗法的反应的任何临床观察或测量。临床结局的非限制性实例包括肿瘤反应(TR)、总生存期(OS)、无进展生存期(PFS)、无疾病生存期、肿瘤复发时间(TTR)、肿瘤进展时间(TTP)、相对风险(RR)、毒性或副作用。
本文所用的“组合”是指除了一个或多个额外的活性形式之外提供第一活性形式(其中可使用一个或多个活性形式)。预计在本文所述组合的范围内的是组合形式或伴侣(即活性化合物、组分或剂)的任何方案,包含在单个或多个化合物和组合物中。要理解,单一组合物、制剂或单位剂型(即固定剂量组合)内的任何形式都必须有相同的给药方案和递送途径。这并不旨在暗示必须将各形式配制成一起递送(例如,以相同的组合物、制剂或单位剂型)。可以通过相同或不同的制造商来制造和/或配制组合形式。因此,组合伴侣可以是例如彼此还独立销售的完全分开的药物剂型或药物组合物。
本文所用的“组合疗法”、“与…组合”或“与…结合”表示具有至少两种不同治疗形式(即化合物、组分、靶向剂或治疗剂)的任何形式的并存、平行、同时、连续或间歇的治疗。因此,该术语是指在对受试者施用其他治疗形式之前、期间或之后施用一种治疗形式。可以以任何顺序施用组合形式。按医疗护理人员处方或根据监管机构的方式和给药方案一起施用(例如同时地以相同或分开的组合物、制剂或单位剂型)或单独施用(例如在同一天或不同天并根据分开的组合物、制剂或单位剂型的适当给药方案以任何顺序)治疗活性形式。一般来说,每种治疗形式都将按为该治疗形式所确定的剂量和/或时间表施用。任选地,在组合疗法中可能使用四种或更多的形式。另外,本文提供的组合疗法可以与其他类型的治疗结合使用。例如,在用于受试者的现有护理标准相关的其他治疗中,其他抗癌治疗可以尤其选自化疗、手术、放疗(辐射)和/或激素疗法。
“完全反应”或“完全缓解”是指对治疗反应,癌症的所有病征消失。这并不总是意味着癌症已经治愈。
本文所用的“包含”旨在意为组合物和方法包括所记载的元素,但不排除其他元素。当用于定义组合物和方法时,“基本由…组成”应当意为排除对组合物或方法有任何基本意义的其他元素。
“由…组成”应当意为对所要求保护的组合物和基本方法步骤,排除不只是微量元素的其他成分。通过每一个这些过渡术语定义的实施方案都在本发明范围内。因此,方法和组合物旨在可以包括另外的步骤和组分(包含)或可替代地包括无意义的步骤和组合物(基本由…组成),或可替代地旨在仅包括所述的方法步骤或组合物(由…组成)。
“剂量(dose)”和“剂量(dosage)”是指用于给药的活性剂或治疗剂的特定量。这些量包括在“剂型”中,其指适合作为人类受试者和其他哺乳动物的单位剂量的物理离散单位,每单位含有预定量的活性剂,联合一种或多种合适的药物赋形剂(例如载体),经计算以产生所需的起始、耐受性和治疗效果。
根据本发明的“药物缀合物”或“药物”是根据本发明的EGFR Fcab与选自包括但不限于以下组的药物的缀合物:蒽环霉素、多柔比星、甲氨蝶呤、澳瑞他汀包括单甲基澳瑞他汀E(MMAE)和单甲基澳瑞他汀F(MMAF)、美坦生类化合物及其美坦生类化合物衍生物(DM)、卡奇霉素、倍癌霉素和吡咯并苯二氮(PBD)二聚体、V-ATP酶抑制剂、促凋亡剂、Bcl2抑制剂、MCL1抑制剂、HSP90抑制剂、IAP抑制剂、mTor抑制剂、微管稳定剂、微管失稳剂、鹅膏蕈碱、吡咯并苯二氮/>、RNA聚合酶抑制剂、多拉司他汀、美坦生类化合物、MetAP(甲硫氨酸氨基肽酶)、蛋白质CRM1的核输出抑制剂、DPPIV抑制剂、蛋白酶体抑制剂、线粒体中磷酰基转移反应抑制剂、蛋白质合成抑制剂、激酶抑制剂、CDK2抑制剂、CDK9抑制剂、驱动蛋白抑制剂、HDAC抑制剂、DNA损伤剂、DNA烷基化剂、DNA嵌入剂、DNA小沟结合剂或DHFR抑制剂。
根据本发明的“Fcab”是基于IgG1的同源二聚体Fc区,其将Fc效应器功能与位于CH3结构域的C端结构环的工程化抗原结合位点组合。21-23包含例如以高亲和力结合EGFR的修饰lgG1 Fc结构域的抗原结合Fc片段(也称为FcabTM[具有抗原结合的Fc片段])在WO2009/132876 A1和WO 2009/000006 A1中描述,在此通过引用以其整体并入。本文所述特异性结合成员包括本文所述的抗原结合Fc片段,其每一个在至少一个结构环区内具有一个或多个氨基酸修饰,其中修饰的结构环区与抗原(例如EGFR)表位特异性结合,未修饰的Fc片段不与其显著结合。
“Fc”是包含通过二硫化物维系在一起的两条H链的羧基端部分的片段。抗体的效应器功能由Fc区序列决定,某些类型细胞中发现的Fc受体(FcR)也识别该区。抗原结合Fc片段可包含Fc片段的恒定结构域(例如CH2或CH3结构域)的一个或多个结构环区内的工程化抗原结合位点。抗原结合Fc片段的制备在WO 2006/072620和WO2009/132876中描述。用于本发明的特异性结合成员优选是(或包含)抗原结合Fc片段,也称为FcabTM。更优选地,用于本发明的特异性结合成员是抗原结合Fc片段。特异性结合成员可以是IgA1、IgA2、IgD、IgE、IgG、IgG2、IgG3、IgG4或IgM抗原结合Fc片段。最优选地,本文所指的特异性结合成员是IgG1(例如人IgG1)抗原结合Fc片段。在某些实施方案中,特异性结合成员是包含铰链或其部分、CH2结构域和CH3结构域的IgG1抗原结合Fc片段。
“Fv”是最小抗体片段,其含有完整的抗原识别和抗原结合位点。该片段由一个重链可变区结构域和一个轻链可变区结构域以紧密、非共价缔合形式的二聚体组成。这两个结构域的折叠产生出六个高变环(H链和L链各有3个环),其为抗原结合贡献氨基酸残基并赋予抗体抗原结合特异性。然而,即使单个可变结构域(或仅包含三个对抗原有特异性的HVR的一半Fv)也具有识别和结合抗原的能力,尽管其亲和力比整个结合位点更低。
“人抗体”是拥有与人产生的抗体的氨基酸序列相对应的氨基酸序列的抗体,和/或使用了本文公开的任何用于制备人抗体的技术制成的抗体。这种人抗体的定义具体排除包含非人抗原结合残基的人源化抗体。可使用本领域已知的各种技术产生人抗体,包括噬菌体展示文库(参见例如Hoogenboom和Winter(1991),JMB227:381;Marks等(1991)JMB222:581)。Cole等(1985)Monoclonal Antibodies and Cancer Therapy,Alan R.Liss,第77页;Boerner等(1991),J.Immunol.147(l):86;van Dijk和van de Winkel(2001)Curr.Opin.Pharmacol.5:368)描述的方法中也可获得制备人单克隆抗体的方法。可通过向转基因动物施用抗原来制备人抗体,该转基因动物已被修饰为对抗原挑战反应以产生这种抗体,而其内源性基因座已失效,例如免疫异种小鼠(xenomice)(关于XENOMOUSE技术参见例如美国专利号6,075,181;和6,150,584)。关于经由人B细胞杂交瘤技术生成人抗体,也参见例如Li等(2006)PNAS USA,103:3557。
非人(例如鼠)抗体的“人源化”形式是包含来源于非人免疫球蛋白的最小序列的嵌合抗体。在一个实施方案中,人源化抗体是人免疫球蛋白(受体抗体),其中以非人物种(供体抗体)例如小鼠、大鼠、兔或非人灵长类中具有所需特异性、亲和力/或能力的HVR的残基取代受体内HVR的残基。在一些实例中,以相应的非人残基取代人类免疫球蛋白的框架(“FR”)残基。此外,人源化抗体可包含在受体抗体或供体抗体中未发现的残基。可以进行这些修饰以进一步完善抗体性能,例如结合亲和力。一般来说,人源化抗体基本上将包含至少一个,和典型地两个,可变结构域的全部,其中所有或基本上所有高变环对应于非人免疫球蛋白序列的高变环,并且所有或基本所有FR区是人免疫球蛋白序列的FR区,尽管FR区可能包括一个或多个改善抗体性能(例如结合亲和力、异构化、免疫原性等)的个别FR残基取代。FR中这些氨基酸取代的数量典型地在H链中不超过6个和在L链中不超过3个。任选地人源化抗体还将包含至少一部分的免疫球蛋白恒定区(Fc),典型为人免疫球蛋白恒定区。进一步的细节参见例如Jones等(1986)Nature 321:522;Riechmann等(1988),Nature 332:323;Presta(1992)Curr.Op.Struct.Biol.2:593;Vaswani和Hamilton(1998),Ann.Allergy,Asthma&Immunol.1:105;Harris(1995)Biochem.Soc.Transactions 23:1035;Hurle和Gross(1994)Curr.Op.Biotech.5:428;和美国专利号6,982,321和7,087,409。
“输注(infusion)”或“输注(infusing)”是指为治疗目的经静脉将含有药物的溶液引入体内。这一般经由静脉(IV)输液袋来实现。
“转移性”癌症是指已从身体的一个部位(例如肺)扩散到身体另一个部位的癌症。
如本文所用,“单克隆抗体”是指从基本上同质的抗体群体中获得的抗体,即除了可少量存在的可能的天然存在的突变和/或翻译后修饰(例如异构化和酰胺化)外,组成该群体的个别抗体是相同的。单克隆抗体是针对单一抗原位点高度特异的。与典型地包括针对不同决定簇(表位)的不同抗体的多克隆抗体制剂相反,每种单克隆抗体针对抗原上的单一决定簇。除了其特异性之外,单克隆抗体的优势在于它们是通过杂交瘤培养合成的,并且不被其他免疫球蛋白污染。修饰语“单克隆”表明抗体的特征是从基本上同质的抗体群体中获得,并且不会被理解为需要通过任何特定方法来产生抗体。例如,根据本发明要使用的单克隆抗体可以通过各种技术制备,包括例如杂交瘤方法(例如,Kohler和Milstein(1975)Nature 256:495;Hongo等(1995)Hybridoma 14(3):253;Harlow等(1988)Antibodies:ALaboratory Manual(Cold Spring Harbor Laboratory Press,第2版.;Hammerling等(1981)载于Monoclonal Antibodies和T-CeIl Hybridomas 563(Elsevier,N.Y.)、重组DNA方法(参加例如美国专利号4,816,567)、噬菌体展示技术(参加例如Clackson等(1991)Nature 352:624;Marks等(1992)JMB 222:581;Sidhu等(2004)JMB 338(2):299;Lee等(2004)JMB 340(5):1073;Fellouse(2004)PNAS USA 101(34):12467;和Lee等(2004)J.Immunol.Methods 284(1-2):119),和在具有部分或全部人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物中产生人抗体或类人抗体的技术(参加例如WO 1998/24893;WO 1996/34096;WO 1996/33735;WO 1991/10741;Jakobovits等(1993)PNAS USA 90:2551;Jakobovits等(1993)Nature 362:255;Bruggemann等(1993)Year in Immunol.7:33;美国专利号5,545,807;5,545,806;5,569,825;5,625,126;5,633,425;和5,661,016;Marks等(1992)Bio/Technology 10:779;Lonberg等(1994)Nature 368:856;Morrison(1994)Nature 368:812;Fishwild等(1996)Nature Biotechnol.14:845;Neuberger(1996),Nature Biotechnol.14:826;和Lonberg和Huszar(1995),Intern.Rev.Immunol.13:65-93)。
本文的单克隆抗体特别包括嵌合抗体(免疫球蛋白),其中重链和/或轻链的一部分与来源于特定物种或属于特定抗体类别或亚类别的抗体中的对应序列相同或同源,而链的其余部分与来源于另一物种或属于另一抗体类别或亚类别的抗体以及这些抗体的片段(只要其展现出所需生物活性)的对应序列相同或同源(参见例如美国专利号4,816,567;Morrison等(1984)PNAS USA,81:6851)。
“客观反应”是指可测量的反应,包括完全反应(CR)或部分反应(PR)。
“部分反应”是指对治疗作出反应,一种或多种肿瘤或损伤的尺寸减少或体内癌症程度减少。
在本文中互换使用的“患者”和“受试者”,是指需要癌症治疗的哺乳动物。一般地,患者是被诊断患有癌症的一种或多种症状或有该风险的人。在某些实施方案中,“患者”或“受试者”可指非人哺乳动物,例如非人灵长类、狗、猫、兔、猪、小鼠或大鼠或用于例如筛选、表征和评价药物和疗法的动物。
关于肽或多肽序列的“序列同一性百分比(%)”的定义为:在比对序列并引入间隙(如必要)以实现最大序列同一性百分比后,且不考虑任何保守的取代作为序列同一性的一部分,候选序列中的氨基酸残基与特定肽或多肽序列的氨基酸残基相同的百分比。用于测定氨基酸序列同一性百分比目的的比对可以以本领域技术范围内的多种方法实现,例如,使用公开可获得的计算机软件,例如BLAST、BLAST-2或ALIGN软件。本领域技术人员可以测定用于测量比对的适当参数,包括在被比较序列的全长上实现最大比对的任何所需算法。
“药学上可接受的”表明该物质或组合物必须与构成制剂的其他成分和/或用其处理的哺乳动物,在化学和/或毒理学上兼容。“药学上可接受的载体”包括任何和所有生理相容的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等等。药学上可接受的载体的实例包括一种或多种水、盐水、磷酸盐缓冲盐水、右旋糖、甘油、乙醇等等,及其组合。
EGFR Fcab-药物缀合物的“药学上可接受的盐”形式绝大部分是通过常规方法制备的。如果本发明的EGFR Fcab-药物缀合物含有羧基,则一种其合适的盐可以通过将本发明的化合物与合适的碱反应以给出相应的碱加成盐来形成。所述碱例如是碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,例如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;以及各种有机碱,例如哌啶、二乙醇胺和N-甲基谷氨酰胺。
此外,本发明的EGFR Fcab-药物缀合物的碱盐包括铝盐、铵盐、钙盐、铜盐、铁(III)盐、铁(II)盐、锂盐、镁盐、锰(III)盐、锰(II)盐、钾盐、钠盐和锌盐,但这并不旨在代表一种限定。
在上文提到的盐中,优选为铵盐;碱金属盐钠盐和钾盐以及碱土金属盐钙盐和镁盐。来源于药学上可接受的有机无毒性碱的本发明的EGFR Fcab-药物缀合物的盐,包括伯胺、仲胺和叔胺、取代胺的盐,也包括天然存在的取代胺、环状胺和碱性离子交换树脂的盐,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N'-二苄基乙二胺(苄星(benzathine))、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海巴明、异丙胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲胺(氨丁三醇),但这并不旨在代表一种限定。
如所提到的,EGFR Fcab-药物缀合物的药学上可接受的碱加成盐用金属或胺形成,例如碱金属和碱土金属或有机胺。优选的金属是钠、钾、镁和钙。优选的有机胺是N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
本发明的EGFR Fcab-药物缀合物的碱加成盐是通过将游离酸形式与足够量的所需碱接触来制备,使得盐以常规方式形成。游离酸可以常规方式通过将盐形式与酸接触并分离游离酸来再生。关于某些物理性质,游离酸形式与对应的盐形式在某一方面不同,例如在极性溶剂中的溶解性;然而用于本发明目的,在其他方面,盐对应于其各自的游离酸形式。
“前药”是指本发明的EGFR Fcab-药物缀合物的衍生物,其已通过例如烷基或酰基(也参见下文的氨基和羟基保护基团)、糖或寡肽的方式修饰,并且在生物体内快速裂解或释放以形成有效分子。这些前药还包括本发明的EGFR Fcab-药物缀合物的生物可降解聚合物衍生物,例如如Int.J.Pharm.115(1995),61-67中所述。
“复发性”癌症是一种在对初始疗法(例如手术)作出反应后,在初始位点或者远处位点再生长的癌症。局部“复发性”癌症是在与之前治疗过癌症的相同地方,在治疗后复发的癌症。
一个或多个症状(及该短语的语法等价物)的“降低”是指症状严重性或频率的减少或症状的消除。
“单链Fv”,也缩写为“sFv”或“scFv”是包含连接至单个多肽链的VH和VL抗体结构域的抗体片段。在一些实施方案中,sFv多肽进一步包含VH和VL结构域之间的多肽接头以使sFv能够形成用于抗原结合的所需结构。关于sFv的综述,参见例如Pluckthun(1994),载于thePharmacology of Monoclonal Antibodies,第113卷,Rosenburg和Moore(编辑),SpringerVerlag,New York,第269页。
“溶剂化物”是指将惰性溶剂分子加合至本发明的EGFR Fcab-药物缀合物上,由于它们相互间的吸引力而形成。例如溶剂化物是水合物,例如一水合物或二水合物或醇化物,即具有醇例如甲醇或乙醇的加成化合物。
“基本相同”意为(1)查询氨基酸序列与主题氨基酸序列展现了至少75%、85%、90%、95%、99%或100%的氨基酸序列同一性,或(2)查询氨基酸序列与主题氨基酸序列的氨基酸序列差异不超过其20%、30%、20%、10%、5%、1%或0%的氨基酸位置,并且其中氨基酸位置的差异是任何的氨基酸取代、缺失或插入。
“全身”治疗是一种药物物质经血液传输,到达并影响全身各处细胞的治疗。
EGFR Fcab-药物缀合物的“治疗有效量”是指这样的有效量,当以必要的剂量和在必要的时间段内向癌症患者施用时,其将具有预期治疗效果,例如缓解、改良、减轻或消除癌症在患者内的一种或多种表现,或治疗癌症患者过程中的任何其他临床结果。治疗效果不必然通过施用一个剂量发生,并且可能仅在施用一系列剂量之后发生。因此,可以以一次或多次给药施用治疗有效量。这种治疗有效量可以根据如个体的疾病状态、年龄、性别和体重以及EGFR Fcab-药物缀合物在个体中引起所需反应的能力等因素而变化。治疗有效量也是一种EGFR Fcab-药物缀合物的治疗有益效果超过任何毒性或有害效果的量。术语“有效量”表示在组织、系统、动物或人中,造成例如研究人员或医生所寻求或所需的生物或医学反应的药物的量或药物活性化合物的量。
此外,术语“治疗有效量”表示与没有接受该量的对应受试者相比,具有以下后果的量:改善治疗、痊愈、预防或消除疾病、综合征、疾病状态、病、病症或预防副作用或也降低疾病、病或病症的进展。术语“治疗有效量”还涵盖对增加正常生理功能有效的量。
“治疗”病况或患者或病况或患者的“治疗”是指采取措施以获得有益的或需要的结果,包括临床结果。为了本发明的目的,有益的或需要的临床结果包括但不限于缓解、改良癌症的一种或多种症状;减小疾病程度;延迟或减缓疾病进展;改良、减轻或稳定疾病状态;或其他有益结果。要理解,提及“治疗(treating)”或“治疗(treatment of)”包括预防以及缓解病况的确定症状。因此“治疗”状态、病症或病况或状态、病症或病况的“治疗”包括:(1)防止或延迟出现在受试者中发展的状态、病症或病况的临床症状,所述受试者可能患有或易患该状态、病症或病况但至今还没经历或显现该状态、病症或病况的临床或亚临床症状,(2)抑制状态、病症或病况,即阻止、降低或延迟疾病的发展或其复发(在维持治疗的情况下)或至少一种其临床或亚临床症状,或(3)减缓或减弱疾病,即造成状态、病症或病况或至少一种其临床或亚临床症状的消退。
本文所用的“单位剂型”是指适用于待治疗的受试者的治疗制剂的物理离散单位。然而要理解,本发明组合物的每日总用量将由主治医生在合理的医学判断范围内决定。对任何特定受试者或生物体的特定有效剂量水平将取决于多种因素,包括治疗中的病症和病症的严重性;采用的特定活性剂的活性;采用的特定组合物;受试者的年龄、体重、大体健康状况、性别和饮食;采用的特定活性剂的给药时间和排出率;治疗持续时间;与所采用的特定化合物组合使用或同时使用的药物和/或另外的疗法,以及医学领域中熟知的类似因素。
抗体的“可变区”或“可变结构域”是指抗体重链或轻链的氨基端结构域。重链和轻链的可变结构域可以分别称为“VH”和“VL”。这些结构域大体上是抗体最可变的部位(相对于同一类别的其他抗体),并且含有抗原结合位点。如本文所用,为方便起见,多个项目、结构元件、组成元件和/或材料可以在共同列表中呈现。然而,这些列表应被理解为如同将列表中的每一个成员个别地识别为一个单独且独特的成员。
可以在本文中以范围形式表达或呈现浓度、量和其他数值数据。要理解,使用该范围形式仅是为了方便和简洁,并且因此应当灵活地解释为不仅包括明确记载为该范围界限的数值,也包括被涵盖在该范围内的所有个别数值或子范围,如同明确记载每个数值和子范围。作为说明,“约1至约5”的数值范围应被解释为不仅包括明确记载的约1至约5的值,也包括在指示范围内的个别值和子范围。因此,在此数值范围中包括例如2、3和4的个别值和例如1-3、2-4和3-5等的子范围,以及个别的1、2、3、4和5。同样的原则适用于只列举一个数值作为最小值或最大值的范围。此外,不论所描述的特征或范围的宽度,这种解释都应当适用。
当发现和开发治疗剂时,本领域技术人员尝试优化药代动力学参数同时保留所需的体外特性。合理地假设是,很多药代动力学特征差的化合物易受氧化代谢影响。目前可获得的体外肝微粒体测定法提供关于这类氧化代谢过程的有价值信息,这反过来允许合理设计本发明的氘化化合物,通过对该氧化代谢的抗性来改善其稳定性。因此,本发明的EGFRFcab-药物缀合物的药代动力学特征获得显著改善,并且可以根据体内半衰期(T/2)、最大治疗效果浓度(Cmax)、剂量反应曲线下面积(AUC)和F的增加;以及根据清除、剂量和材料成本的降低,来定量表达。
特别地,本发明还涉及包含至少一种根据本发明的EGFR Fcab-药物缀合物的药物,其用于治疗和/或预防生理状态和/或病理生理状态。
生理状态和/或病理生理状态意为医学相关的生理状态和/或病理生理状态,例如疾病或患病和医学病症、病、症状或并发症等,特别是疾病。
本发明的优选实施方案是包含至少一种根据本发明的EGFR Fcab-药物缀合物的药物,其用于治疗和/或预防生理状态和/或病理生理状态,该生理状态和/或病理生理状态选自过度增殖性疾病和病症。
而本发明更优选的实施方案是用于治疗和/或预防生理状态和/或病理生理状态的根据本发明的药物,该生理状态和/或病理生理状态选自过度增殖性疾病和病症,其中该过度增殖性疾病或病症是癌症。
本发明的另一优选实施方案是用于治疗癌症的根据本发明的药物,其中所述癌症选自急性和慢性淋巴细胞性白血病、急性粒细胞性白血病、肾上腺皮质癌、膀胱癌、脑癌、乳腺癌、宫颈癌、宫颈增生、绒毛膜癌、慢性粒细胞性白血病、慢性淋巴细胞性白血病、结肠癌、子宫内膜癌、肾癌、胆道癌、肝细胞瘤、肝癌、食管癌、原发性血小板增多症、泌尿生殖系统癌、神经胶质瘤、胶质母细胞瘤、毛细胞白血病、头颈癌、霍奇金病、卡波西肉瘤、肺癌、淋巴瘤、恶性类癌、恶性高钙血症、恶性黑色素瘤、恶性胰腺胰岛素瘤、甲状腺髓样癌、黑色素瘤、软骨肉瘤、多发性骨髓瘤、蕈样肉芽肿病、髓性和淋巴细胞性白血病、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、成骨肉瘤、卵巢癌、胰腺癌、真性红细胞增多症、原发性脑癌、原发性巨球蛋白血症、前列腺癌、肾细胞癌、横纹肌肉瘤、皮肤癌、小细胞肺癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌和威尔姆斯瘤。
特别优选与EGFR有联系的生理状态和/或病理生理状态。因此,本发明涉及用于治疗EGFR阳性癌症的根据本发明的药物。
本文所指的癌症可以是胃癌、乳腺癌、结肠直肠癌、卵巢癌、胰腺癌、肺癌(例如,非小细胞肺癌)、胃部癌症或子宫内膜癌。所有这些癌症都显示过表达EGFR。优选地,癌症是胃癌、乳腺癌或结肠直肠癌。更优选地,癌症是胃癌或乳腺癌。在一个优选实施方案中,癌症是胃癌。本文所指的胃癌包括食管癌。在另一优选实施方案中,癌症是乳腺癌。癌症的EGFR基因拷贝数如上述所示。该癌症可以称为EGFR阳性(EGFR+)的或过表达EGFR的。因此,本文所指的癌症可以是EGFR阳性的。另外,或备选地,本文所指的癌症可以过表达EGFR。癌症是否是EGFR阳性的或过表达EGFR的,可以使用例如免疫组织化学(IHC)来初步测定,任选地随后通过如以上所概述的方法例如qPCR。
进一步优选的实施方案是用于治疗实体瘤的根据本发明的药物,该实体瘤包括乳腺癌、胃癌、胃部癌症、结肠直肠癌、卵巢癌、胰腺癌、子宫内膜癌或非小细胞肺癌。
在优选实施方案中,癌症选自肺癌例如非小细胞肺癌[NSCLC]、多形性胶质母细胞瘤、皮肤癌如皮肤鳞状细胞癌、头颈癌例如头颈鳞状细胞癌[HNSCC]、乳腺癌、胃部癌症(胃癌)、结肠直肠癌(CRC)、卵巢癌、胰腺癌和子宫内膜癌。
上述公开的药物旨在包括根据本发明的EGFR Fcab-药物缀合物在制备用于治疗和/或预防上述生理状态和/或病理生理状态的药物中的对应用途。
另外地,上述公开的药物旨在包括用于治疗和/或预防上述生理状态和/或病理生理状态的对应方法,其中向需要该治疗的患者施用至少一种根据本发明的EGFR Fcab-药物缀合物。
因此,本发明的另一个实施方案是根据本发明的EGFR Fcab-药物缀合物用于治疗癌症的用途。
因此,本发明的另一个实施方案是EGFR Fcab-药物缀合物在制造用于治疗癌症的药物中的用途。
因此,本发明的另一个实施方案是用于治疗受试者癌症的方法,其中该方法包括向受试者施用根据本发明的EGFR Fcab-药物缀合物或药物制剂。
因此,本发明的另一个实施方案是用于治疗癌症的方法的应用,其包括向有其需要的受试者施用根据本发明的EGFR Fcab-药物缀合物或药物制剂。
在一个实施方案中,本发明的EGFR Fcab-药物缀合物用于治疗人类受试者。用EGFR Fcab和药物的治疗组合进行治疗的主要预期益处是这些人类患者在风险/收益比率上的获益。施用本发明的EGFR Fcab-药物缀合物可能比施用个别的治疗剂更有利,因为与单独施用单一治疗剂相比,EGFR Fcab和药物的组合可能提供一个或多个下列改善的特性:i)抗癌效果比活性最高的单一药剂更好,ii)抗癌活性协同或高度协同,iii)提供增强的抗癌活性伴随降低的副作用特征的给药方案,iv)毒性效应特征降低,v)治疗窗口增加,和/或vi)一种或两种治疗剂的生物利用率增加。
在某些实施方案中,本发明提供了以过度或异常细胞增殖为特征的疾病、病症和病况的治疗。该疾病包括增殖性或过度增殖性疾病。增殖性和过度增殖性疾病的实例包括癌症和骨髓增殖性病症。
在另一实施方案中,癌症选自癌、淋巴瘤、白血病、母细胞瘤和肉瘤。所述癌症的更多特定实例包括鳞状细胞癌、骨髓瘤、小细胞肺癌、非小细胞肺癌、神经胶质瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性髓性白血病、多发性骨髓瘤、胃肠(道)癌、肾癌、卵巢癌、肝癌、淋巴母细胞性白血病、淋巴细胞性白血病、结肠直肠癌、子宫内膜癌、肾癌、前列腺癌、甲状腺癌、黑色素瘤、软骨肉瘤、神经母细胞瘤、胰腺癌、胶质母细胞瘤、宫颈癌、脑癌、胃部癌症、膀胱癌、肝细胞瘤、乳腺癌、结肠癌、胆道癌和头颈癌。所讨论的疾病或医学病症可以选自在WO2015118175、WO2018029367、WO2018208720、PCT/US18/12604、PCT/US19/47734、PCT/US19/40129、PCT/US19/36725、PCT/US19/732271、PCT/US19/38600、PCT/EP2019/061558公开的那些中任何一种。
在一个实施方案中,癌症选自:阑尾癌、膀胱癌、乳腺癌、宫颈癌、结肠直肠癌、子宫内膜癌、食管癌(特别是食管鳞状细胞癌)、输卵管癌、胃癌、神经胶质瘤(例如弥漫性内生性脑桥神经胶质瘤)、头颈癌(特别是头颈鳞状细胞癌和口咽癌)、白血病(特别是急性淋巴母细胞性白血病、急性髓性白血病)、肺癌(特别是非小细胞肺癌)、淋巴瘤(特别是霍奇金淋巴瘤、非霍奇金淋巴瘤)、黑色素瘤、间皮瘤(特别是恶性胸膜间皮瘤)、默克尔细胞癌、神经母细胞瘤、口腔癌、骨肉瘤、卵巢癌、前列腺癌、肾癌、唾液腺肿瘤、肉瘤(特别是尤因肉瘤或横纹肌肉瘤)、鳞状细胞癌、软组织肉瘤、胸腺瘤、甲状腺癌、尿路上皮癌、子宫癌、阴道癌、外阴癌或威尔姆斯瘤。在进一步的实施方案中,癌症选自:阑尾癌、膀胱癌、宫颈癌、结肠直肠癌、食管癌、头颈癌、黑色素瘤、间皮瘤、非小细胞肺癌、前列腺癌和尿路上皮癌。在进一步的实施方案中,癌症选自宫颈癌、子宫内膜癌、头颈癌(特别是头颈鳞状细胞癌和口咽癌)、肺癌(特别是非小细胞肺癌)、淋巴瘤(特别是非霍奇金淋巴瘤)、黑色素瘤、口腔癌、甲状腺癌、尿路上皮癌或子宫癌。在另一实施方案中,癌症选自头颈癌(特别是头颈鳞状细胞癌和口咽癌)、肺癌(特别是非小细胞肺癌)、尿路上皮癌、黑色素瘤或宫颈癌。
在一个实施方案中,人患有实体瘤。在一个实施方案中,实体瘤是晚期实体瘤。在一个实施方案中,癌症选自头颈癌、头颈鳞状细胞癌(SCCHN或HNSCC)、胃癌、黑色素瘤、肾细胞癌(RCC)、食管癌、非小细胞肺癌、前列腺癌、结肠直肠癌、卵巢癌和胰腺癌。在一个实施方案中,癌症选自:结肠直肠癌、宫颈癌、膀胱癌、尿路上皮癌、头颈癌、黑色素瘤、间皮瘤、非小细胞肺癌、前列腺癌、食管癌和食管鳞状细胞癌。一方面,人患有下列一种或多种:SCCHN、结肠直肠癌、食管癌、宫颈癌、膀胱癌、乳腺癌、头颈癌、卵巢癌、黑色素瘤、肾细胞癌(RCC)、食管鳞状细胞癌、非小细胞肺癌、间皮瘤(例如胸膜恶性间皮瘤)和前列腺癌。另一方面,人患有液体肿瘤,例如弥漫性大B细胞淋巴瘤(DLBCL)、多发性骨髓瘤、慢性淋巴母细胞性白血病、滤泡性淋巴瘤、急性髓性白血病和慢性骨髓细胞性白血病。
在一些实施方案中,癌症是晚期癌症。在一些实施方案中,癌症是转移性癌症。在一些实施方案中,癌症是复发性癌症(例如复发性妇科癌症,例如复发性上皮卵巢癌、复发性输卵管癌、复发性原发性腹膜癌或复发性子宫内膜癌)。在一个实施方案中,癌症是复发性的或晚期的。
在各种实施方案中,本发明的方法被用作第一、第二、第三或之后的治疗线。治疗线是指患者接受的具有不同药物治疗或其他疗法的治疗顺序中的位置。第一线疗法方案是首先给予的治疗,而第二线疗法或第三线疗法分别是在第一线疗法之后或第二线疗法之后给予。因此,第一线疗法是疾病或病症的第一次治疗。在癌症患者中,第一线疗法,有时被称为初级疗法或初级治疗,可以是手术、化疗、放疗或这些疗法的组合。典型地,给予患者随后的化疗方案(第二或第三线疗法),因为患者或没有显示积极的临床结局,或只对第一或第二线疗法显示亚临床反应,或显现积极临床反应但之后经历了复发,有时候患有对引起早期积极反应的早期疗法现在有了抗性的疾病。
在一些实施方案中,癌症的治疗是癌症的第一线治疗。在一个实施方案中,癌症的治疗是癌症的第二线治疗。在一些实施方案中,该治疗是癌症的第三线治疗。在一些实施方案中,该治疗是癌症的第四线治疗。在一些实施方案中,该治疗是癌症的第五线治疗。在一些实施方案中,所述第二线、第三线、第四线或第五线癌症治疗的先前治疗包含放疗、化疗、手术或放化疗中的一种或多种。
在一个实施方案中,先前治疗包括用以下进行的治疗:二萜类化合物例如紫杉醇、nab-紫杉醇或多烯紫杉醇;长春花生物碱例如长春碱、长春新碱或长春瑞滨;铂配位复合物例如顺铂或卡铂;氮芥例如环磷酰胺、马法兰或苯丁酸氮芥;烷基磺酸盐例如白消安;亚硝基脲例如卡莫司汀;三氮烯例如达卡巴嗪;放线菌素例如放线菌素D;蒽环素例如柔红霉素或多柔比星;博来霉素;表叶毒素(epidophyllotoxin)例如依托泊苷或替尼泊苷;抗代谢抗肿瘤剂例如氟尿嘧啶、甲氨蝶呤、阿糖胞苷、巯基嘌呤、巯鸟嘌呤或吉西他滨;甲氨蝶呤;喜树碱例如伊立替康或拓扑替康;利妥昔单抗;奥法木单抗(ofatumumab);曲妥珠单抗;西妥昔单抗;贝沙罗汀(bexarotene);索拉非尼(sorafenib);erbB抑制剂例如拉帕替尼(lapatinib)、厄洛替尼或吉非替尼(gefitinib);帕妥珠单抗;伊匹木单抗(ipilimumab);纳武单抗(nivolumab);FOLFOX;卡培他滨;FOLFIRI;贝伐珠单抗(bevacizumab);阿特珠单抗(atezolizumab);塞鲁单抗(Selicrelumab);奥滨尤妥珠单抗(obinotuzumab)或其任何组合。在一个实施方案中,所述第二线癌症治疗、第三线、第四线或第五线癌症治疗的先前治疗包括伊匹木单抗和纳武单抗。在一个实施方案中,所述第二线癌症治疗、第三线、第四线或第五线癌症治疗的先前治疗包括FOLFOX、卡培他滨、FOLFIRI/贝伐珠单抗和阿特珠单抗/塞鲁单抗。在一个实施方案中,所述第二线癌症治疗、第三线、第四线或第五线癌症治疗的先前治疗包括卡铂/Nab-紫杉醇。在一个实施方案中,所述第二线癌症治疗、第三线、第四线或第五线癌症治疗的先前治疗包括纳武单抗和电化学疗法。在一个实施方案中,所述第二线癌症治疗、第三线、第四线或第五线癌症治疗的先前治疗包括放疗、顺铂和卡铂/紫杉醇。
在一个实施方案中,本发明的方法进一步包含向所述人类施用至少一种肿瘤剂或癌症辅助剂。本发明的方法也可以与癌症治疗的其他治疗方法一起使用。
典型地,在本发明的癌症的治疗中,可以共同施用对治疗中的肿瘤(例如易感肿瘤)有活性的任何抗肿瘤剂或癌症辅助剂。所述药剂的实例可在Cancer Principles andPractice of Oncology,V.T.Devita、T.S.Lawrence和S.A.Rosenberg(编辑),第10版(12月5日,2014),Lippincott Williams&Wilkins Publishers中找到。
在一个实施方案中,之前已经用一种或多种不同的癌症治疗形式对人进行过治疗。在一些实施方案中,癌症患者群体中至少一些患者之前已经用一种或多种疗法治疗,例如手术、放疗、化疗或免疫疗法。在一些实施方案中,癌症患者群体中至少一些患者之前已经用化疗(例如基于铂的化疗)治疗。例如,接受过二线癌症治疗的患者可以被识别为2L癌症患者(例如2L NSCLC患者)。在一些实施方案中,患者接受过二线或更多线癌症治疗(例如2L+癌症患者例如2L+子宫内膜癌患者)。在一些实施方案中,患者之前没有接受过抗体疗法,例如抗PD-1疗法。在一些实施方案中,患者之前接受过至少一线癌症治疗(例如,患者之前接受过至少一线或至少二线癌症治疗)。在一些实施方案中,患者之前接受过至少一线转移性癌症治疗(例如患者之前接受过一线或二线转移性癌症治疗)。
如实施例所述,根据本发明的EGFR Fcab-药物缀合物优选地展现有利的生物活性,其可以容易地在酶测定法和动物实验中证明。在该基于酶的测定法中,根据本发明的EGFR Fcab-药物缀合物优选地展现和造成抑制效果,其通常通过在合适范围内的IC50值记录,优选地在微摩尔范围内和更优选地在纳摩尔范围内。
本发明的EGFR Fcab-药物缀合物可用于制备药物制剂,特别是通过非化学方法。在这种情况下,将EGFR Fcab-药物缀合物与至少一种固态、液态和/或半液态的赋形剂或辅助剂一起制成合适的剂型,并且任选地与一种或多种额外的活性化合物组合。
因此,本发明进一步涉及包含根据本发明的EGFR Fcab-药物缀合物的药物制剂。
在本发明的另一实施方案中,这种药物制剂包含额外的赋形剂和/或辅助剂。另外地,根据本发明的另一实施方案是包含至少一种根据本发明的EGFR Fcab-药物缀合物和至少一种额外的药物活性化合物的药物制剂。
本发明进一步涉及制备药物制剂的方法,其特征在于将根据本发明的EGFR Fcab-药物缀合物与固态、液态或半液态的赋形剂或辅助剂一起制成合适的剂型。
根据本发明的药物制剂可用作人用药物或兽医用药,并可用于人体或动物体的治疗性治疗和可用于对抗上文所述的疾病。患者或宿主可以属于任何哺乳动物物种,例如灵长类物种,特别是人类;啮齿类,包括小鼠、大鼠和仓鼠;兔;马、牛、狗、猫等。动物模型有利于实验研究,其为治疗人类疾病提供了模型。此外该药物制剂可以用作诊断剂或试剂。
合适的载体物质是适用于肠内(例如口服)、肠胃外或局部给药且不与新型化合物反应的有机或无机物质,例如水、植物油(例如葵花油或鱼肝油)、苄醇、聚乙二醇、明胶、碳水化合物(例如乳糖或淀粉)、硬脂酸镁、滑石、羊毛脂或凡士林。由于本领域技术人员的专业知识,他熟悉哪些辅助剂适用于所需的药物制剂。除了溶剂,例如水、生理盐水溶液或醇(例如乙醇、丙醇或甘油)、糖溶液(例如葡萄糖或甘露醇溶液)、或所述溶剂的混合物、凝胶形成剂、片剂助剂和其他活性成分载体,也可以使用例如润滑剂、稳定剂和/或润湿剂、乳化剂、用于影响渗透压的盐、抗氧化剂、分散剂、消泡剂、缓冲物质、香料和/或芳香剂或矫味剂、防腐剂、增溶剂或染料。如需要,根据本发明的制剂或药物可以包含一种或多种额外的活性化合物,例如一种或多种维生素。
如有需要,根据本发明的制剂或药物可以包含一种或多种额外的活性化合物和/或一种或多种作用增强剂(辅助剂)。
为了本发明目的,术语“药物配方(pharmaceutical formulation)”和“药物制剂(pharmaceutical preparation)”用作同义词。
如本文所用,“药学上耐受的(pharmaceutically tolerated)”涉及药物、沉淀试剂、赋形剂、辅助剂、稳定剂、溶剂和其他剂,其有利于向哺乳动物施用由此获得的药物制剂,而没有不期望的生理副作用,例如恶心、头晕、消化问题等。
在用于肠胃外给药的药物制剂中,对制剂、采用的辅助剂和初级包装的等渗性、水合性(euhydration)和耐受性和安全性(低毒性)有需求。令人惊讶地,根据本发明的EGFRFcab-药物缀合物优选地具有的优点是可能直接使用,以及因此在药物制剂中使用根据本发明的EGFR Fcab-药物缀合物之前,用于去除毒理学上不可接受的剂,例如高浓度的有机溶剂或其他毒理学上不可接受的辅助剂的额外纯化步骤不是必需的。
优选地,本发明还特别涉及药物制剂,其包含至少一种沉淀非结晶、沉淀结晶或溶解或悬浮形式的根据本发明的EGFR Fcab-药物缀合物,以及任选的赋形剂和/或辅助剂和/或额外的药物活性化合物。
优选地,根据本发明的EGFR Fcab-药物缀合物能制备高浓度制剂,而不发生根据本发明的EGFR Fcab-药物缀合物的不利的、不期望的聚集。因此,在根据本发明的EGFRFcab-药物缀合物的帮助下,在水性溶剂或水性介质中可制备具有高活性成分含量的即用型溶液。
也可以冷冻干燥根据本发明的EGFR Fcab-药物缀合物,并且将所得的冷冻干燥物用于例如制备注射制剂。
可以通过将根据本发明的EGFR Fcab-药物缀合物溶解或悬浮在水性溶液中并任选地添加辅助剂来制备水性制剂。为此,将限定体积的包含限定浓度的所述额外辅助剂的储备溶液,有利地添加至具有限定浓度的根据本发明的EGFR Fcab-药物缀合物的溶液或悬浮液中,并且任选地用水将混合物稀释至预先计算的浓度。备选地,可以添加固体形式的辅助剂。随后可以将每种情况下必需量的储备溶液和/或水添加至所获得的水性溶液或悬浮液中。也可将根据本发明的EGFR Fcab-药物缀合物有利地直接溶解或悬浮在包含所有额外辅助剂的溶液中。
可有利地制备包含根据本发明的EGFR Fcab-药物缀合物并且具有4-10的pH(优选地具有5-9的pH)和250-350mOsmol/kg的渗透压摩尔浓度的溶液或悬浮液。因此,基本上可直接静脉内、动脉内、关节内、皮下或经皮地无痛施用该药物制剂。另外,也可将制剂添加至输注溶液(其还可能含有额外的活性化合物)中,例如葡萄糖溶液、等渗盐水溶液或林格溶液,因此也能够施用相对大量的活性化合物。
根据本发明的药物制剂还可以包含多种根据本发明的EGFR Fcab-药物缀合物的混合物。
根据本发明的制剂在生理学上良好耐受,易于制备,可以精确分配,并且优选地在整个储存和运输过程中以及在多次冷冻和解冻过程期间,关于测定、分解产物和聚集体是稳定的。优选地,在冰箱温度(2-8℃)和在室温(23-27℃)和60%相对大气湿度(R.H.)下,在至少三个月到两年的时间里,可将制剂以稳定的方式储存。
例如,通过干燥可将根据本发明的EGFR Fcab-药物缀合物以稳定的方式储存,并且必要时通过溶解或悬浮将其转换为即用型药物制剂。可能的干燥方法例如但不限于这些实例,氮气气体干燥、真空烘箱干燥、冷冻干燥、用有机溶剂洗涤并且随后空气干燥、液床干燥、流化床干燥、喷雾干燥、滚筒干燥、分层干燥、室温下空气干燥和额外的方法。
在使用根据本发明的制剂或药物时,根据本发明的EGFR Fcab-药物缀合物大体上与已知的、商业上可获得的制剂或制剂类似使用,优选地每使用单位的剂量为0.1和500mg之间,特别是5和300mg之间。优选地,每日剂量为0.001和250mg/kg体重之间,特别是0.01和100mg/kg体重之间。可每日施用该制剂一次或多次,例如每天两次、三次或四次。然而,患者的个别剂量取决于大量的个别因素,例如使用的特定化合物的功效、年龄、体重、大体健康状况、性别、营养、给药时间和方法、排出率、与其他药物的组合以及特定疾病的严重性和持续时间。
生物体内药物活性化合物的摄取的量度是其生物利用率。如果药物活性化合物以注射溶液的形式静脉内递送至生物体内,其绝对生物利用率,即药物以不变的形式到达全身血液(即主要循环)的比例为100%。在治疗活性化合物口服给药的情况下,活性化合物在制剂中一般是是固态形式,因此必须首先溶解,从而能克服进入障碍(例如胃肠道、口腔粘膜、鼻黏膜或皮肤,特别是角质层),或可被身体吸收。药代动力学数据(即生物利用率数据),可用与J.Shaffer等,J.Pharm.Sciences,88(1999),313-318类似的方法获得。
此外,可通过制药领域中普遍知晓的方法之一制备这种类型的药物。
药物可适于经由任何所需的合适途径给药,例如通过口服(包括颊部或舌下)、直肠、肺、鼻、局部(包括颊部、舌下或经皮)、阴道或肠胃外(包括皮下、肌肉内、静脉内、皮内以及特别是关节内)途径。这种类型的药物可以通过制药领域已知的所有方法制备,例如通过将活性EGFR Fcab-药物缀合物与赋形剂或辅助剂组合。
肠胃外给药优选地适用于根据本发明的药物给药。在肠胃外给药的情况下,特别优选关节内给药。
根据本发明的EGFR Fcab-药物缀合物也适用于制备具有缓慢、持续和/或可控的活性化合物释放的待肠胃外给药的药物。因此所述药物缀合物也适用于制备延迟释放制剂,这对患者是有利的,因为仅需要以相对大的时间间隔给药。
适于肠胃外给药的药物包括水性和非水性无菌注射溶液,其包含抗氧化剂、缓冲剂、抑菌剂和溶质,以该方法使制剂与待治疗受体的血液或滑液变得等渗;以及水性和非水性无菌悬浮液,其可包含悬浮介质和增稠剂。可在单剂量或多剂量容器中递送制剂,例如密封的安瓿和小瓶,并以冷冻-干燥(冻干)状态储存,从而仅有必要在使用前即刻添加无菌载液,例如注射用水。根据制剂制备的注射溶液和悬浮液可由无菌粉末、颗粒和片剂制备。
也可以以脂质体递送系统的形式施用根据本发明的EGFR Fcab-药物缀合物,例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可以由多种磷脂(例如胆固醇、硬脂胺或磷脂酰胆碱)形成。
可将根据本发明的EGFR Fcab-药物缀合物偶联至可溶性聚合物作为靶向药物赋形剂。这种聚合物可涵盖聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬酰氨基苯酚或聚环氧乙烷聚赖氨酸,其被棕榈酰基取代。另外,可将根据本发明的EGFR Fcab-药物缀合物偶联至一类适用于实现药物缓释的生物可降解聚合物,所述聚合物例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯、聚乳酸-羟基乙酸、聚合物,例如右旋糖酐和甲基丙烯酸酯的缀合物、聚磷酸酯、多种多糖和聚胺以及聚-ε-己内酯、白蛋白、壳聚糖、胶原或改性明胶以及水凝胶的交联或两亲性嵌段共聚物。
特别适用于肠内给药(口服或直肠)的是片剂、糖衣丸、胶囊、糖浆、汁液(juice)、滴剂或栓剂,适用于局部使用的是软膏、乳膏、糊剂、乳液、凝胶、喷剂、泡沫剂、气雾剂、溶液(例如醇溶液,例如乙醇或异丙醇、乙腈、DMF、二甲基乙酰胺、1,2-丙二醇或其与彼此和/或与水的混合物)或粉末。脂质体制剂也特别适用于局部使用。
在配制成软膏的情况下,可采用具有石蜡基质或水混溶的乳膏基质的活性化合物。备选地,可将活性EGFR Fcab-药物缀合物配制成具有水包油乳膏基质或油包水基质的乳膏。
适用于经皮给药的药物可以作为独立的药膏递送以与受体的表皮进行延长的、紧密的接触。因此,例如可用离子电渗法从药膏供应活性EGFR Fcab-药物缀合物,如Pharmaceutical Research,3(6),318(1986)中的一般术语所述。
不言自明,关于特定类型的药物制剂,除了上述特别提到的组分之外,根据本发明的药物也可以包含本领域中的其他常见剂。
本文所述的EGFR Fcab-药物缀合物也可以是药物配方、药物制剂、套件或试剂盒的形式。
本发明进一步涉及一种由下列单独包装组成的套件(试剂盒):
a)有效量的包含至少一种根据本发明的EGFR Fcab-药物缀合物,和
b)有效量的额外的药物活性化合物。
该套件包含合适的容器,例如盒子或纸箱、单个的瓶、袋或安瓿。例如,该套件可以包含单独的安瓿,每个安瓿含有有效量的溶解或冷冻干燥形式的根据本发明的EGFR Fcab-药物缀合物和有效量的溶解或冷冻干燥形式的额外的药物活性化合物。
在一个实施方案中,每2-6周(例如2周、3周或4周,特别是3周)施用一次根据本发明的EGFR Fcab-药物缀合物。在一个实施方案中,每两周施用一次EGFR Fcab-药物缀合物(“Q2W”)。在一个实施方案中,每三周施用一次EGFR Fcab-药物缀合物(“Q3W”)。在一个实施方案中,每6周施用一次EGFR Fcab-药物缀合物(“Q6W”)。在一个实施方案中,在2-6个给药周期中(例如前3个、前4个或前5个给药周期,特别是前4个给药周期)以Q3W施用EGFR Fcab-药物缀合物。
在某些实施方案中,待治疗的癌症是EGFR阳性的。例如,在某些实施方案中,待治疗的癌症展现EGFR+表达(例如,高EGFR表达)。检测癌症或肿瘤上的生物标志物(例如EGFR)的方法在本领域是常规的且本文已考虑到。非限制性实例包括免疫组织化学、免疫荧光和荧光激活细胞分选(FACS)。在一些实施方案中,通过Q2W静脉内施用剂量约为1200mg的抗EGFR Fcab-药物缀合物来治疗具有高EGFR癌症的受试者或患者。在一些实施方案中,通过Q3W静脉内施用剂量约为1800mg的EGFR Fcab-药物缀合物来治疗具有高EGFR癌症的受试者或患者。在一些实施方案中,通过Q3W静脉内施用剂量约为2100mg的EGFR Fcab-药物缀合物来治疗具有高EGFR癌症的受试者或患者。在一些实施方案中,通过Q3W静脉内施用剂量约为2400mg的EGFR Fcab-药物缀合物来治疗具有高EGFR癌症的受试者或患者。在一些实施方案中,通过Q3W静脉内施用剂量约为15mg/kg的EGFR Fcab-药物缀合物来治疗具有高EGFR癌症的受试者或患者。
在某些实施方案中,在肿瘤微环境中待治疗的癌症的腺苷水平升高。
在某些实施方案中,给药方案包括施用抗EGFR Fcab-药物缀合物,剂量为约0.01-3000mg(例如,剂量为约0.01mg;剂量为约0.08mg;剂量为约0.1mg;剂量为约0.24mg;剂量为约0.8mg;剂量为约1mg;剂量为约2.4mg;剂量为约8mg;剂量为约10mg;剂量为约20mg;剂量为约24mg;剂量为约30mg;剂量为约40mg;剂量为约48mg;剂量为约50mg;剂量为约60mg;剂量为约70mg;剂量为约80mg;剂量为约90mg;剂量为约100mg;剂量为约160mg;剂量为约200mg;剂量为约240mg;剂量为约300mg;剂量为约400mg;剂量为约500mg;剂量为约600mg;剂量为约700mg;剂量为约800mg;剂量为约900mg;剂量为约1000mg;剂量为约1100mg;剂量为约1200mg;剂量为约1300mg;剂量为约1400mg;剂量为约1500mg;剂量为约1600mg;剂量为约1700mg;剂量为约1800mg;剂量为约1900mg;剂量为约2000mg;剂量为约2100mg;剂量为约2200mg;剂量为约2300mg;剂量为约2400mg;剂量为约2500mg;剂量为约2600mg;剂量为约2700mg;剂量为约2800mg;剂量为约2900mg;或剂量为约3000mg)。在一些实施方案中,剂量为约500mg的剂量。在一些实施方案中,剂量为约1200mg。在一些实施方案中,该剂量为约2400mg。在一些实施方案中,EGFR Fcab-药物缀合物的剂量为约0.001-100mg/kg(例如,剂量约0.001mg/kg;剂量约0.003mg/kg;剂量约0.01mg/kg;剂量约0.03mg/kg;剂量约0.1mg/kg;剂量约0.3mg/kg;剂量约1mg/kg;剂量约2mg/kg;剂量约3mg/kg;剂量约10mg/kg;剂量约15mg/kg;或剂量约30mg/kg)。
本文公开的所有固定剂量都被认为与基于80kg参考体重的体重剂量相当。因此,当参考2400mg的固定剂量时,以此类似地公开了30mg/kg的体重剂量。
在本发明的EGFR Fcab-药物缀合物的治疗之外并且考虑到对患者的健康有必要,治疗医生可以酌情给予并行治疗。在一些实施方案中,本发明提供治疗、稳定或减少本文所述的一种或多种疾病或病症的严重性或进展的方法,其包括向有该需要的患者施用EGFRFcab-药物缀合物及另外的疗法,例如化疗、放疗或放化疗。
在一个实施方案中,进一步施用二萜类化合物,例如紫杉醇、nab-紫杉醇或多烯紫杉醇;长春花生物碱,例如长春碱、长春新碱或长春瑞滨;铂配位复合物,例如顺铂或卡铂;氮芥,例如环磷酰胺、马法兰或苯丁酸氮芥;烷基磺酸盐,例如白消安;亚硝基脲,例如卡莫司汀;三氮烯,例如达卡巴嗪;放线菌素,例如放线菌素D;蒽环素例如柔红霉素或多柔比星;博来霉素;表叶毒素,例如依托泊苷或替尼泊苷;抗代谢抗肿瘤药物,例如氟尿嘧啶、培美曲塞、甲氨蝶呤、阿糖胞苷、甲巯嘌呤、硫鸟嘌呤或吉西他滨;甲氨蝶呤;喜树碱,例如伊立替康或拓扑替康;利妥昔单抗;奥法木单抗;曲妥珠单抗;西妥昔单抗;贝沙罗汀;索拉非尼;erbB抑制剂例如拉帕替尼、厄洛替尼或吉非替尼;帕妥珠单抗;伊匹木单抗;替西木单抗(tremelimumab);纳武单抗;帕博利珠单抗(pembrolizumab);FOLFOX;卡培他滨;FOLFIRI;贝伐珠单抗;阿特珠单抗;塞鲁单抗;奥滨尤妥珠单抗或其任何组合。
在一个实施方案中,进一步将放疗与EGFR-Fcab药物缀合物并行或顺序施用。在一些实施方案中,放疗选自全身放射疗法、外射束放射疗法、图像引导放射疗法、断层放射疗法(tomotherapy)、立体定向放射外科、立体定向体部放射疗法和质子疗法。在一些实施方案中,放射疗法包括外射束放射疗法、内照射疗法(近距离放射疗法)或全身放射疗法。参见,例如Amini等,Radiat Oncol.“Stereotactic body radiation therapy(SBRT)forlung cancer patients previously treated with conventional radiotherapy:areview”9:210(2014);Baker等,Radiat Oncol.“A critical review of recentdevelopments in radiotherapy for non-small cell lung cancer”11(1):115(2016);Ko等,Clin Cancer Res“The Integration of Radiotherapy with Immunotherapy forthe Treatment of Non–Small Cell Lung Cancer”(24)(23)5792-5806;和Yamoah等,IntJRadiat Oncol Biol Phys“Radiotherapy Intensification for Solid Tumors:ASystematic Review of Randomized Trials”93(4):737–745(2015)。
在一些实施方案中,放疗包括外射束放射疗法,并且外射束放射疗法包括强度调制放射疗法(IMRT)、图像引导放射疗法(IGRT)、断层疗法、立体定向放射外科、立体定向体部放射疗法、质子疗法或其他带电粒子束。
在一些实施方案中,放疗包括立体定向体部放射疗法。
除了根据本发明的EGFR Fcab-药物缀合物外,根据本发明的药物制剂还可以包含额外药物活性化合物(例如用于治疗癌症)、其他抗肿瘤药物。为了治疗提到的其他疾病,除了根据本发明的EGFR Fcab-药物缀合物外,根据本发明的药物制剂还可以在其治疗中包含本领域技术人员已知的额外药物活性化合物。
在一个实施方案中,方法包括向宿主施用与抗体组合或交替的本发明的EGFRFcab-药物缀合物。在特定的子实施方案中,抗体是治疗抗体。在一个特定实施方案中,提供增强被动抗体疗法的功效的方法,其包括将本发明的EGFR Fcab-药物缀合物与一种或多种被动抗体组合或交替施用。该方法可以增强抗体疗法用于治疗异常细胞增殖性病症(例如癌症)的功效,或者可以增强治疗或预防传染病的疗法的功效。例如,本发明的EGFR Fcab-药物缀合物可以与抗体(例如利妥昔单抗、赫塞汀或西妥昔单抗)组合或交替施用。
在另一主要实施方案中,提供治疗或预防异常细胞增殖的方法,其包括在基本上不存在另一种抗癌剂的情况下向有该需要的宿主施用本发明的EGFR Fcab-药物缀合物。
在另一主要实施方案中,提供在有该需要的宿主中治疗或预防异常细胞增殖的方法,其包括将本发明的第一EGFR Fcab-药物缀合物基本上与第一种抗癌剂组合向宿主施用,并且随后施用第二EGFR Fcab-药物缀合物。在一个子实施方案中,基本上在不存在另一种抗癌剂的情况下施用第二EGFR Fcab-药物缀合物。在另一主要实施方案中,提供在有该需要的宿主中治疗或预防异常细胞增殖的方法,其包括将本发明的EGFR Fcab-药物缀合物基本上与第一种抗癌剂组合向宿主施用,并且随后在不存在EGFR Fcab-药物缀合物的情况下施用第二种抗癌剂。
因此,本文公开的癌症治疗可以作为具有本发明的EGFR Fcab-药物缀合物的疗法或与手术、放疗或化疗组合的疗法进行。这种类型的化疗可以包括使用下列抗肿瘤活性化合物分类的一种或多种活性化合物:
(i)如医学肿瘤学中使用的抗增殖/抗肿瘤/DNA损伤的活性化合物及其组合,例如烷基化活性化合物(例如顺铂、parboplatin、环磷酰胺、氮芥、马法兰、苯丁酸氮芥、白消安和亚硝基脲);抗代谢物(例如叶酸抗代谢物,例如氟嘧啶,例如5-氟尿嘧啶和替加氟、雷替曲塞(raltitrexed)、甲氨蝶呤、阿糖胞苷、羟基脲和吉西他滨);抗肿瘤抗生素(例如蒽环素,例如阿霉素(adriamycin)、博来霉素、多柔比星、柔红霉素、表阿霉素、伊达比星、丝裂霉素-C、放线菌素D和光神霉素(mithramycin));抗有丝分裂活性化合物(例如长春花生物碱,例如长春新碱、长春碱、长春地辛和长春瑞滨,和紫衫烷类物质,例如紫杉醇和泰索帝(taxotere));拓扑异构酶抑制剂(例如表鬼臼毒素,例如依托泊苷和替尼泊苷、安吖啶、拓扑替康、伊立替康和喜树碱)和细胞分化活性化合物(例如全反式维甲酸、13-顺式维甲酸和芬维A胺);
(ii)细胞抑制活性化合物,例如抗雌激素(例如他莫昔芬、托雷米芬、雷洛昔芬、屈洛昔芬和碘氧芬)、雌激素受体调节剂(例如氟维司群)、抗雄激素(例如比卡鲁胺、氟他胺、尼鲁米特和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林),孕酮(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏氯唑(vorazole)和依西美坦)和5α-还原酶抑制剂,例如非那雄胺;
(iii)抑制癌症侵袭的活性化合物,包括例如金属蛋白酶抑制剂如马立马司他,以及尿激酶型纤溶酶原激活物受体功能抑制剂;
(iv)生长因子功能抑制剂,例如生长因子抗体、生长因子受体抗体,例如抗erbb2抗体曲妥珠单抗[赫塞汀TM]和抗erbbl抗体西妥昔单抗[C225])、法尼酰转移酶抑制剂、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂,例如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,AZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI-74)和6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)喹唑啉-4-胺(CI1033),例如血小板衍生生长因子家族抑制剂,和例如肝细胞生长因子家族抑制剂;
(v)抗血管生成活性化合物,例如贝伐珠单抗、血管抑素、内皮抑素、三羧氨基喹啉(Linomide)、巴马司他(Batimastat)、卡托普利(Cartopril)、软骨衍生抑制剂、染料木黄酮(Genistein)、白细胞介素12、薰草菌素(Lavendustin)、醋酸甲羟孕酮、重组人血小板因子4、替可加兰(Tecogalan)、血小板反应蛋白、TNP-470、抗VEGF单克隆抗体、可溶性VEGF受体嵌合蛋白、抗VEGF受体抗体,抗PDGF受体、整合素抑制剂、酪氨酸激酶抑制剂、丝氨酸/苏氨酸激酶抑制剂、反义寡核苷酸、反义寡脱氧核苷酸、siRNA、抗VEGF适配体、色素上皮衍生因子和已在国际专利申请WO 97/22596、WO 97/30035、WO97/32856和WO 98/13354中公布的化合物);
(vi)血管破坏剂,例如康普瑞汀(Combrestatin)A4和已在国际专利申请WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公布的化合物;
(vii)反义疗法,例如针对上文提到的靶标的疗法,例如ISIS 2503(一种抗Ras反义疗法);
(viii)基因疗法方法,包括,例如,置换异常的、经修饰的基因的方法,例如异常的p53或异常的BRCA1或BRCA2,GDEPT方法(基因导向酶前药疗法),例如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的方法,以及增加患者对化疗或放疗耐受性的方法,例如多药抗性疗法;和
(ix)免疫疗法方法,包括,例如,用于增加患者肿瘤细胞的免疫原性的离体和体内方法,例如用细胞因子(例如白细胞介素2、白细胞介素4或粒细胞巨噬细胞集落刺激因子)转染;减少T细胞无反应性的方法;使用转染的免疫细胞的方法,例如细胞因子转染的树突状细胞;使用细胞因子转染的肿瘤细胞的方法和使用抗独特型抗体的方法;
(x)化疗剂包括例如阿巴瑞克(Abarelix)、阿地白介素(Aldesleukin)、阿来珠抗体(Alemtuzumab)、阿利维甲酸、别嘌呤醇、六甲蜜胺、氨磷汀(Amifostine)、阿那曲唑、三氧化二砷、天冬酰胺酶、BCG Live、贝伐珠单抗、贝沙罗汀、博来霉素、硼替佐米、白消安、二甲睾酮(calusterone)、喜树碱、卡培他滨、卡铂、卡莫司汀、塞来考昔(Celecoxib)、西妥昔单抗,苯丁酸氮芥、西那卡塞、顺铂、克拉屈滨、环磷酰胺、阿糖胞苷、达卡巴嗪、放线菌素D、阿法达贝泊汀(Darbepoetin)、柔红霉素、地尼白介素-毒素连接物(Denileukin-diftitox)、右丙亚胺(Dexrazoxane)、多西他赛、多柔比星、屈他雄酮(Dromostanolone)、表柔比星、阿法依泊汀(epoetin alfa)、雌二醇氮芥(Estramustine)、依托泊苷、依西美坦、非格司亭(Filgrastim)、氟尿苷、氟达拉滨、氟尿嘧啶、氟维司群和吉西他滨。
表1中的药物可以与本发明的EGFR Fcab-药物缀合物优选但不排他地组合。
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本公开进一步提供使用本文所述的EGFR Fcab-染料缀合物的诊断、预测、预后和/或治疗性方法。这些方法基于(至少部分)测定感兴趣的生物标志物的表达水平的特征。特别地,在癌症患者样品中任何一种人EGFR的量都可以用作生物标志物,以预测患者是否可能对利用本发明治疗组合的癌症疗法作出有利反应。
因此,本发明的另一实施方案是包含式Fcab-(L)m-(La)n的EGFR Fcab-标记缀合物,其中:
a)Fcab包含EGFR Fcab,
b)L包含接头,
c)La包含标记,
d)m是1-5的整数和n是1-10的整数。
本发明的优选实施方案是根据本发明的EGFR Fcab-标记缀合物,其中EGFR Fcab选自Fcab-1、Fcab-2、Fcab-3、Fcab-4、Fcab-5和Fcab-6,其具有如SEQ ID No.1-6中所示的氨基酸序列。
本发明进一步优选的实施方案是根据本发明的EGFR Fcab-标记缀合物,其中EGFRFcab选自Fcab-1、Fcab-2和Fcab-3,其具有如SEQ ID No.1-3中所示的氨基酸序列。
在本发明的优选实施方案中,m是1至3和n是1至5。
本发明还涉及EGFR Fcab-标记缀合物,其中通过添加标记来修饰根据本发明的EGFR Fcab,产生标记的EGFR Fcab缀合物。标记可以通过多种长度的间隔基/接头与EGFRFcab偶联以降低潜在的空间位阻。该接头可以与上文对根据本发明的EGFR Fcab-药物缀合物的描述相同。
术语“标记”或“标记基团”是指任何可检测的标记。示例性标记包括但不限于同位素标记,其可以是放射性或重同位素,例如放射性同位素或放射性核素(例如3H、14C、15N、35S、89Zr、90Y、99Tc、111In、125I、131I);磁性标记(例如磁性颗粒);氧化还原活性部分;光学染料(包括但不限于发色团、磷光体和荧光团)例如荧光基团(例如FITC、罗丹明、镧系磷光体)、化学发光基团和可以是“小分子”荧光团或蛋白质荧光团的荧光团;酶促基团(例如辣根过氧化物酶、~-半乳糖苷酶、萤光素酶、碱性磷酸酶);生物素化基团;或被次级报告物识别的预定多肽表位(例如亮氨酸拉链配对序列、二级抗体的结合位点、金属结合结构域、表位标签等)。
本发明的优选实施方案是本发明的EGFR Fcab-标记物缀合物,其中该标记选自同位素标记、磁性标记、氧化还原活性部分、光学染料和酶促基团。
本发明进一步的优选实施方案是本发明的EGFR Fcab-标记缀合物,其中该标记是pHAb-染料。
根据本发明的标记也可以是标签,例如帮助纯化和分离抗体的亲和标签。这种另外结构域的非限制性实例包括肽基序,称为Myc-标签、HAT-标签、HA-标签、TAP-标签、GST-标签、几丁质结合结构域(CBD-标签)、麦芽糖结合蛋白(MBP-标签)、Flag-标签、Strep-标签及其变体(例如StrepII-标签)和His-标签。
因此,本发明进一步的优选实施方案是本发明的EGFR Fcab-标记缀合物,其中该标记是标签。
本发明的另一实施方案是含有根据本发明的EGFR Fcab-标记缀合物的诊断组合物。
任何合适的样品都可以用于该方法。该样品的非限制性实例包括血清样品、血浆样品、全血、胰液样品、组织样品、肿瘤裂解物或肿瘤样品的一种或多种,其可以从针刺活检、核心活检和针头抽吸中分离。例如,在用本发明的治疗组合治疗前和任选地治疗中从患者采集组织样品、血浆样品或血清样品。将治疗中所获得的表达水平与患者开始治疗前所获得的值比较。所获得的信息可以是预后的,因为它能指示患者对癌症疗法是否作出了有利或不利反应。
要理解,使用本文所述的诊断测定所获得的信息可以单独使用或与其他信息组合使用,其他信息例如但不限于其他基因的表达水平、临床化学参数、组织病理学参数或受试者的年龄、性别和体重。当单独使用时,使用本文所述的诊断测定所获得的信息可用于测定或鉴定治疗的临床结局、为治疗选择患者或治疗患者等。另一方面,当与其他信息组合使用时,使用本文所述的诊断测定所获得的信息可用于帮助测定或鉴别治疗的临床结局、帮助为治疗选择患者或帮助治疗患者等。在特定方面,该表达水平可以用于诊断面板(diagnostic panel),其每个都促成最终诊断、预后或为患者选择的治疗。
任何合适的方法都可分别用于测量生物标志物蛋白质或生物标志物水平的其他合适读出,其实例在本文进行了描述和/或为本领域技术人员所熟知。
在一些实施方案中,测定生物标志物水平包括测定生物标志物表达。在一些实施方案中,通过患者样品中的生物标志物蛋白质浓度来测定生物标志物水平,例如用生物标志物特异性配体,例如抗体或特异性结合配偶体。例如可以通过竞争性或非竞争性方法检测结合事件,包括使用标记的配体或生物标志物特异性部分,例如抗体或标记的竞争性部分,其包括与标记的蛋白质竞争结合事件的标记的生物标志物标准物。如果生物标志物特异性配体能够与生物标志物形成复合物,则复合物的形成可以指示样品中生物标志物的表达。在各种实施方案中,通过包括定量蛋白质印迹、多种免疫测定形式、ELISA、免疫组织化学、组织化学的方法或使用肿瘤裂解物的FACS分析、免疫荧光染色、基于珠的悬浮免疫测定、Luminex技术或邻近连接测定来测定生物标志物蛋白质水平。在一个实施方案中,通过使用一种或多种与生物标志物特异性结合的一级抗体的免疫组织化学来测定生物标志物的表达。
然而在本发明的优选实施方案中,将根据本发明的EGFR Fcab-标记缀合物用来测定EGFR蛋白质在细胞、类器官、血清样品、血浆样品、全血、胰液样品、组织样品、肿瘤裂解物或肿瘤样品中的表达。
在一个实施方案中,用肿瘤样品中EGFR的表达来预测本发明治疗组合的功效。
本公开还提供用于测定本发明的组合是否适用于癌症患者的治疗性治疗的试剂盒,其包含用于在从患者分离的样品中测定EGFR蛋白质水平的组件(means)和使用说明。在本发明的一方面,高EGFR水平的测定表明,当用本发明的EGFR Fcab-药物缀合物治疗患者时,PFS或OS增加。在试剂盒的一个实施方案中,用于测定生物标志物蛋白质水平的组件是具有对生物标志物的特异性结合的抗体。
附图说明
图1显示Fcab-药物缀合物相比于其他基于抗体片段的药物缀合物(VHH11,12、scFv8,9、Fab6,7)和常规的基于IgG的ADC4的优点的概念表示。
图2显示本发明的EGFR Fcab-药物缀合物的图形摘要。
图3显示Fcab的结构和pHAb-染料标记。(A)在CH3结构域的C端具有工程化抗原结合位点的同源二聚体Fcab的图示。(B)人IgG1-Fc单体,描绘在所选EGFR结合的Fcab中工程化的CH3 AB、CD和EF环。为了清楚,并未显示糖基化(PDB ID 5JII)。(C)pHAb-染料标记的图示。
图4显示相对于C-IgG-pHAb在MDA-MB-468细胞上的积累率(100%),Fcab-、huFc-、C-Fab-和C-IgG-pHAb染料缀合物的细胞内积累。细胞内积累率来源于在100nM下0-26h的孵育,并相对于细胞数量和每个构建体的个别pHAb染料荧光归一化。下列条形图表明相对的EGFR表达特征(MDA MB 468>A431>MCF 7)。误差条显示一式三份的标准偏差。
图5显示Fcab-药物缀合物。(A)人Fc部分的代表图(PDB ID 5VGP),显示EGFR结合位点位于CH3区域以及缀合位点Q295、Q311和Q438(EU编号)。(B)接头-有效载荷1的结构。(C)MMAE缀合的图示。
图6显示识别缀合位点。消化的Fcab-1-MMAE的LC-MS色谱图显示在Fcab-1制备物中未检测到的缀合肽(e-i,k-m)。由于疏水的MMAE,在更高的保留时间下洗脱出缀合肽。与Fcab-1相比,在Fcab-1-MMAE制备物中,在更低的保留时间下洗脱出配对的未缀合肽(a-d)和峰消失(a、b)或显示了降低的强度(c)。
图7显示细胞增殖测定。(A)EGFR阳性细胞(MDA-MB-468、A431)和EGFR阴性细胞(MCF 7)的细胞活力。在分析细胞活力之前,将细胞与MMAE缀合物和游离MMAE的连续稀释液一起孵育4天。误差条代表一式三份的标准偏差(SD)。(B)MMAE缀合物和游离MMAE的抑制活性。IC50值以三次独立实验的平均值给出(IC50±SD)。
图8显示表达的Fcab的蛋白质A纯化过程。(A)Xpress(HiTrapTM MabSelectSuReTM 5mL和HiPrepTM 26/10脱盐柱)示例性色谱图,显示从蛋白质A柱洗脱后(50mM乙酸(HOAc),pH 3.2)的Fcab-2蛋白质峰和在随后的更换缓冲液步骤后的第二蛋白质峰。(B)对还原的Expi293F上清液、蛋白A穿流液和纯化的Fcab的SDS-PAGE分析。4-12%Bis-Tris凝胶(InvitrogenTM),MES SDS运行缓冲液(1x),在200V下40min,用InstantBlueTM(基于考马斯(Coomassie))染色2小时,标志物:Precision Plus ProteinTMTM Unstained standards(BioRad)。(C)每体积Expi-293F表达培养物的纯化的Fcab和huFc阴性对照的产量。
图9显示,LC-MS分析确认Fcab和huFc对照的身份。(A)Fcab的解卷积MS谱图。(B)计算质量和实测质量之间的质量偏差说明糖基化形式和标准测量的偏差。仅列出了最强烈的糖基化形式(G1F)。
图10Fcab和huFc对照分子的热稳定性。显示热解折叠曲线的一阶导数(A)以及解折叠转变中点(Tm)(B)。为测定热解折叠,将Fcab和huFc(PBS pH 6.8)加载到nanoDSF级标准毛细管中,然后将其转移到Prometheus NT.PLEX nanoDSF(NanoTemper Technologies)仪器中。使样品经受斜率为1℃/min的从20℃到95℃的线性热斜坡,同时记录350nm和330nm处的荧光。由350nm/330nm荧光比的一阶导数测定解折叠转变中点(Tm)。一式两份地测量所有样品。n.d.–未检测到。
图11显示Fcab和对照分子在EGFR阳性(MDA MB 468和A431)和EGFR阴性(MCF 7)细胞上的细胞结合分析。Fcab和C-IgG选择性结合表达EGFR的细胞,而huFc和二级检测抗体不显示任何结合。将细胞与100nM Fcab/C IgG在4℃下孵育60min,用PBS-1%BSA洗涤两次,与500nM AF488标记的检测抗体(109-546-008,Jackson ImmunoResearch)在黑暗中在4℃孵育30min,用PBS-1% BSA洗涤两次,以及最终应用Attune NxT流式细胞仪(InvitrogenTM)测量荧光强度。
图12显示测定细胞解离常数(KD)。(A)将EGFR阳性(MDA MB 468和A431)和EGFR阴性(MCF 7)细胞与不同浓度的Fcab孵育,然后用AF488标记的检测抗体染色,洗涤和细胞仪分析,如图S4所示。MDA MB 468和A431细胞之间变化的结合饱和水平反映不同的细胞特异性EGFR表达密度。使用GraphPad Prism(GraphPad Software,Inc.)的非对称(五个参数)拟合函数拟合剂量反应曲线以获得KD。(B)Fcab的细胞解离常数与来源于经由BLI与重组EGFR结合的KD值(表2)和文献数据[1]非常一致。
图13显示pHAb-染料标记和标记程度(DOLF,DOLA)测定。(A)pHAb胺反应性染料2的结构,该染料携带可以与赖氨酸的ε-氨基反应的NHS酯基。(B)pHAb染料在SE-HPLC缓冲液(pH 6.3)中的吸收和荧光光谱。(C)用pHAb-染料经由随机的赖氨酸偶联标记蛋白质。几种因素可以影响荧光团量子产量。[4](D)测定DOLF和DOLA值的公认SE-HPLC方法的概述。通过装配有二极管阵列(DAD)和荧光(FLD)检测器的SE-HPLC装置分析未缀合蛋白质、游离pHAb-染料和pHAb-染料缀合物。由峰面积和物质的注射量计算未缀合蛋白质和游离pHAb-染料的摩尔消光系数(MEC)以及游离pHAb-染料的摩尔荧光系数(MFC)。然后,MEC和MFC用于计算缀合荧光pHAb-染料的量和由pHAb-染料缀合物的峰面积计算蛋白质的量。最终,DOLF和DOLA可以来源于这些数据。
图14显示用于测定DOLF和DOLA的SE-HPLC分析,以pHAb-染料缀合的Fcab为例显示。(A)未缀合Fcab不吸收535nm处的光。(B)因此,当在535nm处激发时(pHAb-染料吸收最大值),Fcab在566nm处不显示荧光。(C)Fcab在280nm处的吸收(芳香族氨基酸)。Fcab(54kDa)在9.3min洗脱。(D)游离pHAb-染料在535nm处其吸收最大值的吸收。根据其较小的尺寸,游离pHAb-染料(786g/mol,羧酸形式)较晚在11.2min洗脱。(E)当在535nm处激发时,游离pHAb染料在566nm处发出荧光(pHAb-染料荧光最大值)。(F)游离pHAb-染料在280nm处也有吸收。在11.8min的较小峰是由缓冲组分造成的并且在对峰积分中忽略。(G)Fcab pHAb缀合物在535nm处的吸收。标志为红色的第一个峰代表缀合pHAb-染料分子的吸收,而标志为蓝色的第二个峰显示不能通过ZebaTM旋转脱盐柱纯化整体去除的游离pHAb-染料。(H)Fcab pHAb缀合物在566nm处的荧光。描绘为红色的峰显示缀合pHAb-染料的荧光,而蓝色峰显示游离pHAb-染料的荧光。当比较荧光峰和吸收峰(535nm)的峰面积时,缀合pHAb-染料的荧光相对于游离pHAb-染料低得多。这确认了局部分子环境对荧光团量子产量的影响。(I)Fcab pHAb在280nm处的吸收由其蛋白质和pHAb-染料组分的吸收构成。
图15显示本研究使用的pHAb-染料缀合物的表征。(A)纯化的pHAb-染料缀合物的分析性尺寸排阻SE-HPLC显示在280nm(蛋白质和pHAb-染料)和535nm(pHAb-染料)处的吸收以及pHAb-染料荧光(激发535nm,发射566nm)。未缀合pHAb-染料可以在tR 11–12min洗脱。(B)基于吸收和基于荧光的pHAb染料标记程度(DOLF,DOLA)来源于(A)中所示的SE-HPLC数据。
图16显示pHAb-染料标记的构建体的细胞摄取动力学。(A)细胞积累时间序列,以Fcab 1pHAb在MDA MB 468细胞上为例显示。使用装配有DAPI和RFP滤光片立方体和BioSpa8自动化培养箱(BioTec)的Cytation 5细胞成像检测仪(Cytation 5cell imagingreader)(BioTek),在37℃、80%湿度和5%CO2下将细胞与100nM Fcab 1pHAb孵育,并在26h内每2h记录RFP通道图像(激发531nm,发射593nm)。(B)将图像的总荧光强度相对于细胞数量和pHAb-染料标记的构建体的DOLF值归一化,并按时间作图以由线性回归(GraphPadSoftware,Inc.)的斜率得出归一化的细胞内积累率。随后可以由这些积累率计算相对细胞内积累。(C)来源于所述的基于成像仪测定的归一化细胞摄取率可以在利用相同pHAb-染料标记的构建体的第二次基于FACS的细胞摄取测定中验证。(D)来源于基于FACS的测定的在MDA MB 468中的相对细胞内积累与基于成像的细胞摄取数据非常一致(图3)。
图17显示以Fcab-MMAE缀合物为例显示的缀合和纯化策略。(A)通过酶促转谷氨酰胺酶缀合生成MMAE缀合物。缀合后,通过制备性SEC去除过量的微生物转谷氨酰胺酶(mTG)和Gly3-Val-Cit-MMAE(1)。(B)以Fcab-2-MMAE和huFc-MMAE为例显示,通过制备性SEC纯化转谷氨酰胺酶缀合的MMAE构建体。将含有缀合蛋白(和未缀合种类)的级分合并、浓缩、无菌过滤并进行分析。
图18显示生成的MMAE缀合物的色谱表征,以Fcab-1 MMAE、Fcab-2 MMAE、Fcab-3MMAE和huFc MMAE为例显示。(A)分析性尺寸排阻SE-HPLC显示一个不同的单峰,其证明形成不具有聚集体的单体药物缀合物。信号强度代表在214nm处的吸收。(B)反相RP-HPLC揭示Gly3-Val-Cit-MMAE1的缀合。由个别DAR种类的峰面积计算RP-DAR(Fcab 1MMAE RP DAR2.6;Fcab 2MMAE RP AR2.5;Fcab 3 MMAE RP DAR 2.5;huFc MMAE RP DAR 2.0)。例如,DAR1种类的25%相对峰面积和DAR 2种类的75%相对峰面积揭示最终的RP-DAR为1.75。信号强度代表在214nm处的吸收。
图19显示通过质谱法测定Fcab-MMAE缀合物的DAR。解卷积质谱图显示携带0–3个Gly3-Val-Cit-MMAE(1)的不同糖基化的重链(HC)基团。使用携带0-3个接头有效载荷的HC种类的TIC面积来计算MS-DAR。
图20显示EGFR结合的动力学参数。使用重组产生的EGFR通过BLI在pH 7.4下测量解离常数(KD)、结合速率(kon)和解离速率(koff)。误差是使用FortéBio数据分析软件9.1拟合的标准误差。拟合质量以R2表征。
图21显示FcRn结合的动力学参数。使用重组产生的FcRn通过BLI测量解离常数(KD)、结合速率(kon)和解离速率(koff)。在pH 6.0下测定与FcRn的结合亲和力。误差是使用FortéBio数据分析软件9.1拟合的标准误差。拟合质量以R2表征。
图22显示未缀合Fcab、西妥昔单抗变体和各MMAE缀合物的受体结合BLI传感图。(A)EGFR结合分析。在pH 7.4下记录缔合和解离,并通过1:1全局完全拟合结合模型拟合。(B)FcRn结合分析。在pH 6.0下记录分析物的缔合和解离并通过1:1全局部分解离模型拟合。拟合以红色显示。对每个传感图,给出缔合期间分析物的最高浓度及其稀释因子。
即使没有进一步的实施方案,也假定本领域技术人员将能够在最广泛的范围内使用以上描述。因此优选实施方案应当仅被视为描述性公开,其在任何方面都绝对不限制。
本文引用的所有参考文献都通过引用在此并入本发明的公开内容。
尽管在本发明的实践或测试中可以使用与本文所述的方法和材料相似或等同的方法和材料,但合适的实例如下所述。在实例中,使用无污染活性(只要可行)的标准试剂和缓冲液。特别地这些实例要被理解为其不限于明确显示的特征组合,而是只要解决了本发明的技术问题,示例的特征可以不限制地再组合。同样地,任何权利要求的特征都可以与一个或多个其他权利要求的特征组合。已经概括和详细描述的本发明,通过下列实施例进行说明而不被其限制。
除非另外指出,百分比数据表示重量百分比。所有温度以摄氏度指示。“常规后处理(work-up)”:如必要则添加水,如必要则将pH调节至2和10之间的值(取决于终产物的组成),用乙酸乙酯或二氯甲烷萃取混合物,分离各相,用硫酸钠干燥有机相,过滤并蒸发,并通过硅胶色谱法和/或通过结晶法纯化产物。
硅胶上的Rf值;质谱法:EI(电子碰撞电离):M+,FAB(快速原子轰击):(M+H)+,THF(四氢呋喃),NMP(N-甲基吡咯烷酮),DMSO(二甲基亚砜),EA(乙酸乙酯),MeOH(甲醇),TLC(薄层色谱法)。
缩写列表
AUC 血浆药物浓度-时间曲线下面积
Cmax 最大血浆浓度
CL 清除
CV 变异系数
CYP 细胞色素P450
DMSO 二甲基亚砜
F 生物利用率
fa 吸收部分
iv 静脉内
LC-MS/MS液相色谱串联质谱法
LLOQ 定量下限
NC 未计算
ND 未测定
PEG 聚乙二醇
Pgp 渗透性糖蛋白
PK 药代动力学
po 经口(口服)
t1/2 半衰期
tmax 血浆药物浓度达到最大值时的时间
UPLC 超高效液相色谱法
Vss 分布容积(稳态时)
v/v 体积比
实施例
实施例1:制备Fcab、对照和pHAb-染料标记的构建体
首先,我们从文献中选择三种不同的结合EGFR的Fcab(Fcab-1、Fcab-2、Fcab-3)。对全部三种Fcab与EGFR的个位数纳摩尔结合亲和力进行了描述(KD 0.7–2.6nM)。[20]我们加入了未修饰的人Fc(huFc)片段作为阴性对照。作为结合EGFR的参比,包括基于西妥昔单抗的全长IgG(C-IgG)和西妥昔单抗衍生的Fab(C-Fab)片段,二者都在轻链C末端装配有分选酶A(SrtA)识别基序(LPETG)。表达的Fcab和huFc具有D265A突变[21,22]以避免Fcγ受体(I、II、III)介导的细胞毒性[23],并且通过亲和色谱法纯化(图8)。质谱法分析(LC-MS,图9)确认了所有分子的身份。差式扫描荧光测定法显示了Fcab较低的解折叠转变中点(Tm)(例如Tm,1 59℃比66℃;图10),表明与huFc相比Fcab的热稳定性降低但仍可接受。此外,我们评估了纯化的构建体的功能性和选择性细胞结合(图11、图12)。对于细胞摄取研究,全部构建体都用荧光染料(pHAb-染料)经由胺偶联在随机的赖氨酸上进行标记(图3c),该荧光染料在细胞外中性pH下展现很低的荧光而在内体和溶酶体区室内酸性pH下展现强烈增加的荧光(图13)。[24]通过分析性尺寸排阻色谱法(SE-HPLC)确认了成功的pHAb-染料标记以及不存在聚集体(图15)。为了确保由不同标记的构建体得到的个别荧光强度之间的可比性,将荧光信号归一化。在SI中可以找到对基础实验程序的全面描述。
实施例2:细胞摄取研究
为评价结合EGFR的Fcab用于细胞内药物递送的总体适用性,对它们进入癌症细胞中的摄取和积累进行了研究。因此,在EGFR过表达的(MDA-MB-468、A431)和EGFR阴性的(MCF-7)贴壁细胞上孵育pHAb-染料标记的构建体,并在26小时内持续测量荧光(图16A)。将荧光强度归一化以说明个别细胞数量和标记的构建体的荧光强度。将这些强度按时间作图以通过线性回归测定细胞内积累率(图16B)。所有积累率都相对于显示了最快摄取的C-IgG-pHAb积累率(在MDA-MB-468上的C-IgG-pHAb)来表达(图4)。MDA-MB-468和A431细胞之间在积累方面的差异与特定EGFR表达密度的差异直接相关。引人注意地,所有Fcab都经历了选择性的EGFR介导的细胞摄取。有趣的是,二价对照和单价对照C-IgG-pHAb和C-Fab-pHAb展现了最显著的内化,这可能起因于西妥昔单抗和Fcab针对的表位不同。[20]为了测量各Fcab-药物缀合物的治疗阈值(IC50),将Fcab缀合至细胞毒性的有效载荷并且测试它们的细胞杀伤活性。
实施例3:生成Fcab-药物缀合物
通过靶向Q295的工程化转谷氨酰胺酶(mTG)[27]将Fcab-1、Fcab-2、Fcab-3和huFc与拥有三甘氨酸手柄的Val-Cit-PAB-MMAE(1)缀合(图5)(表1),并通过制备性尺寸排阻色谱法纯化(图17)。通过SrtA[28,29]将C-Fab和C-IgG缀合至1,使DAR达到DAR 0.8-1.1范围内。纯化的缀合物的分析性尺寸排阻色谱法显示不存在高分子量的种类(图18A)(表1)。令人惊讶地,经由反相色谱法(RP-HPLC)(图18B)、疏水相互作用色谱法(HI-HPLC)(表4)和LC-MS(图19)分析揭示了全部三种Fcab都显示了在2.7-2.9之间的升高DAR。对huFc(DAR2.0)没有观察到此情况,表明底物1已与只在Fcab支架中的另外的残基偶联(表1)。随后经由LC-MS肽图谱法可以鉴定出另外的缀合位点为在恒定区CH2和CH3的Q311和Q438(图5A)(图6)。在消化的Fcab-1-MMAE混合物中分配给含有Q295的未缀合肽的峰的消失表明Fcab在Q295位置几乎全部缀合,而在Q311和Q438位置仅部分缀合。由于之前mTG缀合至在HER2 Fcab或天然IgG中的相同恒定区没有导致Q311或Q438缀合[14],最有可能通过邻近区域的结构变化驱动mTG的可接近性。可以通过插入CH3区域的EGFR互补位或通过EGFR Fcab缺失的铰链区来诱导该变化。Q311和Q438二者都位于溶剂暴露的Fcab外部中。Q311位于紧靠FcRn处而Q438位于紧靠EGFR结合位点处。因此,在Q311和Q438的缀合理论上可以影响血清蛋白酶的可接近性并且干扰FcRn和EGFR结合。为了评定该概念,随后对Fcab-1-MMAE、Fcab-2-MMAE和Fcab-3-MMAE的FcRn和EGFR结合以及血清稳定性进行了测试。
表1.缀合Fcab和对照的概述。尺寸是指通过LC-MS测量的包括最丰富的糖基化模式的未缀合蛋白质。DAR以来自RP-HPLC和LC-MS分析的平均数给出。SE-HPLC纯度是指最终药物缀合物并且在一次冷冻-解冻循环后进行分析。
实施例4:Fcab-药物缀合物的受体结合特性
对Fcab-MMAE缀合物以及对照和未缀合母体分子与靶受体EGFR和延长半衰期的FcRn的结合亲和力一起进行分析(表2)(图20-22)。生物层干涉术(BLI)测量揭示了缀合未损害EGFR解离常数和FcRn解离常数(KD),表明在位置Q438、Q311和Q295处附接的有效载荷不影响两种受体的结合功能性。
表2.Fcab-药物缀合物和对照的结合亲和力和血清稳定性。通过BLI测量解离常数(KD)。分别在pH7.4和pH6.0测量与重组产生的EGFR和FcRn的结合。误差为来自使用FortéBio数据分析软件9.1拟合的标准误差。在37℃下在小鼠和人血清中孵育96h后(n=3),经由LC MS/MS测量游离MMAE。数值显示了相对于初始缀合MMAE的释放分数。n.d.-未测定。
实施例5:Fcab-药物-缀合物的血清稳定性
几项研究已表明,连接蛋白质与细胞毒性药物的接头的过早裂解可强烈影响缀合物的药代动力学。[30-32]Val-Cit接头基序尤其容易被存在于小鼠血清而不存在人血清的羧酸酯酶(mCes1c)裂解。[33]这种不稳定性的程度严重依赖于所选的缀合位点。当Fcab-MMAE缀合物在小鼠和人血清中孵育96h时,对所有构建体均不能检测到游离MMAE。这表明不管在Q295位置还是在新的Q311和Q438位置,对于mCes1c,Val-Cit接头基序都不可接近,因此所有位点都保护缀合物免于过早裂解(表2)。
实施例6:Fcab-药物缀合物的体外细胞毒性
随后,我们在体外细胞增殖测定中评估了Fcab-药物缀合物的选择性细胞杀伤能力(图7)。所有的Fcab-药物缀合物都在EGFR阳性的MDA-MB-468细胞和A431细胞(分别为IC500.18–0.22nM和0.23–0.32nM)上显示了相似的亚纳摩尔抑制性活性,而对EGFR阴性的MCF-7细胞的毒性减少了几个数量级(IC50>100nM),表明强烈的靶标依赖性细胞杀伤。非靶向huFc-MMAE也显示了低毒性(MDA-MB-468:IC50>300nM;A431和MCF-7:IC50>100nM),这确认主要是由特异性受体介导的摄取来驱动Fcab-MMAE毒性。与在MDA-MB-468细胞上比A431细胞更高的细胞摄取一致的是(图5),Fcab-药物缀合物和西妥昔单抗对照在MDA-MB-468细胞上显示了比A431细胞更高的活性(图7B)。此外,相比C-Fab-MMAE(IC50 0.78–0.99nM)或C-IgG-MMAE(IC50 0.44–0.50nM),Fcab-药物缀合物在EGFR阳性细胞上的更高效力(IC50 0.18–0.32nM)表明,可以通过另外缀合至Q311和Q438(分别为2.7–2.9比0.8和1.1)上使得Fcab的DAR较高来补偿Fcab的降低细胞内积累(图5)。总之,结果表明尽管它们为单价结合模式,但Fcab-药物缀合物的体外效力仍在ADC典型的亚纳摩尔范围内。
实施例7:细胞摄取测定
对细胞摄取研究我们使用了基于pH依赖性荧光团(pHAb-染料)的测定。[35]我们通过应用随机的赖氨酸偶联用pHAb-染料直接标记构建体,并通过测量当构建体到达酸性内体和/或溶酶体时生成的荧光随时间增加,来获得它们的细胞内积累动力学。重要的是,pHAb-染料的局部分子环境可以改变随机偶联的pHAb-染料分子的荧光(图13C),其可能导致偶联的pHAb-染料分子的数量与构建体个别的荧光之间的非线性关系。[35-37]考虑到这一点,我们开发了与Wang等相似的方法,以由SE-HPLC数据得出基于荧光和基于吸收的pHAb-染料标记程度(DOLF和DOLA)。[38]SE-HPLC方法具有同时分析标记构建体的DOLF和DOLA以及聚集和纯化(游离pHAb-染料)状态的优点。然后每个pHAb-染料标记构建体的DOLF值可以用于归一化细胞内积累动力学的荧光值。下文给出了该方法的详细描述。图13D简要总结了该方法。
SE-HPLC分析
在装配有二极管阵列(DAD)和荧光(FLD)检测器模块以及TSKgel SuperSW3000或SuperSW2000柱子的来自Agilent Technologies的1260Infinity装置上进行SE-HPLC。流动相由50mM磷酸钠、400mM高氯酸钠组成,pH6.3且其流速设为0.35mL/min。DAD设为检测在280nm(芳香族氨基酸)和535nm(pHAb-染料)处的吸收。FLD的激发波长和发射波长设为535nm和566nm以记录pHAb-染料的荧光(图13B)。
然后通过SE-HPLC分析游离pHAb-染料、pHAb-染料缀合蛋白质及其所对应的未缀合蛋白质。图14示例性描绘了未缀合蛋白质、游离pHAb-染料和pHAb-染料缀合蛋白质的所得色谱图。下一步,由这些数据得出摩尔消光系数或摩尔荧光系数。
由SE-HPLC的峰面积计算未缀合蛋白质和游离pHAb-染料的摩尔消光系数/摩尔荧
光系数(MEC/MFC)
由SE-HPLC的峰面积计算未缀合蛋白质和游离pHAb-染料的MEC/MFC。在错误!未找到引用源.C(未缀合蛋白质)和图14D-F(游离pHAb-染料)中可以找到示例性色谱图。使用Agilent的ChemStation分析软件对相关峰积分。由对应的峰面积,应用来源于Wang等[5]的下列等式可以测定未缀合蛋白质的MEC280nm以及游离pHAb-染料的MEC535nm/MFC566nm。
其中εi是在波长λi处的MEC或MFC,Ar是计算出的峰面积,F是SE-HPLC流速,l是流通池通道长度,c是注入样品的浓度,以及Uinj是注入样品体积。表3总结了未缀合蛋白质和游离pHAb-染料的所得MEC和MFC。
表3.在不同波长下的摩尔消光系数/摩尔荧光系数。MEC和MFC以平均数±SD给出。在连续三次SE-HPLC运行中注入不同体积的未缀合蛋白质或游离pHAb-染料溶液,并且使用所得峰面积根据等式(1)计算MEC或MFC。例如,当注入vinj=7.5μL的c=18.3μM的Fcab,在9.3min洗脱出峰面积Ar280nm为1825的单峰(图14C)。当恒定的SE-HPLC流速为F=5.8μL/s时,计算出MEC280nm为77122(mM·cm)-1。
根据pHAb-染料缀合蛋白质的SE-HPLC峰面积和MEC/MFC来计算DOLF和DOLA
为了由pHAb-染料标记构建体计算DOLF值,首先计算出缀合荧光pHAb-染料(npHAb,566nm)和蛋白质(n蛋白质,280nm)的摩尔量。因此,通过SE-HPLC分析pHAb-染料标记构建体并且计算出缀合pHAb-染料的吸收和荧光峰面积(图14G-H峰标为红色)以及来自在280nm处的吸收的峰面积(图14I)。在280nm处的吸收不仅是由蛋白质结构也是由缀合pHAb-染料造成的(图14F)。为了根据此峰计算注入蛋白质的量,必须减去由pHAb-染料贡献的峰面积。如等式(2)所示,pHAb-染料在280nm处的吸收部分可以来源于其在535nm处的峰面积(Ar535nm)并从在280nm处的总峰面积(Ar280nm)中减去。
随后,通过等式(3)根据经矫正的峰面积(Ar280nm,经矫正的)可以计算注入蛋白质的量。
同样地,缀合荧光pHAb-染料的量可以根据它在566nm处的荧光信号的峰面积(Ar566nm)计算:
缀合荧光pHAb-染料分子与蛋白质的量之间的比率定义了构建体个别的荧光的DOLF值:
类似地,应用等式(6)和(7)可以根据pHAb-染料在535nm处的吸收的峰面积计算每个蛋白质的缀合pHAb-染料分子的绝对量(DOLA)。
相关的pHAb-染料缀合物的SE-HPLC色谱图以及DOLF和DOLA值显示在错误!未找到引用源。与我们所期望的一致,每个蛋白质的荧光pHAb-染料分子数量(DOLF)比缀合pHAb-染料分子的绝对数量(DOLA)更低。由于荧光代表细胞摄取测定的读出,可以将荧光值对其DOLF值归一化以说明pHAb-染料标记构建体的个别荧光。因此,DOLF和细胞数量归一化的细胞内积累率允许可比性。
实施例8:材料和方法
制备抗体片段:
从文献中取得Fcab的氨基酸序列。[20]在SI中将修饰的Fcab序列(D265A)与修饰的huFc序列(D265A)和西妥昔单抗序列(SrtA标签)一起给出。订购密码子优化版本的编码序列并克隆至pTT5载体上用于哺乳动物的表达(GeneArt,Thermo Fisher Scientific)。按照制造商的说明通过瞬时转染Expi293FTM细胞来表达Fcab和huFc对照,并且在转染5天后收获上清液。C-Fcab含有用于纯化的His6标签,并且使用AKTA Pure设备(GE Healthcare)通过固定化金属亲和色谱法(1mL HisTrapTM HP,GE Healthcare)在纯化前于磷酸盐缓冲盐水(PBS)pH7.4中对C-Fab进行透析。使用HiTrapTM Mab Select SuRe 5mL柱子(GEHealthcare)通过蛋白质A亲和色谱法纯化Fcab、huFc和CIgG,并且随后使用HiPrepTM 26/10脱盐柱在PBS pH6.8中对其进行配制。使用SuperSW3000柱子(TosohBioscience)通过分析性SE-HPLC以及通过SDS凝胶电泳法分析抗体纯度。使用Exion LC和6600+质谱仪(AB Sciex)经由完整质量分析确认了蛋白质身份。使用超速离心过滤器单元(3K MWCO,/>)浓缩蛋白质,无菌过滤,并且通过在280nm处的UV–VIS光谱法测定蛋白质浓度。将蛋白质在液氮中快速冷冻并在-80℃下储存。
制备MMAE缀合物:
使用遗传工程化mTG将Fcab和huFc缀合至药物接头Gly3-Val-Cit-PAB-MMAE(1,Levena)。[27]在具有至多10%DMSO的PBS pH 6.8中使用5mg/mL Fcab/huFc、20摩尔当量药物接头和60U/mL mTG进行mTG介导的抗体缀合。将反应混合物在37℃下孵育18h且轻柔震荡,冷却至10℃并通过制备性尺寸排阻色谱法(SEC)纯化。
对于SrtA缀合,在150mM NaCl、50mM Tris-HCl、5mM CaCl2 pH7.5中配制C IgG或CFab(5mg/mL)。将SrtA[29]与每SrtA识别基序10当量的Gly3 Val-Cit-PAB-MMAE(1)一起添加至13μM的终浓度。将反应混合物在25℃下孵育90min,通过添加EDTA(最终10mM)停止并且通过制备性SEC纯化。在以PBS pH 6.8为运行缓冲液的1260液相色谱系统(AgilentTechnologies)或Avant装置(GE Healthcare)中,使用SuperdexTM 200 Increase10/300GL、SuperdexTM 75 10/30GL或SuperdexTM 200制备级16/60柱进行制备性SEC。使用超速离心过滤器单元(10K MWCO,/>)浓缩纯化的缀合物,无菌过滤并且在280nm处通过UV–VIS光谱法测定蛋白质浓度。如别处所述[27]通过SE-HPLC和DAR测定(RP HPLC,LC-MS)对纯化的缀合物进行分析,在液氮中快速冷冻并在-80℃下储存。
制备pHAb-染料缀合物:
在10mM碳酸氢钠缓冲液pH 8.5中配制Fcab、huFc和西妥昔单抗对照。以2:1摩尔比(pHAb:抗体)(Fcab 1、Fcab 2、Fcab 3、C IgG、C Fab)或10:1摩尔比(huFc)添加pHAb胺反应性染料(10mg/mL 1:1(v/v)DMSO/H2O,Promega),随后在不存在光的情况下在25℃、450rpm下孵育1h。根据制造商的说明通过杜氏磷酸盐缓冲盐水(DPBS)平衡的ZebaTM Spin脱盐柱(ThermoFisher Scientific)去除过多的染料。通过SI中描述的SE-HPLC方法测定pHAb-染料缀合物的聚集以及标记的荧光程度(DOLF)。肽图谱:根据使用说明书用GlycINATOR(Genovis)将Fcab-1和Fcab-1-MMAE去糖基化。然后在56℃将去糖基化分子用10mM DTT还原30min,并在黑暗中室温下用55mM碘乙酰胺烷基化30min。在37℃下用0.5μg胰蛋白酶(质谱级,Promega)将10μg蛋白质消化过夜。
使用偶联至TripleTOF 6600+质谱仪(Sciex)的Exion HPLC系统进行LC-MS分析。将7.5μg肽溶液加载到Aeris PEPTIDE XB-C18柱(Phenomenex,零件号00F-4506-AN)上,并且在49min内用5%到50%线性梯度的缓冲液B(乙腈,0.1%甲酸;缓冲液A:水,0.1%甲酸)洗脱。用正极性并且用质量范围在350到2500m/z间的TOF-MS和质量范围在50到2500m/z间的TOF-MS/MS获取数据。其他的仪器设置如下:离子喷雾电压为5.5kV,源温度为450℃,TOF-MS积累时间为0.25s以及TOF-MS/MS积累时间为0.08s,气体1为45psi,气体2为45psi,气帘气为35psi,去簇电位为80V,以及碰撞能量设置为动态。用Genedata Expressionist处理数据。
细胞培养:
从美国典型培养物保藏中心(American Type Culture Collection)获得人癌症细胞系(EGFR阳性:MDA MB 468、A431;EGFR阴性:MCF7)并根据标准培养条件维持(37℃、5%CO2、95%湿度)。在补充了10%胎牛血清(FBS)、2mM L-谷氨酰胺和1mM丙酮酸钠的DMEM高葡萄糖培养基内培养A431和MCF7细胞。在补充了10%FBS、2mM L-谷氨酰胺和1mM丙酮酸钠的洛斯维帕克纪念研究所(RPMI)1640培养基内培养MDA-MBA-468细胞。对于亚培养,通过添加0.05%的胰蛋白酶-EDTA使贴壁生长的细胞脱离,用新鲜培养基稀释并且转移至新的培养瓶内。
细胞摄取:
将细胞在500x g下离心5min,弃去上清液并且将细胞以300,000细胞/mL重悬于不具有酚红的各培养基中。将细胞悬浮液(40μL/孔)接种于黑色384透明底板上,随后在潮湿的室内孵育(37℃、5%CO2)过夜。用0.3%Tween-20(最终)补充pHAb-染料标记蛋白质,稀释至3μM并且使用D300e数字分液仪(Tecan)一式三份地添加至细胞(最终100nM)。立即将细胞转移至装配有DAPI和RFP滤光片立方体和BioSpa 8自动化培养箱(BioTek)的Cytation 5细胞成像检测仪(Cytation 5cell imaging reader)(BioTek)内。在26h的时间内每2h拍摄一次亮视野通道图像(物镜:10x,LED,强度:10,积分时间:13ms,相机增益:24)和RFP通道图像(激发:531nm,发射:593nm,LED强度:10,积分时间:50ms,相机增益:24)。在26h测量前约30min,从BioSpa 8装置中取出板并且经由Tecan D300e数字分液仪添加1μg/mL Hoechst33342(ThermoFisher Scientific),以得到另外的26h终点的DAPI图像。通过BioTek gen5数据分析软件处理图像。将每张图像pHAb染料荧光强度积分的总和对在DAPI通道中测定的细胞数量归一化,并减去在0h时的RFP信号积分的总和(背景信号)。将细胞数量和背景归一化的强度除以每个构建体的pHAb-染料DOLF并且按时间作图。在GraphPad Prism(GraphPadSoftware,Inc.)中通过线性回归拟合归一化的数据用并衍生出细胞内积累率(斜率)。最终,相对于最高细胞内积累率(本文将在MDA MB 468上的C IgG-pHAb设为100%)计算出每个构建体的相对细胞内积累。
FcRn和EGFR结合:
通过BLI在30℃和1,000rpm搅动速度下,使用RED96系统(FortéBio,Pall)测定Fcab、西妥昔单抗变体及它们的各MMAE缀合物的动力学参数。
对于EGFR结合分析,将Fcab变体(在DPBS中10μg/mL)、CIgG(在DPBS中2.5μg/mL)和各MMAE缀合物加载到抗人IgG Fc捕获生物传感器(AHC)上60–180s。将C Fab(在DPBS中2.5μg/mL)加载于抗人Fab CH1第二代生物传感器(FAB2G)上180s。然后将生物传感器转移至动力学缓冲液(DPBS pH 7.4、0.02%Tween 20和0.1%牛血清白蛋白)中并且孵育60s,随后是与EGFR-His6(内部产生)的缔合步骤。将EGFR-His6连续稀释于动力学缓冲液中,其浓度范围从20nM到0.313nM变化。对缔合监测180s、240s或300s,随后是在动力学缓冲液中600s的解离步骤以测定kon和koff值。用动力学缓冲液取代EGFR-His6,用作阴性对照和参考。在每个实验中各未结合huFc用作阴性对照。从抗体测量值中减去缓冲液参考测量值(对照曲线)用于数据拟合,并且通过在Savitzky-Golay滤波后,使用应用1:1全局全拟合结合模型的FortéBio数据分析软件12.0来测定动力学参数。如别处所述[14]进行FcRn结合测定。
血清稳定性:
如前面所述[27]进行血清稳定性测定,并进行一些小改动:在人和小鼠血清中以5μM缀合MMAE的终浓度(考虑每个构建体的DAR)将MMAE缀合物进行孵育。此外,在96h血清孵育之前用5μM氘化D8-MMAE内标物补充血清样品。
细胞增殖测定:
为评估C IgG-、C Fab-和Fcab MMAE缀合物和相关化合物,将40uL活细胞悬液(MDAMB 468:2500细胞/孔,A431:9000细胞/孔,MCF 7:5000细胞/孔)接种至不透明的384-孔板中,随后在潮湿室内孵育(37℃、5%CO2)过夜。使用D300e数字分液仪(Tecan)添加测试化合物。用0.3%Tween 20(终)补充游离MMAE溶液、蛋白质/蛋白质-缀合物溶液并且稀释至6μM(MMAE)或10μM(蛋白质)。将所有孔对添加的Tween 20的最大量归一化。根据制造商的说明使用Cell Titer Glo试剂(Promega)在4d后测定细胞活力。将发光值对未处理的细胞的发光归一化,并且使用GraphPad Prism(GraphPad Software,Inc.)的非对称(五个参数)拟合函数,拟合剂量反应以得到IC50值。
实施例9:注射小瓶
用2N盐酸将100g本发明的缀合物和5g磷酸氢二钠在3l双蒸馏水中的溶液调至pH6.5,在无菌条件下过滤,转移至注射小瓶,在无菌条件下冷冻干燥并且在无菌条件下密封。每个注射小瓶含有5mg本发明的缀合物。
实施例10:溶液
由1g本发明的缀合物、9.38g NaH2PO4 2H2O、28.48gNa2HPO4·12H2O和0.1g苯扎氯氨在940ml双蒸馏水中制备溶液。将pH调至6.8和将溶液补充至1l并且通过照射灭菌。
实施例11:安瓿
将1kg本发明的缀合物在60l双蒸馏水中的溶液在无菌条件下过滤,转移至安瓿,在无菌条件下冷冻干燥并且在无菌条件下密封。每个安瓿含有10mg本发明的缀合物。
实施例12:表达的蛋白质的氨基酸序列
D265A,Q295,Q311,Q438
SEQ ID No.1-Fcab-1(修饰的FS1-60[1]):
SEQ ID No.2-Fcab-2(修饰的FS1-65[1]):
SEQ ID No.3-Fcab-3(修饰的FS1-67[1]):
SEQ ID No.4-Fcab-4(FS1-60[1]):
SEQ ID No.5-Fcab-5(FS1-65[1]):
SEQ ID No.6-Fcab-6(FS1-67[1]):
SEQ ID No.7-huFc(修饰的人IgG1 Fc片段):
C-IgG(以用于缀合的LC C端(G4S)3-LPETGS分选酶A识别标签来修饰的西妥昔单抗):
SEQ ID No.8-轻链
SEQ ID No.9-重链
C-Fab(以用于缀合的LC C端(G4S)3-LPETGS分选酶A识别标签和用于纯化的HC C端G4S-His6标签来修饰的西妥昔单抗Fab片段):
SEQ ID No.10-轻链
SEQ ID No.11-重链
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序列表
<110> 默克专利股份公司
<120> 靶向EGFR的Fc抗原结合片段-药物缀合物
<130> P21-081
<140> EP21175808.1
<141> 2021-05-25
<150> EP21175808.1
<151> 2021-05-25
<160> 11
<170> BiSSAP 1.3.6
<210> 1
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> Fcab-1 (修饰的FS1-60
<400> 1
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Asp Glu Gly Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
130 135 140
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn
145 150 155 160
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
165 170 175
Leu Tyr Ser Arg Leu Thr Val Ser His Trp Arg Trp Tyr Ser Gly Asn
180 185 190
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
195 200 205
Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 2
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> Fcab-2 (修饰的FS1-65)
<400> 2
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Asp Glu Gly Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
130 135 140
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn
145 150 155 160
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
165 170 175
Leu Tyr Ser Lys Leu Thr Val Ser Tyr Trp Arg Trp Val Lys Gly Asn
180 185 190
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
195 200 205
Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 3
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> Fcab-3 (修饰的FS1-67)
<400> 3
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Ala Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Thr
115 120 125
Asp Asp Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Ser Tyr Trp Arg Trp Tyr Lys Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 4
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> Fcab-4 (FS1-60[1])
<400> 4
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Asp Glu Gly Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
130 135 140
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn
145 150 155 160
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
165 170 175
Leu Tyr Ser Arg Leu Thr Val Ser His Trp Arg Trp Tyr Ser Gly Asn
180 185 190
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
195 200 205
Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 5
<211> 217
<212> PRT
<213> 人工序列
<220>
<223> Fcab-5 (FS1-65)
<400> 5
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
115 120 125
Asp Glu Gly Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
130 135 140
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn
145 150 155 160
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
165 170 175
Leu Tyr Ser Lys Leu Thr Val Ser Tyr Trp Arg Trp Val Lys Gly Asn
180 185 190
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
195 200 205
Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 6
<211> 216
<212> PRT
<213> 人工序列
<220>
<223> Fcab-6 (FS1-67)
<400> 6
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
1 5 10 15
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
20 25 30
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
35 40 45
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
50 55 60
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
65 70 75 80
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
85 90 95
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
100 105 110
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Thr
115 120 125
Asp Asp Gly Pro Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
130 135 140
Ser Asp Ile Ala Val Glu Trp Glu Ser Thr Tyr Gly Pro Glu Asn Asn
145 150 155 160
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
165 170 175
Tyr Ser Lys Leu Thr Val Ser Tyr Trp Arg Trp Tyr Lys Gly Asn Val
180 185 190
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
195 200 205
Lys Ser Leu Ser Leu Ser Pro Gly
210 215
<210> 7
<211> 222
<212> PRT
<213> 人工序列
<220>
<223> huFc (修饰的human IgG1 Fc fragment)
<400> 7
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
1 5 10 15
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
20 25 30
Pro Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu
35 40 45
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
50 55 60
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
65 70 75 80
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
85 90 95
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
100 105 110
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115 120 125
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130 135 140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145 150 155 160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
165 170 175
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180 185 190
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195 200 205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
210 215 220
<210> 8
<211> 235
<212> PRT
<213> 人工序列
<220>
<223> C-IgG轻链
<400> 8
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Leu Pro Glu Thr Gly Ser
225 230 235
<210> 9
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> C-IgG重链
<400> 9
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val
290 295 300
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 10
<211> 235
<212> PRT
<213> 人工序列
<220>
<223> C-Fab轻链
<400> 10
Asp Ile Leu Leu Thr Gln Ser Pro Val Ile Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Val Ser Phe Ser Cys Arg Ala Ser Gln Ser Ile Gly Thr Asn
20 25 30
Ile His Trp Tyr Gln Gln Arg Thr Asn Gly Ser Pro Arg Leu Leu Ile
35 40 45
Lys Tyr Ala Ser Glu Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Val Glu Ser
65 70 75 80
Glu Asp Ile Ala Asp Tyr Tyr Cys Gln Gln Asn Asn Asn Trp Pro Thr
85 90 95
Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
210 215 220
Gly Gly Gly Gly Ser Leu Pro Glu Thr Gly Ser
225 230 235
<210> 11
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> C-Fab重链
<400> 11
Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln
1 5 10 15
Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr
20 25 30
Gly Val His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Leu
35 40 45
Gly Val Ile Trp Ser Gly Gly Asn Thr Asp Tyr Asn Thr Pro Phe Thr
50 55 60
Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe
65 70 75 80
Lys Met Asn Ser Leu Gln Ser Asn Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Arg Ala Leu Thr Tyr Tyr Asp Tyr Glu Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu
130 135 140
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
145 150 155 160
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
180 185 190
Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys
210 215 220
Thr His Thr Gly Gly Gly Gly Ser His His His His His His
225 230 235
Claims (15)
1.EGFR Fcab-药物缀合物或其药学上可接受的盐,包含式Fcab-(L)m-(D)n,其中:
e)Fcab包含EGFR Fcab,
f)L包含接头,
g)D包含药物,
h)m是1-5的整数和n是1-10的整数。
2.根据权利要求1所述的EGFR Fcab-药物缀合物,其中所述EGFR Fcab选自Fcab-1、Fcab-2、Fcab-3、Fcab-4、Fcab-5和Fcab-6,其具有如SEQ ID No.1-6所示的氨基酸序列。
3.包含式Fcab-(L)m-(La)n的EGFR Fcab-标记缀合物,其中:
e)Fcab包含EGFR Fcab,
f)L包含接头,
g)La包含标记,
h)m是1-5的整数和n是1-10的整数。
4.包含至少一种根据权利要求1或2所述的EGFR Fcab-药物缀合物的药物制剂。
5.根据权利要求4所述的药物制剂,其包含额外赋形剂和/或辅助剂。
6.包含至少一种根据权利要求1或2所述的EGFR Fcab-药物缀合物以及至少一种额外药物活性化合物的药物制剂。
7.制备药物制剂的方法,特征在于将根据权利要求1或2所述的EGFR Fcab-药物缀合物与固态、液态或半液态的赋形剂或辅助剂一起制成合适的剂型。
8.包含至少一种根据权利要求3所述的EGFR Fcab-标记缀合物的诊断组合物。
9.包含至少一种根据权利要求1或2所述的EGFR Fcab-药物缀合物的药物,用于治疗和/或预防生理状态和/或病理生理状态。
10.包含至少一种根据权利要求1或2所述的EGFR Fcab-药物缀合物的药物,用于治疗和/或预防生理状态和/或病理生理状态,所述生理状态和/或病理生理状态选自过度增殖性疾病和病症。
11.根据权利要求10所述的药物,其中所述过度增殖性疾病或病症是癌症。
12.根据权利要求11所述的药物,其中所述癌症是EGFR阳性癌症。
13.根据权利要求11所述的药物,其中所述癌症选自急性和慢性淋巴细胞性白血病、急性粒细胞性白血病、肾上腺皮质癌、膀胱癌、脑癌、乳腺癌、宫颈癌、宫颈增生、绒毛膜癌、慢性粒细胞性白血病、慢性淋巴细胞性白血病、结肠癌、子宫内膜癌、肾癌、胆道癌、肝细胞瘤、肝癌、食管癌、原发性血小板增多症、泌尿生殖系统癌、神经胶质瘤、胶质母细胞瘤、毛细胞白血病、头颈癌、霍奇金病、卡波西肉瘤、肺癌、淋巴瘤、恶性类癌、恶性高钙血症、恶性黑色素瘤、恶性胰腺胰岛素瘤、甲状腺髓样癌、黑色素瘤、软骨肉瘤、多发性骨髓瘤、蕈样肉芽肿病、髓性和淋巴细胞性白血病、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌、成骨肉瘤、卵巢癌、胰腺癌、真性红细胞增多症、原发性脑癌、原发性巨球蛋白血症、前列腺癌、肾细胞癌、横纹肌肉瘤、皮肤癌、小细胞肺癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、甲状腺癌和威尔姆斯瘤。
14.根据权利要求11所述的药物,其中所述癌症选自乳腺癌、胃癌、胃部癌症、结肠直肠癌、卵巢癌、胰腺癌、子宫内膜癌或非小细胞肺癌。
15.由下列单独包装组成的套件(试剂盒):
a)有效量的包含至少一种根据权利要求1或2所述的EGFR Fcab-药物缀合物,和
b)有效量的额外药物活性化合物。
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GB201700345D0 (en) * | 2017-01-09 | 2017-02-22 | F-Star Beta Ltd | Conditional agonists of immune responses |
US11440963B2 (en) | 2017-05-09 | 2022-09-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Combination PDL1 and TGF-beta blockade in patients with HPV+ malignancies |
WO2019068758A1 (en) * | 2017-10-03 | 2019-04-11 | Universität Für Bodenkultur Wien | MODIFIED CYSTEINE MOLECULES BINDING TO ANTIGEN |
GB201811410D0 (en) * | 2018-07-12 | 2018-08-29 | F Star Beta Ltd | OX40 Binding molecules |
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- 2022-05-23 EP EP22730424.3A patent/EP4346905A1/en active Pending
- 2022-05-23 CA CA3221411A patent/CA3221411A1/en active Pending
- 2022-05-23 CN CN202280037398.9A patent/CN117999101A/zh active Pending
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AU2022280341A1 (en) | 2024-01-04 |
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WO2022248380A1 (en) | 2022-12-01 |
IL308818A (en) | 2024-01-01 |
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