CN112119095A - Muc16单克隆抗体及其用途 - Google Patents
Muc16单克隆抗体及其用途 Download PDFInfo
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- CN112119095A CN112119095A CN201980031339.9A CN201980031339A CN112119095A CN 112119095 A CN112119095 A CN 112119095A CN 201980031339 A CN201980031339 A CN 201980031339A CN 112119095 A CN112119095 A CN 112119095A
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Abstract
本文描述了与O‑聚糖粘蛋白型糖蛋白MUC16结合的抗体或抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3)和三个可变轻域CDR(CDR L1、L2和L3)。本发明还涉及药物组合物、核酸载体、包含所述核酸载体的细胞以及抑制表达O‑聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法。
Description
相关申请的交叉引用
本申请要求于2019年5月9日提交的美国临时专利申请62/669,058的优先权,其说明书以整体通过引用并入本文。
背景
(a)领域
所公开的主题总体上涉及针对O-聚糖粘蛋白型糖蛋白的单克隆抗体。更具体地,该主题涉及针对O-聚糖粘蛋白型糖蛋白MUC16的单克隆抗体及其使用方法。
(b)相关现有技术
胰腺癌是美国癌症相关死亡的第四大原因,其5年生存率小于4%,中位生存期小于6个月。根据美国癌症协会的统计,2013年美国因胰腺癌引起的新病例和死亡人数分别估计为45,220和38,460。在诊断时,超过80%的胰腺癌患者患有局部晚期或高度转移性疾病。
当前,Folfirinox是患有转移性疾病和具有良好表现状态的患者的第一线治疗方案,单用吉西他滨或与白蛋白结合型紫杉醇组合是用于治疗其他胰腺癌患者的一线化学治疗剂。但是,缓解率不高,中位总体生存率仍然令人沮丧。患者对化疗的不良响应和不良预后部分归因于致癌信号通路的组成性激活,这与耐药性的发展、侵袭性致瘤性和早期转移有关。
这些不利影响导致需要新的分子靶向疗法来对抗致死性癌症,所述致死性癌症通常包括但不限于胰腺癌。
众所周知,膜粘蛋白MUC16的异常表达与诸如卵巢癌和胰腺癌之类的肿瘤进展和转移有关。MUC16在肿瘤进展和转移中的作用是通过与致癌调节剂相互作用而发生的。例如,据了解,MUC16在卵巢癌细胞中的异常表达通过与间皮素(肿瘤分化因子)的相互作用以及通过阻断自然杀伤细胞介导的细胞毒性而通过免疫抑制功能促进了腹膜转移,而MUC16的过表达则通过刺激Janus激酶2(JAK2)来增加乳腺癌细胞的增殖。还应了解,MUC16在胰腺癌中上调,并且在肝转移中表达增加-尽管在胰腺上皮内瘤变(PanIN)和正常胰腺中均未检测到MUC16的表达,这表明MUC16的表达可能在疾病发展的后期出现。
尽管已知MUC16在疾病进展中的作用,但是对关于寡糖(O-连接的糖基化)修饰对粘蛋白型糖蛋白的可能作用了解的很少。研究表明,相对于其他类型的癌,胰腺癌中出现较高百分比的截短的O-聚糖(Tn和sialylTn,STn)的表达,并且公认的是,截短的O-聚糖的异常表达与肿瘤进展和不良患者预后相关。例如,STn抗原在超过80%的人类癌中表达,并且在所有情况下,STn的检测都与预后不良和患者总体生存率降低相关。此外,在粘蛋白型糖蛋白上与肿瘤相关的截短的碳水化合物抗原Tn和STn的表达是在腺癌中观察到的最常见的肿瘤特异性寡糖改变。Tn和STn表位在癌细胞表面的出现是由于ST6GalNAc-1的过表达或缺乏核心3合酶/核心1合酶活性和/或核心1合酶特异性分子伴侣–Cosmc中的缺陷。在许多上皮癌细胞中已观察到STn抗原的过度表达,但在胰腺癌中观察到了最高的频率。例如,STn的过度表达发生在上皮癌细胞(例如早期上皮良性病变)和胰腺癌(例如胰腺上皮内瘤变III期(PanIN-3),这被认为是胰腺癌发展之前的恶性病变)的肿瘤进展的早期。总而言之,这些发现表明截短的O-聚糖的过表达是导致胰腺癌发展的早期事件。然而,这些截短的O-聚糖在胰腺肿瘤发生过程中的确切生物学机制可能尚不清楚。
尽管进行了超过二十年的研究,但在开发针对癌症的分子靶向疗法中利用诸如粘蛋白型O-聚糖MUC16等已知的癌症生物标志物的尝试失败了。
因此,需要使用靶向粘蛋白型糖蛋白上的O-聚糖的单克隆抗体的新方法来抑制促存活细胞信号通路的激活。
因此,需要用于靶向O-聚糖粘蛋白型糖蛋白MUC16的替代性分子靶向疗法。
概述
根据一个实施方式,提供了与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3)以及三个可变轻域CDR(CDR L1、L2和L3),其中所述CDR H1、H2、H3、L1、L2和L3包含的氨基酸序列分别包括:
CDR H1:GFTFSTF(SEQ ID NO:1),
CDR H2:SSGSST(SEQ ID NO:2),
CDR H3:SGYDYDPIYYALDY(SEQ ID NO:3),
CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),
CDR L2:GASNQGS(SEQ ID NO:5),和
CDR L3:QQTKEVPWT(SEQ ID NO:6)。
根据另一个实施方式,提供了与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3),其中所述CDR H1、H2和H3包含的氨基酸序列分别包括:
CDR H1:GFTFSTF(SEQ ID NO:1),
CDR H2:SSGSST(SEQ ID NO:2),和
CDR H3:SGYDYDPIYYALDY(SEQ ID NO:3)。
根据另一个实施方式,提供了与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变轻域互补决定区(CDR)(CDR L1、L2和L3),其中所述CDR L1、L2和L3包含的氨基酸序列分别包括:
CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),
CDR L2:GASNQGS(SEQ ID NO:5),和
CDR L3:QQTKEVPWT(SEQ ID NO:6)。
本发明的抗体或抗原结合片段还可包含四个可变重域框架区(HFR)(HFR 1、2、3和4),其中所述HFR1、2、3和4包含的氨基酸序列包括:
HFR 1:EVQLVESGGGLVQPGGSRKLSCAAS(SEQ ID NO:7),
HFR 2:GMHWVRQAPEKGLEWVAYI(SEQ ID NO:8),
HFR 3:IYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDEDTAMYYCAR(SEQ ID NO:9),和
HFR 4:WGQGTSVTVSS(SEQ ID NO:10)。
本发明的抗体或其抗原结合片段还可包含四个可变轻域框架区(LFR)(LFR 1、2、3和4),其中所述LFR1、2、3和4包含的氨基酸序列包括:
LFR 1:DIVLTQSPASLAVSLGQRATISC(SEQ ID NO:11),
LFR 2:WFQQKPGHPPKLLIY(SEQ ID NO:12),
LFR 3:GVPARFSGSGSGTDFSLNIHPMEEDDAAMYFC(SEQ ID NO:13),和
LFR 4:FGGGTKVEIKR(SEQ ID NO:14)。
本发明的抗体或其抗原结合片段可进一步包括包含氨基酸序列的可变重链结构域(VH),该氨基酸序列包括:
EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15)。
本发明的抗体或其抗原结合片段可进一步包括包含氨基酸序列的可变轻链结构域(VL),该氨基酸序列包括:
DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYGASNQGSGVPARFSGSGSGTGTSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ ID NO:16)。
本发明的抗体或其抗原结合片段可以进一步包括包含氨基酸序列的可变重链结构域(VH),该氨基酸序列包括:
EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15),以及
包含氨基酸序列的可变轻链结构域(VL),该氨基酸序列包括:DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYYGASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ ID NO:16)。
所述抗体或其抗原结合片段可以是IgA,IgD,IgE,IgG或IgM。
所述抗原结合片段可以是单域抗体(sdAb)或单链可变片段(scFv)。
所述sdAb可包括3个CDR(CDR1、2和3),分别包含SEQ ID NO:1,SEQ ID NO:2和SEQID NO:3。
所述sdAb可包括三个CDR(CDR1、2和3),分别包含SEQ ID NO:4,SEQ ID NO:5和SEQID NO:6。
所述抗体或其抗原结合片段可以被人源化或部分人源化。
所述抗体或其抗原结合片段可以是POCmAb。
根据另一个实施方式,提供了一种组合物,其包含本发明的抗体或其抗原结合片段,以及药学上可接受的稀释剂、载体或赋形剂。
根据另一个实施方式,提供了一种在其需要的受试者中抑制表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法,该方法包括向该受试者施用本发明所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段或本发明所述的组合物。
所述抗体或其抗原结合片段可以是抗体。
所述抗体可以是单克隆抗体。
所述O-聚糖粘蛋白型糖蛋白MUC16可包含截短的O-聚糖。
所述截短的O-聚糖可包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
所述方法可以进一步包括施用第二治疗剂,其包括细胞毒性剂,额外的抗体或其治疗活性片段或化疗方案中的至少一种。
所述细胞毒性剂可以是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
所述细胞毒性剂可以是吉西他滨和白蛋白结合型紫杉醇的至少一种。
所述ErbB信号传导抑制剂可以是沙必替尼(Sapitinib)。
所述额外的抗体或其治疗片段可以是奥戈伏单抗(oregovomab)B43.13、AR9.6抗体、或其组合。
所述化疗方案可以是Folfirinox(福尔菲林)。
所述肿瘤可以选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
所述方法可以用于治疗癌症。
所述抗体或其抗原结合片段可以与串联重复(TR)SEA结构域5和6的构象表位结合,而没有O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
根据另一个实施方式,提供了一种在其需要的受试者中检测表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的方法,包括向所述受试者施用本发明所述的对O-聚糖粘蛋白型糖蛋白MUC16特异的抗体或其抗原结合片段,并检测所述抗体或抗原结合片段。
所述抗体或其抗原结合片段还包含可检测标记。
所述可检测标记可以是荧光标记、放射性标记、MRI造影剂、或其组合。
根据另一个实施方式,提供了一种核酸载体,其包含编码本发明所述的抗体或其抗原结合片段的核苷酸序列。
根据另一个实施方式,提供了一种细胞,其包含用于表达本发明的抗体或其抗原结合片段的本发明的核酸载体。
根据另一个实施方式,提供了本发明所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段,或本发明所述的组合物的用途,用于在其需要的受试者中抑制表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长。
所述抗体或其抗原结合片段可以是抗体。
所述抗体可以是单克隆抗体。
所述O-聚糖粘蛋白型糖蛋白MUC16可包含截短的O-聚糖。
所述截短的O-聚糖可以包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
所述用途还可进一步包括施用第二治疗剂,所述第二治疗剂包括细胞毒性剂、额外的抗体或其治疗活性片段或化疗方案中的至少一种。
所述细胞毒性剂可以是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
所述细胞毒性剂可以是吉西他滨和白蛋白结合型紫杉醇中的至少一种。
所述ErbB信号传导的抑制剂可以是沙必替尼(Sapitinib)。
所述额外的抗体或其治疗性片段可以是奥戈伏单抗B43.13、AR9.6抗体、或其组合。
所述化疗方案可以是Folfirinox(福尔菲林)。
所述肿瘤可以选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
所述方法可以用于治疗癌症。
所述抗体或其抗原结合片段可以与串联重复(TR)SEA结构域5和6的构象表位结合,而没有O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
根据另一个实施方式,提供了本发明所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段在抑制其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长中的用途。
根据另一个实施方式,提供了本发明所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段在在抑制其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法中的用途。
用于本发明的抗体或抗原结合片段可以是抗体。
所述抗体可以是单克隆抗体。
所述O-聚糖粘蛋白型糖蛋白MUC16可包含截短的O-聚糖。
所述截短的O-聚糖可以包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
用于本发明的抗体或抗原结合片段还可包括施用第二治疗剂,其包括细胞毒性剂、额外的抗体或其治疗活性片段或化疗方案中的至少一种。
所述细胞毒性剂可以是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
所述细胞毒性剂可以是吉西他滨和白蛋白结合型紫杉醇的至少一种。
ErbB信号传导的抑制剂可以是沙必替尼(Sapitinib)。
所述额外的抗体或其治疗片段可以是奥戈伏单抗B43.13、AR9.6抗体、或其组合。
所述化疗方案可以是Folfirinox(福尔菲林)。
所述肿瘤可以选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
用于本发明的抗体或抗原结合片段可以用于治疗癌症。
所述抗体或其抗原结合片段可以与串联重复(TR)SEA结构域5和6的构象表位结合,而没有O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
以下术语定义如下。
如本文所用,术语“抗体”在本领域中也被称为“免疫球蛋白”(Ig),是指由成对的重和轻多肽链构建的蛋白质;存在各种Ig同种型,包括IgA,IgD,IgE,IgG和IgM。当抗体被正确折叠时,每条链会折叠成多个由更多线性的多肽序列连接的独特球状结构域。例如,免疫球蛋白轻链折叠成可变(VL)和恒定(CL)结构域,而重链折叠成可变(VH)和三个恒定(CH,CH2,CH3)结构域。重链和轻链可变结构域(VH和VL)的相互作用导致抗原结合区(Fv)的形成。每个结构域具有本领域技术人员熟悉的完善的结构。
所述轻链和重链可变区负责结合靶抗原,因此可以显示抗体之间显著的序列多样性。恒定区显示较少的序列多样性,并且负责结合许多天然蛋白以引发重要的生化事件。抗体的可变区含有分子的抗原结合决定簇,并因此确定抗体对其靶抗原的特异性。大多数序列变异发生在六个高变区,每个可变重链(VH)和轻链(VL)各3个;高变区结合形成抗原结合位点,并有助于结合和识别抗原决定簇。抗体对其抗原的特异性和亲和力取决于高变区的结构以及它们呈现给抗原的表面的大小、形状和化学性质。存在多种用于识别高变区域的方案,最常见的两个方案是Kabat以及Chothia和Lesk的方案。Kabat等人(1991)基于VH和VL结构域的抗原结合区的序列可变性定义了“互补决定区”(CDR)。Chothia和Lesk(1987)根据VH和VL结构域中结构环区域的位置定义了“高变区环”(H或L)。这些单独的方案定义了相邻或重叠的CDR和高变区环区域,抗体领域技术人员经常互换使用术语“CDR”和“高变区环”,并且它们可以在本文中如此使用。此处根据Kabat方案鉴定CDR/环(即每个可变区的CDR1、2和3)。
本文所指的“抗体片段”,“抗原结合片段”和“其抗原结合片段”可以包括本领域已知的任何合适的抗原结合抗体片段。该抗体片段可以是天然存在的抗体片段,或者可以通过操作天然存在的抗体或通过使用重组方法来获得。例如,抗体片段可包括但并不限于Fv、单链Fv(scFv;由与肽接头连接的VL和VH组成的分子)、Fab,F(ab')2、单域抗体(sdAb;由单个VL或VH组成的片段),以及这些中任何一个的多价形式。诸如刚刚描述的抗体片段可能需要接头序列,二硫键或其他类型的共价键来连接片段的不同部分;本领域技术人员将熟悉不同类型片段的要求以及其构建的各种方法。
在非限制性实施例中,抗体片段可以是源自天然来源的sdAb。骆驼科动物来源的重链抗体(Hamers-Casterman等人,1993)缺少轻链,因此它们的抗原结合位点由一个结构域组成,称为VHH。在鲨鱼中也发现了sdAb,被称为VNAR(Nuttall等人,2003)。可以基于人Ig重链和轻链序列工程改造其他sdAb(Jespers等人,2004;To等人,2005)。如本文所用,术语“sdAb”包括通过噬菌体展示或其他技术直接从任何来源的VH,VHH,VL或VNAR库中分离的那些sdAb,衍生自上述sdAb的sdAb,重组产生的sdAb以及通过人源化、亲和力成熟、稳定化、增溶、骆驼化或其他抗体工程改造方法对此类sdAb进行进一步修饰而生成的那些sdAb。本发明还包括保留sdAb的抗原结合功能和特异性的同系物、衍生物或片段。
SdAb具有抗体分子所需的特性,例如高热稳定性、高耐洗涤剂性、对蛋白酶的相对高抗性(Dumoulin等人,2002)和高产率(Arbabi-Ghahroudi等人,1997);通过从免疫文库中分离(Li等人,2009)或通过体外亲和力成熟(Davies和Riechmann,1996),它们也可以被设计为具有非常高的亲和力。sdAb还可以进行进一步的修饰以提高稳定性,例如引入非规范的二硫键(Hussack等人,2011a,b;Kim等人,2012)。
本领域技术人员将十分熟悉单域抗体的结构(参见,例如,蛋白质资料库中的3DWT、2P42)。sdAb包含保留免疫球蛋白折叠的单个免疫球蛋白结构域;最值得注意的是,仅三个CDR/高变区环形成抗原结合位点。然而,并且如本领域技术人员将理解的,并非所有CDR都可能需要结合抗原。例如,但不希望受到限制,一个、两个或三个CDR可有助于本发明的sdAb对抗原的结合和识别。sdAb或可变结构域的CDR在本文中称为CDR1、CDR2和CDR3。
术语“scFv”旨在指单链可变片段,尽管scFv实际上不是抗体的片段,而是免疫球蛋白的重链可变区(VH)和轻链可变区(VL)的融合蛋白,与10至约25个氨基酸的短接头肽连接。接头通常富含甘氨酸以提高柔韧性,并富含丝氨酸或苏氨酸以提高溶解度,并且可以将VH的N端与VL的C端相连,反之亦然。尽管去除了恒定的Fc区并引入了接头,该scFv蛋白仍保留了原始免疫球蛋白的特异性。构建了ScFv分子以促进噬菌体展示,在其中将抗原结合结构域表达为单个肽非常方便。或者,可以直接从杂交瘤衍生的亚克隆重链和轻链中构建scFv。
二价scFv(di-scFv,bi-scFv)可以通过连接两个scFv而被工程化。这可以通过产生具有两个VH和两个VL区的单条肽链来完成,从而产生串联scFv。另一种可能性是用接头肽产生scFv,接头肽太短,以至于两个可变区不能折叠在一起(约五个氨基酸),迫使scFv二聚。这种类型被称为双体。已显示双体的解离常数比相应的scFv低40倍,这意味着它们对其靶标具有更高的亲和力。例如,双体药物的剂量可以比其他治疗性抗体低得多,并且能够在体内高度特异性地靶向肿瘤。更短的接头(一个或两个氨基酸)导致三聚体的形成,即所谓的三体。还产生了四体。与双体相比,它们对其靶标的亲和力更高。
所有这些形式可以由对两种不同抗原具有特异性的可变片段组成,在这种情况下,它们是双特异性抗体的类型。其中最发达的是双特异性串联di-scFv,称为双特异性T细胞衔接子(BiTE抗体构建体)。
本发明还包括使用本领域已知的任何合适方法“人源化”的抗体或抗原结合片段,例如但不限于CDR移植和镶饰。抗体或抗体片段的人源化包括将在人的共有序列中发现的序列中的氨基酸替换为其人的对应物,而不会失去抗原结合能力或特异性;当引入人类受试者时,该方法降低了抗体或其片段的免疫原性。在CDR移植过程中,可以将本文定义的一个或多个CDR之一融合或移植到人可变区(VH或VL)、其他人抗体(IgA,IgD,IgE,IgG和IgM)、其他人抗体片段框架区(Fv,scFv,Fab)、或与可以移植CDR的大小和性质相似的其他蛋白质(Nicaise等人,2004)。在这种情况下,一个或多个高变区环的构象可能被保留,而sdAb对其靶标(即MUC16)的亲和力和特异性可能受到的影响最小。CDR移植在本领域中是已知的,并且至少在以下内容中有描述:美国专利号为6180370的专利申请,美国专利号为5693761的专利申请,美国专利号为6054297的专利申请,美国专利号为5859205的专利申请和欧洲专利号为626390的专利申请。镶饰,在本领域中称为“可变区镶面”,涉及人源化抗体或片段在溶剂中暴露的位置;因此,保留了可能对CDR构象很重要的埋藏的非人源化残基,同时最大程度降低了对溶剂暴露区域的免疫反应潜力。镶饰在本领域中是已知的,并且至少在以下内容中进行了描述:美国专利号为5869619的专利申请,美国专利号为5766886的专利申请,美国专利号为5821123的专利申请和欧洲专利号为519596的专利申请。本领域技术人员也将充分熟悉制备此类人源化抗体片段和人源化氨基酸位置的方法。
本发明的抗体或其抗原结合片段也可以包含附加序列,以有助于表达、检测、定位或纯化。可以使用本领域技术人员已知的任何此类序列或标签。例如但不希望限于,抗体或其抗原结合片段可包含靶向或信号序列[例如,但不限于内质网膜定位信号(KDEL)、检测/纯化标签(例如,但不限于c-Myc、His5或His6)、或其组合。在另一个实施例中,附加序列可以是生物素识别位点,例如由Cronan等人在WO 95/04069或Voges等人在WO/2004/076670中描述的。如本领域技术人员还已知的,接头序列可以与附加序列或标签结合使用,或者可以用作检测/纯化标签。
本发明的抗体或其抗原结合片段也可以是多价展示形式,在本文中也称为多价呈递。可以通过本领域已知的任何合适的方法来实现多聚化。例如,但不希望以任何方式进行限制,可以使用自组装分子来实现多聚化,所述自组装分子为例如在Zhang等人(2004a;2004b)和WO2003/046560中描述的那些,其中五体通过表达包含以下内容的融合蛋白而产生:本发明的抗体或其片段和AB5毒素家族的B亚基的五聚化结构域(Merritt和Hol,1995)。也可以使用Zhu等人所述的多聚化结构域形成多聚体(2010);该形式在本文中被称为“抗体”形式,是本发明的抗体或片段与卷曲螺旋肽的融合体,产生多聚体分子(Zhu等人,2010)。本发明还涵盖其他形式的多价展示。例如,但不希望受到限制,抗体或其片段可以以二聚体、三聚体或任何其他合适的寡聚体形式存在。这可以通过本领域已知的方法来实现,例如直接接头连接(Nielson等人,2000),c-jun/Fos相互作用(de Kruif和Logtenberg,1996),“旋杵臼结构”相互作用(Ridgway等人,1996)。
本领域已知的用于多聚化的另一种方法是使用例如但不限于人Fc结构域的Fc结构域使抗体或其片段二聚化。Fc结构域可以选自各种类型,包括但不限于IgG、IgM、或各种亚类,包括但不限于IgG1、IgG2等。在这种方法中,将Fc基因与sdAb基因一起插入载体中以生成sdAb-Fc融合蛋白(Bell等人,2010;Iqbal等人,2010);融合蛋白被重组表达,然后纯化。例如,但不希望以任何方式进行限制,多价展示形式可涵盖与Fc结构域连接的抗体VHH的嵌合或人源化形式,或与具有识别独特表位的两种或三种抗体VHH的双或三特异性抗体融合体。此类抗体易于制造和生产,可以大大延长sdAb的血清半衰期,并且可能是出色的肿瘤成像试剂(Bell等人,2010)。
刚刚描述的多聚体复合物中的Fc结构域可以是本领域已知的任何合适的Fc片段。所述Fc片段可以来自任何合适的来源。例如,Fc可以是小鼠或人来源的。在一个具体的非限制性实例中,Fc可以是小鼠Fc2b片段或人Fc1片段(Bell等人,2010;Iqbal等人,2010)。Fc片段可与本发明的VHH或人源化形式的N-末端或C-末端融合。
上述多聚体的每个亚基可以包含相同或不同的本发明的抗体或其片段,其可以具有相同或不同的特异性。另外,根据需要,可以使用接头将多聚化结构域连接至抗体或抗体片段;这样的接头应具有足够的长度和适当的组成以提供两个分子的柔性连接,但不应妨碍抗体的抗原结合性质。
根据以下对选定实施方式的详细描述,如附图所示,本发明的主题的特征和优点将变得更加明显。将会认识到,所公开和要求保护的主题能够在各个方面进行修改,而全部不脱离权利要求的范围。因此,附图和说明书应被认为本质上是说明性的,而不是限制性的,并且在权利要求中阐明了本主题的全部范围。
附图的简要说明
通过结合附图进行的以下详细描述,本发明的其他特征和优点将变得显而易见,其中:
图1显示了O-聚糖粘蛋白型糖蛋白MUC16以及目标抗原所来自的该蛋白质的区域。
图2A显示了人源化(POCmAb)抗MUC16抗体对不同胰腺癌细胞的结合特异性。
图2B显示了鼠(mAR9.6)抗MUC16抗体对不同胰腺癌细胞的结合特异性。
图3A显示了人源化(POCmAb)抗体与用唾液酸酶、O-聚糖酶和N-聚糖酶糖苷酶处理的胰腺癌细胞的结合特异性。
图3B显示了鼠(mAR9.6)抗体与用唾液酸酶、O-聚糖酶和N-聚糖酶糖苷酶处理的胰腺癌细胞的结合特异性。
图4显示了人源化(POCmAb)或鼠(mAR9.6)抗体与从用唾液酸酶、O-聚糖酶和N-聚糖酶糖苷酶处理的WT CHO细胞纯化的MUC16 TR1.2的结合特异性。
图5A显示了人源化(POCmAb)抗体对胰腺癌患者腹水样品的结合特异性。
图5B显示了鼠(mAR9.6)抗体对胰腺癌患者腹水样品的结合特异性。
图6显示了用本发明的对照IgG抗体、mAR9.6单克隆抗体和POCmAb单克隆抗体处理T3M4 WT细胞和SC细胞的结果。左列代表活细胞和死细胞的合并图像,中间列代表活细胞,而右边列代表死细胞。
图7显示了根据图6中所述的处理对细胞死亡进行的定量。
图8显示了用1)对照IgG抗体;2)mAR9.6单克隆抗体;3)沙必替尼(Sapitinib)与对照IgG或mAR9.6之一;4)LY294002与对照IgG或mAR9.6之一;5)沙必替尼(Sapitinib)和LY294002与对照IgG或mAR9.6之一的组合处理T3M4WT细胞的结果。左列代表活细胞和死细胞的合并图像,中间列代表活细胞,而右边列代表死细胞。
图9显示了根据图8中描述的每种治疗条件对细胞死亡进行的定量。
图10显示了用1)对照IgG抗体;2)POCmAb单克隆抗体;3)沙必替尼(Sapitinib)与对照IgG或POCmAb之一;4)LY294002与对照IgG或POCmAb之一;5)沙必替尼(Sapitinib)和LY294002与对照IgG或POCmAb之一的组合处理T3M4 WT细胞的结果。左列代表活细胞和死细胞的合并图像,中间列代表活细胞,而右边列代表死细胞。
图11显示了根据图10中描述的每种治疗条件对细胞死亡进行的定量。
图12显示了根据图8-11所示的结果的归一化倍数变化。结果显示,在诱导PDAC细胞的细胞死亡方面,发现POCmAb抗体比mAR9.6抗体出乎意料地和令人惊讶地更有效。
详述
本发明涉及与O-聚糖粘蛋白型糖蛋白MUC16结合的替代抗体或其抗原结合片段,用作治疗剂或用于诊断成像。
在第一实施方式中,公开了与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段。所述抗体或其抗原结合片段包含三个可变重链结构域互补决定区(CDR)(CDRH1、H2和H3)和三个可变轻链结构域CDR(CDR L1、L2和L3)。这些CDR H1、H2、H3、L1、L2和L3分别包含一氨基酸序列,所述氨基酸序列包含CDR H1:GFTFSTF(SEQ ID NO:1),CDR H2:SSGSST(SEQ ID NO:2),CDR H3:SGYDYDPIYYALDY(SEQ(ID NO:3),CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),CDR L2:GASNQGS(SEQ ID NO:5)和CDR L3:QQTKEVPWT(SEQ ID NO:6)。
根据第二实施方式,公开了与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3),其分别包含一氨基酸序列,所述氨基酸序列包括:CDR H1:GFTFSTF(SEQ ID NO:1),CDR H2:SSGSST(SEQ ID NO:2)和CDR H3:SGYDYDPIYYALDY(SEQ ID NO:3)。
根据第三实施方式,公开了结合至O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段,其包含三个可变轻域互补决定区(CDR)(CDR L1、L2和L3),其分别包含一氨基酸序列,所述氨基酸序列包括:CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),CDR L2:GASNQGS(SEQ ID NO:5)和CDR L3:QQTKEVPWT(SEQ ID NO:6)。
在实施方式中,本发明的抗体或其抗原结合片段还可进一步包含四个可变重链结构域框架区(HFR)(HFR 1、2、3和4),其包括包含以下序列的氨基酸序列:HFR 1:EVQLVESGGGLVQPGGSRKLSCAAS(SEQ ID NO:7),HFR 2:GMHWVRQAPEKGLEWVAYI(SEQ ID NO:8),HFR 3:IGYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDEDTAMYYCAR(SEQ ID NO:9)和HFR 4:WGQGTSVTVSS(SEQ ID NO:10)。
在其他实施方式中,本发明的抗体或其抗原结合片段还可进一步包含四个可变轻链结构域框架区(LFR)(LFR 1、2、3和4),其包括包含以下序列的氨基酸序列:LFR 1:DIVLTQSPASLAVSLGQRATISC(SEQ ID NO:11),LFR 2:WFQQKPGHPPKLLIY(SEQ ID NO:12),LFR3:GVPARFSGSGSGTDFSLNIHPMEEDDAAMYFC(SEQ ID NO:13),以及LFR 4:FGGGTKVEIKR(SEQ IDNO:14)。
根据一实施方式,本发明的抗体或其抗原结合片段可包括包含一氨基酸序列的可变重域(VH),所述氨基酸序列包括:EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15)。
根据一实施方式,本发明的抗体或其抗原结合片段可包括包含一氨基酸序列的可变轻域(VL),所述氨基酸序列包括:DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYGASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ ID NO:16)。
根据另一实施方式,本发明的抗体或其抗原结合片段可以包括包含一氨基酸序列的可变重域(VH),所述氨基酸序列包括:EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15),和包含一氨基酸序列的可变轻域(VL),所述氨基酸序列包含:DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYGASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ ID NO:16)。
根据其他实施方式,本发明的抗体或抗原结合片段可具有与以上公开的序列基本相同的序列,可操作的结合O-聚糖粘蛋白型糖蛋白MUC16。基本相同的序列可以包含一个或多个保守氨基酸突变。本领域中已知,与参考序列相比,一个或多个保守氨基酸突变可以产生突变肽,其与参考序列相比在生理、化学、物理化学或功能性质上没有实质性变化;在这种情况下,参考和突变序列将被认为是“基本相同的”多肽。保守氨基酸取代在本文中定义为一个氨基酸残基被具有相似化学性质(例如大小、电荷或极性)的另一个氨基酸残基取代。根据一个实施方式,可以在保持上述列出的CDR序列和抗体或片段的CDR的整体结构的同时,对抗体或抗原结合片段的框架区进行这些保守的氨基酸突变;因此,抗体的特异性和结合得以保持。根据另一实施方式,可以对抗体或抗原结合片段和上述列出的CDR序列的框架区进行这些保守的氨基酸突变,同时保持抗体或片段CDR整体结构的抗原结合功能;因此,抗体的特异性和结合得以保持。
在非限制性实施例中,保守突变可以是氨基酸取代。这样的保守氨基酸取代可以用碱性、中性、疏水性或酸性氨基酸替代相同组中的另一个。术语“碱性氨基酸”是指侧链pK值大于7的亲水性氨基酸,其通常在生理pH下带正电荷。碱性氨基酸包括组氨酸(His或H)、精氨酸(Arg或R)和赖氨酸(Lys或K)。术语“中性氨基酸”(也称为“极性氨基酸”)是指亲水性氨基酸,其侧链在生理pH下不带电荷,但其具有至少一个键的其中两个原子共同共享的一对电子被一个原子更紧密地结合。极性氨基酸包括丝氨酸(Ser或S)、苏氨酸(Thr或T)、半胱氨酸(Cys或C)、酪氨酸(Tyr或Y)、天冬酰胺(Asn或N)和谷氨酰胺(GIn或Q)。术语“疏水性氨基酸”(也称为“非极性氨基酸”)是指包括根据Eisenberg(1984)的标准化共识疏水性标度表现出大于零的疏水性的氨基酸。疏水氨基酸包括脯氨酸(Pro或P)、异亮氨酸(lie或1)、苯丙氨酸(Phe或F)、缬氨酸(Val或V)、亮氨酸(Leu或L)、色氨酸(Trp或W)、甲硫氨酸(Met或M)、丙氨酸(Ala或A)和甘氨酸(Gly或G)。“酸性氨基酸”是指侧链pK值小于7的亲水性氨基酸,其通常在生理pH下带负电荷。酸性氨基酸包括谷氨酸(Glu或E)和天冬氨酸(Asp或D)。
序列同一性用于评估两个序列的相似性;通过计算两个序列比对时残基的相同百分比来确定残基位置之间的最大对应关系。可以使用任何已知的方法来计算序列同一性。例如,计算机软件可用于计算序列同一性。不希望受到限制,可以通过软件,如由瑞士生物信息学会维护的NCBI BLAST2服务(可在ca.expasy.org/tools/blast/处找到)、BLAST-P、Blast-N、或FASTA-N或任何其他本领域已知的适当软件来计算序列同一性。
本发明的基本相同的序列可以是至少90%的相同;在另一个实施例中,在相对于本文所述的序列的氨基酸水平上,基本上相同的序列可以是至少90、91、92、93、94、95、96、97、98、99或100%相同,或它们之间的任何百分比。重要的是,基本相同的序列保留了参考序列的活性和特异性。在非限制性实施方式中,序列同一性的差异可能归因于保守氨基酸突变。在非限制性实施例中,本发明可指向包含与本文所述抗体的序列的至少95%、96%、97%、98%或99%相同的序列的抗体或抗原结合片段。
根据实施方式,本发明的抗体或其抗原结合片段可以是IgA、IgD、IgE、IgG或IgM。
在另一个实施方式中,本发明的抗体或其抗原结合片段可以是单域抗体(sdAb)或单链可变片段(scFv)。根据一个实施例,sdAb可包含三个CDR(CDR1、2和3),其分别包含SEQID NO:1,SEQ ID NO:2和SEQ ID NO:3。在另一个实施例中,sdAb可包含三个CDR(CDR1、2和3),其分别包含SEQ ID NO:4,SEQ ID NO:5和SEQ ID NO:6。
根据一个实施方式,所述抗体或其抗原结合片段可以被人源化或部分人源化。
根据一个实施方式,所述抗体或其抗原结合片段可以是抗体POCmAb。
在另一个实施方式中,公开了一种组合物,其包含本发明的抗体或其抗原结合片段,以及药学上可接受的稀释剂、载体或赋形剂。所述组合物可以包含如上所述的本发明的单一抗体或其抗原结合片段,或者可以是本发明的抗体或其抗原结合片段的混合物。此外,在包含本发明的抗体或其抗原结合片段的混合物的组合物中,所述抗体或其抗原结合片段可以具有相同的特异性,或在其特异性上也可以有所不同;例如,但不希望以任何方式进行限制,所述组合物可以包含对MUC16(相同或不同表位)具有特异性的本发明的抗体或其抗原结合片段。
所述组合物还可以包含药学上可接受的稀释剂、赋形剂或载体。所述稀释剂、赋形剂或载体可以是本领域已知的任何合适的稀释剂、赋形剂或载体,并且必须与组合物中的其他成分、组合物的递送方法相容,并且对组合物的接受者无害。该组合物可以是任何合适的形式;例如,组合物可以悬浮液形式、粉末形式(例如,但限于冻干的或包囊的)、胶囊或片剂形式提供。例如,但不希望受到限制,当以悬浮液形式提供组合物时,载体可包含水、盐水、合适的缓冲液或添加剂以改善溶解度和/或稳定性;在适当pH的缓冲液中进行重构以产生悬浮液,以确保抗体或抗原结合片段的活力。干粉还可以包含用于改善稳定性的添加剂和/或用于增加容量/体积的载体;例如,但不希望受到限制,干粉组合物可包含蔗糖或海藻糖。在一个具体的非限制性实施例中,可以将组合物配制为将抗体或抗原结合片段递送至受试者的胃肠道。因此,该组合物可以包含用于递送本发明的抗体或其抗原结合片段的包囊,定时释放或其他合适的技术。制备包含抗体或其抗原结合片段的合适组合物将在本领域技术人员的能力范围内。
在另一个实施方式中,公开了一种在其需要的受试者中抑制表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法,所述方法包括向该受试者施用本发明的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段。
在一个实施方式中,本发明的抗体或其抗原结合片段是抗体,以便存在抗体的恒定结构域并与免疫系统的效应细胞相互作用,以进行适当的免疫应答。不希望受到理论的束缚,申请人认为,这种相互作用对于实施本发明的方法可能是必需的。在本发明的一个具体实施方式中,所述抗体是单克隆抗体。
根据一个实施方式,由抗体或其抗原结合片段靶向的O-聚糖粘蛋白型糖蛋白MUC16包含截短的O-聚糖,例如包含Tn抗原、唾液酸Tn抗原(STn)、或其组合的截短的O-聚糖。根据一些实施方式,本发明的抗体或其抗原结合片段结合串联重复(TR)SEA结构域5和6的构象表位而没有O-聚糖粘蛋白型糖蛋白MUC16的糖基化。根据本发明的此类实施方式,认为靶向截短的粘蛋白型糖蛋白抑制它们在致瘤性和肿瘤进展中的作用。
在实施方式中,治疗有效量的本发明的抗体或其抗原结合片段可以用于靶向MUC16糖蛋白上的截短的O-聚糖,从而抑制磷脂酰肌醇3-激酶/Akt(PI3K/Akt)信号通路。
除其他之外,本方法教导了MUC16糖蛋白(也称为CA125)上的O-聚糖的癌症特异性截短产生了Her2/Neu(也称为ErbB2)受体的配体,这导致通过Akt的致癌信号级联反应增加了癌细胞的致癌潜能。该方法提供了MUC16的异常糖型除了可以用作癌的生物标志物外,还可以用作致癌细胞因子的一种形式。
MUC16是膜结合的,高度糖基化的细胞表面糖蛋白,其在子宫内膜、气管和角膜的正常上皮中表达。MUC16的表达也经常在恶性肿瘤中被上调,其也产生循环可溶形式的MUC16。已知膜粘蛋白MUC16的异常表达与癌症如胰腺癌的致瘤性和转移有关。此外,在胰腺上皮内瘤变(PanIN)中未检测到MUC16,而在原发肿瘤和转移性病变中MUC16升高,表明该粘蛋白的表达是疾病进展中的较晚事件。MUC16在卵巢癌细胞中的异常表达通过与间皮素(一种肿瘤分化因子)相互作用,并通过阻断自然杀伤细胞介导的细胞毒性而具有免疫抑制功能,从而促进了腹膜转移。最近的研究还表明,过表达的MUC16通过刺激Janus激酶2(JAK2)来增加乳腺癌细胞的增殖。这些报道强烈暗示MUC16通过与致癌调节剂的相互作用在肿瘤进展和转移中起主要作用。因此,研究表明,MUC16通过与致癌调节剂相互作用而在癌症中起主要作用,然而,对粘蛋白型糖蛋白(例如MUC16)的寡糖(O连接的糖基化)修饰,特别是作为潜在的癌症治疗方法的研究很少。
根据另一个实施方式,本发明的方法可以进一步包括施用包含细胞毒性剂、额外的抗体或其治疗活性片段或化学疗法方案中的至少一种的第二治疗剂。
确实,可以预期的是,本方法和治疗策略可以单独使用或与细胞毒性剂联合使用以增加患者的总体存活率。细胞毒性治疗剂包括但不限于,血管生成抑制剂、抗增殖药物、激酶抑制剂、受体酪氨酸激酶抑制剂、极光激酶抑制剂、polo样激酶抑制剂、bcr-abl激酶抑制剂、生长因子抑制剂、COX-2抑制剂、非甾体抗炎药(NSAIDS)、抗有丝分裂剂、烷基化剂、抗代谢药、嵌入抗生素、含铂试剂、生长因子抑制剂、电离辐射、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物反应修饰剂、免疫药,抗体、激素疗法、类视黄醇类物质/三角烷植物生物碱(retinoids/deltoids plant alkaloids)、蛋白酶体抑制剂、HSP-90抑制剂、组蛋白去乙酰酶抑制剂(HDAC)抑制剂、嘌呤类似物、嘧啶类似物、MEK抑制剂、CDK抑制剂、ErbB(例如ErbB2)受体抑制剂、磷脂酰肌醇3激酶(PI3Ks)/Akt信号传导抑制剂、mTOR抑制剂及其组合以及其他抗肿瘤药物。
血管生成抑制剂包括但不限于,EGFR抑制剂、PDGFR抑制剂、VEGFR抑制剂、TTE2抑制剂、IGF1R抑制剂、基质金属蛋白酶2(MMP-2)抑制剂、基质金属蛋白酶9(MMP-9)抑制剂、血小板反应蛋白类似物如血小板反应蛋白-1和N-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-He-Arg-Pro-NHCH2CH3或其盐和N-Ac-Sar-Gly-Val-D-allolle-Thr-Nva-Ile-Arg-PrO-NHCH2CH3的类似物,例如N-Ac-GlyVal-D-alle-Ser-Gln-Ile-Arg-ProNHCH2CH3或其盐。
EGFR抑制剂的实例包括但不限于,易瑞沙(吉非替尼)、特罗凯(埃罗替尼或OSI-774)、埃克替尼、爱必妥(西妥昔单抗)、EMD-7200,ABX-EGF、HR3、IgA抗体、TP-38(IVAX)、EGFR融合蛋白、EGF-疫苗、抗EGFr免疫脂质体、Tykerb(拉帕替尼)和AZD-8931(沙必替尼)。
PDGFR抑制剂的实例包括但不限于,CP-673、451和CP-868596。
VEGFR抑制剂的实例包括但不限于,阿瓦斯汀(贝伐单抗)、索坦(舒尼替尼,SU1248)、多吉美(索拉非尼,BAY43-9006)、CP-547、CP-632、阿昔替尼(AG13736)、阿帕替尼、卡博替尼、Zactima(凡德他尼,ZD-6474)、AEE788、AZD-2171、新型血管生成素抑制剂(VEGFtrap)、瓦他拉尼碱(PTK-787,ZK-222584)、哌加他尼钠、M862、帕唑帕尼(GW786034)、ABT-869和核酶(angiozyme)。
血小板反应蛋白类似物的实例包括但不限于TSP-1和ABT-510。
极光激酶抑制剂的实例包括但不限于VX-680、AZD-1152和MLN-8054。polo样激酶抑制剂的实例包括但不限于BI-2536。
bcr-abl激酶抑制剂的实例包括但不限于格列卫(伊马替尼)和达沙替尼(BMS354825)。
含铂试剂的实例包括但不限于顺铂、伯尔定(卡铂)、依铂、洛铂、奈达铂、乐沙定(奥沙利铂)或赛特铂。
mTOR抑制剂的实例包括但不限于CCI-779、雷帕霉素、西罗莫司脂化物、依维莫司、RAD001、INK-128和地磷莫司。
HSP-90抑制剂的实例包括但不限于格尔德霉素、根赤壳菌素、17-AAG、KOS-953、17-DMAG、CNF-101、CNF-1010、17-AAG-nab、NCS-683664、麦克格(Mycograb)、CNF-2024、PU3、PU24FC1、VER49009、IPI-504、SNX-2112和STA-9090。
组蛋白去乙酰酶抑制剂(HDAC)的实例包括但不限于辛二酰苯胺异羟肟酸(SAHA)、MS-275、丙戊酸、TSA、LAQ-824、毒素(Trpoxin)、他波森(tubacin)、图巴斯塔特(tubastatin)、ACY-1215和缩酚酸肽(Deptipeptide)。
MEK抑制剂的实例包括但不限于PD325901、ARRY-142886、ARRY-438162和PD98059。
CDK抑制剂的实例包括但不限于黄酮哌啶醇(flavopyridol)、MCS-5A、CVT-2584、塞利西利卜(seliciclib,CYC-202、R-罗斯科维汀)、ZK-304709、PHA-690509、BMI-1040、GPC-286199、BMS-387、BMS-032、PD0332991和AZD-5438。
COX-2抑制剂的实例包括但不限于CELEBREXTM(塞来昔布)、帕瑞昔布、地拉考昔、ABT-963、MK-663(依托昔布)、COX-189(罗美昔布)、BMS347070、RS 57067、NS-398、伐地考昔(伐地昔布)、塞莱昔布、万络(罗非昔布)、SD-8381、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基-苯基-1H-吡咯)、T-614、JTE-522、S-2474、SVT-2016、CT-3、SC-58125和安痛易(依托昔布)。
非甾体抗炎药(NSAID)的实例包括但不限于:水杨酰水杨酸(双水杨酸酯)、二氟尼柳(Dolobid)、布洛芬(摩特灵)、酮基布洛芬(酮洛芬)、萘丁美酮(Relafen)、吡罗昔康(Feldene)、萘普生(Aleve、Naprosyn)、双氯芬酸(扶他林)、吲哚美辛(Indocin)、舒林酸(奇诺力)、托美汀(Tolectin)、依托度酸(Lodine)、酮咯酸(Toradol)和奥沙普秦(Daypro)。
ErbB(例如ErbB2)受体抑制剂的实例包括但不限于CP-724-714、CI-1033、(卡奈替尼)、赫赛汀(曲妥单抗)、奥米塔格(Omitarg,2C4、佩妥珠单抗)、TAK-165、GW-572016(艾那法尼布(Ionafarnib))、GW-282974、EKB-569、PI-166、AZD-8931(沙必替尼(sapitinib))、dHER2(HER2疫苗)、APC8024(HER2疫苗)、抗HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三功能双特异性抗体,mAB AR-209和mAB 2B-1。
磷脂酰肌醇3-激酶抑制剂的例子包括但不限于渥曼青霉素、LY294002、木槿酮C(hibiscone C)、艾代拉里斯、库潘尼西、杜韦利西布、塔塞利西布(Taselisib)、哌立福辛、艾代拉里斯、布帕利西布(Buparlisib)、杜韦利西布、阿培利司、厄布利塞、库潘尼西、PX-866、达科(Dactolisib),CUDC-907、伏他利塞(也称为SAR245409、XL765)、CUDC-907、ME-401、IPI-549、SF1126、RP6530、INK1117、哌替昔布(pictilisib)XL147(也称为SAR245408)、帕洛米德529(Palomidd 529)、GSK1059615、ZSTK474、PWT33597、IC871 14、TG100-1 15、CAL263、RP6503、PI-103、GNE-477和AEZS-136。
烷化剂的实例包括但不限于氮芥N-氧化物、环磷酰胺、异环磷酰胺、曲洛磷胺、苯丁酸氮芥、美法仑、白消安、二溴甘露醇、卡波醌、噻替派、雷莫司汀、尼莫斯汀、替莫唑胺、AMD-473、六甲蜜胺、AP-5280、阿帕齐醌、溴他利星、苯达莫司汀、卡莫司汀、雌莫司汀、福莫司汀、葡磷酰胺、KW-2170、马磷酰胺和二溴卫矛醇、卡莫司汀(BCNU)、环己亚硝脲(CCNU)、白消安、苏消安、达卡巴嗪和替莫唑胺。
抗代谢药的实例包括但不限于甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、尿嘧啶类似物例如5-氟尿嘧啶(5-FU)单独或与亚叶酸组合、喃氟啶、UFT、去氧氟尿苷、卡莫氟、阿糖孢苷、阿糖胞苷烷磷酯、依诺他滨、S-I、爱宁达(培美曲塞二钠(premetrexed disodium)、LY231514、MTA)、健择(吉西他滨)、氟达拉滨、5-氮杂胞苷、卡培他滨、克拉屈滨、氯法拉滨、地西他滨、依洛尼塞、乙炔基胞苷(ethnylcytidine)、阿糖胞苷、羟基脲、TS-I、美法仑、奈拉滨、洛拉曲塞、烷磷酯(ocfosate)、前曲塞二钠(disodium premetrexed)、喷司他丁、培立特索(pelitrexol)、雷替曲塞、[(3-氨基吡啶-2-基)亚甲基氨基]硫脲(triapine)、三甲曲沙、阿糖腺苷、长春新碱、长春瑞滨、霉酚酸、噻唑羧胺核苷、利巴韦林、EICAR、羟基脲和去铁胺。
抗生素的实例包括嵌入抗生素,但不限于阿柔比星、放线菌素(例如放线菌素D)、氨柔比星、安那霉素、阿霉素(adriamycin)、博来霉素a、博来霉素b、道诺霉素、阿霉素(doxorubicin)、依沙芦星、表柔比星、格列比星(glarbuicin)、伊达比星、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、司他莫尔(stimalamer)、链脲菌素、戊柔比星、净司他丁、或其组合。
拓扑异构酶抑制剂的实例包括但不限于选自下组的一种或多种药剂:阿柔比星、氨萘非特、贝洛替康、喜树碱、10-羟基喜树碱、9-氨基喜树碱、二氟替康、盐酸依列替康(伊立替康)、依德卡林(edotecarin)、表柔比星(表阿霉素)、依托泊苷、依喜替康、吉马替康、勒托替康、卢比替康(Supergen)、BN-80915、米托蒽醌、吡柔比星、匹杉琼、鲁比替康、索布佐生、SN-38、他氟泊苷和拓扑替康。
抗体的实例包括但不限于利妥昔单抗、西妥昔单抗、贝伐单抗、曲妥珠单抗、特异性CD40抗体和特异性IGF1R抗体,
激素疗法的实例包括但不限于依西美坦(阿诺新)、醋酸亮丙瑞林、阿那曲唑(Arimidex)、斯雷福林(fosrelin,诺雷德)、戈舍瑞林、度骨化醇、法倔唑、福美司坦、枸橼酸他莫西芬(他莫昔芬)、康士得、阿巴瑞克、曲普瑞林、非那雄胺、氟维司群、托瑞米芬、雷洛昔芬、拉索昔芬、来曲唑、氟他米特、比卡鲁胺、甲地孕酮、米非司酮、尼鲁米特、地塞米松、泼尼松和其他糖皮质激素。
类视黄醇类物质/三角烷的实例包括但不限于:西奥骨化醇(EB 1089,CB 1093)、莱卡钙醇(KH 1060)、芬维A胺、阿里维甲酸(Aliretinoin)、贝沙罗汀和LGD-1550。
植物生物碱的实例包括但不限于长春新碱、长春花碱、长春地辛和长春瑞滨。
蛋白酶体抑制剂的实例包括但不限于硼替佐米(万珂)、MG132、NPI-0052和PR-171。
免疫药的实例包括但不限于干扰素和许多其他免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素,α-2b、干扰素β、干扰素γ-1a、干扰素γ-1b(Actimmune)、或干扰素γ-nl和其组合。其他药物包括非格司亭、香菇多糖、裂裥菌素、塞拉克斯(TheraCys)、乌苯美司、WF-10、阿地白介素、阿仑单抗、BAM-002、鸨烯咪胺、达克珠单抗、地尼白介素、吉妥单抗、替伊莫单抗、咪喹莫特、来格司亭、香菇多糖、黑素瘤疫苗(Corixa)、莫拉司亭、OncoVAC-CL、沙莫司亭、他索纳明、肌白蛋白(tecleukin)、胸腺素、托西莫单抗、维如利金、Z-100、依帕珠单抗、米妥莫单抗、奥戈伏单抗、彭杜单抗(pemtumomab)(Y-muHMFG1)、普列威(丹德里昂)、CTLA4(细胞毒性淋巴细胞抗原4)抗体和能够阻断CTLA4的药物如MDX-010。
生物反应调节剂的实例是修饰活生物体或生物反应的防御机制的药物,例如组织细胞的存活、生长或分化,以指导它们具有抗肿瘤活性。这样的药物包括云芝胞内多糖、香菇多糖、西佐弗兰(sizofrran),沙培林和乌苯美司。
嘧啶类似物的实例包括但不限于5-氟尿嘧啶、氟尿苷、去氧氟尿苷、雷替曲塞、阿糖胞苷(ara C)、阿糖胞苷、氟达拉滨和吉西他滨。
嘌呤类似物的实例包括但不限于巯嘌呤和硫鸟嘌呤。
抗有丝分裂剂的实例包括但不限于ABT-751、紫杉醇、多西他赛、埃博霉素D(KOS-862)和ZK-EPO。
本发明的抗体或其抗原结合片段也旨在用作增强放射疗法功效的放射致敏剂。放射疗法的实例包括但不限于外部光束放射治疗(XBRT)、或远距放射疗法、短距离放射治疗或密封源放射疗法、开放源放射治疗。
本发明的抗体或其抗原结合片段也可以与不同种类的Bcl-2抑制剂例如ABT263或ABT737组合使用。
根据一些实施方式,所述细胞毒性剂可以是吉西他滨和白蛋白结合型紫杉醇中的至少一种。
根据另一个实施方式,所述额外的抗体或其治疗性片段可以是奥戈伏单抗抗体B43.13、AR9.6抗体或其组合。
根据一个实施方式,所述化学疗法方案可以是Folfirinox(福尔菲林)。
在本发明的实施方案中,所述肿瘤可以选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤,并且所述方法可以用于治疗癌症。
在另一个实施方式中,公开了本发明的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段或本发明的组合物用于抑制在其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的用途。
在另一个实施方式中,公开了本发明的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段,其用于抑制在其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长。
在另一个实施方式中,公开了本发明的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段,其用于抑制在其需的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法。
在另一个实施方式中,公开了一种在其需要的受试者中检测表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的方法,其包括向受试者施用对O-聚糖粘蛋白型糖蛋白MUC16具有特异性的本发明的抗体或其抗原结合片段,并检测抗体或抗原结合片段。根据一个实施方式,抗体或其抗原结合片段可进一步包含可检测的标记,例如本领域已知的荧光标记、放射性标记、MRI造影剂或其组合。
本发明还涵盖包含编码本发明的抗体或其抗原结合片段的核苷酸序列的核酸载体,以及包含该核酸载体的细胞,用于表达本发明的抗体或其抗原结合片段,以及表达本发明的抗体或其抗原结合片段的细胞。
通过参考以下实施例将更容易理解本发明,所述实施例是为了说明本发明而不是限制其范围。
实施例1
MUC16片段的表达
表达载体,其编码包含MUC16串联重复(TR)SEA结构域5和6(SEQ ID NO:17)的MUC16(TR 1.2构建体)的片段。该片段含有TR 5的SEA结构域,一侧是TR 4的富PST序列,另一侧是TR6。TR1.2 MUC16片段在CHO细胞中表达,并根据标准技术纯化。
实施例2
抗MUC16单克隆抗体的产生
动物免疫。给四只六周大的雌性A/J小鼠(杰克逊实验室,巴尔港,缅因州)放血(免疫前血清),并在第0天和第21天在腹膜内和皮下注射100μg在Titermax佐剂中乳化的TR1.2MUC16抗原。在第31或38天,将血液收集在微量采血管CB 300Z中,并将血清储存在-20℃直至进一步使用。
ELISA(血清滴度测定)。通过ELISA评估动物的免疫前和免疫后血清滴度。除非另有说明,否则所有孵育均在室温下进行。简而言之,将半区96孔每孔用20μg/ml的PBS的25μl免疫原包被,并在4℃孵育过夜。将微孔反应板在PBS中洗涤3次,并用含1%牛血清白蛋白(BSA)的PBS封闭30分钟。除去封闭缓冲液,并加入25μl血清样品的系列稀释液。孵育2小时后,用0.05%的PBS-吐温20将微孔反应板洗涤4次,并加入25μl的1/5,000稀释的碱性磷酸酶缀合的山羊抗小鼠IgG(H+L)的封闭缓冲液。孵育1小时后,将微孔反应板洗涤4次,然后加入25μl pH 9.6的碳酸盐缓冲液中的1mg/ml的磷酸对硝基苯酯(pNPP)底物,并进一步温育30分钟。使用酶标仪在405nm处读取吸光度。免疫前所有出血均为阴性,而免疫后所有出血均对重组蛋白非常强(1/12800以上)。融合实验前3天,使用PBS中的100μg重组蛋白进行了最终的腹膜内加强注射。
收获的脾细胞的融合。所有操作均在无菌条件下进行。在Iscove的改良Dulbecco培养基(IMDM)中收获脾细胞,并使用聚乙二醇融合到NS0骨髓瘤细胞系中。在IMDM中洗涤脾细胞和骨髓瘤细胞,在RBC裂解缓冲液中计数,并以5∶1的比例混合在一起。通过在1分钟内逐滴加入在37℃下预热的1ml 50%的PEG 4000的PBS的溶液,将沉淀的细胞融合在一起,并在37℃下再孵育90秒。通过在22℃下历时2分钟添加30ml IMDM来终止反应。孵育10分钟后,将新鲜融合的细胞旋转10分钟。在补充有10%热灭活的FBS的IMDM中将细胞洗涤一次,并以每毫升2x105输入骨髓瘤细胞的浓度悬浮在HAT选择培养基中(IMDM,包含20%热灭活的FBS,青霉素-链霉素,1ng/ml小鼠IL-6,HAT培养基补充剂和L-谷氨酰胺),在37℃,5%CO2下孵育。第二天,洗涤杂交瘤细胞,并以每毫升2-3x105输入骨髓瘤细胞的浓度悬浮在补充了5%热灭活的FBS,1ng/ml小鼠IL-6和10μg/ml FITC-F(ab')2山羊抗小鼠IgG的半固体培养基D中( )。将细胞混合物铺在培养皿中,并在37℃,5%CO2下进一步孵育6-7天。然后使用哺乳动物细胞克隆选择器将荧光分泌物克隆转移到含有200μl补充有20%热灭活的FBS,青霉素-链霉素,1ng/ml小鼠IL-6,HT培养基补充剂(货号H0137)和L-谷氨酰胺的IMDM的无菌96孔平板中,在37℃,5%CO2下孵育2-3天。
筛选。通过ELISA筛选杂交瘤上清液以检测特异性结合物。为此,在96孔半区板中包被25μl的TR1.2 MUC16(浓度为20μg/ml)或无关的对照蛋白(浓度为5μg/ml)的PBS溶液,并在4℃孵育过夜。用PBS洗涤微孔反应板3次,用1%PBS-BSA封闭,加入25μl杂交瘤上清液,并在37℃,5%CO2下孵育2小时。将板用0.05%的PBS-吐温20洗涤4次,并在37℃,5%CO2中与稀释1/5000的封闭缓冲液的25μl二级抗体碱性磷酸酶缀合的F(ab')2山羊抗小鼠IgG孵育一小时。用0.05%的PBS-吐温20洗涤4次后,加入25μl的1mg/ml pNPP底物溶液,并进一步在37℃下孵育1小时。使用酶标仪进行O D405nm的测量。使用碱性磷酸酶偶联的F(ab')2山羊抗小鼠IgG Fcγ特异性抗体可确定命中,并选择50mAb进行进一步表征。
杂交瘤的再克隆。通过有限稀释使选择的杂交瘤再克隆以确保其单克隆性。
实施例3
重组抗MUC16的制备
将针对MUC16 TR1.2A的候选抗体的VH和VL区测序、合成并克隆到具有人IgG1重链恒定结构域(包含CH1、CH2和CH3区)的pTT5载体中,或在人κ轻链恒定结构域的框内,根据Delafosse等人,生物技术杂志,227(2016)的方法,通过瞬时转染在CHO-3E7细胞中产生了重组mAb。该抗体被称为POCmAb。
表1–抗体POCmAb的VH和VL区的氨基酸序列
表2–VH序列的Chothia编号
CDR H1预计为规范的1类(1/10A)
CDR H2预计为规范的3类(3/10B)
表3-CDR序列(Chothia)和CDR规范类
表4-VL序列的Chothia编号
CDR L1没有规范的类别匹配
CDR L2–1类
CDR L3–1类
表5-CDR序列(Chothia)和CDR规范类
实施例4
抗MUC16 TR1.2A的结合特异性
现在参考图2。测试了抗MUC16 TR1.2A的人源化形式,即(POCmAb)对各种胰腺癌细胞的结合特异性。图2A显示,与另一种抗-MUC16抗体,小鼠抗-MUC16mAb AR9.6(也称为mAR9.6;图2B)相比,POCmAb在不同的胰腺癌细胞中识别MUC16的各种同种型。接下来,测试了鼠mAR9.6和人源化POCmAb抗MUC16抗体对用唾液酸酶、O-聚糖酶和N-聚糖酶处理的人胰腺癌细胞(T3M4)的结合特异性。图3A和3B显示了用N-聚糖酶处理的样品与任一抗体(泳道2和5)的反应性降低。然而,单独或组合用O-聚糖酶和唾液酸酶处理的样品显示与任一抗体的反应性增加(泳道3、4和6)。接下来,测试了鼠mAR9.6和人源化POCmAb抗MUC16抗体对用不同的糖苷酶如唾液酸酶、O-聚糖酶和N-聚糖酶处理的从CHO野生型细胞纯化的MUC16 TR1.2的结合特异性。图4显示用N-聚糖酶处理的样品与任一抗体(泳道2和5)的反应性降低。然而,单独或组合用O-聚糖酶和唾液酸酶处理的样品显示与任一抗体的反应性增加(泳道3、4和6)。综上所述,这些结果表明,MUC16糖蛋白上的N-聚糖对于抗体结合至关重要。但是,MUC16上的O-聚糖和唾液酸基团会阻断或掩盖抗MUC16抗体反应性的表位。图5A显示,与小鼠抗MUC16 mAb AR9.6相比,POCmAb在胰腺导管腺癌(PDAC)患者腹水(37.5%;6/16)中识别MUC16的各种同种型。
实施例4
活/死细胞细胞毒性测定:
进行活/死细胞毒性测定以比较mAR9.6和POCmAb抗体在诱导PDAC细胞中细胞死亡中的作用。小鼠AR9.6抗体对MUC16具有亲和力和特异性反应性,使其能够抑制体内胰腺肿瘤的生长和转移。mAb AR9.6显著诱导PDAC细胞的细胞死亡,并选择性抑制致癌信号的激活。
材料和方法。将T3M4野生型(WT)和缺失的COSMC(SimpleCells,SC)用等量的mAR9.6(5μg/ml)和POCmAb(5μg/ml)或同种型匹配的(小鼠或人)对照IgG抗体处理24小时。为了比较抗体诱导细胞死亡的效果,单独使用Sapitinib(ErbB受体酪氨酸激酶抑制剂,5.4μM)和LY294002(PI3K/Akt抑制剂,11.3μM)或与mAR9.6(5μg/ml)和POCmAb(5μg/ml)联合使用处理T3M4 WT细胞24小时。用细胞培养级PBS充分洗涤细胞。将20μl双嵌入剂乙锭均二聚物-1(EthD-1,2mM)溶解在10ml PBS中。向该溶液中加入5μl钙荧光素乙酰氧基甲酯(钙黄绿素-AM,4mM)。将150μl的这种混合试剂添加到盖玻片上生长的细胞中,孵育30-45分钟。在UNMC的共聚焦激光扫描荧光显微镜核心设施处,使用蔡司LSM 710TM共焦激光扫描显微镜(卡尔·蔡司公司,美国纽约州桑伍德)检测活细胞和死细胞的数量。计算死细胞与总细胞的比例以进行定量比较。进行了未配对t检验,以计算经抗体处理的T3M4 WT和T3M4 SC细胞(n=4)之间的统计学意义(p<0.05被认为具有统计学意义)。进行了方差的双向分析(ANOVA),以计算抑制剂与抗体处理的T3M4细胞之间的统计学意义(n=4)(p<0.05被认为具有统计学意义)。
结果-单克隆抗体mAR9.6和POCmAb诱导PDAC细胞中的细胞死亡。用mAR 9.6(5μg/ml)、POCmAb(5μg/ml)或同型匹配的对照IgG抗体处理T3M4野生型(WT)和COSMC缺失型(SimpleCells,SC)24小时。通过活/死细胞毒性试验分析了抗体在T3M4 WT和SC细胞中诱导细胞死亡的作用。如图6和7中所示,活细胞被染成绿色,死细胞被染成红色。与小鼠或人IgG对照相比,mAR 9.6(p<0.0001)和POCmAb(p<0.0001)两种抗体均能显著诱导T3M4 WT细胞死亡。在比较抗体之间诱导细胞死亡的作用时,发现POCmAb比mAR9.6更有效(约39%对15%;p<0.0001)。COSMC缺失的T3M4细胞是高度致瘤细胞,因为它们在其表面表达许多截短的O-聚糖。有趣的是,两种抗体都诱导T3M4 SC细胞中更多的细胞死亡。与mAR9.6抗体诱导的细胞死亡相比,POCmAb诱导的细胞死亡在T3M4 SC细胞中明显更高(约55%对22%;p<0.0001)。
作为POCmAb抗体与mAR9.6在诱导细胞死亡中的作用的另一比较,单独用Sapitinib(ErbB受体酪氨酸激酶抑制剂,5.4μM)和LY294002(PI3K/Akt抑制剂,11.3μM)或与mAR9.6(5μg/ml)和POCmAb(5μg/ml)或同型匹配的对照IgG抗体联合使用处理T3M4细胞24小时。如图9-10所示,与单独的抑制剂处理的细胞相比,mAR9.6的联合疗法在T3M4细胞中诱导显著的细胞死亡。与sapitinib和小鼠IgG处理的细胞相比,mAR9.6和Sapitinib诱导更多的细胞死亡(约17%对约27%,p=0.0003)。同样,与LY294002和小鼠IgG处理的细胞相比,mAR9.6和LY294002诱导更多的细胞死亡(约15%对约21%,p=0.0016)。更有趣的是,与Sapitinib和LY294002和小鼠IgG处理的细胞相比,mAR9.6和Sapitinib以及LY294002的组合进一步诱导了更多的细胞死亡(约43%对约59%,p=0.0141)。这项研究的结果表明,mAR9.6与Sapitinib和LY294002组合可有效诱导PDAC细胞死亡。
还仅用POCmAb或与Sapitinib或LY294002组合使用处理细胞。现在参考图10-11,显示与Sapitinib和人IgG处理的细胞相比,POCmAb与Sapitinib一起诱导的细胞死亡数目显著增加(约17%对约55%,p<0.0001)。同样,与LY294002和人IgG处理的细胞相比,POCmAb和LY294002诱导的细胞死亡数目显著增加(约15%对约65%,p<0.0001)。更有趣的是,与Sapitinib和LY294002和人IgG处理的细胞相比,POCmAb与Sapitinib和LY294002的组合进一步诱导了显著地更多的细胞死亡(约20%对约70%,p<0.0001)。综上所述,当比较mAR9.6相对于POCmAb抗体在诱导PDAC细胞中的细胞死亡中的作用时,发现POCmAb抗体出乎意料且令人吃惊地更有效(图12)。
尽管以上已经描述了并且在附图中示出了优选实施方式,但是对于本领域技术人员显而易见的是,可以在不脱离本公开的情况下进行修改。这样的修改被认为是包含在本公开范围内的可能的变型。
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序列表
<110> 奎斯特制药科技公司
<120> MUC16单克隆抗体及其用途
<130> P4509CN00
<150> 62/669,058
<151> 2018-05-09
<150> PCT/CA2019050565
<151> 2019-04-30
<160> 17
<170> PatentIn version 3.5
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115 120
<210> 16
<211> 112
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 氨基酸
<400> 16
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr
20 25 30
Gly Ile Ser Phe Met Asn Trp Phe Gln Gln Lys Pro Gly His Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Gly Ala Ser Asn Gln Gly Ser Gly Val Pro Ala
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His
65 70 75 80
Pro Met Glu Glu Asp Asp Ala Ala Met Tyr Phe Cys Gln Gln Thr Lys
85 90 95
Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 17
<211> 194
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 氨基酸
<400> 17
Ile Pro Val Pro Thr Ser Ser Thr Pro Gly Thr Ser Thr Val Asp Leu
1 5 10 15
Gly Ser Gly Thr Pro Ser Ser Leu Pro Ser Pro Thr Thr Ala Gly Pro
20 25 30
Leu Leu Val Pro Phe Thr Leu Asn Phe Thr Ile Thr Asn Leu Lys Tyr
35 40 45
Glu Glu Asp Met His Cys Pro Gly Ser Arg Lys Phe Asn Thr Thr Glu
50 55 60
Arg Val Leu Gln Ser Leu Leu Gly Pro Met Phe Lys Asn Thr Ser Val
65 70 75 80
Gly Pro Leu Tyr Ser Gly Cys Arg Leu Thr Leu Leu Arg Ser Glu Lys
85 90 95
Asp Gly Ala Ala Thr Gly Val Asp Ala Ile Cys Thr His Arg Leu Asp
100 105 110
Pro Lys Ser Pro Gly Val Asp Arg Glu Gln Leu Tyr Trp Glu Leu Ser
115 120 125
Gln Leu Thr Asn Gly Ile Lys Glu Leu Gly Pro Tyr Thr Leu Asp Arg
130 135 140
Asn Ser Leu Tyr Val Asn Gly Phe Thr His Gln Thr Ser Ala Pro Asn
145 150 155 160
Thr Ser Thr Pro Gly Thr Ser Thr Val Asp Leu Gly Thr Ser Gly Thr
165 170 175
Pro Ser Ser Leu Pro Ser Pro Thr Ser Ala Gly Pro Leu Leu Val Pro
180 185 190
Phe Thr
Claims (63)
1.一种与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3)和三个可变轻域CDR(CDR L1、L2和L3),其中所述CDR H1、H2、H3、L1、L2和L3包含的氨基酸序列分别包括:
CDR H1:GFTFSTF(SEQ ID NO:1),
CDR H2:SSGSST(SEQ ID NO:2),
CDR H3:SGYDYDPIYYALDY(SEQ ID NO:3),
CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),
CDR L2:GASNQGS(SEQ ID NO:5),和
CDR L3:QQTKEVPWT(SEQ ID NO:6)。
2.一种与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变重域互补决定区(CDR)(CDR H1、H2和H3),其中所述CDR H1、H2和H3包含的氨基酸序列分别包括:
CDR H1:GFTFSTF(SEQ ID NO:1),
CDR H2:SSGSST(SEQ ID NO:2),和
CDR H3:SGYDYDPIYYALDY(SEQ ID NO:3)。
3.一种与O-聚糖粘蛋白型糖蛋白MUC16结合的抗体或其抗原结合片段,其包含三个可变轻域互补决定区(CDR)(CDR L1、L2和L3),其中所述CDR L1、L2和L3包含的氨基酸序列分别包括:
CDR L1:RASESVDNYGISFMN(SEQ ID NO:4),
CDR L2:GASNQGS(SEQ ID NO:5),和
CDR L3:QQTKEVPWT(SEQ ID NO:6)。
4.如权利要求1-2中任一项所述的抗体或其抗原结合片段,其还包含四个可变重域框架区(HFR)(HFR 1、2、3和4),其中所述HFR1、2、3和4包含的氨基酸序列包括:
HFR 1:EVQLVESGGGLVQPGGSRKLSCAAS(SEQ ID NO:7),
HFR 2:GMHWVRQAPEKGLEWVAYI(SEQ ID NO:8),
HFR 3:IYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDEDTAMYYCAR(SEQ ID NO:9),和
HFR 4:WGQGTSVTVSS(SEQ ID NO:10)。
5.如权利要求1或3中任一项所述的抗体或其抗原结合片段,其还包含四个可变轻域框架区(LFR)(LFR 1、2、3和4),其中所述LFR1、2、3和4包含的氨基酸序列包括:
LFR 1:DIVLTQSPASLAVSLGQRATISC(SEQ ID NO:11),
LFR 2:WFQQKPGHPPKLLIY(SEQ ID NO:12),
LFR 3:GVPARFSGSGSGTDFSLNIHPMEEDDAAMYFC(SEQ ID NO:13),和
LFR 4:FGGGTKVEIKR(SEQ ID NO:14)。
6.如权利要求1至5中任一项所述的抗体或其抗原结合片段,其包含含有氨基酸序列的可变重域(VH),所述氨基酸序列包括:EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15)。
7.如权利要求1至5中任一项所述的抗体或其抗原结合片段,其包含含有氨基酸序列的可变轻域(VL),所述氨基酸序列包括:DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYGASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ IDNO:16)。
8.如权利要求1至5中任一项所述的抗体或其抗原结合片段,其包含含有氨基酸序列的可变重域(VH),所述氨基酸序列包括:EVQLVESGGGLVQPGGSRKLSCAASGFTFSTFGMHWVRQAPEKGLEWVAYISSGSSTIYYGDTLQGRFIISRDNPKNTLFLQMTSLRSEDTAMYYCARSGYDYDPIYYALDYWGQGTSVTVSS(SEQ ID NO:15),和
包含氨基酸序列的可变轻域(VL),所述氨基酸序列包括:DIVLTQSPASLAVSLGQRATISCRASESVDNYGISFMNWFQQKPGHPPKLLIYYGASNQGSGVPARFSGSGSGTDFSLNIHPMEEDDAAMYFCQQTKEVPWTFGGGTKVEIKR(SEQ ID NO:16)。
9.如权利要求1至7中任一项所述的抗体或其抗原结合片段,其中所述抗体是IgA、IgD、IgE、IgG或IgM。
10.如权利要求1至7中任一项所述的抗体或其抗原结合片段,其中所述抗原结合片段是单域抗体(sdAb)或单链可变片段(scFv)。
11.如权利要求10所述的抗体或其抗原结合片段,其中所述sdAb包含三个CDR(CDR1、2和3),其分别包含SEQ ID NO:1,SEQ ID NO:2和SEQ ID NO:3。
12.如权利要求10所述的抗体或其抗原结合片段,其中所述sdAb包含三个CDR(CDR1、2和3),分别包含SEQ ID NO:4,SEQ ID NO:5和SEQ ID NO:6。
13.如权利要求1至12中任一项所述的抗体或其抗原结合片段,其中所述抗体或其抗原结合片段是人源化的或部分人源化的。
14.如权利要求1所述的抗体或其抗原结合片段,其中所述抗体是POCmAb。
15.一种组合物,其包含权利要求1至14中任一项所述的抗体或其抗原结合片段,以及药学上可接受的稀释剂、载体或赋形剂。
16.一种在其需要的受试者中抑制表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法,包括向所述受试者施用权利要求1-14中任一项所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段或权利要求15所述的组合物。
17.如权利要求16所述的方法,其中所述抗体或其抗原结合片段是抗体。
18.如权利要求17所述的方法,其中所述抗体是单克隆抗体。
19.如权利要求16所述的方法,其中所述O-聚糖粘蛋白型糖蛋白MUC16包括截短的O-聚糖。
20.如权利要求19所述的方法,其中所述截短的O-聚糖包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
21.如权利要求16-20中任一项所述的方法,其还包括施用第二治疗剂,所述第二治疗剂包括细胞毒性剂,额外的抗体或其治疗活性片段或化疗方案中的至少一种。
22.如权利要求21所述的方法,其中所述细胞毒性剂是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
23.如权利要求21所述的方法,其中,所述细胞毒性剂是吉西他滨和白蛋白结合型紫杉醇的至少一种。
24.如权利要求22所述的方法,其特征在于,所述ErbB信号转导抑制剂是沙必替尼(Sapitinib)。
25.如权利要求21所述的方法,其中所述额外的抗体或其治疗性片段是奥戈伏单抗B43.13、AR9.6抗体、或其组合。
26.如权利要求21所述的方法,其特征在于,所述化疗方案是Folfirinox(福尔菲林)。
27.如权利要求16-226中任一项所述的方法,其中所述肿瘤选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
28.如权利要求16至27中任一项所述的方法,其中,所述方法用于治疗癌症。
29.如权利要求16-28中任一项所述的方法,其中所述抗体或其抗原结合片段结合串联重复(TR)SEA结构域5和6的构象表位,而没有所述O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
30.一种在其需要的受试者中检测表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的方法,包括向所述受试者施用权利要求1至14中任一项所述的对O-聚糖粘蛋白型糖蛋白MUC16特异的抗体或其抗原结合片段,并检测所述抗体或其抗原结合片段。
31.如权利要求30所述的方法,其中所述抗体或其抗原结合片段还包含可检测标记。
32.如权利要求31所述的方法,其中所述可检测标记是荧光标记、放射性标记、MRI造影剂、或其组合。
33.一种核酸载体,其包含编码权利要求1至14中任一项所述的抗体或其抗原结合片段的核苷酸序列。
34.一种细胞,其包含权利要求33所述的核酸载体,用于表达权利要求1至14中任一项所述的抗体或其抗原结合片段。
35.权利要求1至14中任一项所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段或权利要求15所述的组合物在抑制其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长中的用途。
36.如权利要求35所述的用途,其中所述抗体或其抗原结合片段是抗体。
37.如权利要求36所述的用途,其中所述抗体是单克隆抗体。
38.权利要求35所述的用途,其中所述O-聚糖粘蛋白型糖蛋白MUC16包括截短的O-聚糖。
39.如权利要求38所述的用途,其中所述截短的O-聚糖包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
40.如权利要求35至39中任一项所述的用途,其还包括施用第二治疗剂,所述第二治疗剂包括细胞毒性剂、额外的抗体或其治疗活性片段或化疗方案中的至少一种。
41.如权利要求41所述的用途,其中所述细胞毒性剂是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
42.如权利要求41所述的用途,其中所述细胞毒剂是吉西他滨和白蛋白结合型紫杉醇的至少一种。
43.如权利要求42所述的用途,其中所述ErbB信号转导抑制剂是沙必替尼(Sapitinib)。
44.如权利要求41所述的用途,其中所述额外的抗体或其治疗性片段是奥戈伏单抗B43.13、AR9.6抗体、或其组合。
45.如权利要求41所述的用途,其中所述化疗方案是Folfirinox(福尔菲林)。
46.如权利要求35至45中任一项所述的用途,其中所述肿瘤选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
47.如权利要求35至46中任一项所述的用途,其中所述用途用于治疗癌症。
48.如权利要求35-47中任一项所述的用途,其中所述抗体或其抗原结合片段结合串联重复(TR)SEA结构域5和6的构象表位,而没有所述O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
49.如权利要求1至14中任一项所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段在抑制其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长中的用途。
50.如权利要求1至14中任一项所述的靶向O-聚糖粘蛋白型糖蛋白MUC16的抗体或其抗原结合片段在抑制其需要的受试者中表达O-聚糖粘蛋白型糖蛋白MUC16的肿瘤的肿瘤生长的方法中的用途。
51.如权利要求49-50中任一项所述的抗体或抗原结合片段的用途,其中,所述抗体或其抗原结合片段是抗体。
52.如权利要求51所述的抗体或抗原结合片段的用途,其中所述抗体是单克隆抗体。
53.如权利要求49-50中任一项所述的抗体或抗原结合片段的用途,其中所述O-聚糖粘蛋白型糖蛋白MUC16包含截短的O-聚糖。
54.如权利要求53所述的抗体或抗原结合片段的用途,其中所述截短的O-聚糖包含Tn抗原、唾液酸Tn抗原(STn)、或其组合。
55.如权利要求49-54中任一项所述的抗体或抗原结合片段的用途,其还包括施用包含细胞毒性剂、额外的抗体或其治疗活性片段或化疗方案中的至少一种的第二治疗剂。
56.如权利要求55所述的抗体或抗原结合片段的用途,其中所述细胞毒性剂是如下的至少一种:ErbB信号传导抑制剂、磷脂酰肌醇-3-激酶(PI3Ks)/Akt信号传导的抑制剂、或其组合。
57.如权利要求55所述的抗体或抗原结合片段的用途,其中所述细胞毒性剂是吉西他滨和白蛋白结合型紫杉醇的至少一种。
58.如权利要求56所述的抗体或抗原结合片段的用途,其中所述ErbB信号转导抑制剂是沙必替尼(Sapitinib)。
59.如权利要求55所述的抗体或其抗原结合片段的用途,其中,所述额外的抗体或其治疗片段是奥戈伏单抗B43.13、AR9.6抗体、或其组合。
60.如权利要求55所述的抗体或抗原结合片段的用途,其中所述化疗方案是Folfirinox(福尔菲林)。
61.如权利要求49-60中任一项所述的抗体或抗原结合片段的用途,其中所述肿瘤选自胰腺肿瘤、胆囊肿瘤、胃肿瘤、结肠肿瘤、卵巢肿瘤、乳腺肿瘤和肝肿瘤。
62.如权利要求49-61中任一项所述的抗体或抗原结合片段的用途,其中,所述抗体或抗原结合片段用于治疗癌症。
63.如权利要求49-52中任一项所述的抗体或抗原结合片段的用途,其中所述抗体或其抗原结合片段与串联重复(TR)SEA结构域5和6的构象表位结合,而没有所述O-聚糖粘蛋白型糖蛋白MUC16的糖基化。
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