CN110958889A - 结合lgr5的抗体药物缀合物 - Google Patents
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Abstract
本文提供的方法和组合物的实施方案涉及抗体药物缀合物,其包含与人LGR5特异性结合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经由接头缀合至治疗剂,例如药物。一些实施方案涉及使用此类抗体药物缀合物的治疗方法,以及制备此类抗体药物缀合物的方法。
Description
相关申请
本申请要求2017年6月16日提交的美国临时申请号62/520,726的优先权,其全部内容并入本文。
发明领域
本文提供的方法和组合物的实施方案涉及抗体药物缀合物(ADC),其包含特异性结合人LGR5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与治疗剂例如药物经由接头缀合。一些实施方案涉及使用此类ADC的治疗方法以及制备此类ADC的方法。
对序列表的引用
本申请与电子格式的序列表一起提交。序列表以名为BIONO15WOSEQLISTING.TXT的文件提供,创建于2018年6月7日,大小约为40Kb。序列表的电子格式中的信息通过引用完整并入本文。
发明背景
含有亮氨酸富集重复的G蛋白偶联受体5(Leucine-rich repeat containing G-protein-coupled receptor 5,LGR5),也称为GPR49/HG38/FEX,属于结构上与糖蛋白激素受体相似的受体蛋白的含有亮氨酸富集重复的G蛋白偶联受体(LGR)/G蛋白偶联受体(GPR)蛋白家族。LGR分为三个亚组:(1)糖蛋白激素受体,包括促甲状腺素(TSH)受体、促卵泡激素(FSH)受体和黄体化激素(LH)受体;(2)松弛素受体LGR7和LGR8;和(3)LRG4、LGR5和LGR6。LGR5在包括肠、骨骼肌、胎盘、脑和脊髓在内的几种组织中表达。
发明内容
本文提供的方法和组合物的一些实施方案包括抗体药物缀合物,其包含与人的含有亮氨酸富集重复的G蛋白偶联受体5(LGR5)特异性结合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经由接头与药物缀合。
在一些实施方案中,所述抗体或其抗原结合片段包含:包含SEQ ID NO:23或其保守性变异的重链互补决定区1(CDR1),包含SEQ ID NO:25或其保守性变异的重链互补决定区2(CDR2),包含SEQ ID NO:27或其保守性变异的重链互补决定区3(CDR3),包含SEQ IDNO:29或其保守性变异的轻链CDR1,包含SEQ ID NO:31或其保守性变异的轻链CDR2,以及包含SEQ ID NO:33或其保守性变异的轻链CDR3。在一些实施方案中,所述抗体或其抗原结合片段包含重链CDR1,其包含SEQ ID NO:23。在一些实施方案中,该抗LGR5抗体或其抗原结合片段包含IgG1。
在一些实施方案中,所述接头是不可切割的接头。在一些实施方案中,所述接头是可切割的接头。
在一些实施方案中,所述药物选自微管蛋白抑制剂和DNA损伤剂。在一些实施方案中,微管蛋白抑制剂选自下组:卡巴他赛(cabazitaxel)、秋水仙酰胺(colcemid)、秋水仙素(colchicine)、念珠藻素(cryptophycin)、脱羰秋水仙碱(demecolcine)、多西他赛(docetaxel)、2-甲氧基雌二醇、docodazole、紫杉醇、根薯酮内酯(taccalonolide)、紫杉烷和长春碱。在一些实施方案中,所述药物选自下组:单甲基奥瑞他汀(auristatin)F、单甲基奥瑞他汀E、单甲基多拉司他汀(dolastatin)10、倍癌霉素(duocarmycin)、maytansanoid1、dualstatin 3、加利车霉素(calicheamicin)和duocamycin。
本文提供的方法和组合物的一些实施方案包括药物组合物,其包含本文提供的抗体药物缀合物和药学可接受的载体。
本文提供的方法和组合物的一些实施方案是治疗患有癌症的受试者的方法,其包括向有此需要的受试者施用有效量的本文提供的抗体药物缀合物。在一些实施方案中,所述癌症包括实体瘤。在一些实施方案中,所述癌症包括癌症干细胞。在一些实施方案中,所述癌症选自下组:肺癌、乳腺癌、结肠癌和胰腺癌。在一些实施方案中,所述癌症包含选自下组的细胞:三阴性乳腺癌细胞,具有选自由K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO组成的组的基因中的突变的结肠癌细胞,以及小细胞肺癌细胞。在一些实施方案中,所述受试者是哺乳动物。在一些实施方案中,所述受试者是人。
一些实施方案还包括与抗体药物缀合物组合施用另外的疗法,其中所述另外的疗法选自放射疗法和化疗剂。在一些实施方案中,所述抗体药物缀合物的施用与陈述另外的疗法的施用同时进行。在一些实施方案中,所述化疗剂选自下组:亚叶酸、氟尿嘧啶、伊立替康(irinotecan)、吉西他滨、紫杉醇、nab-紫杉醇、ERBITUX(西妥昔单抗(cetuximab))、PI3K/mTOR双重抑制剂(NVP)和SN38。在一些实施方案中,所述另外的疗法包括亚叶酸、氟尿嘧啶和伊立替康。
本文提供的方法和组合物的一些实施方案是制备本文提供的抗体药物缀合物的方法,包括:将接头连接至药物;并将经连接的药物与抗体缀合。一些实施方案还包括纯化所述缀合的抗体。
附图的简要说明
图1A描绘了用抗LGR5一抗(C12)和缀合有NC-MMAF的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1B描绘了用抗LGR5一抗(C12)和缀合有CL-MD10的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1C描绘了用抗LGR5一抗(C12)和缀合有CL-MMAE的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1D描绘了用抗LGR5一抗(C12)和缀合有CL-DMSA的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1E描绘了用抗LGR5一抗(C12)和缀合有NC-DM1的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1F描绘了用抗LGR5一抗(C12)和缀合有CK-DUA3的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图1G描绘了用抗LGR5一抗(C12)和缀合有CK-CAL的二抗ADC处理的细胞的细胞存活图。均值+/-SEM,n=2。
图2描绘了用不同的抗LGR5一抗和缀合有NC-MMAF的二抗ADC处理的细胞的一系列细胞存活图。不同的抗LGR5一抗包括:C12(左上图);18G7Ch(右上图);18G7H6A1(左下图);和18G7H6A3(右下图)。均值+/-SEM。
图3描绘了用不同的抗LGR5一抗和缀合有CL-DMSA的二抗ADC处理的细胞的肿瘤球形成的一系列图。不同的抗LGR5一抗包括:C12(左上图);18G7Ch(右上图);18G7H6A1(左下图);和18G7H6A3(右下图)。均值+/-SEM。
图4描绘了用与倍癌霉素(左图)或与MMAE(右图)缀合的抗LGR5一抗处理的细胞的肿瘤球形成的一系列图。均值+/-SEM。
图5A描绘了在用与MMAE缀合的抗LGR5抗体(BNC101)或PBS(n=6)处理的异种移植模型中肿瘤体积随时间的图。
图5B描绘了在用与MMAE缀合的抗LGR5抗体(BNC101)、MOPC-MMAE或PBS(n=6)处理的异种移植模型中肿瘤体积随时间的图。
图5C描绘了在用与倍癌霉素缀合的抗LGR5抗体(BNC101)、MOPC-倍癌霉素或PBS(n=6)处理的异种移植模型中肿瘤体积随时间的图。
图6A描绘了接头和DMSA的结构的实例。
图6B描绘了与抗体连接的DMSA的结构的实例。
详细说明
本文提供的方法和组合物的实施方案涉及包含抗体或其抗原结合片段的抗体药物缀合物(ADC),所述抗体或其抗原结合片段特异性结合人LGR5并缀合至治疗剂。该治疗剂可以是通过接头与抗体或其抗原结合片段结合的药物。一些实施方案涉及使用此类ADC的治疗方法以及制备此类ADC的方法。
以下参考内容各自涉及可用于本文提供的方法和组合物中的特异性结合人LGR5的抗体:美国专利号9221906;美国专利号9220774;美国专利号9221907;美国专利号9546214;和美国专利号9631024,其各自通过参考全文明确地并入本文。例如,美国专利号9221906;美国专利号9220774;和美国专利号9221907各自公开了可用于本文提供的方法和组合物中的特异性结合人LGR5的抗体。美国专利号9546214公开了可用于本文提供的方法和组合物中的特异性结合人LGR5的人源化抗体。
通过谱系追踪研究,LGR5被鉴定为是消化道中正常干细胞和肿瘤起始细胞的高度特异性标志物。先前已鉴定出约150个其表达在Wnt表达消除后被淬灭(quench)的基因。对这些“Wnt靶基因”的全面表征发现,LGR5在隐窝基部的10-14个增殖的楔形细胞群体上选择性表达。这些基于隐窝的柱状细胞先前被提出为候选的干细胞群体。使用可遗传的lacZ–LGR5报告基因进行体内谱系追踪,已证实LGR5肠干细胞是成体肠干细胞的多能性的、自更新的群体,其产生lacZ+后代细胞从隐窝基部开始并延伸至绒毛尖端的不间断的带。
LGR5在癌症干细胞(CSC)上的特异性表达提供了选择性地且有效地靶向CSC的机会。与正常组织相比,LGR5在结直肠癌(CRC)、胰腺癌和大多数其他实体瘤中高度过表达,从而为在CRC、胰腺癌、乳腺癌、卵巢癌、肺癌、胃癌和肝癌中靶向CSC提供了广阔的治疗窗口。
LGR5在癌症中的功能作用已通过核糖核酸干扰(RNAi)敲低研究得到证实。在一组CRC肿瘤细胞系中敲低LGR5显著抑制了体外软琼脂集落的生长,以及体内HCT116结肠肿瘤异种移植物的生长。随后显示LGR5 RNAi敲低还在体外降低了来自患者来源的CRC肿瘤细胞的CSC集落的生长(数据未显示)。最后,发现与对照LGR5(-)细胞相比,分选的LGR5(+)患者来源的异种移植CRC肿瘤细胞在体内具有高度致瘤性。
在用外科手术和标准护理化疗治疗的许多癌症患者中,CSC被认为引起了肿瘤复发的高发生率。例如,发现乳腺癌患者的CD44+CSC在化疗后富集,而高水平的CSC与对化疗的不良临床反应相关。类似地,在转移性CRC中,化疗后受损的肝中LGR5表达上调,表明应答化疗而增加的LGR5 CSC引发和/或加剧转移性疾病。实际上,已经发现LGR5在转移性部位的表达与原发性CRC肿瘤相比显著更高。
抗LGR5抗体
本文提供的方法和组合物的实施方案包括特异性结合人LGR5的抗体或其抗原结合片段。如本文所用,术语“抗体”包括但不限于,合成抗体、单克隆抗体、重组产生的抗体、胞内抗体、多特异性抗体(包括双特异性抗体)、人抗体、人源化抗体、嵌合抗体、合成抗体、单链Fv(scFv)、Fab片段、F(ab')片段、二硫键连接的Fv(sdFv)(包括双特异性sdFv)和抗独特型(抗Id)抗体,以及上述任一项的表位结合或抗原结合片段,其中抗原是LGR5。本文提供的几个实施方案的抗体可以是单特异性、双特异性、三特异性或更大的多特异性的。多特异性抗体可以对多肽的不同表位具有特异性,或者对多肽以及异源表位(例如异源多肽或固体支持材料)两者都具有特异性。参见,例如,PCT公开文本WO 93/17715;WO 92/08802;WO91/00360;WO 92/05793;Tutt等人,J.Immunol.147:60-69(1991);美国专利号4,474,893;4,714,681;4,925,648;5,573,920;5,601,819;Kostelny等人,J.Immunol.148:1547-1553(1992);其各自均通过参考完整并入本文。
如本文所用,LGR5包括但不限于,包含NCBI登录号NP_003658.1的多肽或其片段(其由NM_003667.2内的编码核苷酸序列或其片段编码)的人LGR5。NCBI登录号NP_003658.1的氨基酸序列和完整条目以及NM_003667.2的核苷酸序列和完整条目通过引用完整并入。本文涵盖的LGR5片段的实例包括LGR5胞外域、跨膜域或胞内域及其部分。
一些实施方案涉及编码抗LGR5抗体的轻链或重链的核酸分子,所述抗LGR5抗体包括本文提供的被称为18G7Ch、18G7H6A3和18G7H6A1的任一种抗LGR5抗体。在一些方面,核酸分子编码人源化或全人单克隆抗体,例如本文提供的抗体18G7Ch、18G7H6A3和18G7H6A1的轻链或重链。
多个实施方案针对载体,该载体包含编码抗LGR5抗体的轻链和/或重链的一种或多种核酸分子,所述抗LGR5抗体包括本文提供的称为18G7Ch、18G7H6A3和18G7H6A1的任一种抗LGR5抗体。
在多个实施方案中,可以修饰抗体的糖基化。例如,可以制备无糖基化的抗体(即,该抗体缺乏糖基化)。可以改变糖基化以例如增加抗体对靶抗原的亲和力。此类碳水化合物修饰可通过例如改变抗体序列内一个或多个糖基化位点来实现。例如,可以进行导致一个或多个可变区框架糖基化位点消除的一个或多个氨基酸取代,从而消除在该位点的糖基化。这种无糖基化可以增加抗体对抗原的亲和力。这种方法在美国专利号5,714,350和6,350,861中有更详细的描述;其各自通过引用完整并入本文。
在几个实施方案中,抗体特异性结合包含LGR5多肽或其片段或者由其组成的多肽,所述LGR5多肽与NCBI登录号NP_003658.1(SEQ ID NO:47)的人LGR5多肽具有至少60%的同一性,或至少70%的同一性,或至少80%的同一性,至少85%的同一性,至少90%的同一性,至少95%的同一性,或至少97%的同一性,或至少99%的同一性或100%的同一性。此类片段可以是例如,所述LGR5多肽的至少约5、10、15、20、25、50、75、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850或900个连续或非连续的氨基酸,或任何上述长度之间的任何数目的连续或非连续的氨基酸。
在几个实施方案中,所述抗体是抗体18G7H6A3,并且包含SEQ ID NO:13的重链氨基酸序列和SEQ ID NO:11的DNA序列。在一些实施方案中,所述抗体是抗体18G7H6A3,并且具有包含SEQ ID NO:19的重链可变域。在几个实施方案中,所述抗体是抗体18G7H6A3,并包含SEQ ID NO:14的轻链序列。在其他实施方案中,所述抗体是抗体18G7H6A3,并包含SEQ IDNO:21的轻链可变域。
在一些实施方案中,所述抗体包含与上述序列之中的序列80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的序列。在一些实施方案中,所述抗体包含在上述序列的重链、轻链或可变域的29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117或118个残基的跨度上与上述抗体序列100%相同的序列。
在一些实施方案中,所述抗体包含与所述抗体序列80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的序列。在一些实施方案中,所述抗体包含与所述抗体序列84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%相同的序列。在一些实施方案中,所述抗体包含在33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110或111个残基的跨度上与所述抗体序列100%相同的序列。
在一些实施方案中,本文提供的抗LGR5抗体包含:包含GYSFTAYW(SEQ ID NO:23)的重链CDR1,包含ILPGSDST(SEQ ID NO:2)的重链CDR2和包含ARSGYYGSSQY(SEQ ID NO:3)的重链CDR3。在一些实施方案中,本文提供的抗LGR5抗体包含:包含ESVDSYGNSF(SEQ IDNO:4)的轻链CDR1,包含LTS的轻链CDR2和包含QQNAEDPRT(SEQ ID NO:33)的轻链CDR3。
在一些实施方案中,本文提供的抗LGR5抗体包含:(a)重链CDR1,其包含具有1、2、3或4个氨基酸取代的上述序列的变体。所述抗体还可具有重链CDR2,其具有包含1、2、3或4个氨基酸取代的变体。所述抗体还可具有重链CDR3,其具有包含1、2、3或4个氨基酸取代的变体。除了重链的这些修饰之外,所述抗体还可具有轻链CDR1,其具有包含1、2、3或4个氨基酸取代的变体。所述抗体还可具有轻链CDR2,其具有包含1、2、3或4个氨基酸取代的变体。所述抗体还可具有轻链CDR3,其具有1、2、3或4个氨基酸取代。在一些实施方案中,氨基酸取代是保守氨基酸取代。
在一些实施方案中,本文提供的抗LGR5抗体包含以下抗体,其包含与所附序列表中的本文描述的序列具有至少80%或90%序列同一性的重链可变区。所述抗体还可具有与本文描述的抗体序列具有至少80%或90%序列同一性的轻链可变区。
两个氨基酸序列(或两个核酸序列)的同一性百分比可以例如通过为了最佳比较目的而对序列比对来确定(例如,可以在第一序列的序列中引入缺口)。然后比较相应位置处的氨基酸或核苷酸,两个序列之间的同一性百分比是序列共有的相同位置数的函数(即,%同一性=相同位置数/位置总数×100)。两个序列的实际比较可以通过众所周知的方法,例如使用数学算法来完成。这种数学算法的具体的非限制性示例在Karlin等人,Proc.Natl.Acad.Sci.USA,90:5873-5877(1993)中描述,其全部内容通过引用并入本文。将这种算法并入BLASTN和BLASTX程序(2.2版)中,如Schaffer等人,Nucleic Acids Res.,29:2994-3005(2001)中所述,其全部内容通过引用并入本文。当使用BLAST和Gapped BLAST程序时,可以使用各个程序的默认参数(例如BLASTN)。参见http://www.ncbi.nlm.nih.gov,2002年4月10日可获得。在一个实施方案中,搜索的数据库是非冗余(NR)数据库,并且可以将用于序列比较的参数设为:无过滤;期望值为10;词长为3;矩阵是BLOSUM62;和缺口成本(Gap Cost)的存在值(Existence)为11,扩展值(Extension)为1。
几个实施方案还涵盖上述抗体(包括本文提供的命名为18G7Ch、18G7H6A3和18G7H6A1的任何一种抗LGR5抗体)的变体,其在可变轻链(VL)域和/或可变重链(VH)域中包含一个或多个氨基酸残基取代。几个实施方案还涵盖上述抗体的变体,其在一个或多个VLCDR和/或一个或多个VH CDR中具有一个或多个其他氨基酸残基取代。可以在体外和体内测试通过在上述抗体的VH结构域、VH CDR、VL结构域和/或VL CDR中引入取代产生的抗体,例如,测试其与LGR5结合的能力(例如,通过免疫测定法,包括但不限于ELISA和BIAcore)。
多个实施方案包括特异性结合LGR5的抗体,其包含特异性结合LGR5的抗LGR5抗体(例如本文提供的命名为18G7Ch、18G7H6A3和18G7H6A1的任一种抗LGR5抗体)的VH结构域、VHCDR、VL结构域或VL CDR的衍生物。可以使用本领域技术人员已知的标准技术在编码抗体的核苷酸序列中引入突变(例如,添加、缺失和/或取代),包括例如常规使用定点诱变和PCR介导的诱变来产生氨基酸取代。在一个实施方案中,VH和/或VL CDR衍生物相对于原始的VH和/或VL CDR包含少于25个氨基酸取代,少于20个氨基酸取代,少于15个氨基酸取代,少于10个氨基酸取代,少于5个氨基酸取代,少于4个氨基酸取代,少于3个氨基酸取代或少于2个氨基酸取代。在另一个实施方案中,VH和/或VL CDR衍生物具有在一个或多个预测的非必需氨基酸残基(即,对于抗体特异性结合LGR5非关键的氨基酸残基)处进行的保守氨基酸取代(例如上文)。或者,可以例如通过饱和诱变沿着全部或部分VH和/或VL CDR编码序列随机引入突变,并且可以筛选所得突变体的生物学活性以鉴定保留活性的突变体。诱变后,可以表达编码的抗体并可以测定抗体的活性。
几个实施方案还涵盖特异性结合LGR5或其片段的抗体,所述抗体包含与任一种本文所述的抗体(包括任一种抗LGR5抗体,包括本文提供的被称为18G7Ch、18G7H6A3和18G7H6A1的那些抗体)的可变重链和/或轻链的氨基酸序列至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%相同的可变重链和/或可变轻链的氨基酸序列。
另一个实施方案包括在抗LGR5抗体,例如本文提供的命名为18G7Ch、18G7H6A3和18G7H6A1的任一种抗LGR5抗体的任何部分中引入保守氨基酸取代。在本领域中众所周知,“保守氨基酸取代”是指取代功能上等同的氨基酸的氨基酸取代。保守的氨基酸变化导致所得肽的氨基酸序列的沉默变化。例如,极性相似的一个或多个氨基酸充当功能等同物,在肽的氨基酸序列内引起沉默改变。电荷中性且用较小残基取代残基的取代也可被视为“保守取代”,即使这些残基在不同的组中(例如,用较小的异亮氨酸取代苯丙氨酸)。本领域中已定义了具有相似侧链的氨基酸残基家族。表1显示了几个保守氨基酸取代家族。
表1
家族 | 氨基酸 |
非极性 | Trp、Phe、Met、Leu、Ile、Val、Ala、Pro |
不带电荷的极性 | Gly、Ser、Thr、Asn、Gln、Tyr、Cys |
酸性/带负电荷 | Asp、Glu |
碱性/带正电荷 | Arg、Lys、His |
Beta-分支 | Thr、Val、Ile |
影响链取向的残基 | Gly、Pro |
芳香族 | Trp、Tyr、Phe、His |
在一些实施方案中,本文提供的抗LGR5抗体以小于约200nM、小于约100nM、小于约80nM、小于约50nM、小于约20nM、小于约10nM、小于约1nM,以及任何前述值之间的范围内的KD结合人LGR5。在一些实施方案中,本文提供的抗LGR5抗体以小于约10nM、5nM、4nM、3nM、2nM、1nM以及任何前述值的范围内的亲和力结合LGR5。在一些实施方案中,本文提供的抗LGR5抗体以大于约0.0001nM、0.001nM、0.01nM以及任何前述值的范围内的亲和力结合LGR5。
在一些实施方案中,本文提供的抗LGR5抗体结合以下表位,该表位包含SEQ IDNO:47的氨基酸T175、E176、Q180、R183、S186、A187、Q189、D247、E248、T251、R254、S257、N258、K260或由其组成或在其内。在一些实施方案中,本文提供的抗LGR5抗体结合以下表位,该表位包含亮氨酸富集重复6-9或由其组成或在其内(参见例如Chen等人,GenesDev.27(12):1345-50,其通过引用完整并入)。在一些实施方案中,本文提供的抗LGR5抗体结合以下表位,该表位包含LGR5胞外域的凸表面或由其组成或在其内(参见例如Chen等人,Genes Dev.27(12):1345-50,其通过引用完整并入)。
某些人源化抗LGR5抗体
本文提供的方法和组合物的一些实施方案包括使用某些抗LGR5抗体或其抗原结合片段,包括衍生自鼠抗体“18G7.1”的那些。将人种系序列用作人源化鼠抗体18G7.1的接受体框架。为了找到最接近的种系序列,通过NCI IgBLAST(ncbi.nlm.nih.gov/igblast/)在种系序列数据库中鉴定最相似表达的轻链和最相似的重链。在该搜索中,屏蔽18G7.1的CDR序列。最合适表达序列的选择包括检查规范残基和界面残基的序列同一性,以及检查CDR环长度的相似性。
为了鉴定候选的人源化序列与亲本鼠单克隆抗体18G7.1之间关键的结构性框架残基中的潜在结构冲突,生成了三维模型。使用抗体结构的复合体来创建具有嫁接的候选人源化序列的同源性模型,然后将分子能量最小化。使用计算机软件Pymol进行结构分析,以鉴定可能对正确折叠产生负面影响的残基。
通过该分析,构建了六种候选VH链,其包含:1)基于对折叠可能的影响的分析,在候选人源化框架区域内含有选择的取代的功能性人框架,以及ii)亲本18G7.1鼠抗体CDR(SEQ ID NO:1、2和3)。化学合成了符合阅读框地融合于人IgG1恒定区的融合物。
类似地,构建了两种候选VL链,其包含:1)基于对折叠可能的影响的分析,在候选人源化框架区域内包含选择的取代的功能性人框架,以及ii)亲本18G7.1鼠抗体CDR(SEQID NO:4、5和6)。化学合成了符合阅读框地融合于人IgG1恒定区的候选VL链和候选VH链。
通过共转染到哺乳动物细胞中来测试选择的候选变体人源化的重链和轻链组合的功能性。将上述六种候选的人源化18G7.1重链中的每一种与候选的18G7.1轻链之一共转染到HEK 293细胞中,并通过流式细胞术测定条件培养基的LGR5抗原结合活性。另外,将上述三种候选的人源化18G7.1重链与第二种候选的18G7.1轻链共转染到HEK 293细胞中,并通过流式细胞术测定条件培养基的LGR5抗原结合活性。选择表现出最有力的结合的称为18G7H6的18G7.1候选重链/轻链组合(人源化变体)进行亲和力成熟。
为了增加所选择的人源化变体18G7H6的亲和力,使用了丙氨酸扫描诱变和饱和诱变的组合。将重链CDR1以及轻链CDR1和CDR3中的残基突变为丙氨酸,转染到HEK 293细胞中,并通过流式细胞术测定所得条件培养基的LGR5抗原结合活性。在重链CDR3上进行饱和诱变,其中将CDR3中的每个残基都突变为除该位置处原始氨基酸身份以外的19种天然存在的氨基酸的每种。将每种突变体转染到HEK 293细胞中,并通过流式细胞术测定所得条件培养基的LGR5抗原结合活性。
将这些突变以递增数目掺入3种构建体中。然后将这三种构建体转染到HEK 293细胞中,并通过流式细胞术测定所得条件培养基的LGR5抗原结合活性。选择两种构建体18G7H6A1和18G7H6A3(也称为BNC101)进行进一步表征。表2列出了所述抗体的某些序列。
表2
抗LGR5抗体例如18G7H6A3的某些特征在美国专利号9546214中公开,其通过引用明确地完整并入。某些特征汇总如下。
某些抗LGR5抗体的特征
在使用表达重组LGR5的中国仓鼠卵巢(CHO)细胞的基于FACS的测定中,测定得18G7H6A1和18G7H6A3各自对于人LGR5结合具有的EC50<10nM。在另一项研究中,发现18G7H6A3与人和食蟹猴LGR5强结合,但不结合大鼠或小鼠LGR5。在基于ELISA的平板结合测定中,测得18G7H6A3以300pM的EC50结合LGR5胞外域-IgG-Fc融合蛋白。
使用流式细胞术对各种人类细胞系测定了LGR5的细胞表面表达水平。CT1结直肠肿瘤细胞和胰腺癌细胞系Panc-1、Capan2和CFPAC属于最高的LGR5表达者。在胰腺癌细胞系(AsPC-1、SW1990、HPAFII)、顺铂耐药性卵巢癌细胞系(OVCAR8/CP、A2780/CP和Igrov1/CP)以及结肠癌、乳腺癌和卵巢癌细胞系(SW48、Hs578T和OVCAR3)中观察到中等表达水平。在结肠癌(SW480、LoVo)和乳腺癌细胞系(MDA-MB-231)中观察到较低但可检测水平的LGR5细胞表面表达。表3总结了18G7H6A3对多种肿瘤细胞系的FACS结合数据。
表3
在过表达LGR5的CHO细胞上检查了18G7H6A3的内化。用100nM抗体将细胞在4℃染色30分钟至2小时,洗去多余的抗体,并将染色的细胞在4℃或37℃孵育。在多个时间点将细胞用缀合有AlexaFluor488的二抗染色,以监测细胞表面结合的抗体的内化。在37℃温育时,内化速率对于表面定位的t1/2测量值为6.703±1.282分钟。通过在4℃孵育很大程度上阻止了内化,尽管观察到表面结合的抗体有一些降低。
使用氢氘交换质谱法进行了表位作图实验,以表征抗体18G7H6A3结合的LGR5的一个或多个特定区域。氢/氘(H/D)交换数据表明18G7H6A3与亮氨酸富集重复6-9的凸表面内的SEQ ID NO:47的氨基酸T175、E176、Q180、R183、S186、A187、Q189、D247、E248、T251、R254、S257、N258、K260结合,该亮氨酸富集重复6-9的凸表面在R-spondin结合位点的面的反面,如通过X射线晶体学研究确定的。(参见例如,Chen等,Genes Dev.27(12):1345-50,其通过引用整体并入本文)。这些数据表明,参与LGR5与R-spondin结合的残基不参与结合18G7H6A3。这些初步结果并不排除LGR5中的其他结构元件可能参与18G7H6A3的结合位点的事实。
某些抗LGR5抗体的体内活性
在使用源自患有IV期转移性结肠癌的患者的人结肠CT1细胞移植到小鼠中的异种移植模型中,在4个剂量(15mg/kg,每周两次)的过程中,18G7H6A3与PBS和MOPC抗体对照相比在体内显示出显著的抗肿瘤活性。尽管抗体18G7H6A1显示出抗肿瘤活性,但单克隆18G7H6A3显示出优于18G7H6A1和亲本鼠嵌合18G7Ch抗体的活性。表4显示了1-4个剂量的Lgr5+抗体后CT1肿瘤体积减少的百分比(每组相对于MOPC)。
表4
剂量数 | 1 | 2 | 3 | 4 |
18G7Ch | 9.2% | 30.6% | 19.5% | 29.0% |
18G7H6A1 | 17.5% | 19.1% | 14.2% | 19.0% |
18G7H6A3 | 38.8% | 42.0% | 28.9% | 35.4% |
在使用源自IV期转移性结肠癌患者的人结肠CT3细胞移植到小鼠中的异种移植模型中,在4个剂量(15mg/kg,每周两次)后,相比于PBS和MOPC抗体对照,18G7H6A1显示出抗肿瘤活性,而18G7H6A3显示出显著的抗肿瘤活性。18G7H6A3显示出优于亲本鼠嵌合18G7Ch抗体的活性,并显示出与18G7H6A1等同的活性。表5显示了测试抗体的n个剂量后CT3肿瘤体积减少的百分比(每组相对于MOPC)。
表5
抗体剂量数: | 1 | 2 | 3 | 4 |
18G7Ch | 22.6% | 8.9% | 17.0% | 13.8% |
18G7H6A1 | 18.3% | 12.6% | 28.8% | 28.7% |
18G7H6A3 | 34.2% | 38.1% | 23.4% | 28.2% |
在使用在CSC条件下生长的人CT3细胞的异种移植模型中,用18G7H6A3联合FOLFIRI方案处理,对肿瘤体积的分析显示,施用18G7H6A3和FOLFIRI相比于仅使用FOLFIRI而言进一步减少了CT3肿瘤的生长。将从用18G7H6A3与FOLFIRI联合处理的小鼠中分离的细胞再移植到小鼠中。与从单独用FOLFIRI处理的小鼠中分离的细胞相比,该移植细胞的致瘤性大大降低。此外,与单独的FOLFIRI相比,来自18G7H6A3 FOLFIRI联合的再植入细胞具有显著更缓慢的肿瘤生长模式(profile)和延迟的进展时间。这些数据表明18G7H6A3与FOLFIRI联合有效地靶向肿瘤起始或癌症干细胞群体。
在使用人胰腺AsPC-1细胞的异种移植模型中,与盐水和/或对照IgG相比,作为单一药剂的18G7H6A3在植入后第41天时将小鼠中的肿瘤生长抑制高达近40%。另外,与单独的吉西他滨相比,18G7H6A3和吉西他滨的联合在AsPC-1模型中显著抑制了肿瘤生长(在植入后第61天时高达36%)。直到第65天时,与PBS和对照IgG相比,作为单一药剂的18G7H6A3也对肿瘤生长提供了一定的抑制。
在使用人乳腺MDA-MB-231-LM3细胞的异种移植模型中,与PBS(60.7%肿瘤生长抑制)或MOPC抗体(49.3%肿瘤生长抑制)对照相比,18G7H6A3在小鼠中显示出显著的抗肿瘤活性。将从用18G7H6A3联合紫杉醇治疗的小鼠中分离的细胞移植到小鼠中。与从单独用紫杉醇治疗的小鼠分离的细胞相比,这类细胞的致瘤性大大降低。此外,与单独使用紫杉醇相比,来自18G7H6A3加上紫杉醇肿瘤的再植入细胞具有显著更缓慢的肿瘤生长模式和延迟的进展时间。这些数据表明18G7H6A3与紫杉醇联合有效地靶向肿瘤起始或癌症干细胞群体。
在使用人胰腺PANC1细胞的异种移植模型中,单独使用18G7H6A3抑制小鼠的肿瘤生长(在植入后第70天高达30%),与吉西他滨联合使用18G7H6A3相比于单独使用吉西他滨的组显著抑制了肿瘤生长(在植入后第80天高达52%)。将从用18G7H6A3与吉西他滨联合治疗的小鼠中分离的细胞移植到小鼠中。与从单独用吉西他滨治疗的小鼠分离的细胞相比,此类细胞的致瘤性大大降低。用吉西他滨和18G7H6A3联合治疗的再植入的PANC1肿瘤在移植4500个细胞的小鼠(吉西他滨40%相对于联合20%)还有移植13500个细胞的小鼠(吉西他滨100%相对于联合70%)中均显示植入(engraftment)频率降低。这些数据表明18G7H6A3与吉西他滨联合有效地靶向了肿瘤起始或癌症干细胞群体。
在使用人胰腺JH109细胞的异种移植模型中,单独的18G7H6A3治疗未影响小鼠中的肿瘤生长。与单独化疗相比,将18G7H6A3与Nab-紫杉醇和吉西他滨化疗联合导致显著提高的肿瘤抑制程度。与单独化疗相比,18G7H6A3与化疗联合导致增加肿瘤生长抑制77%。用18G7H7A3化疗联合治疗的3只小鼠已完全根除其肿瘤。
在使用人BMCRC086细胞的异种移植模型中,与单独的FOLFIRI相比,18G7H6A3与FOLFIRI联合在小鼠中显示出显著的抗肿瘤活性。
在使用源自BLG293肿瘤的人小细胞肺癌细胞的异种移植模型中,与PBS(24.9%肿瘤生长抑制)和MOPC抗体(24.7%肿瘤生长抑制)对照相比,18G7H6A3在小鼠中显示出显著的抗肿瘤活性。
抗体药物缀合物
本文提供的方法和组合物的实施方案包括ADC。在一些这样的实施方案中,与人LGR5特异性结合的抗体或其抗原结合片段与治疗剂例如药物缀合。在一些实施方案中,所述治疗剂包括细胞生长抑制剂或细胞毒性剂。在一些实施方案中,所述治疗剂是DNA损伤剂或微管抑制剂。治疗剂的实例包括多拉司他汀类(dolastatins)和奥瑞他汀类,包括单甲基奥瑞他汀E(MMAE)和单甲基奥瑞他汀F(MMAF),鹅膏蕈碱(amanitins)例如α-鹅膏蕈碱、β-鹅膏蕈碱或γ-鹅膏蕈碱,DNA小沟结合剂例如倍癌霉素衍生物,烷基化剂例如经修饰或二聚的吡咯并苯并二氮杂类(PBD),二氯甲基二乙胺(mechlorethamine),thioepa,苯丁酸氮芥,美法仑(melphalan),卡莫司汀(carmustine),洛莫司汀(lomustine),环磷酰胺(cyclothosphamide),白消安(busulfan),二溴甘露醇,链脲霉素(streptozotocin),丝裂霉素C和顺二氯二胺铂(II)(DDP)顺铂,剪接抑制剂例如meayamycin类似物或衍生物,管结合剂例如埃博霉素(epothilone)类似物和紫杉醇以及DNA损伤剂例如加利车霉素和埃斯培拉霉素(esperamicin),抗代谢物例如甲氨蝶呤(methotrexate),6-巯基嘌呤,6-硫鸟嘌呤,阿糖胞苷和5-氟尿嘧啶decarbazine,抗有丝分裂剂例如长春碱和长春新碱以及蒽环类药物(anthracycline),例如柔红霉素(daunorubicin)(也称为道诺霉素(daunomycin))和阿霉素(doxorubicin),以及其药学可接受的盐或溶剂合物、酸或衍生物。在一些实施方案中,治疗剂包括抗有丝分裂剂,例如别秋水仙碱(allocolchicine);奥瑞他汀类,例如MMAE和MMAF;软海绵素(halichondrin)B;西马多丁(cemadotin);秋水仙素;秋水仙素衍生物(N-苯甲酰基-脱乙酰基苯甲酰胺);多拉司他汀-10;多拉司他汀-15;美登素(maytansine);美登素类化合物(maytansinoids),例如DM1;rhozoxin;紫杉醇;紫杉醇衍生物((2'-N-[3-(二甲基氨基)丙基]戊二酸紫杉醇);多西他赛(docetaxel);硫代秋水仙碱(thiocolchicine);三苯甲基半胱氨酸;硫酸长春碱和硫酸长春新碱。在一些实施方案中,治疗剂包括烷基化抗肿瘤剂,例如卡波醌(Carboquone);卡莫司汀;萘氮芥(Chlornaphazine);氯脲霉素(Chlorozotocin);倍癌霉素;艾伏磷酰胺(Evofosfamide);福莫司汀(Fotemustine);葡磷酰胺(Glufosfamide);洛莫司汀;甘露舒凡(Mannosulfan);尼莫司汀(Nimustine);Phenanthriplatin;哌泊溴烷(Pipobroman);雷莫司汀(Ranimustine);司莫司汀(Semustine);链脲霉素;ThioTEPA;曲奥舒凡(Treosulfan);三亚胺醌(Triaziquone);三亚乙基蜜胺(triethylenemelamine)和四硝酸三铂(Triplatin tetranitrate)。在一些实施方案中,治疗剂可包括MMAF、MMAE、单甲基多拉司他汀10、倍癌霉素、maytansanoid 1、dualstatin 3、加利车霉素和duocamycin。在一些实施方案中,治疗剂是DNA损伤剂或微管抑制剂。微管抑制剂的实例包括卡巴他赛、秋水仙酰胺、秋水仙素、念珠藻素、细胞骨架药物、脱羰秋水仙碱、多西他赛、2-甲氧基雌二醇、诺考达唑(Nocodazole)、紫杉醇、根薯酮内酯、紫杉烷和长春碱。可用于本文提供的方法和组合物的治疗剂的更多实例公开于US2017/0137533;US2017/0158769;US2017/0151344和US2017/0136130,其各自通过引用整体并入本文。
在一些这样的实施方案中,与人LGR5特异性结合的抗体或其抗原结合片段通过接头与治疗剂缀合。在一些实施方案中,接头可以是多价的从而使其将多于一个药剂共价连接至抗体或其抗原结合片段上的单个位点,或是单价的从而使其将单个药剂共价连接至抗体或其抗原结合片段上的单个位点。可用于连接本文中提供的治疗剂和抗体或其抗原结合片段的接头实例描述于美国专利号7,223,837;美国专利号8,568,728;美国专利号8,535,678;WO 2009/073445;WO 2010/068795;WO 2010/138719;WO 2011/120053;WO 2011/171020;WO 2013/096901;WO 2014/008375;WO 2014/093379;WO 2014/093394;和WO 2014/093640,其各自通过引用整体并入本文。
在一些实施方案中,接头可以是可切割的接头。可切割的接头可包括化学或酶促不稳定或可降解的连接。可切割的接头通常依赖于细胞内部的过程来释放治疗剂,例如细胞质中的还原,暴露于溶酶体中酸性条件或被细胞内特定的蛋白酶或其他酶切割。可切割的接头通常掺入一个或多个可化学或酶促切割的化学键,而接头的其余部分不可切割。在某些实施方案中,接头包含化学不稳定的基团,例如腙(hydrazone)和/或二硫化物基团。包含化学不稳定基团的接头利用血浆和一些细胞质区室之间的差异特性。对于含腙的接头促进治疗剂释放的细胞内条件是内体和溶酶体的酸性环境,而含二硫键的接头在含有高硫醇浓度(例如谷胱甘肽)的胞质溶胶中被还原。在某些实施方案中,可以通过使用靠近化学不稳定基团的取代基引入空间位阻来提高包含化学不稳定基团的接头的血浆稳定性。
在一些实施方案中,接头可以是不可切割的接头。对于不可切割的接头,治疗剂的释放可以不依赖于血浆与一些细胞质区室之间的差异特性。假定治疗剂的释放发生在ADC通过抗原介导的内吞作用内在化并递送至溶酶体区室后,在该处抗体通过细胞内蛋白水解降解被降解至氨基酸水平。该过程释放药物衍生物,该药物衍生物由治疗剂、接头和接头共价附接的氨基酸残基形成。与具有可切割的接头的缀合物相比,来自具有不可切割的接头的缀合物的氨基酸药物代谢物更亲水,并且通常具有更低的膜渗透性,这导致更小的旁侧效应和更小的非特异性毒性。通常,具有不可切割接头的ADC比具有可切割接头的ADC具有更高的循环稳定性。不可切割的接头可以是亚烷基链,或者可以是聚合性质的,如例如基于聚亚烷基二醇聚合物、酰胺聚合物的那些,或可以包括亚烷基链、聚亚烷基二醇和/或酰胺聚合物的区段。可用于连接本文提供的治疗剂和抗体或其抗原结合片段的可切割和不可切割的接头实例描述于US2017/0151344中,其通过引用整体并入本文。将药物连接至抗体或其抗原结合片段的方法的实例方法公开于Behrens C.R.等人,MAbs.2014Jan 1;6(1):46–53;和Zhou q.等人,Anticancer Agents Med Chem.2015;15(7):828-36中,其各自通过引用整体并入。
本文提供的方法和组合物的一些实施方案包括制备ADC。一些这样的实施方案可以包括将接头与治疗剂连接,并且经连接的治疗剂可以通过该接头与抗体或其抗原结合片段缀合。一些这样的实施方案可以包括将接头连接至抗体或其抗原结合片段,并且可以通过该接头将经连接的抗体或其抗原结合片段缀合于治疗剂。一些实施方案还包括纯化ADC。
治疗方法
本文提供的方法和组合物的一些实施方案包括治疗患有癌症的受试者。如本文所用,“处理”或“治疗”或“去治疗”可指治愈、减慢、减轻所诊断的病理状况或病症(例如癌症)的症状和/或中止其进展的治疗效果,以及预防和/或减缓目标病理状况或病症(例如癌症)的发展的预防性措施。一些此类实施方案包括向有此需要的受试者施用有效量的本文提供的ADC。在一些实施方案中,所述癌症包括实体瘤。在一些实施方案中,所述癌症可以包括肺癌、乳腺癌、结肠癌和胰腺癌。在一些实施方案中,所述癌症可以包括细胞,例如三阴性乳腺癌细胞,在选自由K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO组成的组的基因中具有突变的结肠癌细胞,以及小细胞肺癌细胞。在一些实施方案中,所述癌症可以包括癌症干细胞。在一些实施方案中,受试者是哺乳动物,例如人。
一些实施方案还包括与本文提供的ADC组合施用另外的疗法。在一些实施方案中,所述另外的疗法可以包括放射疗法和化疗剂。在一些实施方案中,ADC的施用与另外疗法的施用同时进行。在一些实施方案中,所述化疗剂可包括亚叶酸、氟尿嘧啶、伊立替康、吉西他滨、紫杉醇、nab-紫杉醇、ERBITUX(西妥昔单抗)、PI3K/mTOR双重抑制剂(NVP)和SN38。在一些实施方案中,所述另外的疗法包括亚叶酸、氟尿嘧啶和伊立替康。可用于本文提供的方法和组合物的化疗剂的更多实例公开于US2017/0137533,其通过引用整体并入本文。
本文提供的方法和组合物的一些实施方案包括抑制赘生性细胞的生长。一些这样的实施方案包括使细胞与本文提供的ADC接触。在一些实施方案中,赘生性细胞可包括肺癌细胞、乳腺癌细胞、结肠癌细胞和胰腺癌细胞。在一些实施方案中,赘生性细胞可以包括细胞,例如三阴性乳腺癌细胞,在选自由K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO组成的组的基因中具有突变的结肠癌细胞,以及小细胞肺癌细胞。在一些实施方案中,赘生性细胞可包括癌症干细胞。在一些实施方案中,赘生性细胞是哺乳动物,例如人的。在一些实施方案中,赘生性细胞是在体外。在一些实施方案中,赘生性细胞是在体内。
在本文提供的一些实施方案中,可以使用本领域公认的技术以各种方式配制ADC。在一些实施方案中,本文提供的治疗组合物可以纯地或与最少的附加组分一起施用,而其他则可以任选地配制为含有合适的药学可接受的载体。如本文所用,“药学可接受的载体”包括本领域众所周知的赋形剂、媒介物、佐剂和稀释剂,并且可以从商业来源获得用于药物制备(参见例如,Gennaro(2003)Remington:The Science and Practice of Pharmacywith Facts and Comparisons:Drugfacts Plus,第20版,Mack Publishing;Ansel等人(2004)Pharmaceutical Dosage Forms and Drug Delivery Systems,第7版,LippencottWilliams and Wilkins;Kibbe等人(2000)Handbook of Pharmaceutical Excipients,3.sup.rd ed.,Pharmaceutical Press)。
本文提供的方法和组合物的一些实施方案包括适合于肠胃外施用(例如,通过注射)的ADC的制剂,并且可以包括水性或非水性、等渗、无热原的无菌液体(例如溶液、悬浮液),其中将活性成分溶解、悬浮或以其他方式提供(例如,在脂质体或其他微粒中)。
某些实施方案的特定剂量方案,即剂量、时间安排和重复,可以取决于具体的受试者以及经验性考虑例如药代动力学(例如半衰期、清除速率等)。施用频率可以由本领域技术人员例如主治医师基于对状况和所治疗的状况的严重性、所治疗的受试者的年龄和总体健康状态等的考虑来确定。可以基于所选组合物和给药方案的功效评估在治疗过程中调整施用频率。可以基于特定疾病、病症或状况的标志物进行这类评估。在个体患有癌症的实施方案中,这些包括通过触诊或视觉观察来直接测量肿瘤大小;通过X射线或其他成像技术间接测量肿瘤大小;通过直接肿瘤活组织检查和肿瘤样品的显微镜检查来评估改善;测量根据本文所述方法鉴定的替代生物标志物或抗原;减少增殖性或致瘤性细胞的数量,维持这类赘生性细胞的减少;减少赘生性细胞的增殖;或延迟转移的发展。
试剂盒
本文提供的方法和组合物的一些实施方案包括试剂盒。在一些实施方案中,试剂盒可包括本文提供的ADC。在一些实施方案中,ADC是冻干的。在一些实施方案中,ADC处于水溶液中。在一些实施方案中,试剂盒包含用于施用ADC的药学载体。在一些实施方案中,试剂盒还包含化疗剂。在一些实施方案中,所述化疗剂选自亚叶酸、氟尿嘧啶、伊立替康、吉西他滨和Abraxane。在一些实施方案中,试剂盒包含维持ADC活性的组分,例如冷却剂如冰或干冰。
实施例
实施例1—使用缀合的二抗的增殖测定
将中国仓鼠卵巢细胞(CHO)和表达人LGR5的CHO细胞(CHO-LGR5)用人抗LGR5一抗(C12)和将结合一抗的二抗抗人抗体药物缀合物(ADC)处理。抗体C12在美国专利号9221906中公开,其通过引用整体并入。将细胞以5000个细胞/孔铺板到96孔板中的F12培养基+10%胎牛血清+抗生素/抗有丝分裂剂中以形成单层。表6中列出了ADC(Moradec,San DiegoCA)。
表6
二抗ADC | 缀合的药物 | 接头 |
NC-MMAF | 单甲基奥瑞他汀F(MMAF) | 不可切割 |
CL-MD10 | 单甲基多拉司他汀10(MD10) | 可切割 |
CL-MMAE | 单甲基奥瑞他汀E(MMAE) | 可切割 |
CL-DMSA | 倍癌霉素(DMSA) | 可切割 |
NC-DM1 | maytansanoid 1(DM1) | 不可切割 |
CK-DUA3 | dualstatin 3(DUA3) | 赖氨酸可切割 |
CK-CAL | 加利车霉素(CAL) | 赖氨酸可切割 |
表7列出了用于处理细胞的一抗和二抗ADC的浓度。未在30nM C12评估用CK-CAL处理的细胞,且未在30pM C12评估用CK处理的细胞。
表7
一抗C12 | 二抗ADC |
0 | 0 |
30pM | 150pM |
100pM | 500pM |
300pM | 1.5nM |
1nM | 5nM |
3nM | 15nM |
10nM | 50nM |
30nM | 150nM |
处理3天后,使用MTS增殖测定法测定细胞存活。简而言之,将包含四唑化合物[3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)-2H-四唑,内盐;MTS]和电子偶联试剂(吩嗪乙基硫酸盐(phenazine ethosulfate);PES)的20μl MTS试剂加入在96孔板中生长的细胞中,至总体积为100μl。将平板在37℃孵育1-4小时,并在490nm测量细胞培养基的吸光度。通过490nm吸光度的量测量的甲瓒(formazan)产物的量与培养物中活细胞的数量成正比例。还确定了IC50值。结果在图1A-1G和表8中描述。
表8
二抗ADC | IC50(nM) | 曲线最小(%) |
NL-MMAF | 0.140 | 35.8 |
CL-MD10 | 1.04 | 39.4 |
CL-MMAE | 5.81 | 69.9 |
CL-DMSA | 0.765 | 0 |
NC-DM1 | 1.45 | 46.2 |
CK-DUA3 | 0.159 | 49.7 |
CK-CAL | 0.060 | 34.4 |
如显示的,C12抗体和赖氨酸可切割的加利车霉素(CK-CAL)抗体的组合具有最低的IC50得分0.060。与单甲基奥瑞他汀F(NL-MMAF)不可切割地结合的该抗人抗体具有次低的IC50值0.140。
实施例2—使用缀合的二抗的增殖测定
将CHO和CHO-LGR5用多种人抗LGR5一抗和二抗抗人ADC(NL-MMAF)处理3天。如实施例1中所述使用MTS测定法测量细胞存活。一抗包括:C12、18G7Ch、18G7H6A1和18G7H6A3。表9列出了用于处理细胞的一抗和二抗ADC的浓度。结果示于图2和表10中。
表9
表10
四种测试的一抗中的每一种与二抗抗人ADC(NL-MMAF)一起均有效降低表达人LGR5的CHO的细胞存活。
实施例3—在人细胞中使用缀合的二抗进行肿瘤球测定
肿瘤球是由单一的癌症干细胞/祖细胞增殖形成的实体球形结构。通过使细胞在无血清和/或非粘附条件下生长可以诱导从细胞群形成肿瘤球。因此,肿瘤球可以指示细胞群中癌症干细胞的数量。人CT3细胞是源自患有IV期转移性结肠癌的患者的低代原代细胞,其可被诱导形成肿瘤球,并包含以下基因中的突变:K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO。
在正常条件下培养生长表达LGR5的人CT3细胞,使用Accutase细胞解离试剂收获,并通过使细胞通过细胞滤网形成单细胞悬液。将单细胞悬液以500个细胞/孔铺板到96孔低附着平板中的特定癌症干细胞(CSC)培养基中。用多种人抗LGR5一抗和二抗抗人ADC(CL-DMSA)以一抗和二抗为1:1的比率以如下浓度处理细胞:0.03、0.1、0.3、1、3和10nM。一抗包括:C12、18G7Ch、18G7H6A1和18G7H6A3。将处理过的细胞温育7天,并对肿瘤球的数量计数。
结果描绘在图3和表11中,其显示一抗和ADC抗体的每种组合都具有减少在测定时段内形成的肿瘤球的数量的一定活性。与对照相比,在较低的组合浓度下,C12抗体和ADC抗体的组合在降低肿瘤球形成方面具有的活性相当低。但是,C12抗体和ADC抗体的组合在高于3nM的浓度时抑制肿瘤球形成的效果越来越强。18G7H6A1抗体和ADC抗体的组合具有最低的IC50得分,为0.931nM。
表11
实施例4—在人细胞中使用缀合的抗LGR5抗体进行肿瘤球测定
使用表达LGR5的人CT1细胞进行肿瘤球测定,该细胞用经由可切割的接头缀合于倍癌霉素(DMSA)(CL-DMSA)的人抗LGR5抗体18G7H6A3(BNC101)或经由不可切割的接头缀合于单甲基奥瑞他汀E(MMAE)(NL-MMAE)的人抗LGR5抗体18G7H6A3(BNC101)处理过。CT1细胞是源自患有IV期转移性结肠癌的患者的低传代原代细胞,其可被诱导形成肿瘤球,并包括以下基因中的突变:K-Ras、PI3K、PTEN、p53和APC。缀合的抗LGR抗体以及与CL-DMSA和NL-MMAE缀合的对照MOPC抗体由Concortis Biotherapeutics,San Diego CA制备。如实施例3所述将细胞铺板,并用缀合的18G7H6A3或对照MOPC抗体以0.01、0.03、0.1、0.3、1、3、10和30nM处理。7天后,对肿瘤球计数。结果描述在图4和表12中,其显示与CL-DMSA或NL-MMAE缀合的18G7H6A3的IC50浓度比与相同接头-药物缀合的对照MOPC抗体的IC50浓度低至少两个数量级。与CL-DMSA缀合的18G7H6A3的IC50低于与NL-MMAE缀合的18G7H6A3的IC50。
表12
实施例5—使用抗LGR5药物缀合物对异种移植模型的体内治疗
给七至八周大的雌性CB.17SCID小鼠(Charles River Laboratories)接种2000个CT1细胞(1:1基质胶:培养基)。肿瘤发展25天达到平均体积为120-130mm3。在第25、32和39天对动物施用不同的ADC治疗。ADC包括与DMSA或MMAE缀合的18G7H6A3(BNC101)。与DMSA或MMAE缀合的18G7H6A3由Concortis Biotherapeutics,San Diego CA提供,且包括使用Seattle Genetics缀合技术的vc-PAB缀合。图6A和6B描绘了与本实施例中所使用的那些基本相似的接头和DMSA的结构。在图6A中,该结构包括MA-PEG4-vcPAB-二氨基乙基-氨基甲酰基-倍癌霉素,DMSA显示在框中。在图6B中,DMSA与抗体连接。对照抗体包括与DMSA或MMAE缀合的MOPC抗体。
治疗组包括:PBS;3mg/kg MOPC-倍癌霉素;10mg/kg MOPC-倍癌霉素;3mg/kgMOPC-MMAE;10mg/kg MOPC-MMAE;3mg/kg BNC101-倍癌霉素;10mg/kg BNC101-倍癌霉素;3mg/kg BNC101-MMAE;和10mg/kg BNC101-MMAE,(n=6)。使用自动化数字卡尺每3-4天测量肿瘤,其通过对肿瘤长度和宽度的三次测量取平均值。实验在第42天终止,收集肿瘤并解离用于FACS和肿瘤球形成测定。结果在图5A-5C中描绘。图5A显示在第42天,使用与MMAE缀合的18G7H6A3治疗与PBS对照治疗相比将肿瘤生长抑制了至少约37%。图5B和5C显示,与使用缀合的MOPC对照的治疗相比,使用与MMAE缀合的18G7H6A3(图5B)或与倍癌霉素缀合的18G7H6A3(图5C)治疗有效地抑制肿瘤生长达至少40天。
某些实施方案
本文提供的某些实施方案包括以下方面。
方面1.一种抗体药物缀合物,其包含特异性结合人的含有亮氨酸富集重复的G蛋白偶联受体5(LGR5)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经由接头缀合至药物。
方面2.方面1的抗体药物缀合物,其中所述抗体或其抗原结合片段包含:包含SEQID NO:23或其保守性变异的重链互补决定区1(CDR1),包含SEQ ID NO:25或其保守性变异的重链互补决定区2(CDR2),包含SEQ ID NO:27或其保守性变异的重链互补决定区3(CDR3),包含SEQ ID NO:29或其保守性变异的轻链CDR1,包含SEQ ID NO:31或其保守性变异的轻链CDR2,和包含SEQ ID NO:33或其保守性变异的轻链CDR3。
方面3.方面1的抗体药物缀合物,其中所述抗体或其抗原结合片段包含重链CDR1,所述重链CDR1包含SEQ ID NO:23。
方面4.方面1-3中任一项的抗体药物缀合物,其中所述抗LGR5抗体或其抗原结合片段包含IgG1。
方面5.方面1-4中任一项的抗体药物缀合物,其中所述接头是不可切割的接头。
方面6.方面1-4中任一项的抗体药物缀合物,其中所述接头是可切割的接头。
方面7.方面1-6中任一项的抗体药物缀合物,其中所述药物选自微管蛋白抑制剂和DNA损伤剂。
方面8.方面7的抗体药物缀合物,其中所述微管蛋白抑制剂选自下组:卡巴他赛(cabazitaxel)、秋水仙酰胺(colcemid)、秋水仙素、念珠藻素(cryptophycin)、脱羰秋水仙碱(demecolcine)、多西他赛、2-甲氧基雌二醇、docodazole、紫杉醇、根薯酮内酯(taccalonolide)、紫杉烷和长春碱。
方面9.方面1-6中任一项的抗体药物缀合物,其中所述药物选自下组:单甲基奥瑞他汀F、单甲基奥瑞他汀E、单甲基多拉司他汀10、倍癌霉素、maytansanoid 1、dualstatin3、加利车霉素和duocamycin。
方面10.一种药物组合物,其包含方面1-9中任一项的抗体药物缀合物和药学可接受的载体。
方面11.一种治疗患有癌症的受试者的方法,其包括向有此需要的受试者施用有效量的方面1-9中任一项的抗体药物缀合物。
方面12.方面11的方法,其中所述癌症包括实体瘤。
方面13.方面11的方法,其中所述癌症包含癌症干细胞。
方面14.方面11的方法,其中所述癌症选自下组:肺癌、乳腺癌、结肠癌和胰腺癌。
方面15.方面11的方法,其中所述癌症包含选自下组的细胞:三阴性乳腺癌细胞,具有选自由K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO组成的组的基因中的突变的结肠癌细胞,以及小细胞肺癌细胞。
方面16.方面11-15中任一项的方法,其中所述受试者是哺乳动物。
方面17.方面11-16中任一项的方法,其中所述受试者是人。
方面18.方面11-17中任一项的方法,其包括与抗体药物缀合物组合施用另外的疗法,其中所述另外的疗法选自下组:放射疗法和化疗剂。
方面19.方面18的方法,其中所述抗体药物缀合物的施用与所述另外的疗法的施用同时进行。
方面20.方面18的方法,其中所述化疗剂选自下组:亚叶酸、氟尿嘧啶、伊立替康、吉西他滨、紫杉醇、nab-紫杉醇、ERBITUX(西妥昔单抗)、PI3K/mTOR双重抑制剂(NVP)、和SN38。
方面21.方面18的方法,其中所述另外的疗法包括亚叶酸、氟尿嘧啶和伊立替康。
方面22.一种制备方面1-9中任一项的抗体药物缀合物的方法,其包括:将接头连接至药物;以及将经连接的药物与抗体缀合。
方面23.方面22的方法,其包括纯化缀合的抗体。
如本文所用,术语“包括”与“包含”、“含有”或“特征在于”同义,并且是包括性的或开放性的,不排除另外的、未叙述的要素或方法步骤。
上面的描述公开了本发明的几种方法和材料。本发明易于对所述方法和材料进行修改,以及改变制造方法和设备。通过考虑本公开或本文公开的本发明的实践,这样的修改对于本领域技术人员将变得显而易见。因此,不意图将本发明限制于本文公开的特定实施方案,而是其涵盖了落入本发明的真实范围和精神内的所有修改和备选。
本文引用的所有参考内容,包括但不限于已公开和未公开的申请、专利和文献参考内容,均通过引用全文并入本文,并因此成为本说明书的一部分。在通过引用并入的出版物和专利或专利申请与说明书中所包含的公开内容有冲突时,本说明书旨在取代和/或优先于任何此类有冲突的材料。
序列表
<110> 生物诺米克斯股份有限公司
<120> 结合LGR5的抗体药物缀合物
<130> BIONO.015WO
<150> 62/520726
<151> 2017-06-16
<160> 49
<170> FastSEQ for Windows Version 4.0
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<220>
<223> 18G7.1重链CDR1氨基酸
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Gly Tyr Thr Phe Ser Gly Tyr Trp
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Ile Leu Pro Gly Ser Asp Ser Thr
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Met Gln Gln Asn Asn Glu Asp Pro Arg Thr
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<211> 354
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<220>
<223> 18G7H6A1重链DNA
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gaggtgcagc tggtgcagag cggagccgag gtgaagaagc ccggcgagag cctgaggatc 60
agctgcaagg gcagcggcta cagcttcacc gcgtactgga tcgagtgggt gaggcaggct 120
cccggcaagg gcctggagtg gatcggcgag atcctgcccg gcagcgacag caccaactac 180
aacgagaagt tcaagggcca cgtgaccatc agcgccgaca agagcatcag caccgcctac 240
ctgcagtgga gcagcctgaa ggccagcgac accgccgtgt actactgcgc ccgcagcggc 300
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gacatcgtgc tgacccagag ccccgccagc ctggccgtga gccccggcca gagggccacc 60
atcacctgcc gcgccagcga gagcgtggac agctacggca acagcttcat gcactggtat 120
cagcagaagc ccggccagcc ccccaagctg ctgatctacc tgaccagcaa cctggagtcc 180
ggcgtgcccg acaggttcag cggcagcggc agcggcaccg acttcaccct gaccatcaac 240
cccgtggagg ccaacgacgc cgccacctac tactgccagc agaacgccga ggaccccagg 300
accttcggcg gcggcaccaa gctggagatc aag 333
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<223> 18G7H6A1重链氨基酸
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Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly
465
<210> 10
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1轻链氨基酸
<400> 10
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
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Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 11
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<212> DNA
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<220>
<223> 18G7H6A3重链DNA
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aagcttgccg ccaccatgga atggtcctgg gtgttcctgt tcttcctgtc cgtgaccacc 60
ggcgtgcact ccgaagtgca gctggtgcag tctggcgccg aagtgaagaa gcctggcgag 120
tccctgcgga tctcctgcaa gggctccggc tactccttca ccgcctactg gattgagtgg 180
gtgcgacagg cccctggcaa gggcctggaa tggatcggag agatcctgcc cggctccgac 240
tccaccaact acaacgagaa gttcaagggc cacgtgacca tctccgccga caagtccatc 300
tctaccgcct acctgcagtg gtcctccctg aaggcctctg acaccgccgt gtactactgc 360
gccagatccg gcctgtacgg ctcctctcag tattggggcc agggcaccct cgtgaccgtg 420
tcctctgctt ctaccaaggg cccaagcgtg ttccccctgg cccccagcag caagagcacc 480
agcggcggca cagccgccct gggctgcctg gtgaaggact acttccccga gcccgtgacc 540
gtgtcctgga acagcggagc cctgacctcc ggcgtgcaca ccttccccgc cgtgctgcag 600
agcagcggcc tgtacagcct gagcagcgtg gtgaccgtgc ccagcagcag cctgggcacc 660
cagacctaca tctgtaacgt gaaccacaag cccagcaaca ccaaggtgga caagaaggtg 720
gagcccaaga gctgtgacaa gacccacacc tgccccccct gcccagcccc cgagctgctg 780
ggcggaccca gcgtgttcct gttccccccc aagcccaagg acaccctgat gatcagcaga 840
acccccgagg tgacctgtgt ggtggtggac gtgtcccacg aggacccaga ggtgaagttc 900
aactggtacg tggacggcgt ggaggtgcac aacgccaaga ccaagcccag agaggagcag 960
tacaacagca cctacagggt ggtgtccgtg ctgaccgtgc tgcaccagga ctggctgaac 1020
ggcaaggagt acaagtgtaa ggtgtccaac aaggccctgc cagccccaat cgaaaagacc 1080
atcagcaagg ccaagggcca gccaagagag ccccaggtgt acaccctgcc acccagcagg 1140
gacgagctga ccaagaacca ggtgtccctg acctgtctgg tgaagggctt ctacccaagc 1200
gacatcgccg tggagtggga gagcaacggc cagcccgaga acaactacaa gaccaccccc 1260
ccagtgctgg acagcgacgg cagcttcttc ctgtacagca agctgaccgt ggacaagagc 1320
agatggcagc agggcaacgt gttcagctgc tccgtgatgc acgaggccct gcacaaccac 1380
tacacccaga agagcctgag cctgtcccca ggctgatgaa ttc 1423
<210> 12
<211> 739
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3轻链DNA
<400> 12
aagcttgccg ccaccatgtc cgtgcctacc caggtgctgg gactgctgct gctgtggctg 60
accgacgcca gatgcgacat cgtgctgacc cagagccctg cctctctggc tgtgtctcct 120
ggccagaggg ccaccatcac ctgtagagcc tccgagtccg tggactccta cggcaactcc 180
ttcatgcact ggtatcagca gaagcccggc cagcccccca agctgctgat ctacctgacc 240
tccaacctgg aatccggcgt gcccgacaga ttctccggct ctggctctgg caccgacttc 300
accctgacca tcaaccccgt ggaagccaac gacgccgcca cctactactg ccagcagaac 360
gccgaggacc ccagaacctt tggcggaggc accaagctgg aaatcaagcg tacggtggcc 420
gctcccagcg tgttcatctt ccccccaagc gacgagcagc tgaagagcgg caccgccagc 480
gtggtgtgtc tgctgaacaa cttctacccc agggaggcca aggtgcagtg gaaggtggac 540
aacgccctgc agagcggcaa cagccaggag agcgtcaccg agcaggacag caaggactcc 600
acctacagcc tgagcagcac cctgaccctg agcaaggccg actacgagaa gcacaaggtg 660
tacgcctgtg aggtgaccca ccagggcctg tccagccccg tgaccaagag cttcaacagg 720
ggcgagtgct gatgaattc 739
<210> 13
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3重链氨基酸
<400> 13
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Leu Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly
465
<210> 14
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3轻链氨基酸
<400> 14
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 15
<211> 354
<212> DNA
<213> 人工序列
<220>
<223> 18G7Ch重链DNA
<400> 15
caggttcagc tgcagcagtc tggagctgag ctggtgaagc ctggggcctc agtgaagata 60
tcctgcaagg ctactggcta cacattcagt ggctactgga tagagtgggt aaagcagagg 120
cctggacatg gccttgagtg gattggagag attttgcctg gaagtgatag tactaactac 180
aatgagaagt tcaagggcaa ggccacattc actgcagata catcctccaa cacagtctac 240
atgcaattca gcagcctgac atctgaggac tctgccgtct attactgtgc aagatcgggt 300
tactacggta gtagtcagta ctggggccaa ggcaccactc tcacagtctc ctca 354
<210> 16
<211> 334
<212> DNA
<213> 人工序列
<220>
<223> 18G7Ch轻链DNA
<400> 16
aacattgtgc tgacccaatc tcctgcttct ttggctgtgt ctctagggca gagggccacc 60
atatcctgca gagccagtga aagtgttgat agttatggca atagttttat gcactggtac 120
cagcagaaac caggacagcc acccaaactc ctcatctatc ttacatccaa cctagaatct 180
ggggtccctg ccaggttcag tggcagtggg tctaggacag acttcaccct caccattgat 240
cctgtggagg ctgatgatgc tgcaacctat tactgtcagc aaaataatga ggatcctcgg 300
acgttcggtg gaggcaccaa gctggaaatc aaac 334
<210> 17
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 18G7Ch重链氨基酸
<400> 17
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Thr Gly Tyr Thr Phe
35 40 45
Ser Gly Tyr Trp Ile Glu Trp Val Lys Gln Arg Pro Gly His Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Phe Thr Ala Asp Thr Ser Ser Asn
85 90 95
Thr Val Tyr Met Gln Phe Ser Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
130 135 140
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
145 150 155 160
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
195 200 205
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
210 215 220
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
225 230 235 240
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
245 250 255
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
275 280 285
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
290 295 300
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
305 310 315 320
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
325 330 335
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
340 345 350
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
355 360 365
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
370 375 380
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
420 425 430
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
435 440 445
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
450 455 460
Pro Gly
465
<210> 18
<211> 238
<212> PRT
<213> 人工序列
<220>
<223> 18G7ch轻链氨基酸
<400> 18
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Asn Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
130 135 140
Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu
145 150 155 160
Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
165 170 175
Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
195 200 205
Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
210 215 220
Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 19
<211> 137
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3重链可变域氨基酸
<400> 19
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 20
<211> 411
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3重链可变域 DNA
<400> 20
atggaatggt cctgggtgtt cctgttcttc ctgtccgtga ccaccggcgt gcactccgaa 60
gtgcagctgg tgcagtctgg cgccgaagtg aagaagcctg gcgagtccct gcggatctcc 120
tgcaagggct ccggctactc cttcaccgcc tactggattg agtgggtgcg acaggcccct 180
ggcaagggcc tggaatggat cggagagatc ctgcccggct ccgactccac caactacaac 240
gagaagttca agggccacgt gaccatctcc gccgacaagt ccatctctac cgcctacctg 300
cagtggtcct ccctgaaggc ctctgacacc gccgtgtact actgcgccag atccggcctg 360
tacggctcct ctcagtattg gggccagggc accctcgtga ccgtgtcctc t 411
<210> 21
<211> 131
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3轻链可变域
<400> 21
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys
130
<210> 22
<211> 393
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3轻链可变域 DNA
<400> 22
atgtccgtgc ctacccaggt gctgggactg ctgctgctgt ggctgaccga cgccagatgc 60
gacatcgtgc tgacccagag ccctgcctct ctggctgtgt ctcctggcca gagggccacc 120
atcacctgta gagcctccga gtccgtggac tcctacggca actccttcat gcactggtat 180
cagcagaagc ccggccagcc ccccaagctg ctgatctacc tgacctccaa cctggaatcc 240
ggcgtgcccg acagattctc cggctctggc tctggcaccg acttcaccct gaccatcaac 300
cccgtggaag ccaacgacgc cgccacctac tactgccagc agaacgccga ggaccccaga 360
acctttggcg gaggcaccaa gctggaaatc aag 393
<210> 23
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR1氨基酸
<400> 23
Gly Tyr Ser Phe Thr Ala Tyr Trp
1 5
<210> 24
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR1 DNA
<400> 24
ggctactcct tcaccgccta ctgg 24
<210> 25
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR2氨基酸
<400> 25
Ile Leu Pro Gly Ser Asp Ser Thr
1 5
<210> 26
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR2 DNA
<400> 26
atcctgcccg gctccgactc cacc 24
<210> 27
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR3氨基酸
<400> 27
Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr
1 5 10
<210> 28
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3重链CDR3 DNA
<400> 28
gccagatccg gcctgtacgg ctcctctcag tat 33
<210> 29
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR1氨基酸
<400> 29
Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe
1 5 10
<210> 30
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR1 DNA
<400> 30
gagtccgtgg actcctacgg caactccttc 30
<210> 31
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR2氨基酸
<400> 31
Leu Thr Ser
1
<210> 32
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR2 DNA
<400> 32
ctgacctcc 9
<210> 33
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR3氨基酸
<400> 33
Gln Gln Asn Ala Glu Asp Pro Arg Thr
1 5
<210> 34
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A3轻链CDR3 DNA
<400> 34
cagcagaacg ccgaggaccc cagaacc 27
<210> 35
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR1氨基酸
<400> 35
Gly Tyr Ser Phe Thr Ala Tyr Trp
1 5
<210> 36
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR1 DNA
<400> 36
ggctactcct tcaccgccta ctgg 24
<210> 37
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR2氨基酸
<400> 37
Ile Leu Pro Gly Ser Asp Ser Thr
1 5
<210> 38
<211> 24
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR2 DNA
<400> 38
atcctgcccg gcagcgacag cacc 24
<210> 39
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR3氨基酸
<400> 39
Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr
1 5 10
<210> 40
<211> 33
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1重链CDR3 DNA
<400> 40
gcccgcagcg gctactacgg cagcagccag tac 33
<210> 41
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR1氨基酸
<400> 41
Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe
1 5 10
<210> 42
<211> 30
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR1 DNA
<400> 42
gagagcgtgg acagctacgg caacagcttc 30
<210> 43
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR2氨基酸
<400> 43
Leu Thr Ser
1
<210> 44
<211> 9
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR2 DNA
<400> 44
ctgaccagc 9
<210> 45
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR3氨基酸
<400> 45
Gln Gln Asn Ala Glu Asp Pro Arg Thr
1 5
<210> 46
<211> 27
<212> DNA
<213> 人工序列
<220>
<223> 18G7H6A1轻链CDR3 DNA
<400> 46
cagcagaacg ccgaggaccc caggacc 27
<210> 47
<211> 561
<212> PRT
<213> 人
<400> 47
Met Asp Thr Ser Arg Leu Gly Val Leu Leu Ser Leu Pro Val Leu Leu
1 5 10 15
Gln Leu Ala Thr Gly Gly Ser Ser Pro Arg Ser Gly Val Leu Leu Arg
20 25 30
Gly Cys Pro Thr His Cys His Cys Glu Pro Asp Gly Arg Met Leu Leu
35 40 45
Arg Val Asp Cys Ser Asp Leu Gly Leu Ser Glu Leu Pro Ser Asn Leu
50 55 60
Ser Val Phe Thr Ser Tyr Leu Asp Leu Ser Met Asn Asn Ile Ser Gln
65 70 75 80
Leu Leu Pro Asn Pro Leu Pro Ser Leu Arg Phe Leu Glu Glu Leu Arg
85 90 95
Leu Ala Gly Asn Ala Leu Thr Tyr Ile Pro Lys Gly Ala Phe Thr Gly
100 105 110
Leu Tyr Ser Leu Lys Val Leu Met Leu Gln Asn Asn Gln Leu Arg His
115 120 125
Val Pro Thr Glu Ala Leu Gln Asn Leu Arg Ser Leu Gln Ser Leu Arg
130 135 140
Leu Asp Ala Asn His Ile Ser Tyr Val Pro Pro Ser Cys Phe Ser Gly
145 150 155 160
Leu His Ser Leu Arg His Leu Trp Leu Asp Asp Asn Ala Leu Thr Glu
165 170 175
Ile Pro Val Gln Ala Phe Arg Ser Leu Ser Ala Leu Gln Ala Met Thr
180 185 190
Leu Ala Leu Asn Lys Ile His His Ile Pro Asp Tyr Ala Phe Gly Asn
195 200 205
Leu Ser Ser Leu Val Val Leu His Leu His Asn Asn Arg Ile His Ser
210 215 220
Leu Gly Lys Lys Cys Phe Asp Gly Leu His Ser Leu Glu Thr Leu Asp
225 230 235 240
Leu Asn Tyr Asn Asn Leu Asp Glu Phe Pro Thr Ala Ile Arg Thr Leu
245 250 255
Ser Asn Leu Lys Glu Leu Gly Phe His Ser Asn Asn Ile Arg Ser Ile
260 265 270
Pro Glu Lys Ala Phe Val Gly Asn Pro Ser Leu Ile Thr Ile His Phe
275 280 285
Tyr Asp Asn Pro Ile Gln Phe Val Gly Arg Ser Ala Phe Gln His Leu
290 295 300
Pro Glu Leu Arg Thr Leu Thr Leu Asn Gly Ala Ser Gln Ile Thr Glu
305 310 315 320
Phe Pro Asp Leu Thr Gly Thr Ala Asn Leu Glu Ser Leu Thr Leu Thr
325 330 335
Gly Ala Gln Ile Ser Ser Leu Pro Gln Thr Val Cys Asn Gln Leu Pro
340 345 350
Asn Leu Gln Val Leu Asp Leu Ser Tyr Asn Leu Leu Glu Asp Leu Pro
355 360 365
Ser Phe Ser Val Cys Gln Lys Leu Gln Lys Ile Asp Leu Arg His Asn
370 375 380
Glu Ile Tyr Glu Ile Lys Val Asp Thr Phe Gln Gln Leu Leu Ser Leu
385 390 395 400
Arg Ser Leu Asn Leu Ala Trp Asn Lys Ile Ala Ile Ile His Pro Asn
405 410 415
Ala Phe Ser Thr Leu Pro Ser Leu Ile Lys Leu Asp Leu Ser Ser Asn
420 425 430
Leu Leu Ser Ser Phe Pro Ile Thr Gly Leu His Gly Leu Thr His Leu
435 440 445
Lys Leu Thr Gly Asn His Ala Leu Gln Ser Leu Ile Ser Ser Glu Asn
450 455 460
Phe Pro Glu Leu Lys Val Ile Glu Met Pro Tyr Ala Tyr Gln Cys Cys
465 470 475 480
Ala Phe Gly Val Cys Glu Asn Ala Tyr Lys Ile Ser Asn Gln Trp Asn
485 490 495
Lys Gly Asp Asn Ser Ser Met Asp Asp Leu His Lys Lys Asp Ala Gly
500 505 510
Met Phe Gln Ala Gln Asp Glu Arg Asp Leu Glu Asp Phe Leu Leu Asp
515 520 525
Phe Glu Glu Asp Leu Lys Ala Leu His Ser Val Gln Cys Ser Pro Ser
530 535 540
Pro Gly Pro Phe Lys Pro Cys Glu His Leu Leu Asp Gly Trp Leu Ile
545 550 555 560
Arg
<210> 48
<211> 137
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1重链可变氨基酸
<400> 48
Met Glu Trp Ser Trp Val Phe Leu Phe Phe Leu Ser Val Thr Thr Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Glu Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe
35 40 45
Thr Ala Tyr Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Ile Gly Glu Ile Leu Pro Gly Ser Asp Ser Thr Asn Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser
85 90 95
Thr Ala Tyr Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Tyr Tyr Gly Ser Ser Gln Tyr Trp Gly
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 49
<211> 131
<212> PRT
<213> 人工序列
<220>
<223> 18G7H6A1轻链可变氨基酸
<400> 49
Met Ser Val Pro Thr Gln Val Leu Gly Leu Leu Leu Leu Trp Leu Thr
1 5 10 15
Asp Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Pro Gly Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Glu Ser
35 40 45
Val Asp Ser Tyr Gly Asn Ser Phe Met His Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Leu Thr Ser Asn Leu Glu Ser
65 70 75 80
Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Asn Pro Val Glu Ala Asn Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gln Asn Ala Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys
130
Claims (22)
1.一种抗体药物缀合物,其包含特异性结合人的含有亮氨酸富集重复的G蛋白偶联受体5(LGR5)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经由接头缀合至药物,其中所述抗体或其抗原结合片段包含:
包含SEQ ID NO:23或其保守性变异的重链互补决定区1(CDR1),
包含SEQ ID NO:25或其保守性变异的重链互补决定区2(CDR2),
包含SEQ ID NO:27或其保守性变异的重链互补决定区3(CDR3),
包含SEQ ID NO:29或其保守性变异的轻链CDR1,
包含SEQ ID NO:31或其保守性变异的轻链CDR2,和
包含SEQ ID NO:33或其保守性变异的轻链CDR3。
2.权利要求1的抗体药物缀合物,其中所述抗体或其抗原结合片段包含重链CDR1,所述重链CDR1包含SEQ ID NO:23。
3.权利要求1的抗体药物缀合物,其中所述抗LGR5抗体或其抗原结合片段包含IgG1。
4.权利要求1的抗体药物缀合物,其中所述接头是不可切割的接头。
5.权利要求1的抗体药物缀合物,其中所述接头是可切割的接头。
6.权利要求1的抗体药物缀合物,其中所述药物选自微管蛋白抑制剂和DNA损伤剂。
7.权利要求6的抗体药物缀合物,其中微管蛋白抑制剂选自下组:卡巴他赛(cabazitaxel)、秋水仙酰胺(colcemid)、秋水仙素、念珠藻素(cryptophycin)、脱羰秋水仙碱(demecolcine)、多西他赛、2-甲氧基雌二醇、docodazole、紫杉醇、根薯酮内酯(taccalonolide)、紫杉烷和长春碱。
8.权利要求1的抗体药物缀合物,其中所述药物选自下组:单甲基奥瑞他汀(auristatin)F、单甲基奥瑞他汀E、单甲基多拉司他汀(dolastatin)10、倍癌霉素(duocarmycin)、maytansanoid 1、dualstatin 3、加利车霉素(calicheamicin)和duocamycin。
9.一种药物组合物,其包含权利要求1-9中任一项的抗体药物缀合物和药学可接受的载体。
10.一种治疗患有癌症的受试者的方法,其包括向有此需要的受试者施用有效量的权利要求1-8中任一项的抗体药物缀合物。
11.权利要求10的方法,其中所述癌症包括实体瘤。
12.权利要求10的方法,其中所述癌症包含癌症干细胞。
13.权利要求10的方法,其中所述癌症选自下组:肺癌、乳腺癌、结肠癌和胰腺癌。
14.权利要求10的方法,其中所述癌症包含选自下组的细胞:三阴性乳腺癌细胞,在选自由K-Ras、H-Ras、APC、PI3K、PTEN、STK11、RB1、TP53、FGFR2、VANGL2和ISCO组成的组的基因中具有突变的结肠癌细胞,以及小细胞肺癌细胞。
15.权利要求10的方法,其中所述受试者是哺乳动物。
16.权利要求15的方法,其中所述受试者是人。
17.权利要求10的方法,其包括与所述抗体药物缀合物组合施用另外的疗法,其中所述另外的疗法选自下组:放射疗法和化疗剂。
18.权利要求17的方法,其中所述抗体药物缀合物的施用与所述另外的疗法的施用同时进行。
19.权利要求17的方法,其中所述化疗剂选自下组:亚叶酸、氟尿嘧啶、伊立替康、吉西他滨、紫杉醇、nab-紫杉醇、ERBITUX(西妥昔单抗)、PI3K/mTOR双重抑制剂(NVP)和SN38。
20.权利要求17的方法,其中所述另外的疗法包括亚叶酸、氟尿嘧啶和伊立替康。
21.一种制备权利要求1-8中任一项的抗体药物缀合物的方法,其包括:
将接头与药物连接;和
使经连接的药物与抗体缀合。
22.权利要求21的方法,其包括纯化缀合的抗体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201762520726P | 2017-06-16 | 2017-06-16 | |
US62/520,726 | 2017-06-16 | ||
PCT/US2018/037613 WO2018232164A1 (en) | 2017-06-16 | 2018-06-14 | Antibody drug conjugates that bind lgr5 |
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US (1) | US20200114017A1 (zh) |
EP (1) | EP3638309A4 (zh) |
JP (1) | JP2020523414A (zh) |
KR (1) | KR20200017493A (zh) |
CN (1) | CN110958889A (zh) |
AU (1) | AU2018285523A1 (zh) |
WO (1) | WO2018232164A1 (zh) |
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MX2016012873A (es) * | 2014-04-04 | 2017-03-07 | Bionomics Inc | Anticuerpos humanizados que se unen al receptor 5 acoplado a proteina g que contiene repeticion rica en leucina (lgr5). |
KR20220004226A (ko) | 2016-03-22 | 2022-01-11 | 바이오노믹스 리미티드 | 항-lgr5 단클론성 항체의 투여 |
JP2019529418A (ja) * | 2016-09-16 | 2019-10-17 | バイオノミックス リミテッド | 抗体およびチェックポイント阻害剤の併用療法 |
IL303015A (en) * | 2020-11-18 | 2023-07-01 | Carina Biotech Pty Ltd | T cells that express CHIMERIC ANTIGEN RECEPTOR and method |
Citations (4)
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CN104411721A (zh) * | 2012-03-30 | 2015-03-11 | 基因泰克公司 | 抗lgr5抗体和免疫缀合物 |
US20160130358A1 (en) * | 2014-09-12 | 2016-05-12 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
CN106211774A (zh) * | 2013-08-02 | 2016-12-07 | 辉瑞公司 | 抗cxcr4抗体及抗体‑药物缀合物 |
CN106536556A (zh) * | 2014-04-04 | 2017-03-22 | 生态学有限公司 | 结合lgr5的人源化抗体 |
-
2017
- 2017-06-16 US US16/621,897 patent/US20200114017A1/en not_active Abandoned
-
2018
- 2018-06-14 EP EP18817891.7A patent/EP3638309A4/en not_active Withdrawn
- 2018-06-14 JP JP2020519003A patent/JP2020523414A/ja active Pending
- 2018-06-14 AU AU2018285523A patent/AU2018285523A1/en active Pending
- 2018-06-14 WO PCT/US2018/037613 patent/WO2018232164A1/en unknown
- 2018-06-14 KR KR1020207001231A patent/KR20200017493A/ko not_active Application Discontinuation
- 2018-06-14 CN CN201880052274.1A patent/CN110958889A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104411721A (zh) * | 2012-03-30 | 2015-03-11 | 基因泰克公司 | 抗lgr5抗体和免疫缀合物 |
CN106211774A (zh) * | 2013-08-02 | 2016-12-07 | 辉瑞公司 | 抗cxcr4抗体及抗体‑药物缀合物 |
CN106536556A (zh) * | 2014-04-04 | 2017-03-22 | 生态学有限公司 | 结合lgr5的人源化抗体 |
US20160130358A1 (en) * | 2014-09-12 | 2016-05-12 | Genentech, Inc. | Cysteine engineered antibodies and conjugates |
Non-Patent Citations (1)
Title |
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MELISSA R. JUNTTILA ET AL.: "Targeting LGR5+ cells with an antibody-drug conjugate for the treatment of colon cancer" * |
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US20200114017A1 (en) | 2020-04-16 |
AU2018285523A1 (en) | 2020-01-02 |
EP3638309A1 (en) | 2020-04-22 |
KR20200017493A (ko) | 2020-02-18 |
JP2020523414A (ja) | 2020-08-06 |
EP3638309A4 (en) | 2021-03-24 |
WO2018232164A1 (en) | 2018-12-20 |
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