CN116113439A - 抗ceacam5抗体和缀合物及其用途 - Google Patents
抗ceacam5抗体和缀合物及其用途 Download PDFInfo
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- CN116113439A CN116113439A CN202180054670.XA CN202180054670A CN116113439A CN 116113439 A CN116113439 A CN 116113439A CN 202180054670 A CN202180054670 A CN 202180054670A CN 116113439 A CN116113439 A CN 116113439A
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Abstract
本发明提供了结合人CEACAM5蛋白的抗体,以及包含编码所述抗体的序列的分离的核酸和宿主细胞。本发明还提供了包含连接至生长抑制剂的所述抗体的免疫缀合物,和包含本发明的抗体或免疫缀合物的药物组合物。本发明还提供了本发明的抗体、免疫缀合物和药物组合物用于治疗癌症或用于诊断目的的用途。
Description
技术领域
本发明涉及结合人CEACAM5蛋白的抗体,以及包含编码所述抗体的序列的分离的核酸和宿主细胞。本发明还涉及包含连接至生长抑制剂的所述抗体的免疫缀合物,并涉及包含本发明的抗体或免疫缀合物的药物组合物。本发明还涉及本发明的抗体、免疫缀合物和药物组合物用于治疗癌症或用于诊断目的的用途。
发明背景
癌胚抗原(CEA)是一种参与细胞粘附的糖蛋白。CEA在1965年首次被鉴定(Gold和Freedman,J Exp Med,121,439,1965)为在妊娠的前六个月期间由胎儿肠道正常表达的蛋白,并且在许多癌症(诸如结肠直肠癌或胰腺癌)中被发现。CEA家族属于免疫球蛋白超家族。CEA家族由18个基因组成,其被细分为两个蛋白亚组:癌胚抗原相关细胞粘附分子(CEACAM)亚组和妊娠特异性糖蛋白亚组(Kammerer&Zimmermann,BMC Biology 2010,8:12)。
在人中,CEACAM亚组由7个成员组成:CEACAM1、CEACAM3、CEACAM4、CEACAM5、CEACAM6、CEACAM7和CEACAM8。与最初鉴定的CEA相同的CEACAM5已经报道在癌细胞(诸如结肠直肠、胃、肺和胰腺肿瘤细胞)的表面上高度表达,并且在正常组织中的表达限于少数正常上皮细胞,诸如结肠和食管上皮细胞。由此,CEACAM5可构成适于肿瘤特异性靶向方法(诸如免疫缀合物)的治疗靶标。
CEACAM家族成员的胞外结构域由重复的免疫球蛋白样(Ig样)结构域构成,所述免疫球蛋白样结构域已根据序列同源性被分为3类,A、B和N。CEACAM5含有七个此类结构域,即N、A1、B1、A2、B2、A3和B3。一方面,CEACAM5的A1、A2和A3结构域,和另一方面CEACAM5的B1、B2和B3结构域显示出高度的序列同源性,人CEACAM5的A结构域显示84至87%的成对序列相似性,而B结构域显示69至80%的成对序列相似性。此外,在其结构中存在A和/或B结构域的其他人CEACAM成员,即CEACAM1、CEACAM6、CEACAM7和CEACAM8显示出与人CEACAM5的同源性。特别地,人CEACAM6蛋白的A和B结构域分别表现出与人CEACAM5的A1和A3结构域和B1至B3结构域的任一个的序列同源性,所述序列同源性甚至高于在人CEACAM5的A结构域和B结构域中观察到的那些。
已经产生了抗CEA抗体用于CEA靶向诊断或治疗目的。对相关抗原的特异性一直作为本领域的关注点被提及,例如由Sharkey等人(1990,Cancer Research 50,2823)。由于上述同源性,一些先前描述的抗体可表现出例如结合至不同免疫球蛋白结构域中存在的CEACAM5的重复表位,并显示出对其他CEACAM家族成员(诸如CEACAM1、CEACAM6、CEACAM7或CEACAM8)的交叉反应性,由此缺乏对CEACAM5的特异性。但是,CEA靶向疗法需要抗CEACAM5抗体的特异性,以使其结合至表达人CEACAM5的肿瘤细胞但不结合至表达其他CEACAM家族成员的某些正常组织。值得注意的是,CEACAM1、CEACAM6和CEACAM8已被描述为由人和非人灵长类的嗜中性粒细胞表达(Ebrahimmnejad等人,2000,Exp Cell Res,260,365;Zhao等人,2004,J Immunol Methods 293,207;Strickland等人,2009J Pathol,218,380),其中它们已显示调节粒细胞生成并在免疫应答中起作用。为了治疗目的,抗CEACAM5抗体与CEACAM1、CEACAM6、CEACAM7或CEACAM8的交叉反应性可因正常组织中的毒性提高而由此降低化合物的治疗指数。因此,需要不与CEACAM家族的其他分子交叉反应的特异性针对CEACAM5的抗体,例如用作抗体药物缀合物(ADC)的一部分或以任何其他方式使用,导致杀伤靶细胞。
此外,由于CEACAM5被描述为在一些正常细胞组织中表达,因此合意的是开发能够结合至人CEACAM5以及食蟹猴(cynomolgus monkey)(食蟹猴,Macaca fascicularis)CEACAM5的抗CEACAM5抗体,因为此类抗体可以在食蟹猴的临床前毒理学研究中容易地测试以评估其安全性概况。
结合对a)物种交叉反应性与b)对人和食蟹猴CEACAM5的特异性的需要(即与其他食蟹猴和人CEACAM家族成员不具有交叉反应性),进一步增加了开发新的抗CEACAM5抗体的复杂程度,尤其是考虑到人和食蟹猴CEACAM蛋白之间的整体序列同源性。
此外,CEACAM5在文献中被描述为内化差的表面蛋白(综述在Schmidt等人,2008,Cancer Immunol.Immunother.57,1879中),提出了针对该靶标蛋白的抗体药物缀合物的进一步挑战。
已知的抗CEACAM5抗体包括Immunomedics的拉贝珠单抗(也称为hMN14;Sharkey等人,1995,Cancer Research 55,5935)。该抗体已显示不结合至相关抗原,但也不与来自食蟹猴的CEACAM5交叉反应。拉贝珠单抗也已经用作抗体-药物缀合物(ADC)的一部分,即作为拉贝珠单抗戈维替康(labetuzumab govitecan)。拉贝珠单抗戈维替康是由经由接头(称为CL2A)缀合到抗CEACAM5抗体拉贝珠单抗上的细胞毒性药物SN38构成的ADC,所述接头包含pH敏感的碳酸酯和短聚乙二醇(PEG)链。拉贝珠单抗戈维替康的特征在于所用的接头结构的显著不稳定性,其导致在肠胃外施用后细胞毒性有效负载的早期全身性损失。这种降解过程可限制抗肿瘤活性,并提高副作用风险。另一种已知的抗CEACAM5 ADC是Sanofi的SAR408701(特赛妥单抗ravtansine),其包含经由4-(2-吡啶基二硫代)丁酸-N-琥珀酰亚胺酯(SPDB)接头共价连接至细胞毒性剂DM4(一种强有力的微管去稳定化美登素)的抗CEACAM5抗体SAR408377(特赛妥单抗;也称为huMab2-3)。SAR408701与对包括眼角膜的几种器官和组织的毒副作用(包括角膜炎和角膜病)相关。此外,基于微管抑制剂的ADC的有效性可在某些癌症适应症(诸如结肠直肠癌)中受到限制。迄今为止,尚未批准抗CEACAM5抗体或ADC的任何临床中的治疗用途;一般来说,很少有ADC被批准用于治疗实体肿瘤。仍然需要新的和改善的治疗剂用于治疗癌症,例如用于不同的实体肿瘤适应症,包括例如CRC、胰腺癌、胃癌、NSCLC、食管癌和前列腺癌。
发明内容
本发明尤其通过提供针对CEACAM5(与人和食蟹猴蛋白二者反应)的单克隆抗体和通过提供包含所述抗体的免疫缀合物(在本文中也称为抗体-药物缀合物(ADC))来解决本领域的此类需求和其他需求;这些免疫缀合物具有细胞毒性作用,其在体外杀伤肿瘤细胞并在体内抑制肿瘤生长。本发明涉及权利要求中以及下文的进一步描述中描述的实施方案。
为了产生用于治疗目的的具有最佳特性的针对CEACAM5的新抗体(特别是以免疫缀合物的形式),本发明人进行了广泛的研究和开发,以便选择具有有利概况的抗体并在此基础上开发免疫缀合物。
本发明人能够选择和产生预料不到地包含若干期望特征的优化IgG。这些抗体以高亲和力结合至人CEACAM5的A2-B2结构域,并且不识别人CEACAM1、CEACAM6、CEACAM7和CEACAM8蛋白。在细胞背景下,这些抗体对表达CEACAM5的肿瘤细胞表现出高亲和力并被内化。此外,这些抗体还结合至食蟹猴CEACAM5蛋白,其中对猴和人蛋白的亲和力分别在彼此的10倍内。本发明的抗体结合至食蟹猴CEACAM5的A2-B2结构域,但它们不识别另一食蟹猴CEACAM蛋白CEACAM6。
本发明人还已经显示,他们已制得的抗体当在免疫缀合物中与细胞毒性药物组合时,能够在体外诱导对肿瘤细胞的细胞毒性作用。与细胞毒性药物缀合的抗体(即本发明的免疫缀合物)也能够在带有表达CEACAM5的肿瘤的小鼠中显著抑制肿瘤生长。连接药物和抗体的接头设计为在肠胃外施用后使全身稳定性最大化。在靶标细胞内,依沙替康从本发明的免疫缀合物中释放导致极高的效力和显著的旁观者效应。强有力的旁观者效应可对治疗具有异源靶标表达的患者有益。
附图说明
图1:在ELISA测定中,mAb1与重组人(rh)CEACAM5 ECD或其结构域N-A1-B1、A2-B2、A3-B3或与重组食蟹猴(mf)CEACAM5 ECD的结合。
图2:结合至MKN-45细胞的抗CEACAM5抗体的EC50:与抗体huMab2-3和hmn-14相比,mAb1在表达CEACAM5的MKN45细胞系上的细胞结合。
图3:pHrodo标记的抗体内化至细胞的晚期核内体和溶酶体中(每个细胞的总荧光强度,三次重复的平均值)。
图4:来自700分钟至1200分钟的时间的每个细胞的荧光强度,其为曲线的线性部分。测量线性斜率并在样品之间比较(参见实施例1.6.5)。
图5:用抗体rb8G4在FFPE癌细胞系上的IHC染色。
图6:104种癌细胞系的CEACAM5 mRNA表达和IHC染色的相关性。
图7:用抗体rb8G4在正常人组织上的IHC染色。
图8:正常人组织中的CEACAM5 mRNA表达。
图9:用抗体rb8G4在人结肠直肠癌组织上的IHC染色。
图10:用抗体rb8G4在人胃癌组织上的IHC染色。
图11:用抗体rb8G4在人食管癌组织上的IHC染色。
图12:用抗体rb8G4在人非小细胞肺癌组织上的IHC染色。
图13:通过蛋白印迹(Western Blots)研究的mAb1(图13A)和rb8G4(图13B)与癌细胞系裂解物中的CEACAM5的结合。
图14:显示储备mAb、UF后缀合物和最终BDS的纯度的典型SEC层析图。
图15:显示轻链和重链的分离的典型RP-HPLC层析图。该层析图显示了储备mAb、粗ADC和最终BDS的重叠。
图16:显示NAC标准和最终BDS的游离药物水平的典型层析图。
图17:显示储备mAb和最终BDS的纯度的典型SEC层析图。
图18:显示轻链和重链的分离的典型RP-HPLC层析图。该层析图显示了储备mAb和最终BDS的重叠。
图19:显示NAC标准和最终BDS的游离药物水平的典型层析图。
图20:人、小鼠和食蟹猴血清的ADC稳定性。使用游离依沙替康(归一化数据)计算缀合依沙替康浓度(初始剂量约10μM)。
图21:小鼠血清和缓冲液的ADC3对照稳定性。使用游离SN38(未归一化)计算缀合SN38浓度(初始剂量50微克/毫升ADC蛋白浓度)。
图22:人肝脏溶酶体中ADC1和ADC2的有效负载释放概况(pH 5.0)。使用例如游离依沙替康(初始浓度~10μM依沙替康)归一化数据计算缀合药物浓度。
图23:ADC分解代谢物分析证实游离依沙替康为溶酶体释放产物。
图24:与抗原阴性MDA-MB-231(图24C)细胞系相比,ADC1、ADC2和游离有效负载针对抗原阳性SK-CO-1(图24A)和SNU-16(图24B)细胞系的体外效力。显示了一个代表性实验,三次重复的平均值±SD。如图24C中所示,分别将三个不同系列的数据点分配给ADC1、ADC2和有效负载的图例也适用于图24A和图24B。
图25:在SK-CO-1细胞系上比较ADC1和ADC2与各自的同种型对照。显示了一个代表性实验,三次重复的平均值±SD。
图26:与抗原阴性MDA-MB-231(图26B)细胞系相比,ADC1、ADC2、ADC SAR DM4、ADCmAb1 DM4和游离有效负载针对抗原阳性SK-CO-1(图26A)的体外效力。显示了一个代表性实验,三次重复的平均值±SD;图26B中显示的图例也适用于图26A。
图27:ADC1和ADC2对与抗原阳性SK-CO-1细胞共同培养的抗原阴性MDA-MB-231细胞的强有力的旁观者效应(图27A)。ADC1或ADC2对单独的MDA-MB-231细胞没有非特异性效应(图27B)。显示了一个代表性实验,两次重复的平均值±SD。
图28:ADC1和ADC2对与抗原阳性SK-CO-1细胞共同培养的抗原阴性MDA-MB-231细胞的旁观者效应(图28A和图28B)。测试的ADC对单独的MDA-MB-231细胞没有非特异性效应(图28C)。显示了一个代表性实验,两次重复的平均值±SD。
图29:单次治疗后ADC1和ADC2在CRC PDX模型(COPF217)中的功效。
图30:单次治疗后ADC1在NSCLC PDX模型(LUPF160151)中的功效。
图31:单次治疗后ADC1在胃癌PDX模型(GAX066)中的功效。
图32:胰腺异种移植模型(HPAF-II)中ADC1与ADC3相比的功效。
图33:CRC PDX模型(COPF230)中ADC1与ADC SAR DM4相比的功效。
图34:CRC PDX模型(REPF210)中ADC1与ADC SAR DM4相比的功效。
图35:胃PDX模型GAPF313(正在进行的实验的中期分析)中ADC1与ADC SAR DM4相比的功效。
具体实施方式
定义
本文中使用的“CEACAM5”是指“癌胚抗原相关细胞粘附分子5”,也称为“CD66e”(分化簇66e)或CEA。CEACAM5是一种参与细胞粘附的糖蛋白。CEACAM5尤其在例如结肠直肠癌、胃癌、非小细胞肺癌、胰腺癌、食管癌、前列腺癌和其他实体肿瘤的表面上高度表达。全长人CEACAM5的参考序列包括信号肽(位置1-34)和前肽(位置686-702),其可以以登录号AAA51967.1获自GenBank数据库;该氨基酸序列读取如下:
MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVLVGVALI(SEQ ID NO:1)。已经鉴定了五种非同义SNP,其在高加索人群体中的频率高于2%,其中四种定位在人CEACAM5的N结构域(在位置80、83、112、113处)中,最后一种定位在人CEACAM5的A2结构域(在位置398处)中。GenBank AAA51967.1含有主要单倍型(haplotype)(I80、V83、I112、I113和E398)。
“结构域”或“区域”可以是蛋白的任何区域,通常基于序列同源性来定义,并且通常与特定结构或功能实体相关。已知CEACAM家族成员由Ig样结构域构成。术语结构域在本文中用于指单独的Ig样结构域,诸如“N-结构域”,或指连续结构域的组,诸如“A2-B2结构域”。
人CEACAM5的结构域组序(organization)如下(基于GenBank AAA51967.1序列;SEQ ID NO:1):
人CEACAM5结构域 | 在SEQ ID NO:1中的位置 |
N | 35-142 |
A1 | 143-237 |
B1 | 238-320 |
A2 | 321-415 |
B2 | 416-498 |
A3 | 499-593 |
B3 | 594-685 |
因此,人CEACAM5的A2-B2结构域由SEQ ID NO:1的氨基酸321-498组成。
食蟹猴CEACAM5蛋白的参考序列是可得的(NCBI参考序列XP_005589491.1),并且该氨基酸序列读取如下:
“编码序列”或“编码”表达产物,诸如多肽、蛋白或酶的序列是在表达时导致产生该多肽、蛋白或酶的核苷酸序列,即该核苷酸序列编码该多肽、蛋白或酶的氨基酸序列。蛋白的编码序列可包括起始密码子(通常为ATG)和终止密码子。
如本文中所用,提及特定蛋白(例如抗体)可包括具有天然氨基酸序列的多肽,以及变体和修饰形式,无论其来源或制备方法如何。具有天然氨基酸序列的蛋白是具有与获自自然界的相同氨基酸序列的蛋白。此类天然序列蛋白可以从自然界分离,或者可以使用标准重组和/或合成方法来制备。天然序列蛋白具体包括天然存在的截短或可溶形式、天然存在的变体形式(例如可变剪接形式)、天然存在的等位基因变体和包括翻译后修饰的形式。天然序列蛋白包括携带翻译后修饰的蛋白,所述翻译后修饰诸如糖基化或磷酸化,或某些氨基酸残基的其他修饰。
术语“基因”是指编码或对应于包含一种或多种蛋白或酶的全部或部分的特定氨基酸序列的DNA序列,并且可以包括或不包括调节性DNA序列,诸如启动子序列,其决定例如表达基因的条件。一些并非结构基因的基因可以从DNA转录成RNA,但不翻译成氨基酸序列。其他基因可以充当结构基因的调节子(regulator)或DNA转录的调节子。特别地,术语基因可以用于编码蛋白的基因组序列,即包含调节子、启动子、内含子和外显子序列的序列。
在本文中,与参考序列有“至少85%同一性”的序列是在其全长上与参考序列的全长具有85%或更高(例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%)的序列同一性的序列。“序列同一性”的百分比由此可以通过使用Needleman和Wunsch算法的全局双序列比对(J.Mol.Biol.48:443(1970)),例如使用具有BLOSUM62矩阵的程序Needle(EMBOSS)和以下参数,通过在两个此类序列的全长上比较它们来确定:空位开放=10,空位延伸=0.5,末端空位罚分=假,末端空位开放=10,末端空位延伸=0.5(其是标准设置)。
“保守氨基酸取代”是其中一个氨基酸残基被具有化学性质(例如电荷、尺寸或疏水性)类似的侧链的另一氨基酸残基取代的氨基酸取代。通常,保守氨基酸取代将基本不会改变蛋白的功能性质。具有化学性质类似的侧链的氨基酸组的实例包括1)脂族侧链:甘氨酸、丙氨酸、缬氨酸、亮氨酸和异亮氨酸;2)脂族羟基侧链:丝氨酸和苏氨酸;3)含酰胺侧链:天冬酰胺和谷氨酰胺;4)芳族侧链:苯丙氨酸、酪氨酸和色氨酸;5)碱性侧链:赖氨酸、精氨酸和组氨酸;6)酸性侧链:天冬氨酸和谷氨酸;和7)含硫侧链:半胱氨酸和蛋氨酸。保守氨基酸取代组也可基于氨基酸大小来定义。
“抗体”(也称为“免疫球蛋白”)可以例如是天然或常规类型的抗体,其中两条重链通过二硫键彼此连接,并且每条重链通过二硫键与轻链连接。存在两种类型的轻链,λ(I)和κ(k)。存在五种主要的重链类别(或同种型),其决定抗体分子的功能活性的方面:IgM、IgD、IgG、IgA和IgE。每个抗体链含有不同的序列结构域(或区域)。典型的IgG抗体的轻链包括两个区域,可变区(VL)和恒定区(CL)。典型的IgG抗体的重链包括四个区域,即可变区(VH)和恒定区(CH),后者由三个恒定结构域(CH1、CH2和CH3)构成。轻链和重链二者的可变区决定了与抗原的结合和特异性。轻链和重链的恒定区可赋予重要的生物学性质,诸如抗体链缔合、分泌、经胎盘移动性、补体结合和与Fc受体(FcR)的结合。Fv片段是抗体的Fab片段的N-端部分,且其由一条轻链和一条重链的可变部分组成。
抗体的特异性在于抗体结合位点和抗原决定簇之间的结构互补性。抗体结合位点由主要来自所谓高变区或互补决定区(CDR)的残基构成。因此,互补决定区(CDR)是指一起限定抗体的Fv区域的结合亲和力和特异性的氨基酸序列。抗体的轻(L)和重(H)链各自具有三个CDR,分别命名为CDR1-L、CDR2-L、CDR3-L和CDR1-H、CDR2-H、CDR3-H。因此,常规抗体的抗原结合位点包括六个CDR,其包含来自重链和轻链可变区的每一个的CDR组。
“框架区”(FR)是指插在CDR之间的氨基酸序列,即指在单一物种中的不同的免疫球蛋白中相对保守的免疫球蛋白轻链和重链可变区的那些部分。免疫球蛋白的轻链和重链各自具有四个FR,分别命名为FR1-L、FR2-L、FR3-L、FR4-L和FR1-H、FR2-H、FR3-H、FR4-H。本文中使用的“人框架区”是与天然存在的人抗体的框架区基本相同(大约85%或更高,例如90%、91%、92%、93%、94%、95%、96%、97%、98%或99%)的框架区。
在本发明的背景下,免疫球蛋白轻链或重链中的CDR/FR定义基于IMGT定义(Lefrnc等人,Dev.Comp.Immunol.,2003,27(1):55-77;www.imgt.org)来确定。
本文中使用的术语“抗体”包括常规抗体及其片段,以及单结构域抗体及其片段,诸如单结构域抗体的可变重链;本文中使用的术语“抗体”还包括嵌合、人源化、双特异性或多特异性抗体,以及其他类型的工程化抗体。术语“抗体”包括单克隆抗体。
本文中使用的术语“单克隆抗体”或“mAb”是指针对特定抗原的单一氨基酸序列的抗体分子,并且不应解释为需要通过任何特定方法来产生该抗体。单克隆抗体可以例如通过B细胞或杂交瘤的单个克隆产生,但也可以是重组的,例如通过涉及遗传工程或蛋白工程的方法产生。
术语“嵌合抗体”是指工程化抗体,其在最广泛的意义上含有来自一种抗体的一个或多个区域和来自一种或多种其他抗体的一个或多个区域。在一个实施方案中,嵌合抗体包含与另一种抗体(其在一些实施方案中为人抗体)的CH和CL结合的来源于非人动物的抗体的VH和VL。作为非人动物,可以使用任何动物,诸如小鼠、大鼠、仓鼠、兔等。嵌合抗体还可以表示对至少两种不同的抗原具有特异性的多特异性抗体。
术语“人源化抗体”是指完全或部分非人来源的抗体,并且其已经经过修饰以替换例如在VH和VL的框架区中的某些氨基酸,以避免或最小化在人体中的免疫应答。人源化抗体的恒定区通常是人CH和CL区。
抗体(例如常规抗体)的“片段”包含完整抗体(诸如IgG)的一部分,特别是完整抗体的抗原结合区或可变区。抗体片段的实例包括Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2F、双抗体(diabody)以及由抗体片段形成的双特异性和多特异性抗体。常规抗体的片段也可以是单结构域抗体,诸如重链抗体或VHH。
术语“Fab”表示具有大约50,000Da的分子量和抗原结合活性的抗体片段,其中重链的N-端侧的大约一半和整个轻链通过二硫键结合在一起。其通常通过用蛋白酶木瓜蛋白酶处理IgG而在片段中获得。
术语“F(ab')2”是指具有大约100,000Da的分子量和抗原结合活性的抗体片段,其稍大于经由铰链区的二硫键结合的2个相同Fab片段。其通常通过用蛋白酶胃蛋白酶处理IgG而在片段中获得。
术语“Fab'”是指具有大约50,000Da的分子量和抗原结合活性的抗体片段,其通过切割F(ab')2的铰链区的二硫键而获得。
单链Fv(“scFv”)是共价连接的VH::VL异二聚体,其通常由包括通过肽编码接头连接的VH和VL编码基因的基因融合体来表达。本发明的人scFv片段包括例如通过使用基因重组技术保持在适当构象的CDR。二价和多价抗体片段可通过单价scFv的缔合自发地形成,或者可以通过经由肽接头偶联单价scFv而生成(诸如二价sc(Fv)2)。“dsFv”是通过二硫键稳定的VH::VL异二聚体。“(dsFv)2”表示经由肽接头偶联的两个dsFv。
术语“双特异性抗体”或“BsAb”表示包含两个不同的抗原结合位点的抗体。由此,BsAb能够例如同时结合两种不同的抗原。如例如在EP 2 050 764 A1中描述的那样,遗传工程已经越来越频繁地用于设计、修饰和产生具有期望的结合性质和效应子功能组的抗体或抗体衍生物。
术语“多特异性抗体”表示包含两个或更多个不同的抗原结合位点的抗体。
术语“双抗体”是指具有两个抗原结合位点的小抗体片段,该片段在同一多肽链(VH-VL)中包含连接到轻链可变结构域(VL)的重链可变结构域(VH)。通过使用太短以至于不允许在同一链的两个结构域之间配对的接头,迫使结构域与另一链的互补结构域配对并产生两个抗原结合位点。
术语“杂交瘤”表示通过对通过用抗原免疫非人哺乳动物而制备的B细胞与来源于小鼠等的骨髓瘤细胞进行细胞融合而获得的细胞,其产生具有抗原特异性的所需单克隆抗体。
当涉及多肽(例如抗体)或核苷酸序列时,“纯化的”或“分离的”是指所示分子在基本不存在相同类型的其他生物大分子的情况下存在。本文中使用的术语“纯化的”是指存在按重量计至少75%、85%、95%、96%、97%或98%的相同类型的生物大分子。编码特定多肽的“分离的”核酸分子是指基本不含不编码主体多肽的其他核酸分子的核酸分子;但是,该分子可以包括某些另外的碱基或部分,其不会有害地影响组合物的基本特性。
本文中使用的术语“受试者”表示哺乳动物,诸如啮齿类动物、猫、犬、灵长类或人。在本发明的实施方案中,受试者(或患者)是人。
本发明的抗体
本发明人已成功生成、筛选和选择了特异性抗CEACAM5抗体,所述抗CEACAM5抗体出乎意料地表现出了几种特性的组合,使它们理想地适用于癌症疗法,特别是作为免疫缀合物(抗体-药物缀合物)的一部分。例如,本发明的抗体对人和食蟹猴CEACAM5蛋白二者都表现出高亲和力,并且它们不与人CEACAM1、CEACAM6、CEACAM7和CEACAM8蛋白或食蟹猴CEACAM6蛋白显著地交叉反应。本发明人已经确定了根据本发明的此类单克隆抗体的氨基酸序列。
本发明提供了一种分离的抗体,其结合人至CEACAM5蛋白,并且其包含由氨基酸序列DGSVSRGGYY(SEQ ID NO:3)组成的CDR1-H、由氨基酸序列IYYSGST(SEQ ID NO:4)组成的CDR2-H、由氨基酸序列ARGIAVAPFDY(SEQ ID NO:5)组成的CDR3-H、由氨基酸序列QSVRSN(SEQ ID NO:6)组成的CDR1-L、由氨基酸序列AAS(SEQ ID NO:7)组成的CDR2-L和由氨基酸序列QQYTNWPFT(SEQ ID NO:8)组成的CDR3-L。该抗体也可结合至食蟹猴CEACAM5蛋白。
在本发明的实施方案中,具有上述六个CDR序列的抗体包含含有与氨基酸序列
在本发明的实施方案中,具有上述六个CDR序列的抗体包含含有SEQ ID NO:9的氨基酸序列的重链可变区(VH)和含有SEQ ID NO:10的氨基酸序列的轻链可变区(VL)。
在本发明的实施方案中,抗体进一步包含含有与氨基酸序列ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:11)有至少85%同一性的氨基酸序列的重链恒定区(CH)和含有与氨基酸序列RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:12)有至少85%同一性的氨基酸序列的轻链恒定区(CL)。
在本发明的实施方案中,抗体包含含有SEQ ID NO:11的氨基酸序列的重链恒定区(CH)和含有SEQ ID NO:12的氨基酸序列的轻链恒定区(CL)。
在更特别的实施方案中,本发明的抗体是分离的抗体,其结合至人CEACAM5蛋白,并且其包含含有与氨基酸序列EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO:13)有至少85%同一性的氨基酸序列的重链(HC)和含有与氨基酸序列EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQID NO:14)有至少85%同一性的氨基酸序列的轻链(LC)。在本发明的甚至更特别的实施方案中,抗体包含含有SEQ ID NO:13的氨基酸序列的重链(HC)和含有SEQ ID NO:14的氨基酸序列的轻链(LC)。在本发明的再更特别的实施方案中,抗体由两个相同的含有SEQ ID NO:13的氨基酸序列的重链(HC)和两个相同的含有SEQ ID NO:14的氨基酸序列的轻链(LC)组成。
在一些实施方案中,本发明的抗体的一个或多个单独的氨基酸可在一个或多个上述序列(包括CDR序列)中通过取代,特别是通过保守取代来改变。此类改变可以意在例如去除(例如与抗体的人源化有关的)糖基化位点或脱酰胺位点。
在一些实施方案中,本发明的抗体是分离的抗体,其结合至人CEACAM5蛋白,并且其由两个相同的由SEQ ID NO:13的氨基酸序列组成的重链(HC)和两个相同的由SEQ IDNO:14的氨基酸序列组成的轻链(LC)组成;这种特定的抗体在本文中也被称为“mAb1”。
在一些实施方案中,本发明的抗体结合至人和食蟹猴CEACAM5的A2-B2结构域。本发明还提供了一种与包含mAb1的重链和轻链可变区(即分别对应于SEQ ID NO:9和10的VH和VL)的抗体竞争与人和/或食蟹猴CEACAM5蛋白的A2-B2结构域的结合的抗体。
候选抗体与包含mAb1的VH和VL的抗体(下文中,在与候选抗体竞争的情况下,称为“参考”抗体)竞争与人和/或食蟹猴CEACAM5蛋白的A2-B2结构域的结合的能力可以例如通过竞争性ELISA容易地测定,在竞争性ELISA中,将抗原(即人或食蟹猴CEACAM5的A2-B2结构域,或包含包括A2-B2结构域,特别是人或食蟹猴CEACAM5的胞外结构域的人或食蟹猴CEACAM5的片段或由所述片段组成的多肽)结合到固体支持物上,并且分别加入含有候选抗体和参考抗体的两种溶液,并允许抗体竞争与抗原的结合。随后可以测量结合到抗原的参考抗体的量,并与针对阴性对照(例如不含抗体的溶液)进行测量时结合到抗原的参考抗体的量进行比较。与在阴性对照存在的情况下结合的参考抗体的量相比,在候选抗体存在的情况下结合的参考抗体的量减少,表明候选抗体与参考抗体竞争。方便地,可以标记(例如荧光标记)参考抗体以促进检测结合的参考抗体。可以用候选抗体和/或参考抗体的系列稀释物进行重复测量。
在一些实施方案中,本发明的抗体不结合至人CEACAM1、人CEACAM6、人CEACAM7、人CEACAM8和食蟹猴CEACAM6蛋白或不与它们显著地交叉反应。在一些实施方案中,抗体不结合至除CEACAM5以外的前述人和食蟹猴CEACAM蛋白的胞外结构域或不与其显著地交叉反应。
“亲和力”在理论上定义为整个抗体和抗原之间的平衡缔合。其可以通过多种已知方法进行实验评估,诸如用表面等离子体共振测量缔合和解离速率,或在免疫化学测定(ELISA、FACS)中测量EC50(或表观KD)。在这些测定中,EC50是通过ELISA(酶联免疫吸附测定)在限定浓度的抗原上或通过FACS(荧光激活细胞分选)在表达该抗原的细胞上,在一定的特定暴露时间后诱导基线与最大值之间一半的应答的抗体浓度。
当对两种抗原的EC50在相似范围内时,结合至抗原1(Ag1)的单克隆抗体与抗原2(Ag2)是“交叉反应的”。在本申请中,当结合Ag1的单克隆抗体对Ag2的亲和力与其对Ag1的亲和力相差在10倍或更少以内(例如5倍以内)时,其与Ag2是交叉反应的,用相同的方法测量对于两种抗原的亲和力。
当对两种抗原的亲和力非常不同时,结合至Ag1的单克隆抗体与Ag2是“不显著交叉反应的”。如果结合应答过低,对Ag2的亲和力可能无法测得。在本申请中,在相同的实验设置中和在相同的抗体浓度下,当单克隆抗体对Ag2的结合应答小于相同单克隆抗体对Ag1的结合应答的5%时,结合至Ag1的单克隆抗体与Ag2是不显著交叉反应的。实际上,所用抗体浓度可以是EC50或达到用Ag1获得的饱和平台所需的浓度。当单克隆抗体与Ag2不显著地交叉反应时,该单克隆抗体“特异性结合至”Ag1(或对Ag1“是特异性的”)。
在一些实施方案中,根据本发明的抗体对食蟹猴CEACAM5具有与其对人CEACAM5的亲和力相差在10倍或更少以内(例如在5倍以内)的亲和力。由此,根据本发明的抗体可用于在猴中进行的毒理学研究,因为在猴中观察到的毒性概况将与预期在人中的潜在不利作用相关。
在一些实施方案中,本发明的抗体具有对人CEACAM5或食蟹猴CEACAM5或二者的亲和力,其为≤10nM;例如,本发明的抗体可以具有对人CEACAM5的亲和力,其为1至10nM,诸如对人CEACAM5的亲和力为大约6nM。
对人CEACAM5或对食蟹猴CEACAM5的亲和力可以例如作为使用可溶性重组CEACAM5作为捕获抗原的ELISA中的EC50值来确定。
备选地,对本发明的抗体而言,可以通过FACS分析,例如在肿瘤细胞系MKN45(DSMZ,ACC 409)上确定表观解离常数(表观KD)。
此外,根据本发明的抗体已显示能够通过免疫组织化学,例如在冷冻和福尔马林固定和石蜡包埋(FFPE)的组织切片中检测CEACAM5表达。
上文和下文中描述的实施方案的任意组合构成本发明的部分。
在一些实施方案中,根据本发明的抗体是常规抗体,诸如常规单克隆抗体,或抗体片段,双特异性或多特异性抗体。
在一些实施方案中,根据本发明的抗体包含IgG或其片段,或由IgG或其片段组成。
在一些实施方案中,本发明的抗体可以是例如鼠抗体、嵌合抗体、人源化抗体或人抗体。用于抗体序列的人源化的许多方法是本领域已知的;参见例如Almagro&Fransson(2008)Front Biosci.13:1619-1633的综述。一种常用的方法是CDR移植或抗体重构(reshaping),其涉及将供体抗体(通常是小鼠抗体)的CDR序列移植到不同特异性的人抗体的框架骨架(framework scaffold)中。由于CDR移植可降低CDR移植的非人抗体的结合特异性和亲和力,并由此降低其生物活性,因此可以在CDR移植抗体的选定位置处引入回复突变,以保持亲本抗体的结合特异性和亲和力。可以使用文献和抗体数据库中可得的信息进行可能的回复突变的位置的鉴定。作为回复突变的候选物的氨基酸残基通常是位于抗体分子表面的那些,而被埋藏或具有低表面暴露程度的残基通常不会被改变。CDR移植和回复突变的替代人源化技术是表面重塑(resurfacing),其中保留非人来源的非表面暴露残基,而表面残基被改变为人残基。另一种替代技术称为“定向选择(guided selection)”(Jespers等人(1994)Biotechnology 12,899),且其可用于从鼠抗体得到保留亲本抗体的表位和结合特性的完全人抗体。
对于嵌合抗体,人源化通常涉及可变区序列的框架区的修饰。
作为CDR的一部分的氨基酸残基通常不会因人源化而改变,尽管在某些情况下改变单独的CDR氨基酸残基(例如除去糖基化位点、脱酰胺位点或不期望的半胱氨酸残基)可以是合意的。通过将寡糖链连接到三肽序列Asn-X-Ser或Asn-X-Thr中的天冬酰胺残基上来发生N-连接的糖基化,其中X可以是除Pro外的任何氨基酸。N-糖基化位点的去除可以通过使Asn或Ser/Thr残基突变为不同的残基(例如通过保守取代)来实现。天冬酰胺和谷氨酰胺残基的脱酰胺可取决于诸如pH和表面暴露的因素而发生。天冬酰胺残基特别容易脱酰胺,主要是当存在于Asn-Gly序列中时,而在其他二肽序列(诸如Asn-Ala)中的脱酰胺程度较低。当在CDR序列中存在此类脱酰胺位点(例如Asn-Gly)时,可因此合意的是除去该位点,通常通过保守取代以除去所涉及的残基中的一个。本发明也意在包括在CDR序列中进行取代以除去所涉及的残基中的一个。
在人源化抗体或其片段中,重链和轻链的可变结构域可包含人接受者构架区。如果存在的话,人源化抗体可进一步包含人恒定重链和轻链结构域。
在一些实施方案中,根据本发明的抗体可以是选自选自Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2和双抗体的抗体片段(例如人源化抗体片段)。
在一些实施方案中,根据本发明的抗体可以是由抗体片段形成的双特异性或多特异性抗体,至少一个抗体片段是根据本发明的抗体的片段。如描述在例如EP 2 050 764 A1或US 2005/0003403 A1中的,多特异性抗体是多价蛋白复合物。
根据本发明的双特异性或多特异性抗体可以对(a)人和食蟹猴CEACAM5蛋白和(b)至少一种其他抗原具有特异性。在一些实施方案中,至少一种其他抗原不是人或食蟹猴CEACAM家族成员。在另一些实施方案中,至少一种其他抗原可以是人或食蟹猴CEACAM5上除mAb1靶向的表位之外的表位。
本发明的抗体可以通过本领域已知的任何技术来产生。根据本发明的抗体可以例如以分离的(例如纯化的)形式使用或包含在载体中,所述载体诸如膜或脂囊泡(例如脂质体)。
本发明的核酸和宿主细胞
本发明的另一方面涉及一种分离的核酸,其包含编码如上定义的本发明的抗体的核酸序列或由所述核酸序列组成。
通常,所述核酸是DNA或RNA分子,其可以包含在任何合适的载体中,所述载体诸如质粒、粘粒、游离体、人工染色体、噬菌体或病毒载体。
术语“载体”、“克隆载体”和“表达载体”是指载体,通过该载体可以将DNA或RNA序列(例如外来基因)引入到宿主细胞中,以便转化宿主并促进所引入序列的表达(例如转录和翻译)。
因此,本发明的另一方面涉及包含如上定义的本发明的核酸的载体。
此类载体可包含调控元件,诸如启动子、增强子、终止子等,以便在施用于受试者后引起或指导所述多肽的表达。在用于动物细胞的表达载体中使用的启动子和增强子的实例包括SV40的早期启动子和增强子(Mizukami T等人,1987)、莫洛尼氏小鼠白血病病毒的LTR启动子和增强子(Kuwana Y等人,1987)、免疫球蛋白H链的启动子(Mason JO等人,1985)和增强子(Gillies SD等人,1983)等。
可以使用任何用于动物细胞的表达载体,只要可以插入编码人抗体C区的基因并表达。合适的载体的实例包括pAGE107(Miyaji H等人,1990)、pAGE103(Mizukami T等人,1987)、pHSG274(Brady G等人,1984)、pKCR(O'Hare K等人,1981)、pSG1βd2-4-(Miyaji H等人,1990)等。
质粒的其他实例包括包含复制起点的复制质粒,或整合质粒,诸如pUC、pcDNA、pBR等。
病毒载体的其他实例包括腺病毒、逆转录病毒、疱疹病毒和AAV载体。此类重组病毒可通过本领域已知的技术(诸如通过转染包装细胞或通过用辅助质粒或病毒瞬时转染)来产生。病毒包装细胞的典型实例包括PA317细胞、PsiCRIP细胞、GPenv+细胞、293细胞等。用于产生此类复制缺陷型重组病毒的详细方案可见于例如WO 95/14785、WO 96/22378、US5,882,877、US 6,013,516、US 4,861,719、US 5,278,056和WO 94/19478。
本发明的另一对象涉及已经用根据本发明的核酸和/或载体转染、感染或转化的宿主细胞。
术语“转化”是指将“外来”(即外部的)基因、DNA或RNA序列引入宿主细胞,使得宿主细胞将表达引入的基因或序列,以产生所需物质,其通常是由引入的基因或序列编码的蛋白或酶。接受并表达引入的DNA或RNA的宿主细胞被“转化”。
本发明的核酸可用于在合适的表达系统中产生本发明的抗体。术语“表达系统”是指在合适的条件下(例如适于由载体携带并引入宿主细胞的外来DNA编码的蛋白的表达)的宿主细胞和相容载体。
常见的表达系统包括大肠杆菌(E.coli)宿主细胞和质粒载体、昆虫宿主细胞和杆状病毒(Baculovirus)载体,以及哺乳动物宿主细胞和载体。宿主细胞的其他实例包括但不限于原核细胞(诸如细菌)和真核细胞(诸如酵母细胞、哺乳动物细胞、昆虫细胞、植物细胞等)。具体实例包括大肠杆菌、克鲁维酵母属(Saccharomyces)或酿酒酵母属(Saccharomyces)酵母、哺乳动物细胞系(例如Vero细胞、CHO细胞、3T3细胞、COS细胞等)以及原代或已建立的哺乳动物细胞培养物(例如由成淋巴细胞、成纤维细胞、胚胎细胞、上皮细胞、神经细胞、脂肪细胞等产生的)。实例还包括小鼠SP2/0-Ag14细胞(ATCC CRL1581)、小鼠P3X63-Ag8.653细胞(ATCC CRL1580)、其中二氢叶酸还原酶基因(下文称为“DHFR基因”)为缺陷型的CHO细胞(Urlaub G等人;1980)、大鼠YB2/3HL.P2.G11.16Ag.20细胞(ATCCCRL1662,下文称为“YB2/0细胞”)等。在一些实施方案中,使用YB2/0细胞,因为当在该细胞中表达时,嵌合或人源化抗体的ADCC活性增强。
为了表达人源化抗体,表达载体可以是其中编码抗体重链的基因和编码抗体轻链的基因存在于分开的载体上的类型,或者其中两种基因存在于相同载体上的类型(串联型)。就构建人源化抗体表达载体的容易性、引入动物细胞中的容易性和动物细胞中抗体H和L链的表达水平之间的平衡而言,人源化抗体表达载体是串联型的(Shitara K等人,JImmunol Methods.1994Jan.3;167(1-2):271-8)。串联型人源化抗体表达载体的实例包括pKANTEX93(WO 97/10354)、pEE18等。
本发明还涉及产生表达根据本发明的抗体的重组宿主细胞的方法,所述方法包括由以下组成的步骤:(i)将如上所述的重组核酸或载体体外或离体引入到感受态宿主细胞中,(ii)体外或离体培养获得的重组宿主细胞,和(iii)任选地,选择表达和/或分泌所述抗体的细胞。
此类重组宿主细胞可用于产生本发明的抗体。
产生本发明的抗体的方法
本发明的抗体可以通过本领域已知的任何技术产生,所述技术诸如但不限于任何单独或组合的化学、生物学、遗传学或酶技术。
已知所需抗体的氨基酸序列,本领域技术人员可以使用用于生产多肽的标准技术容易地生产所述抗体或免疫球蛋白链。例如,它们可以使用公知的固相方法,使用商业可获得的肽合成装置(诸如由A Applied Biosystems,Foster City,California制造的装置)并按照制造商的说明书来合成。备选地,如本领域公知的那样,本发明的抗体和免疫球蛋白链可通过重组DNA技术产生。例如,在将编码所需多肽的DNA序列合并到表达载体中并将此类载体引入到将表达所需多肽的合适的真核或原核宿主(随后可以使用公知的技术从宿主中分离所述多肽)后,可以获得作为DNA表达产物的这些多肽(例如抗体)。
例如,本发明提供了编码抗体mAb1的以下DNA序列:
mAb1重链核苷酸序列
其中mVk信号肽为下划线,
起始和终止密码子为斜体,
VH区序列为粗体字,且
CDR用双下划线表示:
mAb1轻链核苷酸序列
其中uPA信号肽为下划线,
起始和终止密码子为斜体,
VL区序列为粗体字,且
CDR用双下划线表示:
本发明进一步涉及产生本发明的抗体的方法,该方法包括由以下组成的步骤:(i)培养根据本发明的转化的宿主细胞;(ii)表达抗体;和(iii)回收表达的抗体。
本发明的抗体可以通过常规免疫球蛋白纯化方法(诸如蛋白A-琼脂糖、羟基磷灰石层析、凝胶电泳、透析或亲和层析)从培养基中适当地分离。
在一些实施方案中,本发明的人源化嵌合抗体可以通过以下方法产生:如前所述获得编码人源化VL和VH区的核酸序列,通过将它们插入到具有编码人抗体CH和人抗体CL的基因的用于动物细胞的表达载体中来构建人嵌合抗体表达载体,并通过将表达载体引入到动物细胞中来表达编码序列。
作为人嵌合抗体的CH结构域,可以使用属于人免疫球蛋白重链的任何区域,例如IgG类的那些是合适的,并且可以使用属于IgG类的任一亚类,诸如IgG1、IgG2、IgG3和IgG4。同样,作为人嵌合抗体的CL,可以使用属于人免疫球蛋白轻链的任何区域,并且可以使用κ类或λ类的那些。
产生人源化或嵌合抗体的方法可涉及本领域公知的常规重组DNA和基因转染技术(参见例如Morrison SL等人,(1984)和专利文献US5,202,238;和US5,204,244)。
基于常规重组DNA和基因转染技术产生人源化抗体的方法是本领域中公知的(参见例如Riechmann L等人,1988;Neuberger MS等人,1985)。可以使用本领域中已知的多种技术将抗体人源化,所述技术包括例如申请WO2009/032661中公开的技术、CDR移植(EP239,400;PCT公开WO91/09967;美国专利号5,225,539;5,530,101;和5,585,089)、镶饰(veneering)或表面重塑(EP 592,106;EP 519,596;Padlan EA(1991);Studnicka GM等人(1994);Roguska MA等人(1994))和链替换(chain shuffling)(美国专利号5,565,332)。制备此类抗体的一般重组DNA技术也是已知的(参见欧洲专利申请EP 125023和国际专利申请WO 96/02576)。
本发明的Fab可通过用蛋白酶(诸如木瓜蛋白酶)处理本发明的抗体(例如IgG)来获得。此外,Fab可以通过将编码抗体Fab的两条链的DNA序列插入到用于原核表达或用于真核表达的载体中,并将该载体引入到原核或真核细胞中(视情况而定)以表达Fab来产生。
本发明的F(ab')2可通过用蛋白酶胃蛋白酶处理本发明的抗体(例如IgG)来获得。此外,F(ab')2可以通过经由硫醚键或二硫键结合下述Fab'来产生。
本发明的Fab'可通过用还原剂(诸如二硫苏糖醇)处理本发明的F(ab')2来获得。此外,Fab'可通过将编码抗体Fab'链的DNA序列插入到用于原核表达的载体或用于真核表达的载体中,并将该载体引入到原核或真核细胞中(视情况而定)以进行其表达来产生。
本发明的scFv可通过以下方法来产生:取用于本发明抗体的如前所述的CDR或VH和VL结构域的序列,随后构建编码scFv片段的DNA,将该DNA插入到原核或真核表达载体中,并随后将该表达载体引入到原核或真核细胞中(视情况而定)以表达scFv。为了产生人源化scFv片段,可以使用称为CDR移植的公知技术,其涉及选择根据本发明的互补决定区(CDR),并将它们移植到具有已知三维结构的人scFv片段框架上(参见例如W098/45322;WO 87/02671;US5,859,205;US5,585,089;US4,816,567;EP0173494)。
本发明的抗体的修饰
设想了本文中描述的抗体的一种或多种氨基酸序列修饰。例如,改善抗体的结合亲和力和/或其他生物学性质可以是合意的。
可以在本发明的抗体的结构和编码它们的DNA序列中进行修饰和改变,并仍然产生具有所需特性的功能抗体或多肽。
在多肽的氨基序列中进行改变时,可以考虑氨基酸的亲水指数。亲水氨基酸指数对于蛋白的相互作用生物功能的重要性是本领域中通常理解的。公认的是,氨基酸的相对亲水特征有助于所得蛋白的二级结构,二级结构又限定了蛋白与其他分子(例如酶、底物、受体、DNA、抗体、抗原等)的相互作用。基于其疏水性和电荷特性,给每个氨基酸分配了亲水指数,这些是:异亮氨酸(+4.5);缬氨酸(+4.2);亮氨酸(+3.8);苯丙氨酸(+2.8);半胱氨酸(+2.5);蛋氨酸(+1.9);丙氨酸(+1.8);甘氨酸(-0.4);苏氨酸(-0.7);丝氨酸(-0.8);色氨酸(-0.9);酪氨酸(-1.3);脯氨酸(-1.6);组氨酸(-3.2);谷氨酸(-3.5);谷氨酰胺(-3.5);天冬氨酸(-3.5);天冬酰胺(-3.5);赖氨酸(-3.9);和精氨酸(-4.5)。
本发明的另一方面还包括本发明的多肽的功能保守性变体。
例如,在蛋白结构中某些氨基酸可以被其他氨基酸取代而不会明显损失活性。由于蛋白的相互作用能力和性质限定了其生物功能活性,因此可以在蛋白序列中进行某些氨基酸取代,且当然也可以在其编码DNA序列中进行某些氨基酸取代,同时仍然获得具有类似性质的蛋白。由此可以设想的是,可以在本发明的抗体序列中或编码所述多肽的相应DNA序列中进行各种改变,而不会明显损失它们的生物学活性。
本领域已知的是,某些氨基酸可以被具有类似亲水指数或评分的其他氨基酸取代,并仍产生具有类似生物活性的蛋白,即仍获得生物功能等同的蛋白。还可以使用已知的技术,诸如丙氨酸扫描方法,来鉴定本发明的抗体或多肽中所有可以被取代而不显著损失与抗原的结合的氨基酸。此类残基可以被认定为是中立(neutral)的,因为它们不参与抗原结合或维持抗体的结构。这些中立位置中的一个或多个可以被丙氨酸或被另一氨基酸取代,而不会改变本发明的抗体或多肽的主要特性。
中立位置可以看作是可以并入任何氨基酸取代的位置。实际上,在丙氨酸扫描的原理中,选择丙氨酸,因为这种残基不携带特定的结构或化学特征。通常认为如果丙氨酸可以在不改变蛋白的性质的情况下取代特定的氨基酸,则许多其他(如果不是全部)氨基酸取代也可能是中立的。在丙氨酸是野生型氨基酸的相反情况下,如果特定的取代可以被证明为中立的,则其他取代也可能是中立的。
如上所述,氨基酸取代通常基于氨基酸侧链取代基的相对相似性,例如它们的疏水性、亲水性、电荷、大小等。考虑任何前述特性的示例性取代是本领域技术人员公知的并包括:精氨酸和赖氨酸;谷氨酸和天冬氨酸;丝氨酸和苏氨酸;谷氨酰胺和天冬酰胺;以及缬氨酸、亮氨酸和异亮氨酸。
在效应子功能方面修饰本发明的抗体也可以是合意的,例如以便增强抗体的抗原依赖性细胞介导的细胞毒性(ADCC)和/或补体依赖性细胞毒性(CDC),或例如改变与Fc受体的结合。这可以通过在抗体的Fc区中引入一个或多个氨基酸取代来实现。备选地或此外,可在Fc区中引入一个或多个半胱氨酸残基,由此允许在该区域中形成链间二硫键。由此生成的同二聚体抗体可具有改善的内化能力和/或提高的补体介导的细胞杀伤和/或抗体依赖性细胞毒性(ADCC)(Caron PC等人,1992;和Shopes B.1992)。在一些实施方案中,本发明的抗体可以是具有修饰的氨基酸序列的抗体,所述修饰的氨基酸序列导致减少或消除了与大多数Fcγ受体的结合,这可以减少在表达此类受体的正常细胞和组织(例如巨噬细胞、肝窦细胞等)中的摄取和毒性。此类抗体的一个实例是包括在位置234和235处将两个亮氨酸(L)残基取代为丙氨酸(A)的抗体(即LALA);这种双重取代已证明能减少Fc与FcγR的结合,并因此降低ADCC以及减少补体结合/激活。此类抗体的另一实例是除LALA双重取代外还包括取代P329G的抗体(即PG-LALA;参见例如Schlothauer等人,Novel human IgG1 and IgG4Fc-engineered antibodies with completely abolished immune effector functions,Protein Engineering,Design and Selection,第29卷,第10期,2016年10月,第457–466页)。在一些实施方案中,本发明的抗体由此可以是具有以下氨基酸序列的抗体:(i)含有例如LALA或PG-LALA取代组,和(ii)在其他方面与上文参考相应SEQ ID NO描述的本发明的抗体之一的氨基酸序列相同。
本发明的抗体的另一种类型的氨基酸修饰可用于改变抗体的原始糖基化模式,即通过缺失抗体中发现的一个或多个碳水化合物部分,和/或添加抗体中不存在的一个或多个糖基化位点。三肽序列天冬酰胺-X-丝氨酸和天冬酰胺-X-苏氨酸(其中X是除脯氨酸外的任何氨基酸)中的任一种的存在产生了潜在的糖基化位点。通过改变氨基酸序列,使其含有一个或多个上述三肽序列(对于N-连接的糖基化位点),可以方便地实现向抗体添加或缺失糖基化位点。
另一种类型的修饰涉及除去在计算机上或经实验鉴定为可能导致抗体制剂的降解产物或异质性的序列。作为实例,天冬酰胺和谷氨酰胺残基的脱酰胺可取决于诸如pH和表面暴露的因素而发生。天冬酰胺残基特别容易脱酰胺,主要是当存在于Asn-Gly序列中时,而在其他二肽序列(诸如Asn-Ala)中的脱酰胺程度较低。当抗体或多肽中存在此类脱酰胺位点,特别是Asn-Gly时,可以因此考虑除去该位点,通常通过保守取代以除去所涉及的残基中的一个。在序列中除去一个或多个所涉及的残基的此类取代也意在被本发明涵盖。
另一类型的共价修饰涉及将糖苷化学或酶促偶联到抗体上。这些方法的优点在于它们不需要在具有N-或O-连接糖基化的糖基化能力的宿主细胞中产生抗体。取决于所用的偶联模式,一个或多个糖可以连接至(a)精氨酸和组氨酸,(b)游离羧基基团,(c)游离巯基基团,诸如半胱氨酸的那些,(d)游离羟基基团,诸如丝氨酸、苏氨酸或羟基脯氨酸的那些,(e)芳族残基,诸如苯丙氨酸、酪氨酸或色氨酸的那些,或(f)谷氨酰胺的酰胺基团。例如,在WO87/05330中描述了此类方法。
可以化学或酶促地实现抗体上存在的碳水化合物部分的去除。化学去糖基化需要将抗体暴露于化合物三氟甲磺酸或等效化合物。这种处理导致除连接糖(N-乙酰葡糖胺或N-乙酰半乳糖胺)外的大多数或全部糖的切割,而保留抗体完整。Sojahr H等人(1987)和Edge,AS等人(1981)描述了化学去糖基化。抗体上碳水化合物部分的酶促切割可以如Thotakura,NR.等人(1987)所述那样通过使用多种内切和外切糖苷酶来实现。
抗体的另一类型的共价修饰包括例如以美国专利号4,640,835;4,496,689;4,301,144;4,670,417;4,791,192或4,179,337中阐述的方式,将抗体连接到多种非蛋白聚合物中的一种上,所述非蛋白聚合物例如聚乙二醇、聚丙二醇或聚氧化烯。
本领域已知的其他氨基酸序列修饰也可应用于本发明的抗体。
本发明的免疫缀合物
本发明提供免疫缀合物,在本文中也称为抗体-药物缀合物,或更简洁地称为缀合物。如本文中所用,所有这些术语具有相同的含义,并且是可互换的。用于制备免疫缀合物的合适方法是本领域中已知的。本发明的免疫缀合物可通过体外方法(例如如本文中所述)来制备。
本发明提供了一种免疫缀合物,其包含经由接头共价连接至至少一种生长抑制剂的本发明的抗体(诸如mAb1,或具有与mAb1相同的六个CDR的抗体)。
术语“生长抑制剂”(也称为“抗增殖剂”)是指在体外和/或体内抑制细胞(诸如肿瘤细胞)生长的分子或化合物或组合物。
在一些实施方案中,生长抑制剂是细胞毒性药物(也称为细胞毒性剂)。在一些实施方案中,生长抑制剂是放射性部分。
本文中所用的术语“细胞毒性药物”是指直接或间接抑制或阻碍细胞的功能和/或引起细胞破坏的物质。术语“细胞毒性药物”包括例如化疗剂、酶、抗生素、毒素,诸如小分子毒素或酶活性毒素、类毒素、长春花类(vincas)、紫杉烷类(taxanes)、美登素类(maytansinoids)或美登素类似物、托马霉素(tomaymycin)或吡咯并苯并二氮杂衍生物、念珠藻素(cryptophycin)衍生物、来普霉素(leptomycin)衍生物、澳瑞他汀(auristatin)或海兔毒素(dolastatin)类似物、前药、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、DNA烷化剂、抗微管蛋白剂、CC-1065和CC-1065类似物。
拓扑异构酶I抑制剂是抑制人酶拓扑异构酶I的分子或化合物,所述拓扑异构酶I通过催化DNA单链的瞬时断裂和重接(rejoining)而参与改变DNA的拓扑结构。拓扑异构酶I抑制剂对例如哺乳动物的分裂细胞具有高度毒性。合适的拓扑异构酶I抑制剂的实例包括喜树碱(CPT)及其类似物,诸如托泊替康(topotecan)、伊立替康(irinotecan)、silatecan、cositecan、依沙替康(exatecan)、勒托替康(lurtotecan)、吉马替康(gimatecan)、贝洛替康(belotecan)和卢比替康(rubitecan)。
在一些实施方案中,本发明的免疫缀合物包含细胞毒性药物依沙替康作为生长抑制剂。依沙替康具有化学名称(1S,9S)-1-氨基-9-乙基-5-氟-1,2,3,9,12,15-六氢-9-羟基-4-甲基-10H,13H-苯并(de)吡喃并(3',4':6,7)吲哚嗪并(1,2-b)喹啉-10,13-二酮。依沙替康由以下结构式(I)来表示:
在本发明的另一些实施方案中,可以使用其他CPT类似物和其他细胞毒性药物,例如如上文所列举的。在通过引用并入的申请WO2008/010101中进一步给出了一些细胞毒性药物和缀合方法的实例。
术语“放射性部分”是指包含适于治疗癌症的放射性同位素或由其组成的化学实体(诸如分子、化合物或组合物),所述放射性同位素诸如At211、Bi212、Er169、I131、I125、Y90、In111、P32、Re186、Re188、Sm153、Sr89或Lu的放射性同位素。此类放射性同位素通常主要发射β-辐射。在一些实施方案中,放射性同位素是发射α放射性同位素,例如发射α辐射的钍227。免疫缀合物可以例如如申请WO2004/091668中所述来制备。
在本发明的免疫缀合物中,本发明的抗体经由接头共价连接至至少一种生长抑制剂。本文中使用的“接头”是指包含将生长抑制剂共价连接到抗体上的共价键和/或任何原子链的化学部分。接头是本领域中公知的,并且其包括例如二硫基团(disulfide group)、硫醚基团、酸不稳定基团、光不稳定基团、肽酶不稳定基团和酯酶不稳定基团。本发明的抗体与细胞毒性药物或其他生长抑制剂的缀合可以例如使用多种双功能蛋白偶联剂进行,所述偶联剂包括但不限于吡啶基二硫代丁酸-N-琥珀酰亚胺酯(SPDB)、丁酸-4-[(5-硝基-2-吡啶基)二硫代]-2,5-二氧代-1-吡咯烷基酯(硝基-SPDB)、4-(吡啶-2-基二硫烷基)-2-磺基-丁酸(磺基-SPDB)、(2-吡啶基二硫代)丙酸-N-琥珀酰亚胺酯(SPDP)、(N-马来酰亚胺甲基)环己烷-1-甲酸琥珀酰亚胺酯(SMCC)、亚氨基硫杂环戊烷(IT)、酰亚胺酯的双官能衍生物(诸如己二酰亚胺酸二甲酯HCl)、活性酯(诸如辛二酸二琥珀酰亚胺酯)、醛类(诸如戊二醛)、双-叠氮化合物(诸如双(对叠氮基苯甲酰基)-己二胺)、双-重氮衍生物(如双-(对重氮苯甲酰基)-乙二胺)、二异氰酸酯(诸如甲苯-2,6-二异氰酸酯)和双活性氟化合物(诸如1,5-二氟-2,4-二硝基苯)。例如,可以如Vitetta等人(1987)中所述制备蓖麻毒素免疫毒素。碳标记的1-异硫代氰基苄基甲基二亚乙基三胺五乙酸(MX-DTPA)是用于将放射性核苷酸与抗体缀合的示例性螯合剂(WO 94/11026)。
在本发明的实施方案中,接头可以是“可裂解接头”,其可以促进细胞毒性药物或其他生长抑制剂在细胞(例如肿瘤细胞)内部或附近的释放。在一些实施方案中,接头是可在哺乳动物细胞的核内体中裂解的接头。例如,可以使用酸不稳定接头、肽酶敏感接头、酯酶不稳定接头、光不稳定接头或含二硫键的接头(disulfide-containing linker)(参见例如美国专利号5,208,020)。
当提及代表免疫缀合物的结构式时,本文还使用以下命名法:生长抑制剂和接头一起也被称为[(接头)-(生长抑制剂)]部分;例如,依沙替康分子和接头一起也被称为[(接头)-(依沙替康)]部分。
在本发明的一些特定实施方案中,接头是可由人酶葡萄糖醛酸酶裂解的接头。例如,本发明的免疫缀合物可由此具有下式(II),其包括可由葡萄糖醛酸酶裂解的接头:
其中抗体是本发明的抗体,其中S是抗体的硫原子,并且其中n是共价连接至抗体的[(接头)-(生长抑制剂)]部分的数量。数量n可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,S是抗体的半胱氨酸的硫原子。在一些实施方案中,抗体是mAb1。
数量n也被称为“药物与抗体比”(或“DAR”);该数量n始终应理解为任何给定免疫缀合物(的制剂)的平均数量。
在本发明的另一些特别实施方案中,接头是可由人酶天冬酰胺内肽酶(legumain)裂解的接头。例如,本发明的免疫缀合物可由此具有下式(III),其包括可由天冬酰胺内肽酶裂解的接头:
其中抗体是本发明的抗体,其中S是抗体的硫原子,并且其中n是共价连接至该抗体的[(接头)-(生长抑制剂)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,S是抗体的半胱氨酸的硫原子。在一些实施方案中,抗体是mAb1。
在上式(II)和(III)的每一个中,抗体的硫原子和生长抑制剂之间的化学结构是接头。这些接头之一也包含在下文进一步描绘的式(IV)至(IX)的每一个中。
在具有可由葡萄糖醛酸酶或天冬酰胺内肽酶裂解的接头的实施方案的任一个中,如上所述,生长抑制剂可以是例如依沙替康。
因此,在一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的根据本发明的抗体的免疫缀合物,其中缀合物具有下式(IV):
其中S是抗体的硫原子,并且其中n是共价连接至抗体的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,抗体是mAb1。
在另一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的根据本发明的抗体的免疫缀合物,其中缀合物具有下式(V):
其中S是抗体的硫原子,并且其中n是共价连接至抗体的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,抗体是mAb1。
在一些实施方案中,在本发明的免疫缀合物(例如如上所述的具有葡萄糖醛酸酶或天冬酰胺内肽酶可裂解接头的依沙替康缀合物)中,接头在抗体的半胱氨酸残基的硫原子处共价连接到抗体上。例如,抗体的半胱氨酸残基可以是能够形成链间二硫键(在本文中也称为链间二硫桥)的半胱氨酸残基之一。由于在IgG1抗体中存在四个链间二硫键,涉及总计八个半胱氨酸残基,在此类半胱氨酸残基的硫原子处将接头连接至抗体提供了可以高达8的DAR,并且在此类情况下,DAR通常为7至8,诸如7.5至8.0(即大约8),条件是抗体为IgG1或具有与IgG1相同数量的链间二硫键。
因此,在一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的根据本发明的抗体的免疫缀合物,其中缀合物具有下式(VI):
其中S是抗体的半胱氨酸的硫原子,并且其中n是共价连接至抗体的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。
在另一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的根据本发明的抗体的免疫缀合物,其中缀合物具有下式(VII):
其中S是抗体的半胱氨酸的硫原子,并且其中n是共价连接至抗体的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。
在任何上述免疫缀合物中,可以使用任何本发明的抗体(如上文和下文所描述的)。在一些实施方案中,本发明的免疫缀合物包含mAb1作为抗体。
因此,在一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的mAb1的免疫缀合物,其中缀合物具有下式(VIII):
其中S是抗体mAb1的半胱氨酸的硫原子,并且其中n是共价连接至mAb1的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,S是能够形成链间二硫桥的mAb1的半胱氨酸的硫原子,并且DAR为大约8。在实施例中进一步描述了此类免疫缀合物的一个实例(即“ADC1”)。
在另一些实施方案中,本发明提供了包含经由接头共价连接至依沙替康的mAb1的免疫缀合物,其中缀合物具有下式(IX):
其中S是抗体mAb1的半胱氨酸的硫原子,并且其中n是共价连接至mAb1的[(接头)-(依沙替康)]部分的数量。数量n(也称为DAR)可以为例如1至10;在更特别的实施方案中,n为7至8;在甚至更特别的实施方案中,n为7.5至8.0(即大约8)。在一些实施方案中,S是能够形成链间二硫桥的mAb1的半胱氨酸的硫原子,并且DAR为大约8。在实施例中进一步描述了此类免疫缀合物的一个实例(即“ADC2”)。
在本发明的另一些实施方案中,接头可以是“不可裂解接头”(例如SMCC接头)。生长抑制剂从抗体的释放可以在抗体的溶酶体降解时发生。
在本发明的另一些实施方案中,免疫缀合物可以是包含本发明抗体和细胞毒性或生长抑制多肽(作为生长抑制剂)的融合蛋白;此类融合蛋白可以通过重组技术或通过肽合成(即本领域中公知的方法)来制备。编码DNA的分子可包含编码缀合物的两个部分(分别为抗体和细胞毒性或生长抑制多肽)的相应区域,所述两个部分彼此相邻或被编码接头肽的区域分开。
本发明的抗体也可通过将抗体缀合到前药激活酶上来用于导向酶前药疗法(诸如抗体导向酶前药疗法),所述前药激活酶将前药(例如肽基化疗剂,参见WO81/01145)转换为活性细胞毒性药物(参见例如WO 88/07378和美国专利号4,975,278)。可用于ADEPT的免疫缀合物的酶组分可包括能够以将前药转换为其更具活性的细胞毒性形式的方式作用于前药的任何酶。在这种情况下有用的酶包括但不限于可用于将含磷酸酯的前药转换为游离药物的碱性磷酸酶;可用于将含硫酸酯的前药转换为游离药物的芳基硫酸酯酶;可用于将无毒的氟胞嘧啶转换为抗癌药物5-氟尿嘧啶的胞嘧啶脱氨酶;可用于将含肽的前药转换为游离药物的蛋白酶,诸如沙雷氏菌蛋白酶、嗜热菌蛋白酶、枯草杆菌蛋白酶、羧肽酶和组织蛋白酶(诸如组织蛋白酶B和L);可用于转换含有D-氨基酸取代基的前药的D-丙氨酰羧肽酶;可用于将糖基化前药转换为游离药物的碳水化合物裂解酶,诸如O-半乳糖苷酶和神经氨酸酶;可用于将用P-内酰胺衍生的药物转换为游离药物的P-内酰胺酶;和可用于将分别用苯氧乙酰基或苯乙酰基基团在其胺氮处衍生的药物转换为游离药物的青霉素酰胺酶,诸如青霉素V酰胺酶或青霉素G酰胺酶。酶可以通过本领域公知的技术(诸如使用上述接头)共价结合到本发明的抗体上。
用于制备本发明的免疫缀合物的合适方法是本领域中公知的(参见例如Hermanson G.T.,Bioconjugate Techniques,第三版,2013,Academic Press)。例如,经由共价连接到抗体的链间二硫桥的半胱氨酸残基上的接头将细胞毒性药物缀合到抗体上的方法是公知的。
通常,本发明的免疫缀合物可以例如通过包括以下步骤的方法来获得:
(i)制备包含接头和生长抑制剂(例如细胞毒性药物)的化合物,在本文中也称为“药物-接头化合物”;
(ii)使根据本发明的抗体的任选缓冲的水溶液与药物-接头化合物的溶液接触;
(iii)随后任选将(ii)中形成的缀合物与未反应的抗体和/或药物-接头化合物分离。
抗体的水溶液可以用缓冲剂缓冲,所述缓冲剂诸如组氨酸、磷酸钾、乙酸盐、柠檬酸盐或N-2-羟乙基哌嗪-N'-2-乙磺酸(Hepes缓冲液)。可以根据抗体的性质选择缓冲剂。药物-接头化合物可溶解在例如有机极性溶剂(诸如二甲亚砜(DMSO)或二甲基乙酰胺(DMA))中。
为了缀合到抗体的半胱氨酸残基上,在步骤(ii)之前对抗体进行还原(例如使用TCEP)。用于仅还原链间二硫键的合适还原条件是本领域中已知的。
用于缀合的反应温度通常为20至40℃。反应时间可以不等,并且通常为1至24小时。抗体和药物-接头化合物之间的反应可以通过带有折射计和/或UV检测器的体积排阻层析(SEC)来监测。如果缀合物产率过低,则可以延长反应时间。
本领域技术人员可以使用许多不同的层析方法来进行步骤(iii)的分离:缀合物可以例如通过SEC、吸附层析(诸如离子交换层析,IEC)、疏水相互作用层析(HIC)、亲和层析、混合载体层析(诸如羟基磷灰石层析)或高效液相层析(HPLC)(诸如反相HPLC)来纯化。也可以使用通过透析或过滤或渗滤的纯化。
在步骤(ii)和/或(iii)之后,可以对含有缀合物的溶液进行另外的(例如通过层析、超滤和/或渗滤的)纯化步骤(iv)。在其中在缀合之前进行还原的情况下,此类另外的(例如通过层析、超滤和/或渗滤的)纯化步骤也可以在还原反应之后用含有抗体的溶液来进行。
在此过程结束时,在水溶液中回收缀合物。药物与抗体比(DAR)是可以随所用抗体和药物-接头化合物的性质,以及用于缀合的实验条件(诸如(药物-接头化合物)/(抗体)的比、反应时间、溶剂和助溶剂(如果有的话)的性质)而改变的数值。由此,抗体与药物-接头化合物之间的接触可以产生包含因不同的药物与抗体比而彼此不同的几种缀合物的混合物。所确定的DAR由此是平均值。
使用具有四个链间二硫桥的抗体(例如mAb1或任何IgG1抗体)在链间二硫桥的半胱氨酸残基处进行缀合——这是本领域中公知的方法——提供了以下优点:通过选择允许缀合进行至完成(或至少接近完成)的反应条件,可以实现大约8的相对均一的DAR。
可用于确定DAR的示例性方法由以下组成:用分光光度法测量纯化缀合物的溶液在λD和280nm处的吸光度的比。280nm是通常用于测量蛋白浓度(诸如抗体浓度)的波长。选择波长λD以便允许将药物与抗体区分开,即如技术人员容易知晓的那样,λD是药物具有高吸光度的波长,并且λD离280nm足够远以避免药物和抗体的吸收峰的明显重叠。例如,对于依沙替康(或对于喜树碱或其他喜树碱类似物)λD可以选择为370nm,或对于美登素分子λD可以选择为252nm。
DAR计算的方法可以例如来源于Antony S.Dimitrov(编),LLC,2009,TherapeuticAntibodies and Protocols,第525卷,445,Springer Science:在体积排阻层析(SEC)分析的单体峰上(允许计算“DAR(SEC)”参数)或使用经典的分光光度计装置(允许计算“DAR(UV)”参数)测量缀合物在λD(AλD)和在280nm(A280)处的吸光度。吸光度可以表示如下:
AλD=(CD XεDλD)+(CA XεAλD)
A280=(CD XεD280)+(CA XεA280)
其中:
·CD和CA分别是药物和抗体在溶液中的浓度
·εDλD和εD280分别是药物在λD和280nm处的摩尔消光系数
·εAλD和εA280分别是抗体在λD和280nm处的摩尔消光系数。
解析这两个具有两个未知数的方程得到以下方程:
CD=[(εA280 X AλD)-(εAλD X A280)]/[(εDλD XεA280)-(εAλD XεD280)]
CA=[A280-(CD XεD280)]/εA280
随后由药物浓度与抗体浓度的比计算平均DAR:DAR=CD/CA。
用于制备本发明的免疫缀合物的示例性方法描述在实施例中。
药物-接头化合物
本发明还提供了包含接头和生长抑制剂(例如细胞毒性药物)的化合物,在本文中也称为“药物-接头化合物”。例如,本发明提供了下式(X)的化合物:
或其生理上可接受的盐;这种化合物在本文中也称为“药物-接头化合物1”、“化合物DL1”或“DL1”。
本发明还提供了下式(XI)的化合物:
或其生理上可接受的盐;这种化合物在本文中也称为“药物-接头化合物2”、“化合物DL2”或“DL2”。
这些药物-接头化合物可用于制备如上文和下文中描述的本发明的免疫缀合物。
本发明的药物-接头化合物(例如上文描绘的式(X)或(XI)的那些)可以通过化学合成制备,例如如下文的实施例中进一步描述的那样。
药物组合物
本发明的抗体或免疫缀合物可以与药学上可接受的载体、稀释剂和/或赋形剂以及任选与缓释基质组合以形成药物组合物,所述缓释基质包括但不限于可生物降解的聚合物、不可生物降解的聚合物、脂质或糖的类别。
由此,本发明的另一方面涉及包含本发明的抗体或免疫缀合物和药学上可接受的载体、稀释剂和/或赋形剂的药物组合物。
“药物的”或“药学上可接受的”是指在适当情况下当施用于哺乳动物(尤其是人)时不产生不利的、过敏的或其他不期望的反应的分子实体和组合物。药学上可接受的载体、稀释剂或赋形剂是指任何类型的无毒固体、半固体或液体填充剂、稀释剂、包封材料或制剂助剂。
本文中使用的“药学上可接受的载体”包括生理上相容的任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂等。合适的载体、稀释剂和/或赋形剂的实例包括但不限于以下的一种或多种:水、氨基酸、盐水、磷酸盐缓冲盐水、缓冲磷酸盐、乙酸盐、柠檬酸盐、琥珀酸盐;氨基酸和衍生物,诸如组氨酸、精氨酸、甘氨酸、脯氨酸、甘氨酰甘氨酸;无机盐,诸如NaCl或氯化钙;糖或多元醇,诸如右旋糖、甘油、乙醇、蔗糖、海藻糖、甘露醇;表面活性剂,诸如聚山梨醇酯80、聚山梨醇酯20、泊洛沙姆188;等等,以及其组合。在许多情况下,在药物组合物中包括等渗剂(诸如糖、多元醇或氯化钠)是有用的,并且制剂还可以含有抗氧化剂,诸如色胺和/或稳定剂,诸如吐温20。
药物组合物的形式、施用途径、剂量和方案自然取决于待治疗的状况、疾病的严重程度、患者的年龄、重量和性别等。
本发明的药物组合物可以配制用于局部、口服、肠胃外、鼻内、静脉内、肌内、皮下或眼内施用等。
在一个实施方案中,药物组合物含有对注射制剂而言药学上可接受的溶媒。这些可以是等渗的、无菌的、盐水溶液(磷酸二氢钠或磷酸氢二钠、氯化钠、氯化钾、氯化钙或氯化镁等等,或此类盐的混合物),或干燥的(尤其是冷冻干燥的)组合物,其在加入无菌水或生理盐水(视情况而定)后能够构成可注射溶液。
药物组合物可通过药物混合装置(drug combination device)来施用。
用于施用的剂量可以作为各种参数的函数,且例如作为所用的施用模式、相关病理学或备选的所需治疗持续时间的函数来进行调整。
为了制备药物组合物,可以将有效量的本发明的抗体或免疫缀合物溶解或分散在药学上可接受的载体或水性介质中。
适于注射用途的药物形式包括无菌水溶液或分散体;包括芝麻油、花生油或丙二醇水溶液的制剂;和用于临时制备无菌可注射溶液或分散体的无菌粉末;在所有此类情况下,形式必须是无菌的,并且可用适当的用于递送的装置或系统注射而不降解,并且其必须在制造和储存条件下稳定,并且必须防止微生物(诸如细菌和真菌)的污染作用。
作为游离碱或药学上可接受的盐的活性化合物的溶液可以在适当地混有表面活性剂的水中制备。分散体也可以在甘油、液体聚乙二醇及其混合物中和在油中制备。在通常的储存和使用条件下,这些制剂可含有防腐剂以防止微生物的生长。
本发明的抗体或免疫缀合物可以配制为中性或盐形式的药物组合物。药学上可接受的盐包括酸加成盐(与蛋白的游离氨基基团形成),其与无机酸(诸如盐酸或磷酸)或有机酸(诸如乙酸、草酸、酒石酸或扁桃酸)等形成。与游离羧基基团形成的盐也可以衍生自无机碱(诸如氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁),以及有机碱(诸如异丙胺、三甲胺、甘氨酸、组氨酸、普鲁卡因)等。
载体还可以是溶剂或分散介质,其含有例如水、乙醇、多元醇(例如甘油、丙二醇和液体聚乙二醇等)、其合适的混合物、以及植物油。例如,通过使用包衣(诸如卵磷脂)、在分散体的情况下通过保持所需的粒度、以及通过使用表面活性剂,可以保持适当的流动性。可以通过各种抗细菌剂和抗真菌剂(例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等)来防止微生物的作用。在一些情况下,包括等渗剂(例如糖或氯化钠)可以是合意的。通过在组合物中使用延迟吸收的试剂,例如单硬脂酸铝和明胶,可以实现可注射组合物的延长吸收。
通过将活性化合物以所需量在适当的溶剂中与上面所列的任何其他成分(视需要而定)混合,随后过滤灭菌来制备无菌可注射溶液。通常,通过将各种灭菌的活性成分混入无菌溶媒中来制备分散体,所述无菌溶媒含有基础分散基质和来自上文所列的那些的所需其他成分。在用于制备无菌可注射溶液的无菌粉末的情况下,制备方法包括真空干燥和冷冻干燥技术,其从先前无菌过滤的活性成分加任何另外的所需成分的溶液产生其粉末。
还设想了制备更浓缩或高度浓缩的用于直接注射的溶液,其中设想使用DMSO作为溶剂以产生极快的渗透,将高浓度的活性剂递送至小的肿瘤区域。
在配制时,可以以与剂量制剂相容的方式并以治疗有效的量施用溶液。制剂易于以多种剂型施用,诸如上述可注射溶液的类型,但也可使用药物释放胶囊等。
例如,对于以水溶液肠胃外施用,如果需要的话,溶液可以适当地缓冲,并且首先用足够的盐水或葡萄糖使液体稀释物等渗。这些水溶液尤其适于静脉内、肌内、皮下和腹膜内施用。在这方面,鉴于本公开,可以使用的无菌水性介质将是本领域技术人员已知的。例如,可以将一个剂量溶解在1毫升等渗NaCl溶液中,并添加到1000毫升皮下灌注液中或者在建议的输注部位处注射(参见例如“Remington's Pharmaceutical Sciences”,第15版,第1035-1038和1570-1580页)。取决于治疗的受试者的状况,剂量将必然发生一定变化。在任何情况下,负责施用的人员将确定用于个体受试者的适当剂量。
本发明的抗体或免疫缀合物可以在治疗混合物中配制成包含例如每剂大约0.01至100毫克左右。
除了配制用于肠胃外施用(诸如静脉内或肌内注射)的抗体或免疫缀合物外,其他药学上可接受的形式包括例如用于口服施用的片剂或其他固体、定时释放胶囊和目前使用的任何其他形式。
在一些实施方案中,考虑使用脂质体和/或纳米颗粒以便将多肽引入到宿主细胞中。脂质体和/或纳米颗粒的形成和使用是本领域技术人员已知的。
纳米胶囊通常可以以稳定和可重现的方式包裹(entrap)化合物。为了避免细胞内聚合物过载引起的副作用,通常使用能够在体内降解的聚合物来设计此类超细颗粒(尺寸为大约0.1μm)。考虑在本发明中使用满足这些要求的可生物降解的聚烷基-氰基丙烯酸酯纳米颗粒或可生物降解的聚乳酸或聚乳酸-羟基乙酸共聚物纳米颗粒,并且此类颗粒可以由本领域技术人员容易地制得。
脂质体可以由分散在水性介质中并自发形成多层同心双层囊泡(也称为多层囊泡(MLV))的磷脂形成。MLV通常具有25nm至4μm的直径。超声处理MLV导致形成直径范围为200至500A的小单层囊泡(SUV),其在核心中含有水溶液。脂质体的物理特性取决于pH、离子强度和二价阳离子的存在。
除了上述实例外,还考虑了其他药物形式,诸如纳米颗粒、微颗粒和微胶囊、植入物(例如脂质植入物)或自凝或自乳化体系。
治疗方法和用途
本发明人已经发现,本发明的抗体(例如mAb1)在结合后能够作为CEACAM5-抗体复合物的一部分内化。此外,他们已经显示,与细胞毒性药物(依沙替康)缀合的此类抗体在体外介导对肿瘤细胞的细胞毒性作用。本发明人还已经显示,在用单次注射,以10毫克/千克的剂量使用时,本发明的这些免疫缀合物在体内(例如在来源于患者的人结肠直肠癌的鼠异种移植模型中)诱导显著的抗肿瘤活性。事实上,本发明的免疫缀合物在一大组体外和体内模型中显示出广泛的活性。细胞毒性效力与靶标(CEACAM5)表达密切相关,并且在靶标阴性细胞中低得多。在不同癌症类型的几种细胞系来源的异种移植(CDX)模型和患者来源的异种移植(PDX)模型中,证实了非常好的抗肿瘤活性。在非人灵长类剂量范围探索研究中,免疫缀合物耐受良好,具有对于拓扑异构酶-I抑制剂化疗典型的副作用概况。临床前数据指示了用于随后临床测试的良好治疗窗口。本发明的抗体、免疫缀合物和药物组合物由此可用于治疗癌症。
因此,本发明提供了用作药物的本发明的抗体、免疫缀合物或药物组合物。例如,本发明提供了用于治疗癌症的本发明的抗体、免疫缀合物或药物组合物。本发明进一步提供了治疗癌症的方法,其包括向有需要的受试者施用本发明的抗体、免疫缀合物或药物组合物。
与相同组织来源的正常(即非肿瘤)细胞相比,待用本发明的抗体、免疫缀合物或药物组合物治疗的癌症优选是表达CEACAM5的癌症,更优选是过度表达CEACAM5的癌症。细胞的CEACAM5表达可以例如通过使用根据本发明的抗体(或商业可获得的抗CEACAM5抗体)(例如如在下文的“诊断用途”部分中所述),和例如通过免疫组织化学方法容易地测定。
在一些实施方案中,待用本发明的抗体、免疫缀合物或药物组合物治疗的癌症是结肠直肠癌、非小细胞肺癌、胰腺癌、胃癌、子宫颈癌、食管癌(例如食管腺癌)、胆管癌、乳腺癌、前列腺癌、卵巢癌、尿路上皮癌、膀胱癌,或胃、子宫、子宫内膜、甲状腺或皮肤的癌症。在一些特定实施方案中,待用本发明的抗体、免疫缀合物或药物组合物治疗的癌症是结肠直肠癌、胃癌、非小细胞肺癌、胰腺癌、食管癌或前列腺癌。
本发明的抗体或免疫缀合物可单独或与任何合适的生长抑制剂组合用于癌症疗法。
如上所述,本发明的抗体可以缀合(连接)至生长抑制剂。本发明的抗体由此可用于将所述生长抑制剂靶向至在其表面上表达或过度表达CEACAM5的癌细胞。
同样公知的是,治疗性单克隆抗体可导致携带由该抗体特异性识别的抗原的细胞的耗尽。此类耗尽可以通过至少三种机制介导:抗体介导的细胞毒性(ADCC)、补体依赖性裂解和通过由抗体靶向的抗原介导的信号直接抑制肿瘤生长。
“抗体依赖性细胞介导的细胞毒性”或“ADCC”是指细胞毒性的一种形式,其中与存在于某些细胞毒性细胞(例如自然杀伤(NK)细胞、嗜中性粒细胞和巨噬细胞)上的Fc受体(FcR)结合的抗体使这些细胞毒性效应细胞能够特异性结合至携带抗原的靶标细胞,并随后杀伤该靶标细胞。为了评估感兴趣分子的ADCC活性,可进行体外ADCC测定,诸如美国专利号5,500,362或5,821,337中描述的测定。
“补体依赖性细胞毒性”或“CDC”是指在补体的存在下裂解靶标细胞。经典补体途径的激活是通过使补体系统的第一组分与结合至其同源抗原的抗体的结合来引发的。为了评估补体激活,可以进行CDC测定,例如如Gazzano-Santoro等人(Journal ofImmunological Methods.1997Mar;202(2):163-171)中所述。
在一些实施方案中,本发明的抗体可以是具有修饰的氨基酸序列的抗体,所述修饰的氨基酸序列导致减少或消除了与大多数Fcγ受体的结合,这可以减少在表达此类受体的正常细胞和组织(例如巨噬细胞、肝窦细胞等)中的摄取和毒性。
本发明的一个方面涉及治疗癌症的方法,其包括向有需要的受试者施用治疗有效量的本发明的抗体、免疫缀合物或药物组合物。
在本发明的背景下,本文中使用的术语“治疗(treat)”或“治疗(treatment)”是指逆转、减轻、抑制此类术语所应用的病症或状况或此类病症或病况的一种或多种症状的进展,或预防其。本文中使用的术语“治疗癌症”是指抑制肿瘤的恶性细胞的生长和/或从所述肿瘤转移的进展。此类治疗还可以导致肿瘤生长的消退,即,可测量肿瘤的尺寸减小。例如,此类治疗可以导致肿瘤或转移的完全消退。
在本发明的治疗应用的背景下,术语“受试者”或“患者”或“有需要的受试者”或“有需要的患者”是指受肿瘤影响或可能受肿瘤影响的受试者(例如人或非人哺乳动物)。例如,所述患者可以是例如根据下文中所述的方法已确定对靶向CEACAM5的治疗剂(特别是根据本发明的抗体或免疫缀合物)敏感的患者。
“治疗有效量”是指足以以适用于任何医学治疗的合理收益/风险比治疗所述癌症疾病的量。但是,要理解的是,本发明的抗体、免疫缀合物和药物组合物(统称为“治疗剂”)的每日总用量将由主治医师在合理的医学判断范围内决定。对任何具体患者的特定治疗有效剂量水平将取决于多种因素,包括所治疗的病症和病症的严重程度;所用特定治疗剂的活性;患者的年龄、体重、一般健康状况、性别和饮食;施用时间、施用途径和所用特定治疗剂的排泄率;治疗的持续时间;与所用特定治疗剂联合或同时使用的药物;以及医学领域中公知的类似因素。例如,在本领域技术人员中公知的是,以低于实现期望治疗作用所需的那些的水平开始化合物的剂量,并逐渐增加剂量直至达到期望作用。
本发明的抗体、免疫缀合物或药物组合物还可用于抑制癌症转移的进展。
本发明的抗体、免疫缀合物或药物组合物还可以与用于治疗癌症(例如辅助疗法)和/或用于减少转移性癌症的生长的任何其他治疗干预组合使用。例如,用于此类组合的其他治疗干预可以是用于待治疗的癌症的标准治疗(standard-of-care,SOC)治疗剂。
用根据本发明的抗体或免疫缀合物或药物组合物进行治疗的功效可以在体内(例如在癌症的小鼠模型中)并通过测量例如治疗组与对照组之间的肿瘤体积的改变、%肿瘤消退、部分消退或完全消退来容易地测定。
诊断用途
CEACAM5已经报道在癌细胞(诸如结肠直肠、胃、肺和胰腺肿瘤细胞)的表面上高度表达,并且在正常组织中的表达限于少数正常上皮细胞,诸如结肠和食管上皮细胞。
因此,CEACAM5构成癌症标志物,并具有例如用于指示抗癌疗法的有效性或检测疾病复发的潜力。
在一个实施方案中,本发明的抗体在靶向表达CEACAM5的肿瘤的疗法的背景下可用作测定的组分,以确定患者对治疗剂的敏感性,监测抗癌疗法的有效性或检测治疗后疾病的复发。在一些实施方案中,本发明的该抗体可以用作治疗剂的组分和诊断测定的组分。
由此,本发明的另一方面涉及根据本发明的抗体用于在来自受试者的生物样品中离体检测CEACAM5表达的用途。本发明的另一方面涉及本发明的抗体用于在受试者中体内检测CEACAM5表达的用途。当用于检测CEACAM5时,抗体可以用可检测分子(诸如荧光团或酶)来标记。
检测CEACAM5可以意在通过检测肿瘤细胞上表面蛋白CEACAM5的表达用于例如:
a)诊断受试者中癌症的存在,或
b)确定患有癌症的患者对靶向CEACAM5的治疗剂(特别是根据本发明的抗体或免疫缀合物)的敏感性,或
c)监测抗CEACAM5癌症疗法的有效性或检测抗CEACAM5癌症疗法后的癌症复发,特别是其中所述疗法是用根据本发明的抗体或免疫缀合物的疗法。
在实施方案中,抗体意在用于体外或离体诊断用途。例如,CEACAM5可使用本发明的抗体在获自受试者的生物样品中体外或离体检测。根据本发明的用途也可以是体内用途。例如,可以将根据本发明的抗体施用于受试者,并且可以检测和/或定量抗体-细胞复合物,由此所述复合物的检测指示癌症。
本发明进一步涉及在受试者中检测癌症存在的体外或离体方法,其包括以下步骤:
(a)使来自受试者的生物样品与根据本发明的抗体接触,特别是在适于该抗体与所述生物样品形成复合物的条件下;
(b)测量结合至所述生物样品的抗体的水平;以及
(c)通过将测得的结合抗体的水平与对照进行比较来检测癌症的存在,与对照相比结合抗体的水平提高指示癌症。
本发明还涉及确定患有癌症的患者对靶向CEACAM5的治疗剂(特别是根据本发明的抗体或免疫缀合物)的敏感性的体外或离体方法,该方法包括以下步骤:(a)使来自患有癌症的患者的生物样品与根据本发明的抗体接触,特别是在适于该抗体与所述生物样品形成复合物的条件下;
(b)测量结合至所述生物样品的抗体的水平;以及
(c)将测得的结合至所述生物样品的抗体的水平与结合至对照的抗体的水平进行比较;
其中与对照相比结合至所述生物样品的抗体水平提高指示患者对靶向CEACAM5的治疗剂敏感。
在上述方法中,所述对照可以是相同类型的正常非癌生物样品,或确定为代表相同类型的正常生物样品中的抗体结合水平的参考值。
在一个实施方案中,本发明的抗体可用于诊断表达CEACAM5的癌症,诸如结肠直肠癌、胃癌、非小细胞肺癌、胰腺癌、食管癌、前列腺癌或其他表达CEACAM5的实体肿瘤。
本发明进一步涉及监测抗CEACAM5癌症疗法的有效性的体外或离体方法,其包括以下步骤:
(a)使来自经历了抗CEACAM5癌症疗法的受试者的生物样品与根据本发明的抗体接触,特别是在适于该抗体与所述生物样品形成复合物的条件下;
(b)测量结合至所述生物样品的抗体的水平;以及
(c)将测得的结合抗体的水平与结合至对照的抗体的水平进行比较;
其中与对照相比,结合至所述生物样品的抗体的水平降低指示所述抗CEACAM5癌症疗法的有效性。在所述方法中,与对照相比,结合至所述生物样品的抗体的水平提高将指示所述抗CEACAM5癌症疗法无效。在监测有效性的这种方法的一个实施方案中,所述对照是与进行分析的生物样品相同类型的生物样品,但其在抗CEACAM5癌症疗法的过程期间在较早的时间点获自受试者。
本发明进一步涉及在抗CEACAM5癌症疗法后检测癌症复发的体外或离体方法,其包括以下步骤:
(a)使来自受试者(该受试者已完成抗CEACAM5癌症疗法)的生物样品与根据本发明的抗体接触,特别是在适于该抗体与所述生物样品形成复合物的条件下;
(b)测量结合至所述生物样品的抗体的水平;以及
(c)将测得的结合抗体的水平与结合至对照的抗体的水平进行比较;
其中与对照相比,结合至所述生物样品的抗体水平提高指示抗CEACAM5癌症疗法后癌症复发。所述对照特别可以是与进行分析的生物样品相同类型的生物样品,但其先前(即在完成抗CEACAM5癌症疗法之时或之后)获自受试者。
所述抗CEACAM5癌症疗法是例如使用根据本发明的抗体或免疫缀合物的疗法。所述抗CEACAM5癌症疗法靶向表达CEACAM5的癌症,诸如结肠直肠癌、胃癌、非小细胞肺癌、胰腺癌、食管癌、前列腺癌或表达CEACAM5的其他实体肿瘤。
在一些实施方案中,本发明的抗体可以用可检测的分子或物质标记,诸如荧光分子或荧光团、放射性分子、酶或本领域已知的(直接或间接)提供信号的任何其他标记。
就根据本发明的抗体而言,本文中使用的术语“标记的”意在包括通过将可检测物质,诸如放射性试剂或荧光团(例如异硫氰酸荧光素(FITC)或藻红蛋白(PE)或吲哚菁(Cy5))偶联(即物理连接)到多肽上来直接标记抗体,以及通过与可检测物质的反应性而间接标记多肽。
本发明的抗体可以通过本领域已知的任何方法用放射性分子标记。例如,放射性分子包括但不限于用于闪烁扫描研究的放射性原子,诸如I123、I124、In111、Re186、Re188、Tc99。本发明的抗体也可以用用于核磁共振(NMR)成像(也称为磁共振成像,MRI)的自旋标记物来标记,诸如碘-123、铟-111、氟-19、碳-13、氮-15、氧-17、钆、锰或铁。
“生物样品”包括获自受试者的多种样品类型,其可用于诊断或监测测定。生物样品包括但不限于血液和生物来源的其他液体样品、固体组织样品,诸如活检标本或组织培养物或来源于此的细胞,及其子代。因此,生物样品包括临床样品、培养中的细胞、细胞上清液、细胞裂解物、血清、血浆、生物流体和组织样品,诸如肿瘤样品。
在一些实施方案中,生物样品可以是福尔马林固定和石蜡包埋(FFPE)的组织样品。
本发明还涉及在受试者中检测癌症的存在的体内方法,其包括以下步骤:
a)向患者施用根据本发明的抗体,其中该抗体用可检测分子标记;
b)通过成像,例如通过检测可检测分子,检测所述抗体在患者中的定位。
在所述方法中,癌症可以是表达CEACAM5的癌症,诸如结肠直肠癌、胃癌、非小细胞肺癌、胰腺癌、食管癌、前列腺癌或表达CEACAM5的其他实体肿瘤。
本发明的抗体还可用于(例如在放射成像中)癌症的分期。它们可以单独或与其他癌症标志物组合使用。
本文中使用的术语“检测”或“检测的”包括参考或不参考对照的定性和/或定量检测(即测量水平)。
在本发明的背景下,本文中使用的术语“诊断”是指基于多个收集的数据确定医学状况的性质,其旨在鉴定影响受试者的病理学。
试剂盒
最后,本发明还提供了包含至少一种本发明的抗体或免疫缀合物的试剂盒。含有本发明的抗体的试剂盒可用于检测表面蛋白CEACAM5,或用于治疗或诊断测定。本发明的试剂盒可以含有与固体载体(例如组织培养板或珠(例如琼脂糖珠))偶联的抗体。可以提供试剂盒,其含有用于在体外(例如在ELISA或蛋白印迹中)检测和定量表面蛋白CEACAM5的抗体。可以提供具有标记(诸如荧光或放射性标记)的可用于检测的此类抗体。
序列的简要描述
氨基酸序列:
SEQ ID NO:1根据GenBank登录号AAA51967.1的人CEACAM5蛋白序列
SEQ ID NO:2食蟹猴CEACAM5蛋白序列(NCBI参考序列XP_005589491.1)
SEQ ID NO:3mAb1的CDR1-H
SEQ ID NO:4mAb1的CDR2-H
SEQ ID NO:5mAb1的CDR3-H
SEQ ID NO:6mAb1的CDR1-L
SEQ ID NO:7mAb1的CDR2-L
SEQ ID NO:8mAb1的CDR3-L
SEQ ID NO:9mAb1的VH
SEQ ID NO:10mAb1的VL
SEQ ID NO:11mAb1的CH
SEQ ID NO:12mAb1的CL
SEQ ID NO:13mAb1的HC
SEQ ID NO:14mAb1的LC
核酸序列:
SEQ ID NO:15编码mAb1的HC的DNA序列
SEQ ID NO:16编码mAb1的LC的DNA序列
氨基酸序列:
SEQ ID NO:17抗体hu8G4的HC
SEQ ID NO:18抗体hu8G4的LC
SEQ ID NO:19优化抗体变体1的HC
SEQ ID NO:20优化抗体变体1的LC
SEQ ID NO:21优化抗体变体2的LC
SEQ ID NO:22优化抗体变体4的LC
SEQ ID NO:23优化抗体变体5的LC
SEQ ID NO:24优化抗体变体6的HC
SEQ ID NO:25huMab2-3(同种异型)的HC
SEQ ID NO:26huMab2-3的LC
SEQ ID NO:27hmn-14的HC
SEQ ID NO:28hmn-14的LC
SEQ ID NO:29rb8G4的HC
SEQ ID NO:30rb8G4的LC
实施例
实施例1:抗CEACAM5抗体
1.1转基因大鼠的免疫和杂交瘤的分离
为了生成针对人CEACAM5蛋白(癌胚抗原相关细胞粘附分子5;CD66e)的单克隆抗体,人免疫球蛋白基因转基因大鼠(OmniRatTM)获自CHARLES RIVER LABORATORIESINTERNATIONAL INC(WILMINGTON,MA)。用克隆到Aldevron专有免疫载体(pB8-CEA-hum-MC)中并使用基因枪瞬时转染到OMT大鼠细胞中的CEACAM5 cDNA(编码具有UniProt ID号P06731的人CEACAM5蛋白序列的氨基酸35-675;除了SEQ ID NO:1的E398被K398取代之外,P06731的序列与SEQ ID NO:1相同)将5只动物免疫4次。
通过基于细胞的ELISA(CELISA)测定,使用在其细胞膜上表达CEACAM5的细胞评估抗CEACAM5效价(效价结果显示在下文中)。在4轮遗传物质免疫(IS31d-4)后,在免疫方案的第31天采集免疫动物血清。在PBS+3% FBS中稀释的血清通过流式细胞术,在用克隆到Aldevron专有表达载体(pB1-CEA-hum-MC)中的CEACAM5 cDNA瞬时转染的哺乳动物细胞上进行测试。山羊抗大鼠IgG R-藻红蛋白缀合物(Southern Biotech,#3030-09)以10微克/毫升用作第二抗体。
将所有动物处死,并汇集(pool)来自淋巴结的淋巴细胞,并冷冻保存以备将来使用。使细胞与Ag8小鼠骨髓瘤细胞系融合以产生活的杂交瘤。然后将来自该融合的杂交瘤细胞转移至十个96孔板。
1.2CEACAM5特异性
使用基于细胞的ELISA(CELISA)测定来筛选杂交瘤上清液,以检测不结合CEACAM1(BGP)、CEACAM3(CGM1a)、CEACAM4(CGM7)、CEACAM6(NCA)和CEACAM8(NCA-95)的抗CEACAM5抗体。山羊抗大鼠IgG R-藻红蛋白缀合物(Southern Biotech,#3030-09)以10微克/毫升用作第二抗体。
将显示出对人CEACAM5的特异性而无对其相关蛋白的特异性的克隆转移到一个96孔板中,并在ELISA测定中评估杂交瘤上清液的特异性和交叉反应性。在该测定中,8G4杂交瘤克隆及其亚克隆显示出对人CEACAM5的特异性,以及对食蟹猴CEACAM5的交叉反应性。
1.3检测抗体序列和克隆
通过qPCR对所得cDNA进行质量控制,并通过PCR来扩增VH和Vk。PCR产物使用与KingFisher仪器结合的AMpure XP PCR纯化试剂盒来纯化。
使用同源重组程序(所谓“Lucigen克隆”)将8G4亚克隆的VH和Vk基因分别克隆到目标载体hi00_pTT5_VH_ccdB和hh00_pTT5_Vk_ccdB中。在OneMach1TM-T1R化学感受态大肠杆菌中转化反应混合物。通过Sanger测序证实正确重组的克隆。
1.4标的(hit)的人源化和生化表征以及候选物选择
将8G4和其他克隆重排(reformat)并表达为人IgG1分子。通过SDS-PAGE、体积排阻层析(SEC)、选择性、亲和力、细胞结合和效力对它们进行评估。基于结果,选择一种命名为hu8G4的人源化候选抗体用于氨基酸序列优化以改善可制造性和亲和力。
人源化候选抗体hu8G4的氨基酸序列如下:
重链:
EVQLVESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:17)
轻链:
ETTLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYFCQQYTNWPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:18)。
1.5尤其产生mAb1的hu8G4的生物物理改善策略
hu8G4的可变区序列的评估鉴定了轻链框架中的六个非种系氨基酸残基和重链框架中的两个非种系氨基酸残基。对可能倾向于翻译后修饰的氨基酸和序列基序,诸如脱酰胺基序、表面可及的蛋氨酸和游离半胱氨酸的评估并未鉴定任何具有提高的倾向性(liability)的氨基酸残基。生成了几种设计的抗体序列,其中某些氨基酸在该位置处被种系相关氨基酸替换。随后使不同的VH和VL优化设计在HEK 293 6E细胞中共表达为Fab和完全IgG1分子,纯化并测试(参见例如下面的优化变体1-10)。
完全IgG1格式的10种优化抗体变体的氨基酸序列如下:
变体1(VH1.00/VL1.00)
HC:
EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRLTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:19)
LC:
ETTLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYFCQQYTNWPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:20)
变体2(VH1.00/VL1.01)
HC:SEQ ID NO:19
LC:
EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYFCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:21)
变体3(VH1.00/VL1.02)
HC:SEQ ID NO:19
LC:SEQ ID NO:14
变体4(VH1.00/VL1.03)
HC:SEQ ID NO:19
LC:
EIVMTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYFCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:22)
变体5(VH1.00/VL1.04)
HC:SEQ ID NO:19
LC:
EIVMTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:23)
变体6(VH1.02/VL1.00)
HC:
EVQLQESGPG LVKPSQTLSL TCTVSDGSVS RGGYYLTWIR QHPGKGLEWI GYIYYSGSTYFNPSLRSRVT MSVDTSKNQF SLKLSSVTAA DTAVYYCARG IAVAPFDYWG QGTLVTVSSA STKGPSVFPLAPSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTYICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK DTLMISRTPE VTCVVVDVSHEDPEVKFNWY VDGVEVHNAK TKPREEQYNS TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISKAKGQPREPQV YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYSKLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK(SEQ ID NO:24)
LC:SEQ ID NO:20
变体7(VH1.02/VL1.01)
HC:SEQ ID NO:24
LC:SEQ ID NO:21
变体8(VH1.02/VL1.02)
HC:SEQ ID NO:24
LC:SEQ ID NO:14
变体9(VH1.02/VL1.03)
HC:SEQ ID NO:24
LC:SEQ ID NO:22
变体10(VH1.02/VL1.04)
HC:SEQ ID NO:24
LC:SEQ ID NO:23
所有优化变体1至10在以下方面类似地表现良好:通过体积排阻层析由聚集百分比测定的质量保持、基于荧光监测的热解折叠(FMTU)的保持的稳定性、保持的与MKN-45癌细胞系的结合和保持的对靶标的选择性。作为具有与种系特别相似的序列的优化变体,选择变体8(即包括VH1.02和VL1.02的变体)用于进一步开发。
然后对所选变体8进行进一步的序列优化,尤其是为了减少IgG Fc效应子功能。与亲本克隆相比,命名为so8G4(在本文中也称为mAb1)的所得最终序列优化(so)克隆,显示改善的亲和力和改善的可制造性,并还显示与FcγRI、FcγRIIa、FcγRIIIa、FcγRIIIa/复合物、C1q、FcγRIIb和FcγRIIIb的结合减少或不结合,同时保持对CEACAM5和FcRn的亲和力。这种最终序列优化抗体so8G4(在本文中也称为mAb1)的氨基酸序列如下:
重链(HC):SEQ ID NO:13(如上文中所定义)
轻链(LC):SEQ ID NO:14(如上文中所定义)
1.6mAb1的体外表征
用体外测定表征了抗体mAb1的几种性质,包括:结合亲和力、选择性和内化。
1.6.1结合亲和力
·为了测定可溶性抗体分析物对捕获的靶标蛋白CEACAM5(人或食蟹猴)的结合亲和力。在Octet Red仪器上使用以下实验条件:
·涂有链霉亲和素的生物传感器。
·生物素化靶标蛋白浓度(其中ECD代表胞外结构域):
ο在1000rpm下以2.5微克/毫升捕获人_CEACAM5_ECD-his-生物素R&D Systems(使用常规方法生物素化)900秒。
ο在1000rpm下以5微克/毫升捕获获自Syngene的重组食蟹猴CEACAM5_ECD-His-生物素(使用常规方法生物素化)900秒。
·分析物抗体浓度:200、100、50、25、12.5、6.25、0nM。
·用Octet评估软件,由测得的结合动力学缔合(ka)和解离(kd)速率常数确定结合亲和力KD(平衡解离常数)值,其中KD=kd/ka
·使用以Fab格式的抗体
由mAb1产生的Fab的结果:
对人CEACAM5的结合亲和力KD为6.3±1.98nM。
对食蟹猴-CEACAM5的结合亲和力KD为14.1±2.53nM。
1.6.2.选择性
a)物种和结构域
mAb1选择性的测定通过将抗体从4nM滴定至0.25pM,并在ELISA测定中将其应用于1微克/毫升结合的重组人(rh)CEACAM5 ECD或其结构域N-A1-B1、A2-B2、A3-B3上或结合的重组食蟹猴(mf)CEACAM5 ECD上(所有均获自Syngene)来进行。结果显示在图1中并概括如下:
对rhCEACAM5的结合EC50为153.4pM。
对rhA2-B2结构域的结合EC50为166.9pM。
对mfCEACAM5的结合EC50为324.3pM。
没有检测到与rhN-A1-B1或rhA3-B3或BSA(牛血清白蛋白,用作阴性对照)的结合。
b)不同的CEACAM蛋白
在ELISA测定中进行mAb1的Fab对人CEACAM5和其他人CEACAM家族成员的选择性测定。将蛋白涂覆在96孔测定板上:huCEACAM5-His6(R&D Systems#4128-CM)、huCEACAM6-His6(3934-CM R&D Systems和获自Syngene的重组蛋白)、huCEACAM1-His6(2244-CM R&DSystems)、huCEACAM3-His6(C449 Novoprotein)、huCEACAM7-His6(C926 Novoprotein)、huCEACAM8-His6(C583 Novoprotein)、huPSG1-His6(CC66 Novoprotein),每种蛋白以12nM浓度涂覆板。
结果:
在ELISA测定中,mAb1的Fab结合人CEACAM5(EC50为3.04nM),但不结合其他人CEACAM家族成员,即使在使用1000nM的mAb1的Fab(这是结合至人CEACAM5的EC50的超过300倍的浓度)时也如此。
在ELISA测定中,mAb1的Fab在所有测试浓度下都不结合至无关蛋白(BSA)。
1.6.3mAb1的细胞结合
通过在表达靶标(例如人CEACAM5)的细胞上滴定抗体并测量细胞的荧光MFI来确定抗体结合其在细胞上的靶标蛋白的能力。用于抗体结合比较的模型细胞是表达人CEACAM5的MKN45细胞系以及表达mfCEACAM5的CHO细胞系。滴定用10点×4稀释,曲线起始浓度2000nM在测定缓冲液(含有1% BSA的PBS×1)中的进行。
示例性数据:
mAb1结合至表达人CEACAM5的MKN-45细胞系的EC50=10.62±1.6nM。
mAb1结合至表达mfCEACAM5的CHO细胞系的EC50=4.8±0.6nM。
1.6.4与已知抗体的细胞结合比较
我们的前导抗体mAb1的细胞结合在表达CEACAM5的MKN45细胞系上与ADC相关的已知抗体huMab2-3(如在已知的ADC SAR408701中的)和hMN14(在本文中也称为hman-14)(如在已知的ADC拉贝珠单抗戈维替康或IMMU-130中的)进行比较。
在下文中描述的实验中,以下氨基酸序列用于上述已知抗体:
huMab2-3:
HC(同种异型):
EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:25)
LC:
DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:26)
hmn-14:
HC:
EVQLVESGGGVVQPGRSLRLSCSASGFDFTTYWMSWVRQAPGKGLEWIGEIHPDSSTINYAPSLKDRFTISRDNAKNTLFLQMDSLRPEDTGVYFCASLYFGFPWFAYWGQGTPVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:27)
LC:
DIQLTQSPSSLSASVGDRVTITCKASQDVGTSVAWYQQKPGKAPKLLIYWTSTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYSLYRSFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:28)。
利妥昔单抗作为对照包括在比较中。抗体与细胞结合的结果显示在图2中并概括如下:
mAb1(so8G4)=8.3nM
huMab2-3=6nM
hmn-14=11.8nM
几个实验的平均值(EC50):
mAb1(so8G4)=10.4nM±1.6nM(n=12)
huMab2-3=4.9nM±1.6nM(n=3)
hmn-14=16nM(n=2)
抗CEACAM5抗体与MKN45细胞系的细胞结合显示mAb1和已知抗体的结合是相似的。
1.6.5使用Cell Discoverer的内化测定
ADC的相关特性是其内化至表达靶标的细胞和溶酶体中,且由此内化是待用作ADC的一部分的抗体的相关性质。通过用pH敏感染料(pHrodo)直接标记抗体可以监测抗体内化至晚期核内体和溶酶体(低pH囊泡)中的速率,所述pH敏感染料在低于6.0的pH下在激发后发射强荧光。这种荧光可以在Cell-Discoverer7(Zeiss)中成像,并可以计算内化速率。
为了分析几种抗体的内化速率,将MKN45细胞以25,000个细胞/孔接种在96孔、深色、扁平透明底部平板(Cellvis)中。用100微升/孔的RMPI-1640+10%FBS(Thermo)培养细胞过夜。除去细胞培养基,并将细胞用100微升的在PBS×1中稀释的10微克/毫升的Hoechst染料在室温(RT)下在黑暗中染色15分钟。随后用PBS×1洗涤细胞两次。
抗CEACAM5人IgG抗体(so8G4(即mAb1)、humab2-3、hmn-14)和抗MerTK抗体(Merck)直接用pHrodo标记,在不含酚红的温热RPMI1640+10% FBS中稀释至100nM的浓度并加入到其各自的孔中。如下文进一步描述的那样,将板在Cell Discoverer中在37℃、5% CO2下温育20小时,并且每20分钟获取图像。
pHrodo标记的抗体内化至细胞的晚期核内体和溶酶体中通过Cell-Discoverer7(Zeiss),使用在567nm的激发下的荧光和592/25nm的发射检测器来成像。细胞核用Hoechst标记,并在385nm的激发和425/30nm的发射检测器下成像。
每20分钟记录每个孔的荧光,持续20小时。通过Zen Software(ZEN3.1)和线性回归的Excel分析计算每个细胞的总荧光强度(SFI)的分析。
结果显示在图3及图4中,并且曲线的线性部分的斜率(参见图4)也概括在下表中:
样品 | 曲线斜率 | R^2 |
so8G4 | 28519 | 99.41 |
so8G4 | 29844 | 99.66 |
so8G4 | 28513 | 99.92 |
humab2-3 | 19154 | 99.42 |
humab2-3 | 17398 | 99.19 |
humab2-3 | 20201 | 99.68 |
hmn-14 | 24350 | 98.61 |
hmn-14 | 18754 | 99.56 |
hmn-14 | 23701 | 99.58 |
结论:
1.so8G4(mAb1)具有高于humab2-3(18917±1416)和hmn-14(22268±3060)的平均结合速率(28958±766)。
2.与humab2-3和hmn-14相比,so8G4(mAb1)还具有更高的内化强度。
1.7产生例如用于与药物-接头化合物缀合的mAb1的示例性方法
抗CEACAM5抗体mAb1在重组CHO-K1Sv细胞系中产生。细胞培养以分批模式在200升一次性生物反应器中进行。细胞在补充有葡萄糖的专有CHO分批补料生长培养基中在37℃下生长。在接种后第3、5、7和10天用专有补料组分的混合物对培养进行补料。
使用3×1.1m2 Millistak+Pod DOHC(Millipore MD0HC10FS1)和1.1m2Millistak+Pod XOHC(Millipore#MX0HC01 FS1)过滤器净化来自生物反应器运行的粗条件培养基,接着用Millipore Opticap XL3 0.5/0.2μm过滤器(Millipore#KHGES03HH3)进行最终过滤。
在净化后,使用标准抗体纯化方法纯化抗体mAb1,所述方法由蛋白A捕获步骤和离子交换层析步骤组成。抗CEACAM5抗体mAb1用作产生ADC分子的中间体。
1.8mAb1的人/兔嵌合变体的表达和纯化及其在甲醛固定和石蜡包埋的细胞系和人肿瘤组织上的免疫组织化学(IHC)中的用途
通过常规重组方法产生mAb1的人/兔嵌合变体。mAb1的人/兔嵌合变体(在本文中也称为“rb8G4”)具有以下氨基酸序列:
重链
EVQLQESGPGLVKPSQTLSLTCTVSDGSVSRGGYYLTWIRQHPGKGLEWIGYIYYSGSTYFNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGIAVAPFDYWGQGTLVTVSSQPKAPSVFPLAPCCGDTPSSTVTLGCLVKGYLPEPVTVTWNSGTLTNGVRTFPSVRQSSGLYSLSSVVSVTSSSQPVTCNVAHPATNTKVDKTVAPSTCSKPTCPPPELLGGPSVFIFPPKPKDTLMISRTPEVTCVVVDVSEDDPEVQFTWYINNEQVRTARPPLREQQFNSTIRVVSTLPIAHEDWLRGKEFKCKVHNKALPAPIEKTISKARGQPLEPKVYTMGPPREELSSRSVSLTCMINGFYPSDISVEWEKNGKAEDNYKTTPAVLDSDGSYFLYSKLSVPTSEWQRGDVFTCSVMHEALHNHYTQKSISRSPGK(SEQ IDNO:29)
轻链
EIVLTQSPATLSVSPGERATLSCRTSQSVRSNLAWYQQKPGQAPRLLIYAASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYTNWPFTFGPGTKVDIKRDPVAPSVLLFPPSKEELTTGTATIVCVANKFYPSDITVTWKVDGTTQQSGIENSKTPQSPEDNTYSLSSTLSLTSAQYNSHSVYTCEVVQGSASPIVQSFNRGDC(SEQ IDNO:30)。
rb8G4通过瞬时转染在HEK细胞(Expi 293悬浮细胞)中表达,并使用MabSelectSuRe和柠檬酸盐缓冲液纯化。随后将rb8G4用于甲醛固定的和石蜡包埋的细胞系和人肿瘤组织上的IHC:
材料和方法
细胞系和组织
从Merck细胞库培养人癌细胞系,在4%缓冲的甲醛中固定,并包埋在石蜡(FFPE)中。将石蜡包埋的细胞系排列成细胞系微阵列(CMA)(Zytomed)。具有人器官的组织微阵列(TMA)的FFPE组织切片来自amsbio(FDA Standard Tissue Array,T8234701)。FFPE人肿瘤样品由BioIVT和IndivuMed GmbH提供。
方法
对于用抗CEACAM-5抗体rb8G4的IHC染色,将来自甲醛固定石蜡包埋(FFPE)癌细胞系微阵列(CMA)和人肿瘤组织的4μm切片固定在带电载玻片(SuperFrost Ultra Plus,Thermo Fisher Scientific或TOMO,Matsunami)上。使用Discovery XT(RocheDiagnostics)染色平台进行染色程序。在去石蜡后,在Tris-EDTA缓冲液pH 8(CC1,RocheDiagnostics)中加热切片用于表位修复。将切片与在磷酸盐缓冲盐水(PBS)或抗体稀释缓冲液(DCS)中稀释至0.5或0.7微克/毫升的第一单克隆抗体rb8G4一起温育。克隆DA1E(兔单克隆IgG,NEB)用作同种型对照抗体。第一抗体之后是HQ抗兔IgG检测试剂盒(RocheDiagnostics)。载玻片用苏木精复染,在自来水中洗涤,脱水,并在Entellan Neu(VWR)永久封片介质中固定在玻璃盖玻片上。
将CMA和TMA与人器官组织一起染色,并用NanoZoomer(Hamamatsu)以0.46μm/像素的分辨率扫描。将人肿瘤切片染色并使用AxioScan.Z1(Zeiss)仪器扫描,其中分辨率为0.44μm/像素。CMA的扫描用图象分析软件HALO(Indica Labs,USA)进行分析。为了确定存在的抗原量,阳性棕色染色面积计算为活组织面积的百分比面积。染色(任意单位)计算为
抗体染色(AU)=%阳性组织面积*棕色颜色的平均光密度(OD范围为0至1)。抗体染色的最大值是100=100%的组织区域为黑色(灰度OD值为1)。
癌细胞系的CEACAM-5mRNA数据获自癌细胞系百科全书(Cancer Cell LineEncyclopedia)(CCLE;MIT&Harvard的Broad研究所)。
结果
癌细胞系和人正常组织的验证
抗体rb8G4在FFPE癌细胞系上显示在细胞质和质膜中的信号(图5)。
通过将104个癌细胞系上的染色信号与这些细胞系的mRNA表达(CCLE数据集)进行比较,显示抗体rb8G4在FFPE组织/细胞上的特异性。所得皮尔逊相关系数r=0.88支持了抗体rb8G4(也称为SO8G4AB323)在FFPE组织/细胞中检测CEACAM-5表位的结论(图6)。该癌细胞系微阵列和单独选择的阳性和阴性细胞系在对人正常和肿瘤组织进行的染色中用作对照基质。
在正常人组织中用抗体rb8G4的染色(图7)与CEACAM-5mRNA表达(图8)(来源:http://www.proteinatlas.org/ENSG00000105388-CEACAM5/tissue)一致,进一步支持了该抗体对CEACAM-5的特异性。
人肿瘤组织
如结肠直肠癌(图9)、胃癌(图10)、食管癌(图11)和非小细胞肺癌(图12)中显示的那样,抗体rb8G4在几种人肿瘤适应症中染色呈阳性。信号位于细胞质中和质膜上。
1.9使用mAb1和rb8G4的流式细胞术和蛋白印迹
比较mAb1、rb8G4和商业可获得的抗CEACAM5抗体与CEACAM5阳性和阴性细胞系的结合。
所用方法:在5毫升聚苯乙烯管中的5E5至1E6细胞用于使用BD FACScanto II(BDBiosciences)的流式细胞术分析。在50微升1% PBS/BSA中在4℃下进行用10微克/毫升第一抗体(mAb1、rb8G4、小鼠单克隆Agilent Dako#M7072克隆#IL7)和各自的荧光标记的第二抗体(驴抗人IgG Jackson-Dianova#709-116-149;驴抗小鼠IgG JacksonImmunoResearch#715-116-150;驴抗兔IgG Jackson-Dianova#711-116-152)的染色。在染色步骤之间和之后,将细胞用1%PBS/BSA洗涤三次并重新悬浮在500微升1% PBS/BSA(包含0.2微克/毫升DAPI用于活细胞门控)中用于流式细胞术分析。为评估数据,使用FlowJo软件(BD Biosciences)。
结果:mAb1和rb8G4显示出仅对应于在CEACAM5阳性细胞系上的mRNA表达水平数据(下表1;MKN-45,NCI-H441)的结合。相反,对于商业抗体,结合较弱,并限于CEACAM5-高的细胞系(下表1;MKN-45)。总之,mAb1和rb8G4特异性检测CEACAM5阳性癌细胞,并可用作检测剂。
表1.不同抗体与CEACAM5阳性细胞系及CEACAM5阴性细胞系的结合。每个细胞系列举各自抗体的中值荧光强度(MFI)除以仅有第二抗体的对照的MFI的商。
还通过蛋白印迹研究了人mAb1和rb8G4与CEACAM5阳性和阴性细胞系裂解物的结合。
所用方法:根据标准方案(Sambrook,J.&Russell,D.W.,2001.molecularCloning:A Laboratory Manual,第1卷,CSHL Press)进行蛋白印迹。对于SDS-PAGE和随后的湿膜印迹,每个泳道装载通过BCA试剂盒(Thermo Scientific,#23227)定量的RIPA细胞裂解物的15微克总蛋白。在标准电泳池(Bio-Rad,#1656001)中使用用MOPS电泳缓冲液(Bio-Rad,#1610788)的标准XT 4-12%凝胶(Bio-Rad,#3450125)。通过丽春红染色确认蛋白的转移。在用0.5微克/毫升至1微克/毫升的第一抗体(mAb1或rb8G4)和第二抗体(抗人IgG,Jackson ImmunoResearch#109-035-098或抗兔IgG,CellSignaling#7074)进行染色之前和之间对膜进行洗涤。使用Fusion FX成像系统(Vilber),通过ECL检测试剂使染色的膜可视化。
结果显示在图13A和图13B中:两种抗体均以对应于高度糖基化的CEACAM5的预期迁移速度的可比较模式结合。mAb1(图13A)和rb8G4(图13B)的CEACAM5检测对CEACAM5阳性细胞系是特异性的,且强度与mRNA表达水平相关。以较低强度观察到的第二条带对应于先前描述的潜在第二同种型(Hatakeyama等人:Novel protein isoforms ofcarcinoembryonic antigen are secreted from pancreatic,gastric and colorectalcancer cells.BMC Research Notes 2013 6:381)。
实施例2:合成具有葡萄糖醛酸基接头的药物-接头化合物:药物-接头化合物1
(DL1)
到化合物9(在本文中也称为药物-接头化合物1(DL1))的合成途径。
化学制备的方案
步骤1:化合物1
向(2S,3S,4S,5R,6R)-3,4,5-三乙酰氧基-6-溴-四氢-吡喃-2-甲酸甲酯(8.30克;20.90毫摩尔;1.00当量)和4-羟基-3-硝基-苯甲醛(5.24克;31.35毫摩尔;1.50当量)在乙腈(83.00毫升;10.00V)中的搅拌溶液中加入氧化银(I)(9.69克;41.80毫摩尔;2.00当量)。反应混合物在室温下搅拌16小时。反应混合物通过硅藻土过滤。滤液在真空下浓缩以获得固体。固体溶解在EtOAc中并用NaHCO3的10%水溶液洗涤以除去过量的4-羟基-3-硝基-苯甲醛。有机层在真空下浓缩以获得作为沙色固体的化合物1。
产量:9.0克百分比产率:89.1%
分析数据:
NMR:1H-NMR(400MHz,DMSO-d6):9.98(s,1H),8.46(s,1H),8.25-8.21(m,1H),7.64(d,J=11.60Hz,1H),5.94(d,J=10.00Hz,1H),5.51-5.44(m,1H),5.20-5.09(m,2H),4.80(d,J=13.20Hz,1H),3.64(s,3H),2.09(s,9H)。
步骤2:化合物2
向化合物1(9.00克;18.62毫摩尔;1.00当量)在丙-2-醇(33.00毫升;3.67V)和CHCl3(167.00毫升;18.56V)中的搅拌溶液中加入硅胶60-120(3.60克;112.09毫摩尔;6.02当量),接着是硼氢化钠(1.80克;46.55毫摩尔;2.50当量)。反应混合物在室温下搅拌1小时。完成后,反应混合物用冷却的H2O猝灭并通过硅藻土过滤。滤液用二氯甲烷萃取并在Na2SO4上干燥。将溶剂浓缩以获得作为灰白色粉末的化合物2。
产量:8.70克
百分比产率:92.4%
分析数据
LCMS:柱:ATLANTIS dC18(50×4.6mm)5μm;流动相A:在H2O中的0.1%HCOOH:ACN(95:5);B:ACN
RT(分钟):2.05;M+H:503.2,纯度:96.6%
步骤3:化合物3
向化合物2(8.70克;17.21毫摩尔;1.00当量)在乙酸乙酯(100.00毫升;11.49V)和THF(100.00毫升;11.49V)中的搅拌溶液中加入钯碳(10%w/w)(2.50克;2.35毫摩尔;0.14当量)。反应混合物在氢气气氛下在室温下搅拌3小时。完成后,反应混合物通过硅藻土过滤掉。将溶剂在真空下浓缩以获得作为灰白色固体的化合物3。
产量:8.5克
百分比产率:100%
分析数据:
LCMS:柱:ATLANTIS dC18(50×4.6mm)5μm;流动相A:在H2O中的0.1%HCOOH:ACN(95:5);B:ACN
RT(分钟):1.73;M+H:456.10,纯度:95.1%
步骤4:化合物4
在0℃下向化合物3(10.00克;20.89毫摩尔;1.00当量)和(9H-芴-9-基甲氧基羰基氨基)-乙酸(7.60克;25.06毫摩尔;1.20当量)在DCM(250.00毫升;25.00V)中的搅拌溶液中加入2-乙氧基-2H-喹啉-1-甲酸乙酯(15.65克;62.66毫摩尔;3.00当量)。反应混合物在室温下搅拌16小时。完成后,在减压下除去溶剂以获得粗产物。粗产物通过柱层析(56%EtOAc:石油醚)纯化以获得纯度80%的化合物。该化合物通过用30% EtOAc和石油醚(petether)洗涤进一步纯化以获得作为白色固体的化合物4。
产量:8.5克
百分比产率:50.7%
分析数据:
LCMS:柱:ATLANTIS dC18(50×4.6mm)5μm;流动相A:在H2O中的0.1%HCOOH:ACN(95:5);B:ACN
RT(分钟):3.03;M+H:735.2,纯度:81.9%
步骤5:化合物5
在0℃下向化合物4(2.00克;2.49毫摩尔;1.00当量)在THF(40.00毫升;20.00V)中的搅拌溶液中加入碳酸双(4-硝基-苯基)酯(3.06克;9.97毫摩尔;4.00当量)和DIPEA(4.40毫升;24.92毫摩尔;10.00当量)。反应混合物在室温下搅拌12小时。反应完成后,反应混合物在真空下浓缩。粗产物通过使用硅胶(230-400)和作为洗脱剂的石油醚/乙酸乙酯的柱层析来纯化以提供作为淡黄色固体的化合物5。
产量:2.0克
百分比产率:84.6%
分析数据:
LCMS:柱:X-Bridge C8(50×4.6)mm,3.5μm;流动相A:在MilliQ水中的0.1%TFA;B:ACN
RT(分钟):3.24;M+H:900.20,纯度:94.9%
步骤6:化合物6
将化合物5(1,369克;1,00当量)溶解在N,N-二甲基甲酰胺(15,00毫升)中,加入依沙替康甲磺酸盐(679,7毫克;1,00当量)、用于合成的4-甲基吗啉(0,422毫升;3,00当量)和1-羟基苯并三唑(172,8毫克;1,00当量)。反应混合物在室温下搅拌过夜。在搅拌时间后,反应混悬液变为棕色溶液。通过LC-MS监测反应,其显示原材料的完全转换。反应混合物经由RP快速层析纯化。将含有产物的级分合并,真空浓缩并冻干过夜以提供作为黄色固体的化合物6。
产量:1.59克
百分比产率:87.5%
分析数据:
LCMS:柱:Chromolith HR RP-18e(50-4,6mm);流动相A:在H2O中的0.05%HCOOH;B:在ACN中的0.04% HCOOH和1% H2O;T:40℃;流速:3,3毫升/分钟;MS:100-2000,amu正电荷;1%->100% B:0->2,0分钟;100% B:2,0->2,5分钟
RT(分钟):1.95;M+H:1196.40,纯度:84.4%.
步骤7:化合物7
将化合物6(1,586克;1,00当量)溶解在四氢呋喃(50,00毫升)中,并在0℃下逐滴添加LiOH的溶液(0.1M)(含有在水(67,100毫升)中的氢氧化锂水合物(281,77毫克;6,00当量))。在添加期间检查pH值。pH不应超过10。1.5小时后完成LiOH溶液的添加。通过LC-MS监测反应,其显示原材料的完全转换。将反应用柠檬酸溶液猝灭,pH调节至5。反应混合物在减压下浓缩。粗产物通过制备HPLC纯化。将含有产物的级分合并并冻干以提供作为深黄色固体的化合物7。
产量:728毫克
百分比产率:54.8%
分析数据:
LCMS:柱:Chromolith HR RP-18e(50-4,6mm);流动相A:在H2O中的0.05%HCOOH;B:在ACN中的0.04% HCOOH和1% H2O;T:40℃;流速:3,3毫升/分钟;MS:100-2000,amu正电荷;1%->100% B:0->2,0分钟;100% B:2,0->2,5分钟
RT(分钟):1.68;M+H:1056.30,纯度:98.5%.
步骤8:化合物8
将化合物7(728,000毫克;1,00当量)溶解在N,N-二甲基甲酰胺(20,00毫升)中。加入哌啶(136,513微升;2,00当量),并将溶液在室温下搅拌总共4小时。通过LC-MS监测反应,其显示原材料的完全转换。反应混合物在减压下浓缩,并且粗产物通过RP快速层析纯化。将含有产物的级分合并,部分除去溶剂,并将其冻干过夜以提供作为黄色固体的化合物8。
产量:706毫克
百分比产率:100%
分析数据:
LCMS:柱:Chromolith HR RP-18e(50-4,6mm);流动相A:在H2O中的0.05%HCOOH;B:在ACN中的0.04% HCOOH和1% H2O;T:40℃;流速:3,3毫升/分钟;MS:100-2000,amu正电荷;1%->100% B:0->2,0分钟;100% B:2,0->2,5分钟
RT(分钟):1.22;M+H:834.30,纯度:97.6%.
步骤9:化合物9
向化合物8(854毫克;1,00当量)在二甲基甲酰胺(30,00毫升)中的溶液中加入N-乙基二异丙胺(149,234微升;1,00当量)和3-(2,5-二氧代-2,5-二氢-吡咯-1-基)-丙酸-2,5-二氧代-吡咯烷-1-基酯(233,61毫克;1,00当量)。反应混合物在室温下搅拌3小时。通过LC-MS监测反应,其显示原材料的完全转化。反应混合物在减压下浓缩,并且粗产物通过RP快速层析。将含有产物的级分合并,浓缩并冻干以获得纯度为91%的所需产物。该材料再次通过RP层析纯化以获得作为黄色固体的化合物9。
产量:580毫克百分比产率:60.1%
分析数据:
LCMS:柱:Chromolith HR RP-18e(50-4,6mm);流动相A:在H2O中的0.05%HCOOH;B:在ACN中的0.04% HCOOH和1% H2O;T:40℃;流速:3,3毫升/分钟;MS:100-2000,amu正电荷;1%->100% B:0->2,0分钟;100% B:2,0->2,5分钟
RT(分钟):1.38;M+H:985.30,纯度:90%(另外10%的异构体可通过HPLC除去)1HNMR(500MHz,DMSO-d6)δ13.10–12.44(m,1H),9.08(s,1H),8.32(t,J=5.8Hz,1H),8.16(s,1H),8.02(d,J=8.8Hz,1H),7.76(d,J=10.9Hz,1H),7.31(s,1H),7.15–7.09(m,2H),6.98(s,2H),5.48–5.38(m,2H),5.32–5.22(m,3H),5.11–5.01(m,2H),4.87(d,J=7.6Hz,1H),3.92–3.88(m,1H),3.89–3.84(m,2H),3.65–3.61(m,2H),3.46–3.41(m,1H),3.42–3.37(m,1H),3.38–3.31(m,1H),3.28–3.20(m,1H),3.15–3.07(m,1H),2.48–2.44(m,2H),2.38(s,3H),2.24–2.13(m,2H),1.94–1.80(m,2H),0.88(t,J=7.3Hz,3H)。
实施例3:合成具有天冬酰胺内肽酶-可裂解接头的药物-接头化合物:药物-接头
化合物2(DL2)
步骤1
将4-硝基苯基碳酸{4-[(2S)-3-氨基甲酰基-2-[(2S)-2-[(2S)-2-({[(9H-芴-9-基)甲氧基]羰基}氨基)丙酰胺基]丙酰胺基]丙酰胺基]苯基}甲酯(400毫克;0,52毫摩尔;1,00当量)[可商业获得自Levena Biopharma US]溶解在N,N-二甲基甲酰胺(5,00毫升)中。加入依沙替康甲磺酸盐(277,30毫克;0,52毫摩尔;1,00当量)、N-乙基二异丙基胺(0,27毫升;1,57毫摩尔;3,00当量)和1-羟基苯并三唑(HOBT)(3,52毫克;0,03毫摩尔;0,05当量)。反应混合物在室温下搅拌过夜。LC/MS指示完全转换。
粗反应混合物经由制备HPLC纯化并冻干,产生365毫克(0.343毫摩尔)的((S)-1-(((S)-1-(((S)-4-氨基-1-((4-(((((1S,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-2,3,9,10,13,15-六氢-1H,12H-苯并[de]吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-1-基)氨基甲酰基)氧基)甲基)苯基)氨基)-1,4-二氧代丁烷-2-基)氨基)-1-氧代丙烷-2-基)氨基)-1-氧代丙烷-2-基)氨基甲酸(9H-芴-9-基)甲酯
LC/MS:[M+H]=1064.2
制备HPLC:
柱:sunfire prep c18 obd-75.0克(250bar)
溶剂A:0.1%TFA水溶液溶剂C:
溶剂B:0.1%TFA乙腈溶液
步骤2
将((S)-1-(((S)-1-(((S)-4-氨基-1-((4-(((((1S,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-2,3,9,10,13,15-六氢-1H,12H-苯并[de]吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-1-基)氨基甲酰基)氧基)甲基)苯基)氨基)-1,4-二氧代丁烷-2-基)氨基)-1-氧代丙烷-2-基)氨基)-1-氧代丙烷-2-基)氨基甲酸(9H-芴-9-基)甲酯(365毫克;0,34毫摩尔;1,00当量)溶解在N,N-(4,00毫升)中。加入用于合成的哌啶(0,07毫升;0,69毫摩尔;2,00当量),并将反应溶液在室温下搅拌1小时。
反应混合物经由制备HPLC纯化,产生300毫克(0.314毫摩尔)的((1S,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-2,3,9,10,13,15-六氢-1H,12H-苯并[de]吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-1-基)氨基甲酸-4-((S)-4-氨基-2-((S)-2-((S)-2-氨基丙酰胺基)丙酰胺基)-4-氧代丁酰胺基)苄酯。
LC/MS:[M+H]:841.3
用于纯化的制备HPLC:
RediSep柱:C18 130克
SN:E0410A0D24BE1 Lot:262118923W
流速:75毫升/分钟
条件-体积:390,0毫升
洗脱剂:A1 0.1%TFA水溶液
洗脱剂:B1 0.1%TFA乙腈溶液
步骤3
向((1S,9S)-9-乙基-5-氟-9-羟基-4-甲基-10,13-二氧代-2,3,9,10,13,15-六氢-1H,12H-苯并[de]吡喃并[3',4':6,7]吲哚嗪并[1,2-b]喹啉-1-基)氨基甲酸-4-((S)-4-氨基-2-((S)-2-((S)-2-氨基丙酰胺基)丙酰胺基)-4-氧代丁酰胺基)苄酯(571毫克;0,60毫摩尔;1,00当量)在N,N-二甲基甲酰胺(20毫升)中的溶液中加入N-乙基二异丙胺(203微升;1,20毫摩尔;2,00当量)和3-马来酰亚胺基丙酸-N-琥珀酰亚胺酯(162毫克;0,60毫摩尔;1,00当量)。随后将反应混合物搅拌10分钟并经由LC/MS监测。
反应混合物经由制备HPLC纯化,获得378毫克(0.35毫摩尔)的DL2。
LC/MS:[M+H]:992.4
用于纯化的制备HPLC:
RediSep柱:C18 86克
SN:E0410A8B46130 Lot:281729189W
流速:60毫升/分钟
条件-体积:264,0毫升
洗脱剂1:A1 0.1%TFA水溶液
洗脱剂2:B1 0.1%TFA乙腈溶液
序列分析:
方法信息:A:H2O+0,05% HCOOH|B:MeCN+0,04% HCOOH+1% H2O
T:40℃|流速:3,3毫升/分钟|MS:100-2000amu正电荷
柱:Chromolith HR RP-18e 50-4,6mm
0%->100% B:0->2,0分钟|100% B:2,0->2,5min
实施例4:制备免疫缀合物:mAb1的葡萄糖醛酸基缀合物(称为ADC1)
4.1缀合方法
抗体制备
在缀合前将抗体mAb1(如上文中所定义)在2-8℃下解冻最多3天,并在2-8℃下储存直至使用。在使用前,在缀合当天,在室温下平衡mAb1(>10g)。将mAb(9.6毫克/毫升)等分(10.0克,1041.7毫升)并使用缀合缓冲液(200mM组氨酸,pH 6.5)稀释至5.59毫克/毫升。将mAb溶液加入到3升ChemSlass夹套反应器中并设定为25±2℃,同时在50rpm下搅拌。
抗体的还原
将7.0摩尔当量(9.7毫升)的50mM TCEP溶液(在缀合缓冲液中的50mM TCEP)加入到mAb溶液小瓶中,并使反应在25±2℃下进行3小时。
缀合
称量式(X)的药物-接头化合物1(DL1)并溶解在DMSO中以制备20mM溶液。将90%(148.6毫升)所需DMSO加入到反应器中。在加入DMSO后立即将10.0摩尔当量(38.2毫升)的20mM药物-接头溶液加入到反应器中。随后,用10%(18.2毫升)剩余的所需DMSO冲洗药物-接头小瓶以确保完全转移。在最终添加后,使反应在25±2℃下进行1小时。缀合期间的总体积为1997.0毫升。
注意:反应的总DMSO浓度为10%(v/v)(DMSO+药物接头溶液)。
猝灭
向反应器中加入35摩尔当量(48.5毫升)的50mM NAC,并使反应在25±2℃下进行30分钟。
过滤
将过滤的粗缀合物溶液从反应器中转移并随后使用Millipak Gamma Gold 60(MPGL06GH2)过滤以获得1993.6毫升(过滤器负载:324.7克/m2[蛋白],66.5升/m2[溶液])的过滤的粗缀合物。
渗滤
用Pellicon 3(30kDa)Biomax膜(1×0.11m2,300LMH(550毫升/分钟),16psi TMP,实际负载88.5克/m2)对过滤的粗缀合物溶液进行缓冲液交换(DV=1993.6毫升)。渗滤缓冲液(10mM组氨酸,pH 5.5)用于将粗缀合物缓冲液交换16个渗滤体积(diavolume)。在缓冲液交换后,将溶液浓缩至≥25毫克/毫升,转移到瓶中,并用渗滤缓冲液冲洗膜。从UF/DF回收的总体积为361.5毫升。
配制
用112.1毫升渗滤缓冲液(10mM组氨酸,pH 5.5)将浓缩的ADC(即ADC1)稀释至20.0毫克/毫升。用157.6毫升的4×配制缓冲液(10mM组氨酸,12%(w/v)海藻糖二水合物,400mMNaCl,pH 5.5)将所得溶液稀释至15.0毫克/毫升,使最终目标原料药(bulk drugsubstance)(BDS)浓度为15.0毫克/毫升。
过滤
使用0.2μm Millipak Gamma Gold 40(MPGL04GH2)过滤器过滤最终配制的ADC以产生619.6毫升(过滤器负载:464.6克/m2[蛋白],31.0升/m2[溶液])的ADC1 BDS。将材料包装到HDPE瓶中并储存在≤-65℃下。
4.2方法:药物物质表征:ADC1
体积排阻层析(SEC)方法
SEC方法参数
波长 280nm
柱 Tosoh TSKgel 7.8mm×300mm,5μm(P/N 0008541)
流动相0.14M磷酸二氢钾
50mM磷酸二氢钠
0.06M磷酸氢二钾
0.25M氯化钾
5%IPA
注射体积 20微升
温度 25℃
流速 0.5毫升/分钟
运行时间 30分钟
显示储备mAb、UF后缀合物和最终BDS的纯度的典型SEC层析图:图14。
对于上面显示的BDS材料,已经报道了1.7% HMWS和96.9%的单体纯度。反相HPLC(RP HPLC)方法
RP HPLC方法参数
波长 280nm
流动相A含有0.01% TFA的0.1%甲酸水溶液
流动相B含有0.01% TFA的0.1%甲酸ACN溶液
梯度
注射体积 10微升
柱温 80℃
流速 1.0毫升/分钟
运行时间 30分钟
样品制备将样品稀释至2毫克/毫升,并将40微升加入到微量离心管中。加入60微升的约8M盐酸胍、约130mM Tris、约1mM EDTA,pH 7.6缓冲液。加入2微升的500mM DTT并涡旋混合。在37±2℃下温育样品30±2分钟。
显示轻链和重链的分离的典型RP-HPLC层析图:图15。该层析图显示了储备mAb、粗ADC和最终BDS的重叠。
对于上述ADC1 BDS材料。报道了7.9的DAR。
游离药物方法
游离药物方法参数
波长 254nm
柱 Phenomenex Gemini,C18,2×150mm,3μm(P/N 00F-4439-B0)
流动相A 0.1%甲酸水溶液
流动相B 0.1%甲酸乙腈溶液
梯度
注射体积 10.00微升
柱温度 50℃
流速 0.75毫升/分钟
样品制备蛋白滴(drop):100微升的药物物质+250微升的冷MeOH+50微升的3MMgCl2。在20,000rpm下旋转10分钟。
标准制备混合20微升的20mM DL1(在DMSO中的药物-接头化合物1)+20微升DMSO+40微升MeOH+20微升的在渗滤缓冲液中的200mM NAC。温育过夜以提供4mM DL-NAC。在MeOH中稀释4mM DL-NAC以提供4μMDL-NAC标准。
显示NAC标准和最终BDS的游离药物水平的典型层析图:图16。
对于上文显示的ADC1 BDS材料,已经报道了低于2.4%(按摩尔比计)的残余游离药物水平。
实施例5:制备免疫缀合物:mAb1的肽基缀合物(称为ADC2)
5.1缀合方法
抗体制备
在缀合前将抗体mAb1(如上文中所定义)在2-8℃下解冻最多3天,并在2-8℃下储存直至使用。在使用前,在缀合当天,在室温下平衡mAb1(>9.5g)。将mAb(9.6毫克/毫升)等分(9.5g,989.6毫升)并使用缀合缓冲液(200mM组氨酸,pH 6.5)稀释至5.59毫克/毫升。将mAb溶液加入到3升ChemSlass夹套反应器中并设定为25±2℃,同时在50rpm下搅拌。
抗体的还原
将8.0摩尔当量(10.5毫升)的50mM TCEP溶液(在缀合缓冲液中的50mM TCEP)加入到mAb溶液小瓶中,并使反应在25±2℃下进行3小时。
渗滤
使用Pellicon 3(30kDa)Biomax膜(1×0.11m2,300LMH(550毫升/分钟),16psiTMP,实际负载86.3克/m2)将还原的mAb溶液针对6DV(DV=1706.9毫升)进行缓冲液交换。缀合缓冲液(200mM组氨酸,pH 6.5)用于对还原抗体进行缓冲液交换。在缓冲液交换后,将还原的mAb溶液回收回反应器中,并用缀合缓冲液冲洗膜。
缀合
称量式(XI)的药物-接头化合物2(DL2)并溶解在DMSO中以制备20mM药物-接头溶液。将90%(142.6毫升)所需DMSO加入到反应器中。在加入DMSO后立即将9.5摩尔当量(31.2毫升)的20mM药物-接头溶液加入到反应器中。随后,用10%(15.8毫升)剩余的所需DMSO冲洗药物-接头小瓶以确保完全转移。在最终添加后,使反应在25±2℃下进行2小时。缀合反应期间的总体积为1894.5毫升。
猝灭
向反应器中加入35摩尔当量(46毫升)的50mM NAC,并使反应在25±2℃下进行45分钟。
过滤
将粗缀合物溶液从反应器中转移并随后使用Millipak Gamma Gold 60(MPGL06GH2)过滤以获得1897.3毫升(过滤器负载:308.9克/m2[蛋白],63.2升/m2[溶液])的过滤的粗缀合物。
渗滤
用Pellicon 3(30kDa)Biomax膜(1×0.11m2,300LMH(550毫升/分钟),16psi TMP,实际负载84.2克/m2)对过滤的粗缀合物溶液进行缓冲液交换(DV=1897.3毫升)。使用缀合缓冲液(200mM组氨酸,pH 6.5)进行初始的12DV,并随后切换至标准渗滤缓冲液(10mM组氨酸,pH 5.5)进行8个另外的DV。在缓冲液完成缓冲液交换后,随后将溶液浓缩至≥25毫克/毫升,转移到瓶中,并用渗滤缓冲液冲洗膜。从UF/DF回收的总汇集体积为335.7毫升。
配制
用84.7毫升渗滤缓冲液(10mM组氨酸,pH 5.5)将浓缩的ADC(即ADC2)稀释至20.0毫克/毫升。用138.6毫升的4×配制缓冲液(10mM组氨酸,12%(w/v)海藻糖二水合物,400mMNaCl,pH 5.5)稀释所得溶液,使最终目标BDS浓度为15.0毫克/毫升。
过滤
使用Millipak Gamma Gold 60(MPGL06GH2)无菌过滤最终配制的ADC以产生549.3毫升(过滤器负载:411.4克/m2[蛋白],27.5升/m2[溶液])的ADC2 BDS。将该材料包装到HDPE瓶中并储存在≤-65℃下。
5.2方法:药物物质表征:ADC2
体积排阻层析(SEC)方法
SEC方法参数
波长 280nm
柱 Tosoh TSKgel 7.8mm×300mm,5μm(P/N 0008541)
流动相 50mM磷酸二氢钾
0.4M高氯酸钠
pH 6.3
注射体积 1微升
柱温 25℃
流速 0.5毫升/分钟
运行时间 30分钟
显示储备mAb和最终BDS的纯度的典型SEC层析图:图17。
对于上面显示的ADC2 BDS材料,已经报道了4.2% HMWS和95.8%的单体纯度。
反相HPLC(RP HPLC)方法
RP HPLC方法参数
波长 280nm
流动相A含有0.01% TFA的0.1%甲酸水溶液
流动相B含有0.01% TFA的0.1%甲酸ACN溶液
梯度
注射体积 10微升
柱温 80℃
流速 1.0毫升/分钟
运行时间 30分钟
样品制备将样品稀释至2毫克/毫升,并将40微升加入到微量离心管中。加入60微升的约8M盐酸胍、约130mM Tris、约1mM EDTA,pH 7.6缓冲液。加入2微升的500mM DTT并涡旋混合。在37±2℃下温育样品30±2分钟。
显示轻链和重链的分离的典型RP-HPLC层析图:图18。该层析图显示了储备mAb和最终BDS的重叠。
对于上述ADC2 BDS材料。报道了7.6的DAR。
游离药物方法
游离药物方法参数
波长 254nm
柱 Phenomenex Gemini,C18,2×150mm,3μm(P/N 00F-4439-B0)
流动相A 0.1%甲酸水溶液
流动相B 0.1%甲酸乙腈溶液
梯度
注射体积 10.00微升
柱温 50℃
流速 0.75毫升/分钟
样品制备蛋白滴:100微升的药物物质+250微升的冷MeOH+50微升的3M MgCl2。在20,000rpm下旋转10分钟。
标准制备混合20微升的20mM DL2(在DMSO中的药物-接头化合物2)+20微升DMSO+40微升MeOH+20微升的在渗滤缓冲液中的200mM NAC。温育过夜以提供4mM DL-NAC。在MeOH中稀释4mM DL-NAC以提供4μM DL-NAC标准。
显示NAC标准和最终BDS的游离药物水平的典型层析图:图19。
对于上文显示的ADC2 BDS材料,已经报道了低于1.9%(按摩尔比计)的残余游离药物水平。
实施例6:ADC SAR408701的类似物
6.1抗体
为了进一步的对比实验的目的,基于具有以下序列的单克隆抗体制备Sanofi的抗CEACAM5 ADC SAR408701的类似物:
重链:SEQ ID NO:25
轻链:SEQ ID NO:26
6.2药物-接头化合物
作为待与上述抗体缀合的药物-接头分子,使用SPDB-DM4(获自LevenaBiopharma):
产品名:SPDB-DM4
结构:
预期质量:994.35
观察到的平均质量:995.5(Ms+H+)
质谱分析:一致,表现出正确的MW
HPLC分析:纯度>95%
外观:白色粉末
6.3缀合
在缀合前将抗体在2-8℃下解冻最多3天,并在2-8℃下储存直至使用。在使用前,在缀合当天,在室温下平衡抗体(175毫克)。使用缀合缓冲液(PBS pH 7.4)和SPDB-DM4(Levena Biopharma)的5mM DMSO溶液(相对于抗体为8摩尔当量),将抗体(7.9毫克/毫升)稀释至5毫克/毫升。混合反应溶液并在25℃下温育4小时。
6.4制备型体积排阻层析、脱盐和过滤
使用制备型体积排阻层析纯化反应混合物。将Superdex 200pg(50/60)柱连接到Avant 25系统(GE Healthcare)并根据制造商的说明书用PBS pH 7.4平衡。随后,注入反应混合物并用10毫升/分钟的流速和作为运行缓冲液的PBS pH 7.4流穿该柱。经由280nM处的UV光吸收确定含有ADC的级分,汇集并浓缩。根据制造商的说明书使用15毫升Amicon Ultra 50kDa截流离心装置(Merck Millipore)浓缩ADC材料。根据制造商的说明书,使用HiPrep 26/10脱盐柱(GE Healthcare)以10毫升/分钟的流速在Avant 25系统(GE Healthcare)上将浓缩的ADC材料转移至配制缓冲液(10mM组氨酸、130mM甘氨酸、5%蔗糖,pH 5.5)中。使用0.2μm过滤器(Merck Millipore)过滤所得ADC材料,等分并随后在液氮中快速冷冻。ADC材料的最终浓度为5.82毫克/毫升,并将该材料保持在-80℃下直到进一步使用。从该工作获得的ADC在本文中也称为“ADC SAR DM4”,或者简称为“ADC SAR”;该ADC是SAR408701的类似物。
实施例7:基于mAb1和SPDB-DM4的ADC
基于抗体mAb1(如上文中所述)和药物-接头化合物SPDB-DM4(即与上述ADC SARDM4中相同的药物-接头化合物)制备另一ADC。从该工作获得的ADC在本文中称为“ADC mAb1DM4”,并如下制备:
7.1所用材料:
·抗体:mAb1,在10mM HEPES中1毫克/毫升,pH 5.8
·缀合缓冲液:10mM HEPES,pH 5.8
·药物-接头化合物:SPDB-DM4,在DMF中2毫克/毫升
7.2方法:
·缀合:大约30倍摩尔过量的药物-接头分子用于缀合(75毫升抗体+7.1毫升SPDB-DM4药物-接头),在室温下缓慢摇动温育5小时
·纯化:将ADC进行缓冲液交换至20mM组氨酸,150mM NaCl,pH 6.0以除去游离药物
·配制缓冲液:20mM组氨酸,150mM NaCl,pH 6.0
7.3纯化的ADC分析细节:
·最终产量:40mg
·浓度:2.2毫克/毫升
·DAR:4.4
实施例8:释放自ADC1和ADC2的药物的表征
8.1材料和方法
8.1.1测试制品
8.1.2材料
根据制造商的说明书储存所有试剂和缓冲液并在批次有效期前使用。
8.1.3仪器
仪器 | 供应商 |
CO2培养器 | Heraeus |
恒温混匀器 | Eppendorf |
HTC PAL自动进样器 | CTC Analytics |
1200HPLC | Agilent Technologies |
API4000三重四极杆 | Sciex |
8.1.4程序
8.1.4.1血清样品制备
2M HEPES溶液:将52.1克HEPES溶解在75毫升MiliQ水和15毫升25%HCl中,调节至pH 7.55,并添加至总共100毫升。将该溶液以15%v/v与血清混合以获得pH 7.3-7.4的稳定化血清。将来自Biowest的人血清(批号S15594S4200)解冻。将100毫升血清与15毫升2MHEPES缓冲液混合。将来自Biowest的小鼠血清(批号S18169S2160)解冻。将100毫升血清与15毫升2M HEPES缓冲液混合。将食蟹猴血清解冻,并将8.5毫升血清与1.5毫升2M HEPES缓冲液混合。测量pH(7.37)并将血清无菌过滤。将2毫升的等分试样冷冻在-20℃下。
将制备的血清在室温下解冻。所需ADC蛋白浓度以180微克/毫升制备为三次重复,用于后续经由LC-MS进行游离有效负载分析。在将ADC加入到血清中后,将单独的批次混合并分成20微升等分试样。此外,对于每个ADC吸取一个20微升的96小时样品,并用于总后处理分析以测量回收。将0小时样品直接冷冻在-80℃下,剩余样品在37℃和5% CO2下温育,并经由在-80℃下储存而将反应停止在2/4/6/24/48/72/96小时温育处。
8.1.4.2人肝脏溶酶体样品制备
使用测定缓冲液将pH调节至pH 5.0或pH 4.0。溶酶体稳定性制剂:如对ADC1(n=3)示例性显示的那样,制备80微升人肝脏溶酶体用于三次重复测量:2.76微升ADC1+6微升人肝脏溶酶体+71.2微升天冬酰胺内肽酶测定缓冲液。MeOH+PIC(1:200)的制备:10微升PICIII+1990微升MeOH。将Eppendorf管转移到预热至37℃的Thermomix中开始反应。随后,在0、1、2、4、24和48小时后抽取10微升等分试样并与40微升PIC III(1:200)混合。
8.2结果
人、小鼠和食蟹猴血清的ADC稳定性(图20)。使用游离依沙替康(归一化数据)计算缀合的依沙替康浓度(初始剂量约10μM)。获得了人、食蟹猴和小鼠血清的类似概况。仅观察到少量弹头(warhead)释放,对于ADC2(在96小时初始缀合物有效负载的5.9%游离)和ADC1(1.4%),在小鼠血清中最显著。
小鼠血清和缓冲液的ADC3对照稳定性(图21)。使用游离SN38(未归一化)计算缀合的SN38浓度(初始剂量50微克/毫升ADC蛋白浓度)。对两种基质均观察到显著的SN-38释放。
ADC1和ADC2在人肝脏溶酶体(pH 5.0)中的有效负载释放概况(图22)。使用例如游离依沙替康(初始浓度约10μM依沙替康)的归一化数据计算缀合的药物浓度。对于ADC1和ADC2裂解介导的有效负载释放,观察到中等水平的有效负载释放(均为初始总缀合物有效负载的约40%)。
ADC分解代谢物分析证实游离的依沙替康为溶酶体释放产物(图23)。为了证实依沙替康为主要释放产物,在人溶酶体提取物中进行ADC1分解代谢物分析研究。此时,在不同时间点的TIC-MS和提取的离子层析图的比较显示,预期的依沙替康分解代谢物随后在温育期间(0小时、4小时、24小时)从ADC1释放。保留时间9.33分钟,检测的分解代谢物的检测质量m/z 436.1671([M+H]+,C24H23O4N4 F)和MS/MS图谱与依沙替康的那些一致。
实施例9:ADC1和ADC2以高效力在体外特异性杀伤癌细胞
使用人癌细胞系评估ADC1和ADC2杀伤癌细胞的潜力。ADC1和ADC2对不同的CEACAM5阳性细胞系显示亚纳摩尔的体外效力,而对CEACAM5阴性细胞系显示较小的影响(下表2)。如示例性剂量-应答曲线中显示的那样(图24A/B),ADC1和ADC2对CEACAM5阳性细胞系SK-CO-1和SNU-16非常有效。相反,ADC1和ADC2对抗原阴性MDA-MB-231的影响限于测试的最高浓度(图24C)。
使用与ADC1和ADC2相同的接头有效负载的同种型对照ADC显示出低得多的对SK-CO-1细胞系的影响(图25)。
总之,ADC1和ADC2在体外以高效力特异性杀伤表达CEACAM5的人癌细胞系。
表2.ADC1、ADC2和游离有效负载对多种人细胞系的效力。在最高测试化合物浓度下与未处理对照相比的最大作用显示在括号中。对每种细胞系,显示CEACAM5表达。
方法——活力测定:
ADC对癌细胞系的细胞毒性作用通过细胞活力测定来测量。在处理前一天,将细胞以90微升的体积接种在96孔板中。将测试化合物(ADC或游离有效负载)以10倍起始浓度配制在细胞培养基中。将测试化合物连续稀释(1:4),并将10微升的每种稀释物一式三份加入到细胞中。将板在CO2培养箱中在37℃下培养六天。为了细胞活力测量,将Cell Titer-试剂(PromegaTM Corp,Madison,WI)加入到每个孔中,并根据制造商的说明书处理板。使用Varioskan读板器(Thermo Fisher)测量发光信号。将发光读数转换为相对于未处理细胞的%活力。使用log(抑制剂)对应答、可变斜率、使用GraphPad Prism的4参数拟合方程,用非线性回归分析拟合数据。数据显示为%相对细胞活力对摩尔化合物浓度,误差条指示三次重复的标准偏差(SD)。计算来源于多个实验的IC50的几何平均值。
使用与上文相同的方法,还将ADC1和ADC2与ADC SAR DM4在它们对抗原阳性SK-CO-1和抗原阴性MDA-MB-231细胞系的细胞毒性作用方面进行比较。ADC1和ADC2分别显示出ADC SAR DM4对SK-CO-1癌细胞的2.9倍和2.7倍的效力(图26A)。与ADC1和ADC2相比,ADCSAR DM4针对抗原阴性MDA-MB-231的非特异性作用略高(图26B)。ADC SAR DM4和ADC mAb1DM4针对SK-CO-1显示出可比较的效力,其中ADC mAb1 DM4略微倾向于更高效力(图26A)。
实施例10:ADC1和ADC2在与抗原阳性细胞的共培养中介导针对抗原阴性细胞的强效旁观者效应
在旁观者测定中评估ADC1和ADC2介导针对紧邻抗原阳性细胞的抗原阴性细胞的旁观者效应的潜力。在CEACAM5阳性SK-CO-1的存在下,ADC1和ADC2显示出针对CEACAM5阴性MDA-MB-231细胞的强效旁观者效应(图27A)。在单培养物活力测定中,在1E-9M的测试浓度下,ADC1和ADC2处理导致对SK-CO-1细胞的最大作用(图26A),而对MDA-MB-231没有观察到作用(图26B)。与这些发现一致,在仅MDA-MB-231对照的旁观者测定设置中没有观察到ADC1或ADC2的非特异性作用(图27B)。
总之,ADC1和ADC2在与抗原阳性细胞的共培养中介导针对抗原阴性癌细胞的强效旁观者效应。这些发现指示有效靶向具有异源靶标表达的肿瘤的潜力。
与ADC SAR相比,ADC1和ADC2在与抗原阳性细胞的共培养中介导对抗原阴性细胞的强效得多的旁观者效应(图28A、图28B)。使用与ADC1和ADC2(即mAb1)中相同的抗体以及用于ADC SAR DM4的药物-接头分子(即SPDB-DM4)的ADC mAb1 DM4也显示出比ADC SAR DM4更显著的旁观者效应(图28A,图28B)。这指示与使用不同抗体的ADC SAR相比,mAb1有助于观察到的ADC1和ADC2的更高的旁观者效应。
对于所有测试的ADC,旁观者效应的程度随着加入到恒定数量的抗原阴性细胞中的抗原阳性细胞数量的增加而增加(比较图28A和图28B)。这指示更多的ADC被抗原阳性细胞加工以释放负责对抗原阴性细胞的旁观者效应的游离有效负载。
在单独的MDA-MB-231细胞上没有观察到测试的ADC的非特异性作用(图28C)。
方法——旁观者测定
通过旁观者测定测量ADC对与抗原阳性癌细胞系共培养的抗原阴性癌细胞系的细胞毒性作用。在共培养实验中,每孔接种一千个CEACAM5阴性MDA-MB-231细胞与750或3000个CEACAM5阳性SK-CO-1细胞。作为对照,仅平行接种1000个MDA-MB-231细胞。在处理前一天,将细胞以90微升的总体积接种在96孔板中。将测试化合物以1E-9M的10倍最终浓度配制在细胞培养基中,并将10微升一式两份加入到细胞中。将板在CO2培养箱中在37℃下培养六天。
在免疫荧光染色之前,除去培养基,并用100%甲醇(-20℃)处理细胞30分钟。在除去甲醇和一个PBS洗涤步骤后,将细胞用PBS中含0.2% Triton X-100的2.5%多聚甲醛(PFA)在室温下处理15分钟。在除去溶液和一个PBS洗涤步骤后,将细胞用PBS中的1% BSA/0.1%吐温/0.1%叠氮化钠在室温下处理至少一小时。通过用10微克/毫升人抗CEACAM5(mAb1)第一抗体和荧光(藻红蛋白)标记的驴抗人IgG第二抗体(Jackson ImmunoResearch#709-116-149)的1:2000稀释物的免疫荧光染色来区分抗原阳性和抗原阴性细胞。通过使用1微克/毫升Hoechst 33342(Life technologies,cat#H3570)染料的细胞核染色来鉴定细胞。在室温下在1%BSA/0.1%叠氮化钠PBS溶液中进行染色30分钟。将第二抗体染色与Hoechst染料染色组合。在染色步骤之间和之后,细胞用PBS洗涤三次。
用共焦定量图像细胞计数器CQ1(Electric Corporation,Tokyo,Japan)对板进行成像。分析由CQ1软件(Yokogawa)模板“细胞核和假细胞体”进行调整,并且FCS输出文件使用FlowJo(BD)进行分析。基于细胞核周围荧光标记抗体的染色或未染色,区分抗原阳性和抗原阴性细胞并定量。柱状图显示了每种处理条件下鉴定的抗原阳性和抗原阴性细胞的数量。
实施例11:ADC1和ADC2在结肠直肠癌(CRC)患者来源的异种移植(PDX)小鼠模型中的功效
已经在人类患者来源的CRC异种移植模型COPF217(Shanghai LideBiotech CO.,LTD)中评估了体内抗肿瘤功效。将COPF217肿瘤碎片皮下移植到六至八周龄免疫缺陷雌性小鼠(NU-Foxn1nu,Charles River)的右胁腹。当肿瘤达到165mm3的平均体积时,用溶媒(盐水溶液)或用ADC1或ADC2(每个的剂量为10毫克/千克;第0天)静脉内治疗6只小鼠/组一次。用测径器测量肿瘤长度(L)和宽度(W),并使用公式L×(W^2)/2计算肿瘤体积。
以10毫克/千克的剂量用ADC1或ADC2的单次治疗导致显著的抗肿瘤作用。两种物质均显示了导致肿瘤停滞的可比较作用(图29)。用ADC1或ADC2的治疗对体重没有显著影响(数据未显示)。
用其他CRC PDX模型的进一步实验:
在对应于上文所述COPF217的实验的另外的实验中,用ADC1的单次治疗也导致在具有高CEACAM5表达的12个其他CRC PDX模型中的肿瘤停滞或肿瘤消退。
实施例12:ADC1在非小细胞肺癌(NSCLC)PDX小鼠模型中的功效
已经在人类患者来源的NSCLC异种移植模型LUPF160151(Shanghai LideBiotechCO.,LTD)中评估了体内抗肿瘤功效。将LUPF160151肿瘤碎片皮下移植到六至八周龄免疫缺陷雌性小鼠(NU-Foxn1nu,Charles River)的右胁腹。当肿瘤达到180mm3的平均体积时,用溶媒(盐水溶液)或用ADC1(6毫克/千克;第0天)静脉内治疗5只小鼠/组一次。用测径器测量肿瘤长度(L)和宽度(W),并使用公式L×(W^2)/2计算肿瘤体积。
以6毫克/千克的剂量用ADC1的单次治疗导致显著的抗肿瘤作用(图30),对体重没有影响(数据未显示)。在CEACAM5阴性肿瘤细胞与CEACAM5阳性肿瘤细胞相邻的情况下,模型LUPF160151显示出异源CEACAM5表达。ADC1在该模型中的良好功效由此指示ADC的强效旁观者效应。
实施例13:ADC1在胃癌PDX小鼠模型中的功效
在人类患者来源的胃癌异种移植模型GAX066(Shanghai ChemPartner Co.,Ltd)中评估了体内抗肿瘤功效。将肿瘤碎片皮下移植到免疫缺陷雌性小鼠(Nu/Nu小鼠,BeijingVital River Lab Animal Technology Co.Ltd,18-22克)的右胁腹。当肿瘤达到220mm3的平均体积时,用溶媒(盐水溶液)或用ADC1(3或10毫克/千克;第0天)静脉内治疗6只小鼠/组一次。用测径器测量肿瘤长度(L)和宽度(W),并使用公式L×(W^2)/2计算肿瘤体积。
用3或10毫克/千克ADC1的单次治疗引起显著的抗肿瘤作用(图31),对体重没有影响(数据未显示)。在六个肿瘤中的五个中,用10毫克/千克的治疗导致完全的肿瘤消退。
实施例14:ADC1与ADC3相比在胰腺细胞系来源的肿瘤模型中的功效
已经在人胰腺细胞系来源的异种移植模型HPAF-II(ATCC,CRL-1997)中评估了ADC1与ADC3相比的功效。将5×106个HPAF-II细胞皮下注射到六至八周龄免疫缺陷雌性小鼠(Hsd:Athymic Nude-Foxn1nu,Envigo)的右胁腹。当肿瘤达到150mm3的平均体积时,用溶媒(盐水溶液)或用ADC1(1毫克/千克或6毫克/千克;第0天)或用ADC3(1毫克/千克或6毫克/千克;第0天)静脉内治疗10只小鼠/组一次。用测径器测量肿瘤长度(L)和宽度(W),并使用L×(W^2)/2计算肿瘤体积。
以6毫克/千克的剂量用ADC1的单次治疗导致显著的抗肿瘤作用。该作用是剂量依赖性的,因为用1毫克/千克的单次治疗仅导致温和但显著的、短暂的抗肿瘤作用。相反,用相同剂量的ADC3的单次治疗在任一剂量下均未显示显著的抗肿瘤作用(图32)。所有治疗对体重均无显著影响(数据未显示)。
实施例15:ADC1与ADC SAR DM4相比在两种CRC PDX小鼠模型中的功效
在人类患者来源的CRC异种移植模型COPF230和REPF210(Shanghai LideBiotechCO.,LTD)中评估了体内抗肿瘤功效。将肿瘤碎片皮下移植到六至八周龄免疫缺陷雌性小鼠(NU-Foxn1nu,Charles River)的右胁腹。当肿瘤达到大约170mm3的平均体积时,用溶媒(盐水溶液)、ADC1(6毫克/千克)或ADC SAR DM4(6毫克/千克)静脉内治疗6只小鼠/组一次(第0天)。用测径器测量肿瘤长度(L)和宽度(W),并使用公式L×(W^2)/2计算肿瘤体积。
用ADC1的单次治疗在PDX模型COPF230(图33)和REPF210(图34)中均导致显著的抗肿瘤作用。相反,用相同剂量的ADC SAR DM4的单次治疗在任一CRC PDX模型中均未显示抗肿瘤作用(图33、图34)。在任何治疗组中都没有观察到对体重的显著影响(数据未显示)。
实施例16:ADC1与ADC SAR DM4相比在胃PDX小鼠模型(GAPF313)中的功效
在人类患者来源的胃异种移植模型GAPF313(Shanghai LideBiotech CO.,LTD)中评估了体内抗肿瘤功效。将肿瘤碎片皮下移植到六至八周龄免疫缺陷雌性小鼠(NU-Foxn1nu,Charles River)的右胁腹。当肿瘤达到大约180mm3的平均体积时,从第0天开始,每两周用溶媒(盐水溶液)、ADC1(4毫克/千克或7毫克/千克Q2W×3)或ADC SAR DM4(4.7毫克/千克Q2W×3)静脉内治疗6只小鼠/组3次(第0天)。用测径器测量肿瘤长度(L)和宽度(W),并使用公式L×(W^2)/2计算肿瘤体积。
正在进行的实验的中期数据分析证明ADC1在该模型中的明确抗肿瘤功效,并且ADC SAR DM4没有作用(图35)。所有治疗均耐受良好(数据未显示)。
实施例17:ADC1的安全性概况——在食蟹猴中的初步毒性研究
为了研究安全性概况,将ADC1以0、3、10和30毫克/千克的剂量通过30分钟静脉内输注以3周时间间隔施用于食蟹猴三次(在第1、22和43天),并在第50天处死动物用于总体和组织病理学检查。作为结果,发现ADC1具有相对有利的安全性概况,因为ADC1在某些受已知ADC的毒副作用影响的器官中没有毒性。
<110> Merck Patent GmbH
<120> 抗CEACAM5抗体和缀合物及其用途
<130> P20-166 WO-PCT
<150> EP20195559.8
<151> 2020-09-10
<150> EP20194711.6
<151> 2020-09-04
<160> 30
<170> BiSSAP 1.3.6
<210> 1
<211> 702
<212> PRT
<213> 智人
<220>
<223> 根据GenBank登录号AAA51967.1的人CEACAM5蛋白序列
<400> 1
Met Glu Ser Pro Ser Ala Pro Pro His Arg Trp Cys Ile Pro Trp Gln
1 5 10 15
Arg Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Lys Leu Thr Ile Glu Ser Thr Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Val His Asn Leu Pro Gln His Leu Phe Gly
50 55 60
Tyr Ser Trp Tyr Lys Gly Glu Arg Val Asp Gly Asn Arg Gln Ile Ile
65 70 75 80
Gly Tyr Val Ile Gly Thr Gln Gln Ala Thr Pro Gly Pro Ala Tyr Ser
85 90 95
Gly Arg Glu Ile Ile Tyr Pro Asn Ala Ser Leu Leu Ile Gln Asn Ile
100 105 110
Ile Gln Asn Asp Thr Gly Phe Tyr Thr Leu His Val Ile Lys Ser Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Thr Gln Asp Ala Thr Tyr
165 170 175
Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Gln
180 185 190
Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn Val Thr Arg Asn
195 200 205
Asp Thr Ala Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Ala Arg
210 215 220
Arg Ser Asp Ser Val Ile Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
225 230 235 240
Thr Ile Ser Pro Leu Asn Thr Ser Tyr Arg Ser Gly Glu Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser Trp Phe
260 265 270
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Thr Cys Gln Ala His Asn Ser
290 295 300
Asp Thr Gly Leu Asn Arg Thr Thr Val Thr Thr Ile Thr Val Tyr Ala
305 310 315 320
Glu Pro Pro Lys Pro Phe Ile Thr Ser Asn Asn Ser Asn Pro Val Glu
325 330 335
Asp Glu Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Ile Gln Asn Thr
340 345 350
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg
355 360 365
Leu Gln Leu Ser Asn Asp Asn Arg Thr Leu Thr Leu Leu Ser Val Thr
370 375 380
Arg Asn Asp Val Gly Pro Tyr Glu Cys Gly Ile Gln Asn Glu Leu Ser
385 390 395 400
Val Asp His Ser Asp Pro Val Ile Leu Asn Val Leu Tyr Gly Pro Asp
405 410 415
Asp Pro Thr Ile Ser Pro Ser Tyr Thr Tyr Tyr Arg Pro Gly Val Asn
420 425 430
Leu Ser Leu Ser Cys His Ala Ala Ser Asn Pro Pro Ala Gln Tyr Ser
435 440 445
Trp Leu Ile Asp Gly Asn Ile Gln Gln His Thr Gln Glu Leu Phe Ile
450 455 460
Ser Asn Ile Thr Glu Lys Asn Ser Gly Leu Tyr Thr Cys Gln Ala Asn
465 470 475 480
Asn Ser Ala Ser Gly His Ser Arg Thr Thr Val Lys Thr Ile Thr Val
485 490 495
Ser Ala Glu Leu Pro Lys Pro Ser Ile Ser Ser Asn Asn Ser Lys Pro
500 505 510
Val Glu Asp Lys Asp Ala Val Ala Phe Thr Cys Glu Pro Glu Ala Gln
515 520 525
Asn Thr Thr Tyr Leu Trp Trp Val Asn Gly Gln Ser Leu Pro Val Ser
530 535 540
Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Thr Leu Thr Leu Phe Asn
545 550 555 560
Val Thr Arg Asn Asp Ala Arg Ala Tyr Val Cys Gly Ile Gln Asn Ser
565 570 575
Val Ser Ala Asn Arg Ser Asp Pro Val Thr Leu Asp Val Leu Tyr Gly
580 585 590
Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Ser Ser Tyr Leu Ser Gly
595 600 605
Ala Asn Leu Asn Leu Ser Cys His Ser Ala Ser Asn Pro Ser Pro Gln
610 615 620
Tyr Ser Trp Arg Ile Asn Gly Ile Pro Gln Gln His Thr Gln Val Leu
625 630 635 640
Phe Ile Ala Lys Ile Thr Pro Asn Asn Asn Gly Thr Tyr Ala Cys Phe
645 650 655
Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Ser Ile
660 665 670
Thr Val Ser Ala Ser Gly Thr Ser Pro Gly Leu Ser Ala Gly Ala Thr
675 680 685
Val Gly Ile Met Ile Gly Val Leu Val Gly Val Ala Leu Ile
690 695 700
<210> 2
<211> 705
<212> PRT
<213> 食蟹猴
<220>
<223> 食蟹猴CEACAM5蛋白序列(NCBI参考序列XP_005589491.1)
<400> 2
Met Gly Ser Pro Ser Ala Pro Leu His Arg Trp Cys Ile Pro Trp Gln
1 5 10 15
Thr Leu Leu Leu Thr Ala Ser Leu Leu Thr Phe Trp Asn Pro Pro Thr
20 25 30
Thr Ala Gln Leu Thr Ile Glu Ser Arg Pro Phe Asn Val Ala Glu Gly
35 40 45
Lys Glu Val Leu Leu Leu Ala His Asn Val Ser Gln Asn Leu Phe Gly
50 55 60
Tyr Ile Trp Tyr Lys Gly Glu Arg Val Asp Ala Ser Arg Arg Ile Gly
65 70 75 80
Ser Cys Val Ile Arg Thr Gln Gln Ile Thr Pro Gly Pro Ala His Ser
85 90 95
Gly Arg Glu Thr Ile Asp Phe Asn Ala Ser Leu Leu Ile His Asn Val
100 105 110
Thr Gln Ser Asp Thr Gly Ser Tyr Thr Ile Gln Val Ile Lys Glu Asp
115 120 125
Leu Val Asn Glu Glu Ala Thr Gly Gln Phe Arg Val Tyr Pro Glu Leu
130 135 140
Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro Val Glu Asp Lys
145 150 155 160
Asp Ala Val Ala Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr Thr Tyr
165 170 175
Leu Trp Trp Val Asn Asn Gln Ser Leu Pro Val Ser Pro Arg Leu Glu
180 185 190
Leu Ser Ser Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro Arg Asn
195 200 205
Asp Thr Thr Ser Tyr Lys Cys Glu Thr Gln Asn Pro Val Ser Val Arg
210 215 220
Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp Ala Pro
225 230 235 240
Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn Leu Asn
245 250 255
Leu Ser Cys His Ala Ala Ser Asn Pro Thr Ala Gln Tyr Phe Trp Phe
260 265 270
Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile Pro Asn
275 280 285
Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His Asn Ser
290 295 300
Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val Tyr Ala
305 310 315 320
Glu Leu Pro Lys Pro Tyr Ile Thr Ser Asn Asn Ser Asn Pro Ile Glu
325 330 335
Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Glu Thr Gln Asp Thr
340 345 350
Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser Ser Arg
355 360 365
Leu Glu Leu Ser Asn Asp Asn Arg Thr Leu Thr Val Phe Asn Ile Pro
370 375 380
Arg Asn Asp Thr Thr Phe Tyr Glu Cys Glu Thr Gln Asn Pro Val Ser
385 390 395 400
Val Arg Arg Ser Asp Pro Val Thr Leu Asn Val Leu Tyr Gly Pro Asp
405 410 415
Ala Pro Thr Ile Ser Pro Leu Asn Thr Pro Tyr Arg Ala Gly Glu Asn
420 425 430
Leu Asn Leu Ser Cys His Ala Ala Ser Asn Pro Ala Ala Gln Tyr Ser
435 440 445
Trp Phe Val Asn Gly Thr Phe Gln Gln Ser Thr Gln Glu Leu Phe Ile
450 455 460
Pro Asn Ile Thr Val Asn Asn Ser Gly Ser Tyr Met Cys Gln Ala His
465 470 475 480
Asn Ser Ala Thr Gly Leu Asn Arg Thr Thr Val Thr Ala Ile Thr Val
485 490 495
Tyr Val Glu Leu Pro Lys Pro Tyr Ile Ser Ser Asn Asn Ser Asn Pro
500 505 510
Ile Glu Asp Lys Asp Ala Val Thr Leu Thr Cys Glu Pro Val Ala Glu
515 520 525
Asn Thr Thr Tyr Leu Trp Trp Val Asn Asn Gln Ser Leu Ser Val Ser
530 535 540
Pro Arg Leu Gln Leu Ser Asn Gly Asn Arg Ile Leu Thr Leu Leu Ser
545 550 555 560
Val Thr Arg Asn Asp Thr Gly Pro Tyr Glu Cys Gly Ile Gln Asn Ser
565 570 575
Glu Ser Ala Lys Arg Ser Asp Pro Val Thr Leu Asn Val Thr Tyr Gly
580 585 590
Pro Asp Thr Pro Ile Ile Ser Pro Pro Asp Leu Ser Tyr Arg Ser Gly
595 600 605
Ala Asn Leu Asn Leu Ser Cys His Ser Asp Ser Asn Pro Ser Pro Gln
610 615 620
Tyr Ser Trp Leu Ile Asn Gly Thr Leu Arg Gln His Thr Gln Val Leu
625 630 635 640
Phe Ile Ser Lys Ile Thr Ser Asn Asn Asn Gly Ala Tyr Ala Cys Phe
645 650 655
Val Ser Asn Leu Ala Thr Gly Arg Asn Asn Ser Ile Val Lys Asn Ile
660 665 670
Ser Val Ser Ser Gly Asp Ser Ala Pro Gly Ser Ser Gly Leu Ser Ala
675 680 685
Arg Ala Thr Val Gly Ile Ile Ile Gly Met Leu Val Gly Val Ala Leu
690 695 700
Met
705
<210> 3
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR1-H
<400> 3
Asp Gly Ser Val Ser Arg Gly Gly Tyr Tyr
1 5 10
<210> 4
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR2-H
<400> 4
Ile Tyr Tyr Ser Gly Ser Thr
1 5
<210> 5
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR3-H
<400> 5
Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr
1 5 10
<210> 6
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR1-L
<400> 6
Gln Ser Val Arg Ser Asn
1 5
<210> 7
<211> 3
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR2-L
<400> 7
Ala Ala Ser
1
<210> 8
<211> 9
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CDR3-L
<400> 8
Gln Gln Tyr Thr Asn Trp Pro Phe Thr
1 5
<210> 9
<211> 119
<212> PRT
<213> 人工序列
<220>
<223> mAb1的VH
<400> 9
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 10
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> mAb1的VL
<400> 10
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys
100 105
<210> 11
<211> 328
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CH
<400> 11
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
1 5 10 15
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65 70 75 80
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100 105 110
Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
115 120 125
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
130 135 140
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
145 150 155 160
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
165 170 175
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
180 185 190
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
195 200 205
Ala Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
210 215 220
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
225 230 235 240
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
245 250 255
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
260 265 270
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
275 280 285
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
290 295 300
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
305 310 315 320
Lys Ser Leu Ser Leu Ser Pro Gly
325
<210> 12
<211> 107
<212> PRT
<213> 人工序列
<220>
<223> mAb1的CL
<400> 12
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
1 5 10 15
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
20 25 30
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
35 40 45
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
50 55 60
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
65 70 75 80
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
85 90 95
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 13
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> mAb1的HC
<400> 13
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser 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 Pro Val Ala Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ser Ser Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 14
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> mAb1的LC
<400> 14
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 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
210
<210> 15
<211> 1404
<212> DNA
<213> 人工序列
<220>
<223> 编码mAb1的HC的DNA序列
<400> 15
atggagaccg acaccctgct gctgtgggtg ctgctgctgt gggtgcccgg gtcgaccggt 60
gaggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 120
acctgcactg tctctgatgg ctccgtcagc aggggtggtt actacttgac ctggatccgc 180
cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcacctac 240
ttcaacccgt ccctcaggag tcgggttacc atgtcagtag acacgtctaa gaaccagttc 300
tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagaggg 360
atagcagtgg ctccctttga ctactggggc cagggaaccc tggtcaccgt ctcttcagct 420
agcaccaagg gccccagcgt gttccccctg gcccccagca gcaagtccac aagcggagga 480
acagccgccc tgggctgcct ggtgaaggac tacttccccg agcccgtgac cgtgtcctgg 540
aacagcggag ccctgacctc cggcgtgcac accttccccg ccgtgctgca gagcagcggc 600
ctgtacagcc tgagcagcgt ggtgacagtg ccaagcagca gcctgggaac ccagacctac 660
atctgcaacg tgaaccacaa gcccagcaac accaaggtgg acaagagagt ggagcccaag 720
agctgcgaca agacccatac ctgtccaccc tgcccagccc ccccagtggc cggaccctcc 780
gtgttcctgt tcccccccaa gcccaaggac accctgatga tcagcaggac ccccgaggtg 840
acctgcgtgg tggtggacgt gagccacgag gacccagagg tgaagttcaa ttggtatgtg 900
gacggcgtgg aggtgcacaa cgccaagacc aagcccagag aggaacagta caacagcacc 960
tacagggtgg tgtccgtgct gaccgtgctg caccaggact ggctgaacgg caaggaatac 1020
aagtgcaagg tctccaacaa ggccctgccc tccagcatcg agaaaaccat cagcaaggcc 1080
aagggccagc cacgggagcc ccaggtgtac acactgcccc catctcggga agaaatgacc 1140
aagaaccagg tgtccctgac ctgtctggtg aagggctttt accccagcga catcgccgtg 1200
gagtgggaga gcaacggcca gcccgagaac aactacaaga ccaccccccc tgtgctggac 1260
agcgacggca gcttcttcct gtacagcaag ctgaccgtgg acaagtccag gtggcagcag 1320
ggcaacgtgt tcagctgcag cgtgatgcac gaggccctgc acaaccacta cacacagaag 1380
agcctgagcc tgtcccccgg ctga 1404
<210> 16
<211> 708
<212> DNA
<213> 人工序列
<220>
<223> 编码mAb1的LC的DNA序列
<400> 16
atgagggccc tgctggctag actgctgctg tgcgtgctgg tcgtgtccga cagcaagggc 60
gaaatcgtac tcacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 120
ctctcctgca ggaccagtca gagtgttcgc agcaacttag cctggtacca gcagaagcct 180
ggccaggctc ccaggctcct catctatgct gcatccacca gggccactgg tatcccagcc 240
aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 300
gaagattttg cagtttatta ctgtcagcag tatactaact ggccattcac tttcggccct 360
gggaccaaag tggacatcaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 600
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gttgatag 708
<210> 17
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 抗体hu8G4的HC
<400> 17
Glu Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Leu Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser 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> 18
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 抗体hu8G4的LC
<400> 18
Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Glu Ile 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
210
<210> 19
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体1的HC
<400> 19
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Leu Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser 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> 20
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体1的LC
<400> 20
Glu Thr Thr Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Gly Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Glu Ile 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
210
<210> 21
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体2的LC
<400> 21
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 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
210
<210> 22
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体4的LC
<400> 22
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 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
210
<210> 23
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体5的LC
<400> 23
Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 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
210
<210> 24
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 优化抗体变体6的HC
<400> 24
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser 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> 25
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> huMab2-3 (同种异型)的HC
<400> 25
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Val Phe Ser Ser Tyr
20 25 30
Asp Met Ser Trp Val Arg Gln Thr Pro Glu Arg Gly Leu Glu Trp Val
35 40 45
Ala Tyr Ile Ser Ser Gly Gly Gly Ile Thr Tyr Ala Pro Ser Thr Val
50 55 60
Lys Gly Arg Phe Thr Val Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ala His Tyr Phe Gly Ser Ser Gly Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 26
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> huMab2-3的LC
<400> 26
Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Phe Ser Tyr
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Val
35 40 45
Tyr Asn Thr Arg Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Phe
85 90 95
Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile 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
210
<210> 27
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> hmn-14的HC
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15
Ser Leu Arg Leu Ser Cys Ser Ala Ser Gly Phe Asp Phe Thr Thr Tyr
20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile His Pro Asp Ser Ser Thr Ile Asn Tyr Ala Pro Ser Leu
50 55 60
Lys Asp Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80
Leu Gln Met Asp Ser Leu Arg Pro Glu Asp Thr Gly Val Tyr Phe Cys
85 90 95
Ala Ser Leu Tyr Phe Gly Phe Pro Trp Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Pro Val Thr Val Ser Ser 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> 28
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> hmn-14的LC
<400> 28
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Ser
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Thr Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Leu Tyr Arg Ser
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 29
<211> 441
<212> PRT
<213> 人工序列
<220>
<223> rb8G4的HC
<400> 29
Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Asp Gly Ser Val Ser Arg Gly
20 25 30
Gly Tyr Tyr Leu Thr Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Thr Tyr Phe Asn Pro Ser
50 55 60
Leu Arg Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys Asn Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr
85 90 95
Cys Ala Arg Gly Ile Ala Val Ala Pro Phe Asp Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser Gln Pro Lys Ala Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Cys Cys Gly Asp Thr Pro Ser Ser Thr Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Leu Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Thr Leu Thr Asn Gly Val Arg Thr Phe Pro Ser Val Arg Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Ser Val Thr Ser Ser
180 185 190
Ser Gln Pro Val Thr Cys Asn Val Ala His Pro Ala Thr Asn Thr Lys
195 200 205
Val Asp Lys Thr Val Ala Pro Ser Thr Cys Ser Lys Pro Thr Cys Pro
210 215 220
Pro Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys
225 230 235 240
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
245 250 255
Val Val Asp Val Ser Glu Asp Asp Pro Glu Val Gln Phe Thr Trp Tyr
260 265 270
Ile Asn Asn Glu Gln Val Arg Thr Ala Arg Pro Pro Leu Arg Glu Gln
275 280 285
Gln Phe Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Ala His
290 295 300
Glu Asp Trp Leu Arg Gly Lys Glu Phe Lys Cys Lys Val His Asn Lys
305 310 315 320
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Arg Gly Gln
325 330 335
Pro Leu Glu Pro Lys Val Tyr Thr Met Gly Pro Pro Arg Glu Glu Leu
340 345 350
Ser Ser Arg Ser Val Ser Leu Thr Cys Met Ile Asn Gly Phe Tyr Pro
355 360 365
Ser Asp Ile Ser Val Glu Trp Glu Lys Asn Gly Lys Ala Glu Asp Asn
370 375 380
Tyr Lys Thr Thr Pro Ala Val Leu Asp Ser Asp Gly Ser Tyr Phe Leu
385 390 395 400
Tyr Ser Lys Leu Ser Val Pro Thr Ser Glu Trp Gln Arg Gly Asp Val
405 410 415
Phe Thr Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
420 425 430
Lys Ser Ile Ser Arg Ser Pro Gly Lys
435 440
<210> 30
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> rb8G4的LC
<400> 30
Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
1 5 10 15
Glu Arg Ala Thr Leu Ser Cys Arg Thr Ser Gln Ser Val Arg Ser Asn
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Thr Asn Trp Pro Phe
85 90 95
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg Asp Pro Val Ala
100 105 110
Pro Ser Val Leu Leu Phe Pro Pro Ser Lys Glu Glu Leu Thr Thr Gly
115 120 125
Thr Ala Thr Ile Val Cys Val Ala Asn Lys Phe Tyr Pro Ser Asp Ile
130 135 140
Thr Val Thr Trp Lys Val Asp Gly Thr Thr Gln Gln Ser Gly Ile Glu
145 150 155 160
Asn Ser Lys Thr Pro Gln Ser Pro Glu Asp Asn Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Ser Leu Thr Ser Ala Gln Tyr Asn Ser His Ser Val Tyr
180 185 190
Thr Cys Glu Val Val Gln Gly Ser Ala Ser Pro Ile Val Gln Ser Phe
195 200 205
Asn Arg Gly Asp Cys
210
Claims (42)
1.一种分离的抗体,其结合至人CEACAM5蛋白,并且其包含由SEQ ID NO:3的氨基酸序列组成的CDR1-H、由SEQ ID NO:4的氨基酸序列组成的CDR2-H、由SEQ ID NO:5的氨基酸序列组成的CDR3-H、由SEQ ID NO:6的氨基酸序列组成的CDR1-L、由SEQ ID NO:7的氨基酸序列组成的CDR2-L和由SEQ ID NO:8的氨基酸序列组成的CDR3-L。
2.根据权利要求1的抗体,其包含含有与SEQ ID NO:9的氨基酸序列有至少85%同一性的氨基酸序列的重链可变区(VH)和含有与SEQ ID NO:10的氨基酸序列有至少85%同一性的氨基酸序列的轻链可变区(VL)。
3.根据权利要求1或2的抗体,其包含含有SEQ ID NO:9的氨基酸序列的重链可变区(VH)和含有SEQ ID NO:10的氨基酸序列的轻链可变区(VL)。
4.根据权利要求1至3任一项的抗体,其包含含有与SEQ ID NO:11的氨基酸序列有至少85%同一性的氨基酸序列的重链恒定区(CH)和含有与SEQ ID NO:12的氨基酸序列有至少85%同一性的氨基酸序列的轻链恒定区(CL)。
5.根据权利要求1至4任一项的抗体,其包含含有SEQ ID NO:11的氨基酸序列的重链恒定区(CH)和含有SEQ ID NO:12的氨基酸序列的轻链恒定区(CL)。
6.根据权利要求1至5任一项的抗体,其包含含有SEQ ID NO:13的氨基酸序列的重链(HC)和含有SEQ ID NO:14的氨基酸序列的轻链(LC)。
7.一种分离的抗体,其与包含SEQ ID NO:9的氨基酸序列的重链可变区(VH)和SEQ IDNO:10的氨基酸序列的轻链可变区(VL)的抗体竞争与人CEACAM5蛋白的A2-B2结构域的结合。
8.根据权利要求7的抗体,其中所述抗体还与包含SEQ ID NO:9的氨基酸序列的重链可变区(VH)和SEQ ID NO:10的氨基酸序列的轻链可变区(VL)的抗体竞争与食蟹猴(Macacafascicularis)CEACAM5蛋白的A2-B2结构域的结合。
9.根据权利要求7或8的抗体,其中所述抗体不与人CEACAM1、人CEACAM6、人CEACAM7、人CEACAM8和食蟹猴CEACAM6显著地交叉反应。
10.根据权利要求1至9任一项的抗体,其中所述抗体是抗体片段。
11.根据权利要求10的抗体,其中所述抗体是选自Fv、Fab、F(ab')2、Fab'、dsFv、(dsFv)2、scFv、sc(Fv)2和双抗体(diabody)的抗体片段。
12.根据权利要求1至11任一项的抗体,其是双特异性或多特异性抗体。
13.一种分离的抗体,其结合至人CEACAM5蛋白,并且其由两个相同的含有SEQ ID NO:13的氨基酸序列的重链(HC)和两个相同的含有SEQ ID NO:14的氨基酸序列的轻链(LC)组成。
14.一种分离的核酸,其包含编码根据权利要求1至13任一项的抗体的核酸序列。
15.一种宿主细胞,其已经用根据权利要求14的核酸转化。
16.一种免疫缀合物,其包含经由接头共价连接至至少一种生长抑制剂的根据权利要求1至13任一项的抗体。
17.根据权利要求16的免疫缀合物,其中所述生长抑制剂是细胞毒性药物或放射性部分。
19.根据权利要求16至18任一项的免疫缀合物,其中所述生长抑制剂是依沙替康(exatecan)。
20.根据权利要求16至19任一项的免疫缀合物,其中接头是可裂解接头。
21.根据权利要求16至20任一项的免疫缀合物,其中所述接头是可在哺乳动物细胞的核内体中裂解的接头。
22.根据权利要求16至21任一项的免疫缀合物,其中所述接头是可由选自葡萄糖醛酸酶和天冬酰胺内肽酶(legumain)的人酶裂解的接头。
27.根据权利要求16至26任一项的免疫缀合物,其中所述S是所述抗体的半胱氨酸的硫原子。
28.根据权利要求27的免疫缀合物,其中所述抗体的半胱氨酸是能够形成链间二硫键的半胱氨酸中的一种。
29.根据权利要求23至28任一项的免疫缀合物,其中n为7至8。
30.根据权利要求23至29任一项的免疫缀合物,其中n为7.5至8.0。
31.一种包含根据权利要求1至13任一项的抗体或根据权利要求16至30任一项的免疫缀合物的药物组合物,其进一步包含药学上可接受载体、稀释剂和/或赋形剂。
32.根据权利要求1至13任一项的抗体或根据权利要求16至30任一项的免疫缀合物或根据权利要求31的药物组合物,其用作药物。
33.根据权利要求1至13任一项的抗体或根据权利要求16至30任一项的免疫缀合物或根据权利要求31的药物组合物,其用于治疗癌症。
34.用于根据权利要求33所述使用的抗体、免疫缀合物或药物组合物,其中所述癌症是表达CEACAM5的癌症。
35.用于根据权利要求33或34所述使用的抗体、免疫缀合物或药物组合物,其中所述癌症是结肠直肠癌、胃癌、肺癌、胰腺癌、食管癌或前列腺癌。
36.治疗癌症的方法,其包括向受试者施用根据权利要求1至13任一项的抗体或根据权利要求16至30任一项的免疫缀合物或根据权利要求31的药物组合物。
37.根据权利要求36的方法,其中所述癌症是表达CEACAM5的癌症。
38.根据权利要求36或37的方法,其中所述癌症是结肠直肠癌、胃癌、肺癌、胰腺癌、食管癌或前列腺癌。
39.使用根据权利要求1至13任一项的抗体在来自受试者的生物样品中离体检测CEACAM5表达的方法。
40.根据权利要求39的方法,其中所述抗体用可检测分子标记。
41.根据权利要求1至13任一项的抗体用于在来自受试者的生物样品中离体检测CEACAM5表达的用途。
42.根据权利要求41的用途,其中所述抗体用可检测分子标记。
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EP20194711.6 | 2020-09-04 | ||
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EP20195559 | 2020-09-10 | ||
EP20195559.8 | 2020-09-10 | ||
PCT/EP2021/072595 WO2022048883A1 (en) | 2020-09-04 | 2021-08-13 | Anti-ceacam5 antibodies and conjugates and uses thereof |
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CN (1) | CN116113439A (zh) |
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WO2023172968A1 (en) * | 2022-03-09 | 2023-09-14 | Merck Patent Gmbh | Anti-gd2 antibodies, immunoconjugates and therapeutic uses thereof |
WO2024091437A1 (en) * | 2022-10-25 | 2024-05-02 | Merck Sharp & Dohme Llc | Exatecan-derived adc linker-payloads, pharmaceutical compositions, and uses thereof |
WO2024108053A1 (en) * | 2022-11-17 | 2024-05-23 | Sanofi | Ceacam5 antibody-drug conjugates and methods of use thereof |
WO2024110905A1 (en) * | 2022-11-24 | 2024-05-30 | Beigene, Ltd. | Anti-cea antibody drug conjugates and methods of use |
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