CN116419929B - 亲和力降低的改造的egfr抗体、药物偶联物及其用途 - Google Patents
亲和力降低的改造的egfr抗体、药物偶联物及其用途 Download PDFInfo
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Abstract
本发明提供了与人EGFR蛋白结合的分离的抗体和所述抗体的ADC。本发明还提供了包括所述抗体和ADC的药物组合物以及治疗癌症的方法。
Description
相关申请的交叉引用
本申请要求申请日为2020年11月20日的国际申请PCT/CN2020/130409和申请日为2020年11月20日的国际申请PCT/CN2020/130417的优先权。本申请通过引用合并上述两份专利申请所公开的全文。
背景技术
抗体是对抗外源病原体的关键免疫分子。单克隆抗体(monoclonal antibody,mAb)技术的发展使得单克隆抗体在疾病的研究、诊断和治疗中的被广泛应用。第一代mAb(主要是单特异性的二价mAb)的治疗应用在治疗多种疾病方面取得了成功,包括癌症、自身免疫病和传染病。然而,许多疾病,如实体瘤,已显示出对基于抗体的疗法具有很强的抵抗力。
抗体偶联药物(Antibody Drug Conjugate,ADC)是与活性毒性药物化学连接的mAb,因此具有mAb的靶向特异性和细胞毒性药物的癌症杀伤能力。选择特定的mAb-毒性药物组合的能力以及mAb和药物连接的进展为靶向癌症提供了新的可能性,同时最大限度地减少了对健康组织的暴露。截至2019年,FDA共批准了7种ADC,包括:恩美曲妥珠单抗(ado-trastuzumab emtansine,KadcylaTM)、维布妥昔单抗(brentuximab vedotin,AdcetrisTM)、奥英妥珠单抗(inotuzumab ozogamicin,BesponsaTM)、吉妥珠单抗(gemtuzumabozogamicin,MylotargTM)、泊洛妥珠单抗(polatuzumab vedotin-piiq,PolivyTM)、维汀-恩弗妥单抗(Enfortumab vedotin,PadcevTM)和德喜曲妥珠单抗(Trastuzumab deruxtecan,EnhertuTM),它们都包含细胞毒性药物与二价mAb的偶联。除了已获准上市的这七种ADC药物外,目前还有大量的ADC正在临床开发中。
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR,也称为HER1或c-erbB-1)是一种170kDa的跨膜糖蛋白,是细胞表面受体酪氨酸激酶家族的成员[1,2]。EGFR在许多上皮肿瘤中异常激活,包括非小细胞肺癌,乳腺癌,结肠直肠癌,头颈癌和胶质母细胞瘤[3-8]。受体的过表达、基因扩增、激活突变、受体配体的过表达和/或EGFR活性调节剂的缺失可以引起EGFR的异常激活。
通过阻断受体胞外结构域上的EGFR结合位点或通过抑制胞内酪氨酸激酶活性来中断EGFR的信号传导,可以抑制表达EGFR的肿瘤的生长并改善患者的病情[9-11]。抗EGFR抗体通过结合细胞表面的受体来干扰配体结合而发挥抗肿瘤作用,从而抑制其下游信号通路[12,13]。
EGFR的几种配体阻断抗体,包括西妥昔单抗(cetuximab)、尼妥珠单抗(nimotuzumab)、帕尼单抗(panitumumab)和耐昔妥珠单抗(necitumumab),已被批准用于治疗各种类型的癌症[13]。帕尼单抗是一种经临床验证的抗体,可有效且特异地靶向EGFR。然而,由于EGFR也在正常组织中表达,帕尼单抗的临床反应通常伴有显着的毒性[14]。此外,尽管帕尼单抗的极高亲和力(KD=10-11M)使其成为EGFR/EGF结合的强效阻断剂,但由于帕尼单抗与细胞毒性药物潜在的进一步复合的副作用,使其不适合用于ADC的构建。
发明内容
本公开的一方面提供了一种分离的抗体,所述抗体包含(a1)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示的氨基酸序列,和(b1)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQ ID NO:21和SEQ ID NO:23所示的氨基酸序列。本公开提供了另一种分离的抗体,所述抗体包含(a2)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQID NO:16和SEQ ID NO:17所示的氨基酸序列,和(b2)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:19、SEQ ID NO:22和SEQ ID NO:23所示的氨基酸序列。本公开提供了另一种分离的抗体,所述抗体包含(a3)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示的氨基酸序列,和(b3)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQ ID NO:22和SEQID NO:23所示的氨基酸序列。本公开提供了另一种分离的抗体,所述抗体包含(a4)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:16和SEQ IDNO:18所示的氨基酸序列,和(b4)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQ ID NO:21和SEQ ID NO:23所示的氨基酸序列。这些抗体与人EGFR蛋白特异性结合。在一些实施方案中,所述抗体与人EGFR结合的KD值的范围在约1×10-9M至约5×10-8M之间。
本公开的一方面提供了一种分离的抗体,所述抗体包含:(a)具有包含如SEQ IDNO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链;或者(b)具有包含如SEQ ID NO:5所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:6所示氨基酸序列的可变结构域的轻链;或者(c)具有包含如SEQ IDNO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:2所示氨基酸序列的可变结构域的轻链;或者(d)具有包含如SEQ ID NO:3所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链。
本公开的另一方面提供了一种分离的抗体,所述抗体包含:(a)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者(b)包含如SEQ ID NO:13所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者(c)包含如SEQ ID NO:11所示氨基酸序列的重链,以及包含如SEQ ID NO:12所示氨基酸序列的轻链;或者(d)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ IDNO:8所示氨基酸序列的轻链;或者(e)包含如SEQ ID NO:9所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链。
本申请所述的抗体可以为单克隆抗体。在一些实施方案中,本公开所述的抗体可以被视为重链的一个氨基酸突变和轻链的一个氨基酸突变的抗体帕尼单抗(Panitumumab),其为首个靶向EGFR的全人源单克隆抗体。当轻链的突变为Y32A时重链的突变可以为T103A,或者当轻链的突变为D50A时重链的突变可以为T59A。
在进一步的方面中还提供了一种编码如本发明所述的抗体的核酸分子、一种含有所述核酸分子的表达载体和一种含有所述表达载体的宿主细胞。
本公开的更进一步的方面提供了一种抗体偶联药物(ADC)或其药学上可接受的盐,其包含如本发明所述的抗体通过化学连接子与细胞毒性药物偶联。在一些实施方案中,所述细胞毒性药物可以选自由以下组成的组:单甲基奥瑞他汀E(monomethyl auristatinE、MMAE)、单甲基奥瑞他汀F(monomethylauristatinF、MMAF)、奥瑞他汀E(auristatin E)、奥瑞他汀F(auristatin F)、美登素DM1(maytansine DM1)和DM4、美登素醇(maytansino1)、山德霉素(sandramycin)、吡咯并苯并二氮杂卓(pyrrolobenzodiazepine)、吡咯并苯并二氮杂卓二聚体(pyrrolobenzodiazepine dimer)、蒽环类(anthracycline)、卡奇霉素(calicheamicin)、多拉司他汀10(dolastatin 10)、多卡霉素(duocarmycin)、多柔比星(doxorubicin)、泰兰斯他汀A(thailanstatinA)、钩霉素(uncialamycin)、鹅膏菌素(amanitin)、蓖麻毒素(ricin)、白喉毒素(diphtheriatoxin)、艾立布林(eribulin)、131I、白细胞介素(interleukin)、肿瘤坏死因子(tumornecrosis factor)、趋化因子(chemokine)、伊立替康(irinotecan,SN38)、依喜替康(exatecan)和纳米颗粒(nanoparticle)。
连接所述抗体部分和所述细胞毒性药物的化学连接子可以是可裂解的或不可裂解的。在一些实施方案中,所述连接子包含一个PEGn间隔区,其中n为1至20(即具有1至20个重复单元的(CH2CH2O))。在一些实施方案中,所述化学连接子进一步包含一个与所述PEGn间隔区相连的连接子片段。在一些实施方案中,所述化学连接子包含不含PEGn间隔区的连接子片段。在一些实施方案中,所述连接子片段可以选自由以下组成的组:6-马来酰亚胺基己酰基(6-maleimidocaproyl,MC)、马来酰亚胺丙酰基(maleimidopropionyl,MP)、缬氨酸-瓜氨酸(Val-Cit)、丙氨酸-苯丙氨酸(Ala-Phe)、对氨基苄氧羰基(p-aminobenzyloxycarbonyl,PAB)、6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-Val-Cit-PAB)、Mal-PEGn-Val-Cit-PAB(n=1-20)、Phe-Lys(Fmoc)-PAB、Aloc-D-Ala-Phe-Lys(Aloc)-PAB-PNP、Boc-Phe-(Alloc)Lys-PAB-PNP和3-(吡啶-2-基二硫基)丙酸全氟苯基酯(perfluorophenyl 3-(pyridine-2-yldisulfanyl)propanoate),或其组合。
本公开的进一步的方面提供了一种药物组合物,所述药物组合物包含本发明的一种或多种抗体、一种或多种ADC或其药学上可接受的盐,和药学上可接受的载体。
本公开的进一步的方面提供了一种治疗人类受试者疾病例如癌症的方法,所述方法包含向所述受试者施用治疗有效量的本发明所述的药物组合物。所述癌症可以包括非小细胞肺癌(non-small cell lung cancer)、表皮样癌(epidermoid carcinoma)、乳腺癌(breast cancer)、结肠直肠癌(colorectal cancer)、卵巢癌(ovariancancer)、宫颈癌(cervical cancer)、膀胱癌(bladder cancer)、食道癌(oesophageal cancer)、头颈癌(head and neck cancer)、胶质母细胞瘤(glioblastom)和鼻咽癌(nasopharyngealcancer)。
附图说明
图1显示了EGFR蛋白的抗体结合部位表面与帕尼单抗的CDR相互作用的示意图。(A)帕尼单抗轻链CDR与EGFR结构域III的末端β=链相互作用。上方的EGFR与下方的帕尼单抗的L1、L2和L3 CDR相互作用。(B)帕尼单抗重链CDR与EGFR结构域III的β-折叠表面相互作用,并结合EGFR。EGFR显示在H1、H2和H3 CDR区域的上方。发生突变的氨基酸被圈出。
图2显示了根据本发明的一些实施例的抗体的特征。(a)HEK293细胞产生的特定抗体的纯度和产量;(b)还原(R)抗体和非还原(NR)抗体的SDS-PAGE图谱;(c)纯化抗体的SEC-HPLC分析。
图3显示了根据本发明实施例的特定抗体以及其它抗体与EGFR的结合曲线。
图4显示了根据本发明实施例的由特定抗体制得的两个ADC的HIC谱图。
图5显示了根据本发明实施例的特定ADC和对比ADC对表达EGFR的癌细胞的细胞毒性曲线:(a)A431细胞,(b)NUGC3细胞,(b)A431细胞,(d)NUGC3细胞。
图6显示了与用溶媒治疗的小鼠中的肿瘤体积相比,用本公开的特定示例性ADC治疗的小鼠中的肿瘤体积随时间的变化。
具体实施方式
本公开提供了基于对帕尼单抗的氨基酸序列进行修饰的抗体。在不丧失对EGFR的结合特异性的情况下,修饰的(或突变的)抗体对抗原的亲和力降低,并且对正常组织的毒性降低。本发明还提供了基于这些抗体的ADC。根据一些实施方案,与由亲本野生型帕尼单抗和相同毒素制备的ADC相比,由突变抗体制备的ADC在杀死EGFR高表达肿瘤细胞方面保留相当的效力,同时对EGFR低表达细胞具有显著降低的效力。因此,使用由这种突变抗体制成的ADC治疗可以具有更好的治疗窗口,对与帕尼单抗治疗相关的EGFR低表达正常皮肤组织的非肿瘤靶向(on-target-off-tumor)毒性更小。
本文所使用的术语“单克隆抗体”是指单分子组成的抗体分子的制剂。
“与人EGFR特异性结合”的抗体或分子是指,与人EGFR蛋白结合但基本上不与非人EGFR蛋白结合的抗体或多肽分子。
本公开的一方面提供了一种分离的抗体,所述抗体包含(a1)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示的氨基酸序列,和(b1)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQ ID NO:21和SEQ ID NO:23所示的氨基酸序列。本公开提供了另一种分离的抗体,所述抗体包含(b1)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQID NO:16和SEQ ID NO:17所示的氨基酸序列,和(b2)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:19、SEQ ID NO:22和SEQ ID NO:23所示的氨基酸序列。提供了另一种分离的抗体,所述抗体包含(a3)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示的氨基酸序列,和(b3)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQ ID NO:22和SEQ ID NO:23所示的氨基酸序列。提供了另一种分离的抗体,所述抗体包含(a4)重链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:14、SEQ ID NO:16和SEQ ID NO:18所示的氨基酸序列,和(b4)轻链可变区,包含CDR1区、CDR2区和CDR3区,分别包含如SEQ ID NO:20、SEQID NO:21和SEQ ID NO:23所示的氨基酸序列。这些抗体与人EGFR蛋白特异性结合。在一些实施方案中,所述抗体与人EGFR结合的KD值的范围在约1×10-9M至约5×10-8M之间。
本公开的一方面提供了一种分离的抗体,所述抗体包含:(a)具有包含如SEQIDNO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链;或者(b)具有包含如SEQ ID NO:5所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:6所示氨基酸序列的可变结构域的轻链;或者(c)具有包含如SEQID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:2所示氨基酸序列的可变结构域的轻链;或者(d)具有包含如SEQ ID NO:3所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链。
本公开的另一方面提供了一种分离的抗体,所述抗体包含:(a)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者(b)包含如SEQ ID NO:13所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者(c)包含如SEQ ID NO:11所示氨基酸序列的重链,以及包含如SEQ ID NO:12所示氨基酸序列的轻链;或者(d)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ IDNO:8所示氨基酸序列的轻链;或者(e)包含如SEQ ID NO:9所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链。
可通过本领域已知的多种方法制备编码起始多肽的氨基酸序列变体的DNA。这些制备方法包括但不限于通过对初期制备的编码多肽的DNA进行定点(或寡核苷酸介导的)诱变、PCR诱变和盒式诱变。重组抗体的变体也可以通过限制性片段操作或与合成的寡核苷酸重叠延伸PCR来构建。诱变引物编码半胱氨酸密码子替换。可采用标准诱变技术产生编码此类突变工程改造抗体的DNA。
本公开的更进一步的方面提供了一种编码如本发明所述的抗体或任何所述抗体的抗原结合部分的核酸分子。一种包含含有所述核酸分子的表达载体的宿主细胞(例如,CHO细胞、人胚胎肾细胞、淋巴细胞或微生物(例如大肠杆菌,和真菌例如酵母)),其可被用于生产本公开的抗体,优选单克隆抗体。在一个实施方案中,编码本公开的部分或全长抗体的DNA可通过标准分子生物学技术获得,其被插入一个或多个表达载体中,使得基因可操作地连接至转录和翻译调控序列。术语“可操作地连接(operativelylinked)”旨在表示抗体基因被连接到载体中,使得载体中的转录和翻译控制序列发挥其调节抗体基因的转录和翻译的预期功能。术语“调控序列(regulatory sequence)”旨在包括控制抗体基因的转录或翻译的启动子、增强子和其它表达控制元件(例如,聚腺苷酸化信号)。例如,在Goeddel(Gene Expression Technology.Methods in Enzymology 185,Academic Press,SanDiego,Calif.(1990))中描述了此类调控序列。哺乳动物宿主细胞表达的优选调控序列包括在哺乳动物细胞中引导蛋白质高水平表达的病毒元件,例如来源于巨细胞病毒(cytomegalovirus,CMV)、猿猴病毒40(SimianVirus40,SV40)、腺病毒(adenovirus,例如腺病毒主要晚期启动子(AdMLP))和多瘤病毒(polyoma)的启动子和/或增强子。或者,可以使用非病毒调节序列,如泛素启动子或β-珠蛋白启动子。此外,调节元件由来自不同来源的序列组成,例如SRα启动子系统,其包含来自SV40早期启动子和人T细胞白血病病毒1型的长末端重复的序列(Takebe et al.,(1988)Mol.Cell.Biol.8:466-472)。选择与所使用的表达宿主细胞兼容的表达载体和表达控制序列。
可将编码抗体的DNA插入所述表达载体中。重组表达载体可编码促进抗体链从宿主细胞分泌的信号肽。可将编码抗体的DNA克隆进载体中,使得信号肽在框内与编码抗体氨基末端的DNA连接。所述信号肽可以是免疫球蛋白信号肽或异源信号肽(即来自非免疫球蛋白的信号肽)。
本公开的进一步的方面提供了一种抗体偶联药物(ADC)或其药学上可接受的盐,其包含如本发明所述的抗体通过化学连接子与细胞毒性药物偶联。在一些实施方案中,所述细胞毒性药物可以选自由以下组成的组:单甲基奥瑞他汀E(monomethyl auristatin E、MMAE)、单甲基奥瑞他汀F(monomethyl auristatinF、MMAF)、奥瑞他汀E(auristatin E)、奥瑞他汀F(auristatin F)、美登素DM1(maytansine DM1)和DM4、美登素醇(maytansinol)、山德霉素(sandramycin)、吡咯并苯并二氮杂卓(pyrrolobenzodiazepine)、吡咯并苯并二氮杂卓二聚体(pyrrolobenzodiazepine dimer)、蒽环类(anthracycline)、卡奇霉素(calicheamicin)、多拉司他汀10(dolastatin 10)、多卡霉素(duocarmycin)、多柔比星(doxorubicin)、泰兰斯他汀A(thailanstatinA)、钩霉素(uncialamycin)、鹅膏菌素(amanitin)、蓖麻毒素(ricin)、白喉毒素(diphtheriatoxin)、艾立布林(eribulin)、131I、白细胞介素(interleukin)、肿瘤坏死因子(tumornecrosis factor)、趋化因子(chemokine)、伊立替康(irinotecan,SN38)、依喜替康(exatecan)和纳米颗粒(nanoparticle)。
连接所述抗体部分和所述细胞毒性药物的化学连接子可以是可裂解的或不可裂解的。在一些实施方案中,所述连接子包含一个PEGn间隔区,其中n为1至20(即具有1至20个重复单元的(CH2CH2O))。在一些实施方案中,所述化学连接子进一步包含一个与所述PEGn间隔区相连的连接子片段。在一些实施方案中,所述化学连接子包含不含PEGn间隔区的连接子片段。在一些实施方案中,所述连接子片段可以选自由以下组成的组:6-马来酰亚胺基己酰基(6-maleimidocaproyl,MC)、马来酰亚胺丙酰基(maleimidopropionyl,MP)、缬氨酸-瓜氨酸(Val-Cit)、丙氨酸-苯丙氨酸(Ala-Phe)、对氨基苄氧羰基(p-aminobenzyloxycarbonyl,PAB)、6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基(MC-Val-Cit-PAB)、Mal-PEGn-Val-Cit-PAB(n=1-20)、Phe-Lys(Fmoc)-PAB、Aloc-D-Ala-Phe-Lys(Aloc)-PAB-PNP、Boc-Phe-(Alloc)Lys-PAB-PNP和3-(吡啶-2-基二硫基)丙酸全氟苯基酯(perfluorophenyl 3-(pyridine-2-yldisulfanyl)propanoate),或其组合。
本公开的进一步的方面提供了一种药物组合物,所述药物组合物包含本发明的一种或多种抗体、一种或多种ADC或其药学上可接受的盐,和药学上可接受的载体。如本文所用,“药学上可接受的载体”包括药学上可接受的载体、赋形剂或稳定剂。它们包括但不限于生理学上相容的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂、表面活性剂、增稠剂或乳化剂、固体粘合剂、分散或悬浮助剂、增溶剂、着色剂、调味剂、崩解剂、润滑剂、甜味剂、防腐剂和等渗剂等。合适载体的选择在本领域技术人员的知识范围内。组合物可以包含一种或多种额外的药物活性成分,例如另一种抗体和药物(例如细胞毒性剂或抗肿瘤剂)。本发明的药物组合物还可以在联合治疗中给药,例如与另一种抗癌剂和另一种抗炎剂等。
所述药物组合物可适用于静脉内(intravenous)、肌肉内(intramuscular)、皮下(subcutaneous)、肠胃外(parenteral)、表皮(epidermal)和其它给药途径。根据给药途径,活性成分可以包被于一种材料或以其他方式负载在材料或结构中,以保护其免受酸和可能使其失活的其他自然条件的作用。本文所用的短语“肠胃外给药”是指除肠内和局部(topical)给药之外的给药模式,通常通过注射,并且包括但不限于静脉内、肌内、动脉内(intraarterial)、鞘内(intrathecal)、囊内(intracapsular)、眼眶内(intraorbital)、心内(intracardiac)、皮内(intradermal)、腹膜内(intraperitoneal)、经气管(transtracheal)、皮下(subcutaneous)、表皮下(subcuticular)、关节内(intraarticular)、包膜下(subcapsular)、蛛网膜下(subarachnoid)、椎管内(intraspinal)、硬膜外(epidural)和胸骨内(intrasternal)注射和输注。或者,本发明的组合物可以通过非肠胃外途径给药,例如局部、表皮或粘膜给药途径(例如鼻内、口服、阴道、直肠、舌下或外用给药)。
本公开的另一方面提供了一种用于治疗人类受试者疾病例如癌症的方法,所述方法包含向所述受试者施用治疗有效量的本发明所述的药物组合物。所述癌症可以包括非小细胞肺癌(non-small cell lung cancer)、表皮样癌(epidermoid carcinoma)、乳腺癌(breast cancer)、结肠直肠癌(colorectal cancer)、卵巢癌(ovariancancer)、宫颈癌(cervical cancer)、膀胱癌(bladder cancer)、食道癌(oesophageal cancer)、头颈癌(head and neck cancer)、胶质母细胞瘤(glioblastom)和鼻咽癌(nasopharyngealcancer)。
在向受试者施用所述组合物时,可以调节给药方案以提供最佳的期望应答(例如治疗应答)。可根据受试者、待治疗的疾病等给予单次大剂量或分剂量给药。本文所用的剂量单位形式是指适合作为待治疗受试者的单一剂量的物理离散单位。每个单位含有经计算的预定量的活性成分,其与所需药物载体一起产生期望的治疗效果。在使用缓释制剂的情况下,需要更少的给药频率。
对于本公开的抗体或其ADC药物盐的给药,所述剂量可以为受试者体重的约0.0001至100mg/kg,更通常为0.01至10mg/kg。例如,剂量可以是0.3mg/kg体重、1mg/kg体重、3mg/kg体重、5mg/kg体重或10mg/kg体重,或在1-10mg/kg范围内。合适的治疗方案可以是每周一次、每两周一次、每三周一次、每四周一次和每月一次等。本发明的抗EGFR抗体的示例性给药方案可以包括以1mg/kg体重或3mg/kg体重的剂量静脉内给药。
本发明的抗体或ADC或其药物盐的“治疗有效量”或“有效量”优选导致疾病症状严重程度的降低、疾病无症状期的频率和/或持续时间的增加、预防或降低由于疾病痛苦导致的损伤或残疾的可能性、或抑制或延缓疾病的进展。例如,对于荷瘤受试者的治疗,相对于未治疗的受试者,“治疗有效量”的抗体组合物可抑制至少约20%、更优选至少约40%、进一步更优选至少约60%、并且再进一步优选至少约80%的肿瘤生长。
实施例
1.具有较低抗原亲和力的帕尼单抗突变抗体的设计。
帕尼单抗/EGFR复合物的高分辨率3D结构分析显示,尽管L3 CDR通常对抗原结合的贡献最大,但L2 CDR仅通过EGFR结构域III的D50和K465之间的溶剂暴露盐桥进行单独的相互作用,L1 CDR通过EGFR结构域III的Y32和I466之间的溶剂暴露氢键桥进行另一单独的相互作用(图1的A部分)。这与L1/L2 CDR通常只作出较小的结合贡献这一普遍观点是一致的。在重链方面,虽然H2和H3 CDR占据了帕尼单抗和EGFR结构域III之间大部分的中心嵌入的特定相互作用,但一个结合包括EGFR结构域III的T59至K443的羰基的H2 CDR氢键高度暴露于溶剂中。H3在EGFR结构域III的T103和K465的羰基之间形成一个额外的氢键,该结构域也高度暴露于溶剂中(图1的B部分)。上述相互作用的溶剂暴露性质促使本发明人假设,用含有较短侧链的氨基酸取代CDR中的L2D50、L1Y32、H2T59或H3T103氨基酸残基只会引起轻微的亲和力损失,并且可能仅对抗体/抗原相互作用界面造成不显著的破坏。
使用丙氨酸扫描技术,以制备对每个鉴定出的氨基酸进行丙氨酸取代的突变体。产生突变抗体时,每个突变的重链或轻链均与野生型(帕尼单抗)的或突变的轻链或重链配对。对8种产生的具有单突变或双突变的突变抗体(其VH和VL区以及相应的SEQ ID NO如下表所示)进行EGFR结合测定。
表1:突变抗体和对照抗体列表
进行密码子优化和基因合成以表达突变抗体。将特定的全长重链和全长轻链DNA分别克隆到一个单独的pcDNA3质粒中。使用成对质粒的HEK293细胞瞬时转染和并进行一步蛋白A纯化以制备用于检测的足够蛋白。以这种形式制备的抗体表达良好,产率可观,可通过一步蛋白A纯化过程进行高纯度纯化(图2的a、b、c部分)。
2.突变抗体的EGFR结合亲和力的测定
使用ELISA法检测并比较突变抗体与对照野生型(wt)抗体之间的EGFR结合能力。将突变抗体样品或对照抗体从10μg/mL开始连续5倍稀释,共稀释8次,包被在96孔板上,4℃孵育过夜。以40000倍稀释的HRP标记的山羊抗人IgGFc抗体(Sigma,A0170)作为检测试剂,使用TMB进行比色反应,在450/650nm下用酶标仪(美谷分子仪器,SpectraMax 190)读取平板上的吸光度,并使用四参数逻辑模型的剂量反应曲线格式进行数据分析。
图3中的结果显示,H2T59(BB0500-2f1)或L2D50(BB0500-2f2)单点丙氨酸取代对该突变抗体的EGFR结合活性的ECs0影响较小。相反,H3T103(BB0500-2g1)单点丙氨酸取代对该突变抗体的EGFR结合活性有很大影响(EC50~100倍变化),L1Y32(BB0500-2g2)突变导致EGFR结合活性完全丧失。这些结果表明,H2T59和L2D50对帕尼单抗的整体靶向结合活性的贡献极小,而H3T103和L1Y32要么在与帕尼单抗/EGFR复合物的高亲和力缔合中起关键作用,要么在这些位置的丙氨酸取代不利于抗原结合表面的正确构像。BB0500-2f1和BB0500-2f2的结合曲线的上平台均未达到wt对照水平,这表明两种取代均对靶向结合动力学的偏离率产生了影响。
双突变的结合图谱揭示了更为复杂的情况。首先,在H2T59和L2D50处均有丙氨酸取代的BB0500-2f似乎确实具有累加效应,对EC50的影响极小,但上平台更低。其次,H3T103/L2D50(BB0500-2gf)或H2T59/L1Y32(BB0500-2fg)上的双丙氨酸取代分别与H3T103或L1Y32(BB0500-2g1或BB0500-2g2)上的单突变表现非常相似,表明H3T103或L1Y32上的丙氨酸取代对突变抗体的整体结合活性具有主导作用。最后,也是最令人惊讶的是,H3T103和L1Y32的双突变(BB0500-2g)表现出良好的结合活性,类似于H2T59和L2D50双突变(BB0500-2f)。这种通过双突变而极大挽救的结合活性表明,除了失去侧链与靶点的相互作用之外,每个单突变都可能诱导H2环或L2环的构象变化。突变的H2环可能与wt L2环碰撞,反之亦然。相比之下,突变H2环和突变L2环可能适合聚合,因此,具有这一对特定双突变的突变抗体在很大程度上保留了整体EGFR结合活性。
在Octet RED96e(Pall FortéBio)上测量突变抗体和对照(wt)抗体对人EGFR的EGFR结合亲和力。使用AHC(anti-human Fc Capture)生物传感器在SD缓冲液(含0.02%Tween-20和0.1%BSA的PBS缓冲液,pH 7.4)中进行亲和检测。抗体样本或缓冲液被配置到96孔微量滴定板中。使用SD缓冲液对AHC生物传感器(Pall FortéBio)进行预湿,以在蛋白质固定前建立基线。抗体样品固定在生物传感器上。监测突变抗体或对照(wt)抗体与EGFR的结合缔合,并监测随后在SD缓冲液中的解离。在各EGFR浓度下评估突变抗体和对照抗体的结合。数据由数据采集软件自动生成,并使用FortéBio数据分析软件进行数据分析。
表2所示为结合亲和力数据。计算出wt对照抗体(帕尼单抗)的KD为10-10M,而突变体(BB0500-2f1、BB0500-2f2、BB0500-2n和BB0500-2g)的KD具有10-100倍的降低(在1×10-9-5×10-8M范围内),与低亲和力抗体BB05D3(尼妥珠单抗)相似。这种降低主要是由于解离速率更快且缔合速率变化不大所致。这些数据与ELISA数据一致,支持了突变抗体饱和结合能力的降低确实是由突变抗体/目标复合物更快解离引起的假设。
表2:突变抗体和wt抗体动力学结合亲和力参数结果
样品 | kon(1/Ms) | kdis(1/s) | KD(M) |
Ctl(wt) | 6.33E+05 | 8.07E-05 | 1.27E-10 |
BB05D3 | 1.04E+05 | 2.87E-03 | 2.77E-08 |
BB0500-2f1 | 6.55E+05 | 7.36E-04 | 1.12E-09 |
BB0500-2f2 | 5.43E+05 | 1.54E-02 | 2.83E-08 |
BB0500-2n | 5.43E+05 | 2.40E-02 | 4.41E-08 |
BB0500-2g | 7.01E+05 | 2.72E-02 | 3.88E-08 |
3.突变抗EGFR抗体的偶联生成ADC。
在温和的还原条件下(TCEP:mAb=1-3,中性pH,室温下<240分钟),抗体的链间二硫键可以部分还原并与药物-连接子偶联形成ADC。向中性pH的磷酸盐缓冲液中的纯化抗体加入TCEP进行部分还原,以生成偶联药物。将药物-连接子(Mal-PEG2-Val-Cit-PAB-艾立布林(eribulin)或MC-Val-Cit-PAB-MMAE)加入到DMA中,并使其与抗体反应,以获得所需的药物抗体比(drug-to-antibody ratio,DAR)。为表征抗体和ADC,使用疏水作用色谱(Hydrophobic Interaction Chromatography,HIC)评估ADC中的药物分布以及药物与抗体的摩尔比。还对非还原性ADC进行了CE-SDS,以评估ADC产品中非共价连接组分的百分比,如游离轻链(L)、游离重链(H)、半抗体(HL)、完整抗体(LHHL)和缺失一条或两条轻链的抗体(HHL或HH)。
为了制备适用于位点特异性药物偶联的抗体,以含有特殊铰链序列的形式制备了含有wt帕尼单抗(和wt尼妥珠单抗)可变序列和丙氨酸取代序列的抗体,所述特殊铰链序列位于天然H-H双二硫键上游并具有额外的H-H链间二硫键。该额外的H-H二硫键比链间其他二硫键更容易还原。因此经LC-MS验证,形成该二硫键的半胱氨酸残基成为了药物偶联的优选位点。由这些工程抗体制成的ADC主要由DAR2ADC的形式组成(图4的a部分:BB0500-2f偶联艾立布林,图4的b部分:BB0500-2g偶联艾立布林,图4的c部分:BB0500-2n偶联艾立布林;图4的d部分:BB0500-2f偶联MMAE,图4的e部分:BB0500-2g偶联MMAE,图4的f部分:BB0500-2n偶联MMAE)。
4.由突变抗体制成的ADC对EGFR高/低表达细胞的细胞毒性。
为了研究突变ADC(BB0500-2f/2g/2n-艾立布林,BB0500-2f/2g/2n-MMAE)的细胞毒性,在基于比色的细胞毒性试验中,通过与低亲和力ADC BB05D3-艾立布林/MMAE(尼妥珠单抗ADC)和野生型帕尼单抗ADC BB0500-2d-艾立布林/MMAE(Ctl ADC)进行比较,评估了这些ADC对EGFR表达水平不同的靶点表达癌细胞的体外细胞毒性。为进行试验,将靶细胞以每个细胞系的优化细胞密度接种到96孔平底组织培养板中,并在37℃、5%CO2下孵育过夜(16-20小时)。将连续稀释的ADC样本转移至细胞平板,并将待测平板培养一段特定的时间(3-5天,取决于细胞系),以实现最佳杀伤效果。数据分析采用四参数逻辑模型的剂量反应曲线。
如图5的a部分/5的b部分所示,由三种突变抗体(BB0500-2f、BB0500-2g和BB0500-2n)和毒素艾立布林组成的ADC对EGFR高表达细胞(A431细胞,图5的a部分)展现出与由含有wt帕尼单抗序列的抗体组成的ADC(BB0500-2d-艾立布林)相似的有力细胞毒性活性。这四种ADC对这种EGFR高表达细胞的作用都比由低亲和力抗EGFR抗体尼妥珠单抗组成的ADC(BB05D3-艾立布林)有效。相反地,对EGFR低表达细胞系(NUGC3细胞,图5的b部分)来说,由三种突变抗体(BB0500-2f/2g/2n)制成的ADC的细胞毒性效价更接近于BB05D3-艾立布林,而由含有wt帕尼单抗序列的抗体制成的ADC的细胞毒性显著更强。
如图5的c部分/5的d部分所示,由三种突变抗体(BB0500-2f、BB0500-2g和BB0500-2n)和毒素MMAE组成的ADC对EGFR高表达细胞系(A431细胞,图5的c部分)或EGFR低表达细胞系(NUGC3细胞,图5的d部分)展现出与由低亲和力抗EGFR抗体尼妥珠单抗(BB05D3-艾立布林)组成的ADC相似的有力细胞毒性活性。这四种ADC都不如由含wt帕尼单抗序列的抗体组成的ADC(BB0500-2d-MMAE)对EGFR高表达或低表达细胞都有效。
5.由突变抗体制成的ADC对移植瘤的体内疗效
在裸鼠中建立的表皮样癌移植瘤模型和肺癌移植瘤模型中评估了由突变抗体和MMAE制成的ADC的抗肿瘤活性。将A431(表皮样癌)和NCI-H441(肺癌)细胞植入无胸腺裸鼠背部。荷瘤小鼠接受一次溶媒(对照组)或5mg/kgADC(BB0500-2fl-MMAE、BB0500-2f2-MMAE、BB0500-2g-MMAE或BB0500-2n-MMAE)的治疗。在给药后的不同时间点测量肿瘤体积。结果如图6所示,在A431移植瘤模型(图6的a部分)和NCI-H441移植瘤模型(图6的b部分)中,与用溶媒治疗的小鼠中的肿瘤体积相比,用由突变抗体制成的ADC治疗的小鼠中的肿瘤体积减小了。
虽然已经详细描述了本发明的具体实施例,但是本领域技术人员将理解,根据已经公开的所有教导,可以对这些细节进行各种修改和替换,并且所有这些改变都落入本发明的范围内。本发明的全部范围由所附权利要求及其任何等同方案限定。
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本文所述的所有专利和非专利文献参考文献均通过引用全文并入本文。
虽然前文已经结合一个或多个实施例描述了本发明,但是应当理解,本发明不限于这些实施例,并且该描述旨在涵盖所有可包括在所附权利要求的精神和范围内的替换、修改和等同方案。
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SEQUENCE LISTING
<110> 百力司康生物医药(杭州)有限公司
<120> 亲和力降低的改造的EGFR抗体、药物偶联物及其用途
<130> P21408901C
<150> PCT/CN2020/130409
<151> 2020-11-20
<150> PCT/CN2020/130417
<151> 2020-11-20
<160> 23
<170> PatentIn version 3.5
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Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Pro Lys Ser Asp Cys Lys
210 215 220
Thr His Thr Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 10
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f2/2f/2gf/2n轻链
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ala Ala Ser Asn Leu Glu 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 Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly 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> 11
<211> 451
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2g1/2g/2gf重链
<400> 11
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Thr Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Ala Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Pro Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
290 295 300
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ser Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 12
<211> 214
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2g2/2g/2fg轻链
<400> 12
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Ala
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Asp Ala Ser Asn Leu Glu 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 Phe Cys Gln His Phe Asp His Leu Pro Leu
85 90 95
Ala Phe Gly Gly 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> 13
<211> 452
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2n重链
<400> 13
Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu
1 5 10 15
Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly
20 25 30
Asp Tyr Tyr Trp Thr Trp Ile Arg Gln Ser Pro Gly Lys Gly Leu Glu
35 40 45
Trp Ile Gly His Ile Tyr Tyr Ser Gly Asn Ala Asn Tyr Asn Pro Ser
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Ile Asp Thr Ser Lys Thr Gln Phe
65 70 75 80
Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Ile Tyr Tyr
85 90 95
Cys Val Arg Asp Arg Val Thr Gly Ala Phe Asp Ile Trp Gly Gln Gly
100 105 110
Thr Met Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
115 120 125
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro
195 200 205
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Pro Pro Lys Ser Asp Cys
210 215 220
Lys Thr His Thr Val Glu Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala
225 230 235 240
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
245 250 255
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
260 265 270
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
275 280 285
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
290 295 300
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
340 345 350
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
355 360 365
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
370 375 380
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
385 390 395 400
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
405 410 415
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
420 425 430
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
435 440 445
Ser Pro Gly Lys
450
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f1/2f2/2g1/2g2/2f/2g/2fg/2gf/2n及wt的VH CDR1
<400> 14
Gly Gly Ser Val Ser Ser Gly Asp Tyr
1 5
<210> 15
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f/2f1/2fg/2n的VH CDR2,具有T59A突变
<400> 15
Tyr Tyr Ser Gly Asn Ala
1 5
<210> 16
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f2/2g1/2g2/2g/2gf及wt的VH CDR2
<400> 16
Tyr Tyr Ser Gly Asn Thr
1 5
<210> 17
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2g/2g1/2gf的VH CDR3,具有T103A突变
<400> 17
Asp Arg Val Ala Gly Ala Phe Asp Ile
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f1/2f2/2g2/2f/2fg/2n及wt的VH CDR3
<400> 18
Asp Arg Val Thr Gly Ala Phe Asp Ile
1 5
<210> 19
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2g2/2g/2fg的VL CDR1,具有Y32A突变
<400> 19
Gln Ala Ser Gln Asp Ile Ser Asn Ala Leu Asn
1 5 10
<210> 20
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f1/2f2/2g1/2f/2gf/2n及wt的VL CDR1
<400> 20
Gln Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 21
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f2/2f/2gf/2n的VL CDR2,具有D50A突变
<400> 21
Ala Ala Ser Asn Leu Glu Thr
1 5
<210> 22
<211> 7
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f1/2g1/2g2/2g/2fg及wt的VL CDR2
<400> 22
Asp Ala Ser Asn Leu Glu Thr
1 5
<210> 23
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> BB0500-2f1/2f2/2g1/2g2/2f/2g/2fg/2gf/2n及wt的VL CDR3
<400> 23
Gln His Phe Asp His Leu Pro Leu Ala
1 5
Claims (18)
1.一种分离的抗体,所述抗体包含:
(a1)重链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示,和(b1)轻链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:20、SEQ ID NO:21和SEQ ID NO:23所示;或者
(a2)重链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:16和SEQ ID NO:17所示,和(b2)轻链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:19、SEQ ID NO:22和SEQ ID NO:23所示;或者
(a3)重链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:15和SEQ ID NO:18所示,和(b3)轻链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:20、SEQ ID NO:22和SEQ ID NO:23所示;或者
(a4)重链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:14、SEQ ID NO:16和SEQ ID NO:18所示,和(b4)轻链可变区,包含CDR1区、CDR2区和CDR3区,其氨基酸序列分别如SEQ ID NO:20、SEQ ID NO:21和SEQ ID NO:23所示;
其中所述分离的抗体与人EGFR蛋白特异性结合。
2.一种分离的抗体,所述抗体包含:
(a)具有包含如SEQ ID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQID NO:4所示氨基酸序列的可变结构域的轻链;或者
(b)具有包含如SEQ ID NO:5所示氨基酸序列的可变结构域的重链和具有包含如SEQID NO:6所示氨基酸序列的可变结构域的轻链;或者
(c)具有包含如SEQ ID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQID NO:2所示氨基酸序列的可变结构域的轻链;或者
(d)具有包含如SEQ ID NO:3所示氨基酸序列的可变结构域的重链和具有包含如SEQID NO:4所示氨基酸序列的可变结构域的轻链。
3.如权利要求2所述的分离的抗体,其中所述抗体包含:具有包含如SEQ ID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链。
4.一种分离的抗体,所述抗体包含:
(a)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者
(b)包含如SEQ ID NO:13所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链;或者
(c)包含如SEQ ID NO:11所示氨基酸序列的重链,以及包含如SEQ ID NO:12所示氨基酸序列的轻链;或者
(d)包含如SEQ ID NO:7所示氨基酸序列的重链,以及包含如SEQ ID NO:8所示氨基酸序列的轻链;或者
(e)包含如SEQ ID NO:9所示氨基酸序列的重链,以及包含如SEQ ID NO:10所示氨基酸序列的轻链。
5.如权利要求3所述的分离的抗体,其中所述抗体包含:包含如SEQ ID NO:7所示的氨基酸序列的重链,以及包含如SEQ ID NO:10所示的氨基酸序列的轻链。
6.如权利要求1-5中任一项所述的分离的抗体,其中所述抗体是单克隆抗体。
7.编码如权利要求1-5中任一项所述的抗体的核酸分子。
8.含有如权利要求7所述的核酸分子的表达载体。
9.含有如权利要求8所述的表达载体的宿主细胞。
10.一种抗体偶联药物(ADC)或其药学上可接受的盐,包含:如权利要求1-6中任一项所述的抗体通过化学连接子与细胞毒性药物偶联。
11.如权利要求10所述的ADC或其药学上可接受的盐,其中所述细胞毒性药物选自由以下组成的组:艾立布林、单甲基奥瑞他汀E(MMAE)、单甲基奥瑞他汀F(MMAF)、奥瑞他汀E、奥瑞他汀F、美登素DM1和DM4、美登素醇、山德霉素、吡咯并苯并二氮杂卓、吡咯并苯并二氮杂卓二聚体、蒽环类、卡奇霉素、多拉司他汀10、多卡霉素、多柔比星、泰兰斯他汀A、钩霉素、鹅膏菌素、蓖麻毒素、白喉毒素、131I、白细胞介素、肿瘤坏死因子、趋化因子、伊立替康SN38、依喜替康和纳米颗粒。
12.如权利要求11所述的ADC或其药学上可接受的盐,其中所述化学连接子包含的部分选自由以下组成的组:6-马来酰亚胺基己酰基MC、马来酰亚胺丙酰基MP、缬氨酸-瓜氨酸Val-Cit、丙氨酸-苯丙氨酸Ala-Phe、对氨基苄氧羰基PABC、6-马来酰亚胺基己酰基-缬氨酸-瓜氨酸-对氨基苄氧羰基MC-Val-Cit-PABC、Mal-PEGn-Val-Cit-PABC(n=1-20)、Phe-Lys(Fmoc)-PABC、Aloc-D-Ala-Phe-Lys(Aloc)-PABC-PNP、Boc-Phe-(Alloc)Lys-PABC-PNP和3-(吡啶-2-基二硫基)丙酸全氟苯基酯。
13.如权利要求10-12中任一项所述的ADC或其药学上可接受的盐,其中所述细胞毒性药物为艾立布林。
14.如权利要求13所述的ADC或其药学上可接受的盐,其中所述抗体包含:具有包含如SEQ ID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链。
15.如权利要求10-12中任一项所述的ADC或其药学上可接受的盐,其中所述细胞毒性药物为MMAE。
16.如权利要求15所述的ADC或其药学上可接受的盐,其中所述抗体包含:具有包含如SEQ ID NO:1所示氨基酸序列的可变结构域的重链和具有包含如SEQ ID NO:4所示氨基酸序列的可变结构域的轻链。
17.一种药物组合物,所述药物组合物包含:
(a)如权利要求1-6中任一项所述的抗体,或如权利要求10-16中任一项所述的ADC或其药学上可接受的盐,和
(b)药学上可接受的载体。
18.如权利要求17所述的药物组合物在制备治疗人类受试者癌症的药物中的应用,其特征在于,所述癌症选自非小细胞肺癌、表皮样癌、结肠直肠癌和头颈癌。
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CNPCT/CN2020/130409 | 2020-11-20 | ||
PCT/CN2020/130417 WO2022104697A1 (en) | 2020-11-20 | 2020-11-20 | Modified egfr antibody with reduced affinity |
PCT/CN2020/130409 WO2022104692A1 (en) | 2020-11-20 | 2020-11-20 | Engineered antibody, antibody-drug conjugate, and use thereof |
CNPCT/CN2020/130417 | 2020-11-20 | ||
PCT/CN2021/131780 WO2022105878A1 (en) | 2020-11-20 | 2021-11-19 | Modified egfr antibody with reduced affinity, drug conjugate, and use thereof |
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CN102971342A (zh) * | 2010-01-28 | 2013-03-13 | Ab生物科学公司 | 亲和力降低的新抗体和制备所述抗体的方法 |
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