CN110522909A - 一种协同增强抗her2阳性肿瘤效果的药物组合 - Google Patents
一种协同增强抗her2阳性肿瘤效果的药物组合 Download PDFInfo
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Abstract
本发明公开了一种协同增强抗HER2阳性肿瘤效果的药物组合。本发明提供了一种抗肿瘤组合物,由抗HER2人源化抗体和甲氯芬那酸组成。将甲氯芬那酸这种“老药”与人源化抗肿瘤抗体药物以一定的配比联合使用,既可大大降低各自药物的用量,减小毒副作用,也可显著增强药效,克服肿瘤细胞的耐药性。这种协同药物组合式的“鸡尾酒药物疗法”在肿瘤治疗中将具有广阔的前景。
Description
技术领域
本发明涉及生物医学领域,涉及具体一种协同增强抗HER2阳性肿瘤效果的药物组合。
背景技术
曲妥珠单抗(赫塞汀,英文名Trastuzumab/Herceptin)是Genetech公司开发的抗人类表皮生长因子受体2(human epidermal growth factor receptor-2,HER2)人源化单克隆抗体药物,美国FDA于1998年批准上市,目前曲妥珠单抗联合化疗药物(紫杉醇等)已经成为HER2过表达晚期转移性乳腺癌和晚期胃癌的一线治疗方案。美国FDA于2012年又批准Genetech公司的另一个抗HER2人源化单克隆抗体药物帕妥珠单抗(英文名Pertuzumab/Perjeta)上市,帕妥珠单抗联合曲妥珠单抗及化疗药物可进一步提高HER2过表达晚期转移性乳腺癌的临床治疗效果。
但是,大量临床应用中发现,相当部分肿瘤病人对曲妥珠治疗初始治疗无效,或者治疗一段时间后肿瘤复发,促使人们对曲妥珠单抗的耐药性产生机制开展更深入的研究(Bailey TA,Luan H,Clubb RJ,Naramura M,Band V,Raja SM,Band H.Mechanisms ofTrastuzumab resistance in ErbB2-driven breast cancer and newer opportunitiesto overcome therapy resistance.J.Carcinog.2011,10:28)。与此同时也迫切需要开发新的抗体药物及新的药物联用方案,以满足临床需求,提高肿瘤治疗效果。
HuA21是一种靶向HER2胞外区的新型人源化单链抗体的融合抗体药物(中国专利申请号201410489895.X),它不同于曲妥珠单抗及其他已知抗体药物,具有独特的的识别表位,它的独特的识别表位也导致了其抗肿瘤作用机制的特性,包括较强的内吞作用,以及与曲妥珠单抗联合使用时的协同增强作用(Li RL,Hu SY,Chang Y,Zhang ZH,Zha Z,HuangH,Shen GD,Liu J,Song LH,Wei W.Development and Characterization of a HumanizedAnti-HER2 Antibody HuA21 with Potent Anti-tumor Properties in Breast CancerCells.Int J Mol Sci.2016.17(4):563)。由于HuA21在临床上将会与曲妥珠单抗相似,也会遇到耐药性问题。因此,有必要制备具有低毒高效的抗HER2人源化抗体与降低耐药性的常规药物联合使用的组合物。
最近发现,脂肪组织与肥胖相关蛋白质(Fto)基因是白血病、乳腺癌与成胶质细胞脑瘤等癌症发生的重要致癌基因之一。目前已知甲氯芬那酸(meclofenamic acid,化学名为2-[(2,6-二氯-3-甲基苯基)氨基]-苯甲酸,分子式:C14H11Cl2NO2)是FTO的特异性抑制剂,在临床上用于类风湿关节炎、骨关节炎及其他原因关节炎的关节肿痛,并可缓解其他疾病所致的轻、中度疼痛。与阿司匹林相比,不良反应较轻,具有更好的人体耐受性。
目前对恶性肿瘤的药物治疗以化学药品及靶向治疗药物为主,开发费用昂贵,且高剂量下毒副作用大,病人常难以承受。临床的研究表明,发展一种癌症药物的成本是十亿美元,并且从理论到被美国食品药品管理局批准的过程需要耗费15年的时间。
发明内容
本发明所要解决的技术问题是如何提高抗HER2人源化抗体对肿瘤的抑制作用并降低肿瘤耐药问题。
第一方面,本发明要求保护一种抗肿瘤组合物。
本发明所要求保护的抗肿瘤组合物由抗HER2人源化抗体和甲氯芬那酸(meclofenamic acid,MA)或其衍生物组成。
其中,所述HER2人源化抗体可为一种或两种。
进一步地,所述抗HER2人源化抗体可为抗体A1和/或抗体A2。
所述抗体A1的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ IDNo.1自N端起第26-35位、第50-66位、第99-109位所示;所述抗体A1的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第24-40位、第56-62位、第95-103位所示。
所述抗体A2的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ IDNo.3自N端起第26-35位、第50-66位、第99-109位所示;所述抗体A2的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.4自N端起第24-34位、第50-56位、第89-97位所示。
更进一步地,所述抗体A1的重链可变区的氨基酸序列为SEQ ID No.1的第1-120位;所述抗体A1的轻链可变区的氨基酸序列为SEQ ID No.2的第1-114位。
更进一步地,所述抗体A2的重链可变区的氨基酸序列为SEQ ID No.3;所述抗体A2的轻链可变区的氨基酸序列为SEQ ID No.4。
更加具体地,所述抗体A1的重链的氨基酸序列为SEQ ID No.1;所述抗体A1的轻链的氨基酸序列为SEQ ID No.2。所述抗体A1为由SEQ ID No.1所示重链单体和SEQ ID No.2所示轻链单体的同二聚体,是通过铰链区的3个半胱氨酸形成的三对链间二硫键聚合而成的HuA21抗体。
更加具体地,所述抗体A2为曲妥珠单抗。
当所述抗肿瘤组合物由所述抗体A1、所述抗体A2和甲氯芬那酸或其衍生物组成时,所述抗体A1、所述抗体A2和甲氯芬那酸的配比可为(0.05-50mg):(0.05-50mg):10μmol(如0.5mg:0.5mg:1μmol)。
当所述抗肿瘤组合物由所述抗体A1和甲氯芬那酸或其衍生物组成时,所述抗体A1和甲氯芬那酸的配比为(0.1-100mg):10μmol(如1mg:1μmol)。
当所述抗肿瘤组合物由所述抗体A2和甲氯芬那酸或其衍生物组成时,所述抗体A2和甲氯芬那酸的配比为(0.1-100mg):10μmol(如1mg:1μmol)。
第二方面,本发明要求保护前文所述的抗肿瘤组合物在如下任一中的应用:
(A1)治疗和/或预防肿瘤,或制备用于治疗和/或预防肿瘤的产品;
(A2)抑制肿瘤或肿瘤细胞生长,或制备用于抑制肿瘤或肿瘤细胞生长的产品;
(A3)诱导肿瘤细胞死亡(抑制肿瘤细胞增殖),或制备用于诱导肿瘤细胞死亡(抑制肿瘤细胞增殖)的产品;
(A4)提高所述抗HER2人源化抗体对肿瘤的抑制作用,或制备能够提高所述抗HER2人源化抗体对肿瘤的抑制作用的产品;
(A5)降低肿瘤对所述抗HER2人源化抗体的耐药性,或制备能够降低肿瘤对所述抗HER2人源化抗体的耐药性的产品。
第三方面,本发明要求保护一种产品。
本发明所要求保护的产品,其活性成分为前文所述的抗肿瘤组合物。
所述产品具有如下功能中的任一种:
(B1)治疗和/或预防肿瘤;
(B2)抑制肿瘤或肿瘤细胞生长;
(B3)诱导肿瘤细胞死亡(抑制肿瘤细胞增殖);
(B4)提高所述抗HER2人源化抗体对肿瘤的抑制作用;
(B5)降低肿瘤对所述抗HER2人源化抗体的耐药性。
第四方面,本发明要求保护甲氯芬那酸或其衍生物在如下任一中的应用:
(C1)提高抗HER2人源化抗体对肿瘤的抑制作用,或制备能够提高抗HER2人源化抗体对肿瘤的抑制作用的产品;
(C2)降低肿瘤对抗HER2人源化抗体的耐药性,或制备能够降低肿瘤对抗HER2人源化抗体的耐药性的产品。
进一步地,所述抗HER2人源化抗体可为前文第一方面中所述的抗体A1和/或所述的抗体A2。
进一步地,所述产品可为前文第一方面中所述的抗肿瘤组合物。
在上述各方面中,所述甲氯芬那酸的衍生物具体可为甲氯芬那酸乙酯(MA2)。
在上述各方面中,所述肿瘤可为HER2阳性肿瘤;所述肿瘤细胞可为HER2阳性肿瘤细胞。
进一步地,所述HER2阳性肿瘤可为乳腺癌或胃癌;所述HER2阳性肿瘤细胞可为BT-474乳腺癌细胞、N87胃癌细胞、BT-474/HR乳腺癌细胞(对曲妥珠单抗耐药)或N87/HR胃癌细胞(对曲妥珠单抗耐药)。
甲氯芬那酸是一种传统的非甾体抗炎药,本发明将其应用与抗肿瘤,是对一种已获批准的药物进行“老药新用”。将“老药”与人源化抗肿瘤抗体药物以一定的配比联合使用,既可大大降低各自药物的用量,减小毒副作用,也可显著增强药效,克服肿瘤细胞的耐药性。这种协同药物组合式的“鸡尾酒药物疗法”在肿瘤治疗中将具有广阔的前景。
实验证明,一定浓度的抗HER2人源化抗体及甲氯芬那酸或其衍生物联合用药能有效诱导肿瘤细胞的死亡;通过在BALB/c裸鼠皮下接种人肿瘤细胞建立裸鼠移植瘤模型,肿瘤的生长曲线和肿瘤重量检测结果表明,联合用药有明显的抑制肿瘤生长作用,特别是对曲妥珠单抗(Trastuzumab)耐药的肿瘤。本发明实施例证实,含曲妥珠单抗(Trastuzumab)、HuA21及甲氯芬那酸乙酯(MA2)的药物组合所取得的抗肿瘤作用显著优于单一的曲妥珠单抗或HuA21,具有明显协同增效作用,为临床联合应用上述药物抗肿瘤提供了依据,是一种潜在的高效低毒的肿瘤药物。
附图说明
图1为CCK-8法检测人源化抗体HuA21、曲妥珠单抗单独或联合甲氯芬那酸乙酯(MA2)体外抑制肿瘤细胞增殖的能力。A为BT-474乳腺癌细胞;B为N87胃癌细胞;C为BT-474/HR乳腺癌细胞;D为N87/HR胃癌细胞。
实验结果显示,人源化抗体HuA21在浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL时,对BT-474乳腺癌细胞的增殖抑制率分别为69.22%±3.95%、55.84%±4.22%、33.63%±4.06%、13.95%±2.86%、2.91%±2.14%,对N87胃癌细胞的增殖抑制率分别为34.72%±4.52%、26.17%±3.76%、17.35%±3.31%、9.25%±2.75%、3.91%±1.28%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为27.32%±4.52%、18.73%±3.64%、14.37%±3.8%、9.95%±2.75%、2.51%±1.79%,对N87/HR胃癌细胞的增殖抑制率分别为18.21%±4.67%、13.66%±4.72%、10.34%±3.52%、5.81%±2.92%、2.41%±1.74%;曲妥珠单抗在浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL时,对BT-474乳腺癌细胞的增殖抑制率分别为72.44%±4.83%、61.24%±5.41%、41.57%±3.95%、18.02%±3.63%、3.23%±2.66%,对N87胃癌细胞的增殖抑制率分别为27.46%±5.07%、18.60%±3.84%、10.34%±3.37%、4.46%±2.62%、1.23%±2.07%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为19.25%±3.82%、12.61%±3.16%、8.17%±2.34%、6.02%±1.78%、1.97%±1.13%,对N87/HR胃癌细胞的增殖抑制率分别为11.46%±3.49%、7.16%±2.64%、4.48%±1.79%、3.02%±1.24%、0.93%±1.35%;曲妥珠单抗+HuA21在抗体总浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL时,对BT-474乳腺癌细胞的增殖抑制率分别为83.71%±6.69%、76.87%±5.14%、63.48%±4.45%、27.65%±4.22%、4.71%±2.37%,对N87胃癌细胞的增殖抑制率分别为55.32%±5.44%、41.37%±4.37%、32.42%±3.92%、18.65%±3.26%、5.77%±2.38%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为46.21%±3.68%、31.73%±3.41%、22.37%±2.59%、15.65%±2.26%、4.71%±1.62%,对N87/HR胃癌细胞的增殖抑制率分别为36.15%±5.63%、28.43%±4.14%、21.68%±3.18%、14.65%±2.43%、4.71%±1.27%;HuA21+MA2在抗体浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL且MA2浓度恒定为10μM时,对BT-474乳腺癌细胞的增殖抑制率分别为73.61%±5.28%、59.73%±4.94%、37.48%±4.27%、16.7%±3.76%、4.31%±1.62%,对N87胃癌细胞的增殖抑制率分别为51.45%±5.44%、37.70%±4.37%、28.37%±3.92%、15.70%±3.26%、6.44%±2.48%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为46.21%±3.68%、31.73%±3.41%、22.37%±2.59%、15.65%±2.26%、4.71%±1.62%,对N87/HR胃癌细胞的增殖抑制率分别为31.46%±4.73%、24.35%±4.08%、19.28%±3.14%、10.47%±2.63%、5.41%±1.25%;曲妥珠单抗+MA2在抗体浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL且MA2浓度恒定为10μM时,对BT-474乳腺癌细胞的增殖抑制率分别为75.36%±5.69%、64.76%±5.14%、43.44%±4.45%、20.15%±4.22%、3.91%±2.37%,对N87胃癌细胞的增殖抑制率分别为46.09%±5.44%、32.57%±4.37%、21.44%±3.92%、10.55%±3.26%、4.64%±2.48%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为46.21%±3.68%、31.73%±3.41%、22.37%±2.59%、15.65%±2.26%、4.71%±1.62%,对N87/HR胃癌细胞的增殖抑制率分别为28.31%±5.33%、20.57%±4.28%、14.34%±3.14%、7.19%±2.43%、2.48%±1.52%;曲妥珠单抗+HuA21+MA2在抗体总浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL与0.01μg/mL且MA2浓度恒定为10μM时,对BT-474乳腺癌细胞的增殖抑制率分别为86.47%±7.22%、79.27%±5.93%、6733%±5.45%、25.95%±4.84%、5.82%±2.28%,对N87胃癌细胞的增殖抑制率分别为64.16%±6.23%、54.40%±5.18%、40.73%±4.52%、22.80%±3.65%、10.82%±3.03%,对BT-474/HR乳腺癌细胞的增殖抑制率分别为76.32%±6.92%、62.87%±6.38%、45.47%±5.49%、27.55%±5.32%、5.28%±2.53%,对N87/HR胃癌细胞的增殖抑制率分别为50.16%±5.63%、39.24%±4.71%、30.23%±4.26%、18.24%±3.38%、8.75%±2.14%。
图2为人源化抗体HuA21、曲妥珠单抗单独或联合甲氯芬那酸乙酯(MA2)使用能有效抑制肿瘤生长。A为BT-474乳腺癌细胞;B为N87胃癌细胞;C为BT-474/HR乳腺癌细胞;D为N87/HR胃癌细胞。
图2中A实验结果显示,在用抗体溶液或PBS对荷BT-474乳腺癌肿瘤细胞的BalB/C雌性裸鼠处理第0天和处理第25天,注射PBS的BalB/C雌性裸鼠的肿瘤大小分别为189.7mm3±33.5mm3、748.5mm3±197.1mm3;注射HuA21溶液的BalB/C雌性裸鼠的肿瘤大小依次为187.0mm3±37.2mm3、138.6mm3±52.2mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.99倍和0.19倍;注射曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为185.2mm3±35.5mm3、114.1mm3±46.4mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.98倍和0.15倍;注射HuA21+曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为192.5mm3±44.2mm3、12.5mm3±9.2mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.01倍和0.02倍;注射HuA21+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为186.7mm3±37.4mm3、85.9mm3±28.1mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.04倍和0.08倍;注射曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为182.7mm3±40.5mm3、73.3mm3±23.0mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.96倍和0.10倍;注射HuA21+曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为193.4mm3±39.8mm3、2.6mm3±2.4mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.96倍和0.003倍。
图2中B实验结果显示,在用抗体溶液或PBS对荷N87胃癌肿瘤细胞的BalB/C雌性裸鼠处理第0天和处理第25天,注射PBS的BalB/C雌性裸鼠的肿瘤大小分别为141.4mm3±31.5mm3、1792.5mm3±454.6mm3;注射HuA21溶液的BalB/C雌性裸鼠的肿瘤大小依次为148.6mm3±32.0mm3、721.1mm3±170.4mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.05倍和0.40倍;注射曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为145.2mm3±29.3mm3、894.1mm3±209.0mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.03倍和0.50倍;注射HuA21+曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为152.2mm3±39.0mm3、77.5mm3±29.0mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.08倍和0.04倍;注射HuA21+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为144.5mm3±37.5mm3、207.5mm3±58.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.02倍和0.12倍;注射曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为140.6mm3±34.1mm3、254.5mm3±58.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.99倍和0.14倍;注射HuA21+曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为151.3mm3±33.6mm3、7.3mm3±2.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.07倍和0.004倍。
图2中C实验结果显示,在用抗体溶液或PBS对荷BT-474/HR乳腺癌肿瘤细胞的BalB/C雌性裸鼠处理第0天和处理第25天,注射PBS的BalB/C雌性裸鼠的肿瘤大小分别为163.8mm3±29.5mm3、458.9mm3±197.1mm3;注射HuA21溶液的BalB/C雌性裸鼠的肿瘤大小依次为169.3mm3±25.4mm3、261.1mm3±86.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.03倍和0.57倍;注射曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为164.7mm3±30.1mm3、326.4mm3±98.2mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.01倍和0.71倍;注射HuA21+曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为171.4mm3±27.3mm3、52.3mm3±13.8mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.05倍和0.11倍;注射HuA21+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为162.4mm3±26.8mm3、72.5mm3±15.4mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.99倍和0.16倍;注射曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为157.5mm3±24.2mm3、87.5mm3±18.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.96倍和0.19倍;注射HuA21+曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为170.9mm3±31.4mm3、6.4mm3±2.6mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.04倍和0.01倍。
图2中D实验结果显示,在用抗体溶液或PBS对荷N87/HR胃癌肿瘤细胞的BalB/C雌性裸鼠处理第0天和处理第25天,注射PBS的BalB/C雌性裸鼠的肿瘤大小分别为127.3mm3±28.9mm3、1136.5mm3±197.1mm3;注射HuA21溶液的BalB/C雌性裸鼠的肿瘤大小依次为128.9mm3±27.2mm3、531.1mm3±145.5mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.01倍和0.47倍;注射曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为130.4mm3±33.7mm3、712.1mm3±166.7mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.02倍和0.63倍;注射HuA21+曲妥珠单抗溶液的BalB/C雌性裸鼠的肿瘤大小依次为132.3mm3±35.6mm3、73.7mm3±19.4mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.04倍和0.06倍;注射HuA21+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为125.4mm3±27.8mm3、207.9mm3±43.2mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.99倍和0.18倍;注射曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为122.8mm3±32.3mm3、268.8mm3±71.8mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的0.96倍和0.24倍;注射HuA21+曲妥珠单抗+MA2溶液的BalB/C雌性裸鼠的肿瘤大小依次为134.6mm3±29.5mm3、13.3mm3±3.8mm3,分别为注射PBS的BalB/C雌性裸鼠的肿瘤大小的1.06倍和0.01倍。
各图中,Tra或T表示曲妥珠单抗;H表示HuA21;Control表示PBS对照。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明,均为常规方法。
下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中的pSectag2A(Zeo+)载体为Invitrogen公司产品,目录号为V900-20。
实施例1、HuA21抗体、曲妥珠单抗和甲氯芬那酸及其衍生物
一、HuA21抗体
本发明所用到的HuA21抗体是按照如下方法制备得到的:
1、用于表达HuA21抗体重链的重组表达载体pSectag2A(Zeo+)/HuA21-H:将SEQ IDNo.5所示的核苷酸序列替换pSectag2A(Zeo+)载体中SfiI和KpnI位点间的核苷酸序列,保持pSectag2A(Zeo+)的其他序列不变,得到的重组载体命名为pSectag2A(Zeo+)/HuA21-H。
2、用于表达HuA21抗体轻链的重组表达载体pSectag2A(Zeo+)/HuA21-L:将SEQ IDNo.6所示的核苷酸序列替换pSectag2A(Zeo+)载体中SfiI和KpnI位点间的核苷酸序列,保持pSectag2A(Zeo+)的其他序列不变,得到的重组载体命名为pSectag2A(Zeo+)/HuA21-L。
3、在6cm细胞培养皿中接种1×106个CHO-S细胞(Thermo Fisher Scientific公司),将15μL的脂质体转染试剂Lipofectamine3000(Invitrogen公司)和5μg重组载体(重组载体pSectag2A(Zeo+)/HuA21-H和pSectag2A(Zeo+)/HuA21-L等量混合)加至500μLOptiMEM培养基中,混合均匀后静置30分钟,将得到的混合物加入上述含有待转染的CHO-S细胞的培养皿中,置于CO2培养箱中6小时,然后将培养基更换为无血清培养基CHO-S-SFMII(GibcoTM)。细胞继续培养24小时后,胰酶消化传代至10块96孔细胞培养板,每孔加入100μL含有0.3mg/mL Zeocin的选择性培养基筛选抗性克隆。待细胞克隆长出后(约2周),取培养上清,用ELISA检测单克隆细胞的抗体表达量:取1:4000稀释的羊抗人IgG-F多抗(Pierce公司)包被ELISA板,4℃孵育过夜;用含有3%脱脂奶粉的PBST(PBS+0.1%Tween20)于37℃封闭1小时;加入待测抗体克隆的细胞培养上清或标准抗体(chA21或人IgG);室温振荡温育1小时;加入1:2000稀释的HRP-羊抗人IgG(Pierce公司),室温振荡温育1小时;加入OPD底物显色5分钟,最后用10%硫酸溶液终止反应,用EXL800酶标仪(Biotek公司)测量OD490nm光吸收值。按照上述ELISA检测方法检测不同单克隆细胞的上清中的抗体表达量,根据不同上清中人源化抗体HuA21的含量选出HuA21高表达的克隆。
将人源化抗体HuA21高表达的克隆逐级扩大培养,直至滚瓶培养。然后取滚瓶培养的上清液,经ProteinA亲和层析柱和S200分子筛层析柱(均为GE公司产品)两步法纯化,最后用30KDa超滤离心管(Millipore公司)浓缩,得到纯化的人源化抗体HuA21,并用BCA蛋白定量试剂盒(Pierce公司)测定抗体浓度。
HuA21抗体的重链氨基酸序列如SEQ ID No.1所示,轻链氨基酸序列如SEQ IDNo.2所示。
单体1:SEQ ID No.1,自N端第1-120位氨基酸残基组成重链可变区VH(其中,第26-35位氨基酸残基组成HCDR1,第50-66位氨基酸残基组成HCDR2,第99-109位氨基酸残基组成HCDR3),第121-357位氨基酸组成Fc片段,其中IgG1的Fc片段含有铰链区Hinge和两个恒定区结构域——CH2和CH3,铰链区含有3个半胱氨酸。
单体2:SEQ ID No.2,自N端第1-114位氨基酸残基组成轻链可变区VL(其中,第24-40位氨基酸残基组成LCDR1,第56-62位氨基酸残基组成LCDR2,第95-103位氨基酸残基组成LCDR3),第115-220位氨基酸残基组成轻链恒定区CL。
本发明完整的人源化HuA21抗体是由上述2个单体的同二聚体是通过铰链区的3个半胱氨酸形成的三对链间二硫键聚合而成。
二、曲妥珠单抗
曲妥珠单抗(赫塞汀,英文名Trastuzumab/Herceptin)为Roche/Genetech公司产品。
曲妥珠单抗的重链可变区的氨基酸序列如SEQ ID No.3所示(HCDR1、HCDR2和HCDR3分别为SEQ ID No.3自N端起第26-35位、第50-66位、第99-109位);轻链可变区的氨基酸序列如SEQ ID No.4所示(LCDR1、LCDR2和LHCDR3分别为SEQ ID No.4自N端起第24-34位、第50-56位、第89-97位)。
三、甲氯芬那酸及其衍生物
甲氯芬那酸(meclofenamic acid,MA)的化学结构如式I所示。本发明中所用的甲氯芬那酸衍生物为甲氯芬那酸乙酯(MA2)。
实施例2、抗HER2人源化抗体和甲氯芬那酸联合使用能有效抑制肿瘤细胞增殖
CCK-8法检测人源化抗体HuA21、曲妥珠单抗单独或联合甲氯芬那酸乙酯(MA2)体外抑制肿瘤细胞增殖的能力。实验重复三次,每次重复实验的步骤如下:
体外培养HER2高表达的BT-474乳腺癌细胞(中国科学院上海细胞库)。BT-474乳腺癌细胞经胰酶消化后接种于96孔细胞培养板(Corning公司),每孔含有2×103个细胞,培养板中每孔均有100μL含有10%特级胎牛血清的RPMI1640培养基,在CO2培养箱中培养24小时后,将培养基更换为含有人源化抗体HuA21和10%特级胎牛血清的RPMI1640新鲜培养基,进行人源化抗体HuA21对BT-474乳腺癌细胞的处理,培养基中人源化抗体HuA21浓度分别为100μg/mL、10μg/mL、1μg/mL、0.1μg/mL、0.01μg/mL,每个浓度4个平行孔(即每个浓度4个重复),继续培养72h后,将培养基更换为含有10μLCCK-8(上海东仁化学公司)显色试剂的RPMI1640新鲜培养基并孵育2小时,用酶标仪在490nm下测定每孔中溶液的光密度吸收值(OD值),分别得到不同HuA21抗体浓度处理BT-474乳腺癌细胞的OD值。
按照上述方法,将BT-474乳腺癌细胞替换为HER2高表达的N87胃癌细胞(上海细胞库),其他步骤不变,分别得到不同人源化抗体HuA21浓度处理的N87胃癌细胞的OD值。
按照上述方法,将BT-474乳腺癌细胞替换为HER2高表达且对曲妥珠单抗耐药的BT-474/HR乳腺癌细胞(参见中国专利申请CN 104762264A),其他步骤不变,分别得到不同人源化抗体HuA21浓度处理的BT-474/HR乳腺癌细胞的OD值。
按照上述方法,将BT-474乳腺癌细胞替换为HER2高表达且对曲妥珠单抗耐药的N87/HR胃癌细胞(具体是参照中国专利申请CN 104762264A中公开的对曲妥珠单抗耐药的BT-474/HR乳腺癌细胞的构建方法构建所得),其他步骤不变,分别得到不同人源化抗体HuA21浓度处理的N87胃癌细胞的OD值。
按照上述方法,将人源化抗体HuA21分别替换为曲妥珠单抗、曲妥珠单抗+HuA21(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度)、曲妥珠单抗+MA2(MA2浓度恒定为10μmol/L)、HuA21+MA2(MA2浓度恒定为10μmol/L)或者曲妥珠单抗+HuA21+MA2(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度,MA2浓度恒定为10μmol/L),其他步骤不变,分别得到人源化抗体曲妥珠单抗或HuA21不同浓度处理BT-474乳腺癌细胞的OD值及二种抗体与MA2(浓度恒定为10μmol/L)联合处理BT-474乳腺癌细胞的OD值。
按照上述方法,将人源化抗体HuA21分别替换为曲妥珠单抗、曲妥珠单抗+HuA21(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度)、曲妥珠单抗+MA2(MA2浓度恒定为10μmol/L)、HuA21+MA2(MA2浓度恒定为10μmol/L)或者曲妥珠单抗+HuA21+MA2(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度,MA2浓度恒定为10μmol/L),其他步骤不变,分别得到人源化抗体曲妥珠单抗或HuA21不同浓度处理N87胃癌细胞的OD值及二种抗体与MA2(浓度恒定为10μmol/L)联合处理N87胃癌细胞的OD值。
按照上述方法,将人源化抗体HuA21分别替换为曲妥珠单抗、曲妥珠单抗+HuA21(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度)、曲妥珠单抗+MA2(MA2浓度恒定为10μmol/L)、HuA21+MA2(MA2浓度恒定为10μmol/L)或者曲妥珠单抗+HuA21+MA2(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度,MA2浓度恒定为10μmol/L),其他步骤不变,分别得到人源化抗体曲妥珠单抗或HuA21不同浓度处理BT-474/HR乳腺癌细胞的OD值及二种抗体与MA2(浓度恒定为10μmol/L)联合处理BT-474/HR乳腺癌细胞的OD值。
按照上述方法,将人源化抗体HuA21分别替换为曲妥珠单抗、曲妥珠单抗+HuA21(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度)、曲妥珠单抗+MA2(MA2浓度恒定为10μmol/L)、HuA21+MA2(MA2浓度恒定为10μmol/L)或者曲妥珠单抗+HuA21+MA2(曲妥珠单抗和HuA21的质量比为1:1,抗体浓度为曲妥珠单抗和HuA21抗体的总浓度,MA2浓度恒定为10μmol/L),其他步骤不变,分别得到人源化抗体曲妥珠单抗或HuA21不同浓度处理N87/HR胃癌细胞的OD值及二种抗体与MA2(浓度恒定为10μmol/L)联合处理N87/HR胃癌细胞的OD值。
根据细胞增殖抑制率计算公式:抑制率=(1-实验组OD值/对照组OD值)×100%,分别计算上述不同浓度的不同抗体对不同细胞的增殖的抑制率。其中,对照组为PBS溶液。
实验结果如图1所示。结果显示,不同浓度的人源化抗体HuA21对BT-474乳腺癌细胞增殖的抑制率接近于曲妥珠单抗,对N87胃癌细胞、BT-474/HR乳腺癌细胞以及N87/HR胃癌细胞增殖的抑制率均高于曲妥珠单抗;与曲妥珠单抗或者HuA21抗体相比,曲妥珠单抗与HuA21联合使用在不同抗体浓度下对BT-474乳腺癌细胞、N87胃癌细胞、BT-474/HR乳腺癌细胞以及N87/HR胃癌细胞增殖的抑制率均增强;与曲妥珠单抗或者HuA21抗体相比,曲妥珠单抗、HuA21单独或者联合与MA2(浓度恒定为10μmol/L)组合使用在不同抗体浓度下对BT-474乳腺癌细胞、N87胃癌细胞、BT-474/HR乳腺癌细胞以及N87/HR胃癌细胞增殖的抑制率均增强。结果表明人源化抗体HuA21对肿瘤细胞增殖有较强的抑制作用,人源化抗体HuA21与曲妥珠单抗联用具有协同增强效应,MA2对人源化抗体HuA21与曲妥珠单抗发挥肿瘤抑制的作用具有协同增强效应,对于对曲妥珠单抗耐药的肿瘤抑制作用尤其显著。
实施例3、抗HER2人源化抗体和甲氯芬那酸联合使用能有效抑制肿瘤生长
使用PBS分别溶解实施例1中的人源化抗体HuA21与曲妥珠单抗,使用DMSO溶解MA2,分别得到浓度为2mg/mL的HuA21溶液,浓度为2mg/mL的曲妥珠单抗溶液,HuA21浓度为2mg/mL且MA2浓度为2mmol/L的HuA21和MA2混合溶液,曲妥珠单抗浓度为2mg/mL且MA2浓度为2mmol/L的曲妥珠单抗和MA2混合溶液,抗体总浓度为2mg/mL的曲妥珠单抗和HuA21混合溶液(HuA21和曲妥珠单抗各1mg/mL),以及HuA21浓度为2mg/mL且曲妥珠单抗浓度为2mg/mL且MA2浓度为2mmol/L的HuA21、曲妥珠单抗和MA2混合溶液。
取42只5-6周龄BalB/C雌性裸小鼠(北京维通利华实验动物技术有限公司),每只于***垫部位皮下接种5×106个HER2高表达的BT-474乳腺癌细胞,同时包埋0.72mg***缓释片(Innovative Research of American公司)。每周两次测量肿瘤长径和短径,根据公式TV=1/2×a×b2计算肿瘤体积。待肿瘤平均体积长至约100mm3时,将荷瘤BalB/C雌性裸小鼠随机分为7组,每组6只,而后对每组的每只荷瘤裸小鼠注射不同的药物溶液或PBS进行治疗,将第一次注射不同的药物溶液或PBS记为处理第0天,分别在处理第0天、第4天、第7天、第11天、第14天、第18天与第21天注射,每次对每只荷瘤裸小鼠都注射与第一次相同的药物溶液或PBS,每次注射的体积均为100μL,在每次注射前和处理第25天分别测量荷瘤BalB/C雌性裸小鼠的体重和肿瘤体积。每次注射的具体方法如下:在第1组的每只荷瘤裸小鼠的静脉中注射100μLPBS作为对照组,在第2组的每只荷瘤裸小鼠的静脉中注射100μL上述HuA21溶液,在第3组的每只荷瘤裸小鼠的静脉中注射100μL上述曲妥珠单抗溶液,在第4组的每只荷瘤裸小鼠的静脉中注射100μL上述曲妥珠单抗+HuA21溶液,在第5组的每只荷瘤裸小鼠的静脉中注射100μL上述曲妥珠单抗+MA2溶液,在第6组的每只荷瘤裸小鼠的静脉中注射100μL上述HuA21+MA2溶液,在第7组的每只荷瘤裸小鼠的静脉中注射100μL上述曲妥珠单抗+HuA21+MA2溶液。不同药物对BalB/C雌性荷瘤裸小鼠的BT-474乳腺癌移植瘤的治疗情况见图2中A。
按照上述方法,将BT-474乳腺癌细胞替换为N87胃癌细胞,其他步骤均不变,得到不同药物对BalB/C雌性荷瘤裸小鼠的N87胃癌移植瘤的治疗情况,结果见图2中B。
按照上述方法,将BT-474乳腺癌细胞替换为BT-474/HR乳腺癌细胞,其他步骤均不变,得到不同药物对BalB/C雌性荷瘤裸小鼠的BT-474乳腺癌移植瘤的治疗情况,结果见图2中C。
按照上述方法,将BT-474乳腺癌细胞替换为N87/HR胃癌细胞,其他步骤均不变,得到不同药物对BalB/C雌性荷瘤裸小鼠的N87/HR胃癌移植瘤的治疗情况,结果见图2中D。
实验结果显示,与PBS对照相比,人源化抗体HuA21、曲妥珠单抗、曲妥珠单抗+HuA21及其与MA2的组合药物对BT-474乳腺癌、N87胃癌、BT-474/HR乳腺癌和N87/HR胃癌均有明显的抑制作用(P值<0.05),对BT-474乳腺癌抑制作用的大小为:曲妥珠单抗+HuA21+MA2≥曲妥珠单抗+HuA21>曲妥珠单抗+MA2≥曲妥珠单抗≥HuA21+MA2≥HuA21;对N87胃癌、BT-474/HR乳腺癌和N87/HR胃癌抑制作用的大小均为:曲妥珠单抗+HuA21+MA2>曲妥珠单抗+HuA21>HuA21+MA2>曲妥珠单抗+MA2>HuA21>曲妥珠单抗。表明人源化抗体HuA21对BT-474乳腺癌、N87胃癌、BT-474/HR乳腺癌和N87/HR胃癌均有明显的抑制作用,且和曲妥珠单抗联合使用时,对肿瘤的抑制作用进一步增强,可使大部分肿瘤停止生长或完全消失,表明人源化抗体HuA21与曲妥珠单抗有明显的协同效应;同时,MA2对人源化抗体HuA21与曲妥珠单抗发挥肿瘤抑制的作用具有明显的协同增强效应,对于对曲妥珠单抗耐药的肿瘤抑制作用尤其显著。
本发明前期按照CCK-8细胞增殖检测试剂盒方法研究发现MA2在0.1μM-50μM浓度范围内处理BT-474/HR和N87/HR这二种对曲妥珠单抗耐药的肿瘤细胞,会呈浓度依赖性地发挥促进细胞增殖作用,其中使用50μM MA2分别处理BT-474/HR和N87/HR细胞48小时可使它们的增殖速度提高2-3倍;MA2处理浓度达到80μM及以上则会抑制上述肿瘤细胞的增殖。
本发明实施例证实,含曲妥珠单抗(Trastuzumab)、HuA21及甲氯芬那酸乙酯(MA2)的药物组合所取得的抗肿瘤作用显著优于单一的曲妥珠单抗或HuA21,具有明显协同增效作用,为临床联合应用上述药物抗肿瘤提供了依据,是一种潜在的高效低毒的肿瘤药物。
<110> 安徽省立医院
<120> 一种协同增强抗HER2阳性肿瘤效果的药物组合
<130> GNCLN191858
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aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggacgag 1080
cttaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 1140
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 1200
ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 1260
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1320
cagaagagcc tctccctgtc tccgggtaaa 1350
<210> 6
<211> 660
<212> DNA
<213> Artificial sequence
<400> 6
gacatcgttt tgactcaatc tccagactct ttggctgttt ctttgggtga aagagttact 60
attaactgta agtcttctca accgttggaa tactctaaca accaatggaa ctacttggct 120
tggtatcaac aaaagccagg tcaatctcca aagttgttga tctcttgggc ttccactaga 180
aagtctggtg ttccagacag attctctggt tctggttctg gtactgactt cactttgact 240
atctcttctg ttcaagctga agacgttgct gtttactact gtgggcaata ctctgactac 300
ccaaacactt tcggtgctgg tactaagttg gaaattaaga gaactgtggc tgcaccatct 360
gtcttcatct tcccgccatc tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420
ctgctgaata acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc 480
caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag cacctacagc 540
ctcagcagca ccctgacgct gagcaaagca gactacgaga aacacaaagt ctacgcctgc 600
gaagtcaccc atcagggcct gagctcgccc gtcacaaaga gcttcaacag gggagagtgc 660
Claims (10)
1.一种抗肿瘤组合物,由抗HER2人源化抗体和甲氯芬那酸或其衍生物组成。
2.根据权利要求1所述的抗肿瘤组合物,其特征在于:所述HER2人源化抗体为一种或两种。
3.根据权利要求1所述的抗肿瘤组合物,其特征在于:所述抗HER2人源化抗体为抗体A1和/或抗体A2;
所述抗体A1的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.1自N端起第26-35位、第50-66位、第99-109位所示;所述抗体A1的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.2自N端起第24-40位、第56-62位、第95-103位所示;
所述抗体A2的重链可变区中HCDR1、HCDR2和HCDR3的氨基酸序列依次如SEQ ID No.3自N端起第26-35位、第50-66位、第99-109位所示;所述抗体A2的轻链可变区中LCDR1、LCDR2和LHCDR3的氨基酸序列依次如SEQ ID No.4自N端起第24-34位、第50-56位、第89-97位所示。
4.根据权利要求3所述的抗肿瘤组合物,其特征在于:所述抗体A1的重链可变区的氨基酸序列为SEQ ID No.1的第1-120位;所述抗体A1的轻链可变区的氨基酸序列为SEQ IDNo.2的第1-114位;
所述抗体A2的重链可变区的氨基酸序列为SEQ ID No.3;所述抗体A2的轻链可变区的氨基酸序列为SEQ ID No.4。
5.根据权利要求4所述的抗肿瘤组合物,其特征在于:所述抗体A1的重链的氨基酸序列为SEQ ID No.1;所述抗体A1的轻链的氨基酸序列为SEQ ID No.2;
所述抗体A2为曲妥珠单抗。
6.根据权利要求3-5中任一所述的抗肿瘤组合物,其特征在于:当所述抗肿瘤组合物由所述抗体A1、所述抗体A2和甲氯芬那酸或其衍生物组成时,所述抗体A1、所述抗体A2和甲氯芬那酸或其衍生物的配比为(0.05-50mg):(0.05-50mg):10μmol;
当所述抗肿瘤组合物由所述抗体A1和甲氯芬那酸组成时,所述抗体A1和甲氯芬那酸或其衍生物的配比为(0.1-100mg):10μmol;
当所述抗肿瘤组合物由所述抗体A2和甲氯芬那酸或其衍生物组成时,所述抗体A2和甲氯芬那酸的配比为(0.1-100mg):10μmol。
7.权利要求1-6中任一所述的抗肿瘤组合物在如下任一中的应用:
(A1)治疗和/或预防肿瘤,或制备用于治疗和/或预防肿瘤的产品;
(A2)抑制肿瘤或肿瘤细胞生长,或制备用于抑制肿瘤或肿瘤细胞生长的产品;
(A3)诱导肿瘤细胞死亡,或制备用于诱导肿瘤细胞死亡的产品;
(A4)提高所述抗HER2人源化抗体对肿瘤的抑制作用,或制备能够提高所述抗HER2人源化抗体对肿瘤的抑制作用的产品;
(A5)降低肿瘤对所述抗HER2人源化抗体的耐药性,或制备能够降低肿瘤对所述抗HER2人源化抗体的耐药性的产品。
8.产品,其活性成分为权利要求1-6中任一所述的抗肿瘤组合物;
所述产品具有如下功能中的任一种:
(B1)治疗和/或预防肿瘤;
(B2)抑制肿瘤或肿瘤细胞生长;
(B3)诱导肿瘤细胞死亡;
(B4)提高所述抗HER2人源化抗体对肿瘤的抑制作用;
(B5)降低肿瘤对所述抗HER2人源化抗体的耐药性。
9.甲氯芬那酸或其衍生物在如下任一中的应用:
(C1)提高抗HER2人源化抗体对肿瘤的抑制作用,或制备能够提高抗HER2人源化抗体对肿瘤的抑制作用的产品;
(C2)降低肿瘤对抗HER2人源化抗体的耐药性,或制备能够降低肿瘤对抗HER2人源化抗体的耐药性的产品;
进一步地,所述抗HER2人源化抗体为权利要求3-6任一中的所述抗体A1和/或所述抗体A2;和/或
进一步地,所述产品为权利要求1-6中任一所述的抗肿瘤组合物。
10.根据权利要求1-9中任一所述的抗肿瘤组合物或应用或产品,其特征在于:所述肿瘤为HER2阳性肿瘤;所述肿瘤细胞为HER2阳性肿瘤细胞;和/或
所述衍生物为甲氯芬那酸乙酯。
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