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当代肿瘤药物靶点

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

抗体-药物偶联物 PCMC1D3-Duocarmycin SA 作为一种新型治疗实体，用于靶向治疗异常表达 MET 受体酪氨酸激酶的癌症

卷 22, 期 4, 2022

发表于: 20 January, 2022

页: [312 - 327] 页: 16

弟呕挨: 10.2174/1568009621666211222154129

价格: $65

摘要

背景：MET受体酪氨酸激酶的异常表达是致癌决定因素和癌症治疗的药物靶点。目前，针对 MET 的基于抗体的生物治疗药物正在进行临床试验。 目的：在这里，我们报告了用于靶向癌症治疗的新型抗 MET 抗体-药物偶联物 PCMC1D3-duocarmycin SA (PCMC1D3-DCM) 的临床前和治疗评估。 方法：通过杂交瘤技术产生的单克隆抗体 PCMC1D3 (IgG1a/κ) 对 MET 细胞外结构域之一具有特异性，基于其对人 MET 的高特异性和 1.60 nM 的结合亲和力进行选择。 PCMC1D3 通过可切割的缬氨酸-瓜氨酸二肽接头与 DCM 偶联，形成药物与抗体比率为 3.6:1 的抗体-药物偶联物。体外 PCMC1D3-DCM 快速诱导 MET 内化，内化效力范围为 6.5 至 17.2 小时，具体取决于单个细胞系。 结果：使用不同类型癌细胞系的研究表明，PCMC1D3-DCM 会破坏细胞周期，降低细胞活力，并在治疗开始后 96 小时内导致大量细胞死亡。计算出的细胞活力降低的 IC50 值为 1.5 至 15.3 nM。小鼠异种移植肿瘤模型的结果表明，以 10 mg/kg 体重的单剂量注射 PCMC1D3-DCM 可有效延迟异种移植肿瘤的生长长达两周，而没有肿瘤再生的迹象。计算的肿瘤抑制浓度（平衡肿瘤生长和抑制所需的最小剂量）约为 2 mg/kg 体重。总之，PCMC1D3-DCM 在异种移植模型中可有效靶向抑制肿瘤生长。 结论：该工作为未来开发用于MET靶向癌症治疗的人源化PCMC1D3-DCM奠定了基础。

关键词: MET受体酪氨酸激酶、小鼠单克隆抗体、抗体-药物偶联物、多卡霉素、药物递送、体外细胞毒性、肿瘤异种移植模型、疗效。

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