In Vivo Pharmacology, Global Pharmaceutical Research and Development, Abbvie, 1 N Waukegan Road, North Chicago, IL, 60064, USA.
Oncology Discovery, Global Pharmaceutical Research and Development, Abbvie, 1 N Waukegan Road, North Chicago, IL, 60064, USA.
J Neurooncol. 2021 Apr;152(2):233-243. doi: 10.1007/s11060-021-03703-z. Epub 2021 Jan 30.
Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic.
The efficacy of ADCs, antibodies, TMZ and radiation was tested in xenograft models of GBM, U-87MG and U-87MG EGFRvIII. Both models express EGFR. U-87MG EGFRvIII was transduced to express EGFRvIII. Changes in tumor volume, biomarkers of cell death and apoptosis after treatment were used to measure efficacy of the various treatments. Synergism of depatux-m and TMZ was verified in three-dimensional cultures of U-87MG and U-87MG EGFRvIII by the method of Chou and Talalay.
Combined with TMZ and radiotherapy (RT), depatux-m inhibited xenograft growth of U-87MG and U-87MG EGFRvIII more than either treatment with depatux-m or TMZ + RT. Durability of the response to depatux-m + TMZ + RT or depatux-m + TMZ was more pronounced in U-87MG EGFRvIII than in U-87MG. Efficacy of depatux-m + TMZ was synergistic in U-87MG EGFRvIII and additive in U-87MG.
Adding depatux-m enhances the efficacy of standard of care therapy in preclinical models of GBM. Durability of response to depatux-m + TMZ in vivo and synergy of the drug-drug interaction correlates with the amount of antigen expressed by the tumor cells.
Depatux-m 是一种抗体药物偶联物 (ADC)，在体外和体内肿瘤模型中靶向并抑制过度表达表皮生长因子受体 (EGFR) 或 2-7 缺失突变体 (EGFRvIII) 的癌细胞的生长。Depatux-m 联合替莫唑胺 (TMZ) 治疗复发性/难治性胶质母细胞瘤 (GBM) 患者的总生存期倾向于延长。为了首先了解两种药物相互作用的性质，我们研究了这种相互作用是协同的、相加的还是拮抗的。
在 GBM 的异种移植模型 U-87MG 和 U-87MG EGFRvIII 中测试 ADCs、抗体、TMZ 和放疗的疗效。这两种模型都表达 EGFR。U-87MG EGFRvIII 被转导以表达 EGFRvIII。治疗后肿瘤体积、细胞死亡和凋亡的生物标志物的变化用于测量各种治疗方法的疗效。通过 Chou 和 Talalay 方法，在 U-87MG 和 U-87MG EGFRvIII 的三维培养物中验证了 depatux-m 与 TMZ 的协同作用。
与 TMZ 和放疗 (RT) 联合使用时，depatux-m 抑制 U-87MG 和 U-87MG EGFRvIII 的异种移植生长比单独使用 depatux-m 或 TMZ+RT 更有效。在 U-87MG EGFRvIII 中，depatux-m+TMZ+RT 或 depatux-m+TMZ 的反应持续时间比在 U-87MG 中更为明显。在 U-87MG EGFRvIII 中，depatux-m+TMZ 的疗效是协同的，在 U-87MG 中是相加的。
在 GBM 的临床前模型中，添加 depatux-m 可提高标准治疗的疗效。体内 depatux-m+TMZ 反应的持久性和药物-药物相互作用的协同作用与肿瘤细胞表达的抗原量相关。
