Abstract

Background

Brain metastases of HER2+ breast cancer persist as a clinical challenge. Many therapeutics directed at human epidermal growth factor receptor 2 (HER2) are antibodies or antibody-drug conjugates (ADCs), and their permeability through the blood–tumor barrier (BTB) is poorly understood. We investigated the efficacy of a biparatopic anti-HER2 antibody-tubulysin conjugate (bHER2-ATC) in preclinical models of brain metastases.

Methods

The compound was evaluated in 2 hematogenous HER2+ brain metastasis mouse models, SUM190-BR and JIMT-1-BR. Endpoints included metastasis count, compound brain penetration, cancer cell proliferation, and apoptosis.

Results

Biparatopic HER2-ATC 3 mg/kg prevented metastasis outgrowth in the JIMT-1-BR model. At 1 mg/kg bHER2-ATC, a 70% and 92% reduction in large and micrometastases was observed. For the SUM190-BR model, an 85% and 53% reduction, respectively, in large and micrometastases was observed at 3 mg/kg, without statistical significance. Proliferation was reduced in both models at the highest dose. At the endpoint, bHER2-ATC uptake covered a median of 4–6% and 7–17% of metastasis area in the JIMT-1-BR and SUM190-BR models, respectively. Maximal compound uptake in the models was 19% and 86% in JIMT-1-BR and SUM190-BR, respectively. Multiple lesions in both models demonstrated ADC uptake in the absence or low diffusion of Texas Red Dextran, a marker of paracellular permeability. Using in vitro BTB assays, the ADC was endocytosed into brain endothelial cells, identifying a potentially new mechanism of antibody permeability.

Conclusions

Biparatopic HER2-ATC significantly prevented JIMT-1-BR brain metastasis outgrowth and showed activity in the SUM190-BR model. The bHER2-ATC penetration into metastases that are impermeable to fluorescent dye suggested an endocytic mechanism of brain penetration.

中文翻译：

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HER2抗体药物偶联物可控制血源性异种移植模型中乳腺癌脑转移瘤的生长，且异质性血液肿瘤屏障的渗透性与被动标记无关。

摘要

背景

HER2 +乳腺癌的脑转移仍然是一项临床挑战。针对人类表皮生长因子受体2（HER2）的许多疗法是抗体或抗体-药物偶联物（ADC），人们对它们穿过血肿瘤屏障（BTB）的渗透性了解甚少。我们在脑转移的临床前模型中研究了双原位抗HER2抗体-微管溶素结合物（bHER2-ATC）的功效。

方法

在2种血源性HER2 +脑转移小鼠模型SUM190-BR和JIMT-1-BR中评估了该化合物。终点包括转移计数，复合脑渗透，癌细胞增殖和凋亡。

结果

在JIMT-1-BR模型中，双对位HER2-ATC 3 mg / kg可以防止转移过度。在1 mg / kg bHER2-ATC下，观察到大和微转移分别降低了70％和92％。对于SUM190-BR模型，以3 mg / kg的剂量观察到大和微转移分别降低了85％和53％，但无统计学意义。在两个模型中，最高剂量的增殖均降低。在终点，在JIMT-1-BR和SUM190-BR模型中，bHER2-ATC的摄取分别覆盖了转移区域的4–6％和7–17％。在JIMT-1-BR和SUM190-BR中，模型的最大复合摄入量分别为19％和86％。在两个模型中的多个病变均表明，在缺乏或低扩散德克萨斯红葡聚糖（一种副细胞通透性的标志物）的情况下，ADC被摄取。使用体外BTB分析，将ADC内吞到脑内皮细胞中，

结论

双原位HER2-ATC显着阻止了JIMT-1-BR脑转移的生长，并在SUM190-BR模型中显示了活性。bHER2-ATC渗透到荧光染料不可渗透的转移灶中提示了脑渗透的内吞机制。