A HER2 Antibody Drug Conjugate Controls Growth of Breast Cancer Brain Metastases in Hematogenous Xenograft Models, with Heterogeneous Blood-Tumor Barrier Penetration Unlinked to a Passive Marker

Brain metastases of HER2+ breast cancer persist as a clinical challenge. Many HER2-directed therapeutics are antibodies or antibody drug conjugates, and their permeability through the blood-tumor barrier is poorly understood. We investigated the efficacy of a biparatopic anti-HER2 Antibody-Tubulysin Conjugate (bHER2-ATC) in preclinical models of brain metastases. The compound was evaluated in two hematogenous HER2+ brain metastasis mouse models, SUM190-BR and JIMT-1-BR. Endpoints included metastasis count, compound brain penetration, cancer cell proliferation and apoptosis. bHER2-ATC 3 mg/kg completely prevented all metastases 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 in large and micrometastases, respectively, 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 new mechanism of potential permeability. bHER2-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 the fluorescent dye suggested an endocytic mechanism of brain penetration. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2020.

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