Targeting brain-metastatic breast tumors with HER3-homing bioparticles

While the median survival for patients with metastatic breast cancer is ~2-5 years depending on the sub-type, metastasis to the brain predicts an average survival of less than one year and drastically reduces therapeutic options as most targeted therapies cannot cross the blood-brain barrier (BBB). Increased cell surface density of HER3 (or ErbB3) associates with tumor progression, therapeutic resistance and metastasis including the brain-metastasis of HER2+ and triple-negative breast tumors. We bioengineered a tumor-invading protein, HPK, that uses HER3 to penetrate breast tumors resisting ErbB receptor family inhibitors. Unlike antibodies, HPK bears a HER3-homing function derived from the natural HER3 ligand neuregulin to mediate tumor-targeting and induce endocytic uptake. HPK also utilizes the capsid-forming and endosomal penetration functions of an adenovirus-derived capsid protein to encapsulate and deposit macromolecular cargo into HER3-expressing cells. Systemic HPK BPs in both orthotopic and subcutaneous mouse breast cancer models show increased accumulation in secondary tumors compared to primary tumors due to the increased HER3 associated with metastasis. We also observed that systemic HPK BPs can enter the brain and subsequently found that the brain vasculature but not the brain parenchyma expresses robust levels of HER3. We have found that systemically administered HPK BPs in mouse models of brain-localized breast cancer can cross the BBB and accumulate in intracranial (IC) TNBC tumors using HER3 to mediate both routes. Our goals in the current study are to advance the development of corrole-loaded BPs guided in part by specific suggestions posed by a previous Nanotechnology Characterization Lab (NCL) panel review. Accordingly, the current studies will test the use of a modified HPK protein (HPK2.0) that shows improved bio-manufacturing yield, purity, homogeneity, cargo loading and receptor-specificity, which we constructed to improve the solubility of scaled-up product. The modifications made to HPK have removed exposed epitopes thus potentially improving its immuno-evasion, which will be evaluated here. HPK2.0 will also be evaluated using computational biophysical methods to understand the mechanism of pH-dependent endosomolytic breakdown and to design new HPK variants with improved therapeutic as well specificity profiles.