Abstract LB183: Enhancing GBM therapy with tumor-targeted nanoparticles

Abstract Glioblastoma Multiforme (GBM) is a highly aggressive malignant brain tumor. Despite decades of research, the tumor is essentially incurable, primarily due to the failure of small molecule drugs to pass the blood-brain barrier (BBB). This molecular "pump" within the brain's blood vessel linings restricts effective drug delivery to the tumor. To address this challenge, we have developed an antibody targeted nanoparticle therapeutic platform, NV103. NV103 employs liposomal nanoparticles with tumor antigen targeted antibodies specifically engineered to deliver otherwise ineffective drugs like irinotecan directly to tumor. GBMs are heterogeneous, characterized by diverse genomic profiles and tumor antigen expression patterns. EGFR is a well-known example. Here we identified a novel GBM tumor antigen, CD99. CD99 is not a commonly recognized GBM biomarker, but we find that GBMs consistently express CD99. We evaluated nearly 100 GBM PDXs in the Mayo Clinic repository and found that nearly all express CD99. We then evaluated NV103's efficacy across multiple GBM tumors with varying levels of CD99 cell surface expression. Importantly, NV103 demonstrated exceptional BBB penetration in an in vitro transwell system utilizing brain endothelial cells derived from human stem cells. NV103 also exhibits prolonged plasma persistence with detectable levels present at 24 hours, compared to free drug which is undetectable within hours. This prolonged drug availability combined with the ability to penetrate the BBB and preferentially bind to tumor cells results in dramatically enhanced anti-GBM activity. In GBM mouse studies, NV103 and its payload exhibited at least 5-fold enhanced delivery to tumor vs. brain. In preclinical animal studies, NV103 extended the survival of orthotopically implanted human PDX glioblastoma (GBMPDX43)-bearing mice by at least three-fold compared to free-drug treatments. We also showed that NV103 effectively induces cytotoxicity across a broad spectrum of CD99-expressing GBMs. NV103 showed significantly enhanced anti-tumor activity, even in low CD99-expressing tumors, such as GBMPDX43. Moreover, dose-response trends in GBM-bearing animals suggest that escalating doses of CD99-targeted nanoparticles could further improve survival outcomes. This targeted approach minimizes drug exposure to normal tissues, including brain. We found no dose limiting toxicity at 50mg/kg, five times higher than the 10mg/kg used for most of the tumor bearing animal studies. These findings underscore NV103's potential to effectively target heterogeneous GBMs, including those with variable CD99 expression levels, not unlike HER2-low tumors treated with HER2-directed ADCs. Further, preclinical data suggest that NV103 dose escalation will amplify its therapeutic impact, positioning this platform as a potential groundbreaking approach to overcome treatment resistant GBM. Citation Format: HyungGyoo Kang, Bryon Upton, Jon Nagy, Jann N. Sarkaria, Timothy J. Triche. Enhancing GBM therapy with tumor-targeted nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB183.