Glioblastoma (GBM) is the most common, aggressive malignant grade 4 tumor with a variant in the wide spectrum of intrinsic glial brain tumors with a poor prognosis and limited treatment options. [1]
Unlike most aggressive malignancies, glioblastoma only seem to thrive in the exclusive microenvironment of the brain and as a result, extracranial metastases are rare. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. To date, glioblastoma remains an incurable disease with a median survival of 15 – 18 months. [2] Current treatment options at diagnosis are multimodal, including surgical resection, radiation, and chemotherapy. Advances in the understanding of the molecular pathology of glioblastoma have opened opportunities for new therapies for recurrent and newly diagnosed disease. However, with a high rate of recurrence, treatment options remain limited, highlighting the urgent unmet medical need for novel treatment approaches.
One of the greatest barriers in treating glioblastoma (and other CNS disorders) is the inability of current chemotherapeutic agents to penetrate the Blood-Brain Barrier (BBB), which limits the delivery of therapeutic agents to target the tumor. [3]
CD99 and glioblastoma
Glioblastoma is a heterogeneous disease, characterized by diverse genomic profiles and tumor antigen expression patterns. Research has identified CD99 as a novel glioblastoma tumor antigen. Although CD99 is not a commonly recognized as a glioblastoma biomarker, glioblastoma does consistently express CD99. Over-expression of CD99 in glioblastoma is generally associated with tumor adaptiveness, potentially influencing and response to treatment, including standard-of-care chemotherapy and radiotherapy. CD99 is linked to hypoxia, one of the most common stress factor in glioblastoma, and immunosuppressive phenotypes. High expression of CD99 is further indicated in shorter recurrence times and poor outcomes observed in patients diagnosed with glioblastoma.[4][5]
At NanoValent Pharmaceuticals, we have developed an investigational novel format nano-ADCs likeTargeted NanoSpheres (nADC/TNS). Based on our targeted drug delivery platform technology, we have developed NV103, a CD99 targeting nADC/TNS with an irinotecan payload which effectively penetrates the BBB, selectively bind to glioblastoma cells while largely bypassing normal, healthy, brain tissue that could significantly improve treatment efficacy.[5][6]
Figure 1.0. Prolonged plasma persistence
NV103 remains far longer in circulation than free drug . Prolonged plasma persistence with detectable levels ( >200x more) were present at 24 hours.
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 preclinical animal models, NV103 prolonged survival at least five-fold over free irinotecan treated animals in bi-weekly single dose level studies, without any treatment-related toxicity.[5] Furthermore, in preclinical animal studies, NV103 also extended the survival of orthotopically implanted human PDX glioblastoma (GBMPDX43)-bearing mice by at least three-fold compared to free-drug treatments. [6]
Figure 1.1 Blood-Brain Barrier
Free small molecules like chemotherapeutics generally show <1% Blood-Brain Barrier (BBB) penetration; NV103 effectively delivers a payload drug to the brain across the BBB. Morphologic evidence, using an in vitro model of BBB (from the National Research Council, Canada). The image shows a section of normal mouse brain and a separate section treated with our nADC)/TNS which are clearly permeating the brain parenchyma.
In pre-clinical studies we also demonstrated that NV103 effectively induces cytotoxicity across a broad spectrum of CD99-expressing glioblastoma cells. Furthermore, NV103 showed significantly enhanced anti-tumor activity, even in low CD99-expressing tumors. Moreover, dose-response trends in glioblastoma-bearing animals suggest that escalating doses of CD99-targeted nADC/TNF could further improve overall survival outcomes.
The targeted approach with NV103, our investigational nADC/TNF, minimizes drug exposure to normal tissues, including brain. In pre-clinical studies 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. This finding underscores the potential of NV103 potential to effectively target heterogeneous glioblastoma, including those with variable CD99-expression levels, not unlike HER2-low tumors treated with traditional human epidermal growth factor receptor 2 (HER2-) directed antibody-drug conjugates (ADC). Overall, the results from pre-clinical studies suggest that data NV103 dose escalation will amplify its therapeutic impact, positioning NV103 as a potential groundbreaking approach to overcome treatment resistant glioblastoma.[6]
Beyond glioblastoma
Beyond our approach to treat glioblastoma, our unique platform technology also allowed us to develop additional investigational agents, including NV101, NV102, NV104, and NV105 to addresses the unmet medical needs of other hard to treat diseases.
Reference
[1] Davis ME. Epidemiology and Overview of Gliomas. Semin Oncol Nurs. 2018 Dec;34(5):420-429. doi: 10.1016/j.soncn.2018.10.001. Epub 2018 Nov 2. PMID: 30392758.
[2] Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):1985-96. doi: 10.1158/1055-9965.EPI-14-0275. Epub 2014 Jul 22. PMID: 25053711; PMCID: PMC4185005.
[3] van Tellingen O, Yetkin-Arik B, de Gooijer MC, Wesseling P, Wurdinger T, de Vries HE. Overcoming the blood-brain tumor barrier for effective glioblastoma treatment. Drug Resist Updat. 2015 Mar;19:1-12. doi: 10.1016/j.drup.2015.02.002. Epub 2015 Mar 6. PMID: 25791797.
[4] Shang E, Sun S, Zhang R, Cao Z, Chen Q, Shi L, Wu J, Wu S, Liu Y, Zheng Y. Overexpression of CD99 is associated with tumor adaptiveness and indicates the tumor recurrence and therapeutic responses in gliomas. Transl Oncol. 2023 Nov;37:101759. doi: 10.1016/j.tranon.2023.101759. Epub 2023 Aug 12. PMID: 37579711; PMCID: PMC10440586.
[5] Kang H, Nagy J, Upton B, Triche T. Superior efficacy of targeted nanoparticle therapy for brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl): Abstract nr 295.
[6] Kang H, Upton B, Nagy J, Sarkaria JN, Triche TJ. Enhancing GBM therapy with tumor-targeted nanoparticles [abstract]. In: Proceedings of the American Association for Cancer research Annual Meeting 2025, April 25 – 30, Chicago, Il.: AACR; 2025. Abstract nr LB183 / 1