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Nanobodies targeting ABCC3 for immunotargeted applications in glioblastoma
Eduardo Ruiz-López1, Ivana Jovčevska2, Ruth González-Gómez1
1Molecular Oncology Group, Instituto de Investigación Sanitaria Aragón (IIS Aragón), 50009, Zaragoza, Spain.
Abstract:
The cancer "omics" reveal many clinically relevant alterations that are transforming the molecular characterization of glioblastomas. However, many of these findings are not yet translated into clinical practice due, in part, to the lack of non-invasive biomarkers and the limitations imposed by the blood-brain barrier. Nanobodies, camelid single-domain antibody fragments, emerge as a promising tool for immunotargeted applications for diagnosing and treating glioblastomas. Performing agnostic bioinformatic analysis from glioblastoma patient datasets, we identified ATP Binding Cassette subfamily C member 3 (ABCC3) as a suitable target for immunotargeted applications. The expression of ABCC3 is associated with poor survival and impaired response to temozolomide. Importantly, high expression of ABCC3 is restricted to glioblastoma, with negligible levels in healthy brain tissue, and further correlates with tumor grade and stemness markers. We identified three immunogenic epitopes of ABCC3 which were used to isolate nanobodies from a glioblastoma-specific phage-display nanobody library. Two nanobodies targeting ABCC3 (NbA42 and NbA213) were further characterized and demonstrated in vivo selective recognition of ABCC3 in glioblastoma xenograft mouse models upon systemic administration. We designate NbA42 and NbA213 as new candidates to implement immunotargeted applications guiding a more personalized and precise diagnosis, monitoring, and treatment of glioblastoma patients.
Insights
New nanobodies target ABCC3, a glioblastoma biomarker. These nanobodies show promise for non-invasive diagnosis and treatment of glioblastoma (GBM) patients, overcoming blood-brain barrier challenges.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Glioblastoma (GBM) molecular characterization is advancing, but clinical translation is limited by non-invasive biomarker scarcity and blood-brain barrier (BBB) challenges.
- Nanobodies, derived from camelid single-domain antibody fragments, offer a promising avenue for targeted glioblastoma diagnosis and therapy due to their small size and stability.
- Identifying specific, GBM-restricted targets is crucial for developing effective immunotargeted strategies.
Purpose of the Study:
- To identify a novel, GBM-specific molecular target for immunotargeting.
- To develop and validate nanobodies against the identified target for potential diagnostic and therapeutic applications in glioblastoma.
Main Methods:
- Agnostic bioinformatic analysis of glioblastoma patient datasets to identify potential targets.
- Isolation and characterization of nanobodies targeting the identified biomarker using a GBM-specific phage-display library.
- In vivo validation of nanobody specificity and tumor recognition in glioblastoma xenograft mouse models.
Main Results:
- ATP Binding Cassette subfamily C member 3 (ABCC3) was identified as a promising glioblastoma-specific target, associated with poor survival and temozolomide resistance.
- High ABCC3 expression is largely restricted to glioblastoma, correlating with tumor grade and stemness markers.
- Two nanobodies, NbA42 and NbA213, demonstrated in vivo selective recognition of ABCC3 in glioblastoma xenografts upon systemic administration.
Conclusions:
- NbA42 and NbA213 are validated as promising candidates for immunotargeted applications in glioblastoma.
- These nanobodies may facilitate personalized diagnosis, monitoring, and treatment strategies for glioblastoma patients.
- Targeting ABCC3 with nanobodies represents a novel approach to overcome current diagnostic and therapeutic limitations in glioblastoma management.
