Extracellular LGALS3BP: a potential disease marker and actionable target for antibody-drug conjugate therapy in glioblastoma

Glioblastoma multiforme (GBM) is a lethal disease characterized by an overall survival of about 1 year, making it one of the most aggressive tumours, with very limited therapeutic possibilities. Specific biomarkers for early diagnosis as well as innovative therapeutic strategies are urgently needed to improve the management of this deadly disease. In this work, we demonstrated that vesicular galectin-3-binding protein (LGALS3BP), a glycosylated protein overexpressed in a variety of human malignancies, is a potential GBM disease marker and can be efficiently targeted by a specific antibody-drug conjugate (ADC). Immunohistochemical analysis on patient tissues showed that LGALS3BP is highly expressed in GBM and, compared with healthy donors, the amount of vesicular but not total circulating protein is increased. Moreover, analysis of plasma-derived extracellular vesicles from mice harbouring human GBM revealed that LGALS3BP can be used for liquid biopsy as a marker of disease. Finally, an ADC targeting LGALS3BP, named 1959-sss/DM4, specifically accumulates in tumour tissue, producing a potent and dose-dependent antitumor activity. In conclusion, our work provides evidence that vesicular LGALS3BP is a potential novel GBM diagnostic biomarker and therapeutic target deserving further preclinical and clinical validation.

Automated summary

This study demonstrates that vesicular galectin-3-binding protein (LGALS3BP) is a potential diagnostic biomarker and therapeutic target for glioblastoma multiforme (GBM). Immunohistochemical analysis shows high expression of LGALS3BP in GBM patient tissues, and the amount of vesicular LGALS3BP is increased compared to healthy donors. Furthermore, analysis of extracellular vesicles from mice with human GBM indicates that LGALS3BP can be used as a marker for liquid biopsy. An antibody-drug conjugate (ADC) targeting LGALS3BP, named 1959-sss/DM4, shows specific accumulation in tumor tissue and produces potent antitumor activity. Overall, this work provides evidence for the importance of LGALS3BP as a diagnostic biomarker and therapeutic target for GBM, warranting further validation in preclinical and clinical studies.