Glioblastoma (GBM) is the most common primary malignant brain tumor, with a poor prognosis due to resistance to radiation therapy (RT) and temozolomide (TMZ). Galectin-3 (Gal-3), a carbohydrate-binding protein, is implicated in GBM progression, treatment resistance, immune evasion, and poor survival. TB006, a humanized monoclonal antibody targeting Gal-3, has shown potential to enhance TMZ efficacy and reverse therapy-induced Gal-3 upregulation in preclinical models. Preliminary data demonstrate that Gal-3 is upregulated in GBM cells and orthotopic models following TMZ treatment, while TB006 reduces Gal-3 expression, suppresses tumor growth, and improves survival. Additional studies show TB006 inhibits GBM cell migration and invasion. Despite a favorable safety profile in Phase Ia and Phase Ib/IIa Alzheimer’s trial, optimal dosing and utility of TB006 in GBM remain unexplored. We propose three aims: (1) investigate PK/PD simulations of TB006 to support a proposed starting clinical dose; (2) evaluate TB006’s antitumor efficacy in combination with RT and TMZ using patient-derived xenograft models; and (3) conduct a Phase 1 window-of-opportunity trial in recurrent GBM patients undergoing reoperation to evaluate tumor concentration of TB006, Gal-3 modulation, and to assess safety, tolerability, PK/PD, and early efficacy. This translational study aims to test the hypothesis that TB006, by targeting Gal-3, will improve glioblastoma sensitivity to standard of care RT and TMZ, resulting in enhanced treatment efficacy and survival. Successful completion will inform dosing strategies, support development of a Phase 2 trial, and lay the groundwork for precision medicine approaches targeting galectin-driven mechanisms in GBM.
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