Work

P01.21.a Exploring Tmclic1omab, a New Potential Adjuvant Therapy Against Glioblastoma Progression

Year: 2025

Type: article

Abstract: BACKGROUND One of the main problems in targeting glioblastoma (GBM) is its extremely high heterogeneity and ability to acquire radio and chemoresistance. It’s generally agreed that glioblastoma stem cells (GSCs) are the main cause of the insensitivity of this tumor to conventional therapies. It was shown that these cells have an altered regulation of several ion channels, which supports the tumor relapse. Nonetheless, most membrane proteins play a key role in normal physiological conditions. Among them all, one potential target could be found in the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1). CLIC1 is classified as a metamorphic protein coexisting in cytoplasmic and transmembrane conformation, the latter associated with chloride conductance. In solid tumors, tmCLIC1 is chronically expressed in the plasma membrane, particularly in the stem cell counterpart, characterized by high oxidative stress. One promising strategy in GBM could be the identification and the consequent inhibition of tmCLIC1 in several GBMs to potentially design a personalized treatment based on the amount of this protein in every patient. To this purpose, our laboratory has developed a monoclonal antibody, tmCLIC1omab, to target tmCLIC1. METHODS tmCLIC1omab was designed to recognize the tmCLIC1 portion that faces the outside of the cell. This peculiarity permitted the analysis of the cellular surface of a living human glioblastoma patient-derived cell population to identify and quantify the amount of protein in the plasma membrane. We have assessed the antibody biodistribution experiments using a murine glioblastoma model. RESULT We have verified in vitro that the interaction between the antibody and its target results in a strong inhibition of tmCLIC1 functional activity, opening a new therapeutic perspective. A preliminary biodistribution and persistence study performed in an orthotopic GBM murine model by optical imaging of the fluorescently labelled antibody demonstrated the ability to localize where tmCLIC1 is expressed, paving the way for the development of a new diagnostic tool. CONCLUSIONS Taking into consideration our preliminary experiments, tmCLIC1omab could be considered a theranostic new tool in GBM.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noaf193.101