NEURONAL AND GLIAL RESPONSES TO INTRAPONTINE DELIVERY OF A SELF-ASSEMBLING POLYPEPTIDE–DRUG CONJUGATE FOR PEDIATRIC DIFFUSE MIDLINE GLIOMA

Pediatric diffuse midline glioma (DMG) is a uniformly lethal tumor with no effective therapies. Excellamol has developed self-assembling polypeptide–drug conjugates (OncoPDCs) composed of an IL13Rα2-targeting ligand and the cytotoxic agent exatecan. Following convection-enhanced delivery (CED), OncoPDCs undergo phase transition to form coacervates, enabling prolonged brain retention and sustained local drug release. While therapeutic activity has been demonstrated in experimental glioma models, comprehensive safety evaluation is required to support its translational and clinical applicability. In the present study, we investigated the safety profile of this platform through a comprehensive toxicity assessment in Sprague–Dawley rats. NeuN, GFAP, and CD68 immunohistochemistry was performed to assess neuronal and glial responses. No treatment-related clinical signs or meaningful body weight loss were observed. Hematoxylin and eosin (H&E) and IHC analyses revealed dose-dependent but localized ischemic and inflammatory changes primarily confined to the injection site, with minimal involvement of surrounding brain regions. These findings suggest that tissue responses were largely volume-related and spatially restricted rather than indicative of systemic or widespread toxicity. Overall, the treatment was well tolerated. Taken together, these results indicate that brain tissue responses to intrapontine CED of the self-assembling OncoPDC are spatially confined, supporting the feasibility of locally retained intracranial drug administration strategies for DMG.