Pharmacokinetics, biodistribution, and neurohistopathological toxicity of self-assembling polypeptide-drug conjugates following intrapontine convection-enhanced delivery

Abstract

Pediatric diffuse midline glioma (DMG) is a uniformly lethal tumor, and patients diagnosed with DMG are in urgent need of novel therapeutics, as no effective treatment options currently exist for this fatal disease. Excellamol has developed self-assembling polypeptide-drug conjugates for oncology (OncoPDCs), which consist of IL13Ra2-binding ligands, intrinsically disordered domains, and the cytotoxic agent Exatecan. Upon CED into the brain, OncoPDCs undergo phase transition to form self-assembled coacervates, which are expected to exhibit prolonged retention within the brain. Preclinical efficacy studies have previously demonstrated the feasibility and therapeutic potential of OncoPDCs in high-grade gliomas. In this study, we evaluated the retention properties of OncoPDCs by comparing the pharmacokinetics of a free fluorescent dye (AZDye647), a dye-labeled polypeptide (XM182-AZDye647), and an OncoPDC (XM182-Exatecan) following convection-enhanced delivery into the pons of naive Balb/c-nu mice and Sprague Dawley rats. Free AZDye647 was rapidly cleared from the brain, with a clearance half-life of 0.38 days. In contrast, XM182-AZDye647 demonstrated prolonged retention in the pons, with a half-life of 16.5 days. To further assess drug kinetics and biodistribution, XM184-Exatecan, a surrogate of XM182-Exatecan, was labeled with iodine-125 (125I), and the resulting 125I-XM184-Exatecan was infused via CED into the rat pons. 125I-XM184-Exatecan exhibited biphasic clearance kinetics: an initial rapid elimination phase (half-life = 2.7 days) followed by a slower clearance phase (half-life = 14.9 days). 125I radioactivity was detected only in the urinary bladder, stomach, and thyroid, with the combined radioactivity accounting for less than 5% of the infused dose. Importantly, no histopathological toxicity was observed in the pons of rats treated with XM182-Exatecan, supporting the safety of this modality. In conclusion, the integration of self-assembling OncoPDC XM182-Exatecan with CED offers a promising therapeutic strategy for the treatment of DMG by significantly enhancing intrapontine drug residence time.