EXTH-49. A NOVEL MULTIVALENT DRUG CONJUGATE FOR HIGH-GRADE GLIOMA TREATMENT

Abstract

Abstract Interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed collectively in almost all patients with glioblastoma (GBM), and also in spontaneous canine gliomas, the most faithful model of human disease. The four receptors are widely present in various compartments of GBM tumors, including tumor core, infiltrating cells, tumor neovasculature and tumor-associated macrophages. Thus, the four receptors are expressed in several GBM compartments involved in tumor progression and/or resistance to therapies, covering almost 100% of the tumor microenvironment. In first-of-a-kind approach, we performed Phase I clinical trial in dogs with gliomas using a cocktail of cytotoxins targeting IL-13RA2 and EphA2 receptor. The cocktail was administered loco-regionally through convection-enhanced delivery, using anti-reflux catheters and real-time MRI monitoring of drugs distribution. We observed prominent anti-tumor responses, including several near complete regressions, prolongation of survival and excellent quality of life, although we did not achieve dose-limiting toxicity (Neuro-Oncol 2021;23(3):422-434). Encouraged by these exceptional results, we pursued the novel idea of targeting the four GBM-associated receptors with one pharmaceutical compound. To this end, we designed, produced, and tested a multivalent ligand binding to all four receptors of our interest, termed QUAD, including murine and canine receptors. However, we found that a conjugate of QUAD with DM1, a microtubule-disrupting agent, demonstrated an extremely high (in low picomolar range) and specific killing potency on GBM cells. The IC50s of QUAD-DM1 are ~50 times higher than that for all other QUAD-based drug conjugates tested thus far, having a favorable toxicity profile in rodents when injected either intracranially or intravenously. QUAD-DM1 has already produced up to 95% tumor reduction in dogs with spontaneous brain tumors. QUAD-DM1 is a highly promising agent for the treatment of human and canine high-grade gliomas.