EXTH-24. Highly effective anti-brain tumor drug candidate in dogs with spontaneous intracranial gliomas

Abstract EphA2, EphA3, EphB2 and interleukin 13 alpha 2 (IL-13RA2) receptors are frequently over-expressed in spontaneous canine gliomas, the most faithful model of human disease. We previously performed the first-of-a-kind formal Phase I clinical trial in dogs with gliomas using a cocktail of cytotoxins based on bacterial toxins targeting IL-13RA2 and EphA2 receptors. The treatment produced remarkable anti-tumor responses and was administered loco-regionally through convection-enhanced delivery, using anti-reflux catheters and real-time MRI monitoring of drug distribution (Neuro-Oncol 2021;23(3):422-434). Encouraged by these exceptional results, we pursued the novel idea of targeting four GBM-associated receptors: EphA2, EphA3, EphB2, and IL-13RA2, with one pharmaceutical agent. We used a multivalent ligand binding to all four receptors, termed QUAD, including murine and canine receptors. We made a conjugate of QUAD with DM1, a microtubule-disrupting agent, which demonstrated a high and specific killing potency, in the low picomolar range, on GBM cells of canine/human origins. In preparation for Phase I trial in humans, we performed a dose-limiting toxicity study in 11 dogs with spontaneous brain tumors. We treated dogs with escalating doses of QUAD-DM1 (or WPD-401) and found that 9.2 µg/ml is dose limiting toxicity (DLT), as 18.4 µg/ml resulted in encephalopathic clinical signs. The treatment with QUAD-DM1 produced remarkable anti-tumor responses in these dogs with up to 95% tumor reduction observed after single treatment with our drug candidate. Three dogs who received the 9.2 µg/ml dose have already survived 7-, 9- and 11-months post-treatment without tumor progression; the average dose of QUAD delivered per dog was 2.95 µg. Thus, the starting dose in human patients with recurring GBM will be 1/6th of the canine MTD, which is 1.5 µg/ml, as stipulated by the FDA. QUAD-DM1 is a highly promising agent for the treatment of canine and human high-grade gliomas.