CADD-42. EFFICACY OF MUTANT INTERLEUKIN-13 ALPHA-2 RECEPTOR–TARGETED LIPOSOMAL DOXORUBICIN IN THE INTRACRANIAL BRAIN TUMOR MODEL

Glioblastoma (GBM) is the most common primary central nervous system (CNS) tumor in the United States and yet despite aggressive treatment, the median survival remains at 8 months. About 75% of human glioblastoma tumors selectively overexpress the α(2) subtype of interleukin 13 (IL-13Rα(2)), considered a “decoy receptor” for GBM, allowing it to evade apoptosis normally induced by IL-13 binding. Our laboratory and others have developed targeting strategies to take advantage of IL-13Rα(2) expression on GBMs. We showed that wildtype IL-13 targeted nanoliposomes delivering doxorubicin (WT-IL13-Dox), resulted in over 5-fold reduction of orthotopic tumors, with 60% of mice surviving for >200 days compared to mice treated with unconjugated liposomes. WT-IL13, however, also binds to the shared IL-13/IL-4 receptor α(1) subunit found in multiple organs, including the heart and lungs, suggesting potential cross-reactivity with surrounding tissues. To address off-target effects, a mutant version of IL-13 was developed known as Targeted Quadruple Mutant-13 (TQM), which display improved binding affinity to the IL-13Rα(2) receptor, and decreased affinity to the IL-13/IL-4 receptor α(1) subunit. Twenty mice were normalized by tumor burden into two groups, one treated with WT-IL13-Dox and the other group with TQM-13-conjugated liposomal doxorubicin (TQM-13-Lip-Dox). Each group received 5mg/kg of doxorubicin in the liposomes for 4 weeks. Mice treated with TQM-targeted liposomes had slower tumor growth, smaller tumor burden, and prolonged survival (33 vs 23 days, p=0.009) than those treated with WT-IL13 liposomes. WBC counts in WT-IL13 mice suggested they were immunocompromised in comparison to TQM mice (p=0.02), which may contribute to worse survival. These findings suggest that TQM-13 bound nanoliposomes may enable the development of targeted therapy with a decreased side effect profile for delivery of chemotherapeutic agents to GBMs.