DEVELOPMENT OF A TOXIC FUSION PROTEIN FOR BRAIN TUMORS

Neurocrine Biosciences, Inc., San Diego CA

Investigators

Abstract

Malignant brain tumors are one of the most life-threatening forms of cancer and glioblastoma is the most aggressive form of brain cancer. It constitutes approximately 35% of all primary brain tumors. There are approximately 17,500 new cases of brain tumors in the U.S. annually. Today's standard therapies consisting of surgery, radiation and chemotherapy have a relatively small effect on the survival of the patients. A targeted toxic protein derived from fusion of interleukin-4 to Pseudomonas exotoxin (IL-4PE) may offer a new treatment approach for recurrent glioblastoma. PE is a very potent toxin and, when internalized, the toxin will cause cell death. Malignant brain tumors express abundant IL-4 receptors, which bind IL-4 with very high affinity. Thus, fusion of IL-4 with PE will provide an efficient means of delivering the exotoxin through endocytosis into the tumor cells. Neurocrine has licensed the IL- 4PE from the FDA and intends to develop this fusion protein into a commercial product. To do so we will first construct an expression vector, which can express the protein in high yield. Second, we will design methodology to purify and chemically characterize the expressed protein. Third, we will set up an in vitro cell culture assay to measure the potency of the purified IL-4PE and lastly we will prepare radiolabeled IL-4PE for pharmacokinetic studies and develop a two-site directed ELISA to measure the intact protein in animal and human tissues. This information will be helpful in our advancement of IL-4PE into Phase II testing. PROPOSED COMMERCIAL APPLICATIONS: The current therapy for treating brain tumors includes surgery, radiation therapy and chemotherapy. The prognosis for these patients however remains poor. The development of a targeted toxin derived from the fusion of IL-4 to Pseudomonas exotoxin (IL-4PE) may provide an effective treatment for those patients with brain tumors. The research proposed in this application will further the development of this novel therapeutic.