Development of Armed and Unarmed Monoclonal Antibodies for the Treatment of Malignant Gliomas and Medulloblastomas
For many years, the thrust of Dr. Darell Bigner’s MERIT Award has been the development of monoclonal antibodies for clinical trial in gliomas and medulloblastomas. Presently, Dr. Bigner’s laboratory has treated over 400 patients with 131I- and 211At-labeled antitenascin monoclonal antibody 81C6 with significant results. For example, median survival in recurrent glioblastoma patients is around 60 weeks, which represents a doubling of that with surgery alone. This treatment is being refined and delivered with a calculated amount of radiolabeled monoclonal antibody to deliver 4400 centigrade to the 2 cm margin of glioma resection cavities. Multi-institutional Phase II and Phase III trials are being planned.
In earlier work, Drs. Bigner and Wikstrand, in collaboration with Drs. Bert Vogelstein and Albert Wong of Johns Hopkins, identified a tumor-specific variant of the wild-type epidermal growth factor receptor gene called EGFRvIII. This EGFRvIII contains a new glycine at the fusion junction of the gene deletion, and forms a tumor-specific epitope on the cell surface of approximately half of malignant gliomas. In collaboration with Dr. Ira Pastan at the National Cancer Institute, Drs. Bigner and Wikstrand have developed an immunotoxin designated MR1-1 which has been produced by the NCI RAID Program. An IND is being prepared to administer it by convection-enhanced delivery in malignant glioma patients and these clinical trials are anticipated to begin in 2004.
Because of the heterogeneity of malignant gliomas, genome data mining methods have been used in collaboration with Dr. Gregory Riggins, Dr. Simon Gregory, and Dr. Hai Yan to identify new extracellular matrix or cell surface antigens of malignant gliomas. From SAGE analysis, two overexpressed genes, MRP-3 and GPNMB, have been discovered. A significant number, more than half, of malignant gliomas express one or both of these antigens and monoclonal antibodies have been prepared against them. These antibodies are being evaluated for development as clinically applicable reagents.
Additional targets, which were identified in collaboration with Professor Lars Svennerholm and Pam Fredman in Sweden several years ago, are the gangliosides 3'-isoLM1 and 3',6'-isoLD1. Earlier attempts at preparing monoclonal antibodies against these gangliosides resulted in the production of highly specific IgM antibodies not suitable for clinical trial. Drs. Bigner and Wikstrand are preparing knockout mice lacking the Lac3 synthase gene which will make the mice immunologically naïve for 3'-isoLM1 and 3',6'-isoLD1. Once these mice are available in 2004, high affinity IgG antibodies will be prepared against these two gangliosides and they will then be developed into therapeutic reagents for clinical trial.
Medulloblastoma efforts presently focus on the somatostatin receptor 2A (SS2A). Both octreotide immunotoxins and monoclonal antibodies are being prepared against SS2A, following which INDs will be obtained for treatment of medulloblastoma neoplastic meningitis.