There will be more than 17,000 new cases of primary malignant brain tumors diagnosed in 2002 and more than 13,100 deaths. There has been little progress in the treatment of malignant gliomas in the last 30 years. Unarmed and armed MAbs are now being approved by the FDA for treatment of systemic cancers such as breast carcinoma, non-Hodgkin's lymphoma and hairy cell leukemia. Our hypothesis is that poor drug delivery and widespread migration of GBM cells will be overcome by using intracranial microdiffusion [(convection-enhanced delivery (CED)] of MAbs or their fragments as unarmed MAbs, toxin conjugates, or radiolabeled conjugates. Genotypic and phenotypic heterogeneity and cellular resistance to chemotherapy will be overcome by targeting multiple cell-surface expressed molecular targets of GBMs, namely EGFRvIII, MRP3, GPNMBwt and GPNMBsv, and 3'-isoLM1 and 3'6'-isoLD1. Anti-EGFRvIII MAbs have been developed in the last period of this grant and an scFv-PE38 KDEL single fragment chain Pseudomonas exotoxin construct will enter clinical trial in late 2002. We propose raising three additional MAbs, one reactive with GPNMBwt and GPNMBsv, another specific for 3'-isoLM1 and 3'6'-isoLD1, and anti-MRP3 MAbs. All of these molecules are involved in the malignant phenotype of GBM. Elimination of cells expressing these four molecules should result in significant survival increases in GBM patients.
Our specific aims are: 1) To prepare high affinity MAbs reactive with GPNMBwt and GPNMBsv, MRP3, and 3'-isoLM1 and 3'6'-isoLD1.2) To use the MAbs from Specific Aim 1 and anti-EGFRvIII MAbs from the previous grant period to determine the true incidence of expression, cell and tissue localization and heterogeneity of expression of GPNMB, MRP3, 3'-isoLM1 and 3'6'-isoLD1, and EGFRvIII in malignant gliomas. 3) To determine in vitro whether unarmed MAbs reactive with GPNMBwt and GPNMBsv, MRP3, and 3'-isoLM1 and 3'6'-isoLD1 have anti-proliferative and/or apoptosis-initiating activity. 4) To prepare scFv-Pseudomonas toxin constructs and 1311 and 211Atlabeled divalent minibodies reactive with GPNMBwt and GPNMBsv, MRP3, and 3'-isoLM1, and 3'6'- isoLD1, and to compare their cystostatic and cytocidal activity in vitro and in vivo. 5) Under D. Bigner's NS 20023-19 Brain Tumor Center grant, perform FDA-required toxicity and efficacy of three best toxin and three best radiolabeled constructs and submit IND and carry out clinical studies in glioma patients.
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