Primary and metastatic brain tumors and neoplastic meningitis (NM) are resistant to present nonspecific therapies which often result in significant toxicity to normal brain. Targeted therapy with radiolabelled monoclonal (MAbs) and immunotoxins is an attractive approach for increasing efficacy for brain tumors and decreasing toxicity to normal CNS but it needs refinement. Anti- epidermal growth factor receptor variant III (anti-EGFRvIII) MAbs react with glioblastoma multiforme, breast and lung carcinoma, but not normal tissue. The applicant's hypothesis is that 1) tumor specific MAbs such as anti-EGFRvIII MAbs, 2) genetically engineered MAb fragments with appropriate affinity, half-life, and tumor penetration and 3) high linear energy transfer radionuclides such as the alpha-emitter 211At and Pseudomonas exotoxin MAb constructs will improve MAb therapy.
The Specific Aims are: 1) To develop additional murine MAbs against different conformational or linear sequence epitopes of cell-surface expressed EGFRvIII; to select from their three characterized and new anti-EGFRvIII MAbs the best localizing radiolabelled MAb and the most toxic immunotoxin-conjugated MAb; and to prepare from the best anti-EGFRvIII murine MAb human/mouse chimeric and humanized MAbs, genetically engineered CH2-domain deleted """"""""F(ab')2,"""""""" Fab, and monovalent (sFv) and divalent (sFv(2)) single-chain fragments with a range of affinities. 2) To construct potent immunoconjugates from the best EGFRvIII MAbs and fragments of Aim 1 by labeling them with 131I or 211At using approaches that maximize tumor retention of radioactivity after internalization and by preparing immunotoxins via chemical or genetic incorporation of regions of Pseudomonas exotoxin A. 3) To select the best MAb or fragment construct on the basis of in vitro localization as determined by projected radiation dosimetry from paired-label biodistribution and quantitative autoradiography; and on the basis of survival prolongation in human intracerebral and NM xenograft models following therapeutic trial of equitoxic doses of radiolabelled MAbs and immunotoxins. To determine the least toxic and most effective route of administration for the radiolabelled MAbs and fragments and immunotoxins comparing intravenous, intratumoral, intraresection cavity, and intrathecal administration. 4) To perform all quality control, toxicologic, pharmacologic, and pathologic evaluation required to obtain FDA approval for Investigational New Drug permits for the best immunotoxin and 131I- and 211At-labeled anti-EGFRvIII constructs; and to pursue clinical trials with support from the NINDS-Duke Specialized Research Brain Tumor Center (NS20023, D. Bigner, Director).
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