Carol Wikstrand Lewis
Research Professor Emeritus in Pathology
The primary research interests of my group are the identification, analysis, and operational establishment of monoclonal antibodies (Mabs) reactive with glioma-associated, oncofetal epitopes such as tenascin, glioma variant epidermal growth factor variant III (EGFRvIII), and medulloblastoma-associated developmental markers for exploitation as targets for immunodetection, modulation, and/or therapy. Experiments performed in the current year have: 1) continued the production, certification, and provision of clinical grade batches of Mab 81C6 and F(ab')2 fragments of Mab Me1-14 for three phase 1/11 clinical trials currently in progress; 2) performed activity and stability determination of chimeric molecules of these therapeutic reagents; 3) established a library of specific anti-EGFRvIII Mabs of various murine Ig classes which have been demonstrated to specifically localize to antigen positive human tumor xenografts in the athymic rodent model systems and to have varying biologic effects, perhaps attributable to Ig class; 4) determined the affinity of the Mab-receptor interaction and internalization kinetics of the EGFRvIII-Mab complex; 5) begun an extensive analysis of EGFR wt and EGFR VIII protein expression correlated with measurement of RNA transcript levles and degree of DNA amplification; 6) demonstrated tumor growth delay in tumor-bearing mice treated with 3/5 anti-Y10 Mab idiotype reagents; 7) characterized a new anti-medulloblastoma distinctive Mab which recognizes a >259 kD glycoprotein which has been affinity-column purified and derived the N-terminal sequence (13aa) of this glycoprotein; and using SAGE analysis, identified two new antigens of potential glioma association, and one of medulloblastoma association to which monoclonal antibodies and derived constructs are currently being generated.
Our objectives for the coming year, then, are to continue the optimization of the defined antibody-antigen pair systems for in vivo application, namely: a) development of the anti-med system for in vivo application; b) examination of anti-EGFRvIII Mab idiotype antibodies in in vivo therapeutic model systems; c) examination of the distribution of EGFRvIII in human neoplasia; and d) cloning and development of the O4 MED system to generate additional high affinity reagents.
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