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Recombinant Therapeutics
Our research goal is to generate original antibody-based medicines for imaging and therapy of cancer. Our focus is on design and construction of the molecules and their interaction with cancer targets. The basic antibody fragment we use is a single chain Fv (scFv) [Fig 1] and our primary cancer target is carcinoembryonic antigen (CEA), a glycoprotein expressed in colorectal adenocarcinomas. MFE-23, our most characterised scFv, reacts with CEA and was the first scFv to target cancers in man. Our other targets include breast and prostate cancer and the avß6 integrin which is present on head and neck cancers. We obtain the cancer-reactive scFvs from filamentous phage libraries that contain many millions of diverse antibody specificities and we engineer the scFvs in a format designed or a particular therapy. For example, antibody-directed enzyme-prodrug therapy (ADEPT) of cancer, a treatment that uses a systemically administered anti-tumour antibody-enzyme complex to localize enzyme in tumours. In a second stage, a prodrug is administered and is selectively converted into an active cytotoxic drug by enzyme at the tumour site. ADEPT has the potential to generate high concentrations of cytotoxic agent selectively within tumours but it is key for success that non-tumour associated enzyme is effectively cleared from blood and other normal tissues before prodrug administration. A recombinant fusion protein, comprising MFE-23 fused to the enzyme carboxypeptidase G2 (CPG2), has been designed and produced by the group to meet this challenge [Sharma et al 2005, Kogelberg et al 2006]. The therapeutic protein is expressed and purified from yeast Pichia pastoris, and the post-translational glycosylation added by this organism is being exploited to control blood clearance via the mannose receptor [Fig 3] and modify bio-distribution. The therapeutic system is effective in pre-clinical tests [Sharma et al., 2006] and is currently in Phase I/II Clinical Trials [Mayer et al., 2006].
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