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Review

131 I-Labeled Recombinant Anti-Glycoprotein A33 Antibody Single Chain Variable Fragment Fused to Cytosine Deaminase

In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013.
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Review

131 I-Labeled Recombinant Anti-Glycoprotein A33 Antibody Single Chain Variable Fragment Fused to Cytosine Deaminase

Arvind Chopra.
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Excerpt

The palmotylated glycoprotein A33 (gpA33) is a cell-surface differentiation antigen that belongs to the immunoglobulin superfamily (1, 2). This antigen is expressed primarily in the normal intestine and in >95% of colon tumors, and it has not been detected in any other tissue (1, 2). Because of its presence only in the intestine or in tumors in the intestine, the gpA33 has been evaluated as a target for the detection and radioimmunotherapy of colon cancer tumors (2). The biodistribution of a radioiodinated humanized monoclonal antibody (Ab) directed against the human gpA33 antigen (huA33) is discussed in a separate MICAD chapter (3). It was reported that the labeled Ab used to treat the colon cancers bound to the entire intestinal tissue, including the tumors; however, although the radioactivity persisted in the tumors for at least 6 weeks, the label was lost from the normal gut tissue within 1 week after administration (1-3). The more rapid clearance of a radioiodinated huA33 from the normal intestinal tissue was observed to correspond to the turnover period of basal colonocytes in this tissue (4). Despite the extensive use of immunotherapy to treat cancers, the efficacy of this regimen is limited by the fact that not all individuals are responsive to this therapy. This is either due to the lack of or irresponsiveness of the receptors (or antigens) to which the Abs are directed. Also, because of its large size, the Ab may not be able to penetrate solid cancerous tumors completely, remain in blood circulation for extended periods, or may not be effective due to other factors as described by von Mehren et al. (5). As an alternative to Abs, investigators have developed Ab fragments such as the single chain variable fragments (scFv), which are much smaller (~30 kDa) than intact Abs (~150 kDa), contain the antigen-binding site, exhibit high tumor penetration, generate excellent tumor/normal tissue concentration ratios, and show rapid clearance through the kidneys (6, 7). Several scFv fragments targeted toward different antigens are under evaluation in clinical trials approved by the United States Food and Drug Administration and by similar regulatory agencies around the world (8). To further enhance scFv efficacy for preclinical or clinical application, these protein chains have been linked, either by synthesis or recombinant methods, to a variety of molecules such as enzymes (for prodrug therapy), toxins (for treatment of cancer), etc., to generate bifunctional molecules (7, 9, 10). The scFv chain directs the enzyme or toxin to a predetermined cellular antigen where the enzyme converts a prodrug into a cytotoxic molecule or the toxin is activated and has a lethal effect on the cell. Therefore, an Ab fused to an enzyme could be used for an Ab-directed enzyme-prodrug therapy for the treatment of cancers or other diseases. On the basis of this principle, Coelho et al. fused a recombinant scFv directed against the A33 antigen (A33scFv) with the yeast cytosine deaminase (CDy) enzyme to generate A33scFv::CDy as a possible colon cancer treatment (6). The CDy part of the recombinant fusion protein deaminates 5-fluorocytosine (5-FC), the prodrug, to produce cytotoxic 5-fluorouracil after the A33scFv part binds to the A33 antigen on the cell surface. Therefore, the A33scFv::CDy fusion protein is selectively lethal to only those cells that overexpress the A33 antigen, i.e., colon cancer cells. Panjideh et al. investigated the binding specificity of 131I-labeled A33scFv::CDy under in vitro conditions and also studied its biodistribution in athymic mice bearing xenograft tumors derived either from LIM 1215 cells, a gpA33-positive human colon carcinoma cell line, or the negative control HT29 cells, a gpA33-negative human colon carcinoma cell line (11).

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