PREPARATION, BIODISTRIBUTION AND DOSIMETRY OF COPPER-64-LABELED ANTI-COLORECTAL CARCINOMA MONOCLONAL-ANTIBODY FRAGMENTS 1A3-F(AB')(2)

Antibody fragments labeled with a radiometal using bifunctional chelat es generally undergo renal clearance followed by trapping of the metab olites, leading to high radiation doses to the kidneys. Copper-64-labe led BAT-2IT-1A3-F(ab')(2) was recently reported to accumulate in color ectal tumors in an animal model, however, kidney uptake was also high. In this study, the preparation of Cu-64-BAT-2IT-1A3-F(ab')(2) was opt imized to reduce the renal uptake. Methods: The bifunctional chelate 6 -bromoacetamidobenzyl-1,4,8,1 1-tetraazacyclotetradecane-N,N',N '',N ' ''-tetraacetic acid (BAT) was conjugated to 1A3-F(ab')(2) using the li nking agent 2-iminothiolane (2IT). The conjugation reaction produced 2 0% of a lower molecular weight (molecular wieght) impurity found to be TETA-1A3-Fab'. The conjugation procedure was optimized to include FPL C purification of the BAT-2IT-1A3-F(ab')(2) from TETA-1A3-Fab' after c onjugation prior to labeling with Cu-64. The biodistribution of Cu-64- labeled FPLC-purified and unpurified conjugates was determined in norm al Sprague-Dawley rats and tumor-bearing Golden Syrian hamsters. Human absorbed doses were calculated from rat biodistribution data and PET imaging of a baboon. Results: Upon FPLC purification of the BAT-2IT-1A 3-F(ab')(2), the immunoreactivity of Cu-64-labeled 1A3-F(ab')(2) was s ignificantly improved over that of non-FPLC-purified Cu-64-BAT-2IT-1A3 -F(ab')(2), and the kidney uptake was decreased in normal rats. The bi odistribution in hamsters showed some improvement in both tumor uptake and kidney clearance with FPLC-purified Cu-64-BAT-2IT-1A3-F(ab')(2). Conclusion: The improved dosimetry of Cu-64-labeled FPLC purified BAT- 2IT-1A3-F(ab')(2) should more readily allow this agent to be investiga ted clinically to image colorectal cancer using PET.