NEW APPROACHES TO DELIVERING METAL-LABELED ANTIBODIES TO TUMORS - SYNTHESIS AND CHARACTERIZATION OF NEW BIOTINYL CHELATE CONJUGATES FOR PRE-TARGETED DIAGNOSIS AND THERAPY

Radiolabeled monoclonal antibodies are widely used in the detection an d treatment of cancer. However, several problems still prevent full cl inical exploitation of these reagents. Low tumor/background ratios in immunoscintigraphy and high background radioactivity in therapy are li miting factors. The strategy of pre-targeting may overcome these limit ations. One of the strategies is based on the avidin-biotin system. Th e use of biotinylated antitumor antibodies, followed by avidin and the n by a biotin-chelate conjugate in a three step procedure to image can cer sites has been demonstrated (G. Paganelli et al., Cancer Res, 51 ( 1991) 5960-5966), In this report we describe the synthesis of several biotin-chelate conjugates. Among these chelate conjugates, biotinyl-LC -DOTA binds the diagnostic and therapeutic radiometals (111)indium, (9 0)yttrium and(67) copper with the required stability and has excellent physiological properties for pre-targeted diagnosis and therapy. Biot inyl-LC-DOTA can be prepared from 2-p-nitrobenzyl-DOTA via p-aminobenz yl-DOTA and 6-((biotinyl)amino)caproic acid (biotin (X) over bar) in a simple two-step synthesis in 90% yield.