PHARMACOKINETICS AND BIOACTIVITY OF 1,4,7,10-TETRA-AZACYLODODECANE N,N',N'',N'''-TETRAACETIC ACID (DOTA)-BISMUTH-CONJUGATED ANTI-TAC ANTIBODY FOR ALPHA-EMITTER (BI-212) THERAPY

A major factor that is critical to the potential effectiveness of alph a-emitter Bi-212 radioimmunotherapy is the design of radiometal-chelat ed antibodies that will be stable in vivo. The chelate should bind the radiometal firmly to minimize release of the radionuclide from the mo noclonal antibody-chelate complex. The present study examines a member of a new class of polyamine carboxylate chelating compounds, the DOTA ligands, for conjugating radiometal ions to antibody. Biocompatibilit y and stability are assessed with the anti-Tac monoclonal antibody tha t is directed against the human interleukin 2 receptor. The scientific basis for the clinical use of this antibody in radioimmunotherapy is that resting normal cells do not express the interleukin 2 receptor, w hereas the receptor is expressed on the surface of certain neoplasms a nd by activated T-cells in select autoimmune diseases and in allograft rejection. First, we examined the impact of the labeling procedure an d the presence of the chelate, DOTA, on antibody bioavailability and s urvival. Next, we studied the capacity of the antibody-chelate complex to retain radiobismuth. Coupling DOTA to antibody or adding Bi(III) t o DOTA-coupled antibody did not disturb antibody immunoreactivity in i n vitro binding studies. In addition, as analyzed by in vivo studies, DOTA-antibody dummy labeled with nonradioactive bismuth showed pharmac okinetics and tissue distribution identical to those of antibody not m odified with DOTA. DOTA-anti-Tac charged with radioactive bismuth show ed pharmacokinetics identical to radioiodinated dummy-labeled DOTA-ant ibody, suggesting little premature release of radioactive bismuth from the antibody complex. Moreover, in the early, therapeutically relevan t time points (2 h and 6 h), there was no significant preferential acc umulation of bismuth in any organ. At the 5-day time point, beyond the range of therapeutic interest, there was delayed excretion of bismuth from reticuloendothelial tissues relative to radioiodine from catabol ized antibody. Excretion of catabolized DOTA-bismuth had an apparent t 1/2 of approximately 1 day without the marked renal accumulation typic al of the free bismuth ion. The compatibility of DOTA conjugation with antibody bioactivity and the stability of the radioactive bismuth com plex in vivo provide important preclinical validation of the potential utility of this new chelating agent for Bi-212 monoclonal antibody ra dioimmunotherapy in humans.