Design and synthesis of 225Ac radioimmunopharmaceuticals

The alpha-particle-emitting radionuclides Bi-213, At-211, Ra-224 are tinder investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. Bi-213 and At-211 were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated Ra-224 chloride selectively seeks bone. Ac-225 possesses favorable physical properties for radioimmunotherapy (10 d half-life and 4 net alpha particles), but has a history of unfavorable radiolabeling chemistry and poor metal-chelate stability. We selected functionalized derivatives of DOTA as the most promising to pursue from out of a group of potential Ac-225 chelate compounds. A two-step synthetic process employing either MeO-DOTA-NCS or 2B-DOTA-NCS as the chelating moiety was developed to attach Ac-225 to monoclonal antibodies. This method was tested using several different IgG systems. The chelation reaction yield in the first step was 93 +/- 8% radiochemically pure (n = 26). The second step yielded Ac-225-DOTA-IgG constructs that were 95 +/- 5% radiochemically pure (n = 27) and the mean percent immunoreactivity ranged from 25% to 81%, depending on the antibody used. This process has yielded several potential novel targeted Ac-225-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans. (C) 2002 Elsevier Science Ltd. All rights reserved.