Design and synthesis of Ac radioimmunopharmaceuticals

The alpha-particle-emitting radionuclides ²¹³Bi, ²¹¹At, ²²⁴Ra are under investigation for the treatment of leukemias, gliomas, and ankylosing spondylitis, respectively. ²¹³Bi and ²¹¹At were attached to monoclonal antibodies and used as targeted immunotherapeutic agents while unconjugated ²²⁴Ra chloride selectively seeks bone. ²²⁵Ac 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 ²²⁵Ac chelate compounds. A two-step synthetic process employing either MeO–DOTA–NCS or 2B–DOTA–NCS as the chelating moiety was developed to attach ²²⁵Ac 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 ²²⁵Ac–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 ²²⁵Ac-labeled immunotherapeutic agents that may now be evaluated in appropriate model systems and ultimately in humans.