Design and synthesis of 225Ac radioimmunopharmaceuticals Journal Article


Authors: McDevitt, M. R.; Ma, D.; Simon, J.; Frank, R. K.; Scheinberg, D. A.
Article Title: Design and synthesis of 225Ac radioimmunopharmaceuticals
Abstract: 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 (10d 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. © 2002 Elsevier Science Ltd. All rights reserved.
Keywords: leukemia; unclassified drug; drug targeting; glioma; radiopharmaceuticals; radiotherapy; drug design; drug synthesis; immunoreactivity; monoclonal antibody; antibodies, monoclonal; chemistry; immunoglobulin g; isotope labeling; bone; radiopharmaceutical agent; antibodies; drug half life; radioimmunotherapy; radioisotopes; technique; chelate; model; diseases; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid; synthesis; drug stability; chelation; radiochemistry; alpha radiation; 225ac; actinium; drug products; actinium 225; astatine 211; bismuth 213; priority journal; article; alpha-emitting radionuclide; in vivo generator; radium 224; ankylosing spondylitis
Journal Title: Applied Radiation and Isotopes
Volume: 57
Issue: 6
ISSN: 0969-8043
Publisher: Pergamon-Elsevier Science Ltd  
Date Published: 2002-12-01
Start Page: 841
End Page: 847
Language: English
DOI: 10.1016/s0969-8043(02)00167-7
PUBMED: 12406626
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Michael R Mcdevitt
    118 Mcdevitt
  2. Dangshe Ma
    21 Ma