A transition metal complex (Venus flytrap cluster) for radioimmunodetection and radioimmunotherapy (
ABSTRACTA novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radiolabeled antibodies. VFC contained "Co, which was held tightly between the faces of two covalently bridged carborane ligands by cluster bonding of the metal with appropriate ligand orbitals. Anti-carcinoembryonic antigen monoclonal antibody T84.66 was conjugated to 57Co-VFC with full retention of immunological activity. Biodistribution studies in nude mice bearing carcinoembryonic antigen-producing tumors showed excellent tumor localization of 57Co-VFC-T84.66. The accumulation of radionuclide in normal liver was low and independent of dose, which may reflect the stability of the radionuclide complex. These results presage the use of VFC systems for binding transition metals that are clinically useful for radioimmunodiagnosis and radioimmunotherapy.The use of monoclonal and engineered antibodies for the selective delivery of diagnostic and therapeutic radiometals to tumors requires suitable bifunctional reagents that efficiently form covalent bonds with antibody and stable radionuclide chelate complexes. With few exceptions, monoclonal antibody (mAb)-chelator conjugates have been prepared with bifunctional reagents that are members of the aminocarboxylate chelator family, with derivatives of diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) being most popular (1-5). These conjugates form stable radiopharmaceuticals with 1"'In that have been used for radioimmunodiagnosis of human tumors (6-8), although there is some concern about their uptake by normal tissues and possible metal release in vivo. Conjugates of this type, however, form less stable radiopharmaceuticals with 90Y and 67Cu (9, 10), which can be used for radioimmunotherapy. There is therefore considerable interest in the development of new bifunctional reagents that will form more stable chelate complexes with these and other clinically relevant radionuclides.Radionuclides such as 67Cu, 991Tc, 105Rh, and '86Re are transition metals. Thus, very efficient ir-bonding ligands would be expected to form complexes of great stability with these radionuclides. Hawthorne and coworkers (11, 12) first described commo-bisdicarbollide transition metal complexes in which the metal ion is held between two ir-bonding[C2B9H11]2-dicarbollide ligands. With d6 metal ions these complexes conform to both the 18-electron and cluster electron-counting rules and display extraordinary stability due to the cluster bonding of the transition metal with ligand orbitals of appropriate symmetry. Metal ions having other than six d electrons, such as d3Cr3+ and d8Cu3+, also form stable bis-dicarbollide clusters, although in the case of electron-rich (d7, d8, etc.) species, the dicarbollide ligands undergo a "slip" distortion (12). The ability to produce these complexes in high yield in aqueous media, their expected stability to physiological co...