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A novel transition metal complex, Venus flytrap cluster (VFC), is described for the preparation of radio-labeled antibodies. VFC contained 57Co, 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.

Of the many methods of selective boron delivery to tumor presently under consideration, the use of boron-labeled tumor-targeted monoclonal antibodies (Mabs) and their immunoreactive fragments appears to offer the most general, but complex, approach.1–4 Assuming that tumor cells generally carry 106 characteristic antigenic sites of any one type and that there are approximately 109 cells per gram of tumor, one calculates that about 600 10B atoms must be attach d to each individual Mab molecule (if all antigenic sites are complexed) for each 10 ppm of 10B supplied to tumor. Rather than randomly attack IgG Mab molecules with a large number of relatively small boron-containing conjugation reagent molecules we have chosen to assemble a series of discrete, precisely synthesized oligomeric reagents (“trailers”) each of which contains a fixed number of B-atoms up to approximately 200. These oligomeric reagents would carry a radioactive or fluorescent group for analytical purposes attached to a terminal-NH2 group of their chain and the remaining -COOH terminus would be free for conjugation with the lysine e-NH2 groups of Mab protein. Two types of oligomeric trailer reagents are envisioned; hydrophilic peptides and polyamides. Both types of reagent are prepared using the solid-supported synthesis methods of Merrifield.5 Figure 1 illustrates two typical a-amino acids which contain the hydrophobic closo-1,2-C2B10H11-cage and the corresponding hydrophilic [nido-7,8-C2B9H11-]-cage fragment. These amino acids are designated closo-CB and nido-CB,respectively, throughout this paper.

Monoclonal antibodies (Mab), when conjugated with bifunctional chelation reagents containing a radiometal, have provided sensitive and accurate imaging agents for the detection of cancer and other diseases. The bifunctional chelates presently in use are generally of the aminocarboxylate family and subject to catabolism with release of metal ion in vivo. The authors have now designed, synthesized, and evaluated a functionalized cluster containing a radiotransition metal (venus flytrap cluster, VFC) which makes use of an inorganic ligand set, incorporates exceedingly strong cluster bonding based upon a bridged commo-bis(dicarbollide) structure, and can be prepared in the aqueous media commonly used to supply radiometal salts. The species reported here presages the existence of a large family of functionalized metallacarborane clusters which may serve as biologically inviolable radio-transition-metal carriers for the antibody-mediated {gamma}-imaging or {beta}-therapy of tumors.