An interdisciplinary effort at the frontiers of chemistry, biology and immunology is proposed which will broaden the scope of research concerned with the application of the boron-10 neutron capture reaction, 10B(n,alpha)7Li, to cancer therapy (BNCT). The approach taken here involves the conjugation of 10B-containing reagents to tumor-seeking antibodies in such a manner that therapeutic amounts of 10B (ca. 10-30 mug 10B/g tumor) can be delivered to tumor cell surface antigens. Approximately 103 10B atoms must be conjugated to each antibody molecule and the use of nearly all specifically targeted antigenic sites is required. The 10B-containing conjugation reagents to be employed in this research will be oligomers (20 mer species) containing about 200 10B-atoms each. These peptide-like oligomers are synthesized using carborane derived alpha- amino acids and Merrifield procedures. A similar family of precisely constructured boron-rich polyamide oligomers is available from dicarboxylic acids and diamines using similar procedures. All oligomers are hydrophilic due to the presence of appropriate substituents. The 20 mer species are such that they may be radio- or fluorescence-labeled prior to direct conjugation with anti-CEA T84.66 Mab or a synthetic manifold linker (MF) capable of binding a definite number (5 or 10) of 20 mer species. The 20 mer-loaded MF. [MF-(20 mer)n], is monofunctional and is reacted (one each) with free thiol functions in fragment species such as Fab or an engineered Fab-SH, both of which are derived from anti-CEA T84.66 hybridoma. An alternative approach is to employ a similarly engineered Fab-(lysgly)n species having a lysine-rich """"""""tail"""""""" as the substrate for lysine-specific 20 mer reagents. Lastly, a bifunctional antibody is sought which will be capable of binding tumor cell antigen and the MF-(20 mer)n species simultaneously, thus avoiding chemical bonds between the boron carrier and tumor-seeking immunoglobulin. A new hybridoma will be required which recognizes a portion of 20 mer. The Mab derived from this hybridoma will be cleaved to a Fab' and chemically linked to the Fab' derived from anti- CEA T84.66 Mab.
