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 hapten-affinity binding of 10B-containing reagents to tumor using bifunctional immunoproteins 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 combined with each bifunctional immunoreactive species and the use of nearly all specifically targeted antigenic sites is required. The 10B-containing reagents to be employed in this research will be oligomers (20 mer species) containing about 200 10B-atoms each and rich in hapten groups. These peptide-like oligomers are synthesized using carborane derived alpha-amino acids and Merrifield procedures. A similar family of precisely constructed 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 a synthetic manifold linker (MF) capable of binding a definite number (5 or 10) of 20 mer species. A bifunctional antibody will be synthesized 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 F(ab')2 derived from anti-CEA Mab T84.12. A second bifunctional antibody will employ the high-affinity streptavidin-biotin binding interaction. In this system, T84.12 F(ab')2 will be chemically linked with streptavidin, and 20 mer and MF-(20 mer)n species will be conjugated with biotin.
| Guan, L; Wims, L A; Kane, R R et al. (1998) Homogeneous immunoconjugates for boron neutron-capture therapy: design, synthesis, and preliminary characterization. Proc Natl Acad Sci U S A 95:13206-10 |
| Primus, F J; Pak, R H; Richard-Dickson, K J et al. (1996) Bispecific antibody mediated targeting of nido-carboranes to human colon carcinoma cells. Bioconjug Chem 7:532-5 |
| Pak, R H; Primus, F J; Rickard-Dickson, K J et al. (1995) Preparation and properties of nido-carborane-specific monoclonal antibodies for potential use in boron neutron capture therapy for cancer. Proc Natl Acad Sci U S A 92:6986-90 |
| Chen, C J; Kane, R R; Primus, F J et al. (1994) Synthesis and characterization of oligomeric nido-carboranyl phosphate diester conjugates to antibody and antibody fragments for potential use in boron neutron capture therapy of solid tumors. Bioconjug Chem 5:557-64 |
| Bibbo, M; Bartels, P H; Pfeifer, T et al. (1993) Belief network for grading prostate lesions. Anal Quant Cytol Histol 15:124-35 |
