The long-term objective of this project is to develop the means to utilize bi-specific immunoproteins for the selective concentration of boron-10 atoms in tumors for the boron neutron capture therapy (BNCT) of cancer. The bi-specific immunoproteins to be investigated in this project will have specificity for both a tumor-associated antigen (CEA) and a nido-carboranyl hapten. The project is focused on the development of methods for the expression of bi-specific immunoproteins using a genetic engineering approach. The genes encoding the anti-nido antibody and anti-CEA antibody are now available for manipulation. While performing research aimed at the development of optimal bi-specific immunoprotein delivery systems, the applicants intend to also conduct research aimed at developing optimal corresponding boron-rich hapten-containing macro molecules. The boron-rich macro molecules to be investigated will be based upon either a phosphate diester or polypeptide backbone. The applicants have developed flexible and efficient methods for the syntheses of both of these types of compounds, which can contain numerous hapten-like nido-carboranyl residues. The applicants will investigate whether these compounds can localize in tumor by pre-targeting bi-specific immunoprotein to tumor cells in vivo and then administering boron-rich macro molecules. This approach will be evaluated against one in which the macro molecules will be pre-bound to the bi-specific antibody and then subsequently administered in vivo. The anti-tumor efficacy of bi-specific antibodies in BNCT will be evaluated in mice bearing CEA+ and CEA- tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA053870-08
Application #
2712649
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mahoney, Francis J
Project Start
1996-08-15
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
8
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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