Novel bifunctional chelates and metal ion complexes will be synthesized and conjugated to anti-CEA (carcinoembryonic antigen) antibodies for their improved targeting in CEA positive tumors. The new bifunctional chelates are based on the macrocycle DOTA and incorporate new pendant functional groups to enhance metal ion binding on the antibody conjugate. the functional groups include carboxyl, sulfhydryl, hydrazides, and acetohydroxamates. these groups are expected to form tight """"""""type I"""""""" complexes with In-111, Y-90, nd Cu-64. The radiometals were chosen for their utility in radioimmuno-imaging and therapy. Conditions of pH, temperature, and choice of transchelator will be optimized for the conjugate for each metal ion, and stability constants for the """"""""type I"""""""" complexes will be measured in serum. in addition the stability constants for the """"""""type II"""""""" complexes will be measured in 10 mM DTPA. Simplified synthetic routes have been devised for each bifunctional chelator. The products will be purified by ion exchange chromatography and analyzed by mass spectrometry and NMR. The bifunctional chelators will be attached with or without linkers to whole and antibody fragments, engineered in Project 2. Non-specific attachment will be to lysine residues and site specific attachment will be to cysteine residues in the hinge region or those engineered into the CH3 domain, and to aldehydes produced by periodate oxidation of engineered glycosyl residues. Chemically labile liners that improve tumor to blood ratios without lowering tumor uptake of the sulfur atom in the linker. Animal studies will be performed to determine the ultimate metabolic fate of the metal complex ina the liver, kidney, and tumor. The overall approach is expected to lead to clinical products with improved labeling and biodistribution properties. The assembled team has unique expertise in chemistry, antibody conjugation, and the use of animal models for evaluating radiolabeled antibodies in pre-clinical and clinical studies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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City of Hope National Medical Center
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