Electrophilic chelating agents for irreversible binding of metal chelates to engineered antibodies.
Radiolabeled monoclonal antibodies are widely used in the detection and treatment of cancer. However, several problems still prevent full clinical exploitation of these reagents. Low tumor/background ratios in radioimmunoscintigraphy and high background radioactivity in therapy are the foremost among these. The strategy of pretargeting which separates the tumor-targeting step from radiolocalization step may overcome these limitations. One pretargeting approach, based on the streptavidin-biotin system, has been demonstrated to successfully treat cancer in preclinical models (Proc. Natl. Acad. Sci. 97 (2000) 1802). In this report we describe the synthesis of several electrophilic chelates, designed for use in vivo. In this new pretargeting approach, we have used protein engineering to prepare an antibody that can bind selectively and irreversibly to certain of these metal chelates. This improves upon approaches based on the immunogenic protein streptavidin and the endogenous ligand biotin.
Chmura
A J
AJ
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA.
Schmidt
Brian D
BD
Corson
Donald T
DT
Traviglia
Stacey L
SL
Meares
Claude F
CF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D002614:Chelating Agents / Q000378:metabolism*; D004355:Drug Stability; D008670:Metals / Q000378:metabolism*; D051379:Mice; D015202:Protein Engineering; D016719:Radioimmunodetection; D016499:Radioimmunotherapy
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D008670:Metals