The purpose of this investigation is to determine the effect of negative charge alterations on the biodistribution of monoclonal antibodies and their localization at target organs in vivo. Although the use of monoclonal antibodies for radioimmunoscintigraphic and therapeutic applications has increased dramatically in recent years, several problems continue to hinder optimal utilization of these reagents. Targeting of non-target organs such as the liver and kidney resulting from non-specific interactions with the antibody, as well as high background activities, render both diagnostic and therapeutic application less than optimal. Furthermore, possible human anti-murine antibody response to the administered murine monoclonal antibodies could negate the beneficial effects of the reagents. Antimyosin antibody or its fragments, or anti-human mammary tumor- associated antigen antibody 323/A3 will be modified with negatively charged synthetic polymers which can be easily radiolabeled with In-111 or radioiodines. The immunoreactivities (apparent affinities) of the modified antibodies will be assessed in vitro; then the preparations showing unchanged immunoreactivities will be used in mice for biodistribution and in acute canine experimental myocardial infarction, or in a nude mouse tumor model for specific target localization. Finally, the immunogenicity of the negatively charge-modified antibodies will be assessed in rats and rabbits. It is expected that modification with polymers will provide antibodies with very high specific radioactivity. Therefore, the concentration of xeno-antibody protein required for in vivo administration will be dramatically reduced. Furthermore, negatively charge-modified antibodies may interact less with non-target cells than with basic native antibody molecules, due to repulsion of the mutual negative charges of the modified antibodies and the acidic cell surface structures of all cells. These effects, as well as the reduced amount of antibody required for achieving the same dose of radioactivity as with the conventionally In-111-labeled antibodies, should promote enhanced target localization and simultaneously decrease the potential immunogenicity of the negatively charged polymer-modified antibodies.
| Narula, J; Torchilin, V P; Petrov, A et al. (1995) In vivo targeting of acute myocardial infarction with negative-charge, polymer-modified antimyosin antibody: use of different cross-linkers. J Nucl Cardiol 2:26-34 |
| Trubetskoy, V S; Narula, J; Khaw, B A et al. (1993) Chemically optimized antimyosin Fab conjugates with chelating polymers: importance of the nature of the protein-polymer single site covalent bond for biodistribution and infarction localization. Bioconjug Chem 4:251-5 |
| Khaw, B A; Klibanov, A; O'Donnell, S M et al. (1991) Gamma imaging with negatively charge-modified monoclonal antibody: modification with synthetic polymers. J Nucl Med 32:1742-51 |
