UTILIZATION OF ANTIDRUG ANTIBODY FRAGMENTS FOR THE OPTIMIZATION OF INTRAPERITONEAL DRUG-THERAPY - STUDIES USING DIGOXIN AS A MODEL-DRUG

The direct administration of chemotherapeutic agents into the peritone al cavity has been investigated as a method to treat cancers residing within the peritoneum. The benefits of i.p. drug administration are li mited, however, by the systemic toxicity of antineoplastic drugs which diffuse out of the peritoneum and into the general circulation. We pr opose that antidrug antibody fragments may be useful in binding chemot herapeutics in the general circulation, thereby reducing the systemic tissue exposure and toxicity resulting from such i.p. therapy. Inasmuc h as antibody fragments directed against antineoplastic agents are not available, we tested our hypothesis by using i.v. administered ovine antidigoxin Fab fragments and determined their ability to limit digoxi n tissue exposure and toxicity in mice after an i.p. digoxin injection . The rate of digoxin disappearance from the peritoneal cavity and the fraction of digoxin unbound in the peritoneal cavity were also assess ed to determine the effect of the antibody fragments on peritoneal exp osure. Our results showed that the antidigoxin antibody fragments can greatly decrease digoxin tissue exposure and toxicity without affectin g peritoneal exposure, unbound fraction of digoxin in the peritoneum o r peritoneal digoxin disappearance rate. Although the utility of drug- binding antibodies and antibody fragments for the treatment of drug in toxication is well known, these results demonstrated the potential abi lity of antidrug antibody fragments to improve the site-specificity of drug therapy.