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Utilization of antidrug antibody fragments for the optimization of intraperitoneal drug therapy: studies using
1Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo.
Abstract:
The direct administration of chemotherapeutic agents into the peritoneal cavity has been investigated as a method to treat cancers residing within the peritoneum. The benefits of i.p. drug administration are limited, however, by the systemic toxicity of antineoplastic drugs which diffuse out of the peritoneum and into the general circulation. We propose that antidrug antibody fragments may be useful in binding chemotherapeutics in the general circulation, thereby reducing the systemic tissue exposure and toxicity resulting from such i.p. therapy. Inasmuch 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 digoxin 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 assessed to determine the effect of the antibody fragments on peritoneal exposure. Our results showed that the antidigoxin antibody fragments can greatly decrease digoxin tissue exposure and toxicity without affecting peritoneal exposure, unbound fraction of digoxin in the peritoneum or peritoneal digoxin disappearance rate. Although the utility of drug-binding antibodies and antibody fragments for the treatment of drug intoxication is well known, these results demonstrated the potential ability of antidrug antibody fragments to improve the site-specificity of drug therapy.
Insights
Antidrug antibody fragments can reduce chemotherapy side effects. This study shows they limit systemic toxicity from intraperitoneal chemotherapy without impacting drug levels in the peritoneal cavity.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Intraperitoneal (IP) chemotherapy is used for peritoneal cancers.
- Systemic toxicity limits IP chemotherapy efficacy due to drug diffusion into circulation.
- Novel strategies are needed to mitigate systemic drug exposure.
Purpose of the Study:
- To investigate the potential of antidrug antibody fragments to reduce systemic toxicity of IP chemotherapy.
- To assess if antibody fragments can bind circulating drugs and limit tissue exposure.
- To evaluate the impact of antibody fragments on peritoneal drug exposure and clearance.
Main Methods:
- Utilized ovine antidigoxin Fab fragments administered intravenously in a mouse model.
- Administered digoxin intraperitoneally to simulate IP chemotherapy drug delivery.
- Measured digoxin levels in tissues, peritoneal cavity, and circulation.
- Assessed toxicity and pharmacokinetic parameters.
Main Results:
- Antidigoxin antibody fragments significantly reduced systemic digoxin tissue exposure and toxicity.
- No significant effect was observed on peritoneal drug exposure, unbound fraction, or clearance rate.
- Demonstrated successful binding of circulating drug by antibody fragments.
Conclusions:
- Antidrug antibody fragments show potential for enhancing the site-specificity of IP drug therapy.
- This approach may reduce systemic toxicity associated with IP chemotherapy.
- Further research into antidrug antibody fragments could improve cancer treatment outcomes.