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Antibody directed enzyme prodrug therapy (ADEPT): clinical report
K D Bagshawe1, S K Sharma, C J Springer
1Department of Medical Oncology, Charing Cross and Westminster Medical School, London.
Abstract:
Following an extensive series of studies in nude mice with human xenografts a pilot scale clinical trial of antibody directed enzyme prodrug therapy has been initiated. The principle is to activate a relatively inert prodrug to an active cytotoxin by a tumour located enzyme. In the first stage of the study a prodrug para-N-(mono-2-chloroethyl monomesyl)-aminobenzoyl glutamic acid was administered to six patients with advanced colorectal cancer in a dose escalating protocol. Nausea and vomiting occurred as the only discernible toxic effect at the higher dose levels. Three of these patients and two other patients with advanced disease have proceeded to the second stage of the study in which an antibody-enzyme conjugate was given IV, followed after 36-48 h by a galactosylated anti-enzyme antibody. When plasma enzyme levels had become undetectable the patients received multiple doses of the prodrug. At the lower doses toxicity was minimal as were clinical responses. Two patients received higher doses which resulted in myelosuppression and temporary regression of advanced disease. No complications resulted from administration of the antibody-enzyme complex or enzyme inactivating antibody. The myelosuppression is attributable to the relatively long half-life of the active drug formed from the prodrug used in the present study.
Insights
Antibody directed enzyme prodrug therapy shows promise for advanced colorectal cancer. Higher doses led to temporary disease regression and myelosuppression, indicating potential therapeutic benefits and areas for optimization.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody-directed enzyme prodrug therapy (ADEPT) utilizes targeted enzymes to activate prodrugs at tumor sites.
- Preclinical studies in nude mice with human xenografts informed the initiation of a clinical trial.
Purpose of the Study:
- To evaluate the safety and efficacy of ADEPT in patients with advanced colorectal cancer.
- To determine dose-limiting toxicities and potential clinical responses.
Main Methods:
- A pilot scale, dose-escalating clinical trial was conducted in two stages.
- Stage 1 involved administering a prodrug (para-N-(mono-2-chloroethyl monomesyl)-aminobenzoyl glutamic acid) to assess toxicity.
- Stage 2 involved administering an antibody-enzyme conjugate followed by the prodrug, with an enzyme-inactivating antibody administered as needed.
Main Results:
- Nausea and vomiting were observed at higher prodrug doses in Stage 1.
- In Stage 2, lower doses showed minimal toxicity and clinical response.
- Higher doses in Stage 2 resulted in myelosuppression and temporary regression of advanced disease.
- No complications arose from the antibody-enzyme complex or enzyme-inactivating antibody administration.
Conclusions:
- ADEPT is a feasible therapeutic strategy for advanced colorectal cancer.
- Myelosuppression at higher doses is linked to the active drug's long half-life, suggesting prodrug modification may be necessary.
- The study demonstrates the potential for ADEPT to induce tumor regression, warranting further investigation.