The group conducted a phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma.
They reported their findings in the latest issue of the British Journal of Cancer.
ADEPT is a targeted therapy in which a prodrug is activated selectively at the tumor site by an enzyme. The enzyme has been targeted to the tumor by an antibody (antibody-enzyme conjugate).
Previous clinical trials have shown evidence of tumor response. However, the activated drug had a long half-life, which resulted in dose-limiting myelosuppression.
Also, the targeting system, although giving high tumor to blood ratios of antibody-enzyme conjugate (10,000:1) required administration of a clearing antibody, in addition to the antibody-enzyme conjugate.
The researchers therefore attempted tumor targeting of the antibody-enzyme conjugate without the clearing antibody.
The new prodrug (bis-iodo phenol mustard, ZD2767P) that they investigated has an activated form that is highly potent and has a short half-life.
| ZD2767P clears rapidly from the circulation.
| British Journal of Cancer |
A total of 27 patients were included in the trial.
Each was treated with ADEPT using A5CP antibody-enzyme conjugate and ZD2767P prodrug.
The maximum tolerated dose of ZD2767P was reached at 15.5 mg/m2 for 3 administrations.
Myelosuppression limited dose escalation. However, other toxicities were mild.
The team found that the patients' quality of life was not adversely affected during the trial.
There were no clinical or radiological responses seen in the study, but 3 patients had stable disease at day 56.
The antibody-enzyme conjugate localization data were found to be consistent with inadequate tumor localization.
The authors note that a clearance system is therefore desirable with this antibody-enzyme conjugate, or a more efficient targeting system is required.
R. J. Francis, of the Royal Free and University College Medical School, University College London, concluded on behalf of fellow authors, "ZD2767P was shown to clear rapidly from the circulation and activated drug was not measurable in the blood.
"ZD2767P has potential for use in future antibody-directed enzyme prodrug therapy systems."