title: A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours.
abstract: Antibody-directed enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been targeted to the tumour by an antibody (antibody-enzyme conjugate). Previous clinical trials have shown evidence of tumour response, however, the activated drug had a long half-life, which resulted in dose-limiting myelosuppression. Also, the targeting system, although giving high tumour to blood ratios of antibody-enzyme conjugate (10 000 : 1) required administration of a clearing antibody in addition to the antibody-enzyme conjugate. The purpose of this current study therefore was to attempt tumour targeting of the antibody-enzyme conjugate without the clearing antibody, and to investigate a new prodrug (bis-iodo phenol mustard, ZD2767P) whose activated form is highly potent and has a short half-life. Twenty-seven patients were treated with antibody-directed enzyme prodrug therapy using A5CP antibody-enzyme conjugate and ZD2767P prodrug, in a dose-escalating phase I trial. The maximum tolerated dose of ZD2767P was reached at 15.5 mg m(-2)x three administrations with a serum carboxypeptidase G2 level of 0.05 U ml(-1). Myelosuppression limited dose escalation. Other toxicities were mild. Patients' quality of life was not adversely affected during the trial as assessed by the measures used. There were no clinical or radiological responses seen in the study, but three patients had stable disease at day 56. Human anti-mouse antibody and human anti-carboxypeptidase G2 antibody were produced in response to the antibody enzyme conjugate (A5CP). The antibody-enzyme conjugate localisation data (carboxypeptidase G2 enzyme levels by HPLC on tumour and normal tissue samples, and gamma camera analysis of I-131 radiolabelled conjugate) are consistent with inadequate tumour localisation (median tumour: normal tissue ratios of antibody-enzyme conjugate of less than 1). A clearance system is therefore desirable with this antibody-enzyme conjugate or a more efficient targeting system is required. 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.
authors.affiliation: Cancer Research UK Targeting and Imaging Group, Department Oncology, Royal Free and University College Medical School, University College London, London NW3 2PF, UK. r.francis@ucl.ac.uk
authors.forename: R J
authors.initials: RJ
authors.lastname: Francis
authors.forename: S K
authors.initials: SK
authors.lastname: Sharma
authors.forename: C
authors.initials: C
authors.lastname: Springer
authors.forename: A J
authors.initials: AJ
authors.lastname: Green
authors.forename: L D
authors.initials: LD
authors.lastname: Hope-Stone
authors.forename: L
authors.initials: L
authors.lastname: Sena
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: K L
authors.initials: KL
authors.lastname: Adamson
authors.forename: A
authors.initials: A
authors.lastname: Robbins
authors.forename: L
authors.initials: L
authors.lastname: Gumbrell
authors.forename: D
authors.initials: D
authors.lastname: O'Malley
authors.forename: E
authors.initials: E
authors.lastname: Tsiompanou
authors.forename: H
authors.initials: H
authors.lastname: Shahbakhti
authors.forename: S
authors.initials: S
authors.lastname: Webley
authors.forename: D
authors.initials: D
authors.lastname: Hochhauser
authors.forename: A J
authors.initials: AJ
authors.lastname: Hilson
authors.forename: D
authors.initials: D
authors.lastname: Blakey
authors.forename: R H J
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020552:Comet Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011788:Quality of Life; D012007:Rectum / Q000378:metabolism; D011795:Surveys and Questionnaires; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C097602:ZD 2767; D011623:gamma-Glutamyl Hydrolase