title: A phase I study of single administration of antibody-directed enzyme prodrug therapy with the recombinant anti-carcinoembryonic antigen antibody-enzyme fusion protein MFECP1 and a bis-iodo phenol mustard prodrug.
abstract: OBJECTIVE
  Antibody-directed enzyme prodrug therapy is a two-stage treatment whereby a tumor-targeted antibody-enzyme complex localizes in tumor for selective conversion of prodrug. The purpose of this study was to establish optimal variables for single administration of MFECP1, a recombinant antibody-enzyme fusion protein of an anti-carcinoembryonic antigen single-chain Fv antibody and the bacterial enzyme carboxypeptidase G2 followed by a bis-iodo phenol mustard prodrug. MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination.
  
  
  METHODS
  Pharmacokinetic, biodistribution, and tumor localization studies were used to test the hypothesis that MFECP1 localizes in tumor and clears from normal tissue via the liver. Firstly, safety of MFECP1 and a blood concentration of MFECP1 that would avoid systemic prodrug activation were tested. Secondly, dose escalation of prodrug was done. Thirdly, the dose of MFECP1 and timing of prodrug administration were optimized.
  
  
  RESULTS
  MFECP1 was safe and well tolerated, cleared rapidly via the liver, and was less immunogenic than previously used products. Eighty-fold dose escalation from the starting dose of prodrug was carried out before dose-limiting toxicity occurred. Confirmation of the presence of enzyme in tumor and DNA interstrand cross-links indicating prodrug activation were obtained for the optimal dose and time point. A total of 28 of 31 patients was evaluable for response, the best response being a 10% reduction of tumor diameter, and 11 of 28 patients had stable disease.
  
  
  CONCLUSIONS
  Optimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.
authors.affiliation: Department of Oncology, Hampstead Campus, University College London, UK. a.mayer@ucl.ac.uk
authors.forename: Astrid
authors.initials: A
authors.lastname: Mayer
authors.forename: Roslyn J
authors.initials: RJ
authors.lastname: Francis
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Sharma
authors.forename: Berend
authors.initials: B
authors.lastname: Tolner
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
authors.forename: Jan
authors.initials: J
authors.lastname: Martin
authors.forename: Geoff M
authors.initials: GM
authors.lastname: Boxer
authors.forename: James
authors.initials: J
authors.lastname: Bell
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Green
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Clare
authors.initials: C
authors.lastname: Cruickshank
authors.forename: Julie
authors.initials: J
authors.lastname: Wren
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Chester
authors.forename: Richard H J
authors.initials: RH
authors.lastname: Begent
mesh_terms: D000368:Aged; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000097:blood / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D049669:History, 16th Century; D049670:History, 17th Century; D006801:Humans; D021621:Imaging, Three-Dimensional; D018796:Immunoconjugates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011623:gamma-Glutamyl Hydrolase / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D002272:Carcinoembryonic Antigen; D018796:Immunoconjugates; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; C000929:hydroxyaniline mustard; D000816:Aniline Mustard; D011623:gamma-Glutamyl Hydrolase