• Astrid Mayer, Roslyn J Francis, Surinder K Sharma, Berend Tolner, Caroline J Springer, Jan Martin, Geoff M Boxer, James Bell, Alan J Green, John A Hartley, Clare Cruickshank, Julie Wren, Kerry A Chester, and Richard H J Begent.
• Department of Oncology, Hampstead Campus, University College London, UK. a.mayer@ucl.ac.uk
• Clin Cancer Res. 2006 Nov 1; 12 (21): 6509-16.

PurposeAntibody-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.Experimental DesignPharmacokinetic, 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.ResultsMFECP1 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.ConclusionsOptimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.

43 keywords...

hide…