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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

Authors' Affiliations: ¹ Department of Oncology, Hampstead Campus and ² Department of Oncology, Gower Street Campus, University College London; ³ Department of Radiology, Royal Free Hampstead NHS Trust; ⁴ Cancer Research UK Drug Development Office, London, United Kingdom and ⁵ Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: Astrid Mayer, Department of Oncology, Hampstead Campus, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom. Phone: 44-207-794-0500; Fax: 44-207-794-3341; E-mail: a.mayer{at}ucl.ac.uk.

Purpose: 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.

Experimental Design: 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.

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