Antibody directed enzyme prodrug therapy (ADEPT) is a drug delivery system developed for the treatment of cancer. ADEPT uses a systemically administered antibody, tethered to an enzyme, to localize enzyme in tumour deposits. When the antibody-enzyme has cleared from the circulation, a low-toxicity prodrug is given. The prodrug is converted by the tumour-bound enzyme into an active cytotoxic drug. The system has potential to generate a highly potent cytotoxic agent at the tumour site. A clinical ADEPT system using MFECP1, a recombinant fusion protein consisting of an anti-carcinoembryonic antigen single chain Fv antibody and the bacterial enzyme carboxypeptidase G2, in combination with a bis-iodo phenol mustard prodrug (BIP) has been developed. A previous phase I/II clinical trial established the maximum tolerated dose of a single treatment cycle of this ADEPT system. In-vivo models with human tumour xenografts indicate that repeated ADEPT treatment with MFECP1/BIP led to greater efficacy without increased toxicity. This thesis aims to establish conditions required for safe and effective ADEPT when using MFECP1/BIP in man. This was achieved by conducting a phase I/II clinical trial of repeat-treatment ADEPT and comparing and combining the results with data from the single-treatment trial. The combined dataset provided mechanistic and clinical information on 43 patients. Multiple parameters were investigated to examine the likely cause of toxicity and clinical risk factors for its occurrence. Efficacy was evaluated using CT, FDG-PET and serum tumour markers. The nature of the immune response to MFECP1 was investigated and possible strategies to reduce immunogenicity were developed. Results showed that repeated therapy was feasible in man and did not increase the risk of MFECP1 infusion reactions. At the maximum tolerated total prodrug dose for 2 ADEPT treatments, one of three patients experienced tumour response on FDG-PET imaging. This MD (Res) thesis significantly increases understanding of the conditions required for safe and effective ADEPT.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:568236 |
| Date | January 2010 |
| Creators | Wilkins, D. K. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/19435/ |
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