Antibody-directed enzyme prodrug therapy (ADEPT) |
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Authors: | Sharma Surinder K Boden Joan A Springer Caroline J Burke Philip J Bagshawe Kenneth D |
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Institution: | (1) Cancer Research Campaign Laboratories, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, W6 8RF London, UK;(2) CRC Laboratories, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK |
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Abstract: | Antibody-directed enzyme prodrug therapy (ADEPT) has been studied in a human ovarian carcinoma xenograft grown subcutaneously
in nude mice. Radioimmunoassay of supernatants obtained from tumor homogenates showed these to contain carcinoembryonic antigen
(CEA). Biodistribution studies with125I-labeled monoclonal anti-CEA antibody, A5B7, and its F(ab′)2 fragment showed localization in these xenografts. The AB57-F(ab′)2 fragment conjugated to a bacterial enzyme, carboxypeptidase G2 (CPG2), and, radiolabeled with125iodine, also localized in the xenografts. The radiolabeled conjugate cleared from blood faster than the antibody alone. The
percentage of injected dose per gram in tumor at 24 h postinjection was about fivefold lower than antibody alone. Tumor-to-blood
ratio at 72 h after injection of the radiolabeled conjugate was 7 and the tumor-to-normal tissue ratios at this time point
ranged from 20 (liver) to 75 (colon).
A three-phase ADEPT antitumor study was carried out in which A5B7-F(ab′)2-CPG2 was allowed to localize and was followed by accelerated inactivation/clearance of blood CPG2 by a galactosylated anti-CPG2
antibody (SB43gal). A benzoic acid mustard-derived prodrug was injected 24 h after the conjugate, which led to growth delay
in this tumor compared to the control untreated group. Further antitumor studies in this model are in progress. |
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Keywords: | ADEPT antibody-enzyme conjugates enzyme inactivation prodrugs ovarian xenografts |
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