Antitumor effects of an antibody-carboxypeptidase g2 conjugate in combination with a benzoic acid mustard prodrug |
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Authors: | D C Blakey B E Valcaccia S East A F Wright F T Boyle C J Springer P J Burke R G Melton K D Bagshawe |
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Institution: | 1. Bioscience 1 ICI Pharmaceuticals, Macclesfield, Cheshire 2. Chemistry 1 ICI Pharmaceuticals, Macclesfield, Cheshire 3. CRC Laboratories, Charing Cross Hospital, London 4. CRC Laboratories, Institute of Cancer Research, Sutton, Surrey 5. Division of Biotechnology, CAMR, Porton Down
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Abstract: | The F(ab’)2 fragment of the antitumor monoclonal antibody, A5B7, was covalently linked to the bacterial enzyme carboxypeptidase G2 (CPG2). The resulting conjugate was used in combination with a prodrug of a benzoic acid mustard alkylating agent to treat human colon tumor xenografts in a two-step targeting strategy, antibody-directed enzyme produrug therapy (ADEPT). The prodrug, 4-(2-chloroethyl) (2-mesyloxyethyl) amino]-benzoyl-l-glutamic acid is rapidly converted by CPG2 to a drug that is at least 15x more toxic in vitro against LS174T colorectal tumor cells than the prodrug. Optimal tumor/ blood ratios of the A5B7-CPG2 were achieved 72 h after administration of the conjugate to athymic mice bearing established LS174T tumor xenografts. Significant antitumor activity was seen in LS174T tumor-bearing mice treated with the conjugate followed 3 d later by the prodrug. In contrast, prodrug, conjugate, or active drug alone did not result in any antitumor activity in this tumor model. These studies demonstrate the advantage of a two-step ADEPT system for the treatment of colorectal cancer. |
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