Biodistribution of an antibody-enzyme conjugate for antibody-directed enzyme prodrug therapy in nude mice bearing a human colon adenocarcinoma xenograft |
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Authors: | Stephen M Stribbling Janet Martin R Barbara Pedley Joan A Boden Surinder K Sharma Caroline J Springer |
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Institution: | (1) CRC Centre for Cancer Therapeutics, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK Tel: 0181-643 8901; Fax: 0181-770 7899, GB;(2) CRC Clinical Research Laboratories, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF, UK, GB |
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Abstract: | The enzyme carboxypeptidase G2 (CPG2) can be targeted to tumors by antibodies and used to activate prodrugs in a treatment
called antibody-directed enzyme prodrug therapy (ADEPT). Different doses of CPG2 conjugated to the anti-CEA antibody A5B7
were administered i.v. to nude mice bearing the LS174T human colon adenocarcinoma xenograft, and the biodistribution of conjugate
activity 48 and 72 h later was determined using a novel high-performance liquid chromatography (HPLC) method. Conjugate doses
of 2,500 and 625 U/kg gave tumor enzyme levels of 0.5–0.6 U/g. Lower doses of 300 and 150 U/kg gave tumor enzyme levels of
0.1–0.3 U/g. Intriguingly, the best tumor:blood ratio of conjugate activity at both 48 and 72 h was achieved after administration
of the 625-U/kg dose, not the 2,500-U/kg dose. After 48 h this ratio was 3.8, whereas after 72 h the value was 5.5. This conjugate
dose also gave the greatest tumor:tissue ratios in all other tissues examined. After 72 h the tumor:colon ratio was 105, whereas
the tumor:kidney ratio was 36. In ADEPT, to obtain maximal tumor damage to LS174T xenografts in nude mice with minimal systemic
toxicity using the A5B7-CPG2 conjugate, prodrug should therefore be administered at least 72 h after a conjugate dose of 625 U/kg.
Received: 21 July 1996 / Accepted: 22 December 1996 |
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Keywords: | Biodistribution Carboxypeptidase G2 ADEPT Mice Xenograft |
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