ZD2767, AN IMPROVED SYSTEM FOR ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY THAT RESULTS IN TUMOR REGRESSIONS IN COLORECTAL TUMOR XENOGRAFTS

ZD2767 represents an improved version of antibody-directed enzyme prod rug therapy. It consists of a conjugate of the F(ab')(2) A5B7 antibody fragment and carboxypeptidase G2 (CPG2) and a prodrug, 4-[N,N-bis(2-i odoethyl)amino]phenoxycarbonyl L-glutamic acid. The IC50 of the prodru g against LoVo colorectal tumor cells was 47 mu M, and cleavage by CPG 2 released the potent bis-iodo phenol mustard drug (IC50 = 0.34 mu M). The drug killed both proliferating and quiescent LoVo cells. Administ ration of the ZD2767 conjugate to nude mice bearing LoVo colorectal xe nografts resulted in approximately 1% of injected ZD2767 conjugate loc alizing/g of tumor after 72 h, and blood and normal tissue levels of t he conjugate were 10-50-fold lower. A single round of therapy involvin g the administration of the prodrug 72 h after the conjugate to athymi c mice bearing established LoVo xenografts resulted in approximately 5 0% of the tumors undergoing complete regressions, tumor growth delays greater than 30 days, and little toxicity (as judged by body-weight lo ss), Similar studies using a control antibody-CPG2 conjugate that does not bind to LoVo tumor cells resulted in a growth delay of less than 5 days, confirming the tumor specificity of this approach. These studi es demonstrate the potential of ZD2767 for the treatment of colorectal cancer.