Therapeutic effects of monoclonal antibody-beta-lactamase conjugates in combination with a nitrogen mustard anticancer prodrug in models of human renal cell carcinoma

Journal of Medicinal Chemistry
H P SvenssonP D Senter

Abstract

A panel of 13 renal cell carcinoma cell lines was evaluated for the expression of antigens recognized by the L6 and L49 monoclonal antibodies. All of the cell lines were strongly positive for the L6 antigen, and 9/13 bound 96.5, which, like the L49 monoclonal antibody, recognizes the p97 melanotransferrin antigen. The L6 and L49 antibodies were chemically conjugated to Enterobacter cloacae beta-lactamase (bL), and their abilities to effect site-selective anticancer prodrug activation on two of the renal cell carcinoma cell lines (SN12P and 1934J) were evaluated in vitro and in vivo. L49-bL was 10-90-fold more potent in vitro than L6-bL for the activation of 7-(4-carboxybutanamido)cephalosporin mustard (CCM), a cephalosporin prodrug of phenylenediamine mustard (PDM). In addition, L49-bL showed higher degrees of specific SN12P and 1934J intratumoral uptake than L6-bL, even though the expression of L6 antigen was 2-fold higher than that of p97. These differences might be due to the high-affinity antigen binding of L49-bL relative to L6-bL. In vivo studies utilizing nude mice with established subcutaneous SN12P and 1934J tumor xenografts demonstrated that L49-bL/CCM combinations led to regressions and cures at well-tolerated doses,...Continue Reading

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Citations

Mar 29, 2002·International Journal of Cancer. Journal International Du Cancer·Virna Cortez-RetamozoHilde Revets
May 15, 2002·Archives of Pharmacal Research·Henry J LeeDong-Hoon Ko
Oct 8, 1999·Pharmacology & Therapeutics·G M Dubowchik, M A Walker
May 6, 2003·Bioorganic & Medicinal Chemistry Letters·Xiaoping TangPeng George Wang
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Oct 1, 2004·Melanoma Research·Markus WolfMichael Eisenhut
Apr 7, 2005·International Journal of Cancer. Journal International Du Cancer·Yu-Wen ChangSteve R Roffler
Mar 6, 2004·Pharmacological Reviews·Martijn RooseboomNico P E Vermeulen
Oct 25, 2001·The Journal of Organic Chemistry·Timothy P. SmythMichael E. O'Donnell
Nov 6, 2004·The Journal of Organic Chemistry·Jonathan W Grant, Timothy P Smyth

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