THERAPEUTIC EFFECTS OF MONOCLONAL ANTIBODY-BETA-LACTAMASE CONJUGATES IN COMBINATION WITH A NITROGEN-MUSTARD ANTICANCER PRODRUG IN MODELS OFHUMAN RENAL-CELL CARCINOMA
Hp. Svensson et al., THERAPEUTIC EFFECTS OF MONOCLONAL ANTIBODY-BETA-LACTAMASE CONJUGATES IN COMBINATION WITH A NITROGEN-MUSTARD ANTICANCER PRODRUG IN MODELS OFHUMAN RENAL-CELL CARCINOMA, Journal of medicinal chemistry, 41(9), 1998, pp. 1507-1512
A panel of 13 renal cell carcinoma cell lines was evaluated for the ex
pression of antigens recognized by the L6 and L49 monoclonal antibodie
s. All of the cell lines were strongly positive for the L6 antigen, an
d 9/13 bound 96.5, which, like the L49 monoclonal antibody, recognizes
the p97 melanotransferrin antigen. The L6 and L49 antibodies were che
mically conjugated to Enterobacter cloacae beta-lactamase (bL), and th
eir abilities to effect site-selective anticancer prodrug activation o
n two of the renal cell carcinoma cell lines (SN12P and 1934J) were ev
aluated in vitro and in vivo. L49-bL was 10-90-fold more potent in vit
ro than L6-bL for the activation of 7-(4-carboxybutanamido)cephalospor
in 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 L
6 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-b
L. In vivo studies utilizing nude mice with established subcutaneous S
N12P and 1934J tumor xenografts demonstrated that L49-bL/CCM combinati
ons led to regressions and cures at well-tolerated doses, while L6-bL/
CCM and the nonbinding control conjugate P1.17-bL in combination with
CCM were ineffective. Conjugate localization in 1934J tumors was much
lower than that observed in SN12P tumors, a finding that might acount
for the higher activities of L49-bL/CCM in the latter model. These dat
a show that the p97 antigen on renal cell carcinomas can be exploited
for selective prodrug activation, even on tumors that localize very sm
all amounts of the L49-bL conjugate.