Cancer research
-
mAbs reactive with epitopes expressed on tumor vessels were evaluated as universal delivery agents of peptides with vasoactive properties to enhance the uptake of macromolecules in tumors. Unlike other reported approaches to target tumor vessels, a mAb designated TV-1 targets a basement membrane antigen that is found in all tissues but that is accessible only in tumor vessels, making it an alternative vehicle for the delivery of biologically active peptides to tumors. A panel of 30 monoclonal and polyclonal antibodies was screened by immunohistochemistry on sections of human tumors, normal vascular endothelium, and connective tissues. ⋯ When TV-1/IL-2 was compared with the specific vasoconjugate (Lym-1/IL-2) as a pretreatment in the Raji lymphoma model, which has low vascularization, TV-1/IL-2 yielded approximately 60% of the tumor uptake seen with Lym-1/IL-2. In comparison, pretreatment with TV-1/IL-2 in the LS174T colon carcinoma model, which has high vascularization, yielded approximately the same tumor uptake seen with the B72.3/IL-2 vasoconjugate, which directly targets the tumor cells. These studies demonstrate that a mAb directed against fibronectin in the endothelial subcellular matrix can be used to deliver vasoactive agents to tumors.
-
Comparative Study
In vitro and in vivo activities of a doxorubicin prodrug in combination with monoclonal antibody beta-lactamase conjugates.
A cephalosporin derivative of doxorubicin (C-Dox) was evaluated as a prodrug for activation by mAb conjugates of the beta-lactamase from Enterobacter cloacae P99 (beta L; EC 3.5.2.6). The conjugates consisted of beta L and the F(ab') fragments of either of the mAbs L6, P1.17, or 96.5. L6 binds to antigens on a variety of carcinomas, including the two lung adenocarcinoma cell lines H2981 and H2987 used in this study. 96.5 binds to the melanoma-associated antigen p97, and P1.17 was used for the control conjugate. ⋯ This finding suggested that the conversion of C-Dox to Dox was tumor specific and dependent on the presence of the targeted antigen. Furthermore, the best antitumor activity against both H2981 and H2987 tumors was obtained by treatment with L6-beta L and C-Dox compared to P1.17-beta L and C-Dox or Dox alone. Thus, higher levels of Dox corresponded to greater therapeutic effects in both of the tumor models studied.