Specific membrane receptor gene expression targeted with radiolabeled peptide employing the erbB-2 and DF3 promoter elements in adenoviral vectors

Radioimmunotherapy is limited by a variety of factors, including poor tumor penetration of monoclonal antibodies and low levels of intratumoral antige n expression. To address these limitations, a gene therapy strategy was dev ised to genetically induce tumor cells to express enhanced levels of membra ne receptors with high affinity for a radiolabeled peptide. We designated t his approach as genetic radioisotope targeting strategy. To this end, an ad enoviral vector (AdCMVGRPr) encoding the murine gastrin-releasing peptide r eceptor (GRPr) was used to achieve a high level of binding of radiolabeled bombesin (BBN). To achieve genetic induction of membrane GRPr specifically to tumor cells, we constructed two adenoviral vectors encoding the GRPr gen e under the control of the tumor-specific regulatory elements, DF3 (AdDF3GR Pr) or erbB-2 (AderbGRPr). We investigated the binding of [I-125]BBN to the GRPr following infection with AdDF3GRPr and AderbGRPr in a panel of human breast, pancreatic, and cholangiocarcinoma tumor cell lines, [I-125]BBN bin ding and GRPr expression increased with increasing multiplicities of infect ion of AdCMVGRPr in all of the cell lines tested. Breast cancer cell lines expressing erbB-2 showed significant GRPr expression using AderbGRPr. A sim ilar result was observed in breast and cholangiocarcinoma cells infected wi th AdDF3GRPr expressing MUC1 as detected by immunohistochemistry but was no t seen in the pancreatic cell lines tested. Thus, adenoviral vectors with t issue-specific promoter elements can be used to achieve a selective express ion of membrane receptors that can be targeted with a radiolabeled peptide. The use of such a transcriptional targeting approach may restrict gene exp ression to tumors and limit the radiation dose deposited in normal tissues in vivo.