| The hepatocyte growth factor (HGF) receptor, also known as c-Met, is a prototypic member of a subfamily of the receptor tyrosine kinases (RTK). It is a heterodimer with unique features, which distinguish it from other RTK. The physiologic actions mediated by c-Met are widespread, and it is dysregulated in the majority of malignancies. This makes c-Met a good target for novel therapeutic interventions. Virotherapy employing oncolytic adenoviruses (Ad) represents a promising biological intervention relevant to a wide array of neoplastic diseases. To date, achieving replicative specificity of oncolytic adenovirus agents has been accomplished by either viral genome deletions or incorporation of tumor selective promoters (TSP).;In context of an oncolytic adenovirus, our recombinant Adenovirus—with NK2 fiber knob modification—showed more efficient viral infectivity in cancer cells overexpressing c-Met as compared with the Ad5 wild-type fiber virus. That infectivity efficiency correlated well with c-Met expression levels. Importantly, our data showed that the cMet retargeted Ad5-NK2 virus showed cell killing and progeny production levels identical/comparable to the wild-type Ad5 virus.;In summary, we successfully designed a replication competent adenovirus (RCAd) vector to cancer cells overexpressing cMet receptor. We used one of HGF antagonists, NK2 isoform (251 amino acid residues), as retargeting molecule inserted into the virus fiber C-Terminus. This achieved dual benefit, detargeting Ad serotype 5 from native Coxsackie and Adenovirus receptor (CAR), and retargeting it to the cMet receptor. Our approach is novel and further validation in an appropriate in vivo cancer model will substantiate our ex vivo data.;To achieve novel specificity of oncolytic adenoviruses for metastatic disease over expressing c-Met, we used a high affinity c-Met ligand to retarget viral infectivity. Specifically, we incorporated 251 amino acid residues of the NK2, a competitive antagonist of the HGF: c-Met association, into the adenovirus fiber. Targeting HGF/SF: cMet pathway was extensively studied using, for example, specific antibodies, decoy receptors, or small molecule inhibitors. To date, almost all targeting strategies using HGF isoforms exploited Ad vectors as vehicles mediating their delivery as transgenes. To our knowledge, we are the first to use HGF/NK2 isoform as a retargeting molecule for Ad vector. |
