It is known that the anti-EGFr monoclonal antibody C225 and its smaller Fab fragment cause growth inhibition and accentuate radiation-induced growth inhibition in vitro and in vivo in cells that overexpress EGFr. This finding has been suggested in the human model as well, and currently a National Phase III trial (J Bonner, PI) is underway to test the efficacy of C225 and radiotherapy vs radiotherapy alone in advanced head and neck malignancies as almost all head and neck malignancies express EGFr and the majority overexpress it. It is known that monoclonal antibodies are limited by the size of the molecule (with respect to penetration into tumor) and the possibility of immune responses against the antibody. These facts may prevent the monoclonal antibodies from eliciting the best possible response in target tumors. Recently technology has been developed to make human recombinant antibodies that are single chain molecules (scFvs) and contain just the critical variable light and heavy chain regions of the antibody and target antigens of interest. We have constructed these molecules for other antigens and have isolated several candidate clones against EGFr. We have also developed the technology to deliver these agents through an adenoviral vector gene therapy-based approach that allows for the secretion of these agents from the cells by the insertion of appropriate peptides. Therefore, it is hypothesized that this gene therapy-based approach will allow for the delivery of high concentrations of anti-EGFr scFv in close proximity to the antigen of interest in a manner that is not possible with the full antibody. Therefore, it is proposed to derive several recombinant antibodies (scFvs) against EGFr and, 1) maximize the anti-proliferative effects of these scFvs; 2) maximize the radiosensitizing properties of these scFvs; and 3) deliver secretory scFvs through a gene therapy-based approach in a manner that will capitalize on the anti-proliferative and radiosensitizing properties of the agents. Human head and neck carcinoma lines will be used to test these questions in vitro and in vivo with an aim toward understanding viable effects with respect to the cells inherent EGFr expression and radiosensitivity. Preliminary data suggests that monoclonal antibody-induced blockade of EGFr results in growth inhibition and radiosensitization through an apoptotic mechanisms. Additionally, the apoptotic events are associated with a dramatic redirection in the anti-apoptotic protein; phosphorylated STAT-3. Studies will be performed to assess the mechanism of scFv-induced growth inhibition and radiosensitization in the context of the above finding.
| Bonner, James A; Trummell, Hoa Q; Willey, Christopher D et al. (2009) Inhibition of STAT-3 results in radiosensitization of human squamous cell carcinoma. Radiother Oncol 92:339-44 |
| Bonner, James A; Buchsbaum, Donald J; Russo, Suzanne M et al. (2004) Anti-EGFR-mediated radiosensitization as a result of augmented EGFR expression. Int J Radiat Oncol Biol Phys 59:2-10 |
| Bonner, James A; Buchsbaum, Donald J; Rogers, Buck E et al. (2004) Adenoviral vector-mediated augmentation of epidermal growth factor receptor (EGFr) enhances the radiosensitization properties of anti-EGFr treatment in prostate cancer cells. Int J Radiat Oncol Biol Phys 58:950-8 |
