The overall objective of the application is to perform necessary studies in preparation for conducting clinical trials in cancer of a humanized antibody that neutralizes hepatocyte growth factor (HGF). Previously, a novel mouse monoclonal antibody (mAb) L2G7 was generated that inhibits the ability of HGF to bind to its receptor Met, to induce proliferation of normal and cancer cells, and to induce angiogenesis. Moreover, L2G7 almost completes inhibits growth of two glioma tumor cell lines in mouse xenograft models. The current goal is to develop a humanized form of L2G7, while conducting additional in vivo studies of the mAb in mouse models to justify clinical trials and to identify the most promising types of cancer to treat. The first specific aim is to investigate the effect of treatment with mAb L2G7 on the in vivo growth of a variety of human tumor cells, including breast and colon, by using established mouse xenograft models. Tumor cells that both secrete HGF and express Met (HGF+/Met+), which therefore utilize HGF in an autocrine manner, will be tested directly. Tumor cells that do not secrete HGF (HGF-/Met+), which are stimulated by HGF in a paracrine manner, will be tested by co-injecting them into mice with human MRC5 fibroblast cells to serve as a surrogate for stromal cells and provide a source of human HGF.
The second aim i s to more thoroughly investigate the effect of L2G7 treatment on gliomas, a deadly type of brain tumor that usually expresses both HGF and Met. In addition to determining the effect of L2G7 on a larger number of glioma cell lines in standard xenograft models, the ability of L2G7 to inhibit growth of glioma tumor cells that are inoculated directly into the brains of mice will be tested. This is necessary to verify that L2G7 can pass through the leaky blood-brain barrier in brain tumors, as has been suggested by previous studies with other mAbs.
The third aim i s to investigate the mechanism of anti-tumor action of L2G7, in particular its ability to induce apoptosis (programmed cell death) of tumor cells and to inhibit angiogenesis (new blood vessel formation) in tumors, by analyzing tumor specimens from mice that have been treated with L2G7.
The fourth aim, which will be carried out concurrently with the other aims, is to develop a humanized form of L2G7 by using established methods of molecular modeling and genetic engineering. The humanized L2G7 mAb is expected to be essentially non-immunogenic in human patients and thus suitable for repeat dosing. Relevance. Despite recent scientific advances, cancer remains a major medical problem, and brain tumors are a particularly deadly form of cancer. The objective of the planned program is to research and develop a humanized monoclonal antibody suitable for testing in human patients, which will have the potential to be an effective drug for the treatment of brain tumors and possibly other types of cancer.
| Wang, Lihong; Park, Hangil; Chhim, Sophea et al. (2012) A novel monoclonal antibody to fibroblast growth factor 2 effectively inhibits growth of hepatocellular carcinoma xenografts. Mol Cancer Ther 11:864-72 |
| Zhao, Wei-meng; Wang, Lihong; Park, Hangil et al. (2010) Monoclonal antibodies to fibroblast growth factor receptor 2 effectively inhibit growth of gastric tumor xenografts. Clin Cancer Res 16:5750-8 |
