Anti-Tgf Beta Receptor Ii Antibody Suppresses Tumor Growth And Metastasis Through Inhibiting Tgf Beta Autocrine Stimulation Of Tumor Cells And Myeloid Cells

Transforming growth factor beta (TGF \#946;) is a pleiotropic cytokine that profoundly regulates the pathogenesis of cancer and metastasis. TGF \#946; stimulates activation of TGF \#946; receptor I kinase and downstream signaling cascades that initiate broad cellular and non cellular processes i.e. survival, proliferation and differentiation, migration and motility, and deposition of the extracellular matrix and induction of cytokines contributing to tumorigenesis, metastasis, angiogenesis, and inflammation during tumor progression. Myeloid cells have been reported to be an important mediator in promoting metastasis and angiogenesis, suppressing immunity against tumor and inducing anti-VEGF resistant tumors. Therefore, targeting this multifunctional cell population will be beneficial for enhancement of antitumor therapeutic efficacy. The binding of TGF \#946; ligands to TGF \#946; receptor II (TGF \#946; RII) is one crucial step to initiate the activation of TGF \#946; signaling pathways. Here, we report that we have developed high affinity monoclonal antibodies with specific blocking activity to TGF \#946; R II binding to TGF \#946; ligands. By using the antibodies, we investigated the mechanism of actions of TGF \#946; mediated activity in promoting cancer cell invasiveness, angiogenesis and the role of Gr-1/CD11b+ myeloid cells in tumor progression and evaluated the therapeutic efficacy of anti-TGF \#946; R II antibodies in suppression of tumor growth and metastasis. Data on cell-based assays displayed the capacity of anti-TGF \#946; R II antibodies in inhibiting TGF \#946; receptor mediated signaling cascades and cellular biological functions in vitro. In vivo studies demonstrated that treatment of tumor bearing mice with the anti-TGF \#946; R II antibodies resulted in suppression of primary tumor growth and metastasis in conjunction with the blockade of cancer cell invasion and VEGF-A secretion, the inhibition of myeloid cell function and the depletion of Gr-1/CD11b/TGF \#946; R II+ myeloid cells. Most importantly, we have for first time revealed that a subset of TGF \#946; R II+ myeloid cells has a major role in promoting tumor growth and metastasis through inducing tumor cell migration and inhibiting cellular immune response. Thus, this study has provided a foundation supporting that anti-TGF \#946; R II antibody mediated abrogation of TGF \#946; R II+ myeloid cells would be an effective approach to controlling the deleterious activity of myeloid cell in cancer, and anti-TGF \#946; RII antibody-based therapeutics may represent a novel strategy for treatment of cancer, particularly for metastatic tumors. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 844.