A dual antibody against EGFR and VEGF as a therapeutic agent for cancer treatment

2401 The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) play important roles in tumor growth and progression. The EGFR and VEGF pathways are closely related and share common down stream signaling pathways. Thus, targeting both EGFR and VEGF offers the potential for improving efficacy over and above targeting any of the single pathways. DMS3008 (a fully human dual targeting IgG) was constructed to directly target both EGFR and VEGF by inserting high affinity domain antibodies (dAbs) to EGFR (VL) and VEGF (VH) into an IgG1 framework. We have evaluated DMS3008 in head and neck and lung cancer cell lines in vitro as presented in this meeting (Zhang et al., AACR 2008 abstract in submission). In this in vivo study, we further evaluate this dual targeting IgG in murine xenograft models using the lung cancer cell line A549 (low EGFR expression) and the head neck squamous cell carcinomas (HNSCC) cell line Tu686 (high EGFR expression). This dual targeting IgG was also compared with cetuximab (an antibody against EGFR) and bevacizumab (an antibody against VEGF). Mice carrying A549 or Tu686 tumors (injected with 5x106 cells in each mouse) were treated with a control IgG, bevacizumab (B), cetuximab (C), bevacizumab plus cetuximab (B+C) and DMS3008 at 200 µg/mouse for each agent (i.p., three times per week for 4 weeks). Mice bearing A549 tumors exhibited significant inhibition of tumor growth when dosed with DMS3008, B, and B+C as compared with the control (p = 0.001, 0.002, and 0.01 respectively). However, the treatment with C did not show significant inhibition of tumor growth as compared with the control (p = 0.28). Therefore, DMS3008 had better efficacy than C (p = 0.03), but was not significantly different when compared with B and B+C. Furthermore, treatment with these agents illustrated significant delay of reaching a tumor volume 1300 mm3 (p = 0.015 by Wilcoxon analysis). Xenograft mice bearing Tu686 tumors displayed significant tumor growth inhibition when given all of the four treatments as compared with the control (p