Abstract 2720: Sym004, a novel anti-EGFR antibody mixture augments radiation response in human lung and head and neck cancer models

Abstract

Abstract Sym004* is a newly developed EGFR targeting agent that is a mixture of two anti-EGFR antibodies directed against distinct epitopes on domain III of EGFR. In contrast to existing anti-EGFR antibodies, Sym004 induces rapid and efficient EGFR internalization and degradation. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck (H&N) cancer model systems. We examined the anti-proliferative effect of Sym004 confirming 40∼60% growth inhibition by Sym004 across a variety of lung and H&N cancer cell lines. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following 9 Gy radiation exposure. Immunoblot analysis showed down-regulation of MAPK and AKT pathways, as well as changes in several key proteins involved in cell cycle progression, DNA damage repair and apoptosis. Flow cytometric analysis confirmed a significant increase of cells in S phase 24 hrs following 6 Gy radiation in control cells. However, treatment with Sym004 preceding radiation induced a significant G1 and G2 arrest accompanied by a reduction in S phase. Interestingly, we found a significant increase in apoptosis 48 hrs after radiation. These results suggest that Sym004 arguments radiation response via the induction of cell cycle arrest followed by the induction of apoptosis and cell death likely reflecting inhibitory effects on DNA damage repair. Finally, using single dose or fractionated radiation experiments in human tumor xenograft models, we found that the combination of Sym004 and radiation resulted in a significant delay in tumor regrowth and superior anti-tumor effects than treatment with drug or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and H&N cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy. (*Pedersen et al., Cancer Res 70:588∼597, 2010) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2720. doi:1538-7445.AM2012-2720