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Pancreatic adenocarcinoma is an aggressive disease with a high mortality rate. Currently, treatment options are limited. In an effort to improve the efficacy of treatments for pancreatic adenocarcinoma, we have newly generated a monoclonal antibody (mAb), Pa65-2, which specifically binds to various cancer cells and tumor blood vessels but not to normal cells. According to immunoaffinity chromatography, LC-MS/MS analysis, co-immunoprecipitation and RNA interference studies, the target protein of Pa65-2 is human clathrin heavy chain (CHC). Knocking down CHC with shRNA reduced tumor cell growth, colony formation and invasion in vitro, and inhibited tumor angiogenesis and growth. One of the key functions of CHC was to bind with the transcription factor subunit HIF-1α, increasing the stability of this protein and facilitating its nuclear translocation, thereby regulating the expression of VEGF. In animal studies using NOD/SCID mice bearing pancreatic cancer xenografts, Pa65-2 and CHC shRNA could each inhibit tumor growth and angiogenesis by regulating HIF-1α and VEGF. Furthermore, the expression of CHC, HIF-1α and VEGF was significantly correlated with tumor stage, suggesting that CHC might be a useful prognostic indicator for cancer. Considered together, our results indicate that CHC interacts with and stabilizes HIF-1α, and plays a role in HIF-1α nuclear localization and HRE promoter binding, leading to an increased production of VEGF. These results suggest that the CHC mAb, Pa65-2, can potentially be used to inhibit tumor angiogenesis and growth. 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 2520. doi:1538-7445.AM2012-2520