Abstract 369: Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications

Abstract

Abstract Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt antagonist DKK1 is expressed in a variety of tumor types which frequently correlates with a poor prognosis, including overall survival. DKK1 has known oncogenic activity by stimulating proliferation, metastasis, and angiogenesis, and recently been implicated in contributing to an immunosuppressive tumor microenvironment. The neutralization of DKK1 is hypothesized to have efficacy from both a direct antitumor effect and through an immune stimulated response. Here we describe the characterization of DKN-01, a humanized monoclonal therapeutic antibody to DKK1. DKN-01 binds DKK1 with high affinity and selectivity, disrupts the interaction of DKK1 with the LRP6 co-receptor, and neutralizes DKK1 activity in a cell based assay. In vivo, DKN-01 has efficacy both as a monotherapy and in combination with chemotherapies in a non-small cell lung (NSCLC) cancer A549 xenograft model. Results suggest that DKN-01 has an antiangiogenic effect and may stimulate a NK cell mediated antitumor response. Clinically, DKN-01 is being evaluated in relapsed/refractory esophageal cancer patients in combination with paclitaxel, and preliminary results demonstrate promising activity. Archival patient tumor samples are currently being analyzed genetically and by IHC for DKK1 and β-catenin staining for biomarker identification. Taken together, our results suggest that DKN-01, a novel therapeutic, has clinical efficacy by disrupting Wnt signaling, which results in a direct anti-tumor effect and stimulates a pro-inflammatory tumor response. Citation Format: Michael H. Kagey, Yinyuan Wu, Xinjun Zhang, Cynthia A. Sirad, Shane E. Mulligan, Xi He, Christopher K. Mirabelli. Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2017-369