Description:
<jats:title>Abstract</jats:title>
<jats:p>Wnt signaling is a fundamental pathway that is dysregulated in oncology. The Wnt signaling modulator DKK1 is expressed in a variety of tumor types and elevated levels frequently correlate with poor survival. DKK1 promotes tumor growth by stimulating proliferation, metastasis, and angiogenesis, and has been implicated in contributing to an immune suppressive tumor microenvironment. DKN-01 is a humanized monoclonal therapeutic antibody that binds DKK1 with high affinity and selectivity. It is currently being evaluated clinically as a monotherapy and in combination with chemotherapies and other immunotherapies in a variety of solid tumors. Here we demonstrate that efficacy from a murine version of DKN-01 (mDKN-01) in a syngeneic tumor model requires NK cells. mDKN-01 also reduces lung metastasis, further supporting a model where DKK1 neutralization stimulates a NK mediated anti-cancer response. In addition, DKN-01 has efficacy in a human prostate xenograft model that expresses high levels of DKK1 and retains functioning NK cells. Taken together, these data support an innate immunotherapeutic mechanism of action of DKN-01 and suggest that tumor expression of DKK1 may predict response. As such, evaluation of peripheral blood and tumor biopsies from patients undergoing treatment with DKN-01 in combination with chemotherapy or other immunotherapies are underway to demonstrate innate immune mediated anti-tumor activity and validate DKK1 expression as a biomarker.</jats:p>
<jats:p>Citation Format: Michael Haas, Heidi Heath, Franziska Schurpf-Huber, Yinyuan Wu, Xinjun Zhang, Xi He, Min Yang, Walter Newman, Michael Kagey. Mechanistic insight into anti-tumor activity of DKN-01, a therapeutic antibody with immune modulatory activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2404.</jats:p>