The anti-DKK1 antibody DKN-01 as an immunomodulatory combination partner for the treatment of cancer

丹麦克朗 Wnt信号通路 医学 癌症 先天免疫系统 生物标志物 免疫系统 免疫学 内科学 免疫疗法 生物信息学 癌症研究 信号转导 生物 生物化学
作者
Jaclyn Wall,Samuel J. Klempner,Rebecca C. Arend
出处
期刊:Expert Opinion on Investigational Drugs [Taylor & Francis]
卷期号:29 (7): 639-644 被引量:48
标识
DOI:10.1080/13543784.2020.1769065
摘要

The Wnt/beta-catenin pathway is a complex signaling pathway known to be dysregulated in several cancers; Dickkopf-1 (Dkk1) is an inhibitor of canonical Wnt signaling via negative feedback. Elevated Dkk1 is associated with a poor prognosis in several cancers, including gynecologic and gastroesophageal malignancies. This review focuses on the potential therapeutic benefit of targeting Dkk1 with the IgG4 monoclonal antibody, DKN-01.We highlight current treatment approaches for advanced gynecologic and esophageal malignancies highlighting the need for more effective therapies, specifically improved immune-modulating agents and combinations. Our discussion of DKN-01 addresses the rationale for targeting Dkk1, available safety, pharmacokinetic and efficacy data.DKN-01 presents an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies. It has been especially promising in patients with high-Dkk1-expressing tumors or known Wnt mutations. We postulate that the complementary mechanisms, limited adverse effects and emerging biomarker data position DKN-01 as a promising agent for combination therapy in patients with advanced malignancies. Specifically, we believe this occurs through an immuno-modulatory effect, primarily acting through the innate arm of the immune system. This highlights the possibility for addressing innate immune resistance and expanding the portion of patients who may benefit, possibly in a biomarker-selected manner.
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