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

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

KEYWORDS:

• Cancer immunology
• gastric cancer
• gynecologic cancer
• Wnt signaling
• anti-DKK1 antibody
• DKN-01
• immunomodulatory combination
• IgG4 monoclonal antibody
• mAb

Box 1. Drug summary.

Article highlights

• DKK1 is a marker of poor prognosis for many cancers

• Targeting DKK1 via the monoclonal antibody DKN-01 may help create an anti-tumor immune response

• DKN-01 is an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies

• DKN-01 has shown potential in patients with high-DKK1-expressing tumors or known Wnt mutations

• DKN-01 has demonstrated clinical activity in ongoing clinical trials across tumor types

• DNK-01 has acceptable safety and patient tolerability in on-going clinical trials

• High DKK1 expression in tumors may be indicative of benefit from treatments targeting Wnt-signaling

This box summarizes key points contained in the article.

Acknowledgments

The authors wish to thank Cyndi Sirard and Mike Kagey for their review of the manuscript and provision of clinical and research data.

Declaration of interest

RC Arend sits on the Advisory Board for Leap Therapeutics, Clovis Pharma, and TESARO. S Klempner has a consulting/advisory role for Eli Lilly, Astellas, Bristol Myers Squibb, Boston Biomedical, and Foundation Medicine, Inc and has stock/equity in Turning Point Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was not funded.