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Tumor Microenvironment and Immunobiology

mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment

Michael S. Haas, Michael H. Kagey, Heidi Heath, Franziska Schuerpf, James B. Rottman and Walter Newman
Michael S. Haas
1Leap Therapeutics, Cambridge, Massachusetts.
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Michael H. Kagey
1Leap Therapeutics, Cambridge, Massachusetts.
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Heidi Heath
1Leap Therapeutics, Cambridge, Massachusetts.
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Franziska Schuerpf
1Leap Therapeutics, Cambridge, Massachusetts.
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James B. Rottman
2Athenaeum Pathology Consulting, LLC, Sudbury, Massachusetts.
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Walter Newman
1Leap Therapeutics, Cambridge, Massachusetts.
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  • For correspondence: wnewman@leaptx.com
DOI: 10.1158/1541-7786.MCR-20-0799
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Abstract

Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with gastric/gastroesophageal junction cancer. The purpose of this study is to characterize a murine version of DKN-01 (mDKN-01) and to better understand its mechanism of action. We examined the efficacy of mDKN-01 in both melanoma and metastatic breast cancer models. Immune depletion experiments revealed a requirement for natural killer (NK) but not B and T cells for tumor growth inhibition. mDKN-01 treatment promotes the induction of the NK-activating cytokines IL15 and IL33 as well as an enhanced recruitment of CD45+ cells. Other treatment-related changes include a reduction of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC) in the tumor and spleen and the upregulation of PD-L1 on MDSCs. In addition, mDKN-01 has a marked effect at reducing pulmonary metastases in the mouse 4T1 breast cancer model. Finally, the mDKN-01/anti-PD-1 combination was more effective at inhibiting melanoma growth than mDKN-01 alone. Taken together, our data demonstrate that mDKN-01 has efficacy by blocking the immunosuppressive effects of DKK1 in the tumor microenvironment (TME) and provides insight into the clinical activity observed with DKN-01–based treatment.

Implications: mDKN-01 reverses a DKK1-mediated innate immune suppression in the TME and has additive efficacy with a PD-1 inhibitor.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;XX:XX–XX

  • Received September 10, 2020.
  • Revision received November 13, 2020.
  • Accepted December 17, 2020.
  • Published first December 22, 2020.
  • ©2020 American Association for Cancer Research.
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This OnlineFirst version was published on February 16, 2021
doi: 10.1158/1541-7786.MCR-20-0799

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mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment
Michael S. Haas, Michael H. Kagey, Heidi Heath, Franziska Schuerpf, James B. Rottman and Walter Newman
Mol Cancer Res February 16 2021 DOI: 10.1158/1541-7786.MCR-20-0799

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mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment
Michael S. Haas, Michael H. Kagey, Heidi Heath, Franziska Schuerpf, James B. Rottman and Walter Newman
Mol Cancer Res February 16 2021 DOI: 10.1158/1541-7786.MCR-20-0799
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Molecular Cancer Research
eISSN: 1557-3125
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