On December 22, 2020 Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company focused on developing targeted and immuno-oncology therapeutics, reported the publication in Molecular Cancer Research of preclinical results from studies of human and murine versions of DKN-01, a humanized monoclonal antibody that binds to and blocks the activity of the Dickkopf-1 (DKK1) protein (Press release, Leap Therapeutics, DEC 22, 2020, View Source [SID1234573220]). The article, entitled "mDKN-01, a Novel Anti-DKK1 Monoclonal Antibody, Enhances Innate Immune Responses in the Tumor Microenvironment," is available online. The studies characterized a murine version of DKN-01 (mDKN-01) in order to better understand the mechanism of action (MOA) of DKK1 inhibition in two mouse cancer models.
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"In the current studies, we demonstrated that the inhibition of DKK1 with a monoclonal antibody in a syngeneic melanoma model led to tumor growth inhibition (TGI) requiring host NK1.1 cells, but not T or B cells, and provided enhanced efficacy when combined with a PD-1 inhibitor. In a second model, the antibody was a potent inhibitor of breast cancer metastases to lung," said Walter Newman, Ph.D., Senior Research Fellow of Leap. "These results show the innate immune system effects of mDKN-01 and support further exploration as to how DKN-01 results in the activation of NK cells and mitigation of metastatic spread."
DKK1, a secreted modulator of Wnt/Beta-catenin and CKAP4/PI3K/AKT signaling, is overexpressed in many cancers, is associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. To better understand the DKN-01 MOA, Leap engineered a murine framework for the DKN-01 CDR domains and examined the efficacy of mDKN-01 in a mouse model of melanoma. These studies show that targeting DKK1 suppresses tumor growth, reduces intra-tumoral myeloid-derived suppressor cells (MDSC) in the tumor and spleen, activates NK cells, and up-regulates PD-L1 expression on MDSC. Tumor cell signaling analysis in these studies indicates that mDKN-01 is not acting as a Wnt/B-catenin pathway agonist, but is inducing a collection of favorable immune changes in the tumor microenvironment.
In the animal model studied, mDKN-01 and an anti-PD-1 antibody demonstrated additive TGI effects. A clinical trial of DKN-01 plus pembrolizumab, an anti-PD-1 antibody, has recently been completed in esophagogastric cancer patients with promising results in patients whose tumors express high levels of DKK1. Leap has recently initiated a trial of DKN-01 in combination with BeiGene’s tislelizumab, an anti-PD-1 antibody, in DKK1-high second line gastroesophageal junction and gastric cancer (GEJ/GC) patients and in combination with tislelizumab, capecitabine, and oxaliplatin in first-line GEJ/GC patients.
About DKN-01
DKN-01 is a humanized monoclonal antibody that binds to and specifically blocks the activity of the Dickkopf-1 (DKK1) protein, a modulator of Wnt/Beta-catenin and CKAP4/PI3K/AKT signaling pathways, frequently implicated in tumorigenesis. The U.S. Food and Drug Administration has granted Orphan Drug Designation for the treatment of gastric and gastroesophageal junction cancer and Fast Track Designation in combination with tislelizumab for the treatment of patients with gastric and gastroesophageal junction adenocarcinoma whose tumors express high DKK1 protein, following disease progression on or after prior fluoropyrimidine- and platinum- containing chemotherapy and if appropriate, human epidermal receptor growth factor (HER2)/neu-targeted therapy