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Newly developed humanized anti‐CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1‐CKAP4 signaling
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Newly developed humanized anti‐CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1‐CKAP4 signaling
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Journal Article
Newly developed humanized anti‐CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1‐CKAP4 signaling
2024
Overview
Cytoskeleton‐associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1–CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti‐CKAP4 antibodies were generated based on an original mouse antibody (3F11‐2B10) and inhibited DKK1–CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11‐2B10. From the 3F11‐2B10 nucleotide sequence, humanized anti‐CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11‐2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11‐2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti‐tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti‐cancer therapy. Oncogenic DKK1–CKAP4 signaling axis is activated in pancreatic cancer and associated with a poor prognosis. In this study, we have for the first time developed a humanized anti‐CKAP4 antibody based on the structure of a previously developed mouse anti‐CKAP4 monoclonal antibody 3F11‐2B10. The novel humanized anti‐CKAP4 antibody Hv1Lt1 efficiently inhibited DKK1‐CKAP4 signaling and suppressed in vivo pancreatic tumor growth either as a monotherapy or in combination with standard therapeutics.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Animals
/ Antibodies, Monoclonal, Humanized - pharmacology
/ Cell Proliferation - drug effects
/ CKAP4
/ Cloning
/ DKK1
/ Female
/ Humans
/ Intercellular Signaling Peptides and Proteins - metabolism
/ Kinases
/ Mice
/ Mutation
/ Original
/ Pancreatic Neoplasms - drug therapy
/ Pancreatic Neoplasms - immunology
/ Pancreatic Neoplasms - metabolism
/ Pancreatic Neoplasms - pathology
/ Proteins
/ Signal Transduction - drug effects
/ Spleen
/ Tumors
