Chemotrap-1: An Engineered Soluble Receptor That Blocks Chemokine-Induced Migration of Metastatic Cancer Cells In vivo

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 20; pp. 8138 - 8148
• Main Authors: LANATI, Silvia, DUNN, Darryl B, GIRARD, Jean-Phillippe, BATES, David O, ROUSSIGNE, Myriam, EMMETT, Maxine S, CARRIERE, Virginie, JULLIEN, Denis, BUDGE, Jessica, FRYER, Justin, ERARD, Monique, CAILLER, Françoise
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.10.2010
• Subjects: Antineoplastic agents; Binding Sites; Biological and medical sciences; Cell Movement; Chemokine CCL2 - metabolism; Chemokine CCL21 - genetics; Chemokine CCL21 - metabolism; Chemokines - antagonists & inhibitors; Chemokines - metabolism; Chemotaxis - physiology; Enzyme-Linked Immunosorbent Assay; Genetic Vectors - metabolism; Glutathione Transferase - metabolism; Humans; Immunoglobulin Fc Fragments - genetics; Immunoglobulin Fc Fragments - metabolism; Lymphatic Metastasis - prevention & control; Medical sciences; Melanoma - metabolism; Melanoma - pathology; Neoplasms - pathology; Pharmacology. Drug treatments; Plasmids; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Tumors; Chemokine; In vivo; Advanced stage; Malignant tumor; Soluble form; Metastasis; Tumor cell; Cell migration; Cancer; Biological receptor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-0175

Cancer and dendritic cells recognize and migrate toward chemokines secreted from lymphatics and use this mechanism to invade the lymphatic system, and cancer cells metastasize through it. The lymphatic-secreted chemokine ligand CCL21 has been identified as a key regulatory molecule in the switch to a metastatic phenotype in melanoma and breast cancer cells. However, it is not known whether CCL21 inhibition is a potential therapeutic strategy for inhibition of metastasis. Here, we describe an engineered CCL21-soluble inhibitor, Chemotrap-1, which inhibits migration of metastatic melanoma cells in vivo. Two-hybrid, pull-down, and coimmunoprecipitation assays allowed us to identify a naturally occurring human zinc finger protein with CCL21 chemokine-binding properties. Further analyses revealed a short peptide (∼70 amino acids), with a predicted coiled-coil structure, which is sufficient for association with CCL21. This CCL21 chemokine-binding peptide was then fused to the Fc region of human IgG1 to generate Chemotrap-1, a human chemokine-binding Fc fusion protein. Surface plasmon resonance and chemotaxis assays showed that Chemotrap-1 binds CCL21 and inhibits CCL21-induced migration of melanoma cells in vitro with subnanomolar affinity. In addition, Chemotrap-1 blocked migration of melanoma cells toward lymphatic endothelial cells in vitro and in vivo. Finally, Chemotrap-1 strongly reduced lymphatic invasion, tracking, and metastasis of CCR7-expressing melanoma cells in vivo. Together, these results show that CCL21 chemokine inhibition by Chemotrap-1 is a potential therapeutic strategy for metastasis and provide further support for the hypothesis that lymphatic-mediated metastasis is a chemokine-dependent process.