Monoclonal Antibodies Directed against Cadherin RGD Exhibit Therapeutic Activity against Melanoma and Colorectal Cancer Metastasis

• Published in: Clinical cancer research Vol. 24; no. 2; pp. 433 - 444
• Main Authors: Bartolomé, Rubén A, Aizpurua, Carmen, Jaén, Marta, Torres, Sofía, Calviño, Eva, Imbaud, Juan I, Casal, J Ignacio
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.01.2018
• Subjects: Activation; Adhesion; Adhesion tests; AKT protein; Biotechnology; Blocking; Breast cancer; Cadherins; Cancer; Cell adhesion; Cell adhesion & migration; Cell proliferation; Colon; Colon cancer; Colorectal cancer; Colorectal carcinoma; Disease control; Experimental design; Extracellular signal-regulated kinase; Immunization; Immunoglobulins; Inoculation; JNK protein; Kinases; Liver; Lungs; Melanoma; Metastases; Metastasis; Monoclonal antibodies; Pancreas; Pancreatic cancer; Peptides; Signal transduction; Signaling; Survival; Survival analysis; Tumor cell lines
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1444

New targets are required for the control of advanced metastatic disease. We investigated the use of cadherin RGD motifs, which activate the α2β1integrin pathway, as targets for the development of therapeutic monoclonal antibodies (mAb). Cadherin 17 (CDH17) fragments and peptides were prepared and used for immunization and antibody development. Antibodies were tested for inhibition of β1 integrin and cell adhesion, proliferation, and invasion assays using cell lines from different cancer types (colorectal, pancreatic, melanoma, and breast cancer). Effects of the mAbs on cell signaling were determined by Western blot analysis. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development. Antibodies against full-length CDH17 failed to block the binding to α2β1 integrin. However, CDH17 RGD peptides generated highly selective RGD mAbs that blocked CDH17 and vascular-endothelial (VE)-cadherin-mediated β1 integrin activation in melanoma and breast, pancreatic, and colorectal cancer cells. Antibodies provoked a significant reduction in cell adhesion and proliferation of metastatic cancer cells. Treatment with mAbs impaired the integrin signaling pathway activation of FAK in colorectal cancer, of JNK and ERK kinases in colorectal and pancreatic cancers, and of JNK, ERK, Src, and AKT in melanoma and breast cancer. , RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively. Blocking the interaction between RGD cadherins and α2β1 integrin with highly selective mAbs constitutes a promising therapy against advanced metastatic disease in colon cancer, melanoma, and, potentially, other cancers. .