Monoclonal antibodies directed against cadherin RGD exhibit therapeutic activity against melanoma and colorectal cancer metastasis

Purpose: 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 (mAbs). Experimental Design: 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. Nude mice were used for survival analysis after treatment with RGD-specific mAbs and metastasis development. Results: 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 VE-cadherin)-mediated β1 integrin activation in melanoma, 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 cancers. In vivo, RGD-specific mAbs increased mouse survival after inoculation of melanoma and colorectal cancer cell lines to cause lung and liver metastasis, respectively. Conclusions: 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.

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