A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo

• Published in: Oncogene Vol. 32; no. 37; pp. 4406 - 4416
• Main Authors: Eberlein, C, Kendrew, J, McDaid, K, Alfred, A, Kang, J S, Jacobs, V N, Ross, S J, Rooney, C, Smith, N R, Rinkenberger, J, Cao, A, Churchman, A, Marshall, J F, Weir, H M, Bedian, V, Blakey, D C, Foltz, I N, Barry, S T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2013; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/67/1857; 631/67/322; Actin; Animals; Antibodies, Monoclonal, Humanized - immunology; Antibodies, Monoclonal, Humanized - metabolism; Antibodies, Monoclonal, Humanized - pharmacology; Antigens, Neoplasm - immunology; Antigens, Neoplasm - metabolism; Apoptosis; Biomarkers - metabolism; Cancer; Care and treatment; Cell activation; Cell Biology; Cell culture; Cell Line; Cell Movement - drug effects; Cell Proliferation - drug effects; Coculture Techniques; Female; Fibroblasts; Fibronectin; Human Genetics; Humans; Integrins; Integrins - antagonists & inhibitors; Integrins - immunology; Integrins - metabolism; Internal Medicine; Latency; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Macaca fascicularis; Matrix metalloproteinase; Matrix Metalloproteinase 9 - biosynthesis; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Metastasis; Mice; Monoclonal antibodies; Neoplasms - metabolism; Neoplasms - pathology; Neoplastic processes; Observations; Oncology; original-article; Properties; Protein Binding; Smooth muscle; Testing; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumors; Xenograft Model Antitumor Assays; United Kingdom; United States > US; Detroit Michigan; beta-6; TGF-β; beta-8; αvβ8; integrin; αvβ6
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.460

αvβ6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits αvβ6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey αvβ6, and inhibits binding to all ligands including the latency-associated peptide of TGF-β. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin αvβ8, but not the integrins α5β1, αvβ3, αvβ5 and α4β1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and αvβ6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-β-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-β by NCI-H358 tumour cells in a tumour cell−fibroblast co-culture assay. In vivo 264RAD showed dose-dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of αvβ6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of αvβ6 integrin, with some activity against αvβ8 integrin, that reduces both tumour growth and metastasis.