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

alpha v beta 6 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 alpha v beta 6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey alpha v beta 6, and inhibits binding to all ligands including the latency-associated peptide of TGF-beta. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin alpha v beta 8, but not the integrins alpha 5 beta 1, alpha v beta 3, alpha v beta 5 and alpha 4 beta 1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and alpha v beta 6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-beta-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-beta 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 alpha v beta 6 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 alpha v beta 6 integrin, with some activity against alpha v beta 8 integrin, that reduces both tumour growth and metastasis.