title: A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo.
abstract: 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.
authors.affiliation: Oncology iMED, AstraZeneca, Macclesfield, UK.
authors.forename: C
authors.initials: C
authors.lastname: Eberlein
authors.forename: J
authors.initials: J
authors.lastname: Kendrew
authors.forename: K
authors.initials: K
authors.lastname: McDaid
authors.forename: A
authors.initials: A
authors.lastname: Alfred
authors.forename: J S
authors.initials: JS
authors.lastname: Kang
authors.forename: V N
authors.initials: VN
authors.lastname: Jacobs
authors.forename: S J
authors.initials: SJ
authors.lastname: Ross
authors.forename: C
authors.initials: C
authors.lastname: Rooney
authors.forename: N R
authors.initials: NR
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Rinkenberger
authors.forename: A
authors.initials: A
authors.lastname: Cao
authors.forename: A
authors.initials: A
authors.lastname: Churchman
authors.forename: J F
authors.initials: JF
authors.lastname: Marshall
authors.forename: H M
authors.initials: HM
authors.lastname: Weir
authors.forename: V
authors.initials: V
authors.lastname: Bedian
authors.forename: D C
authors.initials: DC
authors.lastname: Blakey
authors.forename: I N
authors.initials: IN
authors.lastname: Foltz
authors.forename: S T
authors.initials: ST
authors.lastname: Barry
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008252:Macaca fascicularis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D016212:Transforming Growth Factor beta / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015415:Biomarkers; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D020780:Matrix Metalloproteinase 9