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

Oncogene volume 32, pages 4406–4416 (2013)Cite this article

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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.

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Abbreviations

α-SMA:

alpha smooth muscle actin

GST:

glutathione-S-transferase

MVD:

microvessel density

MVA:

microvessel area

TGF-β LAP:

transforming growth factor β latency-associated peptide

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Acknowledgements

Adrian Churchman was funded by a MRC Pilot Award.

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Authors and Affiliations

  1. Oncology iMED, AstraZeneca, Macclesfield, UK

    C Eberlein, J Kendrew, K McDaid, V N Jacobs, S J Ross, C Rooney, N R Smith, H M Weir, D C Blakey & S T Barry

  2. Amgen (Formerly Abgenix), Burnaby, British Columbia, Canada

    A Alfred, J S Kang, J Rinkenberger & I N Foltz

  3. Oncology iMED, AstraZeneca R&D Boston, Waltham, MA, USA

    A Cao & V Bedian

  4. Barts Cancer Institute, Queen Mary University of London, London, UK

    A Churchman & J F Marshall

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Correspondence to S T Barry.

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Competing interests

CE, JK, KM, VNJ, NRS, HMW, DCB, VB, SJR CR STB are current employees of AstraZeneca. AA, JSK, JR and INF are current or former employees of Amgen/Abgenix. The remaining authors declare no conflict of interest.

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Eberlein, C., Kendrew, J., McDaid, K. et al. A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene 32, 4406–4416 (2013). https://doi.org/10.1038/onc.2012.460

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