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Integrin avß6 Binding Peptides for Imaging

Overview: 

Peptides which potently and selectively bind to the integrin avß6 have been developed. The structural motif required for binding has been elucidated, and the consensus sequence is protected by a patent application. The peptides have utility for targeting tumours in which the integrin is over-expressed (including oral, pancreatic, ovarian, lung, colorectal and breast). The peptides have applications in tumour imaging as well as in cancer therapy via targeting of payloads and functional inhibition of avß6. The ability of radiolabelled versions of the peptide to selectively localise to avß6-expressing tumours in vivo has been demonstrated by PET and SPECT.

The Opportunity: 

The integrin avß6 is an exciting emerging target for both imaging and therapy across many common tumour types including pancreatic, breast, oesophagus, head and neck, skin, lung and ovarian. Each year an estimated 279,000 avß6- positive tumours are diagnosed in the US & UK alone. Peptides with remarkable affinity and selectivity for avß6 have been identified and characterised. In vitro and in vivo data demonstrates the potential of these peptides as the basis for novel PET and SPECT imaging probes, tumour targeting agents and functional inhibitors of avß6. Patent family WO2007/039728 protecting the peptide consensus sequence is available for exclusive licensing or collaborative development.

Scientific Background: 

The epithelial-specific integrin αvβ6 binds to RGD motifs in its ligands including fibronectin, tenascin and the latency associated
peptide (LAP) of TGFβ. Expression of αvβ6 is restricted primarily to epithelial cells where it is expressed at low levels in healthy tissue and significantly up-regulated during wound healing, fibrosis and in tumourigenesis, for example αvβ6 is over-expressed in approximately 90% of oral squamous cell carcinomas, pancreatic and ovarian tumours,and 40% of lung, colon and breast carcinomas. αvβ6 has multiple regulatory functions in tumours including TGF-β activation, cell proliferation, MMP production, cell invasion and survival. Antibody-mediated blockade of αvβ6 has been demonstrated to inhibit tumour growth in vivo (4, 5), supporting the use of αvβ6-targeted agents in cancer therapy. In patients, elevated αvβ6 expression has been correlated with poor prognosis including in colorectal, ovarian and lung cancers. Numerous publications have identified αvβ6 as a key regulator of the epithelial to mesenchymal transition. αvβ6 has also been linked with maintenance of a pluripotent cancer stem cell phenotype in oral cancer, and as a key member of a “K-Ras dependency signature” in lung and pancreatic tumours (6).

References: 

1. Dicara, D. et al. J. Biol. Chem. (2007) Vol. 282(13), p9657-9665
2. Hausner, S.H. et al. Cancer Res. (2007) Vol. 67(16), p7833-7840
3. Hausner, S.H. et al. Cancer Res. (2009) Vol. 69(14), p5843-5850
4. Van Aarsen, L.A. et al. Cancer Res. (2008) Vol. 68(2), p561-570
5. Eberlein, C. et al. Oncogene. (2013) Vol 32(37), p4406-16
6. Singh, A. et al. Cancer Cell (2009) Vol 15(6), p489-500

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