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avB6-binding Peptides for Tumour Targeting
In vivo Proof-of-Principle. Peptides which selectively bind to the integrin ɑvß6 with high affinity 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 ɑvß6. ɑvß6 plays multiple regulatory functions in tumours including TGFß activation, cell proliferation, MMP production, cell invasion and survival. The ability of radiolabelled versions of the peptide to selectively localise to ɑvß6-expressing xenografts in vivo, including breast and pancreatic, has been demonstrated by PET and SPECT.
Peptides with excellent affinity and selectivity for ɑvß6 have been identified and characterised.
In vitro and in vivo data demonstrates the potential of these peptides as novel PET and SPECT imaging probes, tumour targeting agents and functional inhibitors of ɑvß6.
The integrin ɑvß6 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 ɑvß6-positive tumours are diagnosed in the US & UK alone. In addition, ɑvß6 is recognised as an exciting target in fibriotic diseases.
The 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 (6, 7), 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 (8).
Two patent families protecting the peptide consensus sequences are available for licensing or collaborative development
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