21
ɑvß6-binding Peptides for Tumour Targeting and Imaging
Cancer Research Horizons
Peptide
Oncology
Hit To Lead or Lead Optimization
Highlights
• Novel and proprietary peptides with high affinity and selectivity for integrin αvβ6
• Lead peptide selectively targets αvβ6+ve tumours and fibrotic lesions in vivo for imaging and therapy
• Toxin-labelled A20FMDV2 controls or clears in vivo murine xenograft pancreatic tumours
• Granted patents in major territories cover A20FMDV2 lead peptides
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 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, 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.
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 avß6-expressing tumours in vivo has been demonstrated by PET and SPECT.
Two patent families protecting the peptide consensus sequences are available for licensing or collaborative development.
John Marshall
• US 9650416 B2 (2017.05.16)
Patent Family: US, EP, JP, CA
• EP 3615563 B1 (2020.09.23)
Patent Family: KR, US, EP, JP, CN, CA, AU
"The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy". Marshall, J. F. et al. The Journal of Pathology, 2019, 249(3), 332–342. https://doi.org/10.1002/path.5320
