IADR Abstract Archives

Development of Highly Specific Anti-αvβ6 Peptides for Imaging Oral Cancer

OBJECTIVES:

Oral squamous cell carcinoma (OSCC) has a survival rate of only 50%; new treatments are therefore urgently required.  Integrin avb6 is a cell-surface glycoprotein that is undetectable on most normal tissues but is over-expressed in inflammation or wound-healing and by over 95% of OSCC. The purpose of this study was to develop high affinity, specific, radio-labelled, avb6-targeting peptides to image avb6-positive tumours in vivo. METHODS:

20mer peptides, derived from the sequences of natural avb6 ligands, were analysed for avb6 affinity and specificity by ELISA and flow cytometry.  Structure-function analysis over several generations of peptide design identified a lead peptide, A20FMDV2.  18F-A20FMDV2 was injected into mice bearing human xenografts and imaged using small animal PET.  Cyclic A20FMDV2, designed for increased resistance to serum proteases, was also generated. RESULTS:

A20FMDV2 and the cyclic variants, DBD1 and DBD2, inhibited avb6 in ELISA at ≤10nM and on cells at ≤1uM.  Unusually, binding was irreversible, which may enhance in vivo utility.  All peptides were highly avb6 selective; in particular, A20FMDV2 and DBD2 showed no binding at 1uM to the related integrins a5b1, avb3, avb5 and avb8.  For in vivo experiments we generated cell lines that differed only by avb6 expression (DX3puro/DX3b6puroS1 and A375Ppuro/A375Pb6puro). In preliminary studies, 18F-A20FMDV2 injected into mice bearing paired DX3 tumours showed a clear selectivity (5-10 fold at 60') for the avb6-positive tumour.  However, the peptide was degraded rapidly.  Similarly, 125I-DBD1, which was 70% intact after 4h at 37C in serum, showed selective uptake in avb6-positive versus avb6-negative tumours. CONCLUSIONS:

Oral cancers are >95% avb6-positive whereas normal oral mucosa is weak or negative for this integrin. We have successfully generated highly specific peptides that localise selectively to avb6-positive cancers.  We intend to develop these, or related peptides, for image-guided treatment and targeted therapies, for improved management of OSCC. Funding: DebRA


Pan European Federation Meeting
2006 Pan European Federation Meeting (Dublin, Ireland)
Dublin, Ireland
2006
189
Scientific Groups
  • Dicara, Danielle  ( Cancer Research UK Clinical Centre, London, N/A, United Kingdom )
  • Hausner, Sven  ( University of California, Davis, Davis, CA, USA )
  • Howard, Mark J.  ( University of Kent, Kent, N/A, United Kingdom )
  • Sutcliffe-goulden, Julie L.  ( University of California, Davis, Davis, CA, USA )
  • Marshall, J. F.  ( Cancer Research UK Clinical Centre, London, N/A, United Kingdom )
  • Oral Session
    BSDR Junior Colgate Award, BSDR Senior Colgate Award
    09/14/2006