| 2531 Development of anti-αvβ6 peptides for imaging oral cancer | ||
|
D. DICARA1, S.H. HAUSNER2, J.L. SUTCLIFFE2, M.J. HOWARD3, and J.F. MARSHALL1, 1Barts & the London Queen Mary's School of Medicine & Dentistry, United Kingdom, 2University of California - Davis, USA, 3University of Kent, Canterbury, United Kingdom OBJECTIVES: Oral squamous cell carcinoma (OSCC) has a survival rate of only 50%; new treatments are therefore urgently required. Integrin αvβ6 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, αvβ6-targeting peptides to image αvβ6-positive tumours in vivo. METHODS: 20mer peptides, derived from the sequences of natural αvβ6 ligands, were analysed for αvβ6 affinity and specificity by ELISA and flow cytometry. Structure-function analysis over several generations of peptide design identified a lead peptide. [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 αvβ6 in ELISA at ≤10nM and on cells at ≤1uM. All peptides were highly αvβ6 selective; in particular, A20FMDV2 and DBD2 showed no binding at 1uM to the related integrins α5β1, αvβ3, αvβ5 and αvβ8 but strong binding to αvβ6 at 1nM. For in vivo experiments we generated cell lines that differed only by αvβ6 expression (DX3puro/DX3β6puroS1 and A375Ppuro/A375Pβ6puro). In preliminary studies, [18F]A20FMDV2 injected into mice bearing paired DX3 tumours showed a clear selectivity (approximately 4-fold at 120') for the αvβ6-positive tumour. However, the peptide was degraded rapidly. [18F]DBD2 showed improved plasma-stability but slower clearance from background tissues. Preliminary data suggests [125I]DBD1 has improved stability and shows selective uptake in αvβ6-positive versus αvβ6-negative tumours. CONCLUSIONS: Oral cancers are >95% αvβ6-positive whereas normal oral mucosa is weak or negative for this integrin. We have successfully generated highly specific lead peptides that localise selectively to αvβ6-positive cancers. These peptides will be developed for providing image-guided surgery and targeted therapies, for improved management of OSCC. Funding: DebRA | ||
| Seq #265 - Senior - Basic Science Category 10:45 AM-12:00 PM, Saturday, March 24, 2007 Ernest N. Morial Convention Center Exhibit Hall I2-J | ||
|
Back to the IADR/Unilever Hatton Awards Program
| ||