The αvβ6 integrin – a novel target for antibody conjugated magnetic fluid hyperthermia in squamous cell carcinoma


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Daniel Marsh1, Heide Kogelberg1, Kim Vigor1, Paul Southern2, Berend Tolner1, Jag Chana3, Quentin Pankhurst2, Kerry Chester1

1Cancer Institute, UCL, London, UK, 2London Centre of Nanotechnology, London, UK, 3Royal Free Hospital, London, UK

Abstract

Background

Magnetic fluid hyperthermia (MFH) is a novel technique whereby superparamagnetic iron oxide nanoparticles (SPIONs) are placed within and excited by an alternating magnetic field to generate heat [1]. This approach for cancer therapy has previously been demonstrated in patients using direct intratumoural injection of SPIONs [2, 3]. We propose MFH can be delivered more effectively using antibody targeted SPIONs. To test this hypothesis we have developed a recombinant single chain antibody fragment (scFv) to deliver SPIONs to the epithelial restricted αvβ6 integrin, an exciting new target in head and neck cancers [4].

Method and results

Using a rational structural based approach, we engineered MFE-23, a well characterised scFv reactive with carcinoembryonic antigen (CEA), to create a new humized αvβ6-reactive scFv. The new scFv was cloned with a free c-terminal cysteine for site specific attachment to SPIONs and produced in the yeast P.Pastoris. The novel scFv specifically binds αvβ6 ligand on ELISA and is a potent inhibitor of αvβ6 mediated cell adhesion. In parallel experiments, we have developed a method of delivering MFH sufficient to heat several commercially available SPIONs and established methods for scFv-SPION chemical attachments. Optimisation of experimental protocols to assess hyperthermic potential of the scFv-SPION complexes will be discussed along with the feasibility and limits of MFH for therapy in head and neck squamous cell carcinoma.

Conclusion

A new recombinant scFv reactive with αvβ6 has been designed and manufactured. This scFv is biologically active and is currently being investigated for delivery of SPION targeted MFH specifically to squamous cell carcinoma.

References

[1]Alexiou C et al. J Nanosci Nanotechnol. 2006 Sep-Oct;6(9-10):2762-8.
[2]MaierHauff K et al J Neurooncol. 2007 Jan;81(1):53-60

[3]Johannsen M et al Int J Hyperthermia. 2007 May;23(3):315-23

[4]Ramos DM et al. Matrix Biology 2002; 21 : 297–307

Background

Magnetic fluid hyperthermia (MFH) is a novel technique whereby superparamagnetic iron oxide nanoparticles (SPIONs) are placed within and excited by an alternating magnetic field to generate heat [1]. This approach for cancer therapy has previously been demonstrated in patients using direct intratumoural injection of SPIONs [2, 3]. We propose MFH can be delivered more effectively using antibody targeted SPIONs. To test this hypothesis we have developed a recombinant single chain antibody fragment (scFv) to deliver SPIONs to the epithelial restricted αvβ6 integrin, an exciting new target in head and neck cancers [4].

Method and results

Using a rational structural based approach, we engineered MFE-23, a well characterised scFv reactive with carcinoembryonic antigen (CEA), to create a new humized αvβ6-reactive scFv. The new scFv was cloned with a free c-terminal cysteine for site specific attachment to SPIONs and produced in the yeast P.Pastoris. The novel scFv specifically binds αvβ6 ligand on ELISA and is a potent inhibitor of αvβ6 mediated cell adhesion. In parallel experiments, we have developed a method of delivering MFH sufficient to heat several commercially available SPIONs and established methods for scFv-SPION chemical attachments. Optimisation of experimental protocols to assess hyperthermic potential of the scFv-SPION complexes will be discussed along with the feasibility and limits of MFH for therapy in head and neck squamous cell carcinoma.

Conclusion

A new recombinant scFv reactive with αvβ6 has been designed and manufactured. This scFv is biologically active and is currently being investigated for delivery of SPION targeted MFH specifically to squamous cell carcinoma.

References

[1]Alexiou C et al. J Nanosci Nanotechnol. 2006 Sep-Oct;6(9-10):2762-8.
[2]MaierHauff K et al J Neurooncol. 2007 Jan;81(1):53-60

[3]Johannsen M et al Int J Hyperthermia. 2007 May;23(3):315-23

[4]Ramos DM et al. Matrix Biology 2002; 21 : 297–307

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