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Anti-integrin ɑvß6 Antibodies

Overview: 

ɑvß6 integrin is a promising target for cancer therapy. It plays an active role in tumour progression and its high expression is linked to poor prognosis in many tumour types. Humanised single chain Fv and full IgG antibodies have been developed by inserting a proprietary short ɑvß6 binding peptide into a proprietary scaffold. The antibodies shows remarkable binding selectivity for ɑvß6. In vitro studies support their potential utility to block ɑvß6-mediated cancer cell invasion or to deliver and internalize toxins specifically to ɑvß6- expressing tumours.

The Opportunity: 

ɑvß6 integrin is a promising target for cancer therapy. It plays an active role in tumour progression and its high expression is linked to poor prognosis in many tumour types. Humanised single chain Fv and full IgG antibodies have been developed by inserting a proprietary short ɑvß6 binding peptide into a proprietary scaffold. The antibodies shows remarkable binding selectivity for ɑvß6. In vitro studies support their potential utility to block ɑvß6-mediated cancer cell invasion or to deliver and internalize toxins specifically to ɑvß6- expressing tumours.

The Technology: 

A series of anti-αvβ6 antibodies has been generated through a loop grafting approach [1], which involved taking advantage of the A20FMDV2 peptide, which has high affinity and selectivity for αvβ6 [2], by inserting it into the CDR H3 loop of the murine anti-CEA MFE-23 antibody. Therefore, the series of anti-αvβ6 antibodies includes antibodies engineered to be highly αvβ6-specific (B6.2 and humanised B6.3), and an antibody which also cross-reacts with the tumour-associated antigen, CEA (B6.1). Importantly, B6.2 was determined to be as structurally stable as the parent scFv, indicating that insertion of the A20FMDV2 peptide and the Y100bP mutation (removes CEA cross-reactivity) was not detrimental to the protein structure [1]. The humanised variant B6.3 has been generated in diabody [5] and full IgG formats, the diabody variant of which has a Kd of 2.78 nM (as measured by Biacore).

The antibodies have demonstrated specific concentrationdependent binding to αvβ6 transfected cells (versus those expressing other integrins, eg B6.1 scFv - Figure 1), and inhibition of αvβ6-mediated migration and adhesion.

 

References: 

1. Kogelberg, H. et al. J. Mol. Biol. (2008) Vol. 382(2), p385-401
2. Dicara, D. et al. J. Biol. Chem. (2007) Vol. 282(13), p9657-9665
3. Boehm , M. K. et al Biochem. J. (2000) Vol. 346(Pt 2) p519-528
4. Graff, C. P. et al Protein Eng Des Sel (2004) Vol. 17(4), p293-304
5. Kogelberg H. et al PLos ONE (2013) 8(9) e73260
6. Van Aarsen, L.A. et al. Cancer Res. (2008) Vol. 68(2), p561-570
7. Eberlein, C. et al. Oncogene advance online publication 29 October 2012 doi: 10.1038/onc.2012.460
8. Singh, A. et al. Cancer Cell (2009) Vol 15(6), p489-500

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