Invited Speaker

Affibody-Mediated Tumor Targeting for Medical Imaging and Radiotherapy Applications
Stefan Ståhl
Sweden

Background:

Affibody molecules are a class of small and stable protein domains, which can be selected to bind with high affinity and specificity to a wide variety of target proteins. They are designed by randomization of 13 solvent-accessible surface residues of a 58-residue triple-alpha-helical receptor protein derived from staphylococcal protein A. Their small size holds promise for good penetration properties for therapeutic and diagnostic in vivo delivery and they can be efficiently produced in bacteria or by conventional peptide synthesis.
The generation and use of affibody molecules binding with high affinity to the human epidermal growth factor receptors, EFGR and HER2, and their use for medical imaging applications as well as tumor therapy will be described. High contrast gamma camera images in mouse xenografts as well as data on complete eradication of small HER2-expressing tumors in mice will be shown. The first human study for affibody-mediated imaging of HER2-expressing metastatic lesions in recurrent breast cancer will be presented. In addition, the generation of bispecific targeting affibody molecules, targeting both EFGR and HER2, will be described.

References directly related to the topic

1. Wikman, M., Steffen, A.-C., Gunneriusson, E., Tomlmachev, V., Adams, G.P., Carlsson, J. and Ståhl, S. Selection and characterization of HER2/neu-binding affibody ligands. Prot. Engin. Design Select. 17: 455-462 (2004).

2. Steffen, A.-C., Wikman, M., Tolmachev, V., Adams, G.P., Nilsson, F., Ståhl, S. and Carlsson, J. In vitro characterization of a bivalent anti-HER-2 affibody with potential for radionuclide based diagnostics. Cancer Biother. Radiopharmaceut. 20: 239-247 (2005).

3. Orlova, A., Nilsson, F., Wikman, M., Widström, C., Ståhl, S., Carlsson, J. and Tolmachev, V. Comparative in vivo evaluation of technetium and iodine labels on an anti-HER2 affibody for single-photon imaging of HER2 expression in tumors. J. Nuclear Medicine 47: 512-519 (2006).

4. Orlova, A./ Magnusson, M., Eriksson, T., Nilsson, M., Larsson, B., Höiden-Guthenberg, I., Carlsson, J., Tolmachev, V., Ståhl, S. and Nilsson, F.Y. Tumor imaging using a picomolar affinity HER2 binding affibody molecule. Cancer Research 66: 4339-4348 (2006).

5. Steffen, A.-C., Orlova, A., Wikman, M., Nilsson, F.Y., Ståhl, S., Adams, G.P., Tomalchev, V. and Carlsson, J. Affibody-mediated tumor targeting of HER-2 expressing xenografts in mice. Eur. J. Nucl. Med. Mol. Imaging 33: 631-638 (2006).

6. Magnusson, M., Henning, P., Myhre, S., Wikman, M., Uil, T.G., Friedman, M., Andersson, K.E., Hong, S.S., Hoeben, R., Habib, N.A., Ståhl, S., Boulanger, P. and Lindholm, L. An Adenovirus 5 vector genetically re-targeted by an affibody molecule with specificity for tumor antigen HER2/neu. Cancer Gene Therapy 14: 468-479 (2007).

7. Friedman, M., Nordberg, E., Höidén-Guthenberg, I., Brismar, H., Adams, G.P., Nilsson, F.Y., Carlsson, J. and Ståhl, S. Selection and characterization of affibody ligands binding to the epidermal growth factor receptor. Prot. Eng. Design Select. 20: 189-199 (2007).

8. Nordberg, E., Friedman, M., Göstring, L., Adams, G.P., Brismar, H., Nilsson, F.Y., Ståhl, S., Glimelius, B. and Carlsson, J. Cellular studies of binding, internalization and retention of a radiolabeled EGFR-binding affibody molecule Nuclear Med. Biol. 34: 609-618 (2007).

9. Ståhl, S., Nilsson, F.Y., Friedman, M., Feldwisch, J., Wennborg, A., Wikman, M., Orlova, A., Tolmachev, V., Carlsson, J. and Abrahmsén, L. Affibody molecules for tumor targeting applications In: J. Wilce (Editor) Proceedings of the 4th international Peptide Symposium, in conjunction with the 7th Australian Peptide Conference and the 2nd Asia-Pacific International Peptide Symposium, www.peptideoz.org (2007).

10. Friedman, M., Orlova, A., Johansson, E., Eriksson, T., Höidén-Guthenberg, I., Nilsson, F.Y., Tolmachev, V. and Ståhl, S. Directed evolution to low nanomolar affinity of a tumor-targeting epidermal growth factor receptor-binding Affibody molecule. J. Mol. Biol. 376: 1388-1402 (2008).

11. Nordberg, E., Orlova, A., Friedman, M., Tolmachev, V., Ståhl, S., Nilsson, F.Y., Glimelius, B. and Carlsson, J. In vivo and in vitro uptake of ¹¹¹In, delivered with the affibody molecule (Z_EGFR:955)₂ in EGFR expressing tumor cells. Oncology Reports 19: 853-857 (2008).

12. Hoyer, W., Grönwall, C., Jonsson, A., Ståhl, S. and Härd, T. Stabilization of a β-hairpin in monomeric Alzheimer’s amyloid-β peptide inhibits amyloid formation. Proc. Natl. Acad. Sci. USA 105: 5099-5104 (2008).

13. Rockberg, J./Löfblom, J., Hjelm, B., Uhlén, M., and Ståhl, S. Epitope mapping of antibodies using bacterial surface display. Nature Methods 5: 1037-1045 (2008).

14. Tolmachev, V., Friedman, M., Sandström, M., Eriksson, T., Rosik, D., Hodik, M., Ståhl, S., Nilsson, F.Y. and Orlova, A.Affibody molecules for epidermal growth factor receptor targeting in vivo: aspects of dimerization and labeling chemistry. J. Nuclear Med. 50: 274-283 (2009).

15. Myhre, S., Henning, P., Friedman, M., Ståhl., S., Lindholm, L. and Magnusson, M.K. Re-targeted adenovirus vectors with dual specificity; binding specificities conferred by two different affibody molecules in the fiber. Gene Therapy 16: 252-261 (2009).

16. Friedman, M. and Ståhl, S. Engineered affinity proteins for tumor targeting applications. Biotechnol. Applied Biochem. 53: 1-29 (2009).

17. Grönwall, C. and Ståhl, S. Engineered affinity proteins-generation and applications. J. Biotechnol. 140: 254-269 (2009).

18. Friedman, M., Lindström, S., Ekerljung, L., Andersson-Svahn, H., Carlsson, J., Brismar, H., Gedda, L., Frejd, F.Y. and Ståhl, S. Engineering and characterization of a bispecific HER2xEGFR-binding affibody molecule. Biotechnol. Applied Biochem. 54: 121-131 (2009).

19. Ståhl, S., Friedman, M., Carlsson, J., Tolmachev, V. and Frejd, F. Affibody molecules for targeted radionuclide therapy. In: T.W. Speer (Ed.) Lippincott. (2009) Invited review- in press.