This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tolmachev, V. Articles by Nilsson, F. Y. Search for Related Content PubMed PubMed Citation Articles by Tolmachev, V. Articles by Nilsson, F. Y.

Radionuclide Therapy of HER2-Positive Microxenografts Using a ¹⁷⁷Lu-Labeled HER2-Specific Affibody Molecule

¹ Affibody AB, Bromma, Sweden; ² Division of Biomedical Radiation Sciences, Uppsala University; and ³ Department of Hospital Physics, Uppsala University Hospital, Uppsala, Sweden

Requests for reprints: Fredrik Y. Nilsson, Affibody AB, Box 20137, 16102 Bromma, Sweden. Phone: 468-5988-3851; E-mail: fredrik.nilsson{at}affibody.com.

A radiolabeled anti-HER2 Affibody molecule (Z_HER2:342) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z_HER2:342)₂ was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy ß-emitter ¹⁷⁷Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z_HER2:342)₂] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z_HER2:342)₂. Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq ¹⁷⁷Lu-CHX-A''-DTPA-ABD-(Z_HER2:342)₂ completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non–HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight ¹⁷⁷Lu-CHX-A''-DTPA-ABD-(Z_HER2:342)₂ as a candidate for treatment of disseminated tumors with a high level of HER2 expression. [Cancer Res 2007;67(6):2773–82]

This article has been cited by other articles:

				S. B. Lee, M. Hassan, R. Fisher, O. Chertov, V. Chernomordik, G. Kramer-Marek, A. Gandjbakhche, and J. Capala Affibody Molecules for In vivo Characterization of HER2-Positive Tumors by Near-Infrared Imaging Clin. Cancer Res., June 15, 2008; 14(12): 3840 - 3849. [Abstract] [Full Text] [PDF]

				Z. Cheng, O. P. De Jesus, M. Namavari, A. De, J. Levi, J. M. Webster, R. Zhang, B. Lee, F. A. Syud, and S. S. Gambhir Small-Animal PET Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with Site-Specific 18F-Labeled Protein Scaffold Molecules J. Nucl. Med., May 1, 2008; 49(5): 804 - 813. [Abstract] [Full Text] [PDF]

				Stabilization of a {beta}-hairpin in monomeric Alzheimer's amyloid-{beta} peptide inhibits amyloid formation PNAS, April 1, 2008; 105(13): 5099 - 5104.

				N. Kronqvist, J. Lofblom, A. Jonsson, H. Wernerus, and S. Stahl A novel affinity protein selection system based on staphylococcal cell surface display and flow cytometry Protein Eng. Des. Sel., April 1, 2008; 21(4): 247 - 255. [Abstract] [Full Text] [PDF]

				R. Stork, D. Muller, and R. E. Kontermann A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G Protein Eng. Des. Sel., November 3, 2007; (2007) gzm061v1. [Abstract] [Full Text] [PDF]

				M. Friedman, E. Nordberg, I. Hoiden-Guthenberg, H. Brismar, G.P. Adams, F.Y. Nilsson, J. Carlsson, and S. Stahl Phage display selection of Affibody molecules with specific binding to the extracellular domain of the epidermal growth factor receptor Protein Eng. Des. Sel., April 23, 2007; (2007) gzm011v1. [Abstract] [Full Text] [PDF]