Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors

Hadis Honarvar; Cristina Müller; Susan Cohrs; Stephanie Haller; Kristina Westerlund; Amelie Eriksson Karlström; Nicholas P van der Meulen; Roger Schibli; Vladimir Tolmachev

doi:10.1016/j.nucmedbio.2016.10.004

Evaluation of the first ⁴⁴Sc-labeled Affibody molecule for imaging of HER2-expressing tumors

Nucl Med Biol. 2017 Feb:45:15-21. doi: 10.1016/j.nucmedbio.2016.10.004. Epub 2016 Oct 18.

Authors

Hadis Honarvar¹, Cristina Müller², Susan Cohrs³, Stephanie Haller³, Kristina Westerlund⁴, Amelie Eriksson Karlström⁴, Nicholas P van der Meulen⁵, Roger Schibli⁵, Vladimir Tolmachev¹

Affiliations

¹ Institute for Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
² Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland. Electronic address: cristina.mueller@psi.ch.
³ Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland.
⁴ Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden.
⁵ Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland; Laboratory of Radiochemistry, Paul Scherrer Institut, Villigen-PSI, Switzerland; Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.

PMID: 27837664
DOI: 10.1016/j.nucmedbio.2016.10.004

Abstract

Introduction: Affibody molecules are small (58 amino acids) high-affinity proteins based on a tri-helix non-immunoglobulin scaffold. A clinical study has demonstrated that PET imaging using Affibody molecules labeled with ⁶⁸Ga (T_½=68min) can visualize metastases of breast cancer expressing human epidermal growth factor receptor type 2 (HER2) and provide discrimination between tumors with high and low expression level. This may help to identify breast cancer patients benefiting from HER2-targeting therapies. The best discrimination was at 4h post injection. Due to longer half-life, a positron-emitting radionuclide ⁴⁴Sc (T_½=4.04h) might be a preferable label for Affibody molecules for imaging at several hours after injection.

Methods: A synthetic second-generation anti-HER2 Affibody molecule Z_HER2:2891 was labeled with ⁴⁴Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing ⁴⁴Sc-DOTA-Z_HER2:2891 and ⁶⁸Ga-DOTA-Z_HER2:2891 were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of ⁴⁴Sc-DOTA-Z_HER2:2891 and ⁶⁸Ga-DOTA-Z_HER2:2891 were evaluated in Balb/c nude mice bearing HER2-expression xenografts.

Results: The labeling yield of 98±2% and specific activity of 7.8GBq/μmol were obtained. The conjugate demonstrated specific binding to HER2-expressing SKOV3.ip cells in vitro and to SKOV3.ip xenografts in nude mice. The distribution of radioactivity at 3h post injection was similar for ⁴⁴Sc-DOTA-Z_HER2:2891 and ⁶⁸Ga-DOTA-Z_HER2:2891, but the blood clearance of the ⁴⁴Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15±2 for ⁴⁴Sc-DOTA-Z_HER2:2891 vs 46±9 for ⁶⁸Ga-DOTA-Z_HER2:2891). At 6h after injection of ⁴⁴Sc-DOTA-Z_HER2:2891 the tumor uptake was 8±2% IA/g and the tumor-to-blood ratio was 51±8. Imaging using small-animal PET/CT demonstrated that ⁴⁴Sc-DOTA-Z_HER2:2891 provides specific and high-contrast imaging of HER2-expressing xenografts.

Conclusion: The ⁴⁴Sc- DOTA-Z_HER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.

Keywords: (44)Sc; Affibody molecule; DOTA; HER2; PET imaging; Z(HER2:2891).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Transformation, Neoplastic
Gene Expression Regulation, Neoplastic*
Humans
Isotope Labeling
Mice
Positron-Emission Tomography / methods*
Radioisotopes*
Receptor, ErbB-2 / metabolism*
Recombinant Proteins* / pharmacokinetics
Scandium*
Tissue Distribution

Substances

Radioisotopes
Recombinant Proteins
ERBB2 protein, human
Receptor, ErbB-2
Scandium