TY - JOUR
T1 - Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors
AU - Honarvar, Hadis
AU - Müller, Cristina
AU - Cohrs, Susan
AU - Haller, Stephanie
AU - Westerlund, Kristina
AU - Karlström, Amelie Eriksson
AU - van der Meulen, Nicholas P.
AU - Schibli, Roger
AU - Tolmachev, Vladimir
N1 - Funding Information:
The authors thank Dr. Christiaan Vermeulen, Walter Hirzel, Alexander Sommerhalder, Katharina Domnanich and Raffaella Schmid for technical assistance. This research was financially supported by grants from the Swedish Cancer Society (grants 2015/350 and CAN2015/890) and the Swedish Research Council (2013-5135 and 2015-02353) as well as the Swiss National Science Foundation (grants CR23I2_156852 and IZLIZ3_156800).
Publisher Copyright:
© 2016 Elsevier Inc.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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 (T½ = 68 min) 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 4 h post injection. Due to longer half-life, a positron-emitting radionuclide 44Sc (T½ = 4.04 h) might be a preferable label for Affibody molecules for imaging at several hours after injection. Methods A synthetic second-generation anti-HER2 Affibody molecule ZHER2:2891 was labeled with 44Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891 were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891 were evaluated in Balb/c nude mice bearing HER2-expression xenografts. Results The labeling yield of 98 ± 2% and specific activity of 7.8 GBq/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 3 h post injection was similar for 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891, but the blood clearance of the 44Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15 ± 2 for 44Sc-DOTA-ZHER2:2891 vs 46 ± 9 for 68Ga-DOTA-ZHER2:2891). At 6 h after injection of 44Sc-DOTA-ZHER2:2891 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-ZHER2:2891 provides specific and high-contrast imaging of HER2-expressing xenografts. Conclusion The 44Sc- DOTA-ZHER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.
AB - 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 (T½ = 68 min) 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 4 h post injection. Due to longer half-life, a positron-emitting radionuclide 44Sc (T½ = 4.04 h) might be a preferable label for Affibody molecules for imaging at several hours after injection. Methods A synthetic second-generation anti-HER2 Affibody molecule ZHER2:2891 was labeled with 44Sc via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891 were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891 were evaluated in Balb/c nude mice bearing HER2-expression xenografts. Results The labeling yield of 98 ± 2% and specific activity of 7.8 GBq/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 3 h post injection was similar for 44Sc-DOTA-ZHER2:2891 and 68Ga-DOTA-ZHER2:2891, but the blood clearance of the 44Sc-labeled variant was slower and the tumor-to-blood ratio was reduced (15 ± 2 for 44Sc-DOTA-ZHER2:2891 vs 46 ± 9 for 68Ga-DOTA-ZHER2:2891). At 6 h after injection of 44Sc-DOTA-ZHER2:2891 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-ZHER2:2891 provides specific and high-contrast imaging of HER2-expressing xenografts. Conclusion The 44Sc- DOTA-ZHER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.
KW - Sc
KW - Affibody molecule
KW - DOTA
KW - HER2
KW - PET imaging
KW - Z
UR - http://www.scopus.com/inward/record.url?scp=84994908259&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994908259&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2016.10.004
DO - 10.1016/j.nucmedbio.2016.10.004
M3 - Article
C2 - 27837664
AN - SCOPUS:84994908259
VL - 45
SP - 15
EP - 21
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
SN - 0969-8051
ER -