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

详细信息    查看全文

• 作者：Hadis Honarvar^a ; Cristina Mü ; ller^b ; ^{cristina.mueller@psi.ch} ; Susan Cohrs^b ; Stephanie Haller^b ; Kristina Westerlund^c ; Amelie Eriksson Karlströ ; m^c ; Nicholas P. van der Meulen^b ; ^d ; ^e ; Roger Schibli^b ; ^d ; ^e ; Vladimir Tolmachev^a
• 关键词：Affibody molecule ; 44Sc ; DOTA ; ZHER2 ; 2891 ; HER2 ; PET imaging
• 刊名：Nuclear Medicine and Biology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：45
• 期：Complete
• 页码：15-21
• 全文大小：648 K
• 卷排序：45

文摘

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.MethodsA 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.ResultsThe 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.ConclusionThe 44Sc- DOTA-ZHER2:2891 Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.