Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule ¹⁸⁸Re-ZHER2:41071

• Main Authors: Yongsheng Liu (Author), Anzhelika Vorobyeva (Author), Anna Orlova (Author), Mark W. Konijnenberg (Author), Tianqi Xu (Author), Olga Bragina (Author), Annika Loftenius (Author), Erica Rosander (Author), Fredrik Y. Frejd (Author), Vladimir Tolmachev (Author)
• Format: Book
• Published: MDPI AG, 2022-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of this study was to test in an animal model a hypothesis that the second-generation HER2-targeting Affibody molecule ¹⁸⁸Re-ZHER2:41071 might be useful for treatment of HER2-expressing malignant tumors. ZHER2:41071 was efficiently labeled with a beta-emitting radionuclide rhenium-188 (¹⁸⁸Re). ¹⁸⁸Re-ZHER2:41071 demonstrated preserved specificity and high affinity (K_D = 5 ± 3 pM) of binding to HER2-expressing cells. In vivo studies demonstrated rapid washout of ¹⁸⁸Re from kidneys. The uptake in HER2-expressing SKOV-3 xenografts was HER2-specific and significantly exceeded the renal uptake 4 h after injection and later. The median survival of mice, which were treated by three injections of 16 MBq ¹⁸⁸Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using ¹⁸⁸Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ.

Item Description

10.3390/pharmaceutics14051092
1999-4923