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Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule
Yongsheng Liu1, Anzhelika Vorobyeva1, Anna Orlova2
1Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
Abstract:
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 (KD = 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.
Insights
HER2-targeted radionuclide therapy using 188Re-ZHER2:41071 shows promise for treating resistant HER2-expressing cancers. This novel approach significantly improved survival in animal models without causing kidney toxicity.
Area of Science:
- Oncology
- Nuclear Medicine
- Biotechnology
Background:
- HER2-positive cancers (breast, gastric, ovarian) can become resistant to existing therapies.
- Affibody molecules offer a small-molecule alternative for targeted therapy.
- Radionuclide therapy utilizes radioactive isotopes for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy and safety of a second-generation HER2-targeting Affibody molecule, 188Re-ZHER2:41071, in an animal model.
- To test the hypothesis that 188Re-ZHER2:41071 can effectively treat HER2-expressing tumors.
Main Methods:
- ZHER2:41071 Affibody molecule was labeled with the beta-emitting radionuclide rhenium-188 (188Re).
- Binding affinity and specificity of 188Re-ZHER2:41071 to HER2-expressing cells were assessed.
- In vivo studies involved administering 188Re-ZHER2:41071 to mice with HER2-expressing xenografts and monitoring tumor uptake, kidney washout, and survival.
Main Results:
- 188Re-ZHER2:41071 demonstrated high affinity (KD = 5 ± 3 pM) and specificity for HER2-expressing cells.
- Rapid clearance from kidneys was observed, with HER2-specific tumor uptake exceeding renal uptake.
- Mice treated with 188Re-ZHER2:41071 showed significantly prolonged median survival (68 days) compared to control groups (29-27.5 days).
Conclusions:
- 188Re-ZHER2:41071 is a promising candidate for HER2-targeted radionuclide therapy.
- This therapy can enhance survival in HER2-expressing tumors.
- The treatment demonstrated a favorable safety profile with no observed kidney toxicity.
