Liu Yongsheng, Vorobyeva Anzhelika, Orlova Anna, Konijnenberg Mark W, Xu Tianqi, Bragina Olga, Loftenius Annika, Rosander Erica, Frejd Fredrik Y, Tolmachev Vladimir
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden.
Pharmaceutics. 2022 May 20;14(5):1092. doi: 10.3390/pharmaceutics14051092.
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.
HER2靶向放射性核素疗法可能有助于治疗乳腺癌、胃癌和卵巢癌，这些癌症尽管HER2表达水平仍然很高，但已对基于抗体和抗体药物偶联物的疗法产生耐药性。亲和体分子是基于非免疫球蛋白支架的小型靶向蛋白。本研究的目的是在动物模型中检验一个假设，即第二代HER2靶向亲和体分子188Re-ZHER2:41071可能对治疗HER2表达的恶性肿瘤有用。ZHER2:41071用发射β射线的放射性核素铼-188（188Re）进行了有效标记。188Re-ZHER2:41071对HER2表达细胞的结合显示出保留的特异性和高亲和力（KD = 5 ± 3 pM）。体内研究表明，188Re能快速从肾脏清除。注射后4小时及以后，HER2表达的SKOV-3异种移植瘤中的摄取是HER2特异性的，且显著超过肾脏摄取。用16 MBq 188Re-ZHER2:41071进行三次注射治疗的小鼠的中位生存期为68天，这明显长于用载体（29天）或未标记的ZHER2:41071（27.5天）治疗的对照组小鼠的生存期（对数秩Mantel-Cox检验中P<0.0001）。总之，使用188Re-ZHER2:41071的实验性放射性核素疗法可提高患有人类肿瘤小鼠的生存期，且对关键器官肾脏无毒性。
