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

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.

Radionuclide Therapy of HER2-Expressing Xenografts Using [177Lu]Lu-ABY-027 Affibody Molecule Alone and in Combination with Trastuzumab

“…In Affibody-mediated pretargeting, a therapeutic radionuclide is coupled to a small hapten with low reabsorption in kidneys [25,26]. The use of non-residualizing 131 I [27] and 188 Re [28] labels does not prevent reabsorption but promotes the very rapid release of radiometabolites of Affibody molecules from kidneys. A fusion with ABD and subsequent binding to albumin in vivo makes an Affibody-containing therapeutic construct bigger than 65 kDa and prevents or reduces its passage through the glomerular membrane [15].…”

Radiopharmaceuticals for Cancer Imaging and Therapy

“…Dewulf et al, from the university of Antwerp, reported a novel RANKL PET imaging agent, [ 64 Cu]Cu-NOTA-denos-Fab, that allows for fast tumor imaging with improved imaging contrast when compared with its antibody counterpart, showing promise as a potential PET RANKL imaging tool for future clinical applications [ 3 ]. Researchers from the university of Uppsala further illustrated the potential of radiolabeled affibody molecules for both diagnostic and therapeutic applications, with promising results [ 4 , 5 , 6 ].…”