2022-05-26·Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single Domain Antibody Fragment.
作者: Yutian Feng ; Rebecca Meshaw ; Xiao-Guang Zhao ; Stephen A Jannetti ; Ganesan Vaidyanathan ; Michael R Zalutsky
Single-domain antibody fragments (sdAbs) are attractive for targeted α-particle therapy (TAT), particularly with 211At, because of their rapid accumulation in tumor and clearance from normal tissues. Here, we evaluate the therapeutic potential of this strategy with 5F7 and VHH_1028 - two sdAbs that bind with high affinity to Domain IV of human epidermal growth factor receptor type 2 (HER2). Methods: The HER2-specific sdAbs and HER2-irrelevant VHH_2001 were labeled using N-succinimidyl 3-[211At]astato-5-guanidinomethyl benzoate (iso-[211At]SAGMB). The cytotoxicity of iso-[211At]SAGMB-5F7 and iso-[211At]SAGMB-VHH_2001 were compared on HER2-expressing BT474 breast carcinoma cells. Three experiments in mice with subcutaneous BT474 xenografts were performed to evaluate the therapeutic effectiveness of single doses of 1) iso-[211At]SAGMB-5F7 (0.7-3.0 MBq), 2) iso-[211At]SAGMB-VHH_1028 (1.0-3.0 MBq), and 3) iso-[211At]SAGMB-VHH_1028 and iso-[211At]SAGMB-VHH_2001 (~1.0 MBq). Results: Clonogenic survival of BT474 cells was reduced after exposure to iso-[211At]SAGMB-5F7 (D0=1.313 kBq/mL) while iso-[211At]SAGMB-VHH_2001 was ineffective. Dose-dependent tumor growth inhibition was observed with 211At-labeled HER2-specific 5F7 and VHH_1028 but not with HER2-irrelevant VHH_2001. At the 3.0 MBq dose, complete tumor regression was seen in 3 of 4 mice treated with iso-[211At]SAGMB-5F7 and 8 of 11 mice treated with iso-[211At]SAGMB-VHH_1028; prolongation in median survival was 495% and 414%, respectively. Conclusion: Combining rapidly internalizing, high-affinity HER2-targeted sdAbs with the iso-[211At]SAGMB residualizing prosthetic agent is a promising strategy for TAT of HER2-expressing cancers.