Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211 At-Labeled Anti-HER2 Single-Domain Antibody Fragment

The Journal of Nuclear Medicine

article

Yutian Feng¹  Rebecca Meshaw¹  Xiao-Guang Zhao¹  Stephen Jannetti¹  Ganesan Vaidyanathan¹  Michael R. Zalutsky¹ 

[1] Department of Radiology, Duke University Medical Center

关键词: single-domain antibody fragment;    α-emitter;    radiopharmaceutical therapy;    211At;    HER2;    nanobody;   

DOI  :  10.2967/jnumed.122.264071

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Single-domain antibody fragments (sdAbs) are attractive for targeted α-particle therapy, 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—2 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 iso-211At-SAGMB-5F7 (0.7–3.0 MBq), iso-211At-SAGMB-VHH_1028 (1.0–3.0 MBq), and 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) whereas 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 targeted α-particle therapy of HER2-expressing cancers.

【 授权许可】

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