Related Experiment Video
Updated: Sep 22, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain
Yutian Feng1, Rebecca Meshaw1, Xiao-Guang Zhao1
1Department of Radiology, Duke University Medical Center, Durham, North Carolina.
Abstract:
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.
Insights
Single-domain antibody fragments (sdAbs) targeting HER2 show promise for alpha-particle therapy. This study demonstrates significant tumor regression and survival extension in HER2-expressing cancers using 211At-labeled sdAbs.
Area of Science:
- Oncology
- Radiopharmaceuticals
- Immunotherapy
Background:
- Single-domain antibody fragments (sdAbs) offer rapid tumor accumulation and clearance from normal tissues, making them suitable for targeted alpha-particle therapy.
- Human epidermal growth factor receptor type 2 (HER2) is a validated target in several cancers, including breast carcinoma.
Purpose of the Study:
- To evaluate the therapeutic potential of 211At-labeled HER2-specific sdAbs (5F7 and VHH_1028) for targeted alpha-particle therapy.
- To assess the efficacy of these sdAbs in HER2-expressing cancer models.
Main Methods:
- HER2-specific sdAbs (5F7, VHH_1028) and a HER2-irrelevant control (VHH_2001) were labeled with 211At using the residualizing prosthetic agent iso-211At-SAGMB.
- Cytotoxicity was assessed on HER2-expressing BT474 breast carcinoma cells.
- Therapeutic effectiveness was evaluated in mouse xenograft models using single doses of the radiolabeled sdAbs.
Main Results:
- Iso-211At-SAGMB-5F7 significantly reduced clonogenic survival of BT474 cells, while the control VHH_2001 was ineffective.
- Dose-dependent tumor growth inhibition was observed with 211At-labeled HER2-specific sdAbs.
- Complete tumor regression was achieved in a significant proportion of mice treated with iso-211At-SAGMB-5F7 and iso-211At-SAGMB-VHH_1028, leading to substantial increases in median survival.
Conclusions:
- The combination of rapidly internalizing, high-affinity HER2-targeted sdAbs with the iso-211At-SAGMB prosthetic agent is a promising strategy.
- This approach holds potential for the targeted alpha-particle therapy of HER2-expressing cancers.
