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

Publication ,  Journal Article
Feng, Y; Meshaw, R; Zhao, X-G; Jannetti, S; Vaidyanathan, G; Zalutsky, MR
Published in: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
January 2023

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.

Duke Scholars

Published In

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

DOI

EISSN

1535-5667

ISSN

0161-5505

Publication Date

January 2023

Volume

64

Issue

1

Start / End Page

124 / 130

Related Subject Headings

  • Treatment Outcome
  • Single-Domain Antibodies
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Nuclear Medicine & Medical Imaging
  • Mice
  • Humans
  • Heterografts
  • Female
  • Cell Line, Tumor
 

Citation

APA
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ICMJE
MLA
NLM
Feng, Y., Meshaw, R., Zhao, X.-G., Jannetti, S., Vaidyanathan, G., & Zalutsky, M. R. (2023). Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain Antibody Fragment. Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine, 64(1), 124–130. https://doi.org/10.2967/jnumed.122.264071
Feng, Yutian, Rebecca Meshaw, Xiao-Guang Zhao, Stephen Jannetti, Ganesan Vaidyanathan, and Michael R. Zalutsky. “Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain Antibody Fragment.Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine 64, no. 1 (January 2023): 124–30. https://doi.org/10.2967/jnumed.122.264071.
Feng Y, Meshaw R, Zhao X-G, Jannetti S, Vaidyanathan G, Zalutsky MR. Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain Antibody Fragment. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2023 Jan;64(1):124–30.
Feng, Yutian, et al. “Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain Antibody Fragment.Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine, vol. 64, no. 1, Jan. 2023, pp. 124–30. Epmc, doi:10.2967/jnumed.122.264071.
Feng Y, Meshaw R, Zhao X-G, Jannetti S, Vaidyanathan G, Zalutsky MR. Effective Treatment of Human Breast Carcinoma Xenografts with Single-Dose 211At-Labeled Anti-HER2 Single-Domain Antibody Fragment. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2023 Jan;64(1):124–130.

Published In

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

DOI

EISSN

1535-5667

ISSN

0161-5505

Publication Date

January 2023

Volume

64

Issue

1

Start / End Page

124 / 130

Related Subject Headings

  • Treatment Outcome
  • Single-Domain Antibodies
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Nuclear Medicine & Medical Imaging
  • Mice
  • Humans
  • Heterografts
  • Female
  • Cell Line, Tumor