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Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers
Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated h...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864007/ https://www.ncbi.nlm.nih.gov/pubmed/35194100 http://dx.doi.org/10.1038/s41598-022-07006-9 |
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author | Feng, Yutian Meshaw, Rebecca McDougald, Darryl Zhou, Zhengyuan Zhao, Xiao-Guang Jannetti, Stephen A. Reiman, Robert E. Pippen, Erica Marjoram, Robin Schaal, Jeffrey L. Vaidyanathan, Ganesan Zalutsky, Michael R. |
author_facet | Feng, Yutian Meshaw, Rebecca McDougald, Darryl Zhou, Zhengyuan Zhao, Xiao-Guang Jannetti, Stephen A. Reiman, Robert E. Pippen, Erica Marjoram, Robin Schaal, Jeffrey L. Vaidyanathan, Ganesan Zalutsky, Michael R. |
author_sort | Feng, Yutian |
collection | PubMed |
description | Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[(131)I]iodobenzoate (iso-[(131)I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [(131)I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[(131)I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[(131)I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc(2)-iso-[(131)I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[(131)I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[(131)I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted. |
format | Online Article Text |
id | pubmed-8864007 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88640072022-02-23 Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers Feng, Yutian Meshaw, Rebecca McDougald, Darryl Zhou, Zhengyuan Zhao, Xiao-Guang Jannetti, Stephen A. Reiman, Robert E. Pippen, Erica Marjoram, Robin Schaal, Jeffrey L. Vaidyanathan, Ganesan Zalutsky, Michael R. Sci Rep Article Radiopharmaceutical therapy (RPT) is an attractive strategy for treatment of disseminated cancers including those overexpressing the HER2 receptor including breast, ovarian and gastroesophageal carcinomas. Single-domain antibody fragments (sdAbs) exemplified by the HER2-targeted VHH_1028 evaluated herein are attractive for RPT because they rapidly accumulate in tumor and clear faster from normal tissues than intact antibodies. In this study, VHH_1028 was labeled using the residualizing prosthetic agent N-succinimidyl 3-guanidinomethyl 5-[(131)I]iodobenzoate (iso-[(131)I]SGMIB) and its tissue distribution evaluated in the HER2-expressing SKOV-3 ovarian and BT474 breast carcinoma xenograft models. In head-to-head comparisons to [(131)I]SGMIB-2Rs15d, a HER2-targeted radiopharmaceutical currently under clinical investigation, iso-[(131)I]SGMIB-VHH_1028 exhibited significantly higher tumor uptake and significantly lower kidney accumulation. The results demonstrated 2.9 and 6.3 times more favorable tumor-to-kidney radiation dose ratios in the SKOV-3 and BT474 xenograft models, respectively. Iso-[(131)I]SGMIB-VHH_1028 was prepared using a solid-phase extraction method for purification of the prosthetic agent intermediate Boc(2)-iso-[(131)I]SGMIB that reproducibly scaled to therapeutic-level doses and obviated the need for its HPLC purification. Single-dose (SKOV-3) and multiple-dose (BT474) treatment regimens demonstrated that iso-[(131)I]SGMIB-VHH_1028 was well tolerated and provided significant tumor growth delay and survival prolongation. This study suggests that iso-[(131)I]SGMIB-VHH_1028 is a promising candidate for RPT of HER2-expressing cancers and further development is warranted. Nature Publishing Group UK 2022-02-22 /pmc/articles/PMC8864007/ /pubmed/35194100 http://dx.doi.org/10.1038/s41598-022-07006-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Feng, Yutian Meshaw, Rebecca McDougald, Darryl Zhou, Zhengyuan Zhao, Xiao-Guang Jannetti, Stephen A. Reiman, Robert E. Pippen, Erica Marjoram, Robin Schaal, Jeffrey L. Vaidyanathan, Ganesan Zalutsky, Michael R. Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title | Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title_full | Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title_fullStr | Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title_full_unstemmed | Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title_short | Evaluation of an (131)I-labeled HER2-specific single domain antibody fragment for the radiopharmaceutical therapy of HER2-expressing cancers |
title_sort | evaluation of an (131)i-labeled her2-specific single domain antibody fragment for the radiopharmaceutical therapy of her2-expressing cancers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8864007/ https://www.ncbi.nlm.nih.gov/pubmed/35194100 http://dx.doi.org/10.1038/s41598-022-07006-9 |
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