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CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate
PURPOSE: Triple-negative breast cancer (TNBC) is phenotypic of breast tumors lacking expression of the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER2). The paucity of well-defined molecular targets in TNBC, coupled with the increasing...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465649/ https://www.ncbi.nlm.nih.gov/pubmed/37432459 http://dx.doi.org/10.1007/s00432-023-05031-3 |
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author | Mungra, Neelakshi Biteghe, Fleury A. N. Malindi, Zaria Huysamen, Allan M. Karaan, Maryam Hardcastle, Natasha S. Bunjun, Rubina Chetty, Shivan Naran, Krupa Lang, Dirk Richter, Wolfgang Hunter, Roger Barth, Stefan |
author_facet | Mungra, Neelakshi Biteghe, Fleury A. N. Malindi, Zaria Huysamen, Allan M. Karaan, Maryam Hardcastle, Natasha S. Bunjun, Rubina Chetty, Shivan Naran, Krupa Lang, Dirk Richter, Wolfgang Hunter, Roger Barth, Stefan |
author_sort | Mungra, Neelakshi |
collection | PubMed |
description | PURPOSE: Triple-negative breast cancer (TNBC) is phenotypic of breast tumors lacking expression of the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER2). The paucity of well-defined molecular targets in TNBC, coupled with the increasing burden of breast cancer-related mortality, emphasizes the need to develop targeted diagnostics and therapeutics. While antibody–drug conjugates (ADCs) have emerged as revolutionary tools in the selective delivery of drugs to malignant cells, their widespread clinical use has been hampered by traditional strategies which often give rise to heterogeneous mixtures of ADC products. METHODS: Utilizing SNAP-tag technology as a cutting-edge site-specific conjugation method, a chondroitin sulfate proteoglycan 4 (CSPG4)-targeting ADC was engineered, encompassing a single-chain antibody fragment (scFv) conjugated to auristatin F (AURIF) via a click chemistry strategy. RESULTS: After showcasing the self-labeling potential of the SNAP-tag component, surface binding and internalization of the fluorescently labeled product were demonstrated on CSPG4-positive TNBC cell lines through confocal microscopy and flow cytometry. The cell-killing ability of the novel AURIF-based recombinant ADC was illustrated by the induction of a 50% reduction in cell viability at nanomolar to micromolar concentrations on target cell lines. CONCLUSION: This research underscores the applicability of SNAP-tag in the unambiguous generation of homogeneous and pharmaceutically relevant immunoconjugates that could potentially be instrumental in the management of a daunting disease like TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-023-05031-3. |
format | Online Article Text |
id | pubmed-10465649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-104656492023-08-31 CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate Mungra, Neelakshi Biteghe, Fleury A. N. Malindi, Zaria Huysamen, Allan M. Karaan, Maryam Hardcastle, Natasha S. Bunjun, Rubina Chetty, Shivan Naran, Krupa Lang, Dirk Richter, Wolfgang Hunter, Roger Barth, Stefan J Cancer Res Clin Oncol Research PURPOSE: Triple-negative breast cancer (TNBC) is phenotypic of breast tumors lacking expression of the estrogen receptor (ER), the progesterone receptor (PgR), and the human epidermal growth factor receptor 2 (HER2). The paucity of well-defined molecular targets in TNBC, coupled with the increasing burden of breast cancer-related mortality, emphasizes the need to develop targeted diagnostics and therapeutics. While antibody–drug conjugates (ADCs) have emerged as revolutionary tools in the selective delivery of drugs to malignant cells, their widespread clinical use has been hampered by traditional strategies which often give rise to heterogeneous mixtures of ADC products. METHODS: Utilizing SNAP-tag technology as a cutting-edge site-specific conjugation method, a chondroitin sulfate proteoglycan 4 (CSPG4)-targeting ADC was engineered, encompassing a single-chain antibody fragment (scFv) conjugated to auristatin F (AURIF) via a click chemistry strategy. RESULTS: After showcasing the self-labeling potential of the SNAP-tag component, surface binding and internalization of the fluorescently labeled product were demonstrated on CSPG4-positive TNBC cell lines through confocal microscopy and flow cytometry. The cell-killing ability of the novel AURIF-based recombinant ADC was illustrated by the induction of a 50% reduction in cell viability at nanomolar to micromolar concentrations on target cell lines. CONCLUSION: This research underscores the applicability of SNAP-tag in the unambiguous generation of homogeneous and pharmaceutically relevant immunoconjugates that could potentially be instrumental in the management of a daunting disease like TNBC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-023-05031-3. Springer Berlin Heidelberg 2023-07-11 2023 /pmc/articles/PMC10465649/ /pubmed/37432459 http://dx.doi.org/10.1007/s00432-023-05031-3 Text en © The Author(s) 2023 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 | Research Mungra, Neelakshi Biteghe, Fleury A. N. Malindi, Zaria Huysamen, Allan M. Karaan, Maryam Hardcastle, Natasha S. Bunjun, Rubina Chetty, Shivan Naran, Krupa Lang, Dirk Richter, Wolfgang Hunter, Roger Barth, Stefan CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title | CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title_full | CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title_fullStr | CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title_full_unstemmed | CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title_short | CSPG4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant SNAP-tag-based antibody-auristatin F drug conjugate |
title_sort | cspg4 as a target for the specific killing of triple-negative breast cancer cells by a recombinant snap-tag-based antibody-auristatin f drug conjugate |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10465649/ https://www.ncbi.nlm.nih.gov/pubmed/37432459 http://dx.doi.org/10.1007/s00432-023-05031-3 |
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