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Antibody–drug conjugates as novel anti-cancer chemotherapeutics

Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and...

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Detalles Bibliográficos
Autores principales: Peters, Christina, Brown, Stuart
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613712/
https://www.ncbi.nlm.nih.gov/pubmed/26182432
http://dx.doi.org/10.1042/BSR20150089
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author Peters, Christina
Brown, Stuart
author_facet Peters, Christina
Brown, Stuart
author_sort Peters, Christina
collection PubMed
description Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.
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spelling pubmed-46137122015-11-02 Antibody–drug conjugates as novel anti-cancer chemotherapeutics Peters, Christina Brown, Stuart Biosci Rep Review Articles Over the past couple of decades, antibody–drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics. Portland Press Ltd. 2015-07-14 /pmc/articles/PMC4613712/ /pubmed/26182432 http://dx.doi.org/10.1042/BSR20150089 Text en © 2015 Authors http://creativecommons.org/licenses/by/3.0/ This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Review Articles
Peters, Christina
Brown, Stuart
Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title_full Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title_fullStr Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title_full_unstemmed Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title_short Antibody–drug conjugates as novel anti-cancer chemotherapeutics
title_sort antibody–drug conjugates as novel anti-cancer chemotherapeutics
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613712/
https://www.ncbi.nlm.nih.gov/pubmed/26182432
http://dx.doi.org/10.1042/BSR20150089
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