Cargando…

Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment

Antibody–drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with...

Descripción completa

Detalles Bibliográficos
Autores principales: Nader-Marta, Guilherme, Molinelli, Chiara, Debien, Véronique, Martins-Branco, Diogo, Aftimos, Philippe, de Azambuja, Evandro, Awada, Ahmad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331351/
https://www.ncbi.nlm.nih.gov/pubmed/37435563
http://dx.doi.org/10.1177/17588359231183679
_version_ 1785070239620268032
author Nader-Marta, Guilherme
Molinelli, Chiara
Debien, Véronique
Martins-Branco, Diogo
Aftimos, Philippe
de Azambuja, Evandro
Awada, Ahmad
author_facet Nader-Marta, Guilherme
Molinelli, Chiara
Debien, Véronique
Martins-Branco, Diogo
Aftimos, Philippe
de Azambuja, Evandro
Awada, Ahmad
author_sort Nader-Marta, Guilherme
collection PubMed
description Antibody–drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these ‘off-target effects’, such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment.
format Online
Article
Text
id pubmed-10331351
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher SAGE Publications
record_format MEDLINE/PubMed
spelling pubmed-103313512023-07-11 Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment Nader-Marta, Guilherme Molinelli, Chiara Debien, Véronique Martins-Branco, Diogo Aftimos, Philippe de Azambuja, Evandro Awada, Ahmad Ther Adv Med Oncol Review Antibody–drug conjugates (ADCs) are a class of antineoplastic agents whose structure is composed of three main components: a monoclonal antibody (mAB) targeting a specific target antigen, a cytotoxic payload, and a linker binding the antibody to the payload. By combining the specificity of mABs with the high potency of the payloads, ADCs constitute a smart drug delivery system with improved therapeutic index. After recognition and binding of the mAB to its target surface antigen, ADCs are internalized by endocytosis by the tumor cell, releasing the payloads into the cytoplasm, where they exert their cytotoxic activity, eventually leading to cell death. The composition of some of the new ADCs confers additional functional properties that allow expanding their activity to neighboring cells not expressing the target antigen, constituting a valuable strategy to overcome tumor heterogeneity. Some of these ‘off-target effects’, such as the bystander effect, are possibly the mechanism underlying the antitumor activity demonstrated in patients with low expression of the target antigens, which represents an important paradigm shift in anticancer targeted therapy. Three ADCs are currently approved for the treatment of breast cancer (BC); two anti-HER2 (human epidermal growth factor receptor 2) ADCs (trastuzumab emtansine and trastuzumab deruxtecan); and one Trop-2-targeted ADC (sacituzumab govitecan). Based on the unprecedented efficacy data demonstrated by these agents, ADCs have been incorporated as part of standard regimens for all subtypes of advanced BC, as well as for high-risk early HER2-positive BC. Despite the remarkable advances, several hurdles still remain to overcome, including the development of reliable biomarkers for patient selection, prevention, and management of potentially severe toxicities, ADC resistance mechanisms, post-ADC resistance patterns, and optimal treatment sequencing and combinations. In this review, we will summarize the currently available evidence related to the use of these agents, as well as explore the current landscape of ADC development for BC treatment. SAGE Publications 2023-07-08 /pmc/articles/PMC10331351/ /pubmed/37435563 http://dx.doi.org/10.1177/17588359231183679 Text en © The Author(s), 2023 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Review
Nader-Marta, Guilherme
Molinelli, Chiara
Debien, Véronique
Martins-Branco, Diogo
Aftimos, Philippe
de Azambuja, Evandro
Awada, Ahmad
Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title_full Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title_fullStr Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title_full_unstemmed Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title_short Antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
title_sort antibody–drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331351/
https://www.ncbi.nlm.nih.gov/pubmed/37435563
http://dx.doi.org/10.1177/17588359231183679
work_keys_str_mv AT nadermartaguilherme antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT molinellichiara antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT debienveronique antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT martinsbrancodiogo antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT aftimosphilippe antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT deazambujaevandro antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment
AT awadaahmad antibodydrugconjugatestheevolvingfieldoftargetedchemotherapyforbreastcancertreatment