Cargando…
Site-specific antibody drug conjugates for cancer therapy
Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929453/ https://www.ncbi.nlm.nih.gov/pubmed/24423619 http://dx.doi.org/10.4161/mabs.27022 |
_version_ | 1782304393929949184 |
---|---|
author | Panowski, Siler Bhakta, Sunil Raab, Helga Polakis, Paul Junutula, Jagath R |
author_facet | Panowski, Siler Bhakta, Sunil Raab, Helga Polakis, Paul Junutula, Jagath R |
author_sort | Panowski, Siler |
collection | PubMed |
description | Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors—target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris(®)) and ado-trastuzumab emtansine (Kadcyla(®)). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0–8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics. |
format | Online Article Text |
id | pubmed-3929453 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-39294532014-03-05 Site-specific antibody drug conjugates for cancer therapy Panowski, Siler Bhakta, Sunil Raab, Helga Polakis, Paul Junutula, Jagath R MAbs Review Antibody therapeutics have revolutionized the treatment of cancer over the past two decades. Antibodies that specifically bind tumor surface antigens can be effective therapeutics; however, many unmodified antibodies lack therapeutic activity. These antibodies can instead be applied successfully as guided missiles to deliver potent cytotoxic drugs in the form of antibody drug conjugates (ADCs). The success of ADCs is dependent on four factors—target antigen, antibody, linker, and payload. The field has made great progress in these areas, marked by the recent approval by the US Food and Drug Administration of two ADCs, brentuximab vedotin (Adcetris(®)) and ado-trastuzumab emtansine (Kadcyla(®)). However, the therapeutic window for many ADCs that are currently in pre-clinical or clinical development remains narrow and further improvements may be required to enhance the therapeutic potential of these ADCs. Production of ADCs is an area where improvement is needed because current methods yield heterogeneous mixtures that may include 0–8 drug species per antibody molecule. Site-specific conjugation has been recently shown to eliminate heterogeneity, improve conjugate stability, and increase the therapeutic window. Here, we review and describe various site-specific conjugation strategies that are currently used for the production of ADCs, including use of engineered cysteine residues, unnatural amino acids, and enzymatic conjugation through glycotransferases and transglutaminases. In addition, we also summarize differences among these methods and highlight critical considerations when building next-generation ADC therapeutics. Taylor & Francis 2013-11-01 2014-01-01 /pmc/articles/PMC3929453/ /pubmed/24423619 http://dx.doi.org/10.4161/mabs.27022 Text en Copyright © 2014 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited. |
spellingShingle | Review Panowski, Siler Bhakta, Sunil Raab, Helga Polakis, Paul Junutula, Jagath R Site-specific antibody drug conjugates for cancer therapy |
title | Site-specific antibody drug conjugates for cancer therapy |
title_full | Site-specific antibody drug conjugates for cancer therapy |
title_fullStr | Site-specific antibody drug conjugates for cancer therapy |
title_full_unstemmed | Site-specific antibody drug conjugates for cancer therapy |
title_short | Site-specific antibody drug conjugates for cancer therapy |
title_sort | site-specific antibody drug conjugates for cancer therapy |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929453/ https://www.ncbi.nlm.nih.gov/pubmed/24423619 http://dx.doi.org/10.4161/mabs.27022 |
work_keys_str_mv | AT panowskisiler sitespecificantibodydrugconjugatesforcancertherapy AT bhaktasunil sitespecificantibodydrugconjugatesforcancertherapy AT raabhelga sitespecificantibodydrugconjugatesforcancertherapy AT polakispaul sitespecificantibodydrugconjugatesforcancertherapy AT junutulajagathr sitespecificantibodydrugconjugatesforcancertherapy |