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Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform

We herein report the development and evaluation of a novel HER2-targeting antibody–drug conjugate (ADC) based on the topoisomerase I inhibitor payload exatecan, using our hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform (PSARlink). In vitro and in vivo experiments were conducted in...

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Autores principales: Conilh, Louise, Fournet, Guy, Fourmaux, Eric, Murcia, Angélique, Matera, Eva-Laure, Joseph, Benoît, Dumontet, Charles, Viricel, Warren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000490/
https://www.ncbi.nlm.nih.gov/pubmed/33803327
http://dx.doi.org/10.3390/ph14030247
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author Conilh, Louise
Fournet, Guy
Fourmaux, Eric
Murcia, Angélique
Matera, Eva-Laure
Joseph, Benoît
Dumontet, Charles
Viricel, Warren
author_facet Conilh, Louise
Fournet, Guy
Fourmaux, Eric
Murcia, Angélique
Matera, Eva-Laure
Joseph, Benoît
Dumontet, Charles
Viricel, Warren
author_sort Conilh, Louise
collection PubMed
description We herein report the development and evaluation of a novel HER2-targeting antibody–drug conjugate (ADC) based on the topoisomerase I inhibitor payload exatecan, using our hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform (PSARlink). In vitro and in vivo experiments were conducted in breast and gastric cancer models to characterize this original ADC and gain insight about the drug-linker structure–activity relationship. The inclusion of the PSAR hydrophobicity masking entity efficiently reduced the overall hydrophobicity of the conjugate and yielded an ADC sharing the same pharmacokinetic profile as the unconjugated antibody despite the high drug-load of the camptothecin-derived payload (drug–antibody ratio of 8). Tra-Exa-PSAR10 demonstrated strong anti-tumor activity at 1 mg/kg in an NCI-N87 xenograft model, outperforming the FDA-approved ADC DS-8201a (Enhertu), while being well tolerated in mice at a dose of 100 mg/kg. In vitro experiments showed that this exatecan-based ADC demonstrated higher bystander killing effect than DS-8201a and overcame resistance to T-DM1 (Kadcyla) in preclinical HER2+ breast and esophageal models, suggesting potential activity in heterogeneous and resistant tumors. In summary, the polysarcosine-based hydrophobicity masking approach allowsfor the generation of highly conjugated exatecan-based ADCs having excellent physicochemical properties, an improved pharmacokinetic profile, and potent in vivo anti-tumor activity.
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spelling pubmed-80004902021-03-28 Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform Conilh, Louise Fournet, Guy Fourmaux, Eric Murcia, Angélique Matera, Eva-Laure Joseph, Benoît Dumontet, Charles Viricel, Warren Pharmaceuticals (Basel) Article We herein report the development and evaluation of a novel HER2-targeting antibody–drug conjugate (ADC) based on the topoisomerase I inhibitor payload exatecan, using our hydrophilic monodisperse polysarcosine (PSAR) drug-linker platform (PSARlink). In vitro and in vivo experiments were conducted in breast and gastric cancer models to characterize this original ADC and gain insight about the drug-linker structure–activity relationship. The inclusion of the PSAR hydrophobicity masking entity efficiently reduced the overall hydrophobicity of the conjugate and yielded an ADC sharing the same pharmacokinetic profile as the unconjugated antibody despite the high drug-load of the camptothecin-derived payload (drug–antibody ratio of 8). Tra-Exa-PSAR10 demonstrated strong anti-tumor activity at 1 mg/kg in an NCI-N87 xenograft model, outperforming the FDA-approved ADC DS-8201a (Enhertu), while being well tolerated in mice at a dose of 100 mg/kg. In vitro experiments showed that this exatecan-based ADC demonstrated higher bystander killing effect than DS-8201a and overcame resistance to T-DM1 (Kadcyla) in preclinical HER2+ breast and esophageal models, suggesting potential activity in heterogeneous and resistant tumors. In summary, the polysarcosine-based hydrophobicity masking approach allowsfor the generation of highly conjugated exatecan-based ADCs having excellent physicochemical properties, an improved pharmacokinetic profile, and potent in vivo anti-tumor activity. MDPI 2021-03-09 /pmc/articles/PMC8000490/ /pubmed/33803327 http://dx.doi.org/10.3390/ph14030247 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Conilh, Louise
Fournet, Guy
Fourmaux, Eric
Murcia, Angélique
Matera, Eva-Laure
Joseph, Benoît
Dumontet, Charles
Viricel, Warren
Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title_full Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title_fullStr Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title_full_unstemmed Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title_short Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform
title_sort exatecan antibody drug conjugates based on a hydrophilic polysarcosine drug-linker platform
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000490/
https://www.ncbi.nlm.nih.gov/pubmed/33803327
http://dx.doi.org/10.3390/ph14030247
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