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Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay

Antibody–drug conjugate (ADC) linkers play an important role in determining the safety and efficacy of ADC. The Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linker is a newly developed linker in the form of a di-aryl sulfate structure consisting of phenolic payload and self-immolative group (SIG). I...

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Autores principales: Lee, Byeong ill, Park, Seo-jin, Park, Yuri, Shin, Seok-Ho, Choi, Jang-mi, Park, Min-jae, Lim, Jeong-hyeon, Kim, Sun Young, Lee, Hyangsook, Shin, Young G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836004/
https://www.ncbi.nlm.nih.gov/pubmed/33478046
http://dx.doi.org/10.3390/pharmaceutics13010125
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author Lee, Byeong ill
Park, Seo-jin
Park, Yuri
Shin, Seok-Ho
Choi, Jang-mi
Park, Min-jae
Lim, Jeong-hyeon
Kim, Sun Young
Lee, Hyangsook
Shin, Young G.
author_facet Lee, Byeong ill
Park, Seo-jin
Park, Yuri
Shin, Seok-Ho
Choi, Jang-mi
Park, Min-jae
Lim, Jeong-hyeon
Kim, Sun Young
Lee, Hyangsook
Shin, Young G.
author_sort Lee, Byeong ill
collection PubMed
description Antibody–drug conjugate (ADC) linkers play an important role in determining the safety and efficacy of ADC. The Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linker is a newly developed linker in the form of a di-aryl sulfate structure consisting of phenolic payload and self-immolative group (SIG). In this study, using two bioanalytical approaches (namely “bottom-up” and “middle-up” approaches) via the liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method, in vitro and in vivo linker stability experiments were conducted for the OHPAS linker. For comparison, the valine-citrulline-p-aminobenzyloxycarbonyl (VC-PABC) linker was also evaluated under the same experimental conditions. In addition, the catabolite identification experiments at the subunit intact protein level were simultaneously performed to evaluate the catabolic fate of ADCs. As a result, the OHPAS linker was stable in the in vitro mouse/human plasma as well as in vivo pharmacokinetic studies in mice, whereas the VC-PABC linker was relatively unstable in mice in vitro and in vivo. This is because the VC-PABC linker was sensitive to a hydrolytic enzyme called carboxylesterase 1c (Ces1c) in mouse plasma. In conclusion, the OHPAS linker appears to be a good linker for ADC, and further experiments would be warranted to demonstrate the efficacy and toxicity related to the OHPAS linker.
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spelling pubmed-78360042021-01-27 Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay Lee, Byeong ill Park, Seo-jin Park, Yuri Shin, Seok-Ho Choi, Jang-mi Park, Min-jae Lim, Jeong-hyeon Kim, Sun Young Lee, Hyangsook Shin, Young G. Pharmaceutics Article Antibody–drug conjugate (ADC) linkers play an important role in determining the safety and efficacy of ADC. The Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linker is a newly developed linker in the form of a di-aryl sulfate structure consisting of phenolic payload and self-immolative group (SIG). In this study, using two bioanalytical approaches (namely “bottom-up” and “middle-up” approaches) via the liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method, in vitro and in vivo linker stability experiments were conducted for the OHPAS linker. For comparison, the valine-citrulline-p-aminobenzyloxycarbonyl (VC-PABC) linker was also evaluated under the same experimental conditions. In addition, the catabolite identification experiments at the subunit intact protein level were simultaneously performed to evaluate the catabolic fate of ADCs. As a result, the OHPAS linker was stable in the in vitro mouse/human plasma as well as in vivo pharmacokinetic studies in mice, whereas the VC-PABC linker was relatively unstable in mice in vitro and in vivo. This is because the VC-PABC linker was sensitive to a hydrolytic enzyme called carboxylesterase 1c (Ces1c) in mouse plasma. In conclusion, the OHPAS linker appears to be a good linker for ADC, and further experiments would be warranted to demonstrate the efficacy and toxicity related to the OHPAS linker. MDPI 2021-01-19 /pmc/articles/PMC7836004/ /pubmed/33478046 http://dx.doi.org/10.3390/pharmaceutics13010125 Text en © 2021 by the authors. 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/).
spellingShingle Article
Lee, Byeong ill
Park, Seo-jin
Park, Yuri
Shin, Seok-Ho
Choi, Jang-mi
Park, Min-jae
Lim, Jeong-hyeon
Kim, Sun Young
Lee, Hyangsook
Shin, Young G.
Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title_full Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title_fullStr Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title_full_unstemmed Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title_short Assessments of the In Vitro and In Vivo Linker Stability and Catabolic Fate for the Ortho Hydroxy-Protected Aryl Sulfate Linker by Immuno-Affinity Capture Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometric Assay
title_sort assessments of the in vitro and in vivo linker stability and catabolic fate for the ortho hydroxy-protected aryl sulfate linker by immuno-affinity capture liquid chromatography quadrupole time-of-flight mass spectrometric assay
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836004/
https://www.ncbi.nlm.nih.gov/pubmed/33478046
http://dx.doi.org/10.3390/pharmaceutics13010125
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