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High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice

Although improvements in technology for the isolation of potential therapeutic antibodies have made the process increasingly predictable, the development of biologically active monoclonal antibodies (mAbs) into drugs can often be impeded by developability issues such as poor expression, solubility,...

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Autores principales: Kelly, Ryan L, Sun, Tingwan, Jain, Tushar, Caffry, Isabelle, Yu, Yao, Cao, Yuan, Lynaugh, Heather, Brown, Michael, Vásquez, Maximiliano, Wittrup, K Dane, Xu, Yingda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622737/
https://www.ncbi.nlm.nih.gov/pubmed/26047159
http://dx.doi.org/10.1080/19420862.2015.1043503
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author Kelly, Ryan L
Sun, Tingwan
Jain, Tushar
Caffry, Isabelle
Yu, Yao
Cao, Yuan
Lynaugh, Heather
Brown, Michael
Vásquez, Maximiliano
Wittrup, K Dane
Xu, Yingda
author_facet Kelly, Ryan L
Sun, Tingwan
Jain, Tushar
Caffry, Isabelle
Yu, Yao
Cao, Yuan
Lynaugh, Heather
Brown, Michael
Vásquez, Maximiliano
Wittrup, K Dane
Xu, Yingda
author_sort Kelly, Ryan L
collection PubMed
description Although improvements in technology for the isolation of potential therapeutic antibodies have made the process increasingly predictable, the development of biologically active monoclonal antibodies (mAbs) into drugs can often be impeded by developability issues such as poor expression, solubility, and promiscuous cross-reactivity. Establishing early stage developability screening assays capable of predicting late stage behavior is therefore of high value to minimize development risks. Toward this goal, we selected a panel of 16 monoclonal antibodies (mAbs) representing different developability profiles, in terms of self- and cross-interaction propensity, and examined their downstream behavior from expression titer to accelerated stability and pharmacokinetics in mice. Clearance rates showed significant rank-order correlations to 2 cross-interaction related assays, with the closest correlation to a non-specificity assay on the surface of yeast. Additionally, 2 self-association assays correlated with each other but not to mouse clearance rate. This case study suggests that combining assays capable of high throughput screening of self- and cross-interaction early in the discovery stage could significantly lower downstream development risks.
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spelling pubmed-46227372016-02-03 High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice Kelly, Ryan L Sun, Tingwan Jain, Tushar Caffry, Isabelle Yu, Yao Cao, Yuan Lynaugh, Heather Brown, Michael Vásquez, Maximiliano Wittrup, K Dane Xu, Yingda MAbs Report Although improvements in technology for the isolation of potential therapeutic antibodies have made the process increasingly predictable, the development of biologically active monoclonal antibodies (mAbs) into drugs can often be impeded by developability issues such as poor expression, solubility, and promiscuous cross-reactivity. Establishing early stage developability screening assays capable of predicting late stage behavior is therefore of high value to minimize development risks. Toward this goal, we selected a panel of 16 monoclonal antibodies (mAbs) representing different developability profiles, in terms of self- and cross-interaction propensity, and examined their downstream behavior from expression titer to accelerated stability and pharmacokinetics in mice. Clearance rates showed significant rank-order correlations to 2 cross-interaction related assays, with the closest correlation to a non-specificity assay on the surface of yeast. Additionally, 2 self-association assays correlated with each other but not to mouse clearance rate. This case study suggests that combining assays capable of high throughput screening of self- and cross-interaction early in the discovery stage could significantly lower downstream development risks. Taylor & Francis 2015-06-05 /pmc/articles/PMC4622737/ /pubmed/26047159 http://dx.doi.org/10.1080/19420862.2015.1043503 Text en © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Report
Kelly, Ryan L
Sun, Tingwan
Jain, Tushar
Caffry, Isabelle
Yu, Yao
Cao, Yuan
Lynaugh, Heather
Brown, Michael
Vásquez, Maximiliano
Wittrup, K Dane
Xu, Yingda
High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title_full High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title_fullStr High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title_full_unstemmed High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title_short High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice
title_sort high throughput cross-interaction measures for human igg1 antibodies correlate with clearance rates in mice
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622737/
https://www.ncbi.nlm.nih.gov/pubmed/26047159
http://dx.doi.org/10.1080/19420862.2015.1043503
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