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Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries

The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularl...

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Autores principales: Dyson, Michael R., Masters, Edward, Pazeraitis, Deividas, Perera, Rajika L., Syrjanen, Johanna L., Surade, Sachin, Thorsteinson, Nels, Parthiban, Kothai, Jones, Philip C., Sattar, Maheen, Wozniak-Knopp, Gordana, Rueker, Florian, Leah, Rachael, McCafferty, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592150/
https://www.ncbi.nlm.nih.gov/pubmed/33103593
http://dx.doi.org/10.1080/19420862.2020.1829335
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author Dyson, Michael R.
Masters, Edward
Pazeraitis, Deividas
Perera, Rajika L.
Syrjanen, Johanna L.
Surade, Sachin
Thorsteinson, Nels
Parthiban, Kothai
Jones, Philip C.
Sattar, Maheen
Wozniak-Knopp, Gordana
Rueker, Florian
Leah, Rachael
McCafferty, John
author_facet Dyson, Michael R.
Masters, Edward
Pazeraitis, Deividas
Perera, Rajika L.
Syrjanen, Johanna L.
Surade, Sachin
Thorsteinson, Nels
Parthiban, Kothai
Jones, Philip C.
Sattar, Maheen
Wozniak-Knopp, Gordana
Rueker, Florian
Leah, Rachael
McCafferty, John
author_sort Dyson, Michael R.
collection PubMed
description The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularly as proteins are formulated at high concentrations, causing aggregation or polyreactivity. Such late-stage “developability” problems can lead to delay or failure in traversing the development process. Aggregation propensity is also correlated with increased immunogenicity, resulting in expensive, late-stage clinical failures. Using nucleases-directed integration, we have constructed large mammalian display libraries where each cell contains a single antibody gene/cell inserted at a single locus, thereby achieving transcriptional normalization. We show a strong correlation between poor biophysical properties and display level achieved in mammalian cells, which is not replicated by yeast display. Using two well-documented examples of antibodies with poor biophysical characteristics (MEDI-1912 and bococizumab), a library of variants was created based on surface hydrophobic and positive charge patches. Mammalian display was used to select for antibodies that retained target binding and permitted increased display level. The resultant variants exhibited reduced polyreactivity and reduced aggregation propensity. Furthermore, we show in the case of bococizumab that biophysically improved variants are less immunogenic than the parental molecule. Thus, mammalian display helps to address multiple developability issues during the earliest stages of lead discovery, thereby significantly de-risking the future development of protein drugs.
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spelling pubmed-75921502020-11-10 Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries Dyson, Michael R. Masters, Edward Pazeraitis, Deividas Perera, Rajika L. Syrjanen, Johanna L. Surade, Sachin Thorsteinson, Nels Parthiban, Kothai Jones, Philip C. Sattar, Maheen Wozniak-Knopp, Gordana Rueker, Florian Leah, Rachael McCafferty, John MAbs Report The early phase of protein drug development has traditionally focused on target binding properties leading to a desired mode of therapeutic action. As more protein therapeutics pass through the development pipeline; however, it is clear that non-optimal biophysical properties can emerge, particularly as proteins are formulated at high concentrations, causing aggregation or polyreactivity. Such late-stage “developability” problems can lead to delay or failure in traversing the development process. Aggregation propensity is also correlated with increased immunogenicity, resulting in expensive, late-stage clinical failures. Using nucleases-directed integration, we have constructed large mammalian display libraries where each cell contains a single antibody gene/cell inserted at a single locus, thereby achieving transcriptional normalization. We show a strong correlation between poor biophysical properties and display level achieved in mammalian cells, which is not replicated by yeast display. Using two well-documented examples of antibodies with poor biophysical characteristics (MEDI-1912 and bococizumab), a library of variants was created based on surface hydrophobic and positive charge patches. Mammalian display was used to select for antibodies that retained target binding and permitted increased display level. The resultant variants exhibited reduced polyreactivity and reduced aggregation propensity. Furthermore, we show in the case of bococizumab that biophysically improved variants are less immunogenic than the parental molecule. Thus, mammalian display helps to address multiple developability issues during the earliest stages of lead discovery, thereby significantly de-risking the future development of protein drugs. Taylor & Francis 2020-10-25 /pmc/articles/PMC7592150/ /pubmed/33103593 http://dx.doi.org/10.1080/19420862.2020.1829335 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Dyson, Michael R.
Masters, Edward
Pazeraitis, Deividas
Perera, Rajika L.
Syrjanen, Johanna L.
Surade, Sachin
Thorsteinson, Nels
Parthiban, Kothai
Jones, Philip C.
Sattar, Maheen
Wozniak-Knopp, Gordana
Rueker, Florian
Leah, Rachael
McCafferty, John
Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title_full Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title_fullStr Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title_full_unstemmed Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title_short Beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
title_sort beyond affinity: selection of antibody variants with optimal biophysical properties and reduced immunogenicity from mammalian display libraries
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592150/
https://www.ncbi.nlm.nih.gov/pubmed/33103593
http://dx.doi.org/10.1080/19420862.2020.1829335
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