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Intrinsic physicochemical profile of marketed antibody-based biotherapeutics

Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable region...

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Autores principales: Ahmed, Lucky, Gupta, Priyanka, Martin, Kyle P., Scheer, Justin M., Nixon, Andrew E., Kumar, Sandeep
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449350/
https://www.ncbi.nlm.nih.gov/pubmed/34504010
http://dx.doi.org/10.1073/pnas.2020577118
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author Ahmed, Lucky
Gupta, Priyanka
Martin, Kyle P.
Scheer, Justin M.
Nixon, Andrew E.
Kumar, Sandeep
author_facet Ahmed, Lucky
Gupta, Priyanka
Martin, Kyle P.
Scheer, Justin M.
Nixon, Andrew E.
Kumar, Sandeep
author_sort Ahmed, Lucky
collection PubMed
description Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.
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spelling pubmed-84493502021-10-04 Intrinsic physicochemical profile of marketed antibody-based biotherapeutics Ahmed, Lucky Gupta, Priyanka Martin, Kyle P. Scheer, Justin M. Nixon, Andrew E. Kumar, Sandeep Proc Natl Acad Sci U S A Biological Sciences Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations. National Academy of Sciences 2021-09-14 2021-09-09 /pmc/articles/PMC8449350/ /pubmed/34504010 http://dx.doi.org/10.1073/pnas.2020577118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Ahmed, Lucky
Gupta, Priyanka
Martin, Kyle P.
Scheer, Justin M.
Nixon, Andrew E.
Kumar, Sandeep
Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title_full Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title_fullStr Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title_full_unstemmed Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title_short Intrinsic physicochemical profile of marketed antibody-based biotherapeutics
title_sort intrinsic physicochemical profile of marketed antibody-based biotherapeutics
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8449350/
https://www.ncbi.nlm.nih.gov/pubmed/34504010
http://dx.doi.org/10.1073/pnas.2020577118
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