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In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance

In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting mo...

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Autores principales: Shan, Lu, Dyk, Nydia Van, Haskins, Nantaporn, Cook, Kimberly M., Rosenthal, Kim L., Mazor, Ronit, Dragulin-Otto, Sonia, Jiang, Yu, Wu, Herren, Dall’Acqua, William F., Borrok, Martin J., Damschroder, Melissa M., Oganesyan, Vaheh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426389/
https://www.ncbi.nlm.nih.gov/pubmed/34497355
http://dx.doi.org/10.1038/s42003-021-02565-5
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author Shan, Lu
Dyk, Nydia Van
Haskins, Nantaporn
Cook, Kimberly M.
Rosenthal, Kim L.
Mazor, Ronit
Dragulin-Otto, Sonia
Jiang, Yu
Wu, Herren
Dall’Acqua, William F.
Borrok, Martin J.
Damschroder, Melissa M.
Oganesyan, Vaheh
author_facet Shan, Lu
Dyk, Nydia Van
Haskins, Nantaporn
Cook, Kimberly M.
Rosenthal, Kim L.
Mazor, Ronit
Dragulin-Otto, Sonia
Jiang, Yu
Wu, Herren
Dall’Acqua, William F.
Borrok, Martin J.
Damschroder, Melissa M.
Oganesyan, Vaheh
author_sort Shan, Lu
collection PubMed
description In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting molecules. Here we report a structure-guided approach to engineer monomeric Fc molecules to adapt multiple versions of half-life extension modifications. Co-crystal structures of these monomeric Fc variants with Fc neonatal receptor (FcRn) shed light into the binding interactions that could serve as a guide for engineering the half-life of antibody Fc fragments. These engineered monomeric Fc molecules also enabled the generation of a novel monovalent bispecific molecular design, which translated the FcRn binding enhancement to improvement of in vivo serum half-life.
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spelling pubmed-84263892021-09-22 In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance Shan, Lu Dyk, Nydia Van Haskins, Nantaporn Cook, Kimberly M. Rosenthal, Kim L. Mazor, Ronit Dragulin-Otto, Sonia Jiang, Yu Wu, Herren Dall’Acqua, William F. Borrok, Martin J. Damschroder, Melissa M. Oganesyan, Vaheh Commun Biol Article In a biologic therapeutic landscape that requires versatility in targeting specificity, valency and half-life modulation, the monomeric Fc fusion platform holds exciting potential for the creation of a class of monovalent protein therapeutics that includes fusion proteins and bispecific targeting molecules. Here we report a structure-guided approach to engineer monomeric Fc molecules to adapt multiple versions of half-life extension modifications. Co-crystal structures of these monomeric Fc variants with Fc neonatal receptor (FcRn) shed light into the binding interactions that could serve as a guide for engineering the half-life of antibody Fc fragments. These engineered monomeric Fc molecules also enabled the generation of a novel monovalent bispecific molecular design, which translated the FcRn binding enhancement to improvement of in vivo serum half-life. Nature Publishing Group UK 2021-09-08 /pmc/articles/PMC8426389/ /pubmed/34497355 http://dx.doi.org/10.1038/s42003-021-02565-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Shan, Lu
Dyk, Nydia Van
Haskins, Nantaporn
Cook, Kimberly M.
Rosenthal, Kim L.
Mazor, Ronit
Dragulin-Otto, Sonia
Jiang, Yu
Wu, Herren
Dall’Acqua, William F.
Borrok, Martin J.
Damschroder, Melissa M.
Oganesyan, Vaheh
In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title_full In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title_fullStr In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title_full_unstemmed In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title_short In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance
title_sort in vivo pharmacokinetic enhancement of monomeric fc and monovalent bispecific designs through structural guidance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426389/
https://www.ncbi.nlm.nih.gov/pubmed/34497355
http://dx.doi.org/10.1038/s42003-021-02565-5
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