A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.

Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies...

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Autores principales:	Joanne Lin, Stacey L Lee, Anna M Russell, Rong Fong Huang, Micheal A Batt, Shawn S Chang, Andrea Ferrante, Petra Verdino
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b3a2ef3195954b0488eb8607de448e39
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spelling	oai:doaj.org-article:b3a2ef3195954b0488eb8607de448e392021-12-02T20:06:30ZA structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.1932-620310.1371/journal.pone.0254944https://doaj.org/article/b3a2ef3195954b0488eb8607de448e392021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254944https://doaj.org/toc/1932-6203Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies (TE-ADA) and presence of pre-existing ADA in drug-naïve individuals as risk-profiling strategies. Pre-existing ADAs are routinely identified during clinical immunogenicity assessment, but their origin and impact on drug safety and efficacy have not been fully elucidated. One specific class of pre-existing ADAs has been described, which targets neoepitopes of antibody fragments, including Fabs, VH, or VHH domains in isolation from their IgG context. With the increasing number of antibody fragments and other small binding scaffolds entering the clinic, a widely applicable method to mitigate pre-existing reactivity against these molecules is desirable. Here is described a structure-based engineering approach to abrogate pre-existing ADA reactivity to the C-terminal neoepitope of VH(H)s. On the basis of 3D structures, small modifications applicable to any VH(H) are devised that would not impact developability or antigen binding. In-silico B cell epitope mapping algorithms were used to rank the modified VHH variants by antigenicity; however, the limited discriminating capacity of the computational methods prompted an experimental evaluation of the engineered molecules. The results identified numerous modifications capable of reducing pre-existing ADA binding. The most efficient consisted of the addition of two proline residues at the VHH C-terminus, which led to no detectable pre-existing ADA reactivity while maintaining favorable developability characteristics. The method described, and the modifications identified thereby, may provide a broadly applicable solution to mitigate immunogenicity risk of antibody-fragments in the clinic and increase safety and efficacy of this promising new class of biotherapeutics.Joanne LinStacey L LeeAnna M RussellRong Fong HuangMicheal A BattShawn S ChangAndrea FerrantePetra VerdinoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254944 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Joanne Lin Stacey L Lee Anna M Russell Rong Fong Huang Micheal A Batt Shawn S Chang Andrea Ferrante Petra Verdino A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
description	Development of biotherapeutics is hampered by the inherent risk of immunogenicity, which requires extensive clinical assessment and possible re-engineering efforts for mitigation. The focus in the pre-clinical phase is to determine the likelihood of developing treatment-emergent anti-drug antibodies (TE-ADA) and presence of pre-existing ADA in drug-naïve individuals as risk-profiling strategies. Pre-existing ADAs are routinely identified during clinical immunogenicity assessment, but their origin and impact on drug safety and efficacy have not been fully elucidated. One specific class of pre-existing ADAs has been described, which targets neoepitopes of antibody fragments, including Fabs, VH, or VHH domains in isolation from their IgG context. With the increasing number of antibody fragments and other small binding scaffolds entering the clinic, a widely applicable method to mitigate pre-existing reactivity against these molecules is desirable. Here is described a structure-based engineering approach to abrogate pre-existing ADA reactivity to the C-terminal neoepitope of VH(H)s. On the basis of 3D structures, small modifications applicable to any VH(H) are devised that would not impact developability or antigen binding. In-silico B cell epitope mapping algorithms were used to rank the modified VHH variants by antigenicity; however, the limited discriminating capacity of the computational methods prompted an experimental evaluation of the engineered molecules. The results identified numerous modifications capable of reducing pre-existing ADA binding. The most efficient consisted of the addition of two proline residues at the VHH C-terminus, which led to no detectable pre-existing ADA reactivity while maintaining favorable developability characteristics. The method described, and the modifications identified thereby, may provide a broadly applicable solution to mitigate immunogenicity risk of antibody-fragments in the clinic and increase safety and efficacy of this promising new class of biotherapeutics.
format	article
author	Joanne Lin Stacey L Lee Anna M Russell Rong Fong Huang Micheal A Batt Shawn S Chang Andrea Ferrante Petra Verdino
author_facet	Joanne Lin Stacey L Lee Anna M Russell Rong Fong Huang Micheal A Batt Shawn S Chang Andrea Ferrante Petra Verdino
author_sort	Joanne Lin
title	A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
title_short	A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
title_full	A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
title_fullStr	A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
title_full_unstemmed	A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
title_sort	structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/b3a2ef3195954b0488eb8607de448e39
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_version_	1718375382705504256

A structure-based engineering approach to abrogate pre-existing antibody binding to biotherapeutics.

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