Cargando…

Does human homology reduce the potential immunogenicity of non-antibody scaffolds?

Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have...

Descripción completa

Detalles Bibliográficos
Autores principales: De Groot, Anne S., Khan, Sundos, Mattei, Aimee E., Lelias, Sandra, Martin, William D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664710/
https://www.ncbi.nlm.nih.gov/pubmed/38022550
http://dx.doi.org/10.3389/fimmu.2023.1215939
_version_ 1785138676970291200
author De Groot, Anne S.
Khan, Sundos
Mattei, Aimee E.
Lelias, Sandra
Martin, William D.
author_facet De Groot, Anne S.
Khan, Sundos
Mattei, Aimee E.
Lelias, Sandra
Martin, William D.
author_sort De Groot, Anne S.
collection PubMed
description Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use.
format Online
Article
Text
id pubmed-10664710
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-106647102023-01-01 Does human homology reduce the potential immunogenicity of non-antibody scaffolds? De Groot, Anne S. Khan, Sundos Mattei, Aimee E. Lelias, Sandra Martin, William D. Front Immunol Immunology Biologics developers are moving beyond antibodies for delivery of a wide range of therapeutic interventions. These non-antibody modalities are often based on ‘natural’ protein scaffolds that are modified to deliver bioactive sequences. Both human-derived and non-human-sourced scaffold proteins have been developed. New types of “non-antibody” scaffolds are still being discovered, as they offer attractive alternatives to monoclonals due to their smaller size, improved stability, and ease of synthesis. They are believed to have low immunogenic potential. However, while several human-sourced protein scaffolds have not been immunogenic in clinical studies, this may not predict their overall performance in other therapeutic applications. A preliminary evaluation of their potential for immunogenicity is warranted. Immunogenicity risk potential has been clearly linked to the presence of T “helper” epitopes in the sequence of biologic therapeutics. In addition, tolerogenic epitopes are present in some human proteins and may decrease their immunogenic potential. While the detailed sequences of many non-antibody scaffold therapeutic candidates remain unpublished, their backbone sequences are available for review and analysis. We assessed 12 example non-antibody scaffold backbone sequences using our epitope-mapping tools (EpiMatrix) for this perspective. Based on EpiMatrix scoring, their HLA DRB1-restricted T cell epitope content appears to be lower than the average protein, and sequences that may act as tolerogenic epitopes are present in selected human-derived scaffolds. Assessing the potential immunogenicity of scaffold proteins regarding self and non-self T cell epitopes may be of use for drug developers and clinicians, as these exciting new non-antibody molecules begin to emerge from the preclinical pipeline into clinical use. Frontiers Media S.A. 2023-11-07 /pmc/articles/PMC10664710/ /pubmed/38022550 http://dx.doi.org/10.3389/fimmu.2023.1215939 Text en Copyright © 2023 De Groot, Khan, Mattei, Lelias and Martin https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
De Groot, Anne S.
Khan, Sundos
Mattei, Aimee E.
Lelias, Sandra
Martin, William D.
Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title_full Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title_fullStr Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title_full_unstemmed Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title_short Does human homology reduce the potential immunogenicity of non-antibody scaffolds?
title_sort does human homology reduce the potential immunogenicity of non-antibody scaffolds?
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664710/
https://www.ncbi.nlm.nih.gov/pubmed/38022550
http://dx.doi.org/10.3389/fimmu.2023.1215939
work_keys_str_mv AT degrootannes doeshumanhomologyreducethepotentialimmunogenicityofnonantibodyscaffolds
AT khansundos doeshumanhomologyreducethepotentialimmunogenicityofnonantibodyscaffolds
AT matteiaimeee doeshumanhomologyreducethepotentialimmunogenicityofnonantibodyscaffolds
AT leliassandra doeshumanhomologyreducethepotentialimmunogenicityofnonantibodyscaffolds
AT martinwilliamd doeshumanhomologyreducethepotentialimmunogenicityofnonantibodyscaffolds