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Immunogenicity Risk Profile of Nanobodies

Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affini...

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Autores principales: Ackaert, Chloé, Smiejkowska, Natalia, Xavier, Catarina, Sterckx, Yann G. J., Denies, Sofie, Stijlemans, Benoit, Elkrim, Yvon, Devoogdt, Nick, Caveliers, Vicky, Lahoutte, Tony, Muyldermans, Serge, Breckpot, Karine, Keyaerts, Marleen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985456/
https://www.ncbi.nlm.nih.gov/pubmed/33767701
http://dx.doi.org/10.3389/fimmu.2021.632687
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author Ackaert, Chloé
Smiejkowska, Natalia
Xavier, Catarina
Sterckx, Yann G. J.
Denies, Sofie
Stijlemans, Benoit
Elkrim, Yvon
Devoogdt, Nick
Caveliers, Vicky
Lahoutte, Tony
Muyldermans, Serge
Breckpot, Karine
Keyaerts, Marleen
author_facet Ackaert, Chloé
Smiejkowska, Natalia
Xavier, Catarina
Sterckx, Yann G. J.
Denies, Sofie
Stijlemans, Benoit
Elkrim, Yvon
Devoogdt, Nick
Caveliers, Vicky
Lahoutte, Tony
Muyldermans, Serge
Breckpot, Karine
Keyaerts, Marleen
author_sort Ackaert, Chloé
collection PubMed
description Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required. In this study, we assessed the immunogenicity risk profile of two Nbs that are in phase II clinical trials: a first Nb against Human Epidermal growth factor Receptor 2 (HER2) for PET imaging of breast cancer and a second Nb with specificity to the Macrophage Mannose Receptor (MMR) for PET imaging of tumor-associated macrophages. For the anti-HER2 Nb, we show that only one out of 20 patients had a low amount of pre-existing anti-drug antibodies (ADAs), which only marginally increased 3 months after administering the Nb, and without negative effects of safety and pharmacokinetics. Further in vitro immunogenicity assessment assays showed that both non-humanized Nbs were taken up by human dendritic cells but exhibited no or only a marginal capacity to activate dendritic cells or to induce T cell proliferation. From our data, we conclude that monomeric Nbs present a low immunogenicity risk profile, which is encouraging for their future development toward potential clinical applications. ONE SENTENCE SUMMARY: Nanobodies, the recombinant single domain affinity reagents derived from heavy chain-only antibodies in camelids, are proven to possess a low immunogenicity risk profile, which will facilitate a growing number of Nanobodies to enter the clinic for therapeutic or in vivo diagnostic applications.
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spelling pubmed-79854562021-03-24 Immunogenicity Risk Profile of Nanobodies Ackaert, Chloé Smiejkowska, Natalia Xavier, Catarina Sterckx, Yann G. J. Denies, Sofie Stijlemans, Benoit Elkrim, Yvon Devoogdt, Nick Caveliers, Vicky Lahoutte, Tony Muyldermans, Serge Breckpot, Karine Keyaerts, Marleen Front Immunol Immunology Nanobodies (Nbs), the variable domains of camelid heavy chain-only antibodies, are a promising class of therapeutics or in vivo imaging reagents entering the clinic. They possess unique characteristics, including a minimal size, providing fast pharmacokinetics, high-target specificity, and an affinity in the (sub-)nanomolar range in conjunction with an easy selection and production, which allow them to outperform conventional antibodies for imaging and radiotherapeutic purposes. As for all protein theranostics, extended safety assessment and investigation of their possible immunogenicity in particular are required. In this study, we assessed the immunogenicity risk profile of two Nbs that are in phase II clinical trials: a first Nb against Human Epidermal growth factor Receptor 2 (HER2) for PET imaging of breast cancer and a second Nb with specificity to the Macrophage Mannose Receptor (MMR) for PET imaging of tumor-associated macrophages. For the anti-HER2 Nb, we show that only one out of 20 patients had a low amount of pre-existing anti-drug antibodies (ADAs), which only marginally increased 3 months after administering the Nb, and without negative effects of safety and pharmacokinetics. Further in vitro immunogenicity assessment assays showed that both non-humanized Nbs were taken up by human dendritic cells but exhibited no or only a marginal capacity to activate dendritic cells or to induce T cell proliferation. From our data, we conclude that monomeric Nbs present a low immunogenicity risk profile, which is encouraging for their future development toward potential clinical applications. ONE SENTENCE SUMMARY: Nanobodies, the recombinant single domain affinity reagents derived from heavy chain-only antibodies in camelids, are proven to possess a low immunogenicity risk profile, which will facilitate a growing number of Nanobodies to enter the clinic for therapeutic or in vivo diagnostic applications. Frontiers Media S.A. 2021-03-09 /pmc/articles/PMC7985456/ /pubmed/33767701 http://dx.doi.org/10.3389/fimmu.2021.632687 Text en Copyright © 2021 Ackaert, Smiejkowska, Xavier, Sterckx, Denies, Stijlemans, Elkrim, Devoogdt, Caveliers, Lahoutte, Muyldermans, Breckpot and Keyaerts. http://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
Ackaert, Chloé
Smiejkowska, Natalia
Xavier, Catarina
Sterckx, Yann G. J.
Denies, Sofie
Stijlemans, Benoit
Elkrim, Yvon
Devoogdt, Nick
Caveliers, Vicky
Lahoutte, Tony
Muyldermans, Serge
Breckpot, Karine
Keyaerts, Marleen
Immunogenicity Risk Profile of Nanobodies
title Immunogenicity Risk Profile of Nanobodies
title_full Immunogenicity Risk Profile of Nanobodies
title_fullStr Immunogenicity Risk Profile of Nanobodies
title_full_unstemmed Immunogenicity Risk Profile of Nanobodies
title_short Immunogenicity Risk Profile of Nanobodies
title_sort immunogenicity risk profile of nanobodies
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985456/
https://www.ncbi.nlm.nih.gov/pubmed/33767701
http://dx.doi.org/10.3389/fimmu.2021.632687
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