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A novel mouse strain optimized for chronic human antibody administration

Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG f...

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Autores principales: Gupta, Aaron, Smith, Patrick, Bournazos, Stylianos, Ravetch, Jeffrey V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915995/
https://www.ncbi.nlm.nih.gov/pubmed/35235456
http://dx.doi.org/10.1073/pnas.2123002119
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author Gupta, Aaron
Smith, Patrick
Bournazos, Stylianos
Ravetch, Jeffrey V.
author_facet Gupta, Aaron
Smith, Patrick
Bournazos, Stylianos
Ravetch, Jeffrey V.
author_sort Gupta, Aaron
collection PubMed
description Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex–mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma.
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spelling pubmed-89159952022-09-02 A novel mouse strain optimized for chronic human antibody administration Gupta, Aaron Smith, Patrick Bournazos, Stylianos Ravetch, Jeffrey V. Proc Natl Acad Sci U S A Biological Sciences Therapeutic human IgG antibodies are routinely tested in mouse models of oncologic, infectious, and autoimmune diseases. However, assessing the efficacy and safety of long-term administration of these agents has been limited by endogenous anti-human IgG immune responses that act to clear human IgG from serum and relevant tissues, thereby reducing their efficacy and contributing to immune complex–mediated pathologies, confounding evaluation of potential toxicity. For this reason, human antibody treatment in mice is generally limited in duration and dosing, thus failing to recapitulate the potential clinical applications of these therapeutics. Here, we report the development of a mouse model that is tolerant of chronic human antibody administration. This model combines both a human IgG1 heavy chain knock-in and a full recapitulation of human Fc receptor (FcγR) expression, providing a unique platform for in vivo testing of human monoclonal antibodies with relevant receptors beyond the short term. Compared to controls, hIgG1 knock-in mice mount minimal anti-human IgG responses, allowing for the persistence of therapeutically active circulating human IgG even in the late stages of treatment in chronic models of immune thrombocytopenic purpura and metastatic melanoma. National Academy of Sciences 2022-03-02 2022-03-08 /pmc/articles/PMC8915995/ /pubmed/35235456 http://dx.doi.org/10.1073/pnas.2123002119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This 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
Gupta, Aaron
Smith, Patrick
Bournazos, Stylianos
Ravetch, Jeffrey V.
A novel mouse strain optimized for chronic human antibody administration
title A novel mouse strain optimized for chronic human antibody administration
title_full A novel mouse strain optimized for chronic human antibody administration
title_fullStr A novel mouse strain optimized for chronic human antibody administration
title_full_unstemmed A novel mouse strain optimized for chronic human antibody administration
title_short A novel mouse strain optimized for chronic human antibody administration
title_sort novel mouse strain optimized for chronic human antibody administration
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8915995/
https://www.ncbi.nlm.nih.gov/pubmed/35235456
http://dx.doi.org/10.1073/pnas.2123002119
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