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You searched for subject:(deimmunization). Showing records 1 – 2 of 2 total matches.

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1. Sivelle, Coline. Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment.

Degree: Docteur es, Immunologie, 2019, Université Paris-Saclay (ComUE)

L’efficacité des anticorps anti-TNFα peut être particulièrement affectée par leur immunogénicité. Elle se traduit par la production d’anticorps dirigés contre la protéine thérapeutique (ADA) et induisant des effets indésirables. Pour l’adalimumab (Humira®), qui est l’anti-TNFα le plus utilisé, ce phénomène est observé chez plus de 30% des patients pour certaines pathologies. Les épitopes T responsables de cette immunogénicité sont principalement localisés dans les régions CDR impliquées dans l’interaction avec le TNFα. L’objectif de ce travail est de retirer les séquences épitopes T de l’anticorps sans altérer sa fonctionnalité. Afin de maitriser ce problème d’immunogénicité, ces travaux de thèse proposent d’utiliser le Yeast Surface Display (YSD) afin de contrôler la fonctionnalité de l’anticorps tout au long du processus de mutagénèse. Pour cela, une première étape de comparaison des différents formats d’expression d’anticorps en YSD a permis de définir le format d’affichage à utiliser pour la suite du projet. La stratégie de déimmunisation adoptée ensuite est basée sur la suppression des épitopes T. Dans un premier temps, elle réunit une approche de mutagénèse exhaustive (DMS) et l’utilisation d’algorithme afin d’identifier les substitutions délétères pour l’interaction HLA II/épitope T, mais neutre pour la fonction de l’anticorps. Dans un second temps, ces substitutions sont combinées dans des banques pré-enrichies en mutants fonctionnels. Des mutants ayant une immunogénicité potentielle réduite ont ensuite été sélectionnés à partir de ces banques. Plusieurs mutants de l’adalimumab à l’immunogénicité réduite selon l’algorithme de prédiction ont été identifiés et caractérisés. Ils possèdent tous une affinité augmentée pour le TNFα se traduisant par une activité au moins doublée par rapport à l’adalimumab.

Efficacy of anti-TNFα antibodies is well known to be affected by their immunogenicity. Some patients developp anti-drug antibodies (ADA) which can elicit adverse effects and neutralize the therapeutic protein. Adalimumab (Humira®), which is the most used anti-TNFα, is reported to be immunogenic for more than 30% of patients in some diseases. T-cell epitopes that account for its immunogenicity are mostly carried by regions implied in the interaction with TNFα. In the present work, we propose to remove T-cell epitopes from the antibody sequence while maintaining its functionality.To undertake this issue, this PhD project uses Yeast Surface Display (YSD) to monitor the affinity of the biologic during the mutagenesis process. To do so, a comparison of different expression formats of antibody in YSD has been performed in order to define the format that will be used for the deimmunization method. Then, the strategy chosen to reduce immunogenicity is based on T-cell epitopes removal. First, it merges deep mutational scanning and in silico HLA II binding prediction to identify substitutions deleterious for HLA II/T-cell epitopes interaction while neutral for the function of the biologic. Secondly, these substitutions…

Advisors/Committee Members: Maillère, Bernard (thesis director).

Subjects/Keywords: Immunogénicité; Déimmunisation; Epitopes T; Adalimumab; Ingénierie des protéines; Expression à la surface de levure; Immunogenicity; Deimmunization; T-Celle epitopes; Adalimumab; Protein engineering; Yeast Surface Display

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Sivelle, C. (2019). Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2019SACLS603

Chicago Manual of Style (16th Edition):

Sivelle, Coline. “Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment.” 2019. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed January 27, 2021. http://www.theses.fr/2019SACLS603.

MLA Handbook (7th Edition):

Sivelle, Coline. “Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment.” 2019. Web. 27 Jan 2021.

Vancouver:

Sivelle C. Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2019. [cited 2021 Jan 27]. Available from: http://www.theses.fr/2019SACLS603.

Council of Science Editors:

Sivelle C. Conception et production d’anticorps anti-TNFa non immunogènes pour le traitement des maladies inflammatoires : Conception and production of non-immunogenic anti-TNFa antibodies for inflammatory diseases treatment. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2019. Available from: http://www.theses.fr/2019SACLS603

2. King, Chris. Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions.

Degree: PhD, 2014, University of Washington

Proteins possess huge potential as therapeutic agents for the control and modulation of human physiology. Protein interactions regulate most physiological processes, mediating the connection between atomic-­scale self­-assembly and macroscale health and disease. Natural proteins often display exquisite specificity and high affinity for molecular targets while avoiding detection and elimination by the host immune system. The design of synthetic, non­-natural proteins to bind these molecular targets presents the opportunity to suppress, regulate, or enhance the cellular control processes underlying the physiology of both normal and disease states. Here, we demonstrate the development, application, and testing of computational protein design algorithms to predict protein-­binding specificity, model the energetics of designed protein interactions, and reduce the immunogenicity of protein therapeutics. Advisors/Committee Members: Baker, David (advisor).

Subjects/Keywords: biotherapeutics; deimmunization; machine learning; molecular modeling; protein design; Biochemistry; Bioinformatics; Biophysics; biological chemistry

…published deimmunization effort in 2002 [15]. Here, alanine… …methods. Deimmunization of protein therapeutics is a rapidly changing… 

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

King, C. (2014). Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/25382

Chicago Manual of Style (16th Edition):

King, Chris. “Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions.” 2014. Doctoral Dissertation, University of Washington. Accessed January 27, 2021. http://hdl.handle.net/1773/25382.

MLA Handbook (7th Edition):

King, Chris. “Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions.” 2014. Web. 27 Jan 2021.

Vancouver:

King C. Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions. [Internet] [Doctoral dissertation]. University of Washington; 2014. [cited 2021 Jan 27]. Available from: http://hdl.handle.net/1773/25382.

Council of Science Editors:

King C. Computational Design of Protein Therapeutics with Reduced Immunogenicity through Structural Modeling of Protein Interactions. [Doctoral Dissertation]. University of Washington; 2014. Available from: http://hdl.handle.net/1773/25382

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