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Systems Biology Programme Coline Sivelle

Systems Biology Programme Coline Sivelle

19/09/2019
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Systems Biology Programme Coline Sivelle

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19/09/201912:00631Systems Biology ProgrammeColine SivelleUniversity of Paris-Saclay, Institute Frederic Joliot"Dealing with immunogenicity: design of adalimumab mutants with reduced immunogenicity potential and increased activity"Host: Lehner, BenAbstract:Efficacy of anti-TNFa is well known to be potentially affected by their immunogenicity as the produced anti-drug antibodies (ADA) could neutralize their activity and elicit adverse effects. Adalimumab (Humira®), which is the most used anti-TNFa, is reported to be immunogenic for up to 54% of patients. Unfortunately, T-cell epitopes that account for its immunogenicity are mostly carried by regions implied in the interaction with TNFa. Thus, T-cell epitope removal can be very deleterious for the functionality of the biologic. To undertake this issue, we propose to use Yeast Surface Display (YSD) to monitor the affinity of the biologic during the mutagenesis. Our strategy, based on T-cell epitope removal, first merged 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 were combined to obtain libraries pre-enriched with functional sequences. Mutants with reduced immunogenic potential were then identified from these libraries by screening. From these libraries we identified several mutants of adalimumab with reduced immunogenicity potential according to HLA II binding prediction. Three mutants were further characterized and show an increased affinity for TNFa associated with an improvement of activity of two fold comparing to adalimumab. These promising mutants of adalimumab could be less subject to ADA production when administered to patients, in order to validate this hypothesis T-cell assays will be performed.