Introduction of Non-natural Amino Acids Into T-Cell Epitopes to Mitigate Peptide-Specific T-Cell Responses

Frontiers in Immunology

Bernard Maillère¹  Catherine Prades²  Stephane Illiano³  Olivier Duclos⁴  Sergio Mallart⁴  Aurélien Azam⁶ 

[1] Metabolism, Chilly-Mazarin, France;;D, Cardiovascular Diseases &D, Integrated Drug Discovery, Chilly-Mazarin, France;;Sanofi R&Sanofi, Biologics Research, Vitry-sur-Seine, France;Université de Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, SIMoS, Gif-sur-Yvette, France;

关键词: non-natural amino acids;    immunogenicity;    HLA class II molecules;    CD4 T-cell response;    T-cell epitope;   

DOI  :  10.3389/fimmu.2021.637963

来源: DOAJ

【 摘 要 】

Non-natural modifications are widely introduced into peptides to improve their therapeutic efficacy, but their impact on immunogenicity remains largely unknown. As the CD4 T-cell response is a key factor in triggering immunogenicity, we investigated the effect of introducing D-amino acids (Daa), amino isobutyric acid (Aib), N-methylation, Cα-methylation, reduced amide, and peptoid bonds into an immunoprevalent T-cell epitope on binding to a set of HLA-DR molecules, recognition, and priming of human T cells. Modifications are differentially accepted at multiple positions, but are all tolerated in the flanking regions. Introduction of Aib and Daa in the binding core had the most deleterious effect on binding to HLA-DR molecules and T-cell activation. Their introduction at the positions close to the P1 anchor residue abolished T-cell priming, suggesting they might be sufficient to dampen peptide immunogenicity. Other modifications led to variable effects on binding to HLA-DR molecules and T-cell reactivity, but none exhibited an increased ability to stimulate T cells. Altogether, non-natural modifications appear generally to diminish binding to HLA-DR molecules and hence T-cell stimulation. These data might guide the design of therapeutic peptides to make them less immunogenic.

【 授权许可】

Unknown