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Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T cell epitopes

Karle, Anette, Spindeldreher, Sebastian, Maillere, Bernard, Hamze, Moustafa, Meunier, Sylvain, de Bourayne, Marie and Gdoura, Abdelaziz (2017) Impact of human sequences in variable domains of therapeutic antibodies on the location of CD4 T cell epitopes. Frontiers in immunology, 8. ISSN 1664-3224


Although humanization of therapeutic antibodies is widely used to mitigate their immunogenicity, the impact of humanization on T cell response to human(ized) antibodies remains largely unknown. We therefore characterized the peptide specificity of T cells raised against adalimumab (Adm), a human anti-TNF- antibody and natalizumab (Ntz), a humanized anti-integrin α4β1 antibody, both antibodies being immunogenic in patients. Adm-specific T cell response was limited to three regions (HCDR2, HCDR3 and LCDR2) and mainly targeted the HCDR3, which exhibited a broad HLA-DR binding specificity. In contrast, Ntz-specific T cell epitopes resided in HCDR1, HCDR2, HFR3, LCDR1 and LCDR2 but not in HCDR3 demonstrating the uniqueness of a T cell response against therapeutic antibodies. Peptide identification (MAPPs) from HLA-DR molecules of dendritic cells loaded with the antibodies revealed multiple length variants of the presented T cell epitopes across the different donors. Most of the T cell epitopes carry mutations with respect to the germline sequences indicating their potential role for immunogenicity. These data provide molecular determinants involved in the immunogenicity of Adm and Ntz and shed more light on the immunogenicity of human(ized) antibodies in general.

Item Type: Article
Keywords: IMI, innovative medicines initiative, MAPPs, T cell assay, ABIRISK
Date Deposited: 28 Nov 2023 00:46
Last Modified: 28 Nov 2023 00:46


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