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T cell epitope mapping of secukinumab and ixekizumab in healthy donors

Spindeldreher, Sebastian and Karle, Anette and Correia, Evelyne and Tenon, Maxime and Gottlieb, Sascha and Huber, Thomas and Maillere, Bernard and Kolbinger, Frank (2020) T cell epitope mapping of secukinumab and ixekizumab in healthy donors. mAbs, 12 (1). ISSN 19420870

Abstract

Secukinumab, a human monoclonal antibody that selectively neutralizes IL-17A, has consistently shown low
anti-drug antibody responses in patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis.
Secukinumab has also shown lower in vitro immunogenicity potential compared with other monoclonal
antibodies used to treat psoriasis and psoriatic arthritis, and a significantly lower in vitro T cell precursor
frequency compared with ixekizumab, which targets the same antigen. Here, secukinumab and ixekizumab
were further examined regarding their specific T cell epitopes. Secukinumab- or ixekizumab-specific CD4 T
cell lines were generated from 31 healthy, treatment-naïve donors via 28-day co-culture with mature
monocyte-derived dendritic cells exposed to either antibody. Consistent with previous data, the frequency
of preexisting T cells to secukinumab was significantly lower as compared with ixekizumab. Only two T cell
lines from two different donors could be derived for secukinumab, but no specific T cell epitope was
identified. In contrast, 32 T cell lines from eight donors were obtained for ixekizumab. For 11 of these T cell lines, the specific T cell epitopes could be identified and confirmed by major histocompatibility complex–associated peptide proteomics as being naturally presented peptides. All identified T cell Epitopes cluster in four main regions that are overlapping with the complementarity-determining regions HCDR3, LCDR1, LCDR2 and LCDR3. Interestingly, ixekizumab CDRs contain amino acids that are not found in any of the germline family members. These amino acids may be associated with the higher number of T cell epitopes identified for ixekizumab light chain and may contribute to the increased in vitro immunogenicity potential observed for ixekizumab vs. secukinumab.

Item Type: Article
Keywords: epitope mapping immunogenicity in vitro ixekizumab MAPPs Secukinumab T cell lines
Date Deposited: 04 Feb 2020 00:45
Last Modified: 04 Feb 2020 00:45
URI: https://oak.novartis.com/id/eprint/41065

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