T cell epitope mapping of secukinumab and ixekizumab in healthy donors

• Published in: mAbs Vol. 12; no. 1; p. 1707418
• Main Authors: Spindeldreher, Sebastian, Karle, Anette, Correia, Evelyne, Tenon, Maxime, Gottlieb, Sascha, Huber, Thomas, Maillere, Bernard, Kolbinger, Frank
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2020; Taylor & Francis Group
• Subjects: Antibodies, Monoclonal, Humanized - immunology; CD4-Positive T-Lymphocytes - immunology; Epitope Mapping; Epitopes, T-Lymphocyte - immunology; Healthy Volunteers; Humans; immunogenicity; Immunology; in vitro; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - immunology; ixekizumab; Life Sciences; Secukinumab; T cell lines; ixekizumab; MAPPs; in vitro; T cell lines; Secukinumab; epitope mapping; immunogenicity
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2019.1707418

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 immunogenicity potential compared with other monoclonal antibodies used to treat psoriasis and psoriatic arthritis, and a significantly lower 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 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 immunogenicity potential observed for ixekizumab . secukinumab.