title: Secukinumab, a novel anti-IL-17A antibody, shows low immunogenicity potential in human in vitro assays comparable to other marketed biotherapeutics with low clinical immunogenicity.
abstract: Secukinumab is a human monoclonal antibody that selectively targets interleukin-17A and has been demonstrated to be highly efficacious in the treatment of moderate to severe plaque psoriasis, starting at early time points, with a sustained effect and a favorable safety profile. Biotherapeutics--including monoclonal antibodies (mAbs)--can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in unwanted effects, including hypersensitivity reactions or compromised therapeutic efficacy. To gain insight into possible explanations for the clinically observed low immunogenicity of secukinumab, we evaluated its immunogenicity potential by applying 2 different in vitro assays: T-cell activation and major histocompatibility complex-associated peptide proteomics (MAPPs). For both assays, monocyte-derived dendritic cells (DCs) from healthy donors were exposed in vitro to biotherapeutic proteins. DCs naturally process proteins and present the derived peptides in the context of human leukocyte antigen (HLA)-class II. HLA-DR-associated biotherapeutic-derived peptides, representing potential T-cell epitopes, were identified in the MAPPs assay. In the T-cell assay, autologous CD4(+) T cells were co-cultured with secukinumab-exposed DCs and T-cell activation was measured by proliferation and interleukin-2 secretion. In the MAPPs analysis and T-cell activation assays, secukinumab consistently showed relatively low numbers of potential T-cell epitopes and low T-cell response rates, respectively, comparable to other biotherapeutics with known low clinical immunogenicity. In contrast, biotherapeutics with elevated clinical immunogenicity rates showed increased numbers of potential T-cell epitopes and increased T-cell response rates in T-cell activation assays, indicating an approximate correlation between in vitro assay results and clinical immunogenicity incidence.
authors.affiliation: a Novartis Pharma AG , Basel , Switzerland.
authors.forename: Anette
authors.initials: A
authors.lastname: Karle
authors.affiliation: a Novartis Pharma AG , Basel , Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Spindeldreher
authors.affiliation: a Novartis Pharma AG , Basel , Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Kolbinger
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004353:Drug Evaluation, Preclinical; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000494:pharmacology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018984:Epitopes, T-Lymphocyte; C508717:IL17A protein, human; D020381:Interleukin-17; C555450:secukinumab
keywords: AIN457; Anti-drug antibodies; IL-17A; T-cell assay; antigen presentation assay; dendritic cell; immunogenicity prediction; major histocompatibility complex-associated peptide proteomics; psoriasis; secukinumab
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