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.

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.

Figure 1.

Secukinumab exhibits low levels of T-cell responses in a low number of donors. Scatter plot showing the proliferation stimulation index (SI) data (A) and interleukin (IL)-2 enzyme-linked immunospot (ELISpot) SI data (B) from 50 donors incubated with the 6 test samples and humanized A33. Horizontal black lines represent mean values and red-dashed line indicates statistically significant SI ≥1 .9. Summary of T-cell proliferation SI and IL-2 ELISpot SI data for all values where SI ≥1 .9 and P<0.05 (C).

Figure 2.

Consistent cluster maps were generated across secukinumab preparations. Major histocompatibility complex–associated peptide proteomics cluster map of human leukocyte antigen-DR–associated peptides produced by 1.5 × 10⁶ dendritic cells from 9 different donors exposed to 3 different secukinumab preparations. Clusters are indicated as black boxes, Complementarity-determining regions are indicated as shaded areas along the sequence of constant domains in heavy chain (CH; left) and light chain (CL; right) above each monoclonal antibody. H, hinge region.

Figure 3.

Cluster maps vary across different therapeutic antibodies. Major histocompatibility complex–associated peptide proteomics cluster map of human leukocyte antigen-DR–associated peptides produced by 1.5 × 10⁶ dendritic cells from 10 different donors exposed separately to 5 different therapeutic antibodies is shown. Clusters are indicated as black boxes, Complementarity-determining regions are indicated as shaded areas along the sequence of heavy chain (CH; left) and light chain (CL; right) above each monoclonal antibody. H, hinge region.

Figure 4.

Secukinumab contains low numbers of different and total clusters. For comparison of the 3 independent sets (indicated by different symbols) of 10 donors each, different and total clusters for each biotherapeutic were quantified and normalized to adalimumab (100%) as an arbitrary reference. Average normalized cluster responses (C) were obtained from the normalized values of different (A) and total (B) clusters, averaging both values. The horizontal line indicates the mean of the 3 individual values. MAPPs, major histocompatibility complex–associated peptide proteomics.

Figure 5.

Consistent results from major histocompatibility complex–associated peptide proteomics (MAPPs) and T-cell assays. T-cell assay responses for each biotherapeutic from a total of 50 donors were plotted vs MAPPs average normalized cluster responses from a total of 30 donors.