Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus

Abstract

Objectives: To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose and multiple-dose administration of AMG 557, a human anti-inducible T cell co-stimulator ligand (ICOSL) monoclonal antibody, in subjects with systemic lupus erythematosus (SLE).

Methods: Patients with mild, stable SLE (n=112) were enrolled in two clinical trials to evaluate the effects of single (1.8-210 mg subcutaneous or 18 mg intravenous) and multiple (6 -210 mg subcutaneous every other week (Q2W)×7) doses of AMG 557. Subjects received two 1 mg intradermal injections 28 days apart of keyhole limpet haemocyanin (KLH), a neoantigen, to assess PD effects of AMG 557. Safety, PK, target occupancy, anti-KLH antibody responses, lymphocyte subset analyses and SLE-associated biomarkers and clinical outcomes were assessed.

Results: AMG 557 demonstrated an acceptable safety profile. The PK properties were consistent with an antibody directed against a cell surface target, with non-linear PK observed at lower concentrations and linear PK at higher concentrations. Target occupancy by AMG 557 was dose dependent and reversible, and maximal occupancy was achieved in the setting of this trial. Anti-AMG 557 antibodies were observed, but none were neutralising and without impact on drug levels. A significant reduction in the anti-KLH IgG response was observed with AMG 557 administration without discernible changes in the anti-KLH IgM response or on the overall IgG levels. No discernible changes were seen in lymphocyte subsets or in SLE-related biomarkers and clinical measures.

Conclusions: The selective reduction in anti-KLH IgG demonstrates a PD effect of AMG 557 in subjects with SLE consistent with the biology of the ICOS pathway and supports further studies of AMG 557 as a potential therapeutic for autoimmune diseases.

Trial registration numbers: NCT02391259 and NCT00774943.

Keywords: B cells; Inflammation; Systemic Lupus Erythematosus; T Cells.

Figure 1

Study schemas. Upper panel: single-ascending dose study. Subjects with mild, stable systemic lupus erythematosus (SLE) were randomised to receive placebo or AMG 557 at 1.8, 6, 18, 60, 140 and 210 mg subcutaneously (SC) or 18 mg intravenously (IV) in seven sequential rising-dose cohorts. Subjects were immunised with both a prime and boost consisting of a 1 mg intradermal injection of keyhole limpet haemocyanin (KLH) on days 2 and 29 (for 60 mg SC cohort), days 8 and 36 (for 140 and 210 mg SC cohorts), and days 15 and 43. Lower panel: multiple-ascending dose study. Subjects with mild, stable SLE were randomised to receive placebo or AMG 557 at 6, 18, 30, 45, 70, 140  or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85. Subjects were immunised with KLH on days 57 and 85. EOS, end of study.

Figure 2

Mean (SD) AMG 557 serum concentration–time profiles following single-ascending dose (SAD) (A) and multiple-ascending dose (MAD) (B) administration AMG 557 in subjects with systemic lupus erythematosus. The dose levels are indicated in the legend, with the number of values per symbol in parentheses. The lower limit of quantitation (LLOQ) of 15 ng/mL is indicated as a dashed horizontal line on each graph. IV, intravenous; SC, subcutaneous.

Figure 3

ICOSL target occupancy and the pharmacokinetics/pharmacodynamic relationship. (A) ICOSL target occupancy on circulating B cells from the multiple-ascending dose (MAD) study is shown by dose and visit (placebo: 0 mg and AMG 557: 6, 18, 30, 45, 70, 140 and 210 mg). Means from each applicable visit from day 1 to day 253 are graphed and coloured in chronological order within each dose group along with and 95% CIs. The baseline 95% CI of all data points is shown as a grey band. (B) The relationship between AMG 557 serum concentration and ICOSL target occupancy on circulating B cells from the combined single-ascending dose and MAD studies. ICOSL target occupancy is shown on the y-axis, and AMG 557 serum concentration on the x-axis. The observed data are shown as solid black symbols, and the model-predicted median and 80% prediction interval are shown as a solid line and blue shaded area. (C) Relationship between AMG 557 trough concentration at steady state with AMG 557 dose. The model-estimated IC₉₉ (with 95% CI) for the AMG 557 target occupancy is shown as a coloured bar.

Figure 4

Pharmacodynamic effect of AMG 557—inhibition of the anti-keyhole limpet haemocyanin (KLH) IgG response. Anti-IgM and anti-IgG responses are shown for the placebo subjects and the aggregate AMG 557-treated subjects from the single-ascending dose (SAD) (A and B) and multiple-ascending dose (MAD) (C and D) studies. Data are shown for all four graphs by time following the first KLH immunisation on the x-axis and baseline-adjusted anti-KLH IgM (A and C) and anti-KLH IgG (B and D) values. The second KLH immunisation was administered approximately four weeks later (arrow). The fold change over baseline is shown on the right y-axis and the baseline-adjusted value (median fluorescence intensity (MFI) for IgM and concentration for IgG) is shown on the left y-axis; the dashed line indicates a fold change of 1. All AMG 557 doses were pooled for comparison to the placebo group. The number of values per symbol is indicated at the top of each graph. The plots show the mean±SEM.

Figure 5

Effect of dose level on the anti-keyhole limpet haemocyanin (KLH) IgG response in the multiple-ascending dose (MAD) study. (A) anti-KLH IgG serum values by individual cohort in the MAD study (uncensored). (B) Anti-KLH IgG serum values by individual cohort in the MAD study with the nine (of 51) pre-existing (ie, pre-immunisation) anti-KLH IgG-positive subjects removed. For both graphs, data are shown by study day (x-axis) and the anti-KLH IgG mean±SEM (y-axis), the dose level is indicated in the legend and the number of samples per symbol are shown in parentheses. (C) Mean area under the curve (AUC) (±SEM) of the serum anti-KLH IgG from the first KLH to 112 days after the first KLH (y-axis) is shown versus the mean AUC (±SEM) AMG 557 serum concentration from study day 1 to 112 days after the first KLH for the single-ascending dose (SAD) and the MAD studies. Pre-immunisation anti-KLH IgG-positive subjects from both studies were excluded from the analysis.

Figure 6

Serum anti-tetanus toxin IgG and total IgG levels do not change over time in the multiple-ascending dose study. Serum samples were tested at baseline (day 1, pre-dose), and post-dose days 85, 169 and 253 (end of study). Subjects are grouped by dose level. (A) Anti-TT IgG levels. For samples with tetanus antitoxoid concentration >8.30 IU/mL (the upper limit of the assay), 8.30 IU/mL was used for the analysis. (B) Total IgG levels. The number of samples tested is indicated in parentheses in the figure legend.