OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005

Abstract

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (T_max ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (E_max ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema E_max -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.

Trial registration: ClinicalTrials.gov NCT03161288.

Figure 1

Illustrations of LSCI basal flow and erythema assessed as average redness with multispectral imaging. Images were taken at intradermal KLH injection site 2 days after intradermal KLH administration of a subject treated with an initial KY1005 12 mg/kg dose (left images) and a subject that received placebo (right images). KLH, keyhole limpet hemocyanin; LSCI, laser speckle contrast imaging.

Figure 2

KY1005 serum concentrations (μg/mL). Data displayed on log10 scale as mean (SD).

Figure 3

Anti‐KLH IgM (a) and IgG antibody titers (b), anti‐TT IgM (c), and IgG antibody titers (d) 21 days after KLH and TT immunizations, cutaneous blood perfusion by LSCI basal flow (e) and LSCI flare (f), erythema by multispectral imaging average redness (g), and multispectral imaging CIELab a* (h) 2 days after intradermal KLH administration by treatment group. Data are shown as estimated difference percentage change (95% confidence interval) for a to d and as mean CFB (SD) for e to h. AU, arbitrary unit; CFB, change from baseline; ED, estimated difference; i.d., intradermal; KLH, keyhole limpet hemocyanin; LSCI, laser speckle contrast imaging; TT, tetanus toxoid. The P values are based on estimated differences between groups with correction for baseline measurements and saline administration. ^* P < 0.05, ^** P < 0.01, ^*** P < 0.001.

Figure 4

E_max model of KY1005 exposure and anti‐KLH IgM (a), anti‐KLH IgG (b), anti‐TT IgM (c), anti‐TT IgG (d), LSCI basal flow (e), LSCI flare (f), multispectral imaging average redness (g), and multispectral imaging CIELab a* (h). Dots represent individual data points. Black squares (error bars) represent mean (SD) of observed data per dose level. Black line (grey area) represents model predicted mean (90% confidence interval). Data are shown as log10 change from baseline ratios vs. KY1005 concentration. CFB, change from baseline; E_max, maximum effect; KLH, keyhole limpet hemocyanin; LSCI, laser speckle contrast imaging; TT, tetanus toxoid.