TY - JOUR
T1 - OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers
T2 - A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005
AU - Saghari, Mahdi
AU - Gal, Pim
AU - Gilbert, Sally
AU - Yateman, Martin
AU - Porter-Brown, Ben
AU - Brennan, Nuala
AU - Quaratino, Sonia
AU - Wilson, Rosamund
AU - Grievink, Hendrika W.
AU - Klaassen, Erica S.
AU - Bergmann, Kirsten R.
AU - Burggraaf, Jacobus
AU - van Doorn, Martijn B.A.
AU - Powell, John
AU - Moerland, Matthijs
AU - Rissmann, Robert
N1 - Funding Information:
Kymab Ltd. (Cambridge, UK) was the sponsor for the study and funded all study related activities.
Publisher Copyright:
© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2022/5
Y1 - 2022/5
N2 - 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 (Tmax) ~ 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 (Emax) −0.58 AU, 95% CI −1.10 AU to −0.06 AU) and skin response (erythema Emax −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.
AB - 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 (Tmax) ~ 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 (Emax) −0.58 AU, 95% CI −1.10 AU to −0.06 AU) and skin response (erythema Emax −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.
UR - http://www.scopus.com/inward/record.url?scp=85125390006&partnerID=8YFLogxK
U2 - 10.1002/cpt.2539
DO - 10.1002/cpt.2539
M3 - Article
C2 - 35092305
AN - SCOPUS:85125390006
SN - 0009-9236
VL - 111
SP - 1121
EP - 1132
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -