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

Mahdi Saghari; Pim Gal; Sally Gilbert; Martin Yateman; Ben Porter-Brown; Nuala Brennan; Sonia Quaratino; Rosamund Wilson; Hendrika W Grievink; Erica S Klaassen; Kirsten R Bergmann; Jacobus Burggraaf; Martijn B A van Doorn; John Powell; Matthijs Moerland; Robert Rissmann

doi:10.1002/cpt.2539

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

Clin Pharmacol Ther. 2022 May;111(5):1121-1132. doi: 10.1002/cpt.2539. Epub 2022 Mar 1.

Authors

Mahdi Saghari^{1

2}, Pim Gal^{1

2}, Sally Gilbert³, Martin Yateman³, Ben Porter-Brown³, Nuala Brennan³, Sonia Quaratino³, Rosamund Wilson³, Hendrika W Grievink^{1

4}, Erica S Klaassen¹, Kirsten R Bergmann¹, Jacobus Burggraaf^{1

2

4}, Martijn B A van Doorn^{1

5}, John Powell³, Matthijs Moerland^{1

2}, Robert Rissmann^{1

2

4}

Affiliations

¹ Centre for Human Drug Research, Leiden, The Netherlands.
² Leiden University Medical Centre, Leiden, The Netherlands.
³ Kymab Ltd., Cambridge, UK.
⁴ Leiden Academic Centre for Drug Research, Leiden, The Netherlands.
⁵ Department of Dermatology, Erasmus Medical Centre, Rotterdam, The Netherlands.

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.

Publication types

Randomized Controlled Trial

MeSH terms

Antibodies, Monoclonal* / immunology
Antibodies, Monoclonal* / pharmacology
Antibody Formation*
Healthy Volunteers
Hemocyanins* / pharmacology
Humans
Male
OX40 Ligand* / antagonists & inhibitors
OX40 Ligand* / immunology

Substances

Antibodies, Monoclonal
OX40 Ligand
TNFSF4 protein, human
Hemocyanins
keyhole-limpet hemocyanin

Associated data

EudraCT/2016-004839-20
ClinicalTrials.gov/NCT03161288