Evidence of NI‐0101 pharmacological activity, an anti‐TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Issue 2 (17th November 2016)

• Record Type: Journal Article
• Authors: Monnet, E; Lapeyre, G; Poelgeest, E van; Jacqmin, P; Graaf, K de; Reijers, J; Moerland, M; Burggraaf, J; Min, C de
• Is Part Of: Clinical pharmacology & therapeutics. Volume 101:Issue 2(2017)
• Page Start: 200
• Page End: 208
• Publication Date: 2016-11-17
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.522
• Languages: English
• ISSNs: 0009-9236

Abstract

Abstract : Toll‐like receptor‐4 (TLR4) pathways are major contributors to pathological inflammatory responses induced by tissue damage. NI‐0101 is the first monoclonal antibody (mAb) blocking TLR4 signaling. This activity is independent of the ligand type and concentration, therefore, potentially blocking any TLR4 ligands. A phase I single ascending dose study was conducted in 73 healthy volunteers to evaluate NI‐0101 tolerability, preliminary safety, pharmacokinetics (PKs), and pharmacodynamics (PDs), in absence and in presence of a systemic challenge with lipopolysaccharide (LPS), a TLR4 ligand. NI‐0101 was well tolerated without safety concern. The PK profile was characterized by a half‐life of ∼10 days at high concentrations and by a rapid elimination at low concentrations due to expected target‐mediated drug disposition. NI‐0101 prevented cytokine release following ex vivo and in vivo LPS administration and prevented the C‐reactive protein (CRP) increase and the occurrence of flu‐like symptoms expected following the in vivo administration of LPS.