title: Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS.
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.
authors.affiliation: Novimmune SA, Plan-les-Ouates, Switzerland.|MnS, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Monnet
authors.affiliation: Novimmune SA, Plan-les-Ouates, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Lapeyre
authors.affiliation: Center for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: E van
authors.initials: EV
authors.lastname: Poelgeest
authors.affiliation: SGS-Exprimo, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Jacqmin
authors.affiliation: Novimmune SA, Plan-les-Ouates, Switzerland.
authors.forename: K de
authors.initials: K
authors.lastname: Graaf
authors.affiliation: Center for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Reijers
authors.affiliation: Center for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Moerland
authors.affiliation: Center for Human Drug Research (CHDR), Leiden, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Novimmune SA, Plan-les-Ouates, Switzerland.
authors.forename: C de
authors.initials: C
authors.lastname: Min
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; C000619441:NI-0101; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4