title: Autoantibodies to variable heavy (VH) chain Ig sequences in humans impact the safety and clinical pharmacology of a VH domain antibody antagonist of TNF-α receptor 1.
abstract: OBJECTIVE
  To investigate the impact of a new class of anti-Ig autoantibodies reactive with variable heavy (VH) chain framework sequences (human anti-VH autoantibodies) on the pharmacology and safety of an anti-TNFR1 VH domain antibody (GSK1995057) in healthy human subjects.
  
  
  METHODS
  Single-blind, randomised, placebo-controlled dose escalation study in which healthy males (n = 28) received a single GSK1995057 intravenous infusion of 0.0004, 0.002 and 0.01 mg/kg. All enrolled subjects were pre-screened for human anti-VH (HAVH) autoantibody status and prospectively stratified accordingly. Serum samples from drug-naïve, HAVH-positive volunteers were used to investigate the effect of HAVH/GSK1995057 complexes on the activation of TNFR1 and cytokine release in vitro.
  
  
  RESULTS
  Human anti-VH autoantibodies were detected in approximately 50 % of drug-naïve healthy human subjects and clinical and in vitro studies were performed to evaluate their impact on the pharmacology and safety of GSK1995057. We demonstrated that formation of HAVH autoantibody/GSK1995057 complexes activated TNFR1 and caused cytokine release in vitro in some, but not all, of the human cell types tested. When GSK1995057 was administered to healthy subjects, clinical and physiological signs of cytokine release were observed in two HAVH autoantibody-positive subjects following GSK1995057 infusion. In vitro, HAVH autoantibody levels correlated with TNFR1-dependent cytokine release and propensity for cytokine release in humans following GSK1995057 dosing.
  
  
  CONCLUSIONS
  Our data support a greater focus on the impact of pre-existing, drug-reactive autoantibodies on the development of antibody fragments and biotherapeutics targeting cell surface receptors.
authors.affiliation: Research and Development, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Holland
authors.forename: J U
authors.initials: JU
authors.lastname: Wurthner
authors.forename: P J
authors.initials: PJ
authors.lastname: Morley
authors.forename: M A
authors.initials: MA
authors.lastname: Birchler
authors.forename: J
authors.initials: J
authors.lastname: Lambert
authors.forename: M
authors.initials: M
authors.lastname: Albayaty
authors.forename: A P
authors.initials: AP
authors.lastname: Serone
authors.forename: R
authors.initials: R
authors.lastname: Wilson
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: R M
authors.initials: RM
authors.lastname: Forrest
authors.forename: J C
authors.initials: JC
authors.lastname: Cordy
authors.forename: D A
authors.initials: DA
authors.lastname: Lipson
authors.forename: A I
authors.initials: AI
authors.lastname: Bayliffe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001323:Autoantibodies / Q000378:metabolism*; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000276:immunology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010601:Pharmacology, Clinical; D011446:Prospective Studies; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D054316:Biomarkers, Pharmacological; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D047888:Receptors, Tumor Necrosis Factor, Type I