title: Specificity of human anti-variable heavy (VH ) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor-α receptor 1.
abstract: During clinical trials of a tumour necrosis factor (TNF)-R1 domain antibody (dAb™) antagonist (GSK1995057), infusion reactions consistent with cytokine release were observed in healthy subjects with high levels of a novel, pre-existing human anti-VH (HAVH) autoantibody. In the presence of HAVH autoantibodies, GSK1995057 induced cytokine release in vitro due to binding of HAVH autoantibodies to a framework region of the dAb. The epitope on GSK1995057 was characterized and dAbs with reduced binding to HAVH autoantibodies were generated; pharmacological comparability was determined in human in-vitro systems and in-vivo animal experiments. A Phase I clinical trial was conducted to investigate the safety and tolerability of the modified dAb (GSK2862277). A significant reduction in HAVH binding was achieved by adding a single alanine residue at the C-terminus to create GSK2862277. Screening a pool of healthy donors demonstrated a reduced frequency of pre-existing autoantibodies from 51% to 7%; in all other respects, GSK2862277 and the parent dAb were comparable. In the Phase I trial, GSK2862277 was well tolerated by both the inhaled and intravenous routes. One subject experienced a mild infusion reaction with cytokine release following intravenous dosing. Subsequently, this subject was found to have high levels of a novel pre-existing antibody specific to the extended C-terminus of GSK2862277. Despite the reduced binding of GSK2862277 to pre-existing HAVH autoantibodies, adverse effects associated with the presence of a novel pre-existing antibody response specific to the modified dAb framework were identified and highlight the challenge of developing biological antagonists to this class of receptor.
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Cordy
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Morley
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: T J
authors.initials: TJ
authors.lastname: Wright
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Birchler
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: A P
authors.initials: AP
authors.lastname: Lewis
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: R
authors.initials: R
authors.lastname: Emmins
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Chen
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: W M
authors.initials: WM
authors.lastname: Powley
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Bareille
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: R
authors.initials: R
authors.lastname: Wilson
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: J
authors.initials: J
authors.lastname: Tonkyn
authors.affiliation: GlaxoSmithKline, Stevenage, UK.
authors.forename: A I
authors.initials: AI
authors.lastname: Bayliffe
authors.affiliation: GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Lazaar
mesh_terms: D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000918:Antibody Specificity / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002460:Cell Line; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D011485:Protein Binding / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000276:immunology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; C000605830:GSK2862277; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D016209:Interleukin-8; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human
keywords: ADA; Phase I; TNF; clinical trial