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.

Autor: Cordy JC; GlaxoSmithKline, Stevenage, UK., Morley PJ; GlaxoSmithKline, Stevenage, UK., Wright TJ; GlaxoSmithKline, Stevenage, UK., Birchler MA; GlaxoSmithKline, King of Prussia, PA, USA., Lewis AP; GlaxoSmithKline, Stevenage, UK., Emmins R; GlaxoSmithKline, Stevenage, UK., Chen YZ; GlaxoSmithKline, King of Prussia, PA, USA., Powley WM; GlaxoSmithKline, Stevenage, UK., Bareille PJ; GlaxoSmithKline, Stevenage, UK., Wilson R; GlaxoSmithKline, Stevenage, UK., Tonkyn J; GlaxoSmithKline, Stevenage, UK., Bayliffe AI; GlaxoSmithKline, Stevenage, UK., Lazaar AL; GlaxoSmithKline, King of Prussia, PA, USA.
Jazyk: angličtina
Zdroj: Clinical and experimental immunology [Clin Exp Immunol] 2015 Nov; Vol. 182 (2), pp. 139-48. Date of Electronic Publication: 2015 Sep 11.
DOI: 10.1111/cei.12680
Abstrakt: 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.
(© 2015 British Society for Immunology.)
Databáze: MEDLINE
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