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.

摘要: 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 high levels novel, pre-existing human anti-VH (HAVH) autoantibody. In the presence HAVH autoantibodies, GSK1995057 induced vitro due to binding autoantibodies framework region dAb. The epitope on was characterized and dAbs reduced generated; pharmacological comparability determined in-vitro systems in-vivo animal experiments. A Phase I trial conducted investigate safety tolerability modified dAb (GSK2862277). significant reduction achieved by adding single alanine residue at C-terminus create GSK2862277. Screening pool donors demonstrated frequency from 51% 7%; all other respects, GSK2862277 parent comparable. trial, well tolerated both inhaled intravenous routes. One subject experienced mild reaction following dosing. Subsequently, this found have novel specific extended Despite adverse effects associated response identified highlight challenge developing biological antagonists class receptor.