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

To investigate the impact of a new class of anti-Ig autoantibodies reactive with variable heavy (V-H) chain framework sequences (human anti-V-H autoantibodies) on the pharmacology and safety of an anti-TNFR1 V-H domain antibody (GSK1995057) in healthy human subjects. 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-V-H (HAVH) autoantibody status and prospectively stratified accordingly. Serum samples from drug-na < ve, HAVH-positive volunteers were used to investigate the effect of HAVH/GSK1995057 complexes on the activation of TNFR1 and cytokine release in vitro. Human anti-V-H autoantibodies were detected in approximately 50 % of drug-na < ve 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. 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.