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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

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Abstract

Purpose

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.

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Acknowledgments

The authors would like to thank the following for their valuable contributions to this work: Alan Lewis, Shuo Tang, Will Riches, Rodd Polsky, Rajni Fagg, Phil Overend, and Tracey Wright. Tim Hardman, PhD and Gareth Cuttle, PhD from Niche Science and Technology, who provided writing and editorial support to the development of this manuscript and were paid for these services by GlaxoSmithKline.

Conflict of Interest

MCH, PJM, APS, RW, MAB, RF, JCC, YC, DAL, and AIB are full time employees of GSK and hold stock or options in the company. JUW was a full-time employee of GSK at the time the study was ongoing and holds shares in the company. He is now an employee of Novartis. MA and JL, are full time employees of PAREXEL International.

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Authors and Affiliations

  1. Research and Development, GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA

    M. C. Holland, M. A. Birchler, A. P. Serone, Y. Chen & D. A. Lipson

  2. Research and Development, Novartis Pharma AG, Novartis Campus, 4002, Basel, Switzerland

    J. U. Wurthner

  3. Research and Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    P. J. Morley, R. Wilson, R. M Forrest, J. C. Cordy & A. I. Bayliffe

  4. Clinical Pharmacology Research Unit, PAREXEL International, Watford Road, Harrow, Middlesex, HA1 3UJ, UK

    J. Lambert & M. Albayaty

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  1. M. C. Holland
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Corresponding author

Correspondence to A. I. Bayliffe.

Additional information

Holland, M. C and Wurthner, J. U contributed equally to this work

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Holland, M.C., Wurthner, J.U., Morley, P.J. et al. 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. J Clin Immunol 33, 1192–1203 (2013). https://doi.org/10.1007/s10875-013-9915-0

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  • DOI: https://doi.org/10.1007/s10875-013-9915-0

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