An Anti-hTNF-α Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira® in a Transgenic Mouse Autoimmune Polyarthritis Disease Model

Obinna C. Ubah (Corresponding Author), John Steven, Andrew J. Porter, Caroline J. Barelle

Research output: Contribution to journalArticle

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Abstract

Tumour necrosis factor-alpha (TNF-α), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Here, we report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunised nurse shark. Two anti-TNF-α VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X™) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-α ‘best in class’ therapy, Adalimumab (Humira®). Both VNAR formats bind and neutralise anti-TNF-α through an epitope that appears to be different from those recognised by other anti-TNF biologics used clinically. All doses of Quad-X™, from 0.5 mg/kg to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X™, the arthritis score was improved by 76% and the histopathology score by 63%. At 3 mg/kg Quad-X™, control of disease was almost complete at 90% (arthritis) and 88% (histopathology). In marked contrast, 1 mg/kg Humira® saw profound disease breakthrough with scores of 39% and 16 % respectively, increasing to a respectable 82% and 86% inhibition at 10 mg/kg Humira®. We have previously reported the superior potency of anti-TNF-α VNARs in vitro and in these studies translate this superiority into an in vivo setting and demonstrate the potential of VNAR formats to meet the requirements of next-generation anti-TNF-α therapies.
Original languageEnglish
Article number526
Number of pages12
JournalFrontiers in Immunology
Volume10
Early online date22 Mar 2019
DOIs
Publication statusPublished - Mar 2019

Keywords

  • variable new antigen receptors (VNARs)
  • chronic inflammation
  • shark IgNAR
  • anti-TNF biologics
  • rheumatoid arthritis
  • autoimmune disease
  • TNF-alpha
  • RHEUMATOID-ARTHRITIS
  • ADALIMUMAB
  • THERAPEUTIC ANTIBODIES
  • KNOCKOUT MICE
  • DOSE-ESCALATION
  • MURINE MODEL
  • IMMUNOGENICITY
  • TUMOR-NECROSIS-FACTOR
  • TRANSMEMBRANE TNF-ALPHA
  • MONOCLONAL-ANTIBODIES

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