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 language | English |
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Article number | 526 |
Number of pages | 12 |
Journal | Frontiers in Immunology |
Volume | 10 |
Early online date | 22 Mar 2019 |
DOIs | |
Publication status | Published - Mar 2019 |
Bibliographical note
FundingThe Biotechnology and Biological Sciences Research Council (BB/K010905/1), Scottish Enterprise (VNAR_001 (2012), Innovate UK (102865).
Acknowledgments
The authors wish to acknowledge the funding support for this work from Scottish Enterprise (SE), the Biotechnology and Biological Sciences Research Council (BBSRC), and Innovate UK.
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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Andrew Porter
- School of Medicine, Medical Sciences & Nutrition, Microbiology and Immunity
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Chair in Molecular and Cell Biology
- School of Medicine, Medical Sciences & Nutrition, Institute of Medical Sciences
Person: Academic