期刊
FRONTIERS IN IMMUNOLOGY
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.00526
关键词
variable new antigen receptors (VNARs); TNF-alpha; autoimmune disease; rheumatoid arthritis; anti-TNF biologics; shark IgNAR; chronic inflammation
类别
资金
- Biotechnology and Biological Sciences Research Council [BB/K010905/1]
- Scottish Enterprise [VNAR_001 (2012)]
- Innovate UK [102865]
- Innovate UK [102865] Funding Source: UKRI
Tumor necrosis factor-alpha (TNF-alpha), an established pro-inflammatory cytokine plays a central role in the induction and progression of several chronic inflammatory and autoimmune diseases. Targeting TNF-alpha as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-alpha 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-alpha formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunized nurse shark. Two anti-TNF-alpha VNAR formats, a tandem multivalent trimer, D1-BA11-C4 and an Fc-fused quadrivalent D1-Fc-C4 (Quad-X (TM)) construct were tested in a clinically relevant, preclinical mouse efficacy model of polyarthritis (Tg197) and compared to the commercial anti-TNF-alpha best in class therapy, Adalimumab (Humira (R)). Both VNAR formats bind and neutralize TNF-alpha through an epitope that appears to be different from those recognized by other anti-TNF biologics used clinically. All doses of Quad-X (TM), from 0.5 to 30 mg/kg, significantly blocked the development of polyarthritis. At 0.5 mg/kg Quad-X (TM), the arthritis score was improved by 76% and the histopathology score by 63%. At 3 mg/kg Quad-X (TM), control of disease was almost complete at 90% (arthritis) and 88% (histopathology). In marked contrast, 1 mg/kg Humira (R) saw profound disease breakthrough with scores of 39 and 16% respectively, increasing to a respectable 82 and 86% inhibition at 10 mg/kg Humira (R). We have previously reported the superior potency of anti-TNF-alpha 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-alpha therapies.
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