PMID- 30967865 OWN - NLM STAT- MEDLINE DCOM- 20200923 LR - 20200923 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - An Anti-hTNF-alpha Variable New Antigen Receptor Format Demonstrates Superior in vivo Preclinical Efficacy to Humira(R) in a Transgenic Mouse Autoimmune Polyarthritis Disease Model. PG - 526 LID - 10.3389/fimmu.2019.00526 [doi] LID - 526 AB - 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) 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, from 0.5 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(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. FAU - Ubah, Obinna C AU - Ubah OC AD - Elasmogen Ltd, Aberdeen, United Kingdom. FAU - Steven, John AU - Steven J AD - Elasmogen Ltd, Aberdeen, United Kingdom. FAU - Porter, Andrew J AU - Porter AJ AD - Elasmogen Ltd, Aberdeen, United Kingdom. AD - Scottish Biologics Facility, School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom. FAU - Barelle, Caroline J AU - Barelle CJ AD - Elasmogen Ltd, Aberdeen, United Kingdom. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190322 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Tumor Necrosis Factor-alpha) RN - FYS6T7F842 (Adalimumab) SB - IM MH - Adalimumab/*pharmacology MH - Animals MH - *Arthritis, Rheumatoid/drug therapy/immunology/pathology MH - Disease Models, Animal MH - Dogs MH - Humans MH - Mice MH - Mice, Transgenic MH - Sharks MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/genetics/immunology PMC - PMC6439398 OTO - NOTNLM OT - TNF-alpha OT - anti-TNF biologics OT - autoimmune disease OT - chronic inflammation OT - rheumatoid arthritis OT - shark IgNAR OT - variable new antigen receptors (VNARs) EDAT- 2019/04/11 06:00 MHDA- 2020/09/24 06:00 PMCR- 2019/01/01 CRDT- 2019/04/11 06:00 PHST- 2018/08/29 00:00 [received] PHST- 2019/02/26 00:00 [accepted] PHST- 2019/04/11 06:00 [entrez] PHST- 2019/04/11 06:00 [pubmed] PHST- 2020/09/24 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.00526 [doi] PST - epublish SO - Front Immunol. 2019 Mar 22;10:526. doi: 10.3389/fimmu.2019.00526. eCollection 2019.