Trivalent soluble TNF Receptor, a potent TNF-α antagonist for the treatment collagen-induced arthritis

Abstract

Tumor necrosis factor is a major pro-inflammatory cytokine which triggers various physiological consequences by binding to and trimerizing its receptors, and has been the single most sought-after drug target for intervening autoimmune diseases such as rheumatoid arthritis and psoriasis. However, current TNF-α blockers, including soluble receptor-Fc fusion and therapeutic antibodies, are all dimeric in structure, whereas their target TNF-α itself is homotrimeric in nature. Here we describe the development of a trivalent soluble TNF receptor and show that it is a more potent than the dimeric TNF receptor decoys in inhibiting TNF-α signaling both in vitro and in vivo. The process involves gene fusion between a soluble receptor TNFRII with a ligand binding domain and a trimerization tag from the C-propeptide of human collagen (Trimer-Tag), which is capable of self-assembly into a covalently linked trimer. We show that the homotrimeric soluble TNF receptor (TNFRII-Trimer) produced with such method is more potent in ligand binding kinetics and cell based bioassays, as well as more efficacious in attenuating collagen-induced arthritis (CIA) in a mouse model than its dimeric TNFRII-Fc counterpart. Thus, this work demonstrates the proof of concept of Trimer-Tag and provides a new platform for rational designs of next generation biologic drugs.

The Effect of Human Recombinant Tumor Necrosis Factor Receptor-2 on Reducing Inflammatory of Collagen -Induced Arthritis in Balb/c Mice

“…Additionally, it has been recently shown that the expression of TNFR2 on hematopoietic cells decreases the intensity of TNF-driven arthritis. Finally, regulatory T cell (Treg) has appeared as likely mediator of the anti-inflammatory factors of TNFR2 (20, 21).…”

The Long Road Toward COVID-19 Herd Immunity: Vaccine Platform Technologies and Mass Immunization Strategies

“…GSK is also testing their adjuvant in collaboration with Clover Biopharmaceuticals, University of Queensland (Brisbane, Australia), and Xiamen Innovax Biotech (Xiamen, China). Utilizing its patented Trimer-Tag© technology, Clover Biopharmaceuticals has developed a SARS-CoV-2 S-Trimer subunit vaccine candidate SCB-2019 that resembles the native trimeric viral spike ( 182 , 183 ). SCB-2019 is in phase I clinical testing with AS03 ( 94 , 95 ) or CpG 1018 and alum adjuvants [( 84 , 85 ); Table 2 ].…”

Primary graft dysfunction after heart transplantation: a thorn amongst the roses

“…Tumour necrosis factors are produced by lymphocytes and macrophages that cause cell lysis [136]. TNF-α has been implicated in the pathogenesis of numerous inflammatory conditions including arthritis [137], asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) [138], myocarditis [139] and congestive heart failure [140].…”