Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target

ABSTRACT

Introduction: Tumor necrosis factor (TNF) receptor 2 (TNFR2) is one of two receptors of the cytokines, TNF and lymphotoxin-α. TNFR1 is a strong inducer of proinflammatory activities. TNFR2 has proinflammatory effects too, but it also elicits strong anti-inflammatory activities and has protective effects on oligodendrocytes, cardiomyocytes, and keratinocytes. The protective and anti-inflammatory effects of TNFR2 may explain why TNF inhibitors failed to be effective in diseases such as heart failure or multiple sclerosis, where TNF has been strongly implicated as a driving force. Stimulatory and inhibitory TNFR2 targeting hence attracts considerable interest for the treatment of autoimmune diseases and cancer.

Areas covered: Based on a brief description of the pathophysiological importance of the TNF-TNFR1/2 system, we discuss the potential applications of TNFR2 targeting therapies. We also debate TNFR2 activation as a way forward in the search for TNFR2-specific agents.

Expert opinion: The use of TNFR2 to target regulatory T-cells is attractive, but this approach is just one amongst many suitable targets. With respect to its preference for Treg stimulation and protection of non-immune cells, TNFR2 is more unique and thus offers opportunities for translational success.

KEYWORDS:

• Antibody
• antibody fusion proteins
• autoimmune disease
• cancer treatment
• Fc-gamma receptors
• multiple sclerosis
• regulatory T-cell (Treg)
• rheumatoid arthritis
• tumor necrosis factor (TNF)
• TNF receptor 1 (TNFR1)
• TNF receptor 2 (TNFR2)

Article Highlights

• TNF elicits pleiotropic effects in a variety of pathologies such as autoimmune disease, heart failure, and cancer.

• Detrimental and beneficial TNF effects largely segregate with the use of TNFR1 and TNFR2 in some pathologies such as multiple sclerosis and heart failure.

• TNFR2 has proinflammatory and anti-inflammatory and cell-protective activities.

• TNFR2 stimulation could exploit the anti-inflammatory activity of mesenchymal-derived suppressor cells, and regulatory T- and B-cells and may also help to realize immune cell-independent protective activities.

• In contrast, to membrane TNF, soluble TNF interacts with TNFR2 but fails to trigger efficient receptor signaling.

• Nonameric and hexameric variants of established TNF mutants with TNFR2-selectivity are potent TNFR2-specific agonists.

• TNFR2-specific antibodies and antibody fusion proteins require binding to a cell surface exposed structure or oligomerization to become highly agonistic.

This box summarizes key points contained in the article.

Declaration of interest

The University of Würzburg has filed a patent application for the use of anti-TNFRSF receptor antibody fusion proteins and J Medler and H Wajant are two of the inventors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 324392634 – TRR 221 and WA 1025/31-1 and the State of Bavaria (M4-Award).