TNFRSF25 was initially described by several different laboratories and each proposed a distinct name including: DR3, Apo-3, WSL-1, TRAMP and LARD. The function was shown to induce apoptosis in immortalized, but not primary, cell lines.

  • Chinnaiyan et al. Science 1996
  • Kitson et al. Nature 1996
  • Marsters et al. Curr Biol 1996
  • Bodmer et al. Immunity 1997
  • Screaton et al. PNAS 1997

Several years later, in 2002, the ligand for TNFRSF25 was described as TL1A (TNFSF15).

  • Migone et al. Immunity 2002

In 2008, several laboratories all reported the pro-inflammatory role of TL1A and TNFRSF25 using distinct transgenic mouse models as surrogates for multiple sclerosis, type 1 diabetes, inflammatory bowel disease, arthritis and asthma.

  • Fang et al. J Exp Med 2008
  • Pappu et al. J Exp Med 2008
  • Meylan et al. Immunity 2008
  • Bull et al. J Exp Med 2008
  • Takedatsu et al. Gastroenterology 2008

Because all reports to date demonstrated that expression of TL1A and TNFRSF25 was associated with a survival disadvantage to the host, it was proposed that the role of TNFRSF25 as pertaining to increased evolutionary fitness remained undescribed.

  • Schreiber et al. Adv Exp Med Biol 2010

In 2010, TNFRSF25-specific monoclonal antibodies with agonistic activity or TL1A-Ig fusion proteins were shown to selectively expand FoxP3-positive T regulatory cells in mice. Expansion of Tregs was dependent upon endogenous levels of IL-2 and was used in the neo-adjuvant setting to suppress allergic lung inflammation.

  • Schreiber et al. J Clin Invest 2010
  • Khan et al. J Immunol 2013

In 2012, therapeutic expansion of Treg cells using TNFRSF25 agonistic antibodies or TL1A-Ig fusion proteins was shown to suppress chronic lung inflammation, allogeneic heart transplant rejection and ocular inflammation associated with HSV-1 infection.

  • Reddy et al. J Virol 2012
  • Wolf et al. Transplantation 2012

Also in 2012, a systematic comparison of the adjuvant activity between TNFRSF4 and TNFRSF25 agonistic antibodies was performed in combination with vaccination. TNFRSF25 was shown to enhance CD8+ T cell expansion as well as IgG1 and IgG2b antibody subtypes independently and synergistically with TNFRSF4 agonistic antibodies. The adjuvant effect of TNFRSF25 in conjunction with vaccination occurred concurrent with Treg expansion and was vaccine-antigen specific. These data are supported by two additional studies for both anti-tumor and anti-viral T cell immunity.

  • Schreiber et al. J Immunol 2012
  • Slebioda et al. Eur J Immunol, 2011
  • Twohig et al, FASEB J., 2012

A systematic comparison between TNFRSF25, OX40, 4-1BB, GITR and ICOS has demonstrated superior co-stimulation of memory CD8+ T cells by TNFRSF25 as compared to the other targets (ImVACS, Keystone Symposia). This data prompted the clinical development of a humanized anti-human TNFRSF25 agonist antibody (PTX-25).

Selective Stimulation of Memory
CD8+ T Cells

Introducing first-in-class therapeutics to achieve in vivo regulatory T cell expansion in humans