Anti-TNFRSF6B monoclonal antibody, clone C09-46

The tumor necrosis factor receptor super-family member 6b (TNFRSF6B) is over-expressed in various human cancers, but its function in hepatocellular carcinoma (HCC) remains uncertain. The aim of the study was to investigate the relationship between TNFRSF6B expression and apoptosis in HCC and the effect of anti-TNFRSF6B neutralization monoclonal antibody (McAb) on HCC cells. TNFRSF6B mRNA and protein expression were compared with apoptosis in 78 cases of HCC. Proliferation, cell cycle, apoptosis, and migration ability of liver cancer cells co-cultured with anti-TNFRSF6B McAb were also detected. TNFRSF6B mRNA and protein expression in the tumor tissues negatively correlated with apoptosis. Cell proliferation was decreased, cell cycle was arrested in G1/S-phase, apoptosis was increased, and migration ability was inhibited by anti-TNFRSF6B McAb in vitro. Anti-TNFRSF6B McAb could be useful to suppress proliferation and induce apoptosis in HCC. Thus, TNFRSF6B might be a critical, targeted therapy strategy for HCC. (C) 2010 Elsevier GmbH. All rights reserved.

Tumor necrosis factor (TNF)/TNF receptor (TNFR) superfamily members play essential roles in the development of the different phases of the immune response. Mouse LIGHT (TNFSF14) is a type II transmembrane protein with a C-terminus extracellular TNF homology domain (THD) that assembles in homotrimers and regulates the course of the immune responses by signaling through 2 receptors, the herpes virus entry mediator (HVEM, TNFSFR14) and the lymphotoxin beta receptor (LT beta R, TNFSFR3). LIGHT is a membrane-bound protein transiently expressed on activated T cells, natural killer (NK) cells and immature dendritic cells that can be proteolytically cleaved by a metalloprotease and released to the extracellular milieu. The immunotherapeutic potential of LIGHT blockade was evaluated in vivo. Administration of an antagonist of LIGHT interaction with its receptors attenuated the course of graft-versus-host reaction and recapitulated the reduced cytotoxic activity of LIGHT-deficient T cells adoptively transferred into non-irradiated semiallogeneic recipients. The lack of LIGHT expression on donor T cells or blockade of LIGHT interaction with its receptors slowed down the rate of T cell proliferation and decreased the frequency of precursor alloreactive T cells, retarding T cell differentiation toward effector T cells. The blockade of LIGHT/LT beta R/HVEM pathway was associated with delayed downregulation of interleukin-7R alpha and delayed upregulation of inducible costimulatory molecule expression on donor alloreactive CD8 T cells that are typical features of impaired T cell differentiation. These results expose the relevance of LIGHT/LT beta R/HVEM interaction for the potential therapeutic control of the allogeneic immune responses mediated by alloreactive CD8 T cells that can contribute to prolong allograft survival.