Anti-TNFRSF21 monoclonal antibody, clone ES-7-05-FD [PE]

Multiple sclerosis (MS) often starts in the form of clinically isolated syndrome (CIS) and only some of the CIS patients progress to relapsing-remitting MS (RRMS). Biomarkers to predict conversion from CIS to MS are thus greatly needed for making correct treatment decisions. To identify a predictive cerebrospinal fluid (CSF) protein, we analyzed the first-attack CSF samples of CIS patients who converted (CIS-MS) (n=23) and did not convert (CIS-CIS) (n=19) to RRMS in a follow-up period of 5years using proteomics analysis by liquid chromatography tandem-mass spectrometry (LC-MS/MS) and verified by ELISA. Label-free differential proteomics analysis of CSF ensured that 637 proteins were identified and 132 of these proteins were found to be statistically significant. Further investigation with the ingenuity pathway analysis (IPA) software led to identification of three pathway networks mostly comprised proteins involved in inflammatory response, cellular growth and tissue proliferation. CSF levels of four of the most differentially expressed proteins belonging to the cellular proliferation network function, chitinase-3-like protein 1 (CHI3L1), tumor necrosis factor receptor superfamily member 21 (TNFRSF21), homeobox protein Hox-B3 (HOXB3) and iduronate 2-sulfatase (IDS), were measured by ELISA. CSF levels of HOXB3 were significantly increased in CIS-MS patients. Our results indicate that cell and tissue proliferation functions are dysregulated in MS as early as the first clinical episode. HOXB3 has emerged as a potential novel biomarker which might be used for prediction of CIS-MS conversion.

Studies in murine models of cancer as well as in cancer patients have demonstrated that the immune response to cancer is often compromised. This paradigm is viewed as one of the major mechanisms of tumor escape. Many therapies focus on employing the professional antigen presenting dendritic cells (DC) as a strategy to overcome immune inhibition in cancer patients. Death receptor 6 (DR6) is an orphan member of the tumor necrosis factor receptor superfamily (TNFRSF21). It is overexpressed on many tumor cells and DR6(-/-) mice display altered immunity. We investigated whether DR6 plays a role in tumorigenesis by negatively affecting the generation of anti-tumor activity. We show that DR6 is uniquely cleaved from the cell surface of tumor cell lines by the membrane-associated matrix metalloproteinase (MMP)-14, which is often overexpressed on tumor cells and is associated with malignancy. We also demonstrate that > 50% of monocytes differentiating into DC die when the extracellular domain of DR6 is present. In addition, DR6 affects the cell surface phenotype of the resulting immature DC and changes their cytokine production upon stimulation with LPS/IFN-gamma. The effects of DR6 are mostly amended when these immature DC are matured with IL-1 beta/TNF-alpha, as measured by cell surface phenotype and their ability to present antigen. These results implicate MMP-14 and DR6 as a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells.