Generation and characterization of a mouse LIGHT specific inhibitor in a murine model of colitis (THER4P.891)

LIGHT (TNFSF14, CD258) is a member of the TNF superfamily that is expressed on activated T cells, immature DCs, macrophages, and NK cells. LIGHT interacts with its receptors (HVEM and LTβR) and is reported to provide co-stimulatory and pro-inflammatory signals to T cells, B cells, DCs, and macrophages. Numerous studies have implicated the pro-inflammatory effects of LIGHT as an important contributor to disease severity in models of inflammatory bowel disease and fibrosis. However, the inhibitors used in many of these studies (e.g. LTβR-Ig and HVEM-Ig) are not specific for LIGHT, and are likely to impact other pathways such as LTαβ and BTLA. Our focus was to develop domain antibodies (dAbs) that specifically block LIGHT-HVEM and LIGHT-LTβR interactions to better understand the therapeutic potential of LIGHT specific blockade. We were able to develop a mouse LIGHT specific inhibitor that potently blockades LIGHT-HVEM and LIGHT-LTβR interactions in vitro. Notably, this dAb had little effect when used as a monotherapy in a murine model of colitis, but when combined with CD40 blockade showed a high degree of efficacy (equivalent to CTLA4-Ig treatment). These data suggest that LIGHT monotherapy may not be sufficient to impact disease severity, but LIGHT blockade may have potential as part of a combination approach.