Discovery and characterization of SIM0710, a novel BTLA agonist antibody for autoimmune/Inflammatory disease 4654

Abstract Description B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that contributes to the regulation of T cell, B cell and dendritic cell function through its interaction with its ligand herpesvirus entry mediator (HVEM) on cells in trans and on the same cell in cis. SIM0710 is a novel BTLA agonistic monoclonal antibody without interrupting HVEM-BTLA interaction. SIM0710 demonstrates the potential to directly induce co-inhibitory agonistic signaling through BTLA, which is further enhanced by Fc receptor engagement. Additionally, SIM0710 preserves the formation of anti-inflammatory BTLA/HVEM cis complex while simultaneously blocking the pro-inflammatory co-stimulatory signal mediated by HVEM through trans BTLA binding. In vitro, SIM0710 effectively inhibited the proliferation of human primary B cell and T cell with concurrent reduction of IL-6 and multiple Th cytokines. Furthermore, SIM0710 modulated the functions of human primary DCs, including inhibition of the TLR7/9-induced IFN-α secretion from pDC and downregulation of co-stimulatory molecules on mDCs. In vivo, SIM0710 improved overall survival in a humanized GvHD mouse model. Notably, SIM0710 also significantly reduced the anti-dsDNA IgG level in the serum of an IMQ induced SLE model in hu-CD34 HSC NOG-EXL mice. Taken together, SIM0710 shows broad functional inhibition on pathogenic immune cells and may offer potential therapeutic benefit for treating multiple autoimmune diseases. Topic Categories Therapeutic Approaches to Autoimmunity (THER)