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

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.