Background/Purpose: 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. Here we discovered and characterized SIM0710, which is a novel BTLA agonistic monoclonal antibody without interrupting native HVEM-BTLA interaction.

Methods: The binding activities to human BTLA protein were determined by ELISA and BLI while the blockade of BTLA-HVEM interaction were evaluated by ELISA. Agonistic functionality of SIM0710 was evaluated using a BTLA/SHP2 reporter assay. Antibody-mediated inhibition of HVEM cis-signaling was assessed using a light-driven HVEM-dependent NF-κB assay, while trans-signaling blockade was evaluated in a HVEM-dependent NF-κB assay on CHO-K1-BTLA cells. Diverse in vitro functional cellular assays were performed including TLR7/9-mediated IFN-α release in pDCs and modulation of co-stimulatory molecules in LPS-activated mDCs (ELISA or FACS), anti-IgM-stimulated B cell proliferation (FACS) and IL-6 secretion (ELISA), as well as anti-CD3/CD28-activated PBMC proliferation (FACS) and Th1/Th2/Th17/Th22 cytokine profiling (ELISA). In vivo efficacy was further assessed in humanized GvHD and TLR7 agonist-induced humanized SLE mouse models.

Results: SIM0710 demonstrates the potential to directly induce co-inhibitory agonistic signaling through BTLA, which can be 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 interaction. In vitro, SIM0710 effectively inhibited the proliferation of human primary B and T cells 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 TLR7-agonist induced SLE model in hu-CD34 HSC NOG-EXL mice.

Conclusion: Taken together, SIM0710 shows broad functional inhibition in diverse pathogenic immune cells and may offer potential therapeutic benefit for treating multiple autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-and-characterization-of-sim0710-a-novel-b-and-t-lymphocyte-attenuator-btla-agonistic-antibody-for-autoimmune-inflammatory-diseases/