Session Type: Abstract Session
Session Time: 11:15AM-11:30AM
Background/Purpose: Systemic lupus erythematosus is a complex disease in which the immune system is dysfunctional at multiple levels including impaired regulatory responses, altered self-antigen processing and increased autoantibody production. LANCL2 is a novel anti-inflammatory target that has been first targeted by a gut-restricted compound, omilancor (BT-11), currently in Phase II/III clinical development for inflammatory bowel diseases. BT-104 functions through similar immunometabolic mechanisms, increasing the suppressive capacity and stability of regulatory CD4+ T cells while also supporting the metabolic demands of autophagy in phagocytes.
Methods: Based on these immunological effects, we evaluated oral BT-104 in three mouse models of lupus: the NZB/W F1 model, the MRL/lpr model and the bm12 adoptive transfer model. Mice were treated daily with oral BT-104 from ages 24 to 36 wk in the NZB/W F1 model, from ages 12 to 18 wk in the MRL/lpr model and from 1 to 2 wk post-transfer in the bm12 model. Therapeutic efficacy was evaluated by proteinuria, anti-nuclear antibody titers, immune cell changes in the blood and spleen, and histological inflammatory changes in the kidney. Further, the MRL/lpr model was used to identify global transcriptional signatures of BT-104 in blood and spleen after oral treatment. The translational efficacy of BT-104 was evaluated in PBMCs from SLE patients in vitro.
Results: In the NZB/W F1 and MRL/lpr models, BT-104 protected against worsening from baseline in proteinuria grade in greater than 90% of mice, improved proteinuria grade in roughly half of mice, and reduced anti-nuclear antibody levels by three-fold. BT-104 reduced overall histological score in the kidneys, including improvement in interstitial inflammation, glomerular proliferation, and cellular crescents. Immunologically, across all three models, BT-104 significantly reduced IL17+ and IL21+ CD4+ T cells in the spleen while significantly increasing CD25+ FOXP3+ regulatory CD4+ T cells (Treg). BT-104 significantly reduces the production of interferon alpha in human PBMCs from SLE patients in response to general (PMA and ionomycin), TLR7 (gardiquimod) and CpG oligonucleotide (ODN2395) stimuli.
Conclusion: Based on the preclinical data generated, BT-104 is a promising therapeutic for systemic lupus erythematosus and other rheumatic conditions. BT-104 is expected to enter Phase I clinical testing in normal healthy volunteers in Q4 2021.
To cite this abstract in AMA style:Leber A, Hontecillas R, Tubau-Juni N, Fitch S, Chauhan J, Bassaganya-Riera J. Therapeutic Efficacy of BT-104, an Oral LANCL2 Agonist, for the Treatment of Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2021; 73 (suppl 9). https://acrabstracts.org/abstract/therapeutic-efficacy-of-bt-104-an-oral-lancl2-agonist-for-the-treatment-of-systemic-lupus-erythematosus/. Accessed January 31, 2023.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/therapeutic-efficacy-of-bt-104-an-oral-lancl2-agonist-for-the-treatment-of-systemic-lupus-erythematosus/