Preclinical development of SL-325, a novel high-affinity DR3-blocking antibody for durable inhibition of the DR3/TL1A axis in inflammatory bowel disease.

Abstract

Death receptor 3 (DR3; also termed tumor necrosis factor receptor superfamily member 25 [TNFRSF25]) is the sole functional receptor for tumor necrosis factor (TNF)-like cytokine 1A (TL1A) and is constitutively expressed on effector lymphoid cells in peripheral blood and in both inflamed and adjacent noninflamed tissues. Excessive DR3 signaling contributes to chronic inflammation in inflammatory bowel disease (IBD). While clinical trials of anti-TL1A antibodies have demonstrated efficacy in ulcerative colitis and Crohn disease, the stable expression pattern of DR3 suggests that receptor blockade may more effectively and durably inhibit TL1A-driven proinflammatory signaling and limit disease propagation. We describe the preclinical development of SL-325, a fully human, Fc-silent, high-affinity DR3-blocking monoclonal antibody. Binding affinity and specificity of SL-325 were evaluated using biophysical and cell-based assays. Functional activity was assessed in peripheral blood mononuclear cells (PBMCs) from healthy donors and IBD patients, an ex vivo human intestinal inflammation model, and cynomolgus macaque toxicology studies. SL-325 bound to human DR3 with picomolar affinity and high specificity while potently blocking TL1A binding without inducing DR3 agonism. SL-325 suppressed TL1A-induced proinflammatory cytokine secretion in PBMCs from healthy donors and IBD patients. In an ex vivo human intestinal model, SL-325 inhibited TL1A-driven cytokine production and preserved epithelial barrier integrity. In nonhuman primates, SL-325 was safe and well tolerated at doses up to 100 mg/kg, demonstrated dose-proportional pharmacokinetics, and led to prolonged DR3 receptor occupancy (RO) without immune activation or proliferation. These data demonstrate that SL-325 is a novel DR3-blocking antibody with the potential to provide durable inhibition of the TL1A/DR3 axis and support the clinical development of SL-325 to treat IBD.