DOP033 Pre-Clinical Development of SL-325, a High Affinity DR3 Blocking Antibody, for Durable Blockade of the DR3/TL1A Axis in Inflammatory Bowel Disease
Authors: Schreiber T , de Silva S , Hussain M , Lai A , Franklin D , Patel A , Makani V , Wu D , Pate J , Koppu P , Narkhede A , Lenz K , Miller C , Oien N , Fromm G , Shukla A 
Published: January 2025

Abstract

Background
TL1A blocking antibodies have demonstrated promising clinical remission rates in patients with inflammatory bowel disease (Sands B et al, NEJM 2024). TL1A promotes inflammation through binding to a single receptor, DR3. There are no known signaling ligands for DR3 aside from TL1A. Whereas TL1A is transiently expressed by antigen presenting and endothelial cells at sites of active inflammation in the small and large intestine, DR3 is constitutively expressed by lymphoid cells in the peripheral blood, and throughout the GI tract at both inflamed and adjacent non-inflamed tissue.

Methods
A human DR3 blocking antibody, SL-325, was produced from stably transfected CHO cells and purified using an affinity chromatography capture step, followed by two polishing steps. Sequence equivalents of tulisokibart and RO7790121 were produced by transient transfection and affinity purification. The safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SL-325 were evaluated in a GLP toxicology study in cynomolgus macaques over a 6-week in-life period followed by a 4-week recovery at Charles River Laboratories.

Results
SL-325 binding affinity to human DR3 was measured at 1.3 pM. SL-325 bound to both monomeric and trimeric human DR3 prevented recombinant human TL1A binding with an approximately ~10X improvement in potency in comparison to sequence equivalents of tulisokibart or RO7790121. The DR3 epitope bound by SL-325 did not trigger receptor-mediated endocytosis, and no evidence of SL-325 mediated DR3 agonism was observed in the absence or presence of T cell receptor activation of primary human lymphocytes from healthy donors, or donors with Crohn’s Disease or Ulcerative Colitis. Naïve cynomolgus macaques received 3 doses of intravenous SL-325 (vehicle, 1 mg/kg, 10 mg/kg or 100 mg/kg dose groups), each given two weeks apart, and no evidence of toxicity, organ dysfunction or changes to complete blood counts or metabolic panels were observed. Full and durable DR3 receptor occupancy (RO) was observed in peripheral blood lymphocytes at doses of 1 mg/kg and higher within two hours of infusion and throughout the 14 day inter-dose interval. Serum exposure of free SL-325 increased in a dose proportional manner. No evidence of residual DR3 agonist activity was observed.

Conclusion
These results indicate SL-325 is a high-affinity DR3 blocking antibody with no evidence of toxicity or residual agonism in cynomolgus macaques, and with an RO/PK profile suggestive of extended dosing intervals that will be studied in an upcoming Phase 1 clinical trial.

References
Sands BE, Feagan BG, Peyrin-Biroulet L, Danese S, Rubin DT, Laurent O, Luo A, Nguyen DD, Lu J, Yen M, Leszczyszyn J, Kempinski R, McGovern DPB, Ma C, Ritter TE, Targan S. Phase 2 Trial of Anti-TL1A Monoclonal Antobidy Tulisokibart for Ulcerative Colitis. NEJM 2024;391(12):1119-1129