Abstract Background Tumor necrosis factor–like ligand 1A (TL1A) amplifies effector cell responses and contributes to inflammatory bowel disease (IBD) pathogenesis. TL1A is expressed by macrophages, dendritic cells and T cell subsets, and active forms of TL1A can be either membrane-bound or soluble trimers. TL1A primarily signals through death receptor 3 (DR3), activating NF-κB pathways in effector T cells and innate lymphoid cells. Afimkibart, a fully human monoclonal antibody that selectively neutralizes trimeric TL1A, has shown clinical benefit in Phase 2 trials for ulcerative colitis. In addition to blocking TL1A–DR3 signaling, afimkibart inhibits TL1A binding to its decoy receptor DcR3. Because anti-TL1A agents differ in their ability to inhibit TL1A–DcR3 binding, the functional significance of this interaction was investigated. Methods Serum samples from the Ph2a TUSCANY clinical trial were analyzed to assess correlations between DcR3 levels and afimkibart efficacy, measured by modified Mayo score (mMS) and endoscopy score. Additionally, recombinant DcR3 was compared with afimkibart, firstly using surface plasmon resonance (SPR) to evaluate TL1A binding, and secondly in vitro assays to measure NF-κB signaling blockade in primary immune cells and cell lines. Results Baseline serum and tissue DcR3 concentrations showed no correlation with clinical response (remitters vs non-remitters) and remained unchanged after afimkibart treatment. In vitro, DcR3 was approximately 10-fold less potent than afimkibart in blocking TL1A–DR3 signaling, while circulating DcR3 levels were at least 1,000-fold lower than afimkibart concentrations. These findings indicate that afimkibart possesses sufficient potency to effectively compete with DcR3 for TL1A binding, and that its blockade of TL1A–DR3 signaling likely renders TL1A–DcR3 interactions functionally redundant. Furthermore, afimkibart treatment did not alter the levels or downstream signaling of Fas ligand and LIGHT—other known DcR3 binders—compared with placebo, indicating that the protective mechanisms of DcR31-4 to neutralize Fas ligand and LIGHT were not diminished by afimkibart. Conclusion DcR3 appeared to have limited impact on TL1A–DR3 inhibition or clinical response to afimkibart in this exploratory analysis of the TUSCANY study. The lower cellular potency and circulating levels of DcR3, together with the absence of a clear association for DcR3 with clinical remission, suggest that afimkibart may be sufficient for blockade of TL1A signaling. However, given that these findings are based on a single-arm study of 50 patients, they should be confirmed in larger, placebo-controlled studies. References: 1. Migone TS, et al. Immunity 2002;16(3):479–92. 2. Meylan F, et al. Immunity 2008;29(1):79–89. 3. Zhan C, et al. Structure 2011;19(2):162–71. 4. Lin WW, Hsieh SL. Biochem Pharmacol 2011;81(7):838–47. Conflict of interest: Fuh, Franklin: Employment and stock/stock options at Genentech Inc. Varfolomeev, Eugene: I am an employee and shareholder of Genentech-Roche. Nguyen, Allen: I am employed by Genentech, Inc., a subsidiary of Roche, Inc. I own Roche shares/stock. Chang, Sarah: I am a full-time employee of Genentech, Inc., a wholly owned subsidiary of Roche, and receive Roche stock/options. Oh, Angela: I am an employee of Genentech, Inc. and have Roche stock. Merana, Geil: I am an employee and shareholder of Genentech-Roche. Tao, Xiao: I am a full-time employee of Genentech, Inc. (a Roche subsidiary) where the data is sourced/generated. And I am a Roche stock owner. Place, David: Full time employee of Genentech, Inc., a wholly owned subsidiary of Roche. Roche stock/options. Banerjee, Anindita: Employee and stockholder of Pfizer. Chandra, Deepa E.: Employee at Pfizer and own stock at Pfizer. Peeva, Elena: I am a full time employee of Pfizer and hold Pfizer stock. Neelakantan, Srividya: Pfizer employee and hold Pfizer stocks. Vincent, Michael S.: MSV is an employee and shareholder of Pfizer Inc. Dr. Neighbors, Maggie: I am a full-time employee of Genentech, Inc., a wholly owned subsidiary of Roche, and receive Roche stock/options. Vucic, Domagoj: I am an employee and shareholder of Genentech-Roche. Mohanan, Vishnu: Full time employee of Genentech/Roche and holds Roche shares.
Fuh et al. (Thu,) studied this question.