P0122A trimer-disassembling anti-TL1A monoclonal antibody

Abstract Background Dysregulated cytokine networks are associated with inflammatory diseases like inflammatory bowel disease (IBD). TL1A, a TNF superfamily member, plays a key role in both inflammation and fibrosis via interaction with its receptor DR3. Several clinical-stage anti-TL1A antibodies have shown promising efficacy in patients with IBD. However, there remains a need to further improve efficacy, safety, and dosing intervals. Here, we characterize a humanized anti-TL1A antibody with a unique mechanism of action (MoA) that functions by dissociating TL1A trimers into monomers, thereby blocking TL1A-DR3 signaling and minimizing immunogenicity risk. Methods Humanized anti-TL1A antibodies were identified from immune repertoire mining and optimized for FcRn-mediated recycling as described previously. Antibody-TL1A complex formation was analyzed by BLI, SEC-HPLC and cryo-EM. TL1A-mediated signaling was evaluated in TF-1 cells. Pharmacokinetics (PK) study was conducted in non-human primates following a single intravenous dose. Results Monomeric TL1A showed no effector function in TF-1 cells. Distinct from other anti-TL1A antibodies, this antibody dissociated TL1A trimers into monomers in vitro, providing a unique mechanism of functional inhibition and reduced immunogenicity. In SEC-HPLC, the antibody was able to dissociate the partially stabilized TL1A trimer with a separate monomer chain, but not the fully stabilized single-chain TL1A trimer. Further, molecular dynamics simulations indicated a potential conformational change of the TL1A trimer upon antibody binding. Only the antibody-monomer complex, but not the antibody-trimer complex, was well sampled in vitro and resolved by cryo-EM. Consistent with previous preliminary results, a longer-term PK evaluation in NHPs demonstrated an extended serum half-life versus clinical-stage antibodies, potentially contributed by both Fc engineering and unique MoA. Conclusion This humanized anti-TL1A antibody adopts a novel trimer-disassembling mechanism to inhibit TL1A signaling and limit large immune complex formation. Further development of multivalent, multispecific formats targeting TL1A and orthogonal pathways (e.g., IL-23) is warranted to raise the efficacy ceiling for the treatment of IBD. Reference: Zhou Y, Li H, Su H, Zhao M, Wang H, Wang Q, Zhang X, Fan Y, Li L, Wang M, Xia J, Zong W, Li J, Yi S, Zou B, Lu Z, Wang Y, Zhu Y, Yang L, Pei Z, Duplantis B, Wang Y, Li Y, Yu Q. Preclinical Development of a Novel TL1A-Targeting Antibody with Extended Half-life and Low Immunogenicity Risk for the Treatment of Inflammatory Diseases abstract. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/preclinical-development-of-a-novel-tl1a-targeting-antibody-with-extended-half-life-and-low-immunogenicity-risk-for-the-treatment-of-inflammatory-diseases/. Accessed November 17, 2025. Conflict of interest: Zhou, Yali: No conflict of interest Li, Huilin: No conflict of interest Su, Hang: No conflict of interest Zhao, Mingjun: No conflict of interest Wang, Haiying: No conflict of interest Wang, Qiong: No conflict of interest Zhang, Xiaojin: No conflict of interest Fan, Yanliu: No conflict of interest Li, Lulu: No conflict of interest Wang, Miaomiao: No conflict of interest Xia, Jinglu: No conflict of interest Zong, Wenyue: No conflict of interest Li, Jingjing: No conflict of interest Yi, Simin: No conflict of interest Zou, Bing: No conflict of interest Lu, Zhen: No conflict of interest Xu, Jiawei: No conflict of interest Wang, Wanqiu: No conflict of interest Sheng, Xing: No conflict of interest Wang, Yali: No conflict of interest Zhu, Yupeng: No conflict of interest Yang, Lingjian: No conflict of interest Pei, Zenglin: No conflict of interest Duplantis, Barry: No conflict of interest Dr. Wang, Yuhao: No conflict of interest Yu, Quan: No conflict of interest Li, Yi: No conflict of interest