Bispecific antibodies targeting TL1A and IL-12/23p40 suppress pathogenic Th1/Th17 responses and ameliorate colitis in mice

Inflammatory bowel disease (IBD) remains a substantial therapeutic challenge, largely due to the limitations of single-target monotherapies. Here, we engineered two bispecific antibodies, KA-4316 and its half-life-extended derivative KA-5817, which co-target TL1A and IL-12/23p40 utilizing a common light chain design and knobs-into-holes Fc engineering. To improve clinical translatability, KA-5817 was modified with YTE Fc mutations to enhance FcRn binding. KA-4316 exhibited high binding affinity for both targets, high monomer purity, and favorable thermal stability. In vitro functional assays demonstrated that KA-4316 potently blocked TL1A-DR3 and IL-12/23p40-IL-12Rβ1 interactions, suppressing downstream signaling and pro-inflammatory cytokine release. In vivo , KA-5817 alleviated pathological severity in dextran sulfate sodium (DSS)-induced colitis in TL1A/IL23A/IL12B triple-humanized mice and showed a prolonged serum half-life in FcRn-humanized mice. KA-4316 and KA-5817 exhibit beneficial manufacturability and favorable biological activity. Our results support dual inhibition of TL1A and IL-12/23p40 as a potential therapeutic strategy for IBD.