Bispecific antibodies targeting TL1A and IL-12/23p40 suppress pathogenic Th1/Th17 responses and ameliorate colitis in mice
Abstract
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.
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BibTeX
@article{li2026bispecific,
title = {{Bispecific antibodies targeting TL1A and IL-12/23p40 suppress pathogenic Th1/Th17 responses and ameliorate colitis in mice}},
author = {Xia Li and Hao Peng and Feng Hao and Yi Gu and Jinying Ning and Changyuan Yu},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117795},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03176-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Bispecific antibodies targeting TL1A and IL-12/23p40 suppress pathogenic Th1/Th17 responses and ameliorate colitis in mice
AU - Xia Li
AU - Hao Peng
AU - Feng Hao
AU - Yi Gu
AU - Jinying Ning
AU - Changyuan Yu
PY - 2026
DA - 2026/10/09
JO - iScience
DO - 10.1016/j.isci.2026.117795
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03176-7
AB - 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.
SN - 2589-0042
ER -