Bispecific targeting of CHI3L1 and PD-1 as a therapeutic strategy for pulmonary fibrosis

Han-Seok Jeong; Takayuki Sadanaga; Joyce H. Lee; Suchitra Kamle; Bing Ma; Yang Zhou; Sung Jae Shin; Jack A. Elias; Chun Geun Lee

doi:10.1172/jci.insight.201609

Bispecific targeting of CHI3L1 and PD-1 as a therapeutic strategy for pulmonary fibrosis

Han-Seok Jeong,¹ Takayuki Sadanaga,¹ Joyce H. Lee,² Suchitra Kamle,¹ Bing Ma,¹ Yang Zhou,¹ Sung Jae Shin,³ Jack A. Elias,¹ and Chun Geun Lee¹

Published April 28, 2026 - More info

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Abstract

CHI3L1, a chitinase-like protein, is implicated in pulmonary fibrosis, yet its mechanisms incompletely understood. In this study, we demonstrated that CHI3L1 coordinates profibrotic macrophage activation and invasive myofibroblast differentiation, and their crosstalk. In vitro, CHI3L1 drove M2-like macrophage polarization as evidenced by increased CD163, CD206, and PD-L1, and amplified TGF-β1-induced fibroblast responses, including myofibroblast transformation, migration, and invasion. Mechanistically, CHI3L1 enhanced TGF-β1 signaling through SMAD, AKT, and ERK pathways, and PD-L1 was required for CHI3L1/TGF-β1-driven myofibroblast transformation. Co-culture studies further demonstrated the ability of CHI3L1 to induce profibrotic macrophage activation that enhanced myofibroblast transformation mediated via a CD44–PD-L1 axis. In vivo, following bleomycin challenge, CHI3L1 transgenic mice exhibited increased PD-L1⁺ M2 macrophages, PD-L1⁺/PDGFRα⁺ fibroblasts, and PD-1⁺ immune cells compared with wild-type controls. Therapeutically, combined anti-CHI3L1 and anti-PD-1 antibodies, as well as a bispecific anti-CHI3L1-anti-PD-1 antibody, produced greater anti-fibrotic efficacy than monotherapy. These findings demonstrate crosstalk between CHI3L1 and the PD-1/PD-L1 pathway that promotes profibrotic macrophage activation and invasive fibroblast differentiation and support dual targeting of CHI3L1 and PD-1/PD-L1 as a promising therapeutic strategy for pulmonary fibrosis.

Bispecific targeting of CHI3L1 and PD-1 as a therapeutic strategy for pulmonary fibrosis

Han-Seok Jeong,¹ Takayuki Sadanaga,¹ Joyce H. Lee,² Suchitra Kamle,¹ Bing Ma,¹ Yang Zhou,¹ Sung Jae Shin,³ Jack A. Elias,¹ and Chun Geun Lee¹

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Bispecific targeting of CHI3L1 and PD-1 as a therapeutic strategy for pulmonary fibrosis

Han-Seok Jeong,1 Takayuki Sadanaga,1 Joyce H. Lee,2 Suchitra Kamle,1 Bing Ma,1 Yang Zhou,1 Sung Jae Shin,3 Jack A. Elias,1 and Chun Geun Lee1

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Han-Seok Jeong,¹ Takayuki Sadanaga,¹ Joyce H. Lee,² Suchitra Kamle,¹ Bing Ma,¹ Yang Zhou,¹ Sung Jae Shin,³ Jack A. Elias,¹ and Chun Geun Lee¹