Antibody-drug conjugates targeting CD248 inhibits liver fibrosis through specific killing on myofibroblasts

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 28; no. 1; p. 37
• Main Authors: Liu, Shaojie, Han, Donghui, Xu, Chao, Yang, Fa, Li, Yu, Zhang, Keying, Zhao, Xiaolong, Zhang, Jiayu, Lu, Tong, Lu, Shiqi, Shi, Changhong, Zhang, Rui, Yang, An-Gang, Zhao, Aizhi, Qin, Weijun, Yang, Bo, Wen, Weihong
• Format: Journal Article
• Language: English
• Published: England BioMed Central 22.03.2022; BMC
• Subjects: Animals; Antibodies; Antibody-drug conjugate; Antigens, CD - metabolism; Antigens, Neoplasm - adverse effects; Antigens, Neoplasm - metabolism; Apoptosis; CD248; Cytokines; Fibroblasts; Fibrosis; Flow cytometry; Growth factors; Hepatic Stellate Cells - metabolism; Humans; IgG78-DM1; Immunoconjugates - adverse effects; Immunoconjugates - metabolism; Liver - metabolism; Liver cirrhosis; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver fibrosis; Mice; Myofibroblasts; Myofibroblasts - metabolism; Proteins; United States > US; China; IgG78-DM1; CD248; Liver fibrosis; Myofibroblasts; Antibody-drug conjugate
• DOI: 10.1186/s10020-022-00460-1
• ISSN: 1076-1551

Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. CD248 expression was examined in patients with liver cirrhosis and in mice with CCl -induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl -induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. CD248 expression was upregulated in patients with liver cirrhosis and in CCl -induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA) myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248 activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.