Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells

Li，Xinyang1; Zhang，Wei2; Shu，Yu1; Huo，Rui1; Zheng，Chengyang1; Qi，Qi1; Fu，Pengfei1; Sun，Jie1; Wang，Yuhuan1; Wang，Yan1; Lu，Juxu1; Zhao，Xiangjie1; Yin，Guoyou1; Wang，Qingqing3; Hong，Jun1

2024-12-01

10.1038/s41598-024-66290-9

Scientific Reports   影响因子和分区

2045-2322

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce lipids. In 2020, we reported a chimeric camelid-human heavy chain antibody VHH-B11-Fc targeting PCSK9. Recently, it was verified that VHH-B11 binds one linear epitope in the PCSK9 hinge region. To enhance its druggability, we have developed a novel biparatopic B11-H2-Fc Ab herein. Thereinto, surface plasmon resonance (SPR) confirmed the epitope differences in binding-PCSK9 among VHH-B11, VHH-H2 and the approved Repatha. Additionally, SPR revealed the B11-H2-Fc exhibits an avidity of approximately 0.036 nM for PCSK9, representing a considerable increase compared to VHH-B11-Fc (~ 0.69 nM). Moreover, we found the Repatha and B11-H2-Fc exhibited > 95% PCSK9 inhibition efficiency compared to approximately 48% for the VHH-Fc at 7.4 nM (P < 0.0005). Further, we verified its biological activity using the human hepatoma cells G2 model, where the B11-H2-Fc exhibited almost 100% efficiency in PCSK9 inhibition at only 0.75 μM. The immunoblotting results of low-density lipoprotein cholesterol (LDL-c) uptake assay also demonstrated the excellent performance of B11-H2-Fc on recovering the LDL-c receptor (LDLR), as strong as the Repatha (P > 0.05). These findings provide the first evidence of the efficacy of a novel Ab targeting PCSK9 in the field of lipid-lowering drugs.

Epitope Heavy chain antibody LDL-c LDLR

SCI

英语

其他

2-s2.0-85197678420

Scopus

1.College of Life Science and Engineering,Henan University of Urban Construction,Ping Dingshan,467036,China
2.School of Public Health and Emergency Management,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China
3.Employment and Business Startup Service Center,Henan University of Urban Construction,Ping Dingshan,467036,China

Li，Xinyang,Zhang，Wei,Shu，Yu,et al. Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells[J]. Scientific Reports,2024,14(1).

Li，Xinyang.,Zhang，Wei.,Shu，Yu.,Huo，Rui.,Zheng，Chengyang.,...&Hong，Jun.(2024).Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells.Scientific Reports,14(1).

Li，Xinyang,et al."Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells".Scientific Reports 14.1(2024).