Related Experiment Video
Updated: Jul 11, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Biparatopic anti-PCSK9 antibody enhances the LDL-uptake in HepG2 cells
Xinyang Li1, Wei Zhang2, Yu Shu3
1College of Life Science and Engineering, Henan University of Urban Construction, Ping Dingshan, 467036, China. yipinyoulan521@163.com.
Abstract:
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.
Insights
A new biparatopic antibody, B11-H2-Fc, significantly enhances Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for lipid reduction. This novel antibody demonstrates superior efficacy and druggability compared to previous versions, offering a promising therapeutic strategy.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key target for lipid-lowering therapies.
- Previous development yielded VHH-B11-Fc, a camelid-human heavy chain antibody targeting PCSK9.
- VHH-B11 binds a linear epitope in the PCSK9 hinge region, necessitating enhanced therapeutic potential.
Purpose of the Study:
- To develop a novel biparatopic antibody, B11-H2-Fc, with enhanced druggability for PCSK9 inhibition.
- To evaluate the binding affinity, epitope profile, and in vitro efficacy of B11-H2-Fc compared to existing therapies.
Main Methods:
- Surface Plasmon Resonance (SPR) was used to confirm epitope differences and measure binding avidity.
- PCSK9 inhibition efficiency was assessed in vitro at a concentration of 7.4 nM.
- Biological activity was verified using a human hepatoma G2 cell model and low-density lipoprotein cholesterol (LDL-c) uptake assays.
Main Results:
- B11-H2-Fc demonstrated significantly higher avidity (approx. 0.036 nM) for PCSK9 compared to VHH-B11-Fc (approx. 0.69 nM).
- B11-H2-Fc achieved >95% PCSK9 inhibition efficiency, comparable to Repatha, and superior to VHH-Fc (approx. 48%).
- In cellular assays, B11-H2-Fc exhibited nearly 100% PCSK9 inhibition and effectively restored LDL-c receptor (LDLR) function, similar to Repatha.
Conclusions:
- The novel biparatopic antibody B11-H2-Fc shows enhanced avidity and potent PCSK9 inhibition.
- B11-H2-Fc effectively restores LDLR function, indicating strong therapeutic potential for lipid-lowering.
- These findings represent the first evidence of this novel antibody's efficacy in the field of lipid-lowering drugs.
