A Novel Nanobody-Heavy Chain Antibody Against Angiopoietin-Like Protein 3 Reduces Plasma Lipids and Relieves Nonalcoholic Fatty Liver Disease

Background Nonalcoholic fatty liver disease (NAFLD) is a metabolic disease mainly on account of hypercholesterolemia and may progresses to cirrhosis and hepatocellular carcinoma. The discovery of effective therapies for NAFLD is a critical unmet need. Angiopoietin-like protein 3 (ANGPTL3), a critical lipid metabolism regulator, cause elevated blood lipids and are elevated in NAFLD. Here, we develop a nanobody-heavy chain antibody (VHH-Fc) to inhibit ANGPTL3 for NAFLD treatment. Results In this study, we screened out a anti-ANGPTL3 VHH and Fc fusion protein, C44-Fc, which exhibited a high affinity to human and mouse ANGPTL3 proteins at 0.1402~0.2088 nM and rescued ANGPLT3-mediated inhibition of lipoprotein lipase (LPL) activity. The C44-Fc had different ANGPTL3 binding epitope, a double expression yield and better thermostability when compared with the evinacumab, maintaining no obvious degradation or aggregation at low and high pH, 40°C for 28 days, and freeze-thaw. Furthermore, C44-Fc significantly ameliorated the triglyceride (~44.2%), total cholesterol (~36.6%) and LDL-cholesterol (~54.4%) levels in hypercholesterolemic mice and ameliorated hepatic lipid accumulation and liver injury in NAFLD mice. Conclusions We discover a VHH-Fc fusion protein with high affinity to ANGPTL3 and alleviates the progression of NAFLD, which offers a prospective therapy for NAFLD.