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A novel fully human anti‐NT‐ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL‐C lowering activities in hyperlipidemia mice.
- Source :
-
FASEB Journal . Jan2024, Vol. 38 Issue 1, p1-20. 20p. - Publication Year :
- 2024
-
Abstract
- Dyslipidemia is characterized by elevated plasma levels of low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG), and TG‐rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin‐like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519‐D95aA against N‐terminal ANGPTL3 (NT‐ANGPTL3), which potently inhibits NT‐ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519‐D95aA shows higher apolipoprotein B (ApoB) and TG‐lowering, and similar LDL‐C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519‐D95aA‐ANGPTL3 complex (10 hydrogen bonds, −65.51 kcal/mol) is more stable than the Evinacumab‐ANGPTL3 complex (4 hydrogen bonds, −63.76 kcal/mol). Importantly, F1519‐D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519‐D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519‐D95aA is a novel fully human anti‐NT‐ANGPTL3 antibody with potent plasma ApoB, TG, and LDL‐C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08926638
- Volume :
- 38
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- FASEB Journal
- Publication Type :
- Academic Journal
- Accession number :
- 174660962
- Full Text :
- https://doi.org/10.1096/fj.202301564RR