A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice
© 2024 Federation of American Societies for Experimental Biology..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:38 |
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| Enthalten in: |
FASEB journal : official publication of the Federation of American Societies for Experimental Biology - 38(2024), 1 vom: 17. Jan., Seite e23399 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Panpan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.01.2024 Date Revised 05.02.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1096/fj.202301564RR |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366654934 |
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| 100 | 1 | |a Zhang, Panpan |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice |
| 264 | 1 | |c 2024 | |
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| 500 | |a published: Print | ||
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| 520 | |a © 2024 Federation of American Societies for Experimental Biology. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ANGPTL3 | |
| 650 | 4 | |a Dyslipidemia | |
| 650 | 4 | |a Endothelial lipase | |
| 650 | 4 | |a Fully human antibody | |
| 650 | 4 | |a Lipoprotein lipase | |
| 650 | 7 | |a Angiopoietin-Like Protein 3 |2 NLM | |
| 650 | 7 | |a Cholesterol, LDL |2 NLM | |
| 650 | 7 | |a Angiopoietin-like Proteins |2 NLM | |
| 650 | 7 | |a Triglycerides |2 NLM | |
| 650 | 7 | |a Apolipoproteins B |2 NLM | |
| 650 | 7 | |a ANGPTL3 protein, human |2 NLM | |
| 700 | 1 | |a Wang, Ke |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Tuo |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Menglong |e verfasserin |4 aut | |
| 700 | 1 | |a You, Xiangyan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Manman |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Xuan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Huajing |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Yiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Wenfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Shuhua |e verfasserin |4 aut | |
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