Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice.
We used gene knockout mice to explore the role of Angiopoietin-like-4 (Angptl4) in lipid metabolism as well as to generate anti-Angptl4 mAbs with pharmacological activity. Angptl4 -/- mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 -/- suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE -/-, LDLr -/-, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 -/- mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease.
Desai
Urvi
U
Department of Pharmaceutical Biology, Lexicon Pharmaceuticals, Inc., 8800 Technology Forest Place, The Woodlands, TX, 77381, USA.
Lee
E-Chiang
EC
Chung
Kyu
K
Gao
Cuihua
C
Gay
Jason
J
Key
Billie
B
Hansen
Gwenn
G
Machajewski
Dennis
D
Platt
Kenneth A
KA
Sands
Arthur T
AT
Schneider
Matthias
M
Van Sligtenhorst
Isaac
I
Suwanichkul
Adisak
A
Vogel
Peter
P
Wilganowski
Nat
N
Wingert
June
J
Zambrowicz
Brian P
BP
Landes
Greg
G
Powell
David R
DR
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000096:biosynthesis; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000097:blood
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001798:Blood Proteins; D000960:Hypolipidemic Agents; D008055:Lipids; D008079:Lipoproteins, VLDL; D014280:Triglycerides