Novel receptor for advanced glycation end products-blocking antibody to treat diabetic peripheral artery disease

Lynne L. Johnson; Jordan Johnson; Rebecca Ober; April Holland; Geping Zhang; Marina Backer; Joseph Backer; Ziad Ali; Yared Tekabe

doi:10.1161/JAHA.120.016696

Novel receptor for advanced glycation end products-blocking antibody to treat diabetic peripheral artery disease

Lynne L. Johnson, Jordan Johnson, Rebecca Ober, April Holland, Geping Zhang, Marina Backer, Joseph Backer, Ziad Ali, Yared Tekabe

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose-bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti-RAGE antibody (CR-3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent (201Tl) single-photon emission computed tomography/x-ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [99mTc]dodecane tetra-acetic acid-polyethylene glycol-single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR-3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra-acetic acid-polyethylene glycol-scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR-3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher ²⁰¹Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR-3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE-blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR-3 shows promise for clinical treatment in diabetic peripheral artery disease.

Original language	English
Article number	e016696
Pages (from-to)	1-12
Number of pages	12
Journal	Journal of the American Heart Association
Volume	10
Issue number	1
DOIs	https://doi.org/10.1161/JAHA.120.016696
State	Published - 5 Jan 2021
Externally published	Yes

Keywords

Antibodies
Diabetes mellitus
Peripheral artery disease

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10.1161/JAHA.120.016696

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title = "Novel receptor for advanced glycation end products-blocking antibody to treat diabetic peripheral artery disease",

abstract = "BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose-bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti-RAGE antibody (CR-3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent (201Tl) single-photon emission computed tomography/x-ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [99mTc]dodecane tetra-acetic acid-polyethylene glycol-single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR-3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra-acetic acid-polyethylene glycol-scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR-3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher 201Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR-3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE-blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR-3 shows promise for clinical treatment in diabetic peripheral artery disease.",

keywords = "Antibodies, Diabetes mellitus, Peripheral artery disease",

author = "Johnson, {Lynne L.} and Jordan Johnson and Rebecca Ober and April Holland and Geping Zhang and Marina Backer and Joseph Backer and Ziad Ali and Yared Tekabe",

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doi = "10.1161/JAHA.120.016696",

language = "English",

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T1 - Novel receptor for advanced glycation end products-blocking antibody to treat diabetic peripheral artery disease

AU - Johnson, Lynne L.

AU - Johnson, Jordan

AU - Ober, Rebecca

AU - Holland, April

AU - Zhang, Geping

AU - Backer, Marina

AU - Backer, Joseph

AU - Ali, Ziad

AU - Tekabe, Yared

PY - 2021/1/5

Y1 - 2021/1/5

N2 - BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose-bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti-RAGE antibody (CR-3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent (201Tl) single-photon emission computed tomography/x-ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [99mTc]dodecane tetra-acetic acid-polyethylene glycol-single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR-3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra-acetic acid-polyethylene glycol-scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR-3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher 201Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR-3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE-blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR-3 shows promise for clinical treatment in diabetic peripheral artery disease.

AB - BACKGROUND: Expression of receptor for advanced glycation end products (RAGE) plays an important role in diabetic peripheral artery disease. We proposed to show that treatment with an antibody blocking RAGE would improve hind limb perfusion and muscle viability in diabetic pig with femoral artery (FA) ligation. METHODS AND RESULTS: Purpose-bred diabetic Yucatan minipigs with average fasting blood sugar of 357 mg/dL on insulin to maintain a glucose range of 300 to 500 mg/dL were treated with either a humanized monoclonal anti-RAGE antibody (CR-3) or nonimmune IgG. All pigs underwent intravascular occlusion of the anterior FA. Animals underwent (201Tl) single-photon emission computed tomography/x-ray computed tomography imaging on days 1 and 28 after FA occlusion, angiogenesis imaging with [99mTc]dodecane tetra-acetic acid-polyethylene glycol-single chain vascular endothelial growth factor (scVEGF), muscle biopsies on day 7, and contrast angiogram day 28. Results showed greater increases in perfusion to the gastrocnemius from day 1 to day 28 in CR-3 compared with IgG treated pigs (P=0.0024), greater uptake of [99mTc]dodecane tetra-acetic acid-polyethylene glycol-scVEGF (scV/Tc) in the proximal gastrocnemius at day 7, confirmed by tissue staining for capillaries and vascular endothelial growth factor A, and less muscle loss and fibrosis at day 28. Contrast angiograms showed better reconstitution of the distal FA from collaterals in the CR-3 versus IgG treated diabetic pigs (P=0.01). The gastrocnemius on nonoccluded limb at necropsy had higher 201Tl uptake (percentage injected dose per gram) and reduced RAGE staining in arterioles in CR-3 treated compared with IgG treated animals (P=0.04). CONCLUSIONS: A novel RAGE-blocking antibody improved hind limb perfusion and angiogenesis in diabetic pigs with FA occlusion. Contributing factors are increased collaterals and reduced vascular RAGE expression. CR-3 shows promise for clinical treatment in diabetic peripheral artery disease.

KW - Antibodies

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KW - Peripheral artery disease

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Novel receptor for advanced glycation end products-blocking antibody to treat diabetic peripheral artery disease

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Keywords

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