title: Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization.
abstract: Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that stimulates endothelial cell migration, proliferation, and survival in vitro, and tumor angiogenesis in vivo. In this study, we used a humanized monoclonal antibody (sonepcizumab) that selectively binds S1P to investigate its role in retinal and choroidal neovascularization (NV). Intraocular injection of sonepcizumab significantly reduced macrophage influx into ischemic retina and strongly suppressed retinal NV in mice with oxygen-induced ischemic retinopathy. In mice with laser-induced rupture sites in Bruch's membrane, intraocular injection of sonepcizumab significantly reduced the area of choroidal NV and concomitantly reduced fluorescein leakage from the remaining choroidal NV. Four weeks after intraocular injection of up to 1.8 mg of the sonepcizumab in non-human primates, electroretinograms and fluorescein angiograms were normal, and light microscopy of ocular sections showed no evidence of structural damage. These data show for the first time that S1P stimulates both choroidal and retinal NV and suggest that sonepcizumab could be considered for evaluation in patients with choroidal or retinal NV.
authors.affiliation: Department of Ophthalmology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xie
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Aling
authors.initials: A
authors.lastname: Dong
authors.forename: Aymen
authors.initials: A
authors.lastname: Rashid
authors.forename: Glenn
authors.initials: G
authors.lastname: Stoller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D020256:Choroidal Neovascularization / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008252:Macaca fascicularis; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
references.citation: J Biol Chem. 2002 Nov 8;277(45):42997-3001
references.pmid: 12226078
references.citation: Cancer Cell. 2006 Mar;9(3):225-38
references.pmid: 16530706
references.citation: J Cell Physiol. 2001 Aug;188(2):253-63
references.pmid: 11424092
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10664-9
references.pmid: 12963813
references.citation: J Biol Chem. 2002 Jun 28;277(26):23747-54
references.pmid: 11956190
references.citation: Am J Pathol. 2000 Feb;156(2):697-707
references.pmid: 10666398
references.citation: J Clin Invest. 2004 Oct;114(8):1082-9
references.pmid: 15489955
references.citation: J Biol Chem. 2001 Apr 6;276(14):10627-33
references.pmid: 11134047
references.citation: N Engl J Med. 2006 Oct 5;355(14):1419-31
references.pmid: 17021318
references.citation: Circ Res. 2003 Nov 28;93(11):1074-81
references.pmid: 14576200
references.citation: J Leukoc Biol. 2003 Jul;74(1):25-32
references.pmid: 12832439
references.citation: J Clin Invest. 2000 Oct;106(8):951-61
references.pmid: 11032855
references.citation: J Biol Chem. 2001 Apr 13;276(15):11830-7
references.pmid: 11150298
references.citation: Biochem Biophys Res Commun. 1999 Nov 2;264(3):743-50
references.pmid: 10544002
references.citation: Am J Pathol. 1998 Nov;153(5):1641-6
references.pmid: 9811357
references.citation: J Biol Chem. 1990 Jun 5;265(16):9308-13
references.pmid: 2160972
references.citation: N Engl J Med. 2006 Oct 5;355(14):1432-44
references.pmid: 17021319
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10457-61
references.pmid: 7479819
references.citation: Science. 1998 Mar 6;279(5356):1552-5
references.pmid: 9488656
references.citation: J Clin Invest. 2007 Sep;117(9):2506-16
references.pmid: 17710232
references.citation: FASEB J. 2007 Oct;21(12):3219-30
references.pmid: 17522382
references.citation: Ophthalmology. 1992 Jun;99(6):933-43
references.pmid: 1630784
references.citation: J Exp Med. 2005 Jan 3;201(1):49-54
references.pmid: 15623571
references.citation: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4335-41
references.pmid: 17724225
references.citation: Eye (Lond). 1990;4 ( Pt 4):613-21
references.pmid: 2226993