Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization

Sergio Caballero, James Swaney, Kelli Moreno, Aqeela Afzal, Jennifer Kielczewski, Glenn Stoller, Amy Cavalli, William Garland, Geneviève Hansen, Roger Sabbadini, Maria B. Grant

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Abstract

The efficacy of novel monoclonal antibodies that neutralize the pro-angiogenic mediator, sphingosine-1-phosphate (S1P), were tested using in vitro and in vivo angiogenesis models, including choroidal neovascularization (CNV) induced by laser disruption of Bruch's membrane. S1P receptor levels in human brain choroid plexus endothelial cells (CPEC), human lung microvascular endothelial cells, human retinal vascular endothelial cells, and circulating endothelial progenitor cells were examined by semi-quantitative PCR. The ability of murine or humanized anti-S1P monoclonal antibodies (mAbs) to inhibit S1P-mediated microvessel tube formation by CPEC on Matrigel was evaluated and capillary density in subcutaneous growth factor-loaded Matrigel plugs was determined following anti-S1P treatment. S1P promoted in vitro capillary tube formation in CPEC consistent with the presence of cognate S1P1-5 receptor expression by these cells and the S1P antibody induced a dose-dependent reduction in microvessel tube formation. In a murine model of laser-induced rupture of Bruch's membrane, S1P was detected in posterior cups of mice receiving laser injury, but not in uninjured controls. Intravitreous injection of anti-S1P mAbs dramatically inhibited CNV formation and sub-retinal collagen deposition in all treatment groups (p < 0.05 compared to controls), thereby identifying S1P as a previously unrecognized mediator of angiogenesis and subretinal fibrosis in this model. These findings suggest that neutralizing S1P with anti-S1P mAbs may be a novel method of treating patients with exudative age-related macular degeneration by reducing angiogenesis and sub-retinal fibrosis, which are responsible for visual acuity loss in this disease.

Original languageEnglish (US)
Pages (from-to)367-377
Number of pages11
JournalExperimental eye research
Volume88
Issue number3
DOIs
StatePublished - Mar 1 2009

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Keywords

  • age-related macular degeneration
  • animal model
  • anti-angiogenesis
  • choroidal neovascularization
  • fibrosis
  • sphingosine

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Caballero, S., Swaney, J., Moreno, K., Afzal, A., Kielczewski, J., Stoller, G., Cavalli, A., Garland, W., Hansen, G., Sabbadini, R., & Grant, M. B. (2009). Anti-sphingosine-1-phosphate monoclonal antibodies inhibit angiogenesis and sub-retinal fibrosis in a murine model of laser-induced choroidal neovascularization. Experimental eye research, 88(3), 367-377. https://doi.org/10.1016/j.exer.2008.07.012