Sphingosine-1-phosphate antibodies as potential agents in the treatment of cancer and age-related macular degeneration

We explore potential treatment strategies for these disorders, including the utility of anti-S1P antibodies acting as molecular sponges to neutralize dysregulated S1P in relevant tissues

Roger A. Sabbadini

2010

Scholarcy highlights

  • Sphingosine-1-phosphate is a pleiotropic bioactive lipid thought to be dysregulated in a variety of disease conditions
  • Recent reports have shown that S1P exhibits cross-talk with other profibrotic signalling pathways such as transforming growth factor b and platelet-derived growth factor, and S1P stimulates the expression of connective tissue growth factor, a protein implicated in numerous fibrotic disorders as well as in wet age-related macular degeneration
  • While human choroidal and retinal endothelial cells express SphK1 as a potential source for S1P in the posterior segment of the eye, we propose that the retinal pigmented epithelium layer could be the major source of S1P in injured eyes and that the release of S1P from the RPE cells acts in a paracrine manner to stimulate choroidal ECs to participate in pathological neovascularization
  • The profound pro-fibrotic effects of S1P on cells from multiple regions of the eye and the anti-fibrosis data in mice suggest that sonepcizumab or other anti-S1P therapies could be efficacious in disorders such as pigmented epithelial detachment, peripheral vitreoretinopathy and various anterior-segment diseases, including intraocular pressure disorders such as glaucoma
  • Dysfunctional angiogenesis is common to cancer and to wet AMD). Both are hyperproliferative disorders; the cancer being one of transformed, mitotically active primary cells and AMD being complicated by hyperproliferative ECs
  • The pleiotropic nature of S1P in promoting angiogenesis, inflammation, wound healing and cell survival explain the reason why anti-S1P therapy could be useful in controlling both of these disorders
  • The anti-S1P antibody molecular sponge approach is one of several therapeutic strategies that are being explored but holds promise as a novel, first-in-class treatment

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