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

Abstract

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid thought to be dysregulated in a variety of disease conditions. In this review, we discuss the roles of S1P in cancer and in wet age-related macular degeneration. We also 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. AbbreviationsAMD, age-related macular degeneration; CNV, choroidal neovascularization; GLP, good laboratory practices; NHP, non-human primate; PED, pigmented epithelial detachment; RPE, retinal pigmented epithelium; S1P, sphingosine-1-phosphate; SphK, sphingosine kinase Sphingosine-1-phosphate is an attractive target for drug discoveryBioactive lipids are important signalling mediators that are becoming attractive targets for drug discovery because of their roles in cancer, inflammation and other pathological conditions. Examples of such bioactive lipids include: (i) eicosanoids (such as the thromboxanes and leukotrienes); (ii) phospholipids and their lysophospholipid derivatives such as platelet activating factor (PAF) and lysophosphatidic acid; and (iii) sphingolipids such as sphingosine-1-phosphate (S1P). In recent years, receptors and other targets have been discovered for many of these bioactive lipids, suggesting extracellular signalling roles for these lipid mediators and growth factors (Im, 2009). One difficulty in targeting proteins that are responsible for their dysregulation in disease is that there are commonly several biosynthetic pathways for a particular bioactive lipid. Equally challenging is that there are commonly several receptors, ion channels or other proteins responsible for the action of a particular bioactive lipid and, in some cases, not all of the receptors that have been elucidated as novel receptors continue to appear in the literature (Im, 2009).Of the 1000 or so bioactive lipids, sphingolipids are recognized as important intercellular and intracellular signalling molecules participating in physiological and pathological processes associated with cellular survival, proliferation, differentiation and adhesion function (Moolenaar, 1999;Goetzl et al., 2002;Birgbauer and Chun, 2006;Gardell et al., 2006). The key elements of the sphingomyelin-associated signalling pathway include the bioactive lipid mediators, ceramide (CER), sphingosine (SPH) and S1P.The most celebrated sphingolipid mediator is S1P whose well-documented pleiotropic biological activities are mediated via a family of G protein-coupled cell surface receptors (GPCRs) belonging to the family of endothelial differentiation genes (EDG). These high-affinity receptors are S1P 1-5/ EDG-1,3,5,6 and 8 and are coupled to heterotrimeric G-proteins (Gi/o, Gq-, Gi-, G12-13) and small GTPases of the Rho family (Anliker and Chun, 2004). Most of the BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) growth-promoting actions of S1P described in multiple organ sy...

S1PR1 is an effective target to block STAT3 signaling in activated B cell–like diffuse large B-cell lymphoma

“…In addition to FTY720, a promising drug to target this pathway, is an antibody against S1P ligand, which has been shown to effectively inhibit primary tumor growth in various mouse models and has recently entered clinical trials for other indications. 35,40 Another possibility is the use of a novel in vivo siRNA delivery technology, CpG oligonucelotide-conjugated siRNA, to specifically target Toll-like receptor 9-positive cells. 41,42 Toll-like receptor 9-positive cells include normal macrophages and B cells and various types of malignant myeloid and B cells, including ABC-DLBCL.…”

mAbs Targeting Apoptosis, Angiogenesis Inhibitors, and Other mAbs in Phase 1 and 2 Clinical Studies for Immunological Disorders

“…It has high affinity and specificity for S1P and blocks S1P-mediated release of the proangiogenic factors IL-8, IL-6, and VEGF from tumor cells in vitro and in vivo, out-competing S1P receptors in binding to S1P [60,[73][74][75]. Sonepcizumab (or it murine counterpart Sphingomab) has demonstrated antipermeability (reduced vascular leakage) and antiangiogenic activity after IVT administration in murine CNV models [67,68,74] and antiangiogenic activity in several mouse and human cancer models, where it retarded the progression of several orthotopic and SC human tumors implanted in nude mice [60].…”

“…It has shown better efficacy than bevacizumab, tyrosine kinase inhibitors, and paclitaxel in mouse models of renal cell carcinoma (RCC), and ovarian and lung cancer, respectively (www.LPath.com). Regarding safety, 4 weeks after intraocular injection of up to 1.8 mg of sonepcizumab in non-human primate (NHPs), electroretinograms and fluorescein angiograms were normal, and light microscopy of ocular sections showed no evidence of structural damage [75]. Safety was further supported by toxicology studies in NHPs and mice (with Shingomab) with no adverse events observed at high-dose levels and only a slight decrease in blood lymphocytes at 100 mg kg −1 , expected because of the role of S1P in controlling lymphocyte trafficking [75].…”

“…Regarding safety, 4 weeks after intraocular injection of up to 1.8 mg of sonepcizumab in non-human primate (NHPs), electroretinograms and fluorescein angiograms were normal, and light microscopy of ocular sections showed no evidence of structural damage [75]. Safety was further supported by toxicology studies in NHPs and mice (with Shingomab) with no adverse events observed at high-dose levels and only a slight decrease in blood lymphocytes at 100 mg kg −1 , expected because of the role of S1P in controlling lymphocyte trafficking [75]. However, another study showed sphingomab to cause B-and T-cell lymphopenia [77] and hence limiting systemic exposure in AMD through IVT injection should reduce concerns around systemic immunosuppression.…”

Antibodies to Bioactive Lysophospholipids

“…While intracellular targets such as histone deacetylases 1 and 2 (7) as well as TRAF2 (8) have been described, most of the described effects of S1P on cellular processes have been associated with the extracellular functions of S1P mediated through signaling events employing the S1P GPCRs. Thus, one potential therapeutic intervention point is to target the bioactive lipid directly so that it no longer acts as a ligand for its cognate GPCRs or other sites of action (9,10). One way that has been employed to block S1P actions involves the generation of monoclonal antibodies (mAbs) that could act as a molecular sponges to neutralize the bioactive lipid and prevent ligand-receptor signaling (11,12).…”