Inhibition of selectin binding

Abstract

This invention provides compositions for inhibiting the binding between two cells, one expressing P- or L-selectin on the surface and the other expressing the corresponding ligand. A covalently crosslinked lipid composition is prepared having saccharides and acidic group on separate lipids. The composition is then interposed between the cells so as to inhibit binding. Inhibition can be achieved at an effective oligosaccharide concentration as low as 10 6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, these composition scan be used to palliate certain inflammatory and immunological conditions.

What is claimed as the invention is:  
     
         1 . A composition for inhibiting the binding between a first cell having a P- or L selectin and a second cell having a ligand for the selectin, comprising a sheet of lipids wherein a proportion of the lipids are covalently crosslinked, a proportion of the lipids have an attached saccharide, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH.  
     
     
         2 . The composition of    claim 1   , wherein the saccharide is a sialylated fucooligosaccharide or analog thereof.  
     
     
         3 . The composition of    claim 1   , wherein the saccharide is a sulfated fucooligosaccharide.  
     
     
         4 . Th composition of    claim 1    wherein the attached saccharide is a neutral saccharide.  
     
     
         5 . The composition of    claim 1   , wherein the saccharide is selected from the group consisting of lactose and maltose.  
     
     
         6 . The composition of    claim 1    wherein the attached saccharide is a disaccharide.  
     
     
         7 . The composition of    claim 1    wherein a proportion of the lipids having an attached saccharide are covalently crosslinked to other lipids in the sheet.  
     
     
         8 . The composition of    claim 1    wherein a proportion of lipids having an attached saccharide are not covalently crosslinked to other lipids in the sheet.  
     
     
         9 . The composition of    claim 1   , wherein a proportion of the lipids in the lipid sheet have a first attached saccharide, and a separate proportion of the lipids in the lipid sheet have a second attached saccharide that is different from the first.  
     
     
         10 . The composition of    claim 1   , wherein the first attached saccharide is fucose and the second attached saccharide is a sulfated or acidic monosaccharide.  
     
     
         11 . The composition of    claim 1   , wherein the acid group is a carboxylic acid.  
     
     
         12 . The composition of    claim 1   , wherein the acid group is a negatively charged sulfate or phosphate group.  
     
     
         13 . The composition of    claim 1   , wherein the lipid sheet is comprised in the lipid bilayer of a liposome.  
     
     
         14 . The composition of    claim 1   , wherein the lipids each contain a single aliphatic hydrocarbon.  
     
     
         15 . The composition of    claim 1   , wherein the composition inhibits binding of the ligand to the selectin.  
     
     
         16 . The composition of    claim 1   , wherein the composition has a 50% inhibition concentration (IC 50 ) that is 10 2 -fold lower than that of monomer sLe x .  
     
     
         17 . The composition of    claim 1   , wherein the composition has a 50% inhibition concentration (IC 50 ) that is 10 4 -fold lower than that of monomer sLe x .  
     
     
         18 . The composition of    claim 1   , wherein the composition has an IC 50  in a selectin-to-cell binding assay of less than 100 nM.  
     
     
         19 . The composition of    claim 1   , wherein the selectin is P-selectin.  
     
     
         20 . The composition of    claim 1   , wherein the selectin is L-selectin.