Inhibition of selectin binding
AssigneeThe Regents of the University of California
InventorsJon O. Nagy, Wayne R. Spevak, Falguni Dasgupta, Carolyn Bertozzi
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Abstract
This invention provides a system 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.sup.6 fold below that of the free saccharide. Since selectins are involved in recruiting cells to sites of injury, this system can be used to palliate certain inflammatory and immunological conditions.
Claims38
A method of inhibiting binding between a first cell having a P- or L-selectin and a second cell having a ligand for the selectin, comprising the step of permitting a lipid composition to interact with the first cell;
- wherein the lipid composition comprises a sheet of lipids wherein a proportion of the lipids sufficient to stabilize the sheet are covalently crosslinked, a proportion of the lipids have an attached saccharide which meets the carbohydrate binding requirements of selectins, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin.
A method of inhibiting binding between a first cell having a P- or L-selectin and a second cell having a ligand for the selectin, comprising the step of permitting a lipid composition to interact with the first cell;
- wherein the lipid composition comprises a sheet of lipids wherein a proportion of the lipids sufficient to stabilize the sheet are covalently crosslinked, a proportion of the lipids have an attached saccharide that is a neutral saccharide which meets the carbohydrate binding requirements of selectins, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin.
A method of inhibiting binding between a first cell having a P- or L-selectin and a second cell having a ligand for the selectin, comprising the step of permitting a lipid composition to interact with the first cell;
- wherein the lipid composition comprises a sheet of lipids wherein a proportion of the lipids sufficient to stabilize the sheet are covalently crosslinked, a proportion of the lipids have an attached saccharide that is a disaccharide which meets the carbohydrate binding requirements of selectins, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin.
A method of inhibiting binding between a P- or L-selectin and a ligand for the selectin, comprising the step of permitting a lipid composition to interact with the selectin in an environment where the selectin contacts the ligand;
- wherein the lipid composition comprises a sheet of lipids wherein a proportion of the lipids sufficient to stabilize the sheet are covalently crosslinked, a proportion of the lipids have an attached saccharide which meets the carbohydrate binding requirements of selectins, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin.
A method of selecting a polymerized glycoliposome with selectin binding activity, comprising the steps of:
- providing a glycoliposome comprising covalently crosslinked lipids, the crosslinked lipids present in an amount sufficient to stabilize the glycoliposome, a saccharide which meets the carbohydrate binding requirements of selectins attached to a proportion of the covalently crosslinked lipids, and wherein a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin;
- introducing the glycoliposome into an environment comprising a selectin and a cell having a selectin ligand;
- and
- selecting the glycoliposome if the IC.sub.50 is 10.sup.2 -fold lower than that of monomer sLe.sup.x.
A method for treatment of a selectin-mediated disease, comprising administering a pharmacologically effective amount of a composition comprising a sheet of lipids wherein a proportion of the lipids sufficient to stabilize the sheet are covalently crosslinked, a proportion of the lipids have an attached saccharide which meets the carbohydrate binding requirements of selectins, and a proportion of the lipids not having an attached saccharide have an acid group that is negatively charged at neutral pH which meets the anionic binding requirement of P- or L-selectin.
Dependencies are inferred from the claim text.