Compositions and methods for treating rage-associated disorders
AssigneeWyeth and Imperial College Innovations Limited
InventorsDebra Pittman, Brian Clancy, Glenn Larsen, William Trepicchio, Fionula Brennan, Marc Feldmann, Brian John Foxwell, Jeffrey Feldman
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Abstract
Fusion proteins comprising a Receptor for Advanced Glycation End Products Ligand Binding Element (RAGE-LBE) and an immunoglobulin element are disclosed. Also disclosed are fusion proteins comprising a RAGE-LBE and a dimerization domain. Also disclosed are nucleic acids encoding such fusion proteins and methods for using disclosed nucleic acids and proteins to, for example, treat RAGE-related disorders. Additional compositions and methods are also disclosed.
Claims84
A fusion protein comprising a Receptor for Advanced Glycation End Product Ligand Binding Element (RAGE-LBE) and an immunoglobulin element.
The fusion protein of claim I, wherein said RAGE-LBE comprises amino acid residues 1 through 330 of the amino acid sequence set forth in FIG. 7.
A fusion protein comprising a RAGE-LBE and a second domain selected from the group consisting of a dimerizing polypeptide, a purification polypeptide, a stabilizing polypeptide, and a targeting polypeptide.
A fusion protein comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of FIG. 3A.
A nucleic acid sequence encoding a polypeptide fusion comprising a RAGE-LBE and an immunoglobulin element.
A nucleic acid sequence encoding a polypeptide at least 90% identical to the amino acid sequence set forth in FIG. 3A.
An isolated antibody, or fragment thereof, specifically immunoreactive with an epitope of the amino acid sequence as set forth in FIG. 3A.
A protein complex comprising one or more fusion proteins, wherein said fusion proteins are selected from the group consisting of:
- a) a fusion protein comprising a RAGE-LBE and an immunoglobulin element;
- and
- b) a fusion protein comprising a RAGE-LBE and a second domain selected from the group consisting of a dimerizing domain, a stabilizing domain, a purification domain, and a targeting domain.
A pharmaceutical composition comprising a RAGE-LBE and a TNF-α inhibitor.
A pharmaceutical composition comprising a fusion protein and a TNF-α inhibitor, wherein said fusion protein comprises a RAGE-LBE and an immunoglobulin element.
A method of identifying a compound which inhibits interaction of a RAGE-BP polypeptide selected from the group consisting of S100 and amphoterin, with a receptor polypeptide selected from the group consisting of RAGE, RAGE-LBE, and RAGE-LBE-Immunoglobulin fusion, comprising:
- a) forming a reaction mixture including:
- (i) a RAGE-BP polypeptide of S100 or amphoterin;
- (ii) a receptor polypeptide of RAGE, RAGE-LBE or RAGE-LBE-Immunoglobulin fusion;
- and (iii) a test compound, under conditions where, in the absence of the test compound, the RAGE-BP polypeptide and the receptor polypeptide interact;
- and
- b) detecting interaction of the RAGE-BP polypeptide with the receptor polypeptide,
- wherein a decrease in the interaction of the RAGE-BP polypeptide and the receptor polypeptide in the presence of the test compound, relative to the level of interaction in the absence of the test compound, indicates an inhibitory activity for the test compound.
A method of identifying a compound which inhibits the RAGE signaling activity induced by a RAGE-BP polypeptide selected from the group consisting of S100 and amphoterin, comprising:
- a) contacting a cell with a RAGE-BP polypeptide of S100 or amphoterin;
- b) contacting the cell with a test compound, under conditions where, in the absence of the test compound, the signaling activity of the RAGE occurs normally;
- and
- c) detecting the signaling activity of the RAGE induced by the RAGE-BP, wherein a decrease in the signaling activity of the RAGE induced by the RAGE-BP in the presence of the test compound, relative to the level of signaling activity in the absence of the test compound, indicates an inhibitory activity for the test compound.
A method of inhibiting the interaction between Receptor for Advanced Glycation End Product (RAGE) and a RAGE binding partner (RAGE-BP) comprising administering a fusion protein comprising RAGE-LBE and an immunoglobulin.
A method of decreasing the activity of endogenous RAGE comprising administering a fusion protein comprising RAGE-LBE and an immunoglobulin.
A method of treating a RAGE-associated disorder comprising administering a fusion protein comprising RAGE-LBE and an immunoglobulin.
A method of treating a RAGE-associated disorder comprising administering a composition comprising TNF-α inhibitor and at least one RAGE-LBE or a fusion protein comprising RAGE-LBE and an immunoglobulin.
A method of treating a RAGE-associated disorder comprising administering a composition comprising at least a fusion protein comprising RAGE-LBE and an immunoglobulin.
Dependencies are inferred from the claim text.