Rage fusion proteins and methods of use
View Patent ↗Disclosed are RAGE fusion proteins comprising RAGE polypeptide sequences linked to a second, non-RAGE polypeptide. The RAGE fusion protein may utilize a RAGE polypeptide domain comprising a RAGE ligand binding site and an interdomain linker directly linked to an immunoglobulin C H 2 domain. Such fusion proteins may provide specific, high affinity binding to RAGE ligands. Also disclosed is the use of the RAGE fusion proteins as therapeutics for RAGE-mediated pathologies.
1. A method of treating Alzheimer's Disease or amylodosis in a subject comprising administering to a subject a fusion protein,
wherein the fusion protein comprises
(a) a Receptor for Advanced Glycation Endproducts (RAGE) polypeptide which comprises a first RAGE immunoglobulin domain and a first RAGE interdomain linker linked to a second RAGE immunoglobulin domain and a second RAGE interdomain linker, such that the N-terminal amino acid of the first RAGE interdomain linker is linked to the C-terminal amino acid of the first RAGE immunoglobulin domain, the N-terminal amino acid of the second RAGE immunoglobulin domain is linked to the C-terminal amino acid of the first RAGE interdomain linker, and the N-terminal amino acid of the second RAGE interdomain linker is linked to the C-terminal amino acid of the second RAGE immuno globulin domain,
wherein the RAGE polypeptide comprises a RAGE ligand binding site,
wherein the second RAGE interdomain linker comprises SEQ ID NO: 22 or a sequence 90% identical thereto, and
wherein the C-terminal amino acid of the second RAGE interdomain linker is directly linked to the N-terminal amino acid of
(b) a non-RAGE polypeptide comprising at least a portion of a C H 2 domain of an immunoglobulin and a C H 3 domain of an immunoglobulin, and
wherein the fusion protein does not include an immunoglobulin Fc hinge region.
2. The method of claim 1 , wherein the RAGE ligand binding site comprises SEQ ID NO: 9 or a sequence 90% identical thereto, or SEQ ID NO: 10 or a sequence 90% identical thereto.
3. The method of claim 1 , wherein the RAGE polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 7 or the amino acid sequence as set forth in SEQ ID NO: 8.
4. The method of claim 1 , wherein the RAGE polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 13 or the amino acid sequence as set forth in SEQ ID NO: 14.
5. The method of claim 1 , wherein the RAGE polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 17 or the amino acid sequence as set forth in SEQ ID NO: 18.
6. The method of claim 1 , wherein the RAGE polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 19 or the amino acid sequence as set forth in SEQ ID NO: 20.
7. The method of claim 1 , wherein the amino acid sequence of the RAGE polypeptide is as set forth in SEQ ID NO: 19 or SEQ ID NO: 20.
8. The method of claim 1 , wherein the amino acid sequence of the non-RAGE polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 38.
9. The method of claim 1 , wherein the amino acid sequence of the non-RAGE polypeptide is as set forth in SEQ ID NO: 38.
10. The method of claim 1 , wherein the fusion protein comprises the amino acid sequence SEQ ID NO: 33 or SEQ ID NO: 34.
11. The method of claim 1 , wherein the non-RAGE polypeptide is derived from a human IgA, IgD, IgE, IgG or IgM.
12. The method of claim 11 , wherein the non-RAGE polypeptide is derived from a human IgG.
13. The method of claim 12 , wherein the non-RAGE polypeptide is derived from a human IgG 1 .
14. The method of claim 1 , wherein the fusion protein is used to treat Alzheimer's disease.
15. The method of claim 1 , wherein the fusion protein is used to treat amyloidosis.
16. The method of claim 1 , comprising intravenous administration of the fusion protein to the subject.
17. The method of claim 1 , comprising intraperitoneal administration of the fusion protein to the subject.
18. The method of claim 1 , comprising subcutaneous administration of the fusion protein to the subject.