Cytokine-based fusion proteins for treatment of immune disorders
The present invention provides fusion proteins including an autoimmune antigen, an allergen antigen or an alloantigen, and an anti-inflammatory cytokine. Compositions and methods including the fusion proteins are also provided.
1. A fusion protein comprising:
an autoimmune antigen selected from the group consisting of a myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) or myelin-associated oligodendrocytic basic protein; and
an anti-inflammatory cytokine selected from the group consisting of an interleukin, interleukin receptor antagonist, interferon-beta (IFN-β) and transforming growth factor-beta (TGF-β).
2. The fusion protein of claim 1 , wherein the autoimmune antigen comprises an encephalitogenic determinant of the protein.
3. The fusion protein of claim 2 , wherein the encephalitogenic determinant of the myelin basic protein comprises the amino acid sequence of SEQ ID NO:2.
4. The fusion protein of claim 1 , wherein the interleukin is interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin 13 (IL-13), or interleukin-16 (IL-16)) and the interleukin receptor antagonist is interleukin-1RA (IL-1RA).
5. The fusion protein of claim 1 , wherein the autoimmune antigen is covalently linked directly or through a linking moiety.
6. The fusion protein of claim 1 , wherein the autoimmune antigen is a myelin basic protein.
7. The fusion protein of claim 1 , wherein the autoimmune antigen is a proteolipid protein.
8. The fusion protein of claim 1 , wherein the autoimmune antigen is a myelin oligodendrocyte glycoprotein.
9. An isolated nucleic acid encoding the fusion protein of claim 1 .
10. A vector comprising the isolated nucleic acid of claim 9 .
11. An isolated host cell comprising the vector of claim 10 .
12. A method of making a fusion protein comprising:
(a) culturing an isolated host cell of claim 11 ; and
(b) collecting the encoded fusion protein from said culture.
13. A method of treating multiple sclerosis in a subject comprising administering to the subject an effective amount of the fusion protein of claim 1 .
14. The method of claim 13 , wherein the autoimmune antigen is a myelin basic protein.
15. The method of claim 14 , wherein an encephalitogenic determinant of the myelin basic protein comprises the amino acid sequence of SEQ ID NO:2.
16. A composition comprising:
(a) at least one fusion protein comprising (i) an autoimmune antigen selected from the group consisting of a myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) or myelin-associated oligodendrocytic basic protein, and (ii) an anti-inflammatory cytokine selected from the group consisting of an interleukin, interleukin receptor antagonist, interferon-beta (IFN-β) and transforming growth factor-beta (TGF-β); and
(b) a pharmaceutically acceptable carrier, excipient or diluent, and when two or more fusion proteins are present, at least one fusion protein comprises an anti-inflammatory cytokine that is different from the anti-inflammatory cytokine of least one other fusion protein.
17. A kit comprising one or more containers having pharmaceutical dosage units comprising an effective amount of a fusion protein, wherein the container is packaged with optional instructions for the use thereof; said fusion protein comprising an autoimmune antigen selected from the group consisting of a myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) or myelin-associated oligodendrocytic basic protein; and an anti inflammatory cytokine selected from the group consisting of an interleukin, interleukin receptor antagonist, interferon-beta (IFN-β) and transforming growth factor-beta (TGF-β).