Use of HMGB fragments as anti-inflammatory agents
View Patent ↗Compositions and methods are disclosed for inhibiting the release of a proinflammatory cytokine from a vertebrate cell, and for inhibiting an inflammatory cytokine cascade in a patient. The compositions comprise a vertebrate HMGB A box, and an antibody preparation that specifically binds to a vertebrate HMGB B box. The methods comprise treating a cell or a patient with sufficient amounts of the composition to inhibit the release of the proinflammatory cytokine, or to inhibit the inflammatory cytokine cascade.
1. A method of treating a condition in a patient characterized by an increased serum HMGB 1 level as compared to a suitable control, and activation of an inflammatory cytokine cascade, comprising administering to the patient a therapeutically effective amount of a polypeptide, an antagonist of TNF and a pharmaceutically acceptable excipient, wherein said polypeptide does not contain an HMGB B box, and wherein said polypeptide inhibits release of a proinflammatory cytokine from a vertebrate cell and comprises an amino acid sequence selected from the group consisting of:
i) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:22;
ii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:57;
iii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:4;
iv) the amino acid sequence of SEQ ID NO:57;
v) a biologically active fragment of SEQ ID NO:57;
vi) the amino acid sequence of SEQ ID NO:22;
vii) a biologically active fragment of SEQ ID NO:22; and
viii) the amino acid sequence of SEQ ID NO:4.
2. A method of treating a condition in a patient characterized by an increased serum HMGB 1 level as compared to a suitable control, and activation of an inflammatory cytokine cascade, comprising administering to the patient a therapeutically effective amount of a polypeptide and a pharmaceutically acceptable excipient, wherein said polypeptide inhibits release of a proinflammatory cytokine from a vertebrate cell and consists of an amino acid sequence selected from the group consisting of:
i) the amino acid sequence of SEQ ID NO:57;
ii) a biologically active fragment of SEQ ID NO:57;
iii) the amino acid sequence of SEQ ID NO:22;
iv) a biologically active fragment of SEQ ID NO:22; and
v) the amino acid sequence of SEQ ID NO:4.
3. The method of claim 2 , further comprising administering an antagonist of TNF.
4. A method of treating a condition in a patient characterized by an increased serum HMGB 1 level as compared to a suitable control, and activation of an inflammatory cytokine cascade, comprising administering to the patient a therapeutically effective amount of a fusion protein and a pharmaceutically acceptable excipient, wherein said fusion protein comprises a polypeptide, wherein said fusion protein does not contain an HMGB B box, wherein said fusion protein inhibits release of a proinflammatory cytokine from a vertebrate cell, and wherein said polypeptide consists of an amino acid sequence selected from the group consisting of:
i) the amino acid sequence of SEQ ID NO:22;
ii) a biologically active fragment of SEQ ID NO:22;
iii) the amino acid sequence of SEQ ID NO:57;
iv) a biologically active fragment of SEQ ID NO:57; and
v) the amino acid sequence of SEQ ID NO:4.
5. A method of inhibiting release of a proinflammatory cytokine from a mammalian cell, the method comprising treating the cell with a polypeptide comprising a vertebrate high mobility group box protein (HMGB) A box or a non-naturally occurring HMGB A box which can inhibit release of a proinflammatory cytokine from a vertebrate cell treated with high mobility group box (HMGB) protein in an amount sufficient to inhibit release of the proinflammatory cytokine from the cell, wherein said polypeptide does not contain an HMGB B box, and wherein said polypeptide comprises an amino acid sequence selected from the group consisting of:
i) the amino acid sequence of SEQ ID NO:57;
ii) a biologically active fragment of SEQ ID NO:57;
iii) the amino acid sequence of SEQ ID NO:4;
iv) the amino acid sequence of SEQ ID NO:22;
v) a biologically active fragment of SEQ ID NO:22;
vi) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:57;
vii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:4; and
viii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:22.
6. The method of claim 5 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:57.
7. The method of claim 5 , wherein said polypeptide comprises a biologically active fragment of SEQ ID NO:57.
8. The method of claim 5 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:4.
9. The method of claim 5 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:22.
10. The method of claim 5 , wherein said polypeptide comprises a biologically active fragment of SEQ ID NO:22.
11. The method of claim 5 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:57.
12. The method of claim 5 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:4.
13. The method of claim 5 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:22.
14. A method of treating a patient with sepsis, comprising administering to the patient a therapeutically effective amount of a polypeptide, an antagonist of TNF and a pharmaceutically acceptable excipient, wherein said polypeptide does not contain an HMGB B box, and wherein said polypeptide inhibits release of a proinflammatory cytokine from a vertebrate cell and comprises an amino acid sequence selected from the group consisting of:
i) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:22;
ii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:57;
iii) an amino acid sequence having at least 80% sequence identity to SEQ ID NO:4;
iv) the amino acid sequence of SEQ ID NO:57;
v) a biologically active fragment of SEQ ID NO:57;
vi) the amino acid sequence of SEQ ID NO:22;
vii) a biologically active fragment of SEQ ID NO:22; and
viii) the amino acid sequence of SEQ ID NO:4.
15. The method of claim 14 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:22.
16. The method of claim 14 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:57.
17. The method of claim 14 , wherein said polypeptide comprises an amino acid sequence having at least 80% sequence identity to SEQ ID NO:4.
18. The method of claim 14 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:57.
19. The method of claim 14 , wherein said polypeptide comprises a biologically active fragment of SEQ ID NO:57.
20. The method of claim 14 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:22.
21. The method of claim 14 , wherein said polypeptide comprises a biologically active fragment of SEQ ID NO:22.
22. The method of claim 14 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:4.
23. A method of treating a patient with sepsis, comprising administering to the patient a therapeutically effective amount of a polypeptide and a pharmaceutically acceptable excipient, wherein said polypeptide inhibits release of a proinflammatory cytokine from a vertebrate cell and consists of an amino acid sequence selected from the group consisting of:
i) the amino acid sequence of SEQ ID NO:57;
ii) a biologically active fragment of SEQ ID NO:57;
iii) the amino acid sequence of SEQ ID NO:22;
iv) a biologically active fragment of SEQ ID NO:22; and
v) the amino acid sequence of SEQ ID NO:4.
24. The method of claim 23 , further comprising administering an antagonist of TNF.
25. A method of treating a patient with sepsis, comprising administering to the patient a therapeutically effective amount of a fusion protein and a pharmaceutically acceptable excipient, wherein said fusion protein comprises a polypeptide, wherein said fusion protein does not contain an HMGB B box, wherein said fusion protein inhibits release of a proinflammatory cytokine from a vertebrate cell, and wherein said polypeptide consists of an amino acid sequence selected from the group consisting of:
i) the amino acid sequence of SEQ ID NO:22;
ii) a biologically active fragment of SEQ ID NO:22;
iii) the amino acid sequence of SEQ ID NO:57;
iv) a biologically active fragment of SEQ ID NO:57; and
v) the amino acid sequence of SEQ ID NO:4.
26. The method of claim 25 , wherein said polypeptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:22 and a biologically active fragment of SEQ ID NO:22.
27. The method of claim 25 , wherein said polypeptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:57 and a biologically active fragment of SEQ ID NO:57.
28. The method of claim 25 , wherein said polypeptide consists of the amino acid sequence of SEQ ID NO:4.