Histidyl-tRNA synthetases for treating autoimmune and inflammatory diseases
The present invention relates generally to compositions and methods comprising histidyl-tRNA synthetase polypeptides or other specific blocking agents for the treatment autoimmune diseases and other inflammatory diseases, including those related to Jo-1 antibodies.
1. A therapeutic composition, comprising a histidyl-tRNA synthetase (HRS) polypeptide of 500-506 amino acids in length that is least 90% identical to SEQ ID NO:70 (HRS(1-506)) and lacks residues 507-509 of SEQ ID NO:1, wherein the composition is: a) at least about 95% pure; b) less than about 5% aggregated; and c) substantially endotoxin-free, and wherein the HRS polypeptide has reduced interchain disulfide formation under reducing conditions relative to the polypeptide of SEQ ID NO:1 (full-length HRS).
2. The composition of claim 1 , wherein the HRS polypeptide is 505-506 amino acids in length is at least 90% identical to SEQ ID NO:70.
3. The composition of claim 1 , wherein the HRS polypeptide is 506 amino acids in length.
4. The composition of claim 1 , wherein the HRS polypeptide comprises SEQ ID NO:70.
5. The composition of claim 1 , wherein the HRS polypeptide consists of SEQ ID NO:70.
6. The composition of claim 1 , where the HRS polypeptide is 505 amino acids in length.
7. The composition of claim 6 , where the HRS polypeptide comprises residues 2-506 of SEQ ID NO:70 (HRS(2-506)).
8. The composition of claim 7 , where the HRS polypeptide consists of residues 2-506 of SEQ ID NO:70 (HRS(2-506)).
9. The composition of claim 1 , wherein the HRS polypeptide has a mutation of at least one cysteine residue.
10. The composition of claim 9 , wherein the at least one cysteine residue is selected from Cys174, Cys191, Cys224, Cys235, and Cys455.
11. The composition of claim 1 , wherein the HRS polypeptide has increased biological activity, stability, and/or homogeneity relative to a polypeptide of SEQ ID NO:1 (full-length human HRS) under comparable conditions, ranging from about 4-40° C., and a pH of about 6.0-8.0.
12. The composition of claim 11 , wherein the conditions include a temperature of about 20-25° C. (room temperature) or about 37° C. and a pH of about 7.0-7.5, optionally over a period of about 1, 2, 3, 4, 5, 6, or 7 days.
13. The composition of claim 11 , wherein increased activity comprises an absolute increase in an anti-inflammatory activity or specific binding to an anti-Jo-1 antibody of at least about 10%.
14. The composition of claim 11 , wherein the HRS polypeptide has reduced charge heterogeneity relative to the polypeptide of SEQ ID NO:1 (full-length HRS).
15. The composition of claim 11 , wherein the HRS polypeptide has reduced formation of high molecular weight aggregates in solution relative to the polypeptide of SEQ ID NO:1 (full-length HRS).
16. The composition of claim 11 , wherein increased homogeneity comprises at least a 10% increase in the monodispersion of the HRS polypeptide relative to the polypeptide of SEQ ID NO:1.
17. The composition of claim 1 , wherein the HRS polypeptide has increased yield of soluble protein upon recombinant production in E. coli relative to the polypeptide of SEQ ID NO:1 (full-length HRS).
18. The composition of claim 1 , where the HRS polypeptide is fused to a heterologous fusion partner, optionally a T-cell ligand.
19. A method of treating a disease associated with an autoantibody comprising administering to a subject in need thereof a therapeutic composition of claim 1 .
20. The method of claim 19 , wherein the therapeutic composition is administered to the subject prior to the appearance of disease symptoms.
21. The method of claim 19 , wherein the HRS polypeptide results in reduced muscle or lung inflammation.
22. The method of claim 19 , wherein the HRS polypeptide induces tolerance.
23. The method of claim 19 , wherein the disease is selected from the group consisting of inflammatory myopathies, including inflammatory myopathies, polymyositis, dermatomyositis and related disorders, polymyositis-scleroderma overlap, inclusion body myositis (IBM), anti-synthetase syndrome, interstitial lung disease, arthritis, and Reynaud's phenomenon.
24. A method of reducing tissue inflammation comprising administering to a subject in need thereof a composition comprising of claim 1 .
25. The method of claim 24 , wherein the tissue is selected from muscle, gastrointestinal tissue, lung, and skin.
26. A method of treating a muscular dystrophy comprising administering to a subject in need thereof a composition of claim 1 .
27. The method of claim 26 , wherein the muscular dystrophy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Emery-Dreifuss muscular dystrophy, Limb-girdle muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, and congenital muscular dystrophy.
28. A method of treating rhabdomyolysis, muscle wasting, cachexia, muscle inflammation, or muscle injury comprising administering to a subject in need thereof a composition of claim 1 .
29. The method of claim 27 , where the muscular dystrophy is facioscapulohumeral muscular dystrophy.
30. The method of claim 29 , where the facioscapulohumeral muscular dystrophy is infant or child onset.