Histidyl-tRNA synthetase-Fc conjugates
The present invention provides histidyl-tRNA synthetase and Fc region conjugate polypeptides (HRS-Fc conjugates), such as HRS-Fc fusion polypeptides, compositions comprising the same, and methods of using such conjugates and compositions for treating or diagnosing a variety of conditions. The HRS-Fc conjugates of the invention have improved controlled release properties, stability, half-life, and other pharmacokinetic and biological properties relative to corresponding, unmodified HRS polypeptides.
1. A therapeutic composition, comprising a pharmaceutically acceptable carrier or excipient and a histidyl-tRNA synthetase (HRS) fusion polypeptide having at least one Fc region, where the polypeptide has an amino acid sequence that is at least 95% identical to SEQ ID NO: 337, wherein the HRS fusion polypeptide is at least about 95% pure and less than about 5% aggregated, and wherein the composition is substantially endotoxin-free.
2. The therapeutic composition of claim 1 , wherein the HRS fusion polypeptide comprises an amino acid sequence at least 97% identical to SEQ ID NO: 337.
3. The therapeutic composition of claim 1 , wherein the HRS fusion polypeptide comprises an amino acid sequence at least 98% identical to SEQ ID NO: 337.
4. The therapeutic composition of claim 1 , where the Fc region and the HRS polypeptide are separated by a peptide linker.
5. The therapeutic composition of claim 4 , where the peptide linker is about 1-10 amino acids, or 1-5 amino acids in length.
6. The therapeutic composition of claim 1 , wherein the HRS fusion polypeptide has altered pharmacokinetics relative to a corresponding unmodified HRS polypeptide.
7. The therapeutic composition of claim 6 , where said altered pharmacokinetics are increased serum half-life, increased bioavailability, exposure, and/or decreased clearance.
8. The therapeutic composition of claim 7 , wherein the exposure is increased by at least 100 fold.
9. The therapeutic composition of claim 7 , wherein the HRS fusion polypeptide has a half life of at least 30 hours in mice.
10. The therapeutic composition of claim 7 , wherein the bioavailability is subcutaneous bioavailability that is increased by at least about 30%.
11. The therapeutic composition of claim 1 , which is substantially in dimeric form in a physiological solution.
12. The therapeutic composition of claim 1 , which has substantially the same secondary structure a corresponding unmodified HRS polypeptide, as determined via UV circular dichroism analysis.
13. The therapeutic composition of claim 1 , which has a plasma or sera pharmacokinetic AUC profile at least 5-fold greater than a corresponding, unmodified HRS polypeptide when administered to a mammal.
14. The therapeutic composition of claim 1 , where the HRS fusion polypeptide has an anti-inflammatory activity.
15. The therapeutic composition of claim 1 , where the HRS fusion polypeptide has increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity relative to a corresponding, unmodified HRS polypeptide.
16. The therapeutic composition of claim 1 , where the Fc region is a modified Fc glycoform, which has increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity.
17. The therapeutic composition of claim 1 , wherein the HRS fusion polypeptide is produced in E coli.
18. The therapeutic composition of claim 1 , wherein the HRS fusion polypeptide is produced in a mammalian cell.
19. The therapeutic composition of claim 1 , where the composition is formulated for delivery via oral, subcutaneous, intranasal, pulmonary or parental administration.
20. The therapeutic composition of claim 1 , where the composition comprises a delivery vehicle selected from the group consisting of liposomes, micelles, emulsions, and cells.
21. A dosing regimen which maintains an average steady-state concentration of an histidyl-tRNA synthetase (HRS) fusion polypeptide in a subject's plasma of between about 300 pM and about 1,000 nM when using a dosing interval of 3 days or longer, comprising administering to the subject a therapeutic composition of claim 1 .
22. A method for treating an inflammatory or autoimmune disease or condition in a subject in need thereof, comprising administering to the subject a therapeutic composition of claim 1 .