Histidyl-tRNA synthetases for treating autoimmune and inflammatory diseases

Abstract

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 - 192 . (canceled) 
     
     
         193 . An immunogenic vaccine composition, comprising an adjuvant and 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 HRS polypeptide specifically cross reacts with an auto-antibody or auto reactive T-cell from a disease associated with autoantibodies to human HRS, 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). 
     
     
         194 . The composition of  claim 193 , wherein the HRS polypeptide is 505-506 amino acids in length is at least 90% identical to SEQ ID NO:70. 
     
     
         195 . The composition of  claim 193 , wherein the HRS polypeptide is 506 amino acids in length. 
     
     
         196 . The composition of  claim 193 , wherein the HRS polypeptide comprises SEQ ID NO:70. 
     
     
         197 . The composition of  claim 193 , wherein the HRS polypeptide consists of SEQ ID NO:70. 
     
     
         198 . The composition of  claim 193 , wherein the HRS polypeptide is 505 amino acids in length. 
     
     
         199 . The composition of  claim 198 , wherein the HRS polypeptide comprises residues 2-506 of SEQ ID NO:70 (HRS(2-506)). 
     
     
         200 . The composition of  claim 198 , wherein the HRS polypeptide consists of residues 2-506 of SEQ ID NO:70 (HRS(2-506)). 
     
     
         201 . The composition of  claim 193 , wherein the HRS polypeptide has a mutation of at least one cysteine residue. 
     
     
         202 . The composition of  claim 201 , wherein the at least one cysteine residue is selected from Cys174, Cys191, Cys224, Cys235, and Cys455. 
     
     
         203 . The composition of  claim 193 , 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. 
     
     
         204 . The composition of  claim 203 , 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. 
     
     
         205 . The composition of  claim 203 , wherein increased activity comprises specific binding to an anti-Jo-1 antibody of at least about 10%. 
     
     
         206 . The composition of  claim 203 , wherein the HRS polypeptide has reduced charge heterogeneity relative to the polypeptide of SEQ ID NO:1 (full-length HRS). 
     
     
         207 . The composition of  claim 203 , 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). 
     
     
         208 . The composition of  claim 203 , 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. 
     
     
         209 . The composition of  claim 193 , 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). 
     
     
         210 . The composition of  claim 193 , wherein the HRS polypeptide is fused to a heterologous fusion partner, optionally a T-cell ligand. 
     
     
         211 . The composition of  claim 193 , wherein the adjuvant is selected from one or more of 1018 ISS, aluminum salts, Amplivax, AS15, BCG, CP-870,893, CpG7909, CyaA, dSLIM, flagellin or TLR5 ligands derived from flagellin, FLT3 ligand, GM-C SF, IC30, IC31, Imiquimod (ALDARA), ImuFact INIP321, IS Patch, ISS, ISCOMATRIX, ISCOMs, Juvlmmune, LipoVac, MALP2, MF59, monophosphoryl lipid A, Montanide IMS 1312, Montanide ISA 206, Montanide ISA 50V, Montanide ISA-51, water-in-oil and oil-in-water emulsions, OK-432, OM-174, OM-197-MP-EC, ONTAK, OspA, PepTel vector system, PLG microparticles, resiquimod, SRL172, Virosomes and other Virus-like particles, YF-17D, VEGF trap, R848, beta-glucan, Pam3Cys, Aquila's QS21 stimulon, Ribi's Detox, Quil, Superfos, Freund's, GM-CSF, TNF-α, IL-1, IL-4, IL-12, IL-15, IL-23, IL-7, IFN-alpha, IFN-beta, CpG immunostimulatory oligonucleotides, cyclophosphamide, sunitinib, Bavacizumab, celebrex, NCX-4016, sildenafil, tadalafil, vardenafil, sorafinib, XL-999, CP-547632, pazopanib, ZD2171, AZD2171, anti-CTLA4, and SC58175. 
     
     
         212 . A method of eliciting a protective immune response, comprising administering to a subject in need thereof an immunogenic vaccine composition of  claim 193 . 
     
     
         213 . The method of  claim 212 , wherein the composition is administered to the subject prior to the appearance of disease symptoms. 
     
     
         214 . The method of  claim 212 , wherein the subject has inflammation associated with a cancer or a viral infection.