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DEPYROGENATION TUNNEL VALIDATION EPUB

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These mice have an in-frame deletion of bp in the 3' splice junction of exon 45 of dysferlin and develop spontaneous myopathy that is associated with muscle inflammation. As shown in Figure 27B , muscle tissue from HisRS-immunized mice showed regions of cellular infiltration and myositis, and consistent with this histopathology, two immunized mice displayed signs of myositis. Figure 28A shows that there were two thermal transitions for full-length HRS upon incubation at pH Figure 28B shows the thermal stability or melting temperature of HRS over a range of concentrations of histidine buffer. The results demonstrate that the histidine buffer is capable of significantly stabilizing the conformation of HRS polypeptides such as HRS BRIEF SUMMARY Embodiments of the present disclosure are based in part on the surprising discovery that specifically blocking the activity, binding, or production of otherwise pathogenic anti-Jo-1 antibodies also called Jo-1 antibodies , for example, with HRS polypeptides or other antibody-specific blocking agents, can be useful in treating subjects with inflammatory or autoimmune diseases, and can prevent, or significantly delay disease progression.

Anti-U1 RNP, which is frequently found in patients with SLE, may also be found in mixed connective tissue disease, overlap syndromes involving myositis, or in some cases of myositis alone. This antibody reacts with proteins that are uniquely present on the Ul small nuclear ribonucleoprotein, one of the nuclear RNPs that are involved in splicing mRNA.

Anti-Ku has been found in myositis-scleroderma overlap syndrome and in SLE. The Ku antigen is a DNA binding protein complex with two polypeptide components, both of which have been cloned. Anti-Jo-1 and other anti-synthetases are disease-specific. Typically patients with inflammatory muscle disease IMD and interstitial lung disease ILD present when relatively young and in otherwise in good health, unfortunately in a sub set of patients disease progression can result in significant disability and high morbidity.

Moreover currently there are no drugs specifically approved for the treatment of the general population of IMD and ILD. The current standard of care, is to administer non-specific anti-inflammatory and immune modulatory drugs such as methotrexate or azathioprine, and if symptoms don't abate, cyclosporine Wallace et al.

These drugs carry a substantive risk of side effects that can be severe with chronic administration. In severe progressive disease, individuals may be treated with intravenous immune globulin IVIG. The figure shows data from three dilutions of sera obtained from a human serum sample.

The data shows that Resokine does not significantly compete for antibody binding to full-length HisRS until present at concentrations greater than about 1 x M, when full-length histidyl-tRNA synthetase is attached to the surface of the plate.

The data shows that when the assay is run under these conditions the apparent titers for antibodies to Hi5RSN4 in anti-Jo-1 antibody containing serum is comparable to full-length HisRS.

Figure 7 shows a schematic representation of the HRS splice variant and other HRS constructs used in the epitope mapping studies. Figure 10B shows the effects of HRS on reducing muscle troponin levels in the rat model of statin-induced myositis. Figure 12 shows that endogenous serum HRS levels were elevated in statin-treated rats relative to untreated rats. This result suggests that the release of endogenous HRS may play a role in regulating muscle inflammation.

Figure 14 shows the results of RNA profiling performed on hamstring muscles from statin-induced rats, which were treated with increasing amounts of HRS These results demonstrated that all 13 genes that were elevated by more than 5-fold in response to statin treatment were reduced by treatment with HRS Figure 15A shows the results of RNA profiling performed on hamstring muscles from statin-induced rats, and Figure 15B shows the results for statin-induced rats treated with HRS Figure 16 shows the transcriptional profiling of hamstrings from statin-induced rats.

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Figure 17 shows the transcriptional profiling of hamstrings from statin-induced rats. These results revealed that expression of numerous immune cell marker genes was reduced by HRS treatment.

Figure 20 shows the transcriptional profiling of hamstrings from statin-induced rats. These results revealed that expression of numerous inflammatory marker genes was reduced by HRS treatment. Figures show the transcriptional profiling of hamstrings from statin-induced rats. These results revealed that expression of various adhesion, development, and fibrosis-related genes was altered by HRS treatment. These results revealed that expression of various genes associated with muscular wasting, atrophy, and myogenesis was altered by HRS treatment.

These mice have an in-frame deletion of bp in the 3' splice junction of exon 45 of dysferlin and develop spontaneous myopathy that is associated with muscle inflammation. As shown in Figure 27B, muscle tissue from HisRS-immunized mice showed regions of cellular infiltration and myositis, and consistent with this histopathology, two immunized mice displayed signs of myositis. Figure 28A shows that there were two thermal transitions for full-length HRS upon incubation at pH Figure 28B shows the thermal stability or melting temperature of HRS over a range of concentrations of histidine buffer.

The results demonstrate that the histidine buffer is capable of significantly stabilizing the conformation of HRS polypeptides such as HRS One advantage to this discovery is that the negative impact of anti-Jo-1 antibodies can be overcome with little or no debilitation of the subject's immune system, 7 resulting in significantly reduced side-effect profiles.

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Moreover, the approach is broadly applicable to other diseases including inflammatory diseases and related disorders where there is a local or temporal insufficiency of histidyl-tRNA synthetase. In certain embodiments, the HRS polypeptide is at least about amino acids in length.

In some embodiments, the HRS polypeptide is amino acids in length. In some embodiments, the HRS polypeptide has a mutation of at least one cysteine residue. In certain embodiments, the at least one cysteine residue is selected from Cys, Cys, Cys, Cys, and Cys In some embodiments, the HRS polypeptide e. In certain embodiments, the conditions include a temperature of about 37 C and a pH of about 7.

In some embodiments, the non-canonical activity is an anti-inflammatory activity or specific binding to an anti-Jo-1 antibody. In some embodiments, the HRS polypeptide has increased yield of soluble protein upon recombinant production in E.

In certain embodiments, the HRS polypeptide is fused to a heterologous fusion partner, optionally a T-cell ligand.

Epub depyrogenation tunnel validation

In particular embodiments, the HRS polypeptide comprises at least one D-amino acid. In some embodiments, the therapeutic composition comprises a buffer at a concentration ranging from about 0. In some embodiments, the therapeutic composition comprises a buffer at a concentration ranging from about 2 mM to about 50 mM. In certain embodiments, the therapeutic composition comprises a buffer at a concentration ranging from about 40 mM to about 60 mM.

In certain embodiments, the therapeutic composition comprises a comprising a buffer at a concentration ranging from about 45 mM to about 55 mM. In some embodiments, the 9 therapeutic composition comprises a comprising a buffer at a concentration of about 50 mM. In some embodiments, the buffer is a histidine buffer, a citrate buffer, or a phosphate buffer. In certain embodiments, the buffer is a histidine buffer, and wherein the HRS polypeptide has increased stability relative to a corresponding HRS polypeptide in a comparable composition without said histidine buffer, under comparable conditions, ranging from about C, and a pH of about 7.

In certain embodiments, the buffer is a citrate buffer, and wherein the HRS polypeptide has increased stability relative to a corresponding HRS polypeptide in a comparable composition without said citrate buffer, under comparable conditions, ranging from about C, and a pH of about 6. In certain embodiments, the buffer is a phosphate buffer, and wherein the HRS polypeptide has increased stability relative to a corresponding HRS polypeptide in a comparable composition without said phosphate buffer, under comparable conditions, ranging from about C, and a pH of about 7.

In some embodiments, the conditions e. In some embodiments, the conditions include a temperature of about C room temperature , optionally over a period of about 1, 2, 3, 4, 5, 6, or 7 days. In certain embodiments, the conditions include a temperature of about 37 C, optionally over a period of about 1, 2, 3, 4, 5, 6, or 7 days.

In some embodiments, the composition comprises sodium chloride NaC1 at a concentration ranging from about mM, optionally at about mM mM, or optionally at about mM. In certain embodiments, the composition comprises one or more pharmaceutically-acceptable excipients.

In some embodiments, the one or more pharmaceutically-acceptable excipient s are selected from sucrose, mannitol, trehalose, sorbitol, arginine, glycine, and glycerol.

Epub validation depyrogenation tunnel

In some embodiments, the one or more pharmaceutically-acceptable excipient s are at a concentration ranging from about 0. In some embodiments, the composition comprises one or more surfactants.

Tunnel epub depyrogenation validation

In some embodiments, the surfactant is a polysorbate or a poloxamer. In certain embodiments, the polysorbate is PS In certain embodiments, the poloxamer is Pluronic F In some embodiments, the surfactant is present at a range of about 0.

In some embodiments, is about 0.

In certain embodiments, the composition comprises one or more anti-oxidant compounds or reducing agents. In some embodiments, the anti-oxidant compound or reducing agent is selected from cysteine, methionine, and N-acetylcysteine NAC. In some embodiments, the anti-oxidant compound or reducing agent is present at a concentration range of about 0. In certain embodiments, the composition comprises one or more chelating agents. In some embodiments, the chelating agent is ethylenediaminetetraacetate EDTA.

In some embodiments of the present disclosure, the anti-oxidant compound or reducing agent is selected from cysteine, methionine, and N-acetylcysteine NAC. In some embodiments of the present disclosure, the anti-oxidant compound or reducing agent is present at a concentration range of about 0. In certain embodiments of the present disclosure, the composition comprises one or more chelating agents.

In some embodiments of the present disclosure, the chelating agent is ethylenediaminetetraacetate EDTA. In some embodiments of the present disclosure, the chelating agent is present at a concentration range of about 0. In certain embodiments of the present disclosure, the composition has a turbidity of less than about 0.

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In some embodiments of the present disclosure, absorbance at A is measured after at least about 1, 2, 3, 4, 5, 6, or 7 days incubation at room temperature. In certain embodiments of the present disclosure, absorbance at A is measured after freeze-thawing the composition at least 1, 2, 3, 4, or 5 times.

In some embodiments of the present disclosure, the composition has an opalescence of less than about 0. In certain embodiments of the present disclosure, high molecular weight HMW aggregation is measured after at least about 1, 2, 3, 4, 5, 6, or 7 days incubation at room temperature. In some embodiments of the present disclosure, high molecular weight aggregation is measured after freeze-thawing the composition at least 1, 2, 3, 4, or 5 times.

In some embodiments of the present disclosure, the composition has opalescence of less than about 0.

DEPYROGENATION TUNNEL VALIDATION EPUB.

In particular embodiments of the present disclosure, at least one amino acid is a D amino acid. In some aspects of the present disclosure, of any of these medically useful or therapeutic compositions, the polypeptide is comprises full-length HRS polypeptide.

In some aspects of the present disclosure, the HRS polypeptide is truncated at about residue or In some aspects of the present disclosure, the HRS polypeptide has at least one mutation at a cysteine residue. In some aspects of the present disclosure, the cysteine residue is selected from Cys, Cys, Cys, Cys, Cys, Cys and Cys In some aspects of the present disclosure, the polypeptide comprises at least one D amino acid. In some aspects of the present disclosure, the polypeptide comprises a WHEP domain.

In some aspects of the present disclosure, the polypeptide is fused to a heterologous protein. In some aspects of the present disclosure, the heterologous protein comprises a T cell ligand. In some aspects of the present disclosure, the composition is formulated for delivery via oral, intranasal, pulmonary or parental administration.

In some aspects of the present disclosure, the medically useful or therapeutic composition is for use in treating a disease selected from the group consisting of autoimmune diseases, inflammatory diseases, inflammatory myopathies, including idiopathic inflammatory myopathies, polymyositis, dermatomyositis and related disorders, polymyositis-scleroderma overlap, inclusion body myositis IBM , anti-synthetase syndrome, interstitial lung disease, arthritis, Reynaud's phenomenon, Perrault syndrome and Usher syndrome.

The muscle inflammation causes muscle tenderness, muscle weakness, and ultimately muscle atrophy and fibrosis as described by Plotz et al. Musculoskelat Med. Also associated with the muscle inflammation are elevated serum levels of aldolase, creatine kinase, transaminases such as alanine aminotransferase and aspartate aminotransferase and lactic dehydrogenase. Other systems besides muscle can be affected by these conditions, resulting in arthritis, Raynaud's phenomenon, and interstitial lung disease.

Clinically, polymyositis and dermatomyositis are distinguished by the presence of a characteristic rash in patients with dermatomyositis.

Differences in the myositis of these conditions can be distinguished in some studies of muscle pathology.

Interstitial lung disease ILD comprises a heterogeneous group of disorders in which fibrosis and inflammation occur within alveolar walls or in the loose tissue surrounding peribronchovascular sheaths, interlobular septa and the visceral pleura.

Different forms of ILD are known which comprise, or are associated with, various autoimmune diseases in addition to myositis, including for example, hypersensitivity pneumonitis, scleroderma, systemic lupus erythematosus, rheumatoid arthritis, Churg-Strauss syndrome, Wegener's granulomatosis, and Good-pasture Syndrome. Inflammatory muscle disease IMD and interstitial lung disease ILD are serious chronic potentially life threatening autoimmune diseases, for which the current standard of care includes non-specific anti-inflammatory drugs such as corticosteroids with the potential for important side effects.

There are numerous precipitating autoantibody specificities in myositis patients, but each individual antibody specificity occurs in only a fraction of the patients. Many autoantibodies associated with myositis or myositis-overlap syndrome have been defined and in some cases the antibodies have been identified See U. These include antibodies that are present in other disorders and also disease-specific antibodies as described by Targoff and Reichlin, Mt. Sinai J.

Epub depyrogenation tunnel validation

For example, a group of myositis-associated autoantibodies have been identified which are directed at cytoplasmic proteins that are related to tRNA and protein synthesis, particularly aminoacyl-tRNA synthetases. A characteristic group of features is often associated with anti-synthetases Love et al.

Anti-U1 RNP, which is frequently found in patients with SLE, may also be found in mixed connective tissue disease, overlap syndromes involving myositis, or in some cases of myositis alone. This antibody reacts with proteins that are uniquely present on the U1 small nuclear ribonucleoprotein, one of the nuclear RNPs that are involved in splicing mRNA. Anti-Ku has been found in myositis-scleroderma overlap syndrome and in SLE. The Ku antigen is a DNA binding protein complex with two polypeptide components, both of which have been cloned.