Stable Anti-OSMR antibody formulation

Abstract

To provide a stable anti-OSMR antibody formulation.SOLUTION: The present invention provides, among other things, stable formulations comprising an anti-oncostatin M receptor (OSMR) antibody and having a pH ranging from approximately 6.0 to 7.6, where less than approximately 5% of the anti-OSMR antibody exists as high molecular weight (HMW) species in the formulation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Application No. 62 / 484,260, filed April 11, 2017, and U.S. Provisional Application No. 62 / 524,927, filed June 26, 2017, the disclosures of which are incorporated herein by reference. Sequence Listing

[0002] This specification references a Sequence Listing (submitted electronically as a text file entitled "KPL-002WO_SL" on April 11, 2018). The text file was created on April 10, 2018 and is 17,585 bytes in size. The entire contents of the Sequence Listing are incorporated herein by reference. [Background technology]

[0003] Advances in biotechnology have enabled the production of monoclonal antibodies for a wide variety of pharmaceutical applications. Because antibodies are larger and more complex than traditional organic and inorganic drugs, formulating these proteins presents special challenges. One challenge is the increased viscosity of antibody formulations, especially at high protein concentrations. Another challenge is maintaining the stability of antibody formulations, which is a major concern for regulatory agencies. Delivery of high protein concentrations often requires subcutaneous administration due to volume limitations and dosage requirements. Subcutaneous administration is an attractive delivery route because it is less invasive for patients and reduces inconvenience and discomfort. Due to their polymeric nature and the potential for intermolecular interactions, proteins tend to form viscous solutions at high concentrations. Therefore, there is a need to develop viscosity-stable antibody formulations and highly concentrated antibody formulations that simplify antibody production, preparation, and administration. Summary of the Invention [Means for solving the problem]

[0004] In particular, the present invention provides stable formulations for the delivery of anti-oncostatin M receptor (OSMR) antibodies. In one embodiment, the present invention provides a stable formulation containing an anti-oncostatin M receptor (OSMR) antibody and having a pH in the range of approximately 5.0 to 7.6, wherein less than approximately 5% of the anti-OSMR antibody is present as a high molecular weight (HMW) species in the formulation. In one embodiment, the formulation of the present invention is a stable injectable formulation of an anti-oncostatin M receptor (OSMR) antibody comprising 75-250 mg / mL OSMR monoclonal antibody, 10-150 mM L-histidine, 10-150 mM L-arginine hydrochloride, 25-150 mM sodium chloride, 0.005-0.5% (w / v) polysorbate 80 (PS80), at a pH of 6.6-6.8, wherein the solution is isotonic and has an osmolality in the range of 250-350 mOsm, and wherein at least 90% of the protein is present as stable, fully monomeric IgG for at least one month at about -70°C or about 5°C.

[0005] In one embodiment, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody is present as HMW species in the formulation. In one embodiment, the amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25°C for more than two weeks. In one embodiment, the amount of HMW species in the formulation increases by approximately 0.3% to 0.7%, approximately 0.3% to 0.6%, or approximately 0.3% to 0.5% upon storage at 25°C for four weeks. In one embodiment, at least 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% of the anti-OSMR antibody is present as a monomer in the stable formulation. In one embodiment, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% of the drug product is present as intact IgG monomers, while the amount of monomer decreases by less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage for 3 months at −70° C. In one embodiment, the antibody exhibits at least 95%, 96%, 97%, 98%, 99% or 100% antigen-binding activity after storage at −70° C. for about 3 months. In one embodiment, the HMW species (% aggregates) does not increase by more than 1%, or more than 1.5%, or more than 1.6%, or more than 1.7%, or more than 1.8%, or more than 1.9%, or more than 2%, or more than 3%, or more than 4%, or more than 5% upon storage for about 3 months at −70° C. In one embodiment, the amount of monomer decreases by less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage for about 3 months at 2-5° C., while more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the drug product is present as intact IgG monomers. In one embodiment, the antibody exhibits at least 95%, 96%, 97%, 98%, 99% or 100% antigen-binding activity after storage at 2-5°C for about 3 months.In one embodiment, the HMW species (% aggregates) does not increase by more than 1%, or more than 1.5%, or more than 1.6%, or more than 1.7%, or more than 1.8%, or more than 1.9%, or more than 2%, or more than 3%, or more than 4%, or more than 5% upon storage for about 3 months at 2-5° C. In one embodiment, the HMW species and / or monomer are determined by size exclusion chromatography (SEC), analytical ultracentrifugation (AUC), field-flow fractionation (FFF), or light scattering.

[0006] In one embodiment, the pH of the formulation is in the range of about 5.0 to 7.6, about 5.5 to 7.4, about 5.8 to 7.2, about 6.0 to 7.0, about 6.1 to 7.1, about 6.0 to 6.8, about 6.0 to 6.6, about 6.0 to 6.4, about 6.4 to 7.6, about 6.6 to 7.6, about 6.8 to 7.6, about 7.0 to 7.6, about 6.6 to 6.8, about 6.5 to 6.9, about 6.4 to 6.9, or about 7.2 to 7.6. In one embodiment, the pH of the formulation is about 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.2, 7.4, or 7.6.

[0007] In one embodiment, the anti-OSMR antibody is present at a concentration of at least about 50 mg / mL. In one embodiment, the anti-OSMR antibody is present at a concentration of at least about 50 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 225 mg / mL, or 250 mg / mL.

[0008] In one embodiment, the anti-OSMR antibody has a pI in the range of 6.5 to 8.5. In one embodiment, the anti-OSMR antibody has a pI in the range of 7.0 to 8.0. In one embodiment, the anti-OSMR comprises one or more charged species, and the pI of the charged species is in the range of 6.5 to 8.5. In one embodiment, the pI is determined by isoelectric focusing (IEF) or ion exchange chromatography (IEX).

[0009] In one embodiment, the formulation includes one or more amino acids. In one embodiment, the one or more amino acids are present at a concentration of 5 mM to 35 mM, 10 mM to 35 mM, 15 mM to 30 mM, 1 mM to 250 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, or 20 mM to 150 mM. In one embodiment, the one or more amino acids are selected from the group consisting of arginine, glutamic acid, glycine, histidine, and combinations thereof. In one embodiment, the one or more amino acids include arginine. In one embodiment, the arginine is selected from the group consisting of D-arginine and L-arginine, or combinations thereof. In one embodiment, the one or more amino acids do not include glutamic acid. In one embodiment, the amino acid is L-arginine. In one embodiment, arginine is present at a concentration of 20 mM to 30 mM, 15 mM to 35 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 25 mM to 150 mM. In one embodiment, arginine is present at a concentration of 25 mM. In one embodiment, the one or more amino acids comprise glutamic acid. In one embodiment, the one or more amino acids comprise arginine and glutamic acid. In one embodiment, the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In one embodiment, glutamic acid is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 50 mM to 150 mM. In one embodiment, the one or more amino acids include histidine. In one embodiment, the amino acid is L-histidine. In one embodiment, histidine is present at a concentration of 10 mM to 20 mM, 15 mM to 25 mM, 10 mM to 30 mM, 5 mM to 25 mM, 5 mM to 50 mM, 5 mM to 75 mM, 5 mM to 100 mM, 5 mM to 125 mM, or 5 mM to 150 mM. In one embodiment, histidine is present at a concentration of 20 mM.In one embodiment, the one or more amino acids include glycine, hi one embodiment, the glycine is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 150 mM to 200 mM.

[0010] In one embodiment, the formulation further comprises a buffering agent. In one embodiment, the buffering agent is selected from the group consisting of citrate, phosphate, succinate, histidine, and combinations thereof. In one embodiment, the buffering agent is phosphate. In one embodiment, the buffering agent is present at a concentration of 1 mM to 100 mM, 5 mM to 75 mM, 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 25 mM, or 10 mM to 20 mM.

[0011] In one embodiment, the formulation further comprises a salt. In one embodiment, the salt comprises a halide. In one embodiment, the halide is an alkali metal halide. In one embodiment, the salt is NaCl. In one embodiment, NaCl is present at a concentration of 25 mM to 250 mM, 25 mM to 200 mM, 25 mM to 175 mM, 50 mM to 200 mM, 50 mM to 175 mM, 50 mM to 150 mM, 120 mM to 130 mM, 125 mM to 135 mM, or 75 mM to 150 mM. In one embodiment, NaCl is present at a concentration of 125 mM. In one embodiment, the molar ratio of NaCl to arginine is at least 1:1, 1.5:1, 3:1, or 5:1. In one embodiment, the molar ratio of NaCl to arginine is approximately 5:1. In another embodiment, the molar ratio of NaCl to histidine is approximately 6:1.

[0012] In another aspect, the invention provides a formulation comprising an anti-oncostatin M receptor (OSMR) antibody at a concentration of at least 50 mg / mL, at least 100 mg / mL, or at least 150 mg / mL, in each case having a pH in the range of approximately 6.0 to 7.6, wherein the anti-OSMR antibody has a pI in the range of approximately 6.5 to 8.5. In one embodiment, the pH of the formulation is in the range of approximately 6.0 to 7.6, approximately 6.0 to 7.4, approximately 6.0 to 7.2, approximately 6.0 to 7.0, approximately 6.5 to 7.1, approximately 6.0 to 6.8, approximately 6.0 to 6.6, approximately 6.0 to 6.4, approximately 6.4 to 7.6, approximately 6.6 to 7.6, approximately 6.8 to 7.6, approximately 7.0 to 7.6, or approximately 7.2 to 7.6. In one embodiment, the anti-OSMR antibody is present at a concentration of at least 150 mg / mL, the pH is in the range of approximately 6.6 to 6.8, and the pI is in the range of approximately 7.2 to 8.0.

[0013] In one embodiment, the anti-OSMR antibody is present at a concentration of at least about 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 200 mg / mL, 225 mg / mL, or 250 mg / mL. In one embodiment, the anti-OSMR antibody is present at a concentration of approximately 50 mg / mL to 250 mg / mL, approximately 75 mg / mL to 250 mg / mL, approximately 100 mg / mL to 250 mg / mL, approximately 125 mg / mL to 250 mg / mL, approximately 150 mg / mL to 250 mg / mL, approximately 175 mg / mL to 250 mg / mL, approximately 50 mg / mL to 225 mg / mL, approximately 50 mg / mL to 200 mg / mL, approximately 50 mg / mL to 175 mg / mL, approximately 50 mg / mL to 150 mg / mL, approximately 50 mg / mL to 125 mg / mL, approximately 50 mg / mL to 100 mg / mL, approximately 150 mg / mL to 230 mg / mL, or approximately 150 mg / mL to 250 mg / mL.

[0014] In one embodiment, the anti-OSMR antibody has a pI in the range of 6.5 to 8.5, 7.2 to 8.0, or 7.0 to 8.0.

[0015] In one embodiment, the formulation comprises a salt. In one embodiment, the salt comprises a halide. In one embodiment, the halide is an alkali metal halide. In one embodiment, the salt is NaCl. In one embodiment, NaCl is present at a concentration of 25 mM to 250 mM, 25 mM to 200 mM, 25 mM to 175 mM, 50 mM to 200 mM, 50 mM to 175 mM, 50 mM to 150 mM, 120 mM to 130 mM, 125 mM to 135 mM, or 75 mM to 150 mM.

[0016] In one embodiment, the formulation includes one or more amino acids. In one embodiment, the one or more amino acids are present at a concentration of 5 mM to 35 mM, 10 mM to 35 mM, 15 mM to 30 mM, 1 mM to 250 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, or 20 mM to 150 mM. In one embodiment, the one or more amino acids are selected from the group consisting of arginine, glutamic acid, glycine, histidine, and combinations thereof. In one embodiment, the one or more amino acids include arginine. In one embodiment, the one or more amino acids do not include glutamic acid. In one embodiment, arginine is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 25 mM to 150 mM. In one embodiment, the one or more amino acids comprise glutamic acid. In one embodiment, the one or more amino acids comprise arginine and glutamic acid. In one embodiment, the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In one embodiment, glutamic acid is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 50 mM to 150 mM. In one embodiment, the molar ratio of NaCl to arginine is at least 1:1, 1.5:1, 3:1, or 5:1. In one embodiment, the one or more amino acids include histidine. In one embodiment, histidine is present at a concentration of 10 mM to 20 mM, 5 mM to 25 mM, 5 mM to 50 mM, 5 mM to 75 mM, 5 mM to 100 mM, 5 mM to 125 mM, or 5 mM to 150 mM. In one embodiment, the one or more amino acids include glycine. In one embodiment, glycine is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 150 mM to 200 mM.

[0017] In one embodiment, the formulation further comprises a buffering agent. In one embodiment, the buffering agent is selected from the group consisting of citrate, phosphate, succinate, histidine, and combinations thereof. In one embodiment, the buffering agent is phosphate. In one embodiment, the buffering agent is present at a concentration of 1 mM to 100 mM, 5 mM to 75 mM, 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 25 mM, or 10 mM to 20 mM. In one embodiment, the anti-OSMR antibody is present in a stable injectable formulation containing 50-250 mg / mL OSMR monoclonal antibody, 10-150 mM L-histidine, 10-150 mM L-arginine hydrochloride, 25-150 mM sodium chloride, and 0.005% to 0.5% (w / v) polysorbate 80 (PS80) at a pH of 6.6-6.8. The stable injectable formulation comprises an isotonic solution. In some embodiments, the formulation buffer contains 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8. In one embodiment, 75-250 mg / mL of anti-OSMR antibody is present in a stable injectable formulation containing 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8. In one embodiment, the injectable formulation contains an osmolality in the range of 250-350 mOsm. In one embodiment, the osmolality of the formulation is 270-300 mOsm. The stable formulation containing the anti-OSMR antibody has a pI in the range of 6.5-8.5. In one embodiment, a stable formulation containing an anti-OSMR antibody has a pI in the range of 7.0 to 8.0. In one embodiment, a stable formulation containing an anti-OSMR antibody has a pI in the range of 7.2 to 8.0. In one embodiment, a stable formulation containing an anti-OSMR antibody includes one or more charged species, and the charged species have a pI in the range of 6.5 to 8.5.

[0018] In one embodiment, the formulation has a viscosity of less than 50 mPa*s as measured by a microfluidic rheometer. In one embodiment, the formulation has a viscosity of less than 30 mPa*s as measured by a microfluidic rheometer. In one embodiment, the formulation has a viscosity of less than 20 mPa*s as measured by a microfluidic rheometer. In one embodiment, the formulation has a viscosity of less than 15 mPa*s as measured by a microfluidic rheometer. In one embodiment, the formulation has a viscosity of approximately 1-30 mPa*s, approximately 2-28 mPa*s, approximately 4-30 mPa*s, approximately 6-30 mPa*s, approximately 8-30 mPa*s, approximately 10-30 mPa*s, approximately 12-30 mPa*s, approximately 14-30 mPa*s, approximately 16-30 mPa*s, approximately 18-30 mPa*s, approximately 20-30 mPa*s, approximately 22-30 mPa*s, approximately 24-30 mPa*s, approximately 26-30 mPa*s, or approximately 28-30 mPa*s, as measured by a microfluidic rheometer. ... -1 has a shear rate of less than

[0019] In one embodiment, the formulation is a liquid formulation. In one embodiment, the formulation is reconstituted from a lyophilized powder.

[0020] In one embodiment, the formulation can be delivered through a 27G 1 / 2 inch needle at an injection rate of 0.1 mL / second at 25° C. with a pressure of 6.5 lbf or less. In one embodiment, the formulation is easily injectable.

[0021] In one embodiment, an anti-OSMR antibody contains a light chain complementarity determining region 1 (LCDR1) defined by SEQ ID NO:8, a light chain complementarity determining region 2 (LCDR2) defined by SEQ ID NO:9, and a light chain complementarity determining region 3 (LCDR3) defined by SEQ ID NO:10, as well as a heavy chain complementarity determining region 1 (HCDR1) defined by SEQ ID NO:5, a heavy chain complementarity determining region 2 (HCDR2) defined by SEQ ID NO:6, and a heavy chain complementarity determining region 3 (HCDR3) defined by SEQ ID NO:7. In one embodiment, an anti-OSMR antibody contains a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:4 and a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:3. In one embodiment, the light chain variable domain has the amino acid sequence set forth in SEQ ID NO:4, and the heavy chain variable domain has the amino acid sequence set forth in SEQ ID NO:3. In one embodiment, an anti-OSMR antibody contains a CH1, hinge, and CH2 domain derived from an IgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. In one embodiment, an anti-OSMR antibody contains a light chain having an amino acid sequence at least 90% identical to SEQ ID NO: 2 and a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 1. In one embodiment, the light chain has the amino acid sequence set forth in SEQ ID NO: 2 and the heavy chain has the amino acid sequence set forth in SEQ ID NO: 1.

[0022] In another aspect, the invention provides a stable formulation comprising an antibody at a concentration of at least 50 mg / mL and arginine, wherein the arginine is present in an amount greater than any non-arginine amino acid in the formulation. In one embodiment, the formulation does not contain glutamic acid. In one embodiment, the formulation contains glutamic acid. In one embodiment, the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In one embodiment, the amino acid is L-arginine.

[0023] In one embodiment, an anti-OSMR antibody formulation containing a light chain having an amino acid sequence at least 90% identical to SEQ ID NO:2 and a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO:1 contains 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8. In one embodiment, an anti-OSMR antibody formulation containing a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:4 and a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:3 contains 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8. In one embodiment, an anti-OSMR antibody formulation containing a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:4 and a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:3 contains 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8. In one embodiment, an anti-OSMR antibody formulation containing a light chain having the amino acid sequence set forth in SEQ ID NO:2 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:1 contains 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8.

[0024] In another aspect, the present invention provides a method for treating a disease, disorder, or condition associated with OSMR, comprising administering any of the stable formulations described above to a subject in need of treatment. In one embodiment, the formulation is administered intravenously. In one embodiment, the formulation is administered subcutaneously. In one embodiment, the disease, disorder, or condition associated with OSMR is pruritus, atopic dermatitis, inflammation, pain, pruritus nodularis, dermatitis, asthma, autoimmune diseases, paraneoplastic autoimmune diseases, cartilage inflammation, fibrosis (including, but not limited to, pulmonary fibrosis and dermal fibrosis), fibroticdisease), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, abnormal collagen deposition, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, Behçet's disease, nasal polyps, liver cirrhosis, cartilage degeneration, bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, small-articular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reiter's syndrome, SEA syndrome (blood ulcers and arthritis) seronegative, enthesopathy, arthropathy syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, small-articular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, SEA syndrome (seronegative, enthesopathy, arthropathy syndrome), dermatomyositis, psoriatic arthritis, scleroderma, parascleroderma-associated interstitial pneumonia, vasculitis, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Werner's syndrome, Goehner's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis, primary sclerosing cholangitis, sclerosing cholangitis, Sjögren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atherosclerosis, lupus erythematosus, Still's disease, systemic lupus erythematosus (SLE), myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, celiac disease, multiple sclerosis (MS), asthma, COPD, rhinosinusitis, nasal polyps, eosinophilic bowel disease Selected from esophagitis, eosinophilic bronchitis, bronchitis, Guillain-Barre syndrome, type 1 diabetes, thyroiditis (Graves' disease), Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, GVHD, graft rejection, nephropathy, cardiovascular disease, infection, sepsis, HIV infection, trauma, renal allograft nephropathy, IgA nephropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, biliary atresia, congestive heart failure, atherosclerosis, restenosis, radiation-induced fibrosis, chemotherapy-induced fibrosis, burns, surgical trauma, and glomerulosclerosis.

[0025] In another aspect, the present invention provides a method of treating pruritus, comprising subcutaneously administering to a subject in need thereof a formulation comprising an anti-oncostatin M receptor (OSMR) antibody at a concentration of at least 50 mg / mL. In one embodiment, the anti-OSMR antibody is present at a concentration of at least about 75 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 215 mg / mL, 220 mg / mL, 225 mg / mL, or 250 mg / mL. In one embodiment, the anti-OSMR antibody is present at a concentration of approximately 50 mg / mL to 250 mg / mL, approximately 75 mg / mL to 250 mg / mL, approximately 100 mg / mL to 250 mg / mL, approximately 125 mg / mL to 250 mg / mL, approximately 150 mg / mL to 250 mg / mL, approximately 175 mg / mL to 250 mg / mL, approximately 50 mg / mL to 225 mg / mL, approximately 50 mg / mL to 200 mg / mL, approximately 50 mg / mL to 175 mg / mL, approximately 50 mg / mL to 150 mg / mL, approximately 50 mg / mL to 125 mg / mL, or approximately 50 mg / mL to 100 mg / mL, or approximately 150 mg / mL to 250 mg / mL.

[0026] In one embodiment, an anti-OSMR antibody contains a light chain complementarity determining region 1 (LCDR1) defined by SEQ ID NO:8, a light chain complementarity determining region 2 (LCDR2) defined by SEQ ID NO:9, and a light chain complementarity determining region 3 (LCDR3) defined by SEQ ID NO:10, as well as a heavy chain complementarity determining region 1 (HCDR1) defined by SEQ ID NO:5, a heavy chain complementarity determining region 2 (HCDR2) defined by SEQ ID NO:6, and a heavy chain complementarity determining region 3 (HCDR3) defined by SEQ ID NO:7. In one embodiment, an anti-OSMR antibody contains a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:4, and a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:3. In one embodiment, the light chain variable domain has the amino acid sequence set forth in SEQ ID NO:4, and the heavy chain variable domain has the amino acid sequence set forth in SEQ ID NO:3. In one embodiment, an anti-OSMR antibody contains a CH1, hinge, and CH2 domain derived from an IgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. In one embodiment, an anti-OSMR antibody contains a light chain having an amino acid sequence at least 90% identical to SEQ ID NO: 2 and a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 1. In one embodiment, the light chain has the amino acid sequence set forth in SEQ ID NO: 2 and the heavy chain has the amino acid sequence set forth in SEQ ID NO: 1.

[0027] In one embodiment, the formulation is administered in a volume of less than 5 mL, 4 mL, 3 mL, or 2 mL. In one embodiment, the formulation has a viscosity of less than 50 mPa*s, less than 30 mPa*s, less than 20 mPa*s, or less than 15 mPa*s as measured by a microfluidic rheometer. In one embodiment, the formulation has a viscosity of approximately 1-30 mPa*s, approximately 2-28 mPa*s, approximately 4-30 mPa*s, approximately 6-30 mPa*s, approximately 8-30 mPa*s, approximately 10-30 mPa*s, approximately 12-30 mPa*s, approximately 14-30 mPa*s, approximately 16-30 mPa*s, approximately 18-30 mPa*s, approximately 20-30 mPa*s, approximately 22-30 mPa*s, approximately 24-30 mPa*s, approximately 26-30 mPa*s, or approximately 28-30 mPa*s, as measured by a microfluidic rheometer. ... -1 has a shear rate of less than

[0028] In one embodiment, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody is present as HMW species in the formulation. In one embodiment, the amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% when stored at 25°C for two weeks or more. In one embodiment, the amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% when stored at 25°C for four weeks or more. In one embodiment, the amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% when stored at 25°C for three months or more. In one embodiment, the amount of HMW species in the formulation increases by approximately 0.3-0.7%, approximately 0.3-0.6%, or approximately 0.3-0.5% when stored at 25°C for four weeks. In one embodiment, the formulation is stable when stored for 3 months at about 25° C. and the amount of HMW species in the formulation increases by approximately 0.3% to 5%, approximately 0.3% to 3%, or approximately 0.3% to 2.5%. In one embodiment, the formulation is stable when stored for 3 months at about 25° C. and the percentage of intact IgG monomers is greater than 90% of the total protein content.

[0029] In one embodiment, the formulation is stable through multiple freeze-thaw cycles. In one embodiment, the formulation is stable upon storage at about 25°C, and the amount of intact IgG is greater than 90% after multiple freeze-thaw cycles and storage for at least 3 months, or at least 6 months, or at least 12 months, or at least 24 months. In one embodiment, the formulation is stable upon storage at 2-5°C for at least 3 months, or at least 6 months, or at least 1 year, or at least 2 years, or at least 3 years, or at least 4 years, or at least 5 years, or at least 10 years. In one embodiment, the formulation is stable upon storage at -70°C for at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, or at least 10 years. In certain embodiments, for example, the following are provided: (Item 1) A stable formulation comprising an anti-oncostatin M receptor (OSMR) antibody, having a pH in the range of approximately 6.0 to 7.6, wherein less than approximately 5% of the anti-OSMR antibody is present in the formulation as a high molecular weight (HMW) species. (Item 2) 2. The stable formulation of claim 1, wherein less than 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody is present as HMW species in the formulation. (Item 3) 3. The stable formulation of item 1 or 2, wherein the relative amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for more than two weeks. (Item 4) 3. The stable formulation of item 1 or 2, wherein upon storage at 25°C for 4 weeks, the relative amount of HMW species in the formulation increases by approximately 0.3-0.7%, approximately 0.3%-0.6%, or approximately 0.3-0.5%. (Item 5) 3. The stable formulation of item 1 or 2, wherein upon storage at 25° C. for 3 months, the relative amount of HMW species in the formulation increases by approximately 0.3-5%, approximately 0.3%-3%, or approximately 0.3-2.5%. (Item 6) 6. The stable formulation of any one of items 1 to 5, wherein at least 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% of the anti-OSMR antibody is present as a monomer in the stable formulation. (Item 7) 7. The stable formulation of any one of items 1 to 6, wherein the relative amount of monomer decreases by less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% when stored at 25° C. for more than 2 weeks. (Item 8) 8. The stable formulation of any one of items 1 to 7, wherein the relative amount of monomer decreases by less than 10%, 8%, 7%, 6%, 5%, or 4% when stored at 25° C. for more than 4 weeks. (Item 9) 9. The stable formulation of any one of items 1 to 8, wherein the relative amount of monomer decreases by less than 10%, 8%, 6%, 5%, or 4% when stored at 25° C. for about 3 months. (Item 10) 10. The stable formulation of any one of items 1 to 9, wherein the HMW species and / or monomers are determined by size exclusion chromatography (SEC), analytical ultracentrifugation (AUC), field-flow fractionation (FFF) or light scattering. (Item 11) 11. The stable formulation of any one of items 1 to 10, wherein the percentage of HMW species, as determined by size exclusion chromatography (SEC), is less than 5% when stored at −70° C., or 5° C.±3° C., or 25° C. for about 3 months. (Item 12) 12. The stable formulation according to any one of items 1 to 11, wherein the pH of the formulation is in the range of about 5.0 to 7.6, about 5.5 to 7.4, about 6.0 to 7.2, about 6.0 to 7.0, about 6.0 to 6.8, about 6.0 to 6.6, about 6.0 to 6.4, about 6.4 to 7.6, about 6.6 to 7.6, about 6.8 to 7.6, about 7.0 to 7.6, or about 7.2 to 7.6. (Item 13) 13. The stable formulation of any one of items 1 to 12, wherein the pH of the formulation is approximately 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.2, 7.4 or 7.6. (Item 14) 14. The stable formulation of any one of items 1 to 13, wherein the anti-OSMR antibody is present at a concentration of at least about 50 mg / mL. (Item 15) 15. The stable formulation of any one of items 1 to 14, wherein the anti-OSMR antibody is present at a concentration of at least about 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 200 mg / mL, 225 mg / mL, or 250 mg / mL. (Item 16) 16. The stable formulation of any one of paragraphs 1-15, wherein the anti-OSMR antibody is present at a concentration of approximately 75 mg / mL, 100 mg / mL, 105 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 215 mg / mL, 220 mg / mL, 225 mg / mL, or 250 mg / mL. (Item 17) 17. The stable formulation of any one of items 1 to 16, wherein the anti-OSMR antibody has a pI in the range of 6.5 to 8.5. (Item 18) 18. The stable formulation of any one of items 1 to 17, wherein the anti-OSMR antibody has a pI in the range of 7.0 to 8.0. (Item 19) 19. The stable formulation of any one of items 1 to 18, wherein the anti-OSMR antibody comprises one or more charged species, and the pI of the charged species is in the range of 7.2 to 8.0. (Item 20) 20. The stable formulation according to any one of items 17 to 19, wherein the pI is determined by isoelectric focusing (IEF) or ion exchange chromatography (IEX). (Item 21) 21. The stable formulation according to any one of items 1 to 20, wherein the formulation comprises one or more amino acids. (Item 22) 22. The stable formulation according to item 21, wherein the one or more amino acids are present at a concentration of 5 mM to 35 mM, 10 mM to 35 mM, 15 mM to 30 mM, 1 mM to 250 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, or 20 mM to 150 mM. (Item 23) 23. The stable formulation of item 21 or 22, wherein the one or more amino acids are selected from the group consisting of arginine, glutamic acid, glycine, histidine, and combinations thereof. (Item 24) Item 25. The stable formulation according to Item 23, wherein the one or more amino acids include arginine. 25. The stable formulation of item 24, wherein the arginine is selected from the group consisting of D-arginine and L-arginine, or a combination thereof. (Item 26) 25. The stable formulation of item 24, wherein the arginine is L-arginine. (Item 27) 22. The stable formulation of item 21, wherein the one or more amino acids do not include glutamic acid. (Item 28) 28. The stable formulation of any one of items 1 to 27, wherein the arginine is present at a concentration of 20 mM to 30 mM, 15 mM to 35 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 25 mM to 150 mM. (Item 29) Item 30. The stable formulation of Item 28, wherein the arginine is present at a concentration of 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM. 30. The stable formulation of any one of items 24 to 29, wherein the arginine is present at a concentration of 25 mM. (Item 31) 22. The stable formulation of item 21, wherein the one or more amino acids comprises glutamic acid. (Item 32) 22. The stable formulation of item 21, wherein the one or more amino acids comprise arginine and glutamic acid. (Item 33) 33. The stable formulation of item 32, wherein the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. (Item 34) 34. The stable formulation of any one of items 21, 31, 32 or 33, wherein glutamic acid is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 50 mM to 150 mM. (Item 35) 35. The stable formulation of any one of items 21 to 34, wherein the one or more amino acids comprises histidine. (Item 36) 36. The stable formulation of item 35, wherein the one or more amino acids comprises L-histidine. (Item 37) 36. The stable formulation according to item 35, wherein the histidine is present at a concentration of 15 mM to 25 mM, 10 mM to 30 mM, 10 mM to 20 mM, 5 mM to 25 mM, 5 mM to 50 mM, 5 mM to 75 mM, 5 mM to 100 mM, 5 mM to 125 mM, or 5 mM to 150 mM. (Item 38) 38. The stable formulation of any one of items 35 to 37, wherein the formulation comprises 20 mM L-histidine. (Item 39) 39. The stable formulation of any one of items 21 to 38, wherein the one or more amino acids comprises glycine. (Item 40) 40. The stable formulation of item 39, wherein the glycine is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 150 mM to 200 mM. (Item 41) The stable formulation according to any one of Items 1 to 40, wherein the formulation further comprises a buffer. (Item 42) 42. The stable formulation of item 41, wherein the buffering agent is selected from the group consisting of citrate, phosphate, succinate, histidine, and combinations thereof. (Item 43) 43. The stable formulation of item 42, wherein the buffering agent is a phosphate salt. (Item 44) 44. The stable formulation of any one of items 41 to 43, wherein the buffering agent is present at a concentration of 1 mM to 100 mM, 5 mM to 75 mM, 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 25 mM, or 10 mM to 20 mM. (Item 45) 45. The stable formulation according to any one of items 1 to 44, wherein the formulation further comprises a salt. (Item 46) 46. ​​The stable formulation of item 45, wherein the salt comprises a halide. (Item 47) 47. The stable formulation of item 46, wherein the halide is an alkali metal halide. (Item 48) 48. The stable formulation of item 47, wherein the salt is NaCl. (Item 49) 49. The stable formulation of item 48, wherein NaCl is present at a concentration of 120 mM to 130 mM, 125 mM to 135 mM, 25 mM to 250 mM, 25 mM to 200 mM, 25 mM to 175 mM, 50 mM to 200 mM, 50 mM to 175 mM, 50 mM to 150 mM, or 75 mM to 150 mM. (Item 50) Item 51. The stable formulation of Item 48 or 49, wherein NaCl is present at a concentration of 125 mM. 49. The stable formulation of item 48, wherein the molar ratio of NaCl to arginine is at least 1:1, 1.5:1, 3:1, or 5:1. (Item 52) 52. The stable formulation of item 51, wherein the molar ratio of NaCl to arginine is approximately 5:1. (Item 53) 53. The stable formulation according to any one of items 1 to 52, wherein the formulation is isotonic. (Item 54) A stable injectable formulation of an anti-oncostatin M receptor (OSMR) antibody, comprising: 50 to 250 mg / mL of the anti-OSMR monoclonal antibody; 10 to 150 mM arginine, 10 to 150 mM histidine, 25-150 mM sodium chloride (NaCl), 0.05% to 0.5% (w / v) polysorbate 80 (PS80), a pH in the range of 6.0 to 7.6, the formulation is an isotonic solution, and A stable injectable formulation, wherein at least 90% of the antibody exists as stable, fully monomeric IgG at a temperature of about -70°C or about 5°C for at least one month. (Item 55) 55. The stable injectable formulation according to item 54, further having a pI in the range of approximately 6.5 to 8.5. (Item 56) 55. The stable injectable formulation according to item 54, further having a pI in the range of approximately 7.2 to 8.0. (Item 57) 55. The stable formulation according to item 54, wherein the pH of the formulation is in the range of about 6.0 to 7.6, about 6.0 to 7.4, about 6.0 to 7.2, about 6.0 to 7.0, about 6.5 to 7.1, about 6.0 to 6.8, about 6.0 to 6.6, about 6.0 to 6.4, about 6.4 to 7.6, about 6.6 to 7.6, about 6.8 to 7.6, about 7.0 to 7.6, or about 7.2 to 7.6. (Item 58) 58. The stable formulation according to any of items 1 to 57, wherein the pH of the formulation is in the range of approximately 6.6 to 6.8. (Item 59) 59. The stable formulation of item 54 or 58, wherein the anti-OSMR antibody is present at a concentration of at least about 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 180 mg / mL, 200 mg / mL, 210 mg / mL, 225 mg / mL, or 250 mg / mL. (Item 60) 56. The stable formulation of item 54 or 55, wherein the anti-OSMR antibody is present at a concentration of about 50 mg / ml to 250 mg / ml, about 75 mg / ml to 250 mg / ml, about 100 mg / ml to 250 mg / ml, about 125 mg / ml to 250 mg / ml, about 150 mg / ml to 250 mg / ml, about 175 mg / ml to 250 mg / ml, about 175 mg / ml to 225 mg / ml, about 180 mg / ml to 210 mg / ml, about 50 mg / ml to 225 mg / ml, about 50 mg / ml to 200 mg / ml, about 50 mg / ml to 175 mg / ml, about 50 mg / ml to 150 mg / ml, about 50 mg / ml to 125 mg / ml, or about 50 mg / ml to 100 mg / ml, or about 150 mg / ml to 250 mg / ml. (Item 61) 61. The stable formulation of any one of paragraphs 1-60, wherein the anti-OSMR antibody is present at a concentration of approximately 75 mg / mL, 100 mg / mL, 105 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 215 mg / mL, 220 mg / mL, 225 mg / mL, or 250 mg / mL. (Item 62) 62. The stable formulation of any one of items 1 to 61, wherein the anti-OSMR antibody is present at a concentration of approximately 200 mg / mL. (Item 63) 63. The stable formulation of any one of items 1 to 62, wherein the anti-OSMR antibody is present at a concentration of 180 mg / mL. (Item 64) 64. The formulation of any of items 54 to 63, wherein NaCl is present at a concentration of 120 mM to 130 mM, 125 mM to 135 mM, 25 mM to 250 mM, 25 mM to 200 mM, 25 mM to 175 mM, 50 mM to 200 mM, 50 mM to 175 mM, 50 mM to 150 mM, or 75 mM to 150 mM. (Item 65) The formulation according to any one of Items 54 to 64, wherein NaCl is present at a concentration of 125 mM. (Item 66) 66. The stable formulation of any one of items 54 to 65, wherein the formulation comprises L-arginine. (Item 67) 67. The stable formulation of any one of items 54 to 66, wherein the arginine is present at a concentration of 20 mM to 30 mM, 15 mM to 35 mM, 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 25 mM to 150 mM. (Item 68) 68. The stable formulation of any one of items 54 to 67, wherein the arginine is present at a concentration of 25 mM. (Item 69) 69. The stable formulation of any one of items 54 to 68, wherein the molar ratio of NaCl to arginine is at least 1:1, 1.5:1, 3:1, or 5:1. (Item 70) 70. The stable formulation of any one of items 54 to 69, wherein the molar ratio of NaCl to arginine is approximately 5:1. (Item 71) 55. The stable formulation of item 54, wherein the formulation does not contain glutamic acid. (Item 72) 55. The stable formulation of item 54, wherein the formulation comprises glutamic acid. (Item 73) 73. The stable formulation of item 72, wherein the formulation comprises arginine and glutamic acid. (Item 74) 74. The stable formulation of item 73, wherein the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. (Item 75) 75. The stable formulation of any one of items 1-74, wherein glutamic acid is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 50 mM to 150 mM. (Item 76) 76. The stable formulation of any one of items 54 to 75, wherein the formulation comprises L-histidine. (Item 77) 55. The stable formulation of item 54, wherein the histidine is present at a concentration of 15 mM to 25 mM, 10 mM to 30 mM, 10 mM to 20 mM, 5 mM to 25 mM, 5 mM to 50 mM, 5 mM to 75 mM, 5 mM to 100 mM, 5 mM to 125 mM, or 5 mM to 150 mM. (Item 78) 77. The stable formulation of any one of items 54 to 76, wherein the histidine is present at a concentration of 20 mM. (Item 79) 79. The stable formulation of any one of items 54 to 78, wherein the molar ratio of NaCl to histidine is approximately 6:1. (Item 80) 55. The stable formulation of item 54, further comprising glycine, wherein the glycine is present at a concentration of 10 mM to 250 mM, 10 mM to 200 mM, 10 mM to 150 mM, 10 mM to 125 mM, 10 mM to 100 mM, 10 mM to 75 mM, 10 mM to 50 mM, or 150 mM to 200 mM. (Item 81) 80. The stable formulation of any one of items 54 to 79, wherein the formulation further comprises a buffering agent. (Item 82) 81. The stable formulation of item 80, wherein the buffering agent is selected from the group consisting of citrate, phosphate, succinate, histidine, and combinations thereof. (Item 83) 82. The stable formulation of item 81, wherein the buffering agent is a phosphate salt. (Item 84) 83. The stable formulation of any one of items 54 to 82, wherein the buffering agent is present at a concentration of 1 mM to 100 mM, 5 mM to 75 mM, 5 mM to 50 mM, 5 mM to 40 mM, 5 mM to 30 mM, 5 mM to 25 mM, or 10 mM to 20 mM. (Item 85) 85. The stable formulation according to any one of items 1 to 84, wherein the formulation is isotonic. (Item 86) 86. The stable formulation according to any of items 54 to 85, wherein the formulation has an osmolality in the range of 250 to 350 mOsm or 270 to 330 mOsm. (Item 87) Item 88. The stable formulation according to Item 86, wherein the formulation has an osmolality of 300 mOsm. 88. The stable formulation of any one of items 1 to 87, wherein the formulation has a viscosity of less than 50 mPa*s as measured by a microfluidic rheometer. (Item 89) 89. The stable formulation of any one of items 1 to 88, wherein the formulation has a viscosity of less than 30 mPa*s as measured by a microfluidic rheometer. (Item 90) 89. The stable formulation of any one of items 1 to 89, wherein the formulation has a viscosity of less than 20 mPa*s as measured by a microfluidic rheometer. (Item 91) 91. The stable formulation of any one of items 1 to 90, wherein the formulation has a viscosity of less than 15 mPa*s as measured by a microfluidic rheometer. (Item 92) 92. The stable formulation according to any one of items 1-91, wherein the formulation has a viscosity, when measured by a microfluidic rheometer, of approximately 1-30 mPa*s, approximately 2-28 mPa*s, approximately 4-30 mPa*s, approximately 6-30 mPa*s, approximately 8-30 mPa*s, approximately 10-30 mPa*s, approximately 12-30 mPa*s, approximately 14-30 mPa*s, approximately 16-30 mPa*s, approximately 18-30 mPa*s, approximately 20-30 mPa*s, approximately 22-30 mPa*s, approximately 24-30 mPa*s, approximately 26-30 mPa*s, or approximately 28-30 mPa*s. (Item 93) The formulation was heated at 25°C for 1000 s -1 93. The stable formulation according to any one of items 1 to 92, having a shear rate of less than (Item 94) 94. The stable formulation according to any one of items 1 to 93, wherein the formulation is a liquid formulation. (Item 95) 95. The stable formulation of any one of items 1 to 94, wherein the formulation is reconstituted from a lyophilized powder. (Item 96) the anti-OSMR antibody a light chain complementarity determining region 1 (LCDR1) defined in SEQ ID NO: 8, a light chain complementarity determining region 2 (LCDR2) defined in SEQ ID NO: 9, and a light chain complementarity determining region 3 (LCDR3) defined in SEQ ID NO: 10, and 96. The stable formulation according to any one of items 1 to 95, comprising heavy chain complementarity determining region 1 (HCDR1) defined in SEQ ID NO: 5, heavy chain complementarity determining region 2 (HCDR2) defined in SEQ ID NO: 6, and heavy chain complementarity determining region 3 (HCDR3) defined in SEQ ID NO: 7. (Item 97) the anti-OSMR antibody a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:4, and 97. The stable formulation of any one of items 1 to 96, comprising a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO: 3. (Item 98) the light chain variable domain has the amino acid sequence set forth in SEQ ID NO:4, and 97. The stable formulation of item 96, wherein the heavy chain variable domain has the amino acid sequence set forth in SEQ ID NO:3. (Item 99) 99. The stable formulation of any one of items 1 to 98, wherein the anti-OSMR antibody contains CH1, hinge, and CH2 domains derived from an IgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. (Item 100) the anti-OSMR antibody a light chain having an amino acid sequence at least 90% identical to SEQ ID NO:2; and 99. The stable formulation of any one of items 1 to 99, comprising a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 1. (Item 101) the light chain has the amino acid sequence set forth in SEQ ID NO:2, and 101. The stable formulation according to any one of items 1 to 100, wherein the heavy chain has the amino acid sequence set forth in SEQ ID NO: 1. (Item 102) 1. A stable formulation comprising an antibody at a concentration of at least 50 mg / mL and arginine, wherein the arginine is present in an amount greater than any other amino acid in the formulation that is not arginine. (Item 103) 103. The stable formulation of item 102, wherein the formulation is glutamic acid-free. (Item 104) 103. The stable formulation of item 102, wherein the formulation comprises glutamic acid. (Item 105) 103. The stable formulation of item 102, wherein the molar ratio of arginine to glutamic acid is at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. (Item 106) 106. A method for treating a disease, disorder or condition associated with OSMR, comprising administering to a subject in need thereof the stable formulation of any one of items 1 to 105. (Item 107) 107. The method of claim 106, wherein the formulation is administered intravenously. (Item 108) 107. The method of claim 106, wherein the formulation is administered subcutaneously. (Item 109) The diseases, disorders or conditions associated with OSMR include pruritus, atopic dermatitis, inflammation, pain, pruritus nodularis, dermatitis, asthma, autoimmune diseases, paraneoplastic autoimmune diseases, cartilage inflammation, fibrosis (including but not limited to pulmonary fibrosis and dermal fibrosis), fibroticdisease), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, abnormal collagen deposition, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, Behçet's disease, nasal polyps, liver cirrhosis, cartilage degeneration, bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, small-articular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reiter's syndrome, SEA syndrome (seronegative, Enthesopathy, arthropathy syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, small-articular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, SEA syndrome (seronegative, enthesopathy, arthropathy syndrome), dermatomyositis, psoriatic arthritis, scleroderma, parascleroderma-associated interstitial pneumonia, vasculitis, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, Polymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis, primary sclerosing cholangitis, sclerosing cholangitis, Sjogren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atherosclerosis, lupus erythematosus, Still's disease, systemic lupus erythematosus (SLE), myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, celiac disease, multiple sclerosis (MS), asthma, COPD, rhinosinusitis, nasal polyps, eosinophilic esophagitis, eosinophilic bronchitis, bronchitis, 109. The method of any one of items 106 to 108, wherein the inflammatory disease is selected from Guillain-Barre syndrome, type 1 diabetes, thyroiditis (Graves' disease), Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, GVHD, graft rejection, nephropathy, cardiovascular disease, infection, sepsis, HIV infection, trauma, renal allograft nephropathy, IgA nephropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, biliary atresia, congestive heart failure, atherosclerosis, restenosis, radiation-induced fibrosis, chemotherapy-induced fibrosis, burns, surgical trauma, and glomerulosclerosis. (Item 110) A method of treating pruritus, comprising subcutaneously administering to a subject in need thereof a formulation comprising an anti-oncostatin M receptor (OSMR) antibody at a concentration of at least 50 mg / mL. (Item 111) Item 112. The method of item 106 or 110, wherein the anti-OSMR antibody is present at a concentration of at least about 75 mg / mL, 100 mg / mL, 125 mg / mL, 150 mg / mL, 175 mg / mL, 200 mg / mL, 225 mg / mL, or 250 mg / mL. 111. The method of claim 106 or 110, wherein the anti-OSMR antibody is present at a concentration of about 50 mg / mL to 250 mg / mL, about 75 mg / mL to 250 mg / mL, about 100 mg / mL to 250 mg / mL, about 125 mg / mL to 250 mg / mL, about 150 mg / mL to 250 mg / mL, about 175 mg / mL to 250 mg / mL, about 50 mg / mL to 225 mg / mL, about 50 mg / mL to 200 mg / mL, about 50 mg / mL to 175 mg / mL, about 50 mg / mL to 150 mg / mL, about 50 mg / mL to 125 mg / mL, or about 50 mg / mL to 100 mg / mL, or about 150 mg / mL to 250 mg / mL. (Item 113) 113. The stable formulation of any one of paragraphs 1-112, wherein the anti-OSMR antibody is present at a concentration of 75 mg / mL, 100 mg / mL, 105 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 215 mg / mL, 220 mg / mL, 225 mg / mL, or 250 mg / mL. (Item 114) 114. The stable formulation of any one of items 1 to 113, wherein the anti-OSMR antibody is present at a concentration of approximately 200 mg / mL. (Item 115) 115. The stable formulation of any one of items 1 to 114, wherein the anti-OSMR antibody is present at a concentration of 180 mg / mL. (Item 116) the anti-OSMR antibody a light chain complementarity determining region 1 (LCDR1) defined in SEQ ID NO: 8, a light chain complementarity determining region 2 (LCDR2) defined in SEQ ID NO: 9, and a light chain complementarity determining region 3 (LCDR3) defined in SEQ ID NO: 10, and The method according to any one of Items 106 to 115, comprising a heavy chain complementarity determining region 1 (HCDR1) defined in SEQ ID NO: 5, a heavy chain complementarity determining region 2 (HCDR2) defined in SEQ ID NO: 6, and a heavy chain complementarity determining region 3 (HCDR3) defined in SEQ ID NO: 7. (Item 117) the anti-OSMR antibody a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO:4, and 117. The method according to any of items 1 to 116, comprising a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO: 3. (Item 118) the light chain variable domain has the amino acid sequence set forth in SEQ ID NO:4, and 118. The method according to any of items 1 to 117, wherein the heavy chain variable domain has the amino acid sequence set forth in SEQ ID NO: 3. (Item 119) 119. The method of any of items 1 to 118, wherein the anti-OSMR antibody contains CH1, hinge, and CH2 domains derived from an IgG4 antibody fused to a CH3 domain derived from an IgG1 antibody. (Item 120) the anti-OSMR antibody a light chain having an amino acid sequence at least 90% identical to SEQ ID NO:2; and 119. The method according to any of items 1 to 119, comprising a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 1. (Item 121) 121. The method according to any of items 1 to 120, wherein the light chain has the amino acid sequence set forth in SEQ ID NO: 2, and the heavy chain has the amino acid sequence set forth in SEQ ID NO: 1. (Item 122) 122. The method of any one of items 106 to 121, wherein the formulation is administered in a volume of less than 5 mL, 4 mL, 3 mL, or 2 mL. (Item 123) 123. The method of any one of items 106 to 122, wherein the formulation has a viscosity, as measured by a microfluidic rheometer, of less than 50 mPa*s, less than 30 mPa*s, less than 20 mPa*s, or less than 15 mPa*s. (Item 124) 124. The method of any one of items 106 to 123, wherein the formulation has a viscosity, when measured by a microfluidic rheometer, of approximately 1 to 30 mPa*s, approximately 2 to 28 mPa*s, approximately 4 to 30 mPa*s, approximately 6 to 30 mPa*s, approximately 8 to 30 mPa*s, approximately 10 to 30 mPa*s, approximately 12 to 30 mPa*s, approximately 14 to 30 mPa*s, approximately 16 to 30 mPa*s, approximately 18 to 30 mPa*s, approximately 20 to 30 mPa*s, approximately 22 to 30 mPa*s, approximately 24 to 30 mPa*s, approximately 26 to 30 mPa*s, or approximately 28 to 30 mPa*s. (Item 125) The formulation was heated at 25°C for 1000 s -1 125. The method according to any one of items 106 to 124, wherein the shear rate is less than (Item 126) 126. The method of any one of paragraphs 106 to 125, wherein less than 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody is present as HMW species in the formulation. (Item 127) 127. The method of any one of items 106 to 126, wherein the relative amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25° C. for more than 2 weeks. (Item 128) 128. The method of any one of items 106 to 127, wherein the amount of HMW species in the formulation increases by approximately 0.3 to 0.7%, approximately 0.3% to 0.6%, or approximately 0.3 to 0.5% when stored at 25°C for 4 weeks. (Item 129) A stable injectable formulation of an anti-oncostatin M receptor (OSMR) antibody, comprising: 180 mg / mL of said anti-OSMR monoclonal antibody; 25mM arginine hydrochloride, 20mM histidine, 125mM sodium chloride, Contains 0.05% (w / v) polysorbate 80 (PS80), A stable injectable formulation, wherein the composition has a pH of approximately 6.6 and at least 90% of the protein exists as stable, fully monomeric IgG at a temperature of about -70°C or about 5°C for at least one month. (Item 130) The anti-oncostatin M receptor (OSMR) antibody is a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:4, and 130. The formulation of item 129, comprising a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:3. (Item 131) The anti-oncostatin M receptor (OSMR) antibody is a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:2, and 130. The formulation of claim 129, comprising a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:1. (Item 132) 132. The formulation according to any of items 1 to 131, wherein the formulation is stable at 25°C for at least 3 months after 1, 2 or 3 freeze / thaw cycles. (Item 133) 133. The formulation of any of items 1-132, wherein storage of the formulation at -70°C for at least about 3 months results in the formulation containing less than about 5% aggregates and at least more than 90% whole antibody IgG monomers. (Item 134) 134. The formulation of any of items 1-133, wherein storage of the formulation at 5-8°C for at least about 3 months results in the formulation containing less than about 5% aggregates and more than about 90% intact antibody. (Item 135) 135. The formulation of any of items 1-134, wherein storage of the formulation at 25°C results in the formulation containing less than 5% aggregates and more than 90% intact antibody for up to at least 1 month. (Item 136) 136. The formulation of any of items 1 to 135, wherein storage of the formulation at 25°C results in the formulation containing less than 5% aggregates and more than 90% intact antibody for up to at least 3 months. [Brief explanation of the drawings]

[0030] The drawings are for illustration purposes only and are not intended to be limiting.

[0031] [Figure 1] FIG. 1 shows an exemplary graph illustrating the effect of protein concentration on viscosity in two different formulations of anti-OSMR antibody.

[0032] [Figure 2] Figure 2 shows plots of viscosity versus temperature for the 209 mg / mL and 180 mg / mL formulations.

[0033] [Figure 3] FIG. 3 shows an exemplary chromatogram showing HMW species in a sample stressed by storage at 40° C.

[0034] [Figure 4] An exemplary graph showing predicted versus measured monomer content is shown in Figure 4. A partial least squares regression was performed to model the monomer content in the samples after 2 weeks at 40°C.

[0035] [Figure 5]5 shows an exemplary graph illustrating the difference between predicted and measured capillary isoelectric focusing (cIEF) in the major peak fraction. Partial least squares regression was performed to model the cIEF difference in the major peak fraction data from round 1 in samples after 2 weeks at 40° C.

[0036] [Figure 6] 6 shows an exemplary graph illustrating the difference between predicted and measured cIEF in the major peak fraction. Partial least squares regression was performed to model the cIEF difference in the major peak fraction data from round 1 in samples after 4 weeks at 25° C.

[0037] [Figure 7] FIG. 7 shows exemplary correlation coefficients for variables for various round 1 formulations at t2 (samples stored at 40° C. for 2 weeks) and t4 (samples stored at 25° C. for 4 weeks).

[0038] [Figure 8] FIG. 8 shows the properties of an exemplary formulation sample when stored at −70° C. and 5° C. over a 3-month period.

[0039] [Figure 9] FIG. 9 shows the properties of exemplary formulation samples when stored at 25° C.±2° C. (accelerated conditions) and 40° C.±2° C. (stressed conditions) for three months. DETAILED DESCRIPTION OF THE INVENTION

[0040] definition In order that the present invention may be more readily understood, certain terms are first defined as follows: Further definitions of these and other terms are set forth throughout the specification. The publications and other reference materials referred to herein are incorporated by reference to describe the background of the invention and to provide additional details regarding its practice.

[0041] Amino acid: As used herein, the term "amino acid" in its broadest sense refers to any compound and / or substance that can be incorporated into a polypeptide chain. In some embodiments, an amino acid has the general structure HN-C(H)(R)-COHO. In some embodiments, an amino acid is a naturally occurring amino acid. In some embodiments, an amino acid is a synthetic amino acid. In some embodiments, an amino acid is a d-amino acid. In some embodiments, an amino acid is an l-amino acid. A "standard amino acid" refers to any of the 20 standard l-amino acids that are universally present in natural peptides. A "non-standard amino acid" refers to any amino acid other than the standard amino acids, whether prepared synthetically or obtained from a natural source. As used herein, a "synthetic amino acid" encompasses chemically modified amino acids, including, but not limited to, salts, amino acid derivatives (such as amides), and / or substitutions. Amino acids, including the carboxyl-terminal amino acid and / or the amino-terminal amino acid in a peptide, can be modified by methylation, amidation, acetylation, protecting groups, and / or substitutions with other chemical groups that can alter the circulating half-life of the peptide without adversely affecting its activity. Amino acids can participate in disulfide bonds. Amino acids can include single or post-translational modifications, such as attachment to one or more chemical groups (e.g., methyl groups, acetate groups, acetyl groups, phosphate groups, formyl moieties, isoprenoid groups, sulfate groups, polyethylene glycol moieties, lipid moieties, carbohydrate moieties, biotin moieties, etc.). The term "amino acid" is used interchangeably with "amino acid residue" and can refer to free amino acids and / or amino acid residues of peptides. Whether the term refers to a free amino acid or a residue of a peptide will be clear from the context in which the term is used.

[0042] Enhancement: As used herein, the term "enhancement" refers to the prevention, reduction, or alleviation of a condition, or an improvement in a subject's condition. Enhancement includes, but is not required to include, complete amelioration or complete prevention of a disease state. In some embodiments, enhancement includes an increase in the level of, or an increase in the activity of, an associated protein that is deficient in the associated disease tissue.

[0043] Approximately or about: As used herein, the term "approximately" or "about" as applied to one or more values ​​of interest refers to a value similar to a specified reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​that falls within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or lesser) of the specified reference value, unless otherwise stated or apparent from the context (except where such value exceeds 100% of possible values).

[0044] Biological activity: As used herein, the phrase "biological activity" refers to the characteristic of any entity that has activity in a biological system, particularly in an organism. For example, an entity that, when administered to an organism, has a biological activity on that organism is considered to be biologically active. In certain embodiments, if a protein or polypeptide is biologically active, a portion of the protein or polypeptide that shares at least one biological activity of the protein or polypeptide is typically referred to as a "biologically active" portion.

[0045] Diluent: As used herein, the term "diluent" refers to a pharmaceutically acceptable (e.g., safe and non-toxic for human administration) diluent substance useful in preparing a formulation to be reconstituted. Exemplary diluents include sterile water, bacteriostatic water for injection (BWFI), a pH buffered solution (e.g., phosphate-buffered saline), sterile saline, Ringer's solution, or dextrose solution.

[0046] Delivery: As used herein, the term "delivery" encompasses both local and systemic delivery.

[0047] Half-life: As used herein, the term "half-life" is the time required for the concentration or amount of activity of, for example, a nucleic acid or protein, to fall to half of its value measured at the beginning of the period.

[0048] Improved, increased, or decreased: As used herein, the terms "improved," "increased," or "decreased," or grammatical equivalents thereof, refer to a value relative to a reference measurement, such as a measurement in the same individual prior to the initiation of a treatment described herein, or a measurement in a control subject (or control subjects) not receiving a treatment described herein. A "control subject" is a subject suffering from the same type of disease as the subject being treated and who is about the same age as the subject being treated.

[0049] Stability: As used herein, the term "stable" refers to the ability of a therapeutic agent (e.g., a recombinant enzyme) to maintain its therapeutic efficacy (e.g., all or most of its intended biological activity and / or biochemical integrity) over an extended period of time. The stability of a therapeutic agent and the ability of a pharmaceutical composition to maintain the stability of the therapeutic agent can be evaluated over an extended period of time (e.g., at least 1, 3, 6, 12, 18, 24, 30, 36 months or more). Generally, the pharmaceutical compositions described herein are formulated to stabilize, or alternatively slow or prevent degradation of, one or more therapeutic agents formulated therewith (e.g., recombinant proteins). In a formulation, a stable formulation is one in which the therapeutic agent therein essentially retains its physical and / or chemical integrity and biological activity upon storage and during processing (e.g., freeze / thaw, mechanical mixing, lyophilization, etc.). Protein stability can be measured by the formation of high molecular weight (HMW) aggregates, loss of enzymatic activity, generation of peptide fragments, and shifts in charge profile. For purposes of this application, the terms high molecular weight species (HMW) and "aggregates" of the product are used interchangeably.

[0050] Substantial identity: As used herein, the phrase "substantial identity" refers to a comparison between amino acid sequences or nucleic acid sequences. As understood by those skilled in the art, two sequences are generally considered to be "substantially identical" if they contain identical residues at corresponding positions. As is known in the art, amino acid sequences or nucleic acid sequences can be compared using any of a variety of algorithms, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences, and BLASTP, gapped BLAST, and PSI-BLAST for amino acid sequences. Examples of such programs are described in Altschul, et al., Basic local alignment search tool, J Mal. Biol., 215(3):403-410, 1990; Altschul, et al., Methods in Enzymology; Altschul et al., Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener, et al., (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999. In addition to identifying identical sequences, the above-mentioned programs often provide a numerical value for the degree of identity. In some embodiments, sequences are considered substantially identical if at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more of the corresponding residues are identical over the relevant stretch of residues. In some embodiments, the relevant stretch is the complete sequence.In some embodiments, the relevant sequence is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500 or more residues.

[0051] Suitable for subcutaneous delivery: As used herein, the phrase "suitable for subcutaneous delivery" or "formulation for subcutaneous delivery" when referring to a pharmaceutical composition of the invention generally refers to the stability, viscosity, and solubility properties of the composition, as well as the ability of the composition to deliver an effective amount of the antibody contained therein to a targeted delivery site.

[0052] Patient: As used herein, the term "patient" or "subject" refers to any organism to which provided compositions can be administered, for example, for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, the patient is a human. Humans include prenatal and postnatal.

[0053] Pharmaceutically acceptable: As used herein, the term "pharmaceutically acceptable" refers to a material that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0054] Subject: As used herein, the term "subject" refers to a human or any non-human animal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate). Human includes prenatal and postnatal. In many embodiments, the subject is a human. A subject may be a patient, which refers to a human who presents to a health care provider for diagnosis or treatment of a disease. The term "subject" is used interchangeably herein with "individual" or "patient." A subject may be suffering from or susceptible to a disease or disorder, but may or may not exhibit symptoms of the disease or disorder.

[0055] Substantially: As used herein, the term "substantially" refers to the qualitative state of exhibiting all or nearly all extent or degree of a characteristic or property of interest. Those skilled in the art of biology will understand that biological and chemical phenomena rarely reach completion and / or progress to perfection, or achieve or avoid perfect results. Thus, the term "substantially" is used herein to capture the potential lack of perfection inherent in many biological and chemical phenomena.

[0056] Systemic distribution or delivery: As used herein, the terms "systemic distribution," "systemic delivery," or grammatical equivalents thereof, refer to a mechanism or method of delivery or distribution that affects the entire body or an entire organism. Typically, systemic distribution or delivery is achieved via the body's circulatory system, e.g., the bloodstream. Compare with the definition of "local distribution or delivery."

[0057] Target tissue: As used herein, the term "target tissue" refers to any tissue affected by the disease or disorder being treated. In some embodiments, the target tissue includes tissue that exhibits a pathology, symptom, or characteristic associated with the disease.

[0058] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" of a therapeutic agent means an amount that, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of symptoms of the disease, disorder, and / or condition. Those skilled in the art will understand that a therapeutically effective amount is often administered via a dosing regimen comprising at least one unit dose.

[0059] Treatment: As used herein, the terms "treat," "treatment," or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset, reduce severity, and / or reduce incidence of one or more symptoms or characteristics of a particular disease, disorder, and / or condition. Treatment may be administered to subjects who do not exhibit signs of disease and / or who exhibit only early signs of disease, with the intent of reducing the risk of developing pathologies associated with the disease. [Mode for Carrying Out the Invention]

[0060] Specifically, the present invention provides stable formulations containing anti-oncostatin M receptor beta (OSMR) antibodies and having a pH in the range of approximately 6.0-7.6, wherein less than 5% of the anti-OSMR antibody is present as a high molecular weight (HMW) species in the formulation. Also provided are stable formulations containing anti-OSMR antibodies having a pH in the range of approximately 6.0-7.6, wherein the anti-OSMR antibody has a pI in the range of about 6.5-8.5. In some embodiments, the formulations contain arginine and, optionally, NaCl. In some embodiments, the formulations are suitable for subcutaneous delivery. In some embodiments, the stable formulations of the present invention are suitable for treating pruritus or other diseases and disorders associated with OSMR.

[0061] Various aspects of the present invention are described in detail in the following sections. The use of the sections is not intended to limit the invention. Each section may be applicable to any aspect of the present invention. In this application, the use of "or" means "and / or" unless stated otherwise. Anti-oncostatin M receptor (OSMR) antibodies

[0062] In some embodiments, the compositions and methods provided herein are used to deliver anti-OSMR antibodies to a subject in need thereof. In certain embodiments of the present invention, the anti-OSMR antibodies are fully human monoclonal antibodies that specifically inhibit IL-31- and oncostatin M (OSM)-induced activation of the IL-31 receptor and type II OSM receptor, respectively, via binding to OSMR, a subunit common to both receptors. The antibodies are composed of two light chains and two heavy chains. In some embodiments, the light chain contains a lambda constant region. The heavy chain constant region contains the CH1, hinge, and CH2 domains of a human immunoglobulin IgG4 antibody fused to the CH3 domain of a human IgG1 antibody. In other embodiments, the heavy chain of the anti-OSMR antibody contains an S228P modification to improve stability and an N297Q modification to remove an N-linked glycosylation site. Anti-OSMR heavy chain amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEWMGWMNPNSGYTGYAQKFQGRVTMTRDTSISTAYMEMSSLRSEDTAVYYCARDIVAANTDYYFYYGMD VWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1) Anti-OSMR light chain amino acid sequence QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKLLIYNINKRPSGVPDRFSGSSKSGSSASLAISGLQSEDEADYYCSTWDDSLDGVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 2) Anti-OSMR heavy chain variable domain amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYEINWVRQATGQGLEWMGWMNPNSGYTGYAQKFQGRVTMTRDTSISTAYMEMSSLRSEDTAVYYCARDIVAANTDYYFYYGMDVWGQGTTVTVSS (SEQ ID NO: 3) Anti-OSMR light chain variable domain amino acid sequence QSVLTQPPSASGTPGQRVTISCSGSNSNIGSNTVNWYHQLPGTAPKLLIYNINKRPSGVPDRFSGSKSGSSASLAISGLQSEDEADYYCSTWDDSLDGVVFGGGTKLTVLG (SEQ ID NO: 4) Anti-OSMR heavy chain variable domain CDR1 (HCDR1) amino acid sequence SYEIN (SEQ ID NO: 5) Anti-OSMR heavy chain variable domain CDR2 (HCDR2) amino acid sequence WMGWMNPNSGYTGYAQKFQGR (SEQ ID NO: 6) Anti-OSMR heavy chain variable domain CDR3 (HCDR3) amino acid sequence DIVAANTDYYFYYGMDV (SEQ ID NO: 7) Anti-OSMR light chain variable domain CDR1 (LCDR1) amino acid sequence SGSNSNIGSNTVN (SEQ ID NO: 8) Anti-OSMR light chain variable domain CDR2 (LCDR2) amino acid sequence NINKRPS (SEQ ID NO: 9) Anti-OSMR light chain variable domain CDR3 (LCDR3) amino acid sequence STWDDSLDGVV (SEQ ID NO: 10) Anti-OSMR heavy chain signal peptide amino acid sequence MDFGLSLVFLVLILKGVQC (SEQ ID NO: 11) Anti-OSMR light chain signal peptide amino acid sequence MATGSRTSLLLAFGLLCLSWLQEGSA (SEQ ID NO: 12) Anti-OSMR heavy chain amino acid sequence - IgG4 CH1, hinge, and CH2 domains ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK (SEQ ID NO: 13) Anti-OSMR heavy chain amino acid sequence - IgG1 CH3 domain GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 14) Anti-OSMR heavy chain amino acid sequence - constant domain ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFQSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 15) Anti-OSMR light chain amino acid sequence - IgG lambda constant domain QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 16)

[0063] In some embodiments of the invention, an anti-OSMR antibody contains a light chain complementarity determining region 1 (LCDR1) defined by SEQ ID NO:8, a light chain complementarity determining region 2 (LCDR2) defined by SEQ ID NO:9, and a light chain complementarity determining region 3 (LCDR3) defined by SEQ ID NO:10, and a heavy chain complementarity determining region 1 (HCDR1) defined by SEQ ID NO:5, a heavy chain complementarity determining region 2 (HCDR2) defined by SEQ ID NO:6, and a heavy chain complementarity determining region 3 (HCDR3) defined by SEQ ID NO:7.

[0064] In some embodiments of the invention, an anti-OSMR antibody contains a CDR amino acid sequence that has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to one or more of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7.

[0065] In some embodiments of the invention, an anti-OSMR antibody contains a light chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO: 4 and a heavy chain variable domain having an amino acid sequence at least 90% identical to SEQ ID NO: 3. In some embodiments of the invention, an anti-OSMR antibody has a light chain variable domain amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 4 and a heavy chain variable domain amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 3. In some embodiments of the invention, the anti-OSMR antibody contains a light chain variable domain having the amino acid sequence set forth in SEQ ID NO:4 and a heavy chain variable domain having the amino acid sequence set forth in SEQ ID NO:3.

[0066] In some embodiments of the invention, an anti-OSMR antibody comprises a light chain having an amino acid sequence at least 90% identical to SEQ ID NO: 2 and a heavy chain having an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments of the invention, an anti-OSMR antibody has a light chain amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 2 and a heavy chain amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 1. In some embodiments of the invention, the anti-OSMR antibody comprises a light chain having the amino acid sequence set forth in SEQ ID NO:2 and a heavy chain having the amino acid sequence set forth in SEQ ID NO:1.

[0067] In some embodiments of the invention, the heavy chain constant region of an anti-OSMR antibody contains a CH1, hinge, and CH2 domain from an IgG4 antibody fused to a CH3 domain from an IgG1 antibody. In some embodiments, the CH1, hinge, and CH2 domain from an IgG4 antibody contains SEQ ID NO: 13. In some embodiments, the CH3 domain from an IgG1 antibody contains SEQ ID NO: 14. In some embodiments, the heavy chain constant region of an anti-OSMR antibody in accordance with the invention contains an amino acid sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 13. In some embodiments, the heavy chain constant region of an anti-OSMR antibody of the invention contains an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 14. In some embodiments, the heavy chain constant region of an anti-OSMR antibody of the invention contains an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical to SEQ ID NO: 15. In some embodiments, an anti-OSMR antibody of the invention contains a lambda constant domain derived from an IgG antibody. In some embodiments, the lambda constant domain derived from an IgG contains SEQ ID NO: 16. In some embodiments, an anti-OSMR antibody according to the invention contains an amino acid sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:16. formulation

[0068] Exemplary formulations of the present invention are described herein. The formulations of the present invention contain the anti-OSMR antibodies described above. In some embodiments, the formulations are stable formulations for subcutaneous delivery. In particular, the formulations described herein can dissolve high concentrations of anti-OSMR antibodies and are suitable for subcutaneous, intradermal, intramuscular, and / or intraarticular delivery.

[0069] In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 50 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 60 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 70 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 80 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 90 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 100 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 110 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 120 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 130 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 140 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 150 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 160 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 170 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 180 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 190 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 200 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 210 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 220 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 230 mg / mL.In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 240 mg / mL. In some embodiments of the invention, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 250 mg / mL. In some embodiments, the formulation contains about 180 mg / mL of anti-OSMR antibody.

[0070] In some embodiments, the formulation before packaging or filling contains about 5% more drug substance than the intended concentration (target concentration) in the final product formulation. At the time of packaging or filling of the drug product, the formulation containing about 5% more drug substance is diluted to the target concentration with a placebo, i.e., the same formulation buffer but without the drug substance (e.g., 20 mM L-histidine, 25 mM L-arginine HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6-6.8, etc.). amino acid

[0071] In some embodiments of the present invention, the formulation comprises one or more amino acids. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 225 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 200 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 175 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 150 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 125 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 100 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 75 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 50 mM. In some embodiments, the one or more amino acids are present at a concentration of 10 mM to 25 mM. In some embodiments, the one or more amino acids are present at a concentration of 20 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 25 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 50 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 75 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 100 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 125 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 150 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 175 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 200 mM to 250 mM. In some embodiments, the one or more amino acids are present at a concentration of 5 mM to 35 mM, 10 mM to 35 mM, or 15 mM to 30 mM.

[0072] In some embodiments of the present invention, the formulation contains one or more amino acids selected from arginine, glutamic acid, glycine, histidine, and combinations thereof. In some embodiments, the formulation contains arginine. In some embodiments, the formulation contains glutamic acid. In some embodiments, the formulation contains arginine and glutamic acid. In some embodiments, the formulation contains histidine. In some embodiments, the formulation contains glycine.

[0073] In some embodiments, the arginine-containing formulation contains L-arginine or D-arginine. In some embodiments, the arginine-containing formulation contains L-arginine hydrochloride or D-arginine hydrochloride. In some embodiments, the formulation contains L-arginine. In some embodiments, the formulation contains L-arginine hydrochloride. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 225 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 200 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 175 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 150 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 125 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 100 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 75 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 50 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 25 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 10 mM to 20 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 20 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 25 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 50 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 75 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 100 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 125 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 150 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 175 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 200 mM to 250 mM.In some embodiments, the formulation contains arginine at a concentration ranging from 225 mM to 250 mM. In some embodiments, the formulation contains arginine at a concentration ranging from 20 mM to 30 mM or from 15 mM to 35 mM. In some embodiments, the formulation contains arginine at a concentration of 25 mM. In some embodiments, the formulation contains arginine at a concentration of 50 mM. In some embodiments, the formulation contains arginine at a concentration of 75 mM. In some embodiments, the formulation contains arginine at a concentration of 100 mM. In some embodiments, the formulation contains arginine at a concentration of 125 mM. In some embodiments, the formulation contains arginine at a concentration of 150 mM.

[0074] In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 200 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 150 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 100 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 75 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 50 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 25 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 10 mM to 20 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 20 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 25 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 50 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 75 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 100 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 125 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 150 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration ranging from 200 mM to 250 mM. In some embodiments, the formulation contains glutamic acid at a concentration of 50 mM. In some embodiments, the formulation contains glutamic acid at a concentration of 75 mM. In some embodiments, the formulation contains glutamic acid at a concentration of 100 mM. In some embodiments, the formulation contains glutamic acid at a concentration of 125 mM, hi some embodiments, the formulation contains glutamic acid at a concentration of 150 mM.

[0075] In some embodiments, the formulation contains arginine and glutamic acid in a ratio of at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the formulation contains arginine and glutamic acid in a ratio of 1:1 or greater. In some embodiments, the formulation contains arginine and glutamic acid in a ratio of 1:1. In some embodiments, the formulation contains arginine and glutamic acid in a ratio of 2:1. In some embodiments, the formulation contains arginine and glutamic acid in a ratio of 3:1. In some embodiments, the formulation contains arginine and glutamic acid in a ratio of 4:1. In some embodiments, the formulation contains glutamic acid and arginine in a ratio of at least 10:1, 5:1, 4:1, 3:1, 2:1, or 1:1.

[0076] In some embodiments, the formulation contains L-histidine. In some embodiments, the formulation contains histidine at a concentration ranging from 5 mM to 25 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 5 mM to 20 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 5 mM to 15 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 5 mM to 10 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 10 mM to 25 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 15 mM to 25 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 20 mM to 25 mM. In some embodiments, the formulation contains histidine at a concentration ranging from 15 mM to 25 mM or from 10 mM to 30 mM. In some embodiments, the formulation contains histidine at a concentration of 10 mM. In some embodiments, the formulation contains histidine at a concentration of 20 mM.

[0077] In some embodiments, the formulation contains glycine at a concentration ranging from 100 mM to 250 mM. In some embodiments, the formulation contains glycine at a concentration ranging from 100 mM to 200 mM. In some embodiments, the formulation contains glycine at a concentration ranging from 100 mM to 150 mM. In some embodiments, the formulation contains glycine at a concentration ranging from 150 mM to 250 mM. In some embodiments, the formulation contains glycine at a concentration ranging from 200 mM to 250 mM. In some embodiments, the formulation contains glycine at a concentration of 150 mM. In some embodiments, the formulation contains glycine at a concentration of 200 mM. buffer

[0078] In some embodiments of the present invention, the formulation contains a buffering agent to control pH. Suitable buffering agents include, for example, acetate, citrate, histidine, phosphate, succinate, tris(hydroxymethyl)aminomethane (Tris), and other organic acids. In some embodiments, the formulation contains a buffering agent selected from citrate, histidine, phosphate, and succinate. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 75 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 50 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 40 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 30 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 20 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 5 mM to 10 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 10 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 20 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 30 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 40 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 50 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration ranging from 75 mM to 100 mM. In some embodiments, the formulation contains a buffering agent at a concentration of 10 mM. In some embodiments, the formulation contains a buffering agent at a concentration of 20 mM.

[0079] In some embodiments, the formulation contains phosphate. In some embodiments, the formulation contains phosphate at a concentration ranging from 5 mM to 50 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 5 mM to 40 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 5 mM to 30 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 5 mM to 20 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 5 mM to 10 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 10 mM to 50 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 20 mM to 50 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 30 mM to 50 mM. In some embodiments, the formulation contains phosphate at a concentration ranging from 40 mM to 50 mM. In some embodiments, the formulation contains phosphate at a concentration of 10 mM. In some embodiments, the formulation contains phosphate at a concentration of 20 mM.

[0080] In some embodiments, the formulation contains citrate. In some embodiments, the formulation contains citrate at a concentration ranging from 5 mM to 50 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 5 mM to 40 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 5 mM to 30 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 5 mM to 20 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 5 mM to 10 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 10 mM to 50 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 20 mM to 50 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 30 mM to 50 mM. In some embodiments, the formulation contains citrate at a concentration ranging from 40 mM to 50 mM. In some embodiments, the formulation contains citrate at a concentration of 20 mM.

[0081] In some embodiments, the formulation contains succinate. In some embodiments, the formulation contains succinate at a concentration ranging from 5 mM to 50 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 5 mM to 40 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 5 mM to 30 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 5 mM to 20 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 5 mM to 10 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 10 mM to 50 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 20 mM to 50 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 30 mM to 50 mM. In some embodiments, the formulation contains succinate at a concentration ranging from 40 mM to 50 mM. In some embodiments, the formulation contains succinate at a concentration of 20 mM. salt

[0082] In some embodiments of the present invention, the formulation further contains a salt. Suitable salts include, for example, sodium chloride, potassium chloride, sodium sulfate, and magnesium chloride. In some embodiments, the formulation contains a halide. In some embodiments, the halide contains an alkali metal halide. In some embodiments, the salt is sodium chloride (NaCl). In some embodiments, the formulation contains NaCl at a concentration ranging from 50 mM to 175 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 50 mM to 150 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 50 mM to 125 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 50 mM to 100 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 50 mM to 75 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 75 mM to 175 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 100 mM to 175 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 125 mM to 175 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 150 mM to 175 mM. In some embodiments, the formulation contains NaCl at a concentration ranging from 120 mM to 130 mM or 125 mM to 135 mM. In some embodiments, the formulation contains NaCl at a concentration of 75 mM. In some embodiments, the formulation contains NaCl at a concentration of 125 mM. In some embodiments, the formulation contains NaCl at a concentration of 150 mM. In one embodiment, the molar ratio of NaCl to arginine is approximately 5:1. In another embodiment, the molar ratio of NaCl to histidine is approximately 6:1. surfactants

[0083] In some embodiments of the present invention, the formulation further comprises a surfactant. Examples of surfactants include non-ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 40, or polysorbate 80); poloxamers (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glycoside; lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, or stearyl sulfobetaine; lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, or stearyl sarcosine; linoleyl betaine. Examples of surfactants include amine, myristyl betaine, or cetyl betaine; lauramidopropyl betaine, cocamidopropyl betaine, linoleamidopropyl betaine, myristamidopropyl betaine, palmidopropyl betaine, or isostearomidopropyl betaine (e.g., lauramidopropyl); myristamidopropyl dimethylamine, palmidopropyl dimethylamine, or isostearomidopropyl dimethylamine; sodium methyl cocoyl taurate or disodium methylisothiazolinone taurate; and the MONAQUAT™ series (Mona Industries, Inc., Paterson, NJ), polyethylene glycol (PEG), polypropylene glycol, and ethylene and propylene glycol copolymers (e.g., Pluronics, PF68, etc.). Typically, the amount of surfactant added is an amount that reduces antibody aggregation and minimizes particle formation. For example, surfactants can be present in the formulation at a concentration of about 0.001-0.5% (e.g., about 0.075%). In particular, the surfactant may be present in the formulation at a concentration of approximately 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, etc. In some embodiments, the surfactant may be present in the formulation at a concentration of approximately 0.03%. In some embodiments, the surfactant may be present in the formulation at a concentration of approximately 0.07%. In some embodiments, the surfactant may be present in the formulation at a concentration of approximately 0.1%. In some embodiments, the formulation contains polysorbate 80 (PS80) at a concentration of approximately 0.03%.In some embodiments, the formulation contains polysorbate 80 (PS80) at a concentration of approximately 0.07%. In some embodiments, the formulation contains polysorbate 80 (PS80) at a concentration of approximately 0.05%. In some embodiments, the formulation contains polysorbate 80 (PS80) at a concentration of approximately 0.1%. Alternatively, or in addition, a surfactant may be added to the lyophilized formulation, the pre-lyophilized formulation, and / or the reconstituted formulation.

[0084] Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980), may be included in the formulation (and / or lyophilized formulation and / or reconstituted formulation), provided they do not adversely affect the desired characteristics of the formulation. Acceptable carriers, excipients, or stabilizers are non-toxic to recipients at the dosages and concentrations employed and include, but are not limited to, additional buffering agents; preservatives; cosolvents; antioxidants, including ascorbic acid and methionine; chelating agents, such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; and / or salt-forming counterions, such as sodium. In some embodiments of the present invention, the formulation contains an excipient, in which case the excipient is a polyol. Suitable polyol excipients include, for example, mannitol and sorbitol. In some embodiments, the formulation contains mannitol at a concentration ranging from 50 mM to 200 mM. In some embodiments, the formulation contains mannitol at a concentration ranging from 60 mM to 170 mM. In some embodiments, the formulation contains sorbitol at a concentration ranging from 2 to 8% by weight. In some embodiments, the formulation contains sorbitol at a concentration ranging from 2.5 to 5% by weight. pH and isoelectric point (pI)

[0085] In some embodiments of the present invention, formulations were made at different pH levels to determine the effect of pH on formulation properties such as viscosity and stability (e.g., monomer purity, increase in high molecular weight (HMW) species, disappearance of main charge variants, and charge distribution). Typically, pH values ​​close to the isoelectric point (pI) (the pH at which the net charge on the protein is zero) were avoided when making formulations because solubility is typically lowest at or near that pI. Virtually all proteins exhibit a V- or U-shaped curve in a plot of solubility versus pH, with the bottom at the pI. This behavior is due to the presence of minimal electrostatic repulsion at that pI, which reduces the colloidal stability of the protein, resulting in reduced solubility, increased viscosity, and increased likelihood of aggregation. Generally, increasing or decreasing the pH of a formulation increases the overall charge of the protein, increasing electrostatic repulsion and improving colloidal stability. Notably, when different formulations containing anti-OSMR antibodies were tested, it was determined that pH values ​​that were not only close to, but actually overlapping, the pI values ​​(e.g., pH 6.0-7.5, pI 7.0-8.0) were effective in maintaining stability and even achieving antibody concentrations of 200 mg / mL or greater. Furthermore, formulations under these pH conditions exhibited surprisingly low viscosities, despite being highly concentrated monoclonal antibody formulations. This was unexpected, as one skilled in the art would expect low solubility and / or high viscosity under these conditions.

[0086] In some embodiments, a pH value in the range of 6.0 to 7.6 maintains a formulation viscosity (e.g., less than 30 mPa*s) that allows subcutaneous administration when the antibody concentration is, for example, in the range of approximately 150 mg / mL to approximately 250 mg / mL. In some embodiments, an increase in HMW species of anti-OSMR antibodies occurs in formulations at a pH of 6.0 or below. In some embodiments, the disappearance of the major charge diversity peak of anti-OSMR antibodies in formulations correlates with the pH of the formulation. In some embodiments, formulations with higher pHs exhibit a greater loss of the major charge diversity peak after several weeks of storage. This loss is primarily due to the formation of acidic species. In certain embodiments, the increase in HMW species of OSMR antibodies and the disappearance of the charge diversity peak during storage are determined at approximately 5°C, 25°C, or 40°C after 2, 4, 6, or 8 weeks of storage. In some embodiments, formulations of the present invention have a pH in the range of approximately 6.0 to 7.6. In some embodiments, formulations of the present invention have a pH in the range of approximately 6.6 to 7.2. In some embodiments, the formulations of the present invention have a pH selected from 6.6, 6.8, 7.0, 7.2, and 7.6.

[0087] In some embodiments, formulations of the present invention contain an anti-OSMR antibody having a pI in the range of approximately 6.5 to 8.5. In some embodiments, formulations of the present invention contain an anti-OSMR antibody having a pI in the range of approximately 7.2 to 8.0. In some embodiments, formulations of the present invention contain an anti-OSMR antibody having a pI in the range of approximately 6.5 to 8.5 and a pH that overlaps with the pI of the anti-OSMR antibody. In some embodiments, formulations of the present invention have an anti-OSMR antibody concentration of at least 150 mg / mL (e.g., about 150 mg / mL to about 175 mg / mL, about 175 mg / mL to 200 mg / mL, about 200 mg / mL to 225 mg / mL, and about 225 mg / mL to 250 mg / mL), a pH in the range of 6.0 to 7.6, and a pI in the range of 7 to 8. In one embodiment, the anti-OSMR antibody is present at a concentration of about 150 mg / mL to 210 mg / mL, with a pH in the range of approximately 6.6 to 6.8, and a pI in the range of approximately 7.2 to 8.0.

[0088] In some embodiments, the formulation is an isotonic solution. In some embodiments, the isotonic formulation contains an osmolality in the range of 250-350 mOsm. In some embodiments, the osmolality of the formulation is in the range of 260-330 mOsm. In some embodiments, the osmolality of the formulation is in any range between 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350 mOsm. In some embodiments, the osmolality of the formulation is in the range of 270-300 mOsm. viscosity

[0089] In some embodiments of the present invention, the formulation is liquid. In some embodiments of the present invention, the formulation has been optimized to reduce viscosity while maintaining a high antibody concentration. Using a constant rate of 0.1 mL / min, the force required to either draw material into the syringe (syringability) or expel material from the syringe (syringability) can be recorded. In some embodiments, reducing viscosity increases the injectability of the formulation or allows for efficient sample transfer and preparation during manufacturing. In some embodiments, the formulation has a viscosity in the range of 1 mPa*s to 30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of less than 25 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of less than 20 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of less than 15 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 1 to 30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 2-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 4-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 6-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 8-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 10-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 12-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 14-30 mPa*s when measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 16-30 mPa*s when measured by a microfluidic rheometer.In some embodiments, the formulation has a viscosity of approximately 18-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 20-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 22-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 24-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 26-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a viscosity of approximately 28-30 mPa*s as measured by a microfluidic rheometer. In some embodiments, the formulation has a shear rate of less than 1000 s at 25°C.

[0090] In some embodiments, the formulation has a viscosity that allows it to be injected through a standard syringe and needle combination, the needle having a nominal inner diameter of about 0.1 to about 0.6 mm. In some embodiments, the formulation is injectable through a needle having an inner diameter of about 0.1, or about 0.2, or about 0.3, or about 0.4, or about 0.5, or about 0.6 mm. In some embodiments, the formulation has a viscosity that allows it to be injected through a standard syringe and needle combination, the needle having a nominal inner diameter of about 0.18 to about 0.3 mm. In some embodiments, the formulation has a viscosity that allows it to be injected using a needle having an inner diameter of about 0.184 mm to about 0.260 mm. In some embodiments, the formulation has a viscosity that allows it to be injected through a standard syringe and needle combination, the needle having a nominal inner diameter of about 0.184 to 0.210 mm. In some embodiments, the formulation has a viscosity such that it is injectable using a 27G ½ inch gauge needle and a 2 ml syringe. In some embodiments, the pound force required to inject the formulation at a constant rate of 0.1 mL / sec is less than about 8.0 pound force. In some embodiments, the pound force required to inject the formulation at a constant rate of 0.1 mL / sec is less than about 8 pound force, less than about 7.5 pound force, or less than about 6.9 pound force, less than about 6.8 pound force, less than about 6.7 pound force, less than about 6.7 pound force, less than about 6.6 pound force, or less than about 6.5 pound force. Stability:

[0091] In some embodiments of the invention, the formulations are optimized to enhance stability. The stability of antibody formulations can be quantified in several ways. In some embodiments, the stability of antibody formulations is characterized by the amount of HMW species of the anti-OSMR antibody or the rate of increase in the amount of HMW species of the anti-OSMR antibody. In specific embodiments, the rate of increase in HMW species is determined upon storage for 2, 4, 6, or 8 weeks at approximately 5°C, 25°C, or 40°C. In some embodiments, the stability of antibody formulations is characterized by charge distribution, e.g., changes in the amount of antibody charge diversity peaks. In some embodiments, the stability of antibody formulations is characterized by dynamic light scattering, analytical ultracentrifugation (AUC), field-flow fractionation (FFF), isoelectric focusing, and ion exchange chromatography (IEX). In some embodiments, the stability of the antibody formulation is characterized by partial dissociation as measured by sodium dodecyl sulfate capillary electrophoresis (CE-SDS) and / or sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

[0092] The stability of anti-OSMR antibodies and the ability of a formulation to maintain anti-OSMR antibody stability may be evaluated over an extended period of time (e.g., weeks or months). In formulations, a stable formulation is one in which the antibody therein essentially retains its physical and / or chemical integrity and biological activity upon storage and during handling, such as freeze / thaw, mechanical mixing, and lyophilization. Antibody stability can be measured by the formation of high molecular weight (HMW) aggregates, shifts in charge profile, and changes in particle size.

[0093] Antibody stability may be assessed based on the antibody's biological activity or biochemical integrity over an extended period of time. For example, stability at a given time point may be compared to stability at an earlier time point (e.g., upon formulation, day 0), compared to unformulated antibody, or compared to a differently formulated antibody, and the comparison results may be expressed as a percentage. Preferably, antibody formulations of the invention maintain at least 100%, at least 99%, at least 98%, at least 97%, at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, or at least 50% of the antibody's biological activity, biochemical integrity, and / or particle size over an extended period of time (e.g., for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, or 36 months, as measured at room temperature or under accelerated storage conditions). In some embodiments, percentage values ​​indicating levels of proteins disclosed throughout this specification are expressed relative to the total protein in the formulation. In some embodiments, the relative values ​​of any particular species of product disclosed throughout this specification, such as the relative values ​​of monomeric IgG forms or species, or high molecular weight (HMW) forms, or aggregate forms, are expressed relative to the respective values ​​of the total product. In some embodiments, the percentage values ​​of any particular species of antibody are expressed relative to the total amount of all antibody-related species in the formulation. In some embodiments, less than 5%, 4%, 3%, 2%, 1%, or 0.5% of the anti-OSMR antibody is present as HMW species in the formulation. In some embodiments, the amount of HMW species in the formulation increases by less than 5%, 4%, 3%, 2%, 1%, or 0.5% upon storage at 25°C for more than two weeks. In some embodiments, the amount of HMW species in the formulation increases by approximately 0.3% to 0.7%, approximately 0.3% to 0.6%, or approximately 0.3% to 0.5% upon storage at 25°C for four weeks. In some embodiments, at least 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% of the anti-OSMR antibody is present as a monomer in the stable formulation.In some embodiments, the amount of monomer decreases by less than 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% when stored at 25°C for more than 2 weeks, e.g., 4 weeks. Delivery

[0094] In some embodiments of the invention, the formulation contains a high concentration of anti-OSMR antibody suitable for subcutaneous, intradermal, intramuscular, and / or intra-articular delivery. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 50 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 75 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 100 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 125 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 150 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 175 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 200 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 225 mg / mL. In some embodiments, the formulation contains an anti-OSMR antibody at a concentration of at least approximately 250 mg / mL.

[0095] In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 10 mL or less. In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 5 mL or less. In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 4 mL or less. In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 3 mL or less. In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 2 mL or less. In some embodiments, the volume of an anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 1 mL or less. In some embodiments, the volume of the anti-OSMR antibody formulation delivered by subcutaneous, intradermal, intramuscular, and / or intra-articular injection is 0.5 mL or less.

[0096] In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 10 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 5 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 4 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 3 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 2 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 1 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 0.5 mL or less. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 3 mL. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 2 mL. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 1 mL. In some embodiments, the amount of anti-OSMR antibody formulation delivered by subcutaneous injection is 0.5 mL.

[0097] In some embodiments, subcutaneous injections of the anti-OSMR antibody formulation can be performed in the upper arm, front of the thigh, lower abdomen, upper back, or upper buttocks. In some embodiments, injection sites are alternated.

[0098] In some embodiments, the formulations of the present invention may be designed for delivery by any suitable route, including but not limited to subcutaneous, intradermal, intra-articular, oral, rectal and vaginal, as well as parenteral routes, including intravenous, intra-arterial and intramuscular injection. kit

[0099] The present invention further provides kits or other products containing the formulations of the present invention, and (if lyophilized) instructions for their reconstitution and / or use. The kits or other products may include containers, needles, and any other items, devices, or equipment useful for subcutaneous administration. Suitable containers include, for example, bottles, vials, syringes (e.g., pre-filled syringes), subcutaneous pumps, ampoules, cartridges, storage containers, or lyojects. The containers may be formed from a variety of materials, such as glass or plastic. In some embodiments, the container is a pre-filled syringe. Suitable pre-filled syringes include, but are not limited to, baked silicon-coated borosilicate glass syringes, silicon-sprayed borosilicate glass syringes, or silicon-free plastic resin syringes.

[0100] Typically, the container holds the formulation and may have a label on or associated with the container that may provide instructions for reconstitution and / or use. For example, the label may indicate that the formulation is to be reconstituted to a concentration of antibody described above. The label may further indicate that the formulation is useful or intended for subcutaneous administration, for example. In some embodiments, the container may contain a single dose of a stable formulation containing a therapeutic antibody (e.g., an anti-OSMR antibody). In various embodiments, the single dose of the stable formulation is present in a volume of less than about 10 mL, 5.0 mL, 4.0 mL, 3.5 mL, 3.0 mL, 2.5 mL, 2.0 mL, 1.5 mL, 1.0 mL, or 0.5 mL.

[0101] Alternatively, the container holding the formulation may be a multi-use vial, allowing for repeated administration of the formulation (e.g., 2-6 administrations). The kit or other article of manufacture may further include a second container containing a suitable diluent (e.g., BWFI, saline, buffered saline). Upon mixing the diluent and the formulation, the final antibody concentration in the reconstituted formulation will generally be at least 150 mg / mL (e.g., at least 160 mg / mL, at least 170 mg / mL, at least 180 mg / mL, at least 190 mg / mL, at least 200 mg / mL). The kit or other article of manufacture may further include other items desirable from a commercial and user standpoint, including other buffers, diluents, preservatives, filters, needles, syringes, and package inserts with instructions for use. Treatment of diseases and disorders associated with OSMR

[0102] Anti-OSMR antibody formulations and compositions of the invention are used to treat autoimmune disorders, inflammatory disorders, or disorders associated with extracellular matrix deposition or remodeling. In treating these disorders, the anti-OSMR antibodies may target OSMR-expressing cells of the immune system for destruction and / or inhibit the interaction of OSMR with OSM and / or IL-31. Diseases or disorders associated with OSMR-mediated signaling are particularly amenable to treatment with the anti-OSMR antibodies of the invention. One such disorder is pruritus. Other diseases and disorders associated with OSMR-mediated signaling and particularly amenable to treatment with the anti-OSMR antibodies of the invention include inflammation, pain, pruritus nodularis, dermatitis, atopic dermatitis, asthma, autoimmune diseases, paraneoplastic autoimmune diseases, cartilage inflammation, fibrosis (including, but not limited to, pulmonary fibrosis and dermal fibrosis), and fibrotic disorders.disease), chronic obstructive pulmonary disease (COPD), interstitial pneumonia, abnormal collagen deposition, systemic cutaneous amyloidosis, primary cutaneous amyloidosis, Behçet's disease, nasal polyps, liver cirrhosis, cartilage degeneration, bone degradation, arthritis, rheumatoid arthritis, juvenile arthritis, juvenile rheumatoid arthritis, small-articular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile reactive arthritis, juvenile Reiter's syndrome, SEA syndrome (serum allergy syndrome) seronegative, enthesopathy, arthropathy syndrome), juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, small-articular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis, ankylosing spondylitis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, SEA syndrome (seronegative, enthesopathy, arthropathy syndrome), dermatomyositis, psoriatic arthritis, scleroderma, parascleroderma-associated interstitial pneumonia, vasculitis, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis psoriasis, arteritis, polymyalgia rheumatica, sarcoidosis, scleroderma, sclerosis, primary sclerosing cholangitis, sclerosing cholangitis, Sjögren's syndrome, psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, dermatitis, atherosclerosis, lupus erythematosus, Still's disease, systemic lupus erythematosus (SLE), myasthenia gravis, inflammatory bowel disease (IBD), Crohn's disease, ulcerative colitis, celiac disease, multiple sclerosis (MS), asthma, COPD, rhinosinusitis, nasal polyps, eosinophilic esophagitis, eosinophilic These include, but are not limited to, bronchitis, bronchitis, Guillain-Barre syndrome, type 1 diabetes, thyroiditis (Graves' disease), Addison's disease, Raynaud's phenomenon, autoimmune hepatitis, GVHD, graft rejection, nephropathy, cardiovascular disease, infection, sepsis, HIV infection, trauma, renal allograft nephropathy, IgA nephropathy, diabetic nephropathy, diabetic retinopathy, macular degeneration, biliary atresia, congestive heart failure, atherosclerosis, restenosis, radiation-induced fibrosis, chemotherapy-induced fibrosis, burns, surgical trauma, and glomerulosclerosis.

[0103] The formulations, compositions, and methods of the present invention may be used to effectively treat individuals suffering from or susceptible to pruritus. As used herein, the term "treat" or "treatment" refers to the amelioration of one or more symptoms associated with pruritus, the prevention or delay of the onset of one or more symptoms of pruritus, and / or the reduction in the severity or frequency of one or more symptoms of pruritus. [Example]

[0104] While certain formulations, compositions and methods of the present invention have been specifically described according to certain embodiments, the following examples are provided solely to illustrate the compounds of the present invention and are not intended to limit the compounds of the present invention. Example 1: Characterization of anti-OSMR antibodies

[0105] The exemplary anti-OSMR antibodies described herein are fully human monoclonal antibodies that specifically inhibit IL-31- and oncostatin M (OSM)-induced activation of the IL-31 receptor and type II OSM receptor, respectively, through binding to OSMRβ, a subunit common to both receptors. The antibodies contain two light chains and two heavy chains. The light chains contain a lambda constant region. The heavy chain constant region contains the CH1, hinge, and CH2 domains of a human immunoglobulin IgG4 antibody fused to the CH3 domain of a human IgG1 antibody. Additionally, the heavy chains of the anti-OSMR antibodies contain an S228P modification to improve stability and an N297Q modification to remove an N-linked glycosylation site.

[0106] An exemplary anti-OSMR antibody contains the heavy chain amino acid sequence of SEQ ID NO: 1 and the light chain amino acid sequence of SEQ ID NO: 2. An exemplary anti-OSMR antibody also contains the heavy chain variable domain amino acid sequence of SEQ ID NO: 3 and the light chain variable domain amino acid sequence of SEQ ID NO: 4. An exemplary anti-OSMR antibody also contains the heavy chain variable domain CDR1 (HCDR1) of SEQ ID NO: 5, the heavy chain variable domain CDR2 (HCDR2) of SEQ ID NO: 6, the heavy chain variable domain CDR3 (HCDR3) of SEQ ID NO: 7, the light chain variable domain CDR1 (LCDR1) of SEQ ID NO: 8, the light chain variable domain CDR2 (LCDR2) of SEQ ID NO: 9, and the light chain variable domain CDR3 (LCDR3) of SEQ ID NO: 10. An exemplary anti-OSMR antibody also contains the heavy chain signal peptide amino acid sequence of SEQ ID NO: 11, the IgG4 CH1, hinge, and CH2 domains of SEQ ID NO: 12, the heavy chain IgG1 CH3 domain amino acid sequence of SEQ ID NO: 13, and the light chain IgG lambda constant domain amino acid sequence of SEQ ID NO: 14.

[0107] Charge heterogeneity was assessed by imaged capillary isoelectric focusing (icIEF). Protein isoforms were separated based on their pI. Elution profiles were monitored by UV absorbance at 280 nm. Example 2: Formulation design and preparation

[0108] Four rounds of formulations were made to examine the effect of protein concentration, buffer type, pH, and excipient inclusion on variables such as viscosity and stability. Tables 1, 2, 3, and 4 below detail the formulation designs for the four rounds of formulation. Table 1 - Round 1 formulation design [Table 1] Table 2 - Round 2 formulation design [Table 2] Table 3 - Formulation design for Round 3 [Table 3] Table 4 - Formulation design for Round 4 [Table 4]

[0109] Rounds 1, 2, and 3 formulations were prepared by dialyzing the bulk drug substance (BDS) against formulation placebo (buffer and tonicity modifier) ​​using a Slide-A-Lyzer Mini Dialysis device (20 kD MWCO, 2 mL capacity). The following dialysis procedure was used: 4 hours against milliQ water, 2 hours at room temperature against placebo using an orbital shaker at 300 rpm (3 mm orbital radius shaker), then two more exchanges against placebo at room temperature for another 4 hours (2 hours per exchange, 300 rpm orbital shaker), and finally another buffer exchange and dialysis for an additional 17–24 hours at 2–8°C (orbital shaker, 300 rpm). Where necessary, polysorbate 80 (PS80) was mixed into a given formulation from a 10% (w / v) stock solution prepared in milliQ water. Round 4 formulations were prepared similarly, except that dialysis was performed using a Slide-A-Lyzer Dialysis Cassette to reduce the shear experienced by the PS80-free protein during dialysis. All samples were concentrated to target concentrations using centrifugal spin concentrators.

[0110] The drug substance, containing an API concentration of 209 mg / mL in a formulation buffer containing 20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodium chloride, 0.05% (w / v) polysorbate 80, pH 6.6-6.8, was subjected to stress, stability, freeze-thaw, and drug manufacturing stress testing. For point-of-use compatibility testing, the drug substance was diluted to 180 mg / mL with formulation buffer. The placebo control was 20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% (w / v) PS80, pH 6.6.

[0111] Subatmospheric differential scanning calorimetry (DSC) analysis determined that the glass transition temperature (TG') of both the 208.8 mg / mL and 180 mg / mL formulations was -34.3°C. Density measurements performed by a densimeter at 25°C for the 180 mg / mL formulation and placebo were 1.0588 g / cm, respectively. 3 and 1.0050 g / cm 3 All samples were free of visible particles. No change in appearance was detected over the course of 24 hours compared to time zero.

[0112] For preparation of individual stability samples, each formulation (bulk material) was sterile filtered using a Millipore Millex-GV syringe filter (0.22 μm). After filtration, 0.5 mL was dispensed into 1 mL glass vials, stoppered (13 mm rubber stoppers), and sealed with crimped aluminum caps. Sterile filtration and dispensing were performed in a biological safety cabinet using previously sterilized materials (i.e., vials, stoppers, etc.).

[0113] Syringeability was evaluated using an Instron Mechanical Tester. Different needle gauges and lengths, as well as sample temperatures of 18°C ​​and 25°C, were used to verify the pound-force required to expel the drug product at a constant rate of 0.1 mL / min. Results show that 6.5 pound-force is required to expel 180 mg / mL of drug product through a 27G 1 / 2 inch needle at 25°C. Example 3: Viscosity

[0114] The viscosity of samples from round 1 and round 2 was measured relative to the unstressed material (nominal, t0). Viscosity was measured at 1000 s using a Rheosense m-VROC rheometer. -1The viscosity was measured at a shear rate of 100 μL and a temperature of 25° C. Measurements were performed using a 100 μL Hamilton gas-tight syringe filled with 100 μL (nominal) of a given formulation. Generally, four measurements were taken per formulation, with the last two averaged and reported as the formulation viscosity. Viscosity results from Round 1 are shown in Table 5 below. Viscosity results from Round 2 are shown in Table 6 below. Viscosity results from Round 3 are shown in Table 7 below. A graph showing the effect of protein concentration on viscosity from two Round 3 formulations is shown in Figure 1.

[0115] The concentration of anti-OSMR antibody was determined using UV absorbance spectroscopy. Briefly, the absorbance of diluted anti-OSMR antibody was determined at 280 nm in a 1 cm pathlength UV-transparent cuvette and corrected for scattering by subtracting the sample absorbance at 320 nm. Absorbance was determined against a protein-free blank and calculated using Beer's law (ε 280,1cm The concentration was converted to protein content using the RT-PCR (RT = 1.62 ml / mg*cm). Because the samples were diluted to perform the measurements, this concentration had to be multiplied by the dilution factor (by weight) to get the actual concentration. Table 5 - Round 1 Viscosity [Table 5] Table 6 - Round 2 Viscosity [Table 6] Table 7 - Round 3 Viscosity [Table 7]

[0116] Viscosity was relatively low for all round 1 formulations, even those above 150 mg / mL protein (e.g., the viscosity of F09 was only 8.3 mPa*s at 166 mg / mL). Regarding the viscosity-modifying effect of the excipients, Arg*HCl appeared to have the greatest effect on viscosity reduction for equivalent protein concentrations. NaCl also appeared to reduce viscosity, but to a lesser extent than Arg*HCl. Formulations containing sorbitol as a tonicity modifier often exhibited higher viscosities. The effects of pH and buffer on viscosity were less clear. In general, a protein concentration-dependent increase in viscosity, largely pH-independent, was evident.

[0117] In Round 2, it was found that low pH values ​​(in the range of 6.6–7.2) reduced viscosity at protein concentrations of approximately 200 mg / mL. Arginine and NaCl were also found to be particularly effective at reducing viscosity. All Round 2 formulations exhibited viscosities below 23 cP, which is considered excellent for a 200 mg / mL monoclonal antibody. Figure 1 shows that the viscosity of these two formulations can be higher than 30 cP at certain concentrations.

[0118] The viscosity of the drug substance in 20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodium chloride, 0.05% (w / v) polysorbate 80, pH 6.6 was measured at various controlled temperatures (4°C, 15°C, 18°C, 25°C, and 35°C). Three (3) data sets were measured for each temperature. The tabulated results for samples analyzed at 208 mg / mL and 180 mg / mL are shown in Tables 8 and 9, respectively. Figure 2 shows the change in viscosity of the two formulation samples over the indicated temperature range. As shown in Figure 2, the viscosity results verified by rheometry at various controlled temperatures (4°C, 15°C, 18°C, 25°C, and 35°C) for both 180 mg / mL and 209 mg / mL exhibited a significant decrease in viscosity with increasing temperature and / or decreasing active pharmaceutical ingredient (API) concentration. Table 8. Viscosity of 208.8 mg / mL target protein concentration at various temperatures [Table 8] Table 9. Viscosity of 180 mg / mL target protein concentration at various temperatures [Table 9] Example 4: Stability of different formulations over the course of 4 weeks

[0119] Samples from Round 1 were examined to determine the effect of protein concentration, buffer type, pH, and inclusion of other excipients (arginine, NaCl, sorbitol) on the storage stability of anti-OSMR antibodies. Samples were analyzed after two weeks of storage at 40°C (t2) or four weeks of storage at 25°C (t4). The initial osmolality of samples from Round 1 is shown in Table 10 below. The initial osmolality of samples from Round 2 is shown in Table 11 below. The actual pH values ​​and protein concentrations of samples from Round 1 and Round 2 are included in Tables 5 and 6 above, respectively. Protein precipitation was observed in Round 1 samples F15 and F16 stored at 40°C for two weeks. Table 10 - Osmolality of Round 1 [Table 10] Table 11 - Osmolality of Round 2 [Table 11] Monomer Purity

[0120] Size exclusion chromatography was also performed on the Round 1 and Round 2 samples to determine monomer purity at t0, 2 weeks (t2), and 4 weeks (t4). Meanwhile, Round 4 samples were examined for monomer purity after freeze-thaw and agitation. Size exclusion chromatography (SEC) separates molecules based on their size by filtering them through a gel. Gels consist of spherical beads containing pores with a specific size distribution. Separation occurs when molecules of different sizes are included or excluded by the pores in the matrix. Small molecules diffuse into the pores, slowing their flow through the column according to size. Larger molecules, on the other hand, do not enter the pores and elute in the column void. As a result, molecules are separated based on their size as they pass through the column, eluting in ascending order of molecular weight (MW). Operating conditions and gel selection depend on the application and desired resolution. There are two common types of separations performed by SEC: fractionation and desalting (or buffer exchange).

[0121] Table 12 presents exemplary monomer purity data comparing t0 and t2 at 40°C, t0 and t4 at 25°C, and t0 and t4 at 5°C from Round 1. Table 13 presents exemplary monomer purity data comparing t0 and t4 at 40°C, t0 and t4 at 25°C, and t0 and t4 at 5°C from Round 2. Exemplary monomer purity data comparing stirred and freeze / thaw (F / T) samples with controls is presented in Table 14. The proportions of low molecular weight (LMW) and high molecular weight (HMW) species for Round 1 and Round 2 samples were also determined by SEC. Exemplary LMW data comparing t0 and t2 from Round 1 is presented in Table 15. Exemplary LMW data comparing t0 and t4 at 25°C from Round 2 is presented in Table 16. Exemplary LMW data comparing t0 and t4 at 5°C from Round 2 is presented in Table 17. Exemplary HMW data comparing t0 and t2 from Round 1 is presented in Table 18. Exemplary HMW data comparing t0 and t4 at 25°C from Round 1 is presented in Table 19. Exemplary HMW data comparing t0 and t4 at 5°C from Round 1 is presented in Table 20. Exemplary HMW data comparing t0 and t2 at 40°C from Round 2 is presented in Table 21. Exemplary HMW data comparing t0 and t4 at 25°C from Round 2 is presented in Table 22. Exemplary HMW data comparing t0 and t4 at 5°C from Round 2 is presented in Table 23. Exemplary HMW data comparing the stirred and F / T samples with the control are presented in Tables 24 and 25. An exemplary chromatogram showing HMW species in the stressed sample (F02 at 40°C) is presented in Figure 3.

[0122] SEC data from t2 of round 1 show that anti-OSMR antibodies tended to form high molecular weight species under stress conditions, and the formation of low molecular weight species was minimal in most samples. SEC data from t2 of round 1 show that the highest monomer loss was observed in sample F04 when succinate was used at pH 6.0. In round 1, the least monomer loss was observed in samples F05, F06, and F10, which contained histidine buffer with protein concentrations of 50, 100, and 125 mg / mL, respectively. At a protein concentration of 150 mg / mL, there was less monomer loss in samples containing sorbitol (F08 and F14) than in samples with arginine (F03).

[0123] SEC data from t4 at 25°C in Round 1 showed a similar trend to that from t2, with high monomer loss in formulations at pH 6.0 or lower. Additionally, high monomer loss was observed in phosphate formulations at pH 7.2 and pH 7.6 (F07 and F13, respectively). Histidine and citrate formulations were compared similarly with respect to monomer loss. Monomer loss was largely due to HMW formation (primarily HMW2). For nearly all formulations stored at 2-8°C, negligible monomer loss was observed.

[0124] SEC data from the stirred and F / T samples (round 4) show that purity remained essentially unchanged (compared to t0) for all samples except the stirred sample, which did not contain PS80. For these samples, there was an increase in both HMW1 (aggregates) and HMW2 (presumably dimers). These changes were greater in F02 than in F01. Table 12 - Monomer purity (%) for round 1 at t0, t2 (40°C), t4 (25°C), and t4 (5°C) [Table 12] Table 13 - Monomer purity (%) for round 2 at t0, t2 (40°C), t4 (25°C), and t4 (5°C) [Table 13] Table 14 - Monomer purity (%) for round 4 for control, stirred and F / T samples [Table 14] Table 15 - LMW % of Round 1 at t0 and t2 (40°C) [Table 15] Table 16 - LMW % of Round 2 at t0 and t4 (25°C) [Table 16] Table 17 - LMW % of Round 2 at t0 and t4 (5°C) [Table 17] Table 18 - Round 1 HMW % at t0 and t2 (40°C) [Table 18] Table 19 - Round 1 HMW % at t0 and t4 (25°C) [Table 19] Table 20 - Round 1 HMW % at t0 and t4 (5°C) [Table 20] Table 21 - Round 2 HMW % at t0 and t2 (40°C) [Table 21] Table 22 - Round 2 HMW % at t0 and t4 (25°C) [Table 22] Table 23 - Round 2 HMW % at t0 and t4 (5°C) [Table 23] Table 24 - Round 4 HMW1 % for control, stirred and F / T samples [Table 24] Table 25 - Round 4 HMW2 % for control, stirred and F / T samples [Table 25]

[0125] Partial least squares regression was performed to model the monomer content at t2 (samples after 2 weeks at 40°C). Figure 4 shows an exemplary graph showing predicted versus measured monomer content.

[0126] In the Round 1 experiments, the data suggested that Formulation 4 may not be representative. The data indicated that histidine appeared to be stabilizing in this model. Meanwhile, citrate and phosphate showed little ability to maintain monomer content. Furthermore, arginine appeared to destabilize the protein at high storage temperatures (40°C) but was protective or stabilizing at low storage temperatures (below 25°C). Sorbitol was found to have little effect on antibody stability. Of those tested, NaCl appeared to be the best stabilizer. Storage stability appeared constant up to approximately 100 mg / mL protein concentration but decreased above that concentration. Indeed, as with Round 1, the Round 2 SEC data suggest that increasing antibody concentration increases the tendency for antibody aggregation. The amount of HMW components formed in these Round 2 formulations (200 mg / mL) was higher than that measured in formulations with comparable or lower protein concentrations than Round 1. Charge Distribution

[0127] The purity of the major charge variant (major peak) of the round 1 and round 2 samples was determined by capillary isoelectric focusing (cIEF). cIEF was performed on a PA 800 Plus instrument using the Beckman Coulter kit method. cIEF data from round 1 for the major peak percentage at t0, after 2 weeks at 40°C (t2), and after 4 weeks at 25°C (t4) are shown in Table 26 below. cIEF data from round 2 for the major peak percentage at t0, after 2 weeks at 40°C (t2), and after 4 weeks at 25°C (t4) are shown in Table 27 below.

[0128] In general, the disappearance of the major isoform correlated with the pH of the formulation. Formulations with higher pH showed higher disappearance of the major isoform at both t2 / 40°C and t4 / 25°C, manifesting primarily as an increase in its acidic charge form. The exception in round 1 was F04 (pH 6.0) at t2, which showed disappearance of the major peak both on the acidic and basic sides of the main peak. Table 26 - Round 1 Main Peak % t0, t2 and t4 [Table 26] Table 27 - Round 2 Main Peak % t0, t2 and t4 [Table 27]

[0129] Partial least squares regression was performed to model the cIEF differences in the major peak fraction data from round 1 at both t2 (samples after 2 weeks at 40°C) and t4 (samples after 4 weeks at 25°C). The model for t2 used only data from formulations 1-13. Partial least squares (PLS) models were generated from the t2 / 40°C data to compare the stabilization provided by NaCl with that provided by excipient-like mannitol. Figure 5 shows an exemplary graph illustrating the difference between predicted and measured cIEF for the major peak fraction at t2. Figure 6 shows an exemplary graph illustrating the difference between predicted and measured cIEF for the major peak fraction at t4. Correlation coefficients for various formulation variables at t2 and t4 are shown in Figure 7. Susceptibility to interfacial damage

[0130] Samples from round 4 were examined to determine the susceptibility of anti-OSMR antibodies (formulated with varying levels of PS80) to interfacial damage when subjected to freeze-thaw (F / T) and agitation stress. F / T testing was performed by freezing samples at -80°C for at least 17 hours and then thawing at room temperature for approximately 4 hours. Samples were mixed (by rotation) between freeze-thaw cycles. A total of five F / T cycles were performed. Agitation was performed by shaking at 590 rpm (on an orbital shaker, 3 mm orbit) at 25°C for 24 hours. For both F / T and agitation testing, the container / closure consisted of a 1 mL Type 1 glass vial with a Fluorotec stopper. The fill volume was 400 μL, and the vial orientation was vertical and horizontal for F / T and agitation testing, respectively.

[0131] Two formulations were selected for this study (based on their viscosity and stability profiles), and their compositions are listed in Table 4 above. The PS80 content measured for each sample is shown in Table 28 below. The results of these analyses are summarized below. The PS80 content for each formulation was determined by indirectly determining the PS80 content using a PS80 assay, which consisted of measuring free oleic acid using RP-HPLC. Free oleic acid was obtained by hydrolyzing the PS80 contained in the given formulation. This free oleic acid was then analyzed by reverse-phase high-performance liquid chromatography (RP-HPLC), and the concentration was determined against a standard curve constructed using PS80 standards (hydrolyzed to obtain free oleic acid) prepared from the same PS80 (here, JT Baker) used to prepare the given formulation. The standard curve consisted of five PS80 concentrations ranging from 0.0005 to 0.005% (w / v) PS80. Table 28 - Round 4 Measured PS80 Content [Table 28]

[0132] The protein content obtained from UV absorbance at 280 nm (A280) for the stirred and F / T samples is shown below in Table 29. The protein content of all samples was unchanged (within measurement error) compared to the starting material (pre-PS80 material), suggesting that no significant precipitation occurred in these samples that could alter the protein concentration. Table 29 - Round 4 Protein Content (mg / mL) [Table 29]

[0133] Round 4 testing included additional subvisible particle (SVP) and dynamic light scattering (DLS) analyses (data not shown), which suggested that under certain conditions, the anti-OSMR antibody was prone to particle formation in the absence of PS80. In particular, the molecule appeared to be most prone to particle formation during the agitation process. For samples without PS80, SEC results indicated that F01, containing NaCl, was able to suppress impurity formation to a greater extent than F02, which did not contain NaCl. The inclusion of only 0.03% (w / v) PS80 was shown to be sufficient to prevent aggregate formation. SEC and SVP showed that F01 and F02 formulations with 0.03%, 0.07%, and 0.1% (w / v) PS80 similarly prevented aggregate formation. Furthermore, upon agitation, the F01 formulation appeared to have a lower tendency to form SVPs (total particle count) compared to the F02 formulation. Example 5: Stability of drug substance over time at different incubation temperatures

[0134] This example shows that anti-OSRMβ antibody in formulation buffer (20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodium chloride, 0.05% (w / v) polysorbate 80, pH 6.6) is stable for up to at least 3 months at temperatures of -70°C or 5°C. Samples were taken from storage at different temperatures and tested for various properties. Figure 8 shows the observed properties of two exemplary samples taken for the experiment at the specified time periods from storage temperatures of -70°C and 5°C, compared to the baseline (time = 0). Figure 9 shows the observed properties of two exemplary samples taken for the experiment at the specified time periods from storage temperatures of 25°C (accelerated conditions) and 40°C (stressed conditions), compared to the baseline. Size exclusion chromatography (SEC) results for 3 months at different storage temperatures of -70°C and 5°C (Figure 8), as well as under accelerated storage conditions at 25°C (Figure 9), show that the relative amount of aggregates was repeatedly less than 5% over periods as long as 3 months. Additionally, formulation samples at the designated time points over the 3-month period were analyzed by non-reducing capillary gel electrophoresis (CE-SDS(NR)), which detects intact IgG monomer and IgG fragments as a measure of formulation stability. The non-reducing SDS data shown in the figure indicate that greater than 90% of the antibody (drug substance) is present as intact monomer over 3 months at storage temperatures of -70°C and 5°C (Figure 8) and under accelerated storage conditions at 25°C. However, samples stored at 40°C (Figure 9) exhibited a high percentage of aggregates and a low percentage of intact IgG monomer. Example 6: Drug Substance Manufacturing Stress-Robustness Analysis

[0135] In this example study, a freeze / thaw profile was generated using a placebo (20 mM L-histidine, 25 mM L-arginine-HCl, 125 mM NaCl, 0.05% PS80, pH 6.6) in a Sartorius Celsius Flexible Freeze and Thaw (FFT) container. Based on the freeze / thaw profile, the drug substance in the formulation buffer (20 mM L-histidine, 25 mM L-arginine hydrochloride, 125 mM sodium chloride, 0.05% (w / v) polysorbate 80, pH 6.6-6.8) was subjected to repeated freeze / thaw cycles and placed at 25°C to evaluate the formulation's robustness after stress conditions associated with drug substance manufacturing.

[0136] During this drug substance manufacturing stress experiment, the drug substance was stressed by three successive freeze / thaw cycles followed by a three-month incubation at 25°C. An additional drug substance sample (control) was maintained at 2-8°C as a non-stressed control.

[0137] The API in the formulation after being stressed by three cycles of controlled freezing and thawing showed no significant differences in appearance, pH, API concentration, SE-UPLC, IE-HPLC, or MFI from the unstressed control.

[0138] After 3 months of incubation at 25°C, no differences were noted between the stressed and control samples in appearance, pH, or API concentration. Minor physical degradation was observed by SE-UPLC, which was orthogonally supported by CE-SDS. The stressed samples showed an increase in subvisible particle count by MFI compared to the control. Minor chemical alterations were observed by IE-HPLC. These degradations may be due to thermal stress and not the result of freeze-thaw cycling. The major degradants were identified as aggregate species by SE-UPLC and as acidic species by IE-HPLC. Example 7: Suitability of pharmaceutical products for use

[0139] In this example study, 1 mL of drug product was drawn into 3 cc and 1 cc disposable sterile syringes through a 21G, 1 1 / 2 inch needle. The filled syringes with attached needles were then incubated in stability chambers at 25°C ± 2°C and 5 ± 3°C and analyzed at six time points: 0, 1, 4, 8, 16, and 24 hours. At each time point, the drug was expelled from the syringe through a 27G 1 / 2 inch needle into a sterile 2 cc vial. The expelled samples were immediately analyzed by appearance, concentration, SEC, and MFI. All samples were free of visible particles. Visual observations remained unchanged with temperature storage conditions or storage time. Regardless of syringe size or incubation temperature, the API concentration of all samples remained at or near the target concentration (Δ≦2.3%).

[0140] Additionally, regardless of syringe size, no significant differences were detected in the chromatographic profiles or peak percentages compared to the time zero values ​​after 24 hours of incubation at either 5°C or 25°C. Results were comparable to the time zero values ​​as well as to the unstressed control samples. Equal

[0141] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the invention is not intended to be limited to the above description, but is instead set forth in the following claims.

Claims

[Claim 1] The invention described in this specification.

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