Anti-il-36r antibody formulations

Abstract

The present invention relates to anti-IL-36R formulations for administration to a subject.

1 . A pharmaceutical formulation comprising:
 a. An anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration within the range from 0.5 mg/mL to 220 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. A buffer present at a concentration within the range from 20 mM to 80 mM, wherein the buffer comprises acetate, histidine, or citrate;   c. A tonicifying agent present at a concentration within the range from 100 mM to 250 mM, wherein the tonicifying agent is one or more sugar and/or polyol comprising sucrose, trehalose, sorbitol, glycerol, mannitol or dextrose;   wherein the formulation is characterized by a pH within the range from 5 to 8 when in aqueous form.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 127. 
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein the formulation is in liquid or powder form. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein the anti-IL-36R antibody is present at a concentration of within the range from 10 mg/mL to 200 mg/mL. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein the anti-IL-36R antibody is present at a concentration of 20 mg/mL or 60 mg/mL or 150 mg/mL. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the formulation further comprises a stabilizer present at a concentration within the range from 0 mM to 80 mM. 
     
     
         7 . The pharmaceutical formulation of  claim 6 , wherein the stabilizer comprises an amino acid comprising arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartate, glutamate or pharmaceutically acceptable salts thereof. 
     
     
         8 . The pharmaceutical formulation of  claim 6 , wherein the formulation further comprises a salt present at a concentration of within the range from 0 to 150 mM. 
     
     
         9 . The pharmaceutical formulation of  claim 8 , wherein the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl 2 ), magnesium sulfate (MgSO 4 ), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl 2 )), boric acid salts or zinc chloride (ZnCl 2 ). 
     
     
         10 . The pharmaceutical formulation of  claim 1 , wherein the formulation further comprises a surfactant present at a concentration within the range from 0.1 g/L to 1.5 g/L. 
     
     
         11 . The pharmaceutical formulation of  claim 10 , wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. 
     
     
         12 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration within the range from 10 mg/mL to 200 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. acetate and/or histidine buffer present at a concentration within the range from 20 mM to 80 mM;   c. sucrose and/or trehalose present at a concentration within the range from 100 mM to 250 mM;   d. L-arginine and/or pharmaceutically acceptable salts thereof present at a concentration within the range from 0 mM to 80 mM;   e. sodium chloride (NaCl) present at a concentration of within the range from 0 to 150 mM; and   f. polysorbate 20 and/or polysorbate 80 present at a concentration within the range from 0 g/L to 1.5 g/L;   wherein the formulation is characterized by a pH within the range from 5 to 7 when in aqueous form.   
     
     
         13 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration of 20 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. an citrate buffer present at a concentration at a concentration of 25 mM;   c. sucrose and/or trehalose present at a concentration of 200 mM;   d. polysorbate 80 present at a concentration of 0.4 g/L;   wherein the formulation is characterized by a pH within the range from 6 to 7 when in aqueous form.   
     
     
         14 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration of 60 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. an acetate buffer present at a concentration of 45 mM;   c. sucrose and/or trehalose present at a concentration of 150 mM;   d. L-arginine or pharmaceutically acceptable salts thereof present at a concentration of 25 mM; and   e. polysorbate 20 present at a concentration of 0.4 g/L;   wherein the formulation is characterized by a pH within the range from 5 to 6 when in aqueous form.   
     
     
         15 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration of 150 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. an acetate buffer present at a concentration at a concentration of 45 mM;   c. sucrose or trehalose present at a concentration of 150 mM;   d. L-arginine or pharmaceutically acceptable salts thereof present at a concentration of 25 mM; and   e. polysorbate 20 present at a concentration of 0.4 g/L;   wherein the formulation is characterized by a pH within the range from 5 to 8 when in aqueous form.   
     
     
         16 . The pharmaceutical formulation of  claim 1 , wherein the formulation is characterized by an osmolality within the range from 210 mOsmol/kg to 390 mOsmol/kg. 
     
     
         17 . The pharmaceutical formulation of  claim 1 , wherein less than 5% of the antibody is present in an aggregate form in the formulation. 
     
     
         18 . The pharmaceutical formulation of  claim 1 , wherein the formulation is sterile. 
     
     
         19 . The pharmaceutical formulation of  claim 1 , wherein the formulation is stable upon freezing and thawing. 
     
     
         20 . The pharmaceutical formulation of  claim 1 , wherein the formulation comprises water or is reconstituted with water. 
     
     
         21 . The pharmaceutical formulation of  claim 1 , wherein the formulation has a pH of between 5 to 6 in liquid form or when reconstituted with water. 
     
     
         22 . The pharmaceutical formulation of  claim 1 , wherein the formulation has a pH of 6 in liquid or when reconstituted with water. 
     
     
         23 . The pharmaceutical formulation of  claim 1 , wherein the formulation has at least one feature selected from the group consisting of:
 (i) Increased shelf life   (ii) better temperature stability,   (iii) decreased formation of aggregates,   (iv) better chemical stability,   (v) decreased viscosity, and   as compared to a reference formulation.   
     
     
         24 . The pharmaceutical formulation of  claim 1 , wherein the formulation having at least one feature selected from the group consisting of:
 (a) decreased percentage of aggregates as measured by High Performance Size Exclusion Chromatography (HP-SEC),   (b) higher percentage of monomers as measured by HP-SEC,   (c) higher percentage of main peak (less degradation of charge variants) measured by CEX,   (d) lower percentage of subvisible particles such as ≥10 μm and ≥25 μm, and   (e) lower turbidity value in Formazine Nephelometry Units (FNU),   after storage at 40° C. as compared to the reference formulation.   
     
     
         25 . A pharmaceutical product comprising a vial or syringe comprising the pharmaceutical formulation according to  claim 1 . 
     
     
         26 . A pharmaceutical product according to  claim 25  further comprising a pre-assembled injection device. 
     
     
         27 . The pharmaceutical product of  claim 26 , wherein the pre-assembled injection device is an autoinjector or needle safety device. 
     
     
         28 . A pre-assembled injection device comprising a pharmaceutical formulation according to  claim 1 . 
     
     
         29 . The pre-assembled injection device according to  claim 28 , wherein said device is an autoinjector or needle safety device or a syringe. 
     
     
         30 . The pre-assembled injection device according to  claim 29 , wherein said formulation is suitable for subcutaneous administration or intramuscular administration. 
     
     
         31 . A kit of parts, comprising at least a container comprising a pharmaceutical formulation according to  claim 1 , and an injection device. 
     
     
         32 . The kit of  claim 31 , comprising an instruction for subcutaneous or intramuscular administration of the formulation to a subject or an instruction for subcutaneous or intramuscular self-administration. 
     
     
         33 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or antigen-binding fragment thereof comprising:
 i. a light chain comprising an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising an amino acid sequence set forth as SEQ ID NO:127;
 wherein the antibody is present at a concentration of 20 mg/mL, 60 mg/mL or 150 mg/mL; and 
 
   b. acetate buffer present at a concentration of 45 mM;   c. sucrose present at a concentration of 150 mM;   d. L-arginine HCl present at a concentration of 25 mM;   e. polysorbate 20 present at a concentration of 0.4 g/L; and
 wherein the formulation is characterized by a pH within the range from 5 to 6. 
   
     
     
         34 . A powder pharmaceutical formulation wherein when reconstituted with water yields an aqueous solution comprising:
 a. an anti-IL-36R antibody or antigen-binding fragment thereof comprising:
 i. a light chain comprising an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising an amino acid sequence set forth as SEQ ID NO:127; and 
   b. histidine buffer present at a concentration of 25 mM;   c. sucrose and/or mannitol present at a concentration of 180 mM;   d. polysorbate 20 present at a concentration of 0.2 g/L; and
 wherein the formulation is characterized by a pH within the range from 5 to 7 when reconstituted with water. 
   
     
     
         35 . The powder formulation of  claim 34 , wherein the antibody is present at a concentration of 20 mg/mL, 60 mg/mL or 150 mg/mL. 
     
     
         36 . The powder formulation of  claim 34 , wherein the formulation comprises 100 mg to 1500 mg of the antibody and is reconstitutable with water for injection. 
     
     
         37 . A method of making a pharmaceutical formulation comprising:
 a. culturing mammalian cells having stably incorporated into their genome one or more nucleic acids encoding the light and heavy chains of an anti-IL-36R antibody so that the cells secrete the antibody into the cell culture media, and purifying the antibody from the cell culture media; and   b. preparing the formulation according to  claim 1 , wherein the nucleic acid encoding the light of the anti-IL-36R antibody comprises a nucleotide sequence encoding SEQ ID NO:118, and wherein the nucleic acid encoding the heavy chain of the anti-IL-36R antibody comprises a nucleotide sequence encoding SEQ ID NO:127.   
     
     
         38 . A pharmaceutical formulation comprising:
 a. an anti-IL-36R antibody or an antigen binding fragment thereof present at a concentration within the range from 0.5 mg/mL to 220 mg/mL, wherein the anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89;   b. A buffer present at a concentration within the range from 20 mM to 80 mM;   c. A tonicifying agent present at a concentration within the range from 100 mM to 400 mM;   wherein the formulation is characterized by a pH within the range from 5 to 8 when in aqueous form.