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AssigneesChiron Corporation, G. D. Searle & Co.
InventorsGlenn J. Dorin, Bo H. Arve, Gregory L. Pattison, Robert F. Halenbeck, Kirk Johnson, Bao-Lu Chen, Rejsharan K. Bana, Maninder S. Hoba, Hassan Madani, Michael Tsang, Mark E. Gustafson, Gary S. Bild, Gary V. Johnson
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A method of modifying protein solubility employs polyionic polymers. These facilitate the solubilization, formulation, purification and refolding of proteins especially incorrectly folded proteins and aggregated proteins. Compositions are described that are suitable for formulating TFPI. The compositions allow preparation of pharmaceutically acceptable compositions of TFPI at concentrations above 0.2 mg/mL and above 10 mg/mL.
A solution having a pH of from 5 to 10, comprising from 200 mM arginine to 300 mM arginine, and further comprising more than 0.2 mg/ml of a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions.
A solution having a pH of from 5 to 10, comprising more than 0.2 mg/ml of a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and further comprising a solubilizer selected from the group consisting of sucrose, mannitol, sorbitol, citrate, isocitrate, succinate, malate, polyphosphate, acetate, polysorbate-80, polyethylene glycol, histidine, imidazole, glutamate, glycine, ammonium sulfate, and sodium dodecyl sulfate.
An aqueous composition comprising (1) a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and (2) a stabilizer of the polypeptide selected from the group consisting of polysorbate-80, mannitol, sucrose, chloride, acetate, citrate, phosphate, and mixtures thereof, wherein the half-life at 40° C. of the polypeptide in said composition, as determined using prothrombin time, is greater than that of a composition comprising TFPI, 150 mM sodium chloride, and 10 mM sodium phosphate and having a pH of 6.
A solution having a pH of from 5 to 10, comprising more than 0.2 mg/ml of a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and further comprising a solubilizer selected from the group consisting of phosphate at a concentration of less than 20 mM or at least 500 mM;
A solution having a pH of from 5 to 10, comprising more than 0.2 mg/ml of a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and further comprising a solubilizer selected from the group consisting of acetate and more than 20 mM phosphate, wherein the solution does not comprise urea.
A solution having a pH of from 5 to 10, comprising more than 0.2 mg/ml of a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and further comprising a first solubilizer selected from the group consisting of phosphate, sulfate, and acetate, and a second solubilizer selected from the group consisting of sodium chloride at a concentration of at least 1.0 M, magnesium chloride, triphosphate, succinic acid, tartaric acid, malic acid, isocitrate, sodium citrate, phosphate glass, mannitol, sucrose, PEG-400, polysorbate-80, and sorbitol.
An aqueous composition comprising (1) a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and (2) a stabilizer of the polypeptide selected from the group consisting of polysorbate-80, mannitol, sucrose, chloride, acetate, citrate, phosphate, and mixtures thereof, wherein the half-life at 40° C. of the polypeptide in said composition, as determined using prothrombin time, is from about 15 days to about 70 days.
An aqueous composition comprising (1) a polypeptide selected from the group consisting of (i) human Tissue Factor Pathway Inhibitor (TFPI) having the amino acid sequence shown in FIG. 4, (ii) human TFPI having the amino acid sequence shown in FIG. 4 and having one further amino acid which is an amino-terminal alanine, and (iii) muteins of (i) or (ii) having from 1 to 5 amino acid substitutions, and further comprising from 200 mM arginine to 300 mM arginine.
Dependencies are inferred from the claim text.