# US 8,772,462 B2 · Removal of serine proteases by treatment with finely divided silicon dioxide

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- Number: US 8,772,462 B2
- Document ID: US8772462B2
- Status: Granted
- Kind: B2
- Application number: 13/117,028
- Filed: 2011-05-26
- Published: 2011-12-01
- Granted: 2014-07-08
- Earliest claimed: 2010-05-26
- Assignees: Baxter International Inc.; Baxter Healthcare S.A.
- Applicants: Wolfgang Teschner; Hans-Peter Schwarz; Ruth Madlener; Sonja Svatos; Azra Pljevljakovic; Alfred Weber
- Inventors: Wolfgang Teschner; Hans-Peter Schwarz; Ruth Madlener; Sonja Svatos; Azra Pljevljakovic; Alfred Weber
- Web page: https://patentgrep.com/patent/US8772462B2

## CPC

- C07K 16/065: {Purification, fragmentation}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 35/16: Blood plasma; Blood serum (umbilical cord blood A61K35/51)
- A61K 38/1709: {from mammals}
- A61K 39/39525: {Purification}
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 37/00: Drugs for immunological or allergic disorders
- B01D 15/12: relating to the preparation of the feed
- B01D 15/122: {Solid phase extraction}
- B01D 15/362: {Cation-exchange}
- B01D 15/363: {Anion-exchange}
- B01D 15/424: {Elution mode}
- C07K 1/30: by precipitation
- C07K 1/36: by a combination of two or more processes of different types
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B01D: SEPARATION (separating solids from solids by wet methods B03B, B03D; by pneumatic jigs or tables B03B; by other dry methods B07; magnetic or electrostatic separation of solid materials from solid materials or fluids, separation by high-voltage electric fields B03C; centrifuges, vortex apparatus B04; presses per se for squeezing-out liquid from liquid-containing material B30B9/02; treatment of water C02F, e.g. softening by ion-exchange C02F1/42; {arrangements of air intake cleaners in gas turbine plants F02C7/05} ; arrangements or mounting of filters in air-conditioning, air-humidification or ventilation F24F13/28)

## Abstract

The present invention provides novel methods for reducing the serine protease and/or serine protease zymogen content of a plasma-derived protein composition. Also provided are methods for manufacturing plasma-derived protein compositions having reduced serine protease and\or serine protease zymogen content. Among yet other aspects, the present invention provides aqueous and lyophilized compositions of plasma-derived proteins having reduced serine protease and/or serine protease zymogen content. Yet other aspects include methods for treating, managing, and/or preventing a disease comprising the administration of a plasma-derived protein composition having a reduced serine protease or serine protease zymogen content.

## Claims

### Claim 1

A method for reducing the amount of a serine protease or a serine protease zymogen in a plasma-derived target protein composition, the method comprising the steps of:
(a) enriching a plasma-derived target protein, in a first target protein enrichment step comprising alcohol fractionation of a Cohn pool, thereby forming a first enriched plasma-derived target protein composition
(b) contacting the first enriched plasma-derived target protein composition, or a further enriched composition thereof, with finely divided silicon dioxide (SiO2) under conditions suitable to bind at least one serine protease or serine protease zymogen, the conditions comprising a conductivity of from 0.1 mS/cm to 3.0 mS/cm and a pH of from 4.0 to 7.0; and
(c) separating the SiO2 from the enriched plasma-derived target protein composition in (b) to remove the bound serine protease,
wherein the at least one serine protease or serine protease zymogen is Factor XIa (FXIa), Factor XIIa (FXIIa), Factor XI (FXI), or Factor XII (FXII) and further wherein the plasma-derived target protein is selected from albumin, alpha-1-antitrypsin (A1PI), a protein of the complement system, and an inter-alpha-trypsin inhibitor (IαI).

### Claim 2 (depends on 1)

The method of claim 1, wherein the plasma-derived target protein is a protein of the complement system selected from the group consisting of Factor H (FH), Factor D, complement protein C3, and C4 binding protein.

### Claim 3 (depends on 1)

The method of claim 1, wherein the plasma-derived target protein composition is a manufacturing intermediate.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method further comprises a second target protein enrichment step, thereby forming a second enriched plasma-derived target protein composition, after the first target protein enrichment step and prior to contacting the enriched plasma-derived target protein composition with finely divided silicon dioxide (SiO2).

### Claim 5 (depends on 4)

The method of claim 4, wherein the second target protein enrichment step is a protein precipitation step.

### Claim 6 (depends on 4)

The method of claim 4, wherein the second target protein enrichment step is a chromatographic step.

### Claim 7 (depends on 4)

The method of claim 4, wherein the method further comprises a third target protein enrichment step after separating the SiO2 from the enriched plasma-derived target protein composition to remove the bound serine protease.

### Claim 8 (depends on 7)

The method of claim 7, wherein the second target protein enrichment step is a protein precipitation step and the third target protein enrichment step is a chromatographic step.

### Claim 9 (depends on 7)

The method of claim 7, wherein the second target protein enrichment step is a chromatographic step and the third target protein enrichment step is a chromatographic step.

### Claim 10 (depends on 8)

The method of claim 8, wherein the plasma-derived target protein is Factor H.

### Claim 11 (depends on 9)

The method of claim 9, wherein the plasma-derived target protein is Factor H.

### Claim 12 (depends on 8)

The method of claim 8, wherein the plasma-derived target protein is an inter-alpha-trypsin inhibitor (IαI).

### Claim 13 (depends on 9)

The method of claim 9, wherein the plasma-derived target protein is an inter-alpha-trypsin inhibitor (IαI).

### Claim 14 (depends on 1)

The method of claim 1, wherein the composition is contacted with SiO2 at a final concentration of from about 1 g SiO2/g protein to about 5 g SiO2/g protein.

### Claim 15 (depends on 1)

The method of claim 1, wherein the conditions suitable to bind at least one serine protease or serine protease zymogen comprise a conductivity of from 0.1 mS/cm to 2.0 mS/cm and a pH of from 4.0 to 7.0.

### Claim 16 (depends on 1)

The method of claim 1, wherein the conditions suitable to bind at least one serine protease or serine protease zymogen comprise a conductivity of from 0.5 mS/cm to 2.0 mS/cm and a pH of from 4.5 to 6.5.

### Claim 17 (depends on 1)

The method of claim 1, wherein the Cohn pool is cryo-poor plasma.

### Claim 18 (depends on 1)

The method of claim 1, wherein the alcohol is ethanol.