Methods to produce a human plasma-derived IgG preparation enriched in brain disease-related natural IgGs

Patent metadata

Field	Value
Publication number	US-9556261-B2
Application number	US-201414213585-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

The present invention provides, among other aspects, methods for the manufacture of plasma-derived immunoglobulin G compositions highly enriched for anti-brain disease related protein antibodies (e.g., anti-Aβ, anti-RAGE, and anti-α-synuclein antibodies). Advantageously, the methods provided do not affect the manufacturing processes or capabilities for producing plasma-derived IgG therapeutics. Plasma-derived IgG compositions that are highly enriched for anti-brain disease related protein antibodies (e.g., anti-Aβ, anti-RAGE, and anti-α-synuclein antibodies), as also provided here. Methods for the treatment of brain diseases and disorders by administration of plasma-derived IgG compositions highly enriched for anti-brain disease related protein antibodies (e.g., anti-Aβ, anti-RAGE, and anti-α-synuclein antibodies), are also provided.

First claim

What is claimed is:

1. A method for preparing an immunoglobulin preparation enriched in anti-infectious disease-related agent immunoglobulins, the method comprising the steps:
(A) binding a polyclonal, plasma-derived immunoglobulin composition comprising IgG immunoglobulins to a first cation exchange material, the IgG immunoglobulins including an anti-Hib immunoglobulin, anti-Hbs immunoglobulin, anti-PV1 immunoglobulin, anti-HAV immunoglobulin, anti-CMV immunoglobulin, anti-tetanus immunoglobulin, anti-parvo B19 immunoglobulin, or anti- diphtheriae immunoglobulin;
(B) eluting at least 90% of the bound IgG immunoglobulins bound to the first cation exchange material in step (A) from the first cation exchange material, in a first cation exchange elution step, using a first cation exchange elution buffer having a pH of 4.0 to 10.0 and a conductivity of 3.0 mS/cm to 16.0 mS/cm, thereby forming a first cation exchange eluate;
(C) eluting IgG immunoglobulins remaining bound to the first cation exchange material after step (B), in a second cation exchange elution step, using a second cation exchange elution buffer having a pH of 4.0 to 10.0 and a conductivity of 100±80 mS/cm, thereby forming a second cation exchange eluate enriched in an anti-Hib immunoglobulin, anti-Hbs immunoglobulin, anti-PV1 immunoglobulin, anti-HAV immunoglobulin, anti-CMV immunoglobulin, anti-tetanus immunoglobulin, anti-parvo B19 immunoglobulin, anti- diphtheriae immunoglobulin, or a combination thereof.

2. The method of claim 1 , wherein the first cation exchange material is a weak cation exchange material.

3. The method of claim 1 , wherein the first cation exchange material is a carboxymethyl cation exchange resin.

4. The method of claim 1 , wherein the first cation exchange elution buffer has a pH of 7.0 to 9.5.

5. The method of claim 1 , wherein the first cation exchange elution buffer has a pH of 8.0 to 9.0.

6. The method of claim 1 , wherein the first cation exchange elution buffer has a conductivity of 4.0 mS/cm to 15.0 mS/cm.

7. The method of claim 1 , wherein the first cation exchange elution buffer has a conductivity of 5.0 mS/cm to 8.0 mS/cm.

8. The method of claim 1 , wherein the first cation exchange elution buffer has a pH of 8.5±0.2 and a conductivity of 5.0±1 mS/cm.

9. The method of claim 1 , wherein the second cation exchange elution buffer has a pH of 7.0 to 9.5.

10. The method of claim 1 , wherein the second cation exchange elution buffer has a pH of 8.0 to 9.0.

11. The method of claim 1 , wherein the second cation exchange elution buffer has a conductivity of 80 mS/cm to 150 mS/cm.

12. The method of claim 1 , wherein the second cation exchange elution buffer has a conductivity of 80 mS/cm to 120 mS/cm.

13. The method of claim 1 , wherein the polyclonal, plasma-derived immunoglobulin composition bound to the first cation exchange material in step (A) is prepared by a method that includes an alcohol precipitation step.

14. The method of claim 13 , wherein the alcohol precipitation step includes formation of precipitate selected from the group consisting of a Fraction I precipitate, a Cohn Fraction II precipitate, a Cohn Fraction II+III precipitate, a Cohn Fraction I+II+III precipitate, a precipitate G, a Kistler-Nitschmann precipitate A, and a Kistler-Nitschmann gamma-globulin precipitate.

15. The method of claim 1 , wherein the polyclonal, plasma-derived immunoglobulin composition bound to the first cation exchange material in step (A) is a suspended precipitate G.

16. The method of claim 1 , wherein the plasma-derived immunoglobulin composition bound to the first cation exchange material in step (A) is a plasma fraction that has been enriched by at least one prior chromatographic step.

17. The method of claim 16 , wherein the at least one prior chromatographic step is an anion exchange chromatographic step.

18. The method of claim 1 , further comprising enrichment of immunoglobulin G recovered in the second cation exchange eluate.

19. The method of claim 18 , wherein the enrichment of immunoglobulin G recovered in the second cation exchange eluate includes cation exchange chromatography.

20. The method of claim 19 , wherein the enrichment of immunoglobulin G recovered in the second cation exchange eluate includes:
binding immunoglobulin G from the second cation exchange eluate to a second cation exchange material under solution conditions comprising a pH of 4.0 to 10.0 and a conductivity of 1 to 15 mS/cm; and
(H) eluting IgG immunoglobulins bound to the second cation exchange material from the second cation exchange material, in a third cation exchange elution step, using a third cation exchange elution buffer having a pH of 4.0 to 10.0 and a conductivity of 15.0 mS/cm to 300 mS/cm thereby forming a third cation exchange eluate comprising IgG immunoglobulins.

21. The method of claim 20 , wherein the third cation exchange eluate is enriched in anti-Hib immunoglobulins, anti-Hbs immunoglobulins, anti-PV1 immunoglobulins, anti-HAV immunoglobulins, anti-CMV immunoglobulins, anti-tetanus immunoglobulins, anti-parvo B19 immunoglobulins, anti- diphtheriae immunoglobulins, or a combination thereof.

22. The method of claim 20 , wherein the second cation exchange material is a weak cation exchange resin.

23. The method of claim 20 , wherein the second cation exchange material is a carboxymethyl cation exchange resin.

24. The method of claim 18 , wherein the enrichment of IgG immunoglobulins in the second cation exchange eluate includes:
applying IgG immunoglobulins recovered in the second cation exchange eluate to an anion exchange column, in an anion exchange flow through step, under solution conditions comprising a pH of 5.0 to 8.0 and a conductivity of 0.5 mS/cm to 5.0 mS/cm; and
recovering a flow-through fraction from anion exchange flow-through step (J), the flow-through fraction enriched in anti-Hib immunoglobulins, anti-Hbs immunoglobulins, anti-PV1 immunoglobulins, anti-HAV immunoglobulins, anti-CMV immunoglobulins, anti-tetanus immunoglobulins, anti-parvo B19 immunoglobulins, anti- diphtheriae immunoglobulins, or a combination thereof.

25. The method of claim 24 , wherein the solution conditions used to apply the IgG immunoglobulins to the anion exchange column include a pH of 6.2 to 6.6.

26. The method of claim 1 , further comprising a step: (L) of reducing the viral load of the composition by nanofiltration.

27. A method for preparing an immunoglobulin preparation enriched in anti-infectious disease-related agent immunoglobulins, the method comprising admixing a first immunoglobulin composition prepared by a method according to claim 1 with a second immunoglobulin preparation that is not enriched in anti-infectious disease-related agent immunoglobulin.

28. The method of claim 1 , wherein at least 95% of the bound immunoglobulins are eluted from the first cation exchange material in step (B).

Assignees

• Baxalta Inc
• Baxalta GmbH

Inventors

• Gnauer Lucia
• Butterweck Harald Arno
• Bauer Theresa
• Weber Alfred
• Teschner Wolfgang
• Schwarz Hans-Peter

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• B01D61/027

  Nanofiltration · CPC title

• C07K16/18 Primary

  against material from animals or humans · CPC title

• B01D2311/2623

  Ion-Exchange · CPC title

• B01D15/16

  relating to the conditioning of the fluid carrier · CPC title