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CN-121985959-A - IgA-depleting immunoglobulin formulations

CN121985959ACN 121985959 ACN121985959 ACN 121985959ACN-121985959-A

Abstract

IgA-depleted IgG formulations, kits comprising these formulations, and methods of making and using these formulations are provided.

Inventors

  • W. TESCHNER
  • H. Batwek
  • L. Goner
  • L-S. Niki
  • B. Colbert
  • T. Bauer
  • C. Caneval

Assignees

  • 武田药品工业株式会社

Dates

Publication Date
20260505
Application Date
20240926
Priority Date
20230926

Claims (20)

  1. 1. A method of forming a storage-stable IgG pharmaceutical formulation, wherein the pharmaceutical formulation contains no more than about 2 μg/mL of IgA in an aqueous pharmaceutically acceptable carrier, the formulation having properties selected from the group consisting of: (i) A pH of about 4.4 to about 4.9; (ii) About 0.1M to about 0.4M glycine, and A combination of these, The method comprises the following steps: (a) Performing an anion exchange step on an anion exchange precursor solution comprising the IgG, the step comprising: (i) Subjecting the anion exchange precursor solution to anion exchange chromatography in a first portion of a single pass through anion exchange medium contained in a first column and collecting a first anion exchange flow-through from the first column, and (Ii) Optionally, after (i), washing the anion exchange medium with a wash buffer, wherein the washing uses from about 0.25 column volumes to about 1 column volume of the wash buffer.
  2. 2. The process of claim 1, wherein the single pass through the anion exchange medium is performed in the first column and in a second column containing a second portion of the anion exchange medium, the first column and the second column operating in parallel mode, and collecting a second anion exchange flow-through from the second column.
  3. 3. The process of claim 1, wherein the single pass through the anion exchange medium is performed in the first column and in a second column containing a second portion of the anion exchange medium, the first column and the second column being operated in series mode, and a second anion exchange flow-through from the second column being collected.
  4. 4. The method of any preceding claim, wherein the IgG is loaded onto the anion exchange material at a maximum loading of about 70 mg/mL resin.
  5. 5. The process of any one of claims 1 to 4, wherein the first anion exchange flow-through and the second anion exchange flow-through are optionally pooled.
  6. 6. The method of any one of claims 1 to 5, wherein the pH of the anion exchange precursor solution is from about 6.2 to about 7.0, such as from about 6.4 to about 7.0, such as from about 6.7 to about 6.9, and the conductivity is from about 0.5 to about 2.5, such as from about 0.7 to about 1.5, such as from about 0.8 to about 1.0 mS/cm.
  7. 7. The method of any one of claims 1-6, wherein the anion exchange flow-through has a protein concentration of about 3g/L to about 15 g/L.
  8. 8. The method of any one of claims 1 to 7, wherein a wash buffer flow-through is pooled with the anion exchange flow-through.
  9. 9. The method of any one of claims 1 to 8, wherein the anion exchange precursor solution is an eluate from a cation exchange step of an IgG-containing suspension (e.g., from precipitate G) prior to (a).
  10. 10. The method of claim 9, wherein the eluent from the cation exchange step prior to (a) is an eluent from one or more cation exchange columns.
  11. 11. The method of claim 9, wherein the precursor solution for the cation exchange step is a mixture of dissolved precipitate G, solvent, and detergent.
  12. 12. The method of claim 11, wherein the solvent and the detergent are a mixture of octoxynol 9, polysorbate 80, and tri- (n-butyl) phosphate or equivalent.
  13. 13. The method of claim 12, wherein the octoxynol 9 is present at about 1.0 ± 0.5% (v/v), the polysorbate 80 is present at about 0.3 ± 0.15% (v/v), and the tri- (n-butyl) phosphate is present at about 0.3 ± 0.15% (v/v) or an equivalent.
  14. 14. The method of any one of claims 1 to 13, the method further comprising: Before (a), (b) generating a cation exchange chromatography eluent by loading a cation exchange chromatography precursor solution with a cation exchange buffer to a cation exchange medium in one or more columns and collecting the cation exchange chromatography eluent.
  15. 15. The method of claim 14, wherein the cation exchange medium has a protein loading of about 50 mg/mL to about 125 mg/mL of medium.
  16. 16. The method of claim 14, wherein the IgG binds to the cation exchange media within the one or more columns.
  17. 17. The method of claim 16, wherein the bound IgG is washed with about 10 to about 30 column volumes of wash buffer before eluting the bound IgG from the cation exchange material.
  18. 18. The method of claim 14, comprising eluting the bound IgG from the cation chromatographic medium to which IgG binds with a cation exchange elution buffer and collecting the cation exchange eluate.
  19. 19. The method of claim 18, wherein the cation exchange elution buffer comprises sodium dihydrogen phosphate (about 35 mM to about 55 mM) and tris (about 10 mM) wherein the pH is 8.5.+ -. 0.2 and the conductivity is 5.0.+ -. 0.2 mS/cm.
  20. 20. The method of claim 18, wherein the cation exchange eluate is adjusted to a pH of 6.8±0.1 and a conductivity of 0.9±0.1 mS/cm, thereby forming the anion exchange precursor solution.

Description

IgA-depleting immunoglobulin formulations Technical Field The present invention relates to the field of immunoglobulin G (IgG) products (IGI, e.g., IVIG and SCIG compositions) for injection that deplete immunoglobulin a (IgA) and methods of making these products derived from human plasma, and their use in the treatment of diseases or conditions. Background Plasma derived blood products are used not only for the treatment of a variety of blood conditions, but also for the treatment of diseases of other origin. For example, immunoglobulin G (IgG) products from human plasma were first used in 1952 to treat immunodeficiency. Since then, igG preparations have been widely used for at least three general classes of medical conditions, (1) immunodeficiency such as X-linked gammaglobulinemia, hypogammaglobulinemia (primary immunodeficiency) and acquired immune hypo-pathy (secondary immunodeficiency) characterized by low antibody levels, (2) inflammatory and autoimmune diseases, and (3) acute infections. In particular, many people with primary immunodeficiency disorders lack the antibodies required to combat the infection. In some cases, these drawbacks can be remedied by infusion of purified IgG (i.e., IVIG therapy), typically by intravenous administration. Several primary immunodeficiency disorders are typically treated in the form of X-linked gamma globulin deficiency (XLA), common Variable Immunodeficiency (CVID), high IgM syndrome (HIM), severe Combined Immunodeficiency (SCID), and some IgG subclasses defects (Blaese and Winkelstein, J. Patient & Family Handbook for Primary Immunodeficiency Diseases. Towson, MD: Immune Deficiency Foundation; 2007). Although IgG therapy can be extremely effective in managing primary immunodeficiency disorders, it only temporarily replaces antibodies that are not produced in the body and does not cure the disease. Thus, patients who rely on IgG therapy require repeated dosing, typically about once a month, for life. This need places a great demand for the continuous production of IgG compositions. However, unlike other biological agents produced by in vitro expression of recombinant DNA vectors, igG is fractionated from human blood and plasma donors. Thus, igG products cannot be increased by simply increasing the throughput. In contrast, the levels of commercially available IgG are limited by the available supply of blood and plasma donations. Several factors contribute to the need for IgG products, including acceptance of IgG treatment, identification of other indications that are effective for IgG therapy, and patient diagnosis and increase in IgG therapy prescriptions. Notably, blood (i.e., red blood cells) usage was reduced by as much as 40%, but IgG usage was tripled in 2004 to 2018, with estimated annual increases of 5% -7% up to 2024 (brandd, a. Et al Transfusion Clinique et Biologique, 2021, 28 (1), 96-122). Due in part to the increasing global demand and fluctuations in the available supply of IgG products, several countries (including australia and the united kingdom) have begun to implement demand management programs to protect these products from the highest demand patients during product shortages. Many commercial suppliers of IgG offer various immunoglobulin for injection ("IGI") (e.g., IVIG (intravenous immunoglobulin)) products. More than twelve IgG products can be used in north america and europe, which differ in IgG concentration, infusion frequency, route of administration, and other considerations (Perez et al, J ALLERGY CLIN immunol (2017), 139: S1-S46). Current formulations provide ready-to-use sterile liquid preparations of highly purified and concentrated human IgG antibodies of 100 mg/mL and 200 mg/mL, as compared to older lyophilized IVIG products containing 50 mg/mL or 100 mg/mL protein in the reconstituted solution. Recently, igG formulations (i.e., SCIG therapies) have been made (formatted) for subcutaneous administration into the IgG treatment market. These formulations represent a significant advance in the overall patient experience with IgG formulations. For example, a patient or caregiver trained in subcutaneously infusing an IgG formulation can infuse the formulation in virtually any situation. This innovation frees the patient from going to the infusion center, allowing them to infuse, e.g., self-infuse, in their own comfortable environment or anywhere they choose. Exemplary subcutaneously infused IgG preparations include HyQvia ® [ 10% immunoglobulin infusion with recombinant human hyaluronidase (human) ], hizentra ® [20% human subcutaneous immunoglobulin fluid ]. A fraction of patients treated with immunoglobulins may respond to immunoglobulins containing higher levels of immunoglobulin a (IgA) and, therefore, igG preparations risk inducing allergic reactions in IgA-sensitive patients. GAMMAGARD S/D intravenous immunoglobulin (human) [ IVIG ] (solvent/detergent treated (freeze dried concentrate)) has the lowest IgA level in all immunoglobulins