Protein formulations and methods of making same

• US 8,883,146 B2
• Filed: 02/22/2013
• Issued: 11/11/2014
• Est. Priority Date: 11/30/2007
• Status: Active Grant

• Current Assignee: AbbVie Biotechnology Ltd. (Puerto Rico) (Abbvie Incorporated)
• Original Assignee: Abbvie Incorporated
• Inventors: Fraunhofer, Wolfgang, Bartl, Annika, Krause, Hans-Juergen, Tschoepe, Markus, Kaleta, Katharina
• Primary Examiner(s): Landsman, Robert
• Assistant Examiner(s): Hissong, Bruce D
• Application Number:
  US13/774,735
• Publication Number:
  US 20130156760A1
• Time in Patent Office: 627 Days
• Field of Search: None
• US Class Current: 424/130.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/385 Serum albumin
• CPC Class Codes: A61K 38/46 Hydrolases (3)
• CPC Class Codes: A61K 38/4893 Botulinum neurotoxin (3.4.24.69)
• CPC Class Codes: A61K 38/50 acting on carbon-nitrogen bonds, other than peptide bonds (3.5), e.g. asparaginase
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: C07K 1/34 by filtration, ultrafiltration or reverse osmosis
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The invention provides an aqueous formulation comprising water and a protein, and methods of making the same. The aqueous formulation of the invention may be a high protein formulation and/or may have low levels of conductity resulting from the low levels of ionic excipients. Also included in the invention are formulations comprising water and proteins having low osmolality.

Claims

1. An aqueous formulation comprising an antibody, or antigen-binding fragment thereof, at a concentration of at least 50 mg/ml, a non-ionizable excipient, a buffer, and water, wherein the formulation has a conductivity of less than about 2.5 mS/cm, and the antibody, or antigen-binding fragment thereof, has a molecular weight (Mw) greater than about 47 kDa.

2. The formulation of claim 1, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).

3. The formulation of claim 1, wherein the antibody, or antigen-binding fragment thereof, is an anti-tumor necrosis factor alpha (TNFα

) antibody or an anti-interleukin-12 (IL-12) antibody.

4. The formulation of claim 1, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of adalimumab, alemtuzumab, Arcitumomab, cetuximab, trastuzumab, imciromab pentetate, capromab pendetide, infliximab, abciximab, rituximab, basiliximab, palivizumab, nofetumomab, omalizumab, daclizumab, ibritumomab tiuxetan, muromonab-CD3, edrecolomab, gemtuzumab ozogamicin, golimumab, certolizumab pegol, eculizumab, ustekinumab, panitumumab, tositumomab and I131 tositumomab, and bevacizumab.

5. The formulation of claim 1, wherein the concentration of the antibody, or antigen-binding fragment thereof, is 50 to 200 mg/ml.

6. The formulation of claim 1, wherein the non-ionizable excipient is a sugar or a polysorbate.

7. A device comprising the formulation of claim 1.

8. An article of manufacture comprising the device of claim 7.

9. An aqueous formulation comprising an antibody, or antigen-binding fragment thereof, at a concentration of at least 50 mg/ml, a non-ionizable excipient, a buffer, and water, wherein the formulation has a conductivity of less than about 2.5 mS/cm,

wherein the antibody, or antigen-binding fragment thereof, has a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:

3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO;

5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO;

7, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO;

4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO;

6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO;

8.

10. The formulation of claim 9, wherein the antibody, or antigen-binding portion thereof, has an LCVR comprising the amino acid sequence set forth in SEQ ID NO:

1, and an HCVR comprising the amino acid sequence set forth in SEQ ID NO;

2.

11. The formulation of claim 10, wherein the antibody, or antigen-binding portion thereof, is adalimumab.

12. The formulation of claim 9, wherein the non-ionizable excipient is selected from the group consisting of a sugar or a polysorbate.

13. A method of preparing an aqueous formulation of an antibody, or antigen-binding fragment thereof, at a concentration of at least 50 mg/ml, a non-ionizable excipient, and a buffer, the method comprising:

a) providing the antibody, or antigen-binding fragment thereof, in a first solution;

b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved to thereby prepare a diafiltered antibody solution;

c) concentrating the diafiltered antibody solution and

d) adding a non-ionizable excipient and a buffer to the concentrated diafiltered antibody solution, thereby preparing the aqueous formulation of the antibody, or antigen-binding fragment thereof, at a concentration of at least 50 mg/ml, a non-ionizable excipient, and a buffer

wherein the antibody, or antigen-binding fragment thereof, has a molecular weight (Mw) greater than about 47 kDa.

15. The method of claim 14 or 13, wherein the antibody, antibody, or antigen-binding fragment thereof, is selected from the group consisting of a chimeric antibody, a human antibody, a humanized antibody, and a domain antibody (dAb).

16. The method of claim 14 or 13, wherein the antibody, or antigen-binding fragment thereof, is an anti-tumor necrosis factor alpha (TNFα

) antibody or an anti-interleukin-12 (IL-12) antibody.

17. The method of claim 14 or 13, wherein the antibody, or antigen-binding fragment thereof, is selected from the group consisting of adalimumab, alemtuzumab, Arcitumomab, cetuximab, trastuzumab, imciromab pentetate, capromab pendetide, infliximab, abciximab, rituximab, basiliximab, palivizumab, nofetumomab, omalizumab, daclizumab, ibritumomab tiuxetan, muromonab-CD3, edrecolomab, gemtuzumab ozogamicin, golimumab, certolizumab pegol, eculizumab, ustekinumab, panitumumab, tositumomab and I131 tositumomab, and bevacizumab.

14. A method of preparing an aqueous formulation comprising an antibody, or antigen-binding fragment thereof, at a concentration of at least 50 mg/ml, a non-ionizable excipient, and a buffer and water, the method comprising:

a) providing the antibody, or antigen-binding fragment thereof, in a first solution;

b) subjecting the first solution to diafiltration using water as a diafiltration medium until at least a five-fold volume exchange with the water has been achieved, to prepare a second solution; and

c) adding a non-ionizable excipient and a buffer to the second solution, thereby preparing the aqueous formulation,

wherein the antibody, or antigen-binding fragment thereof, has a molecular weight (Mw) greater than about 47 kDa.

18. The method of claim 14 or 15, wherein the non-ionizable excipient is a sugar or a polysorbate.