WO1999037329A1 - Pharmaceutical formulation comprising an antibody and a citrate buffer - Google Patents

Pharmaceutical formulation comprising an antibody and a citrate buffer Download PDF

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Publication number
WO1999037329A1
WO1999037329A1 PCT/SE1999/000049 SE9900049W WO9937329A1 WO 1999037329 A1 WO1999037329 A1 WO 1999037329A1 SE 9900049 W SE9900049 W SE 9900049W WO 9937329 A1 WO9937329 A1 WO 9937329A1
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WO
WIPO (PCT)
Prior art keywords
antibody
formulation
formulation according
present
buffer
Prior art date
Application number
PCT/SE1999/000049
Other languages
French (fr)
Inventor
Ola Flink
Sven PETRÉN
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE9800170A external-priority patent/SE9800170D0/en
Priority claimed from SE9800766A external-priority patent/SE9800766D0/en
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to AU24448/99A priority Critical patent/AU2444899A/en
Publication of WO1999037329A1 publication Critical patent/WO1999037329A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates generally to antibody formulations and particularly to stabilised antibody formulations for storage and for therapeutic administration.
  • Protein preparations are particularly unstable in dilute solutions and must be formulated in such a way as to prevent significant levels of denaturation, agglomeration or degradation. These problems are particularly acute in the formulation of large proteins such as immunoglobulins.
  • Immunoglobulins or antibodies are known to be prone to form aggregates and particulates in solution and this has long provided special problems in generating suitable formulations for the storage and administration of therapeutic antibodies.
  • Existing antibody formulations frequently require to be filtered before injection to remove aggregates or particulate matter which is inconvenient and tends to reduce the accuracy of the injected dose.
  • EP 0 073 371 describes intravenously administrable immunoglobulin compositions which have their pH adjusted to 3.5 to 5.0 as proteins are known to be more stable at low pH. Such low pHs however tend to result in undesirable reactions at the site of injection .
  • US 4650772 describes a method for stabilising thermally unstable monoclonal antibodies which requires the presence of 0.25% to 5% hydrolysed ovalbumin.
  • ovalbumin in pharmaceutical formulations results in the induction of an allergic response which prevents its effective use for repeated administrations.
  • WO 90/11091 describes the use of maltose and buffers in a lyophilised formulation of monoclonal antibodies. Lyophilisation is however an expensive process and the need to 2
  • citrate buffer may be used to buffer the pH at between 3.0 and 6.0.
  • the present invention provides a more simple antibody formulation than those presently known, providing a formulation which is both suitable for administration and has improved storage properties.
  • Existing antibody formulations require the use both of a stabiliser and of a buffer.
  • antibodies in formulations of the present invention are stabilised only by citrate buffer in a saline solution at a physiologically preferable pH.
  • an isotonic pharmaceutical formulation comprising an antibody and a buffer, wherein the antibody is present at 0.5mg/ml to lOmg/ml, the buffer is a citrate buffer present at 5mmol/l to 20mmol l and the pH of the formulation is 5.3 to 7.2.
  • a citrate buffer for use in the present invention may be generated by dissolution of free citric acid or preferably a pharmaceutically acceptable salt of citrate, preferably a sodium salt.
  • a formulation of the present invention may be generated by solubilising the relevant antibody, preferably in saline and adding an amount of citrate buffer necessary to obtain a pH of the solution in the range 5.3 to 7.2.
  • the citrate buffer is preferably present at 5mmol/l to 20mmol/l.
  • a formulation of the present invention may additionally contain other substances desirable for therapeutic efficacy of the antibody e.g. chelators, or other therapeutic compounds desirable to be coformulated with the antibody but it is preferably substantially free of any additional compound known for use in antibody stabilising e.g. Tween, mannitol or maltose.
  • additional compound known for use in antibody stabilising formulations may not be present in formulations of the present 3
  • citrate buffer is present in the formulation at 7.5mmol/l to 15mmol l and most preferably at lOmmol/l.
  • Any pharmaceutically acceptable citrate buffer may be used in the present invention but the citrate buffer is preferably sodium citrate. It is more preferable that sodium citrate dihydrate is used and most preferable that the citrate buffer be generated from a mixture of sodium citrate dihydrate and citric acid monohydrate.
  • the formulation contains about 2.4 mg/ml sodium citrate dihydrate and about 0.387 mg/ml citric acid monohydrate.
  • the present invention is suitable for the formulation of any antibody or antibody fragment. Any reference to an antibody herein will be taken to include a fragment of such antibody.
  • the antibody for use in a formulation of the present invention may be natural or recombinant and may be generated according to any known technique. Natural antibodies may be those isolated either by purification from body fluids or from cell lines and may be polyclonal or monoclonal antibodies. Particularly preferred antibodies for use in formulations of the present invention are recombinant antibodies produced from engineered cell lines. Such cell lines will have been engineered to express the relevant antibody gene.
  • the antibody gene may either be a human gene or a gene from another species which has been humanised by modification of the native sequence to prevent rejection when administered to a human, e.g.
  • the antibody is preferably an antibody directed against the human T cell surface receptor TCR V ⁇ 5.2/5.3 (the method for constructing such an antibody is described in WO 95/16038 and the description of such methods is hereby incorporated by reference) , and is more preferably an IgG, IgGl or IgG/ ⁇ .
  • the antibody is most preferably the antibody produced by the cell line deposited on June 22, 1995 under the Budapest treaty as ATCC (CRL 11949) [herein this antibody is referred to as 'TM27'] or is one comprising the following TM27 VK sequence: 1 DIQMTQSPSSLSASNGDRVTITCSASQGISNYLNWYQQTPGKAPKLLIYY 50
  • the present invention also provides for the use of formulations of the present invention in medical therapy and particularly for the treatment of autoimmune disease and further particularly in the therapy of multiple sclerosis. 5
  • the formulation has a pH in the range 5.5 to 6.5 and is most preferably pH 5.5.
  • the pH may be altered using any pharmaceutically acceptable acid or alkali.
  • the formulation of the present invention may be prepared under aseptic conditions, leading to a sterile formulation.
  • TM27 is a humanised antibody (IgGl) produced in Chinese hamster ovary (CHO) cells by recombinant technology.
  • TM27 used were purified by protein-A affinity chromatography.
  • the TM27 preparations were prepared from two different TM27 bulk solutions. One was 10.8 mg TM27 /ml in 10 mmol 1 citrate buffer pH 5.5 and the other was 11.0 mg TM27 /ml in 10 mmol 1 phosphate buffer pH 6.5.
  • the bulk solutions had sodium chloride added to make them isotonic.
  • TM27 preparations used in this study were prepared under aseptic conditions. The batches were protected from air with nitrogen during the manufacturing and filling processes. Eight batches with different compositions were prepared using the buffers described.
  • TM27 bulk solution was diluted with the appropriate buffer to a concentration of 1 mg/ml TM27 by gentle mixing, while avoiding foaming.
  • the manufactured solutions were filtered through a sterile 0.22 ⁇ m MILLEX-GN filter directly into 10 ml sterile glass vials. Filling was performed from the bottom of the vials under nitrogen protection.
  • Example 3 8 mmol/1 citrate, pH 5.5
  • Citric acid monohydrate for parenteral use 0.581
  • Example 6 18 mmol 1 citrate, pH 5.5
  • Example 7 20 mmol 1 citrate, pH 5.5
  • Citric acid monohydrate for parenteral use 0.387 mg
  • the formulations were studied over a 24 month period.

Abstract

The present invention relates to an isotonic pharmaceutical formulation comprising an antibody and a buffer, wherein the antibody is present at 0.5 mg/ml to 10 mg/ml, the buffer is a citrate buffer present at 5 mmol/l to 20 mmol/l and the pH of the formulation is 5.3 to 7.2. The invention also relates to a method for the storage of antibodies by use of such formulations and to the use of such formulations in therapy.

Description

PHARMACEUTICAL FORMULATION COMPRISING AN ANTIBODY AND A CITRATE BUFFER
The invention relates generally to antibody formulations and particularly to stabilised antibody formulations for storage and for therapeutic administration.
Purified proteins, particularly those produced using recombinant DNA technology are now well established as pharmaceutical agents. Such proteins do however present a range of problems associated with their stable formulation. Many protein preparations are particularly unstable in dilute solutions and must be formulated in such a way as to prevent significant levels of denaturation, agglomeration or degradation. These problems are particularly acute in the formulation of large proteins such as immunoglobulins. Immunoglobulins or antibodies are known to be prone to form aggregates and particulates in solution and this has long provided special problems in generating suitable formulations for the storage and administration of therapeutic antibodies. Existing antibody formulations frequently require to be filtered before injection to remove aggregates or particulate matter which is inconvenient and tends to reduce the accuracy of the injected dose.
Various attempts have been made to overcome the problems of antibody formulation:
EP 0 073 371 describes intravenously administrable immunoglobulin compositions which have their pH adjusted to 3.5 to 5.0 as proteins are known to be more stable at low pH. Such low pHs however tend to result in undesirable reactions at the site of injection .
US 4650772 describes a method for stabilising thermally unstable monoclonal antibodies which requires the presence of 0.25% to 5% hydrolysed ovalbumin. The use of ovalbumin in pharmaceutical formulations results in the induction of an allergic response which prevents its effective use for repeated administrations.
WO 90/11091 describes the use of maltose and buffers in a lyophilised formulation of monoclonal antibodies. Lyophilisation is however an expensive process and the need to 2
resuspend the formulation prior to administration adds to the complexity of the treatment regimen. It was suggested that citrate buffer may be used to buffer the pH at between 3.0 and 6.0.
The present invention provides a more simple antibody formulation than those presently known, providing a formulation which is both suitable for administration and has improved storage properties. Existing antibody formulations require the use both of a stabiliser and of a buffer. However antibodies in formulations of the present invention are stabilised only by citrate buffer in a saline solution at a physiologically preferable pH.
There is therefore provided according to the present invention, an isotonic pharmaceutical formulation comprising an antibody and a buffer, wherein the antibody is present at 0.5mg/ml to lOmg/ml, the buffer is a citrate buffer present at 5mmol/l to 20mmol l and the pH of the formulation is 5.3 to 7.2.
A citrate buffer for use in the present invention may be generated by dissolution of free citric acid or preferably a pharmaceutically acceptable salt of citrate, preferably a sodium salt.
A formulation of the present invention may be generated by solubilising the relevant antibody, preferably in saline and adding an amount of citrate buffer necessary to obtain a pH of the solution in the range 5.3 to 7.2. The citrate buffer is preferably present at 5mmol/l to 20mmol/l.
A formulation of the present invention may additionally contain other substances desirable for therapeutic efficacy of the antibody e.g. chelators, or other therapeutic compounds desirable to be coformulated with the antibody but it is preferably substantially free of any additional compound known for use in antibody stabilising e.g. Tween, mannitol or maltose. By 'substantially free' it is meant that such additional compounds known for use in antibody stabilising formulations may not be present in formulations of the present 3
invention in an amount capable alone or in combination with one or more other stabilisers, of having a stabilising effect upon an antibody in a formulation.
In preferred embodiments of the present invention citrate buffer is present in the formulation at 7.5mmol/l to 15mmol l and most preferably at lOmmol/l. Any pharmaceutically acceptable citrate buffer may be used in the present invention but the citrate buffer is preferably sodium citrate. It is more preferable that sodium citrate dihydrate is used and most preferable that the citrate buffer be generated from a mixture of sodium citrate dihydrate and citric acid monohydrate. In the preferred embodiments of the present invention, the formulation contains about 2.4 mg/ml sodium citrate dihydrate and about 0.387 mg/ml citric acid monohydrate.
The present invention is suitable for the formulation of any antibody or antibody fragment. Any reference to an antibody herein will be taken to include a fragment of such antibody. The antibody for use in a formulation of the present invention may be natural or recombinant and may be generated according to any known technique. Natural antibodies may be those isolated either by purification from body fluids or from cell lines and may be polyclonal or monoclonal antibodies. Particularly preferred antibodies for use in formulations of the present invention are recombinant antibodies produced from engineered cell lines. Such cell lines will have been engineered to express the relevant antibody gene. The antibody gene may either be a human gene or a gene from another species which has been humanised by modification of the native sequence to prevent rejection when administered to a human, e.g. a humanised recombinant antibody. The antibody is preferably an antibody directed against the human T cell surface receptor TCR Vβ 5.2/5.3 (the method for constructing such an antibody is described in WO 95/16038 and the description of such methods is hereby incorporated by reference) , and is more preferably an IgG, IgGl or IgG/κ. The antibody is most preferably the antibody produced by the cell line deposited on June 22, 1995 under the Budapest treaty as ATCC (CRL 11949) [herein this antibody is referred to as 'TM27'] or is one comprising the following TM27 VK sequence: 1 DIQMTQSPSSLSASNGDRVTITCSASQGISNYLNWYQQTPGKAPKLLIYY 50
51 TSSLHSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQYSKLPRTFGQ 100
101 GTKLQIT 107,
and further comprises an amino acid sequence selected from the group consisting of the TM27 VH amino acid sequence:
1 QVQLQESGPGLVRPSQTLSLTCTVSGFSLTAYGVNWVRQPPGRGLEWLGM 50
51 IWGDGNTDYNSALKSRVTMLKDTSKNQFSLRLSSVTAADTAVYYCARDRV 100
101 TATLYAMDYWGQGSLVTVSS 120,
the TM27 VH sequence wherein amino acid residue 48 is replaced with isoleucine (I),
the TM27 VH sequence wherein amino acid residues 78 and 79 are valine (N) and phenylalanine (F),
theTM27 NH sequence above wherein amino acid residues 67 to 70 NTML are replaced with LSIS respectively and amino acid 73 is an aspargine (Ν),
the TM27 NH sequence wherein amino acid residue 92 is an arginine (R).
The present invention also provides for the use of formulations of the present invention in medical therapy and particularly for the treatment of autoimmune disease and further particularly in the therapy of multiple sclerosis. 5
In preferred embodiments of the present invention the formulation has a pH in the range 5.5 to 6.5 and is most preferably pH 5.5. The pH may be altered using any pharmaceutically acceptable acid or alkali.
The formulation of the present invention may be prepared under aseptic conditions, leading to a sterile formulation.
The invention will now be illustrated by reference to the following examples which are in no way intended to be limiting of the scope of the invention described herein.
EXAMPLES
The antibody assayed in the following examples is TM27 which is a humanised antibody (IgGl) produced in Chinese hamster ovary (CHO) cells by recombinant technology.
The bulk batches of TM27 used were purified by protein-A affinity chromatography. The TM27 preparations were prepared from two different TM27 bulk solutions. One was 10.8 mg TM27 /ml in 10 mmol 1 citrate buffer pH 5.5 and the other was 11.0 mg TM27 /ml in 10 mmol 1 phosphate buffer pH 6.5. The bulk solutions had sodium chloride added to make them isotonic.
The TM27 preparations used in this study were prepared under aseptic conditions. The batches were protected from air with nitrogen during the manufacturing and filling processes. Eight batches with different compositions were prepared using the buffers described.
For manufacturing purposes, TM27 bulk solution was diluted with the appropriate buffer to a concentration of 1 mg/ml TM27 by gentle mixing, while avoiding foaming. The manufactured solutions were filtered through a sterile 0.22 μm MILLEX-GN filter directly into 10 ml sterile glass vials. Filling was performed from the bottom of the vials under nitrogen protection.
The solutions were filled into 10 ml injection vials of neutral Type I glass (Ph Eur), 1 ml/vial. Bromobutyl rubber stoppers (FM 257) were used and the vials were sealed with aluminium capsules.
The batches were stored under the following conditions: +5 °C/ambient humidity and +25 °C/30 % relative humidity. All the vials were stored upright. All examples contain antibody at 1 mg/ml. Example 1: lOmmol/l citrate, pH 5.5 amount (mg) Citric acid monohydrate for parenteral use 0.387
Sodium citrate dihydrate for parenteral use 2.400 Sodium chloride for aseptic preparation 8.4
Water for injection to 1 ml
Example 2: 5 mmol/1 citrate ,pH 5.5
Citric acid monohydrate for parenteral use 0.194
Sodium citrate dihydrate for parenteral use 1.200
Sodium chloride for aseptic preparation 8.69
Water for injection to 1 ml
Example 3: 8 mmol/1 citrate, pH 5.5
Citric acid monohydrate for parenteral use 0.310
Sodium citrate dihydrate for parenteral use 1.920
Sodium chloride for aseptic preparation 8.52
Water for injection to 1 ml
Example 4: 12 mmol/1 citrate, pH 5.5
Citric acid monohydrate for parenteral use 0.464
Sodium citrate dihydrate for parenteral use 2.88
Sodium chloride for aseptic preparation 8.28
Water for injection to 1 ml Example 5: 15 mmol/1 citrate, pH 5.5
Citric acid monohydrate for parenteral use 0.581
Sodium citrate dihydrate for parenteral use 3.600
Sodium chloride for aseptic preparation 8.11
Water for injection to 1 ml
Example 6: 18 mmol 1 citrate, pH 5.5
Citric acid monohydrate for parenteral use 0.697
Sodium citrate dihydrate for parenteral use 4.320 Sodium chloride for aseptic preparation 7.93
Water for injection to 1 ml
Example 7: 20 mmol 1 citrate, pH 5.5
Citric acid monohydrate for parenteral use 0.774
Sodium citrate dihydrate for parenteral use 4.800
Sodium chloride for aseptic preparation 7.82
Water for injection to 1 ml
Example8 (pH 5.5)
Citric acid monohydrate for parenteral use 0.387 mg
Sodium citrate dihydrate for parenteral use 2.400 mg Sodium chloride for aseptic preparation 8.4 mg 9
Polysorbat 80 (Tween 80) 0.2 mg
Water for injection to 1 ml
The formulations were studied over a 24 month period.
The results clearly showed that storage temperature, buffer composition and pH influence the stability of TM27. The best stability is achieved at low storage temperature (+5 °C). The formulations exemplified in examples 1-7 were stable for 24 months whereas the formulation in example 8 was stable for 12 months.

Claims

10 CLAIMS.
1. An isotonic pharmaceutical formulation comprising an IgG antibody and a buffer, wherein the antibody is present at from 0.5 mg/ml to 10 mg/ml, the buffer is a citrate buffer present at 5mmol l to 20mmol/l and the pH of the formulation is 5.3 to 7.2.
2. A formulation according to claim 1, wherein the pH is 5.5 to 6.5.
3. A formulation according to claim 1, wherein the pH is 5.5.
4. A formulation according to any one of claims 1 to 3, wherein the citrate is present at 7.5mmol/l to 15mmol/l .
5. A formulation according to any one of claims 1 to 4, wherein the citrate is present at lOmmol/l.
6. A formulation according to any one of claims 1 to 5, wherein the antibody is an IgGl.
7. A formulation according to claim 6, wherein the antibody is an IgGl/κ.
8. A formulation according to any one of the preceding claims, wherein the antibody is a recombinant antibody.
9. A formulation according to claim 8, wherein the antibody is a humanised recombinant antibody.
10. A formulation according to claim 9, wherein the antibody is directed against the human T cell surface receptor TCR Nβ 5.2/5.3. 11
11. A formulation according to claim 10, wherein the antibody is produced by the cell line with the deposition number CRL 11949.
12. A formulation according to claim 11, wherein the antibody comprises the TM27 NK amino acid sequence:
1 DIQMTQSPSSLSASNGDRNTITCSASQGISΝYLΝWYQQTPGKAPKLLIYY 50
51 TSSLHSGNPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQYSKLPRTFGQ 100
101 GTKLQIT 107,
and further comprises an amino acid sequence selected from the group consisting of the TM27 NH amino acid sequence:
1 QNQLQESGPGLNRPSQTLSLTCTNSGFSLTAYGVΝWNRQPPGRGLEWLGM 50
51 IWGDGΝTDYΝSALKSRNTMLKDTSKΝQFSLRLSSNTAADTANYYCARDRV 100
101 TATLYAMDYWGQGSLNTNSS 120,
the TM27 VH sequence wherein amino acid residue 48 is replaced with isoleucine (I),
the TM27 VH sequence wherein amino acid residues 78 and 79 are valine (V) and phenylalanine (F),
theTM27 VH sequence above wherein amino acid residues 67 to 70 VTML are replaced with LSIS respectively and amino acid 73 is an aspargine (Ν),
the TM27 VH sequence wherein amino acid residue 92 is an arginine (R). 12
13. An isotonic pharmaceutical formulation comprising the antibody TM27 and a buffer, wherein the antibody is present at 0.5 mg/ml to 10 mg/ml, the buffer is a citrate buffer present at 5mmol/l to 20mmol/l and the pH of the formulation is 5.3 to 7.2.
14. A formulation according to any one of claims 1 to 13, which is a sterile formulation.
15. A process for the preparation of an isotonic pharmaceutical formulation according to any one of claims 1 to 14, comprising incorporation of the antibody in an isotonic medium wherein the antibody is present at from 0.5 mg/ml to 10 mg/ml, the buffer is a citrate buffer present at 5mmol/l to 20mmol l and the pH of the formulation is 5.3 to
7.2.
16. A formulation according to any one of the previous claims, for use in medical therapy.
17. A formulation according to any one of claims 1 to 14, for use in the therapy of an autoimmune disease.
18. A formulation according to any one of claims 1 to 14, for use in the therapy of multiple sclerosis.
19. Use of a formulation according to any one of claims 1 to 14, in the preparation of a medicament for use in the therapy of an autoimmune disease.
20. Use of a formulation according to any one of claims 1 to 14, in the preparation of a medicament for use in the therapy of multiple sclerosis.
21. A method for improving the storage of an antibody comprising formulating the antibody in a formulation as claimed in any one of claims 1 to 14. 13
22. A method according to claim 21, wherein the formulation is stored at a temperature between 4°C and 10°C.
23. A method according to claim 22, wherein the temperature is 5°C.
PCT/SE1999/000049 1998-01-22 1999-01-15 Pharmaceutical formulation comprising an antibody and a citrate buffer WO1999037329A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
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Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE9800170-4 1998-01-22
SE9800170A SE9800170D0 (en) 1998-01-22 1998-01-22 formulation
SE9800766A SE9800766D0 (en) 1998-03-09 1998-03-09 formulation
SE9800766-9 1998-03-09

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US11071782B2 (en) 2016-04-20 2021-07-27 Coherus Biosciences, Inc. Method of filling a container with no headspace
US11229702B1 (en) 2015-10-28 2022-01-25 Coherus Biosciences, Inc. High concentration formulations of adalimumab

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US10233247B2 (en) 1999-04-09 2019-03-19 Kyowa Hakko Kirin Co., Ltd Method of modulating the activity of functional immune molecules
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