# US 11,433,029 B2 · Formulation of an antibody and use thereof

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- Number: US 11,433,029 B2
- Document ID: US11433029B2
- Status: Granted
- Kind: B2
- Application number: 14/773,478
- Filed: 2014-03-17
- Published: 2016-01-28
- Granted: 2022-09-06
- Earliest claimed: 2013-03-15
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: Markus Rast; Wolfgang Ise; Gerhard Becker; Peter Skufca; Henning Gieseler
- Web page: https://patentgrep.com/patent/US11433029B2

## CPC

- 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)}
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/20: for DNA viruses
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- C07K 16/2887: {against CD20}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- 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
- 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)

## Abstract

The present invention provides a method for preparation of a lyophilized formulation of an anti-CD 20 antibody as well as to a lyophilized formulation of an anti-CD 20 antibody, comprising an anti-CD 20 antibody and having a residual moisture content in the range of 1% to 10%. The present invention also relates to the reconstituted formulation obtained by the method described herein, the use of said antibody formulation as a medicament, the use of the lyophilized formulation for the preparation of a medicament and a method of treating a patient.

## Claims

### Claim 1

A method for providing a lyophilized formulation of an anti-CD 20 antibody, comprising the steps of:
I) providing a solution comprising the anti-CD 20 antibody,
II) freezing the antibody solution and,
III) subjecting the antibody solution to at least one drying step at a shelf temperature of −10° C. to 30° C., in order to obtain the lyophilized formulation, wherein the lyophilized formulation has a residual moisture content in the range of about 1.5% to 1.8%.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the antibody solution is subjected to one drying step.

### Claim 3 (depends on 1)

The method according to claim 1, further including subjecting the antibody solution to a second drying step, wherein the shelf temperature used in the second drying step is lower than the shelf temperature used in the first drying step.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the shelf temperature used in the second drying step is at least 2° C. lower, optionally at least 3° C. lower than the shelf temperature used in the first drying step.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the shelf temperature used in the first drying step is 8° C. and/or the shelf temperature used in the second drying step is 5° C.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the solution provided in step (I) comprises a buffering agent, optionally a buffering agent comprising histidine or phosphate.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the solution provided in step (I) comprises a tonicity modifying agent, optionally sucrose.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the solution provided in step (I) comprises a surfactant, optionally a nonionic surfactant.

### Claim 9 (depends on 1)

The method according to claim 1, wherein the solution provided in step (I) has a pH value in the range of 5.0 to 7.0, optionally a pH value of 5.5±0.3.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the solution provided in step (I) comprises
a) at least 40 mg/g anti-CD 20 antibody,
b) 5-15 mM histidine,
c) 100-150 mM sucrose,
d) 0.05-0.5 mg/g polysorbate 20; and
wherein the solution provided in step (I) has a pH value of 5.5±0.3.

### Claim 11 (depends on 1)

The method according to claim 1, wherein the anti-CD 20 antibody is Veltuzumab or a fragment thereof.

### Claim 12 (depends on 1)

A method for providing a liquid formulation of an anti-CD 20 antibody, comprising providing a lyophilized formulation according to the method of claim 1 and subsequently performing a step IV) of reconstituting the lyophilized formulation.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the liquid formulation obtained in step IV) comprises
a) at least 80 mg/mL anti-CD 20 antibody,
b) 10-40 mM buffering agent, optionally a buffering agent comprising histidine,
c) 200-400 mM tonicity modifying agent, optionally sucrose,
d) 0.2-0.5 mg/mL surfactant, optionally polysorbate 20; and
has a pH value of 5.5±0.3.

### Claim 14

A lyophilized formulation of an anti-CD 20 antibody, obtained by a method comprising the steps of:
I) providing a solution comprising the anti-CD 20 antibody,
II) freezing the antibody solution, and
III) subjecting the antibody solution to at least two drying steps, with a first drying step at a shelf temperature of −10° C. to 30° C., and a second drying step,
wherein the anti-CD 20 antibody is veltuzumab or an antigen-binding fragment thereof,
wherein the first drying step and the second drying step each changes the temperature to the shelf temperature at a rate of 1° C. per minute,
wherein the second drying step is at a shelf temperature lower than the shelf temperature of the first drying step,
wherein the formulation has a residual moisture content in the range of about 1.5% to 1.8%,
and wherein the formulation exhibits increased stability and reduced tendency to form aggregates during storage, as determined by measurement of particulate contamination, or by HP-SEC (high performance size-exclusion chromatography) monomer %.

### Claim 15 (depends on 14)

The lyophilized formulation according to claim 14, further comprising a buffering agent, optionally a buffering agent comprising histidine or phosphate.

### Claim 16 (depends on 14)

The lyophilized formulation according to claim 14, further comprising a tonicity modifying agent, optionally sucrose.

### Claim 17 (depends on 14)

The lyophilized formulation according to claim 14, further comprising a surfactant, optionally a nonionic surfactant.

### Claim 18 (depends on 14)

The lyophilized formulation of claim 14, wherein the residual moisture content is about 1.5%.

### Claim 19 (depends on 14)

The lyophilized formulation according to claim 14, wherein the shelf temperature of the second drying step is at least 2° C. lower than the shelf temperature of the first drying step.

### Claim 20 (depends on 14)

A reconstituted formulation of an anti-CD 20 antibody, obtained by a method comprising reconstituting the lyophilized formulation of claim 14.

### Claim 21 (depends on 19)

A reconstituted formulation of an anti-CD 20 antibody, obtained by a method comprising reconstituting the lyophilized formulation of claim 19.

### Claim 22 (depends on 21)

A medicament comprising the reconstituted formulation according to claim 21.

### Claim 23 (depends on 22)

The medicament according to claim 22, wherein the medicament is formulated for parenteral administration, optionally for subcutaneous administration.

### Claim 24 (depends on 19)

The lyophilized formulation according to claim 19, wherein the shelf temperature of the first drying step is about 8° C., and the shelf temperature of the second drying step is about 5° C.

### Claim 25 (depends on 20)

A medicament comprising the reconstituted formulation according to claim 20.

### Claim 26 (depends on 25)

The medicament according to claim 25, wherein the medicament is formulated for parenteral administration, optionally for subcutaneous administration.

### Claim 27 (depends on 21)

The reconstituted formulation of claim 21, wherein the lyophilized formulation of step III) has a residual moisture content of about 1.5%.

### Claim 28 (depends on 25)

The medicament according to claim 25, wherein the lyophilized formulation has a residual moisture content of about 1.5%.

### Claim 29 (depends on 26)

The medicament according to claim 26, where in the lyophilized formulation has a residual moisture content of about 1.5%.