# US 12,178,858 B2 · Lyophilized preparation

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- Number: US 12,178,858 B2
- Document ID: US12178858B2
- Status: Granted
- Kind: B2
- Application number: 17/181,066
- Filed: 2021-02-22
- Published: 2021-06-24
- Granted: 2024-12-31
- Earliest claimed: 2016-12-28
- Assignees: JCR Pharmaceuticals Co., Ltd.
- Applicants: JCR Pharmaceuticals Co., Ltd.
- Inventors: Hidehito Yasukawa; Yuka Yamaguchi; Shinji Okabe
- Web page: https://patentgrep.com/patent/US12178858B2

## CPC

- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61P 25/00: Drugs for disorders of the nervous system
- 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)}
- A61K 39/39591: {Stabilisation, fragmentation}
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- C07K 14/70503: {Immunoglobulin superfamily}
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- C07K 16/2881: {against CD71}
- C12Y 301/06013: Iduronate-2-sulfatase (3.1.6.13)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/00: Fusion polypeptide
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- 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)
- C12Y: ENZYMES

## Abstract

[Problem] To provide a pharmaceutical composition containing a fusion protein comprising an antibody and a lysosomal enzyme as an active ingredient, which is stable enough to permit its distribution to the market. [Solution] A lyophilized formulation containing; a fusion protein comprising an antibody and a lysosomal enzyme as an active ingredient, and further containing a neutral salt, a disaccharide, a nonionic surfactant, and a buffer. Such a lyophilized formulation includes, for example, as an active ingredient, a fusion protein comprising an anti-transferrin receptor antibody and human iduronate-2-sulfatase, and further containing sodium chloride as the neutral salt, sucrose as the disaccharide, poloxamer as the nonionic surfactant, and phosphate buffer as the buffer.

## Claims

### Claim 1

A lyophilized formulation comprising;
a fusion protein including an anti-human transferrin receptor antibody (anti-hTfR antibody) and human iduronate-2-sulfatase, as an active ingredient, and further
sodium chloride, sucrose, polyoxyethylene (160) polyoxypropylene (30) glycol, and phosphate buffer,
wherein the amounts of the sodium chloride, the sucrose, and the polyoxyethylene (160) polyoxypropylene (30) glycol is 0.16 (w/w), 15 (w/w), and 0.065 (w/w), respectively, relative to the amount of the fusion protein, and the pH is 5.5 to 7.5 when dissolved in pure water.

### Claim 2 (depends on 1)

The lyophilized formulation according to claim 1, wherein the pH is 6.5 when dissolved in pure water.

### Claim 3 (depends on 1)

The lyophilized formulation according to claim 1, wherein the fusion protein is a fusion protein in which the human iduronate-2-sulfatase is linked to the C-terminus or N-terminus of the light chain or the heavy chain of the antibody by a peptide bond.

### Claim 4 (depends on 1)

The lyophilized formulation according to claim 1, wherein the fusion protein is a fusion protein in which the human iduronate-2-sulfatase is linked to the C-terminus of the heavy chain of the antibody by a peptide bond.

### Claim 5 (depends on 1)

The lyophilized formulation according to claim 1, wherein the fusion protein is a fusion protein in which the human iduronate-2-sulfatase is linked to the C-terminus or N-terminus of the light chain or the heavy chain of the antibody via a linker including one or more of amino acids.

### Claim 6 (depends on 1)

The lyophilized formulation according to claim 1, wherein the fusion protein is a fusion protein in which the human iduronate-2-sulfatase is linked to the C-terminus of the heavy chain of the antibody via a linker including one or more of amino acids.

### Claim 7 (depends on 5)

The lyophilized formulation according to claim 5, wherein the linker includes the amino acid sequence of Gly-Ser.

### Claim 8 (depends on 1)

The lyophilized formulation according to claim 1, wherein the anti-hTfR antibody is a humanized anti-hTfR antibody.

### Claim 9 (depends on 8)

The lyophilized formulation according to claim 8,
wherein the light chain of the humanized anti-hTfR antibody has the amino acid sequence set forth as SEQ ID NO: 6, and wherein the heavy chain of the humanized anti-hTfR antibody is linked, on the C-terminus of the heavy chain and via a linker sequence of Gly-Ser, to the human iduronate-2-sulfatase, and the whole linked heavy chain has the amino acid sequence set forth as SEQ ID NO:17.

### Claim 10 (depends on 1)

The lyophilized formulation according to claim 1, sealed in a container formed of a borosilicate glass or a hydrophobic resin.

### Claim 11 (depends on 10)

The lyophilized formulation according to claim 10, wherein the container is formed by a cycloolefin copolymer, a ring-opened polymer of cycloolefin, or a hydrogenated ring-opened polymer of cycloolefin.