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WO2015009052A1 - Protéine de fusion de fc hybride d'immunoglobuline et d'enzyme - Google Patents

Protéine de fusion de fc hybride d'immunoglobuline et d'enzyme Download PDF

Info

Publication number
WO2015009052A1
WO2015009052A1 PCT/KR2014/006432 KR2014006432W WO2015009052A1 WO 2015009052 A1 WO2015009052 A1 WO 2015009052A1 KR 2014006432 W KR2014006432 W KR 2014006432W WO 2015009052 A1 WO2015009052 A1 WO 2015009052A1
Authority
WO
WIPO (PCT)
Prior art keywords
fusion protein
disease
enzyme
type
alpha
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/KR2014/006432
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English (en)
Korean (ko)
Inventor
고종희
김성범
권혜미
정혜윤
권혁상
강재훈
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ildong Pharmaceutical Co Ltd
Original Assignee
Ildong Pharmaceutical Co Ltd
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
Application filed by Ildong Pharmaceutical Co Ltd filed Critical Ildong Pharmaceutical Co Ltd
Publication of WO2015009052A1 publication Critical patent/WO2015009052A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2465—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1) acting on alpha-galactose-glycoside bonds, e.g. alpha-galactosidase (3.2.1.22)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/06—Sulfuric ester hydrolases (3.1.6)
    • C12Y301/06013—Iduronate-2-sulfatase (3.1.6.13)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01022—Alpha-galactosidase (3.2.1.22)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • the present invention provides a use for the preparation of a lysosomal accumulation disease of the lysosomal accumulation disease enzyme and the human immunoglobulin hybrid Fc conjugated with the amino acid sequence of SEQ ID NO: 4 for the prevention or treatment of lysosomal accumulation disease to provide.
  • the present invention is characterized by administering an fusion protein conjugated with a lysosomal accumulation disease enzyme and a human immunoglobulin hybrid Fc represented by the amino acid sequence of SEQ ID NO: 4 to an individual in need thereof.
  • the present invention will be described in detail.
  • alpha-galactosidase A and the hybrid Fc are conjugated is not limited thereto, but may be represented by the amino acid sequence of SEQ ID NO.
  • the fusion protein conjugated with the glucocerebrosidase and the hybrid Fc is not limited thereto, but may be represented by the amino acid sequence of SEQ ID NO.
  • the fusion protein to which the duronate-2-sulfatase and the hybrid Fc are conjugated is not limited thereto, but may be represented by the amino acid sequence of SEQ ID NO: 8.
  • a protein in which alpha ⁇ galactosidase A, glucocerebrosidase and eduronate-2-sulfate was fused with a hybrid Fc was gradated.
  • alpha-galactosidase A-hybrid Fc shows the nucleotide sequence of SEQ ID NO: 2 and amino acid sequence of SEQ ID NO: 3
  • glucocerebrosides-hybrid Fc shows the nucleotide sequence of SEQ ID NO: 5
  • the amino acid sequence of 6 it was confirmed that the eduronate-2-sulfatase-hybrid Fc has the nucleotide sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8.
  • Vectors of the present invention include, but are not limited to, polsmid vectors, cosmid vectors, bacteriophage vectors, and viral vectors.
  • carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose, glycols, and the like, and may further include stabilizers and preservatives.
  • Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-parabens and chlorobutanol.
  • Other pharmaceutically acceptable carriers may be referred to those described in the following references (Remington's Pharmaceutical Sciences, 19th ed. , Mack Publishing Company, East on, PA, 1995).
  • the pharmaceutical composition for preventing or treating the lysosomal accumulation disease of the present invention can be administered to any mammal, including humans.
  • compositions of the present invention are formulated using powders, granules, tablets, pills, sugar tablets, capsulants, liquids, gels, syrups, slurries, suspensions, etc. using methods known in the art.
  • oral formulations can be obtained by tablets or dragees by combining the active ingredients with solid excipients and then grinding them, adding suitable auxiliaries and processing them into granular mixtures.
  • suitable excipients include sugars and corn starch, wheat starch, rice starch and potato starch, including lactose, dextrose, sucrose, solbi, manny, xili, erythritol and malty.
  • the present invention provides a use for the prevention or treatment of Hunter syndrome of the fusion protein conjugated with the duronate-2-sulfatase and the human immunoglobulin hybrid Fc represented by the amino acid sequence of SEQ ID NO: 4.
  • the present invention provides a method for the prevention of lysosomal accumulation disease, characterized in that the lysosomal accumulation disease enzyme and the human immunoglobulin hybrid Fc conjugated with the amino acid sequence of SEQ ID NO: 4 are conjugated to an individual in need thereof. Provide a method of treatment.
  • the fusion protein of the present invention may be administered as it is or may be prepared and administered in various formulations as described above, preferably until a desired effect is obtained, i.e., until a prophylactic or therapeutic effect of lysosome accumulation disease is obtained Can be.
  • the fusion protein of the present invention can be administered by various routes according to methods known in the art. Oral or parenteral, such as oral, intramuscular, intravenous, intradermal, intraarterial, intramedullary, intradural, intraperitoneal, intranasal, intravaginal, intrarectal, sublingual or subcutaneous, gastrointestinal tract, mucosa or hop It can be administered by the group.
  • Fusion proteins conjugated with the enzyme of the present invention and the human immunoglobulin hybrid Fc represented by the amino acid sequence of SEQ ID NO: 4 maintain the enzyme activity while Regardless of the law, half-life and bioavailability have been prolonged over commercially available enzyme therapeutics, and the specific long-term distribution efficiency associated with the etiology is excellent, preventing or treating diseases caused by various types of enzyme deficiencies in the body, including lysosomal accumulation diseases. It is effective to prepare.
  • Figure 2 is a result confirmed by Western blotting (westernbloUing, the same method as in Example 3) that the alpha-galactosidase A-Hybrid Fc fusion protein of the present invention is expressed in the cell.
  • the fusion protein is normally expressed in cells and secreted into the medium. Selected cells were treated with various concentrations of methotrexate (MTX), and every 3-4 days ' cells were selected while changing medium and reached 1-cel l / wel l in 96-wel l piate after reaching normal cell growth rate. Dispense and incubate until colony is formed. After about two weeks, when colony was formed, the medium was recovered, and cell lines with high expression level were selected using a dot-blot system (Bio-rad).
  • MTX methotrexate
  • the protein expressed in each cell line was verified by western blotting.
  • a medium sample of the protein expressed in the Eppendorf tube was added, a loading dye was added to IX, and a 63 ⁇ 4 SDS-PAGE gel was mounted in a running ' tank and electrophoresed between 80 and 100 V. Proteins were transferred to PVDF membrane using Trans-Blot SD Semi Dry Transfer Cell (Bio-Rad). After transfer, the membrane was blocked for 10 minutes at room temperature using TBST containing 5% skim milk powder.
  • 4-methyhimbel liferyl- ⁇ -El-gal act opyranoside (Sigma) was used as a substrate to compare the substrate resolution of Fabrazyme (Genzyme) and alpha-galactosidase A-Hybrid Fc fusion protein expressed in the present invention. It was. Dilute the Fabrazyme and Alpha 2-galactosides A ⁇ hybrid Fc fusion protein (Gal-hyFc) with '' assay buffer (50 mM sodium citrate, 50 mM NaCl, pH4), respectively, and use the 4-methylumbelliferyl-aD-galactopyranoside assay buffer. Dilute the protein and substrate 50 ⁇ by diluting it into 800 ⁇ concentration in black 96-well piate.
  • Gal-hyFc protein expressed in the present invention which remains in plasma by taking a blood sample before administration, 5, 10, 20, 30, 60, 120, 240, 360, 480, 1440, 2880, 4320, 8640 minutes after administration The concentration and activity of the was measured. Protein concentration was measured using ELISA. Affinity purified Human IG capture antibody (Bethyl Laboratories, Inc.) diluted in the coating solution was added 100 N each to Nunc 96 well plates and allowed to stand at room temperature for 1 hour.
  • Antibody-coated plates were washed five times with TBST (Tr is—Buffered Saline Tween-20) wash solution, followed by adding 200% of blocking buffer with 1% BSA (Bovine serum albumin) per well for 30 minutes at room temperature. Replied at. The plate was washed five times with TBST washing solution, and then 100 parts of plasma samples diluted in half or 0 to 500 pg / ml or appropriate proportions were added and allowed to stand at room temperature for 1 hour. Wash 5 times with TBST washing solution and dilute HRP Conjugated Human IgG Detection Antibody to 100 ⁇ for each well.
  • TBST Tetr is—Buffered Saline Tween-20 wash solution
  • BSA Bovine serum albumin
  • the shoots were allowed to react for 1 hour at room temperature, and the plates were washed 5 times with TBST washing solution, and then mixed with TMB substrate solution per well for 15 minutes at dark room temperature. And the absorbance was measured with a late reader at 450nm.
  • the protein concentration was calculated by multiplying the amount calculated from the ELISA by the dilution factor to calculate the protein concentration in plasma.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention porte sur une protéine de fusion de Fc d'immunoglobuline hybride et d'enzyme et, plus particulièrement, sur une protéine de fusion dans laquelle une enzyme est liée à un Fc hybride d'immunoglobuline humaine représentée par une séquence d'acides aminés de SEQ ID No : 4 et sur un procédé pour la production de celle-ci. La protéine de fusion dans laquelle une enzyme est liée à un Fc hybride d'immunoglobuline humaine représentée par une séquence d'acides aminés de SEQ ID No : 4 selon la présente invention conserve l'activité de l'enzyme, a une demi-vie et une biodisponibilité prolongées par comparaison avec des agents de traitement enzymatiques du marché indépendamment du procédé d'administration et présente une excellente efficacité de distribution dans des organes particuliers en association avec des causes de maladies et donc est efficace en prévention de maladies provoquées par la carence en diverses enzymes dans le corps, notamment une maladie liée à l'accumulation lysosomale, ou production d'agents pour le traitement des maladies.
PCT/KR2014/006432 2013-07-16 2014-07-16 Protéine de fusion de fc hybride d'immunoglobuline et d'enzyme Ceased WO2015009052A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2013-0083860 2013-07-16
KR20130083860 2013-07-16

Publications (1)

Publication Number Publication Date
WO2015009052A1 true WO2015009052A1 (fr) 2015-01-22

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20190005803A (ko) * 2017-07-07 2019-01-16 한미약품 주식회사 신규 치료학적 효소 융합단백질 및 이의 용도
WO2019022563A3 (fr) * 2017-07-28 2019-04-11 한미약품 주식회사 Conjugué d'iduronate-2-sulfatase
WO2019070577A1 (fr) * 2017-10-02 2019-04-11 Denali Therapeutics Inc. Protéines de fusion comprenant des enzymes d'enzymothérapie substitutive
KR20190076909A (ko) * 2017-12-22 2019-07-02 한미약품 주식회사 신규한 구조를 갖는 치료학적 효소 융합단백질 및 이의 용도
WO2019190291A1 (fr) * 2018-03-30 2019-10-03 한미약품 주식회사 Conjugué d'enzyme thérapeutique persistant ciblant le cerveau
WO2019190293A1 (fr) * 2018-03-30 2019-10-03 한미약품 주식회사 Conjugué de protéine à action prolongée ciblant le cerveau, son procédé de préparation et composition le contenant
WO2020206320A1 (fr) * 2019-04-03 2020-10-08 Denali Therapeutics Inc. Formulations de molécules protéiques comprenant de l'iduronate 2-sulfatase
WO2020231199A1 (fr) 2019-05-14 2020-11-19 주식회사 프로젠 Nouvelle protéine de fusion fc d'immunoglobuline modifiée et utilisation associée
WO2021006605A1 (fr) 2019-07-08 2021-01-14 주식회사 프로젠 Nouvelle protéine de variant d'il-10 et utilisation de celle-ci
US10918736B2 (en) 2016-01-29 2021-02-16 Hanmi Pharm. Co., Ltd Conjugate of therapeutic enzymes
WO2022103221A1 (fr) * 2020-11-13 2022-05-19 한미약품 주식회사 Utilisation d'une protéine de fusion d'une enzyme thérapeutique pour prévenir et traiter une maladie rénale provoquée par la maladie de fabry ou l'accompagnant
WO2022103220A1 (fr) * 2020-11-13 2022-05-19 한미약품 주식회사 Utilisation d'une protéine de fusion d'enzyme thérapeutique dans la prévention et le traitement de la neuropathie attribuée à ou associée à la maladie de fabry
WO2023177159A1 (fr) * 2022-03-15 2023-09-21 Green Cross Corporation Formulation lyophilisée comprenant une protéine de fusion comprenant l'a-galactosidase a
WO2023177158A1 (fr) * 2022-03-15 2023-09-21 Green Cross Corporation FORMULATION LIQUIDE COMPRENANT UNE PROTÉINE DE FUSION COMPRENANT DE LA α-GALACTOSIDASE A
WO2023198661A1 (fr) * 2022-04-12 2023-10-19 F. Hoffmann-La Roche Ag Protéines de fusion ciblées sur le système nerveux central
WO2025058333A1 (fr) * 2023-09-14 2025-03-20 Green Cross Corporation NOUVELLE FORMULATION LYOPHILISÉE CONTENANT UNE PROTÉINE DE FUSION α-GALACTOSIDASE A

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JP7356222B2 (ja) 2016-01-29 2023-10-04 ハンミ ファーマシューティカル カンパニー リミテッド 治療学的酵素類の結合体
US10918736B2 (en) 2016-01-29 2021-02-16 Hanmi Pharm. Co., Ltd Conjugate of therapeutic enzymes
JP2022046524A (ja) * 2016-01-29 2022-03-23 ハンミ ファーマシューティカル カンパニー リミテッド 治療学的酵素類の結合体
KR20190005803A (ko) * 2017-07-07 2019-01-16 한미약품 주식회사 신규 치료학적 효소 융합단백질 및 이의 용도
IL271837B1 (en) * 2017-07-07 2023-09-01 Hanmi Pharm Ind Co Ltd A new medical fusion protein with an enzyme and its uses
TWI832818B (zh) * 2017-07-07 2024-02-21 南韓商韓美藥品股份有限公司 新穎的治療性酵素融合蛋白及其用途
IL271837B2 (en) * 2017-07-07 2024-01-01 Hanmi Pharm Ind Co Ltd Novel therapeutic enzyme fusion protein and use thereof
CN111094559A (zh) * 2017-07-07 2020-05-01 韩美药品株式会社 新型治疗酶融合蛋白及其用途
EP3650539A4 (fr) * 2017-07-07 2021-08-18 Hanmi Pharm. Co., Ltd. Nouvelle protéine de fusion enzymatique thérapeutique et utilisation associée
JP7697784B2 (ja) 2017-07-07 2025-06-24 ハンミ ファーマシューティカル カンパニー リミテッド 新規治療学的酵素融合タンパク質及びその用途
CN111094559B (zh) * 2017-07-07 2024-12-10 韩美药品株式会社 新型治疗酶融合蛋白及其用途
JP2020530283A (ja) * 2017-07-07 2020-10-22 ハンミ ファーマシューティカル カンパニー リミテッド 新規治療学的酵素融合タンパク質及びその用途
KR102556411B1 (ko) * 2017-07-07 2023-07-18 한미약품 주식회사 신규 치료학적 효소 융합단백질 및 이의 용도
KR20220098092A (ko) * 2017-07-07 2022-07-11 한미약품 주식회사 신규 치료학적 효소 융합단백질 및 이의 용도
KR102413686B1 (ko) * 2017-07-07 2022-06-28 한미약품 주식회사 신규 치료학적 효소 융합단백질 및 이의 용도
WO2019009684A3 (fr) * 2017-07-07 2019-03-28 한미약품 주식회사 Nouvelle protéine de fusion enzymatique thérapeutique et utilisation associée
WO2019022563A3 (fr) * 2017-07-28 2019-04-11 한미약품 주식회사 Conjugué d'iduronate-2-sulfatase
JP2023179600A (ja) * 2017-10-02 2023-12-19 デナリ セラピューティクス インコーポレイテッド 酵素補充療法用酵素を含む融合タンパク質
US10870837B2 (en) 2017-10-02 2020-12-22 Denali Therapeutics Inc. Fusion proteins comprising enzyme replacement therapy enzymes
EP3904389A1 (fr) * 2017-10-02 2021-11-03 Denali Therapeutics Inc. Protéines de fusion comprenant des enzymes d'enzymothérapie substitutive
CN111278859A (zh) * 2017-10-02 2020-06-12 戴纳立制药公司 包含酶替代疗法酶的融合蛋白
JP2021500857A (ja) * 2017-10-02 2021-01-14 デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 酵素補充療法用酵素を含む融合タンパク質
AU2018345303B2 (en) * 2017-10-02 2025-09-18 Denali Therapeutics Inc. Fusion proteins comprising enzyme replacement therapy enzymes
IL273439B2 (en) * 2017-10-02 2025-10-01 Denali Therapeutics Inc Fusion proteins involving enzyme replacement in enzyme therapy
WO2019070577A1 (fr) * 2017-10-02 2019-04-11 Denali Therapeutics Inc. Protéines de fusion comprenant des enzymes d'enzymothérapie substitutive
IL273439B1 (en) * 2017-10-02 2025-06-01 Denali Therapeutics Inc Fusion proteins comprising enzyme replacement therapy enzymes
US11866742B2 (en) 2017-10-02 2024-01-09 Denali Therapeutics Inc. Fusion proteins comprising enzyme replacement therapy enzymes
US12435328B2 (en) 2017-12-22 2025-10-07 Hanmi Pharm. Co., Ltd. Therapeutic enzyme fusion protein having a novel structure and use thereof
KR20190076909A (ko) * 2017-12-22 2019-07-02 한미약품 주식회사 신규한 구조를 갖는 치료학적 효소 융합단백질 및 이의 용도
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JP7715635B2 (ja) 2019-04-03 2025-07-30 デナリ セラピューティクス インコーポレイテッド イズロン酸２－スルファターゼを含むタンパク質分子の製剤
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WO2023177159A1 (fr) * 2022-03-15 2023-09-21 Green Cross Corporation Formulation lyophilisée comprenant une protéine de fusion comprenant l'a-galactosidase a
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