WO2018166468A1 - Protéine de fusion immunitaire à action prolongée de type igg et son utilisation - Google Patents

Protéine de fusion immunitaire à action prolongée de type igg et son utilisation Download PDF

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WO2018166468A1
WO2018166468A1 PCT/CN2018/078951 CN2018078951W WO2018166468A1 WO 2018166468 A1 WO2018166468 A1 WO 2018166468A1 CN 2018078951 W CN2018078951 W CN 2018078951W WO 2018166468 A1 WO2018166468 A1 WO 2018166468A1
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amino acid
sequence listing
molecule
acid sequence
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胡品良
何芸
邹敬
洪伟东
宋凌云
杨泽荣
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北京比洋生物技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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

  • Constructing mutants by constructing mutants to extend the half-life of the protein commonly used methods are: 1. Increase the degree of glycosylation of protein drugs, so as to form a protective effect on the surface of protein drugs, hinder the degradation of protein drugs by proteases, and increase protein stability. At the same time, the molecular weight of the protein drug is increased, and glomerular filtration is reduced.
  • Drugs that have been successfully developed and marketed include recombinant human EPO mutants (Aranesp from Amgen) and recombinant human insulin mutants (Lantus from Aventis).
  • Aranesp uses site-directed mutagenesis to increase the number of N-linked oligosaccharides from 3 to 5, increasing the molecular weight from 30 kDa to 50 kDa, and extending the half-life from 4-13 h to an average of 49 h. 2.
  • the time to release the free drug is prolonged by forming a sustained release microprecipitate.
  • Lantus is a mutant of recombinant human insulin expressed from E. coli K12 strain, which mutates Asp to Gly at the 21st position of the human insulin A chain; and adds two Arg at the 30th position of the B-chain carbon end.
  • the isoelectric point PI of insulin changed from the original pH 4.0 to pH 6.7.
  • PEGylation modified PEGylation ie polyethylene (PEG) covalently modified protein.
  • PEGylated protein drugs mainly reduce the molecular weight of proteins, reduce the filtration of drugs from the renal tubules, and PEG can act as a barrier to block the antigenic determinants on the surface of protein molecules, reduce immunogenicity, reduce the clearance rate in vivo, and the barrier function of PEG can also protect proteins. It is not easily hydrolyzed by proteases. These characteristics of PEGylation are beneficial to prolong the half-life of protein drugs.
  • PEGylated protein drugs such as PEGylated asparaginase (Enzon's Oncaspar), PEGylated IFN ⁇ 2b (Schering's PEGIntron), PEGylated IFN ⁇ 2a (Roche's Pegasys) and PEGylated G - CSF (Neulasta of Amgen).
  • Serum albumin fusion human serum, albumin is a single-chain aglycosylated globular protein with 585 amino acid residues, molecular weight 65kDa, most therapeutic proteins and peptides generally have a short half-life. HSA has a serum half-life of up to 19 days. The results of clinical trials showed that the average half-life of Albuferon ⁇ (HSA/IFN ⁇ fusion protein) was 148 hours, which was longer than the average half-life of Pegasys (80-140 hours) and the average half-life of PEGIntron 40 hours (22-60 hours).
  • Albutropin is a protein expressed by fusion of the HSA gene and the recombinant human growth hormone (rHGH) gene. In monkeys, subcutaneous injection of albutropin (0.3 mg/kg) and HGH (0.3 mg/kg) resulted in a 6-fold increase in half-life and a 8-fold slower clearance.
  • a fusion protein prepared by human Fc The fusion protein prepared by albumin fusion protein and Fc mainly enhances the biological half-life of the drug through two mechanisms, one is to increase the molecular weight of the drug, so that it is not easily filtered by the renal tubule; the other is through the neonatal Fc Binding of the neonatal Fc receptor (FcRn) protects the target protein from clearance in the blood (Rath T, Baker K, Dumont JA, et al. Crit Rev Biotechnol. 2015 Jun; 35(2): 235-54).
  • FcRn neonatal Fc Binding of the neonatal Fc receptor
  • the FcRn receptor encoded by the fcgrt gene, also known as the Brambell receptor, is an MHC class I-like receptor molecule that forms a heterodimer with a non-covalent bond with ⁇ 2 m microglobulin.
  • the binding of the FcRn receptor to albumin and immunoglobulin is strictly pH dependent, and FcRn does not bind to albumin and immunoglobulin under physiological conditions (pH 7.4).
  • albumin and immunoglobulin are endocytosed into the cells through the pinocytosis pathway, in acidic lysosomes (pH 6.0-6.5), the affinity of FcRn with albumin and immunoglobulin is increased to form a complex, FcRn protection.
  • Albumin and immunoglobulin are not degraded and release albumin and immunoglobulin out of the cell through the membranous circulation.
  • the binding of albumin and immunoglobulin to FcRn protects them from being metabolized, extending their biological half-life.
  • the present invention designs an IgG-like immunological fusion protein, which can effectively prolong the biological half-life of the protein drug (effector molecule), which is far better than the similar Fc immunofusion protein.
  • Heavy chain class may be an IgG1, IgG2 and IgG4, the heavy chain comprises a constant region (C H 1, C H 2 and C H 3).
  • the amino acid sequence of the linker peptide may be selected from any one of the following: AKTTPKLEEGEFSEAR (SEQ ID NO: 1); AKTTPKLEEGEFSEARV (SEQ ID NO: 2); AKTTPKLGG (SEQ ID NO: 3); SAKTTPKLGG (SEQ ID NO: 4); SAKTTP (SEQ ID NO: 5); RADAAP (sequence) 6); RADAAPTVS (sequence 7); RADAAAAGGPGS (sequence 8); RADAAAA (sequence 9); SAKTTPKLEEGEFSEARV (sequence 10); ADAAP (sequence 11); DAAPTVSIFPP (sequence 12); TVAAP (sequence 13); TVAAPSVFIFPP (sequence 14) ;QPKAAP (sequence 15); QPKAAPSVTLFPP (sequence 16); AKTTPP (sequence 17); AKTTPPSVTPLAP (se
  • Mode 1 The effector molecule is respectively linked to the two heavy chains of the constant region of the IgG antibody and the N-terminus of the two light chains by the linker peptide; the molecular formula is named: (EL) 2 (EH) 2 , E is Effector molecule. E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
  • Mode 4 The effector molecule is linked to the C-terminus of two light chains of the IgG antibody constant region through the linker peptide, and no heavy chain is attached; the molecular formula is named: (LE) 2 H 2 , and E is an effector molecule.
  • -E represents a C-terminal linkage, L is a light chain, and H is a heavy chain.
  • Mode 5 The effector molecule is linked to the N-terminus of two heavy chains of the IgG antibody constant region through the linker peptide, and no light chain is attached; the molecular formula is named: L 2 (EH) 2 , and E is an effector molecule.
  • E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
  • Mode 6 The effector molecule is linked to the N-terminus of the two heavy chains of the IgG antibody constant region and the C-terminus of the two light chains by the linker peptide, respectively.
  • the molecular formula is named: (LE) 2 (EH) 2 , E is an effector molecule, -E represents a C-terminal linkage, E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
  • Mode 8 The effector molecule is respectively linked to the N-terminus and the two heavy-chain C-termini of two light chains of the IgG antibody constant region by the linker peptide; the molecular formula is named: (EL) 2 (HE) 2 , E is an effector molecule, -E represents a C-terminal linkage, E- represents an N-terminal linkage, L is a light chain, and H is a heavy chain.
  • FIG. 1 See Figure 1 for a schematic diagram of the structure of the IgG-like immunological fusion protein formed by the above eight ligation methods.
  • the targeting molecule for treating the autoimmune disease may be specifically selected from any one of the following: Tumor necrosis factor (TNF- ⁇ ), IL-1, IL-4, IL-5, IL-8, Molecules such as IL-13, IL-17, IL-23, CD80, CD86, CD2, CD110, CD257, and B lymphocyte stimulator (BLyS); mainly by inhibiting inflammatory mediators or by impeding lymphocyte surface receptors Somatic molecules inhibit the activation of lymphocytes.
  • TNF- ⁇ Tumor necrosis factor
  • IL-1 IL-1
  • IL-4 IL-5
  • IL-8 Molecules
  • Molecules such as IL-13, IL-17, IL-23, CD80, CD86, CD2, CD110, CD257, and B lymphocyte stimulator (BLyS)
  • B lymphocyte stimulator mainly by inhibiting inflammatory mediators or by impeding lymphocyte surface receptors Somatic molecules inhibit the activation of lymphocytes.
  • the target molecule for tumor treatment may be specifically selected from any one of the following: vascular endothelial growth factor A (VEGF-A), Fas ligand (FasL), growth differentiation factor 2 (Growth) Differentiation molecules 2, GDF-2), Wnt, Bone morphogenetic protein 11, BMP-11, and activin A (Activin A); mainly by inhibiting tumor angiogenesis and promoting tumor cell apoptosis, Inhibition of tumor cell growth and metastasis to achieve the purpose of treating tumors.
  • VEGF-A vascular endothelial growth factor A
  • Fas ligand Fas ligand
  • GDF-2 growth differentiation factor 2
  • Wnt Wnt
  • Bone morphogenetic protein 11 Bone morphogenetic protein 11
  • activin A activin A
  • the targeting molecule of the endocrine therapy may specifically be a molecule such as a growth hormone receptor (GHR) or a parathyroid hormone receptor (Parathyroid Hormone receptor). It exerts physiological effects through growth hormone and parathyroid hormone and its analogues for the treatment of diseases such as short stature, burns, and osteoporosis.
  • GHR growth hormone receptor
  • Paraathyroid Hormone receptor parathyroid Hormone receptor
  • the disease may be various diseases such as diabetes, autoimmune diseases, tumors or endocrine-related diseases.
  • the BY19.3L coding gene was ligated to the glutamine synthetase high-efficiency expression vector with double expression cassette by XhoI-EcoRI double digestion (see Patent Application No.: 201410441296.0); the BY19.3H coding gene was cloned by XbaI-SaII, respectively.
  • the glutamine synthetase high-efficiency expression vector (the recombinant expression vector was verified and verified by sequencing) to the double expression cassette of the BY19.3L-encoded light chain gene, and the expressed IgG-like fusion protein was named BY19.3, and the molecular formula L 2 (HE) 2 .
  • the high-expressing cells obtained in step 1 were cultured in serum-free CD OptiCHO, and the culture supernatant was collected at a cell viability of about 60%.
  • the HiTrap MabSelect SuRe 1 ml column (GE Healthcare Life Sciences product, Cat. No: 11-0034-93) was equilibrated with a pH 7.4 PBS solution at 10 bed volumes at a flow rate of 0.5 ml/min; the culture supernatant was filtered with a 0.45 ⁇ m filter. Filtration was carried out at a flow rate of 0.5 ml/min.
  • GLP-1R GLP-1R
  • VEGF-A vascular endothelial growth factor
  • VEGF-B TNF- ⁇
  • All products of Yishen Shenzhou were diluted to a concentration of 10 ⁇ g/ml, and covalently immobilized on carboxymethyl glucoside via primary amine by amino coupling.
  • Sugar-coated CM5 chip General Electric product
  • fixed buffer 10 mM sodium acetate (pH 5.0) fixed amount of 1000 RU.
  • Regeneration solution glycine buffer with a pH of 1.5-2.0; injection time: 30 s; flow rate: 30 ⁇ l/min.
  • PBST (formulation: 0.005% by volume of Tween 20 in PBS) is Running buffer; using Kinetic Analysis Wizard mode; Dulaglutide, BY23.2, BY25 and BY19.3 are diluted to 600, 300, 150, respectively. Concentration gradients of 75, 37.5 and 18.75 nM; injection time: 2 min, dissociation time: 5 min, flow rate: 30 ⁇ l/min.
  • Type II diabetes model db/db mice (Changzhou Cavans Experimental Animal Co., Ltd.), measured basal blood glucose after fasting for 3 hours, and blood glucose concentration greater than 10 mmol/L into groups; with a few points 2 groups, each group 6 Only mice.

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Abstract

L'invention concerne une protéine de fusion immunitaire à action prolongée de type IgG et son utilisation. La protéine de fusion immunitaire à action prolongée de type IgG est constituée d'une molécule effectrice et d'une région constante d'un anticorps IgG, et la molécule effectrice est liée à la région constante de l'anticorps IgG au moyen d'un peptide lieur ; la molécule effectrice est une protéine capable d'exercer des fonctions physiologiques dans le corps ; et la région constante de l'anticorps IgG est une structure de l'anticorps IgG avec deux régions variables de chaîne lourde et deux régions variables de chaîne légère déplacées.
PCT/CN2018/078951 2017-03-17 2018-03-14 Protéine de fusion immunitaire à action prolongée de type igg et son utilisation WO2018166468A1 (fr)

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CN201710159592.5A CN108623691B (zh) 2017-03-17 2017-03-17 IgG样长效免疫融合蛋白及其应用
CN201710159592.5 2017-03-17

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CN111378044B (zh) * 2018-12-28 2022-07-15 长春金赛药业有限责任公司 抗体融合蛋白、制备方法及其应用
CN111423512B (zh) * 2019-01-10 2024-01-05 北京比洋生物技术有限公司 阻断血管内皮细胞生长且活化t细胞的多靶向融合蛋白和包含其的药物组合物
CN111458396B (zh) * 2019-01-18 2022-07-08 成都康弘生物科技有限公司 一种蛋白的电荷异质性检测方法
JP2022522787A (ja) * 2019-03-05 2022-04-20 サンシャイン・レイク・ファーマ・カンパニー・リミテッド ポリペプチド分子及びその適用
CN112646042A (zh) * 2019-10-10 2021-04-13 陕西麦科奥特科技有限公司 活性多肽化合物
CN116715749B (zh) * 2023-03-20 2024-04-09 吉林大学 一种与胶原具有特异结合能力vegf活性抑制蛋白及其制备方法与应用
CN117143242B (zh) * 2023-10-30 2024-03-29 南京佰抗生物科技有限公司 抗Galectin-3蛋白的单克隆抗体组合物及应用

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CN105899532A (zh) * 2013-08-30 2016-08-24 艾普丽尔生物有限公司 抗血清白蛋白的fab-效应物部分的融合构建体及其制备方法

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CN1758924A (zh) * 2003-01-10 2006-04-12 株式会社新潟Tlo 基因治疗用载体以及利用该基因治疗用载体在哺乳动物中或培养细胞中进行目的蛋白定量的方法
CN1829533A (zh) * 2003-05-30 2006-09-06 阿莱克申药物公司 包含改造恒定区的抗体和融合蛋白
CN101426519A (zh) * 2004-03-31 2009-05-06 森托科尔公司 人glp-1模拟体、组合物、方法和用途
CN103204944A (zh) * 2013-03-26 2013-07-17 江苏健德生物药业有限公司 用于治疗糖尿病的长效免疫融合蛋白
CN105899532A (zh) * 2013-08-30 2016-08-24 艾普丽尔生物有限公司 抗血清白蛋白的fab-效应物部分的融合构建体及其制备方法

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