WO2023280144A1 - Protéine de fusion et son utilisation médicale - Google Patents

Protéine de fusion et son utilisation médicale Download PDF

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WO2023280144A1
WO2023280144A1 PCT/CN2022/103825 CN2022103825W WO2023280144A1 WO 2023280144 A1 WO2023280144 A1 WO 2023280144A1 CN 2022103825 W CN2022103825 W CN 2022103825W WO 2023280144 A1 WO2023280144 A1 WO 2023280144A1
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fusion protein
seq
fgf21
protein
protein according
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PCT/CN2022/103825
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English (en)
Chinese (zh)
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毛东杰
谢岳峻
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上海翰森生物医药科技有限公司
常州恒邦药业有限公司
江苏豪森药业集团有限公司
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Priority to CN202280046816.0A priority Critical patent/CN117677640A/zh
Publication of WO2023280144A1 publication Critical patent/WO2023280144A1/fr

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    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • 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
    • 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
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to a fusion protein of FGF21 and its medical application.
  • Fibroblast growth factor 21 (Fibroblast growth factor 21, FGF21) is a polypeptide (SEQ ID NO: 1) consisting of 209 amino acids, and its amino acid sequence has about 75% homology with mouse FGF21.
  • the N-terminus of FGF21 contains a signal peptide consisting of 28 amino acids, so mature FGF21 consists of 181 amino acids (SEQ ID NO: 3).
  • Mature FGF21 is the isoform or allelic form of native human FGF21 having Leu substituted for Pro at position 146 of SEQ ID NO: 3 herein. FGF21 is mainly expressed in the liver and pancreas, but also in fat and muscle tissue.
  • FGF21 can induce various signaling pathways and functional activities in the liver, pancreas and adipose tissue, thereby realizing the regulation of glucose and lipid metabolism and the protection of pancreatic ⁇ cells physiological function.
  • FGF21 regulates glucose uptake by adipocytes by activating insulin-independent glucose uptake.
  • studies have also shown that FGF21 can reduce body weight and body fat in a dose-dependent manner. For example, administering FGF21 to diabetic rhesus monkeys found that the levels of fasting plasma glucose, triglycerides, and glucagon were significantly reduced.
  • FGF21 may regulate lipid metabolism by promoting lipolysis and ketogenic effect.
  • FGF21 can inhibit glucose-mediated release of glucagon, stimulate insulin production, and prevent islet cell apoptosis, thereby improving pancreatic cell function.
  • FGF21 also activates signaling pathways in exocrine pancreatic cells and hepatocytes and inhibits hepatic glycogen export.
  • FGF21 is a member of the FGF gene family, and most FGFs have broad-spectrum mitogenic abilities. However, the results of the investigation show that FGF21 neither has the ability to promote cell proliferation nor antagonizes the functions of other members of the FGF family.
  • FGF21 neither has the ability to promote cell proliferation nor antagonizes the functions of other members of the FGF family.
  • Experiments have shown that in the whole life cycle of FGF21 transgenic mice (the amount of FGF21 in the body is about 150 times that of normal mice), no abnormalities such as tumors and tissue hyperplasia were found in the body. At the same time, its metabolic regulating effect is related to the metabolic level of the body, and the regulating effect only plays a role when the metabolism is abnormal. Even if the FGF21 exceeds the pharmacological dose, hypoglycemia will not occur.
  • the medicine (insulin, thiazolidinedione, etc.) of the main treatment diabetes on the market is easy to produce side effects when dosage is inappropriate, as the hypoglycemia that large doses of insulin cause, liver function damage and edema that thiazolidinedione causes, these None of them were found in animal experiments treated with FGF21, which is sufficient to prove that FGF21 is an ideal drug for treating diseases such as diabetes and obesity.
  • FGF21 The physiological function of FGF21 in controlling blood sugar and reducing body weight has brought hope for the treatment of related diseases.
  • wild-type FGF21 is easily hydrolyzed by proteases and can also be filtered by glomeruli, with a half-life of only 0.5-2h. It is difficult to guarantee the effective drug action time.
  • the pharmaceutical industry has improved the half-life of FGF21 by performing site-directed mutagenesis of amino acids at enzyme cleavage sites, preparing long-acting fusion proteins, or linking polyethylene glycol to the polypeptide backbone.
  • a major challenge in the development of FGF21 as a protein formulation also comes from the instability caused by its own aggregation.
  • the ideal effect of the target therapeutic protein is to increase the resistance to proteolysis and reduce the aggregation of the protein, thereby enhancing the half-life and stability of the FGF21 protein preparation, and realizing low-frequency administration to patients.
  • the present invention provides a kind of FGF21 protein or its variant, its general formula is as follows:
  • X 166 is selected from L or F;
  • X 175 is selected from R or W.
  • a preferred embodiment of the present invention is FGF21 protein described in general formula (II) or variant thereof, its sequence is as shown in SEQ ID NO:5 or SEQ ID NO:6.
  • the present invention also provides a fusion protein whose general formula is as follows:
  • F1 is selected from the FGF21 protein or variants thereof as described in general formula (II) ;
  • F 2 is connecting peptide
  • F3 is a domain composed of Fc or fragments of immunoglobulin.
  • F 1 is a sequence as shown in SEQ ID NO:5 or SEQ ID NO:6.
  • F 1 is a sequence as shown in SEQ ID NO:5.
  • F 2 is a sequence as shown in SEQ ID NO:7.
  • said F3 is represented by general formula ( III ):
  • F4 is the Fc fragment of immunoglobulin
  • n is an integer selected from 1-10;
  • n is an integer selected from 1-10.
  • F4 is SEQ ID NO: 8;
  • n 1;
  • n 9.
  • said F3 is SEQ ID NO: 9 .
  • the fusion protein is selected from SEQ ID NO: 12 or SEQ ID NO: 13.
  • the present invention also relates to a polynucleotide encoding the fusion protein described in general formula (I).
  • the coding of said nucleotide comprises FGF21 protein SEQ ID NO:5.
  • the coding of said nucleotides comprises FGF21 fusion protein SEQ ID NO: 12-13.
  • the present invention also relates to an expression vector comprising the polynucleotide as described above.
  • the present invention also relates to a host cell, which introduces or contains the above-mentioned expression vector, wherein the host cell is bacteria, preferably Escherichia coli; or the host cell is yeast, preferably Pichia Yeast; or the host cell is a mammalian cell, preferably a CHO cell or HEK293 cell.
  • the host cell is bacteria, preferably Escherichia coli; or the host cell is yeast, preferably Pichia Yeast; or the host cell is a mammalian cell, preferably a CHO cell or HEK293 cell.
  • the present invention also relates to a method for producing the fusion protein as described above, comprising the steps of:
  • the present invention further includes a pharmaceutical composition, which contains the fusion protein described in general formula (I) and pharmaceutically acceptable excipients, diluents or carriers.
  • the present invention also relates to the use of the fusion protein or the above-mentioned pharmaceutical composition in the preparation of medicines for the treatment or prevention of diabetes, obesity, dyslipidemia, metabolic syndrome, and non-alcoholic fatty liver Or related diseases such as non-alcoholic steatohepatitis.
  • the fusion protein provided by the present invention has the effect of significantly promoting fibroblast proliferation, good plasma stability, and can induce glucose uptake and promote phosphorylation of ERK1/2 protein. These characteristics are beneficial to the preparation and formulation of therapeutic proteins, and It has potential therapeutic effects on related diseases such as diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver or non-alcoholic steatohepatitis.
  • the amino acid position changes in the FGF21 mutants of the present invention are determined from the amino acid positions in the mature human wild-type FGF21 (SEQ ID NO: 3) polypeptide.
  • amino acid sequences of the present invention contain the standard one-letter or three-letter codes for the twenty amino acids.
  • FGF21 polypeptide refers to the naturally occurring wild-type polypeptide expressed in humans. Including SEQ ID NO: 1 consisting of the full-length form encoded by SEQ ID NO: 2 and SEQ ID NO: 3 consisting of the mature form encoded by SEQ ID NO: 4.
  • FGF21 mutant refers to a modified FGF21 polypeptide based on the amino acid sequence of naturally occurring FGF21 (SEQ ID NO: 4). Such modifications include, but are not limited to, one or more amino acid substitutions, including, but not limited to, protease-resistant FGF21 mutants, reduced aggregation FGF21 mutants, and FGF21 combination mutants described herein.
  • patient is a mammal, preferably a human.
  • treating refers to slowing, reducing or reversing the progression or severity of a symptom, disorder or disease.
  • Fc fragment refers to the constant region of the heavy chain of an immunoglobulin.
  • vector refers to any molecule (eg, nucleic acid, plasmid, or virus) used to deliver encoded information to a host cell.
  • expression vector refers to a vector suitable for transformation of host cells and containing nucleic acid sequences that direct and/or control the expression of an inserted heterologous nucleic acid sequence. Including but not limited to processes such as transcription, translation and RNA splicing.
  • host cell is used to refer to a cell transformed or capable of being transformed by a nucleic acid sequence and then capable of expressing a selected gene of interest.
  • the term includes the progeny of a parental cell, whether or not the progeny is identical in morphology or genetic composition to the original parent, predominantly in the presence of selected genes.
  • the FGF21 mutant protein (SEQ ID NO:5-6) was expressed using the ExpiCHO system (Thermo Fisher #A29133).
  • the DNA sequence encoding the FGF21 mutant protein with a His tag at the C-terminal was cloned into the pCDNA3.1 vector, and after sequencing, it was confirmed that a plasmid expressing the fusion protein was obtained.
  • the method of preparing EQ buffer solution is to take a bag of PBS phosphate buffer solution powder, dissolve the powder in 2000ml ultrapure water, and filter it with a 0.22 ⁇ m filter membrane for later use.
  • the method to configure Elution buffer (500mM imidazole, pH7.4) is to weigh 34g of imidazole and add 450ml of EQ buffer, adjust the pH to 7.4, dilute to 500ml, and filter through a 0.22 ⁇ m filter membrane for later use.
  • the harvested supernatant was purified by AKTA Pure instrument. First, equilibrate the instrument with EQ buffer until the pH and conductivity of the effluent are consistent with the EQ buffer; then collect samples with Elution buffer.
  • the fusion protein SEQ ID NO: 10-16 was expressed by the same method, purified using Protein A affinity chromatography column, and the conditioned medium containing the expressed receptor was washed sequentially. The eluate was dialyzed against 10 mM tris-buffered saline, pH 7.2.
  • the concentration and purity of the prepared protein were determined by UV spectrophotometry.
  • 3T3-L1 mouse embryonic fibroblasts express glucose transporter 1 (GLUT1) on the surface of mature adipocytes, and FGF21 protein regulates the level of glucose uptake by adipocytes by regulating the expression level of GLUT1.
  • GLUT1 glucose transporter 1
  • Aspirate the original medium and add the induction medium that is, add 2 ⁇ g/ml human insulin (Sinobiologics , cat#:11038-HNAY) solution, 1 ⁇ M dexamethasone (Sigma, cat#:D4902-25MG) and 0.5mM 3-isobutyl-1-methylxanthine (IBMX) (Sigma, cat#:I7018- 100MG), induced and cultured 3T3-L1 cells for 3 days, observed the number and size of fat granules in the cells under a microscope, and differentiated them into adipocytes, and then replaced the differentiation medium with complete medium containing only 2 ⁇ g/ml human insulin.
  • IBMX 3-isobutyl-1-methylxanthine
  • the adipocytes induced to differentiate and mature were digested to prepare a single-cell suspension, and the cell density was adjusted to 1x10 6 /mL with DMEM complete basal medium, 100uL/well, and seeded in a 96-well plate (Corning, cat#:3610). Adhere to the wall, add the mutant protein to be tested (SEQ ID NO:5) diluted with DMEM basal medium in the experimental group, so that the final concentration is 5000nM, 100uL/well is added to the plate, and the same volume of DMEM basal medium is added to the control group , and incubated overnight at 37°C, 5% carbon dioxide.
  • glucose uptake rate% (experimental group MFI-control group MFI)/control Group MFI*100%.
  • the experimental results showed that the FGF21 mutant (SEQ ID NO:6) significantly induced the uptake of the glucose analog 2-NBDG by adipocytes, and the induction efficiency was good.
  • FGF21 protein regulates the phosphorylation level of ERK1/2 protein through the Ras/Raf/MAPK signaling pathway to transduce cell signals and participate in energy metabolism in vivo. Evaluation Comparing FGF21 protein mutants to regulate the phosphorylation level of ERK1/2 protein can evaluate the level of cell signal transduction.
  • Seed HuH-7 (Chinese Academy of Sciences, cat#: SCSP-526) at 1 ⁇ 10 5 /mL in a 96-well plate, 100uL/well, incubate overnight at 37°C, 5% carbon dioxide, and the next day, the cells were placed in DMEM (gibco, cat #:11995-065) basal medium for 2 hours, add DMEM basal medium to the experimental group to dilute the protein to be tested, adjust the final concentration of the mutant protein to be tested (SEQ ID NO:5) to 50nM, add 100uL/well In the plate, add the same volume of DMEM basal medium to the control group, incubate at 37°C for 20 minutes, add fixative solution (BD Cytofix, cat#: 554655) and fix at 37°C for 30 minutes, centrifuge at 400g, 4°C for 5 minutes, wash twice all over.
  • DMEM gibco, cat #:11995-065
  • SEQ ID NO:5 final concentration of the mutant protein to
  • FGF21 mutants SEQ ID NO:5 and SEQ ID NO:6
  • SEQ ID NO:5 and SEQ ID NO:6 can up-regulate the phosphorylation level of ERK1/2 protein in HuH-7 cells, and the effect is good.
  • the FGF21 fusion protein is composed of functional FGF21 and Fc fragments, in which Fc binds to the extracellular domain of Fc ⁇ R through non-covalent bonding, activates the immunoreceptor tyrosine activation motif, and mediates immunity induced by ADCC (cytotoxicity) The activation effect is not good for disease treatment.
  • the combination of Fc and FcRn is beneficial for the fusion protein to have a longer circulation period in vivo.
  • fusion protein mutant 12 to Fc ⁇ R (Fc ⁇ RI, Fc ⁇ RIIa, Fc ⁇ RIIIa) is weak, and the risk of side effects caused by immune effects is small; the binding to FcRn is strong, which is conducive to its long-term circulation in the blood.
  • the human FcRn transgenic mouse model was used to evaluate the drug metabolism of FGF21 fusion protein mutants in mice.
  • Human FcRn transgenic mice with an average body weight of 18-22g and 18-22 weeks of age were randomly divided into groups, with 3 animals in each group, and the tested FGF21 fusion protein mutant 12 was administered at 4 mpk, s.c., in a single dose, PBS
  • the vehicle was used as a negative control group
  • blood was collected at 0.5, 2, 4, 6, 8, 24, 48, 72, 96, and 120 hours to separate plasma, frozen in a -20°C refrigerator, and then mutated using human KLB protein-FGF21 fusion protein
  • Body-Fc-HRP indirect ELISA method was used to detect the concentration of FGF21 fusion protein mutants in mouse plasma, and the PK solver software was used to analyze the PK parameters of the non-compartmental model and the formula of intravascular administration.
  • the experimental results are shown in the following table:
  • FGF21 fusion protein mutant 12 showed good metabolic activity in vivo.
  • the obesity model of C57BL/6 mice induced by high-fat diet was used to evaluate the effect of FGF21 fusion protein mutants on reducing body weight and liver weight.
  • the 12-week-old DIO male obesity model mice with a body weight of 30-50g were randomly divided into groups, with 8 animals in each group, and the tested FGF21 fusion protein mutants 12 and 13 were administered at 2mpk, s.c., q3d, in PBS vehicle As a negative control group, a total of 3 doses were administered. On the 0th day, the body weight was weighed and the drug was administered, and the body weight was measured every 3 days thereafter, and the food intake was accumulated. On the 9th day, we weighed and fasted overnight. On the 10th day, weighed and collected blood, took the liver, and weighed the liver.
  • test coefficient is p ⁇ 0.05, there is a statistical difference, using one-way ANOVA multi-group comparative analysis,
  • leptin-knockout mouse model of diabetes namely ob/ob model mice
  • FGF21 fusion protein mutant 12 in reducing body weight, blood glucose level, liver-to-weight ratio, and blood lipids: total cholesterol (TC), triglycerides Ester (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels.
  • TC total cholesterol
  • TG triglycerides Ester
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • 12-week-old ob/ob male obesity model mice with a body weight of 30-50g were randomly divided into groups, with 6 animals in each group, and the test FGF21 fusion protein mutant 12 was administered at 2mpk, s.c., q3d, PBS vehicle As a negative control group, a total of 3 doses were administered.
  • the body weight was weighed and the drug was administered, and the body weight was measured every 3 days thereafter, and the food intake was accumulated. Weighed on the 8th day and fasted overnight.
  • On the 9th day weighed and collected blood to detect blood sugar level and four items of blood sugar, separated the liver, weighed the liver and body weight respectively, and calculated the liver-to-body weight ratio.
  • the experimental results show that, compared with the candidate molecules of the vehicle group, they have obvious weight-lowering effects and blood-sugar-lowering effects.
  • CD57BL/6 mice were purchased from Nanjing Jicui Yaokang, and after a week of acclimatization in our laboratory, the NASH model was induced by diet. HFD was induced using a choline-deficient high-fat diet, ie, CDA.
  • the mice in the normal healthy group were fed with conventional feed, and the mice in the vehicle (pH7.4 PB solution) control group and the experimental group were fed with CDA/HFD feed containing 60% high fat and 2% cholesterol, and fed with 10% fructose in the drinking water , induced for 9 weeks. Subsequently, the experimental mice were randomly divided into 4 groups, with 5 animals in each group, and the administration started from the third week (ie, administration after 2 weeks of induction, and administration for 7 weeks).
  • the test drug was administered subcutaneously at q3d frequency at 5 mg/kg for 7 consecutive weeks. After reaching the end point of the experiment, the body weight was weighed, and the animal was euthanized. The liver was collected and weighed, and the liver was stored in 4% neutral formaldehyde. Tissue slices were used to detect indicators such as fat deposition, stem cell balloon-like lesions, and liver cell inflammation levels to evaluate the impact of the test drug on the development of NASH.
  • the experimental results show that compared with the healthy group, the tested drug can significantly reduce body weight by 24.92%, and at the same time significantly reduce the level of liver-to-body weight ratio, which is equivalent to the level of the healthy group; compared with the vehicle group, the candidate molecules can improve NASH fiber There is a statistically significant difference in levels.

Abstract

L'invention concerne une protéine de fusion constituée d'une protéine FGF21 et d'une immunoglobuline Fc ou de fragments de celle-ci, et une méthode de traitement du diabète, de l'obésité, de la dyslipidémie, du syndrome métabolique, du foie gras non alcoolique, de la stéatohépatite non alcoolique, ou d'autres maladies associées en utilisant la protéine de fusion FGF21-Fc et des compositions pharmaceutiques associées.
PCT/CN2022/103825 2021-07-05 2022-07-05 Protéine de fusion et son utilisation médicale WO2023280144A1 (fr)

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