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WO2025185753A1 - Substance inhalée de protéine de fusion pour le traitement de maladies allergiques respiratoires - Google Patents

Substance inhalée de protéine de fusion pour le traitement de maladies allergiques respiratoires

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Publication number
WO2025185753A1
WO2025185753A1 PCT/CN2025/081418 CN2025081418W WO2025185753A1 WO 2025185753 A1 WO2025185753 A1 WO 2025185753A1 CN 2025081418 W CN2025081418 W CN 2025081418W WO 2025185753 A1 WO2025185753 A1 WO 2025185753A1
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WIPO (PCT)
Prior art keywords
drug
fusion protein
lung tissue
allergic
seq
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Application number
PCT/CN2025/081418
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English (en)
Chinese (zh)
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WO2025185753A8 (fr
Inventor
祝道成
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Individual
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Individual
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins

Definitions

  • the present invention belongs to the fields of genetic engineering and immunology, and in particular relates to a fusion protein inhaler for treating respiratory allergic diseases.
  • Allergic diseases are the sixth leading cause of acute and chronic illnesses and have a clear genetic predisposition. Common allergic diseases include allergic asthma, allergic rhinitis, hay fever, atopic dermatitis, allergic arthritis, urticaria, and anaphylactic shock.
  • Allergic rhinitis mainly affects the patient's quality of life, while allergic asthma can be life-threatening in severe cases.
  • the mechanism of allergy development is as follows: when an allergen (antigen) first comes into contact with immune B cells, the B cells and T cells come into contact, differentiate into plasma cells, and produce large amounts of antibodies called IgE. These IgEs then bind to immune cells such as mast cells. Upon subsequent exposure to the allergen, the IgE-bound immune cells become activated, releasing substances like histamine, causing allergic symptoms and impacting the immune response.
  • allergens cross-link specific IgE antibodies with the IgE receptor Fc ⁇ RI on the surface of allergic cells, thereby activating activation signaling pathways within the allergic cells and leading to the release of large numbers of intracellular granules. These granules contain numerous cytokines and chemokines, which act on surrounding tissues and organs, triggering an inflammatory response. This is often associated with clinical symptoms such as increased mucus secretion, nasal congestion, and bronchospasm.
  • the present invention provides a fusion protein inhaler and its application in treating respiratory allergic diseases.
  • the fusion protein inhaler of the present invention can block the degranulation of allergic reaction cells and can effectively treat respiratory allergic asthma.
  • a first aspect of the present invention provides a drug for treating respiratory allergic diseases, the drug comprising a fusion protein having an amino acid sequence as shown in SEQ ID NO: 3; and a medically acceptable excipient;
  • the medically acceptable excipients include anti-adhesive agents, penetration enhancers, buffers, plasticizers, surfactants, defoamers, thickeners, inclusion agents, absorbents, humectants, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, pH regulators, adhesives, disintegrants, fillers, lubricants, wetting agents, integrators, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, foaming agents, suspending agents, coating materials, fragrances, diluents, flocculants and deflocculants, filter aids, release retardants or combinations thereof;
  • the respiratory allergic disease is selected from allergic rhinitis or allergic asthma.
  • the fusion protein has a nucleotide sequence as shown in SEQ ID NO:4.
  • the drug is a drug that reduces inflammatory cell infiltration and alleviates lung tissue fibrosis.
  • the inflammatory cells are peribronchial inflammatory cells or lung tissue inflammatory cells.
  • the drug is a drug that reduces airway hyperresponsiveness.
  • the drug is a drug that reduces eosinophil infiltration of peribronchial or lung tissue.
  • the drug is a drug that reduces neutrophil infiltration in peribronchial or lung tissue.
  • the drug is a drug that reduces lymphocyte infiltration in peribronchial or lung tissue.
  • the drug is a drug that reduces mononuclear cell infiltration of peribronchial or lung tissue.
  • the medicament is a spray or inhaler.
  • the second aspect of the present invention provides the use of a fusion protein in the preparation of a drug for treating or preventing respiratory allergic diseases, wherein the fusion protein has an amino acid sequence as shown in SEQ ID NO: 3.
  • the fusion protein has a nucleotide sequence as shown in SEQ ID NO:4.
  • the respiratory allergic disease is selected from allergic rhinitis or allergic asthma.
  • the drug is a drug that reduces inflammatory cell infiltration and alleviates lung tissue fibrosis.
  • the inflammatory cells are peribronchial inflammatory cells or lung tissue inflammatory cells.
  • the drug is a drug that reduces airway hyperresponsiveness.
  • the drug is a drug that reduces eosinophil infiltration of peribronchial or lung tissue.
  • the drug is a drug that reduces neutrophil infiltration in peribronchial or lung tissue.
  • the drug is a drug that reduces lymphocyte infiltration in peribronchial or lung tissue.
  • the drug is a drug that reduces mononuclear cell infiltration of peribronchial or lung tissue.
  • the medicament is a spray or inhaler.
  • the third aspect of the present invention provides a fusion protein for treating or preventing respiratory allergic diseases, wherein the fusion protein has an amino acid sequence as shown in SEQ ID NO:3.
  • the respiratory allergic disease is selected from allergic rhinitis or allergic asthma.
  • the fusion protein has a nucleotide sequence as shown in SEQ ID NO:4.
  • the fourth aspect of the present invention provides a method for treating or preventing respiratory allergic diseases, administering the drug as described in the first aspect of the present invention or the fusion protein consisting of the amino acid sequence shown in SEQ ID NO: 3 to a subject in need.
  • the respiratory allergic disease is selected from allergic rhinitis or allergic asthma.
  • the fusion protein has a nucleotide sequence as shown in SEQ ID NO:4.
  • the administration is respiratory administration.
  • the level of inflammatory cells in the lung as assessed by total cell counts in bronchoalveolar lavage fluid, bronchial biopsy is reduced relative to pre-administration levels.
  • the reagents and raw materials used in the present invention are commercially available.
  • Fusion protein technology is used to specifically crosslink Fc ⁇ RII and Fc ⁇ RI on the surface of allergic cells, effectively activating inhibitory signaling pathways within the cells, thereby blocking the release of intracellular granules.
  • Further studies in animal disease models have shown that fusion protein inhalers can block degranulation of allergic cells, reduce inflammatory cell infiltration, alleviate lung fibrosis, and reduce airway hyperresponsiveness. Fusion protein inhalers can reduce the infiltration of eosinophils, neutrophils, lymphocytes, and monocytes in peribronchial or lung tissue, and are effective in treating allergic rhinitis, allergic cough, allergic asthma, or anaphylactic shock.
  • Figure 1A shows that mGE2 protein inhibits the degranulation reaction induced by DNP-IgE in wild-type mice; L is injected with mDNP-IgE on the left side, and R is injected with mDNP-IgE+mGE2 on the right side.
  • Figure 1B shows that mGE2 protein inhibits the degranulation reaction induced by DNP-IgE in Fc ⁇ RII-deficient mice; L: mDNP-IgE was injected on the left side, and R: mDNP-IgE+mGE2 was injected on the right side.
  • FIG2 is a schematic diagram of the establishment of an OVA-induced asthma model in mice.
  • FIG3A is a diagram showing cell counts of bronchoalveolar lavage fluid (BAL).
  • FIG3B is a statistical graph showing the number of eosinophils, neutrophils, lymphocytes, and monocytes.
  • FIG3C is a statistical diagram of the number of macrophages.
  • Figure 4 is a stained image of bronchial pathological tissue sections.
  • FIG5 is a dose-response curve diagram showing the maximum drug resistance value after drug administration.
  • Fc ⁇ RIIb is used to refer to the Fc ⁇ RIIb receptor of any species present in nature, including any mammalian species.
  • the mammal is a human.
  • Fc ⁇ RIIb is an isotype of the low-affinity IgG receptor Fc ⁇ RII that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM).
  • ITIM immunoreceptor tyrosine-based inhibitory motif
  • the Fc ⁇ RIIb receptor is found on, for example, basophils, mast cells, B cells, and dendritic cells.
  • Fc ⁇ RIIb has three alternative splicing forms, designated Fc ⁇ RIIb1, Fc ⁇ RIIb1', and Fc ⁇ RIIb2, which differ only in the sequence of the cytoplasmic domain.
  • All three alternative splicing isoforms contain two extracellular immunoglobulin-like loops and a conserved ITIM motif located in the cytoplasmic tail and are explicitly included in the definition of Fc ⁇ RIIb, along with other splicing variants that may be identified in the future.
  • Fc ⁇ RI refers to the Fc ⁇ RI receptor of any species, including any mammalian species found in nature.
  • Fc ⁇ RI is a member of the multiunit immune response receptor (MIRR) family of cell surface receptors. Receptors in the MIRR family of cell surface receptors are generally capable of transducing intracellular signals by binding to cytoplasmic tyrosine kinases.
  • MIRR multiunit immune response receptor
  • Fusion proteins can be prepared, for example, by recombinant DNA technology or by chemical bonding to form a covalent bond or other well-known techniques in the art for forming fusion proteins. Providing an appropriate DNA sequence encoding the desired fusion protein allows the generation of the fusion protein using recombinant techniques well-known in the art.
  • the coding sequence can be obtained from natural resources or synthesized or constructed using widely available starting materials by conventional methods. When the coding DNA is prepared synthetically, the codon preference of the intended host in which the DNA is to be expressed can be utilized.
  • Fusion proteins can be formed by combining the Fc ⁇ fragment with the Fc ⁇ fragment via various linkers well known in the art.
  • fusion proteins of the present invention one of ordinary skill in the art can use known techniques to synthesize or obtain a DNA molecule encoding an Fc ⁇ fragment or a portion thereof from readily available human DNA (combined with a DNA molecule encoding an Fc ⁇ fragment or a portion thereof), and then insert the DNA molecule into a commercially available expression vector for use in known expression systems.
  • Such systems include those in which the relevant fusion protein is produced as a single chain.
  • Transfection/transduction refers to methods for introducing a gene into a cell and expressing the gene in the cell, which are known in the art.
  • the vector can be easily introduced into a host cell, such as a mammalian cell, a bacterial cell, a yeast cell, or an insect cell, by any method in the art.
  • the expression vector can be transferred into the host cell by physical, chemical, or biological means.
  • IgE plays a key role in many acute and chronic allergic reactions, including, for example, asthma, allergic rhinitis, atopic dermatitis, severe food allergies, chronic urticaria and angioedema, and the serious physiological conditions of anaphylactic shock caused by, for example, food allergies, bee stings or penicillin allergies.
  • the Fc portion of human IgE can bind to Fc ⁇ RI or Fc ⁇ RII cell surface receptors on various cell types such as basophils, mast cells, dendritic cells and B lymphocytes (B cells).
  • IgE When antigen binds to IgE, IgE binds to certain cell surface receptors on, for example, basophils and mast cells, and IgE binds to these cells causing vasoactive and proinflammatory mediators, including histamine.
  • the mediators released when antigen-bound IgE bind to certain cell surface receptors significantly cause asthma and acute and late allergic reactions.
  • pharmaceutically acceptable diluent, excipient, carrier or adjuvant refers to a diluent, excipient, carrier or adjuvant that is physiologically acceptable to a subject while retaining the therapeutic properties of the pharmaceutical composition with which it is administered, such as a preservative, antioxidant, buffer, acidifier, alkalizer, solubilizer, complexation-enhancing agent, diluent, electrolyte, dextrose, stabilizer, bulking agent, defoaming agent, emulsifier, flavoring agent, sweetener, taste-masking agent, osmotic pressure regulator, surface tension regulator, viscosity regulator, density regulator or a combination thereof.
  • subject or “individual” may include, but is not limited to, mammals, such as humans or non-human mammals, e.g., domesticated animals, agricultural animals, or wild animals, as well as birds and aquatic animals.
  • a "patient” is a subject who suffers from a disease, disorder, or condition, or is at risk of developing the disease, disorder, or condition, or who is otherwise in need of the compositions and methods provided herein. In some embodiments, the subject suffers from an autoimmune disease as described herein.
  • treatment refers to any sign of successful treatment or improvement of a disease or disorder. Treatment may include, for example, alleviating, delaying, or relieving the severity of one or more symptoms of a disease or disorder, or it may include reducing the frequency with which a patient experiences symptoms of a disease, defect, condition, or adverse condition. As used herein, "treating or preventing” is sometimes used herein to refer to a method that results in some degree of treatment or improvement of a disease or disorder, and contemplates a range of outcomes for that purpose, including, but not limited to, complete prevention of the disorder.
  • prevent refers to the prevention of a disease or condition, such as a tumor, in a patient.
  • a disease or condition such as a tumor
  • Airway hyperreactivity refers to an excessively strong or premature airway constriction in response to various stimuli. If such stimuli, which are unresponsive or mild in normal individuals, cause significant bronchoconstriction in some individuals, this is considered AHR.
  • Bronchial hyperresponsiveness (also known as BH, bronchial hyperresponsiveness, AHR, or airway hypersensitivity) is a condition that predisposes to triggering or inducing bronchospasm.
  • the methods disclosed herein i.e., administering the formulations disclosed herein by inhalation, reduce BH by relaxing the ASM and reducing the sensitivity of the ASM.
  • the disclosure provides methods for reducing airway hyperresponsiveness by administering an effective amount of the formulations disclosed herein by inhalation.
  • Intrathecal injection aims to inject the drug into the subarachnoid space so that it can be delivered and diffused in the cerebrospinal fluid (CSF).
  • CSF cerebrospinal fluid
  • Methacholine is the most commonly used stimulant in bronchial provocation tests.
  • Example 1 Construction and expression of mouse IgE and IgG Fc fusion protein (mGE2)
  • the FP4 gene was synthesized according to the nucleotide sequence shown in SEQ ID NO:3, and the synthesized FP4 (its amino acid sequence is shown in SEQ ID NO:3, and its nucleotide sequence is shown in SEQ ID NO:4) gene was cloned into the p-CI expression vector using SOE PCR and enzyme cutting methods. After verification by sequencing, the expression plasmid was transfected into CHO-S cells. After a large number of cells were cultured in 50% CD CHO + 50% Dynamis medium, the supernatant was collected, and the FP4 protein was isolated and purified from the culture supernatant of the transiently transfected cells using Protein A affinity chromatography.
  • the mGE2 gene was synthesized based on the mouse immunoglobulin IgE Fc ⁇ and IgG Fc ⁇ sequences.
  • the synthesized mouse mGE2 (Fc ⁇ CH2-CH3-CH4-Fc ⁇ Hinge-CH2-CH3) (its amino acid sequence is shown in SEQ ID NQ:1, and its nucleotide sequence is shown in SEQ ID NO:2) gene was cloned into the p-CI expression vector using SOE PCR and enzyme cutting methods. After verification by sequencing, the expression plasmid was transfected into CHO-S cells. After culturing the cells in 50% CD CHO + 50% Dynamis medium, the supernatant was collected and mGE2 was isolated and purified from the culture supernatant of transiently transfected cells using Protein A affinity chromatography.
  • amino acid sequence of the mGE2 fusion protein is shown in SEQ ID NO: 1:
  • the underline represents the B region Fc- ⁇ .
  • Nucleotide sequence encoding FP4 gene (SEQ ID NO: 4):
  • Example 2 mGE2 blocks allergic cell degranulation (PCA)
  • mice were subcutaneously injected into the ears with 10 ⁇ g of mouse DNP-IgE (Sigma).
  • the left ear contained DNP-IgE antibody alone, while the right ear contained DNP-IgE antibody plus 10 ⁇ g of mGE2.
  • the allergen 100 ⁇ g of DNP-human serum albumin (DNP-HAS) and 200 ⁇ L of 1% Evans blue (EVANS)
  • DNP-HAS DNP-human serum albumin
  • EVANS 1% Evans blue
  • Fc ⁇ RIIb was knocked out in C57BL/6 mice, creating Fc ⁇ RIIb-deficient mice.
  • the same procedures as in Example 2 were followed, revealing that the inhibitory effect of mGE2 on allergic cell degranulation was significantly abolished in Fc ⁇ RIIb-deficient mice ( Figure 1B ). This suggests that the inhibitory effect of mGE2 on allergic cell degranulation occurs through cross-linking of Fc ⁇ RI with Fc ⁇ RIIb.
  • OVA ovalbumin
  • Thermo aluminum hydroxide adjuvant
  • sensitizer Weigh 0.018 g of ovalbumin and dissolve it in 6 mL of phosphate buffered saline to prepare an ovalbumin solution with a concentration of 3 mg/mL; take 70 ⁇ L of the 3 mg/mL ovalbumin solution and add it to 2.03 mL of phosphate buffered saline to prepare 2.1 mL of 0.1 mg/mL ovalbumin solution, then add an equal amount (2.1 mL) of aluminum hydroxide adjuvant to prepare a 0.05 mg/mL sensitizer, which is prepared for immediate use.
  • mice Eighteen Balb/C mice weighing approximately 20 g were selected. Six mice were used as negative controls and injected intraperitoneally (i.p.) with saline/aluminum adjuvant at a volume of 200 ⁇ L. The other 12 mice were used as the asthma model group and were sensitized with ovalbumin VI/aluminum adjuvant via intraperitoneal injection. The mice were sensitized twice, on day 0 and day 7, respectively, with an injection volume of 200 ⁇ L.
  • the rats were challenged twice with physiological saline (negative control group) and ovalbumin VI (asthma model group) by subarachnoid injection, with an injection volume of 50 ⁇ L.
  • mice On the 19th day, intravenous treatment was performed, and normal saline was used as a control.
  • the asthma model mice were divided into two groups: an mGE2 treatment group and a positive control group with 6 mice in each group. Subcutaneous injection was used. The injection dose of the mGE2 treatment group was 10 mg/kg, and the positive control group used an equal volume of normal saline.
  • the rats were challenged again with normal saline (negative and positive control groups) and ovalbumin VI (treatment group) injected into the subarachnoid space with an injection volume of 50 ⁇ L.
  • mice bronchoalveolar lavage (BAL) of mice was collected for cell counting and classification, and lung tissue was obtained for section staining and analysis.
  • BAL bronchoalveolar lavage
  • mice were anesthetized with approximately 60 mg/kg of pentobarbital, and the trachea was then intubated with an 18-gauge metal needle.
  • a computer-controlled rodent ventilator (flexiVent) was then used to deliver a tidal volume of 10 mL/kg (approximately 250 ⁇ L/breath) at a rate of 150 breaths per minute, with a positive end-expiratory pressure of 2.5 cm H2O .
  • Dynamic pulmonary resistance was measured by fitting a linear, first-order, single-compartment model of airway mechanics to measurements of airway pressure, volume, and airflow during a single sinusoidal perturbation with an amplitude of 150 ⁇ L at 2.5 Hz for approximately 1.2 seconds, using the manufacturer's software (flexiVent). The mean of two tolerance measurements performed before methacholine administration was then established as a baseline. Subsequently, increasing concentrations of methacholine (1.25, 3.125, 12.5, and 50 mg/mL) were delivered to the airways via the ultrasonic nebulizer reservoir, which temporarily diverted the inspiratory limb of the ventilator for 30 seconds.

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Abstract

La présente invention concerne une substance inhalée de protéine de fusion pour le traitement de maladies allergiques respiratoires. La présente invention concerne l'utilisation d'une protéine de fusion dans la préparation d'un médicament pour le traitement de maladies allergiques respiratoires. La protéine de fusion a une séquence d'acides aminés telle que représentée dans SEQ ID NO : 3. La substance inhalée de protéine de fusion fournie par la présente invention peut réduire efficacement l'infiltration de cellules inflammatoires dans le tissu pulmonaire et autour des bronches, et réduire l'hyperréactivité des voies respiratoires.
PCT/CN2025/081418 2024-03-08 2025-03-07 Substance inhalée de protéine de fusion pour le traitement de maladies allergiques respiratoires Pending WO2025185753A1 (fr)

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CNPCT/CN2024/080787 2024-03-08
CN2024080787 2024-03-08

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WO2025185753A8 WO2025185753A8 (fr) 2025-10-02

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1666996A (zh) * 2004-03-10 2005-09-14 伍祥贵 一种融合蛋白及其编码基因与表达方法和应用
CN101835802A (zh) * 2007-06-01 2010-09-15 马里兰大学巴尔的摩分校 免疫球蛋白恒定区Fc受体结合剂
CN104403000A (zh) * 2014-09-29 2015-03-11 上海科新生物技术股份有限公司 人免疫球蛋白ε重链恒定区(hIgE Fc)片段蛋白以及制备方法和应用
CN104922670A (zh) * 2015-05-06 2015-09-23 武汉奥斯梅得生物医药有限公司 融合免疫蛋白在制备治疗多发性硬化症药物中的应用
CN108245685A (zh) * 2018-01-11 2018-07-06 广西壮族自治区人民医院 基于TIM蛋白和IgG蛋白的融合蛋白的防治变应性疾病的药物及其制备方法
CN116410327A (zh) * 2021-12-31 2023-07-11 祝道成 一种融合蛋白及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1666996A (zh) * 2004-03-10 2005-09-14 伍祥贵 一种融合蛋白及其编码基因与表达方法和应用
CN101835802A (zh) * 2007-06-01 2010-09-15 马里兰大学巴尔的摩分校 免疫球蛋白恒定区Fc受体结合剂
CN104403000A (zh) * 2014-09-29 2015-03-11 上海科新生物技术股份有限公司 人免疫球蛋白ε重链恒定区(hIgE Fc)片段蛋白以及制备方法和应用
CN104922670A (zh) * 2015-05-06 2015-09-23 武汉奥斯梅得生物医药有限公司 融合免疫蛋白在制备治疗多发性硬化症药物中的应用
CN108245685A (zh) * 2018-01-11 2018-07-06 广西壮族自治区人民医院 基于TIM蛋白和IgG蛋白的融合蛋白的防治变应性疾病的药物及其制备方法
CN116410327A (zh) * 2021-12-31 2023-07-11 祝道成 一种融合蛋白及其制备方法和应用

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