WO2016058493A1 - 神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 - Google Patents

神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 Download PDF

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WO2016058493A1
WO2016058493A1 PCT/CN2015/091459 CN2015091459W WO2016058493A1 WO 2016058493 A1 WO2016058493 A1 WO 2016058493A1 CN 2015091459 W CN2015091459 W CN 2015091459W WO 2016058493 A1 WO2016058493 A1 WO 2016058493A1
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heart failure
ejection fraction
nrg
treating
preventing
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PCT/CN2015/091459
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English (en)
French (fr)
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周明东
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上海泽生科技开发有限公司
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Priority to AU2015333335A priority Critical patent/AU2015333335B2/en
Priority to RU2017116973A priority patent/RU2017116973A/ru
Priority to ES15850529T priority patent/ES2924395T3/es
Priority to US15/518,730 priority patent/US10561709B2/en
Application filed by 上海泽生科技开发有限公司 filed Critical 上海泽生科技开发有限公司
Priority to CA2963322A priority patent/CA2963322A1/en
Priority to EP22174662.1A priority patent/EP4112068A1/en
Priority to CN201580054201.2A priority patent/CN108064164A/zh
Priority to KR1020177010326A priority patent/KR102603711B1/ko
Priority to JP2017520447A priority patent/JP2017532343A/ja
Priority to EP15850529.7A priority patent/EP3207940B1/en
Priority to KR1020237039263A priority patent/KR20230159650A/ko
Publication of WO2016058493A1 publication Critical patent/WO2016058493A1/zh
Priority to US16/714,397 priority patent/US20200368317A1/en
Priority to AU2021258063A priority patent/AU2021258063A1/en
Priority to US17/558,451 priority patent/US20220354928A1/en

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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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1883—Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to the use of neuregulin in the manufacture of a medicament for preventing, treating or delaying heart failure retention in a mammalian ejection fraction, and the use of said heart failure for preventing, treating or delaying the retention of ejection fraction in a mammal How to use the drug.
  • the present invention provides a method of preventing, treating or delaying heart failure retention in a mammalian ejection fraction, which is a special population with heart failure retention or heart failure with a fractional retention of heart failure.
  • a drug containing neuregulin is used.
  • the present invention relates to a new indication of neuregulin in the treatment of cardiovascular diseases, heart failure retention of heart failure.
  • Neuregulin also known as glial growth factor (GGF), neu differentiation factor (NDF), is a glycoprotein with a molecular weight of about 44KD, which is in the cell.
  • the signaling pathway is a ligand for the ErbB family of tyrosine kinase receptors.
  • the neuregulin family contains four members: NRG1, NRG2, NRG3, NRG4 (Falls et al., Exp Cell Res. 284: 14-30, 2003).
  • NRG1 plays an important role in the nervous system, heart and mammary gland, and there is evidence that NRG1 signaling plays a role in the development of other organ systems, in the pathogenesis of human diseases, including schizophrenia and breast cancer.
  • NRG1 has many isomers. Studies on genetically modified mice (knockout mice) indicate that isomers differ in the N-terminal region or in the similar region of epidermal growth factor (EGF), and their in vivo functions are also different.
  • the present invention is based on neuregulin 1 ⁇ (NRG1 ⁇ ).
  • Neuregulin 1 ⁇ is a transmembrane protein (Holmes et al., Science 256, 1205-1210, 1992).
  • the extra-membrane portion is the N-terminus, including an immunoglobulin-like region (Ig-like_domain) and an EGF-like domain, and the intra-membrane portion is the C-terminus.
  • Ig-like_domain immunoglobulin-like region
  • EGF-like domain an extra-like domain
  • the intra-membrane portion is the C-terminus.
  • the extramembranous portion of the neuregulin can be cleaved and released in a free state, thereby facilitating binding to the ErbB receptor on the peripheral cell surface and activating the corresponding cell signaling.
  • ErbB receptor family is also divided into four classes, ErbB1, ErbB2, ErbB3 and ErbB4, which are both transmembrane proteins with molecular weights around 180-185 KD.
  • ErbB2 they contain a ligand binding region at the N-terminus of the membrane; in addition to ErbB3, they contain protein tyrosine kinase activity at the C-terminus of the membrane.
  • ErbB1 is a receptor for epidermal growth factor
  • ErbB3 and ErbB4 are both receptors for neuregulin. Of the neuregulin receptors, only ErbB2 and ErbB4 are expressed in higher amounts in the heart (Yarden et al., Nat Rev Mol Cell Biol, 2: 127-137, 2001).
  • the phosphorylated intramembrane portion can further bind to a variety of signaling proteins within the cell, thereby activating downstream ERK or AKT signaling pathways, resulting in A range of cellular responses: including stimulation or inhibition of cell proliferation, apoptosis, cell migration, cell differentiation, or cell adhesion.
  • Neuregulin is particularly important for cardiac development (WO0037095, CN1276381, WO03099300, WO9426298, US6444642, WO9918976, WO0064400, Zhao et al., J. Biol. Chem. 273, 10261-10269, 1998).
  • neuregulin In the early stage of embryonic development, the expression of neuregulin is mainly confined to the endocardium, which is then released to the peripheral cardiomyocytes via the paracrine pathway and binds to the extramembranous portion of the protein tyrosine kinase receptor ErbB4 on the cell membrane. ErbB4 and thus ErbB2 are formed. Heterodimers. The formation and activation of the ErbB4/ErbB2 complex is essential for the formation of trabeculae in early sponge-like hearts. Deletion of any of the three regulatory proteins, neuregulin, ErbB4 and ErbB2, causes the embryo to have no trabeculae and die in the uterus early in development.
  • WO0037095 shows that a certain concentration of neuregulin can activate ERK signaling pathway, promote the growth and differentiation of cardiomyocytes, guide the reconstruction of sarcomere and cytoskeleton of cardiomyocytes and cell adhesion, improve the structure of myocardial cells, and enhance the contraction of cardiomyocytes.
  • WO0037095 and WO003099300 also teach that neuregulins can be used to detect, diagnose and treat a variety of cardiovascular diseases.
  • Cardiac muscle function and manipulation WO0037095; 2. New applications of growth factor neuregulin and its analogues: CN1276381; 3.Neuregulin based methods and composition for treating Cardiovascular diseases: WO03099300; 4.Zhao YY, Sawyer DR, Baliga RR, Opel DJ, Han X, Marchionni MA and Kelly RA. Neuregulins Promote Survival and Growth of Cardiac Myocytes. J. Biol. Chem. 273, 10261-10269 (1998) 5.Methods for treating muscle diseases and disorder: WO9426298; 6.
  • Methods of increasing myotube formation or survival or muscle cell mitogenesis, differentiation or survival using a neuregulin US6444642.7.
  • Therapeutic methods comprise use of a neuregulin: WO9918976; .Methods for treating congestive heart failure: WO0064400; 9. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, et al.
  • HF Heart failure
  • SHF systolic heart failure
  • DHF diastolic heart failure
  • ESC European Society of Cardiology
  • HF-PEF Heart Failure with preserved ejection fraction
  • Heart failure with residual ejection fraction is often referred to as diastolic heart failure due to impaired active relaxation of left ventricular diastolic and decreased myocardial compliance.
  • Cardiomyocyte hypertrophy with interstitial fibrosis increases stiffness , leading to impaired filling of the left ventricle during diastole, reduced stroke volume, left ventricular end-diastolic Heart failure occurs when the period pressure increases.
  • Epidemiological data from the American Heart and Lung Institute in 2006 showed that heart failure or diastolic heart failure retained by the ejection fraction accounted for more than 50% of the total number of heart failures.
  • Heart failure preserved by ejection fraction can exist alone or simultaneously with systolic dysfunction.
  • Heart failure with ejection fraction retention is more common in older women with hypertension, diabetes, and left ventricular hypertrophy.
  • Diastolic heart failure has similar symptoms and signs as systolic heart failure. Patients often have underlying diseases such as high blood pressure. Early heart failure manifests as unexplained fatigue, decreased exercise endurance, and a 15 to 20 heart rate increase per minute, which may be an early sign of a decrease in left ventricular function. In addition, there may be labor dyspnea, nocturnal paroxysmal dyspnea, high sleep, etc. The patient may have abdominal or leg edema, and this is the primary or only symptom, and the patient's exercise tolerance damage is gradually occurring.
  • Diastolic heart is a more complex physiological process involving multiple factors. Therefore, the diagnosis of heart failure or diastolic heart failure retained by ejection fraction is more difficult than contractile heart failure. A diagnosis can be made when the following conditions are clinically met:
  • LVEF is normal (or mildly ⁇ 45%), and the left ventricle is normal;
  • Echocardiography did not see heart valve disease, and excluded pericardial disease, hypertrophic cardiomyopathy, restrictive (invasive) cardiomyopathy.
  • the cause of heart failure or diastolic heart failure preserved by ejection fraction is complex and diverse, and the left ventricular pressure/volume mechanism is a well-recognized pathogenesis.
  • ventricular end-diastolic pressure is significantly increased, left ventricular volume is significantly reduced, affecting ventricular filling, and the pressure and volume curves are shifted to the left to form centripetal remodeling. Long-term stress overload is excessive and diastolic heart failure occurs.
  • the diastolic function includes two stages of relaxation (active energy dissipation process) and compliance of ventricular muscle.
  • Ventricular relaxation is the change in heart chamber pressure (dp/dt) per unit time during diastole, which is the active energy dissipation process.
  • Ventricular compliance is the change in pressure (dp/dv) caused by changes in unit volume during diastole, a passive filling process.
  • Relaxation is the active relaxation of early diastolic ventricular muscle, the ability of myocardial fibers to return to the length and pressure before systole, and is the active energy-consuming process of energy-dependent Ca 2+ transport. It mainly includes isovolumic diastolic and early diastolic rapid filling phases.
  • Parameters reflecting left ventricular relaxation include: isovolumic diastolic (IVRT) duration, maximum rate of pressure drop (-dp/dt), and mitral E-deceleration time (DT). These parameters, obtained from two-dimensional echocardiography and hemodynamic testing, can assess the diastolic function of the heart to some extent.
  • IVRT isovolumic diastolic
  • -dp/dt maximum rate of pressure drop
  • DT mitral E-deceleration time
  • heart failure with preserved ejection fraction also lacks specific treatments.
  • Current treatment principles include the use of controlled blood. Standard treatment for symptoms such as angiotensin-converting enzyme inhibitors/angiotensin II receptor inhibitors, beta-blockers, diuretics, such as angiotensin-converting enzyme inhibitors, angiotensin-converting enzyme inhibitors, and diuretic-reducing ventricular rate Etc., but it does not improve the clinical symptoms and prognosis of heart failure retained by ejection fraction.
  • the prognosis of heart failure or diastolic heart failure retained by the ejection fraction is poor, and the patient has a slightly higher rate of repeated hospitalization and increased medical burden.
  • the outcome of diastolic heart failure is systolic heart failure. How to improve the diastolic performance of the heart and block its further deterioration in the early stage of diastolic heart failure is a great challenge for the treatment of diastolic heart failure.
  • neuregulin for heart failure or diastolic heart failure retained by ejection fraction.
  • the present inventors have found that administration of a neuregulin to a mammal can significantly improve the symptoms of heart failure retained by ejection fraction, and can be used for the preparation of a medicament for preventing, treating or delaying heart failure retention in mammalian ejection fraction.
  • the present invention is based on the scientific discovery that NRG is essential for cardiac development and plays a very important role in the maintenance of adult heart function; based on NRG, it can strengthen the scientific findings of myocardial cell sarcomere and cytoskeleton and the formation of intercellular connections; Scientific findings based on NRG that can improve cardiac function in heart failure animals or patients in various animal models and clinical trials.
  • NRG, NRG polypeptides, NRG mutants or other complexes having NRG-like functions are within the scope of the invention.
  • Neuregulin binds to the ErbB receptor on the surface of cardiomyocytes, continuously activates the ERK signaling pathway in cells, and alters the structure of cardiomyocytes, thereby improving the function of cardiomyocytes.
  • a method of preventing, treating or delaying heart failure in a mammal, particularly a human ejection fraction Including administering an effective amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof, or increasing NRG production and/or a mammal, particularly a human, in a heart failure requiring, or wishing to prevent, treat or delay the retention of ejection fraction.
  • a functional substance that achieves the effect of preventing, treating, or delaying the retention of heart failure by the ejection fraction.
  • a pharmaceutical preparation for preventing, treating or delaying heart failure in a mammal, particularly a human ejection fraction.
  • the pharmaceutical preparations comprise an effective amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof, or a substance that increases NRG production and/or function, and a pharmaceutically acceptable carrier, excipient, and the like.
  • the pharmaceutical preparation can be used with other drugs useful for preventing, treating or delaying the retention of ejection fraction.
  • the present invention provides a composition for preventing, treating or delaying heart failure in a mammal, particularly a human ejection fraction.
  • the composition comprises a pharmaceutical formulation provided by the present invention for preventing, treating or delaying heart failure retention of a mammalian cardiac ejection fraction, as well as other drugs for preventing, treating or delaying the retention of ejection fraction.
  • the invention also provides a medicine for preventing, treating or delaying heart failure of a mammal, especially a human ejection fraction retention
  • a kit comprising one or more doses of a pharmaceutical formulation or composition for preventing, treating or delaying the retention of ejection fraction of heart failure, and instructions for how to use the pharmaceutical formulation or composition.
  • neuregulin or “neuregulin” or “NRG” refers to a protein or polypeptide capable of binding and activating ErbB2, ErbB3, ErbB4 or a heterologous or homodimer thereof, including isomers of neuregulin An EGF-like domain in a neuregulin, a polypeptide comprising a neuregulin EGF-like domain, a mutant or derivative of a neuregulin, and other neuregulin-like gene products capable of activating the above receptor.
  • Neuregulin also includes NRG-1, NRG-2, NRG-3 and NRG-4 proteins, polypeptides, fragments, and complexes with NRG-like functions.
  • the neuregulin is a protein or polypeptide that binds to and activates an ErbB2/ErbB4 or ErbB2/ErbB3 heterodimer.
  • the neuregulin of the invention is a fragment of the NRG-1 ⁇ 2 isoform, the amino acid fragment 177-237, which contains an EGF-like domain.
  • the amino acid sequence of this fragment is:
  • the neuregulin used in the present invention activates the above receptors and regulates their biological functions, such as stimulating skeletal muscle cells to synthesize acetylcholine receptors; promoting cardiomyocyte differentiation, survival, and DNA synthesis.
  • Neuregulin also includes those neuregulin mutants that have conserved mutations that do not materially affect biological function. This technique is well known of ordinary skill in the art, a single amino acid mutations in non-critical areas generally do not cause changes in the biological function of the protein or polypeptide (see, Watson et al., Molecular Biology of the Gene, 4 th Edition, 1987, The Bejacmin/Cummings Pub.co., p. 224).
  • the neuregulin used in the present invention can be isolated from a natural source or obtained by recombinant techniques, artificial synthesis or other means.
  • EGF-like domain or “EGF-like domain” refers to a polypeptide fragment encoded by the neuregulin gene that binds to and activates ErbB2, ErbB3, ErbB4 or a heterologous or homodimer thereof, and
  • the EGF receptor binding regions described in the references have structural similarities: WO 00/64400; Holmes et al, Science, 256: 1205-1210 (1992); U.S. Patents 5, 530, 109 and 5, 716, 930; Hijazi et al, Int. J. Oncol.
  • the EGF-like domain binds to and activates an ErbB2/ErbB4 or ErbB2/ErbB3 heterodimer.
  • the EGF-like domain comprises a receptor binding region amino acid of NRG-1.
  • an EGF-like domain refers to amino acids 177-226, 177-237 or 177-240 of NRG-1.
  • the EGF-like domain comprises a receptor binding region amino acid of NRG-2. In certain embodiments, the EGF-like domain comprises a receptor binding region amino acid of NRG-3. In certain embodiments, the EGF-like domain comprises a receptor binding region amino acid of NRG-4. In certain embodiments, the EGF-like domain comprises the amino acid sequence described in U.S. Patent 5,834,229:
  • Ejection fraction-preserved heart failure is also referred to herein as left ventricular ejection fraction (LVEF) normal heart failure (HFNEF), left ventricular ejection fraction maintained heart failure (HF-PLVEF) ), systolic heart failure (HF-PSF), diastolic heart failure (DHF) or diastolic heart failure, which refers to a normal or mild decrease in left ventricular ejection fraction (LVEF), mainly due to left ventricular diastolic Injury of active relaxation and myocardial compliance, myocardial hypertrophy with interstitial fibrosis increases stiffness, resulting in impaired left ventricular filling during diastole, decreased stroke volume, and increased left ventricular end-diastolic pressure Heart failure. It can exist alone or in conjunction with contractile dysfunction.
  • LVEF left ventricular ejection fraction
  • HNEF left ventricular ejection fraction maintained heart failure
  • HF-PSF systolic heart failure
  • DHF diastolic
  • IVRT isovolumic relaxation time
  • pressure drop rate (-dp/dt) refers to the rate at which isovolumetric diastolic left ventricular pressure drops. The larger the value, the faster the left ventricular pressure drops and the better the diastolic function, which is one of the reliability indicators for evaluating myocardial relaxation.
  • mitral E peak refers to the early diastolic peak (E) of the mitral valve in the heart, reflecting the maximum blood flow velocity through the valve in the rapid filling phase of the left ventricle, and the E peak of the mitral valve blood flow curve.
  • E early diastolic peak
  • E-peak fall time refers to the deceleration time of the mitral valve E peak, which is the blood flow deceleration time formed by the early diastolic mitral valve moving to the left atrium, reflecting the left atrioventricular compartment during rapid filling.
  • the pressure difference changes, and the smaller the value, the faster the pressure difference changes.
  • the reduction of active relaxation usually occurs in the early stage of the disease, which is manifested by a decrease in early left ventricular diastolic volume, a decrease in E peak, and a DT extension of >240 ms.
  • other drugs for the treatment of heart failure with retention of ejection fraction refer to known drugs useful for the treatment of heart failure with retention of ejection fraction, including angiotensin converting enzyme inhibitors/angiotensin II receptors.
  • Inhibitors beta blockers, calcium antagonists, cyclic adenosine monophosphate, catecholamines, nitrates, phosphatase inhibitors, diuretics, renin-angiotensin-aldosterone system (RAS Antagonists, myocardial energy optimizers, and the like.
  • Example 1 Effect of recombinant human New Zealand Green on cardiac function in rats with hypertensive heart failure
  • SHR hypertension strain rats purchased from the Animal Center of the Chinese Academy of Sciences.
  • the WKY strain was used as a control for SHR and was also purchased from the Animal Center of the Chinese Academy of Sciences.
  • Neucardin TM 61 amino acids, produced by Shanghai Zesheng Technology Development Co., Ltd.
  • SHR hypertension rats were used for normal feeding, and the feeding process center super-monitored the changes of cardiac function. After 16 months of feeding, the ejection fraction (EF) of SHR rats decreased to 70%, and LVDd and LVDs increased significantly, suggesting that the heart failure model of hypertensive rats was successfully established.
  • EF ejection fraction
  • the model was randomly assigned to the negative control group, the NRG treatment group, and the captopril treatment group.
  • rhNRG was administered intravenously at a dose of 6.5 ug/kg once daily for 5 days for 5 days as a treatment cycle for a total of 3 treatment cycles.
  • the NRG group was also given drinking water by gavage twice a day; captopril was administered by intragastric administration at a dose of 10 mg/kg twice daily for continuous administration.
  • 3 cycles of NRG excipients were administered to the tail vein.
  • the negative control group was intragastrically administered with drinking water and tail vein injection of NRG excipient.
  • each group of rats underwent cardiac ultrasonography to determine the changes in cardiac function.
  • rats were anesthetized with 3% pentobarbital intraperitoneal injection, a midline incision in the neck, the left common carotid artery was isolated, and the hemodynamic parameters of the arteries and left ventricles were measured.
  • RhNRG was administered to hypertensive heart failure rats at a dose of 6.5 ug/kg for 5 consecutive days, 2 days for one treatment cycle, and 2 or 3 cycles after treatment to prevent left ventricular end-diastolic and end-systolic
  • the volume is further expanded to improve hemodynamics, thereby comprehensively improving cardiac function in rats with hypertension and heart failure.
  • captopril improves blood pressure in rats with hypertensive heart failure by lowering blood pressure
  • rhNRG can increase the rate of left ventricular pressure drop by isovolumic diastolic-dp/dt.
  • Example 2 Cardiac function of recombinant human Newland Green in patients with heart failure retained by ejection fraction
  • LVEF left ventricular ejection fraction
  • Dosage form lyophilized powder for injection
  • Dosage form lyophilized powder for injection

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Abstract

本发明公开了纽兰格林蛋白在制备用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物中的应用，以及所述药物的使用方法。本发明还提供了预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的方法，包括在患有所述疾病或具有所述疾病风险的特殊人群中使用包含纽兰格林蛋白的药物。

Description

神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 技术领域
本发明涉及纽兰格林蛋白在制备用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物中的应用，以及所述用于预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的药物的使用方法。特别地，本发明提供了预防、治疗或延缓哺乳动物射血分数保留的心力衰竭的方法，该方法是在患有射血分数保留的心力衰竭或者具有射血分数保留的心力衰竭风险的特殊人群中使用包含纽兰格林蛋白的药物。具体而言，本发明涉及神经调节蛋白在心血管疾病治疗中的新适应症射血分数保留的心力衰竭。
发明背景
神经调节蛋白(neuregulin，NRG；heregulin，HRG)，又叫神经胶质生长因子(glial growth factor,GGF),neu分化因子(new differentiation_factor,NDF),为分子量在44KD左右的糖蛋白，它们在细胞间传递信号，是酪氨酸激酶受体ErbB家族的配体。神经调节蛋白家族含4个成员：NRG1，NRG2，NRG3，NRG4(Falls et al.,Exp Cell Res.284:14-30,2003)。NRG1在神经系统、心脏和乳腺中起着重要作用，还有证据显示NRG1信号传递在其他一些器官系统的发育、功能以及人类疾病(包括精神分裂症和乳腺癌)的发病机理中起作用。NRG1有很多异构体。对基因突变小鼠(基因敲除小鼠)的研究说明在N末端区或表皮生长因子(EGF)类似区不同的异构体，其在体功能也不一样。本发明是以神经调节蛋白1β(NRG1β)为基础的。
神经调节蛋白1β为一跨膜蛋白(Holmes et al.,Science 256,1205-1210,1992)。膜外部分是N末端，包括免疫球蛋白类似区(Ig-like_domain)和EGF类似区(EGF-like domain)，膜内部分是C末端。在细胞外基质的金属蛋白酶作用下，神经调节蛋白的膜外部分可被酶切下来而呈游离状态，从而有利于和周围细胞表面的ErbB受体结合，激活相应的细胞信号传递。ErbB受体家族也分为四类，ErbB1、ErbB2、ErbB3和ErbB4，它们都是跨膜蛋白，分子量在180-185KD附近。除ErbB2外，它们在膜外的N末端都含配体结合区；除ErbB3外，它们在膜内的C末端都含蛋白酪氨酸激酶活性。其中ErbB1是表皮生长因子的受体，ErbB3和ErbB4都是神经调节蛋白的受体。在神经调节蛋白的受体中，只有ErbB2和ErbB4在心脏表达量较高(Yarden et al.,Nat Rev Mol Cell Biol,2:127-137,2001)。
当神经调节蛋白与ErbB3或ErbB4的膜外部分结合时，将引起ErbB3、ErbB4与其他ErbB受体(常常包括ErbB2)形成异源二聚体，或ErbB4自身形成同源二聚体，然后导致受体的膜内部分被磷酸化(Yarden et al.,Nat Rev Mol Cell Biol,2:127-137,2001)。磷酸化的膜内部分可进一步与细胞内的多种信号传递蛋白结合，从而激活下游ERK或AKT信号通路，引起 一系列细胞反应：包括刺激或抑制细胞增殖、细胞凋亡、细胞迁移、细胞分化或细胞粘连。神经调节蛋白对心脏的发育尤其重要(WO0037095，CN1276381，WO03099300，WO9426298，US6444642，WO9918976，WO0064400，Zhao et al.,J.Biol.Chem.273,10261-10269,1998)。在胚胎发育早期，神经调节蛋白的表达主要局限于心内膜，随后通过旁分泌途径释放到周围心肌细胞并与细胞膜上的蛋白酪氨酸激酶受体ErbB4膜外部分结合，ErbB4进而与ErbB2形成异源二聚体。ErbB4/ErbB2复合物的形成及激活对早期海绵样心脏形成小梁是必须的。神经调节蛋白、ErbB4和ErbB2三个蛋白基因中的任何一个缺失都会使胚胎没有小梁并在发育早期死于子宫。WO0037095显示一定浓度的神经调节蛋白可持续激活ERK信号通路，促进心肌细胞的生长及分化，引导心肌细胞和细胞粘连处肌节和细胞骨架的重建，改善心肌细胞的结构，增强心肌细胞的收缩。WO0037095及WO003099300还指出神经调节蛋白可用于检测、诊断和治疗各种心血管疾病。
下面列举了与本发明有关的一些现有技术文献：1.Cardiac muscle function and manipulation:WO0037095；2.生长因子神经调节蛋白及其类似物的新应用：CN1276381；3.Neuregulin based methods and composition for treating cardiovascular diseases:WO03099300；4.Zhao YY,Sawyer DR,Baliga RR,Opel DJ,Han X,Marchionni MA and Kelly RA.Neuregulins Promote Survival and Growth of Cardiac Myocytes.J.Biol.Chem.273,10261-10269(1998)；5.Methods for treating muscle diseases and disorder:WO9426298；6.Methods of increasing myotube formation or survival or muscle cell mitogenesis,differentiation or survival using a neuregulin:US6444642.7.Therapeutic methods comprising use of a neuregulin:WO9918976；8.Methods for treating congestive heart failure:WO0064400；9.Holmes WE,Sliwkowski MX,Akita RW,Henzel WJ,Lee J,Park JW,Yansura D,Abadi N,Raab H,Lewis GD,et al.Identification of heregulin,a specific activator p185erbB2.Science 256,1205-1210(1992)；10.Falls DL.Neuregulins:functions,forms and signalingstrategies.Experimental Cell Research,284,14-30(2003).11.Yarden Y,Sliwkowski X.Untangling the ErbB signaling Network.Nature Reviews:Molecular Cell Biology,2127-137(2001).
心力衰竭(heart failure，HF)是各种心脏疾病导致心功能不全的一种综合征，包括收缩性心力衰竭(systolic heart failure，SHF)和舒张性心力衰竭(diastolic heart failure，DHF)。2008年，欧洲心脏病学会(ESC)颁布的《急/慢性心衰诊断及治疗指南》又将后者定义为射血分数保留的心力衰竭(Heart Failure with preserved ejection fraction,HF-PEF)。收缩性心力衰竭是指心肌收缩力下降使心排血量不能满足机体代谢的需要，器官、组织血流灌注不足，同时出现肺循环和(或)体循环淤血的表现。射血分数保留的心力衰竭(HF-PEF)常常是指舒张性心力衰竭，是由于左心室舒张期主动松弛能力受损和心肌顺应性降低，心肌细胞肥大伴间质纤维化使其僵硬度增加，导致左心室在舒张期的充盈受损，心搏量减少，左室舒张末 期压增高而发生的心衰。2006年美国心肺研究院的流行病学资料显示，射血分数保留的心力衰竭或舒张性心衰已占心衰总人数的50％以上。射血分数保留的心力衰竭可单独存在，也可与收缩功能障碍同时出现。射血分数保留的心力衰竭多见于有高血压、糖尿病、左室肥厚的老年女性。
舒张性心力衰竭同收缩性心力衰竭具有类似的症状和体征。患者常有高血压等基础疾病。心衰早期表现为不明原因的疲乏，运动耐力下降，心率每分钟增加15～20次，可能是左心功能降低的早期征兆。继而可出现劳力性呼吸困难、夜间阵发性呼吸困难、高枕睡眠等，患者可能出现腹部或腿部水肿，并以此为首要或惟一症状就诊，而患者的运动耐量损害是逐渐发生的。
心脏的舒张是一个涉及多种因素的较收缩更为复杂的生理过程。因此，射血分数保留的心力衰竭或舒张性心衰的诊断较收缩性心衰更为困难。目前临床上符合下列条件时，可作出诊断：
1.有心衰的典型症状和体征；
2.LVEF正常(或轻度下降≥45％)，左心室形态正常；
3.有基础心脏病证据，如高血压患者有左心室肥厚、左心房扩大，超声心动图有左室舒张功能异常的证据；
4.BNP/NT-ProBNP升高；
5.超声心动图未见心瓣膜疾病，并排除心包疾病、肥厚型心肌病、限制性(浸润性)心肌病等。
射血分数保留的心力衰竭或舒张性心衰的发病原因是复杂多样的，而左心室压力/容积机制是一个比较公认的发病机制。高血压病、肥厚型心肌病、主动脉瓣狭窄的患者，心室舒张末压得明显升高，左室容量明显缩小，影响了心室充盈，使压力与容量曲线左移，形成向心性重构，长期存在压力负荷过重而发生舒张性心衰。
心室舒张功能(diastolic function)包括心室肌的松弛性(relaxation)(主动耗能过程)和顺应性(compliance)两个阶段。心室松弛性(relaxation)为舒张期单位时间心腔压力的变化(dp/dt)，系主动耗能过程。心室顺应性(compliance)为舒张期单位容积的变化引起的压力的变化(dp/dv)，系被动充盈过程。松弛是舒张早期心室肌的主动舒张，心肌纤维恢复到收缩期前的长度和压力的能力，是能量依赖Ca2+的转运主动耗能过程。主要包括等容舒张期和舒张早期快速充盈相。反映左室松弛的参数包括：等容舒张期(IVRT)持续时间、压力下降的最大速率(－dp/dt)、二尖瓣E峰减速时间(DT)等。这些由二维超声心动图和血流动力学测试得到的参数能一定程度上评价心脏的舒张功能。
另外，射血分数保留的心力衰竭也缺少特异性的治疗手段，目前的治疗原则包括使用控制血 压，降低心室率，利尿减轻体液潴留等针对收缩性心衰改善症状的标准治疗药物，如血管紧张素转换酶抑制剂/血管紧张素II受体抑制剂，β受体阻滞剂，利尿剂等，但却不能改善射血分数保留的心力衰竭的临床症状和预后。最后，射血分数保留的心力衰竭或舒张性心衰的预后不良，患者再次和反复住院率稍高，增加了医疗负担。舒张性心衰发展的结局是收缩性心衰，如何能在舒张性心衰的早期阶段，改善心脏的舒张性能，阻断其进一步恶化途径，是当前舒张性心衰治疗面临的极大挑战。
现有技术文献中没有关于神经调节蛋白对于射血分数保留的心力衰竭或舒张性心力衰竭方面的报道。本发明发现给予哺乳动物神经调节蛋白能显著改善射血分数保留的心力衰竭的症状，可用于制备预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物。
发明内容
A.发明概述
本发明是基于NRG对心脏发育至关重要，对成年心脏的功能维持也起到非常重要的作用的科学发现；基于NRG可以加强心肌细胞肌小节和细胞骨架以及细胞间连接的形成的科学发现；基于NRG在各种动物模型和临床试验中可以提高心衰动物或病人的心脏功能的科学发现。NRG，NRG多肽，NRG突变体或其它具有NRG样功能的复合物都属于本发明的范畴。神经调节蛋白可与心肌细胞表面的ErbB受体结合，持续激活细胞内的ERK信号通路，改变心肌细胞的结构，从而改善心肌细胞的功能。
本发明的第一个方面，是提供了一种预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的方法。包括对需要或希望预防、治疗或延迟射血分数保留的心力衰竭的哺乳动物特别是人施用有效量的NRG或其功能片段，或编码NRG或其功能片段的核酸，或提高NRG产量和/或功能的物质，从而达到预防、治疗或延迟射血分数保留的心力衰竭的效果。
本发明的第二个方面，是提供了一种预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的药物制剂。该药物制剂包含有效量的NRG或其功能片段，或编码NRG或其功能片段的核酸，或提高NRG产量和/或功能的物质，以及药学上可以接受的载体、赋形剂等。该药物制剂可以和其它可用于预防、治疗或延迟射血分数保留的心力衰竭的药物一起使用。
本发明的另一个方面，是提供了一种用于预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的组合物。该组合物包含了本发明所提供的用于预防、治疗或延迟哺乳动物心脏射血分数保留的心力衰竭的药物制剂，以及其它预防、治疗或延迟射血分数保留的心力衰竭的药物。
本发明还提供了一种用于预防、治疗或延迟哺乳动物特别是人射血分数保留的心力衰竭的药 盒，其中包含了一次或多次使用剂量的上述预防、治疗或延迟射血分数保留的心力衰竭的药物制剂或组合物，以及如何使用该药物制剂或组合物的说明书。
B.定义
除另有定义，这里使用的所有科技术语与本发明所属技术领域的普通技术人员理解含义相同。所有专利文献、专利申请文献、公开的专利文献和其它出版物均作为参考。如本节阐述的定义与上述参考文献所述的定义不一致或相反时，以本节阐述的定义为准。
除非特别指明，在此所用“一个”的意思是“至少一个”或“一个或多于一个”。
此处所用“神经调节蛋白”或“neuregulin”或“NRG”是指能够结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的蛋白或多肽，包括神经调节蛋白的异构体、神经调节蛋白中的EGF样功能域、包含神经调节蛋白EGF样功能域的多肽、神经调节蛋白的突变体或衍生物以及其它能够激活上述受体的神经调节蛋白样的基因产物。神经调节蛋白还包括NRG-1，NRG-2，NRG-3和NRG-4蛋白、多肽、片段以及具有NRG样功能的复合物。优选的，神经调节蛋白是可以结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体的蛋白或多肽。作为例子，但并非为了限制的目的，本发明的神经调节蛋白是NRG-1β2异构体的一个片段，即177-237位氨基酸片段，其中包含了EGF样功能域。该片段的氨基酸序列为：
Figure PCTCN2015091459-appb-000001
Figure PCTCN2015091459-appb-000002
本发明所用神经调节蛋白可以激活上述受体并调节它们的生物学功能，比如刺激骨骼肌细胞合成乙酰胆碱受体；促进心肌细胞的分化、存活以及DNA合成。神经调节蛋白还包括那些具有并不实质性影响生物学功能的保守性突变的神经调节蛋白突变体。本技术领域中普通技术人员熟知，非关键区域的单个氨基酸的突变一般不会引起该蛋白或多肽的生物学功能的改变(参见Watson等人,Molecular Biology of the Gene,4th Edition,1987,The Bejacmin/Cummings Pub.co.,p.224)。本发明所用神经调节蛋白可以从天然的来源分离得到，或者通过重组技术、人工合成或其它手段得到。
此处所用“EGF样功能域”或“EGF-like domain”是指由neuregulin基因所编码的可以结合并激活ErbB2、ErbB3、ErbB4或其异源或同源二聚体的多肽片段，并且与下述参考文献中描述的EGF受体结合区域具有结构相似性：WO 00/64400；Holmes等，Science,256:1205-1210(1992)；美国专利5,530,109和5,716,930；Hijazi等，Int.J.Oncol.,13:1061-1067(1998)；Chang等，Nature，387:509-512(1997)；Carraway等，Nature，387:512-516(1997)；Higashiyama等，J.Biochem.,122:675-680(1997)；以及WO 97/09425。在某些实施方案中，EGF样功能域结合并激活ErbB2/ErbB4或ErbB2/ErbB3异源二聚体。在某些实施方案中，EGF样功能域包含NRG-1的受体结合区氨基酸。在某些实施方案中，EGF样功能域是指NRG-1的第177-226位、177-237位或177-240位氨基酸。在某些实施方案中，EGF样功能域包含NRG-2的受体结合区氨基酸。在某些实施方案中，EGF样功能域包含NRG-3的受体结合区氨基酸。 在某些实施方案中，EGF样功能域包含NRG-4的受体结合区氨基酸。在某些实施方案中，EGF样功能域包含美国专利5,834,229中描述的氨基酸序列：
Figure PCTCN2015091459-appb-000003
Figure PCTCN2015091459-appb-000004
此处所用“射血分数保留的心力衰竭(HF-PEF)”又称之为左心室射血分数(LVEF)正常的心衰(HFNEF)，左心室射血分数保持的心衰(HF-PLVEF)，收缩功能尚存的心衰(HF-PSF)，舒张性心力衰竭(DHF)或舒张性心衰，其是指左心室射血分数(LVEF)正常或轻度下降，主要由于左心室舒张期主动松弛能力受损和心肌顺应性降低，心肌细胞肥大伴间质纤维化使其僵硬度增加，导致左心室在舒张期的充盈受损，心搏量减少，左室舒张末期压增高而发生的心衰。它可单独存在，也可与收缩功能障碍同时出现。
此处所用“等容舒张期(isovolumic relaxation time,IVRT)”是指心室处于压力不断下降的等容封闭状态，此时心室开始舒张，主动脉瓣和房室瓣处于关闭状态。当左心室松弛受损时，IVRT延长。当左心室松弛受损改善时，IVRT减少。
此处所用“压力下降速率(－dp/dt)”是指等容舒张期左心室压力下降的速率。其值越大，表明左心室压力下降越快，心脏舒张功能越好，是评价心肌松弛性的可靠性指标之一。
此处所用“二尖瓣E峰”是指心脏二尖瓣口舒张早期峰值(E)，反映了左心室快速充盈期通过瓣口的最大血流速度，二尖瓣口血流曲线E峰代表舒张早期左心室主动松弛，反应左心室松弛性。
此处所用“E峰下降时间(DT)”是指二尖瓣E峰下降减速时间，是舒张早期二尖瓣向左房方向运动形成的血流减速时间，反映了在快速充盈期左房室压差变化，其值越小表明压差变化越快。主动松弛性降低一般发生于疾病早期，表现为左心室舒张早期充盈量减少，E峰降低，DT延长>240ms。
此处所用“其它用于治疗射血分数保留的心力衰竭的药物”是指已知的可用于治疗射血分数保留的心力衰竭的药物，包括血管紧张素转换酶抑制剂/血管紧张素II受体抑制剂，β受体阻滞剂，钙离子拮抗剂，环磷酸腺苷，儿茶酚胺类药物，硝酸酯类药物，磷酸酯酶抑制剂，利尿剂，肾素-血管紧张素-醛固酮系统(RAS)拮抗剂，心肌能量优化剂等。
具体实施方式
实施例1：重组人纽兰格林对高血压心衰大鼠的心功能作用研究
研究重组人纽兰格林(rhNRG)对SHR高血压大鼠心衰模型的治疗作用。方法：采用SHR高血压品系大鼠，正常饲养，饲养过程中心超监测其心功能变化，16个月时，射血分数(EF)下降至70％，提示高血压大鼠心衰模型成功建立。高血压心衰大鼠随机分为阴性对照组、NRG治疗组以及卡托普利治疗组，rhNRG连续给药5天，停药2天为一个治疗周期，NRG组共接受了3个治疗周期的治疗。分别于第2和第3个治疗周期结束时，对各组大鼠行心超 检查，测定其心功能变化；并于第3个治疗周期结束后，对各组大鼠行血流动力学检测。
1.试验动物
1.1品系、来源：SHR高血压品系大鼠，购自中国科学院动物中心。WKY品系作为SHR的对照，同样购自中国科学院动物中心。
1.2性别、周龄：雄性，6周龄。
1.3饲养：普通啮齿类饲料，自由进食水，12小时光暗循环
2.受试药物
规格：NeucardinTM，61个氨基酸，上海泽生科技开发有限公司生产
3.实验材料
3.1心脏超声诊断仪：Philips Sonos 5500
3.2卡托普利：中美上海施贵宝制药有限公司
4.实验方法
4.1高血压心衰大鼠模型制备
采用SHR高血压品系大鼠，正常饲养，饲养过程中心超监测其心功能变化。饲养16个月后，SHR大鼠射血分数(EF)下降至70％，LVDd、LVDs明显增大，提示高血压大鼠心衰模型成功建立。
4.2分组与给药
模型成功建立后，随机分入阴性对照组、NRG治疗组以及卡托普利治疗组。rhNRG为静脉注射给药，剂量为6.5ug/kg，每日1次，连续给药5天停药2天为一治疗周期，共接受3个治疗周期的治疗。同时，NRG组还灌胃给予饮用水，每日两次；卡托普利的给药方法为灌胃给药，剂量为10mg/kg，每日2次，连续给药。同时尾静脉给予3个治疗周期的NRG赋性剂。阴性对照组分别灌胃给予饮用水及尾静脉注射给予NRG赋性剂。
4.3心超检查
分别于治疗前以及第2和第3个治疗周期结束时，氯胺酮麻醉后对各组大鼠行心超检查，测定其心功能变化。
4.4血流动力学测定
第3个治疗周期结束后，大鼠用3％戊巴比妥腹腔注射麻醉，颈部正中切口，分离左颈总动脉，插管，检测动脉及左心室血流动力学指标。
5.实验结果
与阴性对照组相比，NRG可显著改善高血压大鼠血流动力学，其中-dp/dt显示统计学差异(分别为－7467.6±715.8和－5488.1±1340.3，p＝0.016)；而卡托普利可显著降低高 血压大鼠血压(174.5±33.0vs 216.5±23.2和228.0±26.0；p＝0.029，p＝0.017)。
6.结论
按照6.5ug/kg的剂量给予高血压心衰大鼠rhNRG，连续给药5天，停药2天为一治疗周期，治疗2个周期或3个周期后，可防止左心室舒张末期及收缩末期容积进一步扩大，改善血流动力学，从而全面改善高血压心衰大鼠心功能。从表1的数据来看，卡托普利是通过降血压途径来改善高血压心衰大鼠的心功能，而rhNRG可通过增加等容舒张期左心室压力下降的速率-dp/dt，而非降血压途径来改善高血压心衰大鼠的心功能。
表1给药3个治疗周期后各组血流动力学参数
组别 MAP -dp/dt
阴性对照 174.7±16.8 -5488.1±1340.3
NRG 182.5±18.8 -7467.6±715.8
卡托普利 139.9±24.8 -5441.2±1007.3
实施例2：重组人纽兰格林对射血分数保留的心力衰竭患者的心功能作用研究
为了评估重组人纽兰格林对射血分数保留的心力衰竭患者的心功能作用，在上海交通大学附属第六人民医院进行了初步的临床实验，其中安慰剂组2例，试验组2例。
1.主要入选标准：
1.1左心室射血分数(LVEF)≥50％(二维超声心动图诊断)；
1.2纽约心功能(NYHA)II或III级；
1.3明确诊断慢性心衰(包括病史，症状，体征)，且近1个月临床症状稳定；
1.4接受心衰标准治疗药物已达目标剂量或最大耐受量至少1个月以上，或近1个月内未改变剂量；
1.5理解并签署知情同意书。
2.研究药物：
名称：注射用重组人纽兰格林规格：250μg/支
剂型：注射用冻干粉
给药途径：静脉滴注
安慰剂(零剂量)：
名称：重组人纽兰格林冻干剂的赋形剂
剂型：注射用冻干粉
给药途径：静脉滴注
3.给药途径，用量及疗程见表2：
表2给药剂量、途径和疗程
Figure PCTCN2015091459-appb-000005
4.数据采集：在筛选期、11-13d和30d,测二维超声心动图的二尖瓣血流频谱。
5.结果及讨论：
表3二尖瓣血流频谱中IVRT和DT的数值变化
Figure PCTCN2015091459-appb-000006
从表3中结果可知，给予安慰剂的患者，其IVRT和DT值在逐渐变大；而给予NRG的患者，其IVRT和DT值有明显的下降，显示其舒张功能有一定程度的改善。
上述列举的实施例不会限制本发明的保护范围。在没有背离本发明的宗旨和范围的情况下，本技术领域内的技术人员可以对本发明进行调整和改变。因此，本发明的保护范围应当根据权利要求来定义，而不是通过具体的实施例来限定。

Claims (10)

  1. NRG用于制备预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物的用途。
  2. 根据权利要求1所述的用途，其中所述NRG是NRG-1。
  3. 根据权利要求1所述的用途，其中所述NRG包含SEQ ID NO:1的氨基酸序列。
  4. 根据权利要求1所述的用途，其中所述哺乳动物是人。
  5. 一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药物制剂，其特征在于其含有有效剂量的NRG。
  6. 根据权利要求5所述的制剂，其中所述NRG是NRG-1。
  7. 根据权利要求5所述的制剂，其中所述NRG包含SEQ ID NO:1的氨基酸序列。
  8. 根据权利要求5所述的制剂，其中所述哺乳动物是人。
  9. 一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的组合物，其特征在于其含有如权利要求5所述的药物制剂以及其它用于治疗射血分数保留的心力衰竭的药物。
  10. 一种用于预防、治疗或延迟哺乳动物射血分数保留的心力衰竭的药盒，其中含有如权利要求5所述的药物制剂以及如何使用该药物制剂的说明书。
PCT/CN2015/091459 2014-10-17 2015-10-08 神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物 WO2016058493A1 (zh)

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