WO2022161381A1 - Utilisation d'endostatine dans le traitement et la prévention de maladies associées au coronavirus - Google Patents

Utilisation d'endostatine dans le traitement et la prévention de maladies associées au coronavirus Download PDF

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Publication number
WO2022161381A1
WO2022161381A1 PCT/CN2022/073924 CN2022073924W WO2022161381A1 WO 2022161381 A1 WO2022161381 A1 WO 2022161381A1 CN 2022073924 W CN2022073924 W CN 2022073924W WO 2022161381 A1 WO2022161381 A1 WO 2022161381A1
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endostatin
coronavirus
subject
cov
sars
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PCT/CN2022/073924
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English (en)
Chinese (zh)
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罗永章
刘弘毅
唐嘉泽
付彦
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清华大学
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Priority to CN202280011679.7A priority Critical patent/CN117460533A/zh
Publication of WO2022161381A1 publication Critical patent/WO2022161381A1/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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to the treatment and prevention of coronavirus-related diseases, in particular, to the application of endostatin and its functional variants in the treatment and prevention of coronavirus-related diseases.
  • Novel coronavirus pneumonia (referred to as "new coronary pneumonia”) is an acute infectious pneumonia for which there is currently no specific medicine.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the outbreak of new coronary pneumonia in 2019-2020 [1-4] .
  • the virus has spread widely around the world. As of June 28, 2020, there have been more than 10.04 million confirmed cases worldwide and 500,000 deaths [5] .
  • Nucleolin (NCL) on the cell membrane is a receptor for Endostatin (ES) and is associated with the infection of a variety of RNA viruses, including respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), Influenza A virus (Influenza A), polio virus (Polro virus), human parainfluenza virus (HPIV), etc. [7-10] .
  • NCL is the receptor of RSV fusion protein [10] , and in cell culture and animal models, interfering with the interaction of NCL-RSV fusion protein can effectively treat RSV infection [7-10] .
  • NCL is closely related to the infection and replication process of viruses [11] . During the infection of various viruses, NCL will first undergo membrane localization, and the NCL after membrane localization will directly contact the virus to help the virus enter the cell, and then carry out Virus replication and subsequent infection. It has been reported that the presence of non-structural protein 1 (nsp1) of SARS-COV will increase the content of NCL in the cytoplasm [11] .
  • nsp1 non-structural protein 1
  • non-structural protein 1 in SARS-COV and SARS-CoV-2 the pathogen of new coronary pneumonia virus, is as high as 91.1%.
  • SARS-CoV-2 As an RNA virus associated with severe acute respiratory disease, SARS-CoV-2, its infection and replication process May also be closely related to NCL.
  • the present invention provides the use of endostatin in the preparation of a medicament for preventing or treating coronavirus-related diseases in a subject.
  • the present invention also provides a method of preventing or treating a coronavirus-related disease in a subject, comprising administering to the subject an effective amount of endostatin.
  • the present invention also provides a pharmaceutical composition for preventing or treating coronavirus-related diseases in a subject, comprising: endostatin; and a pharmaceutically acceptable carrier.
  • the present invention also provides a kit for preventing or treating a coronavirus-related disease in a subject, comprising the pharmaceutical composition described above.
  • the coronavirus is selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.
  • the coronavirus-related disease is selected from SARS, MERS, and COVID-19.
  • the subject is a mammal or avian, preferably a human.
  • the dosage form of the medicament is selected from: intravenous injection, oral spray, nasal spray, eye drops.
  • the endostatin is human endostatin.
  • the endostatin is YH-16 or M2ES.
  • the endostatin is pegylated human endostatin or a functional variant thereof.
  • Endostatin is an approved endogenous protein drug that can effectively inhibit angiogenesis.
  • the inventor first reported that the receptor of ES is NCL [12] .
  • M2ES is a long-acting recombinant endostatin whose receptor is also NCL. 273 patients have been enrolled in the phase II clinical trial of this drug for lung cancer indications, and its safety has been verified. We speculate that M2ES may affect the infection and replication process of SARS-CoV-2 by binding to NCL. Therefore, exploring the effects of M2ES on SARS-CoV-2 infection and replication is of great significance for the development of new antiviral drugs.
  • Coronavirus refers to a class of enveloped viruses that can cause disease in vertebrates, especially mammals or birds, having a single-stranded positive-stranded RNA genome. They belong to the order Nidovirales, the family Coronaviridae. Animal or human diseases caused by coronaviruses are referred to herein as "coronavirus-related diseases” or “coronavirus infections”. Seven coronaviruses have been found to infect humans so far, including HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2.
  • COVID-19 Some of the diseases they cause are mild, like the common flu, while others can be deadly, such as SARS, MERS, and COVID-19.
  • the coronavirus that causes COVID-19 is SARS-CoV-2.
  • the most common symptoms of COVID-19 include fever, dry cough and weakness. Patients with mild symptoms may experience only a runny nose or sore throat; in severe cases, breathing difficulties, cytokine storms, and even eventual organ failure may occur.
  • the present invention provides a method of preventing or treating a coronavirus-related disease in a subject, comprising administering to the subject an effective amount of endostatin.
  • subject refers to an individual who has or is suspected of having a disease (eg, COVID-19), or, in predicting risk of disease or for prophylactic applications, may also include healthy individuals .
  • a disease eg, COVID-19
  • the term is often used interchangeably with "patient,” “subject,” “subject,” and the like.
  • the subject is a vertebrate, preferably a mammal and a bird, more preferably a human.
  • Prevention refers to avoiding, reducing or delaying the occurrence of a particular disease or disease-related symptom in a subject that has not occurred prior to administration of the relevant drug. "Prevention” does not necessarily require complete prevention of the occurrence of a disease or disease-related symptoms, for example, to reduce the risk of a particular disease or disease-related symptoms in a subject after administration of the relevant drug, or to reduce the severity of subsequent related symptoms, All can be considered to "prevent” the appearance or development of the disease. “Treatment” refers to alleviating, alleviating, ameliorating, or inhibiting (eg, arresting the development) of a disease that a subject has exhibited or has experienced.
  • treating may include “curing” the disease, but in most cases it is not necessary to completely eliminate all its symptoms, for example, administration of the relevant drug results in the reduction or elimination of at least one symptom in the subject, The subject can then be considered to have been treated.
  • a “therapeutically effective amount” refers to an amount sufficient to induce a biological or medical response expected by a clinician in a subject, which can usually be determined by those skilled in the art according to the route of administration, the subject's weight, age, condition and other factors .
  • a “therapeutically effective amount” can also be considered a “prophylactically effective amount” when used for prophylactic purposes.
  • a typical daily dose may range from 0.01 mg to 100 mg of the active pharmaceutical ingredient per kg body weight of the subject.
  • the term “effective amount” can include “therapeutically effective amount” and “prophylactically effective amount”.
  • a pharmaceutically active ingredient such as endostatin (including functional variants or derivatives thereof), can be used alone or formulated with a pharmaceutically acceptable carrier as a pharmaceutical composition.
  • pharmaceutically acceptable carrier refers to substances such as solid or liquid diluents, fillers, antioxidants, stabilizers, etc., which can be safely administered to animals or humans, and that are suitable for human and/or Animals were administered without excessive adverse side effects.
  • routes of administration a variety of carriers well known in the art can be employed. Common routes of administration include, for example, intravenous infusion, intramuscular injection, subcutaneous injection, subperitoneal, rectal, sublingual, oral spray, nasal spray or inhalation, transdermal, and the like.
  • Commonly used carriers include, but are not limited to, carbohydrates, starch, cellulose and derivatives thereof, maltose, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffers, emulsifiers, isotonic saline, and/or pyrogen-free water, etc.
  • the pharmaceutical composition can be prepared in any clinically acceptable dosage form, such as granules, powders, injections (eg, intravenous injections), eye drops or sprays, and the like.
  • the present invention also provides drug combinations including endostatin and other drugs such as remdesivir.
  • drug combination refers to the combination of two or more pharmaceutically active ingredients.
  • a pharmaceutical combination comprising two active pharmaceutical ingredients, it not only includes the coexistence of the two active pharmaceutical ingredients in the same pharmaceutical preparation (eg, a pharmaceutical composition), but also means that the two active pharmaceutical ingredients can be used as separate pharmaceutical preparations Present in the same pharmaceutical kit, or even the two pharmaceutically active ingredients may be presented as separate pharmaceutical formulations in different pharmaceutical kits.
  • a mode of administration employs such a "drug combination” as long as the administration is such that the two pharmaceutically active ingredients are simultaneously present in the subject at a certain time.
  • These pharmaceutically active ingredients can optionally be formulated with a pharmaceutically acceptable carrier.
  • a pharmaceutical combination includes not only the pharmaceutical composition form, but also other forms in which different pharmaceutical active ingredients may coexist in a subject.
  • the drug combination is in the form of a pharmaceutical composition; in other embodiments, the drug combination is in the form of a non-pharmaceutical composition, eg, endostatin and remdesivir are present in separate pharmaceutical formulations.
  • co-administration includes separate administration of the two drugs, eg, endostatin before or after remdesivir administration.
  • Drugs also include the simultaneous administration of two drugs in the same pharmaceutical formulation or in separate pharmaceutical formulations.
  • Endostatin or “endostatin” (Endostatin, ES for short) should be understood in a broad sense, including natural endostatin, preferably human endostatin, but not limited thereto, for example, it can also be Native endostatins from other mammals such as mice, rats, pigs, dogs, rabbits, sheep, goats, cats, etc.
  • Endostatin also includes functional variants of endostatin, such as engineered functional variants, which have one or more amino acid substitutions, deletions, or additions compared to native endostatin, and It has basically the same biological functions, such as the activity of inhibiting vascular endothelial cell proliferation, migration and angiogenesis in vivo.
  • Endostatin also includes derivatives or modified products of native endostatin or functional variants thereof, such as polyethylene glycol modified products.
  • the term "functional variant” as used herein includes one or several (eg 1-5, 1-10 or 1-15, specifically, for example, may be 1, 2, 3, 4) in the amino acid sequence , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or even more) amino acid substitutions, deletions or additions of endostatin mutants, and the mutants have vascular Endostatin has similar biological activities of inhibiting vascular endothelial cell proliferation, migration and angiogenesis in vivo.
  • the biological activity of a "functional variant" of endostatin may be, for example, native endostatin, eg, 30% or more, 50% or more, 60% or more, of native human endostatin. 70% or higher, 80% or higher or 90% or higher.
  • the "functional variant” may be a naturally occurring mutant or an artificial mutant, such as a mutant obtained by site-directed mutagenesis, or a mutant generated by genetic recombination methods.
  • the biological activity of the "functional variant” can be detected by methods well known in the art for detecting endostatin activity.
  • HMEC cells can be selected, the migration (Tranwell Assay) method can be used to analyze the inhibition rate of functional variants on HMEC cell migration, and the number of cells can reflect the protein activity (refer to Luo yongzhang et al., Endostatin inhibits tumorlymphangiogenesis and lymphatic metastasis via cell surface nucleolin on lymphangiogenic endothelial cells (J Pathol 2010;222:249–260).
  • endostatin can be obtained by engineering native endostatin (eg, native human endostatin or native mammalian endostatin).
  • native endostatin eg, native human endostatin or native mammalian endostatin.
  • endostatins including functional variants, derivatives or modified products thereof
  • Preferred ESs include YH-16 (also known as Endo), an ES variant obtained by adding 9 additional amino acids (MGGSHHHHH) to the N-terminus of ES for increased soluble expression and ease of purification (Fu Y et al. al. IUBMB Life 2009; 61: 613-626; Wang J et al. Zhongguo fei ai za zhi 2005; 8: 283-290; Han B et al. J Thorac Oncol 2011; 6(6): 1104-1109, via is incorporated herein by reference in its entirety).
  • YH-16 also known as Endo
  • MGSHHHHH an ES variant obtained by adding 9 additional amino acids
  • Preferred ESs also include those ES variants disclosed in PCT International Application PCT/CN2012/081210, such as ES006, ES008, ES011, S02, S09, Z006, Z008, ZN1, etc. (the entire contents of which are incorporated herein by reference) ).
  • Preferred ES also include those endostatin variants disclosed in PCT International Publication No. WO2016/070798, such as 003, 007, Z101, 009, S03, 36, 249, 381, 57, 114, 124, 125, 160, 163, 119 (incorporated by reference in their entirety).
  • M2ES refers to polyethylene glycol recombinant human endostatin. M2ES is a long-acting recombinant endostatin, which has entered Phase II clinical trials for lung cancer indications.
  • Preferred ESs also include PEG double-modified ESs.
  • corresponding to the position of native endostatin means that the endostatin functional variant is aligned with the amino acid sequence of native endostatin using software or algorithms well known in the art. Positions on the functional variant of inhibin that correspond to corresponding amino acid residues in the amino acid sequence of native endostatin.
  • the software or algorithms include, but are not limited to, BLAST, FASTA.

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Abstract

L'invention concerne une méthode de prévention ou de traitement de maladies associées au coronavirus (notamment la maladie à coronavirus 2019) chez un sujet, la méthode comprenant l'administration d'une quantité efficace d'endostatine à un sujet.
PCT/CN2022/073924 2021-01-26 2022-01-26 Utilisation d'endostatine dans le traitement et la prévention de maladies associées au coronavirus WO2022161381A1 (fr)

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CN202280011679.7A CN117460533A (zh) 2021-01-26 2022-01-26 血管内皮抑制素在治疗和预防冠状病毒相关疾病中的应用

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101002946A (zh) * 2006-01-20 2007-07-25 清华大学 一种治疗肿瘤的药物及其应用
CN101642560A (zh) * 2009-08-24 2010-02-10 武汉大学 一种抗肿瘤药物组合物
WO2021007094A1 (fr) * 2019-07-10 2021-01-14 Musc Foundation For Research Development Peptides d'endostatine pour le traitement de tumeurs, d'une fibrose et d'une lésion pulmonaire aiguë

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101002946A (zh) * 2006-01-20 2007-07-25 清华大学 一种治疗肿瘤的药物及其应用
CN101642560A (zh) * 2009-08-24 2010-02-10 武汉大学 一种抗肿瘤药物组合物
WO2021007094A1 (fr) * 2019-07-10 2021-01-14 Musc Foundation For Research Development Peptides d'endostatine pour le traitement de tumeurs, d'une fibrose et d'une lésion pulmonaire aiguë

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ASIF SANA, RUGE THORALPH, LARSSON ANDERS, ANDERBERG SARA BÜLOW, LIPCSEY MIKLOS, FRITIOF ROBERT, HULTSTRÖM MICHAEL: "Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure", BIOMARKERS IN MEDICINE, FUTURE MEDICINE, UK, vol. 15, no. 16, 1 November 2021 (2021-11-01), UK , pages 1509 - 1517, XP055955349, ISSN: 1752-0363, DOI: 10.2217/bmm-2021-0111 *
CARLSSON, A. G. ET AL.: "Endostatin Predicts Mortality in Patients with Acute Dyspnea-A Cohort Study of Patients Seeking Care in Emergency Departments.", CLINICAL BIOCHEMISTRY., vol. 75, 28 October 2019 (2019-10-28), XP085965159, DOI: 10.1016/j.clinbiochem.2019.10.004 *

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