WO2021188854A1 - Ribonucléases à des fins de traitement d'infections virales - Google Patents

Ribonucléases à des fins de traitement d'infections virales Download PDF

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Publication number
WO2021188854A1
WO2021188854A1 PCT/US2021/023073 US2021023073W WO2021188854A1 WO 2021188854 A1 WO2021188854 A1 WO 2021188854A1 US 2021023073 W US2021023073 W US 2021023073W WO 2021188854 A1 WO2021188854 A1 WO 2021188854A1
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WIPO (PCT)
Prior art keywords
cov
ranpirnase
coronavirus
sars
covid
Prior art date
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PCT/US2021/023073
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English (en)
Inventor
Jamie Sulley
Luis SQUIQUERA
Tom Hodge
Brian Roberts
Original Assignee
Orgenesis Inc.
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Publication date
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Publication of WO2021188854A1 publication Critical patent/WO2021188854A1/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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • 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
    • 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
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/27—Endoribonucleases producing 3'-phosphomonoesters (3.1.27)
    • C12Y301/27005—Pancreatic ribonuclease (3.1.27.5)

Definitions

  • This disclosure is directed to compounds and pharmaceutical compositions for treating and preventing Covid-19.
  • the invention relates to the use of ranpirnase in the preparation and use of pharmaceutical formulations for the intravenous treatment of said disease.
  • viruses as the common cold, influenza, chickenpox, cold sores, rabies, Ebola virus disease, AIDS (HIV), avian influenza, SARS, and Covid-19. These diseases are usually detected by clinical presentation, for instance severe muscle and joint pains preceding fever, or skin rash and swollen lymph glands.
  • Coronaviruses are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome (SARS-CoV), and Covid-19. Coronaviruses are in the subfamily Orthocoronavirinae in the family Coronaviridae, in the order Nidovirales. They are enveloped viruses with a positive-sense single- stranded RNA genome and a nucleocapsid of helical symmetry. The genome size of coronaviruses ranges from approximately 26 to 32 kilobases, the largest for an RNA virus. Coronaviruses are zoonotic, meaning they are transmitted between animals and people. Coronaviruses further cause colds with major symptoms, such as fever and sore throat from swollen adenoids, primarily in the winter and early spring seasons, pneumonia, and bronchitis, among others.
  • MERS-CoV Middle East Respiratory Syndrome
  • the novel coronavirus SARS-CoV-2 informally known as the Wuhan coronavirus, is a contagious virus that causes acute respiratory diseases, and has been the cause of a major virus outbreak known as 2019-20 Wuhan coronavirus outbreak.
  • the virus is thought to have a zoonotic origin, as suggested by its similarity to SARS-CoV and bat coronaviruses.
  • human-to-human transmission of the virus has been confirmed, primarily through close contact, in particular through respiratory droplets from coughs and sneezes. Viral RNA has also been found in stool samples from infected patients.
  • compositions for treating or preventing Covid-19 in a subject wherein said composition consists of ranpirnase as a single active agent and a pharmaceutical carrier, and is formulated for intravenous delivery.
  • Figure 1 shows an assay of ranpirnase and FDA-Approved Drugs efficacy against SARS-CoV-2 in vitro.
  • compositions for treating or preventing a viral disease in a subject said composition formulated for intravenous delivery and comprising ribonuclease as a single active agent.
  • a composition for treating or preventing a Covid-19 in a subject said composition formulated for intravenous delivery comprising ranpirnase as a single active agent.
  • Ranpirnase is a ribonuclease enzyme found in the oocytes of the Northern Leopard Frog (Rana pipiens).
  • Ranpirnase is a member of the pancreatic ribonuclease (RNase A) protein superfamily and degrades RNA substrates with a sequence preference for uracil and guanine nucleotides.
  • Ranpirnase has been studied as a potential cancer and antiviral treatment due to its unusual mechanism of cytotoxicity tested against transformed cells and antiviral activity.
  • Ranpirnase UniProt identification number is P85073.
  • ranpirnase comprises an amino acid sequence comprising EDWLTFQKKHITNTRDVDCDNIMSTNLFHCKDKNTFIYSRPEPVKAICKGIIASKN VFTT S EF YES DCN VT S RPCKYKFKKS TNKFC VT CEN Q AP VHF V G V GS C (SEQ ID No.: 1).
  • ranpirnase comprises an amino acid sequence comprising at least 80%, 85%, 90%, 95%, or 99% homology to SEQ ID No.:l.
  • ranpirnase comprises an amino acid sequence comprising ED WLTF QKKH VTNTRD VDCNNIMS TNLFHC KDKNTFI Y S RPEP VKAICKGII AS K N VLTT S EF YLS DCN VT S RPCKYKLKKS TNKFC VT CEN Q AP VHF V G V GRC (SEQ ID No.: 2).
  • ranpirnase comprises an amino acid sequence comprising at least 80%, 85%, 90%, 95%, or 99% homology to SEQ ID No.:2.
  • a ribonuclease enters into the cells via receptor- mediated endocytosis and once internalized into the cytosol, selectively degrades tRNA, resulting in inhibition of protein synthesis and induction of cell apoptosis.
  • a viral disease comprises Covid-19.
  • a viral disease is caused by SARS-CoV-2.
  • Covid-19 also termed “novel coronavirus pneumonia”, “NCP”, “SARS-CoV-2 acute respiratory disease”, and “COVID-19” comprises an infectious respiratory disease caused by the 2019 novel coronavirus (SARS-CoV-2), which was first detected during the 2019-20 Wuhan coronavirus outbreak.
  • SARS-CoV-2 is transmitted through human- to-human transmission, generally via respiratory droplets as sneeze, cough or exhalation.
  • NCP symptoms appear after an incubation period of between 2 to 14 days.
  • coronavirus primarily affects the lower respiratory tract. In some embodiments, coronavirus primarily affects the upper respiratory tract. In some embodiments, NCP symptoms comprise fever, coughing, shortness of breath, pain in the muscles, tiredness, pneumonia, acute respiratory distress syndrome, sepsis, septic shock, death, or any combination thereof.
  • SARS-CoV-2 belongs to the broad family of viruses known as coronaviruses. SARS-CoV-2 is a positive-sense single- stranded RNA (+ssRNA) virus. SARS-CoV-2 is a member of the subgenus Sarbecovirus (Beta-CoV lineage B), having an RNA sequence of approximately 30,000 bases in length.
  • coronavirus comprises Human coronavirus 229E (HCoV- 229E).
  • coronavirus comprises Human coronavirus OC43 (HCoV- OC43).
  • coronavirus comprises Severe acute respiratory syndrome- related coronavirus (SARS-CoV).
  • coronavirus comprises Human coronavirus NL63 (HCoV-NL63, New Haven coronavirus).
  • coronavirus comprises Human coronavirus HKU1.
  • coronavirus comprises Middle East respiratory syndrome-related coronavirus (MERS-CoV), previously known as novel coronavirus 2012 and HCoV-EMC.
  • coronavirus comprises Novel coronavirus (SARS-CoV-2), also known as Wuhan coronavirus.
  • the compositions of the invention are used in the methods of the invention described herein.
  • the invention provides a method of preventing or treating a viral disease, for example Covid-2019 in a subject, comprising any of the compositions disclosed herein.
  • treatment refers to any process, action, application, therapy, or the like, wherein a subject, including a human being, is subjected to medical aid with the object of improving the subject's condition, directly or indirectly.
  • the term “treating” refers to reducing incidence, or alleviating symptoms, eliminating recurrence, preventing recurrence, preventing incidence, improving symptoms, improving prognosis or combinations thereof in other embodiments.
  • Treating embraces in another embodiment, the amelioration of an existing condition.
  • treatment does not necessarily result in the complete absence or removal of symptoms.
  • Treatment also embraces palliative effects: that is, those that reduce the likelihood of a subsequent medical condition.
  • the alleviation of a condition that results in a more serious condition is encompassed by this term.
  • subject refers in one embodiment, to a human or any other animal which has been exposed to and is now immune to CoV related disease or Covid-2019.
  • a subject refers to a human presenting to a medical provider for diagnosis or treatment of a disease, such as a CoV related disease or Covid-2019 in another embodiment.
  • a human includes pre- and postnatal forms. In one embodiment, subjects are humans being treated for symptoms associated with a CoV related disease or Covid-2019.
  • terapéuticaally effective amount refers in one embodiment, to an amount of a monovalent or combination vaccine sufficient to elicit a protective immune response in the subject to which it is administered.
  • the immune response may comprise, without limitation, induction of cellular and/or humoral immunity.
  • the dosage regimen for treating a condition with the compositions of this invention is selected in one embodiment, in accordance with a variety of factors, such as the type, age, weight, ethnicity, sex and medical condition of the subject, the severity of the condition treated, and the particular compound employed, and thus may vary widely while still be in the scope of the invention.
  • compositions disclosed herein are formulated for intravenous (iv) delivery.
  • the pharmaceutical preparation of the invention, used in the methods of the invention comprise a carrier, excipient, flow agent, processing aid, a diluent, or a combination thereof.
  • compositions used in the invention further comprise a carrier, or excipient, lubricant, flow aid, processing aid or diluent in other embodiments, wherein the carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof.
  • a carrier, excipient, lubricant, flow aid, processing aid or diluent is a gum, starch, a sugar, a cellulosic material, an acrylate, calcium carbonate, magnesium oxide, talc, lactose monohydrate, magnesium stearate, colloidal silicone dioxide or mixtures thereof.
  • the composition further comprises a binder, a disintegrant, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof.
  • the term “pharmaceutically acceptable carriers” includes, but is not limited to, may refer to 0.01-0.1M and preferably 0.05M phosphate buffer, or in another embodiment 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be in another embodiment aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • compositions of the invention can be prepared by known dissolving, mixing, granulating, or tablet-forming processes.
  • the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient.
  • the lyophilizate prior to administration, is resuspended aseptically in a sterile buffer.
  • a physiologically tolerated buffer is added to facilitate pH control.
  • the formulations of the present invention have pH between about 6.8 and about 7.8.
  • buffers include phosphate buffers, sodium phosphate, or phosphate buffered saline (PBS).
  • the final product lyophilizate may include preformulated isotonicity agents as glycerin, stabilizers excipients, such as carbohydrates (trehaloze, sucrose), an antioxidant, a chelating agent, such as EDTA and EGTA, human serum albumin, or a combination thereof, which can optionally be added to the formulations or compositions to reduce aggregation.
  • surfactants additives are particularly useful if a pump or plastic container is used to administer the formulation.
  • An optional carrier additive is human serum albumin, or an enhancer surfactant as described below. The presence of pharmaceutically acceptable surfactant mitigates the propensity of proteins to aggregate.
  • the term “about” as used herein means in quantitative terms plus or minus 5%, or in another embodiment plus or minus 10%, or in another embodiment plus or minus 15%, or in another embodiment plus or minus 20%.
  • subject refers in one embodiment to a mammal including a human in need of therapy for, or susceptible to, a condition or its sequelae.
  • the subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, and mice and humans.
  • subject does not exclude an individual that is normal in all respects.
  • the objective of this study is to test ranpirnase potency as IV monotherapy in a murine SARS-CoV virus infection in-vivo model.
  • mice (6-8 weeks of age) will be allowed to habituate for 1 week prior to the study.
  • the animals will be housed in climate-controlled quarters (24°C at 50% humidity) with 12 h light/dark cycles and had free access to food and water. All experimental protocols will be approved by an Institutional Animal Welfare Committee.
  • SARS Severe acute respiratory syndrome
  • SARS-Cov Model induction Murine or human strain suitable to work up to BSL- 2 laboratories. Animals will be anesthetized with a mixture of ketamine-xylazine and infected intranasally either with the virus or with phosphate-buffered saline (PBS) in a dose of 50 pi. Virus doses ranged from 1 x 102 to 1 x 105 PFU/50-mI dose, diluted in PBS prior to intranasal administration (Day CW et al. Virology 2009).
  • PBS phosphate-buffered saline
  • Body weight 3 times a week.
  • Lung samples from each test group will be pooled and homogenized in MEM solution and assayed in duplicate for infectious for virus yield assays using triplicate wells of Vero 76 cells.
  • Lung tissues will be fixed in PBS-4% paraformaldehyde (pH 7.3); tissues will be embedded in paraffin; and 5-pm-thick sections will be prepared for histopathology. Extent of inflammation will be determined, sections will be stained with hematoxylin and eosin (H&E) and will be scored from 1 to 5 for overall inflammation, eosinophilia, neutrophilia, alveolitis, bronchiolar denudation, and edema. [48] Hyaline membrane formation will be evaluated in lungs in comparison to control groups.
  • Blood will be harvested from all animals (by terminal bleeding), serum separation and complete blood count and biochemistry panel will be performed.
  • Multiplex ELISA will be performed at different time (serum and lung samples) points following challenge and treatment to measure IL-la and IL-6, and chemokines MIP- la, MCP-1, and RANTES.
  • Ranpirnase was one of 2 drugs to reduce virus concentrations in the assay ( Figure 1) Similarly, UTHSC tested ranpirnase in their high-throughput screening (HTS) method for SARS-CoV-2 with the 50% effective dose (EC50) ⁇ 6 mM.
  • HTS high-throughput screening
  • ranpirnase is expected to be active against SARS-CoV-2 in a hamster infection study, in which hamsters will be challenged with SARS-CoV-2 with analysis of lung infection on days 3, 5, and 7 to evaluate virus reduction in these tissues.
  • the proposed clinical study is expected to present minimal risk to participants while contributing to development of a safe, efficacious COVID-19 therapeutic.
  • the clinical research will be conducted in accordance with applicable International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines and FDA regulations and guidance.
  • Ranpirnase will be tested in a human Phase II/III clinical trial to evaluate the technical feasibility of ranpirnase to reduce viral load and risk of an IL-6 cytokine storm in COVID-19 patients.
  • Table 1 shows the Phase II/III protocol synopsis we are proposing to conduct.
  • the study is designed for participation by adult (> 21 years old) COVID-19 patients.
  • the clinical study will enroll up to 45 subjects with a 3:1 treatmenkplacebo (standard of care) ratio.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Virology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés et des compositions pharmaceutiques pour le traitement et la prévention de maladies virales, telles que la COVID-19. L'invention concerne entre autres l'utilisation de ranpirnase dans la préparation et l'utilisation de formulations pharmaceutiques pour le traitement par voie intraveineuse de ladite maladie.
PCT/US2021/023073 2020-03-20 2021-03-19 Ribonucléases à des fins de traitement d'infections virales WO2021188854A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202062992408P 2020-03-20 2020-03-20
US62/992,408 2020-03-20
US202063040952P 2020-06-18 2020-06-18
US63/040,952 2020-06-18

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WO2021188854A1 true WO2021188854A1 (fr) 2021-09-23

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018214A1 (fr) * 1999-09-10 2001-03-15 Alfacell Corporation Acides nucleiques codant des ribonucleases et leurs methodes de fabrication
WO2015148768A2 (fr) * 2014-03-28 2015-10-01 Tamir Biotechnology, Inc. Rnase pour une utilisation dans le traitement ou la prévention d'infections virales
US9642794B2 (en) * 2014-08-18 2017-05-09 Tamir Biotechnology, Inc. Antiviral pharmaceutical for topical administration

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001018214A1 (fr) * 1999-09-10 2001-03-15 Alfacell Corporation Acides nucleiques codant des ribonucleases et leurs methodes de fabrication
WO2015148768A2 (fr) * 2014-03-28 2015-10-01 Tamir Biotechnology, Inc. Rnase pour une utilisation dans le traitement ou la prévention d'infections virales
US9642794B2 (en) * 2014-08-18 2017-05-09 Tamir Biotechnology, Inc. Antiviral pharmaceutical for topical administration

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: " Orgenesis and Leidos Collaborate on Potential Treatment for COVID-19", LEIDOS, 22 June 2020 (2020-06-22), XP055859327, Retrieved from the Internet <URL:https://investors.leidos.com/news-and-events/news-releases/press-release-details/2020/Orgenesis-and-Leidos-Collaborate-on-Potential-Treatment-for-COVID-19-/default.aspx> [retrieved on 20211109] *
SMITH TODD G., JACKSON FELIX R., MORGAN CLINT N., CARSON WILLIAM C., MARTIN BROCK E., GALLARDO-ROMERO NADIA, ELLISON JAMES A., GRE: "Antiviral Ranpirnase TMR-001 Inhibits Rabies Virus Release and Cell-to-Cell Infection In Vitro", VIRUSES, vol. 12, no. 2, 5 February 2020 (2020-02-05), pages 1 - 12, XP055859330, DOI: 10.3390/v12020177 *

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