WO2020093159A1 - Associations d'anticorps neutralisants à large spectre et d'inhibiteurs de la neuraminidase pour prévenir ou traiter des infections à virus influenza - Google Patents

Associations d'anticorps neutralisants à large spectre et d'inhibiteurs de la neuraminidase pour prévenir ou traiter des infections à virus influenza Download PDF

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WO2020093159A1
WO2020093159A1 PCT/CA2019/051582 CA2019051582W WO2020093159A1 WO 2020093159 A1 WO2020093159 A1 WO 2020093159A1 CA 2019051582 W CA2019051582 W CA 2019051582W WO 2020093159 A1 WO2020093159 A1 WO 2020093159A1
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bnabs
influenza
influenza infection
neuraminidase
solvate
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PCT/CA2019/051582
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English (en)
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Matthew Miller
Ali ZHANG
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Mcmaster University
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present application relates to combination treatments for influenza infections.
  • the present application relates to the use of one or more neuraminidase inhibitors and one or more broadly-neutralizing antibodies (bNAbs) and compositions thereof for the prevention or treatment of influenza infections.
  • bNAbs broadly-neutralizing antibodies
  • Influenza A viruses cause 3-5 million serious illnesses and half a million deaths each year. Vaccination is the best way to prevent infection, but protection provided is narrow and ineffective against pandemic strains due to antigenic drift in the immunodominant hemagglutinin (HA) head domain of the influenza virus. HA is responsible for binding the influenza virus to sialic acid on host cells.
  • Recently discovered broadly-neutralizing antibodies (bNAbs) that target the conserved HA stalk domain of the influenza virus provide great promise towards development of a“universal” influenza vaccine. These bNAbs require Fc receptor binding and effector cell function to confer maximal protection. The mechanism by which bNAbs protect against IAV propagation is incompletely understood.
  • stalk-binding antibody-mediated interaction between the immune effector cell and the infected cell consists of two potential points of contact: between the antibody Fc region and Fc receptor on the immune effector cell, and between the HA head (expressed on the infected cell surface) and sialic acid residues on the Immune effector cell ( Figure 1 ).
  • the cell membrane of the infected cell is also decorated with viral neuraminidase, which can cleave sialic acid residues from the effector cells.
  • the immune interaction is less stable with one fewer point of contact resulting in decreased effector cell activation.
  • Viral neuraminidases are neuraminidases (NA) found on the surface of influenza viruses that cleave sialic acid (neuramimic acid) groups from host cells, for example, host cell glycoproteins, and enables the virus to be released from the host cell.
  • Viral neuraminidase can also cleave sialic acid groups on mucins to help viral particles penetrate the respiratory mucosa. Thus, cleavage of sialic groups allows influenza virus to replicate and spread.
  • Neuraminidase inhibitors have been developed to block neuraminidase function as a method of treating influenza infection.
  • Oseltamivir is a competitive neuraminidase inhibitor used in the treatment of acute uncomplicated influenza.
  • Laninamivir is a neuraminidase inhibitor that is currently undergoing clinical trials.
  • NA inhibitors for example, oseltamivir
  • IAV influenza A virus
  • a neuraminidase inhibitor such as oseltamavir enhances Fc- dependent effector functions elicited by bNAbs.
  • the present application includes a method of treating or preventing an influenza infection in a subject in need thereof comprising administering, to the subject, an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs) wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • the present application also includes a pharmaceutical composition
  • a pharmaceutical composition comprising one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein the one or more neuraminidase inhibitors and bNAbs are present in amounts that are effective to treat an influenza infection or a disease, disorder or condition arising from an influenza infection and wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • HA hemagglutinin
  • the one or more neuraminidase inhibitors are selected from anti-neuraminidase antibodies, anti-neuraminidase proteins, anti-neuraminidase peptides, a portion of anti-neuraminidase antibodies, a portion of anti-neuraminidase proteins, and a portion of anti-neuraminidase peptides.
  • the one or more neuraminidase inhibitors are selected from oseltamivir, zanamivir, laninamivir and peramivir.
  • the neuraminidase inhibitor is oseltamivir.
  • Figure 1 is a schematic showing the stalk-binding antibodies facilitating the interaction between immune effector cells and infected cells via two points of contact.
  • the stalk-binding antibody interacts with the HA stalk domain via its Fab portion and binds to the Fc receptor of the effector via its Fc portion (1 ).
  • the HA head domain interacts with sialic acid residues on the effector cell (2). Although the sialic acid residues are depicted as a moiety on the Fc receptor on the effector cells, the actual location of the sialic acid residues that HA binds to in this context is not known.
  • the lines represent enzymatic inhibition by neuraminidase on the HA head - sialic interaction, and the inhibition of oseltamivir on the neuraminidase enzymatic activity.
  • Figure 2 shows exemplary neuraminidase inhibitor Oseltamivir decreases both neuraminidase activity and viral replication of H1 N1 and H3N2 influenza viruses.
  • Neuraminidase activity of influenza viruses PR8, Cal/09, and X-31 were measured in-vitro using the NA-Star Neuraminidase Kit (ThermoFisher) ( Figure 2 first row).
  • Exemplary neuraminidase inhibitor oseltamivir susceptibility of the strains were then determined using 1x10 6 plaque-forming units (PFU) of the three strains using the NA-Star Neuraminidase Kit (ThermoFisher) ( Figure 2 second and third rows).
  • ICso values are displayed to the right of the graphs.
  • Data for the neuraminidase assays are shown as mean and SD of at least two technical replicates.
  • Exemplary neuraminidase inhibitor oseltamivir susceptibility was also quantified using plaque assays by infecting A549 cells with the virus at a multiplicity of infection (MOI) of 5 before incubating the infected cells with indicated concentrations of oseltamivir for 18 hours (Figure 2 fourth row).
  • MOI multiplicity of infection
  • N.D not detectable.
  • the limit of detection for the plaque assays is 25 PFU/ml.
  • Figure 3 shows broadly-neutralizing antibodies 6F12 and 9H10 bind specifically to A549 cells infected with an H1 N1 or H3N2 viruses respectively.
  • A549 cells infected with PR8 or Cal/09 were stained with 6F12, and cells infected with X-31 were stained with 9H10.
  • Uninfected A549 cells were stained using 6F12 and 9H10 as negative controls.
  • FIG. 4 shows that exemplary neuraminidase inhibitor oseltamivir increases broadly-neutralizing antibody mediated Fc receptor activation (eg. ADCC) of influenza virus infected A549 cells.
  • exemplary neuraminidase inhibitor oseltamivir was found to increase the efficacy and alter the potency of ADCC induction by stalk-binding antibodies in a dose-dependent manner.
  • In vitro ADCC assays were completed using A549 cells infected with PR8 (H1 N1 ), Cal/09 (H1 N1 ) or X-31 (H3N2) at a MOI of 5. Fold induction denotes activation above infected cells without antibody.
  • Concentrations of exemplary neuraminidase inhibitor oseltamivir are denoted in the legend.
  • 6F12 Pan H1 stalk-binding antibody
  • 9H10 Group 2 HA stalk-binding antibody
  • Fold induction data is shown as mean ⁇ SD with biological triplicates.
  • ECso values are shown as mean with SEM.
  • FIG. 5 shows exemplary neuraminidase inhibitor oseltamivir in combination with broadly-neutralizing antibodies is superior at protecting against lethal influenza virus infections in BALB/c mice compared to using either therapeutic alone.
  • 6-8 week old female BALB/c mice were administered intraperitoneally 1 mg/kg of 6F12 or PBS and an oral gavage of 10mg/kg of exemplary neuraminidase inhibitor oseltamivir or PBS. The mice were then infected intranasally with 500 PFU of PR8 two hours later. Mice were given oseltamivir or PBS by oral gavage twice daily for 5 days. Weight change was monitored daily (top panel), and the animals were sacrificed when they reached
  • Figure 6 shows the characterization of polyclonal stalk-binding antibodies in human serum.
  • Human serum was obtained from peripheral blood of two healthy adult donors.
  • A ELISA was performed using chimeric cH6/1 protein to quantify the titers of the serum antibodies to the stalk domain of H1 hemagglutinin. Absorbance data is shown as mean ⁇ SD with technical triplicates.
  • B The area under the curve (AUC) is also shown as mean ⁇ SEM.
  • FIG. 7 shows exemplary neuraminidase inhibitor Oseltamivir is more effective at preventing influenza clinical signs when combined with serum with a higher content of polyclonal stalk-binding antibodies.
  • 6-8 week old female BALB/c mice were administered intraperitoneally with 150ul of heat-inactivated human serum or PBS and an oral gavage of 0.1 mg/kg of exemplary neuraminidase inhibitor oseltamivir or PBS.
  • the serum contains either a low content of polyclonal stalk-binding antibodies (A,B), or a high content of polyclonal stalk-binding antibodies (C,D) as determined by previous experiments.
  • the mice were then infected intranasally with 200 PFU of Viet/05 two hours later.
  • the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • the foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.
  • the term“consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, but exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
  • the second component as used herein is chemically different from the other components or first component.
  • A“third” component is different from the other, first, and second components, and further enumerated or“additional” components are similarly different.
  • influenza infection refers to an invasion of cells or bodily tissues by one or more foreign, undesirable influenza viruses.
  • bNAb hemagglutinin
  • HA stalk-binding or HA stalk-reactive antibodies that are known to target the conserved stalk domain of HA, which may, for example, facilitate functional response such as antibody-dependent cell cytotoxicity (ADCC) in influenza-infected cells.
  • ADCC antibody-dependent cell cytotoxicity
  • the ability of bNAb in targeting the conserved stalk domain of HA allows it to bind to or react with the HA stalk domain of multiple influenza virus strains.
  • HA stalk-binding” or“HA stalk-reactive” as used herein means that the bNAbs bind to/ react with the stalk domain of the HA protein.
  • neuroaminidase refers to an enzyme found, for example, in influenza viruses which cleaves sialic acid groups from glycoproteins on cells, for example, a host cell or an effector cell.
  • neuroaminidase inhibitor refers to a compound capable of inhibiting the function of neuraminidase.
  • oseltamivir refers to a compound having the IUPAC name: Ethyl (3R, 4R, 5S)-4-acetamido-5-amino-3-(1 - ethylpropoxy)-1 - cyclohexene-1 -carboxylate, also known as Tamiflu ® and having the chemical Formula:
  • pharmaceutically acceptable salt means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.
  • bNAb-inducing agent refers to any molecule or composition that produces an effective amount of one or more broadly neutralizing antibodies (bNAbs) in a subject.
  • no treatment or prevention of the influenza infection or“does not treat or prevent the influenza infection” means that there is no effective treatment or prevention of the influenza infection (for example, the desired clinical outcome is not achieved).
  • the term“vaccine” as used herein refers to a preparation that provides acquired immunity to a disease, for example, one caused by an infectious entity.
  • An“influenza vaccine” in particular provides acquired immunity to influenza virus.
  • a vaccine contains an agent that induces a subject’s immune system to recognize the agent as foreign, eliminate the agent, and to further recognize and eliminate any of the infectious entity associated with that agent that the subject’s immune system may encounter in the future.
  • Vaccines can be prophylactic in that it prevents or ameliorates the effects of a future infection, and they can be therapeutic for remediation of health problems associated with a disease, for example, conditions arising from influenza infection.
  • Pan H1 bNAbs refers to bNAbs that bind to and/or react with stalk domain of H1 hemagglutinins of human influenza A viruses.
  • An example of Pan H1 bNAbs is 6F12.
  • Group 1 bNAbs refers to bNAbs that bind to and/or react with stalk domain of Group 1 hemagglutinins of human influenza A viruses.
  • Group 1 hemagglutinins include H1 , H2, H5, H6, H8, H9, H 1 1 , H12, H 13, H16, H17, and H18.
  • Group 2 bNAbs refers to bNAbs that bind to and/or react with stalk domain of Group 2 hemagglutinins of human influenza A viruses.
  • Group 2 hemagglutinins include H3, H4, H7, H10, H14, and H15.
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
  • solvate means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered.
  • prodrug means a compound, or salt of a compound, that, after administration, is converted into an active drug.
  • the expression“disease, disorder or condition arising from an influenza infection” as used herein refers to any disease, disorder or condition that is directly or indirectly caused by the presence of an influenza infection in a subject.
  • composition refers to a composition of matter for pharmaceutical use.
  • parenteral means taken into the body or administered in a manner other than through the gastrointestinal tract.
  • administered means administration of an effective amount of a compound to a cell either in cell culture or in a subject.
  • the term “effective amount” or“therapeutically effective amount” means an amount effective, at dosages and for periods of time necessary to achieve a desired result.
  • treatment means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, diminishment of extent of influenza infection, stabilization (i.e. not worsening) of the state of the influenza infection, preventing spread of the influenza infection, delay or slowing of infection progression, amelioration or palliation of the influenza infectious state, diminishment of the reoccurrence of influenza infection, diminishment, stabilization, alleviation or amelioration of one or more diseases, disorders or conditions arising from the influenza infection, diminishment of the reoccurrence of one or more diseases, disorders or conditions arising from the influenza infection, and remission of the influenza infection and/or one or more symptoms or conditions arising from the influenza infection, whether partial or total, whether detectable or undetectable.“To treat”,“treating” and“treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.“To treat”,“treating” and“treatment” as used herein also include prophylactic treatment. For
  • “Palliating” an infection, disease, disorder and/or condition means that the extent and/or undesirable clinical manifestations of an infection, disease, disorder and/or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the infection, disease, disorder and/or condition.
  • prevention or“prophylaxis” and the like as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with an influenza infection and/or a disease, disorder and/or condition arising from an influenza infection or manifesting a symptom associated with an influenza infection and/or a disease, disorder and/or condition arising from an influenza infection.
  • a subject for example a subject“in need thereof” is a subject who has been diagnosed with, is suspected of having, may come in to contact with, and/or was previously treated for an influenza infection or a disease, disorder or condition arising from an influenza infection.
  • NA inhibitors for example, oseltamivir
  • IAV influenza A virus
  • neuraminidase inhibitors such as oseltamivir surprisingly work in combination and synergistically to potentiate the ability of bNAbs to induce Fc-mediated effector functions of immune cells (e.g., ADCC)
  • NA for example, by an neuraminidase inhibitor such as oseltamavir, enhances Fc- dependent effector functions elicited by bNAbs and therefore the NA /bNAb combination could be used to prevent or treat therapeutic resistance.
  • an neuraminidase inhibitor such as oseltamavir
  • the present application includes a method of treating or preventing an influenza infection in a subject in need thereof comprising administering, to the subject, an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs), wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • the present application also includes a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs), for treating an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are used in an amount that when the bNAbs are used alone there is no treatment or prevention of the influenza infection; a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for preparation of a medicament for treating an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are used in an amount that when the bNAbs are used alone there
  • the present application includes a method of treating or preventing a disease, disorder or condition arising from an influenza infection in a subject comprising administering, to a subject in need thereof, an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs) wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • the present application also includes a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for treating a disease, disorder or condition arising from an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are used in an amount that when the bNAbs are used alone there is no treatment or prevention of the influenza infection; a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for preparation of a medicament for treating a disease, disorder or condition arising from an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are
  • the present application includes a method of improving the efficacy of one or more broadly neutralizing antibodies (bNAbs) for treating an influenza infection comprising administering an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs) to a subject in need thereof wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • the present application also includes a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for improving the efficacy of the one or more broadly neutralizing antibodies (bNAbs), for treating a disease, disorder or condition arising from an influenza infection in a subject, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are used in an amount that when the bNAbs are used alone there is no treatment or prevention of the influenza infection; a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for the preparation of a medicament for improving the efficacy of the one or more broadly neutralizing antibodies (bNAbs) for treating an influenza infection in a subject, where
  • the present application includes a method of improving the efficacy of broadly neutralizing antibodies (bNAbs) for treating a disease, disorder or condition arising from an influenza infection comprising administering an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with an effective amount of one or more broadly neutralizing antibodies (bNAbs) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered alone does not treat or prevent the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • the present application also includes a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for improving the efficacy of one or more broadly neutralizing antibodies (bNAbs), for treating a disease, disorder or condition arising from from an influenza infection in a subject, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are used in an amount that when the bNAbs are used alone there is no treatment or prevention of the influenza infection; a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with one or more broadly neutralizing antibodies (bNAbs), for the preparation of a medicament for improving the efficacy of one or more broadly neutralizing antibodies (bNAbs) for treating a disease, disorder or condition arising from
  • influenza infection is an infection of at least one influenza virus.
  • influenza virus is an influenza A virus or influenza B virus.
  • influenza A virus is a hemagglutinin (“H”) or a neuraminidase (“N”) subtype.
  • influenza A virus subtype is selected from influenza A virus subtype H1 N1 , influenza A virus subtype H1 N2, influenza A virus subtype H2N2, influenza A virus subtype H2N3, influenza A virus subtype H3N1 , influenza A virus subtype H3N2, influenza A virus subtype H3N8, influenza A virus subtype H5N1 , influenza A virus subtype H5N2, influenza A virus subtype H5N3, influenza A virus subtype H5N6, influenza A virus subtype H5N8, influenza A virus subtype H5N9, influenza A virus subtype H6N1 , influenza A virus subtype H6N2, influenza A virus subtype H7N1 , influenza A virus subtype H7N2, influenza A virus subtype H7N3, influenza A virus subtype H7N4, influenza A virus subtype H7N7, influenza A virus subtype H7N9, influenza A virus subtype H9N2 and influenza A virus subtype H10N7.
  • influenza A virus subtype is influenza A virus subtype H5
  • influenza A virus is an influenza A virus variant.
  • influenza A virus variant is from avian influenza virus, human influenza virus, swine influenza virus, equine influenza virus, bat influenza virus, feline influenza virus and canine influenza virus.
  • influenza A virus is human influenza virus.
  • influenza A virus is selected from PR8, Cal/09 and X-31 influenza virus A strains.
  • the one or more bNAbs induce Fc- mediated effector function (eg. ADCC) against influenza-infected cells.
  • the one or more bNAbs are selected from Pan H1 bNAbs, Group 1 bNAbs, Pan H3 bNAbs or Group 2 bNAbs.
  • the Pan H1 bNAb is 6F12.
  • the Group 2 bNAb is 9H10
  • the bNAbs can be prepared using methods known in the art, for example by purification mouse hybridomas as described in Tan, GS et a. J. Virol. 2012 86(11 ):6179-88 (6F12) and Tan GS et al. J. Virol. 2014 88(23) (9H10).
  • the one or more bNAbs are one or more exogenous bNAbs or one or more endogenous bNAbs. In some embodiments, the one or more bNAbs are one or more exogenous bNAbs. In some embodiments, the one or more bNAbs are one or more endogenous bNAbs. In some embodiments, the one or more endogenous bNAbs are produced in a subject as an antibody response to one or more bNAb-inducing agents. [0069] The one or more bNAb-inducing agents may comprise an antigen.
  • the antigen can be, for example, a protein, a peptide, or a fragment thereof, of the conserved HA stalk domain of influenza, which is capable of inducing an immune response and thereby produces antibodies that bind to/react with the antigen and/or amino acid sequence having at least 50% similarity with the antigen.
  • the antigen can also be part of a vaccine.
  • the one or more bNAb-inducing agents comprises an amino acid sequence of the stalk domain for a group 1 HA virus, for example the HA2 component of A/California/07/2009 H1 N1 which is: QTPKGAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNIPSIQSRGLFGAIA GFIEGGWTGMVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEK MNTQFTAVGKEFNHLEKRIENLNKKVDDGFLDIWTYNAELLVLLENERTLDY HDSNVKNLYEKVRSQLKNNAKEIGNGCFEFYHKCDNTCMESVKNGTYDYP KYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASSLVLVVSLGAISFWMCSNG SLQCRICI [SEQ ID NO: 1 ], or an amino acid sequence having at least 50% similarity with this sequence.
  • the one or more bNAb-inducing agents comprises an amino acid sequence of the stalk domain for a group 2 HA virus, for example the HA2 component of A/Hong Kong/1/1968 H3N2 which is:
  • GNIRCNICI [SEQ ID NO:2], or an amino acid sequence having at least 50% similarity with this sequence.
  • the one or more bNAb- inducing agents are one or more antigens.
  • the one or more one or more antigens are part of a vaccine.
  • the disease, disorder or condition arising from influenza infection is selected from influenza (flu), fever, pain, cough, congestion, exhaustion, sore throat, chest discomfort, fatigue, dizziness, vomiting, pneumonia, bronchitis, dehydration, respiratory illnesses, cardiac problems, ear infections, and sinus infections.
  • the one or more neuraminidase inhibitors are selected from anti-neuraminidase antibodies, anti-neuraminidase proteins, anti-neuraminidase peptides, a portion of anti-neuraminidase antibodies, a portion of anti-neuraminidase protein, and a portion of anti-neuraminidase peptide.
  • the one or more neuraminidase inhibitors are selected from oseltamivir, zanamivir, laninamivir and peramivir.
  • the neuraminidase inhibitor is oseltamivir.
  • the present application also includes a method of treating or preventing an influenza infection in a subject comprising administering, to a subject in need thereof, an effective amount of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with a bNAb-inducing agent that endogenously produces an effective amount of one or more broadly neutralizing antibodies (bNAbs) in a subject, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs that is induced is an amount that does not treat or prevent the influenza infection on its own.
  • a bNAb-inducing agent that endogenously produces an effective amount of one or more broadly neutralizing antibodies (bNAbs) in a subject, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs that is induced is an amount that
  • the present application also includes a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with a bNAb-inducing agent that endogenously produces an effective amount of one or more broadly neutralizing antibodies
  • bNAbs for treating an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are induced in an amount that does not treat or prevent the influenza infection on its own; a use of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with a bNAb- inducing agent that endogenously produces an effective amount of one or more broadly neutralizing antibodies (bNAbs), for preparation of a medicament for treating an influenza infection in a subject wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are induced in an amount that does not treat or prevent the influenza infection on its own; and one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with a bNAb-induc
  • the bNAbs are administered or used alone there is no treatment or prevention of the influenza infection” or“when the bNAbs are administered alone does not treat or prevent the influenza infection” means when bNAbs are used alone the desired clinical outcome is not achieved.
  • the one or more neuraminidase inhibitors are available from commercial sources or can be prepared using methods known in the art.
  • oseltamivir is marketed as Tamiflu ® by Hoffmann la Roch
  • zanamivir is marketed as Relenza ® by GlaxoSmithKline
  • peramivir is marketed as Rapivab ® by BioCryst Pharmaceuticals.
  • the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.
  • a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19).
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids.
  • organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2- hydroxyethanesulfonic acid.
  • the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
  • Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins, and the like.
  • organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, di
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Formation of a pharmaceutically-acceptable salt may be achieved using standard techniques. For example, a neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.
  • Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Suitable solvents are physiologically tolerable at the dosage administered.
  • Suitable solvate solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a“hydrate”.
  • the formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • Prodrugs of the compounds may be prepared, for example, by acylating available hydroxy or amino groups using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Similarly, available carboxylic acid groups may be converted to ester groups using known chemistry, for example, by activation in the presence of base and reaction with suitable groups containing a nucleophile.
  • Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
  • an effective amount of the one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof or one or more broadly neutralizing antibodies is an amount that, for example, reduces the influenza infection compared to the influenza infection without administration of the one or more broadly neutralizing antibodies or one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof.
  • an effective amount of the one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof is, for example, an amount that, for example, reduces the influenza infection compared to the reduction of the influenza infection with administration of the one or more broadly neutralizing antibodies alone.
  • reducing the infection it is meant, for example, reducing the amount of the infectious agent in the subject and/or reducing the symptoms of the infection. Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of a given compound or composition that will correspond to such an amount will vary depending upon various factors, such as the given compound or composition, the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • the one or more broadly neutralizing antibodies (bNAbs) are administered to a subject, or used, in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the one or more broadly neutralizing antibodies (bNAbs) are administered to the subject, or used, by oral (including sublingual and buccal) or parenteral (including, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, topical, patch, pump and transdermal) administration and the antibiotic formulated accordingly.
  • bNAbs broadly neutralizing antibodies
  • Such forms include, for example in the form of their pharmaceutically acceptable salts, and in an injectable or infusable suspensions.
  • the one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are also administered to a subject, or used, in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • the one or more neuraminidase inhibitors are administered to the subject, or used, by oral (including sublingual and buccal) or parenteral (including, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, topical, patch, pump and transdermal) administration and the compound, salt and/or solvate, formulated accordingly.
  • oral including sublingual and buccal
  • parenteral including, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, topical, patch, pump and transdermal
  • parenteral including, intravenous, intraperitoneal, subcutaneous, intramuscular, trans
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is sterile and fluid to the extent that easy syringability exists.
  • parenteral administration is by continuous infusion over a selected period of time. Solutions suitable for parenteral administration are prepared by known methods by a person skilled in the art.
  • the one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof is prepared in water optionally mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions are also prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels or powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which take the form of a cartridge or refill for use with an atomising device.
  • the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it contains a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • the aerosol dosage forms take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin and/or glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • the one or more broadly neutralizing antibodies (bNAbs), or one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of a diet.
  • the one or more broadly neutralizing antibodies (bNAbs) or one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are incorporated with excipients and used in the form of, for example, ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • SR sustained-release
  • ER extended-release
  • CR controlled-release
  • Contin continuous-release
  • timed-release compositions are, formulated, as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes are formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • bNAbs broadly neutralizing antibodies
  • neuraminidase inhibitors or a salt, prodrug and/or solvate thereof
  • the one or more broadly neutralizing antibodies are coupled with soluble polymers as targetable drug carriers.
  • soluble polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy- ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the one or more broadly neutralizing antibodies (bNAbs), or one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • bNAbs broadly neutralizing antibodies
  • One or more broadly neutralizing antibodies are used in combination with each other.
  • One or more broadly neutralizing antibodies are either used or administered separately in time and/or in mode of administration (i.e. different administration routes) or they are administered together in the same pharmaceutical preparation.
  • one or more broadly neutralizing antibodies are used or administered separately in time and/or in mode of administration.
  • one or more broadly neutralizing antibodies are administered by injection and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, are administered orally or by inhalation.
  • one or more broadly neutralizing antibodies are administered orally and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, areis administered by injection.
  • both one or more broadly neutralizing antibodies (bNAbs), and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are both administered orally or by injection.
  • one or more broadly neutralizing antibodies (bNAbs), and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are used or administered separately in time and/or in mode of administration, one or more broadly neutralizing antibodies (bNAbs), are administered, or used, either before or after administration, or use, of one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof.
  • one or more broadly neutralizing antibodies (bNAbs), and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are administered contemporaneously.
  • “contemporaneous administration” of two substances to a subject means providing one or more broadly neutralizing antibodies (bNAbs), and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, so that they are both biologically active in the subject at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the one or more broadly neutralizing antibodies (bNAbs), and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, in the presence of each other, and can include administering one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, within a few hours of each other, or even administering one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, within 24 hours or greater of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors or a salt, prodrug and/or solvate thereof are administered to a subject in a single composition or formulation.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are administered to a subject in a non- contemporaneous fashion.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are administered to the subject in a contemporaneous fashion followed by, or alternating with, administration in a non-contemporaneous fashion.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors or a salt, prodrug and/or solvate thereof are administered to a subject in a contemporaneous fashion.
  • Treatment methods comprise administering to a subject one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, and optionally consists of a single administration, or alternatively comprises a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the dosage of one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, the activity of one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, and/or a combination thereof.
  • one or more broadly neutralizing antibodies are administered or used according to treatment protocol that is known for the broadly neutralizing antibodies in the treatment in influenza infections.
  • one or more neuraminidase inhibitors are administered or used according to treatment protocol that is known for the neuraminidase inhibitor in the treatment in influenza infections.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are administered or used as soon as possible after exposure to the influenza virus.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof are administered or used until treatment of the influenza infection is achieved. For example, until complete elimination of the influenza virus is achieved, or until the number of influenza viruses has been reduced to the point where the subject’s defenses are no longer overwhelmed and can kill any remaining influenza viruses.
  • one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof, are administered or used as soon as possible before an expected exposure to the influenza virus.
  • the dosage of the one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof varies depending on many factors such as the pharmacodynamic properties thereof, the mode of administration, the age, health and weight of the subject, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • One or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • the dosage of the one or more broadly neutralizing antibodies, and one or more neuraminidase inhibitors, or a salt, prodrug and/or solvate thereof is equal to or less than the dosage of such agents when used alone.
  • Such dosages are known to or readily determined by those skilled in the art.
  • the one or more broadly neutralizing antibody (bNAb)-inducing agents are administered to a subject, or used, in a variety of forms as described herein for when one or more broadly neutralizing antibodies are used.
  • the dosages of the one or more broadly neutralizing antibody (bNAb)-inducing agents can also be readily determined by those skilled in the art.
  • the effective amount of the one or more neuraminidase inhibitors is about 0.1 mg/kg to about 100 mg/kg, about 0.1 mg/kg to about 75mg/kg, 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 3 mg/kg.
  • the effective amount of the one or more broadly neutralizing antibodies is about 0.1 mg/kg to about 50 mg/kg, about 1 mg/kg to about 40 mg/kg, about 1 mg/kg to about 30 mg/kg or about 1 mg/kg to about 25 mg/kg.
  • the present application also includes a pharmaceutical combination, packaged together in a kit or a single composition, comprising one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein the one or more neuraminidase inhibitors and bNAbs are present in amounts that are effective to treat an influenza infection or a disease, disorder or condition arising from an influenza infection and wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered or used alone there is no treatment or prevention of the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • HA hemagglutinin
  • the present application also includes a pharmaceutical combination, packaged together in a kit or a single composition, comprising one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein the one or more neuraminidase inhibitors and bNAbs are present in amounts that are effective for improving the efficacy of the one or more bNAbs to treat an influenza infection or a disease, disorder or condition arising from an influenza infection, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered or used alone there is no treatment or prevention of the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • HA hemagglutinin
  • influenza the disease, disorder or condition arising from influenza infection is influenza (flu).
  • the present application also includes a kit for the treatment of an influenza infection or a disease, disorder or condition arising from an influenza infection, the kit comprising one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally instructions for administration of the one or more bNAbs and one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are administered or used in an amount that when the one or more bNAbs are administered or used alone there is no treatment or prevention the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • HA hemagglutinin
  • the present application also includes a kit for the treatment of an influenza infection, or a disease, disorder or condition arising from an influenza infection, the kit comprising: one or more neuraminidase inhibitors or a pharmaceutically acceptable salt and/or solvate thereof; and instructions for administration of one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof, to a subject being administered one or more bNAbs for an influenza infection or a disease, disorder or condition arising from an influenza infection wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are administered or used in an amount that when the one or more bNAbs are administered or used alone there is no treatment or prevention the influenza infection.
  • HA hemagglutinin
  • the present application also includes a kit for improving the efficacy of one or more bNAbs for the treatment of an influenza infection or a disease, disorder or condition arising from an influenza infection, the kit comprising one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof; and optionally instructions for administration of the one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to a subject in need thereof wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are administered or used in an amount that when the one or more bNAbs are administered or used alone there is no treatment or prevention the influenza infection.
  • bNAbs broadly neutralizing antibodies
  • HA hemagglutinin
  • the present application also includes a kit for improving the efficacy of one or more bNAbs for the treatment of an influenza infection, or a disease, disorder or condition arising from an influenza infection, the kit comprising one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof; and instructions for administration one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof, to a subject being administered one or more bNAbs for the treatment of an influenza infection or a disease, disorder or condition arising from an influenza infection wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs and the one or more bNAbs are administered or used in an amount that when the one or more bNAbs are administered or used alone there is no treatment or prevention the influenza infection.
  • HA hemagglutinin
  • one or more broadly neutralizing antibodies (bNAbs) and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in the compositions and kits of the present application are formulated as separate pharmaceutical compositions, for separate administration to, or use in, subjects.
  • the separate pharmaceutical compositions are formulated independently of each other and in accordance with the desired mode of administration for each active.
  • the one or more broadly neutralizing antibodies are formulated for administration, or use, by oral delivery or for delivery by injection.
  • one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof is formulated for administration, or use, by oral delivery, for delivery by injection.
  • one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof is formulated for administration, or use, by oral delivery or for delivery by inhalation.
  • one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof, and the one or more broadly neutralizing antibodies (bNAbs) in the compositions and kits of the present application are formulated as a single pharmaceutical composition, for combined, simultaneous administration to, or use in, subjects.
  • the single pharmaceutical composition is formulated for administration, or use, by oral delivery or by injection.
  • the single pharmaceutical composition is formulated for administration, or use, by injection.
  • the present application also includes a pharmaceutical combination, packaged together in a kit or a single composition, comprising one or more broadly neutralizing antibody (bNAb)-inducing agents that endogenously produce an effective amount of one or more broadly neutralizing antibodies (bNAbs) in a subject and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein the one or more neuraminidase inhibitors and bNAbs are present in amounts that are effective to treat an influenza infection or a disease, disorder or condition arising from an influenza infection and wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the amount of the one or more bNAbs is an amount that when the bNAbs are administered or used alone there is no treatment or prevention of the influenza infection
  • bNAb broadly neutralizing antibody
  • HA hemagglutinin
  • the present application also includes a kit for the treatment of an influenza infection or a disease, disorder or condition arising from an influenza infection, the kit comprising one or more broadly neutralizing antibody (bNAb)- inducing agents that endogenously produce an effective amount of one or more broadly neutralizing antibodies (bNAbs) in a subject and one or more neuraminidase inhibitors or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally instructions for administration of the one or more bNAb-inducing agents and one or more neuraminidase inhibitors, or a pharmaceutically acceptable salt and/or solvate thereof, to a subject in need thereof, wherein the bNAbs bind to the stalk domain of hemagglutinin (HA) and the one or more bNAbs are administered or used in an amount that when the one or more bNAbs are administered or used alone there is no treatment or prevention the influenza infection.
  • bNAb broadly neutralizing antibody
  • HA hemagglutinin
  • Example 1 Inhibition of viral replication using a neuraminidase inhibitor
  • Neuraminidase activity of 6x10 6 PFU of PR8 and X-31 and 6x10 5 PFU of Cal/09 were measured using the Neuraminidase Assay Kit from Sigma- Adrich (MAK121 ) per manufacturer’s protocol. Specifically, influenza virus strains PR8 (A/Puerto Rico/8/1934 H1 N1 ); Cal/09 (A/California/7/2009 H1 N1 ); and X-31 , a reassortant virus with HA and NA from A/Hong Kong/1 /1968 H3N2 in the PR8 backbone (Fig. 2 first panel). Approximately 1x10 4 PFU of virus was required before NA activity was detectable by the assay.
  • the NA activity was within in the linear range of the assay until approximately 1x10 6 PFU for all viruses.
  • the oseltamivir acid susceptibility of these viruses using the same kit using 1x10 6 PFU of each strain (Fig. 2 second and third panel) was measured. All three viruses displayed similar levels of oseltamivir acid susceptibility as shown by the ICso values, with PR8 being the most susceptible and X-31 being the least susceptible. Viruses were incubated with exemplary neuraminidase inhibitor oseltamivir acid for 30 minutes at room temperature before measurements were taken. * p ⁇ 0.05, one-way ANOVA with Dunnett’s multiple comparisons test.
  • Exemplary neuraminidase inhibitor oseltamivir acid decreased both neuraminidase activity and viral replication of H1 N1 and H3N2 influenza viruses linfluenza virus strains PR8, Cal/09, and X-31 were used. This experiment verified that oseltamivir carboxylate was indeed active against the neuraminidase proteins on influenza virus particles. It was also found that increasing concentrations of oseltamivir acid also inhibits the ability of influenza viruses to replicate in a dose-dependent manner in cell culture of A549 cells. That is, higher concentrations of oseltamivir acid induced appreciable decreases in viral replication.
  • exemplary neuraminidase inhibitor oseltamivir acid induced the greatest decline in viral replication for X-31 , while PR8 and Cal/09 showed more modest declines in titer. Overall, it was shown that oseltamivir acid can be used as a chemical inhibitor of neuraminidase in subsequent experiments.
  • Example 2 Broadly neutralizing antibodies bind infected cells
  • Example 3 Neuraminidase inhibitor increases broadly-neutralizing antibody mediated ADCC of influenza virus infected A549 cells
  • Figure 1 shows how stalk-binding antibodies facilitate the interaction between immune effector cells and infected cells via two points of contact .
  • the stalk- binding antibody interacts with the HA stalk domain via its Fab portion, and binds to the Fc receptor of the effector via its Fc portion(1 ).
  • the HA head domain interacts with sialic acid residues on the effector cell (2). Although the sialic acid residues are depicted as a moiety on the Fc receptor on the effector cells, the actual location of the sialic acid residues that HA binds to in this context is not known.
  • A549 cells were infected with PR8, Cal/09, or X-31. As shown in Figure 4, ADCC of PR8, Cal/09, or X-31 infected A549 cells were measured using a luciferase-based system. A549 cells were seeded onto 96-well plates and infected 24 hours later with PR8, Cal/09, or X-31 at an MOI of 5.
  • exemplary neuraminidase inhibitor oseltamivir acid OSLT
  • 6F12 or 9H10 antibodies were added. Therefore, the infected cells were incubated with exemplary neuraminidase inhibitor oseltamivir acid and monoclonal stalk- binding antibodies 6F12 for cells infected with PR8 and Cal/09, and 9H10 for cells infected with X-31 .
  • 6F12 is a Pan H1 stalk-binding antibody
  • 9H10 is a group 2 HA stalk-binding antibody.
  • Jurkat reporter cells were then added and incubated for 6 hours before luciferase activity was measured by ADCC ( Figure 4).
  • exemplary neuraminidase inhibitor oseltamivir acid increased broadly-neutralizing antibody mediated ADCC of influenza virus infected A549 cells. Accordingly, it was found that exemplary neuraminidase inhibitor oseltamivir acid had a cooperative effect with broadly-neutralizing antibodies in causing ADCC of influenza virus infected cells. Increasing antibody concentrations with no exemplary neuraminidase inhibitor oseltamivir added ( ⁇ in Figure 4), there was increased fold induction of ADCC of our infected target (A549) cells. The fold induction was compared to cells that did not have antibody added to it.
  • exemplary neuraminidase inhibitor oseltamivir Upon addition of exemplary neuraminidase inhibitor oseltamivir in various concentrations, it was found that the ADCC potency increased (decreased ECso) in PR8 and Cal/09 infected cells, and the efficacy (fold induction) increased in all three viruses tested. The increase in potency and efficacy was also dose-dependent on the amount of oseltamivir that was added. Therefore, it was found that exemplary neuraminidase inhibitor oseltamivir cooperates with broadly-neutralizing antibodies to facilitate ADCC of influenza virus infected cells.
  • Example 4 Exemplary neuraminidase inhibitor oseltamivir in combination with broadly-neutralizing antibodies is superior at protecting against lethal influenza virus infections compared to using either therapeutic alone.
  • exemplary neuraminidase inhibitor oseltamivir phosphate in combination with broadly-neutralizing antibodies was superior at protecting against lethal influenza virus infections in BALB/c mice compared to using either therapeutic alone.
  • This experiment shows that the results from the previous in vitro ADCC experiments translates to better in vivo protection. It was demonstrated that the cooperative interaction between exemplary neuraminidase inhibitor oseltamivir and broadly-neutralizing antibodies in eliciting ADCC of influenza-virus infected cells resulted in better protection of mice that were infected with the same virus strain.
  • mice that received both oseltamivir phosphate and 6F12 displayed fewer clinical signs (less weight loss and fewer reached endpoint) compared to mice that received only oseltamivir, only 6F12, or neither. Therefore, combining oseltamivir phosphate and broadly- neutralizing antibodies as a prophylaxis worked better than using either of the two therapeutics by themselves.
  • Example 5 The cooperative effect of exemplary neuraminidase inhibitor oseltamivir phosphate and stalk-binding antibodies at preventing clinical signs of influenza virus infections is maintained in a polyclonal antibody context.
  • Serum was first purified from peripheral blood of two healthy donors. ELISAs were then performed on the serum samples using a chimeric cH6/1 hemagglutinin protein, where the head domain is derived from A/Mallard/Sweden/81 /02 and the stalk domain is derived from A/Puerto Rico/8/1934 ( Figure 6A, B). The cH6/1 chimera was chosen to quantify antibodies that specifically bind to the group 1 stalk domain. A/Vietnam/1203/2004 HAIo (Viet/04), which is a low pathogenicity human H5N1 virus, was chosen for the downstream experiments.
  • Viet/04 strain was chosen for its high pathogenicity in mice, relevance as a pandemic threat to humans, and the expected cross-reactivity of group 1 stalk-binding antibodies with the hemagglutinin stalk of Viet/04.
  • T o ensure that the serum samples do not contain neutralizing antibodies that bind to the head domain of Viet/04
  • a hemagglutinin inhibition assay was conducted( Figure 6C). Both serum samples exhibited undetectable levels of HA inhibition, indicating that both donors were naive to this virus.
  • ADCC assays were then conducted, which showed that the serum sample with greater titer of stalk binding antibodies elicited stronger ADCC as determined using Jurkat reporter cells (Figure 6D).
  • mice The protective effects of these serum samples against Viet/04 H5N1 challenge in Balb/c mice both alone and in combination with exemplary neuraminidase inhibitor oseltamivir phosphate was next assessed.
  • Six groups of 6-8 week old BALB/c mice were first either administered 150ul of serum low in stalk-binding antibodies, 150ul of serum high in stalk-binding antibodies, or 150ul of PBS.
  • the mice were then given either 10mg/kg exemplary neuraminidase inhibitor oseltamivir phosphate or PBS by oral gavage. Two hours after the treatments were given, the mice were infected with 5LDso of Viet/04 H5N1 (200PFU) intranasally.
  • mice continued to receive either 10mg/kg exemplary neuraminidase inhibitor oseltamivir phosphate or PBS twice daily by oral gavage for 5 days.
  • the mice were monitored for 14 days and sacrificed when they reached 80% of their initial body weight.
  • the data is shown as two sets of graphs with shared negative control groups to separate mice that received serum low and high in stalk-binding antibodies ( Figure 7). All the mice that received either serum low or high in stalk-binding antibodies or exemplary neuraminidase inhibitor oseltamivir phosphate alone demonstrated significant weight loss and mortality, with 4/5 mice reaching endpoint before day 14 in most treatment groups.
  • exemplary neuraminidase inhibitor oseltamivir phosphate When exemplary neuraminidase inhibitor oseltamivir phosphate was combined with serum containing low stalk antibody, the mortality of the mice improved to only 1/5 mice reaching endpoint by day 14. However, the morbidity of the mice remained similar to serum low or high in stalk-binding antibodies alone or exemplary neuraminidase inhibitor oseltamivir phosphate alone. Exemplary neuraminidase inhibitor oseltamivir phosphate combined with serum containing high stalk antibody showed the greatest improvement in morbidity and mortality. Importantly, this group displayed markedly improved mortality and morbidity with minimal weight loss compared to the other combination therapy group.
  • Example 6 The cooperative effect of combining exemplary neuraminidase inhibitor oseltamivir and stalk-binding antibodies is preserved when used to treat acute influenza virus infections
  • mice 6-8 week old BALB/c mice would be infected with 5LD50 of PR8 before starting treatment at various times post-infection (eg. 24, 48 , 72hpi).
  • Various doses of bnAb would be tested (eg. 1 mg/kg, 5mg/kg, 10mg/kg) since administration post-infection is likely to require a higher dose to achieve protection than prophylactic treatment.
  • Mice would be monitored for 14 days post-infection and sacrificed when weight dropped below 80% of pre- infection body weight.
  • the combination of bnAb+NA would be deemed superior than either drug alone if it results in less morbidity (as measured by weight loss) or mortality.
  • neuraminidase inhibitors such as oseltamivir and bnAbs surprisingly work in combination and synergistically to increase the potency of Fc-mediated effector function of immune cells (eg. ADCC mechanism), and not by working by their own distinct mechanisms alone.
  • FIG. 1 This combined mechanism of action is consistent with the“2 point of contact” model of how bnAbs induce ADCC/Fc effector functions as shown in Figure 1.
  • the neuraminidase inhibitors and bnAbs work cooperatively to stabilize HA:sialic acid interactions (which NA generally cleaves).
  • the lines in Figure 1 represent enzymatic inhibition by neuraminidase on the HA head - sialic interaction, and the inhibition of exemplary neuraminidase inhibitor oseltamivir on the neuraminidase enzymatic activity.

Abstract

La présente invention concerne des méthodes et des compositions pharmaceutiques pour la prévention et le traitement d'infections à virus Influenza. En particulier, la présente invention concerne l'utilisation d'un ou de plusieurs anticorps neutralisants à large spectre (bNAB, pour "broadly-neutralizing antibodies") en association avec un ou plusieurs inhibiteurs de la neuraminidase tels que l'oseltamivir pour la prévention ou le traitement d'infections à Influenza. En particulier, le ou les anticorps neutralisants à large spectre se lient au domaine tige de l'hémagglutinine (HA).
PCT/CA2019/051582 2018-11-06 2019-11-06 Associations d'anticorps neutralisants à large spectre et d'inhibiteurs de la neuraminidase pour prévenir ou traiter des infections à virus influenza WO2020093159A1 (fr)

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CN114129706A (zh) * 2020-09-04 2022-03-04 浙江瀛康生物医药有限公司 一种多肽在制备预防和治疗流感病毒感染的药物中的应用
WO2022109317A1 (fr) * 2020-11-23 2022-05-27 Vir Biotechnology, Inc. Anticorps contre la grippe et combinaisons de ces derniers
CN115529815A (zh) * 2021-04-27 2022-12-27 广州共禾医药科技有限公司 经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114129706A (zh) * 2020-09-04 2022-03-04 浙江瀛康生物医药有限公司 一种多肽在制备预防和治疗流感病毒感染的药物中的应用
WO2022109317A1 (fr) * 2020-11-23 2022-05-27 Vir Biotechnology, Inc. Anticorps contre la grippe et combinaisons de ces derniers
CN115529815A (zh) * 2021-04-27 2022-12-27 广州共禾医药科技有限公司 经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途
CN115529815B (zh) * 2021-04-27 2024-04-30 广州共禾医药科技有限公司 经直肠施用的奥司他韦或其药学上可接受的盐的药物组合物、及其制备方法和用途

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