WO2020058827A1 - Immunothérapie transmucosale buccale - Google Patents

Immunothérapie transmucosale buccale Download PDF

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Publication number
WO2020058827A1
WO2020058827A1 PCT/IB2019/057790 IB2019057790W WO2020058827A1 WO 2020058827 A1 WO2020058827 A1 WO 2020058827A1 IB 2019057790 W IB2019057790 W IB 2019057790W WO 2020058827 A1 WO2020058827 A1 WO 2020058827A1
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Prior art keywords
peanut
oral transmucosal
allergy
subject
administration
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PCT/IB2019/057790
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English (en)
Inventor
Sai Ying Ko
Original Assignee
Biolingus Ip Llc
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Priority claimed from AU2018903503A external-priority patent/AU2018903503A0/en
Application filed by Biolingus Ip Llc filed Critical Biolingus Ip Llc
Publication of WO2020058827A1 publication Critical patent/WO2020058827A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • 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
    • A61K39/0005—Vertebrate antigens
    • A61K39/001—Preparations to induce tolerance to non-self, e.g. prior to transplantation
    • 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
    • A61K39/35—Allergens
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/577—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 tolerising response

Definitions

  • the present invention relates generally to methods for use in the treatment and prevention of peanut and tree nut allergies. Specifically the invention relates to such treatment involving the oral transmucosal delivery, typically sublingual delivery, of interleukin-2 (IL-2).
  • IL-2 interleukin-2
  • the present invention provides a method for treating or preventing peanut or tree nut allergy in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • the allergy is peanut allergy.
  • the present invention provides a method for treating or reducing one or more symptoms of peanut or tree nut allergy in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • the allergy is peanut allergy.
  • the present invention provides a method for decreasing sensitivity to one or more peanut or tree nut allergens in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • the allergens are peanut allergens.
  • the invention provides the use of IL-2 or a functional fragment or derivative thereof for the manufacture of a medicament for treating or preventing peanut or tree nut allergy, for decreasing sensitivity to one or more peanut allergens or for treating or reducing one or more symptoms of peanut allergy, wherein the medicament is administered by oral transmucosal administration.
  • the IL-2 may be recombinant human IL-2.
  • the human IL-2 may be administered in the precursor or mature form.
  • the IL-2 may comprise or consist of the amino acid sequence set forth in SEQ ID NO:l or SEQ ID NO:2.
  • the oral transmucosal administration is sublingual or buccal administration. More typically, the oral transmucosal administration is sublingual administration.
  • the IL-2 may be administered in any form suitable for oral transmucosal delivery, typically for sublingual or buccal delivery, such as, for example in solid or liquid unit dosage form.
  • the method may comprise the oral transmucosal administration of a dose of between about 100 IU IL-2 and about 10,000 IU IL-2.
  • the method comprises the sublingual administration of a dose of about 100 IU IL-2.
  • the method comprises the sublingual administration of a dose of about 1,000 IU IL-2.
  • the method comprises the sublingual administration of a dose of about 10,000 IU IL-2.
  • the effective dose may be administered on a per day basis.
  • the method comprises the oral transmucosal administration of a dose of between about 100 IU IL-2 and about 10,000 IU IL-2 per day.
  • the method comprises the sublingual administration of a dose of about 100 IU IL-2 per day.
  • the method comprises the sublingual administration of a dose of about 1,000 IU IL-2 per day.
  • the method comprises the sublingual administration of a dose of about 10,000 IU IL-2 per day.
  • the oral transmucosal administration of the IL-2 may be continued for up to about one week, two weeks, three weeks, one month, two months, three months, six months, 12 months or more.
  • Figure 1 Clinical scores (left panel) and body temperature (right panel) measured at day 38 are shown for each individual mouse. **, p ⁇ 0.0l; ns, not significant.
  • SL sublingual (100 IU, 1,000 IU or 10,000 IU IL-2); i.p., intraperitoneal (50,000 IU IL-2).
  • FIG. 1 A. Clinical scores (left panel) and body temperature (right panel) measured at day 51 are shown for each individual mouse. *, p ⁇ 0.05; ns, not significant.
  • SF sublingual (100 IU, 1,000 IU or 10,000 IU IF-2); i.p., intraperitoneal (50,000 IU IF-2).
  • SEQ ID NO amino acid and nucleotide sequences are referred to by a sequence identifier number (SEQ ID NO).
  • the SEQ ID NOs correspond numerically to the sequence identifiers ⁇ 400>l (SEQ ID NO:l), ⁇ 400>2 (SEQ ID NO:2), etc.
  • the amino acid sequence set forth in SEQ ID NO: 1 represents the precursor form of human IF-2
  • the amino acid sequence set forth in SEQ ID NO: 2 represents the mature form of human IF-2.
  • the nucleotide sequence encoding human IF-2 is set forth in SEQ ID NO:3. Detailed Description of the Invention
  • the term "effective dose” includes within its meaning a non toxic but sufficient dose of IL-2 to provide the desired therapeutic effect.
  • the exact dose required will vary from subject to subject depending on factors such as the age and general condition of the subject, the severity of the subject’s allergy, the form of IL-2 being administered, the dosage form and so forth. Thus, it is not always possible to specify an exact“effective dose”. However, for any given case, an appropriate “effective dose” may be determined by one of ordinary skill in the art using only routine experimentation .
  • treating and“treatment” refer to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.
  • “treatment” refers not only to treatment designed to cure or remove symptoms in an individual, but also to ongoing therapy designed to control and suppress the occurrence of symptoms. Treatment may be for a defined period of time, or provided on an ongoing basis depending on the particular circumstances of any given individual.
  • polypeptide means a polymer made up of amino acids linked together by peptide bonds.
  • polypeptide andprotein are used interchangeably herein, although for the purposes of the present invention a “polypeptide” may constitute a portion of a full length protein.
  • polynucleotide refers to a single- or double-stranded polymer of deoxyribonucleotide, ribonucleotide bases or known analogues or natural nucleotides, or mixtures thereof.
  • the present invention is predicated on the surprising finding in an in vivo animal model that sublingual administration with very low doses of recombinant IL-2 results in a substantial and statistically significant therapeutic benefit in terms of reducing the clinical allergic signs and symptoms associated with peanut allergy upon peanut challenge. In contrast, significantly higher doses of IL-2 are required to achieve a similar outcome when administered by injection.
  • One aspect of the invention provides a method for treating or preventing peanut or tree nut allergy in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • Another aspect provides a method for treating or reducing one or more symptoms of peanut or tree nut allergy in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • Another aspect provides a method for decreasing sensitivity to one or more peanut or tree nut allergens in a subject, the method comprising oral transmucosal administration to the subject of an effective dose of IL-2 or a functional fragment or derivative thereof.
  • Subjects to which methods of the invention may be administered may have an allergy to peanuts and/or to one or more tree nuts, or may be susceptible to or at risk of developing such an allergy. Approximately 25 to 40% of individuals allergic to peanuts are also allergic to at least one tree nut.
  • the allergy, or susceptibility thereto may be identified or diagnosed by, for example, prior exposure to peanut or tree nuts, a skin prick test or a blood test or other biochemical test to determine levels of IgE antibodies or other allergy- specific markers.
  • Tree nuts contemplated by the present invention include, but are not limited to, walnuts, pecans, hazelnuts, brazil nuts, chestnuts, cashews, macadamia nuts, almonds, pistachios, hickory nuts, nangai nuts, bush nuts and beechnuts.
  • Embodiments of the present invention offer significant advantages for peanut allergy sufferers, tree nut allergy sufferers and those susceptible to, or at risk of developing such allergies.
  • the dose of IL-2 required when administered by the oral transmucosal route, such as sublingually is substantially lower than that required when administration is by injection.
  • the need for intravenous or subcutaneous injections of IL-2 also hampers the ability of individuals to self-medicate and manage their own treatment regime.
  • Oral transmucosal administration, such as sublingual administration, of IL-2 offers for the first time a simple, low cost and effective treatment option for peanut and tree nut allergy sufferers which will have greater patient compliance.
  • a feature of the present invention is that oral transmucosal administration of IL-2 enables significantly lower dose to be employed than is possible with prior art approaches whilst retaining therapeutic benefit. Accordingly, the minimum dose of IL-2 that may be used in accordance with the invention can be determined by those skilled in the art, provided that the dose is sufficient to achieve a therapeutic benefit. In terms of the maximum dose, this can also be determined by a person skilled in the art taking into consideration factors such as those discussed herein.
  • an effective dose of IL-2 for oral transmucosal administration in accordance with the present invention may comprise between about 10 IU and about 100,000 IU IL-2, between about 50 IU and about 50,000 IU IL-2, between about 100 IU and about 20,000 IU IL-2, or between about 100 IU and about 10,000 IU IL-2.
  • an effective dose of IL-2 for oral transmucosal administration in accordance with the present invention may comprise about 50 IU, 100 IU, 200 IU, 300 IU, 400 IU, 500 IU, 600 IU, 700 IU, 800 IU, 900 IU, 1,000 IU, 1,200 IU, 1,400 IU, 1,600 IU, 1,800 IU, 2,000 IU, 2,200 IU, 2,400 IU, 2,600 IU, 2,800 IU, 3,000 IU, 3,200 IU, 3,400 IU, 3,600 IU, 3,800 IU, 4,000 IU, 4,200 IU, 4,400 IU, 4,600 IU, 4,800 IU, 5,000 IU, 5,200 IU, 5,400 IU, 5,600 IU, 5,800 IU, 6,000 IU, 6,200 IU,
  • an effective dose of IL-2 for oral transmucosal administration in accordance with the present invention may be between about 10 IU and about 100,000 IU per day, between about 50 IU and about 50,000 IU per day, between about 100 IU and about 20,000 IU per day, or between about 100 IU and about 10,000 IU per day.
  • the daily dose administered to a patient in need thereof may be in the order of about 50 IU, 100 IU, 200 IU, 300 IU, 400 IU, 500 IU, 600 IU, 700 IU, 800 IU, 900 IU, 1,000 IU, 1,200 IU, 1,400 IU, 1,600 IU, 1,800 IU, 2,000 IU, 2,200 IU, 2,400 IU, 2,600 IU, 2,800 IU, 3,000 IU, 3,200 IU, 3,400 IU, 3,600 IU, 3,800 IU, 4,000 IU, 4,200 IU, 4,400 IU, 4,600 IU, 4,800 IU, 5,000 IU, 5,200 IU,
  • the effective dose for any particular subject will depend upon a variety of factors including any one or more of: the severity of the peanut or tree nut allergy; the number and identity of nuts to which the subject is allergic; the composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the duration of the treatment; drugs used in combination or coincidental with the treatment, together with other related factors well known in medicine.
  • One skilled in the art would be able, by routine experimentation, to determine an effective, non-toxic dose which would be suitable for any given subject.
  • the optimal quantity and spacing of individual doses will be determined by the severity of the peanut or tree nut allergy, the form, route and site of administration, and the nature of the particular individual being treated. Also, such optimum conditions can be determined by conventional techniques known to those skilled in the art. For example, a subject may be administered the desired daily dose in a single unit dosage form once per day, or in two unit dosage forms administered twice a day.
  • the IL-2 used in the methods of the invention may be natural, recombinant or synthetic and may be obtained by purification from a suitable source or produced by standard recombinant DNA techniques such as those well known to persons skilled in the art, and described in, for example, Sambrook et ah, Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory Press (the disclosure of which is incorporated herein by reference). Those skilled in the art will appreciate that the precise sequence of the IL-2 to be employed in accordance with the present invention may vary depending on a number of factors, including for example the species to be treated.
  • the IL-2 to be administered is human IL-2 such as recombinant human IL-2.
  • Full length human IL-2 has the amino acid sequence as set forth in SEQ ID NO:l (precursor form) or SEQ ID NO:2 (mature form) and in its native form is an approximately 15,500 Da glycosylated protein.
  • Reference to“IL-2” should be understood as a reference to all forms of this molecule and to functional derivatives, variants and homologues thereof. This includes, for example, any isoforms which arise from alternative splicing of the IL-2 mRNA or functional mutants or polymorphic variants of these proteins. Also encompassed within the scope of the invention are homologs or mimetics which possess qualitative biological activity in common with the full-length mature IL-2.
  • “Derivatives” of IL-2 include analogues, functional fragments, parts, portions or variants from either natural or non-natural sources.
  • Non-natural sources include, for example, recombinant or synthetic sources.
  • recombinant sources is meant that the cellular source from which the IL-2 is harvested has been genetically altered.
  • “Analogue” means a polypeptide which is a derivative of IL-2, which derivative comprises addition, deletion, substitution of one or more amino acids, such that the polypeptide retains substantially the same function as the native IL-2 from which it is derived. Modifications may be made so as to enhance the biological activity or expression level of IL-2 or to otherwise increase the effectiveness of the polypeptide to achieve a desired result.
  • the term“conservative amino acid substitution” refers to a substitution or replacement of one amino acid for another amino acid with similar properties within a polypeptide chain (primary sequence of a protein). For example, the substitution of the charged amino acid glutamic acid (Glu) for the similarly charged amino acid aspartic acid (Asp) would be a conservative amino acid substitution.
  • Amino acid insertional derivatives also include amino and/or carboxylic terminal fusions as well as intrasequence insertions of single or multiple amino acids. Insertional amino acid sequence variants are those in which one or more amino acid residues are introduced into a predetermined site in the protein although random insertion is also possible with suitable screening of the resulting product. Deletional variants are characterised by the removal of one or more amino acids from the sequence. Substitutional amino acid variants are those in which at least one residue in a sequence has been removed and a different residue inserted in its place.
  • the term“functional fragment” refers to a polypeptide that is a constituent of a full-length IL-2 and that possesses qualitative biological activity in common with the full-length IL-2 of which it is a fragment.
  • the fragment may be derived from the full- length IL-2 polypeptide or alternatively may be synthesised by some other means, for example chemical synthesis.
  • a“variant” of IL-2 means a molecule of substantially similar sequence to the iL-2 of which it is a variant and which exhibits at least some of the functional activity of the IL-2 of which it is a variant.
  • a variant may take any form and may be naturally or non-naturally occurring.
  • variant polypeptides may share at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity.
  • a“homologue” means that the IL-2 is derived from a species other than that which is being treated in accordance with the invention. This may occur, for example, where it is determined that a species other than that which is being treated produces a form of IL-2 which exhibits similar or superior, and suitable, functional characteristics to that of the IL-2 which is naturally produced by the subject undergoing treatment.
  • Embodiments of the present invention also provide for the administration of IL-2 in the form of a polynucleotide encoding an IL-2 polypeptide as described above.
  • the polynucleotide encodes human IL-2.
  • an IL-2 polynucleotide of the invention may have the nucleotide sequence as set forth in SEQ ID NOG.
  • the invention also contemplates the use of polynucleotides encoding homologues, fragments and variants thereof.
  • the polynucleotide may be administered in a vector.
  • the vector may be a plasmid vector, a viral vector, or any other suitable vehicle adapted for the insertion and foreign sequences and introduction into eukaryotic cells.
  • the vector is an expression vector capable of directing the transcription of the DNA sequence of the polynucleotide encoding the desired polypeptide into mRNA.
  • the vector may include expression control and processing sequences such as a promoter, an enhancer, ribosome binding sites, polyadenylation signals and transcription termination sequences.
  • suitable viral expression vectors include for example Epstein-barr virus-, bovine papilloma virus-, adenovirus- and adeno-associated virus-based vectors.
  • the vector may be episomal.
  • Embodiments of the present invention provide methods for reducing the sensitivity of a subject to one or more peanut or tree nut allergens.
  • a peanut or tree nut allergen is any agent contained in, produced by, or derived from peanuts or one or more tree nuts, which triggers a measurable immune response.
  • an allergen may include any agent which triggers measurable production of IgE in at least some individuals exposed to the allergen.
  • the allergen comprises an agent that triggers an allergic reaction (type I hypersensitivity reaction) in at least some individuals exposed to the allergen.
  • Reference to a“peanut allergen” and to a“tree nut allergen” as used herein encompasses allergens in the peanut or tree nut, and extracts thereof such as peanut or tree nut oils and butters, for example, as well as allergenic molecules (for example, proteins and polypeptides) that are at least partially purified or substantially purified or isolated from peanut or a tree nut.
  • the present invention provides methods for the delivery of IL-2 via the oral mucosa.
  • the oral transmucosal administration of IL-2 is sublingual administration or buccal administration, whereby a suitably formulated composition is placed into contact with the oral mucosa either under the tongue or in the cheek pouch, allowing entry of the IL-2 directly to the bloodstream by absorption.
  • Suitable forms for oral transmucosal administration include solids, liquids, emulsions, gels and suspensions.
  • a composition is administered in solid unit dosage form, for example in the form of a tablet, capsule, caplet, tabsule or lozenge.
  • the administration may comprise a gel administered to the sublingual or buccal area.
  • IL-2 may be unstable in a given liquid
  • this can be overcome by dissolving freeze dried IL-2 powder in a diluent, for example water plus honey or carboxymethylcellulose, dextran, maltodextrin, gums, albumin, sugars such as dextrose, maltose, mannitol etc.
  • Honey is particularly useful as it contains many antigens which may assist the interleukin immune response.
  • suitable compositions may be prepared according to methods which are known to those of ordinary skill in the art and may include a pharmaceutically acceptable diluent, adjuvant and/or excipient.
  • diluents, adjuvants and excipients must be "acceptable” in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.
  • Examples of pharmaceutically acceptable diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols, for example ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene
  • the diluent may be dextran, dextrin, dextrose, sucrose, maltose, mannitol, gelatin, pregel starch, starch, amino acids trehalose, carboxymethylcellulose, cellulose, methyl cellulose, ethyl cellulose, albumin and propylene glycol.
  • the carrier or carriers will form from 0.1% to 99.9% by weight of the compositions.
  • the IL-2 is administered in the form of a solid unit dosage form such as a tablet, capsule or lozenge suitable for oral, most typically sublingual, administration.
  • Suitable solid compositions may comprise a rapid or slow disintegrating composition comprising IL-2 in a pharmaceutically acceptable water soluble or water dispersible carrier material. Such compositions may disintegrate or dissolve in the mouth upon placement under the tongue or insertion into the buccal pouch.
  • Compositions may be formulated for rapid or immediate release of the IL-2 or alternatively for delayed or controlled release. Techniques and processes for achieving delayed or controlled release of active agents are well known to those skilled in the art.
  • suitable formulations may be prepared by processes including freeze drying under vacuum, supercritical fluid drying, spray drying using heat, and fluid bed spray drying.
  • a process involving microencapsulation whereby the active ingredient is coated onto granules, tablets or microparticles, typically using solvents.
  • One particularly suitable process involves the use of a fluidised bed spray process facilitating the coating onto granules at room temperature of actives including polypeptides with a water solubilising coat, as disclosed in International Patent Application Publication No.
  • Microparticles such as water soluble sugars or gel forming particles may be thus coated, or alternatively a blank tablet, lozenge or capsule core may be spray coated.
  • a blank tablet, lozenge or capsule core may be spray coated.
  • means for the preparation of oral compositions incorporating an effervescent agent as a penetration enhancer to increase the permeability of the active agent across the buccal and sublingual mucosa see for example US Patent No. 6,974,590, the disclosure of which is incorporated herein in its entirety by reference.
  • Other delivery modes contemplated by the present invention include the use of bioadhesives, mucoadhesives and liposomes.
  • compositions of the invention may also be administered in the form of liposomes.
  • Liposomes may be derived from phospholipids or other lipid substances, and are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in aqueous medium. Specific examples of liposomes used in administering or delivering a composition to target cells are DODMA, synthetic cholesterol, DSPC, PEG-cDMA, DLinDMA, or any other non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes.
  • the compositions in liposome form may contain stabilisers, preservatives and/or excipients.
  • compositions may also be administered in the form of microparticles.
  • Biodegradable microparticles formed from polylactide (PLA), polylactide-co-glycolide (PLGA), and epsilon-caprolactone ( ⁇ -caprolactone) may be used.
  • compositions may incorporate a controlled release matrix that is composed of sucrose acetate isobutyrate (SAIB) and an organic solvent or mixture of organic solvents.
  • SAIB sucrose acetate isobutyrate
  • Polymer additives may be added to further increase the viscosity so as to decrease the release rate.
  • Solid forms may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents.
  • Suitable binders include gum acacia, gelatine, com starch, pregel starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol.
  • Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine.
  • Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar.
  • Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
  • Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
  • Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
  • Suitable preservatives include sodium benzoate, vitamin E, alpha- tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
  • Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
  • Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
  • Liquid forms may contain, in addition to the above agents, a liquid carrier.
  • suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, arachis oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
  • Suspensions may further comprise dispersing agents and/or suspending agents.
  • Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, poly-vinyl-pyrrolidone, sodium alginate or acetyl alcohol.
  • Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or - laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
  • Emulsions may further comprise one or more emulsifying agents.
  • Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia or gum tragacanth.
  • Example 1 Sublingually administered IL-2 and peanut allergy
  • a mouse model was used to determine the efficacy of oral transmucosal administration of IL-2 in the treatment of peanut allergy.
  • Recombinant human IL-2 was purchased from Beijing Four Rings Bio Pharmaceutical Co., Ltd. (Beijing, People's Republic of China). The IL-2 was formulated into tablet form, at 1.2 million IU/tablet and then made into a paste with water to the required IU, either 100 IU, 1,000 IU or 10,000 IU. Tablets were stored at 25°C. Formulated IL-2 was used for daily sublingual or intraperitoneal administration of mice as described below.
  • mice were sensitized to peanut intraperitoneally three times at one week intervals (days 0, 7 and 14) with 300 qg peanut extract in aluminium hydroxide, or PBS in aluminium hydroxide. Subsequently mice were orally administered peanut extract between days 24 and 38 and between days 52 and 53.
  • Rats were randomized into six groups:
  • T reg cells Regulatory T cells
  • mice in each of the IF-2 treatment groups displayed significantly less clinical signs of allergic reaction than mice in the PBS and non-treatment control groups.
  • sublingual administration of IF-2 at very low doses of only 100 IU and 1,000 IU had the same effect as 50,000 IU IF-2 administered intraperitoneally. Body temperature changes were not significantly different between each group.
  • sublingual administration of IF-2 at a dose of 10,000 IU still proved to be as effective as the intraperitoneal administration (i.e. at a five times lower dosage).

Abstract

L'invention concerne des méthodes pour traiter ou prévenir une allergie à l'arachide et/ou aux fruits à coque, pour traiter ou atténuer un ou plusieurs symptômes de l'allergie à l'arachide et/ou aux fruits à coque, et pour diminuer la sensibilité à un ou plusieurs allergènes de l'arachide ou des fruits à coque, comprenant l'administration transmucosale buccale, éventuellement une administration sublinguale, au sujet le nécessitant, d'une dose efficace d'IL-2, ou d'un fragment fonctionnel ou d'un dérivé de celle-ci.
PCT/IB2019/057790 2018-09-18 2019-09-17 Immunothérapie transmucosale buccale WO2020058827A1 (fr)

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AU2018903503A AU2018903503A0 (en) 2018-09-18 Oral transmucosal immunotherapy
AU2018903503 2018-09-18

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2002058735A1 (fr) 2001-01-25 2002-08-01 Gainful Plan Limited Procede de preparation de materiaux biologiques et produits resultants
US6974590B2 (en) 1998-03-27 2005-12-13 Cima Labs Inc. Sublingual buccal effervescent
EP2918285A1 (fr) * 2014-03-11 2015-09-16 Université Pierre et Marie Curie (Paris 6) Interleukin-2 pour traiter une allergie alimentaire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6974590B2 (en) 1998-03-27 2005-12-13 Cima Labs Inc. Sublingual buccal effervescent
WO2002058735A1 (fr) 2001-01-25 2002-08-01 Gainful Plan Limited Procede de preparation de materiaux biologiques et produits resultants
EP2918285A1 (fr) * 2014-03-11 2015-09-16 Université Pierre et Marie Curie (Paris 6) Interleukin-2 pour traiter une allergie alimentaire

Non-Patent Citations (2)

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Title
BENJAMIN BONNET ET AL: "Low-Dose IL-2 Induces Regulatory T Cell-Mediated Control of Experimental Food Allergy", THE JOURNAL OF IMMUNOLOGY, vol. 197, no. 1, 3 June 2016 (2016-06-03), US, pages 188 - 198, XP055642199, ISSN: 0022-1767, DOI: 10.4049/jimmunol.1501271 *
SAMBROOK ET AL.: "Molecular Cloning: a Laboratory Manual", vol. XIV, 1976, COLD SPRING HARBOR LABORATORY PRESS, pages: 33

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