US20150250870A1 - Compositions for Immunotherapy - Google Patents

Compositions for Immunotherapy Download PDF

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Publication number
US20150250870A1
US20150250870A1 US14/435,262 US201214435262A US2015250870A1 US 20150250870 A1 US20150250870 A1 US 20150250870A1 US 201214435262 A US201214435262 A US 201214435262A US 2015250870 A1 US2015250870 A1 US 2015250870A1
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allergen
composition
peanut
mammal
immunotherapy
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Joanna Paulina Maria Van Der Kleij
Dirk Jan Elbertus Opstelten
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Hal Allergy Holding BV
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Hal Allergy Holding BV
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Assigned to HAL ALLERGY HOLDING B.V. reassignment HAL ALLERGY HOLDING B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OPSTELTEN, DIRK JAN ELBERTUS, VAN DER KLEIJ, Joanna Paulina Maria
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    • 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
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants

Definitions

  • the present invention relates to compositions which can be used in immunotherapy and especially to compositions which can be used in immunotherapy for mammals, such as human mammals, suffering from peanut allergy.
  • the present invention further relates to the use of the present compositions for the therapeutic treatment for desentizing the immune system of a mammal suffering from an allergy by immunotherapy and the use of the present compositions in a prophylactic treatment of a mammal with high predisposition to develop a certain allergy.
  • Allergen immunotherapy also termed hyposensitization therapy, immunologic desensitization, hyposensibilization, or allergen-specific immunotherapy, is a form of immunotherapy for allergic disorders in which the patient is vaccinated with increasingly larger doses of an allergen, i.e. the substance, or substances, to which they are allergic, with the aim of inducing immunologic tolerance.
  • an allergen i.e. the substance, or substances, to which they are allergic, with the aim of inducing immunologic tolerance.
  • Allergen specific immunotherapy is the only treatment strategy which treats the underlying cause of an allergic disorder. It is a highly cost-effective treatment strategy and results in an improved quality of life.
  • Immunotherapy has been shown to produce long-term remission of allergic symptoms, to reduce severity of associated allergic response, as well to reduce the chances of new sensitizations to allergens developing. Immunotherapy aims to modulate the immune system's response to allergens.
  • Immunotherapy generally encompasses repeated exposure to a specific allergen via, for example, sublingual or subcutaneous routes, thereby providing a desensitization of the allergic patient to the allergen and thus a reduction in allergic symptoms and use of symptomatic based treatments.
  • the exact mechanism underlying immunotherapy is not fully known but it is accepted that immunotherapy leads to alteration of the immune response to an allergen.
  • the modification at least comprises a change in IgE synthesis and the production of IgE blocking antibodies reducing the allergic response of the immune system to specific allergens. Also an increase in conversion of Th2 to Th1/T regulatory cells is observed.
  • part of the underlying mechanism relies on the preferential induction of allergen-specific IgG to neutralize an allergen and a reduction of allergen-specific IgE.
  • Immunotherapy generally involves exposing an allergic patient to low doses of an allergen.
  • the dose is gradually increased on a regular, for example weekly, basis, until a “maintenance” dose is reached. This translates in approximately four months of weekly injections to reach the maintenance dose. Once the maintenance dose is reached, the injections are administered less often, for example once per month for a few years. Generally, the longer the treatment and the higher the dose, the greater the therapeutic benefit.
  • Peanuts are one of the most common foods responsible for food-induced allergy. A curative treatment for peanut allergy is not yet available.
  • Specific immunotherapy (SIT) using aqueous peanut extract displayed an increased tolerance to oral ingestion of peanuts.
  • aqueous peanut extracts resulted in unacceptable systemic reactions, even during the maintenance injections. Accordingly, the Nelson et al. concluded: “For clinical application of this method of treatment, a modified peanut extract is needed.”
  • compositions suitable for immunotherapy and especially immunotherapy effective against peanut allergy need to be, besides providing an alteration of the immune response upon exposure to an allergen, safe, i.e. the compositions must not trigger an allergic reaction and, in the most severe case, an anaphylactic shock.
  • compositions suitable for immunotherapy and especially immunotherapy directed to peanut allergy are provided.
  • this object of the present invention is met, according to a first aspect, by a composition suitable for immunotherapy comprising an allergen, wherein substantially 100% of said allergen in said composition is complexed with aluminum.
  • an allergen is defined as an antigen capable of stimulating a hypersensitivity reaction in atopic mammals through immunoglobulin E (IgE) responses.
  • IgE immunoglobulin E
  • non-parasitic antigens stimulate undesired IgE production, resulting in hypersensitivity or allergy.
  • allergens include antigens found in animal products such as Fel d 1 (cat allergy), fur and dander, cockroach calyx, wool and dust mite excretion; drugs such as penicillin, sulphonamides, and salicylates; foods such as celery and celeriac, corn or maize, eggs (typically egg white), fruit, pumpkin, egg-plant, legumes, beans, peas, peanuts, soybeans, milk, seafood, sesame, soy, tree nuts, pecans, almonds, and wheat; insect stings such as bee sting venom, wasp sting venom, and mosquito stings; mold spores; latex; metal; and plant pollen such as grasses and tree pollen.
  • animal products such as Fel d 1 (cat allergy), fur and dander, cockroach calyx, wool and dust mite excretion
  • drugs such as penicillin, sulphonamides, and salicylates
  • foods such as celery and celeriac, corn
  • allergen refers to any substance that has a wide range of medicinal properties.
  • allergens refers to any substance that has a wide range of medicinal properties.
  • antigens refers to any substance that has a wide range of medicinal properties.
  • antigens refers to any substance that has a wide range of medicinal properties.
  • antigens refers to any substance that has a wide range of medicinal properties.
  • the present inventors have surprisingly found that when substantially 100%, such as more than 99%, of an allergen in a preparation is complexed, or conjugated with, or bound to aluminum, no clinically relevant allergic reactions, i.e. mast cell-mediated systemic responses, are observed although the aluminum complexed allergen is still capable of inducing an IgG response thereby providing a composition especially suitable to be used in immunotherapy.
  • Mast cell-mediated systemic responses can be readily measured by a lowering of the body temperature after exposure to an allergen.
  • the present aluminum complexed, bound, or conjugated allergen is a peanut kernel protein extract, preferably a peanut kernel protein extract being modified by reduction and subsequent alkylation.
  • the present peanut kernel protein extract can be obtained by a) grinding peanuts for providing a peanut powder; b) incubating the peanut powder in acetone during 30 minutes using 5 grams peanut powder per 50 ml acetone for providing a defatted peanut powder; c) drying the defatted peanut powder; d) suspending the dried peanut powder in a buffer with a pH between 7 and 9; and e) isolating the resulting supernatant of step (d) thereby providing a peanut kernel protein extract.
  • Reduction of the present peanut extract can be provided by contacting the extract with one or more reducing agents chosen from the group consisting of 2-mercaptoethanol ( ⁇ -ME), dithiothreitol (DTT), dithioerythritol, cysteine, homocystein, tributylphosphine, sulfite, tris(2-carboxyethyl) phosphine (TCEP), sodium (cyano) borohydride, lye, glutathione, E-mercapto ethylamine, thioglycollic acid, methyl sulfide, and ethyl sulfide.
  • reducing agents chosen from the group consisting of 2-mercaptoethanol ( ⁇ -ME), dithiothreitol (DTT), dithioerythritol, cysteine, homocystein, tributylphosphine, sulfite, tris(2-carboxyethyl) phosphine (
  • the present a peanut kernel protein extract comprises at least the major peanut allergens Ara h1, Ara h2 and Ara h6.
  • Peanut allergenic protein Ara h1 was described as a 63.5 kDa protein occurring naturally in a trimeric form of approximately 180 kDa through non-covalent interactions. The trimeric Ara h1 structures often aggregate, forming multimers of up to 600-700 kDa.
  • Peanut allergenic protein Ara h2 migrates as a doublet at approximately 20 kDa. This doublet consists of two isoforms that are nearly identical except for the insertion of the sequence DPYSPS in the higher molecular weight isoform.
  • Peanut allergenic protein Ara h6 was identified as a protein with a molecular weight of approximately 15 kDa based on SDS-PAGE and 14,981 Da as determined by mass spectroscopy.
  • the present allergen is an allergenic protein, preferably of protein selected from the group consisting of food proteins or venom proteins.
  • the present composition preferably comprises pharmaceutically acceptable carriers, diluents and/or excipients.
  • the present invention relates, according to a second aspect, to a composition comprising an allergen, wherein substantially 100% of said allergen in said composition is complexed with aluminum, for use in a therapeutic or prophylactic treatment of a mammal, preferably a human mammal, suffering from an allergy by immunotherapy.
  • the allergen is a peanut kernel protein extract, preferably modified by reduction and subsequent alkylation, and the allergy is peanut allergy.
  • the present invention relates, according to a third aspect, to a composition comprising an allergen, wherein substantially 100% of said allergen in said composition is complexed with aluminum, for use in a prophylactic treatment for desentizing the immune system of a mammal, preferably a human mammal, for said allergen.
  • the allergen is a peanut kernel protein extract, preferably modified by reduction and subsequent alkylation, and the immune system is desensitized for exposure to peanuts.
  • the present invention relates to a composition
  • a composition comprising an allergen, wherein substantially 100% of said allergen in said composition is complexed with aluminum, for use in medicine.
  • the present invention relates to a method for immunotherapy comprising administering to a mammal, preferably a human mammal, suffering from an allergy a composition comprising an allergen, wherein substantially 100% of said allergen in said composition is complexed with aluminum, in a sufficient amount and during sufficient time to reduce, or eliminate, an allergic response of said mammal to said allergen.
  • a typical sufficient amount will be from about 0.1 ng/kg to 10 mg/kg, 10 ng/kg to about 100 ⁇ g/kg, or 0.1 ⁇ g/kg to 1 ⁇ g/kg of the aluminum complexed allergen relative to the body weight of the individual to which it is administered.
  • a treatment will comprise starting with the administration of dosages at the lower end of these ranges and increasing the dosages as the treatment progresses.
  • desensitization treatment it is typically necessary for the patient to receive frequent administrations, e.g., initially every one, two or three days, gradually reducing to once every two or three weeks.
  • Other suitable desensitization programs include subcutaneous injections once every 2-4 weeks the dosage of which injections may gradually increase over a period of 3-6 months, and then continuing every 2-4 weeks for a period of up to about 5 years. It is also possible, particular for sublingual administration, that daily administrations are given.
  • Desensitization protocols may also comprise a form of treatment conventionally known in various equivalent alternative forms as rapid desensitization, rapid allergen immunotherapy, rapid allergen vaccination, and rapid or rush immunotherapy.
  • this procedure aims to advance an allergic patient to an immunizing or maintenance dose of extract (i.e., allergen) by administering a series of injections (or via another suitable carrier) of increasing doses of the allergen at frequent (e.g. hourly) intervals. If successful, the patient will exhibit an improved resistance to the allergen, possibly even presenting a total non-reactivity to any subsequent allergen exposure.
  • desensitization protocols are known in the art and may for instance comprise a method of treating a patient having an immediate hypersensitivity to an allergen using an accelerated rapid immunotherapy schedule in combination with a method of pre-treating such patient with prednisone and histamine antagonists prior to receiving the accelerated immunotherapy.
  • the allergen is a peanut kernel protein extract, preferably modified by reduction and subsequent alkylation, and the allergy is peanut allergy.
  • FIG. 1 shows temperature changes in sensitized mice challenged with different preparations of peanut extract adsorbed to aluminum. Temperature changes were measured for 90 minutes after challenge with 0.6 mg/mouse, 0.6 mg/mouse adsorbed to 0.18 mg/ml alum, 0.45 mg/mouse alum, 0.9 mg/ml alum or 5.46 mg/ml alum. As a control sensitized mice were challenged with PBS/alum;
  • FIG. 2 shows symptom scores of sensitized mice challenged with different preparations of peanut extract adsorbed to aluminum. Symptom scores were assigned after challenge on a scale from 0 (no symptoms) to 5 (death).
  • FIG. 3 shows a schematic overview of the time lime used for sensitization and challenge
  • FIG. 4 shows the results of an i.p. challenge at day 98 in vivo mouse model for peanut allergy
  • FIG. 5 shows the results of an i.p. challenge at day 112 in vivo mouse model for peanut allergy
  • FIG. 6 shows the results mast protease secretion 1 (mMCP-1) one day after challenge in vivo mouse model for peanut allergy;
  • FIG. 7 shows IgE, IgG1 and IgG2a antibody levels in all groups tested of the in vivo mouse model for peanut allergy.
  • This example demonstrates that the complexing of aluminum with an allergen significantly increases safety of a composition used for immunotherapy. This was demonstrated using an antigenic peanut extract coupled to different concentrations of aluminum hydroxide. In an in vivo mouse model for peanut allergy, these different test preparations were analyzed for safety.
  • mice Five-week-old specific pathogen-free female C3H/HeOuJ mice were purchased from Charles River, France. All mice were housed under specific pathogen-free conditions within the animal care facility at the Utrecht University, The Netherlands. Experiments were approved by the Animal Experiments Committee of the Utrecht University. The diet used contained vegetable protein (including soy) but was free of peanut proteins.
  • the different aluminum concentrations used in the present example were based on the binding of ⁇ 100% (5.46 mg/ml) or ⁇ 90% (0.9 mg/ml alum), ⁇ 70% (0.45 mg/ml alum), ⁇ 40% (0.18 mg/ml alum) of the total extract.
  • a positive control 0.6 mg/ml PE without alum was also included.
  • mice were sensitized by intragastric (i.g.) administration of 6 mg peanut extract (PE) and 15 ⁇ g Cholera Toxin (CT, List Biological Laboratories, Inc.) in 400 ⁇ l PBS per mouse on days 0, 1, 2, 7, 14, 21, 28.
  • Control mice received PBS with 15 ⁇ g CT/mouse in 400 ⁇ l PBS per mouse.
  • all groups of mice were subcutaneously (s.c) challenged in the neck with 200 ⁇ l of the different test preparations or their respective control.
  • body temperature was measured by means of rectal thermometry every 10-20 minutes for 90 minutes after s.c. challenge.
  • clinical symptoms were scored using a scoring system from 0 (no symptoms) to 5 (death).
  • the percentage aluminum complexed peanut extract was determined and the results are summarized in Table 1 below.
  • mice with preparations containing different amounts of aluminum only securing partial adsorption of PE resulted in a delayed response in the groups challenged with the preparation containing 60% and 30% non-adsorbed material.
  • the group challenged with the preparation containing ⁇ 10% non-adsorbed material there was a delay as well as a decrease in the response.
  • Non-sensitized mice did not respond to any of the challenges (data not shown) and sensitized mice that were challenged with aluminum only also showed no response.
  • mice Five-week-old specific pathogen-free female C3H/HeOuJ mice were purchased from Charles River, France. All mice were housed under specific pathogen-free conditions within the animal care facility at the Utrecht University, The Netherlands. Experiments were approved by the Animal Experiments Committee of the Utrecht University. The diet used contained vegetable protein (including soy) but was free of peanut proteins.
  • mice were sensitized by intragastric (i.g.) administration of 6 mg peanut extract (PE) and 15 ⁇ g Cholera Toxin (CT, List Biological Laboratories, Inc.) in 400 ⁇ l PBS per mouse on days 0, 1, 2, 7, 14, 21, 28.
  • Control mice received PBS with 15 ⁇ g CT/mouse in 400 ⁇ l PBS per mouse.
  • From day 42, all groups of mice were subcutaneously (s.c.) de-sensitized in the neck, twice a week for six weeks, with 200 ⁇ l of the different test preparations or their respective control ( FIG. 3 ).
  • the test preparations were tested in a concentration of 0.1 mg/mouse per injection and were either non-adsorbed or adsorbed to 1.82 mg/ml aluminum.
  • body temperature was measured by means of rectal thermometry every 10-20 minutes for 90 minutes after i.p. challenge.
  • blood was taken for the measurement of antibodies and mMCP-1 (mast cell protease 1).
  • mice were challenge i.p. and their body temperature was followed for 90 minutes after challenge.
  • the alum-adsorbed extract showed a greater efficacy compared to the non-adsorbed extract ( FIG. 4 ) demonstrating that the presence of alum results in a preparation that reaches efficacy at an earlier time point compared to the non-alum preparation.
  • Antibodies (IgE, IgG1 and IgG2a) were determined in the serum of all groups ( FIG. 7 ). IgE levels were elevated in all groups compared to the negative control (PBS). The group de-sensitized with the alum-adsorbed peanut extract showed a trend towards an elevated IgE level ( Figure 7 A) demonstrating a boost of the immune system after the injection of an alum-adsorbed preparation.
  • mice that received immunotherapy displayed an increased level of IgG1 in the serum with comparable levels between the alum-adsorbed and non-adsorbed extract ( FIG. 7B ).
  • the increase of IgG2a levels (comparable with IgG4 in human) is dominated by the group treated with the alum-adsorbed peanut preparation ( FIG. 7C ).

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Citations (4)

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WO2010000873A1 (en) * 2008-07-04 2010-01-07 Hal Allergy Holding B.V. Modification of allergens for immunotherapy
US20100136093A1 (en) * 2007-12-03 2010-06-03 Lucie Mondoulet Immunotherapeutic Method For Increasing Groundnut Tolerance In A Subject
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US20120141536A1 (en) * 2007-03-28 2012-06-07 Alk-Abelló A/S Use of an adjuvanted allergy vaccine formulation for parenteral administration
US20100136093A1 (en) * 2007-12-03 2010-06-03 Lucie Mondoulet Immunotherapeutic Method For Increasing Groundnut Tolerance In A Subject
WO2010000873A1 (en) * 2008-07-04 2010-01-07 Hal Allergy Holding B.V. Modification of allergens for immunotherapy
US9526781B2 (en) * 2011-12-16 2016-12-27 Hal Allergy Holding B.V. Pharmaceutical formulations and the use thereof for the treatment of peanut allergy

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HK1212206A1 (en) 2016-06-10
JP6336458B2 (ja) 2018-06-06
WO2014060049A1 (en) 2014-04-24
HUE034729T2 (en) 2018-02-28
PT2908857T (pt) 2017-09-11
CA2888293C (en) 2018-11-06
CN104822388A (zh) 2015-08-05
EP2908857B1 (en) 2017-08-09
AU2012392291A1 (en) 2015-05-07
PL2908857T3 (pl) 2018-05-30
ES2645740T3 (es) 2017-12-07
CA2888293A1 (en) 2014-04-24
DK2908857T3 (da) 2017-11-20
IN2015DN03306A (pl) 2015-10-09
EP2908857A1 (en) 2015-08-26
US20200289642A1 (en) 2020-09-17
JP2015534955A (ja) 2015-12-07

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