EP2790713A1 - Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes - Google Patents

Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes

Info

Publication number
EP2790713A1
EP2790713A1 EP12809215.2A EP12809215A EP2790713A1 EP 2790713 A1 EP2790713 A1 EP 2790713A1 EP 12809215 A EP12809215 A EP 12809215A EP 2790713 A1 EP2790713 A1 EP 2790713A1
Authority
EP
European Patent Office
Prior art keywords
ara
peanut
mammal
extract
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12809215.2A
Other languages
German (de)
English (en)
Inventor
Stefan Johan Koppelman
Joanna Paulina Maria VAN DER KLEIJ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hal Allergy Holding BV
Original Assignee
Hal Allergy Holding BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP2011/073037 external-priority patent/WO2013087119A1/fr
Application filed by Hal Allergy Holding BV filed Critical Hal Allergy Holding BV
Priority to EP12809215.2A priority Critical patent/EP2790713A1/fr
Publication of EP2790713A1 publication Critical patent/EP2790713A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction

Definitions

  • the present invention relates to pharmaceutical formulations, or compositions, which can be used in
  • the present invention further relates to the use of the present invention
  • formulations or 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 formulations or compositions in a prophylactic treatment of a mammal with high predisposition to develop a certain allergy .
  • hyposensitization therapy immunologic desensitization, hyposensibilization, or allergen-specific immunotherapy
  • 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
  • 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
  • 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
  • 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
  • peanut seed storage proteins Ara hi vicilin
  • Ara h2 the peanut seed storage proteins
  • Ara h2 and, to a lesser extent, Ara h6 only form part of the peanut allergy causing agents, Ara h2 and Ara h6 exclusively are likely not sufficient to treat peanut allergic individuals.
  • compositions comprising a modified whole peanut extract and pharmaceutically acceptable diluents and/or excipients, wherein said modified whole peanut extract is a reduced and subsequently alkylated whole peanut extract.
  • an allergen is defined as an antigen capable of stimulating a hypersensitivity reaction in atopic mammals through
  • immunoglobulin E (IgE) responses Most mammals mount
  • hereditary predisposition is also designated atopy.
  • non-parasitic antigens stimulate undesired IgE production, resulting in hypersensitivity or allergy
  • a whole peanut extract denotes a peanut extract comprising substantially all seed kernel proteins found in peanut.
  • a whole peanut extract according to the present invention is representative for the proteins found in peanut and thereby for the causative agents (allergens) of peanut allergy.
  • a whole peanut extract according to the present invention thus comprises, besides Ara h2 and Ara h6, also other peanut allergens amongst which the major peanut allergen Ara hi.
  • the present whole peanut extract is modified by reduction and
  • Suitable agents to reduce disulphide bonds are known and can, for example, be 2-mercaptoethanol ( ⁇ - ⁇ ) , dithiothreitol (DTT) , dithioerythritol , cysteine,
  • Suitable agents to alkylate reduced cysteine residues are known and can, for example, be N-ethylmalimide, cystamine, iodoacetamide, iodoacetic acid, alkylhalogenides , alkylsulfates , alkenes, or enzymes.
  • Subjecting a whole peanut extract comprising the major allergenic protein Ara hi to reduction and methylation thereby reducing the allergenicity thereof is surprising considering that, in contrast to Ara h2 and Ara h6, Ara hi does not comprise disulfide bonds, only a single Cys
  • the present whole peanut extract is a defatted before subjecting the peanut extract to reduction and alkylation. Removing lipids and other fatty substances increases the protein content of the extract and thereby the relative number of immunogenic IgE epitopes and thereby the allergenicity of the extract.
  • the present whole peanut extract comprises soluble peanut kernel proteins, more preferably at least Ara hi, Ara h2 and Ara h6.
  • Soluble peanut kernel proteins represent the majority, if not all, of the allergen causing epitopes of the peanut proteins Ara hi, Ara h2 and Ara h6.
  • the present whole peanut extract is obtainable by:
  • the above method provides a purified extract of soluble peanut allergenic proteins, i.e. an extract enriched for soluble peanut kernel proteins, which can be readily subjected to a subsequent reduction and alkylation.
  • compositions further comprise
  • the present pharmaceutical compositions are especially suitable to be used in a therapeutic treatment for desentizing a peanut allergy in a patient, preferably, by immunotherapy or immunovaccination .
  • immunotherapy comprises administering to a mammal, preferably a human mammal, suffering from an allergy the present composition 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
  • a treatment will comprise starting with the administration of dosages at the lower end of these ranges and increasing the dosages as the treatment
  • 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 extract (i.e., allergen) by administering a series of injections (or via another suitable carrier) of
  • the patient will exhibit an improved resistance to the allergen, possibly even
  • 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.
  • Figure 1 shows an rp-HPLC pattern of individual peanut allergens and extract of Spanish cultivar.
  • Panel A individual peanut allergens
  • Panel B extract of Spanish cultivar: blank (MQ water); Peak at 7.3 ml: Ara h2 ; peak at 9-9.5 ml: Ara h6; peak at 11 ml: Ara hi;
  • Figure 2 shows an rp-HPLC pattern of individual peanut allergens before and after modification.
  • Top panel Ara hi, arrow indicate before (native) and after (RA) modification.
  • Middle panel Ara h2, arrow indicate before (native) and after (RA) modification.
  • Bottom panel Ara h6, arrow indicate before (native) and after (RA) modification;
  • Figure 3 shows far UV CD spectra of individual peanut allergens before and after modification.
  • Top panel Ara hi, arrow indicate before (native) and after (RA) modification.
  • Middle panel Ara h2, arrow indicate before (native) and after (RA) modification.
  • Bottom panel Ara h6, arrow indicate before (native) and after
  • Figure 4 shows body temperature of peanut-allergic mice after challenge.
  • Top panel Challenge with native peanut extract (0.1, 0.6, and 3
  • Figure 5 shows the time line of the sensitization, de- sensitization and challenge protocol used in example 6 (A) and the time line of the
  • Figure 6 shows the temperature (A) of mice challenged on day 91 and mast cell activation (B; mMCP-1) on day 85;
  • Figure 7 shows the temperature of mice challenged on day 112
  • Figure 8 shows the level of mMCP-1 in serum of all
  • Figure 9 shows levels of IgE (A) , IgGl (B) and IgG2a
  • Example 1 Collection of samples and preparing extracts . Twelve peanuts sample were generously supplied by
  • Dr Maleki US Department of Agriculture, New Jersey, USA ) , comprising four different cultivars (Runner, Spanish,
  • the peanuts were grinded manually and defatted with acetone (5 g peanut was defatted with 50 mL of acetone for 30 minutes) , and left to dry overnight at room
  • Example 2 Abundance of Ara hi, Ara h2, and Ara h6 in the peanut kernel.
  • Figure la shows an example of this analysis using the individual, purified forms of Ara hi, Ara h2, and Ara h6. These allergens are baseline separated and the method allows for quantification in extracts.
  • Figure lb shows an example of a peanut extracts and the arrows indicate the peaks corresponding to Ara hi, Ara h2, and Ara h6. It can be seen that Ara hi is the more abundant allergen in this extracts.
  • Table 2 Content of Ara hi, Ara h2 , and Ara h6 in peanut extracts .
  • Purified allergens Ara hi, Ara h2, and Ara h6 were treated as described earlier. In short, the allergens were incubated with DTT for one hour at 60 °C and IAA was added and the mixture was incubated ar room temperature for 1.5 hours .
  • Serum from 20 patients with a peanut allergy was obtained and IgE ELISA.
  • ELISA plates were coated with peanut extract and IgE-binding potency of native peanut extract was defined as 1, and the IgE-binding potency of modified peanut extract was related thereto.
  • Table 3 shows per patient the rest potency of modified peanut extract relative to native peanut extract. The mean rest potency of modified peanut extract is 7 % of the potency of native peanut extract.
  • Table 3 Potency of modified peanut extract relative to native extract for individual patients .
  • Example 5 In vivo safety of modified peanut extract.
  • mice were made allergic to peanut extract as described earlier. These mice (6 per group) were challenged either with native or modified peanut extract. Body
  • test preparations were analyzed for efficacy. These examples demonstrate the potential of a chemically modified peanut extract (with or without adsorption to aluminum hydroxide) to be effectively used to treat mice that have been sensitized to peanut.
  • 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 yg Cholera Toxin (CT, List Biological
  • mice received PBS with 15 yg CT/mouse in 400 ⁇ 1 PBS per mouse. From day 42, different groups of mice were subcutaneously (s.c.) de-sensitized in the neck, three times a week for three weeks (example 5) or twice a week for six weeks (example 6) , with 200 ⁇ of the different test preparations (modified PE +/- aluminum hydroxide) or their respective control ( Figure 5) . Below, groups of non- allergic PBS sensitized mice and allergic PE sensitized mice (without immunotherapy) are depicted as PBS control and PE control, respectively.
  • 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) .
  • mMCP-1 mast cell protease 1
  • the modified PE preparation effectively reduced the anaphylactic response as measured by the drop in temperature after challenge ( Figure 6A) .
  • De-sensitization with different concentrations modified PE demonstrated a small dose-dependent effect comparing 0.03 and 0.1 mg on the improvement of the anaphylactic shock response as measured by temperature ( Figure 6A) .
  • immunotherapy preparations (modified PE alone and adsorbed to alum) effectively reduced the anaphylactic response as measured by the drop in temperature after challenge ( Figure 7) .
  • the alum-adsorbed extract showed a slightly improved efficacy profile compared to the non-adsorbed extract ( Figure 7A) . De-sensitization with different
  • MMCP-1 levels were elevated in all groups compared to the negative PBS control.
  • the group de-sensitized with modified PE showed an increase in mMCP-1 compared to the mice that did not receive immunotherapy (PE control) and the mice that was de-sensitized with alum-adsorbed modified PE (Figure 8) .
  • IgE levels were greater in all groups compared to the negative PBS control. As commonly seen in the clinic, immunotherapy causes an increase in the level of IgE (Figure 9A) . This demonstrates the boost of the immune system due to immunotherapy. The elevation is greater during the course of the injections and slightly decreases in time (data not shown) .
  • mice that received immunotherapy displayed an increased level of IgGl in the serum with comparable levels between the alum-adsorbed and non-adsorbed extract (Figure 9B) .
  • the increase of IgG2a levels (comparable with IgG4 in human) is dominated by the group treated with the alum- adsorbed peanut preparation ( Figure 9C) .
  • a peanut extract modified by reduction is a peanut extract modified by reduction
  • alkylation is capable of improving the anaphylactic response in mice after i.p. challenge.
  • Different immunotherapy models s.c. injections three times a week for 3 weeks or twice a week for 6 weeks
  • Efficacy is slightly greater after the adsorption of the peanut extract to aluminum hydroxide. This could be due to the elevated levels of IgG2a (comparable to IgG4 in human) in the serum of these mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne des compositions qui peuvent être utilisées en immunothérapie et en particulier des compositions qui peuvent être utilisées dans l'immunothérapie pour mammifères, tels que des mammifères humains, souffrant d'allergie aux cacahuètes. La présente invention concerne également l'utilisation des présentes compositions pour le traitement thérapeutique pour désensibiliser le système immunitaire d'un mammifère souffrant d'une allergie par immunothérapie et l'utilisation des présentes compositions dans un traitement prophylactique d'un mammifère ayant une prédisposition élevée à développer une certaine allergie. En particulier, la présente invention concerne des compositions pharmaceutiques comprenant un extrait de cacahuète entière modifié et des excipients et/ou diluants pharmaceutiquement acceptables, ledit extrait de cacahuète entière modifié étant un extrait de cacahuète entière réduit et alkylé ultérieurement, de préférence un extrait de cacahuète dégraissée entière comprenant des protéines d'arachide solubles telles que Ara h1, Ara h2 et Ara h6.
EP12809215.2A 2011-12-16 2012-12-14 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes Withdrawn EP2790713A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12809215.2A EP2790713A1 (fr) 2011-12-16 2012-12-14 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/EP2011/073037 WO2013087119A1 (fr) 2011-12-16 2011-12-16 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes
EP12809215.2A EP2790713A1 (fr) 2011-12-16 2012-12-14 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes
PCT/EP2012/075535 WO2013087837A1 (fr) 2011-12-16 2012-12-14 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes

Publications (1)

Publication Number Publication Date
EP2790713A1 true EP2790713A1 (fr) 2014-10-22

Family

ID=51538745

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12809215.2A Withdrawn EP2790713A1 (fr) 2011-12-16 2012-12-14 Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes

Country Status (1)

Country Link
EP (1) EP2790713A1 (fr)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None *
See also references of WO2013087837A1 *

Similar Documents

Publication Publication Date Title
AU2012351541B2 (en) Pharmaceutical formulations and the use thereof for the treatment of peanut allergy
JP7454519B2 (ja) 経口脱感作のための落花生処方物の製造
Valenta et al. Recombinant allergens: what does the future hold?
Abril-Gil et al. A diet enriched with cocoa prevents IgE synthesis in a rat allergy model
Kasera et al. Enzymatic hydrolysis: A method in alleviating legume allergenicity
EP2790713A1 (fr) Formulations pharmaceutiques et leur utilisation pour le traitement d'allergie aux cacahuètes
Vinje et al. Cross‐allergic reactions to legumes in lupin and fenugreek‐sensitized mice
Luo et al. Immunostimulatory and allergenic properties of emulsified and non-emulsified digestion products of parvalbumin (Scophthalmus maximus) in RBL-2H3 cells and BALB/c mouse models
US20200289642A1 (en) Compositions for Immunotherapy
Bittencourt et al. Immunogenicity and allergenicity of 2S, 7S and 11S soy protein fractions
DK1696951T3 (en) IMMUNTERY THERAPY TO FOOD ALLERGY OF REDUCED AND ALKYLED FOOD ALLERGENCE
Kumar et al. Identification and characterization of major IgE binding of purified allergenic protein (11 kDa) from Buchanania lanzan
Abdugafurova et al. Study of the Immunomodulatory Effect of Polysaccharides Isolated from Seeds of Turnip BRASSICA RAPA
Amara et al. Suppressive effect of Withania somnifera root extract on the induction of anti-ovalbumin IgE antibody response in mice
JP4328514B2 (ja) 抗アレルギー剤
Sztuk Strategies for the prevention and treatment of peanut allergy
Ortiz Effect of extrusion processing on in vivo allergenicity of hazelnut protein extract in an adjuvant-free mouse model
AU2020260379A1 (en) Peanut hypoallergenic formulations for determining the risk of anaphylaxis
Szymkiewicz et al. Pea proteins immunotherapy in peanut allergic mice model
Escobosa et al. Short Communications and Brief Case Notes
JP2005298332A (ja) 過剰自己抗体産生抑制物質、その製造法およびその使用方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140709

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20170228

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170912