WO2021119858A1 - Procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, cellules tolérogènes obtenues, et procédés pour induire la tolérance aux allergènes par immunothérapie autologue - Google Patents

Procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, cellules tolérogènes obtenues, et procédés pour induire la tolérance aux allergènes par immunothérapie autologue Download PDF

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Publication number
WO2021119858A1
WO2021119858A1 PCT/CL2019/050147 CL2019050147W WO2021119858A1 WO 2021119858 A1 WO2021119858 A1 WO 2021119858A1 CL 2019050147 W CL2019050147 W CL 2019050147W WO 2021119858 A1 WO2021119858 A1 WO 2021119858A1
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WO
WIPO (PCT)
Prior art keywords
cells
allergen
tolerogenic
tolerance
obtaining
Prior art date
Application number
PCT/CL2019/050147
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English (en)
Spanish (es)
Inventor
Raquel Elvira Aguilera Insunza
Luis Fernando VENEGAS SALAS
Arturo Jose BORZUTZKY SCHACHTER
Katherinne BUGUEÑO VILLALÓN
Carolina ITURRIAGA ORTIZ
Guillermo PÉREZ MATELUNA
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Pontificia Universidad Católica De Chile
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Priority to PCT/CL2019/050147 priority Critical patent/WO2021119858A1/fr
Publication of WO2021119858A1 publication Critical patent/WO2021119858A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4615—Dendritic cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4622—Antigen presenting cells
    • 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
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/464839—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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues

Definitions

  • the present invention in general terms relates to a method for treating various allergic diseases. More particularly, a method is disclosed for the generation of allergen-specific tolerogenic dendritic cells, to be applied as autologous immunotherapy in allergic diseases. Also described are allergen-specific tolerogenic dendritic cells obtained, and methods for inducing tolerance to allergens.
  • compositions and methods for treating various allergic diseases are described in the state of the art.
  • the prevalence of food allergy is increasing.
  • there are no standardized and validated curative therapies for food allergy and strict avoidance of the offending food remains the only therapeutic option.
  • the Allergen immunotherapy has been used successfully to treat asthma, allergic rhinitis, and hypersensitivity to bee and wasp venom.
  • TI is based on the delivery of increasing doses of specific allergens over time with the aim of inducing desensitization and immune tolerance.
  • the patent of invention WO 2019/076477 discloses a pharmaceutical composition for the induction of food tolerance by means of a combination of subcutaneous immunotherapy based on hydrogel (phase A composition) and subsequent oral (OIT) or sublingual (SLIT) immunotherapy ( phase composition B).
  • the phase A composition comprises a thermogelling hydrogel for release of embedded components comprising a) one or more allergen peptides which is specific for T cells, b) a tolerance promoting dose of synthetic oligodeoxynucleotides (ODN) containing one or more CpG or GpC or GpG motifs, c) one or more molecules integrated into hydrogel to attract peripheral antigen presenting cells (APC) to the site of the administered hydrogel composition, and d) optionally one or more immune modulators that promote tolerance; wherein the Phase B composition comprises one or more modified or unmodified food allergens modified, including natural and recombinant food allergens or their fragments that serve as epitopes for B cells. Additionally, the application of molecules in hydrogel compositions for Phase A to attract peripheral antigen presenting cells (APCs) including cells is described. dendritic cells (DC) and macrophages, to the injection site.
  • ODN synthetic oligodeoxynucleotides
  • APC peripheral antigen
  • patent application WO 2018/146274 describes a gastrointestinal release capsule to desensitize and / or induce tolerance in a patient with peanut allergy.
  • Said capsule comprises a shell and a core, where the core comprises a composition comprising peanuts, at least one oil, at least one first powdered vehicle and optionally at least one second prebiotic excipient.
  • the capsule is supplied and swallowed in an unopened form and is not mixed with the food bolus.
  • the mucosa of the small intestine possesses numerous specialized antigen-presenting cells, in particular macrophage-like mononuclear phagocytes or dendritic cells.
  • the patent application for invention WO 2019/038668 describes a method and composition to induce tolerance to allergens in a patient suffering from atopic allergy or allergic asthma; thus reducing allergy symptoms in these patients, where the invention comprises providing a human milk oligosaccharide for use in inducing allergen tolerance in a patient suffering from atopic allergy and / or allergic asthma, as well as a synthetic composition comprising one or more oligosaccharides from human milk and one or more of an immunotherapeutic allergen and / or an active source of vitamin A.
  • compositions that comprises a delivery vehicle that includes an immunoconjugate, in which the immunoconjugate comprises an immunomodulatory agent covalently linked to an antigen, in which said antigen comprises a tumor antigen. Also provided is a composition comprising an antigen covalently linked to an immunomodulatory compound such as a tolerogen or an adjuvant.
  • a delivery device comprising the composition of the present invention and a dendritic cell (DC) recruitment composition is provided.
  • composition comprising (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and (ii) a second population of synthetic nanocarriers that are coupled to MHC Class restricted epitopes. II of an antigen that generates an unwanted humoral immune response. It is specified that "MHC class II restricted epitopes" are epitopes that are presented to immune cells by MHC class II molecules found on antigen presenting cells (APC), eg professional immune cells that present antigen, such as macrophages, B cells, and dendritic cells.
  • APC antigen presenting cells
  • the patent application for invention WO 2019/160979 discloses a composition that selectively inhibits the interaction between an Fe receptor type I or an Fe receptor type II, FcRn and an immunocomplexed antibody, where the composition comprises a first binding domain that binds specifically to a human Fe type I receptor or a human Fe type II receptor; and a second binding domain that binds specifically to a human FcRn.
  • FcRn plays an important role in MFIC class II antigen presentation and MFIC class I cross-presentation of IgG complex antigen.
  • dendritic cells When antigen is presented as an immune complex (Cl) containing IgG, dendritic cells that are CD8-CD1 Ib + CDI le + (inflammatory dendritic cells) show significant cross-presentation at low doses of antigen in a highly dependent pathway. of FcRn expression.
  • Invention patent US 9,603,800 teaches a method for treating a subject with an inflammatory, allergic or autoimmune disease or disorder that comprises administering to the subject a composition comprising an effective amount of nanolipogels comprising: a polymeric matrix formed by a polymer crosslinked, an amphiphilic polymer, a block copolymer, or a three-block copolymer that has been dispersed therein or covalently bonded to one or more host molecules that reversibly complexed with an agent, where the host molecules are selected from the group consisting of one or more polysaccharides, cryptands, cryptophanes, cavitants, crown ethers, dendrimers, catenanes, carcerands, spherands, carbon nanotubes and fullerenes, for the controlled release of at least one therapeutic, diagnostic or prophylactic agent, and a shell lipid; wherein one or more active agents to reduce, lessen, or alleviate one or more symptoms of inflammatory, allergic, or autoimmune disease or
  • the present invention relates to methods for treating various allergic diseases. More particularly, a method is disclosed for the generation of allergen-specific tolerogenic cells, to be applied as immunotherapy. autologous in allergic diseases. Also described are allergen-specific tolerogenic cells, and methods for inducing allergen tolerance to develop an autologous immunotherapy.
  • the method described in the present invention comprises the following steps: a) obtaining a blood sample from a subject with an allergy to a certain allergen; b) obtaining mononuclear cells from peripheral blood and culturing said cells in appropriate media; c) adding a sufficient quantity of IL-4 and GM-CSF on the cultured cells; d) stimulating the cultured cells with sufficient amounts of Retinoic Acid and Dexamethasone; e) co-culturing the cells of the previous steps with a sufficient amount of a purified extract of the allergen; f) analyzing the cells from the previous steps; and g) obtaining allergen-specific tolerogenic cells.
  • Figure 1 shows that treatment with dexamethasone and retinoic acid does not cause cell death in moDCs.
  • FIG. 2 shows a flow cytometric analysis of CD40 and HLA-DR in moDC stimulated with Dexamethasone and Retinoic Acid.
  • the graphs show the expression of activation markers in monocyte-derived dendritic cells (moDCs) cultured with dexamethasone (Dex) and retinoic acid (RA), with or without post-stimulation for 48 hours with lipopolysaccharide (LPS).
  • Graph A) describes the expression of HLA-DR;
  • Graph B) shows the expression of CD40;
  • Graph C) shows the expression of CD86; and
  • graph D) shows the expression of CD83.
  • FIG. 3 shows the secretion of IL-10, TGF-b, IL-4 and IL-12 by moDC stimulated with Dexamethasone and Retinoic acid.
  • the graphs show that the secretion of cytokines by dendritic cells derived from monocytes (moDCs) cultured with dexamethasone (Dex) and retinoic acid (AR), with or without subsequent stimulation for 48 hours with lipopolysaccharide (LPS), measured by ELISA of the supernatant of cell cultures.
  • Graph A) shows IL-10 secretion;
  • Graph B) shows TGF-b secretion;
  • the graph shows the C) secretion of IL-4; and
  • Graph D) shows IL-12 secretion.
  • n 5.
  • Figure 4 shows a proliferation assay T cell Na ⁇ 've cocultured with moDC previously stimulated with retinoic acid and dexamethasone.
  • Graph A teaches representative Dot-plot naive T cells stained with CFSE and co-cultured with moDC for 5 days. moDC were stimulated with dexamethasone (Dex) and retinoic acid (AR), with or without subsequent stimulation for 48 hours with lipopolysaccharide (LPS).
  • the present invention refers to a process for the generation of allergen-specific tolerogenic dendritic cells, to be applied as autologous immunotherapy in allergic diseases.
  • Said procedure is characterized by comprising the following steps: a) obtaining a blood sample from a subject with an allergy to a certain allergen; b) obtaining mononuclear cells from peripheral blood and culturing said cells in appropriate media; c) adding a sufficient quantity of IL-4 and GM-CSF on the cultured cells; d) stimulate the cultured cells with sufficient amounts of retinoic acid and
  • Dexamethasone e) co-cultivating the cells of the previous steps with a sufficient amount of a purified extract of the allergen; f) analyzing the cells from the previous steps; Y g) obtain allergen-specific tolerogenic cells.
  • step a) comprises obtaining a blood sample through venipuncture, phlebotomy or leukapheresis.
  • step b) comprises obtaining peripheral blood mononuclear cells by dilution of the blood and subsequent density gradient with ficoll.
  • the appropriate media for culturing the cells of step b) are selected from AIM-V culture medium, RPMI RPMI supplemented with human serum, or other means known to a person skilled in the art. technique, in which the culture conditions comprise between 35 to 39 ° C, with 5% CO2.
  • the sufficient amount of IL-4 and GM-CSF from step c) comprises between 500-2000 IU / mL.
  • the sufficient amounts of Retinoic Acid and Dexamethasone from step d) comprise between 0.5-10 uM of Retinoic Acid and between 0.5-10 uM of Dexamethasone.
  • the sufficient amount of the purified extract of the allergen from step e) comprises between 10 to 50 ug / mL.
  • the allergen of stage e) is selected from among peanuts, eggs, milk, wheat, gluten, soy, nuts (walnuts, almonds), fish, shellfish, latex, lupine, fruits, vegetables.
  • step f) comprises analyzing the cells obtained by flow cytometry, ELISA, fluorescence microscopy, and confocal microscopy.
  • a method for inducing tolerance to allergens by means of autologous immunotherapy, wherein said method comprises injecting the cells obtained from claims 1 to 10, to a subject with an allergy to a certain allergen.
  • the allergen is selected from peanuts, eggs, milk, wheat, gluten, soy, nuts (walnuts, almonds), fish, shellfish, latex, lupine, fruits, vegetables.
  • a tolerogenic cell specific to a certain allergen is described to be applied as autologous immunotherapy in allergic diseases, where said cell is obtained by the procedure described in the present invention, and is characterized by having tolerance to a certain allergen, where the allergen It is selected from peanuts, eggs, milk, wheat, gluten, soy, nuts (walnuts, almonds), fish, shellfish, latex, lupine, fruits, vegetables.
  • Example N ° 1 Obtaining tolerogenic cells specific to allergens.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • the cells adhered to the plate were incubated for 7 days in AIM-V medium to which IL-4 and GM-CSF were added at a concentration of 1000 IU / mL. Every 2 days 1/3 of the culture medium was removed and replaced by 1/2 fresh medium with the same concentration of IL-4 and GM-CSF.
  • cells were stimulated with 1 uM Retinoic Acid (AR) and 1 uM Dexamethasone (Dex).
  • AR Retinoic Acid
  • Dex Dexamethasone
  • the cells were co-cultured with purified Peanut extract (PE) at a concentration of 50ug / mL or 10 ug / ml Ara h2 for 48 hours.
  • DCs dendritic cell
  • monocyte-derived DCs were then co-cultured with PE or Ara h2 for 2 days, after which they were reanalyzed by Facs for the same markers mentioned above and then re-injected into the patient.
  • moDCs monocyte-derived DCs
  • LPS lipopolysaccharide
  • RA retinoic acid
  • Dex dexamethasone
  • the measurement of IL-10 shows that moDC LPS secrete a greater amount of IL-10 as well as moDC AR + Dex + LPS, which also secretion of IL-10 is greater than its counterpart moDC AR Dex.
  • the TGF-b results show no differences between any of the groups.
  • the results of IL-4 and IL-10 and TGF-b in moDC AR Dex LPS, would induce a tolerogenic response for T lymphocytes.
  • IL-12 secretion was not detected in moDC AR Dex LPS, indicating that there would be no response to activate other cells.

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Abstract

La présente invention concerne des procédés pour traiter diverses maladies allergiques. Plus particulièrement, l'invention concerne un procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, destinées à être appliquées comme immunothérapie autologue dans des maladies allergiques. L'invention concerne également des cellules tolérogènes spécifiques d'allergènes obtenues, et des procédés pour induire la tolérance aux allergènes par immunothérapie autologue.
PCT/CL2019/050147 2019-12-19 2019-12-19 Procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, cellules tolérogènes obtenues, et procédés pour induire la tolérance aux allergènes par immunothérapie autologue WO2021119858A1 (fr)

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PCT/CL2019/050147 WO2021119858A1 (fr) 2019-12-19 2019-12-19 Procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, cellules tolérogènes obtenues, et procédés pour induire la tolérance aux allergènes par immunothérapie autologue

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PCT/CL2019/050147 WO2021119858A1 (fr) 2019-12-19 2019-12-19 Procédé pour la génération de cellules tolérogènes spécifiques d'allergènes, cellules tolérogènes obtenues, et procédés pour induire la tolérance aux allergènes par immunothérapie autologue

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012160200A1 (fr) * 2011-05-25 2012-11-29 Hospital Clínic De Barcelona Cellules dendritiques tolérogènes et leur utilisation en thérapie cellulaire
WO2013036298A1 (fr) * 2011-09-06 2013-03-14 Selecta Biosciences, Inc. Cellules dendritiques tolérogènes induites, spécifiques d'un allergène, pour une thérapie antiallergique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012160200A1 (fr) * 2011-05-25 2012-11-29 Hospital Clínic De Barcelona Cellules dendritiques tolérogènes et leur utilisation en thérapie cellulaire
WO2013036298A1 (fr) * 2011-09-06 2013-03-14 Selecta Biosciences, Inc. Cellules dendritiques tolérogènes induites, spécifiques d'un allergène, pour une thérapie antiallergique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AGUILERA-INSUNZA, R. ET AL.: "Role of dendritic cells in peanut allergy", EXPERT REVIEW OF CLINICAL IMMUNOLOGY, vol. 14, no. 5, 2018, pages 367 - 378, DOI: 10.1080/1744666X.2018.1467757 *
DAWICKI, WOJCIECH; LI CHUNYAN; TOWN JENNIFER; ZHANG XIAOBEI; GORDON JOHN R: "Therapeutic reversal of food allergen sensitivity by mature retinoic acid -differentiated dendritic cell induction of LAG3+ CD 49b-Foxp3- regulatory T cells", JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 139, no. 5, 2017, pages 1608 - 1620, XP029997466, DOI: 10.1016/j.jaci.2016.07.042 *
KIM, SANG-HYUN, JUNG HO-HYUN, LEE CHONG-KIL: "Generation, characteristics and clinical trials of ex vivo generated tolerogenic dendritic cells", YONSEI MEDICAL JOURNAL, vol. 59, no. 7, 2018, pages 807 - 815, XP055836171, DOI: 10.3349/ymj.2018.59.7.807 *
SIM, WEN JING, MALINARICH FRANO, FAIRHURST ANNA-MARIE, CONNOLLY JOHN EDWARD: "Generation of Immature, Mature and Toierogenic Dendritic Cells with Differing Metabolic Phenotypes", JOURNAL OF VISUALIZED EXPERIMENTE, vol. 112, no. e54128, 2016, pages 12, XP055836168, DOI: 10.3791/54128 *

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