WO2008154350A2 - Utilisation d'agonistes de jonctions serrées pour supprimer des réponses immunes - Google Patents

Utilisation d'agonistes de jonctions serrées pour supprimer des réponses immunes Download PDF

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Publication number
WO2008154350A2
WO2008154350A2 PCT/US2008/066057 US2008066057W WO2008154350A2 WO 2008154350 A2 WO2008154350 A2 WO 2008154350A2 US 2008066057 W US2008066057 W US 2008066057W WO 2008154350 A2 WO2008154350 A2 WO 2008154350A2
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xaa
seq
giy
group
leu
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PCT/US2008/066057
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English (en)
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WO2008154350A3 (fr
Inventor
Amir Tamiz
Niranjan Pandey
Blake Paterson
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Alba Therapeutics Corporation
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Publication of WO2008154350A2 publication Critical patent/WO2008154350A2/fr
Publication of WO2008154350A3 publication Critical patent/WO2008154350A3/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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

Definitions

  • the present invention provides materials and methods to suppress an excessive or undesired immune response.
  • agonists of biological pathways responsible for opening and closing tight junctions e.g., tight junction agonists
  • compositions with antigens to suppress an immune response to the antigen.
  • the immune system serves as the body's defense mechanism against pathogens present in the environment. In some cases, exposure to certain substances causes an excessive immune response in sensitive individuals. Substances that induce the excessive immune response are referred to as allergens and the immune response is typically referred to as an allergic response. Common allergens include pollen, mold, animal dander, and cockroach and house dust mite droppings.
  • allergens include pollen, mold, animal dander, and cockroach and house dust mite droppings.
  • the allergic response is specific to the allergen although a person can be allergic to multiple allergens. Typically, the severity of the response increases with repeated exposure to the allergen.
  • Allergic responses can cause swelling, inflammation, wheezing, excessive production of mucous, rhinitis, or "hay fever," conjunctivitis (an eye reaction), atopic dermatitis, or allergic skin reactions, and urticaria, also known as hives. In severe case, allergic reactions can be life threatening.
  • the present invention provides materials and methods for the suppression of an excessive or undesired immune response.
  • immune responses include, but are not limited to, allergic responses and transplant rejection responses.
  • the present invention provides compositions for suppression of an immune response.
  • Such compositions may comprise one or more antigens and an immune-suppressing amount of one or more tight junction agonists.
  • a tight junction agonist is a compound that mediates or facilitates or augments the physiological, transient opening of tight junctions, for example, the tight junctions between adjacent epithelial cells.
  • An example of a tight junction agonist is zonula occludens toxin (ZOT), which is produced by Vibrio cholerae.
  • a ZOT receptor agonist is a compound which is believed to mediate tight junction opening through the same receptor utilized by ZOT.
  • a tight junction agonist may comprise zonulin.
  • a tight junction agonist may comprise a peptide.
  • a tight junction agonist may be a fragment of ZOT and/or zonulin.
  • a tight junction agonist comprising a peptide may comprise the amino acid sequence FCIGRL (SEQ ID NO:1).
  • a tight junction agonist comprising a peptide may comprise from about 6 to about 50 amino acids, from about 6 to about 25 amino acids, or from about 6 to about 10 amino acids.
  • a peptide tight junction agonist may comprise a sequence selected from the group consisting of Xaal Cys lie GIy Arg Leu (SEQ ID NO: 2), Phe Xaa2 He GIy Arg Leu (SEQ ID NO: 3), Phe Cys Xaa3 GIy Arg Leu (SEQ ID NO: 4), Phe Cys He Xaa4 Arg Leu (SEQ ID NO: 5), Phe Cys He GIy Xaa5 Leu (SEQ ID NO: 6), and Phe Cys He GIy Arg Xaa6 (SEQ ID NO: 7), wherein Xaal is selected from the group consisting of Ala, VaI, Leu, lie, Pro, Trp, Tyr, and Met; Xaa2 is selected from the group consisting of GIy, Ser, Thr, Tyr, Asn, and GIn; Xaa3 is selected from the group consisting of Ala, VaI, Leu
  • a peptide tight junction agonist may comprise a sequence selected from the group consisting of Xaal Xaa2 He GIy Arg Leu (SEQ ID NO: 8), Xaal Cys Xaa3 GIy Arg Leu (SEQ ID NO: 9), Xaal Cys He Xaa4 Arg Leu (SEQ ID NO: 10), Xaal Cys He GIy Xaa5 Leu (SEQ ID NO: 1 1), Xaal Cys He GIy Arg Xaa6 (SEQ ID NO: 12), Phe Xaa2 Xaa3 GIy Arg Leu (SEQ ID NO: 13), Phe Xaa2 He Xaa4 Arg Leu (SEQ ID NO: 14), Phe Xaa2 He GIy Xaa5 Leu (SEQ ID NO: 15), Phe Xaa2 He GIy Arg Xaa6 (SEQ ID NO: 8), Xa
  • the antigen may be an allergen.
  • an antigen is any substance that evokes an immune response and an allergen is any substance that induces allergy. Allergy is an excessive immune response to an antigen.
  • suitable allergens include, but are not limited to, pollen, dust mite allergens, mold spores, pet dander, food, insect stings, and medicines.
  • an antigen e.g., an allergen
  • compositions of the invention may comprise a dust mite allergen, for example, Der pi .
  • compositions of the invention may comprise ragweed pollen.
  • the present invention also provides methods of treating (i.e., suppressing, reducing, ameliorating) an undesired or excessive immune response.
  • Such methods may include administering to the subject a composition comprising the antigen and an immune-suppressing amount of a tight junction agonist.
  • a subject is any mammal, for example, a human.
  • a tight junction agonist may comprise a peptide. Suitable tight junction agonists for use in the methods of the invention include those listed above.
  • Figure 1 is a bar graph showing the results of antibody titer experiments showing an increase in all types of IgG except subclass lgG2a.
  • Figure 2 is a bar graph showing the effects of the tight junction agonist on the relative titers of the subclasses IgGl and IgG2a.
  • Figure 3 is a bar graph showing the effects of the tight junction agonist on the relative titers of the total IgG and on the subclasses IgGl and IgG2a as well as on IgA as a function of the amount of tight junction agonist delivered with the antigen.
  • Figure 4 shows the fluorescent microscopy results of a cytoskeletal rearrangement assay showing the effects of tight junction agonist and PT-gliadin on tight junction structure.
  • Figure 5 is a schematic showing the synthesis of AT1002.
  • Figure 6 is a graph of transepithelial electrical resistance (TEER) as a function of time showing the administration of tight junction agonist causes a reduction in TEER.
  • TEER transepithelial electrical resistance
  • a or “an” may mean one or more.
  • the words “a” or “an” when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.
  • another may mean at least a second or more.
  • a "tight junction agonist” is a compound that mediates or facilitates or augments the physiological, transient opening of tight junctions. Tight junctions are structures that form a barrier between adjacent epithelial cells (Johnson and Quay, Expert Opin DrugDeliv. 2005 Mar;2(2):281-98).
  • An example of a tight junction agonist is zonula occludens toxin (ZOT), which is produced by Vibrio cholerae.
  • ZOT receptor agonist is a tight junction agonist which is believed to mediate tight junction opening through the same receptor utilized by ZOT. Tight junction agonists also include zonulin.
  • compositions of the invention typically comprise one or more tight junction agonists.
  • a tight junction agonist as used herein is a compound that mediates the physiological, transient opening of tight junctions.
  • a tight junction agonist may operate by binding to the ZOT receptor, i.e., may be a ZOT receptor agonist.
  • a tight junction agonist may comprise a peptide comprising the amino acid sequence FCIGRL and/or functional derivatives of this sequence.
  • Functional derivatives of peptide FCIGRL include, for example, Xaai Cys Ue GIy Arg Leu (SEQ ID NO: 2), Phe Xaa 2 He GIy Arg Leu (SEQ ID NO: 3), Phe Cys Xaa 3 GIy Arg Leu (SEQ ID NO: 4), Phe Cys He Xaa 4 Arg Leu (SEQ ID NO: 5), Phe Cys He GIy Xaa 5 Leu (SEQ ID NO: 6), and Phe Cys lie GIy Arg Xaae (SEQ ID NO: 7).
  • Xaaj is selected from the group consisting of Ala, VaI, Leu, He, Pro, Trp, Tyr, and Met
  • Xaa 2 is selected from the group consisting of GIy, Ser, Thr, Tyr, Asn, and GIn
  • Xaa 3 is selected from the group consisting of Ala, VaI, Leu, He, Pro, Trp, and Met
  • Xaa 4 is selected from the group consisting of GIy, Ser, Thr, Tyr, Asn, Ala, and GIn
  • Xaas is selected from me group consisting of Lys and His
  • Xaa6 is selected from the group consisting of Ala, VaI, Leu, He, Pro, Trp, and Met.
  • a tight junction agonist may consist of a peptide having the sequence FCIGRL and/or functional derivatives of this sequence as described herein.
  • FCIGRL peptide FCIGRL
  • Xaai is selected from the group consisting of Ala, VaI, Leu, He, Pro, Trp, Tyr, and Met; Xaai is selected from the group consisting of GIy, Ser, Thr, Tyr, Asn, and GIn; Xaa 3 is selected from the group consisting of Ala, VaI, Leu, lie, Pro, Trp, and Met; Xaa 4 is selected from the group consisting of GIy, Ser, Thr, Tyr, Asn, Ala, and GIn; Xaas is selected from the group consisting of Lys and His; Xaa ⁇ s is selected from the group consisting of Ala, VaI, Leu, He, Pro, Trp, and Met.
  • any length of peptide may be used.
  • an agonist may be about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14 or about 15 amino acids in length.
  • a peptide tight junction agonist may be from about 3 to about 12, from about 4 to about 12, from about 5 to about 12, from about 6 to about 12, from about 7 to about 12, from about 8 to about 12, from about 9 to about 12, from about 10 to about 12, from about 3 to about 10, from about 4 to about 10, from about 5 to about 10, from about 6 to about 10, from about 7 to about 10, from about 8 to about 10, from about 9 to about 10 amino acids in length.
  • a peptide tight junction agonist may be 9 amino acids or less in length.
  • peptides tight junction agonists do not encompass full length ZOT or zonulin.
  • Peptide agonists can be chemically synthesized and purified using well-known techniques, such as described in High Performance Liquid Chromatography of Peptides and Proteins: Separation Analysis and Conformation, Eds. Mant et al., C.R.C. Press (1991), and a peptide synthesizer, such as Symphony (Protein Technologies, Inc.); or by using recombinant DNA techniques, i.e., where the nucleotide sequence encoding the peptide is inserted in an appropriate expression vector, e.g., an E. coli or yeast expression vector, expressed in the respective host cell, and purified from the cells using well-known techniques.
  • an appropriate expression vector e.g., an E. coli or yeast expression vector
  • compositions of the invention may formulated for any type of delivery, for example, parenteral, mucosal or intestinal delivery.
  • compositions of the invention may be formulated for pulmonary delivery (e.g., may be pulmonary dosage forms).
  • Such compositions may be provided as pharmaceutical aerosols, e.g., solution aerosols.
  • pharmaceutical aerosols e.g., solution aerosols.
  • Sciarra and Sciarra, Aerosols in Remington: The Science and Practice of Pharmacy, 20th Ed., Chapter 50, Gennaro et a Eds., Lippincott, Williams and Wilkins Publishing Co., (2000).
  • compositions of the invention may be formulated for enteric delivery, for example, may comprise one or more coatings, for example, delayed release coating containing one or more enteric agents.
  • a delayed release coating is typically substantially stable in gastric fluid and substantially unstable (e.g., dissolves rapidly or is physically unstable) in intestinal fluid, thus providing for substantial release of the tight junction antagonist from the composition in the duodenum or the jejunum.
  • stable in gastric fluid or “stable in acidic environments” refers to a composition that releases 30% or less by weight of the total tight junction antagonist in the composition in gastric fluid with a pH of 5 or less, or simulated gastric fluid with a pH of 5 or less, in approximately sixty minutes.
  • Nasal dosage compositions for nasal delivery are well-known in the art.
  • Such nasal dosage compositions generally comprise water-soluble polymers that have been used extensively to prepare pharmaceutical dosage forms (Martin et al, In: Physical Chemical Principles of Pharmaceutical Sciences, 3rd Ed., pages 592-638 (1983)) that can serve as carriers for peptides for nasal administration (Davis, In: Delivery Systems for Peptide Drugs, 125:1-21 (1986)).
  • the nasal absorption of peptides embedded in polymer matrices has been shown to enhance through retardation of nasal mucociliary clearance (Ilium et al, Int. J. Pharm., 46:261-265 (1988)).
  • compositions comprising a tight junction agonist comprise an immune suppressive amount of the agonist.
  • the immune suppressive amount of agonist e.g., peptide agonist
  • the immune suppressive amount of agonist employed may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • compositions of the invention may comprise one or tight junction agonist at a level of from about 0.000001 wt% to about 50 wt%, from about 0.000001 wt% to about 45 wt%, from about 0.000001 wt% to about 40 wt%, from about 0.000001 wt% to about 35 wt%, from about 0.000001 wt% to about 30 wt%, from about 0.000001 wt% to about 25 wt%, from about 0.000001 wt% to about 20 wt%, from about 0.000001 wt% to about 15 wt%, from about 0.000001 wt% to about 10 wt%, from about 0.000001 wt% to about 5 wt%, from about 0.000001 wt% to about 2.5 wt%, from about 0.000001 wt% to about 1 wt%, from about 0.000001 wt% to about 0.1 wt%, from about 0.000001 wt% to
  • Compositions of the invention may comprise one or more tight junction agonists at a level of about 0.00001 wt%, about 0.00005 wt%, about 0.0001 wt%, about 0.0005 wt%, about 0.001 wt%, about 0.005 wt%, about 0.01 wt%, about 0.05 wt%, about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% based on the total weight of the composition.
  • compositions of the invention may comprise one or more antigens (e.g., allergens) at a concentration sufficient to cause the desired biological response.
  • Compositions of the invention may comprise one or more antigens at from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 45 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 35 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 25 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 15 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 2.5 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt%
  • compositions of the invention may comprise one or more antigens at a level of about 0.1 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% based on the total weight of the composition.
  • compositions of the invention may comprise one or pharmaceutically acceptable excipients at a level of from about 0.1 wt% to about 50 wt%, from about 0.1 wt% to about 45 wt%, from about 0.1 wt% to about 40 wt%, from about 0.1 wt% to about 35 wt%, from about 0.1 wt% to about 30 wt%, from about 0.1 wt% to about 25 wt%, from about 0.1 wt% to about 20 wt%, from about 0.1 wt% to about 15 wt%, from about 0.1 wt% to about 10 wt%, from about 0.1 wt% to about 5 wt%, from about 0.1 wt% to about 2.5 wt%, from about 0.1 wt% to about 1 wt%, from about 0.1 wt% to about 0.5 wt%, from about 0.1 wt% to about 0.2 wt%, from about 1
  • compositions of the invention may comprise one or more pharmaceutically acceptable excipients at a level of about 0.1 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% based on the total weight of the composition.
  • compositions of the invention may be formulated to deliver an immune suppressive amount of a tight junction agonist in combination with an antigen.
  • An immune suppressive amount is typically greater than 1 mg tight junction agonist/kg body weight of the subject.
  • An immune suppressive amount may be from about 5 mg/kg to about 100 mg/kg, from about 5 mg/kg to about 50 mg/kg, from about 5 mg/kg to about 25 mg/kg, or from about 5 mg/kg to about 10 mg/kg.
  • compositions of the invention can be used for treating, ameliorating, and/or preventing an excessive or undesired immune response to an antigen. Any allergy may be treated using the compositions of the invention by selection of an appropriate antigen.
  • Ovalbumin and AT- 1002 simultaneously, four times in 21 day intervals and complete antibody responses to Ovalbumin were measured in the serum and in vaginal washes using quantitative Ova-specific ELISA. Effects of AT- 1002 stimulation on IgG subclasses (IgGl , and IgG2a) and IgA were studied. Mice immunized with Ova in the presence of AT- 1002 exhibit significantly higher antibody titers than those induced by immunization with antigen alone when antigen is administered with a low dose of tight junction agonist.
  • mice Female Balb/c mice (6-7 weeks of age) were obtained from the Jackson
  • Figures 1-3 show the results of the assays.
  • Figure 1 shows an increase in all types of IgG except subclass IgG2a was seen when ovalbumin was delivered with tight junction agonist at low dose.
  • Figure 2 shows that subclass IgGl was increased when ovalbumin was administered with tight junction agonist while subclass IgG2a was decreased.
  • Figure 3 shows the effects of the tight junction agonist on the relative titers of the total IgG and on the subclasses IgGl and IgG2a as well as on IgA as a function of the amount of tight junction agonist delivered with the antigen.
  • mice immunized with ovalbumin in the presence of low doses of AT-1002 exhibit significantly higher antibody titers than those induced by immunization with antigen alone.
  • AT-1002 exhibits Th2 biased adjuvant effect at low dose.
  • AT1002 exhibits immunosuppressive effects. Higher doses of AT 1002 caused a reduction in antibody titer when compared to the administration of ovalbumin alone.
  • high doses of tight junction agonist for example, greater than about 1 mg/kg cause the suppression of the immune response to the antigen ovalbumin.
  • Gliadin treated with the peptidases pepsin and trypsin (termed PT-gliadin or
  • CaCo2 cells form monolayers that exhibit tight junctions between adjacent cells.
  • Treatment of CaCo2 monolayers with peptide FCIGRL decreased TEER 16- fold in CaCo2 monolayers compared to vehicle alone.
  • the TEER assay may be performed as follows:
  • HBSS removing 10ml of HBSS and replacing it with 10ml HEPES buffer pH 7.0. Adjust pH to 7.4 ⁇ 0.1 using concentrated NaOH (10N).

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Abstract

La présente invention concerne des susbtances et des procédés permettant de supprimer une réponse immune excessive ou non désirée. Selon certains modes de mise en oeuvre, des agonistes des voies biologiques responsables de l'ouverture et de la fermeture des jonctions serrées (par exemple, des agonistes de jonctions serrées) sont utilisés dans des compositions présentant des antigènes afin de supprimer une réponse immune contre l'antigène.
PCT/US2008/066057 2007-06-08 2008-06-06 Utilisation d'agonistes de jonctions serrées pour supprimer des réponses immunes WO2008154350A2 (fr)

Applications Claiming Priority (2)

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US94297807P 2007-06-08 2007-06-08
US60/942,978 2007-06-08

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WO2008154350A2 true WO2008154350A2 (fr) 2008-12-18
WO2008154350A3 WO2008154350A3 (fr) 2009-02-26

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4338297A (en) * 1980-02-19 1982-07-06 Michael Jacob G Polypeptide active pollen immunosuppressant fraction
US20050119171A1 (en) * 2001-08-10 2005-06-02 Genset S.A. Human cdnas and proteins and uses thereof
US20060165722A1 (en) * 2005-01-14 2006-07-27 University Of Maryland, Baltimore Peptides for delivery of mucosal vaccines
US20060276399A1 (en) * 1998-08-03 2006-12-07 University Of Maryland - Baltimore Peptide antagonists of zonulin and methods for use of the same
US20070122423A1 (en) * 2001-08-17 2007-05-31 Glaxosmithkline Biologicals Sa Derp1 and proderp1 allergen derivatives

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4338297A (en) * 1980-02-19 1982-07-06 Michael Jacob G Polypeptide active pollen immunosuppressant fraction
US20060276399A1 (en) * 1998-08-03 2006-12-07 University Of Maryland - Baltimore Peptide antagonists of zonulin and methods for use of the same
US20050119171A1 (en) * 2001-08-10 2005-06-02 Genset S.A. Human cdnas and proteins and uses thereof
US20070122423A1 (en) * 2001-08-17 2007-05-31 Glaxosmithkline Biologicals Sa Derp1 and proderp1 allergen derivatives
US20060165722A1 (en) * 2005-01-14 2006-07-27 University Of Maryland, Baltimore Peptides for delivery of mucosal vaccines

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