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WO2007020018A1 - Utilisation d'agonistes des récepteurs purinergiques et pyrimidinergiques pour des immunothérapies à base de cellules dendritiques - Google Patents

Utilisation d'agonistes des récepteurs purinergiques et pyrimidinergiques pour des immunothérapies à base de cellules dendritiques Download PDF

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Publication number
WO2007020018A1
WO2007020018A1 PCT/EP2006/007966 EP2006007966W WO2007020018A1 WO 2007020018 A1 WO2007020018 A1 WO 2007020018A1 EP 2006007966 W EP2006007966 W EP 2006007966W WO 2007020018 A1 WO2007020018 A1 WO 2007020018A1
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formula
antigen
disease
purinergic
adenosine
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Jean-Marie Boeynaems
Michel Goldman
Frédéric MARTEAU
Didier Communi
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Universite Libre de Bruxelles ULB
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Universite Libre de Bruxelles ULB
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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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • 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
    • A61K2039/55511—Organic adjuvants

Definitions

  • the invention relates to the field of immunology, more in particular to the field of immune therapy.
  • the present invention relates to purinergic and pyrimidinergic receptor agonists and pharmaceutical compositions thereof useful in dendritic cells based immunotherapies.
  • DCs Dendritic cells
  • APCs antigen-presenting cells
  • They are considered to be guardians of the immune system. They are in fact located almost everywhere, namely in the thymus, the systemic circulation and the secondary lymphoid organs and also in the peripheral tissues such as the skin and mucous membranes, whether they can be monostratal or of the malpighian type, i.e. comprising a multistratal epithelium, namely those of the vagina, the outer cervix, the vulva, the perianal region, the esophagus and the mouth.
  • dendritic cells are at the center of the triggering of specific immune responses, exerting control over the specificity, intensity and nature of the immune response, and are located at the interface of innate and acquired immunity. Apart from their function of "switching on” the immune response, dendritic cells also have a role to play in the induction of peripheral tolerance.
  • dendritic cells The expression in dendritic cells is induced directly by the biological activity of environmental substances and/or indirectly by the reactivity products (stress and inflammatory mediators, necrotic cells) generated in response to these substances by other cells within the APC tissue micro- environment.
  • cytokines such as TNF- ⁇ and IL-1 ⁇
  • pathogen-related molecules LPS, double-stranded RNA, bacterial DNA
  • T cell-derived signals such as CD40 ligand
  • immature dendritic cells undergo maturation. Maturation of dendritic cells induces the loss of endocytosis, the surface expression of stable MHC-peptide complexes and costimulatory molecules (CD80, CD86) and the production of cytokines like IL-12 (Banchereau J et al. Annu Rev Immunol. 2000;18:767-81 1 ).
  • Maturation is also accompanied by a shift in the expression of chemokines and their receptors allowing dendritic cells migration to lymphoid organs.
  • High secretion of IL-12 by mature dendritic cells induces differentiation of CD4 + T cells into Th1 cells secreting IFN- ⁇ whereas low IL-12 release combined with IL-10 production induces a Th2 response or a T regulatory response associated with induced tolerance (Banchereau J et al. Annu Rev Immunol. 2000;18:767-811 ; Akbari O et al. Nat Immunol. 2001 ;2:725-731 ) .
  • WO 03/028712 discloses the use of purinergic and pyrimidinergic receptor agonists for inhibition of CD4+ T lymphocytes activation and as immunosuppressive agents. These therapies are effective but require continuous use because they do not redirect the immune system to a state of tolerance. This continuous treatment leads to long-term toxicity and suppresses protective immune responses against infection.
  • Therapeutic vaccination constitutes an alternative approach, characterized by its specificity for one or several specific antigens.
  • the objective of therapeutic vaccination is to obtain one of the following outcomes: specific T cell ablation, specific T cell anergy, induction of regulatory T cells, shift of specific T cell phenotype from Th1 to Th2 (in case of rheumatoid arthritis, diabetes or multiple sclerosis...) or from Th2 to Th1 (in case of asthma and other allergic diseases).
  • US Pat. Application 2005/0053612 describes the use of purine receptor antagonists to diminish or decrease an undesirable immune response and describes the use of purine receptor agonists such as ATP and ATP ⁇ S to stimulate the immune system.
  • the present invention provides an alternative strategy which involves the administration of antigen(s) with a particular kind of adjuvant that orient the immune response towards tolerance.
  • nucleotides in particular agonists of the P2Yn receptor, constitute such an adjuvant, via their specific action on dendritic cells.
  • the present invention relates to the use of at least one purinergic and pyrimidinergic receptor agonist of formula (1 ) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inducing immunotolerance to an antigen whereby the individual is immunized with an antigen in combination with the agonist of formula (1 )
  • B 1 is selected from the group comprising adenine, uracil, thymine, cytosine, guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl
  • R 1 and R 2 represent each independently OH, H 1 OR 7 , OCOR 7 , OCOR 7 COR 7 , wherein R 7 represents alkyl or aryl and X is of formula (2), (3) or (4),
  • R 10 represents hydrogen or is of formula (7)
  • B 2 is selected from the group comprising adenine, uracil, thymine, cytosine, guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl, wherein n is O, 1 , 2, 3 or 4, and wherein R 4 , R 4a and R 4b represent each independently O, NH, alkylene, monohaloalkylene or dihaloalkylene and R 3 , R 5 , R 6 , R 8 , R 9 represent each independently OH or SH, and wherein R 11 and R 12 represent each independently OH, H, OR 7 , OCOR 7 , OCOR 7 COR 7 , wherein R 7 is as defined above.
  • the antigen may be present in the body already, as is the case with some allergic diseases.
  • stimulation and/or upregulation of the production of thrombospondin-1 in dendritic cells with the purinergic and pyrimidinergic receptor agonists of formula (1 ) alone will enhance the induction of tolerance. Therefore, in another aspect, the present invention relates to the use of at least one purinergic and pyrimidinergic receptor agonist of formula (1 ) as defined above for the preparation of a medicament for inducing immunotolerance.
  • the present invention relates to the use of at least one purinergic and pyrimidinergic receptor agonist of formula (1 ) as defined above for the preparation of a medicament for inducing immunotolerance to an antigen in an individual whereby said agonist of formula (1 ) is administered to an individual which has previously been exposed to an antigen.
  • said immunotolerance is being induced to prevent or treat autoimmune diseases, allergic diseases and/or transplant rejection and graft-versus-host disease.
  • the purinergic and pyrimidinergic receptor agonists of formula (1 ) are used for the preparation of a tolerogenic vaccine for inducing immunotolerance to an antigen.
  • Said vaccine suitable for immunotolerance therefore comprises at least one compound of formula (1 ) and optionally at least one antigen.
  • said vaccine comprises at least one compound of formula (1 ) and at least one antigen.
  • said vaccine is administered only once, twice or thrice, preferably only once.
  • said purinergic or pyrimidinergic receptor agonist is of formula (5), (6) or (8) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and X have the same meaning as defined above and R 13 is selected from hydrogen, thioalkyl, thioaryl or thioalkylaryl.
  • said purinergic or pyrimidinergic receptor agonist is of formula (5), (6) or (8) wherein R 13 is selected from hydrogen, thiomethyl, thiobutyl, thiopentyl, thiophenyl or thiobenzyl, and R 1 and R 2 are each independently selected from OH, H, OR 7 , OCOR 7 , OCOR 7 COR 7 , wherein R 7 represents alkyl or aryl and X is of formula (2), (3) or (4),
  • interesting purinergic receptor agonists of formula (1 ) are selected from the group comprising ATP, adenosine 5'-O-(3-thiotriphosphate) (ATP ⁇ S), 2'- and 3'-0-(4-benzoyl-benzoyl) adenosine 5'- triphosphate (BzATP), 2-propylthio- ⁇ , ⁇ -dichloromethylene-D-ATP, 2-methylthio-ATP (2-MeSATP), ADP, 2-methylthio-ADP (2-MeSADP), adenosine 5'-O-(2-thiodiphosphate) (ADP ⁇ S), P 1 ,P 3 - di(adenosine-5')triphosphate (Ap 3 A), P 1 ,P 4 -di(adenosine-5')tetraphosphate (Ap 4 A), P 1 , P 5 - di(adenosine-5')pentaphosphate (Ap 5 A), P 1 ,
  • said purinergic or pyrimidinergic receptor agonist of formula (1 ) is selected from the group of compounds 1 to 332 as depicted in tables A, B or C.
  • said agonist of formula (1 ) is a purinergic receptor agonist of formula (1 ) wherein B 1 is selected from the group comprising adenine guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl.
  • said antigen is selected from the group comprising antigens responsible of asthma, including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, antigens responsible of allergic rhinitis, antigens responsible of conjunctivitis, antigens responsible of keratitis, antigens responsible of keratoconjunctivitis, antigens responsible of uveitis, antigens responsible of psoriasis, antigens responsible of eczema, antigens responsible of atopic dermatitis, antigens responsible of contact dermatitis, antigens responsible of cutaneous T cell lymphoma (CTCL), antigens responsible of Sezary syndrome, antigens responsible of pemphigus vulgaris, antigens responsible of bullous pemphigoid, antigens responsible of pemphigus foliaceus, antigens responsible of dermatomyositis, antigens responsible of erythema nodosum, antigens responsible of
  • said antigen is selected from the group comprising antigens responsible of autoimmune disease selected from psoriasis, rheumatoid arthritis, multiple sclerosis and insulin-dependent diabetes mellitus (type 1 ), of antigens responsible of allergic disease selected from bronchial asthma and atopic dermatitis, or antigens responsible of transplant rejection and graft-versus-host disease.
  • the present invention relates to a pharmaceutical composition comprising at least one purinergic and pyrimidinergic receptor agonists of formula (1 ) as defined above, a pharmaceutically acceptable carrier and at least one antigen.
  • the present invention relates to tolerogenic vaccine comprising at least one purinergic and pyrimidinergic receptor agonists of formula (1 ) as defined above as an adjuvant for inducing immune tolerance to an antigen.
  • said tolerogenic vaccine further comprises an antigen.
  • the present invention relates to a method to stimulate the production of TSP- 1 in dendritic cells comprising submitting said cell to at least one purinergic and pyrimidinergic receptor agonists of formula (1 ) as defined above.
  • the present invention relates to a method of inducing immunotolerance to an antigen comprising administering to an individual in need thereof, a therapeutically effective amount of a purinergic or pyrimidinergic receptor agonist of formula (1 ) as defined above.
  • said method comprises stimulating the production of TSP-1 by dendritic cells using at least one purinergic and pyrimidinergic receptor agonists of formula (1 ).
  • Said administration may be by oral, and/or parenteral, and/or intranasal, and/or dermal administration.
  • the method of the present invention comprises co-administering an antigen.
  • said co-administration is sequential.
  • said co-administration is simultaneous.
  • these combination methods offer significant advantages, such as (i) better efficacy leading to stronger reduction of symptoms, (ii) reduction of the need for drugs, in particular glucocorticoids, (iii) prevention of the progression into more severe disease, (iv) faster onset of beneficial effects leading to shorter treatment period (v) use of lower amounts of antigen and (vi) less unwanted side effects.
  • said purinergic or pyrimidinergic receptor agonist of formula (1) are used as adjuvant for inducing immune tolerance to antigens responsible of and/or triggering immune disease, wherein non limiting examples of said immune diseases triggered by said antigens include asthma including bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma, allergic rhinitis, conjunctivitis, keratitis, keratoconjunctivitis, uveitis, psoriasis, eczema, atopic dermatitis, contact dermatitis, cutaneous T cell lymphoma (CTCL), Sezary syndrome, pemphigus vulgaris, bullous pemphigoid, pemphigus foliaceus, dermatomyositis, erythema nodosum, scleroderma, Bechet's disease, sarcoidosis, Sjogren's syndrome, rheumatoid arthritis
  • asthma including
  • said purinergic or pyrimidinergic receptor agonist of formula (1 ) are used as adjuvant for inducing immune tolerance fro the treatment of autoimmune disease including psoriasis, rheumatoid arthritis, multiple sclerosis and insulin-dependent diabetes mellitus (type 1 ), of allergic disease including bronchial asthma and atopic dermatitis, or of transplant rejection and graft- versus-host disease.
  • purinergic or pyrimidinergic receptor agonist of formula (1 ) play a crucial role in up-regulating two targets thrombospondin-1 (TSP-1 ) and indoleamine 2,3- dioxygenase (IDO) involved in immunotolerance.
  • the present invention provides a method for preventing onset of an immune disease in an individual said method comprising administering to said individual an effective amount of an agent (compound of formula (1 )) which selectively increases the levels of TSP-1 production by dendritic cells.
  • said compound of formula (1 ) is administered together with at least one antigen responsible of and/or triggering said immune disease.
  • the immune disease is selected from autoimmune disease including psoriasis, rheumatoid arthritis, multiple sclerosis and insulin- dependent diabetes mellitus (type 1 ), allergic disease including bronchial asthma and atopic dermatitis, or transplant rejection and graft-versus-host disease.
  • the present invention contemplates enhancing the degree of tolerogenicity in an individual, said method comprising administering to said individual a tolerogenic state-enhancing or maintaining effective amount of purinergic and pyrimidinergic receptor agonists of formula (1 ). More specifically, the present invention relates to adjuvant formulations for vaccines with enhanced tolerogenic activity said formulations comprising at least one purinergic and pyrimidinergic receptor agonists of formula (1 ) as defined herein and optionally at least one antigen.
  • the present invention also relates to the use of purinergic and pyrimidinergic receptor agonists of formula (1 ) or a pharmaceutically acceptable salt thereof for the stimulation of TSP-1 production by dendritic cells, wherein B 1 is selected from the group comprising adenine, uracil, thymine, cytosine, guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl, preferably wherein B 1 is selected from the group comprising adenine guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl, more preferably wherein B 1 is adenine optionally substituted by thioalkyl, thioaryl, or thioalkylaryl,
  • R 1 and R 2 represent each independently OH, H, OR 7 , OCOR 7 , OCOR 7 COR 7 , wherein R 7 represents alkyl or aryl and X is of formula (2), (3) or (4),
  • R 10 represents hydrogen or is of formula (7)
  • B 2 is selected from the group comprising adenine, uracil, thymine, cytosine, guanine, xanthine and hypoxanthine, optionally substituted by thioalkyl, thioaryl, or thioalkylaryl, wherein n is 0, 1 , 2, 3 or 4, and wherein R 4 , R 4a and R 4b represent each independently O, NH, alkylene, monohaloalkylene or dihaloalkylene and R 3 , R 5 , R 6 , R 8 , R 9 represent each independently OH or SH, and wherein R 11 and R 12 represent each independently OH, H, OR 7 , OCOR 7 , OCOR 7 COR 7 , wherein R 7 is as defined above.
  • B 1 in the above formula (1 ) is adenine optionally substituted by thioalkyl, thioaryl, or thioalkylaryl, preferably thiomethyl, thio-n-butyl, thio-n pentyl, thiophenyl or thiobenzyl.
  • B 2 preferably is adenine, uracil, cytosine or guanine, preferably adenine, cytosine or guanine.
  • B 2 is adenine in the formula (7) and n is 1 , 2, 3 or 4.
  • the linkage between the nucleotides is from 5' ⁇ 5' (e.g. P 1 , P 3 - di(adenosine-5') triphosphate)
  • the present invention also relates to compounds wherein the linkage between the nucleotides is 2' ⁇ 5' or 3' ⁇ 5 ⁇
  • examples of such compounds which are commercially available are: adenylyl(2' ⁇ 5')cytidine, adenylyl(3' ⁇ 5')cytidine, adenylyl(2'->5') uridine, adenylyl(3' ⁇ 5')uridine, adenylyl(3' ⁇ 5')adenosine, adenylyl(3' ⁇ 5')guanosine, cytidylyl (3' ⁇ 5') cytidine, cytidy
  • R 1 , R 2 and X have the same meaning as defined above and R 13 is selected from hydrogen, thioalkyl, thioaryl or thioalkylaryl.
  • R 13 is selected from hydrogen, thioalkyl, thioaryl or thioalkylaryl.
  • said purinergic or pyrimidinergic receptor agonist is of formula (9), (10), (11 ) or (12) or a pharmaceutically acceptable salt thereof,
  • each R 8 has independently from the other R 8 substituents an individual meaning and can change in each formula, for instance a purinergic or pyrimidinergic receptor agonist of formula (13),
  • interesting purinergic receptor agonists of formula (1 ) are selected from the following groups (i) to (iii) comprising: (i) ATP and derivatives, (ATP ⁇ S, BzATP, 2-MeSATP, deoxyderivatives thereof); (ii) ADP and derivatives (ADP ⁇ S, 2-MeSADP); (iii) dinucleotides.
  • said purinergic receptor agonists of formula (1 ) are adenosine 5'-triphosphate (ATP), adenosine 5'-0-(3-thiotriphosphate) (ATP ⁇ S), T- and 3'-0-(4-benzoyl-benzoyl) adenosine 5'-triphosphate (BzATP), 2-propylthio- ⁇ . ⁇ -dichloromethylene-D-ATPadenosine 5'-diphosphate (ADP), 2-methylthio-ADP (2-MeSADP), adenosine 5'-0-(2-thiodiphosphate) (ADP ⁇ S), P 1 , P 3 - di(adenosine-5')triphosphate (Ap 3 A), P 1 ,P 4 -di(adenosine-5')tetraphosphate (Ap 4 A), P 1 , P 5 - di(adenosine-5')pentaphosphate (Ap 5 A),
  • the compound BzATP is a mixture of positional isomers 2'-O-(4-benzoyl-benzoyl) adenosine 5'- triphosphate and 3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate.
  • the cited nucleotides are potent agonists of the metabotropic P2Yn receptors, which are parts of the superfamily of G-protein-coupled receptors.
  • the purinergic and pyrimidinergic receptor agonists useful according to the present invention may have asymmetric centers, occur as racemates, racemic mixtures, and as individual diastereoisomers, with all possible stereochemical isomers including optical isomers, being included in the present invention.
  • the present invention when referring to purinergic or pyrimidinergic receptor agonist, as cited herein, also includes within its scope not only the specific compound(s) listed or described, but also alternative forms of the compound such as pharmaceutically acceptable salts, solvates, hydrates, and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stea
  • alkyl refers to saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and contains 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1 -8 carbon atoms, still more preferably 1-6 carbon atoms, yet more preferably 1-4 carbon atoms.
  • Alkyl radicals of interest are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl, isoamyl, hexyl, cyclohexyl.
  • aryl as used herein, includes a monovalent organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl.
  • alkylene refers to saturated bivalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and contains 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, still more preferably 1-6 carbon atoms, yet more preferably 1-4 carbon atoms.
  • alkylene radicals are methylene, ethylene, and propylene.
  • halo or "halogen” as used herein is generic for fluoro, chloro, bromo or iodo.
  • monohaloalkylene and “dihaloalkylene” as used herein refers to alkylene radical as defined above substituted by respectively one and two halogen radicals.
  • thioalkyl refers as used herein refers to a radical R'"S-, wherein R'" is an alkyl radical as defined herein. Examples of thioalkyl include, but are not limited to thiomethyl, thioethyl, thiobutyl, thio-n-pentyl and the like.
  • thioaryl refers as used herein refers to a radical R 1 S-, wherein R' is an aryl radical as defined herein. Examples of thioaryl include, but are not limited to thiophenyl and the like.
  • thioalkylaryl refers as used herein refers to a radical R'R"S-, wherein R' is an aryl radical as defined herein, and wherein R" is an alkylene radical as defined herein.
  • thioalkylenearyl include, but are not limited to thiobenzyl and the like.
  • the present invention provides methods of inducing immunotolerance for the prevention or treatment of inflammatory, allergic, autoimmune diseases and graft/transplantation rejection.
  • immunotolerance refers to immune unresponsiveness to an antigen implicated in causing disease.
  • the methods generally comprise administering to an individual in need thereof, a therapeutically effective amount of at least one purinergic and pyrimidinergic receptor agonists of formula (1 ) with or without administering an antigen.
  • said compound is administered only once, twice or thrice, preferably only once.
  • Said purinergic and pyrimidinergic receptor agonists of formula (1 ) stimulate TSP-1 secretion in dendritic cells thereby inducing immunotolerance.
  • the method comprises administering to an individual in need thereof, a therapeutically effective amount of at least one compound of formula (1 ) together with at least one antigen. Therefore, the present invention also teaches a method to induce and/or increase tolerance to an antigen in an individual, comprising stimulation and/or upregulation of the production of thrombospondin-1 in dendritic cells in the presence of an antigen.
  • said antigen may be present in the body already, as is the case with some allergic diseases.
  • stimulation and/or upregulation of the production of thrombospondin-1 in dendritic cells with the purinergic and pyrimidinergic receptor agonists of formula (1 ) alone will enhance the induction of tolerance.
  • said purinergic and pyrimidinergic receptor agonists of formula (1 ) are useful as inducers of immunotolerance.
  • said antigen may be present in the patient surroundings, i.e. may be exogenous, such as pollen and the like.
  • exogenous antigen such as pollen and the like.
  • stimulation and/or upregulation of the production of thrombospondin-1 in dendritic cells with the purinergic and pyrimidinergic receptor agonists of formula (1 ) in the presence of said exogenous antigen will enhance the induction of tolerance.
  • the "therapeutically effective amount" of said above-described purinergic or pyrimidinergic receptor agonist relates to the amount or quantity of said agonist required to achieve the desired therapeutic and/or prophylactic effect, for example the dosage of said agonist which results in inducing immune tolerance in the individual. Effective amounts may be measured from ng/kg body weight to g/kg body weight per minute, hour, day, week or month.
  • the term "individual” as used herein includes inter alia a subject, patient, target, host or recipient regardless of whether the individual is a human or non-human animal including avian species.
  • non-human primate e.g. gorilla, marmoset, African Green Monkey
  • livestock animal e.g. sheep, cow, pig, horse, donkey, goat
  • laboratory test animal e.g. rat, mouse, rabbit, guinea pig,
  • the preferred individual is a human.
  • the individual may be a mouse, rat, pig, sheep, non-human primate or other non-human animal.
  • the present invention provides a method of inducing immunotolerance comprising administering to an individual, in need thereof, a therapeutically effective amount of a purinergic or pyrimidinergic receptor agonist of formula (1 ) or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the use of a purinergic or pyrimidinergic receptor agonist of formula (1 ) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inducing tolerance to antigens, optionally in the presence of said antigens.
  • agonists of formula (1 ) are useful as vaccine adjuvants and promote the development of tolerance to antigens, through stimulation of TSP-1 secretion and potentiation of IDO expression in response to interferon-gamma.
  • Said agonist of formula (1 ) may be given orally, or by inhalation, parenterally or via the skin or a mucosal surface with the purpose to induce tolerance to an antigen.
  • said agonist of formula (1 ) may be combined with said antigens before administration to an individual. Therefore, the present invention also discloses a method to induce immunotolerance to an antigen, as mentioned above wherein said agonist of formula (1 ) is combined with said antigen before administration to an individual. And in another embodiment, the present invention also discloses a method to induce immunotolerance to an antigen, comprising providing the agonist of formula (1 ) and further administering the antigen.
  • the present invention relates to a pharmaceutical composition suitable for inducing immunotolerance to antigen responsible of immune diseases comprising a pharmaceutically acceptable carrier and a purinergic or pyrimidinergic receptor agonist of formula (1 ) or a pharmaceutically acceptable salt thereof, and at least one antigen.
  • compositions increases the induction of tolerance to antigens and may diminish disease symptoms in individuals suffering from hypersensitivity to various antigens.
  • the invention further relates to the use of a purine or pyrimidine analogue or derivative of formula (1 ) or a pharmaceutically acceptable salt of any of the aforementioned nucleotide derivatives, as an immunotolerance inducer.
  • the present invention provides a specific immunotolerance with respect to a particular antigen, leaving the general competence of the immune system intact.
  • immunotolerance and therapeutic vaccination have an improved risk/benefit ratio as well as cost- benefit ratio. Indeed, only a limited number of treatment courses is needed, whereas immunosuppression should be continuous.
  • vaccination according to the invention i.e. with at least one compound of formula (1 ) alone or with at least one antigen, should be specific for said one (or a few) antigen(s) and does not decrease in a non-specific way immune responses against pathogens. It is therefore expected that the side effects and the costs of immunotolerance- based strategies would be much less than for immunosuppression-based strategies.
  • the amount and nature of the material used for administration of the agonist of formula (1 ) and the antigen to confer the desired specific immunotolerance depends on the type of antigen.
  • the agonist of formula (1 ) may be administered simultaneously with the antigen or sequentially.
  • agonist of formula (1 ) refers to injection or administration of one within approximately 24-48 hours of the other. Either may be administered first. It is preferable, however, that the administration of the agonist of formula (1 ) be carried out substantially contemporaneously with or within 48 hours prior to injection or other administration of the antigen.
  • antigen refers to the immunogenic substance of interest which when exposed to an individual induces an immune response in that individual.
  • Said antigens can be exogenous antigens which are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. These antigens can be endogenous antigens that have been generated within the cell, as a result of normal cell metabolism, or because of viral or intracellular bacterial infection.
  • Said antigens can be autoantigens which are usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of subjects suffering from a specific autoimmune disease.
  • antigens include allergens, nucleic acid, globular proteins, carbohydrate, glycoproteins such as immunoglobulins, materials carried on particles such as pollen proteins, polypeptides intended for therapeutic use such as interferon, interleukin-2, or tumor necrosis factor, hormone replacements, such as leutinizing hormone or its analogs or antagonists, and the like.
  • Synthetic peptide analogs of protein therapeutic agents which are used for receptor blockade are another important class of antigen. Still another important subclass is that of allo-antigens, i.e., those which are products of the major histocompatibility complex. It is these allo-antigens which are presumably responsible for rejection of foreign tissue in tissue transplants or skin grafts.
  • the antigenic component may be conveniently administered intravenously in suitable excipients.
  • exposure may mimic "natural" exposure and employ aerosols or oral compositions and quantities approximating the estimated degree of exposure are appropriate.
  • the formulation of appropriate pharmaceutical compositions to administer the antigen is well known to those in the art.
  • the antigen is a therapeutic agent, amounts of antigen approximating those intended to be administered and a similar route of administration may be used. In general, this protection affords a simpler problem as generally speaking the antigen is already available in a suitably formulated pharmaceutical composition and the levels of exposure expected and expected routes of administration are already known.
  • Allografts are multiplicities of cells or associated cells that define a tissue or organ from an individual of the same species as that of the intended recipient, but which derive from an individual genetically dissimilar from the recipient.
  • Endocrine glands pituitary, thyroid, adrenal, parathyroid, and pancreas
  • skin grafts may not contain the major histocompatibility antigens which are responsible for triggering the rejection of the transplant.
  • antigens are carried by passenger cells such as leukocytes which are included in the transplanted cells as impurities.
  • the transplant materials can themselves be used as a source of antigen, or the particular histocompatibility antigens may be obtained separately and administered alone or as cells bearing the histocompatibility antigens of the transplant donor, i.e., peripheral blood lymphocytes.
  • a major antigen responsible for tissue rejection carried of such passenger leukocytes is the murine la-equivalent antigen which in humans is designated HLA-DR (MHC class Il antigens).
  • HLA-DR antigens have been subclassified and if the donor has been typed, suitable antigen, e.g., peripheral blood lymphocytes, associated with the donor tissue is conveniently obtainable and injected prior to transplant along with or within the recovery period of administering the agonist of formula (1 ).
  • the perhaps more crude, but effective, manner of administration is simultaneous injection of the agonist of formula (1 ) along with or just before the transplant itself or a pre-transplant simultaneous injection of a portion of the tissue suitably finely divided and formulated along with the agonist of formula (1 ).
  • the agonist of formula (1 ) may be incorporated in the pharmaceutical composition with a suitable diluent.
  • Said diluent may be any fluid acceptable for intravenous or parenteral inoculation.
  • the suitable diluent may comprise water and/or oil and/or a fatty substance.
  • said agonists are further combined with at least one antigen. Therefore, the present invention teaches a pharmaceutical composition comprising at least one agonists of formula (1 ) and at least one antigen, which may further comprises a suitable diluent.
  • Said agonists of formula (1 ) may be administrated to an individual in need of such treatment before the administration of the antigens.
  • the agonists of formula (1 ) may be administered via another route than said antigens.
  • the agonists of formula (1 ) may be provided orally, or topically, followed by topical administration of the antigens.
  • Said topical administration comprises administration on the skin, and/or on the mucosa of the airways and/or of the oro-nasal cavity, and/or of the gastro-intestinal mucosa.
  • the pharmaceutical composition of the present invention may further include thickeners, buffers, preservatives, surface active agents, liposomes, or lipid formulations, and the like.
  • Pharmaceutically acceptable carriers may include sterile aqueous or non-aqueous solutions, suspensions, and emulsions suitable for ingestion, inhalation, intranasal administration, ocular application, skin application or administration as a suppository to the rectum or vagina.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and certain organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • the pharmaceutical composition may be administered to an individual in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated. Administration may be topical including on the skin, ophthalmic, vaginal, rectal, intranasal, oral, by inhalation, or parenteral, for example by intravenous drip, subcutaneous, intratumor, intraperitoneal, intralymphatic or intramuscular injection.
  • the pharmaceutical composition according to the invention may suitably be provided in the form of a spray, an aerosol, tablets (entero-or not-enterocoated), capsule (hard or soft, entero-or not- enterocoated, controlled ileal release or not), a suspension, a dispersion, granules, a powder, a solution, an emulsion, chewable tablets, tablets for dissolution, drops, a gel, a paste, a syrup, a cream, a lozenge (powder, granulate, tablets), a lotion, a foam, an instillation fluid, a gas, a vapor, an ointment, a patch, a stick, implants (ear, eye, skin, nose, rectal, or vaginal), vagitories, suppositories, enema, foam, or uteritories suitable for administration via the oral, nasal, vaginal, sublingual, ocular, rectal, urinary, intramammary, pulmonary,
  • each specific antigen offers alternative routes for administration appropriate to its nature. All offer the possibility of obtaining purified antigen and utilizing intravenous administration. In certain instances, it is also possible to inject a composition containing a mixture of the specific antigen along with the agonist of formula (1 ) in a suitable pharmaceutical composition.
  • parenteral administration examples include subcutaneous, intraperitoneal, or intramuscular injection.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • the pharmaceutical compositions to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
  • an adjuvant such as complete Freund's adjuvant is generally used.
  • An additional approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained.
  • Systemic administration may be effected via suppository.
  • traditional binders and carriers include, e.g., polyalkalene glycols or triglycerides.
  • Such suppositories may be formed from mixtures containing the agonist of formula (1 ) or antigen in the range of 0.5%-10%; preferably 1 %-2%.
  • the antigen is preferably supplied in finely divided form along with a surfactant and a propellant.
  • Typical percentages of active ingredients are 0.01 % to 20% by weight, preferably 0.4% to 1.0%.
  • Surfactants must, of course, be nontoxic, and preferably soluble in the propellant.
  • Representative of such agents are the esters or partial esters of fatty acids, such as caproic or octanoic acids, polyols such as mannitol or sorbitol, or their anhydrides or esters and their polyoxyethylene and polyoxypropylene derivatives.
  • Preferred surface-active agents include the oleates of sorbitan, e.g., those sold under the trademarks "Arlacel C", “Span 80", and “Span 85”.
  • the surfactant may constitute 0.1 %-20% by weight of the composition, preferably 0.25%-5%.
  • the balance of the composition is ordinarily propellant; for example the lower alkanes, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes, such as are sold under the trademark "Freon”.
  • a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divided active ingredient and surfactant. The ingredients are thus maintained at an elevated pressure until released by action of the valve.
  • Solid compositions of antigen or agonist of formula (1 ) may be used if administered orally or if reconstituted for administration.
  • Conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • the corresponding liquid pharmaceutically administrable compositions can be prepared by dissolving, dispersing, etc, the antigen or agonist of formula (1 ) above and optional pharmaceutical adjuvants in a carrier as described above.
  • composition or formulation to be administered will, in any event, contain a quantity of the agonist of formula (1 ) or antigen in an amount effective to obtain the desired specific immunotolerance.
  • kits for the treatment of allergy would comprise containers with, preferably, unit dosage levels of allergen such as ragweed protein, milk protein, or other allergenic material in suitable excipients including most preferably adjuvant preparations such as Freund's complete adjuvant.
  • An additional container would supply, e.g., the agonist of formula (1 ) in form for administration such as suspension in physiological saline or other pharmaceutical excipient or in solid form to be reconstituted.
  • these components may be supplied as a mixture. Additional components of such kits might be sterile disposable syringes.
  • the present invention relates to a method of inducing immunotolerance to an antigen comprising administering to an individual, in need thereof, a therapeutically effective amount of a purinergic or pyrimidinergic receptor agonist of formula (1 ) or a pharmaceutically acceptable salt thereof alone or with at least one antigen.
  • said immunotolerance is being induced to antigens responsible of asthma including bronchial asthma, allergic asthma, intrinsic asthma and dust asthma.
  • said immunotolerance is being induced to antigens responsible of allergic rhinitis.
  • said immunotolerance is being induced to antigens responsible of conjunctivitis.
  • said immunotolerance is being induced to antigens responsible of keratitis.
  • said immunotolerance is being induced to antigens responsible of keratoconjunctivitis.
  • said immunotolerance is being induced to antigens responsible of uveitis.
  • said immunotolerance is being induced to antigens responsible of psoriasis.
  • said immunotolerance is being induced to antigens responsible of eczema.
  • said immunotolerance is being induced to antigens responsible of atopic dermatitis.
  • said immunotolerance is being induced to antigens responsible of contact dermatitis.
  • said immunotolerance is being induced to antigens responsible of cutaneous T cell lymphoma (CTCL).
  • CTCL cutaneous T cell lymphoma
  • said immunotolerance is being induced to antigens responsible of Sezary syndrome.
  • said immunotolerance is being induced to antigens responsible of pemphigus vulgaris.
  • said immunotolerance is being induced to antigens responsible of bullous pemphigoid.
  • said immunotolerance is being induced to antigens responsible of pemphigus foliaceus.
  • said immunotolerance is being induced to antigens responsible of dermatomyositis.
  • said immunotolerance is being induced to antigens responsible of erythema nodosum.
  • said immunotolerance is being induced to antigens responsible of scleroderma.
  • said immunotolerance is being induced to antigens responsible of Bechet's disease.
  • said immunotolerance is being induced to antigens responsible of sarcoidosis.
  • said immunotolerance is being induced to antigens responsible of Sjogren's syndrome.
  • said immunotolerance is being induced to antigens responsible of rheumatoid arthritis.
  • said immunotolerance is being induced to antigens responsible of juvenile arthritis.
  • said immunotolerance is being induced to antigens responsible of Reiter's syndrome.
  • said immunotolerance is being induced to antigens responsible of lupus erythematosus.
  • said immunotolerance is being induced to antigens responsible of polymyositis.
  • said immunotolerance is being induced to antigens responsible of myocarditis.
  • said immunotolerance is being induced to antigens responsible of primary biliary cirrhosis.
  • said immunotolerance is being induced to antigens responsible of Crohn's disease.
  • said immunotolerance is being induced to antigens responsible of ulcerative colitis.
  • said immunotolerance is being induced to antigens responsible of multiple sclerosis and other demyelinating diseases.
  • said immunotolerance is being induced to antigens responsible of idiopathic thrombocytopenic purpura.
  • said immunotolerance is being induced to antigens responsible of Graves' disease and Hashimoto's disease.
  • said immunotolerance is being induced to antigens responsible of Addison's disease.
  • said immunotolerance is being induced to antigens responsible of insulin-dependent diabetes mellitus (type 1 ).
  • said immunotolerance is being induced to antigens responsible of transplant rejection or graft-versus-host disease.
  • At least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used with at least one antigen responsible of and/or triggering an autoimmune disease, for the preparation of a medicament for treating an autoimmune disease.
  • said autoimmune disease is selected from the group comprising acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, diabetes mellitus (type 1 ), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS) (also known as acute inflammatory demyelinating polyneuropathy, acute idiopathic polyradiculoneuritis, acute idiopathic polyneuritis and Landry's ascending paralysis), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, multiple
  • At least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used alone or with at least one antigen responsible of and/or triggering an autoimmune disease, for the preparation of a medicament for preventing said autoimmune disease, preferably in a subject at risk of developing said disease.
  • at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used with at least one antigen responsible of and/or triggering and autoimmune disease, for the preparation of a medicament for preventing said autoimmune disease, preferably in a subject at risk of developing said disease.
  • an individual at risk of developing an autoimmune disease includes but is not limited to individuals having a history of autoimmune disease or individuals genetically susceptible to the development of autoimmune diseases (with genetic predisposition) or individuals selected on the basis of medical investigation results or relevant biomarkers.
  • the present compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering autoimmune disease to prepare vaccine to prevent autoimmune disease, wherein said autoimmune disease is selected from the group comprising acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, diabetes mellitus (type 1 ), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS) (or acute inflammatory demyelinating polyneuropathy, acute idiopathic polyradiculoneuritis, acute idiopathic polyneuritis and Landry's ascending paralysis), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, multiple sclerosis , myasthenia gravis, opsoclonus myoclonus syndrome (OM
  • the present invention relates to the use of at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating an autoimmune disease wherein said compound is administered only once.
  • the present invention relates to the use of at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating an autoimmune disease wherein said compound is administered for a limited period of time in the early phase of the disease.
  • the present invention relates to the use of at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof alone or with at least one antigen responsible of and/or triggering autoimmune disease, for the preparation of a medicament for preventing or delaying relapsing of a disease of wherein said compound is administered during the relapsing phase of said disease.
  • at least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering multiple sclerosis, for the preparation of a medicament for treating a subject at risk for multiple sclerosis (MS), e.g., at risk of progressive MS or relapsing MS.
  • MS multiple sclerosis
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering multiple sclerosis, for the preparation of a medicament for preventing or delaying (e.g., for at least one year, 2 years, 3 years, 4 years, 5 years, 10 years or more) the onset of clinical manifestations of MS (e.g., relapsing remitting MS) or for minimizing the severity of a subsequent (e.g., a second) clinical manifestation.
  • the subject has had fewer than two clinical episodes of focal neurologic deficit.
  • the subject has experienced one clinical episode of focal neurologic deficit.
  • the neurologic deficit can be evidenced by, e.g., one or more symptoms, such as weakness of one or more extremities, paralysis of one or more extremities, tremor of one or more extremities, uncontrollable muscle spasticity, sensory loss or abnormality, decreased coordination, loss of balance, loss of ability to think abstractly, loss of ability to generalize, difficulty speaking, and difficulty understanding speech.
  • selection of a subject as being at risk for MS is done on the basis of one or more of: (a) cranial scan having evidence of myelin sheath damage, (b) presence of serum antibodies against one or both of MOG and MBP, (c) presence of increased levels of CSF IgG, (d) presence of elevated levels of MBP, and (e) occurrence of one clinical episode of focal neurologic deficit.
  • a "neurologic deficit” is a decrease in a function of the central nervous system. Examples include inability to speak, decreased sensation, loss of balance, weakness, cognitive dysfunction, visual changes, abnormal reflexes, and problems walking.
  • a "focal neurologic deficit” affects either a specific location (such as the left face, right face, left arm, right arm) or a specific function (for example, speech may be affected, but not the ability to write).
  • a neurologic deficit the term “clinical episode” means a neurologic deficit that lasts for hours, days or weeks (but from which partial or complete recovery can take place) and that is directly observable by outward physical signs of a patient, as distinguished from being observable only through a laboratory test or imaging of internal body tissues.
  • a clinical neurologic deficit is typically determined by a medical history and/or a physical neurological exam.
  • a compound of the invention can be administered to a patient with a progressive course of MS to retard or prevent the progression of neurological impairment.
  • a compound of the invention can also be administered to a subject with relapsing-remitting, secondary progressive or progressive- relapsing MS to inhibit relapse (e. g., an acute attack).
  • a compound of the invention can be administered to a subject with relapsing-remitting MS during the remitting phase of the disease to prevent or delay relapse.
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering multiple sclerosis, for the preparation of a medicament for preventing or delaying relapses in an individual having multiple sclerosis wherein said compound is administered during the remitting phase of said multiple sclerosis.
  • relapses involve neurologic problems that occur over a short period, typically days but sometimes as short as hours or even minutes. These attacks most often involve motor, sensory, visual or coordination problems early in the disease. Later, bladder, bowel, sexual and cognitive problems may be shown. Sometimes the attack onset occurs over several weeks. Typical MS relapse involves a period of worsening, with development of neurological deficits, then a plateau, in which the patient is not getting any better but also not getting any worse followed by a recovery (remitting) period. Recovery usually begins within a few weeks.
  • at least one compound of formula (1 ) is used in combination with at least one antigen responsible of and/or triggering an allergic disease for the preparation of a medicament for treating allergy to said antigen.
  • the antigen to be used in combination with the compound of formula (1 ) can be any naturally occurring protein that has been reported to induce allergic, i.e. IgE mediated, reactions upon their repeated exposure to an individual.
  • Suitable antigens include pollen allergens (tree-, herb, weed-, and grass pollen allergens), insect allergens (inhalant, saliva and venom allergens, e.g. mite allergens, cockroach and midges allergens, hymenopthera venom allergens), animal hair and dandruff allergens (from e.g. dog, cat, horse, rat, mouse etc.), and food allergens.
  • pollen allergens tree-, herb, weed-, and grass pollen allergens
  • insect allergens inhalant, saliva and venom allergens, e.g. mite allergens, cockroach and midges allergens, hymenopthera venom allergens
  • Suitable pollen allergens comprises pollen allergens from trees, grasses and herbs are such originating from the taxonomic orders of Fagales, Oleales, Pinales and platanaceae including inter alia (i.a.) birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), cedar (Cryptomeria and Juniperus), Plane tree (Platanus), the order of Poales including i.a.
  • grasses of the genera Lolium, Phleum, Poa, Cynodon, Dactylis, Holcus, Phalaris, Secale, and Sorghum the orders of Asterales and Urticales including i.a. herbs of the genera Ambrosia, Artemisia, and Parietaria.
  • suitable allergens are those from house dust mites of the genus Dermatophagoides and Euroglyphus, storage mite e.g. Lepidoglyphys, Glycyphagus and Tyrophagus, those from cockroaches, midges and fleas e.g.
  • the antigen is selected from the group consisting of a tree pollen allergen, a grass pollen allergen, a dust mite allergen, a herb allergen and an animal allergen.
  • the antigen is selected from the group consisting of a grass pollen allergen, a dust mite allergen, a ragweed allergen, a cedar pollen, a cat allergen and a birch allergen.
  • At least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used alone or with at least one antigen responsible of and/or triggering an allergic disease, for the preparation of a medicament for preventing said allergic disease, preferably in a subject at risk of developing allergy.
  • the present invention relates to the use of at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating an allergy wherein said compound is administered only once, twice or thrice, preferably only once.
  • at least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering atopy, for the preparation of a medicament for preventing atopic syndrome (atopy) in a subject at risk of developing said syndrome.
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering atopic dermatitis, allergic conjunctivitis, allergic rhinitis and/or asthma, for the preparation of a medicament for preventing atopic dermatitis, allergic conjunctivitis, allergic rhinitis and/or asthma in individuals at risk of developing at least one of said disease.
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering allergic conjunctivitis, allergic rhinitis and/or asthma, for the preparation of a medicament for preventing allergic conjunctivitis, allergic rhinitis and/or asthma in individuals having atopic dermatitis.
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering asthma, for the preparation of a medicament for preventing or delaying asthma in individuals having atopic dermatitis or allergic rhinitis.
  • At least one compound of formula (1 ) can be used alone or with at least one antigen responsible of and/or triggering diabetes (type 1 ), for the preparation of a medicament for preventing diabetes in individuals at risk of developing diabetes.
  • at least one compound of formula (1 ) is used in combination with at least one antigen responsible of and/or triggering a graft/transplantation rejection, for the preparation of a medicament for treating graft/transplantation rejection.
  • suitable source of antigen can be the transplant materials can themselves, or the particular histocompatibility antigens may be obtained separately and administered alone or as cells bearing the histocompatibility antigens of the transplant donor, i.e., peripheral blood lymphocytes.
  • At least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used alone or with at least one antigen responsible of and/or triggering a graft/transplantation rejection, for the preparation of a medicament for preventing graft/transplantation rejection, preferably in a subject at risk of developing said rejection.
  • at least one compound of formula (1 ) or a pharmaceutically acceptable salt thereof is used with at least one antigen responsible of and/or triggering graft/transplantation rejection, for the preparation of a medicament for preventing graft/transplantation rejection, preferably in a subject at risk of developing said rejection.
  • Non limiting examples of purinergic and pyrimidinergic receptor agonists of formula (1 ) useful according to the invention are listed Tables A, B and C.
  • the abbreviation “Cpd” refers to "Compound”.
  • Figures 1A to 1 D represent graphs plotting the production of TSP-1 by human monocyte-derived DCs in response to nucleotides.
  • A DCs were stimulated for various periods of time with either ATP ⁇ S (100 ⁇ M), PGE 2 (500 nM) or LPS (100 ng/ml).
  • B DCs were challenged with various concentrations of ATP ⁇ S or PGE 2 during 24 h.
  • C DCs were challenged with various concentrations of ATP ⁇ S or ATP during 24 h.
  • DCs were either untreated (Ctrl) or treated with ATP ⁇ S (100 ⁇ M) or PGE 2 (500 nM) for different periods of time in complete medium. Supematants were collected at the end of incubation to perform Western blotting using an anti- TSP-1 rabbit polyclonal antibody (1 :200).
  • B DCs were treated with ATP ⁇ S (100 ⁇ M) for 4, 8 or 24 h in serum-free medium. At the end of incubation, supematants were collected, proteins were extracted and loaded on a 8% SDS-polyacrylamide gel. After colloidal Coomassie blue staining, proteins of interest (black arrows A and B) were excised and in-gel digested by trypsin.
  • Figures 3A to 3G represent graphs plotting the effect of supematants from ATP-treated DCs on naive T CD4 + cells.
  • Naive T CD4 + cells were partially activated (A) - with coated anti-CD3 - or fully activated (C) - with coated anti-CD3 and soluble anti-CD28 - in the presence of supernatant from non-treated DCs (CTRL) or ATP-treated DCs (ATP) during 48 h. Cell suspensions were then additionally incubated for 16 h in presence of [ 3 H]thymidine (1 ⁇ Ci/well).
  • TSP-1 human recombinant TSP-1 (7 ⁇ g/ml) was also tested on thymidine incorporation of partially activated (B) or fully activated (D) naive T CD4 + cells in fresh medium.
  • E Supernatants from non-treated DCs (left) or ATP-treated DCs (right) were previously incubated 2 h at room temperature in the presence (black bars) or the absence (white bars) of neutralizing anti-TSP-1 mAb at 25 ⁇ g/ml (clone C6.7; that selectively interferes with TSP-1/CD47 interaction). Fully activated T CD4 + cells were incubated in the presence of these DCs supernatants for thymidine incorporation experiments.
  • Figures 4A and 4B represent respectively the result of Western Blotting experiments and a graph showing the synergy between ATP/ATP ⁇ S and IFN- ⁇ on the functional expression of IDO.
  • A DCs were either untreated or treated with ATP (300 ⁇ M) or ATP ⁇ S (100 ⁇ M) alone or in the presence of
  • IFN- ⁇ (10 or 100 U/ml) for 24 h in complete medium. The same amount of total protein were analyzed by Western blotting with an anti-human IDO rabbit polyclonal antibody.
  • B After a similar treatment with ATP (300 ⁇ M) or ATP ⁇ S (100 ⁇ M), DCs were washed and incubated for five additional hours in red-phenol-free RPMI supplemented with 300 ⁇ M L-tryptophan. Kynurenine levels were determined in each supernatants by HPLC. Data were obtained in an experiment performed in duplicate and representative of three independent experiments.
  • ATP and derivatives thereof are shown to induce immunotolerance through their action on DCs.
  • Microarray analysis of ATP-stimulated human DCs revealed inter alia a drastic up-regulation of two genes encoding mediators involved in immunotolerance: thrombospondin-1
  • TSP-1 indoleamine 2,3-dioxygenase
  • IDO indoleamine 2,3-dioxygenase
  • nucleotides derivatives are useful tools for DC-based immunotherapies and are particularly useful either alone or combined with immunogenic agents for inducing immunotolerance.
  • the anti-CD3 mAb OKT3 (Orthoclone OKT3) was provided by Janssen-Cilag (Berchem, Belgium), and the anti-CD28 mAb (clone CD28.2) was supplied by BD
  • the C6.7 mAb that interferes with the ligation of human TSP-1 to CD47 was from LabVision (Fremont, CA).
  • Microarray analysis - Immature DCs were stimulated by ATP ⁇ S (100 ⁇ M) for 6 h in the complete RPMI medium. The stimulation was stopped by addition of TRIZOL ® reagent (Life Technologies,
  • ELISA - Human thrombospondin (TSP-1 ) was measured in DC supematants by ELISA using commercially available kit from Chemicon International (Temecula, USA).
  • IL-10 and IFN-D were measured in supematants by ELISA using commercially available kits from BioSource (Nivelles, Belgium).
  • Mass spectrometry analysis was performed on a Q-TOF Ultima Global mass spectrometer equipped with a MALDI source (Micromass, Manchester, UK). Microsequencing was performed by Argon-induced fragmentation after selection of the parent ion.
  • T cell proliferation assays - DCs were prepared as described above and were stimulated by ATP 300 ⁇ M in complete medium. After 24 h, supernatants of untreated and ATP-treated DCs were collected.
  • naive T CD4 + lymphocytes were prepared using T CD4 + isolation kit Il and CD45RO microbeads (Miltenyi Biotec, Bergish Gladbach, Germany) as previously described (Ia SaIa A, et al., J Immunol. 2001 ;166:1611-1617).
  • the CD4 + CD45RA + T cells (2.10 5 /well) were resuspended in 100 ⁇ l of fresh medium and mixed with 100 ⁇ l of DC supernatant.
  • Kynurenine measurements - DCs were stimulated with IFN- ⁇ (10 and 100 U/ml) alone or in combination with ATP or ATP ⁇ S during 24 h. Then cells were washed and resuspended in red- phenol free complete medium supplemented with 300 ⁇ M L-tryptophan. After 5 h supernatants were collected and kynurenine concentration was quantified by HPLC (Takikawa O, et al., J Biol Chem. 1986;261 :3648-3653).
  • Culture supernatants 400 ⁇ l were extracted with 80 ⁇ l of trichloroacetic acid 10 %, the precipitate was removed by centrifugation, and the supernatant was diluted in the initial mobile phase, composed of deionized water, 5% (v/v) methanol, 1 % (v/v) acetic acid and 5mM of hexane sulfonic acid.
  • Samples were injected onto a ⁇ Bondapak C18 reverse phase (3.9 x 300 mm, Waters, Milford, MA) and eluted with a linear gradient of methanol (5-40% over 35 min) at 1 ml/min. Absorbance was measured at 370 nm and compared against a standard curve of L-kynurenine.
  • Microarray experiments were performed to select relevant target genes in the gene expression profile of adenosine triphosphates in human monocyte-derived DCs.
  • ATP ⁇ S which is more resistant to degradation by ectonucleotidases, was used instead of ATP to avoid additional gene regulations due to its degradation products, more particularly ADP and adenosine.
  • Immature monocyte-derived DCs (10 ⁇ /ml) have been incubated during 6 h with or without ATP ⁇ S 100 ⁇ M.
  • RNAs were then extracted, amplified and labeled to hybridize an array containing 21.005 human sequences. The experiment has been reproduced for two independent donors.
  • Table 1 shows regulated sequences reflecting DC maturation: up- regulation of CXCR4, CCR7, CD83, CD86 mRNAs, and down-regulation of CCR1 , CCR5 and DC- STAMP mRNAs (Table 1 ).
  • RZPD AI682706 Hs.1652 CCR7 chemokine (C-C motif) receptor 7 3.9
  • Table 2 shows regulated genes involved in interactions between DCs and T lymphocytes such as interleukins (IL-10 and IL-23) or chemokines (CXCL10).
  • TSP-1 thrombospondin-1
  • IDO indoleamine 2,3-dioxygenase
  • ATP is a potent activator of TSP-1 release in human DCs
  • TSP-1 production from stimulated DCs was quantified by ELISA DCs were stimulated for various periods of time with ATP ⁇ S, PGE 2 and LPS These last two agents were chosen because LPS is a major DC maturation signal and PGE 2 displays similar effects as ATP in DCs, through cAMP activation As shown in Fig 1A and 1 B, ATP ⁇ S is more efficient than PGE 2 to stimulate TSP-1 release, whereas LPS had no effect Moreover, TSP-1 production was observed already after 3 h for ATP ⁇ S and rose to its maximum after 12 h of stimulation At 24 h of stimulation, PGE 2 effect represents 34 8 ⁇ 6 0% of the ATP ⁇ S effect which represents a peak of 10 ⁇ g/ml of TSP-1 (mean ⁇ S D of three independent experiments) In addition, concentration-action curves of ATP ⁇ S and the physiological hgand ATP have been compared (Fig 1 C) ATP ⁇ S was more potent than ATP with EC 50 values of 6 1 ⁇ 1 3 ⁇ M for
  • a third lower band was slightly regulated and is likely to correspond to the lower band detected with anti-TSP-1 antibody.
  • Intensities of bands A and B were sufficient to expect protein identification by mass spectrometry. They were excised and in-gel digested with trypsin. Peptide mass fingerprinting and microsequencing after fragmentation (sequenced peptide: N 1114 ALWHTGNTPGQVR 1127 ) permitted to unambiguously identify bands A and B as intact human TSP-1 , most probably with distinct post-translational modifications.
  • T cell activation was obtained using coated anti-CD3 mAb (10 ⁇ g/ml) alone (Fig.3A and B) - to mimic TCR activation - or in combination with soluble anti-CD28 mAb (1 ⁇ g/ml) (Fig. 3C 1 D 1 E 1 F, G) - to mimic full activation.
  • CD47 receptor mediates inhibitory effects of TSP-1 on T lymphocyte early activation and proliferation (Li Z et al., J Immunol. 2001 ;166:2427-2436.). Whether TSP-1 was one of the soluble factors responsible of the observed immunosuppressive effect mediated by ATP was evaluated: DCs supernatants were pre-incubated with an anti-human TSP-1 neutralizing antibody named C6.7 (Fig. 3E) which blocks binding of TSP-1 to CD47 receptors (Doyen V, et al., J Exp Med. 2003;198:1277-1283.).
  • Control experiments were also performed using supernatants of ATP-treated or untreated DCs preincubated during 30 min at room temperature with apyrase (50 U/ml) and/or adenosine deaminase (5 U/ml) to avoid any effect of residual ATP or degradation products such as ADP and adenosine.
  • apyrase 50 U/ml
  • adenosine deaminase 5 U/ml
  • IDO - an enzyme involved in the catabolism of tryptophan - was shown to be a target gene of ATP ⁇ S in our microarray experiments.
  • RT-PCR experiments confirmed that ATP ⁇ S and ATP - but not PGE 2 - were able to up-regulate IDO mRNA in monocyte-derived DCs (data not shown).
  • DCs treated with ATP ⁇ S 100 ⁇ M
  • Western blotting experiments were performed with a rabbit polyclonal antibody against human IDO.
  • Figure 4A shows that no detectable signal was observed with ATP ⁇ S or ATP alone whereas a signal was already detectable with 10 U/ml IFN- ⁇ . Strikingly ATP ⁇ S 100 ⁇ M and ATP 300 ⁇ M synergize with IFN- ⁇ , at both 10 U/ml and 100 U/ml, to upregulate IDO expression, ATP ⁇ S being more efficient.
  • TSP-1 and IDO are two major target genes strongly up-regulated by ATP ⁇ S and involved in immunotolerance.
  • stimulation of monocyte-derived DCs with extracellular ATP induces a strong and early expression and secretion of TSP-1 using microarray, ELISA and immunodetection.
  • Additional mass spectrometry analysis has revealed that different forms of intact TSP-1 were up-regulated by ATP ⁇ S.
  • the pharmacological profile supports the involvement of P2Yn receptor in ATP-mediated TSP-1 production.
  • ATP ⁇ S was more potent than ATP and comparable effects of other ATP derivatives like ARC-67085MX and BzATP, known agonists of P2Yn receptor were observed.
  • cAMP increase in TSP-1 production was highlighted by the effect of forskolin and PGE 2 - which elevates cAMP level through activation EP 2 receptors. Calcium-elevating agents were not able to induce any TSP-1 production or to potentiate PGE 2 -mediated TSP-1 production. The stronger effect of ATP ⁇ S and ATP on TSP-1 production could be explained by the activation of additional specific signal transduction proteins.
  • a proliferation assay was designed using supernatants from DCs treated or not with ATP. These experiments show that the high TSP-1 secretion by DCs in response to ATP leads to inhibition of T CD4 + cell proliferation through TSP-1 /CD47 interaction as demonstrated by the use an antibody blocking this interaction.
  • the observed IFN- ⁇ and IL-10 down-regulations suggest that ATP/DC conditioned medium affects proliferation of both Th1 and Th2 lymphocytes.
  • ATP is therefore able to induce immunotolerance indirectly through the activation of P2Y n receptors expressed on immature DCs and subsequent TSP-1 secretion.
  • P2Y n receptors expressed on immature DCs and subsequent TSP-1 secretion.
  • IDO protein - an intracellular enzyme involved in the catabolism of tryptophan Mellor AL, Munn DH. Nat Rev Immunol. 2004;4:762-774.; Grohmann U et al., Trends Immunol. 2003;24:242-248.
  • IDO has been shown to play a crucial role in tumoral immune resistance by depleting tryptophan locally and blocking the proliferation of alloreactive T lymphocytes (Uyttenhove C, et al., Nat Med. 2003;9: 1269-1274.). IDO up-regulation at the mRNA level in response to ATP alone was observed. However, the presence of IFN- ⁇ was necessary to observe the regulation of IDO protein and kynurenine production by ATP and ATP ⁇ S. In the present experiments - the high production of kynurenine (up to 150 ⁇ M) in response to ATP in combination with IFN- ⁇ is sufficient to induce human T cell immunosuppression through tryptophan metabolites.
  • the present examples demonstrate that ATP and derivatives thereof potentiates IDO regulation and induces high TSP-1 release from human DCs that consequently affects immunotolerance. Accordingly, it is possible to manipulate pharmacologically the immune tolerance at the level of DCs.
  • the compounds of formula (1 ) for use in the present invention are therefore particularly suitable vaccination adjuvant for inducing immunotolerance.

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Abstract

La présente invention concerne l'utilisation d'au moins un agoniste des récepteurs purinergiques et pyrimidinergiques de formule (I) pour la préparation d'un médicament servant à induire l'immunotolérance à un antigène, où B1 est sélectionné dans le groupe comprenant les groupes adénine, uracile, thymine, cytosine, guanine, xanthine et hypoxanthine, facultativement substitués par un groupe thioalkyle, thioaryle ou thioalkylaryle, R1 et R2 représentent chacun indépendamment OH, H, OR7, OCOR7, OCOR7COR7, où R7 représente un groupe alkyle ou aryle et X répond à la formule (II), (III) ou (IV), où R10 représente un hydrogène ou répond à la formule (VII), où B2 est sélectionné dans le groupe comprenant les groupes adénine, uracile, thymine, cytosine, guanine, xanthine et hypoxanthine, facultativement substitués par un groupe thioalkyle, thioaryle ou thioalkylaryle, où n est 0, 1, 2, 3 ou 4 et où R4, R4a et R4b représentent chacun indépendamment un groupe O, NH, alkylène, monohalogénoalkylène ou dihalogénoalkylène et R3, R5, R6, R8, R9 représentent chacun indépendamment OH ou SH et où R11 et R12 représentent chacun indépendamment OH, H, OR7, OCOR7, OCOR7COR7, où R7 est tel que défini ci-dessus.
PCT/EP2006/007966 2005-08-12 2006-08-11 Utilisation d'agonistes des récepteurs purinergiques et pyrimidinergiques pour des immunothérapies à base de cellules dendritiques Ceased WO2007020018A1 (fr)

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JP2012107007A (ja) * 2010-10-28 2012-06-07 Medeinetto:Kk 抗原提示細胞の調製方法
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US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
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US10370401B2 (en) 2013-10-11 2019-08-06 Janssen Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof
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WO2021046355A1 (fr) 2019-09-05 2021-03-11 Mitorainbow Therapeutics, Inc. Traitement de troubles d'épuisement de l'adn mitochondrial
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