WO2011051657A1 - Protéine a comme adjuvant de vaccin - Google Patents

Protéine a comme adjuvant de vaccin Download PDF

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Publication number
WO2011051657A1
WO2011051657A1 PCT/GB2010/001976 GB2010001976W WO2011051657A1 WO 2011051657 A1 WO2011051657 A1 WO 2011051657A1 GB 2010001976 W GB2010001976 W GB 2010001976W WO 2011051657 A1 WO2011051657 A1 WO 2011051657A1
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tslp
antigen
antigenic agent
increase
polynucleotide encoding
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PCT/GB2010/001976
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English (en)
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Robin J. Shattock
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St George's Hospital Medical School
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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
    • 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
    • A61K39/12—Viral antigens
    • 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
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/55522—Cytokines; Lymphokines; Interferons
    • 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
    • A61K2039/55583—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the invention relates to adjuvants for antigens. BACKGROUND OF THE INVENTION
  • the immune system is able to respond to, for example, infection by a pathogen or to the development of cancer in an antigen-specific manner.
  • Vaccination with appropriate antigens can thus be used to prevent or treat infections and cancer.
  • administration of the antigen alone to an individual is often insufficient to cause the development of an effective immune response to that antigen.
  • Induction of an immune response to an antigen often requires the use of an adjuvant, an agent that may typically stimulate the immune system and increase the response to an antigen, without having any specific antigenic effect in itself.
  • an adjuvant may initiate, accelerate, modulate, prolong, magnify and/or change the specific nature of antigen-specific immune responses when used in combination with specific antigens.
  • co-administration of an adjuvant with an antigen may result in a lower dose or fewer doses of antigen being necessary to achieve a desired immune response in the subject to which the antigen is administered, or co-administration may result in a qualitatively and/or quantitavely different immune response in the subject.
  • the mode of action of current vaccine adjuvants is complex. Most licensed adjuvants are thought to work through indirect activation of the immune system via induction of different types of inflammation.
  • the major means by which adjuvants may exert their activities are: (i) presentation of the antigen, defined by the physical appearance of the antigen in the vaccine; (ii) antigen/adjuvant uptake; (iii) distribution (targeting to specific cells); (iv) immune potentiation/modulation which includes activities that regulate both quantitative and qualitative aspects of the immune responses; (v) the protection of the antigen from degradation and elimination.
  • Currently used vaccine adjuvants include:
  • Inorganic compounds such as aluminium salts (e.g. aluminium hydroxide and aluminium phosphate) or calcium phosphate.
  • Oil emulsions and surfactant based formulations e.g. MF59 (microfluidised detergent stabilised oil-in- water emulsion), QS21 (purified saponin), AS02
  • Particulate adjuvants e.g. virosomes (unilamellar liposomal vehicles incorporating e.g. influenza haemagglutinin), AS04 ([SBAS4] Al salt with MPL), ISCOMS (structured complex of saponins and lipids), and polylactide co- glycolide (PLG).
  • virosomes unilamellar liposomal vehicles incorporating e.g. influenza haemagglutinin
  • AS04 [SBAS4] Al salt with MPL
  • ISCOMS structured complex of saponins and lipids
  • PLG polylactide co- glycolide
  • Microbial derivatives naturally and synthetic, e.g. monophosphoryl lipid A (MPL), Detox (MPL + M. Phlei cell wall skeleton), AGP [RC-529] (synthetic acylated monosaccharide), DC_Chol (lipoidal immunostimulators able to self organise into liposomes), OM- 174 (lipid A derivative), CpG motifs (synthetic oligonucleotides containing immunostimulatory CpG motifs), and modified LT and CT (genetically modified bacterial toxins to provide non-toxic adjuvant effects).
  • MPL monophosphoryl lipid A
  • Detox MPL + M. Phlei cell wall skeleton
  • AGP [RC-529] synthetic acylated monosaccharide
  • DC_Chol lipoidal immunostimulators able to self organise into liposomes
  • OM- 174 lipid A derivative
  • CpG motifs synthetic oligonucleotides containing immunostimulatory
  • Endogenous human immunomodulators e.g. hGM-CSF or hIL-12 (cytokines that can be administered either as protein or plasmid encoded), and Immudaptin
  • Inert vehicles such as gold particles.
  • Aluminium salts are the most common adjuvants in human vaccines. These salts are unfavorable since they develop their effect by inducing local inflammation, which is also the basis for the extended side-effect pattern of this adjuvant. Many pathological infections occur across mucosal membranes where IgA antibodies represent the first line of immunological adaptive defence against infection by viruses and bacteria. The identification of safe adjuvants for mucosal use remains a scientific priority. The most potent experimental mucosal adjuvants are considered to be too dangerous for routine use in humans; a typical example would be the use of cholera toxin and associated toxin derivatives.
  • the invention provides a composition comprising an antigenic agent and, as an adjuvant, thymic stromal lymphopoietin (TSLP) or a polynucleotide encoding TSLP.
  • TSLP thymic stromal lymphopoietin
  • the invention also provides TSLP or a polynucleotide encoding TSLP for use in a method of modulation of an immune response to an antigenic agent.
  • the invention further provides an antigenic agent and TSLP or a polynucleotide encoding TSLP for simultaneous or sequential use in a method of modulation of an immune response to said antigenic agent.
  • the invention also provides a method of modulation of an immune response to an antigenic agent in a subject, comprising administering to the subject TSLP or a polynucleotide encoding TSLP
  • Figure 1 shows the prime-boost-boost immunization regime and sampling protocol used in experiment 1.
  • FIG. 2 shows that TSLP promotes strong serum IgA and IgG responses to gpl40 (equivalent to that seen against cholera toxin - CT) following intranasal (IN) immunization (open symbols).
  • IgA intradermal
  • FIG. 2 shows that TSLP promotes strong serum IgA and IgG responses to gpl40 (equivalent to that seen against cholera toxin - CT) following intranasal (IN) immunization (open symbols).
  • TSLP, APRIL, BAFF pro B-cell factors
  • APRIL intradermal
  • IgA responses were significantly lower than those seen with IN immunization.
  • Data represent endpoint antibody titres at week 9 following prime-boost-boost vaccination (at weeks 0, 3 and 6).
  • FIG. 3 shows that TSLP promotes strong mucosal IgA responses to gpl40 following intranasal (IN) immunization (open symbols) in vaginal, nasal and rectal mucosae and potent IgG responses in vaginal and rectal compartments. These responses were equivalent to those seen with cholera toxin (CT). Addition of pro B-cell factors did not enhance the response seen with chitosan. In contrast, while intradermal (ID) immunization (closed symbols) induced IgG responses to gpl40 in vaginal and rectal lavage, IgA responses were low or absent.
  • ID intradermal
  • Figure 4 shows that TSLP induces gpl40-specific immune response following intranasal (IN) immunization. This response was comparable to that seen with chitosan.
  • the pro B-cell factors APRIL and BAFF did not induce a response ( Figure 4A and B).
  • systemic IgA responses were lower than those observed for intranasal immunization with gpl40 with TSLP or chitosan.
  • TSLP, APRIL, BAFF or chitosan induced vaginal IgA response to gpl40 when intraderma (ID) immunization was carried out (Figure 4D).
  • Figure 5 shows that TSLP induces sustained humoral immune response to gpl40 following intranasal (IN) immunization three times at three week intervals and then given a fourth immunization 6 months later. Serum specific antibody levels were sustained for 6 months after the third immunization and there was minimal impact of a fourth immunization (Figure 5 A and B). Specific IgA and IgG levels in vaginal lavage of animals immunized intranasally (IN) with gpl40 plus TSLP or chitosan appeared to decrease slightly in the course of 6 months, but this was only significant for IgA with chitosan (p ⁇ 0.01 and IgG with TSLP (p ⁇ 0.05). Boosting at 6 months restored these responses to levels seen after the third boost at day 63 ( Figure 5C and D).
  • Figure 6 shows that the TSLP induces sustained cellular immune response to g l40 following intranasal ( ⁇ ) immunization three times at three week intervals and then given a fourth immunization 6 months later.
  • Chitosan and choler toxin (CT) significantly induced splenocyte T-cell proliferation responses to gpl40 ( Figure 6C).
  • the magnitude of the responses were in the following rank order CT>chitosan>TSLP ( Figure 6C). All three adjuvants induces significantly higher numbers of proliferating CD4+ T-cells that CD8+ T-cells (TSLP: PO.01;
  • This invention relates to the use of TSLP to initiate, accelerate, modulate, prolong, magnify and/or change an antigen-specific immune response when used in combination with a specific antigen (or antigenic agent).
  • a specific antigen or antigenic agent.
  • Such an antigen may be vaccine antigen or a tolerising antigen (a "tolerogen", e.g. an allergen).
  • a tolerising antigen e.g. an allergen.
  • the human origin of TSLP and its defined molecular activity suggest that it will be safe for use as adjuvant given either by injection or, preferably, when applied via mucosal surfaces (e.g. intranasal, vaginal, rectal, sublingual).
  • the use of TSLP as a specific molecular adjuvant avoids the potential adverse reactogenicity associated with existing, non-specific adjuvants.
  • the activity of TSLP appears to be unique in that proteins in the same pathway, BAFF and APRIL, do not appear to augment mucos
  • Thymic stromal lymphopoietin is a hemopoietic cytokine that is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal and stromal-like cells. It is proposed to signal through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor (TSLP-R) and the IL-7R alpha chain (Quentmeier et al. (2001) Leukemia 15(8): 1286-92, and Pandey et al. (2000) Nat Immunol. l(l):59-64). It mainly affects myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of CD1 lc(+) dendritic cells.
  • TSLP-R thymic stromal lymphopoietin receptor
  • TSLP Localized production of TSLP is known to act on localized dendritic cell to cause the production of APRIL and/or BAFF (Wang et al. (2008) Cell mol Immunol. 5(2) 99-106) and this is thought to be the dominant mechanism for enhancement of antibody production.
  • TSLP has been previously associated with the development of asthma and other allergic conditions including dermatitis, and as such has been linked with pathological consequences.
  • the induction of allergy is likely to be multifactorial, involving the nature of the allergen, the context in which it is encountered and the genetic predisposition of the individual.
  • TSLP is unlikely to induce allergy on its own. Its potential use as an adjuvant has gone unrecognized, possibly partly due to its negative association with disease.
  • Alternative splicing of the human TSLP gene results in two transcript variants that each encode a different isoform of the TSLP protein. Isoform 2 is identical to the C-terminal sequence of the isoform 1:
  • This precursor sequence comprises an N-terminal signal sequence
  • MFPFALLYVLSVSFRKIFILQLVGLVLT SEQ ID NO: 2
  • YDFTNCDFEKIKAAYLSTISKDLITYMSGT STEF NTVSCSNRPHCLTEIQ SLTFNPTAGCASLAKEMFAMKTi AALAIWCPGYSETQINATQAMKJ RR RKVTTNKCLEQVSQLQGLWRRFNRPLLKQQ (SEQ ID NO: 3)
  • Isoform 2 (NP_612561.2):
  • the mouse (Mus musculus) TLSP precursor sequence is as follows
  • the precursor sequence comprises an N-terminal signal sequence
  • MVLLRSLFILQVLVRMGLT SEQ ID NO: 6
  • YNFSNCNFTSIT IYCNIIFHDLTGDL
  • GA FEQIEDCESKPACLLKIEYYTL NPrPGCPSLPDKTFAPvRTREALNDHCPGYPETERNDGTQEMAQEVQNICL NQTSQILRLWYSFMQSPE (SED ID NO: 7)
  • the TSLP protein comprises SEQ NO: 1, 3, 4, 5 or 7 or a fragment of this sequence.
  • a fragment retains the ability to act as an adjuvant.
  • TSLP includes fragments thereof that have adjuvant activity (see below for a description of the level of such activity and how to measure it). These fragments are likely to bind to and/or modulate (e.g. inhibit or stimulate) TSLP-R and/or the IL-7R alpha chain.
  • a fragment may be at least 10%, such as at least 20%, at least 30%, at least 40% or at least 50%, preferably at least 60%, more preferably at least 70%, still more preferably at least 80%, even more preferably at least 90%
  • the TSLP protein (or fragment of) generally has a length of at least 10 amino acids, such as at least 20, 25, 30, 40, 50, 60, 80, 100, 120, 140 or 159 amino acids.
  • the sequence of the TSLP protein may have homology with any of SEQ ID NOs: 1, 3, 4, 5 or 7 mentioned above, such as at least 40% identity, preferably at least 60%, at least 80%, at least 90%, at least 95%, at least 97% or at least 99% identity, for example over the full sequence or over a region of at least 20, preferably at least 30, for instance at least 40, at least 50, at least 60, at least 80, at least 100, at least 120, or at least 140 or more contiguous amino acids.
  • Methods of measuring protein homology are well known in the art and it will be understood by those of skill in the art that in the present context, homology is calculated on the basis of amino acid identity (sometimes referred to as "hard homology").
  • the UWGCG Package (Devereux et al (1984) Nucleic Acids Research 12: 387-395) provides the BESTFIT program which can be used to calculate homology (for example used on its default settings).
  • the PILEUP and BLAST algorithms can be used to calculate homology or line up sequences (typically on their default settings), for example as described in Altschul S. F. (1993) J Mol Evol 36:290-300; Altschul, S, F et al (1990) J Mol Biol 215:403-10.
  • HSPs high scoring sequence pair
  • Extensions for the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached.
  • the BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.
  • the BLAST program uses as defaults a word length (W) of 11, the BLOSUM62 scoring matrix (see
  • the BLAST algorithm performs a statistical analysis of the similarity between two sequences; see e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90: 5873-5787.
  • One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance.
  • P(N) the smallest sum probability
  • a sequence is considered similar to another sequence if the smallest sum probability in comparison of the first sequence to the second sequence is less than about 1, preferably less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.
  • the homologous protein typically differs from the original sequence by substitution, insertion or deletion, for example from 1, 2, 3, 4, 5 to 8 or more substitutions, deletions or insertions.
  • the substitutions are preferably
  • the TSLP protein (as described above) may be utilised in the invention in the form of a purified or recombinant protein.
  • the recombinant TSLP protein is fused to the chosen antigen/allergen.
  • the TSLP protein may be comprised as part of vector delivery system, such as a viral or bacterial delivery system or a liposome (for a review of such delivery systems see, for example, Liu at al (2004) PNAS 5; 101 Suppl 2: 14567-71).
  • the TSLP protein may be expressed from a polynucleotide, such as a DNA expression construct, which may optionally be included in a vector delivery system (such as a viral or bacterial delivery system or a liposome).
  • a polynucleotide must be able to give rise to in vivo expression of the antigen or antigens encoded therein.
  • a polynucleotide that "encodes" a selected antigen is a nucleic acid molecule which is transcribed (in the case of DNA) and translated (in the case of mR A) into a polypeptide in vivo or in vitro when placed under the control of appropriate regulatory sequences.
  • the boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxy) terminus.
  • a transcription termination sequence may be located 3' to the coding sequence.
  • a promoter may be located 5' to the coding sequence.
  • a “promoter” is a nucleotide sequence which initiates and regulates transcription of a polypeptide-encoding polynucleotide.
  • Promoters can include inducible promoters (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), repressible promoters (where expression of a polynucleotide sequence operably linked to the promoter is repressed by an analyte, cofactor, regulatory protein, etc.), and constitutive promoters. It is intended that the term "promoter” includes full- length promoter regions and functional (e.g. controls transcription or translation) segments of these regions.
  • an "antigen” refers to any agent, generally a macromolecule, which can elicit or modulate an immunological response in an individual.
  • the term may be used to refer to an individual macromolecule or to a homogeneous or heterogeneous population of antigenic macromolecules.
  • Antigens include vaccine antigens, antigens administered to induce acquired immunity in the recipient, including antigens derived from pathogenic cells or viruses or derived from tumour cells. Preferably such antigens are found on the surface of the pathogen or the tumour cell.
  • a pathogen is a cell or virus that causes disease or illness in a host, preferably a mammalian host, preferably a human.
  • Antigens also include tolerising antigens (or "tolerogens") that are antigens that induce a state of specific immunological unresponsiveness to subsequent challenging doses of the antigen. This state is known as "induced immune tolerance”.
  • tolerogens include allergens (non-self and non-parasitic antigens that can cause allergy) and self antigens associated with autoimmune disease (for a review of tolerance strategies for the prevention and treatment of autoimmune disease see, for example, Miller at al (2007) Nat Rev Immunol 7(9): 665-77) 6
  • an “antigenic agent” refers to an antigen itself or an agent that gives rise to the antigen, such as a polynucleotide encoding a protein antigen (e.g. a DNA
  • Antigens are usually proteins, glycoproteins or polysaccharides. This includes components, such as coats, capsules, cell walls, flagella, fimbrae, and toxins, of bacteria, viruses, and other microorganisms. Lipids and nucleic acids are usually only antigenic when combined with proteins and polysaccharides.
  • a protein antigen may comprise, for instance, a naturally occurring polypeptide, a fragment of such a polypeptide which is immunogenic or a variant form of either which retains immunogenicity.
  • the immune response generated may preferably be capable of recognizing the original polypeptide from which the fragment or variant is derived.
  • Vaccine antigens may be prepared in the following ways:
  • the vaccine antigen to be used in the invention may derive from a pathogen such as, but not limited to, bacteria, including M.tuberculosis, Chlamydia,
  • N. gonorrhoeae Shigella, Salmonella, Vibrio Cholera, Treponema pallidua, Pseudomonas, Bordetella pertussis, Brucella, Franciscella tulorensis,
  • Helicobacter pylori Helicobacter pylori, Leptospria interrogans, Legionella pnumophila, Yersinia pestis, Streptococcus (types A and B), Pneumococcus, Meningococcus,
  • Hemophilus influenza type b
  • Toxoplama gondii Complybacteriosis
  • Moraxella catarrhalis Moraxella catarrhalis
  • Donovanosis and Actinomycosis
  • fungal pathogens including Candidiasis and Aspergillosis
  • parasitic pathogens including Taenia, Flukes, Roundworms, Flatworms, Amebiasis, Giardiasis, Cryptosporidium, Schitosoma, Pneumocystis carinii, Trichomoniasis and Trichinosis.
  • the vaccine antigen is derived from a virus, preferably from a member of the adenoviridae (including for instance a human adenovirus), Caliciviridae (such as Norwalk virus group), herpesviridae (including for instance HSV- 1 , HSV-2, EBV, CMV and VZV),papovaviridae (including for instance Human Papilloma Viruse - HPV), poxviridae (including for instance smallpox and vaccinia), parvoviridae (including for instance parvovirus B 19), reoviridae (including for instance a rotavirus), coronaviridae (including for instance SARS), flaviviridae (including for instance yellow fever, West Nile virus, dengue, hepatitis C and tick-borne encephalitis), picornaviridae (including enteroviruses, polio, rhinovirus, and hepatitis A), togaviridae (including for instance
  • the antigen is derived from a pathogen that infects through a) the respiratory tract, b) the genito-urinary system or c) the gastrointestinal tract.
  • pathogens include a) members of the adenoviridae,
  • Haemophilus ducreyi herpes simplex virus, HPV, HIV, Candida albicans, Treponema pallidum, and Calmatobacterium granulomatis, and c) Shigella, Salmonella, Vibrio Cholera, E.coli, Entamoeba histolytica, Campylobacter, Clostridium, Yersinia, rotavirus, norovirus, adenovirus, astrovirus, Roundworms, Flatworms, Giardiasis, and Cryptosporidium.
  • the viral antigen may be from a retroviradae, more preferably from a lentivirus.
  • the antigen may be a human immunodeficiency virus (HTV) antigen, derived from HTV-1 or HIV-2.
  • HTV human immunodeficiency virus
  • preferred HIV antigens include, for example, gpl20, gp 140, gp 160 gp41, gag antigens such as p24gag and p55gag, as well as proteins derived from the pol, env, tat, vif, rev, nef, vpr, vpu or LTR regions of HIV.
  • the antigen may be HIV gp 140 or a portion of HIV gpl40.
  • the viral antigen may be from influenza.
  • Influenza antigens include the HA (hemagglutinin), NA (neuraminidase), NP (nucleoprotein/nucleocapsid protein), Ml, M2, PB1, PB2, PA, NS1 andNS2 antigens and in particular the HA, NA and M2 antigens.
  • the antigen may be a fragment or variant of such antigens.
  • the antigen may also be used to provide a suitable immune response against numerous veterinary diseases, such as Foot and Mouth diseases, Coronavirus, Pasteurella multocida, Helicobacter, Strongylus vulgaris, Actinobacillus pleuropneumonia, Bovine viral diarrhea virus (BVDV), Klebsiella pneumoniae, E. coli, Bordetella pertussis, Bordetella parapertussis, Bordetella brochiseptica, Reo virus (such as African Horse sickness or Bluetongue virus), Herpes viruses (including equine herpes), tick borne encephalitis virus, dengue virus, SARS, West Nile virus, Hantaan virus, SIV or a feline immunodeficiency virus.
  • BVDV Bovine viral diarrhea virus
  • the vaccine antigen to be used in the invention may derive from a tumour antigen such as, but not limited to, those derived from cancers of the lung, pancreas, bowel, colon, breast, uterus, cervix, ovary, testes, prostate, melanoma, Kaposi's sarcoma, a lymphoma (e.g. EBV-induced B-cell lymphoma) and a leukaemia.
  • a tumour antigen such as, but not limited to, those derived from cancers of the lung, pancreas, bowel, colon, breast, uterus, cervix, ovary, testes, prostate, melanoma, Kaposi's sarcoma, a lymphoma (e.g. EBV-induced B-cell lymphoma) and a leukaemia.
  • tumour associated antigens include, but are not limited to, cancer-testes antigens such as members of the MAGE family (MAGE 1, 2, 3 etc), NY-ESO-1 and SSX-2, differentation antigens such as tyrosinase, gplOO, PSA, Her-2 and CEA, mutated self antigens and viral tumour antigens such as E6 and/or E7 from oncogenic HPV types.
  • cancer-testes antigens such as members of the MAGE family (MAGE 1, 2, 3 etc), NY-ESO-1 and SSX-2
  • differentation antigens such as tyrosinase, gplOO, PSA, Her-2 and CEA
  • mutated self antigens such as E6 and/or E7 from oncogenic HPV types.
  • tumour antigens include MA T-1, Melan-A, p97, beta-HCG, GaT Ac, AGE-1, MAGE-2, MAGE-4, MAGE- 12, MUC1, MUC2, MUC3, MUC4, MUC18, CEA, DDC, PI A, EpCam, melanoma antigen gp75, Hker 8, high molecular weight melanoma antigen, K19, Tyrl, Tyr2, members of the pMel 17 gene family, c-Met, PSM (prostate mucin antigen), PSMA (prostate specific membrane antigen), prostate secretary protein, alpha-fetoprotein, CA125, CA19.9, TAG-72, BRCA-1 and BRCA-2 antigen Tolerogens
  • Tolerogens include allergens: non-self and non-parasitic antigens that can cause allergy.
  • Allergens include animal products such as antigens derived from cats (e.g. Fel dl), fur, dander, cockroach calyx, wool and dust mite excretion, drugs such as penicillin, sulfonamides, salicylates and local anaesthetics, foods such as celery, celeriac, corn, maize, eggs, fruit (e.g. pumpkin), legumes (e.g. beans, peas, peanuts, soybeans), milk, seafood, sesame, soy, tree nuts (e.g. pecans and almonds) and wheat, insect stings (e.g.
  • Tolerogens also include self antigens associated with autoimmune disease. For example, myelin basic protein (MBP) is associated with multiple sclerosis, insulin is associated with type-1 diabetes, and collagen II is associated with rheumatoid arthritis.
  • MBP myelin basic protein
  • the invention provides a method of modulating (e.g. enhancing or potentiaiting) an immune response to an antigenic agent in a subject comprising administering TSLP or a polynucleotide encoding TSLP simultaneously or sequentially with an antigenic agent.
  • the terms “individual” and “subject” are used interchangeably herein to refer to any member of the subphylum cordata, including, without limitation, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs as well as pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • the terms do not denote a particular age. Thus, both adult and newborn individuals are intended to be covered.
  • the methods described herein are intended for use in any of the above vertebrate species, since the immune systems of all of these vertebrates operate similarly.
  • the invention may be administered to any suitable subject and in particular any suitable subject of a given species, preferably a suitable human subject.
  • any suitable subject may, for instance, be subject to administration without emphasis on any particular group of subjects.
  • a population of subjects as a whole, or as many as possible, may be subject to administration. 01976
  • the TSLP protein adjuvant of the invention may be administered simultaneously or sequentially with an antigenic agent.
  • composition of the invention may be one which is to be delivered by injection (such as intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal), transdermal particle delivery, inhalation, topically, orally or transmucosally (such as nasal, sublingual, vaginal or rectal).
  • injection such as intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal
  • transdermal particle delivery inhalation, topically, orally or transmucosally (such as nasal, sublingual, vaginal or rectal).
  • transmucosally such as nasal, sublingual, vaginal or rectal.
  • the composition is to be delivered by needleless injection or
  • compositions may be formulated as conventional pharmaceutical
  • compositions containing the TSLP protein (or polynucleotide encoding it) and/or the antigenic agent can be combined with one or more pharmaceutically acceptable excipients or vehicles to provide a liquid preparation.
  • a pharmaceutical composition comprising an antigenic agent and, as an adjuvant, a TSLP protein or a polynucleotide encoding a TSLP protein, together with a pharmaceutically acceptable carrier or diluent.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like, may be present.
  • compositions are generally pharmaceutical agents which may be administered without undue toxicity and which, in the case of antigenic compositions will not in themselves induce an immune response in the individual receiving the composition.
  • Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, polyethyleneglycol, hyaluronic acid, glycerol and ethanol.
  • Pharmaceutically acceptable salts can also be included therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • the preparation will contain a pharmaceutically acceptable carrier that serves as a stabilizer, particularly for peptide, protein or other like molecules if they are to be included in the composition.
  • suitable carriers that also act as stabilizers for peptides include, without limitation, pharmaceutical grades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, and the like.
  • Other suitable carriers include, again without limitation, starch, cellulose, sodium or calcium phosphates, citric acid, tartaric acid, glycine, high molecular weight polyethylene glycols (PEGs), and combination thereof.
  • transfection facilitating agents can also be included in the compositions, for example, facilitators such as bupivacaine, cardiotoxin and sucrose, and transfection facilitating vehicles such as liposomal or lipid preparations that are routinely used to deliver nucleic acid molecules.
  • facilitators such as bupivacaine, cardiotoxin and sucrose
  • transfection facilitating vehicles such as liposomal or lipid preparations that are routinely used to deliver nucleic acid molecules.
  • Anionic and neutral liposomes are widely available and well known for delivering nucleic acid molecules (see, e.g.,
  • Cationic lipid preparations are also well known vehicles for use in delivery of nucleic acid molecules. Suitable lipid preparations include DOTMA (N-[l-(2,3- dioleyloxy)propyl]-N,N,N-trimemylammomum chloride), available under the tradename LipofectinTM , and DOTAP (l,2-bis(oleyloxy)-3- (trimethylammonio)propane), see, e.g., Feigner et al. (1987) Proc. Natl. Acad. Sci. USA 84:7413-7416; Malone et al. (1989) Proc. Natl.
  • cationic lipids may preferably be used in association with a neutral lipid, for example DOPE (dioleyl phosphatidylethanolamine).
  • DOPE dioleyl phosphatidylethanolamine
  • transfection-facilitating compositions that can be added to the above lipid or liposome preparations include spermine derivatives (see, e.g., International Publication No. WO 93/18759) and
  • membrane-permeabilizing compounds such as GALA, Gramicidine S and cationic bile salts (see, e.g., International Publication No. WO 93/19768).
  • the TSLP protein (or polynucleotide encoding it) and/or the antigenic agent may be encapsulated, adsorbed to, or associated with, particulate carriers.
  • suitable particulate carriers include those derived from polymethyl methacrylate polymers, as well as PLG microparticles derived from poly(lactides) and poly(lactide-co-glycolides). See, e.g., Jeffery et al. (1993) Pharm. Res.
  • particulate systems and polymers can also be used, for example, polymers such as polylysine, polyarginine, polyornithine, spermine, spermidine, as well as conjugates of these molecules.
  • polymers such as polylysine, polyarginine, polyornithine, spermine, spermidine, as well as conjugates of these molecules.
  • polynucleotides can be precipitated onto carriers in the presence of a
  • polynucleotide condensing agent and a metal ion chelating agent.
  • Preferred condensing agents include cationic polymers, in particular polyamines, and in particular a polyargine or a polylysine. In a preferred instance the polyamine is (Arg)4 or (Arg)6.
  • the compositions can be delivered to a subject in vivo using a variety of known routes and techniques.
  • the liquid preparations can be provided as an injectable solution, suspension or emulsion and administered via parenteral, subcutaneous, intradermal, intramuscular, intravenous intraosseous and intraperitoneal injection using a conventional needle and syringe, or using a liquid jet injection system.
  • Liquid preparations can also be administered topically to skin or mucosal tissue (e.g. nasal, sublingual, vaginal or rectal), or provided as a finely divided spray suitable for respiratory or pulmonary administration.
  • Other modes of administration include oral administration, suppositories, and active or passive transdermal delivery techniques.
  • the TSLP protein is administered to a subject in an amount that will be effective in modulating an immune response to an antigenic agent.
  • An appropriate effective amount will fall in a relatively broad range but can be readily determined by one of skill in the art by routine trials.
  • an effective dose in mammals for example in humans, would be between and lOmg, such as between and lOmg, between ⁇ g and lmg, between ⁇ g and 500 g, between ⁇ g and 50 ⁇ , between 5 ⁇ g and lOmg, between 5 ⁇ g and lmg, between 5 ⁇ g and 500 ⁇ g 3 between 5 ⁇ g and 50 ⁇ g, between 50 ⁇ g and lOmg, between 50 ⁇ g and lmg or, preferably, between 50 ⁇ g and 500 ⁇ g.
  • a subsequent administration of the composition of the invention may be performed.
  • a subject may be given a "booster".
  • the booster may be, for instance, a dose chosen from any of those mentioned herein.
  • the booster administration may, for instance, be at least a week, two weeks, four weeks, six weeks, a month, two months or six months after the initial administration.
  • the TSLP protein (or polynucleotide encoding it) and the antigenic agent of the invention may be administered sequentially or simultaneously, preferably simultaneously.
  • the two entities may be administered in the same or different compositions, preferably the same composition.
  • the TSLP protein (or polynucleotide encoding it) will be delivered so that an adjuvant effect is seen, that is the immune response seen will differ from that if the adjuvant had not been administered with the antigen.
  • the two entities may be administered at the same or different sites, preferably the same sites.
  • the two entities are administered in the same composition at the same site at the same time preferably via intranasal or sublingual aciministration.
  • an "immune response" against an antigen of interest is the development in an individual of a humoral and/or a cellular immune response to that antigen.
  • a “humoral immune response” refers to an immune response mediated by antibody molecules, while a “cellular immune response” is one mediated by T-lymphocytes and/or other white blood cells.
  • This invention relates to the use of TSLP to initiate, accelerate, modulate, prolong, magnify and/or change the specificity of an antigen-specific immune response when used in combination with a specific antigen.
  • TSLP is used to enhance or potentiate an antibody response, preferably to increase antigen-specific antibody concentration (or titre).
  • TSLP is used to increase antigen-specific antibody concentration in the serum and/or at the mucosae, preferably at the mucosae, even more preferably at the respiratory tract and/or the vaginal and/or rectal mucosae, even more preferably at the vaginal and rectal mucosae.
  • the antigen-specific antibodies described above are IgG and/or IgA, preferably IgA.
  • the antibody response (e.g. as measured by antigen-specific antibody concentration) to an antigen that is produced with TSLP as an adjuvant is greater than that produced without TSLP as an adjuvant, preferably at least 10%, at least 20%, at least 50%, or at least 100% greater. Even more preferably, the antibody response with TSLP as an adjuvant is at least 3, at least 5, at least 10, at least 10 2 , at least 10 3 , at least 10 4 or at least 10 5 times that produced without TSLP as an adjuvant.
  • the antibody response (e.g. increase in antigen-specific antibody concentration) to an antigen produced using TSLP as an adjuvant is at least 10%, at least 20%, at least 30%, at least 40%), at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of that produced using chitosan as an adjuvant. More preferably the antibody response to an antigen produced using TSLP as an adjuvant is equal to that produced using chitosan as an adjuvant. More preferably, the antibody response to an antigen produced using TSLP as an adjuvant is greater than that produced using chitosan as an adjuvant, preferably at least 10%, at least 20%, at least 50% or at least 75% greater.
  • the antibody response to an antigen produced using TSLP as an adjuvant is at least 2, at least 3, at least 5, at least 10, at least 20 or at least 100 times greater than that produced using chitosan as an adjuvant.
  • the antibody response to an antigen produced using TSLP as an adjuvant is between 25% and 1000% (e.g. 25 % and 500% or 25% and 250%) of that produced using chitosan as an adjuvant, more preferably between 50% and 150%.
  • the comparison of antibody responses to an antigen produced using either TSLP or chitosan as an adjuvant may be carried out in a mouse using intranasal administration at 0, 3 and 6 weeks of antigen plus TSLP or antigen plus chitosan, with sampling at 9 weeks and with a dose of 100 g chitosan.
  • a TSLP protein is used to induce immune tolerance to an antigen (such as an allergen), meaning for example to stimulate formation of antigen-specific suppressor T lymphocytes that will suppress IgE synthesis in response to the antigen.
  • an antigen such as an allergen
  • kits of the invention are provided.
  • the invention further provides a kit comprising an antigenic agent and thymic stromal lymphopoietin (TSLP) or a polynucleotide encoding TSLP.
  • the kit may further comprise a pharmaceutically acceptable carrier or diluent.
  • the antigenic agent, TSLP and any additional carrier or diluent may be selected as described above. Any of the components of the kit may be supplied in solid form or in solution (e.g. aqueous solution.) EXAMPLES
  • Example 1 Experiments were performed in Balbc mice to determine whether TSLP, when given intranasally, could enhance the antibody response to a protein antigen, HIV-1 CN54 gpl40. Preliminary experiments were conducted using a prime- boost-boost immunization regime (applied at 0, 3 and 6 weeks). Serum and mucosal antibody responses were sampled prior to each immunization and at the end of the experiment (see Figure 1). Antigen-specific IgA and IgG levels in plasma, vaginal washes, faecal extracts and nasal lavages were determined by ELISA. Reciprocal endpoint litres were calculated by using GraphPad Prism 4.
  • the cut-off value was 0.1 for all samples with the exception of faecal samples where a cut-off of 0.5 was used.
  • Splenocytes were isolated from spleens and Antigen- specific IgA and IgG B-ELISPOT were performed or ex vivo T-cell proliferation was measured using CellTraceTM CFSE Cell Proliferation Kit, Invitrogen or by [ 3 H] thymidine incorporation into DNA.
  • Recombinant cytokines were purchased from R&D systems (for TSLP - Cat No 555-TS: Tyr20 to Glul40 of murine TSLP, with a C-terminal 10-His tag).
  • TSLP also promoted strong mucosal IgA responses to gpl40 following intranasal (IN) immunization in vaginal, nasal and rectal secretions, and potent IgG responses in vaginal and rectal compartments. Again these were comparable to chitosan and cholera toxin. Addition of pro B-cell factors did not enhance the response seen with chitosan. In contrast, while ID immunization induced IgG responses to gp 140 in vaginal and rectal lavage, IgA responses were low or absent (Figure 3).
  • TSLP was capable of inducing durable humoral and cellular responses to intranasal (IN) immunization with g l40.
  • IgA and IgG levels in vaginal lavage of animals immunized with gpl40 plus TSLP or chitosan appeared to decrease slightly in the course of 6 months, this trend was only significant fro the IgA with chitosan (pO.01 and IgG with TSLP (p ⁇ 0.05).
  • TSLP chitosan and cholera toxin significantly induced splenocyte T-cell proliferation response to gpl40 ( Figure 6C). Also, CD4 T-cell responses were greater than CD8 T-cell responses ( Figure 6D). While TSLP showed the lowest cellular responses, these were significantly greater than those with the antigen alone. Although previous studies have shown that systemic responses to Env rapidly wane in humans after each immunization, TSLP induced sustained systemic IgG and IgA responses in mice that showed no diminution over a six- month period.
  • TSLP works as a potent mucosal adjuvant.
  • the activity of TSLP appears to be unique in that its associated molecules BAFF and APRIL do not appear to augment mucosal immune responses when given alone (data not shown).
  • the ability of TSLP to induce potent systemic and mucosal IgA responses following mucosal application demonstrates a significant advantage over conventional parenteral (injection) approaches e.g. ease of (needle-free) administration. Surprisingly these responses were seen without any evidence of pathological consequences or the induction of IgE, a marker of allergic responses (data not shown).
  • IgE a marker of allergic responses
  • the antigen (gpl40) was administered at l( ⁇ g in all cases.
  • the following groups were included: Intranasal administration

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Abstract

L'invention porte sur une composition qui comporte un agent antigénique et, comme adjuvant, la lymphopoïétine stromale thymique (TSLP) ou un polynucléotide codant pour la TSLP. L'agent antigénique est généralement issu d'un pathogène tel qu'un pathogène qui infecte par le tractus respiratoire, le système uro-génital ou le système gastro-intestinal.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014162007A3 (fr) * 2013-04-04 2014-11-27 Ieo - Istituto Europeo Di Oncologia Srl Fragments de lymphopoïétine stromale thymique et utilisations associées
WO2017170712A1 (fr) * 2016-03-31 2017-10-05 国立大学法人東北大学 Adjuvant de composé à faible poids moléculaire et vaccin l'utilisant
CN114767847A (zh) * 2022-06-22 2022-07-22 深圳大学 新冠重组蛋白疫苗佐剂及其应用

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014162007A3 (fr) * 2013-04-04 2014-11-27 Ieo - Istituto Europeo Di Oncologia Srl Fragments de lymphopoïétine stromale thymique et utilisations associées
WO2017170712A1 (fr) * 2016-03-31 2017-10-05 国立大学法人東北大学 Adjuvant de composé à faible poids moléculaire et vaccin l'utilisant
CN114767847A (zh) * 2022-06-22 2022-07-22 深圳大学 新冠重组蛋白疫苗佐剂及其应用

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