WO2016209959A2 - Combinaisons de peptides et leur utilisation dans le traitement de l'allergie aux pollen de cèdre - Google Patents

Combinaisons de peptides et leur utilisation dans le traitement de l'allergie aux pollen de cèdre Download PDF

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WO2016209959A2
WO2016209959A2 PCT/US2016/038760 US2016038760W WO2016209959A2 WO 2016209959 A2 WO2016209959 A2 WO 2016209959A2 US 2016038760 W US2016038760 W US 2016038760W WO 2016209959 A2 WO2016209959 A2 WO 2016209959A2
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amino acid
seq
peptide
formula
peptides
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WO2016209959A3 (fr
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Claus Lundegaard
Peter Sejer Andersen
Alessandro Sette
Bjoern Peters
Veronique SCHULTEN
John Sidney
Lars Harder CHRISTENSEN
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Alk-Abelló A/S
La Jolla Institute For Allergy And Immunology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A61K39/36—Allergens from pollen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to T cell epitope-containing peptides/polypeptides derived from allergens of the genus Cryptomeria japonica and uses of such peptides for modulating an immune response, for treating an allergic response and/or for inducing or promoting immunological tolerance, mixes thereof and for use in diagnostic methods and kits.
  • allergen-specific immunotherapy based on pollen extract, which is administered to a subject over an extended period of time to induce a state of "tolerance" in the subject.
  • the mechanism of action is thought to involve induction of IgG inhibitory antibodies, suppression of mast cell/basophil reactivity, suppression of T-cell responses, the promotion of T-cell anergy, and/or clonal deletion, and in the long term, decrease in the levels of allergen specific IgE.
  • allergen-specific immunotherapy bears the risk of IgE-mediated adverse events, including serious anaphylactic responses.
  • smaller fragments derived from allergens typically the major allergens, where the smaller fragments (peptides) contain one or more epitopes recognized by T cells regulating the allergic reaction.
  • This concept has been termed peptide immunotherapy (PIT), in which repeated doses of the peptide are administered to a subject. More specifically, on the molecular level, peptides are bound by Human Leucocyte Antigen (HLA) class II on the surface of Antigen Presenting Cells (APC).
  • HLA Human Leucocyte Antigen
  • This peptide-HLA complex is then recognized by specific T-cell receptors on the cell surface of T-cells, which upon interaction with the APCs become activated.
  • a major difference between peptide-based immunotherapy and therapies based on full-length allergens is that this interaction is thought to occur without a concomitant antibody- mediated "danger signal" being elicited. This is thought to drive the T-cell response in a more tolerogenic direction.
  • PIT Peptide-based immunotherapy
  • immunotherapy products sometimes referred to as "allergy vaccines”
  • Peptide immunotherapies are today in clinical development and seem to have a safety profile that is similar to or better than whole allergen based immunotherapies.
  • a shortcoming of using peptides is associated with the restriction of each peptide to only bind a subset of the naturally occurring HLA Class II molecules within the human population. A mix of several peptides covering different HLA Class II molecules is therefore necessary to generate a broadly acting immunotherapy allergy treatment. As this repertoire of HLA Class II molecules varies from one person to another and from one ethnic population to another, it is challenging to provide peptide-based immunotherapies that can be effective in allergic subjects of any ethnic origin and any geographic region in the world unless numerous peptides are included in the immunotherapy product.
  • immunotherapy products that contain as few peptides as possible, but which at the same time are able to treat the majority of Japanese cedar pollen allergic subjects in any population using the same immunotherapy product.
  • T cell epitope containing peptides from Cry j 1 and Cry j 2 have previously been described in the art (see e.g. Sone et al 2009, Sone et al 1998, WO 95/27786, US 2005/0152927 and
  • peptide combinations comprising or consisting of a few peptides, such as three, four, five or six peptides, wherein the peptides in common cover a high fraction of the HLA Class II allele repertoire of a worldwide population, including particularly a Japanese population, produce a T cell response in a high fraction of a population allergic to Japanese cedar pollen and which importantly also are suitable for being used as a vaccine for treating allergy in that the peptides of the composition are found satisfactorily soluble in aqueous solution.
  • compositions may be assembled by - first providing a set of T cell epitope containing peptides of the most important allergens of Japanese cedar, Cry j 1 and Cry j 2 (for example as disclosed in Example 1),
  • Additional parameters which may be considered in the desire of providing optimal peptide combinations may be to estimate the average number of responding peptides per individual of a population because a peptide combination that in average produces a T cell response in an individual with two peptides is considered superior over a peptide combination that in average produces a T cell response with 1 peptide. Therefore, more optimal peptide compositions are considered to have a T cell response coverage of above 80% and a Responding peptides per donor of about 1.2 or above.
  • the present inventors have provided peptide combinations consisting as few as three peptides, which comply with the above-mentioned criteria.
  • peptide mix numbered 242 in Table 7a have a T cell response coverage of 100% and responding peptides per donor of 1.4 as shown in Table 7b (Measures and B). Further peptide combinations are provided in Table 7a throughout Table lib.
  • peptide combination for use as an "allergy vaccine” in the treatment of allergy to Japanese cedar, which combination is suitable for addressing the immune system of the majority of the world population, especially the Japanese population.
  • Such superior peptide combinations may be assembled using a limited number of distinct peptides derived from different regions of the Cry j 1 or Cry j 2 allergen. That is to say that the peptides do not have sequence overlap, or if present, then only with a few number of amino acid residues that would not give rise to the presence of a common T cell epitope. For example, one distinct peptide overlap with few amino acid residues of another distinct peptide such as overlapping with less than 9, 8, 7, 6, 5, amino acid residues.
  • the present invention relates in a first aspect, a composition comprising three peptides, which independently are 13 to 25 amino acid residues in length, wherein a first peptide is selected from group a) comprising peptides of either formula I or I*, a second peptide is selected from group b) comprising peptides of either formula II or II* and a third peptide is selected from group c) comprising peptides of group a) and b), wherein
  • a peptide of formula I has an amino acid sequence defined by: a-Al-Cl-Bl-b
  • a peptide of formula I* has an amino acid sequence defined by: a-Al-Cl*-Bl-b
  • a peptide of formula II has an amino acid sequence defined by: a-A2-C2-B2-b
  • a peptide of formula II* has an amino acid sequence defined by: a-A2-C2*-B2-b and wherein
  • - CI is an amino acid sequence selected from any one of SEQ ID NOs: 77, 48, 56 and 66,
  • - Cl* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in CI with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if CI* is shorter than CI ;
  • - C2 is an amino acid sequence selected from any one of SEQ ID NOs: 97, 107 and 125;
  • - C2* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C2 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C2* is shorter than C2;
  • - Al is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions;
  • - Bl is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions
  • - A2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - B2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ; and wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • a peptide composition of 3 peptides may be extended by further peptides to improve the T cell response coverage to above 80%, such as above 90% and with more responding peptides per donor, such as above 1.7, such as above 1.8, 1.9, 2.0. 2.1, 2.2, 2.3, 2.4 or above.
  • the present inventors have found a five peptide combination (Mix 153) having T cell response coverage of 100% and with responding peptides per donor of 2 (Tables 9a and b in combination), whereas a six peptide mix may be even better, for example the six peptide combination numbered 263 having T cell response coverage of 100% and with responding peptides per donor of 2.6 (Tables 10a and 10b in combination),
  • compositions comprising a first, second and third peptide, which also may comprise a fourth, fifth, sixth and/or further peptide, which peptide(s) independently are 13 to 25 amino acid residues in length, wherein any one of the fourth, fifth, sixth or further peptide is of either formula III or III* or formula IV or IV*, wherein
  • a peptide of formula III has an amino acid sequence defined by: a-A3-C3-B3-b
  • a peptide of formula III* has an amino acid sequence defined by: a-A3-C3*-B3-b
  • a peptide of formula IV has an amino acid sequence defined by: a-A4-C4-B4-b
  • a peptide of formula IV* has an amino acid sequence defined by: a-A4-C4*-B4-b and wherein
  • - C3 is an amino acid sequence selected from any one of SEQ ID NOs: 49, 59, or 64,
  • - C3* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C3 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C3* is shorter than C3;
  • - C4 is an amino acid sequence selected from any one of SEQ ID NOs: 14, 98, 100 or 113,
  • C4* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C4 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C4* is shorter than C4;
  • - A3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions;
  • - B3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions;
  • - A4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - B4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ;
  • C3, C3*, C4, or C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO as CI, CI*, C2, C2*, C3 or C3* or C4 or C4* as any other peptide in the composition.
  • the invention provides a pharmaceutical composition comprising a composition as defined herein.
  • the invention provides in another aspect a method for treating allergy to cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a composition as defined herein.
  • cedar and cypress pollen e.g. Japanese cedar pollen
  • the invention provides a composition as defined herein for use in the treatment of allergy to cedar and cypress pollen, e.g. Japanese cedar pollen allergy, in a subject in need thereof, and a composition as defined herein for the preparation of a medicament for the treatment of allergy to cedar and cypress pollen, e.g. Japanese cedar pollen allergy, in a subject in need thereof.
  • the invention provides in a further aspect, a method for relieving one or more symptoms of an immune response triggered by cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition described herein.
  • cedar and cypress pollen e.g. Japanese cedar pollen
  • the invention provides in a further aspect, a method for inducing immunological tolerance against cedar and cypress pollen, e.g. Japanese cedar pollen, comprising administering to the subject a therapeutically effective amount of a composition described herein.
  • compositions as defined herein for use in a method defined herein e.g. a composition as defined herein for use in relieving an immune response triggered by cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof; for use in relieving one or more symptoms of an immune response triggered by cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof; and/or for inducing immunological tolerance against cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof.
  • cedar and cypress pollen e.g. Japanese cedar pollen
  • the invention relates to the use of a composition as defined herein for the preparation of a medicament for use in a method defined herein, e.g. the use of a composition as defined herein for the preparation of a medicament for use in relieving an immune response triggered by cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof; for use in relieving one or more symptoms of an immune response triggered by cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof; and/or for inducing immunological tolerance against cedar and cypress pollen, e.g. Japanese cedar pollen, in a subject in need thereof.
  • cedar and cypress pollen e.g. Japanese cedar pollen
  • the invention provides an in vitro method of determining whether T cells of a subject in need of treatment recognize a composition as defined herein, comprising contacting T cells obtained from the subject with the peptide combination or single peptides thereof and detecting whether the T cells are stimulated by the peptides.
  • the invention relates to a kit comprising a compartment and instructions, wherein the compartment comprises a composition described herein and wherein the instructions are for use in treating allergy to cedar and cypress pollen, e.g. Japanese cedar pollen,.
  • the invention relates to a method of determining whether T cells of a subject in need of treatment recognize a composition as defined herein, comprising contacting T cells obtained from the subject with said composition or a single peptide thereof and detecting whether the T cells are stimulated by said composition or single peptide.
  • the invention relates to a diagnostic kit comprising a composition defined herein.
  • peptide denotes an individual (e.g. isolated) amino acid molecule having a sequence length of about 13 to 25 amino acid residues.
  • an “epitope” refers to a region or part of an antigen, such as a peptide disclosed herein, that elicits an immune response when administered to a subject.
  • An epitope may be a T cell epitope, i.e., an epitope that elicits, stimulates, induces, promotes, increases or enhances a T cell activity, function or response. For example a Th2 cell epitope.
  • Any peptide or combination of peptides of interest can be analyzed to determine whether they include at least one T cell epitope using any number of assays (e.g. T cell proliferation assays, lymphokine secretion assays, T cell non-responsiveness studies, etc.).
  • assays e.g. T cell proliferation assays, lymphokine secretion assays, T cell non-responsiveness studies, etc.
  • allergen refers to an antigen which elicits, induces, stimulates, or enhances an immune response by a cell of the immune system of an exposed animal (e.g., human).
  • An antigen is an allergen when the specific immune response is the development of enhanced sensitivity or a hypersensitivity to the antigen, but the antigen itself is not typically innately harmful.
  • An allergen is therefore a particular type of antigen that can cause development of enhanced or increased sensitivity or hypersensitivity in a subject.
  • an allergen can elicit production of IgE antibodies in predisposed subjects.
  • An allergen is an allergenic protein.
  • a "region" of an allergen is to be understood as a stretch of contiguous amino acids in the allergen.
  • one peptide is derived from the same region of an allergen as another peptide, it is to be understood as both peptides aligning to the same region of that allergen.
  • T cell response refers to an interleukin or a proliferation response by a T cell. It may be determined as explained in Example 1. It may in some instances be referred to simply as a "response” to a peptide.
  • allergic response is intended to refer to the hypersensitive immune reaction to a normally innocuous environmental substance known as an allergen. The most common mechanism of allergic reactions is the binding of IgE to the su rface of mast cells, which causes asthma, hay fever and other common allergic reactions
  • subject or “individual” is intended to refer to a mammal, in particular to a human being or a person, but the individual may also be an animal, such as a cat, dog, horse.
  • CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide is herein meant that a third peptide is not composed from the same SEQ ID NO selected for CI of the first peptide and not composed from the same SEQ ID NO selected for C2 of the second peptide.
  • a first, second and third peptide is considered distinct in relation to each other.
  • a fourth, fifth and sixth and any further peptide in a composition is considered distinct in relation to each other and any other peptide of the composition.
  • a reference amino acid sequence e.g. CI, C2, C3 or C4
  • the amino acid sequence relates to the reference amino acid sequence if it is either shorter (e.g. a fragment of CI, C2, C3 or C4) or longer (e.g. extended by amino acids of the source allergen (e.g. SEQ ID NO: 1 or 3) or that at most 3 amino acid substitutions is introduced in CI, C2, C3 or C4.
  • a reference amino acid sequence has the amino acid sequence ACGTTVVSLHISTVDD
  • the following sequences are, among other, "defined from” this reference amino acid sequence: CGHHVVSLHISTV, ACGTTVPSLHISTVDD, ECGTTVVSLHISTVDE, STVVSLHISTVDP .
  • cross reactive is in general the ability of a T cell receptor (of an individual) to recognize different antigenic (poly)peptides.
  • the cross reactivity is focused on the ability of a T cell line to respond to a peptide of an allergen which is considered to be a homologue to an allergen used to establish the given T cell line.
  • T cell lines established on Cedar pollen allergens e.g. Cry j 1 and Cry j 2
  • Cry j 1 and Cry j 2 are used to test peptides derived from allergens of species considered to be homologues of Cry j 1 and Cry j 2, e.g. Cha o 1 and Cha o 2.
  • a peptide eliciting a T cell response in such a T cell line is considered to also induce a T cell response in an individual sensitized Cha o 1 and Cha o 2.
  • the human leukocyte antigen (HLA) system is the locus of genes that encode for proteins on the cell surface that present the antigen to T cells and are termed as MHC (Major histocompatibility complex) at protein level.
  • MHC Major histocompatibility complex
  • the HLA term has been commonly used in the patent which should in general be understood as MHC class II molecules.
  • HLA alleles are referred to herein using mostly a simpler notation, such as DRB1_0101 or
  • HLA-X*YY:ZZ The amino acid sequence of an expressed HLA allele can be identified as HLA-X*YY:ZZ where X denotes a specific locus, e.g. the DRB1 locus.
  • YY is a two digit number referring to the allele group, formerly defined by the serotype.
  • ZZ is a two or three digit number (herein always two digits) defining the specific HLA protein.
  • a specific beta chain may be referred to as e.g., HLA-DRB1*01 : 01
  • a specific alpha-beta chain pair may be denoted as HLA-DPA1*02: 01-HLA-DPB1*01 :01.
  • telomere refers to the isoelectric point of a peptide or of a polypeptide. It may be calculated theoretically using programmes readily available on the internet or it may be determined experimentally according to known methods. Herein the pig's used are theoretically determined unless it is mentioned to be experimentally determined.
  • the "pi range of the peptides of the composition” refers to the span between the highest and the lowest pi of all peptides of a composition (peptide combination).
  • an “epitope” refers to a region or part of an antigen, such as a peptide disclosed herein, that elicits an immune response when administered to a subject.
  • An epitope may be a T cell epitope, i.e. an epitope that elicits, stimulates, induces, promotes, increases or enhances a T cell activity, function or response, for example a Th2 cell epitope.
  • Any peptide or a combination of peptides of interest can be analyzed to determine whether they include at least one T cell epitope using any number of assays (e.g. T cell proliferation assays, lymphokine secretion assays, T cell non-responsiveness studies, etc.).
  • assays e.g. T cell proliferation assays, lymphokine secretion assays, T cell non-responsiveness studies, etc.
  • peptide combinations composed of a limited set of peptides.
  • Table A lists such peptides considered parent peptides as indicated by an asterisk(*)in Table A and denoted CI, C2, C3 or C4 in embodiments disclosed herein, as well as peptides considered variants thereof.
  • a variant may be designed according to the principle described in example 2.
  • Peptides are elongated with amino acid residues naturally encoded within the full length source allergen sequence using either isoform sequence Cry j 1.0101 (SEQ ID NO: 1) or isoform Cry j 2.0101 (SEQ ID NO: 2), isoform Cha o 1.0101 (SEQ ID NO: 3), or isoform Cha o 2.0101 (SEQ ID NO: 4) as templates .
  • the Cry j 1 peptide SEQ ID NO: 56 comprises the 16 amino acid sequence GNVLINESFGVEPVHP, which is CI of formula I, and wherein A, B, a, b of formula I are null. No substitutions are introduced in CI, Al, or Bl of formula I.
  • the four amino acid residues are identical to the amino acid residues found in the same position when sequence aligning to isoform Cry j 1.0101 (SED ID NO: 1).
  • B, a, and b of formula I are null, and no substitution have been introduced in C, Al, or Bl .
  • variant SEQ ID NO: 157 illustrates an example defined from peptide SED ID NO: 56 (e.g. CI is SEQ ID NO: 56).
  • Al and Bl of formula I are null but the sequence has been elongated with two and one non-coding amino acid residue (here arginine) in the N-terminal and C-terminal end of the CI respectively.
  • the present invention therefore provides in a first aspect, a composition comprising three peptides, which independently are 13 to 25 amino acid residues in length, wherein a first peptide is selected from group a) comprising peptides of either formula I or I*, a second peptide is selected from group b) comprising peptides of either formula II or II* and a third peptide is selected from group c) comprising peptides of group a) and b), wherein
  • a peptide of formula I has an amino acid sequence defined by: a-Al-Cl-Bl-b - a peptide of formula I* has an amino acid sequence defined by: a-Al-Cl*-Bl-b
  • a peptide of formula II has an amino acid sequence defined by: a-A2-C2-B2-b
  • a peptide of formula II* has an amino acid sequence defined by: a-A2-C2*-B2-b and wherein
  • - CI is an amino acid sequence selected from any one of SEQ ID NOs: 77, 48, 56 and 66,
  • - Cl* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in CI with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if CI* is shorter than CI ;
  • - C2 is an amino acid sequence selected from any one of SEQ ID NOs: 97, 107 and 125;
  • C2* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C2 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C2* is shorter than C2;
  • - Al is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions;
  • - Bl is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions;
  • - A2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions
  • - B2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ; and wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • the only substitution(s) in CI*, C2*, Al, A2, Bl and B2 is cysteine substituted with serine.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or SEQ ID NOs: 48, 56 or 77 with 1 or 2 amino acid substitutions, and a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or SEQ ID NOs: 48, 56 or 77 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48 or 77 of the same length, or SEQ ID NOs: 48 or 77 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48 and 56,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48 or 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48 or 56 of the same length, or SEQ ID NOs: 48 or 77 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions.
  • a first peptide as defined herein is of formula I, that is to say that in any one of the above mentioned embodiments, a first peptide is of formula I, wherein CI, CI*, Al, Bl, a, and b, are defined as above, meaning that a first peptide does not include any substitutions of CI.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97 and 107, C2* in formula II* is either a fragment of SEQ ID NOs: 97 or 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97 or 107 of the same length, or SEQ ID NOs: 97 or 107 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97 or 125 of the same length, or SEQ ID NOs: 97 or 125 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions.
  • a composition comprises a second peptide having formula II, thus meaning that in any one of the above mentioned embodiments, a second peptide is of formula II.
  • a composition comprises a third peptide selected from peptides of formula I, II, I* and II*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • a composition comprises a third peptide selected from peptides of formula I, II, I* and II*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48 or 77 of the same length, or
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • Exemplary peptide mixes is number 242 comprising peptides with SEQ ID NOs: 48, 97 and 125 or mixes comprising a variant of one or more of the SEQ ID NOs: 48, 97 and 125, for example peptide mix 242a comprising peptides with SEQ ID NOs: 148, 184 and 208. Further corresponding peptide mixes may be provided by selecting another variant of SEQ ID NOs: 48, 97 and 125, for example those shown in Table A, herein.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • Exemplary peptide mixes is number 243 comprising peptides with SEQ ID NOs: 48, 97 and 107 or mixes comprising a variant of one or more of the SEQ ID NOs: 48, 97 and 107, for example peptide mixes 243a and 243b. Further corresponding peptide mixes may be provided by selecting another variant of SEQ ID NOs: 48, 97 and 107, for example those shown in Table A, herein.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • Exemplary peptide mixes is number 273 comprising peptides with SEQ ID NOs: 77, 97 and 107 or mixes comprising a variant of one or more of the SEQ ID NOs: 77, 97 and 107, for example peptide mixes 273a and 273b. Further corresponding peptide mixes may be provided by selecting another variant of SEQ ID NOs: 77, 97 and 107, for example those shown in Table A, herein.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • Exemplary peptide mixes is number 240 comprising peptides with SEQ ID NOs: 77, 97 and 125 or mixes comprising a variant of one or more of the SEQ ID NOs: 77, 97 and 125, for example peptide mix 242a. Further corresponding peptide mixes may be provided by selecting another variant of SEQ ID NOs: 77, 97 and 125, for example those shown in Table A, herein
  • compositions comprising three peptides are peptide mixes numbered 242, 242a, 243, 243a, 243b, 273, 273a, 273b, 240, 240a, 246, 246a, 246b, 236, 236a, 236b, 238, 238a, 238b, 238c, 238d, 241, 241a, 241b, 245 and 244, wherein the individual peptides of the mix appears from Table 7a.
  • further corresponding combinations may be provided by selecting another variant of individual peptides, for example a variant disclosed in Table A.
  • a composition comprising a first, second and third peptide may also comprise a fourth, fifth, sixth and/or further peptide independently selected from peptides of formula I, II, I* and II*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 49, 56, 59, 64, 66 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 of the same length, or SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 with 1 or 2 amino acid substitutions,
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 98, 100, 107, 113 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 98, 100, 107, 113 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 98, 100, 107, 113 or 125 of the same length, or SEQ ID NOs: 97, 98, 100, 107, 113 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • composition comprising a first, second and third peptide may also comprise a fourth, fifth, sixth and/or further peptide independently selected from peptides of formula I, II, I* and II*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56, 66 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56, 66 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56, 66 or 77 of the same length, or SEQ ID NOs: 48, 56, 66 or 77 with 1 or 2 amino acid substitutions
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107, and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107, or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107, or 125 of the same length, or SEQ ID NOs: 97, 107, or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • compositions comprising four peptides may be mixes numbered 253, 253a, 253b, 247, 247a, 247b, 293, 293a, 293b, 293c, 293d, 251, 251a, 251b, 248, 248a, 248b, 248c, 248d, 252, 252a, 252b, 252c, 252d, 254, 250, 255 and 249 shown in Table 8a, wherein the individual peptides of the mix appears from Table 8a.
  • further corresponding combinations may be provided by selecting another variant of individual peptides, for example a variant disclosed in Table A.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula II* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • a composition comprises the peptides as defined in mixes 153, 153a, and 153b.
  • composition comprises first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 66,
  • CI* in formula I* is either a fragment of SEQ ID NO: 66 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 66 of the same length, or SEQ ID NO: 66 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • the composition comprises the peptides as defined for mixes 256, 256a or 256b in Table 9a.
  • a composition comprises a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • the composition comprises the peptides as defined for mixes 261, 261a or 261b, 261c, 261d in Table 9a.
  • compositions comprising five peptides as defined in any one of the peptide mixes numbered 153, 153a, 153b, 256, 256a, 256b, 259, 259a, 259b, 259c, 259d, 261, 261a, 261b, 261c and 261d is shown in Table 9a.
  • composition comprising a first, second, third, fourth, fifth peptide may also comprise a sixth peptide selected from peptides of formula I or formula I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 77 and 66,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 77 or 66 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 77 or 66 of the same length, or SEQ ID NOs:
  • composition comprises the peptides as defined for mixes 264, 264a, 264b, 264c, 264d, 265, 265a, 265b, 265c, 265d of Table 10a.
  • a composition comprising a first, second, third, fourth, fifth peptide may also comprise a sixth peptide selected from peptides of formula I or formula I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 77 and 56,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 77 or 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 77 or 56 of the same length, or SEQ ID NOs: 77 or 56 with 1 or 2 amino acid substitutions.
  • the composition comprises the peptides as defined for mixes 262 262a, 262b, 262c, 262d, 262, 262a, 262b of Table 10a.
  • composition comprising a first, second, third, fourth, fifth peptide may also comprise a sixth peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions.
  • compositions comprising six peptides are peptide mixes numbered 263, 263a, 263b, 267, 267a, 267b, 267c, 267d, 264, 264a, 264b, 264c, 264d, 265, 265a, 265b, 265c, 265d, 262, 262a, 262b, 262c and 262d in Table 10a, wherein the individual peptides of the mixes also appears.
  • a composition comprises a first peptide having the amino acid sequence of: a) SEQ ID NO: 48 or SEQ ID NO: 148, b) SEQ ID NO: 56 or SEQ ID NOs: 154, 155, 156 or 157, c) SEQ ID NO: 66 or SEQ ID NOs: 170, 166, 167 or 6, or d) SEQ ID NO: 77 or SEQ ID NO: 176.
  • a composition comprises a first peptide may also comprise a second peptide having the amino acid sequence of: e) SEQ ID NO: 97 or SEQ ID NO: 184, f) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195, or g) SEQ ID NO: 125 or SEQ ID NO: 208.
  • a composition comprises a first peptide as defined above in a) to d) and a second peptide as defined above in e) to g) may also comprise a third peptide, a fourth peptide, a fifth peptide and/or a sixth peptide each having an amino acid sequence as a peptide defined in a) to g) above, and not selected from the same a) to g) as any other peptide in the composition.
  • a composition comprises three peptides, which independently are 13 to 25 amino acid residues in length, said composition comprising : a first peptide having the amino acid sequence of: a) SEQ ID NO: 48 or SEQ ID NO: 148, b) SEQ ID NO: 56 or SEQ ID NOs: 154, 155, 156 or 157, c) SEQ ID NO: 66 or SEQ ID NOs: 170, 166, 167 or 6, d) SEQ ID NO: 77 or SEQ ID NOs: 176; a second peptide having the amino acid sequence of: e) SEQ ID NO: 97 or SEQ ID NO: 184, f) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195, g) SEQ ID NO: 125 or SEQ ID NOs: 208; and a third peptide having the same amino acid sequence as a peptide defined in a) to g), and not selected from the same a)
  • a composition comprises a first peptide having the amino acid sequence of: h) SEQ ID NO: 48 or SEQ ID NO: 148, i) SEQ ID NO: 77 or SEQ ID NO: 176; and/or a second peptide having the amino acid sequence of: j) SEQ ID NO: 97 or SEQ ID NO: 184, k) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195,
  • a composition comprises a first peptide having the amino acid sequence of: m) SEQ ID NO: 148, n) SEQ ID NOs: 155 or 157, o) SEQ ID NOs: 170 or 167, or p) SEQ ID NO: 176; and/or the second peptide having the amino acid sequence of: q) SEQ ID NO: 184, r) SEQ ID NOs: 194 or 195, or s) SEQ ID NO: 208; and/or the third peptide having the same amino acid sequence as a peptide defined above in m) to s), and not selected from the same m) to s) as any other peptide in the composition.
  • a composition comprises a first peptide having the amino acid sequence of: t) SEQ ID NO: 148, u) SEQ ID NO: 176; and/or a second peptide having the amino acid sequence of: v) SEQ ID NO: 184, w) SEQ ID NOs: 194 or 195, x) SEQ ID NO: 208; and/or a third peptide having the same amino acid sequence as a peptide defined in t) to x), and not selected from the same t) to x) as any other peptide in the composition.
  • a composition comprising a first, second and third peptide may also comprise a fourth, fifth or sixth peptide independently having the same amino acid sequence as a peptide selected from a) to g) as defined above, each not from the same a) to g) as any other peptide in the composition.
  • a composition comprising a first, second and third peptide may also comprise a fourth, fifth or sixth peptide independently having the same amino acid sequence as a peptide selected from h) to I) as defined above, each not from the same h) to n) as any other peptide in the composition.
  • a composition comprising a first, second, third, fourth, fifth or sixth peptide may also comprise a further peptide independently having the same amino acid sequence as a peptide selected from a) to I) as defined above, each not from the same a) to g) or h) to I) as any other peptide in the composition.
  • a composition comprises a first, second and third peptide may also comprise a fourth, fifth, sixth and/or further peptide, which peptide(s) independently are 13 to 25 amino acid residues in length, wherein any one of the fourth, fifth, sixth or further peptide is of either formula III or III* or formula IV or IV*, wherein
  • a peptide of formula III has an amino acid sequence defined by: a-A3-C3-B3-b
  • a peptide of formula III* has an amino acid sequence defined by: a-A3-C3*-B3-b
  • a peptide of formula IV has an amino acid sequence defined by: a-A4-C4-B4-b
  • a peptide of formula IV* has an amino acid sequence defined by: a-A4-C4*-B4-b and wherein
  • - C3 is an amino acid sequence selected from any one of SEQ ID NOs: 49, 59, or 64,
  • C3* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C3 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C3* is shorter than C3;
  • - C4 is an amino acid sequence selected from any one of SEQ ID NOs: 14, 98, 100 or 113,
  • C4* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C4 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C4* is shorter than C4;
  • - A3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions;
  • - B3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions
  • - A4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions
  • - B4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ;
  • C3, C3*, C4, or C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO as CI, CI*, C2, C2*, C3 or C3* or C4 or C4* as any other peptide in the composition.
  • Examples of peptides of formula III* and IV* may be found in Table A by looking up peptides that are variants of peptides with SEQ ID NOs: 49, 59, 64, 14, 98, 100 and 113 in Table A.
  • substitution(s) in C3*, C4*, A3, A4, B3 and B4 is cysteine substituted with serine.
  • a composition comprises a fourth, fifth, sixth and/or further peptide selected from peptides of formula III, III*, IV and IV*, wherein C3 in formula III is an amino acid sequence of SEQ ID NO: 49,
  • C3* in formula III* is either a fragment of SEQ ID NO: 49 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 49 of the same length, or SEQ ID NO: 49 with 1 or 2 amino acid substitutions;
  • C4 in formula IV is an amino acid sequence selected from any one of SEQ ID NOs: 98 and 100
  • C4* in formula IV* is either a fragment of SEQ ID NOs: 98 or 100 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 98 or 100 of the same length, or SEQ ID NOs: 98 or 100 with 1 or 2 amino acid substitutions.
  • such a fourth, fifth, sixth and/or further peptide selected from peptides of formula III, III*, IV and IV* may be in a composition with a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions, and peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions.
  • a composition comprises the peptides as defined for mixes numbered 282, 277, 281, 297, 301, 302, 295, 299, 313, 316, 320, 315, 335, 336, 340, 335a, 335b, 335c, 335d, 335e, 335f of Table 11a
  • a composition comprises a first peptide of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions, a fourth peptide selected from peptides of formula IV and IV*, wherein
  • C4 in formula IV is an amino acid sequence of SEQ ID NO: 100
  • C4* in formula IV* is either a fragment of SEQ ID NO: 100 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 100 of the same length, or SEQ ID NO: 100 with 1 or 2 amino acid substitutions
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, C2*, C4, C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI, C2, C4 as any other peptide in the composition.
  • a composition comprises five peptides as defined in any one of the peptide mixes numbered 313, 313a, 313b and 313c as shown in Table 11a.
  • a composition comprises a first peptide of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions
  • a fourth peptide selected from peptides of formula IV and IV* wherein wherein C4 in formula IV is an amino acid sequence of SEQ ID NO: 100, C4* in formula IV* is either a fragment of SEQ ID NO: 100 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 100 of the same length, or SEQ ID NO: 100 with 1 or 2 amino acid substitutions
  • a fifth peptide selected from peptides of formula III and III* wherein wherein C3 in formula III is an amino acid sequence of SEQ ID NO: 49, C3* in formula III* is either a fragment of SEQ ID NO: 49 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 49 of the same length, or S
  • a composition comprises the peptides as defined in mix 315.
  • a composition comprises five peptides as defined in any one of the peptide mixes numbered 315, 315a, 315b, 315c, 315d, 315e and 315f as shown in Table 11a.
  • a composition comprising a first, second, third, fourth and fifth peptide may also comprise a sixth peptide selected from peptides of formula IV and IV*, wherein C4 in formula IV is an amino acid sequence of SEQ ID NO: 98, C4* in formula IV* is either a fragment of SEQ ID NO: 98 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 98 of the same length, or SEQ ID NO: 98 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, C2*, C3, C3*, C4, C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI, C2, C3, C4 as any other peptide in the composition.
  • a composition comprises the peptides as defined in mix 335 of Table 11a.
  • a composition comprises six peptides as defined in any one of the peptide mixes numbered 335, 335a, 335b, 335c, 335d, 335e and 335f as shown in Table 11a.
  • a composition comprises three or at least three peptides having the amino acid sequences as defined for peptide mixes numbered 242, 242a, 243, 243a, 243b, 273, 273a, 273b, 240, 240a, 246, 246a, 246b, 236, 236a, 236b, 238, 238a, 238b, 238c, 238d, 241, 241a, 241b, 245 and 244 as shown in Table 7a.
  • a composition comprises four or at least four peptides having the amino acid sequences as defined for peptide mixes numbered 253, 253a, 253b, 247, 247a, 247b, 293, 293a, 293b, 293c, 293d, 251, 251a, 251b, 248, 248a, 248b, 248c, 248d, 252, 252a, 252b, 252c, 252d, 254, 250, 255 and 249 as shown in Table 8a.
  • a composition comprises five or at least five peptides having the amino acid sequences as defined for peptide mixes numbered 153, 153a, 153b, 256, 256a, 256b, 259, 259a, 259b, 259c, 259d, 261, 261a, 261b, 261c and 261d as shown in Table 9a.
  • a composition comprises six or at least six peptides having the amino acid sequences as defined for peptide mixes numbered 263, 263a, 263b, 267, 267a, 267b, 267c, 267d, 264, 264a, 264b, 264c, 264d, 265, 265a, 265b, 265c, 265d, 262, 262a, 262b, 262c and 262d as shown in Table 10a.
  • a composition comprises three, four, five or six peptides having the amino acid sequences as defined for peptide mixes numbered 282, 277, 281, 297, 301, 302, 295, 299, 316, 320, 313, 313a, 313b, 313c, 315, 315a, 315b, 315c, 315d, 315e, 315f, 335, 336, 340, 335a, 335b, 335c, 335d, 335e and 335f as shown in Table 11a.
  • a composition comprises 4, 5, 6, 7 or 8 peptides or at least 4, 5, 6, 7 or 8 peptides.
  • a composition comprises at the most 4, 5, 6, 7 or 8 peptides.
  • the CI, CI*, C2, or C2* in the third peptide binds at least one additional HLA Class II molecule than is bound by the CI or CI* in the first peptide and the C2 or C2* bound in the second peptide.
  • a composition comprising a fourth, fifth, sixth and/or further peptide the CI, CI*, C2, C2*, C3, C3*, C4, or C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI, C2, C3, C4 as any other peptide in the composition.
  • a composition comprising a fourth, fifth and/or sixth peptide the CI, CI*, C2, C2*, C3, C3*, C4, or C4* in each of the fourth, fifth or sixth peptide binds at least one additional HLA Class II molecule than is bound by the CI, CI*, C2, C2*, C3, C3*, C4, or C4* present in any one of the other peptides in the composition.
  • a composition comprising a fourth, fifth and/or sixth peptide selected from formula III, III*, IV or IV*, the C3, C3*, C4, or C4* in each of the fourth, fifth or sixth peptide binds at least one additional HLA Class II molecule than is bound by the CI, CI*, C2, or C2* present in any one of the other peptides in the composition.
  • at least one of the amino acid substitutions in CI*, C2*, Al, Bl, A2 and B2 is the substitution of a cysteine amino acid residue by a serine amino acid residue or by a 2-aminobutyric acid amino acid residue.
  • At least one of the amino acid substitutions in C3*, C4*, A3, B3, A4 and B4 is the substitution of a cysteine amino acid residue by a serine amino acid residue or by a 2-aminobutyric acid amino acid residue.
  • At least one of the amino acid substitutions in CI*, C2*, Al, Bl, A2 and B2 is the substitution of a cysteine amino acid residue by a serine amino acid residue.
  • At least one of the amino acid substitutions in CI*, C2*, A3, B3, A4 and B4 is the substitution of a cysteine amino acid residue by a serine amino acid residue.
  • any cysteine amino acid residue in any of the peptides of the composition is substituted by a serine amino acid residue or by a 2-aminobutyric acid amino acid residue.
  • any cysteine amino acid residue in any of the peptides of the composition is substituted by a serine amino acid residue.
  • the peptides of the composition in combination bind at least 18 of 26 HLA Class II molecules selected from the group consisting of HLA-DPA10103-DPB10201, HLA- DPA10103-DPB10301, HLA-DPA10103-DPB10401, HLA-DPA10103-DPB10402, HLA-DPA10202- DPB10501, HLA-DPA10201-DPB11401, HLA-DQA10501-DQB10201, HLA-DQA10501-DQB10301, HLA-DQA10301-DQB10302, HLA-DQA10101-DQB10501, HLA-DQA10102-DQB10602, DRB1_0101, DRB1_0301, DRB1_0401, DRB1_0405, DRB1_
  • the peptides of the composition in combination bind at least 70% of the HLA Class II molecules of Table 5, column 3, such as at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules, when binding is determined by in vitro or in silico test conditions.
  • any of the amino acid sequences of the CI* and C2* in the composition binds at least 70% of the HLA Class II molecules that CI and C2 binds, respectively, such as binds at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules that CI and C2 binds, respectively, when binding is determined by similar in vitro or in silico test conditions.
  • any of the amino acid sequence(s) of a peptide of formula I or I* binds at least 70% of the HLA Class II molecules that the respective CI binds, such as bind at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules that the respective CI binds, when binding is determined by similar in vitro or in silico test conditions.
  • the amino acid sequence of a peptide(s) of formula II or II* binds at least 70% of the HLA Class II molecules that the respective C2 binds, such as bind at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules that the respective C2 binds, when binding is determined by similar in vitro or in silico test conditions.
  • the amino acid sequence of a peptide(s) of formula III or III* binds at least 70% of the HLA Class II molecules that the respective C3 binds, such as bind at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules that the respective C3 binds, when binding is determined by similar in vitro or in silico test conditions.
  • the amino acid sequence of a peptide(s) of formula IV or IV* binds at least 70% of the HLA Class II molecules that the respective C4 binds, such as bind at least 75%, 80%, 84%, 88%, 90%, 92%, 94% 96%, 98% of said group of HLA Class II molecules that the respective C4 binds, when binding is determined by similar in vitro or in silico test conditions.
  • the group of HLA Class II molecules consists of HLA- DPA10103-DPB10201, HLA-DPA10103-DPB10301, HLA-DPA10103-DPB10401, HLA-DPA10103- DPB10402, HLA-DPA10202-DPB10501, HLA-DPA10201-DPB11401, HLA-DQA10501-DQB10201, HLA-DQA10501-DQB10301, HLA-DQA10301-DQB10302, HLA-DQA10101-DQB10501, HLA- DQA10102-DQB10602, DRB1_0101, DRB1_0301, DRB1_0401, DRB1_0405, DRB1_0701,
  • the group of HLA Class II molecules consists of the HLA Class II molecules shown in Table 5 column 2 or 3.
  • any peptide of the composition elicits, stimulates or induces an in vitro T cell proliferation response or an in vitro IL-5 cytokine response of T cells or PBMC's obtained from an individual allergic or sensitized to cedar pollen.
  • any peptide of the composition elicits, stimulates or induces an in vitro T cell proliferation response or an in vitro IL-5 cytokine response of T cells or PBMC's obtained from an individual allergic or sensitized to a cedar pollen allergen selected from Cry j 1 and Cry j 2.
  • the 13 to 16 contiguous amino acid residues of the CI* and C2* are independently selected from 14 to 16 contiguous amino acid residues of the CI* and C2*, 15 to 16 contiguous amino acid residues of the CI* and C2* and 16 contiguous amino acid residues of the CI* and C2*.
  • the 13 to 16 contiguous amino acid residues of the C3* and C4* are independently selected from 14 to 16 contiguous amino acid residues of the C3* and C4*, 15 to 16 contiguous amino acid residues of the C3* and C4* and 16 contiguous amino acid residues of the CI* and C2*.
  • the 0-6 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4 are independently selected from 0-5 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively, such as 0-4 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively, such as 0-3 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively, such as 0-2 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively, such as 0-1 contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively, such as 0 contiguous amino acid residues contiguous amino acid residues of Al, A2, A3, A4, Bl, B2, B3 and B4, respectively.
  • the number of amino acid residue substitutions of the CI*, C2*, C3* and C4* are independently selected from 0, 1 or 2.
  • the number of amino acid residue substitutions of the Al, A2, A3, A4, Bl, B2, B3 and B4 are independently selected from 0 or 1.
  • the total number of amino acid residues in the Al and Bl of formulas I and I* independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in A2 and B2 of formulas II and ⁇ independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in A3 and B3 of formulas II and ⁇ independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in A4 and B4 of formulas II and ⁇ independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in the a, Al, Bl and b of formulas I and I* independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in the a, A2, B2 and b of formulas II and ⁇ independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in the a, A3, B3 and b of formulas III and III* independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • the total number of amino acid residues in the a, A4, B4 and b of formulas IV and V* independently is 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0, or does not exceed 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1.
  • amino acid residues of a and b of formulas I, II* II, II* III, III* IV, IV* in each formula independently is 0, 1 or 2 lysine (K).
  • the amino acid residues of a and b of formulas I, II* II, II* III, III* IV, IV* in each formula independently is 0, 1 or 2 arginine (R). In an embodiment disclosed herein, the amino acid residues of a and b of formulas I, II* II, II* III, III* IV, IV* in each formula independently is 0, 1 or 2 aspartic acid (D).
  • amino acid residues of a and b of formulas I, II* II, II* III, III* IV, IV* in total in each formula is 0, 1, 2 or 3 amino residues.
  • the length of the peptides each is independently selected from 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25 amino acid residues in length.
  • each peptide such as parent peptides.
  • parent peptides such as parent peptides.
  • variants such as “variant” or “variants” of (parent) peptides, or when referring to “a derivative” or “derivatives” of (parent) peptides, or when referring to “a salt” or “salts” of a (parent) peptide, the following considerations apply:
  • parent peptide denotes an individually identified peptide, with a region containing at least one T cell epitope that herein is found to elicit an in-vitro T cell response in a high fraction of the donor population and to have broad HLA Class II coverage.
  • the individual peptides having an amino acid sequence shown in Table A and indicated with an asterisk are considered parent peptides.
  • an individual peptide derived from the same region of the allergen as the parent peptide and which overlaps with at least 11 contiguous amino acid residues of the parent peptide is expected to produce a T cell response in a high fraction of the same donors as the parent peptide.
  • Such individual peptides are thus said to belong to the same peptide group of individual peptides as the parent peptide and are considered to be variants (or modifications) of the parent peptide.
  • a (parent) peptide described herein may be modified as described herein.
  • Such peptides are referred to as variant peptides.
  • Some modifications correspond to naturally occurring variations of the original allergens, such as in isoforms (within species or intra species) or in homologous allergens in other cedar species (inter species). Other modifications are non- natural modifications of the parent peptide.
  • a parent peptide described herein may contain one or more modifications, which optionally may result in greater or less activity or function, for example in the ability to elicit, stimulate or induce an in-vitro immune response (e.g. T cell proliferation or T cell cytokine production) ; in the ability to bind HLA Class II alleles; in the ability to induce or enhance immunological tolerance to a relevant antigen, e.g. allergen ; or in the ability to dissolve in solvents e.g. in an aqueous solution, or in the ability to resist oxidation.
  • an in-vitro immune response e.g. T cell proliferation or T cell cytokine production
  • an in-vitro immune response e.g. T cell proliferation or T cell cytokine production
  • a relevant antigen e.g. allergen
  • solvents e.g. in an aqueous solution, or in the ability to resist oxidation.
  • a variant which is also termed a "variant peptide” or “modified peptide” herein, is a peptide, which is derived from but not identical to a parent peptide.
  • a variant may for instance include one or more deletions of amino acid residues from the N- and/or C- terminal end of the parent peptide, one or more additions of amino acid residues to the N- and/or C- terminal of the parent peptide and/or one or more amino acid substitutions, additions or deletions within the amino acid sequence of the parent peptide.
  • a derivative is a "derivative", where chemical modifications are introduced, for instance in the side-chains of the amino acid residues of the parent peptide's amino acid sequence (thus effectively resulting in a peptide that includes an amino acid residue substitution relative to the parent peptide).
  • a derivative can also include a chemical modification that involves the N-terminal amino group and/or the C-terminal COOH group. Derivatives are described in more detail herein. It is important to note that some derivatives of the parent peptides described herein are those that could be obtained by substituting an amino acid residue with another naturally occurring amino acid residue, whereas other derivatives involve chemical modifications that result in the provision of peptides that could not be encoded by a nucleic acid sequence.
  • a longer variant of the parent peptide may be up to 25 amino acids in length, for example up to 24, 23, 22, 21, 20, 19, 18, 17, 16 amino acids in length.
  • the longer variant may comprise the amino acid sequence of a parent peptide disclosed herein, or an amino acid sequence having at least 65% identity or similarity over the length of the amino acid sequence of the parent peptide or a fragment thereof, such as over at least 12 contiguous amino acids, for example over at least 13, 14, 15, 16, 17, 18, 19, 20 contiguous amino acids of the parent peptide.
  • the longer variant comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98% or 99% identity or similarity over the length of the amino acid sequence of the parent peptide or over at least 12 contiguous amino acids, for example over at least 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids of the parent peptide.
  • a variant of the parent peptide is a longer peptide up to 30 amino acid residues in length that comprises one or more additional amino acid residues at the N- and/or C- terminal end of the parent peptide or comprises an amino acid sequence having at least 80%, such as at least 85%, 90% or 95% identity or similarity over at least 14 contiguous amino acids of the parent peptide, such as over at least 15, 16, 17, 18 contiguous amino acids of the parent peptide.
  • a variant of the parent peptide may also include a fragment of a parent peptide disclosed herein.
  • a fragment of the parent peptide can have one or more amino acids less than the parent peptide, either comprising deletions from within the amino acid sequence of the parent peptide and/or amino acid deletions from the N- and/or C- terminus of the parent peptide.
  • a fragment will have a length of at least 13 amino acids, for example at least 14, 15, 16 or 17 amino acids, and will have at least 65% identity or similarity over the length of the fragment, or over the length of at least 12 contiguous amino acids of the parent peptide, when aligned with the parent peptide.
  • the percentage identity or similarity is at least 70%, 75%, 80%, 85%, 90% or 95% over the length of the fragment, or over at least 13, 14 or 15 contiguous amino acids of the parent peptide. Therefore, in some embodiments, a variant thereof may be a shorter peptide comprising an amino acid sequence having at least 80%, such as at least 85%, 90% or 95% identity or similarity over at least 14 contiguous amino acids of the parent peptide, such as over at least 15, 16, 17, 18 contiguous amino acids of the parent peptide. As mentioned, a variant of a parent peptide may comprise additional amino acids or may consist of a fragment of the parent peptide.
  • a variant of a parent peptide may consist of 13-25 amino acids, for example, 14-25, 15-25, 15-25, 13-24, 14-24, 15-24, 16-24, 3-22, 14-22, 15-22, 16-22, 13-20, 14-20, 15-20, 16-20 amino acids, such as particularly 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 amino acids.
  • a variant of a parent peptide may comprise an amino acid sequence having at least 65% sequence identity or similarity over at least 14 contiguous amino acids of the parent peptide sequence, optionally wherein the percent sequence identity or similarity is at least 70% 80%, 85%, 90% or 95% over at least 15 contiguous amino acids of the parent peptide sequence, such as over at least 16 contiguous amino acids of the parent peptide sequence.
  • the variant is a peptide consisting of 15-25 amino acids and comprises an amino acid sequence having at least 80% identity or similarity over at least 11-13 or 14-15 contiguous amino acids of the parent sequence.
  • identity and “identical” and grammatical variations thereof, as used herein, mean that two or more referenced entities are the same (e.g., amino acid sequences). Thus, where two peptides are identical, they have the same amino acid sequence. The identity can be over a defined area, e.g. over at least 13, 14, 15 or 16 contiguous amino acids of the parent peptide sequence, optionally wherein the alignment is the best fit with gaps permitted.
  • the variant peptide may be aligned with the parent peptide and the percent identity calculated with respect to the identical amino acid residues found within the amino acid sequence of the variant peptide that overlaps with the 13 contiguous amino acids of the parent peptide sequence. Identity can be determined by comparing each position in aligned sequences. A degree of identity between amino acid sequences is a function of the number of identical or matching amino acids at positions shared by the sequences, i.e. over a specified region.
  • Optimal alignment of sequences for comparisons of identity may be conducted using a variety of algorithms, as are known in the art, including the Clustal Omega program available at the URL: http://www.ebi.ac.uk/Tools/msa/clustalo/, the local homology algorithm of Smith and
  • BLAST e.g., BLAST 2.0
  • search algorithm see, e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI
  • mismatch -2 e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI
  • mismatch -2 e.g., Altschul et al., J. Mol. Biol. 215:403 (1990), publicly available through NCBI
  • a BLASTP algorithm is typically used in combination with a scoring matrix, such as PAM 100, PAM 250, BLOSUM 62 or BLOSUM 50.
  • FASTA e.g., FASTA2 and FASTA3
  • SSEARCH sequence comparison programs are also used to quantitate the extent of identity (Pearson et al., Proc. Natl. Acad. Sci. USA 85 : 2444 (1988) ; Pearson, Methods Mol Biol. 132: 185 (2000) ; and Smith et al., J. Mol. Biol. 147: 195 (1981).
  • similarity and “similar” and grammatical variations thereof, as used herein, mean that an amino acid sequence contains a limited number of conservative amino acid substitutions compared to a peptide reference sequence, e.g. the variant peptide versus the parent peptide.
  • a variety of criteria can be used to indicate whether amino acids at a particular position in a peptide are similar.
  • substitutions of like amino acid residues can be made on the basis of relative similarity of side-chain substituents, for example, their size, charge, hydrophobicity, hydrophilicity, and the like, and such
  • substitutions may be assayed for their effect on the function of the peptide by routine testing.
  • Substitutions may be conservative or non-conservative amino acid substitutions.
  • “conservative substitution” is the replacement of one amino acid by a biologically, chemically or structurally similar residue.
  • Biological similarity means that the substitution does not destroy a biological activity, e.g. T cell reactivity or HLA coverage.
  • Structural similarity means that the amino acids have side chains with similar length, such as alanine, glycine and serine, or a similar size.
  • Chemical similarity means that the residues have the same charge, or are both either hydrophilic or hydrophobic.
  • a conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain, for example amino acids with basic side chains (e.g., lysine, arginine, histidine) ; acidic side chains (e.g., aspartic acid, glutamic acid) ; uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, histidine) ; nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan) ; beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan).
  • basic side chains e.g., lysine, arg
  • Particular examples include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine or methionine, for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic acid for aspartic acid, or glutamine for asparagine, serine for threonine, and the like.
  • Proline which is considered more difficult to classify, shares properties with amino acids that have aliphatic side chains (e.g., Leu, Val, He, and Ala).
  • substitution of glutamine for glutamic acid or asparagine for aspartic acid may be considered a similar substitution in that glutamine and asparagine are amide derivatives of glutamic acid and aspartic acid, respectively.
  • a variant of a parent peptide disclosed herein may comprise one or more additional amino acid residues at the N- and/or C- terminal end than the parent peptide.
  • Such amino acid residues may be naturally occurring amino acids or non-naturally occurring amino acids.
  • the one or more additional amino acids are the same amino acid or amino acid sequence flanking the N- and/or C- terminal ends of the parent peptide when aligned with the amino acid sequence of the allergen isoform it is present in, based upon or derived from or is aligned with another isoform of the same allergen.
  • additional amino acids may be the amino acids flanking the N- and/or C-terminal ends of the parent peptide when aligned to the respective antigen.
  • the parent peptide may be aligned to an sequence of a different species from the same allergen group when changing amino acids.
  • a variant peptide may include a number of variations compared to the parent peptide, for example to increase or decrease physical or chemical properties of the parent peptide, for example to decrease its ability to resist oxidation, to improve or increase solubility in aqueous solution, to decrease aggregation, to decrease synthesis problems, etc.
  • a variant of a parent peptide comprises: a) one or more (e.g. 1, 2, or 3) amino acid substitutions in the parent peptide sequence, for example a glutamate residue at the N-terminus of the parent peptide may be replaced with pyroglutamate and/or one or more cysteine residues in the parent peptide may be replaced with serine or 2-aminobutyric acid; and/or b) one or more amino acid additions (e.g. 1, 2, 3, 5, 4, 6, 7, 8) to the parent peptide sequence, for example wherein the variant comprises one or more (e.g. 1, 2, 3, or 4) lysine residue(s) and/or one or more (e.g.
  • a variant of a parent peptide may comprise one, two, three or more lysine or arginine amino acid residue(s) added to the N- and/or C-terminus of the parent peptide that have been extended with one or more, e.g. 1, 2, 3, 4, or 5 amino acid residues, optionally of the wild type sequence the peptide is based upon or another wild type isoform.
  • a variant sequence, a derivative or a salt of a peptide described herein is meant to encompass modifications of any such peptide, including variations in the amino acid sequence, derivatives of the peptides, derivatives of a variant sequence, and salts, including a salt of a peptide which itself is a variant sequence and/or a derivative. It should be understood that any peptide specifically disclosed in the present specification and claims may be replaced by a variant sequence, a derivative or a salt thereof, including a salt of a variant, a salt of a derivative, or a salt of a derivative of a variant.
  • variant sequence means that any peptide disclosed herein may be replaced by a variant sequence of the peptide, for example a variant sequence having the same
  • the variant sequence may thus bind to the same or substantially the same HLA Class II alleles as the peptide from which it is modified.
  • the variant sequence binds to the same, substantially the same or at least 80%, such as at least 85%, 90% or 95% or more of the Class HLA II alleles binding to the peptide from which the variant sequence is modified, wherein optionally the Class HLA II alleles consist of the group of HLA-
  • DPA1*02 01-DPB1*01 : 01, HLA-DPA1*01 : 03-DPB1*02 : 01, HLA-DPA1*01 : 03-DPB1*03: 01, HLA-DPA1*01 : 03-DPB1*04: 01, HLA-DPA1*01 : 03-DPB1*04: 02, HLA-DPA1*02: 02- DPB1*05 : 01, HLA-DPA1*02: 01-DPB1*14: 01, HLA-DQA1*05: 01-DQB1*02: 01, HLA- DQA1*05 : 01-DQB1*03 : 01, HLA-DQA1*03 : 01-DQB1*03: 02, HLA-DQA1*04: 01-DQB1*04: 02, HLA-DQA1*01 : 01-DQB1*05 : 01, HLA-DQA1*01 : 02-D
  • a variant sequence may be a homologous peptide of the same length, a longer peptide or a shorter peptide (i.e. a fragment of the parent peptide), including variants comprising the same sequence as the parent peptide or that have at least partial sequence identity or homology with the parent peptide.
  • the identity or homology can be over a defined area of the sequence, such as over at least 15, 16, 17, 18, 19 or 20 contiguous amino acids or over the entire length of the peptide. Identity can be determined by comparing each position in aligned sequences.
  • Optimal alignment of sequences for comparisons of identity may be conducted using a variety of algorithms, as are known in the art, including the ClustalW program, available at http://www.genome.jp/tools/clustalw/. Sequence identity may also be determined using the BLAST algorithm. Software for performing BLAST analysis may be available through the National Center for Biotechnology Information (at
  • a peptide sequence is a "homologue” of, is “homologous” to, or has “homology” to another sequence if the two sequences have substantial identity over a specified region and a functional activity of the sequences is preserved or conserved, at least in part.
  • “homologous” peptides include peptides derived from other related allergens, in particular allergens from the Cupressaceae family such as Cha o 1 and Cha o 2, and which have at least 65%, such as at least 70%, 75%, 80%, 85%, 90% or 95% identity over at least 15, 16, 17, 18, 19 or 20 contiguous amino acids or over the entire length of the peptide.
  • Two sequences are considered to have substantially identity if, when optimally aligned (with gaps permitted), they share at least about 65% sequence identity or greater (e.g. 65%, 70%, 75%, 80%,
  • a variant sequence may be a longer peptide that includes a peptide disclosed herein or a partial sequence thereof.
  • a variant sequence comprises additional amino acid residues at the N- and/or C- terminal end of a peptide disclosed herein, such as additional amino acids selected from amino acids flanking the N- and/or C- terminal ends when the peptide is aligned with the allergen it is present in, based upon or derived from.
  • the additional amino acids may be the amino acids flanking the N- and/or C-terminal ends of the peptide when aligned to allergen Cry j 1.0101 (SEQ ID No. 1).
  • peptides derived from Cry j 2 may comprise additional amino acids flanking the N- and/or C-terminal ends of the peptide when aligned to allergen Cry j 2.0101 (SEQ ID No. 3).
  • a variant sequence of the invention typically has at least 65% identity or homology over at least 15 contiguous amino acids of a peptide disclosed herein, for example least 70%, 75%, 80%, 85%, 90% or 95% identity or homology over at least 15, such as over at least 16, 17, 18, 19 or 20 contiguous amino acids of the peptide. More typically, the variant sequence has a length of 15 to 30 amino acids, and comprises an amino acid sequence having at least about 80%, such as at least about 85%, such as at least about 90% identity or homology over at least 15 contiguous amino acids of the peptide.
  • the variant sequence has a length of 16 to 30 amino acids, and comprises an amino acid sequence having at least about 80%, such as at least about 85%, such as at least about 90% identity or homology over at least 16 contiguous amino acids of the peptide. Still more typically, the variant sequence has a length of 17 to 30 amino acids, and comprises an amino acid sequence having at least about 80%, such as at least about 85%, such as at least about 90% identity or homology over at least 17 contiguous amino acids of the peptide.
  • a variant sequence of the invention may be a peptide selected from among those having SEQ ID Nos. 37-146 and that includes an overlap of at least 9 amino acid residues, preferably identical residues, when aligned with a peptide of the primary pool (SEQ ID Nos. 5 to 14) or a peptide of the secondary pool (SEQ ID Nos. 15 to 36).
  • the overlap is preferably more than 9 amino acid residues, e.g. 10, 11 or 12 amino acid residues or more, such as 13, 14 or 15 amino acid residues.
  • the core binding sequence of MHC II molecules is known to be approximately 9 amino acids long, although MHC II molecules can accommodate longer peptides of 10-30 residues (Murugan and Dai, Immunome Research 2005, 1 : 6). An overlap of 9 amino acids or more with a parent sequence is therefore sufficient for a variant sequence to be able to share a T cell epitope with the parent sequence.
  • a variant sequence may comprise one, two or more lysine or arginine amino acid residue(s) added to the N- and/or C-terminus of the peptide, which may improve the aqueous solubility.
  • a variant sequence may include amino acid deletions, additions and/or substitutions, for example one to three substitutions in the amino acid sequence of the parent peptide.
  • a variant sequence may include naturally-occurring polymorphisms or allelic variants as well as synthetic peptides that contain a limited number of amino acid substitutions in the amino acid sequence, typically conservative substitutions. Substitutions may be conservative or non- conservative amino acid substitutions.
  • a derivative of a peptide refers to a modified form of a peptide disclosed herein including a modified form of a variant sequence thereof. Typically, a derivative is formed by reacting a functional side group of an amino acid, such as a covalent or non-covalent attachment of any type of molecule (naturally occurring or designed), such as a sugar moiety.
  • derivatives of a peptide include glycosylation, acetylation, phosphorylation, amidation, formylation, ubiquitination, and derivatization by protecting/blocking groups and any of numerous chemical modifications. Additional specific non-limiting examples are tagged peptides, fusion peptides, chimeric peptides including peptides having one or more non-amino acyl groups (q.v., sugar, lipid, etc.) covalently linked to the peptide.
  • a derivative comprises one or more modifications, for example selected from any of: (a) N-terminal acetylation ; (b) C-terminal amidation; (c) one or more hydrogens on the side chain amines of arginine and/or lysine replaced with a methylene group; (d) glycosylation and/or (e) phosphorylation.
  • a derivative comprises a fusion (chimeric) sequence of peptides, which optionally may contain an amino acid sequence having one or more molecules not normally present in a reference native (wild type) sequence covalently attached to the peptide amino acid sequence.
  • chimeric and grammatical variations thereof, when used in reference to a sequence, means that the sequence contains one or more portions that are derived from, obtained or isolated from, or based upon other physical or chemical entities.
  • a derivative is one in which a second heterologous sequence, i.e. a heterologous functional domain, is attached to a peptide disclosed herein, (covalent or non- covalent binding) that may confer a distinct or complementary function to a peptide disclosed herein.
  • Heterologous functional domains are not restricted to amino acid residues.
  • a heterologous functional domain can consist of any of a variety of different types of small or large functional moieties.
  • moieties include nucleic acid, peptide, carbohydrate, lipid or small organic compounds, such as a drug (e.g., an antiviral), a metal (gold, silver), or a radioisotope.
  • Linkers such as amino acid or peptidomimetic sequences, may be inserted between the sequence and the addition (e.g., heterologous functional domain) so that the two entities maintain, at least in part, a distinct function or activity.
  • Linkers may have one or more properties that include a flexible conformation, an inability to form an ordered secondary structure or a hydrophobic or charged character, which could promote or interact with either domain.
  • Amino acids typically found in flexible protein regions include Gly, Asn and Ser. Other near neutral amino acids, such as Thr and Ala, may also be used in the linker sequence.
  • a derivative may have the same biological functionality as the peptide which is derivatized, for example have the substantially the same Class II HLA coverage.
  • a peptide of formulas I, I*, II and II* comprises one or more of the modifications selected from the following : a) N-terminal acetylation or methylation
  • any one of the peptides in the composition is a salt .
  • Peptides are typically provided in the form of a salt, for example as a pharmaceutically acceptable and/or a physiologically acceptable salt.
  • the salt may be an acid addition salt with an inorganic acid, an acid addition salt with an organic acid, a salt with a basic inorganic acid, a salt with a basic organic acid, a salt with an acidic or basic amino acid or a mixture thereof.
  • Typical examples on an acid addition salts with an inorganic acid is selected from any of salts with hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, or the like.
  • An acid salt with an organic acid may be selected from any of salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like.
  • Salts with an inorganic base may be selected from a salt of an alkali metal salts such as sodium salts and potassium salts; alkali earth metal salts such as calcium salts and magnesium salts; and aluminium salts and ammonium salts.
  • Salts with a basic organic base may be selected from any salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ⁇ , ⁇ -dibenzylethylenediamine, caffeine, piperidine, and pyridine.
  • Salts with a basic amino acid may be selected from any salt with arginine, lysine, ornithine, or the like.
  • Salts with an acidic amino acid may be selected from any salt with aspartic acid, glutamic acid, or the like.
  • a salt such as a pharmaceutically acceptable salt, is an acetate salt.
  • Peptides disclosed herein and variants, derivatives or salts thereof are typically manufactured synthetically.
  • peptides, or variants, derivatives and salts thereof are synthetic.
  • the peptides, variants, derivatives and salts may be isolated and/or purified, e.g. made by the hand of man, such as by peptide synthesis.
  • the peptides may be combined after synthesis and freeze-dried or dissolved in aqueous solutions, DMSO, glycerol or the like or mixtures thereof.
  • each peptide of a peptide combination is present in equimolar concentrations or substantially equimolar ranges.
  • the peptides are freeze-dried (lyophilized), such as to provide them in a storage-stable form and in a form ready to be re-dissolved.
  • the concentration of each of the re-dissolved peptides may be in a molar concentration in the range of 1 to 1000 ⁇ , for example in the range of 10 to 800 ⁇ , for example in the range of 20 to 500 ⁇ , for example in the range of 20 to 300 ⁇ .
  • the peptides of the composition are obtained synthetically or by recombinant expression.
  • the peptides are freeze-dried, such as in a freeze-dried state.
  • each peptide in the composition is present in a molar concentration of 1 to 1000 ⁇ , preferably 1-100 ⁇ and more preferred in 1-10 ⁇ .
  • each peptide in the composition is present in a soluble form in a molar concentration of 1 to 1000 ⁇ preferably 1-100 ⁇ and more preferred in 1-10 ⁇ .
  • each peptide in the composition is present in equimolar concentrations or in substantially equimolar concentrations.
  • the present invention is based on an initial selection of 32 base peptides and then 28 base peptides that in combinations of three or more of these peptides as described in detail elsewhere herein are predicted to be suitable for allergy immunotherapy, where such allergy immunotherapy is expected to be efficacious for treatment of Japanese cedar pollen allergy, and optionally also allergy to related allergens such as Japanese cypress pollen, in a high percentage of a worldwide population.
  • These first 32 base peptides and then 28 base peptides were selected from among a large number of peptides either described in the literature from the cedar allergens Cry j 1 and Cry j 1, as well as from the cypress allergens Cha o 1 and Cha o 2 or as found by epitope mapping.
  • the present invention thus provides in an aspect B peptides designed to be assembled into peptide combinations having a high worldwide HLA coverage, for example the peptides of SEQ ID Nos. 5 to 14 and optionally SEQ ID Nos. 15 to 36 disclosed herein.
  • composition of this aspect of the invention may thus be defined as one comprising at least three different peptides, wherein :
  • a first peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 9, or a variant sequence, a derivative or a salt thereof;
  • a second peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 10 to 14, or a variant sequence, a derivative or a salt thereof;
  • a third peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 36 or 147, or a variant sequence, a derivative or a salt thereof.
  • the invention provides peptide combinations comprising at least five different peptides, typically five peptides, where said five peptides consist of amino acid sequences selected from the 16-mer peptides of SEQ ID Nos. 37-146. Exemplary peptide combinations of this aspect of the invention are described in Example 6.
  • composition may be one where the first and second peptides of (a) and (b), respectively, are:
  • the third peptide (c) may be selected from among the peptides of the primary pool consisting of an amino acid sequence of SEQ ID NOs. 5 to 14, or from among the peptides of the secondary pool consisting of an amino acid sequence of SEQ ID NOs. 15 to 36, or a variant sequence, a derivative or a salt of any of these.
  • the third peptide (c) may also be a peptide consisting of the amino acid sequence of SEQ ID No. 147, or a variant sequence, a derivative or a salt thereof.
  • the composition may optionally comprise one or more additional peptides, e.g.
  • one, two or three further peptides each of which may be selected from among the peptides of the primary pool consisting of an amino acid sequence of SEQ ID NOs. 5 to 14, or from among the peptides of the secondary pool consisting of an amino acid sequence of SEQ ID NOs. 15 to 36, or a peptide consisting of the amino acid sequence of SEQ ID No. 147, or a variant sequence, a derivative or a salt of any of these.
  • composition of the invention suitable for use in allergy
  • immunotherapy comprises a peptide combination comprising at least four different peptides, including at least two Cry j 1 peptides and at least two Cry j 2 peptides from the primary pool (or variants, derivatives and/or salts thereof), and optionally comprising at least one additional peptide that may be selected from either the primary pool or the secondary pool.
  • the composition may optionally comprise one or more additional peptides, e.g. one or two further peptides, each of which may be selected from among the peptides of the primary pool consisting of an amino acid sequence of SEQ ID NOs. 5 to 14, or from among the peptides of the secondary pool consisting of an amino acid sequence of SEQ ID NOs. 15 to 36, or a variant sequence, a derivative or a salt of any of these.
  • the composition may e.g. comprise one additional peptide, i.e. a total of five peptides, wherein the additional peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 36, or a variant sequence, a derivative or a salt thereof.
  • a composition of the invention will comprise at least three peptides.
  • the composition may for example comprise 3, 4, 5, 6, 7, 8, 9 or 10 peptides.
  • the composition has a sufficient number of peptides to make it likely to be efficacious in most or preferably substantially all Japanese cedar pollen allergy patients, i.e. in terms of efficacy a larger number of peptides is advantageous.
  • factors that make it desirable to limit the number of peptides in a composition include e.g. cost considerations, formulation considerations (e.g.
  • the composition of the invention will preferably include four, five or six peptides, as it is believed that such a composition will be on the one hand efficacious in a large majority of patients while on the other hand sufficiently limited in peptide number that potential cost, formulation and regulatory challenges wil be manageable.
  • compositions comprising a peptide combination comprising at least five different peptides, where said at least five peptides consist of amino acid sequences:
  • compositions also features a pharmaceutical composition comprising a composition, e.g. a peptide combination defined herein.
  • the pharmaceutical composition may be a product, such as a vaccine for allergy immunotherapy, including but not limited to immunotherapy to treat an allergic immune response or allergic disease to Japanese cedar pollen.
  • a pharmaceutical composition comprises in addition to the peptide combination one or more pharmaceutically acceptable or physiologically acceptable excipient(s), carriers and/or adjuvants, which usually are therapeutically inactive ingredients.
  • Excipients for use in pharmaceutical compositions are well-known to the person skilled in the art and include , but are not limited to, solvents, emulsifiers, wetting agents, plasticizers, solubilizers (e.g. solubility enhancing agents), colouring substances, fillers, preservatives, anti-oxidants, anti-microbial agents, viscosity adjusting agents, buffering agents, pH adjusting agents, isotonicity adjusting agents, mucoadhesive substances, and the like. Examples of formulation strategies are well known to the person skilled in the art.
  • the peptide may be formulated (e.g. mixed together) with immune- modifying agents such as adjuvants.
  • the adjuvant(s) may be selected from any conventional adjuvant, including but not limited to oxygen-containing metal salts, e.g. aluminium hydroxide, aluminium phosphate, chitosan, heat-labile enterotoxin (LT), cholera toxin (CT), cholera toxin B subunit (CTB), polymerized liposomes, mutant toxins, e.g. LTK63 and LTR72, microcapsules, interleukins (e.g.
  • IL-1 beta, IL-2, IL-7, IL-12 IFN-gamma, GM-CSF, MDF derivatives, CpG oligonucleotides, LPS, MPL, MPL-derivatives, phosphophazenes, Adju-Phos(R), glucan, antigen formulations, liposomes, DDE, DHEA, DMPC, DMPG, DOC/Alum Complex, Freund's incomplete adjuvant, ISCOMs(R), LT Oral Adjuvant, muramyl dipeptide, monophosphoryl lipid A, muramyl peptide and phospatidylethanolamine.
  • adjuvants are described, for example, in "Vaccine Design--the subunit and adjuvant approach” (Edited by Powell, M. F. and Newman, M. J. ; 1995, Pharmaceutical Biotechnology (Plenum Press, New York and London, ISBN 0-306-44867- X) entitled “Compendium of vaccine adjuvants and excipients” by Powell, M. F. and Newman M.
  • the pharmaceutical composition is a liquid, such as a solution, a suspension, a dispersion or a gelled liquid.
  • the composition may be an emulsion, a powder, for example a re- dissolvable powder, a granulate or a lyophilizate, which may be dissolved to form a liquid before being administered.
  • the pharmaceutical composition is typically provided as a powder, for example freeze-dried.
  • the freeze-dried composition is adapted to be re-dissolved before use, for example re-dissolved in an aqueous, normally sterile, solution, for example a solution having a pH in the range of 3 to 9, such as pH in the range of 3 to 8, such as pH in the range of 4 to 8.
  • an aqueous, normally sterile, solution for example a solution having a pH in the range of 3 to 9, such as pH in the range of 3 to 8, such as pH in the range of 4 to 8.
  • the pharmaceutical composition may be a solid dosage form, such as a tablet such as a freeze dried tablet formulation for fast disintegration, or a capsule.
  • a solid dosage form such as a tablet such as a freeze dried tablet formulation for fast disintegration, or a capsule.
  • Pharmaceutical formulations and delivery systems appropriate for the compositions, methods and uses of the invention are known in the art (see, e.g., Remington : The Science and Practice of Pharmacy (2003) 20th ed., Mack Publishing Co., Easton, PA; Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing Co., Easton, PA; The Merck Index (1996) 12th ed., Merck Publishing Group, Whitehouse, NJ ; Pharmaceutical Principles of Solid Dosage Forms (1993), Technonic Publishing Co., Inc., Lancaster, Pa.
  • compositions can be formulated to be compatible with a particular route of administration.
  • pharmaceutical compositions may include carriers, diluents, or excipients suitable for administration by various routes.
  • the pharmaceutical composition is aqueous, while in other embodiments the composition may be in the form of non-aqueous solutions, suspensions or emulsions of the peptides, which compositions are typically sterile and can be isotonic with the biological fluid or organ of the intended recipient.
  • the pH of an aqueous solution is typically in the range of 3 to 9, such as 3 to 8, such as 4 to 8.
  • formulation ingredients include water, saline, dextrose, fructose, ethanol, vegetable or synthetic oils.
  • a composition can take the form of, for example, tablets or capsules, optionally formulated as fast- integrating tablets/ capsules or slow-release tablets/capsules.
  • the tablet is a freeze-dried, optionally a fast-disintegrating tablet suitable for being administered under the tongue.
  • the pharmaceutical composition may also be formulated into a "unit dosage form", which as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of a peptide or peptide combination, optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, is calculated to produce a desired effect.
  • Unit dosage forms also include, for example, ampules and vials, which may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier can be added prior to administration or delivery in vivo.
  • Unit dosage forms additionally include, for example, ampules and vials with liquid compositions disposed therein.
  • the pharmaceutical composition may be formulated for parenteral administration, such as formulated for injection, e.g. subcutaneous and/or intradermal injection. Therefore, in some embodiments, the pharmaceutical composition may be a liquid (i.e. formulated as a liquid), including a solution, a suspension, a dispersion, and a gelled liquid.
  • a liquid pharmaceutical composition may be formed by dissolving a powder, granulate or lyophilizate of a peptide combination described herein in a suitable solvent and then administering to a subject.
  • Suitable solvents may be any solvent having physiologically acceptable properties and able to dissolve the peptide combination in desired concentrations. A desired concentration may depend on the aliquot to be administered (i.e.
  • the aliquot is in the range of about 10 to 500 microliters, e.g. 50 to 300 microliters or less and a desired single dose is within range of 1 to 1000 nanomole.
  • a suitable solvent should be able to dissolve any peptide of the combination to achieve a final concentration of about 1 to 1000 ⁇ for each of the peptides.
  • a liquid composition comprises each of the peptides of the combination in a concentration of 10 to 800 ⁇ , for Example 20 to 500 ⁇ or20 to 300 ⁇ .
  • the concentration of each peptide is the same, such as in an equimolar concentration, but each peptide of the composition may be present in different concentrations.
  • the solvent is an aqueous solution, optionally mixed with other solvents.
  • a solvent may comprise at least 60% w/w of water, e.g.
  • aqueous solution may comprise other solvents than water, for example DMSO (dimethylsulfoxide), glycerol, ethanol, acetonitrile, vegetable or synthetic oils.
  • DMSO dimethylsulfoxide
  • the pH of the aqueous phase of the solvent may be in a physiological acceptable range, typically in the range of 3 to 9, such as in the range of pH 3 to 8, such as in the range of pH 4 to 8, such as in the range of 5 to 8, such as in the range of 6 to 8.
  • the liquid formulation may comprise a pH controlling agent or buffering agent (e.g. citrate buffer, phosphate buffer, acetate buffer), optionally the pH may be adjusted with dilutions of strong base (e.g. sodium hydroxide or the like) and/or dilutions of strong acids (e.g. hydrochloric acid).
  • the liquid formulation is isotonic, and optionally sterile.
  • the formulation comprises saline, such as isotonic saline.
  • the liquid may contain additional excipients, such as another solvent, a solubilizing enhancing agent (e.g. polyoxyethylene (20) sorbitan monolaurate (Tween® 20), ionic and non-ionic emulsifiers (e.g. poloxamers (Kolliphor®)), a dispersant, a thickener, a preservative, an anti-microbial agent, and/or an antioxidant.
  • a solubilizing enhancing agent e.g. polyoxyethylene (20) sorbitan monolaurate (Tween® 20
  • ionic and non-ionic emulsifiers e.g. poloxamers (Kolliphor®)
  • a dispersant e.g. poloxamers (Kolliphor®)
  • solvents include water, saline, DMSO, glycerol, ethanol, acetonitrile, vegetable or synthetic
  • a pharmaceutical composition may be formulated to contain only a limited amount of water or aqueous solution, e.g. containing less than 10% w/w of water or aqueous solution, such as less than 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5% w/w of water or aqueous solution.
  • aqueous solution e.g. containing less than 10% w/w of water or aqueous solution, such as less than 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5% w/w of water or aqueous solution.
  • Examples of pharmaceutical compositions with limited levels of water may include granulates, powders, for example lyophilizates, i.e. freeze-dried powders.
  • the freeze-dried composition may be dissolved before use, for example dissolved in an aqueous, optionally sterile, solution, for example a solution having a pH in the range of 3-9, such as pH in the range of 3 to 8, such as pH in the range of 4 to 8.
  • a lyophilizate may contain additional ingredients, e.g. bulking agents and lyoprotectants (e.g. sucrose, lactose, trehalose, mannose, mannitol, sorbitol, glucose, raffinose, glycine, histidine or mixtures thereof), buffering agents (e.g.
  • a freeze-dried composition may also be formulated into a solid dosage form that is administered for example by the oral route such as by oral mucosa.
  • the oral route such as by oral mucosa.
  • the pharmaceutical composition may be formulated for oral administration, for example for sublingual administration. Therefore, the pharmaceutical composition may be a solid dosage form, such as a freeze-dried solid dosage form, typically a tablet, a capsule or sachet, which optionally may be formulated for fast disintegration.
  • a solid dosage form such as a freeze-dried solid dosage form, typically a tablet, a capsule or sachet, which optionally may be formulated for fast disintegration.
  • Pharmaceutical formulations and delivery systems appropriate for the compositions, methods and uses of the invention are known in the art (see, e.g.,
  • compositions can be formulated to be compatible with a particular route of administration, such as by intradermal or by sublingual administration.
  • compositions may include carriers, diluents, or excipients suitable for administration by various routes.
  • routes of administration for contact or in vivo delivery for which a composition can optionally be formulated include inhalation, intranasal, oral, buccal, sublingual, subcutaneous, intradermal, epicutaneous, rectal, transdermal, or intralymphatic.
  • a composition may take the form of, for example, tablets or capsules, optionally formulated as fast-disintegrating tablets/capsules or slow-release tablets/capsules.
  • the tablet is freeze-dried, optionally a fast-disintegrating tablet or capsule suitable for being administered under the tongue.
  • the pharmaceutical composition may also be formulated into a "unit dosage form", which used herein refers to physically discrete units, wherein each unit contains a predetermined quantity of a peptide or peptide combination, optionally in association with a pharmaceutical carrier (excipient, diluent, vehicle or filling agent) which, when administered in one or more doses, may produce a desired effect.
  • Unit dosage forms also include, for example, ampules and vials, which may include a composition in a freeze-dried or lyophilized state (a lyophilizate) or a sterile liquid carrier, for example that can be added prior to administration or delivery in vivo.
  • Unit dosage forms additionally include, for example, ampules and vials with liquid compositions disposed therein.
  • the pharmaceutical composition comprises an inert gas, e.g. argon or nitrogen.
  • kits comprising a compartment and instructions, wherein the compartment comprises a composition, e.g. a peptide combination defined herein, or a pharmaceutical composition defined herein and wherein the instructions are for use in treating allergy to Japanese cedar pollen or pollen having cross reactivity to Japanese cedar pollen.
  • a kit may further comprise packaging material comprising corrugated fibre, glass, plastic, foil, ampules, vials, blister pack, preloaded syringes or tubes, optionally that maintain sterility of the components.
  • a kit may further comprise labels or inserts comprising printed matter or computer readable medium optionally including identifying components, dose amounts, clinical pharmacology and instructions for the clinician or for a subject using one or more of the kit components, prophylactic or therapeutic benefits, adverse side effects or manufacturer information.
  • the kit additionally comprises a container comprising a solvent for dissolving the composition before use. Examples of suitable solvents are described supra.
  • the kit may also comprise a device for use in parenteral injection, e.g. for injecting the composition (e.g. dissolved composition) to a subcutaneous or intradermal tissue.
  • a device may be any suitable device for that purpose, such as a needle or microneedle adapted for intradermal or subcutaneous delivery of the composition.
  • the device may be a microneedle or a device comprising a plurality of microneedles designed for intradermal delivery of liquids, e.g. as described in international patent applications WO14064543 Al, WO05049107 A2, WO06054280 A2,
  • an aspect of the invention relates to a method of treating allergy to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross-reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition, a pharmaceutical composition or a kit described herein.
  • Japanese cedar pollen e.g. to an allergen of Japanese cedar pollen
  • pollen cross-reactive with Japanese cedar pollen e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen
  • an aspect of the invention relates to a method of treating allergy in a subject in need thereof, where signs and/or symptoms of said allergy are elicited by exposure to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross-reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition, a pharmaceutical composition or a kit described herein.
  • Japanese cedar pollen e.g. to an allergen of Japanese cedar pollen
  • pollen cross-reactive with Japanese cedar pollen e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen
  • the present aspect also relates to a composition, a pharmaceutical composition or a kit described herein for use in treating allergy to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross- reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof, such as for use in treating allergy in a subject in need thereof, where signs and/or symptoms of said allergy are elicited by exposure to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross-reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof.
  • Japanese cedar pollen e.g. to an allergen of Japanese cedar pollen
  • pollen cross- reactive with Japanese cedar pollen e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen
  • the present aspect also relates to the use of a composition, a pharmaceutical composition or a kit described herein for the preparation of a medicament for use for use in treating allergy to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross- reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof, such as for use in treating allergy in a subject in need thereof, where signs and/or symptoms of said allergy are elicited by exposure to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross- reactive with Japanese cedar pollen (e.g. to allergen cross reacting with an allergen of Japanese cedar pollen) in a subject in need thereof.
  • Japanese cedar pollen e.g. to an allergen of Japanese cedar pollen
  • pollen cross- reactive with Japanese cedar pollen e.g. to an allergen cross reacting with an allergen of
  • signs or symptoms of allergy cf. below for further discussion, but it is generally understood that this means signs or symptoms of IgE mediated allergy including that the patient has elicited IgE-antibodies against an allergen of Japanese cedar pollen or of pollen cross-reactive with Japanese cedar pollen.
  • all embodiments may entail or consist of treating the allergy by relieving or reducing an immune response triggered by exposure to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross-reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen).
  • treating the allergy can in all embodiments of the present aspect comprise or consist of relieving one or more signs/symptoms of an immune response triggered by exposure to Japanese cedar pollen (e.g.
  • treating the allergy may in all embodiments of the present aspect consist of or comprise induction of immunological tolerance against Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross-reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen.
  • treating the allergy may in all embodiments of the present aspect comprise or consist of relieving one or more signs/symptom(s) associated with allergic rhinitis and/or allergic conjunctivitis and/or allergic asthma and/or allergic eczema (e.g. atopic dermatitis).
  • the signs/symptoms of allergy mentioned above are those typically associated with the allergies treated according to the present invention, typically signs/symptoms may include one or more of the following; itchy running nose, itchy watery eyes, itchy skin and shortness of breath and the patient may experience that the signs/symptoms will to some extent be relieved by treatment with antihistamines or steroids.
  • the signs and symptoms may include detectable levels of IgE antibodies against one or more Japanese cedar pollen allergens or cross reacting allergens of interest.
  • compositions disclosed herein may produce a therapeutic or beneficial effect, which optionally may be objectively or subjectively measurable.
  • a therapeutic or beneficial effect can but need not be complete ablation of all or any immune response, or one or more symptoms caused by or associated with an allergen.
  • a satisfactory clinical result is achieved when there is an incremental improvement or a partial reduction in an immune response or one or more symptoms caused by or associated with an allergen, or there is an inhibition, decrease, reduction, suppression, prevention, limit or control of worsening or progression of an immune response or one or more symptoms caused by or associated with an allergen over a short or long duration (hours, days, weeks, months, etc.).
  • the relief is typically
  • a "sign" of allergy is an objectively observable characteristic of the disease
  • a "symptom” is the patient's subjective experience(s) relative to the disease.
  • Some signs can be symptoms and vice versa, but if a patient for instance experiences dizziness due to a disease, this can only be categorized as a symptom, because it is not objectively observable by anybody else than the patient.
  • increasing levels of for example IgE-antibodies is a "sign", since it cannot be sensed by the patient but it can be objectively measured in an appropriate assay.
  • the relief typically comprises
  • treating the allergy comprises or consists of relieving one or more signs or symptoms associated with allergic asthma
  • the relief typically comprises
  • treating the allergy comprises or consists of relieving one or more signs or symptoms associated with atopic dermatitis
  • the relief typically comprises
  • the method may comprise or consist of reducing the patient's need for concomitant treatment with corticosteroids or HI antihistamines to reduce, relieve, or suppress one or more symptoms of an immune response associated with the allergy. In other words, these embodiments have the long term benefit of reducing the patient's need for medication.
  • immunological tolerance refers to a) a decreased or reduced level of a specific immunological response (thought to be mediated at least in part by antigen-specific effector T lymphocytes, B lymphocytes, antibodies, or a combination thereof) ; b) a delay in the onset or progression of a specific immunological response; or c) a reduced risk of the onset or progression of a specific immunological response to mites.
  • the method comprises inducing immunological tolerance in a subject to Japanese cedar pollen (e.g. to an allergen of Japanese cedar pollen) or to pollen cross- reactive with Japanese cedar pollen (e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen to suppress an allergic immune response to the allergen.
  • Japanese cedar pollen e.g. to an allergen of Japanese cedar pollen
  • pollen cross- reactive with Japanese cedar pollen e.g. to an allergen cross reacting with an allergen of Japanese cedar pollen to suppress an allergic immune response to the allergen.
  • Immunological tolerance in a subject to an allergen can also be reflected by reducing the occurrence, frequency, severity, progression, or duration of an allergic response of the subject to the allergen.
  • Induction of immune tolerance also referred to as desensitization
  • induction of immune tolerance can be measured by methods disclosed herein or known to the skilled artisan.
  • induction of immune tolerance can be measured by the modulated lymphokine and/or cytokine level in a subject or animal before versus after administering a peptide combination described herein for the first time.
  • a modulated cytokine level can be an increase of a cytokine level, for instance an increase of a lymphokine and/or cytokine level of at least 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 20, 50 times or more relative to before administering the peptide combination for the first time.
  • modulation can be a decrease of the level of a particular cytokine level, for instance a decrease of the lymphokine and/or cytokine level of at least 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 20, 50 times or more relative to before administering a peptide combination for the first time.
  • the lymphokines/cytokines chosen to be measured can be from any relevant lymphokines/cytokines, such as IL-2, IL-5, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, TNF-alfa, IFN-gamma, TGF-beta, MCP-1, RANK-L and Flt3L.
  • relevant lymphokines/cytokines such as IL-2, IL-5, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, TNF-alfa, IFN-gamma, TGF-beta, MCP-1, RANK-L and Flt3L.
  • the term "inducing immunological tolerance” may include eliciting, stimulating, promoting, increasing or enhancing immunological tolerance.
  • Immunological tolerance may involve modulation of T cell activity, including but not limited to CD4+ T cells, CD8+ T cells, Th l cells, Th2 cells and regulatory T cells (Tregs), and memory T cells, including inflammatory
  • lymphokines/cytokines produced by T cells are lymphokines/cytokines produced by T cells.
  • the method comprises decreasing a T cell response in the patient/subject in need thereof against an allergen of Japanese cedar or a cross reacting allergen.
  • the patients/subjects subjected to the treatment of the present aspect of the invention typically present with an immune response clinically presented as atopic dermatitis, urticaria, contact dermatitis, allergic conjunctivitis, allergic rhinitis, allergic asthma, anapylaxis, and/or hay fever.
  • the treatment thus decreases, reduces, suppresses or inhibits atopic dermatitis, urticaria, contact dermatitis, allergic conjunctivitis, allergic rhinitis, allergic asthma, anaphylaxis, and/or hay fever.
  • the subject's administration of a therapeutically effective amount of a composition described herein may relieve one or more symptoms of the immune response.
  • the method may comprise relieving one or more symptoms associated with allergic rhinitis, allergic conjunctivitis, allergic asthma and/or allergic eczema (e.g. atopic dermatitis).
  • the patients that are subjected to the method of the present aspect of the invention are typically sensitized to at least one allergen of Japanese cedar pollen, e.g. Cry j 1 and/or Cry j 2 or a cross reacting allergen of Cry j 1 and/or Cry j 2. It is to be understood that such patients/subjects may exhibit allergy signs or experience symptoms of allergy, but it is not excluded that subjects which do not exhibit clinical relevant allergy signs allergy will also benefit from the treatment.
  • the allergy treated according to the invention is in all embodiments of the present aspect of the invention allergy towards Japanese cedar pollen and optionally to pollen cross-reactive with Japanese cedar pollen.
  • Japanese cedar pollen may be from the genus Cryptomeria, such as from the species Cryptomeria japonica. Allergens cross- reactive with allergens of Japanese cedar pollen may be allergens of the Cupressaceae family. It is known (see e.g. Schwietz et al., Ann. Allergy Asthma Immunol.
  • cross-reactive pollen allergens include pollen of such "cross-reactive” species, especially cross- reactive pollen allergens of Cupressaceae species.
  • cross-reactive species include, but are not limited to, the following :
  • Juniperus California (California j uniper)
  • Juniperus chinensis (Chinese juniper)
  • Juniperus scapulorum (Rocky Mountain cedar)
  • Juniperus osteosperma (Utah juniper)
  • Juniperus monosperma (One-seed juniper)
  • Juniperus pinchotti Pierot juniper
  • Juniperus occidentalis Hooker western juniper
  • Juniperus virginiana (Eastern red cedar)
  • Japanese cypress ⁇ Chamaecyparis obtusa
  • the amino acid sequence of the relevant pollen allergens have a high degree of similarity between the two species.
  • the amino acid sequence of the Cha o 1 allergen from Japanese cypress has 79-80% identity with the sequence of the Cry j 1 allergen from Japanese cedar (Suzuki et al., Mol Immunol.
  • pollen cross-reactive with Japanese cedar pollen is selected from pollen of the Cupressaceae family, such as from pollen of Japanese cypress (Chamaecyparis obtuse), Common cypress (Cupressus sempervirens) and Mountain cedar (Juniperus ashei).
  • An allergen of Japanese cedar pollen may be Cry j 1 and/or Cry j 2, whereas an allergen cross reacting with Cry j 1 may be Cha o 1, Jun a 1 and/or Cup s 1 and an allergen cross reacting with Cry j 2 may be Cha o 2, Jun a 2 and/or Cup s 2.
  • composition to be administered may be administered by the parenteral route to the patient/subject in need thereof, such as via a route of administration selected from any one of subcutaneous, intradermal, epicutaneous, topical, sublingual, buccal, intranasal, respiratory and the intralymphatic route.
  • a route of administration selected from any one of subcutaneous, intradermal, epicutaneous, topical, sublingual, buccal, intranasal, respiratory and the intralymphatic route.
  • the intradermal route of administration is of interest.
  • the subject in need thereof is a human, a pet such as a dog or a cat, a domestic animal such as a horse, or a laboratory animal (a mouse, a guinea pig or a rabbit).
  • the subject may be sensitized to Japanese cedar pollen or cross reactive pollen (e.g. the subject have specific IgE antibodies against an allergen of Japanese cedar pollen and/or have a T cell response against an allergen of Japanese cedar pollen.
  • a composition is administered several times, i.e. repeatedly, such as in weekly, by- weekly, monthly or quarterly intervals.
  • the allergy is, according to the present aspect of the invention and any embodiments thereof, preferably treated by immunotherapy.
  • the patient in question need not be human.
  • the patient may be human or a mammal, such as a cat, dog, and a horse.
  • a pharmacologically effective amount of a single dose of a polypeptide of the first aspect or a composition of the second aspect may be in the range of 1 to 1000 nanomole, for example 1 to 500 nanomole, for example 1 to 250 nanomole, for example 5 to 250 nanomole.
  • a polypeptide or composition of the invention is administered as a liquid in a volume of about 50 to 150 microliter, such as by intradermal administration.
  • a another aspect of the invention relates to an in-vitro method of determining whether T cells of a subject in need of treatment recognize a composition as described herein, comprising contacting T cells obtained from the subject with said composition or a single peptide thereof and detecting whether the T cells are stimulated by said composition or single peptide.
  • the in-vitro method may be used to determine whether the subject has, or is at risk of developing, an allergy to Japanese cedar pollen or cross reacting pollen.
  • Embodiment 1 A composition comprising a peptide combination comprising at least three different peptides, wherein
  • a first peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 9, or a variant sequence, a derivative or a salt thereof;
  • a second peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 10 to 14, or a variant sequence, a derivative or a salt thereof;
  • a third peptide is selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 36 or 147, or a variant sequence, a derivative or a salt thereof.
  • Embodiment 2 The composition of embodiment 1, where peptides (a) and (b), respectively, are:
  • Embodiment 3 The composition of embodiment 1 or 2, comprising at least one additional peptide selected from any of peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 14 or SEQ ID NOs. 15 to 36, or a variant sequence, a derivative or a salt thereof.
  • Embodiment 4 The composition of embodiment 3, comprising one, two or three additional peptides.
  • Embodiment 5 A composition comprising a peptide combination comprising at least four different peptides, wherein
  • a first peptide and a second peptide are selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 9, or a variant sequence, a derivative or a salt thereof;
  • a third peptide and a fourth peptide are selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 10 to 14, or a variant sequence, a derivative or a salt thereof.
  • Embodiment 6 The composition of embodiment 5, wherein the first, second, third and fourth peptides, respectively, are:
  • Embodiment 7 The composition of embodiment 6, further comprising at least one additional peptide selected from any of the peptides consisting of an amino acid sequence of SEQ ID NOs. 5 to 36 or 147, or a variant sequence, a derivative or a salt thereof.
  • Embodiment 8 The composition of embodiment 7, comprising one or two additional peptides.
  • Embodiment 9 The composition of any of the preceding embodiments, comprising at least one peptide which is a variant sequence selected from peptides having SEQ ID Nos. 37-146, wherein said variant sequence includes an overlap of at least 9 amino acid residues when aligned with a peptide of the primary pool (SEQ ID Nos. 5 to 14) or a peptide of the secondary pool (SEQ ID Nos. 15 to 36).
  • Embodiment 10 The composition of any of the preceding embodiments, comprising at least one peptide having a variant sequence selected from SEQ ID Nos. 58, 59, 66, 68, 69, 75, 76, 77, 78, 98, 107, 113, 119, 131 and 132.
  • Embodiment 11 The composition of any of the preceding embodiments, comprising a peptide consisting of the sequence DLKIKLRRTIEAEGIP (SEQ ID No. 147), or a variant sequence, a derivative or a salt thereof.
  • Embodiment 12 The composition of embodiment 1 which comprises five peptides, where said peptides consist of amino acid sequences:
  • Embodiment 13 A composition comprising a peptide combination comprising at least five different peptides, where said at least five peptides consist of amino acid sequences:
  • Embodiment 14 A pharmaceutical composition comprising a composition according to any of embodiments 1 to 13.
  • Embodiment 15 A kit comprising a compartment and instructions,
  • compartment comprises a composition according to any one of embodiments 1 to 13, and
  • Embodiment 16 A method for treating allergy to Japanese cedar pollen in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a composition according to any of embodiments 1 to 13.
  • Embodiment 17 The method of embodiment 16, wherein the composition further is effective for treatment of allergy to pollen that is cross-reactive with Japanese cedar pollen, e.g. pollen from members of the Cupressaceae family.
  • Embodiment 18 A composition according to any of embodiments 1 to 13 for use in the treatment of allergy to Japanese cedar pollen in a subject in need thereof.
  • Embodiment 19 The composition of embodiment 18, wherein the composition further is for use in the treatment of allergy to pollen that is cross-reactive with Japanese cedar pollen, e.g. pollen from members of the Cupressaceae family.
  • Embodiment 20 Use of a composition according to any of embodiments 1 to 13 for the preparation of a medicament for the treatment of allergy to Japanese cedar pollen in a subject in need thereof.
  • Embodiment 21 Use according to embodiment 20, wherein the medicament is also for treatment of allergy to pollen that is cross-reactive with Japanese cedar pollen, e.g. pollen from members of the Cupressaceae family.
  • Embodiment 22 An in vitro method of determining whether T cells of a subject in need of treatment recognize a composition as defined in any one of embodiments 1 to 13, comprising contacting said T cells obtained from the subject with said peptide combination or single peptides thereof and detecting whether said T cells are stimulated by said peptide.
  • Embodiment 23 The method according to claim 22, which is carried out to determine whether a subject has, or is at risk of developing, an allergy to Japanese cedar pollen.
  • the application further relates to the following embodiments Bl to B134:
  • a composition comprising three peptides, which independently are 13 to 25 amino acid residues in length, wherein a first peptide is selected from group a) comprising peptides of either formula I or I*, a second peptide is selected from group b) comprising peptides of either formula II or II* and a third peptide is selected from group c) comprising peptides of group a) and b), wherein
  • a peptide of formula I has an amino acid sequence defined by: a-Al-Cl-Bl-b
  • a peptide of formula I* has an amino acid sequence defined by: a-Al-Cl*-Bl-b
  • a peptide of formula II has an amino acid sequence defined by: a-A2-C2-B2-b
  • a peptide of formula II* has an amino acid sequence defined by: a-A2-C2*-B2-b and wherein
  • - CI is an amino acid sequence selected from any one of SEQ ID NOs: 77, 48, 56 and 66,
  • - Cl* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in CI with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if CI* is shorter than CI ;
  • - C2 is an amino acid sequence selected from any one of SEQ ID NOs: 97, 107 and 125;
  • C2* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C2 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C2* is shorter than C2;
  • - Al is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions
  • - Bl is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions;
  • - A2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions
  • - B2 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ; and wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or SEQ ID NOs: 48, 56 or 77 with 1 or 2 amino acid substitutions, and a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or SEQ ID NOs: 48, 56 or 77 with 1 or 2 amino acid substitutions. 5.
  • the composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48 or 77 of the same length, or SEQ ID NOs: 48 or 77 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions.
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions. 10.
  • composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97 and 107,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97 or 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97 or 107 of the same length, or SEQ ID NOs: 97 or 107 with 1 or 2 amino acid substitutions. 13.
  • the composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97 or 125 of the same length, or SEQ ID NOs: 97 or 125 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a third peptide selected from peptides of formula I, II, I* and II*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56 or 77 of the same length, or
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising a third peptide selected from peptides of formula I, II, I* and II*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48 or 77 of the same length, or
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • the composition according to any one of the preceding embodiments, comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of the preceding embodiments comprising three peptides having an amino acid sequence as defined for peptide mixes numbered 242, 242a, 243, 243a, 243b, 273, 273a, 273b, 240, 240a, 246, 246a, 246b, 236, 236a, 236b, 238, 238a, 238b, 238c, 238d, 241, 241a, 241b, 245 and 244 in Table 7a.
  • composition according to any one of the preceding embodiments comprising a fourth, fifth, sixt and/or further peptide independently selected from peptides of formula I, II, I* and II*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 49, 56, 59, 64, 66 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 of the same length, or SEQ ID NOs: 48, 49, 56, 59, 64, 66 or 77 with 1 or 2 amino acid substitutions,
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 98, 100, 107, 113 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 98, 100, 107, 113 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 98, 100, 107, 113 or 125 of the same length, or SEQ ID NOs: 97, 98, 100, 107, 113 or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition. 26.
  • the composition according to any one of the preceding embodiments comprising a fourth, fifth, sixt and/or further peptide independently selected from peptides of formula I, II, I* and II*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 48, 56, 66 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 48, 56, 66 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 48, 56, 66 or 77 of the same length, or SEQ ID NOs: 48, 56, 66 or 77 with 1 or 2 amino acid substitutions,
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107, and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107, or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107, or 125 of the same length, or SEQ ID NOs: 97, 107, or 125 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising four peptides as defined in any one of the peptide mixes numbered 253, 253a, 253b, 247, 247a, 247b, 293, 293a, 293b, 293c, 293d, 251, 251a, 251b, 248, 248a, 248b, 248c, 248d, 252, 252a, 252b, 252c, 252d, 254, 250, 255 and 249 in Table 8a.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula II* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition. 29.
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 66,
  • CI* in formula I* is either a fragment of SEQ ID NO: 66 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 66 of the same length, or SEQ ID NO: 66 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein C2 in formula II is an amino acid sequence of SEQ ID NO: 125,
  • C2* in formula II* is either a fragment of SEQ ID NO: 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 125 of the same length, or SEQ ID NO: 125 with 1 or 2 amino acid substitutions; a fourth peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 48,
  • CI* in formula I* is either a fragment of SEQ ID NO: 48 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 48 of the same length, or SEQ ID NO: 48 with 1 or 2 amino acid substitutions; and a fifth peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, or C2* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI or C2 as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising five peptides as defined in any one of the peptide mixes numbered 153, 153a, 153b, 256, 256a, 256b, 259, 259a, 259b, 259c, 259d, 261, 261a, 261b, 261c and 261d as shown in Table 9a.
  • composition according to any one of the preceding embodiments comprising a sixth peptide selected from peptides of formula I or formula I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 77 and 66,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 77 or 66 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 77 or 66 of the same length, or SEQ ID NOs: 77 or 66 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a sixth peptide selected from peptides of formula I or formula I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 77 and 56,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 77 or 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 77 or 56 of the same length, or SEQ ID NOs: 77 or 56 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising a sixth peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is either a fragment of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions.
  • composition according to any one of the preceding embodiments comprising six peptides as defined in any one of the peptide mixes numbered 263, 263a, 263b, 267, 267a, 267b, 267c, 267d, 264, 264a, 264b, 264c, 264d, 265, 265a, 265b, 265c, 265d, 262, 262a, 262b, 262c and 262d shown in Table 10a.
  • composition according to any one of embodiments 1 to 34 comprising : a first peptide having the amino acid sequence of: a) SEQ ID NO: 48 or SEQ ID NO: 148, b) SEQ ID NO: 56 or SEQ ID NOs: 154, 155, 156 or 157, c) SEQ ID NO: 66 or SEQ ID NOs: 170, 166, 167 or 6, or d) SEQ ID NO: 77 or SEQ ID NO: 176.
  • composition according to any one of embodiments 1 to 36 comprising : the second peptide having the amino acid sequence of: e) SEQ ID NO: 97 or SEQ ID NO: 184, f) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195, or g) SEQ ID NO: 125 or SEQ ID NO: 208.
  • composition according to any one of the embodiments 36 and 37 comprising a third peptide having the same amino acid sequence as a peptide defined in a) to d) in embodiment 36 or e) to g) in embodiment 37, and not selected from the same a) to g) as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising a fourth peptide having the same amino acid sequence as a peptide defined in a) to d) in embodiment 36 or e) to g) in embodiment 37, and not selected from the same a) to g) as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising a fifth peptide having the same amino acid sequence as a peptide defined in a) to d) in embodiment 36 or e) to g) in embodiment 37, and not selected from the same a) to g) as any other peptide in the composition.
  • composition according to any one of the preceding embodiments comprising a sixth peptide having the same amino acid sequence as a peptide defined in a) to d) in embodiment 36 or e) to g) in embodiment 37, and not selected from the same a) to g) as any other peptide in the composition.
  • a composition comprising three peptides, which independently are 13 to 25 amino acid residues in length, said composition comprising : a first peptide having the amino acid sequence of: a) SEQ ID NO: 48 or SEQ ID NO: 148, b) SEQ ID NO: 56 or SEQ ID NOs: 154, 155, 156 or 157, c) SEQ ID NO: 66 or SEQ ID NOs: 170, 166, 167 or 6, d) SEQ ID NO: 77 or SEQ ID NOs: 176; a second peptide having the amino acid sequence of: e) SEQ ID NO: 97 or SEQ ID NO: 184, f) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195, g) SEQ ID NO: 125 or SEQ ID NOs: 208; and a third peptide having the same amino acid sequence as a peptide defined in a) to g), and not selected from the same a) to g) as
  • composition according to embodiment 42 comprising : a first peptide having the amino acid sequence of: h) SEQ ID NO: 48 or SEQ ID NO: 148, i) SEQ ID NO: 77 or SEQ ID NO: 176; and/or a second peptide having the amino acid sequence of: j) SEQ ID NO: 97 or SEQ ID NO: 184, k) SEQ ID NO: 107 or SEQ ID NOs: 11, 194 or 195,
  • composition according to embodiment 42 comprising : a first peptide having the amino acid sequence of: m) SEQ ID NO: 148, n) SEQ ID NOs: 155 or 157, o) SEQ ID NOs: 170 or 167, or p) SEQ ID NO: 176; and/or the second peptide having the amino acid sequence of: q) SEQ ID NO: 184, r) SEQ ID NOs: 194 or 195, or s) SEQ ID NO: 208; and/or the third peptide having the same amino acid sequence as a peptide defined above in m) to s), and not selected from the same m) to s) as any other peptide in the composition.
  • composition according to embodiment 42 comprising : a first peptide having the amino acid sequence of: t) SEQ ID NO: 148, u) SEQ ID NO: 176; and/or a second peptide having the amino acid sequence of: v) SEQ ID NO: 184, w) SEQ ID NOs: 194 or 195, x) SEQ ID NO: 208; and/or a third peptide having the same amino acid sequence as a peptide defined in t) to x), and not selected from the same t) to x) as any other peptide in the composition. 46.
  • composition according to any one of the embodiments 42 to 45 comprising a fourth, fifth and/or sixth peptide independently having the same amino acid sequence as a peptide selected from a) to g) of embodiment 42, each not having the same definition a) to g) as another peptide in the composition.
  • composition according to any one of the embodiments 42 to 46 comprising a fourth, fifth and/or sixth peptide independently having the same amino acid sequence as a peptide selected from h) to I) of embodiment 43, each not having the same definition h) to I) as another peptide in the composition.
  • composition according to any one of the embodiments 42 to 47 comprising a further peptide independently having the same amino acid sequence as a peptide selected from a) to g) of embodiment 42 or from h) to I) of embodiment 43, each not having the same definition a) to I) as another peptide in the composition.
  • composition according to any one of the preceding embodiments comprising a fourth, fifth, sixth and/or further peptide, which peptide(s) independently are 13 to 25 amino acid residues in length, wherein any one of the fourth, fifth, sixth or further peptide is of either formula III or III* or formula IV or IV*, wherein
  • a peptide of formula III has an amino acid sequence defined by: a-A3-C3-B3-b
  • a peptide of formula III* has an amino acid sequence defined by: a-A3-C3*-B3-b
  • a peptide of formula IV has an amino acid sequence defined by: a-A4-C4-B4-b
  • a peptide of formula IV* has an amino acid sequence defined by: a-A4-C4*-B4-b and wherein
  • - C3 is an amino acid sequence selected from any one of SEQ ID NOs: 49, 59, or 64,
  • C3* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C3 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C3* is shorter than C3;
  • - C4 is an amino acid sequence selected from any one of SEQ ID NOs: 14, 98, 100 or 113,
  • - C4* consists of 13 to 16 contiguous amino acid residues of the amino acid sequence defined in C4 with either 1, 2 or 3 amino acid residue substitutions or with either 0, 1 or 2 substitutions if C4* is shorter than C4;
  • - A3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of CI in SEQ ID NO: 1 , including 0, 1 or 2 amino acid residue substitutions;
  • - B3 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of CI in SEQ ID NO: 1, including 0, 1 or 2 amino acid residue substitutions
  • - A4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the N-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - B4 is an amino acid sequence of 0-6 contiguous amino acid residues flanking the C-terminal amino acid residue of C2 in SEQ ID NO: 3, including 0, 1 or 2 amino acid residue substitutions;
  • - a and b is independently 0, 1, 2 or 3 amino acid residues selected among the amino acids lysine (K), arginine (R), aspartic acid (D) and glutamic acid (E) ; and wherein C3, C3*, C4, or C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO as CI, CI*, C2, C2*, C3 or C3* or C4 or C4* as any other peptide in the composition.
  • compositions according to embodiment 49 wherein the only substitution(s) in C3*, C4*, A3, A4, B3 and B4 is cysteine substituted with serine.
  • C3* in formula III* is either a fragment of SEQ ID NO: 49 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 49 of the same length, or SEQ ID NO: 49 with 1 or 2 amino acid substitutions;
  • C4 in formula IV is an amino acid sequence selected from any one of SEQ ID NOs: 98 and 100
  • C4* in formula IV* is either a fragment of SEQ ID NOs: 98 or 100 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 98 or 100 of the same length, or SEQ ID NOs: 98 or 100 with 1 or 2 amino acid substitutions.
  • composition according to any one of embodiments 49 to 51 comprising a first peptide selected from peptides of formula I and I*, wherein CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions, and a third peptide selected from peptides of formula I and I*, wherein
  • CI in formula I is an amino acid sequence selected from SEQ ID NOs: 56 and 77,
  • CI* in formula I* is either a fragment of SEQ ID NOs: 56 or 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 56 or 77 of the same length, or SEQ ID NOs: 56 or 77 with 1 or 2 amino acid substitutions, and peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence selected from SEQ ID NOs: 97, 107 and 125,
  • C2* in formula II* is either a fragment of SEQ ID NOs: 97, 107 or 125 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NOs: 97, 107 or 125 of the same length, or SEQ ID NOs: 97, 107 or 125 with 1 or 2 amino acid substitutions wherein CI, CI*, C2, or C2* in the third peptide is neither identical to, nor defined from, the same SEQ ID NO as CI in the first peptide or C2 in the second peptide.
  • composition according to any one of embodiments 49 to 51 comprising a first peptide of formula I and I*, wherein
  • CI in formula I is an amino acid sequence of SEQ ID NO: 77,
  • CI* in formula I* is either a fragment of SEQ ID NO: 77 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 77 of the same length, or SEQ ID NO: 77 with 1 or 2 amino acid substitutions, a second peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 97,
  • C2* in formula II* is of SEQ ID NO: 97 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 97 of the same length, or SEQ ID NO: 97 with 1 or 2 amino acid substitutions, a third peptide selected from peptides of formula II and II*, wherein
  • C2 in formula II is an amino acid sequence of SEQ ID NO: 107,
  • C2* in formula II* is either a fragment of SEQ ID NO: 107 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 107 of the same length, or SEQ ID NO: 107 with 1 or 2 amino acid substitutions, a fourth peptide selected from peptides of formula IV and IV*, wherein
  • C4 in formula IV is an amino acid sequence of SEQ ID NO: 100
  • C4* in formula IV* is either a fragment of SEQ ID NO: 100 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 100 of the same length, or SEQ ID NO: 100 with 1 or 2 amino acid substitutions
  • CI in formula I is an amino acid sequence of SEQ ID NO: 56,
  • CI* in formula I* is either a fragment of SEQ ID NO: 56 with 0, 1, or 2 amino acid substitutions compared to a fragment SEQ ID NO: 56 of the same length, or SEQ ID NO: 56 with 1 or 2 amino acid substitutions, wherein CI, CI*, C2, C2*, C4, C4* in any of the peptides in the composition is neither identical to, nor defined from, the same SEQ ID NO CI, C2, C4 as any other peptide in the composition.
  • composition according to any one of embodiments 49 to 53 comprising five peptides as defined in any one of the peptide mixes numbered 313, 313a, 313b and 313c shown in Table 11a.
  • composition according to any one of embodiments embodiments 49 to 54 comprising a first peptide of formula I and I*, wherein CI in formula I is an amino acid sequence of SEQ ID NO: 56,

Abstract

La présente invention concerne des combinaisons peptidiques pour une utilisation en immunothérapie pour le traitement de l'allergie au pollen de cyprès et de cèdre, par exemple du pollen du cèdre japonais et du pollen à réaction croisée associés de membres de la famille des cyprès (Cupressaceae). Les combinaisons peptidiques, qui sont conçue de façon à avoir une grande couverture HLA dans le monde entier, comprennent au moins trois peptides différents, comprenant au moins un peptide Cry j 1 et au moins un peptide Cry j 2.
PCT/US2016/038760 2015-06-22 2016-06-22 Combinaisons de peptides et leur utilisation dans le traitement de l'allergie aux pollen de cèdre WO2016209959A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017134430A1 (fr) * 2016-02-02 2017-08-10 Circassia Limited Peptides de l'allegène du pollen du japon pour la prévention ou le traitement d'une allergie

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WO2017134430A1 (fr) * 2016-02-02 2017-08-10 Circassia Limited Peptides de l'allegène du pollen du japon pour la prévention ou le traitement d'une allergie

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