WO2010037402A1 - Molecular vaccines for infectious disease - Google Patents

Molecular vaccines for infectious disease Download PDF

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Publication number
WO2010037402A1
WO2010037402A1 PCT/DK2009/050262 DK2009050262W WO2010037402A1 WO 2010037402 A1 WO2010037402 A1 WO 2010037402A1 DK 2009050262 W DK2009050262 W DK 2009050262W WO 2010037402 A1 WO2010037402 A1 WO 2010037402A1
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Prior art keywords
composition according
mhc
beads
active molecules
molecules
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PCT/DK2009/050262
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French (fr)
Inventor
Jørgen SCHØLLER
Henrik Pedersen
Liselotte Brix
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Dako Denmark A/S
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Application filed by Dako Denmark A/S filed Critical Dako Denmark A/S
Priority to US13/122,007 priority Critical patent/US10369204B2/en
Publication of WO2010037402A1 publication Critical patent/WO2010037402A1/en
Priority to US16/455,224 priority patent/US11992518B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/21—Retroviridae, e.g. equine infectious anemia virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55516—Proteins; Peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55583—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6087—Polysaccharides; Lipopolysaccharides [LPS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/625—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier binding through the biotin-streptavidin system or similar
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16211—Human Immunodeficiency Virus, HIV concerning HIV gagpol
    • C12N2740/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to methods for construction of pharmamers i.e. vaccine components characterized by their multimerization domain and the attached biologically active molecules, and their use in preparation of vaccines that contains the pharmamers alone or in combination with other molecules.
  • the individual molecules of the construct can be bound to each other or the multimerization domain(s) by covalent or non-covalent bonds, directly or via linkers.
  • the one or more pharmamers comprises one or more MHC multimers disclosed in PCT/D2002/000169. Some of the molecules in the vaccine may be free i.e. non-attached to the pharmamer itself.
  • the invention further relates to the use of such preparations in vaccine settings aimed to function as preventive/prophylactic or therapeutic vaccines in humans and animals.
  • the present invention relates to a composition for vaccination and/or immune monitoring of a vaccine response comprising one or more pharmamers.
  • the present invention relates to a method of making the composition for vaccination and/or immune monitoring of a vaccine response comprising one or more pharmamers.
  • This invention also relates to a method for vaccination comprising administration to an individual in need thereof an effective amount of a composition comprising one or more pharmamers.
  • the invention further relates to a method for monitoring a vaccine response comprising use of the composition comprising one or more pharmamers.
  • the invention relates to a kit-of-parts comprising a composion comprising one or more pharmamers and use for this kit-of-parts for vaccination of an individual in need thereof or for monitoring of a vaccine response.
  • the present invention relates to methods for construction of pharmamers characterized by their multimerization domain and the attached biologically active molecules, and their use in preparation of vaccines that contains the pharmamers alone or in combination with other molecules.
  • Adjuvant refers to an immunological adjuvant. By this is meant a compound that is able to enhance or facilitate the immune system's response to the ingredient in question, thereby inducing an immune response or series of immune responses in the subject.
  • the adjuvant can facilitate the effect of the therapeutic composition by forming depots (prolonging the half-life of the ingredient), provide additional T-cell help and stimulate cytokine production.
  • Facilitation of antigen survival and unspecific stimulation by adjuvants may, in some cases, be required if the antigenic molecule epitopes or functional molecules of the pharmamer are only weakly antigenic or only exerts weak to moderate interactions with compounds, molecules, or cells of the immune system.
  • an antibody means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigenic epitope. Therefore, an antibody is any form of antibody or fragment thereof that exhibits the desired biological activity, e.g., binding the specific target antigen.
  • Antibodies can derive from multiple species. For example, antibodies include rodent (such as mouse and rat), rabbit, sheep, camel, and human antibodies. Antibodies can also include chimeric antibodies, which join variable regions from one species to constant regions from another species.
  • antibodies can be humanized, that is constructed by recombinant DNA technology to produce immunoglobulins which have human framework regions from one species combined with complementarity determining regions (CDR's) from a another species' immunoglobulin.
  • the antibody can be monoclonal or polyclonal.
  • Antibodies can be divided into isotypes (IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2).
  • the term "antibody” refers to an intact antibody, or a fragment of an antibody that competes with the intact antibody for antigen binding.
  • antibody fragments are produced by recombinant DNA techniques. In certain embodiments, antibody fragments are produced by enzymatic or chemical cleavage of intact antibodies. Exemplary antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, and scFv. Exemplary antibody fragments also include, but are not limited to, domain antibodies, nanobodies, minibodies ((scFv- CH 3 ) 2 ), maxibodies ((scFv-CH 2 -CH 3 ) 2 ), diabodies (noncovalent dimer of scFv).
  • Antigen presenting cell An antigen-presenting cell (APC) as used herein is a cell that displays foreign antigen complexed with MHC on its surface.
  • Antigenic peptide Any peptide molecule that is bound to or able to bind into the binding groove of either MHC I or MHC Il molecules.
  • Avidin as used herein is a glycoprotein found in the egg white and tissues of birds, reptiles and amphibians. It contains four identical subunits having a combined mass of 67,000-68,000 daltons. Each subunit consists of 128 amino acids and binds one molecule of biotin.
  • Biologically active molecules Any molecule having biological activity. Biologically active molecules of the present invention may be attached to pharmamers, adjuvants, other biologically active molecules and/or vaccine enhancers by covalent or non- covalent interaction or they may be individual component(s) of the composition.
  • Bioly active molecules in a pharmamer affect the binding characteristics and/or the effects of the pharmamer.
  • Biotin as used herein, is also known as vitamin H or B 7 . Biotin has the chemical formula Ci 0 H 16 N 2 O 3 S.
  • Covalent binding is used herein to describe a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. Attraction-to-repulsion stability that forms between atoms when they share electrons is known as covalent bonding.
  • Crosslinking is the process of chemically joining two or more molecules by a covalent bond.
  • Crosslinking reagents contain reactive ends to specific functional groups (primary amines, sulfhydryls, etc.) on proteins or other molecules.
  • Dendritic cell The term dendritic cell as used herein is a type of immune cells. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells.
  • Immunologically active molecules is used interchangeably herein with immuno active molecule and is any molecule that as an active part of the pharmamer, pharmamer composition, vaccine or therapeutics is modulating the immuno-activity of the pharmamer, pharmamer composition, vaccine or therapeutics itself or the immune system as such.
  • a carrier as used herein can be any type of molecule that is directly or indirectly associated with a biologically active molecule.
  • a carrier may link biologically active molecules to multimerisation domains and/or be a multimerisation domain itself.
  • Dextran the term dextran as used herein is is a complex, branched polysaccharide made of many glucose molecules joined into chains of varying lengths. The straight chain consists of ⁇ 1 ->6 glycosidic linkages between glucose molecules, while branches begin from ⁇ 1 ->3 linkages (and in some cases, ⁇ 1 ->2 and ⁇ 1 ->4 linkages as well).
  • Linker molecule Linker molecule and linker is used interchangeable herein.
  • a linker molecule is a molecule that covalently or non-covalently connects two or more molecules, thereby creating a larger complex consisting of all molecules including the linker molecule.
  • Liposomes The term liposome as used herein is defined as a spherical vesicle with a membrane composed of a phospholipid and cholesterol bilayer. Liposomes, usually but not by definition, contain a core of aqueous solution; lipid spheres that contain no aqueous material are called micelles.
  • MHC Denotes the major histocompatibility complex.
  • a "MHC Class I molecule" as used everywhere herein is defined as a molecule which comprises 1 -3 subunits, including a heavy chain, a heavy chain combined with a light chain (beta 2 m), a heavy chain combined with a light chain (beta 2 m) through a flexible linker, a heavy chain combined with a peptide, a heavy chain combined with a peptide through a flexible linker, a heavy chain/beta 2 m dimer combined with a peptide, and a heavy chain/beta 2 m dimer with a peptide through a flexible linker to the heavy or light chain.
  • the MHC molecule chain can be changed by substitution of single or by cohorts of native amino acids or by inserts, or deletions to enhance or impair the functions attributed to said molecule.
  • substitution of XX with YY in position nn of human beta 2 m enhance the biochemical stability of MHC Class I molecule complexes and thus can lead to more efficient antigen presentation of subdominant peptide epitopes.
  • MHC complex is herein used interchangeably with MHC-peptide complex, unless it is specified that the MHC complex is empty, i.e. is not complexed with peptide.
  • MHC Class I like molecules include CD1 d, HLA E, HLA G, HLA F, HLA H, MIC A, MIC B, ULBP-1 , ULBP-2, and ULBP-3.
  • a "MHC Class Il molecule” as used everywhere herein is defined as a molecule which comprises 2-3 subunits including an alpha-chain and a beta-chain (alpha/beta-dimer), an alpha/beta dimer with a peptide, and an alpha/beta dimer combined with a peptide through a flexible linker to the alpha or beta chain, an alpha/beta dimer combined through an interaction by affinity tags e.g.
  • MHC Class Il molecule can comprise only 1 subunit.
  • MHC Class Il like molecules include HLA DM, HLA DO, I-A beta2, and I-E beta2.
  • MHC complexes and “MHC constructs” are used interchangably herein.
  • MHC protein and “MHC molecule” are used interchangably herein. Accordingly, a functional MHC peptide complex comprises a MHC protein or MHC molecule associated with a peptide to be presented for cells or binding partners having an affinity for said peptide.
  • MHC complexes and “MHC multimers” as used herein are meant such complexes and multimers thereof, which are capable of performing at least one of the functions attributed to said complex or multimer.
  • the terms include both classical and non-classical MHC complexes.
  • the meaning of “classical” and “non-classical” in connection with MHC complexes is well known to the person skilled in the art.
  • Non- classical MHC complexes are subgroups of MHC-like complexes.
  • MHC complex includes MHC Class I molecules, MHC Class Il molecules, as well as MHC- like molecules (both Class I and Class II), including the subgroup non-classical MHC Class I and Class Il molecules.
  • the MHC molecule can suitably be a vertebrate MHC molecule such as a human, a mouse, a rat, a porcine, a bovine or an avian MHC molecule.
  • a vertebrate MHC molecule such as a human, a mouse, a rat, a porcine, a bovine or an avian MHC molecule.
  • Such MHC complexes from different species have different names. E.g. in humans, MHC complexes are denoted HLA. The person skilled in the art will readily know the name of the MHC complexes from various species.
  • MHC multimer Any molecule complex compricing one or more MHC molecules held together by a multimerization domain.
  • the attachment of MHC molecule to multimerization domain may be directly or in-directly via a linker and may be covalent or non-covalent.
  • a multimerization domain is a molecule, a complex of molecules, a cell, cell-like structure or a solid support, to which one or more biologically active molecules can be attached.
  • a multimerization domain may consist of one or more carriers and/or one or more scaffolds and may also contain one or more linkers connecting carrier to scaffold, carrier to carrier, scaffold to scaffold.
  • Multimerization domains thus include polymers, proteins (e.g. IgG, streptavidin, TCR, scaffold proteins) micelles, cells, beads, other types of solid support, small organic molecules carrying reactive groups or carrying chemical motifs that can bind biologically active mulecules or any other type of multimerization domain as described elsewhere herein.
  • Non-covalent bond is a type of chemical bond, that does not involve the sharing of pairs of electrons, but rather involves more dispersed variations of electromagnetic interactions.
  • Nonsense peptide A peptide that binds efficiently to the peptide binding groove of MHC protein, but that does not support binding of the resultant MHC-peptide complex to desired TCR
  • One or more as used everywhere herein is intended to include one and a plurality.
  • Pharmamer Molecule or molecule complex comprising one or more multimerisation domain(s) and one or more biologically active molecules.
  • Streptavidin as used herein is a tetrameric protein purified from the bacterium Streptomyces avidinii. Streptavidin is widely use in molecular biology through its extraordinarily strong affinity for biotin.
  • Vaccine As used herein the term vaccine is used for an antigenic preparation used to establish patial or total immunity to a disease or illness and thereby protecting, curing or treating the body from a specific disease or illness. Vaccines are either prophylactic and prevent disease or therapeutic and treat disease. Vaccines may contain more than one type of antigen and is then called a combined vaccine.
  • Vaccination The introduction of vaccine into the body of human or animals for the purpose of inducing immunity.
  • treatment refers to prophylactic, ameliorating, therapeutic or curative treatment.
  • Figure 1 List of HLA Class 1 alleles of particular interest of the present invention. From http://www.anthonynolan.org.uk/HIG/lists/class1list.html, 2007
  • Figure 2 List of HLA Class 2 alleles of particular interest of the present invention. From http://hla. alleles. org/alleles/class2. html, 2009
  • Groups 1 , 2 and 3 received full vaccine doses (SC) at the first immunization and half the dose in the 2 nd , 3 rd and 4 th immunizations, with Titermax (0.5ml).
  • Group 5 animals received the same vaccine as group 2 but without Titermax and full vaccine doses at all 4 immunizations administered IM.
  • Figure 4 :
  • Serum neutralizing activity in the 5 groups of macaques after the last immunization.
  • A Complement dependent
  • B Complement independent
  • C correlation with peak viral load
  • D correlation with cumulative loads; ⁇ Groupi , • Group2, ⁇ Group3, O Group4, ⁇ Group ⁇
  • Figure 8 Amino acid sequence of a monomer gp140 molecule compricing biotinylation tag and oligomerization domain enabling biotinylation and trimer formation respectively.
  • Figure 9 Amino acid sequence of Siv p27 encoded by the Gag gene of SIV.
  • Figure 10 Examples of usefull reactive groups compriced in multimerization domains and/or biologically active molecules of the present invention. Detailed description of the invention
  • the present invention relates to a composition compricing one or more pharmamers.
  • Pharmamers are molecules or molecule complexes characterised by having one or more multimerisation domains whereto one or more biologically active molecules are attached either directly or through a linker.
  • the biologically active molecules may also themselves comprice one or more multimerisation domains.
  • Other components may also be attached to the pharmamer in order to broaden, increase, decrease or otherwise modify the binding of and/or effect of the pharmamer.
  • the invention in another embodiment relates to compositions compricing one or more pharmamers and additionally comprices one or more adjuvant(s), one or more vaccine enhance(s) and/or one or more biologically active molecules not attached to the pharmamer construct. These other molecules may broaden, increase, decrease or otherwise modify the binding, effect or uptake of the pharmamer construct(s) or may have an effect themselves affecting the overall effect of the composition.
  • the present invention relates to methods for construction of pharmamers and for making compositions compricing one or more pharmamers.
  • compositions comprising one or more pharmamers for vaccination of an individual in need thereof.
  • Compositions of pharmamers may be used for prophylactic vaccination of individuals to protect the individual against e.g. viral disease, bacterial disease, parasitic disease, cancer disease, autoimmune disease, allergy or other diseases.
  • Pharmamer compositions may also be used for therapeutic vaccination in order to cure, alleviate or prevent/delay progression of one or more diseases e.g. viral disease, bacterial disease, parasitic disease, cancer disease, autoimmune disease, allergy or other diseases.
  • pharmamers will be used to describe any molecule or molecule complex where the number of involved molecules or molecule complexes is larger than one, and where these components are held together in a large complex by covalent or non-covalent interactions to the multimerization domain and/or between the individual components.
  • the components can be identical or different molecules or molecular complexes.
  • organic molecule-based pharmamers include functionalized cyclic structures such as benzene rings where e.g. a benzene ring is functionalized and covalently linked to e.g. three immunologically active molecules;
  • cell-based pharmamers include dendritic cells and antigen presenting cells (APCs);
  • membrane-based pharmamers include liposomes and micelles carying immunologically active molecules or complexes in their membranes;
  • polymer-based pharmamers include molecule constructs where immunologically active molecules or complexes are bound covalently or non-covalently to a dextran backbone/multimerisation domain and;
  • particles include beads or other solid supports with immunologically active molecules immobilized on the surface.
  • any kind of multimerization domain can be used, including any kind of cell, polymer, protein or other molecular structure, or particles and solid supports.
  • a pharmamer i.e. the biologically active molecules and the multimerization domain(s). This can be done by chemical reactions between reactive groups of the multimerization domain and reactive groups on a immunologically active protein, or by non-covalent interaction between a part of the immunologically active protein (e.g. a biotinylated peptide component) and the multimerization domain (e.g. four binding sites for biotin on the strepavidin tetrameric protein).
  • a part of the immunologically active protein e.g. a biotinylated peptide component
  • the multimerization domain e.g. four binding sites for biotin on the strepavidin tetrameric protein.
  • the pharmamer can be formed by the non-covalent association of amino acid helices fused to one component of immunologically active protein, to form a pentameric pharmamer, held together by five helices in a coiled-coil structure making up the multimerization domain.
  • Appropriate chemical reactions for the covalent coupling of molecules or molecular complexes to the multimerization domain include nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation), addition to carbon- hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers), nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines), and cycloadditions.
  • electrophiles e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disul
  • Appropriate molecules capable of providing non covalent interactions between the multimerization domain and the immunologically and/or biologically active molecules or complexes hereof involve the following molecule pairs and molecules: streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA,
  • PNA/PNA LNA/DNA
  • leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag
  • binding entity can be an "anti-tag".
  • anti-tag is meant an antibody binding to the tag and any other molecule capable of binding to such tag.
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000
  • Da for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,600,000 Da to 2,800,
  • 2,800,000 Da to 3,000,000 Da such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to
  • 900,000 for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da,
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight of at least 50,000 Da, such as at least 100,000 Da, for example at least 200,000 Da, such as at least 300,000 Da, for example at least 400,000 Da, such as at least 500,000 Da, for example at least 600,000 Da, such as at least 700,000 Da, for example at least
  • 800,000 Da such as at least 900,000 Da, for example at least 1 ,000,000 Da, such as at least 1 ,100,000 Da, for example at least 1 ,200,000 Da, such as at least 1 ,300,000 Da, for example at least 1 ,400,000 Da, such as at least 1 ,500,000 Da, for example at least 1 ,600,000 Da, such as at least 1 ,700,000 Da, for example at least 1 ,800,000 Da, such as at least 1 ,900,000 Da, for example at least 2,000,000 Da, such as at least 2,100,000 Da, for example at least 2,200,000 Da, such as at least 2,300,000 Da, for example at least 2,400,000 Da, such as at least 2,500,000 Da, for example at least 2,600,000 Da, such as at least 2,700,000 Da, for example at least 2,800,000 Da, such as at least 2,900,000 Da, for example at least 3,000,000 Da, such as at least 3,100,000 Da, for example at least 3,200,000 Da, such as at least 3,300,000 Da, for
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight of less than 5,000,000 Da, such as less than 4,900,000 Da, for example less than 4,800,000 Da, such as less than 4,700,000 Da, for example less than 4,600,000 Da, such as less than 4,500,000 Da, for example less than 4,400,000 Da, such as less than 4,300,000 Da, for example less than 4,200,000 Da, such as less than 4,100,000 Da, for example less than 4,000,000 Da, such as less than 3,900,000 Da, for example less than
  • 3,800,000 Da such as less than 3,700,000 Da, for example less than 3,600,000 Da, such as less than 3,500,000 Da, for example less than 3,400,000 Da, such as less than 3,300,000 Da, for example less than 3,200,000 Da, such as less than 3,100,000 Da, for example less than 3,000,000 Da, such as less than 2,900,000 Da, for example less than 2,800,000 Da, such as less than 2,700,000 Da, for example less than 2,600,000 Da, such as less than 2,500,000 Da, for example less than 2,400,000 Da, such as less than 2,300,000 Da, for example less than 2,200,000 Da, such as less than 2,100,000 Da, for example less than 2,000,000 Da, such as less than 1 ,900,000 Da, for example less than 1 ,800,000 Da, such as less than 1 ,700,000 Da, for example less than 1 ,600,000 Da, such as less than 1 ,500,000 Da, for example less than 1 ,400,000 Da, such as less than 1 ,300,000 Da, for example less than 1
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising more than 1 pharmamer, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200,
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising more than 2 different pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different pharmamers.
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising more than 2 identical pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical pharmamers.
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising less than 10,000 pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 pharmamers.
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising less than 10,000 different pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10,
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising less than 10,000 identical pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500,
  • the pharmemers of the invention in one embodiment comprise one or more multimerization domain(s).
  • the multimerization domain(s) can be a soluble multimerization domain(s) or a not soluble multimerization domain(s).
  • the multimerization domain(s) can be any such which enables attachment of the MHC molecules, the binding entities, and/or the biologically active compounds, while providing advantageous properties of the construct.
  • suitable multimerization domain(s)s are polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O- ethylamino guaran, chitins and chitosans indlucing 6-0- carboxymethyl chitin and N- carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxy- ethyl cellulose, 6-amino-6-deoxy cellulose and O-ethyl- amine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxy-methylated ficoll
  • Fos-Jun or Fos-Jun like or coiled-coiled dimers/trimers/tetramers/pentamers Streptavidin, Avidin, Streptactin, T-cell receptors orther protein receptors and virus- like proteins (VLP), and polynucleotides, DNA, RNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs and small organic molecules including but not limited to steroids, peptides, linear or cyclic structures, aromatic structures, aliphatic structures.
  • cells e.g. dendritic cells, antigen presenting cell, B-cell, T-cell
  • Macrophages Kupfer cells, Langerhans cells, transfected cells expressing biologically active proteins, including hybridoma cells, yeast-cells, insect-cells, CHO cells, any cell biologically active molecules, cell-like structures e.g. micelles, liposomes, and phages e.g. filamenteous phages and viral or viral-like particles.
  • biologically active proteins including hybridoma cells, yeast-cells, insect-cells, CHO cells, any cell biologically active molecules, cell-like structures e.g. micelles, liposomes, and phages e.g. filamenteous phages and viral or viral-like particles.
  • suitable multimerization domains are solid supports including but not limited to beads, particulate matters and other surfaces.
  • multimerization domain(s) Also included in this definition of the multimerization domain(s) is mixed forms, i.e. one or more multimerization domain(s) composed of one or more of the above examples.
  • mixed forms i.e. one or more multimerization domain(s) composed of one or more of the above examples.
  • An example of this is dextran coupled with Streptavidin whereto biotinylated biologically active proteins can bind.
  • multimerization domain(s) depend i.e. on the application of the pharmamer. Of course, several parameters can be varied in the above-given examples of multimerization domain(s), including the length and branching. Furthermore, the multimerization domain(s) can carry various substitutions, including such, which can be protected and/or activated, enabling further derivatisation.
  • the pharmamer construct of the invention can further comprise one or several different biologically active molecules in order to affect the characteristics of the constructs, e. g. with respect to binding properties, effects, antigenecity, specificity, solubility, stability, or detectability. For instance, spacing could be provided between the biologically active molecules.
  • One preferred embodiment of the present invention includes multimerisation domains made of Streptavidin or Avidin whereto biotin, biotin-like peptides or other biotin-like molecules can bind.
  • Another preferred embodiment includes dextran whereto biologically active molecules are attached directly through a linker as described elsewhere herein.
  • the biologically active molecules can also be attached through a second multimerization domain or an entity as described elsewhere herein. Examples include but is not limited to divinylsulfone activated dextran whereto biologically active molecules are coupled directly e.g.
  • dextran coupled with SA whereto biologically active molecules are attached through a biotin on the biologically active molecule
  • dextran with biologically active molecules are attached through a coiled-coil structure where on ⁇ -helix of a coiled-coil dimer is coupled to dextran and the other ⁇ -helix is coupled to the biologically active molecule e.g. as a fusion protein.
  • a preferred embodiment include beads or bead-like structures having an excluded volume (e.g. polysaccharide beads, polystyrene beads, magnetic polystyrene beads, polycarbamate beads, or any other kind of beads that can be dissolved or suspended in aqueous buffer) that carry electrophilic groups (e.g. divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters), and where biologically active molecules have been covalently immobilized to these by reaction of nucleophiles comprised within the biologically active molecule with the electrophiles of the beads.
  • electrophilic groups e.g. divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated est
  • the biologically active molecules described immediately above (where the one or more multimerization domain(s) is a bead) further comprises a flexible or rigid, and water soluble, linker that allows for the immobilized biologically active molecules to interact efficiently with surrounding cells and molecules.
  • the linker is cleavable, allowing for release of the biologically active molecules from the bead.
  • the bead is covalently or non-covalently coated with pharmamers or single biologically active molecules, through non-cleavable or cleavable linkers.
  • the bead can be coated with streptavidin monomers, which in turn are associated with biotinylated pharmamers; or the bead can be coated with streptavidin tetramers, each of which are associated with 0, 1 , 2, 3, or 4 biotinylated biologically active molecules; or the bead can be coated with biologically active molecules where e.g. the reactive groups of the biologically active molecules (e.g. the divinyl sulfone-activated dextran backbone) has reacted with nucleophilic groups on the bead, to form a covalent linkage between the dextran of the dextramer and the beads.
  • the reactive groups of the biologically active molecules e.g. the divinyl sulfone-activated dextran backbone
  • a preferred embodiment including self-assembling multimeric structures are trimeric, tetrameric, pentameric, hexameric or heptameric coiled-coil structures holding together 3, 4, 5, 6 or 7 biologically active molecules.
  • the coiled-coil structures may be attached to biologically active molecules through covalent or non-covalent bonds.
  • multimerization domains e.g. streptavidin tetramers bound to biotinylated biologically active molecules
  • another multimerization domain e.g. the bead
  • the one or more multimerization domain(s) can be any support capable of binding the biologically active molecules.
  • Well-known supports or multimerization domains include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
  • the nature of the one or more multimerization domain(s) can be either soluble to some extent or insoluble for the purposes of the present invention.
  • the support material can have virtually any possible structural configuration so long as the coupled molecule is capable of binding to the biologically active molecule.
  • the support configuration can be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface can be flat such as a sheet, test strip, a membrane, or a plastic surface.
  • the multimerization domain(s) can be a polymer or an oligomer or a non-repeating moiety.
  • the polymer or oligomer moiety can comprise repeat units consisting of a repeat moiety selected from alkyl (e.g., -CH 2 -), substituted alkyl (e.g., --CHR--), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, as well as moieties comprising combinations thereof.
  • a non-repeating multifunctional bridge moiety can be a moiety selected from alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and moieties comprising combinations thereof (in each permutation).
  • a non-repeating moiety can include repeating units (e.g., methylene) within portions or segments thereof without repeating as a whole.
  • the oligomer (or oligomer moiety) or the polymer (or polymer moiety), can generally be soluble or insoluble; can generally be a cross-linked oligomer (or oligomer moiety) or a cross-linked polymer (or polymer moiety); can generally be a homopolymer or a copolymer (including polymers having two monomer-repeat-units, terpolymers and higher-order polymers), including for example random copolymer moieties and block copolymer moieties; can generally include one or more ionic monomer moieties such as one or more anionic monomer moieties; can generally include one or more hydrophobic monomer moieties; can generally include one or more hydrophilic monomer moieties; and can generally include any of the foregoing features in combination.
  • the polymer moiety can be soluble or insoluble, existing for example as dispersed micelles or particles, such as colloidal particles or (insoluble) macroscopic beads.
  • Polymer moieties can be hydrophobic, hydrophilic, amphiphilic, uncharged or non-ionic, negatively or positively charged, or a combination thereof, and can be organic or inorganic.
  • Inorganic polymers also referred to as inorganic multimerization domains in some cases, include silica (e.g., multi-layered silica), diatomaceous earth, zeolite, calcium carbonate, talc, and the like.
  • Suitable water-soluble polymers include polyethylene glycol (PEG), monomethoxy- PEG, mono-(Ci-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, cellulose, or other carbohydrate-based polymers.
  • a conjugate can also comprise a mixture of such water- soluble polymers.
  • polysaccharides useful in the present invention include materials from vegetal or animal origin, including cellulose materials, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin, and/or chitosan.
  • the type of multimerization domain can also be selected from, but is not limited to, the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross- linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethyl
  • the multimerization domain(s) in the present invention is preferable less than 1 ,000 Da (small molecule scaffold). In another embodiment the multimerization domain(s) is preferable between 1 ,000 Da and 10,000 Da (small molecule scaffold, small peptides, small polymers). In another embodiment the multimerization domain(s) is between 10,000 Da and 100,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure). In another embodiment the multimerization domain(s) is preferable between 100,000 Da and 1 ,000,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure).
  • the multimerization domain(s) is preferable larger than 1 ,000,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure, cells, liposomes, artificial lipid bi layers, polystyrene beads and other beads.
  • Da Stel molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure, cells, liposomes, artificial lipid bi layers, polystyrene beads and other beads.
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200,
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 different multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different multimerization domains.
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 identical multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical multimerization domains.
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 multimerization domains.
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 different multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6,
  • the present invention relates in one embodiment to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 identical multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical multimerization domains.
  • the present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from
  • 4,000,000 Da to 4,200,000 Da such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
  • Pharmamers consist of one or more biologically active molecules coupled to a multimerization domain, as defined above.
  • the biologically active molecules can be selected among every known biologically active molecule on basis of their function in order to obtain the desired functionality of the pharmamer and the final vaccine.
  • Biologically active molecules are molecules having biological activity. Biologically active molecules in a pharmamer affect the binding characteristics and/or the effects of the pharmamer.
  • Biologically active molecules of the present invention can be divided into the following categories:
  • Proteins may be full length or truncated and may be modified e.g. by introduction of additional amino acids, mutated, chemically modified (e.g. acetylation, methylation, Pegylation, phosphorylation, glycosylation etc.) or carrying other modifications.
  • the proteins may also be stabilized by covalent or non- covalent attachment of protein linkers or other protein molecules.
  • Biologically active protein molecules of the present invention includes but is not limited to: o Enzymes o Receptor proteins or co-receptor proteins o Immunological proteins (se section below for more details) o Growth factors (proteins capable of stimulating cellular proliferation and differentiation) o Protein hormones o Proteins from microorganisms (viral, bacterial, parasitic, fungal ect.)
  • Example surface protein include any protein on the surface of microorganism e.g. the envelope proteins gp41 , gp120 or gp140 from HIV or truncated version of these.
  • surface proteins may be made as recombinant proteins by cloning, expression and purification.
  • the gene encoding the surface protein or a fragment of the protein may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g. compricing a recognition sequence for the BirA anzyme), chemically biotinylation (e.g.
  • gp140 may be made by cloning gp140 minus the transmembrane part of the protein leaving just the ecto domain of gp41 and gp120. These two molecules are held together through noncovalently association.
  • An example of an amino acid sequence of such a recombinant gp140 protein is shown in figure 8 (SEQ ID NO 9583).
  • gp120 may be produced recombinantly by cloning and expression.
  • Intracellular and internal proteins are proteins inside cells proteins inside an organism e.g. inside envelop vira.
  • proteins may be made as recombinant proteins by cloning, expression and purification.
  • the gene encoding the intracellular or internal protein or a fragment of the protein may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g. compricing a recognition sequence for the BirA anzyme), chemically biotinylation (e.g.
  • Example internal protein includes p27 from HIV that is a protein encoded by the gag gene and is a structural protein of the viral core.
  • Saccharides o Saccharides and derivatives thereof, e.g. phosphorylated, oxidized, reduced, amino derivatives, acetylated etc. Saccharides may have more than one modification
  • Homopolysaccharides e.g. glycans, dextran
  • Lipids o Fatty acyls (e.g. prostaglandins, leukotrienes etc.) o Glycerolipids (e.g. triglycerides) o Glycerophospholipids o Sphingolipids o Sterol lipids (eg. cholesterol, estrogen etc.) o Prenol lipids (eg vitamin E, K) o Polyketides (eg. erythromycin)
  • Small molecules are medicinal drug compounds having a molecular weights less than 1000 Daltons and include: o Natural compounds including but not limited to
  • Amine-drived hormones derivatives of amino acids tyrosine and tryptophan (e.g. catecholamine, thyroxine)
  • Salts e.g. comprising Ca++, Mg++ o Synthetic chemical compound
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000,
  • 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000,
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules.
  • the one or more pharmamers comprises more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000,
  • the present invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000,
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6,
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical biologically active molecules.
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 biological active molecules.
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules.
  • the present invention further relates to a vaccine composition
  • a vaccine composition comprising more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000,
  • the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
  • 10,000 biologically active molecules such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
  • the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different biologically active molecules.
  • the composition comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different biologically active molecules.
  • the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
  • the composition comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
  • the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are not attached to said one or more pharmamers. In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to some but not all of the one or more pharmamers.
  • the invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to one of the one or more pharmamers.
  • the invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to more than one of the one or more pharmamers such as more to than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or to more thani 0,000 of the one or more pharmamers.
  • the invention relates to a vaccine composition
  • a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to less than 10,000 of the one or more pharmamers, such as for example to less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or to less than 2 of the one or more pharmamers.
  • the present invention relates to a vaccine composition, wherein the one or more biologically active molecules and the one or more multimerization domain are coupled together either directly or indirectly.
  • the pharmamer comprises one or more Immunologically active molecules.
  • Immunologically active molecules are compounds that can modulate the immuno-activity of the pharmamer itself or the immune system as such, by affecting binding characteristics or effects of the pharmamer.
  • a pharmamer can comprise several immunologically active molecules which can be the same or different.
  • Immunologically active molecules are a subgroup of biologically active molecules for example proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, antibodies, MHC molecules, TCR's and recombinant binding molecules to any of the foregoing, and combinations thereof.
  • Immunologically active molecules of special interest for the present invention can be selected from the groups listed below: • MHC class 1 proteins including HLA-A, HLA-B, HLA-C alleles. Examples of usefull MHC 1 alleles are listed in figure 1.
  • MHC class proteins usefull as immunologically active molecules may be complete trimer molecule complexes or parts of MHC class 1 molecules as follows: o Heavy chains o Heavy chains combined with beta2microglobulin o Heavy chains combined with beta2microglobulin and antigenic peptide o Heavy chain combined with antigenic peptide o Beta2mcroglobulin
  • MHC class 1 -like molecules o MICA, MICB o CD1d o HLA-E, HLA-F, HLA-G, HLA-H o ULBP-1 , ULBP-2, ULBP-3
  • HLA-DR HLA-DRA, HLA-DRB1 , HLA-DRB3, HLA- DRB4, HLA-DRB5
  • HLA-DQ HLA-DQA1 , HLADQA2, HLA-DQB1 , HLA-
  • HLA-DP HLA-DPAI 1 HLA-DPBI
  • HLA-DO HLA-DOA
  • HLA-DOB HLA-DM
  • HLA-DMA HLA-DMB
  • MHC class proteins usefull as immunologically active molecules may be complete trimer molecule complexes or parts of MHC class 2 molecules as follows: o 1 ⁇ -heavy chain o 1 ⁇ -heavy chain o 1 ⁇ -heavy chain + 1 ⁇ -heavy chain o 1 ⁇ -heavy chain + 1 ⁇ -heavy chain + antigenic peptide o Fragments of ⁇ -heavy chain or ⁇ -heavy chain (MHC ll-like peptides).
  • MHC ll-like proteins of special interest of the present invention are DRB3 * 02 * 03 like peptide: RFLELLKSECHFFNG (SEQ ID NO 9585) , DRB4 * -like peptide RVWNLIRYIYNQEEY (SEQ ID NO 9586), DRB5 * - like peptide FLQQDKYECHFFNGC SEQ ID NO 9587).
  • Cytokines including: o Interferons such as IFN-alpha, IFN-beta, IFN-gamma o lnterleukines such as IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28,-IL-29, IL-30, IL-31 , IL-32, IL-33, IL-34, IL-35
  • TNF-alfa TNF-beta
  • CSFs colony-stimulating factors
  • c-Kit colony-stimulating factors
  • EPO EPO
  • TGF- ⁇ TGF- ⁇
  • CD40L CD40L
  • Cytokine receptors like IL-1 R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9-R, IL-10R, IL-1 1 R, IL-12R, IL-13R, IL-15R, IL-18R, IL-20R, IL-21 R, IL-22R, IL-23R, IL-27R, IL-28R
  • Chemokines such as CXCL1 , CXCL2, CXCL3, CXCL4, CXCL5, CXCL6,
  • Toll-like receptors such as TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10
  • Toll like receptor ligands such as multiple triacyl lipopeptides, multiple diacyl lipopeptides, multiple glycolipids, multiple lipopeptides, multiple lipoproteins, lipoteichoic acid, peptidoglycans, Zymosan, single- and double-stranded RNA, Poly I:C, lipo-polysaccharides, fibrinogen, heparin sulphate fragments, hyaluronic acid fragments, flagellin, imidazoquinoline, loxoribine (guanosine analogue), bropirimine, Imiquimod, unmethylated CpG DNA; Viral entry receptors/molecules such as Ku70, Pvr, PrM , HVEM, EphrinB2, cellular integrins (in particular alpha2beta1 , alpha ⁇ betai alphaVbeta3), CD81 , CD155, SR-B1 , claudin-1 , xCT, human nect
  • Heat shock proteins such as HSP70, HSP90.
  • the heat shock proteins may be full length, truncated and or modified and may originate from any organism (e.g. bacteria, parasites, humans, animals ect.).
  • An embodiment of special interest of the present invention is the C-terminal part of HSP70 from Mycobacteria tuberculosis, e.g. amino acid 359-609.
  • the C- terminal part of HSP70 may be mad as a recombinant protein by cloning, expression and purification.
  • the gene encoding this C-terminal fragment may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g.
  • C-terminal fragments of HSP70 from bacteria that are not Myciobacterium Tuberculosis or C-terminal HSP70 fragment's from other organism may be used as biologically active molecule.
  • Fc ⁇ / ⁇ R Neonatal FcR • Lymphocyte homing receptors such as CD44, L-selectin, VLA-4 (CD49a, b, c, d, e, f), LFA-1
  • Co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD120, CD137 (4-1 BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS,
  • PD-1 Fas (CD95), FasL, CD40, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-L2, CD134L, CD137L, ICOSL
  • NK cell receptors/molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR3DL1 , KIR3DL", KIR3DS1 , KIR2DL1.KIRDL2, KIR2DL3, KIR2DL4, KIR2DL5, CD94/NKG2A, CD94/NKG2C, CD94/NKG2E,
  • Adhesion molecules such as ICAM-1 , ICAM-2, GlyCAM-1 , VCAM, CD34
  • Antibodies (monoclonal, polyclonal, recombinant) directed to a defined antigen e.g. any of the described biologically active molecules, immunologically active molecules, viral antigens, bacterial antigens, parasitic antigens, self-antigens, cancer antigens or any other antigen.
  • Antibodies of the present invention may be full length or derivatives of antibodies including: o Full length antibody o Fab fragments o scFv fragments o antibody-like structures e.g. scaffold proteins having the ability to bind antigens
  • Toxic molecules selected e.g. toxins, toxids
  • a pharmamer composition may have one or more than one immunologically active molecule.
  • the immunologically active molecule can suitably be attached to the multimerization domain(s) either directly, through one or more linkers or via one or more of the binding entities or one or more multimerization domains as described elsewhere herein.
  • the immunologically active molecules can also be linked to another immunologically active molecule and then attached to one or more multimerization domains.
  • the present invention in one aspect refers to a vaccine composition
  • a vaccine composition comprising one or more MHC monomer comprising a-b-P, or a MHC multimer comprising (a-b-P) n , wherein n > 1 ,
  • (a-b-P) is the MHC-peptide complex formed when the antigenic peptide P binds to the functional MHC protein
  • each MHC peptide complex of a MHC multimer is associated with one or more multimerization domains.
  • antigenic peptide P is used interchangeably with antigenic peptide.
  • Another aspect of the present invention refers to a vaccine compositon comprising one or more antigenic peptides not bound to a MHC molecule or an antigenic polypeptide featuring one or more antigenic peptides.
  • MHC monomers and MHC multimers comprising one or more MHC peptide complexes of class 1 or class 2 MHC are covered by the present invention.
  • the present invention covers antigenic peptides able to bind MHC class 1 and/or MHC class 2 molecules or antigenic polypeptides featuring such antigenic peptides.
  • the antigenic peptide of the present invention can have a length of e.g. 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 16-20, or 20-30 amino acid residues.
  • MHC multimer comprising 2 or more MHC-peptide complexes and a multimerization domain to which the 2 or more MHC-peptide complexes are associated.
  • the MHC multimer can generally be formed by association of the 2 or more MHC-peptide complexes with the multimerization domain to which the 2 or more MHC-peptide complexes are capable of associating.
  • the multimerization domain can be a scaffold associated with one or more MHC- peptide complexes, or a carrier associated with one or more, preferably more than one, MHC-peptide complex(es), or a carrier associated with a plurality of scaffolds each associated with one or more MHC-peptide complexes, such as 2 MHC-peptide complexes, 3 MHC-peptide complexes, 4 MHC-peptide complexes, 5 MHC-peptide complexes or more than 5 MHC-peptide complexes. Accordingly, multimerization domain collectively refers to each and every of the above. It will be clear from the detailed description of the invention provided herein below when the multimerization domain refers to a scaffold or a carrier or a carrier comprising one or more scaffolds.
  • the MHC complexes can be associated with this domain either directly or via one or more binding entities.
  • the association can be covalent or non-covalent.
  • a MHC complex comprising one or more entities (a-b-P) n , wherein a and b together form a functional MHC protein capable of binding a antigenic peptide P, and wherein (a-b-P) is the MHC-peptide complex formed when the antigenic peptide P binds to the functional MHC protein, said MHC complex optionally further comprising a multimerization domain comprising a carrier molecule and/or a scaffold.
  • MHC complex refers to any MHC complex, including MHC monomers in the form of a single MHC-peptide complex and MHC multimers comprising a multimerization domain to which more than one MHC peptide complex is associated.
  • n is by definition more than 1 , i.e. at least 2 or more.
  • MHC multimer is used herein specifically to indicate that more than one MHC-peptide complex is associated with a multimerization domain, such as a scaffold or carrier or carrier comprising one or more scaffolds.
  • a single MHC-peptide complex can be associated with a scaffold or a carrier or a carrier comprising a scaffold and a MHC-multimer comprising 2 or more MHC-peptide complexes can be formed by association of the individual MHC-peptide complexes with a scaffold or a carrier or a carrier comprising one or more scaffolds each associated with one or more MHC-peptide complexes.
  • the association can be a covalent linkage so that each or at least some of the n MHC-peptide complexes is covalently linked to the multimerization domain, or the association can be a non-covalent association so that each or at least some of the n MHC-peptide complexes are non-covalently associated with the multimerization domain.
  • the MHC complexes of the invention may be provided in non-soluble or soluble form, depending on the intended application.
  • MHC complexes of the present invention overcome low intrinsic affinities of monomer ligands and counter receptors.
  • the MHC complexes have a large variety of applications that include targeting of high affinity receptors (e.g. hormone peptide receptors for insulin) on target cells. Taken together poly-ligand binding to target cells has numerous practical, clinical and scientifically uses.
  • the present invention provides MHC complexes which present mono-valent or multi-valent binding sites for MHC recognising cells, such as MHC complexes optionally comprising a multimerization domain, such as a scaffold or a carrier molecule, which multimerization domain have attached thereto, directly or indirectly via one or more linkers, covalently or non-covalently, one or more MHC peptide complexes.
  • MHC complexes optionally comprising a multimerization domain, such as a scaffold or a carrier molecule, which multimerization domain have attached thereto, directly or indirectly via one or more linkers, covalently or non-covalently, one or more MHC peptide complexes.
  • a multimerization domain such as a scaffold or a carrier molecule
  • linkers covalently or non-covalently, one or more MHC peptide complexes.
  • the present invention relates to pharmamers or a vaccine composition comprising one or more pharmamers, wherein said phamamers comprise one or more identical or different antigenic peptides, fragments thereof or larger antigenic peptides/proteins comprising one or more of the sequences disclosed in this application.
  • An antigenic peptide is any peptide molecule that is bound to or able to bind into the binding groove of either MHC class 1 or MHC class 2.
  • the antigenic peptides may be directly attached to a multimerisation domain of a pharmamer using principles as described for other biologically active molecules elsewhere herein, they may be part of a larger protein or they may be bound to the peptide binding groove of MHC molecules and the MHC-peptide comlex then attached to the multimerisation domain of the pharmamer.
  • the antigenic peptide(s) can e.g. be 8 mers, 9 mers, 10 mers, 1 1 mers, 12 mers, 13 mers, 14 mers, 15 mers or 16 mers.
  • the antigenic peptides can in one embodiment be any antigenic peptide e.g. peptide(s) predicted by the netMHC algorithm (http://www.cbs.dtu.dk/services/NetMHC/).
  • the peptide(s) are derived from Lentivirus proteins such as HIV (Human immunodeficiency virus) proteins, like HIV-1 proteins or HIV-2 proteins.
  • the peptides are derived from retrovirus proteins such as SIV (Simian immunodeficiency virus) proteins.
  • the antigenic peptide(s) are derived from a cancer antigen.
  • the antigenic peptide(s) are derived from one or more of the HIV-1 proteins NP_057849/Gag-Pol, NP_057850/Pr55(Gag), NP_057851/Vif, NP_057852/Vpr, NP_057853/Tat, NP_057854/Rev, NP_057855/Vpu, NP_057856/Envelope surface glycoprotein gp160 precursor and NP_057857/Nef or any variant or fragment thereof.
  • the antigenic peptide(s) include one or more HIV-1 peptides from the table below (SEQ ID NO 1 -9568) or any variant or fragment thereof such as antigenic peptides comprising the core sequences listed in the table below or variants thereof.
  • HIV-1 peptides derived from the HIV-1 proteins predicted by the netMHC algoritm http://www.cbs.dtu.dk/services/NetMHC/) are listed in the table herein below.
  • NP_057849 8-mers 1 -3715 Gag-Pol MGARASVL;SVLSGGEL;ELDRWEKI;RWEKIRLR;RLRPGGKK;KLK
  • QRPLVTIK QRPLVTIK;TIKIGGQLK;QLKEALLDT;DTVLEEMSL;EEMSLPGRW; EMSLPG RWK;SLPGRWKPK;LPGRWKPKM;KMIGGIGGF;MIGGIG
  • KVYLAW VPA KVYLAW VPAH
  • VYLAW VPAH K
  • YLAW VPAH KG LAW
  • VYYRDSR VYYRDSRNPL;YYRDSRNPLW;RNPLWKGPAK;NPLWK
  • ETW ETWT KETW ETWWTEY; ETW ETWWTEYW ;W ETWWTEYW
  • VLFLDGI VLFLDGI;FLDGIDKAQDE;HSNWRAMASDF;NWRAMASDFNL;AMA
  • WVPAH KG IG VYLAW VPAH ; E KVYLAW VPAH KG IG ; YLAW VPAH K;
  • VAiHLKT A VQMAVFIHNFiLKT A VQMAV;HLLRWGLTTPDKKHQ;LL
  • VHAGPIAPGQMRE VHAGPIAPGQMRE;VHAGPIAPG;HQKEPPFLWMGYELH;KEPPFL
  • PVKTIHTDNG LAGRWPVKT;LAWVPAHKGIGGNEQ;LAWVPAHKG iLCKLLRGTKALTEVIjLRGTKALTEjLDEDFRKYTAFTIPSiFRKYTAF
  • LVGPTPVNIIGRNLL LVGPTPVNI
  • LVKLWYQLEKEPIVG VKLWYQ
  • VTLWQRPLVTIKIG VTLWQRPLVTIKIG;TLWQRPLVT;QVTNSATIMMQRGNF;VTNSATI

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Abstract

The present invention relates to methods for construction of pharmamers i.e. vaccine components characterized by their multimerization domain and the attached biologically active molecules, and their use in preparation of vaccines that contains the pharmamers alone or in combination with other molecules. The individual molecules of the construct can be bound to each other or the multimerization domain(s) by covalent or non-covalent bonds, directly or via linkers. The invention further relates to the use of such preparations in vaccine settings aimed to function as preventive/prophylactic or therapeutic vaccines in humans and animals.

Description

MOLECULAR VACCINES FOR INFECTIOUS DISEASE
All patent and non-patent references cited in the present application are hereby incorporated by reference in their entirety. The content of PCT/D2002/000169 is hereby incorporated by reference in this application.
The Danish patent application PA 2008 01384, and the US provisional patent application US 61/102,126 are hereby incorporated by reference in its entirety.
All patent and non-patent references cited in PA 2008 01384, and US 61/102,126, or in the present application, are also hereby incorporated by reference in their entirety.
The European patent application EP 09154516.0, the PCT patent applications PCT/DK2009/050185 and PCT/DK2008/050167 are hereby incorporated by reference in its entirety.
All patent and non-patent references cited in EP 09154516.0, PCT/DK2009/050185 and PCT/DK2008/050167, are also hereby incorporated by reference in their entirety.
Field of invention
The present invention relates to methods for construction of pharmamers i.e. vaccine components characterized by their multimerization domain and the attached biologically active molecules, and their use in preparation of vaccines that contains the pharmamers alone or in combination with other molecules. The individual molecules of the construct can be bound to each other or the multimerization domain(s) by covalent or non-covalent bonds, directly or via linkers. In one embodiment the one or more pharmamers comprises one or more MHC multimers disclosed in PCT/D2002/000169. Some of the molecules in the vaccine may be free i.e. non-attached to the pharmamer itself. The invention further relates to the use of such preparations in vaccine settings aimed to function as preventive/prophylactic or therapeutic vaccines in humans and animals.
Background of invention
By having functional molecules coupled to the vaccine antigen(s) as in pharmamers presentation of the antigen(s) to the immune system may be directed, enforced or otherwise modified. This can be accomplished by directing the antigens to specific antigen presenting cells by means of co-coupled receptor molecules or ligands.
Summary of invention The present invention relates to a composition for vaccination and/or immune monitoring of a vaccine response comprising one or more pharmamers.
In another embodiment the present invention relates to a method of making the composition for vaccination and/or immune monitoring of a vaccine response comprising one or more pharmamers.
This invention also relates to a method for vaccination comprising administration to an individual in need thereof an effective amount of a composition comprising one or more pharmamers.
The invention further relates to a method for monitoring a vaccine response comprising use of the composition comprising one or more pharmamers.
In a further aspect the invention relates to a kit-of-parts comprising a composion comprising one or more pharmamers and use for this kit-of-parts for vaccination of an individual in need thereof or for monitoring of a vaccine response.
In one embodiment the present invention relates to methods for construction of pharmamers characterized by their multimerization domain and the attached biologically active molecules, and their use in preparation of vaccines that contains the pharmamers alone or in combination with other molecules.
Definitions
Adjuvant: As used herein, the term "adjuvant" refers to an immunological adjuvant. By this is meant a compound that is able to enhance or facilitate the immune system's response to the ingredient in question, thereby inducing an immune response or series of immune responses in the subject. The adjuvant can facilitate the effect of the therapeutic composition by forming depots (prolonging the half-life of the ingredient), provide additional T-cell help and stimulate cytokine production. Facilitation of antigen survival and unspecific stimulation by adjuvants may, in some cases, be required if the antigenic molecule epitopes or functional molecules of the pharmamer are only weakly antigenic or only exerts weak to moderate interactions with compounds, molecules, or cells of the immune system.
Antibodies: As used herein, the term "antibody" means an isolated or recombinant binding agent that comprises the necessary variable region sequences to specifically bind an antigenic epitope. Therefore, an antibody is any form of antibody or fragment thereof that exhibits the desired biological activity, e.g., binding the specific target antigen. Antibodies can derive from multiple species. For example, antibodies include rodent (such as mouse and rat), rabbit, sheep, camel, and human antibodies. Antibodies can also include chimeric antibodies, which join variable regions from one species to constant regions from another species. Likewise, antibodies can be humanized, that is constructed by recombinant DNA technology to produce immunoglobulins which have human framework regions from one species combined with complementarity determining regions (CDR's) from a another species' immunoglobulin. The antibody can be monoclonal or polyclonal. Antibodies can be divided into isotypes (IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2). In another embodiment the term "antibody" refers to an intact antibody, or a fragment of an antibody that competes with the intact antibody for antigen binding. In certain embodiments, antibody fragments are produced by recombinant DNA techniques. In certain embodiments, antibody fragments are produced by enzymatic or chemical cleavage of intact antibodies. Exemplary antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv, and scFv. Exemplary antibody fragments also include, but are not limited to, domain antibodies, nanobodies, minibodies ((scFv- CH3)2), maxibodies ((scFv-CH2-CH3)2), diabodies (noncovalent dimer of scFv).
Antigen presenting cell: An antigen-presenting cell (APC) as used herein is a cell that displays foreign antigen complexed with MHC on its surface.
Antigenic peptide: Any peptide molecule that is bound to or able to bind into the binding groove of either MHC I or MHC Il molecules.
Avidin: Avidin as used herein is a glycoprotein found in the egg white and tissues of birds, reptiles and amphibians. It contains four identical subunits having a combined mass of 67,000-68,000 daltons. Each subunit consists of 128 amino acids and binds one molecule of biotin. Biologically active molecules: Any molecule having biological activity. Biologically active molecules of the present invention may be attached to pharmamers, adjuvants, other biologically active molecules and/or vaccine enhancers by covalent or non- covalent interaction or they may be individual component(s) of the composition.
Biologically active molecules in a pharmamer affect the binding characteristics and/or the effects of the pharmamer.
Biotin: Biotin, as used herein, is also known as vitamin H or B7. Biotin has the chemical formula Ci0H16N2O3S.
Covalent binding: The term covalent binding is used herein to describe a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. Attraction-to-repulsion stability that forms between atoms when they share electrons is known as covalent bonding.
Crosslinking: Crosslinking is the process of chemically joining two or more molecules by a covalent bond. Crosslinking reagents contain reactive ends to specific functional groups (primary amines, sulfhydryls, etc.) on proteins or other molecules.
Dendritic cell: The term dendritic cell as used herein is a type of immune cells. Their main function is to process antigen material and present it on the surface to other cells of the immune system, thus functioning as antigen-presenting cells.
Immunologically active molecules: Immunologically active molecule is used interchangeably herein with immuno active molecule and is any molecule that as an active part of the pharmamer, pharmamer composition, vaccine or therapeutics is modulating the immuno-activity of the pharmamer, pharmamer composition, vaccine or therapeutics itself or the immune system as such.
Carrier: A carrier as used herein can be any type of molecule that is directly or indirectly associated with a biologically active molecule. A carrier may link biologically active molecules to multimerisation domains and/or be a multimerisation domain itself. Dextran: the term dextran as used herein is is a complex, branched polysaccharide made of many glucose molecules joined into chains of varying lengths. The straight chain consists of α1 ->6 glycosidic linkages between glucose molecules, while branches begin from α1 ->3 linkages (and in some cases, α1 ->2 and α1 ->4 linkages as well).
Linker molecule: Linker molecule and linker is used interchangeable herein. A linker molecule is a molecule that covalently or non-covalently connects two or more molecules, thereby creating a larger complex consisting of all molecules including the linker molecule.
Liposomes: The term liposome as used herein is defined as a spherical vesicle with a membrane composed of a phospholipid and cholesterol bilayer. Liposomes, usually but not by definition, contain a core of aqueous solution; lipid spheres that contain no aqueous material are called micelles.
MHC: Denotes the major histocompatibility complex.
A "MHC Class I molecule" as used everywhere herein is defined as a molecule which comprises 1 -3 subunits, including a heavy chain, a heavy chain combined with a light chain (beta2m), a heavy chain combined with a light chain (beta2m) through a flexible linker, a heavy chain combined with a peptide, a heavy chain combined with a peptide through a flexible linker, a heavy chain/beta2m dimer combined with a peptide, and a heavy chain/beta2m dimer with a peptide through a flexible linker to the heavy or light chain. The MHC molecule chain can be changed by substitution of single or by cohorts of native amino acids or by inserts, or deletions to enhance or impair the functions attributed to said molecule. By example, it has been shown that substitution of XX with YY in position nn of human beta2m enhance the biochemical stability of MHC Class I molecule complexes and thus can lead to more efficient antigen presentation of subdominant peptide epitopes.
MHC complex: MHC complex is herein used interchangeably with MHC-peptide complex, unless it is specified that the MHC complex is empty, i.e. is not complexed with peptide.
MHC Class I like molecules (including non-classical MHC Class I molecules) include CD1 d, HLA E, HLA G, HLA F, HLA H, MIC A, MIC B, ULBP-1 , ULBP-2, and ULBP-3. A "MHC Class Il molecule" as used everywhere herein is defined as a molecule which comprises 2-3 subunits including an alpha-chain and a beta-chain (alpha/beta-dimer), an alpha/beta dimer with a peptide, and an alpha/beta dimer combined with a peptide through a flexible linker to the alpha or beta chain, an alpha/beta dimer combined through an interaction by affinity tags e.g. jun-fos, an alpha/beta dimer combined through an interaction by affinity tags e.g. jun-fos and further combined with a peptide through a flexible linker to the alpha or beta chain. The MHC molecule chains can be changed by substitution of single or by cohorts of native amino acids or by inserts, or deletions to enhance or impair the functions attributed to said molecule. Under circumstances where the alpha-chain and beta-chain have been fused, to form one subunit, the "MHC Class Il molecule" can comprise only 1 subunit.
MHC Class Il like molecules (including non-classical MHC Class Il molecules) include HLA DM, HLA DO, I-A beta2, and I-E beta2.
"MHC complexes" and "MHC constructs" are used interchangably herein.
"MHC protein" and "MHC molecule" are used interchangably herein. Accordingly, a functional MHC peptide complex comprises a MHC protein or MHC molecule associated with a peptide to be presented for cells or binding partners having an affinity for said peptide.
By the terms "MHC complexes" and "MHC multimers" as used herein are meant such complexes and multimers thereof, which are capable of performing at least one of the functions attributed to said complex or multimer. The terms include both classical and non-classical MHC complexes. The meaning of "classical" and "non-classical" in connection with MHC complexes is well known to the person skilled in the art. Non- classical MHC complexes are subgroups of MHC-like complexes. The term "MHC complex" includes MHC Class I molecules, MHC Class Il molecules, as well as MHC- like molecules (both Class I and Class II), including the subgroup non-classical MHC Class I and Class Il molecules.
The MHC molecule can suitably be a vertebrate MHC molecule such as a human, a mouse, a rat, a porcine, a bovine or an avian MHC molecule. Such MHC complexes from different species have different names. E.g. in humans, MHC complexes are denoted HLA. The person skilled in the art will readily know the name of the MHC complexes from various species.
MHC multimer: Any molecule complex compricing one or more MHC molecules held together by a multimerization domain. The attachment of MHC molecule to multimerization domain may be directly or in-directly via a linker and may be covalent or non-covalent.
Multimerization domain: A multimerization domain is a molecule, a complex of molecules, a cell, cell-like structure or a solid support, to which one or more biologically active molecules can be attached. A multimerization domain may consist of one or more carriers and/or one or more scaffolds and may also contain one or more linkers connecting carrier to scaffold, carrier to carrier, scaffold to scaffold. Multimerization domains thus include polymers, proteins (e.g. IgG, streptavidin, TCR, scaffold proteins) micelles, cells, beads, other types of solid support, small organic molecules carrying reactive groups or carrying chemical motifs that can bind biologically active mulecules or any other type of multimerization domain as described elsewhere herein.
Non-covalent: The term noncovalent bond as used herein is a type of chemical bond, that does not involve the sharing of pairs of electrons, but rather involves more dispersed variations of electromagnetic interactions.
Nonsense peptide: A peptide that binds efficiently to the peptide binding groove of MHC protein, but that does not support binding of the resultant MHC-peptide complex to desired TCR
"One or more" as used everywhere herein is intended to include one and a plurality.
Pharmamer: Molecule or molecule complex comprising one or more multimerisation domain(s) and one or more biologically active molecules.
'A plurality" as used everywhere herein should be interpreted as two or more. Streptavidin: Streptavidin as used herein is a tetrameric protein purified from the bacterium Streptomyces avidinii. Streptavidin is widely use in molecular biology through its extraordinarily strong affinity for biotin.
Vaccine: As used herein the term vaccine is used for an antigenic preparation used to establish patial or total immunity to a disease or illness and thereby protecting, curing or treating the body from a specific disease or illness. Vaccines are either prophylactic and prevent disease or therapeutic and treat disease. Vaccines may contain more than one type of antigen and is then called a combined vaccine.
Vaccination: The introduction of vaccine into the body of human or animals for the purpose of inducing immunity.
Treatment: As used herein, the term "treatment" refers to prophylactic, ameliorating, therapeutic or curative treatment.
Figure legends
Figure 1 : List of HLA Class 1 alleles of particular interest of the present invention. From http://www.anthonynolan.org.uk/HIG/lists/class1list.html, 2007
Figure 2: List of HLA Class 2 alleles of particular interest of the present invention. From http://hla. alleles. org/alleles/class2. html, 2009
Figure 3:
(A) Immunization schedule used in rhesus macaques and challenge with SHIVSF162.P4 grown in C8166-CCR5+ T cells (HLA-A*01 , DRB1 *04), (B) vaccine components in the 4 immunized groups and control, (C) dose and molecular ratio of the 4 constructs used to produce the 4 vaccines. Recombinant HLA class I proteins used: A*01 , A*02, A*03, A*1 1 , recombinant HLA class II: DRB1 *04, HSP70359-609- All components were biotinylated and linked to streptavidin-bound dextran (total 162mg). Groups 1 , 2 and 3 received full vaccine doses (SC) at the first immunization and half the dose in the 2nd, 3rd and 4th immunizations, with Titermax (0.5ml). Group 5 animals received the same vaccine as group 2 but without Titermax and full vaccine doses at all 4 immunizations administered IM. Figure 4:
(A) Peak viral load (Iog10), (B) Cumulative viral load (Iog10) over 10 weeks (area under curve) for each animal in the 4 immunized (groups 1 ,2,3 and 5) and unimmunized (group 4), (C) Viral load of group 2 ( • ) compared with the unimmunized group 4(0) macaques (mean±sem); One-way Anova: (A) F=3.325, p=0.0054; (B) F=3.9745, p=0.0096, f p<0.05 between group 2 and 4 in A and B. * p<0.05, ** p<0.01
Figure 5:
4 Effect of Immunization on induction of serum antibodies (1 :1000 dilution) to HLA class I A1 , A2, A3, A1 1 , A24 and DR4 in 4 groups of macaques: group 1 ( • HLA class I, II, HSP70 and Titermax), group 2 (O HLA class I, II, HIV gp140, SIV gp27, HSP70 and Titermax), group 3 (>κ HIV gp140, SIV p27, HSP70 and Titermax) and group 5 (A HLA class I, II, HIVgp140, SIVp27 and HSP70. Cross-reactivity between: * A1 , A2 and A1 1 , ** A3 and A24
Figure 6:
Correlation between the Luminex HLA multibead antibody (LHMA) assay for HLA-class 2 and class 1 and specific antibodies induced by immunization with HLA-DR4 and HLA-A*02, respectively
Figure 7:
Serum neutralizing activity (IC50) in the 5 groups of macaques after the last immunization. (A) Complement dependent, (B) Complement independent, (C) correlation with peak viral load, (D) correlation with cumulative loads; □ Groupi , • Group2, ▲ Group3, O Group4, ♦ Groupδ
Figure 8: Amino acid sequence of a monomer gp140 molecule compricing biotinylation tag and oligomerization domain enabling biotinylation and trimer formation respectively.
Figure 9: Amino acid sequence of Siv p27 encoded by the Gag gene of SIV.
Figure 10: Examples of usefull reactive groups compriced in multimerization domains and/or biologically active molecules of the present invention. Detailed description of the invention
The present invention relates to a composition compricing one or more pharmamers. Pharmamers are molecules or molecule complexes characterised by having one or more multimerisation domains whereto one or more biologically active molecules are attached either directly or through a linker. The biologically active molecules may also themselves comprice one or more multimerisation domains. Other components may also be attached to the pharmamer in order to broaden, increase, decrease or otherwise modify the binding of and/or effect of the pharmamer.
In another embodiment the invention relates to compositions compricing one or more pharmamers and additionally comprices one or more adjuvant(s), one or more vaccine enhance(s) and/or one or more biologically active molecules not attached to the pharmamer construct. These other molecules may broaden, increase, decrease or otherwise modify the binding, effect or uptake of the pharmamer construct(s) or may have an effect themselves affecting the overall effect of the composition.
In one embodiment the present invention relates to methods for construction of pharmamers and for making compositions compricing one or more pharmamers.
In another embodiment the present invention relates to the use of compositions comprising one or more pharmamers for vaccination of an individual in need thereof. Compositions of pharmamers may be used for prophylactic vaccination of individuals to protect the individual against e.g. viral disease, bacterial disease, parasitic disease, cancer disease, autoimmune disease, allergy or other diseases. Pharmamer compositions may also be used for therapeutic vaccination in order to cure, alleviate or prevent/delay progression of one or more diseases e.g. viral disease, bacterial disease, parasitic disease, cancer disease, autoimmune disease, allergy or other diseases.
In the following pharmamers and compositions compricing pharmamers are described in more detail.
Design, generation and use of pharmamers As used in the description of this invention, the term "pharmamers" will be used to describe any molecule or molecule complex where the number of involved molecules or molecule complexes is larger than one, and where these components are held together in a large complex by covalent or non-covalent interactions to the multimerization domain and/or between the individual components. The components can be identical or different molecules or molecular complexes.
Example, organic molecule-based pharmamers include functionalized cyclic structures such as benzene rings where e.g. a benzene ring is functionalized and covalently linked to e.g. three immunologically active molecules; example, cell-based pharmamers include dendritic cells and antigen presenting cells (APCs); example, membrane-based pharmamers include liposomes and micelles carying immunologically active molecules or complexes in their membranes; example, polymer-based pharmamers include molecule constructs where immunologically active molecules or complexes are bound covalently or non-covalently to a dextran backbone/multimerisation domain and; example, particles include beads or other solid supports with immunologically active molecules immobilized on the surface. Obviously, any kind of multimerization domain can be used, including any kind of cell, polymer, protein or other molecular structure, or particles and solid supports.
Different approaches can be taken to attach or assemble the various components of a pharmamer, i.e. the biologically active molecules and the multimerization domain(s). This can be done by chemical reactions between reactive groups of the multimerization domain and reactive groups on a immunologically active protein, or by non-covalent interaction between a part of the immunologically active protein (e.g. a biotinylated peptide component) and the multimerization domain (e.g. four binding sites for biotin on the strepavidin tetrameric protein). As an alternative, the pharmamer can be formed by the non-covalent association of amino acid helices fused to one component of immunologically active protein, to form a pentameric pharmamer, held together by five helices in a coiled-coil structure making up the multimerization domain.
Appropriate chemical reactions for the covalent coupling of molecules or molecular complexes to the multimerization domain include nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation), addition to carbon- hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers), nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines), and cycloadditions.
Appropriate molecules, capable of providing non covalent interactions between the multimerization domain and the immunologically and/or biologically active molecules or complexes hereof involve the following molecule pairs and molecules: streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA,
PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity). Combinations of such binding entities are also comprised. In particular, when the MHC complex is tagged, the binding entity can be an "anti-tag". By "anti-tag" is meant an antibody binding to the tag and any other molecule capable of binding to such tag.
In one embodiment the present invention relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000
Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from
2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
In another embodiment the present invention relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to
900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 980,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000.
The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da. The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight of at least 50,000 Da, such as at least 100,000 Da, for example at least 200,000 Da, such as at least 300,000 Da, for example at least 400,000 Da, such as at least 500,000 Da, for example at least 600,000 Da, such as at least 700,000 Da, for example at least
800,000 Da, such as at least 900,000 Da, for example at least 1 ,000,000 Da, such as at least 1 ,100,000 Da, for example at least 1 ,200,000 Da, such as at least 1 ,300,000 Da, for example at least 1 ,400,000 Da, such as at least 1 ,500,000 Da, for example at least 1 ,600,000 Da, such as at least 1 ,700,000 Da, for example at least 1 ,800,000 Da, such as at least 1 ,900,000 Da, for example at least 2,000,000 Da, such as at least 2,100,000 Da, for example at least 2,200,000 Da, such as at least 2,300,000 Da, for example at least 2,400,000 Da, such as at least 2,500,000 Da, for example at least 2,600,000 Da, such as at least 2,700,000 Da, for example at least 2,800,000 Da, such as at least 2,900,000 Da, for example at least 3,000,000 Da, such as at least 3,100,000 Da, for example at least 3,200,000 Da, such as at least 3,300,000 Da, for example at least 3,400,000 Da, such as at least 3,500,000 Da, for example at least 3,600,000 Da, such as at least 3,700,000 Da, for example at least 3,800,000 Da, such as at least 3,900,000 Da, for example at least 4,000,000 Da, such as at least 4,100,000 Da, for example at least 4,200,000 Da, such as at least 4,300,000 Da, for example at least 4,400,000 Da, such as at least 4,500,000 Da, for example at least 4,600,000 Da, such as at least 4,700,000 Da, for example at least 4,800,000 Da, such as at least 4,900,000 Da, for example at least 5,000,000 Da.
The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers has a molecular weight of less than 5,000,000 Da, such as less than 4,900,000 Da, for example less than 4,800,000 Da, such as less than 4,700,000 Da, for example less than 4,600,000 Da, such as less than 4,500,000 Da, for example less than 4,400,000 Da, such as less than 4,300,000 Da, for example less than 4,200,000 Da, such as less than 4,100,000 Da, for example less than 4,000,000 Da, such as less than 3,900,000 Da, for example less than
3,800,000 Da, such as less than 3,700,000 Da, for example less than 3,600,000 Da, such as less than 3,500,000 Da, for example less than 3,400,000 Da, such as less than 3,300,000 Da, for example less than 3,200,000 Da, such as less than 3,100,000 Da, for example less than 3,000,000 Da, such as less than 2,900,000 Da, for example less than 2,800,000 Da, such as less than 2,700,000 Da, for example less than 2,600,000 Da, such as less than 2,500,000 Da, for example less than 2,400,000 Da, such as less than 2,300,000 Da, for example less than 2,200,000 Da, such as less than 2,100,000 Da, for example less than 2,000,000 Da, such as less than 1 ,900,000 Da, for example less than 1 ,800,000 Da, such as less than 1 ,700,000 Da, for example less than 1 ,600,000 Da, such as less than 1 ,500,000 Da, for example less than 1 ,400,000 Da, such as less than 1 ,300,000 Da, for example less than 1 ,200,000 Da, such as less than 1 , 100,000 Da, for example less than 1 ,000,000 Da, such as less than 900,000 Da, for example less than 800,000 Da, such as less than 700,000 Da, for example less than 600,000 Da, such as less than 500,000 Da, for example less than 400,000 Da, such as less than 300,000 Da, for example less than 200,000 Da, such as less than 100,000 Da, for example less than 50,000 Da.
In one embodiment the present invention relates to a vaccine composition comprising more than 1 pharmamer, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200,
300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 pharmamers.
In another embodiment the present invention relates to a vaccine composition comprising more than 2 different pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different pharmamers.
In yet another embodiment the present invention relates to a vaccine composition comprising more than 2 identical pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical pharmamers.
In a further embodiment the present invention relates to a vaccine composition comprising less than 10,000 pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 pharmamers. In a further embodiment the present invention relates to a vaccine composition comprising less than 10,000 different pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10,
9, 8, 7, 6, 5, 4, 3 or less than 2 different pharmamers.
In a further embodiment the present invention relates to a vaccine composition comprising less than 10,000 identical pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500,
400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical pharmamers.
Multimerisation domains The pharmemers of the invention in one embodiment comprise one or more multimerization domain(s). The multimerization domain(s) can be a soluble multimerization domain(s) or a not soluble multimerization domain(s). The multimerization domain(s) can be any such which enables attachment of the MHC molecules, the binding entities, and/or the biologically active compounds, while providing advantageous properties of the construct.
Examples of suitable multimerization domain(s)s are polysaccharides including dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O- ethylamino guaran, chitins and chitosans indlucing 6-0- carboxymethyl chitin and N- carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxy- ethyl cellulose, 6-amino-6-deoxy cellulose and O-ethyl- amine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxy-methylated ficoll, vinyl polymers including poly (acrylic acid), poly (acryl amides), poly (acrylic esters), poly (2-hydroxy ethyl methacrylate), poly (methyl methacrylate), poly (maleic acid), poly (maleic anhydride), poly (acrylamide), poly (ethyl-co- vinyl acetate), poly (methacrylic acid), poly (vinyl- alcohol), poly (vinyl alcohol-co-vinyl chloroacetate), aminated poly (vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly (ethylene oxide-co-propylene oxides) comprising polymer backbones including linear, comb- shaped or StarBurst dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly (ethylene imines), pluriol, proteins including peptides, polypeptides, antigenbinding peptides, albumins, immunoglobulins, coiled-coil helixes e.g. Fos-Jun or Fos-Jun like or coiled-coiled dimers/trimers/tetramers/pentamers, Streptavidin, Avidin, Streptactin, T-cell receptors orther protein receptors and virus- like proteins (VLP), and polynucleotides, DNA, RNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs and small organic molecules including but not limited to steroids, peptides, linear or cyclic structures, aromatic structures, aliphatic structures.
Also included are cells e.g. dendritic cells, antigen presenting cell, B-cell, T-cell
Macrophages, Kupfer cells, Langerhans cells, transfected cells expressing biologically active proteins, including hybridoma cells, yeast-cells, insect-cells, CHO cells, any cell biologically active molecules, cell-like structures e.g. micelles, liposomes, and phages e.g. filamenteous phages and viral or viral-like particles.
Other suitable multimerization domains are solid supports including but not limited to beads, particulate matters and other surfaces.
Also included are self-assembling multimeric structures as described elsewhere herein.
Also included in this definition of the multimerization domain(s) is mixed forms, i.e. one or more multimerization domain(s) composed of one or more of the above examples. An example of this is dextran coupled with Streptavidin whereto biotinylated biologically active proteins can bind.
The choice of multimerization domain(s) depend i.e. on the application of the pharmamer. Of course, several parameters can be varied in the above-given examples of multimerization domain(s), including the length and branching. Furthermore, the multimerization domain(s) can carry various substitutions, including such, which can be protected and/or activated, enabling further derivatisation.
It is to be understood that the pharmamer construct of the invention can further comprise one or several different biologically active molecules in order to affect the characteristics of the constructs, e. g. with respect to binding properties, effects, antigenecity, specificity, solubility, stability, or detectability. For instance, spacing could be provided between the biologically active molecules. One preferred embodiment of the present invention includes multimerisation domains made of Streptavidin or Avidin whereto biotin, biotin-like peptides or other biotin-like molecules can bind.
Another preferred embodiment includes dextran whereto biologically active molecules are attached directly through a linker as described elsewhere herein. The biologically active molecules can also be attached through a second multimerization domain or an entity as described elsewhere herein. Examples include but is not limited to divinylsulfone activated dextran whereto biologically active molecules are coupled directly e.g. through -SH group(s) or amine(s) in the biologically active molecules, dextran coupled with SA whereto biologically active molecules are attached through a biotin on the biologically active molecule, dextran with biologically active molecules are attached through a coiled-coil structure where on α-helix of a coiled-coil dimer is coupled to dextran and the other α-helix is coupled to the biologically active molecule e.g. as a fusion protein.
A preferred embodiment include beads or bead-like structures having an excluded volume (e.g. polysaccharide beads, polystyrene beads, magnetic polystyrene beads, polycarbamate beads, or any other kind of beads that can be dissolved or suspended in aqueous buffer) that carry electrophilic groups (e.g. divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters), and where biologically active molecules have been covalently immobilized to these by reaction of nucleophiles comprised within the biologically active molecule with the electrophiles of the beads.
In another preferred embodiment, the biologically active molecules described immediately above (where the one or more multimerization domain(s) is a bead) further comprises a flexible or rigid, and water soluble, linker that allows for the immobilized biologically active molecules to interact efficiently with surrounding cells and molecules. In another embodiment, the linker is cleavable, allowing for release of the biologically active molecules from the bead.
In another preferred embodiment the bead is covalently or non-covalently coated with pharmamers or single biologically active molecules, through non-cleavable or cleavable linkers. As an example, the bead can be coated with streptavidin monomers, which in turn are associated with biotinylated pharmamers; or the bead can be coated with streptavidin tetramers, each of which are associated with 0, 1 , 2, 3, or 4 biotinylated biologically active molecules; or the bead can be coated with biologically active molecules where e.g. the reactive groups of the biologically active molecules (e.g. the divinyl sulfone-activated dextran backbone) has reacted with nucleophilic groups on the bead, to form a covalent linkage between the dextran of the dextramer and the beads.
A preferred embodiment including self-assembling multimeric structures are trimeric, tetrameric, pentameric, hexameric or heptameric coiled-coil structures holding together 3, 4, 5, 6 or 7 biologically active molecules. The coiled-coil structures may be attached to biologically active molecules through covalent or non-covalent bonds.
In some of the abovementioned embodiments, several multimerization domains (e.g. streptavidin tetramers bound to biotinylated biologically active molecules) are linked to another multimerization domain (e.g. the bead). For the purpose of the invention we shall call both the smaller and the bigger multimerization domain, as well as the combined multimerization domain, for multimerization domain.
In another preferred embodiment the one or more multimerization domain(s) can be any support capable of binding the biologically active molecules. Well-known supports or multimerization domains include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. The nature of the one or more multimerization domain(s) can be either soluble to some extent or insoluble for the purposes of the present invention. The support material can have virtually any possible structural configuration so long as the coupled molecule is capable of binding to the biologically active molecule. The support configuration can be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface can be flat such as a sheet, test strip, a membrane, or a plastic surface.
In another preferred embodiment the multimerization domain(s) can be a polymer or an oligomer or a non-repeating moiety. The polymer or oligomer moiety can comprise repeat units consisting of a repeat moiety selected from alkyl (e.g., -CH2-), substituted alkyl (e.g., --CHR--), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, as well as moieties comprising combinations thereof. Generally, a non-repeating multifunctional bridge moiety can be a moiety selected from alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and moieties comprising combinations thereof (in each permutation). A non-repeating moiety can include repeating units (e.g., methylene) within portions or segments thereof without repeating as a whole.
The oligomer (or oligomer moiety) or the polymer (or polymer moiety), can generally be soluble or insoluble; can generally be a cross-linked oligomer (or oligomer moiety) or a cross-linked polymer (or polymer moiety); can generally be a homopolymer or a copolymer (including polymers having two monomer-repeat-units, terpolymers and higher-order polymers), including for example random copolymer moieties and block copolymer moieties; can generally include one or more ionic monomer moieties such as one or more anionic monomer moieties; can generally include one or more hydrophobic monomer moieties; can generally include one or more hydrophilic monomer moieties; and can generally include any of the foregoing features in combination.
The polymer moiety can be soluble or insoluble, existing for example as dispersed micelles or particles, such as colloidal particles or (insoluble) macroscopic beads. Polymer moieties can be hydrophobic, hydrophilic, amphiphilic, uncharged or non-ionic, negatively or positively charged, or a combination thereof, and can be organic or inorganic. Inorganic polymers, also referred to as inorganic multimerization domains in some cases, include silica (e.g., multi-layered silica), diatomaceous earth, zeolite, calcium carbonate, talc, and the like.
Suitable water-soluble polymers include polyethylene glycol (PEG), monomethoxy- PEG, mono-(Ci-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, cellulose, or other carbohydrate-based polymers. A conjugate can also comprise a mixture of such water- soluble polymers.
Examples of polysaccharides useful in the present invention include materials from vegetal or animal origin, including cellulose materials, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin, and/or chitosan.
The type of multimerization domain can also be selected from, but is not limited to, the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross- linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(d-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, polyvinylcarbamate, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptavidin-monomer coated beads, streptavidin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone- activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly-acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen-fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
In one embodiment the multimerization domain(s) in the present invention is preferable less than 1 ,000 Da (small molecule scaffold). In another embodiment the multimerization domain(s) is preferable between 1 ,000 Da and 10,000 Da (small molecule scaffold, small peptides, small polymers). In another embodiment the multimerization domain(s) is between 10,000 Da and 100,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure). In another embodiment the multimerization domain(s) is preferable between 100,000 Da and 1 ,000,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure). In another embodiment the multimerization domain(s) is preferable larger than 1 ,000,000 Da (Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure, cells, liposomes, artificial lipid bi layers, polystyrene beads and other beads.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200,
300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 different multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 identical multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 different multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6,
5, 4, 3, or less than 2 different multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein one or more pharmamers comprises less than 10,000 identical multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical multimerization domains.
The present invention relates in one embodiment to a vaccine composition comprising one or more pharmamers, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from
4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
Biologically active molecules
Pharmamers consist of one or more biologically active molecules coupled to a multimerization domain, as defined above. The biologically active molecules can be selected among every known biologically active molecule on basis of their function in order to obtain the desired functionality of the pharmamer and the final vaccine. Biologically active molecules are molecules having biological activity. Biologically active molecules in a pharmamer affect the binding characteristics and/or the effects of the pharmamer.
Biologically active molecules of the present invention can be divided into the following categories:
• Proteins. The proteins may be full length or truncated and may be modified e.g. by introduction of additional amino acids, mutated, chemically modified (e.g. acetylation, methylation, Pegylation, phosphorylation, glycosylation etc.) or carrying other modifications. The proteins may also be stabilized by covalent or non- covalent attachment of protein linkers or other protein molecules. Biologically active protein molecules of the present invention includes but is not limited to: o Enzymes o Receptor proteins or co-receptor proteins o Immunological proteins (se section below for more details) o Growth factors (proteins capable of stimulating cellular proliferation and differentiation) o Protein hormones o Proteins from microorganisms (viral, bacterial, parasitic, fungal ect.)
■ Surface proteins, including full length protein, truncated or otherwise modified proteins. Example surface protein include any protein on the surface of microorganism e.g. the envelope proteins gp41 , gp120 or gp140 from HIV or truncated version of these. For vaccine composition purposes surface proteins may be made as recombinant proteins by cloning, expression and purification. Optionally the gene encoding the surface protein or a fragment of the protein may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g. compricing a recognition sequence for the BirA anzyme), chemically biotinylation (e.g. compricing an amino acid with a free -SH group), a multimerisation domain, one half of a coiled coil structure or another protein tag or protein fragment. An example of a protein that can be used in vaccine compositions of the present invention is recombinant gp140 may be made by cloning gp140 minus the transmembrane part of the protein leaving just the ecto domain of gp41 and gp120. These two molecules are held together through noncovalently association. An example of an amino acid sequence of such a recombinant gp140 protein is shown in figure 8 (SEQ ID NO 9583). Likewise gp120 may be produced recombinantly by cloning and expression.)
■ Intracellular and internal proteins. These are proteins inside cells proteins inside an organism e.g. inside envelop vira. For vaccine composition purposes such proteins may be made as recombinant proteins by cloning, expression and purification. Optionally the gene encoding the intracellular or internal protein or a fragment of the protein may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g. compricing a recognition sequence for the BirA anzyme), chemically biotinylation (e.g. compricing an amino acid with a free -SH group), a multimerisation domain, one half of a coiled coil structure or another protein tag or protein fragment Example internal protein includes p27 from HIV that is a protein encoded by the gag gene and is a structural protein of the viral core.
An example of the protein sequence of GAG p27 is shown in figure 9 (SEQ ID NO 9584).
■ Secreted proteins (e.g. toxins)
• Unmodified • Modified (e.g. toxoid) o Chemically modified o Physically modified
• Nucleic acids o DNA ■ Encoding protein
■ Structural not encoding protein o RNA
■ Ribosome's
■ Antisense ■ Silencing RNA (siRNA)
■ MicroRNA o LNA o PNA
• Carbohydrates o Saccharides and derivatives thereof, e.g. phosphorylated, oxidized, reduced, amino derivatives, acetylated etc. Saccharides may have more than one modification
■ Monosaccharide's
■ Disaccharides ■ Polysaccharides
• Homopolysaccharides (e.g. glycans, dextran)
• Polymers of repeating disaccharide units in which one of the sugars are is either N-acetylgalactosamine or N- acetylglucosamine (e.g. Glucosaminoglycans) • Polysaccharide-peptide polymer (Peptidoglycan (bacterial cell wall))
■ Proteins carrying covalent attached oligosaccharides or polysaccharides (Glycoprotein's)
■ Lipids carrying covalent attached oligo- or polysaccharides (Glycolipids)
• Lipids o Fatty acyls (e.g. prostaglandins, leukotrienes etc.) o Glycerolipids (e.g. triglycerides) o Glycerophospholipids o Sphingolipids o Sterol lipids (eg. cholesterol, estrogen etc.) o Prenol lipids (eg vitamin E, K) o Polyketides (eg. erythromycin)
• Small molecules. Small molecules are medicinal drug compounds having a molecular weights less than 1000 Daltons and include: o Natural compounds including but not limited to
■ Hormones
• Lipid and phospholipid derived hormones o Steroids o Eicosanoids
• Amine-drived hormones (derivatives of amino acids tyrosine and tryptophan (e.g. catecholamine, thyroxine)
■ Salts, e.g. comprising Ca++, Mg++ o Synthetic chemical compound
■ Benzodiazepines
■ Short peptides
■ Peptidommimetics
■ Other chemical compounds
In one embodiment the present invention relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000,
7,000, 8,000, 9,000, or more thani 0,000 biological active molecules.
In another embodiment the present invention relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules. In yet another embodiment the present invention relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000,
5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical biological active molecules.
The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6,
5, 4, 3 or less than 2 different biologically active molecules.
The present invention further relates to a vaccine composition comprising one or more pharmamers, wherein the one or more pharmamers comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical biologically active molecules.
The present invention further relates to a vaccine composition comprising more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 biological active molecules. The present invention further relates to a vaccine composition comprising more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules.
The present invention further relates to a vaccine composition comprising more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000,
6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical biological active molecules.
In one embodiment the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
In one embodiment the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different biologically active molecules.
In one embodiment the present invention relates to a vaccine composition, wherein the composition comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are not attached to said one or more pharmamers. In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to some but not all of the one or more pharmamers.
In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to one of the one or more pharmamers.
In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to more than one of the one or more pharmamers such as more to than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or to more thani 0,000 of the one or more pharmamers.
In one embodiment the invention relates to a vaccine composition comprising one or more pharmamers and one or more biologically active molecules, wherein the one or more biologically active molecules are attached to less than 10,000 of the one or more pharmamers, such as for example to less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or to less than 2 of the one or more pharmamers.
In one embodiment the present invention relates to a vaccine composition, wherein the one or more biologically active molecules and the one or more multimerization domain are coupled together either directly or indirectly.
Immunologically active molecules
In many applications, it will be advantageous that the pharmamer comprises one or more Immunologically active molecules. Immunologically active molecules are compounds that can modulate the immuno-activity of the pharmamer itself or the immune system as such, by affecting binding characteristics or effects of the pharmamer. A pharmamer can comprise several immunologically active molecules which can be the same or different.
Immunologically active molecules are a subgroup of biologically active molecules for example proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, antibodies, MHC molecules, TCR's and recombinant binding molecules to any of the foregoing, and combinations thereof.
Immunologically active molecules of special interest for the present invention can be selected from the groups listed below: • MHC class 1 proteins including HLA-A, HLA-B, HLA-C alleles. Examples of usefull MHC 1 alleles are listed in figure 1. MHC class proteins usefull as immunologically active molecules may be complete trimer molecule complexes or parts of MHC class 1 molecules as follows: o Heavy chains o Heavy chains combined with beta2microglobulin o Heavy chains combined with beta2microglobulin and antigenic peptide o Heavy chain combined with antigenic peptide o Beta2mcroglobulin
• MHC class 1 -like molecules: o MICA, MICB o CD1d o HLA-E, HLA-F, HLA-G, HLA-H o ULBP-1 , ULBP-2, ULBP-3
• MHC 2 proteins including HLA-DR (HLA-DRA, HLA-DRB1 , HLA-DRB3, HLA- DRB4, HLA-DRB5), HLA-DQ (HLA-DQA1 , HLADQA2, HLA-DQB1 , HLA-
DQB2), HLA-DP (HLA-DPAI 1 HLA-DPBI ), HLA-DO (HLA-DOA, HLA-DOB), HLA-DM (HLA-DMA, HLA-DMB). Examples of usefull MHC 2 alleles are listed in figure 2. MHC class proteins usefull as immunologically active molecules may be complete trimer molecule complexes or parts of MHC class 2 molecules as follows: o 1 α-heavy chain o 1 β-heavy chain o 1 α-heavy chain + 1 β-heavy chain o 1 α-heavy chain + 1 β-heavy chain + antigenic peptide o Fragments of α-heavy chain or β-heavy chain (MHC ll-like peptides).
MHC ll-like proteins of special interest of the present invention are DRB3*02*03 like peptide: RFLELLKSECHFFNG (SEQ ID NO 9585) , DRB4*-like peptide RVWNLIRYIYNQEEY (SEQ ID NO 9586), DRB5*- like peptide FLQQDKYECHFFNGC SEQ ID NO 9587). o
• Cytokines including: o Interferons such as IFN-alpha, IFN-beta, IFN-gamma o lnterleukines such as IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28,-IL-29, IL-30, IL-31 , IL-32, IL-33, IL-34, IL-35
o Tumor necrosis factors: TNF-alfa, TNF-beta
o Others: CSFs (colony-stimulating factors), c-Kit, EPO, TGF-β, CD40L,
CD27L, CD30L, MIF
• Cytokine receptors like IL-1 R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9-R, IL-10R, IL-1 1 R, IL-12R, IL-13R, IL-15R, IL-18R, IL-20R, IL-21 R, IL-22R, IL-23R, IL-27R, IL-28R
• Chemokines such as CXCL1 , CXCL2, CXCL3, CXCL4, CXCL5, CXCL6,
CXCL7, CXCL8, CXCL9, CXCL10, CXCL1 1 , CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CCL1 , CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL8, CCL9, CCL10, CCL1 1 , CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21 , CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCR4, CCRL2
• Chemokine receptors like CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR1 1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1
• Toll-like receptors such as TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10
• Toll like receptor ligands such as multiple triacyl lipopeptides, multiple diacyl lipopeptides, multiple glycolipids, multiple lipopeptides, multiple lipoproteins, lipoteichoic acid, peptidoglycans, Zymosan, single- and double-stranded RNA, Poly I:C, lipo-polysaccharides, fibrinogen, heparin sulphate fragments, hyaluronic acid fragments, flagellin, imidazoquinoline, loxoribine (guanosine analogue), bropirimine, Imiquimod, unmethylated CpG DNA; Viral entry receptors/molecules such as Ku70, Pvr, PrM , HVEM, EphrinB2, cellular integrins (in particular alpha2beta1 , alphaθbetai alphaVbeta3), CD81 , CD155, SR-B1 , claudin-1 , xCT, human nectin-2, LIGHT, TLR3, LIR, Heparan sulphate proteoglycans, GPI anchored proteins, hemeagglutinin receptor
• Heat shock proteins such as HSP70, HSP90. The heat shock proteins may be full length, truncated and or modified and may originate from any organism (e.g. bacteria, parasites, humans, animals ect.). An embodiment of special interest of the present invention is the C-terminal part of HSP70 from Mycobacteria tuberculosis, e.g. amino acid 359-609. For vaccine composition purposes the C- terminal part of HSP70 may be mad as a recombinant protein by cloning, expression and purification. Optionally the gene encoding this C-terminal fragment may be fused to a gene encoding a protein tag for e.g. enzymatic biotinylation (e.g. compricing a recognition sequence for the BirA anzyme), chemically biotinylation (e.g. compricing an amino acid with a free -SH group), a multimerisation domain, one half of a coiled coil structure or another protein tag or protein fragment. An example of an amino acid sequence of a recombinant C-terminal fragment of HSP70 from is given below:
LLQDFFNGRELNKSINPDEAVAYGAAVQAAILMGDTSGNVQDLLLLDVAPLSL GIETAGGVMTALIKRNTTIPTKQTQTFTTYSDNQPGVLIQVFEGERAMTKDNNL LGKFELTGIPPAPRGVPQIEVTFDIDANGILNVSAADKSTGKQNKITITNDKGRL
SKEEIERMVQEADMYKAEDDLQREKISAKNSLESYAFNMKSSVEDDNLKGKIS EEDKKRVIEKCNEAVSWLENNQLADKEEYEHQLKELEKVCNPVI (SEQ ID NO 9582)
In another embodiment of the present invention C-terminal fragments of HSP70 from bacteria that are not Myciobacterium Tuberculosis or C-terminal HSP70 fragment's from other organism may be used as biologically active molecule.
In yet another embodiment
• Bacterial entry receptors/molecules like CD48, CEACAM-1 , -2, -3, -4, -5, -6, invasion, internalin (InIA), InIB
• Fc receptors like ε (FcεRI, FcεRII) - y (FcγRI, FcyRII, FcγRIII) - a/μ (FcαRI,
Fcα/μR) - Neonatal FcR • Lymphocyte homing receptors such as CD44, L-selectin, VLA-4 (CD49a, b, c, d, e, f), LFA-1
• Co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD120, CD137 (4-1 BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS,
PD-1 , Fas (CD95), FasL, CD40, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-L2, CD134L, CD137L, ICOSL
• NK cell receptors/molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR3DL1 , KIR3DL", KIR3DS1 , KIR2DL1.KIRDL2, KIR2DL3, KIR2DL4, KIR2DL5, CD94/NKG2A, CD94/NKG2C, CD94/NKG2E,
CD94/NKG2H, NKG2ADNKG2D
• Adhesion molecules such as ICAM-1 , ICAM-2, GlyCAM-1 , VCAM, CD34
• Anti microbial peptides such Defensins and cathelicidin derived peptide LL-37
• Antibodies (monoclonal, polyclonal, recombinant) directed to a defined antigen e.g. any of the described biologically active molecules, immunologically active molecules, viral antigens, bacterial antigens, parasitic antigens, self-antigens, cancer antigens or any other antigen. Antibodies of the present invention may be full length or derivatives of antibodies including: o Full length antibody o Fab fragments o scFv fragments o antibody-like structures e.g. scaffold proteins having the ability to bind antigens
• Toxic molecules selected e.g. toxins, toxids
• Enzymes
• Other molecules such as anti-LFA-1 , anti-CD44, anti-beta7, anti-selectin L, anti- selectin E, and anti- selectin P, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15- deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, heavy'metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as
DNP, and digoxiginin
A pharmamer composition may have one or more than one immunologically active molecule.
The immunologically active molecule can suitably be attached to the multimerization domain(s) either directly, through one or more linkers or via one or more of the binding entities or one or more multimerization domains as described elsewhere herein. The immunologically active molecules can also be linked to another immunologically active molecule and then attached to one or more multimerization domains.
MHC monomer/multimers and Antigenic peptides
The present invention in one aspect refers to a vaccine composition comprising one or more MHC monomer comprising a-b-P, or a MHC multimer comprising (a-b-P)n, wherein n > 1 ,
wherein a and b together form a functional MHC protein capable of binding the antigenic peptide P,
wherein (a-b-P) is the MHC-peptide complex formed when the antigenic peptide P binds to the functional MHC protein, and
wherein each MHC peptide complex of a MHC multimer is associated with one or more multimerization domains.
In the following the antigenic peptide P is used interchangeably with antigenic peptide.
Another aspect of the present invention refers to a vaccine compositon comprising one or more antigenic peptides not bound to a MHC molecule or an antigenic polypeptide featuring one or more antigenic peptides. MHC monomers and MHC multimers comprising one or more MHC peptide complexes of class 1 or class 2 MHC are covered by the present invention. In another embodiment the present invention covers antigenic peptides able to bind MHC class 1 and/or MHC class 2 molecules or antigenic polypeptides featuring such antigenic peptides.
Accordingly, the antigenic peptide of the present invention can have a length of e.g. 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 16-20, or 20-30 amino acid residues.
There is also provided a MHC multimer comprising 2 or more MHC-peptide complexes and a multimerization domain to which the 2 or more MHC-peptide complexes are associated. The MHC multimer can generally be formed by association of the 2 or more MHC-peptide complexes with the multimerization domain to which the 2 or more MHC-peptide complexes are capable of associating.
The multimerization domain can be a scaffold associated with one or more MHC- peptide complexes, or a carrier associated with one or more, preferably more than one, MHC-peptide complex(es), or a carrier associated with a plurality of scaffolds each associated with one or more MHC-peptide complexes, such as 2 MHC-peptide complexes, 3 MHC-peptide complexes, 4 MHC-peptide complexes, 5 MHC-peptide complexes or more than 5 MHC-peptide complexes. Accordingly, multimerization domain collectively refers to each and every of the above. It will be clear from the detailed description of the invention provided herein below when the multimerization domain refers to a scaffold or a carrier or a carrier comprising one or more scaffolds.
Generally, when a multimerization domain comprising a carrier and/or a scaffold is present, the MHC complexes can be associated with this domain either directly or via one or more binding entities. The association can be covalent or non-covalent.
Accordingly, there is provided in one embodiment a MHC complex comprising one or more entities (a-b-P)n, wherein a and b together form a functional MHC protein capable of binding a antigenic peptide P, and wherein (a-b-P) is the MHC-peptide complex formed when the antigenic peptide P binds to the functional MHC protein, said MHC complex optionally further comprising a multimerization domain comprising a carrier molecule and/or a scaffold. "MHC complex" refers to any MHC complex, including MHC monomers in the form of a single MHC-peptide complex and MHC multimers comprising a multimerization domain to which more than one MHC peptide complex is associated.
When the invention is directed to a vaccine composition comprising a MHC multimer, i.e. a plurality of MHC peptide complexes of the general composition (a-b-P)n associated with a multimerization domain, n is by definition more than 1 , i.e. at least 2 or more. Accordingly, the term "MHC multimer" is used herein specifically to indicate that more than one MHC-peptide complex is associated with a multimerization domain, such as a scaffold or carrier or carrier comprising one or more scaffolds. Accordingly, a single MHC-peptide complex can be associated with a scaffold or a carrier or a carrier comprising a scaffold and a MHC-multimer comprising 2 or more MHC-peptide complexes can be formed by association of the individual MHC-peptide complexes with a scaffold or a carrier or a carrier comprising one or more scaffolds each associated with one or more MHC-peptide complexes.
When the MHC complex comprises a multimerization domain to which the n MHC- peptide complexes are associated, the association can be a covalent linkage so that each or at least some of the n MHC-peptide complexes is covalently linked to the multimerization domain, or the association can be a non-covalent association so that each or at least some of the n MHC-peptide complexes are non-covalently associated with the multimerization domain.
The MHC complexes of the invention may be provided in non-soluble or soluble form, depending on the intended application.
Effective methods to produce a variety of MHC complexes comprising highly polymorphic human HLA encoded proteins makes it possible to perform advanced analyses of complex immune responses, which may comprise a variety of peptide epitope specific T-cell clones.
One of the benefits of the MHC complexes of the present invention is that the MHC complexes overcome low intrinsic affinities of monomer ligands and counter receptors. The MHC complexes have a large variety of applications that include targeting of high affinity receptors (e.g. hormone peptide receptors for insulin) on target cells. Taken together poly-ligand binding to target cells has numerous practical, clinical and scientifically uses.
Thus, the present invention provides MHC complexes which present mono-valent or multi-valent binding sites for MHC recognising cells, such as MHC complexes optionally comprising a multimerization domain, such as a scaffold or a carrier molecule, which multimerization domain have attached thereto, directly or indirectly via one or more linkers, covalently or non-covalently, one or more MHC peptide complexes. "One or more" as used herein is intended to include one as well as a plurality, such as at least 2. This applies i.a. to the MHC peptide complexes and to the binding entities of the multimerization domain. The scaffold or carrier molecule may thus have attached thereto a MHC peptide complex or a plurality of such MHC peptide complexes, and/or a linker or a plurality of linkers.
In one preferred embodiment the present invention relates to pharmamers or a vaccine composition comprising one or more pharmamers, wherein said phamamers comprise one or more identical or different antigenic peptides, fragments thereof or larger antigenic peptides/proteins comprising one or more of the sequences disclosed in this application.
An antigenic peptide is any peptide molecule that is bound to or able to bind into the binding groove of either MHC class 1 or MHC class 2.
The antigenic peptides may be directly attached to a multimerisation domain of a pharmamer using principles as described for other biologically active molecules elsewhere herein, they may be part of a larger protein or they may be bound to the peptide binding groove of MHC molecules and the MHC-peptide comlex then attached to the multimerisation domain of the pharmamer.
The antigenic peptide(s) can e.g. be 8 mers, 9 mers, 10 mers, 1 1 mers, 12 mers, 13 mers, 14 mers, 15 mers or 16 mers.
The antigenic peptides can in one embodiment be any antigenic peptide e.g. peptide(s) predicted by the netMHC algorithm (http://www.cbs.dtu.dk/services/NetMHC/). In one embodiment the peptide(s) are derived from Lentivirus proteins such as HIV (Human immunodeficiency virus) proteins, like HIV-1 proteins or HIV-2 proteins.
In another embodiment the peptides are derived from retrovirus proteins such as SIV (Simian immunodeficiency virus) proteins.
In yet another embodiment the antigenic peptide(s) are derived from a cancer antigen.
In one embodiment the antigenic peptide(s) are derived from one or more of the HIV-1 proteins NP_057849/Gag-Pol, NP_057850/Pr55(Gag), NP_057851/Vif, NP_057852/Vpr, NP_057853/Tat, NP_057854/Rev, NP_057855/Vpu, NP_057856/Envelope surface glycoprotein gp160 precursor and NP_057857/Nef or any variant or fragment thereof.
In one embodiment the antigenic peptide(s) include one or more HIV-1 peptides from the table below (SEQ ID NO 1 -9568) or any variant or fragment thereof such as antigenic peptides comprising the core sequences listed in the table below or variants thereof.
HIV-1 peptides derived from the HIV-1 proteins predicted by the netMHC algoritm (http://www.cbs.dtu.dk/services/NetMHC/) are listed in the table herein below.
Protein Antigenic peptides SEQ ID NO accession no/ name
NP_057849 8-mers: 1 -3715 Gag-Pol MGARASVL;SVLSGGEL;ELDRWEKI;RWEKIRLR;RLRPGGKK;KLK
HIVWAiIVWASRELiWASRELERiRELERFAViFAVNPGLLiSEGCRQ
ILiQLQPSLQTiLQTGSEELiQTGSEELRiSLYNTVATiLYNTVATLiYN
TV ATLYiTVATLYCViTLYCVHQRiLYCVHQRIiDTKEALDKiKIEEEQ
NKiDTGHSNQViQVSQNYPIiNYPIVQNIiYPIVQNIQiGQMVHQAIiSP
RTLNAW;RTLNAWVK;TLNAWVKV;WVKVVEEK;KVVEEKAF;EKAF
SPEViFSPEVIPMiSPEVIPMFiEVIPMFSAiVIPMFSALiIPMFSALSiF
SALSEGA;ALSEGATP;TPQDLNTM;NTVGGHQA;TVGGHQAA;HQA
AMQML;QAAMQMLK;MQMLKETI;ETINEEAA;EEAAEWDR;EAAEW
DRV;EWDRVHPV;HPVHAGPI;GPIAPGQM;WMTNNPPI;TNNPPIPV
;PPIPVGEI;PIPVGEIY;GEIYKRWI;EIYKRWII;IYKRWIIL;KRWIILGL;
WIILGLNK;IILGLNKI;ILGLNKIV;LGLNKIVR;G LNKIVRMiIVRMYSPT;
RMYSPTSIiMYSPTSILiSPTSILDIiRQGPKEPFiDYVDRFYKiYVDRF
YKT;DRFYKTLR;AEQASQEV;EQASQEVK;ASQEVKNW;EVKNWM
TEiNWMTETLLiWMTETLLViETLLVQNAiNPDCKTILiILKALGPAiAL
GPAATLiTLEEMMTAiEEMMTACQiMMTACQGViGVGGPGHKiVLA
EAMSQ;AEAMSQVT;SQVTNSAT;VTNSATIM;SATIMMQR;IMMQR
GNFiMMQRGNFRiRGNFRNQRiRNQRKIVKiHTARNCRAiRNCRAP
RKiNCRAPRKKiAPRKKGCWiQMKDCTERiCTERQANFiTERQANF
L;ERQANFLR;RQANFLRE;FLREDLAF;DLAFLQGK;AFLQGKAR;FL
QGKARE;LQG KAREF;REFSSEQT;EFSSEQTR;FSSEQTRA;QTRA
NSPT;RANSPTRR;GADRQGTV;TVSFNFPQ;VSFNFPQV;FNFPQV
TLiNFPQVTLWiTLWQRPLViWQRPLVTIiRPLVTIKIiGQLKEALLiTG
ADDTVL;TVLEEMSL;EEMSLPGR;MSLPGRWK;SLPG RWKPiKPK
MIGGIiGIGGFIKViRQYDQILIiEICGHKAIiHKAIGTVLiKAIGTVLViVL
VGPTPViGPTPVNIIiTPVNIIGRiNIIGRNLLiNLLTQIGCiLNFPISPIiF
PISPIETiPISPIETViSPIETVPViIETVPVKLiETVPVKLKiVPVKLKPG;
KVKQWPLTiKQWPLTEEiWPLTEEKIiTEEKIKALiEEKIKALViKIKAL
VEIiLVEICTEMiEICTEMEKiKIGPENPYiENPYNTPViNPYNTPVFiY
NTPVFAI;NTPVFAIK;TPVFAIKK;PVFAIKKK;STKWRKLV;KWRKLV
DF;KLVDFREL;DFRELNKR;RTQDFWEV;QLGIPHPA;GIPHPAGL;I
PHPAGLK;GLKKKKSV;VLDVGDAY;VGDAYFSV;DAYFSVPL;SVPL
DEDF;PLDEDFRK;DFRKYTAF;RKYTAFTI;YTAFTIPS;TAFTIPSI;IP
SINNETiNETPGIRYiETPGIRYQiTPGIRYQYiGIRYQYNViIRYQYNV
L;YQYNVLPQ;NVLPQGWK;IFQSSMTK;FQSSMTKI;MTKILEPF;TKI
LEPFRiKILEPFRKiKQNPDIVIiDIVIYQYMiIYQYMDDLiYQYMDDLY;
QYMDDLYV;YMDDLYVG;DLYVGSDL;YVGSDLEI;DLEIGQHR;EIG
QHRTK;RTKIEELR;IEELRQHL;EELRQHLL;ELRQHLLR;HLLRWGL
T;LLRWGLTT;KEPPFLWM;PPFLWMGY;FLWMGYEL;GYELHPDK;
YELHPDKW;ELHPDKWT;LHPDKWTV;WTVQPIVL;WTVNDIQK;TV
NDIQKL;IQKLVGKL;KLVGKLNW;KLNWASQI;SQIYPGIK;QIYPGIK
ViIYPGIKVRiKVRQLCKLiRQLCKLLRiKLLRGTKAiLLRGTKALiGTK
ALTEV;ALTEVIPL;EVIPLTEE;PLTEEAEL;TEEAELEL;EEAELELA;E
LELAENR;ELAENREI;REILKEPV;KEPVHGVY;EPVHGVYY;GVYYD
PSKiYYD PSKDL;DLIAEIQK;AEIQKQGQ;KQGQGQWT;GQGQWTY
Q;GQWTYQIY;YQIYQEPF;QIYQEPFK;YQEPFKNL;NLKTGKYA;KT
GKYARM;TGKYARMR;RMRGAHTN;HTNDVKQL;QLTEAVQK;KITT
ESIViTTESIVIWiESIVIWGKiVIWGKTPKiIWGKTPKFiTPKFKLPIiKF
KLPIQK;LPIQKETW;IQKETWET;KETWETWW;ETWETWWT;WET
WWTEY;ETWWTEYW;TEYWQATW;EYWQATWI;WQATWIPE;QAT
WIPEW;TWIPEWEF;WIPEWEFV;FVNTPPLV;NTPPLVKL;TPPLVKL
W;PPLVKLWY;PLVKLWYQ;LVKLWYQL;KLWYQLEK;YQLEKEPI;Q LEKEPIViEPIVGAETilVGAETFYjVGAETFYViETFYVDGAjYVDGAA
NR;GAANRETK;KLGKAGYV;KAGYVTNR;GYVTNRGR;VTNRGRQ
K;GRQKVVTL;TLTDTTNQ;LTDTTNQK;TTNQKTEL;KTELQAIY;TEL
QAIYLiELQAIYLAjLQAIYLALjLQDSGLEViSGLEVNIViNIVTDSQY;!
VTDSQYAjVTDSQYALiSQYALGIliYALGIIQAjALGIIQAQiSELVNQII
;NQIIEQLI;QIIEQLIK;IIEQLIKK;QLIKKEKV;LIKKEKVY;KEKVYLAW;
EKVYLAWViYLAWVPAHjLAWVPAHKjWVPAHKGliGIGGNEQViQV
DKLVSAjKLVSAGIRiLVSAGIRKiGIRKVLFLjKVLFLDGliLFLDGIDK;
FLDGIDKA;KAQDEHEK;EKYHSNWR;YHSNWRAM;AMASDFNL;NL
PPVVAKiPPVVAKEIiPVVAKEIViEIVASCDKiCQLKGEAM ;G EAMH
GQV;AMHGQVDC;QVDCSPGI;CSPGIWQL;WQLDCTHL;HLEGKVI
LiVILVAVHViILVAVHVAiAVHVASGYiGYIEAEVIiAEVIPAETiAETG
QETA;ETGQETAY;GQETAYFL;QETAYFLL;ETAYFLLK;FLLKLAGR;
KLAGRW PV;LAGRWPVK;GRWPVKTI;WPVKTIHT;HTDNGSNF;NF
TGATVRiFTGATVRAjTGATVRAAjATVRAACWiAACWWAGIiWAGI
KQEF;GIKQEFGI;KQEFGIPY;NPQSQGVV;SQGVVESM;G VVESM
NK;VESMNKEL;ESMNKELK;SMNKELKK;AEHLKTAV;KT AVQMAV;
TAVQMAVF;VQMAVFIH;MAVFIHNF;AVFIHNFK;VFIHNFKR;FIHNF
KRKjYSAGERIViRIVDIIATilATDIQTKilQTKELQKjLQKQITKliQITKI
QNF;ITKIQNFR;TKIQNFRV;KIQNFRVY;IQNFRVYY;QNFRVYYR;R
VYYRDSR;YRDSRNPL;NPLWKGPA;KGPAKLLW;LLWKGEGA;VIQ
DNSDIjDIKVVPRRiVVPRRKAKiVPRRKAKIiRRKAKIIRjKIIRDYGK;
KQMAGDDC;QMAGDDCV
9-mers:
VLSGGELDR;LSGGELDRW;DRWEKIRLR;KIRLRPGGK;RLRPGGK
KKiGGKKKYKLKjKKYKLKHIViKYKLKHIVWjKLKHIVWASiHIVWAS
REL;WASRELERF;ERFAVNPGL;RFAVNPGLL;AVNPGLLET;GLLE
TSEGCiETSEGCRQlilLGQLQPSLjGQLQPSLQTiSLQTGSEELjLQT
GSEELRiGSEELRSLYjELRSLYNTViSLYNTVATLiLYNTVATLYjNT
VATLYCViATLYCVHQRjTLYCVHQRIjYCVHQRIEliCVHQRIEIKiQR lEIKDTKiEIKDTKEALjALDKlEEEQiQQAAADTGHiHSNQVSQNYjN
QVSQNYPIjQVSQNYPIViQNYPIVQNIjVQNIQGQMVjlQGQMVHQA iMVHQAISPRjHQAISPRTLjAISPRTLNAilSPRTLNAWiSPRTLNAW
ViRTLNAWVKViTLNAWVKVVjAWVKVVEEKjEEKAFSPEViEKAFS
PEVIiFSPEVIPMFjEVIPMFSALilPMFSALSEjALSEGATPQiSEGAT
PQDL;ATPQDLNTM;TPQDLNTML;DLNTMLNTV;NTVGGHQAA;TV
GGHQAAM;HQAAMQMLK;AMQMLKETI;ETINEEAAE;TINEEAAEW
;EEAAEWDRV;EAAEWDRVH;AEWDRVHPV;RVHPVHAGP;HPVHA
GPIA;DIAGTTSTL;TTSTLQEQI;STLQEQIGW;TLQEQIGWM;GWMT
NNPPIjMTNNPPIPVjNPPIPVGEIiPPIPVGEIYilPVGEIYKRiGEIYKR
WlljEIYKRWIILiYKRWIILGLiRWIILGLNKiWIILGLNKIjllLGLNKIViGL
NKIVRMYjKIVRMYSPTjlVRMYSPTSiRMYSPTSILiSPTSILDIRiSIL
DIRQGPilLDIRQGPKiRQGPKEPFRjEPFRDYVDRiPFRDYVDRFjR
DYVDRFYK;DYVDRFYKT;YVDRFYKTL;VDRFYKTLR;RAEQASQE
V;QASQEVKNW;EVKNWMTET;NWMTETLLV;WMTETLLVQ;VQNA
NPDCKiTILKALGPAilLKALGPAAjKALGPAATLiGPAATLEEMjATLE
EMMTAiTLEEMMTACiEEMMTACQGiEMMTACQGViGVGGPGHK
AiGGPGHKARViGPGHKARVLiKARVLAEAMiVLAEAMSQViLAEAM
SQVT;AEAMSQVTN ;AMSQVTNSA;SQVTNSATI ;QVTNSATIM ;VTN
SATIMM;NSATIMMQR;IMMQRGNFR;MMQRGNFRN;RGNFRNQR
KiFRNQRKIVKiNQRKIVKCFiIVKCFNCGKiEGHTARNCRiTARNCR
APRiARNCRAPRKiRNCRAPRKKiAPRKKGCWKiHQMKDCTERiTE
RQANFLR;NFLREDLAF;FLREDLAFL;LAFLQG KAR;FLQG KAREFiK
AREFSSEQiREFSSEQTRiQTRANSPTRiSPTRRELQViPTRRELQV
W;RRELQVWGR;ADRQGTVSF;RQGTVSFNF;TVSFNFPQV;FNFP
QVTLWiFPQVTLWQRiVTLWQRPLViTLWQRPLVTiLWQRPLVTIiW
QRPLVTIK;TIKIGGQLK;QLKEALLDT;DTVLEEMSL;EEMSLPGRW; EMSLPG RWK;SLPGRWKPK;LPGRWKPKM;KMIGGIGGF;MIGGIG
GFIiGGIGGFIKViKVRQYDQILiRQYDQILIEiQYDQILIEIiILIEICGHK;
IEICGHKAIiHKAIGTVLViTVLVGPTPViLVGPTPVNIiLLTQIGCTLiTQ
IGCTLNFiTLNFPISPIiFPISPIETViSPIETVPVKiVPVKLKPGMiGMD
GPKVKQiGPKVKQWPLiKQWPLTEEKiQWPLTEEKIiPLTEEKIKAiL
TEEKIKALiALVEICTEMiCTEMEKEGKiPENPYNTPViNPYNTPVFA;
PYNTPVFAIiYNTPVFAIKiNTPVFAIKKiTPVFAIKKKiFAIKKKDSTiAI
KKKDSTK;KWRKLVDFR;KLVDFRELN;LVDFRELNK;ELN KRTQDF;
KRTQDFW EV;RTQDFWEVQ;TQDFWEVQL;DFWEVQLGI;W EVQL
GIPHiVQLGIPHPAiLGIPHPAGLiGIPHPAGLKJPHPAGLKKiTVLDV
GDAY;VLDVGDAYF;DVGDAYFSV;FSVPLDEDF;SVPLDEDFR;EDF
RKYTAFiDFRKYTAFT ;YTAFTIPSI;FTIPSINNE;TIPSINNET;SINNET
PGIiETPGIRYQYiYQYNVLPQGiQYNVLPQGWiVLPQGWKGSiQG
WKGSPAIiGWKGSPAIFiSPAIFQSSMiAIFQSSMTKiIFQSSMTKIiF
QSSMTKILiSMTKILEPFiMTKILEPFRiKQNPDIVIYiNPDIVIYQYiVIY
QYMDDL;IYQYMDDLY;YQYMDDLYV;YMDDLYVGS;LYVGSDLEI;D
LEIGQHRT;HRTKIEELR;KIEELRQHL;IEELRQHLL;ELRQHLLRW;R
QHLLRWGL;HLLRWGLTT;LLRWGLTTP;RWGLTTPDK;TTPDKKH
QK;EPPFLWMGY;PFLWMGYEL;FLWMGYELH ;MGYELHPDK;GYE
LHPDKW;YELHPDKWT;ELHPDKWTV;KWTVQPIVL;VQPIVLPEK;I
VLPEKDSW;VLPEKDSWT;LPEKDSWTV;SWTVNDIQK;WTVNDIQ
KLiTVNDIQKLViKLVGKLNWAiKLNWASQIYiWASQIYPGIiASQIYP
GIKiSQIYPGIKViQIYPGIKVRiYPGIKVRQLiGIKVRQLCKiLCKLLRG
TKiKLLRGTKALiLLRGTKALTiKALTEVIPLiALTEVIPLTiEVIPLTEEA
;IPLTEEAEL;EEAELELAE;ELAENREIL;LAENREILK;ILKEPVHGV;K
EPVHGVYYiHGVYYDPSKiVYYDPSKDLiYYDPSKDLIiIQKQGQGQ
W;KQGQGQWTY;GQGQWTYQI;TYQIYQEPF;YQIYQEPFK;IYQEP
FKNL;NLKTGKYAR;KTGKYARMR;KYARMRGAH;YARMRGAHT;D
VKQLTEAViKQLTEAVQKiQLTEAVQKIiVQKITTESIiKITTESIVIiITT
ESIVIWiESIVIWGKTiIVIWGKTPKiIWGKTPKFKiKTPKFKLPIiIQKET
WETWiETW ETWWTE;TWETWWTEY;WETWWTEYW;ETWWTEY
WQ;WTEYWQATW;TEYWQATWI;WQATWIPEW;ATWIPEWEF;IPE
WEFVNTiWEFVNTPPLiEFVNTPPLViFVNTPPLVKiNTPPLVKLWiT
PPLVKLWY;PLVKLWYQL;WYQLEKEPI;YQLEKEPIV;EPIVGAETF;
PIVGAETFY;IVGAETFYV;AETFYVDGA;ETFYVDGAA;FYVDGAAN
R;ANRETKLGK;ETKLGKAGY;KLGKAGYVT;YVTNRGRQK;VTNRG
RQKV;RGRQKVVTL;TLTDTTNQK;DTTNQKTEL;TTNQKTELQ;NQK
TELQAIiELQAIYLALiLQAIYLALQiYLALQDSGLiALQDSGLEViEVNI
VTDSQ;IVTDSQYAL;YALGIIQAQ;AQPDQSESE;QPDQSESEL;SES
ELVNQI;ELVNQIIEQ;LVNQIIEQL;QIIEQLIKK;QLIKKEKVY;LIKKEK
VYLiKEKVYLAWViKVYLAWVPAiYLAWVPAHKiKGIGGNEQViEQV
DKLVSAiKLVSAGIRKiLVSAGIRKViVLFLDGIDKiFLDGIDKAQiKYH
SNWRAM;NWRAMASDF;RAMASDFNL;ASDFNLPPV;LPPVVAKEI;
PPVVAKEIViASCDKCQLKiGQVDCSPGIiDCSPGIWQLiIWQLDCTH
LiWQLDCTHLEiTHLEGKVILiHLEGKVILViEGKVILVAViKVILVAVH
ViVILVAVHVAiVAVHVASGYiAVHVASGYIiHVASGYIEAiYIEAEVIP
A;AEVIPAETG;IPAETGQET;AETGQETAY;ETGQETAYF;GQETAYF
LL;QETAYFLLK;ETAYFLLKL;YFLLKLAGR;LKLAGRWPV;KLAGRW
PVK;GRWPVKTIH;WPVKTIHTD;HTDNGSNFT;SNFTGATVR;FTGA
TVRAAiGATVRAACWiATVRAACWWiRAACWWAGIiAACWWAGIK
;WWAGIKQEF;IKQEFGIPY;ESMNKELKK;SMNKELKKI;ELKKIIGQV
;IIGQVRDQA;HLKT A VQMA;LKT AVQMAV;KT AVQMAVF;TAVQMAV
FI;AVQMAVFIH;VQMAVFIHN;QMAVFIHNF;MAVFIHNFK;AVFIHNF
KRiVFIHNFKRKiKRKGGIGGYiIIATDIQTKiELQKQITKIiKQITKIQNF;
QITKIQNFR;ITKIQNFRV;KIQNFRVYY;IQNFRVYYR;FRVYYRDSR;
YYRDSRNPL;PLWKGPAKL;KLLWKGEGA;LLWKGEGAV;VIQDNS
DIKiIQDNSDIKViNSDIKVVPRiKVVPRRKAKiVPRRKAKIIiKQMAGD
DCVjQMAGDDCVA 10-mers:
RASVLSGGEL;SVLSGGELDR;VLSGGELDRW;ELDRWEKIRL;KIRL
RPGGKKiRLRPGGKKKYjRPGGKKKYKLjKKYKLKHIVWiKLKHIVW
ASR;IVWASRELER;VWASRELERF;LERFAVNPGL;ERFAVNPGLL;
FAVNPGLLETiETSEGCRQILjRQILGQLQPSiQILGQLQPSLjILGQL
QPSLQ;SLQTGSEELR;EELRSLYNTV;RSLYNTVATL;SLYNTVATL
YiVATLYCVHQRiATLYCVHQRIjLYCVHQRIElilEIKDTKEALjAADT
GHSNQVjNQVSQNYPIViSQNYPIVQNIjPIVQNIQGQMjlVQNIQGQ
MVjVQNIQGQMVHjNIQGQMVHQAjlQGQMVHQAliQMVHQAISPR;
AISPRTLNAW;RTLNAWVKVV;NAWVKVVEEK;WVKVVEEKAF;VEE
KAFSPEViEEKAFSPEVIjKAFSPEVIPMjAFSPEVIPMFjPEVIPMFSA
L;EVIPMFSALS;PMFSALSEGA;ATPQDLNTML;MLNTVGGHQA;NT
VGGHQAAM;GHQAAMQMLK;AAMQMLKETI;MLKETINEEA;ETINE
EAAEW ;AAEWDRVHPV;RVHPVHAGPI;HPVHAGPIAP;IAPGQMRE
PR;TSTLQEQIGW;STLQEQIGWM;TLQEQIGWMT;WMTNNPPIPV;
NPPIPVGEIYjlPVGEIYKRWiGEIYKRWIILilYKRWIILGLjKRWIILGL
NKiRWIILGLNKIiWIILGLNKIVjIILGLNKIVRjILGLNKIVRMjIVRMYSP
TSliMYSPTSILDIjYSPTSILDIRiSILDIRQGPKiDIRQGPKEPFjEPFR
DYVDRF;DYVDRFYKTL;YVDRFYKTLR;RFYKTLRAEQ;RAEQASQ
EVKiEVKNWMTETLiWMTETLLVQNjLVQNANPDCKjKTILKALGPA;
TILKALGPAAilLKALGPAATjGPAATLEEMMjATLEEMMTACjTLEE
MMTACQiEEMMTACQGViVGGPGHKARVjRVLAEAMSQVjVLAEA
MSQVT;AEAMSQVTNS;EAMSQVTNSA;AMSQVTNSAT;SQVTNSA
TIMiQVTNSATIMMjTNSATIMMQRjATIMMQRGNFjTIMMQRGNFR;
MMQRGNFRNQiMQRGNFRNQRiNFRNQRKIVKjKIVKCFNCGKjKE
GHTARNCRiHTARNCRAPRiTARNCRAPRKjARNCRAPRKKjRAPR
KKGCWK;APRKKGCWKC;RKKGCWKCGK;KCGKEGHQMK;QMKD
CTERQAiCTERQANFLRiRQANFLREDLjNFLREDLAFLjFLREDLAF
LQ;DLAFLQGKAR;AFLQGKAREF;REFSSEQTRA;EQTRANSPTR;
QTRANSPTRR;RANSPTRREL;SPTRRELQVW;NSPSEAGADR;EA
GADRQGTV;GTVSFNFPQV;VSFNFPQVTL;NFPQVTLWQR;QVTL
WQRPLViTLWQRPLVTIjWQRPLVTIKIjVTIKIGGQLKjKIGGQLKEA
L;ALLDTGADDT;LLDTGADDTV;GADDTVLEEM;MSLPGRWKPK;S
LPGRWKPKMiLPGRWKPKMIjRWKPKMIGGIjKMIGGIGGFIjMIGGI
GGFIKjFIKVRQYDQIjKVRQYDQILliRQYDQILIEliQILIEICGHKilLIEI
CGHKAjGTVLVGPTPViVLVGPTPVNIjLVGPTPVNIIiTPVN IIGRNL;!!
GRNLLTQIjNLLTQIGCTLjTQIGCTLNFPiQIGCTLNFPliCTLNFPISPI iFPISPIETVPiPISPIETVPVjISPIETVPVKiSPIETVPVKLjTVPVKLKP
GMiKLKPGMDGPKjKQWPLTEEKliWPLTEEKIKAiPLTEEKIKALjLT
EEKIKALViEEKIKALVEIjKALVEICTEMiLVEICTEMEKjMEKEGKISK lilSKIGPENPYiGPENPYNTPVjPENPYNTPVFjNPYNTPVFAliPYNT
PVFAIK;YNTPVFAIKK;NTPVFAIKKK;FAIKKKDSTK;KKKDSTKWRK
;STKWRKLVDF;KLVDFRELNK;LVDFRELNKR;RELNKRTQDF;RTQ
DFWEVQL;WEVQLGIPHP;EVQLGIPHPA;QLGIPHPAGL;GIPHPAG
LKKjlPHPAGLKKKiGLKKKKSVTViVTVLDVGDAYjTVLDVGDAYFiV
LDVGDAYFS;YFSVPLDEDF;FSVPLDEDFR;SVPLDEDFRK;VPLDE
DFRKYiPLDEDFRKYTjDFRKYTAFTIjKYTAFTIPSIiFTIPSINNETiSI
NNETPGIR;NETPGIRYQY;YQYNVLPQGW;QYNVLPQGWK;LPQG
WKGSPAiSPAIFQSSMTjPAIFQSSMTKjAIFQSSMTKIjlFQSSMTKIL
;SSMTKILEPF;SMTKILEPFR;MTKILEPFRK;KQNPDIVIYQ;NPDIVIY
QYM;IVIYQYMDDL;VIYQYMDDLY;IYQYMDDLYV;YMDDLYVGSD;
DLYVGSDLEI;LEIGQHRTKI;KIEELRQHLL;EELRQHLLRW;RQHLL
RWGLT;HLLRWGLTTP;LLRWGLTTPD;LRWGLTTPDK;RWGLTTP
DKK;LTTPDKKHQK;KHQKEPPFLW;HQKEPPFLWM;KEPPFLWMG
Y;FLWMGYELHP;MGYELHPDKW;YELHPDKWTV;ELHPDKWTVQ;
HPDKWTVQPI;TVQPIVLPEK;VLPEKDSWTV;DSWTVNDIQK;SWT
VNDIQKLiWTVNDIQKLVjKLVGKLNWASiNWASQIYPGIiW ASQIYP GIKiQIYPGIKVRQilYPGIKVRQLjKVRQLCKLLRjRQLCKLLRGTiQL
CKLLRGTKiKLLRGTKALTiALTEVIPLTEiEVIPLTEEAEiVIPLTEEAE
L;PLTEEAELEL;EAELELAENR;LELAENREIL;ELAENREILK;EILKE
PVHGV;ILKEPVHGVY;VYYDPSKDLI;DPSKDLIAEI;AEIQKQGQGQ;
KQGQGQWTYQ;GQGQWTYQIY;WTYQIYQEPF;TYQIYQEPFK;QI
YQEPFKNL;IYQEPFKNLK;EPFKNLKTGK;PFKNLKTGKY;KNLKTG
KYAR;NLKTGKYARM;LKTGKYARMR;RMRGAHTNDV;KQLTEAVQ
KI;AVQKITTESI;VQKπTESIV;KITTESIVIW;TTESIVIWGK;SIVIWGK
TPK;IVIWGKTPKF;VIWGKTPKFK;IWGKTPKFKL;LPIQKETWET;ET
WETWWTEY;ETWWTEYWQA;YWQATWIPEW;WQATWIPEWE;Q
ATWIPEWEFjATWIPEWEFViWIPEWEFVNTiWEFVNTPPLVjEFVN
TPPLVK;FVNTPPLVKL;NTPPLVKLWY;LVKLWYQLEK;QLEKEPIV
GAjEPIVGAETFYiPIVGAETFYViAETFYVDGAAiTFYVDGAANRjYV
DGAANRET;AANRETKLGK;RETKLGKAGY;ETKLGKAGYV;KAGYV
TNRGR;GYVTNRGRQK;YVTNRGRQKV;VTNRGRQKVV;NRGRQK
VVTL;VTLTDTTNQK;TLTDTTNQKT;NQKTELQAIY;TELQAIYLAL;E
LQAIYLALQ;IYLALQDSGL;LALQDSGLEV;LQDSGLEVNI;EVN IVTD
SQYjNIVTDSQYALiSQYALGIIQAiAQPDQSESELiSESELVNQIIjEL
VNQIIEQLiLVNQIIEQLIiNQIIEQLIKKiQLIKKEKVYLiLIKKEKVYLAiE
KVYLAW VPA; KVYLAW VPAH; VYLAW VPAH K; YLAW VPAH KG; LAW
VPAHKGhQVDKLVSAGhKLVSAGIRKViVSAGIRKVLFiKVLFLDGID
K;VLFLDGIDKA;FLDGIDKAQD;DEHEKYHSNW;WRAMASDFNL;M
ASDFNLPPViNLPPVVAKEhLPPVVAKEIViPPVVAKEIVAJVASCDK
CQLiVASCDKCQLKiGIWQLDCTHLiTHLEGKVILViHLEGKVILVAiK
VILVAVHVAiLVAVHVASGYiVASGYIEAEViAEVIPAETGQiIPAETG
QETA;PAETGQETAY;AETGQETAYF;ETGQETAYFL;GQETAYFLL
K;QETAYFLLKL;ETAYFLLKLA;AYFLLKLAGR;YFLLKLAGRW;LLKL
AGRW PViLKLAGRW PVK; KLAG RW PVKT ;TIHTDNGSNF;NGSNFT
GATViGSNFTGATVRiTGATVRAACWiGATVRAACWWiATVRAAC
WWAiRAACWWAGIKiCWWAGIKQEFiGIKQEFGIPYiIPYNPQSQG
ViSQGVVESMNKiGVVESMNKELiVVESMNKELKiSMNKELKKIIiEL
KKIIGQVR;GQVRDQAEHL;QVRDQAEHLK;AEHLKT A VQM;HLKTA
VQMAV;KT AVQMAVFIiTA VQMAVFIH;VQMAVFIHNF;QMAVFIHNF
KiMAVFIHNFKRiAVFIHNFKRKiFKRKGGIGGYiRIVDIIATDIiDIIATDI
QTKiKQITKIQNFRiQITKIQNFRViITKIQNFRVYiKIQNFRVYYRiNFR
VYYRDSR;VYYRDSRNPL;YYRDSRNPLW;RNPLWKGPAK;NPLWK
GPAKL;PLWKGPAKLL;KLLWKGEGAV;LLWKGEGAVV;VVIQDNSD
IKiVIQDNSDIKViIQDNSDIKVViDNSDIKVVPRiNSDIKVVPRRiRRK
AKIIRDYiKAKIIRDYGKiKIIRDYGKQMiIIRDYGKQMAiKQMAGDDC
VAiMAGDDCVASR
1 1 -mers:
VLSGGELDRWEiLSGGELDRWEKiGELDRWEKIRLiELDRWEKIRL
RiKIRLRPGGKKKiRLRPGGKKKYKiHIVWASRELERiWASRELERF
AViELERFAVNPGLiLERFAVNPGLLiGLLETSEGCRQiLLETSEGCR
QIiLETSEGCRQILiSEGCRQILGQLiRQILGQLQPSLiILGQLQPSLQ
T;QPSLQTGSEEL;LQTGSEELRSL;QTGSEELRSLY;SEELRSLYNT
ViRSLYNTV ATLYiSLYNTV ATLYCiLYNTV ATLYCViNTV ATLYCVH
QiTVATLYCVHQRiTLYCVHQRIEIiLYCVHQRIEIKiEIKDTKEALDK;
ALDKIEEEQNKiAAADTGHSNQViHSNQVSQNYPhYPIVQNIQGQM;
PIVQNIQGQMViNIQGQMVHQAhGQMVHQAISPRiMVHQAISPRTL;
QAISPRTLNAWiAISPRTLNAWVJSPRTLNAWVKiSPRTLNAWVKV;
LNAWVKVVEEK;AWVKVVEEKAF;VVEEKAFSPEV;KAFSPEVIPMF
;FSPEVIPMFSA;SPEVIPMFSAL;EVIPMFSALSE;IPMFSALSEGA;A
LSEGATPQDL;EGATPQDLNTM;PQDLNTM LNTV;TMLNTVGGHQA
;MLNTVGGHQAA;TVGGHQAAMQM;GGHQAAMQMLK;QAAMQML
KETI;MQMLKETINEE;QMLKETINEEA;MLKETINEEAA;TINEEAAE
WDR;EAAEWDRVHPV;RVHPVHAGPIA;HPVHAGPIAPG;HAGPIAP GQMRiTTSTLQEQIGWiQIGWMTNNPPIiIPVGEIYKRWIiEIYKRWII
LGLiKRWIILGLNKIiWIILGLNKIVRiIILGLNKIVRMiKIVRMYSPTSIiIV
RMYSPTSILiRMYSPTSILDIiMYSPTSILDIRiTSILDIRQGPKiDIRQG
PKEPFR;RQGPKEPFRDY;QGPKEPFRDYV;EPFRDYVDRFY;PFR
DYVDRFYK;DYVDRFYKTLR;YVDRFYKTLRA;TLRAEQASQEV;AE
QASQEVKNW ;QEVKNWMTETL;EVKNWMTETLL;WMTETLLVQNA iLLVQNANPDCKiNANPDCKTILKiNPDCKTILKALiKTILKALGPAAilL
KALGPAATLiALGPAATLEEMiEEMMTACQGVGiMTACQGVGGPG;
ACQGVGGPGHK;GVGGPGHKARV;KARVLAEAMSQ;AEAMSQVT
NSA;EAMSQVTNSAT;AMSQVTNSATI;MSQVTNSATIM;SQVTNSA
TIMM;VTNSATIMMQR;ATIMMQRGNFR;MMQRGNFRNQR;MQRG
NFRNQRKiFRNQRKIVKCFiHTARNCRAPRKiTARNCRAPRKKiEG
HQMKDCTER;DCTERQANFLR;RQANFLREDLA;QANFLREDLAF;L
AFLQGKAREF;FLQGKAREFSS;KAREFSSEQTR;EQTRANSPTRR;
TRANSPTRREL;NSPTRRELQVW;LQVWGRDNNSP;QGTVSFNFP
QV;TVSFNFPQVTL;VSFNFPQVTLW;FNFPQVTLWQR;FPQVTLW
QRPL;VTLWQRPLVTI;TLWQRPLVTIK;LWQRPLVTIKI;PLVTIKIGG
QL;LVTIKIGGQLK;KIGGQLKEALL;QLKEALLDTGA;ALLDTGADDT
V;LLDTGADDTVL;TGADDTVLEEM;TVLEEMSLPGR;SLPG RWKPK
MIiGRW KPKMIGGI;KPKMIGGIGGF;KMIGGIGGFIK;MIGGIGGFIKV iGFIKVRQYDQliFIKVRQYDQILiRQYDQILIEICiDQILIEICGHKilLIEI
CGHKAIiEICGHKAIGTViTVLVGPTPVNIiVLVGPTPVNIIiTPVNIIGR
NLLiNIIGRNLLTQIiLLTQIGCTLNFiTQIGCTLNFPIiTLNFPISPIETiL
NFPISPIETVjFPISPIETVPVjETVPVKLKPGMjKLKPGMDGPKViGM
DGPKVKQWP;KVKQWPLTEEK;KQWPLTEEKIK;WPLTEEKIKAL;P
LTEEKIKALVjALVEICTEMEKiEICTEMEKEGKjKISKIGPENPYjGPE
NPYNTPVFiENPYNTPVFAIiNPYNTPVFAIKiPYNTPVFAIKKiFAIKK
KDSTKW ;AIKKKDSTKWR;KKDSTKWRKLV;STKWRKLVDFR;KLVD
FRELN KR;TQDFW EVQLGI;WEVQLGIPHPA;VQLGIPHPAGL;QLGI
PHPAGLK;LGIPHPAGLKK;GIPHPAGLKKK;IPHPAGLKKKK;HPAGL
KKKKSV;G LKKKKSVTVL;SVTVLD VG DAY;VTVLDVGDAYF;VLDVG
DAYFSV;DVGDAYFSVPL;AYFSVPLDEDF;YFSVPLDEDFR;FSVPL
DEDFRKiSVPLDEDFRKYiPLDEDFRKYTAiRKYTAFTIPSIiIPSINNE
TPGIiSINNETPGIRYiETPGIRYQYNViTPGIRYQYNVLiRYQYNVLP
QGW;YQYNVLPQGWK;VLPQGWKGSPA;LPQGWKGSPAI;KGSPA
IFQSSMiSPAIFQSSMTKjAIFQSSMTKILjQSSMTKILEPFjSSMTKIL
EPFRiSMTKILEPFRKjEPFRKQNPDIVjKQNPDIVIYQYjDIVIYQYMD
DL;IVIYQYMDDLY;VIYQYMDDLYV;YQYMDDLYVGS;YMDDLYVG
SDL;DLEIGQHRTKI;GQHRTKIEELR;KIEELRQHLLR;ELRQHLLRW
GL;RQHLLRWGLTT;LLRWGLTTPDK;LRWGLTTPDKK;KKHQKEPP
FLW;EPPFLWMGYEL;FLWMGYELHPD;LWMGYELHPDK;ELHPDK
WTVQP;HPDKWTVQPIV;WTVQPIVLPEK;QPIVLPEKDSW;IVLPEK
DSWTV;TVNDIQKLVGK;IQKLVGKLNWA;KLVGKLNWASQ;LVGKL
NW ASQIiKLNWASQ IYPGiWASQIYPGIKViASQIYPGIKVR ;QIYPGI
KVRQL;RQLCKLLRGTK;KLLRGTKALTE;LLRGTKALTEV;GTKALT
EVIPLjALTEVIPLTEEjEVIPLTEEAELilPLTEEAELELjPLTEEAELEL
A;EEAELELAENR;AELELAENREI;ELELAENREIL;AENREILKEPV;
REILKEPVHGVjEILKEPVHGVYjlLKEPVHGVYYjEPVHGVYYDPSiP
VHGVYYDPSK;AEIQKQGQGQW;IQKQGQGQWTY;KQGQGQWTY
QI;QWTYQIYQEPF;WTYQIYQEPFK;YQIYQEPFKNL;QIYQEPFKNL
K;EPFKNLKTGKY;NLKTGKYARMR;RMRGAHTNDVK;HTNDVKQL
TEAiDVKQLTEAVQKiQLTEAVQKITTiEAVQKITTESIiAVQKITTESI
VilTTESIVIWGKjESIVIWGKTPKiSIVIWGKTPKFilVIWGKTPKFKjVI
WGKTPKFKL;KTPKFKLPIQK;KLPIQKETWET;LPIQKETW ETW;IQK
ETW ETWWT; KETW ETWWTEY; ETW ETWWTEYW ;W ETWWTEYW
QAiETWWTEYWQATiTWWTEYWQATWiWWTEYWQATWhEYWQ
ATWIPEW ;WQATWIPEWEF;QATWIPEWEFV;PEWEFVNTPPL;WE
FVNTPPLVKiEFVNTPPLVKLiFVNTPPLVKLWiKLWYQLEKEPIiYQ LEKEPIVGAiEPIVGAETFYViETFYVDGAANRjYVDGAANRETKiGA
ANRETKLGK;RETKLGKAGYV;KLGKAGYVTNR;AGYVTNRGRQK;
YVTNRGRQKVV;VVTLTDTTNQK;LTDTTNQKTEL;TTNQKTELQAI;
KTELQAIYLALjAIYLALQDSGLjYLALQDSGLEViALQDSGLEVNIjLQ
DSGLEVN I V;LEVN I VTDSQY;EVN IVTDSQYA; I VTDSQYALG I ;SQYA
LGIIQAQiAQPDQSESELViSELVNQIIEQLiELVNQIIEQLIiLVNQIIEQ
LIKiQIIEQLIKKEKiIIEQLIKKEKViIEQLIKKEKVYiQLIKKEKVYLAiIKK
EKVYLAWViKVYLAWVPAHKiYLAWVPAHKGIiG IGGNEQVDKLiEQ
VDKLVSAGIiQVDKLVSAGIRiKLVSAGIRKVLiLVSAGIRKVLFiGIRK
VLFLDGI;FLDGIDKAQDE;HSNWRAMASDF;NWRAMASDFNL;AMA
SDFNLPPViMASDFNLPPVViNLPPVVAKEIViLPPVVAKEIVAiEIVA
SCDKCQLiIVASCDKCQLKiQLKGEAMHGQViQVDCSPGIWQLiQL
DCTHLEGKViHLEGKVILVAViILVAVHVASGYiLVAVHVASGYIiAVH
VASGYIEAiHVASGYIEAEViIPAETGQETAYiAETGQETAYFLiETG
QETAYFLL;TGQETAYFLLK;GQETAYFLLKL;TAYFLLKLAGR;AYFL
LKLAGRWiFLLKLAGRWPViLLKLAGRWPVKiKLAGRWPVKTIiKTIH
TDNGSNFiHTDNGSNFTGAiNGSNFTGATVRiFTGATVRAACWiTG
ATVRAACWW ;TVR AACW W AG I ; ACW W AG I KQ E F ; W W AG I KQ E FG I iQEFGIPYN PQSiGIPYN PQSQGViIPYN PQSQGVViNPQSQGVVES
M;QSQGVVESMNK;G VVESMNKELK;VVESMNKELKK;KELKKIIGQ
VR;GQVRDQAEHLK;AEHLKT A VQMA;HLKT AVQMAVFiAVQMAVFI
HNF;VQMAVFIHNFK;QMAVFIHNFKR;MAVFIHNFKRK;FIHNFKRK
GGIiGIGGYSAGERIiGYSAGERIVDIiYSAGERIVDIIiIIATDIQTKELiA
TDIQTKELQKiQTKELQKQITKiLQKQITKIQNFiKQITKIQNFRViQITK
IQNFRVY;ITKIQNFRVYY;TKIQNFRVYYR;QNFRVYYRDSR;RVYY
RDSRNPL;VYYRDSRNPLW;YYRDSRNPLWK;SRNPLWKGPAK;N
PLWKGPAKLL;KLLWKGEGAVV;LLWKGEGAVVI;AVVIQDNSDIK;V
VIQDNSDIKV;VIQDNSDIKVV;DNSDIKVVPRR;DIKVVPRRKAK;VV
PRRKAKIIR;KQMAGDDCVAS;QMAGDDCVASR
15-mer + 9-mer core
ADDTVLEEMSLPG RW;LEEMSLPGR;AEAMSQVTNSATIMM;AMS
QVTNSA;AEAMSQVTNSATIMM;MSQVTNSAT;AEAMSQVTNSATI
MMiQVTNSATIMiAEHLKTAVQMAVFIHiLKTAVQMAViAENREILKE
PVHGVY;ILKEPVHGV;AETFYVDGAANRETK;YVDGAANRE;AFLQ
GKAREFSSEQT;LQGKAREFS;AFSPEVIPMFSALSE;VIPMFSALS;
AFTIPSINNETPGIRiIPSINNETPiAFTIPSINNETPGIRiPSINNETPG;
AGERIVDIIATDIQTiIVDIIATDIiAGIKQEFGIPYNPQSiIKQEFGIPYiA
GLKKKKSVTVLDVGiLKKKKSVTViAGPIAPGQMREPRGSiIAPGQM
REP;AGRWPVKTIHTDNGS;VKTIHTDNG;AGYVTNRGRQKVVTL;V
TNRGRQKV;AGYVTNRGRQKVVTL;YVTNRGRQK;AIFQSSMTKILE
PFR;FQSSMTKIL;AIGTVLVGPTPVNII;IGTVLVGPT;AIGTVLVGPTP
VNII;LVGPTPVNI;AIGTVLVGPTPVNII;VLVGPTPVN;AISPRTLNAW
VKVVE;PRTLNAWVK;AISPRTLNAWVKVVE;TLNAWVKVV;AIYLAL
QDSGLEVNIiYLALQDSGLiAKLLWKGEGAVVIQDiWKGEGAVVIiAL
GIIQAQPDQSESE;IIQAQPDQS;ALGIIQAQPDQSESE;IQAQPDQS
E;AMASDFNLPPVVAKE;DFNLPPVVA;AMASDFNLPPVVAKE;MAS
DFNLPP;AMSQVTNSATIMMQR;AMSQVTNSA;AMSQVTNSATIMM
QR;VTNSATIMM;AREFSSEQTRANSPT;FSSEQTRAN;ARMRGAH
TNDVKQLT;MRGAHTNDV;ARVLAEAMSQVTNSA;LAEAMSQVT;A
RVLAEAMSQVTNSA;VLAEAMSQV;ASDFNLPPVVAKEIV;DFNLPP
VVA;ASQEVKNWMTETLLV;VKNWMTETL;ASQIYPGIKVRQLCK;Y
PGIKVRQLiASRELERFAVN PGLLiLERFAVN PGiATDIQTKELQKQI
TK;IQTKELQKQ;ATIMMQRGNFRNQRK;IMMQRGNFR;ATLEEMMT
ACQGVGGiLEEMMTACQiATPQDLNTMLNTVGGiLNTMLNTVGiAT
VRAACWWAGIKQEiVRAACWWAGiATWIPEWEFVNTPPLiATWIP
EWEF;ATWIPEWEFVNTPPL;PEWEFVNTP;AVFIHNFKRKGGIGG;
FIHNFKRKG;AVFIHNFKRKGGIGG;IHNFKRKGG;AVQKITTESIVIW GK;VQKITTESI;AVQMAVFIHNFKRKG;VQMAVFIHN;AYFLLKLAGR
WPVKTiLKLAGRWPViAYFLLKLAGRWPVKTjLLKLAGRWPiAYFLL
KLAGRWPVKTiYFLLKLAGRiCDKCQLKGEAMHGQViLKGEAMHG
QiCGHKAIGTVLVGPTPiHKAIGTVLViCGHKAIGTVLVGPTPiIGTVL
VGPTiCKLLRGTKALTEVIPiLRGTKALTEiCKTILKALGPAATLEiILK
ALGPAAiCKTILKALGPAATLEiLKALGPAATiCQLKGEAMHGQVDC
SiLKGEAMHGQiCRQILGQLQPSLQTGiGQLQPSLQTiCRQILGQLQ
PSLQTGiLGQLQPSLQiCTHLEGKVILVAVHViLEGKVILVAiCTLNFP
ISPIETVPViFPISPIETViDAYFSVPLDEDFRKYiYFSVPLDEDiDCKTI
LKALGPAATLiILKALGPAAiDCKTILKALGPAATLiLKALGPAATiDDL
YVGSDLEIGQHR;YVGSDLEIG;DDTVLEEMSLPGRWK;LEEMSLP
GRiDEDFRKYTAFTIPSIiFRKYTAFTIiDEDFRKYTAFTIPSIiKYTAFT
IPS;DEHEKYHSNWRAMAS;EKYHSNWRA;DEHEKYHSNWRAMAS
;YHSNWRAMA;DFNLPPVVAKEIVAS;DFNLPPVVA;DFRKYTAFTIP
SINN;FRKYTAFTI;DFRKYTAFTIPSINN;YTAFTIPSI;DFWEVQLGIP
HPAGL;VQLGIPHPA;DGPKVKQWPLTEEKI;VKQWPLTEE;DIAGTT
STLQEQIGW;IAGTTSTLQ;DIIATDIQTKELQKQ;ATDIQTKEL;DIKVV
PRRKAKIIRDiIKVVPRRKAiDIQKLVGKLNWASQIiLVGKLNWASiDI
QTKELQKQITKIQiIQTKELQKQiDIVIYQYMDDLYVGSiYQYMDDLY
ViDKCQLKGEAMHGQVDiLKGEAMHGQiDKLVSAGIRKVLFLDiLVS
AGIRKViDKWTVQPIVLPEKDSiWTVQPIVLPiDLAFLQG KAREFSSE
;FLQGKAREF;DLNTMLNTVGGHQAA;LNTM LNTVGiDLNTM LNTVG
GHQAA;MLNTVGGHQ;DLYVGSDLEIGQHRT;YVGSDLEIG;DNGS
NFTGATVRAACiFTGATVRAAiDNSDIKVVPRRKAKIiIKVVPRRKA;
DQAEHLKTAVQMAVFiLKTAVQMAViDQILIEICGHKAIGTiLIEICGH
KA;DRFYKTLRAEQASQE;DRFYKTLRA;DRFYKTLRAEQASQE;FY
KTLRAEQ;DRFYKTLRAEQASQE;YKTLRAEQA;DRVHPVHAGPIAP
GQ;VHAGPIAPG;DSGLEVN IVTDSQYAiLEVN IVTDSiDSQYALGIIQ
AQPDQ;YALGIIQAQ;DSRNPLWKGPAKLLW;LWKGPAKLL;DTVLE
EMSLPG RWKP;LEEMSLPGR;DVGDAYFSVPLDEDF;YFSVPLDED
;DYVDRFYKTLRAEQA;DRFYKTLRA;DYVDRFYKTLRAEQA;FYKTL
RAEQ;DYVDRFYKTLRAEQA;VDRFYKTLR;DYVDRFYKTLRAEQA;
YVDRFYKTL;EAMSQVTNSATIMMQ;AMSQVTNSA;EAMSQVTNSA
TIMMQiVTNSATIMMiEAVQKITTESIVIWGiVQKITTESIiEDFRKYTA
FTIPSINiFRKYTAFTIiEDFRKYTAFTIPSINiYTAFTIPSIiEDLAFLQG
KAREFSS;FLQGKAREF;EDLAFLQGKAREFSS;LAFLQGKAR;EEKI
KALVEICTEMEiIKALVEICTiEELRQHLLRWGLTTPiLRQHLLRWGiE
ELRSLYNTVATLYCiLRSLYNTVAiEELRSLYNTVATLYCiLYNTVAT
LYiEFGIPYN PQSQGVVEiPYN PQSQGV;EFSSEQTRANSPTRR;FS
SEQTRAN;EFSSEQTRANSPTRR;QTRANSPTR;EFVNTPPLVKLW
YQLiFVNTPPLVKiEFVNTPPLVKLWYQLiVNTPPLVKLiEGCRQILG
QLQPSLQiCRQILGQLQiEGCRQILGQLQPSLQiILGQLQPSLiEGCR
QILGQLQPSLQiRQILGQLQPiEGKISKIGPENPYNTiISKIGPENPiE
GKVILVAVHVASGYiLVAVHVASGiEGKVILVAVHVASGYiVILVAVH
VAiEHEKYHSNW RAMASD;HSNWRAMAS;EHEKYHSNWRAMASD
;YHSNW RAMAiEHLKT AVQMAVFIHNiLKT AVQMAViEICGHKAIGT
VLVGPiHKAIGTVLViEIYKRWIILGLNKIViWIILGLNKIiEIYKRWIILGL
NKIViYKRWIILGLiEKEPIVGAETFYVDGiIVGAETFYViEKIKALVEIC
TEMEKiIKALVEICTiEKVYLAWVPAHKGIGiLAWVPAHKGiEKVYLA
WVPAH KG IG ; VYLAW VPAH ; E KVYLAW VPAH KG IG ; YLAW VPAH K;
EKYHSNW RAMASDFN;HSNWRAMAS;EKYHSNW RAMASDFN ;YH
SNWRAMAiELERFAVN PGLLETSiFAVN PGLLEiELHPDKWTVQPIV
LP;DKWTVQPIV;ELHPDKWTVQPIVLP;KWTVQPIVL;ELQAIYLALQ
DSGLEiLQAIYLALQiELQKQITKIQNFRVYiITKIQNFRViELQKQITKI
QNFRVYiLQKQITKIQiELRQHLLRWGLTTPDiLLRWGLTTPiELRQH
LLRWGLTTPDiLRQHLLRWGiELRSLYNTVATLYCViLYNTVATLYiE
LRSLYNTVATLYCViYNTVATLYCiELVNQIIEQLIKKEKiVNQIIEQLI;
ENREILKEPVHGVYY;ILKEPVHGV;EPFKNLKTGKYARMR;FKNLKT GKY;EPFKNLKTGKYARMR;LKTGKYARM;EPFRKQNPDIVIYQY;F
RKQNPDIV;EPIVGAETFYVDGAA;IVGAETFYV;EPPFLWMGYELH
PDK;FLWMGYELH;EPRGSDIAGTTSTLQ;EPRGSDIAG;EPRGSDIA
GTTSTLQ;GSDIAGTTS;EPRGSDIAGTTSTLQ;RGSDIAGTT;EQAS
QEVKNWMTETL;EVKNWMTET;EQASQEVKNWMTETL;SQEVKN
WMT;EQIGWMTNNPPIPVG;IGWMTNNPP;EQIGWMTNNPPIPVG;
MTNNPPIPV;EQLIKKEKVYLAWVP;IKKEKVYLA;EQVDKLVSAGIR
KVLjLVSAGIRKVjERFAVNPGLLETSEGiFAVNPGLLEjERFAVNPG
LLETSEGiVNPGLLETSiERIVDIIATDIQTKEiIVDIIATDIiESELVNQII
EQLIKK;LVNQIIEQL;ESIVIWGKTPKFKLP;IVIWGKTPK;ESIVIWGK
TPKFKLP;IWGKTPKFK;ESIVIWGKTPKFKLP;VIWGKTPKF;ESMNK
ELKKIIGQVRiMNKELKKIIiETAYFLLKLAGRWPViAYFLLKLAGiETA
YFLLKLAGRWPV;FLLKLAGRW;ETAYFLLKLAGRW PViYFLLKLAG
RiETFYVDGAANRETKLiYVDGAANREiETLLVQNANPDCKTIiVQN
ANPDCKiETPGIRYQYNVLPQGiIRYQYNVLPiETVPVKLKPGMDGP
K;VKLKPGMDG;ETW ETWWTEYWQATW ;W ETWWTEYW; ETWWT
EYWQATWIPE;EYWQATWIP;ETWWTEYWQATWIPE;WWTEYWQ
ATiEVIPMFSALSEGATPiIPMFSALSEiEVIPMFSALSEGATPiMFSA
LSEGA;EVIPMFSALSEGATP;VIPMFSALS;EVKNWMTETLLVQNA;
NWMTETLLV;EVKNWMTETLLVQNA;WMTETLLVQ;EVQLGIPHPA
GLKKK;VQLGIPHPA;EWEFVNTPPLVKLWY;FVNTPPLVK;EWEFV
NTPPLVKLWY;VNTPPLVKL;EWEFVNTPPLVKLWY;WEFVNTPPL;
EYWQATWIPEWEFVNiWQATWIPEWiFAIKKKDSTKWRKLViIKKK
DSTKWiFAVNPGLLETSEGCRiVNPGLLETSiFGIPYNPQSQGVVE
SiPYNPQSQGViFIHNFKRKGGIGGYSiFKRKGGIGGiFKNLKTGKY
ARMRGA;FKNLKTGKY;FKNLKTGKYARMRGA;LKTGKYARM;FKR
KGGIGGYSAGER;FKRKGGIGG;FLLKLAGRWPVKTIH;KLAGRWP
VKiFLLKLAGRW PVKTIHiLAGRW PVKT;FLLKLAGRWPVKTIH;LKL
AGRW PV;FLQG KAREFSSEQTR;FLQGKAREF;FLREDLAFLQGKA
RE;LAFLQG KAR;FNFPQVTLWQRPLVT;FPQVTLWQR;FNFPQ VTL
WQRPLVTiVTLWQRPLViFNLPPVVAKEIVASCiVVAKEIVASiFPISP
IETVPVKLKPiIETVPVKLKiFPISPIETVPVKLKPiISPIETVPViFPQVT
LWQRPLVTIK;LWQRPLVTI;FPQVTLWQRPLVTIK;TLWQRPLVT;F
PQVTLWQRPLVTIK;VTLWQRPLV;FQSSMTKILEPFRKQ;FQSSMT
KILiFQSSMTKILEPFRKQiTKILEPFRKiFRKQNPDIVIYQYMDiFRKQ
NPDIViFRKYTAFTIPSINNEiFRKYTAFTIiFRKYTAFTIPSINNEiYTA
FTIPSIiFRNQRKIVKCFNCGKiFRNQRKIVKiFRVYYRDSRNPLWKG
;FRVYYRDSR;FRVYYRDSRNPLWKG;YRDSRNPLW;FRVYYRDSR
NPLWKGiYYRDSRNPLiFSPEVIPMFSALSEGiVIPMFSALSiFSSEQ
TRANSPTRRE;FSSEQTRAN;FSSEQTRANSPTRRE;QTRANSPTR;
FSSEQTRANSPTRREiTRANSPTRRiFTGATVRAACWWAGIiFTGA
TVRAA;FTIPSINNETPGIRY;INNETPGIR;FVNTPPLVKLWYQLE;FV
NTPPLVK;FVNTPPLVKLWYQLE;VNTPPLVKL;FWEVQLGIPHPAG
LK;VQLGIPHPA;FYKTLRAEQASQEVK;FYKTLRAEQ;FYKTLRAEQ
ASQEVK;YKTLRAEQA;FYVDGAANRETKLGK;VDGAANRET;GAD
DTVLEEMSLPGR;VLEEMSLPG;GAETFYVDGAANRET;YVDGAAN
RE;GATPQDLNTM LNTVG;DLNTMLNTV;GATPQDLNTMLNTVG;P
QDLNTMLNiGATVRAACWWAGIKQiVRAACWWAGiGCRQILGQLQ
PSLQTiLGQLQPSLQiGCTLNFPISPIETVPiFPISPIETViGDAYFSVP
LDEDFRK;YFSVPLDED;GEIYKRWIILGLNKI;IYKRWIILG;GEIYKR
WIILGLNKIiYKRWIILGLiGERIVDIIATDIQTKiIVDIIATDIiGGHQAAM
QMLKETINiAAMQMLKETiGHKAIGTVLVGPTPViHKAIGTVLViGHK
AIGTVLVGPTPViIGTVLVGPTiGHKARVLAEAMSQVTiVLAEAMSQ
ViGIIQAQPDQSESELViIIQAQPDQSiGIIQAQPDQSESELViIQAQP
DQSEiGIKVRQLCKLLRGTKiVRQLCKLLRiGIPYNPQSQGVVESM;
PYNPQSQGV;GIRYQYNVLPQGWKG;IRYQYNVLP;GIRYQYNVLP
QGWKGiYQYNVLPQGiGKAGYVTNRGRQKVViVTNRGRQKViGKA
GYVTNRGRQKVV;YVTNRGRQK;GKAREFSSEQTRANS;FSSEQT RAN;GKISKIGPENPYNTP;IGPENPYNT;GKKKYKLKHIVWASR;YKL
KHIVWAiGKVILVAVHVASGYIiLVAVHVASGiGKVILVAVHVASGYI;
VILVAVHVAjGKYARMRGAHTNDVKjMRGAHTNDVjGKYARMRGA
HTNDVK;YARMRGAHT;GLEVNIVTDSQYALG;VNIVTDSQY;GLKK
KKSVTVLDVGDjLKKKKSVTVjGLNKIVRMYSPTSILjlVRMYSPTSiG
LNKIVRMYSPTSILjLNKIVRMYSjGLNKIVRMYSPTSILjVRMYSPTSI
;GMDGPKVKQWPLTEE;KVKQWPLTE;GNEQVDKLVSAGIRK;VDK
LVSAGIiGNFRNQRKIVKCFNCiFRNQRKIVKiGPAKLLWKGEGAVVI
;LWKGEGAVV;GPKVKQWPLTEEKIK;VKQWPLTEE;GPTPVNIIGR
NLLTQiVNIIGRNLLiGPAATLEEMMTACQGiLEEMMTACQiGQETA
YFLLKLAGRW;YFLLKLAGR;GQLQPSLQTGSEELR;GQLQPSLQT;
GQMVHQAISPRTLNAiMVHQAISPRiGQMVHQAISPRTLNAiVHQAI
SPRTiGRNLLTQIGCTLNFPiGRNLLTQIGiGRQKVVTLTDTTNQKiV
TLTDTTNQ;GRQKVVTLTDTTNQK;VVTLTDTTN ;G RWPVKTIHTDN
GSN;VKTIHTDNG;GSDIAGTTSTLQEQI;IAGTTSTLQ;GSEELRSLY
NTVATL;LRSLYNTVA;GSNFTGATVRAACWW;FTGATVRAA;GSPA
IFQSSMTKILE;FQSSMTKIL;GTTSTLQEQIGWMTN;LQEQIGWMT;
GTVLVGPTPVNIIGR;LVGPTPVNI;GTVSFNFPQVTLWQR;VSFNFP
QVT;GWKGSPAIFQSSMTK;WKGSPAIFQ;GWMTNNPPIPVGEIY;M
TNNPPIPViGYVTNRGRQKVVTLT ;VTNRGRQKV;HEKYHSNWRAM
ASDF;HSNWRAMAS;HEKYHSNWRAMASDF;YHSNWRAMA;HKAI
GTVLVGPTPVNiHKAIGTVLViHKAIGTVLVGPTPVNiIGTVLVGPTiH
KARVLAEAMSQVTNiLAEAMSQVTiHLEGKVILVAVHVASiVILVAVH
VAiHLKT A VQMAVFIHNFiLKT A VQMAV;HLLRWGLTTPDKKHQ;LL
RWGLTTP;HLLRWGLTTPDKKHQ;LRWGLTTPD;HLLRWGLTTPDK
KHQ;WGLTTPDKK;HNFKRKGGIGGYSAG;FKRKGGIGG;HPAGLK
KKKSVTVLDiLKKKKSVTViHPDKWTVQPIVLPEKiWTVQPIVLPiHP
VHAGPIAPGQMRE;VHAGPIAPG;HQKEPPFLWMGYELH;KEPPFL
WMG;HQKEPPFLWMGYELH;QKEPPFLWM;HSNWRAMASDFNLP
P;WRAMASDFN;IAGTTSTLQEQIGWM;IAGTTSTLQ;IATDIQTKELQ
KQITiIQTKELQKQiICGHKAIGTVLVGPTiHKAIGTVLViIEAEVIPAET
GQETA;IPAETGQET;IEELRQHLLRWGLTT;LRQHLLRWG;IEICGH
KAIGTVLVGiICGHKAIGTiIEQLIKKEKVYLAWViIKKEKVYLAiIETVP
VKLKPGMDGPiVKLKPGMDGiIFQSSMTKILEPFRKiFQSSMTKILiIF
QSSMTKILEPFRKiMTKILEPFRiIGCTLNFPISPIETViNFPISPIETiIG
PENPYNTPVFAIKiIGPENPYNTiIGRNLLTQIGCTLNFiGRNLLTQIG;
IGRNLLTQIGCTLNFiIGRNLLTQIiIGTVLVGPTPVNIIGiIGTVLVGPT;
IGTVLVGPTPVNIIGiLVGPTPVNUGTVLVGPTPVNIIGiVLVGPTPV
NiIGWMTNNPPIPVGEIiIGWMTNNPPiIGWMTNNPPIPVGEIiMTNN
PPIPViIGWMTNNPPIPVGEIiWMTNNPPIPiIHNFKRKGGIGGYSAiF
KRKGGIGGiIIATDIQTKELQKQIiIQTKELQKQiIIEQLIKKEKVYLAWiI
KKEKVYLAiIIGRNLLTQIGCTLN ;GRNLLTQIG;IIGRNLLTQIGCTLN;I
GRNLLTQIiIILGLNKIVRMYSPTiILGLNKIVRiIILGLNKIVRMYSPTiL
GLNKIVRMiIILGLNKIVRMYSPTiLNKIVRMYSiIIQAQPDQSESELVN
;IIQAQPDQS;IKKEKVYLAWVPAHK;IKKEKVYLA;IKKEKVYLAWVP
AHKiVYLAWVPAHiIKVRQLCKLLRGTKAiVRQLCKLLRiIKVVPRRK
AKIIRDYiIKVVPRRKAiILEPFRKQNPDIVIYiFRKQNPDIViILGLNKIV
RMYSPTSiILGLNKIVRiILGLNKIVRMYSPTSiLGLNKIVRMiILGLNKI
VRMYSPTSiLNKIVRMYSiILGQLQPSLQTGSEEiGQLQPSLQTiILG
QLQPSLQTGSEEiLGQLQPSLQiILIEICGHKAIGTVLiICGHKAIGTiIL
KALGPAATLEEMMiLKALGPAATiILVAVHVASGYIEAEiLVAVHVAS
G;IMMQRGNFRNQRKIV;IMMQRGNFR;INNETPGIRYQYNVL;INNE
TPGIR;IPEWEFVNTPPLVKL;FVNTPPLVK;IPEWEFVNTPPLVKL;W
EFVNTPPLiIPHPAGLKKKKSVTViGLKKKKSVTiIPHPAGLKKKKSV
TViPAGLKKKKSiIPMFSALSEGATPQDiMFSALSEGAiIPSINNETPG
IRYQYiINNETPGIRiIPVGEIYKRWIILGLiIYKRWIILGiIQDNSDIKVV
PRRKAiIQDNSDIKViIQGQMVHQAISPRTLiMVHQAISPRiIQGQMV
HQAISPRTL;VHQAISPRT;IQKETWETWWTEYWQ;WETWWTEYW; IQKLVGKLNW ASQIY;LVGKLNWAS;IQKLVGKLNWASQIY;VGKLN
WASQ;IQNFRVYYRDSRNPL;IQNFRVYYR;IQTKELQKQITKIQN;LQ
KQITKIQ;IRYQYNVLPQGWKGS;IRYQYNVLP;IRYQYNVLPQGWK
GSiYQYNVLPQGjISKIGPENPYNTPVFjlGPENPYNTjISPIETVPVKL
KPGM;ISPIETVPV;ISPRTLNAWVKVVEE;LNAWVKVVE;ISPRTLNA
WVKVVEE;TLNAWVKVV;ITKIQNFRVYYRDSR;IQNFRVYYR;ITKIQ
NFRVYYRDSRilTKIQNFRVjITTESIVIWGKTPKFjITTESIVIWjITTES
IVIWGKTPKFilVIWGKTPKjlVGAETFYVDGAANRjlVGAETFYVjlVI
WGKTPKFKLPIQ;IVIWGKTPK;IVIWGKTPKFKLPIQ;IWGKTPKFK;I
VIWGKTPKFKLPIQ;VIWGKTPKF;IVIYQYMDDLYVGSD;YQYMDDL
YVjlVQNIQGQMVHQAISilQGQMVHQAjlVRMYSPTSILDIRQjlVRM
YSPTSilVRMYSPTSILDIRQjVRMYSPTSIjlVRMYSPTSILDIRQjYSP
TSILDUVTDSQYALGIIQAQiQYALGIIQAiIYKRWIILGLNKIVRiWIIL
GLNKIiIYKRWIILGLNKIVRiYKRWIILGLiIYLALQDSGLEVN IViLQDS
GLEVNiIYPGIKVRQLCKLLRiIKVRQLCKLiIYPGIKVRQLCKLLRiYP
GIKVRQLiIYQEPFKNLKTGKYAiFKNLKTGKYiKAFSPEVIPMFSAL
SiEVIPMFSALiKAFSPEVIPMFSALSiFSPEVIPMFiKAFSPEVIPMFS
ALSiKAFSPEVIPiKAGYVTNRGRQKVVTiVTNRGRQKViKAGYVTN
RGRQKVVTiYVTNRGRQKiKAIGTVLVGPTPVNIiIGTVLVGPTiKAIG
TVLVGPTPVNIiVLVGPTPVNiKALGPAATLEEMMTAiLGPAATLEE;
KAREFSSEQTRANSPiFSSEQTRANiKARVLAEAMSQVTNSiLAEA
MSQVTiKCQLKGEAMHGQVDCiLKGEAMHGQiKEKVYLAWVPAH
KGIiLAWVPAHKGiKEKVYLAWVPAHKGIiVYLAWVPAHiKEKVYLA
WVPAHKGI;YLAWVPAHK;KELKKIIGQVRDQAE;LKKIIGQVR;KELQ
KQITKIQNFRViLQKQITKIQiKEPIVGAETFYVDGAiIVGAETFYViKE
PPFLWMGYELHPD;FLWMGYELH;KETW ETWWTEYWQAT;WETW
WTEYW;KGSPAIFQSSMTKIL;IFQSSMTKI;KIEELRQHLLRWGLT;L
RQHLLRWG;KIGPENPYNTPVFAI;IGPEN PYNTiKILEPFRKQNPDIV
IiFRKQNPDIViKIQNFRVYYRDSRNPiIQNFRVYYRiKISKIGPENPY
NTPViIGPENPYNTiKITTESIVIWGKTPKiESIVIWGKTiKITTESIVIW
GKTPKiSIVIWGKTPiKIVRMYSPTSILDIRiIVRMYSPTSiKIVRMYSP
TSILDIRiVRMYSPTSIiKIVRMYSPTSILDIRiYSPTSILDIiKKEKVYLA
WVPAHKGiKVYLAWVPAiKKEKVYLAWVPAHKGiVYLAWVPAHiKK
EKVYLAWVPAHKGiYLAWVPAHKiKKKYKLKHIVWASREiLKHIVW
ASRiKKKYKLKHIVWASREiYKLKH IVWAiKKSVTVLDVGDAYFSiVT
VLDVGDAiKKYKLKHIVW ASRELiLKHIVW ASRiKKYKLKHIVW ASR
EL;YKLKHIVWA;KLAGRWPVKTIHTDN;LAGRW PVKTiKLGKAGYV
TNRGRQK;G YVTNRGRQ;KLGKAGYVTNRGRQK;KAGYVTNRG;K
LKHIVWASRELERFiLKHIVWASRiKLLRGTKALTEVIPLiLRGTKALT
E;KLLWKGEGAVVIQDN;WKGEGAVVI;KLVDFRELNKRTQDF;FRE
LNKRTQ;KLVDFRELNKRTQDF;VDFRELN KR;KLVGKLNW ASQIYP
GiKLNWASQIYiKLVGKLNWASQIYPGiLVGKLNWASiKLVSAGIRK
VLFLDG;LVSAGIRKV;KNLKTGKYARMRGAH ;LKTGKYARM;KNW
MTETLLVQNANP;WMTETLLVQ;KQEFGIPYN PQSQGViFGIPYNP
QSiKQITKIQNFRVYYRDiIQNFRVYYRiKQITKIQNFRVYYRDiITKIQ
NFRViKQLTEAVQKITTESIiAVQKITTESiKRWIILGLNKIVRMYiILGL
NKIVRiKRWIILGLNKIVRMYiLGLNKIVRMiKRWIILGLNKIVRMYiWII
LGLNKIiKSVTVLDVGDAYFSViLDVGDAYFSiKTAVQMAVFIHNFKR
;VQMAVFIHN;KTELQAIYLALQDSG;LQAIYLALQ;KTGKYARMRGA
HTND;YARMRGAHT;KTILKALGPAATLEE;ILKALGPAA;KTILKALG
PAATLEEiLKALGPAATiKVILVAVHVASGYIEiLVAVHVASGiKVILVA
VHVASGYIEiVILV AVHVA;KVKQWPLTEEKIKAL;VKQWPLTEE;KV
RQLCKLLRGTKAL;VRQLCKLLR;KVVTLTDTTNQKTEL;VTLTDTTN
Q;KVYLAWVPAHKGIGG;LAWVPAHKG;KVYLAWVPAHKGIGG;VY
LAWVPAHiKVYLAWVPAH KG IGGiWVPAH KG IGiKVYLAWVPAH KG
IGG;YLAWVPAHK;KWRKLVDFRELNKRT;VDFRELNKR;KWTVQPI
VLPEKDSWiWTVQPIVLPiKYARMRGAHTNDVKQiMRGAHTNDViK
YHSNWRAMASDFNL;WRAMASDFN ;KYHSNWRAMASDFNL;YHS NWRAMA;KYKLKHIVWASRELE;LKHIVWASR;LAEAMSQVTNSATI
M;AMSQVTNSA;LAEAMSQVTNSATIM;LAEAMSQVT;LAENREILKE
PVHGV;EILKEPVHG;LAFLQGKAREFSSEQ;FLQGKAREF;LAGRW
PVKTIHTDNG;LAGRWPVKT;LAWVPAHKGIGGNEQ;LAWVPAHKG iLCKLLRGTKALTEVIjLRGTKALTEjLDEDFRKYTAFTIPSiFRKYTAF
TliLDVGDAYFSVPLDEDjDAYFSVPLDjLEEMMTACQGVGGPGjMT
ACQGVGGjLEEMSLPGRWKPKMIjLEEMSLPGRjLEGKVILVAVHV
ASGiKVILVAVHVjLEGKVILVAVHVASGjVILVAVHVAjLEKEPIVGAE
TFYVDjlVGAETFYVjLEPFRKQNPDIVIYQiFRKQNPDIVjLERFAVN
PGLLETSE;FAVNPGLLE;LERFAVNPGLLETSE;VNPGLLETS;LEV
NIVTDSQYALGIiVNIVTDSQYjLGIIQAQPDQSESELjllQAQPDQSiL
GIIQAQPDQSESELjlQAQPDQSEjLGKAGYVTNRGRQKVjYVTNRG
RQKjLGLNKIVRMYSPTSIjlVRMYSPTSiLGLNKIVRMYSPTSIjLGLN
KIVRMjLGLNKIVRMYSPTSIjLNKIVRMYSiLGPAATLEEMMTACQjA
ATLEEMMT;LGQLQPSLQTGSEEL;LGQLQPSLQ;LHPDKWTVQPIV
LPEiWTVQPIVLPjLIEICGHKAIGTVLVilCGHKAIGTjLIKKEKVYLAW
VPAH ;KVYLAWVPA;LKALGPAATLEEMMT;LKALGPAAT;LKH IVWA
SRELERFAiLKHIVWASRjLKKKKSVTVLDVGDAjLKKKKSVTVjLKL
AGRWPVKTIHTD;LAGRWPVKT;LKLAGRWPVKTIHTD;LKLAGRW
PViLKTAVQMAVFIHNFKjLKTAVQMAVjLKTAVQMAVFIHNFKjVQM
AVFIHN;LKTGKYARMRGAHTN;YARMRGAHT;LLKLAGRWPVKTIH
T;LAGRWPVKT;LLKLAGRWPVKTIHT;LKLAGRWPV;LLRWGLTTP
DKKHQK;LLRWGLTTP;LLRWGLTTPDKKHQK;LRWGLTTPD;LLR
WGLTTPDKKHQKjWGLTTPDKKjLLVQNANPDCKTILKjVQNANPD
CKjLLWKGEGAVVIQDNSiWKGEGAVVIiLNFPISPIETVPVKLjlSPIE
TVPVjLNKIVRMYSPTSILDjlVRMYSPTSiLNKIVRMYSPTSILDjLNKI
VRMYS;LNKIVRMYSPTSILD;VRMYSPTSI;LNTM LNTVGGHQAAM;
LNTMLNTVG;LNTMLNTVGGHQAAM;MLNTVGGHQ;LNTVGGHQA
AMQMLKjVGGHQAAMQiLPPVVAKEIVASCDKjVVAKEIVASiLPQG
WKGSPAIFQSSiWKGSPAIFQjLQAIYLALQDSGLEVjLQAIYLALQjL
QEQIGWMTNNPPIP;IGWMTNNPP;LQKQITKIQNFRVYY;ITKIQNF
RV;LQKQITKIQNFRVYY;LQKQITKIQ;LREDLAFLQGKAREF;LAFL
QGKAR;LRQHLLRWGLTTPDK;LLRWGLTTP;LRQHLLRWGLTTPD
KiLRWGLTTPDiLRSLYNTVATLYCVHjLYNTVATLYjLRSLYNTVAT
LYCVHiYNTVATLYCiLRWGLTTPDKKHQKEjLRWGLTTPDjLRWGL
TTPDKKHQKEiWGLTTPDKKjLTEAVQKITTESIVIjVQKITTESIjLTE
EKIKALVEICTEilKALVEICTjLVGKLNWASQIYPGIiKLNWASQIYjLV
GKLNWASQIYPGIjLVGKLNWASiLVGPTPVNIIGRNLLjGPTPVNIIG
;LVGPTPVNIIGRNLL;LVGPTPVNI;LVKLWYQLEKEPIVG;VKLWYQ
LEK;LVSAGIRKVLFLDGI;LVSAGIRKV;LWKGEGAVVIQDNSD;WK
GEGAVVI;LWKGPAKLLWKGEGA;LWKGPAKLL;LWQRPLVTIKIGG
QLiLWQRPLVTIiLYNTVATLYCVHQRIjLYNTVATLYjLYNTVATLYC
VHQRIiYNTVATLYCiMASDFNLPPVVAKEIjDFNLPPVVAjMASDFN
LPPVVAKEIjMASDFNLPPjMAVFIHNFKRKGGIGiFIHNFKRKGiMA
VFIHNFKRKGGIGjlHNFKRKGGjMDDLYVGSDLEIGQHjYVGSDLEI
G;MDGPKVKQWPLTEEK;VKQWPLTEE;MFSALSEGATPQDLN;MF
SALSEGAjMGARASVLSGGELDRjMGARASVLSjMLNTVGGHQAA
MQML;MLNTVGGHQ;MLNTVGGHQAAMQML;VGGHQAAMQ;MM
QRGNFRNQRKIVK;NFRNQRKIV;MMQRGNFRNQRKIVK;QRGNFR
NQR;MMQRGNFRNQRKIVK;RGNFRNQRK;MNKELKKIIGQVRDQ;
LKKIIGQVRjMQRGNFRNQRKIVKCjFRNQRKIVKjMRGAHTNDVKQ
LTEAjMRGAHTNDVjMSQVTNSATIMMQRGiVTNSATIMMjMTETLL
VQNANPDCKjLLVQNANPDjMTETLLVQNANPDCKjMTETLLVQN;
MTNNPPIPVGEIYKRjMTNNPPIPVjMVHQAISPRTLNAWVjMVHQAI
SPR;MVHQAISPRTLNAWV;VHQAISPRT;NDIQKLVGKLNWASQ;L
VGKLNW AS;NEQVDKLVSAGIRKV;VDKLVSAGI;NETPGIRYQYNV
LPQilRYQYNVLPjNFLREDLAFLQGKARjFLREDLAFLjNFPISPIETV
PVKLK;ISPIETVPV;NFPQVTLWQRPLVTI;TLWQRPLVT;NFRNQRK IVKCFNCGiFRNQRKIVKiNFRVYYRDSRNPLWKjFRVYYRDSRiNF
RVYYRDSRNPLWK;YRDSRNPLW;NFRVYYRDSRNPLWK;YYRDS
RN PL;N FTG ATV RAACWWAG ;FTGATVRAA;NGSN FTG ATVRAAC
WiFTGATVRAAiNIIGRNLLTQIGCTLiGRNLLTQIGiNIIGRNLLTQIG
CTLiIGRNLLTQIiNIQGQMVHQAISPRTiIQGQMVHQAiNIQGQMVH
QAISPRT;MVHQAISPR;NKELKKIIGQVRDQA;LKKIIGQVR;NKIVRM
YSPTSILDIiIVRMYSPTSiNKIVRMYSPTSILDIiVRMYSPTSIiNLKTG
KYARMRGAHT;GKYARMRGA;NLKTGKYARMRGAHT;LKTGKYAR
MiNLKTGKYARMRGAHTiNLKTGKYARiNLPPVVAKEIVASCDiVVA
KEIVASiNNETPGIRYQYNVLPiNNETPGIRYiNPDCKTILKALGPAA;
CKTILKALGiNPDCKTILKALGPAAiKTILKALGPiNPDIVIYQYMDDLY
V;IVIYQYMDD;NPLWKGPAKLLWKGE;LWKGPAKLL;NQKTELQAIY
LALQDiLQAIYLALQiNREILKEPVHGVYYDiILKEPVHGViNRGRQK
VVTLTDTTN;RQKVVTLTD;NSATIMMQRGNFRNQ;IMMQRGNFR;N
SDIKVVPRRKAKII;IKVVPRRKA;NTMLNTVGGHQAAMQ;LNTVGG
HQA;NTMLNTVGGHQAAMQ;MLNTVGGHQ;NTPPLVKLWYQLEKE
;VKLWYQLEK;NTPVFAIKKKDSTKW;VFAIKKKDS;NTVGGHQAAM
QMLKE;VGGHQAAMQ;NVLPQGWKGSPAIFQ;GWKGSPAIF;NVLP
QGWKGSPAIFQ;QGWKGSPAI;NWASQ IYPGIKVRQLiSQIYPGIKV;
NWRAMASDFNLPPVV;MASDFNLPP;NW RAMASDFN LPPVV ;WRA
MASDFN;NYPIVQNIQGQMVHQ;VQNIQGQMV;PAGLKKKKSVTVL
DV;LKKKKSVTV;PAIFQSSMTKILEPF;FQSSMTKIL;PAKLLWKGEG
AVVIQiWKGEGAVVliPDCKTILKALGPAATiCKTILKALGiPDCKTILK
ALGPAAT;ILKALGPAA;PDIVIYQYMDDLYVG;YQYMDDLYV;PDKW
TVQPIVLPEKDiWTVQPIVLPiPEVIPMFSALSEGATiVIPMFSALSiP
EWEFVNTPPLVKLW;FVNTPPLVK;PEWEFVNTPPLVKLW;VNTPP
LVKL;PEWEFVNTPPLVKLW;WEFVNTPPL;PFKNLKTGKYARMRG;
FKNLKTGKY;PFKNLKTGKYARMRG;LKTGKYARM;PFRKQNPDIVI
YQYMiFRKQNPDIViPGHKARVLAEAMSQViARVLAEAMSiPGIKVR
QLCKLLRGTiVRQLCKLLRiPGIRYQYNVLPQGWKiIRYQYNVLPiP
GIRYQYNVLPQGWK;YQYNVLPQG;PHPAGLKKKKSVTVL;LKKKK
SVTV;PIETVPVKLKPGMDG;TVPVKLKPG;PIQKETW ETWWTEYW;
KETWETWWTiPISPIETVPVKLKPGJSPIETVPViPIVGAETFYVDGA
AN;IVGAETFYV;PIVQNIQGQMVHQAI;VQNIQGQMV;PKVKQWPLT
EEKIKA;VKQWPLTEE;PLDEDFRKYTAFTIP;FRKYTAFTI;PLTEEKI
KALVEICTiLTEEKIKALiPLVKLWYQLEKEPIViVKLWYQLEKiPLWK
GPAKLLWKGEG;LWKGPAKLL;PMFSALSEGATPQDL;MFSALSEG
A;PPFLWMGYELHPDKW;FLWMGYELH;PPLVKLWYQLEKEPI;VKL
WYQLEKiPPVVAKEIVASCDKCiVVAKEIVASiPQDLNTMLNTVGGH
QiDLNTM LNTV;PQDLNTM LNTVGGHQ;LNTM LNTVGiPQGWKGSP
AIFQSSMiWKGSPAIFQiPQVTLWQRPLVTIKIiLWQRPLVTIiPQVTL
WQRPLVTIKI;TLWQRPLVT;PRGSDIAGTTSTLQE;IAGTTSTLQ;PR
TLNAWVKVVEEKA;LNAWVKVVE;PRTLNAWVKVVEEKA;TLNAWV
KVViPSINNETPGIRYQYNiINNETPGIRiPTPVNIIGRNLLTQIiIIGRNL
LTQ;PTPVNIIGRNLLTQI;VNIIGRNLL;PVFAIKKKDSTKWRK;IKKKD
STKWiPVGEIYKRWIILGLNiYKRWIILGLiPVHAGPIAPGQMREPiVH
AGPIAPG;PVKLKPGMDGPKVKQ;VKLKPGMDG;PVNIIGRNLLTQI
GCiGRNLLTQIGiPVNIIGRNLLTQIGCiVNIIGRNLLiPVVAKEIVASC
DKCQiVVAKEIVASiPAATLEEMMTACQGViLEEMMTACQiQAEHLK
TAVQMAVFIiLKTAVQMAViQAISPRTLNAWVKVViISPRTLNAWiQA
IYLALQDSGLEVN;YLALQDSGL;QASQEVKNWMTETLL;VKNWMT
ETL;QATWIPEWEFVNTPP;ATWIPEWEF;QDEHEKYHSNWRAMA;
KYHSNWRAM ;QDFWEVQLGIPHPAG;VQLGIPHPA;QDLNTM LNTV
GGHQA;LNTMLNTVG;QDLNTM LNTVGGHQA;MLNTVGGHQ;QDN
SDIKVVPRRKAK;IKVVPRRKA;QDSGLEVNIVTDSQY;LEVNIVTDS;
QEFGIPYNPQSQGVViPYNPQSQGViQEPFKNLKTGKYARMiFKNL
KTGKY;QEQIGWMTNNPPIPV;IGWMTNNPP;QETAYFLLKLAGRW
P;FLLKLAGRW;QETAYFLLKLAGRWP;YFLLKLAGR;QEVKNWMTE TLLVQN;VKNWMTETL;QGKAREFSSEQTRAN;AREFSSEQT;QGQ
MVHQAISPRTLNjMVHQAISPRjQGQMVHQAISPRTLNjVHQAISPR
T;QGTVSFNFPQVTLWQ;VSFNFPQVT;QGWKGSPAIFQSSMT;WK
GSPAIFQ;QHLLRWGLTTPDKKH;LLRWGLTTP;QHLLRWGLTTPD
KKH ;LRWGLTTPD;QHLLRWGLTTPDKKH;WGLTTPDKK;QIGWMT
NNPPIPVGEilGWMTNNPPjQIGWMTNNPPIPVGEjMTNNPPIPVjQI
GWMTNNPPIPVGE;WMTNNPPIP;QIIEQLIKKEKVYLA;LIKKEKVYL
;QILGQLQPSLQTGSE;GQLQPSLQT;QILGQLQPSLQTGSE;LGQL
QPSLQiQILIEICGHKAIGTVjlCGHKAIGTjQITKIQNFRVYYRDSilQN
FRVYYRiQITKIQNFRVYYRDSjlTKIQNFRVjQIYPGIKVRQLCKLLjY
PGIKVRQLjQIYQEPFKNLKTGKYjlYQEPFKNLjQIYQEPFKNLKTG
KY;PFKNLKTGK;QIYQEPFKNLKTGKY;YQEPFKNLK;QKEPPFLW
MGYELHP;FLWMGYELH;QKETWETWWTEYWQA;WETWWTEYW
;QKLVGKLNWASQIYP;KLNWASQIY;QKLVGKLNWASQIYP;LVGKL
NWAS;QKQITKIQNFRVYYR;ITKIQNFRV;QKQITKIQNFRVYYR;TKI
QNFRVY;QKTELQAIYLALQDS;LQAIYLALQ;QKVVTLTDTTNQKTE;
LTDTTNQKT;QKVVTLTDTTNQKTE;VTLTDTTNQ;QLCKLLRGTKAL
TEVjLRGTKALTEiQLEKEPIVGAETFYVjLEKEPIVGAjQLIKKEKVYL
AWVPA;IKKEKVYLA;QLTEAVQKITTESIV;VQKITTESI;QMAVFIHN
FKRKGGIiFIHNFKRKGiQMAVFIHNFKRKGGIiVFIHNFKRKiQMVH
QAISPRTLNAW;MVHQAISPR;QMVHQAISPRTLNAW;VHQAISPRT
;QNFRVYYRDSRNPLW;FRVYYRDSR;QNFRVYYRDSRNPLW;YY
RDSRNPLjQNIQGQMVHQAISPRjlQGQMVHQAjQNYPIVQNIQGQ
MVHiVQNIQGQMVjQRGNFRNQRKIVKCFjFRNQRKIVKjQSESELV
NQIIEQLIiLVNQIIEQLiQSSMTKILEPFRKQNiTKILEPFRKiQTGSEE
LRSLYNTVA;SEELRSLYN;QTKELQKQITKIQNF;LQKQITKIQ;QVD
KLVSAGIRKVLFiLVSAGIRKViQVTLWQRPLVTIKIGiLWQRPLVTIiQ
VTLWQRPLVTIKIG;TLWQRPLVT;QVTNSATIMMQRGNF;VTNSATI
MMiQYALGIIQAQPDQSEiIIQAQPDQSiQYALGIIQAQPDQSEiLGII
QAQPD;QYMDDLYVGSDLEIG;LYVGSDLEI;RAMASDFNLPPVVAK
;DFNLPPVVA;RAMASDFNLPPVVAK;MASDFNLPP;RDQAEHLKTA
VQMAV;HLKT AVQMA;RDSRNPLWKGPAKLL;PLWKGPAKL;RDYV
DRFYKTLRAEQ;DRFYKTLRA;RDYVDRFYKTLRAEQ;DYVDRFYKT
;RDYVDRFYKTLRAEQ;VDRFYKTLR;REDLAFLQG KAREFSiFLQG
KAREF;REDLAFLQG KAREFS;LAFLQGKAR;REFSSEQTRANSPTR
;FSSEQTRAN;RELERFAVN PGLLETiFAVN PGLLEiRELERFAVN PG
LLETiLERFAVN PG;RELQVWGRDNNSPSE;WGRDNNSPS;RFAVN
PGLLETSEGCiFAVNPGLLEiRFAVNPGLLETSEGCiVNPGLLETSiR
FYKTLRAEQASQEV;FYKTLRAEQ;RFYKTLRAEQASQEV;YKTLRA
EQAiRGNFRNQRKIVKCFNiFRNQRKIVKiRGRQKVVTLTDTTNQiK
VVTLTDTT;RGRQKVVTLTDTTNQ;RQKVVTLTD;RGRQKVVTLTDT
TNQ;VVTLTDTTN;RGSDIAGTTSTLQEQ;IAGTTSTLQ;RKLVDFREL
NKRTQD;FRELNKRTQ;RKLVDFRELNKRTQD;VDFRELNKR;RKYT
AFTIPSINNETiYTAFTIPSIiRMRGAHTNDVKQLTEiMRGAHTNDViR
MYSPTSILDIRQGP;YSPTSILDI;RNPLWKGPAKLLWKG;LWKGPAK
LL;RQGTVSFNFPQVTLW;VSFNFPQVT;RQHLLRWGLTTPDKK;LL
RWGLTTP;RQHLLRWGLTTPDKK;LRWGLTTPD;RQHLLRWGLTTP
DKK;RWGLTTPDK;RQILGQLQPSLQTGS;GQLQPSLQT;RQILGQL
QPSLQTGS;LGQLQPSLQ;RQKVVTLTDTTNQKT;VTLTDTTNQ;RQ
KVVTLTDTTNQKT ;VVTLTDTTN;RQLCKLLRGTKALTE;CKLLRGTK
AjRRELQVWGRDNNSPSiLQVWGRDNNjRSLYNTVATLYCVHQiLY
NTVATLYjRSLYNTVATLYCVHQjYNTVATLYCjRTKIEELRQHLLRW
G;ELRQHLLRW;RTKIEELRQHLLRWG;IEELRQHLL;RTLNAWVKV
VEEKAF;LNAWVKVVE;RTLNAWVKVVEEKAF;TLNAWVKVV;RVHP
VHAGPIAPGQMjVHAGPIAPGjRVLAEAMSQVTNSATjAMSQVTNS
AjRVLAEAMSQVTNSATjLAEAMSQVTjRVYYRDSRNPLWKGPiYR
DSRNPLW;RVYYRDSRNPLWKGP;YYRDSRNPL;RWGLTTPDKKH
QKEPiWGLTTPDKKiRWIILGLNKIVRMYSilLGLNKIVRjRWIILGLNK IVRMYSiLGLNKIVRMjRWIILGLNKIVRMYSiWIILGLNKIjRWPVKTIH
TDNGSNFjVKTIHTDNGiSAGERIVDIIATDIQilVDIIATDIjSATIMMQR
GNFRNQRjlMMQRGNFRjSCDKCQLKGEAMHGQiQLKGEAMHGiS
DFNLPPVVAKEIVA;FNLPPVVAK;SDIAGTTSTLQEQIG;IAGTTSTL
QjSDIKVVPRRKAKIIRilKVVPRRKAiSDIKVVPRRKAKIIRjVVPRRK
AKIiSEELRSLYNTVATLYjLRSLYNTVAiSELVNQIIEQLIKKEjLVNQII
EQLjSESELVNQIIEQLIKiLVNQIIEQLiSGLEVNIVTDSQYALjLEVNI
VTDSiSINNETPGIRYQYNVjlNNETPGIRjSIVIWGKTPKFKLPIjlVIW
GKTPKiSIVIWGKTPKFKLPIjlWGKTPKFKiSIVIWGKTPKFKLPIjVIW
GKTPKF;SKIGPENPYNTPVFA;IGPENPYNT;SLYNTV ATLYCVHQR iLYNTVATLYjSLYNTVATLYCVHQRjYNTVATLYCiSMNKELKKIIGQ
VRD;LKKIIGQVR;SMTKILEPFRKQNPD;TKILEPFRK;SNFTGATVR
AACWWAjFTGATVRAAiSNWRAMASDFNLPPVjMASDFNLPPiSN
WRAMASDFNLPPV;WRAMASDFN;SPAIFQSSMTKILEP;FQSSMT
KILiSPEVIPMFSALSEGAjVIPMFSALSiSPRTLNAWVKVVEEKjLNA
WVKVVE;SPRTLNAWVKVVEEK;TLNAWVKVV;SQEVKNWMTETL
LVQiVKNWMTETLiSQIYPGIKVRQLCKLjYPGIKVRQLjSQNYPIVQ
NIQGQMVjlVQNIQGQMiSQNYPIVQNIQGQMVjSQNYPIVQNjSQV
TNSATIMMQRGNjVTNSATIMMjSQYALGIIQAQPDQSiLGIIQAQPD
;SQYALGIIQAQPDQS;YALGIIQAQ;SRELERFAVNPGLLE;LERFAV
NPG;SRNPLWKGPAKLLWK;LWKGPAKLL;SSEQTRANSPTRREL;
QTRANSPTR;SSMTKILEPFRKQNP;TKILEPFRK;STLQEQIGWMT
NNPP;LQEQIGWMT;STLQEQIGWMTNNPP;QIGWMTNNP;SWTVN
DIQKLVGKLNjVNDIQKLVGiTAVQMAVFIHNFKRKjVQMAVFIHNjT
AYFLLKLAGRWPVK;FLLKLAGRW;TAYFLLKLAGRWPVK;LKLAGR
WPVjTAYFLLKLAGRWPVKjYFLLKLAGRiTDIQTKELQKQITKIjlQT
KELQKQ;TDNGSNFTGATVRAA;NFTGATVRA;TDSQYALGIIQAQP
DjYALGIIQAQiTEAVQKITTESIVIWjVQKITTESIiTEEKIKALVEICTE
MilKALVEICTjTELQAIYLALQDSGLjLQAIYLALQiTESIVIWGKTPKF
KLilVIWGKTPKiTESIVIWGKTPKFKLjlWGKTPKFKjTESIVIWGKTP
KFKLiVIWGKTPKFiTETLLVQNANPDCKTjVQNANPDCKjTEYWQA
TWIPEWEFV;WQATWIPEW;TFYVDGAANRETKLG;YVDGAANRE;
TGATVRAACWWAG I K; VR AACWW AG ;TG KYARM RGAHTN D V; YA
RMRGAHT;TGQETAYFLLKLAGR;TAYFLLKLA;TGSEELRSLYNTV
ATiLRSLYNTVAjTHLEGKVILVAVHVAjKVILVAVHVjTILKALGPAAT
LEEM;LKALGPAAT;TIMMQRGNFRNQRKI;IMMQRGNFR;TIPSINN
ETPGIRYQilNNETPGIRjTKELQKQITKIQNFRjLQKQITKIQjTKIEEL
RQHLLRWGL;LRQHLLRWG;TKILEPFRKQNPDIV;TKILEPFRK;TKI
QNFRVYYRDSRN;IQNFRVYYR;TKWRKLVDFRELNKR;WRKLVDF
REjTLEEMMTACQGVGGPjMTACQGVGGiTLLVQNANPDCKTILjV
QNANPDCKjTLNAWVKVVEEKAFSiLNAWVKVVEjTLNFPISPIETV
PVK;ISPIETVPV;TLQEQIGWMTNNPPI;IGWMTNNPP;TLWQRPLV
TIKIGGQ;LWQRPLVTI;TMLNTVGGHQAAMQM;MLNTVGGHQ;TML
NTVGGHQAAMQM;VGGHQAAMQ;TNQKTELQAIYLALQ;KTELQAI
YLjTNSATIMMQRGNFRNilMMQRGNFRjTPGIRYQYNVLPQGWjlR
YQYNVLP;TPGIRYQYNVLPQGW;YQYNVLPQG;TPPLVKLWYQLE
KEP;VKLWYQLEK;TPQDLNTMLNTVGGH;LNTMLNTVG;TPVFAIK
KKDSTKWRjlKKKDSTKWjTPVFAIKKKDSTKWRjVFAIKKKDSiTPV
NIIGRNLLTQIGjlGRNLLTQIiTPVNIIGRNLLTQIGiVNIIGRNLLjTQD
FWEVQLGIPHPAjEVQLGIPHPjTSTLQEQIGWMTNNPjLQEQIGW
MT;TTESIVIWGKTPKFK;IVIWGKTPK;TTESIVIWGKTPKFK;VIWGK
TPKF;TTSTLQEQIGWMTNN;LQEQIGWMT;TVGGHQAAMQMLKET
;VGGHQAAMQ;TVLDVGDAYFSVPLD;LDVGDAYFS;TVLEEMSLP
GRWKPKjLEEMSLPGRiTVLVGPTPVNIIGRNjLVGPTPVNIiTVNDI
QKLVGKLNWAjlQKLVGKLNjTVPVKLKPGMDGPKVjVKLKPGMDG;
TVRAACWW AGIKQEF;VRAACWWAG;TWETWWTEYWQATWI;W
ETWWTEYW;TWIPEWEFVNTPPLV;WEFVNTPPL;TWWTEYWQAT
WIPEW;EYWQATWIP;VDGAANRETKLGKAG;VDGAANRET;VDKL VSAGIRKVLFLjLVSAGIRKVjVDRFYKTLRAEQASQiDRFYKTLRAjV
DRFYKTLRAEQASQ;FYKTLRAEQ;VDRFYKTLRAEQASQ;YKTLRA
EQAiVFAIKKKDSTKWRKLjlKKKDSTKWjVFIHNFKRKGGIGGYjFK
RKGGIGG;VFIHNFKRKGGIGGY;IHNFKRKGG;VGAETFYVDGAAN
RE;FYVDGAANR;VGDAYFSVPLDEDFR;YFSVPLDED;VGEIYKRW
IILGLNK;YKRWIILGL;VGGHQAAMQMLKETI;VGGHQAAMQ;VGKL
NWASQIYPGIKjKLNWASQIYiVGPTPVNIIGRNLLTiVNIIGRNLLjVH
AGPIAPGQMREPRjVHAGPIAPGjVHPVHAGPIAPGQMRjVHAGPIA
PG;VHQAISPRTLNAWVK;VHQAISPRT;VILVAVHVASGYIEA;LVAV
HVASGjVIPMFSALSEGATPQjMFSALSEGAjVIPMFSALSEGATPQ;
VIPMFSALSjVIYQYMDDLYVGSDLjYQYMDDLYVjVKLKPGMDGPK
VKQW;VKLKPGMDG;VKLWYQLEKEPIVGA;VKLWYQLEK;VKNWM
TETLLVQNAN ;NWMTETLLV;VKNWMTETLLVQNAN;WMTETLLVQ
;VKQWPLTEEKIKALV;VKQWPLTEE;VLAEAMSQVTNSATI;AMSQV
TNSA;VLAEAMSQVTNSATI;LAEAMSQVT;VLEEMSLPGRWKPKM;
LEEMSLPGR;VLPQGWKGSPAIFQS;WKGSPAIFQ;VLVGPTPVNII
GRNL;LVGPTPVNI;VNDIQKLVGKLNWAS;IQKLVGKLN;VNDIQKLV
GKLNWASiKLVGKLNWAjVNIIGRNLLTQIGCTjGRNLLTQIGiVNIIG
RNLLTQIGCT ;VNIIGRNLL;VNTPPLVKLWYQLEK;LVKLWYQLE;VN
TPPLVKLWYQLEKjVNTPPLVKLjVPLDEDFRKYTAFTIjDFRKYTAF
T;VPVKLKPGMDGPKVK;VKLKPGMDG;VQKITTESIVIWGKT;VQKI
TTESIjVQLGIPHPAGLKKKKjVQLGIPHPAjVQMAVFIHNFKRKGGiF
IHNFKRKGjVQMAVFIHNFKRKGGjMAVFIHNFKjVQMAVFIHNFKR
KGGiVFIHNFKRKjVQNIQGQMVHQAISPjlQGQMVHQAjVRMYSPT
SILDIRQGjMYSPTSILDjVRMYSPTSILDIRQGiVRMYSPTSIjVRMY
SPTSILDIRQGiYSPTSILDIjVRQLCKLLRGTKALTiCKLLRGTKAjVR
QLCKLLRGTKALTjVRQLCKLLRjVRAACWWAGIKQEFGiVRAACW
WAG;VTDSQYALGIIQAQP;YALGIIQAQ;VTLWQRPLVTIKIGG;LWQ
RPLVTIjVTNRGRQKVVTLTDTjVTNRGRQKVjVTNSATIMMQRGNF
RiSATIMMQRGjVTNSATIMMQRGNFRjVTNSATIMMjVTVLDVGDA
YFSVPLjLDVGDAYFSiVVAKEIVASCDKCQLjVVAKEIVASiVYLAW
VPAHKGIGGN;LAWVPAHKG;VYLAWVPAHKGIGGN;WVPAHKGIG
;VYLAWVPAHKGIGGN;YLAWVPAHK;VYYRDSRNPLWKGPA;YRD
SRNPLWjWASQIYPGIKVRQLCjYPGIKVRQLjWDRVHPVHAGPIAP
G;VHPVHAGPI;WEFVNTPPLVKLWYQ;FVNTPPLVK;WEFVNTPPL
VKLWYQ;VNTPPLVKL;WEFVNTPPLVKLWYQ;WEFVNTPPL;WET
WWTEYWQATWIP;WETWWTEYW;WETWWTEYWQATWIP;WWT
EYWQAT ;WEVQLGIPHPAGLKK;VQLGIPHPA;WIILGLNKIVRMYSP
;ILGLNKIVR;WIILGLNKIVRMYSP;LGLNKIVRM;WIILGLNKIVRMYS
PjLNKIVRMYSiWIILGLNKIVRMYSPiWIILGLNKIjWIPEWEFVNTPP
LVK;EFVNTPPLV;WIPEWEFVNTPPLVK;WEFVNTPPL;WKGEGAV
VIQDNSDI;WKGEGAVVI;WKGSPAIFQSSMTKI;WKGSPAIFQ;WMT
NNPPIPVGEIYKjMTNNPPIPVjWPVKTIHTDNGSNFTjVKTIHTDNG;
WQATWIPEWEFVNTP;ATWIPEWEF;WRAMASDFNLPPVVA;MAS
DFNLPP;WRAMASDFNLPPVVA;WRAMASDFN;WRKLVDFRELNK
RTQ;VDFRELNKR;WTEYWQATWIPEWEF;WQATWIPEW;WTVNDI
QKLVGKLNWilQKLVGKLNiWTVQPIVLPEKDSWTjWTVQPIVLPjW
WTEYWQATWIPEWEjEYWQATWIPjYALGIIQAQPDQSESillQAQP
DQSjYALGIIQAQPDQSESilQAQPDQSEiYARMRGAHTNDVKQLjM
RGAHTNDV;YFLLKLAGRWPVKTI;LAGRWPVKT;YFLLKLAGRWPV
KTliLKLAGRWPVjYFLLKLAGRWPVKTIjYFLLKLAGRjYHSNWRAM
ASDFNLP;WRAMASDFN;YIEAEVIPAETGQET;AEVIPAETG;YKLK
HIVWASRELERjLKHIVWASRiYKRWIILGLNKIVRMilLGLNKIVRjYK
RWIILGLNKIVRMjWIILGLNKIiYKTLRAEQASQEVKNjYKTLRAEQA;
YLALQDSGLEVNIVT;LQDSGLEVN;YLAWVPAHKGIGGNE;LAWVP
AHKG;YLAWVPAHKGIGGNE;YLAWVPAHK;YMDDLYVGSDLEIGQ iYVGSDLEIGjYNTVATLYCVHQRIEjYNTVATLYCiYPGIKVRQLCKL
LRGiVRQLCKLLRiYPGIKVRQLCKLLRGiYPGIKVRQLjYPIVQN IQG QMVHQA;VQNIQGQMV;YQEPFKNLKTGKYAR;FKNLKTGKY;YSA GERIVDIIATDIiERIVDIIATiYVDGAANRETKLGKAiYVDGAANREiY VDRFYKTLRAEQAS;DRFYKTLRA;YVDRFYKTLRAEQAS;FYKTLR AEQ;YVDRFYKTLRAEQAS;YKTLRAEQA;YWQATWIPEWEFVNT;A TWIPEWEFjAATLEEMMTACQGVGjLEEMMTACQ
NP_057850 8-mers: 3716-4962 Pr55(Gag) MGARASVL;SVLSGGEL;ELDRWEKI;RWEKIRLR;RLRPGGKK;KLK
HIVWA;IVW ASREL;W ASRELER;RELERFAV;FAVNPGLL;SEGCRQ
IL;QLQPSLQT;LQTGSEEL;QTGSEELR;SLYNTV AT;LYNTV ATL;YN
TVATLYjTVATLYCViTLYCVHQRjLYCVHQRIiDTKEALDKiKIEEEQ
NKjDTGHSNQViQVSQNYPIjNYPIVQNIiYPIVQNIQiGQMVHQAliSP
RTLNAW;RTLNAWVK;TLNAWVKV;WVKVVEEK;KVVEEKAF;EKAF
SPEVjFSPEVIPMiSPEVIPMFiEVIPMFSAiVIPMFSALjlPMFSALSiF
SALSEGA;ALSEGATP;TPQDLNTM;NTVGGHQA;TVGGHQAA;HQA
AMQML;QAAMQMLK;MQMLKETI;ETINEEAA;EEAAEWDR;EAAEW
DRV;EWDRVHPV;HPVHAGPI;GPIAPGQM;WMTNNPPI;TNNPPIPV jPPIPVGEIiPIPVGEIYiGEIYKRWIiEIYKRWIIilYKRWIILjKRWIILGL;
WIILGLNKjIILGLNKIjlLGLNKIViLGLNKIVRiGLNKIVRMjIVRMYSPT;
RMYSPTSIiMYSPTSILiSPTSILDIjRQGPKEPFiDYVDRFYKjYVDRF
YKT;DRFYKTLR;AEQASQEV;EQASQEVK;ASQEVKNW;EVKNWM
TEjNWMTETLLiWMTETLLViETLLVQNAiNPDCKTILilLKALGPAjAL
GPAATLiTLEEMMTAjEEMMTACQiMMTACQGViGVGGPGHKjVLA
EAMSQiAEAMSQVTiSQVTNSATjVTNSATIMiSATIMMQRjIMMQR
GNFiMMQRGNFRiRGNFRNQRiRNQRKIVKiHTARNCRAiRNCRAP
RKiNCRAPRKKiAPRKKGCWiQMKDCTERiCTERQANFiTERQANF
LiRQANFLGKiFLGKIWPSiKGRPGNFLiTAPPEESFiEESFRSGViET
TTPPQKiQEPIDKELiEPIDKELYiELYPLTSLiLYPLTSLRiPLTSLRSL iSLFGNDPS
9-mers:
VLSGGELDR;LSGGELDRW;DRWEKIRLR;KIRLRPGGK;RLRPGGK
KKiGGKKKYKLKiKKYKLKHIViKYKLKHIVWiKLKHIVWASiHIVWAS
REL;W ASRELERFiERFAVN PGLiRFAVN PGLLiAVN PGLLETiGLLE
TSEGCiETSEGCRQIiILGQLQPSLiGQLQPSLQTiSLQTGSEELiLQT
GSEELRiGSEELRSLYiELRSLYNTViSLYNTVATLiLYNTVATLYiNT
VATLYCViATLYCVHQRiTLYCVHQRIiYCVHQRIEIiCVHQRIEIKiQR
IEIKDTKiEIKDTKEALiALDKIEEEQiQQAAADTGHiHSNQVSQNYiN
QVSQNYPIiQVSQNYPIViQNYPIVQNIiVQNIQGQMViIQGQMVHQA
;MVHQAISPR;HQAISPRTL;AISPRTLNA;ISPRTLNAW;SPRTLNAW
ViRTLNAWVKViTLNAWVKVViAWVKVVEEKiEEKAFSPEViEKAFS
PEVIiFSPEVIPMFiEVIPMFSALiIPMFSALSEiALSEGATPQiSEGAT
PQDL;ATPQDLNTM;TPQDLNTML;DLNTMLNTV;NTVGGHQAA;TV
GGHQAAM;HQAAMQMLK;AMQMLKETI;ETINEEAAE;TINEEAAEW
;EEAAEWDRV;EAAEWDRVH;AEWDRVHPV;RVH PVHAGPiHPVHA
GPIA;DIAGTTSTL;TTSTLQEQI;STLQEQIGW;TLQEQIGWM;GWMT
NNPPIiMTNNPPIPViNPPIPVGEIiPPIPVGEIYiIPVGEIYKRiGEIYKR
WIIiEIYKRWIILiYKRWIILGLiRWIILGLNKiWIILGLNKIiIILGLNKIViGL
NKIVRMYiKIVRMYSPTiIVRMYSPTSiRMYSPTSILiSPTSILDIRiSIL
DIRQGP;ILDIRQGPK;RQGPKEPFR;EPFRDYVDR;PFRDYVDRF;R
DYVDRFYK;DYVDRFYKT;YVDRFYKTL;VDRFYKTLR;RAEQASQE
V;QASQEVKNW;EVKNWMTET;NWMTETLLV;WMTETLLVQ;VQNA
NPDCKiTILKALGPAiILKALGPAAiKALGPAATLiGPAATLEEMiATLE
EMMTAiTLEEMMTACiEEMMTACQGiEMMTACQGViGVGGPGHK
AiGGPGHKARViGPGHKARVLiKARVLAEAMiVLAEAMSQViLAEAM
SQVT;AEAMSQVTN ;AMSQVTNSA;SQVTNSATI ;QVTNSATIM ;VTN
SATIMM;NSATIMMQR;IMMQRGNFR;MMQRGNFRN;RGNFRNQR
KiFRNQRKIVKiNQRKIVKCFiIVKCFNCGKiEGHTARNCRiTARNCR
APR;ARNCRAPRK;RNCRAPRKK;APRKKGCWK;HQMKDCTER;R QANFLGKI;QANFLGKIW;FLGKIWPSY;KIWPSYKGR;WPSYKGRP G;SYKGRPGNF;KGRPGNFLQ;FLQSRPEPT;PTAPPEESF;TAPPE ESFRiTPPQKQEPIiPIDKELYPLiKELYPLTSLiELYPLTSLRiYPLTSL RSLiSLFGNDPSS
10-mers:
RASVLSGGEL;SVLSGGELDR;VLSGGELDRW;ELDRWEKIRL;KIRL
RPGGKKiRLRPGGKKKYiRPGGKKKYKLjKKYKLKHIVWiKLKHIVW
ASRiIVW ASRELERiVW ASRELERFiLERFAVN PGLiERFAVN PGLL;
FAVNPGLLETiETSEGCRQILiRQILGQLQPSiQILGQLQPSLiILGQL
QPSLQ;SLQTGSEELR;EELRSLYNTV;RSLYNTVATL;SLYNTVATL
YiVATLYCVHQRiATLYCVHQRIiLYCVHQRIEIiIEIKDTKEALiAADT
GHSNQV;NQVSQNYPIV;SQNYPIVQNI;PIVQNIQGQM;IVQNIQGQ
MV;VQNIQGQMVH;NIQGQMVHQA;IQGQMVHQAI;QMVHQAISPR;
AISPRTLNAW;RTLNAWVKVV;NAWVKVVEEK;WVKVVEEKAF;VEE
KAFSPEV;EEKAFSPEVI;KAFSPEVIPM;AFSPEVIPMF;PEVIPMFSA
L;EVIPMFSALS;PMFSALSEGA;ATPQDLNTML;MLNTVGGHQA;NT
VGGHQAAM;GHQAAMQMLK;AAMQMLKETI;MLKETINEEA;ETINE
EAAEWiAAEWDRVHPViRVHPVHAGPIiHPVHAGPIAPiIAPGQMRE
PR;TSTLQEQIGW;STLQEQIGWM;TLQEQIGWMT;WMTNNPPIPV;
NPPIPVGEIYiIPVGEIYKRWiGEIYKRWIILiIYKRWIILGLiKRWIILGL
NK;RWIILGLNKI;WIILGLNKIV;IILGLNKIVR;ILGLNKIVRM;IVRMYSP
TSIiMYSPTSILDIiYSPTSILDIRiSILDIRQGPKiDIRQGPKEPFiEPFR
DYVDRF;DYVDRFYKTL;YVDRFYKTLR;RFYKTLRAEQ;RAEQASQ
EVK;EVKNWMTETL;WMTETLLVQN;LVQNANPDCK;KTILKALGPA;
TILKALGPAAiILKALGPAATiGPAATLEEMMiATLEEMMTACiTLEE
MMTACQiEEMMTACQGViVGGPGHKARViRVLAEAMSQViVLAEA
MSQVT;AEAMSQVTNS;EAMSQVTNSA;AMSQVTNSAT;SQVTNSA
TIM;QVTNSATIMM;TNSATIMMQR;ATIMMQRGNF;TIMMQRGNFR;
MMQRGNFRNQiMQRGNFRNQRiNFRNQRKIVKiKIVKCFNCGKiKE
GHTARNCRiHTARNCRAPRiTARNCRAPRKiARNCRAPRKKiRAPR
KKGCWK;APRKKGCWKC;RKKGCWKCGK;KCGKEGHQMK;QMKD
CTERQA;TERQANFLGK;RQANFLGKIW;FLGKIWPSYK;SYKGRPG
NFL;FLQSRPEPTA;EPTAPPEESF;PTAPPEESFR;EESFRSGVET;
GVETTTPPQKiTTPPQKQEPIiEPIDKELYPLiELYPLTSLRSiLYPLTS
LRSL;YPLTSLRSLF;SLFGNDPSSQ
1 1 -mers:
VLSGGELDRWEiLSGGELDRWEKiGELDRWEKIRLiELDRWEKIRL
RiKIRLRPGGKKKiRLRPGGKKKYKiHIVWASRELERiWASRELERF
AViELERFAVNPGLiLERFAVNPGLLiGLLETSEGCRQiLLETSEGCR
QIiLETSEGCRQILiSEGCRQILGQLiRQILGQLQPSLiILGQLQPSLQ
T;QPSLQTGSEEL;LQTGSEELRSL;QTGSEELRSLY;SEELRSLYNT
ViRSLYNTVATLYiSLYNTVATLYCiLYNTVATLYCViNTVATLYCVH
QiTVATLYCVHQRiTLYCVHQRIEIiLYCVHQRIEIKiEIKDTKEALDK;
ALDKIEEEQNK;AAADTGHSNQV;HSNQVSQNYPI;YPIVQNIQGQM;
PIVQNIQGQMV;NIQGQMVHQAI;GQMVHQAISPR;MVHQAISPRTL;
QAISPRTLNAW;AISPRTLNAWV;ISPRTLNAWVK;SPRTLNAWVKV;
LNAWVKVVEEK;AWVKVVEEKAF;VVEEKAFSPEV;KAFSPEVIPMF
;FSPEVIPMFSA;SPEVIPMFSAL;EVIPMFSALSE;IPMFSALSEGA;A
LSEGATPQDL;EGATPQDLNTM;PQDLNTM LNTV;TMLNTVGGHQA
;MLNTVGGHQAA;TVGGHQAAMQM;GGHQAAMQMLK;QAAMQML
KETI;MQMLKETINEE;QMLKETINEEA;MLKETINEEAA;TINEEAAE
WDR;EAAEWDRVHPV;RVHPVHAGPIA;HPVHAGPIAPG;HAGPIAP
GQMR;TTSTLQEQIGW;QIGWMTNNPPI;IPVGEIYKRWI;EIYKRWII
LGLiKRWIILGLNKIiWIILGLNKIVRiIILGLNKIVRMiKIVRMYSPTSIiIV
RMYSPTSILiRMYSPTSILDIiMYSPTSILDIRiTSILDIRQGPKiDIRQG
PKEPFR;RQGPKEPFRDY;QGPKEPFRDYV;EPFRDYVDRFY;PFR DYVDRFYK;DYVDRFYKTLR;YVDRFYKTLRA;TLRAEQASQEV;AE
QASQEVKNW ;QEVKNWMTETL;EVKNWMTETLL;WMTETLLVQNA iLLVQNANPDCKiNANPDCKTILKjNPDCKTILKALjKTILKALGPAAilL
KALGPAATLjALGPAATLEEMjEEMMTACQGVGjMTACQGVGGPG;
ACQGVGGPGHKjGVGGPGHKARVjKARVLAEAMSQjAEAMSQVT
NSAjEAMSQVTNSATjAMSQVTNSATIjMSQVTNSATIMiSQVTNSA
TIMM;VTNSATIMMQR;ATIMMQRGNFR;MMQRGNFRNQR;MQRG
NFRNQRKiFRNQRKIVKCFiHTARNCRAPRKjTARNCRAPRKKjEG
HQMKDCTERiCTERQANFLGKjTERQANFLGKIjNFLGKIWPSYKiW
PSYKGRPGNF;KGRPGNFLQSR;EPTAPPEESFR;RSGVETTTPPQ
;SGVETTTPPQK;TTTPPQKQEPI;QEPIDKELYPL;EPIDKELYPLT;D
KELYPLTSLR;ELYPLTSLRSL;LYPLTSLRSLF
15-mer + 9-mer core:
AEAMSQVTNSATIMM;AMSQVTNSA;AEAMSQVTNSATIMM;MSQV
TNSATjAEAMSQVTNSATIMMjQVTNSATIMjAFSPEVIPMFSALSE;
VIPMFSALSjAGPIAPGQMREPRGSjlAPGQMREPjAISPRTLNAWV
KVVE;PRTLNAWVK;AISPRTLNAWVKVVE;TLNAWVKVV;AMSQVT
NSATIMMQRiAMSQVTNSAjAMSQVTNSATIMMQRjVTNSATIMMjA
NFLGKIWPSYKGRPjFLGKIWPSYjANFLGKIWPSYKGRPjGKIWPS
YKG;ANFLGKIWPSYKGRP;LGKIWPSYK;APPEESFRSGVETTT;SF
RSGVETT ;ARVLAEAMSQVTNSA;LAEAMSQVT;ARVLAEAMSQVT
NSA;VLAEAMSQV;ASQEVKNWMTETLLV;VKNWMTETL;ASRELE
RFAVN PGLL;LERFAVN PG ;ATIMMQRGNFRNQRK;IMMQRGNFR;
ATLEEMMTACQGVGGiLEEMMTACQiATPQDLNTMLNTVGGjLNT
MLNTVGiCKTILKALGPAATLEjILKALGPAAjCKTILKALGPAATLEjL
KALGPAATjCRQILGQLQPSLQTGjGQLQPSLQTjCRQILGQLQPSL
QTGiLGQLQPSLQjDCKTILKALGPAATLjILKALGPAAjDCKTILKAL
GPAATLjLKALGPAATjDIAGTTSTLQEQIGWjlAGTTSTLQiDKELYP
LTSLRSLFGiELYPLTSLRjDKELYPLTSLRSLFGjLYPLTSLRSjDLN
TMLNTVGGHQAA;LNTMLNTVG;DLNTMLNTVGGHQAA;MLNTVG
GHQ;DRFYKTLRAEQASQE;DRFYKTLRA;DRFYKTLRAEQASQE;F
YKTLRAEQ;DRFYKTLRAEQASQE;YKTLRAEQA;DRVHPVHAGPIA
PGQ;VHAGPIAPG;DYVDRFYKTLRAEQA;DRFYKTLRA;DYVDRFY
KTLRAEQA;FYKTLRAEQ;DYVDRFYKTLRAEQA;VDRFYKTLR;DY
VDRFYKTLRAEQA;YVDRFYKTL;EAMSQVTNSATIMMQ;AMSQVT
NSAjEAMSQVTNSATIMMQjVTNSATIMMjEELRSLYNTVATLYCiLR
SLYNTVAjEELRSLYNTVATLYCjLYNTVATLYjEESFRSGVETTTPP
QiFRSGVETTTjEGCRQILGQLQPSLQjCRQILGQLQjEGCRQILGQ
LQPSLQilLGQLQPSLjEGCRQILGQLQPSLQjRQILGQLQPjEIYKR
WIILGLNKIViWIILGLNKIjEIYKRWIILGLNKIViYKRWIILGLjELERFA
VNPGLLETSiFAVNPGLLEjELRSLYNTVATLYCVjLYNTVATLYjELR
SLYNTVATLYCVjYNTVATLYCjELYPLTSLRSLFGNDjLTSLRSLFG;
ELYPLTSLRSLFGNDjLYPLTSLRSjEPIDKELYPLTSLRSjlDKELYPL
TjEPRGSDIAGTTSTLQjEPRGSDIAGjEPRGSDIAGTTSTLQiGSDIA
GTTS;EPRGSDIAGTTSTLQ;RGSDIAGTT;EQASQEVKNWMTETL;
EVKNWMTET;EQASQEVKNWMTETL;SQEVKNWMT;EQIGWMTN
NPPIPVGilGWMTNNPPjEQIGWMTNNPPIPVGjMTNNPPIPVjERFA
VN PGLLETSEG;FAVNPGLLE;ERFAVNPGLLETSEG;VN PGLLETS;
ERQANFLGKIWPSYK;FLGKIWPSY;ESFRSGVETTTPPQK;FRSGV
ETTTjETLLVQNANPDCKTIiVQNANPDCKjEVIPMFSALSEGATPjlP
MFSALSEjEVIPMFSALSEGATPjMFSALSEGAjEVIPMFSALSEGAT
PiVIPMFSALSjEVKNWMTETLLVQNAjNWMTETLLVjEVKNWMTET
LLVQNAjWMTETLLVQjFAVNPGLLETSEGCRjVNPGLLETSiFLGKI
WPSYKGRPGN;FLGKIWPSY;FLGKIWPSYKGRPGN;GKIWPSYKG
;FLGKIWPSYKGRPGN;LGKIWPSYK;FLQSRPEPTAPPEES;FLQS
RPEPTjFRNQRKIVKCFNCGKjFRNQRKIVKjFRSGVETTTPPQKQE
;VETTTPPQK;FSPEVIPMFSALSEG;VIPMFSALS;FYKTLRAEQASQ EVK;FYKTLRAEQ;FYKTLRAEQASQEVK;YKTLRAEQA;GATPQDL
NTMLNTVG;DLNTMLNTV;GATPQDLNTMLNTVG;PQDLNTMLN;G
CRQILGQLQPSLQTiLGQLQPSLQiGEIYKRWIILGLNKIiIYKRWIILG
;GEIYKRWIILGLNKI;YKRWIILGL;GGHQAAMQMLKETIN;AAMQML
KET;GHKARVLAEAMSQVT;VLAEAMSQV;GKIWPSYKGRPGNFL;
GKIWPSYKGiGKKKYKLKHIVWASRiYKLKHIVWAiGLNKIVRMYSP
TSILiIVRMYSPTSiGLNKIVRMYSPTSILiLNKIVRMYSiGLNKIVRMY
SPTSILiVRMYSPTSIiGNFLQSRPEPTAPPEiFLQSRPEPTiGNFRN
QRKIVKCFNCiFRNQRKIVKiGPAATLEEMMTACQGiLEEMMTACQ;
GQLQPSLQTGSEELR;GQLQPSLQT;GQMVHQAISPRTLNA;MVHQ
AISPRiGQMVHQAISPRTLNAiVHQAISPRTiGRPGNFLQSRPEPTA;
FLQSRPEPTiGSDIAGTTSTLQEQIiIAGTTSTLQiGSEELRSLYNTVA
TL;LRSLYNTVA;GTTSTLQEQIGWMTN;LQEQIGWMT;GWMTNNP
PIPVGEIY;MTNNPPIPV;HKARVLAEAMSQVTN;LAEAMSQVT;HPV
HAGPIAPGQMRE;VHAGPIAPG;IAGTTSTLQEQIGWM;IAGTTSTLQ
;IDKELYPLTSLRSLF;LYPLTSLRS;IGWMTNNPPIPVGEI;IGWMTNN
PPiIGWMTNNPPIPVGEIiMTNNPPIPViIGWMTNNPPIPVGEIiWMT
NNPPIPiIILGLNKIVRMYSPTiILGLNKIVRiIILGLNKIVRMYSPTiLGL
NKIVRMiIILGLNKIVRMYSPTiLNKIVRMYSiILGLNKIVRMYSPTSiIL
GLNKIVRiILGLNKIVRMYSPTSiLGLNKIVRMiILGLNKIVRMYSPTS;
LNKIVRMYS;ILGQLQPSLQTGSEE;GQLQPSLQT;ILGQLQPSLQTG
SEE;LGQLQPSLQ;ILKALGPAATLEEMM;LKALGPAAT;IMMQRGNF
RNQRKIV;IMMQRGNFR;IPMFSALSEGATPQD;MFSALSEGA;IPVG
EIYKRWIILGL;IYKRWIILG;IQGQMVHQAISPRTL;MVHQAISPR;IQG
QMVHQAISPRTL;VHQAISPRT;ISPRTLNAWVKVVEE;LNAWVKVV
EiISPRTLNAWVKVVEEiTLNAWVKVViIVQNIQGQMVHQAISiIQGQ
MVHQA;IVRMYSPTSILDIRQ;IVRMYSPTS;IVRMYSPTSILDIRQ;VR
MYSPTSI;IVRMYSPTSILDIRQ;YSPTSILDI;IWPSYKGRPGNFLQS;
YKGRPGNFL;IYKRWIILGLNKIVR;WIILGLNKI;IYKRWIILGLNKIVR;
YKRWIILGL;KAFSPEVIPMFSALS;EVIPMFSAL;KAFSPEVIPMFSAL
SiFSPEVIPMFiKAFSPEVIPMFSALSiKAFSPEVIPiKALGPAATLEE
MMTA;LGPAATLEE;KARVLAEAMSQVTNS;LAEAMSQVT;KELYPL
TSLRSLFGNiELYPLTSLRiKELYPLTSLRSLFGNiLYPLTSLRSiKGR
PGNFLQSRPEPT;GRPGNFLQS;KGRPGNFLQSRPEPT;NFLQSRP
EP;KIVRMYSPTSILDIR;IVRMYSPTS;KIVRMYSPTSILDIR;VRMYS
PTSI;KIVRMYSPTSILDIR;YSPTSILDI;KIWPSYKGRPGNFLQ;YKG
RPGNFLiKKKYKLKHIVW ASREiLKHIVW ASRiKKKYKLKHIVW ASR
E;YKLKHIVWA;KKYKLKHIVW ASRELiLKHIVW ASRiKKYKLKHIVW
ASREL;YKLKHIVWA;KLKHIVW ASRELERFiLKHIVW ASRiKNWMTE
TLLVQNANP;WMTETLLVQ;KRWIILGLNKIVRMY;ILGLNKIVR;KRW
1ILGLNKIVRMYiLGLNKIVRMiKRWIILGLNKIVRMYiWIILGLNKIiKTIL
KALGPAATLEE;ILKALGPAA;KTILKALGPAATLEE;LKALGPAAT;KY
KLKHIVW ASRELEiLKHIVW ASR;LAEAMSQVTNSATIM;AMSQVTN
SAiLAEAMSQVTNSATIMiLAEAMSQVTiLEEMMTACQGVGGPGiM
TACQGVGGiLERFAVN PGLLETSEiFAVN PGLLEiLERFAVN PGLLE
TSEiVN PGLLETS;LGKIWPSYKGRPGNF;LGKIWPSYK;LGLNKIVR
MYSPTSIiIVRMYSPTSiLGLNKIVRMYSPTSIiLGLNKIVRMiLGLNKI
VRMYSPTSIiLNKIVRMYSiLGPAATLEEMMTACQiAATLEEMMTiLG
QLQPSLQTGSEEL;LGQLQPSLQ;LKALGPAATLEEMMT;LKALGPA
ATiLKHIVWASRELERFAiLKHIVWASRiLLVQNANPDCKTILKiVQN
ANPDCKiLNKIVRMYSPTSILDiIVRMYSPTSiLNKIVRMYSPTSILDiL
NKIVRMYSiLNKIVRMYSPTSILDiVRMYSPTSIiLNTMLNTVGGHQA
AMiLNTM LNTVGiLNTM LNTVGGHQAAM;MLNTVGGHQ;LNTVGG
HQAAMQMLK;VGGHQAAMQ;LQEQIGWMTNNPPIP;IGWMTNNPP
; LRS LYNTVATLYCVH; LYNTVATLY; LRS LYNTVATLYCVH; YNTV AT
LYCiLTSLRSLFGNDPSSQiLTSLRSLFGiLYNTVATLYCVHQRhLYN
TVATLYiLYNTVATLYCVHQRIiYNTVATLYCiLYPLTSLRSLFGNDP;
LTSLRSLFG;LYPLTSLRSLFGNDP;LYPLTSLRS;MFSALSEGATPQ DLN;MFSALSEGA;MGARASVLSGGELDR;MGARASVLS;MLNTVG
GHQAAMQML;MLNTVGGHQ;MLNTVGGHQAAMQML;VGGHQAA
MQ;MMQRGNFRNQRKIVK;NFRNQRKIV;MMQRGNFRNQRKIVK;Q
RGNFRNQR;MMQRGNFRNQRKIVK;RGNFRNQRK;MQRGNFRNQ
RKIVKCiFRNQRKIVKjMSQVTNSATIMMQRGiVTNSATIMMjMTETL
LVQNANPDCKjLLVQNANPDjMTETLLVQNANPDCKjMTETLLVQN;
MTNNPPIPVGEIYKRjMTNNPPIPVjMVHQAISPRTLNAWVjMVHQAI
SPR;MVHQAISPRTLNAWV;VHQAISPRT;NFLGKIWPSYKGRPG;F
LGKIWPSY;NFLGKIWPSYKGRPG;GKIWPSYKG;NFLGKIW PSYKG
RPG;LGKIWPSYK;NFLQSRPEPTAPPEE;FLQSRPEPT;NFRNQRKI
VKCFNCGiFRNQRKIVKiNIQGQMVHQAISPRTjlQGQMVHQAjNIQ
GQMVHQAISPRTjMVHQAISPRjNKIVRMYSPTSILDIjlVRMYSPTS;
NKIVRMYSPTSILDIjVRMYSPTSIjNPDCKTILKALGPAAjCKTILKAL
GiNPDCKTILKALGPAAjKTILKALGPjNSATIMMQRGNFRNQilMMQ
RGNFR;NTMLNTVGGHQAAMQ;LNTVGGHQA;NTM LNTVGGHQA
AMQ;MLNTVGGHQ;NTVGGHQAAMQMLKE;VGGHQAAMQ;NYPIV
QNIQGQMVHQiVQNIQGQMVjPDCKTILKALGPAATjCKTILKALGiP
DCKTILKALGPAATjILKALGPAAjPEESFRSGVETTTPPjFRSGVET
TTjPEVIPMFSALSEGATjVIPMFSALSiPGHKARVLAEAMSQVjARV
LAEAMSjPGNFLQSRPEPTAPPjFLQSRPEPTjPIDKELYPLTSLRSL
;LYPLTSLRS;PIVQNIQGQMVHQAI;VQNIQGQMV;PLTSLRSLFGN
DPSS;LTSLRSLFG;PMFSALSEGATPQDL;MFSALSEGA;PPEESF
RSGVETTTP;FRSGVETTT;PQDLNTMLNTVGGHQ;DLNTMLNTV;P
QDLNTMLNTVGGHQ;LNTMLNTVG;PRGSDIAGTTSTLQE;IAGTTS
TLQ;PRTLNAWVKVVEEKA;LNAWVKVVE;PRTLNAWVKVVEEKA;T
LNAWVKVV;PSYKGRPGNFLQSRP;YKGRPGNFL;PVGEIYKRWIIL
GLN;YKRWIILGL;PVHAGPIAPGQMREP;VHAGPIAPG;PAATLEEM
MTACQGVjLEEMMTACQiQAISPRTLNAWVKVVjISPRTLNAWiQA
NFLGKIWPSYKGR;FLGKIWPSY;QANFLGKIWPSYKGR;GKIWPSY
KG;QANFLGKIWPSYKGR;LGKIWPSYK;QASQEVKNWMTETLL;VK
NWMTETL;QDLNTMLNTVGGHQA;LNTMLNTVG;QDLNTM LNTVG
GHQA;MLNTVGGHQ;QEQIGWMTNNPPIPV;IGWMTNNPP;QEVKN
WMTETLLVQN;VKNWMTETL;QGQMVHQAISPRTLN;MVHQAISPR
;QGQMVHQAISPRTLN;VHQAISPRT;QIGWMTNNPPIPVGE;IGWM
TNNPPjQIGWMTNNPPIPVGEjMTNNPPIPVjQIGWMTNNPPIPVGE
;WMTNNPPIP;QILGQLQPSLQTGSE;GQLQPSLQT;QILGQLQPSL
QTGSE;LGQLQPSLQ;QMVHQAISPRTLNAW;MVHQAISPR;QMVH
QAISPRTLNAW;VHQAISPRT;QNIQGQMVHQAISPR;IQGQMVHQA iQNYPIVQNIQGQMVHjVQNIQGQMVjQRGNFRNQRKIVKCFjFRN
QRKIVKjQTGSEELRSLYNTVAjSEELRSLYNjQVTNSATIMMQRGN
F;VTNSATIMM;RDYVDRFYKTLRAEQ;DRFYKTLRA;RDYVDRFYK
TLRAEQ;DYVDRFYKT;RDYVDRFYKTLRAEQ;VDRFYKTLR;RELE
RFAVN PGLLET;FAVNPGLLE;RELERFAVNPGLLET;LERFAVN PG;
RFAVN PGLLETSEGCjFAVNPGLLEjRFAVNPGLLETSEGCjVN PGL
LETS;RFYKTLRAEQASQEV;FYKTLRAEQ;RFYKTLRAEQASQEV;
YKTLRAEQAjRGNFRNQRKIVKCFNjFRNQRKIVKjRGSDIAGTTST
LQEQilAGTTSTLQjRMYSPTSILDIRQGPjYSPTSILDIjRPGNFLQSR
PEPTAP;FLQSRPEPT;RQANFLGKIWPSYKG;FLGKIWPSY;RQAN
FLGKIW PSYKG;LGKIWPSYK;RQILGQLQPSLQTGS;GQLQPSLQT;
RQILGQLQPSLQTGSjLGQLQPSLQjRSGVETTTPPQKQEPjVETTT
PPQKjRSLYNTVATLYCVHQiLYNTVATLYjRSLYNTVATLYCVHQiY
NTVATLYCiRTLNAWVKVVEEKAFjLNAWVKVVEjRTLNAWVKVVE
EKAF;TLNAWVKVV;RVHPVHAGPIAPGQM;VHAGPIAPG;RVLAEA
MSQVTNSAT ;AMSQVTNSA;RVLAEAMSQVTNSAT;LAEAMSQVT;
RWIILGLNKIVRMYSilLGLNKIVRjRWIILGLNKIVRMYSjLGLNKIVR
MjRWIILGLNKIVRMYSiWIILGLNKIiSATIMMQRGNFRNQRjlMMQR
GNFRjSDIAGTTSTLQEQIGjlAGTTSTLQiSEELRSLYNTVATLYjLR
SLYNTVA;SFRSGVETTTPPQKQ;FRSGVETTT;SFRSGVETTTPPQ KQ;VETTTPPQK;SGVETTTPPQKQEPI;VETTTPPQK;SLYNTVATL
YCVHQRjLYNTVATLYiSLYNTVATLYCVHQRjYNTVATLYCiSPEVI
PMFSALSEGA;VIPMFSALS;SPRTLNAWVKVVEEK;LNAWVKVVE;
SPRTLNAWVKVVEEK;TLNAWVKVV;SQEVKNWMTETLLVQ;VKN
WMTETL;SQNYPIVQNIQGQMV;IVQNIQGQM;SQNYPIVQNIQGQM
V;SQNYPIVQN;SQVTNSATIMMQRGN;VTNSATIMM;SRELERFAV
NPGLLE;LERFAVNPG;STLQEQIGWMTNNPP;LQEQIGWMT;STLQ
EQIGWMTNNPP;QIGWMTNNP;SYKGRPGNFLQSRPE;YKGRPGN
FLjTERQANFLGKIWPSYiANFLGKIWPjTETLLVQNANPDCKTiVQN
ANPDCKjTGSEELRSLYNTVATjLRSLYNTVAjTILKALGPAATLEEM;
LKALGPAAT;TIMMQRGNFRNQRKI;IMMQRGNFR;TLEEMMTACQ
GVGGPiMTACQGVGGiTLLVQNANPDCKTILjVQNANPDCKjTLNA
WVKWEEKAFS;LNAWVKWE;TLQEQIGWMTNNPPI;IGWMTNNP
P;TMLNTVGGHQAAMQM;MLNTVGGHQ;TMLNTVGGHQAAMQM;
VGGHQAAMQ;TNSATIMMQRGNFRN;IMMQRGNFR;TPQDLNTML
NTVGGH;LNTMLNTVG;TSTLQEQIGWMTNNP;LQEQIGWMT;TTST
LQEQIGWMTNN;LQEQIGWMT;TVGGHQAAMQMLKET;VGGHQAA
MQ;VDRFYKTLRAEQASQ;DRFYKTLRA;VDRFYKTLRAEQASQ;FY
KTLRAEQ;VDRFYKTLRAEQASQ;YKTLRAEQA;VGEIYKRWIILGLN
K;YKRWIILGL;VGGHQAAMQMLKETI;VGGHQAAMQ;VHAGPIAPG
QMREPRjVHAGPIAPGiVHPVHAGPIAPGQMRjVHAGPIAPGjVHQA
ISPRTLNAWVK;VHQAISPRT;VIPMFSALSEGATPQ;MFSALSEGA;
VIPMFSALSEGATPQ;VIPMFSALS;VKNWMTETLLVQNAN;NWMTE
TLLV;VKNWMTETLLVQNAN;WMTETLLVQ;VLAEAMSQVTNSATI;
AMSQVTNSA;VLAEAMSQVTNSATI ;LAEAMSQVT;VQN IQGQMVH
QAISPjlQGQMVHQAjVRMYSPTSILDIRQGiMYSPTSILDjVRMYSP
TSILDIRQGiVRMYSPTSIjVRMYSPTSILDIRQGjYSPTSILDIjVTNSA
TIMMQRGNFR;SATIMMQRG;VTNSATIMMQRGNFR;VTNSATIMM;
WDRVHPVHAGPIAPGjVHPVHAGPIjWIILGLNKIVRMYSPjlLGLNKI
VRjWIILGLNKIVRMYSPiLGLNKIVRMiWIILGLNKIVRMYSPjLNKIV
RMYSjWIILGLNKIVRMYSPiWIILGLNKIiWMTNNPPIPVGEIYKjMTN
NPPIPV;WPSYKGRPGNFLQSR;YKGRPGNFL;YKGRPGNFLQSRP
EPiYKGRPGNFLjYKLKHIVWASRELERjLKHIVWASRiYKRWIILGL
NKIVRMilLGLNKIVRjYKRWIILGLNKIVRMiWIILGLNKIjYKTLRAEQ
ASQEVKNiYKTLRAEQAjYNTVATLYCVHQRIEjYNTVATLYCiYPIV
QNIQGQMVHQAjVQNIQGQMVjYPLTSLRSLFGNDPSjLTSLRSLF
G;YVDRFYKTLRAEQAS;DRFYKTLRA;YVDRFYKTLRAEQAS;FYK
TLRAEQ;YVDRFYKTLRAEQAS;YKTLRAEQA;AATLEEMMTACQG
VG;LEEMMTACQ
8-mers: 4963-5538
MENRWQVM;RWQVMIVW;WQVMIVWQ;QVMIVWQV;MIVWQVDR
;IVWQVDRM;WQVDRMRI;RMRIRTWK;RIRTWKSL;RTWKSLVK;K
SLVKHHM;SLVKHHMY;LVKHHMYV;HMYVSGKA;MYVSGKAR;VS
GKARGWiKARGWFYRiGWFYRHHYjHYESPHPRjYESPHPRIiSPH
PRISSiHPRISSEViRISSEVHIjHIPLGDARilPLGDARLjPLGDARLV;
ARLVITTY;RLVITTYW;VITTYWGL;TTYWGLHT;HLGQGVSI;QGVSI
EWR;GVSIEWRK;VSIEWRKK;SIEWRKKR;TQVDPELA;DPELADQL jLADQLIHLiDQLIHLYYiQLIHLYYFiHLYYFDCFjDCFSDSAliCFSDS
AIRiFSDSAIRKjKALLGHIViALLGHIVSiLGHIVSPRilVSPRCEYjEYQ
AGHNK;YQAGHNKV;KVGSLQYL;SLQYLALA;LQYLALAA;QYLALA
ALjYLALAALliALAALITPiLAALITPKiAALITPKKjALITPKKliPLPSVT
KL;LPSVTKLT;VTKLTEDR;LTEDRWNK;PQKTKGHR
9-mers:
WQVMIVWQV;VMIVWQVDR;MIVWQVDRM;IVWQVDRMR;VWQV
DRMRI;WQVDRMRIR;RMRIRTWKS;RIRTWKSLV;IRTWKSLVK;RT
WKSLVKH;KSLVKHHMY;SLVKHHMYV;KHHMYVSGK;HMYVSGKA
R;SGKARGWFY;KARGWFYRH;RGWFYRHHY;HHYESPHPR;SPH PRISSEiHPRISSEVHilSSEVH IPLiSEVHIPLGDjHIPLGDARUPLGD
ARLViPLGDARLVIiDARLVITTYiLVITTYWGLiWHLGQGVSIiLGQG
VSIEW;GQGVSIEWR;GVSIEWRKK;VSIEWRKKR;ELADQLIHL;LAD
QLIHLYiDQLIHLYYFiIHLYYFDCFiHLYYFDCFSiDCFSDSAIRiALLG
HIVSPiLLGHIVSPRiHIVSPRCEYiKVGSLQYLAiSLQYLALAAiLQYL
ALAAL;QYLALAALI;YLALAALIT;ALAALITPK;LAALITPKK;ALITPKKI
KiTPKKIKPPLiKIKPPLPSViSVTKLTEDRiVTKLTEDRWiKLTEDRW
NK;RWNKPQKTK;KPQKTKGHR;KTKGHRGSH
10-mers:
MENRWQVMIViRWQVM IVWQV;QVM IVWQVDRiVMIVWQVDRM;
MIVWQVDRMR;IVWQVDRMRI;VWQVDRMRIR;WQVDRMRIRT;R
MRIRTWKSL;RIRTWKSLVK;KSLVKHHMYV;SLVKHHMYVS;MYVS
G KARGWiYVSG KARGW F;VSG KARGW FYiSG KARGWFYR;RHHY
ESPHPRiHHYESPHPRIiYESPHPRISSiSPHPRISSEViHPRISSEVH
IiRISSEVHIPLiEVHIPLGDARiHIPLGDARLViIPLGDARLVIiPLGDAR
LVIT;RLVITTYWGL;TTYWGLHTGE;TYWGLHTGER;HLGQGVSIE
W;GQGVSIEWRK;GVSIEWRKKR;VSIEWRKKRY;RYSTQVDPEL;Q
VDPELADQL;DPELADQLIH;PELADQLIHL;ELADQLIHLY;LADQLIH
LYYiYYFDCFSDSAiYFDCFSDSAIiFDCFSDSAIRiAIRKALLGHIiALL
GHIVSPRiLLGHIVSPRCiIVSPRCEYQAiCEYQAGHNKViKVGSLQY
LAL;SLQYLALAAL;LQYLALAALI;YLALAALITP;LALAALITPK;ALAAL
ITPKKiAALITPKKIKiKKIKPPLPSViKPPLPSVTKLiKTKGHRGSHT
1 1 -mers:
MEN RWQVM IVW ;N RWQVM I VWQ V;WQVM I VWQVD R ;Q VM IVWQ
VDRMiVM IVWQVDRMR;MIVWQVDRMRI;IVWQVDRMRIR;WQVD
RMRIRTW;QVDRMRIRTWK;RMRIRTWKSLV;MRIRTWKSLVK;RIR
TWKSLVKH;RTWKSLVKHHM;TWKSLVKHHMY;WKSLVKHHMYV;
LVKHHMYVSGK;KHHMYVSGKAR;HMYVSG KARGW ;M YVSG KAR
GWF;YVSGKARGWFY;VSGKARGWFYR;KARGWFYRHHY;ESPH
PRISSEViEVHIPLGDARLiIPLGDARLVITiPLGDARLVITTiARLVITT
YWGL;RLVITTYWGLH;LVITTYWGLHT;TTYWGLHTGER;YWGLHT
GERDW ;GLHTGERDWHL;WHLGQGVSIEW;HLGQGVSIEWR;KRY
STQVDPEL;TQVDPELADQL;QVDPELADQLI;DPELADQLIHL;PELA
DQLIHLYiELADQLIHLYYiLADQLIHLYYFiQLIHLYYFDCFiYYFDCF
SDSAIiAIRKALLGHIViKALLGHIVSPRiALLGHIVSPRCiHIVSPRCEY
QA;YQAGHNKVGSL;KVGSLQYLALA;GSLQYLALAAL;SLQYLALAA
LIiLQYLALAALITiYLALAALITPKiLALAALITPKKiALAALITPKKIiLAA
LITPKKIK;LITPKKIKPPL;KIKPPLPSVTK;VTKLTEDRWNK;KLTEDR
WNKPQ;LTEDRWNKPQK;KTKGHRGSHTM
15-mer + 9-mer core:
ADQLIHLYYFDCFSDiIHLYYFDCFiAGHNKVGSLQYLALAiVGSLQY
LALiAIRKALLGHIVSPRCiLLGHIVSPRiAIRKALLGH IVSPRCiRKALL
GHIViALLGHIVSPRCEYQAiLLGHIVSPRiARLVITTYWGLHTGEiLVI
TTYWGL;ARLVITTYWGLHTGE;VITTYWGLH;CEYQAGHNKVGSL
QYiYQAGHNKVGiCFSDSAIRKALLGHIiAIRKALLGHiDARLVITTYW
GLHTG;LVITTYWGL;DARLVITTYWGLHTG;VITTYWGLH;DQLIHLY
YFDCFSDSiIHLYYFDCFiDRMRIRTWKSLVKHHiIRTWKSLVKiDSAI
RKALLGHIVSPiAIRKALLGHiDSAIRKALLGHIVSPiIRKALLGHIiDW
HLGQGVSIEWRKKiLGQGVSIEWiELADQLIHLYYFDCFiLIHLYYFD
CiENRWQVMIVWQVDRMiNRWQVMIVWiENRWQVMIVWQVDRM;
VMIVWQVDRiENRWQVM IVWQVDRM;WQVMIVWQV;ERDWHLG
QGVSIEWRiWHLGQGVSIiEVHIPLGDARLVITTiIPLGDARLViEYQA
GHNKVGSLQYL;YQAGHNKVG;FSDSAIRKALLGHIV;AIRKALLGH;
FSDSAIRKALLGHIViIRKALLGHIiFYRHHYESPHPRISSiYESPHPRI
S;GDARLVITTYWGLHT;LVITTYWGL;GDARLVITTYWGLHT;VITTY WGLH;GERDWHLGQGVSIEW;WHLGQGVSI;GHNKVGSLQYLALA
A;VGSLQYLAL;GQGVSIEWRKKRYST;VSIEWRKKR;GSLQYLALA
ALITPK;LALAAUTP;GSLQYLALAALITPK;YLALAAUT;GVSIEWRKK
RYSTQV;IEWRKKRYS;GVSIEWRKKRYSTQV;VSIEWRKKR;GVSI
EWRKKRYSTQV;WRKKRYSTQ;HHMYVSGKARGWFYR;YVSGKA
RGWjHHYESPHPRISSEVHjYESPHPRISiHIPLGDARLVITTYWjLG
DARLVIT;HLGQGVSIEWRKKRY;VSIEWRKKR;HMYVSG KARGWF
YRH;YVSGKARGW;HNKVGSLQYLALAAL;VGSLQYLAL;IEWRKKR
YSTQVDPE;WRKKRYSTQ;IKPPLPSVTKLTEDR;IKPPLPSVT;IPLG
DARLVITTYWGiLGDARLVITjlRKALLGH IVSPRCEjLGHIVSPRCilR
KALLGHIVSPRCEjLLGHIVSPRjlRTWKSLVKHHMYVSjlRTWKSLV
KilRTWKSLVKHHMYVSjWKSLVKHHMjlSSEVHIPLGDARLVjHIPL
GDARL;ITPKKIKPPLPSVTK;IKPPLPSVT;ITTYWGLHTGERDWH;Y
WGLHTGER;IVWQVDRMRIRTWKS;VDRMRIRTW;IVWQVDRMRIR
TWKSiWQVDRMRIRjKALLGHIVSPRCEYQiLLGHIVSPRjKHHMYV
SGKARGWFY;YVSGKARGW;KIKPPLPSVTKLTED;IKPPLPSVT;KK
IKPPLPSVTKLTEjlKPPLPSVTjKKRYSTQVDPELADQjTQVDPELA
D;KSLVKHHMYVSGKAR;VKHHMYVSG;KVGSLQYLALAALIT;LQY
LALAALiKVGSLQYLALAALITiQYLALAALIiLADQLIHLYYFDCFSiIH
LYYFDCFiLALAALITPKKIKPPiLAALITPKKjLGDARLVITTYWGLHjL
GDARLVIT;LGDARLVITTYWGLH;LVITTYWGL;LGQGVSIEWRKKR
YSiVSIEWRKKRjLITPKKIKPPLPSVTjKKIKPPLPSjLITPKKIKPPLP
SVTiPKKIKPPLPjLLGHIVSPRCEYQAGjLLGHIVSPRjLQYLALAALI
TPKKIiLALAALITPiLQYLALAALITPKKIiLAALITPKKiLQYLALAALIT
PKKI;YLALMLIT;LVITTYWGLHTGERD;VITTYWGLH;LVITTYWGL
HTGERD;YWGLHTGER;LVKHHMYVSGKARGW;VKHHMYVSG;ME
NRWQVM IVWQVDR;WQVMIVWQV;MIVWQVDRMRIRTWK;IVWQ
VDRMR;MIVWQVDRMRIRTWK;MIVWQVDRM;MIVWQVDRMRIRT
WK;WQVDRMRIR;MRIRTWKSLVKHHMY;IRTWKSLVK;MRIRTWK
SLVKHHMY;WKSLVKHHM;MYVSGKARGWFYRHH;GKARGWFYR
;MYVSGKARGWFYRHH;YVSGKARGW;NKVGSLQYLALAALI;LQY
LALAAL;NRWQVMIVWQVDRMR;MIVWQVDRM;NRWQVM IVWQV
DRMR;WQVMIVWQV;PKKIKPPLPSVTKLT;IKPPLPSVT;PLGDARL
VITTYWGLiARLVITTYWjPLGDARLVITTYWGLjLGDARLVITjPRCE
YQAGHNKVGSL;YQAGHNKVG;QAGHNKVGSLQYLAL;NKVGSLQ
YLjQGVSIEWRKKRYSTQjlEWRKKRYSiQGVSIEWRKKRYSTQjSI
EWRKKRYjQGVSIEWRKKRYSTQjVSIEWRKKRjQLIHLYYFDCFS
DSAjlHLYYFDCFiQVDRMRIRTWKSLVKjDRMRIRTWKiQVDRMRI
RTWKSLVKjMRIRTWKSLjQVDRMRIRTWKSLVKjRMRIRTWKSiQ
VMIVWQVDRMRIRT;IVWQVDRMR;QVMIVWQVDRMRIRT;MIVWQ
VDRMiQYLALAALITPKKIKjLALAALITPjQYLALAALITPKKIKjLAALI
TPKKiQYLALAALITPKKIKiYLALAAUTiRCEYQAGHNKVGSLQiYQ
AGHNKVG;RDWHLGQGVSIEWRK;WHLGQGVSI;RHHYESPHPRI
SSEV;YESPHPRIS;RIRTWKSLVKHHMYV;IRTWKSLVK;RIRTWKS
LVKHHMYVjWKSLVKHHMjRKALLGHIVSPRCEYjLGHIVSPRCiRK
ALLGHIVSPRCEYjLLGHIVSPRjRKKRYSTQVDPELADjKKRYSTQV
D;RLVITTYWGLHTGER;ITTYWGLHT;RLVITTYWGLHTGER;VITTY
WGLH;RMRIRTWKSLVKHHM;IRTWKSLVK;RMRIRTWKSLVKHHM
;RTWKSLVKH;RTWKSLVKHHMYVSG;WKSLVKHHM;RWQVMIVW
QVDRMRIiMIVWQVDRMiRWQVMIVWQVDRMRIiWQVMIVWQViS
AIRKALLGHIVSPRjAIRKALLGHjSAIRKALLGHIVSPRjRKALLGHIV;
SDSAIRKALLGHIVSjAIRKALLGHjSDSAIRKALLGHIVSjlRKALLGHI
;SEVHIPLGDARLVIT;IPLGDARLV;SIEWRKKRYSTQVDP;WRKKR
YSTQiSLQYLALAALITPKKjALAALITPKjSLQYLALAALITPKKjLALA
ALITPjSLQYLALAALITPKKjYLALAALITjSLVKHHMYVSG KARG;VK
HHMYVSGjSPRCEYQAGHNKVGSjYQAGHNKVGjSSEVHIPLGDA
RLVI;IPLGDARLV;TGERDWHLGQGVSIE;WHLGQGVSI;TPKKIKPP
LPSVTKL;IKPPLPSVT;TWKSLVKHHMYVSGK;VKHHMYVSG;TWK SLVKHHMYVSGK;WKSLVKHHM;VDRMRIRTWKSLVKH;IRTWKSL
VKiVGSLQYLALAALITPiLQYLALAALiVGSLQYLALAALITPjYLALA
ALITiVHIPLGDARLVITTYiIPLGDARLViVITTYWGLHTGERDWiVIT
TYWGLH;VITTYWGLHTGERDW;YWGLHTGER;VKHHMYVSGKAR
GWFiYVSGKARGWiVMIVWQVDRMRIRTWiIVWQVDRMRiVMIVW
QVDRMRIRTW;MIVWQVDRM;VMIVWQVDRMRIRTW;WQVDRMRI
R;VSG KARGWFYRHHYE ;ARGWFYRHH;VSIEWRKKRYSTQVD;IE
WRKKRYS;VSIEWRKKRYSTQVD;VSIEWRKKR;VSIEWRKKRYST
QVDiWRKKRYSTQiVSPRCEYQAGHNKVGiEYQAGHNKViVWQVD
RMRIRTWKSL;RMRIRTWKS;VWQVDRMRIRTWKSL;VDRMRIRT
W;WFYRHHYESPHPRIS;YRHHYESPH;WHLGQGVSIEWRKKR;G
QGVSIEWR;WHLGQGVSIEWRKKR;LGQGVSIEW;WKSLVKHHMY
VSGKA;VKHHMYVSG;WKSLVKHHMYVSGKA;WKSLVKHHM;WQV
DRMRIRTWKSLV;MRIRTWKSL;WQVDRMRIRTWKSLV;RMRIRTW
KS;WQVM IVWQVDRMRIR;MIVWQVDRM;WQVMIVWQVDRMRIR;
VMIVWQVDR;WQVMIVWQVDRMRIR;WQVMIVWQV;YLALAALITP
KKIKP;LAALITPKK;YLALAALITPKKIKP;YLALAALIT;YQAGHNKVG
SLQYLAjYQAGHNKVGiYRHHYESPHPRISSEjYESPHPRISjYVSG
KARGWFYRHHY;ARGWFYRHH;YVSGKARGWFYRHHY;YVSGKA
RGW
NP_057852 8-mers: 5539-5757 Vpr EPHNEWTL;HNEWTLEL;NEWTLELL;TLELLEEL;EELKNEAV;ELKN
EAVR;EAVRHFPR;AVRHFPRI;GQHIYETY;ETYGDTWA;YGDTWA
GViDTWAGVEAiTWAGVEAIiVEAIIRILiRILQQLLFiILQQLLFIiQQLL
FIHFiQLLFIHFRiLLFIHFRIiRIGCRHSRiHSRIGVTRiRIGVTRQRiVT
RQRRAR;RARNGASR
9-mers:
REPHNEWTL;PHNEWTLEL;WTLELLEEL;TLELLEELK;LLEELKNE AiNEAVRHFPRiEAVRHFPRIiFPRIWLHGLiWLHGLGQHIiGLGQHI YET;IYETYGDTW;YETYGDTWA;ETYGDTW AGiTYGDTW AGV;DT WAGVEAIiTWAGVEAIIiAIIRILQQLiIRILQQLLFiRILQQLLFIiLQQLL FIHFiQQLLFIHFRiQLLFIHFRIiFIHFRIGCRiFRIGCRHSRiRIGCRHS RI;RHSRIGVTR;SRIGVTRQR;RIGVTRQRR;G VTRQRRAR;RQRRA RNGAiRRARNGASR
10-mers:
QAPEDQG PQR;EPHNEWTLEL;WTLELLEELK;ELLEELKN EAiLLEE
LKN EAViELKN EAVRHFiKN EAVRHFPR;EAVRHFPRIW;AVRHFPRI
WLiHFPRIWLHGLiFPRIWLHGLGiIWLHGLGQHIiWLHGLGQHIYiG
LGQHIYETY;HIYETYGDTW;ETYGDTW AGViDTW AGVEAIIiTW AG
VEAIIR;EAIIRILQQL;AIIRILQQLL;ILQQLLFIHF;LQQLLFIHFR;QQLL
FIHFRIiLLFIHFRIGCiLFIHFRIGCRiHFRIGCRHSRiFRIGCRHSRIiC
RHSRIGVTR;HSRIGVTRQR;SRIGVTRQRR;QRRARNGASR
1 1 -mers:
EQAPEDQGPQR;REPHNEWTLEL;EPHNEWTLELL;NEWTLELLEE
LiELLEELKN EAViEELKN EAVRHF;EAVRHFPRIWL;RHFPRIWLHG
L;RIWLHGLGQHI;IWLHGLGQHIY;WLHGLGQHIYE;HIYETYGDTW
AiYETYGDTW AGViETYGDTW AGVEiDTW AGVEAIIRiTW AGVEAII
RIiVEAIIRILQQLiEAIIRILQQLLiAIIRILQQLLFiIIRILQQLLFIiRILQQL
LFIHFiILQQLLFIHFRiLQQLLFIHFRIiQLLFIHFRIGCiLLFIHFRIGCR;
IHFRIGCRHSRiRIGCRHSRIGViGCRHSRIGVTRiHSRIGVTRQRR;
RIGVTRQRRARiRQRRARNGASR
15-mer + 9-mer core:
AGVEAIIRILQQLLFiVEAIIRILQiAIIRILQQLLFIHFRiILQQLLFIHiAIIR
ILQQLLFIHFR;IRILQQLLF;AIIRILQQLLFIHFR;LQQLLFIHF;DTWAG
Figure imgf000068_0001
15-mer + 9-mer core:
AIIIAIVVWSIVIIEiIIAIVVWSIiAIIIAIVVWSIVIIEiIVVWSIVIIiAIVALW
AIIIAIVViIVALVVAIIiAIVALVVAIIIAIVViLVVAIIIAIiAIVVWSIVIIEYRKI
;IVVWSIVII;AIVVWSIVIIEYRKI;VVWSIVIIE;AIVVWSIVIIEYRKI;WSI
VIIEYRiALVEMGVEMGHHAPWiLVEMGVEMGiALVVAIIIAIVVWSIiI
I IAIVVWSiALVVAI I IAIVVWS I;VAI I IAIVViALVVAI I IAIVVWS IiVVAI I IAI
V;EGEISALVEMGVEMG;ISALVEMGV;EISALVEMGVEMGHH;LVE
MGVEMG;EMGVEMGHHAPWDVD;MGHHAPWDV;EYRKILRQRKI
DRLIiILRQRKIDRiEYRKILRQRKIDRLIiLRQRKIDRLiEYRKILRQRKI
DRLI;YRKILRQRK;GEISALVEMGVEMGH;LVEMGVEMG;GVEMGH
HAPWDVDDLiMGHHAPWDViIAIVVWSIVIIEYRKiIVVWSIVIIiIEYRK
ILRQRKIDRLiILRQRKIDRiIEYRKILRQRKIDRLiYRKILRQRKiIIAIVV
WSIVIIEYRiIIAIVVWSIiIIAIVVWSIVIIEYRiIVVWSIVIIiIIEYRKILRQR
KIDR;EYRKILRQR;IIEYRKILRQRKIDR;YRKILRQRK;IIIAIVVWSIVII
EYiIIAIVVWSIiIIIAIVVWSIVIIEYiIVVWSIVIIiILRQRKIDRLIDRLIiILR
QRKIDRiIPIVAIVALVVAIIIiIVAIVALVViIPIVAIVALVVAIIIiVAIVALVV
AiISALVEMGVEMGHHAiLVEMGVEMGiIVAIVALVVAIIIAIiIVAIVALV
V; I VAI VALVVAI 11 Al ; IVALVVAI I ; I VAI VALVVAI 11 Al ; VAI VALVVA; IVALV
VAIIIAIVVWiLVVAIIIAIiIVALVVAIIIAIVVWiVAIIIAIVViIVIIEYRKILRQ
RKI;IIEYRKILR;IVIIEYRKILRQRKI;YRKILRQRK;IVVWSIVIIEYRKIL;
IVVWSIVIIiKILRQRKIDRLIDRLiILRQRKIDRiKILRQRKIDRLIDRLiL
RQRKIDRLiLVVAIIIAIVVWSIViIIAIVVWSIiLVVAIIIAIVVWSIViIIIAIV
VWS;LVVAIIIAIVVWSIV;VAIIIAIVV;MGVEMGHHAPWDVDD;MGHH
APWDViMQPIPIVAIVALVVAiIPIVAIVALiMQPIPIVAIVALVVAiIVAIV
ALVViPIPIVAIVALVVAIIiIVAIVALVViPIPIVAIVALVVAIIiVAIVALVVA
;PIVAIVALVVAIIIA;IVAIVALVV;PIVAIVALVVAIIIA;VAIVALVVA;QPIP
IVAIVALVVAIiIVAIVALVViQPIPIVAIVALVVAIiVAIVALVVAiRKILRQ
RKIDRLIDR;ILRQRKIDR;RKILRQRKIDRLIDR;LRQRKIDRL;SALVE
MGVEMGHHAPiLVEMGVEMGiSIVIIEYRKILRQRKiIEYRKILRQiSI
VIIEYRKILRQRKiIIEYRKILRiSIVIIEYRKILRQRKiVIIEYRKILiVAIIIAI
VVWSIVIIiAIVVWSIVIiVAIIIAIVVWSIVIIiIAIVVWSIViVAIIIAIVVWSIV
IlillAIVVWSIiVAIIIAIVVWSIVIIilllAIWWSiVAIVALVVAIIIAIVilVALVV
AIIiVAIVALVVAIIIAIViLVVAIIIAIiVALVVAIIIAIVVWSiLVVAIIIAIiVALV
VAI I IAI VVWSiVAI I IAI VV;VALVVAI 11 Al VVWS;VVAI I IAI V;VEMG VEM
GHHAPWDV;MGVEMGHHA;VIIEYRKILRQRKID;EYRKILRQR;VIIE
YRKILRQRKIDiYRKILRQRKiVVAIIIAIVVWSIVIiIIAIVVWSIiVVAIIIAI
VVWSIVIiIIIAIVVWSiVVWSIVIIEYRKILRiWSIVIIEYRiVWSIVIIEYRK
ILRQiIIEYRKILRiWSIVIIEYRKILRQRiIIEYRKILRiYRKILRQRKIDRLI
D;ILRQRKIDR;YRKILRQRKIDRLID;LRQRKIDRL;YRKILRQRKIDRLI
DjYRKILRQRK
NP_057854 8-mers: 6045-6355 Rev ELIRTVRLiLIRTVRLIiRTVRLIKLiRLIKLLYQiRQARRNRRiQARRNR
RR;RRNRRRRW;RNRRRRWR;RRRRWRER;RRWRERQR;RQRQI
HSIiRQIHSISEiQIHSISERiSERILGTYiILGTYLGRiRSAEPVPLiAEP
VPLQL;VPLQLPPL;LQLPPLER;QLPPLERL;LPPLERLT;PPLERLTL;
GTSGTQGV;VGSPQILV;ILVESPTV;TVLESGTK
9-mers:
EELIRTVRLiELIRTVRLIiLIRTVRLIKiTVRLIKLLYiRLIKLLYQSiGTR
QARRNR;RQARRNRRR;QARRNRRRR;RRNRRRRWR;NRRRRW
RER;RRRRWRERQ;RRRWRERQR;RRWRERQRQ;RQIHSISER;QI
HSISERIiIHSISERILiSISERILGTiISERILGTYiSERILGTYLiRILGTYL
GRiILGTYLGRSiYLGRSAEPViSAEPVPLQLiPVPLQLPPLiLQLPPL
ERLiQLPPLERLTiLPPLERLTLiCGTSGTQGViTQGVGSPQIiGVGS
PQILV;QILVESPTV;ILVESPTVL
10-mers: DSDEELIRTViDEELIRTVRLiELIRTVRLIKiLIRTVRLIKLiRTVRLIKLL
Y;GTRQARRNRR;TRQARRNRRR;RQARRNRRRR;ARRNRRRRW
R;RNRRRRWRER;RRRRWRERQR;RRWRERQRQI;RERQRQIHSI;
RQIHSISERliSISERILGTYjERILGTYLGRjILGTYLGRSAjTYLGRSA
EPV;RSAEPVPLQL;EPVPLQLPPL;PLQLPPLERL;LQLPPLERLT;Q
LPPLERLTLjTLDCNEDCGTjQGVGSPQILVjPQILVESPTV
1 1 -mers:
DSDEELIRTVR;ELIRTVRLIKL;LIRTVRLIKLL;GTRQARRNRRR;QA
RRNRRRRWR;RRNRRRRWRER;RRRRWRERQRQ;RRRWRERQ
RQI;RRWRERQRQIH;RQRQIHSISER;RQIHSISERIL;HSISERILGT
YiSISERILGTYLjRILGTYLGRSAjGTYLGRSAEPVjYLGRSAEPVPL;
AEPVPLQLPPLiVPLQLPPLERLjLQLPPLERLTLjTQGVGSPQILVjE
SPTVLESGTK
15-mer + 9-mer core:
AEPVPLQLPPLERLT;LQLPPLERL;AEPVPLQLPPLERLT;VPLQLP
PLE;ARRNRRRRWRERQRQ;NRRRRWRER;DEELIRTVRLIKLLY;I
RTVRLIKL;DSDEELIRTVRLIKL;EELIRTVRL;DSDEELIRTVRLIKL;LI
RTVRLIK;EELIRTVRLIKLLYQ;IRTVRLIKL;EELIRTVRLIKLLYQ;LIR
TVRLIK;EELIRTVRLIKLLYQ;TVRLIKLLY;EGTRQARRNRRRRWR;
RQARRNRRR;EGTRQARRNRRRRWR;TRQARRNRR;ELIRTVRLIK
LLYQS;IRTVRLIKL;ELIRTVRLIKLLYQS;TVRLIKLLY;ELIRTVRLIKL
LYQS;VRLIKLLYQ;EPVPLQLPPLERLTL;LQLPPLERL;EPVPLQLPP
LERLTLjVPLQLPPLEjERILGTYLGRSAEPVjILGTYLGRSiERILGTY
LGRSAEPVjLGTYLGRSAiGRSAEPVPLQLPPLEjGRSAEPVPLjGR
SAEPVPLQLPPLEjPVPLQLPPLjGSPQILVESPTVLESjILVESPTVL;
GSPQILVESPTVLESjLVESPTVLEjGTRQARRNRRRRWREjRQAR
RNRRRjGTYLGRSAEPVPLQLjYLGRSAEPVjGVGSPQILVESPTVL
;PQILVESPT;HSISERILGTYLGRS;ERILGTYLG;IKLLYQSNPPPNP
EGiLLYQSNPPPjlKLLYQSNPPPNPEGjLYQSNPPPNjlKLLYQSNP
PPNPEGjYQSNPPPNPjILGTYLGRSAEPVPLjILGTYLGRSilLGTYL
GRSAEPVPLjYLGRSAEPVilLVESPTVLESGTKEjILVESPTVLjILVE
SPTVLESGTKEjLVESPTVLEilRTVRLIKLLYQSNPjlRTVRLIKLjlRT
VRLIKLLYQSNPjTVRLIKLLYjlRTVRLIKLLYQSNPjVRLIKLLYQilSE
RILGTYLGRSAEjERILGTYLGjISERILGTYLGRSAEjILGTYLGRSjIS
ERILGTYLGRSAEjLGTYLGRSAjKLLYQSNPPPNPEGTjLYQSNPP
PN;KLLYQSNPPPNPEGT;YQSNPPPNP;LGTYLGRSAEPVPLQ;YL
GRSAEPVjLIKLLYQSNPPPNPEjLLYQSNPPPjLIKLLYQSNPPPNP
EiLYQSNPPPNjLIKLLYQSNPPPNPEjYQSNPPPNPjLIRTVRLIKLL
YQSNiIRTVRLIKLiLIRTVRLIKLLYQSNiTVRLIKLLYiLIRTVRLIKLLY
QSNiVRLIKLLYQiLLYQSNPPPNPEGTRiYQSNPPPNPiLPPLERLT
LDCNEDCiLERLTLDCNiLQLPPLERLTLDCNEiLERLTLDCNiLQLP
PLERLTLDCNEiLQLPPLERLiLYQSNPPPNPEGTRQiYQSNPPPNP
;NPEGTRQARRNRRRR;TRQARRNRR;NRRRRWRERQRQIHS;RR
RWRERQR;NRRRRWRERQRQIHS;WRERQRQIH;PEGTRQARRN
RRRRW;TRQARRNRR;PLQLPPLERLTLDCN;LQLPPLERL;PNPEG
TRQARRNRRRiTRQARRNRRiPPLERLTLDCNEDCGiLERLTLDCN
;PPNPEGTRQARRNRR;EGTRQARRN;PQILVESPTVLESGT;ILVES
PTVLiPQILVESPTVLESGTiLVESPTVLEiPVPLQLPPLERLTLDiLQL
PPLERL;PVPLQLPPLERLTLD;VPLQLPPLE;QARRNRRRRWRERQ
RiNRRRRWRERiQILVESPTVLESGTKiLVESPTVLEiQLPPLERLTL
DCNEDiLERLTLDCNiRILGTYLGRSAEPVPiILGTYLGRSiRILGTYL
GRSAEPVPiYLGRSAEPViRLIKLLYQSNPPPNPiLIKLLYQSNiRLIK
LLYQSNPPPNPiLLYQSNPPPiRLIKLLYQSNPPPNPiLYQSNPPPN;
RNRRRRWRERQRQIH;RRRWRERQR;RQARRNRRRRWRERQ;N
RRRRWRER;RQARRNRRRRWRERQ;RRNRRRRWR;RRNRRRR
WRERQRQI;NRRRRWRER;RRRRWRERQRQIHSI;WRERQRQIH; RRRWRERQRQIHSIS;WRERQRQIH;RRWRERQRQIHSISE;WRER
QRQIH;RSAEPVPLQLPPLER;VPLQLPPLE;RTVRLIKLLYQSNPP;I
KLLYQSNP;RTVRLIKLLYQSNPP;VRLIKLLYQ;SAEPVPLQLPPLER
L;PVPLQLPPL;SAEPVPLQLPPLERL;VPLQLPPLE;SDEELIRTVRLI
KLLjlRTVRLIKLjSERILGTYLGRSAEPjILGTYLGRSiSERILGTYLGR
SAEPjLGTYLGRSAjSISERILGTYLGRSAjERILGTYLGiSISERILGT
YLGRSAjILGTYLGRSiSPQILVESPTVLESGjILVESPTVLjSPQILVE
SPTVLESG;LVESPTVLE;TRQARRNRRRRWRER;RRNRRRRWR;T
VRLIKLLYQSNPPPjlKLLYQSNPjTVRLIKLLYQSNPPPjVRLIKLLYQ;
TYLGRSAEPVPLQLP;YLGRSAEPV;VGSPQILVESPTVLE;ILVESP
TVLiVGSPQILVESPTVLEjVGSPQILVEjVPLQLPPLERLTLDCjLQL
PPLERLjVPLQLPPLERLTLDCjVPLQLPPLEjVRLIKLLYQSNPPPN ;
LLYQSNPPP;YLGRSAEPVPLQLPP;YLGRSAEPV;YQSNPPPNPE
GTRQA;YQSNPPPNP
NP_057855 8-mer 6356-6574 Vpu EPHNEWTL;HNEWTLEL;NEWTLELL;TLELLEEL;EELKNEAV;ELKN
EAVR;EAVRHFPR;AVRHFPRI;GQHIYETY;ETYGDTWA;YGDTWA
GViDTWAGVEAiTWAGVEAIiVEAIIRILiRILQQLLFiILQQLLFIiQQLL
FIHFiQLLFIHFRiLLFIHFRIiRIGCRHSRiHSRIGVTRiRIGVTRQRiVT
RQRRAR;RARNGASR
9-mer
REPHNEWTL;PHNEWTLEL;WTLELLEEL;TLELLEELK;LLEELKNE AiNEAVRHFPRiEAVRHFPRIiFPRIWLHGLiWLHGLGQHIiGLGQHI YET;IYETYGDTW;YETYGDTWA;ETYGDTW AG;TYGDTW AGV;DT WAGVEAIiTWAGVEAIIiAIIRILQQLiIRILQQLLFiRILQQLLFIiLQQLL FIHFiQQLLFIHFRiQLLFIHFRIiFIHFRIGCRiFRIGCRHSRiRIGCRHS RI;RHSRIGVTR;SRIGVTRQR;RIGVTRQRR;G VTRQRRAR;RQRRA RNGAiRRARNGASR
10-mer
QAPEDQG PQR;EPHNEWTLEL;WTLELLEELK;ELLEELKN EAiLLEE
LKN EAViELKN EAVRHFiKN EAVRHFPR;EAVRHFPRIW;AVRHFPRI
WLiHFPRIWLHGLiFPRIWLHGLGiIWLHGLGQHIiWLHGLGQHIYiG
LGQHIYETYiHIYETYGDTWiETYGDTWAGViDTWAGVEAIIiTWAG
VEAIIRiEAIIRILQQLiAIIRILQQLLiILQQLLFIHFiLQQLLFIHFRiQQLL
FIHFRIiLLFIHFRIGCiLFIHFRIGCRiHFRIGCRHSRiFRIGCRHSRIiC
RHSRIGVTR;HSRIGVTRQR;SRIGVTRQRR;QRRARNGASR
1 1 -mer
EQAPEDQGPQR;REPHNEWTLEL;EPHNEWTLELL;NEWTLELLEE
LiELLEELKN EAViEELKN EAVRHF;EAVRHFPRIWL;RHFPRIWLHG
L;RIWLHGLGQHI;IWLHGLGQHIY;WLHGLGQHIYE;HIYETYGDTW
AiYETYGDTW AGViETYGDTW AGVEiDTW AGVEAIIRiTW AGVEAII
RIiVEAIIRILQQLiEAIIRILQQLLiAIIRILQQLLFiIIRILQQLLFIiRILQQL
LFIHFiILQQLLFIHFRiLQQLLFIHFRIiQLLFIHFRIGCiLLFIHFRIGCR;
IHFRIGCRHSRiRIGCRHSRIGViGCRHSRIGVTRiHSRIGVTRQRR;
RIGVTRQRRARiRQRRARNGASR
15-mer + 9-mer core
AGVEAIIRILQQLLFiVEAIIRILQiAIIRILQQLLFIHFRiILQQLLFIHiAIIR ILQQLLFIHFRiIRILQQLLFiAIIRILQQLLFIHFRiLQQLLFIHFiDTWAG VEAIIRILQQiWAGVEAIIRiEAIIRILQQLLFIHFiIIRILQQLLiEAIIRILQ QLLFIHFiILQQLLFIHiEAIIRILQQLLFIHFiIRILQQLLFiEAVRHFPRI WLHGLG;VRHFPRIWL;EELKN EAVRHFPRIWiLKN EAVRHFiELKN EAVRHFPRIWLiLKN EAVRHFiELKN EAVRHFPRIWLiNEAVRHFPR; ELLEELKN EAVRHFP;LKNEAVRHF;ETYGDTWAGVEAIIR;DTW AG VEAI;FIHFRIGCRHSRIGV;FIHFRIGCR;FPRIWLHGLGQHIYE;IWLH GLGQH;FPRIWLHGLGQHIYE;WLHGLGQHI;GDTW AGVEAIIRILQ;
WAGVEAIIRiGVEAIIRILQQLLFIiIRILQQLLFiHFPRIWLHGLGQHIY;!
WLHGLGQH;HFPRIWLHGLGQHIY;WLHGLGQHI;IIRILQQLLFIHFR
ULQQLLFIHJIRILQQLLFIHFRURILQQLLFiIIRILQQLLFIHFRhLQQ
LLFIHFiILQQLLFIHFRIGCRiILQQLLFIH iILQQLLFIHFRIGCRiLLFIH
FRIGiIRILQQLLFIHFRIGiILQQLLFIHiIRILQQLLFIHFRIGiIRILQQLL
FiKNEAVRHFPRIWLHGiVRHFPRIWLiLEELKNEAVRHFPRIiLKNE
AVRHFiLELLEELKN EAVRHFiELKN EAVRHiLELLEELKN EAVRHF;
LEELKNEAViLFIHFRIGCRHSRIGiFIHFRIGCRiLKNEAVRHFPRIW
LH;LKN EAVRHFiLKN EAVRHFPRIWLH;VRHFPRIWL;LLEELKN EA
VRHFPRiLKNEAVRHFiLLFIHFRIGCRHSRIiFIHFRIGCRiLQQLLFI
HFRIGCRHiFIHFRIGCRiNEAVRHFPRIWLHGLiVRHFPRIWLiPRIW
LHGLGQHIYETiWLHGLGQHIiQLLFIHFRIGCRHSRiFIHFRIGCRiQ
QLLFIHFRIGCRHSiFIHFRIGCRiRHFPRIWLHGLGQHIiFPRIWLHG
LiRHFPRIWLHGLGQHIiIWLHGLGQHiRILQQLLFIHFRIGCiILQQLL
FIHiRIWLHGLGQHIYETYiWLHGLGQHIiTYGDTWAGVEAIIRIiWAG
VEAIIR;VEAIIRILQQLLFIH;IRILQQLLF;VRHFPRIWLHGLGQH;FPRI
WLHGLiW AGVEAIIRILQQLLiW AGVEAIIRiYGDTW AGVEAIIRILiWA
GVEAIIR
NP_057856 8-mer 6575-9108
Envelope RVKEKYQH;KEKYQHLW;EKYQHLWR;KYQHLWRW;HLWRWGWR surface ;WGWRWGTM;WRWGTMLL;TMLLGMLM;MLLGMLMI;LLGMLMIC; glycoprotein GMLMICSAiMLMICSATiMICSATEKiCSATEKLWiSATEKLWViEKL gp160 WVTVY;KLWVTVYY;WVTVYYGV;TVYYGVPV;VYYGVPVW;YYGV precursor PVWKiVPVWKEATiKEATTTLFiTTTLFCASiTLFCASDAiCASDAKA
YiYDTEVHNViDTEVHNVWiEVHNVWATiNVWATHACiVWATHACV
;NPQEVVLV;QEVVLVNV;EVVLVNVT;NVTENFNM;VTENFNMW;TE
NFNMWKiNMWKNDMViMHEDIISLiSLWDQSLKiQSLKPCVKiSLKP
CVKLiKLTPLCVSiLTPLCVSLiTPLCVSLKiSLKCTDLKiNTNSSSGR;
SGRMIMEKiMIMEKGEhGEIKNCSFiFN ISTSIRJSTSIRGKiSTSIRG
KV;SIRGKVQK;KVQKEYAF;VQKEYAFF;KEYAFFYK;EYAFFYKL;F
FYKLDIIiYKLDIIPIiIPIDNDTTiLTSCNTSViNTSVITQAiVITQACPKiIT
QACPKViFEPIPIHYiIPIHYCAPiHYCAPAGFiYCAPAGFAiCAPAGF
AIiAPAGFAILiAILKCNNKiGTGPCTNViTVQCTHGIiVQCTHGIRiCT
HGIRPV;GIRPVVST;RPVVSTQL;VVSTQLLL;QLLLNGSL;LLLNGSL
AiSLAEEEVViEEVVIRSViVVIRSVNFiSVNFTDNAiFTDNAKTIiIVQL
NTSViQLNTSVEIiSVEINCTRiRKRIRIQRiRIQRGPGRiRGPGRAFV;
RAFVTIGKiQAHCNISRiRAKWNNTLiTLKQIASKiKQIASKLRiNNKTI
IFKiPEIVTHSFiSFNCGGEFiGEFFYCNSiFYCNSTQLiQLFNSTWF;
STWFNSTWiEGSDTITLiDTITLPCRiTITLPCRIiITLPCRIKiLPCRIKQ
IiRIKQIINMiKQIINMWQiQIINMWQKiIINMWQKViWQKVGKAMiKVG
KAMYAiKAMYAPPIiAPPISGQIiQIRCSSNIiCSSNITGLiITGLLLTRiN
NESEIFR;WRSELYKY;RSELYKYK;ELYKYKVV;LYKYKVVK;KVVKI
EPL;EPLGVAPT;GVAPTKAK;RRVVQREK;RVVQREKR;REKRAVGI
;RAVGIGAL;FLGFLGAA;FLGAAGST;STMGAASM;MGAASMTL;AA
SMTLTV;SMTLTVQA;MTLTVQAR;TVQARQLL;RQLLSG IViQLLSGI
VQ;LLSGIVQQ;VQQQNNLL;QQQNNLLR;QQNNLLRA;NLLRAIEA;L
LRAIEAQ;AIEAQQHL;IEAQQHLL;AQQHLLQL;HLLQLTVW;LQLTV
WGI;QLTVWGIK;TVWGIKQL;GIKQLQAR;KQLQARIL;QLQARILA;L
QARILAV;ILAVERYL;LAVERYLK;RYLKDQQL;YLKDQQLL;QLLGIW
GCiGIWGCSGKiKLICTTAViTTAVPWNAiAVPWNASWiVPWNASW
S;QIWNHTTW;TTWMEWDR;WMEWDREI;WDREINNY;EINNYTSL;
YTSLIHSL;ESQNQQEK;QEKNEQEL;NEQELLEL;LLELDKWA;ELD
KWASLiKWASLWNWiWASLWNWFiSLWNWFNIiNWFNITNWiWFN
ITNWL;FNITNWLW;NITNWLWY;ITNWLWYI;NWLWYIKL;WLWYIKL
FiLWYIKLFIiWYIKLFIMiYIKLFIMIiFIMIVGGLiIMIVGGLViIVGGLVG
LiGLVGLRIViGLRIVFAViIVFAVLSIiAVLSIVNRiVLSIVNRViLSIVNR
VR;VRQGYSPL;SPLSFQTH;PLSFQTHL;FQTHLPTP;QTHLPTPR;L PTPRGPDiRDRDRSIRiRLVNGSLAiLVNGSLALiALIWDDLRiRSLCL
FSYiLCLFSYHRiCLFSYHRLiLFSYHRLRiSYHRLRDLiRLRDLLLIiD
LLLIVTRiLLLIVTRIiLLIVTRIViIVTRIVELiRIVELLGRiIVELLGRRiGR
RGWEAL;RRGWEALK;W EALKYWW ;ALKYWWNL;YWWNLLQY;NL
LQYWSQ;LQYWSQEL;QYWSQELK;SLLNATAI;LLNATAIA;NATAIA
VAiAVAEGTDRiAEGTDRVIiGTDRVIEViEVVQGACRiRAIRHIPRiAI
RHIPRR;RHIPRRIR;IPRRIRQG;RIRQGLER
9-mer
RVKEKYQHLiKEKYQHLWRiYQHLWRWGWiHLWRWGWRWiWR
WGWRWGTiWGWRWGTMLiGWRWGTMLLiTMLLGMLMIiMLLGM
LMICiLGMLMICSAiLMICSATEKiMICSATEKLiICSATEKLWiATEKL
WVTViTEKLWVTVYiEKLWVTVYYiKLWVTVYYGiLWVTVYYGViVT
VYYGVPV;TVYYGVPVW;VYYGVPVWK;VPVWKEATT;VWKEATTT
LiEATTTLFCAiTLFCASDAKiFCASDAKAYiAYDTEVHNViTEVHNV
WATiEVHNVWATHiNVWATHACViPTDPNPQEViDPNPQEVVLiVL
VNVTENF;VTENFNMWK;FNMW KNDMViQMHEDIISLiIISLWDQSL;
ISLWDQSLKiSLWDQSLKPiSLKPCVKLTiKPCVKLTPLiKLTPLCVSL
;LTPLCVSLK;VSLKCTDLK;TNTNSSSGR;NTNSSSGRM;SSGRMIM
EKiRMIMEKGEIiMIMEKGEIKiEIKNCSFNIiCSFNISTSIiSFNISTSIR;
NISTSIRGK;ISTSIRGKV;TSIRGKVQK;KVQKEYAFF;VQKEYAFFY;
KEYAFFYKLiAFFYKLDIIiFYKLDIIPIiIPIDNDTTSiPIDNDTTSYiKLTS
CNTSViLTSCNTSVIiNTSVITQACiSVITQACPKiVITQACPKViTQAC
PKVSFiCPKVSFEPIiKVSFEPIPIiSFEPIPIHYiEPIPIHYCAiIPIHYCA
PAiYCAPAGFAIiCAPAGFAILiAPAGFAILKiFAILKCNNKiILKCNNKT
FiNGTGPCTNViSTVQCTHGIiTVQCTHGIRiCTHGIRPVViRPVVST
QLL;TQLLLNGSL;QLLLNGSLA;LLLNGSLAE;LLNGSLAEE;SLAEEE
VVIiEVVIRSVNFiSVNFTDNAKiNAKTIIVQLiIIVQLNTSViVQLNTSV
EIiTSVEINCTRiCTRPNNNTRiRPNNNTRKRiIQRGPGRAFiQRGPG
RAFViG PGRAFVTIiG RAFVTIGK;VTIGKIGNM;TIGKIGNMR;NMRQ
AHCNIiRQAHCNISRiQAHCNISRAiHCNISRAKWiSRAKWNNTLiRA
KWNNTLK;NTLKQIASK;TLKQIASKL;IASKLREQF;GNNKTIIFK;KQS
SGGDPEiDPEIVTHSFiHSFNCGGEFiSFNCGGEFFiFNCGGEFFY;
GEFFYCNSTiFFYCNSTQLiFYCNSTQLFiSTQLFNSTWiTQLFNST
WFiQLFNSTWFNiNSTWFNSTWiTEGSDTITLiDTITLPCRIiTITLPC
RIKiTLPCRIKQIiLPCRIKQIIiKQIINMWQKiQIINMWQKViNMWQKV
GKAiMWQKVGKAMiWQKVGKAMYiYAPPISGQIiGQIRCSSNIiRCS
SNITGLiCSSNITGLLiNITGLLLTRiNSNNESEIFiSNNESEIFRiMRDN
WRSEL;NWRSELYKY;WRSELYKYK;ELYKYKVVK;LYKYKVVKI;VV
KIEPLGV;EPLGVAPTK;GVAPTKAKR;APTKAKRRV;KAKRRVVQR;
KRRVVQREK;RRVVQREKR;VVQREKRAV;RAVGIGALF;AVGIGAL
FL;IGALFLGFL;ALFLGFLGA;FLGAAGSTM;GAAGSTMGA;STMGA
ASMTiTMGAASMTLiMGAASMTLTiGAASMTLTViSMTLTVQARiTL
TVQARQL;LTVQARQLL;QARQLLSGI;QLLSGIVQQ;LLSGIVQQQ;G
IVQQQNNL;VQQQNNLLR;QQQNNLLRA;QQNNLLRAI;NLLRAIEAQ
;RAIEAQQHL;AIEAQQHLL;EAQQHLLQL;AQQHLLQLT;QQHLLQLT
V;HLLQLTVWG;LLQLTVWGI;LQLTVWGIK;LTVWGIKQL;TVWGIKQ
LQ;GIKQLQARI;KQLQARILA;QLQARILAV;QARILAVER;RILAVERY
LiILAVERYLKiRYLKDQQLLiYLKDQQLLGiQQLLGIWGCiGIWGCS
GKLiIWGCSGKLIiCTTAVPWNAiTTAVPWNASiTAVPWNASWiVPW
NASWSN;KSLEQIWNH;QIWNHTTWM;HTTWMEWDR;TWMEWDR
EIiREINNYTSLiEINNYTSLIiNYTSLIHSLiYTSLIHSLIiSLIEESQNQiQ
EKNEQELL;ELLELDKWA;LELDKW ASL;KW ASLWNWFiSLWNWFN
ITiNWFNITNWLiWFNITNWLWiFNITNWLWYiNITNWLWYIiITNWL
WYIKiNWLWYIKLFiWLWYIKLFIiWYIKLFIMIiYIKLFIMIViFIMIVGGL
ViMIVGGLVGLiIVGGLVGLRiGLVGLRIVFiLVGLRIVFAiVGLRIVFA
ViGLRIVFAVLiRIVFAVLSIiIVFAVLSIViFAVLSIVNRiAVLSIVNRViVL
SIVNRVR;IVNRVRQGY;RVRQGYSPL;RQGYSPLSF;SPLSFQTHL; FQTHLPTPRiRDRDRSIRLiSIRLVNGSLiRLVNGSLALiLVNGSLALI;
SLALIWDDLiLALIWDDLRjLIWDDLRSLjRSLCLFSYHiSLCLFSYHR;
CLFSYHRLRiSYHRLRDLLiYHRLRDLLLjRLRDLLLIVjRDLLLIVTR;
DLLLIVTRIiLLLIVTRIVjLIVTRIVELilVTRIVELLjRIVELLGRRiVELLG
RRGW;LLGRRGWEA;GRRGWEALK;RRGWEALKY;RGWEALKYW
;EALKYWWNL;ALKYWWNLL;KYWWNLLQY;YWWNLLQYW;LLQY
WSQEL;LQYWSQELK;SQELKNSAV;ELKNSAVSL;LKNSAVSLL;SA
VSLLNATiSLLNATAIAiLLNATAIAVjTAIAVAEGTilAVAEGTDRjAVA
EGTDRViEGTDRVIEViGTDRVIEVVjRVIEVVQGAjEVVQGACRAiV
QGACRAIRiRAIRHIPRRjAIRHIPRRIilPRRIRQGLiRRIRQGLERjRI
RQGLERI;RQGLERILL
10-mer
RVKEKYQHLW;KEKYQHLWRW;KYQHLWRWGW;YQHLWRWGW
R;HLWRWGWRWG;WRWGWRWGTM;RWGWRWGTML;WGWRW
GTMLL;WRWGTMLLGM;RWGTMLLGML;TMLLGMLMIC;MLLGML
MICSiLLGMLMICSAjMLMICSATEKjLMICSATEKLiSATEKLWVTV;
ATEKLWVTVY;TEKLWVTVYY;KLWVTVYYGV;WVTVYYGVPV;VTV
YYGVPVW;TVYYGVPVWK;VPVWKEATTT;PVWKEATTTL;VWKEA
TTTLFiTTTLFCASDAiTTLFCASDAKjTLFCASDAKAjLFCASDAKAY
;KAYDTEVHNV;AYDTEVHNVW;EVHNVW ATHA;HNVW ATHACV;P
TDPNPQEVV;DPNPQEVVLV;NPQEVVLVNV;VVLVNVTENF;NVTE
NFNMWK;NMWKNDMVEQ;EQMHEDIISL;DIISLWDQSL;IISLWDQS
LK;SLWDQSLKPC;KLTPLCVSLK;CVSLKCTDLK;DTNTNSSSGR;N
TNSSSGRMIiSSSGRMIMEKiRMIMEKGEIKiGEIKNCSFNIiNCSFNI
STSIiCSFNISTSIRjNISTSIRGKViSTSIRGKVQKiSIRGKVQKEYjRG
KVQKEYAFiKVQKEYAFFYiVQKEYAFFYKjEYAFFYKLDIjFFYKLDII
PlilPIDNDTTSYiYKLTSCNTSVjKLTSCNTSVIjTSVITQACPKiSVITQ
ACPKVilTQACPKVSFjVSFEPIPIHYjEPIPIHYCAPilPIHYCAPAGiH
YCAPAGFAIjYCAPAGFAILiCAPAGFAILKiFAILKCNNKTjAILKCNN
KTFjTGPCTNVSTViSTVQCTHGIRiVQCTHGIRPViGIRPVVSTQLjR
PVVSTQLLL;STQLLLNGSL;TQLLLNGSLA;LLLNGSLAEE;LNGSLA
EEEViSLAEEEVVIRiAEEEVVIRSViEEVVIRSVNFiEVVIRSVNFTiR
SVNFTDNAKiFTDNAKTIIViTIIVQLNTSViNTSVEINCTRiCTRPNNN
TRKiRPNNNTRKRIiNTRKRIRIQRiRIRIQRGPGRiRIQRGPGRAFiIQ
RGPGRAFViPGRAFVTIGKiFVTIGKIGNMiVTIGKIGNMRiMRQAHC
NISRiRQAHCN ISRAiQAHCNISRAKiSRAKWNNTLKiNTLKQIASKL;
TLKQIASKLRiQIASKLREQFiKLREQFGNNKiREQFGNNKTIiQFGN
NKTIIFiFGNNKTIIFKiKQSSGGDPEIiHSFNCGGEFFiSFNCGGEFF
YiEFFYCNSTQLiFFYCNSTQLFiNSTQLFNSTWiSTQLFNSTWFiQL
FNSTWFNSiSTWFNSTWSTiGSDTITLPCRiDTITLPCRIKiTLPCRIK
QIIiLPCRIKQIINiRIKQIINMWQiKQIINMWQKViIINMWQKVGKiNMW
QKVGKAM;MWQKVGKAMY;WQKVGKAMYA;AMYAPPISGQ;MYA
PPISGQI;YAPPISGQIR;NSNNESEIFR;EIFRPGGGDM;DMRDNWR
SEL;MRDNWRSELY;RDNWRSELYK;SELYKYKVVK;ELYKYKVVKI;
KYKVVKIEPL;KVVKIEPLGV;EPLGVAPTKA;GVAPTKAKRR;APTKA
KRRVV;TKAKRRVVQR;AKRRVVQREK;KRRVVQREKR;RVVQREK
RAViKRAVGIGALFiRAVGIGALFLiGIGALFLGFLiALFLGFLGAAiFL
GFLGAAGS;FLGAAGSTMG;LGAAGSTMGA;GAAGSTMGAA;STM
GAASMTLiTMGAASMTLTiMGAASMTLTViASMTLTVQARiSMTLTV
QARQ;MTLTVQARQL;TLTVQARQLL;VQARQLLSGI;QLLSGIVQQQ
;GIVQQQNNLL;IVQQQNNLLR;VQQQNNLLRA;QQQNNLLRAI;NLL
RAIEAQQ;RAIEAQQHLL;IEAQQHLLQL;AQQHLLQLTV;HLLQLTV
WGI;LLQLTVWGIK;QLTVWGIKQL;TVWGIKQLQA;VWGIKQLQAR;
KQLQARILAV;LQARILAVER;RILAVERYLK;VERYLKDQQL;YLKDQ
QLLGIiLLGIWGCSGKiGIWGCSGKLIiKLICTTAVPWiCTTAVPWNA
S;TTAVPWNASW;SWSNKSLEQI;WSNKSLEQIW;SLEQIWNHTT;E
QIWNHTTWM;IWNHTTWMEW;TTWMEWDREI;MEWDREINNY;RE INNYTSLIiNYTSLIHSLIiSLIHSLIEESiSLIEESQNQQiELLELDKWAS iLLELDKW ASL;W ASLWNWFNIiSLWNWFN ITNiLWNWFN ITNWiN
WFN ITNWLW;WFN ITNWLWY;FN ITNWLWYI;NITNWLWYIK;ITNWL
WYIKLiNWLWYIKLFIiWLWYIKLFIMiLWYIKLFIMIiWYIKLFIMIViKLF
IMIVGGLiIMIVGGLVGLiMIVGGLVGLRiGLVGLRIVFAiLVGLRIVFA
ViRIVFAVLSIViVFAVLSIVNRiFAVLSIVNRViAVLSIVNRVRiSIVNRV
RQGY;RVRQGYSPLS;VRQGYSPLSF;SFQTHLPTPR;ERDRDRSIR
L;IRLVNGSLAL;RLVNGSLALI;LVNGSLALIW;SLALIWDDLR;ALIWD
DLRSLiLIWDDLRSLCiDLRSLCLFSYiRSLCLFSYHRiSLCLFSYHRL
;LCLFSYHRLR;FSYHRLRDLL;SYHRLRDLLL;RLRDLLLIVT;DLLLIV
TRIV;LLIVTRIVEL;LIVTRIVELL;VTRIVELLGR;ELLGRRGWEA;LLG
RRGWEAL;LGRRGWEALK;GRRGWEALKY;RGWEALKYWW;WEA
LKYWWNLiEALKYWWNLLiLKYWWNLLQYiKYWWNLLQYWiNLLQ
YWSQEL;LLQYWSQELK;WSQELKNSAV;QELKNSAVSL;ELKNSA
VSLLiSLLNATAIAViLLNATAIAVAiIAVAEGTDRViAVAEGTDRVIiAE
GTDRVIEViEGTDRVIEVViEVVQGACRAIiVVQGACRAIRiACRAIR
HIPRiAIRH IPRRIRiHIPRRIRQGLiRRIRQGLERIiRIRQGLERIL
1 1 -mer
RVKEKYQHLWR;KYQHLWRWGWR;YQHLWRWGWRW;HLWRW
GWRWGT;WRWGWRWGTML;RWGWRWGTMLL;WRWGTMLLGM
LiMLLGMLMICSAiLLGMLMICSATiGMLMICSATEKiMLMICSATEKL
;LMICSATEKLW;MICSATEKLWV;CSATEKLWVTV;SATEKLWVTVY
;ATEKLWVTVYY;EKLWVTVYYGV;WVTVYYGVPVW;VTVYYGVPV
WKiVPVWKEATTTLiPVWKEATTTLFiTTTLFCASDAKiTTLFCASDA
KAiTLFCASDAKAYiKAYDTEVHNVWiNVWATHACVPTiCVPTDPN
PQEV;VPTDPN PQEVV;PTDPNPQEVVL;NPQEVVLVNVT;EVVLVN
VTENF;VLVNVTENFNM;LVNVTENFNMW;NMWKNDMVEQM;DMV
EQMHEDIIiVEQMHEDIISLiDIISLWDQSLKiSLWDQSLKPCViSLKP
CVKLTPLiKPCVKLTPLCViKLTPLCVSLKCiDTNTNSSSGRMiNTNS
SSGRMIMiNSSSGRMIMEKiGRMIMEKGEIKiMEKGEIKNCSFiNCS
FNISTSIRiSFNISTSIRGKiISTSIRGKVQKiTSIRGKVQKEYiSIRGKV
QKEYA;KVQKEYAFFYK;VQKEYAFFYKL;KEYAFFYKLDI;EYAFFY
KLDIIiIIPIDNDTTSYiIPIDNDTTSYKiPIDNDTTSYKLiKLTSCNTSVIT;
NTSVITQACPKiQACPKVSFEPIiCPKVSFEPIPIiKVSFEPIPIHYiEPI
PIHYCAPAiIPIHYCAPAGFiHYCAPAGFAILiAGFAILKCNNKiFAILK
CNNKTFiGTGPCTNVSTViNVSTVQCTHGIiVSTVQCTHGIRiTVQC
THGIRPViGIRPVVSTQLLiLLLNGSLAEEEiLLNGSLAEEEViSLAEE
EVVIRSiEEEVVIRSVNFiEEVVIRSVNFTiNFTDNAKTIIViKTIIVQLN
TSViIIVQLNTSVEIiQLNTSVEINCTiLNTSVEINCTRiCTRPNNNTRK
R;RPNNNTRKRIR;NNTRKRIRIQR;KRIRIQRGPGR;RIQRGPGRAF
ViIQRGPGRAFVTiFVTIGKIGNMRiNMRQAHCNISRiRQAHCNISRA
K;NISRAKWNNTL;ISRAKWNNTLK;NTLKQIASKLR;KQIASKLREQF
;KLREQFGNNKT;REQFGNNKTII;EQFGNNKTIIF;QFGNNKTIIFK;K
QSSGGDPEIViHSFNCGGEFFYiGEFFYCNSTQLiEFFYCNSTQLF;
QLFNSTWFNST;LFNSTWFNSTW;STWSTEGSNNT;EGSDTITLPC
RiLPCRIKQIINMiRIKQIINMWQKiQIINMWQKVGKiIINMWQKVGKA;
NMWQKVGKAMY;KVGKAMYAPPI;AMYAPPISGQI;MYAPPISGQIR iQIRCSSNITGLiSSNITGLLLTRiSEIFRPGGGDMiEIFRPGGGDMR;
RPGGGDMRDNW;DMRDNWRSELY;RSELYKYKVVK;YKYKVVKIE
PL;KIEPLGVAPTK;GVAPTKAKRRV;APTKAKRRVVQ;PTKAKRRVV
QR;KAKRRVVQREK;RRVVQREKRAV;REKRAVGIGAL;AVGIGALF
LGF;FLGFLGAAGST;FLGAAGSTMGA;STMGAASMTLT;TMGAAS
MTLTV;AASMTLTVQAR;SMTLTVQARQL;MTLTVQARQLL;TVQAR
QLLSGIiVQARQLLSGIViGIVQQQNNLLRiVQQQNNLLRAIiQQNNL
LRAIEA;LLRAIEAQQHL;AIEAQQHLLQL;EAQQHLLQLTV;HLLQLTV
WGIK;LQLTVWGIKQL;QLTVWGIKQLQ;TVWGIKQLQAR;VWGIKQ
LQARI;KQLQARILAVE;QLQARILAVER;LQARILAVERY;ARILAVER YLKiAVERYLKDQQLiVERYLKDQQLLiRYLKDQQLLGIiQLLGIWGC
SGKiLLGIWGCSGKLiCTTAVPWNASWfTTAVPWNASWSiAVPWN
ASWSNK;VPWNASWSNKS;Q IWNHTTWMEW ;WMEWDREINNY;W
DREINNYTSLiSLIHSLIEESQiSLIEESQNQQEiQEKNEQELLELiELL
ELDKWASLiKWASLWNWFNIiWASLWNWFNITiSLWNWFNITNWiL
WNWFN ITNWLiNWFN ITNWLWY;WFN ITNWLWYI ;NITNWLWYIKL;I
TNWLWYIKLFiWLWYIKLFIMIiKLFIMIVGGLViFIMIVGGLVGLiIMIV
GGLVGLRiMIVGGLVGLRIiIVGGLVGLRIViGLVGLRIVFAViGLRIVF
AVLSIiIVFAVLSIVNRiFAVLSIVNRVRiLSIVNRVRQGYiRVRQGYSP
LSF;RQGYSPLSFQT;GYSPLSFQTHL;SPLSFQTHLPT;LSFQTHLP
TPR;TPRGPDRPEGI;GERDRDRSIRL;SIRLVNGSLAL;RLVNGSLAL
IWiGSLALIWDDLRiALIWDDLRSLCiLIWDDLRSLCLiIWDDLRSLCL
FiSLCLFSYHRLRiCLFSYHRLRDLiSYHRLRDLLLIiRLRDLLLIVTRiL
LLIVTRIVELiLLIVTRIVELLiIVTRIVELLGRiVTRIVELLGRRiELLGRR
GWEAL;LLGRRGWEALK;GWEALKYWWNL;WEALKYWWNLL;ALK
YWWNLLQY;LKYWWNLLQYW;NLLQYWSQELK;SQELKNSAVSL;
QELKNSAVSLL;SAVSLLNATAI;AVSLLNATAIA;SLLNATAIAVA;NA
TAIAVAEGTiTAIAVAEGTDRiAIAVAEGTDRViVAEGTDRVIEViAEG
TDRVIEVViRVIEVVQGACRiEVVQGACRAIRiGACRAIRHIPRiACR
AIRHIPRR;RAIRHIPRRIR;RRIRQGLERIL;RIRQGLERILL
15-mer + 9-mer core
ACRAIRHIPRRIRQGiIRHIPRRIRiACVPTDPNPQEVVLViVPTDPNP
QEiAEEEVVIRSVN FTDNiVVIRSVN FT ;AFFYKLDIIPIDNDT;YKLDII
PID;AGSTMGAASMTLTVQ;MGAASMTLT;AKTIIVQLNTSVEIN;IVQ
LNTSVE ;AKTIIVQLNTSVEIN;VQLNTSVEI;AKWNNTLKQIASKLR;N
TLKQIASK;AKWNNTLKQIASKLR;TLKQIASKL;AKWNNTLKQIASKL
R;WNNTLKQIA;ALFLGFLGAAGSTMG;FLGFLGAAG;ALFLGFLGAA
GSTMGiFLGAAGSTMiALIWDDLRSLCLFSYiWDDLRSLCLiALKYW
WNLLQYWSQE;LKYWWNLLQ;ALKYWWNLLQYWSQE;WWNLLQ
YWSiALKYWWNLLQYWSQEiYWWNLLQYWiAMYAPPISGQIRCSS
;YAPPISGQI;AQQHLLQLTVWGIKQ;LLQLTVWGI;ARQLLSG IVQQQ
NNL;LLSGIVQQQ;ASLWNWFN ITNWLWYiLWNWFNITN ;ASLWNW
FN ITNWLWYiWFN ITNWLWiASLWNWFN ITNWLWYiWNWFN ITNW
;ASMTLTVQARQLLSG;LTVQARQLL;ATAIAVAEGTDRVIE;IAVAEG
TDRiATEKLWVTVYYGVPViEKLWVTVYYiATHACVPTDPNPQEViV
PTDPNPQEiATTTLFCASDAKAYDiFCASDAKAYiAVGIGALFLGFL
GAA;AVGIGALFL;AVLSIVNRVRQGYSP;LSIVNRVRQ;AVPWNASW
SNKSLEQiWNASWSNKSiAVSLLNATAIAVAEGiLLNATAIAViAYDT
EVHNVWATHACiVHNVWATHAiCGGEFFYCNSTQLFNiFYCNSTQ
LFiCLFSYHRLRDLLLIViYHRLRDLLLiCNISRAKWNNTLKQIiRAKW
NNTLKiCNNKTFNGTGPCTNViFNGTGPCTNiCNSTQLFNSTWFNS
TiLFNSTWFNSiCNTSVITQACPKVSFiITQACPKVSiCRAIRH IPRRI
RQGLiIRHIPRRIRiCRIKQIINMWQKVGKiIINMWQKVGiCRIKQIINM
WQKVGKiIKQIINMWQiCSFNISTSIRGKVQKiFNISTSIRGiCSGKLIC
TTAVPWNAiGKLICTTAViCSGKLICTTAVPWNAiLICTTAVPWiCSS
NITGLLLTRDGGiITGLLLTRDiCTDLKNDTNTNSSSGiLKNDTNTNS;
CTHGIRPVVSTQLLLiIRPVVSTQLiCTRPNNNTRKRIRIQiPNNNTR
KRIiCTTAVPWNASWSNKSiAVPWNASWSiCTTAVPWNASWSNKS iCTT AVPWNAiCTT AVPWNASWSNKSiTT AVPWNASiCTT AVPWN
ASWSNKSiVPWNASWSNiCVKLTPLCVSLKCTDiLTPLCVSLKiDDL
RSLCLFSYHRLRiLRSLCLFSYiDIISLWDQSLKPCVKiLWDQSLKPC
;DKW ASLWNWFN ITNW ;WASLWNWFN;DLLLIVTRIVELLGR;IVTRI
VELLiDLLLIVTRIVELLGRiLIVTRIVELiDLLLIVTRIVELLGRiLLIVTRI
VEiDLRSLCLFSYHRLRDiLRSLCLFSYiDMRDNWRSELYKYKViWR
SELYKYK;DNAKTIIVQLNTSVE;IIVQLNTSV;DNAKTIIVQLNTSVE;TI
IVQLNTS;DNWRSELYKYKVVKI;WRSELYKYK;DRDRSIRLVNGSL
AL;IRLVNGSLA;DREINNYTSLIHSLI;INNYTSLIH;DRSIRLVNGSLAL IWiIRLVNGSLAiDRSIRLVNGSLALIWiLVNGSLALIiDRVIEWQGAC
RAIRiWQGACRAIiDTEVHNVWATHACVPiVHNVWATHAiDTTSYK
LTSCNTSVIiSYKLTSCNTiDTTSYKLTSCNTSVIiYKLTSCNTSiEALK
YWWNLLQYWSQ;LKYWWNLLQ;EALKYWWNLLQYWSQ;WWNLL
QYWS;EALKYWWNLLQYWSQ;YWWNLLQYW;EAQQHLLQLTVW
GIKiLLQLTVWGIiEATTTLFCASDAKAYiLFCASDAKAiEDIISLWDQ
SLKPCViLWDQSLKPCiEEEVVIRSVNFTDNAiVVIRSVNFTiEEVVIR
SVNFTDNAKiVVIRSVNFTiEFFYCNSTQLFNSTWiFYCNSTQLFiEI
KNCSFNISTSIRGilKNCSFNISiEIKNCSFNISTSIRGiSFNISTSIRiEI
NCTRPNNNTRKRIiRPNNNTRKRiEINCTRPNNNTRKRIiTRPNNNT
RKiEINNYTSLIHSLIEEiYTSLIHSLIiEKGEIKNCSFNISTSiIKNCSFN I
S;EKRAVGIGALFLGFL;VGIGALFLG;EKYQHLWRWGWRWGT;LW
RWGWRWG;EKYQHLWRWGWRWGT;QHLWRWGWR;EKYQHLW
RWGWRWGT;YQHLWRWGW;ELDKW ASLWNWFN IT;W ASLWNW
FN;ELKNSAVSLLNATAI;LKNSAVSLL;ELLELDKW ASLWNWFiLDK
WASLWN;ELYKYKVVKIEPLGV;YKVVKIEPL;ELYKYKVVKIEPLGV;
YKYKVVKIE;ENFNMWKNDMVEQMH;FN MWKNDMViENFNMW KN
DMVEQMHiWKNDMVEQMiEPIPIHYCAPAGFAIiHYCAPAGFAiEPL
GVAPTKAKRRVV;VAPTKAKRR;EQELLELDKW ASLWNiLLELDKW
AS;EQFGNNKTIIFKQSS;FGNNKTIIF;EQIWNHTTWMEWDRE;IWN
HTTWMEiEVHNVWATHACVPTDiWATHACVPTiEVVIRSVNFTDNA
KTiVVIRSVN FTiEVVLVN VTENFNMWK;LVNVTENFN;EVVQGACR
AIRHIPRiVVQGACRAIiEWDREINNYTSLIHSiINNYTSLIHiEYAFFY
KLDIIPIDNiYKLDIIPIDiFAVLSIVNRVRQGYSiLSIVNRVRQiFAVLSI
VNRVRQGYS;VLSIVNRVR;FFYKLDIIPIDNDTT;YKLDIIPID;FGNNK
TIIFKQSSGG;FGNNKTIIF;FIMIVGGLVGLRIVF;IMIVGGLVG;FIMIV
GGLVGLRIVFiIVGGLVGLRiFIMIVGGLVGLRIVFiVGGLVGLRIiFLG
FLGAAGSTMGAA;FLGAAGSTM;FLGFLGAAGSTMGAA;LGAAGST
MGiFLGAAGSTMGAASMTiLGAAGSTMGiFNGTGPCTNVSTVQCiF
NGTGPCTNiFNISTSIRGKVQKEYiFNISTSIRGiFNITNWLWYIKLFI
M ;FN ITNWLWY;FN ITNWLWYI KLFIM;ITNWLWYIK;FNMW KNDMVE
QMHED;FNMWKNDMV;FNMWKNDMVEQMHED;WKNDMVEQM;F
NSTWFNSTWSTEGSiFNSTWSTEGiFNSTWFNSTWSTEGSiWFN
STWSTE;FNSTWSTEGSNNTEG;FNSTWSTEG;FNSTWSTEGSNN
TEG;WSTEGSNNT;FQTHLPTPRGPDRPE;FQTHLPTPR;FSYHRLR
DLLLIVTRiLRDLLLIVTiFVTIGKIGNMRQAHCiIGKIGNMRQiGACRA
IRHIPRRIRQiIRH IPRRIRiGALFLGFLGAAGSTMiFLGFLGAAGiGAL
FLGFLGAAGSTMiLGFLGAAGSiGCSGKLICTTAVPWNiGKLICTTA
ViGCSGKLICTTAVPWNiLICTTAVPWiGDMRDNWRSELYKYKiRD
NWRSELYiGEFFYCNSTQLFNSTiFYCNSTQLFiGEIKNCSFNISTSI
RiIKNCSFNISiGFAILKCNNKTFNGTiLKCNNKTFNiGFLGAAGSTM
GAASMiLGAAGSTMGiGGEFFYCNSTQLFNSiFYCNSTQLFiGGLV
GLRIVFAVLSIiLRIVFAVLSiGGLVGLRIVFAVLSIiVGLRIVFAViGIGA
LFLGFLGAAGS;FLGFLGAAG;GIKQLQARILAVERY;IKQLQARIL;GI
RPVVSTQLLLNGS;IRPVVSTQL;G IVQQQNNLLRAIEAiVQQQNNLL
RiGKAMYAPPISGQIRCiYAPPISGQIiGKLICTTAVPWNASWiICTTA
VPWNiGKLICTTAVPWNASWiLICTTAVPWiGLRIVFAVLSIVNRViF
AVLSIVNRiGLRIVFAVLSIVNRViLRIVFAVLSiGLVGLRIVFAVLSIViL
RIVFAVLSiGLVGLRIVFAVLSIViVGLRIVFAViGMLMICSATEKLWV
TiMICSATEKLiGRAFVTIGKIGNMRQiFVTIGKIGNiGSLALIWDDLR
SLCL;LIWDDLRSL;GSTMGAASMTLTVQA;MGAASMTLT;GTMLLG
MLMICSATEiLLGMLMICSiGVAPTKAKRRVVQREiPTKAKRRVViG
VAPTKAKRRVVQRE;VAPTKAKRR;GVPVW KEATTTLFCAiWKEAT
TTLF;GWEALKYWWNLLQYW;LKYWWNLLQ;GWRWGTMLLGMLM
ICiWGTMLLGMLiGWRWGTMLLGMLMICiWRWGTMLLGiGYSPLS
FQTHLPTPR;LSFQTHLPT;GYSPLSFQTHLPTPR;YSPLSFQTH;GA
AGSTMGAASMTLT;STMGAASMT;GAAGSTMGAASMTLT;TMGAA
SMTLiGAASMTLTVQARQLLiTLTVQARQLiHACVPTDPNPQEVVL; VPTDPNPQEiHCNISRAKWNNTLKQiRAKWNNTLKjHEDlISLWDQ
SLKPCiIISLWDQSLiHEDIISLWDQSLKPCiISLWDQSLKiHGIRPVV
STQLLLNG;IRPVVSTQL;HLLQLTVWGIKQLQA;LLQLTVWGI;HLW
RWGWRWGTMLLG;GWRWGTMLL;HLWRWGWRWGTMLLG;LWR
WGWRWG;HLWRWGWRWGTMLLG;WGWRWGTML;HNVWATHA
CVPTDPN;W ATHACVPTjHRLRDLLLIVTRIVEjLLLIVTRIVjHRLRDL
LLIVTRIVE;LRDLLLIVT;HTTWMEWDREINNYT;MEWDREINN ;IASK
LREQFGNNKTIjLREQFGNNKjlCTTAVPWNASWSNKjVPWNASWS
N;IEAQQHLLQLTVWGI;AQQHLLQLT;IEPLGVAPTKAKRRV;VAPTK
AKRRilEVVQGACRAIRHIPiVVQGACRAIjlGALFLGFLGAAGSTjFL
GFLGAAGjlGALFLGFLGAAGSTjLGFLGAAGSjlHYCAPAGFAILKC
NiYCAPAGFAIjllFKQSSGGDPEIVTjFKQSSGGDPillNMWQKVGKA
MYAP;INMWQKVGK;IINMWQKVGKAMYAP;MWQKVGKAM;IINMW
QKVGKAMYAPjWQKVGKAMYjllSLWDQSLKPCVKLjLWDQSLKPC jllVQLNTSVEINCTRilVQLNTSVEillVQLNTSVEINCTRjVQLNTSVEI ilKLFIMIVGGLVGLRjFIMIVGGLVjlKLFIMIVGGLVGLRjlKLFIMIVG;!
KLFIMIVGGLVGLRjIMIVGGLVGjIKNCSFNISTSIRGKjFNISTSIRG;!
KNCSFNISTSIRGKjlKNCSFNISilKQIINMWQKVGKAMjllNMWQKV
G;IKQIINMWQKVGKAM;INMWQKVGK;IKQLQARILAVERYL;IKQLQ
ARILjlMEKGEIKNCSFNISiEKGEIKNCSjlMIVGGLVGLRIVFAjlMIVG
GLVGilMIVGGLVGLRIVFAjlVGGLVGLRjlMIVGGLVGLRIVFAjVGG
LVGLRIilNCTRPNNNTRKRIRjPNNNTRKRIjlNCTRPNNNTRKRIRjT
RPNNNTRK;INMWQKVGKAMYAPP;MWQKVGKAM;INMWQKVGK
AMYAPPjWQKVGKAMYjlNNYTSLIHSLIEESiYTSLIHSLIjlPIHYCAP
AGFAILKjYCAPAGFAIilQRGPGRAFVTIGKIjlQRGPGRAFjlRCSSNI
TGLLLTRDjlRCSSNITGilRIQRGPGRAFVTIGjlQRGPGRAFjlRIQR
GPGRAFVTIG;IRIQRGPGR;IRLVNGSLALIWDDL;IRLVNGSLA;IRL
VNGSLALIWDDLjLVNGSLALIilRPVVSTQLLLNGSLilRPVVSTQLjlS
LWDQSLKPCVKLTjLWDQSLKPCjlSRAKWNNTLKQIASjRAKWNN
TLK;ISRAKWNNTLKQIAS;WNNTLKQIA;ITGLLLTRDGGNSNN;ITG
LLLTRDilTNWLWYIKLFIMIVjlTNWLWYIKjlTNWLWYIKLFIMIVjLW
YIKLFIMjlTNWLWYIKLFIMIViWYIKLFIMIjlTQACPKVSFEPIPIjlTQA
CPKVSjlVELLGRRGWEALKYjlVELLGRRGjlVELLGRRGWEALKY;
LLGRRGWEAjlVFAVLSIVNRVRQGjFAVLSIVNRjlVFAVLSIVNRVR
QGjLSIVNRVRQjlVFAVLSIVNRVRQGiVLSIVNRVRjlVGGLVGLRIV
FAVLjLVGLRIVFAilVGGLVGLRIVFAVLjVGLRIVFAVjlVNRVRQGY
SPLSFQjVRQGYSPLSilVQLNTSVEINCTRPjVQLNTSVEIjlVQQQN
NLLRAIEAQ;IVQQQNNLL;IVQQQNNLLRAIEAQ;VQQQNNLLR;IVT
RIVELLGRRGWEjlVELLGRRGjlVTRIVELLGRRGWEjTRIVELLGR;!
WDDLRSLCLFSYHRjLRSLCLFSYjlWNHTTWMEWDREINjlWNHTT
WMEjKAMYAPPISGQIRCSiYAPPISGQIjKAYDTEVHNVWATHAjTE
VHNVW AT;KCNNKTFNGTGPCTN;TFNGTGPCT;KCTDLKNDTNTN
SSS;LKNDTNTNS;KEKYQHLWRWGWRWG;QHLWRWGWR;KEKY
QHLWRWGWRWGiYQHLWRWGWjKEYAFFYKLDIIPIDjFYKLDIIPI iKEYAFFYKLDIIPIDjYAFFYKLDIjKGEIKNCSFNISTSIilKNCSFNIS;
KIEPLGVAPTKAKRRjLGVAPTKAKjKLFIMIVGGLVGLRIjlMIVGGLV
GiKLFIMIVGGLVGLRIjlVGGLVGLRjKLICTTAVPWNASWSjlCTTAV
PWNiKLICTTAVPWNASWSiLICTTAVPWjKLREQFGNNKTIIFKjFG
NNKTIIFjKLTSCNTSVITQACPjLTSCNTSVIjKLWVTVYYGVPVWKE iVTVYYGVPVjKNCSFNISTSIRGKVjFNISTSIRGjKNSAVSLLNATAI
AViVSLLNATAIjKPCVKLTPLCVSLKCiLTPLCVSLKjKQIINMWQKV
GKAMY;INMWQKVGK;KQIINMWQKVGKAMY;MWQKVGKAM;KRA
VGIGALFLGFLGjVGIGALFLGjKRIRIQRGPGRAFVTjlQRGPGRAF;
KRIRIQRGPGRAFVTjlRIQRGPGRjKSLEQIWNHTTWMEWjlWNHT
TWMEiKTFNGTGPCTNVSTViFNGTGPCTNjKTIIFKQSSGGDPEIjF
KQSSGGDPjKTIIVQLNTSVEINCilVQLNTSVEjKTIIVQLNTSVEINC;
VQLNTSVEIjKVGKAMYAPPISGQIjGKAMYAPPIjKVVKIEPLGVAPT
KA;IEPLGVAPT;KW ASLWNWFN ITNWL;WASLWNWFN;KWNNTLK QIASKLRE;LKQIASKLR;KYKVVKIEPLGVAPT;VKIEPLGVA;KYKVV
KIEPLGVAPT ;VVKIEPLGV;KYQHLWRWGWRWGTM;LWRWGWR
WG;KYQHLWRWGWRWGTM;QHLWRWGWR;KYWWNLLQYWSQ
ELK;KYWWNLLQY;KYWWNLLQYWSQELK;WNLLQYWSQ;KYWW
NLLQYWSQELK;YWWNLLQYW;LAEEEVVIRSVNFTD;VVIRSVNFT iLALlWDDLRSLCLFSiWDDLRSLCLjLCLFSYHRLRDLLLIjYHRLRD
LLL;LDKW ASLWNWFN ITN ;WASLWNWFN;LELDKW ASLWNWFNI;
WASLWNWFN;LEQIWNHTTWMEWDR;IWNHTTWME;LEQIWNHT
TWMEWDR;WNHTTWMEW;LFIMIVGGLVGLRIV;IMIVGGLVG;LFI
MIVGGLVGLRIVjVGGLVGLRIjLFLGFLGAAGSTMGAjFLGFLGAAG
;LFLGFLGAAGSTMGA;FLGAAGSTM;LFLGFLGAAGSTMGA;LGAA
GSTMG;LFNSTWFNSTWSTEG;FNSTWFNST;LFNSTWFNSTWST
EG;LFNSTWFNS;LFNSTWFNSTWSTEG;STWFNSTWS;LFNSTWF
NSTWSTEG;TWFNSTWST;LFNSTWFNSTWSTEG;WFNSTWSTE;
LFSYHRLRDLLLIVT;YHRLRDLLL;LGFLGAAGSTMGAAS;LGAAGS
TMGiLGMLMICSATEKLWVjMLMICSATEjLGVAPTKAKRRVVQRiP
TKAKRRVV;LGVAPTKAKRRVVQR;VAPTKAKRR;LGAAGSTMGAA
SMTLiLGAAGSTMGiLICTTAVPWNASWSNjLICTTAVPWjLICTTAV
PWNASWSNfTT AVPWNAS;LIVTRIVELLGRRGW;IVELLGRRG;LIV
TRIVELLGRRGWjTRIVELLGRjLIWDDLRSLCLFSYHjWDDLRSLCL iLKCTDLKNDTNTNSSiLKNDTNTNSjLKNSAVSLLNATAlAjLKNSAV
SLLiLKPCVKLTPLCVSLKiCVKLTPLCVjLKQIASKLREQFGNNjLKQ
IASKLR;LKYWWNLLQYWSQEL;LKYWWNLLQ;LKYWWNLLQYWS
QEL;YWWNLLQYW;LLELDKWASLWNWFN;LDKWASLWN;LLGML
MICSATEKLWjLLGMLMICSiLLIVTRIVELLGRRGilVTRIVELLjLLIVT
RIVELLGRRGiLLIVTRIVEjLLIVTRIVELLGRRGjTRIVELLGRjLLLIV
TRIVELLGRRiIVTRIVELLiLLLIVTRIVELLGRRiLIVTRIVELiLLLIVTR
IVELLGRRiLLIVTRIVEiLLLIVTRIVELLGRRiTRIVELLGRiLLNATAIA
VAEGTDRiLLNATAIAViLLQLTVWGIKQLQARiLLQLTVWGIiLLQY
WSQELKNSAVS;WSQELKNSA;LLQYWSQELKNSAVS;YWSQELK
NS;LLRAIEAQQHLLQLT;LRAIEAQQH;LLSGIVQQQNNLLRA;IVQQ
QNNLL;LLSGIVQQQNNLLRA;VQQQNNLLR;LNATAIAVAEGTDRV;
LNATAIAVA;LQLTVWGIKQLQARI;WGIKQLQAR;LQYWSQELKNS
AVSL;YWSQELKNS;LRAIEAQQHLLQLTV;LRAIEAQQH;LRDLLLIV
TRIVELLiLIVTRIVELjLRDLLLIVTRIVELLjLLIVTRIVEjLRDLLLIVTRI
VELLiLRDLLLIVTjLREQFGNNKTIIFKQiFGNNKTIIFjLRIVFAVLSIV
NRVRjFAVLSIVNRjLRIVFAVLSIVNRVRjLRIVFAVLSiLRIVFAVLSIV
NRVRiVFAVLSIVNjLRSLCLFSYHRLRDLjLRSLCLFSYiLSFQTHLP
TPRGPDR;FQTHLPTPR;LSFQTHLPTPRGPDR;QTHLPTPRG;LSGI
VQQQNNLLRAI;IVQQQNNLL;LSGIVQQQNNLLRAI;VQQQNNLLR;
LSIVNRVRQGYSPLSjlVNRVRQGYjLSIVNRVRQGYSPLSjRVRQG
YSPLiLSIVNRVRQGYSPLSiVNRVRQGYSiLTSCNTSVITQACPKjL
TSCNTSVIiLTVQARQLLSGIVQQiLTVQARQLLiLTVQARQLLSGIV
QQ;VQARQLLSG;LTVWGIKQLQARILA;IKQLQARIL;LTVWGIKQLQ
ARILAiWGIKQLQARiLVGLRIVFAVLSIVNiLRIVFAVLSiLVNGSLALI
WDDLRS;LVNGSLALI;LWNWFNITNWLWYIK;FNITNWLWY;LWNW
FNITNWLWYIKiWFN ITNWLW;LWRWGWRWGTMLLGM;GWRWG
TMLLiLWRWGWRWGTM LLG M; LW RWGW RWG; LW RWGW RWGT
MLLGM;WRWGTMLLG;LWVTVYYGVPVWKEA;YYGVPVWKE;LW
YIKLFIMIVGGLVilKLFIMIVGiLWYIKLFIMIVGGLViYIKLFIMIViLYKY
KVVKIEPLGVA;VVKIEPLGV;LYKYKVVKIEPLGVA;YKVVKIEPL;ME
KGElKNCSFNISTjlKNCSFNISiMEWDREINNYTSLIHjElNNYTSLIjM
EWDREINNYTSLIH;MEWDREINN ;MGAASMTLTVQARQL;MGAAS
MTLTjMHEDIISLWDQSLKPilSLWDQSLKjMIVGGLVGLRIVFAVilV
GGLVGLRjMIVGGLVGLRIVFAVjLVGLRIVFAjMIVGGLVGLRIVFAV iVGGLVGLRIjMLLGMLMICSATEKLjLLGMLMICSjMRDNWRSELYK
YKVViWRSELYKYKiMRVKEKYQHLWRWGWjMRVKEKYQHjMTLT
VQARQLLSGIViLTVQARQLLiMTLTVQARQLLSGIViVQARQLLSG; MWQKVGKAMYAPPIS;QKVGKAMYA;NAKTIIVQLNTSVEI;IIVQLNT
SViNAKTIIVQLNTSVEIiIVQLNTSVEiNATAIAVAEGTDRVIiTAIAVA
EGTjNCSFNISTSIRGKVQiFNISTSIRGiNCTRPNNNTRKRIRIjPNN
NTRKRI;NCTRPNNNTRKRIRI;TRPNNNTRK;NFNMWKNDMVEQM
HE;FNMWKNDMV;NFNMWKNDMVEQMHE;WKNDMVEQM;NHTT
WMEWDREINNY;MEWDREINN;N ISRAKWNNTLKQIA;AKWNNTLK
Q;NISRAKWNNTLKQIA;RAKWNNTLK;NITGLLLTRDGGNSN;ITGLL
LTRD;NITNWLWYIKLFIMI;ITNWLWYIK;NKSLEQIWNHTTWME;LE
QIWNHTTiNKTFNGTGPCTNVSTjFNGTGPCTNjNKTIIFKQSSGGD
PE;FKQSSGGDP;NLLQYWSQELKNSAV;LQYWSQELK;NLLQYWS
QELKNSAV;YWSQELKNS;NLLRAIEAQQHLLQL;LRAIEAQQH;NM
WQKVGKAMYAPPI;QKVGKAMYA;NMWQKVGKAMYAPPI;WQKV
GKAMYjNNKTFNGTGPCTNVSiFNGTGPCTNjNNKTIIFKQSSGGD
P;IFKQSSGGD;NNLLRAIEAQQHLLQ;LRAIEAQQH;NNTLKQIASKL
REQF;LKQIASKLR;NNTRKRIRIQRGPGR;TRKRIRIQR;NPQEVVLV
NVTENFNiVVLVNVTENjNRVRQGYSPLSFQTHjVRQGYSPLSiNSA
VSLLNATAIAVA;LLNATAIAV;NSTQLFNSTWFNSTW;FNSTWFNST
;NSTQLFNSTWFNSTW;LFNSTWFNS;NSTWFNSTWSTEGSN;FNS
TWSTEG;NSTWFNSTWSTEGSN;WFNSTWSTE;NSTWSTEGSNN
TEGS;WSTEGSNNT;NTLKQIASKLREQFG;LKQIASKLR;NTRKRIRI
QRGPGRAilRIQRGPGRjNTSVITQACPKVSFEjlTQACPKVSiNVTE
NFNMW KNDMVEjFNMWKNDMVjNVWATHACVPTDPNPjHACVPT
DPN;NVW ATHACVPTDPNPiWATHACVPTjNWFNITNWLWYIKLFjF
NITNWLWY;NWFNITNWLWYIKLF;ITNWLWYIK;NWFN ITNWLWYI
KLF;WFNITNWLW;NWLWYIKLFIMIVGG;IKLFIMIVG;NWLWYIKLFI
MIVGGiLWYIKLFIMjNWLWYIKLFIMIVGGjYIKLFIMIVjNWRSELYK
YKVVKIEjWRSELYKYKjPCRIKQIINMWQKVGilKQIINMWQiPCVKL
TPLCVSLKCTjLTPLCVSLKiPIHYCAPAGFAILKCiYCAPAGFAIjPIPI
HYCAPAGFAILiYCAPAGFAIiPLGVAPTKAKRRVVQiPTKAKRRVV;
PLGVAPTKAKRRVVQ;VAPTKAKRR;PLSFQTHLPTPRGPD;FQTHL
PTPR;PLSFQTHLPTPRGPD;QTHLPTPRG;PN PQEVVLVNVTENF;
VVLVN VTEN;PQEVVLVNVTENFNM;LVNVTENFN;PVVSTQLLLNG
SLAEiVSTQLLLNGiPVWKEATTTLFCASDiWKEATTTLFiPWNASW
SNKSLEQIW ;WNASWSNKS;QARQLLSGIVQQQNN;LLSGIVQQQ;
QCTHGIRPVVSTQLLiIRPVVSTQLiQELKNSAVSLLNATAiLKNSAV
SLLiQELLELDKW ASLWNWiLDKW ASLWNiQEVVLVNVTENFNMW
;LVN VTENFNiQFGNNKTIIFKQSSGiFGNNKTIIFiQGACRAIRHIPRR
IRiRAIRHIPRRiQHLLQLTVWGIKQLQiLLQLTVWGIiQHLWRWGW
RWGTMLL;LWRWGWRWG;QHLWRWGWRWGTMLL;QHLWRWG
WR;QHLWRWGWRWGTMLL;WGWRWGTML;Q IASKLREQFGNNK
T;LREQFGNNK;QIINMWQKVGKAMYA;INMWQKVGK;QIINMWQK
VGKAMYA;MWQKVGKAM ;QIINMWQKVGKAMYA;WQKVGKAMY;
QIWNHTTWMEWDREI;IWNHTTWME;QKVGKAMYAPPISGQ;GKA
MYAPPI;QLFNSTWFNSTWSTE;FNSTWFNST;QLFNSTWFNSTWS
TE;LFNSTWFNS;QLFNSTWFNSTWSTE;STWFNSTWS;QLLSGIVQ
QQNNLLR;IVQQQNNLL;QLTVWGIKQLQARIL;WGIKQLQAR;QNNL
LRAIEAQQHLLiLRAIEAQQHiQQHLLQLTVWGIKQLiLLQLTVWGIiQ
QNNLLRAIEAQQHL;LRAIEAQQH;QQQNNLLRAIEAQQH;LLRAIEA
QQ;QQQNNLLRAIEAQQH;NNLLRAIEA;QREKRAVGIGALFLG;AVG
IGALFLiQREKRAVGIGALFLGiRAVGIGALFiQSLKPCVKLTPLCVS;
CVKLTPLCViQTHLPTPRGPDRPEGiQTHLPTPRGiQYWSQELKNS
AVSLL;ELKNSAVSL;QYWSQELKNSAVSLL;WSQELKNSA;RAFVTI
GKIGNMRQA;FVTIGKIGN;RAIRHIPRRIRQGLE;IRHIPRRIR;RAKW
NNTLKQIASKLiWNNTLKQIAiRAVGIGALFLGFLGAiVGIGALFLGiR
CSSNITGLLLTRDGiITGLLLTRDiRDLLLIVTRIVELLGiLIVTRIVELiR
DLLLIVTRIVELLGiLLIVTRIVEiRDLLLIVTRIVELLGiLLLIVTRIViRDN
WRSELYKYKVVK;WRSELYKYK;RDRDRSIRLVNGSLA;DRSIRLVN
GiRDRSIRLVNGSLALIilRLVNGSLAjREINNYTSLIHSLIEjINNYTSLI HiREINNYTSLIHSLIEiYTSLIHSLIiREKRAVGIGALFLGFiVGIGALFL
G;REQFGNNKTIIFKQS;FGNNKTIIF;RGWEALKYWWNLLQY;LKYW
WNLLQ;RIKQIINMWQKVGKA;IINMWQKVG;RIKQIINMWQKVGKA;I
NMWQKVGK;RIQRGPGRAFVTIGK;IQRGPGRAF;RIRIQRGPGRAF
VTIjlQRGPGRAFjRIRIQRGPGRAFVTlilRIQRGPGRjRIVELLGRRG
WEALK;IVELLGRRG;RIVFAVLSIVNRVRQ;FAVLSIVNR;RIVFAVLSI
VNRVRQiVLSIVNRVRjRKRIRIQRGPGRAFVjlQRGPGRAFjRKRIRI
QRGPGRAFVjlRIQRGPGRiRLRDLLLIVTRIVELjLLIVTRIVEjRLRDL
LLIVTRIVELiLLLIVTRIVjRLRDLLLIVTRIVELjLRDLLLIVTjRLVNGSL
ALIWDDLR;VNGSLALIW;RPVVSTQLLLNGSLA;VVSTQLLLN;RQG
YSPLSFQTHLPT ;YSPLSFQTH;RQLLSGIVQQQNNLL;LLSGIVQQQ
;RQLLSGIVQQQNNLL;LSGIVQQQN;RRGWEALKYWWNLLQ;RRG
WEALKY;RRGWEALKYWWNLLQ;WEALKYWWN;RSELYKYKVVKI
EPLiLYKYKVVKliRSELYKYKVVKIEPLjYKYKVVKIEjRSIRLVNGSL
ALIWDilRLVNGSLAjRSIRLVNGSLALIWDjLVNGSLALIjRVIEVVQG
ACRAIRHiVVQGACRAIjRVKEKYQHLWRWGWRjYQHLWRWGW;
RVRQGYSPLSFQTHLjVRQGYSPLSjRWGTMLLGMLMICSAjLLGM
LMICSiRWGTMLLGMLMICSAjWGTMLLGMLjRWGWRWGTMLLG
MLM;WGTMLLGML;RWGWRWGTMLLGMLM;WRWGTMLLG;SAV
SLLNATAIAVAEjLLNATAIAViSCNTSVITQACPKVSiVITQACPKVjS
ELYKYKVVKIEPLGjYKVVKIEPLjSFNISTSIRGKVQKEjFNISTSIRG;
SFQTHLPTPRGPDRPjFQTHLPTPRjSFQTHLPTPRGPDRPjQTHL
PTPRGiSGIVQQQNNLLRAIEjlVQQQNNLLjSGIVQQQNNLLRAIEjV
QQQNNLLRjSGKLICTTAVPWNASilCTTAVPWNjSGKLICTTAVPW
NASiLICTTAVPWiSIRLVNGSLALIWDDjlRLVNGSLAjSIRLVNGSLA
LIWDD;LVNGSLALI;SIVNRVRQGYSPLSF;IVNRVRQGY;SIVNRVR
QGYSPLSFjVRQGYSPLSiSKLREQFGNNKTIIFjLREQFGNNKiSKL
REQFGNNKTIIFjQFGNNKTIliSLAEEEVVIRSVNFTjEEVVIRSVNiS
LAEEEVVIRSVN FTjEVVIRSVNFjSLALIWDDLRSLCLFjWDDLRSL
CLiSLCLFSYHRLRDLLLjFSYHRLRDLiSLEQIWNHTTWMEWDjlW
NHTTWMEjSLEQIWNHTTWMEWDjWNHTTWMEWjSLKCTDLKND
TNTNSiDLKNDTNTNjSLKPCVKLTPLCVSLjVKLTPLCVSiSLLNATA lAVAEGTDjLLNATAIAViSLWDQSLKPCVKLTPjLWDQSLKPCiSLW
NWFNITNWLWYIjFNITNWLWYiSLWNWFNITNWLWYIjWFNITNW
LWiSLWNWFNITNWLWYIjWNWFNITNWiSMTLTVQARQLLSGljLT
VQARQLL;SMTLTVQARQLLSGI;VQARQLLSG;SN ITGLLLTRDGG
NSilTGLLLTRDjSPLSFQTHLPTPRGPjFQTHLPTPRjSPLSFQTHLP
TPRGP;QTHLPTPRG;SQELKNSAVSLLNAT;LKNSAVSLL;SRAKW
NNTLKQIASKjWNNTLKQIAjSSNITGLLLTRDGGNjlTGLLLTRDiST
MGAASMTLTVQAR;MGAASMTLT;STQLFNSTWFNSTWS;FNSTW
FNST;STQLFNSTWFNSTWS;LFNSTWFNS;STQLLLNGSLAEEEV;
LLLNGSLAEiSTVQCTHGIRPVVSTiTHGIRPVVSiSTWFNSTWSTE
GSNN;FNSTWSTEG;STWFNSTWSTEGSNN;WFNSTWSTE;STWS
TEGSNNTEGSDjWSTEGSNNTjSVEINCTRPNNNTRKjINCTRPNN
NiSVITQACPKVSFEPIjlTQACPKVSiSYHRLRDLLLIVTRIjLRDLLLI
VTiSYKLTSCNTSVITQAjLTSCNTSVIiTAIAVAEGTDRVIEVjIAVAE
GTDR;TAVPWNASWSNKSLE;VPWNASWSN;TAVPWNASWSNKS
LEjWNASWSNKSiTDLKNDTNTNSSSGRjLKNDTNTNSiTDNAKTIIV
QLNTSViAKTIIVQLNjTDRVIEVVQGACRAIiEVVQGACRAjTENFN
MWKNDMVEQM;FNMWKNDMV;TENFNMWKNDMVEQM;MWKND
MVEQjTEVHNVWATHACVPTjVHNVWATHAjTFNGTGPCTNVSTV
QiFNGTGPCTNiTHACVPTDPNPQEVVjVPTDPNPQEjTHGIRPVVS
TQLLLNilRPVVSTQLjTIIFKQSSGGDPEIViFKQSSGGDPjTIIVQLN
TSVEINCTilVQLNTSVEjTIIVQLNTSVEINCTiVQLNTSVEIjTLFCAS
DAKAYDTEViFCASDAKAYiTLKQIASKLREQFGNjLKQIASKLRjTLT
VQARQLLSGIVQjLTVQARQLLjTLTVQARQLLSGIVQjVQARQLLS
GiTMGAASMTLTVQARQjMGAASMTLTjTMLLGMLMICSATEKjLLG
MLMICSiTNWLWYIKLFIMIVGiLWYIKLFIMjTNWLWYIKLFIMIVGiW LWYIKLFI;TNWLWYIKLFIMIVG;YIKLFIMIV;TQLFNSTWFNSTWST;
FNSTWFNST;TQLFNSTWFNSTWST;LFNSTWFNS;TQLFNSTWFN
STWST;STWFNSTWS;TRIVELLGRRGWEAL;IVELLGRRG;TRIVEL
LGRRGWEAL;TRIVELLGR;TRKRIRIQRGPGRAF;IRIQRGPGR;TR
KRIRIQRGPGRAFjRKRIRIQRGjTRPNNNTRKRIRIQRjPNNNTRKRI iTSVITQACPKVSFEPilTQACPKVSjTSYKLTSCNTSVITQjLTSCNT
SVI;TTAVPWNASWSNKSL;VPWNASWSN;TT AVPWNASWSNKSL;
WNASWSNKSjTTLFCASDAKAYDTEjFCASDAKAYjTTSYKLTSCN
TSVITiLTSCNTSVIjTTSYKLTSCNTSVITjYKLTSCNTSiTTTLFCAS
DAKAYDTiFCASDAKAYjTTWMEWDREINNYTSiMEWDREINNjTV
QARQLLSGIVQQQjVQARQLLSGjTVQCTHGIRPVVSTQjTHGIRPV
VSiTVWGIKQLQARILAVjlKQLQARILjTVWGIKQLQARILAVjWGIKQ
LQAR;TVYYGVPVWKEATTT;YYGVPVWKE;TWFNSTWSTEGSNN
T;FNSTWSTEG;TWMEWDREINNYTSL;MEWDREINN;VAPTKAKR
RVVQREK;PTKAKRRVV;VAPTKAKRRVVQREK;VAPTKAKRR;VEI
NCTRPNNNTRKRjTRPNNNTRKjVFAVLSIVNRVRQGYjLSIVNRVR
Q ;VFAVLS IVN RVRQG Y;VFAVLS IVN ; VFAVLS IVN RVRQG Y;VLS IV
NRVRjVGGLVGLRIVFAVLSiLVGLRIVFAjVGGLVGLRIVFAVLSjVG
LRIVFAVjVGIGALFLGFLGAAGjlGALFLGFLjVGIGALFLGFLGAAG;
LFLGFLGAAjVGKAMYAPPISGQIRjYAPPISGQIjVGLRIVFAVLSIVN
R;IVFAVLSIV;VGLRIVFAVLSIVNR;LRIVFAVLS;VHNVW ATHACVP
TDP;W ATHACVPT iVIEVVQGACRAIRHIjVVQGACRAIjVITQACPKV
SFEPIPjlTQACPKVSiVKEKYQHLWRWGWRWjQHLWRWGWRjVK lEPLGVAPTKAKRjlEPLGVAPTjVKIEPLGVAPTKAKRjLGVAPTKAK iVKLTPLCVSLKCTDLjLTPLCVSLKjVLSIVNRVRQGYSPLjlVNRVR
QGY;VNGSLALIWDDLRSL;VNGSLALIW;VNRVRQGYSPLSFQT;V
RQGYSPLS;VNVTENFNMWKNDMV;NFNMWKNDM;VNVTENFNM
WKNDMVjTENFNMWKNjVPVWKEATTTLFCASiWKEATTTLFjVPW
NASWSNKSLEQI;WNASWSNKS;VQARQLLSGIVQQQN;VQARQLL
SGiVQCTHGIRPVVSTQLjTHGIRPVVSiVQLNTSVEINCTRPNjVQL
NTSVEI;VQQQNNLLRAIEAQQ;VQQQNNLLR;VQREKRAVGIGALF
LjVQREKRAVGiVRQGYSPLSFQTHLPjVRQGYSPLSjVSLLNATAIA
VAEGTiLLNATAIAVjVSTQLLLNGSLAEEEjLLLNGSLAEjVSTVQCT
HGIRPVVS;VQCTHGIRP;VTENFNMWKNDMVEQ;FNMW KNDMV;
VTIGKIGNMRQAHCNjlGNMRQAHCjVTRIVELLGRRGWEAjlVELL
GRRG;VTRIVELLGRRGWEA;TRIVELLGR;VTVYYGVPVWKEATT;
YYG VPVW KE ;VVI RSVN FTDN AKTI ;VVI RSVN FT;VVKI EPLG VAPTK
AK;IEPLGVAPT;VVKIEPLGVAPTKAK;VKIEPLGVA;VVLVNVTENF
NMWKNiLVNVTENFNjVVSTQLLLNGSLAEEjSTQLLLNGSjVWATH
ACVPTDPNPQiHACVPTDPNjVWGIKQLQARILAVEjlKQLQARILjV
WGIKQLQARILAVE;WGIKQLQAR;VWKEATTTLFCASDA;W KEATT
TLF;VYYGVPVWKEATTTL;PVWKEATTT;VYYGVPVWKEATTTL;Y
YGVPVWKE ;W ASLWNWFN ITNWLW;ASLWNWFNI;WASLWNWFN
ITNWLWiWASLWNWFNjWATHACVPTDPNPQEjHACVPTDPNjWD
DLRSLCLFSYHRLjLRSLCLFSYjWDREINNYTSLIHSLjlNNYTSLIH ;
WEALKYWWNLLQYWS;LKYWWNLLQ;WEALKYWWNLLQYWS;Y
WWNLLQYW;WFN ITNWLWYI KLFI;FNITNWLWY;WFN ITNWLWYIK
LFI;ITNWLWYIK;WFNITNWLWYIKLFI;WFNITNWLW;WFNSTWSTE
GSNNTEjFNSTWSTEGiWFNSTWSTEGSNNTEjNSTWSTEGSjWF
NSTWSTEGSNNTE;WSTEGSNNT;WGCSG KLICTT AVPW;WGCS
GKLICiWGIKQLQARILAVERjlKQLQARILjWGTMLLGMLMICSATjL
GMLMICSAjWGTMLLGMLMICSATjLLGMLMICSjWGWRWGTMLL
GMLMI;WGTMLLGML;WGWRWGTMLLGMLMI;WRWGTMLLG;WK
EATTTLFCASDAKjWKEATTTLFjWLWYIKLFIMIVGGLjlKLFIMIVG;
WLWYIKLFIMIVGGLjYIKLFIMIVjWMEWDREINNYTSLIjMEWDREI
NN;WNASWSNKSLEQIWN;WNASWSNKS;WNHTTWMEWDREINN
;WMEWDREIN;WNLLQYWSQELKNSA;LQYWSQELK;WNLLQYWS
QELKNSA;YWSQELKNS;WNNTLKQIASKLREQ;LKQIASKLR;WNW FNITNWLWYIKL;FNITNWLWY;WNWFNITNWLWYIKL;ITNWLWYIK
;WNWFNITNWLWYIKL;WFNITNWLW;WQKVGKAMYAPPISG;GKA
MYAPPI;WRSELYKYKVVKIEP;WRSELYKYK;WRWGTMLLGMLMI
CSiWGTMLLGMLjWRWGTMLLGMLMICSiWRWGTMLLGjWRWG
WRWGTMLLGML;WGWRWGTML;WRWGWRWGTMLLGML;WRW
GTMLLG;WSQELKNSAVSLLNA;LKNSAVSLL;WVTVYYGVPVWKE
AT;YYGVPVWKE;WWNLLQYWSQELKNS;LLQYWSQEL;WWNLLQ
YWSQELKNSiLQYWSQELKiWYIKLFIMIVGGLVGjFIMIVGGLVjWYI
KLFIMIVGGLVGilKLFIMIVGjYAFFYKLDIIPIDNDiYKLDIIPIDjYCNS
TQLFNSTWFNSjTQLFNSTWFjYDTEVHNVWATHACVjVHNVWAT
HAiYGVPVWKEATTTLFCiWKEATTTLFjYHRLRDLLLIVTRIVjLRDL
LLIVTjYIKLFIMIVGGLVGLjFIMIVGGLViYIKLFIMIVGGLVGLjlKLFIM
IVGiYIKLFIMIVGGLVGLjIMIVGGLVGiYKLTSCNTSVITQACjLTSCN
TSVIiYKWKIEPLGVAPTKiIEPLGVAPTiYKWKIEPLGVAPTKiVKIE
PLGVAiYKYKVVKIEPLGVAPiVVKIEPLGVjYKYKVVKIEPLGVAPjY
KVVKIEPL;YQHLWRWGWRWGTML;LWRWGWRWG;YQHLWRW
GWRWGTML;QHLWRWGWR;YQHLWRWGWRWGTML;WRWGW
RWGT;YSPLSFQTHLPTPRG;FQTHLPTPR;YSPLSFQTHLPTPRG;
SFQTHLPTP;YWSQELKNSAVSLLN;LKNSAVSLL;YWWNLLQYWS
QELKNiLQYWSQELKjYWWNLLQYWSQELKNjYWWNLLQYWiYY
GVPVWKEATTTLF;VWKEATTTL;YYGVPVWKEATTTLF;YYGVPV
WKE;AAGSTMGAASMTLTV;MGAASMTLT;AASMTLTVQARQLLS;
LTVQARQLL
NP_057857 8-mer 9109-9568 Nef GKWSKSSV;KWSKSSVI;SVIGWPTV;VIGWPTVR;WPTVRERM;TV
RERMRR;RMRRAEPA;AEPAADRV;AASRDLEK;NTAATNAA;ATNA
ACAWiTNAACAWLiQEEEEVGFjEEEVGFPViEEVGFPVTjFPVTPQ
VP;PVTPQVPL;VTPQVPLR;VPLRPMTY;PLRPMTYK;RPMTYKAA;
PMTYKAAV;TYKAAVDL;AAVDLSHF;AVDLSHFL;LSHFLKEK;FLKE
KGGL;RRQDILDL;DILDLWIY;ILDLWIYH;DLWIYHTQ;WIYHTQGY;I
YHTQG YF;YFPDWQNY;FPDWQNYT;NYTPGPGV;YTPG PGVR;TP
GPG VRY;GPG VRYPLiGVRYPLTFjRYPLTFGWjYPLTFGWCiLTFG
WCYKiTFGWCYKLjFGWCYKLViWCYKLVPViVPVEPDKIjNTSLLH
PV;SLLHPVSL;LLHPVSLH ;HPVSLHGM;HGMDDPER;PEREVLEW;
REVLEWRF;RFDSRLAF;SRLAFHHV;RLAFHHVA;LAFHHVAR;FHH
VAREL;RELHPEYF;ELHPEYFK
9-mer
WSKSSVIGW;SSVIGWPTV;SVIGWPTVR;PTVRERMRR;TVRERM
RRA;RMRRAEPAA;RRAEPAADR;RAEPAADRV;EPAADRVGA;GA
ASRDLEKiNTAATNAACiTAATNAACAjAATNAACAWiATNAACAWL
;NAACAWLEA;AQEEEEVGF;EEEEVGFPV;VGFPVTPQV;FPVTPQ
VPL;PVTPQVPLR;TPQVPLRPM;QVPLRPMTY;VPLRPMTYK;PLRP
MTYKAiRPMTYKAAViMTYKAAVDLjKAAVDLSHFiAAVDLSHFLjAV
DLSHFLK;DLSHFLKEK;HFLKEKGGL;KEKGGLEGL;GLEGLIHSQ;R
QDILDLWI;ILDLWIYHT;LWIYHTQGY;W IYHTQGYFiHTQG YFPDW;
GYFPDWQNY;FPDWQNYTP;NYTPGPGVR;YTPGPGVRY;VRYPL
TFGWiYPLTFGWCYiPLTFGWCYKjLTFGWCYKLiKLVPVEPDKjEN
TSLLHPV;GMDDPEREV;DPEREVLEW;EVLEWRFDS;VLEWRFDS
R;LEWRFDSRL;WRFDSRLAF;RFDSRLAFH;DSRLAFHHV;RLAFH
HVAR;AFHHVAREL;VARELHPEY;RELHPEYFK
10-mer
KWSKSSVIGWjKSSVIGWPTViSSVIGWPTVRjVIGWPTVRERjAEP
AADRVGAiEPAADRVGAAjNTAATNAACAjTAATNAACAWjWLEAQ
EEEEV;EAQEEEEVGF;EVGFPVTPQV;FPVTPQVPLR;VTPQVPLR
PM;PQVPLRPMTY;QVPLRPMTYK;VPLRPMTYKA;PLRPMTYKAA;
RPMTYKAAVD;MTYKAAVDLS;KAAVDLSHFL;AAVDLSHFLK;GLE GLIHSQRiIHSQRRQDILiRRQDILDLWIiRQDILDLWIYiDILDLWIYHT
;ILDLWIYHTQ;DLWIYHTQGY;LWIYHTQGYF;FPDWQNYTPG;WQ
NYTPG PGV;NYTPG PGVRY ;TPGPGVRYPL;GPGVRYPLTF;RYPLT
FGWCYiYPLTFGWCYKiPLTFGWCYKLjLTFGWCYKLViFGWCYKL
VPViKLVPVEPDKIiGENTSLLHPViNTSLLHPVSLiLLHPVSLHGMiS
LHGMDDPER;HGMDDPEREV;GMDDPEREVL;PEREVLEWRF;EV
LEWRFDSR;VLEWRFDSRL;EWRFDSRLAF;WRFDSRLAFH;SRLA
FHHVAR;LAFHHVAREL;HVARELHPEY
1 1 -mer
SKSSVIGWPTV;KSSVIGWPTVR;SVIGWPTVRER;WPTVRERMRR
A;RMRRAEPAADR;AEPAADRVGAA;EPAADRVGAAS;RVGAASRD
LEKiTSSNTAATNAAjNTAATNAACAWjTAATNAACAWLjLEAQEEE
EVGF;AQEEEEVGFPV;EEVGFPVTPQV;FPVTPQVPLRP;PVTPQV
PLRPM;TPQVPLRPMTY;QVPLRPMTYKA;VPLRPMTYKAA;PLRPM
TYKAAV;RPMTYKAAVDL;MTYKAAVDLSH;TYKAAVDLSHF;YKAA
VDLSHFLjKAAVDLSHFLKjAVDLSHFLKEKjFLKEKGGLEGLiGLIHS
QRRQDI;RRQDILDLWIY;DILDLWIYHTQ;ILDLWIYHTQG;LDLWIYH
TQGY;IYHTQGYFPDW;FPDWQNYTPGP;WQNYTPGPGVR;YTPG
PGVRYPLjVRYPLTFGWCYiRYPLTFGWCYKjYPLTFGWCYKLjPLT
FGWCYKLViCYKLVPVEPDKjVPVEPDKIEEAjSLLHPVSLHGMjHG
MDDPEREVL;GMDDPEREVLE;DPEREVLEWRF;EVLEWRFDSRL;
VLEWRFDSRLA;LEWRFDSRLAF;WRFDSRLAFHH;RFDSRLAFHH
V;DSRLAFHHVAR;RLAFHHVAREL;HVARELHPEYF;VARELHPEY
FK
15-mer + 9-mer core
ADRVGAASRDLEKHG;RVGAASRDL;AEPAADRVGAASRDL;AADR
VGAASiAITSSNTAATNAACAjlTSSNTAATjASRDLEKHGAITSSNjL
EKHGAITSjCYKLVPVEPDKIEEAjYKLVPVEPDjDDPEREVLEWRF
DSR;PEREVLEWR;DLEKHGAITSSNTAA;LEKHGAITS;DPEREVLE
WRFDSRL;VLEWRFDSR;DSRLAFHHVARELHP;FHHVARELH;DW
QNYTPGPGVRYPL;YTPGPGVRY;EEVGFPVTPQVPLRP;GFPVTP
QVPjEEVGFPVTPQVPLRPiVGFPVTPQVjEKHGAITSSNTAATNjlT
SSNTAAT;ENTSLLHPVSLHGMD;LHPVSLHGM;ENTSLLHPVSLHG
MD;LLHPVSLHG;EPAADRVGAASRDLE;RVGAASRDL;EREVLEW
RFDSRLAF;LEWRFDSRL;EREVLEWRFDSRLAF;VLEWRFDSR;ER
MRRAEPAADRVGA;MRRAEPAAD;EVGFPVTPQVPLRPM;VTPQV
PLRP;EVLEWRFDSRLAFHH;VLEWRFDSR;EVLEWRFDSRLAFHH
;WRFDSRLAF;EWRFDSRLAFHHVAR;WRFDSRLAF;FDSRLAFHH
VARELH iFDSRLAFHHiFGWCYKLVPVEPDKIiYKLVPVEPDiFPDW
QNYTPGPGVRY;FPDWQNYTP;FPDWQNYTPGPGVRY;WQNYTP
GPGjFPVTPQVPLRPMTYKjVTPQVPLRPjGAITSSNTAATNAACilT
SSNTAAT;GENTSLLHPVSLHGM;LLHPVSLHG;GFPVTPQVPLRPM
TYjVTPQVPLRPiGWCYKLVPVEPDKIEjYKLVPVEPDjGYFPDWQN
YTPGPGV;FPDWQNYTP;GYFPDWQNYTPGPGV;WQNYTPGPG;H
GAITSSNTAATNAA;ITSSNTAAT;HTQGYFPDWQNYTPG;QGYFPD
WQN;HTQGYFPDWQNYTPG;YFPDWQNYT;ITSSNTAATNAACAW
;ITSSNTAAT;IYHTQGYFPDWQNYT;GYFPDWQNY;IYHTQGYFPD
WQNYT;QGYFPDWQN;KGENTSLLHPVSLHG;NTSLLHPVS;KGEN
TSLLHPVSLHGiSLLHPVSLHjKHGAITSSNTAATNAjlTSSNTAATjK
SSVIGWPTVRERMR;VIGWPTVRE;KWSKSSVIGWPTVRE;KSSVI
GWPT;KWSKSSVIGWPTVRE;KWSKSSVIG;LAFHHVARELHPEYF;
FHHVARELHjLEKHGAITSSNTAATjGAITSSNTAjLEKHGAITSSNTA
AT;HGAITSSNT;LEWRFDSRLAFHHVA;WRFDSRLAF;LHPVSLHG
MDDPERE;LHGMDDPER;LHPVSLHGMDDPERE;LHPVSLHGM;LL
HPVSLHGMDDPER;LHPVSLHGM;LLHPVSLHGMDDPER;LLHPVS
LHGiLRPMTYKAAVDLSHFiMTYKAAVDLjLTFGWCYKLVPVEPDiG WCYKLVPViMGGKWSKSSVIGWPTjMGGKWSKSSiMTYKAAVDLS
HFLKE;MTYKAAVDL;NTSLLHPVSLHGMDD;LHPVSLHGM;NTSLL
HPVSLHGMDD;LLHPVSLHG;NYTPGPGVRYPLTFG;YTPGPGVRY
;PDWQNYTPGPGVRYP;WQNYTPGPG;PDWQNYTPGPGVRYP;Y
TPGPGVRY;PEREVLEWRFDSRLA;VLEWRFDSR;PLRPMTYKAAV
DLSH;MTYKAAVDL;PMTYKAAVDLSHFLK;MTYKAAVDL;PQVPLR
PMTYKAAVD;LRPMTYKAA;PTVRERMRRAEPAAD;ERMRRAEPA;
PVTPQVPLRPMTYKA;VPLRPMTYK;PVTPQVPLRPMTYKA;VTPQ
VPLRP;PAADRVGAASRDLEK;RVGAASRDL;QGYFPDWQNYTPG
PG;QGYFPDWQN;QG YFPDWQNYTPG PG;YFPDWQNYT;QNYTP
GPGVRYPLTF;YTPGPGVRY;QVPLRPMTYKAAVDL;LRPMTYKAA;
RDLEKHGAITSSNTA;LEKHGAITS;RERMRRAEPAADRVG;MRRAE
PAAD;REVLEWRFDSRLAFH;VLEWRFDSR;REVLEWRFDSRLAFH
;WRFDSRLAF;RLAFHHVARELHPEY;FHHVARELH;RPMTYKAAVD
LSHFL;MTYKAAVDL;SKSSVIGWPTVRERM;VIGWPTVRE;SLLHPV
SLHGMDDPE;LHPVSLHGM;SLLHPVSLHGMDDPE;LLHPVSLHG;S
RDLEKHGAITSSNT;LEKHGAITS;SRLAFHHVARELHPE;FHHVARE
LH;SSVIGWPTVRERMRR;VIGWPTVRE;SVIGWPTVRERMRRA;VI
GWPTVRE;TFGWCYKLVPVEPDK;YKLVPVEPD;TPQVPLRPMTYK
AAV;LRPMTYKAA;TPQVPLRPMTYKAAV;VPLRPMTYK;TQGYFPD
WQNYTPGP;QGYFPDWQN;TQGYFPDWQNYTPGP;YFPDWQNYT
;TSLLHPVSLHGMDDP;LHPVSLHGM;TSLLHPVSLHGMDDP;LLHP
VSLHG;TVRERMRRAEPAADR;MRRAEPAAD;VGFPVTPQVPLRP
MT;VTPQVPLRP;VIGWPTVRERMRRAE;VIGWPTVRE;VLEWRFD
SRLAFHHV;VLEWRFDSR;VLEWRFDSRLAFHHV;WRFDSRLAF;V
PLRPMTYKAAVDLS;LRPMTYKAA;VRERMRRAEPAADRV;MRRAE
PAAD;VTPQVPLRPMTYKAA;VPLRPMTYK;VTPQVPLRPMTYKAA;
VTPQVPLRPjWCYKLVPVEPDKIEEjYKLVPVEPDjWQNYTPGPGV
RYPLT ;YTPGPGVRY;WRFDSRLAFHHVARE;WRFDSRLAF;WSKS
SVIGWPTVRER;VIGWPTVRE;YFPDWQNYTPGPGVR;WQNYTPG
PG;YHTQGYFPDWQNYTP;QGYFPDWQN;YHTQGYFPDWQNYTP
;YFPDWQNYT;YKLVPVEPDKIEEAN;YKLVPVEPD;YTPGPGVRYP
LTFGW;YTPGPGVRY;AADRVGAASRDLEKH;RVGAASRDL;AASR
DLEKHGAITSS;LEKHGAITS
In another embodiment the antigenic peptide(s) include one or more of the following peptides IVDCLTEMY (SEQ ID NO 9588), VTDFSVIK ( SEQ ID NO 9589), GLIQLVEGV (SEQ ID NO 9590), RIAAWMATY ( SEQ ID NO 9591 ), EYRALQLHL (SEQ ID NO 9592) or any variant or fragment thereof such as antigenic peptides comprising the core sequences listed above or variants thereof.
The present invention further relates to one or more antigenic peptides such as the antigenic peptides disclosed in this application, wherein the one or more antigenic peptides have one or more amino acid substitutions such as 1 , 2, 3, 4, 5, 6, 7, or 8.
In a preferred embodiment these amino acid substitutions comprise substitution with an "equivalent amino acid residue". An "equivalent amino acid residue" refers to an amino acid residue capable of replacing another amino acid residue in a polypeptide without substantially altering the structure and/or functionality of the polypeptide. Equivalent amino acids thus have similar properties such as bulkiness of the side-chain, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain organization of carbon molecules (aromatic/aliphatic). As such, "equivalent amino acid residues" can be regarded as "conservative amino acid substitutions".
The classification of equivalent amino acids refers in one embodiment to the following classes: 1 ) HRK, 2) DENQ, 3) C, 4) STPAG, 5) MILV and 6) FYW.
Within the meaning of the term "equivalent amino acid substitution" as applied herein, one amino acid may be substituted for another, in one embodiment, within the groups of amino acids indicated herein below:
Amino acids having polar side chains (Asp, GIu, Lys, Arg, His, Asn, GIn, Ser, Thr, Tyr, and Cys,)
Amino acids having non-polar side chains (GIy, Ala, VaI, Leu, lie, Phe, Trp, Pro, and
Met)
Amino acids having aliphatic side chains (GIy, Ala VaI, Leu, lie)
Amino acids having cyclic side chains (Phe, Tyr, Trp, His, Pro) Amino acids having aromatic side chains (Phe, Tyr, Trp)
Amino acids having acidic side chains (Asp, GIu)
Amino acids having basic side chains (Lys, Arg, His)
Amino acids having amide side chains (Asn, GIn)
Amino acids having hydroxy side chains (Ser, Thr) Amino acids having sulphor-containing side chains (Cys, Met),
Neutral, weakly hydrophobic amino acids (Pro, Ala, GIy, Ser, Thr)
Hydrophilic, acidic amino acids (GIn, Asn, GIu, Asp), and
Hydrophobic amino acids (Leu, lie, VaI)
A Venn diagram is another method for grouping of amino acids according to their properties (Livingstone & Barton, CABIOS, 9, 745-756, 1993). In another preferred embodiment one or more amino acids may be substituted with another within the same Venn diagram group.
The present invention also relates to a group of peptides called nonsense peptides. A nonsense peptide is here to be understood as a peptide that binds the MHC protein efficiently, but that does not support binding of the resultant MHC-peptide complex to the desired TCR. An example nonsense peptide is a peptide with an amino acid sequence different from the linear sequence of any peptide derived from any known protein. When choosing an appropriate nonsense peptide the following points are taken into consideration. The peptide should ideally have appropriate amino acids at relevant positions that can anchor the peptide to the peptide-binding groove of the MHC. The remaining amino acids should ideally be chosen in such a way that possible binding to TCR (through interactions with the peptide or peptide-binding site of MHC) are minimized. The peptide should ideally be soluble in water to make proper folding with MHC alpha chain and β2m possible in aqueous buffer. The length of the peptide should ideally match the type and allele of MHC complex. The final peptide sequence should ideally be taken through a blast search or similar analysis, to ensure that it is not identical with any peptide sequence found in any known naturally occurring proteins. Nonsense peptides may be used as negative control peptides in experiments with MHC-peptide molecules or MHC multimers.
Attachment of biologically active molecules to multimerisation domain(s) Pharmamers comprices various molecules covalently or non-covalently attached to multimerisation domains. Such molecules include: biological active molecules, molecules having adjuvant effects; molecules being immune targets e.g. antigens or other molecules as described elsewhere herein. In the following principles for attachement of biologically active molecules to multimerisation domains are described, but same principles may be applied to attachment of adjuvant molecules, immune target molecules or any other molecules to multimerisation domains. In brief, attachment can be done by chemical reactions between reactive groups on the biologically active molecule, e.g. amino groups on the protein surface and reactive groups of the multimerisation domain, e.g. vinyl sulfone functionalities on a dextran polymer and/or between reactive groups on the biologically active molecule. Alternatively, attachment is done by non-covalent interaction between part of the multimerisation domain and part of the biological active molecule. In both covalent and non-covalent attachment of the biologically molecule to the multimerisation domain a linker molecule can connect the two. The linker molecule can be covalent or non- covalent attached to both molecules. Biological active molecules can be attached repetitively aiding to recognition by and stimulation of the innate immune system via Toll or other receptors. The coupling of one or more multimerization domains and biologically active molecules can involve the association of an entity X (attached to or part of the one or more multimerization domain) and an entity Y (attached to or part of biologically active molecule). Thus, the linker that connects the one or more multimerization domain(s) and the biologically active molecule can comprise an XY portion.
The XY linkage can be covalent, in which case X and Y are reactive groups. In this case, X can be a nucleophilic group (such as -NH2, -OH, -SH, -NH-NH2), and Y an electrophilic group (such as CHO, COOH, CO) that react to form a covalent bond XY; or Y can be a nucleophilic group and X an electrophilic group that react to form a covalent bond XY. Other possibilities exist, e.g. either of the reactive groups can be a radical, capable of reacting with the other reactive group. A number of reactive groups X and Y, and the bonds that are formed upon reaction of X and Y, are shown in the table below.
X and Y can be reactive groups naturally comprised within the multimerization domain(s) and/or the biologically active molecule, or they can be artificially added reactive groups. Thus, linkers comprising reactive groups can be linked to either of the multimerization domain(s) and the biologically active molecule; subsequently the introduced reactive group(s) can be used to covalently link the one or more multimerization domain(s) and the biologically active molecule.
Example natural reactive groups of biologically active molecules include amino acid side chains comprising -NH2, -OH, -SH, and -NH-. Example natural reactive groups of multimerization domains include hydroxyls of polysaccharides such as dextrans, but also include amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides, when the polypeptide is used as one or more multimerization domain(s). In some pharmamers, one of the biologically active is linked by a protein fusion to the one or more multimerization domain(s). Thus, during the translation of the fusion protein, an acyl group (reactive group X or Y) and an amino group (reactive group Y or X) react to form an amide bond. Example is where the biologically active polypeptide chains are fused to one alpha-helic of a coiled-coil structure and where the other alpha helic of a coiled-coil structure is attached to the multimerisation domain. Biologically active proteins are then attached to the multimerisation domian through interaction of the two alpha-helices. Example coiled-coil structure include leucine zipper, fos-jun or other coiled coil structures as described elsewhere herein. Example non-native reactive groups include reactive groups that are attached to the one or more multimerization domain(s) or biologically active protein, through association of a linker molecule comprising the reactive group. The activation of dextran by reaction of the dextran hydroxyls with divinyl sulfone, introduces a reactive vinyl group that can react with e.g. amines of biologically active proteins, to form an amine that now links the one or more multimerization domain(s) (the dextran polymer) and the biologically active protein. Reactive vinyl groups may also react with thiols of the biologically active protein. An alternative activation of the dextran multimerization domain(s) involves a multistep reaction that results in the decoration of the dextran with maleimide groups, as described in the patent Siiman et al. US 6,387,622. In this approach, the amino groups of biologically active proteins are converted to -SH groups, capable of reacting with the maleimide groups of the activated dextran. Alternatively -SH groups of natural occuring Cysteine or artificial incorporated Cysteine can react with the maleimide. Thus, in the latter examples, both the reactive group of the multimerization domain(s) (the maleimide) and the reactive group of the biologically active protein (the thiol) are artificially introduced.
Sometimes activating reagents are used in order to make the reactive groups more reactive. For example, acids such as glutamate or aspartate can be converted to activated esters by addition of e.g. carbodiimid and NHS or nitrophenol, or by converting the acid moiety to a tosyl-activated ester. The activated ester reacts efficiently with a nucleophile such as -NH2, -SH, -OH, etc.
For the purpose of this invention, the multimerization domain(s) (including small organic scaffold molecules, proteins, protein complexes, polymers, beads, liposomes, micelles, cells) that form a covalent bond with the biologically active proteins can be divided into separate groups, depending on the nature of the reactive group that the one or more multimerization domain(s) contains. One group comprise multimerization domain(s) that carry nucleophilic groups (e.g. -NH2, -OH, -SH, -CN, -NH-NH2), exemplified by polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine; another group of multimerization domain(s) carry electrophilic groups (e.g. - COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid- anhydrides), exemplified by polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran; yet another group of multimerization domains carry radicals or conjugated double bonds. The one or more multimerization domain(s) appropriate for this invention can be those that comprise any of the reactive groups shown in Figure 10 or that can react with other reactive groups to form the bonds shown in the table herein below.
The biologically active proteins can be divided in a similar way, according to the nature of their reactive groups.
In another preferred embodiment the linker can be selected from, but is not limited to, the group consisting of a disulfide-bridge connecting amino acids, heparin or heparan sulfate-derived oligosaccharides (glycosoaminoglycans), bifunctional or chemical cross-linkers, peptide linker, polypeptide linker, fexible linker, synthetic linker, hydrazones, thioethers, esters, disulfides and peptide-containing linkers.
Examples of linkers include but are not limited to a disulfide-bridge connecting amino acids from both polypeptides; heparin or heparan sulfate-derived oligosaccharides (glycosoaminoglycans) connecting both polypeptides; bifunctional or chemical cross- linkers; and a peptide or polypeptide linker. The unimolecular protein can also be a chimera or fusion polypeptide.
The peptide linker sequence is typically flexibly disposed in the fusion protein so as to position the V-alpha and V-beta chains in a configuration which optimally binds an antigen. The peptide linker preferably predominantly comprises amino acids with small side chains, such as glycine, alanine and serine, to provide flexibility. Preferably, about 80 or 90 percent or greater of the linker sequence comprises glycine, alanine or serine residues, particularly glycine and serine residues. Preferably, the linker sequence does not contain any proline residues, which could inhibit flexibility. The linker sequence is suitably attached to the C-terminus of the V-alpha chain and the N-terminus of the V- beta chain of a fusion protein.
Crosslinkers can be either homobifunctional or heterobifunctional. Homobifunctional crosslinkers have two identical reactive groups and often are used in one-step reaction procedures to crosslink proteins to each other or to stabilize quaternary structure. Heterobifunctional crosslinkers possess two different reactive groups that allow for sequential (two-stage) conjugations, helping to minimize undesirable polymerization or self-conjugation. Crosslinkers that are amine-reactive at one end and sulfhydryl- reactive at the other end are especially useful in this regard. The most widely-used heterobifunctional crosslinkers are those having an amine- reactive succinimidyl ester (i.e., NHS-ester) at one end and a sulfhydrylreactive group on the other end. The sulfhydryl-reactive groups are usually maleimides, pyridyl disulfides and haloacetyls. The NHS-ester reactivity is less stable in aqueous solution and is usually reacted first in sequential crosslinking procedures. NHS-esters react with amines to form amide bonds. Carbodiimides are zero-length crosslinkers and effect direct coupling between carboxylates (-COOH) and primary amines (-NH2).
Other heterobifunctional reagents have one reactive group that is photoreactive rather than thermoreactive. This reactivity allows for specific attachment of the labile thermoreactive group first; subsequently, conjugation to any adjacent N-H or C-H sites can be initiated through the photoreactive group by activation with UV light. Crosslinkers preferably comprise at least two reactive groups. Functional groups that can be targeted for crosslinking include primary amines, sulfhydryls, carbonyls, carbohydrates and carboxylic acids (cf. the Table herein below). Coupling also can be nonselective using a photoreactive phenyl azide crosslinker.
Reactive Crosslinker Groups and Their Functional Group Targets
Reactive Group Functional Group
Aryl Azide Non-selective (or primary amine)
Carbodiimide Amine/Carboxyl
Hydrazide Carbohydrate (oxidized)
Hydroxymethyl Phosphine Amine lmidoester Amine lsocyanate Hydroxyl (non-aqueous)
Maleimide Sulfhydryl
NHS-ester Amine
PFP-ester Amine
Psoralen Thymine (photoreactive intercalator)
Pyridyl Disulfide Sulfhydryl
Vinyl Sulfone Sulfhydryl, amine, hydroxyl
The linker that connects the one or more multimerization domain(s) and the biologically active protein can comprise an XY portion. Above different kinds of covalent linkages XY were described. However, the XY linkage can also be non-covalent. Non-covalent XY linkages can comprise natural dimerization pairs such as antigen- antibody pairs, DNA-DNA interactions, or can include natural interactions, for example between biotin and streptavidin. Likewise, the interaction of biologically active proteins, including their transmembrane portion with the cell membrane of for example dendritic cells, is an example of a non-covalent XY interaction.
Artificial XY examples include XY pairs such as His6 tag (X) interacting with Ni-NTA (Y) and PNA-PNA,
Examples of dimerization- and multimerization domains, appropriate for use as XY non-covalent linkers between the multimerization domain(s) and the biologically active protein, can be found elsewhere in this application.
The abovementioned dimerization- and multimerization domains represent specific binding interactions. Another type of non-covalent interactions involves the non-specific adsorption of e.g. proteins onto surfaces. As an example, the non-covalent adsorption of proteins onto glass beads represents this class of XY interactions.
A preferred embodiment involving non-covalent interactions between X and Y are represented by the pentamer structure described in US patent 2004209295.
Another preferred embodiment involves the use of antibodies, with affinity for a non- biofunctional part of a biologically active protein. Thus, an anti-biomolecule antibody, with its two binding site, will bind two biologically active proteins and in this way generate a bivalent pharmamer. In addition, the antibody in certain instances can stabilize the pharmamer structure through the binding interactions.
The antibodies mentioned above can be selected from, but is not limited to, the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, Chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, Heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody. Another preferred embodiment involves use of Streptavidin or Avidin binding biotin on biotinylated biologically active proteins. Said proteins can be biotinylated enzymatically e.g. using a biotinylation tag recognised by BirA enzyme or they can be chemically biotinylated e.g. using Sulfo-NHS esters of biotin reacting with amino groups or maleimide activated biotin reacting with -SH groups.
The Streptavdin or avidin may further be conjugated to a polymer e.g. dextran as described by Winther et al. in patent WO 02/072631.
Also included in the present invention is genetically or chemically modified Streptavid in/Avid in binding natural biotin and/or chemically or genetically modified biotin; and chemically or genetically modified biotin binding natural Streptavid in/Avid in or chemically or genetically Streptavidin/Avidin.
In the present invention another preferred embodiment involving non-covalent interactions between X and Y are use of dimer coiled-coil structures, where one half the coiled structure are attached to the biologically active protein, e.g. as a fusion protein and the other half is attached to the multimerization domain. Example coiled- coil structures include but are not limited to leucine zippers like Fos-Jun, GCN4 leucine zipper, Fos-Jun like leucine zippers, heterodimeric coiled coil structures consisting of a basic peptide and an acidic peptide, heterodimeric coiled coil structures consisting of a basic peptide and an acidic peptide where Cystein are added to the C-termini of the acid and base peptides either directly or through a linker e.g. GIy-GIy, other heterodimeric coiled-coil structures or homodimeric structures.
Generation of pharmamers
Different approaches to the generation of various types of pharmamers can be applied. In brief, pharmamers can be generated by using molecules purified from natural sources, chemically synthesized or produced by recombinant DNA technology. Use of the latter technology allows for modifications of the natural protein/peptide, most commonly used is fragments that retain special interesting structures or biological function. It involves, first cloning of the genes of interest or modified versions hereof, then expression in a suitable host expression system, and purification of the individual protein components representing antigens, biologically or immunological active proteins, and then combining these components in appropriate numbers and ratios by linking them by covalent or non-covalent bonds to a multimerization domain Size of pharmamers
In one preferred embodiment the pharmamer is between 50,000 Da and 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 980,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000. Use of pharmamers
Pharmamers of the present invention can be used both as preventive vaccines and therapeutic vaccines e.g. therapeutic cancer vaccines and therapeutic anti-viral vaccines. They are a powerful tool in various in vivo and ex vivo therapeutic vaccine applications as will be apparent from the following.
The present invention is also based on the recognition that it is possible to design a poly-ligand pharmamer so as to (I) target specific MHC recognising cells, and (II) induce a response as desired, in specific target MHC recognising cells by addressing receptors on such cells. It was further recognised that with such design of MHC molecule/peptide complexes with a given specificity, it is possible to "add" other stimuli to the therapeutic composition by incorporating other molecules, which will affect the activity of the MHC recognising cells. Thus, it is possible to modulate the activity of specifically targeted MHC recognising cell clones, while leaving other MHC recognising cell clones unaffected. Thereby the immune response can be directed aiding the action of the vaccine.
Furthermore, it is also possible to specifically modulate the activity of more than one MHC recognising cell clone by choosing the before-mentioned other molecules appropriately. The inventions is further based on the recognition that it is possible to obtain specific MHC recognising cells using the pharmamers described herein, to modulate such ex vivo, whereby such cells can be used for in vivo vaccination.
By analogy it is possible to direct the efforts of specific pharmamers to other specialized immune cells by using pharmamers that contains molecules that make one of an interacting pair, such as, anti-X antibody- antigen X, X being any membrane bound protein specifying a single or multiple cell types; receptor ligands-membrane bound receptors, i.e. IL-2-IL2 receptor, FasL-FasR.
Accordingly, the present invention provides for methods of up-regulating, down- regulating, modulate, restoring, enhancing, and/or stimulate the immune system, as well as methods of inducing anergy of cells. This can in accordance with the present invention in general be accomplished in two ways, namely in vivo or ex vivo. By "in vivo" is meant that an effective amount of an active substance or ingredient is administered to a subject by any suitable route, the active substance or ingredient exerting its effect in the subject. By "ex vivo" (can also be termed "in vitro") is meant that cells withdrawn from a subject are in some way affected outside the subject, and then re-introduced to the subject, thereby achieving a desired response.
It is to be understood that the therapeutic compositions of the present invention can comprise one or more pharmamers as defined above. The biologically or immunologically active molecules of each pharmamer can be the same or different..
In particular, the inclusion of biologically active molecules can be important to initiate a response as desired. As mentioned above, the immune system is dependent on several signalling pathways, and thus inclusion of biologically active molecules, either as part of pharmamer or alone, can be an excellent way to control or guide the immune system.
Thus, the present invention relates generally to the pharmamers per se as defined above for use as therapeutic and/or preventive vaccines or constituents in vaccines.
The vaccines can suitably comprise one or more adjuvants and/or excipients as described in the foregoing. If more adjuvants are included they may be combined together with a single antigen or all antigens present in the vaccine, or each adjuvant may be combined with one particular antigen.
As used herein, the term "adjuvant" refers to an immunological adjuvant. By this is meant a compound that is able to enhance or facilitate the immune system's response to the ingredient in question, thereby inducing an immune response or series of immune responses in the subject. The adjuvant can facilitate the effect of the therapeutic composition by forming depots (prolonging the half-life of the ingredient), provide additional T-cell help and stimulate cytokine production. Facilitation of antigen survival and unspecific stimulation by adjuvants may, in some cases, be required if the antigenic molecule epitopes or functional molecules of the pharmamer are only weakly antigenic or only exerts weak to moderate interactions with compounds, molecules, or cells of the immune system.
Included in the term "immune response" is specific humoral, i. e. antibody, as well as cellular immune responses, the antibodies being serologic as well as secretory and pertaining to the subclasses IgM, IgD, IgG, IgA and IgE as well as all isotypes, allotypes, and subclasses thereof. The term is further intended to include other serum or tissue components. The cellular response includes Type-1 and Type-2 T-helper lymphocytes, T-17 regulatory T cells, cytotoxic T-cells as well NK cells. Also included herein is the various responses belonging to the innate immune resonse.
The therapeutic compositions of the invention can suitably be applied in the treatment, prevention, stabilisation, or alleviation of various diseases.
Diseases of relevance are those such as, diseases of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo-or xenogene (graft versus host and host versus graft) origin. In particular, the disease can be a chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox chicken pox, rubella or herpes.
In a preferred embodiment of the invention, the clinical condition is a cancer. The term "cancer" as used herein is meant to emcompass any cancer, neoplastic and preneoplastic disease. Said cancer may for example be selected from the group consisting of colon carcinoma, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangeosarcoma, lymphangeoendothelia sarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystandeocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioblastomas, neuronomas, craniopharingiomas, schwannomas, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroama, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemias and lymphomas, acute lymphocytic leukemia and acute myelocytic polycythemia vera, multiple myeloma, Waldenstrom's macroglobulinemia, and heavy chain disease, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's Disease, non-Hodgkin's lymphomas, rectum cancer, urinary cancers, uterine cancers, oral cancers, skin cancers, stomach cancer, brain tumors, liver cancer, laryngeal cancer, esophageal cancer, mammary tumors, childhood-null acute lymphoid leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytoid leukemia, acute megakaryocytoid leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T cell leukemia, small and large non-small cell lung carcinoma, acute granulocytic leukemia, germ cell tumors, endometrial cancer, gastric cancer, cancer of the head and neck, chronic lymphoid leukemia, hairy cell leukemia and thyroid cancer.
More specifically, the disease can be of inflammatory/auto-immune origin, including asthma, hypersensitivity pneumonitis, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, interstitial lung disease associated with Crohn s Disease or ulcerative colitis or Whipple's disease, interstitial lung disease associated with Wegeners granulomatosis or hypersensitivity vasculitis, vasculitis syndromes, Hennoch-Schonleins purpura, Goodpastures syndrome, Wegeners granulomatosis, renal diseases such as antibody mediated glomerulopathia as in acute glomerulonephritis, nephritis associated with systemic lupus erythematosus, nephritis associated with other systemic diseases such as Wegeners granulomatosis and Goodpastures syndrome and mixed connective tissue disease, chronic interstitial nephritis, chronic glomerulonephritis, gastrointestinal diseases such as Crohn s Disease, Ulcerative colitis, coeliac disease, Whipple's disease, collagenous colitis, eosinophilic colitis, lymphatic colitis, hepatobilliary diseases such as auto-immune hepatitis, alcohol induced hepatitis, periportal fibrosis, primary billiary cirrhosis, sclerosing colangitis, disorders of the central or peripheral nervous system such as demyelinating disease as multiple sclerosis, acute disseminated encephalomyelitis, sub-acute sclerosing panencephalitis, skin disease such as psoriasis, atopic dermatitis, eczema, allergic skin disease, progressive systemic sclerosis (scleroderma), exfoliating dermatitis, pemphigus vulgaris, joint diseases such as rheumatoid arthritis, ankylosing spondylitis, arthritis associated with psoriasis or inflammatory bowel disease, muscoloskelletal diseases such as myastenia gravis, polymyositis, endocrine diseases such as insulin dependent diabetes mellitus, auto-immune thyroiditis (Hashimoto), thyreotoxicosis, Graves, diseases of the hematopoetic system such as auto-immune anaemia, auto-immune thrombocytopenia, cardiovascular diseases such as cardiomyopathia, vasculitis, cardiovascular disease associated with systemic diseases as systemic lupus erythematosus, polyarthritis nodosa, rheumatoid arthritis, scleroderma, sarcoidosis, diseases of cancerous origin, including malignant melanoma, Sezary's syndrome, cutaneous T-cell lymphoma, renal cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, cancer of the uterus, prostatic cancer, hepatic carcinoma, lung cancer, and sarcoma, diseases, disorders or conditions of allergic origin.
In one embodiment the invention relates to treatment of one or more autoimmune diseases. Autoimmune diseases may be loosely grouped into those primarily restricted to specific organs or tissues and those that affect the entire body. Examples of organ- specific disorders (with the organ affected) include multiple sclerosis (myelin coating on nerve processes), type I diabetes mellitus (pancreas), Hashimotos thyroiditis (thyroid gland), pernicious anemia (stomach), Addison's disease (adrenal glands), myasthenia gravis (acetylcholine receptors at neuromuscular junction), rheumatoid arthritis (joint lining), uveitis (eye), psoriasis (skin), Guillain-Barre Syndrome (nerve cells) and Grave's disease (thyroid). Systemic autoimmune diseases include systemic lupus erythematosus and dermatomyositis.
In another embodiment the invention relates to treatment of one or more hypersensitivity disorders. Examples of hypersensitivity disorders include asthma, eczema, atopical dermatitis, contact dermatitis, other eczematous dermatitides, seborrheic dermatitis, rhinitis, Lichen planus, Pemplugus, bullous Pemphigoid, Epidermolysis bullosa, uritcaris, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Alopecia areata, atherosclerosis, primary biliary cirrhosis and nephrotic syndrome. Related diseases include intestinal inflammations, such as Coeliac disease, proctitis, eosinophilia gastroenteritis, mastocytosis, inflammatory bowel disease, Chrohn's disease and ulcerative colitis, as well as food-related allergies.
The most common allergens, to which allergic reactions occur, include, inhalation allergens originating i. a. from trees, grasses, herbs, fungi, house dust mites, storage mites, cockroaches and animal hair, feathers, and dandruff. Important pollen allergens from trees, grasses and herbs are such originating from the taxonomic orders of Fagales, Oleales and Pinales including i. a. birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), the order of Poales including i. a. grasses of the genera Lolium, Phleum, Poa, Cynodon, Dactylis and Secale, the orders of Astrales and Urticales including i. a. herbs of the genera Ambrosia and Artemisia. Important inhalation allergens from fungi are i. a. such originating from the genera Alternaria and Cladosporium. Other important inhalation allergens are those from house dust mites of the genus Dermatophagoides, storage mites from the genus Lepidoglyphys destructor, those from cockroaches and those from mammals such as cat, dog, horse, cow, and bird. Also, allergic reactions towards stinging or biting insects such as those from the taxonomic order of Hymenoptera including bees, wasps, and ants are commonly observed. Specific allergen components are known to the person skilled in the art and include e. g. Bet v 1 (B. verrucosa, birch), AIn g 1 (Alnus glutinosa, alder), Cor a 1 (Corylus avelana, hazel) and Car b 1 (Carpinus betulus, hornbeam) of the Fagales order. Others are Cry j 1 (Pinales), Amb a 1 and 2, Art v 1 (Asterales), Par j 1 (Urticales), Ole e 1 (Oleaves), Ave e 1 , Cyn d 1 , Dae g 1 , Fes p 1 , HoI 1 1 , LoI p 1 and 5, Pas n 1 , PhI p 1 and 5, Poa p 1 ,2 and 5, Sec c 1 and 5, and Sor h 1 (various grass pollens), Alt a 1 and CIa h 1 (fungi), Der f 1 and 2, Der p 1 and 2 (house dust mites, D. farinae and D. pteronyssinus, respectively), Lep d 1 , BIa g 1 and 2, Per a 1 (cockroaches, Blatella germanica and Periplaneta americana, respectively), FeI d 1 (cat), Can f 1 (dog), Equ c 1 ,2 and 3 (horse), Apis m 1 and 2 (honeybee), Ves g 1 ,2 and 5, Pol a 1 ,2 and 5 (all wasps) and Sol i 1 , 2,3 and 4 (fire ant), to mention the most common.
Compositions
The therapeutic compositions of the invention can be formulated in any suitable way, i. a. depending on the route of administration, and the amount of active ingredient to be administered. In particular, the therapeutic compositions of the invention can be formulated for parenteral administration, including intravenous, intramuscular, intraarticular, subcutaneous, intradermal, epicutantous/transdermal, and intraperitoneal administration, for infusion, for oral administration, for nasal administration, for rectal administration, for vaginal administration, or for topic administration.
The pharmamer can suitably be immobilised onto a solid or semi-solid support. Examples of solid and semi-solid support are those mentioned above, i. e. particles, beads, biodegradable particles, sheets, gels, filters, membranes, fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, and chips. In particular, the solid support can be selected from particles and beads, preferably particles and beads, which are polymeric, magnetic or superparamagnetic. For in vivo therapy, biodegradable particles will be especially preferred, while for ex vivo therapy, biodegradable, polymeric, magnetic, paramagnetic or superparamagnetic particles will be especially preferred.
As mentioned, the pharmamers used in therapeutic vaccine settings are very interesting molecule poly-ligand compounds possessing highly appropriate properties for modulation of various immune cells both in vivo and ex vivo.
The poly-ligand pharmamers can, due to the one or more multimerization domain(s), be loaded with a plurality of biologically or immunologically active molecules to ensure high avidity binding to specific counter receptors.
It is to be understood that such responses include inducing anergy leading to apoptosis, up-regulating a response, down-regulating a response, stimulating a response, modulating a response, enhancing a response, inhibiting a response, and in any other way manipulating a response. In this connection, it should be understood that the MHC molecules/peptides of the construct can be chosen so as to induce a number of other responses, or activate signal pathways which results in the production of various signalling substances which can have a beneficial influence on the disease to be treated, prevented or alleviated.
Furthermore, this desired effect of one or more of the molecules of a pharmamer can be ameliorated, enhanced, reduced, inhibited, stimulated or combined with other effects by the further attachment of other biologically active compounds as described above.
A variety of diseases, including cancer causes immunosuppression in the patients. Immunotherapy using therapeutic vaccines is an attempt to stimulate the patient's own immune system to recognise and destroy cancer cells. The tumour can exert its suppressive influence over the immune system through several different mechanisms. Although tumour cells can prime the immune system, tumour escape mechanisms can induce immunological tolerance to the tumour. There are several known mechanisms of tumour escaping immune surveillance. For instance, tumour cells are often inefficient in presenting tumour antigens to effector T- cells. This can be the result of tumour cell down- regulation or mutation of MHC molecules, or down- regulation of co-stimulatory molecules such as B7, or other molecules, such as TAP, that are important in the antigen presenting pathway. Furthermore, tumour cells have been shown to induce tolerance in T-cells by down- regulating the expression of CD3-zeta chain in T-cells. Tumour cells can also suppress T-cell activation by release of inhibitory cytokines, and induce apoptosis in T-cells through Fas-Fas ligand interaction. Tumour cells also have the ability to suppress the immune system through release of cytokines such as IL-12 that inhibits the maturation of immature dendritic cells into fully mature antigen presenting cells. Inhibitory factors released by tumour cells have been shown to suppress granulocyte activation, thus avoiding the killing of tumour cells by activated granulocytes.
Common treatment regimes such as chemotherapy and radiation therapy also suppress immunity in a more general way. It is also known that the immune suppresion that HIV infection cause leads to destruction of immune function cells.
A variety of different prior art strategies have been employed in an attempt to restore or enhance the patient's immune response to tumours, including treatment with monoclonal antibodies, cancer vaccines, cytokine therapy and adoptive cellular immunotherapy using dendritic cells or T-cells. Cellular immunotherapy involving T- cells include CD8+ cytotoxic effector cells that have the capacity to kill tumour cells. Furthermore, it has been shown that CD4+ cytokine producing T-cells also play an important role in maintaining a sustainable anti-tumour cell activity of cytotoxic CD8 cells. The success, however, of the prior art methods have been limited.
As mentioned the present invention relates to methods for the vaccine treatment of human beings and animals, comprising methods of administering a pharmammer as described herein in an effective amount.
The treatment can be such which involves up-regulation, down-regulation, modulation, stimulation, inhibition, restoration, enhancement and/and otherwise manipulation of immune responses. This can indeed be accomplished by the compositions of the present invention. The present invention also relates to methods of inducing anergy in a cell, by which methods a therapeutic composition as described herein is administered.
In a further aspect, the present invention relates to methods of performing adoptive immunotherapy, which methods comprise administrating to an animal, including a human being, a therapeutic composition as described herein. As mentioned above, the therapeutic composition of the invention is suited for in vivo therapy.
The present invention further comprise pharmamer compositions for therapeutic and preventive vaccines that suitably comprise from 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to10, or 1 to more than 10; 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, or 2 to more than 10; 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, or 3 to more than 10; 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to9, 4 to 10, or 4 to more than 10; 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 5 to more than 10; 6 to 7, 6 to 8, 6 to 9, 6 to 10, or 6 to more than 10; 7 to 8, 7 to 9, 7 to 10, or 7 to more than 10; 8 to 9, 8 to 10, or 8 to more than 10; 9 to 10, or 9 to more than 10 different biologically active molecules.
Thus, the inclusion of two, three, four, five, six or more different biologically active molecules are contemplated and believed to be advantageous in some cases. The different molecules can be attached on the multimerization domaine in any desired fixed ratio e.g. for a pharmamer with three different molecules termed A, B, and C, ratios such as but not limited to, 1 :1 :1 , 1 :2:1 , 1 :3:1 , 1 :4:1 , 1 :5:1 , 2:1 :1 , 2:1 :2, 2:3:2,
3:5:8, etc. and for a pharmamer with five different molecules attached, termed G, H, I, J, and K, ratios such as but not limited to, 2:4:3:6:5, 4:6:8:1 :1 , 10:1 :2:5:2, etc. may apply. One or more of the molecules can be functioning as an adjuvant. Adjuvants or biologically active molecules or other ingredients may also be constituents of the final vaccine without being attached to the multimerization domain. These non-pharmamer vaccine constituents can be mixed with the pharmamer in any suitable ratio(s).
Dosage ^administration and preparation
The individual to receive the vaccine composition according to the present invention may be any individual in need thereof, preferably a mammal in need thereof, more preferably a human being in need thereof, such as a newborn, a child, an adult, a woman or a man.
In one preferred embodiment the vaccine composition is administered prophylactically and in this embodiment the individual in need thereof, may be any individual at risk of encountering the given clinical condition against which the vaccine composition is directed. When selecting biologically active molecules to be used in a pharmamer one needs to carefully consider the possibilities of unwanted adverse or serious adverse reactions.
It is further contemplated that the amount of pharmamer construct required to induce a systemic immune response will typically be in the range of from 0.0001 to 10000 ug/kg/dose, such as from 0.01 to 1000 ug/kg/dose, from 0.1 to 100 ug/kg/dose, or from 1 to 10 ug/kg/dose.
In one embodiment, each dosage unit of said vaccine composition preferably comprises in the range of 0.01 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 0.8 μg, for example in the range of 0.05 to 0.6 μg, such as in the range of 0.05 to 0.4 μg, for example in the range of 0.05 to 0.2 μg, such as in the range of 0.1 to 0.8 μg, for example in the range of 0.1 to 0.6 μg, such as in the range of 0.1 to 0.5 μg, for example in the range of 0.1 to 0.4 μg, such as in the range of 0.1 to 0.3 μg, for example in the range of 0.1 to 0.2 μg of the pharmamer or peptide of the present invention.
In one embodiment the daily dosage of the pharmamer may be varied over a wide range from 0.001 to 1 ,000 mg per adult human/per day. For oral administration, the compositions are preferably provided in the form of scored or unscored tablets containing 0.01 , 0.05, 0.1 , 0.5, 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 10 mg/kg of body weight per day. Even more particularly, the range varies from about 0.05 to about 1 mg/kg.
Of course the dosage level will vary depending upon the potency of the particular compound. Certain compounds will be more potent than others. In addition, the dosage level will vary depending upon the bioavailability of the compound. The more bioavailable and potent the compound, the less compound will need to be administered through any delivery route, including but not limited to oral delivery.
The amount of the immunogenic peptide of the invention in the pharmaceutical composition may vary, depending on the particular application. However, a single dose of the immunogen is in one embodiment preferably anywhere from about 10 μg to about 5000 μg, more preferably from about 50 μg to about 2500 μg such as about 100 μg to about 1000 μg.
Modes of administration include intradermal, subcutaneous and intravenous administration, implantation in the form of a time release formulation, etc. Any and all forms of administration known to the art are encompassed herein. Also any and all conventional dosage forms that are known in the art to be appropriate for formulating injectable immunogenic peptide composition are encompassed, such as lyophilised forms and solutions, suspensions or emulsion forms containing, if required, conventional pharmaceutically acceptable carriers, diluents, preservatives, adjuvants, buffer components, etc.
The vaccine compositions may be administered in any suitable manner. For example the vaccine compositions may be administered enterally, parenterally, transdermal^, orally, by inhalation and/or over a mucosal membrane.
In a preferred embodiment, the vaccine compositions are administered parenterally. Examples of parenteral routes of administration include injections and infusions, e.g. intravenous, intraarterial, intramuscular, intracardial, subcutaneous, intraosseous, intradermal, intraperitonal or intrethecal. A preferred route of parenteral administration of the vaccine comporision is by subcutaneous injection. A suitable administration form for parenteral administration is a solution or dispersion.
Pharmammer vaccine compositions administered more than once can be administered by same route or by alternating routes. Similarly the individual components of the vaccine can be administered alone or in combinations by the same route or by alternating/mixed routes
In some embodiments of the present invention it is desirable that the pharmaceutical composition comprises an isotonic agent. In particular when the pharmaceutical composition is prepared for administration by injection or infusion it is often desirable that an isotonic agent is added. Accordingly, the composition may comprise at least one pharmaceutically acceptable additive which is an isotonic agent.
The pharmaceutical composition may be isotonic, hypotonic or hypertonic. However it is often preferred that a pharmaceutical composition for infusion or injection is essentially isotonic, when it is administrated. Hence, for storage the pharmaceutical composition may preferably be isotonic or hypertonic. If the pharmaceutical composition is hypertonic for storage, it may be diluted to become an isotonic solution prior to administration.
The isotonic agent may be an ionic isotonic agent such as a salt or a non-ionic isotonic agent such as a carbohydrate.
Examples of ionic isotonic agents include but are not limited to NaCI, CaCI2, KCI and MgCI2 Examples of non-ionic isotonic agents include but are not limited to mannitol, sorbitol and glycerol.
It is also contained within the present invention that at least one pharmaceutically acceptable additive is a buffer. For some purposes, for example, when the pharmaceutical composition is meant for infusion or injection, it is often desirable that the composition comprises a buffer, which is capable of buffering a solution to a pH in the range of 4 to 10, such as 5 to 9, for example 6 to 8.
However, in other embodiments of the invention the pharmaceutical composition may comprise no buffer at all or only micromolar amounts of buffer.
The buffer may for example be selected from the group consisting of TRIS, acetate, glutamate, lactate, maleate, tartrate, phosphate, citrate, carbonate, glycinate, histidine, glycine, succinate and triethanolamine buffer. TRIS buffer is known under various other names for example tromethamine including tromethamine USP, THAM, Trizma, Trisamine, Tris amino and trometamol. The designation TRIS covers all the aforementioned designations.
The buffer may furthermore for example be selected from USP compatible buffers for parenteral use, in particular, when the pharmaceutical formulation is for parenteral use. For example the buffer may be selected from the group consisting of monobasic acids such as acetic, benzoic, gluconic, glyceric and lactic, dibasic acids such as aconitic, adipic, ascorbic, carbonic, glutamic, malic, succinic and tartaric, polybasic acids such as citric and phosphoric and bases such as ammonia, diethanolamine, glycine, triethanolamine, and TRIS.
The vaccine composition may also comprise antioxidants and/or reducing agents for example acetone sodium bisulfite, ascorbate, bisulfite sodium, butylated hydroxy anisole, butylated hydroxy toluene, cystein/cysteinate HCL, dithionite sodium, gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol, propyl gallate, sulfite sodium and thioglycolate sodium.
In another embodiment the vaccine composition is administered transdermally. Examples of useful administration forms for transdermal administration include ointment, gel, cream, gel-like cream, paste, liquid, lotion, aerosol, spray, liniment, plaster, poultice, foam, bath admixture, a patch and a bandage. Preferably, if the vaccine composition is to be administered transdermally, it is preferably in the form of a patch.
Ointments, lotions, creams and the like may be prepared as described in Remington "The science and practice of pharmacy", chapter 44 pages 845-851 , 20th edition. Patches for transdermal vaccines may be prepared by any conventional methods, for example as described in EP1384403 or WO2004/030696. Preferably patches for transdermal vaccines are prepared essentially as described in Examples 4 to 13 of WO2004/03069 except that the transdermal patches should comprise the vaccine composition according to the present invention. The skilled person will readily be able to make the required adaptations.
For inhalation the vaccine composition may be administered in the form of an aerosol and/or spray dosage form which can be prepared, for example, by filling an aerosol container with above-mentioned solution for example, together with an injection agent such as liquefied petroleum gas. A poultice can be prepared by adding the above mentioned vaccine composition to an ointment base formed from a partially neutralized polyacrylic acid, sodium polyacrylate, and the like. For oral administration, the vaccine composition may be administered in the form of a tablet, capsule, drop, liquid mixture or powder. Tablet, capsules, and drops may be swallowed or chewed. Oral administration may result in uptake via the mucosa in the mouth, such as buccal or sublingual uptake, and/or in uptake via the gastro-intestinal route, such as uptake over the mucosa of the intestines.
As the pH adjuster, for example, lactic acid, citric acid, phosphoric acid and the like can be mentioned for adjusting to a lower pH range, and sodium hydroxide, potassium hydroxide, sodium lactate, sodium citrate, monoethanolamine and diisopropanolamine and the like can be mentioned for adjusting to a higher pH range. Addition of carboxyvinyl polymer, which is a water-soluble polymer, can also achieve a lower pH. Buffers such as acetate buffer, a phosphate buffer, a citrate buffer, a succinate buffer or TRIS may also be included for pH adjustment.
As the stabilizer, for example, ascorbic acid, dibutylhydroxytoluene, sodium thiosulfate, sodium thioglycolate, sodium thiomalate, erythorbic acid, sodium erythorbate, sodium pyrosulfite, benzoic acid, sodium benzoate, sodium alginate, sodium caprylate, L- arginine, L-cysteine, dl-.alpha.-tocopherol, tocopherol acetate, propyl gallate, disodium edetate and the like can be mentioned.
As the preservative, for example, benzethonium chloride, benzalkonium chloride, methylparaben, ethylparaben, propylparaben, chlorobutanol, benzyl alcohol, thimerosal and the like can be mentioned.
The vaccine compositions of the present invention may also be administered over a mucosal membrane. Thus, the vaccine composition may be applied to any mucous membrane including the conjunctiva, nasopharynx, orthopharnyx, vagina, colon, urethra, urinary bladder, lung, large (rectal) and small (enteral) intestine.
When administered ocularly or nasally, the compositions of the present invention can be formulated in an aqueous solution buffered to a pH of between 3.0 and 8.0, most preferably pH 5.0-5.4, by means of a pharmaceutically acceptible buffer system. Any pharmaceutically acceptable buffering system capable of maintaining the pH in the preferred ranges can be used in the practice of this invention. A typical buffer will be, for example, an acetate buffer, a phosphate buffer, a citrate buffer, a succinate buffer, or the like. The concentration of buffer is typically in the range from between 0.005 and 0.1 molar, most preferably about 0.02 molar.
The container, e.g. nasal applicator or eye drop bottle, may contain sufficient composition for a single nasal or ocular dosing or for several sequential dosages.
In one embodiment of the invention, the vaccine compositions of the present invention may be formulated for sustained release. For example, one or more of the immune stimulating complex, carrier protein, saccharide antigen and/or aluminium containing adjuvant may be combined with a silicone elastomer that releases the saccharide antigen over a long period of time. The silicone elastomer can also comprise albumin. See U.S. Pat. No. 4,985,253, the contents of which are fully incorporated by reference herein. The release rate of the antigen from the silicone elastomer can be controlled by incorporation of a water soluble or fat soluble mixing agent or cosolvent (e.g., polyethylene glycol 400, polysorbate 80, sodium alginate, L-alanine, sodium chloride, polydimethylsiloxane) into the silicone elastomer. Any other additive can also be incorporated into the silicone elastomer for the purpose of accelerating the release rate.
The vaccine composition according to the invention may be formulated into unit dosage forms, wherein each unit, for example a sealed container, comprises one dosage of the vaccine composition.
The vaccine compositions may be administered once; however, more often the vaccine compositions are administered more than once, such as more than 2 times, for example more than 5 times, such as more than 10, for example more than 15, such as more than 20, for example more than 30 times, such as more than 50 times, for example more than 100 times. Preferably, the vaccine compositions are administered in the range of 2 to 10 times, more preferably in the range of 2 to 5 times, such as twice.
When the vaccine composition is administered more than once, the time period between two individual administrations is typically in the range of 1 week to 5 years, such as in the range of 1 month to 2 year, for example in the range of 1 month to 1 year, such as in the range of 2 months to 7 months. If the vaccine composition is administered more than twice, then the time period between the individual administrations may each individually be any of the aforementioned. Thus by way of example the interval between the first and second administration may be around 2 months and the interval between the second and the third administration may be around 7 months.
In one embodiment the pharmamer based vaccines can be administered by several routes including but not limited to injection including intravenously, intramuscularly, subcutaneously, inter peritoneal injection and transmucosally (nasal, rectal, vaginal) application, by inhalation, per-orally or by inoculation.
The administration of pharmamers of the invention can be as single doses or as several doses. In certain cases, administration only once can be sufficient. In general, several doses should be given with intervals of a day, a week, two weeks, a month, or several months, etc. For example, a single dose can be given once, or a dose can be given as a primer, followed by one or more administration, or a continuous administration regime like up to four doses per week, followed by one month without administrations, followed by up to four doses per week. Further but not limiting examples are vaccination protocols where administration is performed on week 0, 4, 8, and 16; or on week 0, 2, 4, 6, 8, 10, 12, and 14; or on week 0, 5, 1 1 , 17; or on month 0, 1 , and 2; or on day 0, 7, and 30; or every year. Optionally with increasing amount of pharmamer; optionally with modified ratios of the biologically active molecules of the pharmamer construct; optionally using different adjuvants or combinations of adjuvants in the different administrations. Administration protocol can also be linked to age of the vaccine. Known examples are childhood vaccines. Examples of age related protocols, at the age of 3 month, 5, month, and 12 month; or 3 month, 5, month, 12 month, and 5 years; or 15 month, and 4 years. These examples are not exhaustive. The optimal administration regime depends on the pharmamer construct in question and several other factors. The person skilled in the art will readily know how to optimise this.
Of course, other medicaments can be administered simultaneously in order to enhance or support the vaccine treatment.
Containers for mixing and storage of the pharmamers of the invention can be made of glass or various polymeric materials. The containers chosen should not adsorb the product stored. The containers can suitably be ampoules or capped vials for mono-or multi-dosage.
The invention further relates to methods for producing the pharmamers of the invention, which methods comprise providing a pharmamer as described herein, and solubilising or dispersing (i.e. in suspension) the pharmamer in a medium suitable for therapeutic substances, and optionally adding other adjuvants and/or excipients. The medium can be in the form of a liquid, a gel, or an ointment. The pharmamer can also be embedded in a matrix being part of a solid pill, or powder inside a capsule.
As described herein the pharmamers can be useful as vaccines, as vaccine components or as engineered intelligent adjuvants. The possibility of creating pharmamers that specifically bind certain T cells with molecules that trigger, e.g. the humoral response or the innate immune response, can accelerate vaccine development and improve the efficiency of vaccines.
Vaccine compositions may be prepared and administered using any conventional protocol known by a person skilled in the art. Below is a non-limiting example of preparation of a vaccine composition according to the invention is given as well as a non-limiting example of adminstration of such as a vaccine. It will be appreciated by the person skilled in the art that the protocol may be easily adapted to any of the vaccine compositions described herein.
The peptides can e.g. be synthesized e.g. at the UVA Biomolecular Core Facility with a free amide NH2 terminus and free acid COOH terminus. Each was provided as a lyophilized peptide, which was then reconstituted in sterile water and diluted with
Lactated Ringer's solution (LR, Baxter Healthcare, Deerfield, IL) as a buffer for a final concentration of 67-80% Lactated Ringer's in water. These solutions were then sterile- filtered, placed in borosilicate glass vials, and submitted to a series of quality assurance studies including confirmation of identity, sterility, general safety, and purity, in accordance with FDA guidelines, as defined in IND 6453.
In practical circumstances, patients will receive a vaccine comprising about 100 μg of a class I H LA- restricted HIV peptide with or without a class Il HLA-restricted HIV helper peptide. The patients are vaccinated with e.g. about 100 μg of the class I HLA peptide in adjuvant alone, or vaccinated with e.g. about 100 μg of the HLA class l-restricted peptide plus 190 μg of the class ll-restricted helper peptide. The higher dose of the helper peptide is calculated to provide equimolar quantities of the helper and cytotoxic epitopes. Additionally, patients can be vaccinated with a longer peptide comprising the amino acid sequences of both peptides.
The above peptides, in 1 -ml aqueous solution, can be administered either as a solution/suspension with about 100 μg of QS-21 , or as an emulsion with about 1 ml of Montanide ISA-51 adjuvant.
Patients are immunized e.g. at day 0 and months 1 , 2, 3, 6, 9, and 12, with the peptide pharmamer plus adjuvant, for a total of seven immunizations. With rare exceptions, the vaccinations are administered to the same arm with each vaccine. The peptide pharmamers are administered s.c.
Adjuvants
Pharmamer vaccines of the present invention may be combined with adjuvant in order to improve the effect of the vaccine. Adjuvants are pharmacological or immunological agents that modify the effect of other agents (e.g. vaccines and drugs) while having few if any direct effects when given by themselves.
Adjuvants can be mixed with the vaccine and administered simultaneously with the vaccine. The adjuvant can be attached to one or more components of the vaccine by covalent or non-covalent interaction or be in the vaccine as an individual component. The adjuvant may also be administered before or after the vaccine is administered. More than one type of adjuvant can be used together with a given vaccine likewise one specific type of adjuvant may be used for more than one vaccine.
Immunological adjuvants are substances that stimulate the immune system and increase the response to a vaccine without having any specific antigenic effect itself. An immunological adjuvant either potentiates the immune responses to an antigen and/or modulates it towards the desired immune responses. More than one adjuvant may be present in the final vaccine product. They may be combined together with a single antigen or all antigens present in the vaccine, or each adjuvant may be combined with one particular antigen. Examples of immunological adjuvants include oil emulsions and surfactant based formulations e.g. MF59, QS21 , AS02, Montanide ISA-51 JSA-720, Titermax gold, mineral salts (e.g. aluminiumhydroxide, aluminiumhydroxide gel, aluminium or calcium phosphate gels), particulate adjuvants (e.g. virosomes, AS04, immune stimulatory complexes (ISCOMs), polylactide co-glycolide (PLG)), natural and synthetic microbial derivatives (e.g. monophosphoryl lipid A (MPL), Detox (MPL + M. Phlei cell wall skeleton), AGP [RC-529] (synthetic acylated monosaccharide), DC_Chol (lipoidal immunostimulators able to self organize into liposome's), OM-174 (lipid A derivative), CpG motifs (synthetic oligonucleotides containing immunostimulatory CpG motifs), modified LT and CT (genetically modified bacterial toxins to provide non-toxic adjuvant effects), endogenous human immunomodulators, (e.g., hGM-CSF or hlL-12 (cytokines that can be administered either as protein or plasmid encoded), lmmudaptin (C3d tandem array)), saponins, squalene or phosphate based adjuvants, lipopolysaccharides, Inert vehicles, such as gold particles microbial antigens, copolymers.
Adjuvant pertaining to the present invention may be grouped according to their origin, be it mineral, bacterial, plant, synthetic, or host product. The first group under this classification are the mineral adjuvants, such as aluminium compounds. Antigens precipitated with aluminum salts or antigens mixed with or adsorbed to performed aluminum compounds have been used extensively to augment immune responses in animals and humans. Aluminum particles have been demonstrated in regional lymph nodes of rabbits seven days following immunization, and it may be that another significant function is to direct antigen to T cell containing areas in the nodes themselves. Adjuvant potency has been shown to correlate with intimation of the draining lymph nodes. While many studies have confirmed that antigens administered with aluminum salts led to increased humoral immunity, cell mediated immunity appears to be only slightly increased, as measured by delayed-type hypersensitivity. Aluminum hydroxide has also been described as activating the complement pathway. This mechanism may play a role in the local inflammatory response as well as immunoglobulin production and B cell memory. Primarily because of their excellent record of safety, aluminum compounds are presently the only adjuvants used in humans.
While aluminum salts have been a sufficient adjuvant for strong immunogens that require only antibody responses to elicit protection, they may not always be effective when used with weak immunogens such as e.g. synthetic peptides of malaria, or for introducing cell-mediated immune responses or IgG isotype of the type required to fight infections. Thus, the immunostimulating fragment of TGF according to the present invention may in one embodiment act as an adjuvant or immunostimulator and may be conjugated or non-conjugated to the immunogenic determinant against which it is desirable to raise an immune response.
Another large group of adjuvants are those of bacterial origin. Adjuvants with bacterial origins can be purified and synthesized (e.g. muramyl dipeptides, lipid A) and host mediators have been cloned (Interleukin 1 and 2). The last decade has brought significant progress in the chemical purification of at least three adjuvants of active components of bacterial origin: Bordetella pertussis, lipopolysaccharide and Freund's Complete Adjuvant (FCA). Additionally suitable adjuvants in accordance with the present invention are e.g. Titermax, ISCOMS, Quil A, and ALUN, see US 58767 and 5,554,372, Lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide matrixes, GMDP, and other as well as combined with immunostimulants (US 5,876,735).
B. pertussis is of interest as an adjuvant in the context of the present invention due to its ability to modulate cell-mediated immunity through action on T-lymphocyte populations. For lipopolysaccharide and Freund's Complete Adjuvant, adjuvant active moieties have been identified and synthesized which permit study of structure-function relationships. These are also considered for inclusion in immunogenic compositions according to the present invention.
Lipopolysaccharide and its various derivatives, including lipid A, have been found to be powerful adjuvants in combination with liposome's or other lipid emulsions. It is not yet certain whether derivatives with sufficiently low toxicity for general use in humans can be produced. Freund's Complete Adjuvant is the standard in most experimental studies.
Endogenous human immunomodulators are another group of adjuvants of interest for the present invention and among others include cytokines, interleukins, interferons and growth factors. These immunomodulators can be administered either as protein or plasmid encoded. Many other types of materials can be used as adjuvants in immunogenic compositions according to the present invention. They include plant products such as saponin, animal products such as chitin, inert vehicles, such as gold particles and numerous synthetic chemicals.
Adjuvants according to the present invention can also be categorized by their proposed mechanisms of action. This type of classification is necessarily somewhat arbitrary because most adjuvants appear to function by more than one mechanism. Adjuvants may act through antigen localization and delivery, or by direct effects on cells making up the immune system, such as macrophages and lymphocytes. Another mechanism by which adjuvants according to the invention enhance the immune response is by creation of an antigen depot. This appears to contribute to the adjuvant activity of aluminum compounds, oil emulsions, liposomes, and synthetic polymers. The adjuvant activity of lipopolysaccharides and muramyl dipeptides appears to be mainly mediated through activation of the macrophage, whereas B. pertussis affects both macrophages and lymphocytes. Further examples of adjuvants that may be useful when incorporated into immunogenic compositions according to the present invention are described in US 5,554,372.
At present only a few of the above mentioned adjuvants are approved for human use. Most relevant in this aspect are Alhydrogel (AluminiumHydroxide), MF59 and the proprietary Montanide ISA720.
In one embodiment adjuvants are any substance whose admixture into the vaccine composition increases or otherwise modifies the immune response to the pharmamers of the present invention.
Adjuvants could for example be selected from the group consisting of: AIK(SO4)2, AINa(SO4)2, AINH4 (SO4), silica, alum, AI(OH)3, Ca3 (PO4)2, kaolin, carbon, aluminum hydroxide, muramyl dipeptides, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-
DMP), N-acetyl-nornuramyl-L-alanyl-D-isoglutamine (CGP 1 1687, also referred to as nor-MDP), N-acetylmuramyul-L-alanyl-D-isoglutaminyl-L-alanine-2-(1 '2'-dipalmitoyl-sn - glycero-3-hydroxphosphoryloxy)-ethylamine (CGP 19835A, also referred to as MTP- PE), RIBI (MPL+TDM+CWS) in a 2% squalene/Tween-80.RTM. emulsion, lipopolysaccharides and its various derivatives, including lipid A, Freund's Complete Adjuvant (FCA), Freund's Incomplete Adjuvants, Merck Adjuvant 65, polynucleotides (for example, poly IC and poly AU acids), wax D from Mycobacterium, tuberculosis, substances found in Corynebacterium parvum, Bordetella pertussis, and members of the genus Brucella, liposomes or other lipid emulsions, Titermax, ISCOMS, Quil A, ALUN (see US 58767 and 5,554,372), Lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide matrixes or GMDP, lnterleukin 1 , lnterleukin 2, Montanide ISA-51 and QS-21. Preferred adjuvants to be used with the invention include Montanide ISA-51 and QS-21.
Montanide ISA-51 (Seppic, Inc.) is a mineral oil-based adjuvant analogous to incomplete Freund's adjuvant, which must be administered as an emulsion. QS-21 (Antigenics; Aquila Biopharmaceuticals, Framingham, MA) is a highly purified, water- soluble saponin that handles as an aqueous solution. QS-21 and Montanide ISA-51 adjuvants can be provided in sterile, single-use vials.
Additional preferred adjuvants capable of being used in vaccine compositions comprising one or more of the pharmamers of the present invention are e.g. any substance which promote an immune responses. Frequently, the adjuvant of choice is Freund's complete or incomplete adjuvant, or killed B. pertussis organisms, used e.g. in combination with alum precipitated antigen. A general discussion of adjuvants is provided in Goding, Monoclonal Antibodies: Principles & Practice (2nd edition, 1986) at pages 61 -63. Goding notes, however, that when the antigen of interest is of low molecular weight, or is poorly immunogenic, coupling to an immunogenic carrier is recommended. Examples of such carrier molecules include keyhole limpet haemocyanin, bovine serum albumin, ovalbumin and fowl immunoglobulin. Various saponin extracts have also been suggested to be useful as adjuvants in immunogenic compositions. Recently, it has been proposed to use granulocyte-macrophage colony stimulating factor (GM-CSF), a well known cytokine, as an adjuvant (WO 97/28816).
Desirable functionalities of adjuvants capable of being used in accordance with the present invention are listed in the below table.
Modes of adjuvant action
Action Adjuvant type Benefit 1. Generally small molecules or Upregulation of immune lmmunomodulation proteins which modify the response. Selection of Th1 or cytokine network Th2
2. Presentation Generally amphipathic molecules Increased neutralizing antibody or complexes which interact with response. Greater duration of immunogen in its native response conformation
3. CTL induction • Particles which can bind or Cytosolic processing of protein yielding correct class 1 enclose immunogen and restricted peptides which can fuse with or disrupt
Simple process if promiscuous cell membranes peptide(s) known
• w/o emulsions for direct attachment of peptide to cell surface MHC-1
4. Targeting • Particulate adjuvants which Efficient use of adjuvant and immunogen bind immunogen. Adjuvants which saturate Kupffer cells As above. May also determine type of response if targeting
• Carbohydrate adjuvants which selective target lectin receptors on macrophages and DCs
5. Depot Generation • w/o emulsion for short term Efficiency
Figure imgf000118_0001
A vaccine composition according to the present invention may comprise more than one different adjuvant. Furthermore, the invention encompasses a therapeutic composition further comprising any adjuvant substance including any of the above or combinations thereof. It is also contemplated that one or more of the pharmamers according to the present invention, and the adjuvant can be administered separately in any appropriate sequence.
In one embodiment the present invention relates to a vaccine composition comprising more than 1 vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 vaccine adjuvants. In another embodiment the present invention relates to a vaccine composition comprising more than 1 different vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different vaccine adjuvants.
In yet another embodiment the present invention relates to a vaccine composition comprising more than 1 identical vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000,
5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical vaccine adjuvants.
In one embodiment the present invention relates to a vaccine composition comprising less than 10,000 vaccine adjuvants, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100,
95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 vaccine adjuvants.
In one embodiment the present invention relates to a vaccine composition comprising less than 10,000 different vaccine adjuvants, such as for example less than 9,000,
8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 different vaccine adjuvants.
In one embodiment the present invention relates to a vaccine composition comprising less than 10,000 identical vaccine adjuvants, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical vaccine adjuvants.
Vaccine enhancers
A vaccine enhancer may be present in the pharmamer vaccine independently of an adjuvant. The function of a vaccine enhancer can for example be to increase the molecular weight of the pharmamer in order to increase their activity or immunogenicity, to confer stability, to increase the biological activity, or to increase serum half-life. Furthermore, a vaccine enhancer may aid presenting the pharmamer to T-cells. The vaccine enhancer may be any suitable vaccine enhancer known to the person skilled in the art, for example a protein or an antigen presenting cell. A vaccine enhancer protein could be but is not limited to keyhole limpet hemocyanin, serum proteins such as transferrin, bovine serum albumin, human serum albumin, thyroglobulin or ovalbumin, immunoglobulins, or hormones, such as insulin or palmitic acid. For immunization of humans, the vaccine enhancer must be a physiologically acceptable vaccine enhancer acceptable to humans and safe. However, tetanus toxoid and/or diptheria toxoid are suitable vaccine enhancers in one embodiment of the invention. Alternatively, the vaccine enhancer may be dextrans for example sepharose.
In one embodiment, the vaccine composition may comprise dendritic cells. The dendritic cells (DC) may be prepared and used in therapeutic procedure according to any suitable protocol.
Combination with other vaccines/ vaccine components In another embodiment of the present invention the composition of a pharmamer vaccine may be also comprice one or more other type of vaccines or vaccine components different from pharmamers, i.e. such a composition may have a pharmamer vaccine component and one or more other vaccine components. Such other vaccine components may be categorized depending on several characteristics, including way of action; being prophylactic or therapeutic i.e. whether the vaccine induce complete prevention from disease; or improvement of disease or relief from disease symptoms; way of administration; times of administration; what kind of physical feature or matter is administered; what specific physical feature or matter is treated and how is this feature or matter treated.
Other vaccine components of the present invention include:
A vaccine is an antigenic preparation used to establish immunity to a disease or illness and thereby protects or cures the body from a specific disease or illness. Vaccines are either prophylactic and prevent disease or therapeutic and treat disease. Vaccines may contain more than one type of antigen and is then called a combined vaccine. Example, prophylactic vaccines are conventional vaccines for infectious diseases, such as measles, mumps, and tetanus. These vaccines are effective because they expose the immune system to weakened versions of the disease. This exposure causes the immune system to respond by producing antibodies. Once the immune system has created antibodies, some of the activated immune cells remember the exposure. Therefore, the next time the same antigen enters the body, the immune system can respond more readily to destroy it. For cancer treatment, researchers are developing vaccines that can encourage the immune system to recognize cancer cells. These vaccines can help the body reject tumors and prevent cancer from recurring. In contrast to traditional vaccines against infectious diseases, cancer vaccines are designed to be injected after the disease is diagnosed, rather than before it develops and are therefore therapeutic. By example, it has been shown that immunization with dendritic cells (DC) loaded with appropriate peptides from tumor associated antigens (TAAs) stimulate "tumor specific" T-cells, which in some patients prevent further progression of the disease and eventually lead to regression of the disease.
In the present invention other vaccines/other vaccine components are subdivided into the following categories:
o Vaccines made of living virulent microorganisms. Virulence refers to the degree of pathogenecity of a microbe, or in other words the relative ability of a microbe to cause disease. Examples of such organisms include but is not limited to bacteria, virus, parasites or other pathogens. Most pathogens will not be useful for vaccines if they are fully virulent but certain natural occurring modest virulent strains can be used. The vaccine may result in protection against the organism used for vaccination but may also induce protections against related virulent organisms
■ The organism may be fully virulent
■ The organism may be partly virulent meaning that the virulence of the organism has been reduced. Such organisms are often called live attenuated microorganisms. Attenuated means reducing the virulence of the microorganism while keeping it viable. Examples of reducing the virulence og an microorganism includes but is not limited to
• Modifying the microorganism by physical means, e.g. by heating • Modifying the microorganism by chemical means, e.g. by addition of chemicals to the microorganism. • Genetically modified microorganisms, e.g. recombinant bacteria or virus missing virulence factors
• Cultured under conditions that disable their virulent properties One way to reduce the virulence of an organism is passage through a foreign host e.g. tissue cultures, embryo eggs or live animals.
o Killed microorganisms are another type of vaccine. Microorganisms can be killed in several ways including but not limited to ■ Physically killing
• Killing by heating
• Killing by radioactive irradiation
■ Chemically killing, e.g. by treatment with phenol, formaldehyde or other chemicals able to kill microorganism.
o Subunit/fragment(s) of microorganism can be used as vaccine. The fragments may be isolated directly from microorganism or produced using recombinant DNA technology. Fragments/subunits of microorganisms useful in vaccines of the present invention includes but is not limited to ■ Macromolecules, e.g. naturally occurring or artificial made.
Macromolecules of the present invention includes but is not limited to:
• Proteins. The proteins may be full length or truncated and may be modified e.g. by introduction of additional amino acids, mutated, chemically modified (e.g. acetylation, methylation, Pegylation, phosphorylation, glycosylation ect.) or carrying other modifications e.g. converted into lipoprotein by the N-terminal addition of Nε-palmytoyl-lysine. The proteins may also be stabilized by covalent or non-covalent attachment of protein linkers or other protein molecules.
Proteins of the present invention includes but is not limited to: o Proteins of the immune system ■ Cytokines o lnterleukins (cytokines produces by leukocytes) o Interferon's (cytokines that can induce cells to resist viral replication) ■ Chemokines or their receptors
5 ■ Antibodies (monoclonal, polyclonal, o Full length o Fab fragments o scFv fragments o antibody-like (scaffolds) 10 ■ MHC molecules. o MHC I molecules o MHC I molecules consisting of full length or truncated heavy chain, full length or truncated 15 β2m and peptide o MHC I molecule consisting of full length or truncated heavy chain and full length and truncated β2m but no peptide 20 (empty MHC I molecule) o MHC I molecule consisting of full length or truncated heavy chain and peptide o MHC I molecule consisting of
25 full length or truncated heavy chain o MHC Il molecules o MHC Il molecules consisting of full length or truncated alpha
30 chain and full length or truncated beta chain and peptide o MHC Il molecules consisting of full length or truncated alpha 35 chain and full length and truncated beta chain but no peptide(empty MHC Il molecule)
■ Peptides
5 o Antigenic peptides, meaning any peptide that is bound or able to bind MHC molecules. o With binding motif for MHC I o With binding motif for MHC Il 10 o Other peptides
■ Heat shock proteins e.g. HSP70 and HSP90
■ T cell receptor (TCR) o Full length o Truncated 15 o Stabilized by e.g. a peptidelinker
o Proteins from microorganisms
■ Surface proteins
■ Intracellular proteins
20 ■ Secreted proteins (e.g. toxins) o Unmodified o Modified (e.g. toxoid) o Chemically modified o Physically modified 25
• Nucleic acids o DNA
■ Encoding protein
■ Structural not encoding protein 30 o RNA
■ Ribosome's
■ Antisense
■ Silencing RNA
■ Micro RNA 35 o LNA o PNA
• Carbohydrates o Saccharides and derivatives thereof, e.g. phosphorylated, oxidized, reduced, amino derivatives, acetylated ect. Saccharides may have more than one modification
■ Monosaccharide's
■ Disaccharides
■ Polysaccharides o Homopolysaccharides (e.g. glycans, dextran) o Polymers of repeating disaccharide units in which one of the sugars are is either N-acetylgalactosamine or N- acetylglucosamine (e.g. Glucosaminoglycans) o Polysaccharide-peptide polymer (Peptidoglycan (bacterial cell wall)) o Proteins carrying covalent attached oligosaccharides or polysaccharides (Glycoprotein's) o Lipids carrying covalent attached oligo- or polysaccharides (Glycolipids)
All macromolecules may be individual or in complex (e.g. attached to polymer backbone, solid support e.g. beads or other solid support, microspheres, liposome's or other nanoclusters)
Cell based vaccine is another type of vaccine of the present invention. Characteristics of different cell based vaccines are listed below. ■ Consisting of naturally occurring cells
• Cells are isolated and optionally amplified e.g. by proliferation • Cells are isolated and modified to display specific molecules e.g. specific MHC complexes by incubation with antigenic peptide. Following modification the cells may be proliferated.
■ Consisting of non-naturally occurring cells. Non-naturally occurring cells of the present invention includes but is not limited to:
• Chemically modified cells
• Genetically modified cells o Cells fused to another cell (e.g. hybridomas) o Cells transfected, transformed or transduced with genes or nucleic acids encoding specific proteins
(e.g. with super coiled plasmid DNA linear DNA, RNA, siRNA or other)
Examples of pharmamer vaccines
A pharmamer vaccine can be designed to elicit a multifunctional immune response i.e. a composite immune responses directed against both arms of the immune system being the adaptive and the innate immune system; and both parts of the adaptive system i.e. the humoral and the cellular part.
Example, a pharmamer vaccine against HIV (Human Immunodeficiency virus) can be designed to elicit a multifunctional immune response by combining two or more of the following components:
HLA class 1 and class 2 molecules (Human major histocompatibility antigens) for stimulation of an allo-response i.e. a response against foreign HLA. The HLA class 1 molecules are folded or partly folded with human b2Microglobulin and a peptide fitting into the binding groove. The HLA class 1 heavy chain can be complete, partial or otherwise modified. The HLA class 2 molecules consist of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove. The HLA class 2 alpha- and beta-chains can be complete, partial or otherwise modified. The peptides bound in the binding grooves may be chosen among binding-peptides derived from HIV specific proteins, i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev, Vpu, Nef, gp160 and derivatives such as gp120, gp41 and gp140, or they may be HIV unrelated. HIV virus carries the former host's HLA class 1 and 2 in the viral membrane. The HLA molecules elicit allo-responses directed against the foreign HLA molecules and recently it has been shown that allo-responses upregulate the intracellular anti HIV-1 factor (APOBEC3G) shown to play a crucial part in protection against HIV infection; HLA class 1 peptides derived from regions of the class 1 heavy chain; HLA class 2 peptides derived from regions of the class 2 alpha and/or beta chain; CD4 or part(s) hereof, the major receptor for HIV virus entry;
CCR 5 (Chemokine Receptor 5) or part(s) hereof. CCR5 is an important co-receptor for HIV virus entry into the host cell. In addition the extracellular peptide-loops of CCR5 are known to inhibit strains of HIV and SIV and act synergistically with HSP70 to stimulate the innate immune responses;
CXCR4 or part(s) hereof. CXCR4 can function as co-receptor for HIV virus entry into the host cell;
CCR 2 (Chemokine Receptor 2) or part(s) hereof. CCR2 can function as co-receptor for HIV virus entry into the host cell; CX3CR1 or part(s) hereof. CX3CR1 can function as co-receptor for HIV virus entry into the host cell;
SDF-1 or part(s) hereof. SDF-1 can function as co-receptor for HIV virus entry into the host cell; US28 or part(s) hereof. US28 is a CMV (Cytomegalovirus) protein expressed on already CMV infected cells that can function as co-receptor for HIV virus entry into the host cell;
HIV viral specific proteins i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140; HSP70 (70 kD Heat-shock protein) or part(s) hereof. HSP70 induces a robust mucosal immune response. HSP70 in addition generates a number of anti-HIV functions, such as inducing production of the CCR5 binding CC chemokines, blocking CCR5 directly, and stimulating DC (Dendritic Cells) to produce IL-15 which inhibits HIV-1 and enhances the inhibitory effect of CD8-SF (CD8 Suppressor Factor). HSP70 enhances memory T cells, upregulates the costimulatory CD40-CD40L pathway and induces cross-presentations of antigens. An important feature is that HSP70 upregulate the intracellular anti HIV-1 factor, APOBEC3G (apolipoprotein B mRNA-editing, enzyme- catalytic, polypeptide-like-3G) which has recently been shown to play a crucial role in protection against HIV infection The pharmamer HIV vaccine can be applied at the cervico-vaginal mucosa i.e. vaginally or IM i.e. intra-muscular. The pharmamer HIV vaccine can be administered alone or together with additional adjuvant(s) such as but not limited to Titermax Gold, Alhydrogel (Aluminium-hydroxide), MF59 and the proprietary Montanide ISA720.
Example, a pharmamer vaccine against SIV (Simian Immunodeficiency virus) can be designed to elicit a multifunctional immune response by combining two or more of the following components:
Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens) for stimulation of an allo-response i.e. a response against foreign Mamu. The Mamu class 1 molecules are folded or partly folded with human b2Microglobulin and a peptide fitting into the binding groove. The Mamu class 1 heavy chain can be complete, partial or otherwise modified. The Mamu class 2 molecules consist of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove. The
Mamu class 2 alpha- and beta-chains can be complete, partial or otherwise modified. The peptides bound in the binding grooves may be chosen among binding-peptides derived from SIV specific proteins, i.e. Gag-Pol, Gag, Vif, Vpx, Envelope protein, Nef, or they may be SIV unrelated. HIV virus carries the former host's Mamu class 1 and 2 in the viral membrane. The Mamu molecules elicit allo-responses directed against the foreign Mamu molecules and recently it has been shown that allo-responses upregulate the intracellular anti HIV-1 factor (APOBEC3G) shown to play a crucial part in protection against HIV infection; Mamu class 1 peptides derived from regions of the class 1 heavy chain; Mamu class 2 peptides derived from regions of the class 2 alpha and/or beta chain; CD4 or part(s) hereof, the major receptor for SIV virus entry;
CCR 5 (Chemokine Receptor 5) or part(s) hereof. CCR5 is an important co-receptor for SIV virus entry into the host cell. In addition the extracellular peptide-loops of CCR5 are known to inhibit strains of HIV and SIV and act synergistically with HSP70 to stimulate the innate immune responses;
CXCR4 or part(s) hereof. CXCR4 can function as co-receptor for SIV virus entry into the host cell;
CCR 2 (Chemokine Receptor 2) or part(s) hereof. CCR2 can function as co-receptor for SIV virus entry into the host cell; CX3CR1 or part(s) hereof. CX3CR1 can function as co-receptor for SIV virus entry into the host cell;
SDF-1 or part(s) hereof. SDF-1 can function as co-receptor for SIV virus entry into the host cell; SIV viral specific proteins i.e. Gag-Pol, Gag, Vif, Vpx, Envelope protein, Nef;
HSP70 (70 kD Heat-shock protein) or part(s) hereof. HSP70 induces a robust mucosal immune response. HSP70 in addition generates a number of anti-SIV functions, such as inducing production of the CCR5 binding CC chemokines, blocking CCR5 directly, and stimulating DC (Dendritic Cells) to produce IL-15 which inhibits HIV-1 and enhances the inhibitory effect of CD8-SF (CD8 Suppressor Factor). HSP70 enhances memory T cells, upregulates the costimulatory CD40-CD40L pathway and induces cross-presentations of antigens. An important feature is that HSP70 upregulate the intracellular anti SIV factor, APOBEC3G (apolipoprotein B mRNA-editing, enzyme- catalytic, polypeptide-like-3G) which has recently been shown to play a crucial role in protection against SIV infection
The pharmamer HIV vaccine can be applied at the cervico-vaginal mucosa i.e. vaginally or IM i.e. intra-muscular. The pharmamer HIV vaccine can be administered alone or together with additional adjuvant(s) such as but not limited to Titermax Gold, Alhydrogel (Aluminium-hydroxide), MF59 and the proprietary Montanide ISA720.
Combination therapy
The present invention furthermore relates to pharmceutical compositions and kit-of- parts for use in combination therapy.
Combination therapy as used herein denotes treatment an individual in need thereof with more than one different method. Hence combination therapy may in one aspect involve adminstration of a pharmaceutical composition or a kit of parts comprising a vaccine composition as described herein above and e.g. an anti-cancer or anti-HIV medicament.
Anti-cancer medicaments may be any of the medicaments described herein below, for example a chemotherapeutic agent or a immunotherapeutic agent.
In particular combination therapy may involve administration to an individual of a chemotherapeutic agent and/or an immunotherapeutic agent in combination with one or more of i) the pharmamer of the present invention, ii) an antigen presenting cell presenting the pharmamer of the present invention, and iii) an activated, pharmamer specific T-cell. However, combination therapy may also involve radiation therapy, gene therapy and/or surgery.
Combination therapy thus may include administration, simultaneously, or sequencially in any order, of e.g.:
i) the pharmamer of the present invention + at least one chemotherapeutic agent ii) the pharmamer of the present invention + at least one immunotherapeutic agent iii) Antigen presenting cell presenting the pharmamer of the present invention + at least one chemotherapeutic agent iv) Antigen presenting cell presenting the pharmamer of the present invention + at least one immunotherapeutic agent v) Activated T-cells + at least one chemotherapeutic agent vi) Activated T-cells + at least one immunotherapeutic agent
Further combinations include i) and ii); iii) and iv); v) and vi); i) and iii); i) and iv), i) and v); i) and vi); ii) and iii); ii) and iv); ii) and v); ii) and vi); iii) and v); iii) and vi); iv) and v); iv) and vi); i) and iv) and any of v) and vi).
The chemotherapeutic agent can be e.g. methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MM1270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, MTA/LY231514, LY264618/I_ometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, lncel/VX-710, VX-853, ZD0101 , ISI641 , ODN 698, TA 2516/Marmistat, BB2516/Marmistat, CDP 845, D2163, PD183805, DX8951 f , Lemonal DP 2202, FK 317, Picibanil/OK-432, AD 32/Valrubicin, Metastron/strontium derivative, Temodal/Temozolomide, Evacet/liposomal doxorubicin, Yewtaxan/Placlitaxel, Taxol/Paclitaxel, Xeload/Capecitabine, Furtulon/Doxifluridine, Cyclopax/oral paclitaxel, Oral Taxoid, SPU-077/Cisplatin, HMR 1275/Flavopiridol, CP-358 (774)/EGFR, CP-609 (754)/RAS oncogene inhibitor, BMS- 182751 /oral platinum, UFT(Tegafur/Uracil), Ergamisol/Levamisole, Eniluracil/776C85/5FU enhancer, Campto/Levamisole, Camptosar/lrinotecan, Tumodex/Ralitrexed, Leustatin/Cladribine, Paxex/Paclitaxel, Doxil/liposomal doxorubicin, Caelyx/liposomal doxorubicin, Fludara/Fludarabine, Pharmarubicin/Epirubicin, DepoCyt, ZD1839, LU 79553/Bis-Naphtalimide, LU 103793/Dolastain, Caetyx/liposomal doxorubicin, Gemzar/Gemcitabine, ZD
0473/Anormed, YM 1 16, Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/lfosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331 , Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide,
Asparaginase, Busulfan, Carboplatin, Chlorambucil, Cytarabine HCI, Dactinomycin, Daunorubicin HCI, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH-releasing factor analogue), Lomustine (CCNU), Mechlorethamine HCI (nitrogen mustard),
Mercaptopurine, Mesna, Mitotane (o.p'-DDD), Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m-AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), lnterleukin 2, Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone; MGBG), Pentostatin (2'deoxycoformycin), Semustine (methyl- CCNU), Teniposide (VM-26) and Vindesine sulfate. Furthermore, the chemotheraputic agent may be any of the chemotherapeutic agents mentioned in table 3 of US 6,482,843 column 13 to 18.
The anti-cancer drug can in one preferred embodiment be selected from the group consisting of Aldesleukin/Proleukin (Chiron Corp), Alemtuzumab/Campath (Millennium and ILEX Partners, LP), alitretinoin/Panretin (Ligand Pharmaceuticals), allopurinol/Zyloprim (GlaxoSmithKline), altretamine/Hexalen (US Bioscience), amifostine/Ethyol (US Bioscience), anastrozole/Arimidex (AstraZeneca), arsenic trioxide/Trisenox (Cell Therapeutic), Asparaginase/EIspar (Merck & Co, Inc), BCG Live/TICE BCG (Organon Teknika Corp), bexarotene capsules/Targretin (Ligand Pharmaceuticals), bleomycin/Blenoxane (Bristol-Myers Squibb), busulfan/Busulfex (GlaxoSmithKline), calusterone/Methosarb (Pharmacia & Upjohn Company), capecitabine/Xeloda (Roche), carboplatin/Paraplatin (Bristol-Myers Squibb), carmustine/BCNU, BiCNU (Bristol-Myers Squibb), carmustine with Polifeprosan 20 Implant/Gliadel Wafer (Guilford Pharmaceuticals Inc.), celecoxib/Celebrex (Searle), chlorambucil /Leukeran (GlaxoSmithKline), cisplatin/Platinol (Bristol-Myers Squibb), cladribine/Leustatin, 2-CdA (R.W. Johnson Pharmaceutical Research Institute), cyclophosphamide Cytoxan/ Neosar (Bristol-Myers Squibb), cytarabine/Cytosar-U (Pharmacia & Upjohn Company), dacarbazine/DTIC-Dome (Bayer), dactinomycin/actinomycin D Cosmegen (Merck), Darbepoetin alfa/Aranesp (Amgen, Inc), daunorubicin/daunomycin/Daunorubicin (Bedford Labs), daunorubicin/daunomycin/Cerubidine (Wyeth Ayerst), Denileukin/diftitox/Ontak (Seragen, Inc), dexrazoxane/Zinecard (Pharmacia & Upjohn Company), docetaxel/Taxotere (Aventis Pharmaceutical), doxorubicin Adriamycin/Rubex
(Pharmacia & Upjohn Company), DROMOSTANOLONE PROPIONATE/MASTERONE INJECTION (SYNTEX), Elliott's B Solution (Orphan Medical, Inc), epirubicin/Ellence (Pharmacia & Upjohn Company), etoposide phosphate (Bristol-Myers Squibb), etoposide/VP-16/Vepesid (Bristol-Myers Squibb), exemestane/Aromasin (Pharmacia & Upjohn Company), Filgrastim/Neupogen (Amgen, Inc), floxuridine/FUDR (Roche), fludarabine/Fludara (Berlex Laboratories Inc.), fluorouracil/5-FU/Adrucil (ICN Puerto Rico), fulvestrant/Faslodex (IPR), gemcitabine/Gemzar (EIi Lilly), gemtuzumab/ozogamicin/Mylotarg (Wyeth Ayerst), goserelin acetate/Zoladex Implant (AstraZeneca Pharmaceuticals), hydroxyurea/Hydrea (Bristol-Myers Squibb), lbritumomab Tiuxetan/Zevalin (IDEC Pharmaceuticals Corp), idarubicin/ldamycin (Adria Laboratories), ifosfamide/IFEX (Bristol-Myers Squibb), imatinib mesylate/Gleevec (Novartis), Interferon alfa-2a/Roferon-A (Hoffmann-La Roche Inc), Interferon alfa-2b/lntron A (Schering Corp), irinotecan/Camptosar (Pharmacia & Upjohn Company), letrozole/Femara (Novartis), leucovorin Wellcovorin/Leucovorin (Immunex Corporation), levamisole/Ergamisol (Janssen Research Foundation), lomustine/CCNU/CeeBU (Bristol-Myers Squibb), meclorethamine/nitrogen mustard/Mustargen (Merck), megestrol acetate/Meg ace (Bristol-Myers Squibb), melphalan/L-PAM/Alkeran (GlaxoSmithKline), mercaptopurine/6-MP Purinethol (GlaxoSmithKline), mesna/Mesnex (Asta Medica), methotrexate (Lederle Laboratories), methoxsalen/Uvadex (Therakos), mitomycin C/Mutamycin (Bristol-Myers Squibb), mitomycin C/Mitozytrex (Supergen), mitotane/Lysodren (Bristol-Myers Squibb), mitoxantrone/Novantrone (Lederle Laboratories), nandrolone phenpropionate/Durabolin-50 (Organon), Nofetumomab/Verluma (Boehringer lngelheim Pharma KG (formerly Dr. Karl Thomae GmbH)), Oprelvekin/Neumega (Genetics Institute), oxaliplatin/Eloxatin (Sanofi Synthelabo), paclitaxel/Taxol (Bristol- Myers Squibb), pamidronate/Aredia (Novartis), pegademase/Adagen (Pegademase Bovine) (Enzon), Pegaspargase/Oncaspar (Enzon, Inc), Pegfilgrastim/Neulasta (Amgen, Inc), pentostatin/Nipent (Parke-Davis Pharmaceutical Co.), pipobroman/Vercyte (Abbott Labs), plicamycin/mithramycin/Mithracin (Pfizer Labs), porfimer sodium/Photofrin (QLT Phototherapeutics Inc.), procarbazine/Matulane
(Sigma Tau Pharms), quinacrine/Atabrine (Abbott Labs), Rasburicase/Elitek (Sanofi- Synthelabo, Inc), Rituximab/Rituxan (Genentech, Inc), Sargramostim/Prokine (Immunex Corp), streptozocin/Zanosar(Pharmacia & Upjohn Company), talc/Sclerosol (Bryan), tamoxifen/Nolvadex (AstraZeneca Pharmaceuticals), temozolomide/Temodar (Schering), teniposide/VM-26/Vumon (Bristol-Myers Squibb), testolactone/Teslac (Bristol-Myers Squibb), thioguanine/6-TG/Thioguanine (GlaxoSmithKline), thiotepa/Thioplex (Lederle Laboratories), topotecan/Hycamtin (GlaxoSmithKline), topotecan/Hycamtin (GlaxoSmithKline), toremifene/Fareston (Orion Corp), Tositumomab/Bexxar (Corixa Corporation), Trastuzumab/Herceptin (Genentech, Inc), tretinoin/ATRA/Vesanoid (Roche), Uracil Mustard (Roberts Labs), valrubicin/Valstar (Medeva), vinblastine/Velban (EIi Lilly), vincristine/Oncovin (EIi Lilly), vinorelbine/Navelbine (GlaxoSmithKline), and zoledronate/Zometa (Novartis).
The immunotherapeutic agent can be e.g. Ributaxin, Herceptin, Quadramet, Panorex, IDEC-Y2B8, BEC2, C225, Oncolym, SMART Ml 95, ATRAGEN, Ovarex, Bexxar, LDP- 03, ior .6, MDX-210, MDX-1 1 , MDX-22, OV103, 3622W94, anti-VEGF, Zenapax, MDX- 220, MDX-447, MELIMMUNE-2, MELIMMUNE-1 , CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab-H, GNI-250, EMD-72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.ι-3, ior c5, BABS, anti-FLK-2, MDX-260, ANA Ab, SMART 1 D10 Ab, SMART ABL 364 Ab and ImmuRAIT-CEA. Furthermore the immunotherapeutic agent may be any cytokine or interferon.
The therapeutic compositions or vaccine compositions of the invention can also be used in combination with other anti-cancer strategies, and such combination therapies are effective in inhibiting and/or eliminating tumor growth and metastasis. The methods of the present invention can advantageously be used with other treatment modalities, including, without limitation, radiation, surgery, gene therapy and chemotherapy. The therapeutic compositions or vaccine compositions of the invention can also be used in combination with treatment of HIV. In one embodiment treatment of HIV includes administration of one or more of the drugs listed herein below.
There are five groups of antiretroviral drugs. Each of these groups attacks HIV in a different way.
Figure imgf000134_0001
Multi-class combinations:
Figure imgf000135_0001
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs):
Figure imgf000135_0002
Combined NRTIs:
Figure imgf000135_0003
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
Figure imgf000135_0004
Protease Inhibitors (PIs):
Figure imgf000135_0005
Figure imgf000136_0001
Fusion or Entry Inhibitors:
Figure imgf000136_0002
lntegrase Inhibitors:
Figure imgf000136_0003
Other types of HIV treatments include administration of one or more of the following:
• Atripla - (a single pill that includes efavirenz÷ tenofovir+FTC). People taking a first-line combination of efavirenz and Truvada, with an undetectable viral load for three months, can switch to Atripla
• Atazanavir/r for first-line therapy is currently being researched, and the results are expected shortly. Atavanavir/r is widely used as first line treatment.
• Darunavir/r was approved as a treatment for people with resistance. In a recent study, darunavir did better than Kaletra as first therapy.
• Raltegravir - (an integrase inhibitor) has shown similar potency to efavirenz, but has fewer side effects or interactions with other drugs.
• Maraviroc - (an entry inhibitor).
• Etravirine - (a new NNRTI). "Combination therapy" can include the introduction of heterologous nucleic acids into suitable cells, generally known as gene therapy. For example gene therapy may involve introduction of tumour suppressor genes or apoptosis promoting genes into tumour cells. Alternatively, nucleic acid sequences inhibiting expression of oncogenes or apoptosis inhibiting genes may be introduced to tumour cells. Furthermore, genes that encode enzymes capable of conferring to tumor cells sensitivity to chemotherapeutic agents may be introduced. Accordingly, the present invention in one embodiment provides a method comprising the step of treating cancer by introducing a gene vector, encoding a protein capable of enzymatically converting a prodrug, i.e., a non-toxic compound, into a toxic compound. In the method of the present invention, the therapeutic nucleic acid sequence is a nucleic acid coding for a product, wherein the product causes cell death by itself or in the presence of other drugs. A representative example of such a therapeutic nucleic acid is one, which codes for thymidine kinase of herpes simplex virus. Additional examples are thymidine kinase of varicella zoster virus and the bacterial gene cytosine deaminase, which can convert 5-fluorocytosine to the highly toxic compound 5-fluorouracil.
Kit-of-parts
A kit comprising a composition of the present invention is also provided. The kit can include a separate container containing a suitable vaccine enhancer, diluent or excipient, In addition, the kit can include instructions for mixing or combining ingredients and/or administration route/shemes.
Detection of vaccine results
In one embodiment the present invention relates to use of the pharmamers according to the present invention such as MHC dextramers for use of detection of vaccine results. Dectection of the vaccine response can comprise any method for immune monitoring know in the art inclduing one or more assays described in PCT/DK/2008/050168, PCT/DK2008/050167 and PA 2008 01035. PCT/DK/2008/050168, PCT/DK2008/050167 and PA 2008 01035 are hereby incorporated by reference in there entirety in this application.
In one embodiment a blood sample such as peripheral blood is obtained from a patient before vaccination and subsequent to a series of vaccinations. In order to identify peptide-specific T-cell precursors, periferal blood lymphocytes (PBL) are used e.g. directly in ELISPOT (designated direct ELISPOT) or any other relevant assay know in the art such as ELISA.
In one aspect the invention relates to methods of monitoring immunisation, said method comprising the steps of i) providing a blood sample from an individual ii) providing a peptide or pharmamer of the present invention iii) determining whether said blood sample comprises antibodies or T-cells comprising T-cell receptors specifically binding the peptide or pharmamer of the present invention iv) thereby determining whether an immune response to said peptide or pharmamer has been raised in said individual.
Use of the pharmamers of the present invention for immune monitorering assays such as MHC multimer assays, ELISPOT, CFC and other assays involving formation of MHC-peptide complexes are also part of the present invention.
There is, in still further aspects, provided a diagnostic kit for ex vivo or in situ diagnosis of the presence specific T cells among PBLs or in tissue such as tumour tissue comprising one or more peptides or one or more pharmamers of the invention, and a method of detecting in a patient the presence of such reactive T cells, the method comprising contacting a tissue or a blood sample with a complex of a peptide of the invention and e.g. a Class I HLA molecule or a fragment of such molecule and detecting binding of the complex to the tissue or the blood cells.
Pharmamers comprising peptide sequences In one embodiment the present invention relates to pharmamers comprising one or more peptides. The peptides can in one embodiment be defined as outlined in the items herein below. It is to be understood that said items are not meant to be limiting to the peptide according to the present invention in that said peptide may consist of more than said 8 to 16 amino acids, but at least comprising said 8 to 16 amino acids.
Thus, in one embodiment of the present invention, the peptide may be a fragment or part of a larger protein, wherein the larger protein may be of a total length of 17, such as 18, for example 19, such as 20, for example 21 , such as 22, for example 23, such as 24, for example 25, such as 26, for example 27, such as 28, for example 29, such as 30, for example 31 , such as 32, for example 33, such as 34, for example 35, such as 36, for example 37, such as 38, for example 39, such as 40 amino acids, wherein 8 to 16 of said amino acids are defined in the items below. In another embodiment, the larger protein may be of a total length of between 20 to 30, such as 30-40, for example 40-50, such as 50-60, for example 60-70, such as 70-80, for example 80-90, such as 90-100, for example 100-150, such as 150-200, for example 200-250, such as 250- 300, for example 300-500, such as 500-1000, for example 1000-2000, such as 2000- 3000, for example 3000-4000, such as 4000-5000, for example 5000-10,000, such as 10,000-20,000, for example 20,000-30,000, such as 30,000-40,000, for example 40,000-50,000, such as 50,000-75,000, for example 75,000-100,000, such as 100,000- 250,000, for example 250,000-, 500, 000, such as 500,000-1 ,000,000 amino acids.
It is also to be understood, that the co-translational and post-translational modifications may occur either individually or in combination, on the same or different amino acid residues. Thus, in one embodiment, any one amino acid may be modified once, twice or three times with the same or different types of modifications. Furthermore, said identical and/or different modification may be present on 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17 or 18 of the amino acid residues of the peptide according to the present invention as defined in the items below in 'the first set of items'. In addition, modifications may also be present on amino acid residues outside said 8 to 16 amino acids, in case the peptide is part of a larger protein.
FIRST SET OF ITEMS
I . A peptide of between 8 to 16 consecutive amino acids, comprising at least 8 of amino acid number X1-X2-X3-X4-X5-X6-X7-X8-X9-Xio-XirXi2-Xi3-Xi4-Xi5-Xi6 2. The peptide according to item 1 , wherein Xi is alanine
3. The peptide according to item 1 , wherein Xi is arginine
4. The peptide according to item 1 , wherein Xi is asparagine
5. The peptide according to item 1 , wherein Xi is aspartic acid
6. The peptide according to item 1 , wherein Xi is cysteine 7. The peptide according to item 1 , wherein Xi is glutamic acid
8. The peptide according to item 1 , wherein X1 is glutamine
9. The peptide according to item 1 , wherein X1 is glycine
10. The peptide according to item 1 , wherein X1 is histidine
I 1 . The peptide according to item 1 , wherein X1 is isoleucine 12. The peptide according to item 1 , wherein X1 is leucine
13. The peptide according to item 1 , wherein X1 is lysine
14. The peptide according to item 1 , wherein X1 is methionine
15. The peptide according to item 1 , wherein X1 is phenylalanine
16. The peptide according to item 1 , wherein X1 is proline 17. The peptide according to item 1 , wherein X1 is serine 18. The peptide according to item 1 , wherein Xi is threonine
19. The peptide according to item 1 , wherein Xi is tryptophan
20. The peptide according to item 1 , wherein Xi is tyrosine
21 . The peptide according to item 1 , wherein Xi is valine 22. The peptide according to item 1 , wherein X2 is alanine
23. The peptide according to item 1 , wherein X2 is arginine
24. The peptide according to item 1 , wherein X2 is asparagine
25. The peptide according to item 1 , wherein X2 is aspartic acid
26. The peptide according to item 1 , wherein X2 is cysteine 27. The peptide according to item 1 , wherein X2 is glutamic acid
28. The peptide according to item 1 , wherein X2 is glutamine
29. The peptide according to item 1 , wherein X2 is glycine
30. The peptide according to item 1 , wherein X2 is histidine
31 . The peptide according to item 1 , wherein X2 is isoleucine 32. The peptide according to item 1 , wherein X2 is leucine
33. The peptide according to item 1 , wherein X2 is lysine
34. The peptide according to item 1 , wherein X2 is methionine
35. The peptide according to item 1 , wherein X2 is phenylalanine
36. The peptide according to item 1 , wherein X2 is proline 37. The peptide according to item 1 , wherein X2 is serine
38. The peptide according to item 1 , wherein X2 is threonine
39. The peptide according to item 1 , wherein X2 is tryptophan
40. The peptide according to item 1 , wherein X2 is tyrosine
41 . The peptide according to item 1 , wherein X2 is valine 42. The peptide according to item 1 , wherein X3 is alanine
43. The peptide according to item 1 , wherein X3 is arginine
44. The peptide according to item 1 , wherein X3 is asparagine
45. The peptide according to item 1 , wherein X3 is aspartic acid
46. The peptide according to item 1 , wherein X3 is cysteine 47. The peptide according to item 1 , wherein X3 is glutamic acid
48. The peptide according to item 1 , wherein X3 is glutamine
49. The peptide according to item 1 , wherein X3 is glycine
50. The peptide according to item 1 , wherein X3 is histidine
51 . The peptide according to item 1 , wherein X3 is isoleucine 52. The peptide according to item 1 , wherein X3 is leucine 53. The peptide according to item 1 , wherein X3 is lysine
54. The peptide according to item 1 , wherein X3 is methionine
55. The peptide according to item 1 , wherein X3 is phenylalanine
56. The peptide according to item 1 , wherein X3 is proline 57. The peptide according to item 1 , wherein X3 is serine
58. The peptide according to item 1 , wherein X3 is threonine
59. The peptide according to item 1 , wherein X3 is tryptophan
60. The peptide according to item 1 , wherein X3 is tyrosine
61 . The peptide according to item 1 , wherein X3 is valine 62. The peptide according to item 1 , wherein X4 is alanine
63. The peptide according to item 1 , wherein X4 is arginine
64. The peptide according to item 1 , wherein X4 is asparagine
65. The peptide according to item 1 , wherein X4 is aspartic acid
66. The peptide according to item 1 , wherein X4 is cysteine 67. The peptide according to item 1 , wherein X4 is glutamic acid
68. The peptide according to item 1 , wherein X4 is glutamine
69. The peptide according to item 1 , wherein X4 is glycine
70. The peptide according to item 1 , wherein X4 is histidine
71 . The peptide according to item 1 , wherein X4 is isoleucine 72. The peptide according to item 1 , wherein X4 is leucine
73. The peptide according to item 1 , wherein X4 is lysine
74. The peptide according to item 1 , wherein X4 is methionine
75. The peptide according to item 1 , wherein X4 is phenylalanine
76. The peptide according to item 1 , wherein X4 is proline 77. The peptide according to item 1 , wherein X4 is serine
78. The peptide according to item 1 , wherein X4 is threonine
79. The peptide according to item 1 , wherein X4 is tryptophan
80. The peptide according to item 1 , wherein X4 is tyrosine
81 . The peptide according to item 1 , wherein X4 is valine 82. The peptide according to item 1 , wherein X5 is alanine
83. The peptide according to item 1 , wherein X5 is arginine
84. The peptide according to item 1 , wherein X5 is asparagine
85. The peptide according to item 1 , wherein X5 is aspartic acid
86. The peptide according to item 1 , wherein X5 is cysteine 87. The peptide according to item 1 , wherein X5 is glutamic acid 88. The peptide according to item 1 , wherein X5 is glutamine
89. The peptide according to item 1 , wherein X5 is glycine
90. The peptide according to item 1 , wherein X5 is histidine
91 . The peptide according to item 1 , wherein X5 is isoleucine 92. The peptide according to item 1 , wherein X5 is leucine
93. The peptide according to item 1 , wherein X5 is lysine
94. The peptide according to item 1 , wherein X5 is methionine
95. The peptide according to item 1 , wherein X5 is phenylalanine
96. The peptide according to item 1 , wherein X5 is proline 97. The peptide according to item 1 , wherein X5 is serine
98. The peptide according to item 1 , wherein X5 is threonine
99. The peptide according to item 1 , wherein X5 is tryptophan
100. The peptide according to item 1 , wherein X5 is tyrosine
101 . The peptide according to item 1 , wherein X5 is valine 102. The peptide according to item 1 , wherein X6 is alanine
103. The peptide according to item 1 , wherein X6 is arginine
104. The peptide according to item 1 , wherein X6 is asparagine
105. The peptide according to item 1 , wherein X6 is aspartic acid
106. The peptide according to item 1 , wherein X6 is cysteine 107. The peptide according to item 1 , wherein X6 is glutamic acid
108. The peptide according to item 1 , wherein X6 is glutamine
109. The peptide according to item 1 , wherein X6 is glycine
1 10. The peptide according to item 1 , wherein X6 is histidine
1 1 1 . The peptide according to item 1 , wherein X6 is isoleucine 1 12. The peptide according to item 1 , wherein X6 is leucine
1 13. The peptide according to item 1 , wherein X6 is lysine
1 14. The peptide according to item 1 , wherein X6 is methionine
1 15. The peptide according to item 1 , wherein X6 is phenylalanine
1 16. The peptide according to item 1 , wherein X6 is proline 1 17. The peptide according to item 1 , wherein X6 is serine
1 18. The peptide according to item 1 , wherein X6 is threonine
1 19. The peptide according to item 1 , wherein X6 is tryptophan
120. The peptide according to item 1 , wherein X6 is tyrosine
121 . The peptide according to item 1 , wherein X6 is valine 122. The peptide according to item 1 , wherein X7 is alanine 123. The peptide according to item 1 , wherein X7 is arginine
124. The peptide according to item 1 , wherein X7 is asparagine
125. The peptide according to item 1 , wherein X7 is aspartic acid
126. The peptide according to item 1 , wherein X7 is cysteine 127. The peptide according to item 1 , wherein X7 is glutamic acid
128. The peptide according to item 1 , wherein X7 is glutamine
129. The peptide according to item 1 , wherein X7 is glycine
130. The peptide according to item 1 , wherein X7 is histidine
131 . The peptide according to item 1 , wherein X7 is isoleucine 132. The peptide according to item 1 , wherein X7 is leucine
133. The peptide according to item 1 , wherein X7 is lysine
134. The peptide according to item 1 , wherein X7 is methionine
135. The peptide according to item 1 , wherein X7 is phenylalanine
136. The peptide according to item 1 , wherein X7 is proline 137. The peptide according to item 1 , wherein X7 is serine
138. The peptide according to item 1 , wherein X7 is threonine
139. The peptide according to item 1 , wherein X7 is tryptophan
140. The peptide according to item 1 , wherein X7 is tyrosine
141 . The peptide according to item 1 , wherein X7 is valine 142. The peptide according to item 1 , wherein X8 is alanine
143. The peptide according to item 1 , wherein X8 is arginine
144. The peptide according to item 1 , wherein X8 is asparagine
145. The peptide according to item 1 , wherein X8 is aspartic acid
146. The peptide according to item 1 , wherein X8 is cysteine 147. The peptide according to item 1 , wherein X8 is glutamic acid
148. The peptide according to item 1 , wherein X8 is glutamine
149. The peptide according to item 1 , wherein X8 is glycine
150. The peptide according to item 1 , wherein X8 is an histidine
151 . The peptide according to item 1 , wherein X8 is isoleucine 152. The peptide according to item 1 , wherein X8 is leucine
153. The peptide according to item 1 , wherein X8 is lysine
154. The peptide according to item 1 , wherein X8 is methionine
155. The peptide according to item 1 , wherein X8 is phenylalanine
156. The peptide according to item 1 , wherein X8 is proline 157. The peptide according to item 1 , wherein X8 is serine 158. The peptide according to item 1 , wherein X8 is threonine
159. The peptide according to item 1 , wherein X8 is tryptophan
160. The peptide according to item 1 , wherein X8 is tyrosine
161 . The peptide according to item 1 , wherein X8 is valine 162. The peptide according to item 1 , wherein X9 is alanine
163. The peptide according to item 1 , wherein X9 is arginine
164. The peptide according to item 1 , wherein X9 is asparagine
165. The peptide according to item 1 , wherein X9 is aspartic acid
166. The peptide according to item 1 , wherein X9 is cysteine 167. The peptide according to item 1 , wherein X9 is glutamic acid
168. The peptide according to item 1 , wherein X9 is glutamine
169. The peptide according to item 1 , wherein X9 is glycine
170. The peptide according to item 1 , wherein X9 is an histidine
171 . The peptide according to item 1 , wherein X9 is isoleucine 172. The peptide according to item 1 , wherein X9 is leucine
173. The peptide according to item 1 , wherein X9 is lysine
174. The peptide according to item 1 , wherein X9 is methionine
175. The peptide according to item 1 , wherein X9 is phenylalanine
176. The peptide according to item 1 , wherein X9 is proline 177. The peptide according to item 1 , wherein X9 is serine
178. The peptide according to item 1 , wherein X9 is threonine
179. The peptide according to item 1 , wherein X9 is tryptophan
180. The peptide according to item 1 , wherein X9 is tyrosine
181 . The peptide according to item 1 , wherein X9 is valine 182. The peptide according to item 1 , wherein X9 is alanine
183. The peptide according to item 1 , wherein X9 is arginine
184. The peptide according to item 1 , wherein X9 is asparagine
185. The peptide according to item 1 , wherein X9 is aspartic acid
186. The peptide according to item 1 , wherein X9 is cysteine 187. The peptide according to item 1 , wherein X9 is glutamic acid
188. The peptide according to item 1 , wherein X9 is glutamine
189. The peptide according to item 1 , wherein X9 is glycine
190. The peptide according to item 1 , wherein X9 is an histidine
191 . The peptide according to item 1 , wherein X9 is isoleucine 192. The peptide according to item 1 , wherein X9 is leucine 193. The peptide according to item 1 , wherein X9 is lysine
194. The peptide according to item 1 , wherein X9 is methionine
195. The peptide according to item 1 , wherein X9 is phenylalanine
196. The peptide according to item 1 , wherein X9 is proline 197. The peptide according to item 1 , wherein X9 is serine
198. The peptide according to item 1 , wherein X9 is threonine
199. The peptide according to item 1 , wherein X9 is tryptophan
200. The peptide according to item 1 , wherein X9 is tyrosine
201 . The peptide according to item 1 , wherein X9 is valine 202. The peptide according to item 1 , wherein X10 is alanine
203. The peptide according to item 1 , wherein X10 is arginine
204. The peptide according to item 1 , wherein X10 is asparagine
205. The peptide according to item 1 , wherein X10 is aspartic acid
206. The peptide according to item 1 , wherein X10 is cysteine 207. The peptide according to item 1 , wherein X10 is glutamic acid
208. The peptide according to item 1 , wherein X10 is glutamine
209. The peptide according to item 1 , wherein Xi0 is glycine
210. The peptide according to item 1 , wherein Xi0 is an histidine
21 1 . The peptide according to item 1 , wherein Xi0 is isoleucine 212. The peptide according to item 1 , wherein Xi0 is leucine
213. The peptide according to item 1 , wherein Xi0 is lysine
214. The peptide according to item 1 , wherein Xi0 is methionine
215. The peptide according to item 1 , wherein Xi0 is phenylalanine
216. The peptide according to item 1 , wherein Xi0 is proline 217. The peptide according to item 1 , wherein Xi0 is serine
218. The peptide according to item 1 , wherein X10 is threonine
219. The peptide according to item 1 , wherein X10 is tryptophan
220. The peptide according to item 1 , wherein X10 is tyrosine
221 . The peptide according to item 1 , wherein X10 is valine 222. The peptide according to item 1 , wherein X11 is alanine
223. The peptide according to item 1 , wherein X11 is arginine
224. The peptide according to item 1 , wherein X11 is asparagine
225. The peptide according to item 1 , wherein X11 is aspartic acid
226. The peptide according to item 1 , wherein X11 is cysteine 227. The peptide according to item 1 , wherein X11 is glutamic acid 228. The peptide according to item 1 , wherein Xn is glutamine
229. The peptide according to item 1 , wherein Xn is glycine
230. The peptide according to item 1 , wherein Xn is an histidine
231 . The peptide according to item 1 , wherein Xn is isoleucine
232. The peptide according to item 1 , wherein Xn is leucine
233. The peptide according to item 1 , wherein Xn is lysine
234. The peptide according to item 1 , wherein Xn is methionine
235. The peptide according to item 1 , wherein X11 is phenylalanine
236. The peptide according to item 1 , wherein X11 is proline
237. The peptide according to item 1 , wherein X11 is serine
238. The peptide according to item 1 , wherein X11 is threonine
239. The peptide according to item 1 , wherein X11 is tryptophan
240. The peptide according to item 1 , wherein X11 is tyrosine
241 . The peptide according to item 1 , wherein X11 is valine
242. The peptide according to item 1 , wherein X12 is alanine
243. The peptide according to item 1 , wherein X12 is arginine
244. The peptide according to item 1 , wherein X12 is asparagine
245. The peptide according to item 1 , wherein X12 is aspartic acid
246. The peptide according to item 1 , wherein X12 is cysteine
247. The peptide according to item 1 , wherein X12 is glutamic acid
248. The peptide according to item 1 , wherein X12 is glutamine
249. The peptide according to item 1 , wherein X12 is glycine
250. The peptide according to item 1 , wherein X12 is histidine
251 . The peptide according to item 1 , wherein X12 is isoleucine
252. The peptide according to item 1 , wherein X12 is leucine
253. The peptide according to item 1 , wherein X12 is lysine
254. The peptide according to item 1 , wherein X12 is methionine
255. The peptide according to item 1 , wherein X12 is phenylalanine
256. The peptide according to item 1 , wherein X12 is proline
257. The peptide according to item 1 , wherein X12 is serine
258. The peptide according to item 1 , wherein X12 is threonine
259. The peptide according to item 1 , wherein X12 is tryptophan
260. The peptide according to item 1 , wherein X12 is tyrosine
261 . The peptide according to item 1 , wherein X12 is valine
262. The peptide according to item 1 , wherein X13 is alanine 263. The peptide according to item 1 , wherein Xi3 is arginine
264. The peptide according to item 1 , wherein Xi3 is asparagine
265. The peptide according to item 1 , wherein Xi3 is aspartic acid
266. The peptide according to item 1 , wherein Xi3 is cysteine
267. The peptide according to item 1 , wherein Xi3 is glutamic acid
268. The peptide according to item 1 , wherein Xi3 is glutamine
269. The peptide according to item 1 , wherein Xi3 is glycine
270. The peptide according to item 1 , wherein Xi3 is histidine
271 . The peptide according to item 1 , wherein Xi3 is isoleucine
272. The peptide according to item 1 , wherein Xi3 is leucine
273. The peptide according to item 1 , wherein Xi3 is lysine
274. The peptide according to item 1 , wherein Xi3 is methionine
275. The peptide according to item 1 , wherein Xi3 is phenylalanine
276. The peptide according to item 1 , wherein Xi3 is proline
277. The peptide according to item 1 , wherein Xi3 is serine
278. The peptide according to item 1 , wherein Xi3 is threonine
279. The peptide according to item 1 , wherein Xi3 is tryptophan
280. The peptide according to item 1 , wherein Xi3 is tyrosine
281 . The peptide according to item 1 , wherein Xi3 is valine
282. The peptide according to item 1 , wherein XM is alanine
283. The peptide according to item 1 , wherein XM is arginine
284. The peptide according to item 1 , wherein XM is asparagine
285. The peptide according to item 1 , wherein XM is aspartic acid
286. The peptide according to item 1 , wherein XM is cysteine
287. The peptide according to item 1 , wherein XM is glutamic acid
288. The peptide according to item 1 , wherein XM is glutamine
289. The peptide according to item 1 , wherein XM is glycine
290. The peptide according to item 1 , wherein XM is histidine
291 . The peptide according to item 1 , wherein XM is isoleucine
292. The peptide according to item 1 , wherein XM is leucine
293. The peptide according to item 1 , wherein XM is lysine
294. The peptide according to item 1 , wherein XM is methionine
295. The peptide according to item 1 , wherein XM is phenylalanine
296. The peptide according to item 1 , wherein XM is proline
297. The peptide according to item 1 , wherein XM is serine 298. The peptide according to item 1 , wherein XM is threonine
299. The peptide according to item 1 , wherein XM is tryptophan
300. The peptide according to item 1 , wherein XM is tyrosine
301 . The peptide according to item 1 , wherein XM is valine
302. The peptide according to item 1 , wherein Xi5 is alanine
303. The peptide according to item 1 , wherein Xi5 is arginine
304. The peptide according to item 1 , wherein Xi5 is asparagine
305. The peptide according to item 1 , wherein Xi5 is aspartic acid
306. The peptide according to item 1 , wherein Xi5 is cysteine
307. The peptide according to item 1 , wherein Xi5 is glutamic acid
308. The peptide according to item 1 , wherein Xi5 is glutamine
309. The peptide according to item 1 , wherein Xi5 is glycine
310. The peptide according to item 1 , wherein Xi5 is histidine
31 1 . The peptide according to item 1 , wherein Xi5 is isoleucine
312. The peptide according to item 1 , wherein Xi5 is leucine
313. The peptide according to item 1 , wherein Xi5 is lysine
314. The peptide according to item 1 , wherein Xi5 is methionine
315. The peptide according to item 1 , wherein Xi5 is phenylalanine
316. The peptide according to item 1 , wherein Xi5 is proline
317. The peptide according to item 1 , wherein Xi5 is serine
318. The peptide according to item 1 , wherein Xi5 is threonine
319. The peptide according to item 1 , wherein Xi5 is tryptophan
320. The peptide according to item 1 , wherein Xi5 is tyrosine
321 . The peptide according to item 1 , wherein Xi5 is valine
322. The peptide according to item 1 , wherein Xi6 is alanine
323. The peptide according to item 1 , wherein Xi6 is arginine
324. The peptide according to item 1 , wherein Xi6 is asparagine
325. The peptide according to item 1 , wherein Xi6 is aspartic acid
326. The peptide according to item 1 , wherein Xi6 is cysteine
327. The peptide according to item 1 , wherein Xi6 is glutamic acid
328. The peptide according to item 1 , wherein Xi6 is glutamine
329. The peptide according to item 1 , wherein Xi6 is glycine
330. The peptide according to item 1 , wherein Xi6 is histidine
331 . The peptide according to item 1 , wherein Xi6 is isoleucine
332. The peptide according to item 1 , wherein Xi6 is leucine 333. The peptide according to item 1 , wherein Xi6 is lysine
334. The peptide according to item 1 , wherein Xi6 is methionine
335. The peptide according to item 1 , wherein Xi6 is phenylalanine
336. The peptide according to item 1 , wherein Xi6 is proline 337. The peptide according to item 1 , wherein Xi6 is serine
338. The peptide according to item 1 , wherein Xi6 is threonine
339. The peptide according to item 1 , wherein Xi6 is tryptophan
340. The peptide according to item 1 , wherein Xi6 is tyrosine
341 . The peptide according to item 1 , wherein Xi6 is valine 342. The peptide according to any of items 2, 22, 42, 62, 82, 102, 122, 142,
162, 182, 202, 222, 242, 262, 282, 302 or 322, wherein the alanine is D-alanine
343. The peptide according to any of items 2, 22, 42, 62, 82, 102, 122, 142,
162, 182, 202, 222, 242, 262, 282, 302 or 322, wherein the alanine is L-alanine
344. The peptide according to any of items 3, 23, 43, 63, 83, 103, 123, 143, 163, 183, 203, 223, 243, 263, 283, 303 or 323, wherein the arginine is D- arginine
345. The peptide according to any of items 3, 23, 43, 63, 83, 103, 123, 143,
163, 183, 203, 223, 243, 263, 283, 303 or 323, wherein the arginine is L- arginine 346. The peptide according to any of items 4, 24, 44, 64, 84, 104, 124, 144,
164, 184, 204, 224, 244, 264, 284, 304 or 324, wherein the asparagine is D- asparagine
347. The peptide according to any of items 4, 24, 44, 64, 84, 104, 124, 144,
164, 184, 204, 224, 244, 264, 284, 304 or 324, wherein the asparagine is L- asparagine
348. The peptide according to any of items 5, 25, 45, 65, 85, 105, 125, 145,
165, 185, 205, 225, 245, 265, 285, 305 or 325, wherein the aspartic acid is D- aspartic acid
349. The peptide according to any of items 5, 25, 45, 65, 85, 105, 125, 145, 165, 185, 205, 225, 245, 265, 285, 305 or 325, wherein the aspartic acid is L- aspartic acid
350. The peptide according to any of items 6, 26, 46, 66, 86, 106, 126, 146,
166, 186, 206, 226, 246, 266, 286, 306 or 326, wherein the cysteine is D- cysteine 351 . The peptide according to any of items 6, 26, 46, 66, 86, 106, 126, 146,
166, 186, 206, 226, 246, 266, 286, 306 or 326, wherein the cysteine is L- cysteine
352. The peptide according to any of items 7, 27, 47, 67, 87, 107, 127, 147, 167, 187, 207, 227, 247, 267, 287, 307 or 327, wherein the glutamic acid is D- glutamic acid
353. The peptide according to any of items 7, 27, 47, 67, 87, 107, 127, 147,
167, 187, 207, 227, 247, 267, 287, 307 or 327, wherein the glutamic acid is L- glutamic acid 354. The peptide according to any of items 8, 28, 48, 68, 88, 108, 128, 148,
168, 188, 208, 228, 248, 268, 288, 308 or 328, wherein the glutamine is D- glutamine
355. The peptide according to any of items 8, 28, 48, 68, 88, 108, 128, 148,
168, 188, 208, 228, 248, 268, 288, 308 or 328, wherein the glutamine is L- glutamine
356. The peptide according to any of items 9, 29, 49, 69, 89, 109, 129, 149,
169, 189, 209, 229, 249, 269, 289, 309 or 329, wherein the glycine is D-glycine
357. The peptide according to any of items 9, 29, 49, 69, 89, 109, 129, 149,
169, 189, 209, 229, 249, 269, 289, 309 or 329, wherein the glycine is L-glycine 358. The peptide according to any of items 10, 30, 50, 70, 90, 1 10, 130, 150,
170, 190, 210, 230, 250, 270, 290, 310 or 330, wherein the histidine is D- histidine
359. The peptide according to any of items 10, 30, 50, 70, 90, 1 10, 130, 150,
170, 190, 210, 230, 250, 270, 290, 310 or 330, wherein the histidine is L- histidine
360. The peptide according to any of items 1 1 , 31 , 51 , 71 , 91 , 1 1 1 , 131 , 151 ,
171 , 191 , 21 1 , 231 , 251 , 271 , 291 , 31 1 or 331 , wherein the isoleucine is D- isoleucine
361. The peptide according to any of items 1 1 , 31 , 51 , 71 , 91 , 1 1 1 , 131 , 151 , 171 , 191 , 21 1 , 231 , 251 , 271 , 291 , 31 1 or 331 , wherein the isoleucine is L- isoleucine
362. The peptide according to any of items 12, 32, 52, 72, 92, 1 12, 132, 152,
172, 192, 212, 232, 252, 272, 292, 312 or 332, wherein the leucine is D-leucine
363. The peptide according to any of items 12, 32, 52, 72, 92, 1 12, 132, 152, 172, 192, 212, 232, 252, 272, 292, 312 or 332, wherein the leucine is L-leucine 364. The peptide according to any of items 13, 33, 53, 73, 93, 1 13, 133, 153, 173, 193, 213, 233, 253, 273, 293, 313 or 333, wherein the lysine is D-lysine
365. The peptide according to any of items 13, 33, 53, 73, 93, 1 13, 133, 153,
173, 193, 213, 233, 253, 273, 293, 313 or 333, wherein the lysine is L-lysine 366. The peptide according to any of items 14, 34, 54, 74, 94, 1 14, 134, 154,
174, 194, 214, 234, 254, 274, 294, 314 or 334, wherein the methionine is D- methionine
367. The peptide according to any of items 14, 34, 54, 74, 94, 1 14, 134, 154,
174, 194, 214, 234, 254, 274, 294, 314 or 334, wherein the methionine is L- methionine
368. The peptide according to any of items 15, 35, 55, 75, 95, 1 15, 135, 155,
175, 195, 215, 235, 255, 275, 295, 315 or 335, wherein the phenylalanine is D- phenylalanine
369. The peptide according to any of items 15, 35, 55, 75, 95, 1 15, 135, 155, 175, 195, 215, 235, 255, 275, 295, 315 or 335, wherein the phenylalanine is L- phenylalanine
370. The peptide according to any of items 16, 36, 56, 76, 96, 1 16, 136, 156,
176, 196, 216, 236, 256, 276, 296, 316 or 336, wherein the proline is D-proline
371. The peptide according to any of items 16, 36, 56, 76, 96, 1 16, 136, 156, 176, 196, 216, 236, 256, 276, 296, 316 or 336, wherein the proline is L-proline
372. The peptide according to any of items 17, 37, 57, 77, 97, 1 17, 137, 157,
177, 197, 217, 237, 257, 277, 297, 317 or 337, wherein the serine is D-serine
373. The peptide according to any of items 17, 37, 57, 77, 97, 1 17, 137, 157,
177, 197, 217, 237, 257, 277, 297, 317 or 337, wherein the serine is L-serine 374. The peptide according to any of items 18, 38, 58, 78, 98, 1 18, 138, 158,
178, 198, 218, 238, 258, 278, 298, 318 or 338, wherein the threonine is D- threonine
375. The peptide according to any of items 18, 38, 58, 78, 98, 1 18, 138, 158,
178, 198, 218, 238, 258, 278, 298, 318 or 338, wherein the threonine is L- threonine
376. The peptide according to any of items 19, 39, 59, 79, 99, 1 19, 139, 159,
179, 199, 219, 239, 259, 279, 299, 319 or 339, wherein the tryptophan is D- tryptophan 377. The peptide according to any of items 19, 39, 59, 79, 99, 1 19, 139, 159,
179, 199, 219, 239, 259, 279, 299, 319 or 339, wherein the tryptophan is L- tryptophan
378. The peptide according to any of items 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320 or 340, wherein the tyrosine is D- tyrosine
379. The peptide according to any of items 20, 40, 60, 80, 100, 120, 140, 160,
180, 200, 220, 240, 260, 280, 300, 320 or 340, wherein the tyrosine is L- tyrosine 380. The peptide according to any of items 21 , 41 , 61 , 81 , 101 , 121 , 141 , 161 ,
181 , 201 , 221 , 241 , 261 , 281 , 301 , 321 or 341 , wherein the valine is D-valine
381 . The peptide according to any of items 21 , 41 , 61 , 81 , 101 , 121 , 141 , 161 , 181 , 201 , 221 , 241 , 261 , 281 , 301 , 321 or 341 , wherein the valine is L-valine
382. The peptide according to item 1 to 381 , wherein one or more of said amino acid residues are modified, such as post-translationally modified or co- translationally modified
383. The peptide according to item 382, wherein said modification is acetylation of one or more amino acid residues
384. The peptide according to item 382, wherein said modification is phosphorylation of one or more amino acid residues
385. The peptide according to item 382, wherein said modification is glycosylation of one or more amino acid residues
386. The peptide according to item 382, wherein said modification is non- enzymatic glycosylation (or glycation) of one or more amino acid residues 387. The peptide according to item 382, wherein said modification is methylation of one or more amino acid residues
388. The peptide according to item 382, wherein said modification is amidation of one or more amino acid residues
389. The peptide according to item 382, wherein said modification is deamidation of one or more amino acid residues
390. The peptide according to item 382, wherein said modification is succinimide formation of one or more amino acid residues
391. The peptide according to item 382, wherein said modification is biotinylation of one or more amino acid residues 392. The peptide according to item 382, wherein said modification is formylation of one or more amino acid residues
393. The peptide according to item 382, wherein said modification is carboxylation of one or more amino acid residues 394. The peptide according to item 382, wherein said modification is carbamylation of one or more amino acid residues
395. The peptide according to item 382, wherein said modification is hydroxylation of one or more amino acid residues
396. The peptide according to item 382, wherein said modification is iodination of one or more amino acid residues
397. The peptide according to item 382, wherein said modification is isoprenylation (or prenylation or lipidation or lipoylation) of one or more amino acid residues
398. The peptide according to item 382, wherein said modification is GPI (glycosyl phosphatidylinositol) anchor formation of one or more amino acid residues
399. The peptide according to item 382, wherein said modification is myristoylation of one or more amino acid residues
400. The peptide according to item 382, wherein said modification is farnesylation of one or more amino acid residues
401. The peptide according to item 382, wherein said modification is geranylgeranylation of one or more amino acid residues
402. The peptide according to item 382, wherein said modification is covalent attachment of nucleotides or derivates thereof to one or more amino acid residues
403. The peptide according to item 382, wherein said modification is ADP- ribosylation of one or more amino acid residues
404. The peptide according to item 382, wherein said modification is flavin attachment to one or more amino acid residues 405. The peptide according to item 382, wherein said modification is oxidation of one or more amino acid residues
406. The peptide according to item 382, wherein said modification is oxidative deamination of one or more amino acid residues
407. The peptide according to item 382, wherein said modification is deamination of one or more amino acid residues 408. The peptide according to item 382, wherein said modification is palmitoylation of one or more amino acid residues
409. The peptide according to item 382, wherein said modification is pegylation of one or more amino acid residues 410. The peptide according to item 382, wherein said modification is attachment of phosphatidyl-inositol of one or more amino acid residues
41 1 . The peptide according to item 382, wherein said modification is phosphopantetheinylation of one or more amino acid residues
412. The peptide according to item 382, wherein said modification is polysialylation of one or more amino acid residues
413. The peptide according to item 382, wherein said modification is sulfation of one or more amino acid residues
414. The peptide according to item 382, wherein said modification is selenoylation of one or more amino acid residues 415. The peptide according to item 382, wherein said modification is arginylation of one or more amino acid residues
416. The peptide according to item 382, wherein said modification is glutamylation or polyglutamylation of one or more amino acid residues
417. The peptide according to item 382, wherein said modification is glycylation or polyglycylation of one or more amino acid residues
418. The peptide according to item 382, wherein said modification is acylation (or alkanoylation) of one or more amino acid residues
419. The peptide according to item 382, wherein said modification is Methylidene-imidazolone (MIO) formation of one or more amino acid residues 420. The peptide according to item 382, wherein said modification is p-
Hydroxybenzylidene-imidazolone formation of one or more amino acid residues
421. The peptide according to item 382, wherein said modification is Lysine tyrosyl quinone (LTQ) formation of one or more amino acid residues
422. The peptide according to item 382, wherein said modification is Topaquinone (TPQ) formation of one or more amino acid residues
423. The peptide according to item 382, wherein said modification is Porphyrin ring linkage of one or more amino acid residues
424. The peptide according to item 382, wherein said modification is glypiation (addition of glycosyl phosphatidyl inositol) of one or more amino acid residues 425. The peptide according to item 382, wherein said modification is addition of heme to one or more amino acid residues
426. The peptide according to item 382, wherein said modification is ubiquitination of one or more amino acid residues 427. The peptide according to item 382, wherein said modification is
SUMOylation (Small Ubiquitin-like Modifier) of one or more amino acid residues
428. The peptide according to item 382, wherein said modification is ISGylation of one or more amino acid residues
429. The peptide according to item 382, wherein said modification is citrullination (or deimination) of one or more amino acid residues
430. The peptide according to item 382, wherein said modification is the formation of pyroglutamic acid (or pidolic acid) of one or more amino acid residues
431. The peptide according to item 382, wherein said modification is formation of disulfide bridges (or disulfide bond or SS-bond or persulfide connection) between two amino acid residues
432. The peptide according to item 382, wherein said modification is formation of a desmosine cross-link between two or more amino acid residues
433. The peptide according to item 382, wherein said modification is transglutamination between two or more amino acid residues
434. The peptide according to item 1 , wherein any of Xi, X2, X3, X4, Xs, Xe, X7, X8, X9, X10, X11, X12, Xi3, Xi4, Xi5 and/or Xi6 is an uncommon or modified amino acid
435. The peptide according to item 434, wherein said uncommon amino acid is acetylalanine
436. The peptide according to item 434, wherein said uncommon amino acid is acetylaspartic acid
437. The peptide according to item 434, wherein said uncommon amino acid is acetylcysteine 438. The peptide according to item 434, wherein said uncommon amino acid is acetylglutamic acid
439. The peptide according to item 434, wherein said uncommon amino acid is acetylglutamine
440. The peptide according to item 434, wherein said uncommon amino acid is acetylglycine 441 . The peptide according to item 434, wherein said uncommon amino acid is acetylisoleucine
442. The peptide according to item 434, wherein said uncommon amino acid is acetyllysine 443. The peptide according to item 434, wherein said uncommon amino acid is acetylmethionine
444. The peptide according to item 434, wherein said uncommon amino acid is acetylproline
445. The peptide according to item 434, wherein said uncommon amino acid is acetylserine
446. The peptide according to item 434, wherein said uncommon amino acid is acetylthreonine
447. The peptide according to item 434, wherein said uncommon amino acid is acetyltyrosine 448. The peptide according to item 434, wherein said uncommon amino acid is acetylvaline
449. The peptide according to item 434, wherein said uncommon amino acid is acetyllysine
450. The peptide according to item 434, wherein said uncommon amino acid is acetylcysteine
451. The peptide according to item 434, wherein said uncommon amino acid is alanine amide
452. The peptide according to item 434, wherein said uncommon amino acid is arginine amide 453. The peptide according to item 434, wherein said uncommon amino acid is asparagine amide
454. The peptide according to item 434, wherein said uncommon amino acid is aspartic acid amide
455. The peptide according to item 434, wherein said uncommon amino acid is cysteine amide
456. The peptide according to item 434, wherein said uncommon amino acid is glutamine amide
457. The peptide according to item 434, wherein said uncommon amino acid is glutamic acid amide 458. The peptide according to item 434, wherein said uncommon amino acid is glycine amide
459. The peptide according to item 434, wherein said uncommon amino acid is histidine amide 460. The peptide according to item 434, wherein said uncommon amino acid is isoleucine amide
461 . The peptide according to item 434, wherein said uncommon amino acid is leucine amide
462. The peptide according to item 434, wherein said uncommon amino acid is lysine amide
463. The peptide according to item 434, wherein said uncommon amino acid is methionine amide
464. The peptide according to item 434, wherein said uncommon amino acid is phenylalanine amide 465. The peptide according to item 434, wherein said uncommon amino acid is proline amide
466. The peptide according to item 434, wherein said uncommon amino acid is serine amide
467. The peptide according to item 434, wherein said uncommon amino acid is threonine amide
468. The peptide according to item 434, wherein said uncommon amino acid is tryptophan amide
469. The peptide according to item 434, wherein said uncommon amino acid is tyrosine amide 470. The peptide according to item 434, wherein said uncommon amino acid is valine amide
471. The peptide according to item 434, wherein said uncommon amino acid is an amino acid alcohol
472. The peptide according to item 434, wherein said uncommon amino acid is Aminobenzoic Acid
473. The peptide according to item 434, wherein said uncommon amino acid is Aminobutyric Acid
474. The peptide according to item 434, wherein said uncommon amino acid is Aminocyanobutyric acid 475. The peptide according to item 434, wherein said uncommon amino acid is Aminocyanopropionic acid
476. The peptide according to item 434, wherein said uncommon amino acid is Aminocyclohexanoic acid 477. The peptide according to item 434, wherein said uncommon amino acid is
Aminocyclopropanoic acid
478. The peptide according to item 434, wherein said uncommon amino acid is Aminocylopentanoic acid
479. The peptide according to item 434, wherein said uncommon amino acid is Aminodecanoic acid
480. The peptide according to item 434, wherein said uncommon amino acid is Aminododecanoic acid
481. The peptide according to item 434, wherein said uncommon amino acid is Aminohexanoic acid 482. The peptide according to item 434, wherein said uncommon amino acid is
Aminoisobutyric acid
483. The peptide according to item 434, wherein said uncommon amino acid is Aminomethylbenzoic acid
484. The peptide according to item 434, wherein said uncommon amino acid is Aminomethylcyclohexanoic acid
485. The peptide according to item 434, wherein said uncommon amino acid is Aminononanoic acid
486. The peptide according to item 434, wherein said uncommon amino acid is Aminooctanoic acid 487. The peptide according to item 434, wherein said uncommon amino acid is
Aminophenylalanine
488. The peptide according to item 434, wherein said uncommon amino acid is Amino Salicylic acid
489. The peptide according to item 434, wherein said uncommon amino acid is 2-Amino-2-Thiazoline-4-carboxylic acid
490. The peptide according to item 434, wherein said uncommon amino acid is Aminoundecanoic acid
491. The peptide according to item 434, wherein said uncommon amino acid is Aminovaleric acid 492. The peptide according to item 434, wherein said uncommon amino acid is 4-Benzoylphenylalanine
493. The peptide according to item 434, wherein said uncommon amino acid is Biphenylalanine 494. The peptide according to item 434, wherein said uncommon amino acid is
Bromophenylalanine
495. The peptide according to item 434, wherein said uncommon amino acid is gamma-Carboxyglutamic acid
496. The peptide according to item 434, wherein said uncommon amino acid is canavanine
497. The peptide according to item 434, wherein said uncommon amino acid is Carnitine
498. The peptide according to item 434, wherein said uncommon amino acid is Chlorophenylalanine 499. The peptide according to item 434, wherein said uncommon amino acid is
Chlorotyrosine
500. The peptide according to item 434, wherein said uncommon amino acid is Cine
501. The peptide according to item 434, wherein said uncommon amino acid is Citrulline
502. The peptide according to item 434, wherein said uncommon amino acid is 4-Cyano-2-Aminobutyric acid
503. The peptide according to item 434, wherein said uncommon amino acid is Cyclohexylalanine 504. The peptide according to item 434, wherein said uncommon amino acid is
Cyclohexylglycine
505. The peptide according to item 434, wherein said uncommon amino acid is Diaminobenzoic acid
506. The peptide according to item 434, wherein said uncommon amino acid is 2,4-Diaminobutyric acid
507. The peptide according to item 434, wherein said uncommon amino acid is 2,3-Diaminopropionic acid
508. The peptide according to item 434, wherein said uncommon amino acid is Dibutylglycine 509. The peptide according to item 434, wherein said uncommon amino acid is Diethylglycine
510. The peptide according to item 434, wherein said uncommon amino acid is Dihydrotryptophan 51 1 . The peptide according to item 434, wherein said uncommon amino acid is
Dipropylglycine
512. The peptide according to item 434, wherein said uncommon amino acid is Fluorophenylalanine
513. The peptide according to item 434, wherein said uncommon amino acid is formylmethionine
514. The peptide according to item 434, wherein said uncommon amino acid is formylglycine
515. The peptide according to item 434, wherein said uncommon amino acid is formyllysine 516. The peptide according to item 434, wherein said uncommon amino acid is farnesylcysteine
517. The peptide according to item 434, wherein said uncommon amino acid is hydroxyfarnesylcysteine
518. The peptide according to item 434, wherein said uncommon amino acid is Homoalanine
519. The peptide according to item 434, wherein said uncommon amino acid is Homoarginine
520. The peptide according to item 434, wherein said uncommon amino acid is Homoasparagine 521. The peptide according to item 434, wherein said uncommon amino acid is
Homoaspartic acid
522. The peptide according to item 434, wherein said uncommon amino acid is Homoglutamic acid
523. The peptide according to item 434, wherein said uncommon amino acid is Homoglutamine
524. The peptide according to item 434, wherein said uncommon amino acid is Homoisoleucine
525. The peptide according to item 434, wherein said uncommon amino acid is Homophenylalanine 526. The peptide according to item 434, wherein said uncommon amino acid is Homoserine
527. The peptide according to item 434, wherein said uncommon amino acid is Homotyrosine 528. The peptide according to item 434, wherein said uncommon amino acid is
Hydroxyproline
529. The peptide according to item 434, wherein said uncommon amino acid is Hydroxylysine
530. The peptide according to item 434, wherein said uncommon amino acid is 2-lndanylglycine
531. The peptide according to item 434, wherein said uncommon amino acid is 2-lndolecarboxylic acid
532. The peptide according to item 434, wherein said uncommon amino acid is lndoleglycine 533. The peptide according to item 434, wherein said uncommon amino acid is lodophenylalanine
534. The peptide according to item 434, wherein said uncommon amino acid is lsonipecotic Acid
535. The peptide according to item 434, wherein said uncommon amino acid is Kynurenine
536. The peptide according to item 434, wherein said uncommon amino acid is β-(S-Benzyl)Mercapto-β,β-cyclopentamethylene propionic acid
537. The peptide according to item 434, wherein said uncommon amino acid is Methyltyrosine 538. The peptide according to item 434, wherein said uncommon amino acid is
Methylphenylalanine
539. The peptide according to item 434, wherein said uncommon amino acid is methylalanine
540. The peptide according to item 434, wherein said uncommon amino acid is trimethylalanine
541. The peptide according to item 434, wherein said uncommon amino acid is methylglycine
542. The peptide according to item 434, wherein said uncommon amino acid is methylmethionine 543. The peptide according to item 434, wherein said uncommon amino acid is methylphenylalanine
544. The peptide according to item 434, wherein said uncommon amino acid is dimethylproline 545. The peptide according to item 434, wherein said uncommon amino acid is dimethylarginine
546. The peptide according to item 434, wherein said uncommon amino acid is methylarginine
547. The peptide according to item 434, wherein said uncommon amino acid is methylasparagine
548. The peptide according to item 434, wherein said uncommon amino acid is methylglutamine
549. The peptide according to item 434, wherein said uncommon amino acid is methylhistidine 550. The peptide according to item 434, wherein said uncommon amino acid is trimethyllysine
551. The peptide according to item 434, wherein said uncommon amino acid is dimethyllysine
552. The peptide according to item 434, wherein said uncommon amino acid is methyllysine
553. The peptide according to item 434, wherein said uncommon amino acid is methylcysteine
554. The peptide according to item 434, wherein said uncommon amino acid is glutamic acid 5-methyl ester 555. The peptide according to item 434, wherein said uncommon amino acid is
Naphthylalanine
556. The peptide according to item 434, wherein said uncommon amino acid is Nipecotic acid
557. The peptide according to item 434, wherein said uncommon amino acid is Nitrophenylalanine
558. The peptide according to item 434, wherein said uncommon amino acid is Norleucine
559. The peptide according to item 434, wherein said uncommon amino acid is Norvaline 560. The peptide according to item 434, wherein said uncommon amino acid is Octahydroindolecarboxylic acid
561 . The peptide according to item 434, wherein said uncommon amino acid is ornithine 562. The peptide according to item 434, wherein said uncommon amino acid is
Penicillamine
563. The peptide according to item 434, wherein said uncommon amino acid is Phenylglycine
564. The peptide according to item 434, wherein said uncommon amino acid is phosphocysteine
565. The peptide according to item 434, wherein said uncommon amino acid is phosphohistidine
566. The peptide according to item 434, wherein said uncommon amino acid is phosphoserine 567. The peptide according to item 434, wherein said uncommon amino acid is phosphothreonine
568. The peptide according to item 434, wherein said uncommon amino acid is phosphotyrosine
569. The peptide according to item 434, wherein said uncommon amino acid is phosphoarginine
570. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-adenosine)-tyrosine
571. The peptide according to item 434, wherein said uncommon amino acid is phosphopantetheine-serine 572. The peptide according to item 434, wherein said uncommon amino acid is
(phospho-5'-RNA)-serine
573. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-adenosine)-lysine
574. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-guanosine)-lysine
575. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-DNA)-serine
576. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-RNA)-tyrosine 577. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-adenosine)-threonine
578. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-DNA)-tyrosine 579. The peptide according to item 434, wherein said uncommon amino acid is
(phospho-5'-DNA)-threonine
580. The peptide according to item 434, wherein said uncommon amino acid is (phospho-5'-uridine)-tyrosine
581. The peptide according to item 434, wherein said uncommon amino acid is 4-Phosphonomethylphenylalanine
582. The peptide according to item 434, wherein said uncommon amino acid is palmitoylcysteine
583. The peptide according to item 434, wherein said uncommon amino acid is palmitoyllysine 584. The peptide according to item 434, wherein said uncommon amino acid is palmitoylthreonine
585. The peptide according to item 434, wherein said uncommon amino acid is palmitoylserine
586. The peptide according to item 434, wherein said uncommon amino acid is palmitoylcysteine
587. The peptide according to item 434, wherein said uncommon amino acid is phycoerythrobilin-bis-cysteine
588. The peptide according to item 434, wherein said uncommon amino acid is phycourobilin-bis-cysteine 589. The peptide according to item 434, wherein said uncommon amino acid is pyrrolidone-5-carboxylic acid
590. The peptide according to item 434, wherein said uncommon amino acid is Pipericolic Acid
591. The peptide according to item 434, wherein said uncommon amino acid is Propargylglycine
592. The peptide according to item 434, wherein said uncommon amino acid is Pyridinylalanine
593. The peptide according to item 434, wherein said uncommon amino acid is pyroglutamic acid 594. The peptide according to item 434, wherein said uncommon amino acid is Sarcosine
595. The peptide according to item 434, wherein said uncommon amino acid is Tert-Leucine 596. The peptide according to item 434, wherein said uncommon amino acid is
Tetrahydoisoquinoline-3-carboxylic acid
597. The peptide according to item 434, wherein said uncommon amino acid is Thiazolidinecarboxylic acid
598. The peptide according to item 434, wherein said uncommon amino acid is Thyronine
599. The peptide according to item 434, wherein said uncommon amino acid is selenocysteine
600. The peptide according to item 434, wherein said uncommon amino acid is selenomethionine 601. The peptide according to item 434, wherein said uncommon amino acid is erythro-beta-hydroxyasparagine
602. The peptide according to item 434, wherein said uncommon amino acid is erythro-beta-hydroxyaspartic acid
603. The peptide according to item 434, wherein said uncommon amino acid is gamma-carboxyglutamic acid
604. The peptide according to item 434, wherein said uncommon amino acid is aspartic 4-phosphoric anhydride
605. The peptide according to item 434, wherein said uncommon amino acid is2'-[3-carboxamido-3-(trimethylammonio)propyl]-histidine 606. The peptide according to item 434, wherein said uncommon amino acid is glucuronoylglycine
607. The peptide according to item 434, wherein said uncommon amino acid is geranylgeranylcysteine
608. The peptide according to item 434, wherein said uncommon amino acid is myristoylglycine
609. The peptide according to item 434, wherein said uncommon amino acid is myristoyllysine
610. The peptide according to item 434, wherein said uncommon amino acid is cysteine methyl disulfide 61 1 . The peptide according to item 434, wherein said uncommon amino acid is diacylglycerolcysteine
612. The peptide according to item 434, wherein said uncommon amino acid is isoglutamylcysteine 613. The peptide according to item 434, wherein said uncommon amino acid is cysteinylhistidine
614. The peptide according to item 434, wherein said uncommon amino acid is lanthionine
615. The peptide according to item 434, wherein said uncommon amino acid is mesolanthionine
616. The peptide according to item 434, wherein said uncommon amino acid is methyllanthionine
617. The peptide according to item 434, wherein said uncommon amino acid is cysteinyltyrosine 618. The peptide according to item 434, wherein said uncommon amino acid is carboxylysine
619. The peptide according to item 434, wherein said uncommon amino acid is carboxyethyllysine
620. The peptide according to item 434, wherein said uncommon amino acid is (4-amino-2-hydroxybutyl)-lysine
621. The peptide according to item 434, wherein said uncommon amino acid is biotinyllysine
622. The peptide according to item 434, wherein said uncommon amino acid is lipoyllysine 623. The peptide according to item 434, wherein said uncommon amino acid is pyridoxal phosphate-lysine
624. The peptide according to item 434, wherein said uncommon amino acid is retinal-lysine
625. The peptide according to item 434, wherein said uncommon amino acid is allysine
626. The peptide according to item 434, wherein said uncommon amino acid is lysinoalanine
627. The peptide according to item 434, wherein said uncommon amino acid is isoglutamyllysine 628. The peptide according to item 434, wherein said uncommon amino acid is glycyllysine
629. The peptide according to item 434, wherein said uncommon amino acid is isoaspartylglycine 630. The peptide according to item 434, wherein said uncommon amino acid is pyruvic acid
631 . The peptide according to item 434, wherein said uncommon amino acid is phenyllactic acid
632. The peptide according to item 434, wherein said uncommon amino acid is oxobutanoic acid
633. The peptide according to item 434, wherein said uncommon amino acid is succinyltryptophan
634. The peptide according to item 434, wherein said uncommon amino acid is phycocyanobilincysteine 635. The peptide according to item 434, wherein said uncommon amino acid is phycoerythrobilincysteine
636. The peptide according to item 434, wherein said uncommon amino acid is phytochromobilincysteine
637. The peptide according to item 434, wherein said uncommon amino acid is heme-bis-cysteine
638. The peptide according to item 434, wherein said uncommon amino acid is heme-cysteine
639. The peptide according to item 434, wherein said uncommon amino acid is tetrakis-cysteinyl iron 640. The peptide according to item 434, wherein said uncommon amino acid is tetrakis-cysteinyl diiron disulfide
641. The peptide according to item 434, wherein said uncommon amino acid is tris-cysteinyl triiron trisulfide
642. The peptide according to item 434, wherein said uncommon amino acid is tris-cysteinyl triiron tetrasulfide
643. The peptide according to item 434, wherein said uncommon amino acid is tetrakis-cysteinyl tetrairon tetrasulfide
644. The peptide according to item 434, wherein said uncommon amino acid is cysteinyl homocitryl molybdenum-heptairon-nonasulfide 645. The peptide according to item 434, wherein said uncommon amino acid is cysteinyl molybdopterin
646. The peptide according to item 434, wherein said uncommon amino acid is (8alpha-FAD)-cysteine 647. The peptide according to item 434, wherein said uncommon amino acid is
(8alpha-FAD)-histidine
648. The peptide according to item 434, wherein said uncommon amino acid is (δalpha-FAD)-tyrosine
649. The peptide according to item 434, wherein said uncommon amino acid is dihydroxyphenylalanine
650. The peptide according to item 434, wherein said uncommon amino acid is topaquinone
651. The peptide according to item 434, wherein said uncommon amino acid is tryptophyl quinine 652. The peptide according to item 434, wherein said uncommon amino acid is
(tryptophan)-tryptophyl quinone
653. The peptide according to item 434, wherein said uncommon amino acid is glycosylasparagine
654. The peptide according to item 434, wherein said uncommon amino acid is glycosylcysteine
655. The peptide according to item 434, wherein said uncommon amino acid is glycosylhydroxylysine
656. The peptide according to item 434, wherein said uncommon amino acid is glycosylserine 657. The peptide according to item 434, wherein said uncommon amino acid is glycosylthreonine
658. The peptide according to item 434, wherein said uncommon amino acid is glycosyltryptophan
659. The peptide according to item 434, wherein said uncommon amino acid is glycosyltyrosine
660. The peptide according to item 434, wherein said uncommon amino acid is asparaginyl-glycosylphosphatidylinositolethanolamine
661. The peptide according to item 434, wherein said uncommon amino acid is aspartyl-glycosylphosphatidylinositolethanolamine 662. The peptide according to item 434, wherein said uncommon amino acid is cysteinyl-glycosylphosphatidylinositolethanolamine
663. The peptide according to item 434, wherein said uncommon amino acid is glycyl-glycosylphosphatidylinositolethanolamine 664. The peptide according to item 434, wherein said uncommon amino acid is seryl-glycosylphosphatidylinositolethanolamine
665. The peptide according to item 434, wherein said uncommon amino acid is seryl-glycosylsphingolipidinositolethanolamine
666. The peptide according to item 434, wherein said uncommon amino acid is (phosphoribosyl dephospho-coenzyme A)-serine
667. The peptide according to item 434, wherein said uncommon amino acid is (ADP-ribosyl)-arginine
668. The peptide according to item 434, wherein said uncommon amino acid is (ADP-ribosyl)-cysteine 669. The peptide according to item 434, wherein said uncommon amino acid is glutamyl-glycerylphosphorylethanolamine
670. The peptide according to item 434, wherein said uncommon amino acid is sulfocysteine
671. The peptide according to item 434, wherein said uncommon amino acid is sulfotyrosine
672. The peptide according to item 434, wherein said uncommon amino acid is bromohistidine
673. The peptide according to item 434, wherein said uncommon amino acid is bromophenylalanine 674. The peptide according to item 434, wherein said uncommon amino acid is triiodothyronine
675. The peptide according to item 434, wherein said uncommon amino acid is thyroxine
676. The peptide according to item 434, wherein said uncommon amino acid is bromotryptophan
677. The peptide according to item 434, wherein said uncommon amino acid is dehydroalanine
678. The peptide according to item 434, wherein said uncommon amino acid is dehydrobutyrine 679. The peptide according to item 434, wherein said uncommon amino acid is dehydrotyrosine
680. The peptide according to item 434, wherein said uncommon amino acid is seryl-imidazolinone glycine 681 . The peptide according to item 434, wherein said uncommon amino acid is oxoalanine
682. The peptide according to item 434, wherein said uncommon amino acid is alanyl-imidazolinone glycine
683. The peptide according to item 434, wherein said uncommon amino acid is allo-isoleucine
684. The peptide according to item 434, wherein said uncommon amino acid is isoglutamyl-polyglycine
685. The peptide according to item 434, wherein said uncommon amino acid is isoglutamyl-polyglutamic acid 686. The peptide according to item 434, wherein said uncommon amino acid is aminovinyl-cysteine
687. The peptide according to item 434, wherein said uncommon amino acid is (aminovinyl)-methyl-cysteine
688. The peptide according to item 434, wherein said uncommon amino acid is cysteine sulfenic acid
689. The peptide according to item 434, wherein said uncommon amino acid is glycyl-cysteine
690. The peptide according to item 434, wherein said uncommon amino acid is hydroxycinnamyl-cysteine 691. The peptide according to item 434, wherein said uncommon amino acid is chondroitin sulfate glucuronyl-galactosyl-galactosyl-xylosyl-serine
692. The peptide according to item 434, wherein said uncommon amino acid is dermatan sulfate glucuronyl-galactosyl-galactosyl-xylosyl-serine
693. The peptide according to item 434, wherein said uncommon amino acid is heparan sulfate glucuronyl-galactosyl-galactosyl-xylosyl-serine
694. The peptide according to item 434, wherein said uncommon amino acid is glycosyl-hydroxyproline
695. The peptide according to item 434, wherein said uncommon amino acid is hydroxy-arginine 696. The peptide according to item 434, wherein said uncommon amino acid is isoaspartyl-cysteine
697. The peptide according to item 434, wherein said uncommon amino acid is alpha-mannosyl-tryptophan 698. The peptide according to item 434, wherein said uncommon amino acid is mureinyl-lysine
699. The peptide according to item 434, wherein said uncommon amino acid is chondroitin sulfate-aspartic acid ester
700. The peptide according to item 434, wherein said uncommon amino acid is (6-FMN)-cysteine
701. The peptide according to item 434, wherein said uncommon amino acid is diphytanylglycerol diether-cysteine
702. The peptide according to item 434, wherein said uncommon amino acid is bis-cysteinyl bis-histidino diiron disulfide 703. The peptide according to item 434, wherein said uncommon amino acid is hexakis-cysteinyl hexairon hexasulfide
704. The peptide according to item 434, wherein said uncommon amino acid is cysteine glutathione disulfide
705. The peptide according to item 434, wherein said uncommon amino acid is nitrosyl-cysteine
706. The peptide according to item 434, wherein said uncommon amino acid is (ADP-ribosyl)-asparagine
707. The peptide according to item 434, wherein said uncommon amino acid is beta-methylthioaspartic acid 708. The peptide according to item 434, wherein said uncommon amino acid is
(lysine)-topaquinone
709. The peptide according to item 434, wherein said uncommon amino acid is hydroxymethyl-asparagine
710. The peptide according to item 434, wherein said uncommon amino acid is (ADP-ribosyl)-serine
71 1. The peptide according to item 434, wherein said uncommon amino acid is cysteine oxazolecarboxylic acid
712. The peptide according to item 434, wherein said uncommon amino acid is cysteine oxazolinecarboxylic acid 713. The peptide according to item 434, wherein said uncommon amino acid is glycine oxazolecarboxylic acid
714. The peptide according to item 434, wherein said uncommon amino acid is glycine thiazolecarboxylic acid 715. The peptide according to item 434, wherein said uncommon amino acid is serine thiazolecarboxylic acid
716. The peptide according to item 434, wherein said uncommon amino acid is phenyalanine thiazolecarboxylic acid
717. The peptide according to item 434, wherein said uncommon amino acid is cysteine thiazolecarboxylic acid
718. The peptide according to item 434, wherein said uncommon amino acid is lysine thiazolecarboxylic acid
719. The peptide according to item 434, wherein said uncommon amino acid is keratan sulfate glucuronyl-galactosyl-galactosyl-xylosyl-threonine 720. The peptide according to item 434, wherein said uncommon amino acid is selenocysteinyl molybdopterin guanine dinucleotide
721. The peptide according to item 434, wherein said uncommon amino acid is histidyl-tyrosine
722. The peptide according to item 434, wherein said uncommon amino acid is methionine sulfone
723. The peptide according to item 434, wherein said uncommon amino acid is dipyrrolylmethanemethyl-cysteine
724. The peptide according to item 434, wherein said uncommon amino acid is glutamyl-tyrosine 725. The peptide according to item 434, wherein said uncommon amino acid is glutamyl-poly-glutamic acid
726. The peptide according to item 434, wherein said uncommon amino acid is cysteine sulfinic acid
727. The peptide according to item 434, wherein said uncommon amino acid is trihydroxyphenylalanine
728. The peptide according to item 434, wherein said uncommon amino acid is (sn-1 -glycerophosphoryl)-serine
729. The peptide according to item 434, wherein said uncommon amino acid is thioglycine 730. The peptide according to item 434, wherein said uncommon amino acid is heme P460-bis-cysteine-tyrosine
731 . The peptide according to item 434, wherein said uncommon amino acid is tris-cysteinyl-cysteine persulfido-bis-glutamato-histidino tetrairon disulfide trioxide
732. The peptide according to item 434, wherein said uncommon amino acid is cysteine persulfide
733. The peptide according to item 434, wherein said uncommon amino acid is Lactic acid (2-hydroxypropanoic acid) 734. The peptide according to any of items 434 to 733, wherein said uncommon amino acid is the L-enantiomer
735. The peptide according to any of items 434 to 733, wherein said uncommon amino acid is the D-enantiomer
The present invention is in one embodiment characterized by the items listed herein below in the 'second set of items'.
SECOND SET OF ITEMS:
1. A composition for vaccination and/or immune monitoring of a vaccine response comprising one or more pharmamers.
2. The composition according to item 1 , wherein the one or more phamamers comprises one or more MHC multimers.
3. The composition according to item 2, wherein the one or more MHC multimers comprises a MHC multimer comprising (a-b-P)n, wherein n > 1 ,
wherein a and b together form a functional MHC protein capable of binding the peptide P, when P is present
wherein (a-b-P) is the MHC-peptide complex formed when the peptide P binds to the functional MHC protein,
wherein each MHC peptide complex is associated with one or more multimerization domains. 4. The composition according to item 3, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the one or more multimerization domains.
5. The composition according to item 3, wherein the association is a non-covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the one or more multimerization domains.
6. The composition according to item 3, wherein the one or more multimerization domains comprises one or more scaffolds.
7. The composition according to item 3, wherein the one or more multimerization domains comprises one or more carriers.
8. The composition according to item 3, wherein the one or more multimerization domains comprises at least one scaffold and at least one carrier.
9. The composition according to item 3, wherein the one or more multimerization domains comprise one or more optionally substituted organic molecules.
10. The composition according to item 9, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
1 1. The composition according to item 10, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
12. The composition according to item 9, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
13. The composition according to item 3, wherein the one or more multimerization domains comprises one or more biological cells, such as antigen presenting cells or dendritic cells or cells transfected with one or more genes encoding MHC molecules. 14. The composition according to item 3, wherein the one or more multimerization domains comprises one or more membranes.
15. The composition according to item 14, wherein the one or more membranes comprises liposomes or micelles.
16. The composition according to item 3, wherein the one or more multimerization domains comprises one or more polymers.
17. The composition according to item 16, wherein the one or more polymers are selected from the group consisting of polysaccharides.
18. The composition according to item 17, wherein the polysaccharide comprises one or more dextran moieties.
19. The composition according to item 3, wherein the one or more multimerization domains comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA- PNA, PNA-DNA, DNA-RNA, streptavidin and avidin.
20. The composition according to item 3, wherein the one or more multimerization domains comprises an avidin, such as streptavidin.
21. The composition according to item 3, wherein the one or more multimerization domains comprises an antibody.
22. The composition according to item 21 , wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody.
23. The composition according to item 3, wherein the MHC multimer comprises one or more small organic scaffold molecules.
24. The composition according to item 3, wherein the MHC multimer comprises one or more further polypeptides in addition to a and b.
25. The composition according to item 3, wherein the MHC multimer comprises one or more protein complexes.
26. The composition according to item 3, wherein the MHC multimer comprises one or more beads.
27. The composition according to item 3, wherein the multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG- encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(Ci-Ci0)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin-monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran,
Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly-acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen-fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
28. The composition according to item 3, wherein the one or more multimerization domains comprises a dimerization domain.
29. The composition according to item 3, wherein the one or more multimerization domains comprises a trimerization domain.
30. The composition according to item 3, wherein the one or more multimerization domains comprises a tetramerization domain.
31. The composition according to item 3, wherein the one or more multimerization domains comprises a pentamerization domain.
32. The composition according to item 31 , wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
33. The composition according to item 3, wherein the one or more multimerization domains comprises a hexamerization domain.
34. The composition according to item 33, wherein the hexamerization domain comprises three IgG domains. 35. The composition according to item 3, wherein the one or more multimerization domains comprises a polymer structure to which is attached one or more scaffolds.
36. The composition according to item 35, wherein the polymer structure comprises a polysaccharide.
37. The composition according to item 36, wherein the polysaccharide comprises one or more dextran moieties.
38. The composition according to item 3, wherein the one or more multimerization domains comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
39. The composition according to item 3, wherein the one or more multimerization domains comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or a cyclodextrin.
40. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of less than 1 ,000 Da.
41. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of from 1 ,000 Da to preferably less than 10,000 Da.
42. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of from 10,000 Da to preferably less than 100,000 Da.
43. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of from 100,000 Da to preferably less than
1 ,000,000 Da.
44. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of more than 1 ,000,000 Da. 45. The composition according to item 3, wherein the one or more multimerization domains have a molecular weight of from 50,000 Da to preferably less than 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to
440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to
220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; for example from 100,000 Da to 1 ,000,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 1 ,000,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000.
46. The composition according to item 3, wherein n is 2. 47. The composition according to item 3, wherein n is 3.
48. The composition according to item 3, wherein n is 4.
49. The composition according to item 3, wherein n is 5.
50. The composition according to item 3, wherein n is 6.
51. The composition according to item 3, wherein n is 7.
52. The composition according to item 3, wherein n is 8, 9, 10, 1 1 or 12.
53. The composition according to item 3, wherein n < 12.
54. The composition according to item 3, wherein 1 <n<100.
55. The composition according to item 3, wherein 1 <n<1000.
56. The composition according to item 3, wherein 1 <n.
57. The composition according to item 3, wherein n is billions or trillions or higher.
58. The composition according to item 3, wherein n < 1 ,000,000,000.
59. The composition according to item 3, wherein n < 1 ,000,000,000,000,000,000.
60. The composition according to item 3, wherein n (the total number of MHC molecules of the construct) is in the range from 100 MHC molecules to 1 ,000,000 MHC molecules such as from 100 to 1 ,000 MHC molecules, for example from 1 ,000 to 5,000 MHC molecules, such as from 5,000 to 10,000 MHC molecules, for example from 10,000 to 20,000 MHC molecules, such as from 20,000 to 30,000 MHC molecules, for example from 30,000 to 40,000 MHC molecules, such as from 40,000 to 50,000 MHC molecules, for example from 50,000 to 60,000 MHC molecules, such as from 60,000 to 70,000 MHC molecules, for example from 70,000 to 80,000 MHC molecules, such as from 80,000 to 90,000 MHC molecules, for example from 90,000 to 100,000 MHC molecules, such as from 100,000 to 200,000 MHC molecules, for example from 200,000 to 300,000 MHC molecules, such as from 300,000 to 400,000 MHC molecules, for example from 400,000 to 500,000 MHC molecules, such as from 500,000 to 600,000 MHC molecules, for example from 600,000 to 700,000 MHC molecules, such as from 700,000 to 800,000 MHC molecules, for example from 800,000 to 900,000 MHC molecules, such as from 900,000 to 1 ,000,000 MHC molecules.
61. The vaccine composition according to any of items 3 to 60, wherein n is selected from the group of integers consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 1000.
62. The vaccine composition according to any of items 3 to 60, wherein n has a value of from 1 to 1000, for example from 1 to 10, such as from 10 to 20, for example from 20 to 30, such as from 30 to 40, for example from 40 to 50, such as from 50 to 60, for example from 60 to 70, such as from 70 to 80, for example from 80 to 90, such as from 90 to 100, for example from 100 to 120, such as from 120 to 140, for example from 140 to 160, such as from 160 to 180, for example from 180 to 200, such as from 200 to 250, for example from 250 to 300, such as from 300 to 350, for example from 350 to 400, such as from 400 to 450, for example from 450 to 500, such as from 500 to 550, for example from 550 to 600, such as from 600 to 650, for example from 650 to 700, such as from 700 to 750, for example from 750 to 800, such as from 800 to 900, for example from 900 to 950, such as from 950 to 1000.
63. The composition according to item 3, wherein a and/or b and/or P is of human origin.
64. The composition according to item 3, wherein a and/or b and/or P is of mouse origin. 65. The composition according to item 3, wherein a and/or b and/or P is of primate origin.
66. The composition according to item 3, wherein a and/or b and/or P is of chimpansee origin.
67. The composition according to item 3, wherein a and/or b and/or P is of gorilla origin.
68. The composition according to item 3, wherein a and/or b and/or P is of orangutan origin.
69. The composition according to item 3, wherein a and/or b and/or P is of monkey origin.
70. The composition according to item 3, wherein a and/or b and/or P is of Macaque origin.
71. The composition according to item 3, wherein a and/or b and/or P is of porcine (swine/pig) origin.
72. The composition according to item 3, wherein a and/or b and/or P is of bovine (cattle/antilopes) origin.
73. The composition according to item 3, wherein a and/or b and/or P is of equine (horse) origin.
74. The composition according to item 3, wherein a and/or b and/or P is of Camelides (camels) origin.
75. The composition according to item 3, wherein a and/or b and/or P is of ruminant origin.
76. The composition according to item 3, wherein a and/or b and/or P is of Canine (Dog) origin. 77. The composition according to item 3, wherein a and/or b and/or P is of Feline (Cat) origin.
78. The composition according to item 3, wherein a and/or b and/or P is of Bird origin.
79. The composition according to item 3, wherein a and/or b and/or P is of Chicken origin.
80. The composition according to item 3, wherein a and/or b and/or P is of Turkey origin.
81. The composition according to item 3, wherein a and/or b and/or P is of Fish origin.
82. The composition according to item 3, wherein a and/or b and/or P is of Reptile origin.
83. The composition according to item 3, wherein a and/or b and/or P is of Amphibian origin.
84. The composition according to item 3 to 83, wherein (a-b-P) is a class 1 MHC- peptide complex.
85. The composition according to item 3 to 83, wherein (a-b-P) is a class 2 MHC- peptide complex.
86. The composition according to item 3 to 85, wherein one or more labels are attached directly to the MHC multimer.
87. The composition according to item 3 to 85, wherein one or more labels are used for combinatorial use of labelling of the MHC multimer. 88. The composition according to item 3 to 85, wherein one or more labels are attached indirectly to the MHC multimer such as via one or more marker molecules carrying one or more labels.
89. The composition according to item 3 to 85, wherein one or more labels result in positive selection of that MHC multimer.
90. The composition according to item 3 to 85, wherein one or more labels result in negative selection of that MHC multimer.
91. The composition according to item 3 to 85 comprising one or more covalently attached labels.
92. The composition according to item 3 to 85 comprising one or more non-covalently attached labels.
93. The composition according to item 91 , wherein the one or more labels is covalently attached to the polypeptide a.
94. The composition according to item 91 , wherein the one or more labels is covalently attached to the polypeptide b.
95. The composition according to item 91 , wherein the one or more labels is covalently attached to the peptide P.
96. The composition according to item 91 , wherein the one or more labels is covalently attached to the one or more multimerization domains.
97. The composition according to item 91 , wherein the one or more labels is covalently attached to (a-b-P)n.
98. The composition according to item 92, wherein the one or more labels is non- covalently attached to the polypeptide a. 99. The composition according to item 92, wherein the one or more labels is non- covalently attached to the polypeptide b.
100. The composition according to item 92, wherein the one or more labels is non- covalently attached to P.
101 . The composition according to item 92, wherein the one or more labels is non- covalently attached to the one or more multimerization domains.
102. The composition according to item 92, wherein the one or more labels is non- covalently attached to (a-b-P)n.
103. The composition according to item 92, wherein the one or more labels is non- covalently attached to the antibody in the mutimerization domain.
104. The composition according to item 91 , wherein the one or more labels is covalently attached to an antibody in the mutimerization domain.
105. The composition according to item 92, wherein the one or more labels is non- covalently attached to an aptamer in the mutimerization domain.
106. The composition according to item 91 , wherein the one or more labels is covalently attached to an aptamer in the mutimerization domain.
107. The composition according to item 92, wherein the one or more labels is non- covalently attached to a molecule in the mutimerization domain.
108. The composition according to item 91 , wherein the one or more labels is covalently attached to a molecule in the mutimerization domain.
109. The composition according to item 92, wherein the one or more labels is non- covalently attached to a protein in the mutimerization domain.
1 10. The composition according to item 91 , wherein the one or more labels is covalently attached to a protein in the mutimerization domain. 1 1 1 . The composition according to item 92, wherein the one or more labels is non- covalently attached to a sugar residue in the mutimerization domain.
1 12. The composition according to item 91 , wherein the one or more labels is covalently attached to a sugar residue in the mutimerization domain.
1 13. The composition according to item 92, wherein the one or more labels is non- covalently attached to a DNA in the mutimerization domain.
1 14. The composition according to item 91 , wherein the one or more labels is covalently attached to a DNA in the mutimerization domain.
1 15. The composition according to item 86 to 1 14, wherein the attachment is directly between reactive groups in the labelling molecule and reactive groups in the marker molecule.
1 16. The composition according to item 86 to 1 14, wherein the attachment is through a linker connecting labelling molecule and marker.
1 17. The composition according to item 86 to 1 16, wherein one label is used.
1 18. The MHC multimer according to any of the items 86 to 1 16, wherein more than one label is used.
1 19. The composition according to item 1 18, wherein the more than one label are all identical.
120. The composition according to item 1 18, wherein at least two labels are different.
121 . The composition according to item 86 to 120, wherein the one or more labels is attached to (a-b-P)n via a streptavidin-biotin linkage.
122. The composition according to item 86 to 120, wherein the one or more labels is a fluorophore label. 123. The composition according to item 122, wherein the one or more fluorophore label are selected from the group of fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine.
124. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 2-(4'-maleimidylanilino)naphthalene-6- sulfonic acid, sodium salt.
125. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 5-((((2-iodoacetyl)amino)ethyl)amino) naphthalene-1 -sulfonic acid.
126. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Pyrene-1 -butanoic acid.
127. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of AlexaFluor 350 (7-amino-6-sulfonic acid-4-methyl coumarin-3-acetic acid.
128. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of AMCA (7-amino-4-methyl coumarin-3- acetic acid.
129. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-4-methyl coumarin-3-acetic acid.
130. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Marina Blue (6,8-difluoro-7-hydroxy-4- methyl coumarin-3-acetic acid.
131 . The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 7-dimethylamino-coumarin-4-acetic acid. 132. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Fluorescamin-N-butyl amine adduct.
133. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-coumarine-3-carboxylic acid.
134. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of CascadeBlue (pyrene-trisulphonic acid acetyl azide.
135. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Cascade Yellow.
136. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Pacific Blue (6,8 difluoro-7-hydroxy coumarin-3-carboxylic acid.
137. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 7-diethylamino-coumarin-3-carboxylic acid.
138. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Λ/-(((4-azidobenzoyl)amino)ethyl)- A- amino-3,6-disulfo-1 ,8-naphthalimide, dipotassium salt.
139. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Alexa Fluor 430.
140. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 3-perylenedodecanoic acid.
141 . The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 8-hydroxypyrene-1 ,3,6-trisulfonic acid, trisodium salt. 142. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 12-(Λ/-(7-nitrobenz-2-oxa-1 ,3- diazol-4- yl)amino)dodecanoic acid.
143. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Λ/,/V-dimethyl-/V- (iodoacetyl)-/V-(7- nitrobenz-2- oxa-1 ,3-diazol-4-yl)ethylenediamine.
144. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Oregon Green 488 (difluoro carboxy fluorescein).
145. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of 5-iodoacetamidofluorescein.
146. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of propidium iodide-DNA adduct.
147. The composition according to item 122, wherein the one or more fluorophore label are selected from the group consisting of Carboxy fluorescein.
148. The composition according to any of items 86 to 120, wherein the one or more labels is a fluorescent label.
149. The composition according to item 148, wherein the one or more fluorescent label is a simple fluorescent label.
150. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Fluor dyes, Pacific Blue™, Pacific
Orange™, Cascade Yellow™.
151 . The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group AlexaFluor@(AF), AF405, AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680, AF700, AF710, AF750, AF800.
152. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Quantum Dot based dyes, QDot®
Nanocrystals (Invitrogen, MolecularProbs), Qdot®525, Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800.
153. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group DyLight™ Dyes (Pierce) (DL); DL549, DL649, DL680, DL800.
154. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Fluorescein (Flu) or any derivate of that, such as FITC.
155. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Cy-Dyes, Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7.
156. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Fluorescent Proteins, RPE, PerCp, APC, Green fluorescent proteins; GFP and GFP derivated mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, m RFP 1 , M Banana, mOrange, dTomato, tdTomato, mTangerine, mStrawberry, mCherry.
157. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group Tandem dyes, RPE-Cy5, RPE-Cy5.5, RPE- Cy7, RPE-AlexaFluor® tandem conjugates; RPE-Alexa610, RPE-TxRed, APC- AlecaθOO, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5.
158. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group multi fluorochrome assemblies, Multiple fluorochromes attached to a polymer molecule, such as a peptide/protein, Dextrane, polysaccharide, any combination of the fluorescent dyes involving in generation of FRET (Fluorescence resonance energy transfer) based techniques.
159. The composition according to item 149, wherein the one or more simple fluorescent label is selected from the group ionophors; ion chelating fluorescent props, props that change wavelength when binding a specific ion, such as Calcium, props that change intensity when binding to a specific ion, such as Calcium.
160. The composition according to any of items 86 to 120, wherein the one or more labels is capable of absorption of light.
161 . The composition according to item 160, wherein the one or more labels capable of absorption of light is a chromophore.
162. The composition according to item 160, wherein the one or more labels capable of absorption of light is a dye.
163. The composition according to any of items 86 to 120, wherein the one or more labels is capable of emission of light after excitation.
164. The composition according to item 163, wherein the one or more labels capable of emission of light is one or more fluorochromes.
165. The composition according to item 164, wherein the one or more fluorochrome is selected from the AlexaFluor®(AF) family, which include AFΘ350, AF405, AF430,
AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680, AF700, AF710, AF750 and AF800.
166. The composition according to item 164, wherein the one or more fluorochrome is selected from the Quantum Dot (Qdot®) based dye family, which include Qdot®525,
Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800.
167. The composition according to item 164, wherein the one or more fluorochrome is selected from the DyLight™ Dyes (DL) family, which include DL549, DL649, DL680, DL800. 168. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Small fluorescing dyes, which include FITC, Pacific Blue™, Pacific Orange™, Cascade Yellow™, Marina blue™, DSred, DSred-2, 7-AAD, TO-Pro- 3.
169. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Cy-Dyes, which include Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7.
170. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Phycobili Proteins, which include R-Phycoerythrin (RPE), PerCP, Allophycocyanin (APC), B-Phycoerythrin, C-Phycocyanin.
171 . The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Fluorescent Proteins, which include (E)GFP and GFP
((enhanced) green fluorescent protein) derived mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, m RFP 1 , M Banana, mOrange, dTomato, tdTomato, mTangerine.
172. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Tandem dyes with RPE, which include RPE-Cy5, RPE-
Cy5.5, RPE-Cy7, RPE-AlexaFluor® tandem conjugates; RPE-Alexa610, RPE-TxRed.
173. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Tandem dyes with APC, which include APC-Aleca600, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5.
174. The composition according to item 164, wherein the one or more fluorochrome is selected from the family of Calcium dyes, which include Indo-1 -Ca2+ lndo-2-Ca2+.
175. The composition according to any of items 86 to 120, wherein the one or more labels is capable of reflection of light.
176. The composition according to item 175, wherein the one or more labels capable of reflection of light comprises gold. 177. The composition according to item 175, wherein the one or more labels capable of reflection of light comprises plastic.
178. The composition according to item 175, wherein the one or more labels capable of reflection of light comprises glass.
179. The composition according to item 175, wherein the one or more labels capable of reflection of light comprises polystyrene.
180. The composition according to item 175, wherein the one or more labels capable of reflection of light comprises pollen.
181 . The composition according to any of items 86 to 120, wherein the one or more labels is a chemiluminescent label.
182. The composition according to item 181 , wherein the chemiluminescent labels is selected from the group luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.
183. The composition according to any of items 86 to 120, wherein the one or more labels is a bioluminescent label.
184. The composition according to item 183, wherein the bioluminescent labels is selected from the group luciferin, luciferase and aequorin.
185. The composition according to any of items 86 to 120, wherein the one or more labels is a radioactive label.
186. The composition according to item 185, wherein the one or more radioactive labels is a radionuclide.
187. The composition according to item 185, wherein the one or more radioactive labels is an isotope. 188. The composition according to item 185, wherein the one or more radioactive labels comprises α rays.
189. The composition according to item 185, wherein the one or more radioactive labels comprises β rays.
190. The composition according to item 185, wherein the one or more radioactive labels comprises y rays.
191 . The composition according to any of items 86 to 120, wherein the one or more labels is detectable by NMR (nuclear magnetic resonance form paramagnetic molecules).
192. The composition according to any of items 86 to 120, wherein the one or more labels is an enzyme label.
193. The composition according to item 192, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, producing a light signal (chemi-luminescence).
194. The composition according to item 192, wherein the enzyme catalyzes a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitation of chromophor dyes.
195. The composition according to item 192, wherein the enzyme catalyzes a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitates that can be detected by an additional layer of detection molecules.
196. The composition according to item 192, wherein the enzyme label is selected from the group peroxidases, malate dehydrogenase, staphylococcal nuclease, delta-5- steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. 197. The composition according to item 192, wherein the enzyme label is horseradish peroxidase.
198. The composition according to item 192, wherein the enzyme label is horseradish peroxidase and the substrate is diaminobenzidine (DAB).
199. The composition according to item 192, wherein the enzyme label is horseradish peroxidase and the substrate is 3-amino-9-ethyl-carbazole (AEC+).
200. The composition according to item 192, wherein the enzyme label is horseradish peroxidase and the substrate is biotinyl tyramide.
201 . The composition according to item 192, wherein the enzyme label is horseradish peroxidase and the substrate is fluorescein tyramide.
202. The composition according to item 192, wherein the enzyme label is alkaline phosphatise.
203. The composition according to item 192, wherein the enzyme label is alkaline phosphatase and the substrate is Fast red dye.
204. The composition according to any of items 86 to 120, wherein the one or more labels is a ionophore or chelating chemical compound binding to specific ions such as Ca2+.
205. The composition according to any of items 86 to 120, wherein the one or more labels is a lanthanide.
206. The composition according to item 205, wherein the lanthanide comprises fluorescence.
207. The composition according to item 205, wherein the lanthanide comprises Phosphorescence. 208. The composition according to item 205, wherein the lanthanide is paramagnetic.
209. The composition according to any of items 86 to 120, wherein the one or more labels is a DNA fluorescing stain.
210. The composition according to item 209, wherein the DNA fluorescing stain is Propidium iodide.
21 1 . The composition according to item 209, wherein the DNA fluorescing stain is Hoechst stain.
212. The composition according to item 209, wherein the DNA fluorescing stain is DAPI.
213. The composition according to item 209, wherein the DNA fluorescing stain is AMC.
214. The composition according to item 209, wherein the DNA fluorescing stain is DraQ5™.
215. The composition according to item 209, wherein the DNA fluorescing stain is Acridine orange.
216. The composition according to item 3, wherein the MHC-peptide complex (a-b-P) is attached to a multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety.
217. The composition according to any of items 3 to 216, wherein P and/or a and/or b is chemically modified.
218. The composition according to any of items 3 to 216, wherein P and/or a and/or b is pegylated.
219. The composition according to any of items 3 to 216, wherein P and/or a and/or b is phosphorylated. 220. The composition according to any of items 3 to 216, wherein P and/or a and/or b is glycosylated.
221 . The composition according to any of items 3 to 216, wherein one of the amino acid residues of the peptide P and/or a and/or b is substituted with another amino acid.
222. The composition according to any of items 3 to 216, wherein a and b are both full- length peptides.
223. The composition according to any of items 3 to 216, wherein a is a full-length peptide.
224. The composition according to any of items 3 to 216, wherein b is a full-length peptide.
225. The composition according to any of items 3 to 216, wherein a is truncated.
226. The composition according to any of items 3 to 216, wherein b is truncated.
227. The composition according to any of items 3 to 216, wherein a and b are both truncated.
228. The composition according to any of items 3 to 216, wherein a and b are covalently linked.
229. The composition according to any of items 3 to 216, wherein a and P are covalently linked.
230. The composition according to any of items 3 to 216, wherein b and P are covalently linked.
231 . The composition according to any of items 3 to 216, wherein a, b and P are covalently linked. 232. The composition according to any of items 3 to 216, wherein a and b are non- covalently linked.
233. The composition according to any of items 3 to 216, wherein a and P are non- covalently linked.
234. The composition according to any of items 3 to 216, wherein b and P are non- covalently linked.
235. The composition according to any of items 3 to 216, wherein a, b and P are non- covalently linked.
236. The composition according to any of items 3 to 216, wherein a is not included in the (a-b-P) complex.
237. The composition according to any of items 3 to 216, wherein b is not included in the (a-b-P) complex.
238. The composition according to any of items 3 to 216, wherein P is not included in the (a-b-P) complex.
239. The composition according to any of items 3 to 216, wherein the MHC-peptide complex is linked to at least one of the one or more multimerization domains by a linker moiety.
240. The composition according to item 239, wherein the MHC-peptide complex is linked to at least one of the one or more multimerization domains by a covalent linker moiety.
241 . The MHC multimer according to items 239 and 240, wherein the linkage of at least one of the one or more multimerization domains and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, at least one of the one or more multimerization domains, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes. 242. The composition according to item 239 and 240, wherein the linker moiety linking at least one of the one or more multimerization domains and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
243. The composition according to item 242, wherein the moiety X comprises a nucleophilic group.
244. The composition according to item 243, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2, -CN.
245. The composition according to item 242, wherein the moiety Y comprises an electrophilic group.
246. The composition according to item 245, wherein the electrophilic group is selected from the group consisting of CHO, COOH , CO, NHS-ester, tosyl activated ester, acidanhydride other activated esters.
247. The MHC multimer according to items 239 and 240, wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety.
248. The MHC multimer according to items 239 and 240, wherein X and Y comprises reactive groups natively associated with the one or more multimerization domains and/or the MHC-peptide complexes.
249. The MHC multimer according to items 239 and 240, wherein X and Y comprises reactive groups not natively associated with the one or more multimerization domains and/or the MHC-peptide complex.
250. The MHC multimer according to items 239 and 240, wherein the linker moiety forms a covalent link between at least one of the one or more multimerization domains and at least one of the MHC-peptide complexes. 251 . The MHC multimer according to items 239 and 240, wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group - NH2, -OH, -SH, and -NH-.
252. The MHC multimer according to items 239 and 240, wherein the reactive groups of multimerization domains include hydroxyls of polysaccharides such as dextrans.
253. The MHC multimer according to items 239 and 240, wherein the reactive groups of multimerization domains selected from the group amino acid side chains comprising
-NH2, -OH, -SH, and -NH- of polypeptides.
254. The MHC multimer according to items 239 and 240, wherein one of the polypeptides of the MHC-peptide complex is covlalently or non-covalently linked by a protein fusion to the multimerization domain.
255. The MHC multimer according to items 239 and 240, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the multimerization domain, wherein an acyl group and an amino group react to form an amide bond.
256. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is a β2M polypeptide.
257. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is a MHC I heavy chain polypeptide.
258. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is an antigenic peptide.
259. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is a MHC Il α-chain polypeptide.
259. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is a MHC Il β-chain polypeptide 260. The composition according to item 3, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the multimerization domain
261 . The composition according to item 260, wherein the non-native reactive groups include reactive groups that are attached to the multimerization domain through association of a linker molecule comprising the reactive group.
262. The composition according to item 260, wherein the non-native reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
263. The composition according to item 18, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
264. The composition according to item 263, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups
265. The composition according to item 3, wherein the multimerization domain comprises one or more nucleophilic groups
266. The composition according to item 265, wherein the nucleophilic group is selected from the group -NH2, -OH, -SH, -CN, -NH-NH2
267. The composition according to item 3, wherein the multimerization domain is selected from the group polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
268. The composition according to item 3, wherein the multimerization domain comprises one or more electrophilic groups.
269. The composition according to item 268, wherein the electrophilic group is selected from the group -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides. 270. The composition according to item 3, wherein the multimerization domain is selected from the group of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
271 . The composition according to item 3, wherein the multimerization domain comprises one or more radicals.
272. The composition according to item 3, wherein the multimerization domain comprises one or more conjugated double bonds.
273. The composition according to item 3, wherein the MHC-peptide complex comprises one or more nucleophilic groups.
274. The composition according to item 273, wherein the nucleophilic group is selected from the group -NH2, -OH, -SH, -CN, -NH-NH2
275. The composition according to item 3, wherein the MHC-peptide complex comprises one or more electrophilic groups.
276. The composition according to item 275, wherein the electrophilic group is selected from the group -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides.
277. The composition according to item 3, wherein the MHC-peptide complex comprises one or more radicals.
278. The composition according to item 3, wherein the MHC-peptide complex comprises one or more conjugated double bonds
279. The composition according to item 3, wherein the multimerization domain comprises one or more beads and one or more linker moieties.
280. The composition according to item 279, wherein the linker is a flexible linker. 281 . The composition according to item 279, wherein the linker is a rigid linker.
282. The composition according to item 279, wherein the linker is a water-soluble linker.
283. The composition according to item 279, wherein the linker is a cleavable linker.
284. The composition according to item 283, wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
285. The composition according to item 283, wherein the cleavable linker is cleavable at physiological conditions
286. The MHC multimer according to item 3, wherein the MHC-peptide complex is linked to at least one of the one or more multimerization domains by a non-covalent linker moiety.
287. The composition according to item 286, wherein the non-covalent linkage comprises natural dimerization.
288. The composition according to item 287, wherein the natural dimerization comprises antigen-antibody pairs or coiled coil structures.
289. The composition according to item 287, wherein the natural dimerization comprises DNA-DNA interactions.
290. The composition according to item 286, wherein the non-covalent linkage comprises natural interactions.
291 . The composition according to item 290, wherein the natural interaction comprises biotin and streptavidin.
292. The composition according to item 26, wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes 293. The composition according to item 26, wherein the bead is coated with streptavidin tetramers each of which being independently associated with 0, 1 , 2, 3, or 4 biotinylated MHC complexes
294. The composition according to item 26, wherein the bead is coated with polysaccharide, such as a polysaccharide comprising dextran moieties.
295. The composition according to item 290, wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells
296. The composition according to item 286, wherein the non-covalent linkage comprises artificial interactions
297. The composition according to item 296, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA
298. The composition according to item 296, wherein the artificial interaction comprises PNA-PNA
299. The composition according to item 286, wherein the non-covalent linkage comprises non-specific adsorption
300. The composition according to item 299, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces
301. The composition according to item 286, wherein the non-covalent linkage comprises the pentamer structure
302. The composition according to item 286, wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP- 1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
303. The composition according to any of items 3 to 302, wherein the MHC multimer comprises stabilized empty MHC complexes and/or stabilized MHC-peptide complexes.
304. The composition according to item 303, wherein the MHC multimer comprises a soluble form of MHC I where the transmembrane and cytosolic domains of the membrane-anchored MHC complexes have been removed.
305. The composition according to item 303, wherein the MHC multimer comprises a soluble form of MHC Il where the transmembrane and cytosolic domains of the membrane-anchored MHC complexes have been removed.
306. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes have been stabilized by generation of covalent protein-fusions.
307. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes have been stabilized by stabilization of the MHC I molecules by introduction of one or more linkers between the individual components of the MHC I complex such as generation of a complex consisting of a heavy chain fused with β2m through a linker and a soluble peptide, a heavy chain fused to β2m through a linker, a heavy chain /β2m dimer covalently linked to a peptide through a linker to either heavy chain or β2m, or where there can or can not be a linker between the heavy chain and β2m, a heavy chain fused to a peptide through a linker, or the α1 and α2 subunits of the heavy chain fused to a peptide through a linker.
308. The composition according to item 307, wherein each of the heavy chain, β2m and the peptide are truncated.
309. The composition according to item 307, wherein the linker is a flexible linker.
310. The composition according to item 307, wherein the linker is made of glycine and/or serine.
31 1 . The composition according to item 307, wherein the linker is between 5-20 residues long, such as from 5-6 residues long, for example from 6-8 residues long, such as from 8-10 residues long, for example from 10-12 residues long, such as from 12-14 residues long, for example from 14-16 residues long, such as from 16-18 residues long and for example from 18-20 residues long.
312. The composition according to item 307, wherein the linker is longer than 20 residues long.
313. The composition according to item 307, wherein the linker is shorter than 5 residues long.
314. The composition according to item 307, wherein the linker is rigid with a defined structure.
315. The composition according to item 307, wherein the linker is made of amino acids like glutamate, alanine, lysine, and leucine creating e.g. a more rigid structure.
316. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain-β2m fusion proteins, wherein the COOH terminus of β2m can be covalently linked to the NH2 terminus of the heavy chain, or the NH2 terminus of β2m can be linked to the COOH terminus of the heavy chain. 317. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a fusion-protein comprising a β2m domain, or a truncated β2m domain, inserted into the heavy chain.
318. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a fusion-protein comprising a heavy chain domain, or a truncated heavy chain, inserted into the β2m chain, to form a fusion-protein of the form "β2m(first part)-heavy chain-β2m(last part)".
319. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptide-β2m fusion proteins, wherein the COOH terminus of the peptide is linked to the NH2 terminus of β2m or the peptide is linked to the COOH terminal of β2m via its NH2 terminus.
320. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain-peptide fusion proteins, wherein the NH2 terminus of the heavy chain is fused to the COOH terminus of the peptide, or the fusion is between the COOH terminus of the heavy chain and the NH2 terminus of the peptide.
321 . The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain-β2m- peptide fusion proteins, wherein the NH2 terminus of the heavy chain is fused to the COOH terminus of β2m and the NH2 terminus of β2m can be fused to the COOH terminus of the peptide.
322. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by binding to an unnatural component.
323. The composition according to item 322, wherein the unnatural component bind to both the heavy chain and the β2m.
324. The composition according to item 322, wherein the unnatural component bind to either β2m or heavy chain, and in this way stabilize the polypeptide in its correct conformation, and in this way increase the affinity of the heavy chain for β2m and/or peptide, or increase the affinity of β2m for peptide.
325. The composition according to item 322, wherein the unnatural component is one or more antibodies.
326. The MHC multimer according to calim 325, wherein the one or more antibodies can be selected from the group consisting of as truncated or full-length antibodies (of isotype IgG, IgM, IgA, IgE), Fab, scFv or bi-Fab fragments or diabodies.
327. The MHC multimer according to calim 325, wherein the one or more antibodies is one or more antibodies capable of binding the MHC I molecule by interaction with the heavy chain as well as β2m.
328. The MHC multimer according to calim 325, wherein the one or more antibodies is one or more bispecific antibodies that binds with one arm to the heavy chain and the other arm to the β2m of the MHC complex.
329. The MHC multimer according to calim 325, wherein the one or more antibodies is monospecific, and bind at the interface between heavy chain and β2m.
330. The MHC multimer according to calim 325, wherein the one or more antibodies is one or more antibodies capable of binding the heavy chain but only when the heavy chain is correct folded.
331 . The MHC multimer according to calim 325, wherein the one or more antibodies is the antibody produced by the clone W6/32 such as M0736 or the like that recognizes a conformational epitope on intact human and some monkey MHC complexes comprising β2m, heavy chain and peptide.
332. The composition according to item 322, wherein the unnatural component is one or more peptides.
333. The composition according to item 322, wherein the unnatural component is one or more aptamers. 334. The composition according to item 322, wherein the unnatural component is one or more molecules with the ability to bind peptides stretches of the MHC complex.
335. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of modified proteins or protein components.
336. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises improved stability of a MHC I complex by increasing the affinity of the binding peptide for the MHC complex.
337. The composition according to item 335, wherein the generation of modified proteins or protein components comprises mutagenesis of one or more amino acids at relevant positions in the peptide.
338. The composition according to item 335, wherein the generation of modified proteins or protein components comprises substitution of one or more amino acids at relevant positions in the peptide.
339. The composition according to item 335, wherein the generation of modified proteins or protein components comprises chemical modifications of amino acids at relevant positions in the peptide.
340. The composition according to item 335, wherein the generation of modified proteins or protein components comprises introduction by synthesis of non-natural amino acids at relevant positions in the peptide.
341 . The composition according to item 335, wherein the generation of modified proteins or protein components comprises mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions in the peptide binding cleft, i.e. in the binding pockets that accommodate peptide side chains responsible for anchoring the peptide to the peptide binding cleft. 342. The composition according to item 335, wherein the generation of modified proteins or protein components comprises introduction of one or more reactive groups into the antigenic peptide;
343. The composition according to item 335, wherein the generation of modified proteins or protein components comprises mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions in the heavy chain and/or β2m at positions outside the peptide-binding cleft.
344. The composition according to item 335, wherein the generation of modified proteins or protein components comprises removal of "unwanted cysteine residues" in the heavy chain by mutation, chemical modification, amino acid exchange or deletion.
345. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises covalent stabilization of MHC I complex, wherein a linker is covalently attached between two of the subunits of the MHC complex such as a linker between peptide and heavy chain or between heavy chain and beta2microglobulin.
346. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises eukaryotic expression systems for production of MHC Il molecules such as stable Drosophila cell transfectants, baculovirus infected insect cells, CHO cells or other mammalian cell lines suitable for expression of proteins.
347. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of covalent protein-fusions.
348. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization of MHC Il complexes by introduction of one or more linkers e.g. between the individual components of the MHC Il complex such as a α/β dimer with a linker between α-chain and β-chain; a α/β dimer covalently or non-covalently linked to the peptide via a linker to either the α-chain or β-chain; a α/β dimer, covalently or non-covalently linked by a linker between the α-chain and β-chain, and where the dimer is covalently or non- covalently linked to the peptide or a α/β dimer with a linker between α-chain and β- chain, where the dimer is combined with a peptide covalently or non-covalently linked to either α-chain or β-chain.
349. The composition according to item 348, wherein the linker is a flexible linker.
350. The composition according to item 348, wherein the linker is made of glycine and/or serine.
351 . The composition according to item 348, wherein the linker is between 5-20 residues long, such as from 5-6 residues long, for example from 6-8 residues long, such as from 8-10 residues long, for example from 10-12 residues long, such as from 12-14 residues long, for example from 14-16 residues long, such as from 16-18 residues long and for example from 18-20 residues long.
352. The composition according to item 348, wherein the linker is longer than 20 residues long.
353. The composition according to item 348, wherein the linker is shorter than 5 residues long.
354. The composition according to item 348, wherein the linker is rigid with a more defined structure, e.g. made of amino acids like glutamate, alanine, lysine, and leucine.
355. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptides linked to the NH2- or COOH-terminus of either α-chain or β-chain.
356. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptides linked to the NH2-terminus of the β-chain via their COOH-terminus, since the linker required is shorter than if the peptide is linked to the COOH-terminus of the β-chain. 357. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises linkage of α-chain to β-chain via the COOH-terminus of the β-chain to the NH2-terminus of the α-chain or from the COOH-terminus of the α-chain to the NH2-terminus of the β-chain.
358. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a three-molecule fusion protein consisting of α-chain, β-chain and peptide e.g. where one linker connect the COOH-terminus of the β-chain with the NH2-terminus of the α-chain and another linker connects the COOH-terminal of the peptide with the NH2-terminal of the β-chain or one linker joins the COOH-terminus of the α-chain with the NH2-terminus of the β- chain and the second linker joins the NH2-terminus of the peptide with the COOH- terminus of the β-chain.
359. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by binding ligand.
360. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent binding of ligands to the MHC Il complex to promote assembly of α- and β-chain by bridging the two chains, or by binding to either of the α- or β-chains, and in this way stabilize the conformation of α or β, that binds β or α, respectively, and/or that binds the peptide.
361. The composition according to item 360, wherein the ligands are one or more antibodies.
362. The composition according to item 361 , wherein the one or more antibodies are one or more antibodies binding the MHC complex distal to the interaction site with TCR, i.e. distal to the peptide-binding cleft.
363. The composition according to item 361 , wherein the one or more antibodies are any truncated or full length antibody of any isotype (e.g. IgG, IgM, IgA or IgE), a bi-Fab fragment or a diabody. 364. The composition according to item 361 , wherein the one or more antibodies are bispecific with one arm binding to the α-chain and the other arm binding to the β-chain.
365. The composition according to item 361 , wherein the one or more antibodies are monospecific and directed to a sequence fused to the α-chain as well as to the β-chain.
366. The composition according to item 361 , wherein the one or more antibodies are monospecific and binds to a surface of the complex that involves both the α- and β- chain, e.g. both the α2- and β2- domain or both the α1 - and β1 - domain.
367. The composition according to item 360, wherein the ligands are one or more peptides.
368. The composition according to item 360, wherein the ligands are one or more aptamers.
369. The composition according to item 360, wherein the ligands are one or more molecules with the ability to bind proteins.
370. The composition according to item 360, wherein the ligands are one or more ligand that binds at the α-/β-chain interface, e.g. peptides and aptamers.
371 . The composition according to item 360, wherein the ligands are one or more ligands that bind the peptide, although, in this case it is important that the ligand does not interfere with the interaction of the peptide or binding cleft with the TCR.
372. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by induced multimerization.
373. The composition according to item 372, wherein the multimerization comprises anchoring of the α- and β-chains in the cell membrane leading to stabilization of the MHC Il complexes. 374. The composition according to item 372, wherein the multimerization comprises stabilization of the α/β-dimer by attachment of the MHC Il chains to the Fc regions of an antibody, leading to a stable α/β-dimer, where α and β are held together by the tight interactions between two Fc domains of an antibody.
375. The composition according to item 372, wherein the multimerization comprises one or more dimerization domains.
376. The composition according to item 372, wherein the multimerization comprises MHC Il molecules incorporated into artificial membrane spheres like liposomes or lipospheres.
377. The composition according to item 372, wherein the multimerization comprises MHC Il molecules incorporated as monomers or as dimers in a membrane.
378. The composition according to item 372, wherein the multimerization comprises biotinylation of α- as well as β-chain and the two chains brought together by binding to streptavidin.
379. The composition according to item 372, wherein the multimerization comprises long flexible linkers such as extended glycine-serine tracts used to extend both chains, whereafter the chains are biotinylated at the end of such extended linkers and streptavidin is used as a scaffold to bring the chains together in the presence of the peptide, while the flexible linkers still allow the chains to orientate properly.
380. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of modified proteins or protein components.
381 . The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization of MHC Il complexes by covalent modifications of the protein.
382. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises increase of the affinity of the peptide for the MHC complex e.g. by exchange of the natural amino acids with other natural or non-natural amino acids at relevant positions in the peptide or by chemical modifications of amino acids at relevant positions in the peptide or mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions can be introduced in the peptide-binding cleft or mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions is introduced in α- and/or β- chain at positions outside the peptide-binding cleft.
383. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises replacement of the hydrophobic transmembrane regions of α-chain and β-chain by leucine zipper dimerisation domains (e.g. Fos-Jun leucine zipper; acid-base coiled-coil structure) to promote assembly of α-chain and β-chain.
384. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises introduction of one or more cysteine residues by amino acid exchange at the COOH-terminal of both α-chain and β-chain, to create disulfide bridges between the two chains upon assembly of the MHC complex.
385. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises removalal of "unwanted cysteine residues" in either of the chains by mutation, chemical modification, amino acid exchange or deletion.
386. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stbilization of MHC Il complexes by chemically linking together the subunits and the peptide e.g. by a linker between peptide and α-chain, between peptide and β-chain, between α-chain and β- chain, or combination thereof.
387. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises chemically modified MHC complexes. 388. The composition according to item 387, wherein the chemically modified MHC complexes comprises one or more amino acids reacted with one or more chemical cross linkers.
389. The composition according to item 387, wherein the chemically modified MHC complexes comprises that the amino group at the N-terminal of both chains and of the peptide, as well as amino groups of lysine side chains, are nucleophilic and can be used in a chemical reaction.
390. The composition according to item 389, wherein the chemical reaction is nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation),
391 . The composition according to item 389, wherein the chemical reaction is addition to carbon-hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers).
392. The composition according to item 389, wherein the chemical reaction is nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines).
393. The composition according to item 389, wherein the chemical reaction is one or more cycloadditions.
394. The composition according to item 389, wherein the chemical reaction comprises use of activated carboxylic acids such as NHS-ester, tetra and pentafluoro phenolic esters, anhydrides, acid chlorides and fluorides.
395. The composition according to item 389, wherein the chemical reaction comprises use of sulphonyl chlorides.
396. The composition according to item 389, wherein the chemical reaction comprises use of iso-Cyanates and/or isothiocyanates. 397. The composition according to item 389, wherein the chemical reaction comprises use of Aldehydes, such as formaldehyde and glutardialdehyde.
398. The composition according to item 389, wherein the chemical reaction comprises alkylation by maleimides, vinyl sulphones and halides.
399. The composition according to item 389, wherein the chemical reaction comprises use of carboxylic acids at the C-terminal of both chains and peptide, as well as on the side chains of glutamic and aspartic acid, to introduce cross-links.
400. The composition according to item 389, wherein the chemical reaction use of carbodiimides.
401 . The composition according to item 389, wherein the chemical reaction any chemistries that can be employed to form covalent cross-links.
402. The composition according to item 389, wherein the chemical reaction comprises one or more chemical reagents that are bi-functional.
403. The composition according to item 389, wherein the chemical reaction comprises one or more chemical reagents that are homo bi-functional such as glutardialdehyde.
404. The composition according to item 389, wherein the chemical reaction comprises one or more chemical reagents that are hetero bi-functional such as GMBS
(MaleimidoButyryloxy-Succinimide ester).
405. The composition according to item 389, wherein the chemical reaction comprises use of two or more reagents.
406. The composition according to item 389, wherein the chemical reaction comprises that GMBS is used to introduce maleimides on the α-chain, and iminothiolane is used to introduce thiols on the β-chain, whereafter the malemide and thiol can then form a thioether link between the two chains. 407. The composition according to item 389, wherein the chemical reaction comprises one or more types of cross-links.
408. The composition according to item 389, wherein the chemical reaction comprises that the folded MHC-complex can be reacted with dextrans possessing a large number
(up to many hundreds) of vinyl sulphones, which can react with lysine residues on both the α and β chains as well as with lysine residues on the peptide protruding from the binding site, effectively cross linking the entire MHC-complex.
409. The composition according to item 389, wherein the chemical reaction comprises activation of dextran e.g. with vinyl sulphones.
410. The composition according to item 389, wherein the chemical reaction comprises that a dextran is reacted both with one or several MHC-complexes and one or more fluorescent protein such as APC.
41 1 . The composition according to item 389, wherein the chemical reaction comprises one or more chemical cross linkers.
412. The composition according to item 389, wherein the chemical reaction comprises that one or more lysine residues are inserted into the α-chain, juxtaposed with glutamic acids in the β-chain, where after the introduced amino groups and carboxylic acids are reacted by addition of carbodiimide.
413. The composition according to item 389, wherein the chemical reaction comprises that one or more dextran multimerization domain(s) are cross-linked with appropriately modified MHC-complexes; i.e. one or both chains of the MHC complex can be enriched with lysine residues, increasing reactivity towards the vinylsulphone dextran.
414. The composition according to item 413, wherein the lysine residues are inserted at positions opposite the peptide binding cleft, orienting the MHC-complexes favourably for T-cell recognition.
415. The composition according to item 389, wherein the chemical reaction comprises use of one or more extended and flexible cross-linkers. 416. The composition according to item 303, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization with one or more soluble additives.
417. The composition according to item 416, wherein the one or more soluble additives comprises one or more salts.
418. The composition according to item 416, wherein the one or more soluble additives comprises one or more detergents.
419. The composition according to item 416, wherein the one or more soluble additives comprises one or more organic solvents.
420. The composition according to item 416, wherein the one or more soluble additives comprises one or more polymers.
421 . The composition according to item 416, wherein the one or more soluble additives comprises one or more soluble additives that increase the stability of MHC complexes.
422. The composition according to item 416, wherein the one or more soluble additives comprises one or more soluble additives that increase the surface tension of the MHC complex.
423. The composition according to item 416, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of sucrose, mannose, glycine, betaine, alanine, glutamine, glutamic acid, ammonium sulphate, glycerol, mannitol and sorbitol.
424. The composition according to item 416, wherein the one or more soluble additives comprises one or more soluble additives that increase the surface tension of the MHC complex and simultaneously can interact with charged groups in the protein. 425. The composition according to item 416, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of MgSO4, NaCI, polyethylenglycol, 2-methyl-2,4-pentanediol and guanidiniumsulphate.
426. The composition according to item 416, wherein the one or more soluble additives comprises molar excess of peptide.
427. The composition according to item 416, wherein the one or more soluble additives comprises molar excess β2m.
428. The composition according to item 416, wherein the one or more soluble additives comprises molar excess β2m and molar excess of peptide identical to the peptide bound in the peptide-binding cleft.
429. The composition according to item 416, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of BSA, fetal and bovine calf serum, and other protein components in serum with a protein stabilizing effect.
430. The composition according to item 416, wherein the one or more soluble additives are added to any solution comprising MHC complexes in order to increase the stability of the molecule.
431 . The composition according to item 416, wherein the one or more soluble additives are added during the refolding process.
432. The composition according to item 416, wherein the one or more soluble additives are added to the formed MHC complex.
433. The composition according to item 416, wherein the one or more soluble additives are added to a solution of MHC multimers comprising several MHC complexes. 434. The composition according to any of items 3 to 303 further comprising one or more molecules with adjuvant effect.
435. The composition according to any of items 3 to 303 further comprising one or more immune targets.
436. The MHC multimer according to any of item 435, wherein the one or more immune targets is an antigen.
437. The composition according to any of items 3 to 303 further comprising one or more molecules with biological activity.
438. The composition according to any of items 3 to 303 further comprising one or more molecules with a cytotoxic effect.
439. The composition according to any of items 3 to 303 further comprising one or more molecules selected from the group consisting of enzymes, regulators of receptor activity, receptor ligands, immune potentiators, drugs, toxins, co-receptors, proteins, peptides, sugar moieties, lipid groups, nucleic acids including siRNA, nano particles, and small molecules.
440. The composition according to any of items 3 to 303 further comprising one or more molecules selected from the group consisting of HIV gp120, HIV-GAG gp 27, HSP70, and MHC class Il proteins or peptides or combinations thereof.
441 . The composition according to any of items 3 to 303 further comprising one or more immuno active molecules.
442. The composition according to item 441 , wherein the one or more immuno active molecules are identical.
443. The composition according to item 441 , wherein the one or more immuno active molecules are different. 444. The composition according to item 441 , wherein the one or more immuno active molecules are selected from the group consisting of biological active molecules including proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, as well as antibodies and recombinant binding molecules to any of the foregoing, and combinations thereof.
445. The composition according to item 441 , wherein the one or more immuno active molecules comprises one or more molecules selected from the group consisting of MHC Class Mike proteins like MIC A, MIC B, CDId, HLA E, HLA F, HLA G, HLA H, ULBP-1 , ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1 BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD- 1 , Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-
L2, CD134L, CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN- gamma, IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, CSFs (colony- stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA- 1 , CDIIa/18, CD54 (ICAM- 1 ), CD106 (VCAM), and CD49a, b, c, d, e, f/CD29 (VLA-4), adhesion molecules such as ICAM-1 , ICAM-2, GlyCAM-1 , CD34, anti-LFA-1 , anti- CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti- selectin P, toxic molecules selected from toxins, enzymes, antibodies, radioisotopes, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, heavy'metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and combinations of any of the foregoing, as well as antibodies (monoclonal, polyclonal, and recombinant) to the foregoing, where relevant and antibody derivatives or fragments thereof. 446. The composition according to item 441 , wherein the one or more immuno active molecules are derived from viral or bacterial proteins or fragments thereof.
447. The composition according to item 441 , wherein the one or more immuno active molecules are attached to the multimerization domain(s) either directly, thorugh one or more linkers or via one or more of the binding entities or one or more multimerization domains.
448. The composition according to item 441 , wherein the one or more immuno active molecules are linked to another immunoactive molecules and then attached to one or more multimerization domains.
449. The composition according to any of items 3 to 303, wherein the MHC multimer is covalently or non-covalently associated with various molecules such as molecules with adjuvant effects, immune targets such as antigens, molecules with biological activity such as enzymes, regulators of receptor activity, receptor ligands, immune potentiators, drugs, toxins, co-receptors, proteins and peptides in general; sugar moieties; lipid groups; nucleic acids including siRNA; nano particles; small molecules.
450. The composition according to any of items 3 to 303, wherein the MHC multimer is covalently or non-covalently associated with one or more biologically active molecules and/or one or more immuno active molecules.
451 . The composition according to item 450, wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by chemical reactions between reactive groups on the biologically active molecule or immuno active molecule and reactive groups of the multimerisation domain and/or between reactive groups on the biologically active molecule or immuno active molecule and reactive groups of the MHC-peptide complex.
452. The composition according to item 450, wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by non- covalent interaction between part of the multimerisation domain and part of the biological active molecule or immuno active molecule; or between part of the MHC- peptide complex and part of the biological active molecule or immuno active molecule. 453. The composition according to item 450, wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by covalent and non-covalent attachment of the biologically molecule or immuno active molecule to the multimerisation domain by a linker molecule.
454. The composition according to item 450, wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by repetitively attachment aiding to recognition by and stimulation of the innate immune system via Toll or other receptors.
455. The composition according to any of items 3 to 454 comprising a plurality of identical or different multimerization domains linked by a multimerization domain linking moiety,
wherein at least one of said multimerization domains is associated with (a-b-P)n, wherein n > 1 ,
wherein a and b together form a functional MHC protein capable of binding the peptide P, when P is present
wherein (a-b-P) is the MHC-peptide complex formed when the peptide P binds to the functional MHC protein.
456. The composition according to item 455, wherein the plurality of identical or different multimerization domains is in the range of from 2 to 100, suach as 2 to 5, 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100.
457. The composition according to item 455, wherein the MHC multimer comprises a first multimerization domain linked to a second multimerization domain.
458. The composition according to item 457, wherein the first multimerization domain and the second multimerization domain is independently selected from the group consisting of multimerization domains cited in any of items 4 to 37. 459. The composition according to item 457, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the first multimerization domains.
460. The composition according to item 457, wherein the association is a non-covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the first multimerization domain.
461 . The composition according to item 457, wherein the first multimerization domain comprises one or more scaffolds.
462. The composition according to item 457, wherein the first multimerization domain comprises one or more carriers.
463. The composition according to item 457, wherein the first multimerization domain comprises at least one scaffold and at least one carrier.
464. The composition according to item 457, wherein the first multimerization domain comprises one or more optionally substituted organic molecules.
465. The composition according to item 464, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
466. The composition according to item 465, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
467. The composition according to item 464, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
468. The composition according to item 457, wherein the first multimerization domain comprises one or more biological cells, such as antigen presenting cells or dendritic cells. 469. The composition according to item 457, wherein the first multimerization domain comprises one or more membranes.
470. The composition according to item 469, wherein the one or more membranes comprises liposomes or micelles.
471 . The composition according to item 457, wherein the first multimerization domain comprises one or more polymers.
472. The composition according to item 471 , wherein the one or more polymers are selected from the group consisting of the group consisting of polysaccharides.
473. The composition according to item 472, wherein the polysaccharide comprises one or more dextran moieties.
474. The composition according to item 457, wherein the first multimerization domain comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA-PNA, PNA- DNA, DNA-RNA.
475. The composition according to item 457, wherein the first multimerization domain comprises an avidin, such as streptavidin.
476. The composition according to item 457, wherein the first multimerization domain comprises an antibody.
477. The composition according to item 476, wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody.
478. The composition according to item 457, wherein the first multimerization domain comprises one or more small organic scaffold molecules.
479. The composition according to item 457, wherein the first multimerization comprises one or more further polypeptides in addition to a and b.
480. The composition according to item 457, wherein the first multimerization comprises one or more protein complexes.
481 . The composition according to item 457, wherein the first multimerization comprises one or more beads
482. The composition according to item 457, wherein the first multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG- encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(Ci-Ci0)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin-monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran,
Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly-acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen-fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
483. The composition according to item 457, wherein the first multimerization domain comprises a dimerization domain.
484. The composition according to item 457, wherein the first multimerization domain comprises a trimerization domain.
485. The composition according to item 457, wherein the first multimerization domain comprises a tetramerization domain.
486. The composition according to item 457, wherein the first multimerization domain comprises a pentamerization domain.
487. The composition according to item 486, wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
488. The composition according to item 457, wherein the first multimerization domain comprises a hexamerization domain.
489. The composition according to item 488, wherein the hexamerization domain comprises three IgG domains. 490. The composition according to item 457, wherein the first multimerization domain comprises a polymer structure to which is attached one or more scaffolds.
491 . The composition according to item 490, wherein the polymer structure comprises a polysaccharide.
492. The composition according to item 491 , wherein the polysaccharide comprises one or more dextran moieties.
493. The composition according to item 457, wherein the first multimerization domain comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
494. The composition according to item 457, wherein the first multimerization domain comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or or a cyclodextrin.
495. The composition according to item 457, wherein one or more labels is covalently attached to the first multimerization domain.
496. The composition according to item 457, wherein one or more labels is non- covalently attached to the first multimerization domain.
497. The composition according to item 496, wherein the one or more labels is non- covalently attached to an antibody in the first mutimerization domain.
498. The MHC multimer according item 495, wherein the one or more labels is covalently attached to an antibody in the first mutimerization domain.
499. The MHC multimer according item 496, wherein the one or more labels is non- covalently attached to an aptamer in the first mutimerization domain.
500. The MHC multimer according item 495, wherein the one or more labels is covalently attached to an aptamer in the first mutimerization domain. 501 . The MHC multimer according item 496, wherein the one or more labels is non- covalently attached to a molecule in the first mutimerization domain.
502. The MHC multimer according item 495, wherein the one or more labels is covalently attached to a molecule in the first mutimerization domain.
503. The MHC multimer according item 496, wherein the one or more labels is non- covalently attached to a protein in the first mutimerization domain.
504. The MHC multimer according item 495, wherein the one or more labels is covalently attached to a protein in the first mutimerization domain.
505. The MHC multimer according item 496, wherein the one or more labels is non- covalently attached to a sugar residue in the first mutimerization domain.
506. The MHC multimer according item 495, wherein the one or more labels is covalently attached to a sugar residue in the first mutimerization domain.
507. The MHC multimer according item 496, wherein the one or more labels is non- covalently attached to a DNA in the first mutimerization domain.
508. The MHC multimer according item 495, wherein the one or more labels is covalently attached to a DNA in the first mutimerization domain.
509. The MHC multimer according to any of the items 495 to 508, wherein the attachment is directly between reactive groups in the labelling molecule and reactive groups in the marker molecule.
510. The MHC multimer according to any of the items 495 to 508, wherein the attachment is through a linker connecting labelling molecule and marker.
51 1 . The MHC multimer according to any of the items 495 to 510, wherein one label is used. 512. The MHC multimer according to any of the items 495 to 510, wherein more than one label is used.
513. The composition according to item 512, wherein the more than one label are all identical.
514. The composition according to item 512, wherein at least two labels are different.
515. The composition according to any of items 495 to 514, wherein the one or more labels is a fluorophore.
516. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of selected from the group fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o- phthaldehyde and fluorescamine.
517. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 2-(4'-maleimidylanilino)naphthalene-6- sulfonic acid, sodium salt
518. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 5-((((2-iodoacetyl)amino)ethyl)amino) naphthalene-1 -sulfonic acid
519. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Pyrene-1 -butanoic acid
520. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of AlexaFluor 350 (7-amino-6-sulfonic acid-4-methyl coumarin-3-acetic acid
521 . The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of AMCA (7-amino-4-methyl coumarin-3- acetic acid 522. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-4-methyl coumarin-3-acetic acid
523. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Marina Blue (6,8-difluoro-7-hydroxy-4- methyl coumarin-3-acetic acid
524. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 7-dimethylamino-coumarin-4-acetic acid
525. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Fluorescamin-N-butyl amine adduct
526. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-coumarine-3-carboxylic acid
527. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of CascadeBlue (pyrene-trisulphonic acid acetyl azide
528. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Cascade Yellow
529. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Pacific Blue (6,8 difluoro-7-hydroxy coumarin-3-carboxylic acid
530. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 7-diethylamino-coumarin-3-carboxylic acid
531. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Λ/-(((4-azidobenzoyl)amino)ethyl)- A- amino-3,6-disulfo-1 ,8-naphthalimide, dipotassium salt 532. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Alexa Fluor 430
533. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 3-perylenedodecanoic acid
534. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 8-hydroxypyrene-1 ,3,6-trisulfonic acid, trisodium salt
535. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 12-(Λ/-(7-nitrobenz-2-oxa-1 ,3- diazol-4- yl)amino)dodecanoic acid
536. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Λ/,/V-dimethyl-/V- (iodoacetyl)-/V-(7- nitrobenz-2- oxa-1 ,3-diazol-4-yl)ethylenediamine
537. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Oregon Green 488 (difluoro carboxy fluorescein)
538. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of 5-iodoacetamidofluorescein
539. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of propidium iodide-DNA adduct
540. The composition according to item 515, wherein the one or more fluorophore label are selected from the group consisting of Carboxy fluorescein
541 . The composition according to any of items 495 to 514, wherein the one or more labels is a fluorescent label. 542. The composition according to item 541 , wherein the one or more fluorescent label is a simple fluorescent label
543. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Fluor dyes, Pacific Blue™, Pacific
Orange™, Cascade Yellow™
544. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group AlexaFluor@(AF), AF405, AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680,
AF700, AF710, AF750, AF800.
545. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Quantum Dot based dyes, QDot® Nanocrystals (Invitrogen, MolecularProbs), Qdot®525, Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800.
546. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group DyLight™ Dyes (Pierce) (DL); DL549, DL649, DL680, DL800.
547. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Fluorescein (Flu) or any derivate of that, such as FITC
548. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Cy-Dyes, Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7.
549. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Fluorescent Proteins, RPE, PerCp, APC, Green fluorescent proteins; GFP and GFP derivated mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, m RFP 1 , M Banana, mOrange, dTomato, tdTomato, mTangerine, mStrawberry, mCherry. 550. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group Tandem dyes, RPE-Cy5, RPE-Cy5.5, RPE- Cy7, RPE-AlexaFluor® tandem conjugates; RPE-Alexa610, RPE-TxRed, APC- AlecaθOO, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5.
551 . The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group multi fluorochrome assemblies, Multiple fluorochromes attached to a polymer molecule, such as a peptide/protein, Dextrane, polysaccharide, any combination of the fluorescent dyes involving in generation of FRET (Fluorescence resonance energy transfer) based techniques.
552. The composition according to item 541 , wherein the one or more simple fluorescent label is selected from the group ionophors; ion chelating fluorescent props, props that change wavelength when binding a specific ion, such as Calcium, props that change intensity when binding to a specific ion, such as Calcium.
553. The composition according to any of items 495 to 514, wherein the one or more labels is capable of absorption of light
554. The composition according to item 553, wherein the one or more labels capable of absorption of light is a chromophore.
555. The composition according to item 553, wherein the one or more labels capable of absorption of light is a dye.
556. The composition according to any of items 495 to 514, wherein the one or more labels is capable of emission of light after excitation
557. The composition according to item 556, wherein the one or more labels capable of emission of light is one or more fluorochromes.
558. The composition according to item 557, wherein the one or more fluorochrome is selected from the AlexaFluor®(AF) family, which include AFΘ350, AF405, AF430, AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680, AF700, AF710, AF750 and AF800 559. The composition according to item 557, wherein the one or more fluorochrome is selected from the Quantum Dot (Qdot®) based dye family, which include Qdot®525, Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800
560. The composition according to item 557, wherein the one or more fluorochrome is selected from the DyLight™ Dyes (DL) family, which include DL549, DL649, DL680, DL800
561 . The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Small fluorescing dyes, which include FITC, Pacific Blue™, Pacific Orange™, Cascade Yellow™, Marina blue™, DSred, DSred-2, 7-AAD, TO-Pro- 3.
562. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Cy-Dyes, which include Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7
563. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Phycobili Proteins, which include R-Phycoerythrin (RPE), PerCP, Allophycocyanin (APC), B-Phycoerythrin, C-Phycocyanin.
564. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Fluorescent Proteins, which include (E)GFP and GFP ((enhanced) green fluorescent protein) derived mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, mRFP1 ,MBanana, mOrange, dTomato, tdTomato, mTangerine.
565. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Tandem dyes with RPE, which include RPE-Cy5, RPE- Cy5.5, RPE-Cy7, RPE-AlexaFluor® tandem conjugates; RPE-Alexa610, RPE-TxRed.
566. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Tandem dyes with APC, which include APC-Aleca600, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5. 567. The composition according to item 557, wherein the one or more fluorochrome is selected from the family of Calcium dyes, which include Indo-1 -Ca2+ lndo-2-Ca2+.
568. The composition according to any of items 495 to 514, wherein the one or more labels is capable of reflection of light
569. The composition according to item 568, wherein the one or more labels capable of reflection of light comprises gold
570. The composition according to item 568, wherein the one or more labels capable of reflection of light comprises plastic
571. The composition according to item 568, wherein the one or more labels capable of reflection of light comprises glass
572. The composition according to item 568, wherein the one or more labels capable of reflection of light comprises polystyrene
573. The composition according to item 568, wherein the one or more labels capable of reflection of light comprises pollen
574. The composition according to any of items 495 to 514, wherein the one or more labels is a chemiluminescent label.
575. The composition according to item 574, wherein the chemiluminescent labels is selected from the group luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.
576. The composition according to any of items 495 to 514, wherein the one or more labels is a bioluminescent label.
577. The composition according to item 576, wherein the bioluminescent labels is selected from the group luciferin, luciferase and aequorin. 578. The composition according to any of items 495 to 514, wherein the one or more labels is a radioactive label.
579. The composition according to item 578, wherein the one or more radioactive labels is a radionuclide.
580. The composition according to item 578, wherein the one or more radioactive labels is an isotope.
581 . The composition according to item 578, wherein the one or more radioactive labels comprises α rays.
582. The composition according to item 578, wherein the one or more radioactive labels comprises β rays.
583. The composition according to item 578, wherein the one or more radioactive labels comprises y rays.
584. The composition according to any of items 495 to 514, wherein the one or more labels is detectable by NMR (nuclear magnetic resonance form paramagnetic molecules)
585. The composition according to any of items 495 to 514, wherein the one or more labels is an enzyme label.
586. The composition according to item 585, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, producing a light signal (chemi-luminescence)
587. The composition according to item 585, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitation of chromophor dyes 588. The composition according to item 585, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitates that can be detected by an additional layer of detection molecules
589. The composition according to item 585, wherein the enzyme label is selected from the group peroxidases, malate dehydrogenase, staphylococcal nuclease, delta-5- steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase.
590. The composition according to item 585, wherein the enzyme label is horseradish peroxidase
591 . The composition according to item 585, wherein the enzyme label is horseradish peroxidase and the substrate is diaminobenzidine (DAB)
592. The composition according to item 585, wherein the enzyme label is horseradish peroxidase and the substrate is 3-amino-9-ethyl-carbazole (AEC+)
593. The composition according to item 585, wherein the enzyme label is horseradish peroxidase and the substrate is biotinyl tyramide
594. The composition according to item 585, wherein the enzyme label is horseradish peroxidase and the substrate is fluorescein tyramide
595. The composition according to item 585, wherein the enzyme label is alkaline phosphatase
596. The composition according to item 585, wherein the enzyme label is alkaline phosphatase and the substrate is Fast red dye 597. The composition according to any of items 495 to 514, wherein the one or more labels is a ionophore or chelating chemical compound binding to specific ions such as Ca2+
598. The composition according to any of items 495 to 514, wherein the one or more labels is a lanthanide
599. The composition according to item 598, wherein the lanthanide comprises fluorescence
600. The composition according to item 598, wherein the lanthanide comprises Phosphorescence
601 . The composition according to item 598, wherein the lanthanide is paramagnetic
602. The composition according to any of items 495 to 514, wherein the one or more labels is a DNA fluorescing stain
603. The composition according to item 602, wherein the DNA fluorescing stain is Propidium iodide
604. The composition according to item 602, wherein the DNA fluorescing stain is Hoechst stain
605. The composition according to item 602, wherein the DNA fluorescing stain is DAPI
606. The composition according to item 602, wherein the DNA fluorescing stain is AMC
607. The composition according to item 602, wherein the DNA fluorescing stain is DraQ5™
608. The composition according to item 602, wherein the DNA fluorescing stain is Acridine orange 609. The composition according to item 457, wherein the MHC-peptide complex (a-b- P) is attached to the first multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety.
610. The composition according to any of items 457 to 609, wherein the MHC-peptide complex is linked to the first multimerization domain by a first linker moiety.
61 1 . The composition according to item 610, wherein the MHC-peptide complex is linked to the first multimerization domain by a covalent linker moiety.
612. The MHC multimer according to items 610 and 61 1 , wherein the association of the first multimerization domain and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, the first multimerization domain, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes.
613. The MHC multimer according to items 610 and 61 1 , wherein the linker moiety linking the first multimerization domain and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
614. The composition according to item 613, wherein the moiety X comprises a nucleophilic group.
615. The composition according to item 614, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2.
616. The composition according to item 613, wherein the moiety Y comprises an electrophilic group.
617. The composition according to item 616, wherein the electrophilic group is selected from the group consisting of CHO, COOH and CO. 618. The MHC multimer according to items 610 and 61 1 , wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety.
619. The MHC multimer according to items 610 and 61 1 , wherein X and Y comprises reactive groups natively associated with the first multimerization domain and/or the MHC-peptide complexes.
620. The MHC multimer according to items 610 and 61 1 , wherein X and Y comprises reactive groups not natively associated with the first multimerization domain and/or the MHC-peptide complex.
621 . The MHC multimer according to items 610 and 61 1 , wherein the linker moiety forms a covalent link between the first multimerization domain and at least one of the MHC-peptide complexes.
622. The MHC multimer according to items 610 and 61 1 , wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group consisting of -NH2, -OH, -SH, and -NH-
623. The MHC multimer according to items 610 and 61 1 , wherein the reactive groups of the first multimerization domain include hydroxyls of polysaccharides such as dextrans
624. The MHC multimer according to items 610 and 61 1 , wherein the reactive groups of the first multimerization domain selected from the group consisting of amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides
625. The MHC multimer according to items 610 and 61 1 , wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the first multimerization domain
626. The MHC multimer according to items 610 and 61 1 , wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the first multimerization domain, wherein an acyl group and an amino group react to form an amide bond
627. The composition according to item 457, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the first multimerization domain.
628. The composition according to item 457, wherein the reactive groups include reactive groups that are attached to the first multimerization domain through association of a linker molecule comprising the reactive group.
629. The composition according to item 457, wherein the reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
630. The composition according to item 473, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
631 . The composition according to item 630, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups.
632. The composition according to item 457, wherein the first multimerization domain comprises one or more nucleophilic groups
633. The composition according to item 632, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -CN, -NH-NH2
634. The composition according to item 457, wherein the first multimerization domain is selected from the group consisting of polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
635. The composition according to item 457, wherein the first multimerization domain comprises one or more electrophilic groups. 636. The composition according to item 635, wherein the electrophilic group is selected from the group consisting of -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides.
637. The composition according to item 457, wherein the first multimerization domain is selected from the group consisting of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
638. The composition according to item 457, wherein the first multimerization domain comprises one or more radicals.
639. The composition according to item 457, wherein the first multimerization domain comprises one or more conjugated double bonds.
640. The composition according to item 457, wherein the first multimerization domain comprises one or more beads and one or more linker moieties.
641 . The MHC multimer according to any of the items 610 to 640, wherein the linker is a flexible linker.
642. The MHC multimer according to any of the items 610 to 640, wherein the linker is a rigid linker.
643. The MHC multimer according to any of the items 610 to 640, wherein the linker is a water-soluble linker.
644. The MHC multimer according to any of the items 610 to 640, wherein the linker is a cleavable linker.
645. The composition according to item 644, wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
646. The composition according to item 644, wherein the cleavable linker is cleavable at physiological conditions 647. The MHC multimer according to items 610 or 61 1 , wherein the MHC-peptide complex is linked to the first multimerization domain by a non-covalent linker moiety.
648. The composition according to item 647, wherein the non-covalent linkage comprises natural dimerization
649. The composition according to item 648, wherein the natural dimerization comprises antigen-antibody pairs
650. The composition according to item 648, wherein the natural dimerization comprises DNA-DNA interactions
651 . The composition according to item 647, wherein the non-covalent linkage comprises natural interactions
652. The composition according to item 651 , wherein the natural interaction comprises biotin and streptavidin
653. The composition according to item 481 , wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes
654. The composition according to item 481 , wherein the bead is coated with streptavidin tetramers, each of which being independently associated with 0, 1 , 2, 3, or 4 biotinylated MHC complexes
655. The composition according to item 481 , wherein the bead is coated with a polysaccharide, such as a polysaccharide comprising dextran moieties.
656. The composition according to item 651 , wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells
657. The composition according to item 651 , wherein the non-covalent linkage comprises artificial interactions 658. The composition according to item 657, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA
659. The composition according to item 657, wherein the artificial interaction comprises PNA-PNA
660. The composition according to item 651 , wherein the non-covalent linkage comprises non-specific adsorption
661. The composition according to item 660, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces
662. The composition according to item 651 , wherein the non-covalent linkage comprises the pentamer structure
663. The composition according to item 651 , wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP- 1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
664. The composition according to item 457, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the second multimerization domains. 665. The composition according to item 457, wherein the association is a non-covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the second multimerization domain.
666. The composition according to item 457, wherein the second multimerization domain comprises one or more scaffolds.
667. The composition according to item 457, wherein the second multimerization domain comprises one or more carriers.
668. The composition according to item 457, wherein the second multimerization domain comprises at least one scaffold and at least one carrier.
669. The composition according to item 457, wherein the second multimerization domain comprises one or more optionally substituted organic molecules.
670. The composition according to item 669, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
671 . The composition according to item 670, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
672. The composition according to item 669, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
673. The composition according to item 457, wherein the second multimerization domain comprises one or more biological cells, such as antigen presenting cells or dendritic cells.
674. The composition according to item 457, wherein the second multimerization domain comprises one or more membranes. 675. The composition according to item 674, wherein the one or more membranes comprises liposomes or micelles.
676. The composition according to item 457, wherein the second multimerization domain comprises one or more polymers.
677. The composition according to item 676, wherein the one or more polymers are selected from the group consisting of the group consisting of polysaccharides.
678. The composition according to item 677, wherein the polysaccharide comprises one or more dextran moieties.
679. The composition according to item 457, wherein the second multimerization domain comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA- PNA, PNA-DNA, DNA-RNA.
680. The composition according to item 457, wherein the second multimerization domain comprises an avidin, such as streptavidin.
681 . The composition according to item 457, wherein the second multimerization domain comprises an antibody.
682. The composition according to item 681 , wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE,
IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody. 683. The composition according to item 457, wherein the second multimerization domain comprises one or more small organic scaffold molecules.
684. The composition according to item 457, wherein the second multimerization comprises one or more further polypeptides in addition to a and b.
685. The composition according to item 457, wherein the second multimerization comprises one or more protein complexes.
686. The composition according to item 457, wherein the second multimerization comprises one or more beads
687. The composition according to item 457, wherein the second multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross- linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(Ci-Ci0)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin-monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly-acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen-fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
688. The composition according to item 457, wherein the second multimerization domain comprises a dimerization domain.
689. The composition according to item 457, wherein the second multimerization domain comprises a trimerization domain.
690. The composition according to item 457, wherein the second multimerization domain comprises a tetramerization domain.
691 . The composition according to item 457, wherein the second multimerization domain comprises a pentamerization domain.
692. The composition according to item 691 , wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
693. The composition according to item 457, wherein the second multimerization domain comprises a hexamerization domain.
694. The composition according to item 610, wherein the hexamerization domain comprises three IgG domains.
695. The composition according to item 457, wherein the second multimerization domain comprises a polymer structure to which is attached one or more scaffolds. 696. The composition according to item 695, wherein the polymer structure comprises a polysaccharide.
697. The composition according to item 696, wherein the polysaccharide comprises one or more dextran moieties.
698. The composition according to item 457, wherein the second multimerization domain comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
699. The composition according to item 457, wherein the second multimerization domain comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or a cyclodextrin.
700. The composition according to item 457, wherein one or more labels is covalently attached to the second multimerization domain.
701 . The composition according to item 457, wherein one or more labels is non- covalently attached to the second multimerization domain.
702. The composition according to item 701 , wherein the one or more labels is non- covalently attached to an antibody in the second mutimerization domain.
703. The composition according to item 700, wherein the one or more labels is covalently attached to an antibody in the second mutimerization domain.
704. The composition according to item 701 , wherein the one or more labels is non- covalently attached to an aptamer in the second mutimerization domain.
705. The composition according to item 700, wherein the one or more labels is covalently attached to an aptamer in the second mutimerization domain.
706. The composition according to item 701 , wherein the one or more labels is non- covalently attached to a molecule in the second mutimerization domain. 707. The composition according to item 700, wherein the one or more labels is covalently attached to a molecule in the second mutimerization domain.
708. The composition according to item 701 , wherein the one or more labels is non- covalently attached to a protein in the second mutimerization domain.
709. The composition according to item 700, wherein the one or more labels is covalently attached to a protein in the second mutimerization domain.
710. The composition according to item 701 , wherein the one or more labels is non- covalently attached to a sugar residue in the second mutimerization domain.
71 1 . The composition according to item 700, wherein the one or more labels is covalently attached to a sugar residue in the second mutimerization domain.
712. The composition according to item 701 , wherein the one or more labels is non- covalently attached to a DNA in the second mutimerization domain.
713. The composition according to item 700, wherein the one or more labels is covalently attached to a DNA in the second mutimerization domain.
714. The MHC multimer according to any of the items 700 to 713, wherein the attachment is directly between reactive groups in the labelling molecule and reactive groups in the marker molecule.
715. The MHC multimer according to any of the items 700 to 713, wherein the attachment is through a linker connecting labelling molecule and marker.
716. The MHC multimer according to any of the items 700 to 713, wherein one label is used.
717. The MHC multimer according to any of the items 700 to 713, wherein more than one label is used. 718. The composition according to item 717, wherein the more than one label are all identical.
719. The composition according to item 717, wherein at least two labels are different.
720. The composition according to any of items 700 to 719, wherein the one or more labels is a fluorophore.
721 . The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of selected from the group fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o- phthaldehyde and fluorescamine.
722. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 2-(4'-maleimidylanilino)naphthalene-6- sulfonic acid, sodium salt
723. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 5-((((2-iodoacetyl)amino)ethyl)amino) naphthalene-1 -sulfonic acid
724. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Pyrene-1 -butanoic acid
725. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of AlexaFluor 350 (7-amino-6-sulfonic acid-4-methyl coumarin-3-acetic acid
726. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of AMCA (7-amino-4-methyl coumarin-3- acetic acid
727. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-4-methyl coumarin-3-acetic acid 728. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Marina Blue (6,8-difluoro-7-hydroxy-4- methyl coumarin-3-acetic acid
729. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 7-dimethylamino-coumarin-4-acetic acid
730. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Fluorescamin-N-butyl amine adduct
731 . The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 7-hydroxy-coumarine-3-carboxylic acid
732. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of CascadeBlue (pyrene-trisulphonic acid acetyl azide
733. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Cascade Yellow
734. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Pacific Blue (6,8 difluoro-7-hydroxy coumarin-3-carboxylic acid
735. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 7-diethylamino-coumarin-3-carboxylic acid
736. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Λ/-(((4-azidobenzoyl)amino)ethyl)- 4- amino-3,6-disulfo-1 ,8-naphthalimide, dipotassium salt
737. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Alexa Fluor 430 738. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 3-perylenedodecanoic acid
739. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 8-hydroxypyrene-1 ,3,6-trisulfonic acid, trisodium salt
740. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 12-(Λ/-(7-nitrobenz-2-oxa-1 ,3- diazol-4- yl)amino)dodecanoic acid
741 . The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Λ/,/V-dimethyl-/V- (iodoacetyl)-/V-(7- nitrobenz-2- oxa-1 ,3-diazol-4-yl)ethylenediamine
742. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Oregon Green 488 (difluoro carboxy fluorescein)
743. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of 5-iodoacetamidofluorescein
744. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of propidium iodide-DNA adduct
745. The composition according to item 720, wherein the one or more fluorophore label are selected from the group consisting of Carboxy fluorescein
746. The composition according to any of items 700 to 719, wherein the one or more labels is a fluorescent label.
747. The composition according to item 746, wherein the one or more fluorescent label is a simple fluorescent label 748. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Fluor dyes, Pacific Blue™, Pacific Orange™, Cascade Yellow™
749. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group AlexaFluor@(AF), AF405, AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680, AF700, AF710, AF750, AF800.
750. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Quantum Dot based dyes, QDot® Nanocrystals (Invitrogen, MolecularProbs), Qdot®525, Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800.
751 . The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group DyLight™ Dyes (Pierce) (DL); DL549, DL649, DL680, DL800.
752. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Fluorescein (Flu) or any derivate of that, such as FITC
753. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Cy-Dyes, Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7.
754. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Fluorescent Proteins, RPE, PerCp, APC, Green fluorescent proteins; GFP and GFP derivated mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, mRFP1 ,MBanana, mOrange, dTomato, tdTomato, mTangerine, mStrawberry, mCherry.
755. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group Tandem dyes, RPE-Cy5, RPE-Cy5.5, RPE- Cy7, RPE-AlexaFIuor® tandem conjugates; RPE-Alexa610, RPE-TxRed, APC- AlecaθOO, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5.
756. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group multi fluorochrome assemblies, Multiple fluorochromes attached to a polymer molecule, such as a peptide/protein, Dextrane, polysaccharide, any combination of the fluorescent dyes involving in generation of FRET (Fluorescence resonance energy transfer) based techniques.
757. The composition according to item 747, wherein the one or more simple fluorescent label is selected from the group ionophors; ion chelating fluorescent props, props that change wavelength when binding a specific ion, such as Calcium, props that change intensity when binding to a specific ion, such as Calcium.
758. The composition according to any of items 700 to 719, wherein the one or more labels is capable of absorption of light
759. The composition according to item 758, wherein the one or more labels capable of absorption of light is a chromophore.
760. The composition according to item 758, wherein the one or more labels capable of absorption of light is a dye.
761 . The composition according to any of items 700 to 719, wherein the one or more labels is capable of emission of light after excitation
762. The composition according to item 761 , wherein the one or more labels capable of emission of light is one or more fluorochromes.
763. The composition according to item 762, wherein the one or more fluorochrome is selected from the AlexaFluor®(AF) family, which include AFΘ350, AF405, AF430, AF488,AF500, AF514, AF532, AF546, AF555, AF568, AF594, AF610, AF633, AF635, AF647, AF680, AF700, AF710, AF750 and AF800 764. The composition according to item 762, wherein the one or more fluorochrome is selected from the Quantum Dot (Qdot®) based dye family, which include Qdot®525, Qdot®565, Qdot®585, Qdot®605, Qdot®655, Qdot®705, Qdot®800
765. The composition according to item 762, wherein the one or more fluorochrome is selected from the DyLight™ Dyes (DL) family, which include DL549, DL649, DL680, DL800
766. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Small fluorescing dyes, which include FITC, Pacific Blue™,
Pacific Orange™, Cascade Yellow™, Marina blue™, DSred, DSred-2, 7-AAD, TO-Pro- 3.
767. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Cy-Dyes, which include Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7
768. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Phycobili Proteins, which include R-Phycoerythrin (RPE), PerCP, Allophycocyanin (APC), B-Phycoerythrin, C-Phycocyanin.
769. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Fluorescent Proteins, which include (E)GFP and GFP ((enhanced) green fluorescent protein) derived mutant proteins; BFP, CFP, YFP, DsRed, T1 , Dimer2, m RFP 1 , M Banana, mOrange, dTomato, tdTomato, mTangerine.
770. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Tandem dyes with RPE, which include RPE-Cy5, RPE- Cy5.5, RPE-Cy7, RPE-AlexaFluor® tandem conjugates; RPE-Alexa610, RPE-TxRed.
771 . The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Tandem dyes with APC, which include APC-Aleca600, APC-Alexa610, APC-Alexa750, APC-Cy5, APC-Cy5.5.
772. The composition according to item 762, wherein the one or more fluorochrome is selected from the family of Calcium dyes, which include Indo-1 -Ca2+ lndo-2-Ca2+. 773. The composition according to any of items 700 to 719, wherein the one or more labels is capable of reflection of light
774. The composition according to item 773, wherein the one or more labels capable of reflection of light comprises gold
775. The composition according to item 773, wherein the one or more labels capable of reflection of light comprises plastic
776. The composition according to item 773, wherein the one or more labels capable of reflection of light comprises glass
777. The composition according to item 773, wherein the one or more labels capable of reflection of light comprises polystyrene
778. The composition according to item 773, wherein the one or more labels capable of reflection of light comprises pollen
779. The composition according to any of items 700 to 719, wherein the one or more labels is a chemiluminescent label.
780. The composition according to item 779, wherein the chemiluminescent labels is selected from the group luminol, isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.
781 . The composition according to any of items 700 to 719, wherein the one or more labels is a bioluminescent label.
782. The composition according to item 781 , wherein the bioluminescent labels is selected from the group consisting of luciferin, luciferase and aequorin.
783. The composition according to any of items 700 to 719, wherein the one or more labels is a radioactive label. 784. The composition according to item 783, wherein the one or more radioactive labels is a radionuclide.
785. The composition according to item 783, wherein the one or more radioactive labels is an isotope.
786. The composition according to item 783, wherein the one or more radioactive labels comprises α rays.
787. The composition according to item 783, wherein the one or more radioactive labels comprises β rays.
788. The composition according to item 783, wherein the one or more radioactive labels comprises y rays.
789. The composition according to any of items 700 to 719, wherein the one or more labels is detectable by NMR (nuclear magnetic resonance form paramagnetic molecules)
790. The composition according to any of items 700 to 719, wherein the one or more labels is an enzyme label.
791 . The composition according to item 790, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, producing a light signal (chemi-luminescence)
792. The composition according to item 790, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitation of chromophor dyes
793. The composition according to item 790, wherein the enzyme catalyze a reaction between chemicals in the near environment of the labeling molecules, resulting in precipitates that can be detected by an additional layer of detection molecules 794. The composition according to item 790, wherein the enzyme label is selected from the group peroxidases, malate dehydrogenase, staphylococcal nuclease, delta-5- steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate, dehydrogenase, triose phosphate isomerase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase.
795. The composition according to item 790, wherein the enzyme label is horseradish peroxidase
796. The composition according to item 790, wherein the enzyme label is horseradish peroxidase and the substrate is diaminobenzidine (DAB)
797. The composition according to item 790, wherein the enzyme label is horseradish peroxidase and the substrate is 3-amino-9-ethyl-carbazole (AEC+)
798. The composition according to item 790, wherein the enzyme label is horseradish peroxidase and the substrate is biotinyl tyramide
799. The composition according to item 790, wherein the enzyme label is horseradish peroxidase and the substrate is fluorescein tyramide
800. The composition according to item 790, wherein the enzyme label is alkaline phosphatase
801. The composition according to item 790, wherein the enzyme label is alkaline phosphatase and the substrate is Fast red dye
802. The composition according to any of items 700 to 719, wherein the one or more labels is a ionophore or chelating chemical compound binding to specific ions such as Ca2+
803. The composition according to any of items 700 to 719, wherein the one or more labels is a lanthanide 804. The composition according to item 803, wherein the lanthanide comprises fluorescence
805. The composition according to item 803, wherein the lanthanide comprises Phosphorescence
806. The composition according to item 803, wherein the lanthanide is paramagnetic
807. The composition according to any of items 700 to 719, wherein the one or more labels is a DNA fluorescing stain
808. The composition according to item 807, wherein the DNA fluorescing stain is Propidium iodide
809. The composition according to item 807, wherein the DNA fluorescing stain is Hoechst stain
810. The composition according to item 807, wherein the DNA fluorescing stain is DAPI
81 1 . The composition according to item 807, wherein the DNA fluorescing stain is AMC
812. The composition according to item 807, wherein the DNA fluorescing stain is DraQ5™
813. The composition according to item 807, wherein the DNA fluorescing stain is Acridine orange
814. The composition according to item 457, wherein the MHC-peptide complex (a-b- P) is attached to the second multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety. 815. The composition according to any of items 457 to 814, wherein the MHC-peptide complex is linked to the second multimerization domain by a second linker moiety.
816. The composition according to item 815, wherein the MHC-peptide complex is linked to the second multimerization domain by a covalent linker moiety.
817. The MHC multimer according to items 814 and 815, wherein the linkage of the second multimerization domain and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, the second multimerization domain, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes.
818. The MHC multimer according to items 814 and 815, wherein the linker moiety linking the second multimerization domain and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
819. The composition according to item 818, wherein the moiety X comprises a nucleophilic group.
820. The composition according to item 819, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2.
821. The composition according to item 818, wherein the moiety Y comprises an electrophilic group.
822. The composition according to item 821 , wherein the electrophilic group is selected from the group consisting of CHO, COOH and CO.
823. The MHC multimer according to items 814 and 815, wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety. 824. The MHC multimer according to items 814 and 815, wherein X and Y comprises reactive groups natively associated with the second multimerization domain and/or the MHC-peptide complexes.
825. The MHC multimer according to items 814 and 815, wherein X and Y comprises reactive groups not natively associated with the second multimerization domain and/or the MHC-peptide complex.
826. The MHC multimer according to items 814 and 815, wherein the linker moiety forms a covalent link between the second multimerization domain and at least one of the MHC-peptide complexes.
827. The MHC multimer according to items 814 and 815, wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group consisting of -NH2, -OH, -SH, and -NH-
828. The MHC multimer according to items 814 and 815, wherein the reactive groups of the second multimerization domain include hydroxyls of polysaccharides such as dextrans
829. The MHC multimer according to items 814 and 815, wherein the reactive groups of the second multimerization domain selected from the group consisting of amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides
830. The MHC multimer according to items 814 and 815, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the second multimerization domain
831 . The MHC multimer according to items 814 and 815, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the second multimerization domain, wherein an acyl group and an amino group react to form an amide bond 832. The composition according to item 457, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the second multimerization domain.
833. The composition according to item 457, wherein the reactive groups include reactive groups that are attached to the second multimerization domain through association of a linker molecule comprising the reactive group.
834. The composition according to item 457, wherein the reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
835. The composition according to item 473, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
836. The composition according to item 835, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups.
837. The composition according to item 457, wherein the second multimerization domain comprises one or more nucleophilic groups
838. The composition according to item 837, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -CN, -NH-NH2
839. The composition according to item 457, wherein the second multimerization domain is selected from the group consisting of polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
840. The composition according to item 457, wherein the second multimerization domain comprises one or more electrophilic groups.
841. The composition according to item 840, wherein the electrophilic group is selected from the group consisting of -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides. 842. The composition according to item 457, wherein the second multimerization domain is selected from the group consisting of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
843. The composition according to item 457, wherein the second multimerization domain comprises one or more radicals.
844. The composition according to item 457, wherein the second multimerization domain comprises one or more conjugated double bonds.
845. The composition according to item 457, wherein the second multimerization domain comprises one or more beads and one or more linker moieties.
846. The MHC multimer according to any of the items 814 to 845, wherein the linker is a flexible linker.
847. The MHC multimer according to any of the items 814 to 845, wherein the linker is a rigid linker.
848. The MHC multimer according to any of the items 814 to 845, wherein the linker is a water-soluble linker.
849. The MHC multimer according to any of the items 814 to 845, wherein the linker is a cleavable linker.
850. The composition according to item 849, wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
851 . The composition according to item 849, wherein the cleavable linker is cleavable at physiological conditions
852. The MHC multimer according to items 814 and 815, wherein the MHC-peptide complex is linked to the second multimerization domain by a non-covalent linker moiety. 853. The composition according to item 852, wherein the non-covalent linkage comprises natural dimerization
854. The composition according to item 853, wherein the natural dimerization comprises antigen-antibody pairs
855. The composition according to item 853, wherein the natural dimerization comprises DNA-DNA interactions
856. The composition according to item 852, wherein the non-covalent linkage comprises natural interactions
857. The composition according to item 856, wherein the natural interaction comprises biotin and streptavidin
858. The composition according to item 686, wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes
859. The composition according to item 686, wherein the bead is coated with streptavidin tetramers, which in turn are associated with with 0, 1 , 2, 3, or 4 biotinylated MHC complexes
860. The composition according to item 686, wherein the bead is coated with a polysaccharide, such as a polysaccharide comprising a dextran moiety.
861 . The composition according to item 856, wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells
862. The composition according to item 852, wherein the non-covalent linkage comprises artificial interactions
863. The composition according to item 862, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA 864. The composition according to item 862, wherein the artificial interaction comprises PNA-PNA
865. The composition according to item 852, wherein the non-covalent linkage comprises non-specific adsorption
866. The composition according to item 865, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces
867. The composition according to item 852, wherein the non-covalent linkage comprises the pentamer structure
868. The composition according to item 867, wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
869. The composition according to item 1 , wherein the one or more pharmamers comprises one or more organic molecule-based pharmamers.
870. The composition according to item 1 , wherein the one or more pharmamers comprises one or more functionalized cyclic structures such as benzene rings where e.g. a benzene ring is functionalized and covalently linked to e.g. three immunologically active molecules.
871 . The composition according to item 1 , wherein the one or more pharmamers comprises one or more cell-based pharmamers.
872. The composition according to item 1 , wherein the one or more pharmamers comprises one or more dendritic cells and/or one or more antigen presenting cells (APCs).
873. The composition according to item 1 , wherein the one or more pharmamers comprises one or more membrane-based pharmamers.
874. The composition according to item 1 , wherein the one or more pharmamers comprises one or more liposomes and/or micelles e.g. carrying immunologically active molecules or complexes in their membranes.
875. The composition according to item 1 , wherein the one or more pharmamers comprises one or more polymer-based pharmamers.
876. The composition according to item 1 , wherein the one or more pharmamers comprises one or more molecule constructs where immunologically active molecules or complexes are bound covalently or non-covalently to a dextran.
877. The composition according to item 1 , wherein the one or more pharmamers comprises one or more backbone/multimerisation domain(s).
878. The composition according to item 1 , wherein the one or more pharmamers comprises one or more particles such as beads.
879. The composition according to item 1 , wherein the one or more pharmamers comprises one or more solid supports with immunologically active molecules immobilized on the surface. 880. The composition according to item 1 , wherein the one or more pharmamers comprises one or more multimerization domain(s) such as one or more cells, polymers, proteins or other molecular structures, or particles and solid supports.
881 . The composition according to item 1 , wherein the one or more pharmamers comprises one or more pharmamers in solid form and/or one or more pharmamers in insoluble form and/or one or more pharmamers in soluble form and/or one or more pharmamers in suspension.
882. The composition according to item 1 , wherein the one or more pharmamers comprises one or more biologically active molecules and one or more multimerization domain(s).
883. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more molecules with adjuvant effects.
884. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more immune targets e.g. antigens.
885. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more molecules with biological activity e.g. enzymes.
886. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more regulators of receptor activity.
887. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more receptor ligands.
888. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more immune potentiators.
889. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more drugs. 890. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more toxins.
891 . The composition according to item 882, wherein the one or more biologically active molecules comprises one or more co-receptors.
892. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more proteins.
893. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more peptides.
894. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more sugar moieties.
895. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more lipid groups.
896. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more nucleic acids including siRNA and microRNA.
897. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more nano particles.
898. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more small molecules.
899. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more membranes.
900. The composition according to item 882, wherein the one or more biologically active molecules comprises one or more liposomes.
901 . The composition according to item 882, wherein the one or more biologically active molecules comprises one or more immunological active molecules. 902. The composition according to item 882, wherein the one or more biologically active molecules comprises more than one identical immunological active molecules.
903. The composition according to item 882, wherein the one or more biologically active molecules comprises more than one different immunological active molecules.
904. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more biological active molecules including proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, as well as antibodies and recombinant binding molecules to any of the foregoing, and combinations thereof.
905. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of MHC Class 1 proteins like HLA-A, HLA-B, HLA-C alone or in complex with HLA-b2Microglobulin with or without peptide in the binding groove.
906. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Class 1 -like proteins like MICA, MICB, CD1 d, HLA-E, HLA-F, HLA-G, HLA-H, ULBP-1 , ULBP-2, and ULBP-3.
907. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of HLA class 2 proteins like HLA-DR (HLA-DRA, HLA-DRB1 , HLA-DRB3, HLA-DRB4, HLA-DRB5), HLA-DQ (HLA-DQA1 , HLADQA2, HLA-DQB1 , HLA-DQB2), HLA-DP (HLA-DPA1 , HLA-DPB1 ), HLA-DO (HLA-DOA, HLA-DOB), HLA-DM (HLA- DMA, HLA-DMB) alone or in complexes consisting of class 2 A- and B-chains with or without peptide in the binding groove.
908. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Cytokines; IFN-alpha, IFN-beta, IFN-gamma, IL-1 , IL-2, IL-3, IL-4, IL-6, IL- 7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL- 24, IL-25, IL-26, IL-27, IL-28,-IL-29, IL-30, IL-31 , IL-32, IL-33, IL-34, IL-35, CSFs (colony-stimulating factors), c-Kit, EPO, TNF-alfa, TNF-beta, Lymphotoxin; Cytokine receptors like IL-1 R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9-R, IL-10R, IL- 1 1 R, IL-12R, IL-13R, IL-15R, IL-18R, IL-20R, IL-21 R, IL-22R, IL-23R, IL-27R, IL-28R; Chemokines such as CXCL1 , CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7,
CXCL8, CXCL9, CXCL10, CXCL1 1 , CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CCL1 , CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL8, CCL9, CCL10, CCL1 1 , CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21 , CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCR4, CCRL2; Chemokine receptors like CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR1 1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, and CX3CR1 .
909. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Toll-like receptors such as TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLRI O.
910. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Toll like receptor ligands such as multiple triacyl lipopeptides, multiple diacyl lipopeptides, multiple glycolipids, multiple lipopeptides, multiple lipoproteins, lipoteichoic acid, peptidoglycans, heat shock proteins (HSP70, HSP90 and others), zymosan, single- and double-stranded RNA, Poly I:C, lipo-polysaccharides, fibrinogen, heparin sulphate fragments, hyaluronic acid fragments, flagellin, imidazoquinoline, loxoribine (guanosine analogue), bropirimine, Imiquimod, unmethylated CpG DNA.
91 1 . The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Viral entry receptors/molecules such as Ku70, Pvr, PrM , HVEM,
EphrinB2, cellular integrins (in particular alpha2beta1 , alphaθbetai alphaVbeta3), CD81 , CD155, SR-B1 , claudin-1 , xCT, human nectin-2, LIGHT, TLR3, LIR, Heparan sulphate proteoglycans, GPI anchored proteins, hemeagglutinin receptor. 912. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Bacterial entry receptors/molecules like CD48, CEACAM-1 , -2, -3, -4, -5, - 6, invasion, internalin (InIA), InIB; Fc receptors like ε (FcεRI, FcεRJ]) - y (F1CynR1I, Fey R1II, Fc^Rlil) - o/μ (FcαRj, Fcα/jjR) - Neonatal FcR.
913. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Lymphocyte homing receptors such as CD44, L-selectin, VLA-4 (CD49a, b, c, d, e, f), LFA-1.
914. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD120, CD137 (4-1 BB), CD147, CDw150
(SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, PD-1 , Fas (CD95), FasL, CD40, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-L2, CD134L, CD137L, ICOSL
915. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of NK cell receptors/molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR3DL1 , KIR3DL", KIR3DS1 , KIR2DL1.KIRDL2, KIR2DL3, KIR2DL4, KIR2DL5, CD94/NKG2A, CD94/NKG2C, CD94/NKG2E, CD94/NKG2H, NKG2ADNKG2D.
916. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Adhesion molecules such as ICAM-1 , ICAM-2, GlyCAM-1 , VCAM, CD34.
917. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Anti microbial peptides such Defensins and cathelicidin derived peptide LL-37. 918. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of anti-LFA-1 , anti-CD44, anti-beta7, anti-selectin L, anti-selectin E, and anti- selectin P, toxic molecules selected from toxins, enzymes, antibodies, radioisotopes, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15- deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, heavy'metals like inorganic and organic mercurials, and FN18-CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and combinations of any of the foregoing, as well as antibodies (monoclonal, polyclonal, and recombinant) to the foregoing, where relevant.
919. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of antibody derivatives or fragments thereof.
920. The composition according to item 901 , wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of biologically active molecules derived from viral or bacterial proteins or fragments thereof.
921 . The composition according to item 882, wherein the vaccine further comprises one or more biologically active molecules in order to affect the characteristics of the constructs, e. g. with respect to binding properties, effects, antigenecity, specificity, solubility, stability, or detectability.
922. The composition according to item 882, wherein the one or more biologically active molecules further comprises a flexible or rigid, and water soluble, linker that allows for the immobilized biologically active molecules to interact efficiently with surrounding cells and molecules. 923. The composition according to item 882, wherein the one or more biologically active molecules further comprises a cleavable linker allowing for release of the biologically active molecules from the multimerization domain such as a bead.
924. The composition according to item 1 , wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to
240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 980,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000.
925. The composition according to item 1 , wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from
4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
926. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more soluble multimerization domain(s).
927. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more insoluble multimerization domain(s).
928. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domains selected from the group consisting of polysaccharides, dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O-ethylamino guaran, chitins and chitosans indlucing 6- O- carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxy- ethyl cellulose, 6-amino-6-deoxy cellulose and O-ethyl- amine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxy-methylated ficoll, vinyl polymers including poly (acrylic acid), poly (acryl amides), poly (acrylic esters), poly (2-hydroxy ethyl methacrylate), poly (methyl methacrylate), poly (maleic acid), poly (maleic anhydride), poly (acrylamide), poly (ethyl-co- vinyl acetate), poly (methacrylic acid), poly (vinyl- alcohol), poly (vinyl alcohol-co-vinyl chloroacetate), aminated poly (vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly (ethylene oxide-co-propylene oxides) comprising polymer backbones including linear, comb-shaped or StarBurst dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly (ethylene imines), pluriol, proteins including peptides, polypeptides, antigenbinding peptides, albumins, immunoglobulins, coiled-coil helixes e.g. Fos-Jun or Fos-Jun like or coiled-coiled dimers/trimers/tetramers/pentamers, Streptavidin, Avidin, Streptactin, T-cell receptors orther protein receptors and virus- like proteins (VLP), and polynucleotides, DNA, RNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs and small organic molecules including but not limited to steroids, peptides, linear or cyclic structures, aromatic structures, aliphatic structures.
929. The composition according to item 882, wherein the one or more multimerization domains(s) comprises cells e.g. dendritic cells, antigen presenting cell, B-cell, T-cell Macrophages, Kupfer cells, Langerhans cells, transfected cells expressing biologically active proteins, including hybridoma cells, yeast-cells, insect-cells, CHO cells, any cell biologically active molecules, cell-like structures e.g. micelles, liposomes, and phages e.g. filamenteous phages and viral or viral-like particles.
930. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more solid supports including but not limited to beads, particulate matters and other surfaces.
931 . The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more self-assembling multimeric structures. 932. The composition according to item 882, wherein the one or more multimerization domains(s) comprises mixed forms of multimerization domains such as e.g. dextran coupled with Streptavidin.
933. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerisation domains made of Streptavidin or Avidin whereto biotin, biotin-like peptides or other biotin-like molecules can bind.
934. The composition according to item 882, wherein the one or more multimerization domains(s) comprises dextran whereto biologically active molecules are attached directly through a linker.
935. The composition according to item 882, wherein the one or more multimerization domains(s) comprises divinylsulfone activated dextran whereto biologically active molecules are coupled directly e.g. through -SH group(s) or amine(s) in the biologically active molecules, dextran coupled with SA whereto biologically active molecules are attached through a biotin on the biologically active molecule, dextran with biologically active molecules are attached through a coiled-coil structure where on α-helix of a coiled-coil dimer is coupled to dextran and the other α-helix is coupled to the biologically active molecule e.g. as a fusion protein.
936. The composition according to item 882, wherein the one or more multimerization domains(s) comprises beads or bead-like structures having an excluded volume (e.g. polysaccharide beads, polystyrene beads, magnetic polystyrene beads, polycarbamate beads, or any other kind of beads that can be dissolved or suspended in aqueous buffer) that carry electrophilic groups (e.g. divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters), and where biologically active molecules have been covalently immobilized to these by reaction of nucleophiles comprised within the biologically active molecule with the electrophiles of the beads.
937. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more beads covalently or non-covalently coated with pharmamers or single biologically active molecules, through non-cleavable or cleavable linkers. 938. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more beads coated with streptavidin monomers, which in turn are associated with biotinylated pharmamers.
939. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more beads coated with streptavidin tetramers, each of which are associated with 0, 1 , 2, 3, or 4 biotinylated biologically active molecules.
940. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more beads coated with biologically active molecules where e.g. the reactive groups of the biologically active molecules (e.g. the divinyl sulfone-activated dextran backbone) has reacted with nucleophilic groups on the bead, to form a covalent linkage between the dextran of the dextramer and the beads.
941 . The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more self-assembling multimeric structures such as trimeric, tetrameric, pentameric, hexameric or heptameric coiled-coil structures holding together 3, 4, 5, 6 or 7 biologically active molecules.
942. The composition according to item 882, wherein the one or more multimerization domains(s) comprises several multimerization domains (e.g. streptavidin tetramers bound to biotinylated biologically active molecules) linked to another multimerization domain (e.g. the bead).
943. The composition according to item 882, wherein the one or more multimerization domains(s) comprises any support capable of binding the biologically active molecules.
944. The composition according to item 882, wherein the one or more multimerization domains(s) comprises glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
945. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more spherical supports such as one or more bead. 946. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more cylindrical supports such as the inside surface of a test tube, or the external surface of a rod.
947. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more flat supports such as a sheet, test strip, a membrane, or a plastic surface.
948. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more polymers, oligomers and/or non-repeating moieties.
949. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more polymers or oligomer moieties e.g. comprising repeat units consisting of a repeat moiety selected from alkyl (e.g., -CH2-), substituted alkyl (e.g., -CHR-), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, as well as moieties comprising combinations thereof.
950. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more non-repeating multifunctional bridge moieties selected from alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and moieties comprising combinations thereof.
951 . The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties), that are soluble or insoluble.
952. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more cross-linked oligomer (or oligomer moieties) or cross-linked polymers (or polymer moieties). 953. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more homopolymers and/or one or more copolymers (including polymers having two monomer-repeat-units, terpolymers and higher-order polymers), including for example random copolymer moieties and block copolymer moieties.
954. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more ionic monomer moieties such as one or more anionic monomer moieties.
955. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more hydrophobic and/or hydrophilic monomer moieties.
956. The composition according to item 882, wherein the one or more multimerization domains(s) comprises from 1 to 100 coupling sites for biologically active molecules, such as from 1 to 5 coupling sites, for example from 5 to 10 coupling sites, such as from 10 to 15 coupling sites, for example from 15 to 20 coupling sites, such as from 20 to 25 coupling sites, for example from 25 to 30 coupling sites, such as from 30 to 35 coupling sites, for example from 35 to 40 coupling sites, such as from 40 to 45 coupling sites, for example from 45 to 50 coupling sites, such as from 50 to 55 coupling sites, for example from 55 to 60 coupling sites, such as from 60 to 65 coupling sites, for example from 65 to 70 coupling sites, such as from 70 to 75 coupling sites, for example from 75 to 80 coupling sites, such as from 80 to 85 coupling sites, for example from 85 to 90 coupling sites, such as from 90 to 95 coupling sites, for example from 95 to 100 coupling sites.
957. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more polymer moieties that are soluble or insoluble, exist as dispersed micelles or particles, such as colloidal particles or (insoluble) macroscopic beads. 958. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more polymer moieties that are hydrophobic, hydrophilic, amphiphilic, uncharged or non-ionic, negatively or positively charged, or a combination thereof, and can be organic or inorganic.
959. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more inorganic polymer moieties such as silica (e.g., multi-layered silica), diatomaceous earth, zeolite, calcium carbonate, talc, and the like.
960. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more water-soluble polymers including polyethylene glycol (PEG), monomethoxy-PEG, mono-(Ci-Ci0)alkoxy-PEG, aryloxy-PEG, poly-(N- vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis- succinimidyl carbonate PEG, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, cellulose, or other carbohydrate-based polymers.
961. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more polysaccharides such as materials from vegetal or animal origin, including cellulose materials, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin, and/or chitosan.
962. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG- coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross- linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(d-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, polyvinylcarbamate, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptavidin-monomer coated beads, streptavidin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone- activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly-acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen-fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
963. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of less than 1 ,000 Da (e.g. small molecule scaffold).
964. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 1 ,000 Da and 10,000 Da (e.g. small molecule scaffold, small peptides, small polymers) such as from 1 ,000 Da to 2,000 Da, for example from 2,000 Da to 3,000 Da, such as from 3,000 Da to 4,000 Da, for example from 4,000 Da to 5,000 Da, such as from 5,000 Da to 6,000 Da, for example from 6,000 Da to 7,000 Da, such as from 7,000 Da to 8,000 Da, for example from 8,000 Da to 9,000 Da, such as from 9,000 Da to 10,000 Da.
965. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 10,000 Da and 100,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure) such as from 10,000 Da to 20,000 Da, for example from 20,000 Da to 30,000 Da, such as from 30,000 Da to 40,000 Da, for example from 40,000 Da to 50,000 Da, such as from 50,000 Da to 60,000 Da, for example from 60,000 Da to 70,000 Da, such as from 70,000 Da to 80,000 Da, for example from 80,000 Da to 90,000 Da, such as from 90,000 Da to 100,000 Da.
966. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 100,000 Da and 1 ,000,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure) such as from 100,000 Da to 200,000 Da, for example from 200,000 Da to 300,000 Da, such as from 300,000 Da to 400,000 Da, for example from 400,000 Da to 500,000 Da, such as from 500,000 Da to 600,000 Da, for example from 600,000 Da to 700,000 Da, such as from 700,000 Da to 800,000 Da, for example from 800,000 Da to 900,000 Da, such as from 900,000 Da to 1 ,000,000 Da.
967. The composition according to item 882, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of more than 1 ,000,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure, cells, liposomes, artificial lipid bi layers, polystyrene beads and other beads) such as more than 2,000,000 Da, for example more than 3,000,000 Da, such as more than 5,000,000, for example more than 10,000,000 Da.
968. The composition according to item 882, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled by chemical reactions between reactive groups of the multimerization domain and reactive groups on the biologically active molecule. 969. The composition according to item 882, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled by non- covalent interaction between a part of the biologically active molecule (e.g. a biotinylated peptide component) and the multimerization domain (e.g. four binding sites for biotin on the strepavidin tetrameric protein).
970. The composition according to item 1 , wherein the one or more pharmamers comprises non-covalent association of amino acid helices fused to one component of a biologically active molecule, to form e.g. a pentameric pharmamer, held together by e.g. five helices in a coiled-coil structure making up the multimerization domain.
971 . The composition according to item 882, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled by one or more chemical reactions
972. The composition according to item 971 , wherein the one or more chemical reactions comprises nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation).
973. The composition according to item 971 , wherein the one or more chemical reactions comprises addition to carbon-hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers).
974. The composition according to item 971 , wherein the one or more chemical reactions comprises nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines).
975. The composition according to item 971 , wherein the one or more chemical reactions comprises cycloadditions.
976. The composition according to item 971 , wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled one or more non-covalent interaction(s). 977. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises streptavidin/biotin.
978. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises avidin/biotin.
979. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises antibody/antigen.
980. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises DNA/DNA.
981 . The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises DNA/PNA.
982. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises DNA/RNA.
983. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises PNA/PNA.
984. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises LNA/DNA.
985. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises leucine zipper e.g. Fos/Jun.
986. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises IgG dimeric protein.
987. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises IgM multivalent protein. 988. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises acid/base coiled-coil helices.
989. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises chelate/metal ion-bound chelate.
990. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises streptavidin (SA) and avidin and derivatives thereof.
991 . The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises biotin.
992. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises immunoglobulins.
993. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises antibodies (monoclonal, polyclonal, and recombinant).
994. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises antibody fragments and derivatives thereof.
995. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises leucine zipper domain of AP-1 (jun and fos).
996. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises hexa-his (metal chelate moiety).
997. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises hexa-hat GST (glutathione S-transferase) glutathione affinity.
998. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises Calmodulin-binding peptide (CBP).
999. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises Strep-tag. 1000. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises Cellulose Binding Domain.
1001. The composition according to item 976, wherein the one or more non-covalent interaction(s) comprises one or more of the molecules selected from the group consiting of Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno- reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
1002. The composition according to item 1 , wherein the compsition comprises one or more living virulent organism(s).
1003. The composition according to item 1002, wherein the one or more living virulent organism(s) comprises one or more fully virulent organism(s).
1004. The composition according to item 1002, wherein the one or more living virulent organism(s) comprises one or more partly virulent organism(s).
1005. The composition according to item 1002, wherein the one or more living virulent organism(s) comprises one or more partly virulent organism(s) and one or more fully virulent organism(s).
1006. The composition according to item 1004, wherein the one or more partly virulent organism(s) comprises one or more live attenuated microorganism(s).
1007. The composition according to item 1006, wherein the one or more live attenuated microorganism(s) are modified by physical means.
1008. The composition according to item 1007, wherein the physical means comprises heat. 1009. The composition according to item 1006, wherein the one or more live attenuated microorganism(s) are modified by chemical means.
1010. The composition according to item 1009, wherein the chemical means comprises one or more chemical(s).
101 1. The composition according to item 1006, wherein the one or more live attenuated microorganism(s) are modified by genetic manipulation.
1012. The composition according to item 101 1 , wherein the genetic manipulation comprises generation of a recombinant bacteria missing virulence factors.
1013. The composition according to item 1006, wherein the one or more live attenuated microorganism(s) are cultured under conditions that disable their virulent properties.
1014. The composition according to item 1 , wherein the composition comprises one or more killed organism(s).
1015. The composition according to item 1014, wherein the one or more killed organism(s) comprises one or more physically killed organism(s).
1016. The composition according to item 1015, wherein the one or more physically killed organism(s) is killed by heat.
1017. The composition according to item 1015, wherein the one or more physically killed organism(s) is killed by irradiation.
1018. The composition according to item 1014, wherein the one or more killed organism(s) comprises one or more chemically killed organism(s).
1019. The composition according to item 1018, wherein the one or more chemically killed organism(s) are killed by phenol. 1020. The composition according to item 1018, wherein the one or more chemically killed organism(s) are killed by formaldehyde.
1021. The composition according to item 1 , wherein the composition comprises one or more fragments of one or more microorganism(s).
1022. The composition according to item 1021 , wherein the one or more fragments of one or more microorganism(s) are isolated directly from the one or more microorganism(s).
1023. The composition according to item 1 , wherein the composition comprises early HBV vaccine.
1024. The composition according to item 1021 , wherein the one or more fragments of one or more microorganism(s) are produced by recombinant DNA technology.
1025. The composition according to item 1 , wherein the composition comprises HPV vaccine.
1026. The composition according to item 1 , wherein the composition comprises one or more macromolecule(s).
1027. The composition according to item 1026, wherein the one or more macromolecule(s) comprises one or more naturally occurring protein(s).
1028. The composition according to item 1027, wherein the one or more naturally occurring protein(s) are isolated and used directly.
1029. The composition according to item 1027, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more cytokine(s).
1030. The composition according to item 1027, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more interleukine(s). 1031. The composition according to item 1027, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more interferone(s).
1032. The composition according to item 1027, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more antibodies(s).
1033. The composition according to item 1032, wherein the one or more antibodies(s) comprises one or more monoclonal antibodies.
1034. The composition according to item 1032, wherein the one or more antibodies(s) comprises one or more polyclonal antibodies.
1035. The composition according to item 1027, wherein the one or more naturally occurring protein(s) are isolated and modified.
1036. The composition according to item 1035, wherein the one or more naturally occurring protein(s) that are isolated and modified comprises one or more modified toxin(s).
1037. The composition according to item 1036, wherein the one or more modified toxin(s) are chemically modified.
1038. The composition according to item 1036, wherein the one or more modified toxin(s) are phyically modified.
1039. The composition according to item 1035, wherein the one or more naturally occurring protein(s) that are isolated and modified comprises one or more modified antibodies.
1040. The composition according to item 1039, wherein the one or more modified antibodies are chemically modified. 1041. The composition according to item 1039, wherein the one or more modified antibodies are digested into one or more fragment(s).
1042. The composition according to item 1041 , wherein the one or more fragment(s) comprises one or more Fab fragment(s).
1043. The composition according to item 1026, wherein the one or more macromolecule(s) comprises one or more recombinant protein(s).
1044. The composition according to item 1043, wherein the one or more recombinant protein(s) comprises one or more antibodies.
1045. The composition according to item 1044, wherein the one or more antibodies comprises one or more full length antibodies.
1046. The composition according to item 1044, wherein the one or more antibodies comprises one or more Fab fragments.
1047. The composition according to item 1044, wherein the one or more antibodies comprises one or more scFv fragments.
1048. The composition according to item 1044, wherein the one or more antibodies comprises one or more antibody-like scaffolds.
1049. The composition according to item 1044 to 1048, wherein the one or more antibodies are natural in sequence.
1050. The composition according to item 1044 to 1048, wherein the one or more antibodies are artificial in sequence.
1051. The composition according to item 1050, wherein the one or more antibodies that are artificial in sequence have one or more amino acid substitutions in the binding site. 1052. The composition according to item 1043, wherein the one or more recombinant protein(s) comprises one or more MHC molecule(s).
1053. The composition according to item 1052, wherein the one or more MHC molecule(s) are one or more MHC I molecules.
1054. The composition according to item 1053, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain, full length and/or truncated beta2m and peptide.
1055. The composition according to item 1053, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain and full length and/or truncated beta2m.
1056. The composition according to item 1053, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain and peptide.
1057. The composition according to item 1053, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain.
1058. The composition according to item 1052, wherein the one or more MHC molecule(s) are one or more MHC Il molecules.
1059. The composition according to item 1058, wherein the one or more MHC Il molecules consists of full length and/or truncated alpha chain and full length and/or truncated beta chain and peptide.
1060. The composition according to item 1058, wherein the one or more MHC Il molecules consists of full length and/or truncated alpha chain and full length and/or truncated beta chain.
1061. The composition according to item 1043, wherein the one or more recombinant protein(s) comprises one or more cytokine(s). 1062. The composition according to item 1061 , wherein the one or more cytokine(s) are full length.
1063. The composition according to item 1061 , wherein the one or more cytokine(s) are truncated.
1064. The composition according to item 1043, wherein the one or more recombinant protein(s) comprises one or more interleukine(s).
1065. The composition according to item 1064, wherein the one or more interleukine(s) are full length.
1066. The composition according to item 1064, wherein the one or more interleukine(s) are truncated.
1067. The composition according to item 1064, wherein the one or more recombinant protein(s) comprises one or more interferrone(s).
1068. The composition according to item 1067, wherein the one or more interferrone(s) are full length.
1069. The composition according to item 1067, wherein the one or more interferrone(s) are truncated.
1070. The composition according to item 1026, wherein the one or more macromolecule(s) comprises one or more nucleic acid(s).
1071. The composition according to item 1070, wherein the one or more nucleic acid(s) comprises DNA.
1072. The composition according to item 1071 , wherein the DNA encodes one or more protein(s).
1073. The composition according to item 1071 , wherein the DNA does not encode one or more protein(s). 1074. The composition according to item 1070, wherein the one or more nucleic acid(s) comprises RNA.
1075. The composition according to item 1074, wherein the RNA comprises one or more ribozyme(s).
1076. The composition according to item 1074, wherein the RNA comprises antisense.
1077. The composition according to item 1074, wherein the RNA comprises silencing RNA.
1078. The composition according to item 1070, wherein the one or more nucleic acid(s) comprises LNA.
1079. The composition according to item 1070, wherein the one or more nucleic acid(s) comprises PNA.
1080. The composition according to item 1026, wherein the one or more macromolecule(s) comprises one or more carbohydrate(s).
1081 . The composition according to item 1080, wherein the one or more carbohydrate(s) comprises one or more pure carbohydrates.
1082. The composition according to item 1081 , wherein the one or more pure carbohydrates comprises one or more monosaccharides.
1083. The composition according to item 1082, wherein the one or more monosaccharides are modified.
1084. The composition according to item 1081 , wherein the one or more pure carbohydrates comprises one or more disaccharides. 1085. The composition according to item 1084, wherein the one or more disaccharides are modified.
1086. The composition according to item 1081 , wherein the one or more pure carbohydrates comprises one or more polysaccharides.
1087. The composition according to item 1086, wherein the one or more polysaccharides are modified.
1088. The composition according to item 1080, wherein the one or more carbohydrate(s) comprises one or more glycoprotein(s).
1089. The composition according to item 1080, wherein the one or more carbohydrate(s) comprises one or more glycolipid(s).
1090. The composition according to item 1026, wherein the one or more macromolecule(s) are not part of a complex.
1091 . The composition according to item 1026, wherein the one or more macromolecule(s) are part of one or more complex(es).
1092. The composition according to item 1091 , wherein the one or more complex(es) comprises one or more polymer backbone(s).
1093. The composition according to item 1091 , wherein the one or more complex(es) is attached to one or more solid support(s).
1094. The composition according to item 1091 , wherein the complex is attached to one or more bead(s).
1095. The composition according to item 1 , wherein the composition is a cell-based vaccine.
1096. The composition according to item 1095, wherein the cell based vaccine comprises one or more naturally occurring cell(s). 1097. The composition according to item 1096, wherein the one or more naturally occurring cell(s) are isolated and amplified (by proliferation).
1098. The composition according to item 1096, wherein the one or more naturally occurring cell(s) are isolated and modified.
1099. The composition according to item 1098, wherein the one or more naturally occurring cell(s) that are isolated are modified to display one or more specific MHC complex(es).
1 100. The composition according to item 1099, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are incubated with one or more peptide(s).
1 101. The composition according to item 1099, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are fused to one or more other cells.
1 102. The composition according to item 1 101 , wherein the one or more other cells comprise one or more hybridoma cell(s).
1 103. The composition according to item 1099, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are obtained by one or more transfection(s).
1 104. The composition according to item 1 103, wherein the one or more transfection(s) comprises supercoiled plasmid DNA.
1 105. The composition according to item 1 103, wherein the one or more transfection(s) comprises siRNA.
1 106. The composition according to item 1 103, wherein the one or more transfection(s) comprises protein. 1 107. The composition according to item 1099, wherein the one or more naturally occurring cell(s) that are isolated and modified by one or more chemical modification step(s).
1 108. The composition according to item 1095, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s).
1 109. The composition according to item 1 108, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s) that are chemically modified.
1 1 10. The composition according to item 1 108, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s) that are genetically modified.
1 1 1 1. The composition according to item 1 , wherein the composition is a liposome/micelle-based vaccine.
1 1 12. The composition according to item 1 , wherein the composition is a nanocluster- based vaccine.
1 1 13. The composition according to item 1 , wherein the composition comprises one or more vaccine adjuvant(s).
1 1 14. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) increases or otherwise modifies the immune response to said vaccine.
1 1 15. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) elicit an earlier and/or more potent immune response to said vaccine.
1 1 16. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) elicit a prolonged and/or more potent immune response to said vaccine.
1 1 17. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) results in increased humoral immunity to said vaccine. 1 1 18. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) results in induction of the complement pathway.
1 1 19. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) results in increased cell mediated immunity to said vaccine.
1 120. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more antigenic determinant(s).
1 121. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more haptenic determinant(s).
1 122. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more mineral adjuvant(s).
1 123. The composition according to item 1 122, wherein the one or more mineral adjuvant(s) comprises one or more aluminium compounds such as one or more aluminium salt(s).
1 124. The composition according to item 1 122, wherein the one or more mineral adjuvant(s) comprises aluminium hydroxide.
1 125. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more bacterial adjuvant(s).
1 126. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) are purified.
1 127. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) are chemically purified.
1 128. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) are synthesized. 1 129. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises muramyl dipeptides.
1 130. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises lipid A.
1 131. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises lnterleukin 1.
1 132. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises lnterleukin 2.
1 133. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more cloned host mediator(s).
1 134. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises Bordetella pertussis.
1 135. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s).
1 136. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises Freund's Complete Adjuvant (FCA).
1 137. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises Titermax.
1 138. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises ISCOMS.
1 139. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises Quil A.
1 140. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises ALUN. 1 141. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more Lipid A derivatives.
1 142. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more choleratoxin derivatives.
1 143. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more HSP derivatives.
1 144. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more LPS derivatives.
1 145. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more synthetic peptide matrixes.
1 146. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises GMDP.
1 147. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof.
1 148. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof in combination with one or more liposome(s).
1 149. The composition according to item 1 125, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof in combination with one or more lipid emulsion(s).
1 150. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more plant adjuvant(s).
1 151 . The composition according to item 1 150, wherein the one or more plant adjuvant(s) comprises saponin. 1 152. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more animal products adjuvant(s).
1 153. The composition according to item 1 152, wherein the one or more animal products adjuvant(s) comprises chitin.
1 154. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more synthetic adjuvant(s).
1 155. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more host adjuvant(s).
1 156. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more antigens precipitated with aluminum salt(s).
1 157. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more antigens mixed with or adsorbed to performed aluminum compounds.
1 158. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more oil emulsion(s).
1 159. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more liposome(s).
1 160. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises one or more synthetic polymer(s).
1 161. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) act through antigen localization and delivery.
1 162. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) act by direct effects on cells making up the immune system, such as macrophages and lymphocytes. 1 163. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) act by creation of an antigen depot.
1 164. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises Alhydrogel.
1 165. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) comprises MF59 and/or the proprietary Montanide ISA720.
1 166. The composition according to item 1 1 13, wherein the one or more vaccine adjuvant(s) selected from the group consisting of AIK(SO4)2, AINa(SO4)2, AINH4 (SO4), silica, alum, AI(OH)3, Ca3 (PO4)2, kaolin, carbon, aluminum hydroxide, muramyl dipeptides, N-acetyl-muramyl-L-threonyl-D-isoglutamine (thr-DMP), N-acetyl- nornuramyl-L-alanyl-D-isoglutamine (CGP 1 1687, also referred to as nor-MDP), N- acetylmuramyul-L-alanyl-D-isoglutaminyl-L-alanine-2-(1 '2'-dipalmitoyl-sn -glycero-3- hydroxphosphoryloxy)-ethylamine (CGP 19835A, also referred to as MTP-PE), RIBI (MPL+TDM+CWS) in a 2% squalene/Tween-80.RTM. emulsion, lipopolysaccharides and its various derivatives, including lipid A, Freund's Complete Adjuvant (FCA), Freund's Incomplete Adjuvants, Merck Adjuvant 65, polynucleotides (for example, poly IC and poly AU acids), wax D from Mycobacterium, tuberculosis, substances found in Corynebacterium parvum, Bordetella pertussis, and members of the genus Brucella, liposomes or other lipid emulsions, Titermax, ISCOMS, Quil A, ALUN (see US 58767 and 5,554,372), Lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide matrixes or GMDP, lnterleukin 1 , lnterleukin 2, Montanide ISA-51 and QS-21 , Freund's complete or incomplete adjuvant, and killed B. pertussis organisms, used e.g. in combination with alum precipitated antigen.
1 167. The composition according to any of items 1 to 1 166, wherein the composition comprises at least one biologically active molecule such as from 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to10, or 1 to more than 10; 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, or 2 to more than 10; 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, or 3 to more than 10; 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to9, 4 to 10, or 4 to more than 10; 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 5 to more than 10; 6 to 7, 6 to 8, 6 to 9, 6 to 10, or 6 to more than 10; 7 to 8, 7 to 9, 7 to 10, or 7 to more than 10; 8 to 9, 8 to 10, or 8 to more than 10; 9 to 10, or 9 to more than 10 different biologically active molecules.
1 168. The composition according to any of items 1 to 1 166, wherein the composition comprises two different biologically active molecules termed A and B, wherein the ratio of A:B can be selected from the group consisting of 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 2:3, and 3:5.
1 169. The composition according to any of items 1 to 1 166, wherein the composition comprises three different biologically active molecules termed A, B and C, wherein the ratio of A:B:C can be selected from the group consisting of 1 :1 :1 , 1 :2:1 , 1 :3:1 , 1 :4:1 , 1 :5:1 , 1 :10:1 , 2:1 :1 , 2:1 :2, 2:3:2, and 3:5:8.
1 170. The composition according to any of items 1 to 1 166, wherein the composition comprises five different biologically active molecules termed A, B, C, D, and E, wherein the ratio of A:B:C:D:E can be selected from the group consisting of 1 :1 :1 :1 :1 , 1 :1 :1 :1 :2, 1 :1 :1 :2:2, 1 :2:2:2:2, 2:4:3:6:5, 4:6:8:1 :1 , and 10:1 :2:5:2.
1 171. A method of making the composition according to item 1 -1 170.
1 172. A method for vaccination comprising administration to an individual in need thereof an effective amount of the composition according to item 1 -1 170.
1 173. The method for vaccination according to item 1 172, wherein each dosage unit of said composition comprises in the range of 0.01 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 0.8 μg, for example in the range of 0.05 to 0.6 μg, such as in the range of 0.05 to 0.4 μg, for example in the range of 0.05 to 0.2 μg, such as in the range of 0.1 to 0.8 μg, for example in the range of 0.1 to 0.6 μg, such as in the range of 0.1 to 0.5 μg, for example in the range of 0.1 to 0.4 μg, such as in the range of 0.1 to 0.3 μg, for example in the range of 0.1 to 0.2 μg of pharmamer and/or peptide.
1 174. The method for vaccination according to item 1 172, wherein the daily dosage of the composition comprises pharmamer in the range from 0.001 to 1 ,000 mg per adult human/per day, such as from 0.001 to 0.005 mg per adult human/per day, for example from 0.005 to 0.01 mg per adult human/per day, such as from 0.01 to 0.05 mg per adult human/per day, for example from 0.05 to 0.1 mg per adult human/per day, such as from 0.1 to 0.5 mg per adult human/per day, for example from 0.5 to 1 mg per adult human/per day, such as from 1 to 5 mg per adult human/per day, for example from 5 to 10 mg per adult human/per day, such as from 10 to 50 mg per adult human/per day, for example from 50 to 100 mg per adult human/per day, such as from 100 to 500 mg per adult human/per day, for example from 500 to 1000 mg per adult human/per day.
1 175. The method for vaccination according to item 1 172, wherein the vaccination comprises oral administration of scored or unscored tablets containing e.g. 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, or 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. 1 176. The method for vaccination according to item 1 172, wherein the composition is administered at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day.
1 177. The method for vaccination according to item 1 172, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of pharmamer.
1 178. The method for vaccination according to item 1 172, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of peptide(s).
1 179. The method for vaccination according to item 1 172, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of biologically active molecule.
1 180. The method for vaccination according to item 1 172, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of adjuvans.
1 181. The method for vaccination according to item 1 172, wherein the individual in need thereof is a mammal.
1 182. The method for vaccination according to item 1 172, wherein the individual in need thereof is a human being.
1 183. The method for vaccination according to item 1 172, wherein the individual in need thereof is a newborn.
1 184. The method for vaccination according to item 1 172, wherein the individual in need thereof is a a child.
1 185. The method for vaccination according to item 1 172, wherein the individual in need thereof is an adult. 1 186. The method for vaccination according to item 1 172, wherein the individual in need thereof is a woman.
1 187. The method for vaccination according to item 1 172, wherein the individual in need thereof is a man.
1 188. The method for vaccination according to item 1 172, wherein the individual in need thereof is of any age such as from newborn to 120 years old, for example from 0 to 6 months, such as from 6 to 12 months, for example from 1 to 5 years, such as from 5 to 10 years, for example from 10 to 15 years, such as from 15 to 20 years, for example from 20 to 25 years, such as from 25 to 30 years, for example from 30 to 35 years, such as from 35 to 40 years, for example from 40 to 45 years, such as from 45 to 50 years, for example from 50 to 60 years, such as from 60 to 70 years, for example from 70 to 80 years, such as from 80 to 90 years, for example from 90 to 100 years, such as from 100 to 1 10 years, for example from 1 10 to 120 years.
1 189. The method for vaccination according to item 1 172, wherein the individual in need thereof is of any race such as a Caucasian, a black person, an East Asian person, a person of Mongoloid race, a person of Ethiopian race, a person of Negroid race, a person of American Indian race, or a person of Malayan race.
1 190. The method for vaccination according to item 1 172, wherein the individual in need thereof is healthy.
1 191. The method for vaccination according to item 1 172, wherein the individual in need thereof is ill.
1 192. The method for vaccination according to item 1 172, wherein the individual in need thereof is diagnosed with one or more diseases.
1 193. The method for vaccination according to item 1 172, wherein the individual in need thereof has one or more symptoms of one or more diseases.
1 194. The method for vaccination according to item 1 172, wherein the individual in need thereof is asymptomatic. 1 195. The method for vaccination according to item 1 172, wherein the individual in need thereof is genetically disposed for one or more diseases.
1 196. The method for vaccination according to item 1 172, wherein the individual in need thereof is an animal.
1 197. The method for vaccination according to item 1 172, wherein the individual in need thereof is a bird.
1 198. The method for vaccination according to item 1 172, wherein the individual in need thereof is an insect.
1 199. The method for vaccination according to item 1 172, wherein the individual in need thereof is a plant.
1200. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by oral administration.
1201. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by sublingual administration.
1202. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by nasal administration.
1203. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by inhalation.
1204. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by injection.
1205. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by intravenous administration. 1206. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by intramuscular administration.
1207. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by intrathecal administration.
1208. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by subcutan administration.
1209. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by implantation.
1210. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by rectal administration.
121 1 . The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by vaginal administration.
1212. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by the ocular route.
1213. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by applying it to the skin (cutaneously) for a local (topical) effect.
1214. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by applying it to the skin (cutaneously) for bodywide (systemic) effect.
1215. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by delivering it through the skin (transdermally) for a systemic effect.
1216. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by inter peritoneal injection. 1217. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by transmucosal administration.
1218. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition by inoculation.
1219. The method for vaccination according to item 1 172, wherein the method comprises administration of a single dose of said composition.
1220. The method for vaccination according to item 1 172, wherein the method comprises administration of several doses of said composition such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses.
1221. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition only once.
1222. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 times.
1223. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of a day.
1224. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of a days, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 days.
1225. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of about a week. 1226. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of about two weeks.
1227. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of about three weeks.
1228. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of about a month.
1229. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of several months, such as 2, 3,4, 5, 6, 7, 8, 9, 10, 1 1 or 12 months.
1230. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once with administration with intervals of years, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or 1 10 years.
1231 . The method for vaccination according to item 1 172, wherein the method comprises a continuous administration regime of said composition e.g. like up to four doses per week, followed by one month without administrations, followed by up to four doses per week.
1232. The method for vaccination according to item 1 172, wherein the method comprises a vaccination protocol where administration is performed e.g. on week 0, 4, 8, and 16; or on week 0, 2, 4, 6, 8, 10, 12, and 14; or on week 0, 5, 1 1 , 17; or on month 0, 1 , and 2; or on day 0, 7, and 30; or every year.
1233. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the amount of phamamer and/or peptide is increased from the first administration to one or more of the subsequent administrations. 1234. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the amount of phamamer and/or peptide is decreased from the first administration to one or more of the subsequent administrations.
1235. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the ratio of biologically active molecules in said composition is modified from the first administration to one or more of the subsequent administrations.
1236. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the type of adjuvant(s) in said composition is modified from the first administration to one or more of the subsequent administrations.
1237. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the amount of one or more adjuvant(s) in said composition is modified from the first administration to one or more of the subsequent administrations.
1238. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition more than once and wherein the combination of adjuvants in said composition is modified from the first administration to one or more of the subsequent administrations.
1239. The method for vaccination according to item 1 172, wherein the method comprises use of an administration protocol linked to age of the individual in need of said vaccine.
1240. The method for vaccination according to item 1 172, wherein the method comprises use of an administration protocol for childhood vaccines e.g. wherein the vaccine is administered at the age of 3 month, 5, month, and 12 month; or 3 month, 5, month, 12 month, and 5 years; or 15 month, and 4 years. 1241. The method for vaccination according to item 1 172, wherein the method comprises administration of said composition together with administration of one or more medicament, wherein the administration can be simultaneously or sequentially in any order.
1242. The method for vaccination according to item 1 172, wherein the composition is administered together with one or more adjuvants.
1243. The method for vaccination according to item 1 172, wherein the composition is administered simultaneously with one or more adjuvants.
1244. The method for vaccination according to item 1 172, wherein the composition is administered together with one or more adjuvants sequentially in any order.
1245. The method for vaccination according to item 1 172, wherein the vaccination is prophylactic.
1246. The method for vaccination according to item 1 172, wherein the vaccination if ameliorating.
1247. The method for vaccination according to item 1 172, wherein the vaccination is curative.
1248. A method for monitoring a vaccine response comprising use of the composition according to item 1 -1 170.
1249. A kit-of-parts comprising the composition according to item 1 -1 170 and at least one addition component.
1250. Use of the kit-of-parts according to item 1249 for vaccination of an individual in need thereof.
1251. Use of the kit-of-parts according to item 1249 for monitoring of a vaccine response. 1252. The composition according to item 1 , wherein the one or more pharmamers comprises one or more HIV and/or SIV vaccines.
1253. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier.
1254. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier derivatized by attachment of Streptavidin e.g. such as 8.6 Steptavidin molecules are attached per Dextran molecule.
1255. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier with a molecular weight of 270 kDa.
1256. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier with Simian MHC class 1 molecules attached.
1257. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier with Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569) attached.
1258. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier with Mamu-A*08(KPCVKLTP) attached (SEQ ID NO 9570).
1259. The composition according to item 1 , wherein the one or more pharmamers comprises a dextran carrier with Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ) attached.
1260. The composition according to items 1257 to 1259, wherein attachment is done via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain to streptavidin molecules on the dextran carrier.
1261. The composition according to item 1 , wherein the one or more pharmamers comprises one or more biotinylated synthetic Mamu class 2 peptides. 1262. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-DQB1 *0601 (EFVRFDSA VGEYRA V) (SEQ ID NO 9572).
1263. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-DQB1 *1808(EFVGFDSYLGVYRPV) (SEQ ID NO 9573).
1264. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574).
1265. The composition according to item 1 , wherein the one or more pharmamers comprises recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
1266. The composition according to item 1 , wherein the one or more pharmamers comprises HIV-Gag (CTPYDINQM) (SEQ ID NO 9569).
1267. The composition according to item 1 , wherein the one or more pharmamers comprises HIV-Env (KPCVKLTP) (SEQ ID NO 9570).
1268. The composition according to item 1 , wherein the one or more pharmamers comprises Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ).
1269. The composition according to item 1 , wherein the one or more pharmamers comprises recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
1270. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu-DQB1 *0601 (EFVRFDSAVGEYRAV) (SEQ ID NO 9572) class 2 peptide, HSP70pep3Bio, and Dextran carrier (in the molar ratiol 0:10:4:1 ).
1271. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573) class 2 peptide, HSP70pep3Bio and Dextran carrier (in the molar ratio 10:10:4:1 ). 1272. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) class 2 peptide, HSP70pep3Bio and Dextran carrier (in the molar ratio 10:10:4:1 ).
1273. The composition according to item 1 , wherein the one or more pharmamers comprises Sivp27, HIV-1gp140trimer, HSP70pep3Bio and Dextran carrier (in the molar ratio 3:10:4).
1274. The composition according to item 1 , wherein the one or more pharmamers are absorbed into the adjuvant Alhydrogel (Aluminiumhydroxide gel) as specified by the manufacturer.
1275. The composition according to item 1 , wherein the one or more pharmamers comprises Human MHC class 1 molecules.
1276. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575).
1277. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576).
1278. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577).
1279. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578).
1280. The composition according to item 1 , wherein the one or more pharmamers comprises attachment a COOH-terminal Biotin molecule on recombinant HLA heavy chain to the carrier strepavidin molecules.
1281. The composition according to item 1 , wherein the one or more pharmamers comprises biotinylated recombinant HLA class 2 protein HLA-DR*0401 and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
1282. The composition according to item 1 , wherein the one or more pharmamers comprises USP9Y, ubiquitin specific protease 9 (IVDCLTEMY) (SEQ ID NO 9575).
1283. The composition according to item 1 , wherein the one or more pharmamers comprises TRAG-3_4 (GLIQLVEGV) (SEQ ID NO 9576).
1284. The composition according to item 1 , wherein the one or more pharmamers comprises BCL2L1 (RIAAWMATY) (SEQ ID NO 9577).
1285. The composition according to item 1 , wherein the one or more pharmamers comprises EBV EBNA3B (IVTDFSVIK) (SEQ ID NO 9578).
1286. The composition according to item 1 , wherein the one or more pharmamers comprises a HLA class 2 complex without a peptide in the binding groove.
1287. The composition according to item 1 , wherein the one or more pharmamers comprises a HLA class 2 complex containing unknown peptides derived from either serum or S2 production cells.
1288. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575), HLA-DR*0401 class 2, HSP70pep3Bio, and Dextran carrier (in the molar ratiol 0:10:4:1 ).
1289. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576), HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577), HSP70pep3Bio, and Dextran carrier (in the molar ratio 10:10:4:1 ).
1290. The composition according to item 1 , wherein the one or more pharmamers comprises HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578), HSP70pep3Bio, and Dextran carrier (in the molar ratio 10:4:1 ). 1291. The composition according to item 1 , wherein the one or more pharmamers are emulsified with the adjuvant Titermax Gold as specified by the manufacturer.
1292. The composition according to item 1 , wherein the one or more pharmamers comprises recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
1293. The composition according to item 1 , wherein the one or more pharmamers comprises biotinylated recombinant HSP70pep3Bio-CCR5-tripeptide fragment, a biotinylated fusion protein consisting of the HSP70 fragment spanning amino acid residues 359-609 plus the antigenic CCR5 loops, N-terminal loop, Loopi and Loop2, attached to strepavidin sites.
1294. The composition according to item 1 , wherein the one or more pharmamers comprises the CCR5 peptides representing the three antigenic loops (N-terminal
(MNYQVSSPIYNINYYTSEPC) (SEQ ID NO 9579); Loopi (HYAAAQWNFGNTMCQ) (SEQ ID NO 9580); Loop2 (YSSHFPYSQYQFWKNFQTLK) (SEQ ID NO 9581 )).
1295. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), HSP70pep3Bio-CCR5- tripeptide and Dextran carrier (in the molar ratiol 3:10:1 ).
1296. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), HSP70pep3Bio-CCR5- tripeptide and Dextran carrier (in the molar ratiol 3:10:1 ).
1297. The composition according to item 1 , wherein the one or more pharmamers comprises Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), HSP70pep3Bio-CCR5- tripeptide and Dextran carrier (in the molar ratiol 3:10:1 ).
1298. The method for vaccination according to item 1 172, wherein the composition is administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 weeks. 1299. The method for vaccination according to item 1 172, wherein the composition is administered as intramuscular injections at time points 0, 2, 4, 6, 8, 10, 12 and 14 weeks such that a full dose is given at each time point.
1300. The composition according to item 1 , wherein the composition is designed to elicit a multifunctional immune response i.e. a composite immune responses directed against the adaptive and the innate immune system; and/or both parts of the adaptive system i.e. the humoral and the cellular part.
1301. The composition according to item 1 , wherein the composition comprises one or more HLA class 1 and/or class 2 molecules.
1302. The composition according to item 1 , wherein the composition comprises one or more HLA class 1 molecules that are folded or partly folded with human b2Microglobulin and a peptide fitting into the binding groove.
1303. The composition according to item 1 , wherein the composition comprises one or more complete, partial or otherwise modified HLA class 1 heavy chain(s).
1304. The composition according to item 1 , wherein the composition comprises one or more HLA class 2 molecules consisting of folded or partly folded alpha- and beta- chains with or without a peptide in the binding groove.
1305. The composition according to item 1 , wherein the composition comprises one or more complete, partial or otherwise modified HLA class 2 alpha- and beta-chains.
1306. The composition according to item 1 , wherein the composition comprises one or more binding-peptides derived from HIV specific proteins such as Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev, Vpu, Nef, gp160 and derivatives such as gp120, gp41 and gp140.
1307. The composition according to item 1 , wherein the composition comprises one or more binding-peptides that are HIV unrelated. 1308. The composition according to item 1 , wherein the composition comprises HLA class 1 peptides derived from regions of the class 1 heavy chain.
1309. The composition according to item 1 , wherein the composition comprises HLA class 2 peptides derived from regions of the class 2 alpha and/or beta chain.
1310. The composition according to item 1 , wherein the composition comprises CD4 or part(s) hereof.
131 1. The composition according to item 1 , wherein the composition comprises CCR 5 (Chemokine Receptor 5) or part(s) hereof.
1312. The composition according to item 1 , wherein the composition comprises the extracellular peptide-loops of CCR5.
1313. The composition according to item 1 , wherein the composition comprises HSP70 or part(s) thereof.
1314. The composition according to item 1 , wherein the composition comprises CXCR4 or part(s) hereof.
1315. The composition according to item 1 , wherein the composition comprises CCR 2 (Chemokine Receptor 2) or part(s) hereof.
1316. The composition according to item 1 , wherein the composition comprises CX3CR1 or part(s) hereof.
1317. The composition according to item 1 , wherein the composition comprises SDF- 1 or part(s) hereof.
1318. The composition according to item 1 , wherein the composition comprises US28 or part(s) hereof. 1319. The composition according to item 1 , wherein the composition comprises HIV viral specific proteins i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140.
1320. The composition according to item 1 , wherein the composition comprises Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens).
1321. The composition according to item 1 , wherein the composition comprises one or more Mamu class 1 molecules folded or partly folded with one or more human b2Microglobulin and a peptide fitting into the binding groove.
1322. The composition according to item 1 , wherein the composition comprises one or more complete, partial or otherwise modified Mamu class 1 heavy chain(s).
1323. The composition according to item 1 , wherein the composition comprises one or more Mamu class 2 molecules consisting of folded or partly folded alpha- and beta- chains with or without a peptide in the binding groove.
1324. The composition according to item 1 , wherein the composition comprises one or more complete, partial or otherwise modified Mamu class 2 alpha- and beta-chains.
1325. The composition according to item 1 , wherein the composition comprises one or more binding-peptides derived from SIV specific proteins such as Gag-Pol, Gag, Vif, Vpx, Envelope protein, and/or Nef.
1326. The composition according to item 1 , wherein the composition comprises one or more binding-peptides that are SIV unrelated.
1327. The composition according to item 1 , wherein the composition comprises Mamu class 1 peptides derived from regions of the class 1 heavy chain.
1328. The composition according to item 1 , wherein the composition comprises Mamu class 2 peptides derived from regions of the class 2 alpha and/or beta chain. 1329. The composition according to item 1 , wherein the composition comprises SIV viral specific proteins i.e. Gag-Pol, Gag, Vif, Vpx, Envelope protein, Nef; HSP70 (70 kD Heat-shock protein) or part(s) hereof.
1330. The method for vaccination according to item 1 172, wherein the composition is administered at the cervico-vaginal mucosa i.e. vaginally or IM i.e. intra-muscular. T
1331. The method for vaccination according to item 1 172, wherein the composition is administered alone or together with additional adjuvant(s) such as but not limited to Titermax Gold, Alhydrogel (Aluminium-hydroxide), MF59 and/or the proprietary Montanide ISA720.
1332. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases caused by a viral infection.
1333. The method for vaccination according to item 1332, wherein viral infection is caused by dsDNA vira such as Adenoviruses, Herpesviruses, Poxviruses.
1334. The method for vaccination according to item 1332, wherein viral infection is caused by ssDNA vira (+)sense DNA such as Parvoviruses.
1335. The method for vaccination according to item 1332, wherein viral infection is caused by dsRNA vira such as Reoviruses.
1336. The method for vaccination according to item 1332, wherein viral infection is caused by (+)ssRNA vira (+)sense RNA such as Picornaviruses and Togaviruses.
1337. The method for vaccination according to item 1332, wherein viral infection is caused by (-)ssRNA vira (-)sense RNA such as Orthomyxoviruses and Rhabdoviruses.
1338. The method for vaccination according to item 1332, wherein viral infection is caused by ssRNA-RT vira (+)sense RNA with DNA intermediate in life-cycle such as Retroviruses. 1339. The method for vaccination according to item 1332, wherein viral infection is caused by dsDNA-RT vira such as Hepadnaviruses.
1340. The method for vaccination according to item 1332, wherein viral infection is caused by one or more vira selected from the group consisting of Abelson murine leukemia virus (Ab-MLV, A-MuLV), acute laryngotracheobronchitis virus (or HPIV), Adelaide River virus, Adeno-associated virus group (Dependevirus), Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease, parvovirus, alfalfa mosaic virus, Alphaherpesvirinae (including HSV 1 and 2 and varicella), Alpharetrovirus (Avian leukosis virus, Rous sarcoma virus), Alphavirus, alkhurma virus, ALV related virus, Amapari virus, Andean potato mottle virus, Aphthovirus, Aquareovirus, arbovirus, arbovirus C, arbovirus group A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus, Argentinian hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline herpesvirus group, Aujezky's disease virus, Aura virus, Ausduk disease virus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosis virus, avian infectious bronchitis virus, avian leukemia virus, Avian leukosis virus (ALV), avian lymphomatosis virus, avian myeloblastosis virus, avian paramyxovirus, avian pneumoencephalitis virus, avian reticuloendotheliosis virus, avian sarcoma virus, avian type C retrovirus group, Avihepadnavirus, Avipoxvirus, B virus (Cercopithecine herpesvirus 1 ), B19 virus (Parvovirus B19), Babanki virus, baboon herpesvirus, bacterial virus, baculovirus, barley yellow dwarf virus, Barmah Forest virus, bean pod mottle virus, bean rugose mosaic virus, Bebaru virus, Berrimah virus, Betaherpesvirinae, betaretrovirus, Bird flu, Birnavirus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma disease virus, border disease of sheep virus, borna virus, bovine alphaherpesvirus 1 , bovine alphaherpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukosis virus, bovine mammillitis virus, bovine papillomavirus, bovine papular stomatitis virus, bovine parvovirus, bovine syncytial virus, bovine type C oncovirus, bovine viral diarrhea virus, bracovirus, broad bean mottle virus, broad bean stain virus, brome mosaic virus, Bromovirus, Buggy Creek virus, bullet shaped virus group, Bunyamwera virus, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, Bwattany hetero virus, CA virus (Croup-associated virus/ parainfluenza vius type 2), Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, Capillovirus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, Carlavirus, Carmovirus, carrot mottle virus, Cassia yellow blotch virus, Caulimovirus, Cauliflower mosaic virus, caviid herpesvirus 1 , Cercopithecine herpesvirus 1 , Cercopithecine herpesvirus 2, cereal yellow dwarf virus, Chandipura virus, Changuinola virus, channel catfish virus, Charleville virus, chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, Chordopoxvirinae, chub reovirus, chum salmon virus, Closterovirus, Cocal virus, Coho salmon reovirus, coital exanthema virus, Colorado tick fever virus, Coltivirus Columbia SK virus, Commelina yellow mottle virus, Common cold virus, Comovirus, Condylomata accuminata, congenital cytomegalovirus, contagious ecthyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpea chlorotic mottle virus, cowpea mosaic virus, cowpea virus, cowpox virus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Crypotovirus, Cucumovirus, Cypovirus, Cytomegalovirus (HCMV or Human Herpesvirus 5 HHV-5), cytoplasmic polyhedrosis virus, Cytorhabdovirus, deer papillomavirus, Deltaretrovirus (Human T-lymphotropic virus), Deformed wing virus DWV, Dengue, Densovirus, Dependovirus, Dhori virus, Dianthovirus, diploma virus, DNA virus, Dobrava-Belgrade Virus, Dog Flu, Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1 , duck hepatitis virus 2, duovirus, Duvenhage virus, eastern equine encephalitis virus, eastern equine encephalomyelitis virus, Ebola virus, Ebola-like virus, Echovirus, echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus (Eastern equine encephalitis virus), EIA virus (equine infectious anemia), EMC virus (Encephalomyocarditis), Emiliania huxleyi virus 86, encephalitis virus, encephalomyocarditis virus, Endogenous retrovirus, Enterovirus, Entomopoxvirinae, Entomopoxvirus A, Entomopoxvirus B, Entomopoxvirus C, enzyme elevating virus, epidemic hemorrhagic fever virus, epizootic hemorrhagic disease virus, Epsilonretrovirus, Epstein-Barr virus (EBV; Human herpesvirus 4 HHV-4), equid alphaherpesvirus 1 , equid alphaherpesvirus 4, equid herpesvirus 2, equine abortion virus, equine arteritis virus, equine encephalosis virus, equine infectious anemia virus, equine morbillivirus, equine rhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elk papillomavirus, European swine fever virus, Everglades virus, Eyach virus, Fabavirus, felid herpesvirus 1 , feline calicivirus, feline fibrosarcoma virus, feline herpesvirus, feline immunodeficiency virus, feline infectious peritonitis virus, feline leukemia /sarcoma virus, feline leukemia virus, feline panleukopenia virus, feline parvovirus, feline sarcoma virus, feline syncytial virus, Fijivirus, Filovirus, Flanders virus, Flavivirus, foot and mouth disease virus, Fort Morgan virus, Four Corners hantavirus, fowl adenovirus 1 , Fowlpox virus, Friend virus, Furovirus, Gammaherpesvirinae, gammaretrovirus, GB virus C(GBV-C; formerly Hepatitis G virus), Geminivirus, German measles virus, Getah virus, gibbon ape leukemia virus, green monkey virus (mullburg), glandular fever virus, goatpox virus, golden shinner virus, Gonometa virus, goose parvovirus, granulosis virus, Gross' virus, ground squirrel hepatitis B virus, group A arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pig type C virus, Hantavirus, hard clam reovirus, hare fibroma virus, HCMV (human cytomegalovirus), helper virus, hemadsorption virus 2, hemagglutinating virus of Japan, hemorrhagic fever virus, Hendra virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D (delta) virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus, hepatoencephalomyelitis reovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, Herpes simplex virus, herpes simplex virus 1 , herpes simplex virus 2, Herpesvirus, Herpes zoster, Herpes virus 6, Herpes virus 7, Herpes virus 8,
Herpesvirus ateles, Herpesvirus hominis, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, HIV-1 , hog cholera virus, Hordeivirus, Horse Flu, HTLV-1 , HTLV-2, human adenovirus 2, human alphaherpesvirus 1 , human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, Human enterovirus A, Human enterovirus B, Human Flu, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus 6, human herpesvirus 8, human immunodeficiency virus (HIV), human immunodeficiency virus 1 , human immunodeficiency virus 2, Human metapneumovirus, human papillomavirus, human T cell leukemia virus, human T cell leukemia virus I, human T cell leukemia virus II, human T cell leukemia virus III, human T cell lymphoma virus I, human T cell lymphoma virus II, human T cell lymphotropic virus type 1 , human T cell lymphotropic virus type 2, human T lymphotropic virus I, human T lymphotropic virus II, human T lymphotropic virus III, ichnovirus, llarvirus, infantile gastroenteritis virus, infectious bovine rhinotracheitis virus, infectious haematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus, influenzavirus A, influenzavirus B, influenzavirus C, influenzavirus D, influenzavirus prδ, insect iridescent virus, insect virus, interfering virus, iridovirus, Isavirus, Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, Johnson grass mosaic virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus, Korean hemorrhagic fever virus, kumba virus, Kumlinge virus, Kunjin virus, Kyasanur forest disease, Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus, Lagos bat virus, Lambda phage, langat virus, Langur virus, lapine parvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM virus, Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, louping ill virus, lumpy skin disease virus, Luteovirus, lymphadenopathy associated virus, Lymphocytic choriomeningitis virus (LCMV), Lymph ocryptovirus, lymphocytic choriomeningitis virus, lymphoproliferative virus group, Lyssavirus, Machupo virus, mad itch virus, maize chlorotic dwarf virus, maize rough dwarf virus, mammalian type B oncovirus group, mammalian type B retroviruses, mammalian type C retrovirus group, mammalian type D retroviruses, mammary tumor virus, Mapuera virus, Marafivirus, Marburg virus, Marburg-like virus, Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus, Measles virus, Melandrium yellow fleck virus, Menangle virus, Mengo virus, Mengovirus, Merkel cell polyomavirus, Middelburg virus, milkers nodule virus, mink enteritis virus, minute virus of mice, MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscum contagiosum virus, Moloney murine leukemia virus (M- MuLV), monkey B virus, Monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, Mumps virus, murid betaherpesvirus 1 , murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Necrovirus, Neethling virus, Nelson Bay virus, Nemtick Virus, Nepovirus, neurotropic virus, New World Arenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipah virus, noncytopathogenic virus, Norovirus, Norwalk virus, nuclear polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus, oat sterile dwarf virus, Ockelbo virus, Omsk hemorrhagic fever virus, oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus, Orf virus, Oropouche virus, Orthohepadnavirus, orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus sylvilagi, Papovavirus, Parainfluenza virus human (HPIV), parainfluenza virus type 1 human (HPIV-1 ), parainfluenza virus type 2 human (HPIV-2), parainfluenza virus type 3 human (HPIV-3), parainfluenza virus type 4 human (HPIV-4), Paramyxovirus, Parapoxvirus, paravaccinia virus, parsnip yellow fleck virus, Parvovirus, Parvovirus B19, pea enation mosaic virus, Pestivirus, Phlebovirus, phocine distemper virus, Phytoreovirus, Picodnavirus, Picornavirus, pig cytomegalovirus, pigeonpox virus, Piry virus, Pixuna virus, plant rhabdovirus group, plant virus, pneumonia virus of mice, Pneumovirus, Poliomyelitis virus, Poliovirus, Polydnavirus, polyhedral virus, Polyoma virus, Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2, Polyomavirus maccacae 1 ,
Polyomavirus muris 1 , Polyomavirus muris 2, Polyomavirus papionis 1 , Polyomavirus papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1 , porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, Potato leaf roll virus, Potato mop top virus, Potato virus Y, Potexvirus, Potyvirus, Powassan encephalitis virus, Poxvirus, poxvirus variolae, Prospect Hill virus, provirus, pseudocowpox virus, pseudorabies virus, psittacinepox virus, Puumala virus, Qalyub virus, Quail pea mosaic virus, quailpox virus, Queensland fruitfly virus, Quokkapox virus, rabbit fibroma virus, rabbit kidney vacuolating virus, rabbit papillomavirus, Rabies virus, raccoon parvovirus, raccoonpox virus, radish mosaic virus, Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus, Rauscher's virus, recombinant vaccinia virus, recombinant virus, Red Clover Necrotic Mosaic Virus, reovirus, reovirus 1 , reovirus 2, reovirus 3, reptilian type C virus, Respiratory syncytial virus, respiratory virus, reticuloendotheliosis virus, Retrovirus, Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, Rhinovirus, Rhizidiovirus, rice dwarf virus, rice gall dwarf virus, rice hoja blanca virus, rice ragged stunt virus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA tumor virus, RNA virus, Roseolovirus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, Rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, S6-14-03 virus, SA 1 1 simian virus, SA 15, SA2 virus, SA6 virus, SA8 virus, Sabia virus, Sabio virus, Sabo virus, Saboya virus, Sabulodes caberata GV, Sacbrood virus, Saccharomyces cerevisiae virus L-A, Saccharomyces cerevisiae virus La, Saccharomyces cerevisiae virus LBC, Sagiyama virus, Saguaro cactus virus, Saimiriine herpesvirus 1 , Saimiriine herpesvirus 2, Sainpaulia leaf necrosis virus, SaintAbb's Head virus, Saint-Floris virus, Sakhalin virus, Sal Vieja virus, Salanga virus, Salangapox virus, Salehabad virus, salivary gland virus, Salmonid herpesvirus 1 , Salmonid herpesvirus 2, Salmonis virus, Sambucus vein clearing virus, Samia cynthia NPV, Samia pryeri NPV, Samia ricini NPV, Sammons' Opuntia virus, SanAngelo virus, San Juan virus, San Miguel sealion virus, San Perlita virus, Sand rat nuclear inclusion agents, Sandfly fever Naples virus, Sandfly fever Sicilian virus, Sandjimba virus, Sango virus, Santa Rosa virus, Santarem virus, Santosai temperate virus, Sapphire Il virus, Sapporo-like virus, Saraca virus, Sarracenia purpurea virus, SARS virus, satellite virus, Sathuperi virus, Satsuma dwarf virus, Saturnia pavonia virus, Saturnia pyri NPV, Saumarez Reef virus, Sawgrass virus, Sceliodes cordalis NPV, Schefflera ringspot virus, Sciaphila duplex GV, Scirpophaga incertulas NPV, Sciurid herpesvirus, Sciurid herpesvirus 2, Scoliopteryx NbatFix NPV, Scopelodes contracta NPV, Scopelodes venosa NPV, Scopula subpunctaria NPV, Scotogramma trifolii GV, Scotogramma trifolu NPV, Scrophularia mottle virus, SDAV (sialodacryoadenitis virus), sealpox virus, Selenephera lunigera NPV, Selepa celtis GV, Seletar virus, Selidosema suavis NPV, Semidonta biloba NPV, Semiothisa sexmaculata GV, Semliki Forest Virus, Sena Madureira virus, Sendai virus, SENV-D, SENV-H, Seoul virus, Sepik virus, Serra do Navio virus, Serrano golden mosaic virus, Sesame yellow mosaic virus, Sesamia calamistis NPV, Sesamia cretica GV, Sesamia inferens NPV, Sesamia nonagrioides GV, Setora nitens virus, Shallot latent virus, Shamonda virus, Shark River virus, Sheep associated malignant catarrhal fever, Sheep papillomavirus, Sheep pulmonary adenomatosis associated herpesvirus, sheeppox virus, Shiant Islands virus, Shokwe virus, Shope fibroma virus, Shope papilloma virus, Shuni virus, Siamese cobra herpesvirus, Sibine fusca densovirus, Sida golden mosaic virus (SiGMV), Sida golden yellow vein virus (SiGYVV), Sigma virus, Sikte water-borne virus, Silverwater virus, Simbu virus, Simian adenoviruses 1 to 27, Simian agent virus 12, Simian enterovirus 1 to 18, simian foamy virus, Simian hemorrhagic fever virus, simian hepatitis A virus, simian human immunodeficiency virus, simian immunodeficiency virus, simian parainfluenza virus, Simian rotavirus SA1 1 , Simian sarcoma virus, simian T cell lymphotrophic virus, Simian type D virus 1 , Simian vancella herpesvirus, simian virus, simian virus 40, Simplexvirus, Simulium vittatum densovirus, Sin Nombre virus, Sindbis virus, Sinti em's onion latent virus, Sixgun city virus, Skunkpox virus, Smallpox virus, Smelt reovirus, Smerinthus ocellata NPV, Smithiantha virus, Snakehead rhabdovirus, Snowshoe hare virus, Snyder-Theilen feline sarcoma virus, Sobemovirus, Sofyn virus, Soil-borne wheat mosaic virus, Sokoluk virus, Solanum apical leaf curl virus, Solanum nodiflorum mottle virus, Solanurn yellows virus, Soldado virus, Somerville virus 4, Sonchus mottle virus, Sonchus virus, Sonchus yellow net virus, Sorghum chlorotic spot virus, Sorghum mosaic virus, Sorghum virus, Sororoca virus, Soursop yellow blotch virus, SouthAfrican passiflora virus, South American hemorrhagic fever viruses, SouthAfrican passiflora virus, South River virus, Southern bean mosaic virus, Southern potato latent virus, Sowbane mosaic virus, Sowthistle yellow vein virus, Soybean chlorotic mottle virus, Soybean crinkle leaf virus, Soybean dwarf virus, Soybean mosaic virus, SPAr-2317 virus, Sparganothis pettitana NPV, sparrowpox virus, Spartina mottle virus, Spectacled caimanpox virus, SPH 1 14202 virus, Sphenicid herpesvirus 1 , Sphinx ligustri NPV, Spider monkey herpesvirus, Spilarctia subcarnea NPV, Spilonota ocellana NPV, Spilosoma lubricipeda NPV, Spinach latent virus, Spinach temperate virus, Spiroplasma phage 1 , Spiroplasma phage 4, Spiroplasma phage aa, Spiroplasma phage C1 /TS2, Spodoptera exempta cypovirus, Spodoptera exigua virus, Spodoptera frugiperda virus, Spodoptera latifascia virus, Spodoptera littoralis, Spodoptera mauritia virus, Spodoptera ornithogalli virus, Spondweni virus, spring beauty latent virus, Spring viremia of carp virus, Spumavirus (SFV, HFV), Squash leaf curl virus, squash mosaic virus, squirrel fibroma virus, Squirrel monkey herpesvirus, squirrel monkey retrovirus, SR-1 1 virus, Sri Lankan passionfruit mottle virus, Sripur virus, SSV 1 virus group, StAbbs Head virus, St. Louis encephalitis virus, Staphylococcus phage 107, Staphylococcus phage 187, Staphylococcus phage 2848A, Staphylococcus phage 3A, Staphylococcus phage 44A HJD, Staphylococcus phage 77, Staphylococcus phage B1 1 -M15, Staphylococcus phage Twort, Starlingpox virus, Statice virus Y, P, STLV (simian T lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T lymphotropic virus) type III, stomatitis papulosa virus, Stratford virus, Strawberry crinkle virus, Strawberry latent ringspot virus, Strawberry mild yellow edge virus, Strawberry vein banding virus, Streptococcus phage 182, Streptococcus phage 2BV, Streptococcus phage A25, Streptococcus phage 24, Streptococcus phage PE1 , Streptococcus phage VD13, Streptococcus phage fD8, Streptococcus phage CP-1 , Streptococcus phage Cvir, Streptococcus phage H39, Strigid herpesvirus 1 , Striped bass reovirus, Striped Jack nervous, necrosis virus, Stump-tailed macaque virus, submaxillary virus, Subterranean clover mottle virus, Subterranean clover mottle virus satellite, Subterranean clover red leaf virus, Subterranean clover stunt virus,
Sugarcane bacilliform virus, Sugarcane mild mosaic virus, Sugarcane mosaic virus, Sugarcane streak virus, suid alphaherpesvirus 1 , suid herpesvirus 2, Suipoxvirus, Sulfolobus virus 1 , Sunday Canyon virus, Sunflower crinkle virus, Sunflower mosaic virus, Sunflower rugose mosaic virus, Sunflower yellow blotch virus, Sunflower yellow ringspot virus, Sun-hemp mosaic virus, swamp fever virus, Sweet clover necrotic mosaic virus, Sweet potato A virus, Sweet potato chlorotic leafspot virus, Sweet potato feathery mottle virus, Sweet potato internal cork virus, Sweet potato latent virus, Sweet potato mild mottle virus, Sweet potato russet crack virus, Sweet potato vein mosaic virus, Sweet potato yellow dwarf virus, Sweetwater Branch virus, Swine cytomegalovirus, Swine Flu, Swine infertility and respiratory syndrome virus, swinepox virus, Swiss mouse leukemia virus, Sword bean distortion mosaic virus, Synaxis jubararia NPV, Synaxis pallulata NPV, Synetaeris tenuifemur virus, Syngrapha selecta NPV, T4 phage, T7 phage, TAC virus, Tacaiuma virus, Tacaribe complex virus, Tacaribe virus, Tadpole edema virus LT 1 -4, Taggert virus, Tahyna virus, Tai virus, Taiassui virus, Tamana bat virus, Tamarillo mosaic virus, Tamdy virus, Tamiami virus, Tanapox virus, Tanga virus, Tanjong Rabok virus, Taro bacilliform virus, Badnavirus Tataguine virus, Taterapox virus, Taterapox virus, Teasel mosaic virus, Tehran virus, Telfairia mosaic virus, Telok Forest virus, Tembe virus, Tembusu virus, Tench reovirus, Tensaw virus, Tenvivirus, Tephrosia symptomless virus, Termeil virus, Tete virus, Tetralopha scortealis NPV, Tetropium cinnamoptemm NPV, Texas pepper virus,
Thailand virus, Thaumetopoea pityocampa virus, Theiler's encephalomyelitis virus, Theiler's virus, Theophila mandarina NPV, Theretra japonica NPV , Thermoproteus virus 1 , Thermoproteus virus 2, Thermoproteus virus 3, Thermoproteus virus 4, Thiafora virus, Thimiri virus, Thistle mottle virus, Thogoto virus, Thormodseyjarklettur virus, Thosea asigna virus, Thosea baibarana NPV, Thosea sinensis GV,
Thottapalayam virus, Thylidolpteryx ephemeraeformis NPV, Thymelicus lineola NPV, Tibrogargan virus, Ticera castanea NPV, Tick borne encephalitis virus (TBEV) - European and Far Eastern subtypes, Tillamook virus, Tilligerry virus, Timbo virus, Tilmboteua virus, Tilmaroo virus, Tindholmur virus, Tinea pellionella NPV, Tineola hisselliella NPV, Tinpula paludosa NPV, Tinracola plagiata NPV, Tioman virus,
Tlacotalpan virus, Tobacco bushy top virus, Tobacco etch virus, Tobacco leaf curl virus, Tobacco mild green mosaic virus, tobacco mosaic virus, Tobacco mosaic virus satellite, Tobacco mottle virus, Tobacco necrosis virus, Tobacco necrosis virus satellite, Tobacco necrosis virus small satellite, Tobacco necrotic dwarf virus, tobacco rattle virus, Tobacco ringspot virus, Tobacco streak virus, Tobacco stunt virus, Tobacco vein banding mosaic virus, Tobacco vein distorting virus Tobacco vein mottling virus, Tobacco wilt virus, Tobacco yellow dwarf virus, Tobacco yellow net virus, Tobacco yellow vein virus, Tobamovirus Tobravirus, Togavirus, Tomato apical stunt viroid, Tomato aspermy virus, Tomato black ring virus, Tomato black ring virus satellite, Tomato bunchy top viroid, tomato bushy stunt virus, Tomato bushy stunt virus satellite, Tomato golden mosaic virus, Tomato leaf crumple virus, Tomato leaf curl virus, Tomato leafroll virus, Tomato mosaic virus, Tomato mottle virus, Tomato pale chlorosis virus, Tomato planta macho viroid, Tomato pseudo-curly top virus, Tomato ringspot virus, Tomato spotted wilt virus, Tomato top necrosis virus, Tomato vein yellowing virus, Tomato yellow dwarf virus, Tomato yellow leaf curl virus, Tomato yellow mosaic virus, Tomato yellow top virus, Tombusvirus, Tongan vanilla virus, Torovirus, Torque teno virus, Tortrix loeflingiana NPV, Tortrix viridana NPV, Toscana virus, Tospovirus, Toxorhynchites brevipalpis NPV, Trabala vishnou NPV, Tradescantia/Zebrina virus, Trager duck spleen necrosis virus, Tranosema sp. Virus, transforming virus, Tree shrew adenovirus 1 , Tree shrew herpesvims, Triatoma virus, Tribec virus,
Trichiocampus irregularis NPV, Trichiocampus viminalis NPV, Trichomonas vaginalis virus, Trichoplusia ni cypovirus 5, Trichoplusia ni granulovirus, Trichoplusia ni MNPV, Trichoplusia ni Single SNPV, Trichoplusia ni virus, Trichosanthes mottle virus, Triticum aestivum chlorotic spot virus, Trivittatus virus, Trombetas virus, Tropaeolum virus 1 , Tropaeolum virus 2, Trubanarnan virus, Tsuruse virus, Tucunduba virus, Tulare apple mosaic virus, Tulip band breaking virus, Tulip breaking virus, Tulip chlorotic blotch virus, Tulip top breaking virus, Tulip virus X, tumor virus, Tupaia virus, Tupaiid herpesvirus 1 , Turbot herpesvirus, Turbot reovirus, Turkey adenoviruses 1 to 3, Turkey coronavirus, Turkey herpesvirus 1 , turkey rhinotracheitis virus, turkeypox virus, Turlock virus, Turnip crinkle virus, Turnip crinkle virus satellite, Turnip mild yellows virus, Turnip mosaic virus, Turnip rosette virus, turnip yellow mosaic virus, Turuna virus, Tymovirus, Tyuleniy virus, type C retroviruses, type D oncovirus, type D retrovirus group, Uasin Gishu disease virus, Uganda S virus, Ugymyia sericariae NPV, ulcerative disease rhabdovirus, Ullucus mild mottle virus, Ullucus mosaic virus, Ullucus virus C, Umatilla virus, Umbre virus, Una virus, Upolu virus, UR2 sarcoma virus, Uranotaenia sapphirina NPV, Urbanus proteus NPV, Urucuri virus, Ustilago maydis virus 1 , Ustilago maydis virus 4, Ustilago maydis virus 6, Usutu virus, Utinga virus, Utive virus, Uukuniemi virus group, Vaccinia virus, Vaeroy virus, Vallota mosaic virus, Vanessa atalanta NPV, Vanessa cardui NPV, Vanessa prorsa NPV, Vanilla mosaic virus, Vanilla necrosis virus, Varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, Vellore virus, Velvet tobacco mottle virus, Velvet tobacco mottle virus satellite, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, Vesicular stomatitis virus, Vesiculovirus, Vibrio phage 06N-22P, Vibrio phage 06N-58P, Vibrio phage 4996, Vibrio phage a3a, Vibrio phage I, Vibrio phage II, Vibrio phage m, Vibrio phage IV, Vibrio phage kappa, Vibrio phage nt-1 , Vibrio phage OXN-52P, Vibrio phage OXN-IOOP, Vibrio phage v6, Vibrio phage Vfl2, Vibrio phage Vf 33, Vibrio phage VP1 , Vibrio phage VP1 1 , Vibrio phage VP3, Vibrio phage VP5, Vibrio phage X29, Vicia cryptic virus, Vigna sinensis mosaic virus, Vilyuisk virus, Vinces virus, Viola mottle virus, viper retrovirus, viral haemorrhagic septicemia virus, virus-like particle, Visna Maedi virus, Visna virus, Voandzeia mosaic virus, Voandzeia necrotic mosaic virus, volepox virus, Wad Medani virus, WaIIaI virus, Walleye epidermal hyperplasia, Walrus calicivirus, Wanowrie virus, Warrego virus, Watermelon chlorotic stunt virus, Watermelon curly mottle virus, Watermelon mosaic virus 1 , Watermelon mosaic virus 2, Weddel water-borne virus, Weldona virus, Wesselsbron virus, West Nile virus, western equine encephalitis virus, western equine encephalomyelitis virus, Wexford virus, Whataroa virus, Wheat American striate mosaic virus, Wheat chlorotic streak virus, Wheat dwarf virus, Wheat rosette stunt virus, Wheat streak mosaic virus, Wheat yellow leaf virus, Wheat yellow mosaic virus, White bryony virus, White clover cryptic virus 1 , White clover cryptic virus 2, White clover cryptic virus 3, White clover mosaic virus, White lupinrnosaic virus, Wild cucumber mosaic virus, Wild potato mosaic virus, Wildbeest herpesvirus, Wineberry latent virus, Winter wheat mosaic virus, Winter wheat Russian mosaic virus, Wiseana cervinata virus, Wiseana signata virus, Wiseana umbraculata virus, Wissadula mosaic virus, Wisteria vein mosaic virus, Witwatersrand virus, Wongal virus, Wongorr virus, Winter Vomiting Virus, woodchuck hepatitis B virus, Woodchuck herpesvirus marmota 1 , woolly monkey sarcoma virus, wound tumor virus, WRSV virus, WVU virus 2937, WW virus 71 to 212, Wyeomyia smithii NPV, Wyeomyia virus, Xanthomonas phage Cf, Xanthomonas phage CfIt, Xanthomonas phage RR66, Xanthomonas phage Xf, Xanthomonas phage Xf2, Xanthomonas phage XP5, Xenopus virus T21 , Xiburema virus, Xingu virus, Xylena curvimacula NPV, Y73 sarcoma virus, Yaba monkey tumor virus, Yaba-1 virus, Yaba-7 virus, Yacaaba virus, Yam mosaic virus, Yaounde virus, Yaquina Head virus, Yatapoxvirus, Yellow fever virus, Yogue virus, Yokapox virus, Yokase virus, Yponomeuta cognatella NPV, Yponomeuta evonymella NPV, Yponomeuta malinellus NPV, Yponomeuta padella NPV, Yucca baciliform virus, Yug Bogdanovac virus, ZaNv Terpeniya virus, Zea mays virus, Zegla virus, Zeiraphera diniana virus, Zeiraphera pseudotsugana NPV, Zika virus, Zirqa virus, Zoysia mosaic virus, Zucchini yellow fleck virus, Zucchini yellow mosaic virus and Zygocactus virus. 1341. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases caused by a bacterial infection.
1342. The method for vaccination according to item 1341 , wherein bacterial infection is caused by one or more bacteria selected from the group consisting of Acidobacteria,
Actinobacteria, Aquificae, Bacteroidetes, Chlamydiae, Chlorobi, Chloroflexi, Chrysiogenetes, Cyanobacteria, Deferribacteres, Deinococcus-Thermus, Dictyoglomi, Fibrobacteres, Firmicutes, Fusobacteria, Gemmatimonadetes, Nitrospirae, Planctomycetes, Proteobacteria, Spirochaetes, Thermodesulfobacteria, Thermomicrobia, Thermotogae and Verrucomicrobia bacterial phyla; these may be Gram negative (Spirochetal, Chlamydiae, Proteobacteria α, β, y) and Gram positive bacteria (Firmicutes, Actinobacteria (Mycobacterium, Actinomycetales)).
1343. The method for vaccination according to item 1341 , wherein bacterial infection is caused by one or more bacteria selected from the group consisting of Acetobacter aurantius, Acinetobacter species, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter Iwoffii, Acinetobacter radioresistens, Acinetobacter septicus, Acinetobacter schindleri, Acinetobacter ursingii; Actinomyces species: Actinomyces bovis, Actinomyces bowdenii, Actinomyces canis, Actinomyces cardiffensis, Actinomyces catuli,
Actinomyces coleocanis, Actinomyces dentalis, Actinomyces denticolens, Actinomyces europaeus, Actinomyces funkei, Actinomyces georgiae, Actinomyces gerencseriae, Actinomyces graevenitzii, Actinomyces hongkongensis, Actinomyces hordeovulneris, Actinomyces howellii, Actinomyces humiferus, Actinomyces hyovaginalis, Actinomyces israelii, Actinomyces marimammalium, Actinomyces meyeri, Actinomyces naeslundii, Actinomyces nasicola, Actinomyces neuii, Actinomyces odontolyticus, Actinomyces oricola, Actinomyces radicidentis, Actinomyces radingae, Actinomyces slackii, Actinomyces streptomycini, Actinomyces suimastitidis, Actinomyces suis, Actinomyces turicensis, Actinomyces urogenitalis, Actinomyces vaccimaxillae, Actinomyces viscosus; Actinobacillus species: Actinobacillus actinomycetemcomitans, Actinobacillus arthritidis, Actinobacillus capsulatus, Actinobacillus delphinicola, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus indolicus, Actinobacillus lignieresii, Actinobacillus minor, Actinobacillus muris, Actinobacillus pleuropneumoniae, Actinobacillus porcinus, Actinobacillus rossii, Actinobacillus scotiae, Actinobacillus seminis, Actinobacillus succinogenes, Actinobacillus suis, Actinobacillus ureae; Aeromonas species: Aeromonas allosaccharophila, Aeromonas bestiarum, Aeromonas bivalvium, Aeromonas encheleia, Aeromonas enteropelogenes, Aeromonas euchrenophila, Aeromonas hydrophila, Aeromonas ichthiosmia, Aeromonas jandaei, Aeromonas media, Aeromonas molluscorum, Aeromonas popoffii, Aeromonas punctata, Aeromonas salmonicida, Aeromonas schubertii, Aeromonas sharmana, Aeromonas simiae, Aeromonas sobria, Aeromonas veronii; Afipia felis, Agrobacterium species, Agrobacterium radiobacter, Agrobacterium rhizogenes, Agrobacterium rubi, Agrobacterium tumefaciens; Agromonas species, Alcaligenes species: Alcaligenes aquatilis, Alcaligenes eutrophus, Alcaligenes faecalis, Alcaligenes latus, Alcaligenes xylosoxidans; Alishewanella species, Alterococcus species, Anaplasma phagocytophilum, Anaplasma marginale, Aquamonas species, Arcanobacterium haemolyticum, Aranicola species, Arsenophonus species, Azotivirga species, Azotobacter vinelandii, Azotobacter chroococcum, Bacillary dysentery (Shigellosis), Bacillus species: Bacillus abortus (Brucella melitensis biovar abortus), Bacillus anthracis (Anthrax), Bacillus brevis, Bacillus cereus, Bacillus coagulans, Bacillus fusiformis, Bacillus globigii, Bacillus licheniformis, Bacillus megaterium, Bacillus mycoides, Bacillus natto, Bacillus stearothermophilus, Bacillus subtilis, Bacillus sphaericus, Bacillus thuringiensis; Bacteroides species: Bacteroides forsythus (Tannerella forsythensis), Bacteroides acidifaciens, Bacteroides distasonis (reclassified as Parabacteroides distasonis), Bacteroides gingivalis, Bacteroides gracilis,
Bacteroides fragilis, Bacteroides oris, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides stercoris, Bacteroides suis, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides vulgatus; Bartonella species: Bartonella alsatica, Bartonella bacilliformis, Bartonella birtlesii, Bartonella bovis, Bartonella capreoli, Bartonella clarridgeiae, Bartonella doshiae, Bartonella elizabethae, Bartonella grahamii, Bartonella henselae (cat scratch fever), Bartonella koehlerae, Bartonella muris, Bartonella peromysci, Bartonella quintana, Bartonella rochalimae, Bartonella schoenbuchii, Bartonella talpae, Bartonella taylorii, Bartonella tribocorum, Bartonella vinsonii spp. Arupensis, Bartonella vinsonii spp. Berkhoffii, Bartonella vinsonii spp. Vinsonii, Bartonella washoensis; BCG (Bacille Calmette-Guerin), Bergeyella zoohelcum (Weeksella zoohelcum), Bifidobacterium bifidum, Blastobacter species, Blochmannia species, Bordetella species: 'Bordetella ansorpii', Bordetella avium, Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmesii, Bordetella parapertussis, Bordetella pertussis (Whooping cough), Bordetella petrii, Bordetella trematum; Borrelia species: Borrelia anserine, Borrelia barbouri, Borrelia burgdorferi such as burgdorferi B31 , Borrelia afzelii such as Borrelia afzelii ACA-1 , Borrelia afzelii K78 and/or Borrelia afzelii PKo, Borrelia andersonii, Borrelia anserine, Borrelia bissettii, Borrelia burgdorferi 1 18a, Borrelia burgdorferi 156a, Borrelia burgdorferi 29805, Borrelia burgdorferi 64b, Borrelia burgdorferi 72a, Borrelia burgdorferi 80a, Borrelia burgdorferi 94a, Borrelia burgdorferi B31 , Borrelia burgdorferi Bol26, Borrelia burgdorferi CA-1 1.2a, Borrelia burgdorferi WI91 -23, Borrelia burgdorferi ZS7, Borrelia californiensis, Borrelia garini such as garini PBi, garini PBr, Borrelia genomosp. 1 , Borrelia genomosp. 2, Borrelia japonica, Borrelia lusitaniae, Borrelia spielmanii, Borrelia spielmanii A14S, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia valaisiana VS1 16, Candidatus Borrelia texasensis, Borrelia sp. AA4Pool, Borrelia sp. AI-1 , Borrelia sp. B31 , Borrelia sp. BC-1 , Borrelia sp. CA1 133, Borrelia sp. CA1 176, Borrelia sp. CA128, Borrelia sp. CA13, Borrelia sp. CA134, Borrelia sp. CA142, Borrelia sp. CA20, Borrelia sp. CA22, Borrelia sp. CA27, Borrelia sp. CA28, Borrelia sp. CA29, Borrelia sp. CA31 , Borrelia sp. CA33, Borrelia sp. CA370, Borrelia sp. CA372, Borrelia sp. CA378, Borrelia sp. CA388, Borrelia sp. CA393, Borrelia sp. CA394, Borrelia sp. CA395, Borrelia sp. CA399, Borrelia sp. CA400, Borrelia sp. CA401 , Borrelia sp. CA402, Borrelia sp. CA404, Borrelia sp. CA41 1 , Borrelia sp. CA426, Borrelia sp. CA443, Borrelia sp. CA446, Borrelia sp. CA448, Borrelia sp. CA462, Borrelia sp. CA468, Borrelia sp. CA502, Borrelia sp. CA504, Borrelia sp. CA507, Borrelia sp. CA547, Borrelia sp. CA552, Borrelia sp. CA8, Borrelia sp. D22, Borrelia sp. D35, Borrelia sp. FD-1 , Borrelia sp. FL18, Borrelia sp. FL27, Borrelia sp. FL35, Borrelia sp. FL42., Borrelia sp. HN6, Borrelia sp. HN7, Borrelia sp. HN8, Borrelia sp. HNM13, Borrelia sp. HNM14, Borrelia sp. HNM19, Borrelia sp. IA1 , Borrelia sp. lr-3519, Borrelia sp. lr-4721 , Borrelia sp. lr-4812, Borrelia sp. lr-5215, Borrelia sp. LV5, Borrelia sp. Ml- 2, Borrelia sp. MI-5, Borrelia sp. MI-6, Borrelia sp. MI-8, Borrelia sp. MI-9, Borrelia sp. MOD-1 , Borrelia sp. MOD-5, Borrelia sp. MOK-3a, Borrelia sp. MOS-I b, Borrelia sp. NE49, Borrelia sp. NE581 , Borrelia sp. PHaP, Borrelia sp. PSigll, Borrelia sp. SCGT- 10, Borrelia sp. SCGT-8a, Borrelia sp. SCI-2, Borrelia sp. SCW-30h, Borrelia sp. SI-1 , Borrelia sp. SI-10, Borrelia sp. SM-1 , Borrelia sp. SV1 , Borrelia sp. W97F51 , Borrelia sp. Z41293, Borrelia sp. Z41493, Borrelia coriaceae, Borrelia crocidurae, Borrelia duttonii, Borrelia duttonii Ly, Borrelia hermsii, Borrelia hermsii DAH, Borrelia hispanica, Borrelia Ionestari, Borrelia miyamotoi, Borrelia parkeri, Borrelia persica, Borrelia recurrentis, Borrelia recurrentis A1 , Borrelia sinica, Borrelia theileri, Borrelia turcica, Borrelia turicatae, Borrelia turicatae 91 E135, Borrelia sp., Borrelia sp. 'Lake Gaillard', Borrelia sp. 000133, Borrelia sp. 010298, Borrelia sp. 10MT, Borrelia sp. 5145, Borrelia sp. 57Nsk, Borrelia sp. 5MT, Borrelia sp. 6T04-2, Borrelia sp. BR, Borrelia sp. BR 2007, Borrelia sp. C5-N52, Borrelia sp. CB-A1 , Borrelia sp. CB-A1 1 , Borrelia sp. CB- A3, Borrelia sp. EFL-S01001 10, Borrelia sp. IK/23, Borrelia sp. IM/16, Borrelia sp. IM/19, Borrelia sp. KR1 , Borrelia sp. KR3, Borrelia sp. LB-2001 , Borrelia sp. LB-M56, Borrelia sp. LB-W100, Borrelia sp. MK-N61 , Borrelia sp. NR-N8, Borrelia sp. OkMEI , Borrelia sp. PAnz, Borrelia sp. PJes, Borrelia sp. PMai, Borrelia sp. PMew, Borrelia sp. R57, Borrelia sp. strain Spain, Borrelia sp. TA1 , Borrelia sp. TM, Borrelia sp. TM1 and Borrelia sp. TM2; Bosea species, Bradyrhizobium species, Brenneria species, Brucella species: Brucella abortus, Brucella canis, Brucella melitensis, Brucella neotomae, Brucella ovis, Brucella suis, Brucella pinnipediae; Buchnera species, Budvicia species, Burkholderia species: Burkholderia cepacia (Pseudomonas cepacia), Burkholderia mallei (Pseudomonas mallei/ Actinobacillus mallei), Burkholderia pseudomallei (Pseudomonas pseudomallei); Buttiauxella species, Calymmatobacterium granulomatis, Campylobacter species: Campylobacter coli, Campylobacter concisus, Campylobacter curvus, Campylobacter fetus, Campylobacter gracilis, Campylobacter helveticus, Campylobacter hominis, Campylobacter hyointestinalis, Campylobacter insulaenigrae, Campylobacter jejuni, Campylobacter lanienae, Campylobacter lari, Campylobacter mucosalis, Campylobacter rectus, Campylobacter showae, Campylobacter sputorum, Campylobacter upsaliensis; Capnocytophaga canimorsus (Dysgonic fermenter type 2), Corynebacterium species, Cardiobacterium hominis, Cedecea species, Chlamydia species: Chlamydia trachomatis (Lymphogranuloma venereum), Chlamydia muridarum, Chlamydia suis; Chlamydophila species: Chlamydophila pneumoniae, Chlamydophila psittaci (Psittacosis), Chlamydophila pecorum, Chlamydophila abortus, Chlamydophila felis, Chlamydophila caviae; Citrobacter species: Citrobacter amalonaticus, Citrobacter braakii, Citrobacter farmeri, Citrobacter freundii, Citrobacter gillenii, Citrobacter intermedius, Citrobacter koseri aka Citrobacter diversus, Citrobacter murliniae, Citrobacter rodentium, Citrobacter sedlakii, Citrobacter werkmanii, Citrobacter youngae; Clostridium species: Clostridium botulinum, Clostridium difficile, Clostridium novyi, Clostridium septicum, Clostridium tetani (Tetanus), Clostridium welchii (Clostridium perfringens); Corynebacterium species: Corynebacterium diphtheriae (Diphtheria), Corynebacterium amycolatum, Corynebacterium aquaticum, Corynebacterium bovis, Corynebacterium equi, Corynebacterium flavescens, Corynebacterium glutamicum, Corynebacterium haemolyticum, Corynebacterium jeikeiun (corynebacteria of group JK), Corynebacterium minutissimum (Erythrasma), Corynebacterium parvum (also called Propionibacterium acnes), Corynebacterium pseudodiptheriticum (also called Corynebacterium hofmannii), Corynebacterium pseudotuberculosis (also called Corynebacterium ovis), Corynebacterium pyogenes, Corynebacterium urealyticum (corynebacteria of group D2), Corynebacterium renale, Corynebacterium striatum, Corynebacterium tenuis (Trichomycosis palmellina, Trichomycosis axillaris),
Corynebacterium ulcerans, Corynebacterium xerosis; Coxiella burnetii (Q fever), Cronobacter species: Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter turicensis, Cronobacter muytjensii, Cronobacter dublinensis; Delftia acidovorans (Comamonas acidovorans), Dickeya species, Edwardsiella species, Eikenella corrodens, Enterobacter species: Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii; Enterococcus species: Enterococcus avium, Enterococcus durans, Enterococcus faecalis (Streptococcus faecalis/ Streptococcus Group D), Enterococcus faecium, Enterococcus solitarius, Enterococcus galllinarum, Enterococcus maloratus; Ehrlichia chaffeensis, Erysipelothrix rhusiopathiae, Erwinia species, Escherichia species: Escherichia adecarboxylata, Escherichia albertii,
Escherichia blattae, Escherichia coli, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris; Ewingella species, Flavobacterium species: Flavobacterium aquatile, Flavobacterium branchiophilum, Flavobacterium columnare, Flavobacterium flevense, Flavobacterium gondwanense, Flavobacterium hydatis, Flavobacterium johnsoniae, Flavobacterium pectinovorum, Flavobacterium psychrophilum, Flavobacterium saccharophilum, Flavobacterium salegens, Flavobacterium scophthalmum, Flavobacterium succinans; Francisella tularensis (Tularaemia), Francisella novicida, Francisella philomiragia, Fusobacterium species: Fusobacterium necrophorum (Lemierre syndrome/ Sphaerophorus necrophorus), Fusobacterium nucleatum, Fusobacterium polymorphum, Fusobacterium novum, Fusobacterium mortiferum, Fusobacterium varium; Gardnerella vaginalis, Gemella haemolysans, Gemella morbillorum (Streptococcus morbillorum), Grimontella species, Haemophilus species: Haemophilus aegyptius (Koch-Weeks bacillus), Haemophilus aphrophilus, Haemophilus avium, Haemophilus ducreyi (Chancroid), Haemophilus felis, Haemophilus haemolyticus, Haemophilus influenzae (Pfeiffer bacillus), Haemophilus paracuniculus, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Haemophilus paraphrophilus (Aggregatibacter aphrophilus), Haemophilus pertussis, Haemophilus pittmaniae, Haemophilus somnus, Haemophilus vaginalis; Hafnia species, Hafnia alvei, Helicobacter species: Helicobacter acinonychis, Helicobacter anseris, Helicobacter aurati, Helicobacter bilis, Helicobacter bizzozeronii, Helicobacter brantae, Helicobacter Canadensis, Helicobacter canis, Helicobacter cholecystus, Helicobacter cinaedi, Helicobacter cynogastricus, Helicobacter felis, Helicobacter fennelliae, Helicobacter ganmani, Helicobacter heilmannii (Gastrospirillum hominis), Helicobacter hepaticus, Helicobacter mesocricetorum, Helicobacter marmotae, Helicobacter muridarum, Helicobacter mustelae, Helicobacter pametensis,
Helicobacter pullorum, Helicobacter pylori (stomach ulcer), Helicobacter rappini, Helicobacter rodentium, Helicobacter salomonis, Helicobacter trogontum, Helicobacter typhlonius, Helicobacter winghamensis; Human granulocytic ehrlichiosis (Anaplasma phagocytophilum/ Ehrlichia phagocytophila), Human monocytotropic ehrlichiosis (Monocytic ehrlichiosis/ Ehrlichia chaffeensis), Klebsiella species: Klebsiella granulomatis (Calymmatobacterium granulomatis), Klebsiella mobilis, Klebsiella ornithinolytica, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella planticola, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Klebsiella singaporensis, Klebsiella terrigena, Klebsiella trevisanii, Klebsiella variicola; Kingella kingae, Kluyvera species, Lactobacillus species: Lactobacillus acetotolerans, Lactobacillus acidifarinae,
Lactobacillus acidipiscis, Lactobacillus acidophilus (Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus, Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillus amylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus, Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi, Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillus brevis, Lactobacillus buchneri,
Lactobacillus camelliae, Lactobacillus casei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacillus coleohominis, Lactobacillus collinoides, Lactobacillus composti, Lactobacillus concavus, Lactobacillus coryniformis, Lactobacillus crispatus, Lactobacillus crustorum, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans, Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillus farraginis, Lactobacillus farciminis, Lactobacillus fermentum, Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillus frumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis, Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri, Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillus helveticus, Lactobacillus hilgardii, Lactobacillus homohiochii, Lactobacillus iners, Lactobacillus ingluviei, Lactobacillus intestinalis, Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacillus kefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacillus kunkeei, Lactobacillus leichmannii, Lactobacillus lindneri, Lactobacillus malefermentans, Lactobacillus mali, Lactobacillus manihotivorans, Lactobacillus mindensis, Lactobacillus mucosae, Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis, Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillus oris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillus parabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides, Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillus paralimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae, Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus sanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus, Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri, Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillus ultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis, Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillus vitulinus, Lactobacillus zeae, Lactobacillus zymae; Leclercia species, Legionella species: Legionella adelaidensis, Legionella anisa, Legionella beliardensis, Legionella birminghamensis, Legionella bozemanii, Legionella brunensis, Legionella busanensis, Legionella cherrii, Legionella cincinnatiensis, Legionella donaldsonii, Legionella drancourtii, Legionella drozanskii, Legionella erythra, Legionella fairfieldensis,
Legionella fallonii, Legionella feeleii, Legionella geestiana, Legionella genomospecies, Legionella gratiana, Legionella gresilensis, Legionella hackeliae, Legionella impletisoli, Legionella israelensis, Legionella jamestowniensis, 'Candidatus Legionella jeonii', Legionella jordanis, Legionella lansingensis, Legionella Iondiniensis, Legionella longbeachae, Legionella lytica, Legionella maceachernii, Legionella micdadei, Legionella moravica, Legionella nautarum, Legionella oakridgensis, Legionella parisiensis, Legionella pneumophila, Legionella quateirensis, Legionella quinlivanii, Legionella rowbothamii, Legionella rubrilucens, Legionella sainthelensi, Legionella santicrucis, Legionella shakespearei, Legionella spiritensis, Legionella steigerwaltii, Legionella taurinensis, Legionella tucsonensis, Legionella wadsworthii, Legionella waltersii, Legionella worsleiensis, Legionella yabuuchiae; Leminorella species, Leptospira species: Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira alexanderi, Leptospira weilii, Leptospira genomospecies 1 , Leptospira borgpetersenii, Leptospira santarosai, Leptospira inadai, Leptospira fainei, Leptospira broomii, Leptospira licerasiae, Leptospira biflexa, Leptospira meyeri, Leptospira wolbachii, Leptospira genomospecies 3, Leptospira genomospecies 4, Leptospira genomospecies 5; Lepromatous leprosy (Danielssen-Boeck disease), Leptospira canicola, Leptospira hebdomadis, Leptospirosis (Weil disease/ Leptospira icterohaemorrhagiae/ Leptospira interrogans serovar icterohaemorrhagiae), Leptotrichia, Leuconostoc species: Leuconostoc carnosum, Leuconostoc citreum, Leuconostoc durionis, Leuconostoc fallax, Leuconostoc ficulneum, Leuconostoc fructosum, Leuconostoc garlicum, Leuconostoc gasicomitatum, Leuconostoc gelidum, Leuconostoc inhae, Leuconostoc kimchii, Leuconostoc lactis, Leuconostoc mesenteroides, Leuconostoc pseudoficulneum, Leuconostoc pseudomesenteroides; Listeria species: Listeria grayi, Listeria innocua, Listeria ivanovii, Listeria monocytogenes (Listeriosis), Listeria seeligeri, Listeria welshimeri; Methanobacterium extroquens, Microbacterium multiforme, Micrococcus species: Micrococcus antarcticus, Micrococcus flavus, Micrococcus luteus, Micrococcus lylae, Micrococcus mucilaginosis, Micrococcus roseus, Micrococcus sedentarius; Mobiluncus, Moellerella species, Morganella species, Moraxella species: Moraxella atlantae, Moraxella boevrei, Moraxella bovis, Moraxella canis, Moraxella caprae, Moraxella catarrhalis (Branhamella catarrhalis), Moraxella caviae, Moraxella cuniculi, Moraxella equi, Moraxella lacunata, Moraxella lincolnii, Moraxella nonliquefaciens, Moraxella oblonga, Moraxella osloensis, Moraxella saccharolytica; Morganella morganii, Mycobacterium species: Mycobacterium abscessus, Mycobacterium africanum, Mycobacterium agri, Mycobacterium aichiense, Mycobacterium alvei, Mycobacterium arupense, Mycobacterium asiaticum, Mycobacterium aubagnense, Mycobacterium aurum, Mycobacterium austroafricanum, Mycobacterium avium (Battey disease/ Lady Windermere syndrome), Mycobacterium avium paratuberculosis (implicated in Crohn's disease in humans and Johne's disease in sheep), Mycobacterium avium silvaticum, Mycobacterium avium "hominissuis", Mycobacterium colombiense, Mycobacterium boenickei, Mycobacterium bohemicum, Mycobacterium bolletii, Mycobacterium botniense, Mycobacterium bovis (Bovine tuberculosis), Mycobacterium branderi, Mycobacterium brisbanense, Mycobacterium brumae, Mycobacterium canariasense, Mycobacterium caprae, Mycobacterium celatum, Mycobacterium chelonae,
Mycobacterium chimaera, Mycobacterium chitae, Mycobacterium chlorophenolicum, Mycobacterium chubuense, Mycobacterium conceptionense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium cosmeticum, Mycobacterium diernhoferi, Mycobacterium doricum, Mycobacterium duvalii, Mycobacterium elephantis, Mycobacterium fallax, Mycobacterium farcinogenes, Mycobacterium flavescens, Mycobacterium florentinum, Mycobacterium fluoroanthenivorans, Mycobacterium fortuitum, Mycobacterium fortuitum subsp. Acetamidolyticum, Mycobacterium frederiksbergense, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gilvum, Mycobacterium goodii, Mycobacterium gordonae (Mycobacterium aquae), Mycobacterium haemophilum, Mycobacterium hassiacum, Mycobacterium heckeshornense, Mycobacterium heidelbergense, Mycobacterium hiberniae, Mycobacterium hodleri, Mycobacterium holsaticum, Mycobacterium houstonense, Mycobacterium immunogenum, Mycobacterium interjectum, Mycobacterium intermedium, Mycobacterium intracellular, Mycobacterium kansasii, Mycobacterium komossense, Mycobacterium kubicae, Mycobacterium kumamotonense, Mycobacterium lacus, Mycobacterium lentiflavum, Mycobacterium leprae (causes leprosy or Hansen disease/ Hanseniasis), Mycobacterium lepraemurium, Mycobacterium madagascariense, Mycobacterium mageritense, Mycobacterium malmoense, Mycobacterium marinum (Fish tank granuloma), Mycobacterium massiliense, Mycobacterium microti, Mycobacterium monacense, Mycobacterium montefiorense, Mycobacterium moriokaense, Mycobacterium mucogenicum, Mycobacterium murale, Mycobacterium nebraskense, Mycobacterium neoaurum, Mycobacterium neworleansense, Mycobacterium nonchromogenicum, Mycobacterium novocastrense, Mycobacterium obuense, Mycobacterium palustre, Mycobacterium parafortuitum, Mycobacterium parascrofulaceum, Mycobacterium parmense, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium phocaicum, Mycobacterium pinnipedii, Mycobacterium porcinum, Mycobacterium poriferae, Mycobacterium pseudoshottsii, Mycobacterium pulveris, Mycobacterium psychrotolerans, Mycobacterium pyrenivorans, Mycobacterium rhodesiae,
Mycobacterium saskatchewanense, Mycobacterium scrofulaceum, Mycobacterium senegalense, Mycobacterium seoulense, Mycobacterium septicum, Mycobacterium shimoidei, Mycobacterium shottsii, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium sphagni, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistibile, Mycobacterium tokaiense, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tuberculosis (major cause of human tuberculosis), Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii', Mycobacterium tusciae, Mycobacterium ulcerans (causes Bairnsdale ulcer/ Buruli ulcer), Mycobacterium vaccae, Mycobacterium vanbaalenii, Mycobacterium wolinskyi, Mycobacterium xenopi; Mycoplasma species: Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma penetrans, Mycoplasma phocacerebrale, Mycoplasma pneumoniae, Nanukayami (Seven-day fever/ Gikiyami), Neisseria species: Neisseria gonorrhoea (Gonococcus/ Gonorrhea), Neisseria meningiditis (Meningococcus), Neisseria sicca, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria polysaccharea, Neisseria subflava; Nitrobacter species, Nocardia species: Nocardia asteroides, Nocardia brasiliensis, Nocardia caviae; Noma (cancrum oris/ gangrenous stomatitis), Obesumbacterium, Oligotropha species, Orientia tsutsugamushi (Scrub typhus), Oxalobacter formigenes, Pantoea species: Pantoea agglomerans, Pantoea ananatis, Pantoea citrea, Pantoea dispersa, Pantoea punctata, Pantoea stewartii, Pantoea terrea; Pasteurella species: Pasteurella aerogenes, Pasteurella anatis, Pasteurella avium, Pasteurella bettyae, Pasteurella caballi, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallicida, Pasteurella gallinarum, Pasteurella granulomatis, Pasteurella langaaensis, Pasteurella lymphangitidis, Pasteurella mairii, Pasteurella multocida, Pasteurella pneumotropica,
Pasteurella skyensis, Pasteurella stomatis, Pasteurella testudinis, Pasteurella trehalosi, Pasteurella tularensis, Pasteurella ureae, Pasteurella volantium; Pediococcus species: Pediococcus acidilactici, Pediococcus cellicola, Pediococcus claussenii, Pediococcus damnosus, Pediococcus dextrinicus, Pediococcus ethanolidurans, Pediococcus inopinatus, Pediococcus parvulus, Pediococcus pentosaceus, Pediococcus stilesii; Peptostreptococcus species: Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus harei, Peptostreptococcus hydrogenalis, Peptostreptococcus indoliticus, Peptostreptococcus ivorii, Peptostreptococcus lacrimalis, Peptostreptococcus lactolyticus, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus octavius, Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis; Photorhabdus species, Photorhizobium species, Plesiomonas shigelloides, Porphyromonas gingivalis, Pragia species, Prevotella, Propionibacterium species: Propionibacterium acnes, Propionibacterium propionicus; Proteus species: Proteus mirabilis, Proteus morganii, Proteus penneri, Proteus rettgeri, Proteus vulgaris; Providencia species: Providencia friedericiana, Providencia stuartii; Pseudomonas species: Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas anguilliseptica, Pseudomonas argentinensis, Pseudomonas borbori, Pseudomonas citronellolis, Pseudomonas flavescens, Pseudomonas mendocina, Pseudomonas nitroreducens, Pseudomonas oleovorans, Pseudomonas pseudoalcaligenes, Pseudomonas resinovorans, Pseudomonas straminea, Pseudomonas aurantiaca, Pseudomonas aureofaciens, Pseudomonas chlororaphis, Pseudomonas tragi, Pseudomonas lundensis, Pseudomonas taetrolens, Pseudomonas Antarctica, Pseudomonas azotoformans, Pseudomonas brassicacearum, Pseudomonas brenneri, Pseudomonas cedrina, Pseudomonas corrugate, Pseudomonas fluorescens, Pseudomonas gessardii, Pseudomonas libanensis, Pseudomonas mandelii, Pseudomonas marginalis, Pseudomonas mediterranea, Pseudomonas meridiana, Pseudomonas migulae, Pseudomonas mucidolens, Pseudomonas orientalis, Pseudomonas panacis, Pseudomonas proteolytica, Pseudomonas rhodesiae, Pseudomonas synxantha, Pseudomonas thivervalensis, Pseudomonas tolaasii, Pseudomonas veronii, Pseudomonas denitrificans, Pseudomonas pertucinogena, Pseudomonas cremoricolorata, Pseudomonas fulva, Pseudomonas monteilii, Pseudomonas mosselii, Pseudomonas oryzihabitans, Pseudomonas parafulva, Pseudomonas plecoglossicida, Pseudomonas putida, Pseudomonas balearica, Pseudomonas luteola, Pseudomonas stutzeri, Pseudomonas amygdale, Pseudomonas avellanae, Pseudomonas caricapapayae, Pseudomonas cichorii, Pseudomonas coronafaciens, Pseudomonas ficuserectae, Pseudomonas meliae, Pseudomonas savastanoi, Pseudomonas syringae, Pseudomonas viridiflava, Pseudomonas abietaniphila, Pseudomonas acidophila, Pseudomonas agarici, Pseudomonas alcaliphila, Pseudomonas alkanolytica, Pseudomonas amyloderamosa, Pseudomonas asplenii, Pseudomonas azotifigens, Pseudomonas cannabina, Pseudomonas coenobios, Pseudomonas congelans, Pseudomonas costantinii, Pseudomonas cruciviae, Pseudomonas delhiensis, Pseudomonas excibis, Pseudomonas extremorientalis, Pseudomonas frederiksbergensis, Pseudomonas fuscovaginae, Pseudomonas gelidicola, Pseudomonas grimontii, Pseudomonas indica, Pseudomonas jessenii, Pseudomonas jinjuensis, Pseudomonas kilonensis, Pseudomonas knackmussii, Pseudomonas koreensis, Pseudomonas lini, Pseudomonas lutea, Pseudomonas moraviensis, Pseudomonas otitidis, Pseudomonas pachastrellae, Pseudomonas palleroniana, Pseudomonas papaveris, Pseudomonas peli, Pseudomonas perolens, Pseudomonas poae, Pseudomonas pohangensis, Pseudomonas psychrophila, Pseudomonas psychrotolerans, Pseudomonas rathonis, Pseudomonas reptilivora, Pseudomonas resiniphila, Pseudomonas rhizosphaerae, Pseudomonas rubescens, Pseudomonas salomonii, Pseudomonas segitis, Pseudomonas septica, Pseudomonas simiae, Pseudomonas suis, Pseudomonas thermotolerans, Pseudomonas tremae, Pseudomonas trivialis, Pseudomonas turbinellae, Pseudomonas tuticorinensis, Pseudomonas umsongensis, Pseudomonas vancouverensis, Pseudomonas vranovensis, Pseudomonas xanthomarina; Rahnella species, Ralstonia species: Ralstonia basilensis, Ralstonia campinensis, Ralstonia eutropha, Ralstonia gilardii, Ralstonia insidiosa, Ralstonia mannitolilytica, Ralstonia metallidurans, Ralstonia paucula, Ralstonia pickettii, Ralstonia respiraculi, Ralstonia solanacearum, Ralstonia syzygii, Ralstonia taiwanensis; Raoultella species, Rhodoblastus species, Rhodopseudomonas species, Rhinoscleroma, Rhizobium radiobacter, Rhodococcus equi, Rickettsia species: Rickettsia africae, Rickettsia akari, Rickettsia australis, Rickettsia conorii, Rickettsia felis, Rickettsia japonica, Rickettsia mooseri, Rickettsia prowazekii (Typhus fever), Rickettsia rickettsii, Rickettsia siberica, Rickettsia typhi,
Rickettsia conorii, Rickettsia africae, Rickettsia psittaci, Rickettsia quintana, Rickettsia rickettsii, Rickettsia trachomae; Rothia dentocariosa, Salmonella species: Salmonella arizonae, Salmonella Bongori, Salmonella enterica, Salmonella enteriditis, Salmonella paratyphi, Salmonella typhi (Typhoid fever), Salmonella typhimurium, Salmonella salamae, Salmonella arizonae, Salmonella diarizonae, Salmonella houtenae,
Salmonella indica; Samsonia species, Serratia species: Serratia entomophila, Serratia ficaria, Serratia fonticola, Serratia grimesii, Serratia liquefaciens, Serratia marcescens, Serratia odoriferae, Serratia plymuthica, Serratia proteamaculans, Serratia quinivorans, Serratia rubidaea, Serratia ureilytica; Shewanella putrefaciens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Sodalis species, Spirillum species: Spirillum minus rat bite fever, Staphylococcus species: Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus felis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus saprophyticus, Staphylococcus schleiferi, Staphylococcus simulans, Staphylococcus vitulus, Staphylococcus warneri, Staphylococcus xylosus; Stenotrophomonas species: Stenotrophomonas acidaminiphila, Stenotrophomonas dokdonensis, Stenotrophomonas koreensis, Stenotrophomonas maltophilia, Stenotrophomonas nitritireducens, Stenotrophomonas rhizophila; Streptobacillus species: Streptobacillus moniliformis (Streptobacillary rat bite fever); Streptococcus species: Streptococcus Group A, Streptococcus Group B, Streptococcus agalactiae, Streptococcus aginosus, Streptococcus avium, Streptococcus bovis, Streptococcus canis, Streptococcus cricetus, Streptococcus faceium, Streptococcus faecalis, Streptococcus ferus, Streptococcus gallinarum, Streptococcus lactis, Streptococcus milleri, Streptococcus mitior, Streptococcus mitis, Streptococcus mutans, Streptococcus oralis, Streptococcus peroris, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus ratti, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus sobrinus, Streptococcus parasanguinis, Streptococcus suis, Streptococcus thermophilus, Streptococcus vestibularis, Streptococcus viridans, Streptococcus uberis,
Streptococcus zooepidemicus; Tatumella species, Trabulsiella species, Treponema species: Treponema carateum (Pinta), Treponema denticola, Treponema endemicum (Bejel), Treponema pallidum (Syphilis), Treponema pertenue (Yaws); Tropheryma whipplei (Whipple disease), Tuberculoid leprosy, Ureaplasma urealyticum, Veillonella, Vibrio species: Vibrio aerogenes, Vibrio aestuarianus, Vibrio agarivorans, Vibrio albensis, Vibrio alginolyticus, Vibrio brasiliensis, Vibrio calviensis, Vibrio campbellii, Vibrio chagasii, Vibrio cholerae (Cholera), Vibrio cincinnatiensis, Vibrio Comma, Vibrio coralliilyticus, Vibrio crassostreae, Vibrio cyclitrophicus, Vibrio diabolicus, Vibrio diazotrophicus, Vibrio ezurae, Vibrio fischeri, Vibrio fluvialis, Vibrio fortis, Vibrio furnissii, Vibrio gallicus, Vibrio gazogenes, Vibrio gigantis, Vibrio halioticoli, Vibrio harveyi, Vibrio hepatarius, Vibrio hispanicus, Vibrio ichthyoenteri, Vibrio kanaloae, Vibrio lentus, Vibrio litoralis, Vibrio logei, Vibrio mediterranei, Vibrio metschnikovii, Vibrio mimicus, Vibrio mytili, Vibrio natriegens, Vibrio navarrensis, Vibrio neonatus, Vibrio neptunius, Vibrio nereis, Vibrio nigripulchritudo, Vibrio ordalii, Vibrio orientalis, Vibrio pacinii, Vibrio parahaemolyticus, Vibrio pectenicida, Vibrio penaeicida, Vibrio pomeroyi, Vibrio ponticus, Vibrio proteolyticus, Vibrio rotiferianus, Vibrio ruber, Vibrio rumoiensis, Vibrio salmonicida, Vibrio scophthalmi, Vibrio splendidus, Vibrio superstes, Vibrio tapetis, Vibrio tasmaniensis, Vibrio tubiashii, Vibrio vulnificus, Vibrio wodanis, Vibrio xuii; Vogesella indigofera, Wigglesworthia species, Wolbachia secies, Xenorhabdus species, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, and Yokenella species.
1344. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more infectious diseases.
1345. The method for vaccination according to item 1344, wherein the one orm ore infectious diseases can be selected from the group consisting of Bacteria and bacterial diseases (Specific kind of Infections), Fungus and fungal infections (Specific kind of Infections), Helminths and helminthic conditions (Specific kind of Infections), Prions and prion related diseases (Specific kind of Infections), Protozoa and protozoal infections (Specific kind of Infections), Viruses and viral disease (Specific kind of Infections), Abscess, Acariasis, actinomycetoma, Adenitis, Adenoiditis, African trypanosomiasis, Alpers Syndrome, Alphos, Alveolar osteitis, Amebiasis, Anorectal abscess, Anthrax, Ascariasis, Aspergillosis, Athlete's foot, Atypical pneumonia, Babesiosis, Bejel, Blastocystis hominis, Blastomycosis, Bolivian hemorrhagic fever, Botulism, Botryomycosis, Borna disease, Borreliosis (Lyme disease), Bovine spongiform encephalopathy, Brazilian purpuric fever (BPF), Bronchiolitis, Brucellosis, Bubonic plague, Buruli ulcer, Candidiasis, Campylobacteriosis, Cat scratch fever, Cellulitis, Chagas disease, Chalazion, Chickenpox (Varicella), Chikungunya, Cholangitis, Cholecystitis, Cholera, Clonorchiasis, Coccidioidomycosis, Colorado Tick Fever (CTF), Common cold, Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, Cryptococcosis, Cryptosporidiosis, Cutaneous abscess, Cysticercosis, Cystitis, infective, Dengue fever, Dermatophytosis, Diarrheal diseases, Diphteria, Diphyllobothriasis, Discitis, Donovanosis, Dracunculiasis, Dukes' disease, Dysentery, Ebola hemorrhagic fever, Echinococcosis, Encephalitis, Enterobiasis, Epidural abscess, Erysipelas, Eumycetoma, Fascioliasis, Fatal Familial Insomnia, Filariasis, Finger pulp abscess, Fitz-Hugh-Curtis syndrome, Foodborne trematodiases, Foot-and- mouth disease, Gallbladder empyema, Gas gangrene, Gastroenteritis, Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Gradenigo-Lannois syndrome, Grisel syndrome, Helminthiasis, Hepatitis, Herpes simplex, Herpes zoster, HPV,
Histoplasmosis, HIV/AIDS, Hookworm, Hordeolum externum, Human African trypanosomiasis, Hymenolepiasis, Impetigo, Infectious mononucleosis, Influenza, Intertrigo, Intracranial abscess / granuloma, Intraspinal abscess / granuloma, Isosporiasis, IV catheter infection, Japanese Encephalitis, Kuru, Kyasanur forest disease, Labrea fever, La Crosse encephalitis, Lacrimal canaliculus, Lady Windermere syndrome, Laryngeal papillomatosis, Laryngitis, Lassa fever, Legionellosis, Leishmaniasis, Lemierre's syndrome, Leptospirosis, Leprosy, Listeriosis, Liver abscess, Loa loa filariasis, lobomycosis, Lower respiratory tract infection, Ludwig angina, Lung abscess, Lymphangitis, Lymphatic filariasis, Malaria, Marburg haemorrhagic fever, Measles, Mediastinitis, Melioidosis, Meningitis, Metagonimiasis, Mumps, Murrain, Mycetoma, Mycosis, Myiasis, Necrotizing fasciitis, Neurocysticercosis, Nocardiosis, Omphalitis, Onchocerciasis, Ophthalmia neonatorum, Orbital cellulitis, Oropouche fever, Oroya fever, Osteomyelitis, Paragonimiasis, Paratyphoid fevers, Pediculosis, Periorbital cellulitis, Periodontis, Pertussis (Whooping Cough), Pharyngitis, Pharyngoconjunctival fever, Phlegmon, Pigbel (enteritis necroticans), Pinta, Pinworm Infection, Plantar wart, Pneumonia, Pneumonic plague, Pogosta disease, Poliomyelitis, Pott's disease, Prostatitis, Protothecosis, Psittacosis, Pyelonephritis acute, Pyelonephritis chronic, Pyomyositis, Q fever, Quinsy, Rabies, Rat-bite fever, Relapsing fever, Retropharyngeal abscess, Rheumatic Fever, Rhinosporidiosis, Rickettsialpox, Rift Valley fever, Ringworm, Rodentoleposis, Rocky Mountain Spotted Fever (RMSF), Roseola, Rubella, Salmonellosis, Scabies, Scarlet fever, Schistosomiasis, Septicemic plague, Septic arthropathy, Septic shock, Sepsis, Severe acute respiratory syndrome (SARS), Sexually transmissable disease, Shigellosis, Smallpox (Variola), Sodoku, Spondylodiskitis, Strongyloidiasis, Subdiaphragmatic abscess, Subdural empyema, Suppurative thyroiditis, Surra,
Sweating sickness, Syphilis, Taeniasis, Tetanus, Trachoma, Tick-borne diseases, Tinea barbae, Tinea capitis, Tinea corporis, Tinea cruris, Tinea faciei, Tinea manuum, Tinea nigra, Tinea pedis, Tinea versicolor, Tonsillitis, Toxocariasis, Toxoplasmosis, Tracheolaryngobronchitis, Trachoma, Transmissible spongiform encephalopathy, Traveler's diarrhea, Trench fever, Treponematoses, Trichinellosis, Trichinosis,
Trichomoniasis, Trichuriasis, Tropical diseases, Trypanosomiasis, Tuberculosis (TB), Tularemia, Typhoid fever, Typhus, Upper respiratory tract infection, Urethritis, Urinary tract infection, Venezuelan hemorrhagic fever (VHF), Verruca plana, viral hemorrhagic fevers (VHFs), Wart, West Nile disease, Wound infection, Yaws, Yellow fever, Yersiniosis and Zygomycosis.
1346. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more cancer diseases.
1347. The method for vaccination according to item 1346, wherein the one or more cancer diseases can be selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Related Lymphoma, Anal Cancer, Astrocytoma (e.g. Childhood Cerebellar or Childhood Cerebral), Basal Cell Carcinoma, Extrahepatic Bile Duct Cancer, Bladder Cancer, Bone Cancer, Osteosarcoma/Malignant Fibrous
Histiocytoma, Brain Stem Glioma, Brain Tumor, Breast Cancer, Male Breast Cancer, Bronchial Adenomas/Carcinoids, Burkitt's Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Primary Central Nervous System Lymphoma, Cerebral Astrocytoma/Malignant Glioma, Cervical Cancer, Childhood Cancers, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Disorders, Colon Cancer, Cutaneous T-CeII Lymphoma, Endometrial Cancer, Ependymoma (such as Childhood Epdndymoma), Esophageal Cancer, Ewing's Family of Tumors, Extracranial Germ Cell Tumor (such as Childhood Extracranial Germ Cell Tumor), Extragonadal Germ Cell Tumor, Eye Cancer (Intraocular Melanoma or Retinoblastoma), Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal
Carcinoid Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Hypothalamic and Visual Pathway Glioma (such as Childhood Hypothalamic and Visual Pathway Glioma), Intraocular Melanoma, Islet Cell Carcinoma (Endocrine Pancreas), Kaposi's Sarcoma, Kidney (Renal Cell) Cancer,
Laryngeal Cancer, Lip and Oral Cavity Cancer, Lung Cancer (Non-Small Cell or Small Cell), Lymphoma (such as AIDS-Related Lymphoma, Burkitt's Lymphoma, Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma), Macroglobulinemia (such as Waldenstrom's Macroglobulinemia), Malignant Fibrous Histiocytoma of Bone/Osteosarcoma, Medulloblastoma (such as Childhood Medulloblastoma), Melanoma, Merkel Cell Carcinoma, Mesothelioma (such as Adult Malignant Mesothelioma or childhood Mesothelioma), Metastatic Squamous Neck Cancer with Occult Primary, Multiple Endocrine Neoplasia Syndrome (such as occurring in childhood), Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases, Myeloma (such as Multiple Myeloma), Chronic myeloproliferative disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Nasopharyngeal Cancer (such as Childhood Nasopharyngeal Cancer), Neuroblastoma, Oropharyngeal Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Childhood Ovarian Cancer), Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Cancer, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastoma, Prostate Cancer, Renal Pelvis and Ureter Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma (such as Childhood Rhabdomyosarcoma), Salivary Gland Cancer, Adult-onset soft tissue Sarcoma, Soft Tissue Sarcoma (such as Childhood Soft Tissue Sarcoma), uterine Sarcoma, Sezary Syndrome, Skin Cancer (such as non-Melanoma skin cancer), Merkel Cell Skin Carcinoma, Small Intestine Cancer, Supratentorial Primitive Neuroectodermal Tumors (such as occurring in Childhood), Cutaneous T-CeII Lymphoma, Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (such as Gestational Trophoblastic Tumor), Urethral Cancer, Endometrial uterine cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual Pathway and Hypothalamic Glioma), Waldenstrom's Macroglobulinemia and Wilms' Tumor.
1348. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases selected from the group consisting of diseases of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo-or xenogene (graft versus host and host versus graft) origin.
1349. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft-versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox chicken pox, rubella or herpes.
1350. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of a disease of inflammatory/auto-immune origin, including asthma, hypersensitivity pneumonitis, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, interstitial lung disease associated with Crohn s Disease or ulcerative colitis or Whipple's disease, interstitial lung disease associated with Wegeners granulomatosis or hypersensitivity vasculitis, vasculitis syndromes, Hennoch-Schonleins purpura, Goodpastures syndrome, Wegeners granulomatosis, renal diseases such as antibody mediated glomerulopathia as in acute glomerulonephritis, nephritis associated with systemic lupus erythematosus, nephritis associated with other systemic diseases such as Wegeners granulomatosis and Goodpastures syndrome and mixed connective tissue disease, chronic interstitial nephritis, chronic glomerulonephritis, gastrointestinal diseases such as Crohn s Disease, Ulcerative colitis, coeliac disease, Whipple's disease, collagenous colitis, eosinophilic colitis, lymphatic colitis, hepatobilliary diseases such as auto-immune hepatitis, alcohol induced hepatitis, periportal fibrosis, primary billiary cirrhosis, sclerosing colangitis, disorders of the central or peripheral nervous system such as demyelinating disease as multiple sclerosis, acute disseminated encephalomyelitis, sub-acute sclerosing panencephalitis, skin disease such as psoriasis, atopic dermatitis, eczema, allergic skin disease, progressive systemic sclerosis (scleroderma), exfoliating dermatitis, pemphigus vulgaris, joint diseases such as rheumatoid arthritis, ankylosing spondylitis, arthritis associated with psoriasis or inflammatory bowel disease, muscoloskelletal diseases such as myastenia gravis, polymyositis, endocrine diseases such as insulin dependent diabetes mellitus, auto-immune thyroiditis (Hashimoto), thyreotoxicosis, Graves, diseases of the hematopoetic system such as auto-immune anaemia, auto-immune thrombocytopenia, cardiovascular diseases such as cardiomyopathia, vasculitis, cardiovascular disease associated with systemic diseases as systemic lupus erythematosus, polyarthritis nodosa, rheumatoid arthritis, scleroderma, sarcoidosis, diseases of cancerous origin, including malignant melanoma, Sezary's syndrome, cutaneous T-cell lymphoma, renal cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, cancer of the uterus, prostatic cancer, hepatic carcinoma, lung cancer, and sarcoma, and diseases, disorders or conditions of allergic origin.
1351. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of autoimmune diseases including multiple sclerosis, type I diabetes mellitus, Hashimotos thyroiditis, pernicious anemia, Addison's disease, myasthenia gravis, rheumatoid arthritis, uveitis, psoriasis, Guillain-Barre Syndrome and Grave's disease, systemic lupus erythematosus and dermatomyositis.
1352. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of hypersensitivity disorders like asthma, eczema, atopical dermatitis, contact dermatitis, other eczematous dermatitides, seborrheic dermatitis, rhinitis, Lichen planus, Pemplugus, bullous Pemphigoid, Epidermolysis bullosa, uritcaris, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Alopecia areata, atherosclerosis, primary biliary cirrhosis and nephrotic syndrome. 1353. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of intestinal inflammations, such as Coeliac disease, proctitis, eosinophilia gastroenteritis, mastocytosis, inflammatory bowel disease, Chrohn's disease and ulcerative colitis, as well as food-related allergies.
1354. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more allergic diseases.
1355. The method for vaccination according to item 1354, wherein the allergic diseases involve one or more of the allergens selected from the group consisting of inhalation allergens originating i. a. from trees, grasses, herbs, fungi, house dust mites, storage mites, cockroaches and animal hair, feathers, and dandruff, pollen allergens from trees, grasses and herbs are such originating from the taxonomic orders of Fagales, Oleales and Pinales including i. a. birch (Betula), alder (Alnus), hazel
(Corylus), hornbeam (Carpinus) and olive (Olea), the order of Poales including i. a. grasses of the genera Lolium, Phleum, Poa, Cynodon, Dactylis and Secale, the orders of Astrales and Urticales including i. a. herbs of the genera Ambrosia and Artemisia, inhalation allergens from fungi, allergens originating from the genera Alternaria and Cladosporium, inhalation allergens from house dust mites of the genus
Dermatophagoides, storage mites from the genus Lepidoglyphys destructor, those from cockroaches and those from mammals such as cat, dog, horse, cow, and bird.
1356. The method for vaccination according to item 1 172, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of Bet v 1 (B. verrucosa, birch), AIn g 1 (Alnus glutinosa, alder), Cor a 1 (Corylus avelana, hazel) and Car b 1 (Carpinus betulus, hornbeam) of the Fagales order, Cry j 1 (Pinales), Amb a 1 and 2, Art v 1 (Asterales), Par j 1 (Urticales), Ole e 1 (Oleaves), Ave e 1 , Cyn d 1 , Dae g 1 , Fes p 1 , HoI 1 1 , LoI p 1 and 5, Pas n 1 , PhI p 1 and 5, Poa p 1 ,2 and 5, Sec c 1 and 5, and Sor h 1 (various grass pollens), Alt a 1 and CIa h 1 (fungi), Der f 1 and 2, Der p 1 and 2 (house dust mites, D. farinae and D. pteronyssinus, respectively), Lep d 1 , BIa g 1 and 2, Per a 1 (cockroaches, Blatella germanica and Periplaneta americana, respectively), FeI d 1 (cat), Can f 1 (dog), Equ c 1 ,2 and 3 (horse), Apis m 1 and 2 (honeybee), Ves g 1 ,2 and 5, Pol a 1 ,2 and 5 (all wasps) and Sol i 1 , 2,3 and 4 (fire ant). 1357. The method for vaccination according to item 1 172, wherein the vaccination results in up-regulation of the immune response of said individual.
1358. The method for vaccination according to item 1 172, wherein the vaccination results in down-regulation of the immune response of said individual.
1359. The method for vaccination according to item 1 172, wherein the vaccination results in modulation of the immune response of said individual.
1360. The method for vaccination according to item 1 172, wherein the vaccination results in stimulation of the immune response of said individual.
1361. The method for vaccination according to item 1 172, wherein the vaccination results in inhibition of the immune response of said individual.
1362. The method for vaccination according to item 1 172, wherein the vaccination results in restoration of the immune reponse of said individual.
1363. The method for vaccination according to item 1 172, wherein the vaccination results in induction of anergy in a cell.
1364. The method for vaccination according to item 1 172, wherein the vaccination results in adoptive immunotherapy.
1365. The method for vaccination according to item 1 172, wherein the vaccination comprises in vivo therapy and/or ex vivo therapy.
1366. The method for vaccination according to item 1 172, wherein the vaccination comprises combination therapy such as co-administration of the composition according to item 1 -1 170 and one ore more medicaments.
1367. The method for vaccination according to item 1366, wherein the coadministration comprises that the composition according to item 1 -1 170 and the one ore more medicaments can be administered simulatenously. 1368. The method for vaccination according to item 1366, wherein the coadministration comprises that the composition according to item 1 -1 170 and the one ore more medicaments can be administered sequentially in any order.
1369. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an anti-cancer medicament.
1370. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an anti-cancer drug selected from the group consisting of
1371. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an anti-HIV medicament.
1372. The method for vaccination according to item 1366, wherein the one ore more medicaments can be a chemotherapeutic agent.
1373. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an immunotherapeutic agent.
1374. The method for vaccination according to item 1366, wherein the combination therapy comprises radiation therapy.
1375. The method for vaccination according to item 1366, wherein the combination therapy comprises gene therapy.
1376. The method for vaccination according to item 1366, wherein the combination therapy comprises surgery.
1377. The method for vaccination according to item 1366, wherein the one ore more medicaments can be selected from the group of chemotherapeutic agents including methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MM1270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, MTA/LY231514, LY264618/I_ometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, lncel/VX-710, VX-853, ZD0101 , ISI641 , ODN 698, TA 2516/Marmistat, BB2516/Marmistat, CDP 845, D2163, PD183805, DX8951 f , Lemonal DP 2202, FK 317, Picibanil/OK-432, AD 32/Valrubicin, Metastron/strontium derivative, Temodal/Temozolomide, Evacet/liposomal doxorubicin, Yewtaxan/Placlitaxel, Taxol/Paclitaxel, Xeload/Capecitabine, Furtulon/Doxifluridine, Cyclopax/oral paclitaxel, Oral Taxoid, SPU-077/Cisplatin, HMR 1275/Flavopiridol, CP-358 (774)/EGFR, CP-609 (754)/RAS oncogene inhibitor, BMS-182751 /oral platinum, UFT(Tegafur/Uracil), Ergamisol/Levamisole, Eniluracil/776C85/5FU enhancer, Campto/Levamisole, Camptosar/lrinotecan, Tumodex/Ralitrexed, Leustatin/Cladribine, Paxex/Paclitaxel, Doxil/liposomal doxorubicin, Caelyx/liposomal doxorubicin, Fludara/Fludarabine, Pharmarubicin/Epirubicin, DepoCyt, ZD1839, LU 79553/Bis-Naphtalimide, LU 103793/Dolastain, Caetyx/liposomal doxorubicin, Gemzar/Gemcitabine, ZD
0473/Anormed, YM 1 16, Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/lfosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331 , Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide,
Asparaginase, Busulfan, Carboplatin, Chlorambucil, Cytarabine HCI, Dactinomycin, Daunorubicin HCI, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH-releasing factor analogue), Lomustine (CCNU), Mechlorethamine HCI (nitrogen mustard),
Mercaptopurine, Mesna, Mitotane (o.p'-DDD), Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m-AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), lnterleukin 2, Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone; MGBG), Pentostatin (2'deoxycoformycin), Semustine (methyl- CCNU), Teniposide (VM-26) and Vindesine sulfate.
1378. The method for vaccination according to item 1366, wherein the one ore more medicaments can be selected from the group of anti-cancer drugs consisting of Aldesleukin/Proleukin (Chiron Corp), Alemtuzumab/Campath (Millennium and ILEX Partners, LP), alitretinoin/Panretin (Ligand Pharmaceuticals), allopurinol/Zyloprim (GlaxoSmithKline), altretamine/Hexalen (US Bioscience), amifostine/Ethyol (US Bioscience), anastrozole/Arimidex (AstraZeneca), arsenic trioxide/Trisenox (Cell Therapeutic), Asparaginase/Elspar (Merck & Co, Inc), BCG Live/TICE BCG (Organon Teknika Corp), bexarotene capsules/Targretin (Ligand Pharmaceuticals), bleomycin/Blenoxane (Bristol-Myers Squibb), busulfan/Busulfex (GlaxoSmithKline), calusterone/Methosarb (Pharmacia & Upjohn Company), capecitabine/Xeloda (Roche), carboplatin/Paraplatin (Bristol-Myers Squibb), carmustine/BCNU, BiCNU (Bristol-Myers Squibb), carmustine with Polifeprosan 20 Implant/Gliadel Wafer (Guilford Pharmaceuticals Inc.), celecoxib/Celebrex (Searle), chlorambucil /Leukeran
(GlaxoSmithKline), cisplatin/Platinol (Bristol-Myers Squibb), cladribine/Leustatin, 2-CdA (R.W. Johnson Pharmaceutical Research Institute), cyclophosphamide Cytoxan/ Neosar (Bristol-Myers Squibb), cytarabine/Cytosar-U (Pharmacia & Upjohn Company), dacarbazine/DTIC-Dome (Bayer), dactinomycin/actinomycin D Cosmegen (Merck), Darbepoetin alfa/Aranesp (Amgen, Inc), daunorubicin/daunomycin/Daunorubicin (Bedford Labs), daunorubicin/daunomycin/Cerubidine (Wyeth Ayerst), Denileukin/diftitox/Ontak (Seragen, Inc), dexrazoxane/Zinecard (Pharmacia & Upjohn Company), docetaxel/Taxotere (Aventis Pharmaceutical), doxorubicin Adriamycin/Rubex (Pharmacia & Upjohn Company), DROMOSTANOLONE PROPIONATE/MASTERONE INJECTION (SYNTEX), Elliott's B Solution (Orphan Medical, Inc), epirubicin/Ellence (Pharmacia & Upjohn Company), etoposide phosphate (Bristol-Myers Squibb), etoposide/VP-16/Vepesid (Bristol-Myers Squibb), exemestane/Aromasin (Pharmacia & Upjohn Company), Filgrastim/Neupogen (Amgen, Inc), floxuridine/FUDR (Roche), fludarabine/Fludara (Berlex Laboratories Inc.), fluorouracil/5-FU/Adrucil (ICN Puerto Rico), fulvestrant/Faslodex (IPR), gemcitabine/Gemzar (EIi Lilly), gemtuzumab/ozogamicin/Mylotarg (Wyeth Ayerst), goserelin acetate/Zoladex Implant (AstraZeneca Pharmaceuticals), hydroxyurea/Hydrea (Bristol-Myers Squibb), lbritumomab Tiuxetan/Zevalin (IDEC Pharmaceuticals Corp), idarubicin/ldamycin (Adria Laboratories), ifosfamide/IFEX (Bristol-Myers Squibb), imatinib mesylate/Gleevec (Novartis), Interferon alfa-
2a/Roferon-A (Hoffmann-La Roche Inc), Interferon alfa-2b/lntron A (Schering Corp), irinotecan/Camptosar (Pharmacia & Upjohn Company), letrozole/Femara (Novartis), leucovorin Wellcovorin/Leucovorin (Immunex Corporation), levamisole/Ergamisol (Janssen Research Foundation), lomustine/CCNU/CeeBU (Bristol-Myers Squibb), meclorethamine/nitrogen mustard/Mustargen (Merck), megestrol acetate/Meg ace (Bristol-Myers Squibb), melphalan/L-PAM/Alkeran (GlaxoSmithKline), mercaptopurine/6-MP Purinethol (GlaxoSmithKline), mesna/Mesnex (Asta Medica), methotrexate (Lederle Laboratories), methoxsalen/Uvadex (Therakos), mitomycin C/Mutamycin (Bristol-Myers Squibb), mitomycin C/Mitozytrex (Supergen), mitotane/Lysodren (Bristol-Myers Squibb), mitoxantrone/Novantrone (Lederle Laboratories), nandrolone phenpropionate/Durabolin-50 (Organon), Nofetumomab/Verluma (Boehringer lngelheim Pharma KG (formerly Dr. Karl Thomae GmbH)), Oprelvekin/Neumega (Genetics Institute), oxaliplatin/Eloxatin (Sanofi Synthelabo), paclitaxel/Taxol (Bristol-Myers Squibb), pamidronate/Aredia (Novartis), pegademase/Adagen (Pegademase Bovine) (Enzon), Pegaspargase/Oncaspar
(Enzon, Inc), Pegfilgrastim/Neulasta (Amgen, Inc), pentostatin/Nipent (Parke-Davis Pharmaceutical Co.), pipobroman/Vercyte (Abbott Labs), plicamycin/mithramycin/Mithracin (Pfizer Labs), porfimer sodium/Photofrin (QLT Phototherapeutics Inc.), procarbazine/Matulane (Sigma Tau Pharms), quinacrine/Atabrine (Abbott Labs), Rasburicase/Elitek (Sanofi-Synthelabo, Inc), Rituximab/Rituxan (Genentech, Inc), Sargramostim/Prokine (Immunex Corp), streptozocin/Zanosar(Pharmacia & Upjohn Company), talc/Sclerosol (Bryan), tamoxifen/Nolvadex (AstraZeneca Pharmaceuticals), temozolomide/Temodar (Schering), teniposide/VM-26/Vumon (Bristol-Myers Squibb), testolactone/Teslac (Bristol-Myers Squibb), thioguanine/6-TG/Thioguanine (GlaxoSmithKline), thiotepa/Thioplex (Lederle Laboratories), topotecan/Hycamtin (GlaxoSmithKline), topotecan/Hycamtin (GlaxoSmithKline), toremifene/Fareston (Orion Corp), Tositumomab/Bexxar (Corixa Corporation), Trastuzumab/Herceptin (Genentech, Inc), tretinoin/ATRA/Vesanoid (Roche), Uracil Mustard (Roberts Labs), valrubicin/Valstar (Medeva), vinblastine/Velban (EIi Lilly), vincristine/Oncovin (EIi Lilly), vinorelbine/Navelbine (GlaxoSmithKline), and zoledronate/Zometa (Novartis).
1379. The method for vaccination according to item 1366, wherein the one ore more medicaments can be selected from the group of the immunotherapeutic agents comprising Ributaxin, Herceptin, Quadramet, Panorex, IDEC-Y2B8, BEC2, C225,
Oncolym, SMART Ml 95, ATRAGEN, Ovarex, Bexxar, LDP-03, ior .6, MDX-210, MDX- 1 1 , MDX-22, OV103, 3622W94, anti-VEGF, Zenapax, MDX-220, MDX-447, MELIMMUNE-2, MELIMMUNE-1 , CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab- H, GNI-250, EMD-72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.r3, ior c5, BABS, anti-FLK-2, MDX-260, ANA Ab, SMART 1 D10 Ab, SMART ABL 364 Ab and I mm u RAIT-CEA, a cytokine or an interferon.
1380. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an antiviral drug such as a Nucleoside/Nucleotide Reverse
Transcriptase Inhibitor.
1381. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an antiviral drug such as Non-Nucleoside Reverse Transcriptase Inhibitors.
1382. The method for vaccination according to item 1366, wherein the one ore more medicaments can be a Protease Inhibitor.
1383. The method for vaccination according to item 1366, wherein the one ore more medicaments can be a Fusion or Entry Inhibitor.
1384. The method for vaccination according to item 1366, wherein the one ore more medicaments can be an lntegrase Inhibitor.
1385. The method for vaccination according to item 1366, wherein the one ore more medicaments can be selected from the group consisting of lamivudine, Epivir, abacavir, Ziagen, AZT or ZDV, Zidovudine, Retrovir, d4T, Stavudine, Zerit, ddC, Zalcitabine, Hivid, ddl, didanosine, Videx (tablet), Videx EC (capsule), FTC, emtricitabine, Emtriva, TDF, tenofovir, Viread, Epzicom, Kivexa, Trizivir, Combivir, Truvada, Delavirdine, Rescriptor, Efavirenz, Sustiva, Stocrin, Etravirine, Intelence, Nevirapine, Viramune, amprenavir, Agenerase, fosamprenavir, Lexiva, Telzir, Atazanavir, Reyataz, Darunavir, Prezista, Indinavir, Crixivan, lopinavir, ritonavir, Kaletra, Aluvia, nelfinavir, Viracept, ritonavir, Norvir, saquinavir, Fortovase, Invirase, Tipranavir, Aptivus, Enfuvirtide, Fuzeon, maraviroc, Celsentri, Selzentry, raltegravir, Isentress, Atripla, Atazanavir/r, Darunavir/r, Raltegravir, Maraviroc, and Etravirine.
1386. The composition according to items 1 -1 170, wherein the composition is in solid form. 1387. The composition according to items 1 -1 170, wherein the composition is in insoluble form.
1388. The composition according to items 1 -1 170, wherein the composition is in soluble form.
1389. The composition according to items 1 -1 170, wherein the composition is in suspension.
1390. The composition according to items 1 -1 170, wherein the composition is sterile.
1391. The composition according to items 1 -1 170, wherein the composition is prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non-aqueous.
1392. The composition according to items 1 -1 170, wherein the composition is prepared in solid form suitable for solution, or suspensions, in liquid prior to use.
1393. The composition according to items 1 -1 170, wherein the composition is emulsified.
1394. The composition according to items 1 -1 170, wherein the composition is mixed with excipients which are pharmaceutically acceptable such as water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
1395. The composition according to items 1 -1 170, wherein the composition comprises minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the pharmamer.
1396. The composition according to items 1 -1 170, wherein the composition has a pH within the range of 3.5-8, such as in the range 4.5-7.5, such as in the range 5.5-7, such as in the range 6-7.5, most preferably around 7.3.
1397. The composition according to items 1 -1 170, wherein the composition has a pH within the range 3.5-7, such as 4-6, such as 5-6, such as 5.3-5.7, such as 5.5. 1398. The composition according to items 1 -1 170, wherein the composition is for parenteral administration and wherein the composition is dissolved or suspended in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil.
1399. The composition according to items 1 -1 170, wherein the composition is a liquid composition comprising liquid phases in addition to and to the exclusion of water such as glycerin, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
1400. The composition according to items 1 -1 170, wherein the composition comprises one or more suitable pharmaceutical carriers such as inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
1401. The composition according to items 1 -1 170, wherein the composition comprises one or more solid carriers such as lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
1402. The composition according to items 1 -1 170, wherein the composition comprises one or more liquid carriers such as syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
1403. The composition according to items 1 -1 170, wherein the composition is administered by nasal aerosol or inhalation and wherein the composition is prepared for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents.
1404. The composition according to items 1 -1 170, wherein the composition is prepared in unit dosage form.
1405. The composition according to items 1 -1 170, wherein the composition is prepared as a lyophilisate. 1406. The composition according to items 1 -1 170, wherein the composition comprises a solvent.
1407. The composition according to items 1 -1 170, wherein the composition is prepared as an injectable solution.
1408. The composition according to items 1 -1 170, wherein the composition is prepared as a dispersion.
1409. The composition according to items 1 -1 170, wherein the composition is prepared as a suspension.
1410. The composition according to items 1 -1 170, wherein the composition is prepared as a emulsion.
141 1. The composition according to items 1 -1 170, wherein the composition is prepared as a sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
1412. The composition according to items 1 -1 170, wherein the composition is prepared as suppositories.
1413. The composition according to items 1 -1 170, wherein the composition is prepared as a spray.
1414. The composition according to items 1 -1 170, wherein the composition is prepared as an ointment, creme, or gel.
1415. The composition according to items 1 -1 170, wherein the composition is prepared as an inhalant.
1416. The composition according to items 1 -1 170, wherein the composition is prepared as a dermal patch. 1417. The composition according to items 1 -1 170, wherein the composition is prepared as an implant.
1418. The composition according to items 1 -1 170, wherein the composition is prepared as a pill, tablet, lozenge or capsule.
1419. The composition according to items 1 -1 170, wherein the composition is formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
1420. The composition according to items 1 -1 170, wherein the composition is prepared in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
1421. The composition according to items 1 -1 170, wherein the composition is a powder comprising a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
1422. The composition according to items 1 -1 170, wherein the composition is prepared as a gel.
1423. The composition according to items 1 -1 170, wherein the composition is prepared as a capsules or cartridges of e.g., gelatin or blister packs.
1424. The composition according to items 1 -1 170, wherein the composition is prepared as an aerosol prepared, for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents.
1425. The composition according to items 1 -1 170, wherein the composition is formulated for parenteral administration.
1426. The composition according to items 1 -1 170, wherein the composition is formulated for intravenous administration. 1427. The composition according to items 1 -1 170, wherein the composition is formulated for intramuscular administration.
1428. The composition according to items 1 -1 170, wherein the composition is formulated for intraarticular formulation.
1429. The composition according to items 1 -1 170, wherein the composition is formulated for subcutaneous administration.
1430. The composition according to items 1 -1 170, wherein the composition is formulated for intradermal administration.
1431. The composition according to items 1 -1 170, wherein the composition is formulated for epicutantous/transdermal administration.
1432. The composition according to items 1 -1 170, wherein the composition is formulated for intra- peritoneal administration.
1433. The composition according to items 1 -1 170, wherein the composition is formulated for infusion.
1434. The composition according to items 1 -1 170, wherein the composition is formulated for oral administration.
1435. The composition according to items 1 -1 170, wherein the composition is formulated for nasal administration.
1436. The composition according to items 1 -1 170, wherein the composition is formulated for rectal administration.
1437. The composition according to items 1 -1 170, wherein the composition is formulated for vaginal administration. 1438. The composition according to items 1 -1 170, wherein the composition is formulated for topic administration.
1439. The composition according to items 1 -1 170, wherein the composition comprises one or more pharmamers immobilised onto a solid or semi-solid support such as particles, beads, biodegradable particles, sheets, gels, filters, membranes, fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, and chips.
1440. The composition according to items 1 -1 170, wherein the composition comprises one or more pharmamers immobilised onto particles and beads, which are polymeric, magnetic or superparamagnetic.
1441. The composition according to items 1 -1 170, wherein the composition comprises one or more pharmamers that target specific MHC recognising cells.
1442. The composition according to items 1 -1 170, wherein the composition comprises one or more pharmamers capable of induction of a response in specific target MHC recognising cells by addressing receptors on such cells.
1443. The composition according to item 882, wherein the one or more biological active molecules and the one or more multimerization domain by a mechanism comprising biotinylation.
1444. The composition according to item 1443, where the mechanism comprises Streptavidin and/or Avidin and Biotin.
1445. The composition according to item 1443, where the mechanism comprises enzymatic biotinylation.
1446. The composition according to item 1443, where the mechanism comprises non-enzymatic biotinylation.
1447. The composition according to item 882, wherein the one or more biological active molecules are directly or indirectly bound to the multimerization domain. 1448. The composition according to item 882, wherein the one or more biological active molecules are not directly or indirectly bound to the multimerization domain.
Examples:
Example 1 : Example of a vaccine consisting of pharmamers for vaccination against HIV/SIV in monkeys.
The vaccine is composed of a Dextran (270 kDa) multimerisation domain that has been derivatized by attaching Strepavidin (on average 8.6 Strepavidin molecules/Dextran molecule). Attached to the streptavidin molecules are Simian MHC class 1 molecules, either Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu-A*08(KPCVKLTP) (SEQ ID NO 9570), or Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ). Attachment is done by non-covalent interaction via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain and the streptavidin molecules on the Dextran multimerisation domain. Likewise are biotinylated synthetic Mamu class 2 peptides representing Mamu-DQB1 *0601 (EFVRFDSA VGEYRA V) (SEQ ID NO 9572); Mamu- DQB1 *1808(EFVGFDSYLGVYRPV) (SEQ ID NO 9573); Mamu-DRB*W201
(TREDILERERAQVDTFY) (SEQ ID NO 9574) and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
The Mamu class 1 bound peptides represents the proteins, HIV-Gag (CTPYDINQM) (SEQ ID NO 9569), HIV-Env (KPCVKLTP) (SEQ ID NO9570) and Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ).
A single full dose of the final vaccine corresponds to, 100 Dg of each MHC class 1 molecule; 4.6 μg of each MHC class 2 peptide; 3x25.9 μg HSP70pep3Bio and 3x162.5 Dg dextran (corresponding to a total of approx 260 μg pharmamer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 mixture of the following three pharmamers:
Pharmamer 1 : Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569) + Mamu-DQB1 *0601
(EFVRFDSAVGEYRAV) (SEQ ID NO 9572) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratiol 0/10/4/1
Pharmamer 2: Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570) + Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Pharmamer 3:
Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ) + Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Administration:
The pharmamer mix is absorbed into the adjuvant Alhydrogel (Aluminiumhydroxide gel) as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 weeks.
Example 2: Example of a vaccine consisting of pharmamers for vaccination against
HIV/SIV in monkeys.
The vaccine is composed of a Dextran (270 kDa) multimerisation domain that has been derivatized by attaching Strepavidin (on average 8.6 Strepavidin molecules/Dextran molecule). Attached to the Dextran-streptavidin multimerisation domain are Simian MHC class 1 molecules, either Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu- A*08(KPCVKLTP) (SEQ ID NO 9570), or Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ). Attachment is done via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain to the streptavidin molecules on the multimerisation domain. Likewise are biotinylated synthetic Mamu class 2 peptides representing Mamu- DQB1 *0601 (EFVRFDSAVGEYRAV) (SEQ ID NO 9572); Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573); Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites. Further to these molecules are recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
The Mamu class 1 bound peptides represents the proteins, HIV-Gag (CTPYDINQM) (SEQ ID NO 9569); HIV-Env (KPCVKLTP) (SEQ ID NO 9570); and Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ). A single full dose of the final vaccine corresponds to, 100 Dg of each MHC class 1 molecule; 4.6 μg of each MHC class 2 peptide; 4x25.9 ug HSP70pep3Bio; 37,1 μg Sivp27; 152,8 μg HIV-1gp140trimer and 4x162,7 μg dextran (corresponding to a total of approx 360 μg pharmamer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 :1 mixture of the following four pharmamers:
Pharmamer 1 :
Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569) + Mamu-DQB1 *0601 (EFVRFDSAVGEYRAV) (SEQ ID NO 9572) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratiol 0/10/4/1
Pharmamer 2:
Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570) + Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Pharmamer 3:
Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ) + Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) class 2 peptide + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Pharmamer 4:
Sivp27 + HIV-1gp140trimer + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 3/10/4
Administration:
The pharmamer mix is absorbed into the adjuvant Alhydrogel (Aluminiumhydroxide gel) as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 weeks.
Example 3: Example of a vaccine consisting of pharmamers for vaccination against HIV/SIV in monkeys. The vaccine is composed of a Dextran (270 kDa) multimerisation domain that has been derivatized by attaching Streptavidin (on average 8.6 Streptavidin molecules/Dextran molecule). Attached to the multimerisation domain are Human MHC class 1 molecules, either HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575), HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576), HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577), HLA-
A*1 101 (IVTDFSVIK) (SEQ ID NO 9578). Attachment is done via a COOH-terminal Biotin molecule on the recombinant HLA heavy chain to the streptavidin molecules on the multimerisation domain. Likewise are biotinylated recombinant HLA class 2 protein HLA-DFT0401 and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to streptavidin sites.
The HLA class 1 bound peptides represents the proteins, USP9Y, ubiquitin specific protease 9 (IVDCLTEMY) (SEQ ID NO 9575); TRAG-3_4 (GLIQLVEGV) (SEQ ID NO 9576); BCL2L1 (RIAAWMATY) (SEQ ID NO 9577); EBV EBNA3B (IVTDFSVIK) (SEQ ID NO 9578). The HLA class 2 complex is produced without a peptide in the binding groove but it cannot be excluded that the groove may contain unknown peptides derived from either serum or the S2 production cells.
Administration: A single full dose of the final vaccine corresponds to, 100 Dg of each HLA class 1 molecule; 1 13,5 μg of HLA class 2; 3x25,8 μg HSP70pep3Bio and 3x162,2 μg dextran (corresponding to a total of approx 300 μg pharmamer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 mixture of the following three pharmamers:
Pharmamer 5:
HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575) + HLA-DR*0401 class 2 + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratiol 0/10/4/1
Pharmamer 6: HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576) + H LA-A*0301 (RIAAWMATY) (SEQ ID
NO 9577) + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Pharmamer 7: HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578) + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/4/1
Administration: The pharmamer mix is emulsified with the adjuvant Titermax Gold as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 weeks.
Example 4: Example of a vaccine consisting of pharmamers for vaccination against HIV/SI V in monkeys
The vaccine is composed of a Dextran (270 kDa) multimerisation domain that has been derivatized by attaching Streptavidin (on average 8.6 Streptavidin molecules/Dextran molecule). Attached to the multimerisation domain are Human MHC class 1 molecules, either HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575), HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576), HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577), or HLA- A*1 101 (IVTDFSVIK) (SEQ ID NO 9578). Attachment is done via a COOH-terminal Biotin molecule on the recombinant HLA heavy chain to the streptavidin molecules on the multimerisation domain. Likewise are biotinylated recombinant HLA class 2 protein HLA-DFT0401 and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to streptavidin sites. Further to these molecules are recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin- Streptavidin binding.
The HLA class 1 bound peptides represents the proteins, USP9Y, ubiquitin specific protease 9 (IVDCLTEMY) (SEQ ID NO 9575); TRAG-3_4 (GLIQLVEGV) (SEQ ID NO 9576); BCL2L1 (RIAAWMATY) (SEQ ID NO 9577); EBV EBNA3B (IVTDFSVIK) (SEQ ID NO 9578). The HLA class 2 complex is produced without a peptide in the binding groove but it cannot be excluded that the groove may contain unknown peptides derived from either serum or the S2 production cells.
A single full dose of the final vaccine corresponds to, 100 μg of each HLA class 1 molecule; 1 13,5 μg of HLA class 2; 4x25,9 ug HSP70pep3Bio; 37,1 μg Sivp27; 152,8 μg HIV-1gp140trimer and 4x162,7 μg dextran (corresponding to a total of approx 415 μg pharmamer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 :1 mixture of the following four pharmamers:
Pharmamer 5: HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575) + HLA-DFT0401 class 2 +
HSP70pep3Bio + Dextran multimerisation domain, in the molar ratiol 0/10/4/1
Pharmamer 6:
HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576) + H LA-A*0301 (RIAAWMATY) (SEQ ID NO 9577) + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/10/4/1
Pharmamer 7:
HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578) + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 10/4/1
Pharmamer 4:
Sivp27 + HIV-1gp140trimer + HSP70pep3Bio + Dextran multimerisation domain, in the molar ratio 3/10/4
Administration:
The pharmamer mix is emulsified with the adjuvant Titermax Gold as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and
16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 weeks.
Example 5: Example of a vaccine consisting of pharmamers for vaccination against HIV/SI V in monkeys.
The vaccine is composed of a Dextran (270 kDa) multimerisation domain that has been derivatized by attaching Streptavidin (on average 8.6 Streptavidin molecules/Dextran molecule). Attached to the multimerisation domain are Simian MHC class 1 molecules, either Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu-A*08(KPCVKLTP) (SEQ ID NO 9570), or Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ). Attachment is done via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain to the streptavidin molecules on the multimerisation domain. Likewise are biotinylated recombinant HSP70pep3Bio-CCR5-tripeptide fragment, a biotinylated fusion protein consisting of the HSP70 fragment spanning amino acid residues 359-609 plus the antigenic CCR5 loops, N-terminal loop, Loopi and Loop2, attached to streptavidin sites.
The Mamu class 1 bound peptides represents the proteins, HIV-Gag (CTPYDINQM) (SEQ ID NO 9569), HIV-Env (KPCVKLTP) (SEQ ID NO 9570) and Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ). The CCR5 peptides representing the three antigenic loops are, N-terminal (MNYQVSSPIYNINYYTSEPC) (SEQ ID NO 9579); Loopi (HYAAAQWNFGNTMCQ) (SEQ ID NO 9580); Loop2 (YSSHFPYSQYQFWKNFQTLK) (SEQ ID NO 9581 ).
A single full dose of the final vaccine corresponds to, 100 Dg of each MHC class 1 molecule; 3x126 Dg HSP70pep3Bio-CCR5-tripeptide and 3x125 Dg dextran
(corresponding to a total of approx 300 Dg pharmamer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 mixture of the following three pharmamers
Pharmamer 8: Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569) + HSP70pep3Bio-CCR5-tripeptide + Dextran multimerisation domain, in the molar ratiol 3/10/1
Pharmamer 9:
Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570) + HSP70pep3Bio-CCR5-tripeptide + Dextran multimerisation domain, in the molar ratiol 3/10/1
Pharmamer 10:
Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ) + HSP70pep3Bio-CCR5-tripeptide + Dextran multimerisation domain, in the molar ratiol 3/10/1
Administration:
The pharmamer mix is administered as intramuscular injections at time points 0, 2, 4,
6, 8, 10, 12 and 14 weeks such that a full dose is given at each time point. Example 6
This is an example of generation of a pharmamers that can be used in a vaccine composition for treatment of SIV/HIV. 4 different vaccine compositions were generated comprising between 1 -4 pharmamers whereto 3-5 different biological active molecules were attached. The multimerization domain in all pharmamers was Streptavidin (SA) coupled Dextran (27OkDa) and the biologically active molecules were attached to the SA-Dextran backbone by a non- covalent interaction between SA and biotin on the biologically active molecules. In the following generation of the individual components in the pharmamers are described:
Generation of multimerization domain:
Dextran270 were coupled with SA using the following procedure. Divinyl sulfone acid activated Dextran270 were mixed with SA in a molar ratio of 1 :13 (Dextran270:SA) in buffer ( 0,025 M NaHCO3, 0.1 M NaCI) for 2 hours at 40<€. The final concentration of Dextran270 was 6 uM. Then the reaction was stopped by adding 10 vol% 0.165 M Cystein, incubation for 30 minutes at 40 °C. Excess SA was removed by gelfiltration on a Superdex 200-column and the buffer exchanged to 0,1 M NaCI; 10 mM CHES; pH 9.0. The final product had a concentration of 0.65 mg/ml and 8.6 SA molecules per Dextran molecule in average.
Generation of biotinylated MHC l-peptide complexes:
Four different biotinylated MHC l-peptide complexes were generated: HLA-A*0101 (IVDCLTEMY )SEQ ID NO 9588), HLA-A*1 101 (IVTDFSVIK)SEQ ID NO
9589), HLA-A*0201 (GLIQLVEGV) SEQ ID NO 9590, HLA-A*0301 (RIAAWMATY) SEQ ID NO 9591.
The protein coding sequences minus the signal peptide and transmembrane regions of all of the 4 human MHC class 1 heavy chain molecules were obtained from GenBank and the sequence backtranslated according to E.coli codon usage using www.entelechon.com. The gene was synthesized by PCR using 10 overlapping DNA primers (DNA Technology, Denmark) and KOD polymerase (EMD Chemicals, Novagen). Sequence was verified by repeated DNA sequencing (MWG Biotech, Ebersberg, Germany) and base errors introduced were corrected using Quick Change multi site-directed mutagenesis kit (Stratagene, La JoIIa, CA) before cloning in pGarboczi (Garboczi et al 1992). Human beta2Microblulin (β2m) (GenBank ace # CAG33347.1 ) was acquired and cloned. Recombinant MHC 1 heavy chain and β2m protein was produces by fermentation, isolated and purified by column chromatography.
MHC-peptide complexes was generated by in vitro refolding of heavy chain, β2m and peptide in a buffer containing reduced and oxidized glutathione. By incubation in this buffer a non-covalent complex between Heavy Chain, β2m and peptide was formed. Heavy chain and β2m was expressed as inclusion bodies in E.coli prior to in vitro refolding following standard procedures as described in Garboczi et al., (1996), Nature 384, 134-141 . Following refolding the MHC complexes was biotinylated using BirA enzyme able to biotinylate a specific amino acid residue in a recognition sequence fused to the C-terminal of the Heavy Chain by genetic fusion. Monomer MHC complexes was then purified by size exclusion chromatography.
1 . 200 ml of refolding buffer (100 mM Tris, 400 mM L-arginin-HCL, 2 mM NaEDTA, 0.5 mM oxidized Gluthathione, 5 mM reduced Glutathione, pH 8.0) was supplied with protease inhibitors PMSF (phenylmethylsulphonyl fluoride), Pepstatin A and Leupeptin (to a final concentration of 1 mM, 1 mg/l and 1 mg/l, respectively). The refolding buffer was placed at 10 0C on a stirrer.
2. 12 mg of peptide was dissolved in DMSO or another suitable solvent (300-500 μl), and added drop-wise to the refolding buffer at vigorous stirring.
3. 4.4 mg of human Light Chain β2m was added drop-wise to the refolding buffer at vigorous stirring.
4. 6.2 mg of Heavy Chain (supplied with DTT to a concentration of 0.1 mM) was added drop-wise to the refolding buffer at vigorous stirring. 5. The folding reaction was placed at 100C at slow stirring for 4-8 hours.
6. After 4-8 hours, step 3 and 4 was repeated and the folding reaction is placed at 1 O0C at slow stirring O/N.
7. Step 3 and 4 was repeated, and the folding reaction is placed at 100C at slow stirring for 6-8 hours. Optionally, steps 5-7 may be done in less time, e.g. a total of 0.5-5 hours.
8. After 6-8 hours the folding reaction was filtrated through a 0.2 μm filter to remove aggregates.
9. The folding reaction was concentrated O/N at 100C shaking gently in a suitable concentrator with a 5000 mw cut-off filter. The folding reaction was concentrated to approximately 5-10 ml. (Optionally the filtrate can be stored at 40C and reused for another folding with the same peptide and heavy chain.)
10. The concentrated folding reaction was buffer-exchanged at least 8 times, into a MHC-buffer (20 mM Tris-HCI, 50 mM NaCI, pH 8.0) and concentrated (at 1 O0C in a suitable concentrator with a 5000 mw cut-off filter) down to approximately 1 ml.
1 1 . The heavy chain part of the MHC-complex was biotinylated by mixing the following components: approximately 1000 μl folded MHC-complex, 100 μl each of Biomix-A, Biomix-B and d-Biotin (all 3 from Biotin Protein Ligase Kit from Avidity, 10 μl birA enzyme (3 mg/ml, from Biotin Protein Ligase Kit from Avidity, 0.5 μl Pepstatin A (2 mg/ml) and 0.5 μl Leupeptin (2 mg/ml). The above was gently mixed and incubated
O/N at room temperature.
12. The biotinylated and folded MHC-complex solution was centrifuged for 5 min. at 170Ox g, room temperature.
13. Correctly folded MHC-complex was separated and purified from excess biotin, excess β2m, excesss heavy chain and aggregates thereoff, by size exclusion chromatography on a column that separates proteins in the 10-100 kDa range. Correctly folded monomer MHC-complex was eluted with a MHC-buffer (20 mM Tris-HCI, 50 mM NaCI, pH 8.0). The elution profile consisted of 4 peaks, corresponding to aggregated Heavy Chain, correctly folded monomer MHC- complex, β2m and excess biotin and peptide.
14. Fractions containing the folded MHC-complex were pooled and concentrated to approximately 1 ml in a suitable concentrator with a 5000 mw cut-off filter. The protein-concentration was estimated from its abosorption at 280 nm.
15. The grade of biotinylation was analyzed by a SDS PAGE SHIFT-assay with Streptavidin and correct folding was confirmed by ELISA, using the antibody W6/32 that recognizes correctly folded MHC-peptide complex.
Generation of biotinylated DR4 molecules:
DR0401 -leucine zipper-biotinylation site-expression vectors were made using the PCR- mediated splicing overlap technique together with the plasmid pUChsneo, which carries the neomycin resistance marker, were co-transfected into Schneider cells S-2 by standard calcium phosphate transfection techniques. The DR*0401 (DR4) molecules were purified by affinity chromatography using L243 antibody as described previously (Stern and Wiley 1992). The DR4 molecules were biotinylated using BirA enzyme and a standard protocol following a standard biotinylation protocol provided by the manufacturer
Construction, purification and production of trimeric HIVqp140 (YU2qp140) (SEQ ID NO 9583L
PCR Cloning was carried out by inserting the Avi tag in the YU2gp140 Foldon trimer; two sets of PCR overlapping primers were designed. The first set of primers was used with YU2 gp140 foldon construct and to amplify the portions of YU2 gp140 region from BamH1 site through the foldon trimerization motif , His tag and some seq. of Avi tag followed by the stop codon. The other set amplified the His Tag followed by Avi tag seq. and the rev primer amplified the Hind III site, a stop codon and the remaining of the Avi tag. After one round of amplification both the reaction were mixed and the PCR was performed using the Fw primer from first set and the rev primer from second set. PCR amplified product was run on 1 % agarose gel at 100V constant and eluted from the gel using standard procedure. The amplified fragment was digested with BamH1 followed by Hind III . The vector DNA was similarly sequentially digested with the following enzymes and a ligation reaction was performed using the Rapid ligation kit from Roche. The Top10 competent cells(lnvitrogen) were transformed with the 5ul of ligation mix and then plated on Carbenicillin containing plates. 10 colonies were picked up and inoculated in LB medium containing the Carbenecillin and Mini prep was performed using Qiagen kit. The DNA was sent for seq. to ACGT, Inc. using YU2 gp140 Fw primer and seq analysis was performed in the Vector NTI program. The 293 freestyle cells were obtained from Invitrogen and were maintained in serum-free media. The transient transfection was performed when cells reached a density of 2-3x10Λ6 /ml and dilute it to 1.2 X10Λ6/ ml with fresh medium in 1 L batches using 293 fectin reagent from Invitrogen. The transfection grade DNA was obtained from Aldeveron and the transfection was set using standard protocol. After 4 days in culture the supernatant was collected by centrifuging cells in 250 ml conical tubes at 1500 rpm for 30'. The protease inhibitors tablets from Roche were added (1 tablet /50ml of sup) and the supernatant was centrifuged using 0.2um filters. The supenatant was checked by immuno-precipitation with monoclonal antibodies such as b12 for protein expression and then loaded onto the Lentil Lectin (GE Health Care) column overnight (Fig 1 B). The column was washed with at least 10V PBS with 0.5M NaCI and the glycoproteins were eluted with 1 M-α D Methyl Mannopyranoside by rocking the column with 10 volumes of elution buffer. The proteins from the first column were loaded onto Ni column and further eluted with 30OmM - imidazole phosphate buffer. The protein was concentrated by using 3OkDa Millipore concentrators and buffer exchanged with PBS. The total amount of the protein was determined using Spectrophotometer 3000 by OD 28OnM. Trimeric HIVgp140 was biotinylated using BirA enzyme following a standard biotinylation protocol provided by the manufacturer.
Generation of SIVp27 (SEQ ID NO 9584)
Recombinant SIV 27gag (SIVp27) was expressed as pGEX-3x glutathione S- transferase fusion protein from Escherichia coli as previously described (Mills et al 1992). Recombinant proteins were reconstituted at 2mg/ml in PBS. A 10 fold molar excess of Sulpho-NHS-LC-LC Biotin (Pierce UK), at -10 mM in PBS, was added to the protein solutions and incubated at room temperature for 30 minutes. Excess biotin was removed by dialysis against sterile PBS overnight at 4° C. The biotinylated proteins were then incubated with 2 rounds of polymyxin B beads to remove LPS (GE Healthcare, UK). Verification of biotinylation was performed as follows. The proteins were analysed by SDS-PAGE followed by Coomaasie Blue staining and western blotting onto nitrocellulose. The nitrocellulose blots were probed directly with avidin conjugated to horse radish peroxidase (ExrAvidin, Sigma-Aldrich UK) and developed with 3 Amino 9 ethylcarbazole tablets and hydrogen peroxide in 50 mM Acetate buffer pH 5.0 (Sigma -Aldrich, UK). The proteins were >90% biotinylated.
Generation of C-terminal fragment of HSP70
The C-terminal fragment of M. tuberculosis HSP70 (359-609) (SEQ ID NO 9582) was subcloned to enable in vitro biotinylation. A primer of 76 bases for PCR was designed that allows fusion of the recognition site for in vivo biotinylation in E. coli to the C- terminal end of HSP359-GOg ■ Together with a forward cloning primer the HSP359-GOg fusion gene was amplified and after restriction with Nde\ and Xho\ inserted into the expression vector pET26. The resulting plasmid pLEXWOI 67-4 was transformed into E. coli BL21 (DE3). This strain was used for production of biomass. The insert of plasmid pLEXWOI 67-4 was confirmed by sequencing.
For rapid purification metal chelate chromatography HSP359-609 was fused to a 6-fold histidine tag. The HSP359-609 gene was again excised from plasmid pLEXWOI 67-4 using restriction endonucleases Nde\ and Xho\ and inserted into pET28 which provides the sequence for the N-terminal histidine tag. The resulting plasmid pLEXWOI 75-4 was transformed into E. coli BL21 (DE3). This strain was used for production of biomass of biotinylated HSP359-GOg with N-terminal histidine tag. 2. Biomass derived from BL21 (DE3) [p LEXW0175-4] was disrupted using sonification and homogenization. The supernatant after centrifugation underwent metal chelate affinity chromatography. To achieve a higher purity the protein underwent two further purification steps, by anion exchange and size exclusion chromatography. The highly purified N-his HSP359-609-bio (40mg) was subjected to final quality control and a Western blot.
Linking the biologically active molecules to multimerization domain The following pharmamer constructs were made:
1 ) Dextran270 + HLA-A*0101 (IVDCLTEMY )(SEQ ID NO 9588) + DR4 + HSP70 (molar ratio 1 :10:10:4)
2) Dextran270 + HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9590) + HLA- A*0301 (RIAAWMATY) (SEQ ID NO 9591 ) + HSP70 (molar ratio 1 :10:10:4) 3) Dextran270 + HLA-A*1 101 (IVTDFSVIK)SEQ ID NO 9589) + HSP70 (molar ratio 1 :10:4)
4) Dextran270 + HIVgp140 + Sivp27 + HSP70 (molar ratio 1 :3:10:4)
The 4 constructs were made by mixing Dextran270 with the above said biotinylated biological molecules (HLA l-peptide complexes, DR4 molecules, trimeric HIVgp140, SIVp27 and/or HSP70 (359-609)) in molar ratios as described. The final concentration of Dextran was 0.014 M.
These pharmamers may be used in a composition for vaccination of individuals with HIV or vaccination of healthy individuals for preventing infection with HIV.
Example 7
This is an example of how pharmamer vaccine compositions compricing one or more of the pharmamers described in example 6 are used for prophylactic vaccination/immunization of rhesus macaques later challenged with simian HIV.
Immunization of macagues
Thirty-eight female rhesus macaques {Macaca mulatta) of Chinese origin, 3-5 years old at the start of the study, were housed in the Astrid Fagraeus laboratory at the Swedish Institute for Infectious Disease Control. Housing and care procedures were in compliance with the provisions and general guidelines of the Swedish Animal Welfare Agency. All procedures were approved by the Local Ethical Committee on Animal Experiments. Animals were housed in pairs in 4 m3 cages, enriched to allow expression of physiological and behavioural needs. They were habituated to the housing conditions for more than 6 weeks before the start of the experiment, and subjected to positive reinforcement training to reduce the stress associated with experimental procedures. All immunizations and blood sampling were performed under sedation with ketamine 10 mg/kg i.m. (Ketaminol 100 mg/ml, Intervet, Sweden). Macaques were weighed and examined for swelling of lymphnodes and spleen at each immunization or sampling occasion. Before entering the study, all animals were confirmed to be negative for simian immunodeficiency virus (SIV), simian T-cell lymphotropic virus and simian retrovirus type D.
32 of the macaques were divided into 4 groups of eight animals and immunized SC at weeks 0 - 4 - 8 and 16 (figure 3A) with vaccine compositions compricing one or more of the pharmamers described in example 6. The different groups were immunized with different pharmamer vaccine compositions as described in figure 3B. The constituents and concentrations of each of the 4 pharmamers used in a single dose are shown in figure 3C. Animals in groups 1 -3 received a full vaccine dose at the first immunization and half doses at the following immunizations. The vaccines for groups 1 -3 were given subcutaneously (s.c.) formulated as an emulsion with the TiterMax® Gold adjuvant (0.5 mL/full dose; Sigma-Aldrich, St Louis, MO, USA). An additional six animals (group 5) received the same vaccine as group 2, but intramuscularly (i.m.) without TiterMax® Gold (figure 3B), and full vaccine doses at all immunizations.
SHIV challenge
A SHIV-SF162P4 stock was expanded in the human T cell line C8166-CCR5, expressing HLA-A*01 and -DRB1 *04. This T cell line expanded stock was designated SHIV-SF162P4/C. A limited in vivo titration was performed in nine rhesus macaques of Chinese origin. 3/3, 2/3 and 0/3 animals became infected after intravenuous (i.v.) inoculation with 1 ml of a 1/1 ,000, a 1/100,000 and a 1/1 ,000,000 dilution, respectively. The approximate animal infectious dose50 (AID50) was determined by Reed-Muench to be 1 .8χ 105AnL. At week 20 group 1 , 2, 3 and 5 animals plus eight naϊve animals (group 4) were challenged i.v. with 1 mL of a 1/10,000 dilution (corresponding to 18 MID50, 5.8x104 RNA equivalents/ml, and 22.4 and 0.3 TCID50 as measured on C8166-CCR5 cells and rhesus PBMC, respectively) of SHIV-SF162P4/C. Measurement of viral load post viral challenge
Viral load was measured in the animals up to 10 weeks apost SHIV challenge with weekly intervals. The viral load was measured by measuring reverse trancriptase activity in plasma using the ExaVir® Load version 2 kit (Cavidi Tech AB, Uppsala, Sweden) as described by Kiepla et al. Nat. Med. (2007) 13:46-532 and translated to RNA equivalents/ml.
The peak viral load (2-3 weeks post-challenge) was significantly lower only in group 2 macaques (p<0.05), which were immunized with all vaccine components, compared with the unimmunized animals (figure 4A). Group 1 and 5 macaques showed peak viral load at week 3 after infection (in 6/8 and 4/6, respectively), similar to those in the control group 4 (6/8). Group 3 animals however, reached a peak viral load 2 weeks after infection (7/8 animals), followed by a faster fall in the viral load. The cumulative viral load over the 10 week period was then determined and this showed similarly that only group 2 macaques had a significantly lower viral load compared with the unimmunized group 4 animals (figure 4B). Two of the 8 macaques in this group remained uninfected and if these are removed the peak (p=0.017) and cumulative (p=0.049) viral load still show a significant decrease in the 6 animals. These results suggest that all vaccine components are required to prevent or inhibit viral infection, as demonstrated in group 2 macaques. The other 3 immunized groups of animals either lacked HIVgp140 and SIVgag p27 (group 1 ) or HLA-I and Il antigens (group 3) or the Titermax adjuvant (group 5).
Measurement of HLA-I and HLA-II antibodies in serum from immunized animals The Luminex HLA antibody method was used to assay specific antibodies to the 5 immunizing HLA-class I and 1 HLA-class Il antigens. The sera were initially screened for the presence, or absence, of antibodies specific to HLA Class I or Class Il molecules using the Luminex bead based technology (kits from OneLambda Inc.).
Briefly, these kits consist of 12 separate bead groups coated with a number of HLA Class I molecules and 5 separate bead groups coated with a number of HLA Class Il molecules. They contain all the common, and many of the rare, HLA specificities. The
HLA molecules for these beads are isolated from the surface of donor cells and attached by covalent bonds to the luminex beads. Two internal control bead groups, one negative (NC) and one positive (PC) provide background binding information and ensure the test is performing correctly. The beads are incubated with the test sera for 30 minutes, washed, to remove any unbound antibodies and proteins, and then incubated for a further 30 minutes with an appropriate PE conjugated anti-human (IgG) antibody. The beads are then passed through the Luminex analyser, where the level of luminescence from any bound PE is detected and recorded as the Median Fluorescence Index or MFI. The results are analysed by the kit-specific HLA Visual software (OneLambda). The calculation used for screening is:
Test bead Ratio = MFI of Test bead with test sample - MFI of Test bead with Neq control / Internal test sample NC bead - Internal Neg control NC bead The calculated ratio then serves as the result for each bead, the current cut-off values are ratio >1 .3 for class I and >2.5 for class II. The screening results are recorded as either 'positive' or 'negative', with a score representing the number of beads groups showing positivity.
The sera were initially screened neat, and any positive samples were then screened at 1 :100 dilutions (in human AB serum) and again, any positive samples were further tested at 1 :1000 dilution. The sera were then tested for the specificity of any HLA antibodies present using Luminex bead based single antigen screening, again, with kits from OneLambda Inc. These kits use the same luminex beads but with 99 bead groups used in the Class I specific kit and 85 in the Class Il specific kit. Here each bead group is coated with molecules of a single HLA specificity. The HLA molecules for these kits are recombinant in nature, which may effect their final conformation. The sera were tested at 1 :1000 dilution, in human AB serum, to reduce non-specific background binding to the beads. The analysis was again performed using the HLA Visual software and the results are presented as MFI in which the internal negative control MFI is subtracted. MFI >1000 was recorded as specific HLA antibody to the antigen coated bead.
High antibody levels were elicited to all the immunizing HLA-I and Il recombinant antigens at a serum dilution of 1 :100 in groups 1 , 2 and 5 and these were absent in the pre-immunization sera. These antibodies were not detected in group 3 (without HLA antigens) or in the unimmunized group 4 animals. However, at a serum dilution of 1 :1000 only groups 1 and 2 showed significant antibody levels expressed as MFI (figure 5).
As the recombinant HLA antigens were not previously used for immunization, the sera from groups 1 and 2 were analysed by the Luminex HLA multibead antibody (LHMA) for HLA class I and II. Significant correlation was found between antibodies to HLA- DR4 immunizing antigen and the LHMA assay with sera from both group 1 (p=0.009) and group 2 (p=0.028) immunized macaques ( figure 6A, B). Whereas antibodies to all 5 HLA-I and the HLA-2 immunizing antigens showed significant correlation with the LHAM assay in group 2 (figure 6B, D; range p=0.017-p=0.0002), this was not found in the sera from group 1 animals (figure 6A, C, representative illustrations of HLA-I A02). These results are consistent with the recombinant HLA-I and Il construct expressing conformational structures recognized by the LHMA assay in group 2 sera (figure 6C). The significance of HLA-class I antibodies was strengthened by the significant inverse correlation of group 2 macaques with the peak viral load of all 5 HLA-I alleles (p=from 0.01 to 0.0001 ) and with the cumulative viral load of HLA-A1 , A2 and A24 (p=from 0.045 to 0.0004). However, HLA-DR4 antibodies failed to show any correlation with the viral load. HLA-I antibodies were also significantly correlated with the neutralizing activity (see below) in group 2 (p=0.032), and so did HLA-II antibodies (p=0.025).
Measurement of Neutralizing activity of sera from immunized macaques Macaque sera obtained at time points before, during, and after the immunization regime were tested for their relative in vitro neutralizing activity against the challenge virus SHIV.SF162 P4. Macaque sera were tested for their neutralization activity against SHIV.SF162 P4 propagated on C8166.CCR5 cells, using a TZM-bl based assay. Neutralization activity in serum was analyzed both in the presence of complement, using serum from a healthy AB+ blood donor as a source of complement, and in the absence of complement, using heat-inactivated AB+ serum. To inhibit replication of the virus in TZM-bl cells, a final concentration of 1 μM indinavir (AIDS reagent program #8145) was added to Iscove's modified Dulbecco medium supplemented with 10% AB+ serum, penicillin (100 U/ml), streptomycin (100 μg/ml), and DEAE dextran (37.5 μg/ml).
TZM-bl cells were seeded one day in advance at 4.000 cells per well. A final inoculum of 20 TCID50 SHIV.SF162 P4 in a volume of 50 μl was incubated for 1 h at 37QC with twofold serial dilutions of macaque serum (range 1 :40 — 1 :1280), and was then added to the TZM-bl cells. Peptide competition assays were performed as described above, except that serum dilutions were pre-incubated with BaL V3 peptide (TRPNNNTRKSIHIGPGRAFYTTG) or scrambled peptide
(NKGTHNIPTARNIYGFPTSRRGT) at a final concentration of 20 μg/ml for 30 min at 37°C before the addition of virus. After 4 h incubation at 37QC, TZM-bl cells were washed once with 150 μl phosphate-buffered saline (PBS), and subsequently replenished in 200 μl IMDM supplemented with 10% fetal bovine serum, penicillin (100 U/ml), streptomycin (100 μg/ml), and DEAE dextran (37.5 μg/ml). After 48 hours, the cells were again washed in 150 μl PBS. Next, 25 μl freshly prepared luciferase substrate (0.83 mM ATP, 0.83 mM d-luciferin [Duchefa Biochemie B. V., Haarlem, The Netherlands], 18.7 mM MgCI2, 0.78 μM Na2H2P2O7, 38.9 mM Tris [pH 7.8], 0.39% [vol/vol] glycerol, 0.03% [vol/vol] Triton X-100, and 2.6 μM dithiothreitol) was added and luminescence was measured for 1 s per well. Experiments were performed in triplicate. For calculations, the background luciferase expression was subtracted from the relative light units (RLU) of the test wells. The percent neutralization was calculated by determining the reduction in luciferase expression in the presence of neutralizing agent compared to the cultures with virus only. When possible, 50% inhibitory concentrations (IC50) were determined by linear regression. For calculations, viruses with IC50S of <40 or >1280 were assigned a value of 20 or 1280, respectively.
Sera from group 1 and group 2 macaques, both immunized with HLA-I and Il containing vaccine, neutralizing activity was observed only in the presence of complement, indicating that the anti-viral activity in these sera may have been mediated by anti-HLA antibodies (figure 7A). In contrast, sera from group 3 animals, immunized with HIVgp140 and SIVp27 but not with HLA antigens yielded significant neutralizing activity without (figure 7B) or with (figure 7A) complement. Neutralizing activity in serum became detectable after the second immunization, and was enhanced in some but not all animals after the third and/or fourth immunization. No inhibition of a VSV-G pseudotyped HIV variant was observed by group 1 and group 2 sera in the presence of complement (data not shown), indicating that the observed neutralizing activity in group 1 and group 2 sera was not the result of an effect of these sera on the viability of the target cells in the neutralization assay. Furthermore, neutralizing activity of sera from 5/8 group 3 animals was inhibited in the presence of BaL V3 peptides, suggesting that the activity in these sera may be directed against the viral envelope. In contrast, the neutralizing activity in sera from group 2 animals was not reduced in the presence of BaL V3 peptides. Together with the lack of neutralizing activity in group 2 sera in the absence of complement, these results indicate that the immunization regime in group 2 animals has not elicited anti-Env neutralizing antibodies at levels that can be detected in this assay. However, the neutralization titers of sera from group 3 animals were lower compared to titers of sera from group 1 and 2 animals. Neutralization activity of sera from group 5 animals obtained after the last immunization was only slightly enhanced in the presence of complement compared to sera from the control animals (figure 7A), suggesting that the Titermax adjuvant was essential for the development of a potent neutralizing activity.
The next point addressed was whether the differential peak and cumulative viral load after challenge in the 5 groups of macaques, may have been the result of inhibition of the challenge virus SHIV SF162.P4 by the neutralizing activity elicited in response to immunization. To this end, we examined any correlation between the complement dependent neutralizing activity IC50 of sera obtained at the time of viral challenge against SHIV.SF162 P4 and the viral load at several time points after viral challenge. The neutralizing activity showed significant inverse correlation with the peak viral load only in group 2 animals (P = 0.043, figure 7C) suggesting that the presence of anti-viral activity in serum may have influenced the early stages of viral replication. The cumulative viral load, however failed to be significantly correlated with the neutralizing activity (figure 7D). It is noteworthy that the neutralizing activity was also significantly correlated with HLA-class I antibodies only in group 2 sera (n=0.032), unlike those of HLA-class 2, which showed significant correlation with sera in group 1 (p=0.025) and 2 (p=0.006).
These data demonstrates that a pharmamer vaccine composition comprising 5 different biologically active molecules (HLA l-peptide complexes, HLA Il molecule, SIVp27, truncated HSP70 and gp140trimer) attached to one or more of 4 Dextran270 multimerization domains can induce an immune response against SHIV. Systemic immunization (SC x4) with a vaccine composition comprising 4 pharmamers compricing 1 -3 of the 5 biologically active molecules denoted above and comprising the adjuvant Titermax Gold in group 2 macaques elicited a significant decrease in both the peak viral load 2-3 weeks after IV challenge with SHIV SF162.P4 and the cumulative viral load over the whole period of 10 weeks (p<0.05). Two of the 8 animals remained uninfected. HLA-class I and Il proteins were essential in protecting the macaques as Group 3 animals immunized without them showed no protection. This indicates that such af pharmamer vaccine composition could be used for prophylactic treatment against HIV infection in uninfected individuals.
Example 8
This is an example of generation of a pharmamers that can be used in a vaccine composition for treatment of SIV/HIV.
4 different vaccine compositions are generated comprising between 1 -4 pharmamers whereto 3-5 different biological active molecules are attached. The multimerization domain in all pharmamers is Streptavidin (SA) coupled Dextran (27OkDa) and the biologically active molecules are attached to the SA-Dextran backbone by a non- covalent interaction between SA and biotin on the biologically active molecules. In the following generation of the individual components in the pharmamers are described:
Generation of multimerization domain:
Dextran270 are coupled with SA using the following procedure. Divinyl sulfone acid activated Dextran270 are mixed with SA in a molar ratio of 1 :13 (Dextran270:SA) in buffer ( 0,025 M NaHCO3, 0.1 M NaCI) for 2 hours at 40<€. The final concentration of Dextran270 was 6 uM. Then the reaction was stopped by adding 10 vol% 0.165 M Cystein, incubation for 30 minutes at 40 °C. Excess SA was removed by gelfiltration on a Superdex 200-column and the buffer exchanged to 0,1 M NaCI; 10 mM CHES; pH 9.0. The final product has between 8 and 9 SA molecules per Dextran molecule in average.
Generation of biotinylated biologically active molecules:
Four different biotinylated MHC l-peptide complexes are generated: HLA-A*0101 (IVDCLTEMY )SEQ ID NO 9588), HLA-A*1 101 (IVTDFSVIK)SEQ ID NO
9589), HLA-A*0201 (GLIQLVEGV) SEQ ID NO 9590, HLA-A*0301 (RIAAWMATY) SEQ ID NO 9591.
The protein coding sequences minus the signal peptide and transmembrane regions of all of the 4 human MHC class 1 heavy chain molecules are obtained from GenBank and the sequence backtranslated according to E.coli codon usage using www.entelechon.com. The gene is synthesized e.g. by PCR using 10 overlapping DNA primers (DNA Technology, Denmark) and KOD polymerase (EMD Chemicals, Novagen). Sequence is verified by repeated DNA sequencing (MWG Biotech, Ebersberg, Germany) and base errors introduced is corrected using Quick Change multi site-directed mutagenesis kit (Stratagene, La JoIIa, CA) before cloning in pGarboczi (Garboczi et al 1992). A a DNA-sequence encoding a C-terminal Cystein residue is introduced by site directed mutagenesis. Human beta2Microblulin (β2m) (GenBank ace # CAG33347.1 ) is acquired and cloned. Recombinant MHC 1 heavy chain and β2m protein is produced by fermentation, isolated and purified by column chromatography. MHC-peptide complexes aregenerated by in vitro refolding of heavy chain, β2m and peptide in a buffer containing reduced and oxidized glutathione as described for generation of MHC l-peptide complexes in example 6. Following refolding the MHC complexes are chemically biotinylated on the C-terminal cystein residue by treating them with Maleimide-biotin (EZ-link Maleimide-PEO2-Biotin). The reaction can be carried out in PBS, PH 7.0 for 21/2 hour at 4^, with a Maleimide-biotin: MHC-peptide molar ratio equal to 1.5 (1 ,6 ug Maleimide-biotin per 100 ug B*0801 -cys-peptide complex). Excess Maleimide-biotin are removed and the buffer optionally exchanged to e.g. 20 mM Tris-HCI, 50 mM NaCI, pH 8.0 by gel filtration in a G-25 column. Efficiency of biotinylation may be determined using a SDS PAGE shift assay with SA. 1 ug Maleimide-biotin treated MHC-peptide complex is incubated with 1.8 ug SA in 12 ul PBS, pH 7.0 for 1 hour at room temperature. Then the sample is analyzed by SDS PAGE together with samples of various concentrations of Maleimide-biotin treated B*0801 -cys-peptide complex not incubated with SA and a sample with SA alone. The degree of biotinylation is estimated by comparing amount of monomer MHC-peptide complex when incubated with SA and without SA.
Generation of biotinylated SIVp27, trimer qp140, DR4 and truncated HSP70 molecules. Trimeric HIVgp140, DR4, C-terminal fragment of HSP70 and SIVp27 molecules are generated as described in example 6 but with the following modification. A C-terminal cystein are introduced in all molecules e.g. by introducing DNA bases encoding Cystein in the C-terminal of the molecules e.g. by sitedirected mutagenesis or by PCR with primers encoding a C-terminal cystein. Following expression, folding and purification of these molecules as dscribed in example 6 the molecules are chemically biotinylated e.g. using the procedure described above for MJHC l-peptide complexes.
Linking the biologically active molecules to multimerization domain The following pharmamer constructs are made:
1 ) Dextran270 + HLA-A*0101 (IVDCLTEMY )(SEQ ID NO 9588) + DR4 + HSP70 (molar ratio 1 :10:10:4)
2) Dextran270 + HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9590) + HLA- A*0301 (RIAAWMATY) (SEQ ID NO 9591 ) + HSP70 (molar ratio 1 :10:10:4)
3) Dextran270 + HLA-A*1 101 (IVTDFSVIK)SEQ ID NO 9589) + HSP70 (molar ratio 1 :10:4) 4) Dextran270 + HIVgp140 + Sivp27 + HSP70 (molar ratio 1 :3:10:4)
The 4 constructs are made by mixing Dextran270 with the above said biotinylated biological molecules (HLA l-peptide complexes, DR4 molecules, trimeric HIVgp140, SIVp27 and/or HSP70 (359-609)) in molar ratios as described. The final concentration of Dextran is 0.005-0.1 M.
These pharmamers may be used in a composition for vaccination of individuals with HIV or vaccination of healthy individuals for preventing infection with HIV, e.g. as described in example 7.
Example 9
This is an example of generation of a pharmamers that can be used in a vaccine composition for treatment of a viral infection.
Different vaccine compositions are generated comprising between one or more pharmamers whereto 1 -8 different biological active molecules are attached. One or more of the biologically active molecules may derive from the virus in question. One or more other biologically active molecules may be immunologically active molecules. The multimerization domain in all pharmamers is Streptavidin (SA) coupled Dextran (27OkDa) and the biologically active molecules are attached to the SA-Dextran backbone by a non-covalent interaction between SA and biotin on the biologically active molecules.
Generation of biologically active molecules
The biologically active molecules are generated by cloning, expression and purification in suitable expression systems known by persons skilled in the art. A C-terminal cystein residue is introduced in all molecules by fusing the dNA sequence encoding the biological molecules in question to a DNA sequence encoding a cystein residue. Following purification of the biologically active molecules they are chemically biotinylated e.g. using the procedure described in example 6.
Generation of multimerization domain:
Dextran270 or another larger or smaller Dextran molecule are activated with Divinyl sulfone acid and coupled with SA using a procedure like the one described in example 6. The amount of SA molecules coupled to the Dextran may be adjusted by altering the molar ratio between activated Dextran and SA during coupling. Linking the biologically active molecules to multimerization domain Biotinylated biologically activated molecules are attached to the SA-Dextran by incubation at room temperature for 10 minutes or longer. The amount of each molecule attached to the SA-Dextran may be adjusted by adjusting the molar ratio between SA- Dextran and the biologically actibe molecule and/or the ratio between the individual biologically active molecules. or HSP70 (359-609)) in molar ratios as described. The final concentration of Dextran is 0.005-0.1 M.
Such pharmamers may be used in a composition for vaccination of individuals with a viral infection or vaccination of healthy individuals for preventing infection with the virus in quetion, e.g. following a procedure as described in example 7 or elsewhere herein.
Example 10 This is an example of how pharmamers with MHC-peptide complexes attached can be used as a borrelia vaccine for monkeys.
The vaccine is composed of a Dextran (270 kDa) multimerization domain that has been derivatized by attaching Strepavidin (on average 8.6 Strepavidin molecules/Dextran molecule). Attached to the carrier are human HLA class 1 and 2 molecules containing antigenic peptides derived from the Borrelia antigen Basic membrane protein A (BmpA). The attached HLA-peptide complexes are:
HLA-A*0201 (YLAPDNVIT), HLA-A*0101 (YSDEIDIIH), HLA-B*0702(APDNVITST), HLA-DRB1 *0401 (IELVLKESSSNSYLS), HLA-BRB1 *1501 (MNKILLLILLESIVF) and
HLA-DRB1 *1 101 (SDLIWLIGYRFSDVA).
A single full dose of the final vaccine corresponds to, 100 μg of each MHC class 1 ; 1 13,5 ug of HLA class 2; 3x25.8 μg HSP70 and 3x162.2 μg dextran (corresponding to a total of approx 300 μg MHC multimer/kg body weight for a monkey of 3.5 kg) and consist of a 1 :1 :1 mixture of the following three MHC multimers:
MHC multimer 1 :
HLA-A*0101 (YSDEIDIIH) + HLA-DR*0401 (IELVLKESSSNSYLS) + HSP70 + Dextran carrier, in the molar ratio 10/10/4/1 MHC multimer 2:
HLA-A*0201 (YLAPDNVIT) + HLA-DR4I SOI (MNKILLLILLESIVF) + HSP70 + Dextran carrier, in the molar ratio"! 0/10/4/1
MHC multimer 2:
HLA-B*0702(APDNVITST) + HLA-DRB1 *1 101 (SDLrWLIGYRFSDVA) +
HSP70 + Dextran carrier, in the molar ratiol 0/10/4/1
Administration:
The MHC multimer mix is emulsified with the adjuvant Titermax Gold as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and
16 weeks such that a full dose is given at 0 weeks and half-full dose at 4, 8, and 16 5 weeks. This vaccine may give protection against infection with Borrelia bacteria.
The biological effect of the vaccination may be determined using immune monitoring assays.
A pharmamer composition as described above may also be used for vaccination of human against Borrelia infecetion. In humans the adjuvant Titermax Gold should be replaced with an adjuant for human use.
Example 11
This is an example of how pharmamers with MHC-peptide complexes attached can be used as a borrelia vaccine for monkeys.
The vaccine is composed of an antigen presenting cell (APC) e.g. a Dendritic cell expressing the HLA class 1 molecules HLA-A*0101 and HLA-B*0702. The APC is loaded with antigenic peptides derived from the Borrelia protein Basic membrane protein A (BmpA) by incubation with the peptides for 2-5 hours at 37QC. The amino acid sequence of the peptides are YSDEIDIIH and APDNVITST.
Administration:
The peptide loaded APC are added the adjuvant Titermax Gold as specified by the manufacturer and administered as intramuscular injections at time points 0, 4, 8, and 16 weeks. This vaccine may give protection against infection with Borrelia bacteria. The biological effect of the vaccination may be determined using immune monitoring assays as described elsewhere herein
A pharmamer composition as described above may also be used for vaccination of human against Borrelia infecetion. In humans the adjuvant Titermax Gold should be replaced with an adjuant for human use.

Claims

Claims
1. A composition comprising one or more pharmamers.
2. The composition according to claim 1 , wherein the composition is a composition for vaccination.
3. The composition according to any of claims 1 -2, wherein the one or more pharmamers comprises one or more organic molecule-based pharmamers.
4. The composition according to any of claims 1 -3, wherein the one or more pharmamers comprises one or more functionalized cyclic structures such as benzene rings where e.g. a benzene ring is functionalized and covalently linked to e.g. three immunologically active molecules.
5. The composition according to any of claims 1 -4, wherein the one or more pharmamers comprises one or more cell-based pharmamers.
6. The composition according to any of claims 1 -5, wherein the one or more pharmamers comprises one or more dendritic cells and/or one or more antigen presenting cells (APCs).
7. The composition according to any of claims 1 -6, wherein the one or more pharmamers comprises one or more membrane-based pharmamers.
8. The composition according to any of claims 1 -7, wherein the one or more pharmamers comprises one or more liposomes and/or micelles e.g. carrying immunologically active molecules or complexes in their membranes.
9. The composition according to any of claims 1 -8, wherein the one or more pharmamers comprises one or more polymer-based pharmamers.
10. The composition according to any of claims 1 -9, wherein the one or more pharmamers comprises one or more molecule constructs where immunologically active molecules or complexes are bound covalently or non- covalently to a dextran.
1 1 . The composition according to any of claims 1 -10, wherein the one or more pharmamers comprises one or more backbone/multimerisation domain(s).
12. The composition according to any of claims 1 -1 1 , wherein the one or more pharmamers comprises one or more particles such as beads.
13. The composition according to any of claims 1 -12, wherein the one or more pharmamers comprises one or more solid supports with immunologically active molecules immobilized on the surface.
14. The composition according to any of claims 1 -13, wherein the one or more pharmamers comprises one or more multimerization domain(s) such as one or more cells, polymers, proteins or other molecular structures, or particles and solid supports.
15. The composition according to any of claims 1 -14, wherein the one or more pharmamers comprises one or more pharmamers in solid form and/or one or more pharmamers in insoluble form and/or one or more pharmamers in soluble form and/or one or more pharmamers in suspension.
16. The composition according to any of claims 1 -15, wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and
1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to
800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to
400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to
200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to
940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to
740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to
540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to
340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 980,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to
820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to
620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to
420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to
220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000.
17. The composition according to any of claims 1 -16, wherein the one or more pharmamers has a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to
900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
18. The composition according to any of claims 1 -17, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 4,000,000 Da; such as from 50,000 Da to 3,000,000 Da; such as from 50,000 Da to 2,000,000; such as from 50,000 Da and 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from
50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from
50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from
50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from
50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000
Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000
Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000
Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000
Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000
Da to 980,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000
Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000
Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000
Da to 180,000; for example from 150,000 Da to 160,000.
19. The composition according to any of claims 1 -18, wherein the one or more pharmamers has an average molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from
100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from
2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to 3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000
Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000 Da.
20. The composition according to any of claims 1 -19, wherein the one or more pharmamers has a molecular weight of at least 50,000 Da, such as at least 100,000 Da, for example at least 200,000 Da, such as at least 300,000 Da, for example at least 400,000 Da, such as at least 500,000 Da, for example at least 600,000 Da, such as at least 700,000 Da, for example at least 800,000 Da, such as at least 900,000 Da, for example at least 1 ,000,000 Da, such as at least 1 ,100,000 Da, for example at least 1 ,200,000 Da, such as at least 1 ,300,000 Da, for example at least 1 ,400,000 Da, such as at least 1 ,500,000 Da, for example at least 1 ,600,000 Da, such as at least 1 ,700,000 Da, for example at least 1 ,800,000 Da, such as at least 1 ,900,000 Da, for example at least 2,000,000 Da, such as at least 2,100,000 Da, for example at least 2,200,000 Da, such as at least 2,300,000 Da, for example at least 2,400,000 Da, such as at least 2,500,000 Da, for example at least 2,600,000 Da, such as at least 2,700,000 Da, for example at least 2,800,000 Da, such as at least 2,900,000 Da, for example at least 3,000,000 Da, such as at least 3,100,000
Da, for example at least 3,200,000 Da, such as at least 3,300,000 Da, for example at least 3,400,000 Da, such as at least 3,500,000 Da, for example at least 3,600,000 Da, such as at least 3,700,000 Da, for example at least 3,800,000 Da, such as at least 3,900,000 Da, for example at least 4,000,000 Da, such as at least 4,100,000 Da, for example at least 4,200,000 Da, such as at least 4,300,000 Da, for example at least 4,400,000 Da, such as at least 4,500,000 Da, for example at least 4,600,000 Da, such as at least 4,700,000 Da, for example at least 4,800,000 Da, such as at least 4,900,000 Da, for example at least 5,000,000 Da.
21 . The composition according to any of claims 1 -20, wherein the one or more pharmamers has a molecular weight of less than 5,000,000 Da, such as less than 4,900,000 Da, for example less than 4,800,000 Da, such as less than 4,700,000 Da, for example less than 4,600,000 Da, such as less than 4,500,000 Da, for example less than 4,400,000 Da, such as less than 4,300,000 Da, for example less than 4,200,000 Da, such as less than 4,100,000 Da, for example less than 4,000,000 Da, such as less than 3,900,000 Da, for example less than 3,800,000 Da, such as less than 3,700,000 Da, for example less than 3,600,000 Da, such as less than 3,500,000 Da, for example less than 3,400,000 Da, such as less than 3,300,000 Da, for example less than 3,200,000 Da, such as less than 3,100,000 Da, for example less than 3,000,000 Da, such as less than 2,900,000 Da, for example less than 2,800,000 Da, such as less than 2,700,000 Da, for example less than 2,600,000 Da, such as less than 2,500,000 Da, for example less than 2,400,000 Da, such as less than 2,300,000 Da, for example less than 2,200,000 Da, such as less than 2,100,000 Da, for example less than
2,000,000 Da, such as less than 1 ,900,000 Da, for example less than 1 ,800,000 Da, such as less than 1 ,700,000 Da, for example less than 1 ,600,000 Da, such as less than 1 ,500,000 Da, for example less than 1 ,400,000 Da, such as less than 1 ,300,000 Da, for example less than 1 ,200,000 Da, such as less than 1 ,100,000 Da, for example less than 1 ,000,000 Da, such as less than 900,000
Da, for example less than 800,000 Da, such as less than 700,000 Da, for example less than 600,000 Da, such as less than 500,000 Da, for example less than 400,000 Da, such as less than 300,000 Da, for example less than 200,000 Da, such as less than 100,000 Da, for example less than 50,000 Da.
22. The composition according to any of claims 1 -21 , wherein the composition comprises more than 1 pharmamer, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 pharmamers.
23. The composition according to any of claims 1 -22, wherein the composition comprises more than 2 different pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different pharmamers.
24. The composition according to any of claims 1 -23, wherein the composition comprises more than 2 identical pharmamers, such as more than 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical pharmamers.
25. The composition according to any of claims 1 -24, wherein the composition comprises less than 10,000 pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20,
15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 pharmamers.
26. The composition according to any of claims 1 -25, wherein the composition comprises less than 10,000 different pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800,
700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different pharmamers.
27. The composition according to any of claims 1 -26, wherein the composition comprises less than 10,000 identical pharmamers, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical pharmamers.
28. The composition according to any of the claims 1 -27, wherein the one or more pharmamers comprises one or more biologically active molecules.
29. The composition according to any of the claims 1 -28, wherein the one or more pharmamers comprises more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 biological active molecules.
30. The composition according to any of the claims 1 -29, wherein the one or more pharmamers comprises more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules.
31 . The composition according to any of the claims 1 -30, wherein the one or more pharmamers comprises more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500,
600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 identical biological active molecules.
32. The composition according to any of claims 1 -31 , wherein one or more pharmamers comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
33. The composition according to any of claims 1 -32, wherein the one or more pharmamers comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different biologically active molecules.
34. The composition according to any of claims 1 -33, wherein the one or more pharmamers comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000,
2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical biologically active molecules.
35. The composition according to any of the claims 1 -31 , wherein the composition comprises one or more biologically active molecules.
36. The composition according to any of the claims 1 -28, wherein the composition comprises more than 1 biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 biological active molecules.
37. The composition according to any of the claims 1 -29, wherein the composition comprises more than 1 different biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 different biological active molecules.
38. The composition according to any of the claims 1 -30, wherein the composition comprises more than 1 identical biologically active molecules such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700,
800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical biological active molecules.
39. The composition according to any of claims 1 -31 , wherein the composition comprises less than 10,000 biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
40. The composition according to any of claims 1 -32, wherein the composition comprises less than 10,000 different biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or less than 2 different biologically active molecules.
41 . The composition according to any of claims 1 -33, wherein the composition comprises less than 10,000 identical biologically active molecules, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 biologically active molecules.
42. The composition according to any of claims 35-41 , wherein the one or more biologically active molecules are not attached to the one or more pharmamers.
43. The composition according to any of claims 35-42, wherein the one or more biologically active molecules are attached to some but not all of the one or more pharmamers.
44. The composition according to any of claims 35-43, wherein the one or more biologically active molecules are attached to one of the one or more pharmamers.
45. The composition according to any of claims 35-44, wherein the one or more biologically active molecules are attached to more than one of the one or more pharmamers such as more to than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000,
6,000, 7,000, 8,000, 9,000, or to more thani 0,000 of the one or more pharmamers.
46. The composition according to any of claims 35-44, wherein the one or more biologically active molecules are attached to less than 10,000 of the one or more pharmamers, such as for example to less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5,
4, 3 or to less than 2 of the one or more pharmamers.
47. The composition according to any of claims 1 -46, wherein the composition comprises at least one biologically active molecule such as from 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to10, or 1 to more than 10; 2 to 3, 2 to 4, 2 to
5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, or 2 to more than 10; 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, or 3 to more than 10; 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to9, 4 to 10, or 4 to more than 10; 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, or 5 to more than 10; 6 to 7, 6 to 8, 6 to 9, 6 to 10, or 6 to more than 10; 7 to 8, 7 to
9, 7 to 10, or 7 to more than 10; 8 to 9, 8 to 10, or 8 to more than 10; 9 to 10, or 9 to more than 10 different biologically active molecules.
48. The composition according to any of claims 1 -47, wherein the composition comprises two different biologically active molecules termed A and B, wherein the ratio of A:B can be selected from the group consisting of 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :10, 2:3, and 3:5.
49. The composition according to any of claims 1 -48, wherein the composition comprises three different biologically active molecules termed A, B and C, wherein the ratio of A:B:C can be selected from the group consisting of 1 :1 :1 , 1 :2:1 , 1 :3:1 , 1 :4:1 , 1 :5:1 , 1 :10:1 , 2:1 :1 , 2:1 :2, 2:3:2, and 3:5:8.
50. The composition according to any of claims 1 -49, wherein the composition comprises five different biologically active molecules termed A, B, C, D, and E, wherein the ratio of A:B:C:D:E can be selected from the group consisting of 1 :1 :1 :1 :1 , 1 :1 :1 :1 :2, 1 :1 :1 :2:2, 1 :2:2:2:2, 2:4:3:6:5, 4:6:8:1 :1 , and 10:1 :2:5:2.
51 . The composition according to any of the claims 28-50, wherein the one or more biologically active molecules comprises one or more molecules with adjuvant effects.
52. The composition according to any of the claims 28-51 , wherein the one or more biologically active molecules comprises one or more immune targets such as one or more antigens.
53. The composition according to any of the claims 28-52, wherein the one or more biologically active molecules comprises one or more molecules with biological activity such as one or more enzymes.
54. The composition according to any of the claims 28-53, wherein the one or more biologically active molecules comprises one or more regulators of one or more receptor activities.
55. The composition according to any of the claims 28-54, wherein the one or more biologically active molecules comprises one or more receptor ligands.
56. The composition according to any of the claims 28-55, wherein the one or more biologically active molecules comprises one or more immune potentiators.
57. The composition according to any of the claims 28-56, wherein the one or more biologically active molecules comprises one or more drugs.
58. The composition according to any of the claims 28-57, wherein the one or more biologically active molecules comprises one or more toxins.
59. The composition according to any of the claims 28-58, wherein the one or more biologically active molecules comprises one or more co-receptors.
60. The composition according to any of the claims 28-59, wherein the one or more biologically active molecules comprises one or more proteins.
61 . The composition according to any of the claims 28-60, wherein the one or more biologically active molecules comprises one or more peptides.
62. The composition according to any of the claims 28-61 , wherein the one or more biologically active molecules comprises one or more sugar moieties.
63. The composition according to any of the claims 28-62, wherein the one or more biologically active molecules comprises one or more lipid groups.
64. The composition according to any of the claims 28-63, wherein the one or more biologically active molecules comprises one or more nucleic acids including siRNA and microRNA.
65. The composition according to any of the claims 28-64, wherein the one or more biologically active molecules comprises one or more nano particles.
66. The composition according to any of the claims 28-65, wherein the one or more biologically active molecules comprises one or more small molecules.
67. The composition according to any of the claims 28-66, wherein the one or more biologically active molecules comprises one or more membranes.
68. The composition according to any of the claims 28-67, wherein the one or more biologically active molecules comprises one or more liposomes.
69. The composition according to any of the claims 28-68, wherein the one or more biologically active molecules comprises one or more immunological active molecules.
70. The composition according to any of the claims 28-69, wherein the one or more biologically active molecules comprises more than one identical immunological active molecules.
71 . The composition according to any of the claims 28-70, wherein the one or more biologically active molecules comprises more than one different immunological active molecules.
72. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more biological active molecules including proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, as well as antibodies and recombinant binding molecules to any of the foregoing, and combinations thereof.
73. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of MHC Class 1 proteins like HLA-A, HLA-B, HLA-C alone or in complex with HLA-b2Microglobulin with or without peptide in the binding groove.
74. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Class 1 -like proteins like MICA, MICB, CD1 d, HLA-E, HLA-F, HLA- G, HLA-H, ULBP-1 , ULBP-2, and ULBP-3.
75. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of HLA class 2 proteins like HLA-DR (HLA-DRA, HLA-DRB1 , HLA- DRB3, HLA-DRB4, HLA-DRB5), HLA-DQ (HLA-DQA1 , HLADQA2, HLA-DQB1 , HLA-DQB2), HLA-DP (HLA-DPA1 , HLA-DPB1 ), HLA-DO (HLA-DOA, HLA-
DOB), HLA-DM (HLA-DMA, HLA-DMB) alone or in complexes consisting of class 2 A- and B-chains with or without peptide in the binding groove.
76. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Cytokines; IFN-alpha, IFN-beta, IFN-gamma, IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28,-IL-29, IL-30, IL-31 , IL-32, IL-33, IL- 34, IL-35, CSFs (colony-stimulating factors), c-Kit, EPO, TNF-alfa, TNF-beta, Lymphotoxin; Cytokine receptors like IL-1 R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R,
IL-7R, IL-8R, IL-9-R, IL-10R, IL-1 1 R, IL-12R, IL-13R, IL-15R, IL-18R, IL-20R, IL-21 R, IL-22R, IL-23R, IL-27R, IL-28R; Chemokines such as CXCL1 , CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL1 1 , CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CCL1 , CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL8, CCL9, CCL10, CCL1 1 , CCL12, CCL13,
CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21 , CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCR4, CCRL2; Chemokine receptors like CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR1 1 , CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, and CX3CR1.
77. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Toll-like receptors such as TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10.
78. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Toll like receptor ligands such as multiple triacyl lipopeptides, multiple diacyl lipopeptides, multiple glycolipids, multiple lipopeptides, multiple lipoproteins, lipoteichoic acid, peptidoglycans, heat shock proteins (HSP70, HSP90 and others), zymosan, single- and double-stranded RNA, Poly I:C, lipo- polysaccharides, fibrinogen, heparin sulphate fragments, hyaluronic acid fragments, flagellin, imidazoquinoline, loxoribine (guanosine analogue), bropirimine, Imiquimod, unmethylated CpG DNA.
79. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Viral entry receptors/molecules such as Ku70, Pvr, PrM , HVEM, EphrinB2, cellular integrins (in particular alpha2beta1 , alpha6beta1 alphaVbeta3), CD81 , CD155, SR-B1 , claudin-1 , xCT, human nectin-2, LIGHT, TLR3, LIR, Heparan sulphate proteoglycans, GPI anchored proteins, hemeagglutinin receptor.
80. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Bacterial entry receptors/molecules like CD48, CEACAM-1 , -2, -3, -4, -5, -6, invasion, internalin (InIA), InIB; Fc receptors like ε (FcεRI, FcεRII) - γ (FcγRI, FcyRII, FcγRIII) - o/μ (FcαRI, Fcα/μR) - Neonatal FcR.
81 . The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Lymphocyte homing receptors such as CD44, L-selectin, VLA-4 (CD49a, b, c, d, e, f), LFA-1.
82. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD120, CD137 (4-1 BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, PD-1 , Fas (CD95), FasL, CD40, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-L2, CD134L, CD137L, ICOSL
83. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of NK cell receptors/molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR3DL1 , KIR3DL", KIR3DS1 , KIR2DL1.KIRDL2, KIR2DL3, KIR2DL4, KIR2DL5, CD94/NKG2A, CD94/NKG2C, CD94/NKG2E, CD94/NKG2H, NKG2ADNKG2D.
84. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Adhesion molecules such as ICAM-1 , ICAM-2, GlyCAM-1 , VCAM, CD34.
85. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of Anti microbial peptides such Defensins and cathelicidin derived peptide LL-37.
86. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of anti-LFA-1 , anti-CD44, anti-beta7, anti-selectin L, anti-selectin E, and anti- selectin P, toxic molecules selected from toxins, enzymes, antibodies, radioisotopes, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, heavy metals like inorganic and organic mercurials, and FN18- CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and combinations of any of the foregoing, as well as antibodies (monoclonal, polyclonal, and recombinant) to the foregoing, where relevant.
87. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of antibody derivatives or fragments thereof.
88. The composition according to claim 69, wherein the one or more immunological active molecules comprises one or more molecule(s) selected from the group consisting of biologically active molecules derived from viral or bacterial proteins or fragments thereof.
89. The composition according to any of claims 28-88, wherein the one or more biologically active molecules affect the characteristics of the one or more pharmamers e. g. with respect to binding properties, effects, antigenecity, specificity, solubility, stability, or detectability.
90. The composition according to any of claims 28-89, wherein the one or more biologically active molecules further comprises a flexible or rigid, and water soluble, linker that allows for the immobilized biologically active molecules to interact efficiently with surrounding cells and molecules.
91 . The composition according to any of claims 28-90, wherein the one or more biologically active molecules further comprises a cleavable linker allowing for release of the biologically active molecules from the one or more pharmamers.
92. The composition according to any of claims 28-91 , wherein the one or more biologically active molecules comprises one or more MHC multimers.
93. The composition according to claim 92, wherein the one or more MHC multimers comprises a MHC multimer comprising (a-b-P)n,
wherein n > 1 , wherein a and b together form a functional MHC protein capable of binding the peptide P, when P is present
wherein (a-b-P) is the MHC-peptide complex formed when the peptide P binds to the functional MHC protein,
wherein each MHC peptide complex is associated with one or more multimerization domains.
94. The composition according to claim 93, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the one or more multimerization domains.
95. The composition according to claim 93, wherein the association is a non- covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the one or more multimerization domains.
96. The composition according to any of claims 93-95, wherein the one or more multimerization domains comprises one or more scaffolds.
97. The composition according to any of claims 93-96, wherein the one or more multimerization domains comprises one or more carriers.
98. The composition according to any of claims 93-97, wherein the one or more multimerization domains comprises at least one scaffold and at least one carrier.
99. The composition according to any of the claims 93-98, wherein the one or more multimerization domains comprise one or more optionally substituted organic molecules.
100. The composition according to claim 99, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
101. The composition according to claim 100, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
102. The composition according to claim 99, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
103. The composition according to any of the claims 93-102, wherein the one or more multimerization domains comprises one or more biological cells, such as antigen presenting cells or dendritic cells or cells transfected with one or more genes encoding MHC molecules.
104. The composition according to any of the claims 93-103, wherein the one or more multimerization domains comprises one or more membranes.
105. The composition according to claim 104, wherein the one or more membranes comprises liposomes or micelles.
106. The composition according to claim 93-105, wherein the one or more multimerization domains comprises one or more polymers.
107. The composition according to claim 106, wherein the one or more polymers are selected from the group consisting of polysaccharides.
108. The composition according to claim 107, wherein the polysaccharide comprises one or more dextran moieties.
109. The composition according to any of claims 93-108, wherein the one or more multimerization domains comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA-PNA, PNA-DNA, DNA-RNA, streptavidin and avidin.
1 10. The composition according to any of claims 93-109, wherein the one or more multimerization domains comprises an avidin, such as streptavidin.
1 1 1. The composition according to any of claims 93-109, wherein the one or more multimerization domains comprises an antibody.
1 12. The composition according to claim 1 1 1 , wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody.
1 13. The composition according to any of claims 93-1 12, wherein the MHC multimer comprises one or more small organic scaffold molecules.
1 14. The composition according to any of claims 93-1 13, wherein the MHC multimer comprises one or more further polypeptides in addition to a and b.
1 15. The composition according to any of claims 93-1 14, wherein the MHC multimer comprises one or more protein complexes.
1 16. The composition according to any of claims 93-1 15, wherein the MHC multimer comprises one or more beads.
1 17. The composition according to any of claims 93-1 16, wherein the multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(Ci-Ci0)alkoxy- PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG,
PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin- monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, polyacrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'- bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen- fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
18. The composition according to any of claims 93-1 17, wherein the one or more multimerization domains comprises a dimerization domain.
1 19. The composition according to any of claims 93-1 18, wherein the one or more multimerization domains comprises a trimerization domain.
120. The composition according to any of claims 93-1 19, wherein the one or more multimerization domains comprises a tetramerization domain.
121. The composition according to any of claims 93-120, wherein the one or more multimerization domains comprises a pentamerization domain.
122. The composition according to claim 121 , wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
123. The composition according to any of claims 93-122, wherein the one or more multimerization domains comprises a hexamerization domain.
124. The composition according to claim 123, wherein the hexamerization domain comprises three IgG domains.
125. The composition according to any of claim 93-124, wherein the one or more multimerization domains comprises a polymer structure to which is attached one or more scaffolds.
126. The composition according to claim 125, wherein the polymer structure comprises a polysaccharide.
127. The composition according to claim 126, wherein the polysaccharide comprises one or more dextran moieties.
128. The composition according to any of claims 93-127, wherein the one or more multimerization domains comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
129. The composition according to any of claims 93-128, wherein the one or more multimerization domains comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or a cyclodextrin.
130. The composition according to any claims 93-129, wherein the one or more multimerization domains have a molecular weight of less than 1 ,000 Da.
131 . The composition according to any of claims 93-130, wherein the one or more multimerization domains have a molecular weight of from 1 ,000 Da to preferably less than 10,000 Da.
132. The composition according to any of claims 93-131 , wherein the one or more multimerization domains have a molecular weight of from 10,000 Da to preferably less than 100,000 Da.
133. The composition according to any of claims 93-132, wherein the one or more multimerization domains have a molecular weight of from 100,000 Da to preferably less than 1 ,000,000 Da.
134. The composition according to any of claims 93-133, wherein the one or more multimerization domains have a molecular weight of more than 1 ,000,000
Da.
135. The composition according to any of claims 93-134, wherein the one or more multimerization domains have a molecular weight of from 50,000 Da to preferably less than 1 ,000,000 Da, such as from 50,000 Da to 980,000; for example from 50,000 Da to 960,000; such as from 50,000 Da to 940,000; for example from 50,000 Da to 920,000; such as from 50,000 Da to 900,000; for example from 50,000 Da to 880,000; such as from 50,000 Da to 860,000; for example from 50,000 Da to 840,000; such as from 50,000 Da to 820,000; for example from 50,000 Da to 800,000; such as from 50,000 Da to 780,000; for example from 50,000 Da to 760,000; such as from 50,000 Da to 740,000; for example from 50,000 Da to 720,000; such as from 50,000 Da to 700,000; for example from 50,000 Da to 680,000; such as from 50,000 Da to 660,000; for example from 50,000 Da to 640,000; such as from 50,000 Da to 620,000; for example from 50,000 Da to 600,000; such as from 50,000 Da to 580,000; for example from 50,000 Da to 560,000; such as from 50,000 Da to 540,000; for example from 50,000 Da to 520,000; such as from 50,000 Da to 500,000; for example from 50,000 Da to 480,000; such as from 50,000 Da to 460,000; for example from 50,000 Da to 440,000; such as from 50,000 Da to 420,000; for example from 50,000 Da to 400,000; such as from 50,000 Da to 380,000; for example from 50,000 Da to 360,000; such as from 50,000 Da to 340,000; for example from 50,000 Da to 320,000; such as from 50,000 Da to 300,000; for example from 50,000 Da to 280,000; such as from 50,000 Da to 260,000; for example from 50,000 Da to 240,000; such as from 50,000 Da to 220,000; for example from 50,000 Da to 200,000; such as from 50,000 Da to 180,000; for example from 50,000 Da to 160,000; such as from 50,000 Da to 140,000; for example from 50,000 Da to 120,000; such as from 50,000 Da to 100,000; for example from 50,000 Da to 80,000; such as from 50,000 Da to 60,000; for example from 100,000 Da to 1 ,000,000; such as from 100,000 Da to 980,000; for example from 100,000 Da to 960,000; such as from 100,000 Da to 940,000; for example from 100,000 Da to 920,000; such as from 100,000 Da to 900,000; for example from 100,000 Da to 880,000; such as from 100,000 Da to 860,000; for example from 100,000 Da to 840,000; such as from 100,000 Da to 820,000; for example from 100,000 Da to 800,000; such as from 100,000 Da to 780,000; for example from 100,000 Da to 760,000; such as from 100,000 Da to 740,000; for example from 100,000 Da to 720,000; such as from 100,000 Da to 700,000; for example from 100,000 Da to 680,000; such as from 100,000 Da to 660,000; for example from 100,000 Da to 640,000; such as from 100,000 Da to 620,000; for example from 100,000 Da to 600,000; such as from 100,000 Da to 580,000; for example from 100,000 Da to 560,000; such as from 100,000 Da to 540,000; for example from 100,000 Da to 520,000; such as from 100,000 Da to 500,000; for example from 100,000 Da to 480,000; such as from 100,000 Da to 460,000; for example from 100,000 Da to 440,000; such as from 100,000 Da to 420,000; for example from 100,000 Da to 400,000; such as from 100,000 Da to 380,000; for example from 100,000 Da to 360,000; such as from 100,000 Da to 340,000; for example from 100,000 Da to 320,000; such as from 100,000 Da to 300,000; for example from 100,000 Da to 280,000; such as from 100,000 Da to 260,000; for example from 100,000 Da to 240,000; such as from 100,000 Da to 220,000; for example from 100,000 Da to 200,000; such as from 100,000 Da to 180,000; for example from 100,000 Da to 160,000; such as from 100,000 Da to 140,000; for example from 100,000 Da to 120,000; such as from 150,000 Da to 1 ,000,000; for example from 150,000 Da to 960,000; such as from 150,000 Da to 940,000; for example from 150,000 Da to 920,000; such as from 150,000 Da to 900,000; for example from 150,000 Da to 880,000; such as from 150,000 Da to 860,000; for example from 150,000 Da to 840,000; such as from 150,000 Da to 820,000; for example from 150,000 Da to 800,000; such as from 150,000 Da to 780,000; for example from 150,000 Da to 760,000; such as from 150,000 Da to 740,000; for example from 150,000 Da to 720,000; such as from 150,000 Da to 700,000; for example from 150,000 Da to 680,000; such as from 150,000 Da to 660,000; for example from 150,000 Da to 640,000; such as from 150,000 Da to 620,000; for example from 150,000 Da to 600,000; such as from 150,000 Da to 580,000; for example from 150,000 Da to 560,000; such as from 150,000 Da to 540,000; for example from 150,000 Da to 520,000; such as from 150,000 Da to 500,000; for example from 150,000 Da to 480,000; such as from 150,000 Da to 460,000; for example from 150,000 Da to 440,000; such as from 150,000 Da to 420,000; for example from 150,000 Da to 400,000; such as from 150,000 Da to 380,000; for example from 150,000 Da to 360,000; such as from 150,000 Da to 340,000; for example from 150,000 Da to 320,000; such as from 150,000 Da to 300,000; for example from 150,000 Da to 280,000; such as from 150,000 Da to 260,000; for example from 150,000 Da to 240,000; such as from 150,000 Da to 220,000; for example from 150,000 Da to 200,000; such as from 150,000 Da to 180,000; for example from 150,000 Da to 160,000.
136. The composition according to any of claims 93-135, wherein n is 2.
137. The composition according to any of claims 93-136, wherein n is 3.
138. The composition according to any of claims 93-137, wherein n is 4.
139. The composition according to any of claims 93-138, wherein n is 5.
140. The composition according to any of claims 93-139, wherein n is 6.
141 . The composition according to any of claims 93-140, wherein n is 7.
142. The composition according to any of claims 93-141 , wherein n is 8, 9, 10, 1 1 or 12.
143. The composition according to any of claims 93-142, wherein n < 12.
144. The composition according to any of claims 93-143, wherein 1 <n<100.
145. The composition according to any of claims 93-144, wherein 1 <n<1000.
146. The composition according to any of claims 93-145, wherein 1 <n.
147. The composition according to any of claims 93-146, wherein n is billions or trillions or higher.
148. The composition according to any of claims 93-147, wherein n <
1 ,000,000,000.
149. The composition according to any of claims 93-148, wherein n < 1 ,000,000,000,000,000,000.
150. The composition according to any of claims 93-149, wherein n (the total number of MHC molecules of the construct) is in the range from 100 MHC molecules to 1 ,000,000 MHC molecules such as from 100 to 1 ,000 MHC molecules, for example from 1 ,000 to 5,000 MHC molecules, such as from 5,000 to 10,000 MHC molecules, for example from 10,000 to 20,000 MHC molecules, such as from 20,000 to 30,000 MHC molecules, for example from 30,000 to 40,000 MHC molecules, such as from 40,000 to 50,000 MHC molecules, for example from 50,000 to 60,000 MHC molecules, such as from 60,000 to 70,000 MHC molecules, for example from 70,000 to 80,000 MHC molecules, such as from 80,000 to 90,000 MHC molecules, for example from
90,000 to 100,000 MHC molecules, such as from 100,000 to 200,000 MHC molecules, for example from 200,000 to 300,000 MHC molecules, such as from 300,000 to 400,000 MHC molecules, for example from 400,000 to 500,000 MHC molecules, such as from 500,000 to 600,000 MHC molecules, for example from 600,000 to 700,000 MHC molecules, such as from 700,000 to 800,000 MHC molecules, for example from 800,000 to 900,000 MHC molecules, such as from 900,000 to 1 ,000,000 MHC molecules.
151. The vaccine composition according to any of claims 93 to 150, wherein n is selected from the group of integers consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10,
1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 1000.
152. The vaccine composition according to any of claims 93 to 151 , wherein n has a value of from 1 to 1000, for example from 1 to 10, such as from 10 to 20, for example from 20 to 30, such as from 30 to 40, for example from 40 to 50, such as from 50 to 60, for example from 60 to 70, such as from 70 to 80, for example from 80 to 90, such as from 90 to 100, for example from 100 to 120, such as from 120 to 140, for example from 140 to 160, such as from 160 to 180, for example from 180 to 200, such as from 200 to 250, for example from 250 to 300, such as from 300 to 350, for example from 350 to 400, such as from 400 to 450, for example from 450 to 500, such as from 500 to 550, for example from 550 to 600, such as from 600 to 650, for example from 650 to 700, such as from
700 to 750, for example from 750 to 800, such as from 800 to 900, for example from 900 to 950, such as from 950 to 1000.
153. The composition according to any of claims 93-152, wherein a and/or b and/or P is of human origin.
154. The composition according to any of claims 93-153, wherein a and/or b and/or P is of mouse origin.
155. The composition according to any of claims 93-154, wherein a and/or b and/or P is of primate origin.
156. The composition according to any of claims 93-155, wherein a and/or b and/or P is of chimpansee origin.
157. The composition according to any of claims 93-156, wherein a and/or b and/or P is of gorilla origin.
158. The composition according to any of claims 93-157, wherein a and/or b and/or P is of orangutan origin.
159. The composition according to any of claims 93-158, wherein a and/or b and/or P is of monkey origin.
160. The composition according to any of claims 93-159, wherein a and/or b and/or P is of Macaque origin.
161. The composition according to any of claims 93-160, wherein a and/or b and/or P is of porcine (swine/pig) origin.
162. The composition according to any of claims 93-161 , wherein a and/or b and/or P is of bovine (cattle/antilopes) origin.
163. The composition according to any of claims 93-162, wherein a and/or b and/or P is of equine (horse) origin.
164. The composition according to any of claims 93-163, wherein a and/or b and/or P is of Camelides (camels) origin.
165. The composition according to any of claims 93-164, wherein a and/or b and/or P is of ruminant origin.
166. The composition according to any of claims 93-165, wherein a and/or b and/or P is of Canine (Dog) origin.
167. The composition according to any of claims 93-166, wherein a and/or b and/or P is of Feline (Cat) origin.
168. The composition according to any of claims 93-167, wherein a and/or b and/or P is of Bird origin.
169. The composition according to any of claims 93-168, wherein a and/or b and/or P is of Chicken origin.
170. The composition according to any of claims 93-169, wherein a and/or b and/or P is of Turkey origin.
171. The composition according to any of claims 93-170, wherein a and/or b and/or P is of Fish origin.
172. The composition according to any of claims 93-171 , wherein a and/or b and/or P is of Reptile origin.
173. The composition according to any of claims 93-172, wherein a and/or b and/or P is of Amphibian origin.
174. The composition according to any of claims 93-173, wherein (a-b-P) is a class 1 MHC-peptide complex.
175. The composition according to any of claims 93-174, wherein (a-b-P) is a class 2 MHC-peptide complex.
176. The composition according to any of claims 93-175, wherein the MHC- peptide complex (a-b-P) is attached to a multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety.
177. The composition according to any of claims 93 to 176, wherein P and/or a and/or b is chemically modified.
178. The composition according to any of claims 93 to 177, wherein P and/or a and/or b is pegylated.
179. The composition according to any of claims 93 to 178, wherein P and/or a and/or b is phosphorylated.
180. The composition according to any of claims 93 to 179, wherein P and/or a and/or b is glycosylated.
181 . The composition according to any of claims 93 to 180, wherein one of the amino acid residues of the peptide P and/or a and/or b is substituted with another amino acid.
182. The composition according to any of claims 93 to 181 , wherein a and b are both full-length peptides.
183. The composition according to any of claims 93 to 182, wherein a is a full- length peptide.
184. The composition according to any of claims 93 to 183, wherein b is a full- length peptide.
185. The composition according to any of claims 93 to 184, wherein a is truncated.
186. The composition according to any of claims 93 to 185, wherein b is truncated.
187. The composition according to any of claims 93 to 186, wherein a and b are both truncated.
188. The composition according to any of claims 93 to 187, wherein a and b are covalently linked.
189. The composition according to any of claims 93 to 188, wherein a and P are covalently linked.
190. The composition according to any of claims 93 to 189, wherein b and P are covalently linked.
191. The composition according to any of claims 93 to 190, wherein a, b and P are covalently linked.
192. The composition according to any of claims 93 to 191 , wherein a and b are non-covalently linked.
193. The composition according to any of claims 93 to 192, wherein a and P are non-covalently linked.
194. The composition according to any of claims 93 to 193, wherein b and P are non-covalently linked.
195. The composition according to any of claims 93 to 194, wherein a, b and P are non-covalently linked.
196. The composition according to any of claims 93 to 195, wherein a is not included in the (a-b-P) complex.
197. The composition according to any of claims 93 to 196, wherein b is not included in the (a-b-P) complex.
198. The composition according to any of claims 93 to 197, wherein P is not included in the (a-b-P) complex.
199. The composition according to any of claims 93 to 198, wherein the MHC- peptide complex is linked to at least one of the one or more multimerization domains by a linker moiety.
200. The composition according to any of claims 93 to 199, wherein the MHC- peptide complex is linked to at least one of the one or more multimerization domains by a covalent linker moiety.
201 . The MHC multimer according to claims 199 and 200, wherein the linkage of at least one of the one or more multimerization domains and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, at least one of the one or more multimerization domains, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes.
202. The composition according to claim 199 and 200, wherein the linker moiety linking at least one of the one or more multimerization domains and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
203. The composition according to claim 202, wherein the moiety X comprises a nucleophilic group.
204. The composition according to claim 203, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2, -CN.
205. The composition according to claim 202, wherein the moiety Y comprises an electrophilic group.
206. The composition according to claim 205, wherein the electrophilic group is selected from the group consisting of CHO, COOH , CO, NHS-ester, tosyl activated ester, acidanhydride other activated esters.
207. The composition according to claims 199 and 200, wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety.
208. The composition according to claims 199 and 200, wherein X and Y comprises reactive groups natively associated with the one or more multimerization domains and/or the MHC-peptide complexes.
209. The composition according to claims 199 and 200, wherein X and Y comprises reactive groups not natively associated with the one or more multimerization domains and/or the MHC-peptide complex.
210. The composition according to claims 199 and 200, wherein the linker moiety forms a covalent link between at least one of the one or more multimerization domains and at least one of the MHC-peptide complexes.
21 1 . The composition according to claims 199 and 200, wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group -NH2, -OH, -SH, and -NH-.
212. The composition according to claims 199 and 200, wherein the reactive groups of multimerization domains include hydroxyls of polysaccharides such as dextrans.
213. The composition according to claims 199 and 200, wherein the reactive groups of multimerization domains selected from the group amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides.
214. The composition according to claims 199 and 200, wherein one of the polypeptides of the MHC-peptide complex is covlalently or non-covalently linked by a protein fusion to the multimerization domain.
215. The composition according to claims 199 and 200, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the multimerization domain, wherein an acyl group and an amino group react to form an amide bond.
216. The composition according to any of claims 93-215, wherein one of the polypeptides of the MHC-peptide complex is a β2M polypeptide.
217. The composition according to any of claims 93-216, wherein one of the polypeptides of the MHC-peptide complex is a MHC I heavy chain polypeptide.
218. The composition according to any of claims 93-217, wherein one of the polypeptides of the MHC-peptide complex is an antigenic peptide.
219. The composition according to any of claims 93-218, wherein one of the polypeptides of the MHC-peptide complex is a MHC Il α-chain polypeptide.
220. The composition according to any of claims 93-219, wherein one of the polypeptides of the MHC-peptide complex is a MHC Il β-chain polypeptide
221. The composition according to any of claims 93-220, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the multimerization domain
222. The composition according to claim 221 , wherein the non-native reactive groups include reactive groups that are attached to the multimerization domain through association of a linker molecule comprising the reactive group.
223. The composition according to claim 221 , wherein the non-native reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
224. The composition according to any of claims 108, 127 or 212, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
225. The composition according to claim 224, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups
226. The composition according to any of claims 93-225, wherein the multimerization domain comprises one or more nucleophilic groups
227. The composition according to claim 226, wherein the nucleophilic group is selected from the group -NH2, -OH, -SH, -CN, -NH-NH2
228. The composition according to any of claims 93-227, wherein the multimerization domain is selected from the group polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
229. The composition according to any of claims 93-228, wherein the multimerization domain comprises one or more electrophilic groups.
230. The composition according to claim 229, wherein the electrophilic group is selected from the group -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides.
231. The composition according to any of claims 93-230, wherein the multimerization domain is selected from the group of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
232. The composition according to any of claims 93-231 , wherein the multimerization domain comprises one or more radicals.
233. The composition according to any of claims 93-232, wherein the multimerization domain comprises one or more conjugated double bonds.
234. The composition according to any of claims 93-233, wherein the MHC- peptide complex comprises one or more nucleophilic groups.
235. The composition according to claim 234, wherein the nucleophilic group is selected from the group -NH2, -OH, -SH, -CN, -NH-NH2
236. The composition according to any of claims 93-235, wherein the MHC- peptide complex comprises one or more electrophilic groups.
237. The composition according to claim 236, wherein the electrophilic group is selected from the group -COOH, -CHO, -CO, NHS-ester, tosyl-activated ester, and other activated esters, acid-anhydrides.
238. The composition according to any of claims 93-237, wherein the MHC- peptide complex comprises one or more radicals.
239. The composition according to any of claims 93-238, wherein the MHC- peptide complex comprises one or more conjugated double bonds
240. The composition according to any of claims 93-239, wherein the multimerization domain comprises one or more beads and one or more linker moieties.
241. The composition according to claim 240, wherein the linker is a flexible linker.
242. The composition according to claim 240, wherein the linker is a rigid linker.
243. The composition according to claim 240, wherein the linker is a water- soluble linker.
244. The composition according to claim 240, wherein the linker is a cleavable linker.
245. The composition according to claim 244, wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
246. The composition according to claim 244, wherein the cleavable linker is cleavable at physiological conditions
247. The composition according to any of claims 93-246, wherein the MHC- peptide complex is linked to at least one of the one or more multimerization domains by a non-covalent linker moiety.
248. The composition according to claim 247, wherein the non-covalent linkage comprises natural dimerization.
249. The composition according to claim 248, wherein the natural dimerization comprises antigen-antibody pairs or coiled coil structures.
250. The composition according to claim 248, wherein the natural dimerization comprises DNA-DNA interactions.
251. The composition according to claim 247, wherein the non-covalent linkage comprises natural interactions.
252. The composition according to claim 251 , wherein the natural interaction comprises biotin and streptavidin.
253. The composition according to claim 1 16, wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes
254. The composition according to claim 1 16, wherein the bead is coated with streptavidin tetramers each of which being independently associated with 0, 1 , 2, 3, or 4 biotinylated MHC complexes
255. The composition according to claim 1 16, wherein the bead is coated with polysaccharide, such as a polysaccharide comprising dextran moieties.
256. The composition according to claim 251 , wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells
257. The composition according to claim 247, wherein the non-covalent linkage comprises artificial interactions
258. The composition according to claim 257, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA
259. The composition according to claim 257, wherein the artificial interaction comprises PNA-PNA
260. The composition according to claim 247, wherein the non-covalent linkage comprises non-specific adsorption
261. The composition according to claim 260, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces
262. The composition according to claim 247, wherein the non-covalent linkage comprises the pentamer structure
263. The composition according to claim 247, wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP- 1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain, Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag
Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
264. The composition according to any of claims 93 to 263, wherein the MHC multimer comprises stabilized empty MHC complexes and/or stabilized MHC- peptide complexes.
265. The composition according to claim 264, wherein the MHC multimer comprises a soluble form of MHC I where the transmembrane and cytosolic domains of the membrane-anchored MHC complexes have been removed.
266. The composition according to claim 264, wherein the MHC multimer comprises a soluble form of MHC Il where the transmembrane and cytosolic domains of the membrane-anchored MHC complexes have been removed.
267. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes have been stabilized by generation of covalent protein-fusions.
268. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes have been stabilized by stabilization of the MHC I molecules by introduction of one or more linkers between the individual components of the MHC I complex such as generation of a complex consisting of a heavy chain fused with β2m through a linker and a soluble peptide, a heavy chain fused to β2m through a linker, a heavy chain /β2m dimer covalently linked to a peptide through a linker to either heavy chain or β2m, or where there can or can not be a linker between the heavy chain and β2m, a heavy chain fused to a peptide through a linker, or the α1 and α2 subunits of the heavy chain fused to a peptide through a linker.
269. The composition according to claim 268, wherein each of the heavy chain, β2m and the peptide are truncated.
270. The composition according to claim 268, wherein the linker is a flexible linker.
271. The composition according to claim 268, wherein the linker is made of glycine and/or serine.
272. The composition according to claim 268, wherein the linker is between 5-20 residues long, such as from 5-6 residues long, for example from 6-8 residues long, such as from 8-10 residues long, for example from 10-12 residues long, such as from 12-14 residues long, for example from 14-16 residues long, such as from 16-18 residues long and for example from 18-20 residues long.
273. The composition according to claim 268, wherein the linker is longer than 20 residues long.
274. The composition according to claim 268, wherein the linker is shorter than 5 residues long.
275. The composition according to claim 268, wherein the linker is rigid with a defined structure.
276. The composition according to claim 268, wherein the linker is made of amino acids like glutamate, alanine, lysine, and leucine creating e.g. a more rigid structure.
277. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain- β2m fusion proteins, wherein the COOH terminus of β2m can be covalently linked to the NH2 terminus of the heavy chain, or the NH2 terminus of β2m can be linked to the COOH terminus of the heavy chain.
278. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a fusion- protein comprising a β2m domain, or a truncated β2m domain, inserted into the heavy chain.
279. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a fusion- protein comprising a heavy chain domain, or a truncated heavy chain, inserted into the β2m chain, to form a fusion-protein of the form "β2m(first part)-heavy chain-β2m(last part)".
280. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptide-β2m fusion proteins, wherein the COOH terminus of the peptide is linked to the NH2 terminus of β2m or the peptide is linked to the COOH terminal of β2m via its NH2 terminus.
281 . The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain- peptide fusion proteins, wherein the NH2 terminus of the heavy chain is fused to the COOH terminus of the peptide, or the fusion is between the COOH terminus of the heavy chain and the NH2 terminus of the peptide.
282. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises heavy chain- β2m-peptide fusion proteins, wherein the NH2 terminus of the heavy chain is fused to the COOH terminus of β2m and the NH2 terminus of β2m can be fused to the COOH terminus of the peptide.
283. The composition according to claim 268, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by binding to an unnatural component.
284. The composition according to claim 283, wherein the unnatural component bind to both the heavy chain and the β2m.
285. The composition according to claim 283, wherein the unnatural component bind to either β2m or heavy chain, and in this way stabilize the polypeptide in its correct conformation, and in this way increase the affinity of the heavy chain for β2m and/or peptide, or increase the affinity of β2m for peptide.
286. The composition according to claim 283, wherein the unnatural component is one or more antibodies.
287. The MHC multimer according to calim 286, wherein the one or more antibodies can be selected from the group consisting of as truncated or full- length antibodies (of isotype IgG, IgM, IgA, IgE), Fab, scFv or bi-Fab fragments or diabodies.
288. The MHC multimer according to calim 286, wherein the one or more antibodies is one or more antibodies capable of binding the MHC I molecule by interaction with the heavy chain as well as β2m.
289. The MHC multimer according to calim 286, wherein the one or more antibodies is one or more bispecific antibodies that binds with one arm to the heavy chain and the other arm to the β2m of the MHC complex.
290. The MHC multimer according to calim 286, wherein the one or more antibodies is monospecific, and bind at the interface between heavy chain and β2m.
291. The MHC multimer according to calim 286, wherein the one or more antibodies is one or more antibodies capable of binding the heavy chain but only when the heavy chain is correct folded.
292. The MHC multimer according to calim 286, wherein the one or more antibodies is the antibody produced by the clone W6/32 such as M0736 or the like that recognizes a conformational epitope on intact human and some monkey MHC complexes comprising β2m, heavy chain and peptide.
293. The composition according to claim 283, wherein the unnatural component is one or more peptides.
294. The composition according to claim 283, wherein the unnatural component is one or more aptamers.
295. The composition according to claim 283, wherein the unnatural component is one or more molecules with the ability to bind peptides stretches of the MHC complex.
296. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of modified proteins or protein components.
297. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises improved stability of a MHC I complex by increasing the affinity of the binding peptide for the MHC complex.
298. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises mutagenesis of one or more amino acids at relevant positions in the peptide.
299. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises substitution of one or more amino acids at relevant positions in the peptide.
300. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises chemical modifications of amino acids at relevant positions in the peptide.
301. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises introduction by synthesis of non- natural amino acids at relevant positions in the peptide.
302. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions in the peptide binding cleft, i.e. in the binding pockets that accommodate peptide side chains responsible for anchoring the peptide to the peptide binding cleft.
303. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises introduction of one or more reactive groups into the antigenic peptide;
304. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions in the heavy chain and/or β2m at positions outside the peptide-binding cleft.
305. The composition according to claim 296, wherein the generation of modified proteins or protein components comprises removal of "unwanted cysteine residues" in the heavy chain by mutation, chemical modification, amino acid exchange or deletion.
306. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises covalent stabilization of MHC I complex, wherein a linker is covalently attached between two of the subunits of the MHC complex such as a linker between peptide and heavy chain or between heavy chain and beta2microglobulin.
307. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises eukaryotic expression systems for production of MHC Il molecules such as stable Drosophila cell transfectants, baculovirus infected insect cells, CHO cells or other mammalian cell lines suitable for expression of proteins.
308. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of covalent protein-fusions.
309. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization of MHC Il complexes by introduction of one or more linkers e.g. between the individual components of the MHC Il complex such as a α/β dimer with a linker between α-chain and β-chain; a α/β dimer covalently or non-covalently linked to the peptide via a linker to either the α-chain or β-chain; a α/β dimer, covalently or non-covalently linked by a linker between the α-chain and β-chain, and where the dimer is covalently or non-covalently linked to the peptide or a α/β dimer with a linker between α-chain and β-chain, where the dimer is combined with a peptide covalently or non-covalently linked to either α-chain or β-chain.
310. The composition according to claim 309, wherein the linker is a flexible linker.
31 1. The composition according to claim 309, wherein the linker is made of glycine and/or serine.
312. The composition according to claim 309, wherein the linker is between 5-20 residues long, such as from 5-6 residues long, for example from 6-8 residues long, such as from 8-10 residues long, for example from 10-12 residues long, such as from 12-14 residues long, for example from 14-16 residues long, such as from 16-18 residues long and for example from 18-20 residues long.
313. The composition according to claim 309, wherein the linker is longer than 20 residues long.
314. The composition according to claim 309, wherein the linker is shorter than 5 residues long.
315. The composition according to claim 309, wherein the linker is rigid with a more defined structure, e.g. made of amino acids like glutamate, alanine, lysine, and leucine.
316. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptides linked to the NH2- or COOH-terminus of either α-chain or β-chain.
317. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises peptides linked to the NH2-terminus of the β-chain via their COOH-terminus, since the linker required is shorter than if the peptide is linked to the COOH-terminus of the β- chain.
318. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises linkage of α- chain to β-chain via the COOH-terminus of the β-chain to the NH2-terminus of the α-chain or from the COOH-terminus of the α-chain to the NH2-terminus of the β-chain.
319. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises a three- molecule fusion protein consisting of α-chain, β-chain and peptide e.g. where one linker connect the COOH-terminus of the β-chain with the NH2-terminus of the α-chain and another linker connects the COOH-terminal of the peptide with the NH2-terminal of the β-chain or one linker joins the COOH-terminus of the α- chain with the NH2-terminus of the β-chain and the second linker joins the NH2- terminus of the peptide with the COOH-terminus of the β-chain.
320. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by binding ligand.
321 . The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent binding of ligands to the MHC Il complex to promote assembly of α- and β-chain by bridging the two chains, or by binding to either of the α- or β-chains, and in this way stabilize the conformation of α or β, that binds β or α, respectively, and/or that binds the peptide.
322. The composition according to claim 321 , wherein the ligands are one or more antibodies.
323. The composition according to claim 322, wherein the one or more antibodies are one or more antibodies binding the MHC complex distal to the interaction site with TCR, i.e. distal to the peptide-binding cleft.
324. The composition according to claim 322, wherein the one or more antibodies are any truncated or full length antibody of any isotype (e.g. IgG, IgM, IgA or IgE), a bi-Fab fragment or a diabody.
325. The composition according to claim 322, wherein the one or more antibodies are bispecific with one arm binding to the α-chain and the other arm binding to the β-chain.
326. The composition according to claim 322, wherein the one or more antibodies are monospecific and directed to a sequence fused to the α-chain as well as to the β-chain.
327. The composition according to claim 322, wherein the one or more antibodies are monospecific and binds to a surface of the complex that involves both the α- and β-chain, e.g. both the α2- and β2- domain or both the α1 - and β1 - domain.
328. The composition according to claim 321 , wherein the ligands are one or more peptides.
329. The composition according to claim 321 , wherein the ligands are one or more aptamers.
330. The composition according to claim 321 , wherein the ligands are one or more molecules with the ability to bind proteins.
331. The composition according to claim 321 , wherein the ligands are one or more ligand that binds at the α-/β-chain interface, e.g. peptides and aptamers.
332. The composition according to claim 321 , wherein the ligands are one or more ligands that bind the peptide, although, in this case it is important that the ligand does not interfere with the interaction of the peptide or binding cleft with the TCR.
333. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises non-covalent stabilization by induced multimerization.
334. The composition according to claim 333, wherein the multimerization comprises anchoring of the α- and β-chains in the cell membrane leading to stabilization of the MHC Il complexes.
335. The composition according to claim 333, wherein the multimerization comprises stabilization of the α/β-dimer by attachment of the MHC Il chains to the Fc regions of an antibody, leading to a stable α/β-dimer, where α and β are held together by the tight interactions between two Fc domains of an antibody.
336. The composition according to claim 333, wherein the multimerization comprises one or more dimerization domains.
337. The composition according to claim 333, wherein the multimerization comprises MHC Il molecules incorporated into artificial membrane spheres like liposomes or lipospheres.
338. The composition according to claim 333, wherein the multimerization comprises MHC Il molecules incorporated as monomers or as dimers in a membrane.
339. The composition according to claim 333, wherein the multimerization comprises biotinylation of α- as well as β-chain and the two chains brought together by binding to streptavidin.
340. The composition according to claim 333, wherein the multimerization comprises long flexible linkers such as extended glycine-serine tracts used to extend both chains, whereafter the chains are biotinylated at the end of such extended linkers and streptavidin is used as a scaffold to bring the chains together in the presence of the peptide, while the flexible linkers still allow the chains to orientate properly.
341. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises generation of modified proteins or protein components.
342. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization of MHC Il complexes by covalent modifications of the protein.
343. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises increase of the affinity of the peptide for the MHC complex e.g. by exchange of the natural amino acids with other natural or non-natural amino acids at relevant positions in the peptide or by chemical modifications of amino acids at relevant positions in the peptide or mutations, chemical modifications, insertion of natural or non- natural amino acids or deletions can be introduced in the peptide-binding cleft or mutations, chemical modifications, insertion of natural or non-natural amino acids or deletions is introduced in α- and/or β- chain at positions outside the peptide-binding cleft.
344. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises replacement of the hydrophobic transmembrane regions of α-chain and β-chain by leucine zipper dimerisation domains (e.g. Fos-Jun leucine zipper; acid-base coiled-coil structure) to promote assembly of α-chain and β-chain.
345. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises introduction of one or more cysteine residues by amino acid exchange at the COOH-terminal of both α-chain and β-chain, to create disulfide bridges between the two chains upon assembly of the MHC complex.
346. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises removalal of "unwanted cysteine residues" in either of the chains by mutation, chemical modification, amino acid exchange or deletion.
347. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stbilization of MHC Il complexes by chemically linking together the subunits and the peptide e.g. by a linker between peptide and α-chain, between peptide and β-chain, between α-chain and β-chain, or combination thereof.
348. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises chemically modified MHC complexes.
349. The composition according to claim 348, wherein the chemically modified MHC complexes comprises one or more amino acids reacted with one or more chemical cross linkers.
350. The composition according to claim 348, wherein the chemically modified MHC complexes comprises that the amino group at the N-terminal of both chains and of the peptide, as well as amino groups of lysine side chains, are nucleophilic and can be used in a chemical reaction.
351. The composition according to claim 350, wherein the chemical reaction is nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation),
352. The composition according to claim 350, wherein the chemical reaction is addition to carbon-hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers).
353. The composition according to claim 350, wherein the chemical reaction is nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines).
354. The composition according to claim 350, wherein the chemical reaction is one or more cycloadditions.
355. The composition according to claim 350, wherein the chemical reaction comprises use of activated carboxylic acids such as NHS-ester, tetra and pentafluoro phenolic esters, anhydrides, acid chlorides and fluorides.
356. The composition according to claim 350, wherein the chemical reaction comprises use of sulphonyl chlorides.
357. The composition according to claim 350, wherein the chemical reaction comprises use of iso-Cyanates and/or isothiocyanates.
358. The composition according to claim 350, wherein the chemical reaction comprises use of Aldehydes, such as formaldehyde and glutardialdehyde.
359. The composition according to claim 350, wherein the chemical reaction comprises alkylation by maleimides, vinyl sulphones and halides.
360. The composition according to claim 350, wherein the chemical reaction comprises use of carboxylic acids at the C-terminal of both chains and peptide, as well as on the side chains of glutamic and aspartic acid, to introduce cross- links.
361. The composition according to claim 350, wherein the chemical reaction use of carbodiimides.
362. The composition according to claim 350, wherein the chemical reaction any chemistries that can be employed to form covalent cross-links.
363. The composition according to claim 350, wherein the chemical reaction comprises one or more chemical reagents that are bi-functional.
364. The composition according to claim 350, wherein the chemical reaction comprises one or more chemical reagents that are homo bi-functional such as glutardialdehyde.
365. The composition according to claim 350, wherein the chemical reaction comprises one or more chemical reagents that are hetero bi-functional such as GMBS (MaleimidoButyryloxy-Succinimide ester).
366. The composition according to claim 350, wherein the chemical reaction comprises use of two or more reagents.
367. The composition according to claim 350, wherein the chemical reaction comprises that GMBS is used to introduce maleimides on the α-chain, and iminothiolane is used to introduce thiols on the β-chain, whereafter the malemide and thiol can then form a thioether link between the two chains.
368. The composition according to claim 350, wherein the chemical reaction comprises one or more types of cross-links.
369. The composition according to claim 350, wherein the chemical reaction comprises that the folded MHC-complex can be reacted with dextrans possessing a large number (up to many hundreds) of vinyl sulphones, which can react with lysine residues on both the α and β chains as well as with lysine residues on the peptide protruding from the binding site, effectively cross linking the entire MHC-complex.
370. The composition according to claim 350, wherein the chemical reaction comprises activation of dextran e.g. with vinyl sulphones.
371. The composition according to claim 350, wherein the chemical reaction comprises that a dextran is reacted both with one or several MHC-complexes and one or more fluorescent protein such as APC.
372. The composition according to claim 350, wherein the chemical reaction comprises one or more chemical cross linkers.
373. The composition according to claim 350, wherein the chemical reaction comprises that one or more lysine residues are inserted into the α-chain, juxtaposed with glutamic acids in the β-chain, where after the introduced amino groups and carboxylic acids are reacted by addition of carbodiimide.
374. The composition according to claim 350, wherein the chemical reaction comprises that one or more dextran multimerization domain(s) are cross-linked with appropriately modified MHC-complexes; i.e. one or both chains of the MHC complex can be enriched with lysine residues, increasing reactivity towards the vinylsulphone dextran.
375. The composition according to claim 374, wherein the lysine residues are inserted at positions opposite the peptide binding cleft, orienting the MHC- complexes favourably for T-cell recognition.
376. The composition according to claim 350, wherein the chemical reaction comprises use of one or more extended and flexible cross-linkers.
377. The composition according to claim 264, wherein the stabilized empty MHC complexes and/or stabilized MHC-peptide complexes comprises stabilization with one or more soluble additives.
378. The composition according to claim 377, wherein the one or more soluble additives comprises one or more salts.
379. The composition according to claim 377, wherein the one or more soluble additives comprises one or more detergents.
380. The composition according to claim 377, wherein the one or more soluble additives comprises one or more organic solvents.
381. The composition according to claim 377, wherein the one or more soluble additives comprises one or more polymers.
382. The composition according to claim 377, wherein the one or more soluble additives comprises one or more soluble additives that increase the stability of MHC complexes.
383. The composition according to claim 377, wherein the one or more soluble additives comprises one or more soluble additives that increase the surface tension of the MHC complex.
384. The composition according to claim 377, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of sucrose, mannose, glycine, betaine, alanine, glutamine, glutamic acid, ammonium sulphate, glycerol, mannitol and sorbitol.
385. The composition according to claim 377, wherein the one or more soluble additives comprises one or more soluble additives that increase the surface tension of the MHC complex and simultaneously can interact with charged groups in the protein.
386. The composition according to claim 377, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of MgSO4, NaCI, polyethylenglycol, 2-methyl-2,4-pentanediol and guanidiniumsulphate.
387. The composition according to claim 377, wherein the one or more soluble additives comprises molar excess of peptide.
388. The composition according to claim 377, wherein the one or more soluble additives comprises molar excess β2m.
389. The composition according to claim 377, wherein the one or more soluble additives comprises molar excess β2m and molar excess of peptide identical to the peptide bound in the peptide-binding cleft.
390. The composition according to claim 377, wherein the one or more soluble additives comprises one or more of the soluble additives selected from the group consisting of BSA, fetal and bovine calf serum, and other protein components in serum with a protein stabilizing effect.
391. The composition according to claim 377, wherein the one or more soluble additives are added to any solution comprising MHC complexes in order to increase the stability of the molecule.
392. The composition according to claim 377, wherein the one or more soluble additives are added during the refolding process.
393. The composition according to claim 377, wherein the one or more soluble additives are added to the formed MHC complex.
394. The composition according to claim 377, wherein the one or more soluble additives are added to a solution of MHC multimers comprising several MHC complexes.
395. The composition according to any of claims 93 to 394 further comprising one or more molecules with adjuvant effect.
396. The composition according to any of claims 93 to 395 further comprising one or more immune targets.
397. The MHC multimer according to any of claim 396, wherein the one or more immune targets is an antigen.
398. The composition according to any of claims 93 to 397 further comprising one or more molecules with biological activity.
399. The composition according to any of claims 93 to 398 further comprising one or more molecules with a cytotoxic effect.
400. The composition according to any of claims 93 to 399 further comprising one or more molecules selected from the group consisting of enzymes, regulators of receptor activity, receptor ligands, immune potentiators, drugs, toxins, co-receptors, proteins, peptides, sugar moieties, lipid groups, nucleic acids including siRNA, nano particles, and small molecules.
401. The composition according to any of claims 93 to 400 further comprising one or more molecules selected from the group consisting of HIV gp120, HIV- GAG gp 27, HSP70, and MHC class Il proteins or peptides or combinations thereof.
402. The composition according to any of claims 93 to 401 further comprising one or more immuno active molecules.
403. The composition according to claim 402, wherein the one or more immuno active molecules are identical.
404. The composition according to claim 402, wherein the one or more immuno active molecules are different.
405. The composition according to claim 402, wherein the one or more immuno active molecules are selected from the group consisting of biological active molecules including proteins, co-stimulatory molecules, cell modulating molecules, receptors, accessory molecules, adhesion molecules, natural ligands, and toxic molecules, as well as antibodies and recombinant binding molecules to any of the foregoing, and combinations thereof.
406. The composition according to claim 402, wherein the one or more immuno active molecules comprises one or more molecules selected from the group consisting of MHC Class Mike proteins like MIC A, MIC B, CDId, HLA E, HLA F, HLA G, HLA H, ULBP-1 , ULBP-2, and ULBP-3, co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD137 (4-1 BB), CD147, CDw150 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, HVEM, HLA Class II, PD- 1 , Fas (CD95), FasL expressed on T and/or NK cells, CD40, CD48, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD-L2, CD134L,
CD137L, ICOSL, LIGHT expressed on APC and/or tumour cells, cell modulating molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR, LIR, CD94/NKG2A, CD94/NKG2C expressed on NK cells, IFN-alpha, IFN-beta, IFN- gamma, IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, CSFs (colony-stimulating factors), vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, accessory molecules such as LFA-1 , CDIIa/18, CD54 (ICAM- 1 ), CD106 (VCAM), and CD49a, b, c, d, e, f/CD29 (VLA-4), adhesion molecules such as ICAM-1 , ICAM- 2, GlyCAM-1 , CD34, anti-LFA-1 , anti-CD44, anti-beta7, chemokines, CXCR4, CCR5, anti-selectin L, anti-selectin E, and anti- selectin P, toxic molecules selected from toxins, enzymes, antibodies, radioisotopes, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin,
Shiga toxin, heavy'metals like inorganic and organic mercurials, and FN18- CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin, and combinations of any of the foregoing, as well as antibodies (monoclonal, polyclonal, and recombinant) to the foregoing, where relevant and antibody derivatives or fragments thereof.
407. The composition according to claim 402, wherein the one or more immuno active molecules are derived from viral or bacterial proteins or fragments thereof.
408. The composition according to claim 402, wherein the one or more immuno active molecules are attached to the multimerization domain(s) either directly, thorugh one or more linkers or via one or more of the binding entities or one or more multimerization domains.
409. The composition according to claim 402, wherein the one or more immuno active molecules are linked to another immunoactive molecules and then attached to one or more multimerization domains.
410. The composition according to any of claims 93 to 409, wherein the MHC multimer is covalently or non-covalently associated with various molecules such as molecules with adjuvant effects, immune targets such as antigens, molecules with biological activity such as enzymes, regulators of receptor activity, receptor ligands, immune potentiators, drugs, toxins, co-receptors, proteins and peptides in general; sugar moieties; lipid groups; nucleic acids including siRNA; nano particles; small molecules.
41 1. The composition according to any of claims 93 to 410, wherein the MHC multimer is covalently or non-covalently associated with one or more biologically active molecules and/or one or more immuno active molecules.
412. The composition according to claim 41 1 , wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by chemical reactions between reactive groups on the biologically active molecule or immuno active molecule and reactive groups of the multimerisation domain and/or between reactive groups on the biologically active molecule or immuno active molecule and reactive groups of the MHC- peptide complex.
413. The composition according to claim 41 1 , wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by non-covalent interaction between part of the multimerisation domain and part of the biological active molecule or immuno active molecule; or between part of the MHC-peptide complex and part of the biological active molecule or immuno active molecule.
414. The composition according to claim 41 1 , wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by covalent and non-covalent attachment of the biologically molecule or immuno active molecule to the multimerisation domain by a linker molecule.
415. The composition according to claim 41 1 , wherein the one or more biologically active molecules and/or one or more immuno active molecules are attachment by repetitively attachment aiding to recognition by and stimulation of the innate immune system via Toll or other receptors.
416. The composition according to any of claims 93 to 415 comprising a plurality of identical or different multimerization domains linked by a multimerization domain linking moiety,
wherein at least one of said multimerization domains is associated with (a-b-P)n, wherein n > 1 ,
wherein a and b together form a functional MHC protein capable of binding the peptide P, when P is present
wherein (a-b-P) is the MHC-peptide complex formed when the peptide P binds to the functional MHC protein.
417. The composition according to claim 416, wherein the plurality of identical or different multimerization domains is in the range of from 2 to 100, suach as 2 to
5, 5 to 10, 10 to 20, 20 to 30, 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100.
418. The composition according to claim 416, wherein the MHC multimer comprises a first multimerization domain linked to a second multimerization domain.
419. The composition according to claim 418, wherein the first multimerization domain and the second multimerization domain is independently selected from the group consisting of multimerization domains cited in any of claims 93 to
415.
420. The composition according to claim 418, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the first multimerization domains.
421. The composition according to claim 418, wherein the association is a non- covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the first multimerization domain.
422. The composition according to claim 418, wherein the first multimerization domain comprises one or more scaffolds.
423. The composition according to claim 418, wherein the first multimerization domain comprises one or more carriers.
424. The composition according to claim 418, wherein the first multimerization domain comprises at least one scaffold and at least one carrier.
425. The composition according to claim 418, wherein the first multimerization domain comprises one or more optionally substituted organic molecules.
426. The composition according to claim 425, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
427. The composition according to claim 426, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
428. The composition according to claim 425, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
429. The composition according to claim 418, wherein the first multimerization domain comprises one or more biological cells, such as antigen presenting cells or dendritic cells.
430. The composition according to claim 418, wherein the first multimerization domain comprises one or more membranes.
431. The composition according to claim 430, wherein the one or more membranes comprises liposomes or micelles.
432. The composition according to claim 418, wherein the first multimerization domain comprises one or more polymers.
433. The composition according to claim 432, wherein the one or more polymers are selected from the group consisting of the group consisting of polysaccharides.
434. The composition according to claim 433, wherein the polysaccharide comprises one or more dextran moieties.
435. The composition according to claim 418, wherein the first multimerization domain comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA-PNA, PNA-DNA, DNA-RNA.
436. The composition according to claim 418, wherein the first multimerization domain comprises an avidin, such as streptavidin.
437. The composition according to claim 418, wherein the first multimerization domain comprises an antibody.
438. The composition according to claim 437, wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG,
IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody.
439. The composition according to claim 418, wherein the first multimerization domain comprises one or more small organic scaffold molecules.
440. The composition according to claim 418, wherein the first multimerization comprises one or more further polypeptides in addition to a and b.
441. The composition according to claim 418, wherein the first multimerization comprises one or more protein complexes.
442. The composition according to claim 418, wherein the first multimerization comprises one or more beads
443. The composition according to claim 418, wherein the first multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG- based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(d-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin- monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly- acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'- bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen- fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
444. The composition according to claim 418, wherein the first multimerization domain comprises a dimerization domain.
445. The composition according to claim 418, wherein the first multimerization domain comprises a trimerization domain.
446. The composition according to claim 418, wherein the first multimerization domain comprises a tetramerization domain.
447. The composition according to claim 418, wherein the first multimerization domain comprises a pentamerization domain.
448. The composition according to claim 447, wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
449. The composition according to claim 418, wherein the first multimerization domain comprises a hexamerization domain.
450. The composition according to claim 449, wherein the hexamerization domain comprises three IgG domains.
451. The composition according to claim 418, wherein the first multimerization domain comprises a polymer structure to which is attached one or more scaffolds.
452. The composition according to claim 451 , wherein the polymer structure comprises a polysaccharide.
453. The composition according to claim 452, wherein the polysaccharide comprises one or more dextran moieties.
454. The composition according to claim 418, wherein the first multimerization domain comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
455. The composition according to claim 418, wherein the first multimerization domain comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or or a cyclodextrin.
456. The composition according to claim 418, wherein the MHC-peptide complex
(a-b-P) is attached to the first multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety.
457. The composition according to any of claims 418 to 456, wherein the MHC- peptide complex is linked to the first multimerization domain by a first linker moiety.
458. The composition according to claim 457, wherein the MHC-peptide complex is linked to the first multimerization domain by a covalent linker moiety.
459. The MHC multimer according to claims 457 and 458, wherein the association of the first multimerization domain and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, the first multimerization domain, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes.
460. The MHC multimer according to claims 457 and 458, wherein the linker moiety linking the first multimerization domain and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
461. The composition according to claim 460, wherein the moiety X comprises a nucleophilic group.
462. The composition according to claim 461 , wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2.
463. The composition according to claim 460, wherein the moiety Y comprises an electrophilic group.
464. The composition according to claim 463, wherein the electrophilic group is selected from the group consisting of CHO, COOH and CO.
465. The MHC multimer according to claims 457 and 458, wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety.
466. The MHC multimer according to claims 457 and 458, wherein X and Y comprises reactive groups natively associated with the first multimerization domain and/or the MHC-peptide complexes.
467. The MHC multimer according to claims 457 and 458, wherein X and Y comprises reactive groups not natively associated with the first multimerization domain and/or the MHC-peptide complex.
468. The MHC multimer according to claims 457 and 458, wherein the linker moiety forms a covalent link between the first multimerization domain and at least one of the MHC-peptide complexes.
469. The MHC multimer according to claims 457 and 458, wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group consisting of -NH2, -OH, -SH, and -NH-
470. The MHC multimer according to claims 457 and 458, wherein the reactive groups of the first multimerization domain include hydroxyls of polysaccharides such as dextrans
471. The MHC multimer according to claims 457 and 458, wherein the reactive groups of the first multimerization domain selected from the group consisting of amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides
472. The MHC multimer according to claims 457 and 458, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the first multimerization domain
473. The MHC multimer according to claims 457 and 458, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the first multimerization domain, wherein an acyl group and an amino group react to form an amide bond
474. The composition according to claim 418, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the first multimerization domain.
475. The composition according to claim 418, wherein the reactive groups include reactive groups that are attached to the first multimerization domain through association of a linker molecule comprising the reactive group.
476. The composition according to claim 418, wherein the reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
477. The composition according to claim 434, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
478. The composition according to claim 477, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups.
479. The composition according to claim 418, wherein the first multimerization domain comprises one or more nucleophilic groups
480. The composition according to claim 479, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -CN, -NH-NH2
481 . The composition according to claim 418, wherein the first multimerization domain is selected from the group consisting of polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
482. The composition according to claim 418, wherein the first multimerization domain comprises one or more electrophilic groups.
483. The composition according to claim 482, wherein the electrophilic group is selected from the group consisting of -COOH, -CHO, -CO, NHS-ester, tosyl- activated ester, and other activated esters, acid-anhydrides.
484. The composition according to claim 418, wherein the first multimerization domain is selected from the group consisting of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
485. The composition according to claim 418, wherein the first multimerization domain comprises one or more radicals.
486. The composition according to claim 418, wherein the first multimerization domain comprises one or more conjugated double bonds.
487. The composition according to claim 418, wherein the first multimerization domain comprises one or more beads and one or more linker moieties.
488. The MHC multimer according to any of the claims 457 to 487, wherein the linker is a flexible linker.
489. The MHC multimer according to any of the claims 457 to 488, wherein the linker is a rigid linker.
490. The MHC multimer according to any of the claims 457 to 489, wherein the linker is a water-soluble linker.
491 . The MHC multimer according to any of the claims 457 to 490, wherein the linker is a cleavable linker.
492. The composition according to claim 491 , wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
493. The composition according to claim 491 , wherein the cleavable linker is cleavable at physiological conditions
494. The MHC multimer according to claims 457 or 458, wherein the MHC- peptide complex is linked to the first multimerization domain by a non-covalent linker moiety.
495. The composition according to claim 494, wherein the non-covalent linkage comprises natural dimerization
496. The composition according to claim 495, wherein the natural dimerization comprises antigen-antibody pairs
497. The composition according to claim 495, wherein the natural dimerization comprises DNA-DNA interactions
498. The composition according to claim 494, wherein the non-covalent linkage comprises natural interactions
499. The composition according to claim 498, wherein the natural interaction comprises biotin and streptavidin
500. The composition according to claim 442, wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes
501. The composition according to claim 442, wherein the bead is coated with streptavidin tetramers, each of which being independently associated with 0, 1 , 2, 3, or 4 biotinylated MHC complexes
502. The composition according to claim 442, wherein the bead is coated with a polysaccharide, such as a polysaccharide comprising dextran moieties.
503. The composition according to claim 498, wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells
504. The composition according to claim 498, wherein the non-covalent linkage comprises artificial interactions
505. The composition according to claim 504, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA
506. The composition according to claim 504, wherein the artificial interaction comprises PNA-PNA
507. The composition according to claim 498, wherein the non-covalent linkage comprises non-specific adsorption
508. The composition according to claim 507, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces
509. The composition according to claim 498, wherein the non-covalent linkage comprises the pentamer structure
510. The composition according to claim 498, wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain,
Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con
A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
51 1. The composition according to claim 418, wherein the association is a covalent linkage so that one or more of the n MHC-peptide complexes is covalently linked to the second multimerization domains.
512. The composition according to claim 418, wherein the association is a non- covalent association so that one or more of the n MHC-peptide complexes is non-covalently associated with the second multimerization domain.
513. The composition according to claim 418, wherein the second multimerization domain comprises one or more scaffolds.
514. The composition according to claim 418, wherein the second multimerization domain comprises one or more carriers.
515. The composition according to claim 418, wherein the second multimerization domain comprises at least one scaffold and at least one carrier.
516. The composition according to claim 418, wherein the second multimerization domain comprises one or more optionally substituted organic molecules.
517. The composition according to claim 516, wherein the optionally substituted organic molecule comprises one or more functionalized cyclic structures.
518. The composition according to claim 517, wherein the one or more functionalized cyclic structures comprises one or more benzene rings.
519. The composition according to claim 516, wherein the optionally substituted organic molecule comprises a scaffold molecule comprising at least three reactive groups, or at least three sites suitable for non-covalent attachment.
520. The composition according to claim 418, wherein the second multimerization domain comprises one or more biological cells, such as antigen presenting cells or dendritic cells.
521. The composition according to claim 418, wherein the second multimerization domain comprises one or more membranes.
522. The composition according to claim 521 , wherein the one or more membranes comprises liposomes or micelles.
523. The composition according to claim 418, wherein the second multimerization domain comprises one or more polymers.
524. The composition according to claim 523, wherein the one or more polymers are selected from the group consisting of the group consisting of polysaccharides.
525. The composition according to claim 524, wherein the polysaccharide comprises one or more dextran moieties.
526. The composition according to claim 418, wherein the second multimerization domain comprises one or more entities selected from the group consisting of an IgG domain, a coiled-coil polypeptide structure, a DNA duplex, a nucleic acid duplex, PNA-PNA, PNA-DNA, DNA-RNA.
527. The composition according to claim 418, wherein the second multimerization domain comprises an avidin, such as streptavidin.
528. The composition according to claim 418, wherein the second multimerization domain comprises an antibody.
529. The composition according to claim 528, wherein the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, IgA, IgG, IgM, IgD, IgE, IgGI , lgG2, lgG3, lgG4, IgAI , lgA2, IgMI , lgM2, humanized antibody, humanized monoclonal antibody, chimeric antibody, mouse antibody, rat antibody, rabbit antibody, human antibody, camel antibody, sheep antibody, engineered human antibody, epitope-focused antibody, agonist antibody, antagonist antibody, neutralizing antibody, naturally-occurring antibody, isolated antibody, monovalent antibody, bispecific antibody, trispecific antibody, multispecific antibody, heteroconjugate antibody, immunoconjugates, immunoliposomes, labeled antibody, antibody fragment, domain antibody, nanobody, minibody, maxibody, diabody, fusion antibody.
530. The composition according to claim 418, wherein the second multimerization domain comprises one or more small organic scaffold molecules.
531. The composition according to claim 418, wherein the second multimerization comprises one or more further polypeptides in addition to a and b.
532. The composition according to claim 418, wherein the second multimerization comprises one or more protein complexes.
533. The composition according to claim 418, wherein the second multimerization comprises one or more beads
534. The composition according to claim 418, wherein the second multimerization domain comprises one or more compounds selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG-encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy-PEG, mono-(d-Cio)alkoxy- PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG,
PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptaivdin- monomer coated beads, streptaivdin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, polyacrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'- bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen- fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
535. The composition according to claim 418, wherein the second multimerization domain comprises a dimerization domain.
536. The composition according to claim 418, wherein the second multimerization domain comprises a trimerization domain.
537. The composition according to claim 418, wherein the second multimerization domain comprises a tetramerization domain.
538. The composition according to claim 418, wherein the second multimerization domain comprises a pentamerization domain.
539. The composition according to claim 538, wherein the pentamerization domain comprises a coiled-coil polypeptide structure.
540. The composition according to claim 418, wherein the second multimerization domain comprises a hexamerization domain.
541. The composition according to claim 540, wherein the hexamerization domain comprises three IgG domains.
542. The composition according to claim 418, wherein the second multimerization domain comprises a polymer structure to which is attached one or more scaffolds.
543. The composition according to claim 542, wherein the polymer structure comprises a polysaccharide.
544. The composition according to claim 543, wherein the polysaccharide comprises one or more dextran moieties.
545. The composition according to claim 418, wherein the second multimerization domain comprises a polyamide and/or a polyethylene glycol and/or a polysaccharide and/or a sepharose.
546. The composition according to claim 418, wherein the second multimerization domain comprises a carboxy methyl dextran and/or a dextran polyaldehyde and/or a carboxymethyl dextran lactone and/or a cyclodextrin.
547. The composition according to claim 418, wherein the MHC-peptide complex (a-b-P) is attached to the second multimerization domain comprising an avidin or streptavidin via a linkage comprising a biotin moiety.
548. The composition according to any of claims 418 to 547, wherein the MHC- peptide complex is linked to the second multimerization domain by a second linker moiety.
549. The composition according to claim 548, wherein the MHC-peptide complex is linked to the second multimerization domain by a covalent linker moiety.
550. The MHC multimer according to claims 547 and 548, wherein the linkage of the second multimerization domain and at least one MHC-peptide complexes is formed by a binding entity X attached to, or being part of, the second multimerization domain, and a binding entity Y attached to, or being part of at least one of the MHC-peptide complexes.
551. The MHC multimer according to claims 547 and 548, wherein the linker moiety linking the second multimerization domain and the MHC-peptide complex comprises the linker moiety XY, wherein the linker moiety XY results from a reaction of the moiety X comprising one or more reactive groups and the moiety Y comprising one or more reactive groups, wherein at least some of said reactive groups are capable of reacting with each other.
552. The composition according to claim 551 , wherein the moiety X comprises a nucleophilic group.
553. The composition according to claim 552, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -NH-NH2.
554. The composition according to claim 551 , wherein the moiety Y comprises an electrophilic group.
555. The composition according to claim 554, wherein the electrophilic group is selected from the group consisting of CHO, COOH and CO.
556. The MHC multimer according to claims 547 and 548, wherein at least one of the reactive groups on one of the moieties X and Y comprises a radical capable of reacting with a reactive group forming part of the other moiety.
557. The MHC multimer according to claims 547 and 548, wherein X and Y comprises reactive groups natively associated with the second multimerization domain and/or the MHC-peptide complexes.
558. The MHC multimer according to claims 547 and 548, wherein X and Y comprises reactive groups not natively associated with the second multimerization domain and/or the MHC-peptide complex.
559. The MHC multimer according to claims 547 and 548, wherein the linker moiety forms a covalent link between the second multimerization domain and at least one of the MHC-peptide complexes.
560. The MHC multimer according to claims 547 and 548, wherein the reactive groups of MHC-peptide complexes include amino acid side chains selected from the group consisting of -NH2, -OH, -SH, and -NH-
561 . The MHC multimer according to claims 547 and 548, wherein the reactive groups of the second multimerization domain include hydroxyls of polysaccharides such as dextrans
562. The MHC multimer according to claims 547 and 548, wherein the reactive groups of the second multimerization domain selected from the group consisting of amino acid side chains comprising -NH2, -OH, -SH, and -NH- of polypeptides
563. The MHC multimer according to claims 547 and 548, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the second multimerization domain
564. The MHC multimer according to claims 547 and 548, wherein one of the polypeptides of the MHC-peptide complex is linked by a protein fusion to the second multimerization domain, wherein an acyl group and an amino group react to form an amide bond
565. The composition according to claim 418, wherein one of the polypeptides of the MHC-peptide complex is linked by non-native reactive groups to the second multimerization domain.
566. The composition according to claim 418, wherein the reactive groups include reactive groups that are attached to the second multimerization domain through association of a linker molecule comprising the reactive group.
567. The composition according to claim 418, wherein the reactive groups include reactive groups that are attached to the MHC-peptide complex through association of a linker molecule comprising the reactive group.
568. The composition according to claim 434, wherein dextran is activated by reaction of the dextran hydroxyls with divinyl sulfon
569. The composition according to claim 568, wherein dextran is activated by a multistep reaction that results in the decoration of the dextran with maleimide groups.
570. The composition according to claim 418, wherein the second multimerization domain comprises one or more nucleophilic groups
571. The composition according to claim 570, wherein the nucleophilic group is selected from the group consisting of -NH2, -OH, -SH, -CN, -NH-NH2
572. The composition according to claim 418, wherein the second multimerization domain is selected from the group consisting of polysaccharides, polypeptides comprising e.g. lysine, serine, and cysteine.
573. The composition according to claim 418, wherein the second multimerization domain comprises one or more electrophilic groups.
574. The composition according to claim 573, wherein the electrophilic group is selected from the group consisting of -COOH, -CHO, -CO, NHS-ester, tosyl- activated ester, and other activated esters, acid-anhydrides.
575. The composition according to claim 418, wherein the second multimerization domain is selected from the group consisting of polypeptides comprising e.g. glutamate and aspartate, or vinyl sulfone activated dextran.
576. The composition according to claim 418, wherein the second multimerization domain comprises one or more radicals.
577. The composition according to claim 418, wherein the second multimerization domain comprises one or more conjugated double bonds.
578. The composition according to claim 418, wherein the second multimerization domain comprises one or more beads and one or more linker moieties.
579. The composition according to any of the claims 547 to 578, wherein the linker is a flexible linker.
580. The composition according to any of the claims 547 to 578, wherein the linker is a rigid linker.
581. The composition according to any of the claims 547 to 578, wherein the linker is a water-soluble linker.
582. The composition according to any of the claims 547 to 578, wherein the linker is a cleavable linker.
583. The composition according to claim 582, wherein the cleavable linker is selected from linkers depicted in (fig 2) in PCT/DK2008/050167.
584. The composition according to claim 582, wherein the cleavable linker is cleavable at physiological conditions
585. The composition according to any of the claims 547 to 578, wherein the MHC-peptide complex is linked to the second multimerization domain by a non- covalent linker moiety.
586. The composition according to claim 585, wherein the non-covalent linkage comprises natural dimerization.
587. The composition according to claim 586, wherein the natural dimerization comprises antigen-antibody pairs.
588. The composition according to claim 586, wherein the natural dimerization comprises DNA-DNA interactions.
589. The composition according to claim 585, wherein the non-covalent linkage comprises natural interactions.
590. The composition according to claim 589, wherein the natural interaction comprises biotin and streptavidin.
591. The composition according to claim 533, wherein the bead is coated with streptavidin monomers, which in turn are associated with biotinylated MHC complexes.
592. The composition according to claim 533, wherein the bead is coated with streptavidin tetramers, which in turn are associated with with 0, 1 , 2, 3, or 4 biotinylated MHC complexes.
593. The composition according to claim 533, wherein the bead is coated with a polysaccharide, such as a polysaccharide comprising a dextran moiety.
594. The composition according to claim 589, wherein the natural interaction comprises the interaction of MHC complexes (comprising full-length polypeptide chains, including the transmembrane portion) with the cell membrane of for example dendritic cells.
595. The composition according to claim 585, wherein the non-covalent linkage comprises artificial interactions.
596. The composition according to claim 595, wherein the artificial interaction comprises His6 tag interacting with Ni-NTA.
597. The composition according to claim 595, wherein the artificial interaction comprises PNA-PNA.
598. The composition according to claim 585, wherein the non-covalent linkage comprises non-specific adsorption.
599. The composition according to claim 598, wherein the non-specific adsorption comprises adsorption of proteins onto surfaces.
600. The composition according to claim 585, wherein the non-covalent linkage comprises the pentamer structure.
601. The composition according to claim 585, wherein the non-covalent linkage comprises interactions selected from the group streptavidin/biotin, avidin/biotin, antibody/antigen, DNA/DNA, DNA/PNA, DNA/RNA, PNA/PNA, LNA/DNA, leucine zipper e.g. Fos/Jun, IgG dimeric protein, IgM multivalent protein, acid/base coiled-coil helices, chelate/metal ion-bound chelate, streptavidin (SA) and avidin and derivatives thereof, biotin, immunoglobulins, antibodies (monoclonal, polyclonal, and recombinant), antibody fragments and derivatives thereof, leucine zipper domain of AP-1 (jun and fos), hexa-his (metal chelate moiety), hexa-hat GST (glutathione S-transferase) glutathione affinity, Calmodulin-binding peptide (CBP), Strep-tag, Cellulose Binding Domain,
Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con
A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
602. The composition according to any of claims 35-601 , wherein the one or more biologically active molecules comprises one or more proteins.
603. The composition according to any of claims 35-602, wherein the one or more biologically active molecules comprises one or more proteins that are full length and/or truncated.
604. The composition according to any of claims 35-603, wherein the one or more biologically active molecules comprises one or more proteins that are modified e.g. by introduction of additional amino acids, mutated, chemically modified (e.g. acetylation, methylation, Pegylation, phosphorylation, glycosylation etc.) or carrying other modifications.
605. The composition according to any of claims 35-604, wherein the one or more biologically active molecules comprises one or more proteins that are stabilized by covalent or non-covalent attachment of protein linkers or other protein molecules.
606. The composition according to any of claims 35-605, wherein the one or more biologically active molecules comprises one or more enzymes.
607. The composition according to any of claims 35-606, wherein the one or more biologically active molecules comprises one or more Receptor proteins and/or co-receptor proteins.
608. The composition according to any of claims 35-607, wherein the one or more biologically active molecules comprises one or more Immunological proteins.
609. The composition according to any of claims 35-608, wherein the one or more biologically active molecules comprises one or more Growth factors (proteins capable of stimulating cellular proliferation and differentiation).
610. The composition according to any of claims 35-609, wherein the one or more biologically active molecules comprises one or more Protein hormones.
61 1. The composition according to any of claims 35-610, wherein the one or more biologically active molecules comprises one or more Proteins from microorganisms.
612. The composition according to any of claims 35-61 1 , wherein the one or more biologically active molecules comprises one or more Proteins from microorganisms selected from the group consisting of surface proteins, intracellular proteins, secreted proteins (e.g. toxins), unmodified secreted proteins, modified secreted proteins (e.g. toxoid), chemically modified secreted proteins, physically and modified secreted proteins.
613. The composition according to any of claims 35-612, wherein the one or more biologically active molecules comprises one or more Nucleic acids.
614. The composition according to any of claims 35-613, wherein the one or more biologically active molecules comprises one or more DNAs.
615. The composition according to any of claims 35-614, wherein the one or more biologically active molecules comprises one or more DNAs selected from the group consisting of DNA, DNA encoding protein, and structural and not protein encoding DNA.
616. The composition according to any of claims 35-615, wherein the one or more biologically active molecules comprises one or more RNA.
617. The composition according to any of claims 35-616, wherein the one or more biologically active molecules comprises RNA selected from the group consisting of ribosomal RNA, antisense RNA, silencing RNA (siRNA), and MicroRNA.
618. The composition according to any of claims 35-617, wherein the one or more biologically active molecules comprises one or more LNA.
619. The composition according to any of claims 35-618, wherein the one or more biologically active molecules comprises one or more PNA.
620. The composition according to any of claims 35-619, wherein the one or more biologically active molecules comprises one or more Carbohydrates.
621. The composition according to any of claims 35-620, wherein the one or more biologically active molecules comprises one or more Saccharides and/or derivatives thereof, e.g. phosphorylated, oxidized, reduced, amino derivatives, acetylated etc. (the Saccharides may have more than one modification)
622. The composition according to any of claims 35-621 , wherein the one or more biologically active molecules comprises one or more saccharides selected from the group consisting of Monosaccharides, Disaccharides, Polysaccharides, Homopolysaccharides (e.g. glycans, dextran), Polymers of repeating disaccharide units in which one of the sugars are is either N- acetylgalactosamine or N-acetylglucosamine (e.g. Glucosaminoglycans), Polysaccharide-peptide polymer (Peptidoglycan (bacterial cell wall)), Proteins carrying covalent attached oligosaccharides or polysaccharides (Glycoprotein's), and Lipids carrying covalent attached oligo- or polysaccharides (Glycolipids).
623. The composition according to any of claims 35-622, wherein the one or more biologically active molecules comprises one or more lipids.
624. The composition according to any of claims 35-623, wherein the one or more biologically active molecules comprises one or more Fatty acyls (e.g. prostaglandins, leukotrienes etc.).
625. The composition according to any of claims 35-624, wherein the one or more biologically active molecules comprises one or more Glycerolipids (e.g. triglycerides).
626. The composition according to any of claims 35-625, wherein the one or more biologically active molecules comprises one or more Glycerophospholipids.
627. The composition according to any of claims 35-626, wherein the one or more biologically active molecules comprises one or more Sphingolipids.
628. The composition according to any of claims 35-627, wherein the one or more biologically active molecules comprises one or more Sterol lipids (eg. cholesterol, estrogen etc.).
629. The composition according to any of claims 35-628, wherein the one or more biologically active molecules comprises one or more Prenol lipids (eg vitamin E, K).
630. The composition according to any of claims 35-629, wherein the one or more biologically active molecules comprises one or more Polyketides (eg. erythromycin).
631. The composition according to any of claims 35-630, wherein the one or more biologically active molecules comprises one or more Small molecules.
632. The composition according to any of claims 35-631 , wherein the one or more biologically active molecules comprises one or more Natural compounds.
633. The composition according to any of claims 35-632, wherein the one or more biologically active molecules comprises one or more natural compounds selected from the group consisting of Hormones, Lipid and phospholipid derived hormones, Steroids, Eicosanoids, Amine-drived hormones (derivatives of amino acids tyrosine and tryptophan (e.g. catecholamine, thyroxine) and Salts, e.g. comprising Ca++, Mg++.
634. The composition according to any of claims 35-633, wherein the one or more biologically active molecules comprises one or more Synthetic chemical compound.
635. The composition according to any of claims 35-634, wherein the one or more biologically active molecules comprises one or more synthetic chemical compounds selected from the group consisting of Benzodiazepines, Short peptides, Peptidommimetics and other chemical compounds.
636. The composition according to any of claims 35-635, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules.
637. The composition according to any of claims 35-636, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 proteins including HLA- A, HLA-B, HLA-C alleles.
638. The composition according to any of claims 35-637, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 complete trimers).
639. The composition according to any of claims 35-638, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 Heavy chain(s).
640. The composition according to any of claims 35-639, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 Heavy chains combined with one or more beta2microglobulin.
641. The composition according to any of claims 35-640, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 Heavy chains combined with one or more beta2microglobulin and one or more antigenic peptide(s).
642. The composition according to any of claims 35-641 , wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 Heavy chain combined with one or more antigenic peptide(s).
643. The composition according to any of claims 35-642, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 Beta2mcroglobulin.
644. The composition according to any of claims 35-643, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC class 1 -like molecules.
645. The composition according to any of claims 35-644, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MICA.
646. The composition according to any of claims 35-645, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MICB.
647. The composition according to any of claims 35-646, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more CD1 d.
648. The composition according to any of claims 35-647, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more molecules selected from the group consisting of HLA-E, HLA-F, HLA-G, and HLA-H.
649. The composition according to any of claims 35-648, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more molecules selected from the group consisting of ULBP-1 , ULBP-2, and ULBP-3.
650. The composition according to any of claims 35-649, wherein the one or more biologically active molecules comprises one or more MHC 2 proteins.
651. The composition according to any of claims 35-650, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more molecules selected from the group consisting of MHC 2 HLA-DR (HLA-DRA, HLA-DRB1 , HLA-DRB3, HLA-DRB4, HLA-DRB5), HLA-DQ (HLA-DQA1 , HLADQA2, HLA-DQB1 , HLA-DQB2), HLA- DP (HLA-DPA1 , HLA-DPB1 ), HLA-DO (HLA-DOA, HLA-DOB), and HLA-DM (HLA-DMA, HLA-DMB).
652. The composition according to any of claims 35-651 , wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC 2 complete trimer molecule(s).
653. The composition according to any of claims 35-652, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC 2 1 α-heavy chain(s).
654. The composition according to any of claims 35-653, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC 2 1 β-heavy chain(s).
655. The composition according to any of claims 35-654, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC 2 1 α-heavy chain(s) and one or more 1 β-heavy chain(s).
656. The composition according to any of claims 35-655, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more MHC 2 1 α-heavy chain(s) and one or morel β-heavy chain(s) and one or more antigenic peptide(s).
657. The composition according to any of claims 35-656, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Cytokines.
658. The composition according to any of claims 35-657, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Interferons such as IFN-alpha, IFN- beta, and IFN-gamma.
659. The composition according to any of claims 35-658, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more lnterleukines such as IL-1 , IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IL-10, IL-1 1 , IL-12, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28,-IL-29, IL-30, IL-31 , IL-32, IL- 33, IL-34, and IL-35.
660. The composition according to any of claims 35-659, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Tumor necrosis factors such as TNF- alfa, and TNF-beta.
661. The composition according to any of claims 35-660, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more molecules selected from the group consisting of CSFs (colony-stimulating factors), c-Kit, EPO, TGF-β, CD40L, CD27L, CD30L, and MIF.
662. The composition according to any of claims 35-661 , wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Cytokine receptors such as IL-1 R, IL- 2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9-R, IL-1 OR, IL-1 1 R, IL-12R, IL-
13R, IL-15R, IL-18R, IL-20R, IL-21 R, IL-22R, IL-23R, IL-27R, and IL-28R.
663. The composition according to any of claims 35-662, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Chemokines such as CXCL1 , CXCL2,
CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL1 1 , CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CCL1 , CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL8, CCL9, CCL10, CCL1 1 , CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21 , CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, CXCR4, and CCRL2.
664. The composition according to any of claims 35-663, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Chemokine receptors such as CCR1 , CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR1 1 ,
CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, and CX3CR1.
665. The composition according to any of claims 35-664, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Toll-like receptors such as TLR1 ,
TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, and TLR10.
666. The composition according to any of claims 35-665, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Toll like receptor ligands such as multiple triacyl lipopeptides, multiple diacyl lipopeptides, multiple glycolipids, multiple lipopeptides, multiple lipoproteins, lipoteichoic acid, peptidoglycans, Zymosan, single- and double-stranded RNA, Poly I:C, lipo-polysaccharides, fibrinogen, heparin sulphate fragments, hyaluronic acid fragments, flagellin, imidazoquinoline, loxoribine (guanosine analogue), bropirimine, Imiquimod, unmethylated CpG DNA; Viral entry receptors/molecules such as Ku70, Pvr, PrM , HVEM, EphrinB2, cellular integrins (in particular alpha2beta1 , alphaθbetai alphaVbeta3), CD81 , CD155, SR-B1 , claudin-1 , xCT, human nectin-2, LIGHT, TLR3, LIR, Heparan sulphate proteoglycans, GPI anchored proteins, and hemeagglutinin receptor.
667. The composition according to any of claims 35-666, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Heat shock proteins such as HSP70, and HSP90.
668. The composition according to any of claims 35-667, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Bacterial entry receptors/molecules such as CD48, CEACAM-1 , -2, -3, -4, -5, -6, invasion, internalin (InIA), and InIB.
669. The composition according to any of claims 35-668, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Fc receptors like ε (FcεRI, FcεRII) - y (FcγRI, FcyRII, FcγRIII) - o/μ (FcαRI, Fcα/μR) - Neonatal FcR.
670. The composition according to any of claims 35-669, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Lymphocyte homing receptors such as CD44, L-selectin, VLA-4 (CD49a, b, c, d, e, f), and LFA-1.
671. The composition according to any of claims 35-670, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Co-stimulatory molecules such as CD2, CD3, CD4, CD5, CD8, CD9, CD27, CD28, CD30, CD69, CD134 (OX40), CD120, CD137 (4-1 BB), CD147, CDwI 50 (SLAM), CD152 (CTLA-4), CD153 (CD30L), CD40L (CD154), NKG2D, ICOS, PD-1 , Fas (CD95), FasL, CD40, CD58, CD70, CD72, B7.1 (CD80), B7.2 (CD86), B7RP-1 , B7- H3, PD-L1 , PD- L2, CD134L, CD137L, and ICOSL
672. The composition according to any of claims 35-671 , wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more NK cell receptors/molecules such as CD16, NKp30, NKp44, NKp46, NKp80,2B4, KIR3DL1 , KIR3DL", KIR3DS1 , KIR2DL1 ,KIRDL2, KIR2DL3, KIR2DL4, KIR2DL5, CD94/NKG2A,
CD94/NKG2C, CD94/NKG2E, CD94/NKG2H, and NKG2ADNKG2D.
673. The composition according to any of claims 35-672, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Adhesion molecules such as ICAM-1 ,
ICAM-2, GIyCAM- 1 , VCAM, and CD34.
674. The composition according to any of claims 35-673, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Anti microbial peptides such
Defensins and cathelicidin derived peptide LL-37.
675. The composition according to any of claims 35-674, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Antibodies (e.g. monoclonal, polyclonal, recombinant) directed to a defined antigen e.g. any of the described biologically active molecules, immunologically active molecules, viral antigens, bacterial antigens, parasitic antigens, self-antigens, cancer antigens or any other antigen.
676. The composition according to any of claims 35-675, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more full length antibodies.
677. The composition according to any of claims 35-676, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more antibody derivatives.
678. The composition according to any of claims 35-677, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more antibody Fab fragments.
679. The composition according to any of claims 35-678, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more antibody scFv fragments.
680. The composition according to any of claims 35-679, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more antibody-like structures e.g. scaffold proteins having the ability to bind antigens.
681. The composition according to any of claims 35-680, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Toxic molecules (e.g. toxins, and toxids).
682. The composition according to any of claims 35-681 , wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more Enzymes.
683. The composition according to any of claims 35-682, wherein the one or more biologically active molecules comprises one or more Immunologically active molecules comprising one or more molecules selected from the group consisting of anti-LFA-1 , anti-CD44, anti-beta7, anti-selectin L, anti-selectin E, and anti- selectin P, chemiluminescent substances, bioluminescent substances, polymers, metal particles, and haptens, such as cyclophosphamide, methrotrexate, Azathioprine, mizoribine, 15-deoxuspergualin, neomycin, staurosporine, genestein, herbimycin A, Pseudomonas exotoxin A, saporin, Rituxan, Ricin, gemtuzumab ozogamicin, Shiga toxin, vitamin D3, IL-2 toxins, cyclosporin, FK-506, rapamycin, TGF- beta, clotrimazole, nitrendipine, and charybdotoxin, heavy'metals like inorganic and organic mercurials, and FN18- CRM9, radioisotopes such as incorporated isotopes of iodide, cobalt, selenium, tritium, and phosphor, and haptens such as DNP, and digoxiginin.
684. The composition according to any of the claims 1 -683, wherein the one or more pharmamers comprises one or more multimerization domain(s).
685. The composition according to any of the claims 1 -684, wherein the one or more pharmamers comprises more than 1 multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 multimerization domains.
686. The composition according to any of the claims 1 -685, wherein the one or more pharmamers comprises more than 1 different multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000,
9,000, or more thani 0,000 different multimerization domains.
687. The composition according to any of the claims 1 -686, wherein the one or more pharmamers comprises more than 1 identical multimerization domain such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical multimerization domains.
688. The composition according to any of claims 1 -687, wherein one or more pharmamers comprises less than 10,000 multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 multimerization domains.
689. The composition according to any of claims 1 -688, wherein one or more pharmamers comprises less than 10,000 different multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75,
70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 different multimerization domains.
690. The composition according to any of claims 1 -689, wherein one or more pharmamers comprises less than 10,000 identical multimerization domains, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical multimerization domains.
691. The composition according to any of claims 684-690, wherein the one or more multimerization domains(s) comprises one or more soluble multimerization domain(s).
692. The composition according to any of claims 684-691 , wherein the one or more multimerization domains(s) comprises one or more insoluble multimerization domain(s).
693. The composition according to any of claims 684-692, wherein the one or more multimerization domains(s) comprises one or more multimerization domains selected from the group consisting of polysaccharides, dextrans, carboxy methyl dextran, dextran polyaldehyde, carboxymethyl dextran lactone, and cyclodextrins, pullulans, schizophyllan, scleroglucan, xanthan, gellan, O- ethylamino guaran, chitins and chitosans indlucing 6-0- carboxymethyl chitin and N-carboxymethyl chitosan, derivatised cellolosics including carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, hydroxy- ethyl cellulose, 6- amino-6-deoxy cellulose and O-ethyl- amine cellulose, hydroxylated starch, hydroxypropyl starch, hydroxyethyl starch, carrageenans, alginates, and agarose, synthetic polysaccharides including ficoll and carboxy-methylated ficoll, vinyl polymers including poly (acrylic acid), poly (acryl amides), poly (acrylic esters), poly (2-hydroxy ethyl methacrylate), poly (methyl methacrylate), poly (maleic acid), poly (maleic anhydride), poly (acrylamide), poly (ethyl-co- vinyl acetate), poly (methacrylic acid), poly (vinyl- alcohol), poly (vinyl alcohol- co-vinyl chloroacetate), aminated poly (vinyl alcohol), and co block polymers thereof, poly ethylene glycol (PEG) or polypropylene glycol or poly (ethylene oxide-co-propylene oxides) comprising polymer backbones including linear, comb-shaped or StarBurst dendrimers, poly amino acids including polylysines, polyglutamic acid, polyurethanes, poly (ethylene imines), pluriol, proteins including peptides, polypeptides, antigenbinding peptides, albumins, immunoglobulins, coiled-coil helixes e.g. Fos-Jun or Fos-Jun like or coiled- coiled dimers/trimers/tetramers/pentamers, Streptavidin, Avidin, Streptactin, T- cell receptors orther protein receptors and virus- like proteins (VLP), and polynucleotides, DNA, RNA, PNA, LNA, oligonucleotides and oligonucleotide dendrimer constructs and small organic molecules including but not limited to steroids, peptides, linear or cyclic structures, aromatic structures, aliphatic structures.
694. The composition according to any of claims 684-693, wherein the one or more multimerization domains(s) comprises cells e.g. dendritic cells, antigen presenting cell, B-cell, T-cell Macrophages, Kupfer cells, Langerhans cells, transfected cells expressing biologically active proteins, including hybridoma cells, yeast-cells, insect-cells, CHO cells, any cell biologically active molecules, cell-like structures e.g. micelles, liposomes, and phages e.g. filamenteous phages and viral or viral-like particles.
695. The composition according to any of claims 684-694, wherein the one or more multimerization domains(s) comprises one or more solid supports including but not limited to beads, particulate matters and other surfaces.
696. The composition according to any of claims 684-695, wherein the one or more multimerization domains(s) comprises one or more self-assembling multimeric structures.
697. The composition according to any of claims 684-696, wherein the one or more multimerization domains(s) comprises mixed forms of multimerization domains such as e.g. dextran coupled with Streptavidin.
698. The composition according to any of claims 684-697, wherein the one or more multimerization domains(s) comprises one or more multimerisation domains made of Streptavidin or Avidin whereto biotin, biotin-like peptides or other biotin-like molecules can bind.
699. The composition according to any of claims 684-698, wherein the one or more multimerization domains(s) comprises dextran whereto biologically active molecules are attached directly through a linker.
700. The composition according to any of claims 684-699, wherein the one or more multimerization domains(s) comprises divinylsulfone activated dextran whereto biologically active molecules are coupled directly e.g. through -SH group(s) or amine(s) in the biologically active molecules, dextran coupled with SA whereto biologically active molecules are attached through a biotin on the biologically active molecule, dextran with biologically active molecules are attached through a coiled-coil structure where on α-helix of a coiled-coil dimer is coupled to dextran and the other α-helix is coupled to the biologically active molecule e.g. as a fusion protein.
701 . The composition according to any of claims 684-700, wherein the one or more multimerization domains(s) comprises beads or bead-like structures having an excluded volume (e.g. polysaccharide beads, polystyrene beads, magnetic polystyrene beads, polycarbamate beads, or any other kind of beads that can be dissolved or suspended in aqueous buffer) that carry electrophilic groups (e.g. divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters), and where biologically active molecules have been covalently immobilized to these by reaction of nucleophiles comprised within the biologically active molecule with the electrophiles of the beads.
702. The composition according to any of claims 684-701 , wherein the one or more multimerization domains(s) comprises one or more beads covalently or non-covalently coated with pharmamers or single biologically active molecules, through non-cleavable or cleavable linkers.
703. The composition according to any of claims 684-702, wherein the one or more multimerization domains(s) comprises one or more beads coated with streptavidin monomers, which in turn are associated with biotinylated pharmamers.
704. The composition according to any of claims 684-703, wherein the one or more multimerization domains(s) comprises one or more beads coated with streptavidin tetramers, each of which are associated with 0, 1 , 2, 3, or 4 biotinylated biologically active molecules.
705. The composition according to any of claims 684-704, wherein the one or more multimerization domains(s) comprises one or more beads coated with biologically active molecules where e.g. the reactive groups of the biologically active molecules (e.g. the divinyl sulfone-activated dextran backbone) has reacted with nucleophilic groups on the bead, to form a covalent linkage between the dextran of the dextramer and the beads.
706. The composition according to any of claims 684-705, wherein the one or more multimerization domains(s) comprises one or more self-assembling multimeric structures such as trimeric, tetrameric, pentameric, hexameric or heptameric coiled-coil structures holding together 3, 4, 5, 6 or 7 biologically active molecules.
707. The composition according to any of claims 684-706, wherein the one or more multimerization domains(s) comprises several multimerization domains
(e.g. streptavidin tetramers bound to biotinylated biologically active molecules) linked to another multimerization domain (e.g. the bead).
708. The composition according to any of claims 684-707, wherein the one or more multimerization domains(s) comprises any support capable of binding the biologically active molecules.
709. The composition according to any of claims 684-708, wherein the one or more multimerization domains(s) comprises glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.
710. The composition according to any of claims 684-709, wherein the one or more multimerization domains(s) comprises one or more spherical supports such as one or more bead.
71 1 . The composition according to any of claims 684-710, wherein the one or more multimerization domains(s) comprises one or more cylindrical supports such as the inside surface of a test tube, or the external surface of a rod.
712. The composition according to any of claims 684-71 1 , wherein the one or more multimerization domains(s) comprises one or more flat supports such as a sheet, test strip, a membrane, or a plastic surface.
713. The composition according to any of claims 684-712, wherein the one or more multimerization domains(s) comprises one or more polymers, oligomers and/or non-repeating moieties.
714. The composition according to any of claims 684-713, wherein the one or more multimerization domains(s) comprises one or more polymers or oligomer moieties e.g. comprising repeat units consisting of a repeat moiety selected from alkyl (e.g., -CH2-), substituted alkyl (e.g., --CHR--), alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, as well as moieties comprising combinations thereof.
715. The composition according to any of claims 684-714, wherein the one or more multimerization domains(s) comprises one or more non-repeating multifunctional bridge moieties selected from alkyl, phenyl, aryl, alkenyl, alkynyl, heterocyclic, amine, ether, sulfide, disulfide, hydrazine, and any of the foregoing substituted with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl, amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl, alkenyl, alkynyl, aryl, heterocyclic, and moieties comprising combinations thereof.
716. The composition according to any of claims 684-715, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties), that are soluble or insoluble.
717. The composition according to any of claims 684-716, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more cross- linked oligomer (or oligomer moieties) or cross-linked polymers (or polymer moieties).
718. The composition according to any of claims 684-717, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more homopolymers and/or one or more copolymers (including polymers having two monomer-repeat-units, terpolymers and higher-order polymers), including for example random copolymer moieties and block copolymer moieties.
719. The composition according to any of claims 684-718, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more ionic monomer moieties such as one or more anionic monomer moieties.
720. The composition according to any of claims 684-719, wherein the one or more multimerization domains(s) comprises one or more oligomers (or oligomer moieties) or polymers (or polymer moieties) comprising one or more hydrophobic and/or hydrophilic monomer moieties.
721 . The composition according to any of claims 684-720, wherein the one or more multimerization domains(s) comprises from 1 to 100 coupling sites for biologically active molecules, such as from 1 to 5 coupling sites, for example from 5 to 10 coupling sites, such as from 10 to 15 coupling sites, for example from 15 to 20 coupling sites, such as from 20 to 25 coupling sites, for example from 25 to 30 coupling sites, such as from 30 to 35 coupling sites, for example from 35 to 40 coupling sites, such as from 40 to 45 coupling sites, for example from 45 to 50 coupling sites, such as from 50 to 55 coupling sites, for example from 55 to 60 coupling sites, such as from 60 to 65 coupling sites, for example from 65 to 70 coupling sites, such as from 70 to 75 coupling sites, for example from 75 to 80 coupling sites, such as from 80 to 85 coupling sites, for example from 85 to 90 coupling sites, such as from 90 to 95 coupling sites, for example from 95 to 100 coupling sites or , 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 coupling sites for biologically active molecules.
722. The composition according to any of claims 684-721 , wherein the one or more multimerization domains(s) comprises one or more polymer moieties that are soluble or insoluble, exist as dispersed micelles or particles, such as colloidal particles or (insoluble) macroscopic beads.
723. The composition according to any of claims 684-722, wherein the one or more multimerization domains(s) comprises one or more polymer moieties that are hydrophobic, hydrophilic, amphiphilic, uncharged or non-ionic, negatively or positively charged, or a combination thereof, and can be organic or inorganic.
724. The composition according to any of claims 684-723, wherein the one or more multimerization domains(s) comprises one or more inorganic polymer moieties such as silica (e.g., multi-layered silica), diatomaceous earth, zeolite, calcium carbonate, talc, and the like.
725. The composition according to any of claims 684-724, wherein the one or more multimerization domains(s) comprises one or more water-soluble polymers including polyethylene glycol (PEG), monomethoxy-PEG, mono-(Cr Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, cellulose, or other carbohydrate-based polymers.
726. The composition according to any of claims 684-725, wherein the one or more multimerization domains(s) comprises one or more polysaccharides such as materials from vegetal or animal origin, including cellulose materials, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin, and/or chitosan.
727. The composition according to any of claims 684-726, wherein the one or more multimerization domains(s) comprises one or more multimerization domain selected from the group consisting of agarose, sepharose, resin beads, glass beads, pore-glass beads, glass particles coated with a hydrophobic polymer, chitosan-coated beads, SH beads, latex beads , spherical latex beads, allele-type beads, SPA bead, PEG-based resins, PEG-coated bead, PEG- encapsulated bead, polystyrene beads, magnetic polystyrene beads, glutathione agarose beads, magnetic bead, paramagnetic beads, protein A and/or protein G sepharose beads, activated carboxylic acid bead, macroscopic beads, microscopic beads, insoluble resin beads, silica-based resins, cellulosic resins, cross-linked agarose beads, polystyrene beads, cross-linked polyacrylamide resins, beads with iron cores, metal beads, dynabeads, Polymethylmethacrylate beads activated with NHS, streptavidin-agarose beads, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, nitrocellulose, polyacrylamides, gabbros, magnetite, polymers, oligomers, non-repeating moieties, polyethylene glycol (PEG), monomethoxy- PEG, mono-(Ci-Cio)alkoxy-PEG, aryloxy-PEG, poly-(N-vinyl pyrrolidone)PEG, tresyl monomethoxy PEG, PEG propionaldehyde, bis-succinimidyl carbonate PEG, polystyrene bead crosslinked with divinylbenzene, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, dextran, aminodextran, carbohydrate-based polymers, cross-linked dextran beads, polysaccharide beads, polycarbamate beads, polyvinylcarbamate, divinyl sulfone activated polysaccharide, polystyrene beads that have been functionalized with tosyl-activated esters, magnetic polystyrene beads functionalized with tosyl-activated esters, streptavidin beads, streptavidin- monomer coated beads, streptavidin-tetramer coated beads, Streptavidin Coated Compel Magnetic beads, avidin coated beads, dextramer coated beads, divinyl sulfone-activated dextran, Carboxylate-modified bead, amine-modified beads, antibody coated beads, cellulose beads, grafted co-poly beads, poly- acrylamide beads, dimethylacrylamide beads optionally crosslinked with N-N'- bis-acryloylethylenediamine, hollow fiber membranes, fluorescent beads, collagen-agarose beads, gelatin beads, collagen-gelatin beads, collagen- fibronectin-gelatin beads, collagen beads, chitosan beads, collagen-chitosan beads, protein-based beads, hydrogel beads, hemicellulose, alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose, sulfoethylcellulose, starch, xylan, amylopectine, chondroitin, hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin and chitosan.
728. The composition according to any of claims 684-727, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of less than 1 ,000 Da (e.g. small molecule scaffold).
729. The composition according to any of claims 684-728, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 1 ,000 Da and 10,000 Da (e.g. small molecule scaffold, small peptides, small polymers) such as from 1 ,000 Da to 2,000 Da, for example from 2,000 Da to 3,000 Da, such as from 3,000 Da to
4,000 Da, for example from 4,000 Da to 5,000 Da, such as from 5,000 Da to 6,000 Da, for example from 6,000 Da to 7,000 Da, such as from 7,000 Da to 8,000 Da, for example from 8,000 Da to 9,000 Da, such as from 9,000 Da to 10,000 Da.
730. The composition according to any of claims 684-729, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 10,000 Da and 100,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure) such as from 10,000 Da to 20,000 Da, for example from 20,000 Da to 30,000 Da, such as from 30,000 Da to 40,000 Da, for example from 40,000 Da to 50,000 Da, such as from 50,000 Da to 60,000 Da, for example from 60,000 Da to 70,000 Da, such as from 70,000 Da to 80,000 Da, for example from 80,000 Da to 90,000 Da, such as from 90,000 Da to 100,000 Da.
731 . The composition according to any of claims 684-730, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of between 100,000 Da and 1 ,000,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure) such as from 100,000 Da to 200,000 Da, for example from
200,000 Da to 300,000 Da, such as from 300,000 Da to 400,000 Da, for example from 400,000 Da to 500,000 Da, such as from 500,000 Da to 600,000 Da, for example from 600,000 Da to 700,000 Da, such as from 700,000 Da to 800,000 Da, for example from 800,000 Da to 900,000 Da, such as from 900,000 Da to 1 ,000,000 Da.
732. The composition according to any of claims 684-731 , wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight of more than 1 ,000,000 Da (e.g. Small molecule scaffold, polymers e.g. dextran, streptavidin, IgG, pentamer structure, cells, liposomes, artificial lipid bi layers, polystyrene beads and other beads) such as more than 2,000,000 Da, for example more than 3,000,000 Da, such as more than 5,000,000, for example more than 10,000,000 Da.
733. The composition according to any of claims 684-732, wherein the one or more multimerization domains(s) comprises one or more multimerization domain(s) with a molecular weight in the range 50,000 Da to 5,000,000 Da, such as from 50,000 Da to 100,000 Da, for example from 100,000 Da to 200,000 Da, such as from 200,000 Da to 300,000 Da, for example from 300,000 Da to 400,000 Da, such as from 400,000 Da to 500,000 Da, for example from 500,000 Da to 600,000 Da, such as from 600,000 Da to 700,000 Da, for example from 700,000 Da to 800,000 Da, such as from 800,000 Da to 900,000 Da, for example from 900,000 Da to 1 ,000,000 Da, such as from 1 ,000,000 Da to 1 ,200,000 Da, for example from 1 ,200,000 Da to 1 ,400,000 Da, such as from 1 ,400,000 Da to 1 ,600,000 Da, for example from 1 ,600,000 Da to 1 ,800,000 Da, such as from 1 ,800,000 Da to 2,000,000 Da, for example from 2,000,000 Da to 2,200,000 Da, such as from 2,200,000 Da to 2,400,000 Da, for example from 2,400,000 Da to 2,600,000 Da, such as from 2,600,000 Da to 2,800,000 Da, for example from 2,800,000 Da to 3,000,000 Da, such as from 3,000,000 Da to 3,200,000 Da, for example from 3,200,000 Da to
3,400,000 Da, such as from 3,400,000 Da to 3,600,000 Da, for example from 3,600,000 Da to 3,800,000 Da, such as from 3,800,000 Da to 4,000,000 Da, for example from 4,000,000 Da to 4,200,000 Da, such as from 4,200,000 Da to 4,400,000 Da, for example from 4,400,000 Da to 4,600,000 Da, such as from 4,600,000 Da to 4,800,000 Da, for example from 4,800,000 Da to 5,000,000
Da.
734. The composition according to any of claims 1 -733, wherein the the one or more biologically active molecules according to any of claims 28-683 and the one or more multimerization domain according to any of claims 684-733 are coupled.
735. The composition according to claim 734, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled by chemical reactions between reactive groups of the multimerization domain and reactive groups on the biologically active molecule.
736. The composition according to any of claims 734-735, wherein coupling comprises coupling by non-covalent interaction between a part of the biologically active molecule (e.g. a biotinylated peptide component) and the multimerization domain (e.g. four binding sites for biotin on the strepavidin tetrameric protein).
737. The composition according to any of claims 734-736, wherein the coupling comprises non-covalent association of amino acid helices fused to one component of a biologically active molecule, to form e.g. a pentameric pharmamer, held together by e.g. five helices in a coiled-coil structure making up the multimerization domain.
738. The composition according to any of claims 734-737, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled by one or more chemical reactions.
739. The composition according to claim 738, wherein the one or more chemical reactions comprises nucleophilic substitution by activation of electrophiles (e.g. acylation such as amide formation, pyrazolone formation, isoxazolone formation; alkylation; vinylation; disulfide formation).
740. The composition according to claim 738, wherein the one or more chemical reactions comprises addition to carbon-hetero multiple bonds (e.g. alkene formation by reaction of phosphonates with aldehydes or ketones; arylation; alkylation of arenes/hetarenes by reaction with alkyl boronates or enolethers).
741 . The composition according to claim 738, wherein the one or more chemical reactions comprises nucleophilic substitution using activation of nucleophiles (e.g. condensations; alkylation of aliphatic halides or tosylates with enolethers or enamines).
742. The composition according to claim 738, wherein the one or more chemical reactions comprises cycloadditions.
743. The composition according to claim 738, wherein the one or more biologically active molecules and the one or more multimerization domains(s) are coupled one or more non-covalent interaction(s).
744. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises streptavidin/biotin.
745. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises avidin/biotin.
746. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises antibody/antigen.
747. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises DNA/DNA.
748. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises DNA/PNA.
749. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises DNA/RNA.
750. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises PNA/PNA.
751 . The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises LNA/DNA.
752. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises leucine zipper e.g. Fos/Jun.
753. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises IgG dimeric protein.
754. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises IgM multivalent protein.
755. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises acid/base coiled-coil helices.
756. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises chelate/metal ion-bound chelate.
757. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises streptavidin (SA) and avidin and derivatives thereof.
758. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises biotin.
759. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises immunoglobulins.
760. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises antibodies (monoclonal, polyclonal, and recombinant).
761. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises antibody fragments and derivatives thereof.
762. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises leucine zipper domain of AP-1 (jun and fos).
763. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises hexa-his (metal chelate moiety).
764. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises hexa-hat GST (glutathione S-transferase) glutathione affinity.
765. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises Calmodulin-binding peptide (CBP).
766. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises Strep-tag.
767. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises Cellulose Binding Domain.
768. The composition according to claim 743, wherein the one or more non- covalent interaction(s) comprises one or more of the molecules selected from the group consiting of Maltose Binding Protein, S-Peptide Tag, Chitin Binding Tag, Immuno-reactive Epitopes, Epitope Tags, E2Tag, HA Epitope Tag, Myc Epitope, FLAG Epitope, AU1 and AU5 Epitopes, GIu-GIu Epitope, KT3 Epitope, IRS Epitope, Btag Epitope, Protein Kinase-C Epitope, VSV Epitope, lectins that mediate binding to a diversity of compounds, including carbohydrates, lipids and proteins, e.g. Con A (Canavalia ensiformis) or WGA (wheat germ agglutinin) and tetranectin or Protein A or G (antibody affinity).
769. The composition according to any of claims 1 -768, wherein the composition comprises one or more vaccine adjuvant(s).
770. The composition according to any of claims 1 -769, wherein the composition comprises more than 1 vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more than 10,000 vaccine adjuvants.
771 . The composition according to any of claims 1 -770, wherein the composition comprises more than 1 different vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35,
40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 different vaccine adjuvants.
772. The composition according to any of claims 1 -771 , wherein the composition comprises more than 1 identical vaccine adjuvant, such as more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1 ,000, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, or more thani 0,000 identical vaccine adjuvants.
773. The composition according to any of claims 1 -772, wherein the composition comprises less than 10,000 vaccine adjuvants, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 vaccine adjuvants.
774. The composition according to any of claims 1 -773, wherein the composition comprises less than 10,000 different vaccine adjuvants, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 different vaccine adjuvants.
775. The composition according to any of claims 1 -774, wherein the composition comprises less than 10,000 identical vaccine adjuvants, such as for example less than 9,000, 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000, 1 ,000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, or less than 2 identical vaccine adjuvants.
776. The composition according to any of claims 769-775, wherein the one or more vaccine adjuvant(s) increases or otherwise modifies the immune response to said vaccine.
777. The composition according to any of claims 769-776, wherein the one or more vaccine adjuvant(s) elicit an earlier and/or more potent immune response to said vaccine.
778. The composition according to any of claims 769-777, wherein the one or more vaccine adjuvant(s) elicit a prolonged and/or more potent immune response to said vaccine.
779. The composition according to any of claims 769-778, wherein the one or more vaccine adjuvant(s) results in increased humoral immunity to said vaccine.
780. The composition according to any of claims 769-779, wherein the one or more vaccine adjuvant(s) results in induction of the complement pathway.
781 . The composition according to any of claims 769-780, wherein the one or more vaccine adjuvant(s) results in increased cell mediated immunity to said vaccine.
782. The composition according to any of claims 769-781 , wherein the one or more vaccine adjuvant(s) comprises one or more antigenic determinant(s).
783. The composition according to any of claims 769-782, wherein the one or more vaccine adjuvant(s) comprises one or more haptenic determinant(s).
784. The composition according to any of claims 769-783, wherein the one or more vaccine adjuvant(s) comprises one or more mineral adjuvant(s).
785. The composition according to claim 784, wherein the one or more mineral adjuvant(s) comprises one or more aluminium compounds such as one or more aluminium salt(s).
786. The composition according to claim 784, wherein the one or more mineral adjuvant(s) comprises aluminium hydroxide.
787. The composition according to any of claims 769-786, wherein the one or more vaccine adjuvant(s) comprises one or more bacterial adjuvant(s).
788. The composition according to claim 787, wherein one or more bacterial adjuvant(s) are purified.
789. The composition according to claim 787, wherein one or more bacterial adjuvant(s) are chemically purified.
790. The composition according to claim 787, wherein one or more bacterial adjuvant(s) are synthesized.
791. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises muramyl dipeptides.
792. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises lipid A.
793. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises lnterleukin 1.
794. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises lnterleukin 2.
795. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more cloned host mediator(s).
796. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises Bordetella pertussis.
797. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s).
798. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises Freund's Complete Adjuvant (FCA).
799. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises Titermax.
800. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises ISCOMS.
801. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises Quil A.
802. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises ALUN.
803. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more Lipid A derivatives.
804. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more choleratoxin derivatives.
805. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more HSP derivatives.
806. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more LPS derivatives.
807. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more synthetic peptide matrixes.
808. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises GMDP.
809. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof.
810. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof in combination with one or more liposome(s).
81 1. The composition according to claim 787, wherein one or more bacterial adjuvant(s) comprises one or more lipopolysaccharide(s) and/or derivatis thereof in combination with one or more lipid emulsion(s).
812. The composition according to any of claims 769-81 1 , wherein the one or more vaccine adjuvant(s) comprises one or more plant adjuvant(s).
813. The composition according to claim 812, wherein the one or more plant adjuvant(s) comprises saponin.
814. The composition according to any of claims 769-813, wherein the one or more vaccine adjuvant(s) comprises one or more animal products adjuvant(s).
815. The composition according to claim 814, wherein the one or more animal products adjuvant(s) comprises chitin.
816. The composition according to any of claims 769-815, wherein the one or more vaccine adjuvant(s) comprises one or more synthetic adjuvant(s).
817. The composition according to any of claims 769-816, wherein the one or more vaccine adjuvant(s) comprises one or more host adjuvant(s).
818. The composition according to any of claims 769-817, wherein the one or more vaccine adjuvant(s) comprises one or more antigens precipitated with aluminum salt(s).
819. The composition according to any of claims 769-818, wherein the one or more vaccine adjuvant(s) comprises one or more antigens mixed with or adsorbed to performed aluminum compounds.
820. The composition according to any of claims 769-819, wherein the one or more vaccine adjuvant(s) comprises one or more oil emulsion(s).
821. The composition according to any of claims 769-820, wherein the one or more vaccine adjuvant(s) comprises one or more liposome(s).
822. The composition according to any of claims 769-821 , wherein the one or more vaccine adjuvant(s) comprises one or more synthetic polymer(s).
823. The composition according to any of claims 769-822, wherein the one or more vaccine adjuvant(s) act through antigen localization and delivery.
824. The composition according to any of claims 769-823, wherein the one or more vaccine adjuvant(s) act by direct effects on cells making up the immune system, such as macrophages and lymphocytes.
825. The composition according to any of claims 769-824, wherein the one or more vaccine adjuvant(s) act by creation of an antigen depot.
826. The composition according to any of claims 769-825, wherein the one or more vaccine adjuvant(s) comprises Alhydrogel.
827. The composition according to any of claims 769-826, wherein the one or more vaccine adjuvant(s) comprises MF59 and/or the proprietary Montanide ISA720.
828. The composition according to any of claims 769-827, wherein the one or more vaccine adjuvant(s) can be selected from the group consisting of AIK(SO4)2, AINa(SO4)2, AINH4 (SO4), silica, alum, AI(OH)3, Ca3 (PO4)2, kaolin, carbon, aluminum hydroxide, muramyl dipeptides, N-acetyl-muramyl-L-threonyl- D-isoglutamine (thr-DMP), N-acetyl-nornuramyl-L-alanyl-D-isoglutamine (CGP 1 1687, also referred to as nor-MDP), N-acetylmuramyul-L-alanyl-D- isoglutaminyl-L-alanine-2-(1 '2'-dipalmitoyl-sn -glycero-3-hydroxphosphoryloxy)- ethylamine (CGP 19835A, also referred to as MTP-PE), RIBI (MPL+TDM+CWS) in a 2% squalene/Tween-80.RTM. emulsion, lipopolysaccharides and its various derivatives, including lipid A, Freund's Complete Adjuvant (FCA), Freund's Incomplete Adjuvants, Merck Adjuvant 65, polynucleotides (for example, poly IC and poly AU acids), wax D from Mycobacterium, tuberculosis, substances found in Corynebacterium parvum, Bordetella pertussis, and members of the genus Brucella, liposomes or other lipid emulsions, Titermax, ISCOMS, Quil A, ALUN (see US 58767 and 5,554,372), Lipid A derivatives, choleratoxin derivatives, HSP derivatives, LPS derivatives, synthetic peptide matrixes or GMDP, lnterleukin 1 , lnterleukin 2, Montanide ISA-51 and QS-21 , Freund's complete or incomplete adjuvant, and killed B. pertussis organisms, used e.g. in combination with alum precipitated antigen.
829. The composition according to any of claims 1 -828, wherein the one or more pharmamers comprise one or more HIV and/or SIV vaccines.
830. The composition according to any of claims 1 -828, wherein the one or more pharmamers do not comprise one or more HIV and/or SIV vaccines.
831 . The composition according to any of claims 1 -830, wherein the one or more pharmamers comprise a dextran carrier.
832. The composition according to any of claims 1 -830, wherein the one or more pharmamers do not comprise a dextran carrier.
833. The composition according to any of claims 1 -832, wherein the one or more pharmamers comprises a dextran carrier derivatized by attachment of Streptavidin e.g. such as 8.6 Steptavidin molecules are attached per Dextran molecule.
834. The composition according to any of claims 1 -832, wherein the one or more pharmamers do not comprise a dextran carrier derivatized by attachment of Streptavidin e.g. such as 8.6 Steptavidin molecules are attached per Dextran molecule.
835. The composition according to any of claims 1 -834, wherein the one or more pharmamers comprise a dextran carrier with a molecular weight of 270 kDa.
836. The composition according to any of claims 1 -834, wherein the one or more pharmamers do not comprise a dextran carrier with a molecular weight of 270 kDa.
837. The composition according to any of claims 1 -836, wherein the one or more pharmamers comprises a dextran carrier with Simian MHC class 1 molecules attached.
838. The composition according to any of claims 1 -836, wherein the one or more pharmamers do not comprises a dextran carrier with Simian MHC class 1 molecules attached.
839. The composition according to any of claims 1 -838, wherein the one or more pharmamers comprise a dextran carrier with Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569) attached.
840. The composition according to any of claims 1 -838, wherein the one or more pharmamers do not comprises a dextran carrier with Mamu-
A*01 (CTPYDINQM) (SEQ ID NO 9569) attached.
841 . The composition according to any of claims 1 -840, wherein the one or more pharmamers comprise a dextran carrier with Mamu-A*08(KPCVKLTP) attached (SEQ ID NO 9570).
842. The composition according to any of claims 1 -840, wherein the one or more pharmamers do not comprise a dextran carrier with Mamu- A*08(KPCVKLTP) attached (SEQ ID NO 9570).
843. The composition according to any of claims 1 -842, wherein the one or more pharmamers comprise a dextran carrier with Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ) attached.
844. The composition according to any of claims 1 -842, wherein the one or more pharmamers do not comprises a dextran carrier with Mamu- B*17(IRFPKTFGW) (SEQ ID NO 9571 ) attached.
845. The composition according to any of claims 839-844, wherein attachment is done via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain to streptavidin molecules on the dextran carrier.
846. The composition according to any of claims 839-844, wherein attachment is not done via a COOH-terminal Biotin molecule on the recombinant Mamu heavy chain to streptavidin molecules on the dextran carrier.
847. The composition according to any of claims 1 -846, wherein the one or more pharmamers comprises one or more biotinylated synthetic Mamu class 2 peptides.
848. The composition according to any of claims 1 -846, wherein the one or more pharmamers do not comprise one or more biotinylated synthetic Mamu class 2 peptides.
849. The composition according to any of claims 1 -848, wherein the one or more pharmamers comprises Mamu-DQB1 *0601 (EFVRFDSAVGEYRAV) (SEQ ID NO 9572).
850. The composition according to any of claims 1 -848, wherein the one or more pharmamers do not comprise Mamu-DQB1 *0601 (EFVRFDSA VGEYRAV)
(SEQ ID NO 9572).
851. The composition according to any of claims 1 -850, wherein the one or more pharmamers comprises Mamu-DQB1 *1808(EFVGFDSYLGVYRPV) (SEQ ID NO 9573).
852. The composition according to any of claims 1 -850, wherein the one or more pharmamers do not comprise Mamu-DQB1 *1808(EFVGFDSYLGVYRPV) (SEQ ID NO 9573).
853. The composition according to any of claims 1 -852, wherein the one or more pharmamers comprises Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574).
854. The composition according to any of claims 1 -852, wherein the one or more pharmamers do not comprise Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574).
855. The composition according to any of claims 1 -854, wherein the one or more pharmamers comprises recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
856. The composition according to any of claims 1 -854, wherein the one or more pharmamers do not comprise recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
857. The composition according to any of claims 1 -856, wherein the one or more pharmamers comprises HIV-Gag (CTPYDINQM) (SEQ ID NO 9569).
858. The composition according to any of claims 1 -856, wherein the one or more pharmamers do not comprises HIV-Gag (CTPYDINQM) (SEQ ID NO 9569).
859. The composition according to any of claims 1 -858, wherein the one or more pharmamers comprises HIV-Env (KPCVKLTP) (SEQ ID NO 9570).
860. The composition according to any of claims 1 -858, wherein the one or more pharmamers do not comprise HIV-Env (KPCVKLTP) (SEQ ID NO 9570).
861 . The composition according to any of claims 1 -860, wherein the one or more pharmamers comprises Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ).
862. The composition according to any of claims 1 -860, wherein the one or more pharmamers do not comprises Siv Nef (IRFPKTFGW) (SEQ ID NO 9571 ).
863. The composition according to any of claims 1 -862, wherein the one or more pharmamers comprises recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
864. The composition according to any of claims 1 -862, wherein the one or more pharmamers do not comprises recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
865. The composition according to any of claims 1 -864, wherein the one or more pharmamers comprises Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu-DQB1 *0601 (EFVRFDSA VGEYRA V) (SEQ ID NO 9572) class 2 peptide, HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratiol 0:10:4:1 ).
866. The composition according to any of claims 1 -864, wherein the one or more pharmamers do not comprise Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), Mamu-DQB1 *0601 (EFVRFDSA VGEYRA V) (SEQ ID NO 9572) class 2 peptide, HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratiol 0:10:4:1 ).
867. The composition according to any of claims 1 -866, wherein the one or more pharmamers comprises Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573) class 2 peptide, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
868. The composition according to any of claims 1 -866, wherein the one or more pharmamers do not comprise Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), Mamu-DQB1 *1808 (EFVGFDSYLGVYRPV) (SEQ ID NO 9573) class 2 peptide, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
869. The composition according to any of claims 1 -868, wherein the one or more pharmamers comprises Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) class 2 peptide, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
870. The composition according to any of claims 1 -868, wherein the one or more pharmamers do not comprise Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), Mamu-DRB*W201 (TREDILERERAQVDTFY) (SEQ ID NO 9574) class 2 peptide, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
871 . The composition according to any of claims 1 -870, wherein the one or more pharmamers comprises Sivp27, HIV-1gp140trimer, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 3:10:4).
872. The composition according to any of claims 1 -870, wherein the one or more pharmamers do not comprise Sivp27, HIV-1gp140trimer, HSP70pep3Bio and Dextran carrier (e.g. in the molar ratio 3:10:4).
873. The composition according to any of claims 1 -872, wherein the one or more pharmamers are absorbed into the adjuvant Alhydrogel (Aluminiumhydroxide gel) as specified by the manufacturer.
874. The composition according to any of claims 1 -872, wherein the one or more pharmamers are not absorbed into the adjuvant Alhydrogel
(Aluminiumhydroxide gel) as specified by the manufacturer.
875. The composition according to any of claims 1 -874, wherein the one or more pharmamers comprises Human MHC class 1 molecules.
876. The composition according to any of claims 1 -874, wherein the one or more pharmamers do not comprise Human MHC class 1 molecules.
877. The composition according to any of claims 1 -876, wherein the one or more pharmamers comprises HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575).
878. The composition according to any of claims 1 -876, wherein the one or more pharmamers do not comprises HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575).
879. The composition according to any of claims 1 -878, wherein the one or more pharmamers comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576).
880. The composition according to any of claims 1 -878, wherein the one or more pharmamers do not comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO
9576).
881. The composition according to any of claims 1 -880, wherein the one or more pharmamers comprises H LA-A*0301 (RIAAWMATY) (SEQ ID NO 9577).
882. The composition according to any of claims 1 -880, wherein the one or more pharmamers do not comprise HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577).
883. The composition according to any of claims 1 -882, wherein the one or more pharmamers comprises HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578).
884. The composition according to any of claims 1 -882, wherein the one or more pharmamers do not comprise HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578).
885. The composition according to any of claims 1 -884, wherein the one or more pharmamers comprises attachment a COOH-terminal Biotin molecule on recombinant HLA heavy chain to the carrier strepavidin molecules.
886. The composition according to any of claims 1 -884, wherein the one or more pharmamers do not comprise attachment a COOH-terminal Biotin molecule on recombinant HLA heavy chain to the carrier strepavidin molecules.
887. The composition according to any of claims 1 -886, wherein the one or more pharmamers comprises biotinylated recombinant HLA class 2 protein HLA-DFT0401 and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
888. The composition according to any of claims 1 -886, wherein the one or more pharmamers do not comprise biotinylated recombinant HLA class 2 protein HLA-DR*0401 and recombinant HSP70pep3Bio fragments (a biotinylated HSP70 fragment spanning amino acid residues 359-609) attached to strepavidin sites.
889. The composition according to any of claims 1 -888, wherein the one or more pharmamers comprises USP9Y, ubiquitin specific protease 9 (IVDCLTEMY) (SEQ ID NO 9575).
890. The composition according to any of claims 1 -888, wherein the one or more pharmamers do not comprises USP9Y, ubiquitin specific protease 9 (IVDCLTEMY) (SEQ ID NO 9575).
891 . The composition according to any of claims 1 -890, wherein the one or more pharmamers comprises TRAG-3_4 (GLIQLVEGV) (SEQ ID NO 9576).
892. The composition according to any of claims 1 -890, wherein the one or more pharmamers do not comprise TRAG-3_4 (GLIQLVEGV) (SEQ ID NO 9576).
893. The composition according to any of claims 1 -892, wherein the one or more pharmamers comprises BCL2L1 (RIAAWMATY) (SEQ ID NO 9577).
894. The composition according to any of claims 1 -892, wherein the one or more pharmamers do not comprise BCL2L1 (RIAAWMATY) (SEQ ID NO 9577).
895. The composition according to any of claims 1 -894, wherein the one or more pharmamers comprises EBV EBNA3B (IVTDFSVIK) (SEQ ID NO 9578).
896. The composition according to any of claims 1 -894, wherein the one or more pharmamers do not comprise EBV EBNA3B (IVTDFSVIK) (SEQ ID NO 9578).
897. The composition according to any of claims 1 -896, wherein the one or more pharmamers comprises a HLA class 2 complex without a peptide in the binding groove.
898. The composition according to any of claims 1 -896, wherein the one or more pharmamers do not comprise a HLA class 2 complex without a peptide in the binding groove.
899. The composition according to any of claims 1 -898, wherein the one or more pharmamers comprises a HLA class 2 complex containing unknown peptides derived from either serum or S2 production cells.
900. The composition according to any of claims 1 -898, wherein the one or more pharmamers do not comprise a HLA class 2 complex containing unknown peptides derived from either serum or S2 production cells.
901. The composition according to any of claims 1 -900, wherein the one or more pharmamers comprises HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575), HLA-DFT0401 class 2, HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratio10:10:4:1 ).
902. The composition according to any of claims 1 -900, wherein the one or more pharmamers do not comprise HLA-A*0101 (IVDCLTEMY) (SEQ ID NO 9575), HLA-DFT0401 class 2, HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratiol 0:10:4:1 ).
903. The composition according to any of claims 1 -902, wherein the one or more pharmamers comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576), H LA-A*0301 (RIAAWMATY) (SEQ ID NO 9577), HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
904. The composition according to any of claims 1 -902, wherein the one or more pharmamers do not comprises HLA-A*0201 (GLIQLVEGV) (SEQ ID NO 9576), HLA-A*0301 (RIAAWMATY) (SEQ ID NO 9577), HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratio 10:10:4:1 ).
905. The composition according to any of claims 1 -904, wherein the one or more pharmamers comprises HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578), HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratio 10:4:1 ).
906. The composition according to any of claims 1 -904, wherein the one or more pharmamers do not comprise HLA-A*1 101 (IVTDFSVIK) (SEQ ID NO 9578), HSP70pep3Bio, and Dextran carrier (e.g. in the molar ratio 10:4:1 ).
907. The composition according to any of claims 1 -906, wherein the one or more pharmamers are emulsified with the adjuvant Titermax Gold as specified by the manufacturer.
908. The composition according to any of claims 1 -906, wherein the one or more pharmamers are not emulsified with the adjuvant Titermax Gold.
909. The composition according to any of claims 1 -908, wherein the one or more pharmamers comprises recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
910. The composition according to any of claims 1 -908, wherein the one or more pharmamers do not comprise recombinant HIV-1gp140 trimer and SIVp27 attached by Biotin-Strepavidin binding.
91 1. The composition according to any of claims 1 -910, wherein the one or more pharmamers comprises biotinylated recombinant HSP70pep3Bio-CCR5- tripeptide fragment, a biotinylated fusion protein consisting of the HSP70 fragment spanning amino acid residues 359-609 plus the antigenic CCR5 loops, N-terminal loop, Loopi and Loop2, attached to strepavidin sites.
912. The composition according to any of claims 1 -910, wherein the one or more pharmamers do not comprise biotinylated recombinant HSP70pep3Bio- CCR5-tripeptide fragment, a biotinylated fusion protein consisting of the HSP70 fragment spanning amino acid residues 359-609 plus the antigenic CCR5 loops, N-terminal loop, Loopi and Loop2, attached to strepavidin sites.
913. The composition according to any of claims 1 -912, wherein the one or more pharmamers comprises the CCR5 peptides representing the three antigenic loops (N-terminal (MNYQVSSPIYNINYYTSEPC) (SEQ ID NO 9579);
Loopi (HYAAAQWNFGNTMCQ) (SEQ ID NO 9580); Loop2 (YSSHFPYSQYQFWKNFQTLK) (SEQ ID NO 9581 )).
914. The composition according to any of claims 1 -912, wherein the one or more pharmamers do not comprise the CCR5 peptides representing the three antigenic loops (N-terminal (MNYQVSSPIYNINYYTSEPC) (SEQ ID NO 9579); Loopi (HYAAAQWNFGNTMCQ) (SEQ ID NO 9580); Loop2 (YSSHFPYSQYQFWKNFQTLK) (SEQ ID NO 9581 )).
915. The composition according to any of claims 1 -914, wherein the one or more pharmamers comprises Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
916. The composition according to any of claims 1 -914, wherein the one or more pharmamers do not comprise Mamu-A*01 (CTPYDINQM) (SEQ ID NO 9569), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
917. The composition according to any of claims 1 -916, wherein the one or more pharmamers comprises Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
918. The composition according to any of claims 1 -916, wherein the one or more pharmamers do not comprise Mamu-A*08 (KPCVKLTP) (SEQ ID NO 9570), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
919. The composition according to any of claims 1 -918, wherein the one or more pharmamers comprises Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
920. The composition according to any of claims 1 -918, wherein the one or more pharmamers do not comprise Mamu-B*17(IRFPKTFGW) (SEQ ID NO 9571 ), HSP70pep3Bio-CCR5-tripeptide and Dextran carrier (e.g. in the molar ratio13:10:1 ).
921 . The composition according to any of claims 1 -920, wherein the composition is designed to elicit a multifunctional immune response i.e. a composite immune responses directed against the adaptive and the innate immune system; and/or both parts of the adaptive system i.e. the humoral and the cellular part.
922. The composition according to any of claims 1 -920, wherein the composition is not designed to elicit a multifunctional immune response i.e. a composite immune responses directed against the adaptive and the innate immune system; and/or both parts of the adaptive system i.e. the humoral and the cellular part.
923. The composition according to any of claims 1 -922, wherein the composition comprises one or more HLA class 1 and/or class 2 molecules.
924. The composition according to any of claims 1 -922, wherein the composition does not comprise one or more HLA class 1 and/or class 2 molecules.
925. The composition according to any of claims 1 -924, wherein the composition comprises one or more HLA class 1 molecules that are folded or partly folded with human b2Microglobulin and a peptide fitting into the binding groove.
926. The composition according to any of claims 1 -924, wherein the composition does not comprise one or more HLA class 1 molecules that are folded or partly folded with human b2Microglobulin and a peptide fitting into the binding groove.
927. The composition according to any of claims 1 -926, wherein the composition comprises one or more complete, partial or otherwise modified HLA class 1 heavy chain(s).
928. The composition according to any of claims 1 -926, wherein the composition does not comprise one or more complete, partial or otherwise modified HLA class 1 heavy chain(s).
929. The composition according to any of claims 1 -928, wherein the composition comprises one or more HLA class 2 molecules consisting of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove.
930. The composition according to any of claims 1 -928, wherein the composition does not comprise one or more HLA class 2 molecules consisting of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove.
931 . The composition according to any of claims 1 -930, wherein the composition comprises one or more complete, partial or otherwise modified HLA class 2 alpha- and beta-chains.
932. The composition according to any of claims 1 -930, wherein the composition does not comprise one or more complete, partial or otherwise modified HLA class 2 alpha- and beta-chains.
933. The composition according to any of claims 1 -932, wherein the composition comprises one or more binding-peptides derived from HIV specific proteins such as Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev, Vpu, Nef, gp160 and derivatives such as gp120, gp41 and gp140.
934. The composition according to any of claims 1 -932, wherein the composition does not comprise one or more binding-peptides derived from HIV specific proteins such as Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev, Vpu, Nef, gp160 and derivatives such as gp120, gp41 and gp140.
935. The composition according to any of claims 1 -934, wherein the composition comprises one or more binding-peptides that are HIV unrelated.
936. The composition according to any of claims 1 -934, wherein the composition comprises one or more binding-peptides that are HIV related.
937. The composition according to any of claims 1 -936, wherein the composition comprises HLA class 1 peptides derived from regions of the class
1 heavy chain.
938. The composition according to any of claims 1 -936, wherein the composition does not comprise HLA class 1 peptides derived from regions of the class 1 heavy chain.
939. The composition according to any of claims 1 -938, wherein the composition comprises HLA class 2 peptides derived from regions of the class
2 alpha and/or beta chain.
940. The composition according to any of claims 1 -938, wherein the composition does not comprise HLA class 2 peptides derived from regions of the class 2 alpha and/or beta chain.
941. The composition according to any of claims 1 -940, wherein the composition comprises CD4 or part(s) hereof.
942. The composition according to any of claims 1 -940, wherein the composition does not comprise CD4 or part(s) hereof.
943. The composition according to any of claims 1 -942, wherein the composition comprises CCR 5 (Chemokine Receptor 5) or part(s) hereof.
944. The composition according to any of claims 1 -942, wherein the composition does not comprise CCR 5 (Chemokine Receptor 5) or part(s) hereof.
945. The composition according to any of claims 1 -944, wherein the composition comprises the extracellular peptide-loops of CCR5.
946. The composition according to any of claims 1 -944, wherein the composition does not comprise the extracellular peptide-loops of CCR5.
947. The composition according to any of claims 1 -946, wherein the composition comprises HSP70 or part(s) thereof.
948. The composition according to any of claims 1 -946, wherein the composition does not comprise HSP70 or part(s) thereof.
949. The composition according to any of claims 1 -948, wherein the composition comprises CXCR4 or part(s) hereof.
950. The composition according to any of claims 1 -948, wherein the composition do not comprise CXCR4 or part(s) hereof.
951. The composition according to any of claims 1 -950, wherein the composition comprises CCR 2 (Chemokine Receptor 2) or part(s) hereof.
952. The composition according to any of claims 1 -950, wherein the composition does not comprise CCR 2 (Chemokine Receptor 2) or part(s) hereof.
953. The composition according to any of claims 1 -952, wherein the composition comprises CX3CR1 or part(s) hereof.
954. The composition according to any of claims 1 -952, wherein the composition does not comprise CX3CR1 or part(s) hereof.
955. The composition according to any of claims 1 -954, wherein the composition comprises SDF-1 or part(s) hereof.
956. The composition according to any of claims 1 -954, wherein the composition does not comprises SDF-1 or part(s) hereof.
957. The composition according to any of claims 1 -956, wherein the composition comprises US28 or part(s) hereof.
958. The composition according to any of claims 1 -956, wherein the composition does not comprise US28 or part(s) hereof.
959. The composition according to any of claims 1 -958, wherein the composition comprises HIV viral specific proteins i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140.
960. The composition according to any of claims 1 -958, wherein the composition does not comprise HIV viral specific proteins i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140.
961. The composition according to any of claims 1 -960, wherein the composition comprises Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens).
962. The composition according to any of claims 1 -960, wherein the composition does not comprise Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens).
963. The composition according to any of claims 1 -962, wherein the composition comprises one or more Mamu class 1 molecules folded or partly folded with one or more human b2Microglobulin and a peptide fitting into the binding groove.
964. The composition according to any of claims 1 -962, wherein the composition does not comprise one or more Mamu class 1 molecules folded or partly folded with one or more human b2Microglobulin and a peptide fitting into the binding groove.
965. The composition according to any of claims 1 -964, wherein the composition comprises one or more complete, partial or otherwise modified Mamu class 1 heavy chain(s).
966. The composition according to any of claims 1 -964, wherein the composition does not comprise one or more complete, partial or otherwise modified Mamu class 1 heavy chain(s).
967. The composition according to any of claims 1 -966, wherein the composition comprises one or more Mamu class 2 molecules consisting of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove.
968. The composition according to any of claims 1 -966, wherein the composition does not comprise one or more Mamu class 2 molecules consisting of folded or partly folded alpha- and beta-chains with or without a peptide in the binding groove.
969. The composition according to any of claims 1 -968, wherein the composition comprises one or more complete, partial or otherwise modified
Mamu class 2 alpha- and beta-chains.
970. The composition according to any of claims 1 -968, wherein the composition does not comprise one or more complete, partial or otherwise modified Mamu class 2 alpha- and beta-chains.
971. The composition according to any of claims 1 -970, wherein the composition comprises one or more binding-peptides derived from SIV specific proteins such as Gag-Pol, Gag, Vif, Vpx, Envelope protein, and/or Nef.
972. The composition according to any of claims 1 -970, wherein the composition does not comprises one or more binding-peptides derived from SIV specific proteins such as Gag-Pol, Gag, Vif, Vpx, Envelope protein, and/or Nef.
973. The composition according to any of claims 1 -972, wherein the composition comprises one or more binding-peptides that are SIV unrelated.
974. The composition according to any of claims 1 -972, wherein the composition comprises one or more binding-peptides that are SIV related.
975. The composition according to any of claims 1 -974, wherein the composition comprises Mamu class 1 peptides derived from regions of the class 1 heavy chain.
976. The composition according to any of claims 1 -974, wherein the composition does not comprise Mamu class 1 peptides derived from regions of the class 1 heavy chain.
977. The composition according to any of claims 1 -976, wherein the composition comprises Mamu class 2 peptides derived from regions of the class 2 alpha and/or beta chain.
978. The composition according to any of claims 1 -976, wherein the composition does not comprise Mamu class 2 peptides derived from regions of the class 2 alpha and/or beta chain.
979. The composition according to any of claims 1 -978, wherein the composition comprises SIV viral specific proteins i.e. Gag-Pol, Gag, Vif, Vpx, Envelope protein, Nef; HSP70 (70 kD Heat-shock protein) or part(s) hereof.
980. The composition according to any of claims 1 -978, wherein the composition does not comprise SIV viral specific proteins i.e. Gag-Pol, Gag, Vif, Vpx, Envelope protein, Nef; HSP70 (70 kD Heat-shock protein) or part(s) hereof.
981. The composition according to any of claims 1 -980, wherein the compsition further comprises one or more living virulent organism(s).
982. The composition according to claim 981 , wherein the one or more living virulent organism(s) comprises one or more fully virulent organism(s).
983. The composition according to claim 981 , wherein the one or more living virulent organism(s) comprises one or more partly virulent organism(s).
984. The composition according to claim 981 , wherein the one or more living virulent organism(s) comprises one or more partly virulent organism(s) and one or more fully virulent organism(s).
985. The composition according to claim 983, wherein the one or more partly virulent organism(s) comprises one or more live attenuated microorganism(s).
986. The composition according to claim 985, wherein the one or more live attenuated microorganism(s) are modified by physical means.
987. The composition according to claim 986, wherein the physical means comprises heat.
988. The composition according to claim 985, wherein the one or more live attenuated microorganism(s) are modified by chemical means.
989. The composition according to claim 988, wherein the chemical means comprises one or more chemical(s).
990. The composition according to claim 985, wherein the one or more live attenuated microorganism(s) are modified by genetic manipulation.
991. The composition according to claim 990, wherein the genetic manipulation comprises generation of a recombinant bacteria missing virulence factors.
992. The composition according to claim 985, wherein the one or more live attenuated microorganism(s) are cultured under conditions that disable their virulent properties.
993. The composition according to any of claims 1 -992, wherein the composition further comprises one or more killed organism(s).
994. The composition according to claim 993, wherein the one or more killed organism(s) comprises one or more physically killed organism(s).
995. The composition according to claim 994, wherein the one or more physically killed organism(s) is killed by heat.
996. The composition according to claim 994, wherein the one or more physically killed organism(s) is killed by irradiation.
997. The composition according to claim 993, wherein the one or more killed organism(s) comprises one or more chemically killed organism(s).
998. The composition according to claim 997, wherein the one or more chemically killed organism(s) are killed by phenol.
999. The composition according to claim 997, wherein the one or more chemically killed organism(s) are killed by formaldehyde.
1000. The composition according to any of claims 1 -999, wherein the composition further comprises one or more fragments of one or more microorganism(s).
1001 . The composition according to claim 1000, wherein the one or more fragments of one or more microorganism(s) are isolated directly from the one or more microorganism(s).
1002. The composition according to any of claims 1 -1001 , wherein the composition comprises early HBV vaccine.
1003. The composition according to claim 1000, wherein the one or more fragments of one or more microorganism(s) are produced by recombinant DNA technology.
1004. The composition according to any of claims 1 -1003, wherein the composition further comprises HPV vaccine.
1005. The composition according to any of claims 1 -1004, wherein the composition further comprises one or more macromolecule(s).
1006. The composition according to claim 1005, wherein the one or more macromolecule(s) comprises one or more naturally occurring protein(s).
1007. The composition according to claim 1006, wherein the one or more naturally occurring protein(s) are isolated and used directly.
1008. The composition according to claim 1006, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more cytokine(s).
1009. The composition according to claim 1006, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more interleukine(s).
1010. The composition according to claim 1006, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more interferone(s).
101 1 . The composition according to claim 1006, wherein the one or more naturally occurring protein(s) that are isolated and used directly comprises one or more antibodies(s).
1012. The composition according to claim 101 1 , wherein the one or more antibodies(s) comprises one or more monoclonal antibodies.
1013. The composition according to claim 101 1 , wherein the one or more antibodies(s) comprises one or more polyclonal antibodies.
1014. The composition according to claim 1006, wherein the one or more naturally occurring protein(s) are isolated and modified.
1015. The composition according to claim 1014, wherein the one or more naturally occurring protein(s) that are isolated and modified comprises one or more modified toxin(s).
1016. The composition according to claim 1015, wherein the one or more modified toxin(s) are chemically modified.
1017. The composition according to claim 1015, wherein the one or more modified toxin(s) are phyically modified.
1018. The composition according to claim 1014, wherein the one or more naturally occurring protein(s) that are isolated and modified comprises one or more modified antibodies.
1019. The composition according to claim 1018, wherein the one or more modified antibodies are chemically modified.
1020. The composition according to claim 1018, wherein the one or more modified antibodies are digested into one or more fragment(s).
1021 . The composition according to claim 1018, wherein the one or more fragment(s) comprises one or more Fab fragment(s).
1022. The composition according to claim 1005, wherein the one or more macromolecule(s) comprises one or more recombinant protein(s).
1023. The composition according to claim 1022, wherein the one or more recombinant protein(s) comprises one or more antibodies.
1024. The composition according to claim 1023, wherein the one or more antibodies comprises one or more full length antibodies.
1025. The composition according to claim 1023, wherein the one or more antibodies comprises one or more Fab fragments.
1026. The composition according to claim 1023, wherein the one or more antibodies comprises one or more scFv fragments.
1027. The composition according to claim 1023, wherein the one or more antibodies comprises one or more antibody-like scaffolds.
1028. The composition according to claim 1023 to 1027, wherein the one or more antibodies are natural in sequence.
1029. The composition according to claim 1023 to 1027, wherein the one or more antibodies are artificial in sequence.
1030. The composition according to claim 1029, wherein the one or more antibodies that are artificial in sequence have one or more amino acid substitutions in the binding site.
1031 . The composition according to claim 1022, wherein the one or more recombinant protein(s) comprises one or more MHC molecule(s).
1032. The composition according to claim 1031 , wherein the one or more MHC molecule(s) are one or more MHC I molecules.
1033. The composition according to claim 1032, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain, full length and/or truncated beta2m and peptide.
1034. The composition according to claim 1032, wherein the one or more MHC I molecules consists of full length and/or truncated heavy chain and full length and/or truncated beta2m.
1035. The composition according to claim 1032, wherein the one or more MHC molecules consists of full length and/or truncated heavy chain and peptide.
1036. The composition according to claim 1032, wherein the one or more MHC molecules consists of full length and/or truncated heavy chain.
1037. The composition according to claim 1031 , wherein the one or more MHC molecule(s) are one or more MHC Il molecules.
1038. The composition according to claim 1037, wherein the one or more MHC Il molecules consists of full length and/or truncated alpha chain and full length and/or truncated beta chain and peptide.
1039. The composition according to claim 1037, wherein the one or more MHC
Il molecules consists of full length and/or truncated alpha chain and full length and/or truncated beta chain.
1040. The composition according to claim 1022, wherein the one or more recombinant protein(s) comprises one or more cytokine(s).
1041 . The composition according to claim 1040, wherein the one or more cytokine(s) are full length.
1042. The composition according to claim 1040, wherein the one or more cytokine(s) are truncated.
1043. The composition according to claim 1022, wherein the one or more recombinant protein(s) comprises one or more interleukine(s).
1044. The composition according to claim 1043, wherein the one or more interleukine(s) are full length.
1045. The composition according to claim 1043, wherein the one or more interleukine(s) are truncated.
1046. The composition according to claim 1043, wherein the one or more recombinant protein(s) comprises one or more interferrone(s).
1047. The composition according to claim 1046, wherein the one or more interferrone(s) are full length.
1048. The composition according to claim 1046, wherein the one or more interferrone(s) are truncated.
1049. The composition according to claim 1005, wherein the one or more macromolecule(s) comprises one or more nucleic acid(s).
1050. The composition according to claim 1049, wherein the one or more nucleic acid(s) comprises DNA.
1051 . The composition according to claim 1050, wherein the DNA encodes one or more protein(s).
1052. The composition according to claim 1050, wherein the DNA does not encode one or more protein(s).
1053. The composition according to claim 1049, wherein the one or more nucleic acid(s) comprises RNA.
1054. The composition according to claim 1053, wherein the RNA comprises one or more ribozyme(s).
1055. The composition according to claim 1053, wherein the RNA comprises antisense.
1056. The composition according to claim 1053, wherein the RNA comprises silencing RNA.
1057. The composition according to claim 1049, wherein the one or more nucleic acid(s) comprises LNA.
1058. The composition according to claim 1049, wherein the one or more nucleic acid(s) comprises PNA.
1059. The composition according to claim 1005, wherein the one or more macromolecule(s) comprises one or more carbohydrate(s).
1060. The composition according to claim 1059, wherein the one or more carbohydrate(s) comprises one or more pure carbohydrates.
1061 . The composition according to claim 1060, wherein the one or more pure carbohydrates comprises one or more monosaccharides.
1062. The composition according to claim 1061 , wherein the one or more monosaccharides are modified.
1063. The composition according to claim 1060, wherein the one or more pure carbohydrates comprises one or more disaccharides.
1064. The composition according to claim 1063, wherein the one or more disaccharides are modified.
1065. The composition according to claim 1060, wherein the one or more pure carbohydrates comprises one or more polysaccharides.
1066. The composition according to claim 1065, wherein the one or more polysaccharides are modified.
1067. The composition according to claim 1059, wherein the one or more carbohydrate(s) comprises one or more glycoprotein(s).
1068. The composition according to claim 1059, wherein the one or more carbohydrate(s) comprises one or more glycolipid(s).
1069. The composition according to claim 1005, wherein the one or more macromolecule(s) are not part of a complex.
1070. The composition according to claim 1005, wherein the one or more macromolecule(s) are part of one or more complex(es).
1071 . The composition according to claim 1070, wherein the one or more complex(es) comprises one or more polymer backbone(s).
1072. The composition according to claim 1070, wherein the one or more complex(es) is attached to one or more solid support(s).
1073. The composition according to claim 1070, wherein the complex is attached to one or more bead(s).
1074. The composition according to any of claims 1 -1073, wherein the composition further comprises a cell-based vaccine.
1075. The composition according to claim 1074, wherein the cell based vaccine comprises one or more naturally occurring cell(s).
1076. The composition according to claim 1075, wherein the one or more naturally occurring cell(s) are isolated and amplified (by proliferation).
1077. The composition according to claim 1075, wherein the one or more naturally occurring cell(s) are isolated and modified.
1078. The composition according to claim 1077, wherein the one or more naturally occurring cell(s) that are isolated are modified to display one or more specific MHC complex(es).
1079. The composition according to claim 1078, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are incubated with one or more peptide(s).
1080. The composition according to claim 1078, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are fused to one or more other cells.
1081 . The composition according to claim 1080, wherein the one or more other cells comprise one or more hybridoma cell(s).
1082. The composition according to claim 1078, wherein the one or more naturally occurring cell(s) that are isolated and modified to display one or more specific MHC complex(es) are obtained by one or more transfection(s).
1083. The composition according to claim 1082, wherein the one or more transfection(s) comprises supercoiled plasmid DNA.
1084. The composition according to claim 1000, wherein the one or more transfection(s) comprises siRNA.
1085. The composition according to claim 1082, wherein the one or more transfection(s) comprises protein.
1086. The composition according to claim 1078, wherein the one or more naturally occurring cell(s) that are isolated and modified by one or more chemical modification step(s).
1087. The composition according to claim 1074, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s).
1088. The composition according to claim 1087, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s) that are chemically modified.
1089. The composition according to claim 1087, wherein the one or more cell based vaccine(s) comprises one or more non-naturally occurring cell(s) that are genetically modified.
1090. The composition according to any of claims 1 -1089, wherein the composition further comprises a liposome/micelle-based vaccine.
1091. The composition according to any of claims 1 -1090, wherein the composition further comprises a nanocluster-based vaccine.
1092. The composition according to claims 1 -1091 , wherein the composition is in solid form.
1093. The composition according to claims 1 -1092, wherein the composition is in insoluble form.
1094. The composition according to claims 1 -1093, wherein the composition is in soluble form.
1095. The composition according to claims 1 -1094, wherein the composition is in suspension.
1096. The composition according to claims 1 -1095, wherein the composition is sterile.
1097. The composition according to claims 1 -1096, wherein the composition is prepared as sterile injectables either as liquid solutions or suspensions, aqueous or non-aqueous.
1098. The composition according to claims 1 -1097, wherein the composition is prepared in solid form suitable for solution, or suspensions, in liquid prior to use.
1099. The composition according to claims 1 -1098, wherein the composition is emulsified.
1 100. The composition according to claims 1 -1099, wherein the composition is mixed with excipients which are pharmaceutically acceptable such as water, saline, dextrose, glycerol, ethanol or the like and combinations thereof.
1 101. The composition according to claims 1 -1 100, wherein the composition comprises minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the pharmamer.
1 102. The composition according to claims 1 -1 101 , wherein the composition has a pH within the range of 3.5-8, such as in the range 4.5-7.5, such as in the range 5.5-7, such as in the range 6-7.5, most preferably around 7.3.
1 103. The composition according to claims 1 -1 102, wherein the composition has a pH within the range 3.5-7, such as 4-6, such as 5-6, such as 5.3-5.7, such as 5.5.
1 104. The composition according to claims 1 -1 103, wherein the composition is for parenteral administration and wherein the composition is dissolved or suspended in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil.
1 105. The composition according to claims 1 -1 104, wherein the composition is a liquid composition comprising liquid phases in addition to and to the exclusion of water such as glycerin, vegetable oils such as cottonseed oil, organic esters such as ethyl oleate, and water-oil emulsions.
1 106. The composition according to claims 1 -1 105, wherein the composition comprises one or more suitable pharmaceutical carriers such as inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
1 107. The composition according to claims 1 -1 106, wherein the composition comprises one or more solid carriers such as lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
1108. The composition according to claims 1 -1107, wherein the composition comprises one or more liquid carriers such as syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
1109. The composition according to claims 1 -1108, wherein the composition is administered by nasal aerosol or inhalation and wherein the composition is prepared for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents.
1110. The composition according to claims 1 -1109, wherein the composition is prepared in unit dosage form.
1111. The composition according to claims 1-1110, wherein the composition is prepared as a lyophilisate.
1112. The composition according to claims 1-1111, wherein the composition comprises a solvent.
1113. The composition according to claims 1-1112, wherein the composition is prepared as an injectable solution.
1114. The composition according to claims 1-1113, wherein the composition is prepared as a dispersion.
1115. The composition according to claims 1-1114, wherein the composition is prepared as a suspension.
1116. The composition according to claims 1-1115, wherein the composition is prepared as a emulsion.
1117. The composition according to claims 1-1116, wherein the composition is prepared as a sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
1 1 18. The composition according to claims 1 -1 1 17, wherein the composition is prepared as suppositories.
1 1 19. The composition according to claims 1 -1 1 18, wherein the composition is prepared as a spray.
1 120. The composition according to claims 1 -1 1 19, wherein the composition is prepared as an ointment, creme, or gel.
1 121. The composition according to claims 1 -1 120, wherein the composition is prepared as an inhalant.
1 122. The composition according to claims 1 -1 121 , wherein the composition is prepared as a dermal patch.
1 123. The composition according to claims 1 -1 122, wherein the composition is prepared as an implant.
1 124. The composition according to claims 1 -1 123, wherein the composition is prepared as a pill, tablet, lozenge or capsule.
1 125. The composition according to claims 1 -1 124, wherein the composition is formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
1 126. The composition according to claims 1 -1 125, wherein the composition is prepared in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
1 127. The composition according to claims 1 -1 126, wherein the composition is a powder comprising a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
1 128. The composition according to claims 1 -1 127, wherein the composition is prepared as a gel.
1 129. The composition according to claims 1 -1 128, wherein the composition is prepared as a capsules or cartridges of e.g., gelatin or blister packs.
1 130. The composition according to claims 1 -1 129, wherein the composition is prepared as an aerosol prepared, for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents.
1 131. The composition according to claims 1 -1 130, wherein the composition is formulated for parenteral administration.
1 132. The composition according to claims 1 -1 131 , wherein the composition is formulated for intravenous administration.
1 133. The composition according to claims 1 -1 132, wherein the composition is formulated for intramuscular administration.
1 134. The composition according to claims 1 -1 133, wherein the composition is formulated for intraarticular formulation.
1 135. The composition according to claims 1 -1 134, wherein the composition is formulated for subcutaneous administration.
1 136. The composition according to claims 1 -1 135, wherein the composition is formulated for intradermal administration.
1 137. The composition according to claims 1 -1 136, wherein the composition is formulated for epicutantous/transdermal administration.
1 138. The composition according to claims 1 -1 137, wherein the composition is formulated for intra- peritoneal administration.
1 139. The composition according to claims 1 -1 138, wherein the composition is formulated for infusion.
1 140. The composition according to claims 1 -1 139, wherein the composition is formulated for oral administration.
1 141. The composition according to claims 1 -1 140, wherein the composition is formulated for nasal administration.
1 142. The composition according to claims 1 -1 141 , wherein the composition is formulated for rectal administration.
1 143. The composition according to claims 1 -1 142, wherein the composition is formulated for vaginal administration.
1 144. The composition according to claims 1 -1 143, wherein the composition is formulated for topic administration.
1 145. The composition according to claims 1 -1 144, wherein the composition comprises one or more pharmamers immobilised onto a solid or semi-solid support such as particles, beads, biodegradable particles, sheets, gels, filters, membranes, fibres, capillaries, needles, microtitre strips, tubes, plates or wells, combs, pipette tips, micro arrays, and chips.
1 146. The composition according to claims 1 -1 145, wherein the composition comprises one or more pharmamers immobilised onto particles and beads, which are polymeric, magnetic or superparamagnetic.
1 147. The composition according to claims 1 -1 146, wherein the composition comprises one or more pharmamers that target specific MHC recognising cells.
1 148. The composition according to claims 1 -1 147, wherein the composition comprises one or more pharmamers capable of induction of a response in specific target MHC recognising cells by addressing receptors on such cells.
1 149. The composition according to any of claims 1 -1 148, wherein the one or more biological active molecules and the one or more multimerization domain are coupled by a mechanism comprising biotinylation.
1 150. The composition according to claim 1 149, where the mechanism comprises Streptavidin and/or Avidin and Biotin.
1 151. The composition according to claim 1 149, where the mechanism comprises enzymatic biotinylation.
1 152. The composition according to claim 1 149, where the mechanism comprises non-enzymatic biotinylation.
1 153. The composition according to any of claims 1 -1 152, wherein the one or more biological active molecules are directly bound to the multimerization domain.
1 154. The composition according to any of claims 1 -1 153, wherein the one or more biological active molecules are indirectly bound to the multimerization domain.
1 155. The composition according to any of claims 1 -1 154, wherein the one or more biological active molecules are not directly bound to the multimerization domain.
1 156. The composition according to any of claims 1 -1 155, wherein the one or more biological active molecules are not indirectly bound to the multimerization domain.
1 157. The composition according to any of the claims 1 -1 156, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-A, HLA-B, HLA-C, HLA-E, HLA- F, HLA-G, A*01010101 B*070201 Cw*010201 E*01010101 F*01010101 G*01010101 ,
A*01010102NB*070202Cw*010202E*01010102F*01010102G*01010102, A*010102B*070203Cw*010203E*01010103F*01010103G*01010103, A*010103B*070204Cw*010204E*01030101 F*01010104G*01010104,
A*010104B*0703Cw*0103E*01030102F*01010105G*01010105, A*0102B*0704Cw*0104E*010302F*01010106G*01010201 , A*0103B*070501 Cw*0105E*010303F*01010107G*01010202, A*0104NB*070502Cw*0106E*010304F*01010108G*010103, A*0106B*070503Cw*0107E*0104F*01010201 G*010104,
A*0107B*0706Cw*0108F*01010202G*010105, A*0108B*0707Cw*0109F*01010203G*010106, A*0109B*0708Cw*01 10F*01010204G*010107, A*01 10B*0709Cw*01 1 1 F*01010205G*010108, A*01 1 1 NB*0710Cw*01 12F*01010301 G*010109,
A*01 12B*071 1 Cw*01 13F*01010302G*0101 10, A*01 13B*0712Cw*020201 F*01010303G*0102, A*01 14B*0713Cw*020202F*01010304G*0103, A*01 15NB*0714Cw*020203F*0102G*010401 , A*01 16NB*0715Cw*020205F*01030101 G*010402,
A*01 17B*0716Cw*0203F*01030102G*010403,
A*01 18NB*0717Cw*0204F*0104G*0105N, A*01 19B*0718Cw*0205G*0106, A*0120B*0719Cw*0206G*0107, A*02010101 B*0720Cw*0207, A*02010102LB*0721 Cw*0208, A*020102B*0722Cw*0209, A*020103B*0723Cw*0210, A*020104B*0724Cw*021 1 ,
A*020105B*0725Cw*0212, A*020106B*0726Cw*0213, A*020107B*0727Cw*0214, A*020108B*0728Cw*0215, A*020109B*0729Cw*0216, A*0201 10B*0730Cw*0217, A*0201 1 1 B*0731 Cw*030201 , A*0201 12B*0732Cw*030202, A*0202B*0733Cw*030301 , A*020301 B*0734Cw*030302,
A*020302B*0735Cw*030303, A*0204B*0736Cw*030304, A*0205B*0737Cw*030305, A*020601 B*0738Cw*030401 , A*020602B*0739Cw*030402, A*020603B*0740Cw*030403, A*0207B*0741 Cw*030404, A*0208B*0742Cw*030405, A*0209B*0743Cw*0305, A*0210B*0744Cw*0306, A*021 1 B*0745Cw*0307, A*0212B*0746Cw*0308, A*0213B*0747Cw*0309, A*0214B*0748Cw*0310, A*0215NB*0749NCw*031 101 , A*0216B*0750Cw*031 102, A*021701 B*0751 Cw*0312, A*021702B*080101 Cw*0313, A*0218B*080102Cw*0314, A*0219B*080103Cw*0315, A*022001 B*0802Cw*0316, A*022002B*0803Cw*0317,
A*0221 B*0804Cw*0318, A*0222B*0805Cw*0319, A*0224B*0806Cw*0320N, A*0225B*0807Cw*0321 , A*0226B*0808NCw*0322Q, A*0227B*0809Cw*0323, A*0228B*0810Cw*0324, A*0229B*081 1 Cw*0325, A*0230B*0812Cw*0326, A*0231 B*0813Cw*0327, A*0232NB*0814Cw*0328, A*0233B*0815Cw*0329, A*0234B*0816Cw*0330, A*023501 B*0817Cw*0331 ,
A*023502B*0818Cw*0332, A*0236B*0819NCw*0333, A*0237B*0820Cw*0334, A*0238B*0821 Cw*0335, A*0239B*0822Cw*04010101 , A*0240B*0823Cw*04010102, A*0241 B*0824Cw*040102, A*0242B*0825Cw*040103, A*0243NB*0826Cw*040104, A*0244B*0827Cw*0403, A*0245B*0828Cw*040401 ,
A*0246B*0829Cw*040402, A*0247B*0830NCw*0405, A*0248B*0831 Cw*0406, A*0249B*1301 Cw*0407, A*0250B*130201 Cw*0408, A*0251 B*130202Cw*0409N, A*0252B*130203Cw*0410, A*0253NB*1303Cw*041 1 , A*0254B*1304Cw*0412, A*0255B*1306Cw*0413, A*0256B*1307NCw*0414,
A*0257B*1308Cw*0415, A*0258B*1309Cw*0416, A*0259B*1310Cw*0417, A*0260B*131 1 Cw*0418, A*0261 B*1312Cw*0419, A*0262B*1313Cw*0420, A*0263B*1314Cw*0421 , A*0264B*1315Cw*0423, A*0265B*1316Cw*0424, A*0266B*1317Cw*050101 , A*0267B*1401 Cw*050102, A*0268B*140201 Cw*050103, A*0269B*140202Cw*0502,
A*0270B*1403Cw*0503, A*0271 B*1404Cw*0504, A*0272B*1405Cw*0505, A*0273B*140601 Cw*0506, A*027401 B*140602Cw*0507N, A*027402B*1407NCw*0508, A*0275B*15010101 Cw*0509, A*0276B*15010102NCw*0510, A*0277B*150102Cw*051 1 , A*0278B*150103Cw*0512, A*0279B*150104Cw*0513,
A*0280B*1502Cw*0514, A*0281 B*1503Cw*0515, A*0282NB*1504Cw*06020101 , A*0283NB*1505Cw*06020102, A*0284B*1506Cw*060202, A*0285B*1507Cw*0603, A*0286B*1508Cw*0604, A*0287B*1509Cw*0605, A*0288NB*1510Cw*0606, A*0289B*151 101 Cw*0607, A*0290B*151 102Cw*0608, A*0291 B*151 103Cw*0609, A*0292B*1512Cw*0610,
A*0293B*1513Cw*061 1 , A*0294NB*1514Cw*0612, A*0295B*1515Cw*0613, A*0296B*1516Cw*0614, A*0297B*15170101 Cw*070101 , A*0299B*15170102Cw*070102, A*03010101 B*151702Cw*070103, A*03010102NB*1518Cw*070104, A*03010103B*1519Cw*070105,
A*030102B*1520Cw*070106, A*030103B*1521 Cw*070107, A*030104B*1523Cw*07020101 , A*030105B*1524Cw*07020102, A*0302B*1525Cw*07020103, A*0303NB*1526NCw*0703, A*0304B*1527Cw*070401 , A*0305B*1528Cw*070402, A*0306B*1529Cw*0705, A*0307B*1530Cw*0706, A*0308B*1531 Cw*0707,
A*0309B*1532Cw*0708, A*0310B*1533Cw*0709, A*031 1 NB*1534Cw*0710, A*0312B*1535Cw*071 1 , A*0313B*1536Cw*0712, A*0314B*1537Cw*0713, A*0315B*1538Cw*0714, A*0316B*1539Cw*0715, A*0317B*1540Cw*0716, A*0318B*1542Cw*0717, A*0319B*1543Cw*0718, A*0320B*1544Cw*0719, A*0321 NB*1545Cw*0720, A*0322B*1546Cw*0721 , A*0323B*1547Cw*0722,
A*0324B*1548Cw*0723, A*0325B*1549Cw*0724, A*0326B*1550Cw*0725, A*1 10101 B*1551 Cw*0726, A*1 10102B*1552Cw*0727, A*1 10103B*1553Cw*0728, A*1 10104B*1554Cw*0729, A*1 10105B*1555Cw*0730, A*1 10106B*1556Cw*0731 , A*1 10201 B*1557Cw*0732N, A*1 10202B*1558Cw*0733N,
A*1 103B*1560Cw*0734, A*1 104B*1561 Cw*0735, A*1 105B*1562Cw*0736, A*1 106B*1563Cw*0737, A*1 107B*1564Cw*0738, A*1 108B*1565Cw*0739, A*1 109B*1566Cw*0740, A*1 1 10B*1567Cw*0741 , A*1 1 1 1 B*1568Cw*0742, A*1 1 12B*1569Cw*0743, A*1 1 13B*1570Cw*0744, A*1 1 14B*1571 Cw*0745, A*1 1 15B*1572Cw*080101 , A*1 1 16B*1573Cw*080102,
A*1 1 17B*1574Cw*0802, A*1 1 18B*1575Cw*0803, A*1 1 19B*1576Cw*0804, A*1 120B*1577Cw*0805, A*1 121 NB*1578Cw*0806, A*1 122B*1579NCw*0807, A*1 123B*1580Cw*0808, A*1 124B*1581 Cw*0809, A*1 125B*1582Cw*0810, A*1 126B*1583Cw*081 1 , A*1 127B*1584Cw*0812, A*1 128B*1585Cw*0813, A*1 129B*1586Cw*0814, A*2301 B*1587Cw*120201 ,
A*2302B*1588Cw*120202, A*2303B*1589Cw*120203, A*2304B*1590Cw*12030101 , A*2305B*1591 Cw*12030102, A*2306B*1592Cw*120302, A*2307NB*1593Cw*120303, A*2308NB*1594NCw*120304, A*2309B*1595Cw*120401 , A*2310B*1596Cw*120402, A*231 1 NB*1597Cw*1205, A*2312B*1598Cw*1206, A*2313B*1599Cw*1207, A*2314B*9501 Cw*1208, A*24020101 B*9502Cw*1209, A*24020102LB*9503Cw*1210, A*240202B*9504Cw*121 1 , A*240203B*9505Cw*1212, A*240204B*9506Cw*1213, A*240205B*9507Cw*1214, A*240206B*9508Cw*1215, A*240207B*9509Cw*1216,
A*240208B*9510Cw*1217, A*240209B*951 1 NCw*1218, A*240210B*9512Cw*1219, A*24021 1 B*9513Cw*140201 , A*240212B*9514Cw*140202, A*240213B*9515Cw*140203, A*240301 B*9516Cw*140204, A*240302B*9517Cw*1403, A*2404B*9518Cw*1404, A*2405B*9519Cw*1405, A*2406B*9520Cw*1406,
A*2407B*9521 Cw*1407N, A*2408B*9522Cw*1408, A*2409NB*180101 Cw*150201 , A*2410B*180102Cw*150202, A*241 1 NB*180103Cw*150203, A*2413B*1802Cw*1503, A*2414B*1803Cw*1504, A*2415B*1804Cw*150501 , A*2417B*1805Cw*150502, A*2418B*1806Cw*150503,
A*2419B*1807Cw*150504, A*2420B*1808Cw*1506, A*2421 B*1809Cw*1507, A*2422B*1810Cw*1508, A*2423B*181 1 Cw*1509, A*2424B*1812Cw*1510, A*2425B*1813Cw*151 1 , A*2426B*1814Cw*1512, A*2427B*1815Cw*1513, A*2428B*1817NCw*1514, A*2429B*1818Cw*1515, A*2430B*1819Cw*1516, A*2431 B*1820Cw*1517, A*2432B*1821 Cw*160101 ,
A*2433B*1822Cw*160102, A*2434B*1823NCw*1602,
A*2435B*1824Cw*160401 , A*2436NB*2701 Cw*1606, A*2437B*2702Cw*1607, A*2438B*2703Cw*1608, A*2439B*270401 Cw*1609, A*2440NB*270402Cw*1701 , A*2441 B*270502Cw*1702, A*2442B*270503Cw*1703, A*2443B*270504Cw*1704,
A*2444B*270505Cw*1801 , A*2445NB*270506Cw*1802, A*2446B*270507, A*2447B*270508, A*2448NB*270509, A*2449B*2706, A*2450B*2707, A*2451 B*2708, A*2452B*2709, A*2453B*2710, A*2454B*271 1 , A*2455B*2712, A*2456B*2713, A*2457B*2714, A*2458B*2715, A*2459B*2716, A*2460NB*2717, A*2461 B*2718, A*2462B*2719, A*2463B*2720,
A*2464B*2721 , A*2465B*2723, A*2466B*2724, A*2467B*2725, A*2468B*2726, A*250101 B*2727, A*250102B*2728, A*2502B*2729, A*2503B*2730, A*2504B*2731 , A*2505B*2732, A*2506B*2733, A*260101 B*2734, A*260102B*2735, A*260103B*2736, A*260104B*350101 , A*2602B*350102, A*2603B*350103, A*2604B*350104, A*2605B*350105, A*2606B*350106, A*260701 B*350201 , A*260702B*350202, A*2608B*3503, A*2609B*350401 , A*2610B*350402, A*261 1 NB*3505, A*2612B*3506, A*2613B*3507, A*2614B*350801 , A*2615B*350802, A*2616B*350901 , A*2617B*350902, A*2618B*3510, A*2619B*351 1 , A*2620B*3512, A*2621 B*3513, A*2622B*351401 , A*2623B*351402, A*2624B*3515, A*2625NB*3516,
A*2626B*3517, A*2627B*3518, A*2628B*3519, A*2629B*3520, A*2630B*3521 , A*2631 B*3522, A*2632B*3523, A*2633B*3524, A*2634B*3525, A*29010101 B*3526, A*29010102NB*3527, A*290201 B*3528, A*290202B*3529, A*290203B*3530, A*2903B*3531 , A*2904B*3532, A*2905B*3533, A*2906B*3534, A*2907B*3535, A*2908NB*3536,
A*2909B*3537, A*2910B*3538, A*291 1 B*3539, A*2912B*3540N, A*2913B*3541 , A*2914B*3542, A*2915B*3543, A*2916B*3544, A*300101 B*3545, A*300102B*3546, A*300201 B*3547, A*300202B*3548, A*300203B*3549, A*3003B*3550, A*3004B*3551 , A*3006B*3552, A*3007B*3553N, A*3008B*3554, A*3009B*3555, A*3010B*3556,
A*301 1 B*3557, A*3012B*3558, A*3013B*3559, A*3014LB*3560, A*3015B*3561 , A*3016B*3562, A*3017B*3563, A*3018B*3564, A*3019B*3565Q, A*310102B*3566, A*3102B*3567, A*3103B*3568, A*3104B*3569, A*3105B*3570, A*3106B*3571 , A*3107B*3572, A*3108B*370101 , A*3109B*370102, A*31 10B*370103, A*31 1 1 B*370104,
A*31 12B*3702, A*31 13B*3703N, A*31 14NB*3704, A*31 15B*3705, A*3201 B*3706, A*3202B*3707, A*3203B*3708, A*3204B*3709, A*3205B*3710, A*3206B*371 1 , A*3207B*3712, A*3208B*380101 , A*3209B*380102, A*3210B*380201 , A*321 1 QB*380202, A*3212B*3803, A*3213B*3804, A*3214B*3805, A*3301 B*3806, A*330301 B*3807, A*330302B*3808,
A*3304B*3809, A*3305B*3810, A*3306B*381 1 , A*3307B*3812, A*3308B*3813, A*3309B*3814, A*3401 B*3815, A*3402B*39010101 , A*3403B*39010102L, A*3404B*390103, A*3405B*390104, A*3406B*390201 , A*3407B*390202, A*3408B*3903, A*3601 B*3904, A*3602B*3905, A*3603B*390601 , A*3604B*390602, A*4301 B*3907, A*6601 B*3908, A*6602B*3909,
A*6603B*3910, A*6604B*391 1 , A*6605B*3912, A*6606B*391301 , A*680101 B*391302, A*680102B*3914, A*680103B*3915, A*680104B*3916, A*680105B*3917, A*68020101 B*3918, A*68020102B*3919, A*680301 B*3920, A*680302B*3922, A*6804B*3923, A*6805B*3924, A*6806B*3925N, A*6807B*3926, A*6808B*3927, A*6809B*3928, A*6810B*3929, A*681 1 NB*3930, A*6812B*3931 , A*6813B*3932, A*6814B*3933, A*6815B*3934, A*6816B*3935, A*6817B*3936, A*6818NB*3937, A*6819B*3938Q, A*6820B*3939, A*6821 B*3940N, A*6822B*3941 , A*6823B*400101 , A*6824B*400102, A*6825B*400103, A*6826B*400104, A*6827B*400105, A*6828B*400201 , A*6829B*400202, A*6830B*400203,
A*6831 B*4003, A*6832B*4004, A*6833B*4005, A*6834B*40060101 , A*6835B*40060102, A*6836B*400602, A*6901 B*4007, A*7401 B*4008, A*7402B*4009, A*7403B*4010, A*7404B*401 1 , A*7405B*4012, A*7406B*4013, A*7407B*401401 , A*7408B*401402, A*7409B*401403, A*7410B*4015, A*741 1 B*4016, A*7412NB*4018, A*8001 B*4019, A*9201 B*4020,
A*9202B*4021 , A*9203B*4022N, A*9204B*4023, A*9205B*4024, A*9206B*4025, A*9207B*4026, A*9208B*4027, A*9209B*4028, B*4029, B*4030, B*4031 , B*4032, B*4033, B*4034, B*4035, B*4036, B*4037, B*4038, B*4039, B*4040, B*4042, B*4043, B*4044, B*4045, B*4046, B*4047, B*4048, B*4049, B*4050, B*4051 , B*4052, B*4053, B*4054, B*4055, B*4056, B*4057,
B*4058, B*4059, B*4060, B*4061 , B*4062, B*4063, B*4064, B*4065, B*4066, B*4067, B*4068, B*4069, B*4070, B*4101 , B*4102, B*4103, B*4104, B*4105, B*4106, B*4107, B*4108, B*4201 , B*4202, B*4204, B*420501 , B*420502, B*4206, B*4207, B*4208, B*4209, B*44020101 , B*44020102S, B*440202, B*440203, B*440204, B*440301 , B*440302, B*4404, B*4405, B*4406, B*4407,
B*4408, B*4409, B*4410, B*441 1 , B*4412, B*4413, B*4414, B*4415, B*4416, B*4417, B*4418, B*4419N, B*4420, B*4421 , B*4422, B*4423N, B*4424, B*4425, B*4426, B*4427, B*4428, B*4429, B*4430, B*4431 , B*4432, B*4433, B*4434, B*4435, B*4436, B*4437, B*4438, B*4439, B*4440, B*4441 , B*4442, B*4443, B*4444, B*4445, B*4446, B*4447, B*4448, B*4449, B*4450, B*4451 ,
B*4501 , B*4502, B*4503, B*4504, B*4505, B*4506, B*4507, B*460101 , B*460102, B*4602, B*4603, B*4604, B*4605, B*4606, B*4607N, B*4608, B*4609, B*47010101 , B*47010102, B*4702, B*4703, B*4704, B*4705, B*4801 , B*4802, B*480301 , B*480302, B*4804, B*4805, B*4806, B*4807, B*4808, B*4809, B*4810, B*481 1 , B*4812, B*4813, B*4814, B*4815, B*4816, B*4901 ,
B*4902, B*4903, B*4904, B*4905, B*5001 , B*5002, B*5004, B*510101 , B*510102, B*510103, B*510104, B*510105, B*510106, B*510107, B*510201 , B*510202, B*5103, B*5104, B*5105, B*5106, B*5107, B*5108, B*5109, B*51 10, B*51 1 1 N, B*51 12, B*51 1301 , B*51 1302, B*51 14, B*51 15, B*51 16, B*51 17, B*51 18, B*51 19, B*5120, B*5121 , B*5122, B*5123, B*5124, B*5126, B*5127N, B*5128, B*5129, B45130, B45131, B45132, B45133, B*5134, B45135, B45136, B45137, B45138, B*5139, B45140, B45141N, B45142, B45143, B*5144N, B45145, B45146, B4520101, B4520102, B*520103, B4520104, B45202, B45203, B45204, B*5205, B45206, B45207, B45208, B45209, B*5210, B4530101, B4530102, B4530103, B*530104, B45302, B45303, B45304, B45305, B*5306,
B*5307, B*5308, B*5309, B*5310, B*5311, B*5312, B*5401, B*5402, B*5403, B*5404, B*5405N, B*5406, B*5407, B*5408N, B*5409, B*5410, B*5411, B*5412, B*550101, B*550102, B*550103, B*550104, B*550201, B*550202, B*5503, B*5504, B*5505, B*5507, B*5508, B*5509, B*5510, B*5511, B*5512, B*5513, B*5514, B*5515, B*5516, B*5517, B*5518, B*5519, B*5520, B*5521,
B*5522, B*5523, B*5524, B*5601, B*5602, B*5603, B*5604, B*560501, B*560502, B*5606, B*5607, B*5608, B*5609, B*5610, B*5611, B*5612, B*5613, B*5614, B*5615, B*5616, B*5617, B*5618, B*5619N, B*570101, B*570102, B*570103, B*5702, B*570301, B*570302, B*5704, B*5705, B*5706, B*5707, B*5708, B*5709, B*5710, B*5711 , B*5801 , B*5802, B*5804, B*5805, B*5806,
B*5807, B*5808, B*5809, B*5810N, B*5811, B*5812, B*5813, B*5814, B*5901, B*5902, B*670101, B*670102, B*6702, B*7301, B*7801, B*780201, B*780202, B*7803, B*7804, B*7805, B*8101, B*8102, B*8201, B*8202, B*8301, HLA- HHLA-JHLA-KHLA-LHLA-P, H4OIOIOIOIJ4OIOIOIOIK4OIOIOIOIL4OIOIOIOIP4OIOIOIOI,
H401010102J401010102K401010102L401010102P401010102, H401010103J401010103K401010103L401010103P402010101, H40102J401010104K401010104L4010102P402010102, H402010101J401010105K40102L40102, H402010102J401010106K40103, H40202J401010107, H40203J401010108, H40204J40201 , H40205, H40206, and
H40301.
1158. The composition according to any of the claims 1 -1157, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRA, DRA4OI 01 , DRA4OI 0201 and DRA4OI 0202.
1159. The composition according to any of the claims 1 -1158, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRB1 , DRB1*010101, DRB1*010102, DRB1*010103, DRB1*010104, DRB1*010105, DRB1*010106, DRB1*010107, DRB1*010108, DRB1*010109, DRB1*010110, DRB1*010201, DRB1*010202, DRB1*010203, DRB1*010204, DRB1*010205, DRB1*0103, DRB1*0104, DRB1*0105, DRB1*0106, DRB1*0107, DRB1*0108, DRB1*0109, DRB1*0110,
DRB1*0111, DRB1*0112, DRB1*0113, DRB1*0114, DRB1*0115, DRB1*0116, DRB1*0117, DRB1*0118, DRB1*0119, DRB1*0120, DRB1*0121, DRB1*0122, DRB1*03010101, DRB1*03010102, DRB1*030102, DRB1*030103, DRB1*030104, DRB1*030105, DRB1*030106, DRB1*030107, DRB1*030201, DRB1*030202, DRB1*0303,
DRB1*0304, DRB1*030501, DRB1*030502, DRB1*030503, DRB1*0306, DRB1*0307, DRB1*0308, DRB1*0309, DRB1*0310, DRB1*0311, DRB1*0312, DRB1*031301, DRB1*031302, DRB1*0314, DRB1*0315, DRB1*0316, DRB1*0317, DRB1*0318, DRB1*0319, DRB1*0320, DRB1*0321, DRB1*0322, DRB1*0323, DRB1*0324, DRB1*0325,
DRB1*0326, DRB1*0327, DRB1*0328, DRB1*0329, DRB1*0330, DRB1*0331, DRB1*0332, DRB1*0333, DRB1*0334, DRB1*0335, DRB1*0336, DRB1*0337, DRB1*0338, DRB1*0339, DRB1*0340, DRB1*0341, DRB1*0342, DRB1*0343, DRB1*0344, DRB1*0345, DRB1*0346, DRB1*0347, DRB1*0348, DRB1*040101, DRB1*040102,
DRB1*040103, DRB1*0402, DRB1*040301, DRB1*040302, DRB1*040303, DRB1*040304, DRB1*0404, DRB1*040501, DRB1*040502, DRB1*040503, DRB1*040504, DRB1*040505, DRB1*040506, DRB1*040601, DRB1*040602, DRB1*040701, DRB1*040702, DRB1*040703, DRB1*0408, DRB1*0409, DRB1*0410, DRB1*0411, DRB1*0412, DRB1*0413,
DRB1*0414, DRB1*0415, DRB1*0416, DRB1*0417, DRB1*0418, DRB1*0419, DRB1*0420, DRB1*0421, DRB1*0422, DRB1*0423, DRB1*0424, DRB1*0425, DRB1*0426, DRB1*0427, DRB1*0428, DRB1*0429, DRB1*0430, DRB1*0431, DRB1*0432, DRB1*0433, DRB1*0434, DRB1*0435, DRB1*0436, DRB1*0437, DRB1*0438,
DRB1*0439, DRB1*0440, DRB1*0441, DRB1*0442, DRB1*0443, DRB1*0444, DRB1*0445, DRB1*0446, DRB1*0447, DRB1*0448, DRB1*0449, DRB1*0450, DRB1*0451, DRB1*0452, DRB1*0453, DRB1*0454, DRB1*0455, DRB1*0456, DRB1*0457, DRB1*0458, DRB1*0459, DRB1*0460, DRB1*0461, DRB1*0462, DRB1*0463, DRB1*0464, DRB1*0465, DRB1*0466, DRB1*0467, DRB1*0468, DRB1*0469, DRB1*0470, DRB1*0471, DRB1*0472, DRB1*0473, DRB1*0474, DRB1*0475, DRB1*0476, DRB1*0477, DRB1*0478, DRB1*07010101, DRB1*07010102, DRB1*070102, DRB1*070103, DRB1*0703, DRB1*0704, DRB1*0705, DRB1*0706, DRB1*0707,
DRB1*0708, DRB1*0709, DRB1*0710N, DRB1*0711, DRB1*0712, DRB1*0713, DRB1*0714, DRB1*0715, DRB1*0716, DRB1*0717, DRB1*080101, DRB1*080102, DRB1*080103, DRB1*080104, DRB1*080201, DRB1*080202, DRB1*080203, DRB1*080302, DRB1*080401, DRB1*080402, DRB1*080403, DRB1*080404, DRB1*0805,
DRB1*0806, DRB1*0807, DRB1*0808, DRB1*0809, DRB1*0810, DRB1*0811, DRB1*0812, DRB1*0813, DRB1*0814, DRB1*0815, DRB1*0816, DRB1*0817, DRB1*0818, DRB1*0819, DRB1*0820, DRB1*0821, DRB1*0822, DRB1*0823, DRB1*0824, DRB1*0825, DRB1*0826, DRB1*0827, DRB1*0828, DRB1*0829, DRB1*0830,
DRB1*0831, DRB1*0832, DRB1*0833, DRB1*0834, DRB1*0835, DRB1*0836, DRB1*090102, DRB1*090103, DRB1*090104, DRB1*090105, DRB1*090201, DRB1*090202, DRB1*0903, DRB1*0904, DRB1*0905, DRB1*0906, DRB1*0907, DRB1*0908, DRB1*100101, DRB1*100102, DRB1*100103, DRB1*1002, DRB1*1003, DRB1*110101, DRB1*110102,
DRB1*110103, DRB1*110104, DRB1*110105, DRB1*110106, DRB1*110107, DRB1*110108, DRB1*110109, DRB1*110110, DRB1*110201, DRB1*110202, DRB1*1103, DRB1*110401, DRB1*110402, DRB1*110403, DRB1*110404, DRB1*110405, DRB1*1105, DRB1*110601, DRB1*110602, DRB1*1107, DRB1*110801, DRB1*110802, DRB1*1109,
DRB1*111001, DRB1*111002, DRB1*111101, DRB1*111102, DRB1*111201, DRB1*111202, DRB1*111301, DRB1*111302, DRB1*111401, DRB1*111402, DRB1*1115, DRB1*1116, DRB1*1117, DRB1*1118, DRB1*111901, DRB1*111902, DRB1*1120, DRB1*1121, DRB1*1122, DRB1*1123, DRB1*1124, DRB1*1125, DRB1*1126,
DRB1*112701, DRB1*112702, DRB1*112801, DRB1*112802, DRB1*1129, DRB1*1130, DRB1*1131, DRB1*1132, DRB1*1133, DRB1*1134, DRB1*1135, DRB1*1136, DRB1*1137, DRB1*1138, DRB1*1139, DRB1*1140, DRB1*1141, DRB1*1142, DRB1*1143, DRB1*1144, DRB1*1145, DRB1*1146, DRB1*1147, DRB1*1148, DRB1*1149, DRB1*1150, DRB1*1151, DRB1*1152, DRB1*1153, DRB1*115401, DRB1*115402, DRB1*1155, DRB1*1156, DRB1*1157, DRB1*1158, DRB1*1159, DRB1*1160, DRB1*1161, DRB1*1162, DRB1*1163, DRB1*1164, DRB1*116501, DRB1*116502, DRB1*1166, DRB1*1167, DRB1*1168, DRB1*1169, DRB1*1170, DRB1*1172, DRB1*1173,
DRB1*1174, DRB1*1175, DRB1*1176, DRB1*1177, DRB1*1178, DRB1*1179, DRB1*1180, DRB1*1181, DRB1*120101, DRB1*120102, DRB1*120201, DRB1*120202, DRB1*120203, DRB1*120204, DRB1*120302, DRB1*1204, DRB1*1205, DRB1*1206, DRB1*1207, DRB1*1208, DRB1*1209, DRB1*1210, DRB1*1211, DRB1*1212,
DRB1*1213, DRB1*1214, DRB1*1215, DRB1*1216, DRB1*1217, DRB1*1218, DRB1*1219, DRB1*130101, DRB1*130102, DRB1*130103, DRB1*130104, DRB1*130105, DRB1*130201, DRB1*130202, DRB1*130203, DRB1*130301, DRB1*130302, DRB1*1304, DRB1*130501, DRB1*130502, DRB1*1306, DRB1*130701, DRB1*130702, DRB1*1308,
DRB1*1309, DRB1*1310, DRB1*131101, DRB1*131102, DRB1*1312, DRB1*1313, DRB1*131401, DRB1*131402, DRB1*131403, DRB1*1315, DRB1*1316, DRB1*1317, DRB1*1318, DRB1*1319, DRB1*1320, DRB1*1321, DRB1*1322, DRB1*1323, DRB1*1324, DRB1*1325, DRB1*1326, DRB1*1327, DRB1*1328, DRB1*1329, DRB1*1330,
DRB1*1331, DRB1*1332, DRB1*133301, DRB1*133302, DRB1*133303, DRB1*1334, DRB1*1335, DRB1*1336, DRB1*1337, DRB1*1338, DRB1*1339, DRB1*1340, DRB1*1341, DRB1*1342, DRB1*1343, DRB1*1344, DRB1*1345, DRB1*1346, DRB1*1347, DRB1*1348, DRB1*1349, DRB1*135001, DRB1*135002, DRB1*1351, DRB1*1352,
DRB1*1353, DRB1*1354, DRB1*1355, DRB1*1356, DRB1*1357, DRB1*1358, DRB1*1359, DRB1*1360, DRB1*1361, DRB1*1362, DRB1*1363, DRB1*1364, DRB1*1365, DRB1*1366, DRB1*1367, DRB1*1368, DRB1*1369, DRB1*1370, DRB1*1371, DRB1*1372, DRB1*1373, DRB1*1374, DRB1*1375, DRB1*1376, DRB1*1377,
DRB1*1378, DRB1*1379, DRB1*1380, DRB1*1381, DRB1*1382, DRB1*1383, DRB1*1384, DRB1*1385, DRB1*1386, DRB1*1387, DRB1*1388, DRB1*1389, DRB1*1390, DRB1*1391, DRB1*1392, DRB1*140101, DRB1*140102, DRB1*140103, DRB1*1402, DRB1*140301, DRB1*140302, DRB1*1404, DRB1*140501, DRB1*140502, DRB1*140503, DRB1*1406, DRB1*140701, DRB1*140702, DRB1*1408, DRB1*1409, DRB1*1410, DRB1*1411, DRB1*1412, DRB1*1413, DRB1*1414, DRB1*1415, DRB1*1416, DRB1*1417, DRB1*1418, DRB1*1419, DRB1*1420, DRB1*1421, DRB1*1422, DRB1*142301, DRB1*142302, DRB1*1424, DRB1*1425, DRB1*1426, DRB1*1427, DRB1*1428,
DRB1*1429, DRB1*1430, DRB1*1431, DRB1*143201, DRB1*143202, DRB1*1433, DRB1*1434, DRB1*1435, DRB1*1436, DRB1*1437, DRB1*1438, DRB1*1439, DRB1*1440, DRB1*1441, DRB1*1442, DRB1*1443, DRB1*144401, DRB1*144402, DRB1*1445, DRB1*1446, DRB1*1447, DRB1*1448, DRB1*1449, DRB1*1450, DRB1*1451,
DRB1*1452, DRB1*1453, DRB1*1454, DRB1*1455, DRB1*1456, DRB1*1457, DRB1*1458, DRB1*1459, DRB1*1460, DRB1*1461, DRB1*1462, DRB1*1463, DRB1*1464, DRB1*1465, DRB1*1467, DRB1*1468, DRB1*1469, DRB1*1470, DRB1*1471, DRB1*1472, DRB1*1473, DRB1*1474, DRB1*1475, DRB1*1476, DRB1*1477,
DRB1*1478, DRB1*1479, DRB1*1480, DRB1*1481, DRB1*1482, DRB1*1483, DRB1*1484, DRB1*1485, DRB1*1486, DRB1*1487, DRB1*1488, DRB1*1489, DRB1*1490, DRB1*15010101, DRB1*15010102, DRB1*150102, DRB1*150103, DRB1*150104, DRB1*150105, DRB1*150106, DRB1*150201, DRB1*150202, DRB1*150203,
DRB1*150204, DRB1*150205, DRB1*150206, DRB1*15030101, DRB1*15030102, DRB1*1504, DRB1*1505, DRB1*1506, DRB1*1507, DRB1*1508, DRB1*1509, DRB1*1510, DRB1*1511, DRB1*1512, DRB1*1513, DRB1*1514, DRB1*1515, DRB1*1516, DRB1*1517N, DRB1*1518, DRB1*1519, DRB1*1520, DRB1*1521, DRB1*1522,
DRB1*1523, DRB1*1524, DRB1*1525, DRB1*1526, DRB1*1527, DRB1*1528, DRB1*1529, DRB1*1530, DRB1*1531, DRB1*1532, DRB1*1533, DRB1*160101, DRB1*160102, DRB1*160201, DRB1*160202, DRB1*1603, DRB1*1604, DRB1*160501, DRB1*160502, DRB1*1607, DRB1*1608, DRB1*1609, DRB1*1610, DRB1*1611, DRB1*1612, and
DRB1*1613N. 0. The composition according to any of the claims 1 -1159, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRB2-9, DRB2*0101 , DRB3*01010201, DRB3*01010202, DRB3*010103, DRB3*010104, DRB3*010105, DRB3*0102, DRB3*0103, DRB3*0104, DRB3*0105, DRB3*0106, DRB3*0107, DRB3*0108, DRB3*0109, DRB3*0110, DRB3*0111, DRB3*0112, DRB3*0113, DRB3*0201, DRB3*020201, DRB3*020202, DRB3*020203, DRB3*020204, DRB3*020205, DRB3*0203,
DRB3*0204, DRB3*0205, DRB3*0206, DRB3*0207, DRB3*0208, DRB3*0209, DRB3*0210, DRB3*0211, DRB3*0212, DRB3*0213, DRB3*0214, DRB3*0215, DRB3*0216, DRB3*0217, DRB3*0218, DRB3*0219, DRB3*0220, DRB3*0221, DRB3*0222, DRB3*0223, DRB3*0224, DRB3*030101, DRB3*030102, DRB3*030103, DRB3*0302,
DRB3*0303, DRB4*01010101 , DRB4*0102, DRB4*01030101, DRB4*01030102N, DRB4*010302, DRB4*010303, DRB4*010304, DRB4*0104, DRB4*0105, DRB4*0106, DRB4*0107, DRB4*0201N, DRB4*0301N, DRB5*010101, DRB5*010102, DRB5*0102, DRB5*0103, DRB5*0104, DRB5*0105, DRB5*0106, DRB5*0107, DRB5*0108N,
DRB5*0109, DRB5*0110N, DRB5*0111, DRB5*0112, DRB5*0113, DRB5*0202, DRB5*0203, DRB5*0204, DRB5*0205, DRB6*0101, DRB6*0201, DRB6*0202, DRB7*010101, DRB7*010102, DRB8*0101 , and DRB9*0101.
1161. The composition according to any of the claims 1 -1160, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DQA1, DQA1*010101, DQA1*010102, DQA1*010201, DQA1*010202, DQA1*010203, DQA1*010204, DQA1*0103, DQA1*010401, DQA1*010402, DQA1*0105,
DQA1*0106, DQA1*0107, DQA1*0201, DQA1*030101, DQA1*0302, DQA1*0303, DQA1*040101, DQA1*040102, DQA1*0402, DQA1*0403N, DQA1*0404, DQA1*050101, DQA1*050102, DQA1*0502, DQA1*0503, DQA1*0504, DQA1*0505, DQA1*0506, DQA1*0507, DQA1*0508, DQA1*0509, DQA1*060101, DQA1*060102, and DQA1*0602.
1162. The composition according to any of the claims 1-1161, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DQB1, DQB1*050101, DQB1*050102, DQB1*050201, DQB1*050202, DQB1*050301, DQB1*050302, DQB1*0504, DQB1*0505, DQB1*020101, DQB1*020102, DQB1*0202, DQB1*0203, DQB1*0204, DQB1*0205, DQB1*030101, DQB1*030102, DQB1*030103, DQB1*030104, DQB1*030201, DQB1*030202, DQB1*030203, DQB1*030204, DQB1*030302, DQB1*030303, DQB1*0304, DQB1*030501, DQB1*030502, DQB1*030503,
DQB1*030504, DQB1*0306, DQB1*0307, DQB1*0308, DQB1*0309, DQB1*0310, DQB1*0311, DQB1*0312, DQB1*0313, DQB1*0314, DQB1*0315, DQB1*0316, DQB1*0317, DQB1*0318, DQB1*0319, DQB1*0320, DQB1*0321, DQB1*0322, DQB1*0323, DQB1*0324, DQB1*0325, DQB1*040101, DQB1*040102, DQB1*0402, DQB1*0403,
DQB1*060101, DQB1*060102, DQB1*060103, DQB1*060104, DQB1*060201, DQB1*060202, DQB1*060301, DQB1*060302, DQB1*060401, DQB1*060402, DQB1*060403, DQB1*060501, DQB1*060502, DQB1*0606, DQB1*0607, DQB1*060801, DQB1*060802, DQB1*0609, DQB1*0610, DQB1*061101, DQB1*061102, DQB1*0612,
DQB1*0613, DQB1*061401, DQB1*061402, DQB1*0615, DQB1*0616, DQB1*0617, DQB1*0618, DQB1*0619, DQB1*0620, DQB1*0621, DQB1*0622, DQB1*0623, DQB1*0624, DQB1*0625, DQB1*0626N, DQB1*0627, DQB1*0628, DQB1*0629, DQB1*0630, DQB1*0631, DQB1*0632, DQB1*0633, DQB1*0634, and DQB1*0635.
1163. The composition according to any of the claims 1 -1162, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DPA1, DPA1*010301, DPA1*010302, DPA1*010303, DPA1*010304, DPA1*0104, DPA1*0105,
DPA1*010601, DPA1*010602, DPA1*0107, DPA1*0108, DPA1*0109, DPA1*0110, DPA1*020101, DPA1*020102, DPA1*020103, DPA1*020104, DPA1*020105, DPA1*020106, DPA1*020201, DPA1*020202, DPA1*020203 DPA1*0203, DPA1*0204, DPA1*0301, DPA1*0302, DPA1*0303, and DPA1*0401.
1164. The composition according to any of the claims 1 -1163, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DPB1 , DPB1 *010101 , DPB1*010102, DPB1*010103, DPB1*0102, DPB1*020102, DPB1*020103, DPB1*020104, DPB1*020105, DPB1*020106, DPB1*020107, DPB1*0202, DPB1*0203, DPB1*030101, DPB1*030102, DPB1*0302, DPB1*040101, DPB1*040102, DPB1*0402, DPB1*0403, DPB1*050101, DPB1*050102, DPB1*0502, DPB1*0601, DPB1*0602, DPB1*0801, DPB1*0802, DPB1*0901, DPB1*0902, DPB1*1001, DPB1*1002, DPB1*110101,
DPB1*110102, DPB1*1102, DPB1*1301, DPB1*1302, DPB1*1401, DPB1*1402, DPB1*1501, DPB1*1502, DPB1*1601, DPB1*1602, DPB1*1701, DPB1*1702, DPB1*1801, DPB1*1802, DPB1*1901, DPB1*1902, DPB1*200101, DPB1*200102, DPB1*2002, DPB1*2101, DPB1*2102, DPB1*2201, DPB1*2202, DPB1*2301, DPB1*2302N,
DPB1*2401, DPB1*2402, DPB1*2501, DPB1*2502, DPB1*260101, DPB1*260102, DPB1*2602, DPB1*2701, DPB1*2801, DPB1*2901, DPB1*3001, DPB1*3101, DPB1*3201, DPB1*3301, DPB1*3401, DPB1*3501, DPB1*3601, DPB1*3701, DPB1*3801, DPB1*3901, DPB1*4001, DPB1*410101, DPB1*410102, DPB1*4401, DPB1*4501,
DPB1*4601, DPB1*4701, DPB1*4801, DPB1*4901, DPB1*5001, DPB1*5101, DPB1*5201, DPB1*5301, DPB1*5401, DPB1*5501, DPB1*5601, DPB1*5701, DPB1*5801, DPB1*5901, DPB1*6001, DPB1*6101N, DPB1*6201, DPB1*6301, DPB1*6401N, DPB1*6501, DPB1*6601, DPB1*6701, DPB1*6801, DPB1*6901, DPB1*7001,
DPB1*7101, DPB1*7201, DPB1*7301, DPB1*7401, DPB1*7501, DPB1*7601, DPB1*7701, DPB1*7801, DPB1*7901, DPB1*8001, DPB1*8101, DPB1*8201, DPB1*8301, DPB1*8401, DPB1*8501, DPB1*8601, DPB1*8701, DPB1*8801, DPB1*8901, DPB1*9001, DPB1*9101, DPB1*9201, DPB1*9301, DPB1*9401, DPB1*9501,
DPB1*9601, DPB1*9701, DPB1*9801, and DPB1*9901.
1165. The composition according to any of the claims 1 -1164, wherein the one or more biologically active molecules do not comprise one or more of the molecules listed in claims 1157-1164.
1166. The composition according to any of the claims 1 -1165, wherein the one or more biologically active molecules are bound to one or more peptide(s).
1167. The compostion according to claim 1166, wherein the one or more peptides comprises one or more peptides selected from the group consisting of the peptides listed in the sequence listing of the present application - i.e. SEQ ID NO 1 to SEQ ID NO 9592.
1 168. The compostion according to claim 1 166, wherein the one or more peptides do not comprise one or more peptides selected from the group consisting of the peptides listed in the sequence listing of the present application - i.e. SEQ ID NO 1 to SEQ ID NO 9592.
1 169. The compostion according to claim 1 166, wherein the one or more peptides comprises one or more nonsense peptides.
1 170. The compostion according to claim 1 166, wherein the one or more peptides do not comprise one or more nonsense peptides.
1 171. The compostion according to claim 1 166, wherein the one or more peptides comprises one or more peptides selected from the group consisting of the peptides listed in the sequence listing of PCT/DK2009/050255.
1 172. The compostion according to claim 1 166, wherein the one or more peptides do not comprise one or more peptides selected from the group consisting of the peptides listed in the sequence listing of PCT/DK2009/050255.
1 173. The compostion according to claim 1 166, wherein the one or more peptides comprises one or more peptides selected from the group consisting of the peptides listed in the sequence listing of PCT/DK2009/050257.
1 174. The compostion according to claim 1 166, wherein the one or more peptides do not comprise one or more peptides selected from the group consisting of the peptides listed in the sequence listing of PCT/DK2009/050257.
1 175. The composition according to any of claims 1 -1 174, wherein the composition comprises HIV viral specific proteins such as Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140 and does not comprise any antigenic peptide.
1 176. The composition according to any of claims 1 -1 175, wherein the composition does not comprise HIV viral specific proteins i.e. Gag-Pol, Pr55(Gag), Vif, Vpr, Tat, Rev,Vpu, Nef, gp160 and derivatives such as but not limited to gp120, gp41 and gp140 and does not comprise any antigenic peptide.
1 177. The composition according to any of claims 1 -1 176, wherein the composition comprises Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens) and does not comprise any antigenic peptide.
1 178. The composition according to any of claims 1 -1 177, wherein the composition does not comprise Simian Mamu class 1 and/or class 2 molecules (Mokey major histocompatibility antigens) and does not comprise any antigenic peptide.
1 179. The composition according to any of claims 1 -1 178, wherein the composition comprises one or more Mamu class 1 molecules folded or partly folded with one or more human b2Microglobulin and a peptide fitting into the binding groove and does not comprise any antigenic peptide.
1 180. The composition according to any of claims 1 -1 179, wherein the composition does not comprise one or more Mamu class 1 molecules folded or partly folded with one or more human b2Microglobulin and a peptide fitting into the binding groove and does not comprise any antigenic peptide.
1 181 . The composition according to any of claims 1 -1 180, wherein the composition comprises one or more complete, partial or otherwise modified Mamu class 1 heavy chain(s) and does not comprise any antigenic peptide.
1 182. The composition according to any of claims 1 -1 181 , wherein the composition does not comprise one or more complete, partial or otherwise modified Mamu class 1 heavy chain(s) and does not comprise any antigenic peptide.
1 183. The composition according to any of the claims 1 -1 182, wherein the one or more biologically active molecules comprises one or more C-terminal fragment(s) of HSP70 (SEQ ID NO 9582).
1 184. The composition according to any of the claims 1 -1 183, wherein the one or more biologically active molecules comprises one or more truncated version(s) of gp140 protein from HIV (SEQ ID NO 9583).
1 185. The composition according to any of the claims 1 -1 184, wherein the one or more biologically active molecules comprises one or more Gag protein p27
(Sivp27) (SEQ ID NO 9584).
1 186. The composition according to any of the claims 1 -1 185, wherein the one or more biologically active molecules comprises one or more HLA- A*0101 (IVDCLTEMY) (SEQ ID NO 9588).
1 187. The composition according to any of the claims 1 -1 186, wherein the one or more biologically active molecules comprises one or more HLA-A*1 101 (VTDFSVIK) (SEQ ID NO 9589).
1 188. The composition according to any of the claims 1 -1 187, wherein the one or more biologically active molecules comprises one or more HLA-
A*0201 (GLIQLVEGV) (SEQ ID NO 9590).
1 189. The composition according to any of the claims 1 -1 188, wherein the one or more biologically active molecules comprises one or more HLA- A*0301 (RIAAWMATY) SEQ ID NO 9591 ).
1 190. The composition according to any of the claims 1 -1 189, wherein the one or more biologically active molecules comprises one or more HLA-
A*2402(EYRALQLHL) (SEQ ID NO 9592).
1 191 . The composition according to any of the claims 1 -1 190, wherein the one or more biologically active molecules comprises one or more HLA DRB1 *04.
1 192. The composition according to any of the claims 1 -1 191 , wherein the one or more biologically active molecules comprises one or more DRB3*02*03 like sequence such as RFLELLKSECHFFNG (SEQ ID NO 9585).
1 193. The composition according to any of the claims 1 -1 192, wherein the one or more biologically active molecules comprises one or more, DRB4*-like sequence such as RVWNLIRYIYNQEEY (SEQ ID NO 9586).
1 194. The composition according to any of the claims 1 -1 193, wherein the one or more biologically active molecules comprises one or more, DRB5*-like sequence such as FLQQDKYECHFFNG (SEQ ID NO 9587).
1 195. The composition according to any of the claims 1 -1 194, wherein the one or more biologically active molecules do not comprise one or more C-terminal fragment(s) of HSP70 (SEQ ID NO 9582).
1 196. The composition according to any of the claims 1 -1 195, wherein the one or more biologically active molecules do not comprise one or more truncated version(s) of gp140 protein from HIV (SEQ ID NO 9583).
1 197. The composition according to any of the claims 1 -1 196, wherein the one or more biologically active molecules do not comprise one or more Gag protein p27 (Sivp27) (SEQ ID NO 9584).
1 198. The composition according to any of the claims 1 -1 197, wherein the one or more biologically active molecules do not comprise one or more HLA- A*0101 (IVDCLTEMY) (SEQ ID NO 9588).
1 199. The composition according to any of the claims 1 -1 198, wherein the one or more biologically active molecules do not comprise one or more HLA-A*1 101
(VTDFSVIK) (SEQ ID NO 9589).
1200. The composition according to any of the claims 1 -1 199, wherein the one or more biologically active molecules do not comprise one or more HLA- A*0201 (GLIQLVEGV) (SEQ ID NO 9590).
1201. The composition according to any of the claims 1 -1200, wherein the one or more biologically active molecules do not comprise one or more HLA- A*0301 (RIAAWMATY) SEQ ID NO 9591 ).
1202. The composition according to any of the claims 1 -1201 , wherein the one or more biologically active molecules do not comprise one or more HLA- A*2402(EYRALQLHL) (SEQ ID NO 9592).
1203. The composition according to any of the claims 1 -1202, wherein the one or more biologically active molecules do not comprise one or more HLA DRB1 *04.
1204. The composition according to any of the claims 1 -1203, wherein the one or more biologically active molecules do not comprise one or more DRB3*02*03 like sequence such as RFLELLKSECHFFNG (SEQ ID NO 9585).
1205. The composition according to any of the claims 1 -1204, wherein the one or more biologically active molecules do not comprise one or more, DRB4*-like sequences such as RVWNLIRYIYNQEEY (SEQ ID NO 9586).
1206. The composition according to any of the claims 1 -1205, wherein the one or more biologically active molecules do not comprise one or more, DRB5*-like sequences such as FLQQDKYECHFFNG (SEQ ID NO 9587).
1207. The composition according to any of the claims 1 -1206, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-A, HLA-B, HLA-C, HLA-E, HLA- F, HLA-G, A*01010101 B*070201 Cw*01020I E4OI OI OI OI F4OI OI OI OI G4OI OI OI 01 ,
A*01010102NB*070202Cw*010202E*01010102F*01010102G*01010102, A*010102B*070203Cw*010203E*01010103F*01010103G*01010103, A*010103B*070204Cw*010204E*01030101 F*01010104G*01010104, A*010104B*0703Cw*0103E*01030102F*01010105G*01010105, A*0102B*0704Cw*0104E*010302F*01010106G*01010201 , A*0103B*070501 Cw*0105E*010303F*01010107G*01010202, A*0104NB*070502Cw*0106E*010304F*01010108G*010103, A*0106B*070503Cw*0107E*0104F*01010201 G*010104, A*0107B*0706Cw*0108F*01010202G*010105, A*0108B*0707Cw*0109F*01010203G*010106,
A*0109B*0708Cw*01 10F*01010204G*010107, A*01 10B*0709Cw*01 1 1 F*01010205G*010108, A*01 1 1 NB*0710Cw*01 12F*01010301 G*010109, A*01 12B*071 1 Cw*01 13F*01010302G*0101 10, A*01 13B*0712Cw*020201 F*01010303G*0102,
A*01 14B*0713Cw*020202F*01010304G*0103, A*01 15NB*0714Cw*020203F*0102G*010401 , A*01 16NB*0715Cw*020205F*01030101 G*010402, A*01 17B*0716Cw*0203F*01030102G*010403, A*01 18NB*0717Cw*0204F*0104G*0105N, A*01 19B*0718Cw*0205G*0106,
A*0120B*0719Cw*0206G*0107, A*02010101 B*0720Cw*0207, A*02010102LB*0721 Cw*0208, A*020102B*0722Cw*0209, A*020103B*0723Cw*0210, A*020104B*0724Cw*021 1 , A*020105B*0725Cw*0212, A*020106B*0726Cw*0213, A*020107B*0727Cw*0214, A*020108B*0728Cw*0215,
A*020109B*0729Cw*0216, A*0201 10B*0730Cw*0217, A*0201 1 1 B*0731 Cw*030201 , A*0201 12B*0732Cw*030202, A*0202B*0733Cw*030301 , A*020301 B*0734Cw*030302, A*020302B*0735Cw*030303, A*0204B*0736Cw*030304, A*0205B*0737Cw*030305, A*020601 B*0738Cw*030401 ,
A*020602B*0739Cw*030402, A*020603B*0740Cw*030403, A*0207B*0741 Cw*030404, A*0208B*0742Cw*030405, A*0209B*0743Cw*0305, A*0210B*0744Cw*0306, A*021 1 B*0745Cw*0307, A*0212B*0746Cw*0308, A*0213B*0747Cw*0309, A*0214B*0748Cw*0310, A*0215NB*0749NCw*031 101 , A*0216B*0750Cw*031 102,
A*021701 B*0751 Cw*0312, A*021702B*080101 Cw*0313, A*0218B*080102Cw*0314, A*0219B*080103Cw*0315, A*022001 B*0802Cw*0316, A*022002B*0803Cw*0317, A*0221 B*0804Cw*0318, A*0222B*0805Cw*0319, A*0224B*0806Cw*0320N, A*0225B*0807Cw*0321 , A*0226B*0808NCw*0322Q, A*0227B*0809Cw*0323, A*0228B*0810Cw*0324, A*0229B*081 1 Cw*0325, A*0230B*0812Cw*0326, A*0231 B*0813Cw*0327, A*0232NB*0814Cw*0328, A*0233B*0815Cw*0329, A*0234B*0816Cw*0330, A*023501 B*0817Cw*0331 , A*023502B*0818Cw*0332, A*0236B*0819NCw*0333, A*0237B*0820Cw*0334, A*0238B*0821 Cw*0335, A*0239B*0822Cw*04010101 ,
A*0240B*0823Cw*04010102, A*0241 B*0824Cw*040102, A*0242B*0825Cw*040103, A*0243NB*0826Cw*040104, A*0244B*0827Cw*0403, A*0245B*0828Cw*040401 , A*0246B*0829Cw*040402, A*0247B*0830NCw*0405, A*0248B*0831 Cw*0406, A*0249B*1301 Cw*0407,
A*0250B*130201 Cw*0408, A*0251 B*130202Cw*0409N, A*0252B*130203Cw*0410, A*0253NB*1303Cw*041 1 ,
A*0254B*1304Cw*0412, A*0255B*1306Cw*0413, A*0256B*1307NCw*0414, A*0257B*1308Cw*0415, A*0258B*1309Cw*0416, A*0259B*1310Cw*0417, A*0260B*131 1 Cw*0418, A*0261 B*1312Cw*0419, A*0262B*1313Cw*0420,
A*0263B*1314Cw*0421 , A*0264B*1315Cw*0423, A*0265B*1316Cw*0424, A*0266B*1317Cw*050101 , A*0267B*1401 Cw*050102, A*0268B*140201 Cw*050103, A*0269B*140202Cw*0502, A*0270B*1403Cw*0503, A*0271 B*1404Cw*0504, A*0272B*1405Cw*0505, A*0273B*140601 Cw*0506, A*027401 B*140602Cw*0507N,
A*027402B*1407NCw*0508, A*0275B*15010101 Cw*0509, A*0276B*15010102NCw*0510, A*0277B*150102Cw*051 1 , A*0278B*150103Cw*0512, A*0279B*150104Cw*0513, A*0280B*1502Cw*0514, A*0281 B*1503Cw*0515, A*0282NB*1504Cw*06020101 , A*0283NB*1505Cw*06020102,
A*0284B*1506Cw*060202, A*0285B*1507Cw*0603,
A*0286B*1508Cw*0604, A*0287B*1509Cw*0605, A*0288NB*1510Cw*0606, A*0289B*151 101 Cw*0607, A*0290B*151 102Cw*0608, A*0291 B*151 103Cw*0609, A*0292B*1512Cw*0610, A*0293B*1513Cw*061 1 , A*0294NB*1514Cw*0612, A*0295B*1515Cw*0613,
A*0296B*1516Cw*0614, A*0297B*15170101 Cw*070101 , A*0299B*15170102Cw*070102, A*03010101 B*151702Cw*070103, A*03010102NB*1518Cw*070104, A*03010103B*1519Cw*070105, A*030102B*1520Cw*070106, A*030103B*1521 Cw*070107, A*030104B*1523Cw*07020101 , A*030105B*1524Cw*07020102, A*0302B*1525Cw*07020103, A*0303NB*1526NCw*0703, A*0304B*1527Cw*070401 , A*0305B*1528Cw*070402, A*0306B*1529Cw*0705, A*0307B*1530Cw*0706, A*0308B*1531 Cw*0707, A*0309B*1532Cw*0708, A*0310B*1533Cw*0709, A*031 1 NB*1534Cw*0710, A*0312B*1535Cw*071 1 , A*0313B*1536Cw*0712, A*0314B*1537Cw*0713,
A*0315B*1538Cw*0714, A*0316B*1539Cw*0715, A*0317B*1540Cw*0716, A*0318B*1542Cw*0717, A*0319B*1543Cw*0718, A*0320B*1544Cw*0719, A*0321 NB*1545Cw*0720, A*0322B*1546Cw*0721 , A*0323B*1547Cw*0722, A*0324B*1548Cw*0723, A*0325B*1549Cw*0724, A*0326B*1550Cw*0725, A*1 10101 B*1551 Cw*0726, A*1 10102B*1552Cw*0727,
A*1 10103B*1553Cw*0728, A*1 10104B*1554Cw*0729, A*1 10105B*1555Cw*0730, A*1 10106B*1556Cw*0731 , A*1 10201 B*1557Cw*0732N, A*1 10202B*1558Cw*0733N, A*1 103B*1560Cw*0734, A*1 104B*1561 Cw*0735, A*1 105B*1562Cw*0736, A*1 106B*1563Cw*0737, A*1 107B*1564Cw*0738, A*1 108B*1565Cw*0739,
A*1 109B*1566Cw*0740, A*1 1 10B*1567Cw*0741 , A*1 1 1 1 B*1568Cw*0742, A*1 1 12B*1569Cw*0743, A*1 1 13B*1570Cw*0744, A*1 1 14B*1571 Cw*0745, A*1 1 15B*1572Cw*080101 , A*1 1 16B*1573Cw*080102, A*1 1 17B*1574Cw*0802, A*1 1 18B*1575Cw*0803, A*1 1 19B*1576Cw*0804, A*1 120B*1577Cw*0805, A*1 121 NB*1578Cw*0806, A*1 122B*1579NCw*0807,
A*1 123B*1580Cw*0808, A*1 124B*1581 Cw*0809, A*1 125B*1582Cw*0810, A*1 126B*1583Cw*081 1 , A*1 127B*1584Cw*0812, A*1 128B*1585Cw*0813, A*1 129B*1586Cw*0814, A*2301 B*1587Cw*120201 , A*2302B*1588Cw*120202, A*2303B*1589Cw*120203, A*2304B*1590Cw*12030101 , A*2305B*1591 Cw*12030102,
A*2306B*1592Cw*120302, A*2307NB*1593Cw*120303, A*2308NB*1594NCw*120304, A*2309B*1595Cw*120401 , A*2310B*1596Cw*120402, A*231 1 NB*1597Cw*1205, A*2312B*1598Cw*1206, A*2313B*1599Cw*1207, A*2314B*9501 Cw*1208, A*24020101 B*9502Cw*1209, A*24020102LB*9503Cw*1210,
A*240202B*9504Cw*121 1 , A*240203B*9505Cw*1212, A*240204B*9506Cw*1213, A*240205B*9507Cw*1214, A*240206B*9508Cw*1215, A*240207B*9509Cw*1216, A*240208B*9510Cw*1217, A*240209B*951 1 NCw*1218, A*240210B*9512Cw*1219, A*24021 1 B*9513Cw*140201 , A*240212B*9514Cw*140202, A*240213B*9515Cw*140203, A*240301 B*9516Cw*140204, A*240302B*9517Cw*1403, A*2404B*9518Cw*1404, A*2405B*9519Cw*1405, A*2406B*9520Cw*1406, A*2407B*9521 Cw*1407N, A*2408B*9522Cw*1408, A*2409NB*180101 Cw*150201 , A*2410B*180102Cw*150202,
A*241 1 NB*180103Cw*150203, A*2413B*1802Cw*1503, A*2414B*1803Cw*1504, A*2415B*1804Cw*150501 , A*2417B*1805Cw*150502, A*2418B*1806Cw*150503, A*2419B*1807Cw*150504, A*2420B*1808Cw*1506, A*2421 B*1809Cw*1507, A*2422B*1810Cw*1508, A*2423B*181 1 Cw*1509, A*2424B*1812Cw*1510,
A*2425B*1813Cw*151 1 , A*2426B*1814Cw*1512, A*2427B*1815Cw*1513, A*2428B*1817NCw*1514, A*2429B*1818Cw*1515, A*2430B*1819Cw*1516, A*2431 B*1820Cw*1517, A*2432B*1821 Cw*160101 , A*2433B*1822Cw*160102, A*2434B*1823NCw*1602, A*2435B*1824Cw*160401 , A*2436NB*2701 Cw*1606, A*2437B*2702Cw*1607,
A*2438B*2703Cw*1608, A*2439B*270401 Cw*1609, A*2440NB*270402Cw*1701 , A*2441 B*270502Cw*1702, A*2442B*270503Cw*1703, A*2443B*270504Cw*1704, A*2444B*270505Cw*1801 , A*2445NB*270506Cw*1802, A*2446B*270507, A*2447B*270508, A*2448NB*270509, A*2449B*2706, A*2450B*2707,
A*2451 B*2708, A*2452B*2709, A*2453B*2710, A*2454B*271 1 , A*2455B*2712, A*2456B*2713, A*2457B*2714, A*2458B*2715, A*2459B*2716, A*2460NB*2717, A*2461 B*2718, A*2462B*2719, A*2463B*2720, A*2464B*2721 , A*2465B*2723, A*2466B*2724, A*2467B*2725, A*2468B*2726, A*250101 B*2727, A*250102B*2728, A*2502B*2729, A*2503B*2730,
A*2504B*2731 , A*2505B*2732, A*2506B*2733, A*260101 B*2734, A*260102B*2735, A*260103B*2736, A*260104B*350101 , A*2602B*350102, A*2603B*350103, A*2604B*350104, A*2605B*350105, A*2606B*350106, A*260701 B*350201 , A*260702B*350202, A*2608B*3503, A*2609B*350401 , A*2610B*350402, A*261 1 NB*3505, A*2612B*3506, A*2613B*3507,
A*2614B*350801 , A*2615B*350802, A*2616B*350901 , A*2617B*350902, A*2618B*3510, A*2619B*351 1 , A*2620B*3512, A*2621 B*3513, A*2622B*351401 , A*2623B*351402, A*2624B*3515, A*2625NB*3516, A*2626B*3517, A*2627B*3518, A*2628B*3519, A*2629B*3520, A*2630B*3521 , A*2631 B*3522, A*2632B*3523, A*2633B*3524, A*2634B*3525, A*29010101 B*3526, A*29010102NB*3527, A*290201 B*3528, A*290202B*3529, A*290203B*3530, A*2903B*3531 , A*2904B*3532, A*2905B*3533, A*2906B*3534, A*2907B*3535, A*2908NB*3536, A*2909B*3537, A*2910B*3538, A*291 1 B*3539, A*2912B*3540N, A*2913B*3541 , A*2914B*3542, A*2915B*3543, A*2916B*3544,
A*300101 B*3545, A*300102B*3546, A*300201 B*3547, A*300202B*3548, A*300203B*3549, A*3003B*3550, A*3004B*3551 , A*3006B*3552, A*3007B*3553N, A*3008B*3554, A*3009B*3555, A*3010B*3556, A*301 1 B*3557, A*3012B*3558, A*3013B*3559, A*3014LB*3560, A*3015B*3561 , A*3016B*3562, A*3017B*3563, A*3018B*3564,
A*3019B*3565Q, A*310102B*3566, A*3102B*3567, A*3103B*3568, A*3104B*3569, A*3105B*3570, A*3106B*3571 , A*3107B*3572, A*3108B*370101 , A*3109B*370102, A*31 10B*370103, A*31 1 1 B*370104, A*31 12B*3702, A*31 13B*3703N, A*31 14NB*3704, A*31 15B*3705, A*3201 B*3706, A*3202B*3707, A*3203B*3708, A*3204B*3709, A*3205B*3710,
A*3206B*371 1 , A*3207B*3712, A*3208B*380101 , A*3209B*380102, A*3210B*380201 , A*321 1 QB*380202, A*3212B*3803, A*3213B*3804, A*3214B*3805, A*3301 B*3806, A*330301 B*3807, A*330302B*3808, A*3304B*3809, A*3305B*3810, A*3306B*381 1 , A*3307B*3812, A*3308B*3813, A*3309B*3814, A*3401 B*3815, A*3402B*39010101 , A*3403B*39010102L,
A*3404B*390103, A*3405B*390104, A*3406B*390201 , A*3407B*390202, A*3408B*3903, A*3601 B*3904, A*3602B*3905, A*3603B*390601 , A*3604B*390602, A*4301 B*3907, A*6601 B*3908, A*6602B*3909, A*6603B*3910, A*6604B*391 1 , A*6605B*3912, A*6606B*391301 , A*680101 B*391302, A*680102B*3914, A*680103B*3915, A*680104B*3916,
A*680105B*3917, A*68020101 B*3918, A*68020102B*3919, A*680301 B*3920, A*680302B*3922, A*6804B*3923, A*6805B*3924, A*6806B*3925N, A*6807B*3926, A*6808B*3927, A*6809B*3928, A*6810B*3929, A*681 1 NB*3930, A*6812B*3931 , A*6813B*3932, A*6814B*3933, A*6815B*3934, A*6816B*3935, A*6817B*3936, A*6818NB*3937,
A*6819B*3938Q, A*6820B*3939, A*6821 B*3940N, A*6822B*3941 , A*6823B*400101 , A*6824B*400102, A*6825B*400103, A*6826B*400104, A*6827B*400105, A*6828B*400201 , A*6829B*400202, A*6830B*400203, A*6831 B*4003, A*6832B*4004, A*6833B*4005, A*6834B*40060101 , A*6835B*40060102, A*6836B*400602, A*6901 B*4007, A*7401 B*4008, A*7402B*4009, A*7403B*4010, A*7404B*401 1 , A*7405B*4012, A*7406B*4013, A*7407B*401401 , A*7408B*401402, A*7409B*401403, A*7410B*4015, A*741 1 B*4016, A*7412NB*4018, A*8001 B*4019, A*9201 B*4020, A*9202B*4021 , A*9203B*4022N, A*9204B*4023, A*9205B*4024, A*9206B*4025, A*9207B*4026, A*9208B*4027, A*9209B*4028, B*4029,
B*4030, B*4031 , B*4032, B*4033, B*4034, B*4035, B*4036, B*4037, B*4038, B*4039, B*4040, B*4042, B*4043, B*4044, B*4045, B*4046, B*4047, B*4048, B*4049, B*4050, B*4051 , B*4052, B*4053, B*4054, B*4055, B*4056, B*4057, B*4058, B*4059, B*4060, B*4061 , B*4062, B*4063, B*4064, B*4065, B*4066, B*4067, B*4068, B*4069, B*4070, B*4101 , B*4102, B*4103, B*4104, B*4105,
B*4106, B*4107, B*4108, B*4201 , B*4202, B*4204, B*420501 , B*420502, B*4206, B*4207, B*4208, B*4209, B*44020101 , B*44020102S, B*440202, B*440203, B*440204, B*440301 , B*440302, B*4404, B*4405, B*4406, B*4407, B*4408, B*4409, B*4410, B*441 1 , B*4412, B*4413, B*4414, B*4415, B*4416, B*4417, B*4418, B*4419N, B*4420, B*4421 , B*4422, B*4423N, B*4424,
B*4425, B*4426, B*4427, B*4428, B*4429, B*4430, B*4431 , B*4432, B*4433, B*4434, B*4435, B*4436, B*4437, B*4438, B*4439, B*4440, B*4441 , B*4442, B*4443, B*4444, B*4445, B*4446, B*4447, B*4448, B*4449, B*4450, B*4451 , B*4501 , B*4502, B*4503, B*4504, B*4505, B*4506, B*4507, B*460101 , B*460102, B*4602, B*4603, B*4604, B*4605, B*4606, B*4607N, B*4608,
B*4609, B*47010101 , B*47010102, B*4702, B*4703, B*4704, B*4705, B*4801 , B*4802, B*480301 , B*480302, B*4804, B*4805, B*4806, B*4807, B*4808, B*4809, B*4810, B*481 1 , B*4812, B*4813, B*4814, B*4815, B*4816, B*4901 , B*4902, B*4903, B*4904, B*4905, B*5001 , B*5002, B*5004, B*510101 , B*510102, B*510103, B*510104, B*510105, B*510106, B*510107, B*510201 ,
B*510202, B*5103, B*5104, B*5105, B*5106, B*5107, B*5108, B*5109, B*51 10, B*51 1 1 N, B*51 12, B*51 1301 , B*51 1302, B*51 14, B*51 15, B*51 16, B*51 17, B*51 18, B*51 19, B*5120, B*5121 , B*5122, B*5123, B*5124, B*5126, B*5127N, B*5128, B*5129, B*5130, B*5131 , B*5132, B*5133, B*5134, B*5135, B*5136, B*5137, B*5138, B*5139, B*5140, B*5141 N, B*5142, B*5143, B*5144N,
B*5145, B*5146, B*520101 , B*520102, B*520103, B*520104, B*5202, B*5203, B*5204, B*5205, B*5206, B*5207, B*5208, B*5209, B*5210, B*530101 , B*530102, B*530103, B*530104, B*5302, B*5303, B*5304, B*5305, B*5306, B*5307, B*5308, B*5309, B*5310, B*531 1 , B*5312, B*5401 , B*5402, B*5403, B*5404, B*5405N, B*5406, B*5407, B*5408N, B*5409, B*5410, B*541 1 , B*5412, B*550101, B4550102, B4550103, B4550104, B4550201, B*550202, B45503, B45504, B45505, B45507, B*5508, B45509, B45510, B45511 , B45512, B45513, B45514, B45515, B45516, B45517, B45518, B45519, B45520, B*5521, B45522, B45523, B45524, B45601, B45602, B45603, B45604, B4560501, B*560502, B45606, B45607, B*5608, B*5609, B*5610, B*5611 , B*5612, B*5613,
B*5614, B*5615, B*5616, B*5617, B*5618, B*5619N, B*570101, B*570102, B*570103, B*5702, B*570301, B*570302, B*5704, B*5705, B*5706, B*5707, B*5708, B*5709, B*5710, B*5711, B*5801, B*5802, B*5804, B*5805, B*5806, B*5807, B*5808, B*5809, B*5810N, B*5811, B*5812, B*5813, B*5814, B*5901, B*5902, B*670101 , B*670102, B*6702, B*7301 , B*7801 , B*780201 , B*780202,
B*7803, B*7804, B*7805, B*8101, B*8102, B*8201, B*8202, B*8301, HLA- HHLA-JHLA-KHLA-LHLA-P,
H4OIOIOIOIJ4OIOIOIOIK4OIOIOIOIL4OIOIOIOIP4OIOIOIOI, H401010102J401010102K401010102L401010102P401010102, H401010103J401010103K401010103L401010103P402010101,
H40102J401010104K401010104L4010102P402010102, H402010101J401010105K40102L40102, H402010102J401010106K40103, H40202J401010107, H40203J401010108, H40204J40201, H40205, H40206, and 1-1*0301.
1208. The composition according to any of the claims 1 -1207, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRA, DRA4OI 01, DRA4OI 0201 and DRA4OI 0202.
1209. The composition according to any of the claims 1 -1208, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRB1,
DRB14010101 , DRB14010102 , DRB14010103 , DRB14010104 , DRB14010105 , DRB14010106 , DRB14010107 , DRB14010108 , DRB14010109 ,
DRB14010110 , DRB14010201 , DRB14010202 , DRB14010203 , DRB14010204 , DRB14010205 , DRB140103 , DRB140104 , DRB140105 , DRB140106 , DRB140107 , DRB140108 , DRB140109 , DRB140110 , DRB140111 , DRB140112 , DRB140113 , DRB140114 , DRB140115 , DRB140116 , DRB140117 , DRB140118 , DRB140119 , DRB140120 , DRB140121 , DRB1*0122 , DRB1*03010101 , DRB1*03010102 , DRB1*030102 , DRB1*030103 , DRB1*030104 , DRB1*030105 , DRB1*030106 , DRB1*030107 , DRB1*030201 , DRB1*030202 , DRB1*0303 , DRB1*0304 , DRB1*030501 , DRB1*030502 , DRB1*030503 , DRB1*0306 , DRB1*0307 , DRB1*0308 , DRB1*0309 , DRB1*0310 , DRB1*0311 , DRB1*0312 , DRB1*031301 ,
DRB1*031302 , DRB1*0314 , DRB1*0315 , DRB1*0316 , DRB1*0317 , DRB1*0318 , DRB1*0319 , DRB1*0320 , DRB1*0321 , DRB1*0322 , DRB1*0323 , DRB1*0324 , DRB1*0325 , DRB1*0326 , DRB1*0327 , DRB1*0328 , DRB1*0329 , DRB1*0330 , DRB1*0331 , DRB1*0332 , DRB1 *0333 , DRB1 *0334 , DRB1 *0335 , DRB1 *0336 , DRB1 *0337 ,
DRB1*0338 , DRB1*0339 , DRB1*0340 , DRB1*0341 , DRB1*0342 , DRB1*0343 , DRB1*0344 , DRB1*0345 , DRB1*0346 , DRB1*0347 , DRB1*0348 , DRB1*040101 , DRB1*040102 , DRB1*040103 , DRB1*0402 , DRB1*040301 , DRB1*040302 , DRB1*040303 , DRB1*040304 , DRB1*0404 , DRB1*040501 , DRB1*040502 , DRB1*040503 , DRB1*040504 , DRB1*040505
, DRB1*040506 , DRB1*040601 , DRB1*040602 , DRB1*040701 , DRB1*040702 , DRB1*040703 , DRB1*0408 , DRB1*0409 , DRB1*0410 , DRB1 *0411 , DRB1 *0412 , DRB1 *0413 , DRB1 *0414 , DRB1 *0415 , DRB1*0416 , DRB1*0417 , DRB1*0418 , DRB1*0419 , DRB1*0420 , DRB1*0421 , DRB1*0422 , DRB1*0423 , DRB1*0424 , DRB1*0425 ,
DRB1*0426 , DRB1*0427 , DRB1*0428 , DRB1*0429 , DRB1*0430 , DRB1*0431 , DRB1*0432 , DRB1*0433 , DRB1*0434 , DRB1*0435 , DRB1*0436 , DRB1*0437 , DRB1*0438 , DRB1*0439 , DRB1*0440 , DRB1*0441 , DRB1*0442 , DRB1*0443 , DRB1*0444 , DRB1*0445 , DRB1 *0446 , DRB1 *0447 , DRB1 *0448 , DRB1 *0449 , DRB1 *0450 ,
DRB1*0451 , DRB1*0452 , DRB1*0453 , DRB1*0454 , DRB1*0455 , DRB1*0456 , DRB1*0457 , DRB1*0458 , DRB1*0459 , DRB1*0460 , DRB1*0461 , DRB1*0462 , DRB1*0463 , DRB1*0464 , DRB1*0465 , DRB1*0466 , DRB1*0467 , DRB1*0468 , DRB1*0469 , DRB1*0470 , DRB1*0471 , DRB1*0472 , DRB1*0473 , DRB1*0474 , DRB1*0475 ,
DRB1*0476 , DRB1*0477 , DRB1*0478 , DRB1*07010101 , DRB1*07010102 , DRB1*070102 , DRB1*070103 , DRB1*0703 , DRB1*0704 , DRB1*0705 , DRB1*0706 , DRB1*0707 , DRB1*0708 , DRB1*0709 , DRB1*0710N , DRB1*0711 , DRB1*0712 , DRB1*0713 , DRB1*0714 , DRB1*0715 , DRB1*0716 , DRB1*0717 , DRB1*080101 , DRB1*080102 , DRB1*080103 , DRB1*080104 , DRB1*080201 , DRB1*080202 , DRB1*080203 , DRB1*080302 , DRB1*080401 , DRB1*080402 , DRB1*080403 , DRB1*080404 , DRB1*0805 , DRB1*0806 , DRB1*0807 , DRB1*0808 , DRB1*0809 , DRB1*0810 , DRB1*0811 , DRB1*0812 , DRB1*0813 , DRB1*0814 , DRB1*0815 , DRB1 *0816 , DRB1 *0817 , DRB1 *0818 , DRB1 *0819 , DRB1 *0820 ,
DRB1*0821 , DRB1*0822 , DRB1*0823 , DRB1*0824 , DRB1*0825 , DRB1*0826 , DRB1*0827 , DRB1*0828 , DRB1*0829 , DRB1*0830 , DRB1*0831 , DRB1*0832 , DRB1*0833 , DRB1*0834 , DRB1*0835 , DRB1*0836 , DRB1*090102 , DRB1*090103 , DRB1*090104 , DRB1*090105 , DRB1*090201 , DRB1*090202 , DRB1*0903 , DRB1*0904 , DRB1*0905 ,
DRB1*0906 , DRB1*0907 , DRB1*0908 , DRB1*100101 , DRB1*100102 , DRB1*100103 , DRB1*1002 , DRB1*1003 , DRB1*110101 , DRB1*110102 , DRB1*110103 , DRB1*110104 , DRB1*110105 , DRB1*110106 , DRB1*110107 , DRB1*110108 , DRB1*110109 , DRB1*110110 , DRB1*110201 , DRB1*110202 , DRB1*1103 , DRB1*110401 , DRB1*110402 , DRB1*110403 ,
DRB1*110404 , DRB1*110405 , DRB1*1105 , DRB1*110601 , DRB1*110602 , DRB1*1107 , DRB1*110801 , DRB1*110802 , DRB1*1109 , DRB1*111001 , DRB1*111002 , DRB1*111101 , DRB1*111102 , DRB1*111201 , DRB1*111202 , DRB1*111301 , DRB1*111302 , DRB1*111401 , DRB1*111402 , DRB1*1115 , DRB1*1116 , DRB1*1117 , DRB1*1118 , DRB1*111901 , DRB1*111902 ,
DRB1*1120 , DRB1*1121 , DRB1*1122 , DRB1*1123 , DRB1*1124 , DRB1*1125 , DRB1*1126 , DRB1*112701 , DRB1*112702 , DRB1*112801 , DRB1*112802 , DRB1*1129 , DRB1*1130 , DRB1*1131 , DRB1*1132 , DRB1*1133 , DRB1*1134 , DRB1*1135 , DRB1*1136 , DRB1*1137 , DRB1*1138 , DRB1*1139 , DRB1*1140 , DRB1*1141 , DRB1*1142 ,
DRB1*1143 , DRB1*1144 , DRB1*1145 , DRB1*1146 , DRB1*1147 , DRB1*1148 , DRB1*1149 , DRB1*1150 , DRB1*1151 , DRB1*1152 , DRB1*1153 , DRB1*115401 , DRB1*115402 , DRB1*1155 , DRB1*1156 , DRB1*1157 , DRB1*1158 , DRB1*1159 , DRB1*1160 , DRB1*1161 , DRB1*1162 , DRB1*1163 , DRB1*1164 , DRB1*116501 , DRB1*116502 ,
DRB1*1166 , DRB1*1167 , DRB1*1168 , DRB1*1169 , DRB1*1170 , DRB1*1172 , DRB1*1173 , DRB1*1174 , DRB1*1175 , DRB1*1176 , DRB1*1177 , DRB1*1178 , DRB1*1179 , DRB1*1180 , DRB1*1181 , DRB1*120101 , DRB1*120102 , DRB1*120201 , DRB1*120202 , DRB1*120203 , DRB1*120204 , DRB1*120302 , DRB1*1204 , DRB1*1205 , DRB1*1206 , DRB1*1207 , DRB1*1208 , DRB1*1209 , DRB1*1210 , DRB1*1211 , DRB1*1212 , DRB1*1213 , DRB1*1214 , DRB1*1215 , DRB1*1216 , DRB1*1217 , DRB1*1218 , DRB1*1219 , DRB1*130101 , DRB1*130102 , DRB1*130103 , DRB1*130104 , DRB1*130105 , DRB1*130201 , DRB1*130202 , DRB1*130203 , DRB1*130301 , DRB1*130302 , DRB1*1304 , DRB1*130501 ,
DRB1*130502 , DRB1*1306 , DRB1*130701 , DRB1*130702 , DRB1*1308 , DRB1*1309 , DRB1*1310 , DRB1*131101 , DRB1*131102 , DRB1*1312 , DRB1*1313 , DRB1*131401 , DRB1*131402 , DRB1*131403 , DRB1*1315 , DRB1*1316 , DRB1*1317 , DRB1*1318 , DRB1*1319 , DRB1*1320 , DRB1*1321 , DRB1*1322 , DRB1*1323 , DRB1*1324 , DRB1*1325 ,
DRB1*1326 , DRB1*1327 , DRB1*1328 , DRB1*1329 , DRB1*1330 , DRB1*1331 , DRB1*1332 , DRB1*133301 , DRB1*133302 , DRB1*133303 , DRB1*1334 , DRB1*1335 , DRB1*1336 , DRB1*1337 , DRB1*1338 , DRB1*1339 , DRB1*1340 , DRB1*1341 , DRB1*1342 , DRB1*1343 , DRB1 *1344 , DRB1 *1345 , DRB1 *1346 , DRB1 *1347 , DRB1 *1348 ,
DRB1*1349 , DRB1*135001 , DRB1*135002 , DRB1*1351 , DRB1*1352 , DRB1*1353 , DRB1*1354 , DRB1*1355 , DRB1*1356 , DRB1*1357 , DRB1*1358 , DRB1*1359 , DRB1*1360 , DRB1*1361 , DRB1*1362 , DRB1*1363 , DRB1*1364 , DRB1*1365 , DRB1*1366 , DRB1*1367 , DRB1*1368 , DRB1*1369 , DRB1*1370 , DRB1*1371 , DRB1*1372 ,
DRB1*1373 , DRB1*1374 , DRB1*1375 , DRB1*1376 , DRB1*1377 , DRB1*1378 , DRB1*1379 , DRB1*1380 , DRB1*1381 , DRB1*1382 , DRB1*1383 , DRB1*1384 , DRB1*1385 , DRB1*1386 , DRB1*1387 , DRB1*1388 , DRB1*1389 , DRB1*1390 , DRB1*1391 , DRB1*1392 , DRB1*140101 , DRB1*140102 , DRB1*140103 , DRB1*1402 , DRB1*140301 ,
DRB1*140302 , DRB1*1404 , DRB1*140501 , DRB1*140502 , DRB1*140503 , DRB1*1406 , DRB1*140701 , DRB1*140702 , DRB1*1408 , DRB1*1409 , DRB1*1410 , DRB1*1411 , DRB1*1412 , DRB1*1413 , DRB1*1414 , DRB1*1415 , DRB1*1416 , DRB1*1417 , DRB1*1418 , DRB1*1419 , DRB1*1420 , DRB1*1421 , DRB1*1422 , DRB1*142301 , DRB1*142302 ,
DRB1*1424 , DRB1*1425 , DRB1*1426 , DRB1*1427 , DRB1*1428 , DRB1*1429 , DRB1*1430 , DRB1*1431 , DRB1*143201 , DRB1*143202 , DRB1*1433 , DRB1*1434 , DRB1*1435 , DRB1*1436 , DRB1*1437 , DRB1*1438 , DRB1*1439 , DRB1*1440 , DRB1*1441 , DRB1*1442 , DRB1*1443 , DRB1*144401 , DRB1*144402 , DRB1*1445 , DRB1*1446 , DRB1*1447 , DRB1*1448 , DRB1*1449 , DRB1*1450 , DRB1*1451 , DRB1*1452 , DRB1*1453 , DRB1*1454 , DRB1*1455 , DRB1*1456 , DRB1*1457 , DRB1*1458 , DRB1*1459 , DRB1*1460 , DRB1*1461 , DRB1*1462 , DRB1*1463 , DRB1*1464 , DRB1*1465 , DRB1*1467 , DRB1*1468 , DRB1*1469 , DRB1*1470 , DRB1*1471 , DRB1*1472 ,
DRB1*1473 , DRB1*1474 , DRB1*1475 , DRB1*1476 , DRB1*1477 , DRB1*1478 , DRB1*1479 , DRB1*1480 , DRB1*1481 , DRB1*1482 , DRB1*1483 , DRB1*1484 , DRB1*1485 , DRB1*1486 , DRB1*1487 , DRB1*1488 , DRB1*1489 , DRB1*1490 , DRB1*15010101 , DRB1*15010102 , DRB1*150102 , DRB1*150103 , DRB1*150104 , DRB1*150105 , DRB1*150106
, DRB1*150201 , DRB1*150202 , DRB1*150203 , DRB1*150204 , DRB1*150205 , DRB1*150206 , DRB1*15030101 , DRB1*15030102 , DRB1*1504 , DRB1*1505 , DRB1*1506 , DRB1*1507 , DRB1*1508 , DRB1*1509 , DRB1*1510 , DRB1*1511 , DRB1*1512 , DRB1*1513 , DRB1*1514 , DRB1*1515 , DRB1*1516 , DRB1*1517N , DRB1*1518 ,
DRB1*1519 , DRB1*1520 , DRB1*1521 , DRB1*1522 , DRB1*1523 , DRB1*1524 , DRB1*1525 , DRB1*1526 , DRB1*1527 , DRB1*1528 , DRB1*1529 , DRB1*1530 , DRB1*1531 , DRB1*1532 , DRB1*1533 , DRB1*160101 , DRB1*160102 , DRB1*160201 , DRB1*160202 , DRB1*1603 , DRB1 *1604 , DRB1 *160501 , DRB1 *160502 , DRB1 *1607 , DRB1 *1608 ,
DRB1*1609 , DRB1*1610 , DRB1*1611 , DRB1*1612 , and DRB1*1613N.
0. The composition according to any of the claims 1 -1209, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DRB2-9, DRB2*0101 ,
DRB3*01010201 , DRB3*01010202 , DRB3*010103 , DRB3*010104 , DRB3*010105 , DRB3*0102 , DRB3*0103 , DRB3*0104 , DRB3*0105 , DRB3*0106 , DRB3*0107 , DRB3*0108 , DRB3*0109 , DRB3*0110 , DRB3*0111 , DRB3*0112 , DRB3*0113 , DRB3*0201 , DRB3*020201 , DRB3*020202 , DRB3*020203 , DRB3*020204 , DRB3*020205 , DRB3*0203 ,
DRB3*0204 , DRB3*0205 , DRB3*0206 , DRB3*0207 , DRB3*0208 , DRB3*0209 , DRB3*0210 , DRB3*0211 , DRB3*0212 , DRB3*0213 , DRB3*0214 , DRB3*0215 , DRB3*0216 , DRB3*0217 , DRB3*0218 , DRB3*0219 , DRB3*0220 , DRB3*0221 , DRB3*0222 , DRB3*0223 , DRB3*0224 , DRB3*030101 , DRB3*030102 , DRB3*030103 , DRB3*0302 , DRB3*0303 , DRB4*01010101 , DRB4*0102 , DRB4*01030101 , DRB4*01030102N , DRB4*010302 , DRB4*010303 , DRB4*010304 , DRB4*0104 , DRB4*0105 , DRB4*0106 , DRB4*0107 , DRB4*0201N , DRB4*0301N , DRB5*010101 , DRB5*010102 , DRB5*0102 , DRB5*0103 , DRB5*0104 , DRB5*0105 , DRB5*0106 , DRB5*0107 , DRB5*0108N ,
DRB5*0109 , DRB5*0110N , DRB5*0111 , DRB5*0112 , DRB5*0113 , DRB5*0202 , DRB5*0203 , DRB5*0204 , DRB5*0205 , DRB6*0101 , DRB6*0201 , DRB6*0202 , DRB7*010101 , DRB7*010102 , DRB8*0101 , and DRB9*0101.
1211. The composition according to any of the claims 1 -1210, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DQA1, DQA1*010101 , DQA1*010102 , DQA1*010201 , DQA1*010202 , DQA1*010203 , DQA1 *010204 , DQA1 *0103 , DQA1 *010401 , DQA1 *010402 , DQA1 *0105 ,
DQA1*0106 , DQA1*0107 , DQA1*0201 , DQA1*030101 , DQA1*0302 , DQA1*0303 , DQA1*040101 , DQA1*040102 , DQA1*0402 , DQA1*0403N , DQA1*0404 , DQA1*050101 , DQA1*050102 , DQA1*0502 , DQA1*0503 , DQA1*0504 , DQA1*0505 , DQA1*0506 , DQA1*0507 , DQA1*0508 , DQA1 *0509 , DQA1 *060101 , DQA1 *060102 , and DQA1 *0602.
1212. The composition according to any of the claims 1-1211, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DQB1 , DQB1*050101 , DQB1*050102 , DQB1*050201 , DQB1*050202 , DQB1*050301 ,
DQB1*050302 , DQB1*0504 , DQB1*0505 , DQB1*020101 , DQB1*020102 , DQB1*0202 , DQB1*0203 , DQB1*0204 , DQB1*0205 , DQB1*030101 , DQB1*030102 , DQB1*030103 , DQB1*030104 , DQB1*030201 , DQB1*030202 , DQB1*030203 , DQB1*030204 , DQB1*030302 , DQB1*030303 , DQB1*0304 , DQB1*030501 , DQB1*030502 , DQB1*030503 ,
DQB1*030504 , DQB1*0306 , DQB1*0307 , DQB1*0308 , DQB1*0309 , DQB1*0310 , DQB1*0311 , DQB1*0312 , DQB1*0313 , DQB1*0314 , DQB1*0315 , DQB1*0316 , DQB1*0317 , DQB1*0318 , DQB1*0319 , DQB1*0320 , DQB1*0321 , DQB1*0322 , DQB1*0323 , DQB1*0324 , DQB1 *0325 , DQB1 *040101 , DQB1 *040102 , DQB1 *0402 , DQB1 *0403 , DQB1*060101 , DQB1*060102 , DQB1*060103 , DQB1*060104 , DQB1*060201 , DQB1*060202 , DQB1*060301 , DQB1*060302 , DQB1*060401 , DQB1*060402 , DQB1*060403 , DQB1*060501 , DQB1*060502 , DQB1*0606 , DQB1*0607 , DQB1*060801 , DQB1*060802 , DQB1 *0609 , DQB1 *0610 , DQB1 *061101 , DQB1 *061102 , DQB1 *0612 ,
DQB1*0613 , DQB1*061401 , DQB1*061402 , DQB1*0615 , DQB1*0616 , DQB1*0617 , DQB1*0618 , DQB1*0619 , DQB1*0620 , DQB1*0621 , DQB1*0622 , DQB1*0623 , DQB1*0624 , DQB1*0625 , DQB1*0626N , DQB1*0627 , DQB1*0628 , DQB1*0629 , DQB1*0630 , DQB1*0631 , DQB1 *0632 , DQB1 *0633 , DQB1 *0634 , and DQB1 *0635.
1213. The composition according to any of the claims 1 -1212, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DPA1, DPA1*010301 , DPA1 *010302 , DPA1 *010303 , DPA1 *010304 , DPA1 *0104 , DPA1 *0105 ,
DPA1*010601 , DPA1*010602 , DPA1*0107 , DPA1*0108 , DPA1*0109 , DPA1 *0110 , DPA1 *020101 , DPA1 *020102 , DPA1 *020103 , DPA1 *020104 , DPA1*020105 , DPA1*020106 , DPA1*020201 , DPA1*020202 , DPA1*020203 DPA1*0203 , DPA1*0204 , DPA1*0301 , DPA1*0302 , DPA1*0303 , and DPA1*0401.
1214. The composition according to any of the claims 1 -1213, wherein the one or more biologically active molecules can be selected from the group of biologically active molecules consisting of HLA-DPB1, DPB1*010101 , DPB1*010102 , DPB1*010103 , DPB1*0102 , DPB1*020102 , DPB1*020103 ,
DPB1*020104 , DPB1*020105 , DPB1*020106 , DPB1*020107 , DPB1*0202 , DPB1*0203 , DPB1*030101 , DPB1*030102 , DPB1*0302 , DPB1*040101 , DPB1*040102 , DPB1*0402 , DPB1*0403 , DPB1*050101 , DPB1*050102 , DPB1*0502 , DPB1*0601 , DPB1*0602 , DPB1*0801 , DPB1*0802 , DPB1*0901 , DPB1*0902 , DPB1*1001 , DPB1*1002 , DPB1*110101 ,
DPB1*110102 , DPB1*1102 , DPB1*1301 , DPB1*1302 , DPB1*1401 , DPB1*1402 , DPB1*1501 , DPB1*1502 , DPB1*1601 , DPB1*1602 , DPB1*1701 , DPB1*1702 , DPB1*1801 , DPB1*1802 , DPB1*1901 , DPB1*1902 , DPB1*200101 , DPB1*200102 , DPB1*2002 , DPB1*2101 , DPB1*2102 , DPB1*2201 , DPB1*2202 , DPB1*2301 , DPB1*2302N , DPB1*2401 , DPB1*2402 , DPB1*2501 , DPB1*2502 , DPB1*260101 , DPB1*260102 , DPB1*2602 , DPB1*2701 , DPB1*2801 , DPB1*2901 , DPB1*3001 , DPB1*3101 , DPB1*3201 , DPB1*3301 , DPB1*3401 , DPB1*3501 , DPB1*3601 , DPB1*3701 , DPB1*3801 , DPB1*3901 , DPB1*4001 , DPB1*410101 , DPB1*410102 , DPB1*4401 , DPB1*4501 ,
DPB1*4601 , DPB1*4701 , DPB1*4801 , DPB1*4901 , DPB1*5001 , DPB1*5101 , DPB1*5201 , DPB1*5301 , DPB1*5401 , DPB1*5501 , DPB1*5601 , DPB1*5701 , DPB1*5801 , DPB1*5901 , DPB1*6001 , DPB1*6101N , DPB1*6201 , DPB1*6301 , DPB1*6401N , DPB1*6501 , DPB1*6601 , DPB1*6701 , DPB1*6801 , DPB1*6901 , DPB1*7001 ,
DPB1*7101 , DPB1*7201 , DPB1*7301 , DPB1*7401 , DPB1*7501 , DPB1*7601 , DPB1*7701 , DPB1*7801 , DPB1*7901 , DPB1*8001 , DPB1*8101 , DPB1*8201 , DPB1*8301 , DPB1*8401 , DPB1*8501 , DPB1*8601 , DPB1*8701 , DPB1*8801 , DPB1*8901 , DPB1*9001 , DPB1*9101 , DPB1*9201 , DPB1*9301 , DPB1*9401 , DPB1*9501 ,
DPB1*9601 , DPB1*9701 , DPB1*9801 , and DPB1*9901.
1215. The composition according to any of claims 1-1214, wherein one or more of the pharmamers comprises the biologically active molecule HSP 70.
1216. The composition according to any of claims 1-1215, wherein one or more of the pharmamers do not comprise the biologically active molecule HSP 70.
1217. The composition according to any of claims 1-1216, wherein one or more of the pharmamers comprises DR*04.
1218. The composition according to any of claims 1-1216, wherein one or more of the pharmamers do not comprises DR*04.
1219. The composition according to any of claims 1-1218, wherein one or more of the pharmamers comprises gp140.
1220. The composition according to any of claims 1-1218, wherein one or more of the pharmamers do not comprise gp140.
1221. The composition according to any of claims 1 -1220, wherein one or more of the pharmamers comprises and/or the composition comprises TiterMax ® Gold.
1222. The composition according to any of claims 1 -1220, wherein one or more of the pharmamers do not comprise and/or the composition do not comprise TiterMax ©Gold.
1223. The composition according to any of claims 1 -1222, wherein one or more of the pharmamers comprises and/or the composition comprises
Aluminiumhydroxide gel or Alhydrogel.
1224. The composition according to any of claims 1 -1222, wherein one or more of the pharmamers do not comprise and/or the composition do not comprise Aluminiumhydroxide gel or Alhydrogel.
1225. The composition according to any of claims 1 -1224, wherein the composition comprises a phamamer with two different biologically active molecules.
1226. The composition according to any of claims 1 -1225, wherein the composition comprises a phamamer with two different biologically active molecules, termed A and B, wherein the molar ratio between A and B can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23,
1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50.
1227. The composition according to any of claims 1 -1226, wherein the composition does not comprises a phamamer with two different biologically active molecules, termed A and B, wherein the molar ratio between A and B can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31 , 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1:50.
1228. The composition according to any of claims 1 -1227, wherein the composition comprises a phamamer with two different biologically active molecules, termed A and B, wherein the molar ratio between A and B can be selected from the group consisting of 1 :0.1-0.5, 1 :0.5-1 , 1 :1-2, 1 :2-3, 1 :3-4, 1 :4- 5, 1:5-6, 1:6-7, 1:7-8, 1:8-9, 1:9-10, 1:10-11, 1:11-12, 1:12-13, 1:13-14, 1:14-15, 1:15-16, 1:16-17, 1:17-18, 1:18-19, 1:19-20, 1:21-22, 1:22-23, 1:23-24, 1:24-25, 1 :25-26, 1 :26-27, 1 :27-28, 1 :28-29, 1 :29-30, 1 :30-35, 1 :35-40, 1 :40-45, and
1 :45-50.
1229. The composition according to any of claims 1 -1228, wherein the composition does not comprises a phamamer with two different biologically active molecules, termed A and B, wherein the molar ratio between A and B can be selected from the group consisting of 1 :0.1-0.5, 1 :0.5-1 , 1 :1-2, 1 :2-3, 1:3-4, 1:4-5, 1:5-6, 1:6-7, 1:7-8, 1:8-9, 1:9-10, 1:10-11, 1:11-12, 1:12-13, 1:13- 14, 1:14-15, 1:15-16, 1:16-17, 1:17-18, 1:18-19, 1:19-20, 1:21-22, 1:22-23, 1 :23-24, 1 :24-25, 1 :25-26, 1 :26-27, 1 :27-28, 1 :28-29, 1 :29-30, 1 :30-35, 1 :35-40, 1 :40-45, and 1 :45-50.
1230. The composition according to any of claims 1 -1229, wherein the composition comprises a phamamer with three different biologically active molecules, termed A, B, and C wherein the molar ratio between A, B and C (A:B:C) can be selected from the group consisting of 1:1:1, 1 :2:1 , 1 :3:1 , 1 :4:1 , ,
1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:11:1, 1:12:1, 1:13:1, 1:14:1, 1:15:1, 1:16:1, , 1:17:1, 1:18:1, 1:19:1, 1:20:1, 1:21:1, 1:22:1, 1:23:1, 1:24:1, 1:25:1, 1 :26:1 , 1 :27:1 , , 1 :28:1 , 1 :29:1 , 1 :30:1 , 1 :31 :1 , 1 :32:1 , 1 :33:1 , 1 :34:1 , 1 :35:1 , 1 :36:1 , 1 :37:1 , 1 :38:1 , 1 :39:1 , 1 :40:1 , 1 :41 :1 , 1 :42:1 , 1 :43:1 , 1 :44:1 , 1 :45:1 , 1 :46:1 , 1 :47:1 , 1 :48:1 , and 1 :49:1 , and 1 :50:1.
1231. The composition according to any of claims 1 -1230, wherein the composition comprises a phamamer with three different biologically active molecules, termed A, B, and C wherein the molar ratio between A, B and C (A:B:C) can be selected from the group consisting of 1:1:1, 1 :2:1 , 1 :3:1 , 1 :4:1 , , 1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:11:1, 1:12:1, 1:13:1, 1:14:1, 1:15:1, 1:16:1, , 1:17:1, 1:18:1, 1:19:1, 1:20:1, 1:21:1, 1:22:1, 1:23:1, 1:24:1, 1:25:1, 1 :26:1 , 1 :27:1 , , 1 :28:1 , 1 :29:1 , 1 :30:1 , 1 :31 :1 , 1 :32:1 , 1 :33:1 , 1 :34:1 , 1 :35:1 , 1 :36:1 , 1 :37:1 , 1 :38:1 , 1 :39:1 , 1 :40:1 , 1 :41 :1 , 1 :42:1 , 1 :43:1 , 1 :44:1 , 1 :45:1 , 1 :46:1 , 1 :47:1 , 1 :48:1 , and 1 :49:1 , and 1 :50:1.
1232. The composition according to any of claims 1 -1231 , wherein the composition does not comprise a phamamer with three different biologically active molecules, termed A, B, and C wherein the molar ratio between A, B and C (A:B:C) can be selected from the group consisting of 1:1:1, 1 :2:1 , 1 :3:1 , 1 :4:1 ,
1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:11:1, 1:12:1, 1:13:1, 1:14:1, 1:15:1, 1:16:1, , 1:17:1, 1:18:1, 1:19:1, 1:20:1, 1:21:1, 1:22:1, 1:23:1, 1:24:1, 1:25:1, 1 :26:1 , 1 :27:1 , , 1 :28:1 , 1 :29:1 , 1 :30:1 , 1 :31 :1 , 1 :32:1 , 1 :33:1 , 1 :34:1 , 1 :35:1 , 1 :36:1 , 1 :37:1 , 1 :38:1 , 1 :39:1 , 1 :40:1 , 1 :41 :1 , 1 :42:1 , 1 :43:1 , 1 :44:1 , 1 :45:1 , 1 :46:1 , 1 :47:1 , 1 :48:1 , and 1 :49:1 , and 1 :50:1.
1233. The composition according to any of claims 1 -1232, wherein the composition comprises a phamamer consiting of a multimerization domain and two different biologically active molecules, termed A, and B.
1234. The composition according to any of claims 1 -1233, wherein the composition comprises a phamamer consiting of a multimerization domain and three different biologically active molecules, termed A, B, and C.
1235. The composition according to any of claims 1 -1234, wherein the composition comprises a phamamer consiting of a multimerization domain and four different biologically active molecules, termed A, B, C, and D.
1236. The composition according to any of claims 1 -1235, wherein the composition comprises a phamamer consiting of a multimerization domain and five different biologically active molecules, termed A, B, C, D and E.
1237. The composition according to any of claims 1 -1236, wherein the composition comprises a phamamer consiting of a multimerization domain and six different biologically active molecules, termed A, B, C, D, E and F.
1238. The composition according to any of claims 1 -1237, wherein the composition comprises a phamamer consiting of a multimerization domain and seven different biologically active molecules, termed A, B, C, D, E, F, and G.
1239. The composition according to any of claims 1233-1238, wherein the molar ratio between the multimerization domain and the biologically active molecule A (molar multimerization domain:molar biologically active molecule A) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22,
1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31 , 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1240. The composition according to any of claims 1233-1239, wherein the molar ratio between the multimerization domain and the biologically active molecule A (molar multimerization domain:molar biologically active molecule A) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34,
1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1241. The composition according to any of claims 1233-1240, wherein the molar ratio between the multimerization domain and the biologically active molecule B (molar multimerization domain:molar biologically active molecule B) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and
1 :50 and any ranges combined by these ratioes.
1242. The composition according to any of claims 1233-1240, wherein the molar ratio between the multimerization domain and the biologically active molecule B (molar multimerization domain:molar biologically active molecule B) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1243. The composition according to any of claims 1234-1242, wherein the molar ratio between the multimerization domain and the biologically active molecule C (molar multimerization domain:molar biologically active molecule C) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8,
1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1244. The composition according to any of claims 1234-1242, wherein the molar ratio between the multimerization domain and the biologically active molecule C (molar multimerization domain:molar biologically active molecule C) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20,
1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1245. The composition according to any of claims 1235-1244, wherein the molar ratio between the multimerization domain and the biologically active molecule D (molar multimerization domain:molar biologically active molecule D) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36,
1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1246. The composition according to any of claims 1235-1244, wherein the molar ratio between the multimerization domain and the biologically active molecule D (molar multimerization domairrmolar biologically active molecule D) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48,
1 :49, and 1 :50 and any ranges combined by these ratioes.
1247. The composition according to any of claims 1236-1246, wherein the molar ratio between the multimerization domain and the biologically active molecule E (molar multimerization domain:molar biologically active molecule E) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1248. The composition according to any of claims 1236-1246, wherein the molar ratio between the multimerization domain and the biologically active molecule E (molar multimerization domain:molar biologically active molecule E) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6,
1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1249. The composition according to any of claims 1237-1248, wherein the molar ratio between the multimerization domain and the biologically active molecule F (molar multimerization domain:molar biologically active molecule F) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22,
1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1250. The composition according to any of claims 1237-1248, wherein the molar ratio between the multimerization domain and the biologically active molecule F (molar multimerization domain:molar biologically active molecule F) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20,
1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1251. The composition according to any of claims 1238-1250, wherein the molar ratio between the multimerization domain and the biologically active molecule G (molar multimerization domain:molar biologically active molecule G) can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36,
1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1252. The composition according to any of claims 1238-1250, wherein the molar ratio between the multimerization domain and the biologically active molecule G (molar multimerization domain:molar biologically active molecule G) is different from one or more of the following ratios 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1 :22, 1 :23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48,
1 :49, and 1 :50 and any ranges combined by these ratioes.
1253. The composition according to any of claims 1 -1252, wherein the composition comprises two different pharmamers, wherein the first phamamer can be any pharmamer according to any of claims 1 -1252, and wherein the second pharmamer can be any pharmamer according to any of claims 1-1252.
1254. The composition according to any of claims 1 -1252, wherein the composition comprises three different pharmamers, wherein the first phamamer can be any pharmamer according to any of claims 1 -1252, wherein the second pharmamer can be any pharmamer according to any of claims 1 -1252, and wherein the third pharmamer can be any phamamer according to any of claims 1-1252.
1255. The composition according to any of claims 1 -1252, wherein the composition comprises four different pharmamers, wherein the first phamamer can be any pharmamer according to any of claims 1-1252, wherein the second pharmamer can be any pharmamer according to any of claims 1 -1252, wherein the third pharmamer can be any phamamer according to any of claims 1-1252, and wherein the fourth pharmamer can be any pharmamer according to any of the claims 1-1252.
1256. The composition according to any of claims 1 -1252, wherein the composition comprises four different pharmamers, wherein the first phamamer can be any pharmamer according to any of claims 1 -1252, wherein the second pharmamer can be any pharmamer according to any of claims 1 -1252, wherein the third pharmamer can be any phamamer according to any of claims 1-1252, wherein the fourth pharmamer can be any pharmamer according to any of the claims 1-1252, and wherein the fifth pharmamer can be any pharmamer according to any of the claims 1 -1252.
1257. The composition according to any of the claims 1253-1256, wherein the molar ratio between the first pharmamer and the second pharmamer can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23,
1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1258. The composition according to any of the claims 1253-1256, wherein the molar ratio between the first pharmamer and the second pharmamer differes from one or more of the ratios 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31 , 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1259. The composition according to any of the claims 1253-1258, wherein the molar ratio between the first pharmamer and the third pharmamer can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1260. The composition according to any of the claims 1253-1258, wherein the molar ratio between the first pharmamer and the third pharmamer differes from one or more of the ratios 1:1, 1:2, 1:3, 1 :4, 1 :5, 1 :6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25,
1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1261. The composition according to any of the claims 1253-1260, wherein the molar ratio between the first pharmamer and the fourth pharmamer can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1262. The composition according to any of the claims 1253-1260, wherein the molar ratio between the first pharmamer and the fourth pharmamer differes from one or more of the ratios 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10,
1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31 , 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1263. The composition according to any of the claims 1253-1262, wherein the molar ratio between the first pharmamer and the fifth pharmamer can be selected from the group consisting of 1:1, 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1 :24, 1 :25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1:31, 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37,
1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1264. The composition according to any of the claims 1253-1262, wherein the molar ratio between the first pharmamer and the fifth pharmamer differes from one or more of the ratios 1 :1 , 1 :2, 1 :3, 1 :4, 1 :5, 1 :6, 1 :7, 1 :8, 1 :9, 1 :10, 1 :11 , 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1 :26, 1 :27, 1 :28, 1 :29, 1 :30, 1 :31 , 1 :32, 1 :33, 1 :34, 1 :35, 1 :36, 1 :37, 1 :38, 1 :39, 1 :40, 1:41, 1 :42, 1 :43, 1 :44, 1 :45, 1 :46, 1 :47, 1 :48, 1 :49, and 1 :50 and any ranges combined by these ratioes.
1265. The composition according to any of claims 1 -1264, wherein the one or more pharmamers are different.
1266. The composition according to any of claims 1 -1265, wherein the one or more pharmamers are identical.
1267. The composition according to any of claims 1 -1265, wherein some of the one or more pharmamers are identical and some of the one or more pharmamers are different.
1268. The composition according to any of claims 1 -1267 further comprising one or more adjuvants.
1269. The composition according to any of claims 1 -1268 further comprising one or more adjuvants that are not linked to the one or more pharmamers.
1270. The composition according to any of claims 1 -1269 further comprising one or more adjuvants that are linked to one or more of the one or more pharmamers.
1271. The composition according to any of claims 1 -1270 further comprising one or more adjuvants that are linked another component in the composition than the one or more pharmamers.
1272. The composition according to any of claims 1 -1271 further comprising one or more adjuvants that are not linked another component in the composition than the one or more pharmamers.
1273. The composition according to any of claims 1266-1272, wherein the one or more adjuvants can be any adjuvant according to any of the previous claims.
1274. The composition according to any of claims 1 -1273 further comprising one or more biologically active molecules.
1275. The composition according to any of claims 1 -1274 further comprising one or more biologically active molecules that are not linked to the one or more pharmamers.
1276. The composition according to any of claims 1 -1275 further comprising one or more biologically active molecules that are linked to one or more of the one or more pharmamers.
1277. The composition according to any of claims 1 -1276 further comprising one or more biologically active molecules that are linked another component in the composition than the one or more pharmamers.
1278. The composition according to any of claims 1 -1277 further comprising one or more biologically active molecules that are not linked another component in the composition than the one or more pharmamers.
1279. The composition according to any of claims 1266-1278, wherein the one or more biologically active molecules can be any biologically active molecule according to any of the previous claims.
1280. The composition according to any of claims 1 -1279 further comprising one or more vaccine enhancers.
1281. The composition according to any of claims 1 -1280 further comprising one or more vaccine enhancers that are not linked to the one or more pharmamers.
1282. The composition according to any of claims 1 -1281 further comprising one or more vaccine enhancers that are linked to one or more of the one or more pharmamers.
1283. The composition according to any of claims 1 -1282 further comprising one or more vaccine enhancers that are linked another component in the composition than the one or more pharmamers.
1284. The composition according to any of claims 1 -1283 further comprising one or more vaccine enhancers that are not linked another component in the composition than the one or more pharmamers.
1285. The composition according to any of claims 1280-1284, wherein the one or more vaccine enhancers can be any vaccine enhancers according to any of the previous claims.
1286. The composition according to any of claims 1 -1285 further comprising one or more other vaccines.
1287. The composition according to any of claims 1 -1286 further comprising one or more other vaccines that are not linked to the one or more pharmamers.
1288. The composition according to any of claims 1 -1287 further comprising one or more other vaccines that are linked to one or more of the one or more pharmamers.
1289. The composition according to any of claims 1 -1288 further comprising one or more other vaccines that are linked another component in the composition than the one or more pharmamers.
1290. The composition according to any of claims 1 -1289 further comprising one or more other vaccines that are not linked another component in the composition than the one or more pharmamers.
1291. The compostion according to any of claims 1 -1290, wherein the coupling between the multimerization domain and the one or more biologically active molecules is the same type of coupling as the association between the MHC peptide complex and the multimerization domain in the MHC multimer according to claims 92-601.
1292. A method of making the composition according to any of claims 1 -1291 .
1293. A method for vaccination comprising administration to an individual in need thereof an effective amount of the composition according to any of claims 1 -1291.
1294. The method for vaccination according to claim 1293, wherein each dosage unit of said composition comprises in the range of 0.01 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 1 μg, for example in the range of 0.1 to 1 μg, such as in the range of 0.05 to 0.8 μg, for example in the range of 0.05 to 0.6 μg, such as in the range of 0.05 to 0.4 μg, for example in the range of 0.05 to 0.2 μg, such as in the range of 0.1 to 0.8 μg, for example in the range of 0.1 to 0.6 μg, such as in the range of 0.1 to 0.5 μg, for example in the range of 0.1 to 0.4 μg, such as in the range of 0.1 to 0.3 μg, for example in the range of 0.1 to 0.2 μg of pharmamer and/or peptide.
1295. The method for vaccination according to any of claims 1293-1294, wherein the daily dosage of the composition comprises pharmamer in the range from 0.001 to 1 ,000 mg per adult human/per day, such as from 0.001 to 0.005 mg per adult human/per day, for example from 0.005 to 0.01 mg per adult human/per day, such as from 0.01 to 0.05 mg per adult human/per day, for example from 0.05 to 0.1 mg per adult human/per day, such as from 0.1 to 0.5 mg per adult human/per day, for example from 0.5 to 1 mg per adult human/per day, such as from 1 to 5 mg per adult human/per day, for example from 5 to 10 mg per adult human/per day, such as from 10 to 50 mg per adult human/per day, for example from 50 to 100 mg per adult human/per day, such as from 100 to 500 mg per adult human/per day, for example from 500 to 1000 mg per adult human/per day.
1296. The method for vaccination according to any of claims 1293-1295, wherein the vaccination comprises oral administration of scored or unscored tablets containing e.g. 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, or 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
1297. The method for vaccination according to any of claims 1293-1296, wherein the composition is administered at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about
0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day.
1298. The method for vaccination according to any of claims 1293-1297, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of pharmamer.
1299. The method for vaccination according to any of claims 1293-1298, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of peptide(s)., , The method for vaccination according to any of claims 1293-1082, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of biologically active molecule.
1300. The method for vaccination according to any of claims 1293-1299, wherein the composition is administered at a dosage level comprising of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day, such as from about 0.0001 mg/kg to about 0.0005 mg/kg of body weight per day, for example from about 0.0005 mg/kg to about 0.001 mg/kg of body weight per day, such as from about 0.001 mg/kg to about 0.005 mg/kg of body weight per day, for example from about 0.005 mg/kg to about 0.01 mg/kg of body weight per day, such as from about 0.01 mg/kg to about 0.05 mg/kg of body weight per day, for example from about 0.05 mg/kg to about 0.1 mg/kg of body weight per day, such as from about 0.1 mg/kg to about 0.5 mg/kg of body weight per day, for example from about 0.5 mg/kg to about 1 mg/kg of body weight per day, such as from about 1 mg/kg to about 5 mg/kg of body weight per day, for example from about 5 mg/kg to about 10 mg/kg of body weight per day, such as from about 10 mg/kg to about 50 mg/kg of body weight per day, for example from about 50 mg/kg to about 100 mg/kg of body weight per day of adjuvans.
1301. The method for vaccination according to any of claims 1293-1300, wherein the composition is administered at a dosage level comprising of from about 10 μg/kg to about 1500 μg/kg of body weight per administration, such as from about 10 μg/kg to about 30 μg/kg of body weight per administration, such as from about 30 μg/kg to about 50 μg/kg of body weight per administration, such as from about 50 μg/kg to about 70 μg/kg of body weight per administration, such as from about 70 μg/kg to about 90 μg/kg of body weight per administration, such as from about 90 μg/kg to about 1 10 μg/kg of body weight per administration, such as from about 1 10 μg/kg to about 130 μg/kg of body weight per administration, such as from about 130 μg/kg to about 150 μg/kg of body weight per administration, such as from about 150 μg/kg to about 170 μg/kg of body weight per administration, such as from about 170 μg/kg to about 190 μg/kg of body weight per administration, such as from about 190 μg/kg to about 210 μg/kg of body weight per administration, such as from about
210 μg/kg to about 230 μg/kg of body weight per administration, such as from about 230 μg/kg to about 250 μg/kg of body weight per administration, such as from about 250 μg/kg to about 270 μg/kg of body weight per administration, such as from about 270 μg/kg to about 290 μg/kg of body weight per administration, such as from about 290 μg/kg to about 310 μg/kg of body weight per administration, such as from about 310 μg/kg to about 330 μg/kg of body weight per administration, such as from about 330 μg/kg to about 350 μg/kg of body weight per administration, such as from about 350 μg/kg to about 370 μg/kg of body weight per administration, such as from about 370 μg/kg to about 390 μg/kg of body weight per administration, such as from about 390 μg/kg to about 410 μg/kg of body weight per administration, such as from about 410 μg/kg to about 430 μg/kg of body weight per administration, such as from about 430 μg/kg to about 450 μg/kg of body weight per administration, such as from about 450 μg/kg to about 470 μg/kg of body weight per administration, such as from about 470 μg/kg to about 490 μg/kg of body weight per administration, such as from about 490 μg/kg to about 510 μg/kg of body weight per administration, such as from about 510 μg/kg to about 530 μg/kg of body weight per administration, such as from about 530 μg/kg to about 550 μg/kg of body weight per administration, such as from about 550 μg/kg to about 570 μg/kg of body weight per administration, such as from about 570 μg/kg to about 590 μg/kg of body weight per administration, such as from about 590 μg/kg to about 610 μg/kg of body weight per administration, such as from about 610 μg/kg to about 630 μg/kg of body weight per administration, such as from about 630 μg/kg to about 650 μg/kg of body weight per administration, such as from about 650 μg/kg to about 670 μg/kg of body weight per administration, such as from about 670 μg/kg to about 690 μg/kg of body weight per administration, such as from about 690 μg/kg to about 710 μg/kg of body weight per administration, such as from about 710 μg/kg to about 730 μg/kg of body weight per administration, such as from about 730 μg/kg to about 750 μg/kg of body weight per administration, such as from about 750 μg/kg to about 770 μg/kg of body weight per administration, such as from about 770 μg/kg to about 790 μg/kg of body weight per administration, such as from about 790 μg/kg to about 810 μg/kg of body weight per administration, such as from about 810 μg/kg to about 830 μg/kg of body weight per administration, such as from about 830 μg/kg to about 850 μg/kg of body weight per administration, such as from about 850 μg/kg to about 870 μg/kg of body weight per administration, such as from about 870 μg/kg to about 890 μg/kg of body weight per administration, such as from about 890 μg/kg to about 910 μg/kg of body weight per administration, such as from about 910 μg/kg to about 930 μg/kg of body weight per administration, such as from about 930 μg/kg to about 950 μg/kg of body weight per administration, such as from about 950 μg/kg to about 970 μg/kg of body weight per administration, such as from about 970 μg/kg to about 990 μg/kg of body weight per administration, such as from about 990 μg/kg to about 1010 μg/kg of body weight per administration, such as from about 1010 μg/kg to about 1030 μg/kg of body weight per administration, such as from about 1030 μg/kg to about 1050 μg/kg of body weight per administration, such as from about 1050 μg/kg to about 1070 μg/kg of body weight per administration, such as from about 1070 μg/kg to about 1090 μg/kg of body weight per administration, such as from about 1090 μg/kg to about 1 1 10 μg/kg of body weight per administration, such as from about 1 1 10 μg/kg to about 1 130 μg/kg of body weight per administration, such as from about 1 130 μg/kg to about 1 150 μg/kg of body weight per administration, such as from about 1 150 μg/kg to about 1 170 μg/kg of body weight per administration, such as from about 1 170 μg/kg to about 1 190 μg/kg of body weight per administration, such as from about 1 190 μg/kg to about 1210 μg/kg of body weight per administration, such as from about 1210 μg/kg to about 1230 μg/kg of body weight per administration, such as from about 1230 μg/kg to about 1250 μg/kg of body weight per administration, such as from about 1250 μg/kg to about 1270 μg/kg of body weight per administration, such as from about 1270 μg/kg to about 1290 μg/kg of body weight per administration, such as from about 1290 μg/kg to about 1310 μg/kg of body weight per administration, such as from about 1310 μg/kg to about 1330 μg/kg of body weight per administration, such as from about 1330 μg/kg to about 1350 μg/kg of body weight per administration, such as from about 1350 μg/kg to about 1370 μg/kg of body weight per administration, such as from about 1370 μg/kg to about 1390 μg/kg of body weight per administration, such as from about 1390 μg/kg to about 1410 μg/kg of body weight per administration, such as from about 1410 μg/kg to about 1430 μg/kg of body weight per administration, such as from about 1430 μg/kg to about 1450 μg/kg of body weight per administration, such as from about 1450 μg/kg to about 1470 μg/kg of body weight per administration, such as from about 1470 μg/kg to about 1490 μg/kg of body weight per administration, such as from about 1490 μg/kg to about 1500 μg/kg of body weight per administration, or any combination thereof. 2. The method for vaccination according to any of claims 1293-1301 , wherein the composition is not administered at a dosage level selected from the group consinting of from about 10 μg/kg to about 30 μg/kg of body weight per administration, from about 30 μg/kg to about 50 μg/kg of body weight per administration, from about 50 μg/kg to about 70 μg/kg of body weight per administration, from about 70 μg/kg to about 90 μg/kg of body weight per administration, from about 90 μg/kg to about 1 10 μg/kg of body weight per administration, from about 1 10 μg/kg to about 130 μg/kg of body weight per administration, from about 130 μg/kg to about 150 μg/kg of body weight per administration, from about 150 μg/kg to about 170 μg/kg of body weight per administration, from about 170 μg/kg to about 190 μg/kg of body weight per administration, from about 190 μg/kg to about 210 μg/kg of body weight per administration, from about 210 μg/kg to about 230 μg/kg of body weight per administration, from about 230 μg/kg to about 250 μg/kg of body weight per administration, from about 250 μg/kg to about 270 μg/kg of body weight per administration, from about 270 μg/kg to about 290 μg/kg of body weight per administration, from about 290 μg/kg to about 310 μg/kg of body weight per administration, from about 310 μg/kg to about 330 μg/kg of body weight per administration, from about 330 μg/kg to about 350 μg/kg of body weight per administration, from about 350 μg/kg to about 370 μg/kg of body weight per administration, from about 370 μg/kg to about 390 μg/kg of body weight per administration, from about 390 μg/kg to about 410 μg/kg of body weight per administration, from about 410 μg/kg to about 430 μg/kg of body weight per administration, from about 430 μg/kg to about 450 μg/kg of body weight per administration, from about 450 μg/kg to about 470 μg/kg of body weight per administration, from about 470 μg/kg to about 490 μg/kg of body weight per administration, from about 490 μg/kg to about 510 μg/kg of body weight per administration, from about 510 μg/kg to about 530 μg/kg of body weight per administration, from about 530 μg/kg to about 550 μg/kg of body weight per administration, from about 550 μg/kg to about 570 μg/kg of body weight per administration, from about 570 μg/kg to about 590 μg/kg of body weight per administration, from about 590 μg/kg to about 610 μg/kg of body weight per administration, from about 610 μg/kg to about 630 μg/kg of body weight per administration, from about 630 μg/kg to about 650 μg/kg of body weight per administration, from about 650 μg/kg to about 670 μg/kg of body weight per administration, from about 670 μg/kg to about 690 μg/kg of body weight per administration, from about 690 μg/kg to about 710 μg/kg of body weight per administration, from about 710 μg/kg to about 730 μg/kg of body weight per administration, from about 730 μg/kg to about 750 μg/kg of body weight per administration, from about 750 μg/kg to about 770 μg/kg of body weight per administration, from about 770 μg/kg to about 790 μg/kg of body weight per administration, from about 790 μg/kg to about 810 μg/kg of body weight per administration, from about 810 μg/kg to about 830 μg/kg of body weight per administration, from about 830 μg/kg to about 850 μg/kg of body weight per administration, from about 850 μg/kg to about 870 μg/kg of body weight per administration, from about 870 μg/kg to about 890 μg/kg of body weight per administration, from about 890 μg/kg to about 910 μg/kg of body weight per administration, from about 910 μg/kg to about 930 μg/kg of body weight per administration, from about 930 μg/kg to about 950 μg/kg of body weight per administration, from about 950 μg/kg to about 970 μg/kg of body weight per administration, from about 970 μg/kg to about 990 μg/kg of body weight per administration, from about 990 μg/kg to about 1010 μg/kg of body weight per administration, from about 1010 μg/kg to about 1030 μg/kg of body weight per administration, from about 1030 μg/kg to about 1050 μg/kg of body weight per administration, from about 1050 μg/kg to about 1070 μg/kg of body weight per administration, from about 1070 μg/kg to about 1090 μg/kg of body weight per administration, from about 1090 μg/kg to about 1 1 10 μg/kg of body weight per administration, from about 1 1 10 μg/kg to about 1 130 μg/kg of body weight per administration, from about 1 130 μg/kg to about 1 150 μg/kg of body weight per administration, from about 1 150 μg/kg to about 1 170 μg/kg of body weight per administration, from about 1 170 μg/kg to about 1 190 μg/kg of body weight per administration, from about 1 190 μg/kg to about 1210 μg/kg of body weight per administration, from about 1210 μg/kg to about 1230 μg/kg of body weight per administration, from about 1230 μg/kg to about 1250 μg/kg of body weight per administration, from about 1250 μg/kg to about 1270 μg/kg of body weight per administration, from about 1270 μg/kg to about 1290 μg/kg of body weight per administration, from about 1290 μg/kg to about 1310 μg/kg of body weight per administration, from about 1310 μg/kg to about 1330 μg/kg of body weight per administration, from about 1330 μg/kg to about 1350 μg/kg of body weight per administration, from about 1350 μg/kg to about 1370 μg/kg of body weight per administration, from about 1370 μg/kg to about 1390 μg/kg of body weight per administration, from about 1390 μg/kg to about 1410 μg/kg of body weight per administration, from about 1410 μg/kg to about 1430 μg/kg of body weight per administration, from about 1430 μg/kg to about 1450 μg/kg of body weight per administration, from about 1450 μg/kg to about 1470 μg/kg of body weight per administration, from about 1470 μg/kg to about 1490 μg/kg of body weight per administration, from about 1490 μg/kg to about 1500 μg/kg of body weight per administration, or any combination thereof.
1303. The method for vaccination according to any of claims 1293-1302, wherein the individual in need thereof is a mammal.
1304. The method for vaccination according to any of claims 1293-1303, wherein the individual in need thereof is a human being.
1305. The method for vaccination according to any of claims 1293-1304, wherein the individual in need thereof is a newborn.
1306. The method for vaccination according to any of claims 1293-1304, wherein the individual in need thereof is a child.
1307. The method for vaccination according to any of claims 1293-1304, wherein the individual in need thereof is an adult.
1308. The method for vaccination according to any of claims 1293-1307, wherein the individual in need thereof is a woman/female.
1309. The method for vaccination according to any of claims 1293-1307, wherein the individual in need thereof is a man/male.
1310. The method for vaccination according to any of claims 1293-1309, wherein the individual in need thereof is of any age such as from newborn to 120 years old, for example from 0 to 6 months, such as from 6 to 12 months, for example from 1 to 5 years, such as from 5 to 10 years, for example from 10 to 15 years, such as from 15 to 20 years, for example from 20 to 25 years, such as from 25 to 30 years, for example from 30 to 35 years, such as from 35 to 40 years, for example from 40 to 45 years, such as from 45 to 50 years, for example from 50 to 60 years, such as from 60 to 70 years, for example from 70 to 80 years, such as from 80 to 90 years, for example from 90 to 100 years, such as from 100 to 1 10 years, for example from 1 10 to 120 years.
131 1. The method for vaccination according to any of claims 1293-1310, wherein the individual in need thereof is of any race such as a Caucasian, a black person, an East Asian person, a person of Mongoloid race, a person of Ethiopian race, a person of Negroid race, a person of American Indian race, or a person of Malayan race.
1312. The method for vaccination according to any of claims 1293-131 1 , wherein the individual in need thereof is healthy.
1313. The method for vaccination according to any of claims 1293-131 1 , wherein the individual in need thereof is ill.
1314. The method for vaccination according to any of claims 1293-1313, wherein the individual in need thereof is diagnosed with one or more diseases.
1315. The method for vaccination according to any of claims 1293-1314, wherein the individual in need thereof has one or more symptoms of one or more diseases.
1316. The method for vaccination according to any of claims 1293-1315, wherein the individual in need thereof is asymptomatic.
1317. The method for vaccination according to any of claims 1293-1316, wherein the individual in need thereof is genetically disposed for one or more diseases.
1318. The method for vaccination according to any of claims 1293-1317, wherein the individual in need thereof is an animal.
1319. The method for vaccination according to any of claims 1293-1318, wherein the individual in need thereof is a bird.
1320. The method for vaccination according to any of claims 1293-1318, wherein the individual in need thereof is an insect.
1321. The method for vaccination according to any of claims 1293-1317, wherein the individual in need thereof is a plant.
1322. The method for vaccination according to any of claims 1293-1321 , wherein the method comprises administration of said composition by oral administration.
1323. The method for vaccination according to any of claims 1293-1322, wherein the method comprises administration of said composition by sublingual administration.
1324. The method for vaccination according to any of claims 1293-1323, wherein the method comprises administration of said composition by nasal administration.
1325. The method for vaccination according to any of claims 1293-1324, wherein the method comprises administration of said composition by inhalation.
1326. The method for vaccination according to any of claims 1293-1325, wherein the method comprises administration of said composition by injection.
1327. The method for vaccination according to any of claims 1293-1326, wherein the method comprises administration of said composition by intravenous administration.
1328. The method for vaccination according to any of claims 1293-1327, wherein the method comprises administration of said composition by intramuscular administration.
1329. The method for vaccination according to any of claims 1293-1328, wherein the method comprises administration of said composition by intrathecal administration.
1330. The method for vaccination according to any of claims 1293-1329, wherein the method comprises administration of said composition by subcutan administration.
1331 . The method for vaccination according to any of claims 1293-1330, wherein the method comprises administration of said composition by implantation.
1332. The method for vaccination according to any of claims 1293-1331 , wherein the method comprises administration of said composition by rectal administration.
1333. The method for vaccination according to any of claims 1293-1332, wherein the method does not comprise administration of said composition by rectal administration.
1334. The method for vaccination according to any of claims 1293-1333, wherein the method comprises administration of said composition by vaginal administration.
1335. The method for vaccination according to any of claims 1293-1334, wherein the method does not comprise administration of said composition by vaginal administration.
1336. The method for vaccination according to any of claims 1293-1335, wherein the method comprises administration of said composition by the ocular route.
1337. The method for vaccination according to any of claims 1293-1336, wherein the method comprises administration of said composition by applying it to the skin (cutaneously) for a local (topical) effect.
1338. The method for vaccination according to any of claims 1293-1337, wherein the method comprises administration of said composition by applying it to the skin (cutaneously) for bodywide (systemic) effect.
1339. The method for vaccination according to any of claims 1293-1338, wherein the method comprises administration of said composition by delivering it through the skin (transdermal^) for a systemic effect.
1340. The method for vaccination according to any of claims 1293-1339, wherein the method comprises administration of said composition by inter peritoneal injection.
1341. The method for vaccination according to any of claims 1293-1340, wherein the method comprises administration of said composition by transmucosal administration.
1342. The method for vaccination according to any of claims 1293-1341 , wherein the method comprises administration of said composition by inoculation.
1343. The method for vaccination according to any of claims 1293-1342, wherein the method comprises administration of said composition by intravenous injection.
1344. The method for vaccination according to any of claims 1293-1343, wherein the method does not comprise administration of said composition by intravenous injection.
1345. The method for vaccination according to any of claims 1293-1344, wherein the method comprises administration of said composition by subcutaneous injection.
1346. The method for vaccination according to any of claims 1293-1345, wherein the method does not comprise administration of said composition by subcutaneous injection.
1347. The method for vaccination according to any of claims 1293-1346, wherein the method comprises administration of said composition by intradermal injection.
1348. The method for vaccination according to any of claims 1293-1347, wherein the method does not comprise administration of said composition by intradermal injection.
1349. The method for vaccination according to any of claims 1293-1348, wherein the composition is administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half- full dose at 4, 8, and 16 weeks.
1350. The method for vaccination according to any of claims 1293-1349, wherein the composition is not administered as intramuscular injections at time points 0, 4, 8, and 16 weeks such that a full dose is given at 0 weeks and half- full dose at 4, 8, and 16 weeks.
1351 . The method for vaccination according to any of claims 1293-1350, wherein the composition is administered as intramuscular injections at time points 0, 2, 4, 6, 8, 10, 12 and 14 weeks such that a full dose is given at each time point.
1352. The method for vaccination according to any of claims 1293-1351 , wherein the composition is not administered as intramuscular injections at time points 0, 2, 4, 6, 8, 10, 12 and 14 weeks such that a full dose is given at each time point.
1353. The method for vaccination according to any of claims 1293-1352, wherein the method comprises administration of a single dose of said composition.
1354. The method for vaccination according to any of claims 1293-1353, wherein the method comprises administration of several doses of said composition such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 doses.
1355. The method for vaccination according to any of claims 1293-1354, wherein the method comprises administration of said composition only once.
1356. The method for vaccination according to any of claims 1293-1355, wherein the method comprises administration of said composition more than once such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 times.
1357. The method for vaccination according to any of claims 1293-1356, wherein the method comprises administration of said composition more than once with administration with intervals of a day.
1358. The method for vaccination according to any of claims 1293-1357, wherein the method comprises administration of said composition more than once with administration with intervals of a days, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 days.
1359. The method for vaccination according to any of claims 1293-1358, wherein the method comprises administration of said composition more than once with administration with intervals of about a week.
1360. The method for vaccination according to any of claims 1293-1359, wherein the method comprises administration of said composition more than once with administration with intervals of about two weeks.
1361. The method for vaccination according to any of claims 1293-1360, wherein the method comprises administration of said composition more than once with administration with intervals of about three weeks.
1362. The method for vaccination according to any of claims 1293-1361 , wherein the method comprises administration of said composition more than once with administration with intervals of about a month.
1363. The method for vaccination according to any of claims 1293-1362, wherein the method comprises administration of said composition more than once with administration with intervals of several months, such as 2, 3,4, 5, 6, 7,
8, 9, 10, 1 1 or 12 months.
1364. The method for vaccination according to any of claims 1293-1363, wherein the method comprises administration of said composition more than once with administration with intervals of years, such as 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 14, 16, 18, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or 1 10 years.
1365. The method for vaccination according to any of claims 1293-1364, wherein the method comprises a continuous administration regime of said composition e.g. like up to four doses per week, followed by one month without administrations, followed by up to four doses per week.
1366. The method for vaccination according to any of claims 1293-1365, wherein the method comprises a vaccination protocol where administration is performed e.g. on week 0, 4, 8, and 16; or on week 0, 2, 4, 6, 8, 10, 12, and 14; or on week 0, 5, 1 1 , 17; or on month 0, 1 , and 2; or on day 0, 7, and 30; or every year.
1367. The method for vaccination according to any of claims 1293-1366, wherein the method comprises administration of said composition more than once and wherein the amount of phamamer and/or peptide is increased from the first administration to one or more of the subsequent administrations.
1368. The method for vaccination according to any of claims 1293-1367, wherein the method comprises administration of said composition more than once and wherein the amount of phamamer and/or peptide is decreased from the first administration to one or more of the subsequent administrations.
1369. The method for vaccination according to any of claims 1293-1368, wherein the method comprises administration of said composition more than once and wherein the ratio of biologically active molecules in said composition is modified from the first administration to one or more of the subsequent administrations.
1370. The method for vaccination according to any of claims 1293-1369, wherein the method comprises administration of said composition more than once and wherein the type of adjuvant(s) in said composition is modified from the first administration to one or more of the subsequent administrations.
1371. The method for vaccination according to any of claims 1293-1370, wherein the method comprises administration of said composition more than once and wherein the amount of one or more adjuvant(s) in said composition is modified from the first administration to one or more of the subsequent administrations.
1372. The method for vaccination according to any of claims 1293-1371 , wherein the method comprises administration of said composition more than once and wherein the combination of adjuvants in said composition is modified from the first administration to one or more of the subsequent administrations.
1373. The method for vaccination according to any of claims 1293-1372, wherein the method comprises use of an administration protocol linked to age of the individual in need of said vaccine.
1374. The method for vaccination according to any of claims 1293-1373, wherein the method comprises use of an administration protocol for childhood vaccines e.g. wherein the vaccine is administered at the age of 3 month, 5, month, and 12 month; or 3 month, 5, month, 12 month, and 5 years; or 15 month, and 4 years.
1375. The method for vaccination according to any of claims 1293-1374, wherein the method comprises administration of said composition more than once such as 2, 3, 4, 5, 6, 7 or 8 times with 1 to 2 weeks interval.
1376. The method for vaccination according to any of claims 1293-1375, wherein the method does not comprise administration of said composition more than once such as 2, 3, 4, 5, 6, 7 or 8 times with 1 to 2 weeks interval.
1377. The method for vaccination according to any of claims 1293-1376, wherein the method comprises administration of said composition together with administration of one or more medicament, wherein the administration can be simultaneously or sequentially in any order.
1378. The method for vaccination according to any of claims 1293-1377, wherein the composition is administered together with one or more adjuvants.
1379. The method for vaccination according to any of claims 1293-1378, wherein the composition is administered simulataneously with one or more adjuvants.
1380. The method for vaccination according to any of claims 1293-1379, wherein the composition is administered together with one or more adjuvants sequentially in any order.
1381. The method for vaccination according to any of claims 1293-1380, wherein the composition is administered more than once and wherein each administration comprises the same amount of the composition.
1382. The method for vaccination according to any of claims 1293-1381 , wherein the composition is administered more than once and wherein each administration comprises different amounts of the composition.
1383. The method for vaccination according to any of claims 1293-1382, wherein the composition is administered more than once and wherein each administration comprises increasing amounts of the composition.
1384. The method for vaccination according to any of claims 1293-1383, wherein the composition is administered more than once and wherein each administration comprises decreasing amounts of the composition.
1385. The method for vaccination according to any of claims 1293-1384, wherein the composition is administered more than once and wherein each administration does not comprise the same amount of the composition.
1386. The method for vaccination according to any of claims 1293-1385, wherein the composition is administered more than once and wherein each administration does not comprise different amounts of the composition.
1387. The method for vaccination according to any of claims 1293-1386, wherein the composition is administered more than once and wherein each administration does not comprise increasing amounts of the composition.
1388. The method for vaccination according to any of claims 1293-1387, wherein the composition is administered more than once and wherein each administration does not comprise decreasing amounts of the composition.
1389. The method for vaccination according to any of claims 1293-1388, wherein the vaccination is prophylactic.
1390. The method for vaccination according to any of claims 1293-1389, wherein the vaccination is ameliorating.
1391. The method for vaccination according to any of claims 1293-1390, wherein the vaccination is curative.
1392. The method for vaccination according to any of claims 1293-1391 , wherein the vaccination is life prolonging.
1393. The method for vaccination according to any of claims 1293-1392, wherein the composition is administered at the cervico-vaginal mucosa i.e. vaginally or IM i.e. intra-muscular.
1394. The method for vaccination according to any of claims 1293-1393, wherein the composition is administered alone or together with additional adjuvant(s) such as but not limited to Titermax Gold, Alhydrogel (Aluminium- hydroxide), MF59 and/or the proprietary Montanide ISA720.
1395. The method for vaccination according to any of claims 1293-1394, wherein the vaccination is for treatment of one or more diseases caused by one or more viral infection(s).
1396. The method for vaccination according to claim 1395, wherein viral infection is caused by dsDNA vira such as Adenoviruses, Herpesviruses, Poxviruses.
1397. The method for vaccination according to any of claims 1395-1396, wherein viral infection is caused by ssDNA vira (+)sense DNA such as
Parvoviruses.
1398. The method for vaccination according to any of claims 1395-1397, wherein viral infection is caused by dsRNA vira such as Reoviruses.
1399. The method for vaccination according to any of claims 1395-1398, wherein viral infection is caused by (+)ssRNA vira (+)sense RNA such as Picornaviruses and Togaviruses.
1400. The method for vaccination according to any of claims 1395-1399, wherein viral infection is caused by (-)ssRNA vira (-)sense RNA such as Orthomyxoviruses and Rhabdoviruses.
1401. The method for vaccination according to any of claims 1395-1400, wherein viral infection is caused by ssRNA-RT vira (+)sense RNA with DNA intermediate in life-cycle such as Retroviruses.
1402. The method for vaccination according to any of claims 1395-1401 , wherein viral infection is caused by dsDNA-RT vira such as Hepadnaviruses.
1403. The method for vaccination according to any of claims 1395-1402, wherein viral infection is caused by one or more vira selected from the group consisting of Abelson murine leukemia virus (Ab-MLV, A-MuLV), acute laryngotracheobronchitis virus (or HPIV), Adelaide River virus, Adeno- associated virus group (Dependevirus), Adenovirus, African horse sickness virus, African swine fever virus, AIDS virus, Aleutian mink disease, parvovirus, alfalfa mosaic virus, Alphaherpesvirinae (including HSV 1 and 2 and varicella), Alpharetrovirus (Avian leukosis virus, Rous sarcoma virus), Alphavirus, alkhurma virus, ALV related virus, Amapari virus, Andean potato mottle virus,
Aphthovirus, Aquareovirus, arbovirus, arbovirus C, arbovirus group A, arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus, Argentinian hemorrhagic fever virus, Arterivirus, Astrovirus, Ateline herpesvirus group, Aujezky's disease virus, Aura virus, Ausduk disease virus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosis virus, avian infectious bronchitis virus, avian leukemia virus, Avian leukosis virus (ALV), avian lymphomatosis virus, avian myeloblastosis virus, avian paramyxovirus, avian pneumoencephalitis virus, avian reticuloendotheliosis virus, avian sarcoma virus, avian type C retrovirus group, Avihepadnavirus, Avipoxvirus, B virus (Cercopithecine herpesvirus 1 ), B19 virus (Parvovirus B19), Babanki virus, baboon herpesvirus, bacterial virus, baculovirus, barley yellow dwarf virus, Barmah Forest virus, bean pod mottle virus, bean rugose mosaic virus, Bebaru virus, Berrimah virus, Betaherpesvirinae, betaretrovirus, Bird flu, Birnavirus, Bittner virus, BK virus, Black Creek Canal virus, bluetongue virus, Bolivian hemorrhagic fever virus, Boma disease virus, border disease of sheep virus, borna virus, bovine alphaherpesvirus 1 , bovine alphaherpesvirus 2, bovine coronavirus, bovine ephemeral fever virus, bovine immunodeficiency virus, bovine leukemia virus, bovine leukosis virus, bovine mammillitis virus, bovine papillomavirus, bovine papular stomatitis virus, bovine parvovirus, bovine syncytial virus, bovine type C oncovirus, bovine viral diarrhea virus, bracovirus, broad bean mottle virus, broad bean stain virus, brome mosaic virus, Bromovirus, Buggy Creek virus, bullet shaped virus group, Bunyamwera virus, Bunyavirus, Burkitt's lymphoma virus, Bwamba Fever, Bwattany hetero virus, CA virus (Croup-associated virus/ parainfluenza vius type 2), Calicivirus, California encephalitis virus, camelpox virus, canarypox virus, canid herpesvirus, canine coronavirus, canine distemper virus, canine herpesvirus, canine minute virus, canine parvovirus, Cano Delgadito virus, Capillovirus, caprine arthritis virus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus, Cardiovirus, Carlavirus, Carmovirus, carrot mottle virus, Cassia yellow blotch virus, Caulimovirus, Cauliflower mosaic virus, caviid herpesvirus
1 , Cercopithecine herpesvirus 1 , Cercopithecine herpesvirus 2, cereal yellow dwarf virus, Chandipura virus, Changuinola virus, channel catfish virus, Charleville virus, chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, Chordopoxvirinae, chub reovirus, chum salmon virus, Closterovirus, Cocal virus, Coho salmon reovirus, coital exanthema virus,
Colorado tick fever virus, Coltivirus Columbia SK virus, Commelina yellow mottle virus, Common cold virus, Comovirus, Condylomata accuminata, congenital cytomegalovirus, contagious ecthyma virus, contagious pustular dermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpea chlorotic mottle virus, cowpea mosaic virus, cowpea virus, cowpox virus, coxsackie virus,
CPV (cytoplasmic polyhedrosis virus), cricket paralysis virus, Crimean-Congo hemorrhagic fever virus, croup associated virus, Crypotovirus, Cucumovirus, Cypovirus, Cytomegalovirus (HCMV or Human Herpesvirus 5 HHV-5), cytoplasmic polyhedrosis virus, Cytorhabdovirus, deer papillomavirus, Deltaretrovirus (Human T-lymphotropic virus), Deformed wing virus DWV,
Dengue, Densovirus, Dependovirus, Dhori virus, Dianthovirus, diploma virus, DNA virus, Dobrava-Belgrade Virus, Dog Flu, Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1 , duck hepatitis virus 2, duovirus, Duvenhage virus, eastern equine encephalitis virus, eastern equine encephalomyelitis virus, Ebola virus, Ebola-like virus, Echovirus, echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus (Eastern equine encephalitis virus), EIA virus (equine infectious anemia), EMC virus (Encephalomyocarditis), Emiliania huxleyi virus 86, encephalitis virus, encephalomyocarditis virus, Endogenous retrovirus, Enterovirus, Entomopoxvirinae, Entomopoxvirus A, Entomopoxvirus B, Entomopoxvirus C, enzyme elevating virus, epidemic hemorrhagic fever virus, epizootic hemorrhagic disease virus, Epsilonretrovirus, Epstein-Barr virus (EBV; Human herpesvirus 4 HHV-4), equid alphaherpesvirus 1 , equid alphaherpesvirus 4, equid herpesvirus 2, equine abortion virus, equine arteritis virus, equine encephalosis virus, equine infectious anemia virus, equine morbillivirus, equine rhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elk papillomavirus, European swine fever virus, Everglades virus, Eyach virus, Fabavirus, felid herpesvirus 1 , feline calicivirus, feline fibrosarcoma virus, feline herpesvirus, feline immunodeficiency virus, feline infectious peritonitis virus, feline leukemia /sarcoma virus, feline leukemia virus, feline panleukopenia virus, feline parvovirus, feline sarcoma virus, feline syncytial virus, Fijivirus, Filovirus, Flanders virus, Flavivirus, foot and mouth disease virus, Fort Morgan virus, Four Corners hantavirus, fowl adenovirus 1 , Fowlpox virus, Friend virus, Furovirus, Gammaherpesvirinae, gammaretrovirus, GB virus C(GBV-C; formerly Hepatitis G virus), Geminivirus, German measles virus, Getah virus, gibbon ape leukemia virus, green monkey virus (mullburg), glandular fever virus, goatpox virus, golden shinner virus, Gonometa virus, goose parvovirus, granulosis virus, Gross' virus, ground squirrel hepatitis B virus, group A arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pig type C virus, Hantavirus, hard clam reovirus, hare fibroma virus, HCMV (human cytomegalovirus), helper virus, hemadsorption virus 2, hemagglutinating virus of Japan, hemorrhagic fever virus, Hendra virus, Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D (delta) virus, hepatitis E virus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus, hepatoencephalomyelitis reovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, Herpes simplex virus, herpes simplex virus 1 , herpes simplex virus 2, Herpesvirus, Herpes zoster, Herpes virus 6, Herpes virus 7, Herpes virus 8, Herpesvirus ateles, Herpesvirus hominis, Herpesvirus saimiri, Herpesvirus suis, Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, HIV-1 , hog cholera virus, Hordeivirus, Horse Flu, HTLV-1 , HTLV-2, human adenovirus 2, human alphaherpesvirus 1 , human alphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropic virus, human betaherpesvirus 5, human coronavirus, Human enterovirus A, Human enterovirus B, Human Flu, human foamy virus, human gammaherpesvirus 4, human gammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group, human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus 4 group, human herpesvirus 6, human herpesvirus 8, human immunodeficiency virus (HIV), human immunodeficiency virus 1 , human immunodeficiency virus 2, Human metapneumovirus, human papillomavirus, human T cell leukemia virus, human T cell leukemia virus I, human T cell leukemia virus II, human T cell leukemia virus III, human T cell lymphoma virus
I, human T cell lymphoma virus II, human T cell lymphotropic virus type 1 , human T cell lymphotropic virus type 2, human T lymphotropic virus I, human T lymphotropic virus II, human T lymphotropic virus III, ichnovirus, llarvirus, infantile gastroenteritis virus, infectious bovine rhinotracheitis virus, infectious haematopoietic necrosis virus, infectious pancreatic necrosis virus, influenza virus, influenzavirus A, influenzavirus B, influenzavirus C, influenzavirus D, influenzavirus pr8, insect iridescent virus, insect virus, interfering virus, iridovirus, Isavirus, Japanese B virus, Japanese encephalitis virus, JC virus, Junin virus, Johnson grass mosaic virus, Kaposi's sarcoma-associated herpesvirus, Kemerovo virus, Kilham's rat virus, Klamath virus, Kolongo virus,
Korean hemorrhagic fever virus, kumba virus, Kumlinge virus, Kunjin virus, Kyasanur forest disease, Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus, Lagos bat virus, Lambda phage, langat virus, Langur virus, lapine parvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM virus, Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus, louping ill virus, lumpy skin disease virus, Luteovirus, lymphadenopathy associated virus, Lymphocytic choriomeningitis virus (LCMV), Lymphocryptovirus, lymphocytic choriomeningitis virus, lymphoproliferative virus group, Lyssavirus, Machupo virus, mad itch virus, maize chlorotic dwarf virus, maize rough dwarf virus, mammalian type B oncovirus group, mammalian type B retroviruses, mammalian type C retrovirus group, mammalian type D retroviruses, mammary tumor virus, Mapuera virus, Marafivirus, Marburg virus, Marburg-like virus, Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus, Measles virus, Melandrium yellow fleck virus, Menangle virus, Mengo virus, Mengovirus, Merkel cell polyomavirus, Middelburg virus, milkers nodule virus, mink enteritis virus, minute virus of mice, MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscum contagiosum virus, Moloney murine leukemia virus (M-MuLV), monkey B virus, Monkeypox virus, Mononegavirales, Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouse encephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouse leukemia virus, mouse mammary tumor virus, mouse minute virus, mouse pneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mouse sarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosal disease virus, Mumps virus, murid betaherpesvirus 1 , murid cytomegalovirus 2, murine cytomegalovirus group, murine encephalomyelitis virus, murine hepatitis virus, murine leukemia virus, murine nodule inducing virus, murine polyomavirus, murine sarcoma virus, Muromegalovirus, Murray Valley encephalitis virus, myxoma virus, Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheep disease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus, Necrovirus, Neethling virus, Nelson Bay virus, Nemtick Virus, Nepovirus, neurotropic virus, New World Arenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipah virus, noncytopathogenic virus, Norovirus, Norwalk virus, nuclear polyhedrosis virus (NPV), nipple neck virus, O'nyong'nyong virus, oat sterile dwarf virus, Ockelbo virus, Omsk hemorrhagic fever virus, oncogenic virus, oncogenic viruslike particle, oncornavirus,
Orbivirus, Orf virus, Oropouche virus, Orthohepadnavirus, orthomyxovirus, Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovine catarrhal fever virus, owl monkey herpesvirus, Palyam virus, Papillomavirus, Papillomavirus sylvilagi, Papovavirus, Parainfluenza virus human (HPIV), parainfluenza virus type 1 human (HPIV-1 ), parainfluenza virus type 2 human
(HPIV-2), parainfluenza virus type 3 human (HPIV-3), parainfluenza virus type 4 human (HPIV-4), Paramyxovirus, Parapoxvirus, paravaccinia virus, parsnip yellow fleck virus, Parvovirus, Parvovirus B19, pea enation mosaic virus, Pestivirus, Phlebovirus, phocine distemper virus, Phytoreovirus, Picodnavirus, Picornavirus, pig cytomegalovirus, pigeonpox virus, Piry virus, Pixuna virus, plant rhabdovirus group, plant virus, pneumonia virus of mice, Pneumovirus, Poliomyelitis virus, Poliovirus, Polydnavirus, polyhedral virus, Polyoma virus, Polyomavirus, Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2, Polyomavirus maccacae 1 , Polyomavirus muris 1 , Polyomavirus muris 2, Polyomavirus papionis 1 , Polyomavirus papionis 2, Polyomavirus sylvilagi, Pongine herpesvirus 1 , porcine epidemic diarrhea virus, porcine hemagglutinating encephalomyelitis virus, porcine parvovirus, porcine transmissible gastroenteritis virus, porcine type C virus, Potato leaf roll virus, Potato mop top virus, Potato virus Y, Potexvirus, Potyvirus, Powassan encephalitis virus, Poxvirus, poxvirus variolae, Prospect Hill virus, provirus, pseudocowpox virus, pseudorabies virus, psittacinepox virus, Puumala virus, Qalyub virus, Quail pea mosaic virus, quailpox virus, Queensland fruitfly virus, Quokkapox virus, rabbit fibroma virus, rabbit kidney vacuolating virus, rabbit papillomavirus, Rabies virus, raccoon parvovirus, raccoonpox virus, radish mosaic virus, Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus,
Rauscher's virus, recombinant vaccinia virus, recombinant virus, Red Clover Necrotic Mosaic Virus, reovirus, reovirus 1 , reovirus 2, reovirus 3, reptilian type C virus, Respiratory syncytial virus, respiratory virus, reticuloendotheliosis virus, Retrovirus, Rhabdovirus, Rhabdovirus carpia, Rhadinovirus, Rhinovirus, Rhizidiovirus, rice dwarf virus, rice gall dwarf virus, rice hoja blanca virus, rice ragged stunt virus, Rift Valley fever virus, Riley's virus, rinderpest virus, RNA tumor virus, RNA virus, Roseolovirus, Ross River virus, Rotavirus, rougeole virus, Rous sarcoma virus, Rubella virus, rubeola virus, Rubivirus, Russian autumn encephalitis virus, S6-14-03 virus, SA 1 1 simian virus, SA 15, SA2 virus, SA6 virus, SA8 virus, Sabia virus, Sabio virus, Sabo virus, Saboya virus,
Sabulodes caberata GV, Sacbrood virus, Saccharomyces cerevisiae virus L-A, Saccharomyces cerevisiae virus La, Saccharomyces cerevisiae virus LBC, Sagiyama virus, Saguaro cactus virus, Saimiriine herpesvirus 1 , Saimiriine herpesvirus 2, Sainpaulia leaf necrosis virus, SaintAbb's Head virus, Saint- Floris virus, Sakhalin virus, Sal Vieja virus, Salanga virus, Salangapox virus,
Salehabad virus, salivary gland virus, Salmonid herpesvirus 1 , Salmonid herpesvirus 2, Salmonis virus, Sambucus vein clearing virus, Samia cynthia NPV, Samia pryeri NPV, Samia ricini NPV, Sammons' Opuntia virus, SanAngelo virus, San Juan virus, San Miguel sealion virus, San Perlita virus, Sand rat nuclear inclusion agents, Sandfly fever Naples virus, Sandfly fever
Sicilian virus, Sandjimba virus, Sango virus, Santa Rosa virus, Santarem virus, Santosai temperate virus, Sapphire Il virus, Sapporo-like virus, Saraca virus, Sarracenia purpurea virus, SARS virus, satellite virus, Sathuperi virus, Satsuma dwarf virus, Saturnia pavonia virus, Saturnia pyri NPV, Saumarez Reef virus, Sawgrass virus, Sceliodes cordalis NPV, Schefflera ringspot virus, Sciaphila duplex GV, Scirpophaga incertulas NPV, Sciurid herpesvirus, Sciurid herpesvirus 2, Scoliopteryx NbatFix NPV, Scopelodes contracta NPV, Scopelodes venosa NPV, Scopula subpunctaria NPV, Scotogramma trifolii GV, Scotogramma trifolu NPV, Scrophularia mottle virus, SDAV (sialodacryoadenitis virus), sealpox virus, Selenephera lunigera NPV, Selepa celtis GV, Seletar virus, Selidosema suavis NPV, Semidonta biloba NPV, Semiothisa sexmaculata GV, Semliki Forest Virus, Sena Madureira virus, Sendai virus, SENV-D, SENV- H, Seoul virus, Sepik virus, Serra do Navio virus, Serrano golden mosaic virus, Sesame yellow mosaic virus, Sesamia calamistis NPV, Sesamia cretica GV, Sesamia inferens NPV, Sesamia nonagrioides GV, Setora nitens virus, Shallot latent virus, Shamonda virus, Shark River virus, Sheep associated malignant catarrhal fever, Sheep papillomavirus, Sheep pulmonary adenomatosis associated herpesvirus, sheeppox virus, Shiant Islands virus, Shokwe virus, Shope fibroma virus, Shope papilloma virus, Shuni virus, Siamese cobra herpesvirus, Sibine fusca densovirus, Sida golden mosaic virus (SiGMV), Sida golden yellow vein virus (SiGYVV), Sigma virus, Sikte water-borne virus, Silverwater virus, Simbu virus, Simian adenoviruses 1 to 27, Simian agent virus 12, Simian enterovirus 1 to 18, simian foamy virus, Simian hemorrhagic fever virus, simian hepatitis A virus, simian human immunodeficiency virus, simian immunodeficiency virus, simian parainfluenza virus, Simian rotavirus SA1 1 ,
Simian sarcoma virus, simian T cell lymphotrophic virus, Simian type D virus 1 , Simian vancella herpesvirus, simian virus, simian virus 40, Simplexvirus, Simulium vittatum densovirus, Sin Nombre virus, Sindbis virus, Sinti em's onion latent virus, Sixgun city virus, Skunkpox virus, Smallpox virus, Smelt reovirus, Smerinthus ocellata NPV, Smithiantha virus, Snakehead rhabdovirus,
Snowshoe hare virus, Snyder-Theilen feline sarcoma virus, Sobemovirus, Sofyn virus, Soil-borne wheat mosaic virus, Sokoluk virus, Solanum apical leaf curl virus, Solanum nodiflorum mottle virus, Solanurn yellows virus, Soldado virus, Somerville virus 4, Sonchus mottle virus, Sonchus virus, Sonchus yellow net virus, Sorghum chlorotic spot virus, Sorghum mosaic virus, Sorghum virus,
Sororoca virus, Soursop yellow blotch virus, SouthAfrican passiflora virus, South American hemorrhagic fever viruses, SouthAfrican passiflora virus, South River virus, Southern bean mosaic virus, Southern potato latent virus, Sowbane mosaic virus, Sowthistle yellow vein virus, Soybean chlorotic mottle virus, Soybean crinkle leaf virus, Soybean dwarf virus, Soybean mosaic virus, SPAr- 2317 virus, Sparganothis pettitana NPV, sparrowpox virus, Spartina mottle virus, Spectacled caimanpox virus, SPH 1 14202 virus, Sphenicid herpesvirus 1 , Sphinx ligustri NPV, Spider monkey herpesvirus, Spilarctia subcarnea NPV, Spilonota ocellana NPV, Spilosoma lubricipeda NPV, Spinach latent virus, Spinach temperate virus, Spiroplasma phage 1 , Spiroplasma phage 4,
Spiroplasma phage aa, Spiroplasma phage C1 /TS2, Spodoptera exempta cypovirus, Spodoptera exigua virus, Spodoptera frugiperda virus, Spodoptera latifascia virus, Spodoptera littoralis, Spodoptera mauritia virus, Spodoptera ornithogalli virus, Spondweni virus, spring beauty latent virus, Spring viremia of carp virus, Spumavirus (SFV, HFV), Squash leaf curl virus, squash mosaic virus, squirrel fibroma virus, Squirrel monkey herpesvirus, squirrel monkey retrovirus, SR-1 1 virus, Sri Lankan passionfruit mottle virus, Sripur virus, SSV 1 virus group, StAbbs Head virus, St. Louis encephalitis virus, Staphylococcus phage 107, Staphylococcus phage 187, Staphylococcus phage 2848A, Staphylococcus phage 3A, Staphylococcus phage 44A HJD, Staphylococcus phage 77, Staphylococcus phage B1 1 -M15, Staphylococcus phage Twort, Starlingpox virus, Statice virus Y, P, STLV (simian T lymphotropic virus) type I, STLV (simian T lymphotropic virus) type II, STLV (simian T lymphotropic virus) type III, stomatitis papulosa virus, Stratford virus, Strawberry crinkle virus, Strawberry latent ringspot virus, Strawberry mild yellow edge virus, Strawberry vein banding virus, Streptococcus phage 182, Streptococcus phage 2BV, Streptococcus phage A25, Streptococcus phage 24, Streptococcus phage PE1 , Streptococcus phage VD13, Streptococcus phage fD8, Streptococcus phage CP-1 , Streptococcus phage Cvir, Streptococcus phage H39, Strigid herpesvirus 1 , Striped bass reovirus, Striped Jack nervous, necrosis virus, Stump-tailed macaque virus, submaxillary virus, Subterranean clover mottle virus, Subterranean clover mottle virus satellite, Subterranean clover red leaf virus, Subterranean clover stunt virus, Sugarcane bacilliform virus, Sugarcane mild mosaic virus, Sugarcane mosaic virus, Sugarcane streak virus, suid alphaherpesvirus 1 , suid herpesvirus 2, Suipoxvirus, Sulfolobus virus 1 , Sunday
Canyon virus, Sunflower crinkle virus, Sunflower mosaic virus, Sunflower rugose mosaic virus, Sunflower yellow blotch virus, Sunflower yellow ringspot virus, Sun-hemp mosaic virus, swamp fever virus, Sweet clover necrotic mosaic virus, Sweet potato A virus, Sweet potato chlorotic leafspot virus, Sweet potato feathery mottle virus, Sweet potato internal cork virus, Sweet potato latent virus, Sweet potato mild mottle virus, Sweet potato russet crack virus, Sweet potato vein mosaic virus, Sweet potato yellow dwarf virus, Sweetwater Branch virus, Swine cytomegalovirus, Swine Flu, Swine infertility and respiratory syndrome virus, swinepox virus, Swiss mouse leukemia virus, Sword bean distortion mosaic virus, Synaxis jubararia NPV, Synaxis pallulata NPV, Synetaeris tenuifemur virus, Syngrapha selecta NPV, T4 phage, T7 phage, TAC virus, Tacaiuma virus, Tacaribe complex virus, Tacaribe virus, Tadpole edema virus LT 1 -4, Taggert virus, Tahyna virus, Tai virus, Taiassui virus, Tamana bat virus, Tamarillo mosaic virus, Tamdy virus, Tamiami virus, Tanapox virus, Tanga virus, Tanjong Rabok virus, Taro bacilliform virus, Badnavirus Tataguine virus,
Taterapox virus, Taterapox virus, Teasel mosaic virus, Tehran virus, Telfairia mosaic virus, Telok Forest virus, Tembe virus, Tembusu virus, Tench reovirus, Tensaw virus, Tenvivirus, Tephrosia symptomless virus, Termeil virus, Tete virus, Tetralopha scortealis NPV, Tetropium cinnamoptemm NPV, Texas pepper virus, Thailand virus, Thaumetopoea pityocampa virus, Theiler's encephalomyelitis virus, Theiler's virus, Theophila mandarina NPV, Theretra japonica NPV , Thermoproteus virus 1 , Thermoproteus virus 2, Thermoproteus virus 3, Thermoproteus virus 4, Thiafora virus, Thimiri virus, Thistle mottle virus, Thogoto virus, Thormodseyjarklettur virus, Thosea asigna virus, Thosea baibarana NPV, Thosea sinensis GV, Thottapalayam virus, Thylidolpteryx ephemeraeformis NPV, Thymelicus lineola NPV, Tibrogargan virus, Ticera castanea NPV, Tick borne encephalitis virus (TBEV) - European and Far Eastern subtypes, Tillamook virus, Tilligerry virus, Timbo virus, Tilmboteua virus, Tilmaroo virus, Tindholmur virus, Tinea pellionella NPV, Tineola hisselliella NPV, Tinpula paludosa NPV, Tinracola plagiata NPV, Tioman virus,
Tlacotalpan virus, Tobacco bushy top virus, Tobacco etch virus, Tobacco leaf curl virus, Tobacco mild green mosaic virus, tobacco mosaic virus, Tobacco mosaic virus satellite, Tobacco mottle virus, Tobacco necrosis virus, Tobacco necrosis virus satellite, Tobacco necrosis virus small satellite, Tobacco necrotic dwarf virus, tobacco rattle virus, Tobacco ringspot virus, Tobacco streak virus,
Tobacco stunt virus, Tobacco vein banding mosaic virus, Tobacco vein distorting virus Tobacco vein mottling virus, Tobacco wilt virus, Tobacco yellow dwarf virus, Tobacco yellow net virus, Tobacco yellow vein virus, Tobamovirus Tobravirus, Togavirus, Tomato apical stunt viroid, Tomato aspermy virus, Tomato black ring virus, Tomato black ring virus satellite, Tomato bunchy top viroid, tomato bushy stunt virus, Tomato bushy stunt virus satellite, Tomato golden mosaic virus, Tomato leaf crumple virus, Tomato leaf curl virus, Tomato leafroll virus, Tomato mosaic virus, Tomato mottle virus, Tomato pale chlorosis virus, Tomato planta macho viroid, Tomato pseudo-curly top virus, Tomato ringspot virus, Tomato spotted wilt virus, Tomato top necrosis virus, Tomato vein yellowing virus, Tomato yellow dwarf virus, Tomato yellow leaf curl virus, Tomato yellow mosaic virus, Tomato yellow top virus, Tombusvirus, Tongan vanilla virus, Torovirus, Torque teno virus, Tortrix loeflingiana NPV, Tortrix viridana NPV, Toscana virus, Tospovirus, Toxorhynchites brevipalpis NPV, Trabala vishnou NPV, Tradescantia/Zebrina virus, Trager duck spleen necrosis virus, Tranosema sp. Virus, transforming virus, Tree shrew adenovirus 1 , Tree shrew herpesvims, Triatoma virus, Tribec virus, Trichiocampus irregularis NPV, Trichiocampus viminalis NPV, Trichomonas vaginalis virus, Trichoplusia ni cypovirus 5, Trichoplusia ni granulovirus, Trichoplusia ni MNPV, Trichoplusia ni Single SNPV, Trichoplusia ni virus, Trichosanthes mottle virus, Triticum aestivum chlorotic spot virus, Trivittatus virus, Trombetas virus, Tropaeolum virus 1 , Tropaeolum virus 2, Trubanarnan virus, Tsuruse virus, Tucunduba virus, Tulare apple mosaic virus, Tulip band breaking virus, Tulip breaking virus, Tulip chlorotic blotch virus, Tulip top breaking virus, Tulip virus X, tumor virus, Tupaia virus, Tupaiid herpesvirus 1 , Turbot herpesvirus, Turbot reovirus, Turkey adenoviruses 1 to 3, Turkey coronavirus, Turkey herpesvirus 1 , turkey rhinotracheitis virus, turkeypox virus, Turlock virus, Turnip crinkle virus, Turnip crinkle virus satellite, Turnip mild yellows virus, Turnip mosaic virus, Turnip rosette virus, turnip yellow mosaic virus, Turuna virus, Tymovirus, Tyuleniy virus, type C retroviruses, type D oncovirus, type D retrovirus group, Uasin
Gishu disease virus, Uganda S virus, Ugymyia sericariae NPV, ulcerative disease rhabdovirus, Ullucus mild mottle virus, Ullucus mosaic virus, Ullucus virus C, Umatilla virus, Umbre virus, Una virus, Upolu virus, UR2 sarcoma virus, Uranotaenia sapphirina NPV, Urbanus proteus NPV, Urucuri virus, Ustilago maydis virus 1 , Ustilago maydis virus 4, Ustilago maydis virus 6, Usutu virus,
Utinga virus, Utive virus, Uukuniemi virus group, Vaccinia virus, Vaeroy virus, Vallota mosaic virus, Vanessa atalanta NPV, Vanessa cardui NPV, Vanessa prorsa NPV, Vanilla mosaic virus, Vanilla necrosis virus, Varicella zoster virus, Varicellovirus, Varicola virus, variola major virus, variola virus, Vasin Gishu disease virus, Vellore virus, Velvet tobacco mottle virus, Velvet tobacco mottle virus satellite, Venezuelan equine encephalitis virus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagic fever virus, Vesicular stomatitis virus, Vesiculovirus, Vibrio phage 06N-22P, Vibrio phage 06N-58P, Vibrio phage 4996, Vibrio phage a3a, Vibrio phage I, Vibrio phage II, Vibrio phage m, Vibrio phage IV, Vibrio phage kappa, Vibrio phage nt-1 , Vibrio phage
OXN-52P, Vibrio phage OXN-IOOP, Vibrio phage v6, Vibrio phage Vfl2, Vibrio phage Vf33, Vibrio phage VP1 , Vibrio phage VP1 1 , Vibrio phage VP3, Vibrio phage VP5, Vibrio phage X29, Vicia cryptic virus, Vigna sinensis mosaic virus, Vilyuisk virus, Vinces virus, Viola mottle virus, viper retrovirus, viral haemorrhagic septicemia virus, virus-like particle, Visna Maedi virus, Visna virus, Voandzeia mosaic virus, Voandzeia necrotic mosaic virus, volepox virus, Wad Medani virus, WaIIaI virus, Walleye epidermal hyperplasia, Walrus calicivirus, Wanowrie virus, Warrego virus, Watermelon chlorotic stunt virus, Watermelon curly mottle virus, Watermelon mosaic virus 1 , Watermelon mosaic virus 2, Weddel water-borne virus, Weldona virus, Wesselsbron virus, West Nile virus, western equine encephalitis virus, western equine encephalomyelitis virus, Wexford virus, Whataroa virus, Wheat American striate mosaic virus, Wheat chlorotic streak virus, Wheat dwarf virus, Wheat rosette stunt virus, Wheat streak mosaic virus, Wheat yellow leaf virus, Wheat yellow mosaic virus, White bryony virus, White clover cryptic virus 1 , White clover cryptic virus 2,
White clover cryptic virus 3, White clover mosaic virus, White lupinrnosaic virus, Wild cucumber mosaic virus, Wild potato mosaic virus, Wildbeest herpesvirus, Wineberry latent virus, Winter wheat mosaic virus, Winter wheat Russian mosaic virus, Wiseana cervinata virus, Wiseana signata virus, Wiseana umbraculata virus, Wissadula mosaic virus, Wisteria vein mosaic virus,
Witwatersrand virus, Wongal virus, Wongorr virus, Winter Vomiting Virus, woodchuck hepatitis B virus, Woodchuck herpesvirus marmota 1 , woolly monkey sarcoma virus, wound tumor virus, WRSV virus, WVU virus 2937, WW virus 71 to 212, Wyeomyia smithii NPV, Wyeomyia virus, Xanthomonas phage Cf, Xanthomonas phage CfIt, Xanthomonas phage RR66, Xanthomonas phage
Xf, Xanthomonas phage Xf2, Xanthomonas phage XP5, Xenopus virus T21 , Xiburema virus, Xingu virus, Xylena curvimacula NPV, Y73 sarcoma virus, Yaba monkey tumor virus, Yaba-1 virus, Yaba-7 virus, Yacaaba virus, Yam mosaic virus, Yaounde virus, Yaquina Head virus, Yatapoxvirus, Yellow fever virus, Yogue virus, Yokapox virus, Yokase virus, Yponomeuta cognatella NPV, Yponomeuta evonymella NPV, Yponomeuta malinellus NPV, Yponomeuta padella NPV, Yucca baciliform virus, Yug Bogdanovac virus, ZaNv Terpeniya virus, Zea mays virus, Zegla virus, Zeiraphera diniana virus, Zeiraphera pseudotsugana NPV, Zika virus, Zirqa virus, Zoysia mosaic virus, Zucchini yellow fleck virus, Zucchini yellow mosaic virus and Zygocactus virus.
1404. The method for vaccination according to any of claims 1293-1403, wherein the vaccination is for treatment of one or more diseases caused by one or more bacterial infection(s).
1405. The method for vaccination according to claim 1404, wherein bacterial infection is caused by one or more bacteria selected from the group consisting of Acidobacteria, Actinobacteria, Aquificae, Bacteroidetes, Chlamydiae, Chlorobi, Chloroflexi, Chrysiogenetes, Cyanobacteria, Deferribacteres, Deinococcus-Thermus, Dictyoglomi, Fibrobacteres, Firmicutes, Fusobacteria,
Gemmatimonadetes, Nitrospirae, Planctomycetes, Proteobacteria, Spirochaetes, Thermodesulfobacteria, Thermomicrobia, Thermotogae and Verrucomicrobia bacterial phyla; these may be Gram negative (Spirochetal, Chlamydiae, Proteobacteria α, β, y) and Gram positive bacteria (Firmicutes, Actinobacteria (Mycobacterium, Actinomycetales)).
1406. The method for vaccination according to any of claims 1404-1405, wherein bacterial infection is caused by one or more bacteria selected from the group consisting of Acetobacter aurantius, Acinetobacter species, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter johnsonii,
Acinetobacter junii, Acinetobacter Iwoffii, Acinetobacter radioresistens, Acinetobacter septicus, Acinetobacter schindleri, Acinetobacter ursingii; Actinomyces species: Actinomyces bovis, Actinomyces bowdenii, Actinomyces canis, Actinomyces cardiffensis, Actinomyces catuli, Actinomyces coleocanis, Actinomyces dentalis, Actinomyces denticolens, Actinomyces europaeus,
Actinomyces funkei, Actinomyces georgiae, Actinomyces gerencseriae, Actinomyces graevenitzii, Actinomyces hongkongensis, Actinomyces hordeovulneris, Actinomyces howellii, Actinomyces humiferus, Actinomyces hyovaginalis, Actinomyces israelii, Actinomyces marimammalium, Actinomyces meyeri, Actinomyces naeslundii, Actinomyces nasicola, Actinomyces neuii, Actinomyces odontolyticus, Actinomyces oricola, Actinomyces radicidentis, Actinomyces radingae, Actinomyces slackii, Actinomyces streptomycini, Actinomyces suimastitidis, Actinomyces suis, Actinomyces turicensis, Actinomyces urogenitalis, Actinomyces vaccimaxillae, Actinomyces viscosus; Actinobacillus species: Actinobacillus actinomycetemcomitans, Actinobacillus arthritidis, Actinobacillus capsulatus, Actinobacillus delphinicola, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus indolicus, Actinobacillus lignieresii, Actinobacillus minor, Actinobacillus muris, Actinobacillus pleuropneumoniae, Actinobacillus porcinus, Actinobacillus rossii, Actinobacillus scotiae, Actinobacillus seminis, Actinobacillus succinogenes, Actinobacillus suis,
Actinobacillus ureae; Aeromonas species: Aeromonas allosaccharophila, Aeromonas bestiarum, Aeromonas bivalvium, Aeromonas encheleia, Aeromonas enteropelogenes, Aeromonas euchrenophila, Aeromonas hydrophila, Aeromonas ichthiosmia, Aeromonas jandaei, Aeromonas media, Aeromonas molluscorum, Aeromonas popoffii, Aeromonas punctata,
Aeromonas salmonicida, Aeromonas schubertii, Aeromonas sharmana, Aeromonas simiae, Aeromonas sobria, Aeromonas veronii; Afipia felis, Agrobacterium species, Agrobacterium radiobacter, Agrobacterium rhizogenes, Agrobacterium rubi, Agrobacterium tumefaciens; Agromonas species, Alcaligenes species: Alcaligenes aquatilis, Alcaligenes eutrophus, Alcaligenes faecalis, Alcaligenes latus, Alcaligenes xylosoxidans; Alishewanella species, Alterococcus species, Anaplasma phagocytophilum, Anaplasma marginale, Aquamonas species, Arcanobacterium haemolyticum, Aranicola species, Arsenophonus species, Azotivirga species, Azotobacter vinelandii, Azotobacter chroococcum, Bacillary dysentery (Shigellosis), Bacillus species: Bacillus abortus (Brucella melitensis biovar abortus), Bacillus anthracis (Anthrax), Bacillus brevis, Bacillus cereus, Bacillus coagulans, Bacillus fusiformis, Bacillus globigii, Bacillus licheniformis, Bacillus megaterium, Bacillus mycoides, Bacillus natto, Bacillus stearothermophilus, Bacillus subtilis, Bacillus sphaericus, Bacillus thuringiensis; Bacteroides species: Bacteroides forsythus (Tannerella forsythensis), Bacteroides acidifaciens, Bacteroides distasonis (reclassified as Parabacteroides distasonis), Bacteroides gingivalis, Bacteroides gracilis, Bacteroides fragilis, Bacteroides oris, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides stercoris, Bacteroides suis, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides vulgatus; Bartonella species: Bartonella alsatica, Bartonella bacilliformis, Bartonella birtlesii, Bartonella bovis, Bartonella capreoli, Bartonella clarridgeiae, Bartonella doshiae, Bartonella elizabethae, Bartonella grahamii, Bartonella henselae (cat scratch fever), Bartonella koehlerae, Bartonella muris, Bartonella peromysci, Bartonella quintana, Bartonella rochalimae, Bartonella schoenbuchii, Bartonella talpae, Bartonella taylorii, Bartonella tribocorum, Bartonella vinsonii spp. Arupensis, Bartonella vinsonii spp. Berkhoffii, Bartonella vinsonii spp. Vinsonii, Bartonella washoensis; BCG (Bacille Calmette-Guerin), Bergeyella zoohelcum (Weeksella zoohelcum), Bifidobacterium bifidum, Blastobacter species, Blochmannia species, Bordetella species: 'Bordetella ansorpii', Bordetella avium, Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmesii, Bordetella parapertussis, Bordetella pertussis (Whooping cough), Bordetella petrii, Bordetella trematum; Borrelia species: Borrelia anserine, Borrelia barbouri, Borrelia burgdorferi such as burgdorferi B31 , Borrelia afzelii such as Borrelia afzelii ACA-1 , Borrelia afzelii K78 and/or Borrelia afzelii PKo, Borrelia andersonii, Borrelia anserine, Borrelia bissettii, Borrelia burgdorferi 1 18a, Borrelia burgdorferi 156a, Borrelia burgdorferi 29805, Borrelia burgdorferi 64b, Borrelia burgdorferi 72a, Borrelia burgdorferi 80a, Borrelia burgdorferi 94a, Borrelia burgdorferi B31 , Borrelia burgdorferi Bol26, Borrelia burgdorferi CA- 1 1.2a, Borrelia burgdorferi WI91 -23, Borrelia burgdorferi ZS7, Borrelia californiensis, Borrelia garini such as garini PBi, garini PBr, Borrelia genomosp. 1 , Borrelia genomosp. 2, Borrelia japonica, Borrelia lusitaniae, Borrelia spielmanii, Borrelia spielmanii A14S, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia valaisiana VS1 16, Candidatus Borrelia texasensis, Borrelia sp. AA4Pool, Borrelia sp. AI-1 , Borrelia sp. B31 , Borrelia sp. BC-1 , Borrelia sp.
CA1 133, Borrelia sp. CA1 176, Borrelia sp. CA128, Borrelia sp. CA13, Borrelia sp. CA134, Borrelia sp. CA142, Borrelia sp. CA20, Borrelia sp. CA22, Borrelia sp. CA27, Borrelia sp. CA28, Borrelia sp. CA29, Borrelia sp. CA31 , Borrelia sp. CA33, Borrelia sp. CA370, Borrelia sp. CA372, Borrelia sp. CA378, Borrelia sp. CA388, Borrelia sp. CA393, Borrelia sp. CA394, Borrelia sp. CA395, Borrelia sp. CA399, Borrelia sp. CA400, Borrelia sp. CA401 , Borrelia sp. CA402, Borrelia sp. CA404, Borrelia sp. CA41 1 , Borrelia sp. CA426, Borrelia sp. CA443, Borrelia sp. CA446, Borrelia sp. CA448, Borrelia sp. CA462, Borrelia sp. CA468, Borrelia sp. CA502, Borrelia sp. CA504, Borrelia sp. CA507, Borrelia sp. CA547, Borrelia sp. CA552, Borrelia sp. CA8, Borrelia sp. D22, Borrelia sp. D35, Borrelia sp. FD-1 , Borrelia sp. FL18, Borrelia sp. FL27, Borrelia sp. FL35, Borrelia sp. FL42., Borrelia sp. HN6, Borrelia sp. HN7, Borrelia sp. HN8, Borrelia sp. HNM13, Borrelia sp. HNM14, Borrelia sp. HNM19, Borrelia sp. IA1 , Borrelia sp. lr-3519, Borrelia sp. lr-4721 , Borrelia sp. lr-4812, Borrelia sp. lr-5215, Borrelia sp. LV5, Borrelia sp. MI-2, Borrelia sp. Ml-
5, Borrelia sp. MI-6, Borrelia sp. MI-8, Borrelia sp. MI-9, Borrelia sp. MOD-1 , Borrelia sp. MOD-5, Borrelia sp. MOK-3a, Borrelia sp. MOS-I b, Borrelia sp. NE49, Borrelia sp. NE581 , Borrelia sp. PHaP, Borrelia sp. PSigll, Borrelia sp. SCGT-10, Borrelia sp. SCGT-8a, Borrelia sp. SCI-2, Borrelia sp. SCW-30h, Borrelia sp. SI-1 , Borrelia sp. SI-10, Borrelia sp. SM-1 , Borrelia sp. SV1 ,
Borrelia sp. W97F51 , Borrelia sp. Z41293, Borrelia sp. Z41493, Borrelia coriaceae, Borrelia crocidurae, Borrelia duttonii, Borrelia duttonii Ly, Borrelia hermsii, Borrelia hermsii DAH, Borrelia hispanica, Borrelia lonestari, Borrelia miyamotoi, Borrelia parkeri, Borrelia persica, Borrelia recurrentis, Borrelia recurrentis A1 , Borrelia sinica, Borrelia theileri, Borrelia turcica, Borrelia turicatae, Borrelia turicatae 91 E135, Borrelia sp., Borrelia sp. 'Lake Gaillard', Borrelia sp. 000133, Borrelia sp. 010298, Borrelia sp. 10MT, Borrelia sp. 5145, Borrelia sp. 57Nsk, Borrelia sp. 5MT, Borrelia sp. 6T04-2, Borrelia sp. BR, Borrelia sp. BR 2007, Borrelia sp. C5-N52, Borrelia sp. CB-A1 , Borrelia sp. CB- A1 1 , Borrelia sp. CB-A3, Borrelia sp. EFL-S01001 10, Borrelia sp. IK/23,
Borrelia sp. IM/16, Borrelia sp. IM/19, Borrelia sp. KR1 , Borrelia sp. KR3, Borrelia sp. LB-2001 , Borrelia sp. LB-M56, Borrelia sp. LB-W100, Borrelia sp. MK-N61 , Borrelia sp. NR-N8, Borrelia sp. OkMEI , Borrelia sp. PAnz, Borrelia sp. PJes, Borrelia sp. PMai, Borrelia sp. PMew, Borrelia sp. R57, Borrelia sp. strain Spain, Borrelia sp. TA1 , Borrelia sp. TM, Borrelia sp. TM1 and Borrelia sp. TM2; Bosea species, Bradyrhizobium species, Brenneria species, Brucella species: Brucella abortus, Brucella canis, Brucella melitensis, Brucella neotomae, Brucella ovis, Brucella suis, Brucella pinnipediae; Buchnera species, Budvicia species, Burkholderia species: Burkholderia cepacia (Pseudomonas cepacia), Burkholderia mallei (Pseudomonas mallei/ Actinobacillus mallei),
Burkholderia pseudomallei (Pseudomonas pseudomallei); Buttiauxella species, Calymmatobacterium granulomatis, Campylobacter species: Campylobacter coli, Campylobacter concisus, Campylobacter curvus, Campylobacter fetus, Campylobacter gracilis, Campylobacter helveticus, Campylobacter hominis, Campylobacter hyointestinalis, Campylobacter insulaenigrae, Campylobacter jejuni, Campylobacter lanienae, Campylobacter lari, Campylobacter mucosalis, Campylobacter rectus, Campylobacter showae, Campylobacter sputorum, Campylobacter upsaliensis; Capnocytophaga canimorsus (Dysgonic fermenter type 2), Corynebacterium species, Cardiobacterium hominis, Cedecea species, Chlamydia species: Chlamydia trachomatis (Lymphogranuloma venereum),
Chlamydia muridarum, Chlamydia suis; Chlamydophila species: Chlamydophila pneumoniae, Chlamydophila psittaci (Psittacosis), Chlamydophila pecorum, Chlamydophila abortus, Chlamydophila felis, Chlamydophila caviae; Citrobacter species: Citrobacter amalonaticus, Citrobacter braakii, Citrobacter farmeri, Citrobacter freundii, Citrobacter gillenii, Citrobacter intermedius, Citrobacter koseri aka Citrobacter diversus, Citrobacter murliniae, Citrobacter rodentium, Citrobacter sedlakii, Citrobacter werkmanii, Citrobacter youngae; Clostridium species: Clostridium botulinum, Clostridium difficile, Clostridium novyi, Clostridium septicum, Clostridium tetani (Tetanus), Clostridium welchii (Clostridium perfringens); Corynebacterium species: Corynebacterium diphtheriae (Diphtheria), Corynebacterium amycolatum, Corynebacterium aquaticum, Corynebacterium bovis, Corynebacterium equi, Corynebacterium flavescens, Corynebacterium glutamicum, Corynebacterium haemolyticum, Corynebacterium jeikeiun (corynebacteria of group JK), Corynebacterium minutissimum (Erythrasma), Corynebacterium parvum (also called
Propionibacterium acnes), Corynebacterium pseudodiptheriticum (also called Corynebacterium hofmannii), Corynebacterium pseudotuberculosis (also called Corynebacterium ovis), Corynebacterium pyogenes, Corynebacterium urealyticum (corynebacteria of group D2), Corynebacterium renale, Corynebacterium striatum, Corynebacterium tenuis (Trichomycosis palmellina,
Trichomycosis axillaris), Corynebacterium ulcerans, Corynebacterium xerosis; Coxiella burnetii (Q fever), Cronobacter species: Cronobacter sakazakii, Cronobacter malonaticus, Cronobacter turicensis, Cronobacter muytjensii, Cronobacter dublinensis; Delftia acidovorans (Comamonas acidovorans), Dickeya species, Edwardsiella species, Eikenella corrodens, Enterobacter species: Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii; Enterococcus species: Enterococcus avium, Enterococcus durans, Enterococcus faecalis (Streptococcus faecalis/ Streptococcus Group D), Enterococcus faecium, Enterococcus solitarius, Enterococcus galllinarum, Enterococcus maloratus; Ehrlichia chaffeensis, Erysipelothrix rhusiopathiae, Erwinia species, Escherichia species: Escherichia adecarboxylata, Escherichia albertii, Escherichia blattae, Escherichia coli, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris; Ewingella species, Flavobacterium species: Flavobacterium aquatile, Flavobacterium branchiophilum, Flavobacterium columnare, Flavobacterium flevense, Flavobacterium gondwanense, Flavobacterium hydatis, Flavobacterium johnsoniae, Flavobacterium pectinovorum, Flavobacterium psychrophilum, Flavobacterium saccharophilum, Flavobacterium salegens, Flavobacterium scophthalmum, Flavobacterium succinans; Francisella tularensis (Tularaemia), Francisella novicida, Francisella philomiragia, Fusobacterium species: Fusobacterium necrophorum (Lemierre syndrome/ Sphaerophorus necrophorus), Fusobacterium nucleatum, Fusobacterium polymorphum, Fusobacterium novum, Fusobacterium mortiferum, Fusobacterium varium; Gardnerella vaginalis, Gemella haemolysans, Gemella morbillorum (Streptococcus morbillorum), Grimontella species, Haemophilus species: Haemophilus aegyptius (Koch-Weeks bacillus), Haemophilus aphrophilus, Haemophilus avium, Haemophilus ducreyi (Chancroid), Haemophilus felis, Haemophilus haemolyticus, Haemophilus influenzae (Pfeiffer bacillus), Haemophilus paracuniculus, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Haemophilus paraphrophilus (Aggregatibacter aphrophilus), Haemophilus pertussis, Haemophilus pittmaniae, Haemophilus somnus, Haemophilus vaginalis; Hafnia species, Hafnia alvei, Helicobacter species: Helicobacter acinonychis, Helicobacter anseris, Helicobacter aurati, Helicobacter bilis, Helicobacter bizzozeronii, Helicobacter brantae, Helicobacter Canadensis, Helicobacter canis, Helicobacter cholecystus, Helicobacter cinaedi,
Helicobacter cynogastricus, Helicobacter felis, Helicobacter fennelliae, Helicobacter ganmani, Helicobacter heilmannii (Gastrospirillum hominis), Helicobacter hepaticus, Helicobacter mesocricetorum, Helicobacter marmotae, Helicobacter muridarum, Helicobacter mustelae, Helicobacter pametensis, Helicobacter pullorum, Helicobacter pylori (stomach ulcer), Helicobacter rappini,
Helicobacter rodentium, Helicobacter salomonis, Helicobacter trogontum, Helicobacter typhlonius, Helicobacter winghamensis; Human granulocytic ehrlichiosis (Anaplasma phagocytophilum/ Ehrlichia phagocytophila), Human monocytotropic ehrlichiosis (Monocytic ehrlichiosis/ Ehrlichia chaffeensis), Klebsiella species: Klebsiella granulomatis (Calymmatobacterium granulomatis), Klebsiella mobilis, Klebsiella ornithinolytica, Klebsiella oxytoca, Klebsiella ozaenae, Klebsiella planticola, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Klebsiella singaporensis, Klebsiella terrigena, Klebsiella trevisanii, Klebsiella variicola; Kingella kingae, Kluyvera species, Lactobacillus species: Lactobacillus acetotolerans, Lactobacillus acidifarinae, Lactobacillus acidipiscis, Lactobacillus acidophilus (Doderlein bacillus), Lactobacillus agilis, Lactobacillus algidus, Lactobacillus alimentarius, Lactobacillus amylolyticus, Lactobacillus amylophilus, Lactobacillus amylotrophicus, Lactobacillus amylovorus, Lactobacillus animalis, Lactobacillus antri, Lactobacillus apodemi, Lactobacillus aviarius, Lactobacillus bifermentans, Lactobacillus brevis,
Lactobacillus buchneri, Lactobacillus camelliae, Lactobacillus casei, Lactobacillus catenaformis, Lactobacillus ceti, Lactobacillus coleohominis, Lactobacillus collinoides, Lactobacillus composti, Lactobacillus concavus, Lactobacillus coryniformis, Lactobacillus crispatus, Lactobacillus crustorum, Lactobacillus curvatus, Lactobacillus delbrueckii, Lactobacillus delbrueckii subsp. Bulgaricus, Lactobacillus delbrueckii subsp. Lactis, Lactobacillus diolivorans, Lactobacillus equi, Lactobacillus equigenerosi, Lactobacillus farraginis, Lactobacillus farciminis, Lactobacillus fermentum, Lactobacillus fornicalis, Lactobacillus fructivorans, Lactobacillus frumenti, Lactobacillus fuchuensis, Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus gastricus, Lactobacillus ghanensis, Lactobacillus graminis, Lactobacillus hammesii, Lactobacillus hamsteri, Lactobacillus harbinensis, Lactobacillus hayakitensis, Lactobacillus helveticus, Lactobacillus hilgardii, Lactobacillus homohiochii, Lactobacillus iners, Lactobacillus ingluviei, Lactobacillus intestinalis, Lactobacillus jensenii, Lactobacillus johnsonii, Lactobacillus kalixensis, Lactobacillus kefiranofaciens, Lactobacillus kefiri, Lactobacillus kimchii, Lactobacillus kitasatonis, Lactobacillus kunkeei, Lactobacillus leichmannii, Lactobacillus lindneri, Lactobacillus malefermentans, Lactobacillus mali, Lactobacillus manihotivorans, Lactobacillus mindensis, Lactobacillus mucosae, Lactobacillus murinus, Lactobacillus nagelii, Lactobacillus namurensis, Lactobacillus nantensis, Lactobacillus oligofermentans, Lactobacillus oris, Lactobacillus panis, Lactobacillus pantheris, Lactobacillus parabrevis, Lactobacillus parabuchneri, Lactobacillus paracollinoides, Lactobacillus parafarraginis, Lactobacillus parakefiri, Lactobacillus paralimentarius, Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus perolens, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus psittaci, Lactobacillus rennini, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus rimae, Lactobacillus rogosae, Lactobacillus rossiae, Lactobacillus ruminis, Lactobacillus saerimneri, Lactobacillus sakei, Lactobacillus salivarius, Lactobacillus sanfranciscensis, Lactobacillus satsumensis, Lactobacillus secaliphilus, Lactobacillus sharpeae, Lactobacillus siliginis, Lactobacillus spicheri, Lactobacillus suebicus, Lactobacillus thailandensis, Lactobacillus ultunensis, Lactobacillus vaccinostercus, Lactobacillus vaginalis, Lactobacillus versmoldensis, Lactobacillus vini, Lactobacillus vitulinus, Lactobacillus zeae, Lactobacillus zymae; Leclercia species, Legionella species: Legionella adelaidensis, Legionella anisa, Legionella beliardensis, Legionella birminghamensis, Legionella bozemanii, Legionella brunensis, Legionella busanensis, Legionella cherrii, Legionella cincinnatiensis, Legionella donaldsonii, Legionella drancourtii, Legionella drozanskii, Legionella erythra, Legionella fairfieldensis, Legionella fallonii,
Legionella feeleii, Legionella geestiana, Legionella genomospecies, Legionella gratiana, Legionella gresilensis, Legionella hackeliae, Legionella impletisoli, Legionella israelensis, Legionella jamestowniensis, 'Candidatus Legionella jeonii', Legionella jordanis, Legionella lansingensis, Legionella Iondiniensis, Legionella longbeachae, Legionella lytica, Legionella maceachernii, Legionella micdadei, Legionella moravica, Legionella nautarum, Legionella oakridgensis, Legionella parisiensis, Legionella pneumophila, Legionella quateirensis, Legionella quinlivanii, Legionella rowbothamii, Legionella rubrilucens, Legionella sainthelensi, Legionella santicrucis, Legionella shakespearei, Legionella spiritensis, Legionella steigerwaltii, Legionella taurinensis, Legionella tucsonensis, Legionella wadsworthii, Legionella waltersii, Legionella worsleiensis, Legionella yabuuchiae; Leminorella species, Leptospira species: Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira alexanderi, Leptospira weilii, Leptospira genomospecies 1 , Leptospira borgpetersenii, Leptospira santarosai, Leptospira inadai, Leptospira fainei,
Leptospira broomii, Leptospira licerasiae, Leptospira biflexa, Leptospira meyeri, Leptospira wolbachii, Leptospira genomospecies 3, Leptospira genomospecies 4, Leptospira genomospecies 5; Lepromatous leprosy (Danielssen-Boeck disease), Leptospira canicola, Leptospira hebdomadis, Leptospirosis (Weil disease/ Leptospira icterohaemorrhagiae/ Leptospira interrogans serovar icterohaemorrhagiae), Leptotrichia, Leuconostoc species: Leuconostoc carnosum, Leuconostoc citreum, Leuconostoc durionis, Leuconostoc fallax, Leuconostoc ficulneum, Leuconostoc fructosum, Leuconostoc garlicum, Leuconostoc gasicomitatum, Leuconostoc gelidum, Leuconostoc inhae, Leuconostoc kimchii, Leuconostoc lactis, Leuconostoc mesenteroides,
Leuconostoc pseudoficulneum, Leuconostoc pseudomesenteroides; Listeria species: Listeria grayi, Listeria innocua, Listeria ivanovii, Listeria monocytogenes (Listeriosis), Listeria seeligeri, Listeria welshimeri; Methanobacterium extroquens, Microbacterium multiforme, Micrococcus species: Micrococcus antarcticus, Micrococcus flavus, Micrococcus luteus,
Micrococcus lylae, Micrococcus mucilaginosis, Micrococcus roseus, Micrococcus sedentarius; Mobiluncus, Moellerella species, Morganella species, Moraxella species: Moraxella atlantae, Moraxella boevrei, Moraxella bovis, Moraxella canis, Moraxella caprae, Moraxella catarrhalis (Branhamella catarrhalis), Moraxella caviae, Moraxella cuniculi, Moraxella equi, Moraxella lacunata, Moraxella lincolnii, Moraxella nonliquefaciens, Moraxella oblonga, Moraxella osloensis, Moraxella saccharolytica; Morganella morganii, Mycobacterium species: Mycobacterium abscessus, Mycobacterium africanum, Mycobacterium agri, Mycobacterium aichiense, Mycobacterium alvei, Mycobacterium arupense, Mycobacterium asiaticum, Mycobacterium aubagnense, Mycobacterium aurum, Mycobacterium austroafricanum, Mycobacterium avium (Battey disease/ Lady Windermere syndrome), Mycobacterium avium paratuberculosis (implicated in Crohn's disease in humans and Johne's disease in sheep), Mycobacterium avium silvaticum, Mycobacterium avium "hominissuis", Mycobacterium colombiense,
Mycobacterium boenickei, Mycobacterium bohemicum, Mycobacterium bolletii, Mycobacterium botniense, Mycobacterium bovis (Bovine tuberculosis), Mycobacterium branderi, Mycobacterium brisbanense, Mycobacterium brumae, Mycobacterium canariasense, Mycobacterium caprae, Mycobacterium celatum, Mycobacterium chelonae, Mycobacterium chimaera, Mycobacterium chitae,
Mycobacterium chlorophenolicum, Mycobacterium chubuense, Mycobacterium conceptionense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium cosmeticum, Mycobacterium diernhoferi, Mycobacterium doricum, Mycobacterium duvalii, Mycobacterium elephantis, Mycobacterium fallax, Mycobacterium farcinogenes, Mycobacterium flavescens, Mycobacterium florentinum, Mycobacterium fluoroanthenivorans, Mycobacterium fortuitum, Mycobacterium fortuitum subsp. Acetamidolyticum, Mycobacterium frederiksbergense, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gilvum, Mycobacterium goodii, Mycobacterium gordonae (Mycobacterium aquae), Mycobacterium haemophilum, Mycobacterium hassiacum, Mycobacterium heckeshornense, Mycobacterium heidelbergense, Mycobacterium hiberniae, Mycobacterium hodleri, Mycobacterium holsaticum, Mycobacterium houstonense, Mycobacterium immunogenum, Mycobacterium interjectum, Mycobacterium intermedium, Mycobacterium intracellular, Mycobacterium kansasii,
Mycobacterium komossense, Mycobacterium kubicae, Mycobacterium kumamotonense, Mycobacterium lacus, Mycobacterium lentiflavum, Mycobacterium leprae (causes leprosy or Hansen disease/ Hanseniasis), Mycobacterium lepraemurium, Mycobacterium madagascariense, Mycobacterium mageritense, Mycobacterium malmoense, Mycobacterium marinum (Fish tank granuloma), Mycobacterium massiliense, Mycobacterium microti, Mycobacterium monacense, Mycobacterium montefiorense, Mycobacterium moriokaense, Mycobacterium mucogenicum, Mycobacterium murale, Mycobacterium nebraskense, Mycobacterium neoaurum, Mycobacterium neworleansense, Mycobacterium nonchromogenicum,
Mycobacterium novocastrense, Mycobacterium obuense, Mycobacterium palustre, Mycobacterium parafortuitum, Mycobacterium parascrofulaceum, Mycobacterium parmense, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium phocaicum, Mycobacterium pinnipedii, Mycobacterium porcinum, Mycobacterium poriferae, Mycobacterium pseudoshottsii,
Mycobacterium pulveris, Mycobacterium psychrotolerans, Mycobacterium pyrenivorans, Mycobacterium rhodesiae, Mycobacterium saskatchewanense, Mycobacterium scrofulaceum, Mycobacterium senegalense, Mycobacterium seoulense, Mycobacterium septicum, Mycobacterium shimoidei, Mycobacterium shottsii, Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium sphagni, Mycobacterium szulgai, Mycobacterium terrae, Mycobacterium thermoresistibile, Mycobacterium tokaiense, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tuberculosis (major cause of human tuberculosis), Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium pinnipedii', Mycobacterium tusciae, Mycobacterium ulcerans (causes Bairnsdale ulcer/ Buruli ulcer), Mycobacterium vaccae, Mycobacterium vanbaalenii, Mycobacterium wolinskyi, Mycobacterium xenopi; Mycoplasma species: Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma penetrans, Mycoplasma phocacerebrale, Mycoplasma pneumoniae, Nanukayami (Seven- day fever/ Gikiyami), Neisseria species: Neisseria gonorrhoea (Gonococcus/ Gonorrhea), Neisseria meningiditis (Meningococcus), Neisseria sicca, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria polysaccharea, Neisseria subflava; Nitrobacter species, Nocardia species: Nocardia asteroides, Nocardia brasiliensis,
Nocardia caviae; Noma (cancrum oris/ gangrenous stomatitis), Obesumbacterium, Oligotropha species, Orientia tsutsugamushi (Scrub typhus), Oxalobacter formigenes, Pantoea species: Pantoea agglomerans, Pantoea ananatis, Pantoea citrea, Pantoea dispersa, Pantoea punctata, Pantoea stewartii, Pantoea terrea; Pasteurella species: Pasteurella aerogenes,
Pasteurella anatis, Pasteurella avium, Pasteurella bettyae, Pasteurella caballi, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallicida, Pasteurella gallinarum, Pasteurella granulomatis, Pasteurella langaaensis, Pasteurella lymphangitidis, Pasteurella mairii, Pasteurella multocida, Pasteurella pneumotropica, Pasteurella skyensis, Pasteurella stomatis, Pasteurella testudinis, Pasteurella trehalosi, Pasteurella tularensis, Pasteurella ureae, Pasteurella volantium; Pediococcus species: Pediococcus acidilactici, Pediococcus cellicola, Pediococcus claussenii, Pediococcus damnosus, Pediococcus dextrinicus, Pediococcus ethanolidurans, Pediococcus inopinatus, Pediococcus parvulus, Pediococcus pentosaceus, Pediococcus stilesii;
Peptostreptococcus species: Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus harei, Peptostreptococcus hydrogenalis, Peptostreptococcus indoliticus, Peptostreptococcus ivorii, Peptostreptococcus lacrimalis, Peptostreptococcus lactolyticus, Peptostreptococcus magnus, Peptostreptococcus micros,
Peptostreptococcus octavius, Peptostreptococcus prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis; Photorhabdus species, Photorhizobium species, Plesiomonas shigelloides, Porphyromonas gingivalis, Pragia species, Prevotella, Propionibacterium species: Propionibacterium acnes, Propionibacterium propionicus; Proteus species: Proteus mirabilis, Proteus morganii, Proteus penneri, Proteus rettgeri, Proteus vulgaris; Providencia species: Providencia friedericiana, Providencia stuartii; Pseudomonas species: Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas anguilliseptica, Pseudomonas argentinensis, Pseudomonas borbori, Pseudomonas citronellolis, Pseudomonas flavescens, Pseudomonas mendocina, Pseudomonas nitroreducens, Pseudomonas oleovorans, Pseudomonas pseudoalcaligenes, Pseudomonas resinovorans, Pseudomonas straminea, Pseudomonas aurantiaca, Pseudomonas aureofaciens, Pseudomonas chlororaphis, Pseudomonas tragi, Pseudomonas lundensis, Pseudomonas taetrolens, Pseudomonas Antarctica, Pseudomonas azotoformans, Pseudomonas brassicacearum, Pseudomonas brenneri, Pseudomonas cedrina, Pseudomonas corrugate, Pseudomonas fluorescens, Pseudomonas gessardii, Pseudomonas libanensis, Pseudomonas mandelii, Pseudomonas marginalis, Pseudomonas mediterranea, Pseudomonas meridiana, Pseudomonas migulae, Pseudomonas mucidolens, Pseudomonas orientalis, Pseudomonas panacis, Pseudomonas proteolytica, Pseudomonas rhodesiae, Pseudomonas synxantha, Pseudomonas thivervalensis, Pseudomonas tolaasii, Pseudomonas veronii, Pseudomonas denitrificans, Pseudomonas pertucinogena, Pseudomonas cremoricolorata, Pseudomonas fulva, Pseudomonas monteilii, Pseudomonas mosselii, Pseudomonas oryzihabitans, Pseudomonas parafulva, Pseudomonas plecoglossicida, Pseudomonas putida, Pseudomonas balearica, Pseudomonas luteola, Pseudomonas stutzeri, Pseudomonas amygdale, Pseudomonas avellanae, Pseudomonas caricapapayae, Pseudomonas cichorii, Pseudomonas coronafaciens, Pseudomonas ficuserectae, Pseudomonas meliae,
Pseudomonas savastanoi, Pseudomonas syringae, Pseudomonas viridiflava, Pseudomonas abietaniphila, Pseudomonas acidophila, Pseudomonas agarici, Pseudomonas alcaliphila, Pseudomonas alkanolytica, Pseudomonas amyloderamosa, Pseudomonas asplenii, Pseudomonas azotifigens, Pseudomonas cannabina, Pseudomonas coenobios, Pseudomonas congelans,
Pseudomonas costantinii, Pseudomonas cruciviae, Pseudomonas delhiensis, Pseudomonas excibis, Pseudomonas extremorientalis, Pseudomonas frederiksbergensis, Pseudomonas fuscovaginae, Pseudomonas gelidicola, Pseudomonas grimontii, Pseudomonas indica, Pseudomonas jessenii, Pseudomonas jinjuensis, Pseudomonas kilonensis, Pseudomonas knackmussii, Pseudomonas koreensis, Pseudomonas lini, Pseudomonas lutea, Pseudomonas moraviensis, Pseudomonas otitidis, Pseudomonas pachastrellae, Pseudomonas palleroniana, Pseudomonas papaveris, Pseudomonas peli, Pseudomonas perolens, Pseudomonas poae, Pseudomonas pohangensis, Pseudomonas psychrophila, Pseudomonas psychrotolerans, Pseudomonas rathonis, Pseudomonas reptilivora, Pseudomonas resiniphila, Pseudomonas rhizosphaerae, Pseudomonas rubescens, Pseudomonas salomonii, Pseudomonas segitis, Pseudomonas septica, Pseudomonas simiae, Pseudomonas suis, Pseudomonas thermotolerans, Pseudomonas tremae, Pseudomonas trivialis, Pseudomonas turbinellae, Pseudomonas tuticorinensis, Pseudomonas umsongensis, Pseudomonas vancouverensis, Pseudomonas vranovensis, Pseudomonas xanthomarina; Rahnella species, Ralstonia species: Ralstonia basilensis, Ralstonia campinensis, Ralstonia eutropha, Ralstonia gilardii, Ralstonia insidiosa, Ralstonia mannitolilytica, Ralstonia metallidurans, Ralstonia paucula,
Ralstonia pickettii, Ralstonia respiraculi, Ralstonia solanacearum, Ralstonia syzygii, Ralstonia taiwanensis; Raoultella species, Rhodoblastus species, Rhodopseudomonas species, Rhinoscleroma, Rhizobium radiobacter, Rhodococcus equi, Rickettsia species: Rickettsia africae, Rickettsia akari, Rickettsia australis, Rickettsia conorii, Rickettsia felis, Rickettsia japonica,
Rickettsia mooseri, Rickettsia prowazekii (Typhus fever), Rickettsia rickettsii, Rickettsia siberica, Rickettsia typhi, Rickettsia conorii, Rickettsia africae, Rickettsia psittaci, Rickettsia quintana, Rickettsia rickettsii, Rickettsia trachomae; Rothia dentocariosa, Salmonella species: Salmonella arizonae, Salmonella Bongori, Salmonella enterica, Salmonella enteriditis, Salmonella paratyphi, Salmonella typhi (Typhoid fever), Salmonella typhimurium, Salmonella salamae, Salmonella arizonae, Salmonella diarizonae, Salmonella houtenae, Salmonella indica; Samsonia species, Serratia species: Serratia entomophila, Serratia ficaria, Serratia fonticola, Serratia grimesii, Serratia liquefaciens, Serratia marcescens, Serratia odoriferae, Serratia plymuthica,
Serratia proteamaculans, Serratia quinivorans, Serratia rubidaea, Serratia ureilytica; Shewanella putrefaciens, Shigella boydii, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Sodalis species, Spirillum species: Spirillum minus rat bite fever, Staphylococcus species: Staphylococcus aureus, Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus caprae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus felis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus intermedius, Staphylococcus lugdunensis, Staphylococcus pettenkoferi, Staphylococcus saprophyticus, Staphylococcus schleiferi, Staphylococcus simulans, Staphylococcus vitulus, Staphylococcus warneri, Staphylococcus xylosus; Stenotrophomonas species: Stenotrophomonas acidaminiphila, Stenotrophomonas dokdonensis, Stenotrophomonas koreensis, Stenotrophomonas maltophilia, Stenotrophomonas nitritireducens, Stenotrophomonas rhizophila; Streptobacillus species: Streptobacillus moniliformis (Streptobacillary rat bite fever); Streptococcus species:
Streptococcus Group A, Streptococcus Group B, Streptococcus agalactiae, Streptococcus aginosus, Streptococcus avium, Streptococcus bovis, Streptococcus canis, Streptococcus cricetus, Streptococcus faceium, Streptococcus faecalis, Streptococcus ferus, Streptococcus gallinarum, Streptococcus lactis, Streptococcus milleri, Streptococcus mitior, Streptococcus mitis, Streptococcus mutans, Streptococcus oralis, Streptococcus peroris, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus ratti, Streptococcus salivarius, Streptococcus sanguinis, Streptococcus sobrinus, Streptococcus parasanguinis, Streptococcus suis, Streptococcus thermophilus, Streptococcus vestibularis, Streptococcus viridans, Streptococcus uberis,
Streptococcus zooepidemicus; Tatumella species, Trabulsiella species, Treponema species: Treponema carateum (Pinta), Treponema denticola, Treponema endemicum (Bejel), Treponema pallidum (Syphilis), Treponema pertenue (Yaws); Tropheryma whipplei (Whipple disease), Tuberculoid leprosy, Ureaplasma urealyticum, Veillonella, Vibrio species: Vibrio aerogenes, Vibrio aestuarianus, Vibrio agarivorans, Vibrio albensis, Vibrio alginolyticus, Vibrio brasiliensis, Vibrio calviensis, Vibrio campbellii, Vibrio chagasii, Vibrio cholerae (Cholera), Vibrio cincinnatiensis, Vibrio Comma, Vibrio coralliilyticus, Vibrio crassostreae, Vibrio cyclitrophicus, Vibrio diabolicus, Vibrio diazotrophicus, Vibrio ezurae, Vibrio fischeri, Vibrio fluvialis, Vibrio fortis, Vibrio furnissii, Vibrio gallicus, Vibrio gazogenes, Vibrio gigantis, Vibrio halioticoli, Vibrio harveyi, Vibrio hepatarius, Vibrio hispanicus, Vibrio ichthyoenteri, Vibrio kanaloae, Vibrio lentus, Vibrio litoralis, Vibrio logei, Vibrio mediterranei, Vibrio metschnikovii, Vibrio mimicus, Vibrio mytili, Vibrio natriegens, Vibrio navarrensis, Vibrio neonatus, Vibrio neptunius, Vibrio nereis, Vibrio nigripulchritudo, Vibrio ordalii, Vibrio orientalis, Vibrio pacinii, Vibrio parahaemolyticus, Vibrio pectenicida, Vibrio penaeicida, Vibrio pomeroyi, Vibrio ponticus, Vibrio proteolyticus, Vibrio rotiferianus, Vibrio ruber, Vibrio rumoiensis, Vibrio salmonicida, Vibrio scophthalmi, Vibrio splendidus, Vibrio superstes, Vibrio tapetis, Vibrio tasmaniensis, Vibrio tubiashii, Vibrio vulnificus, Vibrio wodanis, Vibrio xuii;
Vogesella indigofera, Wigglesworthia species, Wolbachia secies, Xenorhabdus species, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, and Yokenella species.
1407. The method for vaccination according to any of claims 1293-1406, wherein the vaccination is for treatment of one or more infectious diseases.
1408. The method for vaccination according to claim 1407, wherein the one or more infectious diseases can be selected from the group consisting of Bacteria and bacterial diseases (Specific kind of Infections), Fungus and fungal infections (Specific kind of Infections), Helminths and helminthic conditions (Specific kind of Infections), Prions and prion related diseases (Specific kind of Infections), Protozoa and protozoal infections (Specific kind of Infections), Viruses and viral disease (Specific kind of Infections), Abscess, Acariasis, actinomycetoma, Adenitis, Adenoiditis, African trypanosomiasis, Alpers
Syndrome, Alphos, Alveolar osteitis, Amebiasis, Anorectal abscess, Anthrax, Ascariasis, Aspergillosis, Athlete's foot, Atypical pneumonia, Babesiosis, Bejel, Blastocystis hominis, Blastomycosis, Bolivian hemorrhagic fever, Botulism, Botryomycosis, Borna disease, Borreliosis (Lyme disease), Bovine spongiform encephalopathy, Brazilian purpuric fever (BPF), Bronchiolitis, Brucellosis,
Bubonic plague, Buruli ulcer, Candidiasis, Campylobacteriosis, Cat scratch fever, Cellulitis, Chagas disease, Chalazion, Chickenpox (Varicella), Chikungunya, Cholangitis, Cholecystitis, Cholera, Clonorchiasis, Coccidioidomycosis, Colorado Tick Fever (CTF), Common cold, Creutzfeldt- Jakob disease, Crimean-Congo hemorrhagic fever, Cryptococcosis,
Cryptosporidiosis, Cutaneous abscess, Cysticercosis, Cystitis, infective, Dengue fever, Dermatophytosis, Diarrheal diseases, Diphteria, Diphyllobothriasis, Discitis, Donovanosis, Dracunculiasis, Dukes' disease, Dysentery, Ebola hemorrhagic fever, Echinococcosis, Encephalitis, Enterobiasis, Epidural abscess, Erysipelas, Eumycetoma, Fascioliasis, Fatal Familial Insomnia, Filariasis, Finger pulp abscess, Fitz-Hugh-Curtis syndrome, Foodborne trematodiases, Foot-and-mouth disease, Gallbladder empyema, Gas gangrene, Gastroenteritis, Giardiasis, Glanders, Gnathostomiasis, Gonorrhea, Gradenigo-Lannois syndrome, Grisel syndrome, Helminthiasis, Hepatitis, Herpes simplex, Herpes zoster, HPV, Histoplasmosis, HIV/AIDS,
Hookworm, Hordeolum externum, Human African trypanosomiasis, Hymenolepiasis, Impetigo, Infectious mononucleosis, Influenza, Intertrigo, Intracranial abscess / granuloma, Intraspinal abscess / granuloma, Isosporiasis, IV catheter infection, Japanese Encephalitis, Kuru, Kyasanur forest disease, Labrea fever, La Crosse encephalitis, Lacrimal canaliculus, Lady Windermere syndrome, Laryngeal papillomatosis, Laryngitis, Lassa fever, Legionellosis, Leishmaniasis, Lemierre's syndrome, Leptospirosis, Leprosy, Listeriosis, Liver abscess, Loa loa filariasis, lobomycosis, Lower respiratory tract infection, Ludwig angina, Lung abscess, Lymphangitis, Lymphatic filariasis, Malaria, Marburg haemorrhagic fever, Measles, Mediastinitis, Melioidosis, Meningitis,
Metagonimiasis, Mumps, Murrain, Mycetoma, Mycosis, Myiasis, Necrotizing fasciitis, Neurocysticercosis, Nocardiosis, Omphalitis, Onchocerciasis, Ophthalmia neonatorum, Orbital cellulitis, Oropouche fever, Oroya fever, Osteomyelitis, Paragonimiasis, Paratyphoid fevers, Pediculosis, Periorbital cellulitis, Periodontis, Pertussis (Whooping Cough), Pharyngitis,
Pharyngoconjunctival fever, Phlegmon, Pigbel (enteritis necroticans), Pinta, Pinworm Infection, Plantar wart, Pneumonia, Pneumonic plague, Pogosta disease, Poliomyelitis, Pott's disease, Prostatitis, Protothecosis, Psittacosis, Pyelonephritis acute, Pyelonephritis chronic, Pyomyositis, Q fever, Quinsy, Rabies, Rat-bite fever, Relapsing fever, Retropharyngeal abscess, Rheumatic
Fever, Rhinosporidiosis, Rickettsialpox, Rift Valley fever, Ringworm, Rodentoleposis, Rocky Mountain Spotted Fever (RMSF), Roseola, Rubella, Salmonellosis, Scabies, Scarlet fever, Schistosomiasis, Septicemic plague, Septic arthropathy, Septic shock, Sepsis, Severe acute respiratory syndrome (SARS), Sexually transmissable disease, Shigellosis, Smallpox (Variola),
Sodoku, Spondylodiskitis, Strongyloidiasis, Subdiaphragmatic abscess, Subdural empyema, Suppurative thyroiditis, Surra, Sweating sickness, Syphilis, Taeniasis, Tetanus, Trachoma, Tick-borne diseases, Tinea barbae, Tinea capitis, Tinea corporis, Tinea cruris, Tinea faciei, Tinea manuum, Tinea nigra, Tinea pedis, Tinea versicolor, Tonsillitis, Toxocariasis, Toxoplasmosis, Tracheolaryngobronchitis, Trachoma, Transmissible spongiform encephalopathy, Traveler's diarrhea, Trench fever, Treponematoses, Trichinellosis, Trichinosis, Trichomoniasis, Trichuriasis, Tropical diseases, Trypanosomiasis, Tuberculosis (TB), Tularemia, Typhoid fever, Typhus, Upper respiratory tract infection, Urethritis, Urinary tract infection, Venezuelan hemorrhagic fever (VHF), Verruca plana, viral hemorrhagic fevers (VHFs), Wart, West Nile disease, Wound infection, Yaws, Yellow fever, Yersiniosis and Zygomycosis.
1409. The method for vaccination according to any of claims 1293-1408, wherein the vaccination is for treatment of one or more cancer diseases.
1410. The method for vaccination according to any of claims 1293-1409, wherein the vaccination is for prevention of one or more cancer diseases.
141 1. The method for vaccination according to any of claims 1293-1410, wherein the vaccination is for amelioration of one or more cancer diseases.
1412. The method for vaccination according to any of claims 1409-141 1 , wherein the one or more cancer diseases can be selected from the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, AIDS-Related Lymphoma, Anal Cancer, Astrocytoma (e.g. Childhood Cerebellar or Childhood Cerebral), Basal Cell Carcinoma, Extrahepatic Bile Duct Cancer, Bladder Cancer, Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma, Brain Stem Glioma,
Brain Tumor, Breast Cancer, Male Breast Cancer, Bronchial Adenomas/Carcinoids, Burkitt's Lymphoma, Carcinoid Tumor, Carcinoma of Unknown Primary, Primary Central Nervous System Lymphoma, Cerebral Astrocytoma/Malignant Glioma, Cervical Cancer, Childhood Cancers, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic
Myeloproliferative Disorders, Colon Cancer, Cutaneous T-CeII Lymphoma, Endometrial Cancer, Ependymoma (such as Childhood Epdndymoma), Esophageal Cancer, Ewing's Family of Tumors, Extracranial Germ Cell Tumor (such as Childhood Extracranial Germ Cell Tumor), Extragonadal Germ Cell Tumor, Eye Cancer (Intraocular Melanoma or Retinoblastoma), Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Hypothalamic and Visual Pathway Glioma (such as Childhood Hypothalamic and Visual Pathway Glioma), Intraocular Melanoma, Islet Cell
Carcinoma (Endocrine Pancreas), Kaposi's Sarcoma, Kidney (Renal Cell) Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Lung Cancer (Non- Small Cell or Small Cell), Lymphoma (such as AIDS-Related Lymphoma, Burkitt's Lymphoma, Cutaneous T-CeII Lymphoma, Non-Hodgkin's Lymphoma), Macroglobulinemia (such as Waldenstrom's Macroglobulinemia), Malignant
Fibrous Histiocytoma of Bone/Osteosarcoma, Medulloblastoma (such as Childhood Medulloblastoma), Melanoma, Merkel Cell Carcinoma, Mesothelioma (such as Adult Malignant Mesothelioma or childhood Mesothelioma), Metastatic Squamous Neck Cancer with Occult Primary, Multiple Endocrine Neoplasia Syndrome (such as occurring in childhood), Multiple Myeloma/Plasma Cell
Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases, Myeloma (such as Multiple Myeloma), Chronic myeloproliferative disorders, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Nasopharyngeal Cancer (such as Childhood Nasopharyngeal Cancer), Neuroblastoma, Oropharyngeal Cancer,
Osteosarcoma/Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Childhood Ovarian Cancer), Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Ovarian Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Cancer, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pineoblastoma and Supratentorial Primitive
Neuroectodermal Tumors, Pituitary Tumor, Pleuropulmonary Blastoma, Prostate Cancer, Renal Pelvis and Ureter Transitional Cell Cancer, Retinoblastoma, Rhabdomyosarcoma (such as Childhood Rhabdomyosarcoma), Salivary Gland Cancer, Adult-onset soft tissue Sarcoma, Soft Tissue Sarcoma (such as Childhood Soft Tissue Sarcoma), uterine
Sarcoma, Sezary Syndrome, Skin Cancer (such as non-Melanoma skin cancer), Merkel Cell Skin Carcinoma, Small Intestine Cancer, Supratentorial Primitive Neuroectodermal Tumors (such as occurring in Childhood), Cutaneous T-CeII Lymphoma, Testicular Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (such as Gestational Trophoblastic Tumor), Urethral Cancer, Endometrial uterine cancer, Uterine Sarcoma, Vaginal Cancer, Visual Pathway and Hypothalamic Glioma (such as Childhood Visual Pathway and Hypothalamic Glioma), Waldenstrom's Macroglobulinemia and Wilms' Tumor.
1413. The method for vaccination according to any of claims 1293-1412, wherein the vaccination is for treatment of one or more diseases selected from the group consisting of diseases of inflammatory, auto-immune, allergic, viral, cancerous, infectious, allo-or xenogene (graft versus host and host versus graft) origin.
1414. The method for vaccination according to any of claims 1293-1413, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of chronic inflammatory bowel disease such as Crohn's disease or ulcerative colitis, sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, malignant melanoma, renal carcinoma, breast cancer, lung cancer, cancer of the uterus, prostatic cancer, brain cancer, head and neck cancer, leukaemia, cutaneous lymphoma, hepatic carcinoma, colorectal cancer, bladder cancer, rejection-related disease, Graft- versus-host-related disease, or a viral disease associated with hepatitis, AIDS, measles, pox chicken pox, rubella or herpes.
1415. The method for vaccination according to any of claims 1293-1414, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of a disease of inflammatory/auto-immune origin, including asthma, hypersensitivity pneumonitis, interstitial lung disease, sarcoidosis, idiopathic pulmonary fibrosis, interstitial lung disease associated with Crohn s Disease or ulcerative colitis or Whipple's disease, interstitial lung disease associated with Wegeners granulomatosis or hypersensitivity vasculitis, vasculitis syndromes, Hennoch-Schonleins purpura, Goodpastures syndrome, Wegeners granulomatosis, renal diseases such as antibody mediated glomerulopathia as in acute glomerulonephritis, nephritis associated with systemic lupus erythematosus, nephritis associated with other systemic diseases such as Wegeners granulomatosis and Goodpastures syndrome and mixed connective tissue disease, chronic interstitial nephritis, chronic glomerulonephritis, gastrointestinal diseases such as Crohn s Disease, Ulcerative colitis, coeliac disease, Whipple's disease, collagenous colitis, eosinophilic colitis, lymphatic colitis, hepatobilliary diseases such as auto- immune hepatitis, alcohol induced hepatitis, periportal fibrosis, primary billiary cirrhosis, sclerosing colangitis, disorders of the central or peripheral nervous system such as demyelinating disease as multiple sclerosis, acute disseminated encephalomyelitis, sub-acute sclerosing panencephalitis, skin disease such as psoriasis, atopic dermatitis, eczema, allergic skin disease, progressive systemic sclerosis (scleroderma), exfoliating dermatitis, pemphigus vulgaris, joint diseases such as rheumatoid arthritis, ankylosing spondylitis, arthritis associated with psoriasis or inflammatory bowel disease, muscoloskelletal diseases such as myastenia gravis, polymyositis, endocrine diseases such as insulin dependent diabetes mellitus, auto-immune thyroiditis (Hashimoto), thyreotoxicosis, Graves, diseases of the hematopoetic system such as auto-immune anaemia, auto-immune thrombocytopenia, cardiovascular diseases such as cardiomyopathia, vasculitis, cardiovascular disease associated with systemic diseases as systemic lupus erythematosus, polyarthritis nodosa, rheumatoid arthritis, scleroderma, sarcoidosis, diseases of cancerous origin, including malignant melanoma, Sezary's syndrome, cutaneous T-cell lymphoma, renal cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, cancer of the uterus, prostatic cancer, hepatic carcinoma, lung cancer, and sarcoma, and diseases, disorders or conditions of allergic origin.
1416. The method for vaccination according to any of claims 1293-1415, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of autoimmune diseases including multiple sclerosis, type I diabetes mellitus, Hashimotos thyroiditis, pernicious anemia, Addison's disease, myasthenia gravis, rheumatoid arthritis, uveitis, psoriasis,
Guillain-Barre Syndrome and Grave's disease, systemic lupus erythematosus and dermatomyositis.
1417. The method for vaccination according to any of claims 1293-1416, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of hypersensitivity disorders like asthma, eczema, atopical dermatitis, contact dermatitis, other eczematous dermatitides, seborrheic dermatitis, rhinitis, Lichen planus, Pemplugus, bullous Pemphigoid, Epidermolysis bullosa, uritcaris, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Alopecia areata, atherosclerosis, primary biliary cirrhosis and nephrotic syndrome.
1418. The method for vaccination according to any of claims 1293-1417, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of intestinal inflammations, such as Coeliac disease, proctitis, eosinophilia gastroenteritis, mastocytosis, inflammatory bowel disease, Chrohn's disease and ulcerative colitis, as well as food-related allergies.
1419. The method for vaccination according to any of claims 1293-1418, wherein the vaccination is for treatment of one or more allergic diseases.
1420. The method for vaccination according to claim 1419, wherein the allergic diseases involve one or more of the allergens selected from the group consisting of inhalation allergens originating i. a. from trees, grasses, herbs, fungi, house dust mites, storage mites, cockroaches and animal hair, feathers, and dandruff, pollen allergens from trees, grasses and herbs are such originating from the taxonomic orders of Fagales, Oleales and Pinales including i. a. birch (Betula), alder (Alnus), hazel (Corylus), hornbeam (Carpinus) and olive (Olea), the order of Poales including i. a. grasses of the genera Lolium,
Phleum, Poa, Cynodon, Dactylis and Secale, the orders of Astrales and Urticales including i. a. herbs of the genera Ambrosia and Artemisia, inhalation allergens from fungi, allergens originating from the genera Alternaria and Cladosporium, inhalation allergens from house dust mites of the genus Dermatophagoides, storage mites from the genus Lepidoglyphys destructor, those from cockroaches and those from mammals such as cat, dog, horse, cow, and bird.
1421. The method for vaccination according to any of claims 1293-1420, wherein the vaccination is for treatment of one or more diseases diseases selected from the group consisting of Bet v 1 (B. verrucosa, birch), AIn g 1 (Alnus glutinosa, alder), Cor a 1 (Corylus avelana, hazel) and Car b 1 (Carpinus betulus, hornbeam) of the Fagales order, Cry j 1 (Pinales), Amb a 1 and 2, Art v 1 (Asterales), Par j 1 (Urticales), Ole e 1 (Oleaves), Ave e 1 , Cyn d 1 , Dac g 1 , Fes p 1 , HoI 1 1 , LoI p 1 and 5, Pas n 1 , PhI p 1 and 5, Poa p 1 ,2 and 5, Sec c 1 and 5, and Sor h 1 (various grass pollens), Alt a 1 and CIa h 1 (fungi), Der f 1 and 2, Der p 1 and 2 (house dust mites, D. farinae and D. pteronyssinus, respectively), Lep d 1 , Bla g 1 and 2, Per a 1 (cockroaches, Blatella germanica and Periplaneta americana, respectively), FeI d 1 (cat), Can f 1 (dog), Equ c 1 ,2 and 3 (horse), Apis m 1 and 2 (honeybee), Ves g 1 ,2 and 5, Pol a 1 ,2 and 5 (all wasps) and Sol i 1 , 2,3 and 4 (fire ant).
1422. The method for vaccination according to any of claims 1293-1421 , wherein the vaccination results in up-regulation of the immune response of said individual.
1423. The method for vaccination according to any of claims 1293-1422, wherein the vaccination results in down-regulation of the immune response of said individual.
1424. The method for vaccination according to any of claims 1293-1423, wherein the vaccination results in modulation of the immune response of said individual.
1425. The method for vaccination according to any of claims 1293-1424, wherein the vaccination results in stimulation of the immune response of said individual.
1426. The method for vaccination according to any of claims 1293-1425, wherein the vaccination results in inhibition of the immune response of said individual.
1427. The method for vaccination according to any of claims 1293-1426, wherein the vaccination results in restoration of the immune reponse of said individual.
1428. The method for vaccination according to any of claims 1293-1427, wherein the vaccination results in induction of anergy in a cell.
1429. The method for vaccination according to any of claims 1293-1428, wherein the vaccination results in adoptive immunotherapy.
1430. The method for vaccination according to any of claims 1293-1429, wherein the vaccination comprises in vivo therapy and/or ex vivo therapy.
1431. The method for vaccination according to any of claims 1293-1430, wherein the vaccination comprises combination therapy such as coadministration of the composition according to claims 1 -1291 and one ore more medicaments.
1432. The method for vaccination according to claim 1431 , wherein the coadministration comprises that the composition according to claims 1 -1291 and the one ore more medicaments can be administered simulatenously.
1433. The method for vaccination according to claim 1431 , wherein the coadministration comprises that the composition according to claims 1 -1291 and the one ore more medicaments can be administered sequentially in any order.
1434. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an anti-cancer medicament.
1435. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an anti-HIV medicament.
1436. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be a chemotherapeutic agent.
1437. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an immunotherapeutic agent.
1438. The method for vaccination according to claim 1431 , wherein the combination therapy comprises radiation therapy.
1439. The method for vaccination according to claim 1431 , wherein the combination therapy comprises gene therapy.
1440. The method for vaccination according to claim 1431 , wherein the combination therapy comprises surgery.
1441. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be selected from the group of chemotherapeutic agents including methotrexate, vincristine, adriamycin, cisplatin, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MM1270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, MTA/LY231514, LY264618/Lometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412,
Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, lncel/VX-710, VX-853, ZD0101 , ISI641 , ODN 698, TA 2516/Marmistat, BB2516/Marmistat, CDP 845, D2163, PD183805, DX8951f, Lemonal DP 2202, FK 317, Picibanil/OK-432, AD 32/Valrubicin, Metastron/strontium derivative, Temodal/Temozolomide,
Evacet/liposomal doxorubicin, Yewtaxan/Placlitaxel, Taxol/Paclitaxel, Xeload/Capecitabine, Furtulon/Doxifluridine, Cyclopax/oral paclitaxel, Oral Taxoid, SPU-077/Cisplatin, HMR 1275/Flavopiridol, CP-358 (774)/EGFR, CP- 609 (754)/RAS oncogene inhibitor, BMS-182751 /oral platinum, UFT(Tegafur/Uracil), Ergamisol/Levamisole, Eniluracil/776C85/5FU enhancer,
Campto/Levamisole, Camptosar/lrinotecan, Tumodex/Ralitrexed, Leustatin/Cladribine, Paxex/Paclitaxel, Doxil/liposomal doxorubicin, Caelyx/liposomal doxorubicin, Fludara/Fludarabine, Pharmarubicin/Epirubicin, DepoCyt, ZD1839, LU 79553/Bis-Naphtalimide, LU 103793/Dolastain, Caetyx/liposomal doxorubicin, Gemzar/Gemcitabine, ZD 0473/Anormed, YM 1 16, Iodine seeds, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/Dexifosamide, Ifes/Mesnex/lfosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331 , Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide,
Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorambucil, Cytarabine HCI, Dactinomycin, Daunorubicin HCI, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH-releasing factor analogue), Lomustine (CCNU),
Mechlorethamine HCI (nitrogen mustard), Mercaptopurine, Mesna, Mitotane (o.p'-DDD), Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m-AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), lnterleukin 2, Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone;
MGBG), Pentostatin (2'deoxycoformycin), Semustine (methyl-CCNU), Teniposide (VM-26) and Vindesine sulfate. 2. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be selected from the group of anti-cancer drugs consisting of Aldesleukin/Proleukin (Chiron Corp), Alemtuzumab/Campath (Millennium and ILEX Partners, LP), alitretinoin/Panretin (Ligand Pharmaceuticals), allopurinol/Zyloprim (GlaxoSmithKline), altretamine/Hexalen (US Bioscience), amifostine/Ethyol (US Bioscience), anastrozole/Arimidex (AstraZeneca), arsenic trioxide/Trisenox (Cell Therapeutic),
Asparaginase/Elspar (Merck & Co, Inc), BCG Live/TICE BCG (Organon Teknika Corp), bexarotene capsules/Targretin (Ligand Pharmaceuticals), bleomycin/Blenoxane (Bristol-Myers Squibb), busulfan/Busulfex (GlaxoSmithKline), calusterone/Methosarb (Pharmacia & Upjohn Company), capecitabine/Xeloda (Roche), carboplatin/Paraplatin (Bristol-Myers Squibb), carmustine/BCNU, BiCNU (Bristol-Myers Squibb), carmustine with Polifeprosan 20 Implant/Gliadel Wafer (Guilford Pharmaceuticals Inc.), celecoxib/Celebrex (Searle), chlorambucil /Leukeran (GlaxoSmithKline), cisplatin/Platinol (Bristol- Myers Squibb), cladribine/Leustatin, 2-CdA (R.W. Johnson Pharmaceutical Research Institute), cyclophosphamide Cytoxan/ Neosar (Bristol-Myers Squibb), cytarabine/Cytosar-U (Pharmacia & Upjohn Company), dacarbazine/DTIC-Dome (Bayer), dactinomycin/actinomycin D Cosmegen (Merck), Darbepoetin alfa/Aranesp (Amgen, Inc), daunorubicin/daunomycin/Daunorubicin (Bedford Labs), daunorubicin/daunomycin/Cerubidine (Wyeth Ayerst), Denileukin/diftitox/Ontak
(Seragen, Inc), dexrazoxane/Zinecard (Pharmacia & Upjohn Company), docetaxel/Taxotere (Aventis Pharmaceutical), doxorubicin Adriamycin/Rubex (Pharmacia & Upjohn Company), DROMOSTANOLONE PROPIONATE/MASTERONE INJECTION (SYNTEX), Elliott's B Solution (Orphan Medical, Inc), epirubicin/Ellence (Pharmacia & Upjohn Company), etoposide phosphate (Bristol-Myers Squibb), etoposide/VP-16/Vepesid (Bristol- Myers Squibb), exemestane/Aromasin (Pharmacia & Upjohn Company), Filgrastim/Neupogen (Amgen, Inc), floxuridine/FUDR (Roche), fludarabine/Fludara (Berlex Laboratories Inc.), fluorouracil/5-FU/Adrucil (ICN Puerto Rico), fulvestrant/Faslodex (IPR), gemcitabine/Gemzar (EIi Lilly), gemtuzumab/ozogamicin/Mylotarg (Wyeth Ayerst), goserelin acetate/Zoladex Implant (AstraZeneca Pharmaceuticals), hydroxyurea/Hydrea (Bristol-Myers Squibb), lbritumomab Tiuxetan/Zevalin (IDEC Pharmaceuticals Corp), idarubicin/ldamycin (Adria Laboratories), ifosf amide/I FEX (Bristol-Myers Squibb), imatinib mesylate/Gleevec (Novartis), Interferon alfa-2a/Roferon-A
(Hoffmann-La Roche Inc), Interferon alfa-2b/lntron A (Schering Corp), irinotecan/Camptosar (Pharmacia & Upjohn Company), letrozole/Femara (Novartis), leucovorin Wellcovorin/Leucovorin (Immunex Corporation), levamisole/Ergamisol (Janssen Research Foundation), lomustine/CCNU/CeeBU (Bristol-Myers Squibb), meclorethamine/nitrogen mustard/Mustargen (Merck), megestrol acetate/Meg ace (Bristol-Myers Squibb), melphalan/L-PAM/Alkeran (GlaxoSmithKline), mercaptopurine/6-MP Purinethol (GlaxoSmithKline), mesna/Mesnex (Asta Medica), methotrexate (Lederle Laboratories), methoxsalen/Uvadex (Therakos), mitomycin C/Mutamycin (Bristol-Myers Squibb), mitomycin C/Mitozytrex (Supergen), mitotane/Lysodren
(Bristol-Myers Squibb), mitoxantrone/Novantrone (Lederle Laboratories), nandrolone phenpropionate/Durabolin-50 (Organon), Nofetumomab/Verluma (Boehringer lngelheim Pharma KG (formerly Dr. Karl Thomae GmbH)), Oprelvekin/Neumega (Genetics Institute), oxaliplatin/Eloxatin (Sanofi Synthelabo), paclitaxel/Taxol (Bristol-Myers Squibb), pamidronate/Aredia (Novartis), pegademase/Adagen (Pegademase Bovine) (Enzon), Pegaspargase/Oncaspar (Enzon, Inc), Pegfilgrastim/Neulasta (Amgen, Inc), pentostatin/Nipent (Parke-Davis Pharmaceutical Co.), pipobroman/Vercyte (Abbott Labs), plicamycin/mithramycin/Mithracin (Pfizer Labs), porfimer sodium/Photofrin (QLT Phototherapeutics Inc.), procarbazine/Matulane (Sigma
Tau Pharms), quinacrine/Atabrine (Abbott Labs), Rasburicase/Elitek (Sanofi- Synthelabo, Inc), Rituximab/Rituxan (Genentech, Inc), Sargramostim/Prokine (Immunex Corp), streptozocin/Zanosar(Pharmacia & Upjohn Company), talc/Sclerosol (Bryan), tamoxifen/Nolvadex (AstraZeneca Pharmaceuticals), temozolomide/Temodar (Schering), teniposide/VM-26/Vumon (Bristol-Myers
Squibb), testolactone/Teslac (Bristol-Myers Squibb), thioguanine/6- TG/Thioguanine (GlaxoSmithKline), thiotepa/Thioplex (Lederle Laboratories), topotecan/Hycamtin (GlaxoSmithKline), topotecan/Hycamtin (GlaxoSmithKline), toremifene/Fareston (Orion Corp), Tositumomab/Bexxar (Corixa Corporation), Trastuzumab/Herceptin (Genentech, Inc), tretinoin/ATRA/Vesanoid (Roche), Uracil Mustard (Roberts Labs), valrubicin/Valstar (Medeva), vinblastine/Velban (EIi Lilly), vincristine/Oncovin (EIi Lilly), vinorelbine/Navelbine (GlaxoSmithKline), and zoledronate/Zometa (Novartis).
1443. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be selected from the group of the immunotherapeutic agents comprising Ributaxin, Herceptin, Quadramet, Panorex, IDEC-Y2B8, BEC2, C225, Oncolym, SMART Ml 95, ATRAGEN, Ovarex, Bexxar, LDP-03, ior t6, MDX-210, MDX- 1 1 , MDX-22, OV103, 3622W94, anti-VEGF, Zenapax, MDX-
220, MDX-447, MELIMMUNE-2, MELIMMUNE-1 , CEACIDE, Pretarget, NovoMAb-G2, TNT, Gliomab-H, GNI-250, EMD-72000, LymphoCide, CMA 676, Monopharm-C, 4B5, ior egf.r3, ior c5, BABS, anti-FLK-2, MDX-260, ANA Ab, SMART 1 D10 Ab, SMART ABL 364 Ab and ImmuRAIT-CEA, a cytokine or an interferon.
1444. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an antiviral drug such as a Nucleoside/Nucleotide Reverse Transcriptase Inhibitor.
1445. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an antiviral drug such as Non-Nucleoside Reverse Transcriptase Inhibitors.
1446. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be a Protease Inhibitor.
1447. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be a Fusion or Entry Inhibitor.
1448. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be an lntegrase Inhibitor.
1449. The method for vaccination according to claim 1431 , wherein the one ore more medicaments can be selected from the group consisting of lamivudine,
Epivir, abacavir, Ziagen, AZT or ZDV, Zidovudine, Retrovir, d4T, Stavudine, Zerit, ddC, Zalcitabine, Hivid, ddl, didanosine, Videx (tablet), Videx EC (capsule), FTC, emtricitabine, Emtriva, TDF, tenofovir, Viread, Epzicom, Kivexa, Trizivir, Combivir, Truvada, Delavirdine, Rescriptor, Efavirenz, Sustiva, Stocrin, Etravirine, Intelence, Nevirapine, Viramune, amprenavir, Agenerase, fosamprenavir, Lexiva, Telzir, Atazanavir, Reyataz, Darunavir, Prezista, Indinavir, Crixivan, lopinavir, ritonavir, Kaletra, Aluvia, nelfinavir, Viracept, ritonavir, Norvir, saquinavir, Fortovase, Invirase, Tipranavir, Aptivus, Enfuvirtide, Fuzeon, maraviroc, Celsentri, Selzentry, raltegravir, Isentress, Atripla, Atazanavir/r, Darunavir/r, Raltegravir, Maraviroc, and Etravirine.
1450. A kit-of-parts comprising the composition according to any of claims 1 - 1291 and at least one addition component.
1451. Use of the kit-of-parts according to claim 1450 for vaccination of an individual in need thereof.
1452. Use of the kit-of-parts according to claim 1450 for vaccination of an individual in need thereof according to the method of any of claims 1293-1449.
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