WO2016103192A1 - Amino acid and peptide conjugates and uses thereof - Google Patents

Amino acid and peptide conjugates and uses thereof Download PDF

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Publication number
WO2016103192A1
WO2016103192A1 PCT/IB2015/059901 IB2015059901W WO2016103192A1 WO 2016103192 A1 WO2016103192 A1 WO 2016103192A1 IB 2015059901 W IB2015059901 W IB 2015059901W WO 2016103192 A1 WO2016103192 A1 WO 2016103192A1
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Prior art keywords
amino acid
peptide
seq
sequence
6alkyl
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PCT/IB2015/059901
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English (en)
French (fr)
Inventor
Margaret Anne Brimble
Peter Roderick Dunbar
Geoffrey Martyn Williams
Daniel VERDON
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Individual
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Priority to US15/535,956 priority Critical patent/US10253062B2/en
Priority to MX2017008406A priority patent/MX2017008406A/es
Priority to EP15872074.8A priority patent/EP3237374A4/en
Priority to BR112017013574A priority patent/BR112017013574A2/pt
Priority to SG11201704962WA priority patent/SG11201704962WA/en
Priority to CN201580076680.8A priority patent/CN107250103A/zh
Priority to CA2971677A priority patent/CA2971677A1/en
Priority to KR1020177020221A priority patent/KR20170094449A/ko
Priority to AU2015370479A priority patent/AU2015370479B2/en
Application filed by Individual filed Critical Individual
Priority to JP2017534727A priority patent/JP2018505152A/ja
Priority to RU2017126206A priority patent/RU2017126206A/ru
Publication of WO2016103192A1 publication Critical patent/WO2016103192A1/en
Priority to IL252902A priority patent/IL252902A0/en
Anticipated expiration legal-status Critical
Priority to US16/251,136 priority patent/US11014960B2/en
Priority to AU2020256429A priority patent/AU2020256429A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
    • C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
    • C07K1/1075—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of amino acids or peptide residues
    • 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
    • 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
    • A61K47/54—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 compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • A61K2039/6018—Lipids, e.g. in lipopeptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
    • C12N2710/16222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
    • C12N2710/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates to amino acid and peptide conjugates, methods for making amino acid and peptide conjugates, conjugates produced by the methods,
  • compositions comprising the peptides and conjugates, methods of eliciting immune responses in a subject and methods of vaccinating a subject, uses of the peptides and conjugates for the same, and uses of the peptides and conjugates in the manufacture of medicaments for the same.
  • Synthetic peptide vaccines generally comprise a synthetic copy of an immunogenic part of protein antigens. This approach to vaccine development has a number of advantages, including ease of synthesis, avoidance of potentially toxic biological by-products and straightforward characterisation.
  • peptide vaccines A key issue in the development of peptide vaccines is the lack of immunogenicity displayed by peptides as sole vaccine components. It is usually necessary to include in the vaccine an adjuvant, designed to activate components of the innate immune system (e.g. Freund's adjuvant).
  • an adjuvant designed to activate components of the innate immune system (e.g. Freund's adjuvant).
  • An alternative strategy in peptide vaccine design is to create self-adjuvanting vaccines in which the peptide epitope of interest is covalently linked to an appropriate adjuvant.
  • Such self-adjuvanting vaccines may have enhanced antigen uptake, presentation and dendritic cell maturation compared to simple co-formulation of the antigen with an external adjuvant.
  • the present invention provides a method for making a peptide conjugate, the method comprising
  • lipidated amino acid or peptide to one or more amino acids or peptides to provide a peptide conjugate, and wherein the peptide conjugate comprises one or more EBV LMP2 epitopes.
  • the present invention provides a method for making a peptide conjugate, the method comprising reacting
  • the method further comprising coupling the amino acid of the amino acid conjugate to an amino acid or a peptide to provide a peptide conjugate, and wherein the peptide conjugate comprises one or more EBV LMP2 epitopes.
  • the present invention provides a method for making a peptide conjugate, the method comprising reacting
  • peptide-comprising conjugation partner comprises one or more EBV LMP2 epitopes
  • the present invention provides an amino acid conjugate or peptide conjugate as herein described.
  • the amino acid conjugate or peptide conjugate comprises one or more EBV LMP2 epitopes.
  • the amino acid conjugate or peptide conjugate is an amino acid conjugate or peptide conjugate made by a method of the present invention.
  • the present invention provides a peptide conjugate comprising one or more EBV LMP2 epitopes.
  • the one or more EBV LMP2 epitopes are MHCI epitopes.
  • the peptide conjugate comprises one or more EBV LMP2 epitopes selected from the group consisting of any one of SEQ ID NOs 76 - 101.
  • the peptide conjugate comprises a peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the the peptide conjugate comprises a peptide comprising or consisting of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprising or consisting of 20 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the present invention provides an isolated, purified, or recombinant peptide comprising or consisting of 12 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the isolated, purified, or recombinant peptide comprises or consists of 15 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75, or comprises or consists of 20 or more contiguous amino acids from the amino acid sequence of any one of SEQ ID NOs 1 - 75.
  • the peptide comprises, consists of, or consists essentially of an amino acid sequence selected from the group consisting of any one of SEQ ID NOs 1 - 75.
  • the lipidated amino acid or peptide comprises one or more of the following : PamlCys, Pam2Cys, and Pam3Cys.
  • the lipidated amino acid or peptide comprises one or more of the following : PamlCSK 4 , Pam2 CSK 4 , and Pam3 CSK 4 .
  • the lipidated amino acid or peptide is acetylated or amidated, for example, the lipidated amino acid or peptide comprises acetylated
  • PamlCys acetylated Pam2Cys, or acetylated Pam3Cys, or amidated PamlCys, amidated Pam2Cys, or amidated Pam3Cys.
  • the amino acid-comprising conjuation partner is a peptide- containing conjugation partner
  • the lipid-containing conjugation partner is coupled to the peptide of the peptide-containing conjugation partner.
  • the lipid-containing conjugation partner is conjugated to the or an amino acid of the amino acid-containing conjugation partner or the peptide of the peptide-containing conjugation partner.
  • the lipid-containing conjugation partner is conjugated to the or an amino acid of the amino acid-containing conjugation partner.
  • the present invention provides a method for making a peptide conjugate, the method comprising reacting
  • peptide-containing conjugation partner wherein the peptide-comprising partner comprises one or more EBV LMP2 epitopes
  • the conjugate is a lipopeptide, such that the method is for making a lipopeptide.
  • the lipid-containing conjugation partner comprises the carbon- carbon double bond
  • the peptide of the peptide-containing conjugation partner comprises the thiol
  • the amino acid-comprising conjugation partner comprises one or more EBV LMP2 epitopes. In one embodiment, the peptide-containing conjugation partner comprises one or more EBV LMP2 epitopes. In one embodiment, the amino acid- comprising conjugation partner comprises two or more EBV LMP2 epitopes. In one embodiment, the peptide-containing conjugation partner comprises two or more EBV LMP2 epitopes. In one embodiment, the peptide conjugate comprises two or more EBV LMP2 epitopes. In one embodiment, the epitope is a peptide epitope. In one
  • the amino acid-comprising conjugation partner consists of a peptide. In one embodiment, the amino acid-comprising conjugation partner consists of a peptide comprising a peptide epitope. In one embodiment, the peptide-containing conjugation partner consists of a peptide. In one embodiment, the peptide-containing conjugation partner consists of a peptide comprising a peptide epitope.
  • the amino acid-comprising conjugation partner comprises an epitope bound to the or an amino acid of the conjugation partner.
  • the peptide-containing conjugation partner comprises an epitope bound to the peptide of the peptide-containing conjugation partner. In some embodiments, the epitope is bound to the peptide via linker group. In some embodiments, the amino acid-comprising conjugation partner comprises a peptide epitope bound to the or an amino acid of the conjugation partner via a linker group. In some embodiments, the peptide-containing conjugation partner comprises a peptide epitope bound to the peptide via a linker group.
  • the amino acid-comprising conjugation partner and/or the peptide-containing conjugation partner comprises an antigenic peptide.
  • the peptide conjugate comprises an antigenic peptide.
  • the method further comprises coupling the amino acid of the amino acid conjugate to an amino acid or a peptide to provide a peptide conjugate, wherein the peptide conjugate comprises one or more EBV LMP2 epitopes.
  • coupling a peptide comprises individually coupling one or more amino acids and/or one or more peptides.
  • the method further comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate to an amino acid or a peptide so as to provide a peptide conjugate comprising a linker group or one or more amino acids thereof.
  • the method further comprises coupling an amino acid of the peptide conjugate comprising a linker group or one or more amino acids thereof to an amino acid or a peptide so as to provide a peptide conjugate comprising one or more EBV LMP2 epitopes bound to the amino acid to which lipid-containing conjugation partner is conjugated via a linker group.
  • the amino acid of the peptide conjugate to which the lipid- containing conjugate is conjugated is an N-terminal amino acid residue.
  • the method further comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate to an amino acid or a peptide so as to provide a peptide conjugate comprising one or more EBV LMP2 epitopes.
  • the method further comprises coupling one or more EBV LMP2 epitopes to the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate. In some embodiments, the method further comprises coupling one or more EBV LMP2 epitopes to the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate. In some embodiments, the epitope is coupled or bound via a linker group. In some embodiments, the method further comprises coupling an epitope to the peptide of the peptide conjugate. In some embodiments, the method further comprises coupling a peptide epitope to the peptide of the peptide conjugate. In some embodiments, the epitope is bound to the peptide via a linker group. In various examples, the epitope is a EBV LMP2 epitope.
  • the amino acid-comprising conjugation partner consists of an amino acid.
  • the carboxyl group of the C-terminus of the amino acid is protected with a carboxyl protecting group and/or the Na-amino group of the amino acid is protected with an amino protecting group.
  • the carboxyl group of the C-terminus of the peptide is protected with a carboxyl protecting group and/or the Na-amino group of the peptide is protected with an amino protecting group.
  • the lipid-containing conjugation partner comprises one or more optionally substituted straight or branched aliphatic or heteroaliphatic chains each containing at least 4 chain-linked atoms. In one embodiment, the lipid-containing conjugation partner comprises one or more optionally substituted straight or branched aliphatic or heteroaliphatic chains each containing at least 6 chain-linked atoms. In one specifically contemplated embodiment, the one or more chains are aliphatic. In one specifically contemplated embodiment, the one or more chains are saturated.
  • the one or more chains are optionally substituted. In some embodiments, the one or more chains are optionally substituted with one or more aryl groups.
  • the one or more chains comprise at least 4, 6, 8, 10, 12, or 14 chain-linked atoms. In some embodiments, the one or more chains comprise from 4-22, 6-22, 8-22, 10-22, 12-22, or 14-22 chain-linked atoms.
  • the one or more chains are covalently bound to a moiety comprising the carbon-carbon double bond or the thiol by a heteroatom-containing functional group.
  • heteroatom-containing functional groups include but are not limited to ether, amine, sulfide, sulfoxide, sulfone, ester, amide, carbonate, carbamate, and urea groups.
  • the one or more chains are covalently bound to the moiety by ester functional groups.
  • the lipid-containing conjugation partner comprises one or more saturated or unsaturated fatty acid esters.
  • the fatty acid is saturated.
  • one or more fatty acid ester is bound to the moiety comprising to carbon-carbon double bond or thiol.
  • the ester is an ester of the carboxyl group of the fatty acid and an alcohol of the moiety.
  • the fatty acid is a C4-22 fatty acid. In one embodiment, the fatty acid is a C6-22 fatty acid. In another embodiment, the fatty acid is a ClO-22 fatty acid. In yet another embodiment, the fatty acid is a C12-22 fatty acid. In one exemplary embodiment, the fatty acid is a C12, C14, C16, C18, or C20 fatty acid.
  • the fatty acid is lauric acid, myristic acid, palmitic acid, stearic acid, arachic acid, palmitoleic acid, oleic acid, elaidic acid, linoleic acid, a-linolenic acid, and arachidonic acid.
  • the fatty acid is lauric acid, myristic acid, palmitic acid, or stearic acid. In a specifically contemplated embodiment, the fatty acid is palmitic acid.
  • the lipid-containing conjugation partner comprises one or two fatty acid esters. In a specifically contemplated embodiment, the lipid-containing conjugation partner comprises one fatty acid ester.
  • the fatty acid ester is an ester of an alcohol comprising the carbon-carbon double bond or thiol.
  • the alcohol is a monohydric, dihydric, or trihydric C2-6 aliphatic alcohol.
  • the alcohol is a monohydric or dihydric C2-4 aliphatic alcohol.
  • the alcohol is a monohydric C2 aliphatic or monohydric or dihydric C3 aliphatic alcohol.
  • the alcohol is a monohydric C2 alcohol.
  • the lipid-containing conjugation partner comprises the carbon- carbon double bond.
  • the alcohol comprises the carbon-carbon double bond.
  • the alcohol is vinyl alcohol.
  • the peptide is a synthetic peptide.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises a synthetic peptide.
  • the synthetic peptide is a peptide prepared by a method comprising solid phase peptide synthesis (SPPS).
  • the or an amino acid of the amino acid-comprising conjugation partner comprises the carbon-carbon double bond or thiol.
  • an amino acid residue of the peptide of the peptide-containing conjugation partner comprises the carbon-carbon double bond or thiol.
  • the amino acid residue comprising the carbon-carbon double bond or thiol is a terminal amino acid residue.
  • the terminal amino acid residue is an N-terminal residue.
  • the Na-amino group of the amino acid comprising the carbon- carbon double bond or thiol is acylated.
  • the method further comprises acylating the Na-amino group of the amino acid of the amino acid conjugate or the amino acid residue of the peptide conjugate to which the lipid-containing conjugation partner is conjugated. In certain embodiments, the method further comprises acylating the ⁇ -amino group with a C2-20 fatty acid.
  • the or an amino acid of the amino acid-comprising conjugation partner comprises the thiol.
  • an amino acid residue of the peptide of the peptide-containing conjugation partner comprises the thiol.
  • the thiol is the thiol of a cysteine residue.
  • the cysteine residue is a terminal residue.
  • the cysteine residue is an N-terminal residue.
  • the amino group of the cysteine residue is acylated.
  • the amino group is acylated with a C2-20 fatty acid.
  • the C2-20 fatty acid is acetyl or palmitoyl. In another exemplary embodiment, the C2-20 fatty acid is acetyl.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises from 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • the peptide-containing conjugation partner comprises from 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises a peptide comprising from 8 to 60 amino acids. In one exemplary embodiment, the peptide comprises from 8 to 60 amino acids.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises from 5 to 220, 8 to 220, 5 to 175, 8 to 175, 8 to 150, 10 to 150, 15 to 125, 20 to 100, 20 to 80, 20 to 60, 25 to 100, 25 to 80, 25 to 60, 30 to 80, 40 to 60, or 50 to 60 amino acids.
  • the peptide-containing conjugation partner comprises from 5 to 220, 8 to 220, 5 to 175, 8 to 175, 8 to 150, 10 to 150, 15 to 125, 20 to 100, 20 to 80, 20 to 60, 25 to 100, 25 to 80, 25 to 60, 30 to 80, 40 to 60, or 50 to 60 amino acids.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises from 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • the peptide-containing conjugation partner comprises from 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • the amino acid-comprising conjugation partner and/or peptide conjugate comprises one or more solubilising groups.
  • the peptide- containing conjugation partner comprises one or more solubilising groups.
  • the solubilising group is an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain. In certain embodiments, the solubilising group is an amino acid sequence comprising a sequence of two or more consecutive hydrophilic amino acid residues in the peptide chain. In one embodiment, the hydrophilic amino acid residues are cationic amino acid residues. In one
  • the cationic amino acid residues are arginine or lysine residues. In one specifically contemplated embodiment, the cationic amino acid residues are lysine residues. In one embodiment, the sequence comprises from 2 to 20, 2 to 15, 2 to 10, 3 to 7, or 3 to 5 amino acids. In one embodiment, the solubilising group is a tri-, tetra-, penta-, hexa-, or hepta- lysine sequence. In one specifically contemplated embodiment, the solubilising group is a tetralysine sequence.
  • the peptide conjugate and/or amino-acid comprising conjugation partner comprises a serine residue adjacent to the amino acid residue to which the lipid- containing conjugation partner is conjugated.
  • the peptide of the peptide-containing conjugation partner comprises a serine residue adjacent to the amino acid residue to which the lipid-containing
  • the conjugation partner is conjugated.
  • the amino acid residue to which the lipid-containing conjugation partner is conjugated is N-terminal.
  • the peptide further comprises a consecutive sequence of two or more hydrophilic amino acid residues adjacent to the serine residue.
  • the peptide conjugate and/or amino-acid comprising
  • conjugation partner comprises a consecutive sequence of two or more hydrophilic amino acid residues adjacent to the serine residue.
  • the peptide conjugate and/or amino acid-comprising are independently selected from the group consisting of: the peptide conjugate and/or amino acid-comprising
  • conjugation partner comprises only naturally occuring amino acids.
  • the peptide-containing conjugation partner comprises only naturally occuring amino acids. In other embodiments, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, or 99% or more of the amino acid residues in the peptide are naturally occuring amino acids.
  • 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, or 99% or more of the amino acid residues in the peptide conjugate and/or amino acid-comprising conjugation partner are naturally occuring amino acids.
  • the peptide conjugate and/or amino acid-comprising conjugation partner comprises a peptide comprising an EBV LMP2 epitope.
  • the peptide of the peptide-containing conjugation partner comprises one or more EBV LMP2 epitopes.
  • the peptide comprises, consists of, or consists essentially of an amino acid sequence selected from the group consisting of
  • XaaiXaa 2 Xaa 3 Xaa 4 DRHSDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: l], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 DRHSDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 2], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 DRHSDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 3], wherein Xaa l is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 SLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 6], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 SLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 7], wherein Xaa l is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 SLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 8], wherein Xaa l is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 SDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 11], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 SDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 12], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 SDYQPLGTQDQSLYLGLQHDGNDGL [SEQ ID NO: 13], wherein Xaa x is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids, (n) 8 or more contiguous amino acid residues from the sequence
  • XaaiXaa 2 Xaa 3 Xaa 4 DRHSDYQPLGTQDQSLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 16], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 DRHSDYQPLGTQDQSLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 17], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 DRHSDYQPLGTQDQSLYLGLQHDGNDGLPPPPYSPRDDSSQHIYEEA [SEQ ID NO: 18], wherein Xaa x is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO: 21], wherein Xaa x is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO: 22], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids, (w) 8 or more contiguous amino acid residues from the sequence
  • XaaiXaa 2 LLWTLVVLLICSSCSSCPLSKILLARLFLYALALLL [SEQ ID NO: 23], wherein Xaai is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 26], wherein Xaai is absent or is S or a hydrophiiic amino acid, Xaa 2 is absent or is a hydrophiiic amino acid, Xaa 3 is absent or is a hydrophiiic amino acid, and Xaa 4 is absent or is one or more hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO:27], wherein Xaa x is absent or is S or a hydrophiiic amino acid, Xaa 2 is absent or is a hydrophiiic amino acid, and Xaa 3 is absent or is from one to ten hydrophiiic amino acids,
  • XaaiXaa 2 LMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 28], wherein Xaa x is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 LMLLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 31], wherein Xaai is absent or is S or a hydrophiiic amino acid, Xaa 2 is absent or is a hydrophiiic amino acid, Xaa 3 is absent or is a hydrophiiic amino acid, and Xaa 4 is absent or is one or more hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 LMLLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 32], wherein Xaa x is absent or is S or a hyd rophilic amino acid, Xaa 2 is absent or is a hyd rophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 LMLLWTLVVLLICSSCSSCPLSKILL [SEQ ID NO: 33], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 LLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 36], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 LLICSSCSSCPLSKILLARLFLYALALLLLA [SEQ ID NO: 38], wherein Xaa x is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 LNLTTMFLLMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLASALIAGGSI [SEQ ID NO:43], wherein Xaai is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids,
  • XaaiXaa 2 FLLMLLWTLVVLLICSSCSSCPLSKILLARLFLYALALLLLASA [SEQ ID NO:48], wherein Xaa x is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids,
  • XaaiXaa 2 LQGIYVLVMLVLLILAYRRRWRRLTVCGGIMFLACVLVLIVDAVLQLSPLL [SEQ ID NO: 53], wherein Xaai is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 SGNRTYGPVFM(C)(S)LGGLLTMVAGAVWLTVMSNTLLSAWILTAGFLI FLIGFA [SEQ ID NO: 56], wherein Xaa x is absent or is S or a hydrophiiic amino acid, Xaa 2 is absent or is a hydrophiiic amino acid, Xaa 3 is absent or is a hydrophiiic amino acid, and Xaa 4 is absent or is one or more hydrophiiic amino acids,
  • XaaiXaa 2 Xaa 3 SGNRTYGPVFM(C)(S)LGGLLTMVAGAVWLTVMSNTLLSAWILTAGFLIFLIG FA [SEQ ID NO: 57], wherein Xaa x is absent or is S or a hydrophiiic amino acid, Xaa 2 is absent or is a hydrophiiic amino acid, and Xaa 3 is absent or is from one to ten hydrophiiic amino acids,
  • XaaiXaa 2 SGNRTYGPVFM(C)(S)LGGLLTMVAGAVWLTVMSNTLLSAWILTAGFLIFLIGFA [SEQ ID NO: 58], wherein Xaai is absent or is S or a hydrophiiic amino acid, and Xaa 2 is absent or is from one to four hydrophiiic amino acids, (ggg) 8 or more contiguous amino acid residues from the sequence
  • XaaiXaa 2 Xaa 3 Xaa 4 SNEEPPPPYEDPYWGNGDRHSDYQPLGTQDQSLYLGLQHDGNDGLPP [SEQ ID NO: 61], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 SNEEPPPPYEDPYWGNGDRHSDYQPLGTQDQSLYLGLQHDGNDGLPP [SEQ ID NO: 62], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 SNEEPPPPYEDPYWGNGDRHSDYQPLGTQDQSLYLGLQHDGNDGLPP [SEQ ID NO: 63], wherein Xaa x is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 GNDGLPPPPYSPRDDSSQHIYEEAGRGSMNPVCLPVIVAPYLFWLAAIAA S [SEQ ID NO: 66], wherein Xaa x is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 GNDGLPPPPYSPRDDSSQHIYEEAGRGSMNPVCLPVIVAPYLFWLAAIAAS [SEQ ID NO: 67], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hyd rophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 GNDGLPPPPYSPRDDSSQHIYEEAGRGSMNPVCLPVIVAPYLFWLAAIAAS [SEQ ID NO: 68], wherein Xaai is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 Xaa 4 AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID NO: 71], wherein Xaai is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, Xaa 3 is absent or is a hydrophilic amino acid, and Xaa 4 is absent or is one or more hydrophilic amino acids,
  • XaaiXaa 2 Xaa 3 AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID NO: 72], wherein Xaa x is absent or is S or a hydrophilic amino acid, Xaa 2 is absent or is a hydrophilic amino acid, and Xaa 3 is absent or is from one to ten hydrophilic amino acids,
  • XaaiXaa 2 AAIAASCFTASVSTVVTATGLALSLLLLAAVASSYAAAQRKLLTPVTVLT [SEQ ID NO: 73], wherein Xaa x is absent or is S or a hydrophilic amino acid, and Xaa 2 is absent or is from one to four hydrophilic amino acids,
  • LGTQDQSLY [SEQ ID NO: 81]
  • the peptide comprises one or more epitopes derived from Latent Membrane Protein 2 (LMP2), for example, from full-length EBV LMP2 (amino acids 1-497).
  • LMP2 Latent Membrane Protein 2
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 12 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 15 or more, 18 or more, 20 or more, or 25 or more contiguous amino acid residues from any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 4, 5, 9, 10, 14, 15, 19, 20, 24, 25, 29, 30, 34, 35, 39, 40, 44, 45, 49, 50, 54, 55, 59, 60, 64, 65, 69, 70, 74, or 75.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 15 or more, 18 or more, 20 or more, or 25 or more contiguous amino acid residues from any one of SEQ ID NOs: 1 to 75.
  • the peptide comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 1 to 75.
  • the peptide comprises an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 76 to 101. In one example, the peptide comprises an amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 76 to 93.
  • the peptide comprises an amino acid sequence selected from the group consisting of any two or more of SEQ ID NOs: 76 to 101. In one example, the peptide comprises an amino acid sequence selected from the group consisting of any two or more of SEQ ID NOs: 76 to 93.
  • the reactive functional groups of the amino acids of the peptide-containing conjugation partner are unprotected. In certain embodiments, one or more reactive functional groups of one or more amino acids of the peptide conjugate are unprotected.
  • one or more reactive functional groups of the amino acid of the amino acid conjugate are unprotected.
  • one or more reactive functional groups of one or more amino acids of the amino acid-comprising conjugation partner are unprotected.
  • the amino acid-comprising conjugation partner comprises a peptide, wherein the reactive functional groups of the side chains of the amino acids of the peptide are unprotected, with the exception of any thiols other than the thiol to be reacted.
  • the reactive functional groups of the amino acids of the peptide of the peptide-containing conjugation partner are unprotected. In one specifically contemplated embodiment, the reactive functional groups of the amino acids of the peptide of the peptide-containing conjugation partner are unprotected, with the exception of any thiols other than the thiol to be reacted.
  • the invention relates to a method of making a peptide-conjugate comprising a structure of the formula (A) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and - NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted;
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl is L2-C(0)-OCl-6alkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R3 is L2-C(0)-OCl-6alkyl; or R9 is an amino protecting group, L3-C(0), or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently an amino acid or a peptide; or Al is OH or OPl, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R3 is L2-C(0)-OCl-6alkyl, Rl is not L2-C(0)-OCl-6alkyl; and hen m is an integer from 2 to 4, no more than one Rl is L2-C(0)-0C1-
  • the method comprises making a peptide-conjugate comprising a structure of the formula (A) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and - NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted;
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl is L2-C(0)-OCl-6alkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R3 is L2-C(0)-OCl-6alkyl;
  • R9 is L3-C(0) or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101 ;
  • R3 is L2-C(0)-OCl-6alkyl
  • Rl is not L2-C(0)-OCl-6alkyl
  • m is an integer from 2 to 4, no more than one Rl is L2-C(0)-OCl-
  • the method comprises making an amino acid or peptide-conjugate comprising a structure of the formula (B) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and - NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyi is optionally substituted;
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2;
  • Rl l and R22 at each instance of p are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl l is L2-C(0)-OCl-6alkyl;
  • R33, R44, R55, R66, R77, R8, and R9 are each independently hydrogen, Cl- 6alkyl, or C3-6cycloalkyl; or R33 is L2-C(0)-OCl-6alkyl;
  • R9 is an amino protecting group, L3-C(0), or A2;
  • Ra and Rb at each instance of q are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl;
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently an amino acid or a peptide; or Al is OH or OPl, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R33 is L2-C(0)-OCl-6alkyl
  • Rll is not L2-C(0)-OCl-6alkyl
  • p is an integer from 2 to 4
  • no more than one Rl l is L2-C(0)-OCl-
  • the method comprises making a peptide-conjugate comprising a structure of the formula (B) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and - NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted;
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2;
  • Rll and R22 at each instance of p are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl l is L2-C(0)-OCl-6alkyl;
  • R33, R44, R55, R66, R77, R8, and R9 are each independently hydrogen, Cl- 6alkyl, or C3-6cycloalkyl; or R33 is L2-C(0)-OCl-6alkyl;
  • R9 is L3-C(0) or A2;
  • Ra and Rb at each instance of q are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl; L3 is Cl-21alkyl or C4-20heteroalkyl;
  • Al and A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R33 is L2-C(0)-OCl-6alkyl
  • Rll is not L2-C(0)-OCl-6alkyl
  • p is an integer from 2 to 4
  • no more than one Rl l is L2-C(0)-0C1-
  • the lipid-containing conjugation partner is a compound of the formula (Al) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted;
  • n is an integer from 0 to 4.
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, o C3-6cycloalkyl; or Rl is L2-C(0)-OCl-6alkyl;
  • R3, R4, and R5 are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; R3 is L2-C(0)-OCl-6alkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • R3 is L2-C(0)-OCl-6alkyl, Rl is not L2-C(0)-OCl-6alkyl; and hen m is an integer from 2 to 4, no more than one Rl is L2-C(0)-0C1-
  • any alkyl, cycloalkyl or heteroalkyl present in any of Rl, R2, R3, R4, R5, LI, and L2 is optionally substituted, or a pharmaceutically acceptable salt or solvate thereof.
  • the lipid containing conjugation partner is a compound of the formula (Bl) :
  • Z is selected from the group consisting of -0-, -NR-, -S-, -S(O)-, -S0 2 -, - C(0)0-, -OC(O)-, -C(0)NR-, -NRC(O)-, -OC(0)0-, -NRC(0)0-, -OC(0)NR-, and - NRC(0)NR-;
  • R is hydrogen, Cl-6alkyl, or C3-6cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted;
  • p is an integer from 0 to 4.
  • Rll and R22 at each instance of p are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl l is L2-C(0)-OCl-6alkyl;
  • R33 and R44 are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or R33 is L2-C(0)-OCl-6alkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • R33 is L2-C(0)-OCl-6alkyl
  • Rll is not L2-C(0)-OCl-6alkyl
  • p is an integer from 2 to 4
  • no more than one Rl l is L2-C(0)-0C1-
  • any alkyl, cycloalkyl, or heteroalkyl present in any of Rl l, R22, R 33, R44, LI, and L2 is optionally substituted;
  • the lipid-containing conjugation partner is a compound of the formula (II) as defined in any of the embodiments described herein.
  • the lipid-containing conjugation partner is a compound of the formula (IIA) as defined in any of the embodiments described herein.
  • the amino acid-comprising conjugation partner is a compound of the formula (III) as defined in any of the embodiments described herein.
  • the peptide-containing conjugation partner is a compound of the formula (III) as defined in any of the embodiments described herein.
  • the amino acid-comprising conjugation partner is a compound of the formula (IIIA) as defined in any of the embodiments described herein.
  • the peptide-containing conjugation partner is a compound of the formula (IIIA) as defined in any of the embodiments described herein.
  • the method comprises making an amino acid or peptide conjugate comprising a structure of the formula (I)
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl is L2-C(0)-OCl-6alkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R3 is L2-C(0)-OCl-6alkyl;
  • R9 is an amino protecting group, L3-C(0), or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Aland A2 are each independently an amino acid or a peptide; or Al is OH or OP1, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R3 is L2-C(0)-OCl-6alkyl
  • Rl is not L2-C(0)-OCl-6alkyl
  • m is an integer from 2 to 4, no more than one Rl is L2-C(0)-OCl-
  • any alkyl, cycloalkyl or heteroalkyl present in any of Rl, R2, R3, R4, R5, R6, R7, R8, R9, LI, L2 and L3 is optionally substituted; or a pharmaceutically acceptable salt or solvate thereof; the method comprising reacting a lipid-containing conjugation partner of the formula (II)
  • n, R6, R7, R8, R9 and Al are as defined in the compound of formula (I); under conditions effective to conjugate the compound of formula (II) with the compound of formula (III) by hydrothiolation of the carbon-carbon double bond in the compound of formula (II) with the thiol in the compound of formula (III).
  • the method comprises making a peptide conjugate comprising a structure of the formula (I)
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl is L2-C(0)-OCl-6alkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R3 is L2-C(0)-OCl-6alkyl; or R9 is L3-C(0) or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Aland A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R3 is L2-C(0)-OCl-6alkyl
  • Rl is not L2-C(0)-OCl-6alkyl
  • m is an integer from 2 to 4, no more than one Rl is L2-C(0)-OCl-
  • the method comprises making an amino acid or peptide conjugate comprising a structure of the formula (IA),
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2;
  • Rll and R22 at each instance of p are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl l is L2-C(0)-OCl-6alkyl;
  • R33, R44, R55, R66, R77, R8, and R9 are each independently hydrogen, Cl- 6alkyl, or C3-6cycloalkyl; or R33 is L2-C(0)-OCl-6alkyl;
  • R9 is an amino protecting group, L3-C(0), or A2;
  • Ra and Rb at each instance of q are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently an amino acid or a peptide; or Al is OH or OPl, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R33 is L2-C(0)-OCl-6alkyl
  • Rll is not L2-C(0)-OCl-6alkyl
  • p is an integer from 2 to 4
  • no more than one Rl l is L2-C(0)-OCl-
  • the method comprises making a peptide conjugate comprising a structure of the formula (IA),
  • p is an integer from 0 to 4.
  • q is an integer from 0 to 2;
  • Rll and R22 at each instance of p are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl; or Rl l is L2-C(0)-OCl-6alkyl;
  • R33, R44, R55, R66, R77, R8, and R9 are each independently hydrogen, Cl- 6alkyl, or C3-6cycloalkyl; or R33 is L2-C(0)-OCl-6alkyl;
  • R9 is L3-C(0) or A2;
  • Ra and Rb at each instance of q are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl; Al and A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • R33 is L2-C(0)-OCl-6alkyl
  • Rll is not L2-C(0)-OCl-6alkyl
  • p is an integer from 2 to 4
  • no more than one Rl l is L2-C(0)-OCl-
  • At least one of LI and L2 is C5-22alkyl.
  • p is an integer from 0 to 2. In another embodiment, p is 0 or 1.
  • Rll and R22 at each instance of p are each independently hydrogen; or Rll is L2-C(0)-OCH2. In one embodiment, Rll on the carbon adjacent to Ll-C(0)-0 is L2-C(0)-OCH2.
  • Rl l and R22 at each instance of p are each independently hydrogen.
  • R33 is hydrogen or L2-C(0)-OCH2. In one embodiment, R33 and R44 are each hydrogen.
  • q is 0 or 1.
  • q is 0.
  • R55, R66, and R77 are each hydrogen.
  • Ra and Rb are at each instance of q are each hydrogen.
  • LI is Cll-21alkyl; p is 1; Rll is hydrogen or L2-C(0)-OCH2; R22 is hydrogen; R33 is hydrogen or L2-C(0)-OCH2; R44 is hydrogen; and L2 is Cll-21alkyl.
  • R55, R66, R77, Ra, Rb and R8 are each hydrogen; and R9 is hydrogen, L3-C(0), or A2. In one embodiment, R55, R66, R77, Ra, Rb and R8 are each hydrogen; and R9 is hydrogen or L3-C(0).
  • LI is Cll-21alkyl; p is 1; Rll is hydrogen or L2-C(0)-OCH2; R22 is hydrogen; R33 is hydrogen or L2-C(0)-OCH2; R44 is hydrogen; L2 is Cll-21alkyl; R55, R66, R77, Ra, Rb and R8 are each hydrogen; and R9 is hydrogen, L3-C(0), or A2.
  • LI is C5-21alkyl. In another embodiment, LI is C9-21alkyl. In yet another embodiment, LI is Cll-21alkyl. In one exemplary embodiment, LI is Cl l, C13, C15, C17, or C19alkyl. In one specifically contemplated embodiment, LI is C15alkyl.
  • LI comprises a linear chain of 9-21 carbon atoms. In one specifically contemplated embodiment, LI is linear C15alkyl.
  • n is an integer from 0 to 2. In another embodiment, m is 0 or 1. In one specifically contemplated embodiment, m is 0.
  • Rl and R2 at each instance of m are each independently hydrogen; or Rl is L2-C(0)-OCH2. In one embodiment, Rl on the carbon atom adjacent to Ll-C(0)-0 is L2-C(0)-OCH2. In one specifically contemplated embodiment, Rl and R2 at each instance of m are each independently hydrogen.
  • R3 is hydrogen or L2-C(0)-OCH2. In one specifically contemplated embodiment, R3 is hydrogen.
  • L2 is C5-21alkyl. In another embodiment, L2 is C9-21alkyl. In yet another embodiment, L2 is Cl l-21alkyl. In one exemplary embodiment, L2 is Cl l, C13, C15, C17, or C19alkyl. In another exemplary embodiment, L2 is C15alkyl.
  • R4 and R5 are each hydrogen.
  • n 1
  • R6 and R7 are each hydrogen.
  • R8 is hydrogen.
  • R8 and R9 are each hydrogen; or R9 is L3-C(0) or A2. In one exemplary embodiment R8 is hydrogen and R9 is L3-C(0).
  • L3 is Cl-21alkyl. In one specifically contemplated embodiment, L3 is methyl or linear C15alkyl. In exemplary embodiments, L3 is methyl.
  • formula (III) and (IIIA) may comprise a peptide of the peptide-containing conjugation partner.
  • the peptide may be optionally substituted, modified, or bound to various other moieties as described herein to provide the peptide-containing conjugation partner.
  • Al is a peptide comprising an EBV LMP2 epitope.
  • embodiment A2 is a peptide comprising an EBV LMP2 epitope.
  • Al is a peptide substituted with an epitope.
  • A2 is a peptide substituted with an epitope.
  • the epitope is bound to the peptide via a linker group. In one embodiment, the epitope is a peptide epitope.
  • Al and/or A2 are each independently a peptide comprising from about 8 to 220, 8 to 200, 8 to 175, 8 to 150, 8 to 125, 8 to 100, 8 to 90, 8 to 80, 8 to 70, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, or 8 to 15 amino acids. In one exemplary embodiment, Al and A2 are each independently a peptide comprising from about 8 to 60 amino acids.
  • Al and/or A2 are each independently a peptide comprising from about 5 to 150, 5 to 125, 5 to 100, 5 to 75, 5 to 60, 5 to 50, 5 to 40, 5 to 30, 5 to 25, 5 to 20, 8 to 150, 8 to 125, 8 to 100, 8 to 75, 8 to 60, 8 to 50, 8 to 40, 8 to 30, 8 to 25, or 8 to 20 amino acids.
  • Al and/or A2 are each independently a peptide, wherein the peptide comprises 8 to 60 amino acids.
  • Al and/or A2 are each independently a peptide comprising or substituted with a peptide epitope, wherein the peptide epitope comprises from 8 to 60 amino acids.
  • Al and/or A2 are each independently a peptide comprising or substituted with a peptide epitope, wherein the peptide comprises, consists of, or consists essentially of an amino acid sequence selected from the group consisting of 8 or more, 10 or more, 12 or more, 15 or more, 20 or more, or 25 or more contiguous amino acids from the sequence of any one of SEQ ID NOs: 1 - 101, for example from the sequence of any one of SEQ ID NOs: 1 - 75.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen or L2-C(0)-OCH2; L2 is Cl l-21alkyl; and R4 and R5 are each hydrogen.
  • n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen, L3- C(O), or A2. In one embodiment, n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0). In one embodiment, L3 is methyl or linear C15alkyl.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen or L2-C(0)-OCH2; L2 is Cl l-21alkyl; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen, L3-C(0), or A2.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen or L2-C(0)-OCH2; L2 is Cl l-21alkyl; R4 and R5 are each hydrogen; n is 1; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0).
  • LI is Cl l-21alkyl
  • m is 0
  • R3 is hydrogen
  • R4 and R5 are each hydrogen.
  • n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen, L3- C(O), or A2. In one embodiment, n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0). In one embodiment, n is 1 ; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen, L3-C(0), or A2.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0).
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • LI is Cl l-21alkyl
  • m is 0
  • R3 is hydrogen
  • R4 and R5 are each hydrogen.
  • n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen, L3- C(O), or A2. In one embodiment, n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0). In one embodiment, n is 1 ; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen, L3-C(0), or A2.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0).
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • Al is a peptide comprising serine as the first N-terminal amino acid residue.
  • Al and/or A2 is a peptide comprising a solubilising group.
  • the solubilising group comprises an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • Al is a peptide comprising a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • Al is a peptide comprising serine as the first N-terminal amino acid residue and a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain adjacent to the serine.
  • the solubilising group comprises an amino acid sequence comprising two or more consecutive hydrophilic amino acid residues in the peptide chain.
  • the hydrophilic amino acid residues are cationic amino acid residues.
  • the cationic amino acid residues are arginine or lysine residues.
  • the cationic amino acid residues are lysine residues.
  • the sequence comprises from 2 to 20, 2 to 15, 2 to 10, 3 to 7, or 3 to 5 amino acids.
  • the solubilising group is a tri-, tetra-, penta-, hexa-, or hepta- lysine sequence. In one specifically contemplated embodiment, the solubilising group is a tetralysine sequence.
  • R9 is hydrogen, an amino protecting group or L3-C(0). In some embodiments, R9 is hydrogen or L3-C(0).
  • R9 is hydrogen or an amino protecting group
  • the method further comprises acylating the amino acid conjugate or peptide conjugate so as to replace the hydrogen or amino protecting group at R9 with L3-C(0).
  • acylating the amino acid conjugate or peptide conjugate so as to replace the amino protecting group at R9 with L3-C(0) comprises removing the amino protecting group at R9 to provide a hydrogen at R9.
  • Al and/or A2 is an amino acid or a peptide.
  • Al and/or A2 is a peptide.
  • Al is OH or OPl and/or R9 is hydrogen, an amino protecting group or L3-C(0). In some embodiments, Al is OPl or OH and/or R9 is hydrogen, an amino protecting group or L3-C(0). In some embodiments, Al is a OPl or OH and R9 is hydrogen, an amino protecting group or L3-C(0).
  • Al is a OPl or OH and/or R9 is hydrogen, an amino protecting group or L3-C(0), and the method comprises coupling an amino acid or a peptide so as to replace Al and/or R9 with the amino acid or peptide.
  • Al is a OPl or OH and R9 is hydrogen, an amino protecting group or L3-C(0) and the method further comprises coupling an amino acid or a peptide so as to replace Al and/or R9 with the amino acid or peptide.
  • coupling a peptide comprises individually coupling one or more amino acids and/or one or more peptides.
  • coupling the amino acid or peptide provides a peptide conjugate comprising a peptide epitope. In some embodiments, the coupling the amino acid or peptide provides a peptide conjugate comprising a linker group or one or more amino acids thereof. In some embodiments, coupling the amino acid or peptide provides a peptide conjugate comprising a peptide epitope bound to the amino acid to which lipid- containing conjugation partner is conjugated via a linker group.
  • the amino protecting group is Boc, Fmoc, Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl) and Dde (l-(4,4-dimethyl-2,6-dioxohexylidene)ethyl).
  • the amino protecting group is Boc or Fmoc.
  • the carboxyl protecting group is tert-butyl or benzyl.
  • the compound of the formula (I) is a compound of the formula (IV) :
  • R3 is hydrogen or L2-C(0)-OCH2
  • R9 is hydrogen, an amino protecting group, L3-C(0), or A2;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently an amino acid or a peptide; or Al is OH or OPl, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • the compound of the formula (I) is a compound of the formula (IV) :
  • R3 is hydrogen or L2-C(0)-OCH2
  • R9 is hydrogen, L3-C(0), or A2;
  • LI and L2 are each independently C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-21alkyl or C4-20heteroalkyl
  • Al and A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101 ;
  • LI, Al, A2, L2, and L3 in the compound of formula (IV) are each independently as defined in any of the embodiments relating to the compound of the formula (I).
  • R3 is hydrogen
  • R9 is acetyl
  • R3 is hydrogen and R9 is acetyl.
  • the method is for making a compound of the formula (IV), wherein LI is C15 linear alkyl, R3 is hydrogen, R9 is Fmoc, and Al is OH, and the method comprises reacting vinyl palmitate and Fmoc-Cys-OH.
  • the amino protecting group is not Fmoc. In some embodiments, the amino protecting group is Boc.
  • the amino acid-comprising conjugation partner is not Fmoc-Cys- OH.
  • the peptide conjugate comprises 3 or more, 4 or more, or 5 or more contiguous amino acids. In some embodiments, the compound of formula (I) comprises 3 or more, 4 or more, or 5 or more contiguous amino acids.
  • the conditions effective to conjugate the lipid-containing conjugation partner to the amino acid-comprising conjugation partner comprises the generation of one or more free radicals. In one embodiment, the conditions effective to conjugate the lipid-containing conjugation partner to the peptide-containing conjugation partner comprises the generation of one or more free radicals.
  • the generation of one or more free radicals is initiated thermally and/or photochemically. In certain embodiments, the generation of one or more free radicals is initiated by the thermal and/or photochemical degradation of a free radical initiator. In exemplary embodiments, the generation of one or more free radicals is initiated by the thermal degradation of a thermal initiator or the photochemical degradation of a photochemical initiator.
  • thermal degradation of the free radical initiator comprises heating the reaction mixture at a suitable temperature.
  • the reaction mixture is heated at a temperature from about 40 °C to about 200 °C, from about 50 °C to about 180 °C, from about 60 °C to about 150 °C, from about 65 °C to about 120 °C, from about 70 °C to about 115 °C, from about 75 °C to about 110 °C, or from about 80 °C to about 100 °C.
  • the reaction mixture is heated at a temperature of at least about 40 °C, at least about 50 °C, at least about 60 °C, or at least about 65 °C.
  • the reaction mixture is heated at a temperature of about 90 °C.
  • photochemical degradation of the free radical initiator comprises irradiation with ultraviolet light.
  • the ultraviolet light has a wavelength of about 365 nm.
  • photochemical degradation of the free radical initiator is carried out at about ambient temperature.
  • the thermal initiator is 2,2'- azobisisobutyronitrile (AIBN).
  • AIBN 2,2'- azobisisobutyronitrile
  • the photoinitiator is 2,2-dimethoxy-2-phenylacetophenone (DMPA).
  • the reaction is carried out in a liquid medium.
  • the liquid medium comprises a solvent.
  • the solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), ⁇ , ⁇ -dimethylformamide (DMF), dichloromethane (DCM), 1,2-dichloroethane, and mixtures thereof.
  • NMP N-methylpyrrolidone
  • DMSO dimethylsulfoxide
  • DMF dichloromethane
  • 1,2-dichloroethane 1,2-dichloroethane
  • the solvent comprises NMP, DMSO, or a mixture thereof.
  • the solvent comprises DMSO.
  • the reaction is carried out in the presence of one or more additives that inhibit dimerisation, telomerisation, or polymerisation.
  • the additive is selected from the group consisting of reduced glutathione (GSH), 2,2'-(ethylenedioxy)diethanethiol (DODT), 1,4-dithiothreitol (DTT), and protein.
  • GSH reduced glutathione
  • DODT 2,2'-(ethylenedioxy)diethanethiol
  • DTT 1,4-dithiothreitol
  • protein protein.
  • the additive is DTT.
  • the additive is DTT or tert-butyl mercaptan.
  • the one or more additive is selected from the group consisting of TFA, tert-butyl mercaptan, and a combination thereof. In certain embodiments, the one or more additive is a combination of TFA and tert-butyl mercaptan. In some embodiments,
  • the reaction is carried out for a period of time from about 5 minutes to about 48 h, 5 minutes to about 24 h, from about 5 minutes to about 12 hours, from about 5 minutes to about 6 hours, from about 5 minutes to about 3 hours, 5 minutes to 2 hours, or form about 5 minutes to about 1 hour. In exemplary embodiments, the reaction is carried out for a period of time from about 5 minutes to about 1 h. In some embodiments, the reaction is carried out until one of the conjugation partners is at least about 70%, 80%, 90%, 95%, 97%, 99%, or 100% consumed. In certain embodiments, the reaction is carried out under substantially oxygen free conditions.
  • the method comprises
  • SPPS solid phase peptide synthesis
  • the method further comprises acylating the Na-amino group of the amino acid of the amino acid conjugate or the amino acid to which the lipid- containing conjugation partner is conjugated of any one of the peptide conjugates.
  • the method comprises cleaving the peptide conjugate from the solid phase support.
  • the method comprises
  • SPPS solid phase peptide synthesis
  • the method comprises
  • the peptide-containing conjugation partner is not purified prior to reaction with the lipid-containing conjugation partner.
  • one or more protecting groups are removed on cleaving the peptide from the solid phase support. In certain embodiments, all of the protecting groups present in the peptide are removed.
  • the SPPS is Fmoc-SPPS.
  • the amino acid residue in the peptide of the peptide-containing conjugation partner bearing the carbon-carbon double bond or thiol to be reacted is an N-terminal amino acid residue and the method comprises acylating the N-terminal amino group prior to cleaving the peptide from the solid phase.
  • the amino acid residue is an N-terminal residue.
  • the N-terminal residue is a cysteine residue.
  • the method further comprises separating the peptide conjugate from the reaction medium and optionally purifying the peptide conjugate.
  • the present invention provides a compound of the formula (V) :
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R9 is an amino protecting group, L3-C(0), or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl,
  • LI is C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-6alkyl or C3-6cycloalkyl
  • Aland A2 are each independently an amino acid or a peptide; or Al is OH or OP1, wherein PI is a carboxyl protecting group, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101 ; and
  • any alkyl, cycloalkyl or heteroalkyl present in any of Rl, R2, R3, R4, R5, R6, R7, R8, R9, LI, and L3 is optionally substituted, and
  • the present invention provides a compound of the formula (V) :
  • n is an integer from 0 to 4.
  • n 1 or 2;
  • Rl and R2 at each instance of m are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • R3, R4, R5, R8, and R9 are each independently hydrogen, Cl-6alkyl, or C3- 6cycloalkyl; or R9 is L3-C(0) or A2;
  • R6 and R7 at each instance of n are each independently hydrogen, Cl-6alkyl, or C3-6cycloalkyl;
  • LI is C5-21alkyl or C4-20heteroalkyl
  • L3 is Cl-6alkyl or C3-6cycloalkyl
  • Aland A2 are each independently a peptide; or Al is OH, and wherein Al or A2 comprise one or more EBV LMP2 epitopes, or wherein Al, A2 or both Al and A2 comprise one or more peptides selected from the group consisting of SEQ ID NOs: 1 - 101;
  • any alkyl, cycloalkyl or heteroalkyl present in any of Rl, R2, R3, R4, R5, R6, R7, R8, R9, LI, and L3 is optionally substituted, and
  • m, n, R6, R7, Al and A2 are each independently as defined in any of the embodiments relating to the compound of formula (I).
  • LI is C5-21alkyl. In one embodiment, LI is C5-21alkyl. In another embodiment, LI is C9-21alkyl. In yet another embodiment, LI is Cll-21alkyl. In one exemplary embodiment, LI is Cll, C13, C15, C17, or C19alkyl. In one specifically contemplated embodiment, LI is C15alkyl.
  • LI comprises a linear chain of 9-21 carbon atoms. In one specifically contemplated embodiment, LI is linear C15alkyl.
  • m is an integer from 0 to 2. In another embodiment, m is 0 or 1. In one specifically contemplated embodiment, m is 0. In one specifically contemplated embodiment, Rl and R2 at each instance of m are each independently hydrogen.
  • R3 is hydrogen
  • R4 and R5 are each hydrogen.
  • n 1
  • R6 and R7 are each hydrogen.
  • R8 is hydrogen.
  • R8 is hydrogen and R9 is hydrogen, an amino protecting group, L3-C(0), or A2.
  • R8 and R9 are each hydrogen; or R9 is L3-C(0) or A2.
  • R8 is hydrogen and R9 is L3-C(0) .
  • L3 is methyl.
  • Al is OP1 or OH and R9 is hydrogen, an amino protecting group or L3-C(0).
  • Al and/or A2 is an amino acid or a peptide.
  • the peptide comprises an epitope.
  • Al is serine or a peptide comprising serine as the first N-terminal amino acid residue.
  • Al and/or A2 is a peptide comprising a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain.
  • Al is a peptide comprising serine as the first N-terminal amino acid residue and a solubilising group comprising an amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain adjacent to the serine.
  • LI is Cl l-21alkyl
  • m is 0
  • R3 is hydrogen
  • R4 and R5 are each hydrogen.
  • n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen, L3- C(O), or A2. In one embodiment, n is 1; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0). In one embodiment, n is 1 ; R6, R7, and R8 are each hydrogen; and R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen, L3-C(0), or A2. In one embodiment, LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0).
  • LI is Cl l-21alkyl; m is 0; R3 is hydrogen; R4 and R5 are each hydrogen; n is 1 ; R6, R7, and R8 are each hydrogen; R9 is hydrogen or L3-C(0), wherein L3 is methyl.
  • LI is C15 linear alkyl; m is 0; n is 1; R3, R4, R5, R6, R7, and R8 are each hydrogen; R9 is Fmoc, and Al is OH in the compound of the formula (V).
  • the amino protecting group of R9 is not Fmoc. In some embodiments, the amino protecting group of R9 is Boc.
  • the compound of formula (V) comprises 3 or more, 4 or more, or 5 or more contiguous amino acids.
  • amino and/or carboxyl protecting groups are as defined in any of the embodiments relating to the compound of formula (I).
  • compound of formula (V) is a peptide conjugate and certain embodiments relating to the peptide conjugates of the conjugation method described herein also apply to the compounds of formula (V).
  • the compound of formula (V) is a self adjuvanting peptide.
  • the compound comprises a linker or one or more amino acids thereof.
  • the peptide comprises a linker or one or more amino acids thereof.
  • the peptide comprises a peptide epitope bound to via a linker to the amino acid to which LI is bound.
  • the peptide comprises two or more epitopes.
  • the linker is an amino acid sequence from about 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, or 2 to 8 amino acids in length.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a peptide conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an immunogenic composition. In one embodiment, the composition does not include an extrinsic adjuvant. In some embodiments, the composition is a vaccine.
  • the pharmaceutical composition comprises an effective amount of two or more peptide conjugates of the present invention, for example the pharmaceutical composition comprises an effective amount of three or more peptide conjugates of the present invention. In one example, the pharmaceutical composition comprises an effective amount of two or more peptide conjugates of the invention, wherein the two or more peptide conjugates comprise substantially all of the immunogenic regions of LMP2.
  • the present invention provides a pharmaceutical composition comprising an effective amount of a peptide of the present invention or a
  • the pharmaceutical composition comprises an effective amount of two or more peptides of the present invention, for example the pharmaceutical composition comprises an effective amount of three or more peptides of the present invention.
  • the pharmaceutical composition comprises an effective amount of one or more peptide conjugates of the present invention together with one or more peptides of the present invention, or any combination thereof.
  • the pharmaceutical composition comprises an effective amount of two or more peptide conjugates of the present invention and one or more peptides of the present invention, or an effective amount of one or more peptide conjugates of the present invention and two or more peptides of the present invention.
  • the present invention provides a method of vaccinating or eliciting an immune response in a subject comprising administering to the subject an effective amount of a peptide conjugate or peptide of the present invention.
  • the present invention provides use of a peptide conjugate or peptide of the invention for vaccinating or eliciting an immune response in a subject.
  • the present invention provides use of a peptide conjugate or a peptide of the invention in the manufacture of a medicament for vaccinating or eliciting an immune response in a subject.
  • the present invention provides a method of vaccinating or eliciting an immune response in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of the present invention.
  • the present invention provides use of a pharmaceutical composition of the invention for vaccinating or eliciting an immune response in a subject.
  • the present invention provides use of one or more peptides of the present invention or one or more peptide conjugates of the present invention in the manufacture of a medicament for vaccinating or eliciting an immune response in a subject.
  • the present invention provides a method of eliciting an immune response in a subject comprising administering to the subject an effective amount of a peptide conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides use of a peptide conjugate of the invention or a pharmaceutically acceptable salt or solvate thereof for eliciting an immune response in a subject.
  • the present invention provides use of a peptide conjugate of the invention or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for eliciting an immune response in a subject.
  • the present invention provides a method of vaccinating a subject comprising administering to the subject an effective amount of a peptide conjugate of the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides use of a peptide conjugate of the present invention for vaccinating a subject or a pharmaceutically acceptable salt or solvate thereof.
  • the present invention provides use of a peptide conjugate of the invention or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for vaccinating a subject.
  • the method comprises the administration of one or more peptides of the present invention and/or one or more peptide conjugates of the present invention, for example one or more peptides in combination with one or more peptide conjugates to the subject.
  • one or more peptides of the present invention and/or one or more peptide conjugates of the present invention are used for vaccinating or eliciting an immune response in the subject or in the manufacture of a medicament for vaccinating or eliciting an immune response in the subject.
  • two or more peptides, two or more peptide conjugates, or one or more peptides and one or more peptide conjugates are used or administered. In some embodiments the two or more peptides, two or more peptide conjugates, or one or more peptides and one or more peptide conjugates are used or administered simultaneously, sequentially, or separately.
  • Asymmetric centers may exist in the compounds described herein.
  • the asymmetric centers may be designated as (R) or (S), depending on the configuration of substituents in three dimensional space at the chiral carbon atom.
  • All stereochemical isomeric forms of the compounds, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and l-isomers, and mixtures thereof, including enantiomerically enriched and diastereomerically enriched mixtures of stereochemical isomers, are within the scope of the invention.
  • Individual enantiomers can be prepared synthetically from commercially available enantiopure starting materials or by preparing enantiomeric mixtures and resolving the mixture into individual enantiomers. Resolution methods include conversion of the enantiomeric mixture into a mixture of diastereomers and separation of the
  • the compounds described herein may also exist as conformational or geometric isomers, inlcuding c/ ' s, trans, syn, anti,
  • E
  • Z
  • All such isomers and any mixtures thereof are within the scope of the invention.
  • tautomeric isomers or mixtures thereof of the compounds described are any tautomeric isomers or mixtures thereof of the compounds described.
  • a wide variety of functional groups and other structures may exhibit tautomerism. Examples include, but are not limited to, keto/enol, imine/enamine, and thioketone/enethiol tautomerism.
  • the compounds described herein may also exist as isotopologues and isotopomers, wherein one or more atoms in the compounds are replaced with different isotopes.
  • Suitable isotopes include, for example, H 2 H (D), 3 H (T), 12 C, 13 C, 14 C, 16 0, and 18 0. Procedures for incorporating such isotopes into the compounds described herein will be apparent to those skilled in the art. Isotopologues and isotopomers of the compounds described herein are also within the scope of the invention.
  • salts and solvates including hydrates of the compounds described herein.
  • Such salts include, acid addition salts, base addition salts, and quaternary salts of basic nitrogen-containing groups.
  • Acid addition salts can be prepared by reacting compounds, in free base form, with inorganic or organic acids.
  • inorganic acids include, but are not limited to, hydrochloric, hydrobromic, nitric, sulfuric, and phosphoric acid.
  • organic acids include, but are not limited to, acetic, trifluoroacetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, fumaric, pyruvic, aspartic, glutamic, stearic, salicylic, methanesulfonic, benzenesulfonic, isethionic, sulfanilic, adipic, butyric, and pivalic.
  • Base addition salts can be prepared by reacting compounds, in free acid form, with inorganic or organic bases.
  • inorganic base addition salts include alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal salts, for example, aluminium, calcium, lithium, magnesium, potassium, sodium, or zinc salts.
  • organic base addition salts include amine salts, for example, salts of trimethylamine, diethylamine, ethanolamine, diethanolamine, and ethylenediamine.
  • Quaternary salts of basic nitrogen-containing groups in the compounds may be may be prepared by, for example, reacting the compounds with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, and the like.
  • alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, and the like.
  • aliphatic is intended to include saturated and unsaturated, nonaromatic, straight chain, branched, acyclic, and cyclic hydrocarbons. Those skilled in the art will appreciate that aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups. In some embodiments, the aliphatic group is saturated.
  • heteroaliphatic is intended to include aliphatic groups, wherein one or more chain carbon atoms are replaced with a heteroatom. In some embodiments, the heteroaliphatic is saturated.
  • alkyl is intended to include saturated or unsaturated straight chain and branched chain hydrocarbon groups.
  • saturated hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and the like.
  • Unsaturated alkyl groups have one or more carbon-carbon double bonds or triple bonds.
  • unsaturated alkyl groups include vinyl, prop-2-enyl, crotyl, isopent-2-enyl, 2-butadienyl, penta-2,4-dienyl, penta-l,4-dienyl, ethynyl, prop-3-ynyl, but-3-ynyl, and the like.
  • the alkyl is saturated.
  • heteroalkyl is intended to include alkyl groups, wherein one or more chain carbon atoms are replaced with a heteroatom. In some embodiments, the heteroalkyl is saturated.
  • cycloalkyi is intended to include non-aromatic cyclic alkyl groups.
  • examples of cycloalkyi groups include but are not limited to cyclopentyl, cyclohexyl, cyclohex-1- enyl, cyclohex-3-enyl, cycloheptyl.
  • the cycloalkyi is saturated.
  • heteroatom is intended to include oxygen, nitrogen, sulfur, or phosphorus. In some embodiments, the heteroatom is selected from the group consisting of oxygen, nitrogen, and sulfur.
  • aryl is intended to include aromatic radicals. Examples include, but are not limited to, phenyl, tolyl, naphthyl, indanyl, and the like. In some embodiments, aryl groups comprise from 4 to 8 or from 6 to 8 carbon atoms in the aromatic ring system.
  • substituted is intended to mean that one or more hydrogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituent/s are attached is not exceeded, and that the substitution results in a stable compound.
  • optional substituents for aliphatic, heteroaliphatic, alkyl, heteroalkyl, and cycloalkyi groups in the compounds described herein include but are not limited to halo, CN, N0 2 , OH, NH 2 , NHR1, NR1R2, Cl-6haloalkyl, Cl-6haloalkoxy, C(0)NH 2 , C(0)NHR1, C(0)NR1R1, S0 2 R1, OR1, SRI, S(0)R1, C(0)R1, and Cl-6aliphatic; wherein Rl and R2 are each independently Cl-6alkyl.
  • carboxyl protecting group as used herein is means a group that is capable of readily removed to provide the OH group of a carboxyl group and protects the carboxyl group against undesirable reaction during synthetic procedures.
  • Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455- 2504.
  • Examples include, but are not limited to, alkyl and silyl groups, for example methyl, ethyl, tert-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl, and the like.
  • amine protecting group means a group that is capable of being readily removed to provide the NH 2 group of an amine group and protects the amine group against undesirable reaction during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al.
  • acyl and acyloxy groups for example acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyi, aminocaproyi, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2- trimethylsilylethoxy-carbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p- nitrobenzyloxycarbon
  • Cbz carboxybenzyl
  • Nosyl o- or p-nitrophenylsulfonyl
  • Bpoc 2-(4- biphenyl)isopropoxycarbonyl
  • Dde l-(4,4-dimethyl-2,6-dioxohexylidene)ethyl
  • the invention may also be said broadly to consist in the parts, elements and features referred to or indicated in the specification of the application, individually or collectively, in any or all combinations of two or more of said parts, elements or features, and where specific integers are mentioned herein which have known equivalents in the art to which the invention relates, such known equivalents are deemed to be incorporated herein as if individually set forth.
  • Figure 1 shows an RP-HPLC trace of LMP2 SI, as described herein in Example 4.
  • Figure 2 shows an RP-HPLC trace of LMP2 S2, as described herein in Example 4.
  • Figure 3 shows an RP-HPLC trace of Paml-C(Ac)SK4-LMP2 S4, as described herein in
  • the present invention relates to amino acid and peptide conjugates, and methods of making peptide conjugates and using the peptides and peptide conjugates in
  • immunotherapeutic treatments particularly immunotherapeutic treatments of conditions associated with EBV.
  • Particular methods of making the conjugates comprises reacting an lipid-containing conjugation partner and an amino acid-comprising conjugation partner under conditions effective to conjugate the lipid-containing conjugation partner to the amino acid-comprising conjugation partner in a thiol-ene reaction.
  • the method comprises reacting an lipid-containing conjugation partner and a peptide-containing conjugation partner under conditions effective to conjugate the lipid-containing conjugation partner to the peptide of the peptide-containing conjugation partner in a thiol-ene reaction.
  • the thiol-ene reaction involves the addition of a thiol across a non-aromatic carbon- carbon double bond (i.e. hydrothiolation of the carbon-carbon double bond).
  • the reaction proceeds via a free radical mechanism.
  • There are three distinct phases in the reaction initiation, polymerisation or coupling, and termination. Radical generation gives rise to an electrophilic thiyl radical which propagates across the ene group, forming a carbon-centred radical. Chain transfer from an additional thiol molecule then quenches the radical on carbon to give the final product.
  • one conjugation partner comprises the thiol and the other comprises the carbon carbon double bond.
  • One or more free radicals may be generated in the method of the present invention by any method known in the art.
  • the free radicals may be generated thermally and/or photochemically.
  • One or more free radical initiators may be used to initiate the generation of free radicals. Suitable free radical initiators include thermal initiators and photoinitiators.
  • Free radicals are generated from thermal initiators by heating.
  • the rate of degradation of the thermal initiator and resulting free radical formation depends on the initiator and the temperature at which the initiator is heated. Higher temperatures generally result in faster decomposition. A person skilled in the art will be able to select an appropriate temperature for heating the initiator without undue experimentation.
  • thermal initiators include but are not limited to tert-amyl peroxybenzoate, 1,1'- azobis(cyclohexanecarbonitrile), 2,2'-azobisisobutyronitrile (AIBN), benzoyl peroxide, tert-butyl hydroperoxide, tert-butyl peracetate, tert-butyl peroxide, tert-butyl
  • peroxybenzoate tert-butylperoxy isopropyl carbonate, lauroyl peroxide, peracetic acid, and potassium persulfate.
  • Free radicals may be generated from photoinitiators by irradiation with light.
  • the frequency of light necessary to induce degradation of the photoinitiators and free radical formation depends on the initiator.
  • Many photoinitiators can be initiated with ultraviolet light.
  • Light of a specific wavelength or wavelength range may be used to selectively irradiate the initiator, where the lipid-containing conjugation partner or amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner, comprises photosensitive groups.
  • a frequency of about 365 nm is used. Light of this frequency is generally compatible with the side chains of naturally occurring amino acids.
  • photoinitiators include but are not limited to acetophenone, anisoin, anthraquinone, anthraquinone-2- sulfonic acid, benzil, benzoin, benzoin ethyl ether, benzoin isobutyl ether, benzoin methyl ether, benzophenone, 3,3',4,4'-benzophenonetetracarboxylic dianhydride, 4- benzoylbiphenyl, 2-benzyl-2-(dimethylamino)-4'-morpholinobutyrophenone, 4'- bis(diethylamino)benzophenone, 4,4'-bis(dimethylamino)benzophenone,
  • the initiator is present in the reaction in a stoichiometric ratio relative to the starting material comprising the thiol of from about 20: 1 to about 0.05: 1, from about 10 : 1 to about 0.05 : 1, from about 5: 1 to about 0.05: 1, from about 3: 1 to about 0.5: 1.
  • the lipid-containing conjugation partner and amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner, in the reaction are as defined in any of the embodiments described herein.
  • the lipid-containing conjugation partner and amino acid-comprising conjugation partner may be prepared using known synthetic chemistry techniques (for example, the methods generally described in Louis F Fieser and Mary F, Reagents for Organic Synthesis v. 1-19, Wiley, New York (1967-1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag Berlin, including supplements (also available via the Beilstein online database)) or, in some embodiments, may be commercially available.
  • Lipid-containing conjugation partner compounds of the formula (II) Lipid-containing conjugation partner compounds of the formula (II)
  • compounds of the formula (IIA) may be prepared by reacting a compound of the formula (VI) as defined above with a compound of the formula (IX) :
  • Preparation of the compounds may involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by a person skilled in the art.
  • Protecting groups and methods for protection and deprotection are well known in the art (see e.g. T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999)).
  • compounds of formula (VII), (VIII), and (IX) are also commercially available or may be prepared from commercially available precursors using standard synthetic chemistry techniques.
  • the order in which the lipid-containing conjugation partner and amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner, and any other components present in the reaction mixture are introduced into the reaction vessel may vary.
  • the reaction may be carried out as a one-pot procedure.
  • the stoichiometry of the lipid-containing conjugation partner and amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner, in the reaction may vary.
  • the stoichiometric ratio of amino acid- comprising conjugation partner to lipid-containing conjugation partner is from about 1 : 0.5 to about 1 : 20, from about 1 : 1 to about 1 : 10, from about 1 : 1 to about 1 : 5, from about 1 : 1 to about 1 : 3.
  • the stoichiometric ratio of peptide- containing conjugation partner to lipid-containing conjugation partner is from about 1 : 0.5 to about 1 : 20, from about 1 : 1 to about 1 : 10, from about 1 : 1 to about 1 : 5, from about 1 : 1 to about 1 : 3.
  • the reaction may be carried out at any suitable temperature. In some embodiments, the reaction is carried out at a temperature from about -25 °C to about 200 °C, from about - 10 °C to about 150 °C, from about 0 °C to about 125 °C, from about ambient
  • the reaction is carried out at a temperature of less than about 200 °C, less than about 175 °C, less than about 150 °C, less than about 125 °C, or less than about 100 °C.
  • the reaction is carried out at a temperature above ambient temperature. In one embodiment, the reaction is carried out at a temperature from 40 to 200 °C, from 50 to 150 °C, from 60 to 100 °C, from 65 to 90 °C, or from 70 to 80 °C. In some embodiments, the reaction is carried out at a temperature greater than 40 °C, greater than 50 °C, greater than 75 °C, greater than 100 °C, or greater than 150 °C.
  • the temperature at which the reaction is carried out may depend on how free radicals are generated in the reaction.
  • the temperature used may be selected to control the rate of the reaction.
  • the temperature may be adjusted during the course of the reaction to control the rate of the reaction. By controlling the rate of the reaction it may be possible to minimise or obviate the formation of undesirable by products (e.g. telomerisation or polymerisation products).
  • the reaction will generally be carried out at a temperature above ambient temperature. The temperature will depend on the reactivity of the species from which free radicals are generated.
  • the reaction may be carried out, advantageously, at ambient temperature. In certain embodiments, it may be desirable to cool the reaction mixture to slow the rate of reaction or conversely heat the reaction mixture to increase the rate of reaction.
  • the temperature at which the reaction is carried out may be controlled by heating or cooling the reaction mixture.
  • the temperature of the reaction mixture may be controlled by suitable method known in the art.
  • Heat may be applied to the reaction mixture, for example, using a heat exchanger within the reaction vessel, a heating jacket surrounding the reaction vessel, or by immersing the reaction vessel in a heated liquid (e.g. an oil or sand bath).
  • a heated liquid e.g. an oil or sand bath.
  • the reaction mixture is heated by microwave irradiation.
  • the progress of the reaction may be monitored by any suitable means, for example, by thin layer chromatography (TLC) or high performance liquid chromatorgraphy (HPLC).
  • the reaction may be allowed to proceed to substantial completion, as monitored by the consumption of at least one of the starting materials.
  • the reaction is allowed to proceed for a period of time from 1 minute to 7 days, 5 minutes to 72 hours, 10 minutes to 48 hours, 10 minutes to 24 hours.
  • the reaction is allowed to proceed for a period of time less than 72 h, less than 48 h, less than 24 h, less than 12 h, less than 6 h, less than 4 h, less than 2 h, or less than 1 h.
  • the reaction is carried out until at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99% of the lipid-containing conjugation partner or amino acid-comprising conjugation partner, whichever is stoichiometrically less, has been consumed.
  • the reaction is carried out until at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, at least about 99% of the lipid-containing conjugation partner or peptide-containing conjugation partner, whichever is stoichiometrically less, has been consumed .
  • the consumption of starting materials may be monitored by any suitable method, for example, HPLC.
  • the reaction mixture may be mixed by any suitable method known in the art, for example, using a magnetic or mechanical stirrer.
  • the method used may depend on the scale on which the reaction is carried out.
  • the reaction is generally carried out in a liquid reaction medium.
  • the liquid reaction medium may comprise a solvent.
  • suitable solvents include
  • the solvent may be selected based on the solubility of the lipid-containing conjugation partner and amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner, in the solvent.
  • the solubility of the free radical initiator may also be relevant.
  • the lipid-containing conjugation partner is hydrophobic.
  • the hydrophobicity or hydrophilicity of an amino acid-comprising conjugation partner, for example a peptide-containing conjugation partner may vary depending on, for example, amino acid sequence of the peptide of a peptide-containing conjugation partner.
  • the presence of a solubilising group in the peptide-containing conjugation partner may increase solubility in polar solvents, such as water. A person skilled in the art will be able to select an appropriate solvent without undue experimentation.
  • the reaction may be carried out under substantially oxygen-free conditions. Oxygen may quench free radicals formed in the reaction.
  • the reaction mixture may be degassed with an inert gas (e.g. nitrogen or argon) that is substantially oxygen-free to remove any dissolved oxygen before free radicals are generated.
  • an inert gas e.g. nitrogen or argon
  • components of the reaction mixture may be degassed with inert gas that is substantially oxygen-free prior to being combined in the reaction vessel.
  • the reaction may be carried out under an atmosphere of inert gas that is substantially oxygen-free.
  • the method of the present invention may be carried out at ambient pressure.
  • An additive that inhibits dimerisation, telomerisation, or polymerisation may be included in the reaction mixture in the method of the present invention.
  • the inventors have found that in some embodiments the inclusion of an extraneous thiol that facilitates chain transfer as an additive in the reaction mixture reduces the formation of undesirable by products.
  • the extraneous thiol may, in some embodiments, increase the efficiency of the desired thiol ene reaction.
  • suitable extraneous thiols include but are not limited to reduced glutathione, DODT, DTT, protein, and the like.
  • the inventors have found that in some embodiments the inclusion of DTT resulted in no undesirable by products.
  • the extraneous thiol is a sterically hindered thiol.
  • a suitable sterically hindered extraneous thiol include tert-butyl mercaptan and 1-methylpropyl mercaptan.
  • an acid in some embodiments may also inhibit dimerisation
  • the acid may be a strong inorganic acid, for example HCI, or organic acid, for example TFA.
  • the additive is TFA.
  • the reaction mixture comprises a combination of TFA and tert-butyl mercaptan.
  • the additive is generally used in an amount sufficient to minimise the formation of undesirable by products without adversely affecting the reaction or any, optional, subsequent steps in the method.
  • the additive is present in the reaction a stoichiometric ratio relative to the starting material comprising the thiol of from about 20 : 1 to about 0.05: 1, from about 10: 1 to about 0.5: 1, from about 5: 1 to about 1 : 1, from about 3 : 1 to about 1 : 1.
  • less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or less than about 1% by weight of the lipid- containing conjugation partner and amino acid-comprising conjugation partner starting materials used in the reaction are undesirable by products resulting from dimerisation, telomerisation, or polymerisation.
  • less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 3%, or less than about 1% by weight of the lipid-containing conjugation partner and peptide- containing conjugation partner starting materials used in the reaction are undesirable by products resulting from dimerisation, telomerisation, or polymerisation.
  • the purity of the products of the reaction may be determined by, for example, HPLC.
  • the concentration of the lipid-containing conjugation partner and amino acid-compirsing conjugation partner, for example a peptide-containing conjugation partner, respectively, in the reaction mixture may also affect the reaction.
  • concentration of the lipid-containing conjugation partner and peptide- containing conjugation partner in the reaction mixture may be varied to e.g. optimise yield and purity without undue experimentation.
  • the starting material comprising the thiol is present in a concentration from about 0.05 mM to about 1 M, from about 0.5 mM to about 1 M, from about 1 mM to about 1 M. In some embodiments, the concentration is at least about 0.05 mM, 0.5 mM, or 1 mM.
  • the concentration of the starting material comprising the alkene is at least about 0.05 mM, 0.5 mM, or 1 mM .
  • the amino acid conjugate or peptide conjugate may be separated from the reaction medium after the reaction and optionally purified.
  • the peptide conjugate may be separated from the reaction medium after the reaction and optionally purified.
  • the conjugate may be separated from the reaction medium using any suitable method known in the art, for example, by precipitation.
  • the amino acid or peptide conjugate is purified after separating it from the reaction medium.
  • the peptide conjugate is purified after separating it from the reaction medium.
  • the conjugate is purified by HPLC using one or more suitable solvents.
  • the peptide conjugate produced by and/or the peptide-containing conjugation partner in the method of the present invention may comprise a synthetic peptide. Synthetic peptides may be prepared using solid phase peptide synthesis (SPPS).
  • SPPS solid phase peptide synthesis
  • the amino acid to be coupled to the resin is protected at its Na-terminus by a chemical protecting group.
  • the amino acid may also have a side-chain protecting group.
  • Such protecting groups prevent undesired or deleterious reactions from taking place during the process of forming the new peptide bond between the carboxyl group of the amino acid to be coupled and the unprotected Na-amino group of the peptide chain attached to the resin.
  • the amino acid to be coupled is reacted with the unprotected ⁇ -amino group of the N- terminal amino acid of the peptide chain, increasing the chain length of the peptide chain by one amino acid.
  • the carboxyl group of the amino acid to be coupled may be activated with a suitable chemical activating agent to promote reaction with the ⁇ -amino group of the peptide chain.
  • the ⁇ -protecting group of N-terminal amino acid of the peptide chain is then removed in preparation for coupling with the next amino acid residue. This technique consists of many repetitive steps making automation attractive whenever possible.
  • peptides may be coupled to the Na- amino group of the solid phase bound amino acid or peptide instead of an individual amino acid, for example where a convergent peptide synthesis is desired.
  • the peptide is cleaved from the solid phase support at the linker molecule.
  • SPPS may be carried out using a continuous flow method or a batch flow method .
  • the solid phase support used for synthesis can be a synthetic resin, a synthetic polymer film or a silicon or silicate surface (e.g. controlled pore glass) suitable for synthesis purposes.
  • a resin is used, commonly polystyrene suspensions, or polystyrene-polyethyleneglycol, or polymer supports for example polyamide.
  • resins functionalized with linkers suitable for Boc-chemistry include PAM resin, oxime resin SS, phenol resin, brominated Wang resin and brominated PPOA resin.
  • resins suitable for Fmoc chemistry include AMPB-BHA resin, Sieber amide resin, Rink acid resin, Tentagel S AC resin, 2- chlorotrityl chloride resin, 2-chlorotrityl alcohol resin, TentaGel S Trt-OH resin, Knorr-2- chlorotrityl resin, hydrazine-2-chlorotrityl resin, ANP resin, Fmoc photolabile resin, HMBA- MBHA resin, TentaGel S HMB resin, Aromatic Safety Catch resinBAI resin and Fmoc- hydroxylamine 2 chlorotrityl resin.
  • Other resins include PL Cl-Trt resin, PL-Oxime resin and PL-HMBA Resin.
  • Preparation of the solid phase support includes solvating the support in an appropriate solvent (e.g. dimethylformamide).
  • an appropriate solvent e.g. dimethylformamide.
  • the solid phase typically increases in volume during solvation, which in turn increases the surface area available to carry out peptide synthesis.
  • Linker molecules are then attached to the support for connecting the peptide chain to the solid phase support.
  • Linker molecules are generally designed such that eventual cleavage provides either a free acid or amide at the C-terminus.
  • Linkers are generally not resin- specific. Examples of linkers include peptide acids for example 4- hydroxymethylphenoxyacetyl-4'-methylbenzyhydrylamine (HMP), or peptide amides for example benzhydrylamine derivatives.
  • HMP 4- hydroxymethylphenoxyacetyl-4'-methylbenzyhydrylamine
  • peptide amides for example benzhydrylamine derivatives.
  • the first amino acid of the peptide sequence may be attached to the linker after the linker is attached to the solid phase support or attached to the solid phase support using a linker that includes the first amino acid of the peptide sequence.
  • Linkers that include amino acids are commercially available.
  • the next step is to deprotect the Na-amino group of the first amino acid.
  • deprotection of the Na-amino group may be carried out with a mild base treatment (piperazine or piperidine, for example). Side-chain protecting groups may be removed by moderate acidolysis (trifluoroacetic acid (TFA), for example).
  • TFA trifluoroacetic acid
  • the amino acid chain extension, or coupling proceeds by the formation of peptide bonds.
  • This process requires activation of the C-a-carboxyl group of the amino acid to be coupled. This may be accomplished using, for example, in situ reagents, preformed symmetrical anhydrides, active esters, acid halides, or urethane- protected N-carboxyanhydrides.
  • in situ reagents include carbodiimide derivatives, for example ⁇ , ⁇ '- dicyclohexylcarbodiimide or ⁇ , ⁇ -diisopropylcarbodiimide.
  • Coupling reagents also include uronium or phosphonium salt derivatives of benzotriazol.
  • uronium and phosphonium salts include HBTU (0-lH-benzotriazole-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate), BOP (benzotriazole-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate), PyBOP (Benzotriazole-l-yl-oxy- tripyrrolidinophosphonium hexafluorophosphate), PyAOP, HCTU (0-(lH-6-chloro- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate), TCTU (O-lH-6- chlorobenzotriazole-l-yl)-l,l,3,3-t
  • the coupling reagent is HBTU, HATU, BOP, or PyBOP.
  • the peptide is cleaved from the resin.
  • the conditions used in this process depend on the sensitivity of the amino acid composition of the peptide and the side-chain protecting groups. Generally, cleavage is carried out in an environment containing a plurality of scavenging agents to quench the reactive carbonium ions that originate from the protective groups and linkers. Common cleaving agents include, for example, TFA and hydrogen fluoride (HF).
  • cleaving agents include, for example, TFA and hydrogen fluoride (HF).
  • the conditions used for cleaving the peptide from the resin may concomitantly remove one or more side-chain protecting groups.
  • protective groups in SPPS are well established. Examples of common protective groups include but are not limited to acetamidomethyl (Acm), acetyl (Ac), adamantyloxy (AdaO), benzoyl (Bz), benzyl (Bzl), 2-bromobenzyl, benzyloxy (BzIO), benzyloxycarbonyl (Z), benzyloxymethyl (Bom), 2-bromobenzyloxycarbonyl (2-Br-Z), tert-butoxy (tBuO), tert-butoxycarbonyl (Boc), tert-butoxy methyl (Bum), tert-butyl (tBu), tert-butylthio (tButhio), 2-chlorobenzyloxycarbonyl (2-CI-Z), cyclohexyloxy (cHx
  • additional protective groups may be necessary.
  • Mtr, Pmc, Pbf may be used for the protection of Arg
  • Trt, Tmob may be used for the protection of Asn and Gin
  • Boc may be used for the protection of Trp and Lys
  • tBu may be used for the protection of Asp, Glu, Ser, Thr and Tyr
  • Acm, tBu, tButhio, Trt and Mmt may be used for the protection of Cys.
  • the peptide may be separated from the reaction medium, e.g. by centrifugation or filtration.
  • the peptide may then be subsequently purified, e.g . by HPLC using one or more suitable solvents.
  • the inventors have found that in some embodiments the peptide- containing conjugation partner may be used in the method of the present invention without purification following cleavage of the peptide from the resin.
  • the method of the present invention can be carried out using a peptide-containing conjugation partner, wherein the peptide does not contain an Na-amino group protecting group or any side chain protecting groups.
  • the reaction is generally selective for reaction of a thiol and a non-aromatic carbon- carbon double bond.
  • thiol groups present in the peptide-containing conjugation partner e.g. in cysteine residues of the peptide
  • the thiol groups may be protected with a protective group that is not removable under the conditions used to remove one or more other protecting groups present in the peptide or to cleave the peptide from the resin.
  • the peptide will be synthesised using amino acids bearing the appropriate protecting groups. A person skilled in the art will be able to select appropriate protecting groups without undue experimentation.
  • the amino acid-comprising conjugation partner and lipid- containing conjugation partner comprise one or more unsaturated carbon-carbon bonds in addition to the carbon-carbon double bond to be reacted.
  • the peptide-containing conjugation partner and lipid-containing conjugation partner comprise one or more unsaturated carbon-carbon bonds in addition to the carbon-carbon double bond to be reacted.
  • selectivity of the thiol for the carbon-carbon double bond to be reacted in such embodiments may depend on, for example, the steric and/or electronic environment of the carbon-carbon double bond relative to the one or more unsaturated carbon-carbon bonds.
  • the carbon-carbon double bond to be reacted is activated relative to any other
  • the carbon-carbon double bond to be reacted is activated relative to any other unsaturated carbon-carbon bonds in the peptide-containing conjugation partner and lipid-containing conjugation partner.
  • the ⁇ -amino group of the amino acid of the amino acid- comprising conjugation partner comprising the carbon-carbon double bond or thiol is acylated, for example acetylated.
  • the method of the present invention may comprise acylating, for example acetylating, the ⁇ -amino group of the amino acid of the amino acid-comprising conjugation partner comprising the carbon- carbon double bond or thiol to be reacted.
  • acylation may be carried out prior to or after cleavage from the resin.
  • the amino acid residue of the peptide-containing conjugation partner bearing the carbon- carbon double bond or thiol to be reacted is an N-terminal amino acid residue
  • the method comprises acylating the N-terminal amino group prior to cleaving the peptide
  • the method further comprises acylating the Na-amino group of the amino acid of the amino acid conjugate or the amino acid residue of the peptide conjugate to which the lipid-containing conjugation partner is conjugated.
  • Acylation of the Na-amino group of an amino acid may be carried out by reacting an amino acid or peptide with an acylating agent in the presence of base in a suitable solvent, for example DMF.
  • acylating agents include acid halides, for example acid chlorides such as acetyl chloride, and acid anhydrides, for example acetic anhydride. Such agents maybe commercially available or may be prepared by methods well known in the art.
  • suitable bases include triethylamine, diisopropylethylamine, 4-methylmorpholine, and the like.
  • conjugation partner comprises coupling an amino acid or a peptide comprising an amino acid that is acylated at the ⁇ -amino group and comprises the carbon-carbon double bond or thiol to be reacted to one or more amino acids and/or one or more peptides.
  • the method comprises coupling the amino acid of the amino acid conjugate to an amino acid or a peptide to provide a peptide conjugate. In some embodiments, the method comprises coupling the amino acid of the amino acid
  • the method comprises coupling the amino acid of the amino acid conjugate to a peptide bound to a solid phase resin support by SPPS.
  • the method may comprise synthesising the peptide bound to the solid phase resin support by SPPS.
  • the method further comprises coupling the amino acid of the amino acid conjugate or an amino acid of the peptide conjugate to one or more amino acids or peptides so as to provide a peptide conjugate comprising one or more EBV LMP2 epitopes.
  • the peptide to be coupled comprises one or more EBV LMP2 epitopes.
  • one or more EBV LMP2 epitopes is formed on coupling. The coupling may be carried out by SPPS as described herein.
  • the method comprises coupling the amino acid of the amino acid conjugate to a peptide bound to a solid phase resin support by SPPS so as to provide a peptide conjugate comprising one or more EBV LMP2 epitopes.
  • the peptide of the peptide conjugate to be coupled is bound to a solid phase resin support, and the method comprises coupling an amino acid of the peptide conjugate to be coupled to an amino acid or a peptide so as to provide a peptide conjugate comprising one or more EBV LMP2 epitopes.
  • the method comprises coupling an amino acid of the peptide conjugate to an amino acid or peptide bound to a solid phase resin support by SPPS so as to provide peptide conjugate comprising a peptide epitope.
  • the method further comprises coupling an epitope, for example a peptide epitope, to the amino acid conjugate or peptide conjugate.
  • an epitope for example a peptide epitope
  • the coupling may be carried out by SPPS as described herein.
  • the epitope for example one or more EBV LMP2 epitopes, is coupled or bound via a linker group.
  • the linker group is an amino sequence, for example a sequence of two or more, three or more, or four or more contiguous amino acids.
  • the linker comprises from about 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 4 to 20, 4 to 18, 4 to 16, 4 to 14, 4 to 12, or 4 to 10 amino acids.
  • coupling an amino acid or a peptide to another amino acid or peptide as described herein may comprise forming a peptide bond between the Na-terminus of the amino acid or an amino acid of the peptide of one coupling partner and the C-terminus of the amino acid or an amino acid of the peptide of the other coupling partner.
  • the method of the present invention comprises synthesising the amino acid sequence of the peptide of the peptide-containing conjugation partner by SPPS; and reacting the lipid-containing conjugation partner with the peptide-containing conjugation partner.
  • synthesising the amino acid sequence of the peptide of the peptide-containing conjugation partner by SPPS comprises coupling an amino acid or peptide to an amino acid or peptide bound to a solid phase resin support to provide the amino acid sequence of the peptide or a portion thereof.
  • the amino acid sequence of the entire peptide of the peptide-containing conjugation partner is synthesised by SPPS.
  • the peptide-containing conjugation partner may be reacted with the lipid-containing conjugation partner while bound to a solid phase resin support.
  • the peptide may be cleaved from the solid phase resin support, and optionally purified, prior to reaction with the lipid-containing conjugation partner.
  • the peptide conjugate and/or amino acid-comprising conjugation partner may comprise one or more solubilising groups.
  • the one or more solubilising groups increase the solubility of, for example, the peptide- containing conjugation partner in polar solvents, such as water.
  • the solubilising group does not adversely affect the biological activity of the peptide conjugate.
  • a solubilising group may be advantageous for formulation and/or administration of the peptide conjugate as a pharmaceutical composition.
  • the solubilising group is bound to the peptide of the peptide conjugate and/or peptide-containing conjugation partner. In some embodiments, the solubilising group is bound to the peptide of the peptide-containing conjugation partner. In some embodiments, the peptide of the peptide conjugate and/or the peptide of the peptide-containing partner comprises a solubilising group. In some embodiments, the peptide of the peptide-containing partner comprises a solubilising group.
  • the solubilising group is bound to the side chain of an amino acid in the peptide chain. In some embodiments, the solubilising group is bound to the C- or N-terminus of the peptide chain. In some embodiments, the solubilising group is bound between two amino acid residues in the peptide chain. In some embodiments, the solubilising group is bound to the Na-amino group of one amino acid residue in the peptide chain and the carboxyl group of another amino acid residue in the peptide chain.
  • solubilising groups include, but are not limited to, hydrophilic amino acid sequences or polyethylene glycols (PEGs).
  • the solubilising group is a hydrophilic amino acid sequence comprising two or more hydrophilic amino acid residues in the peptide chain. In some embodiments, the solubilising group is an amino acid sequence comprising a sequence of two or more consecutive hydrophilic amino acid residues in the peptide chain. Such solubilising groups may be formed by adding each amino acid of the solubilising group to the peptide chain by SPPS.
  • the solubilising group is a polyethylene glycol.
  • the polyethylene glycol is bound to the Na-amino group of one amino acid residue in the peptide chain and the carboxyl group of another amino acid residue in the peptide chain.
  • the polyethylene glycol comprises from about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, about 2 to about 10, or about 2 to about 4 ethylene glycol monomer units. Methods for coupling polyethylene glycols to peptides are known.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises an antigen, for example, an antigenic peptide.
  • the peptide of the peptide conjugate or peptide-containing conjugation partner is or comprises an antigen; or an antigen is bound to peptide, optionally via a linker.
  • the peptide-containing conjugation partner comprises an antigen, for example, an antigenic peptide.
  • the peptide of the peptide- containing conjugation partner is or comprises an antigen; or an antigen is bound to peptide, optionally via a linker.
  • the antigen comprises a peptide comprising an epitope. In one embodiment, the peptide comprising an epitope is a glycopeptide comprising an epitope. In one embodiment, the antigen comprises a glycopeptide comprising an epitope.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises an epitope. In some embodiments, the peptide of the peptide conjugate and/or peptide-containing conjugation partner comprises an epitope. In some embodiments, the peptide-containing conjugation partner comprises an epitope. In some embodiments, the peptide of the peptide-containing conjugation partner comprises an epitope.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises two or more EBV LMP2 epitopes, for example, the peptide of the peptide conjugate and/or peptide-containing conjugation partner comprises two or more EBV LMP2 epitopes.
  • the peptide conjugate and/or peptide-containing conjugation partner is or comprises a glycopeptide comprising one or more EBV LMP2 epitopes.
  • the peptide of the peptide conjugate and/or peptide-containing conjugation partner is a glycopeptide.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises a glycopeptide comprising one or more EBV LMP2 epitopes bound to the peptide of the peptide conjugate and/or peptide-containing conjugation partner.
  • the peptide-containing conjugation partner is or comprises a glycopeptide comprising one or more EBV LMP2 epitopes.
  • the peptide of the peptide-containing conjugation partner is a glycopeptide.
  • the peptide-containing conjugation partner comprises a glycopeptide comprising one or more EBV LMP2 epitopes bound to the peptide of the peptide-containing conjugation partner.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises a proteolytic cleavage site. In some embodiments, the peptide of the peptide conjugate and/or peptide-containing conjugation partner comprises a proteolytic cleavage site. In some embodiments, the peptide-containing conjugation partner comprises a proteolytic cleavage site. In some embodiments, the peptide of the peptide- containing conjugation partner comprises a proteolytic cleavage site.
  • the peptide of the peptide conjugate and/or peptide-containing conjugation partner comprises one or more linker groups. In some embodiments, the peptide of the peptide-containing conjugation partner comprises one or more linker groups.
  • the peptide conjugate and/or peptide-containing conjugation partner comprises a linker group. In some embodiments, the peptide-containing conjugation partner comprises a linker group.
  • the peptide conjugate and/or peptide-containing conjugataion partner comprises an epitope bound to the peptide of the peptide conjugate and/or peptide-containing conjugation partner via a linker group. In some embodiments, the peptide-containing conjugation partner comprises an epitope bound to the peptide of the peptide-containing conjugation partner via a linker group.
  • linker groups include but are not limited to amino acid sequences (for example, a peptide), polyethylene glycol, alkyl amino acids, and the like.
  • the linker is or comprises a proteolytic cleavage site.
  • the linker is or comprises a solubilising group.
  • the linker is bound between two amino acid residues in the peptide chain.
  • the linker group is bound to the Na-amino group of one amino acid residue in the peptide conjugate and/or peptide-containing conjugation partner and the carboxyl group of another amino acid residue in the peptide-containing conjugation partner. In some embodiments, the linker group is bound to the Na-amino group of one amino acid residue in the peptide-containing conjugation partner and the carboxyl group of another amino acid residue in the peptide-containing conjugation partner.
  • the linker group is cleavable in vivo from the amino acids to which it is bound. In certain embodiments, the linker group is cleavable by hydrolysis in vivo. In certain embodiments, the linker group is cleavable by enzymatic hydrolysis in vivo. Linker groups may be introduced by any suitable method known in the art.
  • the method may further comprise coupling an epitope to the amino acid of the amino acid conjugate or the peptide of the peptide conjugate.
  • the epitope may be bound via a linker group, as described above.
  • the epitope is a peptide epitope.
  • the method comprises coupling a glycopeptide
  • the peptide conjugates of the invention maintain appropriate uptake, processing, and presentation by antigen presenting cells.
  • the lipid-containing conjugate does not interfere with presentation of any antigenic peptide present in the conjugate by antigen presenting cells.
  • the examples presented herein establish that conjugates of the invention are presented by antigen presenting cells comparably with non-conjugated, related peptides.
  • Confirmation of the identity of the peptides synthesized may be conveniently achieved by, for example, amino acid analysis, mass spectrometry, Edman degradation, and the like.
  • the method of the present invention may further comprise separating the amino acid conjugate from the liquid reaction medium.
  • the method of the present invention may further comprise separating the peptide conjugate from the liquid reaction medium. Any suitable separation methods known in the art may be used, for example, precipitation and filtration.
  • the conjugate may be subsequently purified, for example, by HPLC using one or more suitable solvents.
  • the present invention also relates to amino acid conjugates and peptide conjugates made by the method of the present invention.
  • the conjugates are as defined in any of the embodiments described herein.
  • the present invention also relates to a compound of the formula (V), which is an amino acid conjugate.
  • the present invention also relates to a compound of the formula (V), which is a peptide conjugate.
  • the peptide conjugates may be pure or purified, or substantially pure.
  • purified does not require absolute purity; rather, it is intended as a relative term where the material in question is more pure than in the environment it was in previously. In practice the material has typically, for example, been subjected to fractionation to remove various other components, and the resultant material has substantially retained its desired biological activity or activities.
  • substantially purified refers to materials that are at least about 60% free, preferably at least about 75% free, and most preferably at least about 90% free, at least about 95% free, at least about 98% free, or more, from other components with which they may be associated during manufacture.
  • amino acid refers to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the a-carbon.
  • Suitable amino acids include, without limitation, both the D- and L-isomers of the naturally- occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. Unless the context specifically indicates otherwise, the term amino acid, as used herein, is intended to include amino acid analogs.
  • the peptide-containing conjugation partner comprises only natural amino acids.
  • naturally occurring amino acid refers to any one of the twenty amino acids commonly found in peptides synthesized in nature, and known by the one letter abbreviations A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y and V.
  • amino acid analog or “non-naturally occurring amino acid” refers to a molecule which is structurally similar to an amino acid and which can be substituted for an amino acid.
  • Amino acid analogs include, without limitation, compounds which are structurally identical to an amino acid, as defined herein, except for the inclusion of one or more additional methylene groups between the amino and carboxyl group (e.g., a- amino ⁇ -carboxy acids), or for the substitution of the amino or carboxy group by a similarly reactive group (e.g., substitution of the primary amine with a secondary or tertiary amine, or substitution or the carboxy group with an ester).
  • peptide and the like is used herein to refer to any polymer of amino acid residues of any length .
  • the polymer can be linear or non-linear (e.g. , branched), it can comprise modified amino acids or amino acid analogs.
  • the term also encompasses amino acid polymers that have been modified naturally or by intervention, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other modification or manipulation, for example conj ugation with la beling or bioactive component.
  • the inventors have found that the certain peptide conj ugates of the present invention have immunological activity.
  • Cell-mediated immunity is primarily mediated by T-lymphocytes.
  • Pathogenic antigens are expressed on the surface of antigen presenting cells (such as macrophages, B- lymphocytes, and dendritic cells), bound to either major histocompatibility MHC Class I or MHC Class II molecules. Presentation of pathogenic antigen coupled to MHC Class II activates a helper (CD4+) T-cell response.
  • CD4+ T-cells Upon binding of the T-cell to the antigen-MHC II complex, release cytokines and proliferate.
  • CD8+ cytotoxic T-cell response.
  • CD8+ cells Upon binding of the T-cell to the antigen-MHC I complex, CD8+ cells secrete perforin and other mediators, resulting in target cell death .
  • an enhanced response by CD8+ cells is achieved in the presence of one or more epitopes recognised by CD4+ cells.
  • exemplary methods include those in which the presence of or the level of one or more cytokines associated with a cell-mediated response, such as those identified herein, is assessed .
  • cell-based methods to assess or monitor the onset and progression of a cell-mediated response a re amenable to use in the present invention, and may include cell proliferation or activation assays, including assays targeted at identifying activation or expansion of one or more
  • T-lymphocytes populations of immune cells, such as T-lymphocytes.
  • methods of the invention elicit both a cell-mediated immune response and a humoral response.
  • the humoral immune response is mediated by secreted antibodies produced by B cells.
  • the secreted antibodies bind to antigens presented on the surface of invading pathogens, flagging them for destruction .
  • methods to assess and monitor the onset or progression of a humoral response are well known in the art. These include antibody binding assays, ELISA, skin-prick tests and the like.
  • TLRs Toll like receptors
  • TLRs Toll-like receptors
  • PRRs pattern recognition receptors
  • TLR2 is a cell-surface receptor expressed on a range of different cell types, including dendritic cells, macrophages and lymphocytes (Coffman, R. L, Sher, A., Seder, R. A., Immunity 2010, 33, 492-503).
  • TLR2 recognises a wide range of microbial components including lipopolysaccharides, peptidoglycans and lipoteichoic acid. It is unique amongst TLRs in that it forms heterodimers, with either TLR1 or TLR6; the ability to form complexes with other PRRs may explain the wide range of agonists for TLR2 (Feldmann, M., Steinman, L., Nature 2005, 435, 612-619). Upon ligand binding and heterodimerisation, signalling takes place via the MyD88 pathway, leading to N FKB activation and consequent production of inflammatory and effector cytokines.
  • Di- and triacylated lipopeptides derived from bacterial cell-wall components have been extensively studied as TLR2 agonists (Eriksson, E. M. Y., Jackson, D. C, Curr. Prot. and Pept. Sci. 2007, 8, 412-417). Lipopeptides have been reported to promote dendritic cell maturation, causing the up-regulation of co-stimulatory molecules on the cell surface and enhanced antigen-presentation. Lipopeptides have also been reported to stimulate macrophages to release cytokines and promote the activation of lymphocytes including B cells and CD8+ T cells.
  • the peptide conjugate has TLR2 agonist activity. In some embodiments, the peptide conjugate has TLR2 agonist activity comparable to Pam3CSK4. In some embodiments, the peptide conjugate has TLR2 agonist activity at least about 50%, about 60%, about 70%, about 80%, about 90% that of Pam3CSK4. In some embodiments, for example in embodiments where a modulated immune response is desirable, the peptide conjugate has TLR2 agonist activity less that that of Pam3CSK4. For example, the peptide conjugate has TLR2 agonist activity less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10% that of Pam3CSK4.
  • the peptide of the peptide conjugate and/or peptide-containing conjugation partner comprises a serine amino acid residue adjacent to the amino acid through which the lipid-containing conjugation partner is conjugated to the peptide.
  • the peptide of the peptide-containing conjugation partner comprises a serine amino acid residue adjacent to the amino acid through which the lipid-containing conjugation partner is conjugated to the peptide. The presence of the serine amino acid residue in this position may enhance TLR2 binding.
  • the serine amino acid residue is bound to the C-termini of the amino acid through which the lipid- containing conjugation partner is conjugated to the peptide.
  • the peptide conjugate may comprise an epitope, including, for example two or more epitopes.
  • the epitope is a peptide epitope.
  • a person skilled in the art will appreciate that a wide range of peptide epitopes may be employed in the present invention.
  • tumour antigens or antigens from various pathogenic organisms have been characterised and are suitable for use in the present invention, for example in combination with compositions, vaccines and conjugates comprising the EBV LMP2 epitopes and peptides specifically recited herein. All antigens, whether or not presently characterized, that are capable of eliciting an immune response are contemplated.
  • the peptides and conjugates of the present invention find application in a wide range of immunotherapies, including but not limited to the treatment and prevention of conditions or diseases associated with EBV, including but not limited to the treatment and
  • cancer and neoplastic conditions including Hodgkin's disease, non- Hodgkin's lymphoma, lymphomas, and lymphoepitheliomas including NPC, and the treatment of viral re-activation during or following immunosuppression, for example in patients who have had bone marrow transplants or haematopoietic stem cell transplants.
  • antigens particularly EBV LMP2 peptide antigens, comprising one or more amino acid substitutions, such as one or more conservative amino acid
  • a “conservative amino acid substitution” is one in which an amino acid residue is replaced with another residue having a chemically similar or derivatised side chain.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid,
  • Amino acid analogs e.g., phosphorylated or glycosylated amino acids
  • Amino acid analogs are also contemplated in the present invention, as are peptides substituted with non-naturally occurring amino acids, including but not limited to N- alkylated amino acids (e.g. N-methyl amino acids), D-amino acids, ⁇ -amino acids, and ⁇ - amino acids.
  • a "fragment" of a peptide is a subsequence of the peptide that performs a function that is required for the enzymatic or binding activity and/or provides three dimensional structure of the peptide, such as the three dimensional structure of a polypeptide.
  • variant refers to peptide sequences, including for example peptide sequences different from the specifically identified sequences, wherein one or more amino acid residues is deleted, substituted, or added. Variants are naturally- occurring variants, or non-naturally occurring variants. Variants are from the same or from other species and may encompass homologues, paralogues and orthologues. In certain embodiments, variants of peptides including peptides possess biological activities that are the same or similar to those of the wild type peptides.
  • variant with reference to peptides encompasses all forms of peptides as defined herein.
  • conjugates of the present invention are in certain embodiments particularly suited for stimulating T-cell responses, for example in the treatment of neoplastic diseases, including cancer.
  • Conjugates, compositions, and vaccines of the present invention comprising one or more tumour antigens are contemplated.
  • tumour antigens contemplated for use in the preparation of compositions, vaccines, and/or peptide conjugates of the invention will generally comprise one or more peptides.
  • one or more additional tumour antigens may be present, including tumour antigens wherein the one or more tumour antigens does not comprise peptide.
  • Tumour antigens are typically classified as either unique antigens, or shared antigens, with the latter group including differentiation antigens, cancer-specific antigens, and over-expressed antigens. Examples of each class of antigens are amenable to use in the present invention. Representative tumour antigens for use in the treatment, for example immunotherapeutic treatment, or vaccination against neoplastic diseases including cancer, are discussed below. Compounds, vaccines and compositions comprising one or more antigens prepared using those methods of immunisation are specifically contemplated.
  • the tumour antigen is a peptide-containing tumour antigen, such as a polypeptide tumour antigen or glycoprotein tumour antigens.
  • the tumour antigen is a saccharide-containing tumour antigen, such as a glycolipid tumour antigen or a ganglioside tumour antigen.
  • the tumour antigen is a polynucleotide-containing tumour antigen that expresses a polypeptide-containing tumour antigen, for instance, an RNA vector construct or a DNA vector construct, such as plasmid DNA.
  • Tumour antigens appropriate for the use in the present invention encompass a wide variety of molecules, such as (a) peptide-containing tumour antigens, including peptide epitopes (which can range, for example, from 8-20 amino acids in length, although lengths outside this range are also common), lipopolypeptides and glycoproteins, (b) saccharide-containing tumour antigens, including poly-saccharides, mucins, gangliosides, glycolipids and glycoproteins, including and (c) polynucleotides that express antigenic polypeptides.
  • peptide-containing tumour antigens including peptide epitopes (which can range, for example, from 8-20 amino acids in length, although lengths outside this range are also common), lipopolypeptides and glycoproteins
  • saccharide-containing tumour antigens including poly-saccharides, mucins, gangliosides, glycolipids and glycoproteins, including and (c) polynucleotides that express
  • one or more conjugates comprises a tumour antigen that does not itself comprise peptide, but for example is bound to the amino acid-comprising or peptide-containing conjugation partner, are contemplated.
  • compositions of the invention in which one or more tumour antigens that does not itself comprise peptide is present are contemplated.
  • the tumour antigens are, for example, (a) full length molecules associated with cancer cells, (b) homologues and modified forms of the same, including molecules with deleted, added and/or substituted portions, and (c) fragments of the same, provided said fragments remain antigenic or immunogenic.
  • the tumour antigens are, for example, (a) full length molecules associated with cancer cells, (b) homologues and modified forms of the same, including molecules with deleted, added and/or substituted portions, and (c) fragments of the same, provided said fragments remain antigenic or immunogenic.
  • the tumour antigens are provided in recombinant form.
  • the tumour antigens include, for example, class I-restricted antigens recognized by CD8+ lymphocytes or class II-restricted antigens recognized by CD4+ lymphocytes.
  • Shared tumour antigens are generally considered to be native, unmutated sequences that are expressed by tumours due to epigenetic changes that allow de-repression of developmentally-repressed genes. Accordingly, shared antigens are typically considered preferable to over-expressed or differentiation-associated antigens because there is no expression in normal tissues. Also, the same antigens can be targeted in a number of cancer patients. For example, the cancer-testis antigen NY-ESO-1 is present in the majority of patients with many tumours, and a sizeable minority of patients with other tumours. In another example, breast differentiation tumour antigens NYBR-1 and NYBR- 1.1 are found in a proportion of breast cancer sufferers. Shared tumour antigens thus represent an attractive target for development.
  • cancer-testis antigens including NY-ESO-1, CTSP-1, CTSP-2, CTSP-3, CTSP-4, SSX2, and SCPl
  • breast cancer antigens NYBR-1 and NYBR-1.1 in combination with peptides or conjugates of the present invention is specifically contemplated herein.
  • the peptide of the invention for example, the peptide of the peptide-containing conjugation partner or of the peptide conjugate, comprises one or more epitopes derived from EBV LMP2. Representative epitopes derived from LMP2 are shown in Table 1 below.
  • the peptide of the invention for example, the isolated, purified, or recombinant peptide or the peptide of the peptide-containing conjugation partner or of the peptide conjugate, comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous, 10 or more contiguous, 12 or more contiguous, 15 or more contiguous, 20 or more contiguous, or 25 or more contiguous amino acids from any one of SEQ ID NOs: 1 to 101, for example, from any one of SEQ ID NOs: 1 to 93, including for example any one of SEQ ID NOs: 1 to 75.
  • the peptide comprises more that one amino acid sequence selected from the group consisting of any one of SEQ ID NOs: 1 to 101. In one embodiment, the peptide comprises one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 76 - 101, or from the group consisting of SEQ ID NOs: 76 - 93.
  • the peptide of the invention for example, the isolated, purified, or recombinant peptide or the peptide of the peptide-containing conjugation partner or of the peptide conjugate, comprises, consists essentially of, or consists of an amino acid sequence selected from the group consisting of 8 or more contiguous, 10 or more contiguous, 12 or more contiguous, 15 or more contiguous, 20 or more contiguous, or 25 or more contiguous amino acids from any one of the sequences depicted in Table 2 below.
  • NAME LMP2 SEQUENCE SEQ ID residues NO.
  • the prostate vaccine Sipuleucel-T (APC8015, Provenge ), which comprises the antigen prostatic acid phosphatase (PAP), is present in 95% of prostate cancer cells. At least in part due to this potential for efficacy in a significant proportion of prostate cancer sufferers, Sipuleucel-T was approved by the FDA in 2010 for use in the treatment of asymptomatic, hormone-refractory prostate cancer. The use of PAP antigen in conjugates of the present invention is specifically contemplated in the present invention.
  • Unique antigens are considered to be those antigens that are unique to an individual or are shared by a small proportion of cancer patients, and typically result from mutations leading to unique protein sequences.
  • Representative examples of unique tumour antigens include mutated Ras antigens, and mutated p53 antigens.
  • the methods of the present invention enable the ready preparation of conjugates comprising one or more unique tumour antigens, for example to elicit specific T-cell responses to one or more unique tumour antigens, for example in the preparation of patient-specific therapies.
  • representative tumour antigens include, but are not limited to, (a) antigens such as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-1, GAGE- 2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12 (which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumours), (b) mutated antigens, for example, p53
  • antigens such as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-1, GAGE- 2, MAGE-1, MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12 (which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumours)
  • mutated antigens for example, p53
  • p21/Ras associated with, for example, melanoma, pancreatic cancer and colorectal cancer
  • CDK4 associated with, for example, melanoma
  • MUM 1 associated with, for example, melanoma
  • caspase-8 associated with, for example, head and neck cancer
  • CIA 0205 associated with, for example, bladder cancer
  • HLA-A2-R1701 associated with, for example, beta catenin
  • TCR associated with, for example, T- cell non-Hodgkins lymphoma
  • BCR-abl associated with, for example, chronic
  • Galectin 4 associated with, for example, colorectal cancer
  • Galectin 9 associated with, for example, Hodgkin's disease
  • proteinase 3 associated with, for example, chronic myelogenous leukemia
  • Wilm's tumour antigen-1 WT 1, associated with, for example, various leukemias
  • carbonic anhydrase associated with, for example, renal cancer
  • aldolase A associated with, for example, lung cancer
  • PRAME associated with, for example, melanoma
  • HER-2/neu associated with, for example, breast, colon, lung and ovarian cancer
  • alpha-fetoprotein associated with, for example, hepatoma
  • KSA associated with, for example, colorectal cancer
  • gastrin associated with, for example, pancreatic and gastric cancer
  • telomerase catalytic protein associated with, for example, breast and ovarian cancer
  • G-250 associated with, for example, renal cell carcinoma
  • p53 associated with, for example, breast, colon cancer
  • carcinoembryonic antigen associated with, for example, breast cancer, lung cancer, and cancers of the gastrointestinal tract such as colorectal cancer
  • shared antigens for example, melanoma-melanocyte
  • differentiation antigens such as MART-l/Melan A, gplOO, MC1R, melanocyte-stimulating hormone receptor, tyrosinase, tyrosinase related protein- 1/TRPl and tyrosinase related protein-2/TRP2 (associated with, for example, melanoma),
  • prostate associated antigens such as PAP, prostatic serum antigen (PSA), PSMA, PSH-P1, PSM-P1, PSM-P2, associated with for example, prostate cancer,
  • PSMA prostatic serum antigen
  • PSMA prostatic serum antigen
  • PSH-P1, PSM-P1, PSM-P2 associated with for example, prostate cancer
  • immunoglobulin idiotypes associated with myeloma and B cell lymphomas, for example
  • other tumour antigens such as polypeptide- and saccharide-containing antigens including (i) glycoproteins such as sialyl Tn and sialyl Le.sup.
  • tumour antigens amenable to use in the present invention include TAG-72, (See, e.g., U.S. Pat. No. 5,892,020; human carcinoma antigen (See, e.g., U.S. Pat. No. 5,808,005); TP1 and TP3 antigens from osteocarcinoma cells (See, e.g., U.S. Pat. No. 5,855,866); Thomsen-Friedenreich (TF) antigen from adenocarcinoma cells (See, e.g., U.S. Pat. No. 5,110,911); KC-4 antigen from human prostrate adenocarcinoma (See, e.g., U.S. Pat. No.
  • TAG-72 See, e.g., U.S. Pat. No. 5,892,020
  • human carcinoma antigen See, e.g., U.S. Pat. No. 5,808,005
  • DF3 antigen from human breast carcinoma See, e.g., U.S. Pat. Nos.
  • carcinoma or orosomucoid-related antigen See, e.g., U.S. Pat. No. 4,914,021); T and Tn haptens in glycoproteins of human breast carcinoma, MSA breast carcinoma glycoprotein; MFGM breast carcinoma antigen; DU-PAN-2 pancreatic carcinoma antigen; CA125 ovarian carcinoma antigen; YH206 lung carcinoma antigen, Alphafetoprotein (AFP), hepatocellular carcinoma antigen; Carcinoembryonic antigen (CEA); bowel cancer antigen; Epithelial tumour antigen (ETA); breast cancer antigen; Tyrosinase; the raf oncogene product; gp75; gplOO; EBV-LMP 1 & 2; EBV-EBNA 1, 2 & 3C; HPV-E4, 6, 7; C017-1A; GA733; gp72; p53; proteinase 3; telomerase; and melanoma gangliosides.
  • CORA
  • the tumour antigens are derived from mutated or altered cellular components.
  • altered cellular components include, but are not limited to ras, p53, Rb, altered protein encoded by the Wilms' tumour gene, ubiquitin, mucin, protein encoded by the DCC, APC, and MCC genes, as well as receptors or receptor-like structures such as neu, thyroid hormone receptor, platelet derived growth factor (PDGF) receptor, insulin receptor, epidermal growth factor (EGF) receptor, and the colony stimulating factor (CSF) receptor.
  • PDGF platelet derived growth factor
  • EGF epidermal growth factor
  • CSF colony stimulating factor
  • Polynucleotide-containing antigens used in the present invention include polynucleotides that encode polypeptide tumour antigens such as those listed above.
  • the polynucleotide-containing antigens include, but are not limited to, DNA or RNA vector constructs, such as plasmid vectors (e.g., pCMV), which are capable of expressing polypeptide tumour antigens in vivo.
  • plasmid vectors e.g., pCMV
  • the present invention also contemplates the preparation of conjugates comprising viral antigens that are capable of stimulating T-cell to elicit effective anti-viral immunity in patients who are or have been immunosuppressed, for example patients who have had bone marrow transplants, haematopoietic stem cell transplants, or are otherwise undergoing immunosuppression.
  • antigens derived from viruses associated with increased incidence of cancer or that are reported to be cancer-causing, such as human papillomavirus, hepatitis A virus, and hepatitis B virus, are contemplated for use in the present invention.
  • the tumour antigens include, but are not limited to, pl5, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Epstein Barr virus antigens, human papillomavirus (HPV) antigens, including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, pl85erbB2, pl80erbB-3, c-met, mn-23Hl, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, pl6, TAGE, PSCA, CT7, 43-9F, 5T4, 791 Tgp72, beta-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29 ⁇ BCAA), CA 195, CA 242, CA-50, CAM43, CD68 ⁇ KP1, CO-029,
  • the present invention also relates to pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a peptide conjugate of the present invention or a pharmaceutically acceptable salt or solvent thereof, and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a peptide of the present invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • compositions may comprise an effective amount of two or more peptides of the invention, two or more peptide conjugates of the invention, or one more peptides of the invention and one or more peptide conjugates of the invention in combination.
  • pharmaceutically acceptable carrier refers to a carrier (adjuvant or vehicle) that may be administered to a subject together with the peptide or peptide conjugate of the present invention, or a pharmaceutically acceptable salt or solvent thereof, and a pharmaceutically acceptable carrier.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, poly
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-3- cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery.
  • Oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents, which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • the compositions are formulated to allow for administration to a subject by any chosen route, including but not limited to oral or parenteral (including topical, subcutaneous, intramuscular and intravenous) administration.
  • compositions may be formulated with an appropriate pharmaceutically acceptable carrier (including excipients, diluents, auxiliaries, and combinations thereof) selected with regard to the intended route of administration and standard pharmaceutical practice.
  • an appropriate pharmaceutically acceptable carrier including excipients, diluents, auxiliaries, and combinations thereof
  • the compositions may be administered orally as a powder, liquid, tablet or capsule, or topically as an ointment, cream or lotion.
  • suitable formulations may contain additional agents as required, including emulsifying, antioxidant, flavouring or colouring agents, and may be adapted for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release.
  • compositions may be formulated to optimize bioavailability, immunogenicity, or to maintain plasma, blood, or tissue concentrations within the immunogenic or therapeutic range, including for extended periods. Controlled delivery preparations may also be used to optimize the antigen concentration at the site of action, for example.
  • compositions may be formulated for periodic administration, for example to provide continued exposure.
  • Strategies to elicit a beneficial immunological response for example those that employ one or more "booster" vaccinations, are well known in the art, and such strategies may be adopted.
  • compositions may be administered via the parenteral route.
  • parenteral dosage forms include aqueous solutions, isotonic saline or 5% glucose of the active agent, or other well-known pharmaceutically acceptable excipients.
  • Cyclodextrins for example, or other solubilising agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic agent.
  • dosage forms suitable for oral administration include, but are not limited to tablets, capsules, lozenges, or like forms, or any liquid forms such as syrups, aqueous solutions, emulsions and the like, capable of providing a therapeutically effective amount of the composition.
  • Capsules can contain any standard pharmaceutically acceptable materials such as gelatin or cellulose.
  • Tablets can be formulated in accordance with conventional procedures by compressing mixtures of the active ingredients with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. Active ingredients can also be administered in a form of a hard shell tablet or a capsule containing a binder, e.g ., lactose or mannitol, a conventional filler, and a tabletting agent.
  • Examples of dosage forms suitable for transdermal administration include, but are not limited, to transdermal patches, transdermal bandages, and the like.
  • Examples of dosage forms suitable for topical administration of the compositions include any lotion, stick, spray, ointment, paste, cream, gel, etc., whether applied directly to the skin or via an intermediary such as a pad, patch or the like.
  • dosage forms suitable for suppository administration of the compositions include any solid dosage form inserted into a bodily orifice particularly those inserted rectally, vaginally and urethrally.
  • dosage of forms suitable for injection of the compositions include delivery via bolus such as single or multiple administrations by intravenous injection,
  • subcutaneous, subdermal, and intramuscular administration or oral administration are subcutaneous, subdermal, and intramuscular administration or oral administration.
  • dosage forms suitable for depot administration of the compositions include pellets of the peptides or peptide conjugates or solid forms wherein the peptides or peptide conjugates are entrapped in a matrix of biodegradable polymers,
  • microemulsions liposomes or are microencapsulated.
  • infusion devices for the compositions include infusion pumps for providing a desired number of doses or steady state administration, and include implantable drug pumps.
  • implantable infusion devices for compositions include any solid form in which the peptides or peptide conjugates are encapsulated within or dispersed throughout a biodegradable polymer or synthetic, polymer such as silicone, silicone rubber, silastic or similar polymer.
  • dosage forms suitable for transmucosal delivery of the compositions include depositories solutions for enemas, pessaries, tampons, creams, gels, pastes, foams, nebulised solutions, powders and similar formulations containing in addition to the active ingredients such carriers as are known in the art to be appropriate.
  • dosage forms include forms suitable for inhalation or insufflation of the compositions, including compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixture thereof and/or powders.
  • Transmucosal administration of the compositions may utilize any mucosal membrane but commonly utilizes the nasal, buccal, vaginal and rectal tissues.
  • Formulations suitable for nasal administration of the compositions may be administered in a liquid form, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, including aqueous or oily solutions of the polymer particles.
  • Formulations may be prepared as aqueous solutions for example in saline, solutions employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bio-availability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • dosage forms suitable for buccal or sublingual administration of the compositions include lozenges, tablets and the like.
  • dosage forms suitable for opthalmic administration of the compositions include inserts and/or compositions comprising solutions and/or suspensions in pharmaceutically acceptable, aqueous, or organic solvents.
  • compositions including vaccines
  • sweetman S. C. (Ed.). Martindale. The Complete Drug Reference, 33rd Edition, Pharmaceutical Press, Chicago, 2002, 2483 pp. ; Aulton, M. E. (Ed.)
  • the United States Pharmacopeia also provides examples of modified-release oral dosage forms, including those formulated as tablets or capsules. See, for example, The United States Pharmacopeia 23/National Formulary 18, The United States Pharmacopeial Convention, Inc., Rockville MD, 1995 (hereinafter "the USP"), which also describes specific tests to determine the drug release capabilities of extended- release and delayed-release tablets and capsules.
  • the USP test for drug release for extended-release and delayed-release articles is based on drug dissolution from the dosage unit against elapsed test time. Descriptions of various test apparatus and procedures may be found in the USP.
  • Extended release oral dosage forms development, evaluation, and application of in vitro/in vivo correlations. Rockville, MD: Center for Drug Evaluation and Research, Food and Drug Administration, 1997).
  • composition may comprise one or more extrinsic adjuvants, advantageously in some embodiments this is not necessary.
  • the peptide conjugate comprises an epitope and is self adjuvanting.
  • the present invention provides a method of vaccinating or eliciting an immune response in a subject comprising administering to the subject an effective amount of a peptide conjugate or peptide of the present invention.
  • the present invention also relates to use of a peptide conjugate or peptide of the invention for vaccinating or eliciting an immune response in a subject, and to use of a peptide conjugate or a peptide of the invention in the manufacture of a medicament for vaccinating or eliciting an immune response in a subject.
  • the present invention also provides a method of vaccinating or eliciting an immune response in a subject comprising administering to the subject an effective amount of the pharmaceutical composition of the present invention.
  • the present invention also relates to use of a pharmaceutical composition of the invention for vaccinating or eliciting an immune response in a subject, and to the use of one or more peptides of the present invention or one or more peptide conjugates of the present invention in the manufacture of a medicament for vaccinating or eliciting an immune response in a subject.
  • the present invention provides a method of eliciting an immune response in a subject comprising administering to the subject an effective amount of a peptide of the present invention.
  • the present invention also relates to use of a conjugate of the invention for eliciting an immune response, and to use of a peptide conjugate of the invention in the manufacture of a medicament for eliciting an immune response in a subject.
  • the present invention provides a method of vaccinating a subject comprising
  • the present invention also relates to use of a conjugate of the invention for eliciting an immune response, and to use of a peptide conjugate of the invention in the manufacture of a medicament for eliciting an immune response in a subject.
  • peptides of the present invention administered or use of one or more peptides of the present invention and/or one or more peptide conjugates of the present invention, for example one or more peptide in together with one or more peptide conjugates, for vaccinating or eliciting an immune response in the subject is contemplated herein.
  • two or more peptides, two or more peptide conjugates, or one or more peptides and one or more peptide conjugates are administered or used, the two or more peptides, two or more peptide conjugates, or one or more peptides and one or more peptide conjugates may be administered or used simultaneously, sequentially, or separately.
  • a “subject” refers to a vertebrate that is a mammal, for example, a human. Mammals include, but are not limited to, humans, farm animals, sport animals, pets, primates, mice and rats.
  • an “effective amount” is an amount sufficient to effect beneficial or desired results including clinical results.
  • An effective amount can be administered in one or more administrations by various routes of administration.
  • the effective amount will vary depending on, among other factors, the disease indicated, the severity of the disease, the age and relative health of the subject, the potency of the compound administered, the mode of administration and the treatment desired . A person skilled in the art will be able to determine appropriate dosages having regard to these any other relevant factors.
  • compositions can be evaluated both in vitro and in vivo.
  • the composition can be tested in vitro or in vivo for its ability to induce a cell-mediated immune response.
  • the composition can be fed to or injected into an animal (e.g., a mouse) and its effects on eliciting an immune response are then assessed . Based on the results, an appropriate dosage range and administration route can be determined.
  • composition may be administered as a single dose or a multiple dose schedule.
  • Multiple doses may be used in a primary immunisation schedule and/or in a booster immunisation schedule.
  • eliciting an immune response comprises raising or enhancing an immune response.
  • eliciting an immune response comprises eliciting a humoral and a cell mediated response.
  • eliciting an immune response provides immunity.
  • the immune response is elicited for treating a disease or condition.
  • a disease or condition A person skilled in the art will appreciate that the peptides and peptide conjugates described herein are useful for treating a variety of diseases and conditions associated with EBV, including one or more diseases or conditions selected from EBV-associated neoplastic conditions, including B and T cell non-Hodgkin's lymphomas, Hodgkin's disease, and
  • lymphoepithelioma-like carcinomas including but not limited to nasopharyngeal carcinoma (NPC).
  • NPC nasopharyngeal carcinoma
  • the disease or condition is an infectious disease, cancer, or viral re-activation post-bone marrow transplant or following induction of profound
  • treatment relates generally to treatment, of a human or a non-human subject, in which some desired therapeutic effect is achieved.
  • the therapeutic effect may, for example, be inhibition, reduction, amelioration, halt, or prevention of a disease or condition.
  • compositions may be used to elicit systemic and/or mucosal immunity.
  • Enhanced systemic and/or mucosal immunity may be reflected in an enhanced TH1 and/or TH2 immune response.
  • the enhanced immune response may include an increase in the production of IgGl and/or IgG2a and/or IgA.
  • Thin layer chromatography is performed on Merck Kieselgel F 254 200 ⁇ silica plates.
  • Ultraviolet light is used as a visualising agent and the general developing agents of potassium permanganate in an aqueous basic solution and vanillin in an ethanolic solution.
  • Specific developing agents used are ethanolic solutions of ninhydrin with acid for the identification of primary amines. Heating is applied when using any developing agent.
  • Silica gel (0.063-0.100 mm) is used for flash column chromatography.
  • Nuclear magnetic resonance (NMR) spectra are acquired at room temperature in CDCI 3 or D 2 0 on a Bruker DRX400 spectrometer operating at 400 MHz for X H nuclei and 100 MHz for 13 C nuclei. Reference peaks for 1 H and 13 C spectra are respectively set to ⁇ .00 and ⁇ 77.0 for CDCI 3 and ⁇ 4.79 for 1 H spectra in D 2 0. NMR data are reported in values of chemical shift as parts per million (ppm) on the ⁇ scale, and coupling constants in hertz (Hz).
  • Analytical high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) chromatograms are acquired on either a Dionex UltiMate 3000 HPLC system with a Finnigan Surveyor MSQ Plus mass spectrometer or an Agilent 1120 Compact LC system with a Hewlett Packard Series 1100 MSD mass spectrometer.
  • Analytical reverse phase (RP) HPLC is performed using the MeCN/H 2 0 + 0.1% TFA solvent system.
  • Semipreparative RP HPLC is performed on a Dionex UltiMate 3000 HPLC system using the MeCN/H 2 0 + 0.1% TFA solvent system.
  • Microwave reactions are performed using a CEM Liberty Automated Microwave system.
  • Swelled peptide-resin is treated with 20% v/v piperidine in DMF (5.0 mL) and shaken for 20 min at r.t. The solution is drained and the resin washed with DMF (x 2) and DCM (x 2). A coupling mixture of Fmoc-AA-OH (2.0 eq.), HBTU (2.0 eq) and / ' Pr 2 NEt (4.0 eq.) in DMF (1 mL) is added and the resin shaken for 1 hr. Resin is drained and washed again. The procedure is repeated for the remaining residues in the sequence.
  • Peptide-resin is transferred to the reaction vessel of a Tribute automated peptide synthesiser. Automated synthesis is undertaken with cycles of Fmoc deprotection and Fmoc-AA-OH coupling steps. Deprotection is undertaken by addition of 20% v/v piperidine in DMF (6.0 mL) and agitation (2 x 7 min). Following resin drainage and DMF washing (4 mL x 3), a coupling step is performed with 5 eq. Fmoc-AA-OH dissolved in HBTU (0.24 mM, in DMF, 4 mL). 2 M /V-methylmorpholine (NMM) in DMF (4 mL) is utilised in the base-addition step. Coupling proceeded for 1 hr. After DMF washing steps, the next cycle of deprotection and coupling commenced, repeating until all amino acids are coupled.
  • Peptide-resin is swelled in 1 : 1 CH 2 CI 2 : DMF for 30 min, then drained.
  • a coupling mixture of a Cys amino acid (0.2 mmol, 2 eq.), BOP (0.4 mmol, 4 eq .) and HOBt.H 2 0 (0.4 mmol, 4 eq.) is dissolved in 1 : 1 CH 2 CI 2 : DMF (2 mL). 2,4,6-collidine (0.4 mmol, 4 eq.) is then added and the resultant solution added to the peptide-resin.
  • the resin is agitated for 1 hr, or until ninhydrin test indicated no free amines.
  • the resin is then drained, washed with DMF (2x) and CH 2 CI 2 (2x), and dried.
  • Fmoc-Cys(Trt)-OH (1.0 g, 1.7 mmol) is dissolved in CH 2 CI 2 (50 mL). TFA (1.5 mL, 19.6 mmol) and / ' Pr 3 SiH (0.75 mL) are added, causing the solution to turn yellow. The solution is agitated for 2 hrs at room temperature, at which point the solution turns colourless. The mixture is basified to pH 9 by addition of Na 2 C0 3 . H 2 0 and washed with EtOAc. The solution is acidified with 10M HCI, extracted with EtOAc and concentrated in vacuo to give a white powder and a pink residue. The powder and residue are dissolved in 4: 1 MeCN : H 2 0 and lyophilised, giving a crude pink-white powder (424 mg, crude yield 73.1%). This crude product is carried through to the thiol-ene reactions described below.
  • Fmoc-Cys-OH 100 mg, 0.29 mmol
  • vinyl palmitate 476 ⁇ , 1.5 mmol
  • AIBN 9.6 mg, 59 ⁇
  • the reaction mixture is then heated under reflux (90°C) for 24 hr, after which TLC indicated complete consumption of Fmoc-Cys-OH.
  • the solution is then allowed to cool to r.t..
  • the solvent is removed under reduced pressure. Presence of the desired product 200 in the crude reaction mixture is confirmed by mass spectrometry.
  • Fmoc-Cys-OH 100 mg, 0.29 mmol is dissolved in degassed, anhydrous DMF (500 ⁇ ).
  • the two solutions are combined and the resultant mixture irradiated for 6 hr (365 nm UV) in a standard photochemical apparatus. When no further change in the reaction mixture can be observed by TLC, solvent is removed under reduced pressure.
  • the crude product is purified by silica gel flash chromatography (3: 1 EtOAc: n-hexanes + 2% AcOH), followed by lyophilization from 1 : 1 H20: MeCN + 0.1% TFA to afford the title compound as a powdery white solid (24 mg, 13%). Structure of the desired product 200 is confirmed by mass spectrometry.

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