WO2004014957A1 - Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (ctl) epitopes - Google Patents
Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (ctl) epitopes Download PDFInfo
- Publication number
- WO2004014957A1 WO2004014957A1 PCT/AU2003/001019 AU0301019W WO2004014957A1 WO 2004014957 A1 WO2004014957 A1 WO 2004014957A1 AU 0301019 W AU0301019 W AU 0301019W WO 2004014957 A1 WO2004014957 A1 WO 2004014957A1
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- WIPO (PCT)
- Prior art keywords
- lipopeptide
- seq
- epitope
- group
- amino acid
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- C12N2770/24011—Flaviviridae
- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
- C12N2770/24234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
Definitions
- a vaccine preparation will comprise a mixture of polypeptides comprising the T-helper cell epitope and CTL epitope, however it is also known to consist of a single polypeptide comprising both the T-helper epitope and the CTL epitope.
- the inventors sought to improve methods for producing highly immunogenic lipopeptides having a lipid moiety and a polypeptide moiety comprising both a T helper epitope and a CTL epitope against which an immune response is desired.
- the inventors showed that a highly immunogenic lipopeptide comprising both T-helper and CTL epitopes can be produced by synthesizing a single polypeptide molecule comprising said epitopes with an internal lysine residue or internal lysine analog residue and then coupling the lipid moiety to the side-chain amino group of said internal lysine residue or said internal lysine analog residue, as opposed to the N-terminal attachments described previously. This enables the lipopeptide of the present invention to be synthesized conveniently using a single amino acid chain, thereby requiring no post-synthesis modification to incorporate both epitopes.
- the attachment site of the lipid is readily specified. Positioning of the lipid moiety in the lipopeptide can thus be targeted to enhance the utility of the end-product for vaccine or adjuvant formulations.
- the lipid moiety is attached via the epsilon-amino group of a lysine residue or via the terminal side-chain group of a lysine analog residue positioned between the amino acid sequences of the T helper epitope and the CTL epitope.
- [CTL] consisting of an immunodominant H-2 d -restricted CTL epitope consisting of amino acid residues 147-155 of the nucleoprotein of influenza virus strain A/Puerto Rico/8/34 (PR8;H1 N1 ) as set forth in SEQ ID NO: 2;
- Figure 3 is a graphical representation showing the reduced viral load of mice primed with lipopeptides referred to in the legend to Figure 1 and subsequently challenged with influenza virus.
- Mice were inoculated intranasally with 9 nmol of the lipopeptides [Th]-Lys(Pam 3 Cys-Ser-Ser)-[CTL] and [Th]-Lys(Pam 2 Cys-Ser- Ser)-[CTL] in 50 ⁇ l PBS (columns 2 and 3, respectively), or for the [Th]-/_ys-[CTL] peptide in 50 ⁇ l PBS (column 1), or with PBS alone (column 4).
- Peptide and lipopeptide designations are as for the legend to Figure 2.
- Figure 14 is a graphical representation showing therapeutic treatment of Lewis Lung tumour with a lipopeptide immunogen, as determinbed by the percentage of animals that remain tumor free following immunization. Mice were injected with 3x10 4 Lewis Lung tumour cells that had been transfected with ovalbumin and therefore expressed the CTL epitope SIINFEKL [Nelson et al, J Immunol. 166: 5557-5566, 2001].
- the T helper epitope and CTL epitope are separated by at least one or two or three or four or five amino acid residues including a single internal lysine residue or internal lysine analog residue.
- a T-helper epitope may be recognised by one or more mammals of different species. Accordingly, the designation of any T-helper epitope herein is not to be considered restrictive with respect to the immune system of the species in which the epitope is recognised.
- a rodent T-helper epitope can be recognised by the immune system of a mouse, rat, rabbit, guinea pig, or other rodent, or a human or dog.
- a polypeptide comprising an amino acid sequence that comprises: (a) the amino acid sequence of a T helper cell (Th) epitope and the amino acid sequence of a CTL epitope, wherein said amino acid sequences are different; and (b) one or more internal lysine residues or internal lysine analog residues; and (iii) covalently attaching each of said one or more lipid moieties directly or indirectly to an epsilon-amino group of said one or more internal lysine residues or to the terminal side-chain group of said one or more internal lysine analog residues so as to produce a lipopeptide having the lipid moiety attached to the epsilon amino group of said internal lysine residue or having the lipid moiety attached to the terminal side-chain group of said internal lysine analog residue.
- CTL precursor is meant a naive T cell (ie. a T cell that expresses one or more T cell receptors on its surface and is capable of proliferating and differentiating into a memory T cell or effector T cell).
- mice are accepted models for equivalent diseases in humans and the skilled person will readily be capable of extending the findings presented herein for such models to a human disease context without undue experimentation.
- Peptides comprising a CTL epitope expressed by B16-OVA tumour cell line.
- An immunogenic peptide was synthesized that incorporated a CTL epitope with amino acid sequence SIINFEKL (SEQ ID NO: 173) and a T-helper epitope from CDV-F (SEQ ID NO: 20).
- the lipopeptide [P25]-Lys(Pam 2 Cys-Ser-Ser)-[HCV] described in the legend to Figure 2 was tested for its ability to up-regulate the expression of MHC class II, CD83 and CD86 on human dendritic cells.
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Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP03783852.1A EP1546206B1 (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising T-helper and cytotoxic T lymphocyte (CTL) epitiopes |
CA002494193A CA2494193A1 (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (ctl) epitopes |
US10/524,936 US7833532B2 (en) | 2002-08-12 | 2003-08-12 | Immunogenic lipopeptides comprising T-helper and cytotoxic T lymphocyte (CTL) epitopes |
BR0313101-7A BR0313101A (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising t-helper lymphocyte epitopes and cytotoxic t lymphocytes (ctl), and methods for their production and use |
CN038241455A CN1688605B (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising T-helper and cytotoxic T lymphocyte (CTL) epitopes |
ES03783852.1T ES2535451T3 (en) | 2002-08-12 | 2003-08-12 | New immunogenic lipopeptides comprising helper T and cytotoxic T lymphocyte (CTL) epitopes |
JP2004526518A JP4619121B2 (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising a T helper epitope and a cytotoxic T lymphocyte (CTL) epitope |
AU2003249778A AU2003249778B2 (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising T-helper and cytotoxic T lymphocyte (CTL) epitopes |
US12/901,457 US8986700B2 (en) | 2002-08-12 | 2010-10-08 | Immunogenic lipopeptides comprising T-helper and cytotoxic T-lymphocyte (CTL) epitopes |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40332802P | 2002-08-12 | 2002-08-12 | |
US60/403,328 | 2002-08-12 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US10/524,936 A-371-Of-International US7833532B2 (en) | 2002-08-12 | 2003-08-12 | Immunogenic lipopeptides comprising T-helper and cytotoxic T lymphocyte (CTL) epitopes |
US12/901,457 Continuation US8986700B2 (en) | 2002-08-12 | 2010-10-08 | Immunogenic lipopeptides comprising T-helper and cytotoxic T-lymphocyte (CTL) epitopes |
Publications (1)
Publication Number | Publication Date |
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WO2004014957A1 true WO2004014957A1 (en) | 2004-02-19 |
Family
ID=31715974
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AU2003/001019 WO2004014957A1 (en) | 2002-08-12 | 2003-08-12 | Novel immunogenic lipopeptides comprising t-helper and cytotoxic t lymphocyte (ctl) epitopes |
Country Status (10)
Country | Link |
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US (2) | US7833532B2 (en) |
EP (2) | EP2314630A1 (en) |
JP (2) | JP4619121B2 (en) |
KR (1) | KR101151368B1 (en) |
CN (2) | CN1688605B (en) |
AU (1) | AU2003249778B2 (en) |
BR (1) | BR0313101A (en) |
CA (1) | CA2494193A1 (en) |
ES (1) | ES2535451T3 (en) |
WO (1) | WO2004014957A1 (en) |
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CN1688605A (en) | 2005-10-26 |
EP2314630A1 (en) | 2011-04-27 |
CN101113178A (en) | 2008-01-30 |
EP1546206A1 (en) | 2005-06-29 |
US8986700B2 (en) | 2015-03-24 |
US20070160631A1 (en) | 2007-07-12 |
JP5265512B2 (en) | 2013-08-14 |
CA2494193A1 (en) | 2004-02-19 |
US7833532B2 (en) | 2010-11-16 |
ES2535451T3 (en) | 2015-05-11 |
BR0313101A (en) | 2005-06-28 |
EP1546206A4 (en) | 2007-10-10 |
JP2006513979A (en) | 2006-04-27 |
JP4619121B2 (en) | 2011-01-26 |
US20110280899A1 (en) | 2011-11-17 |
JP2010132663A (en) | 2010-06-17 |
EP1546206B1 (en) | 2014-12-17 |
CN1688605B (en) | 2011-01-12 |
AU2003249778B2 (en) | 2010-09-23 |
AU2003249778A1 (en) | 2004-02-25 |
KR20050049472A (en) | 2005-05-25 |
KR101151368B1 (en) | 2012-06-08 |
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