WO2015162204A1 - Soluble hla-i/peptide monomers and applications as therapeutic treatments in cancer - Google Patents
Soluble hla-i/peptide monomers and applications as therapeutic treatments in cancer Download PDFInfo
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- WO2015162204A1 WO2015162204A1 PCT/EP2015/058786 EP2015058786W WO2015162204A1 WO 2015162204 A1 WO2015162204 A1 WO 2015162204A1 EP 2015058786 W EP2015058786 W EP 2015058786W WO 2015162204 A1 WO2015162204 A1 WO 2015162204A1
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- hla
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Classifications
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001102—Receptors, cell surface antigens or cell surface determinants
- A61K39/001103—Receptors for growth factors
- A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
-
- 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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001176—Heat shock proteins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001186—MAGE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001184—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
- A61K39/001188—NY-ESO
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001191—Melan-A/MART
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/00119—Melanoma antigens
- A61K39/001192—Glycoprotein 100 [Gp100]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
- A61K39/001194—Prostate specific antigen [PSA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/605—MHC molecules or ligands thereof
Definitions
- the present invention relates to soluble HLA-l/peptide monomers and applications thereof as therapeutic treatments in cancer.
- antibody-drug conjugates targeted therapies, vaccination and adoptive immunotherapy, electrochemotherapy, and hyperthermia may be cited.
- Peptides have been used as antigens in cancer vaccines. However said peptides have a short duration of life in the human body.
- a cancer immunogenic peptide is bound to a soluble HLA-I monomer to obtain a soluble HLA-l/peptide monomer molecule.
- This molecule is able to trigger antigen-specific activation of CD8 T cells.
- a subject of the present application is therefore a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide.
- HLA-I Soluble monomeric HLA-I are well known in the literature. These include classical HLA-I molecules (HLA-la) and non-classical HLA-I molecules (HLA-lb). So-called "classical" monomeric HLA-I soluble molecules are preferred.
- the peptide of the invention bound to soluble monomeric HLA-I derives from a protein expressed by cancer cells or virus-infected cells.
- the peptide is selected because of its antigenic properties and additionally because of its immunogenic properties. Accordingly, the man skilled in the art understands that the present invention applies to various cancers and virus infections.
- the antigenic peptide makes it possible to trigger antigen-specific activation of CD8 T cells and to obtain antibodies, which are protective against antigen expressing cells.
- a peptide according to the invention corresponds to a limited number of tumour or virus protein epitopes.
- peptides of the invention originate or derive from a tumour or virus protein.
- osteoinate is meant that their amino acid sequence is identical to that of the tumour or virus protein.
- derive is meant that their amino acid sequence is mostly identical to that of the tumour or virus protein but comprises a few differences as will be seen hereafter.
- the above peptides advantageously comprise between 8 and 1 1 amino acids.
- tumour or virus peptides can therefore also be mentioned, which are highly homologous to these natural sequences, for example having more than 80% homology or even more than 90% homology with the corresponding native peptide whilst retaining the immunological properties of this epitopic site of the native peptide.
- the main modifications concern amino acid located at the HLA anchor positions by substituting amino acids by optimal residues for a given HLA-I allele.
- the peptide derivatives should not reduce the immunogenicity, and should, like the native peptides, induce specific T cell activation. These modifications are within the scope of a person skilled in the art, who can check the incidence of the modifications by simple tests.
- the immunogenicity of such modified derivatives can be evaluated in vitro with specific T cells or in vivo using humanized mice.
- the possible modifications preferably affect less than 3 amino acids, such as 2 or 1 single amino acid.
- Preferred peptides of the invention are selected in the group consisting in:
- EAAGIGILTV (Melan-A/M ART- 126-35) Seq. Id N ° 4 and its modified analogs EAAGIGILTY (Melan-A/M ART- 126-35, V35Y) Seq. Id N ° 5 and EPAGIGILTY (Melan-A/MART-1 26-3 5, A27P, V35Y) Seq. Id N ° 6,
- AAGIGILTV Mellan-A/MART-127-35 Seq. Id N ° 10, EAAGIGILTV
- IPIPSSWAF HBV env 313 . 321
- VLEETSVML (HCMV IE-I316-324) Seq. Id N°25
- GLCTLVAML (BMLF-1 , EBV early lytic antigen) Seq. Id N 0 27
- the peptide is selected in the group consisting in:
- VLPDVFIRC (NA17Ai- 9 ) Seq. Id N° 13, SLLMWITQC (NY-ESO-1 157-165) Seq. Id N ° 14,
- the peptide is selected in the group consisting in ELAGIGILTV (Melan-A/MART- I 26-35, A27L) Seq. Id N ° 1 1 and TLNDECWPA (Meloe1 36 -44) Seq. Id N ° 12.
- the peptides used in the invention can in particular be produced by chemical synthesis.
- the cancer or virus native peptides or derivatives according to the invention possess very useful pharmacological properties. They are in particular endowed with remarkable anti-tumour and anti-virus properties. They are in fact immunogens and capable of generating in a subject T lymphocytes or antibodies recognizing the native tumor or virus protein. Indeed, they trigger a T cell response, specifically a CD8 T cell response in a patient.
- a subject of the present application is therefore also a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, for use in a method of therapeutic treatment of the human or animal body, that is to say as a medicament or drug.
- the medicaments according to the present invention are used for example in both the curative treatment of cancers and infection diseases.
- immunogenic active ingredients according to the invention can be used as follows:
- a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer antigenic peptide (or peptide derivative) or immunogenic compound according to the present invention is administered to a patient, for example by sub-cutaneous or intravenous route, in a sufficient quantity to be effective at a therapeutic level, to a subject needing such treatment.
- the dose administered can for example range from 1 to 1000 g, in particular 10 to 500 g, by sub-cutaneous route, once a month for three months, then periodically as a function of the induced specific T cell responses, for example every 2-6 months.
- two or more different immunogenic molecules can be administered in order to induce various specific T cell responses targeting tumor or virus-infected cells in the case where a single immunogenic molecule does not carry all the active sites of the tumour or infected cells.
- a subject of the invention is also the pharmaceutical compositions in particular the vaccines which contain at least one abovementioned soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide (or peptide derivative) or immunogenic compound, preferably a cancer antigenic peptide, as active ingredient.
- the vaccines which contain at least one abovementioned soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide (or peptide derivative) or immunogenic compound, preferably a cancer antigenic peptide, as active ingredient.
- a monomeric HLA-l/peptide molecule (or peptide derivative or immunogenic compound) of the invention can be incorporated into pharmaceutical compositions intended for any standard route in use in the field of vaccines, in particular by sub-cutaneous route or by intravenous route.
- the administration can take place in a single dose or repeated once or more after a certain period of time.
- a subject of the present Application is also a curative pharmaceutical composition, characterized in that it comprises as active ingredient, one or more monomeric HLA-l/peptide molecule as defined above.
- the immunogenic agent can be conditioned alone or mixed with an excipient or mixture of pharmaceutically acceptable excipients as an adjuvant.
- a subject of the present application is more particularly a vaccine containing as immunogenic compound, an abovementioned monomeric HLA-l/peptide molecule.
- a subject of the present invention is also a process for preparing a composition described above, characterized in that, according to methods known per se, the active ingredient or ingredients are mixed with acceptable, in particular pharmaceutically acceptable excipients.
- the administration to a patient of a monomeric HLA-l/peptide molecule according to the invention corresponds to an active immunotherapy.
- the vaccine preparations of the present invention may particularly be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with or without an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily but preferably aqueous vehicles.
- oily or non-aqueous carriers, diluents solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil, and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
- the active ingredient may also be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- Drugs for parenteral administration are sterile.
- a subject of the present application is a process for active immunization of patients characterized in that as immunogen, a monomeric HLA-l/peptide molecule according to the invention is used, as defined above, advantageously associated with a mineral, oily or synthetic immunity adjuvant.
- Immunizations can be done in a standard fashion preferably in the presence of an adjuvant, for example ISA 51 or Alum.
- a further subject of the present application is a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, preferably a cancer antigenic peptide, for use in a method for triggering a CD8 T cell response in a patient.
- a subject of the present application is additionally a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, preferably a cancer antigenic peptide, for use in a method of treatment of a condition, which may be treated by a TCD8+ response in a patient.
- a subject of the present application is additionally a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, for use in a method of treatment of a cancer or virus for which specific epitopes are identified such as melanoma, colorectal carcinomas and breast cancers.
- CD8 epitopes derived from melanoma antigens have been reported. These peptides are presented by diverse classical HLA-la contexts, involving HLA-A2 molecules that are expressed in about 40-50% of Caucasian population (for Melan-A/MART-1 , eloe-1 , NA17A, NY-ESO-1 antigens), HLA-A1 (for Mage-A1 , Mage-A3 , Tyrosinase antigens) and HLA-B35 (for Melan-A MART-1 , gp100 , NY- ESO-1 , Mage-A3 antigens) molecules.
- HLA-A2 epitopes derived from HER2 Human Epidermal growth factor Receptor 2
- CEA CarcinoEmbryonic Antigen
- PSA1 Prostate Specific Antigen 1
- anti-virus vaccines may be cited:
- HLA-A2/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes as pp65 and IE1 ,
- - anti-EBV (Epstein-Barr Virus) vaccine HLA-A2 and -B8/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes from EBV latent and lytic antigens.
- HLA-A2 and -B8/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes from EBV latent and lytic antigens.
- HLA-A2, -A1 and -B7/peptide monomers employing synthetic peptides comprising epitopes from HBV antigens and HBV X protein (HBx) which is a multifunctional regulatoryprotein that may participate in viral pathogenesis and carcinogenesis.
- HBV X protein HBV X protein
- peptides such as the peptide derived from hsp60 (hsp60io-ie: QMRPVSRVL Seq. Id N ° 38) may be cited.
- HLA-E/peptide monomers may be used in patients immunocompromised as for example a result of HIV. However, this treatment does not concern transplant patients.
- a further subject of the present application is the use of a monomeric HLA-l/peptide molecule of the invention for the preparation of a curative or preventative medicament intended for the treatment or prevention of diseases or conditions which may be treated by a CD8 T cell response in a patient, particularly those cited above.
- Figure 1 represents the results of stability of HLA- E*01 01/VMAPRTLLL (A) and HLA-A*0201 /VLPDVFIRC (B) monomers under assay conditions analyzed by gel filtration (Superdex 200 column) after up to 6H of incubation at 37 °C in 5% C02 atmosphere.
- Figure 2 represents the kinetics of intracellular Ca2+ levels (340/380nm ratio) in an experiment of induction of calcium mobilization upon activation of CD8 T cells (HLA-E- (A) and HLA-A2-restricted (B) T cells) with soluble HLA-I monomers.
- Figures 3 and 4 represent the ability soluble HLA-I monomers (loaded with the specific peptide on the right) to trigger antigen-specific activation of CD8 T cells in vitro (HLA-E- (Fig. 3) and HLA-A2-restricted (Fig.4) T cells), respectively by the increase of surface expression of A/ CD69 (activation marker), B/ CD1 07a (degranulation marker), C/ the production of TNF-oc and D/ the induction of apoptosis.
- the negative control using HLA-E monomer loaded with an irrelevant peptide is represented on the left.
- Figure 5 represents results of the response of HLA-E- (A) and HLA-A2-restricted (B) T cells to incubation with various concentrations (from 1 0 " 9 to 1 0 "6 M) of monomers or peptides wherein T cell activation was assessed by TNF-a staining.
- Example 1 Peptides and recombinant peptide/HLA-E monomers
- the peptides used were: HLA-A*0201 binding peptides, NA17-A1 -9 (VLPDVFIRC) (Guilloux, Y., S. Lucas, V. G. Brichard, A. Van Pel, C. Viret, E. De Plaen, F. Brasseur, B. Lethe, F. Jotereau, and T. Boon. 1996.
- a peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N- acetylglucosaminyltransferase V gene. J Exp Med 183:1 173-1 183).
- HLA-E an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287:1031 ).
- HLA-B * 3501 binding self peptide 37F LPFDFTPGY
- HLA- B * 3501 -peptide interactions role of anchor residues of peptides in their binding to HLA-B * 3501 molecules. Int Immunol 6:255-261 ).
- HLA-A * 0201/VLPDVFIRC, HLA-A * 0201 /ELAGIGILTV, HLA- E * 0101/VMAPRTLLL and HLA-E * 0101/VMAPRTLVL monomers were generated by the local recombinant protein facility (SFR Sante, France) as described by Bodinier et al. (Bodinier, M., M. A. Peyrat, C. Tournay, F. Davodeau, F. Romagne, M. Bonneville, and F. Lang. 2000; Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding. Nat Med 6:707-710).
- recombinant proteins were produced as inclusion bodies in Escherichia coli XA90'Lacq1 , dissolved in 8M urea, and refolded 5 days at 4°C with the peptide of interest.
- the solution was then concentrated and the buffer changed on amicon membrane 10 Kd (Millipore, Bedford, MA).
- Folded MHC/peptide complexes were biotinylated with the BirA enzyme (Avidity, Denvers CO) for 2h at 30 °C and desalted on Hiprep 26/10 desalting column (GE Healthcare).
- MHC/peptide complexes were then purified by anion exchange Q- Sepharose chromatography to remove unfolded proteins, any free heavy, light chain or free peptide.
- Biotinylation was tested by tetramerisation with streptavidin (Sigma Aldrich) at a molar ratio of 4:1 .
- HLA-E * 0101/VMAPRTLLL and HLA-A * 0201/VLPDVFIRC monomers under assay conditions was analyzed by gel filtration (Superdex 200 column) after up to 6H of incubation at 37 °C in 5% C0 2 atmosphere.
- (B) monomers were analyzed by gel filtration on a Superdex 200 column. At TO or after incubation at 37°C during 1 (T1 h) and 6 hours (T6h), monomers were injected on the column. Specific peak of monomers for HLA-E * 0101/VMAPRTLLL has a retention volume of 15,5ml_ and the area under the curve was 147,81 mAU at TO, 134mAU at T1 h (decrease of 9,4%) and 1 1 1 ,02mAU at T6h (decrease of 24,9%).
- HLA- E * 0101/VMAPRTLLL and HLA-A * 0201/VLPDFIRC The ability of soluble recombinant HLA-l/peptide monomers (HLA- E * 0101/VMAPRTLLL and HLA-A * 0201/VLPDFIRC) to activate CD8 T cells expressing cognate T-cell receptors was assessed.
- CD8 T cell clones a CMV reactive clone, MART.22, specific for the UL40 15 - 2 3 HLA-E-restricted V APRTLLL epitope and a melanoma reactive clone, H2, specific for the NA17-Ai -9 HLA-A * 0201 -restricted VLPDFIRC epitope.
- Figure 2 shows that incubation with antigenic soluble HLA-I /peptide monomers (1 0 ⁇ ig/ml) triggered an increase in intracellular free calcium (Ca 2+ ) concentration in both MART.22 (Fig. 2A) and H2 (Fig. 2B) clones. In contrast, no significant Ca 2+ increase was detected with monomers refolded with irrelevant peptides (HLA-E*0101 /VMAPRTLVL for MART.22 clone and HLA-A*0201 /ELAGIGILTV for H2 clone).
- T cells stimulated by antigenic soluble monomers displayed an activated phenotype characterized by an increased expression of the early activation marker CD69 (Fig. 3A, Fig. 4A).
- the induction of TNF-a production (48% and 87% of TNF-a producing T cells, for MART.22 and H2 clones respectively) (Fig. 3B, Fig. 4B) and CD1 07a surface mobilization reflecting T cell degranulation (Fig. 3C, Fig. 4C) was observed.
- HLA-E- (A) and HLA-A2-restricted (B) T cells were assessed .
- T cell activation was assessed by TNF-alpha staining. The results are shown in Figure 5.
- soluble HLA-I monomers of the invention have a comparable efficiency versus free peptide transfer activation of CD8 T cells. Accordingly, there is no loss of activity of the peptide upon binding said peptide to soluble HLA-I monomers.
- both classical and non-classical HLA-l/peptide monomers of the invention can efficiently activate antigen-specific CD8 T cells in vitro. The activation is obtained according to a mechanism that involves the passive transfer of monomer-derived peptide to cell-bound HLA-I molecules.
- the soluble HLA-I monomers protect peptides from proteolytic degradation by proteases and so provide the peptides with a long duration of action in the human body without loss of activity of the peptide.
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Abstract
A soluble monomeric HLA-I/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, particularly for use in a method of therapeutic treatment of the human or animal body, more particularly cancer, and pharmaceutical compositions.
Description
Soluble HLA-l/peptide monomers and applications as therapeutic treatments in cancer
FIELD OF THE INVENTION
The present invention relates to soluble HLA-l/peptide monomers and applications thereof as therapeutic treatments in cancer.
BACKGROUND OF THE INVENTION
Treatment of cancers remains a challenge. Conventional therapies as chemotherapy or irradiation do not always work, and even when it is useful, it may not completely destroy the cancer.
Among new and experimental strategies, antibody-drug conjugates, targeted therapies, vaccination and adoptive immunotherapy, electrochemotherapy, and hyperthermia may be cited.
Today, cancer vaccines are making promising successes in the prophylaxis and treatment of tumours. This is why the demand of anti cancer vaccines in the tumour treatment or in the cancer treatment is increasing.
Peptides have been used as antigens in cancer vaccines. However said peptides have a short duration of life in the human body.
SUMMARY OF THE INVENTION
It is an object of the present invention to eliminate or at least to substantially mitigate the drawbacks of existing cancer vaccines.
Now the applicant has discovered a new satisfactory technique for obtaining effective vaccines. According to the invention, a cancer immunogenic peptide is bound to a soluble HLA-I monomer to obtain a soluble HLA-l/peptide monomer molecule. This molecule is able to trigger antigen-specific activation of CD8 T cells.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A subject of the present application is therefore a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is
bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide.
Soluble monomeric HLA-I are well known in the literature. These include classical HLA-I molecules (HLA-la) and non-classical HLA-I molecules (HLA-lb). So-called "classical" monomeric HLA-I soluble molecules are preferred.
The peptide of the invention bound to soluble monomeric HLA-I derives from a protein expressed by cancer cells or virus-infected cells. The peptide is selected because of its antigenic properties and additionally because of its immunogenic properties. Accordingly, the man skilled in the art understands that the present invention applies to various cancers and virus infections.
The antigenic peptide makes it possible to trigger antigen-specific activation of CD8 T cells and to obtain antibodies, which are protective against antigen expressing cells.
A peptide according to the invention corresponds to a limited number of tumour or virus protein epitopes.
The peptides of the invention originate or derive from a tumour or virus protein. By "originate" is meant that their amino acid sequence is identical to that of the tumour or virus protein. By "derive" is meant that their amino acid sequence is mostly identical to that of the tumour or virus protein but comprises a few differences as will be seen hereafter.
The above peptides advantageously comprise between 8 and 1 1 amino acids.
As is known by the person skilled in the art of immunology, modifications of natural peptide sequences are possible without however modifying the nature of the immunological properties of the immunogenic peptides. Derivatives of tumour or virus peptides can therefore also be mentioned, which are highly homologous to these natural sequences, for example having more than 80% homology or even more than 90% homology with the corresponding native peptide whilst retaining the immunological properties of this epitopic site of the native peptide. The main modifications concern amino acid located at the HLA anchor positions by substituting amino acids by optimal residues for a given HLA-I allele.
The peptide derivatives should not reduce the immunogenicity, and should, like the native peptides, induce specific T cell activation.
These modifications are within the scope of a person skilled in the art, who can check the incidence of the modifications by simple tests. The immunogenicity of such modified derivatives can be evaluated in vitro with specific T cells or in vivo using humanized mice. The possible modifications preferably affect less than 3 amino acids, such as 2 or 1 single amino acid.
Preferred peptides of the invention are selected in the group consisting in:
- Cancer:
in HLA-A1 context:
EADPTGHSY (Mage-A1 161.169) Seq. Id N 0 1
EVDPIGHLY (Mage-A3i68-176) Seq. Id N ° 2
SSDYVIPIGTY (Tyrosinases se) Seq. Id N ° 3
and
in HLA-B35 context:
EAAGIGILTV (Melan-A/M ART- 126-35) Seq. Id N ° 4 and its modified analogs EAAGIGILTY (Melan-A/M ART- 126-35, V35Y) Seq. Id N ° 5 and EPAGIGILTY (Melan-A/MART-126-35, A27P, V35Y) Seq. Id N ° 6,
VPLDCVLYRY (gp10047i-48o) Seq. Id N ° 7
MPFATPMEA (NY-ESO-194-102) Seq. Id N ° 8
EVDPIGHLY (Mage-A3i68-176) Seq. Id N ° 9
in HLA-E context:
(hsp6010-18: QMRPVSRVL Seq. Id N ° 38).
and preferably in the group consisting in
in HLA-A2 context:
AAGIGILTV (Melan-A/MART-127-35) Seq. Id N ° 10, EAAGIGILTV
(Melan-A/MART-126.35) Seq. Id N ° 4 and its modified analog ELAGIGILTV (Melan-A/MART-126-35, A27L) Seq. Id N 0 1 1 ,
TLNDECWPA (Meloe136-44) Seq. Id N ° 12,
VLPDVFIRC (NA17Ai-9) Seq. Id N ° 13,
SLLMWITQC (NY-ESO-1 157-165) Seq. Id N 0 14,
KIFGSLAFL (HER2369-377) Seq. Id N ° 15,
IISAVVGIL (HER2654-662) Seq. Id N ° 1 6,
YLSGANLNL (CEA605-613) Seq. Id N ° 17,
FLTPKKLQCV (PSA165-174) Seq. Id N ° 18;
- Infectious diseases:
in HLA-A*0101 context:
WMMWYWGPSLY (HBV env359-369) Seq. Id N° 19
DLLDTASALY (HBV core419-428) Seq. Id N°20
and
in HLA-B*0702 context:
IPIPSSWAF (HBV env313.321) Seq. Id N°21
FPHCLAFSYM (HBV pol53o-539) Seq. Id N°22
and
in HLA-B*0801 context:
RAKFKQLL (BZLF-1, EBV early lytic antigen) Seq. Id N°23
FLRGRAYGL (EBNA-3A, EBV latent antigen) Seq. Id N°24 and preferably in the group consisting in:
in HLA-A*0201 context:
VLEETSVML (HCMV IE-I316-324) Seq. Id N°25
NLVP VATV (HCMV pp65495-503) Seq. Id N°26
GLCTLVAML (BMLF-1 , EBV early lytic antigen) Seq. Id N 027
CLGGLLTMV (LMP-2A, EBV latent antigen) Seq. Id N°28
DLMGYIPLV (HCV corei32-i4o) Seq. Id N°29
KLVALGINAV (HCV NS3U06-1415) Seq. Id N 030
ALYDVVTKL (HCV NS5B2594-2602) Seq. Id N°31
FLLTRILTI (HBV env183-191) Seq. Id N°32
FLPSDFFPSV (HBV corei8.27) Seq. Id N°33
YMDDVVLGV (HBV pol538-546) Seq. Id N°34
HLSLRGLPV (HBx52-6o) Seq. Id N 035
VLHKRTLGL (HBx92-ioo) Seq. Id N°36
CLFKDWEEL (HBX115-123) Seq. Id N°37.
Under preferred conditions for implementing the invention, the peptide is selected in the group consisting in:
AAGIGILTV (Melan-A/M ART- 127-35) Seq. Id N° 10,
EAAGIGILTV (Melan-A/MART- ss) Seq. Id N°4
ELAGIGILTV (Melan-A/MART-126-35, A27L) Seq. Id N° 11
TLNDECWPA (Meloe136-44) Seq. Id N° 12,
VLPDVFIRC (NA17Ai-9) Seq. Id N° 13,
SLLMWITQC (NY-ESO-1 157-165) Seq. Id N ° 14,
KIFGSLAFL (HER2369-377) Seq. Id N ° 15,
IISAVVGIL (HER2654-662) Seq. Id N ° 1 6,
YLSGANLNL (CEA605-613) Seq. Id N ° 1 7,
FLTPKKLQCV (PSA165-i 74) Seq. Id N 0 18.
Under further preferred conditions for implementing the invention, the peptide is selected in the group consisting in ELAGIGILTV (Melan-A/MART- I 26-35, A27L) Seq. Id N ° 1 1 and TLNDECWPA (Meloe136-44) Seq. Id N ° 12.
The peptides used in the invention can in particular be produced by chemical synthesis.
The cancer or virus native peptides or derivatives according to the invention possess very useful pharmacological properties. They are in particular endowed with remarkable anti-tumour and anti-virus properties. They are in fact immunogens and capable of generating in a subject T lymphocytes or antibodies recognizing the native tumor or virus protein. Indeed, they trigger a T cell response, specifically a CD8 T cell response in a patient.
These properties are illustrated hereafter in the experimental part. They justify the use of a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide described above, preferably a cancer antigenic peptide, as medicament.
A subject of the present application is therefore also a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, for use in a method of therapeutic treatment of the human or animal body, that is to say as a medicament or drug.
The medicaments according to the present invention are used for example in both the curative treatment of cancers and infection diseases.
The immunogenic active ingredients according to the invention can be used as follows:
A soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer antigenic peptide (or peptide derivative) or immunogenic compound according to the present invention, is administered to a patient, for example by sub-cutaneous
or intravenous route, in a sufficient quantity to be effective at a therapeutic level, to a subject needing such treatment. The dose administered can for example range from 1 to 1000 g, in particular 10 to 500 g, by sub-cutaneous route, once a month for three months, then periodically as a function of the induced specific T cell responses, for example every 2-6 months. In the same preparation two or more different immunogenic molecules can be administered in order to induce various specific T cell responses targeting tumor or virus-infected cells in the case where a single immunogenic molecule does not carry all the active sites of the tumour or infected cells.
A subject of the invention is also the pharmaceutical compositions in particular the vaccines which contain at least one abovementioned soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide (or peptide derivative) or immunogenic compound, preferably a cancer antigenic peptide, as active ingredient.
As medicaments, a monomeric HLA-l/peptide molecule (or peptide derivative or immunogenic compound) of the invention can be incorporated into pharmaceutical compositions intended for any standard route in use in the field of vaccines, in particular by sub-cutaneous route or by intravenous route. The administration can take place in a single dose or repeated once or more after a certain period of time.
This is why a subject of the present Application is also a curative pharmaceutical composition, characterized in that it comprises as active ingredient, one or more monomeric HLA-l/peptide molecule as defined above.
The immunogenic agent can be conditioned alone or mixed with an excipient or mixture of pharmaceutically acceptable excipients as an adjuvant. A subject of the present application is more particularly a vaccine containing as immunogenic compound, an abovementioned monomeric HLA-l/peptide molecule.
A subject of the present invention is also a process for preparing a composition described above, characterized in that, according to methods known per se, the active ingredient or ingredients are mixed with acceptable, in particular pharmaceutically acceptable excipients.
The administration to a patient of a monomeric HLA-l/peptide molecule according to the invention corresponds to an active immunotherapy.
The vaccine preparations of the present invention may particularly be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with or without an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily but preferably aqueous vehicles. Examples of oily or non-aqueous carriers, diluents solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil, and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. The active ingredient may also be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. Drugs for parenteral administration are sterile.
Additionally, a subject of the present application is a process for active immunization of patients characterized in that as immunogen, a monomeric HLA-l/peptide molecule according to the invention is used, as defined above, advantageously associated with a mineral, oily or synthetic immunity adjuvant.
Immunizations can be done in a standard fashion preferably in the presence of an adjuvant, for example ISA 51 or Alum.
A further subject of the present application is a soluble monomeric HLA-l/peptide recombinant molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, preferably a cancer antigenic peptide, for use in a method for triggering a CD8 T cell response in a patient.
A subject of the present application is additionally a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, preferably a cancer antigenic peptide, for use in a method of treatment of a condition, which may be treated by a TCD8+ response in a patient.
A subject of the present application is additionally a soluble monomeric HLA-l/peptide molecule wherein a peptide ligand is bound to soluble
monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide, for use in a method of treatment of a cancer or virus for which specific epitopes are identified such as melanoma, colorectal carcinomas and breast cancers.
This strategy is particularly relevant in melanoma wherein multiple
CD8 epitopes derived from melanoma antigens have been reported. These peptides are presented by diverse classical HLA-la contexts, involving HLA-A2 molecules that are expressed in about 40-50% of Caucasian population (for Melan-A/MART-1 , eloe-1 , NA17A, NY-ESO-1 antigens), HLA-A1 (for Mage-A1 , Mage-A3, Tyrosinase antigens) and HLA-B35 (for Melan-A MART-1 , gp100, NY- ESO-1 , Mage-A3 antigens) molecules. That strategy also applies to breast, ovary, kidney, prostate, colorectal, gastrointestinal and lung cancers with HLA-A2 epitopes derived from HER2 (Human Epidermal growth factor Receptor 2), CEA (CarcinoEmbryonic Antigen ) and PSA1 (Prostate Specific Antigen 1 ) antigens.
As regards anti-virus vaccines, may be cited:
- anti-HCMV (Human CytoMegaloVirus) vaccine: HLA-A2/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes as pp65 and IE1 ,
- anti-EBV (Epstein-Barr Virus) vaccine: HLA-A2 and -B8/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes from EBV latent and lytic antigens.
- anti-HCV (Hepatitis C Virus) vaccine: HLA-A2 and -B8/peptide monomers employing synthetic peptides comprising immunodominant cytotoxic-T cell epitopes from EBV latent and lytic antigens.
- anti-HBV (Hepatitis B Virus) vaccine HLA-A2, -A1 and -B7/peptide monomers employing synthetic peptides comprising epitopes from HBV antigens and HBV X protein (HBx) which is a multifunctional regulatoryprotein that may participate in viral pathogenesis and carcinogenesis.
As regards HLA-E/peptide monomers in cancer vaccination, peptides such as the peptide derived from hsp60 (hsp60io-ie: QMRPVSRVL Seq. Id N ° 38) may be cited.
In CMV infection, HLA-E/peptide monomers may be used in patients immunocompromised as for example a result of HIV. However, this treatment does not concern transplant patients.
A further subject of the present application is the use of a monomeric HLA-l/peptide molecule of the invention for the preparation of a curative or preventative medicament intended for the treatment or prevention of diseases or conditions which may be treated by a CD8 T cell response in a patient, particularly those cited above.
DESCRIPTION OF THE DRAWINGS
Figure 1 represents the results of stability of HLA- E*01 01/VMAPRTLLL (A) and HLA-A*0201 /VLPDVFIRC (B) monomers under assay conditions analyzed by gel filtration (Superdex 200 column) after up to 6H of incubation at 37 °C in 5% C02 atmosphere.
Figure 2 represents the kinetics of intracellular Ca2+ levels (340/380nm ratio) in an experiment of induction of calcium mobilization upon activation of CD8 T cells (HLA-E- (A) and HLA-A2-restricted (B) T cells) with soluble HLA-I monomers.
Figures 3 and 4 represent the ability soluble HLA-I monomers (loaded with the specific peptide on the right) to trigger antigen-specific activation of CD8 T cells in vitro (HLA-E- (Fig. 3) and HLA-A2-restricted (Fig.4) T cells), respectively by the increase of surface expression of A/ CD69 (activation marker), B/ CD1 07a (degranulation marker), C/ the production of TNF-oc and D/ the induction of apoptosis. The negative control using HLA-E monomer loaded with an irrelevant peptide is represented on the left.
Figure 5 represents results of the response of HLA-E- (A) and HLA-A2-restricted (B) T cells to incubation with various concentrations (from 1 0" 9 to 1 0"6M) of monomers or peptides wherein T cell activation was assessed by TNF-a staining.
EXAMPLES
Example 1 : Peptides and recombinant peptide/HLA-E monomers
The peptides (Millegen, Labege, France, purity >80%) used were: HLA-A*0201 binding peptides, NA17-A1 -9 (VLPDVFIRC) (Guilloux, Y., S. Lucas, V. G. Brichard, A. Van Pel, C. Viret, E. De Plaen, F. Brasseur, B. Lethe, F.
Jotereau, and T. Boon. 1996. A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N- acetylglucosaminyltransferase V gene. J Exp Med 183:1 173-1 183). and Melan- A26-35 (ELAGIGILTV) (Valmori, D., J. F. Fonteneau, C. M. Lizana, N. Gervois, D. Lienard, D. Rimoldi, V. Jongeneel, F. Jotereau, J. C. Cerottini, and P. Romero. 1998. Enhanced generation of specific tumor-reactive CTL in vitro by selected Melan-A/MART-1 immunodominant peptide analogues. J Immunol 160:1750-175. derived from two human melanoma-associated antigens, HLA-E*0101/03 binding peptides, UL4015-23 (VMAPRTLLL and VMAPRTLV) derived from human cytomegalovirus (CMV) strains (Towne and Toledo) (Cerboni, C, M. Mousavi- Jazi, H. Wakiguchi, E. Carbone, K. Karre, and K. Soderstrom. 2001 . Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E- dependent protection from NK cell-mediated cytotoxicity. Eur J Immunol 31 :2926- 2935 ; Tomasec, P., V. M. Braud, C. Rickards, M. B. Powell, B. P. McSharry, S. Gadola, V. Cerundolo, L. K. Borysiewicz, A. J. McMichael, and G. W. Wilkinson. 2000. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287:1031 ). and HLA-B*3501 binding self peptide 37F (LPFDFTPGY) (Takamiya, Y., C. Schonbach, K. Nokihara, M. Yamaguchi, S. Ferrone, K. Kano, K. Egawa, and M. Takiguchi. 1994. HLA- B*3501 -peptide interactions: role of anchor residues of peptides in their binding to HLA-B*3501 molecules. Int Immunol 6:255-261 ).
HLA-A*0201/VLPDVFIRC, HLA-A*0201 /ELAGIGILTV, HLA- E*0101/VMAPRTLLL and HLA-E*0101/VMAPRTLVL monomers were generated by the local recombinant protein facility (SFR Sante, Nantes, France) as described by Bodinier et al. (Bodinier, M., M. A. Peyrat, C. Tournay, F. Davodeau, F. Romagne, M. Bonneville, and F. Lang. 2000; Efficient detection and immunomagnetic sorting of specific T cells using multimers of MHC class I and peptide with reduced CD8 binding. Nat Med 6:707-710).
Briefly, recombinant proteins were produced as inclusion bodies in Escherichia coli XA90'Lacq1 , dissolved in 8M urea, and refolded 5 days at 4°C with the peptide of interest. The solution was then concentrated and the buffer changed on amicon membrane 10 Kd (Millipore, Bedford, MA). Folded MHC/peptide complexes were biotinylated with the BirA enzyme (Avidity, Denvers CO) for 2h at 30 °C and desalted on Hiprep 26/10 desalting column (GE
Healthcare). MHC/peptide complexes were then purified by anion exchange Q- Sepharose chromatography to remove unfolded proteins, any free heavy, light chain or free peptide.
Biotinylation was tested by tetramerisation with streptavidin (Sigma Aldrich) at a molar ratio of 4:1 .
Stability of HLA-E*0101/VMAPRTLLL and HLA-A*0201/VLPDVFIRC monomers under assay conditions was analyzed by gel filtration (Superdex 200 column) after up to 6H of incubation at 37 °C in 5% C02 atmosphere.
The results are shown in figure 1 .
Purified HLA-E*0101 VMAPRTLLL (A) and HLA-A*0201/VLPDFIRC
(B) monomers were analyzed by gel filtration on a Superdex 200 column. At TO or after incubation at 37°C during 1 (T1 h) and 6 hours (T6h), monomers were injected on the column. Specific peak of monomers for HLA-E*0101/VMAPRTLLL has a retention volume of 15,5ml_ and the area under the curve was 147,81 mAU at TO, 134mAU at T1 h (decrease of 9,4%) and 1 1 1 ,02mAU at T6h (decrease of 24,9%). Specific peak of monomers for HLA-A*0201/VLPDFIRC has a retention volume of 15,2ml_ and the area under the curve was 10,24mAU at TO, 10,05mAU at T1 h (decrease of 1 ,8%) and 7,46mAU at T6h (decrease of 27%). Experimentation 1 . Activation of CD8 T cell clones by classical and non-classical soluble HLA class I monomers
The ability of soluble recombinant HLA-l/peptide monomers (HLA- E*0101/VMAPRTLLL and HLA-A*0201/VLPDFIRC) to activate CD8 T cells expressing cognate T-cell receptors was assessed.
To this end, experiments were carried out in parallel on two human
CD8 T cell clones: a CMV reactive clone, MART.22, specific for the UL4015-23 HLA-E-restricted V APRTLLL epitope and a melanoma reactive clone, H2, specific for the NA17-Ai-9 HLA-A*0201 -restricted VLPDFIRC epitope.
In order to prevent proteolytic degradation of HLA-peptide complexes, all experiments were carried out in serum free AI -V medium. Moreover, to exclude that HLA-l/peptide monomer activity could rely on their adventitious immobilization on plastic, culture wells were pre-incubated with a saturating dose of BSA (1 mg/ml).
The results are shown in Figures 2, 3 and 4.
Figure 2 shows that incubation with antigenic soluble HLA-I /peptide monomers (1 0^ig/ml) triggered an increase in intracellular free calcium (Ca2+) concentration in both MART.22 (Fig. 2A) and H2 (Fig. 2B) clones. In contrast, no significant Ca2+ increase was detected with monomers refolded with irrelevant peptides (HLA-E*0101 /VMAPRTLVL for MART.22 clone and HLA-A*0201 /ELAGIGILTV for H2 clone).
Several activation and function markers were next analyzed after 6 hours of incubation with anti-CD3 mAb or soluble HLA-l/peptide monomers (Fig. 3, Fig. 4 for MART.22 T and H2 clones respectively). T cells stimulated by antigenic soluble monomers displayed an activated phenotype characterized by an increased expression of the early activation marker CD69 (Fig. 3A, Fig. 4A). In addition, the induction of TNF-a production (48% and 87% of TNF-a producing T cells, for MART.22 and H2 clones respectively) (Fig. 3B, Fig. 4B) and CD1 07a surface mobilization reflecting T cell degranulation (Fig. 3C, Fig. 4C) was observed. Finally, incubation of CD8 T cells with soluble monomers showed induced significant T cell apoptosis (36% and 46% Annexin-V+7AAD+ for MART.22 and H2 clones respectively) (Fig. 3D, Fig. 4D). In agreement with Ca2+ flux experiments, T cell activation was not observed with irrelevant monomers.
Thus, these data evidence that sHLA-l peptide monomers are able to induce antigen-specific activation of CD8 T cell clones.
Experimentation 2. response of HLA-E- and HLA-A2-restricted T cells to incubation with various concentrations of monomers or peptides.
The response of HLA-E- (A) and HLA-A2-restricted (B) T cells to incubation with various concentrations (from 1 0"9 to 1 0"6M) of monomers or peptides was assessed .T cell activation was assessed by TNF-alpha staining. The results are shown in Figure 5.
The results evidence that soluble HLA-I monomers of the invention have a comparable efficiency versus free peptide transfer activation of CD8 T cells. Accordingly, there is no loss of activity of the peptide upon binding said peptide to soluble HLA-I monomers.
In summary, both classical and non-classical HLA-l/peptide monomers of the invention can efficiently activate antigen-specific CD8 T cells in vitro. The activation is obtained according to a mechanism that involves the passive transfer of monomer-derived peptide to cell-bound HLA-I molecules.
The soluble HLA-I monomers protect peptides from proteolytic degradation by proteases and so provide the peptides with a long duration of action in the human body without loss of activity of the peptide.
Claims
1. A soluble monomeric HLA-l/peptide molecule wherein a peptide Iigand is bound to soluble monomeric HLA-I and wherein the peptide is a cancer or virus antigenic peptide.
2. A soluble monomeric HLA-l/peptide molecule of claim 1, wherein the peptide is a cancer antigenic peptide.
3. A soluble monomeric HLA-l/peptide molecule of claim 1, wherein the peptide is selected in the group consisting in:
EADPTGHSY (Mage-A1i6i-i69) Seq. Id N°1
EVDPIGHLY (Mage-A3i68-i76) Seq. Id N°2
SSDYVIPIGTY (Tyrosinasei46-i56) Seq. Id N°3
EAAGIGILTV (Melan-A/MART-126-35) Seq. Id N°4
EAAGIGILTY (Melan-AMART-126-35, V35Y) Seq. Id N ° 5
EPAGIGILTY (Melan-AMART-126-35, A27P, V35Y) Seq. Id N°6,
VPLDCVLYRY (gp10047i-48o) Seq. Id N°7
MPFATPMEA (NY-ESO-194-102) Seq. Id N°8
EVDPIGHLY (Mage-A3i68-i76) Seq. Id N°9
AAGIGILTV (Melan-A/MART-127-35) Seq. Id N° 10,
EAAGIGILTV (Melan-A/MART-126-35) Seq. Id N°4,
ELAGIGILTV (Melan-A/MART-126-35, A27L) Seq. Id N° 11 ,
TLNDECWPA (Meloe136-44) Seq. Id N° 12,
VLPDVFIRC (NA17Ai-g) Seq. Id N° 13,
SLLMWITQC (NY-ESO-1157.165) Seq. Id N 014,
KIFGSLAFL (HER2389-377) Seq. Id N° 15,
IISAVVGIL (HER2654-662) Seq. Id N° 16,
YLSGANLNL (CEAeos-eis) Seq. Id N° 17,
FLTPKKLQCV (PSA m) Seq. Id N° 18,
WMMWYWGPSLY (HBV env359-369) Seq. Id N 019,
DLLDTASALY (HBV core4i9-428) Seq. Id N°20,
IPIPSSWAF (HBV env3i 3-321) Seq. Id N°21,
FPHCLAFSYM (HBV pol530-539) Seq. Id N°22,
RAKFKQLL (BZLF-1 , EBV early lytic antigen) Seq. Id N°23,
FLRGRAYGL (EBNA-3A, EBV latent antigen) Seq. Id N°24,
VLEETSVML (HCMV IE-I316-324) Seq. Id N°25,
NLVPMVATV (HCMV pp65495-503) Seq. Id NT 26,
GLCTLVAML (BMLF-1 , EBV early lytic antigen) Seq. Id N 027,
CLGGLLTMV (LMP-2A, EBV latent antigen) Seq. Id N°28,
DLMGYIPLV (HCV corei32-i4o) Seq. Id N°29,
KLVALGINAV (HCV NS31406-1415) Seq. Id N°30,
ALYDVVTKL (HCV NS5B2594-2602) Seq. Id N°31,
FLLTRILTI (HBV env1B3-i9i) Seq. Id N°32,
FLPSDFFPSV (HBV corei8-27) Seq. Id N 033,
YMDDVVLGV (HBV pol538-546) Seq. Id N°34,
HLSLRGLPV (HBx52-6o) Seq. Id N°35,
VLHKRTLGL (HBx92-i00) Seq. Id N°36,
CLFKDWEEL (HBx115-i23) Seq. Id N°37,
QMRPVSRVL (hsp60i0-i8) Seq. Id N 038.
4. A soluble monomeric HLA-l/peptide molecule of one of claims 1 to 3, wherein the peptide is selected in the group consisting in:
AAGIGILTV (Melan-A/MART-127-35) Seq. Id N° 10,
EAAGIGILTV (Melan-A/MART-126-35) Seq. Id N°4,
ELAGIGILTV (Melan-A/MART-125-35, A27L) Seq. Id N° 11 ,
TLNDECWPA (Meloe136-44) Seq. Id N° 12,
VLPDVFIRC (NA17A1-9) Seq. Id N° 13,
SLLMWITQC (NY-ESO-1157-165) Seq. Id N°14,
KIFGSLAFL (HER2369-377) Seq. Id N° 15,
IISAVVGIL (HER2654-662) Seq. Id N° 16,
YLSGANLNL (CEA605-613) Seq. Id N° 17,
FLTPKKLQCV (PSA165-i74) Seq. Id N° 18.
5. A soluble monomeric HLA-l/peptide molecule of one of claims 1 to 4, wherein the peptide is selected in the group consisting in: ELAGIGILTV (Melan-A/MART-126-35, A27L) Seq. Id N° 11, and TLNDECWPA (Meloe136-44) Seq. Id N°12.
6. A soluble monomeric HLA-l/peptide molecule of one of claims 1 to 5, for use in a method of therapeutic treatment of the human or animal body.
7. A soluble monomeric HLA-l/peptide molecule of claim 1 or 2, for use in a method of therapeutic treatment of cancer.
8. A pharmaceutical composition, which contains one or several soluble monomeric HLA-l/peptide molecules of any one of claims 1 to 5, as active ingredient and a pharmaceutically acceptable excipient.
9. A soluble monomeric HLA-l/peptide molecule molecules of any one of claims 1 to 5, for use in a method for triggering a CD8 T cell response in a patient.
10. A soluble monomeric HLA-l/peptide molecule molecules of any one of claims 1 to 5, for use in a method of any one of claims 6 to 9 wherein the patient sufferers from a cancer or tumour.
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| CERBONI, C.; M. MOUSAVI-JAZI; H. WAKIGUCHI; E. CARBONE; K. KARRE; K. SODERSTROM: "Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity", EUR J IMMUNOL, vol. 31, 2001, pages 2926 - 2935 |
| E. JAGER ET AL: "Impact of Antigen Presentation on TCR Modulation and Cytokine Release: Implications for Detection and Sorting of Antigen-Specific CD8+ T Cells Using HLA-A2 Wild-Type or HLA-A2 Mutant Tetrameric Complexes", THE JOURNAL OF IMMUNOLOGY, vol. 168, no. 6, 15 March 2002 (2002-03-15), pages 2766 - 2772, XP055139749, ISSN: 0022-1767, DOI: 10.4049/jimmunol.168.6.2766 * |
| GUILLOUX, Y.; S. LUCAS; V. G. BRICHARD; A. VAN PEL; C. VIRET; E. DE PLAEN; F. BRASSEUR; B. LETHE; F. JOTEREAU; T. BOON: "A peptide recognized by human cytolytic T lymphocytes on HLA-A2 melanomas is encoded by an intron sequence of the N-acetylglucosaminyltransferase V gene", J EXP MED, vol. 183, 1996, pages 1173 - 1183 |
| M. ALLARD ET AL: "Soluble HLA-I/Peptide Monomers Mediate Antigen-Specific CD8 T Cell Activation through Passive Peptide Exchange with Cell-Bound HLA-I Molecules", vol. 192, no. 11, 21 April 2014 (2014-04-21), pages 5090 - 5097, XP055139667, ISSN: 0022-1767, Retrieved from the Internet <URL:http://www.jimmunol.org/content/192/11/5090.full.pdf+html> [retrieved on 20140911], DOI: 10.4049/jimmunol.1303226 * |
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