EP1635862A1 - Peptides derives de la proteine mmp-2 et leur utilisation en immunotherapie antitumorale - Google Patents
Peptides derives de la proteine mmp-2 et leur utilisation en immunotherapie antitumoraleInfo
- Publication number
- EP1635862A1 EP1635862A1 EP04767441A EP04767441A EP1635862A1 EP 1635862 A1 EP1635862 A1 EP 1635862A1 EP 04767441 A EP04767441 A EP 04767441A EP 04767441 A EP04767441 A EP 04767441A EP 1635862 A1 EP1635862 A1 EP 1635862A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmp
- metalloprotease
- mhc
- fragment
- cytotoxic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- 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
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6489—Metalloendopeptidases (3.4.24)
- C12N9/6491—Matrix metalloproteases [MMP's], e.g. interstitial collagenase (3.4.24.7); Stromelysins (3.4.24.17; 3.2.1.22); Matrilysin (3.4.24.23)
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/124—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells the cells being hematopoietic, bone marrow derived or blood cells
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- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
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- A—HUMAN NECESSITIES
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- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
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- A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
Definitions
- the present invention relates to peptides derived from the MMP-2 protein and to their use in tumor immunotherapy.
- Vaccination or peptide immunotherapy is a therapeutic approach which is currently the subject of great interest in the context of the prevention or treatment of cancers. Its principle is based on the induction of an immune response towards peptides representing T epitopes of tumor antigens recognized by cytotoxic T lymphocytes (CTL), which play a major role in the elimination of cancer cells expressing these antigens on their surface.
- CTL cytotoxic T lymphocytes
- the CTLs do not recognize the entire protein antigens, but peptide fragments thereof, presented by the molecules of the major histocompatibility complex (MHC) expressed on the surface of different cells. It is these peptide fragments which constitute the T epitopes.
- MHC major histocompatibility complex
- the epitopes presented by the major histocompatibility class I complex (MHC I) generally have 8 to 11 amino acids, and are recognized by the CD8 + T cells, which represent the major component. of the cytotoxic response.
- the epitopes presented by the major class II histocompatibility complex (MHC II) generally have 13 to 18 amino acids and are recognized by CD4 + T cells.
- MMPs Matrix metalloproteases
- MMP-2 also known as gelatinase A or type IV collagenase; OMIM 120360
- OMIM 120360 cleaves type IV collagen, gelatin, as well as other components of the extracellular matrix. This protein is expressed in many healthy cells and tissues; it is also over-expressed in many cancers.
- MMP-2 could be efficiently primed by melanoma cells to generate T epitopes presented by MHC I, and inducing cytotoxic T lymphocytes capable of lyzing these tumor cells.
- the present invention therefore relates to the use of a molecule chosen from: - the metalloprotease MMP-2; - a fragment of said metalloprotease comprising a T epitope presented by MHC I; - a polynucleotide encoding said metalloprotease or for said fragment; for obtaining a medicament intended for anti-tumor immunotherapy, and more particularly for the treatment of melanomas expressing MMP-2.
- Fragments of MMP-2 which can be used in accordance with the present invention include in particular any immunogenic peptide constituted by 8 to 11 consecutive amino acids of said metalloprotease, and constituting a T epitope presented by MHC I.
- immunogenic peptides as well as the polynucleotides encoding these peptides are also part of the subject of the present invention.
- T epitope presented by the MHC I a peptide capable of inducing a specific CTL response against the antigen from which it is derived.
- the inventors have identified a peptide presented by HLA-A * 0201, of sequence (code 1 letter) GLPPDVQRV (SEQ ID NO: 1).
- This peptide is capable of inducing a specific CTL response with respect to HLA-A * 0201 melanoma cells expressing MMP-2, and is therefore in particular usable for obtaining medicaments intended for the treatment of HLA-A * patients 0201.
- Other T epitopes according to the invention can be obtained in various ways from the MMP-2 antigen.
- anchoring residues For example, it is known that peptides capable of forming a complex with a given MHC I allele have in common the presence, at certain positions, of particular amino acid residues, called “anchoring residues”. We have thus defined for the different alleles of the MHC I, specific anchoring patterns, involving amino acids called “primary anchoring residues”. It has also been shown that residues located outside the primary anchoring motifs (secondary anchoring residues) can exert a favorable or unfavorable effect on the affinity of the peptide for MHC.
- the choice of peptide sequences capable of constituting epitopes presented by a given MHC I allele can be carried out, in a conventional manner, by analysis of the peptide sequence of the MMP-2 antigen, in order to select the peptides having all or part of the primary anchor pattern corresponding to this allele.
- Different databases listing the known anchoring patterns are available: as an example, the SYFPEITHI database (http://www.uni-tuebingen.de/uni/kxi/; RAMMENSEE et al., Immunogenetics, 50, 213-219, 1999), or the base BIMAS (http://bimas.dcrt.nih.gov/molbio/hla_bind; Parker et al., J.
- compositions comprising at least one immunogenic peptide in accordance with the invention or a polynucleotide coding for said peptide, which may in particular be multiepitopic compositions capable of generating a polyspecific CTL response, and which for this purpose also comprise one or more other epitope (s)
- These other epitopes can be derived from MMP-2, or from one or more other antigens.
- Multiepitopic compositions in accordance with the invention can comprise, in order to be widely usable in a population in which individuals carry HLA alleles different, epitopes presented by different MHC I molecules.
- compositions according to the invention can also further comprise at least one epitope presented by a MHC II molecule, and capable of inducing an auxiliary T response.
- a composition according to the invention it comprises at least one chimeric polypeptide comprising one or more copies of an immunogenic peptide according to the invention.
- said chimeric polypeptide further comprises one or more copies of at least one other immunogenic epitope. It is possible, for example, to inject the patient to be treated with an immunogenic peptide, or a composition in accordance with the invention as defined above, optionally combined with an appropriate adjuvant.
- polynucleotides in accordance with the invention preferably integrated into nucleic acid vectors, in particular viral vectors such as adenoviruses, can also be directly administered by injection to the patient to be treated.
- the present invention also encompasses antigen presenting cells having a T epitope derived from MMP-2 according to the invention.
- Antigen presenting cells according to the invention can be obtained from all cells capable of presenting an antigen via the MHC I. In particular, they can be obtained from professional antigen presenting cells, for example dendritic cells. According to a preferred embodiment of the present invention, said antigen presenting cells are loaded in vi tro using an immunogenic peptide according to the invention, as described for example by BAKKER et al.
- said antigen-presenting cells are transfected in vitro with a polynucleotide comprising a sequence coding for an immunogenic peptide in accordance with the invention, for example a polynucleotide coding for the protein MMP- 2 or for a fragment thereof.
- the antigen presenting cells according to the invention can then be injected into the patient to be treated, as described for example by KAPLAN et al. (J. Immunol., 163 (2), 699-707, 1999) or KIM and aZ.
- the present invention also encompasses the use of the protein MMP-2, or a fragment thereof, and in particular of an immunogenic peptide according to the invention, for the detection of CTLs directed against MMP-2 in a sample.
- These peptides can also be used to carry out the specific sorting of these CTLs.
- the CTLs thus isolated can then be amplified in vitro and reinjected in large numbers (of the order of a billion) to the patient.
- the present invention thus relates to a process for the preparation of CTLs directed against MMP-2, characterized in that it comprises the selection, from CTLs taken from a patient suffering from melanoma, of those recognizing the protein MMP-2, or a fragment thereof, and in particular a peptide in accordance with the invention, and the in vitro multiplication of the T lymphocytes thus selected.
- the present invention also relates to a preparation of CTLs directed against the MMP-2 protein, and in particular a preparation of CTLs capable of being obtained by the process defined above.
- the present invention also encompasses drugs comprising an active principle chosen from: an immunogenic peptide in accordance with the invention; - a multiepitopic composition in accordance with the invention; - a polynucleotide according to the invention; an antigen presenting cell according to the invention; a preparation of CTLs in accordance with the invention.
- an active principle chosen from: an immunogenic peptide in accordance with the invention; - a multiepitopic composition in accordance with the invention; - a polynucleotide according to the invention; an antigen presenting cell according to the invention; a preparation of CTLs in accordance with the invention.
- EXAMPLE 1 CHARACTERIZATION OF A CTL CLONE (CLONE M134.12) RECOGNIZING HLA-A2 MELANOMA LINES.
- CTL clones were obtained by stimulating with autologous tumor cells (according to the protocol described by PANDOLFINO et al., 1992, Eur. J. Immunol.,
- TIL lymphocytes infiltrating tumors
- HLA A * 0201, B * 0801, Cw * 0701 lymphocytes infiltrating tumors
- CTL M134.12 lymphocytes infiltrating tumors
- the CTL clone M134.12 was co-cultivated in the presence of the autologous line M134, and of various allogenic lines (M17, M113, M147, M153, M204, FM25, FM29, IPC 277/5, M25, M44, M88, M102, M117, M171, M199, M200) from melanomas of different HLA A * 0201 patients. After 6 hours of culture, the supernatants were removed and their TNF ⁇ concentration was determined by measuring the cytotoxicity of these culture supernatants for clone 13 of WEHI 164, as described by DE PLAEN et al. (Methods, 12, 125-42, 1997). The results are illustrated in Figure 1.
- the CTL clone M134.12. recognizes, in addition to the M134 line, nine allogeneic melanoma cell lines expressing HLA A * 0201. This indicates that this CTL clone recognizes an antigen common to these lines and presented by the HLA A * 0201 allele.
- EXAMPLE 2 IDENTIFICATION OF THE ANTIGEN RECOGNIZED BY THE CLONE CTL M134.12.
- a cDNA library was constructed from the mRNAs of the tumor cell line M134. Construction of the cDNA Library The Poly- (A) + mRNAs were extracted from M134 cells using the Fast Track 2.0 kit (Invitrogen Corp., Oxon, UK). The synthesis of cDNA from purified mRNAs was carried out using a kit (Stratagene Inc., La Jolla, CA).
- the neo-synthesized cDNAs were ligated to Eco RI adapters, then digested with Xho I and finally inserted at the Eco RI and Xho I sites of the eukaryotic expression vector pcDNA3.1 (Invitrogen Corp.).
- the recombinant plasmids obtained were electroporated in the E. coli XL1 strain (Stratagene Inc., La Jolla, CA). After electroporation, nearly 60,000 clones resistant to ampicillin were isolated. To allow the screening of these clones, 574 groups (each of 100 bacterial clones resistant to ampicillin) were created.
- the plasmid DNA of each of the groups was extracted by alkaline lysis using the QIAprep Spin Miniprep kit (Qiagen S.A., Courtaboeuf, France). This plasmid DNA was then co-transfected, in COS-7 cells, with an HLA A * 0201 vector (pHLA A * 0201, obtained from T. Boon, LICR, Brussels, Belgium).
- DMEM fetal calf serum
- antibiotics and L-glutamine were transfected with the vector pHLA- A * 0201, alone or in combination with the plasmid DNA from one of the groups in the M134 cDNA library.
- the transfection was performed according to the DEAE-dextran-chloroquine protocol (BRICHARD, Exp. Med. 1993, 1 (78): 489-495).
- 2.10 4 COS-7 cells were transfected with 100 ng of plasmid pHLA-A * 0201 and, for co-transfection, 100 ng of plasmid DNA from the M134 library.
- the sequencing of pNA134-A shows that it contains a 1.3 kb cDNA whose sequence corresponds to the 3 'end of the sequence coding for the metalloprotease MMP-2 (accession number: NM_004530).
- the MMP-2 protein is therefore the antigen recognized by the CTL clone M134.12.
- the insert of plasmid pNA134-A codes for amino acids 501-661 of MMP-2.
- the CTL clone M134.12 of the plasmids containing truncated variants of the cDNA insert of NA134-A fragment 20 coding for amino acids 501-661 of MMP-
- MMP-2 was also built. Each of these plasmids was co-transfected with pHLA A * 0201 in COS-7 cells, which were then tested for their capacity to induce the secretion of TNF ⁇ by the CTL clone M134.12. The constructs tested are shown diagrammatically in FIG. 3 which also indicates their capacity to induce or not the secretion of TNF ⁇ by the CTL clone M134.12. These results show that the T epitope recognized by the CTL clone M134.12 is located between amino acids 556 and 593 of MMP-2.
- GLPPDVQRV sequences SEQ ID NO: 1
- LGLPPDVQRV SEQ ID NO: 2
- LPPDVQRV SEQ ID NO: 3
- GLPPDVQR SEQ ID NO: 4
- EXAMPLE 3 EXPRESSION OF MMP-2 IN DIFFERENT CELL TYPES AND SPECIFIC RECOGNITION OF MELANOMA CELLS BY M134.12 CTLS It is known that MMP-2 is expressed constitutively by tissues such as the endometrium, the liver or aorta (KHASIGOV, Biochemistry, 2001), and by a large number of cell types such as macrophages, trophoblasts (YAMAMOTO, Cancer.
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FR0307659A FR2856598B1 (fr) | 2003-06-25 | 2003-06-25 | Peptides derives de la proteine mmp-2 et leur utilisation en immunotherapie antitumorale |
PCT/FR2004/001585 WO2005000342A1 (fr) | 2003-06-25 | 2004-06-24 | Peptides derives de la proteine mmp-2 et leur utilisation en immunotherapie antitumorale |
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CN103823068B (zh) * | 2013-12-16 | 2016-05-25 | 周菊华 | 一种抗肿瘤淋巴细胞的鉴定方法 |
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US20020151481A1 (en) * | 2000-04-27 | 2002-10-17 | Lawrence Weissbach | MMP-2 propeptide for use as antiangiogenic or antitumor agent |
US7019108B2 (en) * | 2001-06-01 | 2006-03-28 | University Of Southern California | Method and composition for inhibition of angiogenesis and tumor growth using compounds based on a sequence within MMP-2 |
PL209827B1 (pl) * | 2002-01-23 | 2011-10-31 | Rath Matthias | Zastosowanie oligopeptydu i oligopeptydy |
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