EP1161443A2 - Mage-3 derived immunogenic peptides presented by mhc of class ii and the use thereof - Google Patents

Mage-3 derived immunogenic peptides presented by mhc of class ii and the use thereof

Info

Publication number
EP1161443A2
EP1161443A2 EP00907601A EP00907601A EP1161443A2 EP 1161443 A2 EP1161443 A2 EP 1161443A2 EP 00907601 A EP00907601 A EP 00907601A EP 00907601 A EP00907601 A EP 00907601A EP 1161443 A2 EP1161443 A2 EP 1161443A2
Authority
EP
European Patent Office
Prior art keywords
mage
cells
peptides
hla
peptide
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Withdrawn
Application number
EP00907601A
Other languages
German (de)
English (en)
French (fr)
Inventor
Maria Pia Protti
Paolo Dellabona
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fondazione Centro San Raffaele del Monte Tabor
Original Assignee
FOND CT SAN ROMANELLO DEL MONT
Fondazione Centro San Raffaele del Monte Tabor
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by FOND CT SAN ROMANELLO DEL MONT, Fondazione Centro San Raffaele del Monte Tabor filed Critical FOND CT SAN ROMANELLO DEL MONT
Publication of EP1161443A2 publication Critical patent/EP1161443A2/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to peptides derived from MAGE-3 protein and to the use thereof as immunostimulants, specifically as agents capable of stimulating the CD4 + T cell immune response.
  • CD4 + T lymphocytes exert helper activity for the induction and maintenance of anti-tumor CD8 + T cells (Greenberg, P.D., 1991,. Adv. Immunol. 49:281-355; Chen, P., et al . , 1993, J. Immunol. 151:244-255; Mandelboim, 0., et al . , 1995,. Nat. Med. 1:1179-1183; Mayordomo, J.I., et al .
  • MAGE-3 is a tumor-specific antigen encoded by a gene expressed in a high proportion of melanomas and in several other tumor histotypes (head and neck squamous cell carcinomas, bladder carcinomas, lung carcinomas and sarcomas) and not in normal tissues, with the exception of testis and placenta (Van den Eynde, B.J., et al. 1997. Immunol. Today 9:684-693).
  • CD8 + CTL from melanoma patients recognize HLA class I restricted MAGE-3 epitopes (Van den Eynde, B.J., et al . 1997. Immunol. Today
  • the invention relates to
  • MHC class II molecules Such peptides have length from 12 to 15 residues and correspond to MAGE-3 fragments (according to the amino acid sequence reported in Gaugler B. et al. 1994, J. Exp . Med. 179, 921-930) 21-35, 111-125, 161-175, 251-265, 286-300, preferably 141-155, 146-160, 156-170, more preferably 171-185, 191-205 and 281-295.
  • the corresponding amino acid sequences are reported in SEQ ID No. 1-11.
  • the peptides of the invention are characterized by promiscuous binding to different alleles of MHC class II molecules, such characteristic being advantageous in that one same peptide can be recognized by a wider patient population.
  • the peptides of the invention proved capable of binding different purified molecules belonging to widespread HLA-DR alleles, and of inducing activation of CD4 + cells. More particularly, it has been observed that stimulation with the peptides of the invention induces a remarkable proliferation of CD4 + T cells and of their cytolytic activity. CD4+ T cells exposed to such peptides were able to cause lysis of melanoma cells expressing the MAGE-3 protein and the HLA-DR molecules. Details of such experimental evidence are reported in the examples .
  • the peptides are preferably prepared synthetically, for example according to the procedures described in Merrifield, (1986) Science 232:341-347, and Barany and
  • the synthesis can be carried out in solution or in solid phase or with an automatized synthesizer (Stewart and Young, Solid Phase
  • the recombinant DNA technology can be used, or the peptides can be prepared starting from the natural protein by fragmentation or enzymatic digestion.
  • the amino acid residues can be replaced, preferably conservatively, by other residues of L- or D- amino acids, or added to the disclosed peptides, or they can be chemically modified, for example by amidation of the terminal carboxylic group or by binding with lipophilic groups (e.g. myristyl) , or by glycosylation or conjugations with other peptides, to obtain more favourable properties, such as higher affinity to the MHC molecule, higher immunogenicity, better selectivity in inducing the immune response or higher bioavailability after administration.
  • lipophilic groups e.g. myristyl
  • the peptides of the invention can also be chemically derivatized at the side chains which are therefore modified. For example, free carboxylic groups can be derivatized to form salts, methyl- and ethyl- esters or other types of esters or hydrazides .
  • the peptides of the invention can also be conjugated with known epitopes, for example with epitopes binding HLA molecules of class I, in order to induce a more complete spectrum of responses, of both the cytotoxic and helper type, and to enhance the response against the tumour.
  • epitopes for example with epitopes binding HLA molecules of class I, in order to induce a more complete spectrum of responses, of both the cytotoxic and helper type, and to enhance the response against the tumour.
  • the provision of new epitopes from an antigen not significantly expressed in normal tissues, such as MAGE-3 would allow to prepare vaccines for use in immunotherapy of patients with tumors expressing the same antigen.
  • T cells such as CD8 + T cells, as well as through macrophages activation.
  • the invention provides pharmaceutical compositions containing an effective amount of a peptide of the invention, optionally in combination with other known peptides binding MHC class I molecules and corresponding to CD8 + T cell epitopes, such as the peptides described in W095/19783.
  • the compositions will contain pharmaceutically acceptable excipients .
  • Effective amount herein means a sufficient amount to activate specific lymphocytes and induce an effective response against the tumor. Such an amount will depend on the peptide used, the administration, the severity of the disease to be treated and the general conditions of the patient and will usually range from 1 to 50 ⁇ g/ml, for example in case of peptides being loaded on dendritic cells .
  • compositions will be used for the preventive vaccination of patients with predisposition to neoplasias or in the therapeutical vaccination of neoplastic patients.
  • Vaccination herein means both active immunization, i.e. the in vivo administration of the peptides to elicit an in vivo immune response directly in the patient, as in conventional vaccination protocols, for example against pathogens, and passive immunization, i.e. the use of the peptides to activate in vitro anti-tumor CD4 + cells, which are subsequently re-inoculated into the patient.
  • Vaccines are conventionally prepared in the form of injectables, suspensions or solutions, but they can also be used in the form of solid preparations or liposomes.
  • the immunogenic ingredients can be mixed with pharmacologically acceptable excipients, such as emulsifiers, buffering agents and adjuvants which increase the efficacy of the vaccine. The latter can be administered according to single or multiple dosage schedule.
  • Multiple dose provides 1 to 10 separate doses, each containing a quantity of antigen varying from 1 ⁇ g to 1000 ⁇ g, followed by further doses at subsequent time intervals, necessary to maintain or to reinforce the immune response and, if required by the subject, a further dose after several months.
  • the treatment regimen will depend on the response elicited in the treated patient, general conditions and progress of the tumor.
  • the invention provides a method for inducing an immune response against tumor cells expressing a MAGE-3 antigen which comprises incubating APC cells (Antigen Presenting Cells) with the peptides of the invention in conditions suitable for the activation of effectors T CD4 + .
  • APC cells Antigen Presenting Cells
  • Such conditions comprise loading autologous APC with the peptides and the subsequent exposure to purified T CD4 + lymphocites .
  • Suitable APC cells are autologous peripheral blood mononuclear cells (PBMC) , dendritic cells, macrophages or activated B cells.
  • T cells are taken from the treated patient and optionally purified, then, after activation as described above and expansion in suitable culture medium, they are reintroduced in the same patient.
  • Culture media can contain one or more cytokines (such as IL-2 or T-cell Growth Factor) which contribute to the expansion of CD4 + precursors .
  • cells playing an important role in the induction of the immune response are genetically engineered with vectors encoding the peptides of the invention (for example viral or retroviral vectors, such as those from adenovirus or lentivirus or MLV) .
  • vectors encoding the peptides of the invention for example viral or retroviral vectors, such as those from adenovirus or lentivirus or MLV.
  • the peptides can also be fused with a suitable protein carrier, to have a satisfactory processing and expression at the cell surface.
  • the DNA encoding for the epitopes of the invention may be inserted in a suitable expression vector, under the control of a suitable viral promoter, such as CMV or SV40, when a very efficient expression is required, or an inducible promoter such as that controlled by ecdysone .
  • a suitable viral promoter such as CMV or SV40
  • an inducible promoter such as that controlled by ecdysone .
  • the invention also relates to antibodies, fragments or derivatives thereof, directed to the above described peptides.
  • the general methodology for producing antibodies is well known and is disclosed per example in Kohler and Milstein, 1975, Nature 256, 494 or in J.G.R. Hurrel, Monoclonal Hybridoma Antibodies: Techniques and Applications, CRC Press Inc., Boco Raron, FL (1982).
  • the antibodies can be polyclonal or, preferably, monoclonal, or antibody fragments like be F(ab')2, Fab, Fv or scFv.
  • Still a further aspect of the invention is a method for monitoring the frequency and the expansion of specific precursors for the peptides or the complete MAGE-3 protein, in neoplastic patients subject to active vaccination, by the ELISPOT technique (Herr, W. Et al . , 1997, J. Immunol. Methods 203:141-52) or by cytofluorimetric analysis using tetramers consisting of tetrameric soluble molecules avidin-biotin-MHC class II, pulsed with the relevant peptide (Yee, C. et al . 1999, J. Immunol. 162:2227-2234). Description of the Figures
  • Fig. 1 Proliferative activity of CD4 + T cells challenged with the MAGE-3 Pool, tested in 2-d microproliferation assays .
  • the blank i.e. the basal level of proliferation of CD4 + T cells in the presence of APC only
  • the blank was 1,251-444, the proliferation of CD4 + T cells in the presence of MAGE-3 pool was 28,191 ⁇ 373, and the proliferation in the presence of sequence 281-295 was 22,504 ⁇ 141.
  • Fig. 2 Cytolytic activity of MAGE-3 specific CD4 + T cells.
  • Fig. 3 CD4 ⁇ T cells recognize MAGE-3 (281-295) in association with HLA-DR11 on OI TC cells.
  • HLA-DR molecules were isolated from the following human lymphoblastoid cell lines (LCL) : DR1
  • DRB1*0701 from EKR
  • DR8 DRB1*0801
  • BM9 BM9
  • Peptide competition assay was conducted to measure the ability of unlabeled peptides to compete with a biotinylated indicator peptide for binding to purified DR molecules.
  • the following biotinylated indicator peptides were used: GFKA 7 for DR1 and DR7 ; GIRA 2 YA 4 for DR2 ; LAYDA 5 for DR3; UD4 for DR4 (Hammer, J., et al . 1995. J. Exp . Med. 181:1847-1855); TT 830-843 for DR5 ; and GYRAgL for DR8.
  • biotinylated indicator peptide and HLA-DR molecules were incubated with 10-fold dilutions (0.001-100 ⁇ iM) of the unlabeled competitor peptides (peptides corresponding to the MAGE-3 predicted sequences) .
  • the promiscuous ⁇ 307-319 peptide from influenza hemagglutinin (Roche, P.A., et al . 1990. J.
  • VFGIELMEVDPIGHL >100 0.6 28 10 100 >100 100
  • VQENYLEYRQVPGSD >100 >100 >100 26 10 60 5
  • the binding data are expressed as relative binding capability (IC 5Q ⁇ M) , calculated as concentration of competitor peptide required to inhibit 50% of binding of the biotinylated indicator peptide (indicator peptide) .
  • IC 5Q ⁇ M relative binding capability
  • Peptides were synthetized on a 9050 Millipore synthesizer (Millipore Volketswil, Switzerland). The purity of the peptides was evaluated by RP-HPLC and electron spray mass spectrometry . Synthetic peptides were lyophilized and then reconstituted in DMSO at 2 mg/ml concentration and diluted in PBS as needed.
  • the synthetic peptides corresponding to the MAGE-3 sequences most promiscuous (141, 155, 146-160, 156-170, 171-185, 281-295) for HLA-DR binding were pooled (MAGE-3 Pool) and used to stimulate the PBMC of an healthy donor whose HLA type, identified by standard serologic typing, is: Al , A2/B41, B52/DR11, as described in Protti, M.P., et al . 1990. J. Immunol. 144:1711-1720. Briefly, 20xl0 6 PBMC were cultivated for 7 days in RPMI 1460 (GIBCO, Grand Island, NY) supplemented with 10% heat inactivated human serum
  • TCM Walkersville, MD
  • MAGE-3 Pool (1 ⁇ g/ml of each peptide) .
  • the reactive lymphoblasts were isolated on a Percoll gradient (Protti, M.P., et al . 1990. J. Immunol. 144:1711-1720), further expanded in T cell growth factor (Lymphocult, Biotest Diagnostic Inc., Dreieich, West Germany) and restimulated at weekly intervals with the same amount of antigen plus irradiated (4000 rad) autologous PBMC as APC.
  • CD4 + T cells and autologous irradiated PBMC were diluted in TCM to 2x10 /ml and 2xl0°/ml, respectively and plated in triplicate in 96 round-bottom well plates (100 ⁇ l of
  • CD4 + T cells and 100 ⁇ l of APC were stimulated with different concentrations of MAGE-3 pool (0.05, 0.1, 0.5, 1 and 5 ⁇ g/ml), each peptide (10 ⁇ g/ml) and different concentrations of rMAGE-3 protein (5, 10 and 20 ⁇ g/ml) .
  • MAGE-3 pool 0.05, 0.1, 0.5, 1 and 5 ⁇ g/ml
  • rMAGE-3 protein 5, 10 and 20 ⁇ g/ml
  • CD4 + T cells plus APC did not receive any stimulus to determine the basal growth rate (blank) .
  • different concentrations of mAb L243 or an isotype matched irrelevant mAb (0.25 and 0.5 ⁇ g/ml) were added in triplicate wells of CD4 + cells plus APC stimulated with MAGE-3 pool (5 ⁇ g/ml) or MAGE-3 281 _ 2 g 5 (10 ⁇ g/ml) .
  • MAGE-3 pool 5 ⁇ g/ml
  • MAGE-3 281 _ 2 g 5 10 ⁇ g/ml
  • T cells were 94% CD4 + after 1 week of culture and could be propagated in long term culture by weekly restimulation with the MAGE-3 Pool in the presence of autologous irradiated PBMC.
  • Fig. 1 microproliferation assays (Fig. 1) the cells responded vigorously to the MAGE-3 Pool (Panel A) , even at low concentrations (100-500 ng/ml) .
  • MAGE-3 sequences was HLA-DR restricted.
  • the HLA-DR11+ PBMC from the healthy donor were also stimulated with a second pool of synthetic peptides corresponding to the MAGE-3 sequences 21-35, 111-125, 161-175, 191-205, 251-265 and 286-300.
  • the CD4 + T cells proliferated in a dose dependent manner to different concentrations of the MAGE-3 pool II, and the study of the epitope repertoire of the MAGE-3 specific CD4 + T cells showed recognition of sequences MAGE_3 m-i25 ' MAGE-3 161 _ 175 and predominantly MAGE-3 191 _ 205 .
  • MAGE-3 specific CD4 + T cells from a melanoma patient whose HLA-DR type is HLA-DR4/DR11 , recognized the sequences MAGE_3 i4i-i55 MAGE_3 146-160 ' MAGE-3 156 _ 170 , MAGE-3 171 _ 185 and MAGE-3 281 _ 295 .
  • the study of the restriction element showed that all sequences were recognized in association with the HLA-
  • CD4 + T cells were tested for specific lytic activity in a standard 4-h Cr release assay as described in Protti, M.P., et al . 1996. Cancer Res.
  • melanoma cells SK-Mel 28, HT144, OI TC described in Imro, M.A., et al. 1998. Hum. Gene Ther. 9:1335-1344 and MD TC established in our laboratory from a cutaneous metastasis
  • LCL LCL
  • HLA-DR type of target cells identified by molecular or serologic typing, was: SK-Mel
  • CD4 + T cells showed cytolytic activity against OI TC and MD TC which express the HLA-DRll restricting allele, while they did not kill SK-Mel 28 and HT144 which express unrelated HLA-DR alleles ( Figure 2a) .
  • cytolytic CD4 + T cells recognized HLA-DRll restricted MAGE-3 epitopes on melanoma cells, first was tested their lytic activity against HLA-DR11 + LCL unpulsed, or pulsed with the synthetic peptides recognized in microproliferation assays.
  • CD4 + T cells specific for sequence MAGE-3 191 _ 2Q5 also showed cytolytic activity against MAGE-3/HLA-DR11+ melanoma cells and cold/target inhibition experiments showed that the sequence 191-205 was indeed recognized at the surface of the melanoma cells in association with the HLA-DRll allele and therefore this epitope is naturally processed.
  • the CD4 + T cells showed cytolytic activity against the autologous tumor that expresses the MAGE-3 antigen, and against the SK-Mel 28 melanoma cells that express the antigen and the HLA-DR4 retriction allele, while they did not kill melanoma cells expressing the MAGE-3 protein but an unrelated HLA-DR allele.

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EP00907601A 1999-02-26 2000-02-23 Mage-3 derived immunogenic peptides presented by mhc of class ii and the use thereof Withdrawn EP1161443A2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITMI990396 1999-02-26
IT1999MI000396A IT1309584B1 (it) 1999-02-26 1999-02-26 Peptidi immunogenici derivati da mage-3 presentati da mhc di classeii e loro uso.
PCT/EP2000/001458 WO2000052045A2 (en) 1999-02-26 2000-02-23 Mage-3 derived immunogenic peptides presented by mhc of class ii and the use thereof

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EP1161443A2 true EP1161443A2 (en) 2001-12-12

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EP (1) EP1161443A2 (ja)
JP (1) JP2002538166A (ja)
AU (1) AU2913400A (ja)
CA (1) CA2364002A1 (ja)
IT (1) IT1309584B1 (ja)
WO (1) WO2000052045A2 (ja)

Families Citing this family (9)

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Publication number Priority date Publication date Assignee Title
WO2001074847A2 (en) * 2000-03-30 2001-10-11 The Government Of The United States Of America Represented By The Secretary, Department Of Health And Human Services T-cell epitope of mage-12 and related nucleic acids, vectors, cells, compositions and methods of inducing an immune response to cancer
US20060222656A1 (en) 2005-04-01 2006-10-05 University Of Maryland, Baltimore MAGE-A3/HPV 16 peptide vaccines for head and neck cancer
AU2002322009A1 (en) 2001-05-18 2002-12-03 Mayo Foundation For Medical Education And Research Chimeric antigen-specific t cell-activating polypeptides
US7049413B2 (en) 2001-05-18 2006-05-23 Ludwig Institute For Cancer Research MAGE-A3 peptides presented by HLA class II molecules
FR2837837B1 (fr) * 2002-03-28 2006-09-29 Roussy Inst Gustave Epitopes peptidiques communs a des antigenes d'une meme famille multigenique
EP1715343B1 (en) * 2005-04-20 2009-12-09 F. Hoffmann-La Roche Ag Method for the identification of epitopes related to immunogenicity in biopharmaceuticals
WO2008053573A1 (fr) * 2006-10-30 2008-05-08 National University Corporation Hokkaido University Remède pour néoplasme malin
JP6313478B2 (ja) * 2014-05-30 2018-04-18 アカデミア シニカＡｃａｄｅｍｉａ Ｓｉｎｉｃａ Ｍａｇｅ−ａ３ペプチド標的アプタマー及びその使用
GB201804468D0 (en) * 2018-03-21 2018-05-02 Valo Therapeutics Oy PeptiCRAd Cancer Therapy

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US5662907A (en) * 1992-08-07 1997-09-02 Cytel Corporation Induction of anti-tumor cytotoxic T lymphocytes in humans using synthetic peptide epitopes
NZ263050A (en) * 1993-03-05 1997-11-24 Cytel Corp Compositions of immunogenic peptides with hla-a2.1 binding motifs
CA2278189A1 (en) * 1997-01-31 1998-08-06 Epimmune, Inc. Peptides and peptide-loaded antigen presenting cells for the activation of ctl
CN1268738C (zh) * 1997-07-15 2006-08-09 宝生物工程株式会社 细胞毒性t淋巴细胞
US5965535A (en) * 1997-09-12 1999-10-12 Ludwig Institute For Cancer Research Mage-3 peptides presented by HLA class II molecules
CA2323632A1 (en) * 1998-03-13 1999-09-16 Epimmune Inc. Hla-binding peptides and their uses

Non-Patent Citations (1)

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Title
See references of WO0052045A2 *

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WO2000052045A2 (en) 2000-09-08
IT1309584B1 (it) 2002-01-24
JP2002538166A (ja) 2002-11-12
ITMI990396A1 (it) 2000-08-26
AU2913400A (en) 2000-09-21
WO2000052045A3 (en) 2001-01-04
CA2364002A1 (en) 2000-09-08

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