WO1996010413A1 - Compositions contenant des precurseurs d'antigenes de rejet de tumeurs ou des antigenes de rejet de tumeurs, et un adjuvant et/ou un facteur de croissance - Google Patents

Compositions contenant des precurseurs d'antigenes de rejet de tumeurs ou des antigenes de rejet de tumeurs, et un adjuvant et/ou un facteur de croissance Download PDF

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Publication number
WO1996010413A1
WO1996010413A1 PCT/US1995/012463 US9512463W WO9610413A1 WO 1996010413 A1 WO1996010413 A1 WO 1996010413A1 US 9512463 W US9512463 W US 9512463W WO 9610413 A1 WO9610413 A1 WO 9610413A1
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gag
ctg
gaa
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aag
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PCT/US1995/012463
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English (en)
Inventor
Pierre Van Der Bruggen
Thierry Boon-Falleur
Benoit Van Den Eynde
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Ludwig Institute For Cancer Research
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Application filed by Ludwig Institute For Cancer Research filed Critical Ludwig Institute For Cancer Research
Priority to AU38864/95A priority Critical patent/AU690371B2/en
Priority to JP8512031A priority patent/JPH10511639A/ja
Priority to EP95938112A priority patent/EP0782453A1/fr
Publication of WO1996010413A1 publication Critical patent/WO1996010413A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001178—Tumor rejection antigen precursor [TRAP]
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/5555—Muramyl dipeptides
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compositions useful in the generation of an immune response against the classes of molecules referred to as tumor rejection antigen precursors ("TRAPs”) and tumor rejection antigens ("TRAs").
  • the immune response includes, inter alia, the production of antibodies against the TRAPs and TRAs, as well as T cells specific for complexes of TRA and major histocompatibility molecules (“MHCs").
  • T cells and antibodies may be generated, e.g., in a mouse, rat, rabbit, sheep, goat or other non-human animal, and then used in diagnostic methods to identify tumor presence.
  • compositions may also be used, therapeutically, via administration to a subject afflicted with a cancerous condition or one where cell transformation has taken place, such as melanoma or dysplastic nevi, to provoke an immune response against tumors, cancer cells, and transformed cells.
  • T-cell mediated immune responses were observed for the types of tumor described supra. spontaneous tumors were thought to be generally non-immunogenic. These were therefore believed not to present antigens which provoked a response to the tumor in the tumor carrying subject. See Hewitt, et al., Brit. J. Cancer 33: 241-259 (1976).
  • antigen presenting cell lines are immunogenic variants obtained by mutagenesis of mouse tumor cells or cell lines, as described by Boon et al., J. Exp. Med. 152: 1184-1193 (1980), the disclosure of which is incorporated by reference.
  • tum " antigens are obtained by mutating tumor cells which do not generate an immune response in syngeneic mice and will form tumors (i.e., "turn*" cells). When these turn* cells are mutagenized, they are rejected by syngeneic mice, and fail to form tumors (thus "turn "”). See Boon et al., Proc. Natl. Acad. Sci. USA 74: 272 (1977), the disclosure of which is incorporated by reference.
  • TRAs tumor rejection antigens
  • CTL cytolytic T cell characterization studies in vitro i.e., the study of the identification of the antigen by a particular cytolytic T cell (“CTL” hereafter) subset. The subset proliferates upon recognition of the presented tumor rejection antigen, and the cells presenting the antigen are lysed. Characterization studies have identified CTL clones which specifically lyse cells expressing the antigens.
  • a tumor exemplary of the subject matter described supra is known as P815. See DePlaen et al., Proc. Natl. Acad. Sci. USA 85: 2274-2278 (1988); Szikora et al. , EMBO J 9: 1041-1050 (1990), and Sibille et al., J. Exp. Med. 172: 35-45 (1990), the disclosures of which are incorporated by reference.
  • the P815 tumor is a mastocytoma, induced in a DBA/2 mouse with methylcholanthrene and cultured as both an in vitro tumor and a cell line.
  • the P815 line has generated many tum " variants following mutagenesis, including variants referred to as P91A (DePlaen, supra.. 35B (Szikora, supra.. and P198 (Sibille, supra.. In contrast to tumor rejection antigens - and this is a key distinction - the tum " antigens are only present after the tumor cells are mutagenized. Tumor rejection antigens are present on cells of a given tumor without mutagenesis.
  • a cell line can be turn*, such as the line referred to as "PI”, and can be provoked to produce tum ' variants. Since the tum " phenotype differs from that of the parent cell line, one expects a difference in the DNA of tum" cell lines as compared to their turn* parental lines, and this difference can be exploited to locate the gene of interest in turn" cells. As a result, it was found that genes of tum " variants such as P91A, 35B and P198 differ from their normal alleles by point mutations in the coding regions of the gene. See Szikora and Sibille, supra. and Lurquin et al.. Cell 58: 293-303 (1989).
  • the genes are useful as a source for the isolated and purified tumor rejection antigen precursor and the TRA themselves, either of which can be used as an agent for treating the cancer for which the antigen is a "marker", as well as in various diagnostic and surveillance approaches to oncology, discussed infra.
  • tum " cells can be used to generate CTLs which lyse cells presenting different tum” antigens as well as tum + cells. See, e.g., Maryanski et al., Eur. J. Immunol 12: 401 (1982); and Van den Eynde et al., Modern Trends in Leukemia IX (June 1990) , the disclosures of which are incorporated by reference.
  • the tumor rejection antigen precursor may be expressed in cells transfected by the gene, and then used to generate an immune response against a tumor of interest.
  • MLTC autologous mixed lymphocyte-tumor cell cultures
  • tyrosinase is described as a tumor rejection antigen precursor. This is a well known molecule as per Kwon, U.S. Patent No. 4,898,814. This reference discloses that a molecule which is produced by some normal cells (e.g., melanocytes) , is processed in tumor cells to yield a tumor rejection antigen that is presented by HLA-A2 molecules. The peptide presented thereby is described in U.S. Application Serial No. 54,714, filed April 28, 1993. SEQ ID NO: 35 sets forth this peptide. Additional tyrosinase derived peptides presented by HLA molecules are set forth in Serial Nos. 203,054, and 233,305 filed February 28, 1994 and April 26, 1994 and incorporated by reference (SEQ ID NOS: 36-41).
  • SEQ ID NOS: 42-44 sets forth three peptides (SEQ ID NOS: 42-44 herein), which are derived from MAGE-1 and which complex with HLA-Cw * 1601.
  • Serial No. 196,630 filed February 15, 1994, discloses an unrelated tumor rejection antigen precursor, the so-called "BAGE" gene, and peptides derived therefrom, which are processed and then presented by HLA-Cw * 1601.
  • SEQ ID NOS: 45-48 is the tumor rejection antigen.
  • Additional coding sequences for a tumor rejection antigen precursor are set forth in Serial No. 32,978, filed March 18, 1993 and incorporated by reference. These are included herein as SEQ ID NOS: 49 and 50.
  • a more extended seguence for this gene is set forth in Serial No. 272,351, filed July 8, 1994 incorporated by reference, and is SEQ ID NO: 51.
  • Serial No. 96,039, filed July 22, 1993 the sequence of tumor rejection antigen precursor GAGE is set forth. See SEQ ID NO: 52 for this information.
  • a series of peptides which provoke lysis by cytolytic T cells when presented by MHC molecules are set forth in Serial No. 217,186, Serial No. 08/217,188, and Serial No. 217,187, all filed on March 24, 1994, and all of which are incorporated by reference herein.
  • the first of these applications discloses MAGE-3 derived peptides presented by HLA-A2. Five peptides are of interest. These are repeated here as SEQ ID NOS: 53-57.
  • the second application presents 11 seguences derived from MAGE-2, believed to complex with HLA-A2.1 molecules (SEQ ID NOS: 58-68).
  • DAGE tumor rejection antigen precursor known as DAGE (SEQ ID NO:76) is set forth.
  • DAGE is found almost universally on tumor cells, and only on testis cells with respect to normal cell expression. This makes it especially useful for cancer diagnosis and in the applications disclosed herein.
  • the above listing should not be presumed to be exhaustive of the TRAP and TRA literature, but is presented to show its diversity and the fact that these materials not only provoke T cell proliferation, but also stimulate production of antibodies. It is well known that antibody producing cells can be used as a source to produce hybridomas, which in turn produce monoclonal antibodies. Thus, when the term "antibodies” is used herein, it encompasses both polyclonal and monoclonal antibodies.
  • Adjuvants broadly defined, are substances which promote immune responses. Frequently, the adjuvant of choice if Freund's complete adjuvant, or killed fi. pertussis organisms, used in combination with alum precipitated antigen. A general discussion of adjuvants is provided in Goding, Monoclonal Antibodies: Principles & Practice (Second edition, 1986) , at pages 61-63, which are incorporated by reference herein.
  • Godin ⁇ notes, however, that when the antigen of interest is of low molecular weight, or is poorly immunogenic, coupling to an immunogenic carrier is recommended.
  • Such molecules according to Godin ⁇ . generally have molecular weights below about 1000.
  • the carriers suggested by Goding at page 283, are keyhole limpet hemocyanin, bovine serum albumin, ovalbumin, and fowl immunoglobulin.
  • the immune response may be a general one, with part, most, or all of it being directed against the carrier molecule rather than the immunogen itself.
  • Kensil et al disclose the preparation of various saponin extracts, which are useful as adjuvants in immunogenic compositions. As natural products, the extracts are not completely defined. Kensil, et al do provide a complete and enabling disclosure for how various extracts, including QA-7, QA-19, and QA-21 (also referred to as QS-21) are prepared.
  • bovine serum albumin (“BSA”) was combined with various extracts (examples 8 and 9), and where feline leukemia virus recombinant glycoprotein "gp70R ⁇ was tested, following absorption to aluminum hydroxide (alum).
  • the two immunogens tested are expected to be immunogenic in their own right (gp70R ⁇ has a molecular weight of 70 kd, and serum albumin has about the same molecular weight) .
  • MTP-MF59 an adjuvant referred to as "MTP-MF59” is disclosed.
  • This adjuvant is used in connection with a Plasmodiu falciparum protein, "Pfs-25-B". This combination is described as a transmission blocking vaccine.
  • the E. falciparum protein is itself large enough to be immunogenic.
  • the improved adjuvants can be used in combination with presumptively non-immunogenic proteins and peptides to yield immunologically effective compositions. This is especially true for TRAP and TRA molecules, as outlined supra.
  • compositions comprising tumor rejection antigen precursors or tumor rejection antigens can be made which, when administered to a subject animal, provoke an immunogenic response.
  • the immunogenic portion of the composition consists of TRAP or, more preferably TRA molecules, of one or more types, and an adjuvant.
  • the adjuvant is QS21, as is disclosed in the Kensil, et al patent, incorporated by reference supra.
  • the immunogens of this invention consist of TRAPs or
  • compositions consist essentially of the immunogen and the adjuvant.
  • Stage IV patients have a median survival time of one year following diagnosis, and only a 15% chance of long-term survival (Balch, et al, Cutaneous Melanoma. J.b. Lippincott, Philadelphia, 1992).
  • the standard therapy for these patients includes treatment with decarbazine or drug combinations with decarbazine; however, response rates only range from 8-25%, and there is no evidence of the treatment extending survival. Balch et al. supra.
  • Stage III melanoma patients with high risk Stage III melanoma (pT4 thick truncal primary tumors or extremity melanomas, with five or more positive regional lymph nodes) have a median survival of 1-2 years following onset, and a 19% chance of long term survival. Balch, et al, supra ⁇
  • Injections are given at day 1, and then at days 8, 15, 22, and 57. Patients are monitored over a course of 12 weeks, unless intervention is required (as determined by the investigator). Any patients who show stabilization or tumor response remain in the study until disease progression is evidenced. Patients may also be removed from the study or receive different doses of the peptide, if toxicity reactions are observed.
  • the patients show response as follows. In a complete response, all signs, symptoms, biochemical and imaging evidence of tumor disappear for a period of at least 30 days. In a partial response, there is a decrease in size of all measurable tumors of at least 50% of the sum of products of the greatest and perpendicular diameters for at least 30 days, without the appearance of new lesions or progression of any new lesions. In a minor response, there is a decrease in size of all measurable tumors of at least 25% of the sum of products of greatest and perpendicular diameters, for at least 30 days, without appearance of new lesions or progression of any lesion.
  • the foregoing example demonstrates a composition comprising an amount of a tumor rejection antigen, i.e., MZ2E, and an adjuvant, i.e., QS21, and the use of the composition in the in vivo treatment of cancer (i.e., melanoma).
  • a tumor rejection antigen i.e., MZ2E
  • an adjuvant i.e., QS21
  • the tumor rejection antigen is used in an amount sufficient to provoke an immune response against tumor cells which present it on their surface.
  • compositions of the invention comprise any tumor rejection antigen precursor (“TRAP”) or tumor rejection antigen (“TRA”), in combination with a pharmaceutically acceptable adjuvant.
  • TRAP tumor rejection antigen precursor
  • TRA tumor rejection antigen
  • Preferred embodiments of the invention utilize the TRAPs and TRAs discussed supra and set forth in SEQ ID NO: 65, as well as the adjuvants described in the Background section.
  • an important aspect of the invention is stimulation of proliferation of T cells.
  • This can be an initial stimulation or an augmentation of a prior stimulation.
  • the cytolytic T cells recognize these complexes of MHC and peptide, bind thereto via their receptor, and proliferate. They also lyse the recognized cells.
  • This response can be used not only in vivo, but in vitro. as it is well established that cytolytic T cells specific for particular complexes of MHC and peptide are present in the blood of subjects who have experienced cell transformation.
  • any cytolytic T cells in the blood sample will expand, i.e., proliferate.
  • This proliferation an be measured via any of the well known assays designed therefor.
  • the radioactive chromium ( 51 Cr) release assay and the measurement of release of tumor necrosis factor (TNF) .
  • the compositions are also useful as stimulators of B cell proliferation, or antibody production. Again, it is well known that B cells produce antibodies, and the size of their targets are well within the sizes of the tumor rejection antigens, and certainly the tumor rejection antigen precursors.
  • the stimulation may be "ab initio", or an augmentation of a prior response, in vitro or in vivo.
  • the amount of TRAP or TRA used will vary, depending upon the purpose of the immunization and the subject to which it is administered. For example, in the case of generating murine antibodies which can then be used, e.g. , to diagnose for the presence of cancer cells presenting a TRA, the amount of protein or peptide may be less than that used in a course of in vivo therapy, such as that described in the example, supra.
  • a preferred dose can range from about l ug to about 750 ug of protein or peptide per dose. In a preferred embodiment, the range is from about 10 ug to about 500 ug. Most preferably, anywhere from about 30 ug to about 300 ug per dose may be used.
  • the investigator will modify the dose, as a six month old infant will require dosing different from a full grown man, e.g.
  • the mode of administration may vary, with preferred forms being oral, subcutaneous, intramuscular, intravenous and intraperitoneal adminstration.
  • TRAP or TRA protein or peptide in the composition will depend upon parameters determinable by the artisan. It is art recognized, for example, that different TRAs are presented by the various MHC molecules. As such, if a subject is typed, using well known techniques, as presenting HLA-A2 molecules on the surface of tumor cells, one will use a TRA presented by HLA-A2 molecules rather than one presented by, e.g., HLA-Cw * 1601. Similarly, using techniques such as polymerase chain reaction (“PCR”), lysis studies, and other assay methodologies which are well known in the art, one can determine which tumor rejection antigen precursor gene or genes are being expressed by a subject patient. This will lead to the decision as to what protein or peptide to use.
  • PCR polymerase chain reaction
  • the peptide used in immunization should be derived from MAGE-3, and not MAGE-1. While the molecules discussed herein are referred to as
  • tumor rejection antigens and “tumor” rejection antigen precursors it is intended that their use, in a therapeutic and also a diagnostic context, extends beyond cancer per se.
  • pathological conditions such as displastic nevis, which are not cancer per se, but where the cells of the afflicted individuals are in fact characterized by transformation. Any and all such conditions are within the intended ambit of the invention.
  • CTCTTGCCCA CATCTGTAGT AAAGACCACA TTTTGGTTGG GGGTCATTGC 1016
  • CCTCCCCCTC TTTGCTCGAC TTTTAGCAGC CTTACCTCTC CCTGCTTTCT 1916 GCCCCGTTCC CCTTTTTTGT GCCTTTCCTC CTGGCTCCCC TCCACCTTCC 1966
  • CTTTGTCCCC AGACCCTACA GTATCCTGTG CACAGGAAGT GGGAGGTGCC 2866
  • CTGGAGGCCA CAGAGGAGCA CCAAGGAGAA GATCTGTAAG TAGGCCTTTG 500 TTAGAGTCTC CAAGGTTCAG TTCTCAGCTG AGGCCTCTCA CACACTCCCT 550
  • NAME/KEY MAGE-1 gene
  • SEQUENCE DESCRIPTION SEQ ID NO: 8: CCCGGGGCAC CACTGGCATC CCTCCCCCTA CCACCCCCAA TCCCTCCCTT 50
  • GAGAGCCCCA AATATTCCAG CCCCGCCCTT GCTGCCAGCC CTGGCCCACC 950
  • CCCATCTCCT CAGCTACACC TCCACCCCCA TCCCTACTCC TACTCCGTCA 1250 CCTGACCACC ACCCTCCAGC CCCAGCACCA GCCCCAACCC TTCTGCCACC 1300
  • ATCCAGTACC ACCCCTGCTG CCAGCCCTGG ACCACCCGGC CAGGACAGAT 1650
  • GGGAGGACTC AGGGGACCTT GGAATCCAGA TCAGTGTGGA CCTCGGCCCT 2250
  • TTCCATTCTC ACTTGTACCA CAGGCAGGAA GTTGGGGGGC CCTCAGGGAG 2550
  • GGGCAGGATC CAGGCCCTGC CAGGAAAAAT ATAAGGGCCC TGCGTGAGAA 3300
  • GAG GAG GAA ATC TGG GAG GAG CTG AGT GTG ATG GAG GTG TAT 4552 GAT GGG AGG GAG CAC AGT GCC TAT GGG GAG CCC AGG AAG CTG 4594
  • TCCCATCTCC TCCCCCACCA CCATCCTGGC AGAATCCGGC TTTGCCCCTG 600
  • CAAGCCAGCA AAAGGGTGGG ATTAGGCCCT ACAAGGAGAA AGGTGAGGGC 2000
  • MOLECULE TYPE cDNA to mRNA
  • FEATURE
  • GACAGGCTGA CCTGGAGGAC CAGAGGCCCC CGGAGGAGCA CTGAAGGAGA 100 AGATCTGCCA GTGGGTCTCC ATTGCCCAGC TCCTGCCCAC ACTCCCGCCT 150
  • GGC CTT GAG GCC CGA GGA GAG GCC CTG GGC CTG GTG GGT GCG 255
  • GATAGTGCCA ACGGTGAAGG TTTGCCTTGG ATTCAAACCA AGGGCCCCAC 250
  • CTCCCGCCTG TTGCCCTGAC CAGAGTCATC 580 ATG CCT CTT GAG CAG AGG AGT CAG CAC TGC AAG CCT GAA GAA 622
  • ATC AAA AAT TAC AAG CGC TGC TTT CCT GTG ATC TTC GGC AAA 1086
  • AACTCCATTT TCTTCTGAGG GATCTGATTC TAATGAAGCT TGGTGGGTCC 2428 AGGGCCAGAT TCTCAGAGGG AGAGGGAAAA GCCCAGATTG GAAAAGTTGC 2478
  • MOLECULE TYPE cDNA to mRNA
  • FEATURE
  • CTCCGTCCAG TAGTTTCCCC TGCCTTAATG TGACATGAGG CCCATTCTTC 1608
  • CAGTAGTCAC ACATAGTGCT GTTTATATAG TTTAGGAGTA AGAGTCTTGT 1808
  • GAT GGC CTG CTG GGT GAC AAT CAG ATC ATG CCC AGG ACA GGC 168 TTC CTG ATA ATC ATC CTG GCC ATA ATC GCA AGA GAG GGC GAC 210
  • GGC AAA GCC TCA GAG TGC ATG CAG GTG ATG TTT GGC ATT GAC 853
  • GAG GGT TCC AGC AAT GAA GAG GAG GGG CCA AGC ACC TCC 745
  • GGG GAG CCC AGG AAG CTG CTC ACC CAA GAT TGG GTG CAG GAA 1183
  • GGCCCCATCA CCCAGATATT TCCCACAGTT CGGCCTGCTG ACCTAACCAG 200 AGTCATCATG CCTCTTGAGC AAAGAAGTCA GCACTGCAAG CCTGAGGAAG 250
  • GGA AGG GAG CAC TTC CTC TTT GGG GAG CCC AAG AGG CTC CTT 952 ACC CAA AAT TGG GTG CAG GAA AAG TAC CTG GTG TAC CGG CAG 994
  • GGT GTA TCC TGC ACA GGC TCT GGT ATA GGT GGT AGA AAT GCT 772 GCT GTC CTG CCT GAT ACA AAA AGT TCA GAT GGC ACC CAG GCA 814
  • CAGCAGTCAC GCAGGGAGGT TCCAGTAGTT
  • CAGCCCACTG CAGAGGAAGC 650 AGGGTCTTCT CCTGTTGACC AGAGTGCTGG GTCCAGCTTC CCTGGTGGTT 700
  • MOLECULE TYPE protein
  • MOLECULE TYPE protein
  • TTTTAAACTT CAACCAATGT ATTTACTGAA AATAACAAAT GTTGTAAATT CCCTGAGTGT 720

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Abstract

L'invention se rapporte à des compositions présentant de meilleurs effets immunogènes. Ces compositions contiennent au moins un peptide qui, lorsqu'il est complexé à une molécule d'une surface cellulaire, telle qu'un MCH (complexe majeur d'histocompatibilité), HLA (système majeur d'histocompatibilité) ou un récepteur des lymphocytes B, provoque une réponse immune. Les compositions renferment des adjuvants tels que les saponines qui potentialisent la réponse immune. Les compositions notamment préférées sont celles qui stimulent les réponses cytolytiques des lymphocytes T, tels que les peptides qui satisfont aux critères de liaison du CMH, et tels que les peptides dérivés des précurseurs d'antigènes de rejet de tumeurs, y compris les peptides dérivés de MAGE, BAGE et GAGE.
PCT/US1995/012463 1994-09-30 1995-09-27 Compositions contenant des precurseurs d'antigenes de rejet de tumeurs ou des antigenes de rejet de tumeurs, et un adjuvant et/ou un facteur de croissance WO1996010413A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU38864/95A AU690371B2 (en) 1994-09-30 1995-09-27 Compositions containing tumor rejection antigen precursors or tumor rejection antigens, and an adjuvant and/or growth factor
JP8512031A JPH10511639A (ja) 1994-09-30 1995-09-27 腫瘍拒絶抗原前駆体または腫瘍拒絶抗原を含有する組成物ならびにアジュバント及び／又は成長因子
EP95938112A EP0782453A1 (fr) 1994-09-30 1995-09-27 Compositions contenant des precurseurs d'antigenes de rejet de tumeurs ou des antigenes de rejet de tumeurs, et un adjuvant et/ou un facteur de croissance

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US31596194A 1994-09-30 1994-09-30
US08/315,961 1994-09-30

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WO1996010413A1 true WO1996010413A1 (fr) 1996-04-11

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EP (1) EP0782453A1 (fr)
JP (1) JPH10511639A (fr)
CN (1) CN1159759A (fr)
AU (1) AU690371B2 (fr)
CA (1) CA2201327A1 (fr)
WO (1) WO1996010413A1 (fr)
ZA (1) ZA958229B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0771358A1 (fr) * 1994-06-03 1997-05-07 Ludwig Institute For Cancer Research Molecule d'acide nucleique isolee codant pour un precurseur d'antigene de rejet de tumeur et ses utilisations
EP0789591A1 (fr) * 1994-02-14 1997-08-20 Ludwig Institute For Cancer Research Procede d'identification des individus atteints d'anomalie cellulaire
WO1999004265A2 (fr) * 1997-07-17 1999-01-28 Ludwig Institute For Cancer Research Acides nucleiques et polypeptides associes au cancer
WO1999040188A2 (fr) * 1998-02-05 1999-08-12 Smithkline Beecham Biologicals S.A. Derives antigenes associes aux tumeurs de la famille mage, et sequences d'acides nucleiques codant ces derives, utilises pour la preparaiton de proteines de fusion et de compositions destinees a la vaccination
US6686147B1 (en) 1998-07-15 2004-02-03 Ludwig Institute For Cancer Research Cancer associated antigens and uses therefor
US6809179B1 (en) 1999-08-04 2004-10-26 Boehringer Ingelheim International Gmbh Tumor-associated antigen (R11)
US8834514B2 (en) 2006-08-30 2014-09-16 Xennovate Medical Llc Resilient band medical device
US8852224B2 (en) 1997-01-29 2014-10-07 Peter J. Cronk Therapeutic delivery system

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0789591A1 (fr) * 1994-02-14 1997-08-20 Ludwig Institute For Cancer Research Procede d'identification des individus atteints d'anomalie cellulaire
EP0789591A4 (fr) * 1994-02-14 1998-07-01 Ludwig Inst Cancer Res Procede d'identification des individus atteints d'anomalie cellulaire
EP0771358A1 (fr) * 1994-06-03 1997-05-07 Ludwig Institute For Cancer Research Molecule d'acide nucleique isolee codant pour un precurseur d'antigene de rejet de tumeur et ses utilisations
EP0771358A4 (fr) * 1994-06-03 1999-05-19 Ludwig Inst Cancer Res Molecule d'acide nucleique isolee codant pour un precurseur d'antigene de rejet de tumeur et ses utilisations
US8852224B2 (en) 1997-01-29 2014-10-07 Peter J. Cronk Therapeutic delivery system
WO1999004265A2 (fr) * 1997-07-17 1999-01-28 Ludwig Institute For Cancer Research Acides nucleiques et polypeptides associes au cancer
WO1999004265A3 (fr) * 1997-07-17 1999-08-26 Ludwig Inst Cancer Res Acides nucleiques et polypeptides associes au cancer
CZ298364B6 (cs) * 1998-02-05 2007-09-05 Smithkline Beecham Biologicals S. A. Deriváty antigenu asociovaných s nádory z MAGE rodiny a sekvence nukleových kyselin kodující tyto deriváty, jejich použití pro prípravu fúzních proteinu a prostredku pro vakcinaci
EP1659178A3 (fr) * 1998-02-05 2007-01-17 GlaxoSmithKline Biologicals SA Dérivés antigènes associés aux tumeurs de la famille mage, et séquences d'acides nucléiques codant ces dérivés, utilisés pour la préparation de protéines de fusion et de compositions destinées à la vaccination
WO1999040188A2 (fr) * 1998-02-05 1999-08-12 Smithkline Beecham Biologicals S.A. Derives antigenes associes aux tumeurs de la famille mage, et sequences d'acides nucleiques codant ces derives, utilises pour la preparaiton de proteines de fusion et de compositions destinees a la vaccination
US8597656B2 (en) 1998-02-05 2013-12-03 Glaxosmithkline Biologicals S.A. Process for the production of immunogenic compositions
EP1584685A3 (fr) * 1998-02-05 2005-12-07 Glaxosmithkline Biologicals S.A. Dérivés antigènes associés aux tumeurs de la famille mage, et séquences d'acides nucléiques codant ces dérivés, utilisés pour la préparation de protéines de fusion et de compositions destinées à la vaccination
EP1659178A2 (fr) * 1998-02-05 2006-05-24 GlaxoSmithKline Biologicals SA Dérivés antigènes associés aux tumeurs de la famille mage, et séquences d'acides nucléiques codant ces dérivés, utilisés pour la préparation de protéines de fusion et de compositions destinées à la vaccination
EP1659179A3 (fr) * 1998-02-05 2007-01-17 GlaxoSmithKline Biologicals S.A. Dérivés antigènes associés aux tumeurs de la famille mage, et séquences d'acides nucléiques codant ces dérivés, utilisés pour la préparation de protéines de fusion et de compositions destinées à la vaccination
AU737337B2 (en) * 1998-02-05 2001-08-16 Smithkline Beecham Biologicals (Sa) Tumor-associated antigen derivatives from the mage family, and nucleic acid sequences encoding them, used for the preparation of fusion proteins and of compositions for vaccination
WO1999040188A3 (fr) * 1998-02-05 1999-10-14 Smithkline Beecham Biolog Derives antigenes associes aux tumeurs de la famille mage, et sequences d'acides nucleiques codant ces derives, utilises pour la preparaiton de proteines de fusion et de compositions destinees a la vaccination
CZ298347B6 (cs) * 1998-02-05 2007-09-05 Glaxosmithkline Biologicals S.A. Fúzní protein z rodiny MAGE, kódová sekvence nukleové kyseliny, vektor, hostitelská bunka, vakcina a použití fúzního proteinu pro výrobu vakciny
KR100824105B1 (ko) * 1998-02-05 2008-04-21 글락소스미스클라인 바이오로지칼즈 에스.에이. 백신접종을 위한 융합 단백질 및 조성물의 제조를 위해사용되는 ｍａｇｅ 군으로부터의 종양 관련 항원 유도체 및이들을 암호화하고 있는 핵산 서열
US8044183B2 (en) 1998-02-05 2011-10-25 Glaxosmithkline Biologicals S.A. Process for the production of immunogenic compositions
US8097257B2 (en) 1998-02-05 2012-01-17 Glaxosmithkline Biologicals S.A. MAGE3 polypeptides
US6686147B1 (en) 1998-07-15 2004-02-03 Ludwig Institute For Cancer Research Cancer associated antigens and uses therefor
US6809179B1 (en) 1999-08-04 2004-10-26 Boehringer Ingelheim International Gmbh Tumor-associated antigen (R11)
US8834514B2 (en) 2006-08-30 2014-09-16 Xennovate Medical Llc Resilient band medical device

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JPH10511639A (ja) 1998-11-10
ZA958229B (en) 1996-04-24
CA2201327A1 (fr) 1996-04-11
AU3886495A (en) 1996-04-26
CN1159759A (zh) 1997-09-17
AU690371B2 (en) 1998-04-23
EP0782453A1 (fr) 1997-07-09

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